Pd-catalyzed tandem C-H azidation and N-N bond formation of arylpyridines: A direct approach to pyrido[1,2-b ]indazoles

Article abstract of DOI:10.1021/ol402060q

A novel Pd-catalyzed nitrogenation of arylpyridines via C-H azidation has been developed. Direct C-N and N-N formations are achieved for this N-atom incorporation transformation using azides as the N-atom source. This method provides an alternatively concise approach for the construction of bioactively important pyrido[1,2-b]indazoles.

Full text of DOI:10.1021/ol402060q

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Pd-Catalyzed Tandem CÀH Azidation and
NÀN Bond Formation of Arylpyridines: A
Direct Approach to Pyrido[1,2‑b]indazoles
Qing-Zhong Zheng,† Peng Feng,† Yu-Feng Liang,† and Ning Jiao*,†,‡
State Key Laboratory of Natural and Biomimetic Drugs, Peking University, School of
Pharmaceutical Sciences, Peking University, Xue Yuan Road 38, Beijing 100191, China,
and Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology,
Peking University Shenzhen Graduate School, Shenzhen, China, 518055
jiaoning@bjmu.edu.cn
Received July 22, 2013
ABSTRACT
A novel Pd-catalyzed nitrogenation of arylpyridines via CÀH azidation has been developed. Direct CÀN and NÀN formations are achieved for this
N-atom incorporation transformation using azides as the N-atom source. This method provides an alternatively concise approach for the
construction of bioactively important pyrido[1,2-b]indazoles.
Recently, transition-metal-catalyzed organic reactions
involving CÀH bond cleavage have been significantly
developed as atom- and step-economical tools in organic
synthesis.1 During the past several decades, transition-
metal-catalyzed dehydrogenation cyclization to construct
dibenzofurans, carbazoles, phenanthridin-6(5H)-ones,
fluorens, and fluorenones have been well developed2À4
(Scheme 1a). Foreseeably, the incorporation of an atom
into the above systems through the degydrogenative
strategy would substantially broaden the field of cycli-
zation and offer more functionalized cyclic compounds.
However, there is a rare example of incorporating one
(hetero-) atom into biaryl to construct heterocycles.
Very recently, Lei and co-workers achieved a significant
Pd-catalyzed dehydrogenative carbonylation of diaryl
ethers to form xanthones (Scheme 1b).5
† Peking University.
‡ Peking University Shenzhen Graduate School.
(1) For some recent reviews on CÀH functionalization, see: (a) Song,
G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651. (b) Wencel-Delord,
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r
10.1021/ol402060q
XXXX American Chemical Society

some elegant examples of catalytic CÀN formation
via CÀH activation with azides as the nitrogen source
have been reported,10À12 the direct CÀH azidation13 and
subsequent transformation of arenes still offer a distinct
challenge. Recently, by using a pyridyl directing group,
Yu et al. achieved the elegant Cu-mediated CÀH function-
alizations of 2-phenylpyridines with various nucleophilic
anion sources.14 However, the direct CÀH azidation of
2-phenylpyridine did not occur under the reported condi-
tions. Herein, the present study demonstrates the first
example of Pd-catalyzed direct CÀH azidation of arylpyr-
idines and subsequent relay of intramolecular NÀN bond
formation. (3) This transformation provides as well an
alternatively concise approach to bioactive pyrido[1,2-b]-
indazoles from readily available arylpyridines.
Scheme 1. Dehydrogenative and Atom-Incorporation Strategies
Table 1. Effects of the Reaction Parameters in the
Palladium-Catalyzed Nitrogenation Reactiona
Due to the diverse pharmacological activities, indazoles
are widely used in the pharmaceutical industry in many
drugs and drug candidates.6 Pyrido[1,2-b]indazoles are
a class of bioactive molecules containing this pharmaco-
phore, and some analogues are known to exhibit anti-
cancer activities.7 Therefore, the efficient synthesis of
pyrido[1,2-b]indazoles has attracted much attention for
a long time due to the promise of drug candidates which
contain this skeleton. The traditional strategies toward
the synthesis of pyrido[1,2-b]indazole derivatives suffer
from multistep procedures, the lack of atom economy,8
or a limited substrate scope.9 We envisioned that pyrido-
[1,2-b]indazoles could be constructed by incorporating
one N-atom into heteroarenes. Herein, we report the first
Pd-catalyzed nitrogenation reaction of 2-arylpyridines for
the synthesis of pyrido[1,2-b]indazoles (Scheme 1c).
yield of
entry
change from the “standard conditions”
2a (%)b
1
2
3
4
5
6
none
77
0
no Pd(OAc)2
no Ce(SO4)2 [with 1.0 equiv of Pd(OAc)2]
no FeCI2
0
56
61
10
Ar instead of O2
Selectfluor instead of Ce(SO4)2
dioxane instead of DMSO
CAN instead of Ce(SO4)2
DDQ instead of Ce(SO4)2
TMSN3 instead of NaN3
DMF instead of DMSO
7
15
0
8
9
0
10
0
The significance of the present finding is threefold:
(1) To the best our knowledge, this is the first example of
implanting one N-atom from an external nitrogen source
into 2-arylpyridines via CÀH activation. (2) Although
a Reaction conditions: 1a (0.3 mmol), NaN3 (2.0 equiv), Pd(OAc)2
(15 mol %), Ce(SO4)2 (2.0 equiv), FeCl2 (20 mol %), DMSO (4 mL),
stirred at 100 °C under O2 (1 atm) for 79 h. CAN = Ceric ammonium
nitrate, DDQ =2,3-Dichloro-5,6-dicyano-1,4-benzoquinone, TMSN3 =
Trimethylsilyl azide. b Isolated yields.
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please visit the PubChem website (http://pubchem.ncbi.nlm.nih.gov/),
which provides the compound structure, bioactivity, published studies,
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niraparib, granisetron, pazopanib, linifanib, axitinib, and GDC-0941.
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Katzenellenbogen, K. A. J. Med. Chem. 2005, 48, 1132.
We commenced our hypothesis with 3-methoxy-2-phe-
nylpyridine 1a and sodium azide (NaN3) as a model
reaction (Table 1). After extensive screening of different
parameters, the optimum reaction conditions were deter-
mined to be Pd(OAc)2 (15 mol %), Ce(SO4)2 (2.0 equiv),
FeCl2 (20 mol %), and DMSO (4 mL), under O2 (1 atm) at
100 °C, which provided the desired nitrogenation product
2a in 77% yield (entry 1). The structure of 2a was further
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Org. Lett., Vol. XX, No. XX, XXXX

corroborated by X-ray diffraction (see Figure S1, Supporting
Information (SI)). Both Pd(OAc)2 and Ce(SO4)2 were re-
quired for this transformation (entries 2 and 3). The efficiency
of this transformation can be promoted by the addition of
FeCl2 or under a molecular oxygen atmosphere (entries 4
and 5). The yield decreased when Selectfluor was employed
as the oxidant (entry 6). The other commonly used
single electron oxidants such as CAN and DDQ were less
effective or ineffective for the reaction (entries 7 and 8).
Notably, no products were detected with TMSN3 as the
nitrogen source (entry 9). The reaction in DMF did not work
(entry 10).
product in 41% yield. It is noteworthy that the use of
3-methyl-2-phenylpyridine proved to be effective, resulting
in the formation of the corresponding pyrido[1,2-b]indazole
derivative in 70% yield (entry 9, Table 2). However,
4-methyl, 5-methyl, or 3,5-dimethyl-substituted-2-phenyl-
pyridines produced the corresponding products with rela-
tively diminished efficiencies (entries 10À12, Table 2).
Notably, nitrogenation of the sterically hindered ortho-
alkoxy, or phenoxy-substituted substrates proceeded well
giving the corresponding products in 55À72% yields
(entries 13À21, Table 2). Meanwhile, substrates with either
electron-donating groups (e.g., Me, tBu) or electron-with-
drawing groups (e.g., F, Cl) at the para position of the
phenyl ring were tolerated in this transformation, leading
to the corresponding products in moderate yields (entries
23À26, Table 2). Furthermore, when 1-phenylisoquinoline
was employed, the desired indazolo[3,2-a]isoquinoline prod-
uct 2aa was obtained in 43% yield (Table 2, entry 27).
Table 2. Palladium-Catalyzed Nitrogenation Reactiona
To further obtain insights into this unique procedure,
preliminary mechanistic experiments were investigated.
A significant kinetic isotope effect (KIE, kH/kD = 4.0)
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a Reaction conditions: 1 (0.3 mmol), NaN3 (2.0 equiv), Pd(OAc)2
(15 mol %), Ce(SO4)2 (2.0 equiv), FeCl2 (20 mol %), DMSO (4 mL),
stirred at 100 °C under O2 (1 atm) for 79À82 h. b Isolated yields.
With these optimized conditions in hand, the scope of
the present protocol was investigated (Table 2). 3-Methoxy-
2-arylpyridines could be smoothly transformed into the
desired products (entries 1À8, Table 2). A significant vari-
ation on the benzene ring of 3-methoxy-2-arylpyridines was
tolerated, including electron-donating groups (e.g., Me, iPr,
tBu) and electron-withdrawing groups(e.g., F, Cl, COOMe).
Substrates bearing a stronger electron-withdrawing group
(e.g., CF3) also could be successfully converted to the desired
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Lubriks, D.; Sokolovs, I.; Suna, E. J. Am. Chem. Soc. 2012, 134, 15436.
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Org. Lett., Vol. XX, No. XX, XXXX
C

Onthe basisof the aboveresults, apossiblemechanismis
proposed in Scheme 2. A Pd-catalyzed nitrogenation
reaction is initiated by the chelation-directed cyclopallada-
tion to form cyclopalladium(II) dimeric intermediate A.
Subsequently, Pd(II) A is involved in ligand exchange with
the azide group to generate species B, which is then oxi-
dized into a possible Pd(IV) intermediate C by Ce(SO4)2.16
The reductive elimination of Pd(IV) intermediate C then
occurs to afford the ortho-azido product 3 with the regenera-
tion of the Pd(II) catalyst. The reaction of 5 did not work
under the standard conditions (eq 3), which excludes the
possibility of the reductive elimination of Pd(IV) intermedi-
ate C to form 517 as the intermediate. Finally, the thermal
decomposition of the azide product 3 delivers pyrido[1,2-b]-
indazole 2v under reaction conditions with heating.8d,18
In conclusion, we have developed a novel Pd-catalyzed
nitrogenation of arylpyridines via CÀH activation using
azides as the N-atom source. This study realized the Pd-
catalyzed relay of direct CÀH azidation of arylpyridines
and subsequent intramolecular NÀN bond formation. The
bioactively important pyrido[1,2-b]indazoles can be easily
constructed from readily available 2-arylpyridines by this
concise approach. Further mechanistic studies and applica-
tions of this transformation are underway in our laboratory.
Scheme 2. Proposed Mechanism
was observed (eq 1; also see SI), suggesting that the CÀH
bond cleavage is likely involved in the rate-limiting step.15
We envisioned that the direct CÀH azidation products
may serve as the key intermediates in this transformation.
To verify this possibility, compound 3 was synthesized and
subjected to the standard conditions (eq 2). As expected,
the desired pyrido[1,2-b]indazole 2v was obtained in 80%
yield. Moreover, 2-(2-azidophenyl)-3-methoxy-pyridine
(4) was detected during the nitrogenation process of
3-methoxy-2-phenylpyridine (1a) with NaN3 (see SI).
To further explore the reaction mechanism, the reaction
progress of 1a was monitored by 1H NMR spectroscopy
(see SI). The relatively apparent signal of methoxyl hydro-
gen in the azidation product 4appeared 4 h after the reaction
started. This signal became strong during the early stage and
disappeared at the end of the reaction. Meanwhile, the
consumption of 1a and production of 2a were also observed
in the spectrum as the reaction proceeded (see SI). These
results indicate that the azidation product 4 is indeed the key
intermediate of this transformation.
Acknowledgment. Financial support from National
Basic Research Program of China (973 Program) (Grant
No. 2009CB825300), National Science Foundation of China
(No. 21172006), and the Ph.D. Programs Foundation of the
Ministry of Education of China (No. 20120001110013) is
greatly appreciated. We thank Prof. Vladimir Gevorgyan at
University of Illinois at Chicago for the helpful discussion on
the mechanism. We thank Xiaoyang Wang in our group for
reproducing the results of entries 1 and 27 in Table 2.
Supporting Information Available. Experimental details,
NMR spectra analysis of the products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(18) In our experiments, the transformation of azide product 3 to
pyrido[1,2-b]indazole 2v under the standard conditions in the presence
and absence of a catalyst gave the same yields (80%), which also
indicated that the catalyst was not involved in the last step.
(15) Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51,
3066.
(16) Mei, T.-S.; Wang, X.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131,
10806.
(17) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004,
126, 2300.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX