Organocatalyzed michael-michael cascade reaction: Asymmetric synthesis of polysubstituted chromans

Article abstract of DOI:10.1021/jo400476b

An enantioselective cascade Michael-Michael reaction between chalcones enolates and nitromethane catalyzed by a bifunctional thiourea is developed. This reaction provides a mild but efficient approach to chiral benzopyrans bearing three consecutive stereocenters in high yields with excellent stereoselectivities, and the benzopyrans can be easily transformed to the corresponding tricyclic product.

Full text of DOI:10.1021/jo400476b

Article
pubs.acs.org/joc
Organocatalyzed Michael−Michael Cascade Reaction: Asymmetric
Synthesis of Polysubstituted Chromans
Zhen-Xin Jia,† Yong-Chun Luo,*,† Xi-Na Cheng,† Peng-Fei Xu,*,† and Yu-Cheng Gu‡
†State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou
730000, P. R. China
‡Syngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire RG42 6EY, United Kingdom
S
* Supporting Information
ABSTRACT: An enantioselective cascade Michael−Michael reaction
between chalcones enolates and nitromethane catalyzed by a
bifunctional thiourea is developed. This reaction provides a mild but
efficient approach to chiral benzopyrans bearing three consecutive
stereocenters in high yields with excellent stereoselectivities, and the
benzopyrans can be easily transformed to the corresponding tricyclic
product.
tetrahydroquinolines with diverse stereochemical features
through a cascade Michael−aza-Henry reaction and a cascade
aza-Michael−Michael reaction.8 Inspired by the previous work,
we reasoned that the chiral polysubstituted chromans 3 could
be directly constructed from commercially available raw
materials nitromethane and chalcones enolates 2 via a cascade
Michael−Michael reaction using suitable chiral bifunctional
thiourea catalyst 1.
INTRODUCTION
■
It is well-known that chiral chroman and benzopyran structures
belong to an important class of heterocycles that constitute the
core of numerous natural products and synthetic analogs
possessing an extensive array of biological activities (Figure 1).1
RESULTS AND DISCUSSION
■
For the preliminary study, chalcone enolate 2a and nitro-
methane were chosen as model substrates for the feasibility of
the proposed cascade double Michael reaction in the presence
of various chiral bifunctional organocatalysts in toluene.
Initially, organocatalyst 1a was investigated at room temper-
ature. To our delight, the expected product 3a was formed with
excellent enantioselectivity (98% enantiomeric excess (ee)),
albeit in low yield (Table 1, entries 1 and 2). When the reaction
temperature was increased to 40 °C, the reaction yield was
improved to 66% (Table 1, entry 3). In order to reduce the
reaction time and further improve the reaction yield, a 4 Å
molecular sieve (MS) was added to the reaction system. The
results showed the yield was improved, even with reduced
reaction time, when a 4 Å MS was added (Table 1, entry 4). On
the basis of these results, several commonly used bifunctional
organocatalysts (Figure 2) were screened for this cascade
reaction for their reactivity and selectivity. Among them,
organocatalyst 1a was identified as the best catalyst for this
double Michael reaction process (Table 1, entries 4−11).
Subsequently, the reaction medium was investigated for this
cascade reaction. It was found that the solvents had little
Figure 1. Examples of biologically active chroman derivatives.
For example, α-tocopherol, as one of the most well-known
chiral chromans, is an important member of the vitamin E
family, which serve as natural lipophilic antioxidants and radical
scavengers.2 (+)-Catechin, commonly found in land plants such
as the traditional Chinese medicine plant Uncaria rhynchophylla
and green alga Myriophyllum spicatum, displays modest
antitumor and antioxidant activity.3 Bitucarpin A, isolated
from the aerial parts of Mediterranean plants Bituminaria
bituminosa (Leguminosae), exhibited potent antibacterial and
anticlastogenic activity against both mytomicin C and
bleomycin C.4 Due to the importance of the chiral chroman
frameworks, the development of new and more general catalytic
asymmetric strategies for their preparation has become an
active field of research.5
Over the past a few years, organocatalyzed cascade reactions
have emerged as powerful synthetic tools for the construction
of new multiple bonds and newly created stereocenters, which
are characterized by the highly efficient, facile, and stereo-
selective assembly of complex and diverse molecules without
the need for costly protection/deprotection processes as well as
the purification of the intermediates.6 Recently, our group has
developed some methods for the organocatalytic asymmetric
cascade reaction.7 In particular, we could make substituted
Received: March 13, 2013
Revised: May 31, 2013
Accepted: June 10, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo400476b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Table 1. Conditions Optimization for the Double Michael
Cascade Reaction
Table 2. Substrates Scope of the Double Michael Addition
Reaction
a
b
c
d
time
(d)
ee
(%)
entry
ef
catalyst
solvent
time (d) yield (%)
dr
ee (%)
a
b
c
d
entry
R1
R2
yield (%)
dr
,
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1b
1c
1d
1e
1f
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCM
4
6
6
4
5
5
5
4
5
5
5
4
4
4
4
4
4
36
57
66
86
78
75
70
80
56
45
50
84
78
85
81
80
84
1
H
H
H
H
H
H
H
H
H
H
Ph
4
5
5
5
6
4
4
4
4
3
4
4
4
5
4
4
4
6
4
86 (3a)
88 (3b)
85 (3c)
84 (3d)
78 (3e)
85 (3f)
90 (3g)
87 (3h)
80 (3i)
85 (3j)
84 (3k)
84 (3l)
9:1
9:1
8:1
9:1
6:1
10:1
9:1
10:1
9:1
9:1
7:1
7:1
9:1
12:1
8:1
8:1
7:1
nd
>99
>99
>99
>99
97
ef
,
9:1
9:1
9:1
8:1
8:1
8:1
8:1
4:1
3:1
6:1
9:1
10:1
9:1
9:1
8:1
9:1
98
98
2
4-CH3C6H4
4-CH3OC6H4
3-CH3OC6H4
2-CH3OC6H4
4-BrC6H4
4-ClC6H4
3-BrC6H4
2-ClC6H4
2-FC6H4
Ph
f
3
>99
98
4
5
>99
96
6
>99
97
7
96
8
>99
97
>99
93
9
10
11
12
13
14
15
16
17
1g
1h
1a
1a
1a
1a
1a
1a
10
11
12
13
14
15
16
17
18
19
>99
>99
>99
>99
>99
95
95
4-Cl
98
4-Br
Ph
THF
98
4-CH3
Ph
86 (3m)
82 (3n)
87 (3o)
80 (3p)
85 (3q)
nr (3r)
82 (3s)
CHCl3
DCE
>99
98
4-CH3O Ph
5-CH3
H
Ph
CH3CN
xylene
98
furyl
thienyl
CH3
4-Br
>99
>99
nd
>99
H
a
Unless otherwise specified, the reaction was carried out with
nitromethane (4 mmol), 2a (0.2 mmol), organocatalyst (20 mol %),
and a 4 Å MS (60 mg) in the indicated solvent (1.0 mL) at 40 °C.
The yields are the combined yields of the mixtures of diastereomers
after flash chromatography. Determined by H NMR analysis of the
crude products. Determined by chiral-phase HPLC analysis (OD-H
column). The reaction was conducted at room temperature. The
reaction was carried out without a 4 Å MS added.
H
4-Br
9:1
>99
a
b
Unless otherwise specified, the reaction was carried out with
nitromethane (4 mmol), 2 (0.2 mmol), 1a (20 mol %), and a 4 Å
MS (60 mg) in toluene (1.0 mL) at 40 °C. The yields are the
c
1
b
d
e
f
combined yields of the mixtures of diastereomers after flash
c
chromatography. Determined by 1H NMR analysis of the crude
d
products. Determined by chiral-phase HPLC analysis.
the electron-deficient substituents (Table 2, entries 2−5 versus
entries 6−10). Furthermore, corresponding products could also
be obtained in high yields with excellent enantioselectivities
with various substituents in the phenyl ring (R1 substituents)
(Table 2, entries 11−15). Chalcones with heteroaromatic
groups could also be employed to afford the products with
excellent results (Table 2, entries 16 and 17). However, when
an aliphatic chalcone was tested, the reaction did not occur,
which is probably due to its low reactivity (Table 2, entry 18).
Fortunately, a single crystal of 3s was obtained, and the
absolute configuration was determined as (2S,3S,4R) by X-ray
crystallographic analysis (see Supporting Information).9
A mechanism similar to that of the Michael addition reaction
of chalcones with nitromethane catalyzed by the bifunctional
organocatalysts was proposed for the double Michael
reaction.10 As outlined in Figure 3, α,β-unsaturated ketones 2
activated by catalyst 1a containing H-bond donors and
nitromethane activated by the tertiary amine moiety react to
form intermediate A, which undergoes the Michael reaction to
afford the intermediate B. Then the intermediate B undergoes
an intramolecular Michael addition to generate a cyclized
intermediate to deliver the product 3 and regenerate the
catalyst 1a.
Figure 2. Bifunctional thiourea catalysts examined in this study.
influence on the reaction. The corresponding product 3a could
be obtained in either a polar solvent or a nonpolar solvent in
high yields with excellent enantioselectives (Table 1, entries
12−17). Given the above results, the optimal conditions were
found to be using catalyst 1a (20 mol %) in toluene at 40 °C.
Based on the established optimal reaction conditions, the
scope of the double Michael addition reaction was explored by
employing a variety of chalcones enolates 2 with different steric
and electronic properties. As shown in Table 2, all the reactions
afforded the corresponding chromans in high yields with
excellent enantioselectivities. Electronic properties (R2 sub-
stituents) had an apparent effect on this cascade reaction.
Substrates with electron-deficient substituents had higher
reactivity than those with electron-rich substituents. Although
all the substrates tested could afford products in high yields
with excellent enantioselectivities (78 to 88% yields, 97 to
>99% ee), it took less time for the reaction to complete with
The polycyclic frameworks of chiral chromans play an
important role in various therapeutic areas.4,11 We tried to
apply this cascade reaction to the synthesis of tricyclic
chromans. The reduction amination of product 3a with zinc
powder and acetic acid, shown in Scheme 1, successfully
B
dx.doi.org/10.1021/jo400476b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
(E)-Ethyl 3-(2-((E)-3-Oxo-3-phenylprop-1-en-1-yl)phenoxy)-
acrylate (2a). White solid in a 45% yield of two steps (870 mg).
1
Mp: 78−79 °C. H NMR (400 MHz, CDCl3): δ 8.02−7.95 (m, 3H),
7.81−7.73 (m, 2H), 7.60−7.56 (m, 2H), 7.50 (t, J = 7.2 Hz, 2H),
7.45−7.41 (m, 1H), 7.26 (t, J = 7.2 Hz, 1H), 7.09 (dd, J = 0.4 Hz, 8.0
Hz, 1H), 5.56 (d, J = 12.4 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 1.28 (t, J
= 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 190.3, 166.7, 158.6,
154.4, 137.9, 137.8, 132.8, 131.7, 128.7, 128.6, 128.5, 126.1, 125.4,
124.3, 118.7, 103.1, 103.0, 60.1, 14.2. IR (KBr): 3437, 3077, 1705,
1603, 1484, 1284, 1211, 1152, 1044, 984, 755 cm−1. HRMS (ESI) for
C20H19O4 [M + H]+: calcd, 323.1278; found, 323.1293.
(E)-Ethyl 3-(2-((E)-3-Oxo-3-(p-tolyl)prop-1-en-1-yl)phenoxy)-
acrylate (2b). White solid in a 51% yield of two steps (1.03 g). Mp:
1
106−108 °C. H NMR (400 MHz, CDCl3): δ 7.97−7.91 (m, 3H),
7.79 (d, J = 12.0 Hz, 1H), 7.74 (dd, J = 1.2 Hz, 7.6 Hz, 1H), 7.57 (d, J
= 16.0 Hz, 1H), 7.44−7.40 (m, 1H), 7.31−7.23 (m, 3H), 7.10 (d, J =
8.0 Hz, 1H), 5.56 (d, J = 12.4 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 2.43
(s, 3H), 1.28 (t, J = 7.2 Hz, 3H). 13CNMR (100 MHz, CDCl3): δ
189.8, 166.7, 158.7, 154.4, 143.7, 137.4, 135.4, 131.6, 129.3, 128.7,
128.6, 126.3, 125.4, 124.4, 118.7, 103.1, 60.1, 21.6, 14.2. IR (KBr):
3441, 2985, 1709, 1658, 1604, 1482, 1283, 1214, 1047, 850, 767 cm−1.
HRMS (ESI) for C21H21O4 [M + H]+: calcd, 337.1434; found,
337.1449.
Figure 3. Proposed catalytic cycle for the cascade reaction.
Scheme 1. Synthetic Application of the Chiral Chromans 3
(E)-Ethyl 3-(2-((E)-3-(4-Methoxyphenyl)-3-oxoprop-1-en-1-yl)-
phenoxy)acrylate (2c). White solid in a 48% yield of two steps
1
(1.01 g). Mp: 92−93 °C. H NMR (400 MHz, CDCl3): δ 8.03−8.01
(m, 2H), 7.94 (d, J = 12.0 Hz, 1H), 7.79 (d, J = 12.0 Hz, 1H), 7.74
(dd, J = 1.2 Hz, 8.0 Hz, 1H), 7.58 (d, J = 16.0 Hz, 1H), 7.44−7.40 (m,
1H), 7.28−7.23 (m, 1H), 7.10 (d, J = 8.0 Hz, 1H), 6.99−6.96 (m,
2H), 5.56 (d, J = 12.4 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.88 (s, 3H),
1.28 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 188.5, 166.8,
163.4, 158.7, 154.3, 137.0, 131.5, 130.8, 130.7, 128.7, 126.3, 125.4,
124.2, 118.7, 113.8, 103.0, 102.9, 60.1, 55.4, 14.2. IR (KBr): 3441,
2961, 1709, 1602, 1483, 1301, 1218, 1172, 1042, 847, 754 cm−1.
HRMS (ESI) for C21H21O5 [M + H]+: calcd, 353.1384; found,
353.1396.
afforded the tricyclic framework 4a in good yield with excellent
diastereoselectivity and enantioselectivity (78% yield, 18:1 dr,
>99% ee). The ring-fused benzopyran 4a contained a new
chiral center with the configuration determined by an NOE
experiment.
(E)-Ethyl 3-(2-((E)-3-(3-Methoxyphenyl)-3-oxoprop-1-en-1-yl)-
phenoxy)acrylate (2d). Light yellow oil in a 50% yield of two steps
1
(1.06 g). H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 16.0 Hz, 1H),
CONCLUSION
■
7.78 (d, J = 12.4 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.59−7.53 (m,
3H), 7.42 (dd, J = 8.0 Hz, 18.4 Hz, 2H), 7.27−7.24 (m, 1H), 7.14−
7.09 (m, 2H), 5.57 (d, J = 12.0 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.88
(s, 3H), 1.28 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
190.0, 166.7, 159.9, 158.6, 154.5, 139.3, 137.9, 131.7, 129.5, 128.8,
126.2, 125.4, 124.4, 121.0, 119.4, 118.7, 112.8, 103.1, 60.2, 55.4, 14.2.
IR (KBr): 3324, 2976, 1712, 1663, 1596, 1485, 1225, 1123, 1042, 848,
756 cm−1. HRMS (ESI) for C21H21O5 [M + H]+: calcd, 353.1384;
found, 353.1396.
(E)-Ethyl 3-(2-((E)-3-(2-Methoxyphenyl)-3-oxoprop-1-en-1-yl)-
phenoxy)acrylate (2e). Yellow solid in a 42% yield of two steps
(887 mg). Mp: 38−40 °C. 1H NMR (400 MHz, CDCl3): δ 7.81−7.75
(m, 2H), 7.70−7.68 (m, 1H), 7.63 (dd, J = 1.6 Hz, 7.6 Hz, 1H), 7.49−
7.438 (m, 3H), 7.27−7.21 (m, 1H), 7.08−6.98 (m, 3H), 5.51 (d, J =
12.4 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 3.89 (s, 3H), 1.28 (t, J = 7.2
Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 192.5, 166.8, 158.8, 158.2,
154.3, 136.0, 133.0, 131.4, 130.5, 129.1, 129.0, 128.7, 126.5, 125.4,
120.7, 118.8, 111.6, 102.9, 60.1, 55.6, 14.2. IR (KBr): 3443, 2980,
1710, 1645, 1485, 1326, 1224, 1119, 1031, 844, 750 cm−1. HRMS
(ESI) for C21H21O5 [M + H]+: calcd, 353.1384; found, 353.1399.
(E)-Ethyl 3-(2-((E)-3-(4-Bromophenyl)-3-oxoprop-1-en-1-yl)-
phenoxy)acrylate (2f). Light yellow solid in a 52% yield of two
steps (1.25 g). Mp: 111−112 °C. 1H NMR (400 MHz, CDCl3): δ 7.96
(d, J = 16.0 Hz, 1H), 7.87 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 12.4 Hz,
1H), 7.73 (d, J = 7.2 Hz, 1H), 7.63 (d, J = 7.6 Hz, 2H), 7.51 (d, J =
16.0 Hz, 1H), 7.47−7.42 (m, 1H), 7.26 (d, J = 7.2 Hz, 1H), 7.10 (d, J
= 7.6 Hz, 1H), 5.57 (d, J = 12.0 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 1.29
(t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 189.1, 166.7,
158.5, 154.5, 138.4, 136.7, 132.0, 131.9, 130.0, 128.8, 128.0, 125.9,
125.4, 123.7, 118.7, 103.3, 60.2, 14.2. IR (KBr): 3440, 3078, 1702,
1662, 1601, 1482, 1284, 1213, 1154, 1040, 1006, 839, 752 cm−1.
In summary, we have developed a highly enantioselective
cascade double Michael addition reaction for the synthesis of
chiral chromans in good yields from starting materials
chalcones enolates and nitromethane using the commonly
available bifunctional organocatalysts. This cascade reaction
showed remarkably broad substrate scope and generated the
products with three consecutive stereogenic carbons, which are
synthetically useful. Furthermore, these products can be
transformed into tricyclic chromans in good yields with high
diastereo- and enantioselectivity. This synthetic method is a
powerful strategy for constructing multiple stereocenters of
polysubstituted chromans.
EXPERIMENTAL SECTION
■
General Procedure for Synthesis of Chalcones Enolates (2a−
2s). Aryl ketone (10 mmol) was added to a solution of 50% KOH (5
mL) in MeOH (25 mL). After complete dissolution, substituted
salicyaldehyde (10 mmol) was added slowly. The mixture was then
stirred overnight at room temperature; the product was formed as a
precipitate. The precipitate was filtered out and then washed with
H2O, cold MeOH, and ethyl acetate. The residue was dried to obtain
chalcones.
N-Methylmorpholine (36 mg, 0.36 mmol) was added to a mixture
of chalcones (6 mmol), ethyl propiolate (8 mmol), and CH3CN (5
mL). The mixture was stirred for 2 h, and deionized water was added.
The mixture was then extracted with CH2Cl2. The combined organic
phase was dried over Na2SO4, filtered, concentrated in vacuo, and
purified with flash chromatography (eluent, 1/9 ethyl acetate/
petroleum ether) to yield Z chalcones enolates.
C
dx.doi.org/10.1021/jo400476b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
HRMS (ESI) for C20H18BrO4 [M + H]+: calcd, 401.0383; found,
401.0396.
(E)-Ethyl 3-(4-Methyl-2-((E)-3-oxo-3-phenylprop-1-en-1-yl)-
phenoxy)acrylate (2m). White solid in a 44% yield of two steps
(885 mg). Mp: 91−92 °C. 1H NMR (400 MHz, CDCl3): δ 8.02−8.00
(m, 2H), 7.91 (d, J = 16.0 Hz, 1H), 7.76 (d, J = 12.4 Hz, 1H), 7.60−
7.48 (m, 5H), 7.22 (dd, J = 1.6 Hz, 8.0 Hz, 1H), 6.98 (d, J = 8.4 Hz,
1H), 5.50 (d, J = 12.0 Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 2.38 (s, 3H),
1.28 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 190.3, 166.8,
159.2, 152.4, 138.0, 137.9, 135.2, 132.8, 132.4, 128.9, 128.6, 128.5,
125.8, 124.1, 118.8, 102.6, 102.5, 60.1, 20.7, 20.6, 14.2. IR (KBr):
3441, 3057, 2974, 1708, 1664, 1603, 1488, 1291, 1204, 1040, 960, 859,
797, 686 cm−1. HRMS (ESI) for C20H21O4 [M + H]+: calcd, 337.1434;
found, 337.1446.
(E)-Ethyl 3-(2-((E)-3-(4-Chlorophenyl)-3-oxoprop-1-en-1-yl)-
phenoxy)acrylate (2g). White solid in a 50% yield of two steps
(1.07 g). Mp: 127−128 °C. 1H NMR (400 MHz, CDCl3): δ 7.96 (t, J
= 8.4 Hz, 3H), 7.78 (d, J = 12.4 Hz, 1H), 7.73 (d, J = 6.8 Hz, 1H),
7.55−7.43 (m, 4H), 7.28−7.24 (m, 1H), 7.10 (d, J = 8.4 Hz, 1H), 5.57
(d, J = 12.4 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ 189.0, 166.7, 158.6, 154.5, 139.3,
138.4, 136.2, 132.0, 129.9, 128.9, 128.8, 125.9, 125.4, 123.7, 118.7,
103.2, 60.2, 14.2. IR (KBr): 3439, 3062, 1705, 1661, 1602, 1483, 1284,
1213, 1041, 840, 752 cm−1. HRMS (ESI) for C20H18ClO4 [M + H]+:
calcd, 357.0888; found, 357.1161.
(E)-Ethyl 3-(4-Methoxy-2-((E)-3-oxo-3-phenylprop-1-en-1-yl)-
phenoxy)acrylate (2n). White solid in a 45% yield of two steps
(E)-Ethyl 3-(2-((E)-3-(3-Bromophenyl)-3-oxoprop-1-en-1-yl)-
1
(950 mg). Mp: 104−105 °C. H NMR (400 MHz, CDCl3): δ 8.00−
phenoxy)acrylate (2h). White solid in a 43% yield of two steps
1
7.98 (m, 2H), 7.86 (d, J = 16.0 Hz, 1H), 7.74 (d, J = 12.4 Hz, 1H),
7.60−7.56 (m, 1H), 7.54−7.48 (m, 3H), 7.21 (d, J = 2.8 Hz, 1H), 7.03
(d, J = 9.2 Hz, 1H), 6.96 (dd, J = 2.8 Hz, 8.8 Hz, 1H), 5.43 (d, J = 12.4
Hz, 1H), 4.18 (q, J = 7.2 Hz, 2H), 3.85 (s, 3H), 1.27 (t, J = 7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 190.3, 166.9, 160.0, 157.0,
148.3, 137.9, 137.8, 132.9, 128.6, 128.5, 127.2, 124.6, 120.6, 117.2,
112.9, 102.1, 60.1, 55.8, 55.7, 14.2. IR (KBr): 3442, 2974, 1703, 1645,
1599, 1490, 1293, 1231, 1132, 1031, 859, 694 cm−1. HRMS (ESI) for
C20H21O5 [M + H]+: calcd, 353.1384; found, 353.1397.
(1.03 g). Mp: 98−99 °C. H NMR (400 MHz, CDCl3): δ 8.12 (s,
1H), 7.99−7.91 (m, 2H), 7.81−7.70 (m, 3H), 7.52−7.43 (m, 2H),
7.38 (t, J = 7.6 Hz, 1H), 7.28−7.25 (m, 1H), 7.10 (d, J = 8.0 Hz, 1H),
5.58 (d, J = 12.4 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 188.8, 166.7, 158.5, 154.5,
139.7, 138.7, 135.6, 132.0, 131.5, 130.2, 128.7, 127.0, 125.9, 125.4,
123.6, 122.9, 118.7, 103.3, 60.2, 14.2. IR (KBr): 3441, 3075, 1707,
1641, 1599, 1480, 1288, 1209, 1153, 1039, 858, 751 cm−1. HRMS
(ESI) for C20H18BrO4 [M + H]+: calcd, 401.0383; found, 401.0399.
(E)-Ethyl 3-(2-((E)-3-(2-Chlorophenyl)-3-oxoprop-1-en-1-yl)-
phenoxy)acrylate (2i). White solid in a 47% yield of two steps (1.0
(E)-Ethyl 3-(5-Methyl-2-((E)-3-oxo-3-phenylprop-1-en-1-yl)-
phenoxy)acrylate (2o). Light yellow solid in a 36% yield of two
steps (726 mg). Mp: 68−70 °C. 1H NMR (400 MHz, CDCl3): δ 7.99
(d, J = 8.0 Hz, 2H), 7.93 (d, J = 15.6 Hz, 1H), 7.78 (d, J = 12.0 Hz,
1H), 7.61 (d, J = 8.0 Hz, 1H), 7.59−7.47 (m, 4H), 7.05 (d, J = 8.0 Hz,
1H), 6.90 (s, 1H), 5.56 (d, J = 12.0 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H),
2.39 (s, 3H), 1.29 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
190.4, 166.9, 158.8, 154.5, 142.9, 138.1, 138.0, 132.7, 128.6, 128.5,
126.3, 123.3, 123.2, 119.3, 103.0, 60.1, 21.4, 14.2. IR (KBr): 3443,
2981, 1708, 1644, 1601, 1253, 1129, 1013, 784, 689 cm−1. HRMS
(ESI) for C21H21O4 [M + H]+: calcd, 337.1434; found, 337.1447.
(E)-Ethyl 3-(2-((E)-3-(Furan-2-yl)-3-oxoprop-1-en-1-yl)phenoxy)-
acrylate (2p). White solid in a 39% yield of two steps (730 mg).
Mp: 78−79 °C. 1H NMR (400 MHz, CDCl3): δ 8.02 (d, J = 16.0 Hz,
1H), 7.79 (d, J = 13.2 Hz, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.66 (s, 1H),
7.49 (d, J = 16.0 Hz, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.33 (d, J = 3.6 Hz,
1H), 7.29−7.23 (m, 1H), 7.09 (d, J = 8.0 Hz, 1H), 6.60 (t, J = 2.0 Hz,
1H), 5.57 (d, J = 12.4 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 1.29 (t, J =
7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 177.7, 166.7, 158.6,
154.5, 153.6, 146.6, 137.0, 131.8, 128.8, 125.9, 125.4, 123.4, 118.6,
117.6, 112.5, 103.2, 103.1, 60.1, 14.2. IR (KBr): 3442, 3119, 2995,
1711, 1660, 1466, 1397, 1289, 1213, 1158, 1046, 956, 839, 758 cm−1.
HRMS (ESI) for C18H17O5 [M + H]+: calcd, 313.1071; found,
313.1085.
1
mg). Mp: 68−70 °C. H NMR (400 MHz, CDCl3): δ 7.74−7.66 (m,
3H), 7.49−7.40 (m, 4H), 7.38−7.34 (m, 1H), 7.27−7.17 (m, 2H),
7.08 (d, J = 8.0 Hz, 1H), 5.49 (d, J = 12.4 Hz, 1H), 4.20 (q, J = 7.2 Hz,
2H), 1.29 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 193.4,
166.7, 158.5, 154.4, 139.0, 138.8, 132.1, 131.5, 131.3, 130.3, 129.5,
128.7, 128.1, 126.8, 125.7, 125.5, 118.7, 103.2, 60.2, 14.2. IR (KBr):
3441, 2996, 1657, 1605, 1485, 1329, 1226, 1135, 1066, 979, 846, 744
cm−1. HRMS (ESI) for C20H18ClO4 [M + H]+: calcd, 357.0888;
found, 357.1180.
(E)-Ethyl 3-(2-((E)-3-(2-Fluorophenyl)-3-oxoprop-1-en-1-yl)-
phenoxy)acrylate (2j). Yellow solid in a 49% yield of two steps
(998 mg). Mp: 68−69 °C. 1H NMR (400 MHz, CDCl3): δ 7.89 (d, J
= 1.2 Hz, 1H), 7.85−7.80 (m, 1H), 7.78 (d, J = 12.0 Hz, 1H), 7.72
(dd, J = 1.2 Hz, 8.0 Hz, 1H), 7.56−7.50 (m, 1H), 7.48−7.41 (m, 2H),
7.28−7.23 (m, 2H), 7.16 (dd, J = 8.8 Hz, 10.8 Hz, 1H), 7.09 (d, J = 8.0
Hz, 1H), 5.55 (d, J = 12.4 Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 1.29 (t, J
= 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 188.7, 188.6, 166.7,
162.5, 160.0, 158.5, 154.5, 137.8, 134.1, 134.0, 131.9, 131.0, 130.9,
128.8, 127.7, 127.6, 126.9, 126.8, 126.0, 125.4, 124.5, 124.4, 118.6,
116.6, 116.4, 103.2, 60.1, 14.2. IR (KBr): 3440, 1708, 1649, 1609,
1451, 1333, 1232, 1185, 1128, 1016, 847, 756 cm−1. HRMS (ESI) for
C20H18FO4 [M + H]+: calcd, 341.1184; found, 341.1189.
(E)-Ethyl 3-(2-((E)-3-Oxo-3-(thiophen-2-yl)prop-1-en-1-yl)-
phenoxy)acrylate (2q). Light yellow solid in a 42% yield of two
steps (827 mg). Mp: 84−85 °C. 1H NMR (400 MHz, CDCl3): δ 7.98
(d, J = 15.6 Hz, 1H), 7.85 (dd, J = 0.8 Hz, 3.6 Hz, 1H), 7.79 (d, J =
12.4 Hz, 1H), 7.72 (dd, J = 1.2 Hz, 8.0 Hz, 1H), 7.69 (dd, J = 0.8 Hz,
4.8 Hz, 1H), 7.50−7.41 (m, 2H), 7.28−7.24 (m, 1H), 7.18 (dd, J = 4.0
Hz, 4.8 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 5.58 (d, J = 12.4 Hz, 1H),
4.19 (q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 181.8, 166.7, 158.5, 154.5, 145.3, 137.2, 134.0, 131.9,
131.8, 129.0, 128.2, 125.9, 125.4, 124.0, 118.7, 103.2, 60.2, 14.2. IR
(KBr): 3442, 2985, 1959, 1707, 1646, 1596, 1485, 1328, 1226, 1133,
979, 841, 754, 720 cm−1. HRMS (ESI) for C18H17O4S [M + H]+:
calcd, 329.0842; found, 329.0855.
(E)-Ethyl 3-(4-Chloro-2-((E)-3-oxo-3-phenylprop-1-en-1-yl)-
phenoxy)acrylate (2k). Light yellow solid in a 46% yield of two
steps (982 mg). Mp: 41−42 °C. 1H NMR (400 MHz, CDCl3): δ 8.01
(d, J = 7.6 Hz, 2H), 7.88 (d, J = 16.0 Hz, 1H), 7.75−7.71 (m, 2H),
7.62−7.49 (m, 4H), 7.38 (dd, J = 2.4 Hz, 8.8 Hz, 1H), 7.05 (d, J = 8.4
Hz, 1H), 5.56 (d, J = 12.4 Hz, 1H), 4.19 (q, J = 7.2 Hz, 2H), 1.28 (t, J
= 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 189.7, 166.5, 158.2,
152.8, 137.7, 136.3, 133.1, 131.3, 130.9, 128.7, 128.5, 128.1, 127.8,
125.2, 120.1, 103.7, 60.3, 14.2. IR (KBr): 3442, 2979, 1718, 1645,
1605, 1484, 1321, 1223, 1134, 992, 826, 685 cm−1. HRMS (ESI) for
C20H18ClO4 [M + H]+: calcd, 357.0888; found, 357.0894.
(E)-Ethyl 3-(4-Bromo-2-((E)-3-oxo-3-phenylprop-1-en-1-yl)-
phenoxy)acrylate (2l). White solid in a 51% yield of two steps
1
(1.22 g). Mp: 109−110 °C. H NMR (400 MHz, CDCl3): δ 8.02−
(E)-Ethyl 3-(2-((E)-3-Oxobut-1-en-1-yl)phenoxy)acrylate (2r).
1
8.00 (m, 2H), 7.89−7.85 (m, 2H), 7.73 (d, J = 12.4 Hz, 1H), 7.62−
7.49 (m, 5H), 6.99 (d, J = 8.4 Hz, 1H), 5.57 (d, J = 12.0 Hz, 1H), 4.19
(q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 189.7, 166.5, 158.0, 153.3, 137.7, 136.2, 134.3, 133.1, 131.1,
128.7, 128.5, 128.2, 125.2, 120.3, 118.3, 103.8, 60.3, 14.2. IR (KBr):
3441, 2977, 1717, 1646, 1605, 1481, 1321, 1223, 1137, 993, 826, 687
cm−1. HRMS (ESI) for C20H18BrO4 [M + H]+: calcd, 401.0383;
found, 401.0396.
Light yellow oil in a 40% yield of two steps (624 mg). H NMR
(400 MHz, CDCl3): δ 7.78 (d, J = 12.0 Hz, 1H), 7.70 (d, J = 16.4 Hz,
1H), 7.65−7.63 (m, 1H), 7.45−7.41 (m, 1H), 7.23 (t, J = 7.6 Hz, 1H),
7.09 (d, J = 8.4 Hz, 1H), 6.73 (d, J = 16.4 Hz, 1H), 5.56 (d, J = 12.4
Hz, 1H), 4.20 (q, J = 7.2 Hz, 2H), 2.38 (s, 3H), 1.29 (t, J = 7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 198.1, 166.6, 158.5, 154.1,
136.2, 131.7, 129.0, 128.1, 125.6, 125.4, 118.6, 103.1, 103.0, 60.1, 27.4,
14.2. IR (KBr): 3407, 2982, 1712, 1650, 1483, 1364, 1227, 1124, 976,
D
dx.doi.org/10.1021/jo400476b | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
839, 753, 569 cm−1. HRMS (ESI) for C15H17O4 [M + H]+: calcd,
261.1121; found, 261.1133.
enantiomeric excess was determined by HPLC with an OD-H column
(70/30 n-hexane/i-PrOH), 1.0 mL/min, tR(minor) = 20.6 min, tR(major)
=
(E)-Ethyl 3-(4-Bromo-2-((E)-3-(4-bromophenyl)-3-oxoprop-1-en-
27.3 min. 1H NMR (400 MHz, CDCl3): δ 7.53−7.50 (m, 2H), 7.38 (t,
J = 7.6 Hz, 1H), 7.20−7.13 (m, 3H), 7.03−6.99 (m, 1H), 6.88 (d, J =
8.4 Hz, 1H), 5.07 (s, 1H), 4.68−4.64 (m, 1H), 4.22−4.15 (m, 3H),
3.85 (s, 3H), 3.56 (dd, J = 3.2 Hz, 18.8 Hz, 1H), 3.37 (dd, J = 10.8 Hz,
18.4 Hz, 1H), 2.99−2.85 (m, 2H), 1.26 (t, J = 7.2 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 196.1, 169.8, 159.9, 153.4, 137.2, 129.8, 128.7,
128.1, 122.3, 122.0, 120.6, 120.4, 117.1, 112.2, 83.5, 68.4, 61.2, 55.5,
45.4, 36.3, 33.3, 14.1. IR (KBr): 2956, 1733, 1682, 1586, 1457, 1352,
1283, 1191, 1041, 759 cm−1. HRMS (ESI) for C22H27N2O7 [M +
NH4]+: calcd, 431.1813; found, 431.1807.
1-yl)phenoxy)acrylate (2s). White solid in a 54% yield of two steps
1
(1.55 g). Mp: 95−96 °C. H NMR (400 MHz, CDCl3): δ 7.90−7.85
(m, 4H), 7.73 (d, J = 12.0 Hz, 1H), 7.65 (d, J = 8.8 Hz, 2H), 7.55−
7.48 (m, 2H), 7.00 (d, J = 8.8 Hz, 1H), 5.58 (d, J = 12.0 Hz, 1H), 4.20
(q, J = 7.2 Hz, 2H), 1.29 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 188.6, 166.5, 157.9, 153.4, 136.7, 136.3, 134.5, 132.0, 131.0,
130.0, 128.3, 127.8, 124.4, 120.2, 118.3, 103.9, 60.3, 14.2. IR (KBr):
3439, 2979, 1713, 1642, 1603, 1481, 1398, 1319, 1222, 1136, 1033,
1008, 829, 740 cm−1. HRMS (ESI) for C20H17Br2O4 [M + H]+: calcd,
478.9488; found, 478.9494.
Ethyl 2-((2S,3S,4R)-4-(2-(2-Methoxyphenyl)-2-oxoethyl)-3-nitro-
chroman-2-yl)acetate (3e). Colorless oily solid in a 78% yield (64
mg), ee = 97%, dr = 6:1. [α]D20 = −38.0 (c 1.0, CH2Cl2, 97% ee). The
enantiomeric excess was determined by HPLC with an OD-H column
Typical Experimental Procedure for the Synthesis of
Chromans (3a−3s). A mixture of chalcone enolate (2a; 0.2 mmol,
64 mg), nitromethane (4.0 mmol, 214 μL), organocatalyst 1a (0.04
mmol, 23 mg), and a 4 Å MS (60 mg) in toluene (1.0 mL) was stirred
at 40 °C. The reaction was stirred until 2a was completely consumed,
as monitored by TLC. The crude mixture was purified by flash
chromatography on silica gel to afford product 3a as a colorless oil in
86% yield (66 mg), >99% ee, dr = 9:1.
Ethyl 2-((2S,3S,4R)-3-Nitro-4-(2-oxo-2-phenylethyl)chroman-2-
yl)acetate (3a). Colorless oily solid in an 86% yield (66 mg), >99%
ee, dr = 9:1. [α]2D0 = −34.0 (c 1.0, CH2Cl2, >99% ee). The
enantiomeric excess was determined by HPLC with an OD-H column
(70/30 n-hexane/i-PrOH), 1.0 mL/min, tR(minor) = 10.4 min, tR(major)
=
12.7 min. 1H NMR (400 MHz, CDCl3): δ 7.82 (dd, J = 1.6 Hz, 7.6 Hz,
1H), 7.54−7.50 (m, 1H), 7.26−7.15 (m, 2H), 7.07−6.97 (m, 3H),
6.87 (d, J = 8.0 Hz, 1H), 5.06 (s, 1H), 4.71−4.68 (m, 1H), 4.23−4.17
(m, 3H), 3.90 (s, 3H), 3.57 (dd, J = 3.2 Hz, 18.8 Hz, 1H), 3.43 (dd, J
= 10.8 Hz, 18.4 Hz, 1H), 2.98−2.85 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ 198.2, 169.9, 159.0, 153.4, 134.5,
130.7, 128.9, 127.9, 126.8, 122.5, 122.2, 120.9, 117.0, 111.6, 83.9, 68.4,
61.1, 55.6, 50.4, 36.6, 33.8, 14.1. IR (KBr): 3072, 2925, 1734, 1667,
1551, 1487, 1286, 1188, 1023, 759 cm−1. HRMS (ESI) for
C22H27N2O7 [M + NH4]+: calcd, 431.1813; found, 431.1822.
Ethyl 2-((2S,3S,4R)-4-(2-(4-Bromophenyl)-2-oxoethyl)-3-nitro-
chroman-2-yl)acetate (3f). Colorless oily solid in an 85% yield (78
mg), >99% ee, dr = 10:1. [α]D20 = −63.0 (c 1.0, CH2Cl2, >99% ee). The
enantiomeric excess was determined by HPLC with an OD-H column
(90/10 n-hexane/i-PrOH), 1.0 mL/min, tR(minor) = 44.9 min, tR(major)
=
47.6 min. 1H NMR (400 MHz, CDCl3): δ 7.98−7.96 (m, 2H), 7.63−
7.59 (m, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.20−7.16 (m, 2H), 7.03−6.99
(m, 1H), 6.98 (d, J = 8.4 Hz, 1H), 5.07 (t, J = 1.2 Hz, 1H), 4.69−4.65
(m, 1H), 4.23−4.15 (m, 3H), 3.57 (dd, J = 3.2 Hz, 18.8 Hz, 1H), 3.38
(dd, J = 10.8 Hz, 18.8 Hz, 1H), 2.99−2.85 (m, 2H), 1.25 (t, J = 7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 196.2, 169.9, 153.4, 135.9,
133.9, 128.8, 128.7, 128.1, 128.0, 122.3, 122.1, 117.1, 83.5, 68.4, 61.2,
45.3, 36.3, 33.2, 14.0. IR (KBr): 3063, 2957, 1733, 1683, 1490, 1355,
1231, 1191, 758 cm−1. HRMS (ESI) for C21H25N2O6 [M + NH4]+:
calcd, 401.1707; found, 401.1711.
(70/30 n-hexane/i-PrOH), 1.0 mL/min, tR(minor) = 25.4 min, tR(major)
=
1
36.6 min. H NMR (400 MHz, CDCl3): δ 7.82 (d, J = 8.4 Hz, 2H),
7.62 (d, J = 8.4 Hz, 2H), 7.18 (t, J = 6.8 Hz, 2H), 7.01 (t, J = 7.2 Hz,
1H), 6.88 (d, J = 8.0 Hz, 1H), 5.05 (s, 1H), 4.65 (dd, J = 6.4 Hz, 6.8
Hz, 1H), 4.21−4.15 (m, 3H), 3.53 (dd, J = 3.6 Hz, 18.8 Hz, 1H), 3.35
(dd, J = 10.8 Hz, 18.8 Hz, 1H), 2.99−2.86 (m, 2H), 1.26 (t, J = 7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 195.3, 169.9, 153.4, 134.6,
132.2, 129.5, 129.2, 128.7, 128.2, 122.4, 121.9, 117.1, 83.4, 68.4, 61.2,
45.2, 36.2, 33.1, 14.1. IR (KBr): 2957, 1732, 1684, 1551, 1489, 1398,
1281, 1191, 1071, 814, 759 cm−1. HRMS (ESI) for C21H24BrN2O6 [M
+ NH4]+: calcd, 479.0812; found, 479.0811.
Ethyl 2-((2S,3S,4R)-3-Nitro-4-(2-oxo-2-(p-tolyl)ethyl)chroman-2-
yl)acetate (3b). Colorless oily solid in an 88% yield (70 mg), >99%
ee, dr = 9:1. [α]2D0 = −50.0 (c 1.0, CH2Cl2, >99% ee). The
enantiomeric excess was determined by HPLC with an OD-H column
(70/30 n-hexane/i-PrOH), 1.0 mL/min, tR(minor) = 14.3 min, tR(major)
=
1
24.0 min. H NMR (400 MHz, CDCl3): δ 7.86 (d, J = 8.0 Hz, 2H),
7.29−7.26 (m, 2H), 7.18 (t, J = 8.0 Hz, 2H), 7.01 (t, J = 7.6 Hz, 1H),
6.87 (d, J = 8.0 Hz, 1H), 5.06 (s, 1H), 4.67 (t, J = 6.4 Hz, 1H), 4.22−
4.15 (m, 3H), 3.54 (dd, J = 3.2 Hz, 18.4 Hz, 1H), 3.35 (dd, J = 10.8
Hz, 18.8 Hz, 1H), 2.98−2.85 (m, 2H), 2.42 (s, 3H), 1.26 (t, J = 7.2
Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 195.8, 169.9, 153.4, 144.9,
133.5, 129.5, 128.8, 128.2, 128.0, 122.3, 122.2, 117.1, 83.6, 68.4, 61.2,
45.2, 36.4, 33.3, 21.7, 14.1. IR (KBr): 2956, 1733, 1678, 1490, 1353,
1282, 1185, 1025, 810, 759 cm−1. HRMS (ESI) for C22H27N2O6 [M +
NH4]+: calcd, 415.1864; found, 415.1873.
Ethyl 2-((2S,3S,4R)-4-(2-(4-Chlorophenyl)-2-oxoethyl)-3-nitro-
chroman-2-yl)acetate (3g). Colorless oily solid in a 90% yield (75
mg), 97% ee, dr = 9:1. [α]D20 = −49.0 (c 1.0, CH2Cl2, 97% ee). The
enantiomeric excess was determined by HPLC with an OD-H column
(70/30 n-hexane/i-PrOH), 1.0 mL/min, tR(minor) = 22.8 min, tR(major)
=
1
28.8 min. H NMR (400 MHz, CDCl3): δ 7.90 (d, J = 8.4 Hz, 2H),
7.46 (d, J = 8.8 Hz, 2H), 7.20−7.17 (m, 2H), 7.01 (t, J = 7.2 Hz, 1H),
6.88 (d, J = 8.4 Hz, 1H), 5.05 (s, 1H), 4.67−4.64 (m, 1H), 4.22−4.16
(m, 3H), 3.54 (dd, J = 3.2 Hz, 18.8 Hz, 1H), 3.35 (dd, J = 10.8 Hz,
18.8 Hz, 1H), 3.00−2.86 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 195.0, 169.9, 153.4, 140.4, 134.2, 129.5, 129.2,
128.7, 128.2, 122.4, 121.9, 117.1, 83.4, 68.4, 61.2, 45.3, 36.2, 33.1, 14.1.
IR (KBr): 2957, 1732, 1684, 1552, 1490, 1402, 1282, 1023, 821, 760
cm−1. HRMS (ESI) for C21H24ClN2O6 [M + NH4]+: calcd, 435.1317;
found, 435.1304.
Ethyl 2-((2S,3S,4R)-4-(2-(4-Methoxyphenyl)-2-oxoethyl)-3-nitro-
chroman-2-yl)acetate (3c). Colorless oily solid in an 85% yield (70
mg), >99% ee, dr = 8:1. [α]D20 = −52.0 (c 1.0, CH2Cl2, >99% ee). The
enantiomeric excess was determined by HPLC with an OD-H column
(70/30 n-hexane/i-PrOH), 1.0 mL/min, tR(minor) = 33.4 min, tR(major)
=
45.2 min. 1H NMR (400 MHz, CDCl3): δ 7.95−7.93 (m, 2H), 7.19−
7.15 (m, 2H), 7.02−6.98 (m, 1H), 6.95−6.92 (m, 2H), 6.87 (d, J = 8.0
Hz, 1H), 5.07 (t, J = 1.2 Hz, 1H), 4.69−4.65 (m, 1H), 4.21−4.15 (m,
3H), 3.87 (s, 3H), 3.51 (dd, J = 3.2 Hz, 18.4 Hz, 1H), 3.32 (dd, J =
10.8 Hz, 18.4 Hz, 1H), 2.97−2.84 (m, 2H), 1.25 (t, J = 7.2 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ 194.6, 169.8, 164.0, 153.4, 130.4,
Ethyl 2-((2S,3S,4R)-4-(2-(3-Bromophenyl)-2-oxoethyl)-3-nitro-
chroman-2-yl)acetate (3h). Colorless oily solid in an 87% yield (80
mg), >99 ee, dr = 10:1. [α]D20 = −31.0 (c 1.0, CH2Cl2, >99% ee). The
enantiomeric excess was determined by HPLC with an OD-H column
(70/30 n-hexane/i-PrOH), 1.0 mL/min, tR(minor) = 14.9 min, tR(major)
=
1
16.5 min. H NMR (400 MHz, CDCl3): δ 8.09 (t, J = 2.0 Hz, 1H),
7.88 (d, J = 8.0 Hz, 1H), 7.73 (dd, J = 0.8 Hz, 8.0 Hz, 1H), 7.37 (t, J =
8.0 Hz, 1H), 7.20−7.17 (m, 2H), 7.03−6.99 (m, 1H), 6.89−6.87 (m,
1H), 5.05 (s, 1H), 4.67−4.63 (m, 1H), 4.23−4.15 (m, 3H), 3.54 (dd, J
= 3.2 Hz, 18.8 Hz, 1H), 3.36 (dd, J = 10.8 Hz, 19.2 Hz, 1H), 3.00−
2.86 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3):
δ 194.9, 169.9, 153.4, 137.5, 136.7, 131.2, 130.4, 128.7, 128.2, 126.6,
123.2, 122.4, 121.8, 117.1, 83.4, 68.4, 61.2, 45.4, 36.2, 33.1, 14.1. IR
129.0, 128.8, 128.0, 122.3, 122.2, 117.0, 113.9, 83.6, 68.4, 61.1, 55.5,
44.9, 36.4, 33.3, 14.0. IR (KBr): 2957, 2925, 2847, 1733, 1673, 1600,
1552, 1512, 1354, 1262, 1242, 1174, 1112, 1027, 834, 760 cm−1.
HRMS (ESI) for C22H27N2O7 [M + NH4]+: calcd, 431.1813; found,
431.1821.
Ethyl 2-((2S,3S,4R)-4-(2-(3-Methoxyphenyl)-2-oxoethyl)-3-nitro-
chroman-2-yl)acetate (3d). Colorless oily solid in an 84% yield (69
mg), >99% ee, dr = 9:1. [α]D20 = −30.0 (c 1.0, CH2Cl2, >99% ee). The
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1
(KBr): 2959, 1732, 1688, 1552, 1490, 1353, 1226, 1194, 1024, 791,
758 cm−1. HRMS (ESI) for C21H24BrN2O6 [M + NH4]+: calcd,
479.0812; found, 479.0823.
Ethyl 2-((2S,3S,4R)-4-(2-(2-Chlorophenyl)-2-oxoethyl)-3-nitro-
chroman-2-yl)acetate (3i). Colorless oily solid in an 80% yield (67
mg), ee = 97%, dr = 9:1. [α]D20 = −51.0 (c 1.0, CH2Cl2, 97% ee). The
enantiomeric excess was determined by HPLC with an OD-H column
tR(major) = 14.7 min. H NMR (400 MHz, CDCl3): δ 7.98−7.96 (m,
2H), 7.60 (d, J = 7.2 Hz, 1H), 7.51−7.47 (m, 2H), 6.98 (d, J = 7.2 Hz,
2H), 6.77 (d, J = 8.8 Hz, 1H), 5.04 (d, J = 1.2 Hz, 1H), 4.65−4.61 (m,
1H), 4.17 (dd, J = 7.2 Hz, 14.4 Hz, 3H), 3.58 (dd, J = 3.2 Hz, 18.8 Hz,
1H), 3.38 (dd, J = 10.8 Hz, 18.8 Hz, 1H), 2.98−2.84 (m, 2H), 2.29 (s,
3H), 1.25 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 196.3,
169.9, 151.3, 135.9, 133.9, 131.7, 129.0, 128.9, 128.8, 128.1, 121.7,
116.8, 83.6, 68.4, 61.1, 45.4, 36.4, 33.2, 20.6, 14.1. IR (KBr): 3060,
2957, 1732, 1683, 1552, 1450, 1355, 1226, 1189, 1025, 818, 758 cm−1.
HRMS (ESI) for C22H27N2O6 [M + NH4]+: calcd, 415.1864; found,
415.1871.
(70/30 n-hexane/i-PrOH), 1.0 mL/min, tR(minor) = 12.0 min, tR(major)
=
1
14.0 min. H NMR (400 MHz, CDCl3): δ 7.54 (d, J = 7.6 Hz, 1H),
7.44−7.43 (m, 2H), 7.38−7.34 (m, 1H), 7.22−7.18 (m, 1H), 7.17−
7.15 (m, 1H), 7.02−6.98 (m, 1H), 6.86 (d, J = 8.4 Hz, 1H), 5.13 (s,
1H), 4.69−4.65 (m, 1H), 4.24−4.19 (m, 3H), 3.55 (dd, J = 3.6 Hz,
18.8 Hz, 1H), 3.39 (dd, J = 10.4 Hz, 18.8 Hz, 1H), 3.02−2.89 (m,
2H), 1.29 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 199.6,
169.8, 153.3, 138.0, 132.5, 131.0, 130.7, 129.2, 128.7, 128.2, 127.2,
122.4, 121.7, 117.1, 83.2, 68.5, 61.2, 49.4, 36.2, 33.5, 14.1. IR (KBr):
3066, 2957, 1733, 1699, 1552, 1489, 1352, 1282, 1191, 1028, 758
cm−1. HRMS (ESI) for C21H24ClN2O6 [M + NH4]+: calcd, 435.1317;
found, 435.1316.
Ethyl 2-((2S,3S,4R)-6-Methoxy-3-nitro-4-(2-oxo-2-phenylethyl)-
chroman-2-yl)acetate (3n). Colorless oily solid in an 82% yield (68
mg), >99% ee, dr = 12:1. [α]D20 = −11.0 (c 1.0, CH2Cl2, >99% ee). The
enantiomeric excess was determined by HPLC with an AS-H column
(80/20 n-hexane/i-PrOH), 1.0 mL/min, tR(major) = 24.7 min, tR(minor)
=
1
30.3 min. H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 7.2 Hz, 2H),
7.63−7.59 (m, 1H), 7.48 (t, J = 8.0 Hz, 2H), 6.81 (d, J = 8.8 Hz, 1H),
6.76−6.70 (m, 2H), 5.03 (s, 1H), 4.64−4.60 (m, 1H), 4.21−4.13 (m,
3H), 3.74 (s, 3H), 3.57 (dd, J = 3.2 Hz, 18.8 Hz, 1H), 3.39 (dd, J =
10.8 Hz, 18.8 Hz, 1H), 2.96−2.84 (m, 2H), 1.25 (t, J = 7.2 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ 196.2, 169.9, 154.6, 147.4, 135.9,
133.9, 128.8, 128.0, 122.7, 117.8, 114.2, 113.0, 83.5, 68.6, 61.1, 55.6,
55.5, 45.2, 36.3, 33.5, 14.0. IR (KBr): 3062, 2956, 1731, 1682, 1552,
1354, 1276, 1040, 812, 758, 690 cm−1. HRMS (ESI) for C22H27N2O7
[M + NH4]+: calcd, 431.1813; found, 431.1819.
Ethyl 2-((2S,3S,4R)-4-(2-(2-Fluorophenyl)-2-oxoethyl)-3-nitro-
chroman-2-yl)acetate (3j). Colorless oily solid in an 85% yield (68
mg), >99% ee, dr = 9:1. [α]D20 = −41.0 (c 1.0, CH2Cl2, >99% ee). The
enantiomeric excess was determined by HPLC with an OD-H column
(70/30 n-hexane/i-PrOH), 1.0 mL/min, tR(minor) = 9.7 min, tR(major)
=
15.2 min. 1H NMR (400 MHz, CDCl3): δ 7.99−7.94 (m, 1H), 7.60−
7.55 (m, 1H), 7.30−7.26 (m, 1H), 7.22−7.13 (m, 3H), 7.03−6.99 (m,
1H), 6.87 (d, J = 8.0 Hz, 1H), 5.08 (s, 1H), 4.69−4.65 (m, 1H), 4.23−
4.16 (m, 3H), 3.63−3.57 (m, 1H), 3.42−3.34 (m, 1H), 2.99−2.86 (m,
2H), 1.27 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 194.5,
194.4, 169.8, 163.5, 161.0, 153.4, 135.6, 135.5, 130.8, 128.8, 128.0,
124.8, 124.7, 124.5, 124.3, 122.3, 121.9, 117.0, 116.9, 116.7, 83.5, 68.4,
61.1, 50.1, 50.0, 36.3, 33.3, 33.2, 14.1. IR (KBr): 3070, 2957, 1734,
1683, 1552, 1454, 1357, 1282, 1191, 1026, 761 cm−1. HRMS (ESI) for
C21H24FN2O6 [M + NH4]+: calcd, 419.1613; found, 419.1624.
Ethyl 2-((2S,3S,4R)-6-Chloro-3-nitro-4-(2-oxo-2-phenylethyl)-
chroman-2-yl)acetate (3k). Colorless oily solid in an 84% yield (70
mg), >99% ee, dr = 7:1. [α]D20 = −10.0 (c 1.0, CH2Cl2, >99% ee). The
enantiomeric excess was determined by HPLC with an OD-H column
Ethyl 2-((2S,3S,4R)-7-Methyl-3-nitro-4-(2-oxo-2-phenylethyl)-
chroman-2-yl)acetate (3o). Colorless oily solid in an 87% yield (69
mg), dr = 8:1. [α]2D0 = −47.0 (c 1.0, CH2Cl2, 95% ee). The
enantiomeric excess was determined by HPLC with an OD-H column
(90/10 n-hexane/i-PrOH), 1.0 mL/min, tR(minor) = 22.4 min, tR(major)
=
1
25.6 min. H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 7.6 Hz, 2H),
7.60 (t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.07 (d, J = 8.0 Hz,
1H), 6.82 (d, J = 7.6 Hz, 1H), 6.71 (s, 1H), 5.05 (s, 1H), 4.65 (t, J =
6.8 Hz, 1H), 4.17 (dd, J = 7.2 Hz, 14.0 Hz, 3H), 3.45 (dd, J = 7.2 Hz,
18.8 Hz, 1H), 3.35 (dd, J = 10.8 Hz, 18.8 Hz, 1H), 2.97−2.83 (m,
2H), 2.29 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 196.3, 169.9, 153.2, 138.3, 135.9, 133.8, 128.8, 128.5, 128.0,
123.4, 118.9, 117.4, 83.7, 68.4, 61.1, 45.3, 36.4, 33.0, 21.0, 20.9, 14.1.
IR (KBr): 3060, 2957, 1733, 1683, 1552, 1450, 1352, 1189, 1026, 807,
745 cm−1. HRMS (ESI) for C22H27N2O6 [M + NH4]+: calcd,
415.1864; found, 415.1870.
(70/30 n-hexane/i-PrOH), 1.0 mL/min, tR(minor) = 12.0 min, tR(major)
=
22.6 min. 1H NMR (400 MHz, CDCl3): δ 7.97−7.95 (m, 2H), 7.62 (t,
J = 7.2 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.18 (d, J = 2.4 Hz, 1H), 7.13
(dd, J = 2.4 Hz, 8.8 Hz, 1H), 6.81 (d, J = 8.8 Hz, 1H), 5.06 (d, J = 1.2
Hz, 1H), 4.66−4.62 (m, 1H), 4.16 (dd, J = 7.2 Hz, 14.4 Hz, 3H), 3.54
(dd, J = 3.2 Hz, 18.8 Hz, 1H), 3.38 (dd, J = 10.8 Hz, 18.8 Hz, 1H),
2.97−2.84 (m, 2H), 1.25 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 195.8, 169.7, 152.0, 135.7, 134.0, 128.9, 128.4, 128.2, 128.1,
127.1, 123.8, 118.5, 83.1, 68.6, 61.2, 45.1, 36.2, 33.2, 14.0. IR (KBr):
3063, 2957, 1732, 1683, 1553, 1484, 1354, 1235, 1194, 1025, 818, 757
cm−1. HRMS (ESI) for C21H24ClN2O6 [M + NH4]+: calcd, 435.1317;
found, 435.1313.
Ethyl 2-((2S,3S,4R)-4-(2-(Furan-2-yl)-2-oxoethyl)-7-methyl-3-ni-
trochroman-2-yl)acetate (3p). Colorless oily solid in an 80 yield
(60 mg), dr = 8:1. [α]D20 = −79.0 (c 1.0, CH2Cl2, >99% ee). The
enantiomeric excess was determined by HPLC with an AS-H column
(90/10 n-hexane/i-PrOH), 1.0 mL/min, tR(major) = 44.1 min, tR(minor)
=
1
51.0 min. H NMR (400 MHz, CDCl3): δ 7.60 (d, J = 1.2 Hz, 1H),
7.27 (d, J = 3.6 Hz, 1H), 7.22−7.15 (m, 2H), 7.02−6.98 (m, 1H), 6.86
(d, J = 8.4 Hz, 1H), 6.57 (dd, J = 1.6 Hz, 3.6 Hz, 1H), 5.08 (s, 1H),
4.71−4.67 (m, 1H), 4.23−4.15 (m, 3H), 3.55 (dd, J = 3.6 Hz, 18.0 Hz,
1H), 3.22 (dd, J = 10.8 Hz, 18.0 Hz, 1H), 3.00−2.86 (m, 2H), 1.28 (t,
J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 185.5, 169.8, 153.3,
152.0, 146.9, 128.8, 128.1, 122.3, 121.8, 117.9, 117.1, 112.7, 83.4, 68.4,
61.2, 44.9, 36.3, 33.0, 14.0. IR (KBr): 3135, 2983, 1733, 1673, 1552,
1466, 1397, 1283, 1189, 1024, 761 cm−1. HRMS (ESI) for
C19H23N2O7 [M + NH4]+: calcd, 391.1500; found, 391.1490.
Ethyl 2-((2S,3S,4R)-6-Bromo-3-nitro-4-(2-oxo-2-phenylethyl)-
chroman-2-yl)acetate (3l). Colorless oily solid in an 84% yield (78
mg), >99% ee, dr = 7:1. [α]D20 = −5.0 (c 1.0, CH2Cl2, >99% ee). The
enantiomeric excess was determined by HPLC with an OD-H column
(70/30 n-hexane/i-PrOH), 1.0 mL/min, tR(minor) = 10.5 min, tR(major)
=
1
19.6 min. H NMR (400 MHz, CDCl3): δ 7.96 (d, J = 7.6 Hz, 2H),
7.62 (t, J = 7.2 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H), 7.33−7.26 (m, 2H),
6.76 (d, J = 8.8 Hz, 1H), 5.06 (s, 1H), 4.64 (t, J = 6.8 Hz, 1H), 4.17
(dd, J = 7.2 Hz, 14.4 Hz, 3H), 3.54 (dd, J = 3.2 Hz, 18.8 Hz, 1H), 3.38
(dd, J = 10.8 Hz, 18.8 Hz, 1H), 2.97−2.84 (m, 2H), 1.25 (t, J = 7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 195.8, 169.7, 152.6, 135.7,
134.0, 131.4, 131.1, 128.9, 128.1, 124.3, 118.9, 114.4, 83.1, 68.6, 61.3,
45.1, 36.2, 33.1, 14.0. IR (KBr): 3062, 2956, 1732, 1683, 1552, 1481,
1354, 1275, 1193, 1025, 817, 752, 691 cm−1. HRMS (ESI) for
C21H20BrNaNO6 [M + Na]+: calcd, 484.0366; found, 484.0371.
Ethyl 2-((2S,3S,4R)-6-Methyl-3-nitro-4-(2-oxo-2-phenylethyl)-
chroman-2-yl)acetate (3m). Colorless oily solid in an 86% yield
(68 mg), >99% ee, dr = 9:1. [α]2D0 = −11.0 (c 1.0, CH2Cl2, >99% ee).
The enantiomeric excess was determined by HPLC with an OD-H
column (70/30 n-hexane/i-PrOH), 1.0 mL/min, tR(minor) = 10.6 min,
Ethyl 2-((2S,3S,4R)-7-Methyl-3-nitro-4-(2-oxo-2-(thiophen-2-yl)-
ethyl)chroman-2-yl)acetate (3q). Colorless oily solid in an 85%
yield (66 mg), >99% ee, dr = 7:1. [α]2D0 = −60.0 (c 1.0, CH2Cl2, >99%
ee). The enantiomeric excess was determined by HPLC with an AS-H
column (70/30 n-hexane/i-PrOH), 1.0 mL/min, tR(major) = 21.1 min,
1
tR(minor) = 24.3 min. H NMR (400 MHz, CDCl3): δ 7.74−7.70 (m,
2H), 7.26−7.15 (m, 3H), 7.03−6.99 (m, 1H), 6.89−6.87 (m, 1H),
5.10 (t, J = 1.2 Hz, 1H), 4.71−4.67 (m, 1H), 4.19 (dd, J = 7.2 Hz, 14.0
Hz, 3H), 3.52 (dd, J = 3.6 Hz, 18.0 Hz, 1H), 3.31 (dd, J = 10.8 Hz,
18.0 Hz, 1H), 3.00−2.87 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ 189.1, 169.9, 153.4, 143.0, 134.7, 132.5, 128.8,
128.4, 128.2, 122.4, 121.8, 117.1, 83.4, 68.4, 61.2, 45.7, 36.4, 33.4, 14.1.
IR (KBr): 3094, 2958, 1773, 1660, 1552, 1415, 1282, 1190, 1026, 856,
F
dx.doi.org/10.1021/jo400476b | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
759, cm−1. HRMS (ESI) for C19H23N2O6S [M + NH4]+: calcd,
407.1271; found, 407.1279.
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2255.
Ethyl 2-((2S,3S,4R)-6-Bromo-4-(2-(4-bromophenyl)-2-oxoethyl)-
3-nitrochroman-2-yl)acetate (3s). White solid in an 82% yield (86
mg), >99% ee, dr = 9:1. Mp: 99−101 °C. [α]2D0 = −15.0 (c 1.0,
CH2Cl2, >99% ee). The enantiomeric excess was determined by
HPLC with an OD-H column (70/30 n-hexane/i-PrOH), 1.0 mL/
1
min, tR(minor) = 15.5 min, tR(major) = 35.9 min. H NMR (400 MHz,
CDCl3): δ 7.83 (d, J = 8.8 Hz, 2H), 7.64 (d, J = 8.4 Hz, 2H), 7.33−
7.29 (m, 2H), 6.77 (d, J = 8.8 Hz, 1H), 5.04 (s, 1H), 4.62 (t, J = 6.4
Hz, 1H), 4.18 (q, J = 6.8 Hz, 3H), 3.51 (dd, J = 3.2 Hz, 18.8 Hz, 1H),
3.35 (dd, J = 10.8 Hz, 18.8 Hz, 1H), 2.98−2.85 (m, 2H), 1.26 (t, J =
7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 194.8, 169.8, 152.5,
134.4, 132.2, 132.1, 131.3, 131.2, 129.5, 129.3, 124.1, 118.9, 114.5,
82.9, 68.6, 45.0, 36.1, 33.0, 14.1. IR (KBr): 3436, 2927, 1724, 1688,
1551, 1416, 1237, 1192, 1071, 811 cm−1. HRMS (ESI) for
C21H19Br2NO6Na [M + Na]+: calcd, 561.9471; found, 561.9469.
Synthesis of Tricyclic Chroman 4a by Reductive Amination
Reaction. Zinc powder (30 equiv, 390 mg) was added in portions to a
solution of 3a (77 mg, 0.2 mmol) in AcOH (2 mL) at 55 °C. The
resultant mixture was stirred for 2.0 h at 65 °C (monitored by TLC).
After the zinc powder was filtered off, the filtrate was cooled to 0 °C.
The filtrate was diluted with ethyl acetate and neutralized by the
addition of saturated sodium hydrogen carbonate. The mixture was
extracted with dichloromethane, washed with brine, and dried with
sodium sulfate. Concentration and flash chromatography (1:4 ethyl
acetate/hexane) afforded 4a as a colorless oil in a 78% yield (53 mg),
>99% ee, dr = 18:1.
Ethyl 2-((2S, 3aS, 4S, 9bR)-2-Phenyl-1, 2, 3, 3a, 4, 9b-
hexahydrochromeno[3,4-b]pyrrol-4-yl)acetate (4a). Colorless oil in
a 78% yield (53 mg), >99% ee, dr = 18:1. [α]2D0 = −80.0 (c 1.0,
CH2Cl2, >99% ee). The enantiomeric excess was determined by
HPLC with an OD-H column (80/20 n-hexane/i-PrOH), 1.0 mL/
1
min, tR(major) = 11.5 min, tR(minor) = 17.3 min. H NMR (400 MHz,
(6) For reviews of organocatalyzed cascade reactions, see: (a) Guo,
CDCl3): δ 7.34−7.31 (m, 4H), 7.28−7.25 (m, 1H), 7.14 (t, J = 7.6 Hz,
1H), 7.03 (d, J = 7.6 Hz, 1H), 6.87 (t, J = 7.6 Hz, 2H), 5.13−5.09 (m,
1H), 4.55 (dd, J = 6.4 Hz, 9.6 Hz, 1H), 4.18 (dd, J = 7.2 Hz, 14.0 Hz,
2H), 3.75 (dd, J = 5.2 Hz, 11.6 Hz, 1H), 3.05−2.97 (m, 1H), 2.91 (dd,
J = 4.8 Hz, 16.0 Hz, 1H), 2.85−2.79 (m, 1H), 2.60 (dd, J = 4.8 Hz,
16.0 Hz, 1H), 1.92−1.84 (m, 1H), 1.74 (s, 1H), 1.26 (t, J = 7.2 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 171.7, 152.9, 145.8, 128.9,
127.9, 127.4, 126.4, 125.9, 124.6, 120.1, 116.4, 63.2, 61.2, 60.6, 38.2,
37.3, 34.9, 14.2. IR (KBr): 3352, 2957, 1733, 1485, 1299, 115, 1033,
758, 701 cm−1. HRMS (ESI) for C21H24NO3 [M + H]+: calcd,
338.1751; found, 338.1756.
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ASSOCIATED CONTENT
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* Supporting Information
Chiral HPLC chromatograms of 3 and 4a, X-ray crystallo-
1
graphic data for 3s (CIF), and H and 13C NMR spectra. This
(9) CCDC 859341 (3s) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
material is available free of charge via the Internet at http://
pubs.acs.org.
́ ́
(10) (a) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org. Lett. 2005,
AUTHOR INFORMATION
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7, 1967. (b) Corey, E. J.; Zhang, F.-Y. Org. Lett. 2000, 2, 4257.
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Corresponding Author
*E-mail: Y.-C.L., luoych@lzu.edu.cn; P.-F.X., xupf@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the NSFC (21032005, 21172097,
21202070), the International S&T Cooperation Program of
China (2013DFR70580), the National Basic Research Program
of China (2010CB833203), the “111” program from MOE of
P. R. China, and a Syngenta fellowship to Z.-X.J.
G
dx.doi.org/10.1021/jo400476b | J. Org. Chem. XXXX, XXX, XXX−XXX