1
A Palladium Iodide – Catalyzed Oxidative Aminocarbonylation-Heterocyclization
Approach to Functionalized Benzimidazoimidazoles
Lucia Veltri,*,† Salvatore V. Giofr,‡ Perry Devo,§ Roberto Romeo,‡ Adrian P. Dobbs,§ and Bartolo Gabriele
†Laboratory of Industrial and Synthetic Organic Chemistry (LISOC), Department of Chemistry and Chemical
Technologies,
University of Calabria, Via P. Bucci 12/C, 87036 Arcavacata di Rende (CS), Italy
‡Dipartimento di Scienze Chimiche, Biologiche, Farmaceutiche e Ambientali, University of Messina, Via SS
Annunziata, 98168
Messina, Italy
§School of Science, University of Greenwich, Central Avenue, Chatham Maritime, Kent ME4 4TB, U.K.
lucia.veltri@unical.it (L.V.); bartolo.gabriele@unical.it (B.G.)
Abstract
A novel carbonylative approach to the synthesis of functionalized 1H-benzo[d]imidazo[1,2-a]imidazoles is
presented. The method consists in the oxidative aminocarbonylation of N-substituted-1-(prop-2-yn-1-yl)-1H-
benzo[d]imidazol-2-amines, carried out in the presence of secondary nucleophilic amines, to give the
corresponding alkynylamide intermediates, followed by in situ conjugated addition and double bond
isomerization, to give 2-(1-alkyl-1H-benzo[d]imidazo[1,2-a]imidazol-2-yl)acetamides. Products were
obtained in good to excellent yields (64-96%) and high turnover numbers (192-288 mol of product per mol
of catalyst) under relatively mild conditions (100 °C under 20 atm of a 4:1 mixture of CO-air), using a simple
catalytic system, consisting of PdI
2
(0.33 mol%) in conjunction with KI (0.33 equiv).
2
Introduction
1H-benzo[d]imidazo[1,2-a]imidazoles are an important class of polyheterocyclic derivatives, which display a
wide range of pharmacological properties, including analgesic, anti-inflammatory, hypotensive, anti-
aggregant, hypoglycemic and anti-cancer activities.
1
Although several methods for the preparation of these
compounds are currently known,
2
the possibility to obtain functionalized 1H-benzo[d]imidazo[1,2-
a]imidazole derivatives in one step by a catalytic multicomponent approach, starting from simple and/or
readily available building blocks, is still of high synthetic interest.
In this Note, we report a novel carbonylative approach
3
to the direct synthesis of functionalized
benzimidazoimidazoles, that are, N,N-dialkyl-2-(1-alkyl-1H-benzo[d]imidazo[1,2-a]imidazol-2-yl)acetamides
3, starting from N-substituted-1-(prop-2-yn-1-yl)-1H-benzo[d]imidazol-2-amines 1 (Equation 1) Our method
is based on PdI
2
/KI-catalyzed
4
oxidative monoaminocarbonylation-heterocyclization of 1, carried out in the
presence of a nucleophilic secondary amine 2 as the external nucleophile and oxygen as the oxidant, and
allows the direct synthesis of polyheterocyclic derivatives 3 in good to excellent yields in a multicomponent
fashion under relatively mild conditions (Equation 1)
Results and Discussion
PdI
2
-KI catalyzed sequential oxidative monoaminocarbomylation of the triple bond followed by
heterocyclization has emerged as a powerful method for the direct synthesis of carbonylated hetero- or
carbocycles starting from readily acetylenic substrates bearing a suitably placed hetero- or carbo-
nucleophile.
4a,5
The process, carried out in the presence of a secondary amine as external nucleophile and
oxygen as external oxidant, starts with the formation of an alkynylapalladium species from the reaction
between the substrate triple bond and PdI
2
, with the amine acting as a base (Scheme 1). After CO insertion
and nucleophilic displacement by the amine (now acting as nucleophile), an alkynylamide intermediate is
formed, from which the final product is produced by in situ intramolecular conjugate addition (Scheme 1; in
this and in the following Schemes anionic palladium ligands are omitted for clarity)
3
Scheme 1. PdI
2
/KI-catalyzed sequential oxidative aminocarbonylation of terminal trible bond followed by
intramolecular conjugate addition leading to heter- or carbocyclic derivatives (YH = nucleophilic group)
In this paper, this kind of chemistry has been applied to the direct carbonylative synthesis of N,N-dialkyl-
2-(1-alkyl-1H-benzo[d]imidazo[1,2-a]imidazol-2-yl)acetamides 3, starting from N-substituted-1-(prop-2-yn-
1-yl)-1H-benzo[d]imidazol-2-amines 1 (readily available by propargylation of 1H-benzo[d]imidazole-2-
amines)
6
and amines 2. According to Scheme 2, heterocyclization of the 2-alkynylamide intermediate I by
intramolecular conjugate addition of the amino group at C-2 to the triple bond followed by double bond
isomerization would afford the desired products 3.
Scheme 2. Work hypothesis: PdI
2
/KI-catalyzed sequential oxidative aminocarbonylation-conjugate addition-
isomerization leading to N,N-dialkyl-2-(1-alkyl-1H-benzo[d]imidazo[1,2-a]imidazol-2-yl)acetamides 3,
starting from N-substituted-1-(prop-2-yn-1-yl)-1H-benzo[d]imidazol-2-amines 1
Initial studies were focused on the reaction of N-methyl-1-(prop-2-yn-1-yl)-1H-benzo[d]imidazol-2-amine
1a, carried out in the presence of PdI
2
(0.33 mol %), KI (0.33 equiv), Et
2
NH 2a (5 equiv), CO (16 atm) and air
(4 atm).
7
After 6 h, according to our work hypothesis, analysis of the reaction mixture revealed the formation
of N,N-diethyl-2-(1-methyl-1H-benzo[d]imidazo[1,2-a]imidazol-2-yl)acetamide 3aa, which was isolated in
4
75% yield based on starting 1a, at 85% substrate conversion (Table 1, entry 1). Although this yield was already
quite satisfactory, an optimization study on reactions conditions was carried out; the results obtained are
shown in Table 1. As can be seen from Table 1, the best conditions with respect to 3aa yield corresponded
to those reported in entry 14, that are: PdI
2
:KI:1a:2a molar ratio = 1:100:300:900, MeCN as the solvent at
100 °C for 24 h under 20 atm (at 25 °C) of a 4:1 CO-air mixture. In fact, under these optimized conditions, the
3aa yield was practically quantitative (97% by GLC, 95% isolated).
Table 1. PdI
2
-Catalyzed Oxidative Aminocarbonylation-Heterocyclization-Isomerization of N-methyl-1-
(Prop-2-yn-1-yl)-1H-benzo[d]imidazol-2-amine 1a Under Different Conditions
a
.
Entry
Solvent
PdI
2
:KI:1a:2a molar
ratio
T (°C)
t (h)
Conversion
of 1a
b
(%)
Yield of 3aa
c
(%)
1
MeCN
1:100:300:1500
100
6
85 (76)
78 (75)
2
DME
1:100:300:1500
100
6
69
67
3
dioxane
1:100:300:1500
100
6
63
60
4
MeOH
1:100:300:1500
100
6
55
52
5
MeCN
1:50:300:1500
100
6
72
36
6
MeCN
1:300:300:15000
100
6
81
74
7
MeCN
1:100:300:300
100
6
65
39
8
CH
3
CN
1:100:300:600
100
6
84
76
9
MeCN
1:100:300:900
100
6
86
83
10
MeCN
1:100:300:1500
80
6
60
56
11
MeCN
1:100:500:2500
100
6
64
58
12
MeCN
1:100:300:900
100
6
86
82
5
13
MeCN
1:100:300:900
100
15
95
93
14
MeCN
1:100:300:900
100
24
100
97 (95)
a
Unless otherwise noted, all reactions were carried out with a substrate concentration of 0.1 mmol of 1a per mL of solvent under 20 atm (at 25 °C)
of a 4:1 mixture of CO-air.
b
GLC conversion (isolated conversio) based on starting 1a.
c
GLC yields (isolated yield) based on starting 1a.
Under the optimized conditions, other differently substituted substrates, bearing electron-releasing or
electron-withdrawing groups on the benzene ring, were smoothly converted into the corresponding
benzimidazoimidazole derivatives , as shown by the results reported in Table 2, entries 2 (1b, R
2
= Me; 3ba
yield 78%) and 3 (1c, R
2
= Cl; 3ca yield 79%). Good product yields were also observed in the case of N-
substituted-1-(prop-2-yn-1-yl)-1H-benzo[d]imidazol-2-amines bearing an alkyl substituent on the amino
group at C-2 different from methyl, as shown in Table 2, entries 4 (1d, R
1
= propyl; 3da yield 78%), 5 (1e, R
1
=
benzyl, 3ea yield 64%), and 6 (1f, R
1
= isopentyl, 3fa yield 94%). On the other hand, the use of different
nucleophilic secondary amines, such as dibutylamine 2b (Table 2, entry 7; 3ab yield 74%), N-
methylpropylamine 2c (Table 2, entry 8; 3ac yield 96%), N-ethylcyclohexylamine (Table 2, entry 9; 3ad yield
86%), morpholine (Table 2, entry 10; 3ae yield 76%), and piperidine (Table 2, entry 11; 3af yield 93%), also
led to excellent results.
Table 2. Synthesis of N,N-dialkyl-2-(1-alkyl-1H-benzo[d]imidazo[1,2-a]imidazol-2-yl)acetamides 3 by PdI
2
-
Catalyzed Oxidative Aminocarbonylation-Heterocyclization-Isomerization of (1-Prop-2-ynyl-1H-
benzimidazol-2-yl)amines 1
a
Entry
1
2
3
Yield of 3
b
(%)
TON
c
1
95
285