Synthetic studies toward 3-(acylamino)-1 H-indazoles and development of a one-pot, microwave-assisted, oxadiazole condensation/Boulton-Katritzky rearrangement

Article abstract of DOI:10.1055/s-0031-1289893

Studies on the Boulton-Katritzky rearrangement of 3-(2-aminoaryl)-1,2,4- oxadiazoles have led to the identification of additional electronic factors that govern the rearrangement as well as a competitive thermal rearrangement pathway for select substrates

Full text of DOI:10.1055/s-0031-1289893

3018
LETTER
Synthetic Studies toward 3-(Acylamino)-1H-indazoles and Development of a
One-Pot, Microwave-Assisted, Oxadiazole Condensation/Boulton–Katritzky
Rearrangement
Synthetic Studies
toward
3
e
-(Acylamin
g
o)-1
H
-
i ndazo
o
les ry R. Ott,* Andrew V. Anzalone
Department of Medicinal Chemistry, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA
Fax +1(610)3440065; E-mail: gott@cephalon.com
Received 21 September 2011
With an interest in a varied set of 3-(acylamino)-1H-inda-
Abstract: Studies on the Boulton–Katritzky rearrangement of 3-(2-
aminoaryl)-1,2,4-oxadiazoles have led to the identification of addi-
tional electronic factors that govern the rearrangement as well as a
competitive thermal rearrangement pathway for select substrates.
zoles, this approach appeared attractive since diversity is
incorporated in a highly convergent manner. Direct acyla-
tion of 3-aminoindazoles has been reported though the use
To circumvent the limitations of the conventional thermal conver- of an acid chloride and/or protection of the indazole nitro-
gen are often required.7 The Boulton–Katritzky methodol-
sion sequence an improved protocol that employs microwave irra-
diation has been devised that allows access to rearrangement
ogy obviated the need for protecting groups on the
products in good to excellent isolated yields. Furthermore, we have
indazole; the oxadiazole is generated from the condensa-
developed a two-component, one-pot sequence using a microwave-
tion of simple esters 3 and oxime amides 2, the latter pre-
assisted oxadiazole condensation/Boulton–Katritzky rearrange-
pared from 2-aminobenzonitriles 1. The envisioned set of
3-(acylamino)-1H-indazoles targeted a range of function-
ality at the acyl position (R1) as well as on the phenyl of
the indazole (R2, R3). Our initial foray using the pre-
scribed conditions for aryl derivatives at R1 (DMF, 150
°C)6b revealed the limitations of this methodology for in-
dazoles lacking N1 substitution (R4 = H): extended reac-
tion times (12–70 h) and the use of melt conditions for
nonaromatic R1 functionality were required. The docu-
mented electronic factors at R1 also proved to be problem-
atic for expansion of this methodology with electron-rich
moieties being disfavored. Furthermore, substituent ef-
fects on the 2-aminoaryl ring (R2, R3), undocumented pri-
or to this report, proved challenging. At this juncture, we
decided to revisit the specifics of this rearrangement for
indazoles lacking N1 substitution (R4 = H). Herein, we re-
port an expanded scope of the Boulton–Katritzky scheme
to produce 3-(acylamino)-1H-indazoles detailing elec-
tronic factors on the 2-aminoaryl ring that govern the re-
arrangement as well as an improved, general protocol
using microwave irradiation. This simple, effective proce-
dure negates the use of melts, decreases reaction times to
two hours or less and, importantly, allows rapid access to
rearrangement products in good to excellent isolated
yields. Furthermore, we have parlayed these results into a
one-pot, microwave-assisted oxadiazole condensation/
Boulton–Katritzky rearrangement sequence to deliver the
desired indazoles from 2-amino-N-hydroxy benzamidine
and simple esters.
ment to deliver 3-(acylamino)-1H-indazoles from simple esters and
2-amino-N-hydroxy-benzamidine
Key words: Boulton–Katritzky rearrangement, indazole, micro-
wave-assisted, oxadiazole condensation, substituent effects
The 3-(acylamino)-1H-indazole motif contains a unique
array of staggered hydrogen-bond donors and acceptors.
Importantly, members of this structural class have a di-
verse biological representation with documented activi-
ties against kinase1 and cysteine protease2 molecular
targets as well as broader-based antifungal3 and antiprolif-
erative activity.4 The Boulton–Katritzky rearrangement
has been recognized as a powerful transformation for the
formation of a variety of heterocycles,5 and an elegant ex-
tension of this methodology, reported independently by
Vivona and Korbonits, has led to the formation of 3-(acyl-
amino)-1H-indazoles from 3-(2-aminoaryl)-1,2,4-oxadi-
azoles (Scheme 1, 4 → 5).6
R4
R4
R3
R2
NH
R3
R2
NH
O
NH2OH
+
OEt
R1
N
NaHCO3
CN
OH
NH2
1
2
3
R4
R4
7
R3
R2
NH
R3
R2
N
Δ
NaOEt
EtOH
1
N
N
To benchmark the electronic effects we used the previous-
ly derived thermal conditions (DMF at 150 °C).6b Analy-
sis of substituent effects at the R2 and R3 positions on the
phenyl ring were explored with electron donating (OMe),
electron withdrawing (NO2), and halogen (Cl). Reactions
were halted at the time indicated and examined for pro-
gression by both HPLC and NMR of the crude isolates.
The results of these studies are depicted in Table 1. For
3
O
4
O
5
NH
N
R1
R1
4
Scheme 1
SYNLETT 2011, No. 20, pp 3018–3022
x
x
.x
x
.2
0
1
1
Advanced online publication: 23.11.2011
DOI: 10.1055/s-0031-1289893; Art ID: S09011ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthetic Studies toward 3-(Acylamino)-1H-indazoles
3019
R1, methyl (4a) and electron-rich phenyl moieties (4c,d) evident. The nitro group (4i) led to facile conversion
were disfavored as expected; conversion reached 19–36% which was predictable since, inductively, the nitrogen of
for this subset after 48 hours of heating. Consistent with the oxadiazole would be more electrophilic. The chloro
the reported paradigm, unsubstituted phenyl 4b reached (4j) derivative proceeded only to 38% after 96 hours, with
68% conversion after 48 h, and the electron withdrawing a diminished inductive capacity to influence the oxadiaz-
4-nitrophenyl derivative 4e yielded complete consump- ole. The methoxy derivative 4k proved particularly inter-
tion of the starting material, though only 64% conversion esting. Conversion into the acyl-aminoindazole over 96
was attained due to a significant accumulation of uniden- hours was 48%, however, a substantial portion was con-
tified byproducts.
verted into an alternative product with the same molecular
weight in a 1.5:1 ratio of indazole/byproduct. We deter-
mined that this product was the benzimidazole derivative
6 (Scheme 2)8 which arises through an alternative (most
likely concerted) rearrangement involving cleavage of the
N–O bond of the oxadiazole and then migration of the aryl
to the nitrogen and formation of the N-acylcarbodiimide.
Collapse of the aniline nitrogen forms the benzimidazole.
Prior to this report, this type of rearrangement had only
been observed photochemically for which a similar mech-
anism had been suggested.9,10 Since this competing reac-
tion path arises only with example 4k, we inferred that the
ensuing positive charge on the first putative intermediate
is stabilized by the presence of the electron-donating
methoxy group. There was no interconversion between 5k
and 6 when either was resubjected to the reaction condi-
tions independently.
The substituent effects on the 2-aminoaryl ring were fairly
pronounced. For R2, an electron-withdrawing substituent
decreased propensity for rearrangement, presumably due
to decreased nucleophilicity of the aniline. For example,
4f provided only 8% conversion after 96 hours. The long-
er reaction times indicated were necessary to provide ac-
curate conversion numbers. In addition, when combined
with an electron-rich substituent at R1 scant conversion
was observed even up to 120 hours (4l, 6%). For R2, reac-
tion rates increased from halogen (4g, 62% conversion, 96
h) to methoxy (4h, >95% conversion, 96 h). This repre-
sented the opposite inductive effect as compared to R1,
most likely due to increased nucleophilicity of the aniline.
For R3, meta to the aniline, electronic perturbation of the
aniline nucleophilicity would be mild, though the impact
on the reaction through influence on the oxadiazole was
Table 1 Comparison of the Results of the Thermal and Microwave Rearrangement
7
H
R3
R2
R3
R2
5
4
1
NH2
N
1
N
N
2
3
4
O
NH
N
O
R1
R1
4
5
Entry
4, 5
R1
R2
R3
Thermal conversion (%), Microwave isolated yield
time (h)a
19, 48
68, 48
36, 48
25, 48
64,b 24
8, 96
after 1 h (%)
1
2
a
b
c
d
e
f
Me
H
H
H
H
H
H
85
96
93
86
90
62
91
75
80
88
53
76c
Ph
H
3
4-MeO-C6H4
H
4
4-Me2N-C6H4
H
5
4-NO2-C6H4
H
6
Ph
NO2
Cl
H
7
g
h
i
Ph
H
62, 96
>95, 96
>95, 96
38, 96
46, 96
6, 120
8
Ph
MeO
H
H
9
Ph
NO2
Cl
MeO
H
10
11
12
j
Ph
H
k
l
Ph
H
4-MeO-C6H4
NO2
a Conversion as measured by HPLC and 1H NMR.
b100% consumption of 4e.
c Reaction time: 2 h.
Synlett 2011, No. 20, 3018–3022 © Thieme Stuttgart · New York

3020
G. R. Ott et al.
LETTER
pot. Towards this end, the various conditions required for
the condensation reported by Wang, which involved car-
boxylic acid activation or in situ acid chloride formation,
were effective for oxadiazole condensation but also led to
concomitant acylation of the aniline, providing complex
mixtures. Alternatively, Adib and co-workers demonstrat-
ed that Meldrum’s acid derivatives are effective partners
for the condensation to oxadiazoles using solvent-free
conditions, though the extent of their findings was limited
to Meldrum’s acid or the monomethyl derivative.13 For
ease and utility, we decided to use the ester functionality
as the condensation partner, and in DMF we were unable
to effect condensation even at elevated temperatures (200
°C). We then surveyed a series of bases including Hünig’s
base, MP-carbonate, sodium ethoxide and potassium tert-
butoxide. With minor experimentation we found that
treating a mixture of the oxime amide and the ester in
DMF with 0.3 equivalent of potassium tert-butoxide us-
ing microwave heating at 200 °C the reaction could be
effected, albeit with significant formation of the 2-ami-
nobenzonitrile, resulting from loss of hydroxylamine
from the oxime amide. We could achieve higher yields by
increasing the stoichiometry of the oxime amide and by
running the reaction first at 160 °C to induce the conden-
sation and then heating to 200 °C to promote the rear-
rangement. Alternatively, to suppress this side reaction,
we followed Adib’s solvent-free protocol which led to
clean conversion into the oxadiazole followed by rear-
rangement to the indazole upon further heating. In in-
stances where incomplete conversion of the oxadiazole
into the indazole was observed, DMF could be added, and
then the reaction was resubjected to microwave heating to
result in a complete transformation.
MeO
NH2
N+
MeO
NH2
N
Δ
O–
O
N
N
4k
MeO
NH2
N
H
N
MeO
H+
NH
O
N
N
O
6
Scheme 2
Pursuant to establishing a general protocol, we first exam-
ined conventional heating at 200 °C in a sealed tube in the
presence of the preferred solvent (DMF). Similar to the
melt conditions first reported, improved rates were ob-
served but still extended reaction times were required. For
example, substrate 4b did lead to 5b in >95% conversion,
but only after 17 hours. Since all the reactions proceeded
with extended reaction times, melts, or with the use of a
sealed tube, it appeared that the major constraints were the
efficiency of heating and increased pressure. These spe-
cific limitations suggested that microwave irradiation
would be a viable alternative.11 With minor experimenta-
tion, we found that heating at 200 °C in DMF for one hour
led to clean conversion of the oxadiazole into the inda-
zole. We were gratified to find that this process was gen-
eral for the substrates indicated in Table 2. Importantly,
for an electron-rich R1 group, high yields for 5a, 5c, and
5d were obtained. The nitro derivative 5f was isolated in
more moderate yield (62%).
Table 2 One-Pot Microwave-Assisted Reaction
H
NH2
N
O
KOt-Bu
+
N
200 °C
MW
N
EtO
R1
OH
The R3 methoxy derivative 4k required only 20 minutes to
give complete consumption of the starting material. The
isolated yield of the desired product 5k was 53% and, not
surprisingly, we observed the presence of benzimidazole
6 in a similar ratio to that observed previously (5k/6 =
1.5:1). Finally, we tested our newly devised conditions
against the most electronically challenging substrates,
namely, an electron-rich R1 group (4-MeOC6H4) com-
bined with an electron-withdrawing R2 group (NO2). Sig-
nificantly, example 4l gave facile rearrangement to the
desired 5l in good isolated yield (76%) though a slightly
longer time (2 h) was recorded for complete conversion.
NH
NH2
O
2
3
R1
5
Entry
3, 5
a
R1
Time (h)
Yield of 5 (%)
1
2
3
4
Me
Ph
2
2
2
2
67
71
58
48
b
c
4-MeO-C6H4
4-NO2-C6H4
e
This procedure appeared general for the substitution on
the ester (Table 2), encompassing alkyl (R1 = Me), aryl
(R1 = Ph), electron-rich (R1 = 4-MeO-C6H4) and electron-
poor aryl derivatives (R1 = 4-NO2-C6H4). Albeit, moder-
ate isolated yields (48–71%) were obtained following this
protocol, the rapid generation of pharmacologically rele-
vant structures using commercially available or readily
obtained starting materials demonstrates the usefulness of
The results presented thus far led us to consider expanding
the utility of this microwave-assisted reaction. Recently,
Wang and co-workers have documented the use of micro-
waves to assist in the synthesis of 1,2,4-oxadiazoles.12 In
light of our own data, we envisioned that if an ortho-
aniline is incorporated into this scheme, we could effect
a two-component oxadiazole condensation/Boulton–
Katritzky sequence to provide the desired indazole in one
Synlett 2011, No. 20, 3018–3022 © Thieme Stuttgart · New York

LETTER
Synthetic Studies toward 3-(Acylamino)-1H-indazoles
3021
this sequence. Extension to substituted 2-amino-N-
hydroxy-benzamidines did, however, complicate the one-
pot sequence and a general protocol for these substrates is
currently under development.
References and Notes
(1) (a) Katritzky, A. R.; Pacureanu, L. M.; Dobchev, D. A.;
Fara, D. C.; Duchowicz, P. R.; Karelson, M. Bioorg. Med.
Chem. 2006, 14, 4987. (b) Aronov, A. M.; Murcko, M. A.
J. Med. Chem. 2004, 47, 5616. (c) Witherington, J.; Bordas,
V.; Gaiba, A.; Naylor, A.; Rawlings, A. D.; Slingsby, B. P.;
Smith, D. G.; Takle, A. K.; Ward, R. W. Bioorg. Med. Chem.
Lett. 2003, 13, 3059; and references therein. (d) Vadivelan,
S.; Sinha, B. N.; Irudayam, S. J.; Jagarlapudi, S. A. R. P.
J. Chem. Inf. Model. 2007, 47, 1526.
(2) (a) Tavares, F. X.; Deaton, D. N.; Miller, A. B.; Miller, L. R.;
Wright, L. L.; Zhou, H.-Q. J. Med. Chem. 2004, 47, 5049.
(b) Tavares, F. X.; Boncek, V.; Deaton, D. N.; Hassell, A.
M.; Long, S. T.; Miller, A. B.; Payne, A. A.; Miller, L. R.;
Shewchuk, L. M.; Wells-Knecht, K.; Willard, D. H. Jr.;
Wright, L. L.; Zhou, H.-Q. J. Med. Chem. 2004, 47, 588.
(3) Raffa, D.; Daidone, G.; Plescia, F.; Schillaci, D.; Maggio,
B.; Torta, L. Farmaco 2002, 57, 183.
In conclusion, we have further documented electronic fac-
tors that govern the Boulton–Katritzky rearrangement of
3-(2-aminoaryl)-1,2,4-oxadiazoles to 3-(acylamino)-1H-
indazoles. Specifically, the propensity for the thermal re-
arrangement of 3-(2-aminoaryl)-1,2,4-oxadiazole sub-
strates bearing substituents at the 4-position (R2) follows
the paradigm methoxy > halogen > nitro. In addition, a
competing rearrangement pathway for substrates with an
electron-donating substituent (MeO) at the 5-position (R3)
of the substrate has been demonstrated that, prior to this
report, has only been observed photochemically. Further-
more, we have devised microwave-irradiation conditions
which rely on an improved efficiency in heating with in-
creased pressure that negate the use of melt or convention-
al sealed-tube conditions, decrease reaction times to two
hours or less and offer the rearrangement products in good
to excellent isolated yields. Finally, we have devised a
two-component, one-pot protocol using a microwave-
assisted oxadiazole condensation/Boulton–Katritzky rear-
rangement to deliver 3-(acylamino)-1H-indazoles from
esters and 2-amino-N-hydroxy-benzamidine.
(4) Raffa, D.; Daidone, G.; Maggio, B.; Schillaci, D.; Plescia, F.
Arch. Pharm. (Weinheim, Ger.) 1999, 332, 317.
(5) Boulton, A. J.; Fletcher, I. J.; Katritzky, A. R. J. Chem. Soc.
C 1971, 1193.
(6) (a) Vivona, N.; Cusmano, G.; Macaluso, G.; Frenna, V.;
Ruccia, M. J. Heterocycl. Chem. 1979, 16, 783.
(b) Korbonits, D.; Kanzel-Szoboda, I.; Horvath, K. J. Chem.
Soc., Perkin Trans. 1 1982, 759.
(7) Krishnamurty, R.; Brock, A. M.; Maly, D. J. Bioorg. Med.
Chem. Lett. 2011, 21, 550.
(8) The structure was confirmed by independent synthesis.
Coupling 6-methoxy-1H-benzoimidazol-2-ylamine with
benzoic acid provided 6, spectroscopically equivalent to the
material from the rearrangement (Scheme 3). For a similar
procedure, see: Hasegawa, M.; Nishigaki, N.; Washio, Y.;
Kano, K.; Harris, P. A.; Sato, H.; Mori, I.; West, R. I.;
Shibahara, M.; Toyoda, H.; Wang, L.; Nolte, R. T.; Veal,
J. M.; Cheung, M. J. Med. Chem. 2007, 50, 4453.
General Procedure for Microwave Rearrangements
The 1,2,4-oxadiazole (0.50 mmol) in DMF (2.0 mL) was heated at
200 °C for 1 h. After cooling, the contents of the reaction were
poured into H2O (25 mL) and extracted with EtOAc (3 × 25 mL).
The combined organics were washed with brine and dried over
MgSO4 and then concentrated under reduced pressure to remove all
residual solvent. The remaining residue was triturated and recrystal-
lized in CH2Cl2–hexanes, and the resulting solids were filtered.
H
H
HOOC
MeO
MeO
N
N
NH
O
NH2
HBTU
Representative Procedure for the One-Pot Condensation–Rear-
rangement
N
N
HOBt
Et3N
DMF
7
6
2-Amino-N-hydroxybenzimidamide (106 mg, 0.701 mmol), ethyl
benzoate (126 mg, 0.841 mmol), and KOt-Bu (10 mg, 0.0891
mmol) were combined and heated in the microwave reactor for 60
min at 200 °C (with optional addition of DMF (1.5 mL) after 30 min
followed by the remaining 30 min of heating at 200 °C). The reac-
tion mixture was then brought up in 20 mL of H2O and extracted
with EtOAc (3 × 25 mL). The combined organics were washed with
brine, dried over MgSO4, and concentrated to afford a yellow oil.
The crude product was purified by flash chromatography (30–60%
EtOAc–hexanes) to give 118 mg of 5b as a white solid (71%) which
was spectroscopically equivalent to that reported in the literature.6b
Scheme 3
(9) Buscemi, S.; Vivona, N.; Caronna, T. J. Org. Chem. 1996,
61, 8397.
(10) An alternative mechanism suggested by a reviewer involves
protonation of the oxadiazole which promotes the observed
rearrangement as shown below (Scheme 4).
MeO
NH2
MeO
NH2
N
Δ
N
O
+
O
H+
N
N
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett. Experimen-
tal procedures, spectral data and copies of 1H, 13C NMR and HRMS
for all new compounds are included.
H
4k
MeO
NH2
N
H
N
MeO
– H
Acknowledgment
NH
O
+
N
H
N
The Authors gratefully acknowledge the support of Dr. Kevin
Wells-Knecht for obtaining high-resolution mass spectra for all new
compounds. The authors thank Dr. Bruce D. Dorsey and Dr. Keith
Learn for helpful discussions during the writing of this manuscript.
6
O
Scheme 4
Synlett 2011, No. 20, 3018–3022 © Thieme Stuttgart · New York

3022
G. R. Ott et al.
LETTER
(12) Wang, Y.; Miller, R. L.; Sauer, D. R.; Djuric, S. W. Org.
Lett. 2005, 7, 925.
(13) Adib, M.; Jahromi, A. H.; Tavoosi, N.; Mahdavi, M.;
Bijanzadeh, H. R. Synlett 2006, 1765.
(11) Heating was performed in a CEM Discover® microwave for
organic synthesis at 300 W for the time indicated with a
ramp time of 2 min with a vertically focused IR temperature
sensor.
Synlett 2011, No. 20, 3018–3022 © Thieme Stuttgart · New York

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