Enantioselective aza-Michael addition to conjugated nitroenynes catalyzed by chiral arylaminophosphonium barfates

Article abstract of DOI:10.1055/s-0030-1260541

Enantioselective aza-Michael addition to conjugated nitroenynes has been developed. P-Spiro heterochiral arylaminophosphonium barfate 1bBArF effectively catalyzes the reaction, and the corresponding conjugate adducts, β-amino homopropargylic nitro compounds, are obtained in good chemical yields with high enantioselectivities. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0030-1260541

CLUSTER
1265
Enantioselective Aza-Michael Addition to Conjugated Nitroenynes Catalyzed
by Chiral Arylaminophosphonium Barfates
Enantioselective
A
a
za-Michael
i
A
dditi
s
on to
C
on
u
jugated
N
itr
k
oenynes e Uraguchi, Natsuko Kinoshita, Tomohito Kizu, Takashi Ooi*
Department of Applied Chemistry, Graduate School of Engineering, Nagoya University, Nagoya 464-8603 Japan
Fax +81(52)7893338; E-mail: tooi@apchem.nagoya-u.ac.jp
Received 2 March 2011
nitroolefins.11–13 Here, we present the results of this study
by describing the highly enantioselective conjugate addi-
tion of 2,4-dimethoxyaniline to various nitroenynes effi-
ciently catalyzed by P-spiro chiral arylamino-
Abstract: Enantioselective aza-Michael addition to conjugated ni-
troenynes has been developed. P-Spiro heterochiral arylaminophos-
phonium barfate 1b·BArF effectively catalyzes the reaction, and the
corresponding conjugate adducts, b-amino homopropargylic nitro
compounds, are obtained in good chemical yields with high enantio- phosphonium barfate 1b·BArF.
selectivities.
We initiated our investigations by evaluating the ability of
Key words: phosphonium salt, Brønsted acid, aza-Michael addi-
the chiral arylaminophosphonium barfates 1·BArF and
2·BArF as a Brønsted acid catalyst in the Michael donor–
acceptor combination of 2,4-dimethoxyaniline and nitro-
enyne 3a having a terminal phenyl substituent. The focus
was then directed toward the relationship between the cat-
alyst structure and the profile of reactivity and selectivity
(Table 1). When 3a was treated with 2,4-dimethoxy-
aniline in toluene at 0 °C under the influence of homo-
chiral 2a·BArF with a phenyl group at 3,3¢-positions of
one binaphthyl subunit (Ar), aza-Michael addition took
place smoothly, and the desired b-amino homopropargyl-
ic nitro compound 4a was isolated in 89% yield (Table 1,
entry 1). Because the enantiomeric excess of 4a thus ob-
tained was revealed to be only 30%, we applied arylami-
nophosphonium barfate 2b·BArF bearing a 3,4,5-
trifluorophenyl moiety to this reaction under similar con-
ditions (Table 1, entry 2). Although notable rate enhance-
ment was attained, the facial discrimination of prochiral
3a remained insufficient, indicating that the structural
modification on the aromatic substituents may not have a
major impact on the enantioselectivity. This selectivity is-
sue was fortunately solved by switching the axial chirality
of unsubstituted binaphthyl unit (right side of the drawing
structures in Figure 1), as we previously observed.10 In
fact, heterochiral arylaminophosphonium barfate 1·BArF
catalyzed the present aza-Michael addition with high effi-
ciency and good enantioselectivity (78% ee) irrespective
of the electronic property of the pendant aromatic groups
(Table 1, entries 3 and 4). Finally, we found that perform-
ing the reaction with 1b·BArF at a lower temperature re-
sulted in a critical improvement in enantioselectivity
(92% ee, Table 1, entry 5).
tion, propargyl amine, asymmetric synthesis
The catalytic asymmetric conjugate addition to extended
Michael acceptors occupies a unique place in the realm of
the stereoselective conjugate addition chemistry.1,2 With
rigorous control of both regio- and stereoselectivities, this
Michael technology serves as an expedient means for the
facile synthesis of functionalized chiral building blocks,
which are not readily accessible by other asymmetric
methodologies. As one of the suitable acceptors, nitro-
enynes possess their own attractive features because the
conjugate addition to this class of substrate generally pro-
ceeds in a 1,4-manner and hence the corresponding ad-
ducts, homopropargylic nitro compounds, could enjoy the
rich chemistry of functional-group transformations asso-
ciated with the nitro3 and alkynyl4 moieties.5–7 In 2006,
the first example of this type of bond-forming reaction
was reported by Trost et al. as a part of their study on the
conjugate addition of a-hydroxy ketones to nitroolefins
catalyzed by a chiral heterodinuclear metal complex.5
More recently, Alexakis et al. developed highly enanti-
oselective conjugate additions of carbonyl compounds
and organometallic reagents to nitroenynes in the context
of catalytic regio- and stereocontrols with extended nitro-
Michael acceptors.6 However, these pioneering research
efforts have focused on the use of carbon nucleophiles,
and thus heteroatom-centered nucleophiles have never
been employed in combination with nitroenynes despite
the significant synthetic potential of the corresponding
conjugate adducts, namely, chiral b-hetero-substituted
homopropargylic nitro compounds. In this situation, we
have been interested for some time in developing asym-
metric conjugate addition of aniline derivatives to extend-
ed nitro-Michael acceptors using chiral ionic Brønsted
acid8,9 of type 1·BArF10 as a catalyst on the basis of its ef-
fectiveness in aza-Michael reaction of simple conjugated
These optimized reaction conditions were used for further
experiments to probe the substrate scope.14 As shown in
Table 2, a series of conjugated nitroenynes 3 with substit-
uents of different electronic and steric properties on the
alkyne terminus were employable, demonstrating the gen-
eral applicability of this asymmetric aza-Michael proto-
col. In detail, slight electronic effect on enantioselectivity
was observed in the reactions with 3b and 3c having
p-methoxy- and p-chlorophenyl moieties, respectively
SYNLETT 2011, No. 9, pp 1265–1267
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Advanced online publication: 20.04.2011
DOI: 10.1055/s-0030-1260541; Art ID: Y03911ST
© Georg Thieme Verlag Stuttgart · New York

1266
D. Uraguchi et al.
CLUSTER
Table 1 Optimization of the Structure of Chiral Arylaminophos-
phonium Barfate 1·BArF and 2·BArF for Aza-Michael Reaction of
Nitroenyne 3aa
Table 2 Substrate Scopea
NHAr'
NO2
NO2
1b·BArF (2 mol%)
NHAr'
Ar'NH2 (1.1 equiv)
toluene, –20 °C
1⋅BArF or 2⋅BArF
R
R
NO2
NO2
(2 mol%)
3
4
Ar'NH2 (1.1 equiv)
toluene
Ph
Ar' = 2,4-(MeO)2-C6H3
Ph
3a
4a
Ar' = 2,4-(MeO)2-C6H3
Entry R
3
Time Yield ee
Product
4
(h)
15
14
14
14
13
12
13
10
(%)b (%)c
Entry
Catalyst
Temp (°C) Time (h) Yield (%)b ee (%)c
1
2
3
4
5
6
7
8
4-MeOC6H4
4-ClC6H4
n-Hex
3b
3c
3d
3e
3f
94
91
93
90
91
99
99
99
94
86
92
96
92
95
90
90
4b
4c
4d
4e
4f
4g
4h
4i
1
2
3
4
5
2a
2b
1a
1b
1b
0
0
15
6
89
93
97
89
92
30
32
78
78
92
0
15
i-Bu
0
5.5
14
c-Hex
–20
Cl(CH2)3
BnO(CH2)2
3g
3h
a All reaction was performed on a 0.1 mmol scale in 1.0 mL of toluene.
b Isolated yield.
c Determined by chiral stationary phase HPLC analysis. Absolute
stereochemistry was determined as described in Scheme 1.
t-BuMe2SiO(CH2)2 3i
a All reaction was performed on a 0.1 mmol scale in 1.0 mL of tolu-
ene.
Ar
b Isolated yield.
H
N
H
N
c Determined by chiral stationary phase HPLC analysis. Absolute
configuration of 4 was assigned on the analogy of 4a.
P
N
H
N
H
hydrogenation of 4a with Adam’s catalyst followed by
acetylation of the primary amino functionality gave N-
protected, saturated diamine 5a in 79% yield. Oxidative
removal of the dimethoxyphenyl moiety using ceric am-
monium nitrate (CAN) and a subsequent protection–
deprotection sequence furnished essentially pure 6a with-
out significant loss of its enantiomeric excess. The abso-
lute configuration of 6a was assigned to be R by
comparison of its observed optical rotation with that re-
ported in literature.15
Ar
1·BArF
BArF
Ar
H
N
H
N
P
N
H
N
H
Ar
BArF
2·BArF
a: Ar = Ph
b: Ar = 3,4,5-F3-C6H2
NHAr'
PtO2, H2
NHAr'
Figure 1 P-Spiro chiral arylaminophosphonium barfates 1·BArF
and 2·BArF; BArF = [3,5-(CF3)2C6H3]4B
2,6-t-Bu2-pyridine
NO2
NHAc
∗
∗
5a
Ph
toluene, r.t., 12 h
then Ac2O, 1 h
79%
Ph
4a (92% ee)
Ar' = 2,4-(MeO)2-C6H3
(Table 2, entry 1 vs. 2). The substrates with liner and
branched saturated alkyl chains (3d–f) were effectively
converted into the corresponding b-amino homopropar-
gylic nitroalkanes 4d–f with uniformly high levels of
enantiomeric excess (Table 2, entries 3–5). The present
system was compatible with primary alkyl chloride, as the
reaction with 3g led to the quantitative formation of 4g
with 95% ee (Table 2, entry 6). Further, incorporation of
an ethereal functionality such as benzyl and tert-
butyldimethylsilyl ethers (3h,i) was also tolerated without
any detrimental effects on the reactivity and selectivity
(Table 2, entries 7 and 8).
CAN, MeCN–H2O
0 °C, 10 min
NH2
HCl
NHAc
then Boc2O
0 °C to r.t., 18 h
42%
MeOH
50 °C, 2 h
92%
Ph
6a [α]D23 +6.67
(88% ee, c 0.51, CHCl3)
lit.: [α]D23 –6.40 (S)
(75% ee, c 1.21, CHCl3)
..
Scheme 1 Procedure for the determination of the absolute configu-
ration of 4a
In conclusion, we have achieved highly enantioselective
aza-Michael addition to conjugated nitroenynes for the
first time using P-spiro chiral arylaminophosphonium
barfate 1b·BArF as a catalyst. The chemistry described
here expands the synthetic utility of weakly acidic aryl-
Absolute configuration of the conjugate adduct 4a was de-
termined after the derivatization to known N-monoacetyl
diamine 6a,15 which was performed via the straightfor-
ward processes illustrated in Scheme 1. The catalytic
Synlett 2011, No. 9, 1265–1267 © Thieme Stuttgart · New York

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Enantioselective Aza-Michael Addition to Conjugated Nitroenynes
1267
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Acknowledgment
This work has been partially supported by the Global COE Program
in Chemistry of Nagoya University, Grants of JSPS for Scientific
Research, the Mitsubishi Foundation, and the Funding Program for
Next Generation World-Leading Researchers.
References and Notes
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(14) Representative Procedure for 1b·BArF Catalyzed Aza-
Michael Addition to Nitroenyne 3
To a solution of nitroenyne 3a (17.3 mg, 0.10 mmol) and
chiral arylaminophosphonium barfate 1b·BArF (3.44 mg,
2.0 mmol) in toluene (0.80 mL) was slowly added a solution
of 2,4-dimethoxyaniline (16.8 mg, 0.11 mmol) in toluene
(0.20 mL) at –20 °C. After being stirred for 14 h, the reaction
mixture was directly subjected to purification by column
chromatography on silica gel (hexane–EtOAc = 20:1 to 3:1
as eluent) to afford b-amino nitroalkyne 4a (30.0 mg, 92%
yield). The ee of 4a was determined by chiral stationary
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Analytical Data for Compound 4a
HPLC (DICEL CHIRALPAK IA, hexane–2-PrOH = 10:1,
flow rate = 1.0 mL/min, l = 210 nm): tR = 17.3 min (R), 18.9
min (S). 1H NMR (400 MHz, CDCl3): d = 7.37 (2 H, dd,
J = 7.8, 1.6 Hz), 7.35–7.24 (3 H, m), 6.81 (1 H, d, J = 8.6
Hz), 6.48 (1 H, d, J = 2.4 Hz), 6.44 (1 H, dd, J = 8.6, 2.4 Hz),
5.05 (1 H, t, J = 6.6 Hz), 4.76 (1 H, dd, J = 12.4, 6.6 Hz),
4.69 (1 H, dd, J = 12.4, 6.6 Hz), 4.38 (1 H, br), 3.82 (3 H, s),
3.77 (3 H, s). 13C NMR (101 MHz, CDCl3): d = 154.1, 149.6,
132.0, 128.9, 128.8, 128.4, 121.9, 114.2, 104.0, 99.5, 85.8,
84.5, 78.1, 55.8, 46.3, one carbon was not found, probably
due to overlapping. IR (neat): 3363, 2939, 2834, 1555, 1514,
1463, 1378, 1291, 1258, 1206, 1157, 1033, 917, 835, 758
cm–1. HRMS–FAB: m/z calcd for C18H19N2O4+ [M + H]+:
327.1339; found: 327.1329.
(15) Takaoka, Y.; Kajimoto, T.; Wong, C.-H. J. Org. Chem.
1993, 58, 4809.
Synlett 2011, No. 9, 1265–1267 © Thieme Stuttgart · New York