Tetrahedron 60 (2004) 12095–12099

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

Abstract—A 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 Å
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 sources and stirring at room temperature for a period of 24 h

without using any catalysts (Eq. (1), Scheme 1).9b 4 Å
1,2-Vicinal diamines play an important role in medicinal Molecular sieves were found to be crucial for controlling the
and pharmaceutical research.1–3 For example, the ability of diamine products at the stage of 1-o-nitrobenzenesulfonyl-
a,b-unsaturated carboxylate-derived diamines to mimic a 3-dichloromethyl-4,5-imidazolines. Under slightly modified
and b amino acids is of great importance in peptide and conditions, we were also able to control the reaction at the
protein studies. Meanwhile, these compounds have also stage of 1-o-nitrobenzenesulfonyl-3-trichloromethyl-4,5-
been widely utilized as auxiliaries and ligands in asym- imidazolines (Eq. (2), Scheme 1). The latter reaction was
metric synthesis and catalysis.4–7 Until now, most of the achieved by performing the reaction at an elevated
syntheses of these compounds have centered around the use temperature in the absence of 4 Å molecular sieves.
of transition metal precusors.2b,5 The development of A similar synthesis has also been achieved for the p-tosyl-
efficient synthetic approaches to this functionality in based diamination in which rhodium (II) acetate was
regio- and stereoselective fashions is still a challenging utilized as the catalyst.8e
topic, especially when functionalized olefins such as
cinnamic esters and a,b-unsaturated ketones are employed Very recently, we found that the diamination reaction can
as the substrates. proceed with the combination of 4-TsNH2 and NCS as the
nitrogen source to replace 4-TsNCl2 which is relatively
Recently, we and others have developed the regio- and unstable at room temperature.9a This method alleviates the
stereoselective diamination of a,b-unsaturated ketones for need to prepare and store the relatively unstable 4-TsNCl2
the synthesis of 2-nitrobenzenesulfonyl-protected diamine and demonstrates the first example for the aziridinium
derivatives.3b,8–10 Our diamination reaction was carried out intermediate formation from the reaction of TsNHCl with
in a tandem manner by using N,N-dichloro-2-nitrobenzene- olefins. We next attempted to use 2-NsNH2 to replace
sulfonamide (2-NsNCl2) and acetonitrile as the nitrogen 4-TsNH2 with the anticipation of forming 1-o-nitrobenzene-
sulfonyl-3-dichloromethyl-4,5-imidazolines. In this paper,
Keywords: Diamination; Diamine; NCS; N,N-Dichloro-2- we would like to report the successful diamination of
nitrobenzenesulfonamide.
* Corresponding author. Tel.: C1 8067423015; fax: C1 8067421289;
a,b-unsaturated ketones by using the new combination of
e-mail: [email protected] 2-NsNH 2/NCS and MeCN as the electrophilic and

0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.022
12096 C. Timmons et al. / Tetrahedron 60 (2004) 12095–12099

Scheme 1.

nucleophilic nitrogen sources. The reaction is described by based diamination proceeded at a much slower speed. Also,
Scheme 2, with the results summarized in Table 1. 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 sub-
strates 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 1–5) and aliphatic
(entries 6–8) enone substrates worked well for this new
process. Aliphatic enones typically gave faster reaction rates
than aromatic ones, but no significant differences in
Scheme 2. chemical yields were observed. In no cases were the
aminohalogenation side-product observed. Interestingly, the
Similar to our previous diamination, the present diamination
dienone substrate (entry 7) did not give any diamine product
is conveniently performed by simply by mixing olefin
under the previous 2-NsNCl2-based condition, but worked
(1.0 mmol), 2-NsNH2 (2.0 mmol), NCS (4.0 mmol), and
well in the present system and gave a chemical yield
4 Å molecular sieves (0.40 g) in freshly distilled aceto- of 74%.
nitrile. The reaction vessel was capped, and the mixture was
stirred at 50 8C for 1 day (without special protection of an We believe that the mechanism of this reaction is similar to
inert gas atmosphere), at which time a second portion of that of the TsNH2/NCS-based diamination.9a The first step
NCS (2.0 mmol) was added. The reaction was again capped involves the formation of N-monochloro-2-nitrobenzene-
and stirred at 50 8C until the alkene starting materials were sulfonamide (2-NsNHCl) which reacts with olefin to form
completely consumed, as determined by TLC or NMR N-(2-nosyl)aziridinium intermediate (A, in Scheme 3). This
spectroscopy. intermediate joins the family of three other aziridinium
ion intermediates, N-(p-tosyl),N-chloroaziridinium ion,
The initial optimization experiments employed trans-4- N-(2-nosyl),N-chloroaziridinium ion and N-(p-tosyl),
phenyl-3-buten-2-one as the substrate. 4 Å Molecular sieves N-protonaziridinium ion, that have been found to serve for
were found to play a crucial role in the reaction, which is also both electrophilic diamination and aminohalogenation
similar to the previous system, which used the p-TsNH2/NCS reactions that we have established so far.8–9 The next step
mixture. Although the reaction could proceed at room of aziridinium ring opening proceeds through [2C3] cyclic
temperature, much longer reaction times were required for addition by acetonitrile and A to form 1N-(2-nosyl)imida-
completion. Two-step of addition of NCS again proved to zolinium (B). This is the key step for explanation of regio-
increase yields w10–15%. Eight enone examples were selectivity and anti stereoselectivity (from syn addition).
examined under the present condition (Table 1). The following repeated deprotonation, chlorination and
SN2 0 type displacement result in the final products.
Interestingly, several obvious differences were found
between the current 2-NsNH2/NCS-based reaction and the In summary, a new regio-, stereo- and chemoselective
previous 2-NsNCl2-based imidazoline formation. First, diamination of enones has been established without the
in the absence of 4 Å molecular sieves, the nitrogen-source observation of any haloamines. The reaction employs the
mixture of 2-NsNH2 and NCS did not result in any readily available and inexpensive combination of NCS and
trichlorinated products. This is in contrast to the previous 2-NsNH2 as electrophilic nitrogen source, and acetonitrile
diamination in which the resulting 3-dichloromethylimida- as nucleophilic nitrogen source. A new aziridinium
zolines can proceed with a third chlorination on the intermediate formed from enones and 2-NsNHCl has been
3-dichlomethyl group to give 1-o-nitrobenzenesulfonyl-3- proposed to exist during the reaction process, and to react
dichloromethyl-4,5-imidazolines if 4 Å molecular sieves with nitrile via a [2C3] cycloaddition mechanism. The
were not employed. Second, the current 2-NsNH2/NCS- concerted [2C3] cycloaddition for the aziridinium ring
 C. Timmons et al. / Tetrahedron 60 (2004) 12095–12099 12097

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

Entry Substrate Product no. Mp/8C Selectivitya Time/h Yieldb

1 1 161–163 O95% 72 80

2 2 150–152 O95% 72 66

3 3 124–126 O95% 72 79

4 4 142–144 O95% 72 60

5 5 134–136 O95% 72 65

6 6 170–172 N/A 60 83

7 7 148–150 N/A 60 74

8 8 144 (dec) O95% 60 67

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

opening determines the regio- and stereoselectivity of the 50 8C for 24 h. A second portion of NCS (2.0 mmol) was
resulting diamination products. 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
2. Experimental pressure, and purified via column chromatography to afford
the pure product 7, 1-(2-Dichloromethyl-3-(2-nitrobenz-
2.1. General enesulfonyl)-5,5-dimethyl-4,5-dihydro-3H-imidazol-4-yl)-
3-methyl-but-2-en-1-one, as a white solid (332 mg, 74%
The representative procedure is demonstrated by the yield). Mp 148–150 8C. 1H NMR (500 MHz, CDCl3):
reaction of phorone with 2-nitrobenzenesulfonamide and 8.21–8.18 (m, 1H), 7.90–7.28 (m, 3H), 6.94 (s, 1H), 6.37
NCS (entry 7, Table 1). Into a dry vial was added phorone (m, 1H), 3.93 (s, 1H), 2.18 (d, JZ1 Hz, 3H), 1.96 (d, JZ
(1.0 mmol), 2-NsNH2 (2.0 mmol), NCS (4.0 mmol) and 1 Hz, 3H), 1.29 (s, 3H), 1.02 (s, 3H). 13C NMR (125 MHz,
acetonitrile (6.0 mL). The vial was capped and stirred at CDCl3): 195.0, 161.3, 153.3, 147.8, 135.4, 133.2, 132.8,
12098 C. Timmons et al. / Tetrahedron 60 (2004) 12095–12099

Scheme 3.

125.5, 120.1, 70.5, 63.3, 30.2, 28.2, 23.1, 21.4. HRMS (ESI- (125 MHz, CDCl3) 191.3, 167.5, 165.5, 156.4, 147.9, 137.8,
TOF high-acc) m/z (MCC1) found 448.0493, expected 135.3, 132.6, 132.0, 131.8, 131.7, 131.2, 129.3, 129.1,
448.0495. FTIR (cmK1): 2980.8, 2937.0, 1686.9, 1617.6. 126.5, 125.1, 116.6, 116.4, 72.4, 72.3, 62.4. Spectroscopic
data are identical with previously reported literature
2.1.1. (2-Dichloromethyl-3-(2-nitrobenzenesulfonyl)-5- values.9b
phenyl-4,5-dihydro-3H-imidazol-4-yl)-phenyl-metha-
none (1). Isolated as a white solid (414 mg, 80% yield). Mp 2.1.4. [5-(2-Chloro-phenyl)-2-dichloromethyl-3-(2-nitro-
161–163 8C. 1H NMR (500 MHz, CDCl3) 8.24–8.30 benzenesulfonyl)-4,5-dihydro-3H-imidazol-4-yl]-phenyl-
(m, 1H), 7.80–7.86 (m, 2H), 7.70–7.80 (m, 3H), 7.62–7.70 methanone (4). Isolated as a white solid (329 mg, 60%
(m, 1H), 7.46–7.53 (m, 2H), 7.28–7.35 (m, 3H), 7.20 yield). Mp 142–144 8C. 1H NMR (500 MHz, CDCl3)
(s, 1H), 7.05–7.14 (m, 2H), 5.73 (d, JZ4.0 Hz, 1H), 5.10 8.16–8.20 (m, 1H), 7.80–7.86 (m, 2H), 7.74–7.80 (m, 2H),
(d, JZ4.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) 192.7, 7.68–7.74 (m, 1H), 7.58–7.66 (m, 1H), 7.42–7.49 (m, 2H),
156.4, 147.9, 137.9, 135.2, 134.5, 133.0, 132.6, 132.0, 7.29–7.35 (dd, JZ7.5, 1.5 Hz, 1H), 7.17–7.28 (m, 2H),
131.2, 129.2, 129.1, 129.0, 128.9, 126.5, 125.1, 72.3, 72.2, 7.08–7.17 (m, 2H), 5.71 (d, JZ5.0 Hz, 1H), 5.55 (d, JZ
62.4. HRMS (MALDI-FTMS) m/z (M CC1) found 5.0 Hz, 1H). 13C NMR (125 MHz, CDCl3) 193.7, 157.2,
518.0348, calcd for C23H17N3O5SCl2 518.0339. 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,
2.1.2. (4-Chloro-phenyl)-(2-dichloromethyl-3-(2-nitro- 69.1, 62.4. Spectroscopic data are identical with previously
benzenesulfonyl)-5-phenyl-4,5-dihydro-3H-imidazol-4- reported literature values.9b
yl)-methanone (2). Isolated as a white solid (364 mg, 66%
yield). Mp 150–152 8C. 1H NMR (500 MHz, CDCl3) 8.22– 2.1.5. 1-(2-Dichloromethyl-3-(2-nitrobenzenesulfonyl)-
8.30 (m, 1H), 7.70–7.86 (m, 5H), 7.43–7.51 (m, 2H), 7.29– 5-phenyl-4,5-dihydro-3H-imidazol-4-yl)-ethanone (5).
7.38 (m, 3H), 7.19 (s, 1H), 7.03–7.12 (m, 2H), 5.67 (d, JZ Isolated as a white solid (295 mg, 65% yield). Mp 134–
4.0 Hz, 1H), 5.07 (d, JZ4.0 Hz, 1H). 13C NMR (125 MHz, 136 8C. 1H NMR (500 MHz, CDCl3) 7.93–8.00 (dd, JZ8.0,
CDCl3) 191.6, 156.3, 147.8, 141.1, 137.7, 135.3, 132.6, 1.5 Hz, 1H), 7.66–7.77 (m, 2H), 7.55–7.65 (m, 1H), 7.13
131.9, 131.2, 131.0, 130.2, 129.5, 129.2, 129.0, 126.4, (s, 1H), 7.00–7.10 (m, 3H), 6.94–7.00 (m, 2H), 5.22 (d, JZ
125.1, 77.2, 72.2, 62.3. Spectroscopic data are identical with 3.5 Hz, 1H), 4.23 (d, JZ3.5 Hz, 1H), 2.50 (s, 3H). 13C NMR
previously reported literature values.9b (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,
2.1.3. (2-Dichloromethyl-3-(2-nitrobenzenesulfonyl)-5- 26.3. Spectroscopic data are identical with previously
phenyl-4,5-dihydro-3H-imidazol-4-yl)-(4-fluoro-phe- reported literature values.9b
nyl)-methanone (3). Isolated as a white solid (421 mg, 79%
yield). Mp 124–126 8C. 1H NMR (500 MHz, CDCl3) 8.25– 2.1.6. 1-(2-Dichloromethyl-3-(2-nitrobenzenesulfonyl)-
8.30 (m, 1H), 7.83–7.90 (m, 2H), 7.73–7.83 (m, 3H), 7.28– 5,5-dimethyl-4,5-dihydro-3H-imidazol-4-yl)-ethanone
7.36 (m, 3H), 7.13–7.21 (m, 3H), 7.06–7.12 (m, 2H), 5.69 (6). Isolated as a white solid (338 mg, 83% yield). Mp 170–
(d, JZ4.0 Hz, 1H), 5.08 (d, JZ4.0 Hz, 1H). 13C NMR 172 8C. 1H NMR (500 MHz, CDCl3) 8.13–8.21 (m, 1H),
 C. Timmons et al. / Tetrahedron 60 (2004) 12095–12099 12099

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