A convenient synthesis of highly substituted 3-N,N-dialkylamino-1,2,4- triazoles

Article abstract of DOI:10.1055/s-2008-1078208

The title compounds are prepared from S-methylisothioureas and acyl hydrazides in moderate to good yields. The reaction is characterized by relatively mild conditions and very broad functional group tolerance. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078208

LETTER
2421
A Convenient Synthesis of Highly Substituted 3-N,N-Dialkylamino-1,2,4-
triazoles
S
ynthesis of
H
ighl
a
y Substitute
v
d 3-
N
,
N
-Dia
i
lkylam
d
ino-1,2,4-triazole
s
V. Batchelor, David M. Beal, T. Bruce Brown, David Ellis, David W. Gordon, Patrick S. Johnson,
Helen J. Mason, Michael J. Ralph, Toby J. Underwood, Simon Wheeler*
Sandwich Chemistry, Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent, CT13 9NJ, UK
Fax +44(1304)651987; E-mail: simon.wheeler@pfizer.com
Received 1 May 2008
In the thirty years since this reaction was disclosed its
scope has become clearer. The reaction works quickly and
well under neutral conditions when R1–R3 are small,11
however, when R1–R3 are large, neutral conditions require
prolonged reaction times and high temperatures.12 We
therefore postulated that the catalytic PTSA employed by
Maffrand must have an important role as he was able to
cyclise substrates where R3 = phenyl.13 Our experimenta-
tion supported this hypothesis: we found that when
R3 = aryl multiple equivalents of acyl hydrazine were of-
ten needed along with prolonged heating at reflux in n-bu-
tanol. We therefore desired to identify conditions for the
cyclisation of challenging substrates, which would also be
able to tolerate a broad range of functional groups, partic-
ularly those amenable to further manipulation. We also
wished these conditions to be milder than those used by
Maffrand (refluxing pyridine for 40 h).
Abstract: The title compounds are prepared from S-methylisothio-
ureas and acyl hydrazides in moderate to good yields. The reaction
is characterized by relatively mild conditions and very broad func-
tional group tolerance.
Key words: heterocycles, cyclisations, sulfur, medicinal chemis-
try, drugs
A diverse body of methods is available to the synthetic
chemist wishing to prepare 3-N,N-dialkylamino-1,2,4-tri-
azoles. Apart from specific methods based on dipolar ni-
trile imines1 and dichlorodiazabutadienes,2 a variety of
general strategies are available. The first of these, dis-
placement of a halo or thio derivative from an existing tri-
azole ring,3 often suffers from the need to use multiple
equivalents of amine, high temperatures, and prolonged
reaction times.4 The second strategy, cyclisation of an
amidrazone,5 requires the preparation of a Viehe salt, a
procedure needing multiple steps and often harsh reagents
incompatible with certain functional groups.6 A third pos-
sibility is the condensation of an amino-guanidine with a
carboxylic acid7 (requiring reflux in the neat acid) or cor-
responding acid chloride.8 The advantages of using the
acid chloride should be qualified by the low yields some-
times experienced with this technique.9 The synthetic
strategy most commonly employed for the preparation of
the molecules under discussion was introduced by
Maffrand and co-workers10 and involves the condensation
of an S-methylisothiourea with an acyl hydrazine
(Scheme 1).
For the successful realisation of this ambitious synthetic
goal, a robust flexible synthesis of the starting S-methyl-
isothiourea was required. We have used the method
shown in Scheme 2.
Thus di-2-pyridyl-thiocarbonate14 was treated sequential-
ly with the primary amine bearing the R3 residue followed
by the secondary amine corresponding to the desired N,N-
dialkylamino side chain. The thioureas accessed in this
way could be converted into the S-methylisothioureas by
treatment with potassium tert-butoxide and methyl
tosylate.15 Alternatively, the thioureas could be prepared
in one step from an isothiocyanate of the R3 group where
that was commercially available.16 Either of these meth-
SMe
N
R3
O
a
S
S
R1
NH2
R3
H2N
+
R4
+
N
R2
N
H
N
O
NH
R3
N
O
O
N
R1
NH
R2
b
N
N
R1
N
R4
N
R3
R2
SMe
S
R1
c
R1
Scheme 1
N
N
N
NH
R3
R2
R3
R2
SYNLETT 2008, No. 16, pp 2421–2424
Advanced online publication: 22.08.2008
DOI: 10.1055/s-2008-1078208; Art ID: D14308ST
x
x
.x
x
.2
0
0
8
Scheme 2 Reagents and conditions: a) CH2Cl2, r.t.; b) CH2Cl2, r.t.;
c) KOt-Bu, MeOTs, THF, r.t. All steps typically 90–100%.
© Georg Thieme Verlag Stuttgart · New York

2422
D. V. Batchelor et al.
LETTER
ods required, at the very most, a slight excess of each reaction – this promotes the transformation so that it can
amine component.
now be performed in refluxing THF. Less acidic condi-
tions were also identified: an excess of AcOH also allows
the reaction to be performed in refluxing THF. A repre-
sentative range of examples is shown in Table 1.
We then identified two sets of conditions capable of pro-
ducing the desired aminotriazoles. Our preferred condi-
tions involved adding 0.5 equivalents of TFA to the
Table 1 Synthesis of Aminotriazoles
Acyl hydrazide
Isothiourea
Conditionsa
Reaction Yield Product
time (h) (%)b
N
N
SMe
N
NHBoc
N
O
N
N
F
HO
F
HO
H2N
NHBoc
A
B
4
6
46
52
N
H
1a
F
F
2a
3a
N
N
SMe
N
O
O
N
N
N
BocN
H2N
BocN
N
H
1b
Ph
Ph
N
2b
3b
F
SMe
N
H2N
N
N
H
N
N
F
N
A
16
33
F
HO
OH
N
Boc
N
F
Boc
2c
1c
3c
SMe
N
N
N
N
NC
N
N
O
O
O
NC
H2N
B
4
53
N
H
N
N
1b
OMe
N
OMe
3d
2d
N
SMe
N
N
N
N
O
O
H2N
B
3
57
N
H
O
O
N
N
1b
OMe
OMe
2e
3e
F
SMe
N
N
F
OMe
N
N
N
N
O
H2N
O
B
1.5
67
Cl
N
H
Cl
OMe
N
N
1d
OMe
OMe
2f
3f
Synlett 2008, No. 16, 2421–2424 © Thieme Stuttgart · New York

LETTER
Synthesis of Highly Substituted 3-N,N-Dialkylamino-1,2,4-triazoles
2423
Table 1 Synthesis of Aminotriazoles (continued)
Acyl hydrazide
Isothiourea
Conditionsa
Reaction Yield Product
time (h) (%)b
SMe
N
N
N
O
N
N
N
H2N
N
O
H
N
O
B
4
68
72
61c
O
N
N
N
N
N
O
Cl
Cl
1e
3g
2g
N
N
SMe
N
N
N
O
O
N
O
N
N
N
N
H2N
HN
N
H
HN
A
16
N
N
Cl
N
Cl
N
1f
2h
3h
SMe
N
N
N
NHBoc
N
O
H2N
NHBoc
B
22
OTBDMS
OTBDMS
N
H
1a
Cl
Cl
2i
3i
a Conditions A: hydrazide (2.1 equiv), THF–AcOH (10:1), reflux. Conditions B: hydrazide (1–2 equiv), TFA (0.5 equiv), reflux.
b Yields refer to isolated pure material.
c Yield could be improved to 89% overall (34% product and 55% of the desilyated product) by using 1 equiv of TFA.
As will be readily seen from Table 1, this reaction is tol- tecting groups, and which allow the rapid assembly of mo-
erant of a broad range of functional groups including ni- lecular complexity from simple starting materials. These
triles (compound 3d) and amides (compound 3h). Tertiary conditions give reasonable yields and are scalable to gram
alcohols (compounds 3a and 3c) also survive the reaction quantities. We expect these improved conditions will fur-
unscathed although primary alcohols cause the yields to ther popularise the use of this aminotriazole motif in drug
reduce significantly (examples not shown). Sensitive discovery.
alkoxy-substituted heterocycles are also immune to the re-
action conditions (compounds 3d–g). Perhaps more sig-
Representative Experimental Procedures
nificantly, various protecting groups can also be carried in
this reaction, including Boc (compounds 3a–c,i), ketal
(compound 3e), and TBDMS (compound 3i). We were
unable to prepare any of compound 3i under neutral con-
ditions even with prolonged heating, demonstrating that
the acid-mediated conditions reported herein cope re-
markably well with severe steric encumbrance. This is
also shown in the fact that a variety of R3 substituents
could be tolerated (n-alkyl in compounds 3a,b; cycloalkyl
in compound 3c and aryl in compounds 3d–i) in contrast
to the neutral conditions.12 It is possible to reduce the
amount of acid used in the reaction (e.g., to add only 0.25
equiv of TFA) but not without significantly extending the
reaction time. The reaction has been performed on scales
up to 4 g, for the preparation of compound 3e amongst
others, indicating its suitability for larger-scale synthesis.
Method A
To a stirred solution of S-methylisothiourea 2a (1 g, 2.5 mmol) in
THF–AcOH (10:1, 11 mL) was added acyl hydrazine 1a (1 g, 5.2
mmol) and the whole was heated at 60 °C until TLC showed all
starting material had been consumed (4 h). The reaction was then
cooled and solvent was removed in vacuo. The residue was purified
by column chromatography on SiO2 eluting with 0–5% MeOH in
CH2Cl2. Appropriate fractions were combined and evaporated to
give triazole 3a as a foam (606 mg, 1.15 mmol, 46%).
1H NMR (400 MHz, CDCl3): d = 0.52 (6 H, d, J = 7 Hz), 1.39 (9 H,
s), 2.28 (2 H, m), 3.00 (2 H, dd, J = 12, 4 Hz), 3.19 (2 H, t, J = 12
Hz), 4.39 (2 H, d, J = 6 Hz), 5.19 (2 H, s), 5.33 (1 H, br s), 6.84–
6.93 (4 H, m), ca. 7.24 (1 H, m, obscured by CHCl3 signal), 7.32–
7.37 (3 H, m).
ESI-MS: m/z = 528 [M + 1]+.
Method B
To a stirred solution of S-methylisothiourea 2i (300 mg, 0.6 mmol,
1 equiv) in THF (5 mL) was added acyl hydrazine 1a (140 mg, 0.74
mmol, 1.5 equiv). Then, TFA was added (15 mL, 0.4 mmol, 0.4
equiv) and the whole was heated at reflux for 22 h. The mixture was
In conclusion, we have demonstrated refined conditions
for the synthesis of 3-N,N-dialkylamino-1,2,4-triazoles
which are tolerant of a wide range of functional and pro-
Synlett 2008, No. 16, 2421–2424 © Thieme Stuttgart · New York

2424
D. V. Batchelor et al.
LETTER
cooled, diluted with EtOAc, washed with dil. NH3 (aq) then with
brine, dried over MgSO4, and evaporated to a yellow oil. This was
purified by column chromatography on SiO2 eluting with EtOAc
then with 5% MeOH–CH2Cl2. Appropriate fractions were com-
bined, evaporated, dissolved in Et2O, and evaporated again to yield
triazole 3i as a white foam (229 mg, 0.37 mmol, 61%).
1H NMR (400 MHz, CDCl3): d = 0.07 (3 H, s), 0.08 (3 H, s), 0.88
(9 H, s), 1.36 (9 H, s), 1.53–1.68 (2 H, m), 1.71 (1 H, br d, J = 13
Hz), 1.88 (1 H, br d, J = 13 Hz), 2.60 (1 H, tt, J = 12, 3 Hz), 2.84 (1
H, td, J = 12, 3 Hz), 3.08 (1 H, td, J = 12, 3 Hz), 3.34 (1 H, br d,
J = 13 Hz), 3.57 (1 H, br d, J = 13 Hz), 4.12 (2 H, d, J = 5 Hz), 4.37
(1 H, d, J = 14 Hz), 4.62 (1 H, d, J = 14 Hz), 5.15 (1 H, br s), 7.13–
7.19 (4 H, m), 7.21 (1 H, d, J = 7 Hz), 7.29 (1 H, d, J = 8 Hz), 7.40
(1 H, dd, J = 8, 2 Hz), 7.67 (1 H, d, J = 2 Hz).
(6) See, for example, the use of PCl5 reported in: Vilkas, M.;
Qasmi, D. Synth. Commun. 1990, 20, 2769.
(7) Kröger, C.-F.; Schoknecht, G.; Beyer, H. Chem. Ber. 1964,
97, 396.
(8) Akerblom, A. Acta Chem. Scand. 1965, 19, 1135.
(9) Edwards, L.; Isaac, M.; Johansson, M.; Kers, A.; Malmberg,
J.; McLeod, D.; Mindis, A.; Staff, K.; Slassi, A.; Stefanac,
T.; Stormann, T.; Wensbo, D.; Xin, T.; Arora, J. US
0272779, 2005; Chem. Abstr. 2005, 144, 36353.
(10) Maffrand, J.-P.; Pereillo, J.-M.; Eloy, F.; Aubert, D.;
Rolland, F.; Barthélémy, G. Eur. J. Med. Chem. 1978, 469.
(11) (a) Sitarz, M.; Foks, H.; Janowiec, M.; Augustynowicz-
Kopec, E. Chem. Heterocycl. Compd. 2005, 41, 200.
(b) Cardoza, M. G.; Powers, J. P.; Goto, H.; Harada, K.;
Imamura, K.; Kakutani, M.; Matsuda, I.; Ohe, Y.; Yata, S.
WO 044192, 2005; Chem. Abstr. 2005, 142, 482046.
(12) For example, see: Wallberg, A.; Nilsson, K.; Holm, B.;
Nagard, M.; Granberg, K.; Slassi, A.; Edwards, L.; Isaac,
M.; Xin, T.; Stefanac, T. US 0259862, 2007; Chem. Abstr.
2007, 147, 522250.
(13) Support was leant to this conclusion by the observation that
an analogous preparation of triazolones (R3 = aryl or
cyclohexyl) did not proceed in the absence of acid. See:
Dupin, S.; Pesson, M. Bull. Soc. Chim. Fr. 1963, 144.
(14) This material is commercially available from Alfa Aesar. Its
use in the synthesis of thioureas is demonstrated in: Kim, S.;
Yi, K. Y. Tetrahedron Lett. 1985, 26, 1661.
ESI-MS: m/z = 634 [M + 23]+.
References and Notes
(1) Boyd, G. V.; Cobb, J.; Lindley, P. F.; Mitchell, J. C.;
Nicolaou, G. A. J. Chem. Soc., Chem. Commun. 1987, 99.
(2) O’Halloran, J. K.; Scott, F. L. J. Chem. Soc., Perkin Trans. 1
1972, 2219.
(3) For a kinetic study, see: Maury, G.; Souad, F.-T.; Arriau, J.;
Sauvaitre, H.; Benardini, A. J. Heterocycl. Chem. 1977, 14,
1311.
(4) (a) Barascut, J.-L.; Viallefont, P.; Daunis, J. Bull. Soc. Chim.
Fr. 1975, 1649. (b) Wang, T.; Kadow, J. F.; Zhang, Z.; Yin,
Z.; Meanwell, N. A.; Regueiro-Ren, A.; Swidorski, J.; Han,
Y.; Carini, D. J. US 0249579, 2007; Chem. Abstr. 2007, 147,
502389.
(5) (a) Zhang, Q.; Keenan, S. M.; Peng, Y.; Nair, A. C.; Yu,
S. J.; Howells, R. D.; Welsh, W. J. J. Med. Chem. 2006, 49,
4044. (b) Zhang, Q.; Peng, Y.; Welsh, W. J. Heterocycles
2006, 68, 2635.
(15) This avoided the use of the carcinogenic MeI and gave the S-
methylisothiourea as the free base rather than the HI salt
thereby allowing for simpler assessment of the role of acid
in the cyclisation reaction.
(16) For a representative example, see: Moore, M. L.; Crossley,
F. S. Org. Synth., Coll. Vol. III; John Wiley and Sons:
London, 1955, 599.
Synlett 2008, No. 16, 2421–2424 © Thieme Stuttgart · New York