Direct Synthesis of Benzimidazoles by Dehydrogenative Coupling of Aromatic Diamines and Alcohols Catalyzed by Cobalt

Article abstract of DOI:10.1021/acscatal.7b02777

Herein, we present the base-metal-catalyzed dehydrogenative coupling of primary alcohols and aromatic diamines to selectively form functionalized 2-substituted benzimidazoles, liberating water and hydrogen gas as the sole byproducts. The reaction is catalyzed by pincer complexes of Earth-abundant cobalt under base-free conditions.

Full text of DOI:10.1021/acscatal.7b02777

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Letter
Direct Synthesis of Benzimidazoles by Dehydrogenative
Coupling of Aromatic Diamines and Alcohols Catalyzed by Cobalt
Prosenjit Daw, Yehoshoa Ben-David, and David Milstein
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b02777 • Publication Date (Web): 27 Sep 2017
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ACS Catalysis
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Direct Synthesis of Benzimidazoles by Dehydrogenative Coupling of
Aromatic Diamines and Alcohols Catalyzed by Cobalt
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Prosenjit Daw, Yehoshoa Ben-David, and David Milstein*†
Department of Organic Chemistry, Weizmann Institute of Science, Rehovot, 76100, Israel
ABSTRACT: Herein we present the base-metal catalyzed dehydrogenative coupling of primary alcohols and aromatic diamines to
selectively form functionalized 2-substituted benzimidazoles, liberating water and hydrogen gas as the sole by-products. The reac-
tion is catalyzed by pincer complexes of earth-abundant cobalt under base-free conditions.
KEYWORDS: Cobalt, Pincer, Benzimidazole, Alcohol, Dehydrogenative Coupling
Benzimidazole and its derivatives are important building
blocks for the pharmaceutical industry due to their prominent
biological activity such as anti-arrhythmic, antihistaminic, antiul-
cer, anticancer, inotropic, antifungal, antihelmintic, and antiviral
activities.1 A number of drugs which exhibit significant activity
against viruses such as HIV, herpes (HSV-1) or influenza contain
the benzimidazole motif in the molecule. Furthermore, benzimid-
azoles have significant contributions to industrial chemistry appli-
cations such as in cases of chemical UVB filters, pigments, opti-
cal brighteners for coatings, and thermo stable membranes for fuel
cells.2 Typically benzimidazoles are synthesized by reaction of
1,2-diaminobenzene with carboxylic acid derivatives, under
strongly acidic conditions.3 A regular procedure for the synthesis
of benzimidazole involves heating of 1,2-diaminobenzene in con-
centrated formic acid.3a This approach, although extensively used,
suffers from formation of stoichiometric amounts of waste due to
substrate leaving groups or additives. Recently, use of aldehydes
as substrates and iodine as catalyst in the presence of hydrogen
peroxide resulted in improved reaction conditions.4
lyst using a stoichiometric amount of base.5b Developments of
heterogeneous catalysts for this process were also reported.7
Figure 1. Synthesis of functionalised benzimidazole derivatives:
Classical methods and metal catalysed dehydrogenative coupling
method.
In terms of sustainable synthesis, an environmentally benign
route to the synthesis of benzimidazoles from renewable resources
with high atom economy would be highly desirable. Among the
methods used for the synthesis of benzimidazoles,3b-d dehydro-
genative coupling between primary alcohols and derivatives of
1,2-phenylenediamine is an one of the most efficient effective
synthetic pathway,5-7 since the only by-products are stoichio-
metric amounts of water and two equivalent of valuable molecular
hydrogen (Figure 1). Since alcohols are abundantly available, the
development of efficient reactions whereby alcohols are converted
into useful classes of compounds is desirable. Indeed, progress
has been made in recent years on sustainable benzimidazole syn-
thesis based on acceptorless dehydrogenation of alcohols followed
by coupling with aromatic diamines using noble metal-based
complexes.5 An initial report catalysed by ruthenium phosphine
complexes required a reaction temperature of over 200°C.5a Re-
cently, several synthetic protocols for the synthesis of benzimid-
azoles were reported using homogeneous catalysts which operate
at lower temperatures, but require stoichiometric amounts of hy-
drogen acceptors or strong bases.5b-d,6 Kempe and co-workers
recently synthesized benzimidazole derivatives via acceptorless
dehydrogenative coupling of primary alcohols and 1,2-
diaminobenzene catalysed by a triazine-based iridium pincer cata-
The development of synthetic reactions catalysed by base-
metal complexes is a central goal in homogeneous catalysis, from
the perspective of abundance, low cost, lower toxicity and
sustainability of base metals. Indeed considerable progress has
been made by several groups employing complexes of base metals
(Fe, Co, Mn, Ni) in various (de)hydrogenation reactions.8-10 Ho-
mogeneous cobalt catalysts have been reported in hydrogenation
reactions of olefins, ketones, imines and CO2. Ester and nitrile
hydrogenation, catalyzed by a (pyridine-based PNNH pincer) Co
complex, was reported by us.11 Recently we also reported selecti-
ve N-formylation of primary and secondary amines using a CO2
and H2 gas mixture, catalysed by a Co-iPrPNHP complex.12 Ho-
mogeneous cobalt catalysts were recently exploited for dehydro-
genation and dehydrogenative coupling reactions by several
groups.10a-g We reported the dehydrogenative coupling of diols
and amines to selectively form functionalized 1,2,5-substituted
pyrroles, liberating water and hydrogen gas as the sole by-
products employing a Co-PNNH pincer catalyst.13
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Page 2 of 6
cantly, quantitative convertion to the desired product under simi-
lar conditions took place even in absence of BuOK (entry 2).
Lowering the temperature to 120°C resulted in yield drop to 48%
(entry 3). Analysis of the gas phase by GC revealed the formation
of H2.
Table 1. Optimization of the reaction conditions for the dehy-
drogenative coupling of 1,2-diaminobenzene and alcohols.
t
1
2
3
4
5
6
7
8
In the absence of molecular sieves, under similar reaction
conditions, a significantly lower yield of the benzimidazole deri-
vative (29%) was obtained (entry 4) after 48h. Upon decreasing
the loading of complex 1 and NaBEt3H to 2.5 mol%, the product
was formed in 87% yield after 24h, and in 95% yield after 36h
(entries 5 and 6) under base free conditions. Surprisingly, cataly-
Entrya
Cata-
lyst
1
NaHBEt3
(x mol%)
Base
(y mol%)
5
-
Yieldb (%)
9
1
5
5
5
5
2.5
2.5
-
99
99
48
29
87
95
67
80
92
70
28
00
00
00
23
34
24
53
82
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
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2
1
t
sis was observed even in the absence of NaBEt3H and BuOK,
3d
1
-
using complex 1 (5 mol%), although benzimidazole was obtained
in a lower yield of 67% (entry 7). Upon addition of 5 mol%
tBuOK in the absence of NaBEt3H, the product was isolated in
80% yield (entry 8). While we don’t have mechanistic evidence at
this stage, it seems that the Co(II) precursor can be reduced to the
presumed Co(I) active species even just by the alcohol and diami-
nobenzene, although the process is more efficient with a hydride
reagent.
A reaction using 5 mol% pre-catalyst 1 and 5 mol% Na-
BEt3H under the same conditions in the presence of 300 equiva-
lents of Hg showed no decrease in product formation or selectivi-
ty (Table 1, entry 9), indicating that Co nanoparticle formation is
unlikely, and supporting the homogeneity of the reaction. Chan-
ging the solvent to 1,4-dioxane or THF using the catalyst and
NaBEt3H (5 mol% each) at 150 °C resulted in a lower yield of the
benzimidazole product (entries 10, 11). It should be noted that a
minor amount of 1-hexyl-2-pentyl benzimidazole was observed as
a side product in a few cases (Table 1, entry 4 (22%), entry 7
(7%)).
4e
1
5
-
5c
1
6c
1
-
7
1
-
8
9f
1
-
5
-
1
5
5
5
-
10g
11h
12
13
14
15
16
17
18
19c, i
1
-
1
-
CoCl2
CoCl2
-
-
5
-
5
-
2a
5
5
5
5
-
-
2b
-
3
-
4
-
1-Cl
-
aConditions: 1,2-diaminobenzene (0.5 mmol), 1-hexanol (0.5 mmol),
catalyst (5 mol%), NaHBEt3, base, and dry toluene (2 mL), heated in
a closed Teflon Schlenk tube at 150°C (bath temperature) in the
presence of 4Å molecular sieves for 24h. bIsolated yield. ccatalyst
Using CoCl2 as pre-catalyst, in the presence or absence of
(2.5 mol%) dAt 120°C (bath temperature). Reaction carried out in
e
t
both NaBEt3H and BuOK, under the same conditions, resulted in
f
the absence of molecular sieves for 48h. Reaction carried out in
presence of 300 equivalents of Hg with respect to catalyst. g1,4-
no product formation (entry 12, 13). No product was formed in
the absence of any catalyst (entry 14).
Dioxane used as solvent. hTHF used as solvent. (PNNH)CoICl (1-
i
Cl) used as catalyst.
Our previously reported dihalo Co-PNP and Co-PNN com-
plexes 2a, 2b,15 311a and 416 (Figure 1) were then screened.
t
Recently, formation of benzimidazoles catalysed by a Cu-
triazole-phosphine complex using excess stoichiometric base was
reported.6 Redox condensation of selective o-substituted nitroben-
zenes with alkylamines or alcohols, to form 2-arylbenzimidazoles
catalysed by an iron complex, was reported.14 However, to the
best of our knowledge, synthesis of benzimidazoles by acceptor-
less dehydrogenative coupling of primary alcohols with 1,2-
diaminobenzenes under base-free conditions, catalysed by a base-
metal complex, was not reported. Herein, we report such a reac-
tion, catalyzed by a cobalt complex, to selectively generate 2-
substituted benzimidazoles under base-free conditions, with the
extrusion of water and H2 as the only by products.
Employing the Bu substituted Co-PNP complex 2a, only 23%
product yield was observed at 150°C (Table 1, entry 15), whereas
the isopropyl-substituted analogue 2b catalyzed formation of the
2-pentylbenzimidazole in 34% yield (entry 16), and complex 3
yielded 24% of the product (entry 17). A higher yield of 2-
pentylbenzimidazole (53%) was obtained with the bipyridine-
based Co-PNN complex 4 (entry 18). The higher catalytic activity
of the PNNH complex 1 as compared with that of complexes 2-4
may be related to its potential ability to function by two modes of
metal−ligand cooperation, amine−amide and aromatiza-
tion−dearomatization, as opposed to complexes 2-4.9f,17
Using the optimized reaction conditions in absence of base (to-
luene, 150°C, 5 mol% 1, 5 mol% NaHBEt3), the scope of this
base-metal catalyzed dehydrogenative coupling reaction was pro-
bed with 1,2-diaminobenzene and various primary alcohols. As
shown in Table 2, various linear primary alcohols underwent de-
hydrogenative coupling with 1,2-diaminobenzene to yield the
corresponding 2-substituted benzimidazole derivatives in
excellent isolated yields (entries 1-4). Exploring the scope further,
reactions of 1,2- diaminobenzene with various substituted benzyl
alcohols were studied, resulting in good isolated yields using
electron rich benzyl alcohol derivatives (entries 5-9).
Initially, we explored the possibility of benzimidazole for-
mation by reaction of 1,2-diaminobenzene and alcohols using our
Co-PNNH pre-catalyst 111a (Figure 1). To generate the presumed
active Co(I) species, the use of one equiv. of NaBEt3H as a hydri-
t
de source, and BuOK as a base was envisioned, as observed in
our earlier work on Co-PNNH catalyzed pyrrole synthesis from
2,5-hexanediol and primary amines.13 Reaction of 1,2-
diaminobenzene (0.5 mmol) with 1-hexanol (0.5 mmol) using
NaHBEt3 (5 mol%), tBuOK (5 mol%) and the Co-PNNH complex
1 (5 mol%) in toluene in a closed system in the presence of 4Å
molecular sieves resulted in the formation of 2-pentyl benzimida-
zole in 99% yield at 150°C after 24 h (Table 1, entry 1). Signifi-
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ACS Catalysis
On the other hand, dehydrogenative coupling of the electron
Table 2. Dehydrogenative coupling of 1,2-diaminobenzenes
and alcohols catalyzed by complex 1a
1
2
3
4
5
6
7
8
deficient trifluoromethylbenzylalcohol and 4-cholobenzylalcohol
with 1,2-diaminobenzene resulted in moderate (74% and 55%)
isolated yields of the corresponding benzimidazole products,
respectively (entries 10, 11). 1-Naphthylmethyl alcohol dehydro-
genatively coupled with 1,2-diaminobenzene to yield the corres-
ponding product in 50% isolated yield (entry 12). Reaction of 4-
nitrobenzyl alcohol and 1,2 diaminobenzene under the optimized
conditions afforded 54% conversion, including 28% of the desired
2-(4-nitrophenyl) benzimidazole along with the hydrogenated
product 2-(4-aminophenyl)benzimidazole as detected by GCMS
(entry 13). Using the electron deficient 4-cyanobenzyl alcohol
resulted in 36% conversion to a mixture of products, including 4-
(1H-benzimidazol-2-yl)benzonitrile.. In the presence of 5 mol%
tBuOK under the same reaction conditions, an conversion increa-
sed and 45% yield of 4-(1H-benzimidazol-2-yl)benzonitrile as
major product was detected by GCMS, in addition to 1,4-bis(1H-
benzoimidazol-2-yl)benzene as side product (entry 14). Reaction
of 3-phenyl-2-en-1-propanol resulted in formation of 2-
phenethylbenzoimidazole with hydrogenation of the conjugated
double bond,, whereas in the presence of 2 equivalents of croto-
nonitrile as hydrogen acceptor, 82% of 2-styrylbenzimidazole was
formed (entry 15). The catalytic performance of 1 in the dehydro-
genative coupling of primary alcohols with 3,4-diaminotoluene
was also checked, producing excellent isolated yields of the cor-
responding substituted benzimidazole products (entries 16-18)
under base-free conditions. However, 2-pyridinemethanol gave
only 16% of the corresponding benzimidazole product, whereas
the phenolic substrates 4-hydroxybenzyl alcohol and 2-(4-
hydroxyphenyl)ethanol were completely inactive.
As we recently reported, treatment of (PNNH)CoCl2 (1)
with one equiv of NaBEt3H at room temperature gave the para-
magnetic complex (PNNH)CoICl, characterized by X-ray crystal-
lography.11a This Co(I) complex was prepared and tested in the
dehydrogenative coupling of 1,2-diaminobenzene and 1-hexanol
at 150°C, in the absence of any base or hydride source, yielding
82% of 2-pentylbenzimidazole after 24 h, using 2.5 mol% catalyst
loading, which is comparable to the results obtained with the
Co(II) complex 1 in the presence of NaBEt3H (Table 1, entries
19). This result is in line with the Co(I) complex being the active
catalyst.
To gain mechanistic insight, a toluene solution containing 1-
hexanol, complex 1 (5 mol%) and NaBEt3H was heated at 150°C
in a closed system for 24h, resulting in 30% yield of 1-hexanal as
the sole product. Treatment of equivalent amounts of 1-hexanol
and aniline under the same conditions gave a quantitative amount
of N-hexylaniline as the only product. Thus, initially Co(I) cata-
lyzed dehydrogenation of the primary alcohol to give the aldehyde
and H2 takes place. The formed aldehyde subsequently couples
with the amine, forming an imine intermediate by water elimina-
tion, followed by cyclization to from 2-phenyl-2,3-dihydro-1H-
benzimidazole which is rapidly dehydrogenated to form the corre-
sponding benzimidazole derivatives (Scheme 1). A blank experi-
ment using equivalent amounts of 1,2-diaminobenzene and ben-
zaldehyde resulted in 28% formation of 2-phenyl benzimidazole
with N-benzyl-2-phenylbenzimidazole as major product.7e Using
1-hexanal as the reactant also resulted in 30% yield of 2-
pentylbenzimidazole, with N-hexyl-2-pentylbenzimidazole as
major side-product under the same conditions. The second catalyt-
ic dehydrogenation step results in good and selective yield of the
corresponding 2-substituted benzimidazole product.
Entry
1
Alcohols
Product
Yield (%)b
96
9
2
3
4
93
95
80
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5
99
6
7
70
89
8 d
92
87
9
10
11
74
55
12
50
13e
14f
28
45
15g
16c
17c
18c
82
99
99
99
aConditions: 1,2-diaminobenzene (0.5 mmol), primary alcohols (0.5
mmol), catalyst 1 (5 mol%), NaHBEt3 (5 mol%), and dry toluene (2 mL),
heated in a closed Teflon Schlenk tube at 150°C bath temperature in the
presence of 4Å molecular sieves for 24h. bIsolated yields. c3,4-
d
e
Diaminotoluene was used (0.5 mmol), Reaction time 36h, 54% GCMS
conversion using mesitylene internal standard, 24% 2-(4-
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f
aminophenyl)benzimidazole as hydrogenated product. In presence of 5
mol% tBuOK, 66% GCMS conversion using mesitylene internal stand-
ard, g In presence of 1 mmol of crotononitrile as hydrogen acceptor.

ACS Catalysis
Page 4 of 6
Pigments, Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2002,
In conclusion, dehydrogenative coupling of aromatic dia-
mines and alcohols to form benzimidazoles, catalyzed for the first
time under base free conditions by a homogeneous earth-abundant
(Co) complex was discovered. The reaction is applicable to a wide
range of primary alcohols with excellent yields. A plausible
mechanism is proposed. We believe that this transformation pro-
vides an attractive benzimidazole synthesis, being environmental-
ly benign and atom efficient, using an earth-abundant metal, and
forming H2O and H2 as the sole by-products. Efforts aimed at the
development of efficient and chemoselective catalysts based on
complexes of other earth-abundant metals (Mn, Fe, Ni) for dehy-
drogenative coupling reactions are continuing.
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures, GC-MS and NMR spectra of benzimid-
azole products are provided in the supporting information. “This
material is available free of charge via the Internet at
http://pubs.acs.org.”
AUTHOR INFORMATION
Corresponding Author
*E-mail: david.milstein@weizmann.ac.il.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This research was supported by the European Research Council
(ERC AdG 692775), and by the Israel Science Foundation. D.M.
holds the Israel Matz Professorial Chair. P.D. is thankful to the
Planning and Budgeting Committee (PBC) for a postdoctoral
fellowship.
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