T. Suyama et al.
Bull. Chem. Soc. Jpn., 78, No. 5 (2005)
875
Table 3. Preparation of 4
of crystals was obtained after concentration of the filtrate.
3-Cyano-2-ethyl-1-phenylisourea (2a). Yield: 72%. Needles
(EtOH). Mp 122–123 ꢁC (lit.7 126–127 ꢁC). IR (KBr) 3161, 2200,
Starting
X
R
Product and yield/%
1643, and 1037 cmꢂ1
.
1H NMR (CDCl3) ꢀ 1.37 (3H, t, J ¼ 7:1
materials
10a
1aa)
10b
1ba)
1ca)
11a
SMe
Ph
Ph
4a
4a
4b
4b
4c
4a
87
88
91
86
65
92b)
Hz, CH3), 4.49 (2H, q, J ¼ 7:1 Hz, CH2), 7.22–7.40 (5H, m,
Ph), 7.62 (1H, b, NH). MS (70 eV) m=z 189 (M).
1-Benzyl-3-cyano-2-ethylisourea (2b). Yield: 86%. Needles
PhCH2
PhCH2
Bu
(H2O). Mp 90–91 ꢁC. IR (KBr) 3251, 2188, 1626, and 1045 cmꢂ1
.
1H NMR (CDCl3) ꢀ 1.32 (3H, t, J ¼ 7:1 Hz, CH3), 4.31 (2H, q,
J ¼ 7:1 Hz, CH2), 6.14 (1H, b, NH), 7.25–7.37 (5H, m, Ph).
HRMS (EI): calcd for C8H15N3O 169.1215, found 169.1220.
1-Butyl-3-cyano-2-ethylisourea (2c). Yield: 90%. granules
(toluene). Mp 43–44 ꢁC. IR (KBr) 3240, 2193, 1637, and 1041
OEt
Ph
a) Bis-silyl compound (10) was not isolated before methanol-
ysis. b) Methanolysis was performed in the presence of NaOH.
When methanolysis was carried out in the absence of NaOH,
83% yield of 7 was isolated.
cmꢂ1
.
1H NMR (CDCl3) ꢀ 0.93 (3H, t, J ¼ 7:3 Hz, CH3), 1.32
(3H, t, J ¼ 7:1 Hz, CH3), 1.36 (2H, tq, J ¼ 7:3, 6.3 Hz, CH2),
1.54 (2H, tt, J ¼ 6:3, 6.3 Hz, CH2), 3.24 (2H, q, J ¼ 6:3 Hz,
N-CH2), 4.28 (2H, q, J ¼ 7:1 Hz, O-CH2), 6.14 (1H, s, NH).
HRMS (EI): calcd for C11H13N3O 203.1059, found 203.1062.
General Procedure for Preparation of 3 in the Presence of
Alkali. To a solution of hydroxylamine hydrochloride (2.15 g,
0.03 mol) in water (5 mL) was added a solution of 97% sodium
hydroxide (0.03–0.05 mol) in ethanol (20 mL). After stirring for
15 min, the precipitated sodium chloride was filtered off. To the
filtrate was added 0.01 mol of 2 and the mixture was allowed to
stand for 2–24 h at 30 ꢁC. After neutralization by adding acetic
acid, the solvent was removed in vacuo and the residue was re-
crystallized to afford oxadiazole 3. Yields are summarized in
Table 1. The products were identified with regard to physical
and spectral data (mp, IR, MS) by comparison with those report-
ed.2
3a: Mp 182–183 ꢁC (lit.2 183–184 ꢁC). 1H NMR (300 MHz,
DMSO) ꢀ 6.85 (2H, t, J ¼ 8:1 Hz, Ph), 7.23 (2H, t, J ¼ 8:1 Hz,
Ph), 7.39 (2H, d, J ¼ 8:1 Hz, Ph), 7.58 (2H, s, NH2), 9.20 (1H,
s, NH). 13C NMR (75 MHz, DMSO) ꢀ 116.97, 120.40, 128.92,
140.85, 165.57, 169.83.
3b: Mp 177–178 ꢁC (lit.2 179–181 ꢁC). 1H NMR (300 MHz,
DMSO) ꢀ 4.17 (2H, d, J ¼ 6:3 Hz, Ph), 6.74 (1H, t, J ¼ 6:3
Hz, NH), 7.17–7.33 (7H, m, Ph, NH2). 13C NMR (75 MHz,
DMSO) ꢀ 45.85, 126.82, 127.33, 128.32, 140.33, 168.91, 170.38.
3c: Mp 92–93 ꢁC (lit.2 90–93 ꢁC). 1H NMR (300 MHz, DMSO)
ꢀ 0.85 (3H, t, J ¼ 7:3 Hz, CH3), 1.27 (2H, tq, J ¼ 7:3 Hz, 7.3 Hz,
CH2), 1.43 (2H, tt, J ¼ 7:3, 7.3 Hz, CH2), 2.92 (2H, dt,
J ¼ 5:9{7:3, 7.3 Hz, CH2), 6.07 (1H, t, J ¼ 5:9 Hz, NH), 7.25
(2H, s, NH2). 13C NMR (75 MHz, DMSO) ꢀ 13.95, 19.80,
31.39, 42.07, 168.94, 170.22.
good yield as expected.
The one-pot conversion of 1 to 4 was also achieved without
isolation of 10 or 11 (Table 3). In addition, even in the case of
1c in which the bis-silyl compound (10) was not obtained, the
corresponding oxadiazole 4c could be obtained.
In conclusion, we have developed a method for regioselec-
tive preparation of 3,5-diamino-1,2,4-oxadiazole bearing a
substituent on one or the other amino group by the reaction
of 2 with hydroxylamine in the presence of alkali, or the reac-
tion of 1 or 2 with 9 and subsequent methanolysis.
Experimental
General. Commercially available reagent-grade solvents were
used after purification by distillation. The reactions using trimeth-
ylsilyl compounds are carried out under nitrogen atmosphere.
The melting points were determined on a Yamato Mp Aparatus
Model Mp-21. The 1H and 13C NMR was recorded on a JEOL
JNM-LA300; tetramethylsilane (TMS) was used as an internal
standard. The IR spectra were determined on a Hitachi 260-10
spectrophotometer. MS and high resolution MS spectra were
measured on a Shimadzu GCMS-QP 1000A and a Hitachi M-
80B, respectively. HPLC analysis was performed under the fol-
lowing conditions: column, shim-Pack CLC-SIL; eluent, dichloro-
methane/methanol (9/1, v/v); flow rate, 1 mL minꢂ1; detect,
230 nm.
Preparation of 1-Substituted 3-Cyano-2-methylisothioureas
(1). Compounds 1 were readily prepared from cyanamide by im-
proving the previous methods.5,6 To a solution of 0.20 mol of cy-
anamide and 0.40 mol of aqueous sodium hydroxide in acetone
(100 mL) was added dropwꢁise 0.24 mol of carbon disulfide with
vigorous stirring below 10 C. After the mixture was stirred for
1.5 h, methyl iodide (0.40 mol) was added dropwise with stirring
below 10 ꢁC and the mixture was stirred for 2.5 h at rt. To the
resulting solution of dimethyl N-cyanoimidodithiocarbonate was
added 0.20 mol of amine, and then the mixture was allowed to
stand overnight. A precipitate was collected by filtration and
recrystallized. The second crop of crystals was obtained after
concentration of the filtrate.
The Reaction of 2a with Hydroxylamine under Neutral
Conditions. A similar reaction procedure similar to that describ-
ed above was carried out using 0.01 mol of 2a, 0.03 mol of hy-
droxylamine hydrochloride, and 0.03 mol of sodium hydroxide.
The solvent was removed in vacuo and the residue was extracted
with 20 mL ꢃ 2 of ethyl acetate. This solution was found to con-
tain 14% of 4a, 52% of 7, and 13% of 8 by HPLC analysis (see
Table 1, Run 1).
Reaction of 1 or 2 with N,O-Bis(trimethylsilyl)hydroxyl-
amine (9). To a solution of 1a, 1b, or 2a (20 mmol) in carbon
tetrachloride (30 mL) was added 98 (30 mmol) and the mixture
was refluxed for 3–12 h. The solvent was removed under reduced
pressure and the residue was recrystallized from hexane to afford
the corresponding 10 or 11 as needles. Reaction time and yields
are summarized in Table 2.
1a (R ¼ Ph): 58%. Flakes (EtOH). Mp 191–192 C (lit.6 191
ꢁ
ꢁC). 1b (R ¼ PhCH2): 75%. Needles (EtOH). Mp 156–157 ꢁC
(lit.6ꢁ157 ꢁC). 1c (R ¼ n-Bu): 70%. Flakes (toluene). Mp 121–
ꢁ
122 C (lit.6 122 C).
Preparation of 1-Substituted 3-Cyano-2-ethylisoureas (2).
A methanolic solution of O-ethyl S-methyl N-cyanoimodothiocar-
bonate5 and amine was refluxed for 1 h. After cooling, a precipi-
tate was collected by filtration and recrystallized. The second crop
2-Methyl-3-[N-trimethylsilyl-N0-(trimethylsilyloxy)amidino]-
ꢁ
1-phenylisothiourea 10a. (R ¼ Ph): Mp 111–112 C. IR (KBr)