One-step synthesis of complex nitrogen heterocycles from lmines and alkyl-substituted maleic anhydrides

Article abstract of DOI:10.1021/ol901018k

Substituted maleic anhydrides react with imines to form poly cyclic lactam products. Diastereoselectivity can be controlled by altering the reaction conditions in some cases, and regiochemistry is dictated by the structure of the allylic substituents on t

Full text of DOI:10.1021/ol901018k

ORGANIC
LETTERS
2009
Vol. 11, No. 17
3802-3805
One-Step Synthesis of Complex
Nitrogen Heterocycles from Imines and
Alkyl-Substituted Maleic Anhydrides
Yuchen Tang, James C. Fettinger, and Jared T. Shaw*
Department of Chemistry, UniVersity of California, One Shields AVenue,
DaVis, California 95616
shaw@chem.ucdaVis.edu
Received May 11, 2009
ABSTRACT
Substituted maleic anhydrides react with imines to form polycyclic lactam products. Diastereoselectivity can be controlled by altering the
reaction conditions in some cases, and regiochemistry is dictated by the structure of the allylic substituents on the anhydride. Cyclic imines,
including dihydro-ꢀ-carbolines and dihydroisoquinolines, exhibit the highest level of reactivity in these new annulation reactions.
Five-membered ring heterocycles are common structural
subunits in polycyclic natural products1 and medicinal leads.2
A one-step synthesis of γ-lactams is possible from imines
and succinic anhydrides through a formal cycloaddition
process, as first demonstrated by Castagnoli.3 Favorable
substrates for this reaction have substituents, such as an
aromatic ring, capable of stabilizing an enolate intermediate
formed from iminolysis of the anhydride.4 Our own studies
revealed that a thioether substituent enabled the synthesis
of γ-lactams in high yield and with a high level of
diastereoselectivity.5 The acylation step was shown to be
reversible, and this finding led to the discovery of a new
four-component synthesis of γ-lactams.6 Our ongoing studies
of the iminolysis mechanism prompted us to explore the
possibility of accessing a zwitterionic enolate intermediate
from a maleic anhydride by a prototropic shift to provide
allylic stabilization (Scheme 1). We envisioned that zwitte-
rion 3, resulting from iminolysis of anhdyride 2, could
isomerize to 4. Attack of the R- or γ-position of the dienolate
(1) (a) Yang, Y.-L.; Chang, F.-R.; Wu, Y.-C. HelV. Chim. Acta 2004,
87, 1392–1399. (b) Williams, D. E.; Davies, J.; Patrick, B. O.; Bottriell,
H.; Tarling, T.; Roberge, M.; Andersen, R. J. Org. Lett. 2008, 10, 3501–
3504. (c) Sano, T.; Toda, J.; Kashiwaba, N.; Ohshima, T.; Tsuda, Y. Chem.
Pharm. Bull. 1987, 35, 479–500. (d) Raheem, I. T.; Thiara, P. S.; Peterson,
E. A.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404–13405.
(2) (a) Keith, J. M.; Gomez, L. A.; Barbier, A. J.; Wilson, S. J.; Boggs,
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Bioorg. Med. Chem. Lett. 2007, 17, 4374–4377. (b) Hoefgen, B.; Decker,
M.; Mohr, P.; Schramm, A. M.; Rostom, S. A. F.; El-Subbagh, H.;
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Chem. 2006, 49, 760–769. (c) Bertrand, M.; Poissonnet, G.; Theret-Bettiol,
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Dodd, R. H. Bioorg. Med. Chem. 2001, 9, 2155–2164. (d) Le Quement,
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(3) Castagnoli, N., Jr. J. Org. Chem. 1969, 34, 3187–3189.
(4) (a) Cushman, M.; Madaj, E. J. J. Org. Chem. 1987, 52, 907–915.
(b) Masse, C. E.; Ng, P. Y.; Fukase, Y.; Sanchez-Rosello, M.; Shaw, J. T.
J. Comb. Chem. 2006, 8, 293–296. (c) Gonzalez-Lopez, M.; Shaw, J. T.
Chem. ReV. 2009, 109, 164–189.
(5) Ng, P. Y.; Masse, C. E.; Shaw, J. T. Org. Lett. 2006, 8, 3999–4002.
(6) Wei, J.; Shaw, J. T. Org. Lett. 2007, 9, 4077–4080.
10.1021/ol901018k CCC: $40.75
Published on Web 08/10/2009
 2009 American Chemical Society

Scheme 1
.
Potential Reaction Pathways of Imines with
Substituted Maleic Anhydrides
Scheme 2
.
Polycyclic Products from the Reactions of Anhydride
7a with Imines 6a and 6b
would lead to products 5a or 5b, respectively. Herein we
report our preliminary findings on the synthesis of unsatur-
ated lactams from the reactions of imines 6a-e with maleic
anhydrides 7a-d (Figure 1).
noteworthy that lactam 8 has all of the structural features
and the correct stereochemistry of the natural product jamtine
N-oxide9 and several related alkaloids10 from the medicinal
plant Cocculus hirsutus. Independent syntheses of jamtine,
the presumed biosynthetic precursor of jamtine N-oxide, have
cast doubt on the core structures of these natural products.11
Figure 1. Imines (6a-e) and substituted anhydrides (7a-d).
Tetrahydrophthalic anhydride 7a reacted with imines 6a
and 6b to form the anticipated formal cycloaddition products
(Scheme 2). In both cases reaction by path A, i.e., attack of
the R-carbon of the presumed dienolate on the iminium ion,
was observed. Dihydroisoquinoline 6a and dihydrocarboline
6b each reacted with high diastereoselectivity and in accept-
able yields as judged by converting initially formed acids 8
and 10 to their respective methyl esters 9 and 11. The anti
configuration of the major isomer in each case was identified
through X-ray crystallographic analysis.7
Methyl- and dimethyl-substituted anhydrides 7c and 7d
were also investigated. No reaction with imines 6a or 6d,e
was observed in either case. Only the reaction of 6b, which
shows the highest reactivity of all of the imines, was observed
to react with 7c to provide exomethylene-substituted lactam
12 in good yield and high diastereoselectivity (eq 2). The
configuration of methyl ester 13 could not be determined
and is tentatively assigned on the basis of analogy to 8 and
10.
The diastereoselectivity of the reaction of 6a with tet-
rahydroisoquinoline 7a is reversed when the reaction is
conducted in the presence of triethylamine and triethylam-
monium hydrochloride (eq 1). Density functional theory
calculations for the two diastereomeric core structures
indicate that syn-8 is more stable by 1.4 kcal/mol, suggesting
that the alternate conditions enable equilibration of the less
stable and presumably kinetically formed anti-8.8 It is
Acyclic imines derived from aromatic aldehydes (6d-f)
react with anhydride 7a to provide [6,5]-fused lactams with
yields and selectivities that depend on the substituents of
the aromatic ring (Scheme 1, Table 1). Electron-rich imine
(7) Data summaries for all of the X-ray crystal structures are provided
in Supporting Information. In addition, crystallographic information files
(CIF) files have been deposited in the Cambridge Crystallographic Database
(CCDB).
Org. Lett., Vol. 11, No. 17, 2009
3803

7b initially appeared to be consistent with one of the
anticipated adducts, X-ray crystallographic analysis revealed
the product to be N,O-acetal 16. Similar N,O-acetal products
were formed with 6b and 6c. Although a similar structure is
proposed as an intermediate in the reactions of succinic
anhydrides,3 continued heating of 16 failed to produce any
lactam products.
Scheme 3. Reactions of Acyclic Imines 6d-f with 7a
We next turned our attention to the reactions of ketimine
6c. Although ketimines are known to be less reactive toward
homophthalic anhydride,12 we reasoned that 6c might be
sufficiently reactive based on the higher reactivity of cyclic
imines 6a and 6b relative to their acyclic analogues. Upon
heating 6c and 7c, we observed conversion to a new product
(Scheme 5). Although the 1H NMR spectrum suggested the
Table 1. Reactions of Acyclic Imines with Anhydride 7a
imine
R1
dr (14a-c)
yield (%)
6d
6e
6f
OCH3
H
Cl
>95:5 (14a)
>95:5 (14b)
50:50 (14c)
70 (15a)
51 (14b)
45 (15c)
Scheme 5
6d reacts in high yield and with high (>95:5) diastereose-
lectivity when heated for 1 h. This reduced reactivity of
acyclic imines, when compared to cyclic imines, is consistent
with previous observations in reactions of homophthalic
anhydride.4c Although benzaldehyde-derived imine 6e reacts
with similar diastereoselectivity, incomplete conversion and
a correspondingly lower yield is observed. p-Chlorophenyl
imine 6f gave poor conversion. The relative configuration
of 14b was demonstrated by X-ray crystallography, and those
of 14a and 14c are assigned by analogy on the basis of their
1
similar H NMR spectra.
Cyclopentane-fused maleic anhydride 7b exhibited inter-
esting reactivity with imines (Scheme 4). Upon mixing the
imines 6a with anhydride 7b, a precipitate instantly formed.
1
Although the H NMR spectrum of the product of 6a and
Scheme 4. Reactions of 7b with Imines 6a, 6b, and 6d
expected fused lactam had formed, X-ray crystallographic
analysis of the major diastereomer indicated a completely
different reaction manifold had produced tricyclic unsaturated
lactam 22. This product arises from acylation of the imine
followed by prototropic shift to enamide carboxylic acid 20.
(8) Relative energies (B3LYP/6-31+G(d,p) + unscaled zero point energy
corrections) for the core compounds lacking the methoxy groups were
calculated by Prof. D. J. Tantillo, UC Davis (djtantillo@ucdavis.edu). See
Supporting Information.
(9) Ahmad, V. U.; Atta ur, R.; Rasheed, T.; Habib ur, R. Heterocycles
1987, 26, 1251–1255.
(10) (a) Rasheed, T.; Khan, M. N. I.; Zhadi, S. S. A.; Durrani, S. J.
Nat. Prod. 1991, 54, 582–584. (b) Ahmad, V. U.; Iqbal, S. Nat. Prod. Lett.
1993, 2, 105–109. (c) Viqar Uddin, A.; Iqbal, S. Phytochemistry 1993, 33,
735–736.
(11) (a) Gill, C. D.; Greenhalgh, D. A.; Simpkins, N. S. Tetrahedron
2003, 59, 9213–9230. (b) Simpkins, N. S.; Gill, C. D. Org. Lett. 2003, 5,
535–537. (c) Padwa, A.; Danca, M. D. Org. Lett. 2002, 4, 715–717. (d)
Padwa, A.; Danca, M. D.; Hardcastle, K. I.; McClure, M. S. J. Org. Chem.
2003, 68, 929–941.
(12) (a) Cushman, M.; Gentry, J.; Dekow, F. W. J. Org. Chem. 1977,
42, 1111–1116. (b) Xiao, X.; Morrell, A.; Fanwick, P. E.; Cushman, M.
Tetrahedron 2006, 62, 9705–9712.
3804
Org. Lett., Vol. 11, No. 17, 2009

This intermediate is poised for an intramolecular Michael-
type addition of the enamide to the unsaturated acid and
formation of 22 after elimination.13 A modest preference (75:
25) for the formation of the syn isomer depicted is observed,
and the configuration was determined by X-ray crystal-
lographic analysis. Anhydrides 7d and 7a reacted similarly
to produce 24 and 26, respectively, the latter case consisting
of 50:50 mixture of the two diastereomers. Continued heating
of 26 under the reaction conditions shifted to a 70:30 mixture
favoring the anti isomer for which X-ray crystallographic
analysis confirmed the structural assignment (Scheme 6).
Scheme 7
Scheme 6
Michael reaction of anhydrides via an enamide intermediate.
The polycyclic products of these new reactions are reminis-
cent of dihydroisoquinoline and ꢀ-carboline natural products
and will be useful in target-oriented and diversity-oriented
synthesis efforts.
Acknowledgment. This work was funded by startup funds
from UC Davis. The authors acknowledge Prof. Dean
Tantillo (UC Davis) for helpful discussions and for perform-
ing DFT calculations.
Supporting Information Available: Experimental pro-
cedures for the preparation of all new compounds and X-ray
crystallographic data (including CIF files) for 8, 10, 14b,
16, 18, 22, 26, and 28b. This material is available free of
charge via the Internet at http://pubs.acs.org.
Anhydride 7b exhibited higher reactivity toward imine 6b
(Scheme 7). Upon mixing at room temperature, a reaction
occurred immediately and the expected product of conjugate
addition (28a) was formed as a mixture of diastereomers. A
small quantity of direct C-acylation product 28b was also
isolated as a precipitate. This result is consistent with the
C-acylation of 2-methyl-substituted pyridines by acetic and
trifluoroacetic anhydride that has been previously observed14
and is a testament to the increased reactivity of 7b.
In summary, we have discovered a series of new reactions
between imines and substituted maleic anhydrides to produce
complex, polycyclic lactams in a single step. Aldimines react
in a new manifold that was predicted by the acylation/
Mannich mechanism previously observed for succinic and
homophthalic anhydrides. Ketimine 6c produces related
lactam products through an entirely new acylation/aza-
OL901018K
(13) For related conjugate addition reactions of enamines, see: (a)
Dannhardt, G.; Wiegrebe, W. Arch. Pharm. 1977, 310, 802–810. (b) Calabi,
L.; Danieli, B.; Lesma, G.; Palmisano, G. Tetrahedron Lett. 1982, 23, 2139–
2142. (c) Danieli, B.; Lesma, G.; Palmisano, G.; Tollari, S. Synthesis 1984,
353–356. (d) Mashevskaya, I. V.; Duvalov, A. V.; Rozhkova, Y. S.;
Shklyaev, Y. V.; Racheva, N. L.; Bozdyreva, K. S.; Maslivets, A. N.
MendeleeV Commun. 2004, 75–76. (e) Bannikova, Y. N.; Maslivets, A. N.;
Rozhkova, Y. S.; Shklyaev, Y. V.; Aliev, Z. G. MendeleeV Commun. 2005,
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A. N. Russ. J. Org. Chem. 2008, 44, 697–700. (g) Worayuthakarn, R.;
Thasana, N.; Ruchirawat, S. Org. Lett. 2006, 8, 5845–5848.
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J.-F.; Franck, X.; Hocquemiller, R.; Figadere, B. Bioorg. Med. Chem. 2003,
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