Prolinethiol ether catalysis in an asymmetric michael reaction: Solvent-free synthesis of functionalized monohaloalkenes

Article abstract of DOI:10.1021/jo302288z

The organocatalytic Michael reaction of ketones with γ- monohalonitrodienes catalyzed by chiral prolinethiol ether under solvent-free conditions was developed. The described method represents a novel approach for accessing highly functionalized monohaloalkenes with α, β-stereocenters of up to >99% ee.

Full text of DOI:10.1021/jo302288z

Note
pubs.acs.org/joc
Prolinethiol Ether Catalysis in an Asymmetric Michael Reaction:
Solvent-Free Synthesis of Functionalized Monohaloalkenes
Ai-Bao Xia,† Chao Wu,† Dan-Qian Xu,*,† Yi-Feng Wang,† Xiao-Hua Du,† Zhao-Bo Li,‡
and Zhen-Yuan Xu*,†
†State Key Laboratory Breeding Base of Green Chemistry−Synthesis Technology, Zhejiang University of Technology, Hangzhou
310014, People’s Republic of China
‡Hangzhou Minsheng Pharmaceutical Group Co., Ltd., Hangzhou 310014, People’s Republic of China
S
* Supporting Information
ABSTRACT: The organocatalytic Michael reaction of ketones with γ-monohalonitrodienes catalyzed by chiral prolinethiol ether
under solvent-free conditions was developed. The described method represents a novel approach for accessing highly
functionalized monohaloalkenes with α, β-stereocenters of up to >99% ee.
lkenyl halides are present in a variety of natural products
On the basis of these considerations and previous results,6
the organocatalyzed solvent-free Michael reaction was
performed with the addition reaction of cyclohexanone (1a)
to γ-monobromonitrodiene (2a) as a model. Different
parameters (Table 1), such as the catalyst and acid additive,
were studied. The catalysts L-proline 3a and L-prolinol 3b could
promote the efficient formation of 5a with high diastereose-
lectivities (10:1 dr to 23:1 dr) but modest to good
enantioselectivities (30% ee to 83% ee) (entries 1 to 3). The
Jørgensen−Hayashi and MacMillan catalysts 3c and 3d were
almost completely inactive (entries 4 to 5). We speculated that
using a multifunctional catalyst capable of simultaneously
activating both the substrates 1a and 2a might lead to higher
catalytic activity and better enantioselectivity. To our delight,
the promising chiral prolinethiol ether catalyst 3e showed
better catalytic performance (entry 6). Moreover, chiral
prolinethiol ether 3f was found to be the best catalyst for this
reaction, providing 5a in 98% conversion, 8:1 dr with
corresponding 93% and 96% ee after 1 h (entry 7). Next, a
series of different organic acid additives 4 was tested. Chiral
prolinethiol ether 3f can catalyze the Michael reaction with
different acid additives to obtain 5a with 88% ee to 94% ee and
8 to 14:1 dr (entries 7−19). 4-CF3C6H4CO2H (4i) proved to
be a suitable additive among the screened organic acids. The
reduced amounts of catalyst 3f and additive 4i to 10 mol %
(entry 20) or 5 mol % (entry 21) led to an increase in the
reaction time needed to achieve the similar conversions. In
1
Aand bioactive compounds. These frameworks are also
very important building blocks in the synthesis of many natural
products and useful intermediates in organic synthesis.2
Although several synthetic protocols in the achiral or chiral
alkenyl halide synthesis have been well established in recent
years,3 more practical, direct asymmetric reactions of carbonyl
compounds with electrophiles containing alkenyl halide for
generating highly functionalized monohaloalkenes with α, β-
stereocenters were less developed (Scheme 1).
Scheme 1
In the past decades, organocatalysis has gained considerable
attention in chemistry as an efficient approach for synthesizing
enantiopure molecules under mild, environmentally benign
conditions.4 Furthermore, the absence of any organic solvent in
organocatalysis is an ideal synthetic condition for achieving a
more efficient and greener process.5 Present reports mainly
focus on the development of the first highly enantioselective,
organocatalytic, direct Michael addition of ketones to γ-
monohalonitrodienes without solvents to obtain enantioselec-
tive monohaloalkenes.
Received: November 15, 2012
Published: January 3, 2013
© 2013 American Chemical Society
1254
dx.doi.org/10.1021/jo302288z | J. Org. Chem. 2013, 78, 1254−1259

The Journal of Organic Chemistry
Note
a
Table 1. Evaluation of Reaction Parameters
b
c
d
entry
cat.
additive
none
time (h)
conv (%)
dr (anti/syn)
ee (%) (anti/syn)
1
3a
3a
3b
3c
3d
3e
3f
3f
3f
3f
3f
3f
3f
3f
3f
3f
3f
3f
3f
3f
3f
48
48
48
48
48
1
78
81
64
<1
1
10:1
23:1
17:1
34/39
83/50
30/33
2
C6H5CO2H (4a)
C6H5CO2H (4a)
3
4
C6H5CO2H (4a)
5
C6H5CO2H (4a)
6
C6H5CO2H (4a)
84
98
98
53
96
87
98
97
97
96
98
98
84
98
98
92
6:1
8:1
88/82
91/94
93/93
94/93
92/94
91/94
91/94
91/93
94/93
92/94
91/88
93/93
93/92
91/87
95/95
95/94
7
C6H5CO2H (4a)
1
8
4-CH3C6H4CO2H (4b)
2-FC6H4CO2H (4c)
4-FC6H4CO2H (4d)
2-NO2C6H4CO2H (4e)
3-NO2C6H4CO2H (4f)
4-NO2C6H4CO2H (4g)
2-CF3C6H4CO2H (4h)
4-CF3C6H4CO2H (4i)
CH3CO2H (4j)
1
8:1
9
1
9:1
10
11
12
13
14
15
16
17
18
19
1
9:1
1
10:1
8:1
1
1
8:1
1
8:1
1
10:1
11:1
8:1
1
C6H5CH2CO2H (4k)
2-C10H7CH2CO2H (4l)
C6H5CHCHCO2H (4m)
4-CF3C6H4CO2H (4i)
4-CF3C6H4CO2H (4i)
1
1
12:1
14:1
17:1
16:1
1
e
20
3
f
21
4
a
Unless otherwise stated, the reaction was conducted by stirring without a solvent using 1a (0.65 mmol) and 2a (0.13 mmol) with 20 mol % of
b
c
catalyst and 20 mol % of additive at room temperature. Conversion into the product was determined using GC. Determined by chiral phase
HPLC. Determined through HPLC analysis on a Chiralcel AS-H. Using 10 mol % of catalyst and 10 mol % of additive. Using 5 mol % of catalyst
d
e
f
and 5 mol % of additive.
addition, a slight increase in diastereoselectivities and
enantioselectivities was observed.
in Table 2. The balance between steric effects and stability of
the enamines derived from catalyst 3f and ketones presumably
favors the terminal Michael product formation.7
The reaction scope was determined after the optimal catalytic
conditions were obtained. As shown in Table 2, the
enantioselectivity of the reaction was minimally affected by
the substituents on the cyclic ketone (entries 1−5). Moreover,
the substitutions on the aryl of 2 were well tolerated (entries 6
and 7). Cyclopentanone (entry 8) was also well activated as a
cyclic substrate. It provided a 57% yield, >99:1 dr, and 95% ee
after 168 h. Moderate to high yields (47% to 85%) and high to
excellent enantioselectivities (83−92%) of the Michael
products were achieved when the acyclic ketones were
subjected to this reaction (entries 9−12). Moreover, the
asymmetric additions of aliphatic aldehyde to γ-monobromoni-
trodiene 2a were also examined (entry 13). The reaction was
performed at −10 °C to obtain the desired product 5m with
93% yield, with 2:1 dr and corresponding >99% and 92% ee.
Of particular note is the addition of 4-methylpentan-2-one or
4-methoxy-4-methylpentan-2-one to γ-monobromonitrodiene
2a to obtain the Michael products at 38% yield with 87% ee and
43% yield with 93% ee (Scheme 2). The principal issue in these
reactions is that the reactions proceed on the sterically less
hindered carbon, which is opposite to the other acyclic ketones
The investigation on the scope of electrophiles 2 with
different substituents on the γ-position of the nitryl showed that
nucleophiles bearing substituents can be employed to form the
desired adducts in good to high diastereoselectivities and high
to excellent enantioselectivities (Table 3, entries 1−4). In
addition, the nonsubstituent electrophile 2e also performed
well and produced 5s at 95% yield with >99:1 dr and 79% ee
(Table3, entry 5).
A transition-state model was proposed on the basis of the X-
ray crystallographic analysis of the absolute configuration of
adduct 5a (Figure 1). γ-Monohalonitrodiene 2a was activated
well through the positive inducing effect and hydrogen-bonding
interaction between the protonated thiopyridine group of 3f
and nitro group of 2a. Therefore, the enamine formed from 3f
and 1a attacked the activated 2a from the Re face to afford the
major stereoisomer of Michael adduct 5a with the (S,S)
configuration (TS I). In the case of 4-substituent ketone 1b, the
steric interactions between the enamine activated ketone 1b
and the activated 2a will make the transition state TS II more
stable than TS II′.8 And the synergistic cooperative activation of
1255
dx.doi.org/10.1021/jo302288z | J. Org. Chem. 2013, 78, 1254−1259

The Journal of Organic Chemistry
Note
a
Table 2. Michael Reactions of 1 with 2 by Catalyst 3f under Solvent-Free Conditions
b
c
c
entry
R1, R2 (1)
−(CH2)4− (1a)
R3
5
time (h)
yield (%)
dr (anti/syn)
ee (%) (anti/syn)
1
2
3
4
5
6
7
H
5a
5b
5c
5d
5e
5f
2
2
92
92
92
90
91
95
95
57
85
54
47
60
93
17:1
3:1
95/95
94/94
97/90
96/−
97/83
>99/96
94/93
95/−
−CH2CH2CH(Me)CH2− (1b)
−CH2CH2CH(Et)CH2− (1c)
−CH2CH2OCH2− (1d)
−CH2CH2N(CO2Et)CH2− (1e)
−CH2CH2N(CO2Et)CH2− (1f)
−CH2CH2N(CO2Et)CH2− (1g)
−(CH2)3− (1h)
H
H
2
4:1
H
24
24
24
24
168
48
120
120
24
48
>99:1
2:1
H
4-Cl
4-CF3
H
7:1
5g
5h
5i
5:1
d
8
d
>99:1
8:1
9
Me, Me (1i)
H
92/80
d
10
Et, Me (1j)
H
5j
>99:1
2:1
98/−
d
11
Me, CH2CHCH2 (1k)
H
5k
5l
83/85
88/87
>99/92
d
12
Me, (CH2)3CH3 (1l)
H
2:1
d,e
13
H, i-Pr (1m)
H
5m
2:1
a
Unless otherwise stated, the reaction was conducted by stirring without a solvent using 1 (0.65 mmol) and 2 (0.13 mmol) in the presence of 3f (10
b
c
d
mol % catalyst) and 4i (10 mol % additive) at room temperature. Isolated yield. Determined by chiral-phase HPLC. Using 20 mol % of catalyst
and 20 mol % of additive. Reaction was conducted at −10 °C.
e
Scheme 2. Further Investigation of the Substrate Scope
EXPERIMENTAL SECTION
■
1
General Information. The H NMR and 13C NMR spectra were
recorded in CDCl3 at 500 and 125 MHz, respectively, with TMS as the
internal standard. GC−MS experiments were performed on a GC
system with a mass selective detector. HRMS data were measured on a
LC/TOF-MS with ESI source or GC/TOF-MS with EI source.
Column chromatography and flash chromatography experiments were
performed on silica gel (200−300 mesh) eluting with ethyl ether and
petroleum ether. TLC experiments were carried out on glass-backed
silica plates. In each case, enantiomeric ratio was determined on a
chiral column in comparison with authentic racemates by chiral HPLC.
Chemicals were used without purification as commercially available.
Typical Experimental Procedure for the Michael Reaction To
Achieve Functionalized Monohaloalkenes. Various cyclic ketones
1 (0.65 mmol) and γ-monohalonitrodienes 2 (0.13 mmol) were stirred
under solvent-free conditions in the presence of catalyst 3f (0.013
mmol) and acid 4i (0.013 mmol) at room temperature. In the case of
acyclic ketone or aldehyde substrates, catalyst 3f (0.026 mmol) and
acid 4i (0.026 mmol) were used at room temperature or −10 °C. The
reaction conversion was monitored by GC−MS. After completion, the
reaction mixture was washed with water, extracted with EtOAc (3 × 10
mL), dried, and concentrated. The residue was purified by flash
chromatography to give the functionalized monohaloalkenes. The
enantiomeric ratio was determined by HPLC analysis on a chiral
column.
Table 3. Michael Reactions of 1a with 2 by Catalyst 3f under
Solvent-Free Conditions for 2 h
a
b
c
c
entry
X (2/5)
yield (%) dr (anti/syn) ee (%) (anti/syn)
1
2
3
4
5
Cl (2b/5p)
Br (2a/5a)
I (2c/5q)
95
92
91
90
95
17:1
17:1
3:1
96/87
95/95
95/93
92/>99
79/−
Me (2d/5r)
H (2e/5s)
36:1
>99:1
(S)-2-((S,Z)-3-Bromo-1-nitro-4-phenylbut-3-en-2-yl)cyclo-
hexanone (5a). Yield: 42 mg, 92%; 95% ee (anti), 95% ee (syn).
White solid. Mp: 99−101 °C. The enantiomeric excess was
determined by HPLC on Daicel Chiralpak AS-H with hexane/i-
PrOH (85:15) as the eluent. Flow: 1.0 mL/min; UV = 254 nm;
a
Unless otherwise stated, the reaction was conducted by stirring
without a solvent using 1 (0.65 mmol) and 2 (0.13 mmol) in the
presence of 3f (10 mol % catalyst) and 4i (10 mol % additive) at room
b
c
temperature. Isolated yields. Determined by chiral-phase HPLC.
tantiminor =17.57 min, tantimajor = 25.28 min; tsynminor = 10.67 min, tsyn
major
= 13.91 min. 1H NMR (500 MHz, CDCl3): δ 7.52 (d, J = 7 Hz, 2H),
7.36−7.29 (m, 3H), 6.96 (s, 1H), 4.81−4.78 (m, 1H), 4.62−4.57 (m,
1H), 3.64−3.59 (m, 1H), 2.65−2.59 (m, 1H), 2.59−2.47 (m, 1H),
2.42−2.36 (m, 1H), 2.29−2.24 (m, 1H), 2.17−2.12 (m, 1H), 1.97−
1.90 (m, 1H), 1.76−1.66 (m, 2H), 1.44−1.36 (m, 1H) ppm. 13C NMR
(125 MHz, CDCl3): δ 211.0, 134.8, 133.7, 129.1 (×2), 128.4, 128.2
(×2), 123.5, 76.3, 50.0, 49.1, 43.0, 33.1, 28.6, 25.2 ppm. GC−MS: m/z
128, 211, 225, 272 (100), 304, 306.
both the substrates 1a and 2a may explain the excellent
performance of the present prolinethiol ether catalytic system.9
In conclusion, the first enantioselective, organocatalytic
Michael reaction of ketones with γ-monohalonitrodienes
under solvent-free conditions was successfully demonstrated.
The new reaction sequence provides an easy approach to highly
functionalized monohaloalkenes with α,β-stereocenters at 38−
95% yields with 2:1 to >99:1 regioselectivities and 79% to
>99% enantioselectivities. Further applications of this organo-
catalytic system are ongoing in our laboratory.
(2S,4S)-2-((S,Z)-3-Bromo-1-nitro-4-phenylbut-3-en-2-yl)-4-meth-
ylcyclohexanone (5b). Yield: 44 mg, 92%; 94% ee (anti), 94% ee
(syn). White solid. Mp: 108−110 °C. The enantiomeric excess was
1256
dx.doi.org/10.1021/jo302288z | J. Org. Chem. 2013, 78, 1254−1259

The Journal of Organic Chemistry
Note
Figure 1. Proposed transition state for the reaction.
determined by HPLC on Daicel Chiralpak AS-H with hexane/i-PrOH
eluent. Flow: 1.0 mL/min; UV = 256 nm; tantiminor =25.08 min, tanti
major
(90:10) as the eluent. Flow: 1.0 mL/min; UV = 260 nm; tanti
=
=12.68 min; tsynminor = 21.96 min, tsynmajor = 50.18 min. 1H NMR (500
MHz, CDCl3): δ 7.55 (d, J = 7.0 Hz, 2H), 7.38−7.33 (m, 3H), 7.00 (s,
1H), 4.81−4.78 (m, 1H), 4.69−4.64 (m, 1H), 4.46−4.29 (m, 2H),
4.25−4.15 (m, 2H), 3.69−3.64 (m, 1H), 3.37−3.21 (m, 1H), 3.03−
2.98 (m, 1H), 2.77 (s, 1H), 2.62−2.50 (m, 2H), 1.27−1.26 (m, 3H)
ppm. 13C NMR (125 MHz, CDCl3): δ 207.4, 155.2, 134.5, 134.5,
129.1 (×2), 128.7, 128.3 (×2), 121.7, 76.038, 62.2, 49.5, 47.6, 47.2,
44.4, 41.9, 14.9 ppm.
minor
16.49 min, tanti
= 21.98 min; tsyn
= 11.83 min, tsyn
= 18.92
major
minor
major
min. 1H NMR (500 MHz, CDCl3): δ 7.50 (d, J = 8.5 Hz, 2H), 7.35−
7.27 (m, 3H), 6.97 (s, 1H), 4.74−4.69 (m, 1H), 4.60−4.56 (m, 1H),
4.05−4.01 (m, 1H), 3.06−3.01 (m, 1H), 2.46−2.42 (m, 2H), 2.18−
2.14 (m, 1H), 2.11−1.99 (m, 2H),1.46−1.38 (m, 1H), 1.23−1.15 (m,
1H), 1.04 (d, J = 6.5 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ
209.4, 135.2, 132.2, 129.1 (×2), 128.2, 128.1 (×2), 124.1, 75.4, 50.5,
49.9, 41.6, 38.2, 35.8, 32.3, 21.3 ppm. GC−MS: m/z 128, 225, 239,
286 (100), 318, 320.
(R)-Ethyl 3-((S,Z)-3-Bromo-1-nitro-4-phenylbut-3-en-2-yl)-4-oxo-
piperidine-1-carboxylate (5f). Yield: 56 mg, 95%; 99.9% ee (anti),
96% ee (syn). White solid. The enantiomeric excess was determined by
HPLC on Daicel Chiralpak AS-H with hexane/i-PrOH (80:20) as the
(2S,4S)-2-((S,Z)-3-Bromo-1-nitro-4-phenylbut-3-en-2-yl)-4-ethyl-
cyclohexanone (5c). Yield: 45 mg, 92%; 97% ee (anti), 90% ee (syn).
White solid. The enantiomeric excess was determined by HPLC on
Daicel Chiralpak OD-H with hexane/i-PrOH (99:1) as the eluent.
eluent. Flow: 1.0 mL/min; UV = 254 nm; tantiminor = 30.46 min, tanti
major
= 54.83 min; tsynminor = 33.75 min, tsynmajor = 25.44 min. 1H NMR (500
MHz, CDCl3): δ 7.48 (d, J = 8.5 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H),
6.95 (s, 1H), 4.81−4.79 (m, 1H), 4.67−4.62 (m, 1H), 4.41−4.15 (m,
4H), 3.68−3.63 (m, 1H), 3.29 (s, 1H), 3.02−2.98 (m, 1H), 2.76 (s,
1H), 3.61−2.49 (m, 2H), 1.32−1.27 (m, 3H) ppm. 13C NMR (125
MHz, CDCl3): δ 207.2, 155.1, 134.5, 133.4, 132.9, 130.4 (×2), 128.5
(×2), 122.6, 76.0, 62.2, 49.4, 47.6, 47.2, 44.0, 41.9, 14.6 ppm.
Flow: 0.5 mL/min; UV = 256 nm; tanti
= 83.49 min, tanti
= 59.22 min. H NMR (500
=
minor
major
1
73.08 min; tsyn
= 68.57 min, tsyn
minor
major
MHz, CDCl3): δ 7.53 (d, J = 7.5 Hz, 2H), 7.38−7.31 (m, 3H), 6.99 (s,
1H), 4.65−4.4.63 (m, 2H), 3.65−3.57 (m, 1H), 2.73−2.68 (m, 1H),
2.53−2.48 (m, 1H), 2.44−2.39 (m, 1H), 2.00−1.91 (m, 2H), 1.86−
1.71 (m, 3H), 1.58−1.50 (m, 2H), 0.99−0.96 (m, 3H) ppm. 13C NMR
(125 MHz, CDCl3): δ 212.0, 134.7, 134.0, 129.1 (×2), 128.5, 128.2
(×2), 123.1, 76.4, 49.1, 46.5, 39.0, 35.5, 33.9, 32.0, 25.6, 12.2 ppm.
GC−MS: m/z 128, 239, 253, 300 (100), 332, 334.
(R)-3-((S,Z)-3-Bromo-1-nitro-4-phenylbut-3-en-2-yl)dihydro-2H-
pyran-4(3H)-one (5d). Yield: 41 mg, 90%; 96% ee (anti); White solid.
The enantiomeric excess was determined by HPLC on Daicel
Chiralpak AS-H with hexane/i-PrOH (85:15) as the eluent. Flow:
1.0 mL/min; UV = 254 nm; tantiminor = 62.78 min, tantimajor =32.72 min.
1H NMR (500 MHz, CDCl3): δ 7.52 (d, J = 7.0 Hz, 2H), 7.94−7.31
(m, 3H), 6.99 (s, 1H), 4.82−4.79 (m, 1H), 4.70−4.65 (m, 1H), 4.26−
4.23 (m, 2H), 3.82−3.77 (m, 1H), 3.72−3.67 (m, 1H), 3.54−3.49 (m,
1H), 2.90−2.84 (m, 1H), 2.73−2.67 (m, 1H), 2.56−2.52 (m, 1H)
ppm. 13C NMR (125 MHz, CDCl3): δ 206.6, 134.4, 134.3, 129.0 (×2),
128.7, 128.3 (×2), 121.5, 76.0, 71.3, 69.1, 50.4, 46.5, 43.2 ppm. GC−
MS: m/z 128, 183 (100), 213, 227, 274, 306, 308.
(R)-Ethyl 3-((S,Z)-3-Bromo-1-nitro-4-phenylbut-3-en-2-yl)-4-oxo-
piperidine-1-carboxylate (5e). Yield: 50 mg, 91%; 97% ee (anti), 83%
ee (syn). White solid. The enantiomeric excess was determined by
HPLC on Daicel Chiralpak AS-H with hexane/i-PrOH (80:20) as the
(R)-Ethyl 3-((S,Z)-3-Bromo-1-nitro-4-(4-(trifluoromethyl)phenyl)-
but-3-en-2-yl)-4-oxopiperidine-1-carboxylate (5g). Yield: 60 mg,
95%; 94% ee (anti), 93% ee (syn). White solid. The enantiomeric
excess was determined by HPLC on Daicel Chiralpak OD-H with
hexane/i-PrOH (80:20) as the eluent. Flow: 1.0 mL/min; UV = 256
nm; tanti
= 19.81 min, tanti
= 17.38 min; tsyn
= 32.42 min,
minor
major
minor
1
tsyn
= 26.38 min. H NMR (500 MHz, CDCl3): δ=7.62 (s, 4H),
major
7.04 (s, 1H), 4.85−4.80 (m, 1H), 4.68−4.64 (m, 1H), 4.45−4.42 (m,
1H), 4.26−4.10 (m, 3H), 3.71−3.66 (m, 1H), 3.44−3.20 (m, 1H),
3.10−2.99 (m, 1H), 2.77 (s, 1H), 2.63−2.51 (m, 2H), 1.33−1.25 (m,
3H) ppm. 13C NMR (125 MHz, CDCl3): δ 207.1, 155.1, 138.1, 133.4,
132.3, 129.4 (×4), 125.3 (×2), 75.9, 62.3, 49.4, 47.6, 47.2, 44.4, 41.9,
14.6 ppm.
(S)-2-((S,Z)-3-Bromo-1-nitro-4-phenylbut-3-en-2-yl)-
cyclopentanone (5h). Yield: 25 mg, 57%; 95% ee (anti). White solid.
The enantiomeric excess was determined by HPLC on Daicel
Chiralpak AS-H with hexane/i-PrOH (90:10) as the eluent. Flow:
1.0 mL/min; UV = 240 nm; tantiminor = 46.09 min, tantimajor = 40.58 min.
1H NMR (500 MHz, CDCl3): δ 7.53 (d, J = 7.0 Hz, 2H), 7.37−7.30
1257
dx.doi.org/10.1021/jo302288z | J. Org. Chem. 2013, 78, 1254−1259

The Journal of Organic Chemistry
Note
(m, 3H), 6.94 (s, 1H), 5.47−5.44 (m, 1H), 4.76−4.72 (m, 1H), 3.36−
3.31 (m, 1H), 2.46−2.40 (m, 1H), 2.36−2.22 (m, 3H), 2.09−2.04 (m,
1H), 1.88−1.77 (m, 1H), 1.73−1.65 (m, 1H) ppm. 13C NMR (125
MHz, CDCl3): δ 218.5, 134.6, 133.7, 129.1 (×2), 128.6, 128.2 (×2),
123.8, 75.5, 50.2, 47.8, 38.8, 28.9, 20.1 ppm. GC−MS: m/z 128, 169,
211, 258 (100), 290, 292.
hexane/i-PrOH (90:10) as the eluent. Flow: 1.0 mL/min; UV = 254
nm; tminor = 12.45 min, tmajor = 16.41 min. 1H NMR (500 MHz,
CDCl3): δ 7.51 (d, J = 7.0 Hz, 2H), 7.35−7.28 (m, 3H), 7.03 (s, 1H),
4.67−4.63 (m, 1H), 4.56−4.52 (m, 1H), 3.96−3.91 (m, 1H), 2.96−
2.91 (m, 1H), 2.62−2.58 (m, 1H), 2.37−2.29 (m, 2H), 2.19−2.12 (m,
1H), 0.92−0.91 (m, 6H) ppm. 13C NMR (125 MHz, CDCl3): δ 206.6,
134.8, 132.6, 129.0 (×2), 128.4, 128.2 (×2), 123.8, 77.2, 52.3, 44.4,
43.7, 24.6, 22.6, 22.5 ppm. GC−MS: m/z 128 (100), 227, 274.
(S,Z)-7-Bromo-2-methoxy-2-methyl-6-(nitromethyl)-8-phenyloct-
7-en-4-one (5o). Yield: 21 mg, 43%; 93% ee. Colorless oil. The
enantiomeric excess was determined by HPLC on Daicel Chiralpak
AS-H with hexane/i-PrOH (85:15) as the eluent. Flow: 1.0 mL/min;
(3S,4S,Z)-5-Bromo-3-methyl-4-(nitromethyl)-6-phenylhex-5-en-2-
one (5i). Yield: 36 mg, 85%; 92% ee (anti), 80% ee (syn). Colorless oil.
The enantiomeric excess was determined by HPLC on Daicel
Chiralpak AS-H with hexane/i-PrOH (90:10) as the eluent. Flow:
1.0 mL/min; UV = 272 nm; tantiminor = 40.81 min, tantimajor = 21.93 min;
tsyn
= 19.80 min, tsyn
= 25.09 min. 1H NMR (500 MHz,
minor
major
1
UV = 254 nm; tminor = 10.92 min, tmajor = 14.09 min. H NMR (500
CDCl3): δ 7.54 (d, J = 7.0 Hz, 2H), 7.37−7.30 (m, 3H), 7.00 (s, 1H),
4.66−4.61 (m, 1H), 4.43−4.40 (m, 1H), 3.60−3.56 (m, 1H), 2.91−
2.84 (m, 1H), 2.27 (s, 3H), 1.25−1.22 (m, 3H) ppm. 13C NMR (125
MHz, CDCl3): δ 209.5, 134.7, 133.9, 129.1 (×2), 128.5, 128.2 (×2),
123.2, 76.2, 50.7, 46.9, 29.3 15.8 ppm. GC−MS: m/z 97, 128, 185,
199, 246 (100), 278, 280.
(4S,5S,Z)-6-Bromo-4-methyl-5-(nitromethyl)-7-phenylhept-6-en-
3-one (5j). Yield: 24 mg, 54%; 98% ee (anti), >99% ee (syn). Colorless
oil. The enantiomeric excess was determined by HPLC on Daicel
Chiralpak AD-H with hexane/i-PrOH (95:5) as the eluent. Flow: 1.0
MHz, CDCl3): δ 7.51 (d, J = 7.0 Hz, 2H), 7.38−7.28 (m, 3H), 7.03 (s,
1H), 4.66−4.62 (m, 1H), 4.54−4.50 (m, 1H), 3.96−3.91 (m, 1H),
3.21 (s, 3H), 3.05−3.00 (m, 1H), 2.79−2.74 (m, 1H), 2.62−2.54 (m,
2H), 1.24 (s, 3H), 1.23 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ
206.1, 135.0, 132.4, 129.0 (×2), 128.3, 128.1 (×2), 124.2, 77.2, 74.7,
53.8, 49.4, 45.6, 44.3, 24.8, 24.6 ppm. GC−MS: m/z 128 (100), 211,
249, 272, 304.
(S)-2-((S,Z)-3-Chloro-1-nitro-4-phenylbut-3-en-2-yl)cyclo-
hexanone (5p). Yield: 38 mg, 95%; 96% ee(anti), 87% ee(syn). White
solid. The enantiomeric excess was determined by HPLC on Daicel
Chiralpak AD-H with hexane/i-PrOH (99:1) as the eluent. Flow: 1.0
mL/min; UV = 254 nm; tanti
= 10.85 min, tanti
= 12.08 min;
minor
major
tsynmajor = 10.16 min. H NMR (500 MHz, CDCl3): δ 7.54 (d, J = 7.0
Hz, 2H), 7.37−7.30 (m, 3H), 7.01 (s, 1H), 4.65−4.61 (m, 1H), 4.36−
4.33 (m, 1H), 3.63−3.38 (m, 1H), 2.92−2.85 (m, 1H), 2.74−2.66 (m,
1H), 2.47−2.39 (m, 1H), 1.19 (d, J = 7.0 Hz, 3H), 1.10 (t, J = 7.5 Hz,
3H) ppm. 13C NMR (125 MHz, CDCl3): δ 212.3, 134.8, 133.8, 129.1
(×2), 128.5, 128.2 (×2), 123.3, 76.2, 50.9, 46.0, 35.6, 16.2, 7.8 ppm.
GC−MS: m/z 128, 199, 213, 260 (100), 292, 294.
1
mL/min; UV = 268 nm; tanti
= 54.19 min, tanti
= 49.84 min;
minor
major
tsyn
= 73.45 min, tsyn
= 60.18 min. 1H NMR (500 MHz,
minor
major
CDCl3): δ 7.56 (d, J = 7.0 Hz, 2H), 7.36−7.28 (m, 3H), 6.66 (s, 1H),
4.81−4.78 (m, 1H), 4.61−4.57 (m, 1H), 3.71−3.66 (m, 1H), 2.66−
2.60 (m, 1H), 2.49−2.47 (m, 1H), 2.42−2.35 (m, 1H), 2.26−2.22 (m,
1H), 2.17−2.12 (m, 1H), 1.93−1.91 (m, 1H), 1.73−1.68 (m, 2H),
1.46−1.37 (m, 1H) ppm. 13C NMR (125 MHz, CDCl3): δ 211.1,
133.7, 130.5, 129.5(×2), 129.3, 128.4(×2), 128.3, 75.7, 49.4, 48.2,
42.9, 33.0, 28.6, 25.2 ppm. GC−MS: m/z 115, 129(100), 163, 225,
272, 307, 309. HRMS: (EI+) m/z calcd for [C16H18ClNO3]+
307.0987, found 307.0975.
(3S,4S,Z)-3-Allyl-5-bromo-4-(nitromethyl)-6-phenylhex-5-en-2-
one (5k). Yield: 21 mg, 47%; 83% ee (anti), 85% ee (syn). White solid.
The enantiomeric excess was determined by HPLC on Daicel
Chiralpak AS-H with hexane/i-PrOH (90:10) as the eluent. Flow:
1.0 mL/min; UV = 276 nm; tantiminor = 9.61 min, tantimajor = 13.33 min;
tsyn
= 16.05 min, tsyn
= 18.29 min. 1H NMR (500 MHz,
(S)-2-((S,Z)-3-Iodo-1-nitro-4-phenylbut-3-en-2-yl)cyclohexanone
(5q). Yield 47 mg, 91%; 95% ee (anti), 93% ee (syn). White solid. The
enantiomeric excess was determined by HPLC on Daicel Chiralpak
AS-H with hexane/i-PrOH (85:15) as the eluent. Flow: 1.0 mL/min;
minor
major
CDCl3): δ 7.52 (d, J = 7.0 Hz, 2H), 7.37−7.30 (m, 3H), 6.98 (s, 1H),
5.71−5.63 (m, 1H), 5.14−5.09 (m, 2H), 4.66−4.62 (m, 1H), 4.41−
4.39 (m, 1H), 3.66−3.61 (m, 1H), 3.02−2.97 (m, 1H), 2.55−2.50 (m,
1H), 2.41−2.35 (m, 1H), 2.24 (s, 3H) ppm. 13C NMR (125 MHz,
CDCl3): δ 208.8, 134.6, 134.3, 132.5, 129.1 (×2), 128.6, 128.2 (×2),
122.6, 119.1, 76.2, 51.5, 49.2, 34.1, 31.0 ppm. GC−MS: m/z 128, 211,
225, 272 (100), 304, 306.
(S)-3-((S,Z)-3-Bromo-1-nitro-4-phenylbut-3-en-2-yl)heptan-2-one
(5l). Yield: 29 mg, 60%; 88% ee (anti), 87% ee (syn). White solid. The
enantiomeric excess was determined by HPLC on Daicel Chiralpak
AS-H with hexane/i-PrOH (85:15) as the eluent. Flow: 1.0 mL/min;
UV = 248 nm; tantiminor = 7.53 min, tantimajor = 9.47 min; tsynminor = 10.92
min, tsynmajor = 13.59 min. 1H NMR (500 MHz, CDCl3): δ 7.51 (d, J =
7.0 Hz, 2H), 7.37−7.30 (m, 3H), 6.99 (s, 1H), 4.67−4.63 (m, 1H),
4.37−4.34 (m, 1H), 3.65−3.61 (m, 1H), 2.93−2.89 (m, 1H), 2.26 (s,
3H), 1.72−1.66 (m, 2H), 1.31−1.26 (m, 4H), 0.87 (t, J = 7 Hz, 3H)
ppm. 13C NMR (125 MHz, CDCl3): δ 209.8, 134.8, 133.8, 129.0 (×2),
128.5, 128.2 (×2), 123.2, 76.3, 52.0, 49.5, 30.6, 29.5, 27.7, 22.7, 13.8
ppm. GC−MS: m/z 128, 227, 242, 288 (100), 320, 322.
UV = 280 nm; tanti
= 13.97 min, tanti
= 20.12 min; tsyn
=
minor
major
minor
9.67 min, tsynmajor = 12.16 min. 1H NMR (500 MHz, CDCl3): δ 7.39−
7.30 (m, 5H), 7.01 (s, 1H), 4.79−4.76 (m, 1H), 4.55−4.51 (m, 1H),
3.20−3.15 (m, 1H), 2.58−2.52 (m, 1H), 2.50−2.47 (m, 1H), 2.44−
2.36 (m, 1H), 2.28−2.23 (m, 1H), 2.18−2.13 (m, 1H), 1.95−1.93 (m,
1H), 1.75−1.70 (m, 2H), 1.41−1.32 (m, 1H) ppm. 13C NMR (125
MHz, CDCl3): δ 210.9, 140.0, 128.6 (×2), 128.3, 128.1 (×2), 127.8,
105.7, 77.5, 51.0, 50.0, 43.1, 33.3, 28.7, 25.3 ppm. GC−MS: m/z 128,
211, 225, 272 (100).
(S)-2-((R,E)-3-Methyl-1-nitro-4-phenylbut-3-en-2-yl)cyclo-
hexanone (5r). Yield: 33 mg, 90%; 92% ee (anti), >99% ee (syn).
White solid. The enantiomeric excess was determined by HPLC on
Daicel Chiralpak AD-H with hexane/i-PrOH (85:15) as the eluent.
Flow: 1.0 mL/min; UV = 272 nm; tanti
= 10.67, tanti
= 12.16
minor
major
min, tsynmajor = 11.40 min. H NMR (500 MHz, CDCl3): δ 7.31−7.28
(m, 2H), 7.21−7.18 (m, 3H), 6.39 (m, 1H), 4.84−4.80 (m, 1H),
4.43−4.39 (m, 1H), 3.36−3.31 (m, 1H), 2.51−2.43 (m, 2H), 2.39−
2.33 (m, 1H), 2.09−2.03 (m, 2H), 1.89−86 (m, 1H), 1.80 (s, 3H),
1.76−1.60 (m, 2H), 1.47−1.39 (m, 1H) ppm. 13C NMR (125 MHz,
CDCl3): δ 211.8, 137.0, 133.0, 131.3, 129.0 (×2), 128.1 (×2), 126.8,
77.0, 50.0, 48.1, 42.7, 33.0, 28.5, 25.0, 14.0 ppm; GC−MS: m/z 129,
143(100), 240, 287. HRMS: (EI+) m/z calcd for [C17H21NO3]+
287.1521, found 287.1531.
1
(2S,3S,Z)-4-Bromo-2-isopropyl-3-(nitromethyl)-5-phenylpent-4-
enal (5m). Yield: 41 mg, 93%; >99% ee (anti), 92% ee (syn). Colorless
oil. The enantiomeric excess was determined by HPLC on Daicel
Chiralpak AS-H with hexane/i-PrOH (85:15) as the eluent. Flow: 1.0
mL/min; UV = 254 nm; tanti
= 14.63 min; tsyn
= 12.87 min,
major
minor
1
tsyn
= 11.75 min. H NMR (500 MHz, CDCl3): δ 9.90 (s, 1H),
major
7.53 (d, J = 7.0 Hz, 2H), 7.36−7.30 (m, 3H), 7.00 (s, 1H), 4.63−4.59
(m, 1H), 4.53−4.49 (m, 1H), 3.79−3.74 (m, 1H), 2.78−2.75 (m, 1H),
2.22−2.16 (m, 1H), 1.26 (d, J = 7.5 Hz, 3H), 0.97 (d, J = 7.0 Hz, 3H)
ppm. 13C NMR (125 MHz, CDCl3): δ 203.2, 134.6, 134.0, 129.1 (×2),
128.6, 128.2 (×2), 122.9, 76.3, 56.1, 47.0, 28.2, 21.9, 16.7 ppm. GC−
MS: m/z 91, 129 (100), 171, 199, 260.
(S)-2-((S,E)-1-Nitro-4-phenylbut-3-en-2-yl)cyclohexanone (5s).
Yield: 34 mg, 95%, 79% ee (anti). White solid. The enantiomeric
excess was determined by HPLC on Daicel Chiralpak OD-H with
hexane/i-PrOH (85:15) as the eluent. Flow: 1.0 mL/min; UV = 250
nm; tanti
= 18.44, tanti
= 13.76 min. 1H NMR (500 MHz,
minor
major
CDCl3): δ 7.33−7.26 (m, 4H), 7.25−7.20(m, 1H), 6.47 (d, J = 15.5
Hz, 1H), 6.03−5.98 (m, 1H), 4.67−4.63 (m, 1H), 4.54−4.50 (m, 1H),
3.37−3.31 (m, 1H), 2.53−2.48 (m, 1H), 2.42−2.39 (m, 1H), 2.35−
(S,Z)-7-Bromo-2-methyl-6-(nitromethyl)-8-phenyloct-7-en-4-one
(5n). Yield: 17 mg, 38%; 87% ee. Colorless oil. The enantiomeric
excess was determined by HPLC on Daicel Chiralpak AS-H with
1258
dx.doi.org/10.1021/jo302288z | J. Org. Chem. 2013, 78, 1254−1259

The Journal of Organic Chemistry
Note
2.29 (m, 1H), 2.15−2.11 (m, 1H), 2.07−2.02 (m, 1H), 1.87−1.85 (m,
1H), 1.68−1.59 (m, 2H), 1.46−1.37 (m, 1H) ppm. 13C NMR (125
MHz, CDCl3): δ 211.2, 136.4, 134.3, 128.6 (×2), 127.9, 126.4 (×2),
125.9, 78.1, 51.7, 42.6, 41.9, 32.5, 28.1, 25.0 ppm. GC−MS: m/z 129
(100), 197, 226, 273. HRMS: (EI+) m/z calcd for [C16H19NO3]+
273.1365, found 273.1362.
Nature 2008, 455, 304. (e) Bertelsen, S.; Jørgensen, K. A. Chem. Soc.
Rev. 2009, 38, 2178. (f) Moyano, A.; Ríos, R. Chem. Rev. 2011, 111,
4703. (g) Albrecht, L.; Jiang, H.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2011, 50, 8492.
(5) For reviews, see: (a) Metzger, J. O. Angew. Chem., Int. Ed. 1998,
37, 2975. (b) Tanaka, K. Solvent-Free Organic Synthesis; Wiley-VCH:
Weinheim, 2003. (c) Kaupp, G. Top. Curr. Chem. 2005, 95. For
selected recent examples, see: (d) Carlone, A.; Marigo, M.; North, C.;
Landa, A.; Jørgensen, K. A. Chem. Commun. 2006, 4928. (e) Guillena,
ASSOCIATED CONTENT
* Supporting Information
■
S
́ ́
G.; Hita, M. C.; Najera, C.; Viozquez, S. F. J. Org. Chem. 2008, 73,
Copies of NMR spectra, HPLC analysis of the products, as well
as X-ray structures of compounds 5a and 5b (CIF). This
material is available free of charge via the Internet at http://
pubs.acs.org.
5933. (f) Tan, B.; Zeng, X.; Lu, Y.; Chua, P. J.; Zhong, G. Org. Lett.
2009, 11, 1927. (g) Wang, L.; Liu, J.; Miao, T.; Zhou, W.; Li, P.; Ren,
K.; Zhang, X. Adv. Synth. Catal. 2010, 352, 2571. (h) Martínez-
Castaneda, A.; Poladura, B.; Rodríguez-Solla, H.; Concellon
V. Org. Lett. 2011, 13, 3032.
́
, C.; Amo,
̃
(6) (a) Belot, S.; Massaro, A.; Tenti, A.; Mordini, A.; Alexakis, A. Org.
Lett. 2008, 10, 4557. (b) Xu, D.-Q.; Xia, A.-B.; Luo, S.-P.; Tang, J.;
Zhang, S.; Jiang, J.-R.; Xu, Z.-Y. Angew. Chem., Int. Ed. 2009, 48, 3821.
(c) Li, Z.-B.; Luo, S.-P.; Guo, Y.; Xia, A.-B.; Xu, D.-Q. Org. Biomol.
Chem. 2010, 8, 2505. (d) Xia, A.-B.; Xu, D.-Q.; Luo, S.-P.; Jiang, J.-R.;
Tang, J.; Wang, Y.-F.; Xu, Z.-Y. Chem.Eur. J. 2010, 16, 801. (e) Xia,
A.-B.; Xu, D.-Q.; Wu, C.; Zhao, L.; Xu, Z.-Y. Chem.Eur. J. 2012, 18,
1055.
AUTHOR INFORMATION
Corresponding Author
*E-mail: chrc@zjut.edu.cn, greenchem@zjut.edu.cn.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(7) (a) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev.
2007, 107, 5471. (b) Andrey, O.; Alexakis, A.; Tomassini, A.;
Bernardinelli, G. Adv. Synth. Catal. 2004, 346, 1147.
This work was supported by the National Natural Science
Foundation of China (No. 21202149 and 20772110), the
Zhejiang Provincial Natural Science Foundation of China (No.
Y4110415), and the Foundation of Zhejiang Education
Committee (No. Y201225109).
́
(8) Companyo, X.; Valero, G.; Crovetto, L.; Moyano, A.; Rios, R.
Chem.Eur. J. 2009, 15, 6564.
(9) See the Supporting Information.
REFERENCES
■
(1) (a) Coe, P. L.; Harnden, M. R.; Stanley Jones, A.; Noble, S. A.;
Walker, R. T. J. Med. Chem. 1982, 25, 1329. (b) Herdewijn, P.; Clercq,
E. D.; Balzarini, J.; Vanderhaeghe, H. J. Med. Chem. 1985, 28, 550.
(c) Mitchell, W. L.; Ravenscroft, P.; Hill, M. L.; Knutsen, L. J. S.;
Judkins, B. D.; Newton, R. F.; Scopes, D. I. C. J. Med. Chem. 1986, 29,
809. (d) Balzarini, J.; Baumgartner, H.; Bodenteich, M.; Clercq, E. D.;
Griengl, H. J. Med. Chem. 1989, 32, 1861. (e) Francisco, M. E. Y.;
Erickson, K. L. J. Nat. Prod. 2001, 64, 790. (f) Guenther, S.; Balzarini,
J.; Clercq, E. D.; Nair, V. J. Med. Chem. 2002, 45, 5426. (g) Russ, P.;
Schelling, P.; Scapozza, L.; Folkers, G.; Clercq, E. D.; Marquez, V. E. J.
Med. Chem. 2003, 46, 5045.
(2) For selected recent examples, see: (a) Trost, B. M.; Tang, W.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 14785. (b) Felpin, F. -X. J.
Org. Chem. 2005, 70, 8575. (c) Coleman, R. S.; Walczak, M. C. J. Org.
Chem. 2006, 71, 9841. (d) Fang, Y.; Li, C. J. Am. Chem. Soc. 2007, 129,
8092. (e) Robins, M. J.; Nowak, I.; Rajwanshi, V. K.; Miranda, K.;
Cannon, J. F.; Peterson, M. A.; Andrei, G.; Snoeck, R.; Clercq, E. D.;
́
Balzarini, J. J. Med. Chem. 2007, 50, 3897. (f) Ines, B.; Moreno, I.;
SanMartin, R.; Domínguez, E. J. Org. Chem. 2008, 73, 8448. (g) Fang,
Z.; Liao, P.-C.; Yang, Y.-L.; Yang, F.-L.; Chen, Y.-L.; Lam, Y.; Hua, K.-
F.; Wu, S.-H. J. Med. Chem. 2010, 53, 7967. (h) Xu, S.; Lee, C.-T.; Rao,
H.; Negishi, E. Adv. Synth. Catal. 2011, 353, 2981. (i) Bennasar, M.-L.;
Sole, D.; Zulaica, E.; Alonso, S. Org. Lett. 2011, 13, 2042. (j) Cosner,
C. C.; Helquist, P. Org. Lett. 2011, 13, 3564.
(3) For selected recent examples, see: (a) Lebrun, M.-E.; Marquand,
P. L.; Berthelette, C. J. Org. Chem. 2006, 71, 2009. (b) Venkat Reddy,
C.; Kingston, J. V.; Verkade, J. G. J. Org. Chem. 2008, 73, 3047.
(c) Bull, J. A.; Mousseau, J. J.; Charette, A. B. Org. Lett. 2008, 10, 5485.
(d) Pawluc, P.; Hreczycho, G.; Szudkowska, J.; Kubicki, M.; Marciniec,
B. Org. Lett. 2009, 11, 3390. (e) Wang, D.; Ye, X.; Shi, X. Org. Lett.
2010, 12, 2088. (f) Xu, H.; Gu, S.; Chen, W.; Li, D.; Dou, J. J. Org.
Chem. 2011, 76, 2448. (g) Jacobsen, C. B.; Nielsen, M.; Worgull, D.;
Zweifel, T.; Fisker, E.; Jørgensen, K. A. J. Am. Chem. Soc. 2011, 133,
7398.
́
(4) For selected reviews, see: (a) Berkessel, A.; Groger, H.
Asymmetric Organocatalysis; Wiley-VCH: Weinheim, 2004. (b) List,
B.; Yang, J.-W. Science 2006, 313, 1584. (c) Chem. Rev. 2007, 107,
5413−5883 (special issue on organocatalysis). (d) MacMillan, D.W. C.
1259
dx.doi.org/10.1021/jo302288z | J. Org. Chem. 2013, 78, 1254−1259