One-pot cascade Michael-Michael-Aldol condensation for diastereoselective synthesis of nitro-substituted cyclohexanes

Article abstract of DOI:10.1039/b909766j

A one-pot reaction of nitroalkenes and enones was developed for the preparation of nitro-vinyl-substituted cyclohexanes, which could be simply converted into poly-N-heterocycles. The Royal Society of Chemistry 2009.

Full text of DOI:10.1039/b909766j

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One-pot cascade Michael–Michael–Aldol condensation for
diastereoselective synthesis of nitro-substituted cyclohexanesw
Yunfeng Chen, Cheng Zhong, Xiaohua Sun, Novruz G. Akhmedov, Jeffrey L. Petersen
and Xiaodong Shi*
Received (in College Park, MD, USA) 18th May 2009, Accepted 6th July 2009
First published as an Advance Article on the web 31st July 2009
DOI: 10.1039/b909766j
A one-pot reaction of nitroalkenes and enones was developed for
the preparation of nitro-vinyl-substituted cyclohexanes, which
could be simply converted into poly-N-heterocycles.
Nitroalkenes are important synthetic building blocks due to
their versatile reactivity in producing diverse functional groups
through easy transformations.4 According to literature,
nitroalkenes are commonly used as electrophiles or electron-
deficient dienophiles.5 The Lewis base activation of nitro-
alkenes provides a new and interesting strategy, whereby
the resulting nitro carbanion, A, serves as a nucleophile
for subsequent reaction with an appropriate electrophile.
However, one big challenge with this design is the homo-
condensation of nitroalkenes, leading to their polymerization.6
To solve this problem, our group recently developed an
alternative b-elimination approach, producing the allylic nitro
compound, C, as shown in Scheme 1B.7 The key to the success
of this new strategy is the introduction of one irreversible step in
the overall equilibrium system. Various b-alkyl nitroalkenes
were suitable for this reaction, which made this transformation
an efficient new approach in C–C bond formation for the
preparation of 1,4-difunctional products.
Cascade processes have a long tradition as efficient approaches
in complex molecule synthesis.1 Compared to the Lewis acid-,
radical- and transition metal-promoted cascade reactions,
Lewis base (LB)-mediated cascade transformations are much
less studied. However, with their unique reaction mechanisms,
successful LB-mediated cascade processes can provide new
approaches for complicated molecule construction that are
difficult to achieve using other methods.2
Our interest in developing LB-mediated cascade reactions was
initiated by the investigation of nitroalkene conjugate addition.
With the presence of a more acidic proton, addition of the nitro
compound to the enone was unfavored (formation of stronger
base) if no other reagents were added (Scheme 1A). However,
this transformation is attractive, since it provides different
1,4-difunctional building blocks that can be further converted
into synthetically useful complex molecules.3 Herein, we report a
successful Michael–Michael–aldol cascade reaction of nitro-
alkenes and enones for the synthesis of functional group-enriched
cyclohexanes with excellent yields, and its application in the
preparation of poly-N-heterocycles (Scheme 1B).
Encouraged by this result, we wondered whether this new
cascade process could be further extended to a second Michael
addition and subsequent intramolecular aldol reaction,
leading to nitro-substituted cyclohexane G in one-pot, as
shown in Scheme 1B. This proposed cascade condensation is
very attractive since the resulting nitro-substituted cyclo-
hexanes can be readily converted into functional group
enriched N-heterocycles through simple steps. Moreover, the
mechanism revealed through this process will help the under-
standing of the key factors that control this rather complex
multi-component systems and lead to the possible discovery of
other new cascade reactions. As indicated in the reaction path,
the key for a successful Michael–Michael–aldol process is to
switch the irreversible b-elimination step (B to C) into an
equilibrium, and expect the intramolecular aldol reaction
(formation of G) to be a new irreversible step under proper
reaction conditions. Since the a-proton in the allylic nitro
compound, C, is acidic, deprotonation of C will be one
simple approach in converting the B–C transformation to an
equilibrium. The reactions between allylic nitro compounds 1
and strong base KOtBu were then investigated.
Scheme 1 Lewis base activation of nitroalkenes.
As shown in Scheme 2, treatment of a nitroalkene with an
enone or a,b-unsaturated ester gave allylic nitroalkane 1 in
good yields with the presence of L-proline as a Lewis base. The
cyclohexane was not formed under this condition due to the
irreversible b-elimination. Reactions of 1 with KOtBu caused
the decomposition of 1, producing the nitroalkene. However,
no cyclization product was observed and extension of the
reaction time resulted in polymerization of the nitroalkene.
C. Eugene Bennett Department of Chemistry, West Virginia
University, Morgantown, WV 26506, USA.
E-mail: Xiaodong.Shi@mail.wvu.edu; Fax: 1-304-293-4904;
Tel: 1-304-293-3435 x6438
w Electronic supplementary information (ESI) available: Experimental
details, X-ray measurement, and 1H NMR and 13C NMR for all
compounds. CCDC 728930–728934. For ESI and crystallographic
data in CIF or other electronic format, see DOI: 10.1039/b909766j
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were applied (deprotonation of the more acidic nitro carbon
hydrogen rather than the carbonyl a-proton). Encouraged by
this result, we then investigated the reaction of ketone 1a with
different Michael receptors 2 in the presence of various mild
bases. To our pleasure, reactions between 1a and 2a/2b gave
the desired Michael–aldol product 4a/4b in the presence of
Et3N (entries 7–8), although with low reaction rates. The
reaction rate for enal 2a was later improved with the addition
of a catalytic amount of proline (entry 9, carbonyl activation).
Although NaN3 and K2CO3 could also promote this reaction,
Et3N gave the best results, producing nitro-substituted cyclo-
hexane 4a in excellent yield.
Scheme 2 Decomposition of g-keto allylic nitro compounds.
Since the base indeed led to the deprotonation of 1, converting
the irreversible elimination to an equilibrium, the fact that no
cyclohexane was formed under this reaction may be caused by
either the equilibrium in the intramolecular aldol step (F to G)
or the unfavored equilibrium between A and B. To evaluate
these crucial factors that influence the transformation,
reactions between 1 and carbonyl-activated alkenes 2 were
investigated (Table 1).
Notably, the thermodynamic product, 5, (addition of the
ketone a-carbon to aldehyde) was unobserved in all cases
(even without proline activation, entry 7).9 This was also
confirmed by the reaction between ester 1b and enal 2a, where
Michael addition product 3b was produced in excellent yield
and no further cyclization product formed under the reaction
conditions (entry 15). Moreover, the aldol product, 4, was
stable under even strong basic conditions: treatment of 4a with
KOtBu at 60 1C showed no decomposition, even after 24 h. All
these results strongly suggested that the intramolecular aldol
condensation was a rapid irreversible step in this cascade
process, which drove the equilibrium into the desired cyclo-
hexane product.
As indicated in Table 1, reactions between 1 and 2 would
presumably form three different condensation products: the
simple Michael addition product, 3, the kinetic aldol product,
4, and the thermodynamic aldol product, 5.8 The Michael
addition did not occur between 1 and 2 in the absence of the
base, even for the most reactive enal, 2a, in the presence of
proline (activation of enal) in DMSO (entries 1–2). Enal
polymerization occurred when 2a was treated with base in
DMSO (entry 3). With the addition of a strong base (KOtBu),
allylic nitro compound 1 decomposed (entry 5) through the
reaction path shown in Scheme 2. With the application of a
mild base with 1b and ester 2c, the Michael addition product,
3a, was observed in poor yield (entry 6). However, the
desired intramolecular aldol reaction did not occur, which
was likely to be due to the poor reactivity of the ester group
under the reaction conditions. This result suggested that the
Michael–aldol reaction was possible if proper basic conditions
Meanwhile, although three stereogenic centers were gener-
ated in product 4, only two C-1 diastereomers were obtained.10
This was likely to be caused by the small size difference
between the nitro and the vinyl groups on the C-1 position
in the chair-like transition state. Various enals were applied to
the reactions with allylic nitro compound 1 and the desired
nitro-substituted cyclohexanes 4 were obtained with good
yields and diastereoselectivity (Table 2).
Table 1 Allylic nitro compound Michael–Aldol condensationa
With these optimal conditions for the intramolecular
aldol reaction, we then investigated the direct condensation
between nitroalkenes and enones. As expected, the one-pot
Michael–Michael–aldol condensation was successfully achieved
Table 2 Cascade Michael–Aldol condensation of 1 and enalsa
Sub.
Conditions
Base
Cat.
Conv.
Yield
(20%)
(%) Prod. drc (%)d
Solv. (1.0 equiv.) Time/h
b
1
2
1e 1a 2a Pro
2e 1b 2a Pro
3e 1a 2a Pro
DMSO —
DMSO —
DMSO Et3N
DMSO —
48
48
12
48
20
20
20
20
5
20
5
5
5
5
0
0
—
—
—
—
—
—
o5
n.d. n.d. n.d.
4
5
6
7
8
9
1b 2c —
1b 2c —
1b 2c —
1a 2a —
1a 2b —
1a 2a Pro
0
—
—
trace n.d. trace
—
THF KOtBu
DMSO Et3N
MeOH Et3N
MeOH Et3N
MeOH Et3N
MeOH Et3N
MeOH NaOAc
MeOH NaN3
MeOH K2CO3
MeOH Et3N
100
10
75
o5
100
o5
100
100
100
100
3a
4a
4b
4a
4b
4a
4a
4a
3bf
—
8
2.4:1 68
n.d. o5
2.4:1 90
n.d. o5
4c: 92%, dr = 3.6 : 1 4d: 85%, dr = 3.2 : 1 4e: 84%, dr = 3.0 : 1
10 1a 2b Pro
12 1a 2a Pro
13 1a 2a Pro
14 1a 2a Pro
15 1b 2a Pro
—
0
2.4:1 86
2.3:1 71
—
90
4f: 78%, dr = 4.0 : 1 4g: 82%, dr = 2.2 : 1b 4h: 83%, dr = 12 : 1
a
b
1 : 2 = 1 : 2, c = 0.2 M. Based on the consumption of 1 by
a
1 : 2 = 1 : 2, c = 0.2 M; dr values are based on crude 1H NMR
c
d
NMR. Based on crude NMR analysis of two C-1 isomers. Isolated
b
analysis; isolated yields of all isomers. The relative stereochemistry
e
f
yields of all isomers. Polymerization of enal 2a. Isolated yield of
in situ reduced alcohol.
was not identified.
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Table 3 Cascade Michael–Michael–Aldol condensationa
Yield
(%)c
Yield
(%)c
R
drb
R
drb
CH3 3.7 : 1 7a: 90
C2H5 3.2 : 1 7b: 81
C6H5 8.2 : 1 7c: 82
CH3 6.0 : 1 7d: 88
C2H5 6.4 : 1 7e: 88
C6H5 14 : 1 7f: 82
Scheme 3 Synthesis of complex N-heterocycles from the nitro-
substituted 1,7-diesters and cyclohexanes.
We greatly appreciate the C. Eugene Bennett Department of
Chemistry, the Eberly College of Arts and Science, WVU
research co-op and WV-Nano Initiative at West Virginia
University for financial support.
CH3 4.5 : 1 7g: 80
C2H5 5.1 : 1 7h: 72
C6H5 12 : 1 7i: 77
CH3 3.6 : 1 7j: 84
NO2 3.8 : 1 7k: 87
Cl
4.1 : 1 7l: 83
Notes and references
1 For reviews: (a) K. C. Nicolaou, D. J. Edmonds and P. G. Bulger,
Angew. Chem., Int. Ed., 2006, 45, 7134–7186; (b) D. Enders,
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46, 1570–1581; (c) S. K. Bur and A. Padwa, Adv. Heterocycl.
Chem., 2007, 94, 1–105.
7m: 76%,
dr = 5.0 : 1
7n: 82%, 7o: 76%,
dr = 4.2 : 1 dr = 3.0 : 1
3a: 86%
2 For examples: (a) H. Xie, L. Zu, H. Li, J. Wang and W. Wang,
J. Am. Chem. Soc., 2007, 129, 10886–10894; (b) Y. S. Tran and
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Chim. Acta, 2005, 88, 3069–3088.
a
1 : 2 = 1 : 4, c = 0.2 M, reaction generally finished in 10–20 h.
dr determined by crude 1H NMR analysis. c Isolated yields of all isomers.
b
with excellent yield and good diastereoselectivity. The
substrate scope is summarized in Table 3.
3 See a review: R. Ballini, G. Bosica, D. Fiorini, A. Palmieri and
M. Petrini, Chem. Rev., 2005, 105, 933–971.
As shown in Table 3, proline could successfully promote the
cascade Michael–Michael–Aldol reaction with the addition of
mild bases (Et3N or NaN3). Application of an a,b-unsaturated
ester gave a good yield of Michael–Michael addition product
3a without further Dieckmann condensation.11 The enantio-
selective intramolecular aldol condensation of 1,7-dialdehyde
has been reported with excellent ee using a proline catalyst.12
However, this cascade transformation gave a very low enantio-
selectivity (o20% ee).13 This could be caused by the lack of
formation of an H-bond between the proline carboxylate
group and carbonyl oxygen under basic conditions. Investiga-
tion of different proline derivatives with possible formation of
a stronger H-bond is currently undergoing in our group. As
functional group-enriched compounds, both 3 and 7 can be
readily converted into complex N-heterocycles through simple
transformations. Two effective derivatizations are summarized
in Scheme 3, which further emphasize the strength of the
reported method as a highly efficient new approach in complex
molecule construction.
4 N. Ono, The Nitro Group in Organic Synthesis, Wiley-VCH,
Weinheim, Germany, 2005.
5 For reviews: (a) O. M. Berner, L. Tedeschi and D. Enders, Eur. J.
Org. Chem., 2002, 1877–1894; (b) S. E. Denmark and
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8 For examples: (a) N. Halland, P. S. Aburel and K. A. Jørgensen,
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10 See detailed X-ray crystal structures and NOE experiments in the
In conclusion, a one-pot condensation of nitroalkenes and
carbonyl-activated alkenes was developed. The optimal
conditions were developed with the application of both Lewis
base and mild bases. Through this process, functional group-
enriched cyclohexanes were prepared with excellent yields and
good diastereoselectivity. The asymmetric transformation and
application of this approach in natural product total synthesis
are currently under investigation.
ESIw.
11 Some literature reported examples: (a) C. Reddy, V. Reddy and
J. G. Verkade, J. Org. Chem., 2007, 72, 3093–3096; (b) M. Hirano,
M. Hirai, Y. Ito, T. Tsurumaki, A. Baba, A. Fukuoka and
S. Komiya, J. Organomet. Chem., 1998, 569, 3–14.
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Int. Ed., 2003, 42, 2785–2788.
13 For compounds 4 and 7, less than 20% ee was observed with
L-proline as the catalyst.
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This journal is The Royal Society of Chemistry 2009
5152 | Chem. Commun., 2009, 5150–5152