Facial and practical synthesis of benzimidazole-based N-heterocyclic carbenes

Article abstract of DOI:10.1016/j.tetlet.2013.02.006

An efficient synthesis of benzimidazole-based N-heterocyclic carbenes has been developed. The key step in this synthetic methodology was a one-pot protocol for the synthesis of N,N′-diarylaryldiamines starting from aryldiamine and aryl halides.

Full text of DOI:10.1016/j.tetlet.2013.02.006

Tetrahedron Letters 54 (2013) 2124–2127
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facial and practical synthesis of benzimidazole-based N-heterocyclic carbenes
⇑
Han Wang, Yuyu Xia, Shang Lv, Jingli Xu, Zhihua Sun
College of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, 333 Longteng Road, Shanghai 201620, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient synthesis of benzimidazole-based N-heterocyclic carbenes has been developed. The key step
in this synthetic methodology was a one-pot protocol for the synthesis of N,N0-diarylaryldiamines start-
ing from aryldiamine and aryl halides.
Received 18 December 2012
Revised 24 January 2013
Accepted 1 February 2013
Available online 13 February 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
N-heterocyclic carbene
One-pot
N,N0-Diarylaryldiamine
Cyclization
Introduction
such compounds are limited to the reactions of 1,2-dibromoben-
zene and a primary amine with a catalytic system using mono-
N-heterocyclic carbene (NHC) is an important class of ligands
used in organometallic chemistry. Many NHCs are based on an
imidazole central core, due to its convenient preparation from gly-
oxal and primary amines. However, for NHCs that contain fused
rings as central cores, such as a benzimidazole, the synthetic route
would be different. Such synthesis often requires first the prepara-
tion of N,N0-substituted o-phenylenediamine, followed by ring for-
mation reactions. Therefore, efficient synthesis of N,N0-
disubstituted o-phenylenediamine is of great interest, and can of-
ten be achieved based on aromatic C–N coupling reactions. Such
C–N coupling was explored under Ullmann coupling conditions,1,2
which is usually used for C–C couplings of aryl halides. There has
also been significant progress in Pd catalyzed C–N coupling in
the past few decades. Boger3 reported Pd catalyzed intermolecular
C–N coupling in 1984, followed by more advanced protocol from
Hartwig4 and Buchwald.5,6 One of the initial and also the most
widely used catalytic system is based on Pd2dba3/BINAP in the
presence of a base. This system can catalyze many different cou-
plings of primary or secondary amines with aryl halides. Additional
catalytic systems are based on a variety of ligands, such as Xant-
phos7 and DPEphos.7,8 With respect to the synthesis of o-phenyl-
enediamine or analogs for NHC precursors with a benzimidazole
core, Huang9 used Ullmann coupling to prepare N,N0-diphenyl-o-
phenylenediamine. However, the yield of Ullmann coupling was
only around 30% and required long reaction time. Wenderski10
and Hao11 used Buchwald reaction to prepare N,N0-diaryl-o-pheny-
lenediamines with 37–60% yields. Other reported syntheses of
phosphine ligands.12,13 Reports are also rare on the selectivity of
tertiary amine formation versus the desired di-secondary amine.
In this Letter, we show that N,N0-diaryl-o-phenylenediamines or
analogs can be efficiently prepared from aryldiamine and aryl bro-
mides in high yields with high chemoselectivity.
Result & discussion
As shown in Scheme 1, we used the synthesis of compound 1 as
a model reaction to screen for optimal C–N coupling conditions.
The challenge involved chemoselective preparation of N,N0-di-
phenyl-o-phenylenediamine form two secondary amine moieties
in a one-pot reaction and to minimize the formation of tertiary
amine byproducts. The results are summarized in Table 1. For
the reactions conducted in toluene with sodium tert-butoxide as
a base (entries 1–4), the classical Pd2dba3/BINAP (entry 4) proved
to be the best. Not only the yield of the desired product was high,
the reaction also restricted the formation of byproducts such as
tertiary amines. Entries 5–7 explored additional solvents and bases
for the Pd2dba3/BINAP catalyzed amination reaction. Overall, so-
dium t-butoxide turned out to be the optimal base for the reaction,
even though Cs2CO3 is easier to handle and may serve as a good
alternative with slightly longer reaction time.
Br
NH HN
NH2
NH2
Pd & ligand
base
+
2
1
⇑
Corresponding author. Tel./fax: +86 2167791432.
E-mail address: zhihuasun@sues.edu.cn (Z. Sun).
Scheme 1. Synthesis of N,N0-diphenyl-o-phenylenediamine.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.02.006

H. Wang et al. / Tetrahedron Letters 54 (2013) 2124–2127
2125
Table 1
N,N0-Diphenyl-1,2-diaminobenzene formation using various Pd/ligands and bases (cf. Scheme 1)
Entry
o-Phenylenediamine & bromobenzene
Pd/ligand
Base
Solvent
T (°C)
t (h)
Yield (%)
1
2
3
4
5
6
7
Amine (1 equiv) & bromobenzene (2 equiv)
Amine(1 equiv) & bromobenzene (2 equiv)
Amine(1 equiv) & bromobenzene (2 equiv)
Amine(1 equiv) & bromobenzene (2 equiv)
Amine(1 equiv) & bromobenzene (2 equiv)
Amine(1 equiv) & bromobenzene (2 equiv)
Amine(1 equiv) & bromobenzene (2 equiv)
5%Pd(OAc)2/10%PPh3
5%Pd(OAc)2/10%dppf
5%Pd(OAc)2/10%NHCa
5%Pd2dba3/7.5%BINAP
5%Pd2dba3/7.5%BINAP
5%Pd2dba3/7.5%BINAP
5%Pd2dba3/7.5%BINAP
NaOtBu(3 equiv)
NaOtBu(3 equiv)
NaOtBu(3 equiv)
NaOtBu(3 equiv)
NaOtBu(3 equiv)
Cs2CO3(3 equiv)
K2CO3(3 equiv)
Tol
Tol
Tol
Tol
DME
Tol
Tol
110
110
110
110
110
110
110
11
14
14
16
16
20
20
Trace
23
28
82
80
68
55
a
NHC = N,N0-diphenylbenzimidazolium chloride.
Table 2
Results of tertiary amine products
NH2
NH2
Br
+
n
Entry
Equiv of bromobenzene
T (°C)
t (h)
(1a or 1b) Yield (%)
1
2
3
4
2
2.4
3
110
110
110
110
16
16
18
24
Trace
Trace
Trace
Trace
X
X
4
NH
NH
N
NH
N
In order to confirm the selectivity of BINAP system for complet-
ing the C–N coupling at the secondary amine stage, we increased
the amount of bromobenzene and/or prolonged the reaction time
(Fig. 1 and Table 2) to see if the relative amount of tertiary amine
products such as 1a or 1b would increase or not.
N
LC–MS analysis of the crude reaction mixtures showed that only
a trace amount of mono- or di-tertiary amine was formed even
with an increased amount of halides or prolonged reaction times
(Table 2). Therefore, Pd2dba3/BINAP catalytic system appears to
be ideal for preparing di-secondary amine intermediates. Based
1b
1a
1
Figure 1. Prediction of tertiary amine products.
Table 3
Synthesis of di-secondary amine intermediates
H
NH2
NH2
5%Pd2dba3/7.5% BINAP, 3 equiv NaOtBu
N R2
R2 Br
R1
+
R1
toluene 100°C
N R2
H
NH HN
F
NH HN
F
NH HN
NO2 O2N
NH HN
a
1, 86%
3, 71%
2, 80%
a
4, 82%
NH HN
NH HN
NH HN
F3C
N
NH HN
CF3
N
N
N
N
N
6, 90%
5, 91%
a
8, 83%
7, 84%
N
N
N
N
N
H
NH HN
NH HN
H
N
NH HN
10, 89%
9, 81%
11, 52%
12, 88%
aUse Cs2CO3 instead of NaOtBu.

2126
H. Wang et al. / Tetrahedron Letters 54 (2013) 2124–2127
Table 4
Synthesis of NHC precursorsa
R2
N
NHR2
NHR2
HC(OMe)3
Cl
N
R2
HCl , HCOOH
R1
R1
F
N
N
N
N
N
N
N
Cl
Cl
N
Cl
N
N
N
N
N
Cl
Cl
N
Compound6', 92%
Compound5', 94%
Compound1', 90%
F
Compound2', 93%
Compound3', 90%
N
N
Cl
Cl
N
N
N
Cl
N
Compound8', 97%
Compound11', 88%
Compound9', 93%
a
The reaction conditions: N,N0-diarylaryldiamine was distilled in trimethyl orthoformate. Then concd HCl and formic acid were added to the solution. The mixture was
heated to 80 °C. After 2 h, the mixture was cooled to room temp and concentrated. The product was purified by silica flash column chromatography.
on the above optimized conditions, we extended the one-pot syn-
thetic procedure to other aryldiamines and arylbromides. The re-
sults are summarized in Table 3.
ferent bases used in the reaction, one can also tune the reaction
to be useful for wider ranges of functional groups in the starting
materials. In most cases, further reactions with trimethyl ortho-
formate afforded the corresponding NHC precursors in good to
high yields.
As shown in Table 3, a series of N,N0-diarylaryldiamines were
successfully prepared in high yields. When sodium t-butoxide
was used as the base (entries 1, 2, 5, 6, 8–12), high yields were ob-
tained in relatively short reaction time. On the other hand, when
aryl halides were not compatible with sodium t-butoxide (entries
3, 4, and 7), Cs2CO3 served as a fairly good alternative offering
yields in 71–84% range in 24 h of reaction time. One limitation
for our protocol is that strongly electron deficient aryldiamines
such as 4-nitro-1,2-diaminobenzene or 2,3-diaminopyridine could
not afford the corresponding desired products. In addition, due to
the relatively high reaction temperature, small amounts of Ull-
mann homocoupling products were formed from aryl halides.
Additional work to address these two issues is currently underway.
With a series of N,N0-diarylaryldiamines in hand, we proceeded
to prepare the corresponding NHC precursors through cyclization
with trimethylorthoformate and HCl. The results are summarized
in Table 4. While the cyclization worked well for 8 of the 12 cases,
diamines with strong electron withdrawing substitutions did not
work (entries 4, 7, and 10), nor did the 7-member ring system (en-
try 12).
Acknowledgments
Financial support of this work was provided by Shanghai Saijia
Chemicals Ltd, Shanghai Municipal Science and Technology Com-
mission (Project No.12430501300), and the Students Innovation
Program in Shanghai University of Engineering Science
(cx1204018).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.02.
006.
References and notes
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M.; Goubitz, K.; Fraanje, J. Organometallics 1995, 14, 3081.
In summary, using the classical Pd2dba3/BINAP catalytic sys-
tem for C–N coupling, we developed a one-pot protocol for the
synthesis of N,N0-diarylaryldiamines starting from aryldiamine
and aryl bromides. The synthetic procedure has excellent selectiv-
ity for producing the desired di-secondary amine products while
minimizing the formation of tertiary amine byproducts. With dif-

H. Wang et al. / Tetrahedron Letters 54 (2013) 2124–2127
2127
8. (a) Uozumi, Y.; Hayashi, T. J. Am. Chem. Soc. 1991, 113, 9887; (b) Kurz, L.; Lee,
G., ; Morgans, D., Jr.; Waldyke, M. J.; Ward, T. Tetrahedron Lett. 1990, 31, 6321.
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