Synthesis of 1,1-dialkylindolium-2-thiolates via base-induced transformation of 4-(2-chloro-5-nitrophenyl)-1,2,3-thiadiazole in the presence of secondary amines

Article abstract of DOI:10.1021/jo801801y

(Chemical Equation Presented) 4-(2-Chloro-5-nitrophenyl)-1,2,3-thiadiazole undergoes ring-opening to produce a thioketene intermediate that reacts with secondary amines forming 2-(2-chloro-5-nitrophenyl)-N,N-dialkylthioacetamides. Intramolecular cyclization of these thioamides via nucleophilic substitution of the halogen on the aromatic ring affords nonaromatic 1,1-dialkylindolium-2- thiolates instead of the expected aromatic N,N-dialkylaminobenzo[b]thiophenes.

Full text of DOI:10.1021/jo801801y

SCHEME 1. Reaction of
4-(2-Chloro-5-nitrophenyl)-1,2,3-thiadiazole with Primary
Amines
Synthesis of 1,1-Dialkylindolium-2-thiolates via
Base-Induced Transformation of
4-(2-Chloro-5-nitrophenyl)-1,2,3-thiadiazole in the
Presence of Secondary Amines
Dmitry A. Androsov†
Center for Photochemical Sciences, Bowling Green State
UniVersity, Bowling Green, Ohio 43403
daa@dartmouth.edu
ReceiVed August 11, 2008
SCHEME 2. Reaction of
4-(2-Chloro-5-nitrophenyl)-1,2,3-thiadiazole with Secondary
Amines
4-(2-Chloro-5-nitrophenyl)-1,2,3-thiadiazole undergoes ring-
opening to produce a thioketene intermediate that reacts
with secondary amines forming 2-(2-chloro-5-nitrophe-
nyl)-N,N-dialkylthioacetamides. Intramolecular cyclization
of these thioamides via nucleophilic substitution of the
halogen on the aromatic ring affords nonaromatic 1,1-
dialkylindolium-2-thiolates instead of the expected aro-
matic N,N-dialkylaminobenzo[b]thiophenes.
be an issue. Furthermore, the only general method for the
synthesis of indole-2-thiols having no substituents at the C3-
position is the thionation of 2-oxyindoles.6,7
Recently, we have reported a simple and convenient approach
to a variety of N-substituted indole-2-thiols based on a one-pot
transformation of 4-(2-chloro-5-nitrophenyl)-1,2,3-thiadiazole
in the presence of primary amines. The mechanism of this
reaction was investigated.9 Base-induced deprotonation of the
thiadiazole ring causes anionic ring-opening, accompanied by
a loss of nitrogen to yield acetylene thiolate A. Protonation of
thiolate A produces a tautomeric mixture of acetylene thiol B
and thioketene C. Primary amine traps the highly reactive
thioketene C to form corresponding thioamide D. Finally,
intramolecular cyclization of thioamide D affords N-substituted
indole-2-thiol E (Scheme 1).
In an attempt to expand the scope of this reaction we were
surprised to find the base-induced reaction of 4-(2-chloro-5-
nitrophenyl)-1,2,3-thiadiazole with secondary amines selectively
afforded nonaromatic 1,1-dialkylindolium-2-thiolates instead of
the expected N,N-dialkylaminobenzo[b]thiophenes (Scheme 2).10
The results of our study are summarized in Table 1.
Compound 3g was obtained in low yield (7%) due to the
relatively high nucleophilicity of pyrrolidine which displaces
the chlorine atom on the benzene ring faster than cyclization
occurs, resulting in thioamide 4 (62%) as a major product
(Scheme 3).
The indole nucleus is ubiquitous among natural products, and
its synthesis has often attracted organic chemists.1,2 There are
several procedures that have been documented for the introduc-
tion of sulfur-containing substituents at the C2-position of the
indole ring: coupling of protected tryptophan derivatives with
sulfenyl chloride3 or dialkyl disulfides in the presence of the
silver salt of trifluoromethanesulfonic acid,4 thiol-mediated
radical cyclization of 2-alkenylphenyl isocyanides,5 treatment
of 2-oxyindole with Lawesson’s reagent6 or phosphorus pen-
tasulfide,7 and isomerization of 5-chloro-3-phenylthio-1H-indole
into the corresponding 5-chloro-2-phenylthio-1H-indole in the
polyphosphoric acid.8 However, the substituents that can be
incorporated are few, and/or the stability of the substrates can
† Present address: Department of Chemistry, Dartmouth College, Hanover,
New Hampshire 03755-3564.
(1) Sundberg, R. J. Indoles; Academic Press: London, UK, 1996.
(2) Saxton, J. E. Indoles; Wiley-Interscience: New York, 1983.
(3) Anderson, M. O.; Shelat, A. A.; Guy, R. K. J. Org. Chem. 2005, 70,
4578–4584.
(4) Haramura, M.; Tsuzuki, K.; Okamachi, A.; Yogo, K.; Ikuta, I.; Kozono,
T.; Takanashi, H.; Murayama, E. Bioorg. Med. Chem. 2002, 10, 1805–1811.
(5) Tokuyama, H.; Watanabe, M.; Hayashi, Y.; Kurokawa, T.; Peng, G.;
Fukuyama, T. Synlett 2001, 9, 1403–1406.
(6) Wenkerst, E.; Hanna, J. M.; Leftin, M. H.; Michelotti, E. L.; Potts, K. T.;
Usifer, D. J. Org. Chem. 1985, 50, 1125–1126.
(7) Olgen, S.; Akaho, E.; Nebioglu, D. Farmaco 2005, 60, 497–506.
(8) Hary, U.; Roettig, U.; Paal, M. Tetrahedron Lett. 2001, 42, 5187–5189.
(9) Androsov, D. A.; Neckers, D. C. J. Org. Chem. 2007, 72, 5368–5373.
(10) Solovyev, A. Y.; Androsov, D. A.; Neckers, D. C. J. Org. Chem. 2007,
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8612 J. Org. Chem. 2008, 73, 8612–8614
10.1021/jo801801y CCC: $40.75 2008 American Chemical Society
Published on Web 10/09/2008

TABLE 1. Synthesis of 1,1-Dialkylindolium-2-thiolates
SCHEME 3. Reaction of
4-(2-Chloro-5-nitrophenyl)-1,2,3-thiadiazole with Pyrrolidine
SCHEME 4. Counter-Synthesis of
1-Benzyl-1-methyl-5-nitro-1H-indoliumthiolate
SCHEME 5. Convenient in Situ Generation of
Dimethylamine
In summary, we have found and developed a convenient one-
pot synthesis of 1,1-dialkylindolium-2-thiolates, accomplished
with easily accessible starting materials. This procedure provides
a simple and practical approach to the construction of novel
polyfunctional indoles. Further studies of this reaction (reaction
conditions optimization, scope, and application) are underway.
Experimental Section
General Procedure for the Synthesis of 1,1-Dialkylindolium-2-
thiolates (3a-l). 4-(2-Chloro-5-nitrophenyl)-1,2,3-thiadiazole 1 (0.5
g; 2.07 mmol), K2CO3 (3-7 equiv), the corresponding amine 2a-l
(3-5 equiv), and 10 mL of DMF (in that order; for molar ratios
see Table 1) were charged into a 50-mL round-bottomed flask. The
mixture was stirred for 12 h at 90 °C. DMF was removed under
reduced pressure and the residue was purified via column chroma-
tography (SiO2, CHCl3/hexane (1:3), (1:2), (1:1) (2:1), or CHCl3/
MeOH (40:1), (100:1)) affording the corresponding 1,1-dialkylin-
dolium-2-thiolate 3a-l (yields 7-75%, see Table 1).
1,1-Dimethyl-5-nitro-1H-indolium-2-thiolate (3a). 4-(2-Chloro-
5-nitrophenyl)-1,2,3-thiadiazole 1 (0.5 g; 2.07 mmol), K2CO3 (2
g; 14.49 mmol; 7 equiv), ammonium acetate 2a (0.8 g; 10.35 mmol;
5 equiv), and 10 mL of DMF were charged into a 50-mL round-
bottomed flask. The mixture was stirred for 12 h at 90 °C. DMF
was removed under reduced pressure and the residue was purified
via column chromatography (SiO2, CHCl3/hexane (1:2)) to afford
red crystalline solid, 0.35 g (75%), mp 133-134 °C. 1H NMR (300
MHz, CDCl3) δ 3.04 (s, 6H), 5.97 (s, 1H), 7.59 (d, 1H), 7.82 (dd,
1H), 8.20 (d, 1H); 13C NMR (75 MHz, CDCl3) δ 42.2, 95.5, 114.4,
114.7, 121.5, 138.3, 141.8, 145.9, 159.9; m/z (EI, 70 eV) 222 (M+,
100%), 207 (3), 192 (6), 176 (60), 146 (27); HRMS (EI, 70 eV)
calcd for C10H10N2O2S M+ 222.0463, found 222.0464.
1,1-Diethyl-5-nitro-1H-indolium-2-thiolate (3b). 4-(2-Chloro-
5-nitrophenyl)-1,2,3-thiadiazole 1 (0.5 g; 2.07 mmol), K2CO3 (0.86
g; 6.21 mmol; 3 equiv), diethylamine 2b (0.76 g; 10.35 mmol; 5
equiv), and 10 mL of DMF were charged into a 50-mL round-
bottomed flask. The mixture was stirred for 12 h at 90 °C. DMF
was removed under reduced pressure and the residue was purified
via column chromatography (SiO2, CHCl3/hexane (1:3), (1:2), (1:
1)) to afford red crystalline solid, 0.29 g (55%), mp 41-42 °C. 1H
NMR (300 MHz, CDCl3) δ 1.26 (t, 6H), 3.40 (q, 4H), 5.97 (s,
The formation of 1,1-dialkylindolium-2-thiolates 3a-l was
unambiguously supported by counter-synthesis of compound 3f
from two different precursors. Surprisingly, quaternization of
the endocyclic N-atom and loss of aromaticity is preferable to
alkylation of the exocyclic S-atom, when aromaticity remains
intact (Scheme 4).
It is worthy of note that the best result for the synthesis of
compound 3a was achieved by using the combination NH4OAc/
K2CO3/DMF that made it possible to generate dimethylamine
in situ (Scheme 5).
J. Org. Chem. Vol. 73, No. 21, 2008 8613

1H), 7.58 (d, 1H), 7.81 (dd, 1H), 8.18 (d, 1H); 13C NMR (75 MHz,
CDCl3) δ 12.4, 47.0, 94.2, 114.08, 114.13, 121.3, 137.7, 142.1,
145.9, 157.9; m/z (EI, 70 eV) 250 (M+, 66%), 235 (100), 207 (25),
189 (23), 161 (20). Anal. Calcd for C12H14N2O2S: C 57.58; H 5.64;
N 11.19. Found: C 57.74; H 5.60; N 11.25.
Supporting Information Available: General information,
characterization data for compounds 3c-l and 4 along with
copies of 1H and 13C NMR and mass spectra of all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. I acknowledge the Office of Naval
Research (Grant No. N00014-05-1-0372) for partial support of
this work. I also thank Professor Douglas C. Neckers for his
helpful comments.
JO801801Y
8614 J. Org. Chem. Vol. 73, No. 21, 2008