Asymmetric Conjugate Addition of Nitroalkanes to Enones Using a Sulfonamide-Thiourea Organocatalyst

Article abstract of DOI:10.1021/acs.joc.7b00835

The asymmetric conjugate addition of nitroalkanes to α,β-unsaturated ketones in the presence of a catalytic amount of a novel sulfonamide-thiourea organocatalyst resulted in the corresponding γ-nitro carbonyl products in high yields with excellent enantio

Full text of DOI:10.1021/acs.joc.7b00835

Note
Asymmetric Conjugate Addition of Nitroalkanes to
Enones Using a Sulfonamide-thiourea Organocatalyst
Masahiro Kawada, Kosuke Nakashima, Shin-ichi Hirashima, Akihiro Yoshida, Yuji Koseki, and Tsuyoshi Miura
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 12 Jun 2017
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The Journal of Organic Chemistry
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Asymmetric Conjugate Addition of Nitroalkanes to Enones Using a
Sulfonamide–Thiourea Organocatalyst
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Masahiro Kawada, Kosuke Nakashima, Shin-ichi Hirashima, Akihiro Yoshida, Yuji Koseki,
Tsuyoshi Miura*
Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
ABSTRACT: The asymmetric conjugate addition of nitroalkanes to α,β-unsaturated ketones in the presence of a catalytic
amount of a novel sulfonamide–thiourea organocatalyst resulted in the corresponding γ-nitro carbonyl products in high
yields with excellent enantioselectivities (up to 97% ee).
of 1,3-diketones to nitroalkenes using a sulfonamide–
thiourea organocatalyst (Wang’s catalyst).4 Sulfonamide–
thiourea organocatalysts can effectively catalyze several
significant asymmetric reactions.5
Chiral γ-nitro carbonyl compounds are valuable synthetic
intermediates in the fields of medicinal and organic
chemistry because they can provide access to biologically
active molecules.1 To obtain chiral γ-nitro carbonyl com-
pounds in an efficient and eco-friendly manner, asymmet-
ric conjugate additions of nitroalkanes to enones using
organocatalysts are among the most convenient method-
ologies.2 Although several organocatalytic conjugate addi-
tions of nitroalkanes to α,β-unsaturated ketones have
been reported, reports on the intermolecular conjugate
addition of nitroalkanes to benzylideneacetones using
organocatalysts are relatively rare.3 In addition, most of
these methods require long reaction times (>48 h) and
high catalyst loadings (20 mol%), and do not provide both
satisfactory yields and excellent enantioselectivities. To
the best of our knowledge, there is no report that could
meet all of these requirements, i.e., short reaction time
(within 24 h), low catalyst loading (10 mol% or less), sat-
isfactory yield (>80%), and excellent stereoselectivity
(>95% ee), in the synthesis of γ-nitro ketones from ben-
zylideneacetones. Therefore, the development of a novel
organocatalyst that can efficiently promote the asymmet-
ric conjugate addition of nitroalkanes to benzylideneace-
tone derivatives is highly desirable.
Recently,
aminoalkyl)sulfonamides, which were derived from
phenylalanine or -valine, are good organocatalysts for
several asymmetric reactions.6 Among the tested
-(β-
we
have
reported
that
Ν-(β-
L-
L
Ν
aminoalkyl)sulfonamides, organocatalysts 1 and 2 bearing
the perfluorobutanesulfonamide group exhibited more
preferable catalytic activity.6 In addition, we demonstrat-
ed that an organocatalyst bearing the perfluorobutanesul-
fonamide and squaramide motif effectively promoted the
asymmetric direct vinylogous aldol reaction of furan-
2(5H)-one with aldehydes.7 In our efforts to develop more
effective organocatalysts by the modification of
Ν-(β-
aminoalkyl)sulfonamides 1 and 2, we envisaged develop-
ing an organocatalyst bearing both the perfluorobu-
tanesulfonamide and thiourea motif. Herein, we describe
the highly efficient synthesis of chiral γ-nitro carbonyl
compounds from benzylideneacetones using perfluorobu-
tanesulfonamide–thiourea organocatalysts.
We examined organocatalysts 2–8 (Figure 1) for the enan-
tioselective conjugate addition of nitromethane to (E)-4-
Organocatalysts with motifs involving multiple hydrogen-
bond donors have attracted considerable interest since
Wang et al. reported the asymmetric conjugate addition
phenylbut-3-en-2-one (9a) as shown in Table 1.
Aminoalkyl)sulfonamide 2 was a poor catalyst, affording
low yield and moderate stereoselectivity (entry 1). All ex-
Ν-(β-
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amined sulfonamide–thiourea organocatalysts 3–8 con-
trolled high enantiofacial selection in 94%–97% ee (en-
tries 2–7). In particular, catalyst 3 derived from -valine
was the most suitable catalyst. Notably, excellent enanti-
oselectivity was obtained when organocatalyst 8 was used;
however, the yield was moderate (entry 7). This fact indi-
cated that enantioselectivity was controlled by the chirali-
ty of the cyclohexanediamine, and the yield was increased
amount of 3 in various solvents at 40 °C. Among the ex-
1
2
3
4
5
6
7
8
amined representative reaction solvents, we found that
ethyl acetate was the most suitable solvent in terms of
both yield and enantioselectivity.
L
With these optimal conditions in hand, the scope and
limitations of the conjugate addition of nitroalkanes to
α,β-unsaturated ketones 9 were examined (Table 3). Sub-
strates 9b–f bearing bromo, chloro, and nitro substituents
as representative electron-withdrawing groups on the
aromatic entity smoothly reacted with nitromethane in
the presence of catalyst 3 to afford the corresponding ad-
ducts 10b–f in high yields with excellent enantioselectivi-
ties (entries 1–5). The reaction of enone 9g bearing methyl
substituent as electron-donating groups with nitrome-
thane also proceeded well, affording the corresponding
addition product 10g with excellent enantioselectivity
(entry 6). The conjugate additions to 9h bearing a furan
ring as a heterocycle provided the adduct 10h in moderate
yield; however, excellent enantioselectivity was observed
(entry 7). Cyclohex-2-en-1-one (9i) as a cyclic (Z)-enone
reacted with nitromethane to give the corresponding γ-
nitroketone 10i with excellent stereoselectivity, albeit in
moderate yield (entry 8). Furthermore, the reaction of
enone 9a with other types of nitroalkanes such as 2-
nitropropane also resulted in the corresponding product
10j in high yield with excellent enantioselectivity (entry
9). Although low diastereoselectivity was observed when
nitroethane was used as the nucleophile, the enantiose-
lectivities of the stereoisomers were excellent (entry 10).
Chalcone (9l) was poor substrate to provide low yield
(entry 11). The reaction of 9m as an aliphatic aldehyde
resulted in low yield; however, excellent enantioselectivi-
ty was obtained (entry 12). The stereochemistry of all
products was determined by comparison with reported
optical rotation and chiral-phase HPLC retention times.
by the L-valine unit.
9
10
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Table 2. Study of solvents
3
MeNO2 catalyst
(5 equiv) (10 mol%)
O
O2N
O
Ph
Me
Solvent, 40 °C, 24 h Ph
Me
9a
10a
yield (%)a
solvent
% eeb
entry
1
2
MeOH
DMF
13
56
79
95
3
4
5
6
7
MeCN
60
80
97
97
t-BuOMe
CHCl3
71
73
98
97
CH2Cl2
toluene
hexane
neat
81
67
81
85
94
96
94
97
8
9
EtOAc
10
The optimum reaction conditions for the conjugate addi-
tion of nitromethane to benzylideneacetones using cata-
lyst 3 were investigated (Table 2). The reaction between
(E)-4-phenylbut-3-en-2-one (9a) and nitromethane as test
reactants was performed in the presence of a catalytic
a Isolated yield. b Enantiomeric excess was determined
by chiral HPLC analysis.
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Table 3. Study of substrate scope
nitroalkane
1
2
3
4
catalyst 3
(10 equiv) (10 mol%)
enone
product
9
EtOAc, 40 °C, 24 h
10
5
6
7
8
% eeb
entry
product 10
O2N
yield (%)a
O
1
2
3
4
86
84
84
90
96
9
Me
Me
10
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Br
10b
10c
O2N
O2N
O
O
Based on the stereochemistry of the obtained γ-nitro ke-
96
96
95
tones, we propose that the conjugate addition of nitrome-
thane to the enone using organocatalyst 3 proceeds via
the transition state as shown in Figure 2. The primary
amine group in 3 condenses with enone 9 to form the
stable (Z)-eniminium intermediate. The three acidic pro-
tons of 3 can function as hydrogen-bond donors, provid-
ing a rigid interaction with the two oxygen atoms of ni-
tromethane. These successful interactions can control the
direction (Re-face attack) from which the nitromethide
anion approaches the (Z)-eniminium intermediate. Final-
ly, the transition state subsequently results in the addi-
tion product with excellent enantioselectivity.
Cl
Cl
Me
10d
O2N
O
Me
10e
Cl
O2N
O
5
6
86
84
95
96
Me
Me
10f
O2N
Me
O2N
O
10g
O2N
O
7
8
49
40
97
96
Me
O
O
10h
NO2
10i
O2N
O
In summary, the novel sulfonamide–thiourea organocata-
lyst 3 efficiently promoted the conjugate addition of ni-
troalkanes to α,β-unsaturated ketones to afford the corre-
sponding chiral addition products in high yields with ex-
cellent enantioselectivities. Organocatalyst 3 provided a
shorter reaction time, low catalyst loading, satisfactory
yield, and excellent stereoselectivity for the synthesis of γ-
nitro ketones from benzylideneacetones.
9
92
96
Me
Me
10j
O2N
O
10
11
81c
95 (95)d
10k
O2N
O
Experimental Section
8
52
1H NMR and 13C NMR spectra were recorded on a Bruker
1
Avance III Nanobay 400 MHz spectrometer (400 MHz for H
10l
NMR and 100 MHz for 13C NMR). The chemical shifts are ex-
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pressed in ppm downfield from tetramethylsilane (δ = 0.00) as
NMR (100 MHz, CD3OD): δ = 25.2, 25.8, 31.7, 32.7, 39.2, 56.7, 57.3,
1
2
3
4
5
6
7
8
an internal standard. Mass spectra were recorded by an elec-
trospray ionization-time of flight (ESI-TOF) mass spectrometer
(Micromass LCT). Specific rotations were measured on a Jasco P-
1030. Melting points were obtained with Yanaco MP-J3 and are
uncorrected. For thin layer chromatographic (TLC) analyses,
Merck precoated TLC plates (silica gel 60 F254) were used. Flash
column chromatography was performed on neutral silica gel
(Kanto Silica gel 60N, 40–50 μm). Organocatalysts 1 and 2 were
prepared by the previous reported methods.6a, 6b
58.3, 110.2-120.7 (complex signals of –CF2- and –CF3), 127.3, 129.3,
130.4, 140.1, 184.2; HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C20H26F9N4O2S2 589.1348; Found 589.1353; Anal. Calcd for
C20H25F9N4O2S2: C, 40.82; H, 4.28; N, 9.52. Found: C, 40.78; H,
4.45; N, 9.25.
Preparation of organocatalyst 5
To
a 25-mL round-bottomed flask was added (1R,2R)-
diphenylethylenediamine (1.06 g, 5.0 mmol,), DMAP (112 mg, 1.0
mmol), THF (5.0 mL), triethylamine (1.4 mL, 10 mmol), and per-
fluoro-1-butanesulfonyl fluoride (1.08 mL, 6.0 mmol). The solu-
tion was stirred at 60 °C for 38 h. After starting material was
consumed, the reaction mixture was added to water and extract-
ed three times with EtOAc. The EtOAc layers were combined,
washed with brine, dried over anhydrous Na2SO4, and evapo-
rated. The residue was purified by flash column chromatography
on silica gel (CHCl3:MeOH = 1:0 to 50:1) to afford the pure N-
((1R,2R)-2-amino-1,2-diphenylethyl)-1,1,2,2,3,3,4,4,4-
9
10
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Preparation of organocatalyst 3
To a 50-mL round-bottomed flask was added sulfonamide 2 (2.03
g, 5.27 mmol) and dry Et2O (17 mL). The solution was cooled to 0
°C and added CS2 (2.1 mL, 34.8 mmol) and DCC (1.09 g,
5.27mmol). The reaction mixture was stirred at room tempera-
ture for 23 h. After starting material was consumed, the solution
filtered and concentrated in vacuo to afford a crude product.
Purification by flash column chromatography on silica gel (hex-
ane:EtOAc = 20:1 to 10:1) afforded the mixture of isothiocyanate
and small amount of 1,3-dicyclohexylthiourea. This mixture was
used without further purification in the next step. To a 50-mL
round-bottomed flask was added mixture of isothiocyanate (1.63
g), (1R,2R)-(-)-cyclohexanediamine (877 mg, 7.68 mmol) and
THF (13 mL).The solution was stirred for 16 h. After starting ma-
terial was consumed, the solution concentrated in vacuo to af-
ford a crude product. Purification by flash column chromatog-
raphy on silica gel (CHCl3:MeOH:H2O = 9:1:0.08) afforded the
pure 3 as a white crystal (1.90 g, 67% from 2). mp 128-129 °C;
[α]27D = -13.9 (c 1.00, CHCl3); 1H NMR (400 MHz, CDCl3): δ = 0.91
(d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.9 Hz, 3H), 1.11-1.21 (m, 2H), 1.37-
1.47 (m, 1H), 1.64-1.90 (m, 4H), 2.00 (d, J = 10.9 Hz, 1H), 2.20 (d, J
= 11.2 Hz, 1H), 2.94 (dt, J = 3.2, 11.3 Hz, 1H), 3.20 (t, J = 12.2 Hz,
1H), 3.31 (d, J = 11.5 Hz, 1H), 4.43-4.50 (m, 1H), 4.71-4.78 (m, 1H),
6.41 (d, J = 9.6 Hz, 1H), 6.64 (brs, 3H), 7.49 (d, J = 9.2 Hz, 1H); 13C
NMR (100 MHz, CDCl3): δ = 18.4, 18.6, 24.0, 24.7, 29.8, 31.8, 32.2,
46.6, 54.9, 56.4, 60.3, 106.1-119.2 (complex signals of –CF2- and –
nonafluorobutane-1-sulfonamide as a white crystal (1.48 g, 60%).
1
mp 171-172 °C; [α]23 = -13.0 (c 1.0, CHCl3); H NMR (400 MHz,
D
CDCl3): δ = 3.48 (brs, 3H), 4.39 (d, J = 3.1 Hz, 1H), 4.76 (d, J = 3.1
Hz, 1H), 7.32-7.38 (m, 10H); 13C NMR (100 MHz, CDCl3): δ = 60.3,
64.6, 110.0-118.5 (complex signals of –CF2- and –CF3), 126.0, 126.5,
128.1, 128.3, 128.8, 128.9, 139.3, 140.1; HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C18H16F9N2O2S 495.0783; Found 495.0790.
To a 35-mL round-bottomed flask was added N-((1R,2R)-2-
amino-1,2-diphenylethyl)-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-
sulfonamide (1.59 g, 3.22 mmol) and dry THF (10 mL). The solu-
tion was cooled to 0 °C and added CS2 (1.25 mL, 21.3 mmol) and
DCC (666 mg, 3.23 mmol). The reaction mixture was stirred at
room temperature for 20 h. After starting material was con-
sumed, the solution concentrated in vacuo to afford a crude
product. Purification by flash column chromatography on silica
gel (hexane:EtOAc = 20:1 to 5:1) afforded the mixture of isothio-
cyanate and 1,3-dicyclohexylthiourea. This mixture was used
without further purification in the next step. To a 100-mL round-
bottomed flask was added the mixture (1.93 g), (1R,2R)-(-)-
cyclohexanediamine (738 mg, 6.46 mmol) and THF (20 mL). The
solution was stirred at room temperature for 48 h. After starting
material was consumed, the solution concentrated in vacuo to
afford a crude product. Purification by flash column chromatog-
raphy on silica gel (CHCl3:MeOH = 1:0 to 20:1) afforded the pure
5 as a white powder (496 mg, 24%). mp 233-234 °C; [α]29D = +34.2
CF3), 182.8; HRMS (ESI-TOF) m/z: [M
+
H]+ Calcd for
C16H26F9N4O2S2 541.1348; Found 541.1346; Anal. Calcd for
C16H25F9N4O2S2: C, 35.55; H, 4.66; N, 10.37. Found: C, 35.31; H,
4.73; N, 10.22.
Preparation of organocatalyst 4
1
To a 35-mL round-bottomed flask was added sulfonamide 1 (476
mg, 1.10 mmol) and dry THF (3.5 mL). The solution was cooled to
0 °C and added CS2 (439 ꢀL, 7.26 mmol) and DCC (227 mg, 1.10
mmol). The reaction mixture was stirred at room temperature
for 22 h. After starting material was consumed, the solution con-
centrated in vacuo to afford a crude product. Purification by
flash column chromatography on silica gel (eluent was CHCl3)
(c 1.00, DMSO); H NMR (400 MHz, DMSO-d6): δ = 1.05-1.33 (m,
4H), 1.63 (m, 2H), 1.85-1.94 (m, 2H), 2.91-2.96 (m, 1H), 3.98 (m,
1H), 4.63 (brs, 1H), 5.34 (brs, 1H), 7.08-7.22 (m, 6H), 7.37-7.45 (m,
4H), 7.80 (brs, 1H), 7.88 (brs, 1H), 8.11 (brs, 1H); 13C NMR (100
MHz, DMSO-d6): δ = 23.2, 23.7, 29.4, 31.0, 52.7, 54.9, 64.9, 65.0,
107.0-118.4 (complex signals of –CF2- and –CF3), 125.5, 125.7, 127.0,
127.5, 142.9, 146.4, 182.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C25H28F9N4O2S2 651.1504; Found 651.1504; Anal. Calcd for
C25H27F9N4O2S2: C, 46.15; H, 4.18; N, 8.61. Found: C, 46.11; H, 4.19;
N, 8.58.
afforded
the
mixture
of
isothiocyanate
and
1,3-
dicyclohexylthiourea. This mixture was used without further
purification in the next step. To a 35-mL round-bottomed flask
was added the mixture of isothiocyanate (704 mg), (1R,2R)-(-)-
cyclohexanediamine (251 mg, 2.20 mmol) and THF (3.7 mL). The
solution was stirred for 2 h. After starting material was con-
sumed, the solution concentrated in vacuo to afford a crude
product. Purification by flash column chromatography on silica
gel (CHCl3:MeOH = 1:0 to 10:1) afforded the pure 4 as a white
Preparation of organocatalyst 6
To a 35-mL round-bottomed flask was added sulfonamide 2 (1.30
g, 3.38 mmol) and dry Et2O (11 mL). The solution was cooled to 0
°C and added CS2 (1.31 mL, 22.3 mmol) and DCC (702 mg, 3.38
mmol). The reaction mixture was stirred at room temperature
for 11 h. After starting material was consumed, the solution con-
centrated in vacuo to afford a crude product. Purification by
flash column chromatography on silica gel (hexane:EtOAc = 10:1)
afforded the mixture of isothiocyanate and 1,3-
powder (510 mg, 79% from 1). mp 120-121 °C; [α]29 = -3.8 (c 1.00,
D
MeOH); 1H NMR (400 MHz, CD3OD): δ = 1.26-1.52 (m, 4H), 1.77-
1.81 (m, 2H), 1.95-2.07 (m, 2H), 2.82-2.88 (m, 2H), 2.94 (dd, J =
7.1, 13.6 Hz, 1H), 3.08 (dd, J = 5.1, 12.8 Hz, 1H), 3.45-3.48 (m, 1H),
4.44 (m,1H), 4.58 (m, 1H), 7.15-7.19 (m, 1H), 7.24-7.30 (m, 4H); 13
C
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dicyclohexylthiourea. This mixture was used without further
the reaction mixture was added to water and extracted three
1
2
3
4
5
6
7
8
purification in the next step. To a 35-mL round-bottomed flask
was added mixture of isothiocyanate (1.38 g), (1S, 2S)-(-)-
cyclohexanediamine (776 mg, 6.80 mmol) and THF (14 mL). The
solution was stirred at room temperature for 72 h. After starting
material was consumed, the solution concentrated in vacuo to
afford a crude product. Purification by flash column chromatog-
raphy on silica gel (CHCl3:MeOH = 1:0 to 30:1) afforded the pure
6 as a white powder (1.03 g, 56%). mp 168-170 °C; [α]29D = -25.7 (c
1.00, MeOH); 1H NMR (400 MHz, CD3OD): δ = 0.96 (d, J = 6.5
Hz, 3H), 0.98 (d, J = 6.5 Hz, 3H), 1.29-1.47 (m, 4H), 1.80 (m, 3H),
2.00-2.07 (m, 2H), 2.98-3.03 (m, 1H), 3.12-3.18 (m, 1H), 3.41 (d, J =
11.1 Hz, 2H), 4.54 (m, 1H); 13C NMR (100 MHz, CD3OD): δ = 19.1,
20.0, 25.2, 25.7, 31.3, 32.2, 32.8, 51.2, 56.3, 58.4, 64.2, 109.8-123.2
(complex signals of –CF2- and –CF3), 183.0; HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C16H26F9N4O2S2 541.1348; Found 541.1352;
Anal. Calcd for C16H25F9N4O2S2: C, 35.55; H, 4.66; N, 10.37. Found:
C, 35.37; H, 4.76; N, 10.15.
times with EtOAc. The EtOAc layers were combined, washed
with brine, dried over anhydrous Na2SO4, and evaporated. The
residue was purified by flash column chromatography on silica
gel (CHCl3:MeOH = 1:0 to 30:1) to afford the pure 8 as a white
powder (187 mg, 22%). mp 151-152 °C; [α]28D = +4.4 (c 0.50,
MeOH); 1H NMR (400 MHz, CD3OD): δ = 1.32-1.48 (m, 4H), 1.79-
1.80 (m, 2H), 2.05-2.09 (m, 2H), 2.92 (m, 1H), 3.28 (m, 2H), 3.40-
3.41 (m, 2H), 4.39 (m, 1H); 13C NMR (100 MHz, CD3OD): δ = 25.3,
25.7, 32.0, 32.8, 46.0, 47.6, 56.5, 57.9, 110.2-120.7 (complex signals
of –CF2- and –CF3), 184.4; HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C13H20F9N4O2S2 499.0878; Found 499.0889; Anal. Calcd for
C13H19F9N4O2S2: C, 31.33; H, 3.84; N, 11.24. Found: C, 31.19; H, 3.87;
N, 11.16.
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Typical procedure for asymmetric conjugate addition and char-
acterization date of the products (10a-m).
To a solution of (E)-4-phenylbut-3-en-2-one (9a, 29.2 mg, 0.200
mmol) in ethyl acetate (0.1 mL) was added to organocatalyst 3
(10.8 mg, 0.020 mmol) and nitromethane (108 ꢀL, 2.00 mmol) at
room temperature. After stirring in closed tube at 40 oC for 24 h,
the reaction mixture was directly purified by flash column
chromatography on silica gel with a 3:1 mixture of hexane and
ethyl acetate to afford the pure 10a (36.6 mg, 88%) as a white
powder.
Preparation of organocatalyst 7
To a 35-mL round-bottomed flask was added N-((1R,2R)-2-
amino-1,2-diphenylethyl)-1,1,2,2,3,3,4,4,4-nonafluorobutane-1-
sulfonamide (1.04 g, 2.10 mmol) and dry THF (7 mL). The solu-
tion was cooled to 0 °C and added CS2 (812 ꢀL, 13.9 mmol) and
DCC (434 mg, 2.10 mmol). The reaction mixture was stirred at
room temperature for 18 h. After starting material was con-
sumed, the solution concentrated in vacuo to afford a crude
product. Purification by flash column chromatography on silica
gel (hexane:EtOAc = 10:1) afforded the mixture of isothiocyanate
and 1,3-dicyclohexylthiourea. This mixture was used without
further purification in the next step. To a 35-mL round-
bottomed flask was added mixture of isothiocyanate (1.20 g), (1S,
2S)-(-)-cyclohexanediamine (480 mg, 4.20 mmol) and THF (14
mL). The solution was stirred at room temperature for 60 h.
After starting material was consumed, the solution concentrated
in vacuo to afford a crude product. Purification by flash column
chromatography on silica gel (CHCl3:MeOH = 1:0 to 30:1) afford-
ed the pure 7 as a white powder (833 mg, 61%). mp 147-148 °C;
[α]29D = +1.5 (c 1.00, MeOH); 1H NMR (400 MHz, CD3OD): δ =
1.35-1.36 (m, 3H), 1.4-1.55 (m, 1H), 1.78-1.80 (m, 2H), 1.96-1.98 (m,
1H), 2.06-2.09 (m, 1H), 2.98 (dt, J = 4.0, 11.1 Hz, 1H), 4.47 (brs,
1H), 4.56 (d, J = 9.2 Hz, 1H), 5.55 (d, J = 9.2 Hz, 1H), 7.03-7.14 (m,
10H); 13C NMR (100 MHz, CD3OD): δ = 25.1, 25.7, 31.3, 32.5, 56.8,
57.4, 66.9, 68.0, 109.4-123.1 (complex signals of –CF2- and –CF3),
127.6, 127.8, 128.6, 128.9, 129.0, 129.2, 141.8, 143.6, 184.8; HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C25H28F9N4O2S2 651.1504;
Found 651.1502; Anal. Calcd for C25H27F9N4O2S2: C, 46.15; H, 4.18;
N, 8.61. Found: C, 45.95; H, 4.20; N, 8.38.
(R)-5-nitro-4-phenylpentan-2-one (10a)3a. White solid, 36.6 mg,
88% yield (97% ee). [α]23D = -5.0 (c 0.50, CHCl3); 1H NMR (400
MHz, CDCl3): δ = 2.12 (s, 3H), 2.92 (d, J = 7.0 Hz, 2H), 3.97-4.05
(m, 1H), 4.60 (dd, J = 7.6, 12.3 Hz, 1H), 4.70 (dd, J = 6.9, 12.3 Hz,
1H), 7.21-7.35 (m, 5H); 13C NMR (100 MHz, CDCl3): δ = 30.4, 39.0,
46.1, 79.5, 127.4, 127.9, 129.1, 138.8, 205.4; Enantiomeric excess of
the product was determined by chiral stationary phase HPLC
analysis using a ChiralPak AS-H column (hexane/i-PrOH =
60:40), Flow rate = 1.0 mL/min, λ = 220 nm, t minor = 8.2 min, t
major = 10.6 min.
(R)-4-(4-bromophenyl)-5-nitropentan-2-one (10b) 3a. White sol-
id, 49.4 mg, 86% yield (96% ee). [α]25D = -2.7 (c 1.13, CHCl3); 1H
NMR (400 MHz, CDCl3): δ = 2.13 (s, 3H), 2.87 (dd, J = 7.0, 18.1 Hz,
1H), 2.92 (dd J = 7.0, 18.1 Hz, 1H), 3.95-4.02 (m, 1H), 4.57 (dd, J =
7.9, 12.5 Hz, 1H), 4.68 (dd, J = 6.6, 12.5 Hz, 1H), 7.11 (d, J = 8.4 Hz,
2H), 7.46 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ =
30.4, 38.4, 45.9, 79.0, 121.9, 129.1, 132.2, 137.8, 205.0; Enantiomeric
excess of the product was determined by chiral stationary phase
HPLC analysis using a ChiralPak AD-H column (hexane/i-PrOH
= 90:10), Flow rate = 0.9 mL/min, λ = 220 nm, t minor = 15.1 min, t
major = 17.5 min.
(R)-4-(4-chlorophenyl)-5-nitropentan-2-one (10c)3d. White sol-
id, 40.5 mg, 84% yield, 96% ee. [α]24D = -3.3 (c 1.06, CHCl3); 1H
NMR (400 MHz, CDCl3): δ = 2.13 (s, 3H), 2.87 (dd, J = 7.0, 18.0,
1H), 2.92 (dd, J = 7.0, 18.0 Hz, 1H), 3.96-4.03 (m, 1H), 4.57 (dd, J =
7.9, 12.4 Hz, 1H), 4.68 (dd, J = 6.6, 12.4 Hz, 1H), 7.16 (d, J = 8.5 Hz,
2H), 7.31 (d, J = 8.5 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ = 30.4,
38.4, 46.0, 79.2, 128.8, 129.3, 133.8, 137.3, 205.0; Enantiomeric ex-
cess of the product was determined by chiral stationary phase
HPLC analysis using a ChiralPak AD-H column (hexane/i-PrOH
= 85:15), Flow rate = 0.9 mL/min, λ = 220 nm, t minor = 10.6 min, t
major = 11.9 min.
Preparation of organocatalyst 8
To a 200-mL round-bottomed flask was added ethylenediamine
(24 mL, 0.36 mol), and CH2Cl2 (80 mL). Perfluoro-1-
butanesulfonyl fluoride (1.08 mL, 6.0 mmol) was added dropwise
at room temperature. After 96 h stirring, the reaction mixture
was filtered and wash with CH2Cl2 to afford the white crystalline
residue (1.11 g, 3.24 mmol, 54%). The mono-sulfonamide residue
was used without further purification in the next step.
To a 35-mL round-bottomed flask was added sulfonamide (582.1
mg, 1.70 mmol) and dry DMF (6 mL). The solution was cooled to
0 °C and added CS2 (675 ꢀL, 11.2 mmol) and DCC (351 mg, 1.70
mmol). The reaction mixture was stirred at room temperature
for 20 h. After starting material was consumed, the solution re-
duced pressure to remove the CS2, then (1R, 2R)-(-)-
(R)-4-(3-chlorophenyl)-5-nitropentan-2-one (10d)3d. Colorless
oil, 40.6 mg, 84% yield, 96% ee. [α]26D = -4.9 (c 0.53, CHCl3); 1H
NMR (400 MHz, CDCl3): δ = 2.14 (s, 3H), 2.91 (d, J = 7.0 Hz, 2H),
3.96-4.03 (m, 1H), 4.58 (dd, J = 7.8, 12.5 Hz, 1H), 4.69 (dd, J = 6.7,
12.5 Hz, 1H), 7.10-7.14 (m, 1H), 7.21-7.29 (m, 3H); 13C NMR (100
cyclohexanediamine (388 mg, 3.4 mmol) was added. After 24 h,
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(R)-5-methyl-5-nitro-4-phenylhexan-2-one (10j)3d. Pale-yellow
MHz, CDCl3): δ = 30.4, 38.6, 45.9, 79.0, 125.8, 127.6, 128.2, 130.4,
134.9, 140.9, 204.9; Enantiomeric excess of the product was de-
termined by chiral stationary phase HPLC analysis using a Chi-
ralPak AS-H column (hexane/i-PrOH = 90:10), Flow rate = 0.9
mL/min, λ = 210 nm, t minor = 32.8 min, t major = 52.7 min.
solid, 43.3 mg, 92% yield, 96% ee. [α]25D = +40.7 (c 0.62, CHCl3);
1H NMR (400 MHz, CDCl3): δ = 1.48 (s, 3H), 1.55 (s, 3H), 2.03 (s,
3H), 2.72 (dd, J = 3.5, 17.0 Hz, 1H), 3.09 (dd, J = 10.6, 17.0 Hz, 1H),
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3.93 (dd, J = 3.5, 10.6 Hz, 1H), 7.18-7.20 (m, 2H), 7.26-7.33 (m, 3H);
13C NMR (100 MHz, CDCl3): δ = 22.4, 25.8, 30.4, 44.0, 48.8, 91.1,
127.9, 128.6, 129.2, 137.6, 205.2; Enantiomeric excess of the prod-
uct was determined by chiral stationary phase HPLC analysis
using a ChiralPak AS-H column (hexane/i-PrOH = 90:10), Flow
rate = 0.9 mL/min, λ = 210 nm, t major = 12.3 min, tminor = 19.0 min.
(R)-4-(2-chlorophenyl)-5-nitropentan-2-one (10e)3d. Colorless
oil, 43.4 mg, 90% yield, 95% ee. [α]25D = -24.8 (c 0.53, CHCl3); 1H
NMR (400 MHz, CDCl3): δ = 2.17 (s, 3H), 2.97 (dd, J = 6.0, 18.0
Hz, 1H), 3.06 (dd, J = 7.8, 18.0 Hz, 1H), 4.43-4.50 (m, 1H), 4.74
(dd, J = 6.4, 12.6 Hz, 1H), 4.78 (dd, J = 6.9, 12.6 Hz, 1H), 7.19-7.25
(m, 3H), 7.39-7.42 (m, 1H); 13C NMR (100 MHz, CDCl3): δ = 30.2,
35.8, 44.5, 77.4, 127.4, 128.4, 129.0, 130.4, 133.7, 136.0, 205.3; Enan-
tiomeric excess of the product was determined by chiral station-
ary phase HPLC analysis using a ChiralPak AS-H column (hex-
9
(4R,5R)-5-nitro-4-phenylhexan-2-one (10k major)3d, 9. Colorless
oil, 19.2 mg, 43% yield, 95% ee. [α]26D = -13.1 (c 0.52, CHCl3); 1H
NMR (400 MHz, CDCl3): δ =1.32 (d, J = 6.6 Hz, 3H), 2.01 (s, 3H),
2.74 (dd, J =4.2, 17.1 Hz, 1H), 2.97, (dd, J = 9.5, 17.1 Hz, 1H), 3.71
(ddd, J = 4.2, 9.5, 9.9 Hz, 1H), 4.77 (dq, J = 6.6, 9.9 Hz, 1H), 7.19-
7.21 (m, 2H), 7.25-7.29 (m, 1H), 7.31-7.35 (m, 2H); 13C NMR (100
MHz, CDCl3): δ = 17.8, 30.4, 45.3, 46.3, 87.1, 127.9, 128.2, 129.1,
138.2, 205.0; Enantiomeric excess of the product was determined
by chiral stationary phase HPLC analysis using a ChiralPak AS-H
column (hexane/i-PrOH = 99:1), Flow rate = 0.9 mL/min, λ = 220
nm, t major = 41.2 min, t minor = 47.0 min.
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ane/i-PrOH = 90:10), Flow rate = 0.9 mL/min, λ = 210 nm, t minor
22.7 min, t major = 26.8 min.
=
(R)-5-nitro-4-(4-nitrophenyl)pentan-2-one (10f)3a. Brown solid,
43.3 mg, 86% yield, 95% ee. [α]26D = -4.6 (c 0.53, CHCl3); 1H NMR
(400 MHz, CDCl3): δ = 2.16 (s, 3H), 2.93 (dd, J = 6.9, 18.2 Hz, 1H),
2.99 (dd, J = 6.9, 18.2 Hz, 1H), 4.11-4.18 (m, 1H), 4.65 (dd, J = 8.2,
12.8 Hz, 1H), 4.75 (dd, J = 6.3, 12.8 Hz, 1H), 7.43 (d, J = 8.7 Hz,
2H), 8.20 (d, J = 8.7 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ =
30.3, 38.6, 45.6, 78.6, 124.2, 128.6, 146.4, 147.5, 204.4; Enantio-
meric excess of the product was determined by chiral stationary
phase HPLC analysis using a ChiralPak AD-H column (hexane/i-
PrOH = 90:10), Flow rate = 0.9 mL/min, λ = 254 nm, t minor = 41.9
min, t major = 57.7 min.
(4R,5S)-5-nitro-4-phenylhexan-2-one (10k minor) 3d, 9. Colorless
oil, 16.8 mg, 38% yield, 95% ee. [α]26D = -1.1 (c 0.50, CHCl3); 1H
NMR (400 MHz, CDCl3): δ = 1.48 (d, J = 6.7 Hz, 3H), 2.11 (s, 3H),
2.90 (dd, J = 7.6, 17.6 Hz, 1H), 3.05 (dd, J = 6.7, 17.6 Hz, 1H), 3.70-
3.76 (m, 1H), 4.84-4.91 (m, 1H), 7.13-7.15 (m, 2H), 7.24-7.33 (m,
3H); 13C NMR (100 MHz, CDCl3): δ = 16.7, 30.6, 44.5, 44.7, 85.8,
127.9, 128.1, 128.8, 137.8, 205.8; Enantiomeric excess of the prod-
uct was determined by chiral stationary phase HPLC analysis
using a ChiralPak AS-H column (hexane/i-PrOH = 99:1), Flow
rate = 0.9 mL/min, λ = 220 nm, tminor = 45.6 min, t major = 51.2
min.
(R)-5-nitro-4-(p-tolyl)pentan-2-one (10g)3d: White solid, 37.0
mg, 84% yield, 96% ee. [α]25D = -2.2 (c 1.27, CHCl3); 1H NMR (400
MHz, CDCl3): δ = 2.11 (s, 3H), 2.31 (s, 3H), 2.90 (d, J = 7.0 Hz, 2H),
3.93-4.00 (m, 1H), 4.57 (dd, J = 7.7, 12.2 Hz, 1H), 4.67 (dd, J = 6.9,
12.2 Hz, 1H), 7.10 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 8.2 Hz, 2H); 13C
NMR (100 MHz, CDCl3): δ = 21.1, 30.4, 38.7, 46.2, 79.6, 127.2,
129.7, 135.7, 137.6, 205.6; Enantiomeric excess of the product was
determined by chiral stationary phase HPLC analysis using a
ChiralPak AD-H column (hexane/i-PrOH = 90:10), Flow rate =
0.9 mL/min, λ = 220 nm, t minor = 10.3 min, t major = 11.5 min.
(S)-4-nitro-1,3-diphenylbutan-1-one (10l) 3d, 8. White Solid, 4.1 mg,
8% yield, 52% ee. [α]28D = -9.3 (c 0.20, CHCl3); 1H NMR (400
MHz, CDCl3): δ = 3.43 (dd, J = 7.5, 17.7 Hz, 1H), 3.49 (dd, J = 6.5,
17.7 Hz, 1H), 4.23 (dddd, J = 6.5, 6.6, 7.5, 7.9 Hz, 1H), 4.69 (dd, J =
7.9, 12.5 Hz, 1H), 4.84 (dd, J = 6.6, 12.5 Hz, 1H), 7.25-7.29 (m, 3H),
7.32-7.36 (m, 2H), 7.44-7.48 (m, 2H), 7.55-7.60 (m, 1H), 7.91-7.93
(m, 2H); 13C NMR (100 MHz, CDCl3): δ = 39.4, 41.7, 79.7, 127.6,
128.0, 128.2, 128.9, 129.2, 133.7, 136.5, 139.3, 197.0; Enantiomeric
excess of the product was determined by chiral stationary phase
HPLC analysis using a ChiralPak AS-H column (hexane/i-PrOH
= 90:10), Flow rate = 0.9 mL/min, λ = 254 nm, t major = 25.9 min, t
minor = 35.9 min.
(S)-4-(furan-2-yl)-5-nitropentan-2-one (10h)3a. Brown oil, 19.5
mg, 49% yield, 97% ee. [α]24D = -7.5 (c 0.74, CHCl3); 1H NMR
(400 MHz, CDCl3): δ = 2.18 (s, 3H), 2.90 (dd, J = 7.4, 18.0 Hz, 1H),
2.98 (dd, J = 6.4, 18.0 Hz, 1H), 4.07-4.14 (m, 1H), 4.66 (dd, J = 6.9,
12.5 Hz, 1H), 4.70 (dd, J = 6.3, 12.5 Hz, 1H), 6.14 (d, J = 3.2, 1H),
6.30 (dd, J = 2.0, 3.2 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H); 13C NMR (100
MHz, CDCl3): δ = 30.2, 32.9, 43.5, 77.1, 107.1, 110.5, 142.3, 151.7,
205.1; Enantiomeric excess of the product was determined by
chiral stationary phase HPLC analysis using a ChiralPak AD-H
column (hexane/i-PrOH = 90:10), Flow rate = 0.9 mL/min, λ =
220 nm, t minor = 11.2 min, t major = 12.8 min.
(S)-4-(nitromethyl)-6-phenylhexan-2-one (10ｍ) 3d. Colorless
oil, 12.6 mg, 27% yield, 95% ee. [α]27 = -4.7 (c 0.57, CHCl3); H
1
D
NMR (400 MHz, CDCl3): δ = 1.70-1.76 (m, 2H), 2.16 (s, 3H), 2.53-
2.74 (m, 5H), 4.48 (dd, J = 5.1, 11.9 Hz, 1H), 4.51 (dd, J = 5.4, 11.9
Hz, 1H), 7.15-7.22 (m, 3H), 7.27-7.31 (m, 2H); 13C NMR (100 MHz,
CDCl3): δ = 30.6, 32.8, 33.1, 33.2, 44.7, 78.2, 126.4, 128.4, 128.7,
140.7, 206.6; Enantiomeric excess of the product was determined
by chiral stationary phase HPLC analysis using a ChiralPak AS-H
column (hexane/i-PrOH = 90:10), Flow rate = 0.9 mL/min, λ =
210 nm, t minor = 20.3 min, t major = 25.5 min.
(R)-3-(nitromethyl)cyclohexan-1-one (10i)8. Colorless oil, 13.0
mg, 40% yield, 96% ee. [α]25D = +10.6 (c 0.50, CHCl3); 1H NMR
(400 MHz, CDCl3): δ = 1.47-1.57 (m, 1H), 1.69-1.80 (m, 1H), 1.97-
2.02 (m, 1H), 2.09-2.16 (m, 1H), 2.14-2.21 (m, 1H), 2.26-2.34 (m,
1H), 2.42-2.53 (m, 2H), 2.60-2.71 (m, 1H), 4.34 (dd, J = 6.6, 11.9 Hz,
1H), 4.39 (dd, J = 7.2, 11.9 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ =
24.2, 28.2, 37.2, 40.9, 44.5, 80.1, 208.2; Enantiomeric excess of the
product was determined by chiral stationary phase HPLC analy-
sis using a ChiralPak IC column (hexane/i-PrOH = 60:40), Flow
rate = 0.8 mL/min, λ = 220 nm, tminor = 16.4 min, t major = 20.4
min.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website.
Spectra data, and copies of all new compounds (PDF)
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The Journal of Organic Chemistry
rera, R. P.; Tejero, T.; Merino, P. Tetrahedron: Asymmetry 2010,
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21, 2561. (f) Zhang, Y.; Wang, W. Catal. Sci. Technol. 2012, 2, 42.
(g) Serdyuk, O. V.; Heckel, C. M.; Tsogoeva, S. B. Org. Biomol.
Chem. 2013, 11, 7051. (h) Tsakos, M.; Kokotos, C. G. Tetrahedron
2013, 69, 10199.
AUTHOR INFORMATION
Corresponding Author
(3) For examples of the organocatalytic asymmetric conjugate
additions of nitroalkanes to benzylideneacetones, see: (a) Mei,
K.; Jin, M.; Zhang, S. L.; Li, P.; Liu, W.; Chen, X.; Xue, F.; Duan,
W.; Wang, W. Org. Lett. 2009, 11, 2864. (b) Porta, R.; Benaglia,
M.; Coccia, F.; Cozzi, F.; Puglisi, A. Adv. Synth. Catal. 2015, 357,
377. (c) Porta, R.; Coccia, F.; Annunziata, R.; Puglisi, A. Chem-
CatChem 2015, 7, 1490. (d) Guo, X.-T.; Shen, J.; Sha, F.; Wu, X.-Y.
Synthesis 2015, 47, 2063 and reference cited therein.
(4) Wang, C.-J.; Zhang, Z.-H.; Dong, X-Q.; Wu, X.-J. Chem.
Commun. 2008, 1431.
(5) For review, see: (a) Fang, X.; Wang, C.-J. Chem. Commun.
2015, 51, 1185 and reference cited therein. For selected recent
examples, see: (b) Ogura, Y.; Akakura, M.; Sakakura, A.; Ishihara,
K. Angew. Chem. Int. Ed. 2013, 52, 8299. (c) Li, T.-Z.; Wang, X.-B.;
Shao, F.; Wu, X.-Y. J. Org. Chem. 2014, 79, 4332.
(6) (a) Miura, T.; Imai, K.; Kasuga, H.; Ina, M.; Tada, N.; Imai,
N.; Itoh, A. Tetrahedron 2011, 67, 6340. (b) Nakashima, K.; Mu-
rahashi, M.; Yuasa, H.; Ina, M.; Tada, N.; Itoh, A.; Hirashima, S.;
Koseki, Y.; Miura, T. Molecules 2013, 18, 14529. (c) Kamito, Y.;
Masuda, A.; Yuasa, H.; Tada, N.; Itoh, A.; Nakashima, K.;
Hirashima, S.; Koseki, Y.; Miura, T. Tetrahedron: Asymmetry
2014, 25, 974 and reference cited therein.
(7) Sakai, T.; Hirashima, S.; Yamashita, Y.; Arai, R.;
Nakashima, K.; Yoshida, A.; Koseki, Y.; Miura, T. J. Org. Chem.
2017, 82, 4661.
* E-mail: tmiura@toyaku.ac.jp
ACKNOWLEDGMENT
9
The authors would like to thank Enago (www.enago.jp) for
the English language review.
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REFERENCES
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Tetrahedron Lett. 1991, 32, 5543. (c) Node, M.; Hao, X.-J.; Fuji, K.
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