Tetrahedron 60 (2004) 1209512099

The combination of 2-NsNH2/NCS and MeCN as the nitrogen

sources for the regio- and stereoselective formation of
imidazolines from a,b-unsaturated ketones
Cody Timmons, Dianjun Chen, C. Elizabeth Barney, Sameer Kirtane and Guigen Li*
Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409-1061, USA
Received 23 August 2004; revised 8 October 2004; accepted 8 October 2004
Available online 22 October 2004
Dedicated to Professor Victor J. Hruby on the occasion of his 65th birthday

AbstractA new nitrogen source combination was found for the regio- and stereoselective diamination of a,b-unsaturated ketones. This
combination employs the readily available and inexpensive combination of NCS and 2-NsNH2 as the electrophilic nitrogen source, and

acetonitrile as the nucleophilic nitrogen source, respectively. The reaction is easily performed by mixing olefin, 2-NsNH2, NCS and 4 A
molecular sieves in freshly distilled acetonitrile at room temperature. The reaction is chemoselective without the formation of any haloamine
side products. A new aziridinium ion formed from enones and 2-NsNHCl is suggested to exist and to react with nitrile via a [2C3]
cycloaddition mechanism, which is responsible for the excellent regio-, stereoselectivity of the resulting diamination products.
q 2004 Elsevier Ltd. All rights reserved.

1. Introduction
1,2-Vicinal diamines play an important role in medicinal
and pharmaceutical research.13 For example, the ability of
a,b-unsaturated carboxylate-derived diamines to mimic a
and b amino acids is of great importance in peptide and
protein studies. Meanwhile, these compounds have also
been widely utilized as auxiliaries and ligands in asymmetric synthesis and catalysis.47 Until now, most of the
syntheses of these compounds have centered around the use
of transition metal precusors.2b,5 The development of
efficient synthetic approaches to this functionality in
regio- and stereoselective fashions is still a challenging
topic, especially when functionalized olefins such as
cinnamic esters and a,b-unsaturated ketones are employed
as the substrates.
Recently, we and others have developed the regio- and
stereoselective diamination of a,b-unsaturated ketones for
the synthesis of 2-nitrobenzenesulfonyl-protected diamine
derivatives.3b,810 Our diamination reaction was carried out
in a tandem manner by using N,N-dichloro-2-nitrobenzenesulfonamide (2-NsNCl2) and acetonitrile as the nitrogen
Keywords:
Diamination;
Diamine;
NCS;
N,N-Dichloro-2nitrobenzenesulfonamide.
* Corresponding author. Tel.: C1 8067423015; fax: C1 8067421289;
e-mail: guigen.li@ttu.edu
00404020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.022

sources and stirring at room temperature for a period of 24 h

without using any catalysts (Eq. (1), Scheme 1).9b 4 A

Molecular sieves were found to be crucial for controlling the
diamine products at the stage of 1-o-nitrobenzenesulfonyl3-dichloromethyl-4,5-imidazolines. Under slightly modified
conditions, we were also able to control the reaction at the
stage of 1-o-nitrobenzenesulfonyl-3-trichloromethyl-4,5imidazolines (Eq. (2), Scheme 1). The latter reaction was
achieved by performing the reaction at an elevated
molecular sieves.
temperature in the absence of 4 A
A similar synthesis has also been achieved for the p-tosylbased diamination in which rhodium (II) acetate was
utilized as the catalyst.8e
Very recently, we found that the diamination reaction can
proceed with the combination of 4-TsNH2 and NCS as the
nitrogen source to replace 4-TsNCl2 which is relatively
unstable at room temperature.9a This method alleviates the
need to prepare and store the relatively unstable 4-TsNCl2
and demonstrates the first example for the aziridinium
intermediate formation from the reaction of TsNHCl with
olefins. We next attempted to use 2-NsNH2 to replace
4-TsNH2 with the anticipation of forming 1-o-nitrobenzenesulfonyl-3-dichloromethyl-4,5-imidazolines. In this paper,
we would like to report the successful diamination of
a,b-unsaturated ketones by using the new combination of
2-NsNH 2/NCS and MeCN as the electrophilic and

12096

C. Timmons et al. / Tetrahedron 60 (2004) 1209512099

Scheme 1.

nucleophilic nitrogen sources. The reaction is described by

Scheme 2, with the results summarized in Table 1.

Scheme 2.

Similar to our previous diamination, the present diamination

is conveniently performed by simply by mixing olefin
(1.0 mmol), 2-NsNH2 (2.0 mmol), NCS (4.0 mmol), and
molecular sieves (0.40 g) in freshly distilled aceto4A
nitrile. The reaction vessel was capped, and the mixture was
stirred at 50 8C for 1 day (without special protection of an
inert gas atmosphere), at which time a second portion of
NCS (2.0 mmol) was added. The reaction was again capped
and stirred at 50 8C until the alkene starting materials were
completely consumed, as determined by TLC or NMR
spectroscopy.
The initial optimization experiments employed trans-4 Molecular sieves
phenyl-3-buten-2-one as the substrate. 4 A
were found to play a crucial role in the reaction, which is also
similar to the previous system, which used the p-TsNH2/NCS
mixture. Although the reaction could proceed at room
temperature, much longer reaction times were required for
completion. Two-step of addition of NCS again proved to
increase yields w1015%. Eight enone examples were
examined under the present condition (Table 1).
Interestingly, several obvious differences were found
between the current 2-NsNH2/NCS-based reaction and the
previous 2-NsNCl2-based imidazoline formation. First,
molecular sieves, the nitrogen-source
in the absence of 4 A
mixture of 2-NsNH2 and NCS did not result in any
trichlorinated products. This is in contrast to the previous
diamination in which the resulting 3-dichloromethylimidazolines can proceed with a third chlorination on the
3-dichlomethyl group to give 1-o-nitrobenzenesulfonyl-3 molecular sieves
dichloromethyl-4,5-imidazolines if 4 A
were not employed. Second, the current 2-NsNH2/NCS-

based diamination proceeded at a much slower speed. Also,

for the present system, the use of less than 2 equiv of
2-NsNH2 led to diminished chemical yields. Most substrates
of the current diamination gave similar yields to those of the
2-NsNCl2-based reaction. Unfortunately, the enone substrates with strong electron withdrawing groups (e.g., 3- and
4-nitrochalcone) failed to give any products at all. As can be
seen from Table 1, both aromatic (entries 15) and aliphatic
(entries 68) enone substrates worked well for this new
process. Aliphatic enones typically gave faster reaction rates
than aromatic ones, but no significant differences in
chemical yields were observed. In no cases were the
aminohalogenation side-product observed. Interestingly, the
dienone substrate (entry 7) did not give any diamine product
under the previous 2-NsNCl2-based condition, but worked
well in the present system and gave a chemical yield
of 74%.
We believe that the mechanism of this reaction is similar to
that of the TsNH2/NCS-based diamination.9a The first step
involves the formation of N-monochloro-2-nitrobenzenesulfonamide (2-NsNHCl) which reacts with olefin to form
N-(2-nosyl)aziridinium intermediate (A, in Scheme 3). This
intermediate joins the family of three other aziridinium
ion intermediates, N-(p-tosyl),N-chloroaziridinium ion,
N-(2-nosyl),N-chloroaziridinium ion and N-(p-tosyl),
N-protonaziridinium ion, that have been found to serve for
both electrophilic diamination and aminohalogenation
reactions that we have established so far.89 The next step
of aziridinium ring opening proceeds through [2C3] cyclic
addition by acetonitrile and A to form 1N-(2-nosyl)imidazolinium (B). This is the key step for explanation of regioselectivity and anti stereoselectivity (from syn addition).
The following repeated deprotonation, chlorination and
SN2 0 type displacement result in the final products.
In summary, a new regio-, stereo- and chemoselective
diamination of enones has been established without the
observation of any haloamines. The reaction employs the
readily available and inexpensive combination of NCS and
2-NsNH2 as electrophilic nitrogen source, and acetonitrile
as nucleophilic nitrogen source. A new aziridinium
intermediate formed from enones and 2-NsNHCl has been
proposed to exist during the reaction process, and to react
with nitrile via a [2C3] cycloaddition mechanism. The
concerted [2C3] cycloaddition for the aziridinium ring

C. Timmons et al. / Tetrahedron 60 (2004) 1209512099

12097

Table 1. 2-NsNH2/NCS/MeCN-based Diamination of enones

Entry

Substrate

Product no.

Mp/8C

Selectivitya

Time/h

Yieldb

161163

O95%

72

80

150152

O95%

72

66

124126

O95%

72

79

142144

O95%

72

60

134136

O95%

72

65

170172

N/A

60

83

148150

N/A

60

74

144 (dec)

O95%

60

67

a
b

Determined by crude 1H NMR analysis. O95% Means that no minor isomer was detected.
Yield analytically pure sample after column chromatography.

opening determines the regio- and stereoselectivity of the

resulting diamination products.

2. Experimental
2.1. General
The representative procedure is demonstrated by the
reaction of phorone with 2-nitrobenzenesulfonamide and
NCS (entry 7, Table 1). Into a dry vial was added phorone
(1.0 mmol), 2-NsNH2 (2.0 mmol), NCS (4.0 mmol) and
acetonitrile (6.0 mL). The vial was capped and stirred at

50 8C for 24 h. A second portion of NCS (2.0 mmol) was

added, and the reaction vial was again capped and stirred at
50 8C until phorone was completely consumed. The
resulting slurry was filtered, concentrated under reduced
pressure, and purified via column chromatography to afford
the pure product 7, 1-(2-Dichloromethyl-3-(2-nitrobenzenesulfonyl)-5,5-dimethyl-4,5-dihydro-3H-imidazol-4-yl)3-methyl-but-2-en-1-one, as a white solid (332 mg, 74%
yield). Mp 148150 8C. 1H NMR (500 MHz, CDCl3):
8.218.18 (m, 1H), 7.907.28 (m, 3H), 6.94 (s, 1H), 6.37
(m, 1H), 3.93 (s, 1H), 2.18 (d, JZ1 Hz, 3H), 1.96 (d, JZ
1 Hz, 3H), 1.29 (s, 3H), 1.02 (s, 3H). 13C NMR (125 MHz,
CDCl3): 195.0, 161.3, 153.3, 147.8, 135.4, 133.2, 132.8,

12098

C. Timmons et al. / Tetrahedron 60 (2004) 1209512099

Scheme 3.

125.5, 120.1, 70.5, 63.3, 30.2, 28.2, 23.1, 21.4. HRMS (ESITOF high-acc) m/z (MCC1) found 448.0493, expected
448.0495. FTIR (cmK1): 2980.8, 2937.0, 1686.9, 1617.6.
2.1.1. (2-Dichloromethyl-3-(2-nitrobenzenesulfonyl)-5phenyl-4,5-dihydro-3H-imidazol-4-yl)-phenyl-methanone (1). Isolated as a white solid (414 mg, 80% yield). Mp
161163 8C. 1H NMR (500 MHz, CDCl3) 8.248.30
(m, 1H), 7.807.86 (m, 2H), 7.707.80 (m, 3H), 7.627.70
(m, 1H), 7.467.53 (m, 2H), 7.287.35 (m, 3H), 7.20
(s, 1H), 7.057.14 (m, 2H), 5.73 (d, JZ4.0 Hz, 1H), 5.10
(d, JZ4.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) 192.7,
156.4, 147.9, 137.9, 135.2, 134.5, 133.0, 132.6, 132.0,
131.2, 129.2, 129.1, 129.0, 128.9, 126.5, 125.1, 72.3, 72.2,
62.4. HRMS (MALDI-FTMS) m/z (M CC1) found
518.0348, calcd for C23H17N3O5SCl2 518.0339.
2.1.2. (4-Chloro-phenyl)-(2-dichloromethyl-3-(2-nitrobenzenesulfonyl)-5-phenyl-4,5-dihydro-3H-imidazol-4yl)-methanone (2). Isolated as a white solid (364 mg, 66%
yield). Mp 150152 8C. 1H NMR (500 MHz, CDCl3) 8.22
8.30 (m, 1H), 7.707.86 (m, 5H), 7.437.51 (m, 2H), 7.29
7.38 (m, 3H), 7.19 (s, 1H), 7.037.12 (m, 2H), 5.67 (d, JZ
4.0 Hz, 1H), 5.07 (d, JZ4.0 Hz, 1H). 13C NMR (125 MHz,
CDCl3) 191.6, 156.3, 147.8, 141.1, 137.7, 135.3, 132.6,
131.9, 131.2, 131.0, 130.2, 129.5, 129.2, 129.0, 126.4,
125.1, 77.2, 72.2, 62.3. Spectroscopic data are identical with
previously reported literature values.9b
2.1.3. (2-Dichloromethyl-3-(2-nitrobenzenesulfonyl)-5phenyl-4,5-dihydro-3H-imidazol-4-yl)-(4-fluoro-phenyl)-methanone (3). Isolated as a white solid (421 mg, 79%
yield). Mp 124126 8C. 1H NMR (500 MHz, CDCl3) 8.25
8.30 (m, 1H), 7.837.90 (m, 2H), 7.737.83 (m, 3H), 7.28
7.36 (m, 3H), 7.137.21 (m, 3H), 7.067.12 (m, 2H), 5.69
(d, JZ4.0 Hz, 1H), 5.08 (d, JZ4.0 Hz, 1H). 13C NMR

(125 MHz, CDCl3) 191.3, 167.5, 165.5, 156.4, 147.9, 137.8,

135.3, 132.6, 132.0, 131.8, 131.7, 131.2, 129.3, 129.1,
126.5, 125.1, 116.6, 116.4, 72.4, 72.3, 62.4. Spectroscopic
data are identical with previously reported literature
values.9b
2.1.4. [5-(2-Chloro-phenyl)-2-dichloromethyl-3-(2-nitrobenzenesulfonyl)-4,5-dihydro-3H-imidazol-4-yl]-phenylmethanone (4). Isolated as a white solid (329 mg, 60%
yield). Mp 142144 8C. 1H NMR (500 MHz, CDCl3)
8.168.20 (m, 1H), 7.807.86 (m, 2H), 7.747.80 (m, 2H),
7.687.74 (m, 1H), 7.587.66 (m, 1H), 7.427.49 (m, 2H),
7.297.35 (dd, JZ7.5, 1.5 Hz, 1H), 7.177.28 (m, 2H),
7.087.17 (m, 2H), 5.71 (d, JZ5.0 Hz, 1H), 5.55 (d, JZ
5.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) 193.7, 157.2,
147.7, 135.9, 135.3, 134.3, 133.6, 132.6, 132.5, 132.2,
130.9, 129.9, 129.8, 129.0, 128.9, 128.2, 127.6, 125.2, 70.7,
69.1, 62.4. Spectroscopic data are identical with previously
reported literature values.9b
2.1.5. 1-(2-Dichloromethyl-3-(2-nitrobenzenesulfonyl)5-phenyl-4,5-dihydro-3H-imidazol-4-yl)-ethanone (5).
Isolated as a white solid (295 mg, 65% yield). Mp 134
136 8C. 1H NMR (500 MHz, CDCl3) 7.938.00 (dd, JZ8.0,
1.5 Hz, 1H), 7.667.77 (m, 2H), 7.557.65 (m, 1H), 7.13
(s, 1H), 7.007.10 (m, 3H), 6.947.00 (m, 2H), 5.22 (d, JZ
3.5 Hz, 1H), 4.23 (d, JZ3.5 Hz, 1H), 2.50 (s, 3H). 13C NMR
(125 MHz, CDCl3) 205.4, 156.8, 147.5, 139.0, 135.5, 132.8,
132.6, 129.2, 128.7, 128.0, 125.6, 125.5, 75.7, 71.7, 63.5,
26.3. Spectroscopic data are identical with previously
reported literature values.9b
2.1.6. 1-(2-Dichloromethyl-3-(2-nitrobenzenesulfonyl)5,5-dimethyl-4,5-dihydro-3H-imidazol-4-yl)-ethanone
(6). Isolated as a white solid (338 mg, 83% yield). Mp 170
172 8C. 1H NMR (500 MHz, CDCl3) 8.138.21 (m, 1H),

C. Timmons et al. / Tetrahedron 60 (2004) 1209512099

7.807.96 (m, 3H), 6.92 (s, 1H), 3.89 (s, 1H), 2.37 (s, 3H),
1.29 (s, 3H), 0.98 (s, 3H). 13C NMR (125 MHz, CDCl3)
205.4, 153.5, 147.8, 135.7, 133.2, 132.9, 129.6, 125.7, 77.2,
70.4, 63.2, 30.0, 27.8, 23.0. HRMS (MALDI-FTMS) m/z
(MCC1) found 408.0177, calcd for C14H15N3O5SCl2
408.0182.
2.1.7. 2-Dichloromethyl-3-(2-nitrobenzenesulfonyl)-7amethyl-3,3a,5,6,7,7a-hexahydro-benzoimidazol-4-one
(8). Isolated as a white solid (238 mg, 67% yield). Mp:
decomposed at 144 8C. 1H NMR (500 MHz, CDCl3) 8.18
8.30 (m, 1H), 7.827.90 (m, 3H), 6.92 (s, 1H), 3.87 (s, 1H),
2.692.81 (m, 1H), 2.312.45 (m, 1H), 2.052.15 (m, 1H),
1.842.05 (m, 2H), 1.601.70 (m, 1H), 1.30 (s, 3H). 13C
NMR (125 MHz, CDCl3) 206.1, 154.9, 148.1, 135.4, 133.6,
132.7, 129.8, 125.2, 74.2, 73.3, 62.7, 36.4, 34.0, 27.4, 18.6.
Spectroscopic data are identical with previously reported
literature values.9b

4.

5.

6.

Acknowledgements
We gratefully acknowledge financial support from NIH (CA
99995-1) and the Robert A. Welch Foundation (Grant No.
D-1361). The contents of this paper are solely the
responsibility of the authors and do not necessarily represent
the official views of the National Cancer Institute.

7.

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