Efficient approaches to S-alkyl-N-alkylisothioureas: Syntheses of histamine H3 antagonist clobenpropit and its analogues

Article abstract of DOI:10.1021/jo702181x

(Chemical Equation Presented) S-Alkyl-N-alkylisothioureas were efficiently synthesized via synthetic approach (A) using 3-phenylpro-pionyl isothiocyanate (PPI). The utility of the approach was proved by the syntheses of clobenpropit, a potent histamine H₃ antagonist, and its analogues. Alternatively, clobenpropit could be prepared via intramolecular amide cleavage (B) with use of 2-nitrophenylacetyl isothiocyanate (NPAI).

Full text of DOI:10.1021/jo702181x

Efficient Approaches to S-Alkyl-N-alkylisothioureas: Syntheses of
Histamine H3 Antagonist Clobenpropit and Its Analogues
Hiroki Yoneyama,† Ayako Shimoda,†,‡ Lisa Araki,† Kouta Hatano,§ Yasuhiko Sakamoto,‡
Takushi Kurihara,† Atsushi Yamatodani,§ and Shinya Harusawa*,†
Osaka UniVersity of Pharmaceutical Sciences, 4-20-1, Nasahara, Takatsuki, Osaka 569-1094, Japan,
Alfresa Pharma Co., 2-24-3, Sho, Ibaraki, Osaka 567-0806, Japan, and Department of Bioinformatics,
Graduate School of Allied Health Sciences, Faculty of Medicine, Osaka UniVersity,
Osaka 565-0871, Japan
harusawa@gly.oups.ac.jp
ReceiVed October 8, 2007
S-Alkyl-N-alkylisothioureas were efficiently synthesized via synthetic approach (A) using 3-phenylpro-
pionyl isothiocyanate (PPI). The utility of the approach was proved by the syntheses of clobenpropit, a
potent histamine H3 antagonist, and its analogues. Alternatively, clobenpropit could be prepared via
intramolecular amide cleavage (B) with use of 2-nitrophenylacetyl isothiocyanate (NPAI).
Introduction
thiols,1b whose S-alkyl moieties are good leaving groups. In
recent years, the isothiourea-functional group has been increas-
ingly found in a wide range of biologically active molecules,1c
including NO synthase inhibitors,5 Na+/Ca2+ exchanger inhibi-
tors,6 genotype-selective antitumor agents,7 and anti-HIV com-
pounds.8
On the other hand, the histamine H3 receptor (H3R) is a
presynaptic autoreceptor that is mainly localized in the central
nervous system (CNS) and acts to modulate the biosynthesis
and release of histamine from histaminergic neurons.9 H3R
S-Alkylisothioureas 1 and their salts 1‚HX are synthesized
by mainly reacting thioureas with alkyl halides,1 and other
methods have been little employed so far.2 They are crucial
intermediates for the synthesis of guanidines3 and heterocyclic
systems.4 Treatment of 1 with alkali or amine easily produces
† Osaka University of Pharmaceutical Sciences.
‡ Alfresa Pharma Co.
§ Osaka University.
(1) (a) Sandler, R. S.; Karo, W. Organic Functional Group Preparations,
2nd ed.; Academic Press, Inc.: New York, 1986; pp 206-210. (b) Smith,
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& Sons, Inc.: New York, 2001; pp 495-496. (c) Denk, M. K.; Ye, X.
Tetrahedron Lett. 2005, 46, 7597.
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10.1021/jo702181x CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/16/2008
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J. Org. Chem. 2008, 73, 2096-2104

Efficient Approaches to S-Alkyl-N-alkylisothioureas
SCHEME 1. Reaction of Thiourea with Alkyl Halide
FIGURE 1. Two reagents for S-alkyl-N-alkylisothiourea syntheses.
p-carborane-containing thiourea 3c (see the preparation in
Scheme 4), in which the benzene ring of thiourea 3a was
replaced with p-carborane, did not proceed at all (eq 3). This
may be caused by an electron-withdrawing effect of the
carborane framework, which is an electron-deficient cluster.18
These results indicate that conventional methods for the
S-alkylation of thioureas give poor yields of S-alkylisothioureas
and their salts.
In this paper, we report two efficient synthetic approaches
to S-alkyl-N-alkylisothioureas. One approach involves direct
cleavage of the N-CO bond (A) with hydrazine hydrate starting
from 3-phenylpropionyl isothiocyanate (PPI), producing cloben-
propit in higher yields and in a remarkably shorter time than
those of a known method.11a Further, clobenpropit analogues
were synthesized, proving the applicability of the PPI method.
In addition, an alternative approach for the synthesis of
clobenpropit, which employs 2-nitrophenylacetyl isothiocyanate
(NPAI) and an intramolecular amide cleavage (B), is described
(Figure 1).
antagonists increase central histamine levels and may therefore
be useful for the treatment of a variety of CNS disorders,
including eating disorder, schizophrenia, narcolepsy, epilepsy
and cognitive disorders, and attention-deficit hyperactivity
disorder (ADHD).10 Among them, the S-imidazolylpropyl-N-
phenylalkylisothiourea series was developed by Timmerman and
co-workers, and in particular clobenpropit 1a11a is widely used
in pharmacology as a potent prototype of H3R antagonists.11b
H3R antagonists and agonists were found to bind not only to
H3R but also to histamine H4 receptor (H4R), which was dis-
covered as the fourth subtype of histamine receptor in 2000.12
H4R is now regarded as a new therapeutic target for inflam-
mation.13 Similar to the case of H3R antagonists there are iso-
thioureas that function as important histamine H2 receptor (H2R)
and H3R agonists, e.g., dimaprit14 and imetit,15 respectively.
In a previous work where we aimed to synthesize new H3R
ligands,16 we noted that the formation of S-alkyl-N-alkylisothio-
ureas is not an easy task. The reaction of thioureas with alkyl
halides is often extremely sluggish with reflux and the yields
quoted in the literature vary markedly (Scheme 1). The reaction
of 4-chlorobenzylthiourea (3a) with 4(5)-(3-bromopropyl)-
imidazole‚HBr (4) gave clobenpropit‚2HBr (1a) in only 26%
yield under reflux in ethanol for 6 days (Scheme 1, eq 1).11a
The yield of piperidine analogue FUB 66117 was worse at 8%
(eq 2). Further, the reaction of alkyl bromide 4 with novel
Results and Discussion
We first paid attention to N-benzoyl thiourea 7k, which has
an acidic N-H between CdO and CdS groups (Scheme 2).
The reaction of 4-chlorobenzylamine 6a with benzoyl isothio-
cyanate gave 7k. S-Alkylation of 7k by the Mitsunobu reaction19
with use of N,N,N′,N′-tetramethylazodicarboxamide (TMAD)20
and Bu3P proceeded as expected to give S-alkylated isothiourea
9k. However, selective cleavage of the N-CO bond of 9k failed
owing to the sensitivity of the C-S bond in spite of many trials
(acid, base, hydride anion, or hydrazine hydrate), causing the
formation of disulfide 10.
SCHEME 2. Sensitivity of the C-S Bond of N-Benzoyl-S-
alkylated Isothiourea 9k
(10) Watanabe, T.; Timmerman, H.; Yanai, K. Histamine Research in
the New Millennium; Elsevier: New York, 2001.
(11) (a) Van der Goot, H.; Schepers, M. J. P.; Sterk, G. J.; Timmerman,
H. Eur J. Med. Chem. 1992, 27, 511. (b) Barnes, J. C.; Brown, J. D.; Clarke,
N. P.; Clapham, J.; Evans, D. J.; O’Shaughnessy, C. T. Eur. J. Pharmacol.
1993, 250, 147.
(12) (a) Oda, T.; Morikawa, N.; Saito, Y.; Masuho, Y.; Matsumoto, S.
J. Biol. Chem. 2000, 275, 36781. (b) Nakamura, T.; Itadani, H.; Hidaka,
Y.; Ohta, M.; Tanaka, K. Biochem. Biophys. Res. Commun. 2000, 279, 615.
(c) Hough, L. B. Mol. Pharmacol. 2001, 59, 415 and references cited therein.
(13) de Esch, I. J. P.; Thurmond, R. L.; Jongejian, A.; Leurs, R. Trends
Phamacol. Sci. 2005, 26, 462.
(14) Durant, G. J.; Ganellin, C. R.; Parsons, M. E. Agents Actions 1977,
7, 39.
(15) Garbarg, M.; Arrang, J. M.; Rouleau, A.; Ligneau, X.; Dam Trung
Tuong, M.; Schwartz, J. C.; Ganellin, C. R. J. Pharmacol. Exp. Ther. 1992,
263, 304.
(16) (a) Harusawa, S.; Imazu, T.; Takashima, S.; Araki, L.; Ohishi, H.;
Kurihara, T.; Yamamoto, Y.; Yamatodani, A. Tetrahedron Lett. 1999, 40,
2561. (b) Harusawa, S.; Kawamura, M.; Araki, L.; Taniguchi, R.; Yon-
eyama, H.; Sakamoto, Y.; Kaneko, N.; Nakao, Y.; Hatano, K.; Fujita, T.;
Yamamoto, R.; Kurihara, T.; Yamatodani, A. Chem. Pharm. Bull. 2007,
55, 1245 and references cited therein. (c) Hashimoto, T.; Harusawa, S.;
Araki, L.; Zuiderveld, O. P.; Smit, M. J.; Imazu, T.; Takashima, S.;
Yamamoto, Y.; Sakamoto, Y.; Kurihara, T.; Leurs, R.; Bakker, R. A.;
Yamatodani, A. J. Med. Chem. 2003, 46, 3162.
(17) Meier, G.; Apelt, J.; Reichert, U.; Grassmann, S.; Ligneau, X.; Elz,
S.; Leurquin, F.; Ganellin, C. R.; Schwartz, J.-C.; Schunack, W.; Stark, H.
Eur. J. Pharm. Sci. 2001, 13, 249.
(18) Carboranes; Grimes, R. N., Ed.; Academic: New York, 1970; pp
1-22.
(19) Nagasawa, H.; Mitsunobu, O. Bull. Chem. Soc. Jpn. 1981, 54, 2223.
(20) Tsunoda, T.; Otsuka, J.; Yamamiya, Y.; Itoˆ, S. Chem. Lett. 1994,
539.
J. Org. Chem, Vol. 73, No. 6, 2008 2097

Yoneyama et al.
TABLE 1. Treatment of N-Acylisothioureas with Hydrazine
SCHEME 3. Reaction of 6a with NPPI
PPI method as the general method for the synthesis of
isothioureas 1.
Removal of the Nim-Tr group of thus obtained S-alkylisothio-
urea 2a with hydrochloric acid provided clobenpropit‚2HCl
(1a‚2HCl) in four steps in 51% overall yield from 6a (Table 2,
entry 1). Clobenpropit synthesis by using the PPI method
requires within less than 2 days. In contrast, Timmerman et al.’s
method11a gave only 10% overall yield of clobenpropit‚2HBr
(1a‚2HBr) with the same amine 6a and required at least one
week more to complete the synthesis.
Several analogues of clobenpropit were synthesized to
demonstrate the applicability of this method (Table 2). 1b‚2HBr
(VUF 4598) (24% overall yield, entry 2) was synthesized from
6b. VUF 4598 is the precursor of 125I-labeled iodophenpropit,
which is the first {125I}-labeled selective H3R antagonist having
high specific activity.23 Further, using this method we synthe-
sized novel p-carborane-containing isothioureas 1c and 1d (26%
and 46% overall yields, respectively, entries 3 and 4), although
their syntheses failed with use of the conventional method
(Scheme 1, eq 3). In the carborane derivative 1c, the benzene
ring of clobenpropit is replaced with p-carborane, because
spherical carborane has similar size to adamantane and its
hydrophobicity is comparable to that of hydrocarbons.24 The
starting amines, 1-aminomethyl-1,12-dicarba-closo-dodecabo-
ranes 6c and 6d, were successfully prepared in four or five steps
starting from p-carborane via volatile 14 and 15 under vacuum,
as illustrated in Scheme 4. However, unfortunately, preliminary
investigations of in vivo histamine release in rat hypothalamus
measured by brain microdialysis16a,b showed that 1c and 1d were
inactive against H3R.
a MW irradiation was used (see the Experimental Section). b The reaction
was carried out in the presence of 10% Pd/C. c MeNH2 was used as
nucleophile.
Fortunately, in the case of N-acyl-S-alkylisothioureas (Table
1), we found that treatment of N-phenylpropionyl (PP)-protected
isothiourea 9a with hydrazine hydrate (1.0 equiv) at room
temperature (rt) for 17 h afforded the desired 2a in 69% yield
with retention of the S-alkyl moiety (Table 1, entry 2). The
reaction time could be remarkably shortened to 10 min by
microwave (MW) irradiation (75 °C), giving 2a (51% yield;
entry 3). Acetyl analogue 9h and NPA-protected 9i similarly
afforded 2a (entries 4 and 6), while treatment of N-(2-
nitrophenyl)propionyl (NPP) analogue 9j with hydrazine in the
presence of a catalytic amount of 10% Pd/C provided 2a in
71% yield (entry 8). Use of methylamine (1.0 equiv) as
nucleophile gave 2a in only 14% yield, competing with the thiol
elimination (entry 9). The reaction of 4-nitrobenzoyl isothiourea
9l occurred with only elimination of the S-alkylated moiety
(entry 10).
On the other hand, the first reaction of amine 6 with acyl
isothiocyanate (PPI, acetyl isothiocyanate, NPAI, or NPPI)
usually gives N-acylthiourea 7 accompanied by amide 11 as
byproduct owing to the attack of amine 6 at the carbonyl group
of acyl isothiocyanates. For example, as shown in Scheme 3,
the reaction of amine 6a with NPPI afforded acylthiourea 7j
(39%) and N-(4-chlorobenzyl)-3-(2-nitrophenyl)propionamide
11j (34%), the structure of which was confirmed by condensa-
tion of 3-(2-nitrophenyl)propionic acid with 6a in the presence
of diethyl phosphorocyanidate (DEPC).21 Among isothiocyan-
ates employed, PPI most strongly suppressed the production of
amide 11a, providing 7a in 78% yield (Table 2, entry 1). In
addition, PPI itself can be easily prepared by the one-step
reaction of commercially available 3-phenylpropionyl chloride
with Pb(SCN)2.22 From the results of Table 1 and the suppres-
sion of amide formation in the first reaction, we adopted the
Piperidine analogue 1e‚2HCl (FUB 661)17 of clobenpropit
was previously synthesized in an attempt to replace the
imidazole ring with other heterocycles, but the yield of the key
reaction was only 8% (Scheme 1, eq 2). Our approach afforded
FUB 661 in 38% overall yield from 6a (Table 3, entry 1). Novel
pyrrolidine and morpholine analogues 1f and 1g were similarly
synthesized in 30% and 25% overall yields, respectively (entries
2 and 3). As brain microdialysis experiments of FUB 661 have
not been reported so far, we carried out microdialysis experi-
ments for FUB 661, plus 1f, and 1g. The results indicated that
FUB661 and morpholino derivative 1g increased moderately
histamine release by 130-140% and 140-150%, respectively,
while pyrrolidino derivative 1f was inactive.
We next directed our interest to the alternative synthesis of
clobenpropit using intramolecular amide cleavage,25 as shown
(23) Menge, W. M. P. B.; Van der Goot, H.; Timmerman, H.; Eersels,
J. L. H.; Herscheid, J. D. M. J. Labelled Compd. Radiopharm. 1992, 31,
781.
(21) Shioiri, T.; Yokoyama, Y.; Kasai, Y.; Yamada, S. Tetrahedron 1976,
32, 2211.
(22) Lipp, M.; Dallacker, F.; Koenen, G. Chem. Ber. 1958, 91, 1660.
(24) Endo, Y.; Iijima, T.; Yamakoshi, Y.; Fukasawa, H.; Miyaura, C.;
Inada, M.; Kubo, A.; Itai, A. Chem. Biol. 2001, 8, 341.
(25) Entwistle, I. D. Tetrahedron Lett. 1979, 555.
2098 J. Org. Chem., Vol. 73, No. 6, 2008

Efficient Approaches to S-Alkyl-N-alkylisothioureas
TABLE 2. Syntheses of Imidazole-Containing Isothioureas with PPI
a The reaction was carried out according to Table 1, entry 8.
SCHEME 4. Synthesis of p-Carborane Derivatives 6c, 6d,
SCHEME 5. Second Synthesis of Clobenpropit with NPAI
and 2b
isothiourea 9i. When 9i was treated with sodium phosphinate
and 10% Pd/C,26 isothiourea 2a was obtained in 90% yield with
retention of chlorine and imino double bond, and removal of
1-hydroxy-2-oxindole.27 Removal of the Nim-trityl group of 2a
(26) Entwistle, I. D.; Jackson, A. E.; Johnstone, R. A. W.; Telford, R.
P. J. Chem. Soc., Perkin Trans. 1 1977, 443.
(27) Somei, M.; Yamada, F.; Kurauchi, T.; Nagahama, Y.; Hasegawa,
M.; Yamada, K.; Teranishi, S.; Sato, H.; Kaneko, C. Chem. Pharm. Bull.
2001, 49, 87.
in Scheme 5. We reasoned that elimination of the acyl moiety
in NPA-protected isothiourea 9i could be realized by reductive
cyclization of the NO2 group, such as B. Addition of 6a to NPAI
followed by the Mitsunobu alkylation provided NPA-protected
J. Org. Chem, Vol. 73, No. 6, 2008 2099

Yoneyama et al.
TABLE 3. Syntheses of Cyclic-Amine-Containing Isothioureas with PPI
a 7a was synthesized from 6a in 78% yield (Table 1, entry 1). b Benzene was used as a solvent.
1H); 13C NMR (CDCl3) δ 46.0, 125.2, 127.6, 129.2, 133.2, 133.7,
147.3, 147.7, 164.8; HRMS (FAB) m/z calcd for C9H7N2O3S
233.0177 [M + H]+, found 223.0181.
gave clobenpropit‚2HCl in four steps in 54% overall yield from
6a. NPAI was prepared in two steps from 3-(2-nitrophenyl)-
acetic acid. Therefore, a second method for the synthesis of
clobenpropit was established. Comparing the two methods for
clobenpropit synthesis, the PPI method was found to be more
convenient than the NPAI method, because in the latter method,
the reductive step to 2a from 9i is sluggish (3-10 h) and
somewhat troublesome, requiring repeated addition of aqueous
(aq) saturated sodium phosphinate and monitoring by TLC until
completion of the reaction.
3-Phenylpropionyl Isothiocyanate (PPI). Known PPI was
prepared according to Koenen et al.’s procedure.22 A mixture of
3-phenylpropionyl chloride (1.52 mL, 10 mmol) and Pb(SCN)2
(1.94 g, 6 mmol) in dry benzene (3 mL) was refluxed for 3 h to
give a crude oil, which was subsequently purified by column
chromatography with 20% EtOAc in hexane as eluent to give PPI
(1.49 g, 79%). PPI: orange oil; bp 95-98 °C (0.5 mmHg) [(lit.22
bp 93-95 °C (0.5 mmHg)]; IR (film) νmax 1720, 1940-2000 (br,
1
NCS) cm-1; H NMR (CDCl3) δ 2.85-3.05 (m, 4H), 7.10-7.30
Conclusions
(m, 5H).
3-(2-Nitrophenyl)propionyl Isothiocyanate (NPPI). NPPI
(13.2 g, 80%) was prepared from 3-(2-nitrophenyl)propionic acid28
(1.44 g 7.4 mmol) by using the same procedure as that for the
preparation of NPAI. NPPI: yellow solid; IR (film) νmax 1340,
1510, 1710, 1950-2000 (br, NCS) cm-1; 1H NMR (CDCl3) δ 3.04
(2H, t, J ) 7.3 Hz), 3.25 (2H, t, J ) 7.3 Hz), 7.38-7.45 (m, 2H),
7.57 (1H, td, J ) 7.7, 1.4 Hz), 7.99 (1H, dd, J ) 8.5, 1.4 Hz);
HRMS (FAB) m/z calcd for C10H9N2 O3S 237.0334 [M + H]+,
found 237.0331.
We herein described two efficient synthetic approaches to
S-alkyl-N-alkylisothioureas starting from PPI or NPAI. The
utility of those two approaches was proved by the syntheses of
clobenpropit and its analogues. The two approaches are expected
to supply a variety of H3R or H4R ligand candidates having the
isothiourea moiety by which their biological activities could be
assessed.
Experimental Section
N-(4-Chlorobenzyl)-3-(2-nitrophenyl)propionamide (11j). To
a solution of 3-(2-nitrophenyl)propionic acid (482 mg, 2.47 mmol)
in DMF (10 mL) were added 6a (0.3 mL, 2.47 mmol), 90% DEPC21
(0.55 mL, 3.71 mmol), and Et3N (1.03 mL, 7.42 mmol) in that
order. The resulting mixture was stirred at rt for 4 h, and then diluted
with EtOAc-hexane (1:1) and water. The organic layer was washed
with water, aq saturated NaHCO3, and brine, then dried and
evaporated to give a residue. Chromatography with EtOAc-hexane
(3:10 to 1:1) as eluent gave 11j (78 mg, 10%). 11j: cotton-like
2-Nitrophenylacetyl Isothiocyanate (NPAI). A stirred solution
of 2-nitrophenylacetic acid (1.81 g, 10 mmol) and thionyl chloride
(1.46 mL, 20 mmol) in CH2Cl2 (20 mL) was refluxed for 20 h.
The reaction mixture was evaporated to give crude 2-nitropheny-
lacetyl chloride, which was allowed to stand under reduced pressure
for 2 h. Without additional purification, 2-nitrophenylacetyl chloride
was added to a suspension of Pb(SCN)2 (1.94 g, 6 mmol) in benzene
(10 mL), and the mixture was refluxed for 3 h. After filtration
through Celite, the filtrate was evaporated to give a residue. It was
subsequently diluted with EtOAc and mixed with a small amount
of silica gel. Evaporation of the mixture gave coated silica gel for
use in column chromatography. Chromatography with EtOAc-
hexane (1:9) as eluent gave NPAI (1.90 g, 86%) as an oil. NPAI:
1
fibers; IR (Nujol) νmax 1340, 1510, 1625 cm-1; H NMR (CDCl3)
δ 2.52 (2H, t, J ) 6.3 Hz), 3.16 (2H, t, J ) 6.3 Hz), 4.28 (2H, d,
J ) 4.6 Hz), 5.95 (1H, br s), 7.00-7.50 (7H, m), 7.80-7.90 (1H,
m); 13C NMR (CDCl3) δ 29.6, 37.4, 43.0, 124.5, 127.2, 128.3,
1
IR film νmax 1340, 1518, 1720, 1940-1980 (br, NCS) cm-1; H
NMR (CDCl3) δ 4.23 (s, 2H), 7.34-7.70 (m, 3H), 8.14-8.22 (m,
(28) Lin, B.; Hu, L. Bioorg. Med. Chem. 2003, 11, 3889.
2100 J. Org. Chem., Vol. 73, No. 6, 2008

Efficient Approaches to S-Alkyl-N-alkylisothioureas
128.5, 132.1, 132.7, 132.9, 135.3, 136.2, 148.4, 170.7; HRMS
(FAB) m/z calcd for C16H1635ClN2 O3 [M + H]+ 319.0849, found
319.0847.
N-(4-Chlorobenzyl)-S-{3-[4(5)-imidazolyl]propyl}isothio-
urea Dihydrochloride [Clobenpropit‚2HCl (1a‚2HCl)]. A solu-
tion of 2a (277 mg, 0.50 mmol) in aq 2 N HCl (0.5 mL)-EtOH (5
mL) was refluxed for 30 min and the reaction mixture was
evaporated to give a residue, which was partitioned between
benzene and water. The aq solution was evaporated as a benzene
azeotrope to give 1a‚2HCl (195 mg, quant). 1a‚2HCl: white
Synthetic Approach (A) to Clobenpropit with Use of PPI
(General Procedures to Obtain S-alkyl-N-alkylisothioureas):
N-(4-Chlorobenzyl)-N′-(3-phenylpropionyl)thiourea (7a). PPI
(955 mg, 5.0 mmol) was added to 4-chlorobenzylamine 6a (0.61
mL, 5.0 mmol) in dry benzene (10 mL). The resulting mixture was
stirred for 0.5 h and evaporated to give a crude yellow solid, which
was subsequently purified by column chromatography with 20%
EtOAc in hexane as eluent to give 7a (1.30 g, 78%) and N-(4-
chlorobenzyl)-3-phenylpropionamide (11a)29 (219 mg, 16%) in that
order, using the coated silica gel technique described in the
purification of NPAI. 7a: yellow needles (EtOAc); mp 135-
1
powder; H NMR (CD3OD) δ 2.00-2.20 (2H, br m), 2.85-3.95
(2H, br m), 3.25-3.35 (2H, br m), 4.62 (2H, s), 7.32-7.42 (5H,
m), 8.84 (1H, s); 13C NMR (CD3OD) δ 24.2, 29.1, 31.7, 47.8, 116.8,
129.2, 129.4, 130.0, 133.2, 134.0, 134.2, 134.5, 167.8.
Clobenpropit 1a and Its Dihydrobromide 1a‚2HBr. Thus
obtained 1a‚2HCl was confirmed by conversion into dihydrobro-
mide previously synthesized by Timmerman et al.11a To a MeOH
solution of 1a‚2HCl (50 mg) was added a small amount of NH-
silica gel, and this mixture was subsequently placed on a column
(NH-silica gel). Chromatography with CHCl3-MeOH-28% NH4-
OH (50:5:1) as eluent gave salt-free clobenpropit 1a (36 mg, 74%)
as a colorless oil. 1a: 1H NMR (CDCl3) δ 1.97(2H, quint, J ) 6.7
Hz), 2.70 (2H, t, J ) 6.7 Hz), 2.90 (2H, t, J ) 6.7 Hz), 4.37 (2H,
s), 6.70 (1H, s), 7.16-7.28 (4H, m), 7.32 (1H, s); 13C NMR (CD3-
OD) δ 25.2, 29.6, 30.2, 47.1, 117.0, 128.2, 128.3, 132.4, 134.1,
135.2, 136.6, 159.5. Aq 48% HBr solution (33 µL, 5 equiv) was
added to a solution of 1a (36 mg) in EtOH (4 mL). The mixture
was stirred at rt for 20 min and evaporated to give a residue, which
was subsequently washed with acetone and dried to give 1a‚2HBr11a
1
141 °C; H NMR [(CD3)2CO] δ 2.78-3.00 (4H, m), 2.88 (2H, d,
J ) 6.0 Hz), 7.15-7.50 (9H, m), 10.15 (1/2H, br s), 11.00 (1/2H,
br s); 13C NMR (CDCl3) δ 31.1, 38.6, 48.2, 126.3, 128.4, 128.5,
128.6, 129.6, 132.7, 135.9, 140.6, 173.6, 180.8; HRMS (EI) m/z
calcd for C17H1735ClN2OS (M)+ 332.0750, found 332.0748. 11a:29
1
cotton-like fibers; H NMR (CDCl3) δ 2.72 (2H, t, J ) 7.2 Hz),
2.96 (2H, t, J ) 7.2 Hz), 4.32 (2H, d, J ) 5.8 Hz), 5.72 (1H, br s),
7.00-7.35 (9H, m).
N-(4-Chlorobenzyl)-N′-(3-phenylpropionyl)-S-{3-[1-(triphe-
nylmethyl)imidazol-4-yl]propyl}isothiourea (9a). To a solution
of 3-[1-(triphenylmethyl)-1H-imidazol-4-yl]propanol (8a)30 (405
mg, 1.1 mmol) in dry benzene (10 mL) were added 7a (333 mg,
1.0 mmol) and Bu3P (0.37 mL, 1.5 mmol) in dry benzene (10 mL)
at rt. Then, TMAD (258 mg, 1.5 mmol) was added rapidly and the
mixture was stirred continuously for 15 h. The insoluble material
was removed by filtration and the filtrate was evaporated to give a
residue, which was purified by chromatography with EtOAc-
hexane (1:1) as eluent by using the coated silica gel technique to
1
(48 mg, 64%) as a white powder. H NMR (CD3OD) δ 1.94 (2H,
quint, J ) 7.4 Hz), 2.77 (2H, t, J ) 7.4 Hz), 3.31 (2H, t, J ) 7.4
Hz), 4.62 (2H, d, J ) 5.4 Hz), 7.32-7.54 (5H, m), 9.10 (1H, s),
9.42 (2H, br d, J ) 10.2 Hz), 10.12 (1H, br t, J ) 5.4 Hz), 14.05
(1H, br s), 14.25 (1H, br s); 13C NMR (DMSO-d6) δ 22.8, 27.5,
30.0, 45.7, 115.3, 127.9, 129.0, 131.2, 131.8, 133.2, 133.8, 165.1;
HRMS (FAB) m/z calcd for C14H1835ClN4OS [M + H]+ 309.0940,
found 309.0932.
1
yield 9a (640 mg, 94%). 9a: oil; H NMR (CDCl3) δ 1.93 (2H,
quint, J ) 6.8 Hz), 2.50-2.70 (4H, m), 2.87 (2H, t, J ) 7.5 Hz),
3.04 (2H, t, J ) 6.8 Hz), 4.37 (2H, s), 6.45 (1H, s), 6.90-7.40
(25H, m), 11.15 (1/4H, br s); 13C NMR (CDCl3) δ 27.6, 28.5, 29.3,
30.9, 32.1, 42.7, 47.1, 75.1, 117.8, 125.4, 127.6, 127.9, 128.1, 128.3,
128.5, 129.3, 137.9, 139.9, 141.2, 141.9, 172.3, 184.4; HRMS
(FAB) m/z calcd for C42H4035ClN4OS [M + H]+ 683.2612;, found
683.2615.
N-[2-(4-Bromophenyl)ethyl]-N′-(3-phenylpropionyl)thio-
urea (7b). 4-Bromophenethylamine 6b (0.31 mL, 2.0 mmol) and
PPI (420 mg, 2.2 mmol) were reacted to yield 7b (352 mg, 45%)
according to the synthetic procedure for 7a. 7b: white powder; 1H
NMR (CDCl3) δ 2.62 (2H, t, J ) 7.6 Hz), 2.85-3.00 (4H, m),
3.84 (2H, td, J ) 7.6, 5.6 Hz), 7.00-7.50 (9H, m), 9.00 (1H, s),
10.55 (1H, br t, J ) 5.6 Hz); 13C NMR (CDCl3) δ 30.8, 34.0, 38.9,
46.7 120.3, 126.3, 127.8, 128.3, 130.0, 131.3, 136.6, 138.9, 172.3,
179.0; HRMS (EI) m/z calcd for C18H1981BrN2OS 392.0381 (M+),
found 392.0369.
N-(4-Chlorobenzyl)-S-{3-[1-(triphenylmethyl)imidazol-4-yl]-
propyl}isothiourea (2a). A mixture of 9a (137 mmol, 0.20 mmol)
and 80% hydrazine hydrate (12 µL) in EtOH (2 mL) was stirred at
rt (16 h). A heaping microspatula of 10% Pd/C was added and the
resulting mixture was stirred for 30 min. After filtration through
Celite, the filtrate was evaporated to give a residue, which was
purified by column chromatography with MeOH-EtOAc (0:100,
20:80, to 50:50) as eluent to give the eliminated 3-phenylpropionyl
hydrazide (22 mg, 61%) and 2a (76 mg, 69%) in that order. 2a:
oil; 1H NMR (CDCl3) δ 2.04 (2H, quint, J ) 7.2 Hz), 2.62 (2H, t,
J ) 7.2 Hz), 3.20 (2H, t, J ) 7.2 Hz), 4.42 (2H, s), 6.54 (1H, s),
7.05-7.40 (20H, m); 13C NMR (CDCl3) δ 25.2, 28.6, 30.1, 47.0,
75.3, 117.9, 127.6, 128.3, 128.4, 129.2, 133.0, 134.5, 137.7, 138.4,
141.7, 168.9; HRMS (FAB) m/z calcd for C33H3235ClN4S [M +
H]+ 551.2036, found 551.2032. 3-Phenylpropionyl hydrazide:
white powder; IR (film) νmax 1620 cm-1; 1H NMR (CDCl3) δ 2.45
(2H, t, J ) 7.6 Hz), 2.97 (2H, t, J ) 7.6 Hz), 3.54 (2H, br s), 6.84
(1H, br s), 7.05-7.40 (5H, m).
N-[2-(4-Bromophenyl)ethyl]-N′-(3-phenylpropionyl)-S-{3-[1-
(triphenylmethyl)imidazol-4-yl]propyl}isothiourea (9b). Thiourea
7b (350 mg, 0.90 mmol) was converted into 9b (626 mg, 94%)
1
according to the synthetic procedure for 9a. 9b: oil; H NMR
(CDCl3) δ 1.98 (2H, quint, J ) 7.2 Hz), 2.55-2.70 (4H, m), 2.82
(2H, t, J ) 7.2 Hz), 2.94 (2H, t, J ) 7.8 Hz), 3.10 (2H, t, J ) 7.8
Hz), 3.48 (2H, t, J ) 7.2 Hz), 6.54 (1H, s), 7.00-7.50 (25H, m),
11.00 (1/2H, br s); 13C NMR (CDCl3) δ 27.6, 29.3, 30.7, 32.1,
35.2, 42.7, 45.1, 75.0, 117.7, 120.3, 125.3, 127.6, 127.8, 128.0,
129.3, 130.0, 131.3, 136.3, 137.9, 140.0, 141.9, 172.1, 184.3; HRMS
(FAB) m/z calcd for C43H4279BrN4OS [M + H]+ 741.2263, found
741.2263.
N-[2-(4-Bromophenyl)ethyl]-S-{3-[1-(triphenylmethyl)imida-
zol-4-yl]propyl}isothiourea (2b). 9b (626 mg, 0.84 mmol) was
converted into 2b (290 mg, 57%) according to the synthetic
Synthesis of 2a by MW Irradiation. In a 5 mL Teflon MW
reaction vessel were dissolved 9a (68 mg, 0.1 mmol) and 80%
hydrazine hydrate (6 µL, 0.1 mmol) in EtOH (1.0 mL). The vessel
was sealed, heated in the MW reactor to 75 °C for 10 min, and
cooled thereafter. The same workup as that for the previous 2a
gave 3-phenylpropionyl hydrazide (12 mg, 67%) and 2a (28 mg,
51%).
1
procedure for 2a. 2b: oil; H NMR (CDCl3) δ 1.97 (2H, quint, J
) 7.0 Hz), 2.62 (2H, t, J ) 7.0 Hz), 2.75-2.90 (4H, m), 3.48 (2H,
t, J ) 7.0 Hz), 5.60 (1H, br s), 6.55 (1H, s), 7.00-7.50 (20H, m);
13C NMR (CDCl3) δ 27.0, 29.2, 30.3, 35.1, 44.3, 74.9, 117.8, 119.6,
127.5, 129.2, 130.0, 130.9, 137.7, 137.8, 139.5, 141.8, 158.9; HRMS
(FAB) m/z calcd for C34H3479BrN4S [M + H]+ 609.1688, found
609.1695.
N-[2-(4-Bromophenyl)ethyl]-S-{3-(imidazol-4-yl)propyl}-
isothiourea (1b) and Its Dihydrobromide (1b‚2HBr, VUF 4598).
2b (275 mg, 0.45 mmol) was converted into 1b (161 mg, 98%)
(29) Galaffu, N.; Bradley, M. Tetrahedron Lett. 2005, 46, 859.
(30) Stark, H.; Purand, K.; Hu¨ls, A.; Ligneau, X.; Garbarg, M.; Schwartz,
J.-C.; Schunack, W. J. Med. Chem. 1996, 39, 1220.
J. Org. Chem, Vol. 73, No. 6, 2008 2101

Yoneyama et al.
according to the synthetic procedure for 1a. 1b: oil; 1H NMR (CD3-
OD) δ 1.90 (2H, quint, J ) 7.3 Hz), 2.66 (2H, t, J ) 7.3 Hz),
2.75-2.90 (4H, m), 3.40 (2H, t, J ) 7.3 Hz), 6.78 (1H, s), 7.08-
7.14 (2H, m), 7.32-7.38 (2H, m), 7.55 (1H, s); 13C NMR (CD3-
OD) δ 26.6, 30.6, 30.9, 35.8, 45.5, 117.1, 120.3, 131.2, 131.7, 135.3,
136.8, 139.5, 161.5. 1b was confirmed by conversion into the
dihydrobromide (1b‚2HBr, VUF 4598) previously synthesized by
Timmerman et al.23 according to the synthetic procedure for 1a‚
m), 9.62 (1H, br s), 10.66 (1H, br t, J ) 5.0 Hz); 13C NMR (CDCl3)
δ 30.7, 38.6, 50.3, 59.5, 80.6, 126.1, 127.8, 128.1, 138.8, 172.7,
179.1; HRMS (EI) m/z calcd for C13H2410B211B8N2OS (M)+
364.2613, found 364.2616.
N-(1,12-Dicarba-closo-dodecaboranyl)methyl-S-{3-[1-(triph-
enylmethyl)imidazol-4-yl]propyl}-N′-3-phenylpropionylisothio-
urea (9d). Thiourea 7d (600 mg, 1.65 mmol) was converted into
9d (732 mg, 62%) according to the synthetic procedure for 9a. 9d:
oil; 1H NMR (CDCl3) δ 1.20-3.20 (11H, br), 1.97 (2H, quint, J )
6.8 Hz), 2.63 (2H, t, J ) 6.8 Hz), 2.69 (2H, t, J ) 8.5 Hz), 2.94
(2H, t, J ) 8.5 Hz), 3.06 (2H, t, J ) 6.8 Hz), 3.40 (2H, br s), 6.54
(1H, s), 7.05-7.50 (21H, m), 11.00 (1H, br s); 13C NMR (CDCl3)
δ 27.4, 29.0, 30.8, 31.9, 42.6, 49.4, 59.3, 75.0, 81.2, 117.7, 125.3,
126.0, 127.2, 127.5, 127.8, 128.8, 129.0, 129.2, 137.8, 139.6, 141.1,
141.8, 171.4, 184.4; HRMS (FAB) m/z calcd for C38H4710B211B8N4-
OS [M + H]+ 715.4474, found 715.4479.
1
2HBr. 1b‚2HBr:23 oil; H NMR (D2O) δ 1.76 (2H, quint, J ) 7.2
Hz), 2.71 (2H, t, J ) 7.2 Hz), 2.96 (2H, t, J ) 7.2 Hz), 3.03 (2H,
t, J ) 7.2 Hz), 3.60-3.80 (2H, overlapped with H2O in D2O), 7.15-
7.45 (5H, m), 8.62 (1H, s).
N-(12-Chloro-1,12-dicarba-closo-dodecaboranyl)methyl-N′-
(3-phenylpropionyl)thiourea (7c). 6c (110 mg, 0.53 mmol) and
PPI (101 mg, 0.53 mmol) were reacted to obtain 7c (142 mg, 67%)
according to the synthetic procedure for 7a. 7c: oil; 1H NMR
(CDCl3) δ 1.20-3.60 (10H, br), 2.62 (2H, t, J ) 7.7 Hz), 2.96
(2H, t, J ) 7.7 Hz), 3.80 (2H, d, J ) 5.8 Hz), 7.10-7.40 (5H, m),
9.40 (1H, br s), 10.60 (1H, br t, J ) 5.8 Hz); 13C NMR (CDCl3) δ
30.8, 38.7, 48.6, 72.8, 78.9, 126.2, 127.8, 128.3, 138.8, 172.7, 179.6;
HRMS (EI) m/z calcd for C13H2310B311B735ClN2OS (M)+ 399.2187,
found 399.2201.
N-(1,12-Dicarba-closo-dodecaboranyl)methyl-S-{3-[1-(triph-
enylmethyl)imidazol-4-yl]propyl}isothiourea (2d). 9d (65 mg,
0.09 mmol) was converted into 2d (46 mg, 88%) according to the
1
synthetic procedure for 2a. 2d: oil; H NMR (CDCl3) δ 1.20-
3.20 (11H, br), 1.97 (2H, quint, J ) 6.3 Hz), 2.66 (2H, t, J ) 6.3
Hz), 2.88 (2H, t, J ) 6.3 Hz), 3.38 (2H, br s), 6.20 (1/2H, br s),
6.56 (1H, s), 7.05-7.50 (16H, m); 13C NMR (CDCl3) δ 26.8, 29.2,
30.4, 49.0, 58.9, 75.1, 83.8, 117.8, 126.6, 126.9, 127.1, 127.5, 127.8,
128.9, 129.2, 137.9, 139.5, 141.8, 159.0; HRMS (FAB) m/z calcd
for C29H3910B211B8N4S [M + H]+ 583.3899, found 583.3904.
N-(1,12-Dicarba-closo-dodecaboranyl)-S-{3-[4(5)-imidazolyl]-
propyl}isothiourea (1d). 1d‚2HCl, and 1d‚2HBr. 2d (292 mg,
0.50 mmol) afforded 1d (150 mg, 88%) according to the synthetic
procedure for 1a. 1d: oil (150 mg, 88%); IR (film) νmax 1600, 1640
N-(12-Chloro-1,12-dicarba-closo-dodecaboranyl)methyl-S-{3-[1-
(triphenylmethyl)imidazol-4-yl]propyl}-N′-(3-phenylpropionyl)}-
isothiourea (9c). Thiourea 7c (142 mg, 0.36 mmol) was converted
into 9c (227 mg, 84%) according to the synthetic procedure for
1
9a. 9c: oil; H NMR (CDCl3) δ 1.20-3.60 (10H, br), 1.97 (2H,
quint, J ) 7.2 Hz), 2.62 (2H, t, J ) 7.2 Hz), 2.68 (2H, t, J ) 8.2
Hz), 2.94 (2H, t, J ) 8.2 Hz), 3.04 (2H, t, J ) 7.2 Hz), 3.40 (2H,
br s), 6.54 (1H, s), 7.00-7.40 (21H, m), 11.00 (1H, br s); 13C NMR
(CDCl3) δ 27.6, 29.1, 30.8, 31.9, 42.7, 48.0, 73.5, 75.1, 78.7, 117.8,
125.4, 126.1, 127.6, 127.9, 128.1, 129.3, 137.9, 139.8, 141.1, 141.9,
1
cm-1; H NMR (CDCl3) δ 1.20-3.20 (11H, br), 1.98 (2H, quint,
J ) 6.3 Hz), 2.72 (2H, t, J ) 6.3 Hz), 2.87 (2H, t, J ) 6.3 Hz),
3.35 (2H, s), 6.78 (1H, s), 7.53 (1H, s). 13C NMR (CDCl3) δ 25.5,
29.5, 30.2, 49.6, 58.9, 83.8, 116.6, 134.2, 135.5, 157.7. HRMS
(FAB) m/z calcd for C10H2510B211B8N4S [M + H]+ 341.2803, found
341.2802. 1d was converted into 1d‚2HCl and 1d‚2HBr according
to the synthetic procedure for 1a‚2HCl and 1a‚2HBr. 1d‚2HCl:
142.0,142.1,171.4,184.3;HRMS(FAB)m/zcalcdforC38H4610B11B935
-
ClN4OS [M + H]+ 750.4048, found 750.4062.
N-(12-Chloro-1,12-dicarba-closo-dodecaboranyl)methyl-S-{3-
[1-(triphenylmethyl)imidazol-4-yl]propyl}isothiourea (2c). To a
suspension of 9c (227 mg, 0.30 mmol) and 10% Pd/C (25 mg) in
EtOH (3 mL) was added 80% hydrazine hydrate (37 µL, 0.60
mmol). The reaction mixture was stirred at rt for 1 h. After filtration
through Celite, the filtrate was evaporated to give a residue, which
was purified by column chromatography with EtOAc as eluent by
using the coated silica gel technique to give 2c (90 mg, 49%). 2c:
oil; 1H NMR (CDCl3) δ 1.20-3.60 (10H, br), 1.95 (2H, quint, J )
7.3 Hz), 2.63 (2H, t, J ) 7.3 Hz), 2.84 (2H, t, J ) 7.3 Hz), 3.38
(2H, s), 6.55 (1H, s), 7.00-7.50 (16H, m); 13C NMR (CDCl3) δ
1
amorphous product; H NMR (CD3OD) δ 1.20-3.20 (11H, br),
2.00-2.20 (2H, br m), 2.92 (2H, t, J ) 7.0 Hz), 3.20-3.40 (2H,
overlapped with H2O), 3.64 (2H, s), 7.40 (1H, s), 8.82 (1H, s).
1d‚2HBr: 1H NMR (CD3OD) δ 1.20-3.20 (11H, br), 2.10 (2H,
quint, J ) 7.2 Hz), 2.92 (2H, t, J ) 7.2 Hz), 3.24-3.38 (2H, m),
3.62 (2H, br s), 7.42 (1H, s), 8.85 (1H, d, J ) 1.6 Hz); 13C NMR
(D2O) δ 25.0, 29.6, 33.0, 49.7, 62.8, 82.2, 117.7, 133.9, 134.9,
169.8. Further, 1d was converted into the dipicrate form for analysis.
Picric acid (127 mg) in benzene (4 mL) was added to 1d (92 mg,
0.27 mmol) in benzene (2 mL). Picrate was immediately precipi-
tated, filtered, and dried under vacuum to give 1d‚dipicrate (197
26.9, 29.4, 30.4, 47.3, 58.9, 75.1, 78.0, 83.8, 117.9, 127.6, 129.2,
10
137.9, 139.6, 141.8, 157.8; HRMS (FAB) m/z calcd for C29H38
-
B11B937ClN4S [M + H]+ 618.3472, found 618.3495.
1
mg). 1d‚dipicrate: yellow prisms; mp 219-221 °C (MeOH); H
N-(12-Chloro-1,12-dicarba-closo-dodecaboranyl)methyl-S-{3-
[4(5)-imidazolyl]propyl}isothiourea (1c) and Its Dihydrochloride
1c‚2HCl. 2c (165 mg, 0.27 mmol) was converted into 1c (95 mg,
94%) according to the synthetic procedure for 1a. 1c: oil; 1H NMR
(CDCl3) δ 1.20-3.60 (10H, br), 1.96 (2H, quint, J ) 6.3 Hz), 2.72
(2H, t, J ) 6.3 Hz), 2.86 (2H, t, J ) 6.3 Hz), 3.32 (2H, s), 6.79
(1H, s), 7.53 (1H, s); 13C NMR (CDCl3) δ 25.6, 29.6, 30.3, 48.7,
78.2, 83.7, 116.4, 127.4, 129.1, 157.2. HRMS (FAB) m/z calcd for
C10H2410B11B935ClN4S [M + H]+ 376.2377, found 376.2393. 1c
was converted into 1c‚2HCl according to the synthetic procedure
for 1a‚2HCl. 1c‚2HCl: amorphous product; 1H NMR (CD3OD) δ
1.20-3.60 (10H, br), 2.00-2.20 (2H, br m), 2.86-2.96 (2H, br
m), 3.24-3.36 (2H, m), 3.62 (2H, br s), 7.42 (1H, s), 8.86 (1H, s);
13C NMR (D2O) δ 24.2, 29.0, 31.7, 46.9, 80.0, 82.0, 116.8, 128.2,
130.0, 169.1.
N-(1,12-Dicarba-closo-dodecaboranyl)methyl-N′-3-phenylpro-
pionylthiourea (7d). 6d (302 mg, 1.75 mmol) and PPI (333 mg,
1.75 mmol) were reacted to yield 7d (603 mg, 95%) according to
the synthetic procedure for 7a. 7d: white powder; 1H NMR (CDCl3)
δ 1.20-3.30 (10H, br), 2.62 (2H, t, J ) 7.3 Hz), 2.72 (1H, br s),
2.94 (2H, t, J ) 7.3 Hz), 3.80 (2H, d, J ) 5.0 Hz), 7.10-7.35 (5H,
NMR [(CD3)2CO] δ 1.20-3.20 (10H, br), 2.34 (2H, br m), 3.08
(2H, br m), 3.40 (1H, br s), 3.53 (2H, br m), 3.72 (2H, br s), 7.54
(1H, s), 8.72-8.78 (4H, m), 8.89 (1H, s). Anal. Calcd for
C22H30B10N10O14S: C, 33.08; H, 3.79; N, 17.54. Found: C, 32.94;
H, 3.70; N, 17.57.
N-(4-Chlorobenzyl)-N′-(3-phenylpropionyl)-S-(3-piperidino-
propyl)isothiourea (9e). Acyl thiourea 7a (135 mg, 0.41 mmol)
was converted into 9e (120 mg, 64%) according to the synthetic
procedure for 9a. 9e: oil; 1H NMR (CDCl3) δ 1.30-1.70 (6H, m),
1.86 (2H, quint, J ) 6.7 Hz), 2.30-2.50 (6H, m), 2.72 (2H, t, J )
8.0 Hz), 2.98 (2H, t, J ) 8.0 Hz), 3.11 (2H, t, J ) 6.7 Hz), 4.46
(2H, s), 7.10-7.40 (9H, m), 11.20 (1/2H, br s); 13C NMR (CDCl3)
δ 23.9, 24.5, 26.0, 29.3, 38.4, 42.5, 46.9, 54.4, 57.8, 125.2, 127.7,
128.1, 128.3, 133.0, 134.2, 141.0, 172.1, 184.2; HRMS (FAB) m/z
calcd for C25H3335ClN3OS [M + H]+ 458.2033, found 458.2038.
N-(4-Chlorobenzyl)-S-(3-piperidinopropyl)isothiourea (1e). 9e
(120 mg, 0.26 mmol) was converted into 2e (65 mg, 76%) according
1
to the synthetic procedure for 2a. 1e: oil; H NMR (CDCl3) δ
1.40-1.70 (6H, m), 1.82 (2H, quint, J ) 6.8 Hz), 2.32 (4H, br s),
2.43 (2H, t, J ) 6.8 Hz), 2.94 (2H, t, J ) 6.8 Hz), 4.44 (2H, s),
2102 J. Org. Chem., Vol. 73, No. 6, 2008

Efficient Approaches to S-Alkyl-N-alkylisothioureas
7.20-7.40 (4H, m). 1e was confirmed by conversion into a
dihydrochloride (FUB 661) previously synthesized by Schunack
et al.17a
2.48 (2H, t, J ) 7.2 Hz), 2.85 (2H, t, J ) 7.2 Hz), 4.06 (2H, s),
4.38 (2H, s), 6.52 (1H, s), 7.00-7.50 (23H, m), 7.90-8.00 (1H,
m), 11.08 (1H, br s); 13C NMR (CDCl3) δ 27.5, 28.9, 30.8, 45.9,
47.2, 75.1, 117.7, 124.3, 127.1, 127.6, 128.3, 128.5, 129.3, 131.9,
132.5, 132.9, 133.9, 137.9, 139.9, 141.9, 148.7, 173.0, 180.3; HRMS
(FAB) m/z calcd for C41H3735ClN5 O3S [M + H]+ 714.2305, found
714.2299.
Alternative Synthesis of 2a via Intramolecular Amide Cleav-
age. 9i (1.43 g, 2.01 mmol) in THF (15 mL) was stirred with 10%
Pd/C (500 mg). To the suspension were gradually added 1 mL
portions of aq saturated sodium phosphinate26 (slight effervescence
was observed between additions, and the reaction was monitored
by TLC). When the volume of phosphinate added reached 14 mL
after 3 h, TLC was performed to reveal no trace of 9i. Then, the
mixture was filtered and the filtrate was poured into water and
extracted three times with CHCl3. The combined extracts were dried
and evaporated to yield the residue. Chromatography by using the
coated silica gel technique with EtOAc as eluent gave 1-hydroxy-
2-oxindole27 (305 mg quant), and further elution with MeOH-
EtOAc (1:1) gave 2a (991 mg, 90%). 1-Hydroxy-2-oxindole: mp
201-204 °C (EtOAc, hot plate) (lit.27 mp 200.5-202 °C); IR
(Nujol) νmax 1615, 1675 cm-1; 1H NMR (CD3OD) δ 3.55 (2H, s),
7.00-7.50 (4H, m). Thus obtained 2a was converted into 1a‚2HCl
(quant) according to a previously described procedure.
N-(4-Chlorobenzyl)-N′-(3-phenylpropionyl)-S-(3-pyrrolidino-
propyl)isothiourea (9f). Thiourea 7a (166 mg, 0.50 mmol) was
converted into 9f (112 mg, 51%) in THF (5 mL) according to the
synthetic procedure for 9a. 9f: oil; 1H NMR (CDCl3) δ 1.74 (4H,
br m), 1.88 (2H, quint, J ) 7.4 Hz), 2.40-2.60 (6H, br), 2.72 (2H,
t, J ) 7.4 Hz), 2.97 (2H, t, J ) 7.4 Hz), 3.10-3.20 (2H, br), 4.46
(2H, s), 7.10-7.40 (9H, m), 11.20 (1/2H, br s); 13C NMR (CDCl3)
δ 23.7, 29.3, 29.4, 32.0, 42.6, 47.1, 55.2, 125.3, 127.7, 127.8, 128.2,
128.3, 128.5, 133.1, 134.3, 141.2, 172.3, 184.2; HRMS (FAB) m/z
calcd for C24H3135ClN3OS [M + H]+ 444.1876, found 444.1870.
Caution: Use of THF as solvent improved the yield of 9f (51%)
compared to that (39%) when benzene was used.
N-(4-Chlorobenzyl)-S-(3-pyrrolidinopropyl)isothiourea (1f).
Isothiourea 9f (87 mg, 0.19 mmol) was converted into 1f (45 mg,
76%) according to the synthetic procedure for 2a. 1f: oil; 1H NMR
(CDCl3) δ 1.60-1.75 (4H, br), 1.81 (2H, quint, J ) 6.7 Hz), 2.40-
2.54 (4H, br), 2.59 (2H, t, J ) 6.7 Hz), 2.98 (2H, t, J ) 6.7 Hz),
4.42 (2H, s), 7.20-7.40 (4H, m); 13C NMR (CDCl3) δ 23.7, 28.9,
29.0, 46.9, 53.1, 53.7, 128.0, 128.1, 128.2, 131.1, 137.5, 158.8 ;
HRMS (FAB) m/z calcd for C15H2235ClN3S [M + H]+ 311.1222,
found 311.1224.
N-(4-Chlorobenzyl)-N′-(3-phenylpropionyl)-S-{3-morpho-
linopropyl}isothiourea (9g). Thiourea 7a (166 mg, 0.50 mmol)
was converted into 9g (143 mg, 62%) in THF (5 mL) according to
Hydroxymethyl-1,12-dicarba-closo-dodecaborane (12). To a
solution of p-carborane (576 mg, 4.0 mmol) in THF (3 mL) was
added dropwise 1.6 M n-BuLi in hexane (2.50 mL, 4.0 mmol) at
rt, and the mixture was stirred for 15 min at the same temperature.
Paraformaldehyde (120 mg, 4.0 mmol) was added and the reaction
mixture was stirred at rt for 30 min. The reaction was quenched
with H2O and THF was removed. After dissolving the residue with
EtOAc, the organic layer was washed with H2O and brine, dried,
and then evaporated to give a pale yellow solid. It was again diluted
with EtOAc, mixed with a small amount of silica gel, and
evaporated to obtain coated silica gel for use in column chroma-
tography. Chromatography with EtOAc-hexane (1:9) as eluent
gave 12 (696 mg, 70%) as a white powder. 12: colorless leaflets
(hexane); mp 213-215 °C(lit.31 mp 207-208 °C); 1H NMR
[(CD3)2CO] δ 1.1-3.1 (10H, br), 3.30 (1H, br s), 3.44 (2H, d, J )
6.6 Hz), 4.56 (1H, t, J ) 7.5 Hz); HRMS (EI) m/z calcd for
1
the synthetic procedure for 9a. 9g: oil; H NMR (CDCl3) δ 1.86
(2H, quint, J ) 7.0 Hz), 2.35-2.50 (6H, m), 2.72 (2H, t, J ) 7.6
Hz), 2.97 (2H, t, J ) 7.6 Hz), 3.12 (2H, t, J ) 7.0 Hz), 3.65-3.75
(4H, m), 4.46 (2H, s), 7.10-7.40 (9H, m), 11.30 (1H, br s); 13C
NMR (CDCl3) δ 27.5, 28.4, 32.0, 42.7, 47.1, 53.7, 57.5, 66.9, 125.4,
127.8, 127.9, 128.2, 128.5, 133.2, 134.2, 141.1, 172.1, 184.4; HRMS
(FAB) m/z calcd for C24H3135ClN3 O2S [M + H]+ 460.1825, found
460.1833. Caution: Use of benzene as solvent did not give 9g,
although the reason was unknown.
N-(4-Chlorobenzyl)-S-(3-morpholinopropyl)isothiourea (1g).
9g (143 mg, 0.31 mmol) was converted into 1g (53 mg, 52%)
1
according to the synthetic procedure for 2a. 1g: oil; H NMR
(CDCl3) δ 1.82 (2H, quint, J ) 7.0 Hz), 2.35-2.50 (6H, m), 2.94
(2H, t, J ) 7.0 Hz), 3.64-3.74 (4H, m), 4.44 (2H, s), 7.20-7.30
(4H, m); 13C NMR (CDCl3) δ 27.4, 28.3, 46.6, 53.5, 56.2, 66.8,
128.0, 128.3, 132.1, 138.3, 158.5; HRMS (FAB) m/z calcd for
C15H2335ClN3OS [M + H]+ 328.1251, found 328.1251.
11
C3H14 B10O 176.1975 (M+), found 176.1977. Further chromatog-
raphy with EtOAc-hexane (1:4) as eluent provided 1,12-dihy-
droxymethyl-1,12-dicarba-closo-dodecaborane (100 mg, 14%): col-
orless needles (20% EtOAc in hexane); mp 147-150 °C (lit.31a
mp 152-154 °C); 1H NMR [(CD3)2CO] δ 1.2-3.2 (10H, br), 3.44
(2H, d, J ) 6.6 Hz), 4.56 (1H, t, J ) 7.5 Hz).
Alternative Synthesis (B) of Clobenpropit with Use of
NPAI: N-(4-Chlorobenzyl)-N′-(2-nitrophenylacetyl)thiourea (7i).
6a (0.37 mL, 3.0 mmol) was reacted with NPAI (666 mg, 3.0 mmol)
to yield 7i (778 mg, 71%, less polar) together with N-(4-
chlorobenzyl)-2-(2-nitrophenyl)acetamide 11j (266 mg, 29%, more
polar) as the byproduct, according to the synthetic procedure for
12-Chloro-1-hydroxymethyl-1,12-dicarba-closo-dodecabo-
rane (13). To a solution of 12 (174 mg, 1.0 mmol) in THF (4 mL)
was added dropwise 1.6 M n-BuLi in hexane (1.38 mL, 2.2 mmol)
at -78 °C, and the reaction mixture was stirred for 1.5 h at the
same temperature. Then, N-chlorosuccinimide (160 mg, 1.2 mmol)
in THF (5 mL) was added slowly to produce a pale red suspension.
The resulting mixture was stirred at rt for 5 h. The reaction was
quenched with H2O and THF was removed to give a residue that
was partitioned between EtOAc and brine and subsequently
extracted by the salting-out technique. The organic layer was dried
and evaporated to give a crude material. Chromatography with
EtOAc-hexane (1:9) as eluent by using the coated silica gel
technique yielded 13 (145 mg, 70%) as a white powder. The
chromatography provided initially fractions containing 13, followed
by fractions containing both 12 and 13, since their Rf values on
TLC were very similar. In that case, the mixture was subjected
repeatedly to chromatography to obtain pure 13. 13: mp 125-
7a. 7i: white powder; IR (Nujol) νmax 1165, 1340, 1520, 1700 cm-1
;
1H NMR [(CD3)2CO] δ 4.32 (2H, s), 4.87 (2H, d, J ) 5.7 Hz),
7.30-7.75 (7H, m), 8.05-8.15 (1H, m), 10.45 (3/4H, br s), 10.78
(3/4H, br s); 13C NMR (CDCl3) δ 41.7, 48.2, 125.0, 128.5, 128.9,
129.4, 129.6, 132.7, 133.8, 134.0, 136.5, 149.0, 170.8, 180.5; HRMS
m/z calcd for C16H1435ClN3O3S 363.0444, found 363.0437. N-(4-
Chlorobenzyl)-2-(2-nitrophenyl)acetamide (11i): Cotton-like fi-
bers; IR (Nujiol) νmax 1342, 1522, 1638 cm-1; 1H NMR (CDCl3) δ
3.86 (2H, s), 4.39 (2H, d, J ) 6.0 Hz), 6.22 (1H, brs), 7.10-7.65
(7H, m), 8.00-8.06 (1H, m); 13C NMR (CDCl3) δ 41.2, 43.3, 124.8,
128.1, 128.4, 128.6, 129.8, 133.1, 133.2, 136.1, 148.3, 168.3; HRMS
(FAB) m/z calcd for C15H1435ClN2O3 [M+H]+, 305.0693, found
305.0697.
1
N-(4-Chlorobenzyl)-N′-[2-(2-nitrophenyl)acetyl]-S-{3-[1-(triph-
enylmethyl)imidazol-4-yl]propyl}isothiourea (9i). According to
the synthetic procedure for 9a, mixing alcohol 8a30 (1.20 g, 3.27
mmol), 7i (1.08 g, 2.97 mmol), Bu3P (1.10 mL, 4.46 mmol), and
TMAD (766 mg, 4.46 mmol) in dry benzene (20 mL) gave 9i (1.81
g, 85%). 9i: oil; 1H NMR (CDCl3) δ 1.76 (2H, quint, J ) 7.2 Hz),
128 °C; H NMR [(CD3)2CO] δ 1.2-3.4 (10H, br), 3.48 (2H, d,
(31) (a) Stanko, V. I.; Gol’tyapin, Yu. V. Zh. Obschch. Khim. 1971, 41,
2033. (b) Herzog, A.; Knobler, C. B.; Hawthorne, M. F.; Maderna, A.;
Siebert, W. J. Org. Chem. 1999, 64, 1045. (c) Goto, T.; Ohta, K.; Suzuki,
T.; Ohta, S.; Endo, Y. Bioorg. Med. Chem. 2005, 13, 6414.
J. Org. Chem, Vol. 73, No. 6, 2008 2103

Yoneyama et al.
J ) 6.9 Hz), 4.70 (1H, t, J ) 6.9 Hz); 13C NMR [(CD3)2CO] δ
64.9, 78.4, 79.0; HRMS m/z calcd for C3H1311B810B2 35ClO (M+)
208.1658, found 208.1655.
(1H, br s), 10.8 (1H, br s); 13C NMR (CDCl3) δ 49.1, 72.9, 78.8,
127.1, 128.8, 130.9, 133.4, 166.1, 179.8; EIMS m/z 370 (M+
-
2); HRMS m/z calcd for C11H1911B810B235ClN2OS 370.1909, found
370.1898.
12-Chloro-1-(O-tosylmethyl)-1,12-dicarba-closo-dodecabo-
rane (14a). In a 10 mL Teflon MW reaction vessel were dissolved
13 (332 mg, 1.59 mmol) and TsCl (606 mg, 3.18 mmol) in pyridine
(3.0 mL). The vessel was sealed and heated in the MW reactor to
120 °C. The reaction was held at this temperature for 1 h and cooled
thereafter. The contents were partitioned between EtOAc (2 mL)
and 2 N HCl (2 mL). The organic layer was washed first with aq
saturated NaHCO3 and then with brine, dried, and evaporated to
give a residue. This was subjected to the same procedure as that
described for the preparation of 12 to yield 14a (551 mg, 95%) via
chromatography. 14a: colorless plates (hexane); mp 105-106 °C;
1H NMR [(CD3)2CO] δ 1.2-3.4 (10H, br), 2.45 (3H, s), 3.98 (2H,
s), 7.46 (2H, d, J ) 7.2 Hz), 7.72 (2H, d, J ) 7.2 Hz); 13C NMR
[(CD3)2CO] δ 21.6, 69.8, 72.1, 79.7, 127.9, 130.2; EIMS m/z 363
(M+ - 1); HRMS (EI) m/z calcd for C10H191B910B35ClO3S (M+)
363.1710, found 363.1733. Caution: 13a easily sublimes under
vacuum.
1-Azidomethyl-12-chloro-1,12-dicarba-closo-dodecaborane
(15a). With use of the same MW procedure as that for the
preparation of 14a, a suspension of 14a (576 mg, 1.58 mmol) and
NaN3 (412 mg, 6.34 mmol) in DMF (4 mL) and H2O (1 mL) was
heated in the MW reactor at 150 °C for 2 h. Filtration of the
resultant precipitate followed by evaporation gave a residue, which
was diluted with EtOAc-hexane (1:1). The organic layer was
extracted three times by the salting-out technique. The collected
organic layer was washed with brine, dried, and evaporated to give
a residue. With use of the same method as that for the purification
of 12, the residue was chromatographed with hexane to give 15a
(267 mg, 72%) as a colorless oil. 15a: positive in Beilstein’s test;
IR (film) νmax 1280, 2100 (N3) cm-1; 1H NMR [(CD3)2CO] δ 1.2-
3.5 (10H, br), 3.54 (2H, s); 13C NMR [(CD3)2CO] δ 54.6, 75,0,
78.9. The mass spectrum or elementary analysis of 15a could not
be obtained owing to its volatility, but the accuracy of 15a was
guaranteed by synthesizing derivatives 6c, 7m, and 3c.
1-(12-Chloro-1,12-dicarba-closo-dodecaboranyl)methylthio-
urea (3c). K2CO3 (49 mg, 0.36 mmol) dissolved in water (2 mL)
was added to a solution of 7m (16.5 mg, 0.04 mmol) in THF (0.5
mL). The mixture was refluxed for 38 h and then THF was
evaporated to give a residue that was extracted three times with
EtOAc by the salting-out techniques. The organic layer was dried
and evaporated to give a residue. Chromatography with EtOAc-
hexane (3:7) as eluent and the coated NH-silica gel technique gave
3c (11.4 mg, 97%) as a white wax. 3c: positive in Beilstein’s test;
1H NMR (CDCl3) δ 1.0-3.8 (10H, br), 3.69 (2H, br s), 5.96 (2H,
br s), 6.28 (1H, br s); 13C NMR (CD3OD) δ 48.7, 77.2, 79.3, 184.7;
HRMS m/z calcd for C4H1511B810B235ClN2S 266.1647, found
266.1635.
1-(O-Tosylmethyl)-1,12-dicarba-closo-dodecaborane (14b). Ac-
cording to the synthetic procedure for 14a, alcohol 12 (472 mg,
2.71 mmol) was converted into 14b (819 mg, 92%). 14b: white
1
powder; H NMR [(CD3)2CO] δ 1.2-3.2 (10H, br), 2.45 (3H, s),
3.40 (1H, br s), 3.92 (2H, s), 7.46 (2H, d, J ) 7.9 Hz), 7.74 (2H,
d, J ) 7.9 Hz); 13C NMR [(CD3)2CO] δ 21.6, 61.6, 71.0, 79.3,
127.9, 130.1, 132.4, 145.5; HRMS m/z calcd for C10H2010B211B8O3S
328.2137, found 328.2141. Caution: 14b easily sublimes under
vacuum.
1-Azidomethyl-1,12-dicarba-closo-dodecaborane (15b). Ac-
cording to the synthetic procedure for 15a, 14b (1602 mg, 4.90
mmol) was converted into 15b (795 mg, 82%). 15b: prisms; mp
1
34-36 °C (hexane; hot plate); IR (film) νmax 2100 (N3) cm-1; H
NMR [(CD3)2CO] δ 1.2-3.2 (10H, br), 3.2-3.6 (3H, br); 13C NMR
[(CD3)2CO] δ 56.2, 60.7, 82.5. Anal. Calcd for C3H13B10N3: C,
18.08; H, 6.58; N, 21.09. Found: C, 18.22; H, 6.41; N, 21.31.
Caution: 15b easily sublimes under vacuum.
1-Aminomethyl-1,12-dicarba-closo-dodecaborane (6d). Ac-
cording to the synthetic procedure for 6c, 15b (209 mg, 1.05 mmol)
was converted into 6d (146 mg, 81%). 6d: pillars; mp 104-
1
1-Aminomethyl-12-chloro-1,12-dicarba-closo-dodecaborane
(6c). A solution of 15a (41 mg, 0.18 mmol) in a 1:1 solution of
MeOH and AcOEt (3 mL) was hydrogenated over 10% Pd/C (16
mg) at 3.2 kg/cm2 for 2 h. After filtration through Celite, a small
amount of silica gel was added to the filtrate, and the mixture was
subsequently evaporated to give coated silica gel. This was placed
in a column for chromatography with EtOAc-hexane (1:9) as eluent
to yield 6c (31 mg, 86%). 6c: positive in Beilstein’s test; colorless
107 °C (hexane; hot plate); H NMR (CDCl3) δ 1.2-3.3 (11H,
br), 2.70 (2H, s); 13C NMR [(CD3)2CO] δ 49.6, 58.5, 87.5. Anal.
Calcd for C3H14B10ClN: C, 17.35; H, 6.79; N, 6.74. Found: C,
17.44; H, 6.60; N, 6.81.
Acknowledgment. We are grateful to Dr. K. Minoura and
Ms. M. Fujitake of this university for NMR and MS measure-
ments, respectively. This work was supported in part by a Grant-
in-Aid for Scientific Research [No.16590024 (to S.H.)] from
JSPS. We also acknowledge a Grant-in-Aid for “High Technol-
ogy Research Center” Project for Private Universities: matching
fund subsidy from MEXT (Ministry of Education, Sciences,
Sports and Culture), 2007-2009, Japan.
1
needles; mp 75-78 °C; H NMR [(CD3)2CO] δ 1.2-3.4 (10H,
br), 3.25 (2H, s); 13C NMR [(CD3)2CO] δ 55.6, 77.7. Anal. Calcd
for C3H15B10N: C, 20.80; H, 8.73; N, 8.08. Found: C, 20.94; H,
8.70; N, 8.37.
1-(12-Chloro-1,12-dicarba-closo-dodecaboranyl)methyl-3-
benzoylthiourea (7m). Amine 6c (73.0 mg, 0.35 mmol) was added
dropwise to benzoylisothiocyanate (86.4 mg, 0.53 mmol) in THF
(8 mL) and the reaction mixture was refluxed for 1 h. Then, a small
amount of silica gel was added. The same chromatographic
procedure (hexane) as that used in the purification of 12 gave 7m
(123.0 mg, 95%). 7m: colorless oil; positive in Beilstein’s test;
1H NMR (CDCl3) δ 1.2-3.5 (10H, br), 3.90 (2H, d, J ) 6.0 Hz),
7.48-7.55 (2H, m), 7.60-7.67 (1H, m), 7.81-7.85 (2H, m), 9.00
Supporting Information Available: General information and
copies of 1H and/or 13C NMR spectra of all new compounds. This
material is available free of charge via the Internet at http://pubs.
acs.org.
JO702181X
2104 J. Org. Chem., Vol. 73, No. 6, 2008