Synthesis and reactivity of 4-(2-chloro-5-nitrophenyl)-1,2,3-thiadiazole. A novel one-pot synthesis of N-substituted indole-2-thiols

Article abstract of DOI:10.1021/jo0707784

(Chemical Equation Presented) 4-(2-Chloro-5-nitrophenyl)-1,2,3-thiadiazole undergoes ring opening to produce a thioketene intermediate that reacts with an O- or N-nucleophile, forming an ester or an amide of the aryl-substituted thioacetic acid. Intermole

Full text of DOI:10.1021/jo0707784

Synthesis and Reactivity of
4-(2-Chloro-5-nitrophenyl)-1,2,3-thiadiazole. A Novel One-pot
Synthesis of N-Substituted Indole-2-thiols†
Dmitry A. Androsov and Douglas C. Neckers*
Center for Photochemical Sciences, Bowling Green State UniVersity, Bowling Green, Ohio 43403
neckers@photo.bgsu.edu
ReceiVed April 13, 2007
4-(2-Chloro-5-nitrophenyl)-1,2,3-thiadiazole undergoes ring opening to produce a thioketene intermediate
that reacts with an O- or N-nucleophile, forming an ester or an amide of the aryl-substituted thioacetic
acid. Intermolecular cyclization of the thioacetic acid derivative via nucleophilic substitution of halogen
in the aromatic ring gives an N-substituted indole-2-thiol (in case of an N-nucleophile) or a 2-alkoxy-
substituted benzo[b]thiophene (in case of an O-nucleophile). The reaction is also applicable to the synthesis
of heterocyclic analogues of N-substituted indole-2-thiols: 1-butyl-1,3-dihydropyrrolo[2,3-b]pyridine-
2-thione was synthesized as an example. In the presence of potassium thioacetate (an S-nucleophile)
4-nitro-2-(1,2,3-thiadiazol-4-yl)benzenethiol is formed more quickly than thiadiazole ring opening occurs,
making the heterocyclic ring tolerant toward the base.
Introduction
Lawesson’s reagent, and isomerization of 5-chloro-3-(phen-
ylthio)-1H-indole into the corresponding 5-chloro-2-(phen-
ylthio)-1H-indole in the polyphosphoric acid.10 The substituents
that can be incorporated are few, and/or the stability of the
substrates can 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.6-8
Several natural products having specific biological activity
contain the indole-2-thiol fragment. For example, cruciferous
sulfur-containing phytoalexins, such as brassilexin, sinalexin,
and cyclobrassinin occurring in plants, have a broad antimi-
crobial activity, playing crucial roles in their resistance to
pathogen invasion.8,9,11,12 Indole-2-thiol derivatives13 have, for
The indole nucleus is ubiquitous among natural products, and
its synthesis has attracted synthetic chemists.1,2 There are several
problematic procedures that have been documented for the
introduction of the 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 isocya-
nides,5 treatment of 2-oxyindole6-8 or its derivative9 with
† Contribution No. 635 from the Center for Photochemical Sciences.
(1) Sundberg, R. J. Indoles; Academic Press: London, 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.
(8) Pedras, M. S. C.; Jha, M. J. Org. Chem. 2005, 70, 1828-1834.
(9) Pedras, M. S. C.; Zaharia, I. L. Org. Lett. 2001, 3(8), 1213-1216.
(4) Haramura, M.; Tsuzuki, K.; Okamachi, A.; Yogo, K.; Ikuta, I.;
Kozono, T.; Takanashi, H.; Murayama, E. Bioorg. Med. Chem. 2002, 10,
1805-1811.
(10) Hary, U.; Roettig, U.; Paal, M. Tetrahedron Lett. 2001, 42, 5187-
5189.
(11) Pedras, M. S. C.; Okanga, F. I. J. Agric. Food Chem. 1999, 47,
(5) Tokuyama, H.; Watanabe, M.; Hayashi, Y.; Kurokawa, T.; Peng, G.;
Fukuyama, T. Synlett 2001, 9, 1403-1406.
1196-1202.
(12) Pedras, M. S. C.; Khan, A. Q. J. Agric. Food Chem. 1996, 44, 3403-
(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.
3407.
(13) Rewcastle, G. W.; Denny, W. A. Heterocycles 1994, 37(2), 701-
708.
10.1021/jo0707784 CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/07/2007
5368
J. Org. Chem. 2007, 72, 5368-5373

4-(2-Chloro-5-nitrophenyl)-1,2,3-thiadiazole
SCHEME 1
SCHEME 2
medium and MeCN, Me2CO, MeOH, and EtOH could be used
as solvents. The use of DMF allows the reaction even at room
temperature (20-25 °C). Generally, we did not optimize the
reaction conditions (ratio of reagents, choice of solvent, tem-
perature) in each particular case. However, according to our
observations the yield of desirable indole-2-thiol can be
increased at lower reaction temperature (92% (22 h; 25 °C) vs
44% (3 h; 50 °C) for product 5a). Reaction of 3 with aniline
and N-phenylhydrazine under the same conditions gave none
of the desired indole-2-thiols.
example, been demonstrated as useful intermediates in the
synthesis of 2,2′-dithiobisindole tyrosine kinase inhibitors.7,14,15
Wieland et al.16-19 carried out notable synthetic work on
phalloidin as well as natural and nonnatural analogues of the
phallotoxins. Phalloidine is a cyclic heptapeptide fungal toxin
produced by Amanita Phalloides (the Death Cap mushroom)
comprised of a 2-thioindole fragment as a cross-linker. This
compound is a potent stabilizer of filamentous actin, and
fluorescently labeled phallotoxins have been used in cellular
biology to study the actin system.20 Some perspective small-
molecule motilin agonists contain the 2-thioindole unit. These
motilin analogues have been suggested as potential drugs for
the treatment of patients with hypomotility syndromes.4
Herein we report a new, 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. We have investigated the
mechanism of this reaction. It has been shown that the reaction
is applicable to the synthesis of 2-thioindole analogues having
heteroatoms in six-membered rings as well as to the synthesis
of 2-alkoxybenzo[b]thiophenes.
1
The mechanism of this reaction was studied by H NMR
monitoring of a reaction mixture containing 3, 4a, and K2CO3
in DMF at 25 °C (Scheme 3). Initially thiadiazole ring opening
was indicated by the disappearance of the thiadiazole H5 at δΗ
9.19. Decomposition of the electron-withdrawing thiadiazole
ring is accompanied by nitrogen evolution and formation of the
thioamide 3-V. The appearance of NH at δΗ 7.44 and an upfield
shift of phenyl protons at the 3-, 4-, and 6-positions by 0.30,
0.16, and 0.89 ppm, respectively, were observed. We also
followed the progress of the reaction by GC/MS. This supports
formation of the intermediate 3-V (m/z 286). After 22 h the
transformation was complete and the NMR spectrum showed a
clean absorption pattern of 1-butyl-5-nitro-1H-indole-2-thiol (5a)
with δΗ 0.97 (CH3CH2CH2CH2N), 1.46 (CH3CH2CH2CH2N),
1.67 (CH3CH2CH2CH2N), 3.24 (CH3CH2CH2CH2N), 4.28 (SH),
6.12 (H3), 7.59 (H7), 7.87 (H6), and 8.21 (H4). There were no
detectable impurities present. The supposed intermediates 3-I-
3-IV, 3-VI, and 3-VII were not detected by 1H NMR, but their
formation is not in conflict with our observations (see Scheme
8) and has been documented by data on the reactivity of
5-unsubstituted 1,2,3-thiodiazoles.23-25
Results and Discussion
The Hurd-Mori reaction gives access to 4-substituted 1,2,3-
thiadiazoles from methyl ketones via the reaction of the
corresponding ethyl carbazones or tosyl hydrazones with thionyl
chloride.21,22 This procedure was used to obtain the previously
unknown 4-(2-chloro-5-nitrophenyl)-1,2,3-thiadiazole (3) from
the starting 1-(2-chloro-5-nitrophenyl)ethanone (1) in 89%
overall yield (Scheme 1).
The dynamics of the transformation of thiadiazole 3 into
indole 5a via thioamide 3-V is shown in Figure 1.
In order to understand how the electron-withdrawing nitro
group exerts an influence on the reaction, we prepared 4-(2-
chlorophenyl)-1,2,3-thiadiazole (8) (overall yield 37%) from
1-(2-chlorophenyl)ethanone 6 by the Hurd-Mori22 procedure.
After heating 8 in the presence of n-BuNH2 and K2CO3 at 70
°C for 24 h, only the starting material 8 and thioamide 9 was
detected. Complete conversion of 8 into 9 was achieved at
elevated temperature (130 °C), but no trace of cyclized product
10 was found. Thus, the presence of the activating nitro group
at the phenyl ring makes the thiadiazole ring susceptible to
proton abstraction, facilitating anionic ring opening. Addition-
ally, heterocyclization of 9 into 10 does not occur, since the
chlorine atom is inactive to intramolecular nucleophilic attack
by amide nitrogen under the reaction conditions (Scheme 4).
We synthesized 2-chloro-3-(1,2,3-thiadiazol-4-yl)pyridine (13;
overall yield 79%) from 1-(chloropyridin-3-yl)ethanone (11)
When we carried out the base-catalyzed (K2CO3) alkylami-
nation of 3 with a variety of primary alkylamines 4a-l in DMF
at moderate temperature (50-80 °C), the unexpected N-
substituted indole-2-thiols 5a-l were isolated (Scheme 2).
Additionally, we found that the reaction is tolerant to the
(14) Rewcastle, G. W.; Palmer, B. D.; Dobrusin, E. M.; Fry, D. W.;
Kraker, A. J.; Denny, W. A. J. Med. Chem. 1994, 37(13), 2033-2042.
(15) Palmer, B. D.; Rewcastle, G. W.; Thompson, A. M.; Boyd, M.;
Showalter, H. D. H.; Sercel, A. D.; Fry, D. W.; Kraker, A. J.; Denny, W.
A. J. Med. Chem. 1995, 38(1), 58-67.
(16) Wieland, T. Peptides of Poisonous Amanita Mushrooms; Springer-
Verlag: New York, 1986.
(17) Munekata, E.; Faulstich, H.; Wieland, T. J. Am. Chem. Soc. 1977,
99, 6151-6153.
(18) Heber, H.; Faulstich, H.; Wieland, T. Int. J. Pept. Protein Res. 1974,
6, 381-389.
(19) Wieland, T.; Miura, T.; Seeliger, A. Int. J. Pept. Protein Res. 1983,
21, 3-10.
(20) Adams, A. E.; Pringle, J. R. Methods Enzymol. 1991, 194, 729-
731.
(23) Raap, R.; Micetich, R. G. Can. J. Chem. 1968, 46(7), 1057-1063.
(24) Mayer, R.; Hunger, B.; Prousa, R.; Muller, A. K. J. Prakt. Chem.
1967, 35(5-6), 294-301.
(21) Butler, R. N.; O’Donoghue, D. A. J. Chem. Soc., Perkin Trans. 1
1982, 5, 1223-1227.
(22) Hurd, C. D.; Mori, R. I. J. Am. Chem. Soc. 1955, 77, 5359-5364.
(25) Shafiee, A.; Lalezari, I. J. Heterocycl. Chem. 1973, 10(1), 11-14.
J. Org. Chem, Vol. 72, No. 14, 2007 5369

Androsov and Neckers
SCHEME 3
SCHEME 4
SCHEME 5
SCHEME 6 a
according to the Hurd-Mori22 procedure. The reaction of 13
with n-BuNH2 in the presence of K2CO3 (DMF; 70 °C; 12 h)
resulted in 1-butyl-1,3-dihydropyrrolo[2,3-b]pyridine-2-thione
(14; yield 37%). Interestingly, 14 exists as the thione tautomer,
in contrast to compound 5a, which is in the thiol configuration
under the same conditions (CDCl3; 25 °C) (Scheme 5).
Treatment of 3 with MeONa in MeOH under an inert
atmosphere led to the unexpected 2-methoxy-5-nitrobenzo[b]-
thiophene (15; yield 23%). Formation of 15 can be explained
by relying on already known data on the reactivity of 5-unsub-
stituted 1,2,3-thiadiazoles.23-25 In analogy with Scheme 3, after
a Conditions: MeONa/MeOH, reflux, 24 h.
SCHEME 7
the addition of nucleophile (MeONa) to the thioketene 3-IV,
the enethiol anion 3-VIII, stabilized by conjugation, is formed
and the route of the subsequent reaction is cyclization to the
benzothiophene 15 (Scheme 6).
Our attempt to introduce the sulfur-containing nucleophile
potassium thioacetate by reaction with 3 in the presence of
K2CO3 resulted in the product of nucleophilic substitution in
the benzene ring. This gave thiophenolate 16 (Scheme 7) without
decomposition of the heterocyclic ring. Anion 16 can be isolated
as the thiol 17 (yield 80%) after addition of dilute HCl.
Decomposition of 3 under the influence of base (K2CO3,
MeCN; 80 °C, 6 h) in the absence of a nucleophile affords the
FIGURE 1. Transformation of thiadiazole 3 into indole 5a via
intermediate formation of thioamide 3-V in DMF at 25 °C, as monitored
by H NMR spectroscopy.
1
5370 J. Org. Chem., Vol. 72, No. 14, 2007

4-(2-Chloro-5-nitrophenyl)-1,2,3-thiadiazole
SCHEME 8
TABLE 1. Reaction Conditions and Yields of Indole-2-thiols
alkynethiolate 3-II, which converts into thioketene 3-IV after
addition of water with subsequent dimerization to the dithiaful-
vene 18 (Scheme 8).
Conclusion
We have synthesized and studied the reactivity of 4-(2-chloro-
5-nitrophenyl)-1,2,3-thiadiazole 3 with N,O,S-nucleophiles. The
unusual base-induced transformation of 3 in the presence of
various primary aliphatic amines uncovered a simple and
convenient route to potentially important indole-2-thiols and
their heterocyclic analogues. A similar transformation of 3 in
the presence of methanol produces 2-methoxy-5-nitrobenzo[b]-
thiophene. This might be developed for the synthesis of various
2-alkoxybenzo[b]thiophenes in the future.
Experimental Section
N-Ethoxycarbonyl Hydrazone of 1-(2-Chloro-5-nitrophenyl)-
ethanone (2). A mixture of 28.1 g (0.14 mol) of 1-(2-chloro-5-
nitrophenyl)ethanone, 17.5 g (0.17 mol) of ethyl carbazate, and 1
mL of AcOH in 800 mL of EtOH/H2O (1:1) was refluxed for 3 h
and left overnight at room temperature. The precipitate was filtered,
washed with EtOH/H2O (1:1), and dried to give 37.8 g (94%) of 2
1
as a white solid, mp 169-170 °C. H NMR (300 MHz, CDCl3):
δ 1.36 (t, 3H), 4.34 (q, 4H), 7.55 (d, 1H), 7.98 (s, 1H, NH), 8.16
(dd, 1H), 8.31 (d, 1H). 13C NMR (75 MHz, CDCl3): δ 14.5, 16.4,
62.5, 124.5, 125.8, 130.8, 139.3, 140.0, 146.6. MS (EI+ mode):
m/z 285 (M+, 20%), 250 (7), 195 (47), 178 (100), 166 (75), 151
(22), 137 (37), 102 (67). HRMS (EI+ mode): m/z calcd for M+
285.0516, found 285.0514.
4-(2-Chloro-5-nitrophenyl)-1,2,3-thiadiazole (3). A solution of
37.5 g (0.13 mol) of 2 in 60 mL of SOCl2 was refluxed for 2 h,
cooled, and poured into water. The precipitate was thoroughly
washed with water and dried to give 30.2 g (95%) of pure 3 as
light yellow crystals. Product 3 can be crystallized from CHCl3/
MeOH (via azeotropic substitution of MeOH for CHCl3); mp 121
a Yield after column chromatography. b Conversion of 3 into 5, as
monitored by H NMR spectroscopy.
1
1
°C. H NMR (300 MHz, CDCl3): δ 7.75 (d, 1H) 8.26 (dd, 1H),
9.07 (d, 1H), 9.19 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 124.6,
126.8, 131.0, 131.7, 135.9, 138.8, 146.9, 156.9. MS (EI+ mode):
m/z 241 (M+, 2%), 213 (71), 167 (100), 155 (21), 132 (50), 123
(47). HRMS (EI+ mode) m/z calcd for M+ 240.9713, found
240.9710.
1-Butyl-5-nitro-1H-indole-2-thiol (5a). 5a was purified via
column chromatography (SiO2, CHCl3/hexane (1:1)), giving red
crystals: yield 0.52 g (92%); mp 74-75 °C. 1H NMR (300 MHz,
CDCl3): δ 1.00 (t, 3H), 1.40-1.52 (m, 2H), 1.63-1.72 (m, 2H),
3.25 (q, 2H), 4.27 (br t, 1H), 6.12 (s, 1H), 7.59 (d, 1H), 7.87 (dd,
1H), 8.21 (d, 1H). 13C NMR (75 MHz, CDCl3): δ 13.8, 20.2, 31.4,
46.7, 96.0, 114.9, 115.1, 121.6, 138.0, 141.6, 145.9, 156.5. MS
(EI+ mode): m/z 250 (M+, 75%), 207 (100), 194 (15), 161 (65),
148 (22), 134 (16), 120 (9). HRMS (EI+ mode): m/z calcd for M+
250.0776, found 250.0776.
1-tert-Butyl-5-nitro-1H-indole-2-thiol (5b). 5b was purified via
column chromatography (SiO2, CHCl3/hexane (1:1)), giving yellow
crystals: yield 0.20 g (39%); mp 114-115 °C. 1H NMR (300 MHz,
CDCl3): δ 1.41 (s, 9H), 4.18 (br s, 1H), 6.31 (s, 1H), 7.61 (d, 1H),
General Procedure for the Synthesis of Indole-2-thiols (5a-
l). 4-(2-Chloro-5-nitrophenyl)-1,2,3-thiadiazole (3; 0.5 g, 2.07
mmol), K2CO3 (0.57 g, 4.13 mmol), the corresponding amine 4a-l
(1.05-3.0 equiv), and 10 mL of DMF (in that order; for molar
ratios see Table 1) were charged into a 50 mL round-bottom flask.
The mixture was stirred for 3-22 h at 25-80 °C. DMF was
removed under reduced pressure and the residue purified via column
chromatography (SiO2, CHCl3/hexane (1:1), CHCl3/hexane (2:1),
or CHCl3/MeOH (100:1)), affording the corresponding indole-2-
thiol 5a-l (yields 6-92%; see Table 1).
J. Org. Chem, Vol. 72, No. 14, 2007 5371

Androsov and Neckers
7.90 (dd, 1H), 8.26 (d, 1H). 13C NMR (75 MHz, CDCl3): δ 29.3,
53.6, 101.2, 115.3, 115.6, 121.4, 138.9, 141.1, 145.8, 153.8. MS
(EI+ mode): m/z 250 (M+, 37%), 194 (100), 148 (46), 121 (12),
57 (69). HRMS (EI+ mode): m/z calcd for M+ 250.0776, found
250.0775.
115.5, 115.8, 121.7, 138.4, 141.1, 145.9, 154.7, 169.7. MS (EI+
mode): m/z 280 (M+, 30%), 207 (100), 161 (34), 134 (10). HRMS
(EI+ mode): m/z calcd for M+ 280.0519, found 280.0519.
1-[2-(1H-Indol-3-yl)ethyl]-5-nitro-1H-indole-2-thiol (5j). 5j
was purified via column chromatography (SiO2, CHCl3/MeOH (100:
1)), giving yellow crystals: yield 0.20 g (23%); mp 160-161 °C.
1H NMR (300 MHz, CDCl3): δ 3.15 (t, 2H), 3.57 (q, 2H), 4.35
(br t, 1H), 6.13 (s, 1H), 7.08 (d, 1H), 7.13-7.18 (m, 1H), 7.21-
7.27 (m, 1H), 7.40 (d, 1H), 7.57 (d, 1H), 7.62 (d, 1H), 7.86 (dd,
1H), 8.09 (br s, 1H), 8.20 (d, 1H). 13C NMR (75 MHz, CDCl3): δ
25.0, 46.9, 96.5, 111.4, 112.5, 115.0, 115.2, 121.6, 122.3, 122.5,
127.2, 136.5, 138.2, 141.5, 145.9, 156.3. MS (EI+ mode): m/z 337
(M+, 8%), 207 (7), 143 (8), 130 (100). HRMS (EI+ mode): m/z
calcd for M+ 337.0885, found 337.0882.
1-Allyl-5-nitro-1H-indole-2-thiol (5c). 5c was purified via
column chromatography (SiO2, CHCl3/hexane (1:1)), giving dark
1
red crystals: yield 0.20 g (42%); mp 67-68 °C. H NMR (300
MHz, CDCl3): δ 3.87 (br s, 2H), 4.50 (br s, 1H), 5.23-5.38 (m,
2H), 5.89-6.01 (m, 1H), 6.13 (s, 1H), 7.57 (d, 1H), 7.85 (dd, 1H),
8.19 (d, 1H). 13C NMR (75 MHz, CDCl3): δ 49.2, 96.8, 115.0,
115.3, 117.5, 121.6, 133.7, 138.2, 141.4, 145.8, 156.0. MS (EI+
mode): m/z 234 (M+, 100%), 207 (23), 188 (13), 161 (20). HRMS
(EI+ mode): m/z calcd for M+ 234.0463, found 234.0463.
1-Benzyl-5-nitro-1H-indole-2-thiol (5d). 5d was purified via
column chromatography (SiO2, CHCl3/hexane (1:1)), giving red
crystals: yield 0.194 g (33%); mp 99-100 °C. 1H NMR (300 MHz,
CDCl3): δ 2.04 (d, 2H), 4.72 (br t, 1H), 6.10 (s, 1H), 7.26-7.40
(m, 5H), 7.52 (d, 1H), 7.82 (dd, 1H), 8.13 (d, 1H). 13C NMR (75
MHz, CDCl3): δ 50.9, 96.9, 115.0, 115.3, 121.5, 127.6, 127.9,
128.8, 137.5, 138.2, 141.3, 145.8, 155.9. MS (EI+ mode): m/z 284
(M+, 22%), 91 (100), 65 (20). HRMS (EI+ mode): m/z calcd for
M+ 284.0620, found 284.0619.
1-(Adamantan-1-yl)-5-nitro-1H-indole-2-thiol (5k). 5k was
purified via column chromatography (SiO2, CHCl3/hexane (2:1)),
giving dark yellow crystals: yield 0.177 g (26%); mp 126-127
1
°C. H NMR (300 MHz, CDCl3): δ 1.70 (m, 6H), 1.95 (d, 6H),
2.16 (br s, 3H), 4.11 (br s, 1H), 6.34 (s, 1H), 7.58 (d, 1H), 7.88
(dd, 1H), 8.24 (d, 1H). 13C NMR (75 MHz, CDCl3): δ 29.6, 36.3,
42.6, 53.9, 102.4, 115.2, 115.5, 121.4, 139.2, 140.8, 145.7, 153.2.
MS (EI+ mode): m/z 328 (M+, 46%), 193 (6), 166 (17), 135 (100),
107 (35). HRMS (EI+ mode): m/z calcd for M+ 328.1246, found
328.1244.
1-Cyclohexyl-5-nitro-1H-indole-2-thiol (5e). 5e was purified
via column chromatography (SiO2, CHCl3/hexane (1:1)), giving red
1-(2-(Morpholin-4-yl)ethyl)-5-nitro-1H-indole-2-thiol (5l). 5l
was purified via column chromatography (SiO2, CHCl3/MeOH (100:
1)), giving orange crystals: yield 0.388 g (61%); mp 159-160 °C.
1H NMR (300 MHz, CDCl3): δ 2.51 (t, 4H), 2.69 (t, 2H), 3.29 (q,
2H), 3.75 (t, 4H), 5.03 (br t, 1H), 6.13 (s, 1H), 7.61 (d, 1H), 7.88
(dd, 1H), 8.23 (d, 1H). 13C NMR (75 MHz, CDCl3): δ 42.6, 53.3,
56.6, 67.0, 96.3, 115.0, 115.3, 121.6, 138.2, 141.5, 146.0, 156.3.
MS (EI+ mode): m/z 307 (M+, 30%), 207 (7), 161 (31), 100 (100).
HRMS (EI+ mode): m/z calcd for M+ 307.0991, found 307.0992.
1
crystals: yield 0.217 g (38%); mp 130-131 °C. H NMR (300
MHz, CDCl3): δ 1.17-1.48 (m, 5H), 1.60-1.66 (m, 1H), 1.76-
1.83 (m, 2H), 2.10-2.15 (m, 2H), 3.22-3.33 (br m, 1H), 4.23 (br
d, 1H), 6.11 (s, 1H), 7.57 (d, 1H), 7.85 (dd, 1H), 8.19 (d, 1H). 13
C
NMR (75 MHz, CDCl3): δ 24.8, 25.6, 33.0, 55.7, 96.0, 114.6,
114.8, 121.4, 138.0, 141.6, 145.8, 155.6. MS (EI+ mode): m/z 276
(M+, 52%), 233 (17), 194 (100), 166 (10), 148 (47), 136 (8), 121
(12), 83 (9), 55 (87). HRMS (EI+ mode): m/z calcd for M+
276.0933, found 276.0932.
N-Ethoxycarbonyl Hydrazone of 1-(2-Chlorophenyl)ethanone
(7). A mixture of 3 g (19.4 mmol) of 1-(2-chlorophenyl)ethanone
(6), 2.42 g (23.3 mmol) of ethyl carbazate, and 1 drop of AcOH in
40 mL of EtOH/H2O (1:1) was refluxed for 3 h and left overnight
at room temperature. The precipitate was filtered, washed with
EtOH/H2O (1:1), and dried to give 2.19 g (47%) of 7 as white
crystals, mp 130-131 °C. 1H NMR (300 MHz, CDCl3): δ 1.34 (t,
3H), 4.33 (q, 4H), 7.26-7.30 (m, 2H), 7.35-7.38 (m, 1H), 7.41-
7.44 (m, 1H), 7.93 (br s, 1H, NH). 13C NMR (75 MHz, CDCl3):
δ 14.6, 16.8, 62.2, 126.9, 129.7, 129.9, 130.5, 132.3, 138.8, 149.5.
MS (EI+ mode): m/z 240 (M+, 13%), 205 (33), 161 (30), 152 (26),
133 (100), 126 (25), 111 (7). HRMS (EI+ mode): m/z calcd for
M+ 240.0666, found 240.0664.
1-Cyclopentyl-5-nitro-1H-indole-2-thiol (5f). 5f was purified
via column chromatography (SiO2, CHCl3/hexane (1:1)), giving
dark green crystals: yield 0.179 g (33%); mp 124-125 °C. H
1
NMR (300 MHz, CDCl3): δ 1.69-1.82 (m, 5H), 2.02-2.12 (m,
2H), 3.78-3.88 (br m, 1H), 4.31 (br d, 1H), 6.11 (s, 1H), 7.57 (d,
1H), 7.86 (dd, 1H), 8.20 (d, 1H). 13C NMR (75 MHz, CDCl3): δ
24.0, 33.2, 58.1, 96.6, 114.8, 115.1, 121.5, 138.2, 141.6, 145.9,
155.8. MS (EI+ mode): m/z 262 (M+, 65%), 233 (14), 194 (100),
166 (8), 148 (58), 136 (10), 121 (16), 69 (21). HRMS (EI+ mode):
m/z calcd for M+ 262.0776, found 262.0778.
1-Isopropyl-5-nitro-1H-indole-2-thiol (5g). 5g was purified via
column chromatography (SiO2, CHCl3/hexane (1:1)), giving brown
crystals: yield: 0.142 g (29%); mp 84-85 °C. 1H NMR (300 MHz,
CDCl3): δ 1.32 (d, 6H), 3.62-3.69 (br m, 1H), 4.15 (br d, 1H),
6.14 (s, 1H), 7.61 (d, 1H), 7.88 (dd, 1H), 8.23 (d, 1H). 13C NMR
(75 MHz, CDCl3): δ: 22.8, 48.5, 96.4, 114.8, 115.1, 121.5, 138.1,
141.6, 145.9, 155.4. MS (EI+ mode): m/z 236 (M+, 97%), 221
(100), 194 (27), 175 (18), 166 (10), 148 (63), 136 (10), 121 (19),
69 (8). HRMS (EI+ mode): m/z calcd for M+ 236.0620, found
236.0619.
1-Methyl-5-nitro-1H-indole-2-thiol (5h). 5h was purified via
column chromatography (SiO2, CHCl3/hexane (1:1)), giving red
crystals: yield 0.026 g (6%); mp 163-164 °C. 1H NMR (300 MHz,
CDCl3): δ 3.00 (d, 3H), 4.31 (br s, 1H), 6.13 (s, 1H), 7.60 (d,
1H), 7.89 (dd, 1H), 8.24 (d, 1H). 13C NMR (CDCl3): δ 33.2, 95.9,
115.0, 115.3, 121.6, 138.2, 141.5, 145.9, 157.3. MS (EI+ mode):
m/z 208 (M+, 100%), 178 (10), 162 (64), 146 (14), 128 (12), 69
(13). HRMS (EI+ mode): m/z calcd for M+ 208.0307, found
208.0307.
(2-Mercapto-5-nitroindol-1-yl)acetic Acid Ethyl Ester (5i). 5i
was purified via column chromatography (SiO2, CHCl3/hexane (2:
1)), giving yellow crystals: yield 0.052 g (9%); mp 163-164 °C.
1H NMR (300 MHz, CDCl3): δ 1.33 (t, 3H), 4.01 (d, 2H), 4.29
(q, 2H), 4.95 (br t, 1H), 6.13 (s, 1H), 7.62 (d, 1H), 7.91 (dd, 1H),
8.25 (d, 1H). 13C NMR (75 MHz, CDCl3): δ 14.2, 47.8, 61.9, 97.4,
4-(2-Chlorophenyl)-1,2,3-thiadiazole (8). A solution of 3 (2.0
g, 8.32 mmol) in 6 mL of SOCl2 was refluxed for 2 h, cooled, and
poured into water. The precipitate was thoroughly washed with
water and dried to give 1.3 g (79%) of pure 8 as light brown
1
crystals, mp 30-31 °C. H NMR (300 MHz, CDCl3): δ 7.37-
7.47 (m, 2H), 7.55 (dd, 1H), 8.14 (dd, 1H), 9.05 (s, 1H). 13C NMR
(75 MHz, CDCl3): δ 127.4, 129.6, 130.4, 130.6, 131.9, 132.3,
134.6, 159.1. MS (EI+ mode): m/z 196 (M+, 5%), 168 (100), 133
(49), 89 (48). HRMS (EI+ mode): m/z calcd for M+ 195.9862,
found 195.9862.
N-Butyl-2-(2-chlorophenyl)thioacetamide (9). A mixture of 8
(0.086 g, 0.43 mmol), K2CO3 (0.18 g, 1.3 mmol), and n-butylamine
(0.16 g, 2.19 mmol) in 10 mL of DMF was heated and stirred at
130 °C for 24 h. After the mixture was cooled to room temperature,
the solvent was evaporated under vacuum. The residue was
dissolved in CHCl3 and the solution thoroughly washed with water.
Evaporation of the CHCl3 gave 0.088 g (97%) of pure 9 as a brown
1
oil. H NMR (300 MHz, CDCl3): δ 0.90 (t, 3H), 1.30 (m, 2H),
1.56 (m, 2H), 3.61 (t, 2H), 7.29 (m, 2H), 7.40 (m, 2H). 13C NMR
(75 MHz, CDCl3): δ 13.7, 20.0, 29.8, 45.9, 50.2, 127.5, 129.3,
129.8, 131.9, 133.3, 134.3, 200.2. MS (EI+ mode): m/z 206 (M+,
100%), 164 (7), 150 (27), 134 (9), 125 (15), 89 (15), 57 (16).
5372 J. Org. Chem., Vol. 72, No. 14, 2007

4-(2-Chloro-5-nitrophenyl)-1,2,3-thiadiazole
2-Chloro-3-(1,2,3-thiadiazol-4-yl)pyridine (13). A mixture of
1.62 g (10.4 mmol) of 1-(2-chloropyridin-3-yl)-ethanone (11), 1.14
g (11 mmol) of ethyl carbazate, and 3 drops of AcOH in 20 mL of
EtOH was refluxed for 5 h. The solvent was evaporated under
reduced pressure. The residue was dissolved in CHCl3 (100 mL),
and the solution was thoroughly washed with water and dried over
Na2SO4. Thionyl chloride (3.8 mL, 52 mmol) was added to the
dried chloroform solution. The mixture was refluxed for 3 h, cooled
to room temperature, and poured into water (200 mL). The
chloroform layer was thoroughly washed with water (4 × 200 mL)
and dried over Na2SO4. The solvent was evaporated to yield 1.5 g
(74%) of 13 as a brown solid. The product can be crystallized from
MHz, CDCl3): δ 4.04 (s, 3H), 6.46 (s, 1H), 7.70 (d, 1H), 8.04 (dd,
1H), 8.40 (d, 1H). 13C NMR (75 MHz, CDCl3): δ 60.0, 98.3, 116.9,
117.0, 122.3, 138.2, 138.7, 145.7, 168.1. MS (EI+ mode): m/z 209
(M+, 100%), 194 (15), 166 (55), 136 (22), 120 (85). HRMS (EI+
mode): m/z calcd for M+ 209.0147, found 209.0148.
4-Nitro-2-(1,2,3-thiadiazol-4-yl)benzenethiol (17). A mixture
of 3 (0.3 g, 1.24 mmol), K2CO3 (0.52 g, 3.73 mmol), and potassium
thioacetate (0.42 g, 3.73 mmol) in DMF (10 mL) was stirred and
heated at 70 °C for 12 h. The solvent was evaporated under reduced
pressure. The residue was dissolved in 200 mL of water, and the
solution was stirred with charcoal for 10 min at room temperature.
The charcoal was filtered and the resulting solution acidified with
aqueous HCl (3 M) to form a yellow precipitate. The precipitate
was filtered and thoroughly washed with water to yield 1.9 g (80%)
1
MeOH to give light gray crystals, mp 70-72 °C. H NMR (300
MHz, CDCl3): δ 7.47 (m, 1H), 8.51 (dd, 1H), 8.60 (dd, 1H), 9.22
(s, 1H). 13C NMR (75 MHz, CDCl3): δ: 123.0, 126.7, 135.5, 140.4,
148.8, 149.9, 157.4. MS (EI+ mode): m/z 197 (M+, 8%), 169 (95),
133 (100), 106 (24), 63 (39). HRMS (EI+ mode): m/z calcd for
M+ 196.9814, found 196.9814.
1
of 17 as a yellow powder, mp 116-117 °C. H NMR (300 MHz,
CDCl3): δ 4.77 (s, 1H), 7.60 (d, 1H), 8.15 (dd, 1H), 8.54 (d, 1H),
8.92 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 123.9, 125.8, 116.9,
129.4, 131.1, 135.1, 142.2, 159.4. MS (EI+ mode): m/z 237 ([M
- 2]+, 52%), 209 (74), 165 (84), 153 (24), 132 (17), 121 (100).
HRMS (EI+ mode): m/z calcd for M+ 238.9823, found 238.9825.
2-[(E)-2-Chloro-5-nitrobenzylidene]-4-[2-chloro-5-nitrophe-
nyl]-1,3-dithiole (18). A mixture of compound 3 (0.5 g, 2.07 mmol)
and K2CO3 (0.86 g, 6.21 mmol) in MeCN (20 mL) was stirred and
refluxed for 6 h. After it was cooled to room temperature, the
mixture was poured into water (200 mL) and refluxed for an
additional 1 h. The precipitate was filtered and thoroughly washed
with water to yield 0.42 g (95%) of 18 as an orange powder, mp
1-Butyl-1,3-dihydropyrrolo[2,3-b]pyridine-2-thione (14). A
mixture of compound 13 (0.88 g, 4.45 mmol), K2CO3 (1.84 g, 13.4
mmol), and n-butylamine (1.63 g, 22.3 mmol) in DMF (10 mL)
was stirred and heated at 70 °C for 12 h. The solution was cooled
to room temperature and poured into 200 mL of water. The water
layer was extracted with EtOAc (2 × 100 mL). The resulting
organic solution was washed with water (3 × 200 mL) and dried
over Na2SO4. Solvent was evaporated to yield 0.72 g (78%) of crude
14. After purification via column chromatography (SiO2, EtOAc/
hexane (1:2)), 0.34 g (37%) of pure 14 was obtained. Product 14
is an oil that slowly crystallizes as a yellow solid, mp 172-173
1
220-223 °C. H NMR (300 MHz, CDCl3): δ 6.92 (s, 1H), 7.36
(s, 1H), 7.79 (d, 1H), 7.89 (d, 1H), 8.02 (dd, 1H), 8.24 (d, 1H),
8.27 (dd, 1H), 8.34 (d, 1H). MS (EI+ mode): m/z 426 (M+, 100%),
390 (18), 298 (8), 264 (13), 199 (58), 164 (19), 155 (43), 132 (28),
123 (19). HRMS (EI+ mode): m/z calcd for M+ 425.9303, found
425.9305.
1
°C. H NMR (300 MHz, CDCl3): δ 0.93 (t, 3H), 1.33-1.41 (m,
2H), 1.60-1.65 (m, 2H), 3.65 (q, 2H), 4.11 (s, 2H), 7.26-7.30
(m, 1H), 7.85 (dd, 1H), 8.34 (dd, 1H). 13C NMR (75 MHz,
CDCl3): δ 13.7, 20.1, 29.8, 46.2, 49.5, 123.0, 131.3, 140.6, 148.4,
151.0, 199.1. MS (EI+ mode): m/z 207 ([M + 1]+, 100%), 191
(12), 151 (16), 134 (14), 127 (34), 91 (13). HRMS (EI+ mode):
m/z calcd for M+ 206.0878, found 206.0880.
Acknowledgment. We sincerely acknowledge the Office of
Naval Research (Grant No. N00014-05-1-0372) for partial
support of this work. We thank the NSF (Grant No. CHE-
0234796) for the MALDI-TOF mass spectrometer.
2-Methoxy-5-nitrobenzo[b]thiophene (15). Na (0.29 g, 12.42
mmol) was dissolved in 50 mL of dry MeOH. Compound 3 (1.0 g,
4.14 mmol) was added to the resulting solution, and the mixture
was stirred and refluxed for 24 h under an atmosphere of argon.
After the mixture was cooled, several drops of AcOH were added
to neutralize it. Solvent was evaporated under reduced pressure and
the residue chromatographed (SiO2, EtOAc/hexane (1:8)) to give
Supporting Information Available: Text giving general in-
1
formation and figures giving MS, HRMS, and H and 13C NMR
spectra of all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
1
0.2 g (23%) of 15 as yellow crystals, mp 118 °C. H NMR (300
JO0707784
J. Org. Chem, Vol. 72, No. 14, 2007 5373