CuCl-catalyzed regio- and stereoselective aminohalogenation of α,β-unsaturated nitriles

Article abstract of DOI:10.1002/ejoc.200600902

α,β-Unsat1urated nitriles were found to be suitable substrates for aminochlorination with N,N-dichloro-p-toluenesulfonamide (4-TsNCl ₂) in the presence of CuCl as the catalyst (10 mol-%) and 4 A molecular sieves. The reaction is very convenient

Full text of DOI:10.1002/ejoc.200600902

FULL PAPER
DOI: 10.1002/ejoc.200600902
CuCl-Catalyzed Regio- and Stereoselective Aminohalogenation of α,β-
Unsaturated Nitriles
Jian-Lin Han,[a] San-Jun Zhi,[a] Le-Yong Wang,[a] Yi Pan,*[a] and Guigen Li*[b]
Keywords: Aminohalogenation / α,β-Unsaturated nitriles / Copper chloride
α,β-Unsaturated nitriles were found to be suitable substrates
for aminochlorination with N,N-dichloro-p-toluenesulfon-
amide (4-TsNCl2) in the presence of CuCl as the catalyst
(10 mol-%) and 4 Å molecular sieves. The reaction is very
convenient to carry out at room temperature without the pro-
tection of inert gases, and this method provides an easy route
to vicinal haloamino nitriles with excellent regio- and stereo-
selectivities and in good chemical yields. The stereochemis-
try has been unambiguously confirmed by X-ray structural
analysis.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
of this reaction we have now turned our attention to the
aminohalogenation of α,β-unsaturated nitriles, which could
have great potential in pharmaceutical chemistry.[13] In this
work we report the preliminary results of our investigation
of aminohalogenation with these substrates under new cata-
lytic conditions (Scheme 1). The new method provides an
easy route to vicinal haloamino nitriles and represents an
important extension of the substrate scope of our original
aminohalogenation.
Introduction
Aminohalogenation and related reactions of multiply
functionalized alkenes have become an interesting topic in
organic synthesis because the resulting vicinal haloamines
are important building blocks in organic and medicinal
chemistry.[1–5] The products resulting from these processes
can readily be converted into numerous other derivatives
by replacement of the halogen in both intramolecular and
intermolecular reactions. In the past few years, we and
other groups have developed the catalytic aminohalogena-
tion of alkenes with the aid of several nitrogen/halogen
sources such as 4-TsNCl2,[6a,6b] 2-NsNNsCl (2-Ns: 2-ni-
trophenylsulfonyl), a combination of 2-NsNCl2 and 2-
NsNHNa,[6c,6d] and a combination of NBS and TsNH2 in
the presence of metal catalysts.[6e] The processes are be-
lieved to proceed according to a mechanism that involves
aziridinium ion intermediates, which could explain the
stereo- and regioselectivities of the resulting haloamine and
diamine products.[6–9]
Although several synthetic approaches to vicinal
haloamine functionalities have been developed,[6–8,10] the
catalytic aminohalogenation of a series of functionalized al-
kenes has not been well documented. So far, there have
been few substrates, including α,β-unsaturated ketones,[7b]
α,β-unsaturated esters,[6a,11] methylenecyclopropanes, and
vinylidenecyclopropanes[12] that have been subjected to the
aminohalogenation reaction. In our ongoing investigation
Scheme 1.
Results and Discussion
Initially, a readily available starting material – 3,3-di-
phenylacrylonitrile (1a) – was subjected to the reaction un-
der our previous catalytic conditions. The reaction was per-
formed in acetonitrile and catalyzed by use of CuOTf as
the catalyst in the presence of molecular sieves (4 Å) to give
the corresponding aminochlorinated product 2a in a chemi-
cal yield of 67%. To improve the yield, a variety of other
catalysts, such as CuCl, CuCl2, PdCl2, Pd(OAc)2, ZnCl2,
AgOTf, and (salen)MnIII {[N,NЈ-bis(3,5-di-tert-butylsalicyl-
idene)-1,2-cyclohexanediamine]manganese(III) chloride}
were then utilized for this reaction. The results are listed in
Table 1.
As indicated in Table 1, CuCl was found to catalyze the
reaction to completion within 24 h and generated the vici-
nal haloamino nitrile 2a in the highest chemical yield
(79%). The reaction with copper(II) chloride catalyst also
gave the haloamine product, but in a slightly lower yield
[a] School of Chemistry and Chemical Engineering, Nanjing Uni-
versity, and State Key Laboratory of Coordination, Nanjing
University,
Nanjing 210093, P. R. China
E-mail: yipan@nju.edu.cn
[b] Department of Chemistry and Biochemistry, Texas Tech Uni-
versity,
Lubbock, Texas 79409-106, USA
E-mail: guigen.li@ttu.edu
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1332–1337

Selective Aminohalogenation of α,β-Unsaturated Nitriles
FULL PAPER
(75%, Entry 3, Table 1). Surprisingly, when CuOTf, the resulted in a much lower yield of 2a (41%). It was also
most effective catalyst for α,β-unsaturated ketones and found that at least 2 equiv. of TsNCl2 was needed for the
esters, was employed as the catalyst, a lower yield (67%) of complete conversion, the yield being decreased from 79%
product 2a was obtained within the same period of time to 51% when 1.2 equiv. of TsNCl2 was used (Entry 12,
(Entry 1, Table 1).
Table 2).
After the reaction conditions had been optimized, a
Table 1. Aminochlorination of 3,3-diphenylacrylonitrile (1a).[a]
series of α,β-unsaturated nitriles were investigated carefully.
As can be seen in Table 3, this reaction has a broad sub-
strate range: cinnamonitriles (Entries 2 and 3, Table 3), a β-
substituted cinnamonitrile (Entry 1, Table 3), and α-substi-
tuted cinnamonitriles (Entries 4–9, Table 3) can all be em-
ployed to give modest to very good chemical yields (55–
89%). These substrates showed good to excellent stereo-
selectivities, with ratios ranging from 7:1 to Ͼ20:1. In two
cases (Entries 3 and 9, Table 3), only the anti isomers were
observed; only one regioisomer was observed for each of
these cases. In the case of the aromatic substrate with a
strongly electron-withdrawing group (NO2) on the aromatic
ring [3-(4-nitrophenyl)acrylonitrile], only a trace amount of
aminochlorination product was observed even after the re-
action time had been extended to 72 h at 50 °C.
In the cases of cinnamonitriles and β-substituted cinna-
monitriles (Entries 1–3, Table 2), regioselectivities similar to
those observed in aminohalogenation reactions of α,β-un-
saturated esters and ketones were achieved. However, when
α-substituted cinnamonitriles (Entries 4–9, Table 2) were
employed for the reaction, the opposite regioselectivities
were observed for the major isomeric products, which are
β-amino nitriles (Scheme 2). These products can be readily
converted into the useful β-amino acids.
Entry
Catalyst
Yield (%)[b]
1
2
3
4
5
6
7
8
CuOTf
CuCl
CuCl2
PdCl2
Pd(OAc)2
ZnCl2
67
79
75
59
N.R.[c]
N.R.[c]
16
AgOTf
(salen)MnIII
62
[a] Conditions: 1 mmol of nitrile and 2 mmol of TsNCl2 in CH3CN
(4 mL) in the presence of molecular sieves (4 Å) (0.5 g) at room
temperature for 24 h. [b] Isolated yields. [c] No reaction was ob-
served.
To investigate this catalytic reaction further (Table 2),
several other common solvents were also examined, but
CH3CN was found to be the only efficient choice for this
reaction. Other solvents, such as CH2Cl2, toluene, DMF,
and THF, afforded either none or only trace amounts of
the corresponding vicinal haloamino nitriles (Entries 2–6,
Table 2). As in our previous systems, molecular sieves (4 Å)
were found to be essential for the reaction: the yield was
decreased to 41% if molecular sieves (4 Å) were not added
(Entry 7, Table 2). The role of molecular sieves (4 Å) could
be to absorb some of the metal catalyst on their surfaces to
enhance the catalytic activity further. It turned out that the
reaction was not sensitive to temperature change: similar
yields could be obtained either on raising the temperature
to 50 °C or on decreasing it to 5 °C (71% yield for 50 °C
and 78% yield for 5 °C). The reaction generally required
24 h for the complete consumption of the starting α,β-un-
The mechanism of this reaction is believed to be similar
to that of our previously reported aminohalogenation of
α,β-unsaturated esters and ketones. The first step would be
the formation of the aziridinium intermediate, and this pos-
itively charged intermediate would be attacked by a chloride
anion to give the aminohalogenation adducts. The regio-
and stereoselectivity of this reaction can be explained well
on the basis of this mechanistic hypothesis involving these
key aziridinium intermediates.
Of all the products shown in Table 3, only 3d was suc-
saturated nitriles. Shortening of the reaction time to 12 h cessfully recrystallized suitably for X-ray crystallographic
Table 2. Aminochlorination of 3,3-diphenylacrylonitrile (1a).[a]
Entry
Solvent
Molecular sieves (4 Å)
Substrate[b]
Time
(h)
Temperature
(oC)
Yield
(%)[c]
(g)
1
2
3
4
5
6
7
8
9
CH3CN
BnCN
CH2Cl2
toluene
DMF
0.5
0.5
0.5
0.5
0.5
0.5
0
0.5
0.5
0.5
0.5
0.5
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:2
1:1.2
24
24
24
24
24
24
24
24
24
12
48
24
25
25
25
25
25
25
25
5
50
25
25
25
79
20
0
15
0
THF
5
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
41
78
71
41
79
51
10
11
12
[a] Conditions: 1 mmol of 1a and 4 mL of solvent in the presence of CuCl (0.1 mmol, 10 mol-%) were used. [b] Ratio of 1a/TsNCl2.
[c] Isolated yields.
Eur. J. Org. Chem. 2007, 1332–1337
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J.-L. Han, S.-J. Zhi, L.-Y. Wang, Y. Pan, G. Li
FULL PAPER
Table 3. Results of CuCl-catalyzed aminochlorination of α,β-unsaturated nitriles.[a]
Entry
R1
R2
R3
Product
(Ϯ)
Stereoselectivity[b]
Yield[c]
(%)
(anti/syn)
1
2
3
4
5
6
7
8
9
Ph
p-MeC6H4
p-ClC6H4
Ph
H
H
H
H
H
Ph
Ph
2a
2b
2c
3d
3e
3f
3g
3h
3i
N/A
10:1
Ͼ20:1
9:1
10:1
10:1
8:1
79
76
55
76
89
69
67
85
61
H
H
H
H
H
H
Ph
p-ClC6H4
o-ClC6H4
Ph
p-ClC6H4
o-ClC6H4
Ph
p-ClC6H4
p-ClC6H4
p-ClC6H4
7:1
Ͼ20:1
[a] Conditions: 1 mmol of nitrile and 2 mmol of TsNCl2 in CH3CN (4 mL) in the presence of CuCl (0.1 mmol, 10 mol-%) and molecular
1
sieves (4 Å) (0.5 g) at room temperature for 24 h. [b] Estimated by crude H NMR determinations; “Ͼ20:1” means no minor isomer was
detected. [c] The yields after purification by preparative TLC.
Finally, attempts to employ aliphatic nitriles such as ac-
rylonitrile and cyclohexylideneacetonitrile for this reaction
have not been successful. Both CuI and CuII chloride, and
also CuI triflate, failed to give any aminohalogenation ad-
Scheme 2.
ducts, even after the temperature was enhanced with exten-
sion of the reaction time. The poorer stabilization ability of
aliphatic groups in relation to their aromatic counterparts
could be responsible for this observation. Further study of
the use of these substrates for aminohalogenation with the
aid of ionic liquids will be continued in our laboratories in
the future.
analysis. As shown by the ORTEP drawing of 3d in Fig-
ure 1, the stereochemistry was unambiguously confirmed.
In Entries 1–3 in Table 3 the positively charged aziridinium
ion should be better stabilized on the β-position of each
substrate, and the subsequent SN2 ring-opening by the chlo-
ride anion would thus be direced onto this position. In the
α,α-disubstituted cases (Entries 3–9 in Table 3), however, in
which there is only one substituent on their β-positions, the
aziridinium stabilization situation would be reversed and
Conclusions
A regio- and stereoselective aminochlorination of α,β-
the subsequent attack of the chloride anion would be di- unsaturated nitriles under convenient catalytic conditions
rected onto their α-positions to give the opposite regioselec- has been developed. The synthesis is convenient to carry
tivity.
out without the protection with an inert gas at room tem-
Figure 1. ORTEP diagram showing 3d.
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 1332–1337

Selective Aminohalogenation of α,β-Unsaturated Nitriles
FULL PAPER
(Z)-2,3-Bis(4-chlorophenyl)acrylonitrile (1h): This compound was
isolated from the reaction between 4-chlorobenzaldehyde (14.1 g.
0.1 mol) and (4-chlorophenyl)acetonitrile (15.2 g, 0.1 mol) as a light
yellow solid (20.5 g, 75% yield) with m.p. 109–110 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.83 (d, J = 8.6 Hz, 2 H), 7.60 (d, J =
8.6 Hz, 2 H), 7.43–7.48 (m, 5 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 142.9, 141.8, 135.3, 133.5, 131.1, 130.1, 129.8, 129.6,
127.5, 118.3, 109.5 ppm.
perature and the new method provides an easy route to vici-
nal haloamino nitriles. Good chemical yields and excellent
regio- and stereoselectivities have been achieved with nine
different nitriles. Opposite regioselectivities were observed
with α,α-disubstituted β-monosubstituted cinnamonitriles.
The stereochemistry was unambiguously confirmed by X-
ray analysis.
(Z)-3-(2-Chlorophenyl)-2-(4-chlorophenyl)acrylonitrile (1i): This
compound was isolated from the reaction between 2-chlorobenzal-
dehyde (14.1 g. 0.1 mol) and (4-chlorophenyl)acetonitrile (15.2 g,
0.1 mol) as a light yellow solid (20.5 g, 75% yield) with m.p. 109–
110 °C. 1H NMR (300 MHz, CDCl3): δ = 8.11–8.14 (m, 1 H), 7.89
(s, 1 H), 7.60–7.68 (m, 2 H), 7.40–7.52 (m, 5 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 139.2, 136.1, 135.2, 132.7, 132.3, 131.9,
130.3, 129.7, 127.8, 127.7, 117.3, 114.0 ppm.
Experimental Section
General: All moisture-sensitive reactions were performed under ni-
trogen or argon in glassware that had been flame-dried. Solvents
were dried and distilled prior to use. Melting points are uncor-
rected. IR spectra were collected with a Bruker Vector 22 instru-
ment (KBr pellets). 1H and 13C NMR (TMS used as internal stan-
dard) spectra were recorded with a Bruker ARX 300 spectrometer
and CDCl3 or CD3COCD3 were used as solvents. Elemental analy-
ses were performed with a Perkin–Elmer 240 elemental analysis
instrument. Mass spectra of the new compounds were measured
with a Finnigan LCQ Electrospray Mass Spectrometer. Thin layer
chromatography was carried out on silica gel 60 (F-254) TLC
plates. Gel 60 (F-254) TLC plates (20 cmϫ20 cm) were used for
isolation.
Typical Procedure for Aminochlorination of Nitriles: The nitrile
(1.0 mmol), molecular sieves (4 Å) (0.5 g), CuCl (10 mg, 0.1 mmol,
10 mol-%), and freshly distilled acetonitrile (2.0 mL) were placed
in a dry vial. A solution of 4-TsNCl2 (480 mg, 2.0 mmol) in freshly
distilled acetonitrile (2.0 mL) was then slowly added under argon
to the above mixture by syringe over 5 min. The resulting solution
was stirred without argon protection at room temperature for 24 h
and the reaction was then quenched with saturated aqueous
Na2SO3 (5.0 mL) solution. The two phases were separated, and the
aqueous phase was extracted with EtOAc (3ϫ20 mL). The com-
bined organic phases were washed with brine and dried with anhy-
drous sodium sulfate. Purification by TLC (EtOAc/petroleum ether,
1:4 v/v) provided the pure product.
Starting Materials: 2,2-Diphenylacrylonitrile (1a),[14] (E)-4-methyl-
cinnamonitrile (1b),[15] (E)-4-chlorocinnamonitrile (1c),[15] and (Z)-
2,3-diphenylacrylonitrile (1d)[16] were prepared according to the re-
ported methods. Starting materials 1e–1i were prepared according
to the reported method with modifications.[16]
3-Chloro-3,3-diphenyl-2-(tosylamino)propionitrile (2a): This com-
pound was isolated as a white solid (324 mg, 79% yield) from the
reaction between 1a (205 mg, 1.0 mmol) and TsNCl2 (480 mg,
2 mmol) in the presence of CuCl (10 mg, 0.1 mmol, 10 mol-%) in
acetonitrile (4.0 mL). M.p. 159–160 °C. 1H NMR (300 MHz,
CDCl3): δ = 7.73 (d, J = 8.3 Hz, 2 H), 7.47–7.52 (m, 4 H), 7.31–
7.39 (m, 8 H), 5.41 (d, J = 10.4 Hz, 1 H), 5.20 (d, J = 10.3 Hz, 1
H), 2.44 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 145.2,
139.6, 139.5, 136.0, 130.4, 129.5, 129.3, 129.1, 129.0, 128.3, 128.0,
127.7, 115.3, 77.5, 55.1, 22.0 ppm. IR (KBr): ν = 3256, 2933, 1596,
1493, 1333, 1163, 1090 cm–1. MS (ESMS/[M + Na]+): calcd. for
C22H19ClN2O2SNa 433.1; found 432.9. C22H19ClN2O2S (410.92):
calcd. C 64.30, H 4.66, N 6.82; found C 64.38, H 4.73, N 6.91.
(Z)-3-(4-Chlorophenyl)-2-phenylacrylonitrile (1e): A mixture of 4-
chlorobenzaldehyde (14.1 g, 0.1 mol) and purified dry benzyl cya-
nide (11.7 g, 0.1 mol) in ethanol (95%, 65 mL) was placed in a
200 mL beaker, and a solution of sodium ethoxide (1.0 g) in abso-
lute ethanol (7 mL) was added dropwise, with vigorous stirring.
After the addition, the mixture had turned cloudy. Vigorous stir-
ring was continued for another 2 h, then the mixture was cooled in
an ice bath and the product was separated by filtration. The white
mass was washed first with distilled water (50 mL) and then with
cold ethanol (95%, 10 mL) to remove unchanged reagents.
Recrystallization from 95% ethanol afforded 20.3 g of product as
1
a white solid (85%). M.p. 97–99 °C. H NMR (300 MHz, CDCl3):
δ = 7.82 (d, J = 8.5 Hz, 2 H), 7.66–7.69 (m, 2 H), 7.49 (s, 1 H),
7.39–7.48 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 141.0,
136.8, 134.5, 132.5, 130.8, 129.8, 129.6, 129.5, 126.4, 118.1,
112.6 ppm.
3-Chloro-3-(4-methylphenyl)-2-(tosylamino)propionitrile (2b): This
compound was isolated as a white solid (265 mg, 76% yield) from
the reaction between 1b (143 mg, 1.0 mmol) and TsNCl2 (480 mg,
2 mmol) in the presence of CuCl (10 mg, 0.1 mmol, 10 mol-%) in
acetonitrile (4.0 mL). M.p. 140–142 °C. 1H NMR (300 MHz,
CDCl3): δ = 7.75 (d, J = 8.3 Hz, 2 H), 7.35–7.37 (m, 4 H), 7.20 (d,
J = 8.1 Hz, 2 H), 5.38 (d, J = 10.4 Hz, 1 H), 5.11 (d, J = 3.8 Hz,
1 H), 4.63 (dd, J = 10.4, 3.8 Hz, 1 H), 2.45 (s, 3 H), 2.38 (s, 3 H)
ppm. 13C NMR (75 MHz, CD3COCD3): δ = 144.2, 139.7, 137.6,
133.1, 130.0, 129.6, 128.1, 127.4, 116.2, 62.0, 52.2, 20.9, 20.6 ppm.
IR (KBr): ν = 3210, 2919, 1594, 1469, 1323, 1150, 1085 cm–1. MS
(ESMS/[M + Na]+): calcd. for C17H17ClN2O2SNa 371.1; found
371.0. C17H17ClN2O2S (348.85): calcd. C 58.53, H 4.91, N 8.03;
found C 58.43, H 5.12, N 7.94.
(Z)-3-(2-Chlorophenyl)-2-phenylacrylonitrile (1f): This compound
was isolated from the reaction between 2-chlorobenzaldehyde
(14.1 g, 0.1 mol) and benzyl cyanide (11.7 g, 0.1 mol) as a white
solid (19.1 g, 80% yield) with m.p. 102–104 °C. 1H NMR
(300 MHz, CDCl3): δ = 8.12–8.15 (m, 1 H), 7.92 (s, 1 H), 7.72–7.76
(m, 2 H), 7.38–7.53 (m, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ
= 138.9, 135.2, 134.2, 132.6, 131.7, 130.2, 130.1, 129.8, 129.5, 127.6,
126.7, 117.7, 115.2 ppm.
(Z)-2-(4-Chlorophenyl)-3-phenylacrylonitrile (1g): This compound
was isolated from the reaction between benzaldehyde (10.6 g, 0.1
mol) and (4-chlorophenyl)acetonitrile (15.2 g, 0.1 mol) as a white
solid (16.7 g, 70% yield) with m.p. 108–110 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.89–7.92 (m, 2 H), 7.62 (d, J = 8.6 Hz, 2
3-Chloro-3-(4-chlorophenyl)-2-(tosylamino)propionitrile (2c): This
compound was isolated as a white solid (203 mg, 55% yield) from
the reaction between 1c (164 mg, 1.0 mmol) and TsNCl2 (480 mg,
H), 7.42–7.53 (m, 6 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 2 mmol) in the presence of CuCl (10 mg, 0.1 mmol, 10 mol-%) in
142.9, 135.6, 133.8, 133.7, 131.2, 129.7, 129.6, 129.4, 127.6, 118.0,
110.9 ppm.
acetonitrile (4.0 mL). M.p. 142–144 °C. 1H NMR (300 MHz,
CDCl3): δ = 7.74 (d, J = 8.3 Hz, 2 H), 7.35–7.44 (m, 6 H), 5.40 (d,
Eur. J. Org. Chem. 2007, 1332–1337
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1335

J.-L. Han, S.-J. Zhi, L.-Y. Wang, Y. Pan, G. Li
FULL PAPER
J = 10.5 Hz, 1 H), 5.12 (d, J = 3.9 Hz, 1 H), 4.64 (dd, J = 10.5,
C22H18Cl2N2O2SNa 467.0; found 467.1. C22H18Cl2N2O2S (445.36):
3.9 Hz, 1 H), 2.46 (s, 3 H) ppm. 13C NMR (75 MHz, CD3COCD3): calcd. C 59.33, H 4.07, N 6.29; found C 59.18, H 4.17, N 6.13.
δ = 144.3, 137.5, 135.1, 135.0, 130.1, 130.0, 129.0, 127.3, 116.2,
2-Chloro-2,3-bis(4-chlorophenyl)-3-(tosylamino)propionitrile (3h):
60.8, 51.8, 21.0 ppm. IR (KBr): ν = 3209, 2914, 1595, 1471, 1319,
This compound was isolated as a white solid (407 mg, 85% yield)
1150, 1084 cm–1. MS (ESMS/[M
C16H14Cl2N2O2SNa 391.0; found 391.1. C16H14Cl2N2O2S (369.27):
calcd. C 52.04, H 3.82, N 7.59; found C 52.17, H 3.96, N 7.64.
+
Na]+): calcd. for
from the reaction between 1h (274 mg, 1.0 mmol) and TsNCl2
(480 mg, 2 mmol) in the presence of CuCl (10 mg, 0.1 mmol,
10 mol-%) in acetonitrile (4.0 mL). M.p. 141–144 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.30–7.41 (m, 6 H), 7.12 (d, J = 8.4 Hz, 2
H), 7.06 (d, J = 7.9 Hz, 2 H), 6.89 (d, J = 8.3 Hz, 2 H), 5.56 (d, J
= 9.9 Hz, 1 H), 4.93 (d, J = 10.0 Hz, 1 H), 2.37 (s, 3 H) ppm. 13C
NMR (75 MHz, CD3COCD3): δ = 143.5, 138.0, 136.0, 134.6,
133.7, 133.2, 131.2, 129.4, 129.3, 129.1, 128.1, 127.2, 117.0, 78.6,
66.0, 20.7 ppm. IR (KBr): ν = 3241, 2952, 1597, 1492, 1435, 1328,
1 1 6 9 , 1 0 9 4 c m – 1 . M S ( E S M S / [ M + N a ] + ) : c a l c d . fo r
C22H17Cl3N2O2SNa 500.9; found 501.0. C22H17Cl3N2O2S (479.81):
calcd. C 55.07, H 3.57, N 5.84; found C 55.21, H 3.47, N 5.76.
2-Chloro-2,3-diphenyl-3-(tosylamino)propionitrile (3d): This com-
pound was isolated as a white solid (312 mg, 76% yield) from the
reaction between 1d (205 mg, 1.0 mmol) and TsNCl2 (480 mg,
2 mmol) in the presence of CuCl (10 mg, 0.1 mmol, 10 mol-%) in
acetonitrile (4.0 mL). M.p. 154–156 °C. 1H NMR (300 MHz,
CDCl3): δ = 7.31–7.44 (m 7 H), 7.18–7.23 (m, 1 H), 7.00–7.11 (m,
4 H), 6.82 (d, J = 7.6 Hz, 2 H), 5.57 (d, J = 10.0 Hz, 1 H), 5.00 (d,
J = 10.0 Hz, 1 H), 2.30 (s, 3 H) ppm. 13C NMR (75 MHz,
CD3COCD3): δ = 143.1, 138.3, 134.9, 134.1, 130.2, 129.5, 129.3,
128.9, 128.7, 127.8, 127.5, 127.1, 117.7, 67.2, 67.0, 20.7 ppm. IR
(KBr): ν = 3248, 1597, 1450, 1336, 1166, 1089 cm–1. MS (ESMS/
[M + Na]+): calcd. for C22H19ClN2O2SNa 433.1; found 433.1.
C22H19ClN2O2S (410.92): calcd. C 64.30, H 4.66, N 6.82; found C
64.21, H 4.78, N 6.96.
2-Chloro-3-(2-chlorophenyl)-2-(4-chlorophenyl)-3-(tosylamino)-
propionitrile (3i): This compound was isolated as a white solid
(293 mg, 61 % yield) from the reaction between 1i (274 mg,
1.0 mmol) and TsNCl2 (480 mg, 2 mmol) in the presence of CuCl
(10 mg, 0.1 mmol, 10 mol-%) in acetonitrile (4.0 mL). M.p. 198–
201 °C. 1H NMR (300 MHz, CDCl3): δ = 7.40–7.49 (m, 5 H), 7.16–
7.25 (m, 5 H), 7.03 (d, J = 8.1 Hz, 2 H), 5.67 (d, J = 10.5 Hz, 1 H),
5.59 (d, J = 10.4 Hz, 1 H), 2.34 (s, 3 H) ppm. 13C NMR (75 MHz,
CD3COCD3): δ = 143.5, 137.6, 136.1, 135.3, 133.7, 132.5, 130.7,
129.5, 129.4, 129.4, 129.3, 129.1, 127.5, 126.9, 116.8, 66.0, 61.5,
20.79 ppm. IR (KBr): ν = 3260, 2980, 1596, 1493, 1437, 1338, 1164,
1096 cm–1. MS (ESMS/[M + Na]+): calcd. for C22H17Cl3N2O2SNa
500.9; found 501.0. C22H17Cl3N2O2S (479.81): calcd. C 55.07, H
3.57, N 5.84; found C 55.05, H 3.46, N 5.86.
2-Chloro-3-(4-chlorophenyl)-2-phenyl-3-(tosylamino)propionitrile
(3e): This compound was isolated as a white solid (396 mg, 89%
yield) from the reaction between 1e (240 mg, 1.0 mmol) and
TsNCl2 (480 mg, 2 mmol) in the presence of CuCl (10 mg,
0.1 mmol, 10 mol-%) in acetonitrile (4.0 mL). M.p. 177–179 °C. 1H
NMR (300 MHz, CDCl3): δ = 7.33–7.46 (m, 7 H), 7.05–7.27 (m, 4
H), 6.75 (d, J = 8.5 Hz, 2 H), 5.75 (d, J = 9.3 Hz, 1 H), 4.98 (d, J
= 9.8 Hz, 1 H), 2.35 (s, 3 H) ppm. 1 3 C NMR (75 MHz,
CD3COCD3): δ = 143.4, 138.1, 134.6, 134.4, 132.9, 131.2, 130.4,
129.4, 129.0, 127.9, 127.5, 127.2, 117.5, 66.9, 66.3, 20.7 ppm. IR
(KBr): ν = 3251, 2935, 1598, 1444, 1325, 1163, 1092 cm–1. MS
(ESMS/[M + Na]+): calcd. for C22H18Cl2N2O2SNa 467.0; found
467.1. C22H18Cl2N2O2S (445.36): calcd. C 59.33, H 4.07, N 6.29;
found C 59.15, H 4.11, N 6.30.
Crystal Data for 3d: C22H21ClN2O3S (428.92); monoclinic, space
group C2/c; a = 17.8838(16), b = 14.3201(16), c = 18.4191(18) Å;
β = 110.153(2)°; V = 4428.3(8) Å3; Z = 8; Dcalcd. = 1.287 g cm–3;
F(000) = 1792; crystal size 0.22ϫ0.24ϫ0.28 mm; 2θmax = 52.0°;
reflections collected: 11914; unique: 4342 (Rint = 0.034); param-
eters: 272; R1 = 0.0529; wR2 = 0.1351; GOF = 1.03. CCDC-612351
(for 3d) contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
2-Chloro-3-(2-chlorophenyl)-2-phenyl-3-(tosylamino)propionitrile
(3f): This compound was isolated as a white solid (307 mg, 69%
yield) from the reaction between 1f (240 mg, 1.0 mmol) and TsNCl2
(480 mg, 2 mmol) in the presence of CuCl (10 mg, 0.1 mmol,
10 mol-%) in acetonitrile (4.0 mL). M.p. 198–201 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.27–7.52 (m, 8 H), 7.11–7.17 (m, 3 H),
7.01 (d, J = 7.9 Hz, 2 H), 5.72 (d, J = 10.2 Hz, 1 H), 5.63 (d, J =
10. 2 Hz, 1 H), 2. 31 (s, 3 H) ppm. 1 3 C NMR (75 MHz,
CD3COCD3): δ = 143.4, 137.7, 135.3, 134.6, 132.5, 130.5, 129.7,
129.4, 129.2, 129.0, 128.8, 127.5, 127.3, 127.0, 117.2, 66.9, 61.5,
20.7 ppm. IR (KBr): ν = 3257, 1595, 1435, 1339, 1164, 1077 cm–1.
MS (ESMS/[M + Na]+): calcd. for C22H18Cl2N2O2SNa: 467.0;
found 467.0. C22H18Cl2N2O2S (445.36): calcd. C 59.33, H 4.07, N
6.29; found C 59.49, H 4.00, N 6.25.
Acknowledgments
We gratefully acknowledge the 863 High Technology Program (to
Y. P., P. R. China) and the Welch Foundation (D-1361) (to G. L.,
USA) for the generous financial support. The research funds for
Y. P. from the Qing-Lan program of Jiangsu Province and the Kua-
Shi-Ji program of the Education Ministry of China are also ac-
knowledged.
2-Chloro-2-(4-chlorophenyl)-3-phenyl-3-(tosylamino)propionitrile
(3g): This compound was isolated as a white solid (298 mg, 67%
yield) from the reaction between 1g (240 mg, 1.0 mmol) and
TsNCl2 (480 mg, 2 mmol) in the presence of CuCl (10 mg,
0.1 mmol, 10 mol-%) in acetonitrile (4.0 mL). M.p. 192–194 °C. 1H
NMR (300 MHz, CDCl3): δ = 7.35–7.40 (m, 4 H), 7.24–7.29 (m, 3
H), 7.15–7.19 (m, 2 H) 7.03 (d, J = 8.1 Hz, 2 H), 6.96 (d, J =
7.4 Hz, 2 H), 5.40 (d, J = 9.9 Hz, 1 H), 4.95 (d, J = 10.2 Hz, 1 H),
2.34 (s, 3 H) ppm. 13C NMR (75 MHz, CD3COCD3): δ = 143.2,
138.2, 135.8, 134.4, 134.0, 129.4, 129.3, 129.0, 128.9, 128.0, 127.1,
117.2, 66.9, 66.2, 20.7 ppm. IR (KBr): ν = 3256, 1595, 1491, 1416,
1334, 1164, 1094 cm–1. MS (ESMS/[M + Na]+): calcd. for
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Received: October 14, 2006
Published Online: January 17, 2007
Eur. J. Org. Chem. 2007, 1332–1337
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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