Synthesis of substituted chiral chromans via organocatalytic kinetic resolution of racemic 3-nitro-2-aryl-2H-chromenes with ketones catalyzed by pyrrolidinyl-camphor-derived organocatalysts

Article abstract of DOI:10.1016/j.tet.2012.05.019

Efficient kinetic resolution of racemic 2-aryl-3-nitro-2H-chromenes (1a-l) has been explored with the pyrrolidinyl-camphor derivative 2b as a bifunctional organocatalyst under neat conditions in the presence of AcOH at 0 °C. In general, the organocatalytic asymmetric Michael addition of ketones proceeded smoothly to give the functionalized Michael adducts (3a-n) with good-to-high diastereo- and enantioselectivities (up to 92:8 dr, 93% ee, and 47% yield). The less reactive chromenes (S)-1a-h, k, l and (R)-1i-j were recovered in high chemical yields and moderate optical purity (up to 42% chemical yield and 72% ee).

Full text of DOI:10.1016/j.tet.2012.05.019

Tetrahedron 68 (2012) 5810e5816
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of substituted chiral chromans via organocatalytic kinetic resolution
of racemic 3-nitro-2-aryl-2H-chromenes with ketones catalyzed
by pyrrolidinyl-camphor-derived organocatalysts
*
Dhananjay R. Magar, Kwunmin Chen
Department of Chemistry, National Taiwan Normal University, Taipei 116, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
Efficient kinetic resolution of racemic 2-aryl-3-nitro-2H-chromenes (1ael) has been explored with the
pyrrolidinyl-camphor derivative 2b as a bifunctional organocatalyst under neat conditions in the presence
of AcOH at 0 ꢀC. In general, the organocatalytic asymmetric Michael addition of ketones proceeded
smoothly to give the functionalized Michael adducts (3aen) with good-to-high diastereo- and enantio-
selectivities (up to 92:8 dr, 93% ee, and 47% yield). The less reactive chromenes (S)-1aeh, k, l and (R)-1iej
were recovered in high chemical yields and moderate optical purity (up to 42% chemical yield and 72% ee).
Ó 2012 Published by Elsevier Ltd.
Received 17 February 2012
Received in revised form 18 April 2012
Accepted 4 May 2012
Available online 12 May 2012
Keywords:
Kinetic resolution
Organocatalysis
Michael addition
Chromenes
Chromans
1. Introduction
a selective reaction of one enantiomer through a difference in the
reaction rate of the two enantiomers.7 Several metal-mediated ki-
Optically-active chromenes and chromans are important struc-
tural motifs in many complex natural products and pharma-
ceutically-important drug substances with useful biological
activities.1 Therefore, numerous methodologies have been de-
veloped to synthesize these privileged structures.2,3 Of special in-
terest are 3-nitro-2H-chromenes because they are potentially as
useful pesticides, endothelin-A (ETA)-selective receptor antago-
nists, highly potent antihypertensive drugs and important in-
termediates in the synthesis of medicinally-active 2H-benzopyran
derivatives.4 Chiral chromenes have previously been prepared via
kinetic resolution, the dehydrogenation of chromans, by ring-
closing metathesis and by intramolecular acid catalyzed cycliza-
tions of aldehydes and aromatic rings.5 In addition, the oxa-
netic resolution methods are now well established and docu-
mented.8 In contrast, the use of small organic molecules as chiral
catalysts for asymmetric KR processes has only recently emerged as
a practical synthetic approach.9 The creation of new chiral centers
in the products during kinetic resolution via organocatalysis is
conceptually novel and worth pursuing. In the best working sce-
nario, and also with regard to efficient atom economy, both the
product and the unreacted enantiomeric substrate must be
obtained in high chemical yield and optical purity. Recently, Xie and
co-workers have reported the kinetic resolution of 3-nitro-2H-
chromenes through the [3þ2]-cycloadditions of azomethine ylides.
Although the less reactive 3-nitro-2-aryl-2H-chromenes were re-
covered with good optical purity, low-to-moderate stereo-
selectivities of the chiral chroman derivatives were obtained.9a
On the other hand, tremendous efforts have been made towards
developing cascade strategies for the preparation of functionalized
chiral chroman scaffolds.10 Chiral substituted chromans can be
easily prepared by nucleophilic 1,4-addition to chromenes. Michael
addition of dialkylmalonate to chromenes has been reported re-
cently by Yan’s group, and also by Li’s group, as proceeding with
good chemical yield and enantioselectivity.11 As part of our general
research effort in the arena of asymmetric organocatalysis,12 we
wish to present here an organocatalytic Michael addition of cy-
clohexanone to racemic 3-nitro-2-aryl-2H-chromenes for the
Michael-aldol reaction of salicylaldehyde with a,b-unsaturated al-
dehydes/ketones or nitroalkenes is one of the most general
strategies developed so far to such structures.6 However, the
organocatalytic asymmetric synthesis of functionalized chromans
of high optical purity has so far remained elusive.
Kinetic resolution (KR) remains a highly useful protocol for the
preparation of enantiomerically-enriched substances from racemic
starting materials. The process involves a chiral agent promoting
* Corresponding author. Tel.: þ886 2 7734 6124; fax: þ886 2 2932 4249; e-mail
address: kchen@ntnu.edu.tw (K. Chen).
0040-4020/$ e see front matter Ó 2012 Published by Elsevier Ltd.
doi:10.1016/j.tet.2012.05.019

D.R. Magar, K. Chen / Tetrahedron 68 (2012) 5810e5816
5811
Table 1
production of multi-functionalized chiral chromans bearing four
contiguous stereocenters. During this process, 3-nitro-2-aryl-2H-
chromenes (1ael) were resolved with moderate to good optical
purity and high chemical yield.
Catalysts-screening for the kinetic resolution of racemic 3-nitro-2-phenyl-2H-
chromene 1aa
O
O
NO2
Cat 2 (20 mol-%)
H
H
NO2
Ph
neat, rt.
2. Results and discussion
O
O
Ph
(S)-1a
Various organocatalysts, including camphor-based pyrrolidine
rac-1a
3a
(2aek) -proline (2lem), diarylprolinol trimethylsilyl ether (2n),
L
and thiourea catalyst 2o, have proven extremely useful in chiral
enamine catalysis in recent years (Fig. 1). Our previous studies have
indicated that pyrrolidinyl-camphor derivatives 2a and 2b are ef-
ficient bifunctional organocatalysts for the Michael addition of
Entry Cat. t/d Conv.
(%)b
Recovered (S)-1a
Michael adduct 3a
Yield (%)c ee (%)d Yield (%)c ee (%)d drb
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
3
3
5
5
5
5
5
4
2
3
2
6
6
3
5
73
40
24
44
52
31
d
9
40
36
ND
19
ND
19
27
22
28
d
81
90
d
78
d
75
86
74
49
d
66
75
d
d
d
75:25
84:16
d
ketones to a,b
-unsaturated compounds.12c,d Therefore, we began
Traces ND
25 60
Traces ND
25
37
31
52
Traces ND
50
14
our investigations on the kinetic resolution of racemic chromenes
by exploring the catalytic effects of pyrrolidinyl-camphor-derived
organocatalysts. The racemic 3-nitro-2-phenyl-2H-chromenes (1a)
and cyclohexanone were used as model substrates.
70:30
d
d
21
20
14
25
d
2
12
d
d
d
57
58
60
38
75:25
88:12
69:31
65:35
d
9
R
R
Me
Me
Me
Me
10
11
12
13
14
15
O
S
45
79
23
10
d
66:34
77:23
d
S
N
H
N
H
X
X
H
H
O
Traces ND
Traces ND
NR
Y
Y
2a: R = OH, X = Y = O
d
d
2e: R = OTBDPS, X = Y = O
2b: R = OH, X = H, Y = OH
2c: R = H, X = Y = O
d
d
d
2f: R = OTBDPS, X = H, Y = OH
2d: R = H, X = H, Y = OH
a
Unless otherwise noted all reactions were carried out with racemic 1a
(0.2 mmol), cyclohexanone (10 mmol), and organocatalyst (20 mol %) under neat
conditions at ambient temperature.
Me
R
Me
Me
O
O
H
O
O
Me
S
Me
Me
b
Based on 1H NMR analysis of crude mixture.
N
N
H
N
H
N
H
N
H
N
H
H
H
H
H
X
c
H
Isolated yield.
OH
OH
Y
d
Determined by HPLC analysis.6b
2g: X = Y = O
2h: X = H, Y = OH
2j: R = H
2i
2k: R = OH
CF3
R
O
S
catalyze the reaction (Table 1, entries 12 and 13). Almost no reaction
was observed when diphenylprolinol trimethylsilyl ether was used
(Table 1, entry 14). In the presence of the thiourea catalyst 2o, no
reaction took place (Table 1, entry 15). As a result of this extensive
catalyst screening, derivative 2b was found to be the catalyst of
choice for the kinetic resolution of racemic 1a.
Ph
Ph
H OTMS
OH
N
H
N
H
CF3
N
H
N
H
N
H
H
2o
2n
2l: R = H
2m: R = OH
Fig. 1. Structures of organocatalysts 2aeo.
Next, we examined the effect of performing kinetic resolution
with catalyst 2b (20 mol %) in different solvents. The results are
depicted in Table 2. The Michael adduct was isolated with low
The sulfide-linked trans-4-hydroxy-pyrrolidinyl-camphor de-
rivative 2a (20 mol %) was first examined under neat reaction
conditions at ambient temperature. The results are shown in
Table 1. The desired Michael adduct 3a was obtained in high
chemical yield (40%) with good stereoselectivity (81% ee and 75:25
dr) (Table 1, entry 1). The less reactive chromene 1a was isolated
with moderate enantioselectivity. High stereoselectivities of the
Michael adduct 3a (90% ee, 84:16 dr) and recovered chromene 1a
were obtained alongside high chemical yields when the C2-hydroxy
(camphor numbering) analogue catalyst 2b was employed (Table 1,
entry 2). The use of catalyst 2c, containing a C-2 ketone, gave trace
amounts of the product, while the use 2d, with a C-2 hydroxyl
group, restored stereoselectivity (Table 1, entries 3 and 4).
Next, we examined the sulfone- and sulfonamide-linked pyr-
rolidinyl-camphor derivatives 2eeh. Although no adduct was ob-
served in the presence of 2e, the use 2feh produced Michael
adducts with comparable stereoselectivity (Table 1, entries 5e8).
The amide-linked catalyst 2i afforded 3a with decreased stereo-
control (Table 1, entry 9). No desired Michael adduct was isolated
when amide-linked 2j was used over 3 days (Table 1, entry 10). On
the other hand, good results were observed when a C4 hydroxy-
containing pyrrolidine ring catalyst 2k was used in the above
process (Table 1, entry 11). This indicates the C2-hydroxy func-
tionality of the pyrrolidinyl-camphor catalysts plays a crucial role in
determining the stereochemical outcome (compare Table 1, entries
1 and 2). Contrastingly, although good selectivity was observed
Table 2
Solventscreeningforkinetic resolution of racemic 3-nitro-2-phenyl-2H-chromene 1aa
O
O
NO2
Cat 2b (20 mol%)
H
H
NO2
Ph
solvent, rt.
O
O
Ph
(S)-1a
rac-1a
3a
Entry Solvent t/d Conv. Recovered (S)-1a
Michael adduct 3a
(%)b
Yield (%)c ee (%)d Yield (%)c ee (%)d drb
1
2
3
4
5
6
7
8
9
CH2Cl2
CHCl3
Toluene
CH3CN
MeOH
H2O
Ether
TBME
THF
6
8
6
6
8
4
6
6
6
29
d
8
56
3
21
d
d
d
d
22
12
10
d
85
d
d
d
d
79
85
80
d
67:33
d
ND
ND
ND
ND
56
54
58
ND
d
d
d
d
16
8
d
4
d
d
26
14
14
d
d
85:15
81:19
89:11
d
7
d
a
Unless otherwise noted all reactions were carried out with rac-1a (0.2 mmol),
cyclohexanone (10 mmol), and organocatalyst (20 mol %) at ambient temperature in
the solvent indicated.
b
Based on 1H NMR analysis of crude product.
c
Isolated yield.
d
when
L-proline 2l was used, trans-4-hydroxy proline (2m) failed to
Determined by HPLC analysis.6b

5812
D.R. Magar, K. Chen / Tetrahedron 68 (2012) 5810e5816
selectivity when the reaction was conducted in CH2Cl2 (Table 2,
entry 1). No reaction product was observed when CHCl3 was used
(Table 2, entry 2). Very low conversions were observed by crude 1H
NMR analyses when toluene, CH3CN and MeOH were employed as
reaction solvents (Table 2, entries 3e5). Moderate enantiose-
lectivity of the Michael adduct 3a was observed in water, but the
optical purity of 1a was found to be low (Table 2, entry 6). Com-
parable results were observed when diethyl ether and TBME (tert-
butyl methyl ether) were used (Table 2, entries 7 and 8). The
chemical structure and stereochemistry of the chiral chroman 3a so
obtained was fully characterized by IR, 1H-, 13C NMR, HRMS anal-
yses and the absolute stereochemistry was further confirmed by
single-crystal X-ray analysis (Table 4).13
Based on these preliminary results, we further optimized the
reaction conditions and our results are shown in Table 3. As
expected, the reaction proceeded faster in the presence of benzoic
acid as an additive (20 mol %) (Table 3, entry 1). The Michael adduct
3a was isolated in 81% ee and the ee of the recovered chromene (S)-
1a was enhanced to 38%. Only trace amounts of the Michael
product 3a were obtained when 3,5-DNBA (3,5-dinitrobenzoic
acid), p-TsOH, and CF3COOH were added (Table 3, entries 2e4).
This might be due to protonation of the organocatalyst in a manner
that hampers enamine formation. The optical purity of the less
reactive chromene 1a was enhanced to 52% ee when acetic acid
(20 mol %) was added (Table 3, entry 5). A slight improvement was
observed when the reaction was performed at 0 ꢀC (Table 3, entry
6). The optimum reaction conditions were realized when 50 mol %
of acetic acid was present at 0 ꢀC (Table 3, entry 7). The desired
Michael adduct 3a was isolated with 90% ee and 88:12 dr, while the
chromene (S)-1a was determined to be 64% ee. By increasing the
amount of acetic acid (100 mol %) in the reaction mixture, com-
parable results were obtained (Table 3, entry 8). Use of propionic
acid as an additive led to a decrease in enantioselectivity of the
product 3a and the recovered chromene 1a (Table 3, entry 9).
With the optimal reaction conditions identified, various sub-
strates were studied to explore the generality of the KR process. A
host of different racemic 3-nitro-2-aryl-2H-chromenes derivatives
(1ael) were subjected to the reaction conditions at 0 ꢀC and the
results are summarized in Table 4. When electron-donating/with-
drawing functional groups were present on the phenyl substituent
of the chromenes (1aem), this had a negligible effect on the re-
action outcome. The phenyl substituted chromene 1a gave Michael
adduct 3a with 90% ee and the recovered chromene (S)-1a was
obtained with 64% ee (Table 4, entry 1). The use of 3-BrC6H5
substituted chromene (1b) gave the Michael adduct 3b with high
enantioselectivity (93% ee) and the recovered chromene was iso-
lated in 72% ee (Table 4, entry 2). Comparable results were obtained
regarding the enantioselectivities of the Michael adducts 3c and 3d
(80% ee) when 4-Cl-phenyl (1c) and 3-Cl-phenyl (1d) were present
(Table 4, entries 3 and 4). The use of starting substrates containing
electron-donating substituents (1eeh) provided the Michael ad-
ducts with comparable stereoselectivity and varying optical pu-
rities for the recovered substrates (Table 4, entries 5e8). When
heterocyclic substituents were present in the starting chromenes
(1i and 1j), this allowed the Michael adducts (3i and 3j) to be
formed with moderate enantioselectivities (76% ee) (Table 4, en-
tries 9 and 10) but the optical purities of the recovered chromenes
1i and 1j were rather low. The Michael adducts of the 6-substituted
chromene derivatives (3k and 3l) were obtained with 88% and 66%
ee, respectively (Table 4, entries 11 and 12). The kinetic resolution
of racemic 3-nitro-2-alkyl-2H-chromene with cyclohexanone was
studied in the presence of catalyst 2b under optimized reaction
conditions. Unfortunately, only trace amount of the corresponding
Michael adduct (R1¼isobutyl, R2¼H) was observed, most of the
chromene remains after 4 days.
To extend the utility of this kinetic resolution, other nucleophilic
partners, such as tetrahydropyran-4-one (X¼O) and tetrahy-
drothiopyran-4-one (X¼S) were also studied. The results are pre-
sented in Scheme 1. In both cases, the Michael adducts were
produced with moderate selectivities (3m: 66% ee with 75:25 dr
and 3n: 71% ee with 60:40 dr).
3. Conclusion
In summary, we have presented an interesting organocatalytic
kinetic resolution protocol for racemic 3-nitro-2-aryl-2H-chro-
menes (1ael) that uses a pyrrolidinyl-camphor-derived organo-
catalyst. The kinetic resolution process affords densely-
functionalized chromans derivatives (3aen) with good-to-high
stereoselectivities (up to 92:8 dr, 93% ee, and 47% yield) and
these possess four contiguous stereogenic chiral centers. Less re-
active substrates are recovered in high chemical yields and mod-
erate optical purity (up to 42% chemical yield and 72% ee). Taking
account of the high importance of the optically-active chroman and
chromene derivatives, this kinetic resolution provides a new route
for the preparation of functionalized chiral chromans and
chromenes.
Table 3
Additives screening for kinetic resolution of 3-nitro-2-phenyl-2H-chromene (1a)a
Cat 2b (20 mol%),
O
additive (20 mol%),
O
H
NO2
Ph
neat, rt.
H
NO2
Ph
O
(S)-1a
O
3a
rac-1a
Additive
t/h Conv. Recovered (S)-1a
Michael adduct 3a
drb
(%)b
Yield (%)c ee (%)d Yield (%)c ee (%)d
1
2
3
4
PhCO2H
3,5-DNBA 72 Traces ND
TsOH
TFA
AcOH
AcOH
36 45
42
38
d
d
d
52
59
64
64
54
40
d
d
d
42
42
40
39
40
81
d
d
d
82
84
90
90
82
79:21
d
4. Experimental
96
4
ND
d
d
72 NR
15 58
38 50
48 50
96 48
29 48
d
4.1. General remarks
5
40
44
42
35
42
79:21
86:14
88:12
88:12
86:14
6e
7e,f AcOH
All reagents were used as purchased from commercial suppliers
without additional purification. IR spectra were recorded on a Per-
kin Elmer 500 spectrometer. NMR spectra were recorded on
a Bruker Avance 400 NMR spectrometer (400 MHz for 1H and
8e,g AcOH
9e
Pr
COOH
a
Unless otherwise noted, all reactions were carried out with rac-1a (0.2 mmol),
cyclohexanone (10 mmol), organocatalyst (20 mol %) and acid additive (20 mol %)
under neat conditions at ambient temperature.
100 MHz for 13C). Chemical shifts are reported in
d parts per million
referenced to an internal TMS standard for 1H NMR and chloro-
form-d (77.0 ppm) for 13C NMR. Optical rotations were measured on
a JASCO P-1010 polarimeter. The X-ray diffraction measurements
were carried out at 298 K on a KAPPA APEX II CCD area detector
b
Based on 1H NMR analysis of the crude mixture.
c
Isolated yield.
d
Determined by HPLC analysis.6b
e
Reactions carried out at 0 ꢀC temperature.
f
system equipped with a graphite monochromator and a Mo-K
a
AcOH used (50 mol %).
AcOH used (100 mol %).
g
ꢀ
fine-focus sealed tube (l¼0.71073 A). Routine monitoring of

D.R. Magar, K. Chen / Tetrahedron 68 (2012) 5810e5816
5813
Table 4
Substrate scope for kinetic resolution of racemic 3-nitro-2-aryl-2H-chromene (1ael) through Michael addition of cyclohexanonea
Entry
R1
R2
t/h
Conv. (%)b
Recovered 1
Michael adduct 3
drb
Yield (%)c
ee (%)d
Yield (%)c
ee (%)d
1
2
3
4
5
6
7
8
Ph
H
H
H
H
H
H
H
H
H
H
OMe
Cl
48
44
44
36
58
28
96
40
52
41
38
29
50
56
52
59
51
52
54
54
54
47
55
56
42 (1a)
38 (1b)
37 (1c)
35 (1d)
37 (1e)
41 (1f)
39 (1g)
39 (1h)
36 (1i)
38 (1j)
37 (1k)
35 (1l)
64
72
54
70
36
72
25
62
52
35
48
72
40 (3a)
45 (3b)
43 (3c)
47 (3d)
41 (3e)
46 (3f)
33 (3g)
38 (3h)
39 (3i)
34 (3j)
41 (3k)
42 (3l)
90
93
80
80
77
81
75
86
76
76
88
66
88:12
89:11
86:14
88:12
85:15
88:12
89:11
92:08
92:08
85:15
88:12
85:15
3-BrC6H4
4-ClC6H4
3-ClC6H4
2-MeOC6H4
3-MeOC6H4
4-MeOC6H4
4-MeC6H4
2-thienyl
2-furyl
9
10
11
12
Ph
Ph
a
Unless otherwise noted, all reactions were carried out with racemic chromene derivative 1ael (0.2 mmol), cyclohexanone (10 mmol), organocatalyst 2b (20 mol %) and
AcOH (50 mol %) under neat conditions at 0 ꢀC.
b
Based on 1H NMR analysis of the crude mixture.
c
Isolated yield.
d
Determined by HPLC analysis.6b
25 ꢀC):
d 7.40e7.36 (m, 5H), 7.25e7.24 (m, 1H), 7.06e7.03 (m, 2H),
X
H
Cat 2b (20 mol-%)
O
X
6.97 (t, J¼7.4 Hz, 1H), 5.50 (d, J¼2.8 Hz, 1H), 5.11 (dd, J¼2.8, 1.9 Hz,
1H), 3.86 (dd, J¼7.8, 1.4 Hz, 1H), 2.76e2.73 (m, 1H), 2.58e2.53 (m,
1H), 2.45e2.41 (m, 1H), 2.16e2.12 (m, 1H), 2.09e2.04 (m, 1H),
2.00e1.97 (m, 1H), 1.75e1.67 (m, 3H); 13C NMR (100 MHz, CDCl3,
AcOH (50 mol-%)
NO2
Ph
O
NO2
CH2Cl2, 0 o
C
H
+
O
O
3m-n
Ph
(S)-1a
rac-1a
25 ꢀC):
d 210.4, 153.9, 135.7, 130.0, 128.7, 128.6, 128.5, 125.7, 121.2,
X = O: 36%; 45% ee
X = S: 53%; 12% ee
118.5, 117.2, 86.5, 73.4, 55.2, 42.7, 38.1, 32.5, 27.9, 25.1; HRMS-ESI:
3m: 31 %; 75:25 dr, 66% ee
3n: 24 %, 60:40 dr, 71% ee
m/z: [MþNa]þ calculated for C21H21NO4Na 374.1368; found
30
374.1360. [
a]
þ72.42 (c 0.16, CH2Cl2). The enantiomeric excess
D
Scheme 1. Ketones scope for kinetic resolution of rac-1a.
was determined by HPLC with a Chiralcel AD-H (i-PrOH/hexanes: 1/
9; flow rate: 1.0 mL/min;
¼254 nm); tR (major)¼20.8 min; tR
(minor)¼29.6 min; Crystal data for 3a at 200 K: C21H21NO4, M
l
reactions was performed using silica gel, glass-backed TLC plates
(Merck Kieselgel 60 F254) and visualized by UV light (254 nm).
Solutions were evaporated to dryness under reduced pressure on
a rotary evaporator and the residues purified by flash column
chromatography on silica gel (230e400 mesh) with the indicated
eluents. All starting chromenes derivatives were synthesized by
literature methods.3c,f
ꢀ
ꢀ
351.39, triclinic, ‘Pꢁ1’, a¼9.2231(2) A, b¼9.9837(2) A,
ꢀ
c¼10.6747(3) A,
a
¼112.873(1),
b
¼92.635(1),
g
¼99.551(1),
3
ꢀ
ꢀ
V¼886.46(4) A , Z¼2,
l
¼0.71073 A, 3097 reflections, 235 parame-
ters, R¼0.0442, Rw¼0.1560 for all data; recovered starting material,
(S)-3-nitro-2-phenyl-2H-chromene (1a): 21 mg, 42% yield; spectro-
scopic data are in agreement with the literature data;3
HRMS(FABþ): m/z: [MþH]þ calculated for C15H12NO3 254.0817;
found 254.0822. The enantiomeric excess was determined by HPLC
with a Chiralcel AS-H (i-PrOH/hexanes: 2/98; flow rate: 1.0 mL/
4.2. Typical reaction procedure
To the catalyst 2b (11.2 mg, 20 mol %) in a glass vial was added
min;
l
¼254 nm); tR (major)¼28.4 min; tR (minor)¼14.1 min.
cyclohexanone (193.1
2H-chromene 1a (50 mg, 0.2 mmol) in one portion at 0 ꢀC. After
stirring for 10 min, the clear solution was added CH3COOH (6 L,
mL, 10 mmol) and racemic 3-nitro-2-phenyl-
4.2.2. (R)-2-((2R,3R,4S)-2-(3-Bromophenyl)-3-nitrochroman-4-yl)
m
cyclohexanone (3b). Compound 3b: 29 mg, 45% yield; yellow solid,
50 mol %) in one portion. The reaction mixture was then stirred
at 0 ꢀC for the required time. Progress of reaction was monitored
at w50% conversion by using TLC or 1H NMR analysis of the
crude mixture. Then crude reaction mixture was then subject di-
rectly to flash column silica gel chromatography (ethyl acetate/
hexanes¼1/6) to provide Michael adduct 3a (28 mg, 40%) and the
unreacted chromene (S)-1a was recovered (21 mg, 42%).
mp 178e180 ꢀC; IR (CH2Cl2):
n
2939, 2856, 2360, 2334, 1703, 1582,
1551, 1488, 1457, 1423, 1369, 1231, 1121, 1072 cmꢁ1 1H NMR
(400 MHz, CDCl3, 25 ꢀC):
7.57 (s, 1H), 7.47 (d, J¼8.2 Hz,1H), 7.33 (d,
;
d
J¼7.8 Hz,1H), 7.25 (d, J¼2.2 Hz,1H), 7.24 (d, J¼5.8 Hz,1H), 7.06e7.03
(m, 2H), 6.97 (t, J¼8.2 Hz, 1H), 5.48 (d, J¼2.7 Hz, 1H), 5.12 (dd, J¼2.7,
1.8 Hz, 1H), 3.83 (d, J¼7.9 Hz, 1H), 2.79e2.74 (m, 1H), 2.58e2.53 (m,
1H), 2.47e2.39 (m, 1H), 2.16e2.12 (m, 1H), 2.08e2.04 (m, 1H),
2.01e1.98 (m, 1H), 1.77e1.67 (m, 3H); 13C NMR (100 MHz, CDCl3,
4.2.1. (R)-2-((2R,3R,4S)-3-Nitro-2-phenylchroman-4-yl)cyclohexa-
25 ꢀC):
d 210.5, 153.5, 138.1, 131.8, 130.1, 129.9, 128.9, 128.6, 124.3,
none (3a). Compound 3a: 8 mg, 40% yield; yellow solid, mp
122.7, 121.4, 118.4, 117.2, 86.1, 72.7, 55.1, 42.7, 38.4, 32.6, 27.9, 25.0;
181e183 ꢀC; IR (CH2Cl2):
n
2929, 2854, 1703, 1579, 1550, 1488, 1452,
HRMS-ESI: m/z: [MþNa]þ calculated for C21H20NO4NaBr 452.0473;
1363, 1231, 1118, 1060, 1031, 756 cmꢁ1 1H NMR (400 MHz, CDCl3,
;
found 452.0468. [
a
]
D
þ55.15 (c 0.16, CH2Cl2). The enantiomeric

5814
D.R. Magar, K. Chen / Tetrahedron 68 (2012) 5810e5816
excess was determined by HPLC with a Chiralcel AD-H (i-PrOH/
hexanes: 1/9; flow rate: 1.0 mL/min;
68.8, 55.5, 55.4, 42.8, 37.8, 33.0, 28.4, 25.5; HRMS-ESI: m/z:
[MþNa]þ calculated for C22H23NO5Na 404.1474; found 404.1470.
l
¼254 nm); tR (major)¼
16.2 min; tR (minor)¼17.8 min; recovered starting material, (S)-2-
(3-bromophenyl)-3-nitro-2H-chromene (1b): 19 mg, 38% yield;
spectroscopic data are in agreement with the literature data;3
HRMS-EI: m/z: [M]þ calculated for C15H10NO3Br 330.9844; found
330.9854. The enantiomeric excess was determined by HPLC with
a Chiralcel AS-H (i-PrOH/hexanes: 2/98; flow rate: 1.0 mL/min;
[a
]
þ141.33 (c 0.045, CH2Cl2). The enantiomeric excess was de-
D
termined by HPLC with a Chiralcel AD-H (i-PrOH/hexanes: 7/93;
flow rate: 1.0 mL/min;
l¼254 nm); tR (major)¼17.4 min; tR
(minor)¼15.9 min; recovered starting material, (S)-2-(2-methox-
yphenyl)-3-nitro-2H-chromene (1e): 21 mg, 37% yield;spectroscopic
data are in agreement with the literature data.3 HRMS-EI: m/z: [M]þ
calculated for C16H13NO4 283.0845; found 283.0851. The enantio-
meric excess was determined by HPLC with a Chiralcel AS-H
l¼254 nm); tR (major)¼39.3 min; tR (minor)¼18.8 min.
4.2.3. (R)-2-((2R,3R,4S)-2-(4-Chlorophenyl)-3-nitrochroman-4-yl)
cyclohexanone (3c). Compound 3c: 33 mg, 43% yield; yellow solid,
(i-PrOH/hexanes: 1/9; flow rate: 1.0 mL/min;
(major)¼11.8 min; tR (minor)¼10.3 min.
l
¼254 nm); tR
mp 183e185 ꢀC; IR (CH2Cl2):
n
2360, 2342, 1705, 1551, 1490, 1455,
1370, 1231, 1129, 1092, 858, 757 cmꢁ1 1H NMR (400 MHz, CDCl3,
25 ꢀC):
;
4.2.6. (R)-2-((2R,3R,4S)-2-(3-Methoxyphenyl)-3-nitrochroman-4-yl)
cyclohexanone (3f). Compound 3f: 35 mg, 46% yield; yellow solid,
mp 154e156 ꢀC; IR (CH2Cl2): 2939, 2863, 2363, 1705, 1587, 1551,
1489, 1455, 1367, 1232, 1156, 1120 cmꢁ1; 1H NMR (400 MHz, CDCl3,
d
7.38e7.33 (m, 4H), 7.24 (t, J¼7.2 Hz, 1H), 6.99 (m, 3H), 5.50
(d, J¼2.8 Hz, 1H), 5.10 (t, J¼2.0 Hz, 1H), 3.82 (d, J¼7.6 Hz, 1H),
2.79e2.73 (m, 1H), 2.57e2.54 (m, 1H), 2.46e2.38 (m, 1H), 2.15e2.13
(m, 1H), 2.07e2.04 (m, 1H), 2.00e1.98 (m, 1H), 1.79e1.69 (m, 3H);
25 ꢀC):
d
7.29 (t, J¼7.6 Hz, 1H), 7.23 (t, J¼7.6 Hz, 1H), 7.04 (d,
13C NMR (100 MHz, CDCl3, 25 ꢀC):
d
210.5, 153.6, 134.5, 134.3, 129.8,
J¼7.6 Hz, 2H), 6.98e6.94 (m, 3H), 6.87 (dd, J¼7.6, 2.4 Hz, 1H), 5.45
(d, J¼2.8 Hz, 1H), 5.09 (t, J¼2.8 Hz, 1H), 3.84 (dd, J¼7.2 Hz, 1H), 3.80
(s, 3H), 2.77e2.71 (m, 1H), 2.57e2.53 (m, 1H), 2.43e2.40 (m, 1H),
2.16e2.12 (m, 1H), 2.07e2.03 (m, 1H), 1.99e1.96 (m, 1H), 1.74e166
128.8, 128.6, 127.1, 121.4, 118.5, 117.2, 86.3, 72.9, 55.1, 42.7, 38.2, 35.5,
27.9, 25.0; HRMS-ESI: m/z: [MþNa]þ calculated for C21H20NO4NaCl
408.0979; found 408.0983. [
antiomeric excess was determined by HPLC with a Chiralcel AD-H
(i-PrOH/hexanes: 1/9; flow rate: 1.0 mL/min;
(major)¼21.7 min; tR (minor)¼44.6 min; recovered starting mate-
rial, (S)-2-(4-chlorophenyl)-3-nitro-2H-chromene (1c): 21 mg, 37%
yield; spectroscopic data are in agreement with the literature
data;3 HRMS-EI: m/z: [M]þ calculated for C15H10NO3Cl 287.349;
found 287.345. The enantiomeric excess was determined by HPLC
with a Chiralcel AS-H (i-PrOH/hexanes: 2/98; flow rate: 1.0 mL/
a
]
þ54.78 (c 0.50, CH2Cl2). The en-
D
(m, 3H); 13C NMR (100 MHz, CDCl3, 25 ꢀC):
d 210.3, 159.8, 153.8,
l¼254 nm); tR
137.3, 129.9, 129.6, 128.5, 121.2, 118.5, 117.9, 117.2, 114.0, 111.7, 86.5,
73.3, 55.3, 55.2, 42.7, 38.2, 32.5, 27.9, 25.1; HRMS-ESI: m/z:
[MþNa]þ calculated for C22H23NO5Na 404.1474; found 404.1471.
[
a
]
þ39.32 (c 0.39, CH2Cl2). The enantiomeric excess was de-
D
termined by HPLC with a Chiralcel AD-H (i-PrOH/hexanes: 1/9;
flow rate: 1.0 mL/min;
l¼254 nm); tR (major)¼20.5 min; tR
(minor)¼25.9 min; recovered starting material, (S)-2-(3-methox-
yphenyl)-3-nitro-2H-chromene (1f): 23 mg, 41% yield; spectroscopic
data are in agreement with the literature data.3 HRMS-EI: m/z: [M]þ
calculated for C16H13NO4 283.0845; found 283.0843. The enantio-
meric excess was determined by HPLC with a Chiralcel AS-H
min;
l¼254 nm); tR (major)¼35.2 min; tR (minor)¼16.7 min.
4.2.4. (R)-2-((2R,3R,4S)-2-(3-Chlorophenyl)-3-nitrochroman-4-yl)
cyclohexanone (3d). Compound 3d: 36 mg, 47% yield; yellow solid,
mp 175e177 ꢀC; IR (CH2Cl2):
n
2938, 2863, 2361, 1702, 1582, 1551,
1488, 1458, 1364, 1231, 1129 cmꢁ1 1H NMR (400 MHz, CDCl3,
25 ꢀC):
7.43 (s, 1H), 7.33e7.24 (m, 4H), 7.06e7.03 (m, 2H), 6.97 (t,
(i-PrOH/hexanes: 1/9; flow rate: 1.0 mL/min;
(major)¼17.2 min; tR (minor)¼11.5 min.
l¼254 nm); tR
;
d
J¼6.8 Hz, 1H), 5.49 (d, J¼2.8 Hz, 1H), 5.12 (dd, J¼2.7, 1.8 Hz, 1H), 3.83
(d, J¼7.1 Hz, 1H), 2.76e2.74 (m, 1H), 2.57e2.53 (m, 1H), 2.45e2.42
(m, 1H), 2.13e2.12 (m, 1H), 2.08e2.04 (m, 1H) 1.99e1.97 (m, 1H),
4.2.7. (R)-2-((2R,3R,4S)-2-(4-Methoxyphenyl)-3-nitrochroman-4-yl)
cyclohexanone (3g). Compound 3g: 25 mg, 33% yield; yellow solid,
mp 160e162 ꢀC; IR (CH2Cl2): 2926, 2852, 2355, 1702, 1611, 1581,
1547, 1511, 1486, 1454, 1368, 1306, 1250, 1229, 1175, 1118,
1.76e1.66 (m, 3H); 13C NMR (100 MHz, CDCl3, 25 ꢀC):
d 210.5, 153.5,
137.8, 134.6, 129.9, 128.8, 128.6, 126.0, 123.8, 121.4, 118.4, 117.2, 86.1,
1029 cmꢁ1
;
1H NMR (400 MHz, CDCl3, 25 ꢀC):
d
7.31 (d, J¼8.8 Hz,
72.7, 55.1, 42.7, 38.3, 32.6, 27.9, 25.0; HRMS-ESI: m/z: [MþNa]þ
2H), 7.21 (t, J¼6.8 Hz, 1H), 7.03 (t, J¼8.0 Hz, 2H), 6.96 (t, J¼6.8 Hz,
1H), 6.90 (d, J¼8.8 Hz, 2H), 5.45 (d, J¼2.8 Hz, 1H), 5.04 (t, J¼2.4 Hz,
1H), 3.85 (d, J¼6.8 Hz, 1H), 3.80 (s, 3H), 2.76e2.70 (m, 1H),
2.57e2.53 (m, 1H), 2.45e2.37 (m, 1H), 2.16e2.12 (m, 1H), 2.07e2.03
(m, 1H), 1.99e1.97 (m, 1H), 1.78e1.63 (m, 3H); 13C NMR (100 MHz,
calculated for C21H20NO4NaCl 408.0979; found 408.0980. [a]
D
þ72.2 (c 0.21, CH2Cl2). The enantiomeric excess was determined by
HPLC with a Chiralcel AD-H (i-PrOH/hexanes: 1/9; flow rate:
1.0 mL/min;
l
¼254 nm); tR (major)¼14.7 min; tR (minor)¼17.3 min;
recovered starting material, (S)-2-(3-chlorophenyl)-3-nitro-2H-
chromene (1d): 20 mg, 35% yield; spectroscopic data are in agree-
ment with the literature data;3 HRMS-EI: m/z: [M]þ calculated for
C15H10NO3Cl 287.0349; found 287.0358. The enantiomeric excess
was determined by HPLC with a Chiralcel AS-H (i-PrOH/hexanes:
CDCl3, 25 ꢀC):
d 210.4, 159.8, 154.0, 129.9, 128.4, 127.6, 127.0, 121.1,
118.5, 117.2, 114.1, 86.7, 73.0, 55.2, 42.7, 38.0, 32.4, 29.6, 27.9, 25.1;
HRMS-ESI: m/z: [MþNa]þ calculated for C22H23NO5Na 404.1474;
found 404.1468. The enantiomeric excess was determined by HPLC
with a Chiralcel AD-H (i-PrOH/hexanes: 1/9; flow rate: 1.0 mL/min;
1/9; flow rate: 1.0 mL/min;
(minor)¼10.3 min.
l
¼254 nm); tR (major)¼18.7 min; tR
l
¼254 nm); tR (major)¼30.9 min; tR (minor)¼24.2 min; recovered
starting material, (S)-2-(4-methoxyphenyl)-3-nitro-2H-chromene
(1g): 22 mg, 39% yield; spectroscopic data are in agreement with
the literature data.3 HRMS-EI: m/z: [M]þ calculated for C16H13NO4
283.0845; found 283.0839. The enantiomeric excess was de-
termined by HPLC with a Chiralcel AS-H (i-PrOH/hexanes: 1/9; flow
4.2.5. (R)-2-((2R,3R,4S)-2-(2-Methoxyphenyl)-3-nitrochroman-4-yl)
cyclohexanone (3e). Compound 3e: 31 mg, 41% yield; white solid,
mp 186e188 ꢀC; IR (CH2Cl2):
n
2940, 2853, 2368, 1707, 1584, 1548,
1491, 1459, 1369, 1310, 1246, 1229, 1125, 1079, 1038 cmꢁ1; 1H NMR
(400 MHz, CDCl3, 25 ꢀC):
rate: 1.0 mL/min;
13.6 min.
l¼254 nm); tR (major)¼23.5 min; tR (minor)¼
d
7.55 (d, J¼7.6 Hz, 1H), 7.33 (t, J¼7.6 Hz,
1H), 7.22 (t, J¼7.6 Hz, 1H), 7.03 (t, J¼8.0 Hz, 3H), 6.95 (t, J¼7.2 Hz,
1H), 6.89 (d, J¼8.0 Hz, 1H), 5.62 (s, 1H), 5.27 (t, J¼2.0 Hz, 1H), 3.93
(d, J¼9.2 Hz, 1H), 3.83 (s, 3H), 2.69e2.72 (m, 1H), 2.61e2.57 (m, 1H),
2.42e2.39 (m, 1H), 2.19e2.15 (m, 2H), 2.03e1.97 (m, 1H), 1.72e1.59
4.2.8. (R)-2-((2R,3R,4S)-3-Nitro-2-p-tolylchroman-4-yl)cyclohexa-
none (3h). Compound 3h: 28 mg, 38% yield; yellow solid, mp
189e191 ꢀC; IR (CH2Cl2): 2936, 2864, 1706, 1583, 1551, 1485, 1452,
1366, 1232, 1116, 1035, 757 cmꢁ1; 1H NMR (400 MHz, CDCl3, 25 ꢀC):
(m, 3H); 13C NMR (100 MHz, CDCl3, 25 ꢀC):
d
210.2, 155.0, 154.2,
130.9, 129.4, 128.3, 126.8, 124.0, 121.1, 120.8, 118.7, 117.1, 109.8, 83.1,
d
7.28 (d, J¼8.0 Hz, 2H), 7.23 (s, 1H), 7.17 (m, 2H), 7.04 (t, J¼7.2 Hz,

D.R. Magar, K. Chen / Tetrahedron 68 (2012) 5810e5816
5815
2H), 6.95 (t, J¼7.2 Hz, 1H), 5.45 (d, J¼2.8 Hz, 1H), 5.07 (t, J¼2.4 Hz,
1H), 3.85 (d, J¼6.8 Hz, 1H), 2.74e2.71 (m, 1H), 2.58e2.53 (m, 1H),
2.44e2.41 (m, 1H), 2.35 (s, 3H), 2.14e2.12 (m, 1H), 2.07e2.05 (m,
1H), 1.99e1.96 (m, 1H), 1.75e1.66 (m, 3H); 13C NMR (100 MHz,
J¼8.8 Hz, 2.8 Hz, 1H), 6.60 (d, J¼2.8 Hz, 1H), 5.47 (d, J¼2.8 Hz, 1H),
5.05 (t, J¼2.4 Hz, 1H), 3.83 (d, J¼7.2 Hz, 1H), 3.76 (s, 3H), 2.80e2.77
(m, 1H), 2.57e2.53 (m, 1H), 2.44e2.41 (m, 1H), 2.16e2.07 (m, 2H),
1.99e1.98 (m, 1H), 1.77e1.65 (m, 3H); 13C NMR (100 MHz, CDCl3,
CDCl3, 25 ꢀC):
d
210.4, 153.9, 138.5, 132.6, 130.0, 129.3, 128.4, 125.6,
25 ꢀC):
d 210.3, 153.8, 148.0, 135.8, 128.7, 128.6, 125.7, 119.5, 117.8,
121.1, 118.5, 117.2, 86.6, 73.4, 55.2, 42.7, 38.0, 32.5, 27.9, 25.1, 21.1;
HRMS-ESI: m/z: [MþNa]þ calculated for C22H23NO4Na 388.1525;
found 388.1516. The enantiomeric excess was determined by HPLC
with a Chiralcel AD-H (i-PrOH/hexanes: 1/9; flow rate: 1.0 mL/min;
114.7, 114.0, 86.9, 73.8, 55.7, 55.2, 42.7, 38.3, 32.5, 27.9, 25.2; HRMS-
ESI: m/z: [MþNa]þ calculated for C22H23NO5Na 404.1474; found
404.1478. [
a
]
D þ31.73(c 0.76, CH2Cl2). The enantiomeric excess was
determined by HPLC with a Chiralcel AD-H (i-PrOH/hexanes: 1/9;
flow rate: 1.0 mL/min;
l¼254 nm); tR (major)¼23.8 min; tR (minor)¼36.4 min; recovered
l¼254 nm); tR (major)¼22.1 min; tR
starting material, (S)-3-nitro-2-p-tolyl-2H-chromene (1h): 21 mg,
39% yield; spectroscopic data are in agreement with the literature
data.3 HRMS-EI: m/z: [M]þ calculated for C16H13NO3 267.0895;
found 267.0896. The enantiomeric excess was determined by HPLC
with a Chiralcel AS-H (i-PrOH/hexanes: 1/9; flow rate: 1.0 mL/min;
(minor)¼45.7 min; recovered starting material, (S)-6-methoxy-3-
nitro-2-phenyl-2H-chromene (1k): 21 mg, 37% yield; spectroscopic
data are in agreement with the literature data.3 HRMS-EI: m/z: [M]þ
calculated for C16H13NO4 283.0845; found 283.0839. The enantio-
meric excess was determined by HPLC with a Chiralcel AS-H
l
¼254 nm); tR (major)¼13.7 min; tR (minor)¼8.0 min.
(i-PrOH/hexanes: 1/9; flow rate: 1.0 mL/min;
(major)¼25.4 min; tR (minor)¼11.4 min.
l
¼254 nm); tR
4.2.9. (R)-2-((2S,3R,4S)-3-Nitro-2-(thiophen-2-yl)chroman-4-yl)cy-
clohexanone (3i). Compound 3i: 28 mg, 39% yield; yellow solid, mp
156e158 ꢀC; IR (CH2Cl2): 2933, 2862, 2361, 2328, 1704, 1584, 1551,
4.2.12. (R)-2-((2R,3R,4S)-6-Chloro-3-nitro-2-phenylchroman-4-yl)
cyclohexanone (3l). Compound 3l: 22.5 mg, 42% yield; yellow solid,
mp 174e176 ꢀC; IR (CH2Cl2): 2925, 2856, 2361, 2333, 1707, 1552,
1488, 1451, 1369, 1315, 1228, 1129, 1115 cmꢁ1 1H NMR (400 MHz,
;
CDCl3, 25 ꢀC):
d
7.29 (dd, J¼5.0,1.0 Hz,1H), 7.21 (t, J¼7.2 Hz,1H), 7.07
1483, 1368, 1236, 1121 cmꢁ1 1H NMR (400 MHz, CDCl3, 25 ꢀC):
;
(d, J¼4.0 Hz, 2H), 7.01e6.97 (m, 3H), 5.84 (d, J¼3.7 Hz, 1H), 5.19 (t,
J¼3.7 Hz, 1H), 4.06 (dd, J¼6.2, 3.9 Hz, 1H), 2.74e2.71 (m, 1H),
2.56e2.52 (m, 1H), 2.41e2.38 (m, 1H), 2.13e2.11 (m, 1H), 2.03e1.95
(m, 2H), 1.72e1.67 (m, 2H), 1.58e1.55 (m, 1H); 13C NMR (100 MHz,
d
7.39e7.36 (m, 5H), 7.19 (dd, J¼8.8, 2.4 Hz, 1H), 7.05 (d, J¼2.4 Hz,
1H), 6.98 (d, J¼8.8 Hz, 1H), 5.51 (d, J¼2.8 Hz, 1H), 5.08 (dd, J¼2.8,
2.0 Hz, 1H), 3.79 (d, J¼7.2 Hz, 1H), 2.79e2.76 (m, 1H), 2.58e2.54 (m,
1H), 2.46e2.42 (m, 1H), 2.17e2.15 (m, 1H), 2.10e2.06 (m, 1H),
2.04e2.01 (m, 1H), 1.77e1.68 (m, 3H); 13C NMR (100 MHz, CDCl3,
CDCl3, 25 ꢀC):
d 210.1, 153.1, 137.2, 129.8, 128.5, 126.7, 126.2, 125.8,
121.7, 119.1, 117.6, 85.7, 71.3, 55.0, 42.6, 37.0, 31.7, 27.7, 25.2; HRMS-
ESI: m/z: [MþNa]þ calculated for C19H19NO4NaS 380.0932; found
380.0938. The enantiomeric excess was determined by HPLC with
a Chiralcel AD-H (i-PrOH/hexanes: 1/9; flow rate: 1.0 mL/min;
25 ꢀC):
d 210.0, 152.6, 135.2, 129.2, 128.9, 128.7, 128.5, 126.1, 125.6,
120.5, 118.6, 86.4, 73.8, 55.0, 42.7, 38.1, 32.5, 27.9, 25.2; HRMS-ESI:
m/z: [MþNa]þ calculated for C21H20NO4Cl 408.979; found
408.0973. The enantiomeric excess was determined by HPLC with
a Chiralcel AD-H (i-PrOH/hexanes: 1/9; flow rate: 1.0 mL/min;
l
¼254 nm); tR (major)¼17.0 min; tR (minor)¼21.6 min; recovered
starting material, (R)-3-nitro-2-(thiophen-2-yl)-2H-chromene (1i):
19 mg, 36% yield; spectroscopic data are in agreement with the
literature data.3 HRMS-EI: m/z: [M]þ calculated for C13H9NO3S
259.0303; found 259.0298. The enantiomeric excess was de-
termined by HPLC with a Chiralcel AS-H (i-PrOH/hexanes: 1/9; flow
l
¼254 nm); tR (major)¼13.5 min; tR (minor)¼12.2 min; recovered
starting material, (S)-6-chloro-3-nitro-2-phenyl-2H-chromene (1l):
14 mg, 35% yield; spectroscopic data are in agreement with the
literature data.3 HRMS-EI: m/z: [M]þ calculated for C15H10NO3Cl
287.0349; found 287.0348. The enantiomeric excess was de-
termined by HPLC with a Chiralcel AS-H (i-PrOH/hexanes: 1/9; flow
rate: 1.0 mL/min;
10.1 min.
l¼254 nm); tR (major)¼20.9 min; tR (minor)¼
rate: 1.0 mL/min;
7.7 min.
l¼254 nm); tR (major)¼10.5 min; tR (minor)¼
4.2.10. (R)-2-((2S,3R,4S)-2-(Furan-2-yl)-3-nitrochroman-4-yl)cyclo-
hexanone (3j). Compound 3j: 21 mg, 34% yield; yellow solid, mp
4.2.13. (R)-3-((2R,3R,4S)-3-Nitro-2-phenylchroman-4-yl)dihydro-
2H-pyran-4(3H)-one (3m). Compound 3m: 21 mg, 31% yield; white
solid, mp 173e175 ꢀC; IR (CH2Cl2): 2361, 2338, 1712, 1582, 1552,
1488, 1455, 1371, 1232, 1146, 758 cmꢁ1; 1H NMR (400 MHz, CDCl3,
148e150 ꢀC; 1H NMR (400 MHz, CDCl3, 25 ꢀC):
d 7.39 (s, 1H), 7.19 (t,
J¼7.5 Hz, 1H), 7.05 (d, J¼7.5 Hz, 1H), 6.97e6.95 (m, 2H), 6.42 (d,
J¼3.2 Hz, 1H), 6.36 (t, J¼2.6 Hz, 1H), 5.59 (d, J¼3.2 Hz, 1H), 5.19 (t,
J¼3.4 Hz, 1H), 4.10e4.08 (m, 1H), 2.69e2.65 (m, 1H), 2.56e2.53 (m,
1H), 2.41e2.38 (m, 1H), 2.13e2.11 (m, 1H), 2.04e1.97 (m, 2H),
1.70e1.64 (m, 2H), 1.59e1.53 (m, 1H); 13C NMR (100 MHz, CDCl3,
25 ꢀC):
d
7.42e7.36 (m, 5H), 7.27e7.25 (m,1H), 7.10 (d, J¼8.1 Hz,1H),
7.06 (d, J¼8.1 Hz, 1H), 6.99 (t, J¼8.1 Hz, 1H), 5.49 (s, 1H), 5.05 (s, 1H),
4.15e4.09 (m, 1H), 3.99e3.93 (m, 4H), 2.73e2.71 (m, 3H); 13C NMR
25 ꢀC):
d
210.0, 153.1, 148.3, 142.8, 130.0, 128.4, 121.6, 119.1, 117.3,
(100 MHz, CDCl3, 25 ꢀC):
d 207.0, 153.5, 135.4, 130.3, 129.2, 128.7,
110.7,109.1, 83.6, 69.1, 55.0, 42.6, 36.7, 31.7, 27.7, 25.3; HRMS-ESI: m/
z: [MþNa]þ calculated for C19H19NO5Na 364.1161; found 364.1164.
The enantiomeric excess was determined by HPLC with a Chiralcel
128.6, 125.6, 121.4, 117.4, 116.5, 84.9, 72.4, 70.2, 68.6, 56.2, 42.1, 36.6;
HRMS (FABþ): m/z: [MþH]þ calculated for C20H20NO5 354.1341;
found 354.1345. The enantiomeric excess was determined by HPLC
with a Chiralcel AD-H (i-PrOH/hexanes: 1/9; flow rate: 1.0 mL/min;
AD-H (i-PrOH/hexanes: 1/9; flow rate: 1.0 mL/min;
l
¼254 nm); tR
(major)¼10.9 min; tR (minor)¼19.3 min; recovered starting mate-
rial, (R)-2-(furan-2-yl)-3-nitro-2H-chromene (1j): 15 mg, 38% yield;
spectroscopic data are in agreement with the literature data.3
HRMS(FABþ): m/z: [MþH]þ calculated for C13H10NO4 244.0610;
found 244.0614. The enantiomeric excess was determined by HPLC
with a Chiralcel AS-H (i-PrOH/hexanes: 1/9; flow rate: 1.0 mL/min;
l
¼254 nm); tR (major)¼26.3 min; tR (minor)¼30.5 min; recovered
starting material, (S)-3-nitro-2-phenyl-2H-chromene (1a): 18 mg,
36% yield; spectroscopic data are in agreement with the literature
data.3 The enantiomeric excess was determined by HPLC with
a Chiralcel AS-H (i-PrOH/hexanes: 2/98; flow rate: 1.0 mL/min;
l¼254 nm); tR (major)¼22.3 min; tR (minor)¼12.2 min.
l¼254 nm); tR (major)¼15.5 min; tR (minor)¼8.7 min.
4.2.14. (R)-3-((2R,3R,4S)-3-Nitro-2-phenylchroman-4-yl)dihydro-
2H-thiopyran-4(3H)-one (3n). Compound 3n: 18 mg, 24% yield;
yellow solid, mp 184e186 ꢀC; IR (CH2Cl2): 2916, 2360, 2329, 1702,
4.2.11. (R)-2-((2R,3R,4S)-6-Methoxy-3-nitro-2-phenylchroman-4-yl)
cyclohexanone (3k). Compound 3k: 31 mg, 41% yield; yellow solid,
mp 176e178 ꢀC; IR (CH2Cl2): 2931, 2859, 2359, 1702, 1550, 1498,
1447, 1366, 1270, 1220, 1156, 1039 cmꢁ1; 1H NMR (400 MHz, CDCl3,
1583, 1551, 1489, 1454, 1367, 1236, 1117, 755, 698 cmꢁ1 1H NMR
;
(400 MHz, CDCl3, 25 ꢀC):
7.28 (t, J¼7.2 Hz, 1H), 7.09 (q, J¼7.6 Hz, 2H), 6.99 (t, J¼7.6 Hz, 1H),
d 7.41e7.39 (m, 4H), 7.38e7.35 (m, 1H),
25 ꢀC):
d
7.39e7.33 (m, 5H), 6.97 (d, J¼9.2 Hz, 1H), 6.81 (dd,

5816
D.R. Magar, K. Chen / Tetrahedron 68 (2012) 5810e5816
4. (a) Bowers, W. S. In; Gilbert, L. I., Kerkut, G. A., Eds. Comprehensive Insect
Physiology, Biochemistry and Pharmacology; Pergamon: Oxford, 1985; Vol. 8,
p 551; (b) Bowers, W. S.; Ohta, T.; Cleere, J. S.; Marsella, P. A. Science 1976,
193, 542; (c) Ishizuka, N.; Matsumura, K.; Sakai, K.; Fujimoto, M.; Mihara,
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J. Med. Chem. 1990, 33, 492; (e) Burrell, G.; Cassidy, F.; Evans, J. M.;
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pande, S.; Mathur, H. H.; Trivedi, G. K. Synthesis 1983, 835; (i) Booth, H.;
Huckle, D.; Lockhart, I. M. J. Chem. Soc., Perkin Trans. 2 1973, 227.
5. For synthesis of chiral chromenes, see: (a) Velde, S. L. V.; Jacobsen, E. N. J. Org.
Chem. 1995, 60, 5380; (b) Tahtaoui, C.; Demailly, A.; Guidemann, C.; Joyeux, C.;
Schneider, P. J. Org. Chem. 2010, 75, 3781; (c) Chang, S.; Grubbs, R. H. J. Org.
Chem. 1998, 63, 864; (d) Hodgetts, K. J. Tetrahedron 2005, 61, 6860; (e) Kawa-
saki, M.; Kakuda, H.; Goto, M.; Kawabata, S.; Kometani, T. Tetrahedron: Asym-
metry 2003, 14, 1529; (f) Konoike, T.; Matsumura, K.-I.; Yorifuji, T.; Shinomoto,
S.; Ide, Y.; Ohya, T. J. Org. Chem. 2002, 67, 7741.
5.52 (d, J¼2.8 Hz, 1H), 4.94 (q, J¼2.0 Hz, 1H), 4.17 (d, J¼7.6 Hz, 1H),
3.08e3.04 (m, 2H), 3.00e2.96 (m, 3H), 2.94e2.91 (m, 1H),
2.87e2.86 (m, 1H); 13C NMR (100 MHz, CDCl3, 25 ꢀC):
d 208.6, 153.6,
135.4, 130.2, 129.2, 128.8, 128.7, 125.7, 121.3, 117.4, 116.9, 85.1, 72.7,
57.4, 44.1, 38.0, 34.1, 31.1; HRMS(FABþ): m/z: [MþH]þ calculated for
C20H20NO4S 370.1113; found 370.1122. The enantiomeric excess
was determined by HPLC with a Chiralcel AD-H (i-PrOH/hexanes:
1/9; flow rate: 1.0 mL/min;
l
¼254 nm); tR (major)¼20.2 min; tR
(minor)¼24.3 min; recovered starting material, (S)-3-nitro-2-phe-
nyl-2H-chromene (1a): 27 mg, 53% yield; spectroscopic data are in
agreement with the literature data.3 The enantiomeric excess was
determined by HPLC with a Chiralcel AS-H (i-PrOH/hexanes: 2/98;
flow rate: 1.0 mL/min;
(minor)¼12.4 min.
l¼254 nm); tR (major)¼23.2 min; tR
6. For selected references on organocatalysed oxa-Michael-Aldol reactions see:
(a) Das, B. C.; Mohapatra, S.; Campbell, P. D.; Nayak, S.; Mahalingam, S. M.;
Evans, T. Tetrahedron Lett. 2010, 51, 2567; (b) Xu, D.-Q.; Wang, Y.-F.; Luo, S.-P.;
Zhang, S.; Zhong, A.-G.; Chen, H.; Xu, Z.-Y. Adv. Synth. Catal. 2008, 350, 2610;
(c) Karthikeyan, T.; Sankararaman, S. Tetrahedron: Asymmetry 2008, 19, 2741;
Acknowledgements
We thank the National Science Council of the Republic of China
(NSC 99-2113-M-003-002-MY3 and NSC 99-2119-M-003-001-
MY2) and National Taiwan Normal University (100-D-06) for
financial support of this work.
ꢁ
ꢁ
(d) Rios, R.; Sunden, H.; Ibrahem, I.; Cordova, A. Tetrahedron Lett. 2007, 48,
2181; (e) Li, H.; Wang, J.; Nunu, T. E.; Zu, L.; Jiang, W.; Wei, S.; Wang, W. Chem.
Commun. 2007, 507; (f) Wang, W.; Li, H.; Wang, J.; Zu, L. J. Am. Chem. Soc. 2006,
128, 10354; (g) Govender, T.; Hojabri, L.; Moghaddam, F. M.; Arvidsson, P. I.
ꢁ
Tetrahedron: Asymmetry 2006, 17, 1763; (h) Sunden, H.; Ibrahem, I.; Zhao, G.-L.;
Eriksson, L.; Cordova, A. Chem.dEur. J. 2007, 13, 574.
ꢁ
7. For selected reviews in KR reaction, see: (a) Keith, J. M.; Larrow, J. F.; Jacobsen,
E. N. Adv. Synth. Catal. 2001, 343, 5; (b) Robinson, D. E. J. E.; Bull, S. D. Tet-
rahedron: Asymmetry 2003, 14, 1407; (c) Vedejs, E.; Jure, M. Angew. Chem., Int.
Ed. 2005, 44, 3974; (d) For special issue on kinetic resolution, see: Kagan, H.
B.; Fiaud, J. C. In; Eliel, E. L., Fiaud, J. C., Eds. Topics in Stereochemistry; Wiley:
New York, NY, 1988; Vol. 18, p 249.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2012.05.019.
8. For selected references on metal-mediated kinetic resolution, see: (a) Morken,
J. P.; Didiuk, M. T.; Visser, M. S.; Hoveyda, A. H. J. Am. Chem. Soc. 1994, 116, 3123;
(b) Ramdeehul, S.; Dierkes, P.; Aguado, R.; Kamer, P. C. J.; van Leeuwen, P. W.
N. M.; Osborn, J. A. Angew. Chem., Int. Ed. 1998, 37, 3118; (c) Tanaka, K.; Fu, G. C.
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