Highly diastereo- and enantioselective NHC-catalyzed [3+2] annulation of enals and isatins

Article abstract of DOI:10.1039/c1cc13860j

The chiral N-heterocyclic carbene bearing a proximal hydroxy group derived from l-pyroglutamic acid was found to be an efficient catalyst for the [3+2] annulation of enals and isatins to give the corresponding spirocyclic oxindolo-γ-butyrolactones in good yield with good diastereo- and enantioselectivities. The Royal Society of Chemistry 2011.

Full text of DOI:10.1039/c1cc13860j

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COMMUNICATION
Highly diastereo- and enantioselective NHC-catalyzed [3+2] annulation
of enals and isatinsw
Li-Hui Sun, Li-Tao Shen and Song Ye*
Received 28th June 2011, Accepted 25th July 2011
DOI: 10.1039/c1cc13860j
The chiral N-heterocyclic carbene bearing a proximal hydroxy
group derived from L-pyroglutamic acid was found to be an
efficient catalyst for the [3+2] annulation of enals and isatins to
give the corresponding spirocyclic oxindolo-c-butyrolactones in
good yield with good diastereo- and enantioselectivities.
giving the g-butyrolactones with compromising diastereo- and
enantioselectivities (up to 78% ee but 1 : 1 dr).11
Recently, Enders et al.12 and we13 independently reported
a
series of NHCs derived from L-pyroglutamic acid.
Considering its ready availability and high enantioselectivity
observed,14 we are interested in exploring the enantioselective
umpolung reaction of enals catalyzed by chiral NHCs derived
from L-pyroglutamic acid. In this communication, we wish to
report a highly diastereo- and enantioselective [3+2] annula-
tion of enals with isatins.15,16
Due to their unique structure and properties, N-heterocyclic
carbenes (NHCs) have been used as reagents in the synthesis
of heterocycles,1 as ligands for organometallic catalysts2 and
in organocatalysis for uncommon organic transformations.3
The classic NHC-catalyzed a1–d1 umpolung reactions of
aldehydes,4 benzoin and Stetter reaction, involve the Breslow
intermediate generated by the addition of NHC to aldehydes.5
In 2004, Bode et al. and Glorius and Burstein independently
reported the pioneering NHC-catalyzed synthesis of
g-butyrolactones from enal and aldehydes, which involves
the homoenolate generated by the addition of NHC to enals.6
The homoenolate can be considered as d3-nucleophiles, and
thus provides an a3–d3 umpolung of enals. Since then, the
NHC-catalyzed extended umpolung of enals has emerged as a
powerful tool for various transformations.7,8
A series of chiral NHCs were firstly tested for the reaction
of cinnamaldehyde (1a) and N-benzyl isatin (2a) (Table 1).
Unfortunately, no [3+2] annulation was observed when using
NHCs 4a–4c with a silyl ether substituent as the catalyst
(entries 1–3). We then tested the NHCs with a free hydroxy
group.17 We envision that the free hydroxy group may form a
H-bonding with the carbonyl group of isatin and thus enhance
its reactivity. We are happy to find that the reaction catalyzed
by NHCs 4d–4e, with a proximal hydroxy group, gave the
Table 1 Screening of chiral NHCs
Although the reactivity of the NHC-catalyzed [3+2]
annulation of enals and carbonyl compound has been well
established, the diastereo- and enantioselectivities turned out
to be a challenge. For the reaction of enals with aldehydes, the
g-butyrolactones were obtained in around 3 : 1 dr.6 In the
reaction of enals with trifluoromethyl ketones, Glorius et al.
found that the thiazolium NHC showed better dr (up to 8 : 1)
than imidazolium NHC.9 In 2006, Nair et al. reported the
NHC-catalyzed [3+2] annulation of enals with 1,2-diketones
and isatins. However, the corresponding spirocyclic oxindolo-
g-lactone derivatives were obtained with only 1 : 1 dr.10 In
addition, enantioselective NHC-catalyzed annulation of enals
with carbonyl compounds is rarely investigated. To the best of
our knowledge, there is only one report dealing with this issue,
Entry 4 (Ar1, Ar2, R)a
Yieldb (%) drc
eed (%)
1
2
3
4
5
6
4a (Ph, Ph, TBS)
4b (Ph, 2-iPrC6H4, TBS)
4c (Ph, C6F5, TBS)
4d (Ph, Ph, H)
4e (Ph, Mes, H) 83
4f (3,5-(CF3)2C6H3, Ph, H) 90
NR
NR
NR
87
/
/
/
/
/
/
93
90
5 : 1
7 : 1
Key Laboratory of Molecular Recognition and Function, Institute of
Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
E-mail: songye@iccas.ac.cn; Fax: +86 10 6255 4449;
Tel: +86 10 6264 1156
w Electronic supplementary information (ESI) available: Experimental
procedures and compound characterizations (PDF). CCDC 831812.
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c1cc13860j
20 : 1 98
a
NHC 40 was generated from the corresponding triazolium salt 4 in the
presence of Cs2CO3 at room temperature for 1 h, and was used immedi-
b
ately. Isolated yield. c Determined by 1H NMR of the reaction mixture.
d
Determined by chiral HPLC. NR = no reaction, Mes = mesityl.
c
10136 Chem. Commun., 2011, 47, 10136–10138
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Table 2 Optimization of reaction conditionsa
electron-withdrawing groups were then introduced to the
diaryl group (Ar = (3,5-(CF3)2C6H3)) of the NHC in order
to increase the possible H-bonding,18 which led to NHC 4f and
afforded the g-butyrolactone in 90% yield with 20 : 1 dr and
98% ee (entry 6).
Entry
Base
Solvent
Yieldb (%)
drc
eed (%)
1
2
3
4
5
6
7
8
9f
Cs2CO3
K2CO3
KOBut
NEt3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
THF
THF
THF
THF
Ether
DCM
MeCN
Toluene
Toluene
90
93
82
96e
98
98
83
97
97
20 : 1
18 : 1
20 : 1
10 : 1
10 : 1
10 : 1
6 : 1
98
95
98
97
95
93
46
98
98
The reaction conditions were then optimized (Table 2). All
the reactions catalyzed by NHC 4f generated from Cs2CO3,
K2CO3 and t-BuOK gave the desired product in good yield,
with high diastereo- and enantioselectivity (entry 1–3). When
triethylamine was used as the base, no reaction was observed
at room temperature, but reaction worked at 70 1C and
furnished the product in good yield with good diastereo-and
enantioselectivity (entry 4). Reaction proceeded well in varied
solvents, and toluene afforded the best result (entries 5–8).
Decreasing the catalyst loading from 10 mol% to 5 mol%
showed no loss of yield and selectivity (entry 9 vs. 8).
With the optimized reaction conditions in hand, the reaction
scope was then briefly investigated (Table 3). Both cinnamal-
dehydes with electron-withdrawing group (Ar = 4-NO2C6H4)
and electron-donating group (Ar = 4-MeOC6H4) worked well
25 : 1
25 : 1
a
Unless specified, the reaction was carried out using 10 mol% of 4f
b
and 10 mol% base at room temperature. Isolated yield. Deter-
mined by 1H NMR of the reaction mixture. Determined by chiral
c
d
e
HPLC. The reaction was carried out at 70 1C, while only the trace
product was observed at room temperature. 5 mol% of precatalyst 4f
and Cs2CO3 were employed.
f
corresponding spirocyclic g-butyrolactone in good yield with
good dr and enantioselectivity (entries 4 and 5). Strong
Table 3 Enantioselective NHC-catalyzed [3+2] annulation of enals and isatins
c
This journal is The Royal Society of Chemistry 2011
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3 For reviews, see: (a) D. Enders and T. Balensiefer, Acc. Chem.
Res., 2004, 37, 534; (b) D. Enders, O. Niemeier and A. Henseler,
Chem. Rev., 2007, 107, 5606; (c) A. J. Arduengo III and
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4 D. Seeback, Angew. Chem., Int. Ed. Engl., 1979, 18, 239.
5 (a) R. Bresolw, J. Am. Chem. Soc., 1958, 80, 3719; (b) H. Stetter
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44, 7506; (b) V. Nair, S. Vellath and B. P. Babu, Chem. Soc. Rev.,
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Fig. 1 X-Ray structure of compound 3d.
8 For examples, see: (a) M. He and J. W. Bode, Org. Lett., 2005,
7, 3131; (b) A. Chan and K. A. Scheidt, Org. Lett., 2005, 7, 905;
(c) S. S. Sohn and J. W. Bode, Org. Lett., 2005, 7, 3873; (d) V. Nair,
S. Vellalath, M. Poonoth and E. Suresh, J. Am. Chem. Soc., 2006,
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and K. A. Scheidt, Angew. Chem., Int. Ed., 2007, 46, 3107;
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E. M. Phillips, T. E. Reynolds and K. A. Scheidt, J. Am. Chem.
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9 K. Hirano, I. Piel and F. Glorius, Adv. Synth. Catal., 2008,
350, 984.
10 V. Nair, S. Vellalth, M. Poonoth, R. Mohan and E. Suresh, Org.
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Fig. 2 Possible transition state.
for the reaction, giving the lactones 3b, 3c in good yields with
good diastereo- and enantioselectivities. Substituent(s) at
different position(s) (4-ClC6H4, 3-ClC6H4, 2-ClC6H4 and
2,4-Cl2C6H3) has no strong impact on the reaction (3d, 3e,
3f and 3g). The reaction of enal with a 2-furyl group gave the
product in 97% yield with 30 : 1 dr and 86% ee (3h). It is
noteworthy that enal with a b-alkyl substituent (R =
n-propyl) afforded the desired product with 20 : 1 dr and
85% ee albeit in 38% yield (3i). Different substituents
(Cl, F, Me, MeO) are also tolerable for isatin derivatives (3j,
3k, 3l and 3m). However, the reaction with carbonyl com-
pounds other than isatin derivatives, such as benzaldehyde and
propionaldehyde, failed under current reaction conditions.19
The absolute structure of spirocyclic oxindolo-g-lactone 3d
was unambiguously established by the X-ray analysis of its
crystal (Fig. 1).
Based on the strong influence of hydroxy group on the
activity of the catalyst and stereochemical outcome of the
reaction, a possible transition state is proposed in Fig. 2.
The H-bonding between the catalyst and isatin enhances the
reactivity and directs the addition of the homoenolate to the
carbonyl group of isatin.
In conclusion, the NHCs with a proximal hydroxy group were
found to be an efficient catalyst for the [3+2] annulation of enals
with isatins to give the spirocyclic oxindolo-g-butyrolactones in
good yields with high diastereo- and enantioselectivities.
Financial support from National Science Foundation of
China (20932008), the Ministry of Science and Technology
of China (2011CB808600) and the Chinese Academy of
Sciences is greatly acknowledged.
15 For reviews on indole derivatives, see: (a) G. Zeni and
R. C. Larock, Chem. Rev., 2004, 104, 2285; (b) G. Bartoli,
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Biomol. Chem., 2010, 8, 2912.
16 We recently reported the reactions with isatins: (a) X. N. Wang,
Y.-Y. Zhang and S. Ye, Adv. Synth. Catal., 2010, 352, 1892;
(b) H. Lv, X.-Y. Chen, L.-H. Sun and S. Ye, J. Org. Chem.,
2010, 75, 6973.
17 (a) L. He, Y.-R. Zhang, X.-L. Huang and S. Ye, Synthesis, 2008,
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and S. J. Connon, J. Org. Chem., 2009, 74, 9214; (d) X.-L. Huang
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18 For an NHC with N-(3,5-bis(trifluoromethyl))phenyl group, see:
H. Takikawa and K. Suzuki, Org. Lett., 2007, 9, 2713.
19 Reaction with benzaldehyde or propionaldehyde gave no desired
product but a small amount of benzoin or a complex.
Notes and references
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(b) V. Nair, S. Bindu and V. Sreekumar, Angew. Chem., Int. Ed.,
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Y. Cheng, J. Org. Chem., 2010, 75, 6644.
2 For reviews, see: (a) S. P. Nolan, Acc. Chem. Res., 2011, 44, 91;
(b) W. A. Herrmann, Angew. Chem., Int. Ed., 2002, 41, 1290.
c
10138 Chem. Commun., 2011, 47, 10136–10138
This journal is The Royal Society of Chemistry 2011