CHAPTER

Reactions Yielding Alcohol/Hydroxy Carboxylic Acid/Phenols

2.1 MEERWEIN-PONNDORF-VERLEY REDUCTION
The reaction involves the reduction of ketones or aldehydes, by aluminium isopropoxide* in excess of isopropyl alcohol, into corresponding alcohols.13
R C R O Al(Oi Pr)3 HOi Pr R CHOH + R O

The reaction is reversible.** The reaction is specific for carbonyl group.*** The case when two carbonyl groups are present, one group is reduced and other ketonic group is protected by acetal formation from getting reduced. The mechanism of the reaction involves the coordination of aluminium isopropoxide with ketone to form cyclic transition state which undergoes hydride shift from CH bond of the alkoxide to the carbonyl carbon of the ketone to form mixed alkoxide. An excess of isopropyl alcohol is used which exchanges with the mixed alkoxide to form desired alcohol. Hydrogen atoms used in reduction are supplied by the catalyst and the solvent.
R O C R R Al (Oi Pr)3 Coordination C R H O O Oi Pr Al Oi Pr

Cyclic transition state

Footnote * Aluminium isopropoxide in isopropanol Al (O iPr)3 in HOi Pr. ** The reverse reaction is called oppenauer oxidation.4 *** -diketones and -ketoesters (ketones with high enol content do not undergo this reaction.
1. Meerwein, H. and Schmidt, R., Justus Liebigs. Ann. Chem., 444, 221238, 1925. 2. Pondorf, W., Angew. Chem., 39, 138143, 1926. 3. Verley, A., Bull. Soc., Chim., 37, 537542, 1925. 4. Oppenauer, et al., Recl. Trav. Chim. Pays-Bas., 56, 137144, 1937.

119

120
i Pr-O Al O C R R H O C Oi Pr Hydride shift

Advanced Organic Chemistry

Al(OiPr)2 O C O + R H CH R
+

R Al (OCH Me2)3 + R Corresponding alcohol CH OH

In addition to the mechanism through a six-membered cyclic transition state, a radical mechanism is also suggested for some substrates.5 The reaction rate is influenced by the temperature, if the reaction mixture is kept at the temperature slightly above the boiling point of acetone, the reaction proceeds towards completion. In order to shift the equilibrium of the reaction in the forward direction, the low boiling reaction product acetone is to be removed continuously from the reaction solution. If excess of acetone is used, the equilibrium can be shifted in the direction yielding the ketone (A) and isopropanol (B).
H3C CH OH + H3C C O Al [OC (CH3 )3]3 C (A) O + (CH3)2CHOH (B)

Though the Meerwein-Ponndorf-Verley reduction has been replaced by other reducing agents such as LiAlH4, NaBH4 etc. but is known for its mildness and selectivity as it is not affecting carbon-carbon double or tripple bonds of the substrate. Recently, lanthan isopropoxide6 has been found purposeful in place of aluminium propoxide.

Other References
Nishide, K. and Node, M., Chirality, 14, 759, 2002. Jerome, J.E. and Sergent, R.H. Chem., Ind., 89, 97, 2003. Fukuzawa, S.-i.; Nakano, N. and Saitoh, T., Eur. J. Org. Chem., 2863, 2004. Ooi, T.; Miura, T.; Ohmatsu, K.; Saito, A. and Maruoka, K., Org. Biomol. Chem., 2, 3312, 2004.

5. Screttas, C.G. and Cazianis, C.T., Tetrahedron, 34, 933940, 1978. 6. Okano, T.; Matsuoka, M.; Konishi, H. and Kiji, J. Chem. Lett., 181184, 1987.

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121

2.2

BLANC REACTION (Blanc Chloromethylation)

Blanc reaction is Lewis acid-promoted chloromethyl group installation onto the aromatics rings with 1,3,5-trioxane and HCl in the presence of catalyst.78
O + O O + HCl ZnCl2 CH2Cl + H2O

1,3,5 - trioxane

Reaction1 This reaction is comparable to Friedal-Crafts alkylation as the rate determining step is electrophilic SAr. The mechanism of the reaction is initiated by protonation of formaldehyde or trioxane which facilitates its reactivity towards electrophilic aromatic substitution at the benzene ring. The protonated formaldehyde then attacks aromatic ring to form a cationic specie which on subsequent loss of proton gives aromatic hydroxymethyl derivative which on further reaction with HCl gives chloromethylated product.9
O O O C H H O H
+ +

H +O O + H H C

C H

ZnCl2

Cl CH2OH + Cationic specie H H

+

+ OH2 CH2Cl + H2O

CH2OH

+H

CH2

SN2

Reaction2 Lewis acid catalyst, ZnCl28, is used for the reaction. Following is the formation of the electrophilic specie:
HCHO + HCl + ZnCl2 HCHOH ZnCl3
V

The mechanism of the above reaction involving the generation of electrophilic specie is as follows:

7. Blanc, M.G., Bull. Soc. Chim. Fr., 33, 313-319, 1923. 8. Fuson, R.C. and Mckeever, C.H., Org. React., 1, 63-90, 1942. 9. Belenkii, L.I.; Volkenshtein, Yu. B. and Karmanova, I.B., Russ. Chem. Rer., 46, 891-903, 1977.

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H C H O + ZnCl2 H C H O

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ZnCl2

Reaction3 The presence of catalyst is not required for electron rich aromatic substances. Nowadays chloromethyl ether or methoxy acetyl chloride1011 are used for the purpose.

Other References
De Mendoza, J.; Nieto, P.M.; Prados, P. and Sanchez, C., Tetrahedron, 46, 671, 1990. Miller, D.D.; Hamada, A.; Clark, M.T.; Adejare, A.; Patil, P.N.; Shams, G.; Romstedt, K.J.; Kim, S.U. et al., J. Med. Chem., 33, 1138, 1990. Ito, K.; Ohba, Y.; Shinagawa, E.; Nakayama, S.; Takahashi, S.; Honda, K.; Nagafuji, H.; Suzuki, A. and Sone, T.J., Heterocycl. Chem., 37, 1479, 2000. Harms, A.; Ulmer, E. and Kovar, K.-A., Archiv. Pharmazie, 336, 155, 2003.

2.3

BROWN HYDROBORATION

Brown hydroboration is the formation of alcohols by the addition of boranes to olefins followed by basic oxidation of the organoborane adducts.
1 R 2 BH R Alkene 2 H 2O 2, NaOH R Alcohol OH

Reaction4 The mechanism of the reaction can be illustrated as follows:

H R H R

R B R B O

H R H R B R B R

R R

Syn addition

R OH

OH O

Baeyer Villiger Like reaction

O R

B R

OH

O R

B OR

OR

OH

OH

+ B(OH)3

Reaction5
10. Olah, G.A.; Beal, D.A. and Olah, J.A., J. Org. Chem., 41, 16271631, 1976. 11. Mckilloq, A.; Madjdabdi, F.A. and Long, D.A., Tetrahedron Lett., 24, 19331936, 1983.

Reactions Yielding Alcohol/Hydroxy Carboxylic Acid/Phenols

123

It has been observed in Brown hydroboration that syn-addition of hydroboranes to alkenes occurs with predictable selectivity, according to which boron is added preferentially to the least hindered carbon. If the hydroboration is followed by oxidation of the borane, an anti-Markovnikov alcohol is formed. The first addition of borane has been found to be relatively low selective as compared to subsequent additions because of increase in steric bulk, finally leading to antimarkovnikovs selectivity.
H B + BH3 H H H H H2B H H H + BH3 H B H H H H BH2 H BH2 H H H2B

Reaction6

Other References
Kabalka, G.W.; Shoup, T.M. and Goudgaon, N.M., J. Org. Chem., 5930, 5933, 1989. Vice, S.; Bara, T.; Bauer, A.; Evans, C.A.; Fort, J.; Josein, H.; McCombie, S.; Miller, M.; Nazzareno, D.; Palani, A. and Tagat, J., J. Org. Chem., 66, 24872492, 2001. Kanth, J.V.B. and Brown, H.C., J. Org. Chem., 66, 5359-5365, 2001. Ramachandran, P.V. and Jennings, M.P., Org. Lett., 3, 3789-3790, 2001. Hupe, E.; Calaza, M.I. and Knochel, P., Tetrahedron Lett., 42, 8829, 2001. Morrill, T.C.; DSouza, C.A.; Yang, L. and Sampognaro, A.J., J. Org. Chem., 67, 2481, 2002. Carter, K.D. and Panek, J.S., Org. Lett., 6, 55, 2004. Patra, P.K.; Nishide, K.; Fuji, K. and Node, M., Synthesis, 1003-1006, 2004. Clay, J.M. and Vedejs, E., J. Am. Chem. Soc., 127, 5766, 2005. Clay, J.M. and Vedejs, E., J. Am. Chem. Soc., 127, 5766-5767, 2005. Hirano, K.; Yorimitsu, H. and Oshima, K., Org. Lett., 9, 1541-1544, 2007.

2.4

CANNIZZARO REACTION

It is a redox reaction involving disproportionation (simultaneous oxidation and reduction) of aldehydes without -hydrogen atoms, in the presence of a strong base (e.g., NaOH, KOH)1213
12. Cannizzaro, S., Justus Leibigs Ann. Chem., 88, 129-130, 1853. 13. Geissman, T.A., Org. React., 2, 94-113, 1944.

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into corresponding carboxylic acid salt and an alcohol.1415 Disproportionation of aldehydes involves the reduction of one molecule of aldehyde without -hydrogen into an alcohol, while second molecule of aldehyde get oxidized into carboxylic acid.
2 Ar CHO KOH OH Ar CH2OH + Ar COOH

Corresponding alcohol and carboxylic acid.

Reaction7 -keto aldehydes give -hydroxy carboxylic acid on intramolecular disproportionation

O R C CHO a - keto aldehyde Base OH

OH R CH COOH a - hydroxy carboxylic acid

O R C C H O OH

O OH R C C O H

OH + R CH COOH

a - hydroxy carboxylic acid

Reaction8 The key step in the reaction is hydride and proton shift. The reaction get initiated by the nucleophilic addition of a hydroxide anion to the carboxyl carbon of the aldehyde (without any -H), resulting in the formation of an anion (X). In the presence of the base, the resulting anion (X) get deprotonated to from di-anion specie (Y) in strongly basic medium. Intermediates (X) or (Y), can react with second molecule of aldehyde involving hydride shift and proton shift to form products.

Footnote 1. With 2 molecules of same aldehydes (without -H) Cannizzaros reaction is carried out. 2. With 2 molecules of same aldehydes or ketones (with -H) Aldol condensation is carried out. 3. With two molecules of different aldehydes or ketone Cross Aldol condensation is carried out.

14. Cannizzaro, S., Liebigs Annalen., 88, 129-130, 1853. 15. List, K. and Limpricht, H., Liebigs Annalen., 90, 190-210, 1854.

Reactions Yielding Alcohol/Hydroxy Carboxylic Acid/Phenols

125

Reaction Series for the mechanism of the reaction is as follows: Step 1: Formation of anionic/di-anionic intermediates.
O H C H H O C
+

O H C

I molecule of aldehyde without a-hydrogen

OH Base attack

OH Anion (X)

Deprotonation [H ]

O H C

O Di-anion (Y)

Reaction9 Step 2: Hydride and Proton shift (i)

H O C H O C H
+

H II molecule of aldehyde O H C OH (X)

(Z)

Pathway (A)

Addition to intermediate (X) / (Y) H

O C O

Pathway (B) H

(a)

(Y)

Footnote The electron donating effect of one or two O, allows for the transfer of a hydride ion (H ) on to another molecule.

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O H C

O H H Proton shift H C

O H C

(ii)

H (Z)

Hydride O shift

H (Z)

(X)

Hydride O shift (Y)

OH H C H or CH3OH Methanol H +

O C O or HCOO Carboxylate (b)

O H H C H

O H + H C O H
+

CH3OH

HCOOH

Methanol

Formic acid

Reaction10 (a) and (b) The evidence for the mechanism are taken from the experiments with D2O as solvent.
+

O H C H

O H C O

DR HY
IFT

SHIF IDE

OH

H H
RO TO
P

C+ H

D2O 

CH3OH + HCOO

Reaction11
*no deuterium in alcohol.

The resulting alcohol does not contain carbon-bonded deuterium showing that the shifted hydride comes from a second substrate molecule and not from the solvent. The Cannizaro reaction can be further illustrated by

Footnote Pathway A is involving hydride and proton shift while pathway B is involving hydride shift and acidic workup to give the required product.

SH

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127

Illustration 1
O ArCHO C6H6NH Na, THF 0C, 5 hr, 76% H Ar C N C6H6 + Ar CH2OH [16]

Reaction12 Illustration 2
KOH Powder CHO 100C, 5 min solvent free COOH + CH2OH [17]

Reaction13 Recently (2005) following reaction has been given by Ytterbium et al.18
OH OH COCH OH 0.1 eq, Yb (OTf)3. H2O 80C, 18hr, i - PrOH C H COOCH R2

Reaction14

Extension of Cannizzaros Reaction

Cannizzaros reaction is mainly carried out with carboxyl compounds/aldehydes (without any -H), the reaction can be extended by using aldehydes with -hydrogen (Aldol condensation) or two different-aldehydes without any -H (Cross-Cannizzaros reaction).

Cross Cannizzaros Reaction

The acid and alcoholic products of Cannizzaros reaction are obtained in a mixture, therefore, now a days cross Cannizzaros reaction is common. Two different molecules of aldehydes (without any -H) undergo disproportionation to yield cross-products.
CHO Benzaldehyde + HCHO Formaldehyde conc. NaOH Disproportionation CH2OH + HCOOH

Reaction15 More reactive formaldehyde undergoes oxidation while less reactive benzaldehyde undergoes reaction to yield cross-products.

16. Ishihara, K. and Yano, T., Org. Lett., 6, 1983, 2004. 17. Yoshizawa, K.; Toyota, S. and Toda, F., Tetrahedron Lett., 65, 8381, 2001. 18. Curini, M.; Epifano, F.; Genovese, S.; Marcotullio, M.C. and Rosati, O., Org. Lett., 7, 1331, 2005.

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Other References
Reddy, B.V.S.; Srinavas, R.; Yadav, J.S. and Ramalingam, T., Synth. Commun., 32, 219, 2002. Russell, A.E.; Miller, S.P. and Morken, J.P., J. Org. Chem., 65, 8381, 2000. Thakuria, J.A.; Baruah, M. and Sandhu, J.S., Chem. Lett., 995, 1999.

2.5

NOZAKI-HIYAMA-KISHI REACTION

Nozaki-Hiyama-Kishi reaction is a nickel-chromium bimetallic catalyst promoted coupling reaction involving redox addition of vinyl or allyl halides to aldehydes to form an alcohol.1921
CrCl3 0.5 eq LiAlH4 DMF, 0C
++

CrII Salt

+ R CHO

Cr Salt , NiBr2 DMSO - SMe2

R OH

Reaction16 Solvents used in the reaction are DMF and DMSO, one solvent requirement is Cr salt should be soluble in it. Earlier the probability of the reaction to take place depends upon the source of chromium (II) chloride but later Takai et al.21 studied the importance of Ni in the reaction and since then nickel (II) chloride is used as co-catalyst. Yoshita et al.22 independently discovered the catalytic effect of nickel during the total synthesis of polytoxin.22

19. Okude, C. T.; Hirano, S.; Hiyama, T. and Nozaki, H., J. Am. Chem. Soc., 99, 31793181, 1977. 20. Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T. and Nozaki, H., Tetrahedron Lett., 24, 52815284, 1983. 21. Takai, K.; Tagahira, M.; Kuroda, T.; Oshima, K.; Utimoto, K and Nozaki, H., J. Am. Chem. Soc., 108, 60486050, 1986. 22. Jin, H.; Uenishi, J.; Christ, W.J. and Kishi, Y., J. Am. Chem. Soc., 108, 5644, 1986.

Reactions Yielding Alcohol/Hydroxy Carboxylic Acid/Phenols

Bn O O O O O Bn O O Bn H 6 eq. NiCl2 (0, 1%)CrCl2 DMSO , rt, oxygen free O Bn OBn O Bn O Si Ph Ph (Reference 22) O Si Ph Ph O O O Bn O Bn O O Bn OH

129

OBn

Reaction17

Mechanism
1. The first step of the reaction is the reduction of nickel (II) chloride to nickel (0) with chromium (II) chloride (sacrificial catalyst) resulting in chromium (III) chloride. 2. The second step is the oxidative addition of nickel to the carbon adjacent to halide resulting into a alkenylnickel intermediate (A). 3. Third is the transmetellation step exchanging NiX with a Cr (III) group to an alkenylchromium intermediate (B) with the regeneration of Ni (II). 4. Fourth step is the nucleophilic addition of (B) with the carbonyl group followed by hydrolysis.
Step (2) Ni(++ ) Step (1) SMe2 Reduction CrCl2 Step (3) Ni(++) Ni(O) R OCrCl2 CrCl3 R Cr(+++) Cl2 (B) HOH R OH An alcohol Ni(O) R X Oxidative addition

R Ni(++)Br (A) Step (4) R CHO Nucleophilic addition R + CrCl2 X

Transmetellation R

The amount of nickel used in the reaction should be low because a side reaction of direct coupling of alkene to a diene is observed.

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Other References
Kuroboshi, M.; Tanaka, M.; Kishimoto, S.; Goto, K.; Mochizuki, M. and Tanaka, H., Tetrahedron Lett., 41, 81, 2000. Blaauw, R.H.; Benningshof, J.C.J.; Van Ginkel, A.E.; Van Maarseveen, J.H. and Hiemstra, H., J. Chem. Soc., Perkin Trans, 1, 2250, 2001. Berkessel, A.; Menche, D.; Sklorz, C.A. and Schroder, Paterson, I. Angew. Chem., Int. Ed., 42, 1032, 2003. Takai, K., Org. React., 64, 253612, 2004 (Review).

2.6

OPPENAUER OXIDATION

Oppenauer oxidation is the alkoxide catalysed hydrido shift from the -carbon of alcohol to the ketone. It is the oxidation of secondary alcohol to ketones.23
R CHOH R + R C R O R R C O Al [OC(CH3)3]3 R R CHOH

The reaction is opposite of Meerwein-Ponndorf-Verley reduction. The mechanism of the reaction involves a cyclic transition state.
OR OH R R Al (OR)2 R R O Al (OR)2 + R R OH

O Coordination H R

R O O

OR Al OR

RO Al O C H

OR O R

Cyclic T.S.

Hydride Transfer

R C R O + OH

Reaction18

23. Oppenauer, R.V., Rec. Trav. Chim., 56, 137, 1937.

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131

When a secondary alcohol in acetone or cyclic ketone is refluxed with aluminium tertbutoxide in toluene or benzene, the alcohol is dehydrogenated to ketone. The hydrogens so lost by the alcohol are transferred to cyclic ketone or acetone to form alcohols. Byrne et al. (1987)24 gave magnesium Oppenauer oxidation as illustrated below,
OH (1) EtMgBr, i-Pr2O (2) PhCHO, 60% O

The commonly used ketones are acetone, cyclohexanone and methyl ethyl ketone, common bases are aluminium isopropoxide, aluminium tert-butoxide, potassium tert-butoxide etc. Primary alcohols can also be oxidised to aldehydes if p-benzoquinone is used in place of acetone.

Other References
Nait Ajjou, A., Tetrahedron Lett., 42, 13, 2001. Ooi, T.; Otsuka, H.; Miura, T.; Ichi Kawa, H. and Maruoka, K., Org. Lett., 4, 2669, 2002. Suzuki, T.; Morita, K.; Tsuchida, M. and Hiroi, K., J. Org. Chem., 68, 1601, 2003. Hon, Y.-S.; Chang, C.-P.; Wong, Y.-C.; Byrne, B. and Karras, M., Tetrahedron Lett., 45, 3313, 2004. Graves, C.R.; Zeng, B.S. and Nguyen, S.T., J. Am. Chem. Soc., 128 (39), 1259612597, 2006.

2.7

GRIGNARD REACTION

Organomagnesium compounds (Grignards reagent), obtained from organohalides and magnesium metal, are added to electrophiles (polarized multiple bonds).2526
O Mg (O) R C R R C R OH R

MgX

Reaction19 The substrate for the reaction are those containing polar functional groups (such as C=N, etc. C=S, S=O, N=O etc.) e.g., aldehydes, ketones, esters, nitriles, carbon dioxide

24. Byrne, B.; Karras, M., Tetrahedron Lett., 1987, 28, 769. 25. Grignard, V., Acad. Sci. C.R., 130, 13221324, 1900. 26. Nutzel, K.; Gilman, H. and Wright, G.F., Methoden Org. Chem. (Houben-Weyl), Vol. 13/2a, pp. 49527, 1973.

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Grignard reagents are very important class of organometallic compounds with its most common application, formation of alcohol upon reaction with carbonyl compound to give magnesium alkoxide which on hydrolytic workup yield alcohol. Grignards reagent is prepared from the reaction of aryl or alkyl halides with magnesium metal. The reaction occurs on the metal surface, involving the transfer of an electron from magnesium to a halide molecule resulting in formation of an alkyl or aryl radical specie, finally radical specie.
R X R Mg Mg X Mg Single electron transfer (SET) R Mg MgX Mg RMgX (Grignard reagent)

Mg metal

It is point of discussion that the intermediate radical get absorbed on the metal surface27 or desorbed into the solution.28 Umpolung: Umpolung is the reversal of reactivity observed in Grignard reaction, in alkyl halide, C-X bond is highly polarized due to great difference in the electronegativities of the two carbon adjacent to halogen bears partial positive charge and becomes of electrophilic nature, while in Grignards reagent, polarization is reversed, carbon adjacent to magnesium becomes partially negatively charged and acts as a nucleophile, thus, the reactivity get reversed.29 Reaction mechanism to explain Grignard reaction A uniform reaction mechanism is not enough to describe many diverse Grignard reactions, following mechanisms are given to describe the same by taking an illustration of the reaction of GR with ketone as it is explained by both the mechanisms.3031 The polar mechanism includes the transfer of the group R along with the binding electron pair onto the carbonyl carbon center leading to the formation of a magnesium oxygen bond in magnesium alkoxide of a tertiary alcohol.
+ d d C O R d MgX +d R C OMgX

The radical mechanism includes the transfer of a single electron from Grignard reagent into the carbonyl group, called single electron transfer (SET) system, pair of radicals so formed on combination yield the product.
+d C d R d O +d MgX

C R

O + MgX

OMgX

27. Walborsky, H.M., Acc. Chem. Res., 23, 286293, 1990. 28. Garst, J.F., Acc. Chem. Res., 24, 9597, 1991. 29. Seebach, D., Angew. Chem., 91, 259278, 1979. Angew. Chem., Int. Ed. Engl., 18, 239, 1979. 30. Ashby, E.C., Pure Appl. Chem., 52, 545569, 1980. 31. Orchin, M., J. Chem. Educ., 66, 586588, 1989.

Reactions Yielding Alcohol/Hydroxy Carboxylic Acid/Phenols

133

The nature of organomagnesium reagent decides by which mechanism the reaction will proceed, e.g., reaction of benzophenone with GR (methyl magnesium bromide) when t-butylmagnesium chloride is taken as GR, in the same reaction, radical mechanism is followed.

Role of Solvent*
Solvent plays an important role in stabilizing the organomagnesium species through complexation. Solvents can be used for the purpose are ethers (diethylether or tetrahydrofuran). Stereochemistry of the reaction In an unsymmetrical ketone, the carbon of C=O group is prochiral and can be attacked by the Grignards reagent from either side, resulting in the formation of racemic mixture.
OMgX (a) d +d R MgX (a) R2 O
d

C d +d R MgX (b) (b) R2 R1 R R2 R1 OMgX C R Racemic mixture

C +d R1

Either side attack of GR.

Reaction20 When a racemic mixture of an aldehyde/ketone containing a chiral center ( e.g., 2-phenylpropanal) is treated with a chiral GR, four stereospecific products are obtained, as shown below, two diastereomers and their enantiomers.
H Ph O C H + RMgX H Ph (Minor) Me C C R H OH (Major) Me C Me H C Ph C H R (By Crams rule) OH

Reaction21
Footnote * In a nucleophilic solvent, the organomagnesium specie is described Schlenk equilibrium.
X 2RMgX R Mg R Mg X R 2Mg + MgX 2

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Crams rule: According to the Crams rule, the attack direction of reactant reagent to carbon in the process of nucleophilic addition reaction to carbonyl compounds is explained, the Crams rule is based on rule of thumb.3233 This rule predicts that which stereoisomer will be formed predominantly if the reaction forms an additional chiral centre. In other words it is the rule of asymmetric induction which describes the preferential formation of the product in a chemical reaction i.e., if there are two enantiomers or diastereomers are formed in a reaction, which one will be formed in preference to the other as a result of the influence of a chiral feature present in the substrate and reagent.34 Following is the statement of Crams rule: When a compound, in which the rotational conformation of the CC bond is such that the double bond is flanked by the two least bulky groups attached to the adjacent asymmetric centre, is attacked by a reagent, the diastereomer will predominate which is formed due to the approach of the entering group from the least hindered side. In other words, it can be said that the formation of an asymmetric centre in a compound based on steric hinderance, is induced by the asymmetric centre already present in the adjacence. The reactivity of -chiral aldehydes or ketones can be explained by Crams rule.35 Reaction of GR containing -Hydrogen with Carbonyl Compound Grignard reduction: Grignard reagents that contain a -hydrogen can undergo transfer of -hydrogen to reduce a carbonyl substrate.
C O CH C MgX CH2 (GR with b-hydrogen) HC H O + MgX C C CH2 T.S. CH2 Alkene OMg

Carbonyl group

Reaction22 Grignard reagent can react with a variety of carbonyl compounds as a nucleophile, some examples are shown below:

Footnote The reaction results in racemic mixture as long as no asymmetric induction becomes effective.8

32. Ashby, E.C. and Laemmle, J.T., Chem. Rev., 75, 521546, 1975. 33. Radano Kinichi, T., Chemistry, 54-1; 5153, 1999. 34. IUPAC Gold Book definition Link. 35. Nogradi, M., Stereoselective Synthesis, VCH, Weinheim, pp. 131140, 1986.

Reactions Yielding Alcohol/Hydroxy Carboxylic Acid/Phenols

R C OH R 1COCl HCHO R C R1 R 1CN R 1R 2CO CO 2 RCOOH C OH R CHOH R R1 R C R2 OH O

135

R R R1

RCH 2OH

MgX

R 1 COOR 2 R R1 R2

R CHO

Reaction23 Grignards reaction is one of the most important reactions due to its versality in carboncarbon bond formation. One of the most advance application of Grignards reagent, formed from slow reacting alkyl/aryl halides, is given in ultrasound.36

Other References
Cali, P. and Begtrup, M., Synthesis, 6364, 2002. Gandon, V.; Bertus, P. and Szymoniak, J., Synthesis, 1115120, 2002. Krasovski, A. and Knochel, P., Angew. Chem., 116, 33963399, 2004. Wang, X.-J.; Zhang, L.; Sun, X.; Xu, Y.; Krishnamurthy, D. and Senanayake, C.H., Org. Lett., 7, 55935595, 2005. Hatano, M.; Matsumura, T. and Ishihara, K., Org. Lett., 7, 573576, 2005. Handy, S.T., J. Org. Chem., 71, 46594662, 2006. Menzel, K.; Dimichele, L.; Mills, P.; Frantz, D.E.; Nelson, T.D. and Kress, M.H., Synlett., 19481952, 2006. Hatano, H.; Suzuki, S. and Ishihra, K., J. Am. Chem. Soc., 128, 99989999, 2006. Krasovskiy, A.; Kopp, F. and Knochel, P., Angew. Chem., Int. Ed., 45, 497500, 2006. Murai, T. and Asai, F., J. Am. Chem. Soc., 129, 780781, 2007. Grignard Reagents Richey, H.G., Jr., Ed., Wiley, New York, 2000 (Book). Holm, T.; Crossland, I. In Grignard Reagents Richey, H.G., Jr., Ed., Wiley, New York, Chapter 1, pp. 126, 2000 (Review). Toda, N.; Ori, M.; Takami, K.; Tago, K. and Kogen, H. Org. Lett., 5, 269, 2003. Shinokubo, H. and Oshima, K., Eur. J. Org. Chem., 20812091, 2004 (Review). Graden, H. and Kann, N., Cur. Org. Chem., 9, 733763, 2005 (Review). Andersson, H. et al., Org. Lett., 9, 13351337, 2007.

36. Einhorn, C.J.; Einhorn, J. and Luche, J.-L., Synthesis, 787813, 1989.

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2.8

EVANS ALDOL REACTION

Evans Aldol condensation is the asymmetric aldol condensation of aldehyde and chiral acyl oxazolidinone. Evans Aldol condensation is an extension to Aldol condensation reaction. As synthesis of enantiopure compounds is required, many methods are developed. Evans acyl oxazolidinone method3738 is one of the methods developed to control relative as well as absolute stereochemistry. The Evans method creates temporarily by creating a chiral enolate by appending a chiral auxillary (oxazolidinone). The already existing chirality from the auxillary is then transferred to the aldol adduct through a diastereoselective aldol reaction. When the auxillary is removed subsequently, the desired aldol stereoisomer is observed. The product of Evans method is carbonyl compound imide.
O N O imide O (1) Bu2BOT , R3N (2) PhCHO , 78C Ph OH O N O O

Reaction24 The mechanism of the reaction involves following steps:

Bu2 B OT Bu Bu O N H R3N O O Z - (O) - boron enolate formation (Soft enolization mediated by boron)
Bu B Aldol Condensation Ph N O O O O Workup Ph Bu OH O N O O
39

B O N O O PhCHO O H Ph N H H O O Bu B Bu O

Footnote Relative stereochemistry comprises of syn- and anti-forms while absolute stereochemistry comprises of R and S forms.

37. Evans, D.A., Aldrichimica Acta., 15, 23, 1982 (Review). 38. Gage, J.R. and Evans, D.A., Organic Syntheses, Coll., Vol. 8, p. 339, 1993; Vol. 68, p. 83, 1990. 39. Evans, D.A.; Bartroli, J. and Shih, T.L., J. Am. Chem. Soc., 103, 21272129, 1981.

Reactions Yielding Alcohol/Hydroxy Carboxylic Acid/Phenols

137

Other References
Williams, D.R.; Patnaik, S. and Clark, M.P., J. Org. Chem., 66, 8463, 2001. Matsushima, Y.; Itoh, H.; Nakayama, T.; Horiuchi, S.; Eguchi, T. and Kakinuma, K., J. Chem. Soc., Perkin 1, 849, 2002. Hein, J.E. and Hultin, P.G., Syn. Lett., 635, 2003. Zhang, W.; Carter, R.G.; Yokochi, A.F.T., J. Org. Chem., 69, 2569, 2004.

2.9

DIENONE-PHENOL REARRANGEMENT

Dienone-Phenol rearrangement is the acid-promoted rearrangement of 4,4-disubstituted cyclohexadienones to 3,4-disubstituted phenols.4041 The rearrangement inolves the creation of aromatic system.42
O H
+

R R (A) R R (B)

on acid treatment43, one of the alkyl groups in the 4-position, undergoes 1,2-shift. The mechanism of the reaction involves three steps, protonation by an acid, 1,2-alkyl shift and lastly, deprotonation.
+

H OH +d 1,2-alkyl H shift + R (C)

OH

O H
+

O acid promoted protonation

H R

R (A)

R (D)

deprotonation R R

3,4-dialkyl phenol

(B)

whereas, (C) and (D) are arenium ions. Reaction25

40. 41. 42. 43.

Shive, H.J., Aromatic Rearrangements, Elsevier: New York, p. 5568, 1967. Schultz, A.G. and Hardinger, S.A., J. Org. Chem., 56, 1105, 1991. Perkins, et al., Mech. Mol. Migr., 4, 55112, pp. 90103, 1971. Chalais, et al., Tetrahedron Lett., 27, 2627, 1986.

138

Advanced Organic Chemistry

Phenol-Dienone Rearrangement
Reverse rearrangement caused by the reaction of a phenol with an electrophile and it takes place without migration,44 e.g.,
Br Br Br OH Br 2 Br Br Br O Br

Reaction26

Other References
Banerjee, A.K.; Castillo-Melendez, J.A.; Vera, W.; Azocar, J.A. and Laya, M.S., J. Chem. Res. (S), 324, 2000. Kumar, V.S.; Nagaraja, B. M.; Shashikala, V.; Seetharamulu, P.; Padmasri, A.H.; Raju, B.D. and Rao, K.S.R., J. Mol. Catal. A: Chemical, 223, 283, 2004. Kodama, S.; Takita, H.; Kajimoto, T.; Nishide, K. and Node, M. Tetrahedron, 60, 4901, 2004.

2.10

BAMBERGER REARRANGEMENT

Bamberger rearrangement is the acid-mediated rearrangement of N-phenylhydroxylamines to 4-aminophenols.4550

NHOH H 2SO 4 H 2O HO NH 2

Reaction27 The mechanism of the rearrangement includes following steps:

NHOH H
+

H + N

H O + H Nueleophilic attack

Protonation H2O

H + NH2 NH2

+ NH2

Deprotonation H + H O
HSO4

Deprotonation H HSO4

OH

HO

44. 45. 46. 47. 48. 49. 50.

Ershov, et al., Russ. Chem. Rev., 32, 7593, 1963. Bamberger, E., Ber. Dtsch. Chem. Ges., 27, 15481557, 1894. Harman, R.E., Org. Synthesis, 35, 22, 1955. Fishbein, J.C. and McClelland, R.A., Can. J. Chem., 74, 1321, 1996. Naicker, K.P.; Pitchumani, K. and Varma, R.S., Catal. Lett., 58, 167, 1999. Pirrung, M.C.; Wedel, M. and Zhao, Y., Syn Lett., 143, 2002. Qiu, X.; Jiang, J.-J.; Wang, X.-Y. and Shen, Y.-J., Youji Huaxue., 25, 561, 2005.