Palladium-catalyzed coupling of aldehyde-derived hydrazones: Practical synthesis of triazolopyridines and related heterocycles

Article abstract of DOI:10.1002/anie.201001999

The palladium-catalyzed intermolecular coupling of aldehyde-derived hydrazones with chloroazines, followed by oxidative cyclization under mild conditions afforded access to a broad variety of bicyclic heterocyclic scaffolds (see scheme) that have potentia

Full text of DOI:10.1002/anie.201001999

Angewandte
Chemie
DOI: 10.1002/anie.201001999
Synthetic Methods
Palladium-Catalyzed Coupling of Aldehyde-Derived Hydrazones:
Practical Synthesis of Triazolopyridines and Related Heterocycles**
Oliver R. Thiel,* Michal M. Achmatowicz,* Andreas Reichelt, and Robert D. Larsen
In memory of Keith Fagnou
Triazolopyridines constitute an important class of heteroar-
omatic compounds. The [1,2,4]triazolo[4,3-a]pyridine
moiety[1] can be found in a variety of biologically active
compounds, including antibacterial, antithrombotic, antiin-
flammatory, antiproliferative, and herbicidal agents.[2] To
access this class of compounds we became interested in the
palladium-catalyzed coupling reactions of 2-chloropyridines
with hydrazine derivatives and we recently reported the use of
hydrazides as nucleophiles in palladium-catalyzed reactions.[3]
Herein, we describe the use of aldehyde hydrazones for the
efficient synthesis of triazolopyridines and related hetero-
cycles.
desired coupling product were obtained with 2,4-dichloropyr-
idine.[3] As oxidative approaches to triazoles are known,[1,9]
the intermediate C seemed to be a suitable candidate to
explore this synthetic approach (Scheme 1). Attempts to
Buchwald and co-workers have reported the palladium-
catalyzed reaction of benzophenone hydrazone with aryl
halides for the synthesis of indoles,[4a,b] and N-tert-butylhy-
drazones that are derived from aryl aldehydes were reported
À
to undergo intermolecular palladium-catalyzed C C-cou-
pling as acyl-anion equivalents to afford diarylketones.[5]
However, to the best of our knowledge, the use of alde-
hyde-derived un-substituted hydrazones in palladium-cata-
À
lyzed intermolecular C N coupling reactions has not pre-
viously been reported.[6]
Scheme 1. Different approaches to triazolopyridine A.
Our initial targets were 7-chloro-3-aryl-1,2,4-triazolo[4,3-
a]pyridines A, which can serve as useful templates for the
rapid generation of analogues, because the chloro group
offers the possibility of introducing further substituents
through additional palladium-catalyzed coupling reactions.
We sought to prepare these compounds in a highly efficient
fashion starting from 2,4-dichloropyridine as a cheap pre-
cursor. Palladium-catalyzed reactions on this substrate have
been shown to occur selectively at the 2-position,[7] whilst
thermal substitution reactions slightly favor displacement at
the 4-position.[8] We recently reported the reactions of
chloropyridines with benzoic hydrazide but, owing to com-
peting side-reactions, only mediocre yields (30–50%) of the
access this intermediate by introduction of the hydrazine
through palladium-catalyzed coupling with benzophenone
hydrazone, followed by benzophenone hydrolysis and con-
densation with benzaldehyde, failed at the benzophenone-
deprotection step. To succeed with this approach, the
previously unreported coupling of aldehyde-derived hydra-
zones had to be developed.
In the initial screen of reaction conditions, the commer-
cially available benzophenone hydrazone was selected as a
coupling partner. Based on the previously established supe-
riority of bidentate ligands for the coupling of benzophenone
hydrazone with aryl halides[4] or chloropyridines,[10] the dppf
(1,1’-bis(diphenylphosphino)ferrocene) ligand was deemed a
suitable entry point; indeed, this ligand afforded the desired
2-functionalized products in good yields. The undesired
bis(addition) of the nucleophile was significantly less-pro-
nounced with K2CO3, as compared to Na2CO3 or Cs2CO3.
[*] Dr. O. R. Thiel, Dr. M. M. Achmatowicz, Dr. R. D. Larsen
Chemical Process Research & Development, Amgen, Inc.
One Amgen Center Drive, Thousand Oaks, CA 91320-1799 (USA)
E-mail: othiel@amgen.com
michala@amgen.com
Dr. A. Reichelt
Medicinal Chemistry, Amgen, Inc. (USA)
À
Importantly, the conditions could be applied with our C N
coupling partners, aldehyde-derived hydrazones, with equal
success (Scheme 2). Furthermore, the only coupling product
that was detected resulted from substitution at the 2-position
of 2,4-dichloropyridine.[11] The low solubility of the products
allowed for direct isolation by crystallization. Gratifyingly, the
[**] We are grateful to Dr. Tsang-Lin Hwang, Dr. Kevin Turney, and Milan
Petkovic for assistance in the analytical characterization of the
products.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201001999.
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Communications
Table 1: Scope of the coupling and cyclization reaction with 2-chloropyr-
idines.[a]
Entry
1
Coupling product
Yield
[%][b]
Cyclization
product
Yield
[%][c]
47(81)
91
82
89(97)[d]
Scheme 2. Optimized conditions for the palladium-catalyzed coupling
reaction.
reaction was robust, and the products were isolated in
excellent yields on large laboratory scale (86% on 54 g scale).
With suitable conditions for the palladium-catalyzed
coupling reaction in hand, our focus shifted to identifying
mild conditions for the oxidative cyclization. Previously
iodobenzene diacetate,[9a] copper(II) chloride,[9b] bromine,[9c,d]
lead(IV) acetate,[9d] and chloramine-T[9e] have been utilized
for this transformation. Most of these reagents suffer from the
formation of large amounts of toxic by-products, which can
impact product isolation and have a negative environmental
impact. In our hands, chloramine-T afforded rapid conver-
sions (< 2 h) and high yields (> 85%) in most solvents
(ethanol, tetrahydrofuran, and ethyl acetate). The reaction
work-up was initially complicated by the need to remove the
stoichiometric toluenesulfonamide by-product. This issue was
overcome by utilizing 2-methyltetrahydrofuran as a reaction
solvent. Taking advantage of the immiscibility of this solvent
with water, a basic-aqueous workup was used to remove the
toluenesulfonamide. Thereafter, the product could be isolated
by simple crystallization on addition of heptane. Significantly,
no decrease in the yield of isolated product was observed
when the reaction was performed on a 15 g scale (Scheme 3).
2
3
67(77)
69(74)
87
4
5
6
7
85(92)
77(79)
64(81)
64(77)
83
90
88
84
8
9
84(94)
94(95)
75
89
Scheme 3. Optimization of the oxidative cyclization reaction.
These optimized conditions could be applied to a wide
variety of chloropyridines. Various substituted benzaldehyde-
derived hydrazones were competent nucleophiles in the
coupling reactions with 2-chloropyridines. The palladium-
catalyzed coupling and oxidative cyclization reactions toler-
ated electron-donating (Table 1, entries 2 and 3), and elec-
tron-withdrawing substituents (Table 1, entries 7–9). Addi-
tional halogenation in the form of a chloro or fluoro
substituent on the nucleophile did not interfere with the
reaction (Table 1, entries 4–6).
[a] General reaction conditions: [Pd]=0.5 mol% [Pd(dppf)Cl2], K2CO3,
toluene, 1008C; [oxidn]=chloramine-T, 2-Me-THF, 608C. [b] Yield of
isolated product. Assay yield, determined by HPLC, given in brackets.
[c] Yield of isolated product. [d] Reaction in DME at 808C. THF=tetra-
hydrofuran, DME=1,2-dimethoxyethane.
The reaction sequence also had a broad scope with
regards to the electrophile. 2,3-Dichloropyridine (Table 2,
entry 1), 2,4-dichloropyridine (Table 2, entries 2–4), and 2,5-
dichloropyridine (Table 2, entry 5) were all competent cou-
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Table 2: Scope of the coupling and cyclization reaction with disubsti-
Table 3: Scope of the coupling and cyclization reaction with other chloro-
substituted nitrogen heterocycles.[a]
tuted 2-chloropyridines.[a]
Entry
Coupling product
Yield [%][b]
42(71)
Cyclization
product
Yield
[%][c]
Entry
Coupling product
Yield [%][b]
70(84)
Cyclization
product
Yield
[%][c]
1
95
81
1
59
69
2
3
73(84)
78(86)
2
81(91)
80
3
4
20(92)
63(71)
92
99
4
5
6
86
89
93
95
58(65)
57(64)
5
6
73(78)
90(95)
91
79
[a] For general reaction conditions, see Table 1. [b] Yield of isolated
product. Assay yield, determined by HPLC, given in brackets. [c] Yield of
isolated product.
7
58(80)
87(91)
35
77
75
84
82
pling partners. Such scope is particularly useful as the
products provide versatile scaffolds that have the potential
to be utilized in subsequent palladium-catalyzed coupling
reactions with more-active catalysts. 2-Chloro-4-methoxypyr-
idine also performs well in the reaction (Table 2, entry 6).
Having established a robust synthesis of a diverse array of
[1,2,4]triazolo[4,3-a] pyridines, we sought to explore if the
approach could be extended to the synthesis of even more-
complex heterocyclic scaffolds. Annulation on the pyridine
core was not an impediment for the synthesis; both 1-
chloroisoquinoline and 2-chloroquinoline performed well in
the palladium-catalyzed coupling reaction to afford tricylic
scaffolds after cyclization (Table 3, entries 1 and 3). The
reaction with 1,3-dichloroisoquinoline proceeds selectively at
the 1-position (Table 3, entry 2). Bicyclic heterocycles with
four nitrogen atoms are particularly attractive in the develop-
ment of biologically active compounds; representative exam-
8
9
10
79(81)
[a] For general reaction conditions, see Table 1. [b] Yield of isolated
product. Assay yield, determined by HPLC, given in brackets. [c] Yield of
isolated product.
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Communications
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Scheme 4. One-pot synthesis of triazolopyridine 4b.
In conclusion, we have discovered a mild and selective
palladium-catalyzed intermolecular coupling of aldehyde-
derived hydrazones with chloro-substituted heterocycles. The
coupled products undergo a clean oxidative cyclization to
afford triazolopyridines and other related heterocycles. This
novel reaction has a broad substrate scope and a large variety
of six-membered heterocycles with different substituents
were tolerated as reaction partners. This reaction is readily
scalable and can be conducted as a one-pot process if desired.
Based on the large number of commercially available a-
chloroazines, this straightforward two-step reaction allows
access to a broad variety of scaffolds that constitute useful
templates in drug discovery.
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Received: April 4, 2010
Published online: July 26, 2010
Keywords: amination · cyclization · heterocycles · hydrazones ·
.
palladium
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