Unsaturated lactams: New inputs for povarov-type multicomponent reactions

Article abstract of DOI:10.1021/ol902913j

Unsaturated lactams with endo- or exocyclic C-C double bonds constitute a set of reactive inputs that serve as the electron-rich olefin component in Povarov reactions. These substrates afford the multicomponent adducts in convenient yields and offer a wid

Full text of DOI:10.1021/ol902913j

ORGANIC
LETTERS
2010
Vol. 12, No. 4
860-863
Unsaturated Lactams: New Inputs for
Povarov-Type Multicomponent Reactions
Esther Vicente-Garc´ıa,† Federica Catti,† Rosario Ramo´n,† and Rodolfo Lavilla*,†,‡
Barcelona Science Park, Baldiri Reixac 10-12, 08028 Barcelona, Spain, and
Laboratory of Organic Chemistry, Faculty of Pharmacy, UniVersity of Barcelona,
AVda Joan XXIII sn, 08028 Barcelona, Spain
rlaVilla@pcb.ub.es
Received December 18, 2009
ABSTRACT
Unsaturated lactams with endo- or exocyclic C-C double bonds constitute a set of reactive inputs that serve as the electron-rich olefin
component in Povarov reactions. These substrates afford the multicomponent adducts in convenient yields and offer a wide range of structural
diversity. Postcondensation transformations allow direct access to a variety of lactam-fused and amide-substituted quinoline derivatives.
Multicomponent reactions (MCRs) constitute a large group
of transformations of growing relevance in organic chemistry
as they display many features of the ideal synthesis.1 Among
these domino processes, the Povarov MCR, which involves
the interaction of a carbonyl compound (normally an
aldehyde), an aniline, and an activated alkene to yield a
tetrahydroquinoline adduct, is currently the focus of intense
research.2 This transformation links the following three main
steps: the generation of an imine, followed by a Mannich-type
reaction with the activated olefin, and ending with the intramo-
lecular aromatic electrophilic substitution upon the aniline ring.
The presence of tetrahydroquinolines (or oxidized derivatives)
in natural products, bioactive compounds, and drugs has recently
elicited much interest in this process.
The original protocol has been considerably improved, and
recent findings include the possibility to perform catalytic
enantioselective versions of this MCR,3 the introduction of
a fourth component to trap the final iminium ion intermedi-
ate,4 and the spatial-temporal control of this MCR to
functionalize microelectrodes.5 With respect to the reactivity
range, the process is useful with a broad set of anilines,
carbonyl derivatives, and much effort has been devoted to
expand the range of activated olefin input. Apart from alkenes
† Barcelona Science Park, University of Barcelona.
‡ Faculty of Pharmacy, University of Barcelona.
(3) (a) Akiyama, T.; Morita, H.; Fuchibe, K. J. Am. Chem. Soc. 2006,
128, 13070–13071. (b) Liu, H.; Dagousset, G.; Masson, G.; Retailleau, P.;
Zhu, J. J. Am. Chem. Soc. 2009, 131, 4598–4599. (c) Sundararajan, G.;
Prabagaran, N.; Varghese, B. Org. Lett. 2001, 3, 1973–1976. (d) Ishitani,
H.; Kobayashi, S. Terahedron Lett. 1996, 37, 7357–7360. (e) Bergonzini,
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VCH: Weinheim, 2005. (b) Domino Reactions in Organic Synthesis; Tietze,
L. F., Brasche, G., Gericke, K., Eds.; Wiley-VCH: Weinheim, 2006. (c)
Do¨mling, U.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210.
(2) (a) Povarov, L. S. Russ. Chem. ReV. 1967, 36, 656–670. For recent
reviews, see: (b) Glushkov, V. A.; Tolstikov, A. G. Russ. Chem. ReV. 2008,
77, 137–159. (c) Kouznetsov, V. V. Tetrahedron 2009, 65, 2721–275. For
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Pritchard, R. G.; Probert, M. R.; Whiting, A. Org. Biomol. Chem. 2004, 2,
2451–2460. For a reaction variant, see (e) Zhang, J.; Li, C.-J. J. Org. Chem.
2002, 67, 3969–3971.
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2005, 44, 6521–6525. (b) For an enantioselective version, see: Dagousset,
G.; Drouet, F.; Masson, G.; Zhu, J. Org. Lett. 2009, 11, 5546–5549.
(5) Bi, B.; Maurer, K.; Moeller, K. D. Angew. Chem., Int. Ed. 2009,
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10.1021/ol902913j  2010 American Chemical Society
Published on Web 01/21/2010

and cyclic enol ethers which have been used widely in this
MCR (A, Scheme 1), the introduction of enamine-type
Scheme 1. Enol Ethers and Enamides in Povarov MCRs
Figure 1. Unsaturated lactams used in this study.
The first experiment involved the interaction of the
unsaturated lactam 1a, with p-toluidine and ethyl glyoxalate
under Sc(OTf)3 catalysis11,6b in the presence of 4 Å molecular
sieves in acetonitrile at room temperature. After chromato-
graphic purification, the tetrahydroquinolines 4a and 4a′ were
isolated (isomer ratio 4/3) in 43% overall yield (Scheme 2).
functional groups has been successfully exploited.2,6 In this
context, cyclic enamides are specially appealing since they
allow access to a new set of functionalized tetrahydroquino-
lines B.7 Importantly, the development of this chemistry by
Batey has allowed a straightforward synthesis of the alkaloids
Martinelline and Martinellic acid.7a-c The MCR adducts in
these processes show a normal connectivity pattern, thereby
leading to the expected tetrahydroquinolines. In sharp
contrast, when cyclic enol esters were tested in Povarov-
type conditions, the N-aryl lactams C were obtained.8 The
origin of these compounds may lie in the intramolecular
interception of the activated cationic intermediate by the
nucleophilic aniline nitrogen, which overrides the usual
aromatic electrophilic substitution. Here we studied the chem-
istry of unsaturated lactams in Povarov processes to determine
their synthetic usefulness and to establish the mechanistic trends
of these substrates in the MCR (Scheme 1).
Several unsaturated lactams were prepared by known
methods (or modifications thereof), usually from the corre-
sponding N-substituted imides by a reduction-elimination
sequence.9 The set included six- and seven-membered rings,
displaying distinct substituents at the nitrogen atom and also
at the neighboring position (1a-f, Figure 1). The pyrrolidone
derivative 1g with an exo double bond was also considered.10
Scheme 2. Povarov MCR with Unsaturated Lactam 1a
The stereochemical assignment of compounds 4a-4a′ was
performed by spectroscopical means. The low stereoselec-
tivity observed is the usual outcome in these processes.2
Next we examined the scope of the reaction, regarding
all the components (Table 1). The aniline input showed
Table 1. Scope of the Povarov MCR with Unsaturated Lactams
(6) (a) Lavilla, R.; Bernabeu, M. C.; Carranco, I.; Diaz, J. L. Org. Lett.
2003, 5, 717–720. (b) Carranco, I.; Diaz, J. L.; Jimenez, O.; Vendrell, M.;
Albericio, F.; Royo, M.; Lavilla, R. J. Comb. Chem. 2005, 7, 33–41
.
overall isomer
(7) (a) Batey, R. A.; Simoncic, P. D.; Smyj, R. P.; Lough, A. J. Chem.
Commun. 1999, 651–652. (b) Batey, R. A.; Powell, D. A. Chem. Commun.
2001, 2362–2363. (c) Powell, D. A.; Batey, R. A. Org. Lett. 2002, 4, 2913–
2916. (d) Hadden, M.; Nieuwenhuyzen, M.; Osborne, D.; Stevenson, P. J.;
Thompson, N.; Walker, A. D. Tetrahedron 2006, 62, 3977–3984. (e) Xia,
C.; Heng, L.; Ma, D. Tetrahedron Lett. 2002, 43, 9405–9409. (f) Stevenson,
P. J.; Graham, I. ARKIVOC (Vii). 2003, 139–144. (g) Hadden, M.;
Nieuwenhuyzen, M.; Potts, D.; Stevenson, P. J.; Thompson, N. Tetrahedron
2001, 57, 5615–5624.
yield
(%)
ratio
(4/4′)
entry
n
R1
R3
Me
R4
compound
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
2
Bn
Bn
H
CO2Et
CO2Et 2-furyl
4a-4a′
4b
43
38
42
33
42
64
61
56
35
4/3
1/-
3/2
1/-
1/1
1/1
8/5
5/8
3/2
OMe
F
OMe
Me
3-pyridyl 4c-4c′
H
2-furyl
4d
Bu
Bn
4-CF3-Ph 4e-4e′
(8) Isambert, N.; Cruz, M.; Arevalo, M. J.; Gomez, E.; Lavilla, R. Org.
Lett. 2007, 9, 4199–4202.
4-Cl-Ph
CO2Et
4-Cl-Ph
CO2Et
4f-4f′
4g-4g′
4h-4h′
4i-4i′
4-Me-Ph Me
(9) (a) Galbo, F. L.; Occhiato, E. G.; Guarna, A.; Faggi, C. J. Org.
Chem. 2003, 68, 6360–6368. (b) Bennett, D. J.; Blake, A. J.; Cooke, P. A.;
Godfrey, C. R. A.; Pickering, P. L.; Simpkins, N. S.; Walker, M. D.; Wilson,
C. Tetrahedron 2004, 60, 4491–4511. (c) Raheem, I. T.; Thiara, P. S.;
Peterson, E. A.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404–
13405. (d) Hubert, J. C.; Wijnberg, J. B. P. A.; Speckamp, W. N.
Tetrahedron 1975, 31, 1437–1441. (e) Khan, M. M.; Melmon, K. L.; Egli,
M.; Lok, S.; Goodman, M. J. Med. Chem. 1987, 30, 2115–2120. (f)
Yoshifuji, S.; Arakawa, Y.; Nitta, Y. Chem. Pharm. Bull. 1987, 35, 357–
363.
H
H
Me
Me
appropriate reactivity, ranging from deactivated to activated
derivatives (entries 1-4). Also, the carbonyl range included
(11) (a) Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W. L. Chem.
ReV. 2002, 102, 2227–2302. (b) Kobayashi, S. Eur. J. Org. Chem. 1999,
(10) Padwa, A.; Rashatasakhon, P.; Rose, M. J. Org. Chem. 2003, 68,
5139–5146.
15–27
.
Org. Lett., Vol. 12, No. 4, 2010
861

the usual set of aromatic and highly electrophilic aldehydes.12
Thus, ethyl glyoxalate (entries 1 and 7) and diversely
substituted aromatic and heteroaromatic aldehydes (entries
2-6 and 8) afforded the expected adducts. Interestingly,
when using 2-furaldehyde in combination with ethyl p-
aminobenzoate and p-fluoroaniline (Table 1, entries 2 and
4), we detected the formation of only the isomers 4b and
4d, respectively. Finally, we screened the unsaturated lac-
tams, first studying the substitution pattern at the nitrogen
atom (entries 1-8) and looking at the ring size (six- and
seven-membered rings, entries 1-8 and 9, respectively). We
obtained acceptable yields in all cases.
Scheme 4. Spiro-Adduct from Substrate 1g
via a metal-catalyzed alkoxylation of an ω-hydroxyalkyne,
followed by a Povarov reaction.14
Next, we explored some postcondensation reactions upon
the previously prepared Povarov adducts. Thus, the DDQ-
oxidation of the tetrahydroquinolines 4 yielded the corre-
sponding lactam-fused quinolines 8 (Scheme 5).15,16 The
We explored further variations in the structure of the
unsaturated lactams, and alkyl substitution at the R-position
was also examined. When derivative 1e (Scheme 3) was
Scheme 3. R-Substituted Unsaturated Lactam 1e
Scheme 5
.
DDQ oxidation of Povarov adducts 4 and 7
a Unoptimized reaction.
reacted with p-toluidine or 4-methoxyaniline and ethyl
glyoxalate, under the usual conditions, we obtained the Man-
nich-type products 5a and 5b, respectively, in moderate yields.
In these cases, the final electrophilic substitution did not take
place, probably due to steric reasons. In these reactions, the
cationic intermediate evolved via a proton loss at the R-position
of the acyliminium moiety to regenerate the unsaturated lactam
system. This outcome also differed from the described reactivity
of cyclic enol esters, where the aniline nitrogen attacks the
carbonyl group of the intermediate.8 Furthermore, when using
glyoxylic acid as the carbonyl component, the carboxylate
moiety acts as a nucleophile and captures the final iminium
ion intermediate.4a,13 Thus, adduct 6 (37%) was stereoselec-
tively obtained in this way.
b
a Unoptimized result. The overoxidation product 8f (R1 ) H, R3 )
CHO, R4 ) 4-Cl-Ph) was also isolated in 40% yield.
process was satisfactory and afforded the products in
reasonable yields. Adduct 4h suffered overoxidation, thereby
(12) Aliphatic aldehydes are poorly reactive in Povarov MCR under
usual conditions. However, for a protocol allowing their participation in
this process, see: Powell, D. A.; Batey, R. A. Tetrahedron Lett. 2003, 44,
7569–7573.
(13) Lucchini, V.; Prato, M.; Scorrano, G.; Stivanello, M. J. Chem. Soc.,
Perkin Trans. 2 1992, 259–266.
(14) (a) Barluenga, J.; Mendoza, A.; Rodr´ıguez, F.; Fan˜ana´s, F. J. Angew.
Chem., Int. Ed. 2009, 48, 1644–1647. (b) Barluenga, J.; Mendoza, A.;
Rodr´ıguez, F.; Fan˜ana´s, F. J. Angew. Chem., Int. Ed. 2008, 47, 7044–7047.
(15) (a) Borrione, E.; Prato, M.; Scorrano, G.; Stivanello, M.; Lucchini,
V. J. Heterocycl. Chem. 1988, 25, 1831–1835. For a tandem Povarov-
oxidation process, see: (b) Shindoh, N.; Tokuyama, H.; Takemoto, Y.;
Takasu, K. J. Org. Chem. 2008, 73, 7451–7456. (c) Zhao, Y.-L.; Zhang,
W.; Wang, S.; Liu, Q. J. Org. Chem. 2007, 72, 4985–4988. (d) Guchhait,
Finally, the pyrrolidone derivative displaying an exo
double bond (1g) was reacted to afford the spiro-Povarov
adduct (Scheme 4). First, the standard conditions were tested
affording the MCR adduct in low yield (20%). Performing
the reaction under microwave irradiation (MW) resulted in
a substantial optimization (7-7′, 60% overall yield). Bar-
luenga and co-workers recently reported an elegant domino
process for the synthesis of related systems by a sequence
involving the in situ formation of an exocyclic enol ether,
S. K.; Jadeja, K.; Madaan, C. Tetrahedron Lett. 2009, 50, 6861–6865
.
(16) Camps, P.; Formosa, X.; Galdeano, C.; Mun˜oz-Torrero, D.;
Ram´ırez, L.; Go´mez, E.; Isambert, N.; Lavilla, R.; Badia, A.; Clos, M. V.;
Bartolini, M.; Mancini, F.; Andrisano, V.; Arce, M. P.; Rodr´ıguez-Franco,
M. I.; Huertas, O.; Dafni, T.; Luque, F. J. J. Med. Chem. 2009, 52, 5365–
5379
.
862
Org. Lett., Vol. 12, No. 4, 2010

resulting in a mixture of the expected quinoline 8e (22%),
together with the aldehyde derivative 8f (40%).16 The
treatment of spiro-adduct 7 (Scheme 5) with DDQ gave two
compounds arising from an oxidative fragmentation: quino-
line 9 (21%) and its dehydrogenated derivative 10 (17%).
In search for variants of this transformation, we tested a
TFA treatment to promote an acid-catalyzed elimination17
of the amide moiety of the Povarov adducts, which would
lead to a 1,2-dihydroquinoline prone to spontaneus oxidation
to give the 2,3-disubstituted quinoline derivatives (11a,b).
In this way, quinolines 11a and 11b were directly prepared
from compounds 4e and 4g, respectively (Scheme 6). This
type of oxidative fragmentation was also observed at a
reduced extent in the DDQ-oxidation of adduct 4f, which
allowed the isolation of 11c. Also in the Sc(OTf)3-catalyzed
Povarov reactions, the quinolines 11d, 11e, and 11f were
isolated as byproduct (entries 3, 4, and 9, Table 1). These
products may have arisen from the full domino sequence.
In conclusion, unsaturated lactams are synthetically useful
substrates for Povarov MCRs and allow direct and convenient
access to tetrahydroquinoline scaffolds with novel connectiv-
ity and functionalization patterns. These adducts are readily
converted to a variety of quinoline derivatives in a straight-
forward manner.
Acknowledgment. This work was supported by DGICYT
(Spain, Project CTQ2009-07758) and Grupo Ferrer (Barce-
lona). We thank Prof. Albert Padwa (Emory University) for
useful comments.
Scheme 6. Acid-Catalyzed Fragmentation-Oxidation Process
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL902913J
(17) (a) Crousse, B.; Begue´, J.-P.; Bonnet-Delpon, D. J. Org. Chem.
2000, 65, 5009–5013. (b) For another example of an oxidative fragmentation,
see: Kudale, A.; Kendall, J.; Miller, D. O.; Collins, J. L.; Bodwell, G. J. J.
Org. Chem. 2008, 73, 8437–8447. Also see: refs 4 and 8.
a Isolated as byproduct in Povarov MCRs or in DDQ oxidations of the
Povarov adducts 4.
Org. Lett., Vol. 12, No. 4, 2010
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