N-heterocyclic carbene catalyzed homoenolate-addition reaction of enals and nitroalkenes: Asymmetric synthesis of 5-carbon-synthon δ-nitroesters

Article abstract of DOI:10.1002/anie.201203449

Synthesizing synthons: The highly enantioselective title reaction is described. It employs catalytic amounts of N-heterocyclic carbene precursors and transforms a broad range of nitroalkenes, such as nitrodienes, nitroenynes, and nitrostyrenes, through reaction with a broad range of enals, into δ-nitroesters via homoenolate intermediates (see scheme). Copyright

Full text of DOI:10.1002/anie.201203449

Angewandte
Chemie
DOI: 10.1002/anie.201203449
Synthetic Methods
N-Heterocyclic Carbene Catalyzed Homoenolate-Addition Reaction
of Enals and Nitroalkenes: Asymmetric Synthesis of 5-Carbon-Synthon
d-Nitroesters**
Biswajit Maji, Li Ji, Siming Wang, Seenuvasan Vedachalam, Rakesh Ganguly, and Xue-Wei Liu*
Judging by recent trends, N-heterocyclic carbene (NHC)
catalyzed generation of reactive homoenolate intermediates
from enals and the involvement of such intermediates in
reactions with a variety of Michael acceptors has been
gradually recognized as an important research field in organic
synthesis.[1] In 2004, Bode and co-workers[2] and Glorius and
Burstein[3] independently disclosed the first catalytic gener-
ation of homoenolate intermediates from enals by using an
NHC as a nucleophilic organocatalyst. Later, several exten-
À
Figure 1. Strategy for a C C bond formation reaction using nitro-
alkenes.
sions have been made with various types of reactive electro-
philes to prepare synthetically valuable cyclic as well as
acyclic molecular scaffolds via a homoenolate intermediate.[4]
Amongst Michael acceptors, the nitroalkene is probably the
most useful electrophile because transformation of the unique
extensively investigated by using asymmetric Michael reac-
tions of enolizable carbonyl compounds with nitroalkenes.[8]
The synthesis of g-nitroketoesters and g-nitroketoamides has
also been achieved by the activation of 1,2-ketoester and
1,2-ketoanilide pronucleophiles, respectively, for reaction
with nitroalkenes.[9] In 2009, Nair et al. first reported the use
of imidazolinium-based carbenes for catalyzing the addition
of a,b-unsaturated aromatic aldehydes to b-nitrostyrenes, via
homoenolate intermediates, to give racemic 5-carbon-syn-
thon nitroester; however, limitations in substrate scope was
apparent.[4u] For the past few years, our research group has
engaged in the development of NHC-catalyzed variants of
important organic transformations.[10] We envisaged that
a chiral-NHC-catalyzed reaction of enals with a variety of
nitroalkenes such as nitrodienes, nitroenynes, and b-nitro-
styrenes would give enantiomerically enriched highly func-
tionalized 5-carbon-synthon nitroesters (Figure 1). Notably,
these chiral fragments are useful for molecular-scaffold
diversification owing to the presence of either an alkene or
an alkyne moiety together with a nitro group.[11] To the best of
our knowledge, no suitable direct method for preparing
enantiomerically enriched highly functionalized 5-carbon-
synthon d-nitroesters from simple a,b-unsaturated aldehydes
has been reported.
nitro group in the resulting product can facilitate further
structural elaboration.[5] Intermolecular organocatalytic C C
À
bond forming reactions of nitroalkenes can be categorized as
follows: (i) the Stetter reaction for the synthesis of b-nitro-
ketones (3-carbon synthons), (ii) Michael reactions involving
enolizable aldehydes or ketones for the generation of
g-nitroketones (4-carbon synthons), and (iii) the reaction
involving enals to make d-nitroesters (5-carbon synthons),
a reaction that involves an NHC-mediated formation of
a homoenolate intermediate (Figure 1).
Scheidt and co-workers first utilized the reaction of
a preformed protected thiozolium carbinol with a nitroalkene,
which functioned as a Michael acceptor; the reaction was
promoted by a chiral thiourea and fluoride anion and gave
b-nitroketone products with moderate ee values.[6] Recently,
the research group of Rovis reported an efficient and elegant
intermolecular asymmetric Stetter reaction of nitroalkenes;
the reaction employed a special type of chiral triazolium-
based N-heterocyclic carbene, which contained a fluorine
atom in the backbone.[7] The above methods gave enantio-
merically enriched 3-carbon-synthon b-nitroketones. The
synthesis of chiral 4-carbon-synthon g-nitroketones, was also
We began our investigation on the homoenolate-addition
reaction of cinnamaldehyde 1a with nitrodiene 2a, as
catalyzed by chiral imidazolinium carbene precursors
3a–3d. Whereas the use of imidazolinium based chiral
precatalysts 3a–3c gave no reaction, precatalyst 3d gave the
product 4a in 36% yield, the syn diastereoisomer having an
ee value of 19% (Table 1, entries 1–4).[12] The use of the
triazolium-based precatalyst 3e and KHCO3 as a base gave
a low yield of 4a and poor diastereoselectivity (d.r. = 1.4:1) in
favor of the anti stereoisomer (Table 1, entry 5). The use of
mesityl-substituted triazolium precatalyst 3 f in THF gave the
[*] Dr. B. Maji, L. Ji, S. Wang, S. Vedachalam, Dr. R. Ganguly,
Dr. X.-W. Liu
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
Singapore 637371 (Singapore)
E-mail: xuewei@ntu.edu.sg
[**] We gratefully acknowledge the support of Nanyang Technological
University (NTU; RG 50/08) and the Ministry of Health Singapore
(MOH; NMRC/H1N1R/001/2009) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201203449.
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Table 1: Optimization of the reaction.[a]
Table 2: Scope of the reaction of nitrodienes.[a]
Entry
R1
R2
4, Yield [%][b]
d.r.
ee[d]
[%]
[anti/syn][c]
1
2
Ph
Ph
Ph
Ph
4-ClC6H4
2-furyl
Ph
Ph
CH3
4a, 82
4b, 81
4c, 81
4d, 68
4e, 72
4 f, 48
4g, 52
4h, 86
6:1
9:1
10:1
7:1
10:1
–
95
94
99
92
97
82
96
97
4-MeC6H4
4-FC6H4
4-MeC6H4
4-BrC6H4
H
3[e]
4[e]
5[e]
6[f]
7[f]
8
CH3
2-furyl
5:1
6:1
Entry
Precatalyst, Solvent, Base
d.r.
Yield
[%][c]
ee
[anti/syn][b]
[%][d]
[a] Reactions performed with 2.0 equiv of 1 and 1.0 equiv of 2 for 24 h.
1[e]
2[e]
3[e]
4[e]
5
6
7
8
9
10
11
12
13
14
15
16
17
3a–3c, THF, K2CO3
3a–3d, THF, DBU
3d, THF, K2CO3
3d, THF, KHCO3
3e, THF, KHCO3
–
–
1:4
n.r.
n.r.
24
36
23
65
81
67
58
59
82
60
81
69
54
51
82
–
–
[b] Combined yield after column chromatography. [c] Diastereomeric
ratio determined from the H NMR spectrum of the crude reaction
mixture. [d] The ee values (anti diastereoisomer only) were determined
by HPLC analysis using a chiral column. [e] Anti diastereoisomer isolated
in pure form by column chromatography. [f] 3.0 equiv aldehyde added in
two portions over a reaction period of 48 h.
1
n.d.
19[f]
n.d.
86
94
91
95
86
87
87
87
94
94
93
95
1:4
1.4:1
1.7:1
5.5:1
5.5:1
6:1
4:1
1.8:1
3:1
3 f, THF, KHCO3
3 f, toluene, KHCO3
3 f, xylene, KHCO3
3 f, mesitylene, KHCO3
3 f, C6H5CF3, KHCO3
3 f, CH2Cl2, KHCO3
3 f, toluene, DIPEA
3 f, toluene, DMAP
3 f, toluene, NaOAc
3 f, toluene, K2CO3
3 f, toluene, Cs2CO3
3g, toluene, KHCO3
1
study, as concluded by analyzing the H NMR spectra of the
crude reaction mixtures.
The scope of this catalytic transformation was determined
using a variety of a,b-unsaturated aldehydes using precatalyst
3g. The reactions of aromatic, aliphatic, and heteroaromatic
nitrodienes gave good yields of product, had remarkable
levels of enantioselectivity, and had fair to good levels of
diastereoselectivity (Table 2). Both electron-rich and elec-
tron-deficient a,b-unsaturated aromatic aldehydes are good
substrates for this reaction, the corresponding products being
isolated with high ee values and in good yields (Table 2;
entries 2–5). Even aliphatic a,b-unsaturated aldehydes
including the simple nonsubstituted a,b-unsaturated alde-
hyde, acrolein, gave the desired products in moderate yields
with good levels of enantioselectivity (Table 2; entries 6 and
7). An unsaturated aldehydes containing a furyl group also
participated in the reaction with aliphatic nitrodiene to give
the desired product 4h in good yield and with high ee value
(Table 2; entry 8). The salient feature of this methodology is
that the reaction provides exclusively the anti diastereomer of
the 1,4-Michael addition product; not even a trace amount of
1,6-Michael addition product was observed in the given
examples (Table 2). Having established a homoenolate-addi-
tion reaction of nitrodienes, we then decided to investigate,
using the same optimized reaction conditions, the trans-
formation of nitroenynes, (Table 3). All types of enals,
including aromatic as well as heteroaromatic enals, under-
went this catalytic transformation smoothly, with good to high
levels of enantioselectivity (81–97%) and levels of diastereo-
selectivity as high as 12:1 (Table 3, entries 1–4). Interestingly,
the use of acrolein as a substrate led to the desired product in
modest yield and with good ee value (Table 3, entry 5).
Finally, we tested this catalytic method using the optimized
reaction conditions for the transformation of b-nitrostyrene
3:1
5.5:1
5.5:1
5.5:1
6:1
[a] Reaction conditions: aldehyde 1a (2.0 equiv), nitrodiene 2a
(1.0 equiv), chiral precatalyst (10 mol%), base (20 mol%), 24 h.
[b] Diastereomeric ratio determined by 1H NMR spectroscopy. [c] Com-
bined yield after column chromatography. [d] The ee values (anti
diastereoisomer only) were determined by HPLC using a chiral column.
[e] Reaction was carried out at 708C. [f] The ee value of major syn
diastereoisomer. n.d.=not determined, n.r.=no reaction.
desired product in 65% yield, the major product being the
anti diastereoisomer, which had an ee value of 86% (Table 1,
entry 6). After a preliminary screen of solvents and bases, it
was found that the use of triazolium salts 3 f and 3g, which are
derived from mesityl- and 2,6-diethyl-substituted indanol-
amine, respectively, together with toluene/MeOH (20:1) as
the solvent and KHCO3 as the base afforded 4a in compa-
rable yields and selectivity (Table 1, entries 7 and 17); the
diastereoselectivity was acceptable (3 f: d.r. = 5.5:1; 3g: d.r. =
6:1) and the enantioselectivity was high (3 f: 94%; 3g:
95%).[13] To improve the diastereoselectivity, the reaction
was carried out using the optimized reaction conditions but at
a lower temperature (08C); unfortunately, the reaction
showed no improvement in diastereoselectivity (d.r. = 6:1)
and conversion was incomplete even after 24 h. Therefore, we
decided to use chiral carbene precursor 3g for determining
substrate scope (Table 2). Notably, not even a trace amount of
Stetter product was observed during the entire optimization
2
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Table 3: Scope of the reaction of nitroenynes.[a]
entries 8 and 9, respectively).[14] Aliphatic nitroalkenes, such
as b-cyclohexylnitroalkene, do not participate in this catalytic
transformation (Table 4, entry 10).
The relative and absolute stereochemistry of the Michael-
addition products 4 and 8 were confirmed by X-ray crystallo-
graphic analysis of 4d and 8b (see the Supporting Informa-
tion).[15] The absolute stereochemistry of Michael-addition
product 6 was inferred by analogy.
Entry
R1
R2
6, Yield
d.r.
ee
[%][b]
[anti:syn][c]
[%][d]
To establish the importance of this catalytic transforma-
tion, we performed a number reactions with the products of
the homoenolate-addition reaction. d-Nitroester 8 f was
reduced to alcohol 9, which was subsequently oxidized to
aldehyde 10. Next, when treated with a catalytic amount of
DABCO, aldehyde 10 underwent smooth conversion into
cyclopentanol 11 as a mixture of diastereomers (d.r. = 3:1).
The major diastereoisomer of cyclopentanol 11 was isolated
in 71% yield (Scheme 1). The homoenolate-addition reaction
product 8h was prepared using the NHC precursor 3 f and was
obtained in 51% yield and with an ee value of 78%.
Compound 8h was subsequently transformed into d-lactam
12 in 81% yield and with an ee value of 76% when treated
with Raney nickel under an atmosphere of hydrogen
(Scheme 2).[16]
1[e]
2
Ph
Ph
6a, 70
6b, 67
6c, 68
6d, 78
6e, 51
12:1
10:1
9:1
10:1
–
94
81
81
97
83
4-MeC6H4
2-MeOC6H4
2-furyl
H
4-BrC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
3
4
5[f]
[a] Reactions performed with 2.0 equiv of 1 and 1.0 equiv of 5 for 24–
48 h. [b] Combined yield after column chromatography. [c] The d.r was
determined from the 1H NMR spectrum of the crude reaction mixture.
[d] The ee values (anti diastereoisomer only) were determined by HPLC
using a chiral column. [e] Reaction time 48 h. [f] 3.0 equiv of acrolein
added in two portions over a reaction period of 48 h.
derivatives. Various enals gave rise to highly functionalized
nitroester products 8 and diastereoselectivity in favor of the
anti product (Table 4). Electron-rich and electron-deficient
enals are well tolerated in the reactions with ortho- and para-
substituted nitrostyrene derivatives and give the correspond-
ing products in good yields with high levels of enantioselec-
tivity (95–99%), an exception being para-nitro-cinnamalde-
hyde, the reaction of which had moderate enantioselectivity
(81%). The reaction of acrolein with para- and meta-
substituted b-nitrostyrenes gave the desired Michael-addition
products with good selectivity (81 and 86% ee; Table 4,
Table 4: Substrate scope of reaction of b-nitrostyrenes.[a]
Scheme 1. Reaction conditions: a) DIBAL-H (2.2 equiv), toluene, (9,
72%); b) DMP (1.2 equiv), CH2Cl2, (10, 82%); c) DABCO (0.1 equiv),
CH2Cl2, 48 h, 08C, (11, 71%). DABCO=1,4-diazabicyclo[2.2.2]octane,
DIBAL-H=diisobutylaluminum hydride, DMP=Dess—Martin period-
inane.
Entry
R1
R2
8, Yield
d.r.
ee
[%][b]
[anti:syn][c]
[%][d]
1[e]
2[f]
3
Ph
Ph
4-ClC6H4
Ph
4-MeC6H4
2-MeOC6H4
4-MeC6H4
Ph
4-MeC6H4
3-MeOC6H4
cyclohexyl
8a, 66
8b, 58
8c, 78
8d, 63
8e, 73
8 f, 62
8g, 61
8h, 52
8i, 51
n.r.
5:1
6:1
4.5:1
5:1
10:1
10:1
9:1
–
99
91
95
97
95
93
81
81
86
–
4-MeOC6H4
4-MeOC6H4
4-tBuC6H4
4-ClC6H4
4-ClC6H4
4-NO2C6H4
H
4[f]
5
6[f]
7[f]
8[g]
9[g]
10
Scheme 2. Transformation of a d-nitroester into a d-lactam. RaNi=
Raney nickel.
H
Ph
–
–
In conclusion, we have developed methodology employ-
ing catalytic amounts of chiral N-heterocyclic carbene pre-
cursors for the synthesis of highly enantiomerically enriched
and highly functionalized 5-carbon-synthon d-nitroesters. A
broad range of enals in conjunction with a variety of
nitroalkenes, such as nitrodienes, nitroenynes, and nitrostyr-
enes, could be transformed under mild reaction conditions
into chiral nitroester compounds with good to high ee values.
[a] Reactions performed with 2.0 equiv of 1 and 1.0 equiv of 7 for 24 h.
[b] Combined yield after column chromatography. [c] Diastereomeric
1
ratio determined from the H NMR spectrum of the crude reaction
mixture. [d] The ee values (anti diastereoisomer only) were determined
by HPLC using a chiral column. [e] Reaction time 48 h. [f] Anti
diastereoisomer isolated in pure form by column chromatography.
[g] 3.0 equiv of acrolein was added in two portions over a reaction period
of 48 h.
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enantiomerically enriched cyclopentanols and d-lactams.
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Experimental Section
2,6-Diethyl-substituted triazolium salt 3g (7.4 mg, 0.017 mmol,
0.1 equiv), KHCO3 (3.5 mg, 0.034 mmol, 0.2 equiv), and nitrodiene
2a (30 mg, 0.17 mmol, 1.0 equiv) were added to a 10-mL flask fitted
with N2 balloon. Next, cinnamaldehyde 1a (45 mg, 0.34 mmol,
2.0 equiv), as a solution in toluene (0.8 mL), and MeOH (40 mL)
were added to the reaction mixture. After 24 h, the reaction mixture
was diluted with 2–3 mL ethyl acetate and the resulting solution was
purified by column chromatography over silica gel using EtOAc/
n-hexane 1:4 as eluent to afford product 4a in 82% yield.
Received: May 4, 2012
Published online: && &&, &&&&
Keywords: asymmetric synthesis · homoenolates ·
.
N-heterocyclic carbenes · nitroalkenes · organocatalysis
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anti Michael-addition product was the major product; see
Ref. [4u]. While optimizing our reaction (cinnamaldehyde 1a
and nitrodiene 2a), we found that the use of chiral imidazoli-
nium precatalyst 3d gives the syn Michael-addition product (syn-
4a) as
a major product. For details, see the Supporting
Information. Recently, Chen et al. reported a reaction of enals
with a,b-unsaturated carbonyl compounds that gives syn
Michael-addition products; see Ref. [4x].
[13] The use of stronger base and a higher concentration of MeOH,
led to lower yields of the desired product 4a; this result might be
due to slow base-induced decomposition of product. Rovis and
co-workers made a similar observation; see Ref. [7c].
[14] In the reaction of aryl-substituted enals, only product derived
from the Michael addition of homoenolate was observed, see
Ref. [4u].
[15] CCDC 874303 (4d) and 874305 (8b) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
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[12] Nair et al. reported that when an achiral mesityl-substituted
imidazolinium carbene catalyst was used in their reaction, the
Angew. Chem. Int. Ed. 2012, 51, 1 – 6
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.
Angewandte
Communications
Communications
Synthetic Methods
B. Maji, L. Ji, S. Wang, S. Vedachalam,
R. Ganguly, X.-W. Liu*
&&&& — &&&&
N-Heterocyclic Carbene Catalyzed
Homoenolate-Addition Reaction of Enals
and Nitroalkenes: Asymmetric Synthesis
of 5-Carbon-Synthon d-Nitroesters
Synthesizing synthons: The highly enan-
tioselective title reaction is described. It
employs catalytic amounts of N-hetero-
cyclic carbene precursors and transforms
a broad range of nitroalkenes, such as
nitrodienes, nitroenynes, and nitrostyr-
enes, through reaction with a broad range
of enals, into d-nitroesters via homoeno-
late intermediates (see scheme).
6
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Angew. Chem. Int. Ed. 2012, 51, 1 – 6
These are not the final page numbers!