Catalytic enantioselective aziridoarylation of aryl cinnamyl ethers toward synthesis of trans-3-amino-4-arylchromans

Article abstract of DOI:10.1021/jo200711s

Catalytic enantioselective one-pot aziridoarylation reaction of aryl cinnamyl ethers has been demonstrated in detail. Combination of suitable copper catalyst and chiral bis-oxazoline ligand was found to be very efficient for asymmetric aziridination followed by intramolecular arylation (Friedel-Crafts) reaction to provide a general and direct method for the synthesis of trans-3-amino-4-arylchromans with high regio-, diastereo- (dr > 99:1), and enantioselectivity (up to 95% ee) with moderate yield. trans-3-Amino-4- arylchroman is an advanced intermediate for the synthesis of chromenoisoquinoline compounds such as doxanthrine, a potent and selective full agonist for the dopamine-D₁ receptor.

Full text of DOI:10.1021/jo200711s

ARTICLE
pubs.acs.org/joc
Catalytic Enantioselective Aziridoarylation of Aryl Cinnamyl Ethers
toward Synthesis of trans-3-Amino-4-arylchromans
Saumen Hajra* and Debarshi Sinha
Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721 302, India
S Supporting Information
b
ABSTRACT: Catalytic enantioselective one-pot aziridoarylation
reaction of aryl cinnamyl ethers has been demonstrated in detail.
Combination of suitable copper catalyst and chiral bis-oxazoline
ligand was found to be very efficient for asymmetric aziridination
followed by intramolecular arylation (FriedelÀCrafts) reaction to
provide a general and direct method for the synthesis of trans-3-amino-
4-arylchromans with high regio-, diastereo- (dr > 99:1), and enantio-
selectivity (up to 95% ee) with moderate yield. trans-3-Amino-
4-arylchroman is an advanced intermediate for the synthesis of
chromenoisoquinoline compounds such as doxanthrine, a potent
and selective full agonist for the dopamine-D1 receptor.
’ INTRODUCTION
asymmetric synthesis of aminochromans.10 This led us to study
the aziridoarylation of aryl cinnamyl ethers. We herewith de-
scribe a detailed study on catalytic enantioselective aziridination
of aryl cinnamyl ethers 1 followed by intramolecular 6-exotet
arylation [FriedelÀCrafts (FÀC) cyclialkylation] of the tethered
aziridines 2 that lead to the one-pot synthesis of trans-3-amino-4-
aryl-chromans 3 (Scheme 1) with high diastereo- (dr > 99:1) and
enantioselectivity (up to 95%) and moderate yields.
The aziridine ring provides a balanced combination of reac-
tivity and flexibility and therefore can serve as an important
synthetic intermediate. Stereoselective construction of aziridine
followed by its selective opening offers an important chemical
tool to the 1,2-bifunctionalization of alkenes. Asymmetric azir-
idination has been studied quite extensively on styrene, cinna-
mate, and chalcone double bonds.1 Ring-opening chemistry with
the corresponding aziridines has also been broadly addressed.2À4
Carbon nucleophile-based aziridine opening is more frequent with
metallo-carbon nucleophiles2a,c compared to π-nucleophilic hetero-
aromatics3 and benzoaromatics.4 However, cinnamyl alcohol
derivatives are infrequent in this array of aziridine-mediated
functionalization techniques. There are only a few reports on
intramolecular aziridination of cinnamyl carbamates.5 Specific
examples of aziridination of a cinnamyl alcohol,6 ester,7 and
ether8 are also known in the literature. However, detailed study
on aziridination of aryl cinnamyl ethers, in particular, the
asymmetric reaction and subsequent aziridine opening reaction,
has not been investigated. It was presumed that aryl cinnamyl
ethers 1, upon reaction with a suitable nitrene source, would
produce reactive aziridines 2 that would undergo further intra-
molecular arylation to provide trans-3-amino-4-arylchromans 3
(Scheme 1).
Chromans are ubiquitous in medicinal and natural product
chemistry. In particular, the chromenoisoquinoline framework is
receiving increasing interest in synthetic and pharmacological
chemistry. Recently, the Nichols group has emphasized the syn-
thesis and pharmacological characterization of some synthetic trans-
fused chromenoisoquinoline derivatives, such as doxanthrine9 4,
which is a potent and selective full agonist for the dopamine-D1
receptor. trans-3-Amino-4-arylchroman 3 could be an advanced
intermediate for the synthesis of trans-fused chromenoisoquino-
line via PictetÀSpengler reaction. To date, there is no report on
’ RESULTS AND DISCUSSION
One of the most convenient ways for direct and stereoselective
alteration of alkene to aziridine is by the action of iodinane ylides
(ArIdNSO2Ar) under copper-catalyzed reaction conditions.1,11À15
Recently Cu(OTf)2 was found to act as an efficient dual catalyst
for aziridination and subsequent intramolecular FÀC reaction of
the in situ-generated aziridine intermediate.16 In allied studies,
PhINSO2(4-NO2C6H4) [PhINNs] was recognized as a better
nitrene precursor than PhINSO2(4-MeC6H4) [PhINTs]. Thus,
cinnamyl phenyl ether 1a (5.0 equiv) was made to react with
nitrenoid reagent PhINNs (1.0 equiv) in the presence of 0.10
equiv of Cu(OTf)2 as a catalyst and molecular sieves (MS 4A) in
acetonitrile at 30 °C (Scheme 2). Within 30 min, the correspond-
ing trans-aziridine (()-2a was produced in 58% yield. The same
reaction, when carried out in dichloromethane, showed similar
aziridination followed by in situ intramolecular 6-exotet aryl-
cyclization. In the crude reaction mixture, the presence of both
chroman (()-3a and aziridine (()-2a was detected (Scheme 2).
The remainder of the intermediate aziridine was fully cyclized
upon stirring (1 h) with supplementary Cu(OTf)2 (0.10 equiv).
Finally, chroman (()-3a was obtained in 51% overall yield after
column chromatographic purification. In the case of acetonitrile
Received: April 5, 2011
Published: July 28, 2011
r
2011 American Chemical Society
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ARTICLE
Scheme 1. Proposed Aziridoarylation of Aryl Cinnamyl Ethers 1
Scheme 2. Aziridoarylation Reaction of Allyl Phenyl Ethers
Table 2. Effect of Solvents on Asymmetric Aziridoarylation
of 1a
Cu(OTf)2
Cu(ClO4)2 6H2O
3
entry
solvent
CH2Cl2
yield (%)a ee (%)b yield (%)a ee (%)b
Table 1. Screening of Copper Complexes for Aziridoaryla-
tion Reaction
1
2
3
4
5
6
7
8
9
25
26
29
19
23
15
21
10
18
18
50
64
49
35
16
20
40
34
57
42
32
32
39
12
12
16
8
58
76
35
53
43
51
50
57
48
14
CHCl3
CH3CNc
C6H6
C6H5CH3
CCl4
MeOCH2CH2OMec
1,4-dioxanec
ClCH2CH2Cl
entry
catalyst
yield of 3a (%)a
ee (%)b
11
30
13
c
1
2
3
4
5
6
7
8
CuCl2
14
8
10 C6H5Cl
c
Cu(acac)2
20
46
À
58
13
À
16
50
a Isolated yield after column chromatography. b Enantioselectivity was
determined by HPLC using a chiral column. The absolute configuration
of the major enantiomer was assigned by analogy with the literature
report.11b c Intermediate aziridine 2 did not cyclize in one pot; it was
isolated and cyclized separately in dichloromethane with additional
Cu(OTf)2.
d
CuSO4
Cu(ClO4)2 6H2Oe
Cu(OAc)2 H2Oe
NR
32
3
11
3
c
Cu2Cl2
NR
24
c
Cu2I2
c
Cu(OTf)2
25
a Isolated yields after column chromatography, calculated against the
amount of PhINNs. b Enantioselectivity of 3a was determined by HPLC
using a chiral column. c CuCl2, Cu2Cl2, Cu2I2, Cu(acac)2, and Cu(OTf)2
were dried and activated by heating (100 °C) under vacuum (10 mm of
Hg) for 2 h. d CuSO4 was dehydrated with DeanÀStark apparatus using
The reaction was then examined with chiral bis-oxazoline
(Box) chelated copper catalyst for enantioinduction. Cinnamyl
phenyl ether 1a and the benzyl-Box ligand 5a were selected as a
model substrate and ligand, respectively. Various copper reagents
were screened and found that yield and selectivity both depend
on the conjugate anion of copper complexes (Table 1). Copper-
(II) triflate and perchlorate salts were superior to the other
copper catalysts for one-pot aziridoarylation reaction.
The aziridination was found to be very sensitive toward
substrate concentration and temperature. Yield of the given
reaction, under Cu(OTf)2-mediated conditions, dropped to
16% when only a stoichiometric amount of substrate was used.
With lowering temperature, the reaction rate retarded signifi-
cantly, and below 18 °C, there was no aziridine formation at all.
Therefore, with both of the selected Cu-salts, the variation of
solvents and ligands (Tables 2 and 3, respectively) was studied at
30 °C using 5 molar multiples of substrate relative to the nitrene
reagent. It is noteworthy that with both Cu(OTf)2 and Cu-
e
benzene. For the reaction procedure with hydrated copper salts, see
Experimental Section. NR: no reaction.
as the solvent, the intermediate aziridine could not be cyclized
with additional Cu(OTf)2 catalyst in one-pot fashion. Isolated
aziridine (()-2a was cyclized quantitatively to (()-3a in dichloro-
methane upon treatment with 0.10 equiv of Cu(OTf)2 as the
Lewis acid catalyst. Trans stereochemistry of chromans 3 was
confirmed by single crystal X-ray analysis of compound (()-3b,17
obtained by a similar reaction with 1b (63% yield) and crystal-
lized from tolueneÀhexane. When allyl phenyl ether 1c was
subjected to the same reaction in dichloromethane under similar
conditions, it failed to undergo cyclization and thereby termi-
nated at aziridine (()-2c (Scheme 2). Hence, an aryl substituent
on the double bond is essential under the present conditions for
intramolecular cyclialkylation via benzylic substitution.
(ClO4)2 6H2O, yields were maximum (entry 3, Table 2) in
3
acetonitrile with moderate enantioselectivity (49% and 35%).
Solvents such as 1,2-dimethoxyethane and 1,4-dioxane gave very
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ARTICLE
poor yields (entries 7 and 8). Among the solvents, chloroform
showed high enantioselectivity with moderate yield (entry 2).
In the ligand study, indanolamine-derived Box ligand 5e was
found to work well in combination with chloroform for both
Cu(OTf)2 and Cu(ClO4)2 salts (85% and 83% ee, respectively;
entry 5, Table 3). Enantioselectivity exhibited by benzyl Box 5a
and isopropyl Box 5c were moderate (entries 1 and 3). Unlike the
reported styrene substrates lacking an additional binding site,
sterically demanding tert-butyl-Box 5b and phenyl-Box 5d
showed poor enantioselectivity.11,16b Replacement of the Box
ligands with Pybox analogues 5fÀg improved the yield but at the
expense of selectivity (entries 6 and 7).
Table 3. Screening of Ligands in Aziridoarylation of 1a
In order to generalize the scope, this technique was employed
for a variety of aryl cinnamyl ethers, and enantioselectivity up to
95% was achieved (Table 4). All substrates underwent smooth
one-pot aziridoarylation reaction, except for aryl cinnamyl ethers
with chloro and fluoro substituents such as 3j and 3k. Those
corresponding aziridines were isolated and cyclized separately in
dichloromethane using 0.10 equiv of Cu(OTf)2 (entries 9 and
10). This might be because of the low π-nucleophilicity of aryl
units. In contrast to the formation of a mixture of aziridine and
chroman in ligand-free racemic reactions, only aziridine was
formed in the chiral Cu-complex-catalyzed enantioselective reac-
tions, which required additional 0.10 equiv of Cu(OTf)2 for
cyclization. Yields obtained in enantioselective reactions were
also lower than those in corresponding racemic reactions and did
not exceed 50% except for 3j having a 2-chlorophenyl unit.
Substrates with electron-rich arenes and heteroarenes at either
end were studied and found to produce a mixture of unchar-
acterized products. The purity of the nitrene reagent PhINNs is
very important; contaminated reagent not only decreases the
yield but also lowers the ee up to 15%.
Cu(OTf)2
Cu(ClO4)2 6H2O
3
Box/Pybox
Ligand
yield
(%)a
ee
(%)b
yield
(%)a
ee
(%)b
entry
R
1
2
3
4
5
6
7
5a
5b
5c
5d
5ec
5f
CH2Ph
t-Bu
26
15
22
30
28
35
42
64
57
77
23
À85
0
32
23
30
33
31
À
76
43
58
21
- 83
À
i-Pr
Ph
In all cases, only trans-chroman product 3aÀk (dr > 99:1) was
isolated with high regio- and stereoselectivity. Overall retention
of substrate stereochemistry over to the product indicates that
there is no radical pathway for aziridination in the present system.
The concerted addition of the electrophilic nitrene results in
geometrically stereospecific conversion of the pure trans-alkene
to trans-aziridine. In the second step, the stereospecific anti-opening
indenyl
CH2Ph
Ph
5g
4
À
À
a Isolated yield after column chromatography. b Enantioselectivity was
determined by HPLC using a chiral AD-H column. c The enantiomeric
population of the product was reversed.
Table 4. Generalization of Aziridoarylation for the Synthesis of Aminoarylchromans 3
Cu(OTf)2
Cu(ClO4)2 6H2O
3
entry
substrate
R1, R2, R3
Ar
product
yield/%a (time/h)b
ee (%)c
yield/%a (time/h)b
ee (%)c
1
1a
1b
1d
1e
1f
H, H, H
H, H, H
H, H, Me
H, H, Cl
H, H, H
H, H, Me
H, H, Cl
H, H, Me
Cl, H, H
H, H, F
Ph
3a
3b
3d
3e
3f
28 (0.5)
40 (0.5)
48 (0.5)
48 (1.0)
25 (1.5)
28 (0.5)
29 (1.0)
32 (0.5)
55 (1.0)
26 (1.0)
85
90
95
81
85
83
66
73
90
80
31 (0.5)
32 (0.5)
37 (0.5)
30 (1.5)
33 (1.0)
27 (0.5)
26 (0.5)
45 (0.5)
42 (1.0)
31 (1.5)
83
71
86
48
61
56
70
66
67
74
2
4-MeC6H4
Ph
3
4
Ph
5
4-ClC6H4
4-ClC6H4
4-MeC6H4
4-MeC6H4
Ph
6
1g
1h
1i
3g
3h
3i
7
8
9d
10d
1j
3j
1k
Ph
3k
a Isolated yield after column chromatography. b Values in parentheses refer to the aziridination reaction time. c Enantioselectivity was determined by
HPLC using a chiral column. d Aziridine did not cyclize in one pot; it was isolated and cyclized separately in CH2Cl2 using an additional 0.10 equiv of
Cu(OTf)2 catalyst.
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Scheme 3. CÀH Insertion of Nitrene Followed by Oxidative
’ CONCLUSIONS
Cleavage
In summary, this is the first study on catalytic and enantiose-
lective aziridination of aryl cinnamyl ethers and one-pot intra-
molecular arylation of the in situ-generated tethered aziridine.
This method provides an easy access of N-sulfonyl-protected
trans-3-amino-4-arylchromans with high regio-, diastereo- (dr >
99:1), and enantioselectivity (ee up to 95%). These chiral amino-
chromans could be advanced intermediates for the synthesis of
biologically active chromenoisoquinoline compounds such as
doxanthrine, via PictetÀSpengler cyclization. Competitive CÀH
insertion of nitrene at the OÀCH unit followed by oxidative
2
cleavage is the major side reaction, which lowers the overall yield.
’ EXPERIMENTAL SECTION
Melting points (mp) of solid compounds are reported without
correction. 1H NMR chemical shifts are expressed in parts per million
(δ ppm) downfield to CHCl3 (δ = 7.26), C2D6SO (δ = 2.48); 13C NMR
chemical shifts are expressed in ppm (δ) relative to the central CDCl3
resonance (δ = 77.0) and DMSO-d6 (δ = 39.7). Enantioselectivities
were determined by HPLC using Chiralpak AD-H chiral column
(0.46 Â 15.0 cm2 each) with i-PrOH/n-hexane (10:90) solvent, flow
rate 1 mL/min, UV wavelength 220 nm, 20 nm (ref off). Specific rota-
tion values are reported only for the Cu(OTf)2-catalyzed reactions.
General Procedure for Synthesis of Aryl Cinnamyl Ethers.
Allylaryl ethers 1 were prepared by conventional alkylation method via
the reaction of phenol derivatives with corresponding allyl- or cinnamyl
bromides in the presence of K2CO3 in acetone.
Scheme 4. Aziridoarylation of Aryl Cinnamyl Ethers 1l
and 1m
1
Cinnamyl Phenyl Ether, 1a. Yield = 81%, H NMR (200 MHz,
CDCl3): δ 7.48À7.39 (m, 2H), 7.38À7.25 (m, 5H), 7.05À6.90 (m,
3H), 6.74 (d, J = 15.8 Hz, 1H), 6.42 (dt, J = 16.0, 5.6 Hz, 1H), 4.71 (dd,
J = 5.6, 1.4 Hz, 2H).
1
1-Methyl-4-(3-phenylallyloxy)benzene, 1b. Yield = 78%, H NMR
(200 MHz, CDCl3): δ 7.48À7.15 (m, 5H), 7.10 (d, J = 8.2 Hz, 2H), 6.87
(d, J = 8.4 Hz, 2H), 6.73 (d, J = 16.0 Hz, 1H), 6.42 (dt, J = 16.0, 5.6 Hz,
1H), 4.68 (dd, J = 5.6, 1.2 Hz, 2H), 2.30 (s, 3H).
1
Allyl Phenyl Ether, 1c. Yield = 86%, H NMR (200 MHz, CDCl3):
δ 7.38À7.21 (m, 2H), 7.04À6.89 (m, 3H), 6.14À5.97 (m, 1H), 5.48À
5.25 (m, 2H), 4.57À4.51 (m, 2H).
of the aziridine by the intramolecular aromatic nucleophile
produces aminoarylchroman with trans-stereochemistry.16
Average yield of the desired aziridines was low to moderate,
and formation of some side products such as cinnamyl imine and
cinnamaldehyde was detected. Formation of the imine 9 is
reasonable from a nitrene insertion mechanism into the CÀH
bond (Scheme 3).18 The enhanced activation of the oxy-methy-
lene group upon binding with copper makes it facile for nitrene
insertion. Insertion followed by oxidative cleavage of the ethereal
bond finally results in phenol 10 and imine 9, which in turn give
cinnamaldehyde 11. In comparison to our earlier report on the
aziridoarylation reaction of arylethyl styrenes,16 the present
method with the ether variant is relatively faster; however,
because of the additional oxygenÀmetal binding, it requires
higher catalyst loading and provides poor to moderate yields.
To eliminate this undesired nitrene insertion reaction, gem-
dimethylcinnamyl phenyl ethers 1l and 1m were used
(Scheme 4), but under both chiral and achiral reaction condi-
tions, these substrates could not circumvent the ethereal clea-
vage, and only <10% of chromans 3l,m was detected in the
complex mixture of products by 1H NMR. Among the many side
products, phenol 10 and gem-dimethylcinnamyl alcohol 14 were
detected in the reaction mixture, which supports the mechanism
of Lewis acid-catalyzed ethereal cleavage.
1-Methyl-4-(3-phenoxypropenyl)benzene, 1d. Yield = 71%, 1HNMR
(200 MHz, CDCl3): δ 7.39À7.22 (m, 4H), 7.14 (d, J = 8.0 Hz, 2H),
7.04À6.89 (m, 3H), 6.72 (d, J = 16.0 Hz, 1H), 6.38 (dt, J = 16.0, 5.8 Hz,
1H), 4.70 (dd, J = 5.8, 1.0 Hz, 2H), 2.35 (s, 3H).
1
1-Chloro-4-(3-phenylallyloxy)benzene, 1e. Yield = 77%, H NMR
(200 MHz, CDCl3): δ 7.49À7.17 (m, 7H), 6.89 (d, J = 9.2 Hz, 2H), 6.72
(d, J = 16.0 Hz, 1H), 6.39 (dt, J = 16.0, 5.8 Hz, 1H), 4.66 (dd, J = 5.8,
1.4 Hz, 2H).
1-Chloro-4-(3-phenoxypropenyl)benzene, 1f. Yield = 73%, 1H NMR
(200 MHz, CDCl3): δ 7.43À7.28 (m, 6H), 7.08À6.92 (m, 3H), 6.74
(d, J = 16.0 Hz, 1H), 6.44 (dt, J = 16.0, 5.6 Hz, 1H), 4.74 (dd, J = 5.6,
1.4 Hz, 2H).
4-Chlorocinnamyl-4-methylphenyl Ether, 1g. Yield = 80%, 1H NMR
(200 MHz, CDCl3): δ 7.38À7.23 (m, 4H), 7.07 (d, J = 8.6 Hz, 2H), 6.82
(d, J = 8.6 Hz, 2H), 6.66 (d, J = 16.0 Hz, 1H), 6.36 (dt, J = 16.0, 5.4 Hz,
1H), 4.63 (dd, J = 5.6, 1.2 Hz, 2H), 2.27 (s, 3H).
4-Methylcinnamyl-4-chlorophenyl Ether, 1h. Yield = 75%, 1H NMR
(200 MHz, CDCl3): δ 7.30À7.18 (m, 4H), 7.11 (d, J = 8.0 Hz, 2H), 6.85
(d, J = 8.8 Hz, 2H), 6.66 (d, J = 16.0 Hz, 1H), 6.31 (dt, J = 16.0, 5.8 Hz,
1H), 4.62 (d, J = 5.8 Hz, 2H), 2.31 (s, 3H).
4-Methylcinnamyl-4-methylphenyl Ether, 1i. Yield = 71%, 1H NMR
(200 MHz, CDCl 3): δ 7.27 (d, J = 8.0 Hz, 2H), 7.12À7.03 (m, 4H),
6.83 (d, J = 8.6 Hz, 2H), 6.66 (d, J = 16.0 Hz, 1H), 6.33 (dt, J = 15.8, 5.8
Hz, 1H), 4.63 (d, J = 5.8 Hz, 2H), 2.31 (s, 3H), 2.26 (s, 3H).
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1
1-Chloro-2-(3-phenylallyloxy)benzene, 1j. Yield = 87%, H NMR
(200 MHz, CDCl 3): δ 7.43À7.14 (m, 7H), 6.99À6.83 (m, 2H), 6.75
(d, J = 16.0 Hz, 1H), 6.41 (dt, J = 13.4, 5.6 Hz, 1H), 4.76 (dd, J = 5.6,
1.4 Hz, 2H).
4-Nitro-N-(4-phenylchroman-3-yl)benzenesulfonamide, 3a. White
solid, mp: 157À158 °C. FTIR (KBr, cmÀ1): 1523, 1489, 1458, 1448,
1438, 1348, 1309, 1229, 1164, 1099; 1H NMR (400 MHz, CDCl3): δ
8.22 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.25À7.15 (m, 4H),
6.94À6.90 (m, 3H), 6.85 (quasi-t, J = 7.6 Hz, 1H), 6.72 (d, J = 7.6 Hz,
1H), 5.03 (d, J = 7.6 Hz, 1H), 4.24 (dd, J = 11.2, 2.0 Hz, 1H), 4.03 (d,
J = 5.2 Hz, 1H), 3.85 (dd, J = 11.2, 6.0 Hz, 1H), 3.77À3.71 (m, 1H);
13C NMR (50 MHz, CDCl3): δ 153.8, 149.9, 145.9, 141.8, 131.2,
129.0, 128.8 (2C), 128.7 (2C), 127.9 (2C), 127.4, 124.3 (2C), 121.8,
120.8, 116.8, 65.5, 53.7, 47.8. Anal. (CHN %) Calcd for C21H18-
N2O5S: C, 61.45; H, 4.42; N, 6.83. Found: C, 61.39; H, 4.16; N, 6.79;
LRMS (electrosprayionization-MS): Calcd 409.0936 m/z (M À H)À,
found 409.0855 m/z. HPLC (0.46 Â 15.0 cm2 Chialpak AD-H, 90:10
n-hexane/i-PrOH, 1 mL/min, 220, 20 nm wavelength, ref off. Similar
HPLC condition was followed for all other samples): Cu(OTf)2-
catalyzed reaction, tr (minor) 14.34 min, tr (major) 16.28 min, 85% ee;
1
1-Fluoro-4-(3-phenylallyloxy)benzene, 1k. Yield = 70%, H NMR
(200 MHz, CDCl 3): δ 7.45À7.22 (m, 5H), 7.05À6.80 (m, 4H), 6.70
(d, J = 16.0 Hz, 1H), 6.37 (dt, J = 16.0, 5.8 Hz, 1H), 4.63 (dd, J = 5.8,
1.4 Hz, 2H).
Synthesis of 1-Substututed-4-(1,1-dimethyl-3-phenylallyloxy)ben-
zene, 1l,m. Mitsunobu coupling of dimethylcinnamyl alcohol with
corresponding p-methyl- and p-chlorophenols afforded the modified
substrates 1l,m.
1-(1,1-Dimethyl-3-phenylpropoxy)-4-methylbenzene, 1l. Colorless
1
liquid; H NMR (200 MHz, CDCl3): δ 7.36À7.18 (m, 5H), 7.04 (d,
J = 8.6 Hz, 2H), 6.73 (d, J = 8.6 Hz, 2H), 6.52 (d, J = 16.2 Hz, 1H), 6.35
(d, J = 16.2 Hz, 1H), 2.27 (s, 3H), 1.43 (s, 6H).
[R]28 = +29.1 (c 0.10, CHCl3); Cu(ClO4)2 6H2O-catalyzed reac-
1-Chloro-4-(1,1-dimethyl-3-phenylpropoxy)benzene, 1m. Colorless
D
3
1
tion, 83% ee.
liquid; H NMR (200 MHz, CDCl3): δ 7.42À7.28 (m, 5H), 7.20 (d,
4-Nitro-N-(4-p-tolylchroman-3-yl)benzenesulfonamide, 3b. White
solid, mp: 169À170 °C. FTIR (KBr, cmÀ1): 2924, 2869, 1606, 1528,
1512, 1488, 1348, 1335, 1312, 1228, 1163, 1097, 1069, 1050; 1H NMR
(400 MHz, CDCl3): δ 8.20 (d, J = 8.8 Hz, 2H), 7.83 (d, J = 8.8 Hz, 2H),
7.17 (quasi-t, J = 7.8 Hz, 1H), 6.98 (d, J = 8.0 Hz, 2H), 6.89 (d, J = 8.0 Hz,
1H), 6.85À6.80 (m, 1H), 6.79 (d, J = 8.0 Hz, 2H), 6.70 (d, J = 7.2 Hz,
1H), 5.01 (d, J = 7.6 Hz, 1H), 4.28 (dd, J = 11.2, 2.4 Hz, 1H), 3.95 (d,
J = 5.6 Hz, 1H), 3.85 (dd, J = 11.2, 6.4 Hz, 1H), 3.73À3.65 (m, 1H), 2.29
(s, 3H); 13C NMR (50 MHz, CDCl3): δ 153.9, 149.9, 145.8, 138.7,
137.4, 131.1, 129.5 (2C), 128.7 (3C), 128.1 (2C), 124.2 (2C), 121.7,
121.4, 116.8, 66.1, 53.9, 47.7, 20.9. Anal. (CHN %) Calcd for
C22H20N2O5S: C, 62.25; H, 4.75; N, 6.60. Found: C, 62.50; H, 5.10;
N, 6.72; LRMS (EI): Calcd 423.1093 m/z (M À H)À, found 423.1013
m/z. HPLC: Cu(OTf)2-catalyzed reaction, tr (minor) 15.04 min,
J = 9.0 Hz, 2H), 6.76 (d, J = 9.0 Hz, 2H), 6.60 (d, J = 16.0 Hz, 1H), 6.35
(d, J = 16.0 Hz, 1H), 1.43 (s, 6H).
General Procedure for One-Pot Enantioselective Synth-
esis of N-Protected-3-amino-4-arylchromans 3 and Aziri-
dines 2. In dichloromethane, the corresponding copper catalyst
(0.10 equiv) was stirred with the ligand (5, 0.12 equiv) in the presence
of molecular sieves (MS 4A) at rt. [In the case of hydrated copper salts
(e.g., copper acetate and perchlorate), it was stirred with the corre-
sponding ligand for 30 min in dichloromethane, and then the solvent
was removed under vacuum (1.0 mm of Hg) at 50 °C for 20 min. It was
cooled to 30 °C, and chloroform and activated molecular sieves (MS 4A)
were added further and stirred at rt.] After 1 h, alkene 1 (5.0 equiv) and
PhINNs (1.0 equiv) were added and stirred at 30 °C. It was a hetero-
geneous reaction mixture, and completion of the aziridination step was
indicated by the complete dissolution of the reagent. Then a supple-
mentary amount of Cu(OTf)2 (0.10 equiv) was added. Conversion of
the aziridine to chroman was monitored by TLC (approximately 2 h),
and upon completion, the reaction mixture was diluted with ethyl acetate
(10 mL) and filtered through a short plug of silica gel. The silica gel was
washed with an additional 10 mL of ethyl acetate. The filtrate was
concentrated by rotary evaporation under reduced pressure. N-Pro-
tected 3-amino-4-arylchroman 3 was isolated by flash column chroma-
tography, using a combination of ethyl acetate and hexane as an eluent.
Enantioselectivity was determined by HPLC (Solvent: n-hexane/
i-PrOH = 90/10; flow rate: 1.0 mL/min; wavelength: 220 nm, band-
width: 20 nm, column: CHIRALPAK AD-H, 0.46 cm  15.0 cm).
1-(4-Nitrobenzenesulfonyl)-2-phenoxymethyl-3-phenylaziridine, (()-
2a. White solid, mp: 164 °C. FTIR (KBr, cmÀ1): 1654, 1527, 1490, 1342,
1305, 1238, 1166, 1086, 1041, 917, 855; 1H NMR (200 MHz, CDCl3): δ
8.31 (d, J = 7.2 Hz, 2H), 8.14 (d, J = 7.2 Hz, 2H), 7.40À7.15 (m, 7H), 7.01
(quasi-t, J = 7.4 Hz, 1H), 6.91À6.86 (m, 2H), 4.69 (dd, J = 10.8, 6.4 Hz,
1H), 4.52 (dd, J = 10.8, 5.6 Hz, 1H), 3.51À3.42 (m, 1H), 4.12 (d, J =
4.4 Hz, 1H); 13C NMR (50 MHz, CDCl3): δ 157.9, 150.5, 145.3, 133.3,
129.7 (2C), 129.0, 128.9 (2C), 128.8 (2C), 126.9 (2C), 124.2 (2C), 121.8,
114.7 (2C), 64.8, 50.4, 47.4. Anal. (CHN %) Calcd for C21H18N2O5S: C,
61.45; H, 4.42; N, 6.83. Found: C, 61.66; H, 4.39; N, 6.59.
tr (major) 17.27 min, 90% ee; [R]28 = À59.2 (c 0.10, CHCl3);
D
Cu(ClO4)2 6H2O-catalyzed reaction, 71% ee.
3
N-(6-Methyl-4-phenylchroman-3-yl)-4-nitrobenzenesulfonamide,
3d. White solid, mp: 203À204 °C. FTIR (KBr, cmÀ1): 2929, 2373,
1530, 1499, 1426, 1347, 1307, 1222, 1164, 1092; 1H NMR (400 MHz,
CDCl3): δ 8.23 (d, J = 8.8 Hz, 2H), 7.88 (d, J = 8.8 Hz, 2H), 7.22À7.20
(m, 3H), 6.99 (d, J = 8.4 Hz, 1H), 6.96À6.93 (m, 2H), 6.81 (d, J =
8.4 Hz, 1H), 6.52 (s, 1H), 5.05 (d, J = 8.0 Hz, 1H), 4.18 (dd, J = 11.2, 2.0
Hz, 1H), 4.00 (d, J = 4.8 Hz, 1H), 3.80 (dd, J = 11.2, 5.6 Hz, 1H),
3.75À3.70 (m, 1H), 2.15 (s, 3H); 13C NMR (50 MHz, CDCl3): δ 151.9,
149.6, 146.5, 142.4, 131.2, 130.7, 129.1, 129.0 (2C), 128.6 (2C), 127.9
(2C), 127.1, 124.1 (2C), 121.5, 116.5, 66.4, 54.2, 47.6, 20.4. Anal.
(CHN %) Calcd for C22H20N2O5S: C, 62.25; H, 4.75; N, 6.60. Found:
C, 62.15; H, 4.42; N, 6.64; LRMS (EI): Calcd 423.1093 m/z (M À H)À,
found 423.1019 m/z. HPLC: Cu(OTf)2-catalyzed reaction, tr (minor)
12.30 min, tr (major) 13.46 min, 95% ee; [R]28 = À53.2 (c 0.10,
D
CHCl3); Cu(ClO4)2 6H2O-catalyzed reaction, 86% ee.
3
N-(6-Chloro-4-phenyl-chroman-3-yl)-4-nitrobenzenesulfonamide,
3e. White solid, mp: 217 °C. FTIR (KBr, cmÀ1): 1524, 1484, 1420,
1349, 1314, 1260, 1224, 1162, 1096, 1021, 1002; 1H NMR (400 MHz,
CDCl3): δ 8.23 (d, J = 8.8 Hz, 2H), 7.84 (d, J = 8.8 Hz, 2H), 7.23À7.18
(m, 3H), 7.14 (dd, J = 8.8, 2.4 Hz, 1H), 6.94À6.91 (m, 2H), 6.86 (d,
J = 8.8 Hz, 1H), 6.69 (d, J = 2.4 Hz, 1H), 5.01 (d, J = 7.6 Hz, 1H), 4.25
(dd, J = 11.2, 2.4 Hz, 1H), 4.01 (d, J = 5.2 Hz, 1H), 3.85 (dd, J = 11.2,
6.0 Hz, 1H), 3.75À3.69 (m, 1H); 13C NMR (50 MHz, DMSO-d6): δ
152.8, 149.5, 146.5, 141.5, 130.3, 129.0 (2C), 128.6 (2C), 128.2, 127.7
(2C), 127.3, 125.9, 124.4, 124.0 (2C), 118.1, 67.2, 53.7, 47.3. Anal.
(CHN %) Calcd for C21H17ClN2O5S: C, 56.69; H, 3.85; N, 6.30.
Found: C, 56.41; H, 3.78; N, 5.92; LRMS (EI): Calcd 443.0547 m/z
(M À H)À, found 443.0468 m/z. HPLC: Cu(OTf)2-catalyzed reaction,
1-(4-Nitrobenzenesulfonyl)-2-phenoxymethylaziridine, (()-2c.
White solid, mp: 132À133 °C. FTIR (KBr, cmÀ1): 2100, 1655, 1560,
1527, 1348, 1220, 1167, 772; 1H NMR (200 MHz, CDCl3): δ 8.43 (d,
J = 9.0 Hz, 2H), 8.13 (d, J = 9.0 Hz, 2H), 7.25À7.15 (m, 2H), 6.93
(quasi-t, J = 7.4 Hz, 1H), 6.69 (dd, J = 7.8, 1.2 Hz, 2H), 4.19 (dd, J = 10.1,
3.4 Hz, 1H), 3.85 (dd, J = 10.1, 6.8 Hz, 1H), 3.34À3.21 (m, 1H), 2.94 (d,
J = 7.2 Hz, 1H), 2.46 (d, J = 4.6 Hz, 1H); 13C NMR (100 MHz, CDCl3):
δ 157.6, 150.6, 143.4, 129.5 (2C), 129.3 (2C), 124.1 (2C), 121.4, 114.2
(2C), 66.5, 39.4, 31.0. Anal. (CHN %) Calcd for C15H14N2O5S: C,
53.88; H, 4.22; N, 8.38. Found: C, 53.54; H, 4.01; N, 7.99.
tr (minor) 13.08 min, tr (major) 15.77 min, 81% ee; [R]28 = À25.8
D
(c 0.10, CHCl3); Cu(ClO4)2 6H2O-catalyzed reaction, 48% ee.
3
7338
dx.doi.org/10.1021/jo200711s |J. Org. Chem. 2011, 76, 7334–7340

The Journal of Organic Chemistry
ARTICLE
N-[4-(4-Chlorophenyl)chroman-3-yl]-4-nitrobenzenesulfonamide,
3f. White solid, mp: 215À216 °C. FTIR (KBr, cmÀ1): 1530, 1489, 1346,
1310, 1223, 1165, 1090, 1014, 997; 1H NMR (400 MHz, CDCl3): δ 8.27
(d, J = 8.8 Hz, 2H), 7.89 (d. J = 8.8 Hz, 2H), 7.23À7.15 (m, 3H),
6.93À6.85 (m, 4H), 6.73 (d, J = 7.6 Hz, 1H), 5.07 (d, J = 8.4 Hz, 1H),
4.17 (dd, J = 11.2, 2.0 Hz, 1H), 4.04 (d, J = 4.8 Hz, 1H), 3.84 (dd, J =
11.2, 5.6 Hz, 1H), 3.75À3.65 (m, 1H); 13C NMR (50 MHz, CDCl3): δ
153.8, 150.1, 146.0, 140.5, 133.6, 131.2, 130.1 (2C), 129.0 (3C), 128.0
(2C), 124.4 (2C), 122.0, 120.4, 117.1, 65.5, 53.9, 47.4. Anal. (CHN %)
Calcd for C21H17ClN2O5S: C, 56.69; H, 3.85; N, 6.30. Found: C, 56.42;
H, 3.90; N, 6.49; LRMS (EI): Calcd 443.0547 m/z (M À H)À, found
443.0469 m/z. HPLC: Cu(OTf)2-catalyzed reaction, tr (minor) 17.85
J = 8.0Hz, 1H), 6.67 (d, J = 7.6Hz, 1H), 5.03 (d, J = 7.6 Hz, 1H), 4.34 (dd,
J = 11.2, 2.4 Hz, 1H), 4.10 (d, J = 5.2 Hz, 1H), 3.97 (dd, J = 11.2, 5.6 Hz,
1H), 3.79À3.74 (m, 1H); 13C NMR (50 MHz, CDCl3): δ 150.0, 149.6,
145.7, 141.3, 129.7, 129.3, 129.0 (2C), 128.7 (2C), 128.0 (2C), 127.7,
124.4 (2C), 122.9, 121.9 (2C), 66.3, 53.5, 48.0. Anal. (CHN %) Calcd for
C21H17ClN2O5S: C, 56.69; H, 3.85; N, 6.30. Found: C, 57.03; H, 3.73; N,
6.11; LRMS (EI): Calcd 443.0547 m/z (M À H)À, found 443.0466 m/z.
HPLC: Cu(OTf)2-catalyzed reaction, tr (major) 11.34 min, tr (minor)
12.84 min, 90% ee; [R]28D = À26.1 (c 0.10, CHCl3); Cu(ClO4)2 6H2O-
3
catalyzed reaction, 67% ee.
N-(6-Fluoro-4-phenylchroman-3-yl)-4-nitrobenzenesulfonamide, 3k.
White solid, mp: 214 °C. FTIR (KBr, cmÀ1): 1606, 1521, 1492, 1421,
1
min, tr (major) 19.21 min, 85% ee; [R]28 = À81.5 (c 0.10, CHCl3);
1348, 1306, 1258, 1196, 1162, 1098, 1022, 1005, 937; H NMR (400
D
MHz, CDCl3): δ 8.22 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 8.4 Hz, 2H),
7.22À7.17 (m, 3H), 6.94À6.91 (m, 2H), 6.90À6.86 (m, 2H), 6.43 (dd,
J = 8.8, 2.8 Hz, 1H), 5.01 (d, J = 7.6 Hz, 1H), 4.24 (dd, J = 11. 2, 2.4 Hz,
1H), 4.01 (d, J = 5.2 Hz, 1H), 3.83 (dd, J = 11.2, 6.4 Hz, 1H), 3.74À3.70
(m, 1H); 13C NMR (100 MHz, CDCl3): δ 158.6, 156.2, 149.8, 145.6,
141.1, 128.9 (2C), 128.6 (2C), 127.9 (2C), 127.7, 124.3 (2C), 122.2
(d, J = 7.4 Hz), 118.0 (d, J = 8.1 Hz), 116.7 (d, J = 23.2 Hz), 115.9 (d, J =
23.4 Hz), 65.8, 53.5, 48.1. Anal. (CHN %) Calcd for C21H17FN2O5S: C,
58.87; H, 4.00; N, 6.54. Found: C, 59.04; H, 3.65; N, 6.21; LRMS (EI):
Calcd 427.0842 m/z (M À H)À, found 427.0764 m/z. HPLC:Cu(OTf)2-
catalyzed reaction, tr (minor) 13.08 min, tr (major) 15.81 min, 80% ee;
Cu(ClO4)2 6H2O-catalyzed reaction, 61% ee.
3
N-[4-(4-Chlorophenyl)-6-methylchroman-3-yl]-4-nitrobenzenesul-
fonamide, 3g. Pale yellow solid, mp: 202 °C. FTIR (KBr, cmÀ1): 1605,
1530, 1498, 1430, 1350, 1310, 1226, 1165, 1091, 1014; 1H NMR
(400 MHz, CDCl3): δ 8.27 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 8.8 Hz,
2H), 7.17 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 6.4 Hz, 1H), 6.91 (d, J = 8.4 Hz,
2H), 6.81 (d, J = 8.4 Hz, 1H), 6.51 (s, 1H), 5.09 (d, J = 8.4 Hz, 1H), 4.12
(dd, J = 11.2, 2.0 Hz, 1H), 4.01 (d, 4.8 Hz, 1H), 3.79 (dd, J = 11.2, 5.2 Hz,
1H), 3.72À3.67 (m, 1H), 2.16 (s, 3H); 13C NMR (100 MHz, DMSO-
d6): δ 151.9, 149.3, 146.5, 140.8, 132.9, 130.7, 130.5, 130.4 (2C), 129.0,
128.4 (2C), 127.7 (2C), 123.9 (2C), 122.1, 116.4, 67.5, 54.4, 46.9, 20.4.
Anal. (CHN %) Calcd for C22H19ClN2O5S: C, 57.58; H, 4.17; N, 6.10.
Found: C, 57.34; H, 4.03; N, 5.89; LRMS (EI): Calcd 457.0703 m/z
(M À H)À, found 457.0620 m/z. HPLC: Cu(OTf)2-catalyzed reaction,
[R]28D = À12.6 (c 0.10, CHCl3); Cu(ClO4)2 6H2O-catalyzed reaction,
3
74% ee.
tr (minor) 14.64 min, tr (major) 17.09 min, 83% ee; [R]28 = À45.2
D
’ ASSOCIATED CONTENT
(c 0.10, CHCl3); Cu(ClO4)2 6H2O-catalyzed reaction, 56% ee.
3
S
N-(6-Chloro-4-p-tolylchroman-3-yl)-4-nitrobenzenesulfonamide, 3h.
Pale yellow solid, mp: 178À180 °C. FTIR (KBr, cmÀ1): 1608, 1527,
1483, 1438, 1347, 1312, 1229, 1164, 1101, 1037; 1H NMR (400 MHz,
CDCl3): δ 8.21 (d, J = 8.8 Hz, 2H), 7.81 (d, J = 8.8 Hz, 2H), 7.12 (dd, J =
8.8, 2.4 Hz, 1H), 6.98 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 8.8 Hz, 1H), 6.78
(d, J = 8.0 Hz, 2H), 6.66 (d, J = 2.4 Hz, 1H), 4.95 (d, J = 7.2 Hz, 1H), 4.29
(dd, J = 11.2, 2.8 Hz, 1H), 3.92 (d, J = 6.4 Hz, 1H), 3.85 (dd, J = 11.2, 6.4
Hz, 1H), 3.68À3.61 (m, 1H), 2.30 (s, 3H); 13C NMR (50 MHz,
CDCl3): δ 152.5, 149.9, 145.6, 137.8, 137.7, 130.4, 129.6 (2C), 128.7,
128.6 (2C), 128.0 (2C), 126.5, 124.2 (2C), 123.3, 118.3, 66.4, 53.6, 47.5,
20.9. Anal. (CHN %) Calcd for C22H19ClN2O5S: C, 57.58; H, 4.17; N,
6.10. Found: C, 57.20; H, 4.14; N, 5.78; LRMS (EI): Calcd 457.0703
m/z (M À H)À, found 457.0626 m/z. HPLC: Cu(OTf)2-catalyzed reac-
tion, tr (minor) 12.66 min, tr (major) 15.64 min, 66% ee; [R]28D = +51.7
Supporting Information. CIF and ORTEP diagram of
b
compound (()-3b, H and 13C NMR spectra of compounds
1
(()-2a, (()-2c, and 3aÀk and mass spectra and HPLC
chromatogram of 3aÀk. This material is available free of charge
via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Fax: (+91)-3222-255303. E-mail: shajra@chem.iitkgp.ernet.in.
’ ACKNOWLEDGMENT
We thank DST, New Delhi, for providing financial support. D.
S. thanks CSIR, New Delhi, for a fellowship. We are also grateful
to the referees for their valuable suggestions.
(c 0.10, CHCl3); Cu(ClO4)2 6H2O-catalyzed reaction, 70% ee.
3
N-(6-Methyl-4-p-tolylchroman-3-yl)-4-nitrobenzenesulfonamide, 3i.
White solid, mp: 156 °C. FTIR (KBr, cmÀ1): 3106, 2924, 2866, 1608,
1530, 1498, 1420, 1348, 1313, 1224, 1166, 1095, 1066, 1040; 1H NMR
(400 MHz, CDCl3): δ 8.21 (d, J = 8.8 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H),
7.00À6.95 (m, 3H), 6.82À6.77 (m, 3H), 6.50 (s, 1H), 5.02 (d, J =
7.2 Hz, 1H), 4.22 (dd, J = 11.2, 2.0 Hz, 1H), 3.93 (d, J = 5.2 Hz, 1H), 3.80
(dd, J = 11.2, 6.0 Hz, 1H), 3.70À3.65 (m, 1H), 2.30 (s, 3H), 2.13 (s,
3H); 13C NMR (50 MHz, CDCl3): δ 151.7, 149.9, 146.0, 139.0, 137.3,
131.2, 131.1, 129.5 (2C), 129.4, 128.7 (2C), 128.1 (2C), 124.2 (2C),
120.8, 116.5, 65.8, 54.1, 47.6, 20.9, 20.4. Anal. (CHN %) Calcd for
C23H22N2O5S: C, 63.00; H, 5.06; N, 6.39. Found: C, 62.85; H, 4.94; N,
6.28; LRMS (EI): Calcd 437.1249 m/z (M À H)À, found 437.1176 m/z.
HPLC: Cu(OTf)2-catalyzed reaction, tr (minor) 11.79 min, tr (major)
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13.49 min, 73% ee; [R]28 = À19.9 (c 0.10, CHCl3); Cu(ClO4)2
D
3
6H2O-catalyzed reaction, 66% ee.
N-(8-Chloro-4-phenylchroman-3-yl)-4-nitrobenzenesulfonamide, 3j.
White solid, mp: 198 °C. FTIR (KBr, cmÀ1): 1606, 1527, 1475, 1448,
1350, 1240, 1163, 1094, 1078, 1062, 1027; 1H NMR (400 MHz, CDCl3):
δ 8.23 (d, J = 8.8 Hz, 2H), 7.87 (d, J = 8.8 Hz, 2H), 7.29 (dd, J =
8.0, 1.2 Hz, 1H), 7.22À7.19 (m, 3H), 6.95À6.92 (m, 2H), 6.81 (quasi-t,
7339
dx.doi.org/10.1021/jo200711s |J. Org. Chem. 2011, 76, 7334–7340

The Journal of Organic Chemistry
ARTICLE
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(17) The structure was solved by direct methods using Wingx
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