Palladium-catalyzed chemoselective monoarylation of hydrazides for the synthesis of [1,2,4]Triazolo[4,3-a]pyridines

Article abstract of DOI:10.1021/ol902868q

(Chemical Equation Presented) An efficient and convenient method for the synthesis of [1,2,4]triazolo[4,3-a]pyridines was exemplified by the synthesis of 20 analogues bearing a variety of substituents at the 3-position. The methodology involves a palladiu

Full text of DOI:10.1021/ol902868q

ORGANIC
LETTERS
2010
Vol. 12, No. 4
792-795
Palladium-Catalyzed Chemoselective
Monoarylation of Hydrazides for the
Synthesis of
[1,2,4]Triazolo[4,3-a]pyridines
Andreas Reichelt,*,† James R. Falsey,† Robert M. Rzasa,† Oliver R. Thiel,‡
Michal M. Achmatowicz,‡ Robert D. Larsen,‡ and Dawei Zhang†
Departments of Medicinal Chemistry and Chemical Process Research & DeVelopment,
Amgen, Inc., One Amgen Center DriVe, Thousand Oaks, California 91320-1799
andreas.reichelt@amgen.com
Received December 11, 2009
ABSTRACT
An efficient and convenient method for the synthesis of [1,2,4]triazolo[4,3-a]pyridines was exemplified by the synthesis of 20 analogues
bearing a variety of substituents at the 3-position. The methodology involves a palladium-catalyzed addition of hydrazides to 2-chloropyridine,
which occurs chemoselectively at the terminal nitrogen atom of the hydrazide, followed by dehydration in acetic acid under microwave irradiation.
Triazolopyridines represent an important class of heteroaro-
matic compounds. The [1,2,4]triazolo[4,3-a] pyridine moiety
Scheme 1. General Synthesis of [1,2,4]Triazolo[4,3-a]pyridines
can be found in a variety of biologically active compounds,
including antibacterial, antithrombotic, antiinflammatory,
antiproliferative, and herbicidal agents.1 Besides the oxidative
cyclization of 2-pyridylhydrazones, the addition of hydrazine
to pyridines bearing a leaving group in the 2-position
followed by acylation and dehydration under a variety of
conditions is the most commonly used method for the
synthesis of [1,2,4]triazolo[4,3-a]pyridines (Scheme 1).2
In the course of our studies, we became interested in a
general and convenient method for the synthesis of 3-sub-
stituted [1,2,4]triazolo[4,3-a]pyridines with a chemical handle
at the 7-position suited for further elaboration. Although
4-bromo-2-fluoropyridine or 4-bromo-2-chloropyridine would
be suitable starting materials, these compounds are relatively
expensive. We envisioned that addition of hydrazides to a
more economical starting material, 2,4-chloropyridine, fol-
lowed by dehydration would provide a concise route to
3-substituted 7-chloro[1,2,4]triazolo[4,3-a]pyridines. How-
ever, it is documented that under thermal conditions nitrogen
nucleophiles including hydrazine add selectively to the
4-position of the pyridine.3
† Department of Medicinal Chemistry.
‡ Department of Chemical Process Research & Development.
(1) For example, see: (a) Yoshimura, Y.; Tomimatsu, K.; Nishimura,
T.; Miyake, A.; Hashimoto, N. J. Antibiot. 1992, 45, 721. (b) Sadana, A. K.;
Mirza, Y.; Aneja, K. R.; Prakash, O. Eur. J. Med. Chem. 2003, 38, 533. (c)
Lawson, E. C.; Hoekstra, W. J.; Addo, M. F.; Andrade-Gordon, P.; Damiano,
B. P.; Kauffman, J. A.; Mitchell, J. A.; Maryanoff, B. E. Bioorg. Med.
Chem. Lett. 2001, 11, 2619. (d) Kalgutkar, A. S.; Hatch, H. L.; Kosea, F.;
Nguyen, H. T.; Choo, E. F.; McClure, K. F.; Taylor, T. J.; Henne, K. R.;
Kuperman, A. V.; Dombroski, M. A.; Letavic, M. A. Biopharm. Drug
Dispos. 2006, 27, 371. (e) Luethy, C.; Hall, R. G.; Edmunds, A.; Riley, S.;
Diggelmann, M. PCT Int. Appl. WO08006540, 2008. (f) Abel, U.; Deppe,
H.; Feurer, A.; Gra¨dler, U.; Ott, I.; Matassa, V. G. PCT Int. Appl.
WO06058752, 2006.
10.1021/ol902868q  2010 American Chemical Society
Published on Web 01/25/2010

We decided to investigate the use of a transition metal
catalyst to alter the selectivity in reactions of 2,4-dichloro-
pyrdine with hydrazine derivatives (Scheme 2). A report by
Abad et al. describing the regioselective palladium-catalyzed
addition of ureas to 2,4-dichloropyridine at the 2-position
suggested that the desired selectivity could be obtained.4 A
survey of the literature revealed that transition-metal-
catalyzed additions of acylhydrazines to aromatic and hetero-
aromatic systems were indeed documented; in particular, tert-
butylcarbazate (BocHNNH2) is often used as the nucleophile.
However, under palladium or copper catalysis the acylhy-
drazines react preferentially at the internal amide nitrogen
atom rather than the terminal amine nitrogen atom.5-7 This
selectivity can be altered to the terminal nitrogen by
introduction of sterically demanding groups on the
electrophile.5a,6b Only one example is documented, in which
the terminal nitrogen of benzoic hydrazide adds to a sterically
unbiased aryliodide under copper catalysis.6a Therefore, at
the outset of our studies, it was unclear if selectivity at the
nucleophilic and electrophilic partner could be achieved
(Scheme 2).
X-Phos, S-Phos, Q-Phos, DPPF, DtBPF, 2 mol % each).9
Complete conversion was observed only in the reaction
employing Josiphos 3 as the ligand, whereas all other catalyst
systems led to incomplete conversion (<60%) of 2-chloro-
pyridine to the monocoupled product 4a.10,11 The corre-
sponding reaction in the absence of catalyst and ligand
resulted in low conversion to the monoarylated product 4a
(entry 1).
Table 1. Reaction Optimizationsa
entry
solvent
base
conversionb
[4a]/[5a]c
1d
2
3
DMF
DMF
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
NaOtBu
NaOtBu
Cs2CO3
K2CO3
Na2CO3
KHCO3
NaHCO3
NaHCO3
NaHCO3
27
>99
>99
>99
>99
>99
>99
>99
90
>99
95
>99
94
>100
5.3
0.1
1.5
2.3
1.6
6.3
1
22
11
24
25
toluene
toluene
toluene
DME
DMF
DMF
DMF
DMF
DMF
Scheme 2. Desired Regioselectivity
4
5
6e
7f
8f
9f
10f
11f
12g
13h
DMF
DMF
16
We first set out to find an appropriate palladium-based
catalyst system that would provide good conversions as well
as preferential monoarylation of the terminal nitrogen atom
of benzoic hydrazide in a model reaction with 2-chloropy-
ridine (1, Table 1).8 Toward this end, 1 was subjected to 1
equiv of benzoic hydrazide (2a) at 100 °C in DMF in the
presence of Pd2(dba)3 (1 mol %) and a diverse array of
phosphine ligands (Josiphos 3, Xant-Phos, BINAP, DPE,
a Unless otherwise specified, the reactions were performed at 100 °C
using 1 equiv of 2a. b HPLC conversion (215 nm) to product 4a based on
1. c Selectivity of 4a vs 5a determined by HPLC. d No catalyst added.
e Reaction at 80 °C. f Using 1.3 equiv of 2a. g Using 1.5 equiv of 2a. h Using
1.5 equiv of 2a and reduced catalyst and ligand loading (1 mol % Pd, 1
mol % ligand).
Regioisomeric products resulting from the nucleophilic
attack of the internal nitrogen atom of the hydrazide were
not detected under the conditions described above, but a
significant amount of the bis-arylated product 5a (15% by
HPLC) was formed (entry 2). The formation of this by-
product was even more pronounced when toluene or DME
were used as solvents in the presence of cesium carbonate,
sodium tert-butoxide, or potassium phosphate (entries 3-6)
suggesting a significant role of the base in the reaction. In
the screen of alternative carbonate bases using 1.3 equiv of
(2) (a) Sliskovic, D. R. Bicyclic 5-6 Systems with One Ring Junction
Nitrogen Atom: Two Extra Heteroatoms 2: 0. In ComprehensiVe Hetero-
cyclic Chemistry II: A ReView of the Literature 1982-1995: The Structure,
Reactions, Synthesis, and Uses of Heterocyclic Compounds; Katritzky, A. R.,
Rees, C. W., Scriven, E. F. V., Eds.; Pergamon: Oxford, New York, 1996;
Vol. 8, Chapter 13, pp 367-388. (b) Jones, G. AdV. Heterocycl. Chem.
2002, 83, 1, and references cited therein.
(3) Schlosser, M.; Bobbio, C.; Rausis, T. J. Org. Chem. 2005, 70, 2494.
(4) Abad, A.; Agullo´, C.; Cun˜at, A. C.; Vilanova, C. Synthesis 2005,
915.
(5) Palladium-catalyzed additions:(a) Wang, Z.; Skerlj, R. T.; Bridger,
G. J. Tetrahedron Lett. 1999, 40, 3543. (b) Arterburn, J. B.; Rao, K. V.;
Ramdas, R.; Dible, B. R. Org. Lett. 2001, 3, 1351. (c) Lim, Y.-K.; Jung,
J.-W.; Lee, H.; Cho, C.-G. J. Org. Chem. 2004, 69, 5778
.
(9) Table 1 only contains a selected array of the conditions screened.
All ligands were investigated in the presence of potassium phosphate
(toluene), cesium carbonate (toluene, DMF), and sodium tert-butoxide
(toluene, DME).
(10) The structure of 4a was confirmed by NMR and by conversion to
the corresponding triazolopyridine 6a. Conversions were determined by
HPLC (215 nm).
(6) Copper-catalyzed additions: (a) Klapars, A.; Antilla, J. C.; Huang,
X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727. (b) Wolter, M.;
Klapars, A.; Buchwald, S. L. Org. Lett. 2001, 3, 3803. (c) Lavecchia, G.;
Berteina-Raboin, S.; Guillaumet, G. Tetrahedron Lett. 2004, 45, 2389
(7) A selective monoarylation of the terminal nitrogen atom of hydrazides
with organobismuth reagents was reported: Tsˇubrik, O.; Ma¨eorg, U.; Sillard,
.
R.; Ragnarsson, U. Tetrahedron 2004, 60, 8363
(8) Exploration of copper-based catalyst systems was not within the
scope of this investigation.
.
(11) For a leading reference regarding use of 3 for palladium-catalyzed
couplings: Shen, Q.; Shekhar, S.; Stambuli, J. P.; Hartwig, J. F. Angew.
Chem., Int. Ed. 2005, 44, 1371
.
Org. Lett., Vol. 12, No. 4, 2010
793

benzoic hydrazide, an increase in selectivity in the following
order was observed: K2CO3 < Cs2CO3 < KHCO3 < Na2CO3
< NaHCO3 (entries 7-11). A further increase of excess
benzoic hydrazide (1.5 equiv) allowed complete conversions
using 2 mol % of palladium and ligand and allowed for
excellent selectivity toward the desired product 4a (entry 12).
Since the reaction did not proceed to complete conversion
using 1 mol % of catalyst (entry 13), the optimized conditions
can be summarized as follows: 1.5 equiv of 2a, 3 equiv of
NaHCO3, 2 mol % of Josiphos, and 1 mol % of Pd2(dba)3
in DMF at 100 °C.
The 2- vs 4-selectivity in the crude reaction mixture at the
end of the coupling reaction was ∼6:1 (by HPLC), and
exclusive attack at the terminal nitrogen of the hydrazide
was observed. A product incorporating two hydrazine
moieties on a pyridine ring was also detected by LC/MS.
Overall, relatively disappointing assay yields (30-50%) were
obtained, thereby hampering isolation of the coupled product.
The relatively low yield can be explained due to oligomer-
ization reactions of the primary products since the starting
materials contain two potential electrophilic and three
nucleophilic sites. A similar screen of catalysts and conditions
as for 2-chloropyridine was conducted for 2,4-dichloropy-
ridine. While it was successful in identifying alternative
reaction conditions (DPPF, potassium phosphate, toluene)
that led to higher conversions, it failed to significantly
improve assay yields for the desired product.
Scheme 3. Dehydrative Cyclization
We recognized that the novel reactivity in the palladium-
catalyzed coupling of hydrazides would nonetheless offer a
practical approach to a broad array of triazolopyridines. This
methodology is particularly suitable for diversified lead-
generation since a broad array of acyl hydrazides are
commercially available.15 Employing the optimized condi-
tions,16 a variety of 3-aryl-substituted triazolopyridines were
synthesized (Table 2). The palladium-catalyzed addition of
benzoic hydrazides bearing electron-donating groups (methyl,
methoxy, hydroxyl) and of cinnamic hydrazide proceeded
smoothly using 2 mol % of catalyst, whereas 5 mol % of
catalyst was used for the reaction of electron-withdrawing
substituted benzoic hydrazides (fluoro, chloro, difluoro,
trifluoromethyl, carboxamido) to keep the reaction time at a
convenient duration (13-15 h). The reaction conditions are
also compatible with the use of heteroaromatic hydrazides,
even though the corresponding triazolopyridines were iso-
lated in somewhat lower yields (entries 12-16).
In the synthesis of 6h, the addition of 4-carbamoylbenzoic
hydrazide to 2-chloropyridine (entry 8) occurred selectively
at the terminal nitrogen of the hydrazide, demonstrating the
compatibility of amides with this methodology. On the other
hand, the reaction of 4-aminobenzoic hydrazide with 1 under
the standard conditions led to the formation of a mixture
(ca. 1:1) of the desired addition product and another
compound that incorporated one pyridine moiety on the
hydrazide as well as one on the aniline nitrogen. We reached
the steric limitation of our methodology in the synthesis of
the 3-mesityl-substituted triazolopyridine 6k (entry 11). The
Having established optimized conditions for the palladium-
catalyzed coupling reaction, conditions for the dehydrative
cyclization were explored with substrate 4a (Scheme 3). Use
of phosphorus oxychloride (neat or in selected solvents such
as toluene, acetonitrile, or chlorobenzene) at elevated tem-
peratures (90-110 °C) led to formation of the desired
product 6a. However, these conditions were accompanied
by formation of an impurity in varying levels (1-3% by
HPLC),12 which prompted us to turn our attention to
alternative dehydration conditions. Thermal cyclization
(110 °C) of 4a in the presence of polyphosphoric acid13 led
to a clean conversion after 15 h, and the product 6a could
be isolated in 82% yield. To decrease reaction times, we
explored other dehydrating conditions, including Dean-Stark
conditions, molecular sieves, and orthoesters. In the event,
we found that heating a solution of the addition product in
glacial acetic acid in a microwave reactor to 180 °C provided
quantitative formation of the triazolopyridine.14 These condi-
tions proved successful in cyclizing the crude product of the
addition reaction, which was simply filtered through a plug
of silica gel and hence offered a high-yielding and operation-
ally very convenient method for the synthesis of [1,2,4]tria-
zolo[4,3-a]pyridines.
Application of the optimized conditions to the reaction of
2,4-dichloropyridine with arylhydrazides was next attempted.
(12) This impurity was tentatively assigned as structure 8 based on LC/
MS data. The formation of this impurity is most likely caused by
dimerization of intermediate 7, which can be observed by LC/MS.
(15) >3000 according to ACD.
(16) General Experimental Procedure: Neat 2-chloropyridine (2
mmol) was added to a mixture of hydrazide (3 mmol), Pd2(dba)3 (20-50
µmol), 3 (40-100 µmol), and NaHCO3 (6 mmol) in DMF (4 mL), and the
mixture was heated in a sealed vial at 100 °C for 15 h. The mixture was
cooled to rt and filtered through a plug of silica gel (ca. 5 g), which was
washed with i-PrOH/CH2Cl2 (1:9, 30 mL). The combined filtrates were
concentrated under reduced pressure to deliver a brown oil that was taken
on without further purification. A solution of this brown oil in glacial acetic
acid (10 mL) was heated in a microwave reactor at 180 °C for 0.5 h. The
mixture was cooled to rt and concentrated under reduced pressure, and the
residue was partitioned between CH2Cl2 (30 mL) and saturated aqueous
NaHCO3 (30 mL). The layers were separated, and the aqueous layer was
extracted with CH2Cl2 (2 × 30 mL). The combined organic layers were
dried (MgSO4) and concentrated under reduced pressure. The resulting black
oil was purified by flash chromatography to deliver the desired product
(see Supporting Information).
(13) Hansen, K. B.; Balsells, J.; Dreher, S.; Hsiao, Y.; Kubryk, M.;
Palucki, M.; Rivero, N.; Steinhuebel, D.; Armstrong, J. D., III; Askin, D.;
Grabowski, E. J. Org. Process Res. DeV. 2005, 9, 634.
(14) While this manuscript was in preparation, a method for the
formation of [1,2,4]triazolo[4,3-b]pyridazines featuring microwave-assisted
dehydration in acidic medium was published: Aldrich, L. N.; Lebois, E. P.;
Lewis, L. M.; Nalywajko, N. T.; Niswender, C. M.; Weaver, C. D.; Conn,
P. J.; Lindsley, C. W. Tetrahedron Lett. 2009, 50, 212.
794
Org. Lett., Vol. 12, No. 4, 2010

100 °C; however, dehydration attempts in AcOH at 180 °C
under microwave irradiation delivered no product, whereas
acetylated 4k was the major product at 200 °C. However,
alternative dehydration conditions (5 equiv of POCl3, chlo-
robenzene, 110 °C) delivered 6k in 80% overall yield.
This methodology was also applicable to the synthesis of
3-alkyl and 3-alkenyl substituted triazolopyridines (Table 2,
entries 17-20). Alkyl hydrazides proved to be less reactive
substrates in the addition reaction with 2-chloropyridine, and
more forcing conditions (5 mol % of catalyst, 60 h at
100 °C) had to be employed. Interestingly, in the first attempt
toward the synthesis of the cinnamyl analogue (6t, entry 20),
we isolated the desired product in only 60% yield together
with 30% of the saturated analogue. Subjection of 6t to the
dehydration conditions (AcOH, 180 °C, microwave) did not
generate this saturated product, neither in the absence nor
presence of catalyst. The formal hydrogen necessary for the
reduction was suspected to arise from an excess of hydrazide,
but also addition of hydrazide with or without catalyst in
these studies failed to provide any saturated product. Toward
this end, we found that heating 6t in AcOH in the presence
of DMF (the solvent in the addition reaction) and Pd catalyst
indeed produced the saturated undesired side product. Hence,
the synthesis of 6t included a chromatographic purification
of the intermediate addition product, and the desired unsatur-
ated triazolopyridine was obtained in 90% yield over the two
steps.
Table 2. Synthesis of 3-Substituted Triazolopyridines
In summary, we have developed an efficient procedure
for the palladium-catalyzed addition of hydrazides to chlo-
ropyridines, which occurs selectively at the terminal nitrogen
atom of the hydrazide. The products of this reaction were
found to undergo dehydrative cyclizations upon heating in
acetic acid under microwave irradiation. It was found that
the crude products of the palladium-catalyzed addition
reaction cleanly cyclized under these conditions making this
reaction sequence an operationally very convenient and high-
yielding method for the synthesis of [1,2,4]triazolo[4,3-
a]pyridines.
Acknowledgment. We thank Dr. Andrew S. Tasker
(Amgen, Inc.) for his support of this project as well as Prof.
Stephen L. Buchwald (Massachusetts Institute of Technol-
ogy) for insightful discussions.
a All products are characterized by 1H NMR, 13C NMR, IR, and HRMS.
b Isolated yield. c See text. d The reaction required 60 h for complete
conversion.
Supporting Information Available: Detailed experimen-
tal procedures and characterization data of each compound.
This material is available free of charge via the Internet at
http://pubs.acs.org.
addition of 2,4,6-trimethylbenzoic hydrazide to 2-chloropy-
ridine proceeded cleanly using 5% catalyst for 30 h at
OL902868Q
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