Catalytic synthesis of γ-lactams via direct annulations of enals and N-sulfonylimines

Article abstract of DOI:10.1021/ol051234w

(Chemical Equation Presented) Cinnamaldehydes and N-sulfonylimines undergo direct annulations to cis-disubstituted γ-lactams via the intermediacy of catalytically generated homoenolates. Critical to the success of this process was overcoming inhibition of the N-heterocyclic carbene catalyst by the electrophilic imines. The overall process proceeds with good yields and diastereoselectivites and requires no stoichiometric reagents or additives.

Full text of DOI:10.1021/ol051234w

ORGANIC
LETTERS
2005
Vol. 7, No. 14
3131-3134
Catalytic Synthesis of
Direct Annulations of Enals and
N-Sulfonylimines
γ-Lactams via
Ming He and Jeffrey W. Bode*
Department of Chemistry and Biochemistry, UniVersity of California-Santa Barbara,
Santa Barbara, California 93101
bode@chem.ucsb.edu
Received May 25, 2005
ABSTRACT
Cinnamaldehydes and N-sulfonylimines undergo direct annulations to cis-disubstituted γ-lactams via the intermediacy of catalytically generated
homoenolates. Critical to the success of this process was overcoming inhibition of the N-heterocyclic carbene catalyst by the electrophilic
imines. The overall process proceeds with good yields and diastereoselectivites and requires no stoichiometric reagents or additives.
γ-Lactams are widespread structural features of natural and
designed biologically active molecules, including the core
structure of the nootropics, or so-called “smart drugs”.1 Their
utility in pharmaceutical development, however, is dimin-
ished by the need for multistep synthetic sequences for their
preparation; even the few known direct methods require prior
synthesis of complex reactants.2,3 An attractive approach to
γ-lactams would be the addition of a homoenolate equivalent
to an appropriate imine, followed by cyclization (eq 1). While
this strategy has been successfully applied to the synthesis
of γ-lactones,4 only scattered and limited reports of ho-
moenolate additions to imines have appeared,5 presumably
due to incompatibilities of the imine substrates with the harsh
or reductive conditions typically used for homoenolate
formation.6
Recently, we7 and Glorius8 independently reported the
nucleophile-catalyzed generation of homoenolates from R,â-
unsaturated aldehydes and their reaction with an electrophilic
(5) (a) Abbas, M.; Neuhaus, C.; Krebs, B. Synlett 2005, 473-476. (b)
DiMauro, E.; Fry, A. J. Tetrahedron Lett. 1999, 40, 7945-7949. (c)
Okamoto, S.; Teng, X.; Fuji, S.; Takayama, Y. Sato, F. J. Am. Chem. Soc.
2001, 123, 3462-3471.
(1) Gouliaev, A. H.; Senning, A. Brain Res. ReV. 1994, 19, 180-222.
(2) (a) Roberson, C. W.; Woerpel, K. A. J. Org. Chem. 1999, 64, 1434-
1435. (b) Sun, P.-P.; Chang, M.-Y.; Chiang, M. Y.; Chang, N.-C. Org.
Lett. 2003, 5, 1761-1763.
(3) For an elegant and practical two-step approach to trans-disubstituted
γ-lactams, see: Yee, N. K. Tetrahedron Lett. 1997, 38, 5091-5094.
(4) Fukuzawa, S.-I.; Seki, K.; Tatsuzawa, M.; Mutoh, K. J. Am. Chem.
Soc. 1997, 119, 1482-1483.
(6) (a) Kuwajima, I.; Nakamura, E. In ComprehensiVe Organic Synthesis;
Trost, B., Flemming, I., Eds; Pergamon: Oxford, 1991; Vol. 2, pp 441-
454. (b) Hoppe, D. Angew. Chem., Int. Ed. Engl. 1984, 23, 932-948.
(7) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126,
14370-14371.
(8) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205-
6208.
10.1021/ol051234w CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/09/2005

aldehyde, leading to a direct, stereoselective synthesis of
γ-lactones. The nucleophilic catalyst derived from 1,3-
bis(2,4,6-trimethylphenyl)-2-chloroimidazolium chloride
(IMes-Cl) reacted reversibly with either aldehyde, but the
use of a sterically demanding heterocyclic carbene permitted
bond-forming reactions only from the umpolung of the R,â-
unsaturated aldehyde.
Table 1. Effect of Imine Protecting Groups
Although we had hoped this uniquely mild (neutral,
organocatalytic, protic solvent, rt) process would unlock the
long-sought addition of homoenolates to imines, these
reactions were initially limited to a narrow range of aldehyde
electrophiles. N-Alkyl and N-aryl imines were unreactive,
leading to lactone dimers of the starting enal as the only
product. More electrophilic imines such as N-tosyl and
N-phosphinoyl reacted directly with the nucleophilic catalyst,
leading to stable adducts that effectively inhibited any
catalytic reactions. NMR experiments revealed an explana-
tion for this disparate reactivity. The nucleophilic catalyst
reacted preferentially with the N-sulfonylimines, thus ef-
fectively inhibiting the reaction of the catalyst with the
aldehyde (Scheme 1).9
Scheme 1. Electrophilic Inhibition of Nucleophilic Catalysis
We reasoned that an efficient, catalytic process could be
achieved if the initial addition of the catalyst to the imine
was rendered reversible. To accomplish this, we synthesized
and screened a variety of electron-rich N-sulfonyl imines for
reaction with cinnamaldehyde derivative 2 (eq 2, Table 1).
These studies led to the successful realization that N-4-
methoxybenzenesulfonyl imines are ideally suited to cata-
lytic annulations of imines and cinnamaldehydes (eq 3).10
Significantly, NMR investigations revealed that while ad-
dition of the in situ-generated N-heterocyclic carbene to the
imine is still the preferred reaction pathway, this addition is
reversible over the time scale of the reaction and the catalyst
reacts with the cinnamaldehyde, leading to product forma-
tion.11
a All reactions were performed with 1 equiv of 2, 1 equiv of imine, 15
mol % IMes-Cl, and 10 mol % DBU at 0.1 M in tert-BuOH at 60 °C.
b Ratio of remaining enal to lactam and/or lactone products as measured
by 1H NMR analysis of unpurified reaction mixtures. c Isolated yield
following silica gel chromatography. d Lactone homodimer. e Performed
with 10 equiv of NEt3.
tams in good yields under these catalytic conditions (Table
2).12 The lactam products are formed with good to moderate
A variety of functionalized R,â-unsaturated aldehydes and
N-4-methoxybenzenesulfonylimines give disubstituted γ-lac-
(10) Only a few reports on the use of 4-methoxybenzenesulfonyl imines
as electrophiles have appeared. In both cases, these provided few or no
advantages over the N-tosyl imines. See: (a) Fujihara, H.; Nagai, K.;
Tomioka, K. J. Am. Chem. Soc. 2000, 122, 12055-12056. (b) Garc´ıa
Manchen˜o, O.; Go´mez Arraya´s, R.; Carretero, J. C. J. Am. Chem. Soc. 2004,
126, 456-457.
(9) For the irreversible reaction of N-heterocyclic carbenes with strong
electrophiles, see: (a) Nair, V.; Bindu, V.; Sreekumar, V. Angew. Chem.,
Int. Ed. 2004, 116, 5240-5245. (b) Rigby, J. H.; Wang, Z. Org. Lett. 2002,
4, 4289-4291.
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Org. Lett., Vol. 7, No. 14, 2005

Table 2. Catalytic Annulations of Enals and Imines via Catalytically Generated Homoenolates
a Unless otherwise indicated, all reactions were performed with 1 equiv of enal, 1 equiv of imine, 15 mol % IMes-Cl, and 10 mol % DBU at 0.1 M in
tert-BuOH at 60 °C for 14 h. Ar ) 4-MeOC6H4. b Combined yield of lactam diastereoisomers after silica gel chromatography. c Conditions: 2 equiv of 11,
75 °C, 63 h. d Reaction at room temperature. e Performed with addition of 1 equiv of 23 to 3 equiv of 7 over 3 h.
selectivity, with preference for the cis diastereomer.13 Overall,
an unusual reactivity pattern emerges: more electron-
deficient aldehydes make for better nucleophiles, while more
electron-rich imines are the preferred electrophiles. No
stoichometric reagents were used in the annulations; side
reactions arising from benzoin, Stetter, and aza-benzoin
reactions were not observed, and only traces of the undesired
lactone dimer of the enal were detected.14 The annulations
are tolerant of air and moisture, and do not require aqueous
workup. This leads to an operationally simple, truly catalytic
process: simply warming a t-BuOH solution of 1.0 equiv
of enal and 1.0 equiv of imine in the presence of sub-
(12) Typical Procedure for Catalytic Annulations. Cinnamaldehyde
(0.90 g, 6.8 mmol, 1.0 equiv), imine 13 (2.05 g, 6.8 mmol, 1.0 equiv), and
IMes-Cl (0.35 g, 1.0 mmol, 15 mol %) were weighed into an oven-dried
flask. The flask was sealed with a septum, evacuated, and back-filled with
argon. To this mixture was added 68 mL of tert-BuOH followed by DBU
(0.10 mL, 0.68 mmol, 10 mol %), and the resulting solution was stirred for
14 h at 25 °C. The reaction was concentrated under reduced pressure and
purified by flash chromatography (4:1 hexane/EtoAc) to afford the lactam
products as a white solid (1.8 g, 61% yield, 8/1 cis:trans).
(11) For experiments and spectral data, see Supporting Information.
Further studies on the mechanism and kinetics of the reversible addition of
the catalyst to the imine are in progress.
Org. Lett., Vol. 7, No. 14, 2005
3133

stoichiometric amounts of commercially available IMesCl
and DBU leads directly to the γ-lactam products.
Remarkably, optimal conditions mandate the use of protic
reaction solvents; no lactam products are observed when the
annulations are performed in THF, toluene, or CH2Cl2.
Interestingly, these results starkly contrast our recent dis-
covery that homoenolates catalytically generated from tri-
azolium salts can be protonated under mild conditions,
leading to catalytically generated activated carboxylates
suitable for esterifications.15
In summary, we have identified N-4-methoxybenzene-
sulfonyl imines as a solution to electrophilic inhibition of
nucleophilic catalysis in the N-heterocyclic carbene-catalyzed
addition of enals to imines. This unique process affords
disubstituted γ-lactam products through the synthetically
challenging addition of homoenolate equivalents to imines.
Furthermore, it complements ongoing efforts in direct,
organocatalytic methods for carbon-carbon bond formation
and invites further mechanistic investigations on the unique
chemistry of catalytically generated reactive species.
The lactam products are synthetically useful structures for
the synthesis of natural products and pharmaceutical precur-
sors. The N-sulfonyl protecting group is easily removed under
a variety of reductive conditions (Scheme 2).16 Alternatively,
this moiety activates the lactam toward nucleophilic ring
opening by alkoxides and other nucleophiles, leading to
γ-amino acid derivatives.
Acknowledgment. This work has been supported by the
National Science Foundation (CAREER Award to J.W.B.),
the Camille and Henry Dreyfus Foundation (New Faculty
Award to J.W.B.), and the University of California.
Supporting Information Available: Experimental pro-
cedures, characterization data, and 1H NMR studies of
catalyst inhibition. This material is available free of charge
via the Internet at http://pubs.acs.org.
Scheme 2. Deprotection and Ring-Opening of Catalytically
Prepared N-Sulfonyl Lactams
OL051234W
(13) Stereochemistries were assigned by 1H NMR NOE studies (See
Supporting Information) and comparison to known lactams products: (a)
Escalante, J.; Gonza´lex-Tototzin, M. A. Tetrahedron: Asymmetry 2003,
14, 981-985. (b) Yee, N. K.; Nummy, L. J.; Byrne, D. P. J. Org. Chem.
1998, 63, 326-330.
(14) Imine decomposition and unreacted enal constitute the mass balance.
(15) (a) Sohn, S. S.; Bode, J. W. Unpublished results. (b) For our studies
on catalytically generated activated carboxylates from R,â-epoxyaldehydes,
see: Chow, K. Y.-K.; Bode, J. W. J. Am. Chem. Soc. 2004, 126, 8126-
8127. (c) For the protonation of catalytically generated homoenolates by
phenols, see: Chan, A.; Scheidt, K. A. Org. Lett. 2005, 7, 905-908.
(16) (a) Ji, S.; Gortler, L. B.; Waring, A. J. Am. Chem. Soc. 1967, 89,
5311-5312. (b) Nagashima, H.; Ozaki, N.; Washiyama, M. Itoh, K.
Tetrahedron Lett. 1985, 26, 657-660.
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