N-Heterocyclic carbene-catalyzed tandem aza-benzoin/Michael reactions: On site reversal of the reactivity of N-Boc imines

Article abstract of DOI:10.1039/c0cc01769h

A tandem NHC-catalyzed aza-benzoin/Michael reaction has been developed as a method to efficiently produce dihydroindenones and pyrrolidinone-containing tricycles. The novel reaction pattern involves tert-butyl aryl(tosyl) methylcarbamates reacting as both

Full text of DOI:10.1039/c0cc01769h

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N-Heterocyclic carbene-catalyzed tandem aza-benzoin/Michael reactions:
on site reversal of the reactivity of N-Boc imineswz
Ke-Jia Wu, Gong-Qiang Li, Yi Li, Li-Xin Dai and Shu-Li You*
Received 7th June 2010, Accepted 28th September 2010
DOI: 10.1039/c0cc01769h
A tandem NHC-catalyzed aza-benzoin/Michael reaction has
been developed as a method to efficiently produce dihydroindenones
and pyrrolidinone-containing tricycles. The novel reaction
pattern involves tert-butyl aryl(tosyl)methylcarbamates reacting
as both electrophile and nucleophile on the same carbon.
one quaternary carbon.6 To our knowledge, no reports exist
describing this type of reactivity profile for imines. Below, we
describe the results of this exploratory study.
The current study began with an exploration of the reaction
of (E)-ethyl 3-(2-formylphenyl)acrylate 1a with tert-butyl
(4-methoxyphenyl)(tosyl)methylcarbamate 2a, which provided
the results summarized in Table 1. In the presence of thiazolium
salt 4 (10 mol%) and Et3N (2.2 equiv.), reaction of 1a and 2a
did not produce the aza-benzoin/Michael reaction product 3aa
but instead afforded the aza-benzoin product 3aa0 in 62%
yield (Table 1, entry 1). We envisaged that use of a stronger
base would facilitate the subsequent Michael addition reaction
of 3aa0. Screening various bases (Table 1, entries 1–4) led to
the identification of DBU as a suitable base for the tandem
reaction, which generated 3aa in 31% yield with an excellent dr
(420 : 1). The yield of this process was improved to 68% when
Cs2CO3 was employed as the base (Table 1, entry 6). It is
worth noting that the use of a reduced loading of Cs2CO3
(1.5 equiv.) led to formation of a mixture of 3aa and 3aa0 in a
ratio of 1 : 3, while increasing the Cs2CO3 loading (4 equiv.)
resulted in a lower yield (Table 1, entries 7, 8). A probe of
reactions promoted by several catalysts under these conditions
demonstrated that thiazolium salt 4 was optimal (see the SI for
details). An examination of various solvents (toluene, CH3CN,
ether, CH2Cl2, dioxane, t-BuOH, and THF) revealed that
CH2Cl2 was optimal (Table 1, entries 6, 9–15). Specifically,
reaction of 1a with 2a in CH2Cl2 gave 3aa in 76% yield with a
high diastereoselectivity (dr 420 : 1). The relative stereo-
chemistry of 3aa was determined after the subsequent cyclization
(vide infra).
Imines and their precursors serve as equivalents of carbonyl
compounds and represent one of the most important classes of
intermediates used in organic synthesis.1 Owing to their ready
preparation and high stability, tert-butyl aryl(tosyl)methyl-
carbamates have been developed as precursors of N-Boc
imines, thus greatly expanding the utility of imines in synthesis.2
In general, imines and their precursors participate as electro-
philic acceptors in reactions with various nucleophiles. In
recent studies of N-heterocyclic carbene (NHC)-catalyzed
umpolung reactions,3,4 we observed that imines behave
as suitable acyl anion acceptors.5 In efforts aimed at the
development of a new strategy for the facile construction of
the dihydroisoquinolinone scaffold, we designed and explored
a tandem NHC-catalyzed aza-benzoin/aza-Michael reaction
(Scheme 1).
Surprisingly, the process was observed to follow an
unconventional tandem aza-benzoin/Michael pathway that
produces substituted dihydroindenones in a highly diastereo-
selective manner. In this process, tert-butyl aryl(tosyl)methyl-
carbamate acts as both an electrophile and nucleophile at the
same carbon site. Importantly, the substituted dihydroindenones
generated in this process can be readily converted to
pharmaceutically interesting pyrrolidinone-containing tricyc-
lic substances that contain two stereogenic centers including
Reactions under the optimized reaction conditions
(10 mol% thiazolium salt 4, 220 mol% Cs2CO3, in CH2Cl2, rt)
of a variety of substituted (E)-ethyl 3-(2-formylphenyl)acrylates
and N-Boc imine precusors were explored in order to examine
the generality of the tandem reaction. As the results displayed
in Table 2 show, the tert-butyl aryl(tosyl)methylcarbamates
2a–f, which contain either electron-donating (4-MeO, 2-MeO,
4-Me, and 3-Me) or electron-withdrawing (4-Br and 4-Cl)
groups, participate in the tandem reaction to afford the desired
products 3 in 76–93% yields (Table 2, entries 1–6, 9). In
addition, heteroaryl (2-furyl and 2-thienyl) and 1-naphthyl-
derived imine precursors also serve as suitable substrates in
this process (62–90% yields, Table 2, entries 7–8, 10).
Unfortunately, reaction of the alkyl-substituted substrate 2k
failed to produce an adduct under these conditions (Table 2,
entry 11). In the (E)-ethyl 3-(2-formylphenyl)acrylate series,
methyl (1b) and fluoro groups (1c) are tolerated (Table 2,
entries 12–13). Finally, it should be noted that the preformed
N-Boc imine could also be used in this reaction although the
yield is slightly decreased (Table 2, entry 14).
Scheme 1 Tandem aza-benzoin/Michael reaction.
State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
345 Lingling Lu, Shanghai 200032, P. R. China.
E-mail: slyou@mail.sioc.ac.cn; Fax: (+86) 21-54925087
w This article is part of the ‘Emerging Investigators’ themed issue for
ChemComm.
z Electronic supplementary information (ESI) available: Experimental
procedures and analysis data for new compounds, CIF file of 5ae.
CCDC 772193. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0cc01769h
c
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Chem. Commun., 2011, 47, 493–495 493

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Table 1 Optimization of the conditions for the reaction of 1a with 2aa
Entry
Base
Solvent
Time/h
3aa, yield (%)b
3aa, dr
3aa0, yield (%)b
1
2
3
4
5
6
Et3N
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
Toluene
CH3CN
Et2O
8
8
8
5
8
5
5
5
5
5
5
5
5
5
5
—
—
—
31
—
68
18
59
Trace
46
19
76
41
—
—
—
420 : 1
—
420 : 1
420 : 1
420 : 1
—
420 : 1
420 : 1
420 : 1
420 : 1
—
62
63
34
—
71
—
51
—
—
—
—
—
—
—
—
DIPEA
DABCO
DBU
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
7c
8d
9
10
11
12
13
14
15
CH2Cl2
Dioxane
t-BuOH
THF
N.R.
47
420 : 1
a
b
c
d
Reaction conditions: 1a/2a/base = 2.0/1.0/2.2, 0.1 M of 2a in solvent at rt. Isolated yields. 1.5 equiv. of Cs2CO3 was used. 4.0 equiv. of
Cs2CO3 was used.
Table
2 Substrate scope for the tandem aza-benzoin/Michael
reaction of 1 with 2a
Entry
1, R2, R3
2, R1
3, yield (%)b
dr
1
2
3
4
5
6
7
8
1a, H, H
1a, H, H
1a, H, H
1a, H, H
1a, H, H
1a, H, H
1a, H, H
1a, H, H
1a, H, H
1a, H, H
1a, H, H
1b, Me, H
1c, H, F
2a, 4-MeOC6H4
2b, 2-MeOC6H4
2c, 4-MeC6H4
2d, 3-MeC6H4
2e, 4-BrC6H4
2f, 4-ClC6H4
2g, 2-furyl
2h, 2-thienyl
2i, phenyl
2j, 1-naphthyl
2k, c-C6H13
2i, phenyl
3aa, 76
3ab, 83
3ac, 85
3ad, 93
3ae, 82
3af, 81
3ag, 62
3ah, 79
3ai, 77
3aj, 90
N.R.
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
420 : 1
—
9
10
11
12
13
3bi, 52
3ci, 89
420 : 1
420 : 1
Scheme 2 Proposed mechanism for the tandem reaction.
2i, phenyl
intermediate V, which releases the carbene catalyst I and the
key a-amino ketone intermediate 3ai0. The propensity to form
an enolate makes the a-carbon in 3ai0 a stronger nucleophilic
site than the amine nitrogen and drives the exclusive formation
of the intramolecular Michael addition product 3ai rather than
the intramolecular aza-Michael addition product.
14c
1a, H, H
3ae, 62
420 : 1
a
Reaction conditions: 1/2/base = 2.0/1.0/2.2, 0.1 M of 2 in CH2Cl2
b
at rt. Isolated yields. The preformed imine was used.
c
A plausible catalytic cycle for this process is depicted
in Scheme 2. N-Heterocyclic carbene I, generated by base
induced deprotonation of the corresponding thiazolium salt,
reacts with aldehyde 1a to produce the Breslow intermediate
II.7 Intermediate IV is then formed by reaction of II with the
electrophilic intermediate III, generated from 2i under the
basic conditions. Proton transfer from intermediate IV gives
The multi-functionalized products obtained in the aza-benzoin/
Michael reactions have the potential of participating in a variety
of transformations. For instance, upon treatment with TFA
at room temperature, the adducts 3 are converted to the
pyrrolidinone-containing tricyclic products 5 in excellent yields
(77% to 91%) via a sequence involving deprotection of the Boc
group followed by intramolecular lactamization (Table 3).
c
494 Chem. Commun., 2011, 47, 493–495
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Table 3 Conversion of 3 to pyrrolidinone-containing tricycles 5a
We believe that the interesting structural features of the
products of this new reaction along with the novelty of the
reaction pattern of imines will make the results of this effort
particularly interesting to synthetic organic chemists.
We thank the National Natural Science Foundation of
China (20732006, 20821002, 20972177) and National Basic
Research Program of China (973 Program 2009CB825300) for
generous financial support.
Entry
3, R1 R2, R3
5, yield (%)b
,
1
2
3
4
5
6
7
8
3aa, 4-MeOC6H4, H, H
3ab, 2-MeOC6H4, H, H
3ac, 4-MeC6H4, H, H
3ad, 3-MeC6H4, H, H
3ae, 4-BrC6H4, H, H
3af, 4-ClC6H4, H, H
3ag, 2-furyl, H, H
3ah, 2-thienyl, H, H
3ai, phenyl, H, H
3aj, 1-naphthyl, H, H
3bi, phenyl, Me, H
3ci, phenyl, H, F
5aa, 82
5ab, 77
5ac, 86
5ad, 79
5ae, 85
5af, 90
5ag, 91
5ah, 86
5ai, 80
5aj, 81
5bi, 87
5ci, 81
Notes and references
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2 Selected recent examples: (a) E. Gomez-Bengoa, A. Linden,
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9
J. Am. Chem. Soc., 2008, 130, 7955; (b) C. Gianelli, L. Sambri,
A. Carlone, G. Bartoli and P. Melchiorre, Angew. Chem., Int. Ed.,
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Angew. Chem., Int. Ed., 2009, 48, 2553.
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1326; (c) M. Christmann, Angew. Chem., Int. Ed., 2005, 44, 2632;
(d) K. Zeitler, Angew. Chem., Int. Ed., 2005, 44, 7506; (e) N. Marion,
10
11
12
a
Reaction conditions: 3/TFA = 1.0/20.0, 0.03 M of 3 in CH2Cl2
b
at rt. Isolated yields.
S. Dıez-Gonzalez and S. P. Nolan, Angew. Chem., Int. Ed., 2007, 46,
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2988; (f) D. Enders, O. Niemeier and A. Henseler, Chem. Rev., 2007,
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5 (a) G.-Q. Li, L.-X. Dai and S.-L. You, Chem. Commun., 2007, 852.
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Lopez-Calahorra, M. Bassedas and P. Urrios, Synthesis, 1988,
´
Fig. 1 X-ray crystal structure of pyrrolidinone-containing tricycle
5ae (thermal ellipsoids are set at 30% probability).
314; (c) J. A. Murry, D. E. Frantz, A. Soheili, R. Tiller,
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The structure of the pyrrolidinone-containing product 5ae
was confirmed by using X-ray crystallographic analysis
(Fig. 1).8 The tricyclic substances 5 are not only pharma-
ceutically interesting but they also represent a synthetically
challenging family of compounds owing to the presence of two
stereogenic centers including one quaternary carbon.
In summary, the studies described above have led to the
development of an efficient, highly diastereoselective, tandem
NHC-catalyzed aza-benzoin/Michael reaction affording dihydro-
indenones that can be transformed to pyrrolidinone-containing
tricycles. This is the first report of a process in which the N-Boc
imine precursor, tert-butyl aryl(tosyl)methylcarbamate, acts as
both an electrophile and nucleophile at the same carbon site.
7 R. Breslow, J. Am. Chem. Soc., 1958, 80, 3719.
8 CCDC 772193 contains the supplementary crystallographic data
for 5ae.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 493–495 495