Organocatalytic asymmetric Michael/hemiacetalization/acyl transfer reaction of α-nitroketones with o-hydroxycinnamaldehydes: Synthesis of 2,4-disubstituted chromans

Article abstract of DOI:10.1039/c8ob00078f

An organocatalytic asymmetric cascade Michael/hemiketalization/acyl transfer reaction between o-hydroxycinnamaldehydes and α-nitroketones is developed. Prolinol TMS ether catalyst in combination with benzoic acid was found to be the most effective for this reaction which proceeds through an equilibrium of lactols to provide a single diastereomer of enantiopure 2,4-disubstituted chromans.

Full text of DOI:10.1039/c8ob00078f

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

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Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Organocatalytic Asymmetric Michael/Hemiacetalization/Acyl
Transfer Reaction of α‐Nitroketones with o‐
Hydroxycinnamaldehydes: Synthesis of 2,4‐Disubstituted Chro‐
www.rsc.org/
mans
Rajendra Maity and Subhas Chandra Pan*
An organocatalytic asymmetric cascade Michael/ hemiketalization adhesion kinase activation in the min/t mouse (Figure 1).4
/acyl transfer reaction between o‐hydroxycinnamaldehydes and α‐ Though a variety of organocatalytic routes has been reported in
nitroketones is developed. Prolinol TMS ether catalyst in the last decade,5 the development of efficient methods for the
combination with benzoic acid was found to be the most effective enantioselective construction of chroman rings having diverse
for this reaction which proceeds through an equibrium of lactols to substitutions is important for the finding of new chiral drugs and
provide a single diastereomer of enantiopure 2,4‐disubstituted other utilities.
chromans.
In recent years, organocatalytic asymmetric Michael additions,
particularly the Michael addition reaction‐triggered cascade
reactions, have been utilized in the enantioselective synthesis
of a variety of complex molecules in a one‐pot fashion.6,7 Among
which, considerable attention has been provided for the
asymmetric Michael addition of nitroalkanes to α,β‐
unsaturated carbonyl compounds,8 which is synthetically very
useful as it provides highly functionalized synthetic
intermediates such as γ‐aminocarbonyl compounds and
aminoalkanes as well as often initiates a variety of cascade
reactions. However, the scope of nitro compounds are limited
to nitroalkanes and nitro‐esters and surprisingly α‐
nitroketones, another active nucleophiles, failed to provide
products with cinnamaldehydes.9b Only the reactions of α‐
nitroketones with β,γ‐unsaturated α‐keto esters and
unsaturated pyrazolones have been disclosed in the literature.9
We envisioned that bidentate compounds like o‐
hydroxycinnamaldehydes10 might be suitable substrate for the
reaction with α‐nitroketones. Realizing the potential of
chroman compounds, we embark in developing an asymmetric
Michael/hemiacetalization/acyl transfer reaction between α‐
nitroketones and o‐hydroxycinnaldehydes (Scheme 1).
Chiral chromans are one class of privileged structural motifs
present in a plethora of natural products and synthetic analogs
displaying a wide range of biological activities.1 For example
Cromakalim (
hypertensive effects.2 Sorbinil (
1
) was found to have vasodilatory or anti‐
2) uses to act as an addolase
reductase inhibitor and has been shown to recover conduction
Figure 1 Biological active chroman derivatives.
Initially, a model reaction between o‐hydroxycinnamaldehyde
(
1a) and 2‐nitro‐1‐phenylethanone (2a) was studied with α,α‐
Scheme 1 Organocatalytic asymmetric Michael‐acyl transfer reaction between diphenyl‐2‐pyrrolidinemethanol (
I) in combination with benzoic
nitroketones and unsaturated carbonyl compounds.
acid in 1,2‐dichloroethane solvent at room temperature (Table
1, entry 1). After stirring for two days, a product was isolated in
80% yield whose structure was determined to be chroman 3a
by 1H NMR (Table 1, entry 1). The relative structure of pure
velocity in daibatic patients.3 Also natural phenol Catechin (
3)
prevents intestinal tumor formation and suppresses focal
Department of Chemistry, Indian Institute of Technology Guwahati, 781039,
India. E‐mail: span@iitg.ernet.in; Tel: +91‐361‐258‐3304; Fax: +91‐361‐258‐
2349.
†Electronic Supplementary Information (ESI) available: Experimental details,
characterization and analytical data. See DOI: 10.1039/x0xx00000x
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variety of α‐nitroketones
1
having different aryl groups were
Table 1 Catalyst screening and optimization of reaction conditions
tested (Table 2). It was found that a range of substituents can
Table 2 Scope of Nitroketones
O2N
catalyst II
O
(20 mol%)
CHO
O
NO2
+
R
PhCO2H
( 20 mol%)
-20 oC, DCE, 7 d
O
O
R
OH
1a
2
3a-3u
entrya
R
3
yieldb
drc
eed
1
2
Ph
3a
3b
3c
3d
3e
3f
85
76
84
68
90
70
84
78
86
60
84
76
72
70
69
78
80
73
91
91
47
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
94
92
90
90
92
90
96
96
96
88
96
84
82
88
86
86
96
90
84
94
94
4‐MeC6H4
4‐iPrC6H4
4‐tBuC6H4
4‐OMeC6H4
4‐OEtC6H4
4‐OnPrC6H4
4‐OiPrC6H4
4‐OiBuC6H4
4‐OAllC6H4
4‐OBnC6H4
4‐FC6H4
3
entrya
catalyst
temp
rt
yieldb
80
drc
eed
56
78
72
78
‐
4
5
1
2
I
>20:1
>20:1
>20:1
>20:1
‐
6
II
rt
85
7
3g
3h
3i
3
III
IV
V
VI
II
rt
84
8
4
rt
82
9
10
11
12
13
14
15
16
17
18
19
20
21
3j
5
rt
mixture
75
3k
3l
6
rt
>20:1
>20:1
>20:1
>20:1
52
90
94
94
7
0 oC
‐20 oC
‐20 oC
50
4‐ClC6H4
3m
3n
3o
3p
3q
3r
4‐BrC6H4
8
II
40
3‐MeC6H4
3‐ClC6H4
9d
II
85
aUnless otherwise mentioned, reactions were carried out with 0.25 mmol of 1a
with 0.05 mmol of 2a in 0.5 ml DCE using 20 mol% catalyst and 20 mol% PhCO2H.
bIsolated yield after silica gel column chromatography. cDetermined by 1H NMR.
2‐MeC6H4
2‐OMeC6H4
2‐FC6H4
dDetermined
by
chiral
HPLC.
dReaction
time
7
days.
3s
3t
.
____________________________________________________
2,4‐(Me)2C6H3
cyclohexyl
single diastereomer 3a was solved by 2D NMR analysis.
However, the enantioselectivity was only moderate. A slight
higher enantioselectivity was achieved with prolinol TMS ether
catalyst II (entry 2).11 To improve the enantioselectivity, other
silyl ether catalysts III and IV were prepared but they failed to
enhance the enantiomeric excess of the product (entries 3‐4).
3u
aReactions were carried out with 0.5 mmol of 1a and 0.1 mmol of 2 with 20 mol%
catalyst II and 20 mol% PhCO2H in 1 mL DCE at ‐20 oC for 7 days. bIsolated yield
after silica gel column chromatography of a single diastereomer. cDetermined by
1H NMR. dDetermined by HPLC.
Then catalyst
V having aryl groups with bis‐3,5 trifluromethyl
substituents was engaged in the reaction, however only a
complex mixture was attained (entry 5). Screening of other
additives and solvents was also performed with catalyst II but
good result was not achieved (see supporting information for
details). Then we turned our attention on the reaction
temperature and it proved to be beneficial. Lowering the
temperature to 0 C and ‐20 C improved the enantiomeric
excess significantly (entries 7‐8) but the yield dropped.
Pleasingly, a good yield of 85% was achieved by running the
reaction for 7 days at ‐20 oC with enantiomeric excess
unchanged (entry 9).
be incorporated in the ortho‐, meta‐ and para‐position of the
aryl group and the corresponding products were achieved in
high yields and enantioselectivities (entries 1‐20). At first, 4‐
alkyl substituted aryl nitroketones 2b‐d were screened and the
products 3b‐d were isolated in good yields with high
enantioselectivities (entries 2‐4). Then nitroketone 2e with 4‐
anisyl group was employed in the reaction and the desired
product 3e was obtained in 92% ee (entry 5). Inspiring by this
result, other 4‐alkoxy substituted nitroketones were checked in
the reaction and excellent results were observed (entries 6‐11).
4‐Halo substituted aryl nitroketones also participated in the
o
o
reaction delivering the proudcts 3l‐n in good yields with
acceptable enantioselectivities (entries 12‐14). The reaction
After the detection of the best optimized conditions, the scope
and generality of the reaction was investigated. Initially a
2 | J. Name., 2012, 00, 1‐3
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preserved for
containing chroman
glyoxal, aq. formaldehyde and ammonium acetate12 and here
also the enantiomeric excess was nearly retained. Finally, 4‐
substituted chroman
enantiopurity after treatment of 3a with BF3.OEt2 and
triethylsilane (Scheme 2).
6
having N‐Boc protection. Then imidazole
outcome was also gratifying for the ortho‐ and meta‐
substituted nitroketones (entries 15‐19). A 2,4‐disubstituted
nitroketone 2t also participated in the reaction (entry 20).
Finally, α‐nitroketone 2n containing cyclohexyl group was
screened and delightfully excellent enantioselectivity was
maintained albeit the yield was moderate (entry 21).
The next stage of experiments involved screening of different o‐
hydroxyaromatic α,β‐unsaturated aldehydes 1 in this method (Table
3). Thus different 4‐halo and 4,6‐dihalo substituted α,β‐unsaturated
aldehydes 1b‐f were prepared and employed in the reaction. Here
also, the reaction progressed smoothly delivering the products in
moderate to high yields and with high enantioselectivities. In
particular the highest 96% ee was obtained for product 3z having 4‐
Cl, 6‐Br substitutions (entry 5). These halo group containing products
are important as they can be converted to other derivatives via cross‐
7
was synthesized by reaction of 4 with
8 was prepared in high yield and
O2N
H2N
BzHN
Zn
O
Bz2O
O
O
AcOH
O
O
Ph
O
O
Ph
58%
O
O
Ph
3a, 96% ee
99% conv.
4
5, 86% ee
(Boc)2O
glyoxal,
aq. HCHO
NH4OAc
58%
BocHN
BF3.OEt2
Et3SiH
95%
75%
N
O2N
N
O
coupling reactions.
A methoxy group containing o‐hydroxy
O
O
Ph
cinnamaldehyde 1g was also screened but lower enantioselectivity
was obtained for product 3z1 (entry 6). Also, 4‐methyl substituted o‐
hydroxycinnamaldehyde 1h delivered the corresponding product 3z2
with excellent enantiomeric excess (entry 7). However, when o‐
hydroxy cinnamaldehyde having 4‐nitro group 1i was examined, the
enantioselectivity was moderate for product 3z3 (entry 8). Then, 4,6‐
ditbutyl containing o‐hydroxycinnamaldehyde 1j was tested under
the standard reaction condition; unfortunately, no product
formation was observed possibly due to steric reason (entry 9).
O
6, 92% ee
O
O
O
Ph
8, 92% ee
7, 92% ee
Scheme 2 Synthetic transformations of 3a
.
To understand the mechanism of the reaction a cross‐over
experiment between product 3a, nitroketone 2e and o‐
hydroxycinnamaldehyde 1b was carried out in DCE with proline
catalyst (Scheme 3). After stirring the mixture for 2 days, only the
new product 3z5 was detected along with unreacted 3a. No cross‐
over product was found.
Table 3 Scope of o‐Hydroxyaromatic‐α,β‐unsaturated aldehydes
entrya
R
3
yieldb
drc
eed
1
2
3
4
5
6
7
8
9
4‐Cl
4‐Br
3v
3w
3x
89
93
81
51
60
93
85
88
‐
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
‐
90
84
92
90
96
60
90
68
‐
4,6‐diCl
4,6‐diBr
4‐Cl, 6‐Br
5‐OMe
4‐Me
3y
Scheme 3 Cross‐over experiment.
3z
3z1
3z2
3z3
3z4
The absolute configuration of the product 3p was elucidated to be
(2R,4S) by X‐ray crystallography.13 The absolute structure of other
products are expected to be same by analogy. Based on the absolute
configuration a plausible mechanism has been drawn in Scheme 4. It
is believed that at first o‐hydroxycinnamaldehyde 1a reacts with
catalyst II to provide iminium ion A. Since the Si face of the chiral
iminium ion is blocked by bulky diphenylsiloxymethyl group, the
addition of nitroketone 2a occurs only from the Re face to generate
intermediate B after hydrolysis. Intramolecular hemiacetalization
provides two diastereomeric hemiacetals C and D. Since in C, further
ketalization reaction cannot take place due to trans‐orientation, only
D participates in the ketalization step; and thus only E is obtained in
good yield. Finally retro‐Henry reaction of E generates chroman 3a.
4‐NO2
4,6‐ditbutyl
aReactions were carried out with 0.5 mmol of 1 and 0.1 mmol of 2a with 20 mol%
catalyst II and 20 mol% PhCO2H in 1 mL DCE at ‐20 oC for 7 days. bIsolated yield
after silica gel column chromatography. .cDetermined by 1H NMR. dDetermined by
HPLC.
____________________________________________________
Then the synthetic utility of our method was demonstrated by
carrying out few reactions on 3a (Scheme 2). Initially the
reduction of 3a using zinc and acetic acid was performed to
provide amino group containing chroman
Chroman was then subjected to
reactions.Protection of the amino group with benzoic anhydride
leaded to the formation of with slight reduction in
4
in 99% conversion.
4
a
range of
In summary, we have developed an efficient Michael‐
hemiacetalization‐acyl transfer reaction between α‐nitroketones
and o‐hydroxycinnamaldehydes. This reaction delivered single
5
enantiopurity. Gratifyingly, the enantiomeric excess was almost
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o
White solid (85%, 27 mg, >20:1 dr); MP‐115 C; Rf value 0.5
(5:95 EA in hex); 1H NMR (600 MHz, CDCl3) δ 8.02 (d, J = 7.2 Hz,
2H), 7.59 (t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.8 Hz, 2H), 7.24 (t, J = 7.8
Hz, 1H), 7.17 (d, J = 6.7 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 6.98 (d, J
= 8.3 Hz, 1H), 6.84 (t, J = 2.5 Hz, 1H), 5.04 (dd, J = 12.5, 10.3 Hz,
1H), 4.78 (dd, J = 12.5, 5.8 Hz, 1H), 3.93 – 3.85 (m, 1H), 2.45 (ddd,
J = 15.2, 6.6, 3.2 Hz, 1H), 2.37 (dt, J = 15.3, 2.0 Hz, 1H); 13C NMR
(150 MHz, CDCl3) δ 165.5, 151.3, 133.9, 130.0, 129.8, 129.4,
129.2, 128.9, 122.6, 118.8, 118.3, 90.4, 80.3, 30.7, 27.1; ESI‐MS
:
+
+ +
m/z calcd. for C17H19N2O5 [M+NH4 ]
331.1288, found
331.1291; FT‐IR (KBr): 3437, 2925, 1731, 1604, 1584, 1547,
1491, 1451, 1424, 1374, 1270, 1215, 1176, 1137, 1055 cm‐1; The
ee value 94% (tmajor = 20.52 min, tminor = 23.40 min) was
determined by HPLC using Daicel Chiralpak IA with hexane/i‐
PrOH (97:3) as the eluent, flow: 1.0 mL/min, 220 nm, 25 oC.
Scheme 4 Proposed mechanism.
(2
R
,4
S
)‐3,4‐dihydro‐4‐(nitromethyl)‐2
H
‐chromen‐2‐yl
4‐
methylbenzoate (3b):
diastereomer of 2,4‐disubstituted chroman compounds in good
to high yields and with excellent enantioselectivities. Also
selective functionalizations for the synthesis of different di‐
substituted as well as mono‐substituted chromans are
appealing. Given the high pharmaceutical significance of
chroman compounds our method might be beneficial to
synthesize these compounds in a convenient way.
o
White solid (76%, 25 mg, >20:1 dr); MP‐146 C; Rf value 0.5
(5:95 EA in hex); 1H NMR (600 MHz, CDCl3) δ 7.92 (d, J = 8.2 Hz,
2H), 7.27 (s, 2H), 7.24 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H),
7.02 (t, J = 7.4 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 6.84 (t, J = 2.3 Hz,
1H), 5.05 (dd, J = 12.5, 10.3 Hz, 1H), 4.79 (dd, J = 12.6, 5.8 Hz,
1H), 3.92 – 3.86 (m, 1H), 2.45 (ddd, J = 15.3, 6.6, 3.2 Hz, 1H),
2.42 (s, 3H), 2.37 (dt, J = 15.2, 1.7 Hz, 1H); 13C NMR (150 MHz,
CDCl3) δ 165.5, 151.4, 144.8, 130.0, 129.8, 129.6, 129.2, 126.7,
122.5, 118.8, 118.4, 90.3, 80.3, 30.7, 27.2, 21.9; ESI‐MS: m/z
Experiment section:
General Information: Chemicals and solvents were purchased
from commercial suppliers and used as received. 1H NMR
spectra were recorded on 400 MHz and 600 MHz
spectrometer.13C NMR spectra were recorded on 100MHz and
150MHz. Chemical shifts were reported in parts per million
(ppm), and the residual solvent peak was used as an internal
reference: proton (chloroform δ 7.26), carbon (chloroform δ
77.23). Multiplicity was indicated as follows: s (singlet), d
(doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of
doublet), bs (broad singlet),ddd (doublet doublet of doublet), dt
(doublet of triplet). Coupling constants were reported in Hertz
(Hz). HRMS spectra were recorded using ESI mode.
Enantiomeric ratios were determined by HPLC analysis using
Dionex (Ultimate 3000) instrument with chiral columns in
comparison with authentic racemic materials. For single crystal
X‐ray analysis the intensity data we recollected using Bruker
Smart Apex‐II. All solvent were purified using standard
procedure and store under MS 4 Ao .Silica gel (60‐120 mesh) was
used for column chromatography. Reactions were monitored by
TLC on silica gel 60 F254 (0.25mm).
+
+ +
calcd. for C18H21N2O5 [M+NH4 ] 345.1445, found 345.1442; FT‐
IR (KBr): 3436, 2924, 2853, 1730, 1610, 1582, 1548, 1490, 1426,
1375, 1331, 1274, 1215, 1175, 1091, 1074 cm‐1; The ee value
92% (tmajor = 29.78 min, tminor = 37.72 min) was determined by
HPLC using Daicel Chiralpak IA with hexane/i‐PrOH (98:2) as the
eluent, flow: 1.0 mL/min, 220 nm, 25 oC.
(2
R
,4
S)‐3,4‐dihydro‐4‐(nitromethyl)‐2
H
‐chromen‐2‐yl
4‐
isopropylbenzoate (3c):
Colourless sticky oil (84%, 30 mg, >20:1 dr); Rf value 0.5 (5:95
EA in hex); 1H NMR (600 MHz, CDCl3) δ 7.94 (d, J = 8.3 Hz, 2H),
7.31 (d, J = 8.3 Hz, 2H), 7.23 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 7.7 Hz,
1H), 7.00 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.82 (t, J =
2.3 Hz, 1H), 5.06 (dd, J = 12.6, 10.3 Hz, 1H), 4.78 (dd, J = 12.6,
5.8 Hz, 1H), 3.92 – 3.86 (m, 1H), 2.95 (dt, J = 13.8, 6.9 Hz, 1H),
2.44 (ddd, J = 15.2, 6.6, 3.2 Hz, 1H), 2.36 (dt, J = 15.2, 1.9 Hz,
1H), 1.25 (d, J = 6.8 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 165.5,
155.5, 151.3, 130.2, 129.8, 129.2, 127.0, 127.0, 122.5, 118.8,
118.4, 90.2, 80.3, 34.5, 30.7, 27.2, 23.8, 23.8; ESI‐MS: m/z calcd.
+
+ +
for C20H25N2O5 [M+NH4 ] 373.1758, found 373.1762; FT‐IR
(KBr): 3458, 2963, 2927, 2871, 1730, 1610, 1586, 1552, 1490,
1458, 1421, 1379, 1268, 1216, 1180, 1075 cm‐1; The ee value
90% (tmajor = 28.01 min, tminor = 33.01 min) was determined by
HPLC using Daicel Chiralpak IA with hexane/i‐PrOH (98:2) as the
eluent, flow: 1.0 mL/min, 220 nm, 25 oC.
General procedure for the synthesis of compound (3):
To a solution of o‐hydroxycinnamaldehyde
1 (0.5 mmol) in 1 ml
DCE were added II (20 mol%) and PhCO2H (20 mol%) at ‐20 oC,
after 2 hr α‐nitroketones
2
(0.1 mmol) was added. The reaction
o
(2
R,4S)‐3,4‐dihydro‐4‐(nitromethyl)‐2H‐chromen‐2‐yl 4‐tert‐
mixture was stirred at ‐20 C for 7 days. After completion of
reaction, the products were purified by silica gel column
chromatography (hexane/ethyl acetate).
butylbenzoate (3d):
White semisolid (68%, 25 mg, >20:1 dr); Rf value 0.5 (5:95 EA in
hex); 1H NMR (600 MHz, CDCl3) δ 7.95 (d, J = 8.4 Hz, 2H), 7.47
(d, J = 8.4 Hz, 2H), 7.23 (t, J = 8.4 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H),
7.00 (t, J = 7.5 Hz, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.83 (s, 1H), 5.07
(dd, J = 12.5, 10.3 Hz, 1H), 4.78 (dd, J = 12.6, 5.8 Hz, 1H), 3.94 –
(2R,4S)‐3,4‐dihydro‐4‐(nitromethyl)‐2H‐chromen‐2‐yl
benzoate (3a):
4 | J. Name., 2012, 00, 1‐3
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3.84 (m, 1H), 2.44 (ddd, J = 15.2, 6.6, 3.1 Hz, 1H), 2.36 (d, J = 15.2 114.6, 90.1, 80.3, 70.0, 30.7, 27.3, 22.6, 10.6; ESI‐MS: m/z calcd.
Hz, 1H), 1.32 (s, 9H); 13C NMR (150 MHz, CDCl3) δ 165.4, 157.7, for C20H25N2O6 [M+NH4 ] 389.1707, found 389.1703; FT‐IR
151.3, 129.9, 129.8, 129.2, 126.6, 125.9, 122.5, 118.8, 118.4, (KBr): 3418, 2966, 2876, 1723, 1604, 1548, 1510, 1492, 1456,
+
+ +
90.1, 80.4, 35.4, 31.3, 30.7, 27.2; ESI‐MS: m/z calcd. for 1422, 1377, 1314, 1259, 1214, 1165, 1056 cm‐1; The ee value
+ +
C21H27N2O5+ [M+NH4 ] 387.1914, found 387.1918; FT‐IR (KBr)
:
96% (tmajor = 28.97 min, tminor = 39.23 min) was determined by
3438, 2960, 2925, 1732, 1607, 1587, 1489, 1458, 1435, 1407, HPLC using Daicel Chiralpak IA with hexane/i‐PrOH (97:3) as the
1379, 1267, 1184, 1214, 1184, 1131 cm‐1; The ee value 90% eluent, flow: 1.0 mL/min, 254 nm, 25 oC.
(tmajor = 22.39 min, tminor = 24.75 min) was determined by HPLC (2
R
,4
S
)‐3,4‐dihydro‐4‐(nitromethyl)‐2
H
‐chromen‐2‐yl
4‐
using Daicel Chiralpak IA with hexane/i‐PrOH (98:2) as the isopropoxybenzoate (3h):
eluent, flow: 1.0 mL/min, 220 nm, 25 oC.
(2 ,4 )‐3,4‐dihydro‐4‐(nitromethyl)‐2
methoxybenzoate (3e):
Colorless sticky oil (78%, 29 mg, >20:1 dr); Rf value 0.3 (5:95 EA
4‐ in hex); 1H NMR (600 MHz, CDCl3) δ 7.95 (d, J = 8.7 Hz, 2H), 7.23
(t, J = 7.7 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H),
R
S
H
‐chromen‐2‐yl
o
White solid (90%, 31 mg, >20:1 dr); MP‐120 C; Rf value 0.3 6.97 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 8.7 Hz, 2H), 6.81 (s, 1H), 5.04
(5:95 EA in hex); 1H NMR (600 MHz, CDCl3) δ 7.98 (d, J = 8.9 Hz, (dd, J = 12.3, 10.5 Hz, 1H), 4.78 (dd, J = 12.6, 5.8 Hz, 1H), 4.63
2H), 7.23 (t, J = 7.8 Hz, 1H), 7.17 (d, J = 6.8 Hz, 1H), 7.01 (t, J = (dt, J = 12.0, 6.0 Hz, 1H), 3.88 (dd, J = 13.2, 8.6 Hz, 1H), 2.43 (ddd,
7.5 Hz, 1H), 6.97 (d, J = 8.2 Hz, 1H), 6.93 (d, J = 8.9 Hz, 2H), 6.81 J = 15.1, 6.5, 3.1 Hz, 1H), 2.34 (d, J = 15.2 Hz, 1H), 1.35 (dd, J =
(t, J = 2.3 Hz, 1H), 5.04 (dd, J = 12.6, 10.3 Hz, 1H), 4.78 (dd, J = 5.9, 3.1 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 165.1, 162.6,
12.6, 5.8 Hz, 1H), 3.89 (dd, J = 10.4, 5.5 Hz, 1H), 3.86 (s, 3H), 2.43 151.4, 132.1, 129.8, 129.1, 122.4, 121.1, 118.7, 118.4, 115.5,
(ddd, J = 15.2, 6.5, 3.2 Hz, 1H), 2.35 (dt, J = 15.2, 1.9 Hz, 1H); 13
NMR (150 MHz, CDCl3) δ 165.1, 164.1, 151.4, 132.1, 129.8, C20H25N2O6+ [M+NH4 ] 389.1707, found 389.1709; FT‐IR (KBr)
C
90.1, 80.3, 70.4, 30.7, 27.3, 22.1, 22.0; ESI‐MS: m/z calcd. for
+ +
:
129.1, 122.5, 121.6, 118.9, 118.4, 114.1, 90.1, 80.3, 55.7, 30.7, 3444, 2924, 2854, 1875, 1725, 1606, 1551, 1508, 1489, 1457,
+ +
27.2; ESI‐MS: m/z calcd. for C18H21N2O6+ [M+NH4 ] 361.1394, 1426, 1380, 1313, 1256, 1165, 1110, 1072 cm‐1; The ee value
found 361.1399; FT‐IR (KBr): 2924, 2851, 1727, 1605, 1548, 96% (tmajor = 28.68 min, tminor = 36.92 min) was determined by
1512, 1491, 1452, 1425, 1377, 1326, 1214, 1185, 1165, 1134, HPLC using Daicel Chiralpak IA with hexane/i‐PrOH (97:3) as the
1091 cm‐1; The ee value 92% (tmajor = 38.43 min, tminor = 47.84 eluent, flow: 1.0 mL/min, 220 nm, 25 oC.
min) was determined by HPLC using Daicel Chiralpak IA with (2
R
,4
S
)‐3,4‐dihydro‐4‐(nitromethyl)‐2
H
‐chromen‐2‐yl
4‐
hexane/i‐PrOH (97:3) as the eluent, flow: 1.0 mL/min, 220 nm, isobutoxybenzoate (3i):
25 oC.
(2 ,4
ethoxybenzoate (3f):
White semisolid (86%, 33 mg, >20:1 dr); Rf value 0.3 (5:95 EA in
4‐ hex); 1H NMR (600 MHz, CDCl3) δ 7.96 (d, J = 8.8 Hz, 2H), 7.24
(t, J = 7.8 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 7.02 – 6.96 (m, 2H),
R
S)‐3,4‐dihydro‐4‐(nitromethyl)‐2H‐chromen‐2‐yl
White semisolid (70%, 25 mg, >20:1 dr); Rf value 0.3 (5:95 EA in 6.92 (d, J = 8.9 Hz, 2H), 6.81 (t, J = 2.3 Hz, 1H), 5.04 (dd, J = 12.6,
hex); 1H NMR (600 MHz, CDCl3) δ 7.96 (d, J = 8.9 Hz, 2H), 7.23 10.3 Hz, 1H), 4.77 (dd, J = 12.6, 5.8 Hz, 1H), 3.91 – 3.85 (m, 1H),
(t, J = 7.2 Hz, 1H), 7.17 (d, J = 7.1 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 3.76 (d, J = 7.8 Hz, 2H), 2.43 (ddd, J = 15.1, 6.5, 3.2 Hz, 1H), 2.37
6.97 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 8.9 Hz, 2H), 6.81 (t, J = 2.3 Hz, – 2.32 (m, 1H), 2.09 (dt, J = 13.3, 6.6 Hz, 1H), 1.02 (d, J = 6.7 Hz,
1H), 5.04 (dd, J = 12.6, 10.3 Hz, 1H), 4.78 (dd, J = 12.6, 5.8 Hz, 6H); 13C NMR (150 MHz, CDCl3) δ 165.2, 163.9, 151.4, 132.1,
1H), 4.08 (q, J = 7.0 Hz, 2H), 3.88 (dt, J = 11.0, 6.1 Hz, 1H), 2.43 129.8, 129.1, 122.5, 121.3, 118.9, 118.4, 114.6, 90.1, 80.3, 74.8,
+
(ddd, J = 15.1, 6.6, 3.2 Hz, 1H), 2.37 – 2.32 (m, 1H), 1.43 (t, J = 30.7, 28.4, 27.3, 19.4; ESI‐MS: m/z calcd. for C21H27N2O6
7.0 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 165.1, 163.5, 151.4, [M+NH4 ] 403.1864, found 403.1862; FT‐IR (KBr): 3421, 2923,
+ +
132.1, 129.8, 129.1, 122.5, 121.4, 118.8, 118.4, 114.6, 90.1, 2854, 1722, 1605, 1549, 1511, 1492, 1465, 1377, 1259, 1215,
+
80.3, 64.0, 30.7, 27.3, 14.8; ESI‐MS: m/z calcd. for C19H23N2O6
1165, 1113, 1090 cm‐1; The ee value 96% (tmajor = 22.37 min,
+ +
[M+NH4 ] 375.1551, found 375.1548; FT‐IR (KBr): 2984, 2925, tminor = 29.95 min) was determined by HPLC using Daicel
2854, 1724, 1606, 1583, 1549, 1511, 1491, 1455, 1423, 1378, Chiralpak IA with hexane/i‐PrOH (97:3) as the eluent, flow: 1.0
1378, 1324, 1258, 1214, 1168, 1135, 1113, 1075 cm‐1; The ee mL/min, 220 nm, 25 oC.
value 90% (tmajor = 33.46 min, tminor = 44.58 min) was determined (2
R
,4
S
)‐3,4‐dihydro‐4‐(nitromethyl)‐2
H
‐chromen‐2‐yl
4‐
by HPLC using Daicel Chiralpak IA with hexane/i‐PrOH (97:3) as (allyloxy)benzoate (3j):
the eluent, flow: 1.0 mL/min, 220 nm, 25 oC.
(2 ,4 )‐3,4‐dihydro‐4‐(nitromethyl)‐2 ‐chromen‐2‐yl
propoxybenzoate (3g):
White semisolid (60%, 22 mg, >20:1 dr); Rf value 0.35 (5:95 EA
4‐ in hex); 1H NMR (600 MHz, CDCl3) δ 7.97 (d, J = 8.9 Hz, 2H), 7.23
(t, J = 8.6 Hz, 1H), 7.17 (d, J = 7.7 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H),
R
S
H
Yellow semisolid (84%, 31 mg, >20:1 dr); Rf value 0.3 (5:95 EA in 6.97 (d, J = 8.2 Hz, 1H), 6.94 (d, J = 8.9 Hz, 2H), 6.81 (t, J = 2.4 Hz,
hex); 1H NMR (600 MHz, CDCl3) δ 7.96 (d, J = 8.9 Hz, 2H), 7.24 1H), 6.03 (ddd, J = 22.5, 10.5, 5.3 Hz, 1H), 5.41 (d, J = 17.3 Hz,
(t, J = 8.4 Hz, 1H), 7.17 (d, J = 7.7 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 1H), 5.31 (d, J = 9.3 Hz, 1H), 5.04 (dd, J = 12.6, 10.3 Hz, 1H), 4.77
6.97 (d, J = 8.2 Hz, 1H), 6.91 (d, J = 8.9 Hz, 2H), 6.81 (t, J = 2.2 Hz, (dd, J = 12.6, 5.8 Hz, 1H), 4.59 (d, J = 5.3 Hz, 2H), 3.91 – 3.85 (m,
1H), 5.04 (dd, J = 12.6, 10.3 Hz, 1H), 4.77 (dd, J = 12.6, 5.8 Hz, 1H), 2.43 (ddd, J = 15.2, 6.6, 3.3 Hz, 1H), 2.34 (dt, J = 15.2, 1.9
1H), 3.96 (t, J = 6.5 Hz, 2H), 3.91 – 3.85 (m, 1H), 2.43 (ddd, J = Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 165.1, 163.1, 151.4, 132.6,
15.1, 6.4, 3.1 Hz, 1H), 2.35 (d, J = 15.2 Hz, 1H), 1.85 – 1.79 (m, 132.1, 129.8, 129.2, 122.5, 121.8, 118.8, 118.5, 118.4, 114.9,
2H), 1.03 (t, J = 7.4 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 165.2, 90.2, 80.3, 69.1, 30.8, 27.2; ESI‐MS: m/z calcd. for C20H23N2O6
+
+ +
163.7, 151.4, 132.1, 129.8, 129.1, 122.4, 121.3, 118.8, 118.4, [M+NH4 ] 387.1551, found 387.1550; FT‐IR (KBr): 3074, 2924,
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2854, 1724, 1606, 1582, 1549, 1510, 1489, 1456, 1424, 1379, (2
R
,4
S
)‐3,4‐dihydro‐4‐(nitromethyl)‐2
H
‐chromen‐2‐yl
4‐
1258, 1214, 1133, 1073 cm‐1; The ee value 88% (tmajor = 35.34 bromobenzoate (3n):
o
min, tminor = 47.62 min) was determined by HPLC using Daicel White solid (70%, 27 mg, >20:1 dr); MP‐157 C; Rf value 0.5
Chiralpak IA with hexane/i‐PrOH (97:3) as the eluent, flow: 1.0 (5:95 EA in hex); 1H NMR (600 MHz, CDCl3) δ 7.89 (d, J = 8.6 Hz,
mL/min, 220 nm, 25 oC.
(2 ,4 )‐3,4‐dihydro‐4‐(nitromethyl)‐2
(benzyloxy)benzoate (3k):
2H), 7.61 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 8.4 Hz, 1H), 7.18 (d, J =
4‐ 6.9 Hz, 1H), 7.02 (t, J = 7.5 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.81
(t, J = 2.4 Hz, 1H), 4.98 (dd, J = 12.4, 10.7 Hz, 1H), 4.75 (dd, J =
R
S
H‐chromen‐2‐yl
Yellow semisolid (84%, 35 mg, >20:1 dr); Rf value 0.3 (5:95 EA in 12.5, 5.7 Hz, 1H), 3.92 – 3.85 (m, 1H), 2.44 (ddd, J = 15.3, 6.5,
hex); 1H NMR (600 MHz, CDCl3) δ 7.98 (d, J = 8.9 Hz, 2H), 7.42 – 3.2 Hz, 1H), 2.35 (dt, J = 15.3, 1.9 Hz, 1H); 13C NMR (150 MHz,
7.38 (m, 4H), 7.34 (t, J = 7.0 Hz, 1H), 7.24 (t, J = 7.8 Hz, 1H), 7.17 CDCl3) δ 164.8, 151.2, 132.3, 131.4, 129.9, 129.2, 129.1, 128.3,
(d, J = 7.6 Hz, 1H), 7.01 (t, J = 7.1 Hz, 3H), 6.97 (d, J = 8.2 Hz, 1H), 122.7, 118.6, 118.4, 90.8, 80.2, 30.7, 27.0; ESI‐MS: m/z calcd.
+ +
6.81 (s, 1H), 5.12 (s, 2H), 5.03 (dd, J = 12.5, 10.3 Hz, 1H), 4.77 for C17H18BrN2O5+ [M+NH4 ] 409.0394, found 409.0394; FT‐IR
(dd, J = 12.6, 5.8 Hz, 1H), 3.91 – 3.85 (m, 1H), 2.43 (ddd, J = 15.1, (KBr): 3436, 2922, 2847, 1729, 1588, 1543, 1488, 1429, 1377,
6.5, 3.2 Hz, 1H), 2.34 (d, J = 15.2 Hz, 1H); 13C NMR (150 MHz, 1332, 1271, 1217, 1134, 1071, 1010, 934 cm‐1; The ee value 88%
CDCl3) δ 165.0, 163.2, 151.4, 136.2, 132.1, 129.8, 129.1, 128.9, (tmajor = 30.48 min, tminor = 34.88 min) was determined by HPLC
128.5, 127.6, 122.5, 121.9, 118.8, 118.4, 115.0, 90.2, 80.3, 70.4, using Daicel Chiralpak IA with hexane/i‐PrOH (98:2) as the
+
+ +
30.7, 27.2; ESI‐MS: m/z calcd. for C24H25N2O6 [M+NH4 ]
437.1707, found 437.1703; FT‐IR (KBr): 3484, 2923, 1724, 1605, (2
eluent, flow: 1.0 mL/min, 220 nm, 25 oC.
,4 )‐3,4‐dihydro‐4‐(nitromethyl)‐2 ‐chromen‐2‐yl
R
S
H
3‐
1547, 1510, 1455, 1378, 1260, 1215, 1169, 1087, 999, 946 cm‐1; methylbenzoate (3o):
The ee value 96% (tmajor = 55.84 min, tminor = 75.63 min) was Yellow semisolid (69%, 23 mg, >20:1 dr); Rf value 0.5 (5:95 EA in
determined by HPLC using Daicel Chiralpak IA with hexane/i‐ hex); 1H NMR (600 MHz, CDCl3) δ 7.85 (s, 1H), 7.81 (d, J = 7.7 Hz,
PrOH (97:3) as the eluent, flow: 1.0 mL/min, 220 nm, 25 oC.
1H), 7.40 (d, J = 7.5 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.24 (t, J =
4‐ 7.8 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 6.98
(d, J = 8.2 Hz, 1H), 6.82 (t, J = 2.3 Hz, 1H), 5.06 (dd, J = 12.6, 10.4
(2
R,4S)‐3,4‐dihydro‐4‐(nitromethyl)‐2H‐chromen‐2‐yl
fluorobenzoate (3l):
Yellow semisolid (76%, 25 mg, >20:1 dr); Rf value 0.5 (5:95 EA in Hz, 1H), 4.77 (dd, J = 12.7, 5.8 Hz, 1H), 3.92 – 3.86 (m, 1H), 2.44
hex); 1H NMR (600 MHz, CDCl3) δ 8.05 (dd, J = 8.9, 5.4 Hz, 2H), (ddd, J = 15.2, 6.5, 3.2 Hz, 1H), 2.40 (s, 3H), 2.36 (dt, J = 15.2, 1.9
7.24 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 6.8 Hz, 1H), 7.13 (t, J = 8.6 Hz, Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 165.6, 151.4, 138.8, 134.6,
2H), 7.02 (t, J = 7.1 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.81 (t, J = 130.6, 129.8, 129.3, 129.2, 128.8, 127.1, 122.5, 118.8, 118.4,
+
2.5 Hz, 1H), 5.00 (dd, J = 12.5, 10.7 Hz, 1H), 4.76 (dd, J = 12.5, 90.4, 80.2, 30.7, 27.2, 21.4; ESI‐MS: m/z calcd. for C18H21N2O5
+ +
5.7 Hz, 1H), 3.92 – 3.85 (m, 1H), 2.44 (ddd, J = 15.3, 6.6, 3.2 Hz, [M+NH4 ] 345.1445, found 345.1449; FT‐IR(KBr): 3059, 2918,
2855, 1731, 1608, 1548, 1487, 1457, 1434, 1382, 1329, 1298,
167.2, 165.5, 164.5, 151.3, 132.6 (d, J = 9 Hz), 129.9, 129.2, 1276, 1217, 1188, 1130, 1112, 1070, 1051 cm‐1; The ee value
1H), 2.35 (dt, J = 15.3, 2.0 Hz, 1H); 13C NMR (150 MHz, CDCl3)
δ
125.7 (d, J = 3 Hz), 122.6, 118.7, 118.4, 116.1 (d, J = 22.5 Hz), 86% (tmajor = 23.69 min, tminor = 27.79 min) was determined by
+
90.6, 80.2, 30.7, 27.1; ESI‐MS: m/z calcd. for C17H18FN2O5
HPLC using Daicel Chiralpak IA with hexane/i‐PrOH (98:2) as the
[M+NH4 ] 349.1194, found 349.1193; FT‐IR (KBr): 3436, 2924, eluent, flow: 1.0 mL/min, 220 nm, 25 oC.
+ +
2853, 1731, 1603, 1550, 1507, 1490, 1453, 1426, 1375, 1272, (2
R
,4
S
)‐3,4‐dihydro‐4‐(nitromethyl)‐2
H
‐chromen‐2‐yl
3‐
1237, 1154, 1055 cm‐1; The ee value 84% (tmajor = 26.13 min, chlorobenzoate (3p):
o
tminor = 31.26 min) was determined by HPLC using Daicel White solid (78%, 27 mg, >20:1 dr); MP‐127 C, Rf value 0.5
Chiralpak IA with hexane/i‐PrOH (98:2) as the eluent, flow: 1.0 (5:95 EA in hex); 1H NMR (600 MHz, CDCl3) δ 8.03 (t, J = 1.6 Hz,
mL/min, 220 nm, 25 oC.
(2 ,4 )‐3,4‐dihydro‐4‐(nitromethyl)‐2
chlorobenzoate (3m):
White solid (72%, 25 mg, >20:1 dr); MP‐125 C; Rf value 0.5 4.99 (dd, J = 12.4, 10.8 Hz, 1H), 4.77 (dd, J = 12.5, 5.7 Hz, 1H),
(5:95 EA in hex); 1H NMR (600 MHz, CDCl3) δ 7.97 (d, J = 8.6 Hz, 3.92 – 3.86 (m, 1H), 2.44 (ddd, J = 15.3, 6.5, 3.2 Hz, 1H), 2.36 (dt,
2H), 7.44 (d, J = 8.6 Hz, 2H), 7.24 (d, J = 8.4 Hz, 1H), 7.18 (d, J = J = 15.3, 2.0 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 164.4, 151.2,
7.6 Hz, 1H), 7.02 (t, J = 7.8 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.82 135.1, 133.9, 131.2, 130.2, 130.1, 129.9, 129.2, 128.0, 122.7,
(t, J = 2.1 Hz, 1H), 4.98 (dd, J = 12.4, 10.7 Hz, 1H), 4.76 (dd, J = 118.6, 118.4, 90.9, 80.2, 30.7, 27.0; ESI‐MS: m/z calcd. for
1H), 7.91 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.41 (t, J =
4‐ 7.9 Hz, 1H), 7.24 (d, J = 8.4 Hz, 1H), 7.18 (d, J = 7.4 Hz, 1H), 7.03
(t, J = 7.1 Hz, 1H), 6.98 (d, J = 8.2 Hz, 1H), 6.82 (t, J = 2.3 Hz, 1H),
R
S
H
‐chromen‐2‐yl
o
+
+ +
12.5, 5.7 Hz, 1H), 3.92 – 3.85 (m, 1H), 2.44 (ddd, J = 15.3, 6.5, C17H18ClN2O5 [M+NH4 ] 365.0899, found 365.0894; FT‐IR
3.2 Hz, 1H), 2.35 (dt, J = 15.3, 1.8 Hz, 1H); 13C NMR (150 MHz, (KBr): 2920, 2844, 1734, 1579, 1548, 1488, 1461, 1435, 1382,
CDCl3) δ 164.7, 151.2, 140.4, 131.3, 129.9, 129.3, 129.2, 127.9, 1330, 1287, 1254, 1209, 1136, 1117, 1069, 1051 cm‐1; The ee
122.7, 118.6, 118.4, 90.7, 80.2, 30.7, 27.0; ESI‐MS: m/z calcd. value 86% (tmajor = 25.81 min, tminor = 28.60 min) was determined
+ +
for C17H18ClN2O5+ [M+NH4 ] 365.0899, found 365.0898; FT‐IR by HPLC using Daicel Chiralpak IA with hexane/i‐PrOH (98:2) as
(KBr): 3436, 2973, 2924, 1729, 1590, 1548, 1488, 1452, 1400, the eluent, flow: 1.0 mL/min, 220 nm, 25 oC.
1375, 1329, 1274, 1215, 1170, 1136, 1095, 1057, 1008 cm‐1; The (2
R
,4
S
)‐3,4‐dihydro‐4‐(nitromethyl)‐2
H
‐chromen‐2‐yl
2‐
ee value 82% (tmajor = 27.65 min, tminor = 32.06 min) was methylbenzoate (3q):
determined by HPLC using Daicel Chiralpak IA with hexane/i‐ Yellow semisolid (80%, 26 mg, >20:1 dr); Rf value 0.5 (5:95 EA in
PrOH (98:2) as the eluent, flow: 1.0 mL/min, 220 nm, 25 oC.
hex); 1H NMR (600 MHz, CDCl3) δ 7.80 (d, J = 7.8 Hz, 1H), 7.42
6 | J. Name., 2012, 00, 1‐3
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(t, J = 7.5 Hz, 1H), 7.28 – 7.22 (m, 4H), 7.17 (t, J = 9.8 Hz, 1H), 2.43 (ddd, J = 15.1, 6.7, 3.1 Hz, 1H), 2.37 (t, J = 1.9 Hz, 1H), 2.34
7.00 (dd, J = 17.5, 7.9 Hz, 2H), 6.81 (t, J = 2.5 Hz, 1H), 4.98 (dd, J (s, 3H); 13C NMR (150 MHz, CDCl3) δ 165.7, 151.5, 143.5, 141.5,
= 12.4, 10.4 Hz, 1H), 4.72 (dd, J = 12.5, 5.6 Hz, 1H), 3.89 – 3.83 132.9, 130.5, 129.7, 129.2, 126.9, 125.8, 122.5, 119.0, 118.3,
(m, 1H), 2.60 (s, 3H), 2.44 (ddd, J = 15.2, 6.6, 3.1 Hz, 1H), 2.37 89.8, 80.3, 30.8, 27.3, 21.7, 21.6; ESI‐MS: m/z calcd. for
+ +
(dt, J = 15.2, 2.0 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 165.8, C19H23N2O5+ [M+NH4 ] 359.1601, found 359.1601; FT‐IR (KBr)
:
151.4, 141.2, 132.8, 132.1, 130.3, 129.8, 129.2, 128.8, 126.1, 2961, 2931, 1726, 1610, 1582, 1548, 1457, 1429, 1337, 1256,
122.5, 118.9, 118.3, 90.0, 80.3, 30.8, 27.2, 21.7; ESI‐MS: m/z 1217, 1151, 1070, 1044 cm‐1; The ee value 94% (tmajor = 17.84
+ +
calcd. for C17H21N2O5+ [M+NH4 ] 345.1445, found 345.144; FT‐ min, tminor = 28.59 min) was determined by HPLC using Daicel
IR (KBr): 2923, 2853, 1726, 1587, 1550, 1488, 1454, 1432, 1377, Chiralpak IA with hexane/i‐PrOH (98:2) as the eluent, flow: 1.0
1331, 1249, 1214, 1191, 1128, 1065, 1037 cm‐1; The ee value mL/min, 274 nm, 25 oC.
96% (tmajor = 19.05 min, tminor = 32.28 min) was determined by (2
R,4S)‐3,4‐dihydro‐4‐(nitromethyl)‐2H‐chromen‐2‐yl
HPLC using Daicel Chiralpak IA with hexane/i‐PrOH (98:2) as the cyclohexanecarboxylate (3u):
eluent, flow: 1.0 mL/min, 220 nm, 25 oC.
(2 ,4 )‐3,4‐dihydro‐4‐(nitromethyl)‐2 ‐chromen‐2‐yl
methoxybenzoate (3r):
Colorless sticky oil (47%, 15 mg, >20:1 dr); Rf value 0.55 (5:95
2‐ EA in hex); 1H NMR (600 MHz, CDCl3) δ 7.23 (t, J = 8.5 Hz, 1H),
7.14 (d, J = 7.7 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 8.2 Hz,
R
S
H
Colorless sticky oil (73%, 25 mg, >20:1 dr); Rf value 0.3 (5:95 EA 1H), 6.61 (t, J = 2.3 Hz, 1H), 4.92 (dd, J = 12.6, 10.3 Hz, 1H), 4.69
in hex); 1H NMR (600 MHz, CDCl3) δ 7.80 (dd, J = 7.8, 1.7 Hz, 1H), (dd, J = 12.6, 5.8 Hz, 1H), 3.84 – 3.77 (m, 1H), 2.34 – 2.28 (m,
7.48 (t, J = 8.7 Hz, 1H), 7.23 (t, J = 7.1 Hz, 1H), 7.14 (d, J = 7.5 Hz, 2H), 2.19 (dt, J = 15.2, 1.9 Hz, 1H), 1.95 – 1.89 (m, J = 7.5, 3.5,
1H), 7.01 – 6.96 (m, 3H), 6.94 (d, J = 8.4 Hz, 1H), 6.85 (t, J = 2.2 1.8 Hz, 1H), 1.88 – 1.83 (m, 1H), 1.77 – 1.70 (m, 2H), 1.65 – 1.61
Hz, 1H), 5.09 (dd, J = 13.0, 9.2 Hz, 1H), 4.79 (dd, J = 13.0, 6.0 Hz, (m, 1H), 1.46 – 1.39 (m, 2H), 1.30 – 1.27 (m, 1H), 1.24 – 1.18 (m,
1H), 3.85 (dd, J = 14.7, 6.8 Hz, 1H), 3.72 (s, 3H), 2.45 (ddd, J = 2H); 13C NMR (150 MHz, CDCl3) δ 174.5, 151.3, 129.7, 129.2,
15.1, 6.8, 3.1 Hz, 1H), 2.38 (d, J = 15.1 Hz, 1H); 13C NMR (150 122.4, 118.9, 118.3, 89.2, 80.3, 43.4, 30.7, 29.00, 28.9, 27.1,
+
+ +
MHz, CDCl3) δ 165.4, 159.2, 151.4, 134.5, 132.4, 129.6, 129.2, 25.8, 25.5; ESI‐MS: m/z calcd. for C17H25N2O5 [M+NH4 ]
122.4, 120.6, 119.4, 119.3, 118.4, 112.2, 89.7, 80.3, 55.9, 30.5, 337.1758, found 337.1757; FT‐IR (KBr): 3445, 2931, 2855, 1748,
+ +
27.5; ESI‐MS: m/z calcd. for C18H21N2O6+ [M+NH4 ] 361.1394, 1586, 1552, 1490, 1454, 1379, 1221, 1158, 1116, 1076 cm ‐1; The
found 361.1390; FT‐IR (KBr): 2923, 2852, 1726, 1603, 1550, ee value 94% (tmajor = 13.69 min, tminor = 15.63 min) was
1490, 1462, 1436, 1380, 1297, 1251, 1212, 1185, 1037, 946 cm‐ determined by HPLC using Daicel Chiralpak IA with hexane/i‐
1; The ee value 90% (tmajor = 41.06 min, tminor = 33.79 min) was PrOH (98:2) as the eluent, flow: 1.0 mL/min, 220 nm, 25 oC.
determined by HPLC using Daicel Phenomenex Lux Amalyse‐A2 (2
R,4S)‐6‐chloro‐3,4‐dihydro‐4‐(nitromethyl)‐2H‐chromen‐2‐
with hexane/i‐PrOH (90:10) as the eluent, flow: 1.0 mL/min, 220 yl benzoate (3v):
nm, 25 oC.
(2 ,4 )‐3,4‐dihydro‐4‐(nitromethyl)‐2
fluorobenzoate (3s):
White solid (89%, 31 mg, >20:1 dr); MP‐110 C, Rf value 0.5
2‐ (5:95 EA in hex); 1H NMR (600 MHz, CDCl3) δ 8.01 (d, J = 7.2 Hz,
2H), 7.60 (t, J = 6.9 Hz, 1H), 7.47 (t, J = 7.8 Hz, 2H), 7.19 (dd, J =
o
R
S
H‐chromen‐2‐yl
White semisolid (91%, 30 mg, >20:1 dr); Rf value 0.5 (5:95 EA in 16.4, 2.4 Hz, 2H), 6.92 (d, J = 8.7 Hz, 1H), 6.83 (t, J = 2.3 Hz, 1H),
hex); 1H NMR (600 MHz, CDCl3) δ 7.98 (t, J = 7.6 Hz, 1H), 7.55 5.04 (dd, J = 12.7, 10.4 Hz, 1H), 4.76 (dd, J = 12.7, 5.7 Hz, 1H),
(dd, J = 12.6, 6.3 Hz, 1H), 7.23 (t, J = 7.6 Hz, 2H), 7.16 (d, J = 7.4 3.91 – 3.83 (m, 1H), 2.42 (ddd, J = 15.3, 6.5, 3.1 Hz, 1H), 2.36 (dt,
Hz, 1H), 7.15 – 7.10 (m, 1H), 7.01 (t, J = 7.5 Hz, 1H), 6.97 (d, J = J = 15.3, 2.0 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 165.3, 149.9,
8.2 Hz, 1H), 6.87 (s, 1H), 5.14 – 5.05 (m, 1H), 4.75 (dd, J = 12.9, 134.0, 130.0, 129.9, 129.2, 128.9, 128.8, 127.4, 120.4, 119.8,
5.8 Hz, 1H), 3.86 (dd, J = 15.0, 6.3 Hz, 1H), 2.46 (ddd, J = 15.2, 90.2, 79.9, 30.5, 26.9; ESI‐MS: m/z calcd. for C17H14ClNaNO5
6.6, 3.1 Hz, 1H), 2.40 (d, J = 15.3 Hz, 1H); 13C NMR (150 MHz, [M+Na] 370.0458, found 370.0446; FT‐IR (KBr): 3438, 3046,
CDCl3) δ 163.3, 162.8, 161.1, 151.1, 135.5 (d, J = 9 Hz), 132.8, 2922, 1732, 1582, 1549, 1482, 1549, 1485, 1452, 1411, 1379,
129.7, 129.3, 124.6 (d, J = 3 Hz), 122.7, 119.2, 118.3, 118.0 (d, J 1266, 1215, 1179, 1137, 1056 cm‐1; The ee value 90% (tmajor
=
= 10.5 Hz), 117.4 (d, J = 22.5 Hz), 117.3, 90.3, 80.2, 80.1, 30.4, 26.43 min, tminor = 34.29 min) was determined by HPLC using
+ +
27.4; ESI‐MS: m/z calcd. for C17H18FN2O5+ [M+NH4 ] 349.1194, Daicel Chiralpak IB with hexane/i‐PrOH (98:2) as the eluent,
found 349.1199; FT‐IR (KBr): 3463, 2925, 2853, 1744, 1723, flow: 1.0 mL/min, 220 nm, 25 oC.
1612, 1583, 1547, 1489, 1454, 1374, 1330, 1292, 1252, 1161, (2
R,4S)‐6‐bromo‐3,4‐dihydro‐4‐(nitromethyl)‐2H‐chromen‐2‐
1138 cm‐1; The ee value 84% (tmajor = 26.44 min, tminor = 35.42 yl benzoate (3w):
o
min) was determined by HPLC using Daicel Chiralpak IA with White solid (93%, 36 mg, >20:1 dr); MP‐125 C, Rf value 0.5
hexane/i‐PrOH (98:2) as the eluent, flow: 1.0 mL/min, 220 nm, (5:95 EA in hex); 1H NMR (600 MHz, CDCl3) δ 8.01 (d, J = 7.2 Hz,
25 oC.
(2 ,4
dimethylbenzoate (3t):
2H), 7.60 (t, J = 7.4 Hz, 1H), 7.47 (t, J = 7.8 Hz, 2H), 7.35 – 7.31
2,4‐ (m, 2H), 6.87 (d, J = 8.5 Hz, 1H), 6.83 (s, 1H), 5.04 (dd, J = 12.7,
10.4 Hz, 1H), 4.76 (dd, J = 12.7, 5.6 Hz, 1H), 3.90 – 3.84 (m, 1H),
R
S
)‐3,4‐dihydro‐4‐(nitromethyl)‐2
H
‐chromen‐2‐yl
o
White solid (91%, 31 mg, >20:1 dr); MP‐112 C, Rf value 0.5 2.42 (ddd, J = 15.3, 6.5, 3.2 Hz, 1H), 2.36 (dt, J = 15.3, 2.0 Hz,
(5:95 EA in hex); 1H NMR (600 MHz, CDCl3) δ 7.70 (d, J = 8.0 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 165.3, 150.5, 134.0, 132.8,
1H), 7.24 (t, J = 8.4 Hz, 1H), 7.16 (d, J = 7.5 Hz, 1H), 7.08 – 6.97 131.7, 130.0, 129.2, 129.0, 120.9, 120.2, 114.6, 90.2, 79.9, 30.5,
(m, 4H), 6.79 (t, J = 2.4 Hz, 1H), 4.98 (dd, J = 12.5, 10.3 Hz, 1H), 26.9; ESI‐MS: m/z calcd. for C17H18BrN2O5 [M+NH4 ] 409.0394,
4.72 (dd, J = 12.5, 5.7 Hz, 1H), 3.89 – 3.83 (m, 1H), 2.57 (s, 3H), found 409.0386; FT‐IR (KBr): 3436, 2923, 2853, 1731, 1579,
+
+ +
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1549, 1481, 1451, 1429, 1379, 1265, 1213, 1178, 1137, 1053 cm‐ 6.81 (s, 1H), 6.59 (dd, J = 8.6, 2.5 Hz, 1H), 6.51 (d, J = 2.4 Hz, 1H),
1; The ee value 84% (tmajor = 34.03 min, tminor = 32.45 min) was 5.00 (dd, J = 12.3, 10.3 Hz, 1H), 4.74 (dd, J = 12.4, 5.8 Hz, 1H),
determined by HPLC using Daicel Chiralpak IA with hexane/i‐ 3.81 (d, J = 8.7 Hz, 1H), 3.75 (s, 3H), 2.42 (ddd, J = 15.2, 6.6, 3.1
PrOH (98:2) as the eluent, flow: 1.0 mL/min, 220 nm, 25 oC.
(2 ,4 )‐6,8‐dichloro‐3,4‐dihydro‐4‐(nitromethyl)‐2
chromen‐2‐yl benzoate (3x):
Hz, 1H), 2.34 (d, J = 15.2 Hz, 1H); 13C NMR (150 MHz, CDCl3)
δ
165.5, 160.7, 152.1, 133.9, 129.9, 129.8, 129.4, 128.9, 110.7,
R
S
H
‐
109.9, 102.6, 90.4, 80.4, 55.6, 30.2, 27.2; ESI‐MS: m/z calcd. for
o
+ +
White solid (81%, 31mg); MP‐130 C, Rf value 0.5 (5:95 EA in C18H21N2O6+ [M+NH4 ] 361.1394, found 361.1390; FT‐IR (KBr)
:
hex); 1H NMR (600 MHz, CDCl3) δ 8.01 (d, J = 7.3 Hz, 2H), 7.61 2923, 2852, 1726, 1603, 1550, 1490, 1462, 1436, 1380, 1297,
(t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 7.34 (d, J = 2.4 Hz, 1H), 1251, 1212, 1185, 1037, 946 cm‐1; The ee value 60% (tmajor
=
7.10 (d, J = 2.3 Hz, 1H), 6.94 (t, J = 2.4 Hz, 1H), 5.00 (dd, J = 12.8, 26.01 min, tminor = 33.49 min) was determined by HPLC using
10.0 Hz, 1H), 4.76 (dd, J = 12.8, 5.9 Hz, 1H), 3.93 – 3.87 (m, 1H), Daicel Chiralpak IA with hexane/i‐PrOH (97:3) as the eluent,
2.44 (ddd, J = 15.3, 6.3, 3.1 Hz, 1H), 2.39 (dt, J = 15.3, 2.1 Hz, flow: 1.0 mL/min, 220 nm, 25 oC.
1H); 13C NMR (151 MHz, CDCl3) δ 164.8, 146.3, 134.1, 130.3, (2
R,4S)‐3,4‐dihydro‐6‐methyl‐4‐(nitromethyl)‐2H‐chromen‐2‐
130.0, 129.0, 129.0, 127.3, 127.1, 124.3, 121.8, 90.3, 79.7, 30.7, yl benzoate (3z2)
:
27.1; ESI‐MS: m/z calcd. for C17H1Cl2N2O5+ [M+NH4 ] 399.0509, White semisolid (85%, 27 mg >20:1 dr); Rf value 0.5 (5:95 EA in
found 399.0504; FT‐IR (KBr): 3446, 3070, 2925, 1737, 1646, hex); 1H NMR (400 MHz, CDCl3) δ 8.02 (d, J = 7.5 Hz, 2H), 7.58
1552, 1458, 1376, 1319, 1266, 1181, 1128, 1070, 1020 cm‐1; The (t, J = 7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.03 (d, J = 8.3 Hz, 1H),
ee value 92% (tmajor = 41.38 min, tminor = 46.01 min) was 6.97 (s, 1H), 6.90 – 6.78 (m, 2H), 5.03 (dd, J = 12.4, 10.5 Hz, 1H),
determined by HPLC using Daicel Chiralpak IB with hexane/i‐ 4.77 (dd, J = 12.5, 5.6 Hz, 1H), 3.90 – 3.77 (m, 1H), 2.48 – 2.31
+ +
PrOH (98:2) as the eluent, flow: 1.0 mL/min, 220 nm, 25 oC.
(2 ,4 )‐6,8‐dibromo‐3,4‐dihydro‐4‐(nitromethyl)‐2
chromen‐2‐yl benzoate (3y):
Yellow semisolid (51%, 24mg); Rf value 0.5 (5:95 EA in hex); 1
(m, 2H), 2.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.5, 149.1,
133.8, 132.0, 130.5, 130.0, 129.5, 129.3, 128.9, 118.4, 118.1,
R
S
H
‐
+
90.5, 80.4, 30.7, 27.2, 20.7; ESI‐MS: m/z calcd. for C18H21N2O5
+ +
H
[M+NH4 ] 345.1445, found 345.1443; FT‐IR (KBr): 2925, 2853,
NMR (600 MHz, CDCl3) δ 8.01 (d, J = 7.6 Hz, 2H), 7.64 (s, 1H), 1727, 1551, 1500, 1450, 1378, 1318, 1272, 1172, 1142, 1026 cm‐
7.61 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.28 (s, 1H), 6.93 1; The ee value 90% (tmajor = 23.82 min, tminor = 21.75 min) was
(s, 1H), 5.00 (dd, J = 12.6, 10.2 Hz, 1H), 4.75 (dd, J = 12.8, 5.8 Hz, determined by HPLC using Daicel Chiralpak IA with hexane/i‐
1H), 3.95 – 3.83 (m, 1H), 2.43 (ddd, J = 15.2, 6.1, 3.1 Hz, 1H), PrOH (98:2) as the eluent, flow: 1.0 mL/min, 220 nm, 25 oC.
2.38 (d, J = 15.3 Hz, 1H); 13C NMR (150 MHz, CDCl3) δ 164.8,
147.7, 135.9, 134.1, 130.9, 130.0, 129.0, 129.0, 122.2, 114.5, (2
R,4S)‐3,4‐dihydro‐6‐nitro‐4‐(nitromethyl)‐2H‐chromen‐2‐yl
113.5, 90.5, 79.7, 30.7, 27.1; ESI‐MS
:
m/z calcd. for benzoate (3z3)
:
+
+ +
C17H17Br2N2O5 [M+NH4 ] 486.9484, found 486.9469; FT‐IR Yellow semisolid (88%, 31 mg >20:1 dr); Rf value 0.5 (7:93 EA in
(KBr): 3438, 2923, 2853, 1731, 1635, 1549, 1450, 1374, 1314, hex); 1H NMR (600 MHz, CDCl3) δ 8.19 – 8.11 (m, 2H), 8.01 (d, J
1266, 1224, 1162, 1128, 1071, 1046 cm‐1; The ee value 90% = 7.4 Hz, 2H), 7.62 (t, J = 7.4 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H), 7.09
(tmajor = 76.60 min, tminor = 53.67 min) was determined by HPLC (d, J = 9.0 Hz, 1H), 6.91 (t, J = 2.5 Hz, 1H), 5.08 (dd, J = 12.8, 10.5
using Daicel Chiralpak IC with hexane/i‐PrOH (98:2) as the Hz, 1H), 4.84 (dd, J = 12.9, 5.7 Hz, 1H), 4.00 (dd, J = 6.6, 3.5 Hz,
eluent, flow: 1.0 mL/min, 220 nm, 25 oC.
(2 ,4 )‐8‐bromo‐6‐chloro‐3,4‐dihydro‐4‐(nitromethyl)‐2
chromen‐2‐yl benzoate (3z):
White solid (60%, 25 mg , >20:1 dr); MP‐130 C; Rf value 0.5 [M+NH4 ] 376.1139, found 376.1140; FT‐IR (KBr): 2922, 2855,
(5:95 EA in hex); 1H NMR (600 MHz, CDCl3) δ 8.01 (d, J = 7.4 Hz, 1727, 1623, 1586, 1545, 1481, 1446, 1419, 1345, 1270, 1227,
2H), 7.61 (t, J = 7.4 Hz, 1H), 7.49 (dd, J = 16.5, 8.8 Hz, 3H), 7.15 1086, 1022 cm‐1; The ee value 68% (tmajor = 93.50 min, tminor
1H), 2.51 – 2.42 (m, 2H); 13C NMR (150 MHz, CDCl3) δ 165.0,
156.6, 142.7, 134.3, 130.0, 129.0, 128.8, 125.6, 125.5, 119.7,
119.3, 90.3, 79.4, 30.6, 26.8; ESI‐MS: m/z calcd. for C17H18N3O7
R
S
H‐
+
o
+ +
=
(d, J = 2.3 Hz, 1H), 6.93 (s, 1H), 5.00 (dd, J = 12.8, 10.0 Hz, 1H), 90.17 min) was determined by HPLC using Daicel Chiralpak IA
4.76 (dd, J = 12.8, 5.9 Hz, 1H), 3.94 – 3.84 (m, 1H), 2.44 (ddd, J = with hexane/i‐PrOH (97.5:2.5) as the eluent, flow: 1.0 mL/min,
15.3, 6.3, 3.1 Hz, 1H), 2.39 (d, J = 15.3 Hz, 1H); 13C NMR (150 220 nm, 25 oC.
MHz, CDCl3) δ 164.8, 147.2, 134.1, 133.2, 130.0, 129.0, 129.0, (2
R,4S)‐4‐((benzamido)methyl)‐3,4‐dihydro‐2H‐chromen‐2‐yl
128.0, 127.6, 121.7, 113.1, 90.5, 79.7, 30.8, 27.1; ESI‐MS: m/z benzoate (5):
+
+ +
calcd. for C17H17BrClN2O5 [M+NH4 ]
443.0004, found White semisolid (58%, 22 mg); Rf value 0.3 (10:90 EA in hex); 1
H
443.0001; FT‐IR (KBr): 3444, 2920, 2853, 1732, 1601, 1549, NMR (400 MHz, CDCl3) δ 8.03 (d, J = 7.2 Hz, 2H), 7.74 (d, J = 7.2
1454, 1375, 1314, 1268, 1224, 1206, 1171, 1122, 1084, 1066 cm‐ Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.3 Hz, 1H), 7.48 –
1; The ee value 96% (tmajor = 126.00 min, tminor = 106.66 min) was 7.40 (m, 4H), 7.28 (d, J = 9.4 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 6.99
determined by HPLC using Daicel Chiralpak IB with hexane/i‐ (dd, J = 17.4, 7.9 Hz, 2H), 6.83 (s, 1H), 6.39 (s, 1H), 4.06 – 3.97
PrOH (98:2) as the eluent, flow: 1.0 mL/min, 220 nm, 25 oC.
(m, 1H), 3.95 – 3.87 (m, 1H), 3.41 (s, 1H), 2.39 (d, J = 2.4 Hz, 2H);
(2
R
,4
S)‐7‐methoxy‐4‐(nitromethyl)chroman‐2‐yl
benzoate 13C NMR (150 MHz, CDCl3) δ 167.9, 165.6, 151.5, 134.5, 133.8,
(3z1):
131.9, 130.0, 129.7, 129.3, 128.9, 128.8, 128.8, 127.0, 122.7,
White sticky solid (93%, 33 mg, >20:1 dr); Rf value 0.5 (5:95 EA 122.1, 117.9, 91.5, 45.4, 31.8, 28.3; ESI‐MS: m/z calcd. for
in hex) 1H NMR (600 MHz, CDCl3) δ 8.03 (d, J = 7.4 Hz, 2H), 7.59 C17H14NaNO5 [M+Na] 410.1368, found 410.1364; FT‐IR (KBr)
(t, J = 7.4 Hz, 1H), 7.46 (t, J = 7.8 Hz, 2H), 7.06 (d, J = 8.6 Hz, 1H), 3336, 2922, 2851, 1732, 1639, 1580, 1487, 1380, 1451, 1311,
:
8 | J. Name., 2012, 00, 1‐3
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1270, 1214, 1187, 1073 cm‐1; The ee value 86% (tmajor = 25.92 CDCl3) δ 165.0, 164.2, 150.1, 132.1, 129.9, 128.7, 127.3, 121.4,
min, tminor = 29.42 min) was determined by HPLC using Daicel 120.4, 119.8, 114.2, 90.0, 79.9, 55.7, 30.6, 27.0.
Chiralpak IC with hexane/i‐PrOH (88:12) as the eluent, flow: 1.0
mL/min, 220 nm, 25 oC.
Acknowledgements
We thank the Central Instruments Facility, Indian Institute of
Technology Guwahati for the instrumental help.
tert‐butyl((2
yl)methylcarbamate (6):
Yellow semisolid (58%, 22 mg); Rf value 0.5 (10:90 EA in hex); 1
R,4S)‐2‐(benzoyloxy)‐3,4‐dihydro‐2H‐chromen‐4‐
H
NMR (400 MHz, CDCl3) δ 7.98 (d, J = 7.1 Hz, 2H), 7.56 (d, J = 7.4
Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.23 – 7.10 (m, 2H), 7.03 – 6.95
(m, 1H), 6.93 (d, J = 8.3 Hz, 1H), 6.80 (s, 1H), 4.81 (s, 1H), 3.76 –
3.65 (m, 1H), 3.51 (s, 1H), 3.21 (s, 1H), 2.32 (s, 2H), 1.46 (s, 9H);
13C NMR (150 MHz, CDCl3) δ 165.6, 156.2, 151.5, 133.7, 130.0,
129.7, 129.3, 128.8, 128.6, 122.7, 122.0, 117.7, 91.4, 79.7, 46.1,
32.1, 28.6, 27.8; ESI‐MS: m/z calcd. for C17H15BrNO5+ [M+H+]+
384.1805, found 384.1810; FT‐IR (KBr): 3389, 2977, 2926, 1735,
1692, 1528, 1488, 1450, 1371, 1274, 1218, 1174, 1073, 1030 cm‐
1; The ee value 92% (tmajor = 25.82 min, tminor = 31.04 min) was
determined by HPLC using Daicel Chiralpak IA with hexane/i‐
PrOH (97:3) as the eluent, flow: 1.0 mL/min, 220 nm, 25 oC.
Notes and references
1
For selected examples, see: (a) S. R. Trenor, A. R. Shultz, B. J.
Love and T. E. Long, Chem. Rev., 2004, 104, 3059; (b) M. C.
Breschi, V. Calderone, A. Martelli, F. Minutolo, S. Rapposelli,
L. Testai, F. Tonelli and A. Balsamo, J. Med. Chem., 2006, 49
,
7600; (c) S. Khelili, X. Florence, M. Bouhadja, S. Abdelaziz, N.
Mechouch, Y. Mohamed, P. D. de Tullio, P. Lebrun and B.
Pirotte, Bioorg. Med. Chem., 2008, 16, 6124; (d) A. Coi, A. M.
Bianucci, V. Calderone, L. Tstai, M. Digiacomo, S. Rapposelli,
and A. Balsamo, Bioorg. Med. Chem. 2009, 17, 5565.
A. Van de Water, W. Janssen, J. Van Nueten, R. Xhonneux, J.
de Cree, H. Verhaegen, R. S. Reneman and P. A. J. Janssen, J.
Cardiovasc. Pharmacol., 1988, 11, 552.
2
3
(2
R,4S)‐4‐((1H‐imidazol‐1‐yl)methyl)‐3,4‐dihydro‐2H‐
chromen‐2‐yl benzoate (7):
R. G. Judzewitsch, J. B. Jaspan, K. S. Polonsky, C. R. Weinberg,
J. B. Halter, E. Halar, M. A. Pfeifer, C. Vukadinovic, L. Bernstein,
M. Schneider, K. Y. Liang, K. H. Gabbay, A. H. Rubenstein and
D. N. Porte, Engl. J. Med., 1983, 308, 119.
Colorless sticky oil (75%, 25 mg); Rf value 0.5 (50:50 EA in hex);
1H NMR (400 MHz, CDCl3) δ 8.00 (d, J = 7.2 Hz, 2H), 7.60 (t, J =
7.4 Hz, 1H), 7.46 (t, J = 7.7 Hz, 2H), 7.41 (s, 1H), 7.25 – 7.20 (m,
1H), 7.11 (s, 1H), 6.96 (t, J = 7.3 Hz, 3H), 6.87 (t, J = 2.8 Hz, 1H),
6.83 (d, J = 7.8 Hz, 1H), 4.46 – 4.42 (m, 2H), 3.33 (d, J = 7.6 Hz,
1H), 2.31 (ddd, J = 15.0, 6.9, 3.2 Hz, 1H), 2.16 (dt, J = 15.0, 2.4
Hz, 1H; 13C NMR (150 MHz, CDCl3) δ 165.4, 151.1, 137.8, 134.0,
130.2, 129.9, 129.5, 129.3, 129.3, 129.0, 122.3, 120.6, 119.2,
4 For M. J. Weyant, A. M. Carothers, A. J. Dannenberg and M. M.
Bertagnolli, Cancer Res., 2001, 61, 118.
5
For selected recent examples, see: (a) H. Sunden, I. Ibrahem, G.‐
L. Zhao, L. Eriksson and A. Cόrdova, Chem. –Eur. J., 2007, 13, 574;
(b) L. Zu, S. Zhang, H. Xie and W. Wang, Org. Lett., 2009, 11, 1627;
(c) D. B. Ramachary and R. Sakthidevi, Chem. Eur. J., 2009, 15,
4516; (d) T. Inokuma, K. Takasu, T. Sakaeda and Y. Takemoto,
Org. Lett., 2009, 11, 2425; (e) D. B. Ramachary and R. Sakthidevi,
Org. Biomol. Chem., 2010, 8, 4259; (f) D. Enders, C. Wang, X. Yang
and G. Raabe, Adv. Synth. Catal., 2010, 352, 2869; (g) D. Lu, Y. Li
and Y. Gong, J. Org. Chem., 2010, 75, 6900; (g) X. Zhang, S. Zhang,
W. Wang, Angew. Chem. Int. Ed. 2010, 49, 1481; Angew. Chem.
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Liao, Org. Lett., 2010, 12, 776; (j) X.‐F. Wang, Q.‐L. Hua, Y. Cheng,
A.‐L. An, Q.‐Q. Yang, J.‐R. Chen and W.‐J. Xiao, Angew. Chem. Int.
Ed., 2010, 49, 8379; (k) X.‐F. Wang, J. An, X.‐X. Zhang, F. Tan, J.‐R.
Chen and W.‐J. Xiao, Org. Lett., 2011, 13, 808; (l) D. B. Ramachary,
M. S. Shiva Prasad and R. Madhavachary, Org. Biomol. Chem.,
2011, 9, 2715; (m) D. Enders, X. Yang, C. Wang, G. Raabe and J.
Runsik, Chem. Asian J., 2011, 6, 2255; (n) D. Enders, G. Urbanietz
and G. Raabe, Synthesis, 2011, 1905; (o) B.‐C. Hong, P. Kotame
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S. Prasad and R. Madhavachary, Org. Biomol. Chem., 2011, 9,
2715;q) B.‐C. Hong, P. Kotame and J.‐H. Liao, Org. Biomol. Chem.,
2011, 9, 382; (r) H. Mao, A. Lin, Y. Tang, Y. Shi, H. Hu, Y. Cheng
and C. Zhu, Org. Lett., 2013, 15, 4062; (s) K.‐S. Choi and S.‐G. Kim,
Eur. J. Org. Chem., 2012, 1119; (t) C. Wang, X. Yang, G. Raabe and
D. Enders, Adv. Synth. Catal., 2012, 354, 2629; (u) A. Lu, K. Hu, Y.
Wang, H. Song, Z. Zhou, J. Fang and C. Tang, J. Org. Chem., 2012,
77, 6208; (v) D. Enders, G. Urbanietz, R. Hahn and G. Raabe,
Synthesis, 2012, 773; (w) M. Rueping, J. Dufour and M. S. Maji,
Chem. Commun., 2012, 48, 3406; (x) D. B. Ramachary, R.
Madhavachary and M. S. Prasad, Org. Biomol. Chem., 2012, 10,
5825; (y) D. B. Ramachary, R. Sakthidevi and K. S. Shruthi, Chem.
Eur. J., 2012, 18, 8008; (z) Z.‐X. Jia, Y.‐C. Luo, X.‐N. Cheng, P.‐F.
Xu and Y.‐C. Gu, J. Org. Chem., 2013, 78, 6488; (aa) C.‐C. Hsiao,
H.‐H. Liao and M. Rueping, Angew. Chem. Int. Ed., 2014, 53,
13258; (ab) D. B. Ramachary, M. S. Prasad, S. V. Laxmi and R.
Madhavachary, Org. Biomol. Chem., 2014, 12, 574; (ac) D. B.
Ramachary, P. S. Reddy and M. S. Prasad, Eur. J. Org. Chem.,
2014, 3076–3081. (ad) P. Saha, A. Biswas, N. Molletti and V. A.
Singh, J. Org. Chem., 2015, 80, 11115; (ae) Y. Zhu, X. Li, Q. Chen,
+
90.8, 52.6, 34.1, 29.9, 27.2; ESI‐MS: m/z calcd. for C20H19N2O3
[M+H+]+ 335.1390, found 335.1388; FT‐IR (KBr): 3419, 2923,
2853, 1723, 1583, 1489, 1451, 1366, 1266, 1214, 1133, 1050,
995, 936 cm‐1; The ee value 92% (tmajor = 47.05 min, tminor = 38.38
min) was determined by HPLC using Daicel Chiralpak IC with
hexane/i‐PrOH (70:30) as the eluent, flow: 1.0 mL/min, 220 nm,
25 oC.
(S)‐3,4‐dihydro‐4‐(nitromethyl)‐2H‐chromene (8):
Colorless sticky oil (95%, 18 mg); Rf value 0.5 (3:97 EA in hex);
1H NMR (600 MHz, CDCl3) δ 7.18 (t, J = 7.1 Hz, 1H), 7.11 (d, J =
7.6 Hz, 1H), 6.91 (t, J = 8.0 Hz, 1H), 6.86 (d, J = 8.2 Hz, 1H), 4.71
(dd, J = 12.3, 4.7 Hz, 1H), 4.55 (dd, J = 12.2, 10.8 Hz, 1H), 4.27
(dt, J = 11.4, 4.3 Hz, 1H), 4.20 – 4.13 (m, 1H), 3.72 (td, J = 9.9, 4.7
Hz, 1H), 2.24 – 2.16 (m, 1H), 1.96‐1.92 (m, 1H); 13C NMR (150
MHz, CDCl3) δ 155.1, 129.2, 129.0, 121.1, 119.6, 117.9, 80.1,
62.5, 33.0, 25.1; ESI‐MS: m/z calcd. for C10H11NaNO3 [M+Na]
216.0637, found 216.1251; FT‐IR (KBr): 3445, 2923, 2853, 1740,
1582, 1551, 1490, 1456, 1379, 1263, 1226, 1118, 1038 cm‐1; The
ee value 92% (tmajor = 11.57 min, tminor = 22.38 min) was
determined by HPLC using Daicel Chiralpak IB with hexane/i‐
PrOH (98:2) as the eluent, flow: 1.0 mL/min, 220 nm, 25 oC.
(2R,4S)‐6‐chloro‐4‐(nitromethyl)chroman‐2‐yl
methoxybenzoate (3z5):
4‐
White solid (70%, 26mg); 1H NMR (600 MHz, CDCl3) δ 8.00 –
7.92 (m, 2H), 7.20 – 7.15 (m, 2H), 6.92 (dd, J = 13.7, 7.8 Hz, 3H),
6.80 (t, J = 2.5 Hz, 1H), 5.02 (dd, J = 12.8, 10.2 Hz, 1H), 4.76 (dd,
J = 12.8, 5.7 Hz, 1H), 3.88 – 3.83 (m, 4H), 2.40 (ddd, J = 15.2, 6.5,
3.2 Hz, 1H), 2.34 (dt, J = 15.3, 2.1 Hz, 1H); 13C NMR (150 MHz,
This journal is © The Royal Society of Chemistry 20xx
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DOI: 10.1039/C8OB00078F
COMMUNICATION
Journal Name
J. Su, F. Jia, S. Qiu, M. Ma, Q. Sun, W. Yan, K. Wang and R. Wang,
Org. Lett., 2015, 17, 3826; (af) J.‐J. Zhao, S.‐B. Sun, S.‐H. He, Q.
Wu and F. Shi, Angew. Chem. Int. Ed., 2015, 54, 5460; (ag) P. H.
Poulsen, K. S. Feu, B. M. Paz, F. Jensen and K. A. Jørgensen,
Angew. Chem. Int. Ed., 2015, 54, 8203; (ah) C. Gharui, S. Singh
and S. C. Pan, Org. Biomol. Chem., 2017, 15, 7272; (ai) Z. Wang
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A. Valkonen, K. Rissanen and D. Enders, Org.
2017, 19, 3025.
Lett.,
6
7
For reviews on organocatalytic asymmetric conjugate addition,
see: (a) D. Almasi, D. A. Alonso and C. Najera,
Tetrahedron:Asymmetry, 2007, 18, 299; (b) S. B. Tsogoeva, Eur. J.
Org. Chem., 2007, 11, 1701; (c) J. L. Vicario, D. Badía, and L.
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Catal. Sci. Technol., 2012, 2, 42.
For selected reviews on organocatalytic cascade or domino
reactions, see: (a) H. Pellesie Organocatalysis in Domino
Processes, In Domino Reactions; L. F. Tietze, Ed.; Wiley‐VCH:
Weinheim, 2014, pp 325‐405. (b) C. M. R. Volla, I. Atodiresi and
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R. Ballini, G. Bosica, D. Fiorini, A. Palmieri and M. Petrini, Chem.
Rev., 2005, 105, 933.
Only the asymmetric reaction of α‐nitroketones with β,γ‐
unsaturated α‐keto esters and unsaturated pyrazolones is
known: (a) Y. Gao, Q. Ren, W.‐Y. Siau and J. Wang, Chem.
Commun., 2011, 47, 5819; (b) R.‐J. Lu, J.‐Y. Yan, J.‐J. Wang, Q.‐S.
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Lett., 2017, 19, 662.
10 For selected organocatalytic asymmetric cascade reactions with
2‐hydroxycinnamaldehydes, see: Ref. 7b and (a) Y. Lee, S. W. Seo
and S.‐G. Kim, Adv. Synth. Catal., 2011, 353, 2671; (b) K.‐S. Choi
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Palomo and A. Mielgo, Angew. Chem. Int. Ed., 2006, 45, 7876; (b)
A. Mielgo and C. Palomo, Chem. Asian. J., 2008, 3, 922; (c) K. L.
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13 CCDC 1581364 contains the crystallographic data for 3p.
10 | J. Name., 2012, 00, 1‐3
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DOI: 10.1039/C8OB00078F
Ph
Ph
O2N
(20 mol%)
N
CHO
OTMS
O
H
O
R
R
NO2
+
R1
PhCO2H (20 mol%)
-20 oC, DCE, 7 d
O
O
R1
OH
R1 = Ar, Alk
R = 4-Cl, 4-Me, 4,6-diCl etc.
-single diastereomer
-up to 93% yield
-up to 96% ee
28 examples
An organocatalytic asymmetric synthesis of 2,4-disubstituted chroman compounds has been developed
via Michael/ hemiketalization /acyl transfer reaction between o-hydroxycinnamaldehydes and α-
nitroketones.