Nucleophilic intramolecular cyclization reactions of alkynechalcogenolates

Article abstract of DOI:10.1016/S0040-4020(00)00315-X

2-(ortho-Hydroxyphenyl)-alkynethiolates and -selenolates, obtained through base catalyzed ring cleavage of 4-(ortho-hydroxyphenyl)-1,2,3- thiadiazoles and -1,2,3-selenadiazoles, smoothly transform into 2- benzofuranthiolates and -selenolates. These reactive intermediates can be alkylated in high yield. This reaction sequence could be applied to the synthesis of electron rich thiacrown ethers. The 2-(ortho-aminophenyl)- alkynethiolate analogously forms 2-methylsulfanylindole. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00315-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 3933±3940
Nucleophilic Intramolecular Cyclization Reactions
of Alkynechalcogenolates
a
b,
a
a
M. A. Abramov,a,b W. Dehaen,a, B. D'hooge, M. L. Petrov, S. Smeets, S. Toppet
*
*
and M. Voetsa
aDepartment of Chemistry, University of Leuven, Celestijnenlaan 200F, B-3001 Leuven (Heverlee), Belgium
bSt. Petersburg State Institute of Technology, Moskovskii pr. 26, 198013 St. Petersburg, Russian Federation
Received 15 February 2000; accepted 25 April 2000
AbstractÐ2-(ortho-Hydroxyphenyl)-alkynethiolates and -selenolates, obtained through base catalyzed ring cleavage of 4-(ortho-hydroxy-
phenyl)-1,2,3-thiadiazoles and -1,2,3-selenadiazoles, smoothly transform into 2-benzofuranthiolates and -selenolates. These reactive inter-
mediates can be alkylated in high yield. This reaction sequence could be applied to the synthesis of electron rich thiacrown ethers. The
2-(ortho-aminophenyl)-alkynethiolate analogously forms 2-methylsulfanylindole. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
Results
1,2,3-Thiadiazoles and 1,2,3-selenadiazoles, that are unsub-
stituted at the 5 position are usually easily cleaved with
liberation of nitrogen and formation of alkynethiolates1
and alkyneselenolates2 under the action of strong bases,
such as organolithium reagents or potassium ethoxide.
The acetylenic thiolates and selenolates have been widely
used in organic synthesis for the synthesis of acetylenic
sul®des and selenides, in cycloaddition reactions leading
to new heterocycles or, after protonation, as a source of
reactive thioketenes and selenoketenes.3
Some of the results described below have been communi-
cated earlier.4,5
The Hurd±Mori reaction gives access to 4-substituted 1,2,3-
thiadiazoles starting from methyl ketones via the reaction of
the corresponding ethylcarbazones or tosyl hydrazones with
thionyl chloride.6,7 In order to have an entry to 1,2,3-thia-
diazoles, and hence alkynethiolates, having a second
functional group, this procedure was used to obtain
4-(ortho-hydroxyaryl)-1,2,3-thiadiazoles 1±3 from the
Scheme 1. 1: R1ˆR2ˆH; 2: R1ˆOH; R2ˆH; 3: R1ˆH; R2ˆOH; 4: R1ˆR2ˆH; R3ˆMe; 5: R1ˆR2ˆH, R3ˆn-hexadecyl; 6: R1ˆR2ˆH, R3ˆPhCH2;
7: R1ˆOH, R2ˆH, R3ˆn-hexadecyl; 8: R1ˆH, R2ˆOH, R3ˆn-hexadecyl.
Keywords: heterocycles; thiadiazoles; ring opening; cyclization; benzofurans; indoles.
* Corresponding authors. Tel.: 132-16-32-7439; fax: 132-16-32-7990; e-mail: wim.dehaen@chem.kuleuven.ac.be
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00315-X

3934
M. A. Abramov et al. / Tetrahedron 56 (2000) 3933±3940
Scheme 2.
corresponding acetophenones in 37±74% overall yield.8
When we carried out the base-catalyzed (K2CO3) alkylation
of 1±3, the unexpected 2-benzofuransulfanyl derivatives
4±8 were isolated. To obtain a good yield (90%) of the
methylsulfanyl derivative 4 it is necessary to carry out the
decomposition reaction of 1 previous to the addition of
methyl iodide. In all other cases the alkylating agent (benzyl
bromide, 1-bromohexadecane) was present in situ. Reaction
of 1 with the much more reactive methyl iodide under the
latter conditions gave signi®cant amounts of the O-alkylated
thiadiazole 9 (40%), next to the benzofuran 4 (56%).
Interestingly, the hydroxy functions of 7 and 8 are not
alkylated with 1-bromohexadecane under the reaction
conditions (see Scheme 1).
chloride,
4-(4-chloro-1-hydroxy-2-naphthyl)-1,2,3-thia-
diazole 12 formed unexpectedly. Apparently, the electron
rich naphthalene ring is chlorinated under the conditions of
the Hurd±Mori reaction. The treatment of the thiadiazole 12
with potassium carbonate in the presence of 1-bromohexa-
decane lead to 2-n-hexadecylsulfanyl-5-chloronaphtho[2,3-
a]furan 13 in good yield. A small amount of 4-(4-chloro-1-
(hexadecyloxy)-2-naphthyl)-1,2,3-thiadiazole
14
was
isolated at the same time. Probably the alkylation reaction
of the electron rich naphtholate anion is faster than that of
the corresponding phenolate, and will compete with the
decomposition reaction (Scheme 3).
We wanted now to study the scope of this reaction by vary-
ing both the chalcogen and the nucleophile. Thus, 4-(ortho-
hydroxyaryl)-1,2,3-selenadiazole 15 was prepared similarly
from the semicarbazone of 2-hydroxyacetophenone and
selenium dioxide according to the Lalezari procedure10 in
55% yield. Similarly, the selenides 16, 17 were obtained in
good yield by our tandem decomposition/cyclization/alkyl-
ation strategy. When two equivalents of K2CO3 base were
used in the presence of excess methyl iodide, mainly the
acetyleneselenide 18 formed (59% yield), next to small
amounts of the benzofuranselenide 16 (see Scheme 4).
An interesting application of this selective alkylation
reaction is shown in Scheme 2. 4-(2,5-Dihydroxyphenyl)-
1,2,3-thiadiazole 3 was decomposed and alkylated with
0.5 equiv. of 1,11-dichloro-3,6,9-trioxaundecane to give
1,11-bis(5-hydroxybenzofuran-2-sulfanyl)-3,6,9-trioxaun-
decane 10 in 72% yield. The latter could be transformed by
macrocyclization with tetraethylene glycol ditosylate into
thiacrown ether 11 in 38% yield. Normally, the synthesis
of this type of thia(crown) ethers requires protection/depro-
tection of the phenolate functions.9
In addition, 4-(2-aminophenyl)-1,2,3-thiadiazole 19b,
prepared by the Hurd±Mori reaction of the semicarbazone
When 2-acetyl-1-naphthol was treated with thionyl
Scheme 3.

M. A. Abramov et al. / Tetrahedron 56 (2000) 3933±3940
3935
Scheme 4. 16: R1ˆMe; 17: R1ˆPhCH2.
Scheme 5.
Scheme 6. a: XˆS, YˆO; b: XˆSe, YˆO; c: XˆS, YˆNH.

3936
M. A. Abramov et al. / Tetrahedron 56 (2000) 3933±3940
of o-nitroacetophenone, followed by reduction of the nitro
function, formed 2-methylsulfanylindole 20 in 85% yield.
In this case we had to use potassium t-butoxide as the base.
It is very important to add an equivalent amount of acetic
acid after the thiadiazole ring cleavage to obtain the
indole derivative 20. When we carried out the methylation
without working up of the reaction mixture with acid,
only acetylene derivative 21 was isolated in 85% yield
(Scheme 5).
puri®ed by silica gel column chromatography with dichloro-
methane as the eluent. Yield 0.74 g (92%), orange solid, mp
1068C (dichloromethane/n-hexane). 1H NMR spectra
(CDCl3, d, ppm): 7.00 (t£d, 1H), 7.15 (d£d, 1H,), 7.36
(t£d, 1H), 7.67 (d£d, 1H), 8.82 (s, 1H, H5het), 10.54 (s, 1H,
OH). 13C NMR spectra (CDCl3, ppm): 114.5, 118.3, 120.1,
127.4, 130.0, 131.4, 156.0, 162.3 (C4het). Mass spectrum, m/z,
(EI, %): M1 458 (21), 176 (11), 150 (18), 149 (100.0), 121
(18), 89 (13), 45 (34), 43 (11).
4-(2,4-Dihydroxyphenyl)-1,2,3-thiadiazole 2. (a) To a
solution of 2,4-dihydroxyacetophenone (10.00 g, 32.9
mmol) in a mixture of ethanol (75 ml) and water (75 ml)
was added ethyl carbazate (6.84 g, 32.89 mmol). The
reaction mixture was re¯uxed for 22 h and allowed to stay
overnight in the refrigerator. The precipitate was ®ltered off,
washed with diethyl ether (2£50 ml) and dried under
vacuum. Yield of the carbethoxyhydrazone of 2,4-
dihydroxyacetophenone 9.50 g (61%); mp 2098C (ethanol).
1H NMR spectra (DMSO-d6, d, ppm): 1.27 (t, 3H,
CH2CH3), 2.24 (s, 3H, CH3CvN), 4.19 (q, CH2CH3), 6.24
(d, 1H), 6.30 (d£d, 1H), 9.22 (s, 1H, H5het), 9.75 (br s, 1H),
10.50 (br s, 1H), 13.05 (br s, 1H). 13C NMR spectra (DMSO-
d6, d, ppm): 13.3, 14.5, 61.0, 103.1, 106.6, 111.7, 129.3,
154.1, 159.8, 160.1. Mass spectrum, m/z, (EI, %): M1 238
(100.0), 237 (26), 221 (44), 192 (33), 165 (23), 150 (20), 149
(25), 136 (59), 135 (39), and 107 (21).
Mechanism
We followed the progress of the cyclization reaction of
1,2,3-thiadiazole 1 by H NMR spectroscopy in DMSO-d6
1
with 1 equiv. of tetrabutylammonium hydroxide and the
intermediates 22a, 24a, and 26a were detected as described
earlier.4 On the other hand, in the case of 1,2,3-selena-
diazole 15, the formation of 26b was observed clearly,
without the accumulation of intermediates 22b±25b (see
Scheme 6).5
The thiolate 26a apparently results from a multistep process
involving the phenolate 22a which deprotonates the thia-
diazole ring with formation of the unstable heteroanion
23a, which is not detected but immediately decomposes to
the alkynethiolate 24a. Intramolecular proton shift gives the
reactive thioketene 25a, which undergoes intramolecular
nucleophilic cyclization to give the thiolate 26a. Both the
cleavage of the 1,2,3-selenadiazole and the ring closure of
the resulting alkyneselenolate are too fast to be detected,
re¯ecting the higher reactivity of selenium compounds.
The mechanism of the decomposition of aniline goes in a
different way. The amine function of 19b is not acidic
enough to form 22c, therefore 23c and 24c are formed
directly. This will only occur when the stronger t-butoxide
base is used, and not in the presence of potassium carbonate.
Alkynethiolate 24c remains stable to intramolecular hydro-
gen transfer from its amine function and can in fact be
alkylated to the acetylene 21.
(b) To the ethyl carbazone of 2,4-dihydroxyacetophenone
(8.00 g, 33.61 mmol), thionyl chloride (70 ml) was added
while cooling to 2788C. After the liberation of gas ceased,
the reaction mixture was re¯uxed for a further 3 h. The
excess of thionyl chloride was removed under reduced
pressure and the product was puri®ed by silica gel column
chromatography with dichloromethane/ethyl acetate (10:3)
as eluent. Yield of thiadiazole 2 4.00 g (61%), mp 2098C. 1H
NMR spectra (DMSO-d6, d, ppm): 6.43 (d£d, 1H), 6.55 (d,
1H), 8.08 (d, 1H), 9.22 (s, 1H, H5het), 9.7 (v br s, 1H, OH),
10.32 (br s, 1H, OH). 13C NMR spectra (DMSO-d6, d, ppm):
102.9, 107.4, 130.2, 131.9 (C5het), 156.0, 158.8 (C4het), 159.2.
Found, %: C 49.43; H 3.18; N 14.19. C8H6N2O2S. Calcd: C
49.48; H 3.11; N 14.42.
Only after the addition of an external source of protons, the
thioketene 25c can be formed and the cyclization to the
indole-2-thiolate 26c takes place.
4-(2,5-Dihydroxyphenyl)-1,2,3-thiadiazole 3. (a) To 2,5-
dihydroxyacetophenone (2.00 g, 13.1 mmol) in toluene
(50 ml) was added p-tosyl hydrazide (2.45 g, 13.1 mmol).
The reaction mixture was re¯uxed for 2 h with azeotropic
removal of water and allowed to stay overnight in the
refrigerator. The precipitate was ®ltered off and dried
under vacuum. Yield of p-tosyl hydrazone of 2,5-
dihydroxyacetophenone 3.81 g (90%): mp 1928C. 1H
NMR spectra (DMSO-d6, d, ppm): 2.22 (s, 3H, CH3), 2.37
(s, 3H, CH3CvN), 6.66 (d, 1H), 6.71 (d£d, 1H), 6.84 (d,
1H), 7.44 (d, 2H), 7.78 (d, 2H), 8.9 (br s, 1H, NH), 10.93 (s,
1H, OH). 13C NMR spectra (DMSO-d6, d, ppm): 14.6, 21.0,
114.0, 117.4, 118.6, 119.6, 127.4, 129.8, 135.4, 143.9,
149.3, 150.2, 158.1. Mass spectrum, m/z, (EI, %): M1 320
(83), 165 (90), 148 (47), 136 (100.0), 120 (23), 107 (47), 91
(80), 79 (44), 65 (65), 53 (27), 51 (22), and 39 (38).
Experimental
Mp's were determined using a Reichert Thermovar
apparatus. NMR spectra were recorded on a Bruker AMX-
400 spectrometer. Mass spectra were obtained on a
Hewlett±Packard MS Engine no. 5989A in EI (2508C).
The solvents DMF, acetone, acetonitrile were dried on
Ê
molecular sieves 4 A, and THF was freshly distilled from
sodium metal in a nitrogen atmosphere.
4-(o-Hydroxyphenyl)-1,2,3-thiadiazole 1.8 To the ethyl
carbazone of o-hydroxyacetophenone (1.0 g, 4.50 mmol)
thionyl chloride (10 ml) was added while cooling to
2788C with an acetone/CO2 bath. After the liberation of
gas was completed, the reaction mixture was heated gently
and then re¯uxed for 1 h. The excess of thionyl chloride was
removed under reduced pressure and the product was
(b) To the p-tosyl hydrazone of 2,5-dihydroxyacetophenone
(1.10 g, 3.44 mmol) thionyl chloride (10 ml) was added
while cooling to 2788C. After the liberation of gas was

M. A. Abramov et al. / Tetrahedron 56 (2000) 3933±3940
3937
completed, the reaction mixture was allowed to reach room
temperature and stirred for a further 2 h. The excess of thio-
nyl chloride was removed under reduced pressure and the
product was puri®ed by silica gel column chromatography
with dichloromethane/ethyl acetate (10:3) as the eluent.
Yield of 3 0.46 g (69%), mp 2168C. 1H NMR spectra
(DMSO-d6, d, ppm): 6.74 (d, 1H), 6.89 (d£d, 1H), 7.73
(d, 1H), 9.02 (s, 1H, OH), 9.43 (s, 1H, H5het), 9.77 (s, 1H,
OH). 13C NMR spectra (DMSO-d6, d, ppm): 114.9, 117.26,
117.33, 134.7 (Ch5et), 147.4, 150.0, 158.4 (C4het). Mass spec-
trum, m/z, (EI, %): M1 194 (94), 166 (35), 137 (100.0), 110
(37), 105 (28), 94 (27), 82 (20), 66 (31), 65 (31), 55 (21), 53
(28), 45 (26), 39 (44). Found, %: C 49.52; H 3.15; N 14.32.
C8H6N2O2S. Calcd: C 49.48; H 3.11; N 14.42.
69 (11), 57 (31), 55 (27), 43 (65), 41 (44). Found, %: C
76.77; H 10.10. C24H38OS. Calcd: C 76.95; H 10.22.
2-Benzylsulfanylbenzofuran 6. A mixture of thiadiazole 1
(1.0 g, 5.62 mmol), dry acetone (40 ml), K2CO3 (0.93 g,
6.74 mmol), and benzyl chloride (0.85 g, 6.74 mmol) was
stirred overnight under re¯ux. The reaction mixture was
®ltered and the ®ltrate was evaporated under reduced
pressure. The product was puri®ed by silica gel column
chromatography with dichloromethane/cyclohexane (1:2)
as the eluent. Yield of benzofuran 6 1.28 g (91%), light-
1
yellow oil. H NMR spectra (CDCl3, d, ppm): 4.14 (s, 2H,
SCH2), 6.65 (s, 1H, H3het), 7.17±7.45 (m, 9H, Harom). 13C
NMR spectra (CDCl3, d, ppm): 39.3 (CH2S), 110.9, 111.8
(C3het), 120.5, 122.8, 124.8, 127.3, 128.5, 128.8, 137.1, 149.6
(C2het), 156.3. Mass-spectrum, m/z, (EI, %): M1 240 (58),
[M±CH2Ph]1 149 (11), 121 (19), 92 (19), 91 (100.0), 77
(16), 65 (25), 39 (12). HRMS: M 240.0609. C15H12OS.
Calcd: M 240.0609.
2-Methylsulfanylbenzofuran 4 and 4-(ortho-methoxy-
phenyl)-1,2,3-thiadiazole 9. A mixture of thiadiazole 1
(1.0 g, 5.62 mmol), dry acetone (40 ml), K2CO3 (0.93 g,
6.74 mmol), and methyl iodide (1.20 g, 8.43 mmol) was
stirred overnight under re¯ux. The reaction mixture was
®ltered and the ®ltrate was evaporated under reduced
pressure. The product was puri®ed by silica gel column
chromatography with dichloromethane/cyclohexane (1:2)
as the eluent. The ®rst fraction contained 0.52 g (56%) of
benzofuran 4, light-yellow oil. 1H NMR spectra (CDCl3, d,
ppm): 2.52 (s, 3H, SCH3), 6.66 (s, 1H,H3, 3Jˆ0.9 Hz), 7.18
(t£d, 1H), 7.22 (t£d, 1H), 7.41 (d, 1H), 7.46 (d, 1H). 13C
NMR spectra (CDCl3, d, ppm): 17.0 (CH3S), 107.8 (C3het),
110.7, 120.1, 122.8, 123.9, 128.5, 152.2 (C2het), 156.0. Mass
spectrum, m/z, (EI, %): M1 164 (92), 150 (10), [M±CH3]1
149 (100.0), 121 (50), 77 (32), 69 (10), 63 (18), 51 (17).
HRMS: M 164.0298. C9H8OS. Calculated: M 164.0296.
The second fraction contained thiadiazole 9 (0.47 g, 40%).
1H NMR spectra (CDCl3, d, ppm): 3.96 (s, 3H, OCH3), 7.06
(d, 1H,H3), 7.14 (t£d, 1H, H5), 7.41 (t£d, 1H, H4), 8.50
(d£d, 1H, H6), 9.06 (s, 1H, Hh5et). 13C NMR spectra
(CDCl3, d, ppm): 55.5 (CH3O), 111.2, 119.6, 121.1,
130.0,130.3, 133.3 (C5het), 156.3, 158.4(C4het). Mass spec-
trum, m/z, (EI, %): M1 193 (30), M±N2 164 (81), M±N2±
CH3 149 (100.0), 131 (50), 121 (100.0), 119 (43), 91 (40),
77 (71), 51 (41), 49 (28), 45 (29), 39 (27).
2-n-Hexadecylsulfanyl-6-hydroxybenzofuran 7. A mixture
of thiadiazole 2 (0.50 g, 2.58 mmol), K2CO3 (0.429 g,
3.09 mmol), dry acetone (30 ml) and 1-bromohexadecane
(0.79 g, 2.58 mmol) was stirred overnight at room tempera-
ture. The solvent was evaporated under reduced pressure
and product was puri®ed by silica gel column chromato-
graphy with dichloromethane as the eluent. Yield of benzo-
1
furan 7: 0.48 g (46%), white solid, mp 658C. H NMR
spectra (CDCl3, d, ppm): 0.88 (t, 3H, CH3), 1.25 (s, 24H,
(CH2)12), 1.39 (t£d, 2H, SCH2CH2CH2), 1.63 (t£d, 2H,
SCH2CH2), 2.87 (t, 2H, SCH2), 4.95 (br s, 1H), 6.73, (d,
1H, H3), 6.76 (d£d, 1H, H5), 6.95 (d, 1H, H7), 7.32 (d,
1H, H4). 13C NMR spectra (CDCl3, d, ppm): 14.3, 22.7,
28.4, 29.1, 29.4, 29.5, 29.6, 29.7, 31.9, 35.2 (CH2S), 98.1,
111.7 (C3het), 111.9, 120.7, 122.2, 149.2, 153.7, 157.2. Mass
spectrum, m/z, (EI, %): M1 390 (100.0), 167 (12), 166 (83),
165 (21), 137 (12), 69 (11), 57 (24), 55 (23), 43 (44), and 41
(30). Found, %: C 73.64; H 9.81. C24H38O2S. Calcd: C
73.80; H 9.71.
2-(n-Hexadecylsulfanyl)-5-hydroxybenzofuran 8. To a
solution of thiadiazole 3 (0.16 g, 0.82 mmol) and of
t-BuOK (0.10 g, 0.90 mmol) in dry acetone (10 ml) was
added 1-bromohexadecane (0.25 g, 0.82 mmol) and the
reaction mixture was stirred overnight at room temperature.
The solvent was evaporated under reduced pressure and the
product was puri®ed by silica gel column chromatography
with dichloromethane as the eluent. Yield of benzofuran 8
0.31 g (97%), white solid, mp 728C. 1H NMR spectra
(CDCl3, d, ppm): 0.88 (t, 3H, CH3), 1.25 (s, 24H,
(CH2)12), 1.40 (t£d, 2H, SCH2CH2CH2), 1.65 (t£d, 2H,
SCH2CH2), 2.92 (t, 2H, SCH2), 4.69 (br s, 1H), 6.65, (d,
1H, H3), 6.76 (d£d, 1H, H6), 6.89 (d, 1H, H4), 7.27 d (1H,
H7). 13C NMR spectra (CDCl3, d, ppm): 14.3, 22.7, 28.5,
29.1, 29.3, 29.5, 29.6, 29.7, 31.9, 34.7 (CH2S), 105.2, 110.1
(C3het), 111.3, 112.7, 129.5, 151.3, 151.4, 151.9 (C2het).
Mass spectrum, m/z, (EI, %): M1 390 (51), 167 (13), 160
(100.0), 137 (15), 71 (12), 57 (31), 55 (28), 43 (62), 41 (46).
Found, %: C 73.64; H 9.81. C24H38O2S. Calcd: C 73.80; H
9.71.
Note: when MeI was added to a re¯uxing mixture of
thiadiazole 1 and K2CO3 in dry acetone the benzofuran 4
was isolated in 90% yield.
2-n-Hexadecylsulfanylbenzofuran 5. A mixture of thiadia-
zole 1 (0.5 g, 2.81 mmol), dry acetone (40 ml), K2CO3
(0.47 g, 3.37 mmol), and 1-bromohexadecane (1.03 g,
3.37 mmol), was stirred overnight under re¯ux. The reaction
mixture was evaporated under reduced pressure and the
product was puri®ed by silica gel column chromatography
with dichloromethane as eluent. Yield of benzofuran 5
0.97 g (92%), white solid, mp 308C. 1H NMR spectra
(CDCl3, d, ppm): 0.88 (t, 3H, CH3), 1.25 (s, 24H,
(CH2)12), 1.40 (t£d, 2H, SCH2CH2CH2), 1.66 (t£d, 2H,
SCH2CH2), 2.93 (t, 2H, SCH2), 6.76 (d, 1H, H3,
3Jˆ0.9 Hz), 7.20 (t£d, 1H, H5), 7.25 (t£d, 1H, H6), 7.43
(m, 1H, H7), 7.49 (m, 1H, H4). 13C NMR spectra (CDCl3,
ppm): 14.3, 22.7, 28.5, 29.1, 29.4, 29.5, 29.6, 29.7, 31.9,
34.7 (CH2S), 110.6, 110.9, 120.3, 122.8, 124.2, 128.7, 150.9
(C2het), 156.2. Mass spectrum, m/z, (EI, %): M1 374 (100.0),
151 (13), 150 (97), 149 (19, M2C16H33), 121 (15), 71 (11),
1,11-Bis(5-hydroxybenzofuran-2-sulfanyl)-3,6,9-trioxa-
undecane 10. To a mixture of thiadiazole 3 (1.00 g,

3938
M. A. Abramov et al. / Tetrahedron 56 (2000) 3933±3940
5.16 mmol), K2CO3 (0.71 g, 5.16 mmol) in dry acetone
(40 ml) 1,11-dichloro-3,6,9-trioxaundecane (0.5 equiv.,
0.16 g, 2.58 mmol) was added and the reaction mixture
was re¯uxed for 12 h. The resulting suspension was evapo-
rated under reduced pressure and the product was puri®ed
by silica gel column chromatography with dichloromethane/
ethyl acetate (10:3) as eluent. Yield of ether 10 0.90 g
(b) To the ethyl carbazone of 2-acetyl-1-naphthol (0.70 g,
2.57 mmol), thionyl chloride (10 ml) was added while
cooling to 2788C with an acetone/CO2 bath. When the
liberation of gas ceased, the reaction mixture was allowed
to reach room temperature and stirred for a further 1 h. The
excess of thionyl chloride was removed under reduced
pressure and the product was puri®ed by silica gel column
chromatography with dichloromethane as the eluent. Yield
1
(72%): white solid, mp 1258C. H NMR spectra (DMSO,
1
d, ppm): 3.11 (t, 4H, SCH2), 3.62 (t, 4H), 4.45±4.50 (m,
8H), 6.75 (d£d, 2H, H6), 6.86 (d, 2H, H3), 6.87 (d, 2H, H4),
7.31 (d, 2H, H7). 13C NMR spectra (CDCl3, d, ppm): 33.3
(CH2S), 69.1, 69.6, and 69.7 (CH2O), 104.8, 109.3 (C3het),
111.0, 113.0, 129.0, 149.8, 150.2 (C2het), 153.4. Mass spec-
trum, m/z, (EI, %): M1 490 (68), 192 (14), 167 (12), 166
(36), 165 (100.0), 137 (22), 87 (10), 73 (15), 45 (24). Found,
%: C 58.54; H 5.40. HRMS: M 490.1120. C24H26O7S2.
Calcd: C 58.76; H 5.34. M 490.1120.
of 12 0.17 g (25%), orange solid, mp 1538C. H NMR
spectra (DMSO-d6, d, ppm): 7.70 (t, 1H), 7.77 (t, 1H),
8.16 (d, 1H), 8.41 (s, 1H, H3naphth), 8.47 (d, 1H), 9.82 (s,
H5het), 11.17 (s, 1H, OH). 13C NMR spectra (CDCl3, d,
ppm): 111.5, 121.7, 123.4, 123.8, 125.5, 126.4, 126.7,
128.7, 130.7, 135.5 (C5het), 150.3, 158.8 (C4het). Mass
spectrum, m/z, (I, %): M1 262/264 (68/26), 235 (12), 234/
236 (56/21), 205 (40), 199 (89), 173 (19), 171 (100.0), 126
(20), 85 (18). Found, %: C 54.24; H 2.77; N 10.44.
C12H7N2ClOS. Calcd: C 54.86; H 2.69; N 10.66.
1,11-Dithiabis-2,5-benzofuro[36]crown-10 11. A mixture
of NaH (0.70 g, 24.5 mmol, 80% suspension in oil) and THF
(200 ml) was stirred for 30 min and 1,11-bis(5-hydroxy-
benzofuran-2-sulfanyl)-3,6,9-trioxaundecane 10 (0.60 g,
1.22 mmol) in THF (200 ml) was added dropwise. The
reaction mixture was heated to 658C, the solution of 1,11-
bis(tosyloxy)-3,6,9-trioxaundecane (0.74 g, 1.47 mmol) in
THF (200 ml) was added dropwise for 12 h and this solution
was stirred at 658C for 72 h. The reaction mixture was
allowed to cool to room temperature, several drops of
water were added and the solvent was evaporated under
reduced pressure. The residue was dissolved in a mixture
of toluene (200 ml) and water (100 ml), the organic layer
was washed with 0.5 N NaOH (50 ml), 2 N HCl (80 ml) and
water (2£100 ml). This organic layer was evaporated under
reduced pressure and the product was puri®ed by silica gel
column chromatography with ethyl acetate as the eluent.
Yield of crown ether 11 0.30 g (38%): white solid, mp
648C. 1H NMR spectra (CDCl3, d, ppm): 3.09 (t, 4H,
SCH2), 3.58 (t, 8H), 3.65±3.75 (m, 12H), 3.84 (t, 4H),
4.06 (t, 4H), 6.65 (s, 2H, H3), 6.83 (d£d, 2H, H6), 6.87 (d,
2H, H4), 7.23 (d, 2H, H7). 13C NMR spectra (CDCl3, d,
ppm): 33.9 (CH2S), 68.4, 69.8, 70.0, 70.5, 70.7, 70.79,
and 70.84 (CH2O), 104.1, 11.1 (C3het), 111.3, 113.8, 129.0,
150.6 (C2het), 151.4, 155.2. Mass spectrum, m/z, (EI, %): M1
648 (100.0), 192 (10), 191 (21), 165 (28), 148 (11), 89 (10),
45 (50), 43 (19). Found, %: C 59.31; H 6.25. C32H40O10S2.
Calcd: C 59.24; H 6.21.
2-n-Hexadecylsulfanyl-5-chloronaphtho[2,3-a]furan 13.
To a mixture of thiadiazole 12 (0.13 g, 0.48 mmol) and
dry acetone (15 ml) K2CO3 (0.47 g, 3.37 mmol) and
1-bromohexadecane (1.03 g, 3.37 mmol) was added and
this was stirred under re¯ux overnight. The mixture was
®ltered and evaporated under reduced pressure. The reaction
product was puri®ed by silica gel column chromatography
with dichloromethane/cyclohexane (1:1) as the eluent.
Yield of naphthofuran 13 0.18 g (82%), mp 308C. 1H
NMR spectra (CDCl3, d, ppm): 0.88 (t, 3H, CH3), 1.25 (s,
24H, (CH2)12), 1.43 (t£d, 2H, SCH2CH2CH2), 1.69 (t£d,
2H, SCH2CH2), 2.97 (t, 2H, SCH2), 6.88 (s, 1H, H3), 7.59
(t, 1H), 7.64 (t, 1H), 7.69 (s, 1H, H4), 8.31 (d, 1H, H9). 13
C
NMR spectra (CDCl3, d, ppm): 14.1, 22.7, 28.4, 29.1, 29.4,
29.5, 29.55, 29.64, 29.67, 29.8, 31.9, 35.4 (CH2S), 111.9
(C3), 119.0, 120.5, 121.6, 124.0, 125.4, 126.2, 126.9,
127.2, 128.1, 150.6, 151.0. Mass spectrum, m/z, (EI, %):
M1 458 (100.0), 263 (10), 234 (42), 233 (13, M±C16H33),
69 (12), 55 (32), 49 (18), 43 (93), 41 (66). Found, %: M
458.2413. C28H38OSCl. Calcd: M 458.2410.
4-(4-Chloro-1-hexadecyloxy-2-naphthyl)-1,2,3-thiadia-
zole 14 was isolated from the same reaction as a side
1
product with 0.02 g (9%) yield. H NMR spectra (CDCl3,
d, ppm): 0.88 (t, 3H, CH3), 1.26 (s, 24H, (CH2)12), 1.85 (q,
2H, OCH2CH2CH2), 1.98 (q, 2H, OCH2CH2), 3.82 (t, 2H,
OCH2), 7.62±7.69 (m, 2H, H6naphth and Hn7aphth), 8.22 (d), and
8.30 (d, 2H, H5naphth and H8naphth), 8.56 (s, 1H, H3naphth), 9.25 (s,
1H, H5tda). 13C NMR spectra (CDCl3, d, ppm): 14.1, 22.7,
26.1, 29.3, 29.4, 29.5, 29.6, 29.7, 30.4, 31.9, 74.9 (CH2O),
120.4, 123.1, 125.1, 126.8, 127.2, 128.0, 128.1, 129.5,
132.2, 134.2 (Ch5et), 152.0, 158.8 (Ch4et). Mass spectrum,
m/z, (EI, %): M1 486 (23), 413 (25), 262 (54), 234 (61),
234 (26), 202 (67), 43 (100.0), 41 (65).
4-(4-Chloro-1-hydroxy-2-naphtyl)-1,2,3-thiadiazole 12.
(a) To a solution of 2-acetyl-1-naphthol (2.00 g, 10.7
mmol) in a mixture of ethanol (20 ml) and water (20 ml)
was added ethyl carbazide (1.12 g, 10.7 mmol). The
reaction mixture was re¯uxed for 3 h and allowed to cool
overnight. The yellow crystalline precipitate was ®ltered off
and dried under vacuum. Yield of the carbethoxyhydrazone
1
of 2-acetyl-1-naphthol 2.27 g (78%), mp 1708C. H NMR
4-(o-Hydroxyphenyl)-1,2,3-selenadiazole 15. To the semi-
carbazone of o-hydroxyacetophenone (3.8 g, 20 mmol) in
glacial acetic acid (10 ml) SeO2 (2.2 g, 20 mmol) was
added in one portion. The reaction mixture was heated to
608C and stirred for 2 h. The dark, cherry red solution was
diluted with water (20 ml), the precipitate was ®ltered off,
washed with water and dried. Yield of the crude product 15:
3.24 g (72%). After recrystallization from a mixture
ethanol±water 2.48 g (55%) pure selenadiazole 15 was
spectra (CDCl3, d, ppm): 1.43 (t, 3H, CH2CH3), 2.34 (s, 3H,
CH3CvN), 4.37 (q, 2H, CH2CH3), 7.29 (d, 1H), 7.45±7.52
(m, 3H), 7.73 (d, 1H,), 7.8±8.8 (v. br. s, 1H, NH), 8.45 (d,
1H), 13.64 (s, 1H, OH). 13C NMR spectra (CDCl3, d, ppm):
12.4, 14.5, 62.5, 111.9, 117.9, 123.6, 123.7, 125.3, 125.7,
127.0, 127.7, 134.7, 156.4. Mass spectrum, m/z, (EI, %): M1
272 (100.0), 255 (28), 226 (37), 211 (13), 184 (12), 183 (47),
170 (30), 140 (13), 128 (14), 115 (35).

M. A. Abramov et al. / Tetrahedron 56 (2000) 3933±3940
3939
1
isolated as light brown plates, mp 103±1058C. H NMR
spectra (DMSO-d6, d, ppm): 6.99 (q, 1H, H5arom), 7.08 (d,
1H, H3arom), 7.28 (q, 1H, Ha4rom), 8.26 (d, 1H, H6arom), 10.09 (s,
1H, H5het, with satellites 2JHSeˆ42 Hz), 10.35 (br s, 1H, OH).
13C NMR spectra (DMSO-d6, d, ppm): 116.4, 119.5, 129.6,
130.1 (C3, C4, C5, Ca6rom), 118.8 (C1arom), 142.1 d (C5het,
(30 ml) was added dropwise while cooling to 2788C with
an acetone/CO2 bath. After the liberation of gas was
completed, the reaction mixture was re¯uxed for 2 h. The
excess of thionyl chloride was removed under reduced
pressure and the product was puri®ed by silica gel column
chromatography with dichloromethane as the eluent. Yield
of 4-(2-nitrophenyl)-1,2,3-thiadiazole 19a 1.55 g (70%),
yellow-brown plates, mp 75±768C. 1H NMR spectra
(CDCl3, d, ppm): 7.64 (t£d, 1H), 7.73 (t£d, 1H,), 7.81
(d£d, 1H), 8.00 (d£d, 1H), 8.64 (s, 1H, H5het). 13C NMR
spectra (CDCl3, ppm): 124.6, 125.3, 130.3, 132.1, 132.8,
134.1, 149.0, 157.5 (C4het). Mass spectrum, m/z, (EI, %):
MH1 208 (100.0), 135 (2), 134 (2).
1JCHˆ196 Hz, satellites JCSeˆ133 Hz), 155.2 (C4het). Mass
1
spectrum, m/z, (EI, %): M1 226(1.5), 198(11.4), 197(11.3),
118(100.0). Found, %: C 42.23; H 2.91. C8H8N2OSe. Calcd,
%: C 42.69, H 2.69.
2-Methylselenobenzofuran 16. A mixture of selenadiazole
15 (0.4 g, 0.18 mmol), dry acetone (5 ml), and K2CO3
(0.3 g, 22 mmol) was stirred under re¯ux for 2 h and methyl
iodide (0.43 g, 30 mmol) was added. After re¯ux for 1 h the
reaction mixture was ®ltered and the ®ltrate was evaporated
under reduced pressure. The residue obtained was puri®ed
by silica gel column chromatography with heptane/CCl4
(1:1) as eluent. Yield of benzofuran 16 0.29 g (76%),
(b) To a suspension of 5% Pd/C (2 g) in ethanol (160 ml)
4-(2-nitrophenyl)-1,2,3-thiadiazole 19a (1.21 g, 5.85 mmol)
and of hydrazine hydrate (1.46 g, 29.2 mmol) was added.
The reaction mixture was re¯uxed for 24 h, cooled, ®ltered
over Celite and the ®ltrate was evaporated under reduced
pressure. The product was puri®ed by silica gel column
chromatography with dichloromethane as the eluent. Yield
of 4-(2-aminophenyl)-1,2,3-thiadiazole 19b 0.81 g (78%),
1
light-yellow oil. H NMR spectra (CDCl3, d, ppm): 2.41
(s, 3H, SeCH3), 6.80 (s, 1H, H3), 7.16 (m, 1H), 7.24 (m,
1H), 7.48 (d, 1H), 7.57 (d, 1H). 13C NMR spectra (CDCl3, d,
ppm): 8.0 (CH3Se), 110.8 (C3het), 111.5, 120.0, 122.8, 123.9,
128.8, 145.0 (C2het), 157.0. Mass spectrum, m/z, (EI, %): M1
212 (100.0), 197 (83.8), 169 (33.2), 132 (10.2), 131 (15.3),
89 (44.6).
1
light-red plates, mp 84±858C. H NMR spectra (CDCl3, d,
ppm): 5.53 (br s, 2H, NH2, 6.78±6.84 (m, 2H, H3arom and
H5arom), 7.21 (t£d, 1H, Ha4rom), 7.49 (d£d, 1H, H6arom), 8.62
(s, 1H, H5het). 13C NMR spectra (CDCl3, d, ppm): 114.4
1
(ipso-TDA), 117.2, 117.9, 129.5, 130.4 (C5het, JCH
ˆ
2-Benzylselenobenzofuran 17. A mixture of selenadiazole
15 (0.5 g, 22 mmol), dry acetone (5 ml), benzyl chloride
(0.31 g, 24 mmol), and K2CO3 (0.6 g, 43 mmol) was stirred
under re¯ux for 5 h. The reaction mixture was ®ltered and
the ®ltrate was evaporated under reduced pressure. The
reaction product was puri®ed by silica gel column chroma-
tography with benzene as the eluent. Yield of benzofuran 17
190 Hz), 130.8, 145.5 (ipso-NH2), 163.1 (C4het). Mass spec-
trum, m/z, (EI, %): M1 177 (63), 149 (78), 117 (100.0), 89
(33), 77 (26), 49 (32).
(c) To 4-(2-aminophenyl)-1,2,3-thiadiazole 19b (0.15 g,
0.85 mmol) in THF (20 ml) t-BuOK (0.112 g, 1 mmol)
was added under argon and mixture was stirred for
15 min, when the liberation of gas ceased. One drop of
acetic acid was added, and the reaction mixture was stirred
for another 10 min, follow by adding MeI (0.18 g,
1.275 mmol) in one portion. The mixture was stirred for
1 h, the solvent was removed under reduced pressure and
the product was puri®ed by silica gel column chromato-
graphy with hexane/dichloromethane (1:3) as the eluent.
Yield of 2-methylsulfanylindole 20 0.12 g (85%), light-
brown solid, mp 47±488C (mp 48±4911). 1H NMR
spectra (CDCl3, d, ppm): 2.44 (s, 3H, SCH3), 6.52 (s,
1H,H3), 7.07±7.20 (m, 3H), 7.50 (d, 1H), 8.00 (br s,
1H, NH).
1
0.41 g (65%), light-yellow oil. H NMR spectra (CCl4, d,
ppm): 7.61±6.4 (m, 9H, Harom), 6.52 (s, 1H, H3het), 3.96 (s,
2H, CH2Se). 13C NMR spectra (CDCl3, d, ppm): 27.3
(CH2Se), 110.9 (C3het), 111.2, 120.5, 122.8, 124.8, 127.3,
128.4, 128.8, 137.1, 145.6 (C2het), 156.9. Mass spectrum,
m/z, (EI, %): M1 288 (38.7), 197 (19.8), 169 (16.8), 91
(100.0). M287.22.
Methyl (ortho-methoxy-phenylethynyl)selenide 18. A
mixture of selenadiazole 15 (0.4 g, 18 mmol), dry acetone
(5 ml), methyl iodide (0.43 g, 30 mmol), K2CO3 (0.3 g,
22 mmol) was re¯uxed with stirring for 5 h. Then methyl
iodide (0.21 g, 15 mmol) was added and stirring was con-
tinued for 15 min. The reaction mixture was ®ltered and the
®ltrate was concentrated under reduced pressure. The pure
product was obtained by silica gel column chromatography
with benzene as the eluent. The ®rst fraction contained a
small amount of benzofuran 16. Yield of 18 0.13 g (59%),
light-yellow oil. 1H NMR spectra (CDCl3, d, ppm): 2.38 (s,
3H, SeCH3), 3.87 (s, 3H, OCH3), 6.80 (d, 1H, H3arom), 6.88
(q, 1H, H5arom), 7.29 (q, 1H, H4arom), 7.40 (d, 1H, Ha6rom). 13C
NMR spectra (CDCl3, d, ppm): 9.93 (SeCH3), 55.7 (CH3O),
75.0 (CuC±Se), 94.3 (CuC±Se), 110.5, 120.3, 123.1,
129.5, 133.3, 157.0. Mass-spectrum, m/z, (EI, %): M1 226
(63.6), 211 (6.3), 183 (6.3), 168 (14), 131 (100.0), 119
(20.7), 91 (24.7), 77 (9.9).
When the reaction was carried out without the addition of
acetic acid only 2-(2-aminophenyl)ethynylsulfanylmethane
21 was isolated in 85% yield as an oil. H NMR spectra
1
(CDCl3, d, ppm): 2.44 (s, 3H, SCH3), 4.20 (br s, 2H, NH2),
6.65 (m, 2H), 7.08 (m, 1H), 7.23 (m, 1H). Mass spectrum,
m/z, (EI, %): M1 163 (73), 148 (100.0), 121 (21), 104 (11),
77 (13), 49 (8).
Acknowledgements
We thank the University, the Ministerie voor Wetenschaps-
beleid and the FWO Vlaanderen for their continuing
support. B. D. and S. S. thanks the I.W.T. for predoctoral
fellowship.
2-Methylsulfanylindole 20. (a) To the ethyl carbazone of
o-nitroacetophenone (2.2 g, 10.6 mmol) thionyl chloride

3940
M. A. Abramov et al. / Tetrahedron 56 (2000) 3933±3940
5. Petrov, M. L.; Abramov, M. A.; Dehaen, W.; Toppet, S.
Tetrahedron Lett. 1999, 40, 3903.
References
6. Butler, R. N.; O'Donoghue, D. A. J. Chem. Soc., Perkin Trans.
1 1982, 1223.
1. Raap, R.; Micetich, R. G. Can. J. Chem. 1968, 46, 1057.
2. Laishev, V. Z.; Petrov, M. L.; Petrov, A. A. Zh. Org. Khim.
1982, 18, 281 (see also p. 514).
7. Hurd, C. D.; Mori, R. I. J. Am. Chem. Soc. 1955, 77, 5359.
8. The synthesis of thiadiazole 1 has been reported before in a
patent without experimental data: Muchowski, J. M.; Fried, J. H.
US Pat. 3940407, 1976; Chem. Abstr. 1976, 85, P63072a.
9. Asakawa, M.; Ashton, P. R.; Dehaen, W.; L'abbe, G.; Menzer,
S.; Nouwen, J.; Raymo, F. M.; Stoddart, J. F.; Tolley, M. S.;
Toppet, S.; White, A. J. P.; Williams, D. J. Chem. Eur. J. 1997,
3, 772.
3. Zmitrovich, N. I.; Petrov, M. L. Zh. Obsch. Khim. 1999, 35,
781; Murai, T.; Esaka, T.; Kato, S. Bull. Chem. Soc. Jpn 1998, 71,
1193; Murai, T.; Kakami, K.; Hayashi, A.; Komuro, T.; Takada,
H.; Fujii, M.; Kanda, K.; Kato, S. J. Am. Chem. Soc. 1997, 119,
Â
8592; L'abbe, G.; Dehaen, W.; Haelterman, B. J. Chem. Soc.,
Perkin Trans. 1, 1994, 2203; Terenteva, N. A.; Petrov, M. L.;
Potekhin, K. A.; Galichev, B. A.; Struchov, Yu. T. Zh. Org.
Khim. 1994, 30, 1471; Ishihara, H.; Yoshimi, M.; Kato, S.
Angew. Chem. 1990, 102, 572; Petrov, M. L.; Petrov, A. A. Usp.
Khim. 1987, 61, 267.
10. Lalezari, I.; Shaf®ee, A.; Yalpani, M. Tetrahedron Lett. 1969,
58, 5105; Caplin, A. J. Chem. Soc., Perkin Trans. 1, 1974, 30;
Lalezari, I.; Shaf®ee, A.; Yalpani, M. J. Org. Chem. 1971, 36,
2836.
4. D'hooge, B.; Smeets, S.; Toppet, S.; Dehaen, W. J. Chem. Soc.,
Chem. Commun. 1997, 1753.
11. Plate, R.; Ottenheijn, H. C. J. Tetrahedron 1986, 4510.