Enantioselective synthesis of trans -dihydrobenzofurans via primary amine-thiourea organocatalyzed intramolecular michael addition

Article abstract of DOI:10.1021/jo301006e

A primary amine-thiourea organocatalyzed intramolecular Michael addition access was developed for the synthesis of trans-dihydrobenzofurans. Under the catalysis of an (R,R)-1,2-diphenylethylamine derived primary amine-thiourea bearing a glucosyl scaffold, the corresponding trans-dihydrobenzofurans were obtained in high yields with excellent level of enantioselectivities (94 to >99% ee). Moreover, an in situ isomerization occurring at high temperature gave good to excellent trans/cis ratios as well (trans/cis: 84/16-96/4).

Full text of DOI:10.1021/jo301006e

Article
pubs.acs.org/joc
Enantioselective Synthesis of trans-Dihydrobenzofurans via Primary
Amine-Thiourea Organocatalyzed Intramolecular Michael Addition
Aidang Lu, Keling Hu, Youming Wang,* Haibin Song, Zhenghong Zhou,* Jianxin Fang, and Chuchi Tang
State Key Laboratory of Elemento-Organic Chemistry, Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 300071,
P. R. China
S
* Supporting Information
ABSTRACT: A primary amine-thiourea organocatalyzed
intramolecular Michael addition access was developed for the
synthesis of trans-dihydrobenzofurans. Under the catalysis of
an (R,R)-1,2-diphenylethylamine derived primary amine-
thiourea bearing a glucosyl scaffold, the corresponding trans-
dihydrobenzofurans were obtained in high yields with excellent
level of enantioselectivities (94 to >99% ee). Moreover, an in
situ isomerization occurring at high temperature gave good to
excellent trans/cis ratios as well (trans/cis: 84/16−96/4).
pharmaceuticals has motivated chemists to develop various
approaches for the construction of DHBs.1a,b,9 However,
methods for their preparation in a catalytic asymmetric fashion
are limited and rely mainly on the application of transition
metal catalysis. These include Pd,10 Ir,11 and Ru-catalyzed
asymmetric hydrogenation of substituted benzofurans,12 Pd-
catalyzed Wacker-type cyclization of o-allylphenols,13 Ti(IV)-
promoted coupling of (E)-1,2-dimethoxy-4-(prop-1-enyl)-
benzene and 2-methoxy-1,4-benzoquinone,14 Rh-catalyzed C−
H insertion of aryldiazoacetates,15 and Ag-catalyzed Sakurai
condensation of aromatic aldehydes and 2,3-dihydrobenzox-
asilepines.16 Regarding the organocatalyzed asymmetric syn-
thesis of DHBs with high enantioselectivity, to date only three
reports can be found: Through cinchona alkaloid enantiose-
1. INTRODUCTION
The dihydrobenzofurans (DHBs) belong to an important class
of heterocycles, principally because this ring-system constitutes
the core skeleton of an increasing number of biologically active
natural products and pharmaceuticals (Figure 1).1 For example,
́
lective interrupted Feist−Benary reaction and the subsequent
transformations, Calter and co-worker realized the construction
of the DHB core skeleton of (−)-variabilin and (−)-glycinol.17
Jørgensen reported an anodic oxidation/organocatalytic proto-
col for the α-arylation of aldehydes with N-tosyl-4-amino-
phenol, giving access to DHBs in good yields and excellent
enantiomeric excesses.18 Recently, Jørgensen developed anoth-
er elegant organocatalytic approach to optically active DHBs,
under the catalysis of a L-prolinol silylether, three types of
optically active trans-DHBs having three contiguous stereogenic
centers can be efficiently accessed by one-pot reaction
cascades.19 Therefore, the development of alternative asym-
metric reactions able to provide rapid access to optically active
DHBs, especially trans-DHBs, will be of great importance and
highly desirable. Recently, the organocatalyzed asymmetric
intramolecular reactions including intramolecular Michael
addition have been providing powerful and practical method
for the highly stereocontrolled construction of carbo- or
Figure 1. Natural products and pharmaceuticals that contain
dihydrobenzofuran rings.
(+)-Conocarpan (1), which was first isolated from the wood of
Conocarpus erectus,2 exhibits a diverse array of biological
activities, including insecticidal,3 antifungal,4 and antitrypano-
somal properties.5 2,3,4-Trimethyl-5,7-dihydroxy-2,3-dihydro-
benzofuran (2), isolated from a culture broth of Penicillum
citrinum F5, exhibited antioxidant properties.6 Obtusafuran (3),
a simple dihydrobenzofuran isolated from several Dalbergia
species, was shown to have potent induction of the
anticarcinogenic marker enzyme, quinone reductase.7 (2R,3S)-
3′,4-Di-O-methylcedrusin (4), identified as one of the minor
constituents of the red latex called “dragon blood” in traditional
medicine, was found to act as an inhibitor of cell proliferation.1c
Megapodiol (5) is an antileukemic agent.8
The remarkable significance of the 2,3-dihydrobenzofuran
ring system in both natural products and synthetic
Received: May 21, 2012
Published: June 21, 2012
© 2012 American Chemical Society
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heterocyclic compounds.20 However, to the best of our
knowledge, the asymmetric intramolecular nitro-Michael
addition has been so far unexplored. Herein we report an
efficient, mild, and highly enantioselective method for the
preparation of trans-DHBs by organocatalyzed intramolecular
nitro-Michael addition.21
a
Table 1. Catalyst Screening
b
c
d
entry catalyst time (h) yield (%)
dr (trans/cis)
ee (%)
2. RESULTS AND DISCUSSION
1
2
6
7
96
96
120
24
20
6
47
61/39
94/6
87 (97)
52 (48)
Recently, we have demonstrated that primary amine-
thiophosphoramides 6,7 are efficient organocatalysts for the
Michael addition of acetone to nitroolefins.22 Under the
catalysis of 6, adducts from the asymmetric Michael addition of
acetone to both aromatic and aliphatic nitroolefins were
obtained in high yields with excellent enantioselectivities
under mild reaction conditions.22b Encouraged by the
successful results mentioned above, we conceived that 2,3-
dihydrobenzofuran derivatives 17 could be synthesized as well
from the intramolecular Michael addition of keto-nitroolefins
16, which might be generated from readily available
salicylaldehydes, bromoacetone, and nitromethane (Scheme 1).
55
e
3
8
NR
4
9
78
55
82
80
91
51
80
52/48
90/10
66/34
75/25
70/30
74/26
56/44
−23 (−95)
90 (98)
83 (82)
92 (67)
93 (94)
81 (96)
90 (−93)
5
10
11
12
13
14
15
6
7
8
8
4
9
96
24
10
a
All reactions were carried out using keto-nitroolefin (0.25 mmol) in
the presence of catalyst (20 mol %), cocatalyst PhCO2H (10 mol %)
in CH2Cl2 (0.5 mL) at 20 °C. Yield of the isolated product after
chromatography on silica gel. Determined by H NMR and HPLC
analysis. Determined by chiral HPLC analysis. Values in the
parentheses were ee value of the minor isomer. NR means no
reaction occurred.
b
c
1
d
Scheme 1. General Strategy for the Synthesis of
Dihydrobenzofuran Derivatives
e
(Table 1, entry 1, 87% ee for the major isomer). A sharp
decrease in enantioselectivity was observed when thiophos-
phoramide 7 derived from (R,R)-cyclohexane-1,2-diamine was
employed as the catalyst (Table 1, entry 2, 52% ee for the major
isomer). Under identical conditions, thiophosphoramide 8
prepared from (R)-1,1′-binaphthyl-2,2′-diamine was completely
inactive and failed to afford product 17a (Table 1, entry 3). The
readily available cinchona alkaloid derivative 9 exhibited much
higher catalytic activity; the corresponding adduct was obtained
with 78% yield in 24 h albeit with quite low stereocontrol
(Table 1, entry 4, 52/48 dr, 23% ee). Since primary amine-
thioureas have been proven to be efficient catalysts for the
intermolecular nitro-Michael addition,24 to further improve the
enantioselectivity of the reaction, bifunctional primary amine-
thioureas25 10−14 were screened for the model reaction. In
general, bifunctional thioureas are promising catalysts for this
transformation (Table 1, entries 5−9). However, the
substituents on the nitrogen atom of the thiourea moiety and
chiral diamine backbone of these thioureas play a crucial role
on both the catalytic efficacy and chiral induction ability.
Thioureas 10−13 bearing (R,R)-1,2-diphenylethane-1,2-dia-
mine skeleton proved to be highly efficient for this reaction.
The reaction was complete in 4−20 h, giving the corresponding
product 17a with enantioselectivities of 90, 83, 92, and 93% ee
for the major diastereomer, respectively (Table 1, entries 5−8).
In contrast, the use of thiourea 14 derived from (R,R)-
cyclohexane-1,2-diamine resulted in a quite slower reaction and
significant erosion in enantioselectivity (Table 1, entry 9, 81%
ee for the major isomer). In terms of chemical yield and
enantioselectivity of the major diastereomer, thiourea 13
derived from (R,R)-1,2-diphenylethane-1,2-diamine bearing a
glucosyl scaffold26 was the best choice for the model reaction.
In addition, under otherwise identical conditions, thiourea 15
derived from (S,S)-1,2-diphenylethane-1,2-diamine bearing a
glucosyl scaffold demonstrated much lower catalytic activity.
Although almost the same enantioselectivity was observed, the
addition product was obtained at a prolonged reaction time
with marked decrease in diastereoselectivity (Table 1, entry 10
In an initial study, a series of bifunctional primary amine
organocatalysts23 including thiophosphoramides 6−8, cinchona
alkaloid derivative 9, and bifunctional thioureas 10−15 bearing
either different chiral diamine skeletons or different substituents
on the nitrogen atom of the thiourea moiety were chosen as the
catalyst candidates (Figure 2), and the intramolecular Michael
addition of keto-nitroolefin 16a was selected as a model
reaction. The experimental results are summarized in Table 1.
Figure 2. Catalyst candidates.
The results listed in Table 1 clearly indicated that the
catalytic activity and enantioselectivity of the thiophosphor-
amide catalysts are highly dependent on their chiral diamine
skeleton (Table 1, entries 1−3). Under the catalysis of
thiophosphoramide 6 bearing (R,R)-1,2-diphenylethane-1,2-
diamine skeleton, the intramolecular Michael addition of
keto-nitroolefin 16a proceeded smoothly to provide the desired
dihydrobenzofuran product 17a with good enantioselectivity
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a
Table 2. Optimization of the Reaction Conditions
b
c
d
entry
solvent
additive
PhCO2H
time (h)
yield (%)
trans/cis
ee (%)
1
2
3
4
5
6
7
8
CH2Cl2
CHCl3
THF
4
16
24
5
91
56
70/30
51/49
72/28
38/62
8/92
93 (94)
94 (95)
95 (96)
94 (95)
83 (83)
96 (98)
92 (98)
PhCO2H
PhCO2H
PhCO2H
PhCO2H
99
Toluene
MeOH
THF
91
84
6
49
4-NO2C6H4CO2H
CH3CO2H
99
88/12
76/24
THF
168
168
4
95
THF
PhOH
trace
91
e
9
THF
4-NO2C6H4CO2H
4-NO2C6H4CO2H
4-NO2C6H4CO2H
4-NO2C6H4CO2H
70/30
59/41
78/22
96/4
96 (99)
96 (99)
94 (99)
96 (98)
f
10
THF
19
72
6
91
g
11
THF
75
h
12
THF
95
a
Reaction conditions: Keto-nitroolefin 16a (0.25 mmol), cocatalyst (10 mol %) in 0.5 mL of solvent in the presence of 20 mol % of catalyst 13.
b
c
d
Yield of the isolated product after chromatography on silica gel. Determined by 1H NMR and HPLC analysis. Determined chiral HPLC analysis.
e
f
g
Values in the parentheses were ee value of the minor isomer. The reaction was performed at 30 °C . The reaction was performed at 0 °C. The
reaction conducted in the presence of 10 mol % of catalyst. After completion of the reaction, the reaction mixture was warmed to reflux for 8 h.
h
vs entry 8). This indicates that the (R,R)-configuration of 1,2-
diphenylethane-1,2-diamine matched the chirality of glucosyl
moiety to enhance the catalytic activity of the catalyst.
Having confirmed thiourea 13 as the optimum catalyst for
the reaction, other factors, such as solvent, cocatalyst, catalyst
loading, and reaction temperature, influencing the reaction
were thoroughly investigated employing the intramolecular
Michael addition of keto-nitroolefin 16a as the model. The
results are listed in Table 2.
the acetyl group may offer an opportunity to transform the cis-
isomer to the thermodynamically favorable trans-isomer via the
base promoted enolization. When the reaction was complete,
different base (1 equiv) was added, and the resulting mixture
was stirred at room temperature or warmed to reflux for a
period of time. As we expected, the trans/cis ratio was
significantly improved, though unwanted formation of 2-
acetobenzofuran (18), a side product arising via the retro-
Michael addition, severely competed with the desired pathway
(Scheme 2). We then sought to improve the trans/cis ratio
With 20 mol % of 13 in combination of 10 mol % of
PhCO2H as the catalyst at 20 °C, various solvents have been
examined for this reaction (Table 2, entries 1−5). Except for
methanol in which obvious erosion in enantioselectivity was
observed, this asymmetric intramolecular Michael addition
could be carried out smoothly in several conventional solvents
with almost the same high level of enantioselectivity. The use of
THF resulted in both the highest diastereo- (trans/cis: 72/28)
and enantioselectivity (95% ee) (Table 2, entry 3). A survey of
acidic cocatalysts revealed that the acid strength of the
cocatalyst has an important influence on the reaction. The
use of more acidic 4-nitrobenzoic acid instead of benzoic acid as
the cocatalyst resulted in significant acceleration of the reaction
and further improvement of the diastereo- and enantioselec-
tivity to 88/12 (trans/cis) and 96% ee, respectively. The use of
less acidic acetic acid or phenol as the cocatalyst led to a
sluggish reaction, especially when phenol was employed; the
resulting catalytic system was not active at all. Performing the
reaction at higher or lower temperature both resulted in the
decrease of diastereoselectivity albeit with the same high level
of ee value for the major diastereomer (Table 2, entries 9 and
10). In addition, reducing the amount of 13 from 20 to 10 mol
% resulted in a remarkable decrease both in the turnover
frequency and the diastereoselectivity (Table 2, entry 11).
Up to now, under the optimized reaction conditions (20 mol
% of thiourea 13 as the catalyst, 10 mol % 4-nitrobenzoic acid
as the additive, in THF at 20 °C), excellent enantioselectivity
(96% ee) has been obtained albeit with to some extent
unsatisfactory diastereoselectivity (trans/cis: 88/12). We
envisioned that the existence of an acidic proton adjacent to
Scheme 2. Base-Promoted Isomerization of the Product 17a
efficiently while preventing side reactions. We noticed that this
intramolecular Michael addition proceeded via an enamine
mechanism. Since both the substrate 16 and the product 17
have a carbonyl group, the isomerization of product could also
be engineered in the presence of the catalyst 13 under reflux to
give the thermodynamically favorable trans-isomer through
enamine intermediate.27 To our delight, the diastereoselectivity
of the reaction could be further sharply increased to 96/4
(trans/cis) by just simply refluxing the reaction mixture for 8 h
after completion of the reaction (Table 2, entry 12).
To investigate the scope of the process, a wide range of keto-
nitroolefins bearing different substituent on the benzene ring
were subjected to the bifunctional thiourea-catalyzed intra-
molecular Michael addition reaction. The results are
summarized in Table 3.
Indeed, this transformation has a broad substrate generality.
Both electron-rich and electron-deficient salicylaldehydes with
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a
Table 3. Substrate Scope of the Asymmetric Intramolecular Michael Addition Catalyzed by 13
bc
,
cd
,
ce
,
entry
1
R
time (h)
yield (%)
trans/cis
ee (%)
H (a)
6
8
95
91
96/4
98/2
96
>99
f
2
H (a)
3
5-F (b)
8
>99 (82)
99
90/10 (>99/1)
94/6
97 (>99)
97
4
5-Cl (c)
5-Br (d)
5-NO2 (e)
7-MeO (f)
5-MeO (g)
7-Me (h)
6-Me (i)
5-Me (j)
10
12
18
10
11
10
10
10
14
5
97
94/6
97
6
>99 (93)
99 (87)
97 (81)
95 (78)
92
95/5 (98.5/1.5)
92/8 (96.5/3.5)
88/12 (>99/1)
84/16 (99/1)
96/4
94 (97)
97 (>99)
98 (>99)
97 (>99)
98
7
8
9
10
11
12
97 (80)
96
87/13 (>99/1)
96/4
97 (99)
95
4,5-CHCHCHCH (k)
a
Reaction conditions: Keto-nitroolefins 16 (0.25 mmol), 4-nitrobenzoic acid (10 mol %), and catalyst 13 (20 mol %) in THF (0.5 mL) at 20 °C,
then reflux for 8 h. Isolated yield. Values in the parentheses were the data after a single recrystallization. Determined by H NMR and HPLC
analysis. Determined by chiral HPLC analysis. The reaction was carried out on 10 mmol scale.
b
c
d
1
e
f
phenylmethane (1.02 g, 4 mmol) in methylene chloride (15 mL) at 0
various substitution patterns derived keto-nitroolefins partic-
ipate in the intramolecular Michael addition to give DHBs in
excellent yields with excellent diastero- (trans/cis: 84/16−96/
4) and enantioselectivities (94 to >99% ee) (Table 3, entries
1−12). Moreover, it is worth noting that the reaction can also
be carried out in gram scale giving the isolated product without
any erosion in diastereo- and enantioselectivity, which
demonstrates the potential application of this method for
preparative purposes. For example, the reactions of keto-
nitroolefin 16a on 10 mmol scale resulted in the formation of
dihydrobenzofuran 17a in excellent yield and stereocontrol
along (trans/cis: 98/2, >99% ee) (Table 3, entry 2). Since all of
the products 17 were solid, in some cases, the unsatisfactory
trans/cis ratios could be markedly improved via a single
recrystallization (Table 3, entries 3, 6−9 and 11).
°C during 1 h. The resulting mixture was then stirred overnight at
room temperature. After removal of solvent under reduced pressure,
the residue was purified by column chromatography on silica gel to
afford the desired product 12 as a white solid: 1.28 g, 73% yield, mp
76−78 °C, [α]2D0 +10.1 (c 1.0, CHCl3); 1H NMR (CDCl3, 400 MHz)
δ 1.48 (br. s, 2 H), 4.29 (s, 1 H), 5.27 (br. s, 1 H), 6.09 (br. s, 1 H),
6.64 (s, 1 H), 7.06 (s, 2 H), 7.19−7.24 (m, 5 H), 7.28−7.32 (m, 14
H); 13C NMR (CDCl3, 100.6 MHz) 59.8, 62.5, 64.0, 126.5, 127.2,
127.6, 127.7, 128.0, 128.5, 128.8, 128.9, 139.7, 141.5, 180.9; HRMS
(ESI) m/z calc’d for C28H28N3S [M + H]+ 438.1998, found 438.1994.
4.2. Synthesis of Ketone-Nitroolefins 16. To a suspension of
K2CO3 (2.21 g, 16 mmol) in acetone (50 mL) was added 1-
bromopropan-2-one (1 mL, 1.5 equiv) and the corresponding
nitroolefins (8 mmol). The resulting mixture was stirred at 0 °C
until complete consumption of the starting material was observed by
TLC. The solvent was removed under reduced pressure. The crude
product was purified either by recrystallization from methanol or by
column chromatography to furnish the corresponding keto-nitroolefin.
1-(2-((E)-2-Nitrovinyl)phenoxy)propan-2-one (16a): Yellow solid,
67% yield, 1.19 g, mp 93−94 °C; 1H NMR (CDCl3, 400 MHz) δ 2.30
(s, 3 H), 4.74 (s, 2 H), 6.79 (d, J = 8.4 Hz, 1 H), 7.08 (t, J = 7.6 Hz, 1
H), 7.43 (t, J = 7.6 Hz, 1 H), 7.50 (d, J = 7.6 Hz, 1 H), 8.06 (d, J =
13.6 Hz, 1 H), 8.19 (d, J = 13.6 Hz, 1 H); 13C NMR (CDCl3, 100.6
MHz) 26.5, 73.0, 112.0, 119.7, 122.2, 132.4, 133.3, 134.7, 139.0, 157.3,
202.9; HRMS (ESI) m/z calc’d for C11H11NO4Na [M + Na]+
244.0586, found 244.0578.
The relative and absolute configuration of the product 17i is
unequivocally established by X-ray analysis (see the Supporting
Information), and the remaining configurations are assumed by
analogy.
3. CONCLUSION
In summary, we have described a convenient and scalable
procedure for the preparation of trans-dihydrobenzofurans in
high yields with excellent diastereo- and enantioselectivities via
a primary amine-thiourea organocatalyzed intramolecular
Michael addition from readily available starting materials.
1-(4-Fluoro-2-((E)-2-nitrovinyl)phenoxy)propan-2-one (16b): Yel-
1
low solid, 66% yield, 1.32 g, mp 106−107 °C; H NMR (CDCl3, 400
MHz) δ 2.30 (s, 3 H), 4.73 (s, 2 H), 6.75 (dd, J = 8.8 and 4.0 Hz, 1
H), 7.11−7.16 (m, 1 H), 7.21 (dd, J = 8.4 and 2.8 Hz, 1 H), 8.01 (d, J
= 13.6 Hz, 1 H), 8.13 (d, J = 13.6 Hz, 1 H); 13C NMR (CDCl3, 100.6
MHz) 26.4, 73.5, 113.3 (d, J = 8.0 Hz), 117.9 (d, J = 23.7 Hz), 119.5
(d, J = 23.4 Hz), 120.7 (d, J = 7.9 Hz), 133.4, 139.8, 153.5, 157.1 (d, J
= 241.8 Hz), 202.5; HRMS (ESI) m/z calc’d for C11H10FNO4Na [M +
Na]+ 262.0492, found 262.0484.
4. EXPERIMENTAL SECTION
All reagents and solvents were commercial grade and purified prior to
use when necessary. NMR spectra were acquired on either a 300 or
400 MHz instrumental. Chemical shifts are measured relative to
residual solvent peaks as an internal standard set to δ 7.26 and 77.0
(CDCl3) or 2.50 and 39.43 (DMSO-d6). Enantiomeric excesses were
determined on a HPLC instrument (chiral column; mobile phase:
hexane/i-PrOH). All temperatures were uncorrected. Thiophosphor-
amides 6,22b 7,22a 822b and thioureas 10,26d 11,28 13,26e 14,26a 1526e
were synthesized according to the literature procedure.
1-(4-Chloro-2-((E)-2-nitrovinyl)phenoxy)propan-2-one (16c): Yel-
1
low solid, 56% yield, 1.15 g, mp 130−132 °C; H NMR (CDCl3, 400
MHz) δ 2.30 (s, 3 H), 4.74 (s, 2 H), 6.73 (d, J = 8.8 Hz, 1 H), 7.37
(dd, J = 8.8 and 2.4 Hz, 1 H), 7.47 (d, J = 2.4 Hz, 1 H), 8.02 (d, J =
13.6 Hz, 1 H), 8.10 (d, J = 13.6 Hz, 1 H); 13C NMR (CDCl3, 100.6
MHz) 26.4, 73.2, 113.3, 121.1, 127.2, 131.5, 132.6, 133.2, 139.8, 155.7,
202.1; HRMS (ESI) m/z calc’d for C11H10ClNO4Na [M + Na]+
278.0191, found 278.0193.
4.1. Synthesis of Thiourea 12. To a solution of (1R,2R)-1,2-
diphenylethane-1,2-diamine (0.86 g, 4.04 mmol) in methylene
chloride (10 mL) was slowly added a solution of isothiocyanatodi-
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1-(4-Bromo-2-((E)-2-nitrovinyl)phenoxy)propan-2-one (16d): Yel-
low solid, 50% yield, 1.20 g, mp 130−133 °C; 1H NMR (CDCl3, 400
MHz) δ 2.30 (s, 3 H), 4.74 (s, 2 H), 6.68 (d, J = 8.8 Hz, 1 H), 7.51
(dd, J = 8.8 and 2.4 Hz, 1 H), 7.61 (d, J = 2.4 Hz, 1 H), 8.02 (d, J =
13.6 Hz, 1 H), 8.10 (d, J = 13.6 Hz, 1 H); 13C NMR (CDCl3, 100.6
MHz) 26.4, 73.1, 113.8, 114.3, 121.6, 133.1 134.4, 135.5, 139.8, 156.2,
202.0; HRMS (ESI) m/z calc’d for C11H10BrNO4Na [M + Na]+
321.9685, found 321.9679.
1-(4-Nitro-2-((E)-2-nitrovinyl)phenoxy)propan-2-one (16e): Pale
yellow solid, 72% yield, 1.53 g, mp 164−166 °C; 1H NMR (DMSO-d6,
400 MHz) δ 2.20 (s, 3 H), 5.27 (s, 2 H), 7.29 (d, J = 9.2 Hz, 1 H),
8.28 (d, J = 13.6 Hz, 1 H), 8.33 (d, J = 9.2 Hz, 1 H), 8.52 (d, J = 13.6
Hz, 1 H), 8.78 (s, 1 H); 13C NMR (DMSO-d6, 100.6 MHz) 26.0, 73.4,
113.7, 119.4, 128.1, 128.3, 133.0, 140.8, 141.2, 161.9, 201.8; HRMS
(ESI) m/z calc’d for C11H10N2O6Na [M + Na]+ 289.0431, found
289.0426.
mixture was directly purified by column chromatography on silica gel
(100−200 mesh, PE/EtOAc = 15/1) to afford the desired product 17.
The enantiomeric excess of the pure product was determined by chiral
HPLC analysis.
1-((2R,3S)-2,3-Dihydro-3-(nitromethyl)benzofuran-2-yl)ethanone
(17a): White solid, 95% yield, 53 mg, mp 78−80 °C, [α]2D0 −52.3 (c
1.0, CHCl3), 96/4 trans/cis, 96% ee for trans isomer, 98% ee for cis
isomer; 1H NMR (CDCl3, 400 MHz) δ 2.30 (s, 3 H), 4.32 (dt, J = 4.4
and 6.8 Hz, 1 H), 4.62 (d, J = 6.8 Hz, 2 H), 4.91 (d, J = 4.4 Hz, 1 H),
6.94 (t, J = 7.6 Hz, 1 H), 7.15 (d, J = 7.2 Hz, 1 H), 7.23 (d, J = 8.0 Hz,
1 H); 13C NMR (CDCl3, 100.6 MHz) 26.4, 43.2, 77.4, 87.8, 110.4,
122.0, 123.5, 124.7, 130.3, 158.6, 206.4; HRMS (ESI) m/z calc’d for
C11H11NO4Na [M + Na]+ 244.0580, found 244.0587; HPLC analysis
(Chiralpak AD-H column, hexane/2-propanol = 95:5, flow rate = 1.0
mL/min, wavelength = 220 nm) tR = 12.49 (minor, cis isomer), 13.03
(major, cis isomer), 15.28 (major, trans isomer) and 17.25 min (minor,
trans isomer).
1-((2R,3S)-5-Fluoro-2,3-dihydro-3-(nitromethyl)benzofuran-2-yl)-
ethanone (17b): White solid, >99% yield, 60 mg, mp 70−72 °C, [α]D20
−53.0 (c 1.0, CHCl3), 90/10 trans/cis, 97% ee for trans isomer, >99%
ee for cis isomer; 1H NMR (CDCl3, 400 MHz) δ 2.32 (s, 2.70 H, trans
isomer), 2.40 (s, 0.30 H, cis isomer), 4.34 (dt, J = 4.8 and 7.6 Hz, 1 H),
4.64 (d, J = 7.6 Hz, 2 H), 4.92 (d, J = 4.8 Hz, 0.90 H, trans isomer),
5.16 (d, J = 10.0 Hz, 0.10 H, cis isomer), 6.86−6.96 (m, 3 H); 13C
NMR (CDCl3, 100.6 MHz) 26.4, 27.7, 42.1, 43.1, 73.3, 77.0, 86.0,
88.3, 110.8 (d, J = 8.3 Hz), 112.0 (d, J = 25.6 Hz), 116.8 (d, J = 24.3
Hz), 124.8 (d, J = 8.6 Hz), 154.6, 158.0 (d, J = 240.3 Hz), 206.2;
HRMS (ESI) m/z calc’d for C11H10FNO4Na [M + Na]+ 262.0486,
found 262.0487; HPLC analysis (Chiralpak AD-H column, hexane/2-
propanol = 97:3, flow rate = 1.0 mL/min, wavelength = 220 nm) tR =
23.13 (major, cis isomer), 25.61 (major, trans isomer) and 33.88 min
(minor, trans isomer).
1-(2-Methoxy-6-((E)-2-nitrovinyl)phenoxy)propan-2-one (16f):
1
Yellow solid, 70% yield, 1.41 g, mp 90−91 °C; H NMR (CDCl3,
400 MHz) δ 2.30 (s, 3 H), 3.85 (s, 3 H), 4.69 (s, 2 H), 7.02−7.04 (m,
1 H), 7.10−7.15 (m, 2 H), 7.79 (d, J = 13.6 Hz, 1 H), 8.33 (d, J = 13.6
Hz, 1 H); 13C NMR (CDCl3, 100.6 MHz) 26.2, 55.9, 77.4, 115.8,
121.3, 123.9, 124.5, 134.5, 138.7, 147.4, 151.9, 204.7; HRMS (ESI) m/
z calc’d for C12H13NO5Na [M + Na]+ 274.0686, found 274.0685.
1-(4-Methoxy-2-((E)-2-nitrovinyl)phenoxy)propan-2-one (16g):
1
Yellow solid, 56% yield, 1.13 g, mp 118−119 °C; H NMR (CDCl3,
400 MHz) δ 2.28 (s, 3 H), 3.79 (s, 3 H), 4.68 (s, 2 H), 6.73 (d, J = 8.8
Hz, 1 H), 6.95−6.99 (m, 2 H), 8.09 (d, J = 13.6 Hz, 1 H), 8.15 (d, J =
13.6 Hz, 1 H); 13C NMR (CDCl3, 100.6 MHz) 26.4, 55.8, 73.5, 113.3,
116.3, 118.8, 120.1, 134.5, 139.1, 151.7, 154.2, 203.4; HRMS (ESI) m/
z calc’d for C12H13NO5Na [M + Na]+ 274.0686, found 274.0682.
1-(2-Methyl-6-((E)-2-nitrovinyl)phenoxy)propan-2-one (16h): Yel-
1
low solid, 55% yield, 1.04 g, mp 97−98 °C; H NMR (CDCl3, 400
1-((2R,3S)-5-Chloro-2,3-dihydro-3-(nitromethyl)benzofuran-2-yl)-
ethanone (17c): White solid, 99% yield, 63 mg, mp 60−62 °C, [α]D20
−31.8 (c 1.0, CHCl3), 94/6 trans/cis, 97% ee for trans isomer, >99% ee
MHz) δ 2.32 (s, 6 H), 4.44 (s, 2 H), 7.13 (t, J = 7.6 Hz, 1 H), 7.33 (d,
J = 7.6 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 7.70 (d, J = 13.6 Hz, 1 H),
8.26 (d, J = 14.0 Hz, 1 H); 13C NMR (CDCl3, 100.6 MHz) 16.2, 26.4,
77.7, 123.7, 125.7, 127.2, 132.0, 134.2, 135.5, 138.3, 156.6, 203.0;
HRMS (ESI) m/z calc’d for C12H13NO4Na [M + Na]+ 258.0737,
found 258.0730.
1
for cis isomer; H NMR (CDCl3, 400 MHz) δ 2.31 (s, 2.82 H, trans
isomer), 2.40 (s, 0.18 H, cis isomer), 4.33 (dt, J = 4.8 and 6.8 Hz, 1 H),
4.63 (d, J = 6.8 Hz, 2 H), 4.94 (d, J = 4.8 Hz, 0.94 H, trans isomer),
5.16 (d, J = 10.0 Hz, 0.06 H, cis isomer), 6.86 (d, J = 8.8 Hz, 1 H), 7.10
(s, 0.06 H, cis isomer), 7.15 (s, 0.94 H, trans isomer), 7.21 (dd, J = 8.8
and 2.0 Hz, 1 H); 13C NMR (CDCl3, 100.6 MHz) 26.4, 42.9, 77.0,
88.3, 111.5, 124.9, 125.4, 126.9, 130.3, 157.3, 205.7; HRMS (ESI) m/z
calc’d for C11H10ClNO4Na [M + Na]+ 278.0191, found 278.0192;
HPLC analysis (Chiralpak AD-H column, hexane/2-propanol = 97:3,
flow rate = 1.0 mL/min, wavelength = 220 nm) tR = 23.13 (major, cis
isomer), 25.61 (major, trans isomer) and 33.88 min (minor, trans
isomer).
1-(5-Methyl-2-((E)-2-nitrovinyl)phenoxy)propan-2-one (16i): Yel-
1
low solid, 68% yield, 1.28 g, mp 91−93 °C; H NMR (CDCl3, 400
MHz) δ 2.30 (s, 3 H), 2.38 (s, 3 H), 4.72 (s, 2 H), 6.59 (s, 1 H), 6.88
(d, J = 7.6 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1 H), 8.03 (d, J = 13.6 Hz, 1
H), 8.15 (d, J = 13.6 Hz, 1 H); 13C NMR (CDCl3, 100.6 MHz) 22.0,
26.4, 72.9, 112.8, 116.9, 123.0, 132.4, 134.9, 138.1, 144.8, 157.3, 203.1;
HRMS (ESI) m/z calc’d for C12H13NO4Na [M + Na]+ 258.0737,
found 258.0733.
1-(4-Methyl-2-((E)-2-nitrovinyl)phenoxy)propan-2-one (16j): Yel-
low solid, 80% yield, 1.51 g, mp 130−133 °C; 1H NMR (CDCl3, 400
MHz) δ 2.28 (s, 3 H), 2.31 (s, 3 H), 4.69 (s, 2 H), 6.68 (d, J = 8.4 Hz,
1 H), 7.22 (d, J = 8.4 Hz, 1 H), 7.29 (s, 1 H), 8.01 (d, J = 13.6 Hz, 1
H), 8.16 (d, J = 13.6 Hz, 1 H); 13C NMR (CDCl3, 100.6 MHz) 20.2,
26.4, 73.1, 112.0, 119.3, 131.6, 132.6, 133.9, 134.8, 138.7, 155.4, 203.3;
HRMS (ESI) m/z calc’d for C12H13NO4Na [M + Na]+ 258.0737,
found 258.0743.
1-(1-((E)-2-Nitrovinyl)naphthalen-2-yloxy)propan-2-one (16k):
Orange solid, 90% yield, 1.95 g, mp 165−167 °C; 1H NMR
(CDCl3, 300 MHz) δ 2.31 (s, 3 H), 4.91 (s, 2 H), 7.09 (d, J = 9.0
Hz, 1 H), 7.44−7.49 (m, 1 H), 7.60−7.66 (m, 1 H), 7.83 (d, J = 8.1
Hz, 1 H), 7.94 (d, J = 9.0 Hz, 1 H), 8.17 (d, J = 8.4 Hz, 1 H), 8.39 (d, J
= 13.5 Hz, 1 H), 8.82 (d, J = 13.5 Hz, 1 H); 13C NMR (CDCl3, 100.6
MHz) 26.4, 73.4, 112.5, 124.9, 128.7, 129.0, 129.3, 130.4, 133.2, 134.1,
141.3, 156.4, 202.3; HRMS (ESI) m/z calc’d for C15H13NO4Na [M +
Na]+ 294.0737, found 294.0736.
4.3. General Procedure for the Catalytic Asymmetric
Intramolecular Michael Addition. Keto-nitroolefin 16 (0.25
mmol), 4-nitrobenzoic acid (0.025 mmol), and primary amine/
thiourea catalyst (0.05 mmol) were dissolved in THF (0.5 mL). The
resulting solution was stirred at 20 °C until complete consumption of
keto-nitroolefin (TLC monitoring). Then, the reaction mixture was
refluxed for an additional 8 h. After cooling to room temperature, the
1-((2R,3S)-5-Bromo-2,3-dihydro-3-(nitromethyl)benzofuran-2-yl)-
ethanone (17d): White solid, 97% yield, 73 mg, mp 70−72 °C, [α]D20
−21.7 (c 1.0, CHCl3), 94/6 trans/cis, 97% ee for trans isomer, 99% ee
1
for cis isomer; H NMR (CDCl3, 400 MHz) δ 2.31 (s, 2.82 H, trans
isomer), 2.39 (s, 0.18 H, cis isomer), 4.33 (dt, J = 4.8 and 6.8 Hz, 1 H),
4.63 (d, J = 6.8 Hz, 2 H), 4.94 (d, J = 4.8 Hz, 0.94 H, trans isomer),
5.15 (d, J = 10.0 Hz, 0.06 H, cis isomer), 6.82 (d, J = 8.4 Hz, 1 H), 7.24
(s, 0.06 H, cis isomer), 7.29 (s, 0.94 H, trans isomer), 7.35 (dd, J = 8.4
and 1.6 Hz, 1 H); 13C NMR (CDCl3, 100.6 MHz) 26.4, 42.8, 77.0,
88.2, 112.0, 113.9, 125.9, 127.8, 133.2, 157.8, 205.6; HRMS (ESI) m/z
calc’d for C11H10BrNO4Na [M + Na]+ 321.9685, found 321.9688;
HPLC analysis (Chiralpak AD-H column, hexane/2-propanol = 97:3,
flow rate = 1.0 mL/min, wavelength = 220 nm) tR = 21.42 (minor, cis
isomer), 25.19 (major, cis isomer), 26.82 (major, trans isomer) and
37.69 min (minor, trans isomer).
1-((2R,3S)-2,3-Dihydro-5-nitro-3-(nitromethyl)benzofuran-2-yl)-
ethanone (17e): Pale yellow solid, >99% yield, 67 mg, mp 96−100 °C,
[α]2D0 −29.2 (c 1.0, CHCl3), 95/5 trans/cis, 94% ee for trans isomer,
1
>99% ee for cis isomer; H NMR (CDCl3, 400 MHz) δ 2.38 (s, 2.85
H, trans isomer), 2.45 (s, 0.15 H, cis isomer), 4.44 (dt, J = 5.2 and 6.4
Hz, 1 H), 4.74 (d, J = 6.4 Hz, 2 H), 5.18 (d, J = 5.2 Hz, 0.95 H, trans
isomer), 5.33 (d, J = 10.4 Hz, 0.05 H, cis isomer), 7.02 (d, J = 8.8 Hz, 1
H), 8.06 (d, J = 1.6 Hz, 0.05 H, cis isomer), 8.11 (d, J = 1.6 Hz, 0.95 H,
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trans isomer), 8.20 (dd, J = 8.8 and 2.4 Hz, 1 H); 13C NMR (CDCl3,
100.6 MHz) 26.6, 41.9, 76.5, 89.4, 110.5, 121.3, 125.2, 127.4, 142.9,
163.6, 204.1; HRMS (ESI) m/z calc’d for C11H10N2O6Na [M + Na]+
289.0431, found 289.0434; HPLC analysis (Chiralpak AD-H column,
hexane/2-propanol = 95:5, flow rate = 1.0 mL/min, wavelength = 220
nm) tR = 61.89 (major, cis isomer), 69.95 (major, trans isomer) and
110.73 min (minor, trans isomer).
wavelength = 220 nm) tR = 18.92 (minor, cis isomer), 19.83 (major,
cis isomer), 24.08 (major, trans isomer) and 28.77 min (minor, trans
isomer).
1-((2R,3S)-2,3-Dihydro-5-methyl-3-(nitromethyl)benzofuran-2-yl)-
ethanone (17j): White solid, 97% yield, 57 mg, mp 78−79 °C, [α]D20
−31.8 (c 1.0, CHCl3), 87/13 trans/cis, 97% ee for trans isomer, 99% ee
1
for cis isomer; H NMR (CDCl3, 400 MHz) δ 2.28 (s, 3 H), 2.30 (s,
1-((2R,3S)-2,3-dihydro-7-methoxy-3-(nitromethyl)benzofuran-2-
yl)ethanone (17f): White solid, 99% yield, 62 mg, 75−77 °C, [α]D20
−11.5 (c 1.0, CHCl3), 92/8 trans/cis, 97% ee for trans isomer, >99% ee
2.61 H, trans isomer), 2.39 (s, 0.39 H, cis isomer), 4.29 (dt, J = 4.8 and
7.2 Hz, 1 H), 4.61 (d, J = 7.2 Hz, 2 H), 4.87 (d, J = 4.8 Hz, 0.87 H,
trans isomer), 5.12 (d, J = 9.6 Hz, 0.13 H, cis isomer), 6.83 (d, J = 8.8
Hz, 1 H), 6.91 (s, 0.13 H, cis isomer), 6.96 (s, 0.87 H, trans isomer),
7.05 (d, J = 8.0 Hz, 1 H); 13C NMR (CDCl3, 100.6 MHz) 19.1 (cis
isomer), 20.7 (trans isomer), 26.4 (trans isomer), 28.4 (cis isomer),
42.0 (cis isomer), 43.3 (trans isomer), 73.8 (cis isomer), 77.5 (trans
isomer), 86.3 (cis isomer), 87.9 (trans isomer), 110.0, 123.5, 125.1,
130.7, 131.6, 156.6, 206.7; HRMS (ESI) m/z calc’d for C12H13NO4Na
[M + Na]+ 258.0737, found 258.0743; HPLC analysis (Chiralpak AD-
H column, hexane/2-propanol = 98:2, flow rate = 1.0 mL/min,
wavelength = 220 nm) tR = 13.76 (minor, cis isomer), 16.90 (major, cis
isomer), 19.80 (major, trans isomer) and 28.21 min (minor, trans
isomer).
1
for cis isomer; H NMR (CDCl3, 400 MHz) δ 2.34 (s, 2.76 H, trans
isomer), 2.44 (s, 0.24 H, cis isomer), 3.90 (s, 3 H), 4.37 (dt, J = 4.8 and
7.6 Hz, 1 H), 4.62 (d, J = 7.6 Hz, 2 H), 4.95 (d, J = 4.8 Hz, 0.92 H,
trans isomer), 5.19 (d, J = 10.0 Hz, 0.08 H, cis isomer), 6.72 (d, J = 7.2
Hz, 0.08 H, cis isomer), 6.76 (d, J = 7.2 Hz, 0.92 H, trans isomer), 6.85
(d, J = 7.6 Hz, 1 H), 6.91 (t, J = 7.6 Hz, 1 H); 13C NMR (CDCl3,
100.6 MHz) 26.4, 43.7, 56.0, 77.3, 88.3, 113.0, 116.4, 122.9, 124.7,
144.9, 147.0, 206.3; HRMS (ESI) m/z calc’d for C12H13NO5Na [M +
Na]+ 274.0686, found 274.0685; HPLC analysis (Chiralpak AD-H
column, hexane/2-propanol = 99:1, flow rate = 1.0 mL/min,
wavelength = 220 nm) tR = 49.34 (major, cis isomer), 76.17 (major,
trans isomer) and 85.15 min (minor, trans isomer).
1-((1S,2R)-1,2-Dihydro-1-(nitromethyl)naphtho[2,1-b]furan-2-yl)-
ethanone (17k): Pale yellow solid, 96% yield, 65 mg, mp 110−111 °C,
[α]2D0 −35.0 (c 1.0, CHCl3), 96/4 trans/cis, 95% ee for trans isomer,
>99% ee for cis isomer; 1H NMR (CDCl3, 400 MHz) δ 2.21 (s, 3 H),
4.44 (dd, J = 10.0 and 12.4 Hz, 1 H), 4.68 (d, J = 10.0 Hz, 1 H), 4.80
(dd, J = 2.8 and 12.8 Hz, 1 H), 5.12 (d, J = 2.0 Hz, 1 H), 7.14 (d, J =
8.8 Hz, 1 H), 7.29 (t, J = 7.6 Hz, 1 H), 7.46 (t, J = 8.0 Hz, 1 H), 7.57
(d, J = 8.4 Hz, 1 H), 7.72 (d, J = 8.8 Hz, 1 H), 7.76 (d, J = 8.0 Hz, 1
H); 13C NMR (CDCl3, 100.6 MHz) 26.2, 43.2, 76.0, 89.0, 112.1,
114.3, 121.3, 124.0, 128.0, 129.3, 129.6, 129.9, 131.8, 156.8, 206.2;
HRMS (ESI) m/z calc’d for C15H13NO4Na [M + Na]+ 294.0737,
found 294.0735; HPLC analysis (Chiralpak AD-H column, hexane/2-
propanol = 98:2, flow rate = 0.7 mL/min, wavelength = 220 nm) tR =
47.59 (major, cis isomer), 49.69 (major, trans isomer) and 59.32 min
(minor, trans isomer).
4.4. Base-Promoted Isomerization of Product 17a. When 13
catalyzed intramolecular Michael addition of keto-nitroolefin 16a was
complete, different base (1 equiv) was added, and the resulting
mixture was stirred at room temperature or warmed to reflux for a
period of time indicated in Scheme 2. The trans/cis ratio of product
17a and the amount of the side product 18 was determined by GC
analysis. The structure of the side product 18 was determined by NMR
analysis after being purified by column chromatograph on silica gel.
2-Acetobenzofuran (18): Yellow solid, mp 58−60 °C (lit.,29 mp
69−71 °C); 1H NMR (CDCl3, 400 MHz) δ 2.69 (s, 3 H), 7.30 (t, J =
7.6 Hz, 1 H), 7.47 (t, J = 8.0 Hz, 1 H), 7.49 (s, 1 H), 7.57 (d, J = 8.4
Hz, 1 H), 7.70 (d, J = 8.0 Hz, 1 H) (lit.,30 2.60 (s, 3 H), 7.29−7.33 (m,
1 H), 7.45−7.50 (m, 2 H), 7.57 (d, 1 H), 7.70 (d, 1 H)); 13C NMR
(CDCl3, 100.6 MHz) 26.4, 112.4, 113.0, 123.2, 123.8, 127.0, 128.2,
152.5, 155.6, 188.6 (lit.,30 26.8, 112.8, 113.4, 123.7, 124.3, 127.5, 128.7,
153.1, 156.1, 189.0).
1-((2R,3S)-2,3-Dihydro-5-methoxy-3-(nitromethyl)benzofuran-2-
yl)ethanone (17g): Yellow solid, 97% yield, 61 mg, mp 34−36 °C,
[α]2D0 −25.8 (c 1.0, CHCl3), 88/12 trans/cis, 98% ee for trans isomer,
1
>99% ee for cis isomer; H NMR (CDCl3, 400 MHz) δ 2.30 (s, 2.64
H, trans isomer), 2.36 (s, 0.36 H, cis isomer), 3.73 (s, 3 H), 4.30 (dt, J
= 4.4 and 6.8 Hz, 1 H), 4.62 (d, J = 6.8 Hz, 2 H), 4.86 (d, J = 4.4 Hz,
0.88 H, trans isomer), 5.11 (d, J = 9.6 Hz, 0.12 H, cis isomer), 6.67 (d,
J = 2.0 Hz, 0.12 H, cis isomer), 6.72 (d, J = 2.0 Hz, 0.88 H, trans
isomer), 6.78 (dd, J = 2.4 and 8.8 Hz, 1 H), 6.84 (d, J = 8.8 Hz, 1 H);
13C NMR (CDCl3, 100.6 MHz) 26.4 (trans isomer), 27.7 (cis isomer),
42.3 (cis isomer), 43.8 (trans isomer), 56.0, 73.6 (cis isomer), 77.3
(trans isomer), 86.5 (cis isomer), 88.1 (trans isomer), 110.4, 110.6,
115.6, 124.4, 152.5, 155.1, 206.8; HRMS (ESI) m/z calc’d for
C12H13NO5Na [M + Na]+ 274.0686, found 274.0686; HPLC analysis
(Chiralpak AD-H column, hexane/2-propanol = 97:3, flow rate = 1.0
mL/min, wavelength = 220 nm) tR = 25.01 (major, cis isomer), 33.45
(major, trans isomer) and 36.04 min (minor, trans isomer).
1-((2R,3S)-2,3-Dihydro-7-methyl-3-(nitromethyl)benzofuran-2-yl)-
ethanone (17h): White solid, 95% yield, 56 mg, mp 54−56 °C, [α]D20
−29.0 (c 1.0, CHCl3), 84/16 trans/cis, 97% ee for trans isomer, >99%
ee for cis isomer; 1H NMR (CDCl3, 400 MHz) δ 2.28 (s, 3 H), 2.31 (s,
2.52 H, trans isomer), 2.41 (s, 0.48 H, cis isomer), 4.33 (dt, J = 4.4 and
6.8 Hz, 1 H), 4.62 (d, J = 6.8 Hz, 2 H), 4.90 (d, J = 4.4 Hz, 0.84 H,
trans isomer), 5.14 (d, J = 9.6 Hz, 0.16 H, cis isomer), 6.84−6.88 (m, 1
H), 6.99 (d, J = 7.2 Hz, 0.84 H, trans isomer), 7.04−7.08 (m, 1.16 H);
13C NMR (CDCl3, 100.6 MHz) 13.7 (cis isomer), 15.0 (trans isomer),
26.3 (trans isomer), 28.4 (cis isomer), 42.4 (cis isomer), 43.6 (trans
isomer), 73.8 (cis isomer), 77.6 (trans isomer), 85.9 (cis isomer), 87.6
(trans isomer), 120.8 (trans isomer), 121.6 (cis isomer), 121.9 (cis
isomer), 122.0 (trans isomer), 122.8 (trans isomer), 125.5 (cis isomer),
127.2 (cis isomer), 128.8 (trans isomer), 130.9 (cis isomer), 131.4
(trans isomer), 157.0, 206.8; HRMS (ESI) m/z calc’d for
C12H13NO4Na [M + Na]+ 258.0737, found 258.0740; HPLC analysis
(Chiralpak OD-H column, hexane/2-propanol = 97:3, flow rate = 1.0
mL/min, wavelength = 220 nm) tR = 25.20 (major, cis isomer), 27.96
(major, trans isomer) and 35.70 min (minor, trans isomer).
ASSOCIATED CONTENT
■
S
* Supporting Information
1-((2R,3S)-2,3-Dihydro-6-methyl-3-(nitromethyl)benzofuran-2-yl)-
ethanone (17i): White solid, 92% yield, 54 mg, mp 133−135 °C, [α]D20
−23.0 (c 1.0, CHCl3), 96/4 trans/cis, 98% ee for trans isomer, 64% ee
Copies of NMR spectra, HPLC analysis, and the complete data
for the reported crystal structure. This material is available free
of charge via the Internet at http://pubs.acs.org.
1
for cis isomer; H NMR (CDCl3, 400 MHz) δ 2.30 (s, 3 H), 2.33 (s,
2.88 H, trans isomer), 2.40 (s, 0.12 H, cis isomer), 4.28 (dt, J = 4.4 and
6.8 Hz, 1 H), 4.60 (d, J = 6.8 Hz, 2 H), 4.89 (d, J = 4.4 Hz, 0.96 H,
trans isomer), 5.13 (d, J = 10.0 Hz, 0.04 H, cis isomer), 6.76 (d, J = 8.0
Hz, 1 H), 6.77 (s, 1 H), 7.03 (d, J = 8.0 Hz, 1 H); 13C NMR (CDCl3,
100.6 MHz) 21.5, 26.4, 43.1, 77.6, 88.1, 111.1, 120.5, 122.9, 124.3,
140.9, 158.9, 206.7; HRMS (ESI) m/z calc’d for C12H13NO4Na [M +
Na]+ 258.0737, found 258.0740; HPLC analysis (Chiralpak AD-H
column, hexane/2-propanol = 98:2, flow rate = 0.8 mL/min,
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: z.h.zhou@nankai.edu.cn; youmingwang@eyou.com.
Notes
The authors declare no competing financial interest.
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The Journal of Organic Chemistry
Article
(19) Albrecht, Ł.; Ransborg, L. K.; Lauridsen, V.; Overgaard, M.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2011, 50, 12496.
(20) Examples of organocatalytic asymmetric intramolecular Michael
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ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (No. 20972070, 21121002), the National Basic research
Program of China (973 Program 2010CB833300), Program for
New Century Excellent Talents in University (NCET-11-
0265), and the Key laboratory of Elemento-Organic Chemistry
for generous financial support for our programs.
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