Enantioselective Conjugate Addition of 2-Acylimidazoles with Nitroalkenes Promoted by Chiral-at-Metal Rhodium(III) Complexes

Article abstract of DOI:10.1002/adsc.201701377

An enantioselective conjugate addition of 2-acylimidazoles with nitroalkenes catalyzed by chiral-at-metal rhodium(III) complex under mild reaction conditions was developed, affording versatile γ-nitro ketone skeletons in good yields with excellent enantioselectivities (up to >99% ee). (Figure presented.).

Full text of DOI:10.1002/adsc.201701377

Title: Enantioselective Conjugate Addition of 2-Acylimidazoles
with Nitroalkenes Promoted by Chiral-at-Metal Rhodium(III)
Complexes
Authors: Ganesh Kumar Thota, Gui-Jun Sun, Tao Deng, Yi Li, and
Qiang Kang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701377
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10.1002/adsc.201701377
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Enantioselective Conjugate Addition of 2-Acylimidazoles with
Nitroalkenes Promoted by Chiral-at-Metal Rhodium(III)
Complexes
Ganesh Kumar Thota,†a Gui-Jun Sun,†a Tao Deng,b Yi Li,b and Qiang Kanga,*
a
Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, Center for Excellence in Molecular Synthesis,
Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, 155 Yangqiao Road West,
Fuzhou, 350002, P. R. China
[Fax: (+86)-591-63173548; phone: (+86)-591-63173548; e-mail: kangq@fjirsm.ac.cn]
Department of Chemistry, Fuzhou University, 350116, P. R. China
b
†
These authors contributed equally to this work.
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
been studied as extensively.[9] In spite of these notable
Abstract. An enantioselective conjugate addition of 2-
acylimidazoles with nitroalkenes catalyzed by chiral-at-
metal rhodium(III) complex under mild reaction
conditions was developed, affording versatile γ-nitro
ketone skeletons in good yields with excellent
enantioselectivities (up to >99% ee).
advances, highly efficient protocols for the
enantioselective conjugate addition of simple ketones
with nitroalkenes are still desirable. On the basis of our
recent work on chiral-at-metal catalysts,[10] herein, we
disclose the catalytic asymmetric Michael addition of
imidazole-modified ketones with nitroalkenes
catalyzed by a chiral-at-metal Rh(III) complex with as
low as 1 mol% of catalyst loading.[11,12]
Keywords: Rhodium catalysis; Conjugate addition;
Enantioselective; Chiral-at-metal Complex
Nitroalkanes are highly versatile synthetic
intermediates on account of their facile α-alkylation
reactions and interconversions to other important
functional
groups
by
various
possible
transformations.[1] Therefore, catalytic diastereo- and
enantioselective conjugate additions of carbon
pronucleophiles to nitroalkenes has attracted much
attention.[2-4] The substrate-controlled enantioselective
Michael additions of ketones to nitroalkenes have been
intensively investigated before the emergence of
organocatalysts.[2] Since the pioneering contributions
from List[5] and Barbas,[6]
L-proline catalyzed
organocatalysis has represented a convenient approach
for the asymmetric addition of ketones to nitroalkenes.
However, this catalytic system is limited by a relatively
large catalyst loading (usually 10-20 mol%) and a long
reaction time. Complementarily, organometal
complexes have been recognized as attractive catalysts
and received continuous and ever-growing attention in
this research area during the last decade.[4] The
combination of chiral diamine ligands with a metal
such as Ni, Ca, Cu and Mn has been well investigated
in asymmetric conjugate addition with nitroalkenes. In
comparison with the most studied 1,2-[7] and 1,3-
dicarbonyl[8] types of nucleophiles, the reaction of
nitroalkenes with simple α-ketone nucleophiles has not
Scheme 1. Previous protocols and this work on asymmetric
conjugate addition of carbon pronucleophiles to nitroalkenes.
We began the initial optimization studies by
evaluating chiral-at-metal Rh(III) complexes in the
conjugate addition of N-methylimidazole modified
ketone 1a with nitrostyrene 2a. To our delight, in the
presence of 1 mol% of Λ-Rh1, the reaction was
completed within 17 h, giving the corresponding
product 3a in 95% yield with 89% ee (Table 1, entry
1
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10.1002/adsc.201701377
Advanced Synthesis & Catalysis
1). Encouraged by these interesting results, we
examined different chiral chiral Rh(III) complexes Λ-
Rh2, Λ-Rh3, Λ-Rh4 and Λ-Rh5 in the title reaction.
Gratifyingly, Λ-Rh3 was the most effective one among
various R1- and R2-substituted chiral Rh(III)
complexes, probably due to the steric hindrance and
electronic effect of 3,5-(CF3)2-phenyl substitution
(entry 3). Further optimization of reaction conditions
disclosed that tBuOH was the best solvent for the title
reaction (entry 6, for more details see Supporting
Information, Table S2).
led to a relatively lower enantioselectivity (82% ee).
Moreover, naphthyl substituted nitroalkene (2g) gave
quantitative yield with high ee value. Interestingly,
heteroaryl substituted nitroalkenes (2h, 2i) were also
tolerated under the optimal reaction conditions to yield
the corresponding products in moderate yields with
excellent enantioselectivities. Surprisingly, in addition
to aromatic substituents, the aliphatic variants of
nitroalkene 2j also found to be competent partner to
provide desired product in 98% yield with diminished
enantioselectivity (80% ee).
Table 1. Optimization of reaction conditions[a]
Time
[h]
Yield
[%][b]
Entry
Catalyst
Λ-Rh1
Λ-Rh2
Λ-Rh3
Λ-Rh4
Λ-Rh5
Λ-Rh3
ee [%][c]
89
1
17
24
24
48
24
24
95
70
95
80
68
98
2
86
3
91
Scheme 2. Substrate scope of nitroalkenes
4
85
5
84
Next, we examined the adaptability of imidazole-
modified α-ketones (Scheme 3).[13] The bulkiness of
the substituent on the imidazole ring (R’) has influence
on the enantioselectivity, given the fact that sterically
hindered isopropyl substituted imidazole delivered
desired product 3k with 84% ee. The electronic nature
of the R substituents had limited impact on the
reactivity and enantioselectivity, which generated the
desired adducts 3l-3n in quantitative yields with
excellent ee (94-99.4% ee). The ortho-substituted
substrates were also compatible to afford the
corresponding products 3o-3q in 71-99% yields with
90-99% ee. Furthermore, 3-thienyl substituted ketone
could also be used for the title reaction to afford the
desired product 3r in 99% yield with 96% ee, albeit
with moderate diastereoselectivity. Unfortunately,
aliphatic variants of 2-acylimidazoles were not
applicable in this transformation, probably due to low
nucleophilicity of those substrates. Another limitation
is the challenging all-carbon quaternary centres could
not be constructed under current protocol (3u, 0%
yield).[14] Remarkably, the asymmetric conjugate
addition of 1r with 2a was completed within 34 h in
the presence of as low as 0.2 mol% Λ-Rh3 complex as
6[d]
93
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), Λ-
Rh (1 mol%), iPrOH (0.3 mL).
[b] Yields were determined by 1H NMR with CH2Br2 as an
internal standard
[c] Determined by HPLC analysis.
[d] tBuOH as solvent.
With the optimized reaction conditions in hand
(Table 1, entry 6), the substrate scope of various
nitroalkenes was examined. As demonstrated in
Scheme 2, aromatic nitroalkenes with electron-
donating groups (2a, 2b) as well as electron-
withdrawing groups (2c-2e) in the para or meta
position of the phenyl ring, affording the desired
products
in
good
yields
with
excellent
enantioselectivities under the optimal reaction
conditions, albeit diminished yield for para-Cl
substituted nitroalkene 2d. ortho-Substituted aromatic
alkene 2f required a slightly longer reaction time and
2
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10.1002/adsc.201701377
Advanced Synthesis & Catalysis
catalyst, affording 3r in 99% yield (495 catalyst
turnovers) with 96% ee. The absolute configuration of
product 3c was determined by a single-crystal X-ray
analysis (for details, see Supporting Information).[15]
Scheme 5. Proposed mechanism
In conclusion, we have developed a highly efficient
enantioselective conjugate addition of imidazole-
modified ketones with readily available nitroalkenes
catalyzed by a chiral-at-metal Rh(III) complex,
affording versatile γ-nitro ketone skeletons in good
yields with excellent enantioselectivities. The reaction
was applicable to various substrates and proceeded
well in mild reaction conditions. Notably, this protocol
exhibits excellent reactivity and enantioselectivity, as
the fact that by employing as low as 0.2 mol% Λ-Rh3
complex, the reaction could be complete with high
yield and excellent ee value. Further research on the
design new type of chiral Rh(III) complexes and its
application in asymmetric synthesis is ongoing in our
laboratory.
Scheme 3. Substrate scope of imidazole-modified ketones
To illustrate the potential synthetic application of
current protocol, further transformation of product to
useful synthetic building blocks was carried on. The
conjugate adduct 3a could be easily transferred to
corresponding methoxy ester 4 after cleavage of the N-
methylimidazole group without loss in enantiomeric
excess (Scheme 4, 4, 78% yield, 94% ee).
Experimental Section
General Procedure for Catalytic Enantioselective
Michael Addition of 2-Acylimidazoles to Nitroalkenes
To a solution of 2-acyl imidazole substrate 1 (0.2 mmol)
in tBuOH (0.2 mL) or tBuOH:DCE (2:1, 0.3 mL), 1 mol% of
Ʌ-Rh3 was added under argon atmosphere. The reaction
mixture was allowed to stir at RT for 20 minutes before
adding nitroalkenes 2 (1.2 equiv). Then the reaction mixture
was allowed to stir at room temperature under argon
atmosphere. After the reaction was complete as monitored
by TLC, aqueous saturated NH4Cl (2 mL) was added. The
organic layer was separated and the aqueous layer was
extracted with DCM (3×2 mL). The combined organic
layers were washed with brine (4 mL), separated, dried over
Na2SO4, filtered and concentrated under reduced pressure.
The crude product was purified by column chromatography
(silica gel, EtOAc/PE, 1:20) to afford the desired product 3.
Scheme 4. Synthetic transformation of product 3a.
A possible mechanism for chiral-at-metal Rh(III)
complex catalyzed enantioselective conjugate addition
reaction of imidazole-modified ketones with
nitroalkenes is proposed (Scheme 5). Mechanistically,
the chiral Rh(III) complex would activate the 2-
acylimidazoles 1 through ligand exchange and
bidentate N,O-coordination (intermediate A) followed
by deprotonation to generate the enolate (intermediate
B), which react with nitroalkenes 2 to give
intermediate C. Ligand exchange of intermediate C
with 1 delivers the corresponding product 3 followed
by initiation of new catalytic cycle. The
stereochemistry of the product could be rationalized by
approach of the nitroalkene 2 from the less hindered
Re-face of the enolate according to steric shielding.
Acknowledgements
We thank Prof. Daqiang Yuan (Fujian Institute of Research on the
Structure of Matter, Chinese Academy of Sciences) for his kind help
in an X-ray analysis. This work was supported by the Strategic
Priority Research Program of the Chinese Academy of Sciences,
Grant No. XDB20000000 and 100 Talents Programme of the
Chinese Academy of Sciences.
3
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10.1002/adsc.201701377
Advanced Synthesis & Catalysis
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Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201701377
Advanced Synthesis & Catalysis
COMMUNICATION
Enantioselective Conjugate Addition of 2-
Acylimidazoles with Nitroalkenes Promoted by
Chiral-at-Metal Rh(III) Complexes
Adv. Synth. Catal. Year, Volume, Page – Page
Ganesh Kumar Thota,†a Gui-Jun Sun,†a Tao Deng,b
Yi Li,b and Qiang Kanga,*
6
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