An efficient route to 3-aminoindazoles and 3-amino-7-azaindazoles

Article abstract of DOI:10.1016/j.tetlet.2008.05.100

A non-acidic procedure for the preparation of 3-aminoindazoles and 3-amino-7-azaindazoles from 2-fluoroaryl carboxylic acids is reported. The synthesis starts from readily available starting materials and uses mild and practical reaction conditions in a three-step overall procedure. Products were isolated for a number of examples, but yields varied significantly depending on electronic nature of the substituents.

Full text of DOI:10.1016/j.tetlet.2008.05.100

Tetrahedron Letters 49 (2008) 4579–4581
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Tetrahedron Letters
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An efficient route to 3-aminoindazoles and 3-amino-7-azaindazoles
b
Michael J. Burke a, , Brian M. Trantow
*
a Boehringer Ingelheim Pharmaceuticals, Inc. 900 Ridgebury Rd., Ridgefield, CT 06877, United States
b Stanford University, Department of Chemistry, 333 Campus Dr., Stanford, CA 94305, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 March 2008
Revised 5 May 2008
Accepted 21 May 2008
Available online 27 May 2008
A non-acidic procedure for the preparation of 3-aminoindazoles and 3-amino-7-azaindazoles from
2-fluoroaryl carboxylic acids is reported. The synthesis starts from readily available starting materials
and uses mild and practical reaction conditions in a three-step overall procedure. Products were isolated
for a number of examples, but yields varied significantly depending on electronic nature of the
substituents.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Indazole
Thioamide
Azaindazole
Recently, there has been great interest in the use of 3-aminoin-
dazoles as agents interacting with a variety of biological targets
including kinases,1 Factor XIa,2 CB1,3 and PARP1.4 The methods
for the preparation of these compounds typically involved the
reaction of a 2-haloaryl nitrile with hydrazine to provide the 3-
aminoindazole, of which the amine must be further elaborated
(Scheme 1).
Acids 1–3 were coupled with amines a–d using HATU/TEA
in DMF to prepare amides 4–6 in excellent yields.8 Attempts to
directly convert these amides to the desired indazoles via reaction
with hydrazine under a variety of conditions were unsuccessful as
the intermediate aminoamidine could not be detected. In order to
increase the reactivity of these amides, they were converted to
their corresponding thioamide derivatives (7–9) in good yield with
Lawesson’s Reagent in toluene or THF.9 The desired products can
then be prepared by simple dissolution of the thioamide in anhy-
drous DMSO and heating with an excess of anhydrous hydrazine.10
The products prepared in this manner are summarized in Table 1
below.
Examination of the effect of substitution para to the fluoro atom
shows that the electron-donating p-methoxy substituent nega-
tively affects the yield of indazole product when compared to the
outcome with the electron-withdrawing p-fluoro substituent. It
was also evident that the preparation of these methoxy derivatives
required higher temperatures for the reaction to proceed relative
to the electronically neutral proton and electronically deficient
fluoro groups.
Alternatively, use of either 3-chloroindazole3,5 or imidoyl chlo-
rides, prepared with SOCl2 or POCl3,6 can be reacted with the de-
sired amine; however, metal catalysis or protecting group
manipulation is required for these reactions to succeed.
Recently, we required a general method for the preparation of
3-aminoindazoles which avoided the use of harshly acidic condi-
tions, protecting groups, or metal catalysis while allowing for the
incorporation of elaborated amines. Literature examination re-
vealed only two examples of a two-step procedure requiring both
acidic and basic steps through use of a thioamide and hydrazine.7
The work described herein represents a milder approach to the
preparation of these cores using representative amines and 2-fluo-
roaryl acids as starting points (Scheme 2).
Attempts to use hydroxylamine, in place of hydrazine in this
method, failed to produce the desired 3-amino-1,2-benzisoxazoles
as the oxygen atom failed to displace the o-fluoro group, even as
the intermediate hydroxyamidine was observed by mass spectro-
scopy. Similarly, other attempts using substituted hydrazines in
efforts to provide N1 alkylated 3-aminoindazoles gave complex
mixtures of products.
R"
R'
NH2
N
N
R
R
R
CN
X
H2N NH2
N
N
N
H
H
In order to determine if the methodology could be extended to
the preparation of azaindazoles, we investigated the use of either
nicotinic or isonicotinic acids as starting materials and found that
success depended on the position of the pyridyl nitrogen relative
to the halogen atom.
Scheme 1. 3-Aminoindazole preparation from o-halo arylnitriles.
* Corresponding author. Tel.: +1 203 798 4180; fax: +1 203 791 6072.
E-mail address: michael.burke@boehringer-ingelheim.com (M. J. Burke).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.100

4580
M. J. Burke, B. M. Trantow / Tetrahedron Letters 49 (2008) 4579–4581
O
O
F
Lawesson's Reagent
R
TEA / HATU
DMF/rt/18h
R
amine
+
OH
amine
toluene/heat
F
1 R = H
2 R = F
3 R = OMe
a amine = aniline
4-6
b amine = benzyl amine
c amine = morpholine
d amine = dimethyl amine
amine
N
S
R
DMSO/heat
R
+
H2N NH2
amine
N
H
F
7-9
10-12
Scheme 2. Procedure for the preparation of 3-aminoindazoles.
Table 1
Yields and compounds prepared upon reaction of hydrazine with thioamides
R'
N
S
R
DMSO/heat
R
+
H2N NH2
R'
N
H
F
7-9
10-12
R
R0
O
N
H
N
N
N
H
O
H
N
N
H
N
N
N
N
N
H
N
N
H
N
H
N
10a, 73%
N
H
9d, 56%
H
10c,76%
10b, 75%
O
N
HN
H
N
F
N
F
F
N
F
F
N
N
N
N
H
N
H
N
N
H
11d, 74%
H
11a, 86%
11c, 65%
11b, 70%
O
N
H
N
HN
O
N
O
O
N
OMe
O
N
N
N
H
N
N
H
N
H
N
H
12d, 16%
12a, 22%
12c, 27%
12b, 19%

M. J. Burke, B. M. Trantow / Tetrahedron Letters 49 (2008) 4579–4581
4581
Table 2
roisonicotinic thioamides, no conditions were identified that
provided for the preparation of the desired 6-azaindazole systems.
Attempts to produce azaindazoles using 4-chloro-3-thionicotinic
amides also failed as chloro displacement by hydrazine prevailed
which in turn led to intractable products. Future investigations will
examine the use of less reactive leaving groups, such as methoxy or
thiomethyl in place of the halogen, to complete the aza series.
Also, investigation is underway using 2-bromo substituents and
metal catalysis for the preparation of 3-aminoazabenzisoxazole
compounds, which are relatively underrepresented in the litera-
ture. This may also provide a means to improve the yields for
electron-rich ring systems.
Preparation of 3-amino-7-azaindazoles
R'
S
DMSO/80 oC
+
H2N NH2
N
R'
N
N
H
N
13
F
14
R0
Product, yield
HN
N
N
H
Acknowledgments
13a
N
N
The authors would like to thank Dr. John Regan for strategic
discussions; Mr. Mark Ralph for the preparation of some inter-
mediates; as well as the Connecticut Business and Industry Associ-
ation for the summer industrial tenure of Mr. Brian Trantow.
H
14a, 73%
Supplementary data
H
N
H
N
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2008.05.100.
N
13b
N
H
References and notes
N
14b, 84%
1. (a) Klein, M.; Gericke, R.; Mederski, W.; Beier, N.; Lang, F. WO2007/090494,
August 16, 2007.; (b) Bingaman, D. US 2006/0189608, August 24, 2006; (c)
Harmange, J. -C.; Booker, S.; Bauer, D.; Kim, T. -S.; Cheng, Y.; Xu, S.; Ning, X.;
Kim, J.; Tasker, A. WO2005/073224, August 11, 2005.; (d) Woods, K.; Fisher, J.;
Claiborne, A.; Li, T.; Thomas, S.; Zhu, G.-D.; Diebold, R.; Liu, X.; Shi, Y.;
Klinghofer, V.; Han, E.; Guan, R.; Magnone, S.; Johnson, E.; Bouska, J.; Olson, A.;
de Jong, R.; Oltersdorf, T.; Luo, Y.; Rosenberg, S.; Giranda, V.; Li, Q. Bioorg. Med.
Chem. Lett. 2006, 14, 6832; (e) Stocks, M.; Barber, S.; Ford, R.; Leroux, F.; St.
Gallay, S.; Teague, S.; Xue, Y. Bioorg. Med. Chem. Lett. 2005, 15, 3459.
2. Pinto, D.; Smallheer, J.; Corte, J.; Zilun, H.; Cavallaro, C.; Gilligan, P.; Quan, M.
WO2007/070826, June 21, 2007.
O
O
N
N
N
N
N
N
13c
H
3. Santhakumar, V.; Tomaszewski, M. WO2006/052190, May 18, 2006.
4. Guillemont, J.; Kennis, L.; Mertens, J.; Van Dun, J.; Somers, M.; Wouters, W.
WO2006/003146, January 12, 2006.
14c, 80%
5. Bouchet, P.; Lazaro, R.; Benchidmi, M.; Elguero, J. Tetrahedron 1980, 36, 3523.
6. (a) Leroy, V.; Lee, G.; Lin, J.; Herman, S.; Lee, T. Org. Process Res. Dev. 2001, 5,
179; (b) Watson, T.; Ayers, T.; Shah, N.; Wenstrup, D.; Webster, M.; Freund, D.;
Horgan, S.; Carey, J. Org. Process Res. Dev. 2003, 7, 521.
7. Kennis, L. E., Vendenberk, J., Mertens, J. C. US 4, 958, 916, September 18, 1990.
8. General procedure I for amide preparation: To o-fluoro arylacid (1 equiv) in DMF
(5 mL/3.5 mmol acid) were added triethylamine (1.5 equiv), amine (1.1 equiv),
and HATU (1.1 equiv). This mixture was allowed to stirr for 18 h at room
temperature, then diluted with EtOAc and transferred to a separatory funnel.
The mixture was diluted with EtOAc and rinsed with saturated Na2CO3, water,
and brine. The organics were then dried with Na2SO4, filtered, and evaporated.
The residue was then purified via flash chromatography (hexanes/EtOAc) to
provide the desired amide in yields of 80–95%.
N
N
N
N
13d
H
14d, 57%
9. General procedure II for thioamide preparation: To o-fluoro aryl amide (1 equiv)
in toluene (5 mL/1.7 mmol) or THF (for azacompounds) was added Lawesson’s
Reagent (1 equiv) and the mixture was heated at 100 °C (40 °C for
azacompounds). Upon completion (2–18 h), the reaction was filtered through
Celite and the filtrate was evaporated. The residue was purified via flash
chromatography (hexanes/EtOAc) to provide the desired thioamide in yields of
75–85%.
10. General procedure III for indazole preparation: To o-fluorothioamide (1 equiv) in
anhydrous DMSO (5 mL/1.7 mmol) was added hydrazine (10 equiv) in one
portion. The flask was then lowered into a preheated oil bath (150 °C e.g., 10a–
11d; 180 °C e.g., 12a–d; and 80 °C e.g., 14a–d) and allowed to stir. After 2 h, or
until reaction appeared complete via MS, the reaction was cooled to room
temperature, diluted with saturated Na2CO3, and extracted with Et2O. The
combined organics were rinsed with water, brine, dried with Na2SO4, filtered,
and evaporated. The residue was then purified via flash chromatography
(hexanes/EtOAC) to provide the desired products.
Using 2-fluoro nicotinic acid as a starting point, decreased reac-
tion temperatures and extended reaction times were required for
the preparation of the thioamides 13a–d. Under standard condi-
tions, displacement of the fluoro atom by thiol, presumably origi-
nating from decomposition of Lawesson’s reagent was the major
product. Attempts to limit this through the use of 0.25 mol equiv
of Lawesson’s reagent created long reaction times and incomplete
conversion to product. Once conditions were optimized, the
thioamide reaction with hydrazine proceeded quite smoothly to
produce products 14a–d as can be seen in Table 2.
Attempts to extend the method to the preparation of additional
isomeric azaindazoles have so far been unsuccessful. With 3-fluo-