Negishi Approach to 1,5-Disubstituted 3-Amino-1H-1,2,4-triazoles

Article abstract of DOI:10.1021/acs.orglett.5b02021

An efficient synthesis of 1,5-disubstituted 3-amino-1H-1,2,4-triazoles has been achieved via a Negishi coupling of aryl or vinyl bromides and 1-substituted 3-amino-1H-1,2,4-triazoles in the presence of Knochel's base tetramethylpiperidinylzinc chloride li

Full text of DOI:10.1021/acs.orglett.5b02021

Letter
pubs.acs.org/OrgLett
Negishi Approach to 1,5-Disubstituted 3‑Amino‑1H‑1,2,4-triazoles
Jeff Shen,† Brian Wong,† Chunang Gu,‡ and Haiming Zhang*,†
‡
†Small Molecule Process Chemistry and Small Molecule Analytical Chemistry, Genentech, Inc., 1 DNA Way, South San Francisco,
California 94080, United States
S
* Supporting Information
ABSTRACT: An efficient synthesis of 1,5-disubstituted 3-amino-
1H-1,2,4-triazoles has been achieved via a Negishi coupling of aryl
or vinyl bromides and 1-substituted 3-amino-1H-1,2,4-triazoles in
the presence of Knochel’s base tetramethylpiperidinylzinc chloride
lithium chloride (TMPZnCl·LiCl) and catalytic bis(di-tert-butyl-
phenylphosphine)palladium chloride. This chemistry tolerates a
variety of electronically diverse aryl or vinyl bromides and 1-substituted 3-amino-1H-1,2,4-triazoles.
3-Amino-1H-1,2,4-triazoles have been paid much attention by
the agrochemical and medicinal communities because of their
interesting and diverse biological activities. They have been
studied for potential treatment for asthma,1 Alzheimer’s disease,
and Down syndrome.2 3-Amino-1H-1,2,4-triazoles have also
been reported to function as inhibitors for methionine
aminopeptidase-23 and neuropeptide Y receptor4 as well as
catalase5 and histidine biosynthesis6 and act as histamine H2-
receptor7 and CRF1 receptor antagonists.8
We recently reported a highly efficient synthesis of 1-
substituted 3-amino-1H-1,2,4-triazoles from ethyl N-(5-phenyl-
1,2,4-oxadiazol-3-yl)formimidate and anilines or amines.12
A
wide range of benzoyl-protected 1-substituted 3-aminotriazoles
have thus been prepared in good to excellent yields (eq 1).
Various synthetic methods have been developed for 3-amino-
1H-1,2,4-triazoles in the literature.9 The conventional strategies
for the synthesis of 1,5-disubstituted 3-amino-1H-1,2,4-triazoles
usually involve the formation of the aminotriazole core by
employing a strategically functionalized electrophile with a
nitrogen containing nucleophile, for example, N-acylguanidine or
N-acyl carbamimidothioate with hydrazines10 or 1,3,4-oxadiazo-
lium salt with cyanamide (Scheme 1).1a,11 While a number of 1,5-
Inspired by the recent work of Knochel and co-workers,13 we
envisioned that the 5-position of these 3-amino-1H-1,2,4-
triazoles could be metalated by tetramethylpiperidinylzinc
chloride lithium chloride (TMPZnCl·LiCl, TMP = 2,2,6,6-
tetramethylpiperidide) under mild conditions and the resulting
zinc species could undergo Negishi coupling14 with aryl or vinyl
bromides in the presence of a palladium catalyst to generate 1,5-
disubstituted 3-amino-1H-1,2,4-triazoles.
Scheme 1. Synthetic Strategies to 1,5-Disubstituted 3-Amino-
1H-1,2,4-triazoles
Our investigation commenced with the metalation of
representative 3-aminotriazole 1a using commercially available
TMPZnCl·LiCl (2.2 equiv). The resulting homogeneous
solution with organozinc species was then quenched with
1
deuterium oxide (D2O) and H NMR analysis of the crude
products indicated the formation of deuterio-1a with >95% D-
incorporation at the 5-position (eq 2). However, only ca. 50% D-
incorporation was observed when LDA was employed.
A Negishi cross-coupling reaction of the organozinc species
derived from 1a with 1.1 equiv of bromobenzene (2a) proceeded
smoothly under mild conditions with 5 mol % of PdCl2(PPh3)2
as catalyst in THF at 65 °C, which generated 99% conversion and
disubstituted 3-amino-1H-1,2,4-triazoles have been synthesized
by these methods, they suffered from either long synthesis or low
yields or very limited scope. Therefore, a more efficient
alternative is still highly desirable. Our own interest in this
class of heterocycles prompted us to develop a practical synthesis
of a wide variety of 1,5-disubstituted 3-amino-1H-1,2,4-triazoles
via a cross-coupling strategy (Scheme 1).
Received: July 14, 2015
© XXXX American Chemical Society
A
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97% assay yield in 24 h (Table 1, entry 1). Screening of the
palladium catalysts including PdCl2(dppf) (dppf = 1,1′-
Table 2. Negishi Coupling of Aminotriazoles 1 with
Bromobenzene (2a)
a
a
Table 1. Optimization of Negishi Coupling
b
c
entry
catalyst
mol % time (h) conv (%) yield (%)
1
2
PdCl2(PPh3)2
PdCl2(dppf)
5
24
20
24
24
24
3
99
99
71
69
17
99
59
99
99
49
97
96
5
3
PdCl2(PCy3)3
PdCl2(TFP)2
5
4
5
5
PdCl2(PCl-t-Bu2)2
PdCl2(Amphos)2
PEPPSI-i-Pr
5
6
5
100
7
5
24
2
8
PdCl2(PPh-t-Bu2)2
5
99
d
9
2.5
1
4
99 (94)
10
24
a
Reaction conditions: 1a (0.26 g, 1.0 mmol), Pd catalyst (1−5 mol %),
2a (115 μL, 1.1 equiv), TMPZnCl·LiCl (0.65 M in THF, 3.4 mL, 2.2
b
equiv) in THF (1.0 mL), 65 °C. Determined by HPLC analysis.
c
d
Assay yields were obtained by quantitative HPLC analysis. Isolated
yield.
bis(diphenylphosphino)ferrocene), PdCl2(PCy3)2 (PCy3
=
tricyclohexylphosphine), PdCl2(TFP)2 (TFP = trifurylphos-
phine),15 PdCl2(PCl-t-Bu2)2 (PXPd),16 PdCl2(Amphos)2 (Am-
phos =4-(di-tert-butylphosphino)-N,N-dimethylaniline),17 PEP-
PSI-i-Pr,18 and PdCl2(PPh-t-Bu2)2,17 showed that PdCl2(PPh-t-
Bu2)2 was the best catalyst which afforded 99% conversion and
99% assay yield in only 2 h (Table 1, entries 2−8). Further fine-
tuning the catalyst loading led to the optimal conditions which
employed 2.5 mol % of PdCl2(PPh-t-Bu2)2 as the catalyst in THF
at 65 °C (Table 1, entries 9). Under this set of reaction
conditions, the Negishi coupling using aminotriazole 1a and
bromobenzene (2a) afforded 99% assay yield and 94% isolated
yield in 4 h. It is worth noting that the Negishi coupling reaction
involving aminotriazoles and aryl or vinyl bromides was highly
substrate sensitive as we observed later on during our
investigation of the reaction scope and limitation. Therefore, 5
mol % catalyst loading was also frequently employed in order to
obtain high reaction conversion and satisfactory yield.
With a set of optimal conditions available, we then set out to
investigate the scope and limitations of this Negishi coupling
reaction. As shown in Table 2, a variety of 1-substituted 3-
aminotriazoles underwent the Negishi coupling with bromo-
benzene (2a), smoothly generating the desired 1,5-disubstituted
3-amino-1H-1,2,4-triazoles.19 Aminotriazoles substituted with an
electron-neutral or electron-rich aryl group at the N1-position all
produced good to excellent yields of the desired products in the
presence of 2.5 mol % of catalyst (Table 2, entries 1−4).
Electron-deficient substrates, for example, cyano-, fluoro-, or
ester-substituted aminotriazoles 1e−g, afforded the desired
Negishi products 3e−g in satisfactory yields, albeit requiring 5
mol % catalyst (Table 2, entries 5−7). Unfortunately, only 15%
conversion was observed over 24 h when pyridine-substituted
aminotriazole 1h was subjected to the Negishi coupling
conditions. The low conversion was likely caused by the low
solubility of 1h in THF as a slurry was observed throughout the
reaction. In fact, when polar NMP was used as the reaction
a
Reaction conditions: 1 (1.0 mmol), PdCl2(PPh-t-Bu2)2 (15.5 mg, 2.5
mol %), 2a (115 μL, 1.1 equiv), TMPZnCl·LiCl (0.65 M in THF, 3.4
b
c
mL, 2.2 equiv) in THF (1.0 mL), 65 °C. Isolated yield. PdCl2(PPh-t-
Bu2)2 (31 mg, 5 mol %) was employed. NMP (2.0 mL) was used
instead of THF (1.0 mL).
d
solvent, a homogeneous solution was obtained and aminotriazole
1h readily afforded 71% yield of the desired product 3h in 2 h
(Table 2, entry 8). To our delight, cyclohexyl- and benzyl-
substituted aminotriazoles 1i and 1j successfully generated the
desired Negishi coupling products in 81% and 69% yields,
respectively (Table 2, entries 9 and 10). The sterically hindered
aminotriazole 1k, however, did not afford any detectable product
(Table 2, entry 11). As a control experiment, aminotriazole 1k
B
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was treated with 2.2 equiv of TMPZnCl·LiCl and then quenched
Table 3. Negishi Coupling of Aminotriazoles 1a with Aryl or
Vinyl Bromide (2)
1
a
with D2O. H NMR analysis showed >95% D-incorporation at
the 5-position of aminotriazole 1k, which indicates that the zinc
species was formed readily in the reaction but could not undergo
transmetalation with PhPdBr due to the steric bulkiness of the
mesityl group.
We also examined the Negishi coupling by employing 1-
phenyl-substituted aminotriazole 1a and various aryl or vinyl
bromides (Table 3). In most cases, 5 mol % catalyst loading is
necessary to achieve high reaction conversion and yield. As
shown in Table 3, the Negishi coupling of aminotriazole 1a with
electron-rich 4-bromotoluene (2b) and 4-bromoanisole (2c)
proceeded uneventfully, generating the desired aminotriazole 3l
and 3m in 90% and 86% yield (Table 3, entries 1 and 2).
Electron-deficient aryl bromides such as 4-bromobenzotrifluor-
ide (2d) and ethyl 4-bromobenzoate (2e) also underwent the
Negishi coupling smoothly and produced aminotriazoles 3n and
3o in 83% and 85% yield, respectively (Table 3, entries 3−4).
The reaction using 3-bromopyridine (2f) required 10 mol %
catalyst to reach full conversion in 24 h and afforded the desired
aminotriazole 3p in 80% yield (Table 3, entry 5). Unfortunately,
mesityl bromide (2g) did not generate any detectable product 3q
even with 10 mol % catalyst loading, which can be attributed to its
significant steric hindrance (Table 3, entry 6). However, when
less sterically hindered 2-bromotoluene (2h) was subjected to
the Negishi coupling, the desired coupling product 3r was
isolated in 67% yield, which attests that the steric effect has a
profound impact on the Negishi reaction (Table 3, entry 7).
Gratifyingly, vinyl bromides, such as bromomethylenecyclohex-
ane (2i) and β-bromostyrene (2j) successfully afforded excellent
90% and 95% yield of the desired 1,5-disubstituted amino-
triazoles 3s and 3t (Table 3, entries 8 and 9). To our excitement,
4-bromo-N-methylbenzamide (2k), a secondary amide contain-
ing a relatively acidic proton, also underwent the Negishi
coupling smoothly, producing the desired product 3u in 91%
yield, albeit in need of 3.3 equiv of TMPZnCl·LiCl to fully
deprotonate all three acid protons in both reactants 1a and 2k
(Table 3, entry 10).
The benzoyl group on the 3-position amino group can be
readily removed in the presence of an acid. For example, 3-
aminotriazole 3a was treated with 5 equiv of 6 M aqueous sulfuric
acid in MeTHF at 80 °C, successfully producing the deprotected
3-aminotriazole 4 in 75% yield (eq 3). Therefore, one can
envision that a wide spectrum of 1,5-disubstituted 3-amino-1H-
1,2,4-triazoles with the amino group free of substitution can be
achieved in only two steps from aminotriazoles 1 and aryl or vinyl
bromides 2.
Finally, as demonstrated in eq 4, this process is preparatively
useful as the desired Negishi coupling product 3a was isolated in
93% yield on a 5 g (19 mmol) scale.
a
Reaction conditions: 1a (0.26 g, 1.0 mmol), PdCl2(PPh-t-Bu2)2 (31
mg, 5 mol %), 2 (1.1 equiv), TMPZnCl·LiCl (0.65 M in THF, 3.4 mL,
b
c
2.2 equiv) in THF (1.0 mL), 65 °C. Isolated yield. PdCl2(PPh-t-
d
Bu2)2 (15.5 mg, 2.5 mol %) was employed. PdCl2(PPh-t-Bu2)2 (62
mg, 10 mol %) was employed. TMPZnCl·LiCl (0.65 M in THF, 5.1
e
mL, 3.3 equiv) was employed.
In summary, we have developed an efficient protocol for the
synthesis of 1,5-disubstituted 3-amino-1H-1,2,4-triazoles via a
C
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Weinheim, 2004; pp 815−889. (b) Negishi, E.-i. Angew. Chem., Int. Ed.
2011, 50, 6738−6764.
palladium-catalyzed Negishi coupling using in situ generated
organozinc intermediates in the presence of a base, TMPZnCl·
LiCl. We anticipate that this practical method will provide rapid
access to useful quantities of versatile 1,5-disubstituted 3-amino-
1H-1,2,4-triazoles.
(15) Zeng, X.; Hu, Q.; Qian, M.; Negishi, E.-i J. Am. Chem. Soc. 2003,
125, 13636−13637.
(16) Li, G. Y. Angew. Chem., Int. Ed. 2001, 40, 1513−1516.
(17) Guram, A. S.; King, A. O.; Allen, J. G.; Wang, X.; Schenkel, L. B.;
Chan, J.; Bunel, E. E.; Faul, M. M.; Larsen, R. D.; Martinelli, M. J.;
Reider, P. J. Org. Lett. 2006, 8, 1787−1789.
(18) PEPPSI-iPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene]
(3-chloropyridyl)palladium dichloride. For its application in Negishi
coupling, see: Valente, C.; Belowich, M. E.; Hadei, N.; Organ, M. G. Eur.
J. Org. Chem. 2010, 23, 4343−4354.
(19) Under optimal conditions, the reaction of 1a and chlorobenzene
only gave 13% conversion in 24 h.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02021.
General experimental procedures, characterization of new
compounds, and copies of 1H NMR and 13C NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: zhang.haiming@gene.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We authors thank Drs. Chong Han, Francis Gosselin, and
Sushant Malhotra (Genentech, Inc.) for helpful discussions.
■
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