Construction of 1H-indazoles from ortho-aminobenzoximes by the Mitsunobu reaction

Article abstract of DOI:10.1016/j.tetlet.2019.07.020

Recently, there has been an upsurge in the occurrence of the indazole motif in drug discovery. Accordingly, newer, milder and more efficient routes towards their synthesis have emerged in the literature. We recently reported the Mitsunobu-triggered cyclod

Full text of DOI:10.1016/j.tetlet.2019.07.020

Accepted Manuscript
Construction of 1H-indazoles from ortho-aminobenzoximes by the Mitsunobu
reaction
Ivie L. Conlon, Katie Konsein, Yulemni Morel, Alexandria Chan, Steven
Fletcher
PII:
S0040-4039(19)30666-5
https://doi.org/10.1016/j.tetlet.2019.07.020
TETL 50929
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
3 June 2019
1 July 2019
8 July 2019
Please cite this article as: Conlon, I.L., Konsein, K., Morel, Y., Chan, A., Fletcher, S., Construction of 1H-indazoles
from ortho-aminobenzoximes by the Mitsunobu reaction, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/
j.tetlet.2019.07.020
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1
Highlights
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The synthesis of 1H-indazoles from ortho-aminobenzoximes by Mitsunobu chemistry
Secondary amines are suitable substrates, as well as Boc-activated primary amines
Simple access to N -protected, or N -alkylated 1H-indazoles
1H-indazoles may be prepared with or without substitution at the 3-position
The chemistry is compatible with several functional groups
1
1
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Construction of 1H-indazoles from ortho-
aminobenzoximes by the Mitsunobu
reaction.
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Ivie L. Conlon, Katie Konsein, Yulemni Morel, Alexandria Chan and Steven Fletcher

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Construction of 1H-indazoles from ortho-aminobenzoximes by the Mitsunobu
reaction.
a
b
a
a,c
Ivie L. Conlon, Katie Konsein, Yulemni Morel, Alexandria Chan and Steven Fletcher 
a
Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, 20 N. Pine St., Baltimore, MD 21201, USA
School of Chemistry, Cardiff University, Cardiff, CF10 3AT, UK
University of Maryland Greenebaum Cancer Center, 22 S. Greene St., Baltimore, MD 21201, USA
b
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Recently, there has been an upsurge in the occurrence of the indazole motif in drug discovery.
Accordingly, newer, milder and more efficient routes towards their synthesis have emerged in the
literature. We recently reported the Mitsunobu-triggered cyclodehydration of salicylaldoximes to
transient 1,2-benzisoxazoles, and salicylhydroxamic acids to their corresponding 3-
hydroxybenzisoxazoles. We hypothesized that the likewise cyclization of ortho-
aminobenzoximes should deliver the corresponding 1H-indazoles. Indeed, secondary amines
Available online
1
afforded the predicted N -substituted 1H-indazoles, and primary amines, after activation with a
1
Keywords:
Boc group, furnished the N -Boc 1H-indazoles in good to excellent yields. This work further
1
H-indazole
expands the chemical repertoire of the Mitsunobu reaction, representing its unprecedented use in
Mitsunobu
oxime
the construction of the 1H-indazole nucleus.
cyclodehydration
2
019 Elsevier Ltd. All rights reserved.

Corresponding author. Tel.: +1-410-706-6361; fax: +1-410-706-5017; e-mail: steven.fletcher@rx.umaryland.edu

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1
H-Indazoles are incredibly rare in nature but the diverse pharmacological properties imparted to molecules containing
this nucleus has catapulted them firmly into the drug designer’s toolkit. Indeed, molecules presenting the 1H-indazole motif
have featured in the development of drugs spanning a range of pathophysiologies, such as inflammation (benzadac, 1) and
1
-4
renal cell carcinoma (axitinib, 2), as well as towards the discovery of a male contraceptive (gamendazole, 3). Traditional
5
,6
routes to 1H-indazoles involve severe and/or inconvenient conditions, for example diazotization, or suffer from poor
7
1,2
functional group tolerance. Given the significance of 1H-indazoles in medicinal chemistry, it is becoming increasingly
important to develop milder routes to their synthesis that are compatible with a range of functional groups.
Fig 1. Drug molecules featuring a 1H-indazole motif.
Towards this end, there have been several reports of alternative strategies to access 1H-indazoles. Methods include
8
9
iodine- or PIFA-mediated C-H amination of aryl hydrazones, although yields may be poor or moderate at best,
1
0
cyclizations of o-haloaryl hydrazones, but this requires the o-haloaryl aldehyde/ketone, as well as metal-catalyzed C-H
activations of various precursors, including imidate esters and NH imines with nitrosoarenes. In addition, CsF-mediated
,3-dipolar cycloadditions with an α-substituted diazomethylphosphonates and arynes also affords 1H-indazoles. A mild
1
1
1
2
1
procedure was published in 2008 wherein the in situ O-mesylation of ortho-aminobenzoximes results in a transient
1
3
intermediate that cyclizes to the 1H-indazole nucleus. More recently, Manna and colleagues effected the
cyclodehydration of ortho-aminobenzoximes to 1H-indazoles with the highly electrophilic triphenylphospine-I
system,14
2
1
5
which is a commonly employed ring-closing strategy employed in the synthesis of oxazoles, for example. Given these
reports, we considered that the Mitsunobu reaction might effect the same transformation, offering another mild
synthesis of 1H-indazoles. Indeed, we recently utilized the Mitsunobu reaction to effect the heterocyclization of
1
6
salicylhydroxamic acids into 3-hydroxybenzisoxazoles, as well as salicylaldoximes into salicylonitriles via in situ-
1
7
generated 1,2-benzisoxazoles.
The Mitsunobu reaction is a mild and essentially neutral alkylation,
with clean inversion, of an acidic (pro)nucleophile, whose pK should be
around 12 or lower, such as a carboxylic acid, phenol or sulfonamide
a
1
8-20
with a primary or secondary alcohol.
A remarkably versatile reaction,
it has been employed in the construction of C-O, C-N, C-S as well as C-C
1
8-20
bonds.
Due to its mildness, the Mitsunobu reaction is compatible
with a wide range of functional groups. The reaction typically involves
an azodicarboxylate, such as diethyl azodicarboxylate (DEAD) or
diisopropyl azodicarboxylate (DIAD), and a phosphine, usually
triphenylphosphine. The phosphine reacts with DEAD/DIAD in a
phospha-Michael reaction to generate a betaine intermediate, which is the key species that promotes the reaction
between the (pro)nucleophile and the alcohol.
According to the pK
too high. Therefore, we elected to reduce the pK
carbamate, which we have observed likewise activates an analogous 2-aminopyrimidine derivative to Mitsunobu
a
rule, a primary aromatic amine is unable to engage in the Mitsunobu reaction because its pK
a
is
a
of the amino functionality by transforming it into a Boc-protected
2
1
2
chemistry. Briefly, Boc protection of 2’-aminoacetophenone (4) was achieved with Boc O in hot EtOH; crucially, base
was excluded from the reaction mixture to prevent the undesired formation of the corresponding 4-methylene-3,1-
2
2
benzoaxin-2-one. The requisite oxime functional group was next installed by treatment with hydroxylamine.HCl in
pyridine to deliver 5 almost exclusively as the (E)-isomer, wherein the hydroxyl and NHBoc are distal to each other; only
1
3
a trace amount of the readily separable (Z)-isomer was observed, consistent with the literature. Pleasingly, treatment
of 5 with 1.2 eq of PPh and DIAD effected cyclization to the desired indazole 6 in 65% isolated yield with the mass
balance being unreacted starting material. After some experimentation (see Table 1), we arrived at optimal reaction
conditions of 2 eq PPh and 2 eq DIAD at 60 °C for 4 h. Note that extending the reaction time from 4 h to 16 h had no
3
3
benefit to the yield of the indazole (compare entries 5 and 6), likely owing to decomposition of the intermediate betaine.
Activation of an oxime’s hydroxy can result in its conversion to the corresponding amide or nitrile via the Beckmann
2
3
24
rearrangement or, in the case of oximes with -protons, to the -aminoketone via the Neber rearrangement.
However, the almost-quantitative yield of 6 (entry 6) suggests little or no such rearrangements occurred. Therefore,
these conditions were then applied to a range of N-Boc-activated ortho-aminobenzoximes, and the yields are presented
in Table 2.

3
2 2 3 2 2
Scheme 1. a) Boc O, EtOH, 50 °C, 48 h; (b) NH OH.HCl, pyridine; (c) DIAD, PPh , THF, 60 °C, 4 h; (d) TFA/CH Cl , RT, 1 h.
The Mitsunobu reaction was successful with the aldoxime in entry 2 (Table 2), generating the anticipated 3-
unsubstituted 1H-indazole; the moderate yield was due largely to incomplete consumption of the starting material as no
significant by-products were observed. In contrast, Stambuli’s conditions led to the dehydration of their analogous
1
3
aldoxime to the corresponding nitrile. A variety of ketoximes wherein the NHBoc and hydroxyl were distal to one
another (entries 3 – 10) – all of which happened to be the (E)-isomers were then treated with DIAD and PPh ; all cyclized
3
in good to excellent yields to the corresponding 1H-indazoles. However, the (Z)-oxime in entry 11, isomeric to the
successful reaction in entry 10, failed to deliver any 1H-indazole, indicating that the NHBoc and hydroxyl must be distal
to each other for the reaction to proceed.
a
Table 1. Optimization of the Mitsunobu-triggered cyclodehydration. isolated yield after purification by flash column
chromatography
Deprotection of the Boc group of 6 proceeded
smoothly and quantitatively with a 1:1 mixture of
TFA/CH Cl , or 4 M HCl/dioxane in under 1 h at RT to
2 2
furnish 7. To our surprise, unprotected 1H-indazole 7
could also be generated by conducting the Mitsunobu
reaction on the non-Boc-protected/activated analogue of
5
, albeit in low yield (Table 3, entry 1), highlighting the
significance of the activating group. We surmise this
unexpected Mitsunobu reaction was promoted by the
close proximity of the activated oxime hydroxyl.
Replacement of DIAD with azodicarbonyl dimorpholide
(
ADDM), which can tolerate less acidic pronucleophiles
1
9,25
and has the added benefit of excellent water solubility,
did not improve the yield. The finding in entry 1
motivated us to apply the optimized reaction conditions to a range of secondary anilines (entry 2). Pleasingly,
1
(
unactivated) secondary anilines afforded high yields of the N -substituted 1H-indazoles, although the hindered N-
isopropyl oxime (entry 5) did not react. The N-aryl oxime in entry 6 cyclized efficiently under the optimized conditions,
which is especially noteworthy as alternative, newer 1H-indazole synthetic strategies either do not report on such oximes
1
3,14
or report that the chemistry was unsuccessful.
The tosylated substrate yielded a mixture of products.
The proposed mechanism for the Mitsunobu-triggered cyclodehydration is given in Scheme 2. Upon the standard
activation of the oxime’s hydroxyl group, here playing the role of the alcohol, and deprotonation of the pronucleophile,
intermediate 8 is generated. The aniline nitrogen then attacks the oxime nitrogen, displacing the activated alcohol in a 5-
exo-trig heterocyclization that is allowed by Baldwin’s rules. This mechanism is also consistent with the observation that
the (Z)-oxime (Table 2, entry 11) did not afford any of the corresponding 1H-indazole because (a) the hydroxyl of the
oxime is especially hindered, rendering its activation difficult and (b) the oxime nitrogen is sterically inaccessible and so
the cyclization reaction is not possible under these conditions.

4
a
Table 2. Substrate scope for Mitsunobu reaction with NHBoc oximes. Reagents and conditions: The oxime (1 eq) is dissolved in
b
anhydrous THF (0.1 M), then PPh
flash column chromatography; contaminated with DIAD-H
3
(2 eq) and DIAD (2 eq) are added. The reaction is heated at 60 °C for 4 h; isolated yield after purification by
c
2
, yield determined by NMR.
a
Table 3. Substrate scope for Mitsunobu reaction with NHR oximes utilizing optimized reaction conditions. Isolated yield;
b
1
c
2
contaminated with DIAD-H , yield determined by H NMR; ADDM substituted for DIAD.

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Conclusions
In summary, we have further expanded the utility of the Mitsunobu reaction to include the construction of 1H-indazoles
1
from ortho-aminobenzoximes. Primary amines required pre-activation with a Boc group to deliver the N -Boc protected
1
1
H-indazoles in good to excellent yields, whilst secondary amines furnished N -substituted 1H-indazoles directly. The
chemistry exhibits a strict geometric criterion – the amino group and hydroxyl must be distal to each other. We proposed a
mechanism consistent with these observations wherein the cyclization step is a 5-exo-trig reaction that is permitted by
Baldwin’s rules. This chemistry provides not only an alternative to several of the approaches to 1H-indazoles that have
emerged recently but distinct advantages as well. First, the ability to prepare 3-unsubstituted 1H-indazoles from the
precursor aldoxime opens the door to a variety of chemical transformations at the 3-position, including halogenation and
acylation. Second, this methodology permits the synthesis of 1H-indazoles substituted at the N1 position with aryl groups.
Since Mitsunobu chemistry is mild and occurs under essentially neutral conditions, it is predicted that this work will
become a popular strategy in the synthesis of the 1H-indazole motif.
Scheme 2.
Proposed
mechanism for
construction of
the 1H-
indazole
nucleus under
Mitsunobu
conditions.
Acknowledgements
We thank the University of Maryland School of Pharmacy for financially supporting this research.
Notes and references
1
2
2
3
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. Wilmes, L. J.; Pallavicini, M. G.; Fleming, L. M.; Gibbs, J.; Wang, D.; Li, K. L.; Partridge, S. C.; Henry, R. G.; Shalinsky, D. R.; Hu-
Lowe, D.; Park, J. W.; McShane, T. M.; Lu, Y.; Brasch, R. C.; Hylton, N. M. Magn. Reson. Imaging 2007, 25, 319–27.
. Tash, J. S.; Attardi, B.; Hild, S. A.; Chakrasali, R.; Jakkaraj, S. R.; Georg, G. I. Biol. Reprod. 2008, 78, 1127–1138.
4

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5. Eicher, T.; Hauptmann, S.; Speicher, A. Structures, Reactions, Synthesis, and Applications, 3rd, Completely Revised and Enlarged
Edition; Wiley-VCH:ꢀ Weinheim, 2013.
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. O’Dell, D. K.; Nicholas, K. M. Heterocycles 2004, 63, 373–382.
. Cho, C. S.; Lim, D. W.; Heo, N. H.; Kim, T.-J.; Sim, S. C. Chem. Commun. 2004, 104–105.
. Wei, W.; Wang, Z.; Yang, X.K.; Yu, W.Q.; Chang, J.B. Adv. Synth. Catal. 2017,359, 3378–3387.
. Zhang, Z. G.; Huang, Y. Y.; Huang, G. Q.; Zhang, G. S.; Liu, Q. F. J. Heterocyclic. Chem. 2017, 54, 2426–2433.
0. Lukin, K.; Hsu, M. C.; Fernando, D.; Leanna, M. R. J. Org. Chem. 2006, 71, 8166–8172
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4. Paul, S.; Panda, S.; Manna, D. Tetrahedron Lett. 2014, 55, 2480–2483.
5. Wipf, P.; Miller, C. P. J. Org. Chem. 1993, 58, 3604–3606.
6. Van Eker, D.; Chauhan, J.; Murphy, W. A.; Conlon, I. L.; Fletcher, S. Tetrahedron Lett. 2016, 57, 5301–5303.
7. Whiting, E.; Lanning, M. E.; Scheenstra, J. A.; Fletcher, S. J. Org. Chem. 2015, 80, 1229–1234.
8. Mitsunobu, O.; Yamada, M. Bull. Chem. Soc. Jpn. 1967, 40, 2380–2382.
9. Kumara Swamy, K. C.; Bhuvan Kumar, N. N.; Balaraman, E.; Pavan Kumar, K. V. P.; Chem. Rev. 2009, 109, 2551–2651.
0. Fletcher, S. Org. Chem. Front. 2015, 2, 739–752.
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5. Lanning, M. E.; Fletcher, S. Tetrahedron Lett. 2013, 54, 4624–4628.
6. Preparation of (E)-N-Boc-ortho-aminobenzoxime: 2-aminoacetophenone (4; 1 g, 7.40 mmol, 1 eq) was heated at 50°C with Boc O (1.78
2
g, 8.14 mmol, 1.1eq) in ethanol (12 mL) for 48 h. TLC confirmed the reaction was complete. The reaction mixture was concentrated to
dryness, reconstituted in CH Cl , adsorbed to silica gel, then purified by flash column chromatography (eluent: Hex/EtOAc, 2:1) to deliver
tert-butyl (2-acetylphenyl)carbamate (1.5 g, 88%): δ (400 MHz, CDCl ) 10.95 (s, 1H, NH), 8.47 (d, 1H, Ar, J = 8.8 Hz), 7.86 (d, 1H, Ar, J
7.6 Hz), 7.52 (t, 1H, Ar, J = 7.6 Hz), 7.26 (s, 1H, Ar), 7.03 (t, 1H, Ar, J = 8.0 Hz), 2.65 (s, 3H, COCH ), 1.52 (s, 9H, C(CH ); δ (100
) 202.2, 153.1, 141.8, 134.9, 131.6, 121.4, 120.9, 119.1, 80.5, 28.5, 28.3. tert-Butyl (2-acetylphenyl)carbamate (400 mg, 1.70
OH.HCl (472 mg, 6.80 mmol, 4 eq) and pyridine (1.51 mL, 18.7 mmol, 11 eq) in methanol (6 mL)
overnight. The reaction was then cooled to room temperature, and partitioned between 1M HCl and EtOAc. The organic layer was collected,
and the aqueous was extracted once more with further EtOAc. The combined organic layers were washed with H O, brine, dried over
Na SO , filtered and concentrated. The crude residue was adsorbed onto silica gel from CH Cl , then purified by flash column
chromatography, eluting with Hex/EtOAc, 2:1 to furnish tert-butyl (E)-(2-(1-(hydroxyimino)ethyl)phenyl)carbamate 5 (91%): δ (400 MHz,
DMSO-d ) 8.05 (d, 1H, Ar, J = 8.8 Hz), 7.50 (d, 1H, Ar, J = 8 Hz), 7.32 (t, 1H, Ar, J = 8.4 Hz), 7.09 (t, 1H, Ar, J = 7.6 Hz), 2.21 (s, 3H,
CH ), 1.47 (s, 9H, C(CH ); δ (100 MHz, CDCl ) 183.3, 157.9, 153.2, 137.2, 129.7, 128.4, 121.9, 119.8, 80.2, 28.4, 13.4.
7. Typical Mitsunobu procedure: To a solution of tert-butyl (E)-(2-(1-(hydroxyimino)ethyl)phenyl)carbamate (125 mg, 0.5 mmol, 1 eq) in
anhydrous THF (5 mL) were added PPh (262 mg, 1 mmol, 2 eq) and DIAD (197 L, 1 mmol, 2 eq). The reaction was heated at 60 °C for
h. The solvent was removed in vacuo, the crude residue was adsorbed to silica gel from CH Cl , and then purified by flash column
chromatography (eluent: Hex/EtOAc, 3:1) to afford tert-butyl 3-methyl-1H-indazole-1-carboxylate 6 (110 mg, 95%): δ (400 MHz, CDCl
.07 (d, 1H, Ar, J = 7.6 Hz), 7.60 (d, 1H, Ar, J = 8 Hz), 7.47 (t, 1H, Ar, J = 7.6 Hz), 7.26 (t, 1H, Ar, J = 8 Hz), 2.56 (s, 3H, CH ), 1.69 (s,
2
2
H
3
=
3
3
)
3
C
MHz, CDCl
3
mmol, 1 eq) were refluxed with NH
2
2
2
4
2
2
H
6
3
3
)
3
C
3
2
3
4
2
2
H
3
)
8
9
3
3 3 H 3
H, C(CH ) ); 149.3, δ (100 MHz, CDCl ) 149.3, 148.5, 140.1, 128.8, 125.9, 123.2, 120.3, 114.6, 84.5, 28.2, 12.3.

Graphical Abstract
To create your abstract, type over the instructions in the template box below.
Fonts or abstract dimensions should not be changed or altered.
Construction of 1H-indazoles from ortho-
aminobenzoximes by the Mitsunobu
reaction.
Leave this area blank for abstract info.
Ivie L. Conlon, Katie Konsein, Yulemni Morel, Alexandria Chan and Steven Fletcher

7
