Povarov reactions involving 3-aminocoumarins: Synthesis of 1,2,3,4-tetrahydropyrido[2,3-c]coumarins and pyrido[2,3-c]coumarins

Article abstract of DOI:10.1021/jo801411p

(Chemical Equation Presented) Condensation of 3-aminocoumarin (5) with 4-nitrobenzaldehyde (8) afforded a 2-azadiene (9), which reacted with various electron-rich alkenes (10 examples) in the presence of Yb(OTf)₃ to afford 1,2,3,4-tetrahydropyrido[2,3-c]coumarins. Yields were generally good, but the diastereomeric ratios were highly variable. The products arose through a formal [4 + 2] cycloaddition (inverse electron demand Diels-Alder reaction) followed by tautomerization. As such, these are examples of the Povarov reaction. A range of 1,2,3,4-tetrahydropyrido[2,3-c]coumarins was then synthesized using a three-component version of this reaction, which involves in situ formation of the 2-azadiene component. Some of these products were converted into the corresponding pyrido[2,3-c]coumarins upon treatment with various oxidants, the most effective of which proved to be nitrous gases.

Full text of DOI:10.1021/jo801411p

Povarov Reactions Involving 3-Aminocoumarins: Synthesis of
1,2,3,4-Tetrahydropyrido[2,3-c]coumarins and
Pyrido[2,3-c]coumarins
Amit A. Kudale,† Jamie Kendall,† David O. Miller,‡ Julie L. Collins,‡ and
Graham J. Bodwell*,†
Department of Chemistry, Memorial UniVersity, St. John′s, NL, Canada A1B 3X7, and CREAIT Network,
Memorial UniVersity, St. John′s, NL, Canada A1C 5S7
gbodwell@mun.ca
ReceiVed July 21, 2008
Condensation of 3-aminocoumarin (5) with 4-nitrobenzaldehyde (8) afforded a 2-azadiene (9), which
reacted with various electron-rich alkenes (10 examples) in the presence of Yb(OTf)3 to afford 1,2,3,4-
tetrahydropyrido[2,3-c]coumarins. Yields were generally good, but the diastereomeric ratios were highly
variable. The products arose through a formal [4 + 2] cycloaddition (inverse electron demand Diels-Alder
reaction) followed by tautomerization. As such, these are examples of the Povarov reaction. A range of
1,2,3,4-tetrahydropyrido[2,3-c]coumarins was then synthesized using a three-component version of this
reaction, which involves in situ formation of the 2-azadiene component. Some of these products were
converted into the corresponding pyrido[2,3-c]coumarins upon treatment with various oxidants, the most
effective of which proved to be nitrous gases.
Introduction
Povarov initially described the participation of aldimines derived
from aniline and aromatic aldehydes in a formal [4 + 2]
cycloaddition with electron-rich alkenes (rendering it a formal
inverse electron demand Diels-Alder reaction) in the presence
of a Lewis acid catalyst and the subsequent tautomerization of
the initial adduct to give 1,2,3,4-tetrahydroquinoline derivatives
(eq 1, Scheme 1).5 It was only much later that this reaction
was developed into a one-pot operation (MCR), in which the
aldimine was generated in situ.6 In fact, this development
triggered an ongoing period of considerable interest in the
Multicomponent reactions (MCRs) continue to attract atten-
tion as they can result in a substantial increase in molecular
complexity and provide opportunities for high levels of con-
vergence in synthesis.1 The use of MCRs has therefore been
frequently adopted by the pharmaceutical industry for the
development of combinatorial libraries and the identification
of lead compounds.2 MCRs have also been utilized in the total
synthesis of natural products.3
The inherent reactivity of carbonyl compounds with amines
is often exploited in the development of MCRs.4 The one-pot
version of the Povarov reaction is such an example. In its
original form, however, the Povarov reaction was not an MCR.
(2) (a) Blackwell, H. E. Curr. Opin. Chem. Biol. 2006, 10, 203–212. (b)
Do¨mling, A. Chem. ReV. 2006, 106, 17–89. (c) Bra¨uer, S.; Almstetter, M.;
Antuch, W.; Behnke, D.; Taube, R.; Furer, P.; Hess, S. J. Comb. Chem. 2005,
7, 218–226. (d) Shoda, M.; Harada, T.; Kogami, Y.; Tsujita, R.; Akashi, H.;
Kouji, H.; Stahure, F. L.; Xue, L.; Bajorath, J. J. Med. Chem. 2004, 47, 4286–
4290. (e) Ugi, I.; Werner, B.; Do¨mling, A. Molecules 2003, 8, 53–66. (f) Hulme,
C.; Gore, V. Curr. Med. Chem. 2003, 10, 51. (g) Do¨mling, A. Curr. Opin. Chem.
Biol. 2000, 4, 318–323.
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Minassi, A.; Palmisano, G. Eur. J. Org. Chem. 2001, 3711–3717. (b) Eurystatin
A: Schmidt, U.; Weinbrenner, S. J. Chem. Soc., Chem. Commun. 1994, 100,
3–1004. (c) (()-Magnoshinin. Yoshida, S.; Ogiku, T.; Ohmizu, H.; Iwasaki, T.
Synlett 1994, 895–898. (d) (-)-Decarbamoylsaxitoxin. Yong, C.; Kishi, Y. J. Am.
Chem. Soc. 1992, 114, 7001–7006. (e) (+)-Furanomycin. Semple, J. E.; Wang,
P. C.; Lysenko, Z.; Joullie´, M. M. J. Am. Chem. Soc. 1980, 102, 7505–7510.
† Department of Chemistry.
‡ CREAIT Network.
(1) For review articles on multicomponent reactions see: (a) Tejedor, D.;
Garcia-Tellado, F. Chem. Soc. ReV. 2007, 36, 484–491. (b) Zhu, J.; Bienayme´,
H. In Multicomponent Reactions; Wiley-VCH: Weinheim, 2005. (c) Orru,
R. V. A.; de Greef, M. Synthesis 2003, 1471–1499. (d) Bienayme´, H.; Hulme,
C.; Oddon, G.; Schmitt, P. Chem. Eur. J. 2000, 6, 3321–3329. (e) Do¨mling, A.;
Ugi, I. Angew. Chem. 2000, 112, 3300–3344; Angew. Chem., Int. Ed. 2000, 39,
3168-3210. (f) Nefzi, A.; Ostresh, J. M.; Houghten, R. A. Chem. ReV. 1997,
97, 449–472. (g) Armstrong, R. W.; Combs, A. P.; Tempest, P. A.; Brown, S. D.;
Keating, T. A. Acc. Chem. Res. 1996, 29, 123–131.
10.1021/jo801411p CCC: $40.75
Published on Web 09/27/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 8437–8447 8437

Kudale et al.
SCHEME 1. Povarov Reaction
Batey and Mene´ndez have independently shown that aliphatic
aldehydes or aldehyde equivalents can be employed under
appropriate conditions (slow addition of the aldehyde or
aldehyde equivalent to the aniline and dienophile in the
presence of a mild Lewis acid).9 This reaction has also been
carried out in the absence of a Lewis acid catalyst by using
fluorous solvents.10 The Povarov reaction has also found
applications in total synthesis, such as in the synthesis of
(()-martinelline, (()-martinellic acid, luotonin A, and camp-
tothecin.11 Nevertheless, it has so far been limited almost
exclusively to the synthesis of tetrahydroquinolines because,
with very few exceptions,12 only anilines have been used
successfully as the amine component. The application of
amines other than anilines, if successful, would provide a
direct route to a variety of heterocycles, which are uncommon
or otherwise not easily accessible.
During the course of our efforts aimed at the development
of new families of electron-deficient dienes for application
in the inverse electron demand Diels-Alder (IEDDA)
reaction,13 we identified coumarin-fused, electron-deficient
2-azadienes as reasonable candidates for reaction with
electron-rich alkenes. In fact, the IEDDA reaction of this
class of dienes, which should be accessible from the
condensation of 3-aminocoumarin with an aldehyde, coin-
cides with the original form of the Povarov reaction.
3-Aminocoumarin has been known for close to a century,
but there are very few reports of imines derived from this
system.14 There are no previous reports of such imines being
used as dienes in the IEDDA (or Povarov) reaction. The
2-pyrone ring of the coumarin system is partially aromatic.15
As such, 3-aminocoumarins behave like enamines in some
cases (e.g., hydrolysis under acidic aqueous conditions)16 and
like anilines in others (e.g., Fischer indole synthesis).17 We
thus envisioned that 3-aminocoumarin would readily form
an aldimine upon reaction with an aldehyde and then take
part in a Povarov reaction in the presence of an electron-
rich alkene and a suitable Lewis acid catalyst. The partial
aromatic character of the pyrone unit would also be expected
to favor the tautomerization of the initial cycloadduct
(Scheme 2).
Povarov reaction,7 which followed nearly three decades of
relative obscurity since Povarov′s original report.8
An important finding in the mid 1990s was that various
lanthanide metal salts catalyze the one-pot Povarov reaction.6
More recently, a variety of cost-effective and environment-
friendly catalysts have been reported by Perumal7a-g and
others.7i-n In general, aliphatic aldehydes have been found
to be poor participants for this type of chemistry. However,
(4) For example: (a) Elders, N.; Schmitz, R. F.; Kanter, F.; Ruijter, E.; Groen,
M. B.; Orru, R. J. Org. Chem. 2007, 72, 6135–6142. (b) Yang, B.-L.; Tian,
S.-K. Eur. J. Org. Chem. 2007, 4646–4650. (c) El Ka¨ım, L.; Gizolme, M.;
Grimaud, L.; Oble, J. J. Org. Chem. 2007, 72, 4169–4180. (d) Bharadwaj, A. R.;
Scheidt, K. A. Org. Lett. 2004, 6, 2465–2468. (e) Allegretti, M.; Berdini, V.;
Cesta, C.; Curti, R.; Nicolini, L.; Topai, A. Tetrahedron Lett. 2001, 42, 4257–
4259. (f) Jo¨nsson, D.; Molin, H.; Unde´n, A. Tetrahedron Lett. 1998, 39, 1059–
1062. (g) Ugi, I.; Steinbru¨ckner, C. Chem. Ber. 1961, 94, 734–742. (h) Ugi, I.
Angew. Chem., Int. Ed. 1961, 18–21. (i) Robinson, R. J. Chem. Soc. 1917, 762–
768.
(5) (a) Povarov, L. S. Russ. Chem. ReV. 1967, 36, 656–670. (b) Povarov,
L. S.; Grigos, V. I.; Makhailov, B. M. IzV. Akad. Nauk. SSSR 1963, 2039–2041.
(c) Povarov, L. S.; Makhailov, B. M. IzV. Akad. Nauk. SSSR 1963, 955–956.
(6) (a) Ma, Y.; Qian, C.; Xie, M.; Sun, J. J. Org. Chem. 1999, 64, 6462–
6467. (b) Kobayashi, S.; Busujima, T.; Nagayama, S. Synlett 1999, 545–546.
(c) Kobayashi, S.; Nagayama, S.; Busujima, T. J. Am. Chem. Soc. 1998, 120,
8287–8288. (d) Kobayashi, S.; Ishitani, H.; Nagayama, S. Synthesis 1995, 1195–
1202. (e) Makioka, Y.; Shindo, T.; Taniguchi, Y.; Takaki, K.; Fuziwara, Y.
Synthesis 1995, 801–804. (f) Kobayashi, S.; Ishitani, H.; Nagayama, S. Chem.
Lett. 1995, 423–424. (g) Kobayashi, S.; Araki, M.; Ishitani, H.; Nagayama, S.;
Hachiya, I. Synlett 1995, 233–234.
(7) For representative publications, see: (a) Sridharan, V.; Perumal, P. T.;
Avendan˜o, C.; Mene´ndez, J. C. Org. Biomol. Chem. 2007, 5, 1351–1353. (b)
Savitha, G.; Perumal, P. T. Tetrahedron Lett. 2006, 47, 3589–3593. (c)
Arumugam, P.; Perumal, P. T. Chem. Lett. 2006, 35, 632–633. (d) Elamparuthi,
E.; Anniyappan, M.; Muralidharan, D.; Perumal, P. T. ARKIVOC 2005, 6–16.
(e) Kumar, R. S.; Nagarajan, R.; Perumal, P. T. Synthesis 2004, 949–959. (f)
Nagarajan, R.; Mangesh, C. J.; Perumal, P. T. Synthesis 2004, 69–74. (g)
Anniyappan, M.; Muralidharan, D.; Perumal, P. T. Tetrahedron Lett. 2003, 44,
3653–3657. (h) Nagarajan, R.; Chitra, S.; Perumal, P. T. Tetrahedron 2001, 57,
3419–3423. (i) Sridharan, V.; Avendan˜o, C.; Mene´ndez, J. C. Tetrahedron 2007,
63, 673–681. (j) Yadav, J. S.; Subba Reddy, B. V.; Srinivas, R.; Madhuri, C. R.;
Sabitha, G. Synlett 2001, 1065–1068. (k) Yadav, J. S.; Subba Reddy, B. V.;
Srinivas, R.; Madhuri, C.; Ramalingam, T. Synlett 2001, 240–242. (l) Yadav,
J. S.; Reddy, B. V. S.; Sadasiv, K.; Reddy, P. S. R. Tetrahedron Lett. 2002, 43,
3853–3856. (m) Maiti, G.; Kundu, P. Tetrahedron Lett. 2006, 47, 5733–5736.
(n) Xia, M.; Lu, Y. Synlett 2005, 2357–2361. (o) Li, Y.; Zhang, J.; Dong, L.;
Yan, M. Chin. J. Chem. 2006, 24, 929–932. (p) Manian, R.; Jayashankaran, J.;
Ramesh, R.; Ragunathan, R. Tetrahedron Lett. 2006, 47, 7571–7574. (q) Han,
B.; Jia, X.-D.; Jin, X.-L.; Zhou, Y.-L.; Yang, L.; Liu, Z.-L.; Yu, W. Tetrahedron
Lett. 2006, 47, 3545–3547. (r) Zhou, Y.; Xiaodong, J.; Rui, L.; Zhengang, L.;
Zhongli, L.; Longmin, W. Tetrahedron Lett. 2005, 46, 8937–8939. (s) Zhou,
Y.-L.; Jia, X.-D.; Li, R.; Han, B.; Wu, L.-M. Chin. J. Chem. 2007, 25, 422–
425. (t) Gaddam, V.; Nagarajan, R. Tetrahedron Lett. 2007, 48, 7335–7338. (u)
Manina, R.; Jayashankaran, J.; Raghunathan, R. Tetrahedron Lett. 2007, 48,
4139–4142. (v) Reddy, S. M.; Srinivasulu, M.; Reddy, T. S.; Narsimhulu, M.;
Venkateswarlu, Y. Indian J. Heterocycl. Chem. 2007, 16, 315–316. (w)
Kouznetsov, V. V.; Cruz, U. M.; Zubkov, F. I.; Nikitina, E. V. Synthesis 2007,
375–384. (x) Sridharan, V.; Avendan˜o, C.; Mene´ndez, J. C. Synthesis 2008, 1039–
1044. Also see ref 5.
SCHEME 2. Povarov Reaction Involving 3-Aminocoumarin
Results and Discussion
For the initial study of the proposed IEDDA reactions, the
coumarin-fused 2-azadiene 9 was prepared by the condensation
of 3-aminocoumarin (5)18 and 4-nitrobenzaldehyde (8) using
modified Bishnoi conditions (Scheme 3).19 Based on our
previous experience13 of using enamines as electron-rich di-
enophiles in the IEDDA reaction, the enamine derived from
(8) (a) Laschat, S.; Noe, R.; Riedel, M. Organometallics 1993, 12, 3738–
3742. (b) Lucchini, V.; Prato, M.; Scorrano, G.; Stivanello, M.; Valle, G. J. Chem.
Soc. Perkin Trans. 2 1992, 259–266. (c) Grieco, P. A.; Bahsas, A. Tetrahedron
Lett. 1988, 29, 5855–5858. (d) Lucchini, V.; Prato, M.; Scorrano, G.; Tecilla, P.
J. Org. Chem. 1988, 53, 2251–2258. (e) Worth, D. F.; Elslager, E. F.; Perricone,
S. C. J. Heterocycl. Chem. 1974, 11, 69–70.
8438 J. Org. Chem. Vol. 73, No. 21, 2008

PoVaroV Reactions InVolVing 3-Aminocoumarins
SCHEME 3. Reaction between an Enamine and Coumarin-Fused 2-Azadiene 9
SCHEME 4. Povarov Reaction between Diene 9 and DHP (12)
cyclopentanone and pyrrolidine was reacted with 2-azadiene 9
at room temperature for 1 h. Disappointingly, an inseparable
mixture of diastereomeric products 10 arising from 1,2-addition
to the imine was obtained (95% yield). Several attempts to
cyclize these products to the desired cyclic/aromatized systems
under Lewis acid catalysis failed (Scheme 3).20
The use of cyclic vinyl ethers, another commonly used class
of electron-rich dienophiles in the IEDDA reaction, was then
investigated. Accordingly, 3,4-dihydro-2H-pyran (DHP, 3.0
equiv) was allowed to react with diene 9 in the presence of 5
mol % Yb(OTf)3 (Scheme 4). Gratifyingly, a 36:64 mixture of
diastereomeric products arising from the anticipated Povarov
reaction was isolated in 90% combined yield.21 The two
diastereomers were formally the products of endo and exo
addition in an IEDDA reaction followed by tautomerization of
the initial cycloadduct. No other product was isolated from this
reaction. The relative stereochemistry was determined using
standard 1D and 2D NMR techniques. Although the retention
of the relative stereochemistry of the dienophile in both adducts
is entirely consistent with a concerted mechanism, a stepwise
mechanism cannot be ruled out.22 If a stepwise mechanism is
operating, the ring closure must occur in a highly diastereose-
lective fashion.
A series of other dienophiles were reacted with diene 9
under similar reaction conditions (Table 1). Reactions were
initially run at room temperature, and those that showed no
signs of progress after several hours were heated at reflux.
With the exception of ethyl vinyl ether (entry 5, 25%), the
yields were generally good (61-90%). However, the endo/
1
exo ratios, which (like 13a,b) were determined by H NMR
analysis of the crude reaction mixtures, did not appear to
follow any clear trend. Selectivities ranged from >95:5
(entries 6, 8, 10) to 8:92 (entry 7). As expected, the reaction
proceeded more rapidly as the dienophile became more
electron-rich. Vinyl ethers (entries 1, 2, 5) reacted faster than
phenyl vinyl sulfide (entry 4) and N-vinylpyrrolidinone (entry
3). The rates of reactions of the styrene derivatives (entries
7-9) were influenced significantly by the nature of the
substituent at the 4-position (Br < H < OMe),23 which is
consistent with the development of significant positive charge
at the benzylic position of the dienophile at the transition
state. This would be expected for both an asynchronus
concerted mechanism and a stepwise mechanism.
(9) (a) Powell, D. A.; Batey, R. A. Tetrahedron Lett. 2003, 44, 7569–7573.
Also see refs 7k and 10b.
(10) (a) Legros, J.; Crousse, B.; Ourevitch, M.; Bonnet-Delpon, D. Synlett
2006, 1899–1902. (b) Spanedda, M. V.; Hoang, V. D.; Crousse, B.; Bonnet-
Delpon, D.; Be´gue´, J.-P. Tetrahedron Lett. 2003, 44, 217–219.
(11) (a) Twin, H.; Batey, R. A. Org. Lett. 2004, 6, 4913–4916. (b) Powell,
D. A.; Batey, R. A. Org. Lett. 2002, 4, 2913–2916. Also see: (c) Batey, R. A.;
Powell, D. A. Chem. Commun. 2001, 2362–2363. (d) Hadden, M.; Nieuwen-
huyzen, M.; Osborne, D.; Stevenson, P. J.; Thompson, N.; Walker, A. D.
Tetrahedron 2006, 62, 3977–3984.
(12) Povarov, L. S. Chem. Heterocycl. Compd. (N. Y.) 1979, 1694–1695.
(13) (a) Dang, A.-T.; Miller, D. O.; Dawe, L. N.; Bodwell, G. J. Org. Lett.
2008, 10, 233–236. (b) Bodwell, G. J.; Hawco, K. M.; Satou, T. Synlett 2003,
879–881. (c) Bodwell, G. J.; Hawco, K. M.; da Silva, R. P. Synlett 2003, 179–
182. (d) Bodwell, G. J.; Pi, Z.; Pottie, I. R. Synlett 1999, 477–479. (e) Bodwell,
G. J.; Pi, Z. Tetrahedron Lett. 1997, 38, 309–312.
(14) (a) Kulkarni, Y. D.; Srivastava, D.; Bishnoi, A.; Dua, P. R. J. Indian
Chem. Soc. 1996, 73, 173–175. (b) Tripathy, P. K.; Mukerjee, A. K. Indian
J. Chem. 1987, 26B, 61–62. (c) Kumar, P.; Mukerjee, A. K. Indian J. Chem.
1980, 19B, 704–707. (d) Linch, F. W. J. Chem. Soc. 1912, 101, 1759–1765. (e)
Linch, F. W. J. Chem. Soc. 1912, 101, 1755–1759.
(15) Osborne, A. G.; Cremlyn, R. J.; Warmsley, J. F. Spectrochim. Acta,
Part A 1995, 51, 2525–2530.
(16) (a) Trivedi, K.; Sethna, S. J. Org. Chem. 1960, 25, 1817–1819. (b)
Chakravarti, D.; Dutta, S. P.; Mitra, A. K. Curr. Sci. 1965, 177.
(17) Khan, M. A.; Lucia, M. Bol. Soc. Quim. Peru 1979, 45, 42–45.
(18) Kudale, A. A.; Kendall, J.; Warford, C. C.; Wilkins, N. D.; Bodwell,
G. J. Tetrahedron Lett. 2007, 48, 5077–5080.
(19) 4 Å molecular sieves were added to the reaction mixture, and the rest
of the procedure was same as reported by Bishnoi; see ref 14e.
(20) The use of 10 mol % AlCl3, BiCl3, and Yb(OTf)3 resulted in no reaction
at either room temperature or reflux in tetralin.
Having established thatcoumarin-fused 2-azadiene 9 par-
ticipates in the Povarov reaction with various electron-rich
dienophiles, the possibility of developing this reaction into
(21) The diastereomeric ratio was determined from 1H NMR analysis of crude
reaction mixture.
(22) For some discussions on concerted and stepwise mechanisms of Diels-
Alder reactions, see: (a) Bongini, A.; Panunzio, M. Eur. J. Org. Chem. 2006,
972–977. (b) Mayr, H.; Ofial, A. R.; Sauer, J.; Schmied, B. Eur. J. Org. Chem.
2000, 2013–2020. (c) Chen, J. S.; Houk, K. N. J. Am. Chem. Soc. 1998, 120,
12303–12309.
(23) At room temperature, the reaction with 4-bromostyrene showed no signs
of progress after 4 h. So, it was then heated at reflux.
J. Org. Chem. Vol. 73, No. 21, 2008 8439

Kudale et al.
TABLE 1. Povarov Reactions Between Azadiene 9 and Various Electron-Rich Dienophiles
8440 J. Org. Chem. Vol. 73, No. 21, 2008

PoVaroV Reactions InVolVing 3-Aminocoumarins
TABLE 1. Continued
a
Diastereomeric ratios were determined by H NMR analysis of the crude mixtures. b Isolated yields.
1
SCHEME 5. One-Pot Povarov Reaction
products, 33a and 33b, were isolated in a 21:79 ratio in 56%
combined yield (Scheme 6).
Kobayashi and co-workers have shown that various lanthanide
metal salts catalyze the Povarov reaction.6 Therefore, the
performance of Dy(OTf)3 (entry 2) and CeCl3 ·7H2O (entry 3)
were also evaluated in the one-pot reaction. Neither of these
catalysts fared better than the original choice, Yb(OTf)3. Lower
yields (28% and 25%, respectively) and poor diastereselectivity
(43:57 and 38:62, respectively) were obtained. The yields
increased with an increase in the oxophilic character (according
to the oxophilicity scale developed by Imamoto and co-
workers)24 of lanthanide salts. This finding was in agreement
with previous reports on the activity of various lanthanide salts
as Lewis acids.25 Following the reports of the use of cheap and
environmentally benign catalysts for the parent Povarov reaction,
we also studied the effect of catalysts such as molecular iodine
(I2)7n,o (entry 7), potassium hydrogen sulfate (KHSO4)7d (entry
6), and silica gel.26 Silica gel did not catalyze the reaction at
room temperature or reflux (entries 4 and 5). Conversely, I2
and KHSO4 afforded yields and diastereoselectivities compa-
rable to those obtained using Yb(OTf)3.
Using Yb(OTf)3 as the Lewis acid, the effect of solvent was
then investigated. A low yield (10%) and no diastereoselectivity
(50:50) were observed for CHCl3 (entry 11). Although very good
diastereoselectivity (∼1:9) was achieved in polar protic solvents
(methanol and methanol/water), the reaction was very slow.
Traces of one of the starting materials, 3-aminocoumarin (5),
were present in the reaction (by TLC analysis) even after
refluxing for 24 and 48 h, respectively (entries 12 and 13). The
addition of methanol and/or water to the CdN bond of the
2-azadiene may be responsible for the slow reaction of the
azadiene. The use of a somewhat less polar solvent, THF (entry
14), or THF with water as a cosolvent (entry 15) did not improve
the yields (41% and 16%, respectively) as compared to
acetonitrile. It is not obvious why the yield dropped off when
water was a cosolvent, but it does not appear to be attributable
to any reaction between water and the adducts. Stirring a mixture
a one-pot operation, in which the diene would be formed in
situ from 3-aminocoumarin and an aldehyde, was investi-
gated. Indeed, the reaction of 3-aminocoumarin (5), 4-ni-
trobenzaldehyde (8), and DHP (12) in the presence of 5 mol
% Yb(OTf)3 afforded Povarov adducts 13a,b in a ratio (39:
61) similar to that for the reaction of diene 9 with DHP (12)
(36:64), but with a lower yield (40% versus 90%) (Scheme
5). Other products were observed by TLC analysis, but none
of these could be obtained in pure form. The 1H NMR
spectrum of the crude product of this reaction (see Supporting
Information) and those of subsequent three-component Po-
varov reactions typically did not afford much (or any)
information as to the structure of the other products. The
possibility that water generated during the formation of
2-azadiene 9 might have adversely affected the yield was
ruled out when a similar yield (42%) of Povarov adducts
13a,b was obtained when the same reaction was performed
in the presence of anhydrous MgSO4.
The effect of the Lewis acids and solvent on the yield and
diastereoselectivity of the one-pot reaction was then investigated
(Table 2). To this end, a set of reactants was required, the
products of which would be easily separable from the side
products so that the isolated yields and diastereomeric ratios
could be determined easily. After some experimentation, it was
found that the reaction between 3-aminocoumarin (5), 2-naph-
thaldehyde (32), and DHP (12) met this criterion. Under the
previously employed conditions (Table 1), two diastereomeric
(24) Imamoto, T.; Nishiura, M.; Yamanoi, Y.; Tsuruta, H.; Yamaguchi, K.
Chem. Lett. 1996, 875–876.
(25) For representative examples, see: (a) Yamanaka, M.; Nishida, A.;
Nakagawa, M. Org. Lett. 2000, 2, 159–161. (b) Kobayashi, S.; Ishitani, H. J. Am.
Chem. Soc. 1994, 116, 4083–4084.
J. Org. Chem. Vol. 73, No. 21, 2008 8441

Kudale et al.
TABLE 2. Effect of Catalyst and Solvent on Povarov Reaction of 5 with 32 and 12
entry
catalyst
solvent
CH3CN
temp
rt
rt
rt
rt
reflux
rt
rt
endo/exo ratioa
combined yield (%)b
1
2
3
4
5
6
7
8
5 mol % Yb(OTf)3
5 mol % Dy(OTf)3
10 mol % CeCl3 ·7H2O
silica gel
silica gel
40 mol % KHSO4
30 mol % I2
5 mol % Yb(OTf)3
5 mol % Yb(OTf)3
5 mol % Yb(OTf)3
5 mol % Yb(OTf)3
5 mol % Yb(OTf)3
5 mol % Yb(OTf)3
5 mol % Yb(OTf)3
5 mol % Yb(OTf)3
5 mol % Yb(OTf)3
5 mol % Yb(OTf)3
21:79
43:57
38:62
56
28
25
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CHCl3
MeOH
MeOH/H2O
THF
THF/H2O
toluene
DMF
noreaction
noreaction
52
53
44
19
7
10
45
46
41
16
18:82
28:72
15:85
9:91
e5:95
50:50
12:88
8:92
0 °C
9
-20 °C
10
11
12
13
14
15
16
17
-30 °C
rt
reflux
reflux
rt
rt
rt
rt
24:76
53:47
38:62
28
noreaction
a
Diastereomeric ratios were determined by H NMR analysis of crude reaction mixtures. b Isolated yields.
1
SCHEME 6. One-Pot Povarov Reaction between 3-Aminocoumarin (5), 2-Naphthaldehyde (32), and DHP (12)
of adducts 33a,b in THF/water in the presence of 5 mol %
Yb(OTf)3 at room temperature for 1 h and then reflux for 1 h
resulted in the formation of no new products according to TLC
analysis. In a nonpolar solvent, toluene, a low yield (28%) and
a low diastereomeric ratio (38:62) were obtained (entry 16),
whereas in a polar aprotic solvent, DMF, the reaction did not
proceed appreciably after 2 h at room temperature. Except for
CHCl3 and DMF, the yields increased with an increase in the
dielectric constant of the solvent (when the reactions were run
without a cosolvent). Thus, acetonitrile proved to be the best
among the solvents screened.
On the basis of the results of the solvent study, some
comments can be made on the mechanism. If a stepwise
mechanism is in operation, a product arising from the nucleo-
philic addition of methanol to an intermediate oxonium ion
would be expected.6b,7x No such product was isolated from the
above reactions (entries 12 and 13). Moreover, the yield of the
Povarov adducts was not significantly affected. These observa-
tions suggest that, in contrast to the Povarov reactions of aniline-
derived 2-azadienes, the Povarov reactions of 2-azadiene 9 most
likely proceed through a concerted, yet asynchronous, mecha-
nism. The difference in mechanism may be a consequence of
the considerably weaker aromatic character of the 2-pyrone unit
in coumarin-derived azadienes compared to that in the benzene
ring of aniline-derived azadienes. In other words, a concerted
reaction of an aniline-derived azadiene would be disfavored
more than the corresponding reaction of a coumarin-derived
azadiene because of a greater loss of aromatic stabilization
energy in going from the ground state to the transition state.
As anticipated, the diastereomeric ratio could be improved
by lowering the temperature, but this occurred at the expense
of the yield (entries 8-10). Yields of 44%, 19%, and 7% were
obtained when the reactions were performed at 0, -20, and -30
°C, respectively. At -30 °C, the reaction was quite sluggish
and 54% of the starting 3-aminocoumarin (5) was recovered
after running the reaction for 4 h.
On the basis of the preceding optimization studies, it was
decided to test the scope of the one-pot reaction by varying
the three components. To begin with, the aldehyde compo-
nent, which provides C-1 of the azadiene and the substituent
attached to it, was varied while the 3-aminocoumarin (5) and
the dienophile (DHP) were kept constant (Table 3). The
conditions used for the synthesis of 33a,b (entry 1) were
employed. Application of a heterocyclic aldehyde, 3-formyl-
coumarin (34),27 in the three-component reaction with
3-aminocoumarin (5) and DHP (12) in presence of Yb(OTf)3
in acetonitrile (entry 2) proceeded smoothly at room tem-
(26) For examples of silica gel as a Lewis acid, see: (a) Hudlicky, T.; Rinner,
U.; Finn, K. J.; Ghiviriga, I. J. Org. Chem. 2005, 70, 3490–3499. (b) March, P.;
Figueredo, M.; Font, J.; Rodr´ıguez, S. Tetrahedron 2000, 56, 3603–3609. (c)
Kim, D.-K.; Lee, N.; Kim, Y.-W.; Chang, K.; Kim, J. S.; Im, G.-J.; Choi, W.-
S.; Jung, I.; Kim, T.-S.; Hwang, Y.-Y.; Min, D.-S.; Um, K.-A.; Cho, Y.-B.;
Kim, A. H. J. Med. Chem. 1998, 41, 3435–3441.
(27) Pottie, I. R. Ph.D. Dissertation, Memorial University of Newfoundland,
2002.
8442 J. Org. Chem. Vol. 73, No. 21, 2008

PoVaroV Reactions InVolVing 3-Aminocoumarins
TABLE 3. Three-Component Synthesis of Pyrido[2,3-c]coumarins
J. Org. Chem. Vol. 73, No. 21, 2008 8443

Kudale et al.
TABLE 3. Continued
a
Diastereomeric ratios were determined by H NMR analysis of crude mixtures. b Isolated yields are listed. c Numbers in parentheses represent yields
1
obtained by using 1.00:1.05:10.0 ratio of amine:aldehyde:dienophile and 10 mol % catalyst.
perature to afford tetrahydropyrido[2,3-c]coumarins 35a,b in
a ratio of 36:64 in favor of the exo diastereomer and 71%
combined yield. The more electron-deficient nature of the
aldehyde 34 (compared to aldehyde 32) appeared to have a
positive effect on the yield of the Povarov adducts. When
3-aminocoumarin was reacted with methyl 4-formylbenzoate
(36) and DHP (12), Povarov adduct 37b was obtained with
very high selectivity (<5:95) in 54% yield (entry 3). By the
same token, very high selectivity (e5:95) in favor of the
exo diastereomer was obtained when 3-aminocoumarin (5)
was reacted with 4-acetoxybenzaldehyde (38) and DHP (12)
to afford Povarov adduct 39b. However, the yield was only
26% (entry 4). The mild electron-donating ability of the
acetoxy group in 4-acetoxybenzaldehyde, which would be
expected to attenuate the electron-deficient nature of the in
situ formed 2-azadiene, might be responsible for the low
yield. For the highest-yielding reaction in the above set of
reactions (entry 2), changing the dienophile from DHP (12)
to DHF (14) resulted in the formation of Povarov adducts
40a,b in 58% yield. The diastereoselectivity (42:58) was close
to that observed when DHP was used (cf. entries 2 and 5).
Employment of ketone-containing heterocyclic aldehyde 4128
afforded Povarov adducts 42a,b in relatively good yield
(59%, entry 6). Isolation of the endo diastereomer was very
difficult in this reaction. Only the exo diastereomer 42b could
be isolated in pure form. This experiment also demonstrated
that the three-component reaction could be performed in the
presence of a potentially competitive ketone functionality.
When 4-acetoxybenzaldehyde was employed, a low yield
(33%) and poor diastereoselectivity (46:54) were obtained
(entry 7). The reaction had to be heated at reflux for 2.5 days
to achieve complete consumption of the starting 3-aminocou-
marin.
The 3-aminocoumarin was then varied while the dienophile
(DHF) and the aldehyde (methyl 4-formylbenzoate) were kept
constant. In general, all of these reactions afforded low yields
and diastereoselectivities (entries 8-11). In most cases, the
3-aminocoumarins bore an electron-donating substituent on the
carbocyclic ring, which would be expected to deactivate the
(28) Prepared from 4-acetylpyrrole-2-carboxaldehyde by reaction with NaH
and methyl chloroformate. For the preparation of 4-acetylpyrrole-2-carboxalde-
hyde, see: Anderson, H. J.; Loader, C. E.; Foster, A. Can. J. Chem. 1978, 58,
2527–2530.
8444 J. Org. Chem. Vol. 73, No. 21, 2008

PoVaroV Reactions InVolVing 3-Aminocoumarins
TABLE 4. Effect of Catalyst Loading, Concentration of 5, and Ratio of Dienophile on Yield
entry
Yb(OTf)3 (mol %)
concn of 5, ratio of dienophile (equiv)
endo/exo ratioa
combined yield (%)b
1
2
3
4
5
6
7
8
5
10
15
20
10
10
10
10
10
10
10
0.10 M, 3.0
0.10 M, 3.0
0.10 M, 3.0
0.10 M, 3.0
0.10 M, 5.0
0.10 M, 10.0
0.10 M, 15.0
0.10 M, 20.0
0.05 M, 10.0
0.25 M, 10.0
0.50 M, 10.0
21:79
26:74
18:82
24:76
22:78
21:79
19:81
22:78
22:78
21:79
21:79
56
74
72
71
84
89
87
86
89
88
84
9
10
11
a
Diastereomeric ratios were determined by H NMR analysis of crude reaction mixtures. b Isolated yields.
1
SCHEME 7. Reactions of Povarov Adducts 43a and 37b
diene. However, surprisingly, the reaction involving 3-amino-
6-nitrocoumarin (entry 11) afforded the lowest yield of all
(28%). In this case, the formation of the 2-azadiene may have
been retarded. The reaction of 3-amino-8-methoxycoumarin and
4-acetoxybenzaldehyde (38) with DHF under the same reaction
conditions (entry 12) afforded a 60% yield of the Povarov
adducts 48a,b in a 38:62 ratio.
Phenyl vinyl sulfide, when reacted with 3-aminocoumarin (5)
and 4-nitrobenzaldehyde (8), afforded a mixture (59:41) of the
diastereomeric Povarov adducts 18a,b in 38% yield (entry 13).
It is interesting to note that the formation of the endo
diastereomer is preferred in this reaction. Also, the yield of this
reaction was low compared to the Povarov reaction performed
on azadiene 9 with phenyl vinyl sulfide as a dienophile (cf. entry
4, Table 1 and entry 13, Table 2). In general, the reaction times
were usually short and yields were satisfactory for the above
set of aldehyde and dienophile components with the parent
3-aminocoumarin (5). However, attempted variation of the
3-aminocoumarin component resulted in poor yields (entries
8-11). In most cases, small amounts of one or more side
products were observed by TLC analysis and were even isolated
during chromatography. However, their 1H NMR spectra were
complex (see Supporting Information for an example) and could
not be reasonably interpreted. Their mass spectra were also
complicated but often contained major signals corresponding
to M-2 or M-4 for the Povarov adducts. Some intractable
materials were also generated. Self-reaction of the in situ formed
azadienes may be responsible for this result.29
At this stage, other parameters, i.e., the effect of catalyst
loading, ratios of the reactants, and the effect of concentration
on the yield, were investigated. For this purpose, a reaction
having the following features was desired: (1) the two diaster-
eomeric products should be easily separable from other side
products by flash chromatography, (2) the reaction time should
be short, and (3) the aldehyde should be commercially available.
The reaction between 3-aminocoumarin (5), 2-naphthaldehyde
(32), and 3 equiv of DHP (Table 4, entry 1) again met these
criteria. The yield of the Povarov adducts was considerably
improved (74%) when 10 mol % Yb(OTf)3 was used (entry 2).
A further increase in the catalyst loading did not improve the
yields (entries 3 and 4). Increasing the number of equivalents
of DHP to 5 and then 10 resulted in an increase in the yield of
the Povarov adducts (84% and 89%, entries 5 and 6, respec-
tively). A further increase in the number of equivalents of the
dienophile did not have any further beneficial effect on the yield
(entries 7 and 8). Also, the yields were not significantly affected
by the changes in concentration of 3-aminocoumarin (5) (entries
9-11). Thus, a few of the reactions listed in Table 3 were
repeated with the new reaction conditions, i.e., a 1.00:1.05:10.0
ratio of 3-aminocoumarin/aldehyde/dienophile with 10 mol %
Yb(OTf)3. The observation that the yield increased in two cases
(entries 1 and 9, Table 3) and decreased in two cases (entries
10 and 11, Table 3) suggested that optimal conditions may be
somewhat case-specific for the one-pot Povarov reaction.
To ascertain whether the Povarov adducts can equilibrate,
endo diastereomer 40a was resubjected to the original reaction
conditions, i.e., 5 mol % Yb(OTf)3 in acetonitrile. No signs of
conversion to the exo diastereomer (40b) were observed at room
temperature (3 h) or after 24 h at reflux. Also, a 50:50 mixture
of diastereomers 40a,b did not change the ratio when heated to
reflux in acetonitrile in the presence of 5 mol % Yb(OTf)3. These
results suggest that either the tautomerization step is not
reversible under these conditions or that the tautomerization
is reversible and the IEDDA reaction, whether concerted or
stepwise,6b is not. Finally, X-ray quality crystals for exo
(29) Stevenson, P. J.; Nieuwenhuyzen, M.; Osborne, D. ARKIVOC 2007,
129–144.
J. Org. Chem. Vol. 73, No. 21, 2008 8445

Kudale et al.
SCHEME 8. Synthesis of a Terphenyl-Type Compound 53
SCHEME 9. Aromatization of Povarov Adducts
diastereomer 33b were obtained. A single crystal X-ray structure
determination confirmed that the NMR-based assignments of
the relative stereochemistry were correct (see Supporting
Information).
With a set of relatively complex molecules (tricyclic and
tetracyclic heterocycles with 2-3 stereogenic centers) in hand,
some aspects of their chemistry were then investigated. Access
to free hydroxy or carboxylic acid functional groups might be
useful for water solubility and further synthetic transformations.
In this context, compound 43a was chemoselectively hydrolyzed
with K2CO3/MeOH to afford phenol 49 in 72% yield (Scheme
7). Similarly, ester 37b was chemoselectively hydrolyzed to
afford carboxylic acid 50 in 99% yield. Interestingly, when 37b
was subjected to anydrous demethylation conditions, i.e.,
TMSCl/NaI,30 the desired carboxylic acid 50 was not formed.
After heating at 50 °C in DMF for 18 h and then 150 h at 90
°C, 10% of the starting material 37b was recovered after flash
chromatography along with two new products. One of the
products was pyrido[2,3-c]coumarin 51 (R ) H), which was
presumably formed by an elimination/dehydrogenation process.
It was then hydrolyzed with 10 M KOH to afford the ring-
opened terphenyl-type product 53 (Scheme 8). The other new
product was the formate ester 52 (R ) CHO), which could form
from 51, or one of its precursors, via a Vilsmeier-Haack-like
O-formylation.
The observation that Povarov adduct 37b could be converted
into the corresponding pyrido[2,3-c]coumarin, a rather uncom-
mon heteroaromatic system,31 provided incentive to investigate
more efficient ways of achieving this transformation. The
treatment of Povarov adducts with an oxidizing agent, e.g.,
bromine, would be expected to bring about aromatization of
the nitrogen-containing ring through a series of addition and
elimination reactions.32 Accordingly, 37b was reacted with Br2
in the dark. Aromatized product 51 was isolated in 61% yield
after 1 h. An internal elimination reaction, which opened the
tetrahydropyran ring, occurred during the aromatization process.
Similarly, Povarov adducts 43a,b, 13a,b, and 24a,b were
converted into the corresponding pyrido[2,3-c]coumarins 54
(80%), 55 (93%), and 56 (72%), respectively, by the action of
Br2/CH2Cl2 in the dark (Scheme 9). However, only 9% and 39%
yields of the pyrido[2,3-c]coumarins 57 and 58 were obtained
from the reactions (Scheme 9) of Povarov adducts 40a,b and
35a,b, respectively. The low yields are presumably due to the
presence of an additional coumarin unit, which may react
unproductively with Br2.33
Other aromatization methods were then screened. When
compounds 40a,b were refluxed with Pd/C in xylenes, the
reaction was very sluggish. Only traces of the pyrido[2,3-
c]coumarin 57 were observed by TLC analysis after 6 days at
reflux. Acetic acid has been known to accelerate such dehy-
drogenations.34 Therefore, the dehydrogenation was attempted
with acetic acid as the solvent. Again, only traces of the product
were observed (TLC analysis) under these conditions. Another
commonly used reagent for carrying out dehydrogenations is
DDQ.35 Heating the Povarov adducts 40a,b with DDQ in
benzene at reflux afforded pyrido[2,3-c]coumarin 57 and traces
of another product, which could not be obtained in pure form.
(30) Morita, T.; Okamoto, Y.; Sakurai, H. J. Chem. Soc., Chem. Commun.
1978, 874–875.
(31) (a) Majumdar, K. C.; Chattopadhyay, B.; Taher, A. Synthesis 2007,
3647–3652. (b) Markey, M. D.; Fu, Y.; Kelly, R. Org. Lett. 2007, 9, 3255–
3257. (c) Rivkin, A.; Adams, B. Tetrahedron Lett. 2006, 47, 2395–2398. (d)
Pave´, G.; Chalard, P.; Viaud-Massuard, M.-C.; Troin, Y.; Guillaumet, G. Synlett
2003, 987–990. (e) Prasad, K. R.; Darbarwar, M. Synth. Commun. 1992, 22,
2479–2490. (f) Sagi, M.; Wada, K.; Konno, S.; Yamanaka, H. Heterocycles 1990,
30, 1009–1021. (g) Tabakovic, K.; Tabakovic, I.; Juric, A. J. Heterocycl. Chem.
1980, 17, 801–803. (h) Khan, M. A.; Gemal, A. L. J. Heterocycl. Chem. 1977,
14, 1009–1012.
(32) (a) Aksenov, A. V.; Demidova, N. V. Chem. Heterocycl. Compd. 2002,
38, 913–917. (b) Samoshin, V. V.; Kudryavtsev, K. V. Tetrahedron Lett. 1994,
35, 7413–7414. (c) Caputo, R.; Ferreri, C.; Palumbo, G.; Russo, F. Tetrahedron
1991, 47, 4187–4194.
(33) (a) Chaudhuri, S. K.; Roy, S.; Saha, M.; Bhar, S. Synth. Commun. 2007,
37, 271–274. (b) Kothurkar, S.; Shinde, D. B. Bioorg. Med. Chem. Lett. 2006,
6181–6184. (c) Lele, S. S.; Sethna, S. J. Sci. Ind. Res. 1955, 14B, 101–104. (d)
Lele, S. S.; Parikh, R. J.; Sethna, S. J. Indian Chem. Soc. 1953, 30, 610–616.
(e) Dalvi, V. J.; Sethna, S. J. Indian Chem. Soc. 1949, 26, 359–365.
(34) Nakamichi, N.; Kawashita, Y.; Hayashi, M. Org. Lett. 2002, 4, 3955–
3957.
(35) Vanden Eynde, J. J.; Delfosse, F.; Mayence, A.; Haverbeke, Y. V.
Tetrahedron 1995, 51, 6511.
8446 J. Org. Chem. Vol. 73, No. 21, 2008

PoVaroV Reactions InVolVing 3-Aminocoumarins
Experimental Section
Typical Experimental Procedure. (4aS*,5S*,12cS*)-5-(4-Ni-
trophenyl)-3,4,4a,5,6,12c-hexahydro-7H-1,8-dioxa-6-aza-2H-
pyrano[5,6-c]phenanthren-7-one (13a) and (4aS*,5R*,12cS*)-
5-(4-Nitrophenyl)-3,4,4a,5,6,12c-hexahydro-7H-1,8-dioxa-6-aza-
2H-pyrano[5,6-c]phenanthren-7-one (13b). To a solution of diene
9 (0.50 g, 1.7 mmol) and Yb(OTf)3 (0.05 g, 5 mol %) in acetonitrile
(10 mL) was added DHP (0.50 mL, 5.1 mmol, 0.43 g). The reaction
mixture was stirred for 20 min at room temperature. The thick
yellow suspension turned into a bright yellow suspension over the
course of the reaction. The solvent was removed under reduced
pressure to afford a yellow residue. The dr was determined to be
FIGURE 1. A possible side product 59 from conversion of 40a,b to
57 using DDQ.
SCHEME 10. Synthesis of 61 by Oxidation/syn Elimination/
Dehydrogenation
1
36:64 in favor of 13b by H NMR analysis of the crude reaction
mixture. The residue was then subjected to flash chromatography
(dichloromethane), which afforded 13a (0.15 g, 25%) as a yellow
solid and 13b (0.39 g, 1.1 mmol, 65%) as a yellow solid. Combined
yield of Povarov adducts ) 0.62 g, 1.6 mmol, 90%. 13a: mp )
228-229 °C (chloroform/hexane). δH (CDCl3) ) 8.27 (d, 2H, J )
9.1 Hz, H-3′), 8.21 (d, 1H, J ) 7.6 Hz, H-12), 7.63 (d, 2H, J ) 8.7
Hz, H-2′), 7.37-7.34 (m, 2H), 7.30-7.28 (m, 1H), 5.50 (d, 1H, J
) 4.7 Hz, H-12c), 5.07 (s, 1H, H-6), 4.81 (d, 1H, J ) 2.5 Hz,
H-5), 3.65-3.64 (m, 1H, H-2R), 3.25 (td, 1H, J ) 11.0, 1.2 Hz,
H-2ꢀ), 2.38-2.35 (m, 1H, H-4a), 1.76-1.67 (m, 1H), 1.59-1.48
(m, 1H), 1.43-1.41 (m, 2H) ppm. δC (CDCl3) ) 158.5 (C-7), 148.5,
147.9, 147.2, 130.7, 128.0 (C-3′), 127.1, 125.1, 124.8 (C-12), 124.1
(C-2′), 120.3, 116.7, 116.6, 71.8 (C-12c), 62.9 (C-2), 58.9 (C-5),
38.3 (C-4a), 24.3 (C-3), 19.7 (C-4) ppm. IR ν ) 3340 (w), 2854
(w), 1722 (s), 1618 (w), 1598 (w), 1516 (m), 1348 (s), 1181 (m),
1091 (s), 857 (m), 752 (s) cm-1. HRMS m/z [M+] calcd for
C21H18N2O5 378.1214, found 378.1225. 13b: mp ) 263-264 °C
(chloroform/hexane). δH(CDCl3) ) 8.27 (d, 2H, J ) 9.4 Hz, H-3′),
7.62 (d, 2H, J ) 8.2 Hz, H-2′), 7.57-7.55 (m, 1H, H-12),
7.29-7.27 (m, 3H), 5.09 (s, 1H, H-6), 4.87 (d, 1H, J ) 11.4 Hz,
H-5), 4.71 (d, 1H, J ) 3.5 Hz, H-12c), 4.20-4.17 (m, 1H, H-2R),
3.82 (td, 1H, J ) 11.6, 1.7 Hz, H-2ꢀ), 2.12-2.08 (m, 1H, H-4a),
1.94-1.78 (m, 2H), 1.48-1.46 (m, 2H) ppm. δC(CDCl3) ) 158.9
(C-7), 148.6, 148.3, 147.9, 130.0 (C-2′), 129.0, 126.8, 125.1, 124.3
(C-3′), 122.0, 120.3, 116.8, 115.4, 69.7 (C-12c), 69.3 (C-2), 54.2
(C-5), 38.9 (C-4a), 23.6 (C-3), 22.0 (C-4) ppm. IR ν ) 3389 (w),
2946 (w), 1710 (s), 1633 (m), 1509 (s), 1341 (s), 1186 (m), 1090
(m), 752 (s) cm-1. HRMS m/z [M+] calcd for C21H18N2O5 378.1214,
found 378.1230.
1H NMR and LC/MS analysis of this impure and poorly soluble
compound were consistent with the aromatized compound 59
(Figure 1). Following a procedure by Hartmann et al.,36 in which
nitrous gases were used for preparation of 1,2,4,5-tetrazines from
corresponding dihydrotetrazines, a stream of nitrous gases was
passed through a solution of 40a,b in CH2Cl2. Gratifyingly, the
desired product 57 was formed in 90% yield. Other oxidizing
agents, i.e., MnO237 and CAN,38 also delivered 57, but the yields
were lower (MnO2, 24% and CAN, 21%) and the reactions were
considerably slower.
Povarov adducts formed by using phenyl vinyl sulfide as a
dienophile have been converted into quinolines by an oxidation
(NaIO4) and thermolysis of the resulting sulfoxide.39 Treatment
of 18a,b with NaIO4 at room temperature did not show any signs
of reaction (by TLC analysis). However, pyrido[2,3-c]coumarin
61 was obtained when the reaction mixture was heated at reflux
for 23 h. Presumably, the first step in this conversion is the
oxidation of the sulfide to the sulfoxide 60, which then undergoes
a syn elimination reaction (Scheme 10). The resulting diene is then
oxidized to form the aromatized product.
In conclusion, preformed or in situ generated 2-azadienes
derived from the condensation of 3-aminocoumarins and
aromatic aldehydes take part in the Povarov reaction to afford
1,2,3,4-tetrahydropyrido[2,3-c]coumarins. The available evi-
dence points toward a concerted asynchronous IEDDA cycload-
dition rather than a stepwise cyclization during the Povarov
reaction. The multicomponent version of this reaction provides
rapid access to unusual tricyclic and tetracyclic heterocycles.
The corresponding pyrido[2,3-c]coumarins can be formed upon
oxidation of the Povarov adducts with various oxidizing agents.
Further applications of this methodology to the synthesis of
complex heterocycles will be disclosed in due course.
One-Pot Procedure. To a clear colorless solution of 3-ami-
nocoumarin (5) (0.25 g, 1.6 mmol) in acetonitrile (30 mL) was
added 4-nitrobenzaldehyde (8) (0.25 g, 1.6 mmol), followed by the
addition of Yb(OTf)3 (0.05 g, 5 mol %) and DHP (0.42 mL, 4.6
mmol, 0.39 g). The reaction mixture was allowed to stir at room
temperature for 24 h. The progress of the reaction was monitored
by TLC. When the reaction was complete, the solvent was removed
under reduced pressure, and the yellow residue was subjected to
flash chromatography (dichloromethane), which afforded diaster-
eomeric mixture 13a,b (0.23 g, 40%) as a yellow solid. The dr
1
was determined to be 36:64 in favor of 13b by H NMR analysis
of the crude reaction mixture.
Acknowledgment. The Natural Sciences and Engineering
Research Council (NSERC) of Canada and AnorMED Inc. are
gratefully acknowledged for financial support of this work. We
also thank Dr. H. J. Anderson and Dr. C. E. Loader for a sample
of 4-acetylpyrrole-2-carboxaldehyde.25
Supporting Information Available: Experimental proce-
dures, characterization data, 1H and 13C NMR spectra for
individual compounds and crystallographic data in CIF format
for 33b, 43a, and 43b. This material is available free of
charge via the Internet at http://pubs.acs.org.
(36) Hartmann, K.-P.; Heuschmann, M. Tetrahedron 2000, 56, 4213–4218.
(37) Heravi, M. M.; Moosavi, F. S. Sh.; Beheshtihay, Sh.; Ghassemzadeh,
M. Heterocycl. Commun. 2004, 10, 415.
(38) Pfister, J. R. Synthesis 1990, 689–90.
(39) Demaude, T.; Knerr, L.; Pasau, P. J. Comb. Chem. 2004, 6, 768–775.
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