Unexpected direction of iodocyclization of 3-allylthio-5-phenyl-4H-1,2,4- triazole

Article abstract of DOI:10.1023/B:COHC.0000048296.91251.a7

The reaction of 3-allylthio-5-phenyl-4H-1,2,4-triazole with iodine to give a mixture of 5,6-dihydro-5-iodomethyl-3-phenyl[1,3]thiazolo[2,3-c][1,2,4] triazole, 6,7-dihydro-6-iodo-3-phenyl-5H-[1,2,4]triazolo[3,4-b][1,3]thiazine, 5,6-dihydro-6-iodomethyl-2-p

Full text of DOI:10.1023/B:COHC.0000048296.91251.a7

Chemistry of Heterocyclic Compounds, Vol. 40, No. 9, 2004
UNEXPECTED DIRECTION OF IODOCYCLIZATION
OF 3-ALLYLTHIO-5-PHENYL-4H-1,2,4-TRIAZOLE
V. I. Shmygarev and D. G. Kim
The reaction of 3-allylthio-5-phenyl-4H-1,2,4-triazole with iodine to give a mixture of 5,6-dihydro-5-
iodomethyl-3-phenyl[1,3]thiazolo[2,3-c][1,2,4]triazole, 6,7-dihydro-6-iodo-3-phenyl-5H-[1,2,4]triazolo-
[3,4-b][1.3]thiazine,
5,6-dihydro-6-iodomethyl-2-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazole,
and
6,7-dihydro-6-iodo-2-phenyl-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine has been studied. The structure of
the products obtained was established using 1H NMR spectroscopy of their dehydriodination products.
Keywords: 3-allylthio-5-phenyl-4H-1,2,4-triazole, 5,6-dihydro-5-iodomethyl-3-phenyl[1,3]thiazolo-
[2,3-c][1,2,4]triazole, 6,7-dihydro-6-iodo-3-phenyl-5H-[1,2,4]triazolo[3,4-b][1,3]thiazine, 5,6-dihydro-
6-iodomethyl-2-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazole, 6,7-dihydro-6-iodo-2-phenyl-5H-[1,2,4]triazolo-
[5,1-b][1,3]thiazine.
The electrophilic cyclization of S-alkynyl [1-3] and S-allenyl [3] derivatives of 5-phenyl-4H-1,2,4-
triazole-3-thiol under action of acids and mercury salts has been reported. The authors [1, 3] report the
formation of only one regioisomer which is the product of cyclization at the N(2) atom whereas the authors of [2]
observe the formation of two isomers simultaneously, the ratio of which is determined by the reaction
conditions.
We have studied for the first time the electrophilic iodocyclization of 3-allylthio-5-phenyl-4H-1,2,4-
triazole (1) in the presence of iodine. Compound 1 was prepared by the reaction of 5-phenyl-4H-1,2,4-triazole-3-
thiol with allyl bromide in aqueous NaOH solution at 5-7°C. The iodocyclization was carried out in
dichloromethane at room temperature over several days. It was found (see scheme) that not only the two
expected five-membered cyclization products – 5,6-dihydro-5-iodomethyl-3-phenyl[1,3]thiazolo[2,3-c][1,2,4]-
triazole (3) and 5,6-dihydro-6-iodomethyl-2-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazole (5) – were formed but also
the six-membered isomeric products 6,7-dihydro-6-iodo-3-phenyl-5H-[1,2,4]triazolo[3,4-b][1,3]thiazine (2) and
6,7-dihydro-6-iodo-3-phenyl-5H-[1,2,4]triazolo[3,4-b][1,3]thiazine (4) were obtained. In the mixture of reaction
products thiazine 2 predominated (46%) and this was similar to thiazole 3 (which was present at a level of 30%)
in both chromatographic behavior and solubility. The products of cyclization at atom N(2) (compounds 4 and 5)
were formed in smaller amounts (19 and 5% respectively). They are also close in chromatographic behavior and
solubility but significantly less polar than the isomers 2 and 3 (Scheme 1).
The structures of thiazoles 3 and 5 were established by the synthesis from them of the products of fission
of HI in methanolic KOH solution to give 5-methyl-2-phenyl[1,3]thiazolo[2,3-c][1,2,4]triazole (6) from isomer 3
1
and 6-methyl-2-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazole (7) from isomer 5. In both melting point and H NMR
spectra they were identical to those reported previously [2, 4-6] (Table 1).
__________________________________________________________________________________________
Chemistry Faculty, Chelyabinsk State University, Chelyabinsk 454021, Russia; e-mail: bobas@csu.ru,
kim@csu.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1391-1395, September, 2004.
Original article submitted April 23, 2002.
0009-3122/04/4009-1207©2004 Springer Science+Business Media, Inc.
1207

Scheme 1
1
2
N
3
N
N
N
N
N
8a
KOH / MeOH
Ph
S 8
4 N
+
Ph
S
N
Ph
S
N
7
5
6
I
8a
8b
I2 / CH2Cl2
2
1
2
N
N
N
N
N
N
7a
3
I2 / CH2Cl2
S
Ph
N
Ph
Ph
N
4 N
7
S
S
H
5
I
6
Me
1
3
6
7
8
1
N
I
I2 / CH2Cl2
N
N
N
N
N
6
+
2
5
Ph
3a
Ph
N
N
S 4
N
S
Ph
N
S
3
9b
4
9a
Me
1
N
I2 / CH2Cl2
Ph
2
N
3a
5
I
N
6
5
3 N
S
S
Ph
N
4
7
The 1H NMR spectra of the products of elimination of HI from thiazines 2 and 4 were taken for mixtures
of the compounds isomeric by double bond positions in the thiazine ring (8a,b and 9a,b respectively) and were
similar to the spectrum of sulfide 1 since they contain a similar vinyl fragment.
The six-membered isomers 2 and 4 show a set of multiplets, the proton spin-spin coupling constants of
which were calculated by the known rules for higher order spectra [7]. The SSCC seen in thiazines 2 and 4
between the H-6 proton and the protons of the CH2N and CH2S groups point to their existence in a conformation
with pseudoequatorial positioning of the iodine atom.
1
The H NMR spectra of the five-membered isomers 3 and 5 showed both signals for the protons of the
aromatic ring and an H-5 multiplet in isomer 3 or H-6 in compound 5 together with four quartets for the protons
of the thiazole ring and the iodomethyl group. Their spin-spin coupling constants point to a major contribution of
the conformers 10a and 10b with unsymmetrical positioning of the hydrogen atoms of the iodomethyl group
relative to the Hx proton (H-5 in compound 3 and H-6 in compound 5).
H
X
H
X
H
X
H
B
I
H
A
H
B
I
H
A
C
N
C
N
C
N
H
B
I
H
A
10a
10b
10c
1208

TABLE 1. 1H NMR Spectral Characteristics of Compounds 1-9
Com-
pound
Chemical shifts (CDCl3), δ, ppm (J, Hz)
1
2
3
4
14.4 (1H, s, NH); 7.9-8.1 (2H, m, C6H5); 7.4-7.6 (3H, m, C6H5); 5.97 (1H, m, –CH=);
5.27 (1H, dt, 3Jcis = 15.7, =CHH); 5.09 (1H, dt, 3Jtrans = 9.9, =CHH);
3.82 (2H, dt, 4J = 1.3, CH2CH)
7.5-7.7 (5H, m, C6H5); 4.92 (1Н, m, –CHI–);
4.55* (1Н, q, 3JMX = 3.7, 2JMN = –13.0, –NCHHM–); 4.45* (1Н, q, 3JNX = 8.3, –NCHNH–);
3.61* (1H, q, 3JAX = 2.2, 2JAB = –12.9, –SCHHAI); 3.59* (1Н, q, 3JBX = 9.6, –SCHHBI)
7.65-7.80 (2H, m, C6H5); 7.4-7.5 (3H, m, C6H5); 4.99 (1Н, m, –NCH–); 4.38 (1Н, q,
4JMB = 1.3, 3JMX = 7.3, 2JMN = -11.9, –SCHHM–); 3.82 (1Н, q, 3JNX = 1.9, –SCHNH–);
3.36 (1H, q, 3JAX = 10.5, 2JAB = -10.5, –CHHAI); 3.11 (1Н, d, 3JBX = 3.0, –CHHBI)
7.95-8.05 (2H, m, C6H5); 7.35-7.55 (3H, m, C6H5); 4.74* (1Н, m, –CHI–);
4.81* (1Н, dd, 4JMB = 1.6, 3JMX = 5.0, 2JMN = –13.8, –NCHHM–);
4.54 (1Н, sext., 3JNX = 9.5, –NCHNH–);
3.67* (1H, dd, 3JAX = 10.6, 2JAB = -12.6, –SCHHAI); 3.55* (1Н, d, 3JBX = 3.3, –SCHHBI)
5
8.0–8.1 (2H, m, C6H5); 7.4-7.5 (3H, m, C6H5); 4.55 (1Н, m, –NCH–);
4.16 (1Н, q, 3JMX = 8.1, 2JMN = -11.9, –SCHHM–); 3.84 (1Н, q, 3JNX = 5.4, –SCHNH–);
3.70 (1H, q, 3JAX = 3.0, 2JAB = -10.6, –CHHAI); 3.51 (1Н, q, 3JBX = 9.1, –CHHBI)
6
7
7.4-7.7 (5H, m, C6H5); 6.55 (1Н, q, 4J = 1.3, H-6); 2.12 (3H, d, CH3)
8.1-8.2 (2H, m, C6H5); 7.4-7.6 (3H, m, C6H5); 6.59 (1Н, q, 4J = 1.2, H-5);
2.58 (3H, d, CH3)
8a*2
8b*2
9a*2
9b*2
7.5-7.7 (5H, m, C6H5); 6.41 (1Н, dt, 3J = 10.0, 4J = 1.7, –SCH=); 5.96 (1Н, dt, –CH=);
4.79 (2Н, dd, 3J = 3.7, –NCH2–)
7.5-7.7 (5H, m, C6H5); 6.89 (1Н, dt, 3J = 8.0, 4J = 1.4, –NCH=); 5.76 (1Н, dt, –CH=);
3.61 (2Н, dt, 3J = 5.4, –SCH2–)
7.4-8.0 (5H, m, C6H5); 6.31 (1Н, dt, 3J = 10.0, 4J = 1.9, –SCH=); 5.99 (1Н, dt, –CH=);
5.04 (2Н, dd, 3J = 3.4, –NCH2–)
7.4-8.0 (5H, m, C6H5); 7.10 (1Н, dt, 3J = 8.5, 4J = 1.5, –NCH=); 5.51 (1Н, dt, –CH=);
3.72 (2Н, dt, 3J = 5.3, –SCH2–)
_______
* As part of a multiplet.
*2 As a mixture of isomers.
The spin-spin coupling constant values are in good agreement with relative stability of conformers for all
of the cyclization products 2-5 as determined by a full energy semiempirical PM3 calculation (Table 2). Thus,
according to the calculations, the conformers with pseudoequatorial iodine atom have a greater stability in the
six-membered products 2 and 4 and in thiazoles 3 and 5 the conformer 10a is more stable in which the iodine
atom is placed out of the plane of the thiazole ring. The calculation also showed that, for thiazole 3, the
conformation 10b does not overall exist in a potential energy minimum, probably due to the unfavorable steric
interaction of the iodine atom with the phenyl group.
TABLE 2. Relative Energy (E) of the Conformers of the Cyclization
Products 2-5*
E, kJ/mol
Conformer
2
3
4
5
10a
10b
10c
—
—
—
31.1
Unstable
53.7
—
—
—
36.3
58.4
56.7
—
Axial iodine atom
Equatorial iodine atom
21.0
0.0
—
23.7
0.1
—
—
_______
* The energy of the most stable conformer was used as the zero energy value.
1209

EXPERIMENTAL
1H NMR spectra were recorded on a Bruker (200 MHz) spectrometer. TLC was carried out on Sorbfil
PTSK-V-UV plates and revealed using UV irradiation or iodine vapor.
3-Allylthio-5-phenyl-4H-1,2,4-triazole (1). 5-Phenyl-4H-1,2,4-triazole-3-thiol (10.0 g, 56.4 mmol) and
NaOH (3.40 g, 85 mmol) were dissolved in water (200 ml) in a flat-bottomed flask. The solution was cooled to
5-7°C and allyl bromide (5.37 ml, 62.1 mmol) was added dropwise. The mixture was stirred at reduced
temperature for 3-4 h, acidified with acetic acid (1.5 ml) to pH 7, and the precipitated sulfide 1 was filtered off,
washed with water, and dried. The yield after drying was 11.2 g (91%). Recrystallization from a mixture of
benzene (35 ml) and hexane (30 ml) gave 9.97 g of a needle-shaped crystalline product; mp 104°C, Rf 0.29
(CHCl3–acetone, 10:1). Found, %: S 14.7. C11H11N3S. Calculated, %: S 14.8.
5,6-Dihydro-5-iodomethyl-3-phenyl[1,3]thiazolo[2,3-c][1,2,4]triazole (3) and 6,7-Dihydro-6-iodo-3-
phenyl-5H-[1,2,4]triazolo[3,4-b][1,3]thiazine (2); 5,6-Dihydro-6-iodomethyl-2-phenyl[1,3]thiazolo[3,2-b]-
[1,2,4]triazole (4) and 6,7-Dihydro-6-iodo-2-phenyl-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine (5). Sublimed
iodine (19.02 g, 75.0 mmol) was added to suspension of compound 1 (6.51 g, 30.0 mmol) in CH2Cl2 (200 ml).
The mixture was held at room temperature in the dark for several days, then CH2Cl2 was distilled off under
reduced pressure. The residue was dissolved in acetone (70 ml) and solution of Na2S2O3·5H2O (27.07 g,
105 mmol) and Na2CO3 (3.81 g, 36.0 mmol) in water (300 ml) was added with cooling. The precipitated mixture
of cyclization products was separated and dried (9.80 g, 95%). For the separation of the cyclization products 4
and 5 the mixture was treated with benzene (200 ml) at room temperature. The insoluble part (7.15 g, a mixture
of 2 and 3) was recrystallized from 70% acetic acid to give 3.80 g (37% based on sulfide 1) of thiazine 2. The
mother liquor was evaporated at reduced pressure and suspended in water, the insoluble precipitate after two
recrystallizations from ethanol giving 1.93 g (19% based on compound 1) of thiazole 3. The benzene extract
containing the mixture of isomers 4 and 5 was evaporated and the residue (2.24 g) was chromatographed on
alumina column using benzene as eluent to give 0.40 g (4% based on sulfide 1) of thiazole 5 (fraction I) and 1.50
g (14% based on sulfide 1) of thiazine 4 (fraction II).
The mixture of isomers 2 and 3 (500 mg) was quantitatively separated on alumina chromatographic
column (ethyl acetate as eluent) to give 195 mg (39% based on 500 mg of the mixture of 2 and 3) of thiazole 3
and 290 mg (58% based on 500 mg of the mixture of 2 and 3) of thiazine 2.
The mixture of isomers 4 and 5 (500 mg) was quantitatively separated on the alumina chromatographic
column (benzene as eluent) to give 105 mg (21% based on 500 mg of the mixture of 4 and 5) of thiazole 5 and
388 mg (78% based on 500 mg of the mixture of 4 and 5) of thiazine 4.
6,7-Dihydro-6-iodo-3-phenyl-5H-[1,2,4]triazolo[3,4-b][1,3]thiazine (2). Mp 194°C (70% AcOH),
Rf 0.21 (ethyl acetate). Found, %: I 36.5; S 9.4. C11H10IN3S. Calculated, %: I 37.0. S 9.3.
5,6-Dihydro-5-iodomethyl-3-phenyl[1,3]thiazolo[2,3-c][1,2,4]triazole (3). Mp 189°C (ethanol),
Rf 0.24 (ethyl acetate). Found, %: I 36.6; S 9.3. C11H10IN3S. Calculated, %: I 37.0; S 9.3.
6,7-Dihydro-6-iodo-2-phenyl-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine (4). Mp 138°C (benzene–hexane),
Rf 0.32 (ethyl acetate–hexane, 2:3). Found, %: I 36.8; S 9.3. C11H10IN3S. Calculated, %: I 37.0; S 9.3.
5,6-Dihydro-6-iodomethyl-2-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazole (5). Mp 115°C (i-PrOH),
Rf 0.34 (ethyl acetate–hexane, 2:3). Found, %: I 36.9; S 9.5. C11H10IN3S. Calculated, %: I 37.0; S 9.3.
5-Methyl-3-phenyl[1,3]thiazolo[2,3-c][1,2,4]triazole (6). Compound 3 (343 mg, 1.00 mmol) was
dissolved in 5% KOH solution in methanol (15 ml), heated to reflux, and left for several hours at room
temperature. Methanol was evaporated at reduced pressure, the residue was extracted with chloroform
(3 × 10 ml) and the combined extract was dried with anhydrous sodium sulfate and chloroform evaporated. The
residue was recrystallized from a mixture of benzene and hexane to give thiazole 6 (118 mg, 55%); mp 150°C
(mp 150°C [4]), Rf 0.28 (ethyl acetate).
6-Methyl-2-phenyl[1,3]thiazolo[3,2-b][1,2,4]triazole (7) was prepared similarly from compound 5 in
108 mg (50%) yield; mp 125°C (mp 124°C [4]), Rf 0.37 (ethyl acetate–hexane, 2:3).
1210

Mixture of 3-Phenyl-5H-[1,2,4]triazolo[3,4-b][1,3]thiazine (8a) and 3-Phenyl-7H-[1,2,4]triazolo-
[3,4-b][1,3]thiazine (8b). Removal of HI from thiazine 2 (100 mg, 0.29 mmol) was carried out similarly to the
preparation of compound 6. Evaporation of solvent gave 59 mg (95%) of the mixture of the isomers 8a and 8b.
Mixture of 2-Phenyl-5H-[1,2,4]triazolo[5,1-b][1,3]thiazine (9a) and 2-Phenyl-7H-[1,2,4]triazolo-
[5,1-b][1,3]thiazine (9b) was prepared similarly from compound 4 in 61 mg (98%) yield.
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