Copper-catalyzed sequential N-arylation of C-amino-NH-azoles

Article abstract of DOI:10.1039/c4cc05628k

Copper(ii)-catalyzed boronic acid promoted C-N bond cross-coupling reactions have been successfully developed for sequential N-arylation of C-amino-NH-azoles. These general protocols are compatible with a variety of aryl/hetero-aryl boronic acids and provided rapid access to a diverse array of diarylaminoazole derivatives in a two-step sequence or in one-pot. This journal is

Full text of DOI:10.1039/c4cc05628k

ChemComm
View Article Online
View Journal
COMMUNICATION
Copper-catalyzed sequential N-arylation
of C-amino-NH-azoles†
Cite this:DOI: 10.1039/c4cc05628k
D. Nageswar Rao,ab Sk. Rasheed,ab Ram A. Vishwakarmab and Parthasarathi Das*ab
Received 21st July 2014,
Accepted 5th September 2014
DOI: 10.1039/c4cc05628k
www.rsc.org/chemcomm
Copper(II)-catalyzed boronic acid promoted C–N bond cross-coupling
reactions have been successfully developed for sequential N-arylation
of C-amino-NH-azoles. These general protocols are compatible with a
variety of aryl/hetero-aryl boronic acids and provided rapid access to a
diverse array of diarylaminoazole derivatives in a two-step sequence or
in one-pot.
Transition-metal catalyzed N-(hetero) arylation is an important
synthetic tool in organic chemistry.1 Besides the traditional copper
promoted Ullmann type coupling, the palladium-catalyzed reactions
championed by Buchwald and Hartwig has been a major break-
Fig. 1 Ary/hetroaryl-fused C-amino-NH-azoles.
through in this area. However, the application of palladium- and (Fig. 1).7 Therefore, the development of optimized catalytic
copper-mediated N-arylation reactions in the synthesis of N-arylated conditions for the selective N-arylation of these heterocycles
heterocyclic compounds with medicinal properties not always possessing multiple nucleophilic sites is much more challenging
straightforward often required optimized conditions particularly from the synthetic point of view. Furthermore, transition metal-
with the help of expensive ligands.2 Furthermore, use of strong base catalyzed N-arylations using cyclic amidines (e.g. 2-amino-
and elevated temperature makes this procedure less attractive for benzimidazole, 3-aminoindazoles, 3-aminopyrazolopyridine,
functional group tolerability during structure activity relationship 2-aminopyridoimidazoles) as substrates remain always challenging,
(SAR) and lead optimization study in medicinal chemistry.
as these functionalities coordinate strongly with reactive metals.8
Copper salt-promoting Chan–Lam type coupling reactions These limits need to be addressed with a strategy that can be widely
for the synthesis of N-aryl heterocyclic compounds have been applicable.
extensively studied over the past few years.3 The reason behind the
In particular we sought to explore reaction conditions for
popularity of this type of cross-coupling reaction is mild reaction sequential N-arylation of C-amino-NH-azoles9 (bearing different
conditions e.g. room temperature, weak base and ambient atmo- nucleophilic sites). We herein, report Cu-catalyzed boronic acid
sphere (open-flask chemistry).4 N-Aryl azoles are important building promoted N-arylation of C-amino-NH-azoles to access di-aryl
blocks in numerous agro chemicals, pharmaceuticals and bio- amino azoles (Scheme 1) sequentially. To the best of our
logically active compounds. Both Pd-and Cu-catalyzed efficient knowledge for the first time pyrazolopyridine and pyridoimidazole
methods for N1-arylation of azoles have been reported.5,6 However, like substrates bearing two different nucleophilic sites have success-
the transition metal-catalyzed N-arylation strategies have rarely fully been utilized in selective N-arylation.
been applied in selective N-arylation over other nucleophilic
sites including aromatic amines of these important heterocycles
a Academy of Scientific and Innovative Research (AcSIR), Canal Road,
Jammu-180001, India
b Medicinal Chemistry Division, Indian Institute of Integrative Medicine (CSIR),
Canal Road, Jammu-180001, India. E-mail: partha@iiim.ac.in
† Electronic supplementary information (ESI) available: Experimental details and
Scheme 1 Selective N-arylation of C-amino-NH-azoles.
spectroscopic data for all compounds. See DOI: 10.1039/c4cc05628k
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun.

View Article Online
Communication
ChemComm
Table 1 Optimization studies on N1-arylation of 1H-pyrazolo[3,4-b]pyridin-3-
aminea
Table 2 N1-Arylation of 1H-pyrazolo[3,4-b]pyridin-3-aminea
Entry
Catalyst
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Cu(OAc)2 (1 equiv.)
Cu(OAc)2 (1 equiv.)
Cu(OAc)2 (1 equiv.)
Cu(OAc)2 (0.2 equiv.)
Cu(OAc)2 (0.2 equiv.)
Cu(OAc)2 (0.2 equiv.)
Cu(OAc)2 (0.2 equiv.)
Cu(OTf)2 (0.2 equiv.)
CuI (0.2 equiv.)
DCE
n.r.
45 (25)
80
90
10
CH3CN
MeOH
MeOH
DMF
DMSO
DME
MeOH
MeOH
MeOH
MeOH
MeOH
DCM
20
n.r.
50 (30)
n.r.
n.r.
90
30
20
9
10
11c
12d
13e
Cu2O (0.2 equiv.)
Cu(OAc)2 (0.2 equiv.)
Cu(OAc)2 (0.2 equiv.)
Cu(OAc)2 (1 equiv.)
a
Reaction conditions: pyrazolopyridine (1.0 equiv.), phenylboronic acid
b
(1.1 equiv.), Cu(OAc)2 (0.2 equiv.), MeOH (2 mL), rt, air. Isolated yield;
the yield in parentheses refers to recovered starting material 1a. Reac-
tion under 1 atm O2. Reaction under a N2 atmosphere. Et3N
(3 equiv.) used, n.r. = no reaction.
c
a
d
e
Reaction conditions: 1H-pyrazolo[3,4-b]pyridin-3-amine (1 equiv.),
boronic acid (1.1 equiv.), Cu(OAc)2 (0.2 equiv.), MeoH (2 mL), rt, air,
8–24 h.
To find an effective catalytic system for the selective cross-
coupling of C-amino-NH-azoles, our initial attempt was inspired (Table 2). 1H-Pyrazolo[3,4-b] pyridine-3-amine underwent the reac-
by a method developed previously in our group for N-arylation of tion with different boronic acids to give the desired N1-arylated
2-amino-N-heterocycles.10 The 7-aza derivative of 3-aminoindazole products (2a–h) in excellent yields (80–90%). Boronic acids bearing
(i.e. 1H-pyrazolo[3,4-b]pyridine-3-amine,11 1a) became an interesting both electron-donating (2b) and electron-withdrawing groups (2c–h)
choice as a model substrate due to its unique N-atom position in underwent the reaction smoothly and no other isomer or poly
both the rings. Our initial attempt to perform the cross-coupling arylated product was formed. We have investigated two bicyclic
reaction of 1a with phenylboronic acid (1.1 equiv.) by using Cu(OAc)2 boronic acids, in the case of 2-naphthylboronic acid the yield
(1 equiv.) in DCE at room temperature (Table 1, entry 1) was not is 80% (2i) whereas benzo[d][1,3]dioxol-5-ylboronic acid resulted
successful. To our delight by changing the solvent to CH3CN the N1- in 85% (2j) yield. The scope of this reaction was further tested
arylated product (2a) was isolated in 45% yield (Table 1, entry 2). with other heterocyclic boronic acids and to our expectation the
When we used MeOH as the solvent (Table 1, entry 3), the yield N1-arylated products (2k–o) were isolated in high yields. The only
improved dramatically (80%), perhaps due to the increased solu- noticeable point, in the case of 3-pyridylboronic acid (2l) is the
bility of the reagents. Under these conditions the N-arylation is prolonged reaction time (24 h) with diminished yield (60%).
completely regioselective as only N1-aryl azole was isolated.
A further evaluation of the scope of this methodology revealed
Encouraged by this promising result, we used a catalytic amount that the reaction also proceeded smoothly with other C-amino-
of Cu(OAc)2 (0.2 equiv.) and the N1-arylated product (2a) was isolated NH-azoles e.g. 3-aminoindazole and 3-aminopyrazole, providing
in 90% yield (Table 1, entry 4). Further screening showed that access to N1-aryl indazole (2p) and N1-aryl pyrazoles (2q–r) in
solvents like DMF (Table 1, entry 5) and DMSO (Table 1, entry 6) excellent yields (72–88%).
were not effective, while DME (Table 1, entry 7) failed to promote the
Next we focus our attention on selective N1-arylation of another
reaction. We observed a sharp decline in yield when we replaced two important heterocycle 2-aminobenzimidazole13 and 2-amino-
Cu(OAc)2 with Cu(OTf)2 (Table 1, entry 8). Other Cu-salts e.g. CuI pyridoimdazole14 (3H-imidazo[4,5-b]pyridin-2-amines). Synthetic
(Table 1, entry 9) and Cu2O (Table 1, entry 10) failed to give any cross- challenges are associated with selective N-arylation of unprotected
coupled product. Reaction under 1 atm O2 did not show any further 2-aminobenzimidazole or 2-aminopyridoimdazole as the formation
improvement in the yield of the reaction (Table 1 entry 11) while of regioisomer and/or poly arylated products due to the tautomeric
incomplete conversion and poor yields were observed under a N2 nature of these heterocycles. To our delight under the optimized
atmosphere (Table 1 entry 12) suggesting that O2 (air) plays a vital conditions various boronic acids coupled with 2-aminobenz-
role in the catalytic cycle. Under standard Chan–Lam conditions imidazole to give N1-selective arylated products (3a–g, Table 3). Under
(Table 1 entry 13) a mixture of products were formed and the these optimized conditions N2-arylated/poly-arylated (C-NH2) pro-
isolated yield of the N1-arylated product (2a) is only 20%.
ducts were not detected. Here also the electronic nature of the
Under the optimized reaction conditions, first we examined the boronic acids did not play any significant role in the isolated yields
scope of the boronic acids with 1H-pyrazolo[3,4-b]pyridine-3-amine12 (82–92%). In this context heteroaryl boronic acid was also examined,
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2014

View Article Online
ChemComm
Communication
Table 3 Cu-catalyzed N1-arylation of 2-aminobenzimidazolesa
Table 4 Optimization studies on C3-NH-arylation of 1-(3-chlorophenyl)-
1H-pyrazolo[3,4-b]pyridin-3-aminea
Entry
Catalyst
Base
Solvent
T (1C)
Yieldb (%)
1c
2
3
4
5
6
7
8
9
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OTf)2
Cu(OAc)2
Et3N
K3PO4
DCM
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CH3CN
MeOH
DMSO
DMF
DMF
rt
n.r.
35
40
40
30
55
40
65
80
82
87
50
60
40
45
20
100
100
100
100
100
100
100
100
100
50
50
50
50
50
K2CO3
CS2CO3
Na2CO3
NaOAc
tBuOK
NaOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
CsOPiv
10d
11d
12
13
14
15
16e
a
Reaction conditions: 2-aminobenzimidazole (1 equiv.), boronic acid
(1.1 equiv.), Cu(OAc)2 (0.2 equiv.), MeOH (2 mL), rt, air, 12–24 h.
in the case of 3-pyridyl boronic acid the isolated yield is 75% (3h) in
24 h. To further enhance the substrate scope substituted 2-amino
benzimidazoles were investigated, both 5-bromo and 5-nitro deriva-
tives reacted with 3-chlorophenyl boronic acid to give N1-arylated
products in 82% (3i) and 80% (3j) yield respectively. Interestingly,
both bromo and NO2 functionalities were tolerated under these
conditions, amenable to further functional group transformations.
In recent days the imidazo[4,5-b]pyridine heterocycle, a versatile
purine isostere and an important ring system was found to be useful
in medicinal chemistry application of potential therapeutic benefits.
Thus selective functionalization of this heterocycle will be interesting
from the drug discovery point of view. To the best of our knowledge
selective N-arylation of imidazopyridine is unexplored. With our
optimized conditions we subjected 2-aminopyridoimdazole with
different boronic acids and to our delight the N-arylation occurred
selectively to give only the N1-alkylated product (3k–m) in excellent
yields (72–78%). Notably, no N2-arylated/poly-arylated (C-NH2) pro-
ducts were detected under these optimized conditions.
50
a
Reaction conditions: N1-aryl C-NH2-azoles (1.0 equiv.), phenylboronic
acid (1.2 equiv.), Cu(OAc)2 (0.2 equiv.), CsOPiv (0.4 equiv.), DMF (1 mL),
50 1C, air. Isolated yield. Cu(OAc)2 (1 equiv.), Et3N (3 equiv.). CsO-
Piv (0.4 equiv.). Reaction performed under a N2 atmosphere.
b
c
d
e
With the optimized reaction conditions first we explored the
scope of this method with 1-aryl-1H-pyrazolo[3,4-b]pyridin-3-amine.
To our delight, all the electronically diverse boronic acids underwent
clean conversion (Table 5) to give desired C-NH2-arylated products
(4a–e) in excellent yields (78–86%). In this aspect other C-amino-N-
aryl-azole systems were also tested and the resulting C-NH2-arylated
products (4f–h) isolated in good yields (70–76%).
These two step sequential N-arylation protocols can be
performed in one-pot under the optimized conditions. The
Table 5 C-NH2-arylation of N1-aryl-C-NH2-azolesa
After successful optimization of regioselective N1-arylation, we
focused on exploring conditions for second N-arylation at the C-NH2
position of C-amino-NH-azoles. Our initial attempt started with the
reaction of 1-(3-chlorophenyl)-1H-pyrazolo[3,4-b]pyridin-3-amine (2f)
and phenylboronic acid under Chan–Lam conditions and the reac-
tion was unsuccessful (Table 4, entry 1). Then we used the inorganic
base K3PO4 (1.5 equiv.) and DMF as the solvent at 100 1C with
Cu(OAc)2 (0.2 equiv.) as the catalyst. To our delight, the reaction
afforded N-arylated heterocycle, 4a, in 35% yield (Table 4, entry 2). It
was found that employing CsOPiv4a (0.4 equiv.) as the base resulted
in the best activity (87%, Table 4, entry 11) at 50 1C, while other bases
such as Cs2CO3, K2CO3, Na2CO3, NaOAc, tBuOK and NaOPiv were
less effective (Table 4, entries 3–8). We attempted different reaction
temperatures, and 50 1C was found to be optimal (Table 4, entries 10
and 11). Screening of different solvents was also not effective in
improving the further yield (Table 4, entries 12–14). A lower yield was
obtained when employing Cu(OTf)2 as a catalyst (Table 4, entry 15).
Under the nitrogen atmosphere, only a small amount of 4a was
obtained (Table 4, entry 16).
a
Reaction conditions: N1-aryl-C-NH2-azoles (1 equiv.), boronic acid
(1.2 equiv.), Cu(OAc)2 (0.2 equiv.), CsOPiv (0.4 equiv.), DMF (1 mL),
50 1C, air, 16–20 h.
This journal is ©The Royal Society of Chemistry 2014
Chem. Commun.

View Article Online
Communication
ChemComm
4 For recent Chan-Lam type coupling: (a) J. Li, S. Benard, L. Neuville
and J. Zhu, Org. Lett., 2012, 14, 5980; (b) D. S. Raghuvanshi,
A. K. Gupta and K. N. Singh, Org. Lett., 2012, 14, 4326; (c) H.-J. Xu,
Y.-Q. Zhao, T. Feng and Y.-Si. Feng, J. Org. Chem., 2012, 77, 2878;
(d) S.-Y. Moon, J. Nam, K. Rathwell and W.-S. Kim, Org. Lett., 2014,
16, 338; (e) E. Racine, F. Monnier, J.-P. Vors and M. Taillefer, Chem.
Commun., 2013, 49, 7412; ( f ) A. Bruneau, J.-D. Brion, M. Alami and
S. Messaoudi, Chem. Commun., 2013, 49, 8359.
5 Selected examples on Pd-catalyzed N-arylation of azoles: (a) S. Ueda,
M. Su and S. L. Buchwald, J. Am. Chem. Soc., 2012, 134, 700;
(b) S. Ueda, M. Su and S. L. Buchwald, Angew. Chem., Int. Ed.,
2011, 50, 8944.
6 Selected examples on Cu-catalyzed N-arylation of azoles: (a) L. Zhu,
G. Li, L. Luo, P. Guo, J. Lan and J. You, J. Org. Chem., 2009, 74, 2200;
(b) D. Wang, F. Zhang, D. Kuang, J. Yu and J. Li, Green Chem., 2012,
14, 1268; (c) L. Liang, Z. Li and X. Zhou, Org. Lett., 2009, 11, 3294;
(d) A. F. Larsen and T. Ulven, Chem. Commun., 2014, 50, 4997.
7 S. Ueda and S. L. Buchwald, Angew. Chem., Int. Ed., 2012, 51, 10364.
8 T. R. M. Rauws and B. U. W. Maes, Chem. Soc. Rev., 2012, 41, 2463.
9 Selected examples on Chan-Lam coupling for N-arylation of azoles:
(a) P. Y. S. Lam, C. G. Clark, S. Saubern, J. Adams, M. P. Winters,
D. M. T. Chan and A. Combs, Tetrahedron Lett., 1998, 39, 2941;
(b) J. P. Collman and M. Zhong, Org. Lett., 2000, 2, 1233;
(c) T. Onaka, H. Umemoto, Y. Miki, A. Nakamura and T. Maegawa,
J. Org. Chem., 2014, 79, 6703.
isolated yields (4b & 4f) are comparable with the isolated yield
obtained in the sequential two steps (for detailed experimental
procedures see ESI†).
Several mechanistic studies have been reported for Chan–Lam
type of coupling reactions.9b,15 The coupling product [Ar–azole(Nu)]
could be generated by reductive elimination from a copper(III)
intermediate [Ar–Cu(III)–Nu].3a The presence of O2(air) here favors
this step by in situ oxidation of the corresponding [Ar–Cu(II)–Nu]
complex.4d,e,15b Finally, O2 (air) acts as a terminal oxidant to
regenerate the catalytically active species after the reductive
elimination step.10,15b
In summary, we have developed two simple and inexpensive
systems for copper-catalyzed sequential N-arylations of C-amino-
NH-azoles with aryl/heteroaryl boronic acids. Undoubtedly, the
success of these sequential/one-pot Cu-catalyzed C–N bond
formation reactions further extends the usefulness of Chan–
Lam type of coupling with a new substrate class.
D.N.R and Sk. R. thank UGC and CSIR-New Delhi for
research fellowship, respectively. This research work was financially
supported by CSIR-New Delhi (BSC 0108). IIIM communication
No. 1674.
10 D. N. Rao, Sk. Rasheed, S. Aravinda, R. A. Vishwakarma and P. Das,
RSC Adv., 2013, 3, 11472.
11 For synthesis of 1H-pyrazolo[3,4-b]pyridine-3-amine and other C-amino-
NH-azoles see ESI†.
12 For medicinal properties of 1H-pyrazolo[3,4-b]pyridine see:
H. D. Mello, A. Echevarria, A. M. Bernardino, M. Canto-Cavalheiro
and L. L. Leon, J. Med. Chem., 2004, 47, 5427.
Notes and references
1 For selected reviews see: (a) I. P. Beletskaya and A. V. Cheprakov, 13 For medicinal properties of N-aryl-2-aminobenzimidazole see:
Organometallics, 2012, 31, 7753; (b) J. Bariwal and E. van der. Eycken,
Chem. Soc. Rev., 2013, 42, 9283; (c) C. Fischer and B. Koenig, Beilstein
J. Org. Chem., 2011, 7, 59.
2 Selected examples on Pd–Cu-catalyzed N-arylation of N-heterocycles:
(a) J. L. Henderson, S. M. Mcdermott and S. L. Buchwald, Org. Lett.,
2010, 12, 4438; (b) J. L. Henderson and S. L. Buchwald, Org.
Lett., 2010, 12, 4442; (c) M. Su, N. Hoshiya and S. L. Buchwald,
Org. Lett., 2014, 16, 832; (d) F. Perez and A. Minatti, Org. Lett., 2011,
13, 1984; (e) D. Maiti, B. P. Fors, J. L. Henderson, Y. Nakamura and
S. L. Buchwald, Chem. Sci., 2011, 2, 57.
R. D. Carpenter, M. Andrei, E. Y. Lau, F. C. Lightstone, R. Liu,
K. S. Lam and M. J. Kurth, J. Med. Chem., 2007, 50, 5863.
14 For medicinal properties of N-aryl 3H-imidazo[4,5-b]pyridin-2-amines
see: M. A. Ashwell, J.-M. Lapierre, C. Brassard, K. Bresciano, C. Bull,
S. Cornell-Kennon, S. Eathiraj, D. S. France, T. Hall, J. Hill,
E. Kelleher, S. Khanapurkar, D. Kizer, S. Koerner, J. Link, Y. Liu,
S. Makhija, M. Moussa, N. Namdev, K. Nguyen, R. Nicewonger,
R. Palma, J. Szwaya, M. Tandon, U. Uppalapati, D. Vensel,
L. P. Volak, E. Volckova, N. Westlund, H. Wu, R.-Y. Yang and
T. C. K. Chan, J. Med. Chem., 2012, 55, 5291.
3 For reviews on Chan-Lam coupling see: (a) J. Qiao and P. Y. S. Lam, 15 (a) A. E. King, T. C. Brunold and S. S. Stahl, J. Am. Chem. Soc., 2009,
Synthesis, 2011, 829; (b) K. S. Rao and T. S. Wu, Tetrahedron, 2012,
68, 7735.
131, 5044; (b) P. Y. S. Lam, D. Bonne, G. Vicent, C. G. Clark and
A. P. Combs, Tetrahedron Lett., 2003, 44, 1691.
Chem. Commun.
This journal is ©The Royal Society of Chemistry 2014