Copper catalyzed N-arylation of amidines with aryl boronic acids and one-pot synthesis of benzimidazoles by a Chan-Lam-Evans N-arylation and C-H activation/C-N bond forming process

Article abstract of DOI:10.1021/ol3028847

Mono-N-arylation of benzamidines 1 with aryl boronic acids 2 was effectively achieved in the presence of a catalytic amount of Cu(OAc) ₂ and NaOPiv under mild aerobic conditions. Combining this step with an intramolecular direct C-H bond functionalization, catalyzed by the same catalytic system but under oxygen at 120 C, afforded benzimidazoles 3 in good to excellent yields.

Full text of DOI:10.1021/ol3028847

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Copper Catalyzed N‑Arylation of Amidines
with Aryl Boronic Acids and One-Pot
Synthesis of Benzimidazoles by a
ChanꢀLamꢀEvans N‑Arylation and CꢀH
Activation/CꢀN Bond Forming Process
†
Jihui Li, Sebastien Benard, Luc Neuville,* and Jieping Zhu*
†
,†
,†,‡
ꢀ
ꢀ
Centre de Recherche de Gif, Institut de Chimie des Substances Naturelles, Laboratoire
ꢀ
International Associe, CNRS, 91198 Gif-sur-Yvette Cedex, France, and Institut of
Chemical Sciences and Engineering, Ecole Polytechnique Federale de Lausanne,
ꢀ ꢀ
EPFL-SB-ISIC-LSPN, CH-1015 Lausanne, Switzerland
luc.neuville@icsn.cnrs-gif.fr; jieping.zhu@epfl.ch
Received October 19, 2012
ABSTRACT
Mono-N-arylation of benzamidines 1 with aryl boronic acids 2 was effectively achieved in the presence of a catalytic amount of Cu(OAc)2 and
NaOPiv under mild aerobic conditions. Combining this step with an intramolecular direct CꢀH bond functionalization, catalyzed by the same
catalytic system but under oxygen at 120 °C, afforded benzimidazoles 3 in good to excellent yields.
Benzimidazoles are valuable synthetic targets due to
their presence in compounds ranging from pharmaceuti-
cals to materials.1 It is therefore not surprising that many
synthetic methods have been developed to reach this bicyclic
ring system.2 Traditionally these compounds are prepared
by a condensation of substituted ortho-phenylenediamines
with carbonyl derivatives. Following the development of
metal-catalyzedCꢀN bond forming reactions,3 alternative
strategies relying on the use of ortho-functionalized aryl
halides have emerged.4,5 More recently, metal-catalyzed
CꢀH activation6/cyclization processes starting from
simple N-arylated precursors have been developed.7
† Centre de Recherche de Gif, CNRS.
‡
ꢀ ꢀ
Ecole Polytechnique Federale de Lausanne.
(1) (a) Alamgir, M.; Black, D. St. C.; Kumar, N. Synthesis, Reactiv-
ity and Biological Activity of Benzimidazoles. Topics in Heterocyclic
Chemistry; Springer: Berlin, Germany, 2007; Vol. 9, pp 87ꢀ118. (b)
Carvalho, L. C. R.; Fernandes, E.; Marques, M. M. B. Chem.;Eur.
J. 2011, 17, 12544–12555.
(4) (a) Brain, C. T.; Brunton, S. A. Tetrahedron Lett. 2002, 43, 1893–
1895. (b) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133–136. (c) Brain,
C. T.; Steer, J. T J. Org. Chem. 2003, 68, 6814–6816. (d) Szczepankiewicz,
B. G.; Rohde, J. J.; Kurukulasuriyz, R. Org. Lett. 2005, 7, 1833–1835. (e)
Saha, P.; Ramana, T.; Purkait, N.; Ali, M. A.; Paul, R.; Punniyamurthy, T.
J. Org. Chem. 2009, 74, 8719. (f) Hirano, K.; Biju, A. T.; Glorius, F. J. Org.
Chem. 2009, 74, 9570–9572. (g) Peng, J.; Ye, M.; Zong, C.; Hu, F.; Feng, L.;
Wang, X.; Wang, Y.; Chen, C. J. Org. Chem. 2011, 76, 716–719. (h) Yu, H.;
Liu, Y.; Ni, C. Tetrahedron Lett. 2012, 53, 5253–5256.
(5) (a) Zheng, N.; Anderson, K. W.; Huang, X.; Nguyen, H. N.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46, 7509–7512. (b) Zou, B.;
Yuan, Q.; Ma, D. Angew. Chem., Int. Ed. 2007, 46, 2598–2601. (c) Diao,
X.; Wang, Y.; Jiang, Y.; Ma, D. J. Org. Chem. 2009, 74, 7974–7977. (d)
Murru, S.; Patel, B. K.; Le Bras, J.; Muzart, J. J. Org. Chem. 2009, 74,
2217–2220. (e) Lv, X.; Bao, W. J. Org. Chem. 2009, 74, 5618–5621. (f)
Lygin, A. V.; de Meijere, A. Eur. J. Org. Chem. 2009, 5138–5141. (g)
Kim, Y.; Kumar, M. R.; Park, N.; Heo, Y.; Lee, S. J. Org. Chem. 2011,
76, 9577–9583.
(2) For selected recent examples: (a) Way, B. C.; Stambuli, J. P. Org.
Lett. 2010, 12, 4576–4579. (b) El Kaım, L.; Grimaud, L.; Purumandla,
¨
S. R. Eur. J. Org. Chem. 2011, 6177–6180. (c) Bastug, G.; Eviolitte, C.;
Marko, I. E. Org. Lett. 2012, 14, 3502–3505. (d) Pizzetti, M.; De Luca,
E.; Petricci, E.; Porcheddu, A.; Taddei, M. Adv. Synth. Catal. 2012, 354,
2453–2464.
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Angew. Chem., Int. Ed. 2003, 42, 5400–5449. (b) Monnier, F.; Taillefer
Angew. Chem., Int. Ed. 2009, 48, 6954–6971. (c) Liu, T.; Fu, H. Synthesis
2012, 44, 2805–2824. For reviews involving palladium, see: (d) Hartwig,
J. F. Acc. Chem. Res. 2008, 41, 1534–1544. (e) Surry, D. S.; Buchwald,
S. L. Chem. Sci. 2011, 2, 27–50. For general reviews, see: (f) Fischer, C.;
Koenig, B. Beilstein J. Org. Chem. 2011, 7, 59–74. (g) Sadig, J. E. R.;
Willis, M. C. Synthesis 2011, 43, 1–22.
r
10.1021/ol3028847
XXXX American Chemical Society

N-Arylated amidines, an important strutural unit in medic-
inal chemistry,8 have often been used as starting materials
for the synthesis of benzimidazoles.4 Domino processes
combining the in situ formation of amidines with sub-
sequent cyclization have also been developed for the syn-
thesis of benzimidazoles.9
We have been involved in the development of metal-
catalyzed domino processes,10 including sequences con-
taining a direct aromatic CꢀH functionalization step.11
In addition, we recently extended the ChanꢀLamꢀEvans
reaction to the cyclopropylation of nitrogen containing
heterocycles.12 Subsequent to this work, we became inter-
ested indeveloping a dominocopper-catalyzed synthesisof
benzimidazoles from boronic acids and amidines (Scheme 1).
Whereas developing such a sequence might appear trivial
since the second step has been established by Buchwald,7a
several potential pitfalls existed: (1) The ChamꢀLamꢀEvans
reaction has been extended to numerous functionalities,13
but not to unprotected amidines.14 (2) Copper-promoted
N-arylations involving boronic acids are known to occur
under basic or neutral conditions while the importance of
acid has been established for the copper-catalyzed intra-
molecularcyclizationinvolvingtheCꢀH functionalization
step.7a,d Herein, we report the realization of this domino
process for the synthesis of benzimidazoles from easily
available aryl boronic acids and amidines by a sequence
involving ChanꢀLamꢀEvans N-arylation, CꢀH activa-
tion, and CꢀN bond formation.
Scheme 1. Prospected Sequence for the Synthesis of Benzimidazoles
(6) For a monograph, see: (a) CꢀH activation. In Topics in Current
Chemistry; Yu, J.-Q., Shi, Z., Eds.; Springer: 2010; Vol. 292, pp 1ꢀ380. For
€
recent reviews, see: (b) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F.
Chem. Soc. Rev. 2011, 40, 4740. (c) Cho, S.; Kim, J. Y.; Kwak, J.; Chang,
S. Chem. Soc. Rev. 2011, 40, 5068–5083. (d) Stokes, B. J.; Driver, T. G.
Eur. J. Org. Chem. 2011, 39, 4071–4088. (e) Yamaguchi, J.; Yamaguchi,
A. D.; Itami, K. Angew. Chem., Int. Ed. 2012, 51, 8960–9009. (f)
Hickman, A.; Sanford, M. S. Nature 2012, 484, 177–185. (g) Kuhl, N.;
Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew. Chem., Int.
Ed. 2012, 51, 10236–10254.
(7) (a) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
1932–1934. (b) Xiao, Q.; Wang, W.-H.; Liu, G.; Meng, F.-K.; Chen,
J.-H.; Yang, Z.; Shi, Z.-J. Chem.;Eur. J. 2009, 15, 7292–7296. (c) He,
H.-F.; Wang, Z.-J.; Bao, W. Adv. Synth. Catal. 2010, 352, 2905–2912. (d)
Masters, K.-S.; Rauws, T. R. M.; Yadav, A. K.; Herrebout, W. A.; van
der Veken, B.; Maes, B. U. W. Chem.;Eur. J. 2011, 17, 6315–6320. (e)
Kumar, R. K.; Ali, M. A.; Punniyamurthy, T. Org. Lett. 2011, 13, 2102–
2105.
(8) For a review: (a) Rauws, T. R. M.; Maes, B. U. W. Chem. Soc.
Rev. 2012, 41, 2463–2497. See also: (b) McGowan, M. A.; McAvoy,
C. Z.; Buchwald, S. L. Org. Lett. 2012, 14, 3800–3803 and references
therein.
(9) (a) Viirre, R. D.; Evinda, G.; Batey, R. A. J. Org. Chem. 2008, 73,
3452–3459. (b) Deng, X. H.; McAllister, H.; Mani, N. S. J. Org. Chem.
2009, 74, 5742–5745. (c) Deng, X. H.; Mani, N. S. Eur. J. Org. Chem.
2010, 680–686. (d) Yang, D. S.; Fu, H.; Hu, L. M.; Jiang, Y. Y.; Zhao,
Y. F. J. Org. Chem. 2008, 73, 7841–7844. (e) Jin, H.; Xu, X.; Gao, J.;
Zhong, J.; Wang, Y. Adv. Synth. Catal. 2010, 352, 347–350. (f) Shen, G.;
Bao, W. Adv. Synth. Catal. 2010, 352, 981–986. (g) Wang, F.; Cai, S.;
Liao, Q.; Xi, C. J. Org. Chem. 2011, 76, 3174–3180.
To explore the feasibility of our planned domino pro-
cess, we first targeted the synthesis of N-arylated amidine
4a (R1 = Ph, R2 = H, R3 = 4-methyl), and the survey of
reactionconditions issummarizedinTable 1. Treatmentof
benzimidamide (1a) with p-tolylboronic acid (2a) in the
presence of an excess of Cu(OAc)2 under argon in DMF at
rt furnished the desired mono-N-arylated amidine 4a in
77% yield (Table 1, entry 1). Pleasingly, under catalytic
conditions [Cu(OAc)2 (0.2 equiv), air], 4a was formed in
44% yield (entry 2). Heating the reaction at 80 °C in DMF
or at reflux in methanol only marginally improved the
yield, and higher temperatures proved to be deleterious
(entries 3ꢀ5). Among the additives/ligands that were evalu-
ated [1,10-phenantroline (Phen), bipyridine (Bipy), tetra-
methylethylenediamine(TMEDA), triphenylphosphineoxide,
sodium pivalate (NaOPiv), thiophene carboxylate (TC)],
triphenyl phosphine oxide and sodium pivalate significantly
improved the process (entries 6ꢀ12). N,N0-Bis-arylated
amidine 5a was observed in all reactions, but could be
suppressed by reducing the stoichiometry of the arylboro-
nic acid from 2.0 to 1.2 equiv (entries 11 and 12).
The scope of this new Cu-catalyzed N-arylation reaction
was briefly examined (Figure 1). Arylboronic acids includ-
ing pyridin-4-yl boronic acid, bearing an electron-with-
drawing or -donating group at the para position, furnished
the expected mono-N-arylated amidines in good to excel-
lent yields (4aꢀc). Ortho-substitution was also tolerated
affording the corresponding product (4d) in good yield
(62%) if an excess of amidine (1.5 equiv) was used. Potas-
sium aryltrifluoroborates could also be used instead of
boronic acids, albeit with slightly reduced yields.
(10) (a) Pinto, A.; Jia, Y.; Neuville, L.; Zhu, J. Chem.;Eur. J. 2007,
13, 961–967. (b) Jaegli, S.; Erb, W.; Retailleau, P.; Vors, J.-P.; Neuville,
L.; Zhu, J. Chem.;Eur. J. 2010, 16, 5863–5867. (c) Jaegli, S.; Vors, J.-P.;
Neuville, L.; Zhu, J. Tetrahedron 2010, 66, 8911–8921.
(11) (a) Cuny, G.; Bois-Choussy, M.; Zhu, J. Angew. Chem., Int. Ed.
2003, 42, 4774–4777. (b) Cuny, G.; Bois-Choussy, M.; Zhu, J. J. Am.
Chem. Soc. 2004, 126, 14475–14484. (c) Pinto, A.; Neuville, L.; Retailleau,
P.; Zhu, J. Org. Lett. 2006, 8, 4927–4930. (d) Pinto, A.; Neuville, L.; Zhu, J.
Angew. Chem., Int. Ed. 2007, 46, 3291–3295. (e) Salcedo, A.; Neuville, L.;
Rondot, C.; Retailleau, P.; Zhu, J. Org. Lett. 2008, 10 (5), 857–860. (f)
Gerfaud, T.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2009, 48, 572–577.
(g) Pinto, A.; Neuville, L.; Zhu, J. Tetrahedron Lett. 2009, 50, 3602–3605.
(h) Jaegli, S.; Dufour, J.; Wei, H.-L.; Piou, T.; Duan, X.-H.; Vors, J.-P.;
Neuville, L.; Zhu, J. Org. Lett. 2010, 12, 4498–4501. (i) Piou, T.; Neuville,
L.; Zhu, J. Org. Lett. 2012, 14, 3760–3763.
ꢀ
(12) (a) Benard, S.; Neuville, L.; Zhu, J. J. Org. Chem. 2008, 73, 6441–
6444. (b) Benard, S.; Neuville, L.; Zhu, J. Chem. Commun. 2010, 46,
3393–3395.
(13) (a) Qiao, J. X.; Lam, P. Y. S. Synthesis 2011, 829–856. (b) Rao,
K. S.; Wu, T.-S. Tetrahedron 2012, 68, 7735–7754.
(14) Few examples involving N-Protected amidines have been de-
scribed without mentioning yields: (a) Nielsen, F. E.; Korno, H. T.;
Rasmussen, K. G. WO/2004/0010142 A1, January 15, 2004. (b) Burnett,
D. A.; Wu, W.-L; Domalski, M. S.; Caplen, M. A.; Spring, R.; Lachowicz,
J. E. US2005/0137210 A1, June 23, 2005.
The reaction was not limited to primary amidines as
N-(p-tolyl)- and N-(isopropyl)-benzimidamides 1b and 1c
were effectively arylated, furnishing the corresponding N,
N0-adducts 5a and 5c, respectively. Notably, unsymmetri-
cal N,N0-bisarylation of amidines could be accomplished
uponsequentialaddition of two different arylboronicacids
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Survey of Reaction Conditions for the Mono-N-arylation
of Amidines
Table 2. Survey of Reaction Conditions for the One-Pot
Synthesis of Benzimidazoles
1a
entry (equiv) (equiv)
2a
temp
t
yield
entry
catalyst/additive
atm, temp (°C)
solv
yield (%)b
(°C)
(h)
atm additives (%)b
1c
2
Cu(OAc)2
argon, rt
air, rt
DMF
DMF
DMF
DMF
MeOH
DMF
DMF
DMF
DMF
DMF
DMF
DMF
77
1
1
1.2
1.2
1.2
1.2
1
rt/120 48/40 air/air Ph3PO
rt/120 24/24 air/O2 Ph3PO
50/120 12/13 air/O2 Ph3PO
50120 12/12 air/O2 NaOPiv
50/120 12/6 air/O2 NaOPiv
50120 12/6 air/O2 Ph3PO
50/120 12/6 air/O2 NaOPiv
29
44
52
53
85
75
82
73
Cu(OAc)2
42(26)
48(13)
29(15)
46(7)
35
2
1
3
Cu(OAc)2
air, 80
air, 130
air, refux
air, rt
3
1
4
Cu(OAc)2
4c
5c
6
1
5
Cu(OAc)2
1.5
1.5
1.5
1.5
6
Cu(OAc)2/Bipy
Cu(OAc)2/TMEDA
Cu(OAc)2/Phen
Cu(OAc)2/Ph3PO
Cu(TC)
1
7
air, rt
44
7c,d
8c
1
8
air, rt
48
1
120
8
O2
NaOPiv
9
10d
air, rt
60
air, rt
63
a Conditions: Cu(OAc)2 (0.2 equiv), additive (0.2 equiv), oxidant,
DMF. b Isolated yield. c NaOPiv (0.4 equiv). d DMSO as solvent.
11d,e Cu(OAc)2/NaOPiv
air, rt
81 (<5)
77 (<5)
12d
Cu(OAc)2/Ph3PO
air, rt
a Conditions: catalyst (0.2 equiv), additive (0.2 equiv), amidine
(1.0 equiv), p-TolB(OH)2 (2 equiv), 24 h. b Isolated yield; the yield in
parentheses refers to compound 5a. c Catalyst (2 equiv). d 1.2 equiv of
PhB(OH)2. e 0.4 equiv of NaOPiv.
A combination of copper(II) acetate with either Ph3PO
or NaOPiv furnished comparable results (entries 3 and 4).15
The yield could be improved to a useful level by adjusting
here again the stoichiometry between the amidine and the
arylboronic acid (entries 5ꢀ8). It should be noted that the
sequence could be performed in DMSO without signifi-
cantly affecting the yields (entry 5 vs7). Interestingly, when
the above reaction was performed at 120 °C in the presence
of Cu(OAc)2 and NaOPiv the annulation reaction took
place to directly afford the benzimidazole 3a in 73% yield
(entry 8).
The scope of the present annulation protocol was next
examined under the following optimized conditions: Cu-
(OAc)2 H2O (0.2 equiv), NaOPiv (0.4 equiv), air, DMF,
3
50 °C, 24 h, then O2, 120 °C, 4ꢀ24 h; the results are
presented in Schemes 2 and 3.
The electronic nature of the substituent at the aryl
boronic acid only weakly influenced the outcome of the
reaction, as 3aꢀe could be isolated in excellent yields.
However, while groups such as hydrogen, alkyl, ether,
halogen, or ester were well tolerated, 3g bearing a ketone
function was isolated in a modest 24% yield. Substitution
was not limited to the para postion, and interestingly, use
of para- or meta- (methoxyphenyl)-boronic acid afforded
the samecompound 3cin similar yields. Ortho-substitution
on the arylboronic acid was also compatible as demon-
strated by the formation of 3f. The reaction was not limited
to the use of 2-methylbenzimidamide (1d), as 2-chloroben-
zimidamide (1e) furnished the corresponding benzimida-
zoles 3h and 3i in 54% and 58% yield, respectively.
Interestingly, benzimidamide 1a lacking an ortho-substituent
participated well in this domino process (3jꢀ3l) in sharp
Figure 1. Scope of the copper-catalyzed N-arylation of amidines.a
as illustrated by a three-component synthesis of 5b (56%
yield). It should be mentioned that 1.5 equiv of the second
arylboronic acid was necessary to ensure the optimal yield
of the N,N0-bisarylated amidine. The conditions were how-
ever not suitable for the N-arylation of C-alkylamidines
furnishing only a trace amount of 4e.
The intermolecular N-arylation step being established,
we next focused our attention to the synthesis of benzimi-
dazoles (Table 2). We quickly learned that performing the
reaction under oxygen significantly improved the CꢀH
activation/CꢀN functionalization event (entry 1 vs 2).
(15) The presence of a Lewis basic oxygen in Pivalate or Ph3PO could
play a role in (1) the activation of the boronic acid and (2) the cleavage of
the CH bond; see: Lapointe, D.; Fagnou, K. Chem. Lett. 2010, 39, 1118–
1126.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 2. Scope of the Copper-Catalyzed Synthesis of
Benzimidazoles from Primary Benzamidines
Scheme 3. Scope of the Copper-Catalyzed Synthesis of
Benzimidazoles from Secondary Benzamidines
contrast to a previous report on the cyclization of
N-arylbenzamides.16
regioisomers 6j and 6j0 (0.9/1 ratio) was isolated in 58%
overall yield.
Synthesis of 1,2-disubstituted benzimidazoles from
N-substituted benzimidamides was also examined, and the
results are presented in Scheme 3. Benzimidazoles 6aꢀe
could be isolated in moderate to good yield when N-methyl
substituted benzamide 1f was used as a coupling partner.
It should be highlighted that the reaction was selective,
allowing 5- or 6-substituted N-methylbenzimidazoles 6d
and 6eto bebuilt bysimplychanging the boronic acidfrom
the meta-substituted to para-subtituted aryl donor. Whereas
N-n-propyl benzimidazoles (6fꢀg) could be isolated in
modest yields, N-isopropyl was not tolerated in the reac-
tion. In each case, the benzimidazole3a was also isolated in
a variable amount, probably generated through a compe-
tive N-dealkylation reaction known to occur under oxi-
dative conditions.17 Finally, we were able to synthesize
N-arylated benzimidazoles using N-arylated benzamidines.
When 2-methyl-N-phenylbenzimidamide (1h) was reacted
with p-tolylboronic acid (5a), an inseparable mixture of
In summary, we have developed a mild copper-catalyzed
mono-N-arylation of amidines using arylboronic acids
under aerobic conditions. The process has been extended
to a one-pot synthesis of benzimidazoles involving a se-
quence of intermolecular CꢀN bond formation and an
intramolecular CꢀH functionalization/CꢀN bond-form-
ing event. The ready accessibility of starting materials and
the low cost of the catalytic system made this process a
valuable alternative for the construction of these interest-
ing heterocycles.
Acknowledgment. Financial support from ICSN, CNRS.
J.L. thanks the Government of China for a National
Graduate Student Program of Building World-Class Uni-
versities. S.B. thanks ICSN for a doctoral fellowship.
Supporting Information Available. Experimental pro-
1
cedures, product characterization, and copies of the H
and 13C NMR spectra of all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(16) According to ref 7a., intramolecular cyclization required the
presence of an ortho-substitution on the benzamidine.
(17) (a) Mahapatra, S.; Halfen, J. A.; Wilkinson, E. C.; Pan, G.;
Wang, X.; Young, V. G.; Cramer, C. J.; Que, L.; Tolman, W. B. J. Am.
Chem. Soc. 1996, 118, 11555–11574. (b) Mahapatra, S.; Halfen, J. A.;
Tolman, W. B. J. Am. Chem. Soc. 1996, 118, 11575–11586.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX