N-heterocyclic carbene and Bronsted acid cooperative catalysis: Asymmetric synthesis of trans -γ-Lactams

Article abstract of DOI:10.1021/ja205714g

An efficient enantioselective approach to form trans-γ-lactams in up to 99% yield, 93% ee, and >20/1 dr using unactivated imines has been developed. The cyclohexyl-substituted azolium and the weak base sodium o-chlorobenzoate are most suitable for this tr

Full text of DOI:10.1021/ja205714g

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N-Heterocyclic Carbene and Brønsted Acid Cooperative Catalysis:
Asymmetric Synthesis of trans-γ-Lactams
Xiaodan Zhao, Daniel A. DiRocco, and Tomislav Rovis*
Department of Chemistry, Colorado State University, Fort Collins, Colorado 80523, United States
S Supporting Information
b
Scheme 1. Proposed NHC/Brønsted Acid Cooperative Catalysis
ABSTRACT: An efficient enantioselective approach to
form trans-γ-lactams in up to 99% yield, 93% ee, and
>20/1 dr using unactivated imines has been developed.
The cyclohexyl-substituted azolium and the weak base
sodium o-chlorobenzoate are most suitable for this trans-
formation. Notably, the process involves cooperative cata-
lysis by an N-heterocyclic carbene and a Brønsted acid.
cis-γ-lactams,8a,11 γ-butyrolactones,12 cyclopentenes,8b,c,13 and
heterocycles,14 among others.15 With a few exceptions,11d,12d,13b,15c
the enantioselective control of homoenolates still remains chal-
lenging. Keeping this in mind, we turned our attention to
homoenolate chemistry and the design of new types of chiral
azolium salts to achieve products with high enantioselectivity.
We imagined that the conjugate acid of the base used to
generate the carbene could be induced to activate a basic
functionality such as an imine, with the further prospect that a
chiral base would potentially lead to a second means of control-
ling the stereochemistry in the bond-forming event. This combi-
nation may also conceivably give access to an inaccessible
diastereomer and prove complementary to existing methods.
Thus, combining homoenolates and acid-activated imines8,16
was expected to generate valuable γ-lactams17 (Scheme 1).
Herein we report an NHC/Brønsted acid-mediated reaction of
enals with unactivated imines that affords trans-γ-lactams in good
yields, high enantioselectivities, and good diastereoselectivities.
We initiated our study by examining the reaction of sterically
unhindered and unactivated N-(4-methoxycinnamylidene)ani-
line (1a) with strongly electrophilic and commercially available
ethyl trans-4-oxo-2-butenoate (2a) (Table 1). This reaction was
carried out in CH2Cl2 at room temperature in the presence of
base18 and 4 Å molecular sieves (MS) for 15 h using benzyl-
substituted triazolium salt C1 as the catalyst. When strong bases
such as KHMDS or Et3N were used, the product lactam was
generated in poor yield and selectivity. Under these conditions,
enal 2a competitively hydrates or oxidizes with adventitious
water or oxygen to form a carboxylic acid, which may serve as
the activator of the imine. Indeed, when Et3N was used as a
stoichiometric base, this pathway was eliminated (entry 2). The
use of carboxylate bases, on the other hand, was expected to
generate stronger conjugate acids capable of activating aldimine
1a. With NaOAc, the reaction afforded the annulation product,
lactam 3a, in 62% yield.19 Surprisingly, the trans-lactam (42% ee)
was formed in preference to the cis isomer (entry 4). This is the
first NHC-catalyzed synthesis of a trans-γ-lactam as the major
mpolung reactions catalyzed by N-heterocyclic carbenes
U
(NHCs) have become a quickly growing field in the past
decade.1 Since 2000, our group has focused on the design of
carbene precursors and the exploration of new asymmetric
reactions by NHC catalysis. We have developed two families of
catalysts (morpholine-based and pyrrolidine-based triazolium
salts) and successfully applied the azolium salts as precatalysts
for Stetter, redox, and cascade reactions that efficiently afford
versatile products in good enantioselectivity.2À4 Of these cata-
lysts, the triazolium precatalysts with an N-pentafluorophenyl
group installed to tune the electronic and steric nature exhibit
excellent catalytic activity. The corresponding carbenes derived
from this scaffold are far less basic and thus could be compatible
with weak acids. This is in agreement with our previous observa-
tion that sodium acetate can deprotonate the pentafluorophenyl
triazolium salts to give the free carbenes and acetic acid.4a
Interestingly, the presence of the Brønsted acid does not interfere
with the action of the carbenes.
We hypothesized that if an acid with low pKa value does not
neutralize a carbene (eq 1),5 the carbene and the acid could play
different roles in a reaction system, leading to new types of
reactions. On the basis of this hypothesis, we were interested in
exploring an NHC/Brønsted acid cooperative strategy in cata-
lysis. Although the concept of cooperative catalysis, such as
metal/Brønsted acid,6 NHC/Ag,7 and NHC/Mg or Ti,8 has
emerged in organic synthesis, NHC/Brønsted acid cooperative
catalysis has not been demonstrated.9
Homoenolates generated by the reaction of NHCs with enals
are vinylogous acyl anions, and their reactivity was first reported
independently by the Glorius and Bode groups in 2004.10 Since
then, investigations have documented their utility to prepare
Received: June 20, 2011
Published: July 25, 2011
r
2011 American Chemical Society
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Table 1. Base Screena
Table 2. Optimization of Azolium, Temperature, and Solventa
a Conditions: 2a, 0.2 mmol; 1a, 0.1 mmol; base, 20 mol %; C1 (structure
shown in Table 2), 20 mol %; CH2Cl2, 1 mL; 4 Å MS under Ar. b NMR
yields of the trans and cis diastereomers (internal standard). c The trans/
cis ratio, as determined by 1H NMR analysis. d ee of trans-3a as
determined by chiral HPLC. e 1.2 equiv of Et3N was used.
a Conditions: 2a, 0.2 mmol; 1a, 0.1 mmol; A2, 20 mol %; azolium cat., 20
mol %; solvent, 1 mL; 4 Å MS under Ar. b NMR yields of the trans and cis
diastereomers (internal standard). Entries in parentheses are isolated
yields. c The trans/cis ratio, as determined by 1H NMR analysis. d ee of
trans-3a as determined by chiral HPLC.
product.8a When the slightly weaker base PhCOONa was
employed, 3a was formed in 72% yield and 50% ee (entry 5).
Following this trend, the use of the much weaker bases A1 and
A2 (conjugate acids: p-NO2C6H4COOH, pKa[H2O] = 3.1;
o-ClC6H4COOH, pKa[H2O] = 2.9) afforded 3a in higher yields
and higher ee’s (entries 6 and 7). When the bases A3 and A4
derived from chiral amino acids were used, 3a was formed in
lower enantioselectivity, with the difference between the two
entries indicating a match and mismatch (entries 8 and 9).
Notably, the weak bases A3 and A4 were still capable of
deprotonating the azolium to generate the active catalyst.
We envisioned that moderately increased steric hindrance on
the azolium would provide a better chiral environment since the
nucleophilic carbanion on the intermediate homoenolate is
distant from the chiral center. When isopropyl-substituted
triazolium salt C2 was employed as a catalyst with A2, 3a was
generated in 66% ee (Table 2, entry 1). The azoliums C3 and C4,
which have slightly bulkier groups than in C2 and were prepared
from the corresponding amino acids, delivered higher enantios-
electivities (71 and 76% ee, respectively; entries 2 and 3). The
much bulkier azolium C5 was ineffective (entry 4). Triazolium
salt C6 exhibited moderate catalytic activity, affording 3a with
low ee (46%) (entry 5). Next, the reaction temperature and solvent
were investigated using the best catalyst (C4) and base (A2).
When the temperature was lowered to 0 °C, the yield, dr, and ee
were improved (entry 6). A further decrease in the temperature
to À10 °C affected the enantioselectivity slightly (entry 7).
Common solvents such as toluene, CHCl3, and ClCH2CH2Cl
were less effective than CH2Cl2. The use of other solvents (e.g.,
THF, ether, alcohols) delivered 3a in only trace amounts.
However, the use of acetonitrile as a solvent provided 3a with
91% ee, albeit in moderate yield (entry 8). Satisfyingly, when
inexpensive acrylonitrile was used as the solvent instead of
CH3CN, 3a was generated in excellent yield (93%), good ee
(90%), and good diastereoselectivity (11/1) (entry 10).
Under these optimized conditions, the substrate scope of R,β-
unsaturated imines was evaluated, and the results are shown in
Table 3.20 The electronic nature of the imine was investigated
first. When an electron-neutral group (ÀMe) or an electron-
deficient group (pÀCF3, pÀBr, pÀCl, mÀCl, mÀMeO) was
resident on the phenyl group of the aldimine, the cyclization was
slightly affected but afforded the products 3b and 3dÀh,
respectively, in good yield, good dr, and high enantioselectivity
(86À92% ee). In contrast, the reaction was more efficient in
CH2Cl2 when a methoxy group was placed at the para or meta
position (i.e., 3c, 35% yield, 86% ee, 6/1 dr in acrylonitrile and
87% yield, 81% ee, 4/1 dr in CH2Cl2). When the aldimines
derived from cinnamaldehyde, p-nitrocinnamaldehyde, and 3-(2-
furyl)acrylaldehyde were used, the corresponding products 3iÀk
were obtained in excellent yields and good enantioselectivities
(92, 93, and 89% ee, respectively). The imine from (E)-4-
methylpent-2-enal underwent cyclization to give 3l in low yield
in acrylonitrile as a result of decomposition of the imine.21 The
reaction proceeded well in CH2Cl2 to yield 3l in 73% yield and
88% ee. However, the imine generated in situ from enal and
aniline gave 3m in 85% yield, 92% ee, and 8/1 dr.
A variety of enals as suitable substrates were explored
(Table 4). Using a ketone as a substituent on the enal gave the
desired lactam 3n in 62% yield and >15/1 dr but only 66% ee
(entry 1). Less nucleophilic p-nitrocinnamaldehyde was fully
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Table 3. Evaluation of the Imine Substrate Scopea
Table 4. Exploration of Various Enalsa
a Conditions: aldehyde 2, 0.2 mmol; 1a, 0.1 mmol; A2, 20 mol %; C4; 20
mol %; solvent, 0.8 mL. All reactions were carried out under Ar in the
presence of 4 Å MS at 0 °C. The trans/cis ratios were determined by 1H
NMR analysis prior to purification. The ee’s were determined by
chiral HPLC. b 15 h in acrylonitrile. c 36 h in CH2Cl2. d 66 h in CH2Cl2.
Scheme 2. Proposed Pathway for trans-γ-Lactam Formation
a Conditions: 2a, 0.2 mmol; imine 1, 0.1 mmol; A2, 20 mol %; C4, 20
mol %; solvent, 0.8 mL. All reactions were carried out under Ar in the
presence of 4 Å MS at 0 °C for 15 h. The trans/cis ratios were
1
determined by H NMR analysis prior to purification. The ee’s were
determined by chiral HPLC. b CH2Cl2 was used as the solvent instead of
acrylonitrile. c The starting imine was formed in situ.
A few possible reaction pathways involving homoenolate
equivalents have been proposed in the literature.11,14 A plausible
mechanism for our reaction is shown in Scheme 2. The enal 2
first reacts with the carbene to generate a Breslow intermediate,
which attacks the acid-activated imine, perhaps via hydrogen-
bonding intermediate 4. Steric hindrance leads to an anti
orientation of R3 and the alkenyl. Proton transfer then results
in the formation of acyl carboxylate 5. The nitrogen species
replaces the carbene to afford the product 3 and the free carbene.
In conclusion, we have developed an efficient NHC-catalyzed
asymmetric approach for synthesizing trans-γ-lactams in high
yields, high enantioselectivities, and >20/1 dr with unactivated
imines. It is noteworthy that electron-rich carbenes have histori-
cally been used to catalyze homoenolate chemistry.1b Our
findings are promising in the application of homoenolates using
electron-deficient carbene catalysis. This method involves co-
operative NHC/Brønsted acid catalysis. In the transformation,
cyclohexyl-substituted carbene and o-chlorobenzoic acid are
converted to 3o in 93% ee and 14/1 dr. In contrast, much less
nucleophilic p-bromocinnamaldehyde and cinnamaldehyde
underwent cyclization less efficiently to give 3p and 3q in 56
and 48% yield, respectively, with good ee's and dr's.
In order to probe the role of the acid in our system, the
reaction of R,β-unsaturated imine 1a with enal 2a was examined
using an achiral carbene and chiral, enantioenriched amino acids.
We found that amino acids bearing more strongly electron-
withdrawing groups on nitrogen gave higher enantioselectivities.
Product ent-3a was obtained in 96% isolated yield, 17% ee, and
3/1 dr using A3 as the base (eq 2).22 Although the enantioselec-
tivity was low, this result suggests that hydrogen bonding exists in
the transformation and indicates that it is possible to develop an
approach with achiral carbenes and chiral acids16 to deliver
products with high enantioselectivity.
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures,
b
characterization data, determination of the absolute configura-
tions of products, NMR and HPLC spectra, and crystallographic
data (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
rovis@lamar.colostate.edu
’ ACKNOWLEDGMENT
We thank NIGMS (GM72586), Amgen, and Roche for
support. D.A.D. thanks Roche for an Excellence in Chemistry
Award. We thank Kevin M. Oberg (CSU) for solving the crystal
structure to determine the absolute configurations of products.
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Am. Chem. Soc. 2007, 129, 3520. (c) Chiang, P.-C.; Rommel, M.; Bode,
J. W. J. Am. Chem. Soc. 2009, 131, 8714.
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in situ imine exchange, 3m, was also formed (7%).
(20) Other imines: N-Bn and N-acyl R,β-unsaturated imines af-
forded trace amounts of the desired lactams. N-Ts imine did not produce
the lactam. The N-phenylaldimine derived from p-bromobenzaldehyde
delivered the lactam in modest yield and selectivity under these
conditions (∼50% yield, 2:1 trans/cis, 62/58% ee).
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homoenolate was observed.
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(22) When Boc-protected L-valine was utilized, 3a was formed with
lower enantioselectivity.
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