Synthesis of 1,3-diarylsubstituted indazoles utilizing a Suzuki cross-coupling/deprotection/N-arylation sequence

Article abstract of DOI:10.1016/j.tetlet.2010.05.060

Herein we report a general synthesis of 1,3-diarylsubstituted indazoles utilizing a two-step Suzuki crosscoupling/deprotection/N-arylation sequence. This procedure proceeds in excellent overall yield starting from the 3-iodo-N-Boc indazole derivative allowing for rapid access to these compounds.

Full text of DOI:10.1016/j.tetlet.2010.05.060

Tetrahedron Letters 51 (2010) 3796–3799
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 1,3-diarylsubstituted indazoles utilizing a Suzuki
cross-coupling/deprotection/N-arylation sequence
James M. Salovich a,b, Craig W. Lindsley a,b,c, Corey R. Hopkins a,b,
*
a Department of Pharmacology and Vanderbilt Program in Drug Discovery, Nashville, TN 37232-6600, United States
b Vanderbilt Specialized Chemistry Center for Accelerated Probe Development (MLPCN), Nashville, TN 37232-6600, United States
c Department of Chemistry, Vanderbilt University, Nashville, TN 37232-6600, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we report a general synthesis of 1,3-diarylsubstituted indazoles utilizing a two-step Suzuki cross-
coupling/deprotection/N-arylation sequence. This procedure proceeds in excellent overall yield starting
from the 3-iodo-N-Boc indazole derivative allowing for rapid access to these compounds.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 26 April 2010
Revised 12 May 2010
Accepted 13 May 2010
Available online 21 May 2010
The Vanderbilt Specialized Chemistry Center for Accelerated
Probe Development is a member of the Molecular Libraries Produc-
tion Center Network (MLPCN) initiated and supported by the NIH
Molecular Libraries Roadmap.1,2 The MLPCN is a nationwide con-
sortium of facilities that provide high-throughput small-molecule
screening and medicinal chemistry expertise for the development
of chemical probes for use as tools to explore biological targets
or pathways for which small-molecule tools are unavailable.1 As
part of this initiative a high-throughput screen identified a 1,3-dia-
ryl-substituted indazole compound as a potential lead (Fig. 1, CID,
Pubchem Compound ID). Benzannulated nitrogen heterocycles are
ubiquitous in pharmaceutical research.3,4 Over the past decade, the
indazole structural variant (benzo[c]pyrazole) has received much
attention due to a broad range of biological activity.5 The synthesis
of the indazole core, as well as the functionalization of the indazole
ring system has recently been reviewed.6,7
Although the initial iodination proceeded uneventfully (I2, KOH,
quant.), the following N-arylation yielded the desired compound
in a disappointingly low yield (20%).11 Next, the 3-iodo-5-meth-
oxyindazole was reacted under Suzuki–Miyaura coupling condi-
tions,13 however, the reaction did not afford the desired product
and only starting material was obtained (Scheme 1B).12 Lastly,
we attempted the one-pot, diarylation procedure, which did yield
product, but again in very low overall yield (Scheme 1C).12 Note
that the previously reported procedures employed unsubstituted
indazole, whereas our substrate contains the 5-methoxy substrate,
which was required for analog synthesis.
At this time we decided to explore other reaction conditions in
an attempt to improve the overall yield of the sequence; and in
addition, develop a reliable synthesis that allows for both arylation
at the C(3) and N(1) in order to fully evaluate the SAR surrounding
these compounds. Other reports in the literature utilize the N-Boc-
protected indazole under conventional thermal conditions.8,10
However, and much to our surprise, a SciFinder search showing
C(3) arylation followed by N(1) arylation of an indazole had only
the aforementioned reference.12 With this sequence in mind, we
set out to first arylate the C(3) position of 3-iodo-N-Boc-5-meth-
More important to our application, the metal-catalyzed cross-
coupling6 of both the C(3) position (with8–10 or without N-protec-
tion10–12
) and the N(1) position has been reported both
independently and in a one-pot sequence.12 As part of a larger effort
to discover novel heterocycles with interesting biological activities,
we were in need of a flexible synthetic protocol for 1,3-diarylsubsti-
tuted indazoles to derivatize the N(1) and C(3) positions indepen-
dently.
Recent reports from the Rault and co-workers11,12 sparked our
interest as this would provide us a method to synthesize differen-
tially arylated N(1) and C(3) compounds. To this end, we sought to
reproduce the findings in our labs (see Scheme 1). The first attempt
was to obtain the C(3)-iodinated compound followed by N-aryla-
tion and ultimately cross-couple the C(3) position (Scheme 1A).
HO
N
N
CID: 755671
* Corresponding author. Tel.: +1 615 936 6892; fax: +1 615 343 9332.
E-mail address: corey.r.hopkins@vanderbilt.edu (C.R. Hopkins).
Figure 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.060

J. M. Salovich et al. / Tetrahedron Letters 51 (2010) 3796–3799
3797
Table 1
I
O
A
I2, KOH, dioxane;
O
N
N
I
Ar
N
N
H
quant.
ArB(OH)2, Pd(PPh3)4,
N
H
O
O
1
2
N
I
N
2 N Na2CO3, dioxane,
µW, 120 ºC, 40 min
N
O
H
Boc
5
6a-l
N
PhB(OH)2, Cu(OAc)2,
N
Entry
Compd
Ar
Yielda (%)
TEA, CH2Cl2, rt; 20%
3
1
2
3
4
5
6
7
8
9
6a
6b
6c
6d
6e
6f
6g
6h
6i
Phenyl
3-Pyridyl
96
95
98
94
81
81
83
87
92
96
97
87
3-Chlorophenyl
3-Methylphenyl
3-Trifluoromethylphenyl
2,4-Difluorophenyl
4-Trifluoromethylphenyl
4-Pyridyl
1-Methyl-1H-pyrazol-4-yl
2-Furyl
2-Thiophene
I
B
PhB(OH)2, Pd(PPh3)4,
DME, NaHCO3, 80 ºC
O
No reaction
N
N
H
2
10
11
12
6j
6k
6l
4-Methoxyphenyl
I
C
3 eq. PhB(OH)2, Pd(PPh3)4,
O
a
O
Isolated yield.
N
N
Cu(OAc)2, TEA,
NaHCO3, DME, 80 ºC; 24%
N
N
H
2
4
indazole iodide 5 was reacted with 2 equiv of boronic acid in the
presence of an aqueous base in dioxane with Pd(PPh3)4 as catalyst.
The results and isolated yields are summarized in Table 1. The
cross-coupling/N-deprotection is compatible with a variety of aryl
and heteroaryl groups all proceeding in high yield (>80%). Both elec-
tron-withdrawing groups and electron-donating groups proceeded
in high overall yield (6c, 6e, 6f, and 6d). In addition to arylboronic
acids, heteroarylboronic acids also performed well under these
conditions (6b, 6i–k). These reaction conditions allow for access to
NH-3-(hetero)aryl-substituted indazoles that have shown to be
difficult to access previously.9
Following Buchwald’s procedure for the copper-diamine-cata-
lyzed N-arylation,16,17 we then proceeded to arylate the 3-substi-
tuted indazole substrates.18 The reaction was accomplished
utilizing a general procedure which utilized the NH-indazole with
1.2 equiv of aryl iodide, 5 mol % CuI, 2 equiv of base (K3PO4),
20 mol % ligand and toluene under thermal conditions.17 The re-
sults and isolated yields are summarized in Table 2. Table 2 shows
that substitution around the aryl group (ortho, meta, and para) are
tolerated in this reaction—although the 2-methoxy and 2-fluoro-
substiuted compounds reacted in lower yield (7k, 30%; 7l, 28%).
Several functional groups such as amino, methoxy, halogen, and
nitro were also tolerated in this reaction. In addition, heteroaryl
iodides were also well tolerated (7m, 98%).
Scheme 1. Selected attempts to arylate 5-methoxyindazole.
oxyindazole (Scheme 2). Thus, N-Boc formation ((Boc)2O, TEA,
DMAP; 95%) yielded the N-protected indazole in a straightforward
manner.14 Next, Suzuki–Miyaura coupling under thermal condi-
tions did not lead to product and only yielded the starting material
(Scheme 2A). However, Suzuki–Miyaura cross-coupling utilizing
microwave heating conditions not only affected the C–C bond for-
mation but also had concomitant Boc deprotection (Scheme 2B).
There has been a report of N-deprotection of N-Boc indazole during
the cross-coupling conditions9 in which the only product obtained
was the 3-iodo-NH-indazole. This same report also demonstrates
the use of a p-tosyl group which also undergoes N-deprotection;
however, the overall yield of product was 45% (with equivalent
amounts of unreacted de-tosylated starting material).9 The use of
the N-Boc protecting group under microwave heating conditions
has led to high yield of the desired cross-coupled, NH-indazole.
Next we turned our attention to the generality of this cross-cou-
pling, N-deprotection sequence (Table 1).15 The reactions were per-
formed in commercially available heavy-walled Pyrex tubes. The
Having established a three-step, two-pot Suzuki cross-coupling/
deprotection/Buchwald coupling sequence to access the 5-meth-
oxy indazoles we were next able to demethylate to access the ini-
tial screening hit in high yield. To this end, 7a was exposed to 48%
HBr, AcOH under microwave conditions to yield 8 in 90% yield.19
Compound 8 was obtained in an overall yield of 71% from the com-
mercially available 5-methoxyindazole allowing for library synthe-
sis of a number of analogs for further testing in the MLPCN network
of centers.
A
I
I
O
O
(Boc)2O, TEA,
N
N
DMAP, CH3CN; 95%
N
N
H
Boc
5
2
PhB(OH)2, Pd(PPh3)4,
No reaction
º
DME, NaHCO3, 80 C
In conclusion, 3-aryl-NH-indazoles have been prepared in high
yield from the corresponding 3-iodo-N-Boc indazoles under micro-
wave irradiation. The reaction sequence has high functional group
tolerance and excellent overall yield. The concomitant deprotec-
tion of the Boc group led to NH-indazoles that were directly
coupled under Buchwald conditions to yield the desired 1,3-disub-
stituted indazole compounds. Further the 5-hydroxy compound
was realized after demethylation under microwave conditions
(Scheme 3).
B
I
PhB(OH)2, Pd(PPh3)4,
O
O
N
2 N Na2CO3, dioxane,
µW, 140 ºC, 10 min; 96%
N
N
Boc
5
N
H
6
Scheme 2. Suzuki cross-coupling of N-Boc-3-iodo-5-methoxyindazole.

3798
J. M. Salovich et al. / Tetrahedron Letters 51 (2010) 3796–3799
Table 2
Ar-I
CuI/K3PO4
R2
R2
MeO
º
MeO
PhCH3, 110 C. 12 hrs
N
N
NHMe
N
N
H
Ar
NHMe
7a-q
Entry
Compd
R2
Ar
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
H
H
H
H
H
H
H
H
H
H
H
H
Phenyl
4-Fluorophenyl
86
75
62
68
84
90
86
73
65
97
30
28
98
93
73
80
98
94
3-Methoxyphenyl
4-Methylphenyl
4-Methoxyphenyl
4-Aminophenyl
3-Aminophenyl
2-Aminophenyl
3-Fluorophenyl
3-Nitrophenyl
2-Methoxyphenyl
2-Fluorophenyl
2-Pyridyl
H
3-Cl
3-Methyl
3-CF3
2,4-Difluoro
3-Pyridyl
Phenyl
Phenyl
Phenyl
Phenyl
Phenyl
a
Isolated yield.
9. Bouissane, L.; Kazzouli, S. E.; Léonce, S.; Pfeiffer, B.; Rakib, E. M.; Khouili, M.;
Guillaumet, G. Bioorg. Med. Chem. 2006, 14, 1078.
10. Swahn, B.-M.; Huerta, F.; Kallin, E.; Malmström, J.; Weigelt, T.; Viklund, J.;
Womack, P.; Xue, Y.; Öhberg, L. Bioorg. Med. Chem. Lett. 2005, 15, 5095.
11. Collot, V.; Dallemagne, P.; Bovy, P. R.; Rault, S. Tetrahedron 1999, 55, 6917.
12. Collot, V.; Bovy, P. R.; Rault, S. Tetrahedron Lett. 2000, 41, 9053.
13. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
MeO
HO
48% HBr, AcOH,
N
N
N
N
µW, 180 ºC; 90%
14. 3-Iodo-5-methoxy-1H-indazole (2). To a stirred solution of 5-methoxyindazole
(0.50 g, 3.4 mmol) in 1,4-dioxane (34 mL) at 0 °C under argon was added KOH
(1.10 g, 20.0 mmol), followed by iodine (1.71 g, 6.75 mmol). The reaction
mixture was stirred vigorously for 15 min, then warmed to room temperature,
and stirred overnight. The reaction mixture’s color changed from black to
yellow overnight. The pH of the reaction was adjusted to 5 by addition of 20%
aqueous citric acid, and aqueous Na2S2O3 (saturated, 50 mL) was added, and
the mixture was extracted with EtOAc. The combined organic layers were
washed with water, brine, dried over MgSO4, and concentrated under vacuum
to give 929 mg (100%) of the crude product as a yellow solid. This material was
used in the next reaction without further purification. 1H NMR (400 MHz,
DMSO-d6): d 7.44 (d, J = 9.0 Hz, 1H), 7.05 (dd, J = 9.0, 2.1 Hz, 1H), 6.74 (d,
J = 1.7 Hz, 1H), 3.81 (s, 3H). LC/MS: Rt = 1.27 min, m/z = 274.9 [M+1]+.
tert-Butyl 3-iodo-5-methoxy-1H-indazole-1-carboxylate (5). 3-Iodo-5-methoxy-
1H-indazole, 2, (580 mg, 2.12 mmol), triethylamine (0.442 mL, 3.17 mmol),
and DMAP (13 mg, 0.11 mmol) were stirred in acetonitrile (5 mL) for 10 min.
Di-tert-butyl dicarbonate (508 mg, 2.33 mmol) was added and the reaction
mixture was stirred at room temperature for about 10 h. The reaction mixture
was concentrated under vacuum. The residue was dissolved in EtOAc and
water. The aqueous layer was separated and extracted with EtOAc. The
combined organic layers were washed with brine, dried over Na2SO4,
concentrated and the residue was chromatographed on silica gel (12 g)
eluting with a 0–15% EtOAc/hexane gradient to give 749 mg (95%) of the
pure product as a yellow solid. 1H NMR (400 MHz, DMSO-d6): d 7.94 (d,
J = 9.1 Hz, 1H), 7.28 (dd, J = 9.1, 2.5 Hz, 1H), 6.88 (d, J = 2.4 Hz, 1H), 3.86 (s, 3H),
1.63 (s, 9H). LC/MS: Rt = 1.65 min, m/z = 397.0 [M+Na]+.
15. Representative Suzuki coupling example: 5-methoxy-3-phenyl-1H-indazole
(6a). To a microwave reaction vial were added tert-butyl 3-iodo-5-methoxy-
1H-indazole-1-carboxylate, 5, (130 mg, 0.35 mmol), Pd(PPh3)4 (20 mg,
0.02 mmol), phenylboronic acid (85 mg, 0.69 mmol), 1,4-dioxane (3 mL), and
aqueous 2 N Na2CO3 (0.77 mL, 1.54 mmol). The vial was sealed and heated
under microwave irradiation at 120 °C for 40 min. Upon cooling to room
temperature, the reaction mixture was diluted with EtOAc and poured through
Celite, washing with EtOAc. The solute was concentrated under vacuum and
the residue purified by reverse-phase HPLC to afford 75 mg (96%) of the
product as a white solid. 1H NMR (400 MHz, DMSO-d6): d 7.95 (d, J = 7.4 Hz,
2H), 7.53–7.48 (m, 3H), 7.39–7.36 (m, 2H), 7.04 (dd, J = 9.0, 2.1 Hz, 1H), 3.83 (s,
3H). 13C NMR (150 MHz, DMSO-d6) d 154.9, 143.0, 137.8, 134.4, 129.2, 127.7,
127.0, 120.6, 118.5, 112.0, 100.2, 55.8. LC/MS: Rt = 1.76 min, m/z = 225.0
[M+H]+.
8
7a
Scheme 3. Demethylation of indazole.
Acknowledgments
The authors warmly thank the Vanderbilt Department of Phar-
macology and the NIH/MLPCN (5U54MH084659-02) for support of
this research. Vanderbilt is a member of the MLPCN and houses the
Vanderbilt Specialized Chemistry Center for Accelerated Probe
Development.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.05.060.
References and notes
1. For information on the Molecular Libraries Probe Production Centers Network
(MLPCN), see: http://mli.nih.gov/mli/.
2. For information on the Vanderbilt Specialized Chemistry Center, see: http://
www.mc.vanderbilt.edu/centers/mlpcn/index.html.
3. Gribble, G. W.. In Compr. Heterocycl. Chem II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon Press, Inc.: Oxford, 1996; Vol. 2, p 207.
4. Gribble, G. W. J. Chem. Soc., Perkins Trans. 1 2000, 1045.
5. Cerecetto, H.; Gerpe, A.; González, M.; Arán, V. J.; Ochoa de Ocáriz, C. Mini-Rev.
Med. Chem. 2005, 5, 869.
6. Bräse, S.; Gil, C.; Knepper, K. Bioorg. Med. Chem. 2002, 10, 2415.
7. Elguero, J.. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon Press, Inc.: Oxford, 1996; Vol. 3, p 1.
8. Vazquez, J.; De, S. K.; Chen, L.-H.; Riel-Mehan, M.; Emdadi, A.; Cellitti, J.;
Stebbins, J. L.; Rega, M. F.; Pellecchia, M. J. Med. Chem. 2008, 51, 3460.
16. Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123,
7727.

J. M. Salovich et al. / Tetrahedron Letters 51 (2010) 3796–3799
3799
17. Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69,
5578.
(150 MHz, DMSO-d6) d 156.3, 153.7, 148.3, 146.0, 139.5, 135.6, 132.6, 129.5,
129.1, 127.9, 124.1, 120.8, 119.7, 116.6, 113.3, 101.3, 55.9. LC/MS:
Rt = 1.74 min, m/z = 302.2 [M+H]+.
18. Representative Buchwald coupling procedure: 5-methoxy-3-phenyl-1-(pyridin-
2-yl)-1H-indazole (7m). To a microwave reaction vial were added 5-methoxy-
3-phenyl-1H-indazole (70 mg, 0.31 mmol), CuI (3 mg, 0.02 mmol), and K3PO4
(139 mg, 0.66 mmol). The vial was sealed with a septum cap. The vial was
evacuated and back-filled with argon twice. In a separate vial 2-iodopyridine
(0.04 mL, 0.37 mmol), trans-N,N-diamine-1,2-cyclohexanediamine (0.010 mL,
0.06 mmol), and toluene (0.42 mL) were mixed, and then syringed into the
microwave vial. The vial was placed in a 110 °C oil bath and stirred overnight
(18 h). Upon cooling to room temperature, the reaction mixture was diluted
with EtOAc and poured through Celite, washing with EtOAc. The solute was
concentrated under vacuum and the residue purified by reverse-phase HPLC to
give 92 mg (98%) of the desired product as a white solid. 1H NMR (400 MHz,
DMSO-d6): d 8.73 (d, J = 9.2 Hz, 1H), 8.55 (d, J = 4.0 Hz, 1H), 8.09–7.97 (m, 4H),
7.60–7.57 (m, 2H), 7.51–7.45 (m, 2H), 7.31–7.24 (m, 2H), 3.88 (s, 3H). 13C NMR
19. 1,3-Diphenyl-1H-indazol-5-ol (8). 5-Methoxy-1,3-diphenyl-1H-indazole, 7a,
(51 mg, 0.17 mmol), was added to a microwave reaction vial followed by
2.0 mL of (1:1) 48% HBr/acetic acid. The vial was sealed and the reaction
mixture was heated at 180 °C for 10 min. Upon cooling to room temperature,
the reaction mixture was diluted with EtOAc, and aqueous (saturated) NaHCO3
was slowly added until the reaction pH was basic. The aqueous layer was
extracted with EtOAc (3Â). The combined organic layers were dried over
Na2SO4, concentrated under vacuum, and the residue was purified by reverse-
phase HPLC to give 44 mg (90%) of the product as light tan solid. 1H NMR
(400 MHz, DMSO-d6): d 9.51 (s, 1H), 7.95 (d, J = 7.2 Hz, 2H), 7.80 (d, J = 7.6 Hz,
2H), 7.74 (d, J = 9.0 Hz, 1H), 7.61–7.54 (m, 4H), 7.46–7.37 (m, 3H), 7.07 (dd,
J = 9.0, 2.2 Hz, 1H). LC/MS: Rt = 1.54 min, m/z = 287.0 [M+H]+.