Unexpected one-pot synthesis of new polycyclic coumarin[4,3-c]pyridine derivatives via a tandem hetero-Diels-Alder and 1,3-dipolar cycloaddition reaction

Article abstract of DOI:10.1016/j.tetlet.2008.11.033

O-Methyl-4-coumarincarbaldehyde oxime reacted as an azadiene with electron-deficient and electron-rich dienophiles to give, via one-step hetero-Diels-Alder cycloaddition reactions, the corresponding 5H-coumarin[4,3-c]pyridin-5-ones. When excess of the die

Full text of DOI:10.1016/j.tetlet.2008.11.033

Tetrahedron Letters 50 (2009) 448–451
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Tetrahedron Letters
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Unexpected one-pot synthesis of new polycyclic coumarin[4,3-c]pyridine
derivatives via a tandem hetero-Diels–Alder and 1,3-dipolar
cycloaddition reaction
Daman R. Gautam a, John Protopappas a, Konstantina C. Fylaktakidou b, Konstantinos E. Litinas a,
,
*
a,
Demetrios N. Nicolaides a, , Constantinos A. Tsoleridis
*
*
a Laboratory of Organic Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
b Molecular Biology and Genetics Department, Democritus University of Thrace, 68100 Alexandroupolis, Greece
a r t i c l e i n f o
a b s t r a c t
Article history:
O-Methyl-4-coumarincarbaldehyde oxime reacted as an azadiene with electron-deficient and electron-
rich dienophiles to give, via one-step hetero-Diels–Alder cycloaddition reactions, the corresponding
5H-coumarin[4,3-c]pyridin-5-ones. When excess of the dienophile was used, fused azatetracyclo deriva-
tives were also formed via a tandem Diels–Alder and 1,3-dipolar cycloaddition reaction of the dienophile
to an azomethine ylide formed by the intermediate 2,3-dihydro-5H-coumarin[4,3-c]pyridine-5-one. The
regio- and stereoselectivities of the new compounds correspond well with spectroscopic (2D NMR) and
theoretical data. A possible mechanistic scheme is provided.
Received 16 October 2008
Revised 4 November 2008
Accepted 11 November 2008
Available online 17 November 2008
Keywords:
1-Azadienes
Azomethine ylide
Coumarins
Ó 2008 Elsevier Ltd. All rights reserved.
1,3-Dipolar cycloadditions
Hetero-Diels–Alder reactions
Pyridocoumarins
Coumarins represent a class of naturally and synthetically
obtained compounds that possess a wide variety of biological
activities,1,2 often depending on the substituent they bear on their
main benzopyran skeleton. Introduction of an oxy-imino type link-
age at the allylic position with respect to the biogenetic C3@C4
double bond in the form of oximes, amidoximes, oxadiazoles,
isoxazolines, etc. has resulted in compounds with promising anti-
proteolytic, antioxidant, and antiinflammatory properties.3 Fused
3,4-heterocyclic coumarin derivatives2,4 also exhibit a wide range
of biological activities. Specifically, those bearing a benzopyran-
one–pyridine or piperidine skeleton (Fig. 1) were found to interact
with DNA,5 to transfer energy in photophysical processes,6 to be
potential platelet activating factor antagonists,7 depressant or
hypotensive activators8 and potent antipsychotic agents,9 whereas
others exhibited antibacterial,10 antitumor,11 anticholinergic,12
and antimicrobial13 activities. Finally, some naturally occurring
fused heterocyclic chromone alkaloids, such as shumanniophytine
and isoshumanniophytine, were found to possess antiviral
activity.14
X
Y
X
Y
R2
R1
C N
N C
O
O
Figure 1. Coumarin[3,4-c] or [4,3-c]pyridine derivatives.
The preparation of polyheterocyclic nitrogen-containing
compounds, which are found in nature or of synthetic origin, via
hetero-Diels–Alder (HDA) reactions is well documented in the
literature.15–17
1-Azadienes have been reported to undergo HDA reactions, but
with poor conversions of the starting materials.16 Introduction of a
nitrogen atom at position 1 of the diene creates a
p electron-
deficient system, and thus lowering its reactivity in the normal
HOMOdiene-controlled [4+2] HDA cycloaddition reactions with
electron-poor dienophiles. Electronic effects on both the diene
and the dienophile seem to affect the formation of the cycloadduct,
whereas catalysis or variation in the reaction conditions has been
shown to improve the reaction efficiency to only a limited extent.16
Our interest in coumarins as pharmacophores and synthetic
intermediates2,3,18 prompted us to investigate the synthesis of
coumarin[4,3-c]pyridine derivatives in an effort to provide a
convenient and convergent approach for their preparation. Until
* Corresponding authors. Tel.: +30 2310 997864; fax: +30 2310 997679.
E-mail addresses: klitinas@chem.auth.gr (K. E. Litinas), tsolerid@chem.auth.gr
(C. A. Tsoleridis).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.033

D. R. Gautam et al. / Tetrahedron Letters 50 (2009) 448–451
449
now, the synthesis of these compounds19 had been realized via
1 + H2C
CHCOOEt
procedures, often multistep, utilizing as precursors, substituted
four-membered 2-aryl-cyclic nitrones,20 o-cyanocarbonyl-couma-
rin derivatives,21 and suitably substituted oxopiperidinecarboxy-
lates,8 aryl-4-picolines,22 quinolinones,23 and quinolines.24 To the
best of our knowledge, the application of HDA reactions on the
coumarin nucleus is limited.25 The expected coumarin derivatives,
besides their presumable biological activity, are anticipated to be
useful as synthons for the construction of other heterocyclic scaf-
folds, due to the fertile chemistry of the lactone ring,23,24 and the
variation of the substituents on both the coumarin and pyridine
rings.
5
14
CH2COOEt
13
COOEt
EtOOC
CH2
9
10
COOEt
12
N
H
COOEt
N
COOEt
N
11
1
8
7
10
7
1
9
4
2
3
+
+
5
8
6
O
O
O
O
O
O
4
Treatment of O-methyl-4-coumarincarbaldehyde oxime3c (1)
with equimolar amounts of the electron-deficient N-methyl- or
N-phenylmaleimides 2a–b in refluxing xylene for 24 h afforded
coumarin[4,3-c]pyridines 3a (46%) and 3b (38%), respectively
(Scheme 1). When the reaction of 1 was performed in the presence
of 3 equiv of maleimide 2b in refluxing xylene for 24 h, the
unexpected bis-cycloadduct 4 (24%) was formed along with 3b
(50%).
6
7
8
Scheme 2. HDA reaction of 1 with ethyl acrylate in excess as solvent.
OCH3
(CH2)3CH3
O
N
N
MS spectrometry and extensive 2D NMR studies allowed us to
assign structure 4.
+
H2C
C
O
O
O
O
H
The reaction of 1 with ethyl acrylate, used in excess as solvent
(5, bp 99 °C), at reflux for 6 days, resulted after separation, in a
complex mixture of the 3-ethoxycarbonyl-coumarin[4,3-c]pyri-
dine (6, 35%), the bis-cycloadduct 7 (24%) analogous to 4, and an-
other unexpected product26 8 (9%), formed after Michael addition
of 7 to another molecule of ethyl acrylate. Some starting material
was also recovered (15%). Extensive 2D NMR studies allowed us
to assign structures 7 and 8 (Scheme 2).
Next, we tested the reactivity of diene 1 with electron-rich
dienophiles. Therefore, 1 was treated with butyl vinyl ether (9,
bp 94 °C), used in excess as a solvent, under reflux for 8 days to
afford the known22 coumarin[4,3-c]pyridine (10) in 36% yield,
while a significant amount of the starting material (59%) remained
unchanged (Scheme 3).
1
9
10
Scheme 3. HDA reaction of 1 with butyl vinyl ether in excess as solvent.
b
OCH3
R2
H
R2
N
N
H
a
CHR2
R1
R1
-CH3OH
1
+
H
a
O
CHR1
O
O
O
11
12
13
A combination of the mechanistic pathways depicted in Scheme
4 is used to explain the experimental results. Elimination of meth-
anol from the initially formed cycloadduct 12 yields the unstable
intermediate 13. The latter is able to undergo air oxidation (path
a) to give the fully aromatized derivative 14. However, it is known
path a
R2
R1
R2 = ester or
amide group,
11 in excess
N
-2H
path b
O
O
that thermally induced 1,2-prototropic rearrangement of a-amino
acid imines leads to the formation of azomethine ylides.27
14
2
1
R HC CHR
2
1
R
R
O
H
H
2
2
2
R
R
N
R
N
OCH3
N
H
N
1
1
1
R
R
R
O
O
O
O
O
O
+
N
R
16
15b
15a
O
O
O
Scheme 4. Proposed mechanistic pathways.
1
2a-b
a
R = CH3
R = Ph
b
Analogously, when R2 is an ester or amide group, intermediate
13 most probably gives in our case ylide 15 (path b), which in
the presence of excess dienophile undergoes a subsequent 1,3-
dipolar cycloaddition reaction to afford the tetracyclic derivative
16.
The regioselectivities of the HDA and 1,3-dipolar cycloaddition
reactions were confirmed by NMR analysis of the products.
Regarding the HDA reaction, a theoretical study involving calcula-
tions of both HOMOdiene and LUMOdienophile energies (AM1)28,29 led
to the same preferred structures for the intermediate 12 being fully
in accordance with the experimental results. In Figure 2, the
Ph
O
N
N
O
O
N R
O
+
O
N
H
O
O
N
Ph
O
3a-b
O
O
4
Scheme 1. HDA reactions of 1 with maleimides 2a–b.

450
D. R. Gautam et al. / Tetrahedron Letters 50 (2009) 448–451
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1
Favored TSa
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Int. Ed. 2000, 39, 3558–3588; (c) Carruthers, W. In Cycloaddition Reactions in
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Weinreb, S. M. In Hetero Diels Alder Methodology in Organic Synthesis;
C1–C2 = 1.425c
C2–C3 = 1.426
C3–N4 = 1.332
C5–C6 = 1.405
C1–C5 = 1.738
N4–C6 = 2.577
ΔG#TS = 36.81d
C1–C2 = 1.371
C2–C3 = 1.438
C3–N4 = 1.341
C5–C6 = 1.406
C1–C6 = 2.512
N4–C5 = 1.618
ΔG#TS = 41.87
-
e
-
= –591
= –517
ν
ν
ΔΔG#TS = 5.06 kcal/molf
Figure 2. Transition structures optimized at the AM1 level for the interaction of 1
with acrylate 5. (a) TS1: Favored approach of reactants leading to product 6. (b) TS2:
Approach of reactants not leading to products. (c) Bond lengths in Angstroms (Å).
(d) D
G#TS for the transition state in kcal/mol. (e) The imaginary IR frequency for the
newly formed bond. (f) The energy preference of TS1 versus TS2. The numbering of
atoms is arbitrary; only the reacting atoms are indicated.
Academic: San Diego, 1987; Chapters
2 and 9; (e) Weinreb, S. M. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Paquette, L. A., Eds.;
Pergamon: Oxford, 1991; (f) Buonora, P.; Olsen, J. C.; Oh, T. Tetrahedron 2001,
57, 6099–6138; (g) Nicolaides, D. N.; Awad, R. W.; Papageorgiou, G. K.;
Stephanidou-Stephanatou, J. J. Org. Chem. 1994, 59, 1083–1086.
18. (a) Emmanuel-Giota, A.; Fylaktakidou, K. C.; Hadjipavlou-Litina, D. J.; Litinas, K.
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Nicolaides, D. N. J. Chem. Soc., Perkin Trans. 1 2001, 3073–3079; (c) Nicolaides,
D. N.; Gautam, D. R.; Litinas, K. E.; Hadjipavlou-Litina, D.; Fylaktakidou, K. C.
Eur. J. Med. Chem. 2004, 39, 323–332.
19. Mandal, T. K.; Kuznetsov, V. V.; Soldatenkov, A. T. Chem. Heterocycl. Compd.
1994, 30, 867–887.
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1989, 45, 3131–3138.
21. Chandrasekhar, A.; Padmanabhan, P.; Seshadri, S. Indian J. Chem. 1986, 25B,
137–140.
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transition structures TS1 and TS2 optimized at AM1 level for the
interaction of 1 with acrylate 5 are depicted. The bond lengths
involved in the new cyclohexene ring and the free energy of activa-
tion
D
G# of the activated complex along with the vibrating
frequency of the shorter newly formed bond at 372 K are given.
From both methods, the methylene carbon is predicted to react
first with the diene moiety, since the newly formed bonds (in red
color) of the methylene carbon are shorter in both TS1 and TS2.
On the other hand, the regioselectivity of azomethine imines in
1,3-dipolar cycloaddition reactions with monosubstituted dipol-
arophiles, as in the case of 5, is general well predicted30 and again
in agreement with the obtained results.
In conclusion, we have demonstrated a one-step method for the
construction of complex coumarin[4,3-c]pyridine or piperidin-5-
one polycyclic derivatives in a complete regio- and stereoselective
manner, in moderate overall yields. The direct formation of bis-
cycloadducts 4, 7, and 8 via a unique and novel HDA/1,3-dipolar
cycloaddition pathway opens a new approach toward the facile
one-pot synthesis of complicated heterocyclic scaffolds. Exploita-
tion of these results and further optimization regarding the reac-
tion conditions will be our next goal.
23. Kawase, Y.; Yamaguchi, S.; Maeda, O.; Hayashi, A.; Hayashi, I.; Tabata, K.;
Kondo, M. J. Heterocycl. Chem. 1979, 16, 487–491.
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Heterocycl. Chem. 1989, 26, 281–284; (b) Takagi, K.; Hubert-Habart, M.;
Cheutin, A.; Royer, R.; Desvoye, M.-L. Bull. Soc. Chim. Fr. 1966, 10, 3136–3139.
25. (a) Boger, D. L.; Kasper, A. M. J. Am. Chem. Soc. 1989, 111, 1517–1519; (b) Boger,
D. L.; Nakahara, S. J. Org. Chem. 1991, 56, 880–884; (c) Boger, D. L.; Corbett, W.
L.; Curran, T. T.; Kasper, A. M. J. Am. Chem. Soc. 1991, 113, 1713–1729.
26. A solution of oxime ether 1 (0.250 g, 1.23 mmol) in ethyl acrylate (5 mL) was
heated at reflux (100 oC) for 6 days. The reaction mixture was concentrated on
a rotary evaporator, and the residue was purified by chromatography on silica
gel (hexane/EtOAc, 4:1 up to 3:1) to afford in order of elution: unreacted oxime
1 (0.038 g, 15%). Compound 8 (0.045 g, 9%); mp 109–110 oC (ethanol–ether). IR
(Nujol) mmax 1742, 1730, 1720, 1605 cmÀ1 1H NMR (CDCl3, 300 MHz): 1.21 (t,
.
Acknowledgments
J = 7.2 Hz, 3H, 14-CH2CH3), 1.33 (t, J = 7.2 Hz, 3H, 10-CH2CH3), 1.37 (t, J = 7.2 Hz,
3H, 8-CH2CH3), 2.11 (dt, J = 11.0, 4.2 Hz, 1H, 9-Ha), 2.53 (dd, J = 7.1, 2.2 Hz, 2H,
14-H), 2.60 (m, 1H, 13-H), 2.69 (d, J = 19.2 Hz, 1H, 7-Ha), 2.94 (dt, J = 11.0,
2.7 Hz, 1H, 9-Hb), 2.96 (dd, J = 4.2, 2.7 Hz, 1H, 10-H), 3.00 (m, 1H, 13-H), 3.03
(dd, J = 19.2, 1.5 Hz, 1H, 7-Hb), 4.053/4.066 (q, J = 7.2 Hz, 2H, 14-OCH2), 4.269/
4.272 (q, J = 7.2 Hz, 2H, 10-OCH2), 4.279/4.290 (q, J = 7.2 Hz, 2H, 8-OCH2), 5.05
(s, 1H, 11-H), 7.37 (ddd, J = 8.1, 7.2, 1.2 Hz, 1H, 2-H), 7.39 (dd, J = 8.5, 1.2 Hz, 1H,
4-H), 7.56 (ddd, J = 8.5, 7.2, 1.4 Hz, 1H, 3-H), 7.72 (dd, J = 8.1, 1.4 Hz, 1H, 1-H).
13C NMR (CDCl3, 75 MHz) d 14.06 (14-OCH2CH3), 14.10 (10-OCH2CH3), 14.2 (8-
OCH2CH3), 28.5 (C-7), 34.5 (C-14), 38.2 (C-9), 40.9 (C-13), 49.5 (C-10), 59.1 (C-
11), 60.4 (14-OCH2), 61.2 (10-OCH2), 61.5 (8-OCH2), 65.3 (C-8), 117.3 (C-4),
117.7 (C-11b), 119.2 (C-6a), 122.7 (C-1), 124.6 (C-2), 131.4 (C-3), 147.4 (C-11a),
152.7 (C-4a), 160.5 (C-6), 171.6 (10-CO), 172.02 (14-CO), 172.09 (8-CO). MS
(ESI) 472 [M+H]+, 494 [M+Na]+. HRMS calcd for C25H29LiNO8 [M+Li]+:
478.2048, found: 478.1997.
D.R. Gautam thanks State Scholarships Foundation (IKY),
Greece, for financial support and Tribhuvan University, Katmandu,
Nepal, for granting him the PhD study leave.
References and notes
1. Murray, R. D. H.; Mendez, J.; Brown, R. A. The Natural Coumarins; John Wiley &
Sons: New York, 1982.
2. Fylaktakidou, K. C.; Hadjipavlou-Litina, D. J.; Litinas, K. E.; Nicolaides, D. N. Curr.
Pharm. Des. 2004, 10, 3813–3833.
3. (a) Nicolaides, D. N.; Fylaktakidou, K. C.; Litinas, K. E.; Hadjipavlou-Litina, D. J.
Eur. J. Med. Chem. 1998, 33, 715–724; (b) Nicolaides, D. N.; Fylaktakidou, K. C.;
Litinas, K. E.; Hadjipavlou-Litina, D. J. J. Heterocycl. Chem. 1998, 35, 619–625; (c)
Nicolaides, D. N.; Fylaktakidou, K. C.; Litinas, K. E.; Hadjipavlou-Litina, D. J. J.
Heterocycl. Chem. 1996, 33, 967–971.
Compound 6 (0.099 g, 35%); mp 236–237 oC (hexane–EtOAc). IR (Nujol) mmax
1730, 1710, 1610 cmÀ1 1H NMR (CDCl3, 300 MHz) d 1.49 (t, J = 7.3 Hz, 3H, 3-
.
OCH2CH3), 4.55 (q, J = 7.3 Hz, 2H, 3-OCH2), 7.43–7.49 (m, 2H, 7-H, 9-H), 7.64
(dd, J = 7.8, 7.3 Hz, 1H, 8-H), 8.25 (d, J = 7.5 Hz, 1H, 10-H), 8.95 (s, 1H, H-4),
4. Darbarwar, V.; Sundaramurthy, V. Synthesis 1982, 337–388.

D. R. Gautam et al. / Tetrahedron Letters 50 (2009) 448–451
451
9.66 (s, 1H, 1-H). 13C NMR (CDCl3, 75 MHz) d 14.3 (CH3), 62.4 (CH2), 115.1
(C-10a), 118.3 (C-7), 123.2 (C-10), 124.2 (C-9), 125.5 (C-4), 127.6 (C-4a), 131.3
(C-10b), 132.6 (C-8), 145.7 (C-1), 147.9 (C-3), 152.3 (C-6a), 163.9 (C-5), 168.1
(3-C@O). MS (ESI) 270 (M+H)+. Anal. Calcd for C15H11NO4: C, 66.91; H, 4.12; N,
5.20. Found: C, 66.75; H, 4.10; N, 5.09.
NMR (CDCl3, 75 MHz) d 14.19 (10-OCH2CH3), 14.23 (8-OCH2CH3), 35.8 (C-7),
38.8 (C-9), 52.8 (C-10), 58.1 (C-11), 61.68 (10-OCH2), 61.76 (8-OCH2), 65.2
(C-8), 116.8 (C-11b), 117.4 (C-4), 119.1 (C-6a), 122.7 (C-1), 124.7 (C-2), 131.4
(C-3), 150.0 (C-11a), 153.0 (C-4a), 161.2 (C-6), 172.76 (10-CO), 172.84 (8-CO).
MS (ESI) 372 [M+H]+. HRMS calcd for C20H21LiNO6 [M+Li]+: 378.1523, found:
378.1496.
Compound 7 (0.092 g, 24%); mp 151–153 oC (hexane–EtOAc). IR (Nujol) mmax
3400, 1735, 1715, 1605 cmÀ1
.
1H NMR (CDCl3, 300 MHz) d 1.347 (t, J = 7.1 Hz,
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3H, CH3), 1.349 (t, J = 7.2 Hz, 3H, CH3), 2.26 (dd, J = 13.7, 9.0 Hz, 1H, 9-Ha), 2.53
(ddd, J = 13.7, 3.1, 1.7 Hz, 1H, 9-Hb), 2.89 (d, J = 18.4 Hz, 1H, 7-Ha), 2.99 (br s,
1H, NH), 3.03 (dd, J = 18.4, 1.7 Hz, 1H, 7-Hb), 3.19 (dd, J = 9.0, 3.1 Hz, 1H, 10-Ha),
4.27 (q, J = 7.1 Hz, 2H, OCH2), 4.32 (dq, J = 7.2, 2.6 Hz, 2H, OCH2), 5.01 (br s, 1H,
11-H), 7.35 (ddd, J = 8.2, 7.0, 1.2 Hz, 1H, 2-H), 7.37 (dd, J = 8.5, 1.2 Hz, 1H, 4-H),
7.55 (ddd, J = 8.5, 7.0, 1.4 Hz, 1H, 3-H), 7.65 (dd, J = 8.2, 1.4 Hz, 1H, 1-H). 13C