2-Aminobenzimidazole and -benzoxazole as N-nucleophile in palladium-catalysed aminocarbonylation

Article abstract of DOI:10.1016/j.tet.2020.131079

Palladium-catalysed aminocarbonylation of aryl iodides in the presence of 2-aminobenzimidazole and 2-aminobenzoxazole as N-nucleophile was carried out. Single CO insertion took place, however, instead of the expected carboxamides (C(O)NH) the correspondin

Full text of DOI:10.1016/j.tet.2020.131079

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2-Aminobenzimidazole and -benzoxazole as N-nucleophile in palladium-catalysed
aminocarbonylation
Máté Gergely, Attila Bényei, László Kollár
PII:
S0040-4020(20)30199-X
https://doi.org/10.1016/j.tet.2020.131079
TET 131079
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 10 January 2020
Revised Date: 15 February 2020
Accepted Date: 22 February 2020
Please cite this article as: Gergely Máé, Bényei A, Kollár Láó, 2-Aminobenzimidazole and -benzoxazole
as N-nucleophile in palladium-catalysed aminocarbonylation, Tetrahedron (2020), doi: https://
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2-Aminobenzimidazole and -benzoxazole as N-nucleophile in palladium-catalysed aminocarbonylation
M. Gergely, A. Bényei and L. Kollár*
Graphical abstract
1

2-Aminobenzimidazole and -benzoxazole as N-nucleophile in palladium-
catalysed aminocarbonylation
Máté Gergely,a Attila Bényeib and László Kollár a,c,*
a) Department of Inorganic Chemistry, University of Pécs and Szentágothai Research Centre, H-7624
Pécs, P.O. Box 266, Hungary; e-mail: kollar@gamma.ttk.pte.hu
b) Department of Physical Chemistry, University of Debrecen, H-4032 Debrecen, Egyetem tér 1,
Hungary
c) MTA-PTE Research Group for Selective Chemical Syntheses, H-7624 Pécs, Ifjúság u. 6., Hungary
Abstract:
Palladium-catalysed aminocarbonylation of aryl iodides in the presence of 2-
aminobenzimidazole and 2-aminobenzoxazole as N-nucleophile was carried out.
Single CO insertion took place, however, instead of the expected carboxamides
(C(O)NH) the corresponding N-acyl-imine (C(O)N=C) derivatives were obtained. The
structure of the latter compounds can be explained by tautomerization involving the
heterocyclic ring. The above structures without amide-NH moieties were proved by
methylation at the NH groups of the heterocycle. The resulted mono- and dimethylated
benzimidazole derivatives, as well as monomethylated benzoxazole derivatives, like
the parent N-acylated compounds, were fully characterised including single crystal X-
ray crystallography.
Keywords: carbonylation, palladium, triazole, carbon monoxide, tautomerization
2

1. Introduction
Benzimidazole and benzoxazole derivatives are among the most investigated heterocycles1 and have
high biological (pharmaceutical) significance.2 Regarding our title compounds, especially 2-
aminobenzimidazole derivatives possess biological effects in a wide spectrum. In this way, these compounds
have shown immunotropic, diuretic and antihistaminic properties. Moreover, several derivatives have
exhibited antiproliferative properties. Several compounds have been evaluated for antiviral activities.3 As
functionalised (carbonylated) compounds are related directly to our recent investigations, it has to be noted that
benzimidazole- and benzoxazole-based carboxamides and carbamates also have significant pharmacological
importance (Figure 1).4
Figure 1. Benzimidazole and benzoxazole derivatives of practical importance bearing carbamate and
carboxamide functionality.
To introduce various functionalities into a heterocycle backbone a great variety of homogeneous
catalytic reactions can be used effciently.5 Since the carboxamido-substituted derivatives are among the most
investigated ones even in this family, the palladium-catalysed aminocarbonylation (‘Heck-carbonylation’)
provided an efficient methodology to obtain these compounds.6
The aminocarbonylation of iodoaromatics can provide both carboxamides and 2-ketocarboxamides via
single and double CO insertion, respectively.7,8 The chemoselectivity is strongly dependent on the structure of
both the substrate and nucleophile, and reaction conditions such as CO pressure and reaction temperature. In
general, both mono and double carbonylated compounds are formed even under mild conditions (low CO
pressure) using primary and secondary amines of high basicity. However, aryl amines of low basicity provide
carboxamides exclusively. (From mechanistic point of view, the formation of Pd(II)-acyl-carbamoyl catalytic
intermediates, providing 2-ketocarboxamides in reductive elimination, is not favoured using aryl amines.)
3

Among these N-nucleophiles, amino-heteraromatics are of special importance yielding conjugates (hybrides)
with two moieties of equal biological importance.9,10
Both the high efficiency of the aminocarbonylation reaction toward the synthesis of carboxamides and
the preliminary experiences of our laboratory in this field prompted us to investigate the amino-substituted
heterocycles as N-nucleophiles. Furthermore, the structural features of the products were investigated in detail
since the close proximity of the carboxamide functionality and the imidazolyl (oxazolyl) moiety allows
tautomerization.
2. Results and discussion
2.1. Aminocarbonylation using 2-aminobemzimidazole (1) as N-nucleophile
Iodobenzene (a) and substituted iodobenzenes such as 4-fluoroiodobenzene (b), 4-bromoiodobenzene
(c),
4-tert-butyliodobenzene
(d),
4-cyanoiodobenzene
(e),
3-methyliodobenzene
(f),
3.5-
bis(trifluoromethyl)iodobenzene (g), 2-methoxyiodobenzene (h) and 2-iodothiophene (i) were reacted with 2-
aminobenzimidazole (1) as N-nucleophile in palladium-catalysed aminocarbonylation under mild conditions (1
o
bar CO, 70 C) in the presence of a Pd(0) catalyst formed in itu from palladium(II) acetate and
triphenylphosphine (Scheme 1).11 Regarding the number of carbon monoxide molecules embedded in the
substrate molecule, the reaction is completely chemoselective toward monocarbonylation yielding carbonyl
compounds (1a-i) exclusively in 60-98% isolated yields (Figure 2). Since an amine nucleophile of low
basicity was used, chemoselectivities similar to those obtained with anilines were expected. Accordingly, no
double CO insertion leading to 2-ketocarboxamides was observed.
Scheme 1. Aminocarbonylation of iodoaromatics (a-i) in the presence of 2-aminobenzimidazole (1)
4

Figure 2. Products isolated in aminocarbonylation using 2-aminobenzimidazole (1) as N-nucleophile
Single crystal X-ray diffraction study for the compounds of which suitable crystal could be grown
revealed that in several cases instead of the expected benzimidazole-based carboxamides possessing the
C(O)NH functionality (1h), a C(O)N=C functionality was identified (1e, 1g). That is, the (1,3-dihydro-2H-
benzimidazole-2-ylidene)benzamide isomer of the expected products were obtained. Based on this information
detailed NMR investigations were performed and supported the presence of C=N-acyl moiety for further
derivatives (1a-d, 1f, 1i)) in solution, too.
The methylation of these compounds with methyl iodide leads to the corresponding 1-methyl- and 1,3-
dimethylbenzimidazole compounds as primary products, i.e., methylation takes place at the heterocycle
nitrogen atoms (4a, 4c-e, 4g, 4i) and not at the amide-NH which was proved by X-ray diffraction study for
compound 4e. In some cases (5a, 5d, 5i), due to the tautomeric equilibrium, amide-NH methylation have been
carried out as well (Scheme 2, Figure 3). It has to be noted that in some cases even the minor products of
methylation were isolated in analytically pure form, obviously in low isolated yields, and fully characterised.
When the parent iodobenzene (1a) was used, trimethylation of the corresponding acylated derivative took
place resulting in 6a.
5

O
O
HN
O
HN
O
N
N
H
N
N
Ar
Ar
N
Ar
Ar
N
Ar
Ar
N
CH3I
3a, 3c-e, 3h, 3i
4a, 4c-e, 4g-i
K2CO3
16 h, r.t.
N
O
N
O
N
N
H
N
N+
N
H
N
N
I-
1a, 1c-e, 1g-i
5c, 5h, 5i
6a
Scheme 2. Methylation of acylated methylbenzimidazol derivatives 1 (depicted in Fig. 2)
As mentioned above, in addition to conventional characterization methods, several compounds of the
above series 1e, 1g, 1h (parent carbonylation compounds), and 4e (methylated compounds in the
benzimidazole series) were charaterised by single crystal X-ray crystallography as well. (Similarly, the crystal
structure od the parent (2e) and methylated compound (7e) were determined also in the benzoxazole series
(See 2.2.).)
The differentiation between C(O)NH and C(O)N= functionalities was unambigous on the basis of bond
length data.12 Peaks on the difference electron density map were also observed indicating the place of
hydrogen atoms on the heterocyclic ring nitrogen. In the amide tautomers the N1-C12 distance is significantly
shorter, for 1h 1.3601(18) Å, than that of the acylated C=N (acylated guanidine) tautomers, in the range of
1.30-1.34 Å (Figure 4 shows the numbering scheme, see also Table S2 and Table S3).
13
For more recent information search on the Cambridge Structural Database (Version 5.40 updates
14
February, 2019) was performed using the Conquest software (Ver 2.02) and the results vere analysed and
visualized using the Mercury package.15
It was also observed, that in the acylated C=N (acylated guanidine) tautomers the C12-N11 and C12-
N13 bond distances are equal within experimental error. It is noteworthy, that both in solution and in the solid
state the noted tautomeric form was observed for our compounds. The similar tautomeric equilibrium has been
studied by Koeller et al.16 among amido-benzimidazole derivatives at half-equivalence point and it was
concluded, that added salts have crucial effect on the equilibrium. According to our results simple
crystallization resulted only one tautomer which can be explained by solubility differences. In structure 6a the
planarity of the molecule is lost because of the repulsion of methyl substituents. The solid state structures are
stabilized by weak C-H..O interactions.
6

O
HN
O
O
O
O
HN
HN
N
O
HN
N
N
N
N
N
N
N
N
N
Br
NC
3a (7%)
3c (35%)
3e (44%)
N
S
3i (39%)
O
N
O
O
N
N
N
N
N
N
N
N
Br
4a (51%)
4c (61%)
4d (38%)
O
N
N
F3C
N
N
N
N
S
NC
4i (39%)
4g (93%)
4e (35%)
CF3
O
N
O
N
O
N
N
N
N
N
N
N
S
5d (8%)
5a (3%)
5i (12%)
Figure 3. Products isolated in methylation of selected acylated 2-aminobenzimidazoles (isolated yields
in brackets)
Figure 4. ORTEP view of 1e structure at 50% probability level with numbering scheme
2.2. Aminocarbonylation using 2-aminobenzoxazole (2) as N-nucleophile
To widen the scope of the above reaction, as well as to produce novel compounds of practical interest,
a further nucleophiles of similar structure, 2-aminobenzoxazole (2) was used (Scheme 3). This nucleophile
proved to be efficient in aminocarbonylation providing carboxamides depicted in Figure 5. However, the
introduction of the oxygen atom into the heterocycle resulted in a dramatic change in reactivity of the
7

nucleophile. While close to complete conversions can be obtauned with 1 under the given conditions, typically
conversions lower than 50% can be obtained using 2 as nucleophile (Table 1) with the axception of
iodoaromatics g and h. Therefore, the isolation of the aminocarbonylation profucts in the 2a-i series in
analytically pure form can be performed with low yields only. (It has to be noted that the yields can be
substantially increased (up to 70%) by using elevated reaction times (72 h).)
Surprisingly, in case of iodoaromatics h possessing a 2-methoxy substituent, the ‘conventional’
carboxamide (ArC(O)NH) functionality was identified by single crystal X-ray diffraction studies. That is, the
close proximity of the oxygen (OMe) enables the formation of a weak hydrogen bond to amide-NH stabilising
the amide tautomer, and consequently, the tautomerization toward the acylimine =NC(O)Ar form cannot be
observed under normal conditions.
Scheme 3. Aminocarbonylation of iodoaromatics (a-i) in the presence of 2-aminobenzoxazole (2).
Table 1. Conversions obtained in the aminocarbonylation of iodoaromatics (a-i) on.(a
Iodoaromatics
Conversion(b [%]
Nucleophile
1
2
>98
>98
>98
>98
>98
>98
62
24
20
36
24
41
42
87
>98
11
a
b
c
d
e
f
g
h
i
>98
95
(a Reaction conditions: 1 mmol substrate (a-i), 1.2 mmol nucleofile (1, 2); 0.025 mmol of Pd(OAc)2, 0.05
mmol of PPh3, 0.5 mL of Et3N, 10 mL of DMF, 1 bar CO, 70°C, reaction time 24 h.
(b Determined by GC (dodecane as internal standard).
8

As in the benzimidazole series, several compounds from the benzoxazole acyl derivatives and their
methylated compounds (2e and 7e, respectively) were characterised by single crystal X-ray crystallography as
well.
In structure 2e the peak of the proton at the oxazole nitrogen could be found on the difference
electrondensity map while in 7e the place of the methyl group was unambigous. Bond length and bond angle
data are in the expected range, see also Tables S2 and S3.
Figure 5. Products isolated in aminocarbonylation using 2-aminobenzoxazole (2) as N-nucleophile.
As above, methylation experiments were carried out with one of the acylated compounds, 2e, Due to
the equilibrium between the two tautomeric forms, monomethylation on both imidazole-NH and amide-NH
took place and 7e and 8e (as a two-component mixture) were isolated, respectively (Scheme 4).
Scheme 4. Methylation of the acylation product 2e resulting in a mixture of two monomethylatd
compounds 7e/8e
9

The high chemoselectivity can be rationalised on the basis of a generally accepted catalytic cycle
(Scheme 5). That is, the oxidative addition of the iodoaromatics (a-i) onto in situ formed palladium(0)
complexes resulted in the formation of aryl-iodo-palladium(II) intermediate (A). CO is activated as a terminal
carbonyl ligand in B, then inserted into aryl-palladium bond yielding the acyl-complex (C). The coordination
of the amine nucleophile (1 or 2 in D) is followed by HI abstraction by a base (for instance Et3N). The amido-
acyl-palladium(II) intermediate (E) formed in this way undergoes reductive elimination in the product-forming
step and the coordinatively unsaturated palladium(0) species are re-formed.
Scheme 5. A simplified catalytic cycle for the aminocarbonylation of iodoarenes with 1 and 2 as N-
nucleophiles.
Conclusions
Iodoaromatics such as substituted iodobenzenes and 2-iodothiophene underwent aminocarbonylation in the
presence of aminoheterocycles (2-aminobenzimidazole and 2-aminobenzoxazole) as N-nucleophiles. A single
carbon monoxide insertion took place resulting in N-acylimine, the tautomer of the expected carboxamide.
10

The novel structures containing one and two NH groups in benzoxazole and benzimidazole, respectively, were
proved by methylation experiments and full characterization including single crystal X-ray crystallography.
3. Experimental
3.1. General procedures
1H, 19F and 13C NMR spectra were recorded in DMSO on a Bruker Avance III 500 spectrometer at 500,
470.4 and 125.7 MHz, respectively. Chemical shifts δ are reported in ppm relative to DMSO (2.50 and 39.50
1
ppm for H and 13C, respectively). The FT-IR spectra were taken in KBr pellets using an IMPACT 400
spectrometer (Nicolet) applying a DTGS detector in the region of 400-4000 cm-1, the resolution was 4 cm-1.
The amount of the samples was ca. 0.5 mg. Mass spectrometry data have been obtained using a GC-MS
system consisting of a Perkin Elmer AutoSystem XL gas-chromatograph. Melting points are uncorrected and
were measured with a Büchi apparatus. TLC plates (silica gel on TLC Al foils with fluorescence indicator 254
nm) were purchased from Sigma-Aldrich. The eluents used in thin-layer chromatography are specified below.
Iodoaromatics and 2-aminobenzimidazole and 2-aminobenzoxazole were purchased from Aldrich and used
without further purification.
It has to be noted that several compounds below (1a17-20, 1b20, 1h21, 2a18, 19, 22, 23, 2b23, 2d23, 2i23, 3a19)
have been already synthesised. In general, good agreement with analytical details published for these
compounds can be observed. However, due to some missing data or partial characterization, all analytical
details will be given below also in these cases.
3.2. Aminocarbonylation of iodoaromatics using 2-aminobenzimidazole (1) (or 2-aminobenzoxazole (2)) under
atmospheric carbon monoxide pressure
In a typical experiment Pd(OAc)2 (5.6 mg, 0.025 mmol), triphenylphosphine (13.1 mg, 0.05 mmol),
iodobenzene (a) (110 µL, 1.0 mmol) (or an other iodoaromatics, b-i) (1.0 mmol), nucleophile 1 (159.8 mg, 1.2
mmol) (or an other nucleophile, 2-3) (1.2 mmol) and triethylamine (0.5 mL) were dissolved in DMF (10 mL)
under argon in a 100 mL three-necked flask equipped with a gas inlet, reflux condenser with a balloon (filled
with argon, connected via gas inlet) at the top. The argon atmosphere was changed to carbon monoxide by
applying low vacuum/carbon monoxide flushing (three times) through the gas inlet (with tap) equipped to the
flask. (The application of a carbon monoxide atmosphere is sufficient, no bubbling of CO is necessary.) The
reaction was conducted for the given reaction time upon stirring at 70 ˚C and analysed by GC-MS (internal
standard: dodecane). The cooled reaction mixture was then concentrated and evaporated to dryness under
reduced pressure.
Method A. (1d, 1f, 1h, 2a, 2d, 2e, 2h): The residue was dissolved in chloroform (15 mL) and washed
three times with water (30 mL). The organic phase was dried over Na2SO4, filtered and evaporated under
11

reduced pressure to a solid material. Aforesaid compounds were subjected to column chromatography
(Silicagel 60 (Merck), 0.063-0.200 mm), EtOAc/CHCl3 eluent mixtures (the exact ratios are specified in
Characterization for each compound; isolated yields are not optimized.
Method B. (1a-1c, 1e, 1g, 1i, 2b, 2c, 2f, 2g, 2i): Toluene (15 mL) was added to the residue, the insoluble
material (product) was filtered, washed with water on the filter and dried. The powder-like material was
dissolved in methanol, the palladium-black was filtered off and methanol was evaporated.
3.3. Methylation of the carbonylated products
In a typical experiment the carbonylated product 1a (71.2 mg, 0.3 mmol) (or a similar compound of this series)
was dissolved in acetone (10 mL) and potassium-carbonate (82.8 mg, 0.6 mmol) and methyl iodide (200 µL,
3.2 mmol) was added under argon. The reaction mixture was stired for 16 hours at room temperature. It was
then filtered, evaporated to dryness under reduced pressure. The residue was dissolved in chloroform (10 mL)
and washed three times with water (10 mL). See Method A.
Supporting Information
The Supporting Information is available free of charge on the Elsevier Publications website at ….
Experimental detailes of single crystal X-ray diffraction determinations, structures, as well as full analytical
characterization of the compounds obtained in aminocarbonylation and consequent methylation can be found
1
13
in the Supporting Information. In addition, H and C NMR spectra of all products are added. Structures 1e,
1g, 1h, 2e, 4e, 6a, 7e have been deposited under deposition numbers 1969221-1969227, respectively, at
CCDC/CSD.
Acknowledgement: The authors thank the Hungarian Research Fund (K113177) for the financial
support. This work was supported by the GINOP-2.3.2-15-2016-00049 grant. M. G. thanks Talentum Fund of
the Gedeon Richter Chemical Works Ltd. for the scholarship. The present scientific contribution is dedicated
to the 650th anniversary of the foundation of the University of Pécs, Hungary. The research was also supported
by the EU and co-financed by the European Regional Development Fund under the projects GINOP-2.3.2-15-
2016-00008 and GINOP-2.3.3-15-2016-00004.
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•
•
Efficient synthesis of novel benzimidazole and benzoxazole carboxamides.
Detailed analysis of the tautomeric forms of the products by NMR and X-ray
crystallography.
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Synthesis of heterocyclic compounds of potential practical (pharmaceutical)
importance.

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: