First combined selective N- and C-arylations with boronic acids: Application to the synthesis of 1,3-diarylindazoles

Article abstract of DOI:10.1016/S0040-4039(00)01650-6

3-Iodoindazole allows combined N1- and C3-arylations with boronic acids. These two reactions work independently of one another and can be combined in a one pot procedure. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01650-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9053–9057
First combined selective N- and C-arylations with boronic
acids: application to the synthesis of 1,3-diarylindazoles
Vale´rie Collot,a Philippe R. Bovyb and Sylvain Raulta,*
aCentre d’Etudes et de Recherche sur le Me´dicament de Normandie, UFR des Sciences Pharmaceutiques,
5 rue Vaube´nard, 14032 Caen, France
bSynthelabo Recherche, 10 rue des Carrie`res, 92500 Rueil-Malmaison, France
Received 20 July 2000; accepted 20 September 2000
Abstract
3-Iodoindazole allows combined N1- and C3-arylations with boronic acids. These two reactions work
independently of one another and can be combined in a one pot procedure. © 2000 Elsevier Science Ltd.
All rights reserved.
To obtain mild and flexible strategies to design new indazole libraries, we were interested in
the reactivity of 3-iodoindazoles in metal-catalysed coupling reactions. Thus, we recently
published a general and versatile pathway leading to 2-azatryptamines via a Heck cross-coupling
reaction of 3-iodoindazole with methyl acrylate.1 We also developed a Suzuki-type cross-
coupling reaction of 3-iodoindazoles with aryl and heteroaryl boronic acids as a general route
to 3-aryl indazoles.2
Whereas the well-known application of aryl boronic acid in palladium-catalyzed coupling with
aryl halides to produce biphenyls is one of the most powerful tools in CꢀC bond formation,3 the
corresponding aryl/heteroaryl CꢀN bond cross-coupling reactions are less common,4 especially
those involving mild conditions.
In our search for a general and mild methodology for the aryl/heteroaryl CꢀN bond
cross-coupling reaction toward the synthesis of biologically active indazoles, we have explored
the newly discovered aryl boronic acid/cupric acetate N-arylation reaction,5 and studied its
combination with C–C Suzuki type cross coupling reactions.
Only two examples of the N-arylation of indazole have been described in the literature. This
has been shown to work with catalytic cupric acetate/p-tolyllead triacetate6 or cupric acetate/p-
tolylboronic acid7 but gave a mixture of N1 and N2 substituted derivatives, the ratio being in
agreement with the general features of indazole reactivity.8
* Corresponding author. E-mail: rault@pharmacie.unicaen.fr
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01650-6

9054
The general conditions for this latter aryl/heteroaryl CꢀN bond coupling reaction involve the
addition of 2.0 equivalents of p-tolylboronic acid and 2.0 equivalents of triethylamine to 1.0
equivalent of indazole in methylene chloride at room temperature, followed by 1.5 equivalent of
anhydrous cupric acetate.
We observed that the same conditions applied to 3-iodoindazole 1 gave a quantitative
coupling after a brief reaction time (1 h) and provided 67% of isolated product 2c after column
chromatography.9
Beside p-tolyl boronic acid, three different aryl boronic acids (phenyl, p-triflu-
oromethylphenyl, and p-methoxyphenyl) ranging from electron-deficient to electron-rich rings
were studied. The yields are in general good, indicating that this copper-promoted N-arylation
of 3-iodoindazole 1 can tolerate aryl boronic acids of various electronic nature (Table 1).
Table 1
Regioselective copper-promoted N1-arylation of 3-iodoindazole 1a
Ar1
Time (h)
Yield (%)
2a
2b
2c
2d
Phenyl
p-CF3-phenyl
p-Tolyl
2
1
1
1
71
62
67
61
p-OCH3-phenyl
a Couplings were carried out at rt in CH2Cl2 in the presence of 2 equiv. of Ar1B(OH)2, 2 equiv. of TEA and 1.5
equiv. of Cu(OAc)2.
With this first exploration, we showed the N1-regioselectivity of the arylation of 3-iodoinda-
zole 1. In contrast with indazole, a single reaction product is obtained here because of the steric
hindrance in position 3 induced by the presence of iodine, avoiding the formation of regio-
isomers. Moreover, the iodine in position 3 remains unchanged, thus allowing further reactions.
This prompted us to investigate its reactivity in a Suzuki-type coupling reaction. We observed
that arylboronic or heteroarylboronic acids gave with compounds 2 quantitative couplings after
a short time of reaction (Table 2, compounds 3) and provided 67–75% yield of isolated product
after column chromatography.
We also examined the reverse strategy and observed that compounds 3 could be obtained by
N-arylation of the appropriate 3-arylindazoles 4 (route b) in the conditions depicted in Table 1.
Indeed the 1,3-diaryl derivatives 3 could be obtained according to two different successive routes
starting from 3-iodoindazole 1, providing a flexible and selective N- and C-arylations of
3-iodoindazole.
We also investigated whether it could be possible to combine those two selective catalytic N1-
and C3-arylations of 3-iodoindazole in the same reaction. For this purpose, we searched for
compatible experimental conditions (Table 3) able to provide the corresponding 1,3-diaryl
compounds 3.

9055
Table 2
Two different routes to access to 1,3-diarylindazoles 3a–3ca
Ar1
Ar2
Yield (%)
3a
3a
3b
3c
Phenyl
Phenyl
p-Tolyl
Phenyl
p-OCH3-phenyl
p-OCH3-phenyl
2-Thienyl
71
68
67
75
2-Furyl
a (i) Couplings were carried out at 80°C in DME (2–3 h) in the presence of 5% of Pd(PPh3)4, 1.1 equiv. of
Ar2B(OH)2 and 3.0 equiv. of NaHCO3. (ii) Cf reaction conditions depicted in Table 1.
Table 3
Combined N- and C-arylations of 3-iodoindazole in a ‘one pot’ procedurea
Ar
Time (h)
Yield (%)
3d
3e
Phenyl
OCH3-phenyl
5
2.5
65
69
a Reactions were carried out at 80°C in DME in the presence of 3.0 equiv. of ArB(OH)2, 5% of Pd(PPh3)4, 1.5
equiv. of Cu(OAc)2, 3.0 equiv. of NaHCO3 and 2.0 equiv. of TEA.
Thus, we observed that in Suzuki coupling conditions (Table 2), addition of copper acetate
and at least one further equivalent of arylboronic acid allowed the N-arylation without
preventing the C3-arylation to give 1,3-diaryl compounds 3d–e in excellent conditions (Table 3).
Moreover, as we observed that the N-arylation proceeded faster and at lower temperature than
the C-arylation, we managed to dissociate the two reactions to functionalize 3-iodoindazole with
two different aryl substituents in a ‘one pot’ procedure (Table 4).

9056
Table 4
Dissociated N- then C-arylations of 3-iodoindazole with two different boronic acids in a ‘one pot’ procedure10
Ar1
Ar2
Yield (%)
3c
3f
Phenyl
p-OCH3-Phenyl
2-Furyl
3,5-di-Cl-phenyl
71
68
Finally we found that treatment of 1 in DME with only one equivalent of a first aryl boronic
acid in the presence of a mixture of the two different catalysts (Pd(PPh3)4, Cu(OAc)2) totally
consumed this boronic acid and gave firstly the N1-aryl derivative 2. This was then converted
in situ into the diaryl compound 3 by addition of a second boronic acid in the reaction
mixture.10 The reaction was completed after 3 h at 80°C.
In conclusion, this study demonstrates for the first time the possibility of conducting in a ‘one
pot’ procedure two different coupling reactions (N- and C-arylations) with arylboronic acids in
the presence of two catalysts able to work independently of one another. This approach could
provide a flexible and selective scheme to design new libraries from haloarylamines.
References
1. Collot, V.; Varlet, D.; Rault, S. Tetrahedron Lett. 2000, 41, 4363–4366.
2. Collot, V.; Dallemagne, P.; Bovy, P. R.; Rault, S. Tetrahedron 1999, 55, 6917–6922.
3. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
4. Lopez-Alvarado, P.; Avendano, C.; Menendez, J. C. J. Org. Chem. 1995, 60, 5678–5682.
5. Chan, D. M. T.; Monaco, K. L.; Wang, R.-P.; Winters, M. P. Tetrahedron Lett. 1998, 39, 2933–2936.
6. Lopez-Alvarado, P.; Avendano, C.; Menendez, J. C. Tetrahedron Lett. 1992, 33, 659–662.
7. Lam, P. Y. S.; Clark, C. G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A. Tetrahedron
Lett. 1998, 39, 2941–2944.
8. (a) Adger, B. M.; Bradbury, S.; Keating, M.; Rees, C. W.; Storr, R. C.; Williams, M. T. J. Chem. Soc., Perkin
Trans. 1 1975, 31–40. (b) Claramunt, R. M.; Elguero, J.; Garceran, R. Heterocycles 1985, 23, 2895–2906.
9. General procedure for N-arylation: The resulting dark blue to turquoise mixture of 3-iodoindazole2 (1.0 mmol),
aryl boronic (2.0 mmol), anhydrous cupric acetate (1.0 mmol), triethylamine (2.0 mmol) in dry CH2Cl2 (7 mL)
was stirred at room temperature for 1–2 h. The progress of the reaction was monitored by TLC. The products
were isolated by direct flash column chromatography of the crude reaction mixture with pre-absorption on silica
gel (EtOAc/cHex 1:8). Compound 2d: mp 110°C. 1H NMR (CDCl3) l 7.59–7.53 (m, 4H), 7.46 (t, 1H, J=7.9 Hz),
7.27 (t, 1H, J=7.4 Hz), 7.04 (d, 2H, J=7.3 Hz), 3.88 (s, 3H); 13C NMR (CDCl3) l 158.7, 139.6, 132.7, 129.1,
128.0, 124.6, 122.0, 121.8, 119.5, 114.7, 114.6, 110.3, 94.1, 55.6; MS m/z 350. Anal. calcd for C14H11N2OI: C,
48.02; H, 3.17; N, 8.00. Found: C, 48.30; H, 3.01; N, 7.82.
10. Preparation of compound 3f: The resulting green mixture of 3-iodoindazole2 (1.0 mmol), p-OCH3phenylboronic
(1.0 mmol), anhydrous cupric acetate (1.0 mmol), Pd(PPh3)4 (5%), triethylamine (2.0 mmol), NaHCO3 (3.0 mmol)
in DME (10 mL) was stirred at room temperature. The progress of the reaction was monitored by TLC. After
.

9057
1 h 3,5-di-Cl-phenylboronic (1.0 mmol) was added and the mixture was heated at 80°C for 3 h. After filtration,
3f was isolated by flash column chromatography (EtOAc/cHex 1:4; 3f: mp 174°C. 1H NMR (CDCl3) l 8.04
(d, 1H, J=8.2 Hz), 7.94 (s, 1H), 7.68–7.64 (m, 3H), 7.46 (t, 1H, J=7.8 Hz), 7.39 (s, 1H), 7.32 (t, 1H, J=7.9 Hz),
7.08 (d, 2H, J=8.3 Hz), 3.85 (s, 3H); 13C NMR (CDCl3) l 158.8, 143.1, 140.7, 136.6, 136.3, 135.4, 132.8, 127.9,
127.2, 125.8, 125.0, 122.2, 120.8, 114.8, 110.8, 55.6; MS m/z 369. Anal. calcd for C20H14N2OCl2: C, 65.06; H,
3.82; N, 7.58. Found: C, 65.31; H, 3.75; N, 7.72.
.