Alkylation of N-arylcyanamides and electron-deficient phenols with (Chloromethyl)thiirane

Article abstract of DOI:10.1007/s10593-012-0941-2

Alkylation of N-arylcyanamides with (chloromethyl)thiirane in aqueous alkaline solution provides an easy synthetic approach to N-aryl-N-(thietan-3-yl)cyanamides. Yields vary from 34 to 76% and are lower in the case of electron-deficient aryl substituents.

Full text of DOI:10.1007/s10593-012-0941-2

Chemistry of Heterocyclic Compounds, Vol. 47, No. 12, March, 2012 (Russian Original Vol. 47, No. 12, December, 2011)
ALKYLATION OF N-ARYLCYANAMIDES
AND ELECTRON-DEFICIENT PHENOLS
WITH (CHLOROMETHYL)THIIRANE
A. N. Butkevich1, M. Zibinsky2, V. V. Sokolov3*, and A. A. Tomashevskii3
Alkylation of N-arylcyanamides with (chloromethyl)thiirane in aqueous alkaline solution provides an
easy synthetic approach to N-aryl-N-(thietan-3-yl)cyanamides. Yields vary from 34 to 76% and are
lower in the case of electron-deficient aryl substituents. The reaction with phenols containing electron-
withdrawing groups results in formation of 3-(aryloxy)thietanes in 19–45% yields.
Keywords: 3-aminothietanes, N-arylcyanamides, (chloromethyl)thiirane, phenols, thiirane-thietane
rearrangement.
Small molecules comprise a vast majority of successfully designed, tested, and clinically approved drugs
[1, 2]. Structure-activity relationship practices used in early steps of the molecular design call for a large variety of
substituents that one should be able to install onto the desired scaffold for the screening purposes. Therefore,
simple and selective methods for the functionalization of organic molecules (as can be illustrated by examples of
O-alkylation of phenols and N-acylation and N-sulfonylation of amines) play an important role whenever it is
necessary to quickly achieve high molecular diversity or optimize the substrate-target interaction by varying the
substitution pattern of the substrate. The absence of transition metal catalyst in such reactions is an additional
advantage if bioactivity tests are in view.
Small-ring heterocycles provide an attractive extension to the small alkyl and cycloalkyl set of
substituents, as the presence of a heteroatom allows for an additional hydrogen bonding or dipole interactions
between the substrate molecule and its target. Three-membered heterocycles, such as oxirane or aziridine
fragments, often introduce unwanted reactivity because of the possibility of ring-opening reactions resulting in
formation of electrophilic species. Four-membered heterocyclic fragments containing one heteroatom are
inherently stable but notoriously difficult to synthesize. In this work, a simple and versatile method of
introduction of 3-thietanyl substituent is discussed.
_______
*To whom correspondence should be addressed, e-mail: vsokolo@mail.ru.
1University of Southern California, 837 Bloom Walk, Los Angeles, CA 90089, USA; e-mail: butkevic@usc.edu.
2The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA; e-mail:
zibinsky@scripps.edu.
3Saint Petersburg State University, 26 Universitetskii Pr., St. Petersburg 198504, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp. 1809-1815, December, 2011.
Original article submitted November 8, 2010.
0009-3122/12/4712-1509©2012 Springer Science+Business Media, Inc.
1509

The thiirane-thietane rearrangement taking place on interaction of (-haloalkyl)thiiranes and hard weak
nucleophiles (most commonly, phenolates and carboxylates) in the presence of base has been known for over 40
years [3]. The postulated mechanism involves formation of 1-thioniabicyclobutane, which is then attacked at 3
position by a nucleophile [4]:
Nu
Nu–
Cl
S+
– Cl–
S
Cl
S
More recently, the reaction was successfully expanded to include aromatic nitrogen heterocycles
(benzimidazoles [5, 6], xanthines [5], triazoles [7]) as nucleophilic partners. In our group, the reactions of (-halo-
alkyl)thiiranes with N-arylsulfamides [8] and isatins [9] have been demonstrated to provide access to
3-substituted thietanes in satisfactory yields.
Our purpose was to further expand the scope of N-nucleophilic substrates suitable for the alkylation
proceeding with thiirane-thietane rearrangement. N-Arylcyanamides have acidities similar to those of both phenols
and N-arylsulfamides and are soluble in aqueous alkali metal hydroxides; they have also been successfully
alkylated under various conditions [10, 11]. We therefore expected them to exert similar nucleophilic behavior
towards (chloromethyl)thiirane.
Several synthetic approaches to N-arylcyanamides, which are generally not commercially available,
have been reported in the literature. Desulfurization of arylthioureas in aqueous base requires stoichiometric
amounts of a heavy metal salt (usually Pb(OAc)2 [12], but mercury(II) [13], copper(II) [14] or silver(I) [15] salts
may be used instead), which is both toxic and possess significant danger to the environment. Direct cyanation of
anilines involves the use of highly toxic cyanogen bromide or chloride [11, 16, 17], or alkali metal cyanides
[18, 19]. Aryl isothiocyanates also afford N-arylcyanamides in high yields when treated with NaHMDS in THF
at room temperature [20]. More recently, an efficient method for the synthesis of 1-aryltetrazoles has been
proposed [21]. The latter compounds produce N-arylcyanamides when treated with KOH in DMSO [22, 23].
The series of N-arylcyanamides 1a-k was prepared using either of these methods. Many of the
compounds 1a-k were found to have limited stability at room temperature, gradually forming products that were
insoluble in aqueous alkali (likely dimers or polymers [24, 25]), and were therefore either used immediately
upon drying or stored only briefly in the freezer.
Alkylation of N-arylcyanamides 1a-k with (chloromethyl)thiirane in aqueous potassium hydroxide over
48 h resulted in formation of the target N-aryl-N-(thietan-3-yl)cyanamides 2a-k in moderate to good yields
(Tables 1, 2).
CN
N
KOH, H2O
rt, 48 h
Cl
ArNHCN
+
Ar
34–76%
S
S
1a–k
2a–k
a Ar = Ph, b Ar = 2,6-Me2C6H3, c Ar = 4-MeOC6H4, d Ar = 1-naphthyl, e Ar = 2-ClC6H4,
f Ar = 4-ClC6H4, g Ar = 4-BrC6H4, h Ar = 3-FC6H4, i Ar = 2-O2NC6H4,
j Ar = 3-O2NC6H4, k Ar = 4-O2NC6H4
The products 2a,b are viscous colorless oils, compounds 2c-k are crystalline solids, and all are stable at
room temperature.
1510

TABLE 1. Characteristics of the Synthesized N-Aryl-N-(thietan-
3-yl)cyanamides 2a-k
Compound
Empirical formula
mp, C
Yield, %
Appearance
2a
2b
2c
2d
2e
2f
C10H10N2S
—
—
72
34
59
38
63
76
69
74
44
59
38
Yellowish oil
C12H14N2S
Colorless oil
C11H12N2OS
C14H12N2S
67–68
Colorless crystals
Colorless crystals
Colorless crystals
Colorless crystals
Colorless crystals
Colorless crystals
Yellow crystals
Yellow crystals
Yellow crystals
114–115
48–50
C10H9N2SCl
C10H9N2SCl
C10H9BrN2S
C10H9N2FS
C10H9N3O2S
C10H9N3O2S
C10H9N3O2S
104–105
116–117
65–66
2g
2h
2i
79–80
2j
98–99
2k
167–168
TABLE 2. NMR Spectra of Cyanamides 2a-k
Com-
pound
13C NMR spectrum,
δ, ppm (JC–F, Hz)
1H NMR spectrum, δ, ppm (J, Hz)
2a
2b
2c
2d
3.23-3.32 (2H, m, CH2); 3.69-3.79 (2H, m, CH2);
4.87-5.01 (1H, m, CHN); 7.00-7.13 (3H, m, H-2,4,6);
7.27-7.36 (2H, m, H-3,5)
34.2; 54.2; 111.8; 117.1;
125.0; 130.3; 139.3
2.30 (6H, s, Me); 3.21-3.28 (2H, m, CH2);
3.88-3.95 (2H, m, CH2); 4.24-4.35 (1H, m, CHN);
7.04-7.09 (2H, m, H-3,5); 7.10-7.15 (1H, m, H-4)
18.1; 34.9; 58.5; 112.8;
128.6; 129.0; 135.5, 137.1
3.23-3.32 (2H, m, CH2); 3.72-3.82 (2H, m, CH2);
3.76 (3H, s, MeO); 4.77-4.91 (1H, m, CHN);
6.83-6.91 (2H, m, H-2,6); 6.97-7.05 (2H, m, H-3,5)
34.2; 55.7; 56.0; 112.8;
115.5; 120.1; 132.5, 157.6
3.25-3.35 (2H, m, CH2); 3.90-4.00 (2H, m, CH2);
4.68-4.82 (1H, m, CHN); 7.37-7.50 (2H, m, H Ar);
7.54-7.67 (2H, m, H Ar); 7.82-8.00 (3H, m, H Ar)
34.5; 59.2; 114.2; 122.2;
123.3; 125.9; 127.5; 128.0;
129.0; 129.2; 129.5; 135.1;
135.9
2e
2f
3.25-3.32 (2H, m, CH2); 3.84-3.91 (2H, m, CH2);
4.63-4.73 (1H, m, CHN); 7.27-7.34 (3H, m H Ar);
7.45-7.50 (1H, m, H-3)
34.2; 58.2; 112.3; 127.0; 128.3;
129.5; 130.5; 131.2; 136.5
3.28-3.36 (2H, m, CH2); 3.76-3.85 (2H, m, CH2);
4.89-5.00 (1H, m, CHN); 6.98-7.05 (2H, m, H-2,6);
7.29-7.36 (2H, m, H-3,5)
33.5; 53.9; 110.8; 117.9;
129.8; 129.9; 137.4
2g
2h
3.27-3.36 (2H, m, CH2); 3.75-3.83 (2H, m, CH2);
4.89-5.00 (1H, m, CHN); 6.92-6.98 (2H, m, H-2,6);
7.42-7.49 (2H, m, H-3,5)
33.5; 53.8; 110.7; 117.3;
118.1; 132.7; 137.9
3.33-3.39 (2H, m, CH2); 3.81-3.88 (2H, m, CH2);
4.95-5.05 (1H, m, CHN); 6.79-6.92 (3H, m, H-2,4,6);
7.31-7.39 (1H, m, H-5)
33.5; 53.7; 104.2 (26.7);
110.6; 111.4 (21.4);
111.9 (3.1); 131.3 (9.5);
140.4 (9.9); 163.4 (248.3)
2i
3.26-3.33 (2H, m, CH2); 3.82-3.92 (2H, m, CH2);
4.57-4.67 (1H, m, CHN);
34.4; 59.2; 111.4; 126.3; 127.5;
129.1; 133.0; 134.7; 144.0
7.43 (1H, dd, J = 1.2, J = 7.9, H-6);
7.51 (1H, dt, J = 1.2, J = 7.9, H-4);
7.69 (1H, dt, J = 1.2, J = 7.9, H-5);
8.01 (1H, dd, J = 1.2, J = 7.9, H-3)
2j
3.37-3.44 (2H, m, CH2); 3.81-3.89 (2H, m, CH2);
5.05-5.15 (1H, m, CHN); 7.45-7.50 (1H, m, H-6);
7.59 (1H, t, J = 8.3, H-5); 7.89 (1H, t, J = 2.5, H-2);
7.97-8.02 (1H, m, H-4)
33.4; 53.6; 109.8; 110.7; 119.1;
122.2; 131.0; 140.0; 149.0
2k
3.36-3.44 (2H, m, CH2); 3.82-3.89 (2H, m, CH2);
5.08-5.18 (1H, m, CHN); 7.18-7.24 (2H, m, H-2,6);
8.24-8.30 (2H, m, H-4,5)
33.3; 53.3; 109.3; 115.8; 125.8;
143.8; 144.0
1511

Thietanes 2a,b were oxidized to crystalline sulfones 3a,b using hydrogen peroxide in acetic acid in the
presence of Na2WO4 catalyst:
30% H2O2 (10 equiv.)
Na2WO4 (cat.)
AcOH, rt, 15 h
CN
N
2a,b
Ar
SO2
3a,b
3 a Ar = Ph (86%), b Ar = 2,6-Me2C6H3 (75%)
Serious problems were previously encountered when N-nucleophiles bearing strong electron-
withdrawing group were alkylated with (chloromethyl)thiirane. Thus, almost no thietanes were formed in the
reactions of N-(4-nitrophenyl)methanesulfonamide or benzenesulfonamides with (chloromethyl)thiirane [8]. In
the same manner, 5-nitroisatin was not alkylated by this reagent in aqueous media [9]. Fortunately, the presence
of an electron-withdrawing group conjugated with the reaction center does not show such pronounced effect on
the reaction with N-arylcyanamides. For this reason, we have decided to reinvestigate the thietanylation of
nitrophenols 4a–e under identical conditions. As shown in the scheme below, this reaction provides the
corresponding 3-(aryloxy)thietanes 5a–e in acceptable yields:
KOH, H2O
rt, 48 h
Cl
ArO
S
ArOH
+
19–45%
S
4a–e
5a–e
a Ar = 2-O2NC6H4, b Ar = 3-O2NC6H4, c Ar = 4-O2NC6H4,
d Ar = 5-Me-2-O2NC6H3, e Ar = 3-Me-4-O2NC6H3
We have shown the synthetic utility of the thiethanylation reaction for N-arylcyanamides and electron-
deficient phenols. These substrates provide convenient access to novel thietane derivatives. Further studies on the
synthetic approaches to thietanes, their ring opening reactions and their possible applications in medicinal
chemistry are currently underway.
EXPERIMENTAL
The 1H and 13C NMR spectra were recorded on a Bruker DPX-300 spectrometer in CDCl3 using CHCl3
residual signal (δ 7.26 ppm) as internal standard for 1H NMR and CHCl3 (δ 77.0 ppm) for 13C NMR. Elemental
analyses were performed on a Hewlett-Packard HP-185B CHN-analyzer. Low resolution mass spectra (EI
TABLE 3. Characteristics of the Synthesized 3-(Aryloxy)thietanes 5a–e
Com-
pound
Empirical
formula
Found, m/z
Calculated, m/z
mp, C
Yield, %
Appearance
211.0294 [M]+
211.0303
5a
5b
C9H9NO3S
C9H9NO3S
44-45
57-58
35
33
Yellowish crystals
Yellowish crystals
211.0305 [M]+
211.0303
5c
5d
5e
C9H9NO3S
C10H11NO3S
C10H11NO3S
211.0306 [M]+
211.0303
99-100
86-87
63-64
39
45
19
Yellowish flakes
Yellowish crystals
Yellowish crystals
248.0352 [M+Na]+
248.0357
473.0811 [2M+Na]+
473.0817
1512

TABLE 4. NMR Spectra of 3-(Aryloxy)thietanes 5a–e
Com-
pound
1H NMR spectrum, δ, ppm (
J, Hz)
13C NMR spectrum, δ, ppm
5a
3.33-3.43 (2H, m, CH2); 3.60-3.68 (2H, m, CH2);
5.31-5.42 (1H, m, CHO); 6.93 (1H, d, = 8.3, H-6);
7.06 (1H, t, = 7.7, H-4); 7.45-7.53 (1H, m, H-5);
35.2; 72.4; 115.3; 121.3;
125.7; 134.0; 140.1; 149.4
J
J
7.78-7.83 (1H, m, H-3)
5b
3.38-3.45 (2H, m, CH2); 3.53-3.60 (2H, m, CH2);
5.30-5.39 (1H, m, CHO);
35.0; 71.6; 109.3; 116.3;
121.7; 130.2; 149.0; 156.6
7.13 (1H, ddd,
7.42 (1H, t, = 8.3, H-5); 7.60 (1H, t,
7.81 (1H, ddd, = 0.8, = 2.5, = 8.3, H-4)
J
= 0.8,
J
= 2.5,
J
= 8.3, H-6);
J
J
= 2.5, H-2);
J
J
J
5c
3.36-3.45 (2H, m, CH2); 3.52-3.62 (2H, m, CH2);
5.31-5.42 (1H, m, CHO); 6.81-6.89 (2H, m, H-2,6);
8.10-8.18 (2H, m, H-3,5)
34.9; 71.5; 114.7; 125.9;
141.7; 161.0
5d
2.38 (3H, s, CH3); 3.35-3.41 (2H, m, CH2);
3.60-3.67 (2H, m, CH2); 5.30-5.39 (1H, m, CHO);
21.8; 35.3; 72.4; 115.9; 122.0;
125.9; 137.6; 145.7; 149.7
6.70 (1H, s, H-6); 6.84 (1H, d,
7.74 (1H, d, = 8.0, H-3)
J = 8.0, H-4);
J
5e
2.59 (3H, s, CH3); 3.38-3.49 (2H, m, CH2);
3.53-3.60 (2H, m, CH2); 5.30-5.40 (1H, m, CHO);
6.66-6.72 (2H, m, H-2,6); 8.01-8.06 (1H, m, H-5)
21.6; 35.0; 71.4; 112.5; 118.3;
127.6; 137.2; 142.5; 159.5
ionization, 70 eV) were obtained on an MKh-1321 instrument. High-resolution mass spectra (ESI or FAB) were
obtained on an IonSpec Fourier transform mass spectrometer. All melting points are uncorrected. Reactions
were monitored by thin-layer chromatography carried out on Macherey-Nagel ready-to-use plates AluGram
Alox N/UV254 using UV visualization or basic KMnO4 solution as a developing agent. Silica gel SiliCycle (60
mesh) was used for flash chromatography. All reagents and solvents were commercially available and were used
as supplied without additional purification.
The starting N-arylcyanamides 1a–k were synthesized according to literature methods (1a [11], 1b [26],
1c,f,g [17], 1d [23], 1e [12], 1h [27], 1i [28], 1j,k [20]).
Preparation of N-aryl-N-(thietan-3-yl)cyanamides 2a–k (General Method). The corresponding
N-arylcyanamide 1a–k (20 mmol) was added in one portion to a stirred solution of KOH (1.35 g, 24 mmol) in
water (80 ml). Then (chloromethyl)thiirane (2.40 g, 22 mmol) was added in one portion to the resulting solution,
and the reaction mixture was stirred at room temperature for 48 h. After that, CHCl3 (100 ml) was added, the
organic layer was separated, and the aqueous layer was extracted with CHCl3 (2×30 ml). The combined organic
phases were washed with 5% aqueous NaOH (2×50 ml), 100 ml water and 50 ml brine, and dried over MgSO4.
The solution was passed through a plug of silica gel (2 cm) eluting with CHCl3 (200 ml). The solvent was
removed on a rotary evaporator (bath temperature < 50°С) under reduced pressure, and the residue was
recrystallized from CHCl3–hexane (2c–k) or dried at 1 mm Hg (2a,b).
N-Phenyl-N-(thietan-3-yl)cyanamide (2a). Mass spectrum, m/z (Irel, %): 190 [M]+ (21), 144 (8), 104
(12), 91 (8), 77 (21), 73 (100), 65 (9), 51 (14), 45 (51), 39 (18).
N-(2,6-Dimethylphenyl)-N-(thietan-3-yl)cyanamide (2b). Found, m/z: 241.0770 [M+Na]+.
C12H14N2NaS. Calculated, m/z: 241.0775.
N-(4-Methoxyphenyl)-N-(thietan-3-yl)cyanamide (2c). Mass spectrum, m/z (Irel, %): 220 [M]+ (14),
174 (5), 147 (7), 73 (100), 45 (43), 39 (9). Found, %: C 60.09; H 5.65; N 12.65. C11H12N2OS. Calculated, %:
C 59.98; H 5.49; N 12.72.
N-(1-Naphthyl)-N-(thietan-3-yl)cyanamide (2d). Mass spectrum, m/z (Irel, %): 240 [M]+ (20), 115
(13), 73 (100), 45 (18). Found, %: C 70.06; H 5.06; N 11.78; C14H12N2S. Calculated, %: C 69.97; H 5.03;
N 11.66.
N-(2-Chlorophenyl)-N-(thietan-3-yl)cyanamide (2e). Found, m/z: 224.0174 [M]+. C10H9ClN2S.
Calculated, m/z: 224.0175.
1513

N-(3-Fluorophenyl)-N-(thietan-3-yl)cyanamide (2h). Found, m/z: 208.0467 [M]+. C10H9FN2S.
Calculated, m/z: 208.0470.
N-(3-Nitrophenyl)-N-(thietan-3-yl)cyanamide (2j). Found, m/z: 258.0308 [M+Na]+. C10H9N3NaO2S.
Calculated, m/z: 258.0313.
Preparation of Sulfones 3a,b (General Method). Na2WO4·2H2O (20 mg) was dissolved in a minimal
amount of water, and the resulting solution was added to a stirred solution of cyanamide 2a,b (5.3 mmol) in
20 ml glacial acetic acid. Then 30% aqueous H2O2 (6.0 g, 53.0 mmol) was added over 5 min, and the reaction
mixture was stirred for 15 h and poured into 120 ml cold water. The crude product was filtered off, washed with
water, and dried in air. Pure sulfones 3a,b were obtained by reprecipitation from CHCl3 solution with hexane.
N-(1,1-Dioxothietan-3-yl)-N-phenylcyanamide (3a). Yield 1.01 g (86%). Colorless crystals, mp
1
127-128°C. H NMR spectrum, δ, ppm: 4.43–4.75 (5H, m, 2CH2, CHN); 7.07–7.16 (2H, m, H-2,6); 7.20–7.30
13
(1H, m, H-4); 7.34–7.50 (2H, m, H-3,5). C NMR spectrum, δ, ppm: 39.7; 69.9; 110.8; 117.7; 126.1; 130.7;
138.6. Mass spectrum, m/z (Irel, %): 222 [M]+ (25), 144 (100), 118 (15), 117 (16), 104 (77), 91 (21), 77 (62), 65
(31), 51 (35), 41 (93), 39 (84). Found, %: C 53.99; H 4.52; N 12.62. C10H10N2O2S. Calculated, %: C 54.04;
H 4.53; N 12.60.
N-(2,6-Dimethylphenyl)-N-(1,1-dioxothietan-3-yl)cyanamide (3b). Yield 0.99 g (75%). Colorless
crystals, mp 168–170°C (subl. above 150 °C). 1H NMR spectrum, δ, ppm (J, Hz): 2.37 (6H, s, CH3); 4.31–4.45
(5H, m, 2CH2, CHN); 7.13 (2H, d, J = 7.5, H-3,5); 7.21 (1H, t, J = 7.5, H-4). 13C NMR spectrum, δ, ppm: 18.3;
42.4; 68.9; 112.1; 129.6; 129.7; 135.0; 136.3. Found, m/z: 251.0849 [M+H]+. C12H15N2O2S. Calculated, m/z:
251.0854.
Preparation of 3-(aryloxy)thietanes 5a–e. These compounds were prepared in accordance with the
general procedure from the corresponding nitrophenols 4a–e. For physical properties of compounds 5a–e, see
Tables 3 and 4.
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