A novel synthetic approach to 4-acetamido-1-arylindazoles via Semmler-Wolff rearrangement of 1-aryl-6,7-dihydro-5H-indazol-4-one oxime

Article abstract of DOI:10.1016/j.tetlet.2014.04.058

A simple and efficient procedure for the syntheses of 4-acetamido-1- arylindazoles from corresponding 1-aryl-6,7-dihydro-5H-indazol-4-one oximes by Semmler-Wolff aromatization using acetic anhydride and sodium iodide is reported.

Full text of DOI:10.1016/j.tetlet.2014.04.058

Accepted Manuscript
A novel synthetic approach to 4-acetamido-1-arylindazoles via Semmler-Wolff
rearrangement of 1-aryl-6,7-dihydro-5H-indazol-4-one oxime
Sulur G Manjunatha, Sreekanth Bachu, Vasantha Krishna Kadambar,
Andiappan Murugan, Sridharan Ramasubramanian, Puranik Ramachandra,
Sudhir Nambiar
PII:
S0040-4039(14)00670-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.04.058
TETL 44520
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
13 March 2014
11 April 2014
15 April 2014
Please cite this article as: Manjunatha, S.G., Bachu, S., Kadambar, V.K., Murugan, A., Ramasubramanian, S.,
Ramachandra, P., Nambiar, S., A novel synthetic approach to 4-acetamido-1-arylindazoles via Semmler-Wolff
rearrangement of 1-aryl-6,7-dihydro-5H-indazol-4-one oxime, Tetrahedron Letters (2014), doi: http://dx.doi.org/
10.1016/j.tetlet.2014.04.058
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Graphical Abstract
A novel synthetic approach to
4-acetamido-1-arylindazoles via Semmler-Wolff
rearrangement of 1-aryl-6,7-dihydro-5H-indazol-4-one oxime
Sulur G Manjunatha∗, Sreekanth Bachu, Vasantha Krishna Kadambar, Andiappan Murugan, Sridharan Ramasubramanian,
Puranik Ramachandra and Sudhir Nambiar.
AC2O, NaI, Xylene
110-120oC

1
Tetrahedron Letters
journal homepage: www.elsevier.com
A novel synthetic approach to 4-acetamido-1-arylindazoles via Semmler-Wolff
rearrangement of 1-aryl-6,7-dihydro-5H-indazol-4-one oxime
Sulur G Manjunatha∗, Sreekanth Bachu, Vasantha Krishna Kadambar, Andiappan Murugan, Sridharan
Ramasubramanian, Puranik Ramachandra and Sudhir Nambiar.
AstraZeneca India Pvt. Ltd, Off Bellary Road, Bangalore – 560024, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
A simple and efficient procedure for the syntheses of 4-acetamido-1-arylindazoles from corresponding
1-aryl-6,7-dihydro-5H-indazol-4-one oximes by Semmler-Wolff aromatization using acetic anhydride
and sodium iodide is reported.
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
4-acetamido-1-phenylindazole
Dihydroindazol-4-one
Semmler-Wolff aromatization
Acetic anhydride
Sodium Iodide
Indazoles are key building blocks to many pharmaceutically
important molecules having wide range of biological activities.1
Recently 4-substituted aminoindazole derivatives have been
shown to exhibit herbicidal, anti-infective and anti–
inflammatory properties.2 In literature many synthetic procedures
are reported for the preparation of indazoles but very few
methods are described for the synthesis 4-aminoindazoles.
Generally, these are prepared by the reaction of 2,6-
dinitrobenzaldehyde with phenyl hydrazine followed by
reduction of nitro group.3 Another approach followed for 4-
aminoindazole is the diazotization of 2-methyl-3-nitroaniline to
get 4-nitroindazole followed by the reduction of the nitro group
and further derivatised to get the amino derivative.4
notable methods are reported for the syntheses of 4-
aminoindazoles via Buchwald amination of 4-haloindazoles.5 We
believe that there is a need for the development of practical and
safe alternative synthetic route to 4-aminoindazoles. We
envisaged that Semmler-Wolff aromatization protocol would
provide an efficient route to the synthesis of 4-
acetamidoindazoles.
Semmler-Wolff rearrangement, described by Semmler6 and later
developed by Wolff7 is the aromatization of cyclohexenone
,
oximes to corresponding anilines by a variety of acidic reagents.8
The advantage of this reaction is that it places the amine function
on the ring system in a very simple way which otherwise difficult
to introduce by any standard methods. Semmler-Wolff
aromatization has been utilized for the synthesis of benzenoid
rings, fused heterocyclic systems and have been well reported in
literature.9 Generally, this transformation is performed in strong
acidic medium or in a mixture of acetic anhydride and an acid
like acetic acid, hydrogen chloride, phosphoric acid, sulfuric acid
or methanesulfonic acid. These protocols suffer low yield due to
the competing Beckmann rearrangement. Recently while
exploring a safe and scalable manufacturing process for a 4-
aminoindole derivative, we have developed an efficient process
for this transformation which involves sodium iodide and acetic
anhydride as reagents and xylene as solvent. This process was
clean and offered better selectivity towards Semmler-Wolff
rearrangement. We have demonstrated the efficiency of this
O
O–
NH2
O
+O–
N+
N
CHO
NO2
N
N
NH2
2
1
3
Scheme 1
The major limitations of the above synthetic methods are that that
these require 1,2,3-suitably substituted aromatic compounds such
as 1 and 3, as the starting materials. Moreover, these procedures
involve energetic intermediates and starting materials which may
process
in
the
large
scale
synthesis
of
pose significant challenge for the scale up. Recently, a few
———
∗ Corresponding author. Tel.: +91 80 6621300, Extn No: 7260; fax: +91-80-23622011; e-mail: Manjunath.Sulur@astrazeneca.com

2
Tetrahedron
AZD1981.10 We ought to explore the application this protocol
in the syntheses of many other fused carbocylic and heterocyclic
compounds with amine function at a specific position. Herein,
we report a practical synthesis of 1-aryl-4-acetamidoindazoles 5
using our process starting from 1,3-cyclohexanedione as shown
Semmler-Wolff aromatization of 1-phenyl-6,7-dihydro-5H-
indazol-4-one oxime (4a):
As planned, the oxime compound 4a was heated in a mixture
of acetic anhydride and xylene in the presence of catalytic
o
amounts of sodium iodide at 110-120 C for about 2 h. The
in Schemes 2 and 3.
progress of the reaction was monitored by HPLC/LCMS. The
reaction progressed smoothly to get the required 4-acetamido-
1-phenylindazole and no Beckmann products were observed.
However formation of the N,N-diacetyl impurity 6 (5-10%)
was observed under these conditions, which disintegrated in to
the required product during the base work-up. The desired
indazole 5a was then isolated in good yield by basification and
O
O
O
NOH
HN
N
Ac2O, NaI, Xylene
110-120oC
N
N
+
N
N
N
N
4
5
6
aqueous work-up followed by
chromatography.13
a
simple column
R
R
R
The generality of this reaction was studied with a variety of
other oximes (4b-e) prepared in a similar way using substituted
phenylhydrazines and the results are tabulated in Table 2.
Scheme 2
The synthesis of 1-aryl-6,7-dihydro-5H-indazol-4-one oxime
(4) began by reflxing 1,3-cyclohexanedione (7) with N,N-
dimethylformamide diisopropylacetal in toluene to form the
vinylogous enamide 8 in 87% yield. The enamide 8 was
subjected to cyclization with the aryl hydrazines 9 to form the
keto intermediate 10. The keto intermediate 10 was converted
into corresponding oximes 4 by standard process.11,12 The
results are tabulated in Table 1. Practically, the keto
intermediate 10 required no isolation and could be converted to
the oxime in one pot13.
As shown in Table 2, a wide range of oximes underwent
Semmler-Wolff aromatization to afford the desired products in
good yield. In general, this Semmler-Wolff aromatization
reaction condition worked well with both electron rich and
poor aryl systems. Further studies on Semmler-Wolff
aromatization using aryl and hetero-aryl phenylhydrazines with
substituents at various positions were also very successful
yielding indazoles in good yield and are tabulated in Table 3.
O
O
O
NOH
N
a
c
b
N
N
NH+3
Cl–
N
O
O
N
HN
10a-e
7
8
4a-e
a= H,
b= F,
R
R
9a-e
R
c= OMe,
d= CN,
e= Cl
Reaction conditions: (a) Toluene, dimethylfomamide diisopropyl acetal, reflux for 2h. (b) Aq.HCl, IPA, water, 65-70°C, 1-2
h (c) NH2OH.HCl, NaOAc, Water, IPA, 65-70 °C, 2 h
Scheme 3
Table 1: Examples of ketone and oxime intermediates
S.No
1
R
Product Yield
(%)
Product Yield
(%)
Table 2: Examples of Semmeler-Wolff aromatization
S.No
R
Substrate Product Reaction Yield
Time
(h).
H
F
10a
10b
94
4a
94
in (%)
2
3
4
5
90
85
4b
4c
4d
4e
90
85
90
90
1
2
3
4
5
H
F
4a
4b
5a
5b
2.0
2.5
4.5
2.5
2.5
80
75
78
72
75
OCH3 10c
CN
Cl
10d
10e
90
OCH3 4c
5c
90
CN
Cl
4d
4e
5d
Table 1
5e
Table 2

3
Table 3 Semmler-Wolff aromatization of aryl and hetero-aryl substrates
S.No Substrate
Product
Time
3
Yield
72
1
O
NOH
HN
N
N
N
N
4f
5f
O
NOH
2
2.5
75
HN
N
N
N
N
4g
5g
NO2
NO2
O
NOH
HN
3
3
72
N
N
N
N
4h
5h
N
N
F
F
Table 3
The product 4-acetamido-1-arylindazoles
hydrolyzed by heating with sodium hydroxide in ethanol to 4-
amino-1-arylindazoles 11 as shown in Scheme 4.
5
could be
Acknowledgements:
The authors are thankful to management team of AstraZeneca
for their timely support. We also thank Jayan Rapai for
analytical support and Bill Moss for helpful comments.
O
NH2
HN
N
References and notes:
NaOH, EtOH:water (5:1)
70 oC, 4-5 h, 84 % yield
N
N
1. a) Parekh, C.; Modi, A.; Pillai, J.; Patel, B. Int. J. Drug Res.
Tech.; 2012, Vol 2 (3), 279 – 288; b) Lukin, K.; Margaret, C.
H.; Fernando, D.; Robert, L. M. J. Org. Chem. 2006, 71,
8166-8172.
N
11
5a
2.(a). Biggadike, B.; Cooper, A. W. J.; House, D.; Macdonald,
S. J. F.; Skone, P. A.; Weingarten, G. G. WO2008043789 A1.
(b) Biggadike, K.; Cooper, A. W. J.; House, D.; Mclay, I. M.;
Macdonald, S. J. F.; Skone, P. A.; Weingarten, G. G.
;WO 2009050221A1 (c) Biggadike, B; Cooper, A. W. J.;
House, D.; Mclay, I. M.; Macdonald, S. J. F.;
Skone, P. A.; Weingarten, G. G..; WO 2009050243A1 (d)
Scheme 4
In summary, we have described a simple and efficient sodium
iodide catalyzed Semmler-Wolff aromatization method for the
preparation of 4-acetamido-1-arylindazoles from 1-aryl-6,7-
dihydro-5H-indazol-4-one oximes. The method appears to be
general and works well with both aryl and heteroaryl
substituted oximes.

4
Tetrahedron
8 (2.5g, 14.95 mmol ) in isopropanol (37.5 mL) and water (5.0
mL) mixture was added phenylhydrazine hydrochloride 9a
(2.38g, 16.44 mmol) and catalytic amount of concentrated
hydrochloric acid ( 0.054g,1.495 mmol) at 20-25 ºC. The
resultant mixture was allowed to warm to 65-70 ºC and stirred
for 1.0-2.0 h, by which time the reaction was completed as
indicated by TLC. The reaction mixture was then quenched
with excess of water (37.5 mL) and stirred for 2.0 h. The
product was filtered and dried in oven at 50 oC.
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1-phenyl-6,7-dihydro-5H-indazol-4-one oxime (4a): To a
stirred solution of tetrahydoindazole-4-one 10a (1.5g, 7.06
mmol) in isopropanol (22.5 mL) and water (3.0 mL ) mixture,
was added hydroxylamine hydrochloride (0.54g, 7.77 mmol)
and sodium acetate (0.69g, 8.48 mmol) at 20-25ºC. The
resultant mixture was warmed to 65-70 ºC and stirred for 0.5-
1.0 h, by which time the reaction was completed as indicated
by LCMS. The reaction mixture was then quenched with water
(22.5 mL) and stirred for additional 2.0 h. The precipitated
product was then filtered and dried in oven at 50 oC.
3. a) Hu, J.; Cheng, Y.; Yang, Y.; Rao, Y. Chem. Commun.,
2011, 47, 10133-10135 b) Kartrizky, A. R; Rees. C. W;
Comprehensive Heterocyclic Chemistry;Pargamon Press, New
York 1984, Vol. 5, 167-303; c) Pyrazoles, Pyrazolines,
Pyrazolidines, Indazoles and condensed rings Willey, R. H; Ed
Willey Int. New York 1969, P-28; d) Meyer, V. Chem. Ber.
1889, 22, 319; e) Reich, S.; Govigalian, G. Chem. Ber. 1913,
46, 2380-2387.
One-pot synthesis; 1-phenyl-6,7-dihydro-5H-indazol-4-one
oxime (4a):
4. Guo, S.; Song, Y.; Huang, Q.; Yuan, H.; Wan, B.; Wang,
Y.; He, R.; Beconi, M. G.; Franzblau, S. G.; Kozikowski, A. P.
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To
a
stirred solution of 2-dimethylaminomethylene
cyclohexane-1,3-dione 8 (2.5g, 14.95 mmol ) in isopropanol
(37.5 mL) and water (5.0 mL) was added phenylhydrazine
hydrochloride 9a (2.38g, 16.44 mmol) and catalytic amount of
concentrated hydrochloric acid ( 0.054g,1.495 mmol) at 20-25
ºC. The resultant mixture was stirred at 65-70 ºC for 1.0-2.0 h,
by which time the reaction was completed as indicated by
TLC. The reaction mass was cooled to 20-25 ºC followed by
the addition of hydroxylamine hydrochloride (1.14g, 16.44
mmol) and sodium acetate (1.47g, 17.94 mmol). The resultant
mixture was heated to 65-70 ºC and stirred for 0.5-1.0 h, by
which time the reaction was completed as indicated by LCMS.
The reaction mixture was cooled to 20-25 ºC, quenched with
water (22.5 mL) and stirred for additional 2.0 h. The
precipitated product was filtered and dried in oven at 50 oC.
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4-Acetamido-1-phenyl indazol (5a): To a stirred solution of
1-phenyl-6,7-dihydro-5H-indazol-4-one oxime 4a (1.5g, 6.06
mmol) in acetic anhydride (4.5mL) and xylene (15.0 mL )
mixture was added sodium iodide (0.49g, 3.30 mmol) at 20-25
ºC. The resultant mixture was heated to 110-120 ºC and stirred
for 2.0 h, by which time the reaction was completed as
indicated by TLC. The reaction mixture was cooled to 20-25
oC then concentrated under vacuum. The residue was treated
with 1M aqueous sodium hydroxide solution (5 mL) and
extracted with dichloromethane (2X50 mL). The organic layer
was washed with water (2X20 mL), dried over Na2SO4 and
concentrated under reduced pressure to give the crude product
5a. The crude product was then purified by column
chromatography on silica gel (hexane/ethyl acetate, 2:8) to
obtain the pure product as yellow solid.
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Supplementary Material
Supplementary data associated with this article can be found,
in the online version, at
13. Representative Procedures
Synthesis of TetrahydoIndazole-4-one (10a): To a stirred
solution of 2-dimethylaminomethylenecyclohexane-1,3-dione