Synthetic studies toward aryl-(4-aryl-4H-[1,2,4]triazole-3-yl)-amine from 1,3-diarylthiourea as urea mimetics

Article abstract of DOI:10.1021/jo0508189

A thiophile-promoted synthesis of disubstituted 4H-[1,2,4]triazole-3-yl- amines as urea mimetics from the corresponding 1,3-disubstituted thioureas has been studied, and the scope and limitations of this reaction are presented. The reaction proceeds through the formation of a carbodiimide, followed by a sequential addition-dehydration with acyl hydrazides. 1,3-Branched dialkylthioureas result in the formation of the corresponding ureas. The electronic and steric effects of the substitution on the phenyl rings of the 1,3-diarylthioureas play an important role in the formation of the intermediary carbodiimde and the direction of the subsequent ring closure of the N-acyl hydrazide adduct.

Full text of DOI:10.1021/jo0508189

Synthetic Studies toward Aryl-(4-aryl-4H-[1,2,4]triazole-3-yl)-amine
from 1,3-Diarylthiourea as Urea Mimetics
Amarnath Natarajan,† Yuhong Guo,† Haribabu Arthanari,‡ Gerhard Wagner,‡
Jose A. Halperin,† and Michael Chorev*,†
Laboratory for Translational Research, 1 Kendall Square, Building 600 3rd Floor, Harvard Medical
School, Cambridge, Massachusetts 02139, and Department of Biological Chemistry and Molecular
Pharmacology, Harvard Medical School, Boston, Massachusetts 02115
michael_chorev@hms.harvard.edu
Received April 22, 2005
A thiophile-promoted synthesis of disubstituted 4H-[1,2,4]triazole-3-yl-amines as urea mimetics
from the corresponding 1,3-disubstituted thioureas has been studied, and the scope and limitations
of this reaction are presented. The reaction proceeds through the formation of a carbodiimide,
followed by a sequential addition-dehydration with acyl hydrazides. 1,3-Branched dialkylthioureas
result in the formation of the corresponding ureas. The electronic and steric effects of the substitution
on the phenyl rings of the 1,3-diarylthioureas play an important role in the formation of the
intermediary carbodiimde and the direction of the subsequent ring closure of the N-acyl hydrazide
adduct.
Introduction
highly potent and selective human A2B adenosine receptor
antagonists,7 and cyclin-dependent kinase 2 (CDK2)
inhibitors.8 The mode of interaction of different 1,3-
diarylureas with their targets varies. For example, while
some of these urea-based inhibitors bind to an allosteric
site causing a significant rearrangement of the target
protein structure,9,10 others bind to the active site such
as the ATP pocket with the urea function participating
in a bidentate hydrogen bond.11
Several compounds that belong to the class of 1,3-
disubstituted ureas are being developed as drug candi-
dates against a variety of diseases. For example, the
Raf-1 inhibitor BAY 43-9006 is developed for cancer and
inflammatory disorders,1 and the cyclic urea Mozenavir
is studied for HIV.2 1,3-Diarylurea is frequently encoun-
tered as a privileged structure for many biological
targets.3 They constitute an essential part of pharma-
cophores for biological targets such as p38 and raf
kinases,4,6 vascular endothelial growth receptor 2 (VRGFR-
2),5 inosine monophosphate dehydrogenase (IMPDH),6
Bioisosteric replacements of the amide and thioamide
functions included heterocyclic systems such as the
[1,2,4]- and [1,3,4]oxadiazoles and [1,2,4]triazoles.12 Such
† Laboratory for Translational Research.
(7) Baraldi, P. G.; Tabrizi, M. A.; Preti, D.; Bovero, A.; Romagnoli,
R.; Fruttarolo, F.; Zaid, N. A.; Moorman, A. R.; Varani, K.; Gessi, S.;
Merighi, S.; Borea, P. A. J. Med. Chem. 2004, 47, 1434-1447.
(8) Honma, T.; Hayashi, K.; Aoyama, T.; Hashimoto, N.; Machida,
T.; Fukasawa, K.; Iwama, T.; Ikeura, C.; Ikuta, M.; Suzuki-Takahashi,
I.; Iwasawa, Y.; Hayama, T.; Nishimura, S.; Morishima, H. J. Med.
Chem. 2001, 44, 4615-4627.
‡ Department of Biological Chemistry and Molecular Pharmacology.
(1) Dumas, J. Curr. Opin. Drug Discovery Dev. 2002, 5, 718-727.
(2) De Clercq, E. Med. Res. Rev. 2002, 22, 531-565.
(3) DeSimone, R. W.; Currie, K. S.; Mitchell, S. A.; Darrow, J. W.;
Pippin, D. A. Comb. Chem. High Throughput Screening 2004, 7, 473-
494.
(4) Smith, R. A.; Barbosa, J.; Blum, C. L.; Bobko, M. A.; Caringal,
Y. V.; Dally, R.; Johnson, J. S.; Katz, M. E.; Kennure, N.; Kingery-
Wood, J.; Lee, W.; Lowinger, T. B.; Lyons, J.; Marsh, V.; Rogers, D.
H.; Swartz, S.; Walling, T.; Wild, H. Bioorg. Med. Chem. Lett. 2001,
11, 2775-2778.
(5) Cheung, M.; Harris, P. A.; Hasegawa, M.; Ida, S.; Kano, K.;
Nishigaki, N.; Sato, H.; Veal, J. M.; Washio, Y.; West, R. I. (Glaxo
Group Ltd., UK; GlaxoSmithKline K.K.). PCT Int. Appl. (2002);
CODEN: PIXXD2 WO 2002044156 A2 20020606.
(6) Jain, J.; Almquist, S. J.; Shlyakhter, D.; Harding, M. W. J.
Pharm. Sci. 2001, 90, 625-637.
(9) Regan, J.; Breitfelder, S.; Cirillo, P.; Gilmore, T.; Graham, A.
G.; Hickey, E.; Klaus, B.; Madwed, J.; Moriak, M.; Moss, N.; Pargellis,
C.; Pav, S.; Proto, A.; Swinamer, A.; Tong, L.; Torcellini, C. J. Med.
Chem. 2002, 45, 2994-3008.
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Graham, A. G.; Grob, P. M.; Hickey, E. R.; Moss, N.; Pav, S.; Regan, J.
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10.1021/jo0508189 CCC: $30.25 © 2005 American Chemical Society
Published on Web 07/13/2005
6362
J. Org. Chem. 2005, 70, 6362-6368

Synthesis of 4H-[1,2,4]Triazole-3-yl-amines
Katritzky and co-workers reported on a solid-phase
method to prepare [1,2,4]triazoles from acyl hydrazide
resins and amidines in the presence of molecular sieves.20
Larsen and DiPaolo converted N-resin-bound thioamides
to amidrazones, which were then acylated by acyl halides
and cyclized in the presence of acetic acid at room
temperature to the triazoles of interest.21 An efficient one-
pot, three-component synthesis of substituted [1,2,4]-
triazoles was reported by Stocks and co-workers.22 Re-
action of an amine with N′-acetyl-N,N-dimethylhydra-
zonoformamide and acyl hydrazides led to moderate
yields when aromatic amines were employed.
FIGURE 1. [1,2,4]Triazoles as amide mimics and 4H-[1,2,4]-
triazol-3-yl-amine as urea mimics.
We chose to employ a method used to transform the
thioamide function in a thionopeptide into a [1,2,4]-
triazole as a cis-amide bond surrogate by treating the
thionopeptide with formic hydrazide and mercury(II)
acetate as a thiophile.15 This reaction proceeds through
the formation of acyl hydrazide adduct which is cyclized
to the corresponding [1,2,4]triazole under acidic condi-
tions.
However, the problem in extending this methodology
for the thiourea lies in the regioselectivity of the cycliza-
tion (Figure 1). Unlike the unidirectional cyclization of
intermediary acylamidrazone (II) generated from the
thioamides (I), which yields a single [1,2,4]triazole (III),
the intermediary acylureidrazone (V) generated from the
thiourea (IV) can in principle cyclize in either direction,
yielding two isomeric [1,2,4]triazoles (VIa and VIb)
(Figure 1). Herein we report a general method used to
generate substituted [1,2,4]triazol-3-yl-amines as amide
bond mimetics of corresponding ureas. Additionally, we
observe interesting steric and electronic effects of the 1,3-
substitutents on the thiourea that play an important role
on the product distribution and regioselectivity of the
cyclization.
replacements led to [1,2,4]triazoles which were active
antimycobacterials13 and potent, selective 5-HT1D recep-
tor agonists.14 Another interesting application of triazole
was to employ it as a cis-amide bond surrogate.15 Re-
placement of the Ala-NMe-Tyr(OMe) amide bond in RA-
VII, a plant-origin antitumor bicyclic hexapeptide, with
[1,2,4]triazole yielded the pseudopeptide.16 As antici-
pated, the pseudopeptide reproduced the conformation
of the minor cis-peptide isomer but was devoid of cyto-
toxic activity. Interestingly, replacement of urea function
in â3-adrenergic receptor agonists with triazole resulted
in improved oral bioavailability accompanied by retention
of potency, selectivity, and in vivo efficacy.17 Replacement
of the amide bond in Phe-Gly in substance P with a [1,2,4]-
triazole peptide bond surrogate led to dramatic loss of
affinity to the NK1 receptor.18 On the other hand,
introduction of the same modification to dermorphin led
to potent and selective pseudopeptides toward the µ-re-
ceptor subtype.18 We anticipate that replacement of the
amide/thioamide bond in the urea/thiourea with hetero-
cyclic bioiosteric moieties such as the triazoles may
increase the structural diversity and generate novel and
interesting bioactive compounds of therapeutic potential.
In an effort to increase structural diversity and modify
the degrees of conformational freedom of the 1,3-disub-
stituted moieties in the urea/thiourea, we introduced a
bioisosterism used to mimic the amide/thioamide function
and developed a synthetic transformation of 1,3-disub-
stituted thioureas to the corresponding alkyl-(4-aryl/
alkyl-4H-[1,2,4]triazol-3-yl)-amine (Figure 1). Transfor-
mation of an amide to a thioamide using Lawesson’s
reagent can be applied to convert the ureas to the
corresponding thioureas,19 thus generating the starting
material for the synthesis of [1,2,4]triazole. In addition,
thioureas can be generated directly by the addition of
amines to isothiocyanates.
Results and Discussion
The 1,3-disubstituted thioureas were either commer-
cially available or were generated in good yields by the
reaction of the amine with the corresponding isothio-
cyanate in either dichloromethane or acetonitrile. The
objective was to select reagents and optimize various
reaction conditions to develop a general method that can
be used to generate regioselective [1,2,4]triazol-3-yl-
amines as amide bond mimics of 1,3-disubstituted urea
compounds. Mercury salts23 and Mukaiyama reagent24
have been used as thiophiles in the guanylation of amines
by thioureas. Our initial objective was to identify a
suitable thiophile to carry out this reaction in one-pot
without isolation of intermediates. We chose to compare
a variety of mercury(II) salts and the Mukaiyama reagent
as our thiophile (Table 1) and monitored the formation
of phenyl-(4-phenyl-4H-[1,2,4]triazol-3-yl)-amine (2) by
LC-MS in a model reaction using the 1,3-diphenylthio-
urea 1. On the basis of the product yield it was clear that
(12) Patani, G. A.; LaVoie, E. J. Chem. Rev. 1996, 96, 3147-3176.
(13) Kucukguzel, I.; Kucukguzel, S. G.; Rollas, S.; Kiraz, M. Bioorg.
Med. Chem. Lett. 2001, 11, 1703-1707.
(14) Street, L. J.; Baker, R.; Davey, W. B.; Guiblin, A. R.; Jelley, R.
A.; Reeve, A. J.; Routledge, H.; Sternfeld, F.; Watt, A. P.; Beer, M. S.;
Middlemiss, D. N.; Noble, A. J.; Stanton, J. A.; Scholey, K.; Hargreaves,
R. J.; Sohal, B.; Graham, M. I.; Matassat, V. G. J. Med. Chem. 1995,
38, 1799-1810.
(15) Hitotsuyanagi, Y.; Motegi, S.; Fukaya, H.; Takeya, K. J. Org.
Chem. 2002, 67, 3266-3271.
(16) Hitotsuyanagi, Y.; Motegi, S.; Hasuda, T.; Takeya, K. Org. Lett.
2004, 6, 1111-1114.
(17) Brockunier, L. L.; Parmee, E. R.; Ok, H. O.; Candelore, M. R.;
Cascieri, M. A.; Colwell, L. F., Jr.; Deng, L.; Feeney, W. P.; Forrest,
M. J.; Hom, G. J.; MacIntyre, D. E.; Tota, L.; Wyvratt, M. J.; Fisher,
M. H.; Weber, A. E. Bioorg. Med. Chem. Lett. 2000, 10, 2111-2114.
(18) Borg, S.; Vollinga, R. C.; Labarre, M.; Payza, K.; Terenius, L.;
Luthman, K. J. Med. Chem. 1999, 42, 4331-4342.
(19) Jesberger, M.; Davis, T. P.; Barner, L. Synthesis 2003, 1929-
1958.
(20) Katritzky, A. R.; Qi, M.; Feng, D.; Zhang, G.; Griffith, M. C.;
Watson, K. Org. Lett. 1999, 1, 1189-1191.
(21) Larsen, S. D.; DiPaolo, B. A. Org. Lett. 2001, 3, 3341-3344.
(22) Stocks, M. J.; Cheshire, D. R.; Reynolds, R. Org. Lett. 2004, 6,
2969-2971.
(23) Levallet, C.; Lerpiniere, J.; Ko, S.-Y. Tetrahedron 1997, 53,
5291-5304.
(24) Yong, Y. F.; Kowalski, J. A.; Lipton, M. A. J. Org. Chem. 1997,
62, 1540-1542.
J. Org. Chem, Vol. 70, No. 16, 2005 6363

Natarajan et al.
TABLE 1. Reaction of 1,3-Diphenylthiourea 1 and
Formylhydrazide To Generate Phenyl-(4-phenyl-4H-
[1,2,4]triazol-3-yl)-amine 2 Mediated by a Thiophile
TABLE 2. Substituent Effect on the Formation of
[1,2,4]Triazoles from Symmetrical Thioureas
R1
R2
% yield
a
b
c
d
e
f
g
h
i
4-OMe-phenyl
4-Cl-phenyl
3,5-di-CF3-phenyl
tert-butyl
H
H
H
H
H
H
89
thiophile
Hg(OAc)2
% yield
74
36
a
b
c
d
e
f
75
10
6
11
6
22
25
urea
urea
urea
68
Hg(OCOCF3)2
HgCl2
cyclohexyl
n-propyl
HgBr2
phenyl
Me
HgI2
phenyl
phenyl
H
Me
Me
12
HgSO4
phenyl
73
g
Mukaiyama reagent
j
k
4-OMe-phenyl
3,5-di-CF3-phenyl
77
60
cyclohexyl, and n-propyl thioureas (3d-f, Table 2) was
the corresponding 1,3-dialkylurea. This is because the
acetate, released from the thiophile Hg(OAc)2 in the
course of desulfurization, reacts with the intermediary
1,3-dialkylcarbodiimide faster than the addition of acyl-
hydrazide to yield the 2-acetyl-1,3-dialkyl-isourea (Scheme
1). By using the Mukaiyama reagent (N-methyl 2-chloro-
pyridinium iodide) as the thiophile and 1,3-dicylcohexyl-
thiourea, we were able to get ∼15% of the [1,2,4]triazole;
longer incubation times, however, did not improve the
yields. The desulfurization of the substituted 1,3-diphen-
ylthioureas to form the corresponding carbodiimides was
visually monitored based on the formation of the HgS
black precipitate. HgS formation was the fastest in the
thioureas in which phenyl rings substituted with electron-
withdrawing groups and the slowest in those where
phenyl rings were substituted with electron-donating
groups. The data in Table 2 also suggest that 1,3-
diphenylthioureas substituted with electron-withdrawing
groups on the aromatic rings generate lower yields of
[1,2,4]triazole compared to the electron-rich ring systems
(cf. 3a-c, Table 2). In the 4-Cl- and 3,5-di-CF3-disubsti-
tuted phenylthioureas, a significant amount of a high
molecular weight product composed of two units of
carbodiimide and one unit of fromylhydrazide was ob-
served by LC-MS. This product is generated by the
addition of a second carbodiimide to the intermediary
N-acyl hydrazide (V) prior to the ring closure. This
pattern could be explained if the carbodiimides generated
with electron-withdrawing groups on the phenyl rings are
much more reactive toward the formylhydrazide com-
pared to the one with electron-donating group on the
phenyl rings; in addition these are slower to cyclize (cf.
3b and 3c with 3a, Table 2). The stereoelectronic effects
of the acyl group on the acylhydrazine affect the yields
of the [1,2,4]triazole (3g-i, Table 2). A similar pattern
is observed in the [1,2,4]triazole yields (4g, 4j, and 4k,
Table 2) generated using acetylhydrazide with varying
substitutions. The acid-catalyzed dehydration to generate
the corresponding [1,2,4]triazole 4h (Table 2) could be
pushed to ∼75% completion with a stronger acid (p-
TsOH) and higher temperature (reflux).
FIGURE 2. Time course for the conversion of 1,3-diphenyl-
thiourea (1) to phenyl-(4-phenyl-4H-[1,2,4]triazol-3-yl)-amine
(2).
Hg(OAc)2 was the optimal thiophile for this model reac-
tion, and hence we decided to use Hg(OAc)2 for all
subsequent reactions as the thiophile. We then turned
our attention to investigate the time course for this
reaction, employing equimolar amounts of 1 and formyl-
hydrazide. In about 15 min from the start of the reaction,
∼65% of the 1,3-diphenylthiourea was converted to the
1,3-diphenylcarbodiimide, which was isolated and char-
acterized (Figure 2). Therefore, we followed the course
of this reaction by monitoring the disappearance of the
carbodiimide and the formation of 2 by LC-MS. We
observed that in about 2 h the reaction resulted in ∼70%
of 2 and there was not much improvement in the product
yield for the next 22 h. Hence, we decided to use 2 h as
optimal time of incubation for further studies. By using
2.5 equiv of the formylhydrazide in the above reaction,
we were able to increase the yield of the isolated product
to 91%.
Since the [1,2,4]triazole formation is an addition-
dehydration reaction, we hypothesized that the substit-
uents on the thiourea nitrogens would play an important
role in the rate of addition and the regioselectivity of ring
closure. To study the substituent effect on the formation
of the [1,2,4]triazole, a series of symmetrical 1,3-disub-
stituted thioureas were generated. A one-pot reaction was
carried out with the 1,3-disubstituted thiourea, Hg(OAc)2,
and an acylhydrazine (1:1.05:0.95 equiv) mixed together
at room temperature and incubated for 2 h. It is interest-
ing to note that the major product from the reaction in
the case of the 1,3-dialkyl substitutions viz., tert-butyl,
To address the substituent effects on the regioselec-
tivity of ring closure generating the [1,2,4]triazoles, we
studied thioureas in which both nitrogens were differ-
entially substituted. The corresponding [1,2,4]triazoles
6364 J. Org. Chem., Vol. 70, No. 16, 2005

Synthesis of 4H-[1,2,4]Triazole-3-yl-amines
SCHEME 1. Formation of 1,3-Dilakylurea through the 1,3-Dialkyl O-Acetylisourea Intermediate Formed
from a 1,3-Dialkylthiourea
SCHEME 2. N-Benzyl Protection-Deprotection Strategy To Access Regioselective [1,2,4]Triazoles
TABLE 3. Substituent Effect on the Direction of Ring
Closure To Yield the [1,2,4]Triazoles Generated from
Unsymmetrical 1,3-Disubstituted Thioureas (General
Procedure II)a
of the two (5g Table 3), resulting in good yields of the
corresponding [1,2,4]triazole. A strong electron-with-
drawing group on the phenyl ring such as m,m′-di-CF3
(f, Table 3) yields a regioselective product; however, with
p-OMe and p-Cl substituents (d and e, Table 3) we obtain
a mixture of regioisomers. In the case of a reaction
wherein we get a mixture of the two regioisomers, the
ratio and regioselectivity were confirmed by synthesizing
exclusively a single regioisomer using a benzyl protec-
tion-deprotection strategy. In entry 5d of Table 3 the
[1,2,4]triazoles obtained were a 1:5 mixture of regioiso-
mers 6d and 7d. The individual regioisomers were
synthesized starting from the corresponding 1-benzyl-1,3-
diphenylthioureas summarized in Scheme 2. The assign-
ments of 6d and 7d were made on the basis of chemical
shifts in the NMR spectra and retention times on the LC.
R1
R2
% yield
a
b
c
d
e
f
g
h
i
cyclohexyl
phenyl
4-OMe-phenyl
cyclohexyl
4-OMe-phenyl
4-Cl-phenyl
phenyl
4-OMe-phenyl
p-tolyl
o-tolyl
2-i-propyl-phenyl
2-tert-butyl-phenyl
urea
75 (6b)
44 (6c)
76 (1:5)
70 (2:3)
84 (6f)
77
cyclohexyl
3,5-di-CF3-phenyl
phenyl
phenyl
3,5-di-CF3-phenyl
3,5-di-CF3-phenyl
3,5-di-CF3-phenyl
3,5-di-CF3-phenyl
3,5-di-CF3-phenyl
3,5-di-CF3-phenyl
55
50
1
On the basis of H and 13C NMR and LC-MS, all the
j
k
45
other unsymmetrical 1,3-disubstituted thioureas in Table
3 resulted in an overwhelming excess of single regio-
isomer of [1,2,4]triazole (>95:5). The regiochemistry of
the compounds was assigned on the basis of the diag-
nostic NOESY peak. For example, Figure 3 shows the
NOESY spectrum of compound 6g displaying cross-peaks
between Hb and Hc and the lack of cross-peaks between
Hc and Hd (see Supporting Information for TOCSY and
NOESY data for 6c, 6f, and 6g).
From the symmetrical 1,3-disubstituted urea series we
know that N-3,5-bis-trifluoromethylphenyl-substituted
thioureas undergo rapid formation of the carbodiimide
intermediate, thereby making the addition-dehydration
the rate-limiting steps. Also, N-1,3-bis-substituted thio-
ureas that have the 3,5-ditrifluoromethylphenyl substitu-
ent yield regioselective products (see 5f-k, Table 3). To
investigate the steric effects of substituents on the rate
of the addition-dehydration reaction, we synthesized a
series of mixed 1,3-disubstituted thioureas which main-
tain 3,5-bis-trifluoromethylphenyl on one nitrogen and
a phenyl substituted with varying steric bulk on the other
(5h-k, Table 3). The yields of the reactions with N-p-
tolyl- and N-o-tolyl-substituted thioureas (5h and 5i,
Table 3) are almost equivalent. However, the 1-p-tolyl-
3-(3,5-bis-CF3-phenyl)thiourea (5h) yielded a high mo-
lecular weight compound that corresponds to the addition
of two carbodiimides to one formyl hydrazide as the minor
8
a Reaction times a - c ) 48 h and d - k ) 2 h.
were generated using the optimized procedure [1,3-
disubstituted thiourea, Hg(OAc)2, and an acylhydrazine
(1:1.05:0.95 equiv) mixed together and incubated at room
temperature], the results of which are summarized in
Table 3. In the 1-cyclohexyl-3-arylthiourea (5a-c, Table
3) series, the electronic density and distribution on the
phenyl ring were modified by substituting it with either
an electron-donating group (5b, Table 3) or electron-
withdrawing group (5c, Table 3). By LC-MS we observed
a significant amount of the carbodiimide and the inter-
mediate that results from the addition of formyl hy-
drazide to the carbodiimide. These reactions were allowed
to proceed for 48 h at room temperature. The 1-cyclo-
hexyl-3-phenylthiourea (5a, Table 3) yields the urea as
a major product, while the aryl-substituted 1-cyclohexy-
3-arylthioureas (5b and 5c, Table 3) yield the desired
products in good to moderate yields. These observations
do not follow an obvious trend, and at present we can
only speculate that the kinetics of the intermediate
reactions might play an important role in the product
([1,2,4]triazole) formation. The reaction tolerates electron-
withdrawing groups (5e and 5f, Table 3), electron-
donating groups (5d and 5h, Table 3), and a combination
J. Org. Chem, Vol. 70, No. 16, 2005 6365

Natarajan et al.
to generate a library with four points of diversity, which
is currently underway in our laboratories and will be
reported in due course.
Experimental Section
Unless otherwise specified, all reagents were purchased
from commercial sources and were used without further
purification. Flash chromatography was carried out on silica
gel (200-400 mesh). Melting points were recorded on an
electrothermal melting point apparatus and are uncorrected.
Mass spectra were obtained from a single quad instrument
with APCI source. 1D and 2D NMR spectra were collected
using standard pulse sequences.
N-Phenyl-(4-phenyl-4H-[1,2,4]triazol-3-yl)-amine (2):
(Following general procedure II) 72%, colorless solid: mp 214-
216 °C; 1H NMR (DMSO-d6, 400 MHz) δ 8.50 (bs, 1H), 8.47 (s,
1H), 7.57-7.53 (m, 2H), 7.51-7.46 (m, 3H), 7.40 (d, 2H, J ) 8
Hz), 7.20 (t, 2H, J ) 8 Hz), 6.83 (t, 1H, J ) 7.2 Hz); 13C NMR
(DMSO-d6, 100 MHz) δ 150.6, 142.6, 142.1, 134.0, 130.5, 129.4,
129.3, 126.0, 120.9, 117.3; MS+(APCI) 236.9 [M + H]+; Anal.
Calcd for C14H12N4: C, 71.17; H, 5.12; N, 23.71. Found: C,
70.95; H, 4.89; N, 23.77.
1,3-Di-(4-methoxy-phenyl)thiourea (3a): 98%, colorless
1
solid: mp 201-203 °C; H NMR (DMSO-d6, 400 MHz) δ 9.42
(s, 2H), 7.29 (d, J ) 8.8 Hz, 4H), 6.87 (d, J ) 8.8 Hz, 4H), 3.72
(s, 6H); 13C NMR (DMSO-d6, 100 MHz) δ 181.1, 157.2, 132.9,
126.8, 114.3, 55.9; MS+(APCI) 288.84 [M + H]+.
1,3-Bis-(3,5-bis-trifluoromethyl-phenyl)thiourea (3c):
71%, colorless solid: mp 180-181 °C; 1H NMR (DMSO-d6, 400
MHz) δ 10.65 (s, 2H), 8.19 (s, 4H), 7.85 (s, 2H); MS+(APCI)
499.99 [M + H]+.
FIGURE 3. NOESY spectrum showing the diagnostic peak
confirming the direction of the regioselective ring closure to
yield [1,2,4]triazole 6g.
product, while the 1-o-tolyl-3-(3,5-di-CF3-phenyl)thiourea
(5i) gave the intermediate generated by the addition of
formyl hydrazide to carbodiimide as the minor product.
The reactions were monitored by LC-MS, and ratios of
the major to minor products were 5:1 for h (N-p-tolyl
substitution) and 6:1 for i (N-o-tolyl substitution). On the
basis of the product distribution, the steric hindrance in
N-o-tolyl-3-(3,5-di-CF3-phenyl)thiourea (5i) prevents the
addition of second carbodiimde. Similar to 5i, the steric-
hindered ring closure is also compromised in the N-i-
propyl (5j) and remarkably inhibited in the N-tert-butyl-
3-(3,5-di-CF3-phenyl)thiourea (5k) as shown by the lower
yields of the [1,2,4]triazoles (45 and 8%, respectively)
obtained under similar reaction conditions. Extending the
reactions overnight, we found that these ortho-substi-
tuted phenylthiourea reactions proceed to give isolated
yields of ∼70-75% of the corresponding [1,2,4]triazoles.
It is clear from the studies of the series of 1,3-
disubstituted thioureas that the reaction can be fine-
tuned to yield regioselective 1,3-disubstituted [1,2,4]-
triazoles by modifying the substituents on the nitrogens
of the thiourea. At least for the compounds described, the
rate-limiting step in this reaction is the addition-
dehydration step. The ring closure preferentially occurs
on the nitrogen that has the electron-donating substit-
uents. In the case where the difference between the two
N-substituents is not significant leading to the formation
of a mixture of regioisomeric [1,2,4]triazoles, a protec-
tion-deprotection strategy employing a benzyl group as
a transient protecting group can be considered to gener-
ate the regioisomeric [1,2,4]triazole of choice. In sum-
mary, we described a new synthesis of useful 1,3-
disubstituted triazoles as amide bond mimetics of urea
compounds. Furthermore, the central [1,2,4]triazol-3-yl-
amine scaffold under optimized conditions can be used
(4-Methoxy-phenyl)-[4-(4-methoxy-phenyl)-4H-[1,2,4]-
triazol-3-yl]-amine (4a): 89%, colorless solid: mp 183-184
°C; 1H NMR (DMSO-d6, 400 MHz) δ 8.29 (s, 1H), 8.13 (s, 1H),
7.43-7.39 (m, 4H), 7.09 (dd, J ) 6.8, 2.0 Hz, 2H), 6.79 (dd, J
) 6.8, 2.0 Hz, 2H), 3.80 (s, 3H), 3.67 (s, 3H); 13C NMR (DMSO-
d6, 100 MHz) δ 159.4,153.4, 150.9, 141.1, 134.9, 127.3, 125.9,
118.4, 114.9, 113.8, 55.5, 55.2; MS+(ESI) 296.30 [M + H]+.
(4-Chloro-phenyl)-[4-(4-chloro-phenyl)-4H-[1,2,4]tria-
zol-3-yl]-amine (4b): 74%, colorless solid: mp 226-228 °C;
1H NMR (DMSO-d6, 500 MHz) δ 8.74 (s, 1H), 8.48 (s, 1H), 7.61
(dd, J ) 40.5, 9.0 Hz, 2H), 7.41 (dd, J ) 125.0, 9.0 Hz, 2H);
13C NMR (DMSO-d6, 125 MHz) δ 149.7, 141.2, 140.5, 133.5,
132.0, 129.8, 128.4, 127.6, 123.9, 118.3; MS+(ESI) 305.5 [M +
H]+.
(3,5-Bis-trifluoromethyl-phenyl)-[4-(3,5-bis-trifluoro-
methyl-phenyl)-4H-[1,2,4]triazol-3-yl]-amine (4c): 36%; 1H
NMR (DMSO-d6, 400 MHz) δ 9.49 (bs, 1H), 8.65 (s, 1H), 8.44
(s, 2H), 8.35 (s, 1H), 8.18 (s, 2H), 7.53 (s, 1H); 13C NMR
(DMSO-d6, 100 MHz) δ 149.9,143.6, 142.2, 135.3, 132.5, 132.2,
131.6, 131.3, 128.8, 125.4, 124.8, 123.9, 122.7, 122.1, 117.3,
113.7; MS+(APCI) 508.93 [M + H]+.
(5-Methyl-4-phenyl-4H-[1,2,4]triazol-3-yl)-phenyl-
1
amine (4g): 68%, colorless solid: mp 236-238 °C; H NMR
(DMSO-d6, 400 MHz) δ 8.14 (s, 1H), 7.58-7.50 (m, 3H), 7.44-
7.36 (m, 4H), 7.18-7.13 (m, 2H), 6.81-6.77 (m, 1H), 2.10 (s,
3H); 13C NMR (DMSO-d6, 100 MHz) δ 151.3, 148.3, 142.7,
133.8, 130.6, 130.0, 129.2, 128.3, 120.6, 117.1, 11.9; MS+(APCI)
251.01 [M + H]+; Anal. Calcd for C15H14N4: C, 71.98; H, 5.64;
N, 22.38. Found: C, 71.78; H, 5.47; N, 22.41.
(4,5-Diphenyl-4H-[1,2,4]triazol-3-yl)-phenyl-amine (4h):
12%, colorless solid: mp 201-202 °C; 1H NMR (DMSO-d6, 400
MHz) δ 8.36 (s, 1H), 7.54-7.49 (m, 5H), 7.44-7.42 (m, 2H),
7.35-7.33 (m, 1H), 7.33-7.31 (m, 4H), 7.23 (t, J ) 7.2 Hz, 2H),
6.89 (t, J ) 7.2 Hz, 1H); 13C NMR (DMSO-d6, 100 MHz) δ
152.5, 150.6, 141.8, 133.8, 130.7, 130.6, 130.1, 129.4, 129.2,
129.1, 128.5, 127.7, 121.7, 118.3; MS+(APCI) 313.12 [M + H]+.
N-Phenyl-(4-phenyl-4H-[1,2,4]triazol-3-yl)-amine (4i):
(Following general procedure II) 73%. Compound 4i is identical
to 2, which is fully characterized.
6366 J. Org. Chem., Vol. 70, No. 16, 2005

Synthesis of 4H-[1,2,4]Triazole-3-yl-amines
(4,5-Diphenyl-4H-[1,2,4]triazol-3-yl)-phenyl-amine (4k):
(3,5-Bis-trifluoromethyl-phenyl)-(4-cyclohexyl-4H-[1,2,4]-
triazol-3-yl)-amine (6c): 44%, colorless solid; 1H NMR (DMSO-
d6, 500 MHz) δ 9.35 (s, 1H), 8.48 (s, 1H), 8.35 (s, 2H), 7.54 (s,
1H), 4.12 (tt, J ) 4.0, 11.5 Hz, 1H), 1.98-1.96 (m, 2H), 1.86-
1.83 (m, 2H), 1.71-1.61 (m, 3H), 1.45-1.37 (m, 2H), 7.20 (tq,
J ) 4.0, 13.5 Hz, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 148.7,
143.2, 138.8, 130.9, 130.8, 130.6, 130.5, 126.7, 124.5, 122.37,
120.1, 116.2, 112.5, 52.5, 32.8, 25.1, 24.5; MS+(APCI) 378.95
[M + H]+; Anal. Calcd for C16H16N4F6: C, 50.80; H, 4.26; N,
14.81. Found: C, 50.89; H, 4.43; N, 15.00.
(4-Methoxy-phenyl)-(4-phenyl-4H-[1,2,4]triazol-3-yl)-
amine (6d): 63%, pale yellow oil; 1H NMR (DMSO-d6, 400
MHz) δ 8.77 (s, 1H), 7.65-7.60 (m, 6H), 7.15 (dd, J ) 170, 8.8
Hz, 4H), 3.74 (s, 3H); MS+(APCI) 267.03 [M + H]+.
[4-(4-Methoxy-phenyl)-4H-[1,2,4]triazol-3-yl]-phenyl-
amine (7d): 56%, colorless solid; mp 211-212 °C; 1H NMR
(DMSO-d6, 500 MHz) δ 8.37 (s, 1H), 8.36 (bs, 1H), 7.44-7.39
(m, 4H), 7.20 (t, J ) 12 Hz, 2H), 7.11-7.07 (m, 2H), 6.83 (t, J
) 12 Hz, 1H), 3.82 (s, 3H); 13C NMR (DMSO-d6, 125 MHz) δ
159.4, 150.3, 141.8, 141.5, 128.6, 127.1, 125.9, 120.2, 116.6,
114.9, 55.5; MS+(APCI) 267.03 [M + H]+.
1
60%, colorless solid; H NMR (DMSO-d6, 500 MHz) δ 9.56 (s,
1H), 9.06 (s, 1H), 8.34 (s, 2H), 8.27 (s, 1H), 8.07 (s, 2H), 7.38
(s, 1H), 1.71 (s, 3H); 13C NMR (DMSO-d6, 125 MHz) δ 167.9,
149.6, 147.8, 142.9, 134.6, 132.1, 131.8, 130.8, 130.6, 129.8,
124.5, 123.9, 122.3, 121.7, 116.4, 112.8, 10.9; MS+(APCI)
523.13 [M + H]+.
1-Cyclohexyl-3-phenylthiourea (5a):23 80%, colorless
solid: mp 144-145 °C; 1H NMR (DMSO-d6, 400 MHz) δ 10.29
(bs, 1H), 9.31 (s, 1H), 7.61 (s, 1H), 7.42 (d, J ) 8.4 Hz, 2H),
7.27 (d, J ) 7.2 Hz, 2H), 7.05 (t, J ) 7.6 Hz, 1H), 4.07 (s, 1H),
1.89-1.87 (m, 2H), 1.68-1.64 (m, 2H), 1.56-1.52 (m, 1H),
1.32-1.11 (m, 5H); MS+(APCI) 235.23 [M + H]+.
1-Cyclohexyl-3-(4-methoxy-phenyl)thiourea (5b):23 84%,
colorless solid: mp 138-139 °C; 1H NMR (DMSO-d6, 400 MHz)
δ 9.12 (bs, 1H), 7.36 (s, 1H), 7.24 (d, J ) 8.2 Hz, 2H), 6.86 (d,
J ) 8.2 Hz, 2H), 4.04 (s, 1H), 3.72 (s, 3H), 1.86-1.82 (m, 2H),
1.70-1.66 (m, 2H), 1.54-1.52 (m, 1H), 1.30-1.09 (m, 5H); MS+-
(APCI) 264.89 [M + H]+.
1-(3,5-Bis-trifluoromethyl-phenyl)-3-cyclohexylthio-
1
urea (5c):25 86%, colorless solid: mp 164-165 °C; H NMR
(DMSO-d6, 400 MHz) δ 9.84 (s, 1H), 8.21 (s, 2H), 8.14 (s, 1H),
7.70 (s, 1H), 4.09 (bs, 1H), 1.91-1.87 (m, 2H), 1.69-1.66 (m,
2H), 1.57-1.54 (m, 1H), 1.34-1.14 (m, 5H); MS+(APCI) 371.00
[M + H]+.
[4-(4-Chloro-phenyl)-4H-[1,2,4]triazol-3-yl]-phenyl-
amine (7e): 20%, colorless oil; 1H NMR (DMSO-d6, 500 MHz)
δ 8.68 (s, 1H), 8.49 (s, 1H), 7.59-7.56 (m, 2H), 7.52-7.49 (m,
5H), 7.26 (d, J ) 8.5 Hz, 2H); 13C NMR (DMSO-d6, 125 MHz)
δ 158.9, 149.7, 141.5, 140.7, 133.1, 129.9, 128.9, 128.4, 125.4,
123.8, 118.3; MS+(APCI) 271.4 [M + H]+; Anal. Calcd for
C14H11ClN4: C, 62.11; H, 4.10; N, 20.70. Found: C, 61.68; H,
3.86; N, 20.33.
(3,5-Bis-trifluoromethyl-phenyl)-(4-phenyl-4H-[1,2,4]-
triazol-3-yl)-amine (6f): 84%, colorless solid; mp 191-192
°C; 1H NMR (DMSO-d6, 400 MHz) δ 9.40 (s, 1H), 8.54 (s, 1H),
8.31 (s, 2H), 7.62-7.53 (m, 5H), 7.50 (s, 1H); 13C NMR (DMSO-
d6, 100 MHz) δ 149.2, 143.1, 141.7, 132.7, 131.2, 130.8, 130.5,
130.2, 129.9, 129.3, 127.5, 126.0, 124.8, 122.1, 119.4, 116.6,
112.7; MS+(APCI) 372.93 [M + H]+ Anal. Calcd for C16H10-
F6N4: C, 51.62; H, 2.71; N, 15.05. Found: C, 51.57; H, 2.60;
N, 14.93.
(3,5-Bis-trifluoromethyl-phenyl)-[4-(4-methoxy-phen-
yl)-4H-[1,2,4]triazol-3-yl]-amine (6g): 77%, colorless solid;
mp 212-213 °C; 1H NMR (DMSO-d6, 400 MHz) δ 9.27 (s, 1H),
8.45 (s, 1H), 8.35 (s, 2H), 7.51 (s, 1H), 7.47 (dd, J ) 9.2, 2.8
Hz, 2H), 7.13 (dd, J ) 9.2, 2.8 Hz, 2H), 3.82 (s, 3H); MS+(APCI)
403.02 [M + H]+; Anal. Calcd for C14H12N4‚0.5CH3OH: C,
50.25; H, 3.37; N, 13.39. Found: C, 50.49; H, 3.56; N, 13.57.
(3,5-Bis-trifluoromethyl-phenyl)-(4-p-tolyl-4H-[1,2,4]-
triazol-3-yl)-amine (6h): 55%, colorless solid; mp 230-231
°C; 1H NMR (DMSO-d6, 400 MHz) δ 9.33 (s, 1H), 8.48 (s, 1H),
8.32 (s, 2H), 7.51 (s, 1H), 7.41 (dd, J ) 13.6, 8 Hz, 4H), 2.39
(s, 3H); MS+(APCI) 386.85 [M + H]+; Anal. Calcd for
C17H12F6N4: C, 52.86; H, 3.13; N, 14.50. Found: C, 52.62; H,
3.07; N, 14.32.
(3,5-Bis-trifluoromethyl-phenyl)-(4-o-tolyl-4H-[1,2,4]-
triazol-3-yl)-amine (6i): 50%, colorless solid; mp 239-240 °C;
1H NMR (DMSO-d6, 400 MHz) δ 9.26 (s, 1H), 8.43 (s, 1H), 8.40
(s, 2H) 7.51 (s, 1H), 7.49-7.41 (m, 4H), 2.05 (s, 3H); MS+(APCI)
386.97 [M + H]+; Anal. Calcd for C17H12F6N4: C, 52.86; H, 3.13;
N, 14.50. Found: C, 52.71; H, 2.92; N, 14.60.
1-(4-Methoxy-phenyl)-3-phenylthiourea (5d):26 65%, col-
1
orless solid: mp 159-161 °C; H NMR (DMSO-d6, 400 MHz)
δ 9.61 (s, 1H), 9.59 (s, 1H), 7.46-7.43 (m, 2H), 7.32-7.27 (m,
4H), 7.10 (dt, J ) 8, 1.2 Hz, 1H), 6.88 (dd, J ) 8, 1.2 Hz, 2H),
3.76 (s, 3H); MS+(APCI) 258.97 [M + H]+.
1-(3,5-Bis-trifluoromethyl-phenyl)-3-phenylthiourea
1
(5f): 86%, colorless solid: mp 141-143 °C; H NMR (DMSO-
d6, 400 MHz) δ 10.29 (s, 1H), 10.20 (s, 1H), 8.23 (s, 2H), 7.79
(s, 1H), 7.43-7.34 (m, 4H), 7.17 (t, J ) 7.2 Hz, 1H); MS+(APCI)
364.90 [M + H]+.
1-(3,5-Bis-trifluoromethyl-phenyl)-3-(4-methoxy-
phenyl)thiourea (5g): 91%, colorless solid: mp 148-150 °C;
1H NMR (DMSO-d6, 400 MHz) δ 10.12 (s, 1H), 10.01 (s, 1H),
8.23 (s, 2H), 7.76 (s, 1H), 7.11 (dd, J ) 144.0, 8.8 Hz, 4H),
3.73 (s, 3H); MS+(APCI) 394.89 [M + H]+.
1-(3,5-Bis-trifluoromethyl-phenyl)-3-p-tolyl-thiourea
(5h): 64%, colorless solid: mp 153-154 °C; 1H NMR (DMSO-
d6, 400 MHz) δ 10.22 (s, 1H), 10.10 (s, 1H), 8.23 (s, 2H), 7.76
(s, 1H), 7.22 (dd, J ) 48.8, 8.0 Hz, 4H), 3.30 (s, 3H); MS+(APCI)
378.89 [M + H]+.
1-(3,5-Bis-trifluoromethyl-phenyl)-3-o-tolyl-thiourea (5i):
83%, colorless solid: mp 153-154 °C; 1H NMR (DMSO-d6, 400
MHz) δ 10.05 (s, 1H), 9.88 (s, 1H), 8.25 (s, 2H), 7.76 (s, 1H),
7.28-7.17 (m, 4H), 3.33 (s, 3H); MS+(APCI) 378.92 [M + H]+.
1-(3,5-Bis-trifluoromethyl-phenyl)-3-(2-isopropyl-
phenyl)thiourea (5j): 82%, colorless solid: mp 148-150 °C;
1H NMR (DMSO-d6, 400 MHz) δ 10.29 (bs, 1H), 9.87 (s, 1H),
8.26 (s, 2H), 7.77 (s, 1H), 7.37-7.20 (m, 4H), 3.09 (septa, J )
7.2 Hz, 3H), 1.15 (d, J ) 7.2 Hz, 6H); MS+(APCI) 406.93 [M +
H]+.
1-(3,5-Bis-trifluoromethyl-phenyl)-3-(2-tert-butyl-
phenyl)thiourea (5k): 65%, colorless solid: mp 137-138 °C;
1H NMR (DMSO-d6, 400 MHz) δ 9.89 (bs, 1H), 9.75 (bs, 1H),
8.30 (s, 2H), 7.77 (s, 1H), 7.45 (d, J ) 7.2 Hz, 1H), 7.31-7.23
(m, 2H), 7.18 (d, J ) 7.2 Hz, 1H), 1.26 (s, 9H); MS+(APCI)
420.94 [M + H]+.
(3,5-Bis-trifluoromethyl-phenyl)-[4-(2-isopropyl-phen-
yl)-4H-[1,2,4]triazol-3-yl]-amine (6j): 45%, colorless solid;
mp 216-217 °C; 1H NMR (DMSO-d6, 400 MHz) δ 9.21 (s, 1H),
8.46 (s, 1H), 8.43 (s, 2H), 7.60 (m, 2H), 7.53 (s, 1H), 7.42-7.40
(m, 2H), 2.45 (septa, J ) 6.8 Hz, 1H), 1.08 (dd, J ) 6.8, 1.8
Hz, 6H); MS+(APCI) 414.90 [M + H]+; Anal. Calcd for
C19H16F6N4: C, 55.08; H, 3.89; N, 13.52. Found: C, 54.82; H,
3.76; N, 13.66.
(4-Cyclohexyl-4H-[1,2,4]triazol-3-yl)-(4-methoxy-phen-
yl)-amine (6b): 75%, colorless solid; 1H NMR (DMSO-d6, 300
MHz) δ 8.08 (s, 1H), 7.02 (dd, J ) 138.3, 9.0 Hz, 4H), 5.94 (d,
J ) 8.4), 3.44-3.33 (m, 1H), 1.82-1.76 (m, 2H), 1.66-1.63 (m,
2H), 1.54-1.51 (m, 1H), 1.33-1.25 (m, 2H), 1.20-1.10 (m, 3H);
MS+(APCI) 272.98 [M + H]+.
(3,5-Bis-trifluoromethyl-phenyl)-[4-(2-tert-butyl-phen-
yl)-4H-[1,2,4]triazol-3-yl]-amine (6k): (Following general
1
procedure III) 49%, colorless solid; mp 249-250 °C; H NMR
(25) Sohtome, Y.; Tanatani, A.; Hashimoto, Y.; Nagasawa, K.
Tetrahedron Lett. 2004, 45, 5589-5592.
(26) Sahu, M.; Garnaik, B. K.; Behera, R. Indian J. Chem., Sect. B
1987, 26B, 779-81.
(DMSO-d6, 400 MHz) δ 9.11 (s, 1H), 8.49 (s, 2H), 8.48 (s, 1H),
7.73 (dd, J ) 7.6, 1.2 Hz, 1H), 7.58 (dt, J ) 6.8, 1.6 Hz, 1H),
7.52 (s, 1H), 7.40 (dt, J ) 7.6, 1.2 Hz, 1H), 7.23 (dd, J ) 7.6,
J. Org. Chem, Vol. 70, No. 16, 2005 6367

Natarajan et al.
1.2 Hz, 1H), 2.45 (septa, J ) 6.8 Hz, 1H), 1.15 (s, 9H); MS+-
(APCI) 428.98 [M + H]+; Anal. Calcd for C20H18F6N4: C, 56.08;
H, 4.24; N, 13.08. Found: C, 55.94; H, 4.09; N, 13.00.
Benzyl-(4-chloro-phenyl)-(4-phenyl-4H-[1,2,4]triazol-3-
1
yl)-amine (10b): 24%, colorless solid; H NMR (CDCl3, 500
MHz) δ 7.69 (d, J ) 8.0 Hz, 2H), 7.22-7.19 (m, 3H), 7.13-
7.10 (m, 2H), 7.10-6.95 (m, 5H), 6.91 (m, 3H) 5.35 (s, 2H);
13C NMR (DMSO-d6, 125 MHz) δ 141.9, 140.1, 135.7, 134.4,
132.3, 129.5, 128.64, 128.60, 128.53, 128.52, 126.8, 126.6,
126.1, 120.5; MS+(APCI) 361.02 [M + H]+.
Benzyl-(4-methoxy-phenyl)-(4-phenyl-4H-[1,2,4]triazol-
3-yl)-amine (11): 18%, colorless solid; 1H NMR (DMSO-d6,
400 MHz) δ 8.67 (s, 1H), 7.40 (d, J ) 8 Hz, 2H), 7.28-7.19 (m,
5H), 7.04 (t, J ) 7.2 Hz, 2H), 6.90 (d, J ) 8.8 Hz, 2H), 6.71 (t,
J ) 6.8 Hz, 1H), 6.61 (d, J ) 8.4 Hz, 2H), 4.82 (s, 2H), 3.71 (s,
3H); MS+(APCI) 356.89 [M + H]+; RT ) 9.07.
1-Benzyl-1-(4-methoxy-phenyl)-3-phenylthiourea (8a):
1
93%, off-white solid: mp 87-88 °C; H NMR (DMSO-d6, 500
MHz) δ 8.69 (s, 1H), 7.34-7.26 (m, 8H), 7.23 (t, J ) 6.5 Hz,
1H), 7.15-7.10 (m, 1H), 7.03 (dd, J ) 110, 9.0 Hz, 4H), 5.50
(s, 2H), 3.72 (s, 3H); 13C NMR (DMSO-d6, 125 MHz) δ 182.5,
158.3, 140.7, 137.5, 134.4, 128.7, 128.2, 127.8, 127.0, 126.3,
124.9, 114.9, 57.6, 55.2; MS+(APCI) 348.96 [M + H]+; RT )
10.84.
1-Benzyl-1-(4-chloro-phenyl)-3-phenylthiourea (8b):
85%, 1H NMR (CDCl3, 500 MHz) δ 7.38-7.27 (m, 10H), 7.22-
7.19 (m, 1H), 7.06 (dd, J ) 8.5, 2.0 Hz, 1H), 6.95 (bs, 1H), 5.55
(s, 2H); 13C NMR (DMSO-d6, 125 MHz) δ 181.9, 139.2, 138.9,
136.7, 134.9, 130.7, 129.4, 128.6, 128.4, 127.6, 126.2, 125.8,
58.1; MS+(APCI) 352.98 [M + H]+.
1-Benzyl-3-(4-methoxy-phenyl)-1-phenylthiourea (9):
77%, beige solid: mp 141-142 °C; 1H NMR (DMSO-d6, 400
MHz) δ 8.70 (s, 1H), 7.36-7.13 (m, 12H), 6.82 (d, J ) 9 Hz,
2H), 5.49 (s, 2H), 3.69 (s, 3H); MS+(APCI) 348.86 [M + H]+;
RT ) 10.60.
Acknowledgment. We thank Drs. Daniel C. Toste-
son and Magdalena Tosteson for their continuous
encouragement and support. This work was supported
in part by NIH Grant NCDDG 5 U19 CA87427.
Supporting Information Available: General procedures
1
for synthesis, H NMR of 3a, 3c, 4a, 4b, 4c, 4k, 6c, 6d, 7d,
and 6f, 13C NMR of 3a, 4a, 4b, 4k, 6c, 7d, and 6f, LC-MS of
3c, 4c, 6d-7d regioisomeric mixture and 6e-7e regioisomeric
mixture, and NOESY and TOCSY of 6c, 6f, and 6g. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Benzyl-(4-methoxy-phenyl)-(4-phenyl-4H-[1,2,4]triazol-
1
3-yl)-amine (10a): 20%, colorless solid; H NMR (DMSO-d6,
400 MHz) δ 8.57 (s, 1H), 7.38 (d, J ) 7.2 Hz, 2H), 7.32-7.18
(m, 9H), 6.60 (dd, J ) 27.0, 9.0 Hz, 4H), 4.84 (s, 2H), 3.55 (s,
3H); MS+(APCI) 357.03 [M + H]+; RT ) 8.86.
JO0508189
6368 J. Org. Chem., Vol. 70, No. 16, 2005