Enantioselective Aza-morita-baylis-hillman reaction using aliphatic α-amidosulfones as imine surrogates

Article abstract of DOI:10.1002/adsc.200900900

The bifunctional catalyst 6^'-deoxy-6^'-acylamino- β-isocupreidine (1) served both as a base to trigger the in situ generation of N-sulfonylimine from readily available α-amidosulfones and as a chiral nucleophile to initiate the enantioselective aza-Morita-Baylis-Hillman (aza-MBH) reaction. α-Methylene-β-amino-β-alkyl carbonyl compounds, difficultly accessible previously, can now be synthesized in excellent yields and enantioselectivities.

Full text of DOI:10.1002/adsc.200900900

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DOI: 10.1002/adsc.200900900
Enantioselective Aza-Morita–Baylis–Hillman Reaction Using
Aliphatic a-Amidosulfones as Imine Surrogates
Nacim Abermil,a Gꢀraldine Masson,a,* and Jieping Zhua,*
a
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France
Fax : (+33)-1-6907-7247; e-mail: masson@icsn.cnrs-gif.frzhu@icsn.cnrs-gif.fr
Received: December 26, 2009; Published online: February 24, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900900.
Abstract: The bifunctional catalyst 6’-deoxy-6’-acyl-
amino-b-isocupreidine (1) served both as a base to
between aliphatic N-sulfonyl-a-amidosulfones 3 and
various Michael acceptors (MA, 4) in the presence of
a catalytic amount of 1 and 2 to afford the aza-MBH
adducts (5) in excellent yields and enantioselectivities
(Scheme 1). In this catalytic process, catalyst 1 served
both as a base to trigger the formation of N-sulfonyl-
ACHTUNGTRENNUNG
trigger the in situ generation of N-sulfonylimine
from readily available a-amidosulfones and as a
chiral nucleophile to initiate the enantioselective
aza-Morita–Baylis–Hillman (aza-MBH) reaction. a-
Methylene-b-amino-b-alkyl carbonyl compounds,
difficultly accessible previously, can now be synthe-
sized in excellent yields and enantioselectivities.
AHCTUNGTREGUNiNN mine and then as a nucleophile to catalyze the aza-
MBH reaction.
The a-amidosulfones are known to be valuable pre-
cursors of imines.[8–9] Recently, the combination of
proline catalysis with an excess of inorganic base has
been exploited for the development of enantioselec-
tive aza-MBH reactions using aromatic a-amidosul-
fones as imine surrogates.[10] Since the b-isocupreidine
derivative 1 having a tertiary amine could be consid-
ered as a base in addition to its nucleophilicity, we
thought that it might be possible to develop a catalyt-
Keywords: a-amidosulfones; asymmetric synthesis;
aza-Morita–Baylis–Hillman reaction; bifunctional
organocatalysis; b-isocupreidine; organocatalysis
The aza-Morita–Baylis–Hillman (aza-MBH) reaction ic aza-MBH reaction using a-amidosulfones as sub-
is a powerful tool for the preparation of synthetically strates. The underlying principle is depicted in
useful a-methylene-b-amino carbonyl compounds.[1] Scheme 2. Thus, catalyst 1 would act first as a base to
Although significant progress has been made in this convert 3 into N-sulfonylimine 6 and benzenesulfinate
field,[2–6] the development of a catalytic asymmetric 7. Michael addition of 7 to MA 4 would furnish the
aza-MBH reaction with aliphatic imines has proven to enolate 9, which could in turn abstract a proton from
be challenging. One of the main problems associated
with the use of enolizable imines is their instability
under aza-MBH conditions due to imine-enamine
tautomerization and their subsequent side reactions.
Indeed, degradation of aliphatic imines was observed
under most of the reported catalytic condi-
tions.[3b,d,k,4d,6] We recently described a dual catalyst
system involving 6’-deoxy-6’-acylamino-b-isocuprei-
dine (1) and the b-naphthol (2) that was able to con-
vert aliphatic imines to the corresponding aza-MBH
adducts (Scheme 1).[7] Although the enantioselectivity
was excellent, the yield remained moderate at best.
As a continuation of this research program, we as-
sumed that generating the imine in situ under condi-
tions conducive to the aza-MBH reaction could be a
solution to the problem. Herein, we report the devel-
opment of a catalytic asymmetric aza-MBH reaction sulfones.
Scheme 1. Enantioselective aza-MBH reaction of a-amido-
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Enantioselective Aza-Morita-Baylis–Hillman Reaction Using Aliphatic a-Amidosulfones
Scheme 2. a-Amidosulfones 6 as latent sulfonylimines in b-ICD-amide-catalyzed aza-MBH reaction: a postulated catalytic
cycle.
the protonated catalyst 8 to afford the Michael creasing consequently the yield of aza-MBH adduct 5.
adduct 10 with concurrent regeneration of catalyst 1. The inclusion of achiral b-naphthol 2 was thought to
The in situ generated imine and remaining MA would increase the enantioselectivity of the aza-MBH reac-
then enter into the aza-MBH reaction manifold in the tion in accord with our earlier observations.[7]
presence of bifunctional catalyst 1 to provide the
To validate this hypothesis, we carried out the aza-
adduct 5 via intermediates 11 and 12.[10] It is conceiva- MBH reaction of N-p-methoxybenzenesulfonyl-a-
ble that 1 may undergo Michael addition to 4 (step amidosulfone 3a with b-naphthyl acrylate 4a in the
4), before it acted as a base, to generate 11 that could presence of a catalytic amount of 6’-deoxy-6’-benz-
undergo a Rauhut–Currier-type reaction in the ab- amido-b-isocupreidine 1a (Ar=Ph) and b-naphthol 2
sence of electrophilic imine species.[11] However, we (Table 1). At room temperature, the reaction of 3a
assumed that the reversibility of step 4 and the irre- with two equivalents of 4a provided indeed the de-
versible nature of step 1 would guarantee the success- sired product 5a in 44% yield with 88% ee, along with
ful generation of imine 6, hence the overall domino ethyl 3-phenylsulfonylpropionate (10) in quantitative
process.[12] In addition, the fact that imine 6 is gener- yield based on 3a (cf. Supporting Information). By in-
ated gradually in situ could potentially avoid side re- creasing the amount of Michael acceptor 4a to 3
actions associated with the instability of imine 6, in- equivalents, the yield of 5a increased significantly
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Nacim Abermil et al.
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Table 1. Optimization of reaction conditions.
Table 2. (Continued)
Entry[a]
Product 5
Yield
[%][d]
ee
[%][e]
6[b]
5g 75
93
7[c]
8[c])
9[c]
5h 63
5i 91
5j 78
91
91
92
Entry[a] 4a [equiv.] T [8C] Additive Yield [%][b] ee [%]
1
2
3
4
5
6
2
3
3
3
3
3
r.t.
r.t.
r.t.
r.t.
10
–
–
44[a]
71[a]
88[a]
89[a]
88[a]
90[a]
NaHCO3 53[a]
4 ꢂ MS 86[a]
4 ꢂ MS >99 (57)[e] 92(87)[e]
10
4 ꢂ MS 41[f]
77[f]
93
10[c]
11[c]
12[b]
5k 93 (47)[f]
[a]
[b]
[c]
[d]
(À18)[f]
Reaction conditions: 3a/1a/2=1/0.1/0.1 in CH2Cl2 (c 0.35).
Isolated yield after column chromatography.
Determined by chiral HPLC analysis.
The absolute configuration of 4a was determined to be
(S)-enriched. For details see Supporting Information.
Starting from imine.
5l 86
90
86
[e]
[f]
In the absence of b-naphthol (2).
5m 54
13[b]
5n 56
87
Table 2. Enantioselective aza-MBH reaction with represen-
tative aliphatic N-sulfonyl-a-amidosulfones.
[a]
Reaction conditions: 3/4/1/2=1/3/0.1/0.1 in CH2Cl2 (c 0.35)
in the presence of 4 ꢂ MS at 108C, 12 h.
Using 1a as catalyst.
[b]
[c]
[d]
[e]
[f]
Using 1b as catalyst.
Isolated yield after column chromatography.
Determined by chiral HPLC analysis.
In the absence of b-naphthol (2).
(71% yield, entry 2). The addition of inorganic base
(NaHCO3, entry 3) decreased the yield of 5a probably
due to the increased rate of imine generation. By low-
ering the temperature to 108C and adding MS 4 ꢂ as
an additive, the aza-MBH adduct 5a was obtained in
nearly quantitative yield with an enantiomeric excess
of 92% (entry 3). Interestingly, in the absence of 2,
not only the ee, but also the yield of adduct was re-
duced (entry 6). A parallel experiment showed that
use of alkyl a-amidosulfones resulted in a considera-
ble improvement of both yield (99% vs. 57%) and
enantioselectivity (92% vs. 87%) relative to reaction
using preformed imines (entry 5).
Having established the optimal reaction conditions,
we then probed the generality of this catalytic asym-
metric aza-MBH reaction with a variety of Michael
acceptors and aliphatic a-amidosulfones. As shown in
Table 2, the N-sulfonyl-a-amidosulfones worked well
with both a- or b-naphthyl acrylates to afford the cor-
Entry[a]
Product 5
Yield
[%][d]
ee
[%][e]
1[b]
2[b]
3[b]
5b 95
91
92
92
5c 70
5d 67
4[b]
5e >99
5f 88
91
94
5[b]
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Adv. Synth. Catal. 2010, 352, 656 – 660

Enantioselective Aza-Morita-Baylis–Hillman Reaction Using Aliphatic a-Amidosulfones
responding (S)-aza-MBH adducts 5 in high yields Experimental Section
(67–95%) with high enantioselectivities (up to 91%
ee, entries 1–6). The reaction of linear aliphatic ami- General Procedure
dosulfones with methyl vinyl ketone (MVK) provided
To a solution of a-amidosulfone (3, 0.073 mmol) and 50 mg
also the (S)-adduct in excellent yields and ees when
1b (Ar=9-anthracenyl) in combination with b-naph-
thol 2 was used as catalysis (entries 7–9). The reaction
between a-amidosulfones derived from b-branched al-
dehydes with MVK under the same conditions afford-
ed a low yield of adducts. However, when the reaction
was carried out at 08C under otherwise identical con-
ditions, the expected (S)-aza-MBH adducts were iso-
lated in good yields and excellent enantioselectivities
(entry 10). On the other hand, the amidosulfones de-
rived from a-branched aldehydes were poor sub-
strates leading to the aza-MBH adducts in low yields
and low enantioselectivities. In the case of MVK, the
presence of achiral additive 2 was of the utmost im-
portance. In its absence, the aza-MBH reaction of 3a
with MVK gave the corresponding adduct with the
opposite enantioselectivity in moderate yield and
lower ee.[13] The achiral additive-induced reversal of
enantioselectivity of the aza-MBH with MVK as Mi-
chael acceptor has recently been reported by us.[7b]
Acrolein proved to be a suitable Michael acceptor for
the reaction (entries 12 and 13). The a-N-trimethylsi-
lylethanesulfonyl (SES)[14] alkyl sulfones was also ac-
cepted as a substrate to afforded the adduct in excel-
lent yield (> 99%) and ee (91%, entry 4).[3c,4a]
The absolute configuration of adducts 5 was deter-
mined to be (S) by comparison of the specific optical
rotation with known values (cf. Supporting Informa-
tion). Addition of enolate to the Re face of the in situ
generated N-sulfonylimines and the irreversibility of
the Mannich reaction could be evoked to explain the
observed enantioselectivity.[15]
In conclusion, we have demonstrated that a-amido-
sulfones are suitable substrates in the b-ICD-amide 1
and 2-co-catalyzed aza-MBH reaction. In this domino
process, catalyst 1 served both as a base to trigger the
formation of N-sulfonylimine and then as a nucleo-
phile to initiate the aza-MBH reaction. Acrylates,
MVK and acrolein participated in the reaction with in
situ generated alkylimines to afford uniformly the (S)-
adducts in high yields and excellent enantioselectivi-
ties. Besides mild reaction conditions and operational
simplicity, the present method allowed an easy access
to a-methylene-b-amino-b-alkyl carbonyl compounds,
expanding therefore significantly the generality of the
enantioselective aza-MBH reaction.
of molecular sieves in dried dichloromethane at 08C or
108C were added catalyst (1, 0.0073 mmol, 0.1 equiv.), b-
naphthol (2, 0.0073 mmol, 0.1 equiv.) and Michael acceptor
(4, 0.22 mmol, 3.0 equiv.). The reaction mixture was stirred
under argon atmosphere for 12 h. The reaction was stopped
by passing the mixture through a short pad of silica gel
using ethyl acetate as eluent. Solvents were removed under
reduced pressure and the resulting crude product was puri-
fied by preparative TLC (n-heptane/EtOAc, 70/30) to afford
the corresponding aza-MBH product.
Acknowledgements
We gratefully acknowledge CNRS and ICSN for financial
support. N.A. thanks ICSN for a doctoral fellowship.
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