Protected indazole boronic acid pinacolyl esters: Facile syntheses and studies of reactivities in Suzuki-Miyaura cross-coupling and hydroxydeboronation reactions

Article abstract of DOI:10.1055/s-0028-1087922

The paper describes a rapid and efficient synthesis for the isolation of protected indazolylboronic esters. These compounds were synthesized by reaction between prepared protected haloindazoles and bis(pinacolato)diboron. The effects of solvent, temperature, reaction time, and the nature of halogen atom as well as protecting group were investigated. Additionaly, these compounds reacted either with aryl halides in a Suzuki-Miyaura cross-coupling reaction or with hydrogen peroxide in a hydroxydeboronation reaction showing the potential access to new aryl and hydroxyindazole libraries. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087922

LETTER
615
Protected Indazole Boronic Acid Pinacolyl Esters: Facile Syntheses and
Studies of Reactivities in Suzuki–Miyaura Cross-Coupling and
Hydroxydeboronation Reactions
R
eactivities in
r
Suzuki–
a
Miyaura
C
n
r
oss-Couplin
ç
g
ois Crestey, Elodie Lohou, Silvia Stiebing, Valérie Collot,* Sylvain Rault
Université de Caen Basse-Normandie, U.F.R. des Sciences Pharmaceutiques, Centre d’Études et de Recherche sur le Médicament de
Normandie (CERMN), UPRES EA-4258, FR CNRS INC3M, Boulevard Becquerel, 14032 Caen Cedex, France
Fax +33(2)31931188; E-mail: valerie.collot@unicaen.fr
Received 8 October 2008
R
R
N
N
H
R
Abstract: The paper describes a rapid and efficient synthesis for
the isolation of protected indazolylboronic esters. These com-
pounds were synthesized by reaction between prepared protected
haloindazoles and bis(pinacolato)diboron. The effects of solvent,
temperature, reaction time, and the nature of halogen atom as well
as protecting group were investigated. Additionaly, these com-
pounds reacted either with aryl halides in a Suzuki–Miyaura cross-
coupling reaction or with hydrogen peroxide in a hydroxydeborona-
tion reaction showing the potential access to new aryl and hydroxy-
indazole libraries.
Y
N
X
(R'O)2B
N
N
N
I
II
III
R'
R'
X = halogen; R' = protecting group; Y = aryl or OH
Scheme 1
varied, including the nature of protecting group and halo-
gen atom as well as the effects of solvent, temperature,
and reaction time. This was followed by a Pd-catalyzed
coupling reaction of several freshly prepared boronates
showing the reactivity of these functionalized building
blocks and a potential access to a promise heterocyclic li-
brary I. In addition, we now provide as well an alternative
for the synthesis of hydroxyindazoles by hydroxyde-
boronation (Scheme 1).
Key words: indazole boronic acid pinacolyl esters, Suzuki–
Miyaura cross-coupling reaction, palladium-mediated reaction,
protected halo-1H-indazoles, hydroxydeboronation
Our group has long been interested in the design and syn-
thesis of new polyfunctionalized indazole libraries,1 par-
ticularly those derived from the 2-aza bioisosteres of
tryptamine, serotonin, melatonin, or tryptophan.2
R
R
In the present work we extend the studies on our ongoing
research program to the development of a rapid methodol-
ogy for the synthesis of indazolylboronic esters for the
purpose to prepare new valuable building blocks in me-
dicinal chemistry. Boronic acids and esters have emerged
as two of the most useful classes of organoboron com-
pounds in organic synthesis, particularly for the formation
of carbon–heteroatom bonds3 and in Pd-catalyzed cross-
coupling reactions with organic halides and triflates (the
Suzuki–Miyaura reaction).4 Moreover, these synthetic in-
termediates provide a versatile and efficient access to hy-
droxy,5 halo,6 nitro,7 and keto8 compounds as well as
amino acids.9 Furthermore, over the past few years there
has been an increased availability of heteroaromatic bo-
ronic acids and esters.10,11 In contrast, indazolylboronic
acids or esters have been surprisingly poorly investigated,
and an exhaustive survey of literature revealed only few
articles and patents wherein procedures were not always
clearly explained.12–15
i or ii or iii
X
N
X
N
R' = SEM 2a–f
R' = Ac 3a–e
R' = THP 4a–d
N
N
H
R = H, Me
X = Br, I
R'
1a–g
Scheme 2 Reagents and conditions: i) SEMCl (1.1 equiv), TBABr
(0.01 equiv), CH2Cl2/KOH aq 50%, 0 °C for 1 h then at r.t. for 2 h,
52–99%; ii) Ac2O, reflux conditions, 2 h, 80–100%; iii) DHP (2.5
equiv), TFA (cat), EtOAc, reflux conditions, 6 h, 70–100%.
First, indazoles 1a–g bearing bromo or iodo halogen
atoms in position 4, 5, 6, and 7 were prepared from the
corresponding 2-alkylanilines according to a previously
successful method developed in our laboratory.16 Then, it
was required to protect the nitrogen atom of the indazole
nucleus at this stage for potential subsequent reactions as
well as avoiding possible side reactions during the boryla-
tion. Accordingly, the following groups have been used
for the protection step: 2-(trimethylsilanyl)ethoxymethyl
(SEM), acetyl (Ac) and tetrahydropyran-2-yl (THP).
Next, a procedure recently published by Kania and co-
workers,17 protection in a biphasic mixture CH2Cl2/KOH
(50% solution in H2O) in the presence of SEMCl (1.1
equiv) and a catalytic amount of TBABr, provided 1-SEM-
1H-haloindazoles 2a–f. Protected indazoles 3a–e were
obtained by reaction with acetic anhydride for two hours
under reflux conditions with excellent yields. Moreover,
With this in mind, we first evaluated the feasibility of the
transformation of various haloindazoles III into the corre-
sponding boronates II. Several reaction parameters were
SYNLETT 2009, No. 4, pp 0615–0619
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x.
x
x.
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0
0
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Advanced online publication: 16.02.2009
DOI: 10.1055/s-0028-1087922; Art ID: G32908ST
© Georg Thieme Verlag Stuttgart · New York

616
F. Crestey et al.
LETTER
Table 1 Synthesis of Protected Halo-1H-indazoles 2a–f, 3a–e, and 4a–d from the Corresponding Halo-1H-indazoles 1a–g
Indazoles
X
R
Yield (%) of 2
2a
Yield (%) of 3
Yield (%) of 4
1a
1b
1c
1d
1e
1f
4-Br
4-I
H
H
H
Me
H
H
H
96
52
81
–
3a
100
–
4a
–
82
–
2b
2c
–
–
5-Br
5-Br
5-I
3b
3c
–
92
83
–
4b
–
70a
–
2d
2e
2f
99
92
97
–
–
6-Br
7-Br
3d
3e
86
80
4c
100a
76
1g
4d = 4da/4db (3:1)
a The reaction was performed in CHCl3.
taking into account the previously described works in high yields and purities, in a polar solvent. Furthermore,
pyrazole18 and imidazole series,19 in which THP was an the resultant pinacolyl boronate esters have the advantage
excellent N-protecting group to prepare boronic acid de- of being stable compounds which can be purified by chro-
rivatives, haloindazoles 1a,c,f,g reacted with dihydropy- matography. With this in mind and starting from 5-iodo-
ran following a standard procedure described by Young indazole 2d, bis(pinacolato)diboron, PdCl2(dppf), and
and co-workers.20 These conditions provided THP-pro- KOAc, the procedure recently described by Reich and co-
tected indazoles 4a–d in very good yields. For the com- workers was applied using DMSO as solvent at 80 °C for
pounds 4b,c, chloroform was used as solvent instead of two hours (Scheme 3).24 But in our hands, only the
ethyl acetate with increasing yields. Concerning the pro- byproduct 6 (called dimer)2a resulting of the homo-
tected indazole 4d, it has been determinated by 1H NMR coupling reaction was isolated in a 85% yield (Table 2,
that this product was a mixture of (N-1 and N-2)-THP- entry 1).
indazole with a 4da/4db ratio of 3:1 (Scheme 2 and
Table 1).
O
O
i
Br / I
N
B
N
In order to establish conditions that enable an efficient and
convenient protocol for the formation of indazolylboronic
esters and acids in general, our initial focus was on opti-
mizing the synthesis of 5-indazolyl boronic species. Dur-
ing the last decades, alkyl and aryl boronate esters and
acids were occasionally prepared by reacting an organo-
metallic intermediate generated from an arene or an aryl
halide and stoichiometric quantities of a metalating agent
with a boron electrophile.21 Thus, taking into account our
know-how in the laboratory about the halogen–metal
exchange for the synthesis of various boronic species,22
bromine–lithium exchange and iodine–lithium exchange
were carried out (starting from N-SEM indazoles 2c and
N
N
SEM
SEM
2a–f
5a–d
N
SEM
N
N
SEM
N
6
Scheme
3
Reagents and conditions: i) KOAc (4.6 equiv),
PdCl2(dppf)–CH2Cl2 (0.08 equiv), bis(pinacolato)diboron (1.15
equiv), argon, 79–98%.
Table 2 Study of the Formation of Protected Indazolylboronic
Esters 5a–d
2d) in dry THF at –78 °C with n-BuLi or t-BuLi followed Entry Indazoles 2 Solvent
Time (min) Yield (%) of 5 or 6
by a subsequent quench with triisopropylborate [B(Oi-
1
2
3
4
5
6
7
2d
2d
2c
2c
2a
2e
2f
DMSOa
120
15
6
85
85
87
67
98
98
79
Pr)3] as electrophile. Unfortunately, only the deshalo
products were recovered. In front of our unsuccessful pre-
liminary attempts, we decided to modify our strategy to
obtain indazolylboronic esters. In 1995, Miyaura and co-
workers reported the synthesis of arylboronates by the
palladium-mediated cross-coupling reaction of tet-
raalkoxydiboron reagents with haloarenes.23 They used
bis(pinacolato)diboron as an easily handled source of
nucleophilic organoboron reagent, 1,1-bis(diphenylphos-
phino)ferrocenedichloropalladium–CH2Cl2 [PdCl2(dppf)]
as a source of palladium and potassium acetate (KOAc) as
base which is recognized to be a suitable weak base for a
wide variety of aromatic substrates and enables to achieve
DMSO
5b
6
DMSO
15
1,4-dioxaneb
1,4-dioxane
1,4-dioxane
1,4-dioxane
30
5b
5a
5c
5d
45
15
240
a With DMSO as solvent the reactions were performed at 80 °C.
b With 1,4-dioxane as solvent the reactions were performed under
reflux conditions.
Synlett 2009, No. 4, 615–619 © Thieme Stuttgart · New York

LETTER
Reactivities in Suzuki–Miyaura Cross-Coupling
617
R
Subsequently, with the aim to investigate the reactivity of
prepared protected indazole boronic acid pinacolyl esters,
two examples of their potential applications are depicted
in Scheme 5. Boronates were coupled with 4-iodoanisole
or 1-chloro-2-iodobenzene in a standard Suzuki–Miyaura
cross-coupling reaction, furnishing a range of arylinda-
zoles 9–17 (Table 4). Our first attempts at 60 °C in DMF
with K3PO4 (1 equiv) as base and aryl halide (1.2 equiv)
provided the desired compounds in moderate to good
yields (25–65%).26 In order to compare other reaction
conditions, Cs2CO3 (2 equiv) as base in a mixture 1,4-di-
oxane–water (2:1) under reflux conditions with Pd(Ph3P)4
(5 mol%) and aryl halide (1.5 equiv) gave similar or better
yields (37–73%).27,28 Moreover, the synthesis of hydroxy-
indazoles from the corresponding boronic esters has been
examined. Action of hydrogen peroxide for one hour at
room temperature on compounds 5a–d bearing a SEM
group did not afford the expected products. But the same
conditions applied to the acylated 4- and 5-indazolyl-
boronic esters 7a and 7b provided the corresponding
hydroxy compounds 18a and 18b with 98% and 36%
yields, respectively, providing an interesting alternative
for the synthesis of hydroxyindazoles.29,30 These results
R
O
O
i
Br
N
B
N
N
N
R = H, Me
R'
R'
R' = Ac 3a–c
R' = THP 4a–d
R' = Ac 7a–c
R' = THP 8a–d
Scheme
4
Reagents and conditions: i) KOAc (4.6 equiv),
PdCl2(dppf)–CH2Cl2 (0.08 equiv), bis(pinacolato)diboron (1.15
equiv), argon, 1,4-dioxane, reflux, time, 18–98%.
Table 3 Synthesis of Protected Indazolylboronic Esters 7a–c and
8a–d
Indazoles
Time (h)
Yield (%) of 7 or 8
3a
3b
3c
4a
4b
4c
4d
0.25
7a
7b
7c
8a
8b
8c
8d
98
4
24
3
97
90a
87
89
77
18
3
4
4
a The reaction was performed at 80 °C with DMSO as solvent.
O
i
B
N
N
O
N
Y
N
Next, reducing the reaction time to 15 minutes (reaction
was monitored by TLC) resulted in the formation of de-
sired boronate 5b with a very good yield of 85% without
formation of the dimer (Table 2, entry 2). Surprisingly,
the same conditions applied to the protected 5-bromoinda-
zole 2c provided exclusively the dimer 6 with 87% yield
(Table 2, entry 3). To avoid the formation of this byprod-
uct, the effect of the solvent was examined. Gratifyingly,
a high conversion of 2c into the desired boronate 5b
(Table 2, entry 4) was obtained when 1,4-dioxane was
used as solvent. Furthermore, running the reaction in 1,4-
dioxane eliminated the formation of the dimer side prod-
uct 6 and gave the indazolylboronic esters 5a and 5c,d in
excellent yields when the corresponding bromoindazoles
2a and 2e,f were used (Table 2, entries 5–7).
R
R
9–17
R = SEM, Ac or THP
Y = 2-Cl or 4-OMe
O
O
ii
B
N
HO
N
N
N
18a,b
7a,b
O
O
Scheme 5 Reagents and conditions: i) Method I: 4-iodoanisole or 1-
chloro-2-iodobenzene (1.2 equiv), K3PO4 (1 equiv), Pd(Ph3P)4 (0.08
equiv), argon, DMF, 60 °C, 3 h, 25–65%; Method II: 4-iodoanisole
(1.5 equiv), Cs2CO3 (2 equiv), Pd(Ph3P)4 (0.05 equiv), argon, 1,4-
dioxane–water (2:1), reflux, 12 h, 37–73%; ii) H2O2 aq, EtOAc, r.t., 1
h, 36–98%.
Table 4 Synthesis of Protected Arylindazoles 9–17
Finally, the conditions selected for additional studies in
position 4, 5, 6, and 7 of the indazole ring with acetyl and
THP protecting groups encompassed the use of 1,4-di-
oxane as solvent under reflux conditions and starting from
the bromo derivatives with a control of the reaction times
(Scheme 4).25 Similarly, the acetyl-protected indazoles
3a–c were converted into the corresponding boronic
esters 7a–c with excellent yields (90–98%). Unfortunate-
ly, indazoles 3d,e gave the corresponding unprotected
haloindazoles under the same conditions. Next, indazolyl-
boronic esters 8a–c were obtained from the related 1-
THP-1H-haloindazoles 4a–c with very good yields (77–
89%). However, a moderate yield was obtained for the 7-
indazolylboronic ester 8d probably due to the hindrance
generated by the group THP on the C-7 position of the
indazole nucleus (Table 3).
Boronates
Method
Y
Yield (%) of indazole
5a
5b
5c
5d
7a
8a
8b
8c
8d
I
2-Cl
9
10
11
12
13
14
15
16
17
42
65
25
37
40
50
34
64
73
I
4-MeO
4-MeO
4-MeO
4-MeO
4-MeO
4-MeO
4-MeO
4-MeO
I
II
I
II
I
II
II
Synlett 2009, No. 4, 615–619 © Thieme Stuttgart · New York

618
F. Crestey et al.
LETTER
Friedman, L. S.; Hayes, A.; Hancox, T. C.; Kugendradas, A.;
Lensun, L.; Moore, P.; Olivero, A. G.; Pang, J.; Patel, S.;
Pergl-Wilson, G. H.; Raynaud, F. I.; Robson, A.; Saghir, N.;
Salphati, L.; Sohal, S.; Ultsch, M. H.; Valenti, M.;
Wallweber, H. J. A.; Wan, N. C.; Wiesmann, C.; Workman,
P.; Zhyvoloup, A.; Zvelebil, M. J.; Shuttleworth, S. J. Med.
Chem. 2008, 51, 5522. (b) Chuckowree, I.; Folkes, A.;
Hancox, T.; Shuttleworth, S. WO 07129161, 2006; Chem.
Abstr. 2007, 147, 541901. (c) Shuttleworth, S. J.; Folkes,
A. J.; Chuckowree, I. S.; Wan, N. C.; Hancox, T. C.; Baker,
S. J.; Sohal, S.; Latif, M. A. WO 06046040, 2006; Chem.
Abstr. 2006, 144, 450724. (d) Yoon, T.; Yuan, J.; Lee, K.;
Maynard, G. D.; Liu, N. WO 06004589, 2006; Chem. Abstr.
2006, 144, 128985. (e) Lee, K.; Yuan, J.; Maynard, G. D.;
Hutchison, A.; Mitchell, S. WO 05110991, 2005; Chem.
Abstr. 2005, 144, 6683.
demonstrate that construction of new arylindazole as well
as hydroxyindazole libraries are feasible.
In summary, an efficient and rapid protocol for synthesis
of various N-protected indazole boronic acid pinacolyl
esters in good to high yields has been developed, provid-
ing a promising access to new aryl and hydroxyindazole
libraries after subsequent Suzuki–Miyaura cross-coupling
or hydroxydeboronation reactions. Considering the im-
portant properties of indazole derivatives, this methodol-
ogy allowing the facile introduction of indazole moiety on
various scaffolds could be a great interest for organic
chemists to achieve new valuable building blocks for the
use in medicinal chemistry as well as diversity-oriented
synthesis. Further studies concerning construction of new
substituted derivatives are currently in progress.
(13) For the main references at this time to obtain 5-indazolyl-
boronic acids and esters, see: (a) Alberti, M. J.; Jung, D. K.
WO 06044753, 2006; Chem. Abstr. 2006, 144, 432843.
(b) Yamashita, D. S.; Lin, H.; Wang, W. WO 05085227,
2005; Chem. Abstr. 2005, 143, 306183. (c) Hagihara, M.;
Komori, K.-I.; Sunamoto, H.; Nishida, H.; Matsugi, T.;
Nakajima, T.; Hatano, M.; Kido, K.; Hara, H. WO
05035506, 2005; Chem. Abstr. 2005, 142, 411353.
(d) McAlpine, I. J.; Deal, J. G.; Johnson, M. C.; Kephart,
S. E.; Park, J. Y.; Romines, W. H.; Tikhe, J. G. US
05090529, 2005; Chem. Abstr. 2005, 142, 430272.
(e) Shoda, M.; Kuriyama, H. WO 03070686, 2003; Chem.
Abstr. 2003, 139, 214465.
(14) For the main references at this time to obtain 6-indazolyl-
boronic acids and esters, see: (a) Frazee, J. S.; Hammond,
M.; Kano, K.; Manns, S.; Nakamura, H.; Thompson, S. K.;
Washburn, D. G. WO 06063167, 2006; Chem. Abstr. 2006,
145, 62865. (b) Lu, T.; Thieu, T. V.; Player, M. R.; Lee,
Y.-K.; Parks, D. J.; Markotan, T. P.; Pan, W.; Milkiewicz,
K. L. WO 06047415, 2006; Chem. Abstr. 2006, 144,
450703. (c) Bamborough, P.; Campos, S. A.; Patel, V. K.;
Swanson, S.; Walker, A. L. WO 05073189, 2005; Chem.
Abstr. 2005, 143, 211906.
(15) For the main references at this time about 7-indazolyl-
boronic acids and esters, see: (a) Shipps, G. W. Jr.; Cheng,
C. C.; Huang, X.; Fischmann, T. O.; Duca, J. S.; Richards,
M.; Zeng, H.; Sun, B.; Reddy, P. A.; Wong, T. T.;
Tadikonda, P. K.; Siddiqui, M. A.; Labroli, M. M.; Poker,
C.; Guzi, T. J. WO 08054702, 2008; Chem. Abstr. 2008, 148,
552346. (b) Kelly, M.; Lee, Y.; Liu, B.; Fujimoto, T.;
Freundlich, J.; Dorsey, B. D.; Flynn, G. A.; Husain, A.
US 06270686, 2006; Chem. Abstr. 2006, 146, 7835.
(16) Boulouard, M.; Schumann-Bard, P.; Butt-Gueulle, S.;
Lohou, E.; Stiebing, S.; Collot, V.; Rault, S. Bioorg. Med.
Chem. Lett. 2007, 17, 3177.
(17) Kania, R. S.; Bender, S. L.; Borchardt, A. J.; Braganza, J. F.;
Cripps, S. J.; Hua, Y.; Johnson, M. D.; Johnson, T. O. Jr.;
Luu, H. T.; Palmer, C. L.; Reich, S. H.; Tempczyk-Russell,
A. M.; Teng, M.; Thomas, C.; Varney, M. D.; Wallace,
M. B. WO 0102369, 2001; Chem. Abstr. 2001, 134, 100864.
(18) Gérard, A.-L.; Bouillon, A.; Mahatsekake, C.; Collot, V.;
Rault, S. Tetrahedron Lett. 2006, 47, 4665.
Acknowledgment
We thank Dr. Christophe Philippo for helpful discussions.
References and Notes
(1) (a) Crestey, F.; Stiebing, S.; Legay, R.; Collot, V.; Rault, S.
Tetrahedron 2007, 63, 419. (b) Collot, V.; Bovy, P. R.;
Rault, S. Tetrahedron Lett. 2000, 41, 9053. (c) Collot, V.;
Dallemagne, P.; Bovy, P. R.; Rault, S. Tetrahedron 1999,
55, 6917.
(2) (a) Crestey, F.; Collot, V.; Stiebing, S.; Lohier, J.-F.;
Sopkova-de Oliveira Santos, J.; Rault, S. Tetrahedron Lett.
2007, 48, 2457. (b) Crestey, F.; Collot, V.; Stiebing, S.;
Rault, S. Synthesis 2006, 3506. (c) Crestey, F.; Collot, V.;
Stiebing, S.; Rault, S. Tetrahedron 2006, 62, 7772.
(d) Witulski, B.; Azcon, J. R.; Alayrac, C.; Arnautu, A.;
Collot, V.; Rault, S. Synthesis 2005, 771. (e) Arnautu, A.;
Collot, V.; Calvo Ros, J.; Alayrac, C.; Witulski, B.; Rault, S.
Tetrahedron Lett. 2002, 43, 2695. (f) Collot, V.; Varlet, D.;
Rault, S. Tetrahedron Lett. 2000, 41, 4363.
(3) (a) Herradura, P. S.; Pendola, K. A.; Guy, R. K. Org. Lett.
2000, 2, 2019. (b) Chan, D. M. T.; Monaco, K. L.; Wang,
R.-P.; Winters, M. P. Tetrahedron Lett. 1998, 39, 2933.
(c) Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.;
Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron
Lett. 1998, 39, 2941.
(4) (a) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002,
58, 9633. (b) Suzuki, A. J. Organomet. Chem. 1999, 576,
147. (c) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457.
(5) Webb, K. S.; Levy, D. Tetrahedron Lett. 1995, 36, 5117.
(6) Salzbrunn, S.; Simon, J.; Prakash, G. K. S.; Petasis, N. A.;
Olah, G. A. Synlett 2000, 1485.
(7) Thiebes, C.; Prakash, G. K. S.; Petasis, N. A.; Olah, G. A.
Synlett 1998, 141.
(8) Urawa, Y.; Ogura, K. Tetrahedron Lett. 2002, 44, 271.
(9) Petasis, N. A.; Goodman, A.; Zavialov, I. A. Tetrahedron
1997, 53, 16463.
(10) (a) Hall, D. G. Boronic Acids – Preparation and
Applications in Organic Synthesis; Wiley-VCH: Weinheim,
2005. (b) Chincilla, R.; Najera, C.; Yus, M. Chem. Rev.
2004, 104, 2667.
(19) Primas, N.; Mahatsekake, C.; Bouillon, A.; Lancelot, J.-C.;
Sopkova-de Oliveira Santos, J.; Lohier, J.-F.; Rault, S.
Tetrahedron 2008, 64, 4596.
(20) Young, M. B.; Barrow, J. C.; Glass, K. L.; Lundell, G. F.;
Newton, C. L.; Pellicore, J. M.; Rittle, K. E.; Selnick, H. G.;
Stauffer, K. J.; Vacca, J. P.; Williams, P. D.; Bohn, D.;
Clayton, F. C.; Cook, J. J.; Krueger, J. A.; Kuo, L. C.; Lewis,
S. D.; Lucas, B. J.; McMasters, D. R.; Miller-Stein, C.;
(11) For a recent review on heterocyclic boronic acids, see:
Tyrell, E.; Brookes, P. Synthesis 2003, 469.
(12) For the main references at this time to obtain 4-indazolyl-
boronic acids and esters, see: (a) Folkes, A. J.; Ahmadi, K.;
Alderton, W. K.; Alix, S.; Baker, S. T.; Box, G.;
Chuckowree, I. S.; Clarke, P. A.; Depledge, P.; Eccles, S. A.;
Synlett 2009, No. 4, 615–619 © Thieme Stuttgart · New York

LETTER
Pietrak, B. L.; Wallace, A. A.; White, R. B.; Wong, B.; Yan,
Y.; Nantermet, P. G. J. Med. Chem. 2004, 47, 2995.
(21) For example, see: (a) Jiang, Q.; Ryan, M.; Zhichkin, P.
J. Org. Chem. 2007, 72, 6618. (b) Lee, I. Y. C.; Jung, M. H.;
Lim, H.-J.; Lee, H. W. Heterocycles 2005, 65, 2505.
(c) Organ, M. G.; Bilokin, Y. V.; Bratovanov, S. J. Org.
Chem. 2002, 67, 5176. (d) Schinazi, R. F.; Prusoff, W. H.
J. Org. Chem. 1985, 50, 841.
Reactivities in Suzuki–Miyaura Cross-Coupling
619
CDCl3): d = 1.42 (s, 12 H), 2.80 (s, 3 H), 7.55 (t, J = 8.3 Hz,
1 H), 7.82 (d, J = 7.1 Hz, 1 ), 8.54 (d, J = 7.1 Hz, 1 H), 8.55
(s, 1 H). 13C NMR (100 MHz, CDCl3): d = 23.1, 25.0, 84.2,
118.3, 128.6, 130.6, 132.0, 138.3, 141.7, 171.1. MS (EI): m/
z (%) = 286 (53) [M+], 244 (100), 243 (39), 229 (14), 158
(70), 145 (34), 144 (68), 134 (67). Anal. Calcd for
C15H19BN2O3: C, 62.96; H, 6.69; N, 9.79. Found: C, 62.39;
H, 6.48; N, 9.23.
(22) (a) Voisin, A.-S.; Bouillon, A.; Lancelot, J.-C.; Rault, S.
Tetrahedron 2005, 61, 1417. (b) Bouillon, A.; Lancelot,
J.-C.; Sopkova-de Oliveira Santos, J.; Collot, V.; Bovy,
P. R.; Rault, S. Tetrahedron 2003, 59, 10043; and references
cited therein.
(23) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995,
60, 7508.
(24) Reich, S. H.; Bleckman, T. M.; Kephart, S. E.; Romines,
W. H. III.; Wallace, M. B. WO 01053268, 2001; Chem.
Abstr. 2001, 135: 137505.
(26) For Suzuki–Miyaura cross-coupling reactions using K3PO4
as base in DMF, see: (a) Cailly, T.; Fabis, F.; Rault, S.
Tetrahedron 2006, 62, 5862. (b) Watanabe, T.; Miyaura, N.;
Suzuki, A. Synlett 1992, 207.
(27) For Suzuki–Miyaura cross-coupling reactions using Na2CO3
or Cs2CO3 as base in dioxane, see: (a) Song, Y. S.; Lee,
Y.-J.; Kim, B. T.; Heo, J.-N. Tetrahedron Lett. 2006, 47,
7427. (b) Heo, Y.; Song, Y. S.; Kim, B. T.; Heo, J.-N.
Tetrahedron Lett. 2006, 47, 3091. (c) Littke, A. F.; Fu, G. C.
Angew. Chem. Int. Ed. 1999, 37, 3387.
(25) Typical Experimental Procedure for the Synthesis of
Indazolylboronic Esters
(28) 7-(4-Methoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-
indazole (17)
To a solution of 1-(4-bromoindazol-1-yl)ethanone (3a, 1.5 g,
6.3 mmol) in 1,4-dioxane (25 mL) were added successively
bis(pinacolato)diboron (1.8 g, 7.2 mmol, 1.15 equiv) and
KOAc (2.8 g, 23.8 mmol, 4.6 equiv) at r.t. The reaction
mixture was degassed under vacuum with argon
replacement three times, then PdCl2 (dppf)–CH2Cl2 (0.3 g,
0.5 mmol, 0.08 equiv) was added, and the degassing
procedure was repeated twice. The reaction was heated
under reflux conditions for 15 min then concentrated in
vacuo. After the addition of EtOAc, the organic layer was
washed successively with H2O and brine, dried over MgSO4,
and the solvent evaporated in vacuo. The crude material was
purified by flash column chromatography on SiO2 (EtOAc–
cyclohexane, 1:3) to give 1-[4-(4,4,5,5-tetramethyl[1,3,2]-
dioxaborolan-2-yl)indazol-1-yl)ethanone (7a); yield 1.8 g
(98%); pink solid; mp 128 °C. TLC: Rf = 0.6 (EtOAc–
cyclohexane, 1:4). IR (KBr): 2976, 1713, 1601, 1415, 1349,
1325, 1174, 1151, 932, 756 cm–1. 1H NMR (400 MHz,
Yield 0.3 g (73%); white solid. TLC: Rf = 0.1 (EtOAc–
cyclohexane, 1:10). IR (KBr): 3428, 2932, 1611, 1497,
1245, 1078, 1032, 824 cm–1. 1H NMR (400 MHz, CDCl3):
d = 1.37–1.42 (m, 2 H), 1.76–1.78 (m, 1 H), 1.90–1.95 (m,
1 H), 2.56–2.58 (m, 1 H), 2.91–2.96 (m, 1 H), 3.74–3.80 (m,
1 H), 3.91 (s, 3 H), 4.04–4.07 (m, 1 H), 5.00 (dd, J = 12.7,
2.2 Hz, 1 H), 7.02 (dd, J = 7.3, 1.4 Hz, 2 H), 7.18–7.19 (m,
2 H), 7.23–7.26 (m, 2 H), 7.64–7.70 (m, 1 H), 8.12 (s, 1 H).
MS (EI): m/z (%) = 308 (22) [M+], 224 (100), 209 (26), 192
(2), 182 (8), 154 (7), 85 (8). Anal. Calcd for C19H20N2O2: C,
74.00; H, 6.54; N, 9.08. Found: C, 74.30; H, 6.74; N, 9.28.
(29) Schumann, P.; Collot, V.; Hommet, Y.; Gsell, W.; Dauphin,
F.; Sopkova, J.; McKenzie, E. T.; Duval, D.; Boulouard, M.;
Rault, S. Bioorg. Med. Chem. Lett. 2001, 11, 1153.
(30) The use of Oxone® (2KHSO5–KHSO4–K2SO4) as oxidative
reagent in the presence of Na2CO3 in a mixture of H2O–
acetone (1:1) at 0 °C led to the desired compounds but in
lower yields.
Synlett 2009, No. 4, 615–619 © Thieme Stuttgart · New York

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