Regioselective synthesis of 2 H-indazoles using a mild, one-pot condensation-cadogan reductive cyclization

Article abstract of DOI:10.1021/ol5012423

An operationally simple and efficient one-pot synthesis of 2H-indazoles from commercially available reagents is reported. Ortho-imino-nitrobenzene substrates, generated via condensation, undergo reductive cyclization promoted by tri-n-butylphosophine to afford substituted 2H-indazoles under mild reaction conditions. A variety of electronically diverse ortho-nitrobenzaldehydes and anilines were examined. To further extend the scope of the transformation, aliphatic amines were also employed to form N2-alkyl indazoles selectively under the optimized reaction conditions.

Full text of DOI:10.1021/ol5012423

Letter
pubs.acs.org/OrgLett
Regioselective Synthesis of 2H‑Indazoles Using a Mild, One-Pot
Condensation−Cadogan Reductive Cyclization
Nathan E. Genung,* Liuqing Wei, and Gary E. Aspnes
CVMED Medicinal Chemistry, Pfizer Inc., Eastern Point Road, Groton, Connecticut 06340, United States
S
* Supporting Information
ABSTRACT: An operationally simple and efficient one-pot synthesis
of 2H-indazoles from commercially available reagents is reported.
Ortho-imino-nitrobenzene substrates, generated via condensation,
undergo reductive cyclization promoted by tri-n-butylphosophine to
afford substituted 2H-indazoles under mild reaction conditions. A
variety of electronically diverse ortho-nitrobenzaldehydes and anilines
were examined. To further extend the scope of the transformation,
aliphatic amines were also employed to form N2-alkyl indazoles selectively under the optimized reaction conditions.
he utility of 2H-indazoles as pharmacophores in drug
discovery has been exemplified in several recent
zincate addition to diazonium salts,10 intramolecular amina-
tions,11 and acylated azobenzene cyclizations have also been
explored.12 Many of these methods still carry limitations in
terms of scope, use of transition metal catalysts, potential high
energy intermediates at elevated temperature, and/or pro-
tracted syntheses of substrates. Consequently, there is still a
need to develop an operationally simple and mild method to
access this privileged pharmacophore starting from a broad
class of readily available monomers.
T
publications (Figure 1).1 A substantial body of research exists
Of all the reported methods, we felt further optimization of
the Cadogan conditions presented the best opportunity to
develop a more general approach toward the synthesis of 2H-
indazoles. Our efforts were focused on the identification of
milder reaction conditions including lower temperatures and
near stoichimetric amounts of reducing agent in a conventional
solvent, ideally in tandem with, or subsequent to, imine
formation in the same pot. While one-pot methods in various
solvents have been reported, the reactions are frequently
conducted at elevated temperatures (>150 °C) with microwave
heating while maintaining the use of triethylphoshite as the
reductant.
Figure 1. Indazole containing chemotherapeutics.
around enabling the synthesis of such motifs.2 Direct alkylation
or arylation of 1H-indazoles frequently leads to mixtures of 1-
and 2-substituted products in all but very specific cases.3 As an
alternative to direct substitution, considerable effort has been
focused on cyclization reactions to selectively generate 2H-
indazoles. The Cadogan indazole synthesis, or reductive
cyclization of ortho-imino-nitrobenzenes mediated by triethyl
phosphite, was one of the first methods described and remains
one of the more effective synthetic transformations reported for
this purpose.4 Unfortunately, it carries the liabilities of being
run in an excess of neat phosphite at relatively high
temperatures on potentially high energy nitro/nitroso inter-
mediates. Many variations on the reductive cyclization theme
have been examined to address these concerns, including
modifications to the original Cadogan conditions,5 transition
metal catalyzed reductive cyclizations of iminonitroaromatics,6
and thermal/transition metal cyclization of 2-azidoimines.7 A
variety of other methods including reductive cyclizations of
ortho-nitrobenyzlamines,8 sydnone/benzyne cycloaddition,9
Under the generally accepted reaction mechanism (Figure
2), the phosphorus species reduces the nitro group sequentially
Figure 2. Proposed reaction mechanism.
Received: April 30, 2014
Published: May 21, 2014
© 2014 American Chemical Society
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Letter
through addition across the NO bond in both starting material
I and the presumed nitroso intermediate II to ultimately
generate a nitrene or nitrene-like intermediate III which
undergoes cyclization. The analogous nitroso compounds
undergo reductive cyclization at or below room temperature,
supporting the assumption that initial addition to the less
reactive nitro species is typically the rate-limiting step. In
examining the reaction mechanism and kinetics, Cadogan and
co-workers profiled alternative phosphorus(III) reagents and
demonstrated that the rate increased with increasing
nuclepohilicity of phosphorus.13 While other reagents provided
significant rate enhancement, triethyl phospite was adopted as
the preferred reductant based on cost and availability.
Trialkylphosphines were notably absent from these and
subsequent studies. We reasoned that the initial reduction to
nitroso intermediate II would occur appreciably faster with the
more nucleophilic phosphine and provide conditions that might
satisfy our requirements.
(Table 1, entry 5) provided complete conversion to indazole 2
in good yield with no complicating isolation issues. We next
turned our attention to the effect of solvent on the reductive
cyclization. Every solvent surveyed afforded the desired
indazole in good yield (Table 1, entries 6−13). Significant
rate enhancement and improved yields were observed when
alcoholic solvents were employed. Conducting the reaction in i-
PrOH provided the ideal conditions with desired product
indazole 2 obtained in 87% isolated yield.
With the reductive cyclization conditions optimized, we
turned our efforts toward developing a one-pot method to
generate 2H-indazoles. As condensation of arylaldehydes and
anilines occurs readily in i-PrOH at elevated temperature, it was
envisioned that simply adding tri-n-butylphosphine after the
condensation was complete, followed by heating, would afford
the desired product without the complicating factor of isolating
an imine intermediate. Fortunately, this method proved
effective as the one-pot process afforded indazole 2 in 85%
yield (Scheme 1).
Our initial investigations commenced with the comparative
evaluation of phosphites and phosphines to promote the
reductive cyclization of ortho-imino-nitrobenzene 1 to indazole
2 (Table 1). We elected to use THF as a representative solvent
a
Scheme 1. Scope of Benzaldehyde Substitution
a
Table 1. Optimization of Reductive Cyclization
b
entry
solvent
P(R)3
time (h)
yield (%)
1
THF
P(OEt)3
P(Ph)3
24
24
24
24
24
30
30
24
24
24
6
0
0
2
THF
c
3
THF
P(t-Bu)3
P(Cyx)3
P(n-Bu)3
P(n-Bu)3
P(n-Bu)3
P(n-Bu)3
P(n-Bu)3
P(n-Bu)3
P(n-Bu)3
P(n-Bu)3
P(n-Bu)3
62
d
4
THF
51
5
THF
74
73
72
73
62
63
82
77
6
PhMe
EtOAc
MeCN
acetone
NMP
MeOH
EtOH
i-PrOH
7
8
9
10
11
12
13
a
6
The condensation of an o-nitrobenzaldehyde (1.0 equiv) with aniline
(1.1 equiv) was carried out in i-PrOH (0.4 M) at 80 °C for 4 h in a 2-
dram sealed vial, followed by cooling, treatment with P(n-Bu)3 (3.0
equiv), and subsequent heating at 80 °C for a further 16 h.
6
87
a
b
See Supporting Information for optimization procedure. Isolated
c
yield after column chromatography. Contained 61 wt % of imine 1.
d
Contained 48 wt % of phosphine oxide.
After establishing optimized one-pot condensation−reduc-
tive cyclization conditions, the scope of the benzaldehyde was
examined using commercially available ortho-nitroaldehydes
(Scheme 1). Halogen containing aldehydes (3a−e) as well as
electron-rich (3f−h), electron-deficient (3i−k), and hetero-
aromatic nitroaldehydes (3l) all provided desired products in
moderate to good yield. The moderate yield observed for 3a
and no desired product observed in the attempted generation
of 3m suggests steric interactions or electron repulsion (either
during the condensation or in the reductive cyclization,
respectively) are a limitation to the scope of the method with
respect to the aldehyde.
Similarly, we examined the scope of aniline and amino-
pyridine partners under our conditions (Scheme 2). Once
again, halogen containing (5a,d,g,m), electron-rich (5c,f,i), and
electron-deficient anilines (5b,e,h,n) all provided the desired
products. Aminopyridines (5j−l) and sterically hindered
anilines (5o,p) also undergo conversion to the indazole
and 3 equiv of phosphorus(III) reagent. While in theory 2
equiv of reagent should be sufficient for complete conversion,
we chose to use an excess to protect against potential air
oxidation, as all reactions were conducted with no special
precautions with regards to anhydrous solvents or an inert
atmosphere. It was immediately apparent triethyl phosphite and
triphenylphosphine were not suitable reagents for the trans-
formation, as no conversion was observed under the milder
reaction conditions. Fortunately, more nucleophilic trialkyl-
phosphines did demonstrate conversion to the desired product.
Under the initial reaction conditions, tri-tert-butylphosphine
afforded indazole 2 as well as unreacted starting material (Table
1, entry 3). Tricyclohexylphosphine provided complete
conversion (Table 1, entry 4), however, removal of the
phosphine oxide byproducts proved problematic and a less than
ideal isolated yield resulted. Ultimately, tri-n-butylphosphine
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Organic Letters
Letter
a
a
Scheme 2. Scope of Aromatic Amines
Scheme 3. Scope of Aliphatic Amines
a
a
The condensation of o-nitrobenzaldehyde (1.0 equiv) with an
aliphatic amine (1.1 equiv) was carried out in i-PrOH (0.4 M) at 80
°C for 4 h in a 2-dram sealed vial, followed by cooling, treatment with
P(n-Bu)3 (3.0 equiv), and subsequent heating at 80 °C for a further 16
h. b Determined by SFC using a chiral column. c Free base of the HCl
The condensation of o-nitrobenzaldehyde (1.0 equiv) with an
aromatic amine (1.1 equiv) was carried out in i-PrOH (0.4 M) at
80 °C for 4 h in a 2-dram sealed vial, followed by cooling, treatment
with P(n-Bu)3 (3.0 equiv), and subsequent heating at 80 °C for a
further 16 h. b Imine was preformed in toluene at reflux. c Isolated yield
observed using a one-pot procedure.
d
e
salt was used. Condensation conducted at rt over 12 h. Reductive
cyclization conducted at 50 °C.
products under the one-pot reductive cyclization conditions.
Variability observed in the isolated yield when electron-
deficient anilines were employed can be attributed to the
relative stability of the imine intermediate. As illustrated in the
case of 5b, when the condensation was conducted under more
forcing conditions an appreciable decrease in isolated yield was
still observed. The electron-deficient imine intermediate
appeared to be unstable under the reaction conditions, most
likely due to an unfavorable equilibrium throughout the course
of condensation leading to unproductive side reactions during
the reductive cyclization.
with complete retention of stereochemistry at the α-position.
This result suggests that isomerization of the imine
intermediate does not occur under the reaction conditions,
making the developed method very appealing with regard to
asymmetric synthesis of 2H-indazoles substituted with α-
branched aliphatic groups. Interestingly, any exogenous hydro-
chloride salt was deleterious to the reaction; thus, the free bases
of all amine coupling partners were required to obtain the
desired indazole products.
While not well exemplified in the literature, Cadogan
cyclization of aliphatic ortho-imino-nitrobenzenes is known.13
In order to further demonstrate the scope of our method, we
evaluated a variety of aliphatic amines under the standard
conditions developed (Scheme 3). Straight chain (6a) as well as
branched and cyclic primary amines (6b−d) were compatible
with the optimized reaction conditions, providing the
alkylindazole products in good yield. Fortunately, steric effects
do not appear to impede the reductive cyclization pathway, as
tert-butylamine was competent in providing indazole 6d.
Benzylamine worked well in generating indazole 6e; however,
allylamine provided indazole product 6f in only moderate yield.
The decreased reaction efficiency is presumably due to
unproductive reaction pathways of the putative nitrene
intermediate with the pendant olefin, which led to a complex
mixture of undesired products.
As expected, altering the ortho-nitrobenzaldeyde coupling
partner with aliphatic amines provided the desired indazole
products (6g−k). Similar to the studies completed using aniline
(Scheme 1), the electronic nature of the nitroaldehyde had little
effect on the cyclization as electron-rich, electron-deficient, and
halogen containing ortho-nitrobenzaldeydes were all compatible
coupling partners with n-butylamine. Interestingly, using
optically pure α-methyl benzylamine in the reductive
cyclization cascade provided the desired indazole product 6l
Unfortunately, reactions with either glycine or alanine methyl
ester failed to provide desired products (6m,n). Condensation
of glycine methyl ester with ortho-nitrobenzaldehyde at elevated
or room temperature led to a complex mixture of products. A
similar result was observed with alanine methyl ester at elevated
temperatures. However, clean imine formation with alanine
methyl ester was observed when the condensation was
conducted at room temperature over 12 h. Treatment of the
resulting imine with tri-n-butylphosphine at 50 °C over 3 h
resulted in complete consumption of the imine and no desired
indazole. Using methyl α-aminoisobutyrate in the one-pot
procedure provided indazole 6o, albeit in moderate yield,
suggesting the increased acidity of the α-imino proton is not
tolerated under the cyclization conditions at the temperatures
required for reduction.
In conclusion, a general method for the synthesis of a wide
range of structurally diverse 2H-indazoles is presented. The use
of tri-n-butylphosphine and protic solvent provided mild
conditions for the reductive cyclization in a media compatible
with imine formation. The optimized one-pot reaction
improved the synthetic practicality of the transformation and
enhanced the safety margin of the reaction by lowering the
temperature profile and limiting the amount of reducing
reagent compared to previous reports.
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Letter
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ASSOCIATED CONTENT
* Supporting Information
Full experimental details and characterization data. This
material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
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*E-mail: nathan.genung@pfizer.com.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Daniel Canterbury, Kevin Hesp, Daniel Kung, and
Vincent Mascitti for reviewing this manuscript as well as Jason
Ramsay for high resolution mass spectrometry determination.
All colleagues acknowledged are affiliated with Pfizer, Inc.,
Groton, CT, USA.
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