N-heterocyclic carbene-catalyzed chemoselective cross-aza-benzoin reaction of enals with isatin-derived ketimines: Access to chiral quaternary aminooxindoles

Article abstract of DOI:10.1021/ol501286e

A chemo- and enantioselective cross-aza-benzoin reaction between enals and isatin-derived ketimines is disclosed. The high chemoselectivity (of the acyl anion reaction over enal α- and β-carbon reactions) is enabled by the electronic and steric properties of the N-heterocyclic carbene organocatalyst.

Full text of DOI:10.1021/ol501286e

Letter
pubs.acs.org/OrgLett
N‑Heterocyclic Carbene-Catalyzed Chemoselective Cross-Aza-
Benzoin Reaction of Enals with Isatin-Derived Ketimines: Access to
Chiral Quaternary Aminooxindoles
Jianfeng Xu,†,§ Chengli Mou,†,‡,§ Tingshun Zhu,† Bao-An Song,*,‡ and Yonggui Robin Chi*,†,‡
†Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
‡Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural
Bioengineering, Ministry of Education, Guizhou University, Huaxi District, Guiyang 550025, China
S
* Supporting Information
ABSTRACT: A chemo- and enantioselective cross-aza-
benzoin reaction between enals and isatin-derived ketimines
is disclosed. The high chemoselectivity (of the acyl anion
reaction over enal α- and β-carbon reactions) is enabled by the
electronic and steric properties of the N-heterocyclic carbene
organocatalyst.
Scheme 1. NHC Catalyst-Controlled Generation of Different
he formation of different products from identical
Reactive Intermediates from Enals
T
substrates in a precise and selective manner is attractive
in organic synthesis. In the arena of N-heterocyclic carbene
(NHC) organocatalysis,1 the addition of a carbene catalyst to
an α,β-unsaturated aldehyde (enal) can lead to reactive
intermediates bearing at least three reactive carbon centers of
the enal: the enal β-carbon (homoenolate intermediate),2 α-
carbon (enolate intermediate),3 and carbonly carbon (acyl
anion intermediate equivalent) (Scheme 1a).4 In 2004, the
Bode2a group and Glorius2b group reported the NHC-catalyzed
generation of homoenolates from enals and their annulation
with aldehydes to synthesize γ-lactones, in which the enal β-
carbon behaved as a reactive nucleophilic carbon. This
homoenolate chemistry was then further extensively explored
by a number of researchers, including Nair,2c You,2d Zhong,2e
Scheidt,2f Rovis,2g Chi,2h Liu,2i and Ye.2j The reactivity of the
enal α-carbon has also been relatively well studied. A selective
β-carbon protonation of the NHC-bound homoenolate
intermediate generates an enolate intermediate with a reactive
enal α-carbon that can undergo inter- and intramolecular
reactions, as disclosed by Bode,3a Glorius,3b Scheidt,3c You,3d
Nair,3e and Chi.3f
However, in contrast to enal α- and β-carbons, the enal
carbonyl carbon as a reactive nucleophilic carbon (acyl anion
intermediate) for asymmetric reactions is much less studied. To
the best of our knowledge, so far there are only three successful
examples using the carbonyl carbons of enals as nucleophiles to
construct chiral building blocks. In 2011, the Rovis group
reported an elegant Stetter reaction of enals with nitroalkenes
using catechol as a crucial additive.4a At about the same time,
our group discovered a highly enantioselective Stetter reaction
of enals with modified chalcones.4b Very recently, Ye and co-
workers developed an asymmetric benzoin reaction of enals
with trifluoromethyl ketone-derived ketimines catalyzed by a
chiral NHC catalyst containing a hydroxyl group.4c
Here we report a cross-aza-benzoin reaction of enal with
isatin-derived ketimine involving the enal carbonyl carbon as a
Received: May 5, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol501286e | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
nucleophilic reactive carbon (Scheme 1b). The reaction is
highly chemoselective: potential side reactions between the enal
α- and β-carbons with the ketimine substrate are either not
observed or largely suppressed. The cross-aza-benzoin reaction
is enantioselective and affords 3-aminooxindoles bearing a
quaternary stereogenic center with high enantioselectivities.
Such 3-aminooxindoles are found as core skeletons in a variety
of biologically active compounds exhibiting numerous signifi-
cant pharmaceutical properties, such as the vasopressin VIb
receptor antagonist SSR-1494155a,b and the potent gastrin/
CCK-B receptor antagonist AG-041R.5c
Table 1. Optimization of Reaction Conditions
Notably, the same set of substrates (enals and isatin-derived
ketimines) can undergo a cyclization reaction to form γ-lactams
involving the enal β-carbon as a reactive nucleophilic center
(homoenolate intermediate), as previously reported by our
group (Scheme 1b).2h The key factor that controls the
chemoselective reactions of the enal β- and carbonyl carbons
is the NHC catalysts. As documented in Bode’s study6 and
indicated by reactions from others,7a−c an NHC catalyst with
an electron-rich, sterically bulky substituent such as the N-
mesityl group on the triazolium ring favors homoenolate
reactions, while the electron-deficient, less hindered azolium
salts, such as the N- pentafluorophenyl derivatives, are preferred
for acyl anion reactions. Specifically in our reactions (Scheme
1b), aminoindanol-derived NHC with a N-mesityl substituent
previously explored by Bode favors the β-carbon pathway to
form annulation products; the more electron-deficient and less
bulky NHC catalyst with a N-pentafluorophenyl substituent
prefers the carbonyl carbon reaction to afford cross-aza-benzoin
products (Scheme 1b).
conv of 2a yield of 3a yield of 4a
er of
b
a
a
entry cat.
solvent
(%)
(%)
(%)
3a
1
−
A
B
C
D
E
F
F
F
F
F
F
F
F
F
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
toluene
CH2Cl2
THF
0
−
0
−
80
7
−
−
62:38
87:13
−
2
100
100
100
100
32
c
c
3
81 (78)
67 (66)
9
4
13
72
0
5
6
13
−
c
c
c
7
100
100
100
27
75 (73)
62 (58)
65 (60)
10
10
13
18
3
97:3
98:2
94:6
−
−
−
97:3
97:3
97:3
8
9
10
11
12
13
14
EtOAc
CH3CN
CHCl3
CHCl3
52
23
6
26
8
3
d
c
100
100
100
73 (72)
68
9
de
,
10
10
df
,
15
CHCl3
64
Key results for reaction optimization are summarized in
Table 1. Enal 1a and isatin-derived ketimine 2a were used as
the model substrates. In the absence of an NHC precatalyst, no
formation of product 3a or 4a was observed (Table 1, entry 1).
When aminoindanol derived precatalyst A8 with a N-mesityl
substituent was used, the reaction afforded the homoenolate-
derived adduct 4a in 80% yield (entry 2), as reported in our
previous2h studies. Replacing the mesityl group on the NHC
precatalyst A with an electron-deficient substituent, such as
pentafluorophenyl (precatalyst B9) and 2,4,6-trichlorophenyl
(precatalyst C), changed the reaction outcomes and afforded
the desired cross-aza-benzoin product 3a as the major product
with moderate enantioselectivity (entries 3 and 4). Next we
moved to identify NHC catalysts with both good chemo- and
enantioselectivities and examined L-phenylalanine derived
precatalysts D−F. Similar effects of the N-aryl substituent on
the reaction chemoselectivities are observed. N-Mesityl
substituted precatalyst D10 favored the homoenolate reaction
(entry 5), and the NHC catalysts E11 and F with smaller and
electron-deficient substituents favor the aza-benzoin reactions
(entries 6 and 7). To our delight, NHC precatalyst F with a
2,4,6-trichlorophenyl substituent allows a clean reaction with
the formation of 3a in 75% yield with excellent 97:3 er (entry
7). With F as the optimal precatalyst, we also examined the
solvent effect (entries 8−12). Nonpolar solvent toluene gave
product 3a in 62% yield with a slightly better 98:2 er (entry 8),
while CH2Cl2 caused a slight decrease in both yield and
enantioselectivity (entry 9). Polar aprotic solvents such as THF,
EtOAc, and CH3CN were not effective for this reaction (entries
10−12). Finally, we found that 10 mol % of NHC precatalyst F
was enough to afford 3a with 72% yield and 97:3 er (entry 13).
The use of a substoichiometric amount of KOAc gives the
desired product in a slightly lower yield with same er values
a
1
Yield estimated via H NMR analysis using 1,3,5-trimethoxybenzene
b
as an internal standard. Enantiomeric ratio of 3a, determined via
chiral phase HPLC analysis; absolute configuration of the major
enantiomer was assigned based on X-ray structure of 3e (see Figure 1
and Supporting Information). Isolated yield based on 2a. 10 mol %
of F was used. 0.05 mmol of KOAc was used. 0.02 mmol of KOAc
c
d
e
f
was used.
(entries 14, 15). Since KOAc easily absorbs water in the air, we
chose to use 1 equiv of KOAc, as it is easier to weigh an
accurate amount of the base.
With the optimized reaction conditions in hand (Table 1,
entry 13), we then evaluated the scope of this cross-aza-benzoin
reaction (Scheme 2). A variety of enals with diverse electronic
and steric properties were first explored. The use of
cinnamaldehyde furnished the desired product 3a in 72%
yield with 97:3 er. Enals with electron-donating substituents
such as 4-Me and 4-OMe on their β-benzene ring led to the
corresponding cross-aza-benzoin products 3b and 3c respec-
tively in good yields and excellent enantioselectivities. The
presence of electron-withdrawing groups (3-F, 4-Cl, and 4-Br)
was also found to be compatible under the optimal conditions,
affording products 3d−f in moderate to good yields and
excellent er’s. The introduction of a heteroaryl substituent such
as the furyl and thienyl group provided the desired products 3g
and 3h in 52% yield, 92:8 er and 53% yield, 97:3 er,
respectively. It is worth noting that β-alkyl enals were tolerated.
For example, crotonaldehyde and 2-hexenal reacted effectively
to give products 3i (48% yield, 92:8 er) and 3j (50% yield, 93:7
er) respectively. Modifications on the isatin-derived ketimine
substrates were feasible. The N-methyl substituent of imine
substrate 2a could be replaced with other alkyl units such as an
B
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Organic Letters
Letter
a
Scheme 2. Scope of Reactions
Figure 1. ORTEP diagram of 3e.
reaction. The present study provides valuable motivations in
searching for catalyst-controlled chemoselective reactions,
allowing for convenient access to products of different scaffolds
by starting from the same set of readily available substrates.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: robinchi@ntu.edu.sg.
*E-mail: basong@gzu.edu.cn.
Author Contributions
§These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
a
b
c
Reaction for 8 h unless otherwise specified. 12 h. Yield of
homoenolate product was around 70% estimated via 1H NMR analysis
using 1,3,5-trimethoxybenzene as an internal standard.
We thankful for the generous financial support from the
Singapore National Research Foundation (NRF), Singapore
Economic Development Board (EDB), GlaxoSmithKline
(GSK), Nanyang Technological University (NTU), China’s
National Key program for Basic Research (No. 2010CB
126105), the National Natural Science Foundation of China
(No. 21132003), and Guizhou University (China). We thank
Dr. R. Ganguly and Y. Li (NTU) for assistance with X-ray
structure analysis.
allyl (product 3k) and benzyl substituent (product 3l). N-
Phenyl substituted isatin-derived imine (product 3m), rarely
explored in previous reactions involving an isatin-type
substrate,12 reacted effectively as well in our reaction. The
substitution patterns on the isatin phenyl ring were also
investigated, and the use of 5-Me, 5-OMe, and 7-Me
substituted isatin derived ketimines furnished the desired
products 3n−p in good yields and excellent er’s. However,
when isatin derived ketimines with electron-withdrawing
substituents such as 5-Cl and 7-F on the isatin phenyl ring
were used, the reaction favored the homoenolate pathway,
affording cross-aza-benzoin products 3q and 3r in less than
10% yield.
The absolute configuration (R) of the stereogenic center in
compound 3e was unambiguously determined by X-ray
crystallographic analysis (Figure 1).13 The configurations of
other chiral quaternary 3-aminooxindole products were
assigned on the assumption of a uniform mechanistic pathway.
In summary, we have developed an NHC-promoted
intermolecular cross-aza-benzoin reaction of enals with isatin-
derived ketimines to afford chiral quaternary 3-aminooxindoles.
The chemoselectivity is controlled by the NHC catalysts, with
electron-deficient and sterically noncongested carbene catalysts
favoring the enal acyl anion reaction pathway and aza-benzoin
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