Synthesis of thieno[2,3-d]-1,3-dithiol-2-thiones from thieno[2,3-d]-1,2,3- thiadiazoles: Matryoshka-type autoclave for high-temperature, high-pressure thermolysis microscale reactions

Article abstract of DOI:10.3390/70200145

Thieno[2,3-d]-1,2,3-thiadiazoles (1) react with carbon disulfide in a "Matryoshka-type" double compartment autoclave [1] to yield thieno[2,3-d]-1,3-dithiol-2-thiones (2). With BH₃/Me₂S the cyclic trithiocarbonate (2d) is cleaved and the product characterized after methylation as 4b. Compounds 7a and 7b are prepared via the thieno[2,3-d]-1,3- dithiolium salts (6) followed by NaBH₄-reduction.

Full text of DOI:10.3390/70200145

Molecules 2001, 7, 145-154
molecules
ISSN 1420-3049
http://www.mdpi.org
Synthesis of Thieno[2,3-d]-1,3-dithiol-2-thiones from
Thieno[2,3-d]-1,2,3-thiadiazoles: Matryoshka-type autoclave for
high-temperature, high-pressure thermolysis microscale
reactions†
Ulrich Jordis*1, Kaberi Bhattacharya 1, Philip Y. Boamah 1 and Ving J. Lee 2
1 Institute of Organic Chemistry, VUT, A-1060 Vienna, Getreidemarkt 9, Austria.
2
Microcide Pharmaceuticals Inc., 1335 Carvo Court, Los Altos, CA 94024, U.S.A.
† This paper was presented at the Fifth Electronic Conference on Synthetic Organic Chemistry
(ECSOC-5), September 1-30, 2001 (Paper A0045)
* Author to whom correspondence should be addressed; e-mail: ujordis@pop.tuwien.ac.at
Received: 23 December 2001 / Accepted: 6 February 2002 / Published: 28 February 2002
Abstract: Thieno[2,3-d]-1,2,3-thiadiazoles (1) react with carbon disulfide in a "Matryoshka-
type" double compartment autoclave [1] to yield thieno[2,3-d]-1,3-dithiol-2-thiones (2).
With BH3/Me2S the cyclic trithiocarbonate (2d) is cleaved and the product characterized
after methylation as 4b. Compounds 7a and 7b are prepared via the thieno[2,3-d]-1,3-
dithiolium salts (6) followed by NaBH4-reduction.
Keywords: 1,3-dipolar cycloaddition, high pressure reaction.
Introduction
Condensed 1,3-dithiole-2-thiones are valuable intermediates in the preparation of tetrathiafulvalene
(TTF) - type organic metals [2]. Some of these compounds also exhibit antifungal activities [3].
Known methods of preparing thieno[2,3-d]-1,3-dithiole-2-thiones include either the annelation of the
thiophene ring onto suitably substituted 1,3-dithiole-2-thiones [4,5] or the cyclization of thiophene
thiole derivatives [6,7,8]. Thieno[2,3-d]-1,3-dithiole-2-thione has been synthesized by treatment of
.

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O-ethyl-S-(2-oxotetrahydrofuran-3-yl)dithiocarbonate with phosphorous sulfide or sulfur
dehydrogenation of 4,5-dihydrothieno[2,3-d]-1,3-dithiole-2-thione [9a]. The formation of 2c via a thio-
Claisen rearrangement has been described [9b]. The isomeric thieno[3,4-d]-1,3-dithiole-2-thione is
formed as a side product by thermolysis of 4,6-dihydrothieno[3,4-d]-1,2,3-thiadiazole in the presence
of an excess of carbon disulfide (6h, 170°C) [10].
Results and Discussion
In continuation of our previous work on the synthesis of 1,3-benzodithiole-2-thiones [11] we have
investigated the reaction of thieno[2,3-d]-1,2,3-thiadiazoles [12] with carbon disulfide. The carbon
disulfide thermolysis reactions were performed using a micro-scale, Teflon-autoclave within a 2L steel
autoclave (Figures 1a and 1b). By filling both the inner and outer autoclaves with the carbon disulfide
solvent, one could reasonably expect that upon heating only a relatively small pressure difference
would exist between the inside and outside of the Teflon autoclave, while the pressure within the steel
autoclave was between 23 and 35 bar. Indeed, by using this procedure, reactions on a 140-840 mg scale
could be performed routinely in this Matryoshka-autoclave, with the added advantage that
contamination of the product by impurities (due to reaction of the autoclave with carbon disulfide) is
avoided.
Figure 1a: Matryoshka Dolls and Matryoshka-Type Autoclave
a: inner TEFLON autoclave
b: outer steel autoclave

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Figure 1b: Autoclaves used in the experiments
Dimensions: diameter: 50 mm, overall height: 90 mm,
inside volume: 9 mL
2 L steel autoclave
The reaction temperature plays a critical role. The optimal temperature for the conversion of benzo-
1,2,3-thiadiazole to 1,3-benzodithiole-2-thione was found to be 235±5°C [13] with a 67% yield of 2a
formed, whereas below 220°C, 1a was mostly unreacted. Under similar reaction conditions the cyanide
derivative 1f gave, in addition to the thieno[2,3-d]-1,3-dithiole-2-thione (2f), the 1,4,5,8-tetrathia-s-
indacene (3f). The formation of the products 3d and 3f can be explained via head-to-tail dimerization
of the 1,3-dipolar intermediate [14] (Scheme 1).
Scheme 1
R2
R2
R2
S
N
S
S
S
S
CS2
R1
R1
S
R1
R1
N
+
S
S
S
S
R2
1
2
3

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5-Phenylthieno[2,3-d]-1,3-dithiole was not detected upon reduction of 2d using the boron
hydride/dimethyl sulfide complex. Instead, the ring-cleaved dithiole 4a was formed and characterized
as the dimethylated compound 4b (Scheme 2).
Scheme 2
BH3 / Me2S
S
2d
S
S
SR
SR
S
4a:
4b:
R = H
Na2CO3/ MeI
R = CH3
This behavior is in contrast to the analogous conversion of 1,3-benzodithiole-2-thione to benzo-1,3-
dithiole, which was produced routinely with yields of 88-92% in our laboratory [15]. On the other
hand, 5-ethoxycarbonyl-6-methylthieno[2,3-d]dithiole-2-thione (2g) behaved analogously to benzo-
1,3-dithiole-2-thione upon treatment with dimethyl sulfate followed by tetrafluoroboric acid. The
crystalline salt 6 was then reduced to 7a using sodium borohydride in CH3CN/THF. When ethanol was
used for the reduction as described for similar reactions [16] a mixture of 7a and 7b was formed
(Scheme 3):
Scheme 3
-
BF4
H3C
EtO2C
H3C
EtO2C
S+
S
NaBH4
1) (MeO)2SO2
2) HBF4
S
S
SCH3
SCH3
2g
R
S
S
7a
7b
R = H
6
R = OEt
2-Methylthio-thieno[2,3-d]-1,3-dithiolium salts (e.g. 6) could serve as starting materials for a host
of synthetically useful reactions [17].
Conclusions
We have presented a facile route for the formation of thieno[2,3-d]-1,3-dithiol-2-thiones and
developed a nested-type autoclave that allows to the use of Teflon autoclaves even under high pressure.

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Experimental
General
Melting points were measured on a Kofler melting point apparatus. 1H- and 13C-NMR-spectra were
recorded on a Bruker AC-200 (200 MHz) pulse Fourier-transform NMR spectrometer using
tetramethylsilane as an internal standard and, unless otherwise noted, CDCl3 as solvent. Thin layer
chromatography (TLC) was performed on Merck TLC aluminum sheets silica 60 F254. Visualization
was by UV light or spray reagents (molybdophosphoric acid or ninhydrin and heating). Column
chromatography was performed using silica gel (Baker). MPLC (medium pressure liquid
chromatography) was performed using a LC-8A pump (Shimadzu), a SPD-6AV UV-detector
(Shimadzu) and Büchi preparative glass columns. All reactions were magnetically stirred under an
argon atmosphere.
4-Cyano-3-methyl-but-3-enoic acid ethyl ester [18,19]. A mixture of ethyl acetoacetate (130.0 g, 1.0
mol), toluene (150 mL), cyanoacetic acid (90.0 g, 1.06 mol), ammonium acetate (16.0 g, 0.2 mol) and
acetic acid (30 mL) was refluxed until azeotropic water removal ceased (8 h). Volatiles were removed
in vacuo and the residue was partitioned between water and methylene chloride (400 mL). The organic
phase was dried (Na2SO4), evaporated, and the crude product fractionated using a 30 cm Vigreux
column to yield 106.5g (69.6%) of the product with b.p.10 110-118°C (Ref. 14a: b.p.11 114°C).
1
According to H-NMR, the eluted product fraction also contained isomeric 4-cyano-3-methyl-but-2-
enoic acid ethyl ester. This product fraction was used for the preparation of 1a [20] via ethyl 2-amino-
4-methyl-thiophene-5-carboxylate hydrochloride [21].
General procedure for the conversion of thieno[2,3-d]-1,2,3-thiadiazoles (1) to thieno[2,3-d]-1,3-
dithiol-2-thiones (2) using the Matryoshka-autoclave. A 50-mL Teflon autoclave was charged with 1
(140-840 mg) and carbon sulfide (30 mL). This Teflon autoclave was inserted into a 2L steel autoclave
and 100-200 mL carbon sulfide was added. The closed steel autoclave was heated for the time and
temperature indicated in Table 1, developing a pressure of 35-40 bar. The reaction temperature was
measured inside the steel autoclave using a thermocouple attached to a digital voltmeter as well as a
strip chart recorder via an analog/digital interface. Following the prescribed reaction time, the cooled
autoclaves were opened, the contents of the Teflon autoclave were evaporated to dryness with recovery
of the carbon sulfide. The residue was purified by flash column chromatography using methylene
chloride/petroleum ether (b.p. 40-60°C) 1:1 as eluant.

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Table 1: Thermolysis of Thieno[2,3-d]-1,2,3-thiadiazoles
Starting
Scale
(mg)
Temp.
(°C)
Time
(h)
Product
Run
R1
R2
m.p. (°C)
Mat.
(yield, %)
127-130
(toluene)
1
H
H
750
210-220
7
2a (37)
1a
2
3
H
H
H
240
140
230-240
260-270
8
9
2a (67)
127-130
1a
1b
210-215
(LC)
–
Cl
2b (10)a
4
5
6
7
8
CH3
C6H5
H
H
H
H
H
140
150
150
840
140
235-245
240-267
210-220
210-230
230-240
9
9
7
6
9
2c (77)b
3d (35)
2d (80)
2d (80)
2e (10)
1c
1d
1d
1d
1e
223-224
175-177
C6H5
C6H5
175-177
4-F-C6H4
156-158
2f (18);
3f (36)
191-192
302-305
9
C6H5
CN
610
210-220
9
1f
10
11
COOC2H5
COOC2H5
CH3
CH3
8550
3500
207-218
225-232
7
6
2g (29)c
169-170
1g
1g
2g (54)
169-170
Notes: aYield based on 64 mg starting material recovered; b Yield of crude product; cYield based on 3.4
g starting material recovered.
Table 2: Physical Properties of Compounds 2 and 3
MS (m/z)
Produc
Anal.
Remarks, NMR
t
+
Calcd for C5H2S4: C, 31.55; H, 190 (M )
1.06; Found: C, 31.70; H,
1.32.
1H-NMR: δ 6.85 (d, 1H, 4-H), 7.45 (d, 1H, H-
6). C-NMR δ 119.9 (C-6), 130.8 (C-5), 132.5
(C-6a), 138.0 (C-3a), 215.2 (C=S).
2a
13
Calcd for C5HClS4: C, 26.72; 224 (M+, 100), 180, 13C-NMR (CDCl3/d6-DMSO) δ 119.5 (C-6),
H, 0.05. Found: C, 26.74; H, 150, 148, 113, 104, 130.0, 136.1, 134.8 (C-3a, C-5, C-6a), 215.2
2b
2c
0.30.
69.
(C=S).
204 (M+, 100), 169, The crude product contained unreacted 1c and
160, 140, 128, 113, sulfur. A sample for MS was purified by flash-
99, 85, 84, 71, 59, 57. LC on silica using 7:3 petroleum ether/CH2Cl2
1H-NMR δ 2.58 (s, 3H, CH3), 6.6 (s, 1H, C-H).

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Calcd for C11H6S4: C, 49.59; 266 (M+, 100), 222,
2d
2e
H, 2.27. Found: C, 49.35; H,
2.18.
190, 165, 146, 133,
121, 106, 102.
1
Calcd for C11H5FS4: C, 46.45; 284 (M+, 100), 240, H-NMR δ 7.10 (s, 1H, H-6), 7.10-7.20 (m, 2H,
H, 1.77. Found: C, 46.48; H, 208, 164, 139, 120.
1.87.
arom.), 7.40-7.60 (m, 2H, arom.). 13C-NMR δ
115.5 (C-6), 116.2 (C-o ArF), 127.5 (C-m ArF),
128.0 and 132.0 (C-3a and C-6a), 138.5 (C-p
ArF), 145.5 (C-5), 164.0 (C-ipso ArF), 214.5
(C=S).
Calcd for C12H5NS4: C, 49.46; 291 (M+, 100), 247,
H, 1.73; N, 4.81. Found: C, 227, 215, 171, 121.
49.22; H, 1.90; N, 4.47.
2f
2g
3d
3f
Calcd for C9H8O2S4: C, 39.11; 276 (M+, 100)
H, 2.92; S, 46.40. Found: C,
1H-NMR δ 1.45 (t, 3H, CH3CH2), 2.57 (s, 3H,
CH3), 4.38 (q, 2H, OCH2).
38.98; H, 2.67; S, 47.33.
1
Calcd for C20H12S4: C, 63.12; 380 (M+, 100), 348, H-NMR δ 7.05 (s, 2H, 3H and 6-H), 7.25-7.50
H, 3.18. Found: C, 63.05; H, 303, 259, 190.
3.31.
(m, 10H, arom.). 13C-NMR δ 128.3, 128.5,
131.4, 131.5, 131.9, 132.0, 132.2, 133.6.
Calcd for C22H10N2S4: C, 430 (M+, 100), 398,
61.37; H, 2.34; N, 6.51. 215, 121.
Found: C, 60.81; H, 2.09; N,
6.11.
2,3-Bis-methylthio-5-phenyl-thiophene (4b). Borane-dimethylsulfide (200 mg, 26 mol) was added to a
solution of 2d (160 mg, 6.0 mmol) in dry toluene (20 mL), and the reaction kept at 80-90°C until TLC
showed complete consumption of the starting material (30 min). The cooled reaction mixture was
hydrolyzed with dry MeOH and evaporated to dryness. The addition of MeOH and evaporation was
repeated 3 times until the flame test for boron was negative. The crude product did not show any 1H-
NMR signals in the region of 4.5 ppm, indicative of the S-CH2-S moiety of the expected dithioacetal 5.
Alkylation using an excess of MeI and 20% N2CO3 gave, after extraction and Kugelrohr-distillation
1
(0.2 mbar/110°C), 126 mg (72%) of 4b as a oil that solidified on standing, m.p. 36-68°C. H-NMR δ
2.43 (s, 1H, SCH3), 2.49 (s, 1H, SCH3), 7.10 (s, 1H, H-4), 7.25-7.60 (m, 5H, arom.); MS m/z 252 (M+,
92), 237, 203, 173, 160, 145, 121, 102, 91, 77.
Ethyl 2-Methylthio-6-methylthieno[2,3-d]-1,3-dithiole-5-carboxylate (7a) and ethyl 2-ethoxy-2-
methylthio-6-methylthieno[2,3-d]-1,3-dithiole-5-carboxylate (7b). Compound 1g [21](0.32 g, 1.16
mol) was stirred with freshly distilled dimethyl sulfate (4 mL) at 90-100°C under N2 until it was
dissolved (30 min.). To the cooled solution tetrafluoroboric acid (54%, 0.4 mL) was added, followed
by ether (20 mL) to give 0.41g (93%) of crude 6. The yellow salt was dissolved in a 1:1 mixture of

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THF and MeCN (20 mL). NaBH4 (0.2 g, 5.3 mol) was added, resulting in a colorless solution that was
stirred for 1 h. The solvents were evaporated and the residue was partitioned between CH2Cl2/H2O.
The organic layer was dried (Na2SO4) and evaporated to yield 7a (0.25 g, 74%) as colorless crystals,
1
m.p. 71-74°C (from petroleum ether/EtOAc). H-NMR: δ 1.35 (3H, t, O-CH2CH3), 2.26 (s, 3H, C-
CH3), 2.47 (s, 3H, S-CH3), 4.30 (q, 2H, O-CH2), 6.50 (s, 1H, H-2). Anal. for C10H12O2S2: Calcd: C,
41.07; H, 4.14; S, 343.85. Found: C, 41.27; H, 3.86; S, 43.64. Using EtOH instead of THF/MeCN as
the solvent [10] gave, after work-up and column chromatography on silica using 99:1 petroleum ether
(b.p. 40-60°C)/t-BuOMe, a mixture of 7a and 7b. 7b eluted first and was characterized by its 1H-NMR:
δ 1.32 (3H, t, O-CH2CH3), 1.41 (3H, t, O-CH2CH3), 2.43 (s, 3H, C-CH3), 2.47 (s, 3H, S.CH3), 3.75 (q,
2H, O-CH2), 4.30 (q, 2H, O-CH2). The second fraction was identical with 7a prepared using
THF/MeCN by 1H-NMR and HPLC.
References and Notes
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Sample Availability: Compounds 2c-d, 3d and 4b are available from MDPI.

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Appendix: Information on Matryoshkas
Many links to information about Matryoshkas can be found in the Web by using the 3 most common
transliterations in search engines.
Figure 2: Examples of matryoshkas*:
* I thank my friends Victoria & Peter H. for allowing me to take photographs of their impressive
collection of matryoshkas.
© 2002 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.