First stable O-amidinylhydroxylamines and their transformations into sulfenamides by intramolecular 1,5-O→S amine migration

Article abstract of DOI:10.1002/ejoc.200400229

The reaction of 2-chloro-4,5-dihydroimidazole (1) with aliphatic hydroxylamines 2-4 gives O-amidinylhydroxylamines 5-7 in contrast to the analogous reaction of 1 with N-arylhydroxylamines in which N-substitution occurs. A number of thiocarbamoylsulfenamides 8-10 have been prepared by the reaction of 5-7 with carbon disulfide under basic and mild conditions. The key step in the 1,5-O→S amine migration involves the tandem nucleophilic addition-electrophilic amination reaction. The intermolecular version of this process using preformed triethylammonium dithiocarbamates gives the corresponding sulfenamides 14-16. Functionalized ethylenediamines 17-19 are obtained by treatment of 8 and 9 with amines. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400229

FULL PAPER
First Stable O-Amidinylhydroxylamines and Their Transformations into
Sulfenamides by Intramolecular 1,5-OǞS Amine Migration
Franciszek Saczewski,*[a] Anita Kornicka,[a] Maria Gdaniec,[b] Rafal Hałasa,[c] and
˛
Władyslaw Werel[c]
Keywords: O-Amidinylhydroxylamines / Thiocarbamoylsulfenamides / Tandem nucleophilic-electrophilic amination / 1,5-
OǞS Amine migration / Anticancer activity / Antibacterial activity
The reaction of 2-chloro-4,5-dihydroimidazole (1) with ali-
phatic hydroxylamines 2−4 gives O-amidinylhydroxylamines
amination reaction. The intermolecular version of this pro-
cess using preformed triethylammonium dithiocarbamates
5−7 in contrast to the analogous reaction of 1 with N-aryl- gives the corresponding sulfenamides 14−16. Functionalized
hydroxylamines in which N-substitution occurs. A number of
thiocarbamoylsulfenamides 8−10 have been prepared by the
reaction of 5−7 with carbon disulfide under basic and mild
conditions. The key step in the 1,5-OǞS amine migration
involves the tandem nucleophilic addition-electrophilic
ethylenediamines 17−19 are obtained by treatment of 8 and
9 with amines.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2004)
Introduction
Recently, we reported[15] that 2-(hydroxylamino)-4,5-di-
hydroimidazolium O-sulfonate (A), which contains two en-
docyclic nucleophilic nitrogen atoms and an exocyclic elec-
trophilic nitrogen atom (Figure 1), when treated with heter-
ocumulenes such as carbon disulfide or isothiocyanates,
undergoes tandem nucleophilic addition-electrophilic amin-
ation reactions to give a variety of SϪN bond-containing
heterocyclic compounds.
Sulfenamides represent a diverse and important class of
compounds, serving a variety of distinct functions in both
synthetic and industrial chemistry.[1,2] Most of the sulfen-
amides described in the literature possess alkyl or aryl
groups on the sulfur atom. However, the comparatively less
common thiocarbamoylsulfenamides have been used in in-
dustry as rubber vulcanization accelerators[3] and have been
developed as inhibitors of zinc enzyme carbonic anhydrase
in medicinal chemistry.[4,5] In addition, thiocarbamoylsul-
fenamides have attracted increasing interest because of their
use as nucleophilic reagents in the direct amination of nitro-
arenes.[6,7]
The SϪN bond-forming reactions that lead to thiocarba-
moylsulfenamides involve the reaction of CS2, an amine
and chloroamine in the presence of base,[8] the coupling of
sodium or ammonium dithiocarbamates with either
chloroamines[9Ϫ11] or amines in an oxidative environ-
ment[11,12] as well as an electrolytic cross-coupling reaction
of bis(dialkylthiocarbamoyl) disulfides with amines.[13,14]
[a]
Department of Chemical Technology of Drugs, Medical
University of Gdansk,
Figure 1. Calculated[16] atomic charges and atomic charges derived
from the electrostatic potential (underlined) of the nitrogen atoms
of 5
80-416 Gdansk, Poland
E-mail: saczew@amg.gda.pl
[b]
Faculty of Chemistry, A. Mickiewicz University,
60-780 Poznan, Poland
[c]
Department of Pharmaceutical Microbiology, Medical
University of Gdansk,
We have now successfully extended this strategy by using
compounds of type 5 (Figure 1), which have a new O-amidi-
nylhydroxylamine functionality as the core structure. We
80-416 Gdansk, Poland
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2004, 3511Ϫ3516
DOI: 10.1002/ejoc.200400229
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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F. Sa˛czewski, A. Kornicka, M. Gdaniec, R. Hałasa, W. Werel
FULL PAPER
anticipated that these compounds would have the built-in
potential to undergo tandem nucleophilic addition-electro-
philic amination reactions to give novel thiocarbamoylsul-
fenamides that incorporate the 2-oxoimidazolidine moiety.
Results and Discussion
Figure 2. ORTEP drawing of 10 with the atom labeling scheme
When 2-chloro-4,5-dihydroimidazole (1) was allowed to
react with N-cyclohexylhydroxylamines 2Ϫ4 (ambident nu-
cleophiles) in a ratio of 1.5:1, we found that O-heteroalkyl-
ation of the latter occurred to afford O-amidinylhydroxyl-
amines 5Ϫ7 in 19Ϫ22% isolated yields (Scheme 1). This
contrasted with our previous finding that N-arylhydroxyl-
amines upon treatment with 1 underwent N-heteroalkyl-
ation.[17] Apparently, the nucleophilic N-attack of 2Ϫ4 is
hindered sterically and by electronic repulsion of the axial
nitrile group.
A proposed mechanism for this reaction is shown in
Scheme 1. Since the reaction was performed under basic
conditions, the dithiocarbamic acid initially formed should
exist in the anionic form B. Then, intramolecular OǞS am-
ine migration with simultaneous cleavage of the rather weak
NϪO bond produces the thiocarbamoylsulfenamides 8Ϫ10.
Another possible mechanism is the concerted base-me-
diated [1,5]-sigmatropic rearrangement of B, which is not
ruled out by the present evidence. However, the next logical
step in the development of this chemistry was to study the
intermolecular version of this process by using preformed
triethylammonium dithiocarbamates 11Ϫ13. As can be seen
from the results shown in Scheme 2, the use of secondary
aliphatic amines allows the preparation of thiocarbamoyl-
sulfenamides 14Ϫ16 in 33Ϫ64% yields. The structure of 14
thus obtained was analyzed by X-ray diffraction (Figure 3).
Scheme 2. Preparation of thiocarbamoylsulfenamides 14Ϫ16
Scheme 1. Preparation of O-amidinylhydroxylamines 5Ϫ7 and
thiocarbamoylsulfenamides 8Ϫ10
When the ratio of 1/2 was 2:1, so that no hydroxylamine
was left after the initial reaction, the substrate was still pre-
sent. Thus, from our findings it can be inferred that the
products 5Ϫ7 react with excess 1 and upon workup give
back the substrates 2Ϫ4 and 1-(4,5-dihydroimidazol-2-yl)-
2-imidazolidinone as the only identified side product (see
Exp. Sect.).
Treatment of 5Ϫ7 with carbon disulfide in acetone at
room temperature in the presence of Et3N gave rise to the
desired thiocarbamoylsulfenamides 8Ϫ10 in 39Ϫ40%
yields. The structures of these compounds was confirmed
Figure 3. ORTEP drawing of 14 with the atom labeling scheme
Compounds 8 and 9 were used in the synthesis of func-
by IR and NMR spectroscopic data as well as by the X-ray tionalized ethylenediamines 17Ϫ19 (Scheme 3). The
diffraction analysis of 10 (Figure 2). method is based on our finding that the 2-oxoimidazolidine
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First Stable O-Amidinylhydroxylamines and Their Transformations into Sulfenamides
FULL PAPER
derivatives react with primary and secondary amines to give
The minimum inhibitory concentration (MIC) and mini-
the products of a nucleophilic ring-opening reaction. The mum bactericide concentration (MBC) of compounds
structure of 17 thus obtained was analyzed by X-ray diffrac- 8Ϫ10, 15 and 17 in liquid media were also determined by
tion (Figure 4).
the standard broth dilution technique[21] with an innoculum
of approximately 4 ϫ 105 CFU·mLϪ1. Compounds were
tested against three bacterial strains: Escherichia coli
(NCTC 8196), Staphylococcus aureus (NCTC 4163) and
Pseudomonas aeruginosa (NCTC 6749) at concentrations in
the range of 1.9Ϫ250µg·mLϪ1. Compounds 9, 15 and 17
were inactive (MIC у 62.5 µg·mLϪ1), while thiocarbamoyl-
sulfenamides 8 and 10 showed activity against gram-posi-
tive Staphylococcus aureus with MIC and MBC values of
15.6 µg·mLϪ1
.
Scheme 3. Preparation of functionalized ethylenediamines 17Ϫ19
Conclusion
We have described the first synthesis of stable O-amidin-
ylhydroxylamines 5Ϫ7, which are easy to separate and may
be stored under anhydrous conditions for several months
without significant decomposition.
A novel tandem nucleophilic addition-electrophilic amin-
ation rearrangement as a key step provides access to the
otherwise not readily available thiocarbamoylsulfenamides,
for example, 8Ϫ10, 14Ϫ16 and 17Ϫ19.
Experimental Section
General Remarks: Melting points were measured with a Büchi S35
apparatus and are uncorrected. FT-IR spectra were recorded with
a Perkin-Elmer 1600 spectrophotometer as KBr pellets. NMR spec-
tra were recorded with Varian Gemini 200 and Varian Unity Plus
500 spectrometers at 200 or 500 MHz for proton and at 125 MHz
for carbon nuclei. Chemical shifts (δ) were measured relative to the
residual solvent signal at δ ϭ 2.50 or 7.26 ppm and δ ϭ 39.5 or
Figure 4. ORTEP drawing of 17 with the atom labeling scheme
1
77 ppm for H and 13C NMR, respectively. Mass spectra were re-
corded at 70 eV. All reagents were used directly as obtained com-
mercially. 2-Chloro-4,5-dihydroimidazole[22] (1) and the 1-
(hydroxyamino)cyclohexanecarbonitriles[23,24] 2Ϫ4 were prepared
according to previously described procedures.
The structures of the newly prepared compounds were
confirmed by 1H and 13C NMR spectroscopic data (see
Supporting Information).
Reaction of 2-Chloro-4,5-dihydroimidazole (1) with 1-(Hydroxyami-
no)cyclohexanecarbonitrile (2). Preparation of 1-[(4,5-Dihydro-1H-
imidazol-2-yloxy)amino]cyclohexanecarbonitrile (5): 1-(Hydroxyam-
ino)cyclohexanecarbonitrile (2) (2.31 g, 16.5 mmol) was added to a
solution of 2-chloro-4,5-dihydroimidazole (1) (2.5 g, 24 mmol) in
CH2Cl2 (30 mL) and the reaction mixture was stirred at room tem-
perature for 12 h. The solid that precipitated (1.82 g), which con-
Biological Evaluation
It is well known that unstable O-acylhydroxylamines re-
act as electrophiles to form DNA adducts which cause pri-
mary cancer lesion.[18] On the other hand, solid tumors
have lower extracellular pH levels than normal tissues due
to the accumulation of metabolic acids in hypoxic cells.[19] sists of a mixture of 5·HCl and 1-(4,5-dihydroimidazol-2-yl)-2-im-
idazolidinone (NMR evidence), was filtered off (the filtrate denoted
as I was stored for further workup), dissolved in water (15 mL) and
the resulting solution was made alkaline (pH ϭ 9) with 10% aque-
ous NaOH. The precipitated solid was collected by filtration,
washed with water and dried to give free base 5 (0.64 g, 19%) as a
white solid; m.p. 111Ϫ113 °C. 1H NMR (500 MHz, [D6]DMSO):
δ ϭ 1.18Ϫ1.25 (m, 1 H), 1.34Ϫ1.42 (m, 2 H), 1.47Ϫ1.52 (m, 2 H),
1.59Ϫ1.61 (m, 1 H), 1.75 (dd, J ϭ 4.12, 9.34 Hz, 2 H), 1.93 (d, J ϭ
12.9 Hz, 2 H), 3.42 (s, 4 H), 6.23 (br. s, 1 H), 8.35 (s, 1 H) ppm.
13C NMR (500 MHz, [D6]DMSO): δ ϭ 22.17 (two overlapping sig-
nals), 25.09, 32.52 (two overlapping signals), 48.63 (two overlap-
This difference (0.6Ϫ0.8 units) provides new strategies for
tumor-selective activation of cytocidal drugs.[20] We rea-
soned that the electrophilic character of nitrogen electro-
philes like 5Ϫ7 should be enhanced upon protonation of
the imidazoline ring in hypotoxic cells. Therefore, com-
pounds 5Ϫ7 were submitted to the National Cancer Insti-
tute (Bethesda, USA) for evaluation against human tumor
cell lines, and compounds 6 and 7 were found to exhibit
activity against the NCI-H460 cell line (lung cancer) in the
preliminary anticancer assay.
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F. Sa˛czewski, A. Kornicka, M. Gdaniec, R. Hałasa, W. Werel
FULL PAPER
ping signals), 59.86, 121.57, 167.44 ppm. IR (KBr): ν˜ ϭ 3415, 3115,
3-Methyl-1-({[(2-oxoimidazolidin-1-yl)carbonothioyl]thio}amino)-
cyclohexanecarbonitrile (9): This compound was prepared from
nitrile 6 (440 mg, 2 mmol); yellow solid; yield 230 mg (39%); m.p.
136Ϫ138 °C. 1H NMR (500 MHz, [D6]DMSO): δ ϭ 0.80Ϫ0.88 (m,
1 H), 0.91 (d, J ϭ 6.35 Hz, 3 H), 1.24 (t, J ϭ 12.70 Hz, 1 H),
1.36Ϫ1.51 (m, 2 H), 1.55Ϫ1.57 (m, 1 H), 1.64 (d, J ϭ 12.69 Hz, 1
H), 1.74Ϫ1.76 (m, 1 H), 2.11 (d, J ϭ 12.70 Hz, 2 H), 3.50Ϫ3.53
2935, 2920, 2860, 2230, 1630, 1610, 1545, 1490, 1450, 1285 cmϪ1
.
C10H16N4O (208.27): calcd. C 57.68, H 16.13, N 26.93; found C
57.65, H 16.10, N 26.74. The filtrate I was concentrated under re-
duced pressure, and the oily residue was treated with diethyl ether.
The precipitated solid was collected by suction and dried to give 1-
(hydroxyamino)cyclohexanecarbonitrile (2) (0.3 g, 13%). The fol-
lowing compounds were prepared analogously by treating 1 with (m, 2 H), 4.14Ϫ4.17 (m, 2 H), 5.45 (s, 1 H), 8.31 (s, 1 H) ppm. 13
C
the appropriate 1-(hydroxyamino)cyclohexanecarbonitrile 3 or 4.
NMR (500 MHz, [D6]DMSO): δ ϭ 22.3, 23.1, 29.9, 33.7, 36.6,
38.0, 44.7, 50.7, 60.1, 121.8, 155.5, 205.8 ppm. IR (KBr): ν˜ ϭ 3240,
3125, 2950, 2920, 2225, 1730, 1340, 1265 cmϪ1. C12H18N4OS2
(298.43): calcd. C 48.30, H 6.08, N 18.77; found C 48.37, H 6.21,
N 18.52.
1-[(4,5-Dihydro-1H-imidazol-2-yloxy)amino]-3-methylcyclohexane-
carbonitrile (6): This compound was prepared from 1-(hydroxy-
amino)-3-methylcyclohexanecarbonitrile (3) (2.51 g, 16.5 mmol);
white solid; yield 0.7 g (20%); m.p. 102Ϫ104 °C. 1H NMR
(500 MHz, [D6]DMSO): δ ϭ 0.84Ϫ0.89 (m, 1 H), 0.92 (d, J ϭ
6.35 Hz, 3 H), 1.09 (t, J ϭ 12.7 Hz, 1 H), 1.30Ϫ1.46 (m, 2 H),
1.57Ϫ1.59 (m, 1 H), 1.68 (d, J ϭ 12.69 Hz, 1 H), 1.77Ϫ1.80 (m, 1
H), 1.94Ϫ1.96 (m, 2 H), 3.42 (s, 4 H), 6.27 (br. s, 1 H), 8.38 (s, 1
H) ppm. 13C NMR (500 MHz, [D6]DMSO): δ ϭ 22.4, 22.44, 29.3
(two overlapping signals), 32.3, 33.9, 48.7 (two overlapping signals),
60.6, 121.5, 167.5 ppm. IR (KBr): ν˜ ϭ 3400, 3110, 2920, 2860,
2225, 1634, 1615, 1535, 1445, 1285 cmϪ1. C11H18N4O (222.29):
calcd. C 59.43, H 8.16, N 25.20; found C 59.65, H 7.83, N 25.36.
4-Methyl-1-({[(2-oxoimidazolidin-1-yl)carbonothioyl]thio}amino)-
cyclohexanecarbonitrile (10): This compound was prepared from
nitrile 7 (440 mg, 2 mmol); yellow solid; yield 240 mg (41%); m.p.
1
139Ϫ140 °C. H NMR (500 MHz, [D6]DMSO): δ ϭ 0.88 (d, J ϭ
6.83 Hz, 3 H), 1.08 (q, J ϭ 11.72 Hz, 2 H), 1.32Ϫ1.41 (m, 1 H),
1.59Ϫ1.64 (m, 2 H), 1.72 (d, J ϭ 12.7 Hz, 2 H), 2.12 (d, J ϭ
12.21 Hz, 2 H), 3.50Ϫ3.52 (m, 2 H), 4.14Ϫ4.17 (m, 2 H), 5.46 (s,
1 H), 8.30 (s, 1 H) ppm. 13C NMR (500 MHz, [D6]DMSO): δ ϭ
22.4, 31.5, 31.7 (two overlapping signals), 36.7 (two overlapping
signals), 38.0, 50.7, 59.77, 121.7, 155.5, 205.8 ppm. IR (KBr): ν˜ ϭ
3250, 3130, 2925, 2855, 2220, 1730, 1340, 1265 cmϪ1. MS (70 eV,
EI): m/z (%) ϭ 298.1 (35.2) [Mϩ], 143.1 (61.6), 129.1 (100), 128.1
(39.8), 111 (15.5). C12H18N4OS2 (298.43): calcd. C 48.30, H 6.08,
N 18.77; found C 48.15, H 5.92, N 18.51.
1-[(4,5-Dihydro-1H-imidazol-2-yloxy)amino]-4-methylcyclohexane-
carbonitrile (7): This compound was prepared from 1-(hydroxy-
amino)-4-methylcyclohexanecarbonitrile (4) (2.51 g, 16.5 mmol);
white solid; yield 0.8 g (22%); m.p. 104Ϫ105 °C. 1H NMR
(500 MHz, [D6]DMSO): δ ϭ 0.9 (d, J ϭ 6.59 Hz, 3 H), 1.08 (q,
J ϭ 11.67 Hz, 2 H), 1.33Ϫ1.40 (m, 1 H), 1.44Ϫ1.48 (m, 2 H), 1.75
(d, J ϭ 12.36 Hz, 2 H), 1.97 (d, J ϭ 12.91 Hz, 2 H), 3.42 (s, 4 H),
6.27 (br. s, 1 H), 8.38 (s, 1 H) ppm. 13C NMR (500 MHz,
[D6]DMSO): δ ϭ 21.7, 30.3 (two overlapping signals), 31.0, 31.9
(two overlapping signals), 48.0 (two overlapping signals), 59.6,
120.7, 166.8 ppm. IR (KBr): ν˜ ϭ 3145, 2945, 2925, 2870, 2225,
1625, 1610, 1515, 1445, 1285 cmϪ1. C11H18N4O (222.29): calcd. C
59.43, H 8.16, N 25.20; found C 59.68, H 7.92, N 24.95.
Reaction of 5 with Triethylammonium Dithiocarbamates. Prep-
aration
of
1-({[(Amino)carbonothioyl]thio}amino)cyclohexane-
carbonitriles 14؊16. General Procedure: Carbon disulfide (0.11 mL,
1.9 mmol) and Et3N (0.26 mL, 1.9 mmol) were added to a solution
of the appropriate amine 11Ϫ13 (1.9 mmol) in anhydrous THF
(10 mL). After stirring at room temperature for 30 min, a solution
of 5 (320 mg, 1.6 mmol) in anhydrous THF (30 mL) was added
dropwise to the solution or mixture (in the case of pyrrolidine or
1,2,3,4-tetrahydroisoquinoline) . The resulting solution was stirred
at room temperature for 20 h. Then the solvent was evaporated
under reduced pressure, and the residue was treated with methanol
(5 mL). The insoluble product (14Ϫ16) thus obtained was collected
by filtration, washed with methanol (2 mL), dried and purified by
crystallization from a suitable solvent. The following compounds
were obtained according to the above procedure.
Preparation of 1-({[(2-Oxoimidazolidin-1-yl)carbonothioyl]thio}-
amino)cyclohexanecarbonitriles 8؊10. General Procedure: Triethyl-
amine (0.27 mL, 2 mmol) was added dropwise to a mixture of the
appropriate nitrile 5Ϫ7 (2 mmol) and carbon disulfide (1.2 mL,
20 mmol) in anhydrous acetone (10 mL), and the reaction suspen-
sion was stirred at room temperature for 20 h. Then the insoluble
by-product (0.02 g) was filtered off. The solvent of the filtrate and
excess of carbon disulfide were evaporated under reduce pressure,
and the residue was treated with anhydrous methanol (3 mL). The
precipitate thus obtained was filtered and dried. The following
compounds were obtained according to the above procedure.
1-({[(Diethylamino)carbonothioyl]thio}amino)cyclohexanecarbo-
nitrile (14): This compound was prepared from diethylamine
(140 mg, 1.9 mmol); white solid; yield 270 mg (64%); m.p. 104Ϫ106
1
°C (ethanol). H NMR (500 MHz, CDCl3): δ ϭ 1.25Ϫ1.34 (m, 7
H), 1.48Ϫ1.59 (m, 2 H), 1.62Ϫ1.66 (m, 3 H), 1.78Ϫ1.80 (m, 2 H),
2.18 (d, J ϭ 11.72 Hz, 2 H), 3.67 (q, J ϭ 6.84 Hz, 2 H), 4.02 (q,
J ϭ 6.84 Hz, 2 H), 4.77 (s, 1 H) ppm. 13C NMR (500 MHz,
CDCl3): δ ϭ 11.8, 13.2, 22.7 (two overlapping signals), 25.0, 37.2
(two overlapping signals), 46.2, 50.8, 61.0, 120.5, 199.8 ppm. IR
(KBr): ν˜ ϭ 3125, 2985, 2955, 2935, 2855, 2230, 1500, 1455, 1445,
1425, 1350, 1270, 1205, 1150 cmϪ1. C12H21N3S2 (271.45): calcd. C
53.10, H 7.80, N 15.48; found C 53.35, H 7.61, N 15.17.
1-({[(2-Oxoimidazolidin-1-yl)carbonothioyl]thio}amino)cyclohexane-
carbonitrile (8): This compound was prepared from nitrile 5
(410 mg, 2 mmol); yellow solid; yield 220 mg (40%); m.p. 141Ϫ143
°C. 1H NMR (500 MHz, [D6]DMSO): δ ϭ 1.18Ϫ1.23 (m, 1 H),
1.33Ϫ1.40 (m, 2 H), 1.54Ϫ1.56 (m, 1 H), 1.60Ϫ1.66 (m, 2 H),
1.70Ϫ1.73 (m, 2 H), 2.27 (d, J ϭ 12.7 Hz, 2 H), 3.49Ϫ3.52 (m, 2
H), 4.13Ϫ4.16 (m, 2 H), 5.39 (s, 1 H), 8.30 (s, 1 H) ppm. 13C NMR
(500 MHz, [D6]DMSO): δ ϭ 22.8 (two overlapping signals), 24.9, 1-({[(Pyrrolidin-1-yl)carbonothioyl]thio}amino)cyclohexanecarbo-
36.7 (two overlapping signals), 38.0, 50.7, 59.3, 121.9, 155.5, nitrile (15): This compound was prepared from pyrrolidine
203.5 ppm. IR (KBr): ν˜ ϭ 3240, 3130, 2930, 2855, 2225, 1740,
(130 mg, 1.9 mmol); white solid; yield 160 mg (39%); m.p. 108Ϫ111
1
1345, 1265, 1170 cmϪ1. MS (70 eV, EI): m/z (%) ϭ 284.1 (10.4) °C (ethanol). H NMR (500 MHz, CDCl3): δ ϭ 1.19Ϫ1.31 (m, 1
[Mϩ], 129.0 (100), 128 (17.8), 86 (18.8), 72 (18.7). C11H16N4OS2
(284.41): calcd. C 46.45, H 5.67, N 19.70; found C 46.32, H 5.83,
N 19.73.
H), 1.60Ϫ1.66 (m, 5 H), 1.74Ϫ1.83 (m, 2 H), 1.95Ϫ2.03 (m, 2 H),
2.11Ϫ2.18 (m, 4 H), 3.61 (s, 2 H), 3.96 (s, 2 H), 4.67 (s, 1 H) ppm.
13C NMR (500, CDCl3): δ ϭ 22.7 (two overlapping signals), 23.9,
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First Stable O-Amidinylhydroxylamines and Their Transformations into Sulfenamides
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25.0, 26.1, 37.1 (two overlapping signals), 49.1, 55.4, 60.9, 120.6, 6.56Ϫ6.60 (m, 1 H), 7.21Ϫ7.33 (m, 5 H), 9.82 (br. s, 1 H) ppm. 13
196.6 ppm. IR (KBr): ν˜ ϭ 3070, 2930, 2860, 2225, 1480, 1440, NMR (200 MHz, [D6]DMSO): δ ϭ 22.8 (two overlapping signals),
1325, 1250, 1160 cmϪ1. C12H19N3S2 (269.43): calcd. C 53.50, H 24.4, 34.5 (two overlapping signals), 38.6, 43.3, 47.1, 59.3, 121.7,
C
7.11, N 15.59; found C 53.32, H 7.43, N 15.80.
126.9, 127.3 (two overlapping signals), 128.5 (two overlapping sig-
nals), 140.9, 159.1, 196.9 ppm. IR (KBr): ν˜ ϭ 3325, 3225, 3185,
1-({[(1,2,3,4-Tetrahydroisoquinolin-2-yl)carbonothioyl]thio}amino)-
cyclohexanecarbonitrile (16): This compound was prepared from
1,2,3,4-tetrahydroisoquinoline (250 mg, 1.9 mmol); white solid;
yield 170 mg (33%); m.p. 89Ϫ92 °C (2-propanol). 1H NMR
(500 MHz, CDCl3): δ ϭ 1.20Ϫ1.30 (m, 1 H), 1.60 (d, J ϭ 12.7 Hz,
1 H), 1.64Ϫ1.71 (m, 4 H), 1.79Ϫ1.82 (m, 2 H), 2.21 (d, J ϭ
12.2 Hz, 1 H), 3.02 (t, J ϭ 5.61 Hz, 2 H), 3.99 (s, 1 H), 4.41 (br. s,
1 H), 4.80 (s, 1 H), 4.91 (br. s, 1 H), 5.31 (s, 1 H), 7.20Ϫ7.26 (m, 4
H) ppm. IR (KBr): ν˜ ϭ 3020, 2935, 2855, 2225, 1485, 1440, 1275,
1230 cmϪ1. C17H21N3S2 (331.51): calcd. C 61.59, H 6.38, N 12.67;
found C 61.35, H 6.17, N 12.79.
2935, 2855, 2230, 1670, 1610, 1585, 1500, 1450, 1315, 1255 cmϪ1
.
C18H25N5OS2 (391.56): calcd. C 55.21, H 6.43, N 17.88; found C
55.21, H 6.43, N 17.66.
X-ray Structure Analyses: The intensity data for the crystals were
collected using a KumaCCD diffractometer. The crystal structures
were solved with SHELXS-97[25] and refined with SHELXL-97.[26]
Crystal data for C12H18N4OS2 (10): monoclinic, space group P21/
˚
n, a ϭ 5.8706(6), b ϭ 9.6441(9), c ϭ 25.4777(19) A, β ϭ 95.626(7)°,
3
˚
˚
V ϭ 1435.5(2) A , Z ϭ 4, λ ϭ 0.71073 A, T ϭ 140 K, R1 ϭ 0.0558,
wR2 ϭ 0.1302 for 2056 independent reflections with I Ͼ 2σ(I).
¯
Crystal data for C12H21N3S2 (14): triclinic, space group P1, a ϭ
7.433(1), b ϭ 9.862(1), c ϭ 11.172(1) A, α ϭ 70.05(1), β ϭ 88.32(1),
γ ϭ 73.51(1)°, V ϭ 736.1(1) A , Z ϭ 2, λ ϭ 0.71073 A, T ϭ 293 K,
R1 ϭ 0.0359, wR2 ϭ 0.0969 for 2366 independent reflections with
I Ͼ 2σ(I). Crystal data for C15H27N5OS2 (17): triclinic, space group
P1, a ϭ 9.7937(7), b ϭ 10.0943(6), c ϭ 11.0112(9) A, α ϭ 66.388(7),
β ϭ 73.374(7), γ ϭ 70.779(6)°, V ϭ 926.75(11) A , Z ϭ 2, λ ϭ
0.71073 A, T ϭ 140 K, R1 ϭ 0.0343, wR2 ϭ 0.0885 for 2892 inde-
NЈ-{2-[({[(1-Cyanocyclohexyl)amino]thio}carbonothioyl)amino]-
ethyl}ureas 17؊19. General Procedure: A solution of the nitriles 8
or 9 (1.1 mmol) and the appropriate amine (1.3 mmol) in anhy-
drous THF (15 mL) or DMF (5 mL, in the case of benzylamine)
was stirred at room temperature for 20 h. Then the solvent was
evaporated under reduced pressure, and the residue was treated
with methanol (4 mL). The insoluble product (17Ϫ19) thus ob-
tained was collected by filtration, washed with methanol, dried and
purified by crystallization from a suitable solvent. The following
compounds were obtained according to the above procedure.
˚
3
˚
˚
˚
¯
3
˚
˚
pendent reflections with I Ͼ 2σ(I). CCDC-241618 (10), -241619
(14) and -241620 (17) contain the supplementary crystallographic
data for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; Fax: (internat.) ϩ 44-1223-336-033; E-mail:
deposit@ccdc.cam.ac.uk].
NЈ-{2-[({[(1-Cyanocyclohexyl)amino]thio}carbonothioyl)amino]-
ethyl}-N,N-diethylurea (17): This compound was prepared from
nitrile 8 (310 mg, 1.1 mmol) and diethylamine (95 mg, 1.3 mmol);
white solid; yield 120 mg (32%); m.p. 119Ϫ121 °C (2-propanol). 1H
NMR (500 MHz, [D6]DMSO): δ ϭ 1.01 (s, 6 H), 1.11Ϫ1.13 (m, 1
H), 1.33 (d, J ϭ 10.74 Hz, 2 H), 1.55Ϫ1.66 (m, 3 H), 1.69Ϫ1.78
(m, 2 H), 2.08 (d, J ϭ 9.77 Hz, 2 H), 3.18 (s, 4 H), 3.28 (s, 2 H),
3.63 (s, 2 H), 6.16 (s, 1 H), 6.51 (br. s, 1 H), 9.91 (br. s, 1 H)
ppm. 13C NMR (500 MHz, [D6]DMSO): δ ϭ 19.2 (two overlapping
signals), 27.9 (two overlapping signals), 29.6, 39.7, 44.1, 44.5, 45.7
(two overlapping signals), 52.6, 64.5, 126.8, 163.1, 202.0 ppm. IR
(KBr): ν˜ ϭ 3425, 3215, 2975, 2935, 2860, 2225, 1615, 1525, 1505,
1320, 1270, 1120 cmϪ1. C15H27N5OS2 (357.54): calcd. C 50.40, H
7.61, N 19.59; found C 50.23, H 7.73, N 19.34.
Supporting Information: NMR spectra for compounds 5, 6, 9, 18
(see also footnote on the first page of this article).
[1]
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1
1.3 mmol); white solid; yield 220 mg (55%); m.p. 127Ϫ129 °C. H
zafava, Bioorg. Med. Chem. 2001, 9, 703Ϫ714.
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0.90 (d, J ϭ 5.86 Hz, 3 H), 1.28Ϫ1.40 (m, 2 H), 1.48Ϫ1.53 (m, 2
H), 1.66 (d, J ϭ 11.72 Hz, 1 H), 1.78 (s, 5 H), 2.05Ϫ2.15 (m, 2 H),
3.20 (s, 4 H), 3.23 (s, 2 H), 3.61 (d, J ϭ 3.9 Hz, 2 H), 6.19 (s, 1
H), 6.42 (br. s, 1 H), 9.90 (br. s, 1 H) ppm. 13C NMR (500 MHz,
[D6]DMSO): δ ϭ 22.3, 23.1, 25.7, 30.1 (two overlapping signals),
33.7, 34.6, 38.9, 42.8, 46.0 (two overlapping signals), 47.9, 59.9,
122.2, 157.9, 197.3 ppm. IR (KBr): ν˜ ϭ 3380, 3195, 3135, 2940,
[6]
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[10]
[11]
2910, 2860, 2225, 1615, 1550, 1495, 1410, 1360, 1200 cmϪ1
.
C16H27N5OS2 (369.55): calcd. C 52.0, H 7.36, N 18.95; found C
52.15, H 7.46, N 18.76.
[12]
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[13]
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N-Benzyl-NЈ-{2-[(1-Cyanocyclohexyl)amino]thio}carbonothioyl)-
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(310 mg, 1.1 mmol) and benzylamine (140 mg, 1.3 mmol); white
solid; yield 140 mg (32%); m.p. 128Ϫ129 °C (2-propanol). 1H
NMR (200 MHz, [D6]DMSO): δ ϭ 1.13Ϫ1.45 (m, 3 H), 1.58Ϫ1.78
(m, 5 H), 2.08Ϫ2.13 (m, 2 H), 3.25Ϫ3.31 (m, 2 H), 3.61Ϫ3.65 (m,
2 H), 4.25 (d, J ϭ 5.4 Hz, 2 H), 6.22 (s, 1 H), 6.27Ϫ6.29 (m, 1 H),
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The geometry of 5 was optimized by ab initio methods at the
6-31G** level using the Spartan 5.0 program package, Wave-
[15]
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3515

F. Sa˛czewski, A. Kornicka, M. Gdaniec, R. Hałasa, W. Werel
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Received March 2, 2004
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3516
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 3511Ϫ3516