Enantioselective organocatalytic conjugate addition of alkenes to α,β-enones

Article abstract of DOI:10.1002/ejoc.201402353

We report the first example of the enantioselective conjugate addition of alkenes (aromatic enamines) to enones catalyzed by chiral primary amines. The reactions encompass a plethora of α,β-enones including difficult α-substituted vinyl ketones to give vinylation adducts in high yields with good enantioselectivity. The methodology is of synthetic potential in accessing chiral functional materials. Copyright

Full text of DOI:10.1002/ejoc.201402353

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402353
Enantioselective Organocatalytic Conjugate Addition of Alkenes to α,β-Enones
Lingyun Cui,[a] Long Zhang,[a] Sanzhong Luo,*[a,b] and Jin-Pei Cheng[a,b]
Keywords: Synthetic methods / Organocatalysis / Conjugate addition / Enamines / Alkenes / Enantioselectivity
We report the first example of the enantioselective conjugate
addition of alkenes (aromatic enamines) to enones catalyzed
ketones to give vinylation adducts in high yields with good
enantioselectivity. The methodology is of synthetic potential
in accessing chiral functional materials.
by chiral primary amines. The reactions encompass
a
plethora of α,β-enones including difficult α-substituted vinyl
metal catalysts[3] and Lewis acids catalysts.[4] In this con-
text, organocatalytic versions are still rare,[5] and the cata-
lytic asymmetric direct conjugate addition of alkenes to α,β-
unsaturated carbonyls has not been reported so far.
Recently, we found that para-vinylanilines underwent
smooth C–C coupling with aldehydes to afford bisallylic ad-
ducts through Knoevenagel-type 1,2-addition.[6] The para-
vinylanilines demonstrated nucleophilic reactivity closely
resembling that of typical enamines [Scheme 1, Equa-
tion (2)] as a result of the conjugated para-amino groups.
These electron-rich anilines have also been widely utilized
as functional building blocks in organic electronics.[7] This
feature, together with the now extensively explored C–H/C–
X functionalization of anilines,[8] underlies enormous syn-
thetic potential for para-vinylanilines, which remain largely
unexplored. In this context, we have challenged these aro-
matic enamines as nucleophilic synthons in enantioselective
C–C bond formation. Herein, we wish to report the enan-
tioselective conjugate addition of vinylaniline to enones cat-
alyzed by chiral primary amine catalysts to result in unprec-
edented organocatalytic direct addition reactions with alk-
enes.
Introduction
Conjugate addition to α,β-unsaturated carbonyl com-
pounds is among the most utilized organic reactions for C–
C bond formation.[1] Simple alkenes are less employed in
conjugate addition reactions owing to their low nucleophi-
licity as well as difficulties in controlling the chemo- and
stereoselectivity. Alternatively, vinylated organometallics
such as Grignard reagents, organocopper reagents, or-
ganozinc reagents, and organoboron compounds have been
widely employed in conjugate addition reactions to afford
vinylated adducts [Scheme 1, Equation (1)].[2] Recently,
notable progress was achieved in the direct conjugate ad-
dition of simple alkenes to enones by the aid of transition-
Results and Discussion
Our studies started with the examination of the nucleo-
philic addition of vinylaniline 1a to enone 2a. After exten-
sive screening of different diamine catalysts (see the Sup-
porting Information for the screening results), we eventually
identified chiral primary-tertiary diamine 3 derived from
quinine[9,10] as the optimal aminocatalyst, which delivered
the desired adducts in 97% yield with 76%ee (Table 1, en-
try 1). During the extensive screening, we noticed that
acidic additives had a dramatic influence on the reaction
outcome, and in this regard, aryl sulfonic acids were found
to be the optimal acids in terms of both activity and
enantioselectivity. Variations on the aryl ring were then ex-
amined to further improve the enantioselectivity (Table 1,
entries 1–5). 2,4,6-Trimethylbenzenesulfonic acid (5d) was
Scheme 1.
[a] Beijing National Laboratory for Molecular Sciences, CAS Key
Laboratory of Molecular Recognition and Function Institute
of Chemistry, Chinese Academy of Sciences,
Beijing 100190, China
E-mail: luosz@iccas.ac.cn
http://luosz.iccas.ac.cn
[b] Collaborative Innovation Center of Chemical Science and
Engineering,
Tianjin, 300071, China
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402353.
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Organocatalytic Conjugate Addition of Alkenes to α,β-Enones
finally reached with a balance of activity and enantio- aniline 1a; it provided the product in high yield but with
selectivity (Table 1, entry 4). Optimization of the reaction low enantioselectivity (Table 2, entry 14).
parameters revealed that the reaction was more efficient
Table 2. Survey of different substituted enones in the primary
with chloroform as the solvent (Table 1, entry 4 vs. entries 7
and 8), and the addition of molecular sieves (MS, 4 Å) led
to a further improvement in the enantioselectivity (85%
yield, 90%ee; Table 1, entry 10).
amine catalyzed conjugate addition.[a]
Table 1. Optimization of the reaction conditions.[a]
Entry R1
R2
Product
Yield[b]
[%]
ee[c] [%]
1
2
3
4
5
6
7
8
Ph
4-Bu
4-Br
2-Br
H
H
H
H
H
H
H
H
H
H
H
CH3
Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
85
70
94
95
96
93
94
75
87
89
75
75
96
98
90
92
81
84
84
90
91
91
83
90
76
84
54
30
2-Cl
3,5-(CH3)2O
3,4,5-(CH3)3O
2-naphthyl
2-furyl
2-thiophenyl
2-benzofuryl
Ph
Entry
Acid
Solvent
T
[°C]
Additive Yield[b]
[%]
ee[c]
[%]
9
10
11
12
13
14
1
2
3
4
5
6
7
8
5a
5b
5c
5d
5e
5d
5d
5d
5d
5d
5d
5d
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CH2Cl2
PhCl
65
65
65
65
65
40
65
65
65
65
25
65
–
–
–
–
–
–
–
97
68
99
82
30
41
66
47
71
85
Ͻ5
88
76
87
70
87
77
68
81
80
81
90
68
88
Ph
–(CH2)3–
[a] General conditions:
2
(0.1 mmol), 1a (0.2 mmol), 3/5d
(20:20 mol-%), 4 Å MS (2 mg), CHCl3 (0.5 mL), 65 °C. [b] Yield of
isolated product. [c] Determined by HPLC analysis.
THF
–
9[d]
10[e]
11[e]
12[e]
CHCl3
CHCl3
CHCl3
CHCl3
PPh3
4 Å MS
4 Å MS
3 Å MS
The scope of the reaction with respect to the para-vinyl-
anilines was next investigated (Scheme 2). Ethyl substitu-
ents on the para-amino group were tolerated, and corre-
sponding adducts 4o–q were obtained in good yields and
high enantioselectivity. Replacement of the dialkylamino
group with a pyrrolidine ring reduced the reactivity and the
enantioselectivity, as observed with 1c. Unfortunately, no
reaction was observed if the dialkylamino group was re-
placed by the morpholine group (1d), likely a result of its
poor electron-donating ability.
[a] General conditions: 2a (14.6 mg, 0.1 mmol), 1a (53.2 mg,
0.2 mmol), solvent (0.5 mL), (20 mol-%), acid (20 mol-%).
3
[b] Yield of isolated product. [c] Determined by HPLC analysis.
[d] Additive (10 mol-%). [e] MS (2 mg).
With the optimized conditions in hand, we next probed
the scope of the conjugate addition for a variety of enones,
and the results are presented in Table 2. The scope of the
enones is quite general. Enones bearing either electron-do-
nating (Table 2, entries 2, 6, and 7) or electron-withdrawn
(Table 2, entries 3–5) groups were equally applicable in the
reactions. Additionally, heterocyclic enones bearing furyl,
thiophenyl, and benzofuryl substituents all worked very
well to afford the desired products in good yields with good
enantioselectivity (Table 2, entries 9–11). Notably, phenyl
and ethyl ketones could also be used in the reactions, and
they gave high yields of the desired adducts with moderate
to good enantioselectivities (Table 2, entries 12 and13). Cy-
clohexenone was also examined in the reaction with vinyl- Scheme 2. Survey of different para-vinylanilines.
Eur. J. Org. Chem. 2014, 3540–3545
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L. Cui, L. Zhang, S. Luo, J.-P. Cheng
SHORT COMMUNICATION
We next investigated the reactions with α-substituted Table 3. The adducts of the enantioselective protonation reaction
catalyzed by primary amines.[a]
vinyl ketones [Scheme 3, Equation (3)]. The enantioselective
conjugate addition with α-substituted vinyl ketones remains
elusive in asymmetric catalysis, as the stereocenter in this
case is not generated in the C–C formation step, but in a
rather challenging protonation step.[11] As a continuation of
our explorations on asymmetric enamine protonations,[12]
we challenged chiral primary amine catalysts in the direct
alkene addition to vinyl ketones. Identified β-selective cata-
lyst 3/5d gave only 50% yield and 60%ee in the α-stereo-
genic reaction (Scheme 3). After screening, our previously
developed primary amine catalyst 9/trifluoromethanesulfo-
nic acid (TfOH)[12d] was found to give the best results (79%
yield, 90%ee) under the optimized conditions.
Scheme 3. Enantioselective conjugate addition with α-substituted
vinyl ketones.
The substrate scope of the enantioselective protonation
reaction was explored (Table 3). α-Methyl and α-ethyl vinyl
ketones showed very good yield and high enantioselectivity
(Table 3, compounds 8a and 8b). Upon changing the methyl
substituent to a bulky group, such as propyl or benzyl, the
enantioselectivity was maintained, but the reactivity de-
creased (Table 3, compounds 8c and 8d). Enones bearing
either electron-donating (Table 3, compound 8e) and elec-
tron-withdrawing (Table 3, compound 8f) groups were
equally applicable in the reactions. Additionally, the reac-
tion with thiophenyl-substituted enones worked well to af-
ford the desired products with good enantioselectivity
(Table 3, compounds 8g). An ethyl-substituted aromatic en-
amine was also tested in the reaction, and in those reac-
tions, the desired adducts were obtained in moderate to
good yields and enantioselectivities (Table 3, compounds 8h
and 8j).
Anilines are very useful synthons in organic synthesis,
and they can be transformed into many important mo-
lecules by C–H/C–X functionalization. We found that ad-
duct 4a could be successfully converted into ammonium tri-
flates 5 in nearly quantitative yield.[13]
[a] General conditions: 7 (0.1 mmol), 1 (0.12 mmol), 9/TfOH
(18:20 mol-%), 3 Å MS (2 mg), brine (10 equiv.), PhCl (0.5 mL),
In situ generated ammonium salt 5 smoothly underwent
Kumada-type coupling with a Grignard reagent, and in this
instance, Grignard addition also occurred to the ketone
60 °C. [b] 7 (0.1 mmol), 1 (0.12 mmol), 9/TfOH (18:20 mol-%),
PhCl (0.5 mL), 60 °C.
moiety. The triphenylated adduct was isolated in 67% yield
with 3:1dr and maintained enantioselectivity (Scheme 4). phenyl group under Birch reduction conditions (64% yield,
The ammonium moiety was also be reduced to reveal a 90%ee; Scheme 4).[14] Vinylation adduct 4c was also readily
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Organocatalytic Conjugate Addition of Alkenes to α,β-Enones
Scheme 4. Further transformation of the aniline moiety.
derivatized with thiophene and benzothiophene through
A typical iminium-ion cycle is proposed for the alkene
typical Suzuki coupling, which led to conjugated aromatics addition reactions (Scheme 6).[16,17] Critical iminium ion in-
(Scheme 5).[15]
termediate I (m/z = 452.2699) as well as catalyst–product
adduct II/III (m/z = 718.4477) can be detected by ESI-MS
analysis of the reaction mixture, which verifies the amino-
catalytic nature of this reaction.
Conclusions
In summary, we developed an unprecedented enantiose-
lective conjugate addition of alkenes to enones under mild
reaction conditions. The reaction is enabled by chiral pri-
mary amines through a typical iminium ion cycle, and both
β-substituted and unsubstituted α,β-enones can be incorpo-
rated to give vinylation adducts in high yields with good
enantioselectivity.[18] The obtained conjugated adducts, en-
dowed with their versatile derivatization sites as demon-
strated, are of potential as chiral organic electronics. Fur-
ther exploration of the nucleophilic features of para-vinyl-
anilines in catalysis as well as investigations into the appli-
cations of the obtained conjugated molecules are ongoing.
Scheme 5. Further functionalization of adduct 4c.
Scheme 6. Proposed catalytic cycle for the conjugate addition.
Eur. J. Org. Chem. 2014, 3540–3545
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L. Cui, L. Zhang, S. Luo, J.-P. Cheng
SHORT COMMUNICATION
N. Krause, O. Pàmines, M. Diéguez, Chem. Rev. 2008, 108,
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Experimental Section
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General Information: Commercial reagents were used as received,
1
unless otherwise indicated. H NMR and 13C NMR spectra were
1
measured with a NMR instrument (300 MHz for H, 75 MHz for
1
13C). Tetramethylsilane served as the internal standard for the H
NMR spectra, and CDCl3 served as the internal standard for the
13C NMR spectra. The enantiomeric excess values were determined
by HPLC analysis on Chiral Daicel Chiralcel AD-H, IA-H, and
OD-H columns. The IR spectra were obtained by using an FTIR
spectrometer (Thermo Fisher Nicolet 6700). Optical rotations were
measured by using a 0.5 mL cell with a 0.25 dm path length and a
high accuracy polarimeter Rudolph Autopl VI. HRMS was re-
corded with a commercial instrument (EI or ESI Source).
Representative Procedure for the Enantioselective Conjugate Ad-
dition of Alkenes to Enones: To a solution of 3/5d (11.2 mg, 20 mol-
%) in CHCl3 (0.5 mL) was added 2a (0.1 mmol) and 1a (0.2 mmol).
Then, 4 Å MS (2 mg) were added into the tube. The resulting solu-
tion was stirred at 65 °C. The progress of the reaction was moni-
tored by TLC. After completion, the reaction mixture was directly
separated by flash column chromatography on silica gel (petroleum
ether/ethyl acetate). Collected fractions were concentrated, and the
product was dried under high vacuum.
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Representative Procedure for the Enantioselective Protonation Reac-
tions
Method A: Catalyst 9/TfOH (18:20 mol-%) and α-substituted vinyl
ketone 7 (0.1 mmol) were dissolved in PhCl (0.2 mL) and brine
(18 μL), and the mixture was stirred for 15 min under ambient at-
mosphere at room temperature. To the mixture, aromatic enamine
1a (0.12 mmol) was added. Then, 3 Å MS (2 mg) were added into
the tube. The resulting solution was stirred at 60 °C. The progress
of the reaction was monitored by TLC. After completion, the reac-
tion mixture was directly separated by flash column chromatog-
raphy on silica gel (petroleum ether/ethyl acetate). Collected frac-
tions were concentrated, and the product was dried under high vac-
uum.
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[8]
[9]
Method B: Catalyst 9/TfOH (18:20 mol-%) and aromatic enamine
1b (0.05 mmol) were dissolved in PhCl (0.2 mL), and the mixture
was stirred for 5 min under ambient atmosphere at room tempera-
ture. To the mixture, α-substituted vinyl ketone 7 (0.1 mmol) was
added. The resulted solution was stirred at 60 °C. The progress of
the reaction was monitored by TLC. After completion, the reaction
mixture was directly separated by flash column chromatography on
silica gel (petroleum ether/ethyl acetate). Collected fractions were
concentrated, and the product was dried under high vacuum.
[10]
Supporting Information (see footnote on the first page of this arti-
cle): Screening reactions, characterization data, crystallographic
1
data, and copies of the H NMR and 13C NMR spectra.
Acknowledgments
The authors thank the National Natural Science Foundation of
China (NSFC) (grant numbers 21390400 and 21025208 to S. L. and
21202171 to L. Z.) and the National Basic Research Program of
China (2011CB808600) for financial support. The authors thank
Dr. Xiang Hao and Ms. Tongling Liang for assistance in X-ray
crystallographic analysis.
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X-ray crystal structures of compounds 8g and 10 were deter-
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crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
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[18] The para-vinylanilines also reacted with α,β-enals to give
mainly 1,2 adducts, see ref.[6]
Received: April 4, 2014
Published Online: April 28, 2014
Eur. J. Org. Chem. 2014, 3540–3545
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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