Copper-Catalyzed C NH2Arylation of 2-Aminobenzimidazoles and Related C-Amino-NH-azoles

Article abstract of DOI:10.1002/adsc.201600035

A copper(II)-catalyzed selective C NH₂arylation of 2-aminobenzimidazoles and related C-amino-NH-azoles was achieved in presence of 2,2′-bipyridine and cesium carbonate at 60 °C under open air conditions and this is first method for the copper-catalyzed selective C NH₂arylation in the presence of other reactive nucleophilic sites. Previously unexplored heteroaromatics possessing multiple nucleophilic sites that are selectively arylated at the C NH₂position are obtained, providing an exceptional tool for rapid delivery of a diverse array of medicinally important C NH(aryl) derivatives of aminoazoles without any protection/deprotection of ring N H bonds. It is first example for the selective C NH₂arylation of 5-aminoindazole, 4-aminopyrazole, 5-aminopyrazole, 9H-purine-6-amine, and 1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives. (Figure presented.) .

Full text of DOI:10.1002/adsc.201600035

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DOI: 10.1002/adsc.201600035
À
Copper-Catalyzed C NH2 Arylation of 2-Aminobenzimidazoles
and Related C-Amino-NH-azoles
Desaboini Nageswar Rao,a,b Sk. Rasheed,a,b Karampoori Anil Kumar,a,b
Annem Siva Reddy,a,b and Parthasarathi Dasa,b,*
a
Academy of Scientific and Innovative Research (AcSIR), Jammu-Campus, Jammu – 180001, India
Medicinal Chemistry Division, Indian Institute of Integrative Medicine (CSIR), Jammu – 180001, India
b
Fax : (+91)-191-256-9019; e-mail: partha@iiim.ac.in
Received: January 11, 2016; Revised: April 14, 2016; Published online: && &&, 0000
IIIM publication no IIIM/1822/2015.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600035.
À
À
Abstract: A copper(II)-catalyzed selective C NH2 important C NH(aryl) derivatives of aminoazoles
À
arylation of 2-aminobenzimidazoles and related C- without any protection/deprotection of ring N H
À
amino-NH-azoles was achieved in presence of 2,2’- bonds. It is first example for the selective C NH2 ar-
bipyridine and cesium carbonate at 608C under open ylation of 5-aminoindazole, 4-aminopyrazole, 5-ami-
air conditions and this is first method for the copper- nopyrazole, 9H-purine-6-amine, and 1H-pyrazo-
À
catalyzed selective C NH2 arylation in the presence lo[3,4-d]pyrimidin-4-amine derivatives.
of other reactive nucleophilic sites. Previously unex-
plored heteroaromatics possessing multiple nucleo-
À
philic sites that are selectively arylated at the C NH2 Keywords: aminoazoles; Chan–Lam coupling;
position are obtained, providing an exceptional tool copper catalysts; open-flask chemistry; selective N-
for rapid delivery of a diverse array of medicinally arylation
Introduction
Hartwig and Ullmann-type reactions promoted by
palladium, and/or copper, as catalyst.[2]
N-Arylated 2-aminobenzimidazoles, particularly the
À
Transition metal-catalyzed N-(hetero)arylation reac-
tions have emerged as powerful synthetic tools in or- C-2 NH2 arylated 2-aminobenzimidazoles, are a privi-
ganic synthesis.[1] Designing and/or optimizing catalyt- leged heterocyclic class found in a variety of medici-
ic systems for substrates with multiple heteroatom nally important compounds such as Tie-2 kinase in-
sites capable of undergoing cross-coupling reactions is hibitors,[3] aurora kinase inhibitors,[4] and integrin a4b1
a real challenge to the organic chemist. In particular, antagonists[5] (Figure 1). Thus, the selective N-aryla-
selective N-arylation of heteroaromatics possessing tion of these amino-N-heterocycles without protecting
multiple nucleophilic sites without protection/depro- one nucleophilic site (e.g., 2-aminobenzimidazole, 3-
tection, while challenging, would be valuable as it rap- aminopyrazole, 3-aminoindazole, 5-aminoindazole,
idly generates molecular complexity in designed mol- 9H-purine-6-amine,
1H-pyrazolo[3,4-d]pyrimidin-4-
ecules with minimal synthetic manipulations. In this amine) is synthetically important as it provides direct
context, spectacular advancements have been made in access to a diverse array of potentially bioactive N-
À
the efficient construction of selective C N bonds for arylated derivatives. Because of the potential chal-
many biologically potential substrates containing mul- lenges in the case of 2-aminobenzimidazole they rep-
tiple nucleophilic sites (e.g., purines, aminobenz- resent a unique structural class where such an ap-
ACHTUNGTRENNUNGamides, aminoindoles, pyridinones, aminophenols, proach includes the formation of regioisomers and/or
guanidines, unsymmetrical imidazoles, triazoles, etc.) polyarylated products due to the presence of three
capable of undergoing reaction. However, most of adjacent nucleophilic nitrogens (N-1, N-3 and C-2
À
these kinds of chemo/regioselective C N bond forma- amino group). The tautomeric nature of 2-aminobenz-
tion protocols are realized by metal-catalyzed cou-
ACHTUNGTRENiNGNU midazoles makes them a very attractive target for se-
pling reactions, which mainly includes Buchwald– lective N-arylation (Scheme 1).
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AHCTUNGTRENNUNG
imidazoles.[8] Previously it was observed that arylation
happened selectively at the N-1 position of unprotect-
ed 2-aminobenzimidazoles by using different N,N-bi-
dentate and O,O-bidentate ligands under modified
Ullmann-type coupling conditions.[9] In 2012 Buch-
wald et al. developed elegant Pd-catalyzed conditions
for the chemoselective C-2 NH2 arylation of 2-amino-
benzimidazoles for the first time.[10] Copper-catalyzed
arylboronic acid-promoted N/O-arylation, now re-
ferred as Chan–Lam-type coupling, has emerged as
a powerful synthetic tool.[11] The reasons behind the
popularity of this reaction are the mild reaction con-
ditions and the ability to use an ambient atmosphere
(ꢁopen-flask chemistryꢂ).[12] In due course, some exam-
ples of modified Chan–Lam-type of coupling condi-
tions have been developed for the selective N-aryla-
tions of aryl/heteroaromatic compounds containing
multiple nucleophilic sites.[13] But to the best of our
knowledge, copper-catalyzed methods for selective
À
C NH2 arylation of C-amino-NH-azoles have never
been described. During our work on the copper-cata-
lyzed, boronic acid-promoted, N-arylation of nitro-
gen-containing heterocycles,[14] recently we have de-
veloped a method for the N-1 arylation of C-amino-
NH-azoles.[14b] We became interested in using 2-ami-
nobenzimidazoles as potential substrates for selective
Figure 1. Biologically active compounds containing C-2 NH-
arylbenzimidazole subunits.
Many efficient Cu-and Pd-catalyzed N-1 arylations C-2 NH2 arylation (Scheme 1). Herein, we report the
of NH-azole derivatives have been reported.[6,7] In Cu-catalyzed conditions for the selective C NH2 ary-
À
this context, arylation of the C-2 NH2 group has been lation of unprotected 2-aminobenzimidazoles and
carried out initially with N-1 protected 2-aminobenz- other related C-amino-NH-azoles.
À
Scheme 1. Approaches for the C NH2 arylation of C-amino-NH-azoles.
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Table 1. Optimization of the reaction conditions[a]
Results and Discussion
During our previous studies[14b] we have observed that
the selective arylation occurred in the ring N-1 H,
À
which may be due to the higher acidity of the ring N
H when compared with the C NH2 bond of C-amino-
À
NH-azoles. Thus, the use of ligand and/or base combi-
nation may be necessary for changing the selectivity
pattern (N-1 vs. C NH2). To facilitate the reaction for
À
À
C NH2 arylation of C-amino-NH-azoles according to
our observations, we thought that the addition of ni-
trogen-containing ligands would be a good starting
point.[2e] Initially we started our screening of the reac-
tion conditions with 2-aminobenzimidazole (1a) by
using a Cu(OAc)2/CsOPiv combination in DMF at
608C, and we isolated the major N-1 arylated product
(2ab, 80%) along with a trace amount of C-2 NH2
arylated product (2a) (Table 1, entry 1). When we
tried to change to different bases (K2CO3, Cs2CO3)
the product yield was not improved (Table 1, entries 2
and 3). Then we added 1,10-phenanthroline (L1) as
a ligand in the presence of Cs2CO3 in DMF at 608C.
The required C-2 NH2-arylated product (2a) was iso-
lated in 80% yield, with no formation of the N-1 ary- En- Catalyst
Ligand Base
Solvent Yield [%][b]
Atry
of 2a/2ab
lated product (Table 1, entry 4). Bases such as K3PO4,
Na2CO3 and NaOAc remain inferior to the
Cu(OAc)2/1,10-Phen combination, as the products
were formed in the range of 30–40% (Table 1, en-
tries 5–7). When Cu(OTf)2 was used as the Cu source,
the product was isolated in 65% yield (Table 1,
entry 8). Next we used 2,2’-bipyridine (L2) as a ligand
instead of 1,10-phenanthroline (L1), and the desired
C-2 NH2 arylated product (2a) was obtained in 85%
yield (Table 1, entry 9). The other nitrogen ligands
such as terpyridine (L3), 4,4’-dimethyl[2,2’]bipyridine
(L4) and 2,6-di(1H-pyrazol-1-yl)pyridine (L5) were
less effective (Table 1, entries 10–12) in this cross-cou-
pling reaction. We observed that the combinations of
L2 as a ligand with other bases such as K3PO4,
Na2CO3, NaOAc, t-BuOK and KOH were less effec-
tive (Table 1, entries 13–17). Screening of different
solvents did not help in improving the yield (Table 1,
entries 18 and 19). A relatively lower yield was ob-
tained when we employed Cu(OTf)2 as a catalyst
(Table 1, entry 20). We have also attempted different
reaction temperatures, but 608C was found to be opti-
mal for smooth coupling. When we increased the re-
action temperature 2a was isolated in lower yield, and
at room temperature no product formation was ob-
served (for details see the Supporting Information).
Furthermore by varying the catalyst/ligand ratio it
1
2
3
4
5
6
7
8
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
–
–
–
CsOPiv DMF
K2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
trace/80
trace/60
trace/40
80/00
35/00
40/00
30/00
65/00
85/00
60/00
82/00
70/00
40/00
50/00
60/00
20/00
55/00
Cu(OAc)2 L1
Cu(OAc)2 L1
Cu(OAc)2 L1
Cu(OAc)2 L1
Cu(OTf)2 L1
Cu(OAc)2 L2
Cu(OAc)2 L3
Cu(OAc)2 L4
Cu(OAc)2 L5
Cu(OAc)2 L2
Cu(OAc)2 L2
Cu(OAc)2 L2
Cu(OAc)2 L2
Cu(OAc)2 L2
Cu(OAc)2 L2
Cu(OAc)2 L2
Cu(OTf)2 L2
K3PO4
DMF
Na2CO3 DMF
NaOAc DMF
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
Cs2CO3 DMF
9
10
11
12
13
14
15
16
17
18
19
20
K3PO4
DMF
Na2CO3 DMF
NaOAc DMF
t-BuOK DMF
KOH
DMF
Cs2CO3 DMSO 70/00
Cs2CO3 DMA
Cs2CO3 DMF
55/00
75/00
[a]
Reaction conditions: 2-aminobenzimidazole (1.0 equiv.),
phenylboronic acid (1.2 equiv.), Cu(OAc)2 (0.2 equiv.),
2,2’-bipyridine (0.2 equiv.), Cs2CO3 (2.0 equiv.) DMF
(1 mL), 608C, 12 h, air.
[b]
Isolated yield.
was observed that Cu(OAc)2 (0.2 equiv.) and L2 aminobenzimidazole (Table 2). The reaction went
(0.2 equiv.) afforded the highest yield of the product smoothly with different arylboronic acids to give the
2a (for detailed optimization of reaction conditions, desired C-2 NH2 arylated products (2a–y) in excellent
see the Supporting Information).
yields (65–90%). Arylboronic acids with para-substi-
Under the optimized reaction conditions, first we tuted groups such as 4-Me (2b), 4-propyl (2c), 4-cyclo-
examined the scope of various boronic acids with 2- pentyl (2d), 4-OMe (2e), 4-OEt (2f), 4-Br (2h), 4-F
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Table 2. Scope of the Cu-catalyzed C2-NH2-arylation of 2-aminobenzimidazoles.[a]
[a]
Reaction conditions: 2-aminobezimidazole (1.0 equiv.), aryl/heteroarylboronic acid (1.2 equiv.), Cu(OAc)2 (0.2 equiv.),
2,2’-bipyridyl (0.2 equiv.), Cs2CO3 (2.0 equiv.), DMF (1 mL), 608C, air, 12 h.
(2i) and meta-substituted groups 3-Cl (2l, 75%), 3- was tested with substituted 2-aminobenzimidazoles.
NO2 (2m, 73%) afforded good yields and no other When we tested 6-nitro-2-aminobenzimidazole with 4-
isomers were obtained. We observed that the elec- bromophenylboronic acid the yield is 80% (2t), while
tronic nature of the boronic acids did not have any in- on using 6-methoxy-2-aminobenzimidazole with 4-
fluence in the reaction as both electron-rich (2b–f) methylphenylboronic acid we obtained the N-arylated
and electron-poor (2h–n, 2p) arylboronic acids result- product in 81% yield (2u) and by using 6-bromo-2-
ed in excellent yields (73–82%). Functional groups aminobenzimidazole with 3-chlorophenylboronic acid
such as 4-Br (2h, 81%), 4-CN (2j, 75%), 4-CHO (2k, the yield is 75% (2z). The further scope of this reac-
82%) are tolerated under the optimized conditions. tion was tested with different heterocyclic boronic
The reaction was also performed with disubstituted acids, e.g., 3-thienyl- (2v) and 3-pyridylboronic acid
phenylboronic acids, e.g., 2n (3-Cl, 4-F), 2o (3-F, 4- (2y) and the C-2 NH2 arylated products were ob-
CN), 2p (2-OMe, 5-F), and the N-arylated products tained in good yield (2v, 70%; 2y, 65%). A further
were isolated in excellent yields (78–82%).
evaluation of the scope of this method revealed that
We have investigated three bicyclic boronic acids. the reaction also proceeded smoothly with (2-fluoro-
In the case of 2-naphthylboronic acid the yield is 87% [1,1’-biphenyl]-4-yl)boronic acid (2w, 87%), and [4-(4-
(2s) whereas benzo[d][1,3]dioxol-5-ylboronic acid re- fluorobenzyloxy)phenyl]boronic acid (2x, 90%), gave
sulted in 2q in 85% yield and (2,3-dihydrobenzo[b] excellent yields under these optimized reaction condi-
[1,4]dioxin-6-yl) boronic acid afforded 2r in 80% tions (Table 2).
yield. To enhance the substrate scope, the reaction
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[a]
À
Table 3. Selective C NH2 arylation of C-animo-NH-azoles.
[a]
Reaction conditions: C-amino-NH-azole (1.0 equiv.), arylboronic acid (1.2 equiv.), Cu(OAc)2 (0.2 equiv.), 2,2’-bipyridyl
(0.2 equiv.), Cs2CO3 (2.0 equiv.), DMF (1 mL), 608C, air, 12 h.
Encouraged by the versatility of this cross-coupling clouding of PMB protected 4-amino group adjacent
reaction, we decided to enhance the substrate scope. to the 3-animo group (Table 3).
The aminoindazoles/pyrazoles are privileged hetero-
Next, we did the reaction of 2-aminobenzimidazole
cyclics as they are found in many biologically active with potassium phenyltrifluoroborate to extend this
compounds.[15] When we carried out this reaction with method to another aryl source under optimized reac-
3-aminopyrazole (Table 3) under the optimized reac- tion conditions, it was observed that reaction was inef-
tion conditions, various boronic acids coupled to give ficient as compared to the reaction with phenylboron-
exclusively the C-3 NH2 arylated products (4-Me: 3a, ic acid and the corresponding product was isolated in
70%; 4-Br: 3b, 68%). Reaction of 3-aminoindazole lower yields (2a, 60%) aftert a longer reaction period
with 3-nitrophenylboronic acid gave exclusively the of 24 h (Scheme 2).
C-3 NH2 arylated product (3c, 66%) while disubstitut-
ed phenylboronic acid resulted (3d) in 62% yield. 5-
Aminoindazole reacted smoothly with phenylboronic
Then we became interested in the synthesis of di-
AHCTUNGTRENNUNG
À
acid in giving exclusively C NH2 arylated product
(3e) in moderate yield (55%). By using 4-aminopyra-
zole and 5-aminopyrazole with arylboronic acids, it
was found that the reaction was occurred selectively
À
at the C NH2 position ( 3f, 60%; 4-Br: 3g, 65%; 3h,
72%).
À
To enhance the substrate scope further, C NH2 ar-
ylation was performed with medicinally important
heterocycles (e.g., 9H-purin-6-amine and 1H-pyrazo-
lo[3,4-d]pyrimidin-4-amine), under optimized condi-
tions and the coupled N-arylated products were iso-
lated in good yields (3i, 72%; 3j, 62%). It is worthy to
mention that previously no method was reported for
À
the selective C NH2 arylation of these medicinally
important heterocycles. When we used PMB-protect-
ed 1H-pyrazolo[4,3-c]pyridine-3,4-diamine with phe-
nylboronic acid, it gave selectively N-1 arylated prod-
Scheme 2. Selective C-2 NH2 arylation of 2-aminobenzimi-
uct in moderate yield (3k, 0%; 3k’, 55%) due to dazole.
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ous literature reports,[16] we propose a plausible reac-
tion mechanism (Scheme 4). The initial step involves
the formation of Cu complex A generated from
Cu(OAc)2 and 2,2’-bipyridine (L2), subsequently com-
plex A and 2-aminobenzimidazole combine to form
Cu(II) complex B. Phenylboronic acid then undergoes
transmetallation with complex B to form Cu(II) com-
plex C which, on disproportionation reaction, yields
higher oxidation Cu(III) complex D.[16a,b] Now the
Cu(III) complex D undergoes smooth reductive elimi-
nation to form the product 2a with concurrent forma-
tion of Cu(I) complex E. Finally O2 (air) acts as a ter-
minal oxidant to regenerate Cu(II), thus completing
the catalytic cycle.
Conclusions
Scheme 3. Sequential two-step reaction for diarylamino-
ACHTUNGTRENNUNGazoles.
In summary, we have developed a general, efficient,
and ligand controlled copper(II)-catalyzed method for
À
bromophenylboronic acid catalyzed by Cu(OAc)2 in selective C NH2 arylation of 2-aminobenzimidazoles
dichloroethane to afford compound 4 (Scheme 3) in and related C-amino-NH-azoles. It was realized by
72% yield (for screening of reaction conditions see using 2,2’-bipyridine as ligand and Cs2CO3 as base
the Supporting Information). Thus, this new two-step under open air conditions, and it is first method for
À
sequential protocol complements our previous meth- the Cu-catalyzed selective C NH2 arylation in the
od.[14b]
presence of other reactive nucleophilic sites. The
Although the reason for the selectivity at present is method is exemplified with various C-amino-NH-
not clear, however, based on these results and previ- azoles and a broad selection of aryl/heteroarylboronic
Scheme 4. Plausible reaction mechanism.
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À
acids. It is first example for the selective C NH2 ary- General Procedure B for the Selective Two-Step
lation of 5-aminoindazole, 4-aminopyrazole, 5-amino- Synthesis of Diarylated 2-aminobenzimidazoles (4)
pyrazole, 9H-purine-6-amine, and 1H-pyrazolo[3,4-
d]pyrimidin-4-amine derivatives. We believe that
To a stirred solution of N-(3-chlorophenyl)-1H-benzo[d]imi-
dazol-2-amine (1.0 equiv.) in DCE (2 mL), 4-bromophenyl-
these new findings significantly broaden the scope of
Chan–Lam-type coupling and definitely will add
value in de novo design and development of Cu-cata-
boronic acid (1.2 equiv.) and Cu(OAc)2 (0.2 equiv.) were
added. The reaction mixture was stirred at room tempera-
ture for 12 h. The progress of the reaction was monitored by
TLC and, after completion of the reaction, 10 mL of water
were added to the reaction mixture which was extracted
then with EtOAc (10 mL), and further extracted two times
with EtOAc (2ꢃ10 mL). The combined organic phase was
washed with saturated aqueous NaHCO3, dried over Na2SO4
and concentrated under vacuum. The crude product was pu-
rified via flash chromatography (hexanes/EtOAc, 7:3) to
provide the title compound 4 as an off-white solid. Purified
product was characterized by NMR, ESI-MS, and IR tech-
niques.
À
lyzed C N bond formation reactions.
Experimental Section
General Information
All purchased chemicals were used without further purifica-
tion. All reactions were performed under open air. Analyti-
cal thin layer chromatography was performed using TLC
pre-coated silica gel 60 F254 Merck (20ꢃ20 cm). TLC plates
were visualized by exposing UV light or by iodine vapors.
Organic solutions were concentrated by rotatory evapora-
tion on a Bꢄchi (Switzerland) R-120 rotatory evaporator
and vacuum pump V-710. Flash column chromatography
was performed on Merck flash silica gel 100–200 mesh size.
Melting points of solid compounds were determined on
Acknowledgements
D. N. R., Sk. R., K. A. K., and A. S. R., thank UGC-New
Delhi and CSIR for their research fellowships. This research
work financially supported by CSIR-New Delhi (BSC0108).
1
Bꢄchi-B-545 (Switzerland) melting point apparatus. H and
13C NMR spectra were recorded with Bruker 500 and
400 MHz NMR instruments. Proton and carbon magnetic
resonance spectra (1H NMR and 13C NMR) were recorded
using tetramethylsilane (TMS) in the solvent of CDCl3 as
the internal standard (1H NMR: TMS at 0.00 ppm, CHCl3 at
7.24 ppm; 13C NMR: CDCl3 at 77.0 ppm) or were recorded
using tetramethylsilane (TMS) in the solvent of DMSO-d6
as the internal standard (1H NMR: TMS at 0.00 ppm,
DMSO at 2.50 ppm;13C NMR: DMSO at 40.0 ppm) or were
recorded using tetramethylsilane (TMS) in the solvent of
acetone-d6 as the internal standard (1H NMR: TMS at
0.00 ppm, acetone at 2.09 ppm;13C NMR: acetone at
29.9 ppm, 206.7 ppm). All the NMR spectra were processed
in MestReNova. HR-mass spectra were recorded with an
LCMS-QTOF Module No. G6540 A (UHD) instrument.
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À
General Procedure A for the C NH2 Arylation of 2-
Aminobenzimidazoles and Other C-Amino-NH-
azoles
To a stirred solution of 2-aminobenzimidazole (1.0 equiv.) in
DMF (1 mL) was added aryl/heteroarylboronic acid
(1.2 equiv.) and Cu(OAc)2 (0.2 equiv.), 2,2’-bipyridine
(0.2 equiv.) and Cs2CO3 (2 equiv.) at room temperature. The
reaction mixture was stirred at 608C for 12 h. The progress
of the reaction was monitored by TLC and after completion
of the reaction 10 mL of ice-cooled water were added to the
reaction mixture at room temperature. The mixture was ex-
tracted with EtOAc (10 mL) further extracted two times
with EtOAc (2ꢃ10 mL) and the combined organic phase
was washed with saturated aqueous NaHCO3 solution, dried
over Na2SO4 and concentrated under vacuum. The crude
product was purified by column chromatography to give
pure C-2 NH2 arylated 2-aminobenzimidazoles (2a–z) and
À
other C NH(Ar) aminoazoles (3a–k’). Purified products
were characterized by NMR, ESI-MS, and IR techniques.
Adv. Synth. Catal. 0000, 000, 0 – 0
7
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ÞÞ
These are not the final page numbers!

FULL PAPERS
À
Copper-Catalyzed C NH2 Arylation of 2-
Aminobenzimidazoles and Related C-Amino-NH-azoles
9
Adv. Synth. Catal. 2016, 358, 1 – 9
Desaboini Nageswar Rao, Sk. Rasheed,
Karampoori Anil Kumar, Annem Siva Reddy,
Parthasarathi Das*
Adv. Synth. Catal. 0000, 000, 0 – 0
9
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!