Regiospecific alkylation of 5-substituted 2-acylamino-1, 3,4-thiadiazoles

Article abstract of DOI:10.3987/com-00-9147

5-Substituted 2-acylamino-1,3,4-thiadiazoles (2 and 3b) are quantitatively and regiospecifically alkylated with alkyl bromide at the 3-position nitrogen (endo-products) rather than at the 2-position amide-nitrogen (exo-products) under basic conditions. Th

Full text of DOI:10.3987/com-00-9147

HETEROCYCLES, Vol.55, No.3, pp.579 - 587, Received, 19th December, 2000
REGIOSPECIFIC ALKYLATION OF 5-SUBSTITUTED 2-ACYLAMINO-
1,3,4-THIADIAZOLES
Nam Sook Cho,*a Hye Jeong Hwang,a Jin-Gyu Kim,b and Il-Hwan Suh b
aDepartment of Chemistry, and bDepartment of Physics, Chungnam National University,
Taejon, 305-764, Korea
Abstract- 5-Substituted 2-acylamino-1,3,4-thiadiazoles (2 and 3b) are quantita-
tively and regiospecifically alkylated with alkyl bromide at the 3-position nitrogen
(endo-products) rather than at the 2-position amide-nitrogen (exo-products) under
basic conditions. This alkylation required more than 1.5 equivalents of base and
more than four equivalents of alkyl bromide. The structures of the products,
5-substituted 2-acylimino-3-alkyl-1,3,4-thiadiazolines (4 and 5b2), were clearly
established by spectroscopic data. Especially, the structure of 3-ethyl-5-ethylthio-
2-p-toluoylimino-1,3,4-thiadiazoline (4d1) was proven by X-Ray crystallography.
INTRODUCTION
2-Amino-1,3,4-thiadiazoles have received much attention in view of their biological1 and analytical2
interest. 2-Amino-1,3,4-thiadiazoles are ambident compounds; thus, their acylation and alkylation might
take place at either the exocyclic NH2 or the endocyclic NH, depending on reaction conditions.3
Acetylation and tosylation of 2-monosubstituted amino-1,3,4-thiadiazoles have been reported.4 Both
reactions eventually resulted in the same exocyclic products, although the two pathways are quite different.
Acetylation gave 2-acylamino-1,3,4-thiadiazoles directly; while, tosylation yielded 3-tosyl-2-imino-
1,3,4-thiadiazoles and these endo-products were isomerized to the final exo-products. In contrast,
methylation of 2-acylamino-1,3,4-thiadiazoles yielded isomeric mixtures of exo- and endo-N-methylated
products, as expected.5 To prepare 2-acylimino-3-methyl-1,3,4-thiadizoline-5-sulfonamides to test their
biological activities,1f,5 2-acylamino-5-benzylthio-1,3,4-thiadiazoles were methylated, although the yields
were rather low. Most studies of 2-amino-1,3,4-thiadiazoles deal with their synthesis, while very little is
known about their reactivity. To gain more insight into the selectivity of the alkylation reaction of
2-acylamino-1,3,4-thiadiazoles, we decided to examine the alkylation of 2-acylamino-5-ethylthio-
1,3,4-thiadiazoles (2) and 2-benzoylamino-5-ethoxy-1,3,4-thiadiazole (3b) under basic conditions.

RESULT AND DISCUSSION
The substrates chosen for the alkylation study were 2-acylamino-5-ethylthio-1,3,4-thiadiazole (2)1f, 6 and
2-benzoylamino-5-ethoxy-1,3,4-thiadiazole (3b).7-9 To prepare the starting materials, the acylations of
2-amino-5-ethylthio-1,3,4-thiadiazole (1a) and 2-amino-5-ethoxy-1,3,4-thiadiazole (1b) were examined.
Identical reactions took place at the 2-position NH2 (exo-products), with quantitative yields like reactions
of 2-monosubstituted amino-5-phenyl-1,3,4-thiadiazoles,4 as shown in Scheme 1. The structure of the
acylated product of 1b was proven by comparison of spectroscopic data.9 The spectrogram of an acylated
product, 2-benzoylamino-5-ethoxy-1,3,4-thiadiazole (3b), was identical with the reported one. The
structure of the acylated product of 1a was confirmed via X-Ray crystallography. The structure of
5-ethylthio-2-p-toluoylamino-1,3,4-thiadiazoline (2d) shown in Figure 1 was clearly proven. The
chemical shifts of the 13C NMR peaks of 1a and 2d were assigned via HMBC (heteronuclear multiple
bond coupling), as shown in Scheme 2.
R3
N
N
O
N
N
O
N
N
ii
i
R1
NH2
N
R2
S
1
R1
S
N
R2
R1
S
4, 5
H
2, 3
4a1 R1 = SEt R2 = Me R3 = Et
1a R1 = SEt
1b R1= OEt
2a R1 = SEt R2 = Me
2b R1 = SEt R2 = C6H5
2c R1 = SEt R2 = p-NO2-C6H4
2d R1 = SEt R2 = p-Me-C6H4
3b R1 = OEt R2 = C6H5
4b1 R1 = SEt R2 = C6H5 R3 = Et
4b2 R1 = SEt R2 = C6H5 R3 = Pr
4c1 R1 = SEt R2 = p-NO2-C6H4 R3 = Et
4c2 R1 = SEt R2 = p-NO2-C6H4 R3 = Pr
4d1 R1 = SEt R2 = p-Me-C6H4 R3 = Et
4d2 R1 = SEt R2 = p-Me-C6H4 R3 = Pr
5b2 R1 = OEt R2 = C6H5 R3 = Pr
Scheme 1. Reagents: i. R2COCl, TEA; THF; ii. R3Br, base.
The selective alkylation of 21f, 6 and 3b7-9 was investigated under various basic conditions as shown in
Table 1. The purity of the products was checked by HPLC. Surprisingly, under all basic conditions
studied, alkylation yielded a single 3-alkylated endo-product. The alkylation product of 5-ethylthio-2-p-
toluoylamino-1,3,4-thiadiazole (2d) was identified as 3-ethyl-5-ethylthio-2-p-toluoylimino-1,3,4-thiadia-
zoline (4d1) by X-Ray crystallography (Figure 2). To alkylate 2 and 3b quantitatively, the base excess
required is more than 1.5 equivalents and the alkyl halide required an excess of more than 4 equivalents as
shown in Table 1. Under these conditions, the alkylated products are afforded quantitatively.
The structures of the products (2-acylimino-3-alkyl-5-ethylthio-1,3,4-thiadiazolines (4) and 2-benzoyl-
1
imino-5-ethoxy-3-propyl-1,3,4-thiadiazoline (5b2)) were verified by IR, H and 13C NMR spectra. In the
case of 2-benzoylimino-5-ethylthio-3-propyl-1,3,4-thiadiazoline (4b2), the IR spectrum is typically
characterized by an imido group with strong bands at 1605 cm-1 that are shifted to a shorter wave number
than those of the amide (1656 cm-1) of the starting material (2b).5 The same trend is apparent in
2-benzoylimino-3-propyl-5-ethoxy-1,3,4-thiadizoline (5b2); in the IR spectrum, the imido group is seen at

O
Pr
165.7
N
N
N
N
N
O
N
N
151.2
EtS
161.6
N
H
160.3
EtS
170.6
NH2
155.4
EtS
Ph
S
S
Ph
S
165.5
174.2
1605 cm-1
1656 cm-1
4b2
1a
2b
Pr
O
O
N
N
N
N
N
N
163.2
165.2
EtO
164.9
EtO
162.2
NH2
155.6
171.1
EtO
N
Ph
165.4
1674 cm-1
N
174.0
Ph
S
S
S
H
1606 cm-1
1b
3b
5b2
Scheme 2. δH (300 MHz; DMSO-d6; Me4Si), ν ( KBr pellet).
Table 1. Propylation depending on reaction conditions.
Starting Material
Solvent
Base (eq.)
Eq. Of PrBr
Yield (%)
2b
EtOH
EtOH
EtOH
EtOH
EtOH
KOH (1.5)
KOH (1.5)
KOH (2.0)
KOH (1.5)
Cs2CO3 (1.5)
2.0
4.0
85
90
91
97
4.0
Excess
Excess
99 (93)a
98
EtOH
THF
Li2CO3 (1.5)
Et3N (1.5)
Et3N (1.5)
KOH (1.5)
Excess
4.0
72
THF
Excess
4.0
96
85 (78)a
92
3b
EtOH
EtOH
EtOH
KOH (1.5)
Excess
Excess
Li2CO3 (1.5)
99
a Yields in parentheses are isolated ones .
1606 cm-1, which is shifted to a shorter wave number than the amide (1674 cm-1) of 2-benzoyl-
amino-5-ethoxy-1,3,4-thiadizole (3b). The 13C NMR spectra of 4b2 and 5b2 were assigned by HMBC as
shown in Scheme 2. The chemical shifts of C(2), C(5), and the carbonyl carbon of 2-benzoylimino-
5-ethylthio-3-propyl-1,3,4-thiadiazoline (4b2) appear at 165.7, 155.4, and 174.2 ppm, respectively. If the
alkylation takes place at the 2-position (exo-product), the chemical shifts of C(2) and C(5) of the product
are more or less similar to the chemical shifts of 2-benzoylamino-5-ethylthio-1,3,4-thiadiazole (2b).
However, the chemical shifts of C(2) of the alkylated products are shifted at a lower field than the amide
starting material by 5 ppm.5 The same trend is also demonstrated between 2-benzoylimino-5-ethoxy-
3-propyl-1,3,4-thiadiazoline (5b2) and 2-benzoylimino-5-ethoxy-1,3,4-thiadiazole (3b). The chemical
shifts of C(2), C(5), and the carbonyl carbon of 5b2 appear at 163.2, 165.2, and 174.0 ppm, respectively.

Figure 1. The molecular structure of
5-ethylthio-2-p-toluoylamino-1,3,4-
thiadiazole (2d), showing the atomic
numbering used for the crystallographic
analysis.
The chemical shift of C(2) of the alkylated product is 6 ppm lower than that of the starting material.
These identical spectroscopic trends, including the IR spectral data, the hypothesis that the alkylation of
2-benzoylamino-5-ethoxy-1,3,4-thiadiazole (3b) takes place exclusively at the 3-position of nitrogen, like
that of 2-acylamino-5-ethylthio-1,3,4-thiadiazole (2).
Figure 2. The molecular structure of
3-ethyl-2-ethylthio-5-p-toluoylimino-1,3,4-
thiadiazoline (4d1), showing the atomic
numbering used for the crystallographic analysis
EXPERIMENTAL
All melting points were determined on an electrically heated Thomas-Hoover capillary melting point
apparatus and were uncorrected. The IR spectra were recorded on a Jasco Report-100 spectrophotometer.
1
13
The H and C NMR spectra were obtained using a IBM-Bruker DRX 300 spectrometer (Korea Basic
Science Institute, Taeduk, Taejon) at 300 MHz and 75 MHz respectively with tetramethylsilane as
internal reference. The progresses of reaction and purity of products were traced with TLC and HPLC.
Analytical RP-HPLC was performed to check the purity of products on µ Bondapak C18 column (3.9 x
300 mm, 10 µm) using Waters 510 pump and UV detector (λ = 254 nm). Elution condition; MeOH :
CH3CN = 5 : 95 (v/v), flow rate 0.5 mL/min. 2-Amino-5-ethylthio-1,3,4-thiadiazole (1a)6,10 and
2-amino-5-ethoxy- 1,3,4-thiadiazole (1b)8,9 was prepared as previously reported.
2-Amino-5-ethylthio-1,3,4-thiadiazole (1a).10 mp 136-138 °C (lit.,6 133 °C, lit.,10 134-136 °C ), Rf 0.59
(n-hexane : ethyl acetate : EtOH = 5 : 3 : 1). υmax (KBr)/ cm-1: 3250, 3100, 1620, 1520, 1420, 1080, 1050;
δH (300 MHz, DMSO-d6): 7.27 (2H, br, NH2), 3.03 (2H, q, J = 7.2 Hz, SCH2,), 1.27 (3H, t, J = 7.2 Hz,
CH3,); δC (75 MHz, DMSO-d6): 170.6 (N-C=N), 151.2 (S-C-S), 29.9(CH2), 16.0 (CH3).

Acylation of 2-Amino-5-ethylthio-1,3,4-thiadiazole (1a) and 2-Amino-5-ethoxy-1,3,4-thiadiazole
(1b).
General Method
To a solution of compound 1 (1.55 g, 10 mmol) and triethylamine (2.02 g, 20 mmol) in dry THF (80 mL)
was added a solution of acid chloride (20 mmol) in dry THF (20 mL). The reaction mixture was stirred at
rt for 3 h. The solvent was evaporated under the reduced pressure to leave a solid residue, which was
washed with water and n-hexane. The crude product was recrystallized from appropriate solvent.
2-Acetylamimo-5-ethylthio-1,3,4-thiadiazole (2a).
Yield (84%, after recrystallization from methanol), mp 194-196 °C (lit.,6 185 °C), Rf 0.68 (n-hexane :
ethyl acetate : ethanol = 5 : 3 : 1). υmax (KBr)/ cm-1: 3150, 3050, 2950, 2800, 1700 (C=O), 1580, 1400; δH
300 MHz, DMSO-d6): 13.34 (1H, br, NH), 3.23 (2H, q, J = 7.2 Hz, SCH2), 2.47 (3H, s, CH3CO), 1.45
(3H, t, J = 7.2 Hz, CH3); δC (75 MHz, DMSO-d6): 169.5 (C=O), 161.5 (N-C=N), 161.0 (S-C-S),
29.5(SCH2), 23.7 (CH3CO), 15.4 (CH3). Anal. Calcd. for C6H9N3OS2: C, 35.75; H, 4.49; N, 21.21; S,
32.66. Found: C, 35.45; H, 4.46; N, 20.67; S, 31.55.
2-Benzoylamimo-5-ethylthio-1,3,4-thiadiazole (2b).
Yield (82%, after recrystallization from methanol), mp 144-146 °C, Rf 0.73 (n-hexane : ethyl acetate :
ethanol = 5 : 3 : 1). υmax (KBr)/ cm-1: 3159, 1656 (C=O), 1531; δH (300 MHz, CDCl3): 13.02 (1H, br, NH),
8.28-8.26 (2H, m, Ph), 7.70-7.48 (3H, m, Ph), 3.24 (2H, q, J = 8 Hz, SCH2), 1.42 (3H, t, J = 8 Hz, CH3);
δC (75 MHz, CDCl3): 165.5 (C=O), 161.6 (N-C=N), 160.3 (S-C-S), 133.1, 131.0, 128.8, 128.7 (Ph), 28.2
(SCH2), 14.8 (CH3). Anal. Calcd. for C11H11N3OS2: C, 49.79; H, 4.18; N, 15.84; S, 24.17. Found: C,
50.27; H, 4.22; N, 16.70; S, 24.67.
5-Ethylthio-2-p-nitrobenzoylamimo-1,3,4-thiadiazole (2c).
Yield (84%, after recrystallization from THF), mp 255-256°C, Rf 0.22 (n-hexane : ethyl acetate = 7 : 3).
υmax (KBr)/ cm-1: 3130, 1686 (C=O), 1527; δH (300 MHz, DMSO-d6): 13.53 (1H, br, NH), 8.39-8.37 (2H,
m, Ph), 8.32-8.30 (2H, m, Ph), 3.27 (2H, q, J = 7.2 Hz, SCH2), 1.38 (3H, t, J = 7.2 Hz, CH3); δC (75 MHz,
DMSO-d6): 165.2 (C=O), 160.5 (N-C=N), 160.3 (S-C-S), 151.0, 138.3, 131.1, 124.8 (Ph), 29.1(SCH2),
15.6 (CH3). Anal. Calcd. for C11H10N4O3S2: C, 42.57; H, 3.25; N, 18.08; S, 20.66. Found: C, 43.07; H,
3.31; N, 18.88; S, 21.01.
5-Ethylthio-2-p-toluoylamimo-1,3,4-thiadiazole (2d).
Yield (88%, after recrystallization from methanol), mp 175-177°C, Rf 0.33 (n-hexane : ethyl acetate = 7 :
:3). υmax (KBr)/ cm-1: 3172, 1667 (C=O), 1526; δH (300 MHz, CDCl3): 12.74 (1H, br, NH), 8.15 (2H, d, J
= 8.4 Hz, Ph), 7.31 (2H, d, J = 8.4 Hz, Ph), 3.26 (2H, q, J = 7.2 Hz, SCH2), 2.44 (3H, s, CH3Ph), 1.44 (3H,

t, J = 7.2 Hz, CH3); δC (75 MHz, CDCl3): 165.4 (C=O), 161.3 (N-C=N), 160.1 (S-C-S), 143.8, 129.4,
128.7, 128.2 (Ph), 28.2(SCH2), 21.7 (CH3Ph), 14.8 (CH3).
2-Benzoylamino-5-ethoxy-1,3,4-thiadiazole (3b).
Yield (84% after recrystallization from ethanol), mp 184-185 °C, Rf 0.7 (n-hexane : ethyl acetate : ethanol
= 5 : 3 : 1). υmax (KBr)/ cm-1: 2992, 1674 (C=O), 1604, 1559, 1507; δH (300 MHz, CDCl3): 12.74 (1H, br,
NH), 8.28-8.25 (2H, m, Ph), 7.62-7.41 (3H, m, Ph), 4.51 (2H, q, J = 7.1 Hz, OCH2), 1.48 (3H, t, J = 7.1
Hz, CH3); δC (75 MHz, CDCl3): 171.1 (O-C-S), 165.4 (C=O), 155.6 (N-C=N), 132.9, 131.2, 128.8, 128.6
(Ph), 68.1 (OCH2), 14.5 (CH3). Anal. Calcd. for C11H11N3O2S: C, 53.00; H, 4.45 N, 16.86; S, 12.86.
Found: C, 53.56; H, 4.51; N, 17.65; S, 12.96.
Regiospecific Alkylation of 2-Acylamino-5-ethylthio-1,3,4-thiadiazole (2) and 2-Benzoylamino-
5-ethoxy-1,3,4-thiadiazole (3b).
General Method
Compound 2 (2 mmol) was dissolved in 50 mL of an appropriate solvent with base. An alkyl bromide
was added to the solution. The resulting mixture was refluxed with stirring for 24 h. The solvent was
evaporated under the reduced pressure. The residue was dissolved in n-hexane to filter off the insoluble
materials. n-Hexane was evaporated in rotary evaporator and the crude product was crystallized from an
appropriate solvent.
2-Acetylimimo-3-ethyl-5-ethylthio-1,3,4-thiadiazoline (4a1).
mp 41-43°C (recrystallization from diethyl ether), Rf 0.83 (n-hexane : ethyl acetate = 5 : 5). υmax (KBr)/
cm-1: 2950, 1620 (C=O), 1500; δH (300 MHz, DMSO-d6): 4.25 (2H, q, J = 7.2 Hz, NCH2), 3.24 (2H, q, J
= 7.2 Hz, SCH2), 2.20 (3H, s, CH3CO), 1.32 (3H, t, J = 7.2, CH3), 1.28 (3H, t, J = 7.2 Hz, CH3); δC (75
MHz, DMSO-d6): 180.2 (C=O), 165.5 (N-C=N), 155.6 (S-C-S), 46.8 (NCH2), 28.3 (SCH2), 27.5
(CH3CO), 15.7 (CH3), 14.4 (CH3).
2-Benzoylimimo-3-ethyl-5-ethylthio-1,3,4-thiadiazoline (4b1).
mp 108-110°C (recrystallization from methanol), Rf 0.75 (n-hexane : ethyl acetate = 7 : 3). υmax (KBr)/
cm-1: 2970, 1603 (C=O), 1565; δH (300 MHz, acetone-d6): 8.33-8.30 (2H, m, Ph), 7.58-7.47 (3H, m, Ph),
4.53 (2H, q, J = 7.2 Hz, NCH2), 3.28 (2H, q, J =7.2 Hz, SCH2), 1.49 (3H, t, J = 7.2 Hz, CH3), 1.44 (3H, t,
J = 7.2 Hz, CH3); δC (75 MHz, acetone-d6): 174.3 (C=O), 165.9 (N-C=N), 156.0 (S-C-S), 137.1, 132.9,
130.1, 129.0 (Ph), 47.0 (NCH2), 28.2 (SCH2), 15.0, (CH3), 13.8 (CH3). Anal. Calcd. for C13H15N3OS2: C,
53.22; H, 5.15; N, 14.32; S, 21.86. Found: C, 53.38; H, 5.21; N, 14.82; S, 21.93.

2-Benzoylimimo-5-ethylthio-3-propyl-1,3,4-thiadiazoline (4b2).
mp 58-59°C (recrystallization from diethyl ether), Rf 0.83 (n-hexane: ethyl acetate = 7 : 3). υmax (KBr)/
cm-1: 2965, 1605 (C=O), 1571; δH (300 MHz, CDCl3): 8.34-8.32 (2H, m, Ph), 7.57-7.44 (3H, m, Ph), 4.42
(2H, t, J = 7.2 Hz, NCH2), 3.18 (2H, q, J = 7.3 Hz, SCH2), 1.97 (2H, sextet, J = 7.2 Hz, NCH2CH2), 1.45
(3H, t, J = 7.3 Hz, SCH2CH3), 1.02 (3H, t, J = 7.2 Hz, NCH2CH2CH3); δC (75 MHz, CDCl3): 174.2
(C=O), 165.7 (N-C=N), 155.4 (S-C-S), 136.0, 132.0, 129.4, 128.1 (Ph), 52.7 (NCH2), 27.7 (SCH2), 21.9
(NCH2CH2), 14.7, (SCH2CH3), 11.2 (NCH2CH2CH3). Anal. Calcd. for C14H17N3OS2: C, 54.69; H, 5.57;
N, 13.67; S, 20.86. Found: C, 54.71; H, 5.69; N, 13.45; S, 20.35.
3-Ethyl-5-ethylthio-2-p-nitrobenzoylimimo-1,3,4-thiadiazoline (4c1).
mp 125-127°C (recrystallization from diethyl ether), Rf 0.75 (n-hexane : ethyl acetate = 7 : 3). υmax (KBr)/
cm-1: 2975, 1617 (C=O), 1582; δH (300 MHz, CDCl3): 8.48-8.44 (2H, m, Ph), 8.31-8.28 (2H, m, Ph), 4.53
(2H, q, J = 7.2 Hz, NCH2), 3.22 (2H, q, S J = 7.2 Hz, CH2), 1.54 (3H, t, J = 7.2 Hz, CH3), 1.47 (3H, t, J =
7.2 Hz, CH3); δC (75 MHz, CDCl3): 172.1 (C=O), 165.8 (N-C=N), 156.6 (S-C-S), 149.9, 141.5, 130.3,
123.3 (Ph), 46.6 (NCH2), 27.6, (SCH2), 14.6 (CH3), 13.7 (CH3). Anal. Calcd. for C13H14N4O3S2: C, 46.14;
H, 4.17; N, 16.56; S, 18.95. Found: C, 46.18; H, 4.17; N, 16.84; S, 19.11.
2-Ethylthio-5-p-nitrobenzoylimimo-3-propyl-1,3,4-thiadiazoline (4c2).
mp 111-112°C (recrystallization from n-hexane), Rf 0.75 (n-hexane : ethyl acetate = 7 : 3). υmax (KBr)/
cm-1: 2933, 1617 (C=O), 1584; δH (300 MHz, CDCl3): 8.45-8.42 (2H, m, Ph), 8.29-8.26 (2H, m, Ph), 4.44
(2H, t, J = 7.4 Hz, NCH2), 3.21 (2H, q, J = 7.4 Hz, SCH2), 1.99 (2H, sextet, J = 7.4 Hz, NCH2CH2), 1.46
(3H, t, J = 7.4 Hz, SCH2CH3), 1.03 (3H, t, J = 7.4 Hz, NCH2CH2CH3); δC (75 MHz, CDCl3): 172.0
(C=O), 166.2 (N-C=N), 156.4 (S-C-S), 149.8, 141.5, 130.2, 123.2 (Ph), 52.9 (NCH2), 27.7 (SCH2), 21.8
(NCH2CH2), 14.5, (SCH2CH3), 11.1 (NCH2CH2CH3). Anal. Calcd. for C14H16N4O3S2: C, 47.71; H, 4.58;
N, 15.90; S, 18.20. Found: C, 48.33; H, 4.64; N, 16.04; S, 18.33.
3-Ethyl-5-ethylthio-2-p-toluoylimimo-1,3,4-thiadiazoline (4d1).
mp 95-97°C (recrystallization from diethyl ether), Rf 0.75 (n-hexane : ethyl acetate = 7 : 3). υmax (KBr)/
cm-1: 2968, 1603 (C=O), 1563; δH (300 MHz, CDCl3): 8.21 (2H, d, J = 8 Hz, Ph), 7.25 (2H, d, J = 8 Hz,
Ph), 4.49 (2H, q, J = 7.2 Hz, NCH2), 3.18 (2H, q, J = 7.2 Hz, SCH2), 2.41 (3H, s, CH3Ph), 1.50 (3H, t, J =
7.2 Hz, CH3), 1.44 (3H, t, J = 7.2 Hz, CH3); δC (75 MHz, CDCl3): 174.1 (C=O), 165.0 (N-C=N), 155.4
(S-C-S), 142.5, 133.3, 129.5, 128.8 (Ph), 46.2 (NCH2), 27.7 (SCH2), 21.6 (CH3Ph), 14.6 (CH3), 13.6
(CH3).
5-Ethylthio-3-propyl-2-p-toluoylimimo-1,3,4-thiadiazoline (4d2).
mp 83-85°C (recrystallization from diethyl ether), Rf 0.83 (n-hexane : ethyl acetate = 7: 3). υmax (KBr)/

cm-1: 2963, 1604, 1562; δH (300 MHz, CDCl3): 8.20 (2H, d, J = 8 Hz, Ph), 7.24 (2H, d, J = 8 Hz, Ph),
4.40 (2H, t, J = 7.4 Hz, NCH2), 3.16 (2H, q, J = 7.4 Hz, SCH2), 2.41 (3H, s, CH3Ph), 1.96 (2H, sextet, J =
7.4 Hz, NCH2CH2), 1.43 (3H, t, J = 7.4 Hz, SCH2CH3), 1.00 (3H, t, J = 7.4 Hz, NCH2CH2CH3); δC (75
MHz, CDCl3): 174.1 (C=O), 165.5 (N-C=N), 155.2 (S-C-S), 142.4, 133.3, 129.4, 128.8 (Ph), 52.6
(NCH2), 27.7 (SCH2), 21.8 (CH3Ph), 21.6 (NCH2CH2), 14.6, (SCH2CH3), 11.1 (NCH2CH2CH3). Anal.
Calcd. for C15H19N3OS2: C, 56.04; H, 5.96; N, 13.07; S, 19.95. Found: C, 57.06; H, 6.08; N, 13.30; S,
19.97.
2-Benzylimino-5-ethoxy-3-propyl-1,3,4-thiadiazoline (5b2).
mp 87-88°C (recrystallization from diethyl ether), Rf 0.81 (n-hexane : ethyl acetate = 7 : 3). υmax (KBr)/
cm-1: 2962, 1606 (C=O), 1570, 1505; δH (300 MHz, CDCl3): 8.31-8.29 (2H, m, Ph), 7.60-7.42 (3H, m,
Ph), 4.41 (2H, q, J = 7.1 Hz, OCH2), 4.31 (2H, J = 7.4 Hz, NCH2), 1.92 (2H, sextet, J = 7.4 Hz,
NCH2CH2CH3), 1.45 (3H, t, J = 7.1 Hz, OCH2CH3), 1.00 (3H, t, J = 7.4 Hz, NCH2CH2CH3); δC (75 MHz,
CDCl3): 174.0 (C=O), 165.2 (O-C-S), 163.2 (N-C=N), 136.2, 131.8, 129.3, 128.1 (Ph), 67.7 (OCH2), 52.1
(NCH2), 21.7 (NCH2CH2CH3), 14.3 (OCH2CH3), 11.2 (NCH2CH2CH3). Anal. Calcd. for C14H17N3O2S: C,
57.71; H, 5.88; N, 14.42; S, 11.01. Found: C, 58.16; H, 5.94; N, 14.83; S, 11.29.
X-Ray Crystallographic Analysis of 5-Ethylthio-2-p-toluoylamimo-1,3,4-thiadiazole (2d).
Direct methods (SHELX86)11 (all non-H atoms) followed by full-matrix least-squares refinement
(SHELX97)12 on F2 with all non-H atoms anisotropic. Hydrogen atoms were located from ∆F synthesis
and positionally refined. Final R1 [F≥ 2σ (F) ] and wR2 [all data] were 0.0446 and 0.0978 for 202 refined
parameters, S[F2] 1.029. And (∆/δ)max was 0.000. Maximum and minimum features in ∆F synthesis are
0.180 and -0.199 eǺ-3, respectively.
X-Ray Crystallographic Analysis of 3-Ethyl-5-ethylthio-2-p-toluoylimimo-1,3,4-thiadiazoline (4d1).
The structure was determined by the same procedure previously applied for the structure determination of
2d. Final R1 [F≥ 2σ (F) ] and wR2 [all data] were 0.0457 and 0.1011 for 233 refined parameters, S[F2]
1.030. And (∆/δ)max was 0.000. Maximum and minimum features in ∆F synthesis are 0.210 and
-0.187eǺ-3, respectively.
ACKNOWLEDGEMENT
This work was supported by Korea Research Foundation Grant (KRF-1999-015-DI0069).

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