Advances in Quinoline Synthesis

Current Organic Chemistry( 2008),12, 1116-1183
Advances in the syntheses of quinoline and quinoline-annulated ring systems

Sudharshan Madapa, Zehra Tusi and Sanjay Batra* Medicinal and Process Chemistry Division, Central Drug Research Institute, PO Box 173, Lucknow 226001.
Abstract- Quinoline is a heterocyclic scaffold of paramount importance to human race. The utility of quinoline derivatives in the areas of medicine, food, catalyst, dye, materials, refineries and electronics is well established. As a result, the synthesis of quinoline core and its derivatives have been an attractive goal for the synthetic organic chemist. In the recent past there have been several new developments in the chemistry associated with quinolines. In pursuit to develop easy and practical approaches to a variety of quinoline derivatives decorated with useful pharmacophores different research workers have made use of new catalysts, medium or physical conditions in several well established synthetic methodologies. Besides an array of new and innovative strategies from novel substrates have been developed which has rendered the synthesis of quinoline core a much simpler process as compared earlier. An assimilation of the literature related to the advances in the syntheses of quinolines and quinoline-annulated ring systems since 2005 is being presented here.
Current Organic Chemistry( 2008),12, 1116-1183 Contents 1.0 Introduction Quinoline is a heterocyclic scaffold of paramount importance to human race. Several quinoline derivatives isolated from natural resources or prepared synthetically are significant with respect to medicinal chemistry and biomedical use. Indeed quinoline derivatives are some of the oldest compounds which have been utilized for the treatment of a variety of diseases. The bark of Cinchona plant (also known as Jesuits or Cardinals bark) containing quinine was utilized to treat palpitations, [1] fevers and tertians since more than 200 years ago. Quinidine, a diastereoisomer of quinine was in the early 20th century acknowledged as the most potent of the antiarrhythmic compounds isolated from the Cinchona plant. [2] Compounds containing quinoline motif are most widely used as antimalarials, [3] antibacterials, [4] antifungals [5] and anticancer agents. [6] Additionally, quinoline derivatives find use in the synthesis of fungicides, virucides, biocides, alkaloids, rubber chemicals and flavoring agents. [7] They are also used as polymers, catalysts, corrosion inhibitors, preservatives, and as solvent for resins and terpenes. Furthermore, these compounds find applications in chemistry of transitionmetal catalyst for uniform polymerization and luminescence chemistry. [8] Quinoline derivatives also act as antifoaming agent in refineries. [9] Owing to such significance, the synthesis of substituted quinolines has been a subject of great focus in organic chemistry. The first formal synthesis was reported by Skraup over a century ago. [10] It involved treatment of aniline with acrolein under heated sulfuric acid but later several variations to the original Skraup synthesis have been reported. [11] Alternatively, several new methods were unfolded which eventually became conventional for synthesizing the structural core of quinoline. These are (a) Combes synthesis using anilines and diketones; (b) Conrad-Limpach synthesis employing anilines and -ketoesters; (c) Doebner-Miller reaction involving anilines and ,-unsaturated carbonyl compounds; (d) Friedlander synthesis using 2-aminobenzaldehyde and acetaldehyde; (e) Povarov reaction which involves reaction of an aniline, a benzaldehyde and an activated alkene also known as Aza-Diels-Alder reaction; (f) Camps quinoline synthesis utilizing an 2acylaminoacetophenone and hydroxide ion and (g) Niementowski quinoline synthesis
Current Organic Chemistry( 2008),12, 1116-1183 which is the reaction of anthranilic acids and ketones (or aldehydes) to form hydroxyquinoline derivatives.
H OH N HO O N Quinine Cl N Chloroquine N Amodiaquine N CF3 CF3 Mefloquine H H CONHtBu HN N HN N HO
N H H
O N N Et Camptothecin OH O O N
O N H
CONH2 OH H N O
Saquinavir (Roche, R031-8959)
Fig. 1 A few quinoline derivatives in clinical use Although there has been tremendous development for obtaining several quinoline derivatives, different synthetic routes have been highlighted to suffer from various problems viz. (1) harsh conditions, [12] (2) multistep, [13] and (3) a large amount of promoters such as a base, [14] expensive and/or harmful metals, [15] the oxidants for the aromatization, [16] and other additives. [17] Kouznetsov et al. reviewed some of the recent progress made in the synthesis of quinolines in 2005. [18] They rightly mentioned that there are conceptually only two approaches towards the construction of quinoline. The first one relates to the use of the aromatic primary amine as the nucleophilic component providing nitrogen as the C-C-N unit whereas the second one employs the ortho-substituted anilines as the C-C-C-N unit. Strikingly, since 2005 there has been unusual increment in the number of publications describing the construction of quinolines decorated with a variety of functional groups at different positions. Although the basic two approaches described by Kouznetsov are universally relevant, the advancement generally concerns with the use of new catalysts, medium or physical conditions for already known reactions. As a result it was deemed suitable to make an effort to assimilate the literature pertaining to the synthesis of quinoline derivatives. The literature for the present review was obtained from the Sci-finder search using the keyword Quinoline from the period 2005-2007. In addition, other web resources available to us were also utilized to conduct searches related to the synthesis of quinoline derivatives. 3
Current Organic Chemistry( 2008),12, 1116-1183 The scope of this review article is limited to the references describing the synthesis of quinoline core including dihydroquinolines and quinoline annulated ring system. The referral to the bioactivity if described in the original report has been included herein. However no discussion has been provided for several reports describing methodologies towards quinoline synthesis which are well established and robust. For the sake of convenience we have classified all reports on the basis participating carbon skeletons for the construction of quinoline. Further subdivisions have been provided if the strategy concerns with the name reactions or certain specific reactant. Reports relating to the construction of quinoline in total synthesis of a natural product have been provided at the end of the article. 2.0 3+3 Unit approach- From N-C-C+ C-C-C Units 2.1 Skraup-Doebner-Von Miller reactionSkraup [11] and Doebner-Miller [19] synthesis of quinolines adopt similar reaction sequence which involve the reaction of aniline (C-C-N) with the ,-unsaturated carbonyl (C-C-C) compounds. Although Yamashkin and Oreshkina have explicity discussed the progress for these two methods of quinoline synthesis including the traditional and modern approaches [20] recently, some of the very recent reports are only discussed here. Denmark and Venkatraman [21] studied the formation of substituted quinolines (3) (Skraup-Doebner-Von Miller) from anilines and ,-unsaturated ketones mechanistically by the use of
13
C-labeled ketones in cross-over experiment (scheme 1). On the basis of
their studies Skraup quinoline synthesis was proposed to involve a fragmentationrecombination mechanism. The aniline moiety (1) condenses with the ,-unsaturated ketones (2) initially in a conjugate fashion, followed by a fragmentation to the corresponding imine and the ketone itself. These fragments reunite to form an anil (4) which furnishes the quinoline (3) by conjugate addition of a second molecule of aniline (1) followed by cyclization (scheme 2). Later Chen and co-workers [22] discovered a reversal of the standard regiochemistry of the Skraup-Doebner-Von Miller quinoline synthesis when anilines were condensed with -aryl-,-unsaturated -ketoesters in refluxing TFA. These workers postulated that the reaction involve 1,2-addition of anilines to -aryl-,-unsaturated -ketoesters to form Schiffs base followed by cyclization and oxidation to yield the final product (5) (scheme 3).
O CH3 Li PhSCu, Et2O, THF -78o C-0oC 70% CH3 O H3C CH3 O H3C = 13 C label 2
13
i. CS 2, Li +BHTCH3 ii. CH3 I
SCH3O H3CS
3Li PhSCu, CH3 Et2O, THF -78o C-0oC 79% 13CH
CH3 O H3C CH3
CH3 O i-Pr NH2 CH3 O H3C CH3 66% no crossover H3C CH3 i-Pr + N H 3 CH3 30% crossover CH3
CH3
I2 1 toluene 115oC, 8h
CH3
Scheme 1
CH3 O i-Pr H3C + NH2 1 reversible conjugate addition CH3 i-Pr CH3 i-Pr condensation N 4 i-Pr CH3 1 conjugate addition N i-Pr CH3 NH H3C HN O CH3 O i-Pr irreversable CH3 fragmentation N CH3 + CH3
CH3
CH3 i-Pr cyclization rearomarization -1
CH3
N H 3 CH3
Scheme 2
R1 TFA + R NH2 O reflux R2 8-18 h 42-83% R N R2 R N H R2 R1 R1 [O] R N 5 R2 R1
R = H, Cl, F, OH, Me, OMe, NO2 ; R1 = C6 H5 , 4-Cl-C6 H4 , 4-Me-C6H4, 4-OMe-C6H4 R2 = CO 2Me, CO 2Et; R3 = C6H5, 4-Cl-C6H4, 4-Me-C6 H4 , 4-OMe-C6 H4
Scheme 3 Jain and co-workers [23] reported the synthesis of 4-alkyl-5,6-dimethoxy-8-nitro quinoline (6) from 4,5-dimethoxy-2-nitroaniline in the presence of As2O5. Resulting nitroquinolines were transformed to N8-(4-amino-1-methylbutyl)-4-alkyl-2-tert-butyl-6methoxy-5-(3-trifluoromethylphenoxy)-8-quinolinamines (7) (scheme 4). These 8quinolinamine analogs exhibited promising antimalarial, antileishmanial, and antimicrobial activities.
OMe MeO
glycerol, H2SO4, As2O5, MeO 110oC, 21 h, or MVK or 1-chloroNH2 -3-pentanone, H3PO4, As2O5, 80oC, 3 h
OMe R
F3C MeO
N NO2 6 R = H, Me, Et HN
Bu NH2
NO2
Scheme 4 Phosphotungstic acid was demonstrated to be a new catalyst for the Doebner-Miller quinaldine (8a) and lepidine (8b) synthesis by Perumal and co-workers. [24] Reactions of aromatic amines with ,-unsaturated carbonyl compounds via Michael addition, cyclization and aromatization by conventional heating or microwave irradiation were described to afford the corresponding quinolines (8) in high yields as shown in scheme 5. Bose and Kumar [25] were also able to successfully achieve the microwave-assisted synthesis of quinoline (9) and dihydroquinoline (10) derivative under solvent free condition via Skraup synthesis. They demonstrated that 25 mol% of K5CoW12O40 (PDTC) was effective for one-pot reaction of aniline with alkyl vinyl ketones as shown in scheme 6. This reagent was also demonstrated to be an effective catalyst for the Friedlander synthesis.
Phosphotungstic acid (aq), R5 toluene, 100oC, 2 h 1 O R R 75-89% or + 4 5 R R Phosphotungstic acid, R2 NH2 R2 N R4 SiO2, MW, 10-15 min 3 3 R R 8 79-94% R1 = H, Br, Cl, OH, OMe, NO2; R2 = H, Br, Cl, NO2 4 8a. R = Me; 8b. R5 = Me R3 = H, Cl, OH, OMe, NO2; R4 = H, Me; R5 = H, Me;
1
Scheme 5
O H3 C CH3 R = H, Me, OMe, Br R t Bu, CO2 Me CH3 N H CH3 10 H3C CH3 K5 CoW12O40.3H2O R MW 15-20 min 65-80% R
3
O R2 R3 R2 R = H, Me, OMe, OH, Cl Naphthyl; R1 = H, C6H5; 1 R2 = H; R3 = Me, C6H5 R
R1 K5 CoW12O40.3H2O MW R NH2 8-15 min 74-88%
Scheme 6 Quinolines carrying phenyl acetic acid as substitution at 4-position were generated from 2-benzoyl-3-ethoxyacrylate by Hu and co-workers. [26] Treatment of 2-benzoyl-3ethoxyacrylate with 2-trifluoromethyl aniline followed by cyclization afforded the 3benzoyl-4-hydroxyquinoline (11), which on treatment with Tf2NPh or POCl3 gave the
Current Organic Chemistry( 2008),12, 1116-1183 corresponding triflate or chloride. The resulting triflates or chlorides were reacted with phenyl boronic acid in the presence of Pd-catalyst to furnish the 4-phenyl quinolines (12). On alkylation with benzylbromide or reductive amination with benzaldehydes followed by hydrolysis, product 12 resulted in the carboxylic acids 13. The reduction of benzoyl carbonyl was achieved with hydrazine (scheme 7). A few of the analogs were discovered to be potent liver X receptor (member of the nuclear hormone receptor super family which are involved in the regulation of cholesterol and lipid metabolism) agonists useful for the treatment of atherosclerosis.
NH2 O CF3 CO 2Et toluene, 82% OEt Dowtherm 56% CF3 OH O Tf 2NPh, K 2CO3, DMF 65% or POCl3 DMF 11 R1 Y Z CF3 X O PhB(OH) 2, K3PO 4, Pd(PPh3)4 dioxane X = OTf or Cl CF3 N 12 R O
PhCH2Br, K 2CO3 or PhCH2NH2 , NaBH(OAc)3 , DMF aq NaOH, THF, MeOH or N2H4 , KOH, ethanediol
Y = OCH2, NHCH2 , N(Me)CH2 , CH2NH Z = O or H,H R = OH, NH2 , CHO R1 = CO2H, CH2 CO 2H
N CF3 13
Scheme 7 Yadav et al. [27] reported the synthesis of sugar-derived chiral tetrahydroquinolines (14 & 15) in high yields with moderate diastereoselectivity from the reaction of arylamines with 2-deoxy-D-ribose in the presence montmorillonite KSF clay in MeCN at ambient temperature (scheme 8).
HO O OH OH R4 R3 R2 R1 R4 R3 R2 R1 14 + OHC NH2 montmorillonite, KSF H+ OH MeCN r.t., 5-9 h OH 70-87% H O OH + R2 R1 15 N H H R3 R4 R3 R2 R1 R4 H O OH R1 = H, Cl, Me; R2 = H, Cl, Me; R3 = H, Cl, F, Me; R4 = H, Cl, Me N H OH OH OH R3 R2 R1 N H R4 +O H H OH OH
+ +
R4 R3 R2 R1
OH2
N H
OH OH
N H H
Scheme 8 Polanski and co-workers [28] carried out the synthesis of styryl quinolines (17) via condensation of anilines with crotonaldehyde in the presence of HCl, followed by
Current Organic Chemistry( 2008),12, 1116-1183 microwave irradiation of the resulting quinaldine (16) with aldehydes (scheme 9). Some of the synthesized compounds exhibited the photosynthesis inhibiting activity.
R1 crotonaldehyde, HCl R1 NH2 aldehyde, MW R1 30-82% CH3
N N 16 17 R1 = 2-CO2H, 3-CO2H, 4-CO2H, 5-CO2H, 3,5-(CO2H)2, 5-OH; R2 = 3-Br, 4-Br, 2-Cl, 3-Cl, 4-Cl, 2-OH, 3-OH, 4-OH, 2-OMe
R2
Scheme 9 Goswami and co-workers [29] reported one-pot catalyst-free synthesis of functionalized quinolines (19) by microwave assisted reaction. Indeed the synthesis of quinoline carried out by these workers was in order to provide support for the formation of 1,8naphthyridines prepared under identical conditions. Though they claimed that such quinoline synthesis had precedence, their methodology involved irradiation of aniline and -aryl vinyl ketone to produce a Michael adduct (18) by subsequent cyclization and aromatization (scheme 10).
O R + NH2 Ph Michael MW Ar R N H Ar 18 Ph O H Cyclization R N H Ar Ph OH Dehydration R Aromatization N 19 55-75% Ar Ph
R = Me, OMe; Ar = C6H5, 3-Br-C6H4,
Scheme 10 Volochnyuk et al. [30] demonstrated that the reaction of 3-formylchromone with electron rich anilines in the presence of TMSCl ensued the corresponding quinolines (20) in good yields (scheme 11).
O O O + NH2 TMSCl, H2O O OH
DMF, 80oC N R 30-94% 20 R = 3,5-(OMe)2 , 3,4,5-(OMe) 3, 4-OH, 4-OMe, 4-OEt, 4-OPr, 3,4-O(CH2)O-, 3,4-O(CH2) 2O-, 3,4-O(CH2) 3O-, 3,4-OCF2OR
Scheme 11 2.2 From AlkynesYi et al. [31] developed an efficient C-H bond activation/hydroamination strategy for the synthesis of tricyclic quinoline derivatives. Coupling reaction of indoline with excess of alkyne (10-20 eq) in the presence of Ru3(CO)12/NH4PF6 in benzene at 95C, afforded the tricyclic quinolines (21 & 22) in excellent yields as shown in scheme 12.

Ru3(CO)12, NH4PF6 (1-5 mol%) Me benzene 95oC 20 21
+ N H
+ : 1 22
Scheme 12 Korivi and Cheng [32] developed an efficient and convenient Ni-catalyzed cyclization of 2-iodoanilines with alkynyl aryl ketones to give 2,4-disubstituted quinolines (23) (scheme 13). They proposed that the reaction proceeded via formation of 2-amino chalcone on the basis of the regiochemistry of the product isolated.
R3 R
1
I + R3
1
O NiBr 2(dppe)
R2 MeCN, Zn, NH2 80oC, 12 h R = H, Cl, Me, CF3 48-91% R2 = Me, Ph, Naphthyl R3 = n-Bu, Ph
N 23
R2
Scheme 13 Recently a Pd-catalyzed approach to quinolines from 2-iodoanilines was also described by Cho and Kim. [33] The reaction of 2-iodoaniline with ,-unsaturated carbonyl compounds catalyzed by Pd(OAc)2, and NaOAc in DMF afforded the substituted quinolines (24) via Heck coupling and subsequent cyclization as depicted in scheme 14.
Pd(OAc)2, R PPh3, NaOAc + R 100oC R2 NH2 N 40-69% 24 R = H, C6H5, Pr, naphthyl; R1 = Me, C6H5, i-Pr, 4-OMeC6H4; R2 = H, Me, CH2C6H5 I COR1 R2 R1
Scheme 14 2.3 Other 3+ 3 cyclizationsBesides, there have been other strategies too where the synthesis of quinolines were achieved utilizing C-C-N and C-C-C units. Jones and co-workers [34] obtained aryl substituted 2,4-dimethoxyquinolines (25) by reacting bromoanilines with malonic acid in the presence of POCl3 followed by treatment with NaOMe and finally performing the Suzuki-coupling as shown in scheme 15. A few analogs were discovered to show promising activity against drug sensitive and drug resistant strains of an important nematode target.

Cl CH2(COOH)2 Br NH2 POCl3, reflux 5h Br N NaOMe, MeOH reflux Cl 48 h Br OMe ArB(OH)2, OMe Pd(PPh3)4, Na2CO3 toluene, N OMe OMe 80oC, 48 h Ar 25 68-90% Ar = Cl, C6H5, 4-OMe-C6H4
Scheme 15 A selective 1,4-addition of N-aryl phosphazenes, derived from PPh3 to ,-unsaturated carbonyl compounds to furnish 2-quinolinecarboxylates (26) was reported by Polacios et al. [35] However when a more reactive phosphazene species derived from PMe3 was employed, it resulted in a 1,2-addition with their carbonyl carbon to provide N-aryl-1azadienes which upon thermal 6- electrocyclization afforded 4-quinoline carboxylate (27) as per the scheme 16.
R1 for R = Me 1,2
_
R1 R2
R2 N CO2Et
1,4 R1
N PR3 1,2 O
POMe3
N 26 79-85% R2 N 27 79-83%
CO2Et
for R = Ph 1,4 CO2Et

_
CO2Et R2
CO2Et
POPh3
N R1 R1 = Me, OMe; R2 = 4-NO2C6H4
R1
Scheme 16 Tu et al. [36] have reported the synthesis of 4-aza-podophyllotoxin via a three component reaction of an aldehyde, aniline and cyclic diones in H2O under microwave irradiation. Use of tetronic acid as the cyclic diketone provided the 4-aza-podophyllotoxin derivatives (28) (scheme 17). The reaction proceeded via attack of Schiffs base, formed through the condensation between aldehyde and aniline, on tetronic acid resulting into an intermediate which underwent intramolecular cyclization and dehydration to yield the product. The scope of the strategy was enhanced by replacing tetronic acid with 1,3indanedione to generate indenoquinoline derivatives (29).
O O R R1 O MW O RCHO + R1 H2O, 3-7 min 93-98% NH2 O O MW R O
R1 O H2O, 3-7 min N N 93-98% H H 29 28 R = Bu, C6H5, 4-Br-C6H4, 4-Cl-C6H4, 4-F-C6H4, 4-OMe-C6H4, 3-NO2-C6H4, 3,4-Cl2-C6H3 amine = C6H5NH2, 4-Me-C6H4NH2, 1-naphthylamine, 2-naphthylamine
10
Current Organic Chemistry( 2008),12, 1116-1183 Scheme 17 More recently Tu and co-workers [37] described another multicomponent reaction wherein a series of 2-amino-4-aryl benzo[g]quinolin-3-carbonitrile derivatives (30) were synthesized via one-pot condensation of arylaldehyde, a naphthylamine and malononitrile in EtOH without catalyst (scheme 18).
NH2 O Ar H + + CN CN EtOH 5-8 h 80-96% NC H2N N 30 Ar
Scheme 18 In contrast to Tu et al., [36] Labruere et al. [38] utilized the thio- and dithio-analogues of tetronic acid in their three component coupling reaction in EtOH in the absence of a catalyst to afford good yields of thio analogs (31) of 2,3-dihydropodophillotoxin as shown in scheme 19.
CHO R HO + MeO OMe + OMe X S EtOH 72-90% MeO OMe 31 O O S OMe R N X
O O
H N
R = H, Me; X = O, S
Scheme 19 3.0 4+2 Unit approach 3.1 From N-C-C-C+ C-C Units3.1.1 Friedlander SynthesisFriedlander synthesis for quinoline was originally described by Friedlander in 1882 and has been accepted to be one of the most convenient routes to this scaffold. [39] The reaction advances by the condensation of -amino carbonyl compound (N-C-C-C unit) with a derivative having -methylene group with respect to the carbonyl (C-C unit), in the presence of a suitable catalyst. During last couple of years there has been spurt in the number of publications describing the successful accomplishment of Friedlander reaction. This was achieved by making changes in the catalyst or reaction medium or physical parameters though the starting substrates were conceptually similar in these endeavors. These advances have been discussed in this particular section. The section has been 11
Current Organic Chemistry( 2008),12, 1116-1183 subdivided into different classes based on the catalyst employed to effect the Friedlander reaction. 3.1.1.1 Acid-catalyzed Friedlander reactionWang et al. [40] described an environmentally friendly and highly efficient procedure for the synthesis of substituted quinolines (32) by a simple Friedlander reaction of 2aminoarylketone or 2-aminoarylaldehyde with carbonyl compounds in the presence of HCl utilizing H2O as the solvent as delineated in scheme 20. Subsequently Asis and coworkers [41] also demonstrated the successful use of HCl as catalyst for similar reaction under microwave for quinoline synthesis (33). Unlike the conventional heating under which the reaction took 6 h to go to completion, the use of microwave speeded up the reaction to be complete within 1.5 to 12 min (scheme 21).
R1 R O NH2 R2 + O R3 HCl (1.0 eq.) H2O, 6 h, 90oC 85-98% R N 32 R3 R1 R2
R = H, 2,4-(Br) 2; R1 = H, Me, 4-F-C6 H4; R2 = CO2Et, COMe; R3 = Me, n-Pr; R2 & R3 = -(CH2) 2-, -(CH2) 3-, -CO(CH2) 2-, -COCH2CMe2 CH2 -
Scheme 20
R1 R
2
R1 O R + O R3
4
HCl cat. MW, 1.5-12 min 45-89%
R4
N R3 33 R1 = CH3 , C6 H5 ; R2 = H, Cl, NO2 ; R3 = Me, CH2Cl, C6 H5 R4 = H, Me, COMe, CO 2Me, CO 2Et; R3, R4 = -(CH2 )4 -, -(CH2 )5 -
NH2
Scheme 21 Mizuno et al. [42] reported a convenient synthesis of the quinoline base of the antirheumatic drug TAK-603 (35) utilizing the Friedlander reaction as the key step as delineated in scheme 22. The hydrochloride salt form of the amino derivative provided sufficient acidity to act as catalyst in the reaction to afford the desired quinoline unit (34). Subsequently they developed a convenient and efficient method for the generation of different metabolites of TAK-603 (35) in high yields. [43] Here too the Friedlander condensation was one of the key reactions although the required amino derivative for the reaction was generated in a slightly different fashion.
12

MeO MeO MeO NH2 MeO Ac2O, NaOH H2O, 50oC MeO 89% NHAc 3,4-dimethoxybenzoic acid SnCl4, POCl3, CH2Cl2, reflux OMe OMe O Cl CO2Et EtOH, reflux 88% OMe OMe 34 OMe OMe MeO MeO N Cl CO2Et N N NH2 MeO MeO N N N CO2Et N NH2 Br- NaNO2 conc.HCl 5 C, 94%
o
NHAc O conc.HCl EtOH, reflux 89%
MeO MeO
NH2.HCl O
MeO
OMe OMe MeO MeO N N N CO2Et N
N NaBr, DMF 65oC, 79%
OMe OMe 35 overall yield-52%
Scheme 22 Yoshioka and co-workers successfully accomplished the synthesis of 2,2,4-triphenyl-1, 2dihydroquinoline-N-oxyl (37) from the N-oxide product of the quinoline (36) which was in turn obtained via Friedlander annulation in the presence of H2SO4 as shown in scheme 23. [44] These stable oxyl quinolines (37) were prepared with the intent to study their magnetic properties.
Ph O NH2 O + Ph Me H2SO4 44% N Ph m-CPBA CHCl3 Ph 83% Ph PhMgBr N O 36 Ph THF Ph N Ph OH Ph oxidation CHCl3 15% Ph Ph N O 37 Ph
Scheme 23 H2SO4-promoted Friedlander reaction of picoline with 5-bromo-2-amino benzophenone was also utilized by Cheng and co-workers [45] for the preparation of 6-bromo-4-phenyl2-pyridin-2-yl-quinoline (38) which served as precursor for the synthesis of bidentate ligands 39, and 40 via Ullmann reaction (scheme 24).
Ph NH2 O Ph O N H2SO4 AcOH 70-74% R R = H, Br 38 R N N Ph N H CuI, 18-crown-6, K2CO3 59% Ph2NH, CuI 18-crown-6, K2CO3 67% Ph2N N 40 N N N 39 Ph
Scheme 24 Choi et al. [46] carried out the synthesis of a series of compounds bearing a phenylquinoline unit via the Friedlander annulation and studied their photophysical and
13
Current Organic Chemistry( 2008),12, 1116-1183 electric transport properties. The synthesis commenced with the preparation of diacetyl monomer (41) by the reaction of 1,2-bis-(2-methyl-3-thienyl) perfluoro cyclopentene with Ac2O in the presence of SnCl4. The resulting diacetyl monomer (41) upon heating at reflux temperature with 2-amino benzophenone in toluene in the presence of DPP generated the quinolinyl derivative (42), whereas the reaction between diacetyl monomer and 3,3-dibenzoyl benzidine yielded 74% of the polymer (44) which was transformed to closed dyad 43 in UV light ( = 365 nm) in CH2Cl2 (scheme 25). The synthesis of poly quinolines containing spiro bifluorene and phenathiazine units with excellent electroluminescence properties was achieved via Friedlander annulation by Liu et al. [47] As shown in the Scheme 26 bis (2-amino ketone) reacted with 2, 7-diacetyl-10-n-hexyl phenothiazine in an acidic medium comprising of DPP and m-cresol at 140C for 3 d to afford the PQSP (45) in excellent yield.
F F F F F F Ac 2O, SnCl4, CH2 Cl 2, reflux 82% S S O S 41 S O O Ph2HPO4 , toluene, 120oC, 76% NH2 O Ph Ph2 HPO 4, m-cresol, 135o C, 74% F F F Ph Ph H2 N O NH2 Ph F F F F F F
F F
F F >600nm 365nm N
F F
F F
F F F
N N S S N Ph
N n
Ph
43
Ph
Ph
42
Ph
44
Scheme 25
Ph O NH2 H2 N Ph O H3COC + S N C6H13 DPP, m-cresol 140oC, 72 h COCH3 93% Ph 45 N Ph C6H13 N S
N PQSP
Scheme 26
14
Current Organic Chemistry( 2008),12, 1116-1183 Wang et al. [48] utilized p-TSA as the catalyst to demonstrate the synthesis of quinoline derivatives (46) under solvent less condition. They carried out their reaction both under microwave and conventional heating. Although yields of the products were excellent under both conditions, the reaction accomplished in the influence of microwave was reported to be completed a few seconds only (scheme 27).
R1 O + R NH2 O R2 R3 p-TSA (1 eq.) R1 R2
100oC or N R3 R 300 W, 30-60 sec 46 87-96% R = H, 2,4-(Br)2; R1 = H, Me, 4-F-C6H4; R2 = H, CO2Et, CO2Me, COMe; R3 = Me, cy-Pr, i-Pr, C6H5, 4-Cl-C6H4; R2 & R3 = -(CH2)3-, -(CH2)4-, -CO(CH2)3-, -COCH2CMe2CH2-,
Scheme 27 Akue-Gedu et al. [49] described the synthesis of 1,3-dihydro-2H-pyrrolo[3,4-b]quinolin2-carboxylate (47) and methyl 2,3-dihydro-1H-pyrrolo[3,2-b]quinoline-1-carboxylate (48) from the reaction of 3-oxo-pyrrolidine-1-carboxylic acid methyl ester with pyrrolidine, and 2-dimethoxymethyl-phenylamine in the presence of MeSO3H in MeOH or CHCl3 in good yield (scheme 28).
OMe O N O O pyrrolidine, MeSO3H MeOH/CHCl3 O N N O OMe NH2 N 65% 47 O N O + N 25% 48 O N O
Scheme 28 Perumal and co-workers [50] reported the reaction of 2-amino substituted aromatic ketones with -methylene containing ketones in the presence of KHSO4 in aqueous EtOH under heating at reflux to furnish 2,3,4-substituted quinolines (49) as shown in scheme 29.
R2 O R1 NH2 R4 + O R3 KHSO4 H2 O:EtOH (8:2) R1 reflux, 3-8 h 61-94% 49 N R2 R4 R3
R1 = H, 5-Cl; R2 = Me, C6 H5; R3 = Me; R4 = COMe, CO2 Et, CO2 CHMe2; R3 & R4 = -(CH2) 3-, -(CH2) 4-, -(CH2) 5-, -(CH2) 6-, -COCH2CMe2 CH2-,
Scheme 29 3.1.1.2 Lewis acid-catalyzed Friedlander reaction-
15
Current Organic Chemistry( 2008),12, 1116-1183 In the recent times several Lewis-acids have been successfully employed for performing the Friedlander reaction. SnCl22H2O served as a suitable catalyst to initiate the reaction between the 2-aminoarylketones with different carbonyl compounds at room temperature yielding the corresponding 2,3,4-substituted quinolines (50) (scheme 30). [49] Use of cyclic ketones under the same reaction gave the tricyclic quinolines. This protocol was feasible only when both the substrates are solid and renders excellent yields. Similar quinolines (51) were generated in good yields by De and Gibbs by performing the reaction in the presence of Y(OTf)3 at room temperature in MeCN for 4-6 h (scheme 31). [52] Wu and co-workers [53] generated identical quinolines (52 & 53) from similar starting substrates by carrying out reactions in the presence of FeCl3 or Mg(ClO4)2. Strikingly, in the presence of FeCl3 and EtOH the reaction proceeded at room temperature but the use of Mg(ClO4)2 as a catalyst required the reaction to be heated at 60C to furnish quinolines (53) in good yield as delineated in scheme 32. Very recently, Sandhu et al. [54] too reported FeCl3-promoted Friedlander synthesis of quinolines (54) under solvent less condition (scheme 33). Bose and Kumar demonstrated that CeCl37H2O can act as a reusable catalyst during similar reactions to afford quinolines (55) in good to excellent yields (scheme 34). [55] Simultaneously, Varala and associates, [56] demonstrated the utility of Nd(NO3)3 as catalyst in the Friedlander condensation to acquire substituted quinolines (56) (scheme 35). In another variation, Tolmachev et al. [57] recently showed that TMSCl in DMF was also successful to furnish quinolines (57) in excellent yields from same starting substrates (scheme 36). Subsequently, the same group [58] reported the synthesis of ethyl 2-chloro-methyl-3-quinoline carboxylates (58) from the condensation of 2-aminoacetophenone and 2-aminobenzophenone with ethyl 4chloro-3-oxobutanoate in the presence of excess TMSCl, in high yields (scheme 37). Under the same reaction conditions, 1,3-dichloroacetone and 2-chlorocyclohexanone afforded the 3-chloro-2-(chloromethyl)quinolines and 4-chloro-1,2,3,4-tetrahydroacridines, respectively.
Ph Cl O + NH2 R O O R1 SnCl 2.2H2O Cl N 50 R Neat, r.t. 15-140 min 92-98% R = Me, R1 = OEt; R & R1 = -CH2C(Me) 2CH2Ph O R1
Scheme 30 16

O R R1 + R3 NH2 O R2 Y(OTf)3 MeCN, r.t., 4-6 h 76-92% R R3 R1 R2
N 51 R = H, 4-Cl; R1 = Me,C6H5 ; R2 = CO2 Et, COMe; R3 = Me; R2 & R3 = -(CH2) 3-, -(CH2) 4-, -COCH2 CMe2CH2-
Scheme 31
R1 R R N 53
3
Mg(ClO4 )3 (10 mol%) EtOH,60o C,18 h R 62-99%
R1 O NH2 O + R2 R
3
FeCl3 (10 mol%) EtOH,r.t.,12-24 h 63-98% R 52
R1 R3 N R2
R2
R = H, 5-Cl; R1 = H, Me, 2-Cl-C6H4; R2 = Me; R3 =CO 2Et, COMe; R2 & R3 = -(CH2) 3-, -CO(CH2) 3-
Scheme 32
O R R1 + R2 NH2 O
3
R1
R3 FeCl3 R R solvent free N R2 r.t., 45-60 min 54 78-91% R = H, 4-Cl; R1 = Me,C6 H5 , 2-Cl-C6 H4 ; R2 = Me; R3 = CO2 Et, COMe, COCF3; R2 & R3 = -(CH2) 4-, -COCH2 CMe2 CH2-
Scheme 33
R O NH2 O + R1 R2 CeCl3 .7H2 O MeCN, r.t.,1.5 - 5 h 65-95%
2
R R2
N R1 55 R = Me, C6 H5 ; R = Me, Et, CH2 O(CH2) 3NPht; R = Me, CO2 Et, CO 2Me, COMe R1 & R2 = -(CH2) 6-, -COCH2 CMe2CH2-, -CH2 CHt Bu(CH2)2 1
Scheme 34
R O NH2 R2 + O R1 Nd(NO3) 3 EtOH, r.t., 10 h 62-94% N 56 R R2 R1
Scheme 35
R2 R
1
R2 O O + R3 R
4
N R3 57 R1 = H, 4-Cl, 4-NO2, 3,4-CH2O2 ; R2 = Me, C6 H5 ; R3 = Me, CH2Cl, t-Bu, CF3, CO 2Et, C6H5, 4-F-C6H4, 3-Pyridyl, 2-Thienyl, 2-Pyrrolyl, Adamantyl, 2-Furyl, 2-NH2 -C6H4; R4 = H, Me, CN, COMe, CONH2, CO2 H, CO2Et, CH2CH2 Cl, 4-Cl-C6 H4 ; R3 & R4 = (CH2) 3, (CH2) 6, (CH2) 10, (CH2 )4 CHCO2Me, COCH2CMe2CH2, CH2 NBn(CH2) 2, NH2
TMSCl DMF 76-96%
R4 R
1
Scheme 36
17

R1 R1 NH2 O + R3 Cl TMSCl (4 eq.) R2 R3 N . HCl Cl 58 R4
O R
2
DMF R4 75-95%
Scheme 37 In their attempt to develop efficient environmentally benign protocol for obtaining polysubstituted quinolines, Zolfigol and co-workers [59] optimized the Friedlander annulation between 2-aminoarylketones or 2-aminobenzonitrile and ketones or diketones with several Lewis acids viz. Al(HSO4)3, FeCl36H2O, Fe(NO3)39H2O, Bi(NO3)3, Cr(NO3)39H2O, Ni(NO3)36H2O, Zr(NO3)4 and Zr(HSO4)4. It was observed that Zr(NO3)4 and Zr(HSO4)4 in H2O gave the desired products (59 & 60) in excellent yields (scheme 38). Unfortunately, the -cyclohexanedione failed to react with 2aminobenzonitrile under the described condition (scheme 39).
O R Ph NH2 R2 + O R1 Zr(NO 3) 4 or Zr(HSO 4)4 (10 mol%) H2 O, reflux 0.5-40 h 84-100% Ph R N R2 R1
59
R = H, Cl; R1 = Me; R2 = COMe, COC6 H4, CO 2Me R1 & R2 = -(CH2) 2CO-, -(CH2) 3CO-, -(CH2) 4-, -COCH2CMe2 CH2-,
Scheme 38
O CN + NH2 O R R Zr(NO3) 4 (10 mol%) H2 O, reflux R = Me 80% R = H 0% OH O
N 60
R R
Scheme 39 Zhang and Wu [60] recently performed successful Friedlander reaction by the use of a unique Lewis acid-surfactant-combined catalyst. Although during optimization they employed several such catalysts, the best yields of polysubstituted and polycyclic quinolines (61) were obtained when the condensation of 2-aminoarylketone and methylene ketone was carried out in the presence of Sc(O3SOC12H25)3 in H2O at 40C (scheme 40).
R2 R1 O + NH2 R3 O R4 Sc(O 3SOC12 H25) 3 (5 mol%) H2O, air 89-99% R2 R4 R1
N R3 61 R1 = H, 4-Cl; R2 = Me, C6H5; R3 = Me; R4 = CO2Et, CO2 Me, COMe; R2 & R3 = -CO(CH2)3 -, -COCH2CMe2CH2-
18
Current Organic Chemistry( 2008),12, 1116-1183 Scheme 40 Masciadri and co-workers [61] synthesize the substituted quinolines (62 & 63) via Aucatalyst promoted condensation of 2-aminoarylketones with several 1,3-diketones including -keto-esters, -diketones, -keto-amides and -keto-sulfones. When this reaction was performed with 1,1,1-trifluoro-2,4-pentanedione or 1-cyclopropyl-1,3butanedione produced only one regioisomer. The regioselectivity with the trifluoroderivative was rationalized on the basis of preferred hydrate formation of the carbonyl group next to the CF3 whereas the regioselectivity of the cyclopropyl group reflected lower reactivity of the carbonyl group adjacent to the cyclopropyl residue (scheme 41).
R1 R O R + O
2
+ EtOH or N R3 N R2 o PrOH, 80 C 62 63 10-80% R = Br, OCF3, R1 = CH2Cl, C6H5, R2 = Me, Et, iPr, tBu, CH2OMe; R3 = COMe, COEt, CO2Et, COiPr, COtBu, COCF3, CF3, cPr, COC6H5, CONHMe, CONMe2, CONHC6H5, CONH-4-Cl-C6H4, COCH2OMe; R2 = R3 = CO(CH2)2, CO(CH2)3, CO(CH2)4, CONH(CH2)3, NH2 R3
i
NaAuCl4.2H2O R (3 mol%)
R1 R
2
R1 R R3
Scheme 41 3.1.1.3 Base-catalyzed Friedlander reactionChelucci et al. [62] reported a successful protocol for generating quinolines substituted on both pyridine and benzo-fused rings (64). As represented in scheme 42 their method was based on the formylation of a substituted N-(Boc)aniline followed by direct cyclization and aromatization of the intermediate product obtained by condensation of the formed N-Boc-2-aminobenzaldehyde with an enolizable carbonyl compound in the presence of t-BuOK. The Boc group was finally removed with 3 N HCl to generate the substituted quinolines.
carbonyl compound, t-BuOK, 1,4-dioxane, r.t. 1-7 h
3 N HCl NHBoc reflux, 1-4 h R N 64 27-85% R = H, 2-F, 4-F, 3- CF3; R1 = H, C6H5; R2 = Me, Bu; C6 H5 ; R1 & R2 = -(CH2) 4-, -CO(CH2) 3NHBoc _ DMF R 78oC - r.t.
(Boc) 2O THF NH2 60 oC, 15 h R
t-BuLi, THF _ 50 o C, 3 h
CHO
R2 R1
Scheme 42 Denny and co-workers [63] demonstrated an innovative synthetic approach for the preparation of 7-oxo-7H-naptho[1,2,3-de] quinoline-11-carboxamide (66, 67) and
19
Current Organic Chemistry( 2008),12, 1116-1183 analogs using 1-amino-8-chloro anthraquinone (65) as the synthon for the Friedlander annulation reaction with acetone in the presence of NaOH as depicted in scheme 43.
O CDI, dioxane reflux, amine or amine.HCl, . BOP Cl, Et3N, 20oC, 1h 8-32% O
acetone O 4% NaOH, reflux, 1 h N Me X = CO2H O NH2 O X 65 Me2NC(Me) X=H (OMe)2 X = CO2Me EtOH, reflux X = CO2H 1 h Me X
N Me O
O 66
N H
Me2NC(Me) (OMe)2 N O NMe2 X=H X = CO2Me X EtOH, reflux,1 h N 28-64% NMe2 X
SOCl2 amine 33% N O N H R
10% NaOH reflux, 24 h
NMe2 67 R = (CH2)2NMe2 X=H (CH2)3NMe2 X = CO2Me (CH2)2NH(CH2)2OH X = CO2H CH(S-Me)CH2NMe2 CH(R-Me)CH2NMe2,
Scheme 43 Li et al. [64] disclosed a highly effective one-pot Friedlander synthesis by reaction of 2nitrobenzaldehyde with excess of Fe in aq. HCl for the in situ generation of 2aminobenzaldehyde followed by reaction with aldehyde or ketone in the presence of KOH to obtain quinolines (68) in high yields. This procedure was demonstrated to be successful even for the aldehyde containing an active methylene group (scheme 44).
CHO R NO2 i. Fe (4 eq.), aq HCl (5 mol%), EtOH, reflux ii. O R2
R N R1 R2 68 R1 KOH (1.2 eq.), reflux, 44-99% R = H, CO2Me, NMe2; R1 = Me, t-Bu, C6H5, (CH2)4CH3, Cinnamyl, 2-Pyridyl, 2-Thienyl; R2 = H, Me, OMe, (CH2)4CH3
Scheme 44 Yang and group [65] recently reported an efficient Friedlander reaction under basic conditions by treatment of substituted 2-aminobenzaldehyde with an appropriate cyclic ketone in the presence of EtONa to afford the substituted quinolines (69) in moderate to excellent yields (scheme 45). Similarly, MeONa-mediated reaction was reported by Hideg and his group for the synthesis of paramagnetic quinolines (70) in low yields as per the scheme 46. [66] They also demonstrated that the reaction of -bromo-,unsaturated aldehyde with 2-benzyloxyaniline in DMF under nitrogen atmosphere
20
Current Organic Chemistry( 2008),12, 1116-1183 followed by hydrogenation gave the paramagnetic 8-hydroxyquinoline derivative (71) (scheme 47).
O R1 CHO 2 + R NH2 NaOEt R1 N 69 X n
EtOH, reflux X n 2 h, 53-93%
R2
R1 = H, OCH2 O, OMe; R2 = H, Ar X = O, S, NMe, N(CH2) 2, NCO 2Et; n = 0, 1
Scheme 45
O CHO n+ N O n = 0, 1 NH2 NaOMe EtOH, reflux 3 h, 34-56% N 70 N n O
Scheme 46
Br N O CHO + NH2 DMF, N2 N OH 71 N O
120o C OBn 3 h, 44%
Scheme 47 3.1.1.4 Solid catalyst-mediated Friedlander reactionYadav and co-workers [67] utilized the Friedlander annulation to synthesize 4-phenyl quinolines from 2-aminoarylketones and -methylene ketones using sulfamic acid, a recyclable solid catalyst. The reaction proceeded smoothly at 70C under solvent free conditions to furnish quinolines (72) in good yields as presented in scheme 48. Wu et al. [68] demonstrated that identical quinolines (73) can also be easily generated in milder fashion via reaction of same substrates in the presence of molecular iodine (scheme 49).
R1 R O NH2 + R2 O NH2SO3H R R3 5 mol% R1 R3
solvent free N R2 70oC, 30-80 min 72 82-94% R = H, Cl, NO2; R1 = Me, C6H5, 2-Cl-C6H4, 2-NO2-C6H4; R2 = Me, cyclopropyl; R3 = Me, COMe, CO2Me, CO2Et; R2, R3 = -(CH2)3, -(CH2)4-, -(CH2)3CO-
Scheme 48
21

R2 R1 O+ R4 I (1 mol%) 2 R1 R2 R4
EtOH, r.t. R3 air, 16 h N R3 53-98% 73 R1 = H, 4-Cl; R2 = Me, C6 H5 , 2-Cl-C6 H4 ; R3 = Me; R4 = COMe, CO 2Et; R3 & R4 = -(CH2 )3 -, -(CH2)3 CONH2 O
Scheme 49 Recently, Venkateswarlu and co-workers [69] performed rapid one-pot two component condensation of 2-aminoarylketone with carbonyl compound or -keto ester using heterogeneous solid-silica-supported-HClO4 as an efficient recyclizable catalyst (scheme 50). On the contrary, Das et al. [70] during their study with several heterogeneous catalysts observed that Amberlyst-15 gave better results (75) than several silicasupported-acids to affect Friedlander synthesis for the synthesis of quinolines (scheme 51).
R1 O NH2 O + R2 R3 HClO 4-SiO2 R1 R3
MeCN N R2 60oC, 2-3 h 74 92-96% R1 = Me, C6 H5 , R2 = Me; R3 = Me, OEt, OMe, COMe, i-Pr R2 & R3 = -(CH2 )3 -,-(CH2)4 -,-(CH2) 3CO-
Scheme 50
O R R1 + R2 NH2 O R
3
R1 R EtOH, reflux N 2-3.5 h 75 69-93% R = H, 4-Cl; R1 = C6H5, 2-Cl-C6H4; R2 = Me R3 = CO2Et, COMe; R2 & R3 = -(CH2)4Amberlyst-15 R3 R2
Scheme 51 3.1.1.5 Modified Friedlander reactionA reaction wherein the starting 2-aminobenzaldehyde is generated in situ from 2aminobenzyl alcohol has been generally termed as modified Friedlander reaction in the literature. Cho and co-workers have reported several catalysts and conditions to obtain quinolines through this strategy. They discovered that Pd-C in dioxane acts as effective catalyst for the generation of 2-substituted quinolines (77) from the reaction of 2aminobenzyl alcohol and aryl alkyl ketones (76) (scheme 52). [71] It was observed that hydrogenated ketone (78) as the side product was also formed during the reaction. Simultaneously they unfolded similar reaction between alcohol and aliphatic aldehyde to
22
Current Organic Chemistry( 2008),12, 1116-1183 generate 3-substituted quinoline (79) in the presence of RuCl2(PPh3)3, albeit in moderate yields (scheme 53). [72] Extending their study further they found that 2-aminobenzyl alcohol also reacts with ketones in the presence of Rh-catalyst along with KOH in dioxane yielding 2-substituted quinolines (80) through oxidative coupling reaction followed by dehydrative cyclization (scheme 54). [73] Subsequently they also demonstrated the utility of Cu-catalyst for similar reactions. [74] 2-Aminobenzyl alcohol on treatment with several ketones in dioxane in the presence of a catalytic amount of CuCl2 along with KOH under O2 atmosphere afforded the corresponding 2,3-substituted quinolines (81) (scheme 55). Similar reaction when carried out by adding aldehyde as a reactant in the place of ketone under inert atmosphere led to the formation of 3substituted quinolines (81) (scheme 55).
OH + NH2 R
1
O R
2
Pd-C (0.005 mmol) dioxane 100oC
R2 +
1
OH
R2 N R1 R 28-52% 54-87% 76 78 77 R1 = C6H5, 2-Me-C6H4, 3-Me-C6H4, 4-Me-C6H4, 2-MeO-C6H4, 4-MeO-C6H4, 4-F-C6H4, 3-CF3-C6H4, 4-CN-C6H4, 2-Thienyl, 2-Naphthyl, (CH2)4CH3, (CH2)2C6H5; R2 = H, (CH2)3CH3,
Scheme 52
OH NH2 + R RuCl2 (PPh3) 3, KOH CHO dioxane, 80o C, 20 h, 16-66% 79 N R
R = (CH2) 2CH3 , (CH2)5 CH3 , (CH2 )2 CH3, CH2C6H5, CH(Me)C6H5, iPr, tBu, C6H5
Scheme 53
OH + NH2 O RhCl(PPh3)3, KOH Ph dioxane 80oC, 24 h 50-85%
N 80
Ph
Scheme 54
OH + NH2 R1 O R2 CuCl2, KOH, O2 (1 atm) dioxane 41-82% R2
N R1 81 R1 = C6H5, 2-Me-C6H4, 3-Me-C6H4, 4-Me-C6H4, 2-MeO-C6H4, 4-MeO-C6H4, 4-F-C6H4, 3-CF3-C6H4, 4-CN-C6H4, 2-Thienyl, 2-Napthyl, (CH2)4CH3, (CH2)2C6H5; R2 = H, (CH2)3CH3,
Scheme 55 Indirect Friedlander condensation in the presence of [IrCl(cod)] or IrCl3 as catalyst was described by Ishii and his group. [75] Their approach involved treatment of 2-
23
Current Organic Chemistry( 2008),12, 1116-1183 aminobenzyl alcohol with different ketones in the presence of KOH under solvent less condition to obtain 2,3-disubstituted quinolines (82) (scheme 56). The reaction mechanism included the ketimine formation from 2-aminobenzyl alcohol and corresponding ketone followed by oxidation to the respective aldehyde and subsequent intramolecular aldol condensation to provide 2,3-disubstituted quinolines (82).
O R
2
OH + R1 NH2
[IrCl(cod)]2 or IrCl 3
R2 R1
solvent free N 100oC, 3 h 82 22-91% R1 = Me, Et, i-Bu, n-Hex, C6 H5 ; R2 = H, Me R1 & R2 = -(CH2) 5-, -(CH2) 3CHMe-
Scheme 56 More recently Verpoort et al. [76] after examining several Ru-catalysts to accomplish modified Friedlander reaction reported that the Grubbs second generation catalyst was the most efficient surpassing the efficiency of first generation even to effect this reaction for the synthesis of quinoline (83) (scheme 57).
Ru, PCy3 base, R2 Cl Ru 2 dioxane R + o Cl 1 80 C, 1h R PCy3 Ph NH2 N R1 30-100% 83 54% R1 = Me, C6H5, 2-Me-C6H4, 3-Me-C6H4, 4-Me-C6H4, 2-MeO-C6H4, 4-MeO-C6H4, 4-NO2-C6H4; R2 = H, Me, -(CH2)4-,-CHMe(CH2)2OH O R N N Mes Mes N N Mes Cl Ru Cl PCy3 Ph Cl Ru Cl PCy3 Ph
R = methyl 52% Mes = 2,4,6-trimethylphenyl 100% R = cyclohexyl 72% R = n-octyl 75%
Scheme 57 In a variation from the reported strategies for the modified Friedlander reaction, very recently Yus and co-workers described the first synthesis of polysubstituted quinoline derivatives (84) from reaction of 2-aminoacetophenone or benzophenones with aromatic and aliphatic alcohols in the presence of RuCl2(dmso)4 as a catalyst under solvent free conditions. Their protocol involved the in situ oxidation of alcohols to the corresponding carbonyl compounds through hydrogen transfer followed by Friedlanders condensation as shown in scheme 58. It was shown that the reaction was mild and efficient and independent of the nature of alcohol. [77]
R2 R
1
O + NH2 R3
OH R
4
RuCl2 (dmso) 4 (2 mol%), KOtBu (100 mol%), 1 Ph2 CO (100 mol%) R
R2 R3
solvent free N R4 100oC, 48 h 84 R1 = H, Cl, NH2 ; R2 = Me, C6 H5 , 2-F-C6H4, 2-Cl-C6 H4, 4-MeO-C6 H4 ; R3 = H, C6 H5 , 4-Me-C6H4, 4-CF3-C6 H4 , 2-Furyl, t-Bu, (CH2) 4CH3 ; R4 = H, Me, C6H5
24
Current Organic Chemistry( 2008),12, 1116-1183 Scheme 58 3.1.1.6 MiscellaneousRecently, Das et al. [78] successfully performed the Friedlander reaction to generate quinolines (85) utilizing TCT as the catalyst as depicted in scheme 59.
O R R1 + R2 NH2 O R
3
R1 TCT (4 mol%) R3
R EtOH, reflux N R2 25-85 min 85 72-95% R = H, 4-Cl; R1 = Me, C6 H5 , 2-Cl-C6 H4 ; R2 = Me; R3 = CO2 Et, CO 2Me, COMe, CH2 COMe; R2 & R3 = -(CH2) 3-, -(CH2) 4-, -COCH2 CMe2 CH2-
Scheme 59 3.1.2 Pfitzinger synthesisPfitzinger synthesis for quinolines involves reaction between isatin (N-C-C-C) and carbon nucleophile (C-C) in the presence of a base. [79] Ashry and his group [80] reacted isatin with acyclic and cyclic ketones to obtain quinolines-4-carboxylic acids (86 & 88). Replacing ketones with malonic acid provided quinoline-2-hydroxy-4-carboxylic acid (87) as per the scheme 60.
R CH2COR
2 3
R1
CO2H R2 N R3 EtOH, H2SO4 CO2Et R2 R1 N 2 H 4 .H 2 O H2SO4 N R3 MW, 7 min 94-99% 80-92% CONHNH2 R2 N 89 R3
KOH, EtOH, MW, 12.5 min 50-96% R1 N H O CH2(CO2H)2 O MW, 15 min 65-68% O R1
86
MW 10 min CO2H
EtOH, R1 H2SO4 N 87 CO2H OH MW, 10 min
R1 KOH, EtOH MW, 12.5 min 95% N 88
R1 = H, Cl, Br; R2 = H, Me, C6H5 R3 = Me, Et, CH2CHMe2, C6H5
Scheme 60 Ivachtcheko et al. [81] utilized the Pfitzinger reaction between isatin-5-sulphonimide and methylacetoacetate to generate quinoline-3,4-dicarboxylic acid (90) as a synthetic intermediate in the synthesis of pyrrolo[3,4-c]quinolin-1,3-diones (91), which were identified as potent caspase-3 inhibitors (scheme 61). Similar methodology was adopted by these workers [82] for the synthesis of 2-(2-acetyloxyethyl)-8-(morpholine-4-sulfonyl) pyrrolo [3,4-c]quinoline-1,3-diones (92) from the isatin derivatives. The formation of
25
Current Organic Chemistry( 2008),12, 1116-1183 furandiones and their condensation with 2-aminoethanol followed by treatment with Ac2O provided the desired product in good yields (scheme 62). Subsequently they broadened the scope of Pfitzinger reaction for the generation of 2,3,4-tricarboxylic acid (89) of quinoline by employing 2-oxosuccinate as the nucleophile. Indeed they obtained the isatin from 3,3-dichloro-2-oxo-2,3-dihydro-1H-indole derivative (93) and described it to be the first report of utilizing indole as an indirect substrate for Pfitzinger reaction. They further demonstrated the utility of this strategy for the synthesis of series of annulated quinolines (95) as caspase-3-inhibitors to be used for apoptosis as out lined in scheme 63. [83] An alternative method for the generation of same series of compounds was also described. The initial reaction of 2,3-dioxo-2,3-dihydro-1H-indole-5-sulfonate initially with ketoesters afforded the corresponding dicarboxylic acid (96). These acids were transformed to furandiones via treatment with Ac2O. As discussed in above sequence, the reaction of furandione with 2-aminoethanol and treatment with POCl3 and morpholine yielded the 2-(2-acetyloxyethyl)-8-(morpholine-4-sulfonyl) pyrrolo [3,4c]quinoline-1,3-diones (97) (scheme 64). In another strategy the condensation reaction of sulfamoyl isatin was performed with malononitrile. Further hydrolysis to afford the corresponding dicarboxylic acid (98) and conversion to the imides and finally to the chloro derivative (99) was conducted as described above (scheme 65). These were considered to be viable precursors for the various nucleophilic substitution reactions. These compounds exhibited the inhibition of caspase-3 enzyme.
Cl O N H O S Cl Cl O O O NH 1,4-dioxane r.t. 1 h 92% O N O O O R NH2 S O N S O O Cl O Cl AcOH:H2O (1:1) O reflux, 12 h N 89% H O N O N H O N O R N O S O O OEt O 20% aq KOH, r.t., 12 h 68% O N O S O 90 CO2H CO2H N Me
O Ac2O reflux, 3 h 88%
S O O Pyridine, Me r.t., 30 min Me N N 91 45-97% R = H, Me, (CH2)2OH, (CH2)2OCOCH, (CH2)2NMe2, (CH2)3OH, (CH2)2CO2Me, CH(CO2H)CH2C6H5, CH(CO2Me)CH2C6H5, CH2CO2Me, CH2CO2t-Bu, CH(CO2Me)CH2OH, CH(CO2Me)CH2SH
Scheme 61
26

Cl O N H O S Cl O NH O 1,4-dioxane r.t., 1 h, 92% O N O S O N O O R O N O N H S AcOH:H2O O (1:1) O reflux, 12 h 89% O N O O S O N H OAc O N O N 93 R O S N O R O O OMe N
Cl
Cl
Cl
S O aq KOH, r.t., 12 h O 60-87% 92
CO2H CO2H N R = Me, i-Pr R
Ac2O 100 C, 3 h 80-88%

o
2-aminoethanol, O Pyridine, r.t., 1 h Ac2O, 80oC, 0.5 h 60-65%
Scheme 62
Cl O Cl S O N H CO2 Et O CO2 Et Cl O O NH THF,r.t., 3 h 92% O N O N H CO 2H CO2H N 94 CO2H O Pyidine Ac2O, reflux, 2 h 72% O N O S O N O O S Cl Cl O KOH-H2 O O N O S O O O N H NH2 HO Pyridine O r.t., 30 min Ac 2O, 80 C 1.5 h, 48%
o
N O S O
_ O K+ O NH2 OCOCH3
r.t., 12 h 65%
O N S O
O O
O N O 95 N O S
N O CH3
Scheme 63
OAc Na O O N H O NH 1,4-dioxane 60oC, 30 min 65-95% O S O O CO2Me HO S O O aq LiOH, r.t., 12 h 60-85% O N O N O N 97 R R = Ph, 2-furyl S O O CO2H CO2H N OAc O 96 R O Ac2O, HO O Pyridine S o 100 C, 30 min O 80-88% N O O 2-aminoethanol, O X O Pyridine, r.t., 1 h S o O Ac2O, 80 C 30 min R POCl3 75-97% sulfolane 80oC, 2 h 65-85% N O N R X = OH X = Cl
Scheme 64
O O N S O O CH2 (CN)2 , N-methyl morpholine O MeOH, reflux, 30 min, 96% N O O N S O N H O O N S O 99 N N HCl, AcOH (1:1) O reflux, 12 h 43% OAc N O R POCl 3, reflux 1 h, 96% R = OH R = Cl O N O S O 98 CO2H CO2 H N H O Ac2O 100oC, 0.5 h 91%
N H O O O N S O N H
2-aminoethanol, O Pyridine, 80oC, O 15 min Ac2 O, 80oC, 1 h 86%
Scheme 65 Kaila et al. [84,85] demonstrated the synthesis of quinoline salicylic acid derivatives (100, 103, 104) via Pfitzinger reaction for p-selectrin activity (scheme 66, 67 and 68). The precursors for the reaction viz. isatin and -keto acetates were synthesized by various synthetic routes. The 2-bromoquinoline derivatives (102) were further modified to 2benzyl quinoline derivatives using Heck reaction as described in scheme 67.
27

CO2 H OH N R2
O R1 N H O +R
2
100 R1 = H, 4-OH, 5-CF3 , 7-CF3, 4-Me, 5-Me, 6-Me, 7-Me, 7-Et, 5-OMe, 6-OMe, 7-OMe, 5-OCF3, 7-OCF3, i-Pr; R2 = H, Cl, OH, OC6 H5 , SC6 H5, 4-OHC6H4
KOH, H2O reflux R1 EtOH, 1M HCl OAc 64-85%
Scheme 66
O O + Br O KOH, CO2H H2O, EtOH, 1M HCl CO2H OH N CF3 101 Cl CO2H OH N CF3 N H 103 Cl (COCl)2 MeOH CF3 CO2Me OH NBS N 4-chloroaniline, CO2Me Pd(OAc) , 2 OH Cs2CO3, Celite N CF3 102 Br 2-(dicyclohexylpho sphono)biphenyl, t BuOH, toluene, MW, 150oC
CF3
N H
CO2Me OH N CF3 N H
NaOH
Scheme 67
O Cl TMSCN Cl O CN Zn, Ac 2O AcOH Cl O NHAc R1 O O N R1 H Pfitzinger 44-87% CO 2H NHAc N 104 Cl
Cl R1 = H, 6-Me, 7-Me, 6-Et, 7-Et, 7-OCF3, 7-CF3, 7-Br, 7-Cl, 7-F, 7i-Pr
Scheme 68 3.1.3 From AlkynesSakai et al. [86] reported the first dimerization reaction between the identical molecules for the synthesis of quinolines. The 2-ethynyl anilines undergo dimerisation and intermolecular cyclization in the presence of InBr3 to yield the quinoline compounds (105) in excellent yield as shown in scheme 69.
Me R
1
InBr3 (1 eq.)
R1 N H 2N 105 R1 R2
R2
MeOH, 2 NH2 reflux, 24 h R 56-89% R1 = H, Me, F, CN, NO2; R2 = H, Me
Scheme 69 The reaction of acetylenic esters with indole-7-carboxaldehyde in the presence of PPh3 to produce dialkyl 4H-pyrrolo[3,2,1-ij]quinoline-4,5-dicarboxylates (106) proceeded smoothly in CH2Cl2 at ambient temperature as reported by Adib and Sayahi (scheme 70). [87] This method generated products in quantitative yields simply under neutral
28
Current Organic Chemistry( 2008),12, 1116-1183 conditions within a few hours. They claimed it to be an unconventional approach towards compound 106 as compared to the formerly used multi-step synthesis.
PPh3 CH2Cl2, r.t., 6 h 99% N CO2R CO2R 106
RO2C
CO2R + CHO
N H
R= Me, Et, i-Pr, t-Bu
Scheme 70 3.1.4 Other 4+2 approachesHighly functionalized quinolines were prepared from anthranilonitrile by Metwally and Abdelrazek. [88] Anthranilonitrile reacted with ethylcyanoacetate and its dimer to furnish pyrano[2,3-b]quinoline (107) (scheme 71), while reaction with N-acylidene cyanoacetohydrazides afforded triazolo[4,3-a]quinolines (108) as shown in scheme 72.
CN CO2 Et path a CN N H CN O N H NH2 CN O CN CO2Et N H O NH2 NH2 CN CO2 Et
CN NH2 H2N
CN CO2Et CO2Et path b H2N CN N H O CN CO2 Et N O 107 80% O NH2 NH2 CN
Scheme 71
Ar Ar NH2 CN NC O NEt3 170o C 60-75% NHN=CHAr NH2 OH N N=CHAr CN H N N N CN NH2 NH2 108 N NH N CN
H2N
Ar = C6 H5 , 4-Cl-C6 H4 , 4-MeO-C6 H4
Scheme 72 Recently Khalilzadeh and co-workers [89] also utilized anthranilonitrile as a precursor for the synthesis of substituted tacrines (109). This was achieved by the condensation of substituted anthranilonitriles with cyclohexanone in the presence of silica gel/ p-TSA as catalyst under microwave irradiation (scheme 73).
29

NH2 silica gel, R1 p-TSA + MW 2 N R2 NH2 5-12 min R 109 60-95% R1 = H, Me, OMe, Cl, NO2, NH2; R2 = H, Me, OMe, Cl, NO2, F O R1 CN
Scheme 73 Croce and co-workers [90] transformed N-phenylsulfonyl-2-hydroxy-1,2,3,4tetrahydroquinolines to dihydroquinolines in the presence of p-TSA followed by deprotection under basic conditions to generate quinolines (111). The required N-phenyl sulfonyl-2-hydroxy-1,2,3,4-tetrahydroquinolines (110) were obtained from enolates of 1,3-dicarbonyl compounds and N-(2-bromomethylphenyl) benzenesulfonamides in highly stereoselective manner (scheme 74).
SO2Ph OH N NaH p-TSA R1 COR2 toluene, 100oC 2 DMF,r.t., 60oC R 70-82% 80-95% O H RH R 110 R = H, Me, C6H5; R1 = Me, C6H5; R2 = Me, OMe, OEtC6H5 SO2Ph O NH + Br R1 SO2Ph N R1 NaOH, air N R1 COR2 R 111
o COR2 dioxane,100 C
Scheme 74 Cordova and co-workers [91] reported highly enantioselective organocatalytic domino aza-Michael/aldol reaction between 2-aminobenzaldehydes and ,-unsaturated aldehydes for the synthesis of 1,2-dihydro quinolidines (112) (scheme 75).
Ph O H + NH2 R R = alkyl, aryl O N Ph H RO (20 mol%) DMF, -25oC, benzoic acid (20 mol%) N H 112 O
Scheme 75 Cantin et al. [92] described the reaction of bromobenzoate with MeCN in the presence of NaH to yield enolate, which upon treatment with 5-fluoroisatoic anhydride furnished 2,3,4-substituted quinolines (113). The quinolines were transformed to quinoline amino acids 114 as per the reaction sequence shown in scheme 76. These quinoline amino acids were identified as PDE-10A inhibitors as insulin secretagogues in vitro.
30

i. ArB(OH)2, PdCl2(dppb), Na2CO3, DMF, H2O, 120oC F 80-90% Br ii. POCl3 120oC 95%
Br
i. NaH, MeCN, F OEt THF ii. 5-fluoroisatoic anhydride, THF 70%(2 steps)
OH CN N 113
Cl CN N
i. amino acid, Et3N, DMA, R H2O, 120oc F CN 10-50% or ii. aminoester, N Et3N, DMSO Ar iii. LiOH, EtOH, 114 H2O, THF R = aminoacids 30-75%(2steps)
Ar
Scheme 76 3.2 From C-N-C-C+ C-C Units The syntheses of quinolines have been widely accomplished via imines. The two strategies generally adopted for the purpose include either imino-Diels-Alder reaction also termed as Povarov reaction or by the route where it is not the Diels-Alder type reaction though the imine is present in the form of enamine or enaminone. Both these methodologies are being discussed separately. 3.2.1 Aza-Diels-Alder reactionThe Aza-Diels-Alder reaction for quinoline synthesis comprises of formation of a Schiffs base initially which acts as diene (C-N-C-C) to react with the alkene (C-C) that behaves as a dienophile. Generally when the formation of Schiffs base takes place in situ the strategy is one-pot multicomponent whereas if it is formed separately and reacted with the alkene it becomes a two-step procedure. 3.2.1.1 From Aldimine- Two-step procedureSantillan and co-workers [93] put forward a novel imino-Diels-Alder reaction for the synthesis of 3,4-dihydroquinolines and quinolines by the reaction between boron adducts (115) derived from Schiffs bases and sulfolene. The reactions were reported to be highly regioselective yielding 4-substituted dihydroquinolines (116 & 117) with cis relative stereochemistry between the phenyl group on the boron atom and vinyl substitution at 4position as shown in scheme 48. Compounds 116 were treated with a base to furnish quinolines (118) in good yields (scheme 77).
31

B(OH)2 R1 R N OH OH
2
R1 R2 N B O O SO2 N B
R1 R
2
R1 R2 N B
R3 THF, 12 h 58-92%
toluene 2-26 h 67-83%
+ O
115 R3 116 NaOH 2-5 h 85-99% R1 R2 N OH 118 OH R3 117
R 1 = H, Cl, Me, t-Bu, NO2 R 2 = H, Me, NO2 R 3 = H, CO2 Me
Scheme 77 Jia et al. [94] reported the tris-TBPA cation radical catalyzed Aza-Diels-Alder reaction of N-arylamines with N-vinyl lactams for the synthesis of cis 2-aryl-4-(lactam-N-yl) 1,2,3,4tetrahydroquinolines (119) in good yields (scheme 78). Simultaneously, Savitha and Perumal [95] demonstrated that the formation of similar tetrahydroquinolines (69) could be achieved in one-pot by the reaction between anilines, hetero arylaldehydes, and Nvinylpyrrolidin-2-one in the presence of CAN, in H2O or aq. MeCN (Scheme 79). These conditions were mild and reactions were completed in a short reaction time affording good yields and excellent selectivity. The resulting tetrahydroquinolines (120) could be readily aromatized to substituted quinolines (121) through CAN in MeCN under the nitrogen atmosphere at 0C.
n R
1
O n N R3 + R2 O TBPA + R1 N H 119 R2 R3
MeCN, r.t., 1-2 h 63-85%
Scheme 78
32
NH2 + R1-CHO + R N 5 mol% CAN R O H2O or aq. MeCN r.t., 30-50 min 82-90%
O R 2.5 eq. CAN, N2
120 R = H, Cl, Me, OMe; R1= C6H5, 2-Furyl, 2-Thienyl, 3-(2-Cl-quinolinyl), 3-(2-Cl-6-Me-quinolinyl), 3-(2-Cl-6-OMe-quinolinyl)
N H
MeCN, 0oC, 20 min R1 88-93%
N 121
R1
Scheme 79 Recently, Kouznetsov and co-workers [96] developed a straightforward synthesis of new isoindolo[2,1-a]quinolines (123) utilizing analogous intramolecular Diels-Alder reaction as the key step. The 2,4-disubstituted 1,2,3,4-tetrahydroquinolines bearing a furan fragment at 2-position was obtained by the reaction between the Schiffs base (122) and N-vinylpyrrolidin-2-one in the presence of BF3OEt2 (scheme 80). Alternatively, one pot reaction between aniline, 2-furfuraldehyde and N-vinylpyrrolidin-2-one in the presence of p-TSA furnished the same product (123) albeit in lower yields (scheme 81). Interestingly both routes were highly diastereoselective in nature. The resulting 2furyltetrahydroquinolines (123) were N-acylated with maleic anhydride and acryloyl chloride and subsequent intramolecular Diels-Alder reaction with furan moiety yielded 11-oxo-5-(2-oxopyrrolidin-1-yl)-hexahydro-6b,9-epoxyisoindolo[2,1-a]quinoline-10carboxylic acids (124) and epoxyisoindolo[2,1-a]quinolines (125) in good yields as shown in scheme 80.
R3 R2 R1 R2 N R1 NH2 benzene + 2-4 h O 4 R N O 122 R3 O N R3 N H 123 R1 = H, Me, OMe; R2 = H, Cl; R3 = H, Br, Cl, F, Me, OMe; R4 = H, Me H H R1 O O p-TSA MeCN, r.t., 10-15 h R1 10-80% R4 NH2 R3 OHC R2 + O O R4
BF3 .OEt2
OHC
CH2 Cl2, r.t. 2 75-98% R
R4
Scheme 80 A rapid synthesis of quinoline carboxylic acid (126) by the reaction of Narylbenzalimines with 2-methoxy acrylates or acrylamides in the presence of InCl3 was achieved by Duvelleroy and co-workers [97] under microwave irradiation. Although they investigated several Lewis acids including Yb(OTf)3, InBr3, InI3, In(OTf)3, Sc(OTf)3 as catalyst, the reaction proceeded better with InCl3 in MeCN (scheme 82).
33
O O O O R3 R2 R
1
O R
3
H H O
H R2 R4 R1 O 124 N O R4 CO2H
toluene, 48-55 h O 60-83% R3 R2 R

1
N O
H HO2C H N H 123 O Et3N, toluene CH2Cl2, r.t., 2-3 d 60-87% R 1= R 2= R 4= H O R4 Cl R3 N O H H O R O R

4 3
O H N O 125 O
Scheme 81
X R1 N R2 InCl3 (0.5 eq) MeCN, 150 W 3 min 23-57% R1 N 126 R2 COY COY
R = H, 4-Br, 4-Cl, 4-F R2 = H, 2-F, 3-F, 4-F, 3-NO2, 4-NO2 , 3-Br, 4-Br, 3,4-(OMe) 2, 4-CN X = OMe, OTf, Br; Y = OMe, OEt, NHi Pr, NHCH(Ph)Et, NHPh
Scheme 82 Raghunathan and co-workers [98] also utilized InCl3 in MeCN to achieve the synthesis of bis-tetrahydropyrazolo[4',3':5,6]thiopyrano[4,3-b]quinolines (127 & 128) via iminoDiels-Alder reaction. Strategically the initial formation of imine was followed by intramolecular Diels-Alder with the S-prenyl chain (scheme 83). They reported their reaction to be diastereoselective to yield only cis product. Use of 4,4'-methylene or 4,4'oxo bis anilines led to bis-quinoline structure (129-131) wherein cis-cis isomer (129) predominated as outlined in scheme 84.
R N N Ph CHO S + R
1
NH2
InCl3 R1 (20 mol%) MeCN, r.t. 85-96%
HH R1 S + N Ph N
HH S
N H H
cis R 127
N H H
tr ans R 128
N Ph N
R = Me, C6H5; R1 = H, Cl, NO 2, Me, OMe
Scheme 83
34

R N N Ph CHO S + H2 N InCl3 (40 mol%) MeCN, r.t. 86-92% X NH H H H H cis-cis 129 H H H R R HN H H H H H H H cis-tr ans 130 NH H HN R H + NN N N S Ph Ph R X NH H H H H H S H H tr ans-tr ans 131 R N N Ph
X NH2
R = Me, C6 H5 X = O, CH2
X R N N Ph S HN H
+ NN S N N Ph Ph S
Scheme 84 Recently Menendez and co-workers [99] described the first Aza-Diels-Alder reaction involving an ,-unsaturated hydrazones as the dienophile and catalyzed by InCl3 for the stereoselective synthesis of 1,2,3,4-tetrahydroquinoline (132) substituted at 4-position. The process was domino that involved a reaction of 2-stereocenters, one of these quaternary with complete diastereoselectivity and in a single operation (scheme 85). They termed this process as vinylogous aza-Povarov reaction.
NMe2 N R2 N R
1
Me2N R2
InCl3 (10%) MeCN r.t., 2-5 h 70-93% R3
R1
N H H 132 R3
R1 = R2 = H, Me, OMe; R3 = H, Br, Cl, Me, OMe
Scheme 85 More recently, Bhargava and co-workers [100] successfully developed a Lewis acidmediated Aza-Diels-Alder reaction employing MgBr2 and a catalytic amount of AlCl3 as catalyst for the reaction between acyclic-5-dienyl pyrimidinones and N-arylamines to provide the quinolines (133) in good yields as shown in scheme 86. Takasu et al. [101] demonstrated a cascade one-pot strategy which included inverse electron hetero Diels-Alder reaction and oxidative aromatization initiated by Tf2NH to furnish the quinoline derivative (135) from aldimine and allyl silane. The
35
Current Organic Chemistry( 2008),12, 1116-1183 tetrahydroquinolines (134) obtained as additional minor product was easily aromatized with DDQ to yield quinolines (135) (scheme 87).
R2 R3 N Ph N Ph + N O N R1 R1 = H, Me, morpholine; R2, R3, R4 = H, OMe R4 R4 133 R1 CH2Cl2 or MeCN 74-86% R4 MgBr2, AlCl3 Ph N O R2 Ph N R1 R3 Aromatisation N R3 N Ph N O R2
Ph
Scheme 86
TIPS method A or B 39-88% R N H TIPS
+ R N Ar
TIPS
Ar N R 134 135 method A: imine(3 eq.), allyl silane (1 eq.), Tf2NH (10 mol%), toluene, 60oC, 24 h. method B: imine (1.25 eq.), allyl silane (1 eq.), Tf2NH (15 mol%), DCE, 60oC, 3 h, then DDQ (2 eq.), r.t., 10 min. R = H, 2-Br, 4-Br, 4-Cl, 4-OMe, 4-NO2; Ar = C6H5, 4-NO2-C6H4, 2-NO2-C6H4
+ Ar
Scheme 87 Akiyama and co-workers [102] reported the chiral Bronsted acid-catalyzed enantioselctive tetrahydroquinolines (131) via Aza-Diels-Alder reaction of aldimines with electron-rich alkenes in toluene at 0C (scheme 88).
OR 10 mol%(R)-A N + RO Ar toluene, 0o C, 10-15 h 72-95% Ar O P O
N Ar O OH OH 136 Ar Ar = C6 H5, 4-Br-C6 H4 , 2-Cl-C6H4 , 4-Cl-C6H4, 4-Me-C6H4, 2-Naphthyl R = Et, n-Bu, Bn, dihydrofuran, dihydropyran (R)-A; Ar = 9-anthryl OH
Scheme 88 Ramesh et al. [103] described the synthesis of quinoline--lactams (138 & 139) from the reaction of -lactam imines (137) and various electron-rich dienophiles via intermolecular imino-DielsAlder reaction in the presence of Yb(OTf)3 in MeCN at room temperature in excellent yields. The -lactam imine (137) was in turn obtained from the reaction of glyoxal dimethylacetal imine with 2-phenylacetyl chloride to furnish 4dimethylacetal -lactams (138 & 139) followed by hydrolysis and condensation with 4methoxy aniline (scheme 89).
36

Ph OMe O N OMe N HCO2H PMA CHO MeO Yb(OTf)3, dienophile N MeCN, r.t. 87-97% N PMP O 137 = Ph OMe H MeO H N H H Ph H H N H H PMP 139 N Ph O
MeO
OMe O N PhCH2COCl, Et3N dry CH2Cl2 OMe
THF, H2O (3:1) Ph OMe OMe PMP = 4-OMe-C6H4, PMA = 4-OMe-C6H3NH2
N O PMP 138 O , ,
Scheme 89 Zhang and co-workers [104] developed a mild and efficient synthesis of pyrrolo- and pyrrolidino[1,2-a]quinolin-1-ones (140 & 141) from the reaction of 5-hydroxy-1arylpyrrol-2-ones and 5-hydroxy-1-arylpyrrolidin-2-ones with olefins in the presence of BF3OEt2 via formation of N-acyliminium cations followed by Aza-Diels-Alder reaction (scheme 90).
O R N OH R+ R2 R3
1
BF3.OEt2 CH2Cl2 r.t.
3 R4 R R1 R R2 H + N
4 R3 R R2 R1 H N
O tr ans 45-61% 140
O cis 22-49% 141
Scheme 90 Recyclable polymer-supported -acid catalyzed inverse-electron-demand Aza-DielsAlder reaction between an imine and 3,4-dihydro-2-H-pyran to afford pyrano-[3,2c]quinolines (142) was reported by Masaki et al. [105] in H2O and solvent free conditions (scheme 91).
N Ph Ph + O poly-DCKA-1 (0.2. eq) H2O or solvent free r.t., 24 h H O NC H Ph NC O O poly-DCKA-1 O O O O
N H syn:anti 81:19 142
Scheme 91 Kouznetsov and co-workers [106] performed BF3.OEt2 mediated Kametani reaction, an example of [4+2] imino-Diels-Alder cycloaddition reaction, on N-(4-pyridinyliden) anilines and N-benzylidene anilines with 2,2-dimethoxypropane to obtain quinolines (143-147) as shown in scheme 92.
37

R R O + NH N 144 N 143 BF3. OEt2 CH2 Cl 2 r.t., 14 h X=N R=H N O + O BF3 .OEt2 R CH2 Cl 2 , 14 h X N R 146 N R N N 147 X=N R= H, Me, Et, i-Pr NH N N +
O NH N 145 O
Scheme 92 Lu and Shi demonstrated Lewis acid catalyzed reaction between arylvinylidenecyclopropanes and ethyl (arylimino) acetates for the synthesis of 1,2,3,4tetrahydroquinoline derivatives (148). [107] However the formation of the product took place only when the R3 in iminoacetates was an electron rich group (scheme 93).
R1 + R
2
R3
BF3.OEt2 (50 mol%)
R 1 R2 R4 N H 148 CO2Et
CH2Cl2, 0oC, 1 h CO2Et 50-75% R1 = C6H5, 4-Cl-C6H4, 4-F-C6H4, 4-Me-C6H4 R2 = C6H5, 4-Cl-C6H4, 4-F-C6H4, 4-Me-C6H4 R3 = C6H5, 3-Me-C6H4, 4-Me-C6H4; R4 = EDG
Scheme 93 3.2.1.2 Multicomponent One step procedureThe inverse electron demand imino-Diels-Alder reactions of in situ generated Nbenzylidenes with 3,4-dihydro-2-H-pyran and 2,3-dihydro furan to obtain pyrano and furano[3,2-c]quinolines (149 & 150) was efficiently performed in the presence of SbCl3 by Maiti and Kundu as shown in scheme 94. [108] Subsequently Mahajan et al.[109] also reported similar synthesis of pyrano[3,2-c]quinolines (151) using SbCl3-HAP as the catalyst as delineated in scheme 95.
CHO + R1 R2 NH2 O + n SbCl3 (10 mol%) MeCN, r.t. 40-120 min 72-91% O H H nH R2 NH + nH O H H R2 NH
R1 = H, 4-Cl, 4-OMe; R2 = H, 4-Br, 3-Cl, 4-Cl, 4-OH, 2-Me, 4-Me, 4-OMe
R1 cis 149
R1trans 150
Scheme 94
38
NH2 + R1 R2
CHO O + O SbCl3 -HAP MeCN, reflux, 2-3 h 80-85%
H H H NH
R1
R1 = H, 4-Br, 4-F, 2-Me, 4-Me, 4-OMe R2 = H, 4-Cl, 4-OMe, 4-NO2
R2 151
Scheme 95 Synthesis of furano- and pyrano-quinolines (152 & 153) by a TMSCl-catalyzed threecomponent coupling of several aldehydes, anilines and either 2,3-dihydrofurans or 3,4dihydro-2[H]-pyran, respectively in MeCN was reported by More and co-workers (scheme 96). [110] They further demonstrated that same reaction with cycloalkenone yielded phenanthridone derivatives (154 & 155) as delineated in scheme 97. Interestingly, the reaction of aniline with excess of 3,4-dihydro-2[H]-pyran in the absence of benzaldehyde yielded a mixture of new pyranoquinolines (156 & 157) under similar conditions (scheme 98). Subsequently Semwal and Nayak also reported analogous synthesis of pyrano- and furano[3,2-c]quinolines (158 & 159) using CuBr2 as the catalyst as shown in scheme 99. [111]
CHO + R
1
NH2 + R
2
O TMSCl (20 mol%) n MeCN, r.t. O 2 0.5-2 h R 55-95%
n +
N H 152
2 R1 R
N H 153
R1
Scheme 96
O CHO + NH2 + O TMSCl (20 mol%) MeCN, r.t. 0.5-2 h N H 37% 154 O
+ N H 63% 155
Scheme 97
NH2 O + TMSCl (20 mol%) MeCN, r.t. 0.5-2 h O + (CH2) 4OH O
N H 55% 156
N H 45% 157
(CH2 )4 OH
Scheme 98
39

R3 CHO R2 + R1 R3 NH2 O + n CuBr2 (50 mol%) MeCN, r.t., 2-5 h 49-76% H H nH NH R2 + H H nH R2 NH R3
R1 = H, Cl; R2 = H, Me; R3 = H, Br, Me, OMe; n = 0,1
R1 cis 158
R1 tr ans 159
Scheme 99 Menendez and his group [112] successfully accomplished the synthesis of styryl tetrahydroquinoline (160 & 161) via Povarov reaction of anilines, cinnamaldehyde, and cyclic vinyl ether in the presence of CAN as a catalyst (scheme 100). They observed that in the case of non-cyclic vinyl ether, the products were obtained stereoselectively having a cis-conformation between the styryl and alkoxy groups.
R4 R R
3
H + O + O CAN (5 mol%) MeCN 70-85% R4 R

3
R4
O R H + R2
3
R4
O H
NH2 R1 R1 = R2 = R3 = H, Me;
R2
= H, Br, Cl, F, Me
N H H R1 endo 160
R1
N H H exo 161
Scheme 100 Li and co-workers [113] reported the synthesis of tetrahydropyranoand tetrahydrofurano-quinolines in the presence of ionic liquid. Reaction of ionic liquid bounded aldehyde, p-substituted aniline and either 2,3-dihydrofurans or 3,4-dihydro2[H]-pyrans in 2% TFA in MeCN under microwave irradiation followed by treatment of resulting ionic liquid bound adduct (162) with NaOMe in MeOH furnished mixture of trans and cis isomers of tetrahydroquinolines (163 & 164) with high diastereoselectivity (scheme 101). A three component imino-Diels-Alder reaction of aromatic aldehydes, aromatic amines and 3,4-dihydro-2H-pyran or 2,3-dihydrofuran in the presence of SmI2 yielded pyranoand furano[3,2-c]quinolines as reported by Zhou et al. recently. [114] Interestingly they concluded from their study that higher temperatures and lower substrate concentrations give more of the thermodynamically stable trans products (166), whereas lower temperatures and higher substrate concentrations led to fast formation of the kinetically favored cis products (165) (scheme 102).
40

R O i. ClCH2CH2 OH 200 W, N2, 3 min Me N N ii. NaBF4 MeCN 80oC, 24 h 4-Formylbenzoic acid, DCCI, DMAP OH R O O NaOMe, 200 W MeOH, 10 min 83-92% HN n + HN O n O 162 MeCN r.t., 24 h + N BF4 Me N
-
O HN n
O O
+ N BF4 Me N
n p-RC6H4NH2 2% TFA, MeCN, CHO 400 W, 5 min 83-92%
BF4N
Me
R = H, Me, OMe, Cl, F n = 1, 2
CO2 Me tr ans 73-91% 163
CO2Me cis 9-27% 164
Scheme 101
SmI2 (20 mol%) 5 Ao MS NH2 R1 R1 H H i. THF, 50oC, 5 h O O O 39-94% H H + R1+ R2CHO + ( )n NH NH ( )n or ( )n ii. solvent free H 2 H 2 R R 0oC, 24 h R1 = H, 4-Cl, 4-F, 2-Me, 4-Me, 165 166 trans cis 4-OMe; R2 = H, C6H5, 4-Cl-C6H4, 40-80% i. 0-24% 76-100% 4-F-C6H4, 4-Me-C6H4, 4-OMe-C6H4, 2ii. 66-85% 15-34% Furyl, Cyclohexyl, 1-Naphthyl; n = 1,2
Scheme 102 Synthesis of 2,3-disubstituted quinoline bearing an ester group at 3-position (166) by the reaction of aniline, aldehyde and ethyl propionate in the presence of Ga(OTf)3 in refluxing EtOH was achieved by Fukuzawa and co-workers. [115] During this endeavor they investigated catalytic influence of several Lewis acids including Yb(OTf)3, InBr3, AlCl3, BF3OEt2, Ga(OTf)3, In(OTf)3, Sc(OTf)3 and discovered that Ga(OTf)3 and Sc(OTf)3 were most effective. In contrast to the ortho- or meta- substituted anilines, the para-substituted anilines gave better yields of the envisaged quinolines (scheme 103).
NH2 + R
1
CHO + R
2
CO2Et
Sc(OTf)3 (10 mol%) EtOH, reflux, 24 h R1 15-83% N
CO2Et R2
166 R1 = H, 4-Cl, 2-Me, 3-Me, 4-Me, 4-OMe, 4-Et, 4-iPr; R2 = H, 4-Cl, 4-F
Scheme 103 Zhao et al. [116] reported a highly innovative and efficient one-pot procedure for the synthesis of 4-functionalized quinolines (167) by the reaction of ethynyl ketene-S-Sacetals with various arylamines and aldehydes in the presence of TFMSA as per the
41
Current Organic Chemistry( 2008),12, 1116-1183 reaction sequence delineated in scheme 104. Here too the reaction proceeded through imino-Diels-Alder in the first step.
S R S S + NH2 + R2CHO S R
TFMSA CH2Cl2, r.t. 5 min R1 N R2 R1 59-72% 167 R = CO2H, CO2Et; R1 = H, 4-C, 4-F, 3-Me, 4-Me, 2 R = t-Bu, C6H5, 4-Cl-C6H4, 4-F-C6H4, 3,4-(OCH2O)-C6H3, 4-OMe-C6H4, 4-NO2-C6H4, CH2C6H4, 4-Pyridyl, 4-Thienyl
Scheme 104 Provins and co-workers [117] described the synthesis of 2,6-disubstituted quinoline derivatives that acted as orally bioavailable VLA-4/VCAM antagonists. Their synthesis commenced with the esterification of 4-nitro phenylalanine and protection of the amino group with Boc moiety. Reduction of nitro group with HCO2NH4 in the presence of Pd-C gave the amino derivative, which reacted with alkene and aldehydes to produce the tetrahydroquinolines (168), subsequent oxidation and deprotection followed by aroylation and hydrolysis yielded the substituted quinolines (169). Alternatively, similar final
NH2 O2N CO2H SOCl2 MeOH (Boc)2O, NH2 NaOH, THF CO2Me HCO2NH4, O2N MeOH, H2N R2COCl, Pt(S)/C, Pd-C DIPEA, MeOH, H2 CH2Cl2 NHCOR2 H 2N CO2Me 170 R1 N H NHBoc CO2Me R1CHO, CH2=CHSPh, Yb(OTf)3, MeCN, CH2Cl2 NHBoc CO2Me 168
R 1 = C 6H 5 2-Br-C6H4 2-CF3-C6H4 4-Pyridinyl 1,6-(Cl)2-Pyridinyl 2-Cl-5-CF3-C6H3 2,4-(Cl)2-ClC6H3 2,6-(Cl)2-C6H3 2,6-(F)2-C6H3 2,6-(Me)2-C6H3 2-F-6-Cl-C6H3 2-NO2-6-Cl-C6H3 2,6-(OMe)2-C6H3 R 2 = C 6H 5 2,6-(Cl)2-C6H3 2,6-(F)2-C6H3 2,6-(Me)2-C6H3 2-Me-6-Cl-C6H3 2-NO2-6-Cl-C6H3 2,6-(OMe)2-C6H3 2,4-(Cl)2-6-Me-3-pyridinyl
SPh
R1CHO, CH2=CHSPh, NaIO 4 Yb(OTf)3, 80oC MeCN, CH2Cl2
R1
0.1 N NaOH, MeCN, H2O
NaIO4 TFA, 80oC CH2Cl2 R COCl, DIPEA, NHCOR2 CH2Cl2 CO2Me or 1 N R2COOH, R HATU, DIPEA, DMF
2
NH2 CO2Me
NHCOR2 R1 N 169 CO2H
Scheme 105
42
Current Organic Chemistry( 2008),12, 1116-1183 products (169) were obtained from the 4-nitro (D,L) phenylalanine ester. Acylation of the ester followed by reduction of the nitro group by hydrogenation led to formation of corresponding amine (170) which reacted with the alkene and aldehydes (scheme 105). Legros et al. [118] reported a simple and efficient protocol for the synthesis of tetrahydroquinolines (171) via Aza-Diels-Alder reaction of alkyl aldehydes, anilines and electron rich olefins (vinyl ethers) in TFE (scheme 106). It was observed that when the reaction was performed in the presence of formaldehyde and excess of dienophile, the resulting tetrahydroquinoline undergo second Povarov reaction furnishing new julolidine derivative (172).
R2 i. PhNH2, TFE, r.t., 2 h R
1
R2 R1CHO + R2 R3NH2 TFE, r.t., 2 h 56-88% R3 N H 171 R1
N R3
ii. 35% aq HCHO, R3 1 h, 35-80%
172 R1 = i-Pr, n- C5H11; R2 = OEt; R3 = OEt
R1 = i-Pr, i-Bu, n- C5H11, C6H5; R2 = OEt; R3 = 4-OEt, 4-Me
Scheme 106 3.2.2 From aldiminesBeside Aza-Diels-Alder approach, the imines have been utilized for quinoline synthesis in various fashions. These examples are being included in this section. Baba and coworkers [119] reported a simple and practical synthesis of a variety of substituted quinolines (172) from imine (afforded by aniline and aromatic aldehyde) and enolizable carbonyl compounds in the presence of HCl under aerobic conditions. However as the imines afforded from alkyl aldehydes are unstable and difficult to isolate, they demonstrated the success of their strategy by taking 2.5 eq. of the alkylaldehyde and aryl amine in the reaction to obtain quinoline (173) in moderate to excellent yield as shown in scheme 107.
R5 R3 N
2
H R1
4 + R
HCl (5 mol%), R3 R5 air O DMSO, 60oC 43-82% N

2
R4 R1
R R 173 R1 = Furyl, C6H5, 4-Br-C6H4, 4-OMe-C6H4, 4-CO2H-C6H4; R2 = H, OMe; R3 = H, Br, OH, OMe; R4 = H, C6H5, CH2C6H4, (CH2)4CH3; R4 = H, C6H5, CO2Me
Scheme 107 Wang and his group [120] reported the molecular iodine-catalyzed general method of quinoline (174) synthesis from imines and enolizable aldehydes in refluxing benzene. 43
Current Organic Chemistry( 2008),12, 1116-1183 They observed that out of DCE, MeCN, THF, MeOH, DMSO, benzene, best results were obtained when benzene containing 1 mol% of iodine was used for the purpose (scheme 108).
O R1 N + R
2
R3 R3 I2 (1 mol%) R2
benzene N 1 reflux, 0.5 h R 69-82% 174 R1 = H, 4-Br, 4-Me, 4-OMe, 4-OEt; R2 = H, 4-Br, 4-Cl, 4-Me, 3,4-(Me)2; R3 = C6H5, i-C3H7, n-C4H9, n-C5H11, n-C6H13, n-C7H15, n-C8H17,
Scheme 108 Shimizu and co-workers [121] described several variants of three component reaction using transition metal and Lewis-acid catalysts to generate quinolines. Initially they demonstrated a one-step synthesis of ethylquinaldates (175) by Lewis acid mediated reaction between aromatic amines, aliphatic aldehydes and ethylglyoxalate. During this work they investigated the effect of several Lewis-acids including SnCl2, ZnCl2, TiCl4, La(OTf)3, and Yb(OTf)3 and found that these all gave comparable yields though 1.0 mol% of Yb(OTf)3 was the most suitable for this reaction (scheme 109). Subsequently they demonstrated the success of this strategy with Ir-catalyzed three component coupling reaction. [122] A reaction between an arylamine, an aromatic aldehyde or aliphatic aldehyde and an aliphatic aldehyde in the presence of 5 mol% [Ir(cod)Cl]2 yielded quinoline (176) in moderate to good yields (scheme 119). Here they studied as well the effect of several Lewis-acids and reported that Yb(OTf)3 gave comparable yields but AlCl3, TiCl4, and HfCl4 furnished lower yields of quinolines.
NH2 O + R1 H CO2Et + H O R
2
Yb(OTf)3 (1.0 mol%) N 175
R2 CO2Et
DMSO, 90oC 1 R 16 h, under O2 34-90% R1 = H, 4-Br, 4-F, 4-Me, 2-OMe, 4-OMe, 4-CO2Me R2 = H, Bn, Et, Me, n-Pr, i-Pr
Scheme 109
NH2 O R
1
R DMSO N R2 o 90 C, 17 h 176 7-99% R1 = 4-F, 2-Me, 2-OMe, 4-OMe; R2 = Me, Et, Pr, i-Bu, C6H5, 2-OMe-C6H4, 3-OMe-C6H4, 4-CO2H-C6H4, 2-Pyridyl, 2-Furyl; R3 = H, Me, Et, i-Pr, C6H5 + R CHO + H
[Ir(cod)Cl]2 (5 mol%)
R3
1
Scheme 110
44
Current Organic Chemistry( 2008),12, 1116-1183 Later they showed that this coupling could be accomplished in the presence of another Ircatalyst under oxygen as oxidant. [123,124] The reaction proceeded with Mannich-type imine formation followed by nucleophilic addition to give -aminoaldehydes which undergo dehydrative cyclization to give dihydroquinoline. This upon dehydrogenation via aerobic oxidation yielded 2-aryl-3-alkyl quinolines (177). Some of the natural products (Eduline (178a) and Graveoline (178b)) were obtained from these quinolines via methylation followed by oxidation (scheme 111).
NH2 R1 + R2CHO R1 DMSO, O o 90 C, 12 h R3 H 22-79% [IrCl2H(cod)]2 (2.5 mol%), air or O2 O R N 177
2 3 1 MeOTf R (2.5 mol%) 1 K3[Fe(CN)6] R (3.0 mol%) 5
o R2 CH2Cl2, 60 C, 2 h 67-81%
N Me
R4
aq. NaOH r.t., 12 h 23-63%
R = H, 4-Br, 4-F, 4-CN, 2-OMe, 4-CO2Me; R = 2-Furyl, C6H5, 2-Br-C6H4, 2-OMe-C6H4, 4-OMe-C6H4, 3,4-OCH2O-C6H3, 4-CN-C6H4, 4-F-C6H4, 4-CO2Me-C6H4; R3 = H, Et, Pr, i-Pr, Bn
R3 N Me R2 178 1 4 5 a. R = OMe, R = R = H (eduline) b. R1 = H, R4&R5 = OCH2O (graveoline) c. R1 = R4 = OMe, R5 = H
Scheme 111 Kalai et al. [66] reported the different synthetic routes for the synthesis of paramagnetic quinolines. The aniline was treated with paramagnetic aldehyde and pyruvic acid in EtOH to furnish the 2-substituted paramagnetic cinchoninic acid (179) (scheme 112).
CHO N O + NH2 O + CO2H EtOH reflux 3 h 25% N 179 N O CO2H
Scheme 112 4.0 5+1 Unit approach 4.1. From N-C-C-C-C+ C Units 4.1.1 From AlkynesRossi and co-workers [125] reported a highly innovative Pd-mediated multicomponent domino reaction to obtain 2-aryl-4-amino quinolines (180) starting from carbon monoxide, 2-ethynylarylamines, aryl iodides and primary amines. Strategically the Pdmediated process involved a triple domino sequence including carbonylative coupling between 2-ethynylarylamines and aryl iodides followed by inter- and intramolecular nucleophilic addition to a carbon-carbon triple bond and carbon-oxygen double bond, respectively (scheme 113).
45

NHR1 I + NH2 R Pd(OAc)2, TTP + R1NH2 + CO THF or Et3N 42-99%
180 R = 4-Cl, 4-OMe, 3-CF3, 4-COMe; R1 = (CH2)3CH3, CH2CN, CH2CO2Et, CH2C6H4, cy-Hex, CH(C2H5)CO2Et, CH(CHMe2)CO2Et
Scheme 113 The successful synthesis of 2,4-dichloroquinoline (181) was accomplished in good yield from 2-ethynylaniline using diphosgene in MeCN under high temperature (130-150C) as reported by Chi and his group (scheme 114). [126]
Cl R diphosgene R N 181 Cl MeCN, 130-150oC NH2 12 h, 25-74%
Scheme 114 4.1.2 From modified Pictet-Spengler reactionKundu and his group [127] described application of modified Pictet-Spengler reaction for the synthesis of thiazolo- and pyrazolo-quinolines (182 & 184) from thiazolo and pyrazolo amines. A reaction of substituted thiourea with 2-nitrophenacyl bromide yielded [4-(2-nitro phenyl)-thiazol-2-yl]-phenyl amine, which upon reduction followed by PictetSpengler reaction in the presence of TFA afforded thiazoloquinolines (scheme 115). In another variation of their work condensation of substituted acetophenone and 2nitrobenzaldehydes in the presence of ammonium acetate in refluxing toluene followed by treatment with phenylhydrazine resulted in a chalcone which led to pyrazoles. Reduction of the aryl nitro group in pyrazoles followed by Pictet-Spengler cyclization with different aldehydes under the influence of p-TSA in toluene yielded pyrazoloquinolines (184) along with dihydropyrazoloquinolines (183). DDQ mediated oxidation of dihydropyrazoloquinoline (183) afforded pyrazoloquinolines (184) (scheme 116). Adopting a similar approach of modified Pictet-Spengler reaction, El-Abdelah and co-workers [128] recently demonstrated successful synthesis of indolo [2,3-c] quinolines (185) (scheme 117). More recently Lemaires group [129] reported the synthesis of a series of 6-arylbenzo with thieno[3,2-c]quinolines 2-nitroarylbromides to via Heck-type the coupling of benzo[b]thiophene generate 2-(2-nitroaryl)-
46
Current Organic Chemistry( 2008),12, 1116-1183 benzo[b]thiophenes which upon reduction followed by Pictet-Spengler reaction yielded the quinoline derivatives (186) as per the sequence depicted in scheme 118.
O R
1
H N S
NH2
Br 1 NO2 R HN
S N
NO2
R1 . SnCl2 2H2O HN MeOH, reflux 2 h, 95-96%
S N
R2 NH2 R2CHO R HN
1
S N 182
MeOH r.t., 2 h 95-98%
2% TFA, CH2Cl2 0oC, 30 min 1 75-85% R = C6H5, CH2C6H5, CH24-ClC6H4, R2 = 4-NMe2C6H4, 4-NO2C6H4, 4-MeC6H4, 4-BrC6H4, OH
Ph
Scheme 115
O + R1 R
2
CHO NO2 NH4OAc toluene, reflux R1 86-92% Ph N R2 R

1
NO2 PhNHNH2 R2 EtOH, reflux, 7 h R1 82-87% Ph N N R2 N H R3 183
N R2 O2N
DDQ, CH2Cl2, THF r.t., 4 h 83-88% Ph R1
Ph N R2 O2N
CHO R3 p-TSA, toluene, 1 reflux, 4 h R 75-82%
SnCl2 2H2O EtOH, reflux 1.5 h, 86-92%
N + R
1
N R2 N 184
H2N
R1 = H, 4-Me, 4-Cl; R2 = H, 5-F; R3 = 4-Br, 2-OH, 2-OMe, 4-NO2, 4-NMe2, 3,4-(OMe)2
p-TSA, toluene, reflux, 4 h DDQ, CH2Cl2, THF, r.t., 2 h
R3
Scheme 116
CF3 + Cl ZnCl NO2 Et2O 20oC 65% NO2 CF3 NaBH4, Cu(OAc)2 N H MeOH, reflux N H NH2 CF3 RCHO, BF3.OEt2 DCE, reflux 62-75% N H 185 N R CF3
R = CHMe2, 4-Cl-Ph, 4-Pyridyl
Scheme 117
CHO NO2 Br + S Pd(OAc)2(5 mol%), PPh3(10 mol%), K2CO3 (3 eq.) 130oC R 31-77%
1 DMF,
R2 R2
O2N R1 S H2/Pd-C EtOH, r.t. 62-94% S
H2N
R = H, OMe, Cl, CF3 R2 = 4-CN, 4-CF3, 2-NO2, 4-NO2, 3-Cl, H, 4-OMe, 3-OMe
R1 i. toluene, reflux ii. TFA (1 eq.), toluene, 80oC, O2
N R1 S 186
Scheme 118 4.1.3 Other N-C-C-C-C+ C approachesA convenient synthesis for 2-polyfluoromethylquinolines (187-190) via reaction between 2-vinyl anilines with perfluorinated hemiacetals or aldehydes in the presence of TMSCl in toluene (scheme 119) was reported by Taguchi et al. [130] However they observed that if the reaction was performed in pyridine, the 1,2-dihydroquinoline (190) was afforded as the major product (scheme 120).
47

Me 1. TFAE, r.t., 1 h 2. TMSCl, toluene, 100oC, 9 h Me + CF3 Me
NH2
N 187 37%
N 188 H 6%
CF3
Scheme 119
Ph Me 1. TFAE, r.t., 1 h 2. TMSCl (3 eq.), pyridine, 100oC, 10 h Ph Me + N 189 minor CF3 N CF3 H 190 major Ph Me
NH2
Scheme 120 Vieira and Alper described a new atom economical approach for the preparation of 1,2,3,4-tetrahydroquinolines (191) via intramolecular hydroaminomethylation of 2isopropenylanilines mediated by an ionic domino Rh-catalyst. [131] The use of this catalyst did not require phosphines and the reaction was found to be highly chemo- and regioselective (scheme 121).
R Cat. (2.5 mol%), CO, H2 (1000 psi (1:1)) + CO Rh CO Cl catalyst Cl Rh CO CO -
R NHR1 toluene, 100oC, 48 h N 61-98% R1 R = H, 5-Cl, 4-F, 4-Br, 4-Me, 6-Me, OMe 191 R1 = H, Me, CH2C6H5
Scheme 121 The substituted N-Boc 2-amino stilbenes reacted with alkyl lithium to furnish lithiated intermediates which further reacted with DMF and subsequently acidified with dilute acid to obtain 1,2,3,4-tetrasubstituted tetrahydroquinolines (192) as shown in scheme 122. The generated tetrahydroquinolines when treated with dilute HCl provided the fully aromatized quinolines (193). [132] If this reaction was performed with N-benzyl amino stilbene instead of N-Boc amino stilbene 1,4-dihydroquinolines (194) were formed (scheme 123).
NHBoc Ph R1Li THF 25oC, 1h Li Boc NLi R1 Ph i. DMF, _ 25oC 30 min R1 Ph 12 M HCl (aq.) N OH Boc EtOAc, r.t. N 5-16 h 61-78% 193 R1 = Et, n-Bu, t-Bu; R2 = H, Et, n-Bu R2 Ph
ii. 1M HCl (aq.) 63-76%
192
Scheme 122
48

Ph NLi R1 Ph Li i. DMF, _ 25oC 30 min R1 Ph N 194 Ph
ii. 1M HCl (aq.) 51-84% R1 = s-Bu, n-Bu, t-Bu
Scheme 123 4.2 From C-N-C-C-C+ C Units Kobayashi and co-workers [133] developed a new synthetic strategy for the synthesis of 4,5-diamino-pyrrolo[1,2-a]quinolines (195) by reaction of secondary amine hydrochloride with 2-(pyrrol-1-yl)-benzaldehydes and isocyano compounds in the presence of NaI, Et3N and TMSCl. They also exemplified their methodology for the synthesis of desired compounds using secondary amines along with Et3NHCl instead of secondary amine hydrochloride (scheme 124). In a variation to this strategy, subsequently they reported that 4,5-diamino-pyrrolo[1,2-a]quinolines (196) could also synthesized from N-alkyl/N-aryl-2-(pyrrol-1-yl) benzaldimines obtained via reaction of 2-(pyrrol-1yl) benzaldehydes with primary amines which on reaction with aromatic or aliphatic isocyanides in the presence of BF3OEt2 yielded the final product (196) in moderate yields (scheme 125). [134]
N CHO R2 Methd A or B MeCN, CH2Cl2 r.t. or 0oC R2 32-70% N NHR3 NR42
+ R3NC
R1 R1 195 4 + Method A: R 2N H2Cl , NaI, Me3SiCl, Et3N Method B: R42NH, NaI, Me3SiCl, Et3N, Et3N+HClR1 = H, OMe, Cl; R2 = H, OMe; R3 = C6H5, 2-MeC6H4, t-Bu R4 = Me, Et, morpholine, piperidine, pyrrolidine
Scheme 124
N R3NH2 CHO r.t. quantitative N N R3 R4NC, BF3.OEt2 CH2Cl2, 0oC 27-72% 2 R R1 196 N NHR4 NHR3
R2
R2 R1 R1 R1 = H, OMe, Cl; R2 = H, OMe; R3 = C6H5, n-Bu, 2-Me-C6H4, 4-OMe-C6H4, 4-4-i-Pr-C6H4; R4 = C6H5, 2-Me-C6H4, t-Bu
Scheme 125 Sharma et al. [135] utilized the phase transfer catalyst for the synthesis of quinoline derivatives. The cycloaddition reaction of N-phenyl-2,5-dihydroxy-3-arylazo indoles with
49
Current Organic Chemistry( 2008),12, 1116-1183 dibromocarbene (obtained from CHBr3 and KOH) in the presence of TBAB produced the N-phenyl-2,6-dihydroxy-4-arylazo quinolines (197) which possess good antibacterial activity (scheme 126).
CHBr3, KOH, N=N TBAB, toluene, N=N HO Br 3 h, 65-74% HO R or R CHBr3, NaOH, N OH N OH CTEAB, 48 h Ph Ph 43-62% R = H, 4-Me, 2-NO2, 3-NO2, 4-NO2, 2-Cl, 3-Cl, 4-Cl, 3-OH 197
Scheme 126 Chattopadhyay and co-workers [136] obtained quinolines (198) as a side product during the SnCl4-catalyzed 5+1 annulation
R1 O + R R2
1
of
-dicarbonyl
compounds
and
2-
ethoxymethyleneamidinonitriles in refluxing toluene (scheme 127).

R1 O SnCl4, toluene N NH2 OEt N 198 NH2 O R1 + N O NH
CN
reflux, 5 h N OEt 19-48% O 2 R1 = CH3, OMe ; R = CH3, OEt
Scheme 127 4.3 From C-C-N-C-C+ C Units Recently Li and Jones demonstrated the synthesis and mechanism of the 2,3-disubstituted quinolines (199) in moderate to good yields from the diallylanilines in the presence of Co2(CO)8 catalyst in THF (scheme 128). [137] Yields of products was dependent on electronic and steric factors. For example electron donating group at p-position of diallylaniline favoured the reaction, whereas an electron withdrawing group inhibited the reaction.
Co2(CO)8 (10 mol%), CO (1 atm)
R THF, 95oC N R 36-48 h 199 20-87% R = H, 2-Me, 4-Me, 2,3-(Me)2, 3,4-(Me)2, 3,5-(Me)2, 2-Me-4-OMe, 3,5-(OMe)2, 2-CF3, 4-CF3, 3,5-(CF3)2, CN
Scheme 128 Kim and co-workers [138] conducted the synthesis of quinolines (200) from N-phenyl enaminones through reaction with acid anhydrides in PPA. The reaction proceeded via
50
Current Organic Chemistry( 2008),12, 1116-1183 sequential acylation at -position of enaminone, cyclization and dehydration as shown in scheme 129.
O (R1CO)2O R R N H Ph PPA 60-90oC 55-87% R R O R1 O Ph O R1 OH - H 2O R R N 200 O R1
R N N R H H 1 R = H, Me; R = Me, Et, Pr, C6H5
Scheme 129 Miao et al. [139] described the synthesis of cone and partial cone conformations of substituted 2 or 3-carboxylic group substituted chiral calix[4]quinolines from amines. Aniline (201) reacted with a mixture of ethylacetoacetate and Vilsmeier reagent to afford the racemic
R R R NH2
R = H, tBu OPr OPr OPr rO P 201 route-A O EtO O POCl3, DMF , 0-5oC CH3 R R R N CO2R1 a. R = Bu, R = Et b. R = H, R1 = Et c. R = tBu, R1 = H d. R = H, R1 = H
t 1
route-B crotonaldehyde, n-BuOH, H2O, toluene, 72% CH3 But

t
Bu tBu
hydrolysis OPr OPr OPr OPr 204 SeO2, Pyridine, reflux, 70% COOH But
t
OPr OPr OPr PrO 202 DCC, DMAP, (S)-BINOL, CH2Cl2, r.t HO CH3 Bu
t t
SOCl2, (R)-Phenylglycinol, Et3N, CH2Cl2 CH3 N HO
Bu tBu
Bu Bu
COO
H C N O
OPr OPr OPr OPr OPr OPr OPr OPr NaOH, EtOH, H2O reflux (+)-202ca and (-)-202cb OPr OPr OPr OPr (-)-203a and (+)-203b NaOMe, DMC, r.t. CH3 CO2CH3 N But
OPr OPr OPr OPr 205 DCC, DMAP, HO (S)-BINOL, COO CH2Cl2, r.t
t
Bu tBu
OPr OPr OPr OPr NaOH, EtOH, H2O reflux (+)-205a and (-)-205b
51
Current Organic Chemistry( 2008),12, 1116-1183 Scheme 130 chiral calix [4] quinolines (202) which hydrolyzed to a racemic mixture of 3-carboxylic acid quinolines ((+)-202ca & (-)-202cb) on treatment with NaOH in EtOH and H2O. Alternatively the aromatic amine (201) upon condensation with crotonaldehyde in toluene furnished 2-methylquinoline (204) containing chiral calix. On oxidation with SeO2 in pyridine the racemic 2-carboxylic group substituted chiral calix[4]quinolines (205) were formed in good yields as depicted in scheme 130. In a slight variation to their strategy they also demonstrated the synthesis of substituted 2- or 3-carboxylic acid chiral calix [4] quinolines ((+)-207a, (-)-207b & 209) having partial cone conformations via two separate routes A and B. This was possible due to the inversion of configuration of the hydroxyl group at the time of allylation under the influence of CsCO3 (scheme 131).
But
t
Bu tBu
OPr OPr OPr HO
NO2 But allyl bromide, Cs2CO3 DMF r.t., 65%
Bu tBu O H2, Pd-C r.t., 98%
But
Bu tBu OPr
OPr OPr OPr NO2
OPr OPr OPr NH2
POCl3, DMF Bu O O OEt 0-5oC 43% route-A
Bu tBu OPr
But DCC, DMF, (S)-BINOL CH2Cl2 r.t., 40-43% N CO2R
Bu tBu OPr NaOH, EtOH, H2O (+)207a and (-)207b reflux 73-74% HO CO2
OPr OPr OPr 206

t
OPr OPr OPr N But

t
But crotanaldehyde, toluene n BuOH, H2O reflux, 70% route-B
Bu tBu Me OPr SeO2, pyridine reflux 73%
Bu tBu
Me
OPr OPr OPr OPr 209 N CO2H
OPr OPr OPr 208 N Me
Scheme 131 5.0 6 Unit Approach 5.1 From N-C-C-C-C-C Unit 5.1.1 From alkyneHessian and Flynn [140] demonstrated the synthesis of 3-iodoquinoline (211) via iodocyclization of 6-endo-diagonal product (210) obtained from the reaction between 2(N,N-dimethylamino)benzaldehyde and lithium acetylides (scheme 132). 52

HO R1 I2 NMe2 R MeCN or CH2Cl2 71-89% R1 OH I N R Me Me I 6-endo-diagonal 210 heat R1 I N R Me I 211
R = PMP, n-Pr; R1 = H, Me
Scheme 132 Gabriele and his collaborators [141] reported an innovative practical synthesis of substituted quinolines (212) through a two-step procedure involving Grignard addition of alkynylmagnesium bromides to 2-aminoarylketones followed by regioselective Cu- or Pd-catalyzed 6-endo-dig cyclodehydration of the analogous 1-(2-aminophenyl)-2-yn-1ols as shown in scheme 133.
O R2 i. R4CCMgBr 2 R 3 THF R ii. H
+
HO
R3
4
CuCl2 or PdX2, KX
R3 R
2
R MeOH or DME 60 or 100oC R R 66-90% R1 = H, OMe; R2 = H, Cl; R3 = Me, Ph; R4 = Bu, t-Bu, Ph X = Cl, I NH2 NH2
1 1
N R1 212
R4
Scheme 133 A new synthetic approach was developed by Marinelli and co-workers [142] for the synthesis of functionalized quinolines from -(2-aminophenyl)-,-ynones scaffold via sequential hydroarylation or hydrovinylation and heterocyclization. The reaction of -(2aminophenyl)-,-ynones with arylboronic acid or potassium aryl and vinyl trifluoroborates, followed by nucleophilic attack of amino group on carbonyl in the presence of Rh(acac)(C2H2), dppf in aqueous EtOH at 80-100C furnished the desired functionalized quinolines (213) regioselectively as shown in scheme 134. Subsequently Arcadi et al. [143] reacted carbanions obtained from electrolysis of nitroalkanes or MeOH, with -(2-aminophenyl)-,-ynones under solvent free conditions to obtain substituted quinolines (214) in moderate to good yields (scheme 135).
O R2 NH2 R RB(OH)2,
1 Rh(acac)(C2H2)
R R
2
R2 O NH2 R
1
dppf aq EtOH
R -H2O
N R3 213
R1
R3 R = C6H5, 4-F-C6H4, 4-Me-C6H4, 3-COMe-C6H4, CH=CHC6H5, 3-Thiophenyl, 2-Furyl; R1 = 2,4Me2-C6H3, 2-OMe-C6H4, 4-OMe-C6H4, 3-COMe-C6H4, 3-CF3-C6H4, napthyl; R2 = H, F; R2 = H, F
R3
Scheme 134
53

O electrolysis RH TEATFB-DMF, TEAP-DMF, 38-93% R R2 + NH2 R3 R3 R1 R R2 N R1
214 R = MeOH, MeNO2, n-PrNO2, i-PrNO2, CH(CO2Me)2; R1 = 2-OMe-C6H4, 4-OMe-C6H4, 3,5-Me2-C6H4, naphthyl; R2 = H, F; R3 = H, F
Scheme 135 Recently Yamamoto et al. [144] reported the preparation of 2-substituted tetrahydroquinolines via Pd-catalyzed intramolecular hydroamination of anilino alkynes. They extended the scope of the strategy by developing an asymmetric variant of the reaction using chiral Pd-catalyst to obtain tetrahydroquinolines (215) with Rconfiguration (scheme 136).
cat. Pd(0), RCO2H, (R,R)-renorphos NH toluene, 120oC R R1 2-24 h, 63-98% R= H, Me, CH2C6H5; R1= alkyl, aryl N R 215 H R1
Scheme 136 5.1.2 From reductive cyclizationA reductive cyclization strategy involving the reduction of 2-nitro or 2-azido group in aromatic ring to amino group followed by its cyclization with appropriate carbonyl or alkene has been widely applied towards the synthesis of quinoline and quinoline annulated heterocycles. 5.1.2.1 From Baylis-Hillman chemistryThe Baylis-Hillman derivatives originating from 2-nitrobenzaldehyde have been extensively utilized for quinoline synthesis utilizing the reductive cyclization methodology. Kim Lee et al. [145] reported the synthesis of quinoline-N-oxide (216) from Baylis-Hillman adducts of 2-nitrobenzaldehyde via conjugate addition of nitroso intermediate in the presence of Zn and NH4Cl in aqueous THF at 60-70C. The resulting quinoline-N-oxides (216) were refluxed with PPh3 in THF to furnish the corresponding quinolines (217). Alternatively these N-oxides reacted with Ac2O to provide the 2acetoxy derivatives (218) which spontaneously transformed to 2-hydroxy quinolines (219) (scheme 137).
54

PPh3 THF, reflux 70% CO2Et N O 216 Ac2O 58% N 218 CO2Et N 217 CO2Et OAc 219 N CO2Et OH
OH CO2Et Zn, NH Cl 4 NO2 aq. THF 60-70oC
Scheme 137 Kim and co-workers [146] demonstrated the transformation of the Baylis-Hillman adducts to 3-benzylquinolin-2-ols. The synthetic pathway included the SN2 nucleophilic substitution reaction between Baylis-Hillman acetate and aryl amines leading to the formation of 3-arylamino-2-methylene-3-phenylpropanoates, which upon treatment with PPA resulted in of 3-benzylidene-3,4-dihydro-1H-quinolin-2-ones (220). Finally, isomerization in the presence of DBU yielded the 3-benzylquinolin-2-ols (221) as outlined in scheme 138.
OAc i. DABCO, NHAr CO2Me aq. THF CO2Me PPA 30 min ii. ArNH2 80-90oC, 7 h R r.t., 18 h R 75-87% R = H, 4-Me, 4-Cl; R1 = H, Cl O NH DBU THF, r.t., 1 h 88-93% R 221 OH N
220
R1
R1
Scheme 138 They [147] also described the synthesis of 2-methyl-3-benzyl quinolines (222) in good yields from the Baylis-Hillman acetate via SN2- SN2 displacement reaction of substituted aniline followed by PPA-mediated Claisen rearrangement and intramolecular cyclization (scheme 139). Subsequently in our attempts to synthesize 2-methoxy quinoline (224), the starting substrate for antitubercular compound JJ-207910, we demonstrated that the same reaction could be accomplished in the presence of TFA to obtain 3-benzyl-2-quinolinols (223) in excellent yields as per the scheme 140. [148] These compounds were
OAc Ph COCH3 DABCO, PhNH2 32-74% NHPh COCH3 PPA, DBU 1-2.2 h 43-67% Ph COCH3 Ph R H 2N CH3 N R R = H, 4-Me, 3,4-(Me)2, 4-OMe 222 Ph CH3 N R
Ph
Scheme 139
55

O OH R OAc AcCl, anilines, Pyridine EWG DABCO EWG R THF:H2O CH2Cl2, r.t., 3 h (1:1) r.t., 3 h anilines, DABCO THF:H2O (1:1) EWG = CN r.t., 8 h R1 HN R CN TFA 60oC, 24 h 28-53% HN R R TFA, 60oC EWG 8-14 h R1 K2CO3, R NH acetone 60oC R1 10-15 min O NH R1
223 R = C6H5, 2-Cl-C6H4, 2-F-C6H4, 4-Br-C6H4, 2-Pyridyl POCl3, R1 = H, 4-Br, 4-Cl, 4-F, 2-Me, 4-Me, 4-OMe, 3,4,5-(OMe)3 reflux, 30 min EWG = CO2Me, CO2Et, CO2tBu OMe Cl NH2 R N R1 224 R N R1 NaOMe MeOH reflux R N R1
225 R = C6H5, 2-F-C6H4, 2,4-(Cl)2-C6H3; R1 = H, 4-Cl
Scheme 140 transformed to 2-methoxyquinolines (224) in excellent yields without the use of column chromatography. We observed that the Baylis-Hillman adduct of acrylonitrile undergo similar reaction to yield 2-aminoquinolines (225). The acetoxy derivative of Baylis-Hillman adduct of 2-azidobenzaldehyde on Staudinger reaction led to imino phosphorane which after SN2-displacement reaction of the acetate afforded an intermediate that undergo Michaelis-Arbuzov rearrangement to furnish a mixture of 1-diethyl phosphono-1,2-dihydro quinoline (226) and 3-acetoxy methylquinolines (227). It was reported that in case of adducts originating from acrylate the diethyl phosphonoquinoline (226) was the major product while for adducts derived from methyl vinyl ketone the amount of 3-acetoxymethylquinoline (227) was afforded in better quantities (scheme 141). [149]
OAc X Z N P(OEt)3 r.t. or reflux 0.5-48 h OAc X 4-76% N R N 227 X CH2OAc NaOH, THF X reflux, 2 h 91% R reflux 3-48 h X Z
_
X EtOAc 57-91%
Z N O P OEt OEt 226
N OAc EtO P OEt OEt
CH2OH N R
Scheme 141 Kaye and co-workers [150] demonstrated the synthesis of quinolines (228-234) from the Baylis-Hillman adducts of 2-nitrobenzaldehyde via reductive cyclization as per the sequence shown in scheme 142. The reduction was accomplished either by catalytic
56
Current Organic Chemistry( 2008),12, 1116-1183 hydrogenation or by SnCl2 (scheme 143). They suggested that though the formation of products may take place via path-I or II, in most of the cases Path-II predominates.
R4 R3 R2 R1 NO2 OH O R H2/Pd-C R3 R2 R1 Path II R R
3 4
R4
OH O
Path I Conjugate R3 R addition II R2
R4
OH
NHY I
N H R1 228 R4
(Y = H or O) OH R = alkyl R Nucleophilic addition and dehydration R3
R1 = H, OMe R R2 = H, OMe, NO2, -OCH2OR3 = H, OMe, Cl, OH R4 = H, Cl, NO2 R5 = COMe, COEt, CO2Me, CO2Et, CN, SO2Ph R4 R3 + + R2 N R1 O 231 R R2 R1 NO2 R
3
R4 R = COR R N H
3
R4
OH R5
R2 R
1
232
Nucleophilic O acyl R2 substitution
N O R1 H Y 229
R2 R1 230
Scheme 142
R = COR1 OH R NO2 SnCl2.2H2O MeOH or EtOH R = CO2R1 N H 234 N OH 233 R R
Scheme 143 We have also demonstrated the synthesis of 4-vinyl-quinoline derivatives (235-237) utilizing Baylis-Hillman chemistry through the SN2-SN2displacement reaction of BaylisHillman acetate of 2-nitrobenzaldehyde with carbonyl group containing nucleophiles. [151] The SnCl2-mediated reduction of the nitro group triggered a subsequent intramolecular cyclization yielding the final quinoline derivatives (235-237) as shown in scheme 144.
O OH CHOCH2=CHEWG, DABCO r.t., NO2 15 min - 1 h R 80-86% EWG AcCl, Pyridine CH2Cl2, r.t., 2-3 h R 78-84% OAc R1 EWG DABCO, R1COCH2COR2 THF, H2O (1:1), r.t., 30 min, R 62-85% O R2 EWG NO2 H SnCl2 MeOH, reflux, 1 h, 51-62% EWG H COR2 N H 235 O
NO2
NO2
SnCl2, reflux, 1 h, MeOH 50-86% EWG COR2 + R 236 N R1 R 237 N H CN COR2 R1 R = H, 5-Cl, 3,4-OCH2O R1 = Me, C6H5 R2 = Ph, OEt, OMe EWG = CO2Me, CN
Scheme 144 5.1.2.2 Other reductive cyclizations-
57
Current Organic Chemistry( 2008),12, 1116-1183 Baraldi et al. [152] described the synthesis of novel 2-arylpyrazolo[4,3-c]quinolines (239-244) starting from phenyl hydrazines. As shown in scheme 145, the condensation of substituted phenylhydrazines with 2-nitroacetophenone afforded the corresponding phenylhydrazones which on treatment with Vilsmeier reagent furnished the pyrazole-4carbaldehydes (238). Reduction of the nitro group followed by intramolecular cyclization in EtOH produced the pyrazoloquinolines (239). The generated pyrazole-4-carbaldehydes were also converted to their acids by KMnO4 to obtain pyrazoloquinolones (240) via sequential esterification, reduction and cyclization (scheme 146). These quinolones (240) were used as precursors for the pyrazoloquinolines (240-244) by treating them with POCl3 in the presence of PCl5 followed by reaction with amines or MeONa to afford the corresponding pyrazoloquinolines (241). The reaction of 4-chloro-pyrazoloquinolines with 4-chlorobenzoic acid hydrazide in EtOH at 70C yielded 242 whereas the same reaction when performed at 120C resulted in the corresponding tetracyclic compounds (243). The 4-thiomethyl pyrazoloquinolines (244) were also obtained from the corresponding quinolones on reaction with Lawessons reagent followed by methylation (scheme 147). The compounds generated during the endeavor were found to be potent and selective human A3 adenosine receptor antagonists.
NO2 NHNH2 R3 R2 R
1
O Me NO2 AcOH, EtOH, reflux 64-75% N
Me NH R
3
NO2 CHO POCl3, DMF, 0oC reflux 65-80% N N R

3
H2, Pd-C EtOH reflux 90%
N R3 R2 R 239
1
R2
1
R2 R
1
R R1 = H, Cl, F, OMe, Me, Et, n-Bu, i-Pr; R2 = H, Cl; R3 = H, Cl
238
Scheme 145
NO2 CO2H 238 KMnO4 aq KOH, r.t. 70-80% N H2SO4 N R3 R2 R1 R1 EtOH reflux 90-95% N NO2 CO2Et H , Pd-C, 2 EtOH reflux (or) R3 R2 Fe, HCl 2-methoxyethanol, reflux 60-70% NH O N
N R3 R2 R 240
1
Scheme 146
58

240 Lawesson's reagent toluene, reflux 90% NH Cl N N S
PCl5 POCl3, reflux 90% N
amine NaOMe, 120oC MeOH, reflux or 70-86% N R N
EtOH 4-chlorobenzoicacid- 70oC hydrazide, 60% Et3N O N HN NH
acidhy- EtOH o drazide, 120 C Et3N 65-70% R N N N N
NaOAc, MeI, EtOH, reflux 65%
N S
N N
N Cl
241
242
243
244
Scheme 147 Some et al. [153] described a new protocol involving Pd(0)-mediated Ullman crosscoupling of -bromo-, -unsaturated aldehydes with 1-bromo-2-nitrobenzene to produce the -(2-nitrophenyl)-, -unsaturated aldehydes (245), which upon reductive cyclization using either In-NH4Cl or Raney-Ni with hydrogen furnished the quinolines (246) (scheme 148). They developed another route for the synthesis of same set of quinolines (257) utilizing the 2-bromoacetanilides instead of 1-bromo-2-nitrobenzene as shown in the scheme 149.
POBr3 O DMF CHO Br X Cu Pd[0] 10 mol% DMSO, O2N 245 CHO H2 10% Pd-C N 246
+ O 2N
Scheme 148
CHO Br + H3COCHN X Cu Pd[0] 10 mol% DMSO, H3COCHN CHO K2CO3 DMSO, N 247
59
Current Organic Chemistry( 2008),12, 1116-1183 Scheme 149 Vanelle and co-workers [154] performed an original and rapid synthesis of new substituted 6H-indolo[2,3-b]quinolines (248). The reaction of substituted 2nitrobenzylchloride with 1-methyl isatin in the presence of TDAE generated the hydroxy lactams, which were transformed to indoloquinolines by the reduction of nitro group followed by intramolecular cyclization and dehydration in the presence of Fe in AcOH (scheme 150).
R1 R1 R2 O NO2 Cl + O N H 3C
2 TDAE R o DMF, -20 C 36-87%
NO2 Fe AcOH 33-65% R1 R2 248 N
CH3 N
OH O N CH3
R1 = H, Cl, OMe; R2 = H, Me, OMe; R1 & R2 = OCH2O
Scheme 150 2-Nitrochalcones were successfully transformed to 2-aryl quinolines by Kim et al. [155] A reductive cyclization triggered by reduction of nitro group of 2-nitrochalcone in the presence of In-NH4Cl afforded quinoline (249) in moderate to good yields (scheme 151).
O In, MeOH:sat.NH4Cl 3:1 R reflux, 2-6.5 h 40-73%
NO2
N 249 R = H, 2-Cl, 3-Cl, 4-Cl, 2-Br, 3-Br, 4-Br, 2-F, 3-F, 4-F, 2-Me, 4-Me, 3-OMe, 4-OMe
Scheme 151 Shi et al. [156] described that intramolecular reductive cyclization of ketomalononitriles induced by a low valent Ti-reagent made by TiCl4-Zn provided acridines (250) and quinolines (251) as shown in scheme 152, 153.
NC O CN NO2 TiCl4-Zn THF, r.t. R1 75-80% N R1 R2 250
R R1 = H, OMe; R2 = H, OMe, Cl; R1 & R2 = OCH2O
Scheme 152
NC R1 CN O R2 TiCl4-Zn THF, r.t. 78-91% N 251 R1 R3 R2
NO2 R3 2 R = H, Cl; R = H, Br, Cl; R3 = H, Cl

1
60
Current Organic Chemistry( 2008),12, 1116-1183 Scheme 153 Lemaire also demonstrated that benzo[b]thiophene acts as a template for the synthesis of substituted quinolines (253) and tetrahydroquinolines as (254) shown in scheme 154. [157]
O ArCOCl, OMe AlCl3 O 2N OMe H2 35-60% OMe 253 254 OMe 1-5 h S O2N OMe H N a. 2-OMe b. 3-OMe c. 4-OMe OMe OMe Ni, H2 17-90% S 252 X = O, O / MeO X N
desulfurisation OMe 12-66%
Scheme 154 A diastereoselective synthesis of hexahydropyrrolo[1,2-a]quinolines (255 & 258) was described by Bunce et al. [158]. Synthetic sequence involved the alkylation of methyl (2nitrophenyl) acetate with 2-bromomethyl-1,5-hexadiene derivatives using K2CO3 and 18crown-6 in MeCN to produce the nitro dienoic esters, which upon ozonolysis furnished the nitro dicarbonyl compounds. Catalytic hydrogenation of nitro derivative afforded the hexahydropyrrolo [1,2-a] quinolines-5-carboxylic ester (255 & 258) as a single isomer with cis-geometry along with deacetylated product (256) and a fused hemiacetal adduct (257 & 259) (scheme 155). The ratio of the product depended on the catalyst used and the hydrogen pressure applied as shown in table-1.
CO2Me H 2, catalyst CO2Me MeOH R=H + N 255 O O R H 2, catalyst MeOH R = CH3 CO2Me + N N H 256 258 259 N H 256 CO2Me + N O OH CO2Me + N O 257 CO2Me
Br CO2Me + NO2 R R = H, CH3 K2CO3, 18-crown-6 MeCN 84-88%
NO2 CO2Me
i. O3, MeOH - 78oC ii. Me2S, H+ iii. 3% aqHClO4: THF(1:1) 90-95%
NO2
OH CO2Me
Scheme 155 Table-1 Conditions yield% 255 yield% 256 yield% 257 yield% 258 yield% 259
61
Current Organic Chemistry( 2008),12, 1116-1183 5% Pd/C (3 atm, purged) PtO2 or Pt/C (3 atm, purged) 5% Pd/C (1 atm, purged) 5% Pd/C (5 atm, not purged) 36 20-25 29 66 29 (7) 0 (0) 37 (16) 5 (4) 3 48-53 3 3 58 34 48 64 4 36 4 3
Very recently they introduced another synthetic sequence for ()2-alkyl-1,2,3,4tetrahydroquinoline-3-carboxylic esters (260) by reductive cyclization of 2-methyl-2-(2nitrobenzyl)-substituted--keto ester derivatives (scheme 156). [159] The reaction was conducted using different hydrogenation conditions to synthesize the quinoline derivatives (261-263) and to understand the importance of the ester group for outcome of the diastereoselectivity in the procedure (scheme 157). [160] It was observed that even though the final reductive cyclization was not as selective as that observed earlier for ()2-alkyl-1,2,3,4-tetrahydroquinoline-4-carboxylic esters (255-259), it supported the product having a cis relationship between the alkyl and ester.
O + NO2 O Br CO2Me K2CO3 acetone R MeI, R K2CO3 CO2Me acetone NO2 O H 2, 5% Pd-C R Me CO2Me MeOH NO2 78-87% Me CO2Me N H 260 R
R = Me, n-C5H11, CH2CH2C6H5, i-C3H7, c-C6H11, t-C4H9, C6H5
Scheme 156
O R CO2Me NO2 H 2, 5% Pd-C MeOH CO2Me + R 262 CO2Me + N R N H 263 R CO2Me
N 261 H
H2, 5% Pt-C MeOH R = Me, n-C5H11, CH2CH2C6H5, i-C3H7, c-C6H11, t-C4H9, C6H5 68-88%
Scheme 157 We have successfully achieved the synthesis of poly functionalized isoxazolo[4,3-c] quinolines (264-266) from chalcones. [161] As shown schematically 1,3-dipolar cycloaddition of chalcones with 2-nitrobenzonitrile oxide afforded the 2-isoxazolines, which upon reduction of nitro group by SnCl22H2O in MeOH, followed by intramolecular cyclization furnished a mixture of isoxazolo[4,3-c]quinolines (264) and 3,5-dihydroisoxazolo[4,3-c]quinolines (265) (scheme 158). Under similar reaction conditions compounds originating from 4-bromobenzaldehyde afforded the quinoline-Noxide (266) along with isoxazolo[4,3-c]quinolines (264) and 3,5- dihydroisoxazolo[4,3-
62
Current Organic Chemistry( 2008),12, 1116-1183 c]-quinolines (265). In contrast, when the reduction was performed with Fe in AcOH the 3-benzoylquinolin-4-ylamine derivatives (267) were obtained in good yields.
NOH CHO + R2 O aq KOH MeOH 15-30 min R1 8-90% O Cl NO2 Et O, _78 - r.t. R2 2 14-16 h 54-64% O NO2 N O Fe, AcOH R1 reflux, 30 min 56-66% R2 SnCl2.2H2O MeOH, reflux, 30 min 49-68% R1 = 4-Br, 4-Cl, 2,3-(Cl)2, 2,4-(Cl)2, 3,4-(Cl)2 R1 = H, Me N O R1 + N 264 R2 N H 265 R2 N O R1 + N O 266 N O R1 R2 R1 N 267 R2 NH2 O
Scheme 158 We have also reported the synthesis of substituted 4-aminoquinolines (268) from 3-(2nitrophenyl)isoxazoles via Pd-C-catalyzed hydrogenation which proceeded through sequential reduction of the nitro group, isoxazole ring cleavage and regiospecific cyclization of aromatic amino group with the keto of -amino ketone (scheme 159). [162]
N O R R1 R2 10% Pd-C, H2, 40 psi NH2 R1
R MeOH, N R2 NO2 5-7 h 268 79-95% R = H, 6,7-(OMe)2; R1 = H, CHO, CH2OH, CO2Me; R2 = H, Me, CH2OH, CF3, CH(OH)CH(CH2(4-Me-piperazin-2-yl)CO2Me, CH(OH)CHMeCO2Me
Scheme 159 5.1.3 Other N-C-C-C-C-C approachesKumar and Perumal [163] successfully accomplished the synthesis of 4-alkoxy-2arylquinolines (269) via one-pot oxidative cyclization of 2'-aminochalcones employing FeCl3.6H2O as the catalyst as shown in scheme 160. They reported that out of several solvents attempted for optimization, the reaction proceeds in MeOH or EtOH only.
O FeCl3 6H2O MeOH N R 5-7 h 269 55-72% R = H, 4-Cl, 2-F, 2-OMe, 4-OMe, 3,4-(OMe)2 NH2 R
.
OMe
Scheme 160 Black and co-workers [164] conducted the reaction of 2,4-dinitrophenyl ethers of 3arylindole-2-ketoximes in the presence of NaH or Et3N resulting in indolo[2,3c]quinolines (270) as per the reaction sequence shown in scheme 161. 63

X X X NaOEt , fluoro-2,4-di NOH nitrobenzene 49-100% R O
OMe
1. (COCl)2 2. RH N H X MeO NO2
OMe
MeO
N H
NH2OH.HCl base O 51-95% R MeO O X
OMe
N H
OMe N O MeO N H R O NO2
NaH or Et3N 10-69% MeO
OMe N N H 270 R O
R = OEt, NMe2 X = Br, Cl
Scheme 161 Very recently they have extended their synthetic methodology and carried out the mechanistic studies to explain the final step consisting of unusual base-promoted cyclization. [165] They reported that the ester group was responsible for stabilising the intermediate in the electrocyclic process thus facilitating the reaction (scheme 162).
R R O N H i. TFAA ii. TFA iii. KOH, MeO MeOH R 37-44% NO OMe N O N H CO2Et NO2 N H R NH2OH.HCl, AcONa O EtOH 57-97% CO2Et
O Br
3,5-dimethR oxyaniline, NaHCO3 EtOH MeO reflux 80-92% R
OMe
OMe 1. (COCl)2 2. EtOH 18-81% MeO
OMe
N H R
OMe NOH MeO N H
Na, fluoro-2,4-di nitrobenzene EtOH 43-75% CO2Et MeO
Et3N THF, 51-100% MeO
OMe N N H 271 CO2Et O
R = Br, Cl, H, Me, OMe
Scheme 162 Ichikawa and co-workers [166] disclosed the synthesis of 2-fluoro quinolines from N-[2(3,3-difluoroallyl)phenyl]-substituted p-toluenesulfonamide obtained from the Nprotected anilines upon treatment with lithiated base followed by SN2 reaction with 1(trifluoromethyl)vinyl compounds, deprotection and subsequent tosylation. The intramolecular substitution reaction of tosylamide nitrogen and vinylic fluorines in 1,1difluoro-1-alkene in the presence of a base such as NaH or Et3N yielded corresponding 2fluoro tosylated dihydroquinolines (272) and quinolines (273) as illustrated in scheme 163. The dihydroquinolines (272) obtained during the process were reacted with DDQ to afford the quinolines (273). 64

n-BuLi, THF 0oC, 2 hr.t., 20 h R1 t-BuLi, THF 0oC-r.t., 1 h R= Ph (0.8 eq.), TMEDA (1.0 eq.) Li Li o O -78 C-reflux, 5 h N R1 R= SiMe2Ph (1.5 eq.) 0oC-r.t., 20 h R NaH (2.2 eq.) or KH (3.0 eq.) CF NH 2 Ts DMF, 80o C
O N H
HCl (20 eq.), H2O, EtOH(1:1) R reflux, 16 h CF (2.0 eq.), NH 2 Me3SSiI o CHCl3 , 0 C R1 O 2 h-r.t., 20 h R + F R
TsCl (1.5 eq.)
CF2 Pyridine, NH2 0oC-r.t. 10-16 h
N N F 272 Ts 273 9-85% 0-79% DDQ R = C6 H5 , SiMe2C6H5, R1 = t-Bu, O-t-Bu (1.1 eq) benzene reflux, 3 h
Scheme 163 Hranjec and co-workers [167] reported the synthesis of benzimidazo[1,2-a]quinolines (274) from N-amidino-and cyano-substituted E-2-styryl-1H-benzimidazoles (obtained from various methods) via photochemical dehydrocyclization and dehydrohalogenation in the presence of molecular iodine and O2 in EtOH (scheme 164).
X + CHO X + Me CHO CN + Me N CHO H 2N H N N H N H 2N R p-benzo -quinone abs EtOH reflux 49-74% CN Ac2O reflux, 2 h 48-49% N sealed tube 200oC 2 h, 71% X = H, Cl, R1 = H, CN NH2+ClR = H, CN, Me NH , Me H N N H+Cl, NH2 Cl
+ -
R1
X H N
MW, 400 W or hv I2, air or O2 EtOH R 6-7 h 12-78%
R1
NH
274
R NH2+ClNH2
NH , N O
Scheme 164 Deagostino et al. [168] demonstrated a novel metal-catalyzed synthesis of quinoline (275 & 276) from N-tosyl protected dienylaniline under mild conditions. The cyclization reaction proceeded via formation of a -complex between Pd and dienyl fragment which underwent heterocyclization to form a -complex. This complex underwent elimination followed by re-addition of HPdX to the exocyclic bond followed by elimination of Pd(OAc)TS to furnish quinoline (scheme 165). Notably this process does not require reoxidation.
65

LIC-KOR, THF, - 95oC (i-PrO)3B, H2O diol, toluene 25oC 70-85% H N
1O
R1 R2
OEt OEt
Ts R
1
OEt Ts Pd(OAc)2 N DMF, 80oC H 48-65% OEt R2 H+ R1 = Me R2 = H R2 N 275 R2 = H, Me
O OEt
I PdCl2(PPh3)2, THF, K2CO3 50oC 49-94%
R2
OEt TsHN OEt N 276 Ts
Scheme 165 5.2 From C-N-C-C-C-C Unit Bowman and co-workers [169] described a new route for the synthesis of quinolines from amides. Their protocol involved reaction of amides with phosgene followed by diphenyl diselenide in the presence of K-selectride to generate imidoyl selanides. The imidoyl selenides yielded the corresponding indoles (5-exo) (278) and quinolines (6-endo) (277) via imidoyl radical cyclization with alkene in the presence of Bu3SnH. The reaction of imidoylselenides with Bu3SnH and triethyl borane selectively gave the quinolines (277) (scheme 166).
R2 R3 i. COCl2 NH O R
1
R2 R3 Bu3SnH, AIBN
R3 R N 277 R
2
R2 +
1
ii. PhSe
R1 278 N H
K-Selectride PhSe PhSeSePh
toluene, reflux, 6 h N 10-98% R

1
R1 = Me, CH2C6H5, 4-Me-C6H4;R2 = H, Me, Pr, C6H5, CO2Et; R3 = H, Me, Et
Scheme 166 Kobayashi et al. [170] demonstrated the synthesis of 6-substituted indolo[3,2c]quinolines (280). As depicted in the scheme 167, reaction of 2-(2-aminophenyl)-1methyl-H-indole with ethylformate led to the formation of N-formyl derivative, which was treated with POCl3 and Et3N in THF at 0oC to afford 2-(2-isocyanophenyl)-1-methyl1H-indole (279). The 2-(2-isocyanophenyl)-1-methyl-1H-indole was treated with aldehydes, ketones, and acetals in the presence of catalytic amount of BF3OEt2 or N,Ndimethyliminium salts to furnishes the 6-(1-hydroxy or alkoxy alkyl or 1dimethylaminoalkyl)-11H-indolo[3,2-c]quinolines (280) in satisfactory yields.
66

E, BF3.OEt2, NC DCE, 0oC or N R1CH=N+Me2IMe 29-93% E = aldehydes, ketones, acetals 279 E N
NH2 N Me
HCO2Et reflux 78% N Me
NHCHO POCl3, Et3N THF, 0oC 82% N Me 278
Scheme 167 A successful facile synthesis of 3-fluoro quinolines (281-283) through Sn-mediated radical cyclization was reported by Mori and Ichikawa. [171] Radical cyclization of 2cyano substituted ,-difluorostyrenes in a endo-trig fashion followed by transformation of C-Sn bond and dehydrofluorination or reduction as depicted in scheme 168. They further demonstrated that an appropriately substituted 3-fluoroquinoline (281-283) served as excellent precursor for cryptolepines.
R n-BuSnH (1.2 eq.) F F2C cat. AIBN F toluene CN n-Bu3Sn N 80oC, 1 h 281 R = H, i-Pr, Bu; Ar = C6H5, 4-COMe-C6H4 2-OMe-C6H4, 2-BocNH-C6H4, (E)CH=CHC6H4 R i. ArX(1.2 eq.), Pd(PPh3)4, (0.1 eq.), R CuI (0.5 eq.), o F DMF, 80 C R
F F
ii. DBU (1.1 eq.) Np Ar N 80oC, 1 h 282 32-74% i. NpI(1.2 eq), Pd(PPh3)4 (0.1 eq.) CuI (0.5 eq.), 80oC, DMF ii. NaBH4 (1.0 eq.), CH2Cl2, r.t., 2 h, 50%
N H
283
Scheme 168 The isocyanides bearing an electron withdrawing group undergo a highly selective thiotelluration by the use of a disulfide-ditelluride mixture upon irradiation by visible light. Ogawa and co-workers applied this photoinduced reaction to radically cyclize 2allylsubstituted phenylisocyanides to generate quinolines derivatives (284 & 285) as per the reaction sequence shown in scheme 169. [172]
+ (PhS)2 + (PhY)2 NC 0.4 M 0.2 M 0.4 M 0.4 M 0.1 M 1.0 eq 1.2 eq 2.0 eq 1.0 eq 1.0 eq Te, 0.5 eq Te, 1.0 eq Te, 0.5 eq Se, 0.6 eq Se, 0.5 eq hv>400 nm CDCl3 40oC 30 h 30 h 15 h 8h 7h + SPh SPh + SPh
N 284 17% 13% 14% 26% 39%
N 285 17% 22% 31% 0% 0%
N PhS YPh 0% 0% 0% 58% 33%
Scheme 169 Vander Eycken and associates [173] reported significant improvement in yields, for the synthesis of pyrido-fused quinolines (286) from 2-vinyl tert amine when the reaction was performed under solvent free conditions through microwave irradiation (scheme 170).
67

R MW R R 5-22 min or N N heating X X n n 150-180oC 286 35-96% R = CO2Me, CN; X = CH2, O; n = 0, 1 R
Scheme 170 Tverdokhlebov and his group [174] reported the synthesis of hetaryl- and arylsulfonylsubstituted pyrrolo- and pyrido[1,2-a]quinolines (287) from the reaction of 2-tertaminoaryl aldehydes with substituted acetonitriles followed by proton-assisted cyclization of resulting cinnamonitrile derivatives in AcOH at refluxing temperature as shown in scheme 171.
NC CHO X-CH2CN, Et3N EtOH N 80-90% n N X= S , N H N , 4-CH3C6H4SO2X AcOH reflux 78-82% n CN X N 287 n
R N
R = H, 4-F, 3-NO2 n = 1, 2
Scheme 171 5.3 From C-C-N-C-C-C Unit Tapia and co-workers [175] successfully constructed a new class of angular tetracyclic quinolines (290) via Diels-Alder reaction between pyrrroloquinolinequinone (289) and diene. The starting quinoline (288) was obtained from reaction of 3-acetylfuranone with 2,5-dimethyl aniline followed by refluxing in POCl3 as shown in scheme 172.
O OMe O toluene reflux 24 h, 83% O OMe O O POCl 3 reflux Me 4 h, 63% OMe 288 OMe Cl Cl N Me O N 289 Me Me O 290 N Me O Ph N Ph O N
NH2 OMe
OMe
N H
Scheme 172 Boschelli and co-workers [176] carried out the synthesis of 7-ethynyl-3quinolinecarbonitriles and identified the 4-[(2,4-dichloro-5-methoxyphenyl)amino]-6methoxy-7-[4-(4-methylpiperazin-1-yl)but-1-ynyl]-3-quinolinecarbonitrile (SKS-927) as a potent Src inhibitor. Their protocol involved the reaction of 4-ethoxy-3-iodoaniline with 2-cyano-N-(2,4-dichloro-methoxyphenyl)acetamide and triethylorthoformate to yield
68
Current Organic Chemistry( 2008),12, 1116-1183 291, which on treatment with POCl3, provided 4-(2,4-dichloro-5-methoxyphenylamino)6-ethoxy-7-iodoquinoline-3-carbonitrile (292). Reaction of these iodoquinolines (292) with 3-butynol followed by mesylation and reaction with 1-methylpiperazine delivered the 4-[(2,4-dichloro-5-methoxyphenyl)-amino]-6-ethoxy-7-[4-(4-methylpiperazin-1yl)but-1-ynyl]-3-quinolinecarbonitrile (293) as shown in scheme 173. Simultaneously they also synthesized 7-ethynyl-3-quinolinecarbonitrile analogs and bioevaluated them for inhibition of Src kinase activity concluding that they were less potent than the SKS927.
O HO I EtI, K2CO3, EtO DMF, 70oC, 3 h NH2 Fe, NH4Cl, EtOH, I H2O,reflux, 1 h Cl N H Cl OMe EtO I N H Cl Cl HN EtO I N 292 CN i. 3-butanol, (Ph3P)4Pd, CuI, Et3N, dioxane, OMe 95oC, 3 h ii. MsCl, Et3N, DMF,THF 0oC, r.t., 1.25 h iii. 1-methylpiperazine r.t., overnight then 45oC, 7 h Cl HN EtO N N N 293 CN Cl N H Cl OMe Cl POCl3, butyronitrile
CN
NH2 CH(OEt)3, i-PrOH reflux overnight
OMe reflux, overnight
CN 291
Scheme 173 A high yielding synthesis of methyl-4-(4-methylaminoallyoxycarbamate)anilinoquinoline-8-carboxylate was reported by Beal and co-workers. [177] Their strategy involved condensation of meldrum acid with methylanthranilate and ethyl orthoformate followed by thermal cyclization to furnish the methyl 4-hydroxy quinoline-8-caboxylic acid (294) (scheme 174). Hydroxyl quinoline was transformed to bromoquinoline which upon reaction with allyl-4-aminobenzyl aminocarbamate followed by hydrolysis using LiOH afforded the protected amino acid (295). The deprotected 295 was employed as precursor for the synthesis of helix threading peptides (HTPs), which bind to the RNA.
H3CO O O O O + NH2 O OCH3 CH(OEt)3 70-80oC 45 min 94% O O NH O O O Ph2O 255oC 30 min 84% N O OMe 294 X = OH X = Br X AllocHN Allyl-4-aminobenzyl aminocarbamate MeCN reflux 40 min 89% LiOH, THF, H2O r.t., 2 h, 83% NH
N OMe 295 X = Me X=H O
PPh3, NBS, MeCN reflux, 30 min, 84%
69
Current Organic Chemistry( 2008),12, 1116-1183 Scheme 174 More recently Some and Ray [178] reported a chemoselective arylamination on bromovinylaldehydes with arylamines in the presence of Pd2(dba)3, K2CO3, and R-(+)BINAP in inert atmosphere followed by TFA-mediated cyclization to generate polycyclic quinolines (296) as shown in scheme 175.
R Br H 2N Pd2(dba)3, K2CO3 R Br CHO
2
H N
R Br
R2
R1
CH2OH
Br CHO R4 R3 R3 = H, NO2; R4 = H, Me
R1 (R)-(+)-BINAP, R1 CHO N R toluene 2 H R 90 oC, 3-4 h 82-95% Br CHO Br TFA 10-12 h 45-88% CHO R = H, Me, OMe, OH, NO2 R R1 = H, OMe, OH N Br R2 = H, Me, OMe R1 n OHC n = 1, 2, 3, 4
2 296 R
Scheme 175 Larock and his group [179] described the synthesis of quinolines (297) substituted at 3position by an iodo or phenylseleno group in excellent yields from the reaction between propargylic aniline and appropriate electrophiles such as molecular iodine, ICl or PhSeBr. The 3-iodoquinoline compounds (297) were subjected to Pd-catalyzed substitution reaction to increase the molecular complexity leading to products (298) as shown in scheme 176.
N R2 Ph NaHCO3,MeCN 5% PdCl2(PPh3)2, E R R R 43-88% K2CO3, DMF, H2O R1 R1 o R1 100 C, 2h 298 297 73% 1 E = I, C6H5Se; R = H, 3-NO2, 4-CO2Et; R1 = C6H5, 4-OMe-C6H4, R = 2-F-C6H4 4-F-C6H4, 4-COMe-C6H4, 2-NH2-C6H4, n-Bu; R2 = H, Me N R2 H N R2 electrophile B(OH)2
Ph
Scheme 176 Gevorgyan and co-workers [180] demonstrated chemodivergent transformation of alkynyl amine cycloisomerization to quinolines (299) in the presence of CuI in a mixture of dimethyl acetamide and Et3N at 110C (scheme 177).
70

R R + Ph Cl N Ar Sonogashira R 80% Ph CuI, H 93% R1
N Ph N 299 Ar R = H, OMe, OTBS; R1 = H, OMe, CO2Et
Scheme 177 Hill and Movassaghi [181] disclosed a novel methodology for the synthesis of 2substituted quinolines (300) via protodesilylation and cycloisomerization of trimethyl silyl alkynyl imine in the presence of a Ru-catalyst. The required alkynyl imine was generated from N-arylamides in the presence of 2-chloropyridine and Tf2O (scheme 178).
O N H Tf2O, 2-ClPy _ 78 - 0oC CH2Cl2 TMSC CCu _ 78 - 23oC THF, 97% N CpRu(PPh3)2Cl, SPhos, NH4PF6 toluene 105oC TMS 91% N 300
Scheme 178 A new synthetic approach to substituted isoindolo[2,1-a]quinoline carboxylic acids (301304) via intramolecular Diels-Alder reaction of readily available 4-(N-furyl-2)-4 aryl aminobut-1-enes with maleic anhydride in the presence of H3PO4 was reported by Zubkov and his group (scheme 179, 180). [182] Simultaneously they described the synthesis of 1- and 3-halo-substituted isoindolo[2,1-a]quinolines (306) from the same substrate (Scheme 181). [183]
CO2H O H3PO4 O Me N R 10-15 C 1.5 h 37-63%
o
HO2C O
O R N H PPA 65oC
CO2H O N R
R = 3-Me, 1-Et
301 H3PO4 70-80oC, 45 min
302 31-72%
Scheme 179
71

CO2H O O N R HO2C O H H O R N Me + O H HO2C H O R N
H3PO4, H2SO4 (3:1) 100-120oC 1h
R = H, OMe
H 303 major
H Me 304 minor H3PO4, H2SO4 (3:1) CO2H O 100-120oC, 1 h N R 305
H3PO4 65oC, 1 h 52-6%
Scheme 180
CO2H O R1 O R N R2 HO2C O R1 H H3PO4, H2SO4(3:1) N O 125-155oC H R2 R
306 R = H, Me; R1 = H, Br, Cl, F; R2 = H, Br, Cl, F
Scheme 181 Further they [184] performed the synthesis of analogous noncarboxyl substituted isoindolo[2,1-a]quinolines (307). The acetylation of furyl-substituted homoallylamines with acryloyl chloride and subsequent intramolecular [4+2] cycloaddition in the presence of Et3N afforded N-aryl-3-aza-4-oxo-10-oxatricyclo [5.2.1.01,5]dec-8-enes which on treatment with PPA at 90-110C, provided the desired products via intramolecular electrophilic substitution reaction as shown in scheme 182.
O O Me H N acryloyl chloride R Et3N, MeCN reflux 50-87% O Me N [4+2] R O O R N R PPA 90-110oC 61-70% Me N O 307 Me Me
R = H, Me, OMe
Scheme 182 Very recently Rocha et al. [185] have reported the synthesis of several novel anilino thiazolo[5,4-b]quinolines (310) for evaluation of their cyctotoxic activity. These annulated quinolines (311 & 313) were obtained from the thiazole derivative (308 & 312) through PPA/ POCl3-promoted cyclization followed by amination of the chloroderivative (309) (Scheme 183).
72
R HN NH2C6H4R Cl POCl3, PPA 130oC, 4 h SMe HN S O Et2N i. KOH, EtOH ii. CDI, CH2Cl2 reflux, 1 h iii. NH2(CH2)2NEt2, CH2Cl2, reflux, 4 h 75% 312 N H HN N S SMe N SMe N 309 S MeOH, HCl reflux, 6 h 57-76% NH2(CH2)2NEt2 r.t., 2 h 75% N 311 HN N 310 Cl N SMe S
EtO2C
N S N H NEt2
NEt2
308
POCl3, N PPA SMe o 120 C S N 30min 313 30% R = 3-Cl, 4-Cl, 3-CN, 4-CN, 3-OMe, 4-OMe, 3-OH, 3-CF3, 3-NO2, 3-NHMe, 3-CONH(CH2)2NEt2
Scheme 183 Alberti et al. [186] reported the first example of intramolecular interception of a cyclobutyl thionium ion for the synthesis of hexahydrocyclobutaquinolines (314) in the presence of p-TSA (scheme 184).
PhS R SPh N N H R1 OH H 1 314 R = H, 4-Me, 4-OMe; R = H, Me R = 4-OMe; R1 = H 42% p-TSA benzene reflux, 2 h R R1
Scheme 184 Zhang et al. [187] described a highly innovative domino ring opening/ recyclization reaction of doubly activated cyclopropane as a protocol for obtaining the furo-quinolines (315) (scheme 185). They observed that, when the reaction was performed with electron donating group containing aryl moiety excellent yields were obtained while the reaction failed to provide the desired products if performed with electron withdrawing groups containing aryl substrates.
SnCl4.5H2O R R2 xylene R N R 4 O o R N H 120 C R3 R2 45-93% R3 315 R1 = H, Me; R2 = H, Me; R3 = H, Me, OMe; R4 = H, Me, Cl; R5 = H, Me, Cl, COMe O O
4 1
R5
R1
5
Scheme 185 They also reported a new efficient transformation of readily available 1-acetyl-N-aryl cyclopentanecarboxamides to pyrano[2,3-b]quinolines (316) promoted via H2SO4
73
Current Organic Chemistry( 2008),12, 1116-1183 (scheme 186). [188] They proposed that the reaction initiated from H2SO4 mediated Combes-type annulation of the starting cyclopentane derivative to afford an alcohol intermediate. This was followed by cyclization/ ring opening/ recyclization reaction of the intermediate.
R3 R2 N H O R1 O H2SO4 50oC 1.5-4 h 67-96% R3 R2
N O R1 316 R1 = H, Cl, Me, OMe; R2 = H, Cl, Me; R3 = H, Cl, Me, OMe, NHAc
Scheme 186 Kouznetsov et al. [189] reported successful synthesis of new dihydro spiro [1H]quinoline-2,1-cyclohexanes (318) by the internal alkene alkylation of N-(1allylcyclohexanyl) ethyl phenylamine from corresponding ketone and allyl magnesium bromide as shown in scheme 187. They further demonstrated that the 1-allyl-6-ethyl-4methyl-3,4-dihydrospiro[1H]quinoline-2,1-cyclohexane (318) undergoes BF3.OEt2 catalyzed amino-Claisen rearrangement to afford the 8-allyl-6-ethyl-4-methyl substituted spiro quinolines (319) (scheme 188). Interestingly a second internal alkylation promoted by H2SO4 yielded a novel lilolidine spiro derivative (320).
NH2 cyclohexanone, cat. AcOH, toluene MgBr Et2O N H 91% 85% H2SO4 CHCl3, 60oC, 4 h 94% Br N H 317 K2CO3, Acetone N 98%(from A) 91%(from 317) 318 Br K2CO3, Acetone N A 88% 85% H2SO4, CHCl3 60oC, 4 h
Scheme 187
BF3.OEt2 N H 319 318 90oC, 1 h 72% N 85% H2SO4 90oC, 30 h 57% N
320
Scheme 188
74
Current Organic Chemistry( 2008),12, 1116-1183 Adopting a similar strategy this group recently demonstrated an efficient synthesis of new 1H-4-methyl-3,4dihydro spiro[piperidine-4,2-(1H)quinolines] (321) wherein instead of cyclohexanone, 4-pyrimidone was utilized as the starting material as shown in scheme 189. [190] Starting from 2-amino-5-nitrophenol, Tsou and co-workers [191] successfully developed the synthesis of new 6,7-disubstituted-4-arylamino quinolin-3-carbonitriles (323) which act as irreversable inhibitors for human epidermal grouth factor receptor-2 and epidermal growth factor receptor kinases (scheme 190). Synthesis of tricyclic pyrido[3,2-g]quinoline derivatives (324) from the 2,6diaminotoluene have been reported by Tzeng et al. [192] following conventional methodology for quinoline synthesis as shown in scheme 191. They further reported the antiproliferative evaluation of these quinoline derivatives (325 & 326).
Ph N + 1 R Ph 2 toluene, reflux R 6-8 h, 72-85% R3 HN HCO2NH4, Pd-C MeOH, reflux 10 min, 78-95% H N R3 R2 CH3 R1 321 R1 = H, Me R2 = H, Me, OMe, Cl, F R3 = H, Me O AcOH N N R1 R2 R3 Ph BrMg Et2O, 4-5 h 78-89% N H N R3 85% H2SO4 Ph 80oC, 4-6 h R2 51-93% CH3 R1 N H N R3 R2
R1
H2N
Scheme 189
H 2N HO Ac2O AcOH NO2 60oC 96% H N O EtO N H N O HO EtBr, K2CO3 DMF, 60oC NO2 98% POCl3, CN diglyme 100 C 85%
o
H N O EtO 322 Cl
H2, Pd, C NO2 THF O
H N EtO
OH
Dowtherm 250oC 42%
H N O EtO
ArNH2, Pyridine.HCl, H CN i-PrOH N or O methoxyEtO ethanol reflux, 48-80% N
H N CO2Et O toluene NH2 90oC EtO from 320 90% NHAr CN aq HCl reflux 59-94% H2N EtO
EtO
CN
NC N H
CO2Et
NHAr CN N 323
N O
Cl N H N O EtO NHAr CN N O Ar = Cl
Ph N O Cl Cl N
SO2Ph N
N-methyl-2pyrrolidinone, MeCN (or) DMF 0oC -r.t., 43-63%
Scheme 190
75

CO2Et N H EtO2C N H OH CO2Et Ph2O EtO2C 250oC 80% X NH R = H, Me, (CH2)2NMe2, (CH2)3NMe2; X = H, Cl, OMe EtO2C N Me 325 N HN CO2Et EtO2C N Me 326 N N Me 324 N OH CO2Et POCl3 EtO2C 72% N NH2C6H4-p-X K2CO3, DMF X 50-86% NHR N Me RNH2 40-63% NHR CO2Et Cl Cl CO2Et
EMME H2N Me NH2
EtO2C
EtOH, reflux 90%
Me
Scheme 191 Kaila et al. [90] prepared 2-substituted quinoline salicylic acids from tetrahydronapthylamines as shown in scheme 192. Reaction of an amine with 2-(4chlorophenyl) acetyl chloride in the presence of DIPEA afforded the amide which on treatment with PCl5 followed by reaction with diethylmalonate and NaH gave the diester derivative. The diester at 110oC transformed to 2-(4-chlorobenzyl)-4-hydroxy-7,8,9,10tetrahydrobenzo[H]quinoline-3-carboxylic acid (327) via thermal cyclization and saponification.
NH2 + Cl OH CO2Et LiOH N aq MeOH 110oC N O Cl (iPr) NEt 2 N H OH CO2H Cl O Cl PCl5 N Cl Cl diethylmalonate, NaH, toluene 110oC EtO2C N H CO2Et 150oC
Cl
327
Cl
Scheme 192 Nandakumar et al. [193] described the synthesis of certain new quinolines (329-332) by Vilsmeir-Haack reaction of 4-hydroxyquinolines (328) generated using standard methodology of cyclization in diphenyl ether as shown in scheme 193.
R4 R3 R
2
O R OEt
3
R4 CO2Et N H CH3 Ph2O 240oC R3 R2
R4
OH
3 DMF, POCl3 R
R4
Cl R
R4
3
Cl
dil.HCl NH2 1:1 R1
N R
1
R1
CH3 Cl
R2
328 R4
N R1 329
OH + R4
R2 OH
N R1 330 CHO
CH3
R1 = H, Me, Cl R2 = H, Me R3 = H, Me, Cl R4 = H, Me
R2 R
1
N 332
NH2NH2.H2O, R3 EtOH, N reflux NH 1.5-3.5 h R2 63-90%
N R1 331
CH3
Scheme 193
76
Current Organic Chemistry( 2008),12, 1116-1183 Lautens and co workers [194] reported successful Pd-catalyzed intramolecular crosscoupling reaction between an aryl iodide and an allyl moiety for the generation of transisomer of 2,4-disubstituted 1,2,3,4-tetrahydroquinolines (333). Out of the several conditions and catalysts examined it was observed that Pd2(dba)3 and TTP gave the best yield as shown in scheme 194.
R
3
I N H
R1 OAc
Pd2(dba)3 (5 mol%), TTP (22 mol%), R3 n-BuNMe2 (2.0 eq.) R1
R2
MeCN (10:1) N reflux, 6 h H R2 73-84% 333 R1 = C6H5, 4-MeC6H4, 4-BrC6H4, 4-ClC6H4, CO2-c-C6H11 R2 = H, Me, OMe; R3 = H, Me, Cl
Scheme 194 5.4 From C-C-C-N-C-C UnitStrekowski and co-workers [195] reported facile synthetic approaches for diverse 2phenyl-4-aminoquinolines (335-337) comprising of an aminoalkyl group at N4 of the quinolin-4-amine and amino or aminoalkyl groups at the phenyl group (scheme 195). The imine generated from the trifluoromethyl aniline upon reaction with lithiated amino derivatives gave the analogs which were expanded further for the purpose.
HN R4-(CH2)n-NH2 Cl CF3 Me N R
1
( )n 4 R R1 R2 R3 LiR , THF 23oC, 16 h 55-89% R1 N 337 R2 R3 R1= H, F R2 = H, Me R3 = H, F, Me R5

5
i. tBuOK/THF ii. 24% HBr iii. POCl3/PCl5 80-82% R2 N 334
R1 R2 R
3
SnCl4 55-86%
N 335 Me N N
HN
N Me N 336
SnCl4 78-80%
Scheme 195 Goblyos et al. [196] reported new 1H-imidazo [4,5-c]quinolin-4-amine derivatives which were synthesized from anthranillic acid as per the sequence shown in Scheme 196. The 4hydroxy-3-nitro quinoline (338) was generated by the reaction of anthranillic acid with 2nitroacetaldehyde followed by cyclization in Ac2O. They developed SAR for new 1Himidazo [4,5-c]quinolin-4-amine derivatives (339) which were found to be active as allosteric enhancers of the A3 adenosine receptor.
77

2-nitroacetald ehydeoxime COOH .hydrochloride NH2.HCl NH2 89% i. RCO2H, PPA NH2 or RCOCl, NaOH ii. HC(OMe)3 HCO2H 27-81% OH NO2 N 338 N NH POCl3 POCl3 81% R N N NH R1NH2 Cl NO2 NH3 95% R N NH N H R1 N NH2 NO2 H2, Pd, C 98% R
COOH N
AcOK, Ac2O NO2 49% R N NH m-CPBA 36-90% N
26-99% 15-74% N N N Cl 339 O 1 R = H, 2-Furyl, n-C5H11, c-C4H7, c-C5H9, c-C6H11, c-C7H13; R = Ar, CH2C6H5
Scheme 196 Bala and Hailes [197] described the preparation of isoxazoloquinolines (340) from benzaldoxime using NaOCl in H2O via 1,3 dipolar cycloaddition of the aldoxime on to the double bond as per the scheme 197.
H N N H OH NaOCl H2O, r.t. Ph 48 h 92% H N H 340 N O Ph
Scheme 197 Recently, synthesis of enantiopure 4-amino-3-hydroxymethyl-1,2,3,4 tetrahydroquinoline (343 & 344) via intramolecular cycloaddition of chiral nitrones generated from aldehydes and I--(hydroxymethyl)-benzylhydroxylamine was described by Broggini and coworkers (scheme 198). [198]
CO2H i. SOCl2, CHCl3 ii. NaN3 R2 Me3CetylN+BrCH2Cl2/H2O 71-89% CON3 EtOH reflux R 87-91% R2 R
1
NHCO2Et
R2 NaH, THF R1 R N CO2Et POCl3 DMF 90oC R

1
R2 CHO N CO2Et
R2 R1
R Br OH H N O
R1
Ph R2 R1 45-74% R
R2 H2-Pd(OH)2 R1 R 343
NH2 OH N CO2Et
HO HOHN
H Ph R
1
R2
Ph N ON CO2Et
OH H
N CO Et 341 2 OH Ph R2 H N O
MeOH
MgSO4, toluene
R2 H2-Pd(OH)2 R1 R 344
NH2 OH N CO2Et
R1 12-37% R 342 N CO2Et
R = OMe; R = Me, OMe; R2 = H, OMe; R & R1 = -OCH2O-
MeOH
Scheme 198 Ring closing olefin metathesis (RCM) was successfully employed by Sanchez and Pujol [199] for the synthesis of quinoline from a novel diene generated from an acetanilide as shown in scheme 199. The RCM of diene in the presence of dichloro(benzylidene)78
Current Organic Chemistry( 2008),12, 1116-1183 bis(tricyclohexylphosphine)ruthenium (Grubbs catalyst) proceeded via deprotection and isomerization of double bond leading to dihydroquinolines (345) which upon treatment with Pd-C in decalin dehydrogenated to quinoline (346).
t
NHCOMe
NaH
NCOMe
BuLi CH3CHO
NCOMe OH +
NCOMe
CH2=CHCH2Cl DMF
Grubbs cat benzene
N 345 H
Pd/C decalin 346
P2O5, CH2Cl2
Scheme 199 5.5 From C-C-C-C-C-N UnitPratt and co-workers [200] reported the synthesis of substituted quinolines (347) from 2benzylidenecyclopentanone O-alkyl and O-acetyloximes by the photo-irradiation in MeOH (scheme 200). The reaction proceeded through the sequential E to Z-benzylidene group isomerisation and six -electron cyclization followed by aromatization.
R3 R2 R N Ph hv R1 MeOH 17-63% R R1
2
R3
N 347
R1 = H, Me, Cl, F, OMe, NO2 R2 = H, Me, t-Bu, Cl, F, OH, OMe, NO2, NH2, OAc R3 = H, Me, Cl, F, OH, OMe, NO2, NH2, NMe2, OAc
Scheme 200 6.0 Miscellaneous Rao and co-workers [201] achieved the synthesis of quinolines from substituted 2-chloronicotinaldehyde. The Baylis-Hillman acetate of this substrate upon SN2-SNAr reaction sequence with nitro alkane yielded the quinoline (348) as the product. Replacing nitro alkane with cyano ethyl acetate gave 8-cyanoquinoline (349) as delineated in scheme 201.
OAc RO2C N CH3 348 R2 R1 CH3CH2NO2, K2CO3 R2 N Cl
2
CO2R
CNCH2CO2Et, RO C 2 K2CO3 N CN 349
R2 R1
DMF, 50-60oC R1 3-4 h 80-92%

1
DMF, 110-125oC 8-12 h 50-60%
R = Me, Et; R = H, C6H5, CO2Me, R = H, Me, C6H5, 4-OMe-C6H4,
Scheme 201 Serban et al. [202] during their studies toward the synthesis of Toddaquinoline demonstrated the synthesis of its tetrahydro core, the
79
Current Organic Chemistry( 2008),12, 1116-1183 [1,3]dioxolo[4,5:4,5]benzo[h]quinoline. The Wittig reaction of phosphonium salt of piperonylalcohol with 2-bromo pyridine-3-aldehyde in the presence of tBuOK yielded the mixture of trans and cis bromo alkene (1:15) 350 & 351. The cis biaryl compound was converted to deoxytoddaquinolines (352 & 353) in the presence of Pd-catalyst (scheme 202), whereas the biaryl coupling reaction of dibromides via Ullman reaction in the presence of Cu gave the desired products (354) in 38-47% yields (scheme 203).
O O Br O O PPh3+Br+ N CHO Br t-BuOK THF O 350 7% O N O + O Br 351 90% N O O N 353 52% 352 N Cy3P, Pd(OAc)2 25% K2CO3, DMF deoxytoddaquinoline +
Scheme 202
O O Br PPh3+Br+ N CHO Br t-BuOK THF 92% O O Br Br N Cu, DMF 38-47% O O N 354
Scheme 203 Groth et al. [203] reported a regioselective synthesis of tetrahydroquinolines (355) starting from silyl containing diynenitriles precursors in the presence of a Co-complex (scheme 204). These diynenitriles were in turn obtained by sequential treatment of heptynenitrile with BuLi, ClMe2SiNEt2 and various propynyl alcohols.
N
n
N BuLi Si NEt2 ClMe2SiNEt2
R CpCo(CO)2, hv, toluene N reflux OH or CpCo(C2H4)2, 61-83% Si O Et2O, -20oC R = H, Me, SiMe3 5-61%
Si O
N 355
Scheme 204 Mamane and Fort [204] have disclosed an efficient method for accessing the chiral ferrocenoquinolines. Their methodology involved the Negishi coupling of ferrocenyl zinc 3-acetals (obtained from the reaction of ferrocenyl acetal with sec-BuLi and ZnCl2) with 3-bromo-2-chloro pyridines in the presence of PdCl2(PPh3)2 catalyst to afford the chloro pyridine derivative (356). Treatment with MeMgBr in the presence of NiCl2(dppp) catalyst by means of Kumuda coupling followed by deprotection of acetal afforded the
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Current Organic Chemistry( 2008),12, 1116-1183 aldehyde derivatives (357) (scheme 205). These aldehydes were transformed to ferrocenoquinolines (358) by the reaction with 2.0 eq. of tBuOK in DMF at room temperature.
O O i. sBuLi ii. ZnCl2 Fe 356 O O Cl N MeMgBr (3 eq.), NiCl2(dppp) (20 mol%) Et2O, r.t. 20 h O O Me p-TSA (1 eq.) N Fe THF, H2O r.t., 2 h Fe 357 O Me N tBuOK (2 eq.) DMF, r.t. 2h Fe 358 N
Fe
iii. 3-bromo-2chloropyridine, PdCl2(PPh3)2
Scheme 205 Alajarin et al. [205] described the synthesis of dibenzacridine (359, 362 & 363) and benzquinoline (360 & 361) by refluxing N-[2-(2-propenyl)-1-napthyl] ketenimine which was obtained via aza-Wittig reaction of triphenylphosphazene with diphenylketene (scheme 206 & 207). The transformation proceeded through intramolecular Diels-Alder reaction and [1,5]-hydrogen migration followed by 6 electron cyclization. The tetrahydrodibenz[b,h]acridines (362) were oxidized to dibenz[b,h]acridines (363) by refluxing in Pd-C in o-xylene (scheme 207).
Ph Ph3P N Ph2C=C=O toluene r.t., 10 min N C Ph toluene reflux 1h 359 37% Ph Ph HN + N Ph
360 40%
Scheme 206
Ph Ph3P N Me Ph2C=C=O toluene r.t., 10 min N C Ph Me toluene reflux 1h 361 14% Me N + Ph Ph Ph HN Pd, C o-xylene Me reflux, 3 h 362 17% 363 82% Ph N Me
Scheme 207 Piri et al. [206] reported the mild and efficient protocol for the preparation of N-(4methyl-1,2,3,4-tetrahydro-2-quinolinyl)-N-aryl amines (364) from the reaction of isobutyl vinyl ether and aryl amines in refluxing CCl4 (scheme 208).
81
O R + NH2
CCl4 reflux 60 min
R N H R 364 NH
R = H, 2-Cl, 3-Br, 2-I, 2-Me, 4-Me
Scheme 208 Janza and Studer [207] demonstrated a highly efficient tandem radical process comprising a thermal alkoxyamine homolysis, an isonitrile trapping reaction, a 5-exo-trig cyclization and homolytic aromatic substitution to generate substituted dihydroquinolines (366). The readily available alkoxyamines with CSA under heating or microwave irradiation underwent homolytic cleavage followed by reaction with isonitrile and subsequent 5-exo-trig and homolytic aromatic substitution (scheme 209).
R1 N O R2 R2 R3 + R4 NC DMF, 10% CSA 140oC, 3 days or DMF, MW 180oC, 30 min R4 R3 R2 N 365 R1 = Ar 42-63% R2 R1 + R4 R3 R2 R2 N H R1 366 R1 = CO2Me, CN 48-55%
R4 = H, Br, Me, OMe; R2 = H, CO2Me R3 = H, Br; Ar = C6H5, 4-BrC6H5
Scheme 209 Kadutskii and Kozlov [208] obtained high yields of 3-spirosubstituted 1,2,3,4tetrahydroquinolines (367) containing different substituents at the N-atom by conducting the reaction between -diketones, formaldehyde and substituted anilines in EtOH at refluxing temperature (scheme 210).
HN R1 R2 R2 O + H + H O O EtOH R N R1 367 O O R2 R2
reflux 5-min R 75-90% R = Me, OMe; R1 = CH2Ar, mono, di, tri cyclic R2 = H, Me
Scheme 210 Matsumoto, and Okura [209] demonstrated that when 2-(arylamino)-1-(methylthio)-1tosylethene was refluxed with HI, elimination of thiomethyl functionality followed by dimeric cyclization resulted in the formation of quinolines (368) (scheme 211).
NH R Ts SMe 50% HI toluene reflux 1-15 h 40-87% R N NH Ts R Ts
Ts 368 R = 4-Br, 2-Me, 4-Me, 4-OMe, 4-CO2Et, 3,5-(Me)2
82
Current Organic Chemistry( 2008),12, 1116-1183 Scheme 211 Pratap and Ram [210] reported the synthesis of highly functionalized benzo[h]quinolines from corresponding chromenes. Reaction of 2-oxo-dihydrobenzo[h]chromenes (369) with S-methylthiourea sulfate or 1-carboxamidine pyrazole hydrochloride in the presence of KOH in DMF afforded the 2-amino-4-sec-amino-5,6-dihydro-2H-benzo[h]quinoline-3carbonitriles (370) (Scheme 212). Replacing the reactants to formamidine acetate or benzamidine hydrochloride yielded 4-sec-amino-5,6-dihydro-2H-benzo[h]quinoline-3carbonitriles (371) and 2-phenyl-4-sec-amino-5,6-dihydro-2H-benzo[h]chromene-3carbonitriles (372) respectively, by the elimination of ammonia (scheme 213).
NR1R2 H 2N CN N R 371
1 2
NH.CH3CO2H
NR1R2 H 2N CN O O
NH.HCl
NR1R2 CN N NH2
H DMF, KOH 47-54% R
R4 DMF, KOH 71-96% R
369
370
R = H, OMe; NR R = piperidin-1-yl, 4-Me-piperidin-1-yl, 4-Benzyl-piperidin-1-yl, 4-Morpholin-1-yl, tetrahydroisoquinolin-1-yl
Scheme 212
R1 R1
N CN
H 2N +
NH.HCl DMF, KOH
N CN
55-61%
N 372
R1 = H, Me
Scheme 213 Atechian et al. [61] developed new methodology for the synthesis of 3(methylsulfonyl)quinolines from the reaction of anthranilic acid with Ac2O at 100C to produce the 2-methyl-4H-3,4-benzoxazin-4-ones, which on further treatment with methane sulfonyl acetone in the presence of tBuOK in DMF at 100C for 0.5 h to afforded substituted 3-methanesulfonyl-4-hydtroxy quinolines (373). Subsequent treatment with POCl3 followed by reaction with different secondary amines produced the corresponding 4-aminoquinolines (374) (scheme 214).
O O R OH Ac2O R N O O
t
O SO2MeR BuOK, DMF 100oC, 0.5 h
OH SO2Me R POCl3 N 373
Cl SO2Me N
MeO
N SO2M e N 374
o NH2 100 C, 1 h R = Br, I
83
Current Organic Chemistry( 2008),12, 1116-1183 Scheme 214 7.0 Natural product synthesis Quinoline subunit is present in several natural products too. The examples in the literature which described the synthesis of quinoline during the construction of natural product are being included here. The total synthesis of Luotonin A from benzoylene urea was described by Curran and coworkers. [211] The bromination of benzoylene urea using POBr3 followed by hydrolysis yielded the bromoquinazolone which on sequential propargylation with propargyl bromide and photoirradiation with substituted phenyl isonitriles in the presence of Me3Sn-SnMe3 afforded the luotonin (375) and its analogs (scheme 215). The prepared compounds exhibited activity in a topoisomerase I DNA cleavage assay.
O HN O N H POBr3 PhNMe2 52% Br N N Br NaOH THF Br 100% HN N O Br R NaH DMF R Br N N O PhNC, R2 Me3SnSnMe3 h 47-94% R
3
R1
R O N N N 375
R = H, Et, CH2CH2TMS; R1 = H; R2 = H, F, Me, CF3, OMe, OAc, NHBoc; R3 = H; R1 = R2 = -OCH2O-
Scheme 215 Ryu [212] demonstrated hydroarylation strategy for the synthesis of tetrahydroquinoline (376) which involved Mitsunobu reaction of a chiral propargyl alcohol to aniline followed by intramolecular cyclization in the presence of PtCl4. Although he examined gold and mercury catslysts too, PtCl4 was found to yield the product in better yields. This synthetic outcome was applied for the concise total synthesis of (+)-(S)-angustureine (377), which is a quinoline base of alkaloid isolated from G. officinalis (scheme 216).
MsCl, Pyridine NH2 CH2Cl2, 0 C, 1 h, 92%
o
HO
() 3 N Ms () 3
PtCl4 (10 mol%) DCE N Ms 376 () 3 () 3
H2, Pd, C EtOH, r.t. 3 h, 85%
NHMs DEAD, Ph3P THF, r.t. 1 h, 100%
N Ms
Red-Al toluene () 3 80oC, 0.5 h 99%
N H
K2CO3, MeI THF () 3 reflux, 24 h, 99%
N Me 377
Scheme 216 The asymmetric synthesis of (-)-matrinellic acid via dipyrroloquinoline as a key intermediate was reported by Miyata and his group. [213] The treatment of methyl 4bromo-3-methylbenzoate with NBS led to the dibromo derivative which on treatment with AgNO3 yieided the aldehyde. The aldehyde was transformed to O-benzyloxime 84
Current Organic Chemistry( 2008),12, 1116-1183 ether (378) followed by coupling reaction with L-pyroglutamic acid ethyl ester to afford the N-arylpyrrole derivative. N-arylpyrrole derivative was converted to ,-unsaturated ester by sequential reduction oxidation and Wittig reaction. Treatment of ,-unsaturated ester with Bu3SnH in the presence of AIBN afforded the desired 3aR,3bS,11bSdipyrroloquinoline (379) via radical addition cyclization and elimination. Chemoselective reduction of dipyrroloquinoline (379) with LiBH4 under the influence of MeOH in THF furnished the aminoalcohol (380) which was converted to trifluoroacetamide (381) by reduction of lactam and acylation with TFAA as shown in the scheme 217.
O H N CO 2Et NBS, Me AIBN MeO2C Br CCl4 reflux AgNO3, H2 O, MeOH MeO 2C reflux Br .HCl, BnONH2 Br NaOAc, MeOH, CH2 Cl 2, r.t., 82% O HN Br MeO 2C LiBH4 MeOH-THF reflux, 76% Pd2(dba)3, xantphos, MeO2 C Cs2 CO3 NOBn dioxane 100o C, 98% Br 378 O HN BH3 .THF, THF, reflux MeO2C TFAA, Et3N, DMAP, CH2 Cl 2 OH r.t., 79% NOBn CO2Et N O F3COC O N
MeO2 C
NOBn MeO2C N O
CO 2Et MeO2C Bu3 SnH, AIBN benzene reflux, 45%
N O 379
N H 380
N COCF3 381
OH
Scheme 217 More recently Badarinarayana and Lovely [214] also reported the total synthesis of (-)matrinellic acid (383). The key steps involved in their strategy were a Pd-catalyzed aryl amidation reaction of a pyroglutamate derivative (382) followed an intramolecular azomethine ylide-alkene cycloaddition that proceeded without recemization and reductive ring opening reaction as shown in scheme 218. Nourry et al. [215] obtained Lavendamycin analogs using Friedlander annulation and Pictet-Spengler reaction. Condensation of 2-aminobenzaldehyde with methylacetoacetate in the presence of piperidine yielded 2-methyl-quinoline-3-carboxylic acid methyl ester (384) (scheme 219). Reduction of the ester followed by protection with the silyl group and oxidation with SeO2 afforded the aldehyde. Pictet-Spengler reaction of the resulting aldehyde with tryptophan methyl ester in p-xylene on reflux and subsequent desilylation furnished the desired hydroxylester (385). Compound 385 upon treatment with DMP in pyridine furnished the product 386 via oxidation and intramolecular cyclization. Their attempt to prepare the deoxygenated compound through reduction with BH3.THF, resulted in 387.
85

OTBS O2N CO2Me + Br O LiBH4, MeOH 0oC, 80% NH O2N Pd2(dba)3, xantphos Cs2CO3, dioxane TBSO 61% O I N O 382 Bn N BnHNCH2CO2H.HCl I Et3N benzene reflux, 65% CO2Me O N H2 N H2, Pd, C EtOH 90% TBSO Bn N LiBH4 N O MeOH, THF, reflux 88% I N H Bn N CO2Me I O n-C5H11ONO, CH2CI2 N TBAF, THF 70% HO Bn N Ac2O, Et3N, CH2Cl2, 80% OH CO2Me o-NO C H SeCCN, 2 6 4 O PBu3, THF N H2O2 85%
CO2Me O N
MnO2, CH2Cl2 90%
Bn N I N O O
Pd(OAc)2, NaOAc, DMF, MeOH, CO MeO2C NaOMe, OAc MeOH 96%
N H
OH
i. TFAA, Pyridine, CH2Cl2, 79% ii. MsCl, Et3N, CH2Cl2, MeO2C iii. NaN3
NaOMe, MeOH 80%
N H
N3
Pd(OH)2, H2, MeOH, HCl 95% AgNO3 SMe NBoc
NH NBoc N H MeO2C N H H N HN NBoc N HO2C N H 383 H N HN NH N H N
Scheme 218
O CHO NO2 Fe, 10M HCl 68% CHO NH2 OTBDPS tryptophanmethylester p-xylene reflux 46% N HN N CO2Me n-Bu4NF 75% N HN O DIBAL-H CO2Me _ o 78 C 95% Me OH N CO2Me DMP pyridine 50% N N 386 CO2Me CH2OH i. t-BuPh SiCl 2 N Me O N BH3.THF 51% N N CO2Me O N N H ii. SeO2 92% N OTBDPS CHO OH N OMe piperidine MeOH 92% N 384
385
N 387 CO2Me
Scheme 219 Ireland and his group [216] demonstrated the first total synthesis of Neoamphimedine (390) that comprises of a quinoline unit as shown in scheme 220. The key quinoline intermediate was generated from 2-quinolone (389) which in turn was obtained via Knorr cyclization of 388.
86

i. 10% Pd, C cyclohexene, EtOH, reflux 15 min ii. AcOH, Ac2O NO2 OMe i. 10% Pd, C cyclohexene, EtOH, reflux 15 min O NO2ii. m-xylene 160oC, 2 h N OMe O NO2 O H OEt OMe O N H
OMe CH2N2 O 2N OH NO2 O2N
OMe
OMe
OMe
N H 388
NO2 PPA 75oC O O Knorrcyclization
OMe
NO2
N H
OMe
N H
389 N
Et3N, Tf2O CH2Cl2, 20oC 30 min O N H
OMe
NO2
Et3N, HCO2H, DMF Pd(OAc)2, diphenylphosphino ferrocene O N H
OMe
NO2
5 steps N O
N OMe
SO2CF3
N OMe
N O 390
Scheme 220 Parvatkar et al. [217] reported a new and efficient three-step synthesis of indoloquinoline alkaloid cryptotackieine (neocryptolepine) from 2-nitrobenzaldehyde and 2-nitrophenyl acetic acid. A Perkin reaction followed by a one-pot double reduction, double cyclization and isomerization furnished the final product (391) in excellent yield (scheme 221).
CHO + NO2 i. Ac2O, Et3N CO2H reflux, 5 h NO2 ii. EtOH, H2SO4 reflux, 24 h 71% NO2 CO2Et Fe, AcOH, EtOH, H2O, HCl N N H i. MW, Me2SO4, DMF, 140oC, 5 min 75% ii. Me2SO4, MeCN reflux, 6 h, K2CO3 80%
NO2 120oC, 24 h 74%
N N Me 391
Scheme 221 8.0 Conclusion It is evident from the literature assimilated in the preceding text that the synthesis of quinoline nucleus is a subject of great interest for several research groups. As a result impressive spectrum of novel strategies have evolved providing the opportunity to construct quinoline and quinoline annulated derivatives decorated with choicest of substitutions. This has assisted the discovery of new properties in quinoline-based compounds in particular the biological activities associated with them. Although the work towards synthesis of quinoline and quinoline annulated ring systems has come a long way, we believe this area of research will continue of evolve with discovery of newer application s of new catalysts and reagents. 9.0 Abbreviations* hv
o
= = = =
ultraviolet irradiation degree celsius azobisisobutyronitrile 2,6-bis(1,1-dimethylethyl)-4-methylphenol
AIBN BHT
87
Current Organic Chemistry( 2008),12, 1116-1183 BINAP BINOL Boc Boc2O BOP-Cl CAN CDI CSA Cy3P m-CPBA DBU DABCO DCC DCE DDQ DEAD DIBAL-H DIPEA DMAP DMC DME DMF DMP DMSO DPP EMME HATU NBS PPA = = = = = = = = = = = = = = = = = = = = = = = = = = = = = 2,2-bis(diphenylphosphino)-1,1-binapthyl 1,1-bi(2-naphthol) tert-butoxy carbonyl di-tert-butyl dicarbonate Bis(2-oxo-3-oxazolidinyl)phosphinic chloride ceric ammonium nitrate N,N-carbonyl diimidazole camphor-10-sulphonic acid tricymene phosphine meta-chloroperbenzoic acid deoxyribonucleic acid 1,4-diazabicyclo[2.2.2]octane N,N-dicyclohexylcarbodiimide 1,2-dichloroethane 2,3-dichloro-5,6-dicyano-1,4-benzoquinone diethyl azodicarboxylate diisobutyl aluminium hydride diisopropyl ethylamine 4-N,N-dimethylamino pyridine dimethyl carbonate 1,2-dimethoxy ethane N,N-dimethyl formamide dess martin periodnane dimethylsulfoxide diphenyl phosphate diethyl ethoxy methylene malonate 2-(1H-7-Azabenzotriazol-1-yl)1,1,3,3-tetramethyl hexafluorophosphate Methanaminium N-bromo succinimide polyphosphoric acid ulfona
88
Current Organic Chemistry( 2008),12, 1116-1183 PQSP TBAB TBAF TBPA TCT TDAE TEATFB TEAP Tf Tf2NH Tf2NPh TFA TFAA TFAE TFE THF TFMSA TMEDA TMSCl TTP p-TSA = = = = = = = = = = = = = = = = = = = = = Polyquinoline containing spirobifluorene and phenathiazine tetrabutyl ammonium bromide tetra-n-butylammonium fluoride tris(4-bromophenyl)ammonium 2,4,6-trichloro-1,3,5-triazine tetrakis (dimethyl-1-amino)ethylene tetraethylammonium tetrafluoroborate tetraethylammonium perchlorate trifluoromethane sulfonyl N,N- bis (trifluoromethane sulfonamide) N-phenyl bis (trifluoromethane sulfonamide) trifluoroacetic acid trifluoroacetic anhydride trifluoroacetaldehyde ethyl hemiacetal trifluoroethanol tetrahydrofuran trifluoromethyl sulfonic acid N,N,N',N'-tetramethylethylenediamine trimethylsilylchloride tri(o-tolyl)phosphine para-toluene sulfonic acid
*Abbreviations for reagents which have been expressed by chemical formula are not provided
Acknowledgments- One of the authors SM acknowledges the financial support from CSIR, N. Delhi in the form of senior research fellowship. ZT acknowledges the financial assistance from DST, N. Delhi vide project no SR/WOS-A/CS-35/2003. 10.0 References CDRI Communication no. 7428
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Advances in Quinoline Synthesis

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Current Organic Chemistry( 2008),12, 1116-1183

Advances in the syntheses of quinoline and quinoline-annulated ring systems

Saquinavir (Roche, R031-8959)

C-labeled ketones in cross-over experiment (scheme 1). On the basis of

Current Organic Chemistry( 2008),12, 1116-1183

i. CS 2, Li +BHTCH3 ii. CH3 I

CH3 O H3C CH3

CH3 i-Pr cyclization rearomarization -1

Current Organic Chemistry( 2008),12, 1116-1183

O R2 R3 R2 R = H, Me, OMe, OH, Cl Naphthyl; R1 = H, C6H5; 1 R2 = H; R3 = Me, C6H5 R

R1 K5 CoW12O40.3H2O MW R NH2 8-15 min 74-88%

R = Me, OMe; Ar = C6H5, 3-Br-C6H4,

Current Organic Chemistry( 2008),12, 1116-1183

Current Organic Chemistry( 2008),12, 1116-1183

for R = Ph 1,4 CO2Et

N R1 R1 = Me, OMe; R2 = 4-NO2C6H4

HCl cat. MW, 1.5-12 min 45-89%

Current Organic Chemistry( 2008),12, 1116-1183

NHAc O conc.HCl EtOH, reflux 89%

OMe OMe MeO MeO N N N CO2Et N

N NaBr, DMF 65oC, 79%

OMe OMe 35 overall yield-52%

Scheme 29 3.1.1.2 Lewis acid-catalyzed Friedlander reaction-

Current Organic Chemistry( 2008),12, 1116-1183

Mg(ClO4 )3 (10 mol%) EtOH,60o C,18 h R 62-99%

FeCl3 (10 mol%) EtOH,r.t.,12-24 h 63-98% R 52

TMSCl DMF 76-96%

Current Organic Chemistry( 2008),12, 1116-1183

(Boc) 2O THF NH2 60 oC, 15 h R

Me2NC(Me) (OMe)2 N O NMe2 X=H X = CO2Me X EtOH, reflux,1 h N 28-64% NMe2 X

SOCl2 amine 33% N O N H R

10% NaOH reflux, 24 h

NMe2 67 R = (CH2)2NMe2 X=H (CH2)3NMe2 X = CO2Me (CH2)2NH(CH2)2OH X = CO2H CH(S-Me)CH2NMe2 CH(R-Me)CH2NMe2,

EtOH, reflux X n 2 h, 53-93%

R1 = H, OCH2 O, OMe; R2 = H, Ar X = O, S, NMe, N(CH2) 2, NCO 2Et; n = 0, 1

120o C OBn 3 h, 44%

Current Organic Chemistry( 2008),12, 1116-1183

Pd-C (0.005 mmol) dioxane 100oC

R = methyl 52% Mes = 2,4,6-trimethylphenyl 100% R = cyclohexyl 72% R = n-octyl 75%

RuCl2 (dmso) 4 (2 mol%), KOtBu (100 mol%), 1 Ph2 CO (100 mol%) R

EtOH, R1 H2SO4 N 87 CO2H OH MW, 10 min

R1 KOH, EtOH MW, 12.5 min 95% N 88

R1 = H, Cl, Br; R2 = H, Me, C6H5 R3 = Me, Et, CH2CHMe2, C6H5

O Ac2O reflux, 3 h 88%

Current Organic Chemistry( 2008),12, 1116-1183

S O aq KOH, r.t., 12 h O 60-87% 92

CO2H CO2H N R = Me, i-Pr R

Ac2O 100 C, 3 h 80-88%

2-aminoethanol, O Pyridine, r.t., 1 h Ac2O, 80oC, 0.5 h 60-65%

2-aminoethanol, O Pyridine, 80oC, O 15 min Ac2 O, 80oC, 1 h 86%

Current Organic Chemistry( 2008),12, 1116-1183

KOH, H2O reflux R1 EtOH, 1M HCl OAc 64-85%

MeOH, 2 NH2 reflux, 24 h R 56-89% R1 = H, Me, F, CN, NO2; R2 = H, Me

R= Me, Et, i-Pr, t-Bu

CN CO2Et CO2Et path b H2N CN N H O CN CO2 Et N O 107 80% O NH2 NH2 CN

Current Organic Chemistry( 2008),12, 1116-1183

Current Organic Chemistry( 2008),12, 1116-1183

Current Organic Chemistry( 2008),12, 1116-1183

toluene 2-26 h 67-83%

115 R3 116 NaOH 2-5 h 85-99% R1 R2 N OH 118 OH R3 117

R 1 = H, Cl, Me, t-Bu, NO2 R 2 = H, Me, NO2 R 3 = H, CO2 Me

MeCN, r.t., 1-2 h 63-85%