N-heterocyclic carbene-catalyzed enantioselective annulation of indolin-3-ones with bromoenals

Article abstract of DOI:10.1002/asia.201402052

N-Heterocyclic carbene-catalyzed reactions of indolin-3-ones with 2-bromoenals opened an asymmetric access to 3,4-dihydropyrano[3,2-b]indol-2(5 H)-ones in good yields and with good to excellent enantioselectivities. This protocol tolerates a broad substrate scope. In addition, a possible mechanism for the annulation reaction is presented. More NHC-organocatalysis: N-Heterocyclic carbene-catalyzed reactions of indolin-3-ones with 2-bromoenals opened an asymmetric access to 3,4-dihydropyrano[3,2-b]indol-2(5 H)-ones in good yields and with good to excellent enantioselectivities. This protocol tolerates a broad substrate scope. In addition, a possible mechanism for the annulation reaction is presented.

Full text of DOI:10.1002/asia.201402052

COMMUNICATION
DOI: 10.1002/asia.201402052
N-Heterocyclic Carbene-Catalyzed Enantioselective Annulation of Indolin-3-
ones with Bromoenals
Qijian Ni, Xiaoxiao Song, Gerhard Raabe, and Dieter Enders*[a]
Abstract: N-Heterocyclic carbene-catalyzed reactions of in-
dolin-3-ones with 2-bromoenals opened an asymmetric
access to 3,4-dihydropyranoACTHNUGRTENNUG[3,2-b]indol-2ACHTUNGTNER(NUGN 5H)-ones in good
yields and with good to excellent enantioselectivities. This
protocol tolerates a broad substrate scope. In addition, a pos-
sible mechanism for the annulation reaction is presented.
Over the past decade, N-heterocyclic carbene (NHC) cat-
alysis opened an efficient and elegant access for the asym-
metric synthesis of various chiral building blocks, which was
made possible by its unique umpolung ability.[1] The classic
NHC-catalyzed a1-d1-umpolung reactions, such as the ben-
zoin condensation[2] and the Stetter reaction,[3] have been
developed intensively. Since the pioneering reports by the
groups of Glorius, Bode, and Rovis in 2004, homoenolate in-
termediates played an important role as new nucleophiles at
the a or b position of aldehydes accessible for different elec-
trophiles.[4] Recently, a,b-unsaturated acylazolium inter-
mediates opened a new mode of reactions catalyzed by
NHCs and they attracted great attention. Up to now, there
are five kinds of precursors for the generation of a,b-unsatu-
rated acylazoliums, such as ynals,[5] a,b-unsaturated acyl flu-
orides,[6] a,b-unsaturated esters,[6a,7] and stoichiometric oxi-
dation of homoenolates[8] and a-functionalized enals,[9]
which have been documented (Scheme 1).
Scheme 1. Formation of NHC-derived a,b-unsaturated acylazolium inter-
mediates.
ers have developed NHC-catalyzed reactions of enolizable
aldehydes with a,b-unsaturated acylazoliums generated
from 2-bromoenals.[9f] However, indolin-3-ones as a kind of
C-/enol-O dinucleophiles were rarely employed in NHC-cat-
alyzed reactions. To the best of our knowledge, only one
recent paper reported the reaction of indolin-3-ones with
ynals and enals combined with stoichiometric oxidants, thus
leading to the formation of tricyclic indole-fused dihydropyr-
anones.[5e] Based on the previous work, we now report the
enantioselective NHC-catalyzed reaction of 2-bromoenals
with indolin-3-ones, resulting in 3,4-dihydropyranoACHTUNGTRENNUNG[3,2-
b]indol-2-ones, which are regarded as common scaffolds in
many biologically active natural products.[11]
With the development of these new approaches to a,b-un-
saturated acylazolium intermediates, screening the nucleo-
philes was also essential. 1,3-Dicarbonyl compounds were
recognized as the most common Michael donors to conduct
1,4-addition reactions followed by Claisen rearrangements
and intramolecular acylations, which delivered dihydropyra-
nones. Bode and co-workers have recently reported NHC-
catalyzed annulations of a,b-unsaturated acylazoliums with
stable enols such as naphthol[5c] and kojic acid.[5a] In addi-
tion, the NHC-catalyzed rearrangement of a,b-unsaturated
enol esters to form dihydropyranones was demonstrated by
Lupton and co-workers.[10] Very recently, Biju and co-work-
Initially, we investigated the optimal NHC catalysts for
the model reaction of 1-acetylindolin-3-one (1a) with a-bro-
mocinnamaldehyde (2a). The achiral precatalyst A promot-
ed the reaction and gave the desired product in 13% yield
in the presence of NaOAc (Table 1, entry 1). However, the
precatalysts B and E did not yield the product under the
same condition (Table 1, entries 2 and 5). Gratifyingly, good
yields and ee values were obtained when the precatalysts C
and D were used, and the former one proved to be superior
in terms of yield and enantioselectivity (Table 1, entries 3
and 4). Further base screening (Table 1, entries 6–13) re-
vealed that the use of inorganic or organic bases, such as
K3PO4, NEt3, DMAP, DIPEA, DPE, or TMEDA, resulted
in good yields and good to excellent ee values of the desired
product (Table 1, entries 6, 8, 10–13), except DBU, which
led to no reaction (Table 1, entry 7), and DABCO producing
only 15% yield (Table 1, entry 9). It is noteworthy that the
base TMEDA obviously improved the ee value up to 92%.
Based on these conditions, a number of solvents were
screened next. Fortunately, 96% ee and 66% yield were ob-
[a] Q. Ni, X. Song, Prof. Dr. G. Raabe, Prof. Dr. D. Enders
Institute of Organic Chemistry
RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
Fax : (+49)0241-80-92127
E-mail: enders@rwth-aachen.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201402052.
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Dieter Enders et al.
Table 1. Optimization of the reaction conditions.[a]
Table 2. Substrate scope.[a]
3
R1
R2
Yield [%][b]
ee [%][c]
3a
3b
3c
3d
3e
3 f
3g
3h
3i
H
Ph
Ph
Ph
Ph
68
72
62
67
66
66
70
61
71
60
68
60
92
89
93
67
93
98
94
92
89
97
93
95
6-Cl
6-F
5-CF3
H
H
H
H
H
H
H
4-MeC6H4
4-MeOC6H4
2-MeO-5-Br-C6H3
3-MeOC6H4
4-ClC6H4
3-ClC6H4
4-FC6H4
2-furyl
Entry NHC Solvent
Base
t [d] Yield [%][b] ee [%][c]
1
A
B
C
D
E
C
C
C
C
C
C
C
C
C
C
C
C
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CHCl3
NaOAc
NaOAc
NaOAc
NaOAc
NaOAc
K3PO4
2
2
2
2
2
2
2
2
2
2
0.5
1
1
1
1
1
1
13
n.r.
80
63
n.r.
21
n.r.
75
15
75
75
67
69
64
70
66
30
0
–
3j
3k
3l
2
3
4
5
6
7
8
9
80
77
–
81
–
80
90
85
87
89
92
83
70
96
96
H
[a] Reaction conditions:
1
(0.5 mmol),
2
(0.6 mmol),
C
(10 mol%),
TMEDA (1.1 equiv), mesitylene (5 mL), rt. [b] Yield of isolated product
3 after column chromatography. [c] The ee value was determined by
HPLC on a chiral stationary phase.
DBU
DIPEA
DABCO
NEt3
DMAP
DPE
TMEDA
TMEDA
TMEDA
10
11
12
13
14
15
16
17[d]
THF
Mesitylene TMEDA
Mesitylene TMEDA
[a] Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol), NHC
(10 mol%), base (1.1 equiv), solvent (2 mL), rt. [b] Yield of isolated
product 3a after column chromatography. [c] The ee value was deter-
mined by HPLC on a chiral stationary phase. [d] (Z)-2-iodocinnamalde-
hyde instead of 2a. TMEDA=N,N,N’,N’-tetramethylethylenediamine,
DBU=1,8-diazabicyclo-[5.4.0]undec-7-ene, DIPEA=N,N-diisopropyle-
thylamine, DPE=1,2-di(pyrrolidinyl)ethane, Mes=2,4,6-trimethylphenyl,
n.r.=no reaction.
Figure 1. X-ray crystal structure of 3h.
tained when mesitylene was used as solvent (Table 1,
entry 16). Moreover, a switch of substrate 2 from 2a to a-io-
docinnamaldehyde led to an inferior yield (30%) but com-
parable ee value (96%) (Table 1, entry 17).
biguously determined to be the S-configuration by X-ray
crystal-structure analysis (Figure 1).[12] Further expanding
the scope of the reaction revealed that this protocol re-
quired R2 to be an aromatic substituent. Ethyl and iso-
propyl substituents were also tested, but no products were
obtained.
A plausible pathway for the annulation reaction is illus-
trated in Scheme 2. Initially, the nucleophilic addition of the
NHC-catalyst C’, generated by the deprotonation of the tria-
zolium salt C, to the bromoenal 2 affords the Breslow inter-
mediate IN1,[13] which can be drawn as a mesomeric struc-
ture. Tautomerization and loss of bromide via IN2 leads to
the key a,b-unsaturated acylazolium IN3, which undergoes
a Michael addition from the Si face of indolinone 1 attacking
to the Re face of the a,b-unsaturated acylazolium due to the
steric demand of the chiral NHC backbone. The subsequent
lactonization yields the target product 3, thereby releasing
the NHC catalyst for further cycles.
With the optimized conditions in hand, the substrate
scope of the reaction was explored. Initially, we examined
various substituted 1-acetylindolin-3-ones 1. As shown in
Table 2, indolinones bearing different substituents at the C6
position, such as 6-Cl or 6-F, gave the desired products in
good yields and excellent ee values (Table 2, 3b and 3c).
However, when R1 is a 5-CF3 group (Table 2, 3d), only 67%
ee was obtained. Next, a series of 2-bromoenals was tested
for the reaction with 1a in this protocol. Electron-donating
or -withdrawing groups on the aromatic rings were well tol-
erated, delivering the dihydropyranoindol-2-ones in good
yields and excellent enantioselectivities (Table 2, 3e–3k). It
is noteworthy that the (2)-furyl-substituted 2-bromoenal
also underwent the transformation smoothly, yielding the
product in 60% yield and with an ee value of 95% (Table 2,
3l). Moreover, the absolute configuration of 3h was unam-
In conclusion, we have developed an efficient NHC-cata-
lyzed enantioselective annulation of indolin-3-ones with bro-
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Dieter Enders et al.
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Scheme 2. Proposed reaction mechanism of the NHC-catalyzed annula-
tion.
moenals to deliver dihydropyranoindol-2-ones in good
yields and good to excellent ee values. The solvent mesity-
lene and the diamine base played important roles for the
enantioselectivity. In addition, a wide range of substrates are
tolerated under the optimized conditions.
Experimental Section
General Procedure for the Synthesis of 3,4-DihydropyranoACTHNUTRGNE[NUG 3,2-b]indol-2-
ones: To a dried and argon-filled Schlenk flask was added 1-acetylindo-
lin-3-one (1) (0.5 mmol, 1.0 equiv), 2-bromocinnamaldehyde (2)
(0.6 mmol, 1.2 equiv), triazolium salt
C (0.05 mmol, 10 mol%), and
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stirred at room temperature and monitored by thin-layer chromatogra-
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was purified by column chromatography on silica gel (pentane/Et2O 3:1)
to afford the desired product 3 as a solid.
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We thank the BASF SE and the former Degussa AG for the donation of
chemicals. We also thank the China Scholarship Council (scholarship for
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Keywords: annulation
dihydropyranoindol-2-ones
organocatalysis
·
asymmetric
· N-heterocyclic carbenes
synthesis
·
·
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Received: February 13, 2014
Published online: && &&, 0000
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ÝÝ These are not the final page numbers!

COMMUNICATION
More NHC-organocatalysis: N-Hetero-
cyclic carbene-catalyzed reactions of
indolin-3-ones with 2-bromoenals
opened an asymmetric access to 3,4-
Asymmetric Synthesis
Qijian Ni, Xiaoxiao Song,
Gerhard Raabe,
dihydropyrano
H
N
Dieter Enders*
&&&& — &&&&
in good yields and with good to excel-
lent enantioselectivities. This protocol
tolerates a broad substrate scope. In
addition, a possible mechanism for the
annulation reaction is presented.
N-Heterocyclic Carbene-Catalyzed
Enantioselective Annulation of
Indolin-3-ones with Bromoenals
5
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Chem. Asian J. 2014, 00, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
These are not the final page numbers! ÞÞ