Synthesis of 3-substituted bicyclic imidazo[1,2-d][1,2,4]thiadiazoles and tricyclic benzo[4,5]imidazo[1,2-d][1,2,4]thiadiazoles

Article abstract of DOI:10.1021/jo0507486

A versatile synthetic route to potentially useful fused-ring [1,2,4]thiadiazole scaffolds (e.g., 7a and 10b) via exchange reactions of the precursor [1,2,4]thiadiazol-3-(2H)one derivatives (e.g., 6 and 9) with appropriately substituted nitriles (e.g., cyanogen bromide or p-toluenesulfonyl cyanide) under mild conditions is described. For example, the tricyclic 3-bromo [1,2,4]THD derivative (7a) underwent S_NAr substitution with a variety of nucleophiles, which included amines, malonate esters and alcohols. Likewise, the bicyclic 3-p-tosyl [1,2,4]THD (10b) was employed as a template in reaction with diamines, and the resulting substituted diamines (e.g., 12a or 12e) were further selectively derivatized at the N1 and/or N2 positions in a linear fashion. The X-ray crystal structure of the 3-methyl bicyclic [1,2,4]THD (21) was obtained, and selective methylation at the N1 position via a protection-alkylation-deprotection protocol, as illustrated in Scheme 6, was confirmed. Alternatively, a short convergent synthesis of N1-functionalized derivatives from the reaction of 10b with appropriately substituted secondary amines was also developed. Hence, these synthetic strategies were advantageously exploited to provide access to a variety of diversely derivatized 3-substituted fused-ring [1,2,4]thiadiazole derivatives.

Full text of DOI:10.1021/jo0507486

Synthesis of 3-Substituted Bicyclic
Imidazo[1,2-d][1,2,4]thiadiazoles and Tricyclic
Benzo[4,5]imidazo[1,2-d][1,2,4]thiadiazoles
Regis Leung-Toung,* Tim F. Tam, Yanqing Zhao, Craig D. Simpson, Wanren Li,
Denis Desilets, and Khashayar Karimian
Medicinal Chemistry Department, ApoPharma, Inc., 400 Ormont Drive, Toronto, ON M9L 1N9, Canada
rleung@apotex.ca
Received April 14, 2005
A versatile synthetic route to potentially useful fused-ring [1,2,4]thiadiazole scaffolds (e.g., 7a and
10b) via exchange reactions of the precursor [1,2,4]thiadiazol-3-(2H)one derivatives (e.g., 6 and 9)
with appropriately substituted nitriles (e.g., cyanogen bromide or p-toluenesulfonyl cyanide) under
mild conditions is described. For example, the tricyclic 3-bromo [1,2,4]THD derivative (7a) underwent
SNAr substitution with a variety of nucleophiles, which included amines, malonate esters and
alcohols. Likewise, the bicyclic 3-p-tosyl [1,2,4]THD (10b) was employed as a template in reaction
with diamines, and the resulting substituted diamines (e.g., 12a or 12e) were further selectively
derivatized at the N1 and/or N2 positions in a linear fashion. The X-ray crystal structure of the
3-methyl bicyclic [1,2,4]THD (21) was obtained, and selective methylation at the N1 position via a
protection-alkylation-deprotection protocol, as illustrated in Scheme 6, was confirmed. Alterna-
tively, a short convergent synthesis of N1-functionalized derivatives from the reaction of 10b with
appropriately substituted secondary amines was also developed. Hence, these synthetic strategies
were advantageously exploited to provide access to a variety of diversely derivatized 3-substituted
fused-ring [1,2,4]thiadiazole derivatives.
Introduction
group was launched as Firstcin in Japan in 1995 (Figure
1).10 However, the role and importance of the THD moiety
in all of those compounds, with regards to the mechanism
of the biological response of the targeted enzymes, are
not clearly understood at the molecular level.
Monocyclic [1,2,4]thiadiazoles ([1,2,4]THDs) have been
widely claimed to be useful insecticidal, herbicidal and
fungicidal agents.1 For example, 5-ethoxy-3-(trichlorom-
ethyl)-[1,2,4]thiadiazole (1) is a soil fungicide marketed
as etridiazole or terrazole (Figure 1).2
In recent years, many biologically active [1,2,4]THDs
exhibiting interesting medicinal properties for the
potential treatment of human diseases have been dis-
closed.3-9 The injectable cephalosporin antibiotic cefozo-
pran hydrochloride (2), which has a monocyclic THD
(4) Smith, C. W.; Chakrabarti, J. K.; Williamson, W. R. N. Bioorg.
Med. Chem. Lett. 1994, 4, 1673-1678.
(5) Yousif, N. M. Egypt. J. Chem. 1989, 32, 597-605.
(6) (a) van Muijlwijk-Koezen, J. E.; Timmerman, H.; Vollinga, R.
C.; Frijtag von Drabbe Kunzel, J.; de Groote, M.; Visser, S.; Ijzerman,
A. P. J. Med. Chem. 2001, 44, 749-762. (b) van den Nieuwendijk, A.
M.; Pietra, D.; Heitman, L.; Go¨blyo¨s, A.; Ijzerman, A. P. J. Med. Chem.
2004, 47, 663-672. (c) Go¨blyo¨s, A.; de Vries, H.; Brussee, J.; Ijzerman,
A. P. J. Med. Chem. 2005, 48, 1145-1151.
(7) Antonio, Y.; Camargo, C.; Galeazzi, E.; Iriarte, J.; Guzman, M.;
Muchowski, J. M.; Gerrity, K.; Liu, F.; Miller, L. M.; Strosberg, A. M.
J. Med. Chem. 1978, 21, 123-126.
(8) MacLeod, A. M.; Baker, R.; Freedman, S. B.; Patel, S.; Merchant,
K. J.; Ros, M.; Saunders J. J. Med. Chem. 1990, 33, 2052-2059.
(9) Collins, I.; Moyes, C.; Davey, W. B.; Rowley, M.; Bromidge, F.
A.; Quirk, K.; Atack, J. R.; McKernan, R. M.; Thompson, S. A.; Wafford,
K.; Dawson, G. R.; Pike, A.; Sohal, B.; Tsou, N. N.; Ball, R. G.; Castro,
J. L. J. Med. Chem. 2002, 45, 1887-1900.
(10) Cheng, X.-M. Annual Reports in Medicinal Chemistry; Bristol,
J. A., Ed.; Academic Press: London, 1996; Vol. 31, Chapter 34, pp 337-
355; in particular p 339.
* To whom correspondence should be addressed. Phone: 416-749-
9300 ext 8120. Fax: 416-401-3845.
(1) (a) Franz, J. E.; Dhingra, O. P. Compr. Heterocycl. Chem. I 1984,
6, 463-511. (b) Wilkins, D. J.; Bradley, P. A. Compr. Heterocycl. Chem.
II 1996, 4, 307-354. (c) Kurzer, F. Adv. Heterocycl. Chem. 1982, 32,
285-398.
(2) The CAS Registry No. for terrazole is 25-931-59.
(3) (a) Unangst, P. C.; Shrum, G. P.; Connor, D. T.; Dyer, R. D.;
Schrier, D. J. J. Med. Chem. 1992, 35, 3691-3698. (b) Song, Y.; Connor,
D. T.; Sercel, A. D.; Sorenson, R. J.; Doubleday: R.; Unangst, P. C.;
Roth, B. D.; Beylin, V. G.; Gilbertsen, R. B.; Chan, K.; Schrier, D. J.;
Guglietta, A.; Bornemeier, D. A.; Dyer, R. D. J. Med. Chem. 1999, 42,
1161-1169.
10.1021/jo0507486 CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/12/2005
6230
J. Org. Chem. 2005, 70, 6230-6241

Synthesis of 3-Substituted Bicyclic Imidazo[1,2-d][1,2,4]thiadiazoles
FIGURE 2. Fused-ring bicyclic (4) and tricyclic (5) [1,2,4]THD
scaffolds.
We13,15 and others16 have recently disclosed the use of
novel inhibitors based on the monocyclic [1,2,4]THD
scaffold for targeting cysteine proteases (cathepsin B15a
and guinea pig liver transglutaminase16) through S-S
bond formation (Scheme 1). Interestingly, suitably 3-sub-
stituted bicyclic THD derivatives are potent, selective,
and active-site directed inhibitors of plasma trans-
glutaminase (FXIIIa),17 while 3-substituted tricyclic THD
derivatives are preferred for the inhibition of certain
enzymes such as the proton pump (H+/K+ ATPase).18
At the time we started our medicinal chemistry efforts,
the chemistry of monocyclic [1,2,4]THDs were well
documented,1 whereas that of fused-ring bicyclic and
tricyclic THDs remained largely unknown apart from a
few sparse publications.19-21 However, we required an
array of 3-substituted fused-ring THD analogues for
structure-activity relationship (SAR) studies in biologi-
cal systems. We reasoned that [1,2,4]THD scaffolds with
a good leaving group (e.g., Br or p-Ts) at the 3-position
would readily undergo nucleophilic substitution via an
SNAr mechanism.22 In addition, the resulting suitably
substituted [1,2,4]THD derivatives could serve as tem-
plates for further synthetic manipulation, and hence
provide access to a rich diversity of fused-ring [1,2,4]-
THDs. Herein, we discuss our strategies and results on
the synthesis of 3-substituted bicyclic and tricyclic THD
compounds using the 3-bromo or 3-p-tosyl substituted
THD scaffolds.
FIGURE 1. Examples of commercial monocyclic [1,2,4]THD
derivatives.
SCHEME 1. Mechanism of Inhibition of Cysteine
Residues of Biomolecules by [1,2,4]THDs
Early on, in our discovery program on the design of
novel inhibitors targeting cysteine residues of biomol-
ecules,11,12 we recognized the advantage of employing the
[1,2,4]THD heterocycle13 as the thiol trapping electrophile
via S-S bond formation with concomitant N-S ring
opening (Scheme 1). Contrary to the commonly reported
electrophilic “warheads” (e.g., epoxides, chloromethyl
ketones, vinyl sulfones, and aldehydes),11 the [1,2,4]THD
heterocycle displayed lack of reactivity (N-S bond cleav-
age) toward nucleophiles such as amines and alcohols,
but reacted with thiols.1,14
Substituents at the C3- (Y) and C5- (X) positions in
the monocyclic THD (3) can be modified to tune
enzyme affinity and reactivity of the N-S bond
toward the incoming thiol nucleophile,15 whereas an
appropriate C3 substituent (Y) in the fused-ring bicyclic
THD (4) and tricyclic THD (5) can enhance both enzyme
affinity and reactivity (Figure 2). Therefore, enzyme-
specific and/or active site-directed inhibitors can be
designed through a judicious choice of substituents
(recognition arm), and THD “warhead” (monocyclic vs
fused).
Results and Discussion
Preparation of Fused-Ring [1,2,4]Thiadiazole Scaf-
folds. In our hands, a solution of 2-butylbenzo[4,5]-
(16) Marrano, C.; de Macedo, P.; Gagnon, P.; Lapierre, D.; Gravel,
C.; Keillor, J. W. Bioorg. Med. Chem. 2001, 9, 3231-3241.
(17) (a) Leung-Toung, R.; Tam, T. F.; Wodzinska, M. J.; Zhao, Y.;
Lowrie, J.; Simpson, D. C.; Karimian, K.; Spino, M. J. Med. Chem.
2005, 48, 2266-2269. (b) Tam, T. F.; Karimian, K.; Leung-Toung, R.
C. S. H.; Zhao, Y.; Wodzinska, J. M.; Li, W.; Lowrie, J. N. US patent
application 20030225007A1, 2003.
(18) (a) Tam, F. T.; Leung-Toung, R.; Li, W.; Spino, M.; Karimian,
K. Mini-Rev. Med. Chem. 2005, 5, 367-379. (b) Tam, T.; Li, W.; Leung-
Toung, R.; Karimian, K. IDrugs 2000, 3, 1064-1074. (c) Karimian,
K.; Tam, T. F.; Desilets, D.; Lee, S.; Cappelletto, T.; Li, W. US patent
5,677,302, 1997.
(19) Haugwitz, R. D.; Toeplitz, B.; Gougoudas, J. Z. J. Chem. Soc.,
Chem. Commun. 1977, 736-737.
(20) (a) Martin, D.; Tittelbach, F. Tetrahedron 1983, 39, 2311-2314.
(b) Martin, D.; Wenzel, A. J. Prakt. Chem. 1978, 320, 677-684. (c)
Martin, D.; Tittelbach, F. J. Chem. Soc., Perkin Trans. 1 1985, 1007-
1013;
(21) Pentimalli, L.; Milani, G.; Biavati, F. Gazz. Chim. Ital. 1977,
107, 1-5.
(22) For examples of SNAr substitution in heterocycles, see the
following: (a) Chauvie`re, G. Bouteille, B.; Enanga, B.; de Albuquerque,
C.; Croft, S. L.; Dumas, M.; Pe´rie´, J. J. Med. Chem. 2003, 46, 427-
440. (b) Song, Y.; Connor, D. T.; Sercel, A. D.; Sorenson, R. J.;
Doubleday: R.; Unangst, P. C.; Roth, B. D.; Beylin, V. G.; Gilbertsen,
R. B.; Chan, K.; Schrier, D. J.; Guglietta, A.; Bornemeier, D. A.; Dyer,
R. D. J. Med. Chem. 1999, 42, 1161-1169. (c) Zhang, Z.; Yin, Z.; Kadow,
J. F.; Meanwell, N. A.; Wang, T. J. Org. Chem. 2004, 69, 1360-1363.
(d) Guillier, F.; Roussel, P.; Moser, H.; Kane, P.; Bradley, M. Chem.
Eur. J. 1999, 5, 3450-3458. (e) Liu, J.; Janeba, Z.; Robins, M. J. Org.
Lett. 2004, 6, 2917-2919.
(11) (a) For recent reviews on cysteine proteases, see the following:
Leung-Toung, R.; Li, W.; Tam, T. F.; Karimian, K. Curr. Med. Chem.
2002, 9, 979-1002. (b) Powers, J. C.; Asgian, J. L.; Ekici, O¨ . D.; James,
K. L. Chem. Rev. 2002, 12, 4639-4750. (c) Donkor, I. O. Curr. Med.
Chem. 2000, 7, 1171-1188. (d) Talanian, R. V.; Brady, K. D.; Cryns,
V. L. J. Med. Chem. 2000, 43, 3351-3371.
(12) For a review on inhibitors targeting the cysteine residues of
biomolecules, see the following: Scozzafava, A.; Casini, A.; Supuran,
C. T. Curr. Med. Chem. 2002, 9, 1167-1185.
(13) Bryson, S.; Pai, E. F.; Desilets, D.; Li W.; Tam T.; Karimian K.
Evidence for the formation of a disulfide bond between cysteine proteases
and 1,2,4-thiadiazoles; PENCE AGM 2000 Meeting, Montebello,
Quebec, Canada, June 24-26, 2000; PENCE, Inc.: Edmonton, 2000.
(14) (a) Crook, S.; Sykes, P. J. Chem. Soc., Perkin Trans. 1 1977,
1791-1796. (b) Hagiwara, K.; Hashimoto, S.; Shimoda, S. J. Pestic.
Sci. 1992, 17, 251-259. (c) Newton, C. G.; Ollis, D. W. J. Chem. Soc.,
Perkin Trans. 1 1984, 75-84.
(15) (a) Leung-Toung, R.; Wodzinska, J.; Li, W.; Lowrie, J.; Kukreja,
R.; Desilets, D.; Karimian, K.; Tam, T. F. Bioorg. Med. Chem. 2003,
11, 5529-5537. (b) Karimian, K.; Tam, T. F.; Leung-Toung, R. C. S.
H.; Li, W.; Bryson, S.; Wodzinska, J. M. WO0190095, 2001.
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Leung-Toung et al.
SCHEME 2. Preparation of Tricyclic [1,2,4]THD
Scaffolds (7a-f)
SCHEME 4. Nucleophilic Displacement Reactions
of Tricyclic [1,2,4]THD Scaffold (7a)
SCHEME 3. Preparation of Bicyclic [1,2,4]THD
Scaffolds (10a,b)
the corresponding 3-substituted THDs (11a) and (11d)
were readily isolated in good yields (Scheme 4). Similarly,
other nucleophiles such as N-(6-aminohexyl)-2-nitroben-
zene sulfonamide and diethyl malonate in the presence
of triethylamine also afforded substituted THDs 11b and
11c, respectively, in modest unoptimized yields. In the
case of diethyl malonate, extended refluxing (36 h) in
THF was needed for the completion of the reaction. Thus,
derivatization of the tricyclic 3-bromo THD scaffold (7a)
with nitrogen, carbon, and oxygen nucleophiles is shown
to be feasible.
However, synthesis of the analogous bicyclic 3-bromo
THD scaffold (10a) was unreliable and, hence, precluded
access to 3-substituted bicyclic THD derivatives via this
route. Alternatively, it is documented that heterocyclic
vinyl sulfones underwent nucleophilic SNAr substitution
with a variety of nucleophiles including amines.22 Indeed,
N-(6-aminohexyl)-1-naphthylsulfonamide reacted with
the 3-p-tosyl-substituted THD (10b), under mild condi-
tions, in dimethylformamide, and in the presence of
triethylamine to afford 12a in 69% yield, after purifica-
tion by column chromatography.
We then based our strategy for the derivatization of
10b with diamines, as illustrated in Scheme 5. The
synthesis of THD derivatives via route 1 was preferred
when the sulfonyl R group was fixed (e.g., 2-NO2-Ph) and
n was varied (n ) 3-7). The reaction medium was
usually dimethylformamide, with triethylamine as base
(Table 1, 12b-f, entries 2-6). Conversely, with n fixed
(e.g., n ) 4 or 6), route 2 was preferred for the preparation
of THDs with different sulfonyl moieties (Table 1, entries
8-14). The sulfonyl R moiety could be aromatic, hetero-
cyclic (12m, entry 13), or aliphatic (12n, entry 14), and
the nature of the substituents influenced the choice of
reaction medium. We noticed that reactions involving 1,5-
diaminopentane and its THD derivatives were usually
sluggish and more difficult, and yields were lower as
compared to other analogues (entry 4).25 Other reagents
besides sulfonyl halides were employed, and compounds
13 and 14 are examples of THD derivatives that could
be prepared from acylation of 16 with 2-nitrobenzoyl
chloride and from alkylation with the activated 2-chloro-
3-nitropyridine, respectively (entries 15, 16).
imidazo[1,2-d][1,2,4]thiadiazol-3(2H)-one (6), prepared
according to the procedure previously described by Mar-
tin and Wenzel,20a in dichloromethane underwent ex-
change reaction with cyanogen bromide smoothly at room
temperature with extrusion of n-butyl isocyanate. The
tricyclic 3-bromo THD (7a) precipitated out and was
isolated by simple suction filtration in good yield (81%).
No further purification was required after the solid was
washed with dichloromethane. The exchange reaction
could be extended to a variety of substituted nitriles (e.g.,
bromoacetonitrile, cyanamide), and its scope is illustrated
with the straightforward preparation of the tricyclic
[1,2,4]THD scaffolds 7b-f, as depicted in Scheme 2.
The bicyclic 3-substituted [1,2,4]THD scaffolds (10a,b)
were prepared as shown in Scheme 3, following a similar
pathway as that for the tricyclic analogues. The conden-
sation product (8) from 2-mercaptoimidazole and n-butyl
isocyanate23 was subjected to oxidative ring closure with
bromine and triethylamine at ice cold temperature to
afford 2-butyl-imidazo[1,2-d][1,2,4]thiadiazol-3(2H)-one
(9) in >70% combined yield, consistently. However, the
exchange reaction of 9 with cyanogen bromide under
standard conditions was rather problematic, as produc-
tion of the bromo compound 10a was unpredictable. For
example, in one instance, 10a was isolated in 91% yield,
while only insoluble unidentified solid material was
obtained in other experiments under similar conditions.
Gratifyingly, 9 underwent exchange reaction with p-
toluenesulfonyl cyanide24 smoothly to afford 10b in >75%
yield, consistently.
Derivatization of [1,2,4]THD Scaffolds. The tricy-
clic bromo THD (7a) underwent nucleophilic substitution
uneventfully with aqueous dimethylamine or with so-
dium methoxide in methanol, under mild conditions, and
The THD template 15 or 16 (Scheme 5) could be
prepared directly from the reaction of 10b with at least
4-5 equiv of the respective diamines. In some cases,
formation of disubstituted products were non-negligible.
(23) Other isocyanates (methyl, ethyl, propyl) work equally well.
However, we settled for n-butyl isocyanate because of cost and safety
(higher bp) considerations and commercial availability in kilogram
quantity.
(24) For a preparative procedure for p-TsCN, see the following,
Vrijland, M. S. A. In Organic Syntheses; Noland, W. E., Ed; John Wiley
& Sons, Inc.: Toronto, 1988; Collect. Vol. VI, pp 727-730.
(25) We do not have a reasonable explanation for this observation.
However, we also noted that 1,3-, 1,4-, and 1,6-alkyldiamines are
available reasonably cheaply in kg’s quantities from commercial
suppliers, but 1,5-diaminopentane is supplied in small quantities (25
g bottle) and is relatively much more expensive.
6232 J. Org. Chem., Vol. 70, No. 16, 2005

Synthesis of 3-Substituted Bicyclic Imidazo[1,2-d][1,2,4]thiadiazoles
SCHEME 5. Functionalization of Bicyclic [1,2,4]THD Scaffold 10b with Diamines
TABLE 1. Diamine Derivatives from the 3-p-Tosyl-Substituted Bicyclic Scaffold (10b)
entry
compd
n
R
yield (%)
entry
compd
n
R
yield (%)
1
2
3
4
5
6
7
8
12a
12b
12c
12d
12eb
12f
6
3
4
5
6
7
6
6
1-naphthyl
2-NO2-Ph
2-NO2-Ph
2-NO2-Ph
2-NO2-Ph
2-NO2-Ph
2-NH2-Ph
3-COOH-Ph
69a
82
65
24
58c
79
65
80
9
10
11
12
13
14
15
16
12i
12j
12k
12l
12m
12n
13d
14e
6
6
6
6
6
6
6
6
2-CN-Ph
62
89
48
73
45
75
63
43
2,4-di-Br-Ph
2-NO2-4-CN-Ph
2-NO2-4-COOH-Ph
5-[3-Br-2-Cl-Py]
CH3
12g
12h
2-NO2-Bz
3-NO2-2-Py
a 91% yield via route 2. b For spectral data, see ref 17. c 70% yield from route 2. d Acylating agent is 2-nitrobenzoyl chloride. e Alkylating
agent is 2-chloro-3-nitropyridine.
SCHEME 6. Selective Methylation at N1 and N2 Positions of Bicyclic THD (12e)a
a Reagents and conditions: (i) 3 equiv of CH3I, 7.5 equiv of K2CO3, acetone; (ii) excess CH3I, solid K2CO3, powder KOH, cat. n-Bu4N+I-,
toluene; (iii) 1.5 equiv of Boc2O, cat. DMAP/CH3CN; (iv) excess CH3I, solid K2CO3, powder KOH, cat. n-Bu4N+HSO4-, toluene/CH2Cl2
(5/1, v/v); (v) HCl(g), MeOH, then neutralize.
Then, access to 15 or 16, from 10b via a Boc protection-
substitution-deprotection protocol was desirable.
The aqueous solubilities of most of these compounds
at pH 7.4 and at ambient temperature are in the 10 µM
range; for example, the solubility of 12e is 13 µg/mL.17a
However, the solubility can reach mM range in other
media such as in Cremophor (e.g., solubility of 12a in
25% Cremophor EL is 0.38 mg/mL at rt and at native
pH), or in mixtures of poly(ethylene glycol) (PEG)/
ethanol/saline (e.g., solubility of 12a in 60%PEG400/
10%ethanol/30%saline is 0.42 mg/mL at rt and at native
pH).
these nitrogens could be selectively exploited for further
synthetic elaboration. Indeed, reaction of 12e with io-
domethane in the presence of potassium carbonate in
acetone at room temperature afforded the N2-methyl
compound 17, exclusively, in 76% yield, after purification
by column chromatography. When the reaction condition
was slightly modified by the addition of powdered potas-
sium hydroxide, both N1 and N2 were methylated, and
18 was isolated in 88% yield. Based on these results, a
route to selectively introduce a methyl substituent at the
N1 position via a Boc protection-alkylation-deprotection
protocol was employed successfully (Scheme 6).17a Prod-
ucts 17-20 were characterized by 2D-NMR, including
HSQC and HMBC experiments.27
It is quite apparent that the two nitrogens (e.g., N1
and N2 of 12e, Scheme 6) could be different in their
reactivities with electrophiles. This is further supported
by the calculated pKa’s,26 which clearly suggested that
We have recently determined the single-crystal X-ray
structure of 21 (Figure 3), a homologue of 20 but with a
(26) Single pKa calculations of compound 12e using ACD/Labs
(27) Braun, S.; Kalinowski, H.-O.; Berger, S. 150 and More Basic
NMR Experiments: A Practical Course, 2nd expanded ed.; Wiley-
VCH: Toronto, 1998.
+
software were performed: pKa of N1 was calculated to be -2.21 (NH2
)
and that of N2 was 10.72 (NH).
J. Org. Chem, Vol. 70, No. 16, 2005 6233

Leung-Toung et al.
FIGURE 3. (A) X-ray crystal structure of 3-methyl bicyclic [1,2,4]thiadiazole (21). Color code: blue (N), gray (C), red (O), yellow
(S), green (H). (B) ChemDraw structure of 21 with corresponding atom labeling.
SCHEME 7. Selective Functionalization at the N1
Position of 12ea
[1,2,4]THDs, it suffered from several shortcomings.
Namely, the synthesis was linear, and the THD moiety,
which is the expensive part, was carried on in all the
steps to the final product (e.g., Scheme 7). To address
these issues, a disconnection at the 3-position of the THD
was desirable from a retro-synthetic perspective. Conse-
quently, this approach necessitated a nucleophilic dis-
placement of the 3-p-tosyl group of 10b with a secondary
amine (e.g., 23, 24) as depicted in Scheme 8.
However, our initial efforts to react 10b with the
secondary amine 24a under standard conditions (DMF/
Et3N/rt) were unsuccessful, as mainly starting materials
were detected by TLC or by HPLC. Under more vigorous
conditions (warming up to 100 °C), the formation of
unidentified byproducts were observed, and the expected
product 22a was not detected, either by HPLC or by MS.
The reaction was attempted in several different solvents,
including DMPU, dichloromethane, and i-PrOH, without
success. We were, eventually, gratified to find out that
the reaction between 10b and excess amine 24a, when
carried out in DMSO as solvent, yielded the desired
product 22a in reasonable yield (75%), after purification
by column chromatography. With the appropriate choice
of secondary amines, templates such as 25 and 26 were
readily accessible, thereby allowing further derivatization
at the N2 position (Scheme 8). This short synthetic
strategy, thus, provided a convergent route to the N1-
functionalized bicyclic [1,2,4]THDs.
a Reagents and conditions: (i) 1.5 equiv of Boc2O, 0.5 equiv of
DMAP, CH3CN; (ii) excess BrCH2CO2CH3, solid K2CO3, powder
KOH, cat. n-Bu4N+I-, toluene; (iii) HCl(g), MeOH, then neutralize;
(iv) for 22b: 2 N NaOH, MeOH; then neutralize; (v) for 22c: NH3
gas, MeOH/CH2Cl2.
(CH2)4 spacer, obtained via the protection-alkylation-
deprotection route. Thus, unequivocal proof that methy-
lation occurred at the N1 position has been established,
which also confirmed the conclusions reached from the
2D-NMR experiments. Some of the salient features of this
molecule include the C(1)-S(1) and N(1)-S(1) bond
lengths of 1.730 and 1.693 Å, respectively, which are
slightly longer than the C-S (1.707 Å) and N-S (1.649
Å) bond lengths of monocyclic [1,2,4]thiadiazole.1a Acces-
sibility to the sulfur atom of the bicyclic [1,2,4]THD ring
is clearly not hampered by the methyl substituent at the
N(4) nitrogen (Figure 3),11,17,18 which is also referred to
as the N1 position in the text. In addition, the aromatic
ring bearing the nitro group is almost perpendicular to
the plane of the bicyclic thiadiazole-spacer group.
Other electrophiles were also employed using this
pathway. For example, the methyl glycinate moiety was
effectively introduced at the N1 position in the conversion
of 12e to 22a (Scheme 7). The ester group provided a
handle for other functional group interconversion such
as transformation to the acid 22b (79% yield) or the
amide 22c (91% yield).
As in the case of N1 derivatization, other electrophiles
besides iodomethane could be employed for N2 function-
alization. Accordingly, alkylation of 12a with ethyl 4-bro-
mobutyrate in the presence of potassium carbonate in
acetone, under reflux conditions for 16 h, afforded
compound 27a in 72% yield, after purification by column
chromatography. The ester moiety could further be
transformed to other functionalities, such as the acid
(27b) or the amide (27c) (Scheme 9).
While the synthetic route described above (Scheme 7)
provided access to a wide variety of N1-functionalized
SCHEME 8. N1-Functionalized THD Derivatives: Substitution with Secondary Amines
6234 J. Org. Chem., Vol. 70, No. 16, 2005

Synthesis of 3-Substituted Bicyclic Imidazo[1,2-d][1,2,4]thiadiazoles
SCHEME 9. Selective Functionalization at N2
Positions of 12aa
FIGURE 4. Structure of bicyclic THD 29.
volved the initial ring opening of the thiadiazole ring with
phenethyl mercaptan to the disulfide intermediate. The
latter then reacted with excess phenethyl mercaptan
present to form phenethyl disulfide. Depending on the Y
substituent, relatively stable intermediates such as 28a
or 28b could be isolated and identified.28 In the case of
the latter, 28b was further converted to 2-mercaptoben-
zimidazole.
a Reagents and conditions: (i) 2 equiv of Br(CH2)3CO2Et, 7.1
equiv of K2CO3, acetone; (ii) for 27b: 2 N NaOH/MeOH then
neutralize; (iii) for 27c: excess 28% aq NH4OH, MeOH, rt, 16 h.
SCHEME 10. Proposed Ring Opening of Tricyclic
[1,2,4]THD Derivatives with Phenethyl Mercaptan
In contrast to its reactivity with phenethyl mercaptan,
for example, the bicyclic [1,2,4]THD 12a in dichlo-
romethane solution was stable in the presence of 5 equiv.
of n-butylamine at room temperature for 20 h. Addition-
ally, 12a was stable to acid or base in the pH range of
2-9.8 for at least 20 h at room temperature, as monitored
by TLC (95/5 CH2Cl2/MeOH as eluant, Rf ) 0.21), or by
HPLC. However, about 60% of 12a remained after
stirring in a mixture of acetonitrile and 2 N sodium
hydroxide (pH ) 13.8) for 20 h, as monitored by HPLC.
Nevertheless, stability of thiadiazole derivatives in strongly
alkaline medium was dependent on the 3-substituent.
For example, 29 (Figure 4) was stable at pH 13.7 for at
least 20 h.
Stability of Fused-Ring [1,2,4]THDs. Since we have
an interest in the potential use of these compounds as
cysteine protease inhibitors, we sought some information
on the stability of these fused-ring [1,2,4]THD compounds
under stress conditions in chemical systems and also in
the presence of other nucleophiles.
Thus, a suspension of the tricyclic [1,2,4]THD deriva-
tive 7f in the presence of 2.5 equiv. of phenethyl mer-
captan in methanol slowly converted to 2-mercaptoben-
zimidazole (Scheme 10) over a period of 3 days at room
temperature, as monitored by TLC (CHCl3/MeOH as
eluant, 100/2 ratio, v/v).28 However, degradation of 7f in
the presence of a large excess of phenethyl mercaptan
(25 equiv) occurred within ca. 2-3 h at room tempera-
ture. Interestingly, compounds 11a and 11d reacted with
phenethyl mercaptan (25 equiv) in methanol at rt in less
than 1 min to afford compounds 28a and 28b, respec-
tively. After the mixture was stirred for another 2-3 h,
compound 28b further transformed to 2-mercaptobenz-
imidazole.
Conclusion
A simple route to bicyclic and tricyclic 3-substituted
[1,2,4]THD scaffolds is described.29 The fused-ring tem-
plates (e.g., 7a and 10b) are advantageously used in
substitution reactions with various nucleophiles that
include amines, alcohols and malonate esters. With
diamines as nucleophiles, further derivatization of the
adducts can be selectively effected. As a result, an
assortment of 3-substituted [1,2,4]THD derivatives is
readily accessible.
The fused-ring [1,2,4]THDs are stable in the presence
of excess n-butylamine, and in buffers at the pH range
of 2-9.8. However, their stabilities in strongly alkaline
conditions (pH 13.7) are contingent on the nature of the
3-substituents. Additionally, the thiadiazoles decomposed
in the presence of phenethyl mercaptan via heterocyclic
N-S bond cleavage at rates that were dependent on the
nature of the 3-substituents and the amount of phenethyl
mercaptan used.
The results obtained can be rationalized via the
proposed mechanism shown in Scheme 10.14,18a It in-
Results of studies of these classes of compounds in
biological systems will be reported elsewhere.
(28) Based on the experimental design (monitoring of 2-mercapto-
benzimidazole), we cannot preclude the formation of an imine type
intermediate like 28a or 28b in the case of 7f. However, in a different
system and different conditions, the intermediates shown below were
isolated (see ref 18c):
Experimental Section17b,18c
Usual workup and purification means that the organic layer
was dried over Na2SO4, filtered, and evaporated to dryness.
Chromatographic purification was then performed using the
flash chromatography technique30 on silica gel (Merck Kiesel-
gel 60: 230-400 mesh) and the mixed solvent systems are
indicated in the text. Reagents were purchased from com-
(29) A major part of this work has been the subject of US patent
5,677,302, 1997 (ref 17b) and US patent application 20030225007A1,
2003 (ref 18c).
(30) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923-
2925.
J. Org. Chem, Vol. 70, No. 16, 2005 6235

Leung-Toung et al.
mercial sources. 2-Mercaptoimidazole was purchased in bulk
(kg quantity) from Lancaster, n-BuNCO (kg quantity) and
p-TsCN (100’s g) were supplied from Aldrich. 2-Butylbenzo-
[4,5]imidazo[1,2-d][1,2,4]thiadiazol-3(2H)-one (6) was prepared
according to the procedure reported by Martin and Wenzel.20a
the four crops were combined, then suspended in EtOAc (150
mL) and stirred at rt for about 30 min. Hexane (150 mL) was
added, and the solid was collected by suction filtration. 10b
was dried to constant weight (37.0 g) under vacuum at 45 °C
1
for 4 h: yield 76%; mp 185-186 °C; H NMR (CDCl3) δ 8.08
(br s, 1H), 8.01 (d, J ) 7.9 Hz, 2H), 7.52 (br, 1H), 7.45 (d, J )
7.9 Hz, 2H), 2.50 (s, 3H, CH3); 13C NMR (CDCl3 + few drops
of CD3OD) δ 159.6, 147.7, 145.4, 138.5 (CH), 133.2, 130.6 (2C,
CH), 129.1 (2C, CH), 113.3 (CH), 21.8 (CH3); MS m/z 280 [M
+ 1]+, 239, 155, 99 (100). Anal. Calcd for C11H9N3O2S2: C,
47.30; H, 3.25; N, 15.04. Found: C, 46.86; H, 3.31; N, 14.92.
3-Dimethylaminobenzo[4,5]imidazo[1,2-d][1,2,4]-
thiadiazole (11a). To an ice-cooled mixture of 7a (15.4 g,
0.060 mmol) in CH2Cl2 was added dimethylamine (40% solu-
tion in water, 5.44 g, 0.121 mol) dropwise. The resulting
mixture was allowed to warm to rt and stirred for 16 h. The
mixture was diluted with CH2Cl2 and then washed with water.
The organic fraction was collected, dried (Na2SO4), filtered,
and evaporated to dryness. Compound 11a was obtained as a
colorless crystalline solid (10.5 g): yield 80%; mp 102-104 °C;
1H NMR (CDCl3) δ 7.72-7.76 (m, 2H), 7.41 (t, J ) 8.2 Hz,
1H), 7.27 (t, J ) 8.2 Hz, 1H) and 3.06 (s, 6H, 2CH3); MS (EI)
m/z 218 [M]+, 177, 150, 90. Anal. Calcd for C10H10N4S: C,
55.03; H, 4.62; N, 25.69. Found: C, 54.53; H, 4.90; N, 25.50.
3-Bromobenzo[4,5]imidazo[1,2-d][1,2,4]thiadiazole (7a).
A mixture of 6 (5.00 g, 20.2 mmol) and cyanogen bromide (4.28
g, 40.4 mmol) in CH2Cl2 (100 mL) was stirred at room
temperature rt for 26 h. The precipitate was collected by
suction filtration and was thoroughly washed with CH2Cl2.
Compound 7a was obtained as a white powder (4.18 g): yield
81%; mp 189-190 °C; 1H NMR (CDCl3) δ: 8.23 (d, J ) 8.1
Hz, 1H), 7.82 (d, J ) 8.2 Hz, 1H), 7.52 (t, J ) 7.1 Hz, 1H) and
7.42 (d, J ) 7.2 Hz, 1H); 13C NMR (1:1 CDCl3/DMSO-d6) δ
162.8, 149.7, 129.2, 125.5, 122.2, 119.5, 117.3 and 111.3; IR
(KBr) νmax 1601 cm-1; MS (CI) m/z 255 [M + 1]+ (100), 254
(11, M+), 148, 90; HRMS calcd for C8H4N3SBr 252.9309, found
252.9307. Anal. Calcd for C8H4BrN3S: C, 37.81; H, 1.59; N,
16.54. Found: C, 37.44; H, 1.33; N, 16.57.
2-Mercaptoimidazole-1-carboxylic Acid Butylamide
(8). A mixture of 2-mercaptoimidazole (24.4 g, 0.244 mol) and
n-butyl isocyanate (48.3 g, 0.487 mol) was heated at 50 °C for
30 min or until the reaction was complete by TLC (CH2Cl2/
MeOH, 95/5, v/v, Rf of 8 ) 0.22). The reaction mixture was
then cooled to rt, and the solidified mass was triturated with
hexanes (50 mL) for 30 min. The solid was filtered, washed
with a minimum amount of hexane, and dried under reduced
pressure to yield 45.0 g of 8 as beige crystals: yield 93%; mp
N-[6-(Benzo[4,5]imidazo[1,2-d][1,2,4]thiadiazol-3-ylami-
no)hexyl]-2-nitrobenzenesulfonamide (11b).: A mixture
of 7a (381 mg, 1.5 mmol), N-(6-aminohexyl)-2-nitrobenzene-
sulfonamide (903 mg, 3.0 mmol), and Et3N (2.0 mL) in DMF
(15 mL) was stirred at rt for 16 h. Volatiles were removed in
vacuo, and the residue was partitioned between CH2Cl2 and a
solution of 10% citric acid. After usual workup (CH2Cl2/EtOAc,
9/1 then 8/2, v/v, as eluant), 11b was obtained as a light yellow
1
66-68 °C; H NMR (CDCl3) δ 10.67 (br, 1H), 10.32 (br, 1H),
7.63 (s, 1H), 6.71 (s, 1H), 3.47 (br q, J ≈ 6.4 Hz, 2H, NHCH2-
CH2),31 1.65 (quint, J ) 7.6 Hz, 2H, NHCH2CH2CH2), 1.47
(sext, J ) 7.5 Hz, 2H, CH2CH2CH3), 0.98 (t, J ) 7.3 Hz, 3H,
CH3); 13C NMR (CDCl3) δ: 160.9 (CS), 150.0(CO), 117.2 (CH),
113.8 (CH), 40.7(NCH2), 31.2, 20.3, 13.8(CH3); MS m/z 222 [M
+ Na]+, 200 [M + 1]+, 101 (100).
1
solid (420 mg): yield 59%; mp 183-183 °C; H NMR (CDCl3
+ CD3OD) δ 8.01-8.03 (m, 1H), 7.83 (d, J ) 8.1 Hz, 1H), 7.74-
7.77 (m, 1H), 7.63-7.68 (m, 3H), 7.36 (t, J ) 7.7 Hz, 1H), 7.24
(t, J ) 7.8 Hz, 1H), 3.44 (t, J ) 7.1 Hz, 2H, NCH2CH2), 3.01
(t, J ) 6.8 Hz, 2H, NCH2CH2), 1.67 (br quint, 2H, NCH2CH2-
CH2), 1.49 (br quint, 2H, NCH2CH2CH2), 1.32-1.36 (m, 4H,
2CH2); 13C NMR (DMSO-d6) δ 163.9 (C), 150.1 (C), 147.8 (C),
145.8 (C), 133.9 (CH), 132.9 (C), 132.5 (CH), 129.4 (CH), 128.2
(C), 124.31 (CH), 124.29 (CH), 120.9 (CH), 118.3 (CH), 111.9
(CH), 42.6 (NCH2), 42.3 (NCH2), 29.1 (CH2), 28.4 (CH2), 25.9
(CH2), 25.7 (CH2); MS m/z 475 [M + 1]+, 327, 149. Anal. Calcd
for C20H22N6O4S2: C, 50.62; H, 4.67; N, 17.71. Found: C, 50.37;
H, 5.10; N, 17.51.
2-Butylimidazo[1,2-d]-1,2,4-thiadiazole-3(2H)-one (9).
To an ice-cooled suspension of 8 (4.73 g, 23.7 mmol) in CH2Cl2
(15 mL) was added dropwise a bromine (3.79 g, 23.7 mmol)
solution in CH2Cl2 (15 mL) under a blanket of nitrogen. After
the addition was complete, a solution of Et3N (4.81 g, 47.5
mmol) in CH2Cl2 (15 mL) was added at such a rate that the
temperature of the reaction mixture did not exceed 0 °C. The
reaction mixture was maintained at 0 °C for an additional 2 h
and then stirred at rt for 16 h. The mixture was diluted with
CH2Cl2 (150 mL), and the organic layer was washed twice with
water and then with brine. The organic fraction was dried over
MgSO4, filtered, and evaporated to dryness to afford 4.30 g of
9 as an off-white powder: yield 92%; mp 142-143 °C; 1H NMR
(CDCl3) δ 7.60 (s, 1H), 7.35 (s, 1H), 3.78 (t, J ) 7.2 Hz, 2H,
NCH2CH2), 1.76 (quint, J ) 7.4 Hz, 2H, CH2CH2CH2), 1.46
(sext, J ) 7.3 Hz, 2H, CH2CH2CH3), 1.00 (t, J ) 7.4 Hz, 3H,
CH3); 13C NMR (CDCl3) δ 147.2, 145.0, 133.7, 113.1, 44.8
(NCH2), 31.1 (NCH2CH2), 19.7 (CH2CH3), 13.5 (CH3); IR (KBr)
νmax 1702 (CdO) cm-1; MS m/z 199 [M + 1]+, 101 (100), 69.
Anal. Calcd for C8H11N3OS: C, 48.71; H, 5.62; N, 21.30.
Found: C, 48.48; H, 5.44; N, 21.26.
2-Benzo[4,5]imidazo[1,2-d][1,2,4]thiadiazol-3-ylmalon-
ic Acid Diethyl Ester (11c). A mixture of 7a (0.20 g, 0.78
mmol), diethyl malonate (0.15 g, 0.94 mmol), and Et3N (0.13
mL, 0.94 mmol) in THF (8 mL) was refluxed under a nitrogen
atmosphere for 36 h. The resulting mixture was extracted with
EtOAc and washed with water followed by a 10% aqueous
sodium sulfate solution. After usual workup (hexane/EtOAc,
65/35, v/v, as eluant), 11c was obtained as a yellow oil (0.14
g): yield 54%; 1H NMR (CDCl3) δ 9.48 (s, 1H), 8.06 (d, J ) 6.9
Hz, 1H), 7.64 (d, J ) 6.3 Hz, 1H), 7.31-7.35 (m, 2H), 4.39 (q,
J ) 7.3 Hz, 4H, 2 OCH2), 1.35 (t, J ) 7.4 Hz, 6H, 2 CH3); 13C
NMR (CDCl3) δ 163.8, 153.7, 151.3, 149.4, 131.2, 124.9, 123.7,
119.0, 112.8, 69.6, 64.6, 13.7; IR (film) νmax 1748 cm-1; MS (EI)
m/z 333 [M]+ (100%), 215, 161; HRMS calcd for C15H15N3O4S
333.0783, found 333.0794.
3-Methoxybenzo[4,5]imidazo[1,2-d][1,2,4]thiadiazole
(11d). Sodium methoxide (0.967 g, 17.9 mmol) was added in
one portion to an ice-cooled mixture of 7a (4.55 g, 17.9 mmol)
in methanol (50 mL). The cooling bath was removed, and the
mixture was stirred for 4 h at rt. Volatile materials were
removed in vacuo, and the residue was taken up in EtOAc and
washed with water. The organic layer was dried over Na2SO4,
filtered, and evaporated to yield 3.64 g of 11d as colorless
crystals: yield 94%; mp 172-175 °C; 1H NMR (CDCl3) δ 7.83
(d, J ) 8.1 Hz, 1H), 7.75 (d, J ) 8.2 Hz, 1H), 7.42 (t, J ) 8.0
Hz, 1H), 7.27 (t, J ) 8.2 Hz, 1H), 4.32 (s, 3H); 13C NMR (CDCl3)
δ 163.2, 150.3, 148.1, 128.2, 124.9, 121.8, 119.2, 111.7, 57.5;
3-[(4-Methylphenyl)sulfonyl]imidazo[1,2-d][1,2,4]-
thiadiazole (10b). A mixture of 9 (34.5 g, 0.175 mol) and
p-TsCN (36.2 g, 0.200 mol) in CH2Cl2 (600 mL) was stirred at
rt for 16 h. The white solid was collected by suction filtration.
The mother liquor was concentrated to ca. half-volume as more
solid separated. The solid was again collected by filtration. The
latter two steps were repeated twice more. The solids from
(31) We have noticed coupling with NH for NHCH2CH2 protons in
the 1H NMR spectrum (showing a slightly unresolved q signal, or
alternatively an unresolved dt signal) in cases when nonprotic deu-
terated solvents were used (e.g., 13 in DMSO or 8 in CDCl3). However,
t signal is observed in the presence of, or with addition of a protic
deuterated solvent (e.g., 11b in CDCl3 + CD3OD). For a literature
example of the description of the multiplicity (br q or unresolved q) of
a NHCH2CH2 and its associated J value (≈ 6 Hz), see: Grehn, L.;
Ragnarsson, U. J. Org. Chem. 2002, 67, 6557-6559.
6236 J. Org. Chem., Vol. 70, No. 16, 2005

Synthesis of 3-Substituted Bicyclic Imidazo[1,2-d][1,2,4]thiadiazoles
IR (KBr) νmax 1595 cm-1; MS (EI) m/z 205 [M]+, 150, 90. Anal.
Calcd for C9H7N3OS: C, 52.67; H, 3.44; N, 20.49. Found: C,
52.28; H, 3.36; N, 20.45.
(440 mg) was obtained as a white solid: Yield 80%; mp >230
°C dec; 1H NMR (DMSO-d6) δ 8.57 (br t, J ≈ 6.9 Hz, 1H, NH),
8.10 (s, 1H), 7.94 (br t, J ≈ 7.1 Hz, 1H, NH), 7.87 (s, 1H), 7.71-
7.78 (m, 2H), 7.40 (t, J ) 7.7 Hz, 1H), 7.30 (s, 1H), 3.30
(partially HDO masked, br q, 2H, J ≈ 5.8 Hz, 2H, NHCH2-
CH2), 3.34 (br s, HDO), 2.50 (masked under DMSO signal, m,
2H, NHCH2CH2), 2.51 (br, DMSO), 1.63 (br quint, 2H,
NCH2CH2CH2), 1.55 (br quint, 2H, NCH2CH2CH2), 1.30-1.40
(m, 4H, 2CH2); 13C NMR (DMSO-d6) δ 165.8 (CO), 156.8 (C),
148.1 (C), 144.3 (Cipso), 136.8 (CH), 134.4 (CCO), 128.0 (CH),
127.8 (CH), 127.4 (CH), 124.5 (CH), 111.4 (CH), 41.8 (NCH2),
39.7 (NCH2), 29.1 (CH2), 28.6 (CH2), 26.3 (CH2), 26.2 (CH2);
MS m/z 424 [M + 1]+, 326, 143 (100). Anal. Calcd for
C17H21N5O4S2: C, 48.21; H, 5.00; N, 16.54. Found: C, 42.63;
H, 4.95; N, 14.66 (adjusted for water content: Anal. Calcd for
C17H21N5O4S2‚3H2O (12h trihydrate): C, 42.85; H, 5.50; N,
14.70).
Synthesis of Sulfonamides: Route 1. N-[6-(Imidazo-
[1,2-d][1,2,4]thiadiazol-3-ylamino)hexyl]naphthalene-1-
sulfonamide (12a). A mixture of 10b (3.94 g, 14.1 mmol),
N-(6-aminohexyl)naphthalene-1-sulfonamide (6.50 g, 21.2
mmol), and Et3N (5.8 mL, 42 mmol) in DMF (75 mL) was
stirred at rt overnight. Volatile materials were removed in
vacuo, and the residue was partitioned between water (75 mL)
and EtOAc (100 mL). The aqueous layer was extracted with
EtOAc (100 mL). The combined organic fractions were then
successively washed with a 10% citric acid solution (25 mL),
water (50 mL), and a saturated sodium carbonate solution (25
mL). After usual workup (MeOH/CH2Cl2, 3/97, v/v, as eluant),
12a was obtained as a white solid (5.10 g): yield 84%; mp 144-
145 °C; 1H NMR (CDCl3) δ 8.67 (d, J ) 7.7 Hz, 1H), 8.22 (t, J
) 6.9 Hz, 1H), 8.05 (d, J ) 7.8 Hz, 1H), 7.92 (d, J ) 7.2 Hz,
1H), 7.50-7.62 (m, 4H), 7.24-7.28 (m, 1H), 5.61-5.80 (br, 1H,
NH), 5.18-5,32 (br, 1H, NH), 3.37 (br q, J ≈ 6.4 Hz, 2H,
NHCH2CH2), 2.88 (br q, J ≈ 6.3 Hz, 2H, NHCH2CH2), 1.50
(br quint, 2H, NCH2CH2CH2), 1.36 (br quint, 2H, NCH2CH2-
CH2), 1.15-1.25 (m, 4H, 2CH2); 13C NMR (CDCl3) δ 161.3,
158.8, 143.7, 137.2 (CH), 134.7, 134.3 (CH), 129.5 (CH), 129.1
(CH), 128.4 (CH), 128.1, 126.9 (CH), 124.4 (CH), 124.1 (CH),
109.5 (CH), 42.8 (NCH2), 41.5 (NCH2), 29.2 (CH2), 28.7 (CH2),
25.6 (CH2), 25.5 (CH2); MS m/z 430 [M + 1]+, 388, 220. Anal.
Calcd for C20H23N5O2S2: C, 55.92; H, 5.40; N, 16.30. Found:
C, 55.99; H, 5.61; N, 16.30.
2-Amino-N-[6-(imidazo[1,2-d][1,2,4]thiadiazol-3-ylami-
no)hexyl]benzenesulfonamide (12g). A mixture of tert-
butyl 6-{[(2-nitrophenyl)sulfonyl]amino}hexylcarbamate (see
preparation of 30a in the Supporting Information) (5.00 g, 12.5
mmol) and Pd/C (0.400 g, 10% wet) in EtOH (150 mL) was
hydrogenated at 50 psi pressure of hydrogen at ambient
temperature for 16 h. Nitrogen gas was bubbled in the reaction
mixture, and Celite was added. The mixture was filtered over
a pad of Celite, and the cake was thoroughly washed with
MeOH. The filtrate was cooled in an ice bath, and HCl gas
was bubbled through for 25 min. The cooling bath was
removed, and the resulting mixture was stirred at rt for 3 h.
Volatiles were removed in vacuo, and the residue was parti-
tioned between a 1 N NaOH solution and EtOAc. The aqueous
layer was extracted with EtOAc, and the combined organic
fractions were washed with brine, dried, filtered, and concen-
trated to a brown oil (3.30 g).
The 2-amino-N-(6-aminohexyl)benzenesulfonamide obtained
above was used directly in reaction with 10b to afford the
desired compound 12g as a light orange solid: yield 65%; mp
138-139 °C; 1H NMR (DMSO-d6) δ 7.83-7.86 (m, 2H), 7.44-
7.46 (m, 2H), 7.21-7.28 (m, 2H), 6.77-6.79 (m, 1H), 6.57-
6.59 (m, 1H), 5.86 (br, 2H, NH2), 3.31-3.35 (m, 2H, NHCH2-
CH2, masked under HDO peak), 3.33 (br s, HDO), 2.70 (br
unresolved q, 2H, NHCH2CH2), 1.54 (br quint, 2H, NCH2CH2-
CH2), 1.35 (br quint, 2H, NCH2CH2CH2) and 1.20-1.28 (m,
4H, 2CH2); 13C NMR (CDCl3) δ 156.8 (C), 146.2 (Cipso), 144.2
(C), 136.7 (CH), 133.3 (CH), 129.0 (CH), 120.0 (CNO2), 116.8
(CH), 115.0 (CH), 111.3 (CH), 42.0 (NCH2), 41.7 (NCH2), 28.8
(CH2), 28.5 (CH2), 25.9 (CH2), 25.7 (CH2); MS m/z 395 [M +
1]+, 378, 280. Anal. Calcd for C16H22N6O2S2: C, 48.71; H, 5.62;
N, 21.30. Found: C, 47.16; H, 5.56; N, 20.43 (adjusted for water
content: Anal. Calcd for (12g hemihydrate) C16H22N6O2S2‚
0.5H2O: C, 47.62; H, 5.75; N, 20.83).
Synthesis of sulfonamides: Route 2. 3-[6-(Imidazo[1,2-
d][1,2,4]thiadiazol-3-ylamino)hexylsulfamoyl]benzoic
Acid (12h). A mixture of 16 (310 mg, 1.30 mmol), 3-chloro-
sulfonylbenzoic acid (314 mg, 1.40 mmol), and Et3N (0.70 mL,
5.2 mmol) in CH3CN (15 mL) was stirred at ambient temper-
ature for overnight. Silica gel was added, and the mixture was
evaporated to dryness. The residue was poured onto a wet
prepacked silica gel column, and the product was eluted using
a solvent mixture of MeOH/CH2Cl2 (30/70, v/v). Compound 12h
N-[6-(Imidazo[1,2-d][1,2,4]thiadiazol-3-ylamino)hexyl]-
methanesulfonamide (12n). A mixture of 16 (0.42 g, 1.5
mmol), methanesulfonyl chloride (0.12 mL, 1.5 mmol), and K2-
CO3 (0.50 g, 3.6 mmol) in acetone (25 mL) was stirred at rt
for 16 h. The mixture was filtered over a pad of Celite, and
the cake was thoroughly washed with small portions of
acetone. Volatile materials were removed in vacuo, and the
crude product was purified by column chromatography on
silica gel using a mixture of MeOH/CH2Cl2 (5/95, v/v) as eluant.
Compound 12n (0.32 g) was obtained as a waxy white solid:
yield 66%; mp 98-99 °C; 1H NMR (DMSO-d6) δ: 7.94 (br, 1H,
NH), 7.86 (s, 1H), 7.31 (s, 1H), 6.94 (br, 1H, NH), 3.32-3.36
(m, 2H, masked by HDO peak), 3.35 (br s, HDO), 2.92 (br q, J
≈ 6.3 Hz, 2H, NHCH2CH2), 2.87 (s, 3H, CH3), 1.62 (br quint,
2H, NCH2CH2CH2), 1.46 (quint, J ≈ 6.6 Hz, 2H, NCH2CH2-
CH2), 1.30-1.40 (m, 4H, 2CH2); 13C NMR (DMSO-d6) δ: 156.8
(C), 144.2 (C), 136.8 (CH), 111.2 (CH), 42.4 (NCH2), 41.7
(NCH2), 39.1 (CH3), 29.4 (CH2), 28.5 (CH2), 26.0 (CH2), 25.9
(CH2); MS m/z 318 [M + 1]+, 220 (100), 178, 108. Anal. Calcd
for C11H19N5O2S2: C, 41.62; H, 6.03; N, 22.06. Found: C, 42.12;
H, 6.06; N, 21.58.
Cyano-N-[6-(imidazo[1,2-d][1,2,4]thiadiazol-3-ylamino-
)hexyl]benzenesulfonamide (12i): yield 62%; mp 131-132
1
°C; H NMR (CDCl3 + DMSO-d6) δ 7.92 (br, 1H, NH), 7.70-
7.74 (m, 1H), 7.60-7.65 (m, 2H), 7.56 (s, 1H), 7.10 (s, 1H), 7.00
(br, 1H, NH), 3.62 (br q, 2H, NHCH2CH2), 3.26 (br q, J ≈ 6.1
Hz, 2H, NHCH2CH2), 1.73 (br quint, 2H, NCH2CH2CH2), 1.55
(br quint, 2H, NCH2CH2CH2), 1.30-1.36 (m, 4H, 2CH2); 13C
NMR (DMSO-d6) δ 156.8 (C), 152.1 (C), 144.2 (Cipso), 136.8
(CH), 135.8 (CH), 133.8 (CH), 132.8 (CH), 128.7 (CH), 116.2
(CN), 111.2 (CH), 109.0 (CCN), 42.5 (NCH2), 41.7 (NCH2), 29.0
(CH2), 28.4 (CH2), 26.0 (CH2), 25.9 (CH2); MS m/z 405 [M +
1]+, 307 (100), 265, 183. Anal. Calcd for C17H20N6O2S2: C,
50.48; H, 4.98; N, 20.78. Found: C, 50.75; H, 5.34; N, 20.48.
2,4-Dibromo-N-[6-(imidazo[1,2-d][1,2,4]thiadiazol-3-
ylamino)hexyl]benzene sulfonamide (12j): yield 89%; mp
1
61-62 °C; H NMR (DMSO-d6) δ 8.12 (s, 1H), 7.81-7.94 (m,
5H, 3 Ar-H + 2NH), 7.30 (s, 1H), 3.28-3.36 (HDO masked m,
2H, NHCH2CH2), 2.85 (br q, 2H, NHCH2CH2), 1.53 (br quint,
2H, NCH2CH2CH2), 1.37 (br quint, 2H, NCH2CH2CH2), 1.20-
1.30 (m, 4H, 2CH2); 13C NMR (CDCl3) δ 159.0 (C), 144.1 (C),
138.0 (Cipso), 137.6 (CH), 137.2 (CH), 132.6 (CH), 131.3 (CH),
127.9 (CBr), 120.7 (CBr), 110.0 (CH), 43.1 (NCH2), 42.5
(NCH2), 29.4 (CH2), 29.0 (CH2), 26.1 (CH2), 26.0 (CH2); MS m/z
540 [M + 3]+, 539 [M + 2]+, 538 [M + 1]+, 536, 438, 396. Anal.
Calcd for C16H19Br2N5O2S2: C, 35.77; H, 3.56; N, 13.03.
Found: C, 36.14; H, 3.78; N, 12.81.
N-Imidazo[1,2-d][1,2,4]thiadiazol-3-yl-N′-(3-nitropyri-
din-2-yl)-hexane-1,6-diamine (14). Triethylamine (0.9 mL,
6.0 mmol) was added to a suspension of the HCl salt of 16
(0.38 g, 1.2 mmol) in DMF (40 mL) at ambient temperature.
After 10 min, 2-chloro-3-nitropyridine (0.24 g, 1.5 mmol) was
added all at once. The resulting mixture was stirred at rt over
2 days. After usual workup (MeOH/CH2Cl2, 10/90, v/v, as
eluant), 14 was obtained as a solid (0.19 g): yield 43%; mp
J. Org. Chem, Vol. 70, No. 16, 2005 6237

Leung-Toung et al.
1
147-148 °C; H NMR (DMSO-d6) δ: 8.67 (br, 2H), 8.41 (d, J
water, a saturated Na2CO3 solution and water. The organic
layer was dried over Na2SO4, filtered, and evaporated to
dryness. A light yellow solid was obtained upon trituration
with a small amount of CH2Cl2. The solid was collected by
filtration, suspended in EtOAc, and the mixture was stirred
for 10 min. 13 was collected as an off-white solid and was dried
at 45 °C under vacuum for 2 h: yield 0.25 g (63%); mp 152-
153 °C; 1H NMR (DMSO-d6) δ 8.63 (br t, J ≈ 4.8 Hz, 1H, NH),
8.02 (d, J ) 8.0 Hz, 1H), 7.93 (br t, J ≈ 5.0 Hz, 1H, NH), 7.86
(s, 1H), 7.77 (t, J ) 7.3 Hz, 1H), 7.67 (t, J ) 7.7 Hz, 1H), 7.58
(d, J ) 7.4 Hz, 1H), 7.30 (s, 1H), 3.35 (partially masked, br q,
J ≈ 6.6 Hz, 2H, NHCH2CH2), 3.33 (br s, HDO), 3.22 (br q, J ≈
6.5 Hz, 2H, NHCH2CH2), 1.64 (br quint, J ≈ 6.4 Hz, 2H,
NCH2CH2CH2), 1.54 (br quint, J ≈ 6.2 Hz, 2H, NCH2CH2CH2),
1.35-1.45 (m, 4H, 2CH2); 13C NMR (DMSO-d6) δ 165.3 (CO),
156.9 (C), 147.1 (C), 144.2 (C), 136.8 (CH), 133.5 (CH), 132.9
(C), 130.5 (CH), 129.0 (CH), 124.0 (CH), 111.3 (CH), 41.8
(NCH2), 39.0 (NCH2), 28.7 (CH2), 28.6 (CH2), 26.2 (CH2), 26.1
(CH2); MS m/z 389 [M + 1]+, 291, 143 (100).
General Method for N2 Alkylation. N-[6-(Imidazo[1,2-
d][1,2,4]thiadiazol-3-ylamino)hexyl]-N-methyl-2-nitroben-
zenesulfonamide (17). A mixture of 12e (0.26 g, 0.60 mmol),
CH3I (0.11 mL, 1.8 mmol), and potassium carbonate (0.62 g,
4.5 mmol) in acetone (15 mL) was stirred at ambient temper-
ature for 16 h. The mixture was filtered through a pad of
Celite, and the cake was thoroughly washed with acetone. The
filtrate was concentrated in vacuo, and the residue was
purified by column chromatography on silica gel using a
mixture of solvents (5% MeOH in CH2Cl2) as eluant thereby
affording 17 (0.20 g) as a dense light yellow oil: yield 76%; 1H
NMR (CDCl3) δ 7.97 (d, J ) 6.8 Hz, 1H), 7.69-7.74 (m, 2H),
7.64-7.66 (m, 1H), 7.45 (s, 1H), 7.33 (s, 1H), 5.53 (br t, J ≈
5.6 Hz, 1H, NH), 3.52 (br q, J ≈ 6 Hz, 2H, NHCH2CH2), 3.28
(t, J ) 6.6 Hz, 2H, NCH2), 2.88 (s, 3H, NCH3), 1.72 (br quint,
J ≈ 6.4 Hz, 2H, NCH2CH2CH2), 1.63 (br quint, J ≈ 6.4 Hz,
2H, NCH2CH2CH2), 1.30-1.40 (m, 4H, 2CH2); 13C NMR
(CDCl3) δ 158.9 (C), 148.4 (C), 144.1 (C), 137.3 (CH), 133.8
(CH), 132.2 (C), 131.8 (CH), 130.7 (CH), 124.3 (CH), 110.0
(CH), 49.7 (NCH2), 42.2 (NHCH2), 34.3 (CH3), 28.9 (CH2), 27.1
(CH2), 25.8 (CH2), 25.4 (CH2); MS m/z 439[M + 1]+, 341, 229;
HPLC purity: Method 1: 94.9%, Method 2: 95.6%.
) 7.2 Hz, 1H), 7.88-7.94 (br m, 1H), 7.85 (s, 1H), 7.30 (s, 1H),
6.72-6.76 (m, 1H), 3.58 (br q, J ≈ 6.3 Hz, 2H, NHCH2CH2),
3.31-3.38 (m, 2H), 3.30 (br s, HDO), 1.60-1.70 (m, 4H,
2NCH2CH2), 1.35-1.45 (m, 4H, 2CH2); 13C NMR (DMSO-d6)
δ 156.8 (C), 156.1 (CH), 152.0 (Cipsopy), 144.2 (C), 136.8 (CH),
135.2 (CH), 127.2 (CNO2), 111.6 (CH), 111.2 (CH), 41.7 (NCH2),
40.6 (NCH2), 28.7 (CH2), 28.5 (CH2), 26.18 (CH2), 26.20 (CH2);
MS m/z 362 [M + 1]+, 264 (100), 99. Anal. Calcd for
C15H19N7O2S: C, 49.85; H, 5.30; N, 27.13. Found: C, 50.09;
H, 5.30; N, 26.87.
4-Cyano-N-[6-(imidazo[1,2-d][1,2,4]thiadiazol-3-ylami-
no)hexyl]-2-nitrobenzenesulfonamide (12k). A mixture of
the HCl salt of 16 (0.83 g, 3.0 mmol) and 4-cyano-2-nitroben-
zenesulfonyl chloride (prepared according to GB patent 1,426,-
405) in CH2Cl2 (125 mL), water (40 mL), and 2 N NaOH (10
mL) was stirred at rt for 15 min. The organic layer was
collected and successively washed with water, a 10% citric acid
solution, and water. After usual workup (100% CH2Cl2 then
95/5 CH2Cl2/MeOH, v/v, as eluant), 12k (0.65 g) was obtained
as a light brown foamy solid: yield 48%; mp 62-65 °C; 1H
NMR (CDCl3) δ 8.05 (d, J ) 8.2 Hz, 1H), 7.88-7.92 (m, 1H),
7.81 (d, J ) 8.2 Hz, 1H), 7.66 (s, 1H), 7.30 (br, 2H, 2NH), 7.05
(s, 1H), 3.14 (br q, J ≈ 6.0 Hz, 2H, NHCH2CH2), 2.78 (br q, J
≈ 6.0 Hz, 2H, NHCH2CH2), 1.42 (br quint, J ≈ 6.4 Hz, 2H,
NCH2CH2CH2), 1.30 (br quint, J ≈ 6.4 Hz, 2H, NCH2CH2CH2),
1.10-1.15 (m, 4H, 2CH2); 13C NMR (DMSO-d6) δ 156.8 (C),
146.9 (Cipso), 144.2 (C), 137.6 (CH), 136.9 (CH), 132.0 (CH),
130.6 (CNO2), 118.3 (CN), 115.8 (CH), 111.2 (CH), 96.1 (CCN),
42.3 (NCH2), 41.7 (NCH2), 28.5 (CH2), 28.0 (CH2), 26.1 (CH2),
26.0 (CH2); MS m/z 450 [M + 1]+, 352, 240, 99.
4-[6-(Imidazo[1,2-d][1,2,4]thiadiazol-3-ylamino)hexyl-
sulfamoyl]-3-nitrobenzoic Acid (12l). A mixture of the HCl
salt of 16 (1.40 g, 5.1 mmol) and 4-chlorosulfonyl-3-nitrobenzoic
acid methyl ester (1.45 g, 5.2 mmol) in CH2Cl2 (50 mL), water
(40 mL), and 2 N NaOH (10 mL) was stirred at rt for 90 min.
The progress of reaction was monitored by TLC (8/2/0.5 CH2-
Cl2/MeOH/NH4OH, v/v/v as eluant; Rf of 12l ) 0.22). The
aqueous layer was collected and acidified with a 10% citric
acid solution as a dense precipitate separated. The solid was
collected by suction filtration and dried under vacuum at 45
°C for 4 h. 12l was obtained as a white solid (1.80 g): yield
73%; mp 172-175 °C; 1H NMR (DMSO-d6) δ 8.37 (s, 1H), 8.33
(d, J ) 8.3 Hz, 1H), 8.23 (br t, J ≈ 5.1 Hz, 1H, NH), 8.11 (d,
J ) 8.1 Hz, 1H), 7.89 (br t, J ≈ 5.0 Hz, 1H, NH), 7.85 (s, 1H),
7.30 (s, 1H), 3.30 (q, J ≈ 6.2 Hz, 2H, NHCH2CH2), 2.93 (q, J
≈ 6.3 Hz, 2H, NHCH2CH2), 1.54 (br quint, 2H, NCH2CH2CH2),
1.44 (br quint, 2H, NCH2CH2CH2), 1.25-1.30 (m, 4H, 2CH2);
13C NMR (DMSO-d6) δ 164.6 (CO), 147.7 (C), 144.2 (C), 136.9
(CH), 136.2 (C), 135.9 (C), 132.9 (CH), 130.1 (CH), 124.9 (CH),
111.3 (CH), 42.7 (NCH2), 41.6 (NCH2), 29.1 (CH2), 28.5 (CH2),
25.9 (CH2), 25.6 (CH2); MS m/z 469 [M + 1]+, 371, 259.
5-Bromo-6-chloropyridine-3-sulfonic acid [6-(imidazo-
[1,2-d][1,2,4]thiadiazol-3-ylamino)hexyl]amide (12m): yield
45%; mp 146-150 °C; 1H NMR (DMSO-d6) δ 8.76 (s, 1H), 8.51
(s, 1H), 7.97 (br t, J ≈ 5.2 Hz, 1H, NH), 7.90 (br t, J ≈ 5.0 Hz,
1H, NH), 7.85 (s, 1H), 7.30 (s, 1H), 3.31-3.35 (masked under
HDO peak, m, 2H, NHCH2CH2), 3.33 (br s, HDO), 2.85 (br q,
J ≈ 5.6 Hz, 2H, NHCH2CH2), 1.57 (br quint, 2H, NCH2CH2-
CH2), 1.40 (br quint, 2H, NCH2CH2CH2), 1.20-1.30 (m, 4H,
2CH2); 13C NMR (DMSO-d6) δ 156.8 (C), 152.9 (C), 145.9 (CH),
144.2 (C), 140.5 (CH), 137.3 (C), 136.8 (CH), 120.3 (C), 111.2
(CH), 42.5 (NCH2), 41.7 (NCH2), 29.0 (CH2), 28.5 (CH2), 25.9
(CH2), 25.7 (CH2); MS m/z 497 [M + 4]+, 495 [M + 2]+, 493
[M]+, 395 (100), 353, 283. Anal. Calcd for C15H18BrClN6O2S2:
C, 36.48; H, 3.67; N, 17.02. Found: C, 37.08; H, 3.83; N, 17.02.
4-[[6-(Imidazo[1,2-d][1,2,4]thiadiazol-3-ylamino)hexyl]-
(naphthalene-1-sulfonyl)amino]butyric acid ethyl ester
(27a): 2 equiv of bromo compound, reflux for 16 h; yield 72%;
1H NMR (CD3OD) δ 8.58 (d, J ) 11.2 Hz, 1H), 8.11-8.18 (m,
2H), 7.96 (d, J ) 10.8 Hz, 1H), 7.69 (d, J ) 1.8 Hz, 1H), 7.55-
7.66 (m, 3H), 7.30 (d, J ) 2.0 Hz, 1H), 4.04 (q, J ) 9.6 Hz, 2H,
OCH2), 3.24-3.38 (m, 4H, 2CH2), 2.23 (t, J ) 9.6 Hz, 2H,
NCH2), 1.78 (quint, J ) 9.6 Hz, 2H, CH2CH2CH2), 1.39-1.53
(m, 4H, 2CH2), 1.08-1.29 (m, 9H, 3CH2 + CH3); 13C NMR (CD3-
OD) δ 174.7 (CO), 159.8, 146.1, 137.6 (CH), 136.4, 136.1, 135.6
(CH), 131.0 (CH), 130.3 (CH), 130.0, 129.2 (CH), 128.1 (CH),
126.2 (CH), 125.5 (CH), 111.9 (CH), 61.7 (OCH2), 47.9 (NCH2),
47.2 (NCH2), 43.3 (NCH2), 31.8, 29.7, 28.9, 27.4, 27.3, 24.5,
14.6 (CH3); MS m/z 544 [M + 1]+, 400, 210.
N-{6-[Imidazo[1,2-d][1,2,4]thiadiazol-3-yl(methyl)ami-
no]hexyl}-N-methyl-2-nitrobenzenesulfonamide (18). A
mixture of 12e (0.19 g, 0.44 mmol), CH3I (0.50 mL, 8.0 mmol),
K2CO3 (1.0 g), powder KOH (1.0 g), and n-Bu4N+I- (0.15 g) in
toluene (25 mL) was stirred at rt for ca. 10 min. The mixture
was filtered over a pad of Celite, and the cake was thoroughly
washed with acetone. The filtrate was soaked onto silica gel
and evaporated to dryness. The solid was applied on top of a
wet silica gel column and eluted with a solvent mixture of 5%
MeOH in CH2Cl2 as eluant. Thus, 18 was obtained as a thick
1
yellow oil (0.18 g): yield 88%; H NMR (CDCl3) δ 7.97-7.99
N-[6-(Imidazo[1,2-d][1,2,4]thiadiazol-3-ylamino)hexyl]-
2-nitrobenzamide (13). A mixture of 16 (0.24 g, 1.0 mmol),
2-nitrobenzoyl chloride (0.22 mg, 1.2 mmol), and Et3N (0.28
mL, 2.0 mmol) in CH2Cl2 (25 mL) was stirred at rt for 3 d.
The mixture was quenched with a 10% citric acid solution. The
organic fraction was collected and successively washed with
(m, 1H), 7.67-7.70 (m, 2H), 7.60-7.62 (m, 1H), 7.50 (s, 1H),
7.28 (s, 1H), 3.46 (t, J ) 7.4 Hz, 2H, NCH2), 3.23 (t, J ) 7.0
Hz, 2H, NCH2), 3.16 (s, 3H, CH3), 2.87 (s, 3H, CH3), 1.68
(overlapping br quint, 2H, NCH2CH2CH2), 1.62 (overlapping
br quint, 2H, NCH2CH2CH2), 1.37-1.40 (m, 4H, 2CH2); 13C
NMR (CDCl3) δ 160.6 (C), 148.4 (C), 147.0 (C), 137.8 (CH),
6238 J. Org. Chem., Vol. 70, No. 16, 2005

Synthesis of 3-Substituted Bicyclic Imidazo[1,2-d][1,2,4]thiadiazoles
133.6 (CH), 132.4 (C), 131.7 (CH), 130.9 (CH), 124.2 (CH),
112.3 (CH), 51.8 (NCH2), 49.9 (NCH2), 37.6 (CH3), 34.3 (CH3),
27.6 (CH2), 27.5 (CH2), 26.3 (CH2), 26.2 (CH2); MS m/z 453 [M
+ 1]+, 355 (100), 139.
carbamate: yield 88%; 1H NMR (CDCl3) δ 8.31-8.33 (m, 1H),
7.74-7.80 (m, 3H), 7.56 (s, 1H), 7.42 (s, 1H), 3.83 (br t, 2H,
NCH2), 3.55 (br t, 2H, NCH2), 3.21 (s, 3H, CH3), 1.82-1.85
(m, 4H, 2CH2), 1.36 (s, 9H, t-Bu). The Boc group was then
removed (HCl in MeOH) to provide N-{6-[imidazo[1,2-d]-
[1,2,4]thiadiazol-3-yl(methyl)amino]hexyl}-2-nitrobenze-
General Protection-Alkylation-Deprotection Proce-
dures. t-Butyl [6-(imidazo[1,2-d][1,2,4]thiadiazol-3-ylami-
no)hexyl][(2-nitrophenyl)sulfonyl]carbamate (19). A mix-
ture of 12e (0.48 g, 1.1 mmol), di-tert-butyl dicarbonate (0.38
g, 1.7 mmol), and DMAP (0.08 g, 0.61 mmol) in CH3CN (40
mL) was stirred at ambient temperature for 16 h. Volatile
materials were removed in vacuo, and the residue was
partitioned between EtOAc and a solution of 10% citric acid.
After usual workup (4% MeOH in CH2Cl2 as eluant), 19 (500
mg) was obtained as a colorless oil: yield 84%; 1H NMR
(CDCl3) δ 8.25-8.35 (m, 1H), 7.77-7.80 (m, 3H), 7.46 (s, 1H),
7.32 (s, 1H), 5.73 (br, 1H, NH), 3.80 (t, J ) 6.9 hz, 2H, NCH2),
3.53 (br q, J ≈ 6.1 Hz, 2H, NHCH2CH2), 1.65-1.80 (m, 4H,
2NCH2CH2), 1.40-1.50 (m, 4H, 2CH2), 1.39 (s, 9H, t-Bu); 13C
NMR (CDCl3) δ 159.1 (C), 150.5 (CO), 147.7 (C), 143.9 (C),
137.4 (CH), 134.4 (CH), 133.6 (CH), 133.3 (CH), 132.0 (C),
124.5 (CH), 109.6 (CH), 85.3 (OCCH3), 48.0 (NCH2), 42.5
(NCH2), 29.8 (CH2), 29.0 (CH2), 28.0 (3CH3), 26.2 (CH2), 26.0
(CH2); MS m/z 525.6 [M + 1]+, 425 (100), 327, 285, 186.
N-{6-[Imidazo[1,2-d][1,2,4]thiadiazol-3-yl(methyl)ami-
no]hexyl}-2-nitrobenzenesulfonamide (20).17a A mixture
of 19 (0.42 g, 0.80 mmol), CH3I (1.0 mL, 16 mmol), K2CO3 (2.5
g), powder KOH (2.5 g), and n-Bu4N+HSO4- (0.05 g) in toluene
(25 mL) and CH2Cl2 (5 mL) was stirred at rt for ca. 15 min.
The mixture was filtered over a pad of Celite, and the cake
was thoroughly washed with acetone. The filtrate was soaked
onto silica gel and evaporated to dryness. The solid was applied
on top of a wet prepacked silica gel column and eluted with a
solvent mixture of 4% MeOH in CH2Cl2 as eluant. Thus, tert-
butyl [6-(imidazo[1,2-d][1,2,4]thiadiazol-3-yl(methyl)amino)-
hexyl][(2-nitrophenyl)sulfonyl]carbamate (20a) was obtained
as a thick light yellow oil (0.35 g): yield 81%; 1H NMR (CDCl3)
δ 8.32-8.33 (m, 1H), 7.72-7.80 (m, 3H), 7.51 (s, 1H), 7.38 (s,
1H), 3.79 (t, J ) 7.2 Hz, 2H, NCH2), 3.49 (t, J ) 7.4 Hz, 2H,
NCH2), 3.18 (s, 3H, CH3), 1.70-1.80 (2 overlapping br quint,
4H, 2NCH2CH2CH2), 1.42-1.52 (m, 4H, 2CH2), 1.37 (s, 9H,
t-Bu); 13C NMR (CDCl3) δ 160.6 (C), 150.5 (CO), 147.7 (C),
147.0 (C), 137.8 (CH), 134.3 (CH), 133.7 (Cipso), 133.3 (CH),
131.9 (CH), 124.5 (CH), 111.2 (CH), 85.1 (OCCH3), 51.8
(NCH2), 48.0 (NCH2), 37.6 (CH3), 30.0 (CH2), 28.0 (3CH3), 27.7
(CH2), 26.4 (CH2), 26.3 (CH2); MS m/z 539 [M + 1]+, 341.
1
nesulfonamide (21): yield 88%; H NMR (DMSO-d6) δ 8.08
(br t, J ≈ 5.4 Hz, 1H, NH), 7.92-7.99 (m, 3H), 7.82-7.86 (m,
2H), 7.35 (s, 1H), 3.45 (t, J ) 7.2 Hz, 2H, NCH2), 3.11 (s, 3H,
NCH3), 2.94 (br q, J ≈ 6.4 Hz, 2H, NHCH2CH2), 1.57 (br quint,
2H), 1.44 (br quint, 2H); 13C NMR (DMSO-d6) δ 158.6 (C), 147.6
(C), 146.5 (C), 137.3 (CH), 133.9 (CH), 132.8 (C), 132.6 (CH),
129.4 (CH), 124.3 (CH), 114.0 (CH), 50.6 (NCH2), 42.4 (NCH2),
37.3 (CH3), 26.3 (CH2), 24.0 (CH2); MS m/z 411 [M + 1]+, 313,
257; HRMS (ESI) calcd for [MH]+ C15H19N6O4S2 411.0909,
found 411.0922; HPLC purity analysis 97.0% by Method 1 and
97.7% by Method 2. Anal. Calcd for C15H18N6O4S2: C, 43.89;
H, 4.42; N, 20.47. Found: C, 44.02; H, 4.64; N, 20.07.
{Imidazo[1,2-d][1,2,4]thiadiazol-3-yl-[6-(2-nitrobenzene-
sulfonylamino)hexyl]amino}acetic Acid Methyl Ester
(22a). A mixture of 10b (0.14 g, 0.50 mmol) and 24a (0.19 mg,
0.50 mmol) in DMSO (15 mL) was stirred at rt for 16 h. The
reaction mixture was quenched with a saturated NaHCO3
solution and extracted with EtOAc. The organic fraction was
collected and was successively washed with water, a 10% citric
acid solution and water. After usual workup (CH2Cl2/
EtOAc, 1/1, v/v), 22a was obtained as a light yellow oil (0.19
g, 75%). Spectral data were similar to those previously
described.17a
2-{Imidazo[1,2-d][1,2,4]thiadiazol-3-yl-[6-(2-nitroben-
zenesulfonylamino)hexyl]amino}acetamide (22c). Same
procedure as described for 22a above, except 1.1 equiv of 24b
was used and the eluant was CH2Cl2/MeOH (95/5, v/v). Yield
of 22c: 63%. Spectral data were similar to those previously
described.17a
Alternatively, 22c was prepared from 22a in the following
manner:
NH3 gas was bubbled into an ice-cooled solution of 22a (3.40
g, 6.85 mmol) for 1.5 h. The resulting mixture was allowed to
warm to rt and then stirred for overnight. A sample was
removed and analyzed by TLC (95/5 CH2Cl2/CH3OH, v/v, as
eluant, UV and 1.5% aq KMnO4 stain). The reaction was not
complete, as 22a and 22c were present in almost equal
proportions (UV intensity). The reaction mixture was cooled
in ice, and NH3 gas was bubbled into the reaction mixture for
2 h. The resulting mixture was allowed to warm to rt and then
stirred overnight. This time, analysis of the reaction mixture
by TLC indicated the presence of a major spot (22c) and a trace
amount of 22a. The reaction mixture was evaporated to
dryness, and the residue was dissolved in CH3OH. Silica gel
was added, and the mixture was again evaporated to dryness.
The latter residue was then placed on top of a wet-packed silica
gel column chromatography. The desired product was eluted
with a solvent gradient (1/1 CH2Cl2/EtOAc, 95/5 CH2Cl2/CH3-
OH, and 9/1 CH2Cl2/CH3OH, v/v, as eluant). The title
compound17a was obtained as a white solid (3.00 g, 91%).
Compound 20a obtained above (0.30 g, 0.56 mmol) was
dissolved in MeOH (25 mL) and then cooled in ice. HCl gas
was bubbled through the solution for ca. 6 min, and the
resulting mixture was allowed to warm to rt and stirred for
16 h. Volatile materials were removed in vacuo and the residue
was purified by column chromatography on silica gel using a
solvent mixture of 5% MeOH in CH2Cl2 as eluant, thus
affording 20 (0.24 g) as a light yellow oil: yield 98%.
tert-Butyl [6-(imidazo[1,2-d][1,2,4]thiadiazol-3-ylami-
no)butyl][(2-nitrophenyl)sulfonyl]carbamate (21a): yield
86%; 1H NMR (CDCl3) δ 8.27-8.33 (m, 1H), 7.70-7.78 (m, 3H),
7.55 (s, 1H), 7.44 (s, 1H), 7.32 (s, 1H), 5.83 (br t, J ≈ 5.5 Hz,
1H, NH), 3.82 (t, J ) 6.7 Hz, 2H, NCH2CH2), 3.57 (br q, J ≈
6.2 Hz, 2H, NHCH2CH2), 1.86 (quint, J ) 7.4 Hz, 2H,
NCH2CH2CH2), 1.80 (quint, J ) 7.0 Hz, 2H, NCH2CH2CH2),
1.36 (s, 9H, t-Bu); 13C NMR (CDCl3) δ 159.1 (C), 150.6 (C),
147.7 (C), 143.8 (C), 137.5 (CH), 134.5 (CH), 133.5 (C), 133.3
(CH), 132.0 (CH), 124.6 (CH), 109.6 (CH), 85.6 (OCCH3), 47.6
(NCH2), 42.3 (NCH2), 28.0 (CH3), 27.4 (CH2), 25.8 (CH2); MS
Also, 22b can be prepared from 22a in the following manner:
To a solution of 22a (2.49 g, 5.00 mmol) in CH3OH was
added a 2 N NaOH solution (15 mL, 30 mmol) at rt. The
resulting mixture was stirred for 16 h. Volatiles were then
removed in vacuo, and the residue was dissolved in water (50
mL). The aqueous layer was washed with EtOAc (50 mL) and
then was acidified with a 3 N HCl solution to pH about 2. The
whole mixture was evaporated to dryness. The residue was
taken up in acetone, and hexane was added to precipitate out
the product as a light yellow mass. The mixture was again
evaporated to dryness. The latter two steps were repeated
three more times with vigorous stirring. The solid was then
collected by suction filtration, and dried at 40 °C under vacuum
for 3h. 22b was obtained as a light yellow solid (1.91 g, 79%).
Spectral data were similar to those previously described.17a
m/z 497 [M
+
1]+, 397 (100), 299. Anal. Calcd for
C19H24N6O6S2: C, 45.96; H, 4.87; N, 16.92. Found: C, 45.99;
H, 5.03; N, 16.99.
Compound 21a was methylated at the N1 position as
described above to afford tert-butyl [6-(imidazo[1,2-d][1,2,4]-
thiadiazol-3-yl(methyl)amino)butyl][(2-nitrophenyl)sulfonyl]-
J. Org. Chem, Vol. 70, No. 16, 2005 6239

Leung-Toung et al.
[(6-Aminohexyl)imidazo[1,2-d][1,2,4]thiadiazol-3-ylami-
no]acetic Acid Methyl Ester (25). Same procedure as
described for 22a above, except 1.2 equiv of 23a and 2 equiv
of Et3N were used, and the eluant was 100% CH2Cl2 followed
by CH2Cl2/MeOH (95/5, v/v). The intermediate [(6-tert-butoxy-
carbonylaminohexyl)imidazo[1,2-d][1,2,4]thiadiazol-3-ylamino]-
acetic acid methyl ester was obtained as a light brown oil:
4-[[6-(Imidazo[1,2-d][1,2,4]thiadiazol-3-ylamino)hexyl]-
(naphthalene-1-sulfonyl)amino]butyramide (27c). A mix-
ture of 27a (0.27 g, 0.50 mmol) and a 28% NH4OH solution
(20 mL) in MeOH (30 mL) was stirred at rt for 2 days. Volatiles
were removed in vacuo and the residue was purified by column
chromatography on silica gel (CH2Cl2/MeOH, 9/1, v/v). Com-
pound 27c was obtained as a waxy white solid (0.15 g): yield
59%; 1H NMR (CD3OD) δ 8.60 (d, J ) 11.2 Hz, 1H), 8.15 (d, J
) 10.0 Hz, 1H), 8.08 (d, J ) 10.8 Hz, 1H), 7.93 (d, J ) 10.8
Hz, 1H), 7.68 (s, 1H), 7.64 (dt, J ) 10.0 and 1.6 Hz, 1H), 7.51-
7.60 (m, 2H), 7.30 (s, 1H), 3.35 (t, J ) 10.0 Hz, 2H, NCH2),
3.22-3.28 (m, 4H, 2NCH2), 2.17 (t, J ) 9.8 Hz, 2H, CH2CO),
1.80 (br quint, 2H, CH2CH2CH2), 1.36-1.48 (m, 4H, 2CH2),
1.00-1.20 (m, 4H, 2CH2); 13C NMR (CD3OD) δ 178.0 (CO),
160.0, 146.0, 137.5 (CH), 136.4, 136.0, 135.4 (CH), 130.8 (CH),
130.2 (CH), 130.0, 129.1 (CH), 128.0 (CH), 126.2 (CH), 125.4
(CH), 112.0, 48.0 (NCH2), 47.6 (NCH2), 43.3 (NCH2), 33.4 (CH2-
CO), 30.0, 28.9, 27.3, 27.2, 25.4; MS m/z 515 [M + 1]+, 400
(100), 191.
1
yield 49%; H NMR (CDCl3) δ 7.47 (s, 1H), 7.43 (s, 1H), 4.22
(s, 2H, NCH2CO), 3.81 (s, 3H, CH3), 3.62 (t, J ) 7.9 Hz, 2H,
NCH2), 3.11-3.15 (m, 2H, NCH2), 1.72-1.77 (m, 2H, CH2),
1.50-1.54 (m, 2H, CH2), 1.46 (s, 9H, t-Bu), 1.34-1.44 (m, 4H,
2CH2); MS m/z 412 [M + 1]+, 356 (100), 214.
To a solution of the intermediate obtained above (4.6 g, 11
mmol) in CH2Cl2 (110 mL) was added TFA (110 mL) slowly at
rt, and the resulting mixture was stirred at rt for 16 h. The
light yellow solution was evaporated to dryness, and the
residue was purified by column chromatography on silica gel
using a mixture of solvents (CH2Cl2/MeOH, 95/5, v/v, then CH2-
Cl2/MeOH/28% NH4OH, 80/20/0.4, v/v/v) as eluant. Compound
25 was obtained as a yellow powder (1.9 g): yield 55%; 1H
NMR (DMSO-d6) δ 7.88 (s, 1H), 7.50-7.80 (br, 2H, NH2), 7.37
(s, 1H), 4.42 (s, 2H, NCH2CO), 3.70 (s, 3H, CH3), 3.57 (t, J )
5.5 Hz, 2H, NCH2), 2.76 (t, J ) 5.4 Hz, 2H, NCH2), 1.62-1.72
(m, 2H, CH2), 1.55-1.60 (m, 2H, CH2), 1.30-1.40 (m, 4H,
2CH2); MS m/z 312 [M + 1]+, 214 (100), 197.
Reaction of Tricyclic THD Derivative 7f with Phen-
ethyl Mercaptan.28 To a suspension of 7f (26 mg, 0.09 mmol)
in MeOH (10 mL) was added 2.5 equiv of phenethyl mercaptan
(31 µL, 0.23 mmol) via syringe. The progress of the reaction
was monitored by TLC (CHCl3/MeOH, 100/2, v/v) and com-
pared with authentic 2-mercaptobenzimidazole (Aldrich) as
reference (Rf of 7f ) 0.17; Rf of 2-mercaptobenzimidazole )
0.69). After a period of ca. 3 days, 7f was faintly detected by
TLC, and the major component was 2-mercaptobenzimidazole.
A sample was evaporated to dryness and analyzed by MS-EI,
[6-(Carbamoylmethylimidazo[1,2-d][1,2,4]thiadiazol-3-
ylamino)hexyl]carbamic Acid tert-Butyl Ester (26a).
Same procedure as described for 22a above, except 1.2 equiv
of 23b and 2 equiv of Et3N were used. The eluant was CH2-
1
+
Cl2/MeOH (98/2 then 95/5, v/v): yield 42%; H NMR (CDCl3)
which showed [M] at 151.
δ 7.52 (s, 1H), 7.43 (s, 1H), 6.77 (s, 1H), 5.78 (s, 1H), 4.59 (br
s, 1H), 4.17 (s, 2H), 3.60 (t, J ) 8.1 Hz, 2H), 3.11-3.14 (m,
2H), 1.72-1.80 (m, 2H), 1.20-1.50 (m, 15H); MS m/z 397 [M
+ 1]+, 341 (100), 297, 199.
In another experiment, a suspension of 7f (26 mg, 0.09
mmol) and 25 equiv of phenethyl mercaptan (0.32 mL, 2.4
mmol) in MeOH (10 mL) was stirred at rt. Compound 7f was
converted to 2-mercaptobenzimidazole over a period of 2-3 h,
as monitored with authentic material by TLC.
2-[(6-Aminohexyl)imidazo[1,2-d][1,2,4]thiadiazol-3-
ylamino]acetamide (26). Similar procedure as for prepara-
tion of 25 above. Eluant was CH2Cl2/MeOH/28% NH4OH, 75/
25/10, v/v/v). The mixture was then stirred in a mixture of
EtOAc (75 mL) and CH2Cl2 (15 mL). The solid was collected
and dried under vacuum at 40 °C for 3 h. Compound 26 was
obtained as a beige solid: yield 97%; mp 132-133 °C; 1H NMR
(DMSO-d6) δ 7.80 (s, 1H), 7.30 (br, 2H), 7.57 (s, 1H), 7.35 (s,
1H), 7.57 (s, 1H), 7.18 (s, 1H), 4.15 (s, 2H, CH2CO), 3.55 (t, J
) 7.2 Hz, 2H, NCH2), 2.77 (t, J ) 6.5 Hz, 2H, NCH2), 1.60-
1.64 (m, 2H, CH2), 1.51-1.55 (m, 2H, CH2), 1.30-1.35 (m, 4H,
2CH2); 13C NMR (DMSO-d6) δ 174.1 (CO), 162.1 (C), 147.6 (C),
137.9 (CH), 114.7 (CH), 53.5 (NCH2), 52.4 (NCH2), 40.7 (NCH2),
29.0 (CH2), 28.6 (CH2), 27.3 (CH2), 27.2 (CH2); MS m/z 297 [M
+ 1]+, 227, 199 (100), 129.
4-[[6-(Imidazo[1,2-d][1,2,4]thiadiazol-3-ylamino)hexyl]-
(naphthalene-1-sulfonyl)amino]butyric Acid (27b). A
mixture of 27a (0.27 g, 0.50 mmol) and 2 N NaOH solution
(2.0 mL, 4.0 mmol) in MeOH (15 mL) was stirred at rt for 16
h. Volatile materials were removed in vacuo. The residue was
partitioned between water and EtOAc. The aqueous layer was
collected, acidified with 1 N HCl solution, and extracted with
EtOAc (3×). The combined organic fractions were dried,
filtered, and evaporated to dryness. 27b was obtained as a
white solid (0.18 g): yield 68%; mp 119-122 °C; 1H NMR (CD3-
OD) δ 8.59 (d, J ) 11.6 Hz, 1H), 8.16 (d, J ) 9.6 Hz, 1H), 8.12
(d, J ) 10.8 Hz, 1H), 7.95 (d, J ) 10.8 Hz, 1H), 7.72-7.80 (br,
1H), 7.64 (t, J ) 9.2 Hz, 1H), 7.54-7.60 (m, 2H), 7.28-7.38
(br, 1H), 3.36 (t, J ) 9.6 Hz, 2H, NCH2), 3.24-3.31 (m, 4H,
2NCH2), 2.22 (t, J ) 9.4 Hz, 2H, CH2CO), 1.78 (br quint, 2H,
CH2CH2CH2), 1.40-1.52 (m, 4H, 2CH2), 1.10-1.26 (m, 4H,
2CH2); 13C NMR (CD3OD) δ 175.0 (CO), 161.0 (C), 146.1 (C),
137.5 (CH), 136.5 (C), 136.1 (C), 135.6 (CH), 130.9 (CH), 130.3
(CH), 130.0, 129.2 (CH), 128.1 (CH), 126.2 (CH), 125.5 (CH),
111.5, 48.0 (NCH2), 47.4 (NCH2), 43.3 (NCH2), 31.8, 30.0, 29.0,
27.4, 27.3, 24.7; MS m/z 516 [M + 1]+, 400 (100), 210. Anal.
Calcd for C24H29N5O4S2: C, 55.90; H, 5.67; N, 13.58. Found:
C, 55.89; H, 5.86; N, 13.02.
Reaction of Dimethylamino THD 11a with Phenethyl
Mercaptan. To a solution of dimethylamino THD derivative
11a (23 mg, 0.11 mmol) in methanol (10 mL) was added 25
equiv of phenethyl mercaptan (0.36 mL, 2.7 mmol) via syringe.
The progress of the reaction was monitored by TLC using a
mixture of chloroform and methanol as eluant (10/1, v/v, Rf of
11a ) 0.43, Rf of 28a ) 0.60). After 1 min, all of 11a was
consumed. The solvent was evaporated and the crude material
was washed with CHCl3 to afford 2-mercapto-N,N-dimethyl-
benzoimidazole-1-carboxamidine (28a): yield 15 mg (65%); 1H
NMR (DMSO-d6) δ 7.3-7.0 (m, 4H, Ar), 3.35 (br m, 2H, NH,
SH), 2.88 (s, 6H, 2 NCH3); 13C NMR (CDCl3) δ 167.2, 149.7,
132.3, 131.8, 123.4 (CH), 122.5 (CH), 110.2 (CH), 109.4 (CH),
37.7 (CH3), 36.7 (CH3); IR (KBr) ν 3210, 1641, 1475, 1452, 1407,
1319 cm-1; MS (EI) m/z 220 (M+), 150 (M+ - Me2NCdNH,
100), 71.
Reaction of Methoxy THD (11d) with Phenethyl
Mercaptan.18c To a solution of 3-methoxy thiadiazole 11d (23
mg, 0.11 mmol) in MeOH (10 mL) was added 25 equiv of
phenethyl mercaptan (0.38 mL, 2.8 mmol). All the starting
material was consumed in less than 1 min as monitored by
TLC (eluant: CHCl3/MeOH, 100/2, v/v, Rf of 11d ) 0.19, Rf of
28b ) 0.26). 2-Mercaptobenzoimidazole-1-carboximidic acid
methyl ester (28b) was isolated and identified as the major
product of the reaction: 1H NMR (DMSO-d6) δ 13.45 (br s,
1H), 9.80 (s, 1H), 7.70 (d, J ) 8 Hz, 1H, 1 ArH), 7.20-7.35 (m,
3H, 3 ArH), 3.95 (s, 3H, OCH3); 13C NMR (DMSO-D6) δ 168.2,
151.3, 130.1, 129.8, 124.7, 123.2, 114.7, 110.0, 54.4; IR (KBr)
ν 3437, 3095, 1679, 1450, 1440, 1376, 1193, 735 cm-1; MS (EI)
m/z 207 [M]+, 150 (M+ - MeOCdNH, 100), 122, 90. Anal.
Calcd for C9H9N3OS: C, 52.16; H, 4.38; N, 20.27. Found: C,
51.70; H, 4.03; N, 20.21.
In another experiment, the reaction mixture was allowed
to stir at rt for another 2 h. The methyl ester derivative 28b
converted to 2-mercaptobenzimidazole over a period of 2-3 h,
as monitored by TLC.
6240 J. Org. Chem., Vol. 70, No. 16, 2005

Synthesis of 3-Substituted Bicyclic Imidazo[1,2-d][1,2,4]thiadiazoles
Acid/Base Stability of Bicyclic Derivative 12a (pH )
2, 7, 9.8, and 13.7). Four solutions of compound 12a (10.0 mg,
0.023 mmol) were prepared in CH3CN (1 mL), and 4 mL of
the appropriate pH buffer was added (pH 2, 7, 9.8, and 13.7
(2 N NaOH)), respectively. The mixtures were stirred at rt,
and their stability in the different media was verified by TLC
(eluant: CH2Cl2/MeOH, 95/5, v/v) and by HPLC (method 1).
A HPLC calibration curve was constructed with different
concentrations of 12a. Samples for HPLC analyses were
prepared accordingly: 5 µL of reaction sample was withdrawn
by syringe and added to 2 mL of NH4OAc buffer solution at a
pH of 5.5. After 20 h at rt, only the starting material 12a was
detected in the media at the pH of 2, 7, and 9.8. It was deduced
from analysis of the HPLC spectra of 12a in 2N NaOH solution
that 95% remained after 2 h and 60% after 20 h.
Stability of Bicyclic Compound 12a in the Presence
of n-Butylamine. A solution of bicyclic derivative 12a (10 mg,
0.023 mmol) and 7.5 equiv of n-butylamine in CH2Cl2 was
stirred at rt. After 20 h at rt, analysis of the HPLC spectrum
(method 1) indicated presence of starting material 12a only.
Single-Crystal X-ray Structure of Thiadiazole Deriva-
tive (21). A single crystal (size 0.24 × 0.14 × 0.06 mm3)
obtained as a white plate from 1/1 MeOH/THF with slow
evaporation was used for X-ray diffraction measurements.
Crystal data: C15H18N6O4S2, orthorhombic, space group Pbca
with a ) 8.2010(2) Å, b ) 12.2350(3) Å, C, ) 35.1640(11) Å;
R) 90°, â) 90°, γ ) 90°; V ) 3528.33(16) Å3; Z ) 8; d ) 1.545
Mg/m3; R ) 0.0743 for 3986 independent reflections (I > 2σ-
(I); wR2 ) 0.1079 (F2, all data). The structure of compound
21 is depicted in Figure 3 in the text, and the CIF file is
available as Supporting Information.
Acknowledgment. We thank Dr. Glenn Williams
and Lei Shang for the crystal growth of 21, Tullio
Cappelletto for the synthesis of compounds 11a and
11d, and Sandra Agostino for proof-reading the manu-
script.
Supporting Information Available: Detailed synthesis
and spectral data of the intermediates and compounds. NMR
spectra of the following compounds: 8, 12d,k,l, 13, 15, 23a,
24a,b, 25, 26a, 29, 30a,d (1H); 26 (13C); 11c, 12c, 27a,c, 28a
(1H, 13C); 18, 19, 20a (2D-COSY, HSQC, HMBC). The crystal-
lographic data on the single X-ray crystal structure of com-
pound 21 are also provided (CIF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JO0507486
J. Org. Chem, Vol. 70, No. 16, 2005 6241