LETTER 987

New Efficient Synthesis of Pyrido[2,3-c] and Pyrido[3,2-c]coumarin

Derivatives
Synthesisof Pyrido[2,3-c] andPyrido[3,2-c]coumarinDerivatives Grgoire Pav,
a
Pierre Chalard,
b
Marie-Claude Viaud-Massuard,
c
Yves Troin,
b
Grald Guillaumet*
a
a
Institut de Chimie Organique et Analytique, UMR CNRS 6005, Universit dOrlans, BP 6759, 45067 Orlans Cedex 2, France
E-mail: gerald.guillaumet@univ-orleans.fr
b
Laboratoire de Chimie des Htrocycles et des Glucides, EA 987, Ecole Nationale Suprieure de Chimie de Clermont Ferrand,
Universit Blaise Pascal, BP 187, 63174 Aubire Cedex, France
c
Groupe de Recherche en Chimie Htrocyclique et Thrapeutique, EA 3247, UFR Sciences Pharmaceutiques, Universit de Tours,
31 avenue Monge, 37200 Tours, France
Received 5 March 2003
Synlett 2003, No. 7, Print: 02 06 2003.
Art Id.1437-2096,E;2003,0,07,0987,0990,ftx,en;G05303ST.pdf.
Georg Thieme Verlag Stuttgart New York
Abstract: Various substituted pyrido[2,3-c] and pyrido[3,2-c]cou-
marins are efficiently prepared in three steps from 3- and 4-hy-
droxycoumarins, respectively and protected b-aminoketones.
Key words: pyridocoumarins, tetrahydropyridocoumarins, dispro-
portionation, oxidative cyclization, Santiagonamine
The pyrido[2,3-c]coumarin skeleton 1 constitutes the
backbone of Santiagonamine 2 (Figure 1).
1
This alkaloid
has been isolated from Berberis Darwinii (Berberidacea)
and has shown interesting wound healing properties.
2
In
order to explore the range of biological activities of such
compound, we were interested in preparing some non-nat-
ural analogs. Surprisingly, only a few synthesis of pyri-
do[2,3-c]coumarins has been described in the literature.
3
Figure 1
From this observation, we have developed a new method
to prepare substituted pyrido[2,3-c]coumarin derivatives
5 and its tetrahydro derivatives 6 involving condensation
of 3-hydroxycoumarins 3 on b-aminoketones 4 followed
by an intramolecular cyclization (Scheme 1).
The syntheses of 3-hydroxycoumarins 3 were achieved
starting from commercially available substituted a-hy-
droxybenzaldehydes using the standard procedure
4
(Table 1).
a-Hydroxybenzaldehydes react with N-acetylglycine in
presence of acetic acid, acetic anhydride and sodium ace-
tate to afford 7. An acidic treatment lead to 6-, 7- and 8-
methoxy and 6-bromo-3-hydroxycoumarins 3ae.
The suitable aminoketones 4af were prepared in high
yield following the conventional three steps procedure
5
as
described in our previous paper (Table 2).
6
Condensation of 3-hydroxycoumarin 3a and amine 4a in
refluxing toluene with a catalytic amount of camphorsul-
fonic acid (CSA) with a DeanStark apparatus gave ami-
nocoumarin 8 (characterized by its
1
H NMR) (Scheme 2).
Addition of boron trifluoride diethyletherate complex to
the solution permits the cyclization on the C-4 position of
the coumarin. At this stage, a mixture of two products
were isolated in 68% yield, the pyrido[2,3-c]coumarin 5a
and the tetrahydropyrido[2,3-c]coumarin 6a in a 56/44 ra-
tio, respectively (Scheme 2).
As quoted first by Greenhill
7
and more recently by Heber
8
on the studies of enaminones and enones, this kind of con-
densation could produce the not isolable dihydropyridine
9. Its disproportionation afforded a mixture of compounds
5a and 6a. A subsequent in situ oxidation of this mixture
afforded the pyrido only analogue 5a. Indeed, when 6a
reacted with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone
(DDQ) in dichloromethane, the pyrido moiety 5a was
formed in 95% yield (Scheme 3).
Then, a three steps procedure achieved with no purifica-
tion could be performed in order to form exclusively pyri-
do[2,3-c]coumarins. The reaction was carried out as
described in Scheme 2 and after a standard work-up, the
crude was dissolved in methylene chloride and directly
oxidized by DDQ.
Scheme 1
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988 G. Pav et al. LETTER
Synlett 2003, No. 7, 987990 ISSN 1234-567-89 Thieme Stuttgart New York
Thus, treatment of different 3-hydroxycoumarins 3ae
with amines 4af led to pyridocoumarins 5aj in good
yields (Table 3)
9
.
On the other hand, tetrahydropyrido[2,3-c]coumarin de-
rivatives were obtained using the same approach.
After formation of imine and addition of the Lewis acid,
sodium cyanoborohydride was added to the mixture in
acidic conditions. As shown in Table 4, tetrahydro-
pyrido[2,3-c]coumarin derivatives 6ac were obtained,
starting from 3-hydroxycoumarin 3a and protected b-ami-
noketones 4a, 4b and 4d.
10
Table 1 Synthesis of 3-Hydroxycoumarins 3
Entry 3-Hydroxycoumarins Yield
1 3a 58%
2 3b 28%
3 3c 54%
4 3d 36%
5 3e 54%
Table 2 Synthesis of Protected b-Aminoketones 4
Entry Amines Overall Yield
1 4a 75%
2 4b 73%
3 4c 52%
4 4d 56%
5 4e 60%
6 4f 67%
Scheme 2
Scheme 3
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LETTER Synthesis of Pyrido[2,3-c] and Pyrido[3,2-c]coumarin Derivatives 989
Synlett 2003, No. 7, 987990 ISSN 1234-567-89 Thieme Stuttgart New York
We thus turn our attention to the synthesis of pyrido[3,2-
c]coumarins from 4-hydroxycoumarin using this proto-
col. Commercially available 4-hydroxycoumarin reacts
with amines 4a,b,f to afford, after oxidative treatment, the
expected products 10ac.
11
Table 5 summarize the yield
of expected products.
In conclusion, we have developed a new efficient method
for the synthesis of pyrido[2,3-c]coumarins and its tet-
rahydro derivatives starting from its corresponding 3-hy-
droxycoumarins. Their pyrido[3,2-c]coumarins isomers
Table 3 Synthesis of Pyrido[2,3-c]coumarins 5
Entry Pyrido[2,3-c]coumarins Yield
1 5a 54%
2 5b 57%
3 5c 60%
4 5d 60%
5 5e 55%
6 5f 66%
7 5g 57%
8 5h 60%
9 5i 52%
10 5j 61%
Table 3 Synthesis of Pyrido[2,3-c]coumarins 5 (continued)
Entry Pyrido[2,3-c]coumarins Yield
Table 4 Synthesis of Tetrahydropyrido[2,3-c]coumarins 6
Entry Tetrahydropyrido[2,3-c]
coumarins
Yield
1 6a 63%
2 6b 61%
3 6c 57%
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990 G. Pav et al. LETTER
Synlett 2003, No. 7, 987990 ISSN 1234-567-89 Thieme Stuttgart New York
were obtained starting from 4-hydroxycoumarins. Exten-
sion to the first total synthesis of Santiagonamine alkaloid
and non-natural derivatives is under investigation.
Acknowledgment
The authors thank the Ministre de la Jeunesse, de lEducation
Nationale et de la Recherche for a grant (G. P.).
References
(1) Valencia, E.; Patra, A.; Freyer, A. J.; Shamma, M.; Fajardo,
V. Tetrahedron Lett. 1984, 25, 3163.
(2) Lewis, W. H.; Stonard, R. J.; Porras-Reyes, B.; Mustoe, T.
A.; Thomas, A. US Patent 5156847, 1992.
(3) (a) Khan, M. A.; Gemal, A. L. J. Heterocyclic Chem. 1977,
14, 1009. (b) Tabakovic, K.; Tabakovic, I.; Trkovnik, M.;
Juric, A.; Trinajstic, N. J. Heterocycl. Chem. 1980, 17, 801.
(c) Sagi, M.; Wada, K.; Konno, S.; Yamanaka, H.
Heterocycles 1990, 30, 1009.
(4) (a) Dean, F. M.; Robertson, A.; Whalley, W. B. J. Chem.
Soc. 1950, 895. (b) Trivedi, K. N.; Sethna, S. J. Org. Chem.
1960, 25, 1817.
(5) Islam, A. M.; Raphael, R. A. J. Chem. Soc. 1955, 3151.
(6) (a) Ciblat, S.; Calinaud, P.; Canet, J.-L.; Troin, Y. J. Chem.
Soc., Perkin Trans. 1 2000, 353. (b) Rougnon-Glasson, S.;
Canet, J.-L.; Troin, Y. Tetrahedron Lett. 2000, 41, 9797.
(7) Greenhill, J. V.; Mohamed, M. I. J. Chem. Soc., Perkin
Trans. 1 1979, 1411.
(8) Heber, D.; Berghaus, T. J. Heterocycl. Chem. 1994, 31,
1353.
(9) General procedure for the synthesis of pyrido[2,3-
c]coumarins 5. In a round bottom flask equipped with a
Dean-Stark apparatus, 3-hydroxycoumarins 3 in toluene,
CSA (cat.) and amines 4 (1.1 equiv) were added. The
solution was refluxed 5 h. The solution was cooled to r.t and
1.5 equiv of BF
3
Et
2
O was added. The solution was refluxed
18 h and the solvent was evaporated. The residue was
hydrolyzed by a saturated aqueous NaHCO
3
solution,
extracted by CH
2
Cl
2
and dried over MgSO
4
. After
concentration under reduced pressure, the residue was
dissolved in CH
2
Cl
2
and 1 equiv of DDQ was added. The
solution was stirred 18 h and hydrolyzed by a saturated
aqueous K
2
CO
3
solution. After extraction with CH
2
Cl
2
, the
organic layers were washed, dried over MgSO
4
, evaporated
under reduced pressure and purified by flash chromato-
graphy (SiO
2
) to furnish pyrido[2,3-c]coumarins 5.
Compound 5a: Yield: 54%; mp = 133 C; IR (KBr): 1748
cm
1
; MS : 212 (M + 1);
1
H NMR (CDCl
3
, 250 MHz) d 2.95
(s, 3 H, CH
3
), 7.347.58 (m, 4 H, 4CH
Ar
), 8.26 (d, 1 H, J =
8.2 Hz, CH
Ar
), 8.78 (d, 1 H, J = 4.6 Hz, H-6);
13
C NMR
(CDCl
3
, 62.5 MHz) d 24.9 (CH
3
, ArCH
3
), 116,4 (C, C
Ar
),
118.1 (CH, CH
Ar
), 124.5 (CH, CH
Ar
), 127.4 (CH, CH
Ar
),
130.6 (CH, CH
Ar
), 132.0 (CH, CH
Ar
), 139.1 (C, C
Ar
), 145.1
(C, C
Ar
), 150.1 (CH, CH
Ar
), 150.7 (C, C
Ar
), 159.2 (C, C=O).;
Anal. Calcd for C
13
H
9
NO
2
: C, 73.92; H, 4.29; N, 6.63. Found
C, 73.82; H, 4.31; N, 6.72.
(10) General procedure for the synthesis of tetrahydro-
pyrido[2,3-c]coumarins 6. In a round bottom flask
equipped with a DeanStark apparatus, 3-hydroxy-
coumarins 3 in toluene, CSA (cat.) and amines 4 (1.1 equiv)
were added. The solution was refluxed 6 h. The solution was
cooled to r.t. and 1.5 eq of BF
3
Et
2
O was added. The solution
was refluxed 18 h and the solvent was evaporated. The
residue was hydrolyzed by a saturated aqueous NaHCO
3

solution, extracted by CH
2
Cl
2
and dried over MgSO
4
. After
concentration under reduced pressure, the residue was
dissolved in AcOH and 1 equiv of NaBH
3
CN was added.
The solution was stirred 8 h and hydrolyzed by a saturated
aqueous K
2
CO
3
solution. After extraction with CH
2
Cl
2
,
organic layers were washed, dried over MgSO
4
, evaporated
under reduce pressure and purified by flash chromatography
(SiO
2
, CH
2
Cl
2
/MeOH, 98:2) to furnish tetrahydro-
pyrido[2,3-c]coumarins 6. Compound 6a: Yield: 63%; mp =
108 C; IR (KBr): 1705 cm
1
; MS : 216 (M + 1);
1
H NMR
(CDCl
3
, 250 MHz) d 1.31 (d, 3 H, J = 7.0 Hz, CH
3
), 1.79
2.02 (m, 2 H, H-5), 3.173.24 (m, 1 H, H-4), 3.413.47 (m,
2 H, H-6), 4.87 (brs, 1 H, NH), 7.197.51 (m, 4 H, 4CH
Ar
);
13
C NMR (CDCl
3
, 62.5 MHz) d 21.2 (CH
3
, CH
3
), 25.3 (CH,
C-4), 26.8 (CH
2
, C-5), 36.1 (CH
2
, C-6), 116.7 (CH, CH
Ar
),
120.3 (C, C
Ar
), 121.1 (CH, CH
Ar
), 121.1 (C, C
Ar
), 124.5 (CH,
CH
Ar
), 125.6 (CH, CH
Ar
), 127.8 (C, C
Ar
), 148.1 (C, C
Ar
),
159.0 (C, C=O).; Anal. Calcd for C
13
H
13
NO
2
: C, 72.54; H,
6.09; N, 6.51. Found C, 72.61; H, 6.23; N, 6.72.
(11) General procedure for the synthesis of pyrido[3,2-
c]coumarins 10. Following the same protocol described for
the synthesis of pyrido[2,3-c]coumarins 5, pyrido[3,2-
c]coumarins 10 were obtained starting from 4-hydroxy-
coumarin. Compound 10a: Yield: 61%; mp = 160 C; IR
(KBr): 1731 cm
1
; MS: 212 (M + 1);
1
H NMR (CDCl
3
, 250
MHz) d 2.85 (s, 3 H, CH
3
), 7.267.37 (m, 3 H, 3 CH
Ar
), 7.53
(td, 1 H, J = 7.6 Hz, 1.7 Hz, CH
Ar
), 8.53 (dd, 1 H, J = 7.6 Hz,
1.7, CH
Ar
), 8.75 (d, 1 H, J = 4.9 Hz, CH
Ar
);
13
C NMR
(CDCl
3
, 62.5 MHz) d 23.0 (CH
3
, ArCH
3
), 116.5 (CH, CH
Ar
),
116.7 (C, C
Ar
), 119.5 (C, C
Ar
), 124.6 (CH, CH
Ar
), 125.3 (CH,
CH
Ar
), 126.7 (CH, CH
Ar
), 132.1 (CH, CH
Ar
), 152.4 (C, C
Ar
),
153.0 (C, C
Ar
), 153.5 (C, C
Ar
), 154.2 (CH, CH
Ar
), 160.5 (C,
C=O); Anal. Calcd for C
13
H
9
NO
2
: C, 73.92; H, 4.29; N, 6.63.
Found C, 73.78; H, 4.32; N, 6.68.
Table 5 Synthesis of Pyrido[3,2-c]coumarins 10
Entry Pyrido[3,2-c]coumarins Yield
1 10a 61%
2 10b 58%
3 10c 62%
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