Copper-catalyzed Ritter-type reaction of unactivated alkenes with dichloramine-T

Article abstract of DOI:10.1002/hlca.200900214

It was shown that dichloramine-T (1) reacted with cyclohexene in acetonitrile to give N¹-(2-chlorocyclohexyl) amidine 2a and N-(2-chlorocyclohexyl)acetamide (3) via the competitive addition of acetonitrile and N-chloro-N-tosylamino anion to cyc

Full text of DOI:10.1002/hlca.200900214

Helvetica Chimica Acta – Vol. 93 (2010)
233
Copper-Catalyzed Ritter-Type Reaction of Unactivated Alkenes with
Dichloramine-T
by Takumi Abea), Hiroyuki Takedaa), Yoshihisa Miwab), Koji Yamadaa), Reiko Yanadab), and
Minoru Ishikura*a)
a) Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu,
Hokkaido 061-0293, Japan (phone & fax: þ 81-133-23-1245; e-mail: ishikura@hoku-iryo-u.ac.jp)
b) Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure,
Hiroshima 737-0112, Japan
It was shown that dichloramine-T (1) reacted with cyclohexene in acetonitrile to give N1-(2-
chlorocyclohexyl) amidine 2a and N-(2-chlorocyclohexyl)acetamide (3) via the competitive addition of
acetonitrile and N-chloro-N-tosylamino anion to cyclohexenechloronium ion. This reaction can be
catalyzed by Cu(OAc)2, primarily affording 2a. Furthermore, the resulting 2a can be cyclized to
benzimidazol 14a in good yield by treating with KOH in dioxane.
Introduction.
– N-Chlorosulfonylamide derivatives (such as chloramine-T
(TsNClNa), dichloramine-T (¼ N,N-dichloro-4-methylbenzenesulfonamide; TsNCl2;
1)) are known to react with various kinds of functional groups and are used extensively
in various chemical transformations [1]. Recently, Li et al. have reported that treatment
of N,N-dichloro-2-nitrobenzenesulfonamide (2-NsNCl2) with cyclohexene in MeCN
can produce vicinal trans-diamine in high yield through the ring opening of initially
formed N-chloro-N-nosylaziridinium intermediate by attack of MeCN via an Sn2
mechanism [2]. Of particular interest was the metal-catalyzed vicinal cis-diamination
reaction of electron-deficient alkenes (cinnamate esters, a,b-unsaturated ketones) by
treating with 1; a metal-catalyzed Ritter-type reaction of 1 with methyl trans-cinnamate
in MeCN proceeded with a high degree of stereoselectivity and regioselectivity to
afford anti-dihydroimidazoles, in which the ring opening of N-chloro-N-tosylaziridi-
nium intermediate by attack of MeCN in a syn-manner with the aid of metal catalyst,
followed by cyclization to the dihydroimidazole, was postulated as the key step [3].
The noticeable vicinal diamination processes prompted us to reevaluate the
reaction using unactivated alkenes with 1 in MeCN. We found that initial treatment of
cyclohexene with 1 in MeCN without metal catalyst did not afford the expected
diamine; instead, N1-(2-chlorocyclohexyl) amidine 2a and N-(2-chlorocyclohexyl)ace-
tamide 3 were isolated. Furthermore, the reaction was accelerated by catalyzing with
Cu(OAc)2, affording 2a as a primary product. Li et al. have also developed a successful
vicinal chloroamination reaction of 1 with electron-deficient alkenes catalyzed by
Cu(OTf)2 or ZnCl2 in MeCN; this was again explained by the formation of the N-
tosylaziridinium intermediate, followed by ring opening by attack of a chlorine anion
[4]. Intrigued by the alteration of the reaction outcome observed by us compared to the
ꢀ 2010 Verlag Helvetica Chimica Acta AG, Zꢁrich

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reports of Li et al., we have further examined the reaction of 1 with unactivated
alkenes. Our experimental results are described herein.
Results and Discussion. – When cyclohexene was initially subjected to the reaction
with dichloramine-T (1; 1.5 equiv.) in MeCN at room temperature for 3 h, the amidine
2a as a mixture of (E)/(Z) isomers in 45% yield and the known acetamide 3 [5] in 40%
yield were isolated (Table 1, Run 1). The structure of 2a was assigned based on
1H-NMR NOESY experiments; the NOE correlation between Ha (d 3.39 – 3.46 and
3.98 – 4.04; 2m) and Hb (d 3.68 – 3.76) was negligible, while irradiation of NH (d 5.71)
provided large NOE effects on Ha and Me (d 2.36; Fig.).
Table 1. Reaction of Cyclohexene with Dichloramines (1) in RCN
Run
Catalyst (10 mol-%)
RCN
Yield [%]a)
2
3
1
2
3
4
5
6
7
8
9
–
MeCN
MeCN
MeCN
MeCN
45 (2a)
28 (2a)
45 (2a)
58 (2a)
90 (2a)
90 (2a)
75 (2a)
–
40
12
19
10
–
–
–
–
–
Pd(OAc)2
[Rh(COD)Cl]2
CuOTf
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
MeCN
MeCN/H2O 5 : 1
MeCN/THF 1 : 5
EtCN
EtCN/THF 1 : 5
PhCN/THF 1 : 5
ClCH2CN/THF 1 : 5
49 (2b)
40 (2c)
67 (2d)
10
11
–
–
a) Yields based on cyclohexene.
Figure. NOE Correlations of 2a
Next, the reaction of cyclohexene with 1 in MeCN at room temperature was
examined in the presence of various metal catalysts (10 mol-%; Table 1, Runs 2 – 5) [6].
In our evaluation of the effects of a metal catalyst, Cu(OAc)2 proved to be highly
effective, primarily producing 2a, and was chosen for further studies. Performing the

Helvetica Chimica Acta – Vol. 93 (2010)
235
reaction in MeCN containing H2O (MeCN/H2O 5 :1) afforded 2a in 90% yield, while
dilution of MeCN with THF (MeCN/THF 1:5) resulted in a reduction of the yield of
2a to 75% yield (Table 1, Runs 6 and 7, resp.). In EtCN instead of MeCN, the reaction
did not proceed due to the poor solubility of the reagents; then, running the reaction in
EtCN diluted with THF (EtCN/THF 1:5) led to the isolation of 2b in 49% yield
(Table 1, Runs 8 and 9, resp.). Likewise, 2c and 2d were obtained by reacting 1 with
cyclohexene in PhCN/THF 1:5 in 40% yield and ClCH2CN/THF 1:5 in 67% yield,
respectively (Table 1, Runs 10 and 11, resp.).
The most plausible pathway of the Cu-catalyzed cycle is assumed to be as depicted
in Scheme 1 [7]. CuII Catalyst initially intercepts 1 to generate a chlorine cation (Clþ)
and Cu complex 4. The formation of cyclohexene chloronium ion 5 from cyclohexene
and Clþ, and the subsequent Ritter-type addition of MeCN to 5 in an anti-manner leads
to the nitrilium ion 6. Then, 6 is readily converted to 2a via facile transfer of a N-chloro-
N-tosylamino (TsNCl) group from 4.
Scheme 1
Utilizing the above conditions, we explored the reaction with a range of alkenes,
obtaining amidines 7 – 13 in moderate-to-good yields (Table 2). Reduction of the
reaction temperature to ꢀ 208 provided 7 and 10 – 12 in higher purity levels than at
room temperature (Table 2, Runs 1, 4 – 6). Treatment with cyclohexa-1,4-diene at ꢀ 208
provided 7 in high yield, while d-chloro amidine 8 was isolated from the reaction with
cyclohexa-1,3-diene. (E)- and (Z)-4-Methylpent-2-enes reacted with 1 to give 11 and
12, respectively, with high regioselectivity and stereoselectivity (Table 2, Runs 5 and 6,
resp.).
Moreover, it was possible to obtain benzimidazoles 14 and 17 in 50 – 70% yields by
treating 2a – 2c and 7 with KOH in refluxing dioxane/H2O (Scheme 2). In the 1H-NMR
NOE experiments, irradiation of Ha (d 4.03) of 14a produced a large NOE effect on Hb
(d 3.66 – 3.71), revealing that these H-atoms are in a cis-position to each other1). Under
1
)
The trans-isomer of 14a is known [7].

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Table 2. Copper-Catalyzed Reaction of 1a with Alkenes in MeCN
Run
1
Alkene
Conditions
Product
Yield [%]a)
90
ꢀ 208, 6 h
7
2
3
4
r.t., 3 h
8b)
80
46
65
r.t., 72 h
ꢀ 208, 6 h
9
10
5
ꢀ 208, 6 h
11
70
6
7
ꢀ 208, 6 h
12
13
68
75
r.t., 3 h
a) Yield based on alkenes. b) Single stereoisomer, but configuration was not determined.
standard acidic hydrolysis conditions, 14a was successfully converted to 15 in 85% yield.
The structure of 15 was unequivocally confirmed based on the agreement of the
spectral data with those of 15 derived from commercially available cis-cyclohexane-1,2-
diamine (16) through sequential treatment with TsCl and AcCl. Similarly, 11 and 12
were stereoselectively cyclized to dihydroimidazoles 18 and 19, respectively, the
structures of which were confirmed based on NOE experiments.
In summary, we have described that the reaction of dichloramine-T (1) with
cyclohexene produced amidine 2a and acetamide 3 via Ritter-type addition of nitriles to
chloronium ions 5, and the reaction was also found to be catalyzed with Cu(OAc)2 to
afford 2a as a primary product. This is an alternative reaction outcome to the excellent
diamination protocol developed by Li et al. with 1 and electron-deficient alkenes.

Helvetica Chimica Acta – Vol. 93 (2010)
237
Scheme 2
Furthermore, the cyclization of 2a to benzimidazole 14a by treating with KOH,
followed by acidic hydrolysis, produced cis-diamine 15.
Experimental Part
General. Column chromatography (CC): silica gel 60N, Kanto Chemical Co., Ltd. M.p.: Yamato
MP21 apparatus; uncorrected. IR Spectra: Hitachi model 270-30 spectrometer; in cmꢀ1. NMR Spectra:
Jeol-JNM-ECA500 spectrometer; at 500 (1H) and 125 (13C) MHz; chemical shifts d in ppm rel. to Me4Si
as internal reference and coupling constants J in Hz. ESI-MS: Jeol JMS-T100LP AccuTOF mass
spectrometer; in m/z. EI-MS and HR-EI-MS: Micromass AutoSpec 3100 mass spectrometer; in m/z.
Reaction of 1 with Cyclohexene in MeCN. To a soln. of 1 (360 mg, 1.5 mmol) in MeCN (5 ml),
cyclohexene (82 mg, 1 mmol) was added under ice cooling. Then, the mixture was warmed to r.t. and
stirred for 3 h. The solvent was evaporated, and the residue was separated by CC (SiO2; hexane/AcOEt
3 :1) to give 2a and 3 (Table 1, Run 1).
Copper-Catalyzed Reaction of 1 with Cyclohexene in MeCN. After stirring a mixture of 1 (1 mmol)
and Cu(OAc)2 (0.1 mmol) in MeCN (5 ml) at r.t. for 0.5 h, the mixture was cooled in an ice bath, and
cyclohexene (1 mmol) was added. Then, the mixture was warmed to r.t. and stirred for 3 h. The solvent
was evaporated, and the residue was separated by CC (SiO2; hexane/AcOEt 3 :1) to give 2a (Table 1,
Run 5). The analogous treatment of 1 with cyclohexene in the presence of Cu(OAc)2 in EtCN/THF,
PhCN/THF, and ClCH2CN/THF produced 2b, 2c, and 2d, resp. (Table 1, Runs 9 – 11).
(E and Z)-N-[(1R*,2R*)-2-Chlorocyclohexyl]-N’-[(4-methylphenyl)sulfonyl]ethanimidamide (2a).
1
Colorless crystals. M.p. 133 – 1348 (CH2Cl2). IR (CHCl3): 3350, 1640. H-NMR (CDCl3): 1.12 – 1.45 (m,

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Helvetica Chimica Acta – Vol. 93 (2010)
3 H); 1.64 – 1.84 (m, 3 H); 2.06 – 2.09 (m, 0.3 H); 2.19 – 2.26 (m, 1.4 H); 2.29 – 2.34 (m, 0.3 H); 2.36 (s,
3 H); 2.39 (s, 3 H); 3.39 – 3.46 (m, 0.3 H); 3.68 – 3.76 (m, 1 H); 3.98 – 4.04 (m, 0.7 H); 5.71 (d, J ¼ 7.4,
1 H); 7.25, 7.26 (2d, J ¼ 8.0, 2 H); 7.79, 7.80 (2d, J ¼ 8.0, 2 H). 13C-NMR (CDCl3): 21.1; 21.5; 21.6; 21.8;
23.9; 24.2; 24.9; 25.3; 31.6; 35.9; 57.0; 61.4; 126.3; 129.3; 129.5; 140.6; 142.2; 166.1. EI-MS: 328 (Mþ). EI-
HR-MS: 328.1023/330.0969 (Mþ, C15H21ClN2O2Sþ; calc. 328.1012/330.0983). Anal. calc. for
C15H21ClN2O2S: C 54.78, H 6.44, N 8.52; found: C 54.88, H 6.48, N 8.24.
(E and Z)-N-[(1R*,2R*)-2-Chlorocyclohexyl]-N’-[(4-methylphenyl)sulfonyl]propanimidamide
(2b). Colorless crystals. M.p. 125 – 1278 (AcOEt/hexane). IR (CHCl3): 3428, 1596, 1532. 1H-NMR
(CDCl3): 1.13, 1.23 (2t, J ¼ 7.5, 3 H); 1.13 – 1.47 (m, 3 H); 1.63 – 1.83 (m, 3 H); 2.04 – 2.10 (m, 0.5 H);
2.20 – 2.38 (m, 1.5 H); 2.39 (s, 3 H); 2.40 (q, J ¼ 7.5, 1 H); 2.80, 2.83 (2q, J ¼ 7.5, 0.5 H); 2.91, 2.94 (2q, J ¼
7.5, 0.5 H); 3.43 – 3.50 (m, 0.5 H); 3.69, 3.76 (2dt, J ¼ 4.0, 10.0, 1 H); 3.90 – 3.98 (m, 0.5 H); 5.45 (br. s,
1 H); 7.25 (d, J ¼ 8.0, 2 H); 7.81 (d, J ¼ 8.0, 2 H). 13C-NMR (CDCl3): 10.6; 11.9; 21.5; 21.6; 24.0; 24.1;
25.0; 25.3; 27.2; 27.5; 31.5; 33.5; 35.8; 36.0; 56.9; 59.4; 61.5; 62.9; 126.1; 126.2; 129.2; 129.4; 139.5; 141.1;
142.0; 142.9; 169.3; 170.3. EI-MS: 342/344 (Mþ). EI-HR-MS: 342.1163/344.1136 (Mþ, C16H23ClN2O2Sþ;
calc. 342.1169/344.1139). Anal. calc. for C16H23ClN2O2S: C 56.05, H 6.76, N 8.17; found: C 56.26, H 6.78,
N 8.30.
N-[(1R*,2R*)-2-Chlorocyclohexyl]-N’-[(4-methylphenyl)sulfonyl]benzenecarboximidamide (2c).
1
Colorless crystals. M.p. 143 – 1458 (CH2Cl2). IR (CHCl3): 3672, 1570. H-NMR (CDCl3): 1.20 – 1.34 (m,
2 H); 1.41 – 1.51 (m, 2 H); 1.69 – 1.83 (m, 2 H); 2.05 – 2.11 (m, 0.5 H); 2.20 – 2.28 (m, 1.5 H); 2.41, 2.36 (2s,
3 H); 3.34 – 3.42, 4.08 – 4.15 (2m, 1 H); 3.60 – 3.79 (m, 1 H); 5.42, 8.59 (2 br. s, 1 H); 7.13, 7.28 (2d, J ¼ 8.0,
2 H); 7.34 – 7.41 (m, 3 H); 7.42 – 7.48 (m, 2 H); 7.59, 7.89 (2d, J ¼ 8.5, 2 H). 13C-NMR (CDCl3): 21.5; 21.6;
24.0; 24.1; 25.1; 25.4; 31.8; 33.7; 35.8; 36.0; 57.6; 61.2; 61.8; 63.5; 126.5; 126.6; 127.9; 128.0; 128.2; 128.6;
128.9; 129.4; 130.9; 133.6; 134.2; 139.4; 140.7; 141.8; 143.0; 165.6; 166.4. EI-MS: 390/392 (Mþ). EI-HR-
MS: 390.1156/392.1136 (Mþ, C20H23ClN2O2Sþ; calc. 390.1169/392.1139). Anal. calc. for C20H23ClN2O2S: C
61.45, H 5.93, N 7.17; found: C 61.23, H 6.06, N 7.06.
(E and Z)-2-Chloro-N-[(1R*,2R*)-2-chlorocyclohexyl]-N’-[(4-methylphenyl)sulfonyl]ethanimid-
amide (2d). Colorless crystals. M.p. 128.5 – 129.58 (CH2Cl2). IR (CHCl3): 3384, 1554. 1H-NMR (CDCl3):
1.19 – 1.29 (m, 1 H); 1.29 – 1.45 (m, 2 H); 1.68 – 1.74 (m, 2 H); 1.74 – 1.84 (m, 1 H); 2.21 – 2.27 (m, 2 H);
2.41 (s, 3 H); 3.80 (dt, J ¼ 4.5, 9.7, 1 H); 3.94 – 4.01 (m, 1 H); 4.88 (d, J ¼ 16.6, 1 H); 4.94 (d, J ¼ 16.6, 1 H);
6.63 (s, 1 H); 7.27 (d, J ¼ 8.5, 2 H); 7.80 (d, J ¼ 8.5, 2 H). 13C-NMR (CDCl3): 21.6; 23.7; 25.1; 31.2; 35.6;
42.3; 57.4; 60.9; 126.3; 129.4; 139.8; 142.7; 160.0. ESIþ-MS: 363/365/367 ([M þ H]þ). Anal. calc. for
C15H20Cl2N2O2S: C 49.59, H 5.55, Cl 19.52, N 7.71, S 8.83; found: C 49.47, H 5.50, Cl 19.35, N 7.70, S 8.61.
N-[(1R*,2R*)-2-Chlorocyclohexyl]acetamide (3). Colorless crystals. M.p. 123 – 1248 ([5]: 120 – 1228
(CH2Cl2/hexane)). IR (CHCl3): 3376, 3268, 1652. 1H-NMR (CDCl3): 1.17 – 1.41 (m, 3 H); 1.64 – 1.77 (m,
3 H); 1.97 (s, 3 H); 2.07 – 2.14 (m, 1 H); 2.18 – 2.25 (m, 1 H); 3.70 (dt, J ¼ 4.6, 10.9, 1 H); 3.80 – 3.88 (m,
1 H); 6.09 (br. s, 1 H). 13C-NMR (CDCl3): 23.4; 24.2; 25.4; 32.8; 36.1; 54.9; 62.6; 170.0. EI-MS: 175/177
(Mþ). Anal. calc. for C8H14ClNO: C 54.70, H 8.03, Cl 20.18, N 7.97; found: C 54.50, H 7.97, Cl 20.01, N 7.91.
The reaction of 1 with various alkenes in the presence of Cu(OAc)2 in MeCN was performed
according to the procedure for the copper-catalyzed reaction of 1 with cyclohexene (Table 1) to give 7 –
13.
(E)-N-[(1R*,6R*)-6-Chlorocyclohex-3-en-1-yl]-N’-[(4-methylphenyl)sulfonyl]ethanimidamide (7).
Colorless crystals. M.p. 101 – 1028 (AcOEt/hexane). IR (CHCl3): 3350, 1650. 1H-NMR (CDCl3): 1.97, 2.51
(2 br. d, J ¼ 16.0, 1 H); 2.19, 2.44 (2 br. d, J ¼ 17.0, 1 H); 2.40 (s, 3 H); 2.41 (s, 3 H); 2.64 (br. d, J ¼ 17.0,
1 H); 2.80 (br. d, J ¼ 16.0, 1 H); 3.73 – 3.81, 4.14 – 4.20 (2m, 1 H); 4.00 – 4.06, 4.24 – 4.31 (2m, 1 H); 5.59 –
5.64 (m, 3 H); 7.26, 7.27 (2d, J ¼ 8.5, 2 H); 7.80, 7.81 (2d, J ¼ 8.5, 2 H). 13C-NMR (CDCl3): 21.1; 21.5; 21.6;
23.4; 26.2; 29.2; 29.9; 30.2; 31.5; 33.7; 34.2; 34.4; 49.2; 49.9; 52.3; 55.5; 56.3; 56.9; 58.1; 67.3; 122.7; 123.5;
123.6; 124.1; 124.3; 124.4; 124.6; 126.3; 126.5; 129.3; 129.5; 130.9; 140.3; 142.4; 143.4; 166.2; 170.3; 171.4.
EI-HR-MS: 326.0856/328.0836 (Mþ, C15H19ClN2O2Sþ; calc. 326.0856/328.0826). Anal. calc. for
C15H19ClN2O2S: C 55.12, H 5.86, N 8.57; found: C 55.25, H 5.77, N 8.36.
(E and Z)-N-[(1S*,4R*)-4-Chlorocyclohex-2-en-1-yl]-N’-[(4-methylphenyl)sulfonyl]ethanimid-
amide (8). Colorless crystals. M.p. 127 – 1298 (hexane/AcOEt). IR (CHCl3): 3296, 1520. 1H-NMR
(CDCl3): 1.62 (ddd, J ¼ 6.2, 9.0, 11.4, 1 H); 1.95 (ddd, J ¼ 6.3, 9.1, 12.0, 1 H); 2.12 – 2.18 (m, 2 H); 2.40 (s,
3 H); 2.41 (s, 3 H); 4.49 – 4.54 (m, 1 H); 4.56 – 4.62 (m, 1 H); 5.43 (br. d, J ¼ 6.9, 1 H); 5.73 (dd, J ¼ 2.5,

Helvetica Chimica Acta – Vol. 93 (2010)
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10.0, 1 H); 5.95, 6.05 (2ddd, J ¼ 1.7, 4.0, 10.0, 1 H); 7.27 (d, J ¼ 8.0, 2 H); 7.78, 8.05 (2d, J ¼ 8.0, 2 H).
13C-NMR (CDCl3): 21.5; 21.6; 25.4; 29.8; 46.0; 53.4; 126.4; 128.7; 129.3; 129.5; 132.3; 140.4; 142.4; 164.8.
EI-MS: 326/328 (Mþ). EI-HR-MS: 326.0848/328.0838 (Mþ, C15H19ClN2O2Sþ; calc. 326.0856/328.0826).
Anal. calc. for C15H19ClN2O2S: C 55.12, H 5.86, N 8.57; found: C 55.08, H 5.98, N 8.41.
(E and Z)-N-[(1R*,2R*)-2-Chlorocycloheptyl]-N’-[(4-methylphenyl)sulfonyl]ethanimidamide (9).
Viscous oil. IR (CHCl3): 3280, 1543. 1H-NMR (CDCl3): 1.40 – 2.25 (m, 10 H); 2.32, 2.35, 2.38, 2.50, 2.68
(5s, 6 H); 3.63 – 3.70, 4.07 – 4.14, 4.20 – 4.27 (3m, 1 H); 3.88 – 3.94, 3.99 – 4.05, 4.36 – 4.43, 4.53 – 4.60 (4m,
1 H); 6.53 (br. s, 1 H); 7.24, 7.26, 7.45 (3d, J ¼ 8.0, 2 H); 7.76, 7.78, 7.79 (3d, J ¼ 8.0, 2 H). 13C-NMR
(CDCl3): 20.8; 21.0; 21.5; 23.1; 23.3; 23.6; 23.9; 27.0; 27.6; 28.1; 31.1; 32.4; 33.6; 33.7; 35.0; 35.3; 39.0; 51.7;
60.6; 61.9; 63.5; 66.3; 67.3; 126.2; 129.3; 129.5; 139.3; 140.6; 142.5; 143.1; 164.9; 165.3; 165.5. EI-HR-MS:
342.1170/344.1140 (Mþ, C16H23ClN2O2Sþ; calc. 342.1169/344.1139).
(E and Z)-N-[(1R*,2R*)-2-Chloro-2,3-dihydro-1H-inden-1-yl]-N’-[(4-methylphenyl)sulfonyl]ethan-
imidamide (10). Colorless crystals. M.p. 107 – 1088 (AcOEt/hexane). IR (CHCl3): 3424, 1562, 1544.
1H-NMR (CDCl3): 2.40 (s, 3 H); 2.54 (s, 3 H); 3.24 (d, J ¼ 17.2, 1 H); 3.39 (dd, J ¼ 17.2, 5.1, 1 H); 4.93 (t,
J ¼ 5.1, 1 H); 5.75 (dd, J ¼ 8.0, 5.1, 1 H); 5.99 (br. d, J ¼ 8.0, 1 H); 7.19 (d, J ¼ 7.4, 1 H); 7.26 (d, J ¼ 8.5,
2 H); 7.20 – 7.32 (m, 3 H); 7.82 (d, J ¼ 8.5, 2 H). 13C-NMR (CDCl3): 21.4; 21.5; 41.1; 59.2; 63.4; 123.7;
125.5; 126.6; 127.6; 128.8; 129.3; 138.2; 139.0; 140.1; 142.5; 166.1. EI-MS: 362/364 (Mþ). EI-HR-MS:
364.0867/364.0821 (Mþ, C18H19ClN2O2Sþ; calc. 362.0856/364.0826). Anal. calc. for C18H19ClN2O2S: C
59.58, H 5.28, N 7.72; found: C 59.34, H 5.34, N 7.65.
(E and Z)-N-[(1R*,2S*)-2-Chloro-1,3-dimethylbutyl]-N’-[(4-methylphenyl)sulfonyl]ethanimid-
1
amide (11). Colorless crystals. M.p. 106 – 1078 (AcOEt/hexane). IR (CHCl3): 3664. H-NMR (CDCl3):
0.90 (d, J ¼ 6.8, 3 H); 1.05 (d, J ¼ 6.8, 3 H); 1.16 (d, J ¼ 6.8, 3 H); 1.76 – 1.84 (m, 1 H); 2.40 (s, 3 H); 2.42 (s,
3 H); 3.78 (dd, J ¼ 2.3, 9.1, 1 H); 4.46 – 4.53 (m, 1 H); 5.58 (br. s, 1 H); 7.25 (d, J ¼ 8.5, 2 H), 7.79 (d, J ¼
8.5, 2 H). 13C-NMR (CDCl3): 13.6; 19.7; 20.7; 21.4; 21.5; 32.5; 48.9; 72.9; 126.3; 129.2; 140.5; 142.3; 164.5.
EI-MS: 330/332 (Mþ). EI-HR-MS: 330.1164/332.1137 (Mþ, C15H23ClN2O2Sþ; calc. 330.1169/332.1139).
Anal. calc. for C15H23ClN2O2S: C 54.45, H 7.01, N 8.47; found: C 54.56, H 7.08, N 8.55.
(E and Z)-N-[(1R*,2R*)-2-Chloro-1,3-dimethylbutyl]-N’-[(4-methylphenyl)sulfonyl]ethanimid-
amide (12). Colorless crystals. M.p. 115 – 1168 (AcOEt/hexane). IR (CHCl3): 3420, 1582. 1H-NMR
(CDCl3): 0.94 (d, J ¼ 6.9, 3 H); 1.03 (d, J ¼ 6.9, 3 H); 1.25 (d, J ¼ 6.3, 3 H); 1.79 – 1.88 (m, 1 H); 2.39, 2.40
(2s, 6 H); 3.59 (dd, J ¼ 2.3, 8.6, 1 H); 4.61 – 4.68 (m, 1 H); 5.57 (br. s, 1 H); 7.25 (d, J ¼ 8.5, 2 H); 7.79 (d,
J ¼ 8.5, 2 H). 13C-NMR (CDCl3): 19.4; 20.0; 20.3; 21.4; 21.5; 33.0; 48.5; 74.3; 126.4; 129.2; 140.4; 142.3;
165.2. EI-MS: 330/332 (Mþ). EI-HR-MS: 330.1157/332.1151 (Mþ, C15H23ClN2O2Sþ; calc. 330.1169/
330.1139). Anal. calc. for C15H23ClN2O2S: C 54.45, H 7.01, N 8.47; found: C 54.34, H 6.96, N 8.36.
(E and Z)-N-(2-Chloro-1,1-dimethylpropyl)-N’-[(4-methylphenyl)sulfonyl]ethanimidamide (13).
Colorless crystals. M.p. 142 – 1438 (AcOEt/hexane). IR (CHCl3): 3124. 1H-NMR (CDCl3): 1.36 (s,
3 H); 1.40 (d, J ¼ 6.8, 3 H); 1.44 (s, 3 H); 2.34 (s, 3 H); 2.39 (s, 3 H); 4.81 (q, J ¼ 6.8, 1 H); 5.64 (s, 1 H);
7.25, 7.39 (2d, J ¼ 8.5, 2 H); 7.74, 7.76 (2d, J ¼ 8.5, 2 H). 13C-NMR (CDCl3): 19.8; 21.5; 22.1; 22.3; 23.4;
59.6; 62.0; 126.2; 127.3; 129.3; 130.5; 140.5; 142.3; 164.7. EI-MS: 330/332 (Mþ). EI-HR-MS: 316.1031/
318.0995 (Mþ, C14H21ClN2O2Sþ; calc. 316.1012/318.0983). Anal. calc. for C14H21ClN2O2S: C 53.07, H 6.68,
N 8.84; found: C 53.22, H 6.65, N 8.90.
Cyclization of Amidines 2a – 2c, 7, 11, and 12 to Imidazoles 14, 17, 18, and 19: General Procedure. A
mixture of amidines (1 mmol), KOH (3 mmol), H2O (2 ml), and cat. amount of 18-crown-6 in dioxane
(10 ml) was heated at 1008 for 1 h. After cooling, the mixture was diluted with AcOEt (100 ml), washed
with brine, and dried (MgSO4). The solvent was evaporated, and the residue was separated by CC (SiO2;
hexane/AcOEt).
(3aR*,7aS*)-2-Methyl-1-[(4-methylphenyl)sulfonyl]-3a,4,5,6,7,7a-hexahydro-1H-benzimidazole
(14a). M.p. 115 – 1178 (AcOEt/hexane). IR (CHCl3): 1650, 1598. 1H-NMR (CDCl3): 1.16 – 1.28 (m, 1 H);
1.33 – 1.43 (m, 1 H); 1.43 – 1.51 (m, 1 H); 1.53 – 1.69 (m, 3 H); 1.87 – 1.94 (m, 1 H); 1.94 – 2.01 (m, 1 H);
2.26 (d, J ¼ 2.3, 3 H); 2.43 (s, 3 H); 3.66 – 3.71 (m, 1 H); 4.03 (dt, J ¼ 7.0, 8.2, 1 H); 7.32 (d, J ¼ 8.0, 2 H);
7.73 (d, J ¼ 8.0, 2 H). 13C-NMR (CDCl3): 17.5; 19.6; 20.0; 21.6; 26.9; 27.9; 60.9; 63.0; 127.0; 130.0; 137.3;
144.3; 156.1. EI-MS: 292 (Mþ). EI-HR-MS: 292.1245 (Mþ, C15H20N2O2Sþ; 292.1234).
(3aR*,7aS*)-2-Ethyl-1-[(4-methylphenyl)sulfonyl]-3a,4,5,6,7,7a-hexahydro-1H-benzimidazole (14b).
Colorless crystals. M.p. 164 – 1648 (AcOEt/hexane). IR (CHCl3): 1630. 1H-NMR (CDCl3): 1.20 (t,

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Helvetica Chimica Acta – Vol. 93 (2010)
J ¼ 7.5, 3 H); 1.16 – 1.24 (m, 1 H); 1.29 – 1.39 (m, 1 H); 1.42 – 1.52 (m, 2 H); 1.52 – 1.65 (m, 2 H); 1.91 – 1.99
(m, 2 H); 2.41 (s, 3 H); 2.57, 2.59 (2dq, J ¼ 1.7, 7.5, 1 H); 2.66, 2.70 (2dq, J ¼ 1.7, 7.5, 1 H); 3.61 (br. s, 1 H);
3.99 (dt, J ¼ 8.0, 5.7, 1 H); 7.29 (d, J ¼ 8.5, 2 H); 7.70 (d, J ¼ 8.5, 2 H). 13C-NMR (CDCl3): 11.2; 19.6; 20.1;
21.6; 24.0; 26.8; 28.0; 60.8; 63.0; 126.8; 130.0; 137.4; 144.2; 160.8. EI-MS: 306 (Mþ). EI-HR-MS: 306.1401
(Mþ, C16H22N2O2Sþ; 306.1402). Anal. calc. for C16H22N2O2S: C 62.71, H 7.24, N 9.14; found: C 62.56, H
7.45, N 9.02.
(3aR*,7aS*)-2-Phenyl-1-[(4-methylphenyl)sulfonyl]-3a,4,5,6,7,7a-hexahydro-1H-benzimidazole
(14c). Colorless crystals. M.p. 121 – 1228 (AcOEt/hexane). IR (CHCl3): 1640. 1H-NMR (CDCl3): 1.15 –
1.36 (m, 2 H); 1.46 – 1.68 (m, 4 H); 2.07 – 2.18 (m, 2 H); 2.41 (s, 3 H); 3.38 – 3.43 (m, 1 H); 4.22 (dt, J ¼ 9.7,
6.8, 1 H); 7.26 (d, J ¼ 7.3, 2 H); 7.41 (t, J ¼ 7.5, 2 H); 7.49 (t, J ¼ 7.5, 1 H); 7.53 (d, J ¼ 8.0, 2 H); 7.76 (d, J ¼
8.0, 2 H). 13C-NMR (CDCl3): 20.0; 21.1; 21.7; 27.1; 28.8; 61.3; 64.3; 127.0; 127.9; 129.6; 129.9; 131.0; 131.3;
136.9; 144.3; 159.3. EI-MS: 354 (Mþ). EI-HR-MS: 354.1409 (Mþ, C20H22N2O2Sþ; 354.1402). Anal. calc.
for C20H22N2O2S: C 67.77, H 6.26, N 7.90; found: C 67.88, H 6.32, N 8.01.
(3aR*,7aS*)-2-Methyl-1-[(4-methylphenyl)sulfonyl]-3a,4,7,7a-tetrahydro-1H-benzimidazole (17).
1
Colorless crystals. M.p. 102 – 1038 (AcOEt/hexane). IR (CHCl3): 1646. H-NMR (CDCl3): 2.21 (d, J ¼
1.7, 3 H); 2.25 (dt, J ¼ 16.0, 4.6, 1 H); 2.31 (ddd, J ¼ 2.3, 6.3, 16.0, 1 H); 2.34 (ddd, J ¼ 1.7, 4.5, 16.6,
1 H); 2.41 (s, 3 H); 2.48 (dt, J ¼ 16.6, 4.6, 1 H); 4.10 – 4.16 (m, 1 H); 4.19 (dt, J ¼ 10.3, 5.1, 1 H); 5.86 – 5.88
(m, 2 H); 7.31 (d, J ¼ 8.0, 2 H); 7.69 (d, J ¼ 8.0, 2 H). 13C-NMR (CDCl3): 17.2; 21.6; 28.1; 28.9; 60.2; 64.3;
127.0; 127.2; 128.5; 130.1; 136.3; 144.4; 156.3. EI-MS: 290 (Mþ). EI-HR-MS: 290.1090 (Mþ,
C15H18N2O2Sþ; calc. 290.1089).
(4R*,5R*)-2,4-Dimethyl-5-(1-methylethyl)-1-[(4-methylphenyl)sulfonyl]-4,5-dihydro-1H-imidazole
(18). Viscous oil. IR (CHCl3): 1644. 1H-NMR (CDCl3): 0.64 (d, J ¼ 6.9, 3 H); 0.80 (d, J ¼ 6.9, 3 H); 0.88
(d, J ¼ 7.4, 3 H); 2.17 – 2.26 (m, 1 H); 2.30 (d, J ¼ 1.1, 3 H); 2.42 (s, 3 H); 3.41 (t, J ¼ 3.5, 1 H); 3.60 – 3.66
(m, 1 H); 7.33 (d, J ¼ 8.0, 2 H), 7.70 (d, J ¼ 8.0, 2 H). 13C-NMR (CDCl3): 14.9; 17.4; 17.5; 21.6; 22.8; 31.6;
60.5; 71.9; 127.2; 129.9; 135.7; 140.6; 144.5; 155.6. EI-MS: 332 (Mþ). EI-HR-MS: 294.1422 (Mþ,
C15H22N2O2Sþ; calc. 294.1402).
(4R*,5S*)-2,4-Dimethyl-5-(1-methylethyl)-1-[(4-methylphenyl)sulfonyl]-4,5-dihydro-1H-imidazole
(19). Viscous oil. IR (CHCl3): 1644. 1H-NMR (CDCl3): 0.85 (d, J ¼ 6.9, 3 H); 1.06 (d, J ¼ 6.9, 3 H); 1.26
(d, J ¼ 7.4, 3 H); 1.87 – 1.95 (m, 1 H); 2.31 (d, J ¼ 2.3, 3 H); 2.42 (s, 3 H); 3.38 – 3.46 (m, 1 H); 3.92 (dd, J ¼
2.3, 8.0, 1 H); 7.30 (d, J ¼ 8.0, 2 H); 7.70 (d, J ¼ 8.0, 2 H). 13C-NMR (CDCl3): 14.6; 17.4; 17.6; 20.5; 21.6;
28.4; 63.6; 69.4; 126.8; 130.1; 137.1; 144.3; 157.5. EI-MS: 332 (Mþ). EI-HR-MS: 294.1403 (Mþ,
C15H22N2O2Sþ; calc. 294.1402).
Conversion of 14a to 15 by Acid-Catalyzed Hydrolysis. A soln. of 14a (100 mg) and 10% aq. HCl
(1 ml) in MeOH (10 ml) was heated under reflux for 2 h. After cooling, the mixture was concentrated,
and the residue was made alkaline with 10% aq. NaOH. The mixture was extracted with AcOEt, the
extract was washed with H2O and dried (MgSO4) to give 15 in 80% yield.
Preparation of 15 from 16. To a mixture of 16 (114 mg, 1 mmol), Et3N (0.58 ml, 4 mmol), and 4-
(dimethylamino)pyridine (DMAP; 60 mg, 0.4 mmol) in CH2Cl2 (50 ml), TsCl (190 mg, 1 mmol) was
added under ice cooling. After stirring the mixture at r.t. for 1 h, AcCl (70 mg, 1 mmol) was added under
ice cooling, and the mixture was stirred at r.t. for 1 h. The mixture was concentrated, and the residue was
diluted with AcOEt. The org. layer was washed with H2O and dried (MgSO4). The solvent was
evaporated, and the residue was separated by CC (SiO2; hexane/AcOEt 2 :1) to give 15 in 30% yield.
N-((1R*,2S*)-2-{[(4-Methylphenyl)sulfonyl]amino}cyclohexyl)acetamide (15). Colorless crystals.
M.p. 170 – 1718 (AcOEt/hexane). IR (CHCl3): 3376, 3268, 1652. 1H-NMR (CDCl3): 1.16 – 1.39 (m, 4 H);
1.42 – 1.65 (m, 3 H); 1.72 – 1.78 (m, 1 H); 1.93 (s, 3 H); 2.43 (s, 3 H); 3.38 – 3.44 (m, 1 H); 3.78 – 3.85 (m,
1 H); 4.90 (br. s, 1 H); 6.01 (br. s, 1 H); 7.32 (d, J ¼ 8.0, 2 H); 7.75 (d, J ¼ 8.0, 2 H). 13C-NMR (CDCl3):
20.1; 21.5; 23.3; 23.4; 27.6; 29.7; 49.6; 52.9; 127.8; 129.7; 137.3; 143.5; 170.3. EI-MS: 310 (Mþ). Anal. calc.
for C15H22N2O3S: C 58.04, H 7.14, N 9.02, S 10.33; found: C 58.00, H, 7.24, N 8.99, S 10.46.

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Received June 5, 2009