Enantioselective formal α-allylation of nitroalkanes through a chiral iminophosphorane-catalyzed Michael reaction-Julia-Kocienski olefination sequence

Article abstract of DOI:10.1039/c3cc49477b

A two-step sequence for the asymmetric formal α-allylation of nitroalkanes is disclosed. This new methodology relies on the development of a highly diastereo- and enantioselective conjugate addition of nitroalkanes to vinylic 2-phenyl-1H-tetrazol-5-ylsulfones using chiral triaminoiminophosphorane as a requisite base catalyst and subsequent Julia-Kocienski olefination under kinetic conditions.

Full text of DOI:10.1039/c3cc49477b

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Enantioselective formal a-allylation of
nitroalkanes through a chiral iminophosphorane-
catalyzed Michael reaction–Julia–Kocienski
olefination sequence†
Cite this: Chem. Commun., 2014,
50, 3491
Received 13th December 2013,
Accepted 4th February 2014
Daisuke Uraguchi,a Shinji Nakamura,a Hitoshi Sasaki,a Yuki Konakadea and
DOI: 10.1039/c3cc49477b
Takashi Ooi*ab
www.rsc.org/chemcomm
A two-step sequence for the asymmetric formal a-allylation of nitro- of establishing a formal asymmetric a-alkylation of nitroalkanes
alkanes is disclosed. This new methodology relies on the development by the judicious combination of a stereoselective conjugate addi-
of a highly diastereo- and enantioselective conjugate addition of nitro- tion to vinylic sulfones, specifically 2-substituted 1-(1-phenyl-1H-
alkanes to vinylic 2-phenyl-1H-tetrazol-5-ylsulfones using chiral tetrazol-5-ylsulfonyl)ethenes 2, and subsequent Julia–Kocienski
triaminoiminophosphorane as a requisite base catalyst and subsequent olefination.6–8 The total lack of catalytic systems that enable
Julia–Kocienski olefination under kinetic conditions.
rigorous absolute and relative stereocontrol in the Michael-type
reaction of nitroalkanes with vinylic sulfones posed a great
Stereoselective a-functionalization of nitroalkanes offers an attractive challenge;9,10 nonetheless we envisaged that the use of P-spiro
yet powerful tool for the preparation of various chiral organic chiral triaminoiminophosphoranes 1 (Fig. 1) as a catalyst could
molecules having functionalities that can be derived from the nitro pave the way for our objective, considering the ability of their
group.1 Accordingly, the development of reliable catalytic protocols conjugate acids 1ꢀH to precisely recognize reactive nitronates
constitutes a vital area in organic synthesis, and significant progress through hydrogen-bonding-assisted ionic interactions.11–14 Herein,
has been made in attaining sufficient reactivity and selectivity in the we report the development of the highly diastereo- and enantio-
addition of nitroalkanes to carbonyls, imines, and electron-deficient selective conjugate addition of nitroalkanes to vinylic sulfones 2
unsaturated bonds.2 However, simple alkylation of nitroalkanes to under the influence of 1 and the marriage of this new protocol with
access a-chiral nitro compounds has been regarded as a problematic Julia–Kocienski olefination, thereby providing a flexible stereo-
reaction, primarily because of the ambident reactivity of the inter- selective route to a-alkylated chiral nitroalkanes.
mediary generated nitronates. Namely, O-alkylation of nitronates
The investigation was initiated by conducting the addition of
is generally favored over C-alkylation under the standard basic nitroethane to 1-(1-phenyl-1H-tetrazol-5-ylsulfonyl)propene (2a)
conditions, and a single-electron-transfer process is known to in THF at ꢁ78 1C in the presence of L-valine-derived iminophos-
be a prerequisite for implementing the selective C-alkylation.3 phorane 1a (5 mol%) as the catalyst. The reaction proceeded
In fact, currently available methods for the stereoselective smoothly to give the conjugate addition product 3a in good
a-alkylation of nitroalkanes are restricted to asymmetric allylic yield with a diastereomeric ratio of 10: 1, but the enantiomeric
alkylation catalyzed by chiral transition-metal complexes with a excess of the major product anti-3a was revealed to be rather
limited substrate scope and moderate stereoselectivities.4,5 In low (Table 1, entry 1). This result prompted us to examine the
the context of pursuing an alternative approach to address this effect of the catalyst structure mainly on the selectivity profile.
long-standing problem, we became interested in the possibility Interestingly, changing the alkyl side chain of the parent amino
acid origin (R1) from the isopropyl to (S)-sec-butyl group (1b) led to a
dramatic improvement in the stereoselectivity, and anti-3a was pre-
dominantly obtained with a high level of enantiocontrol (entry 2).
a Institute of Transformative Bio-Molecules (WPI-ITbM) and Department of Applied
Chemistry, Graduate School of Engineering, Nagoya University,
Furo-cho B2-3(611), Chikusa, Nagoya 464-8603, Japan.
E-mail: tooi@apchem.nagoya-u.ac.jp; Fax: +81-(0)52-789-3338;
Tel: +81-(0)52-789-4501
b CREST, Japan Science and Technology Agency (JST), Chikusa, Nagoya 464-8603,
Japan
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data of 1e–4, and absolute structure determination of
anti-3h. CCDC 976445. For ESI and crystallographic data in CIF or other electronic
Fig. 1 P-Spiro chiral triaminoiminophosphoranes.
format See DOI: 10.1039/c3cc49477b
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Table 1 Optimization of catalyst (PT = 1-phenyl-1H-tetrazol-5-yl)a
Entry
1
Time (h)
Yieldb (%)
drc
10 : 1
14 : 1
9 : 1
eed (%)
1
2
3
4
5
1a
1b
1c
1d
1e
6
7
20
24
16
89
75
80
68
83
28
92
92
86
95
10 : 1
420 : 1
Fig. 2 ORTEP diagram of anti-3h. The thermal ellipsoids of non-
hydrogen atoms are shown at the 50% probability level. Blue = nitrogen,
red = oxygen, yellow = sulfur, black = carbon.
a
The reaction was performed with 0.1 mmol of 2a, 1.0 mmol of
nitroethane, and 5 mol% of 1 in THF (1.0 mL) with MS4A (100 mg) at
b
c
ꢁ78 1C. See ESI for details. Isolated yield. Diastereomeric ratios were
determined by 400 MHz 1H NMR analysis of crude aliquots. Enantio-
d
meric excesses were analyzed by chiral stationary phase HPLC. Absolute efficient catalyst turnover. With 2-alkyl-substituted vinylic sulfones,
configuration of 3a was assigned by analogy to 3h (Fig. 2).
the present system tolerated not only the elongation of simple
carbon chains but also the incorporation of various functional
groups, and good-to-excellent stereoselectivities were uniformly
observed (entries 1–6).
On the other hand, a certain decrease in the diastereo- or enantio-
selectivity was observed when 4-fluoro (1c) or 4-methylphenyl (1d)
groups were introduced as aromatic substituents (Ar), irrespective
of their electronic properties (entries 3 and 4). Eventually, further
structural tuning of 1 by the replacement of the N-methyl appen-
dage (R2) with an ethyl group (1e) afforded a critical enhancement
of the stereoselectivity, resulting in the exclusive formation of anti-
3a with 95% ee (entry 5).
With the optimal catalyst structure in hand, we studied the
substrate scope of this new asymmetric conjugate addition
protocol; the representative results are listed in Table 2. In general,
5 mol% of 1e was sufficient for the reaction to be completed within
24 h, and the presence of 4A molecular sieves was crucial for
While 2-aryl-substituted vinylic sulfones also appeared to be
good Michael acceptors, the enantioselectivity of the anti-isomer
was affected by the steric and electronic properties of the aromatic
substituents, though it remained at a synthetically useful level
(entries 7–13). In addition, a comparable degree of stereochemical
control was achieved in the reaction with nitropropane as a donor
substrate (entry 14).15 The absolute configuration of anti-3h was
unambiguously determined to be 2S,3R by single crystal X-ray
diffraction analysis (Fig. 2), and the stereochemistries of other
examples were assumed by analogy.
Having realized the desired catalytic Michael technology
with high stereocontrol, we explored the appropriate conditions
for performing the Julia–Kocienski olefination of anti-3 without
loss of stereochemical integrity. In consideration of the low pKa
value of the a-proton of the nitro functionality, almost diastereo-
merically pure anti-3a and 3h were treated with the bulky
mesityllithium in the presence of benzaldehyde, respectively, for
ensuring kinetic deprotonation at the a-position of the sulfonyl
moiety (Scheme 1). As expected, formally a-allylated nitroalkanes
anti-4a and 4h were obtained in good yields and preservation of
the enantiomeric excess of each product was confirmed by HPLC
analysis. Furthermore, we found that one-pot operation of the
consecutive 1e-catalyzed Michael reaction–olefination sequence
was feasible with retention of high stereoselectivity as exemplified
in Scheme 2.
Table 2 Substrate scope (PT = 1-phenyl-1H-tetrazol-5-yl)a
Time Yieldb
eed
(%)
Entry
R
2
R0 (h)
(%)
drc
3
1
2
3
4
Et
2b Me 11
2c Me 12
99
99
92
84
95
99
93
95
99
99
98
91
99
99
420 : 1 94 3b
420 : 1 95 3c
420 : 1 95 3d
19 : 1 97 3e
12 : 1 95 3f
420 : 1 94 3g
420 : 1 88 3h
12 : 1 80 3i
420 : 1 87 3j
13 : 1 90 3k
420 : 1 87 3l
19 : 1 83 3m
420 : 1 93 3n
420 : 1 85 3o
Me(CH2)7
CH2QCH(CH2)8 2d Me
BnO(CH2)3
BzO(CH2)3
PhthN(CH2)3
Ph
7
2e Me 20
2f Me 10
2g Me 24
2h Me 15
5
6e
7
f
8
o-FC6H4
2i
2j
Me
Me 17
9
In conclusion, a two-step sequence for the asymmetric formal
a-allylation of nitroalkanes was established through the development
9e
10
11e
12
13e
14
m-MeC6H4
m-BrC6H4
p-MeC6H4
p-ClC6H4
2-Naph
2k Me
6
2l Me 21
2m Me
2n Me
6
6
Me(CH2)7
2c Et 18
a
Unless otherwise noted, the reaction was performed with 0.1 mmol of
2, 1.0 mmol of nitroalkane, and 5 mol% of 1e in THF (1.0 mL) with
b
c
MS4A (100 mg) at ꢁ78 1C. See ESI for details. Isolated yield. Diaster-
eomeric ratios were determined by 400 MHz 1H NMR analysis of crude
d
aliquots. Enantiomeric excesses were analyzed by chiral stationary
phase HPLC. Absolute configuration of 3h was determined by X-ray
e
Scheme 1 Julia–Kocienski olefination of anti-3 for formal a-allylation of
nitroalkanes (PT = 1-phenyl-1H-tetrazol-5-yl).
diffraction analysis and others were assigned by analogy to 3h. 0.5 mL
f
of THF was used. PhthN = phthaloylimide.
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This work was supported by the NEXT program, JST-CREST, a
Grant-in-Aid for Scientific Research on Innovative Areas ‘‘Advanced
Molecular Transformations by Organocatalysts’’ from MEXT, the
Program for Leading Graduate Schools ‘‘Integrative Graduate Educa-
tion and Research Program in Green Natural Sciences’’ in Nagoya
University, the Asahi Glass foundation, and Grants of JSPS for
Scientific Research. S.N. acknowledges JSPS for financial support.
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This journal is ©The Royal Society of Chemistry 2014
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