A general approach to substituted benzimidazoles and benzoxazoles via heterogeneous palladium-catalyzed hydrogen-transfer with primary amines

Article abstract of DOI:10.1002/adsc.201200253

The synthesis of benzimidazoles starting from o-phenylenediamines and amines in the presence of palladium on charcoal as catalyst is reported. Under microwave dielectric heating it is possible to use a tertiary, a secondary, and even a primary amine as the substrate for a palladium-mediated process to get 2-substituted or 1,2-disubstituted benzimidazoles, depending on the nature of the o-phenylenediamine employed. Primary amines are the most suitable reagents for the atom economy of the overall process that resulted to be general as several different substituted benzimidazoles were obtained in good yield. Benzoxazoles can be also prepared starting from primary amines and o-aminophenol. The reaction is also highly selective as no (poly)-alkylated phenylenediamines or cross-contaminated benzimidazoles are obtained starting from N-monoalkylphenylenediamines. This behavior was interpreted as a scarce aptitude to dehydrogenation of the methylene bonded to the aromatic NH of N-alkylarylamines. The experiments carried out consent to draw an almost complete picture of the reaction pathways occurring during the process. The catalyst can be recycled several times and, although far from optimal performances, catalyst TON=90 is encouraging for further large-scale optimization protocols. In addition, the palladium on charcoal-catalyzed microwave-assisted reaction of o-phenylenediamine gives de-alkylation of tertiary amines and transformation into the secondary ones. Copyright

Full text of DOI:10.1002/adsc.201200253

FULL PAPERS
DOI: 10.1002/adsc.201200253
A General Approach to Substituted Benzimidazoles and
Benzoxazoles via Heterogeneous Palladium-Catalyzed
Hydrogen-Transfer with Primary Amines
Marianna Pizzetti,a Elisa De Luca,a Elena Petricci,a Andrea Porcheddu,b
and Maurizio Taddeia,c,*
a
Dipartimento Farmaco Chimico Tecnologico, Universitꢀ degli Studi di Siena, Via A. Moro 2, 53100 Siena, Italy
Fax : (+39)-0577234333; e-mail: maurizio.taddei@unisi.it
Dipartimento di Chimica, Universitꢀ degli Studi di Sassari, Via Vienna 2, 07100 Sassari, Italy
Istituto di Chimica dei Composti Organometallici (ICCOM-CNR), Via Madonna del Piano 10, 50019 Sesto Fiorentino
b
c
(FI), Italy
Received: March 26, 2012; Revised: May 22, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200253.
Abstract: The synthesis of benzimidazoles starting amines. This behavior was interpreted as a scarce ap-
from o-phenylenediamines and amines in the pres- titude to dehydrogenation of the methylene bonded
ence of palladium on charcoal as catalyst is reported. to the aromatic NH of N-alkylarylamines. The ex-
Under microwave dielectric heating it is possible to periments carried out consent to draw an almost
use a tertiary, a secondary, and even a primary amine complete picture of the reaction pathways occurring
as the substrate for a palladium-mediated process to during the process. The catalyst can be recycled sev-
get 2-substituted or 1,2-disubstituted benzimidazoles, eral times and, although far from optimal performan-
depending on the nature of the o-phenylenediamine ces, catalyst TON=90 is encouraging for further
employed. Primary amines are the most suitable re- large-scale optimization protocols. In addition, the
agents for the atom economy of the overall process palladium on charcoal-catalyzed microwave-assisted
that resulted to be general as several different substi- reaction of o-phenylenediamine gives de-alkylation
tuted benzimidazoles were obtained in good yield. of tertiary amines and transformation into the secon-
Benzoxazoles can be also prepared starting from pri- dary ones.
mary amines and o-aminophenol. The reaction is
also highly selective as no (poly)-alkylated pheny-
ACHTUNGTRENNUNG
Introduction
phoric, hydrochloric, boric or p-toluenesulfonic acids
as dehydrating agents).[7] This methodology has then
The benzimidazole ring plays an important role in the evolved by introducing Lewis acids[8] improving both
discovery of bioactive molecules.[1] Substitution and the yield and the purity of the products obtained. An
structural modifications on this scaffold often lead to alternative way is the condensation of aldehydes and
the identification of compounds with a wide range of o-phenylenediamines to generate benzimidazoline in-
applications throughout the field of medicinal chemis- termediates that are subsequently oxidized in the
try. Several anti-infective,[2] anti-inflammatory[3] and presence of different reagents.[9] Low yields, long re-
antitumor[4] compounds or receptor agonists/antago- action times, drastic reaction conditions, laborious
nists[5] contain this heterocycle. Thus in recent years work-up procedures and the occurrence of side reac-
the synthesis of benzimidazoles has gained considera- tions are the main drawbacks of those classical syn-
ble attention.[6]
The traditional protocol for the preparation of ment in the preparation of the benzimidazole ring
benzimidazoles involves the reaction of 1,2-diamino- overcoming the outlined limitations as well as the
thetic methodologies. As a consequence, any improve-
ACHTUNGTRENNUNG
benzenes with carboxylic acids under harsh reaction search for alternative, milder and more environmen-
conditions (such as, for example, the use of polyphos- tally friendly methods are still challenging targets in
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organic chemistry.[10,11] Looking for a convenient, un-
common and more sustainable synthetic approach to
benzimidazoles, the application of a hydrogen auto-
transfer catalysis-based protocol has been examined.
The hydrogen transfer reaction (sometimes called
also borrowing hydrogen) has been applied to the oxi-
dation of different organic substrates such as alcohols,
amines or aldehydes.[12] The process is based on the
(formal) removal of a hydrogen molecule from the
substrate under the catalysis of a transition metal
complex. The oxidized form (sometimes unstable by
itself) is further treated with other reagents and the
produced hydrogen molecule is charged on the ac-
ceptor compound (generally organic) in order to shift
the reaction and regenerate the catalyst. Catalytic
Scheme 1. Proposed mechanism for the preparation of benz-
AHCTUNGTRENNUNG
imidazoles from tertiary amines (taken from ref.[19]).
Besides, the stability in acidic or basic media and
amination of alcohols,[13] synthesis of tertiary the high surface area make it the leading heterogene-
amines,[14] imines or amides[15,16] are the most explored ous catalyst for industrial applications to date. More-
transformations and homogeneous transition metals over, thanks to the rapid and efficient heat conduc-
have been widely employed as the catalysts. Although tion from the surface of the catalyst to the reaction
in some cases acceptable TON values have been medium,[23] Pd/C can favorably couple with the micro-
reached,[17] the catalysts are often expensive {e.g., waves allowing one to reach the high temperatures
(Cp*IrCl2)2, [Ru
ACHTUNGTRENNUNG
Ph4C4CO)]2HRu2(CO) CTHUNGTRENNUNG
ligands, introducing additional troubles for product
isolation. Thus, the introduction of heterogeneous cat- Results and Discussion
alysis in this kind of hydrogen transfer process is
highly advisable. Recent examples on the use of het- With the aim of improving the method and obtaining
erogeneous catalysts in the N-alkylation of amines more information on the proposed reaction mecha-
were disclosed.[18] Recently one of us described the nism, our attention was focused on expanding the
preparation of benzimidazoles through a Pd/C-medi- scope of the developed procedure to different substi-
ated cyclization of o-phenylenediamine with tertiary tuted amines. These substrates would allow a more
amines.[19] The reaction was carried out by heating o- extensive application of the methodology leading to
phenylenediamine in the presence of a stoichiometric a high variety of possible structural modifications on
amount of a tertiary amine, Pd/C (10 wt% loading) the benzimidazole core. Moreover, the use of tertiary
and crotonitrile as the hydrogen acceptor, at 1708C amines implies the loss of one molecule of secondary
under microwave (MW) dielectric heating. Different amine for each catalytic cycle. From a green chemis-
benzimidazoles were obtained in good to acceptable try point of view,[24] a waste of atoms is thus generated
yields.[20] The proposed mechanism was based on the and the atom economy profile of the transformation
oxidation of the tertiary amine 1 to an iminium ion 2 proves to be poor. In this context, we tried to maxi-
followed by a transamination reaction of this active mize the efficiency of the reaction by reducing nature
intermediate with o-phenylenedi
ACHTUNGTRENNUNG
the corresponding imine 6.[21,22] The secondary amine
7 and butyronitrile 5 are consequently produced by formation on the reaction mechanism, the cyclization
a first borrowing hydrogen process required to regen- of tributylamine 10 and 1,2-phenylenediamine 3 was
erate the catalyst. Cyclization to dihydrobenzimida- performed following the reported conditions[19] and
zole 8 followed by a second borrowing hydrogen oxi- monitoring the product distribution via GC/MS analy-
dation gives the desired benzimidazole 9 with a net sis (Table 1). The result was that 2-propylbenzimida-
consumption of two molecules of H2 (Scheme 1, zole 12 was formed in 78% yield, all o-phenylenedi-
taken from ref.[19]).
ACHTUNGTRENaNUNG mine was consumed, and dibutylamine was detected
Heterogeneous palladium catalysis represents a con- together with a residue of unreacted tributylamine.
venient option to overcome the limitations due to the The amount of tributylamine employed for cyclization
use of a homogeneous catalyst highlighted above. A was then reduced to 0.5 equivalents with respect to o-
large number of heterogeneous palladium sources are phenylenediamine.
nowadays available but among these Pd on carbon
Notwithstanding, the presence of unreacted dibutyl-
can be considered as the most versatile, the less ex- amine and butylamine was detected in the final reac-
pensive and easiest to handle; it can be quickly recov- tion mixture while the yield of 12 was still high
ered and reused many times by simple filtration.
(75%). It is worth noting that even using 0.35 equiva-
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A General Approach to Substituted Benzimidazoles and Benzoxazoles
Table 1. Benzimidazole formation using a substoichiometric
amount of tertiary amine with respect to o-diaminobenzene
3.
Entry
R
Amine (amount)[a]
Product, Yield[b]
1
2
3
4
5
C3H7
C3H7
C3H7
CH3
10 (1.1 equiv.)
10 (0.55 equiv.)
10 (0.35 equiv.)
1 (0.35 equiv.)
11 (0.35 equiv.)
12, 78%
12, 75%
12, 68%
9, 76%
Scheme 3. Pd/C-mediated synthesis of benzimidazoles with
secondary and primary amines.
C7H15
13, 70%
[a]
Reaction conditions: o-phenylenediamine (1 mmol), hy-
drogen acceptor 4 (2.2 mmol), dry toluene (2 mL), Pd/C
(10 wt%, 0.05 mmol), MW 1708C, 90 min.
As the atom economy of the process is better with
a primary amine, a more deep investigation began by
studying the influence of different parameters (i.e.,
temperature, catalysts, hydrogen acceptor, additives)
on the reaction. o-Phenylenediamine 3 and butyl-
[b]
Yields of isolated and fully characterized benzimidazoles.
lents of tributylamine with respect to o-phenylenedi-
ACHTUNGTRENUNaNG mine 16 were chosen as the model substrates in
ACHTUNGTRENNUNG
yield[25] with almost complete consumption of the lated yields of benzimidazole 12. Selected results are
amine. From these data we concluded that at least shown in Table 2. A satisfactory conversion of 3 was
two of the three groups of the tertiary amine could be observed in reactions carried out in toluene at 1708C
transferred to benzimidazole with a neat increment in under MW dielectric heating and in the presence of
the atom economy of the process. Then, the reaction Pd/C (10 wt%, 0.05 equiv.), although 2-propylbenzimi-
with 0.35 equivalents of amine with respect to 3 was dazole 12 was isolated only in moderate yields
repeated on different (symmetric) tertiary amines (1 (Table 2, entry 1). The concentration of the reagents
and 11) and the corresponding benzimidazoles 9 and was then increased without any remarkable improve-
13 were always obtained in satisfactory yields ment. Analogously, an increment of reaction time up
(Table 1, entries 4 and 5). Although this result could to 3 h had no effect. The use of solvents different
be considered as an appreciable achievement in com- from toluene (Table 2, entries 2–4) and the increase
parison with the original discovery, from a preparative of the temperature to 1908C (realized by adding to
point of view, the use of tertiary amines as substrates toluene a small quantity of ionic liquid [bmim]ACHTUNGTRENNUNG[BF4];
is limited by their low availability and by the expected Table 2, entry 6) were detrimental for the yields. Re-
different selectivity in the transferred group when placement of crotonitrile 4 with 1-octene as the hy-
non-symmetrical tertiary amines are employed.[19] As drogen acceptor seemed to have no influence on the
exemplified in Scheme 2, a possible additional inter- reaction outcome (compare entries 1 and
7 in
esting aspect may be the use of o-phenylenediamine 3 Table 2). However, a first improvement in the yield
in conjunction with Pd/C to transform a tertiary was observed upon increasing the amount of catalyst
amine (such as 11) into a secondary one (14), a pro- from 5 to 10% that led to isolation of compound 12
cess that is still difficult to carry out.[26] Supported by with 65% yield (Table 2, entry 8). The yields were fur-
the results of Table 1, o-phenylenediamine 3 was sub- ther enhanced to 85% when a stoichiometric amount
jected to cyclization using dibutylamine (15) and even of Pd/C was employed (Table 2, entry 9). Although
butylamine (16) obtaining a satisfactory conversion not synthetically profitable, this last result suggested
into 2-propylbenzimidazole 12 (Scheme 3).
that the use of a low molecular weight primary amine,
more nucleophilic with respect to the tertiary amine
described in the previous paper, could poison the cat-
alyst by physical absorption on the surface and reduc-
tion of the active site number. Thus, the use of an
acid additive was investigated. An experiment with
HCl was unsuccessful, TFA and TCA gave moderate
yields, while the addition of 10% AcOH afforded an
almost quantitative conversion of 3 into 12 that was
isolated in 87–90% yield regardless of the hydrogen
acceptor molecule employed (Table 2, entries 10–14).
Scheme 2. Pd mediated dealkylation of a tertiary amine in
the presence of o-phenylenediamine.
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Table 2. Optimization for reaction between 3 and 16 to give benzimidazole 12.
Entry
Reaction conditions[a]
Conversion [%][b]
Yield [%][c]
1
2
3
4
Tol., 1708C, Pd/C (0.05 equiv.), (4)
EtOH, 1708C,[d] Pd/C (0.05 equiv.), 4
THF, 1708C,[e] Pd/C (0.05 equiv.), 4
Tol./t-BuOH, 1/1, 1708C, Pd/C (0.05 equiv.), 4
72
45
40
3
58
20
20
–
5
6
Tol./
A
G
N
50
–
36
–
7
8
9
Tol., 1708C, Pd/C (0.05 equiv.), 1-octene
Tol., 1708C, Pd/C (0.1 equiv.), 1-octene
Tol., 1708C, Pd/C (1 equiv.), 1-octene
76
85
98
-
75
81
95
95
80
98
90
–
60
65
85
-
53
60
90
87
61
95
78
–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Tol., 1708C, Pd/C (0.1 equiv.), 4, HCl (35% aqueous, 0.1 equiv.)
Tol., 1708C, Pd/C (0.1 equiv.), 4, TFA (0.1 equiv.)
Tol., 1708C, Pd/C (0.1 equiv.), 4, TCA (0.1 equiv.)
Tol., 1708C, Pd/C (0.1 equiv.), 4, AcOH (0.1 equiv.)
Tol., 1708C, Pd/C (0.1 equiv.), 1-octene, AcOH (0.1 equiv.)
Tol., 1708C, Pd/C (0.1 equiv.), 4, AcOH (1 equiv.)
Tol., 1708C, Pd/C (0.1 equiv.), 4 (20 equiv.), AcOH (1 equiv.)
Tol., 1708C,[f] Pd/C (0.1 equiv.), 4, AcOH (0.1 equiv.)
Tol., 1708C, PdEnCat (0.1 equiv.), 4, AcOH (0.1 equiv.)
Tol., 1708C, Pd/TiO2 (0.5% wt), 4, AcOH (0.1 equiv.)
Tol., 1708C, Pd CPRW (0.6% wt), 4, AcOH (0.1 equiv.)
Tol., 1708C, Ru/C (5% wt) 4, AcOH (0.1 equiv.)
Tol., 1708C, Ni/SiO2-alumina (65% wt), 4, AcOH (0.1 equiv.)
Tol., 1708C, Pd(OH)2/C (20% wt), 4, AcOH (0.1 equiv.)
–
–
30
30
–
10
10
–
30
10
[a]
Tol.=toluene. Reaction conditions: sealed vial, MW (maximum power and internal pressure: 200 W and 300 psi), 90 min,
3 (1 mmol), 16 (1.2 mmol), hydrogen acceptor (2.2 mmol), solvent (2 mL), N2 atmosphere. Pd/C=10% wt Pd on dry
carbon, wet with 50% wt of H2O.
Percentage of 12 with respect to 3 in the final reaction mixture, established by GC/MS analysis.
Yields of isolated compound.
Uncontrolled increase of the internal pressure was observed.
Heating for 4 h was required to reach 40% conversion.
Reaction carried out for 12 h in a sealed tube dipped inside an oil bath pre-heated to 1808C.
[b]
[c]
[d]
[e]
[f]
It is noteworthy that on increasing the amount of exclusively when Pd/C is used as the catalyst and
AcOH to 1 equiv., the yield went down (Table 2, under the influence of an acid additive. Best results
entry 15). Again, increasing the reaction time (from are obtained under microwave dielectric heating (pos-
90 min to 3 h) had no influence in the yield. Using the sible influence of the microwaves with the wet[27]
improved conditions developed so far (Table 2, graphite catalyst support) and also the influence of
entry 13) the reaction was run under traditional heat- the hydrogen acceptor amount was observed, suggest-
ing (sealed vial in a pre-heated oil bath) giving, after ing that probably the final aromatization is a key step
12 h, the expected product although in lower yield of the overall process. When the reaction was carried
(Table 2, entry 17). The amount of the hydrogen ac- out with just one equivalent of crotonitrile 4 (the
ceptor was raised to 20 equiv. and an additional in- double of the molar amount of the reagents as the re-
crease of the yield respect to the experiment with 2.2 action yields two molecules of H2), only 45% of 16
equiv. was observed (compare entries 16 and 13 in was isolated together some starting material. In order
Table 2). Finally different kinds of heterogeneous cat- to verify the reaction scope, the selected better condi-
alysts were screened and their activity compared to tions (Table 2, entry 13) were applied to different pri-
the results obtained using Pd/C.
mary amines and different o-phenylenediamines. The
Among the noble metals examined, none of them results are collected in Table 3. The reaction proved
revealed to have a higher activity, superior efficiency, to be general as most of the benzimidazoles were ob-
or to speed up the process with respect to Pd/C and tained in high yields. Especially aliphatic amines (as
in no cases could benzimidazole 12 be obtained in ac- 23–26, Table 3, entries 1–4) reacted very well giving
ceptable yields (Table 2, entries 18–23). The result of the corresponding benzimidazoles almost pure in the
this large screening is that a primary amine (with the crude reaction mixture. The positive influence of the
nitrogen bonded to a CH2) can be used as the sub- hydrogen acceptor was confirmed by the exceptional
strate in oxidative cyclization of o-phenylenediamine results obtained with allylamine 27 that gave 2-ethyl-
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A General Approach to Substituted Benzimidazoles and Benzoxazoles
benzimidazole 35 (the saturated product) in almost sis of the amines. The introduction of a substituent on
quantitative yield.[28] On the other hand, with benzyl- the diaminobenzene ring is also well tolerated and
ACHTUNGTRENNUNGamines 32 and 33, lower yields were observed due to benzimidazoles 41–46 were obtained in good to ac-
the contemporary formation of anisole and 5-methyl- ceptable yields. The yields of benzimidazoles are re-
1,3-benzodioxole, respectively (25–30% estimated via duced when electron-withdrawing groups are present
GC/MS), the products derived from the hydrogenoly- and the amine nucleophilicity is depressed. However,
Table 3. Preparation of different benzimidazoles from primary amines.
Entry
1
Phenylenediamine
Amine[a]
Product
Yield[b]
83%
1
EtNH2
23
24
25
26
27
28
9
2
3
4
5
6
1
1
1
1
1
Me3CCH2CH2NH2
33
13
34
35
36
76%
72%
82%
95%
74%[c]
CH3ACHTUNGTRNEUNG(CH2)6CH2NH2
Me2CHCH2NH2
CH2 =CHCH2NH2
PhCH2CH2NH2
7
8
1
1
29
30
37
38
56%[c]
66%[c]
9
1
1
p-MeOC6H4CH2NH2
31
32
39
40
45%[d]
42%[d]
10
11
R1 =COPh, R2 =H, 17
16
41
77%
12
13
14
R1 =COOMe, R2 =H, 18
R1 =CN, 19
28
16
16
42
43
44
70%
65%
46%
R1 =Cl, 20
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Yield[b]
FULL PAPERS
Table 3. (Continued)
Entry
Phenylenediamine
Amine[a]
15
R1 =Me, 21
28
28
45
46
82%
80%
16
R1 =R2 =Me, 22
[a]
Reaction conditions: o-phenylendiamine (1 mmol), amine (1.2 mmol), AcOH (0.1 mmol), Pd/C (0.1 mmol), 4 (2.2 mmol),
toluene (2 mL), N2 atmosphere.
Yield of isolated and fully characterized products.
Small quantities of 1,2-disubstituted benzimidazoles were isolated (see below).
The product of amine hydrogenolysis was also formed.
[b]
[c]
[d]
our results are better or comparable with those of added and 47 was used in excess (entry 4). In EtOH,
previously reported procedures.[19,29]
only benzoxazole 48a was isolated in acceptable
The possibility to extend the cyclization reaction of yields (entry 6). Attempts to increase the yields under
primary amines to o-aminophenol 47 in order to more harsh conditions gave also the formation of 2-
obtain benzoxazoles was also investigated.[30] Using ethylbenzoxazole derived from ethanol oxidation
butylamine 15, the standard reaction conditions while the use of t-BuOH as the solvent did not give
proved not effective as only N-butylaminophenol 49a the formation of the oxazole (data not included in
was isolated (entry 1 in Table 4). As most of reaction Table 4). Although yields on 48a were not very high
conditions previously explored for benzimidazoles did (46% isolated yields, 80% accounting the recovered
not give any improvement, we tried to apply the pro- starting material) these cyclization conditions were
tocol previously described for aniline alkylation applied to other amines (26, 50, 51) giving benzoxa-
(entry 2).[19]
zoles 48b–d in 42–52% isolated yields.[31]
No reaction occurred in THF and in the presence
The possibility to extend the method to the prepa-
of the hydrogen acceptor, whereas a mixture of 48a ration of disubstituted benzimidazoles was then ex-
and 49a was exclusively obtained when 4 was not plored based on the observation that, when 2-aryl-
Table 4. Preparation of benzoxazoles.
Entry
R
Reaction conditions[a]
48:49 ratio, product, yield[b]
1
2
3
4
5
6
7
8
C3H7, 15
C3H7, 15
C3H7, 15
C3H7, 15
C3H7, 15
C3H7, 15
C3H7, 15
C3H7, 15
CHMe2, 26
C2H5, 50
cyclo-C6H11, 51
Tol., 1708C, 4 (2 equiv.), AcOH (0.1 equiv.)[c]
THF, 1708C, 4 (2 equiv.)[c]
THF, 1708C[c]
THF, 1708C
DME, 1708C
0:1, 49a, 10%[f]
0:1, 49a, 12%[f]
0:1, 49a, 40%[f]
45:55, 48a, 45%
46:54, 48a, 45%
1:0, 48a 46%
–
EtOH, 1708C
EtOH, 1708C[d]
EtOH, 1708C[e]
–
9
10
11
EtOH, 1708C
EtOH, 1708C
EtOH, 1708C
1:0, 48b, 45%
1:0, 48c, 42%
1:0, 48d, 52%
[a]
Tol.=toluene. Reaction conditions: sealed vial, MW (maximum power and internal pressure: 200 W and 300 psi), 90 min,
47 (2 mmol), amine (1 mmol), Pd/C (0.1 mmol), solvent (2 mL), N2 atmosphere.
Ratio determined via HNMR on the crude reaction mixture.Yield of isolated benzoxazole.
[b]
[c]
[d]
[e]
[f]
1
1 mmol of 47 was used.
Reaction carried out in the presence of 2 mmol of 4.
Reaction carried out for 12 h in a sealed tube dipped inside an oil bath pre-heated to 1808C.
Yield of N-butylaminophenol.
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A General Approach to Substituted Benzimidazoles and Benzoxazoles
Table 5. Synthesis of 1,2-disubstituted benzimidazoles.
Entry Diamine; primary amine Product[a]
Yield[b]
85%
1
2
3
4
5
R1 =Ph, 55; 16
R1 =Me, 56; 28
R1 =C3H7, 57; 28
57; 26
65%
85%
76%
92%
57; 27
Scheme 4. Experiments carried out in order to rationalize
the formation of 1,2-disubstituted benzimidazoles.
6
R1 =C9H19, 58; 27
92%
73%
ACHTUNGTRENNUNGethylamines were used (28–30), in spite of the yields
7
R1 =CH2CH2Ph, 53; 28
of benzimidazoles 39–41 still being good, small
amounts (never higher than 10%) of the N-alkylated
benzimidazoles (such as 52 in Scheme 4) were ob-
tained. This behavior was not observed with other ali-
phatic or benzylamines. The formation of 52 could be
justified through a possible alkylation of the 2-substi-
tuted benzimidazole 36 [reaction (i) in Scheme 4] or
via cyclization of the intermediate monoalkylated de-
rivative 53 with the imine generated from 28 and Pd/
[a]
Reaction conditions: o-phenylendiamine (1 mmol), amine
(1.2 mmol), AcOH (0.1 mmol), Pd/C (0.1 mmol),
(2.2 mmol), toluene (2 mL), N2 atmosphere.
4
[b]
Yield of isolated and fully characterized products.
C [reaction (ii) in Scheme 4]. At first, the postulated possible as reaction of 1-N-tosylphenylenediamine[33]
alkylation of the benzimidazole ring was excluded as with amine 16 in the presence of Pd/C gave a mixture
no reaction occurred between isolated 36 and 28 with of by-products and starting material. It is also worthy
Pd/C, under standard reaction conditions [reaction of note that all amines 56–58 failed in the cyclization
(iii) in Scheme 4].
to monosubstituted benzimidazoles in the absence of
Also attempts to cyclize the mono-alkylated phe- an additional primary amine, corroborating the hy-
nylenediamine 53 alone with Pd/C failed, while cycli- pothesis that Pd-mediated dehydrogenation at CH2 in
zation occurred when 53 was mixed with a primary a-position with respect to the arylamine nitrogen
amine (such as 28), benzimidazole 52 being obtained does not occur.[34] In fact, when the reaction between
in good yield [reaction (iv) in Scheme 4]. As mono-al- N-butylaniline 65 and o-phenylendiamine 3 was car-
kylated phenylenediamine did not seem to be inter- ried out, the expected 2-propylbenzimidazole 12 was
mediate in the process, it could be used as a starting not formed (Scheme 5), while product 12 is obtained
material for the preparation of 1,2-disubstituted ben- on reacting 3 with a aliphatic secondary amine (15 in
zimidazoles, relevant scaffolds for the preparation of Scheme 5). The result confirms that, once the N-aryl-
biologically active compounds.[6a] Thus, a series of N-alkylamine is formed, the Pd/C-mediated oxidation
monosubstituted N-alkyl-o-phenylenediamines (50– at the NCH2 is, for some reasons, prevented.
53)[32] was submitted to cyclization in the presence of
Based on the above results, a possible pathway for
different primary amines producing always the disub- the overall process was proposed (Scheme 6). Palladi-
stituted benzimidazoles with high yields and purity um-mediated dehydrogenation of the primary amine
(see Table 5).
generates the imine A that reacts with o-phenylendi-
The use of an electron-withdrawing group linked to
ACHTUNGTRENNUNG
the phenylenediamine nitrogen (e.g., tosyl) was not nation, imine B. The imine undergoes intramolecular
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Marianna Pizzetti et al.
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Table 6. Reuse test for the catalyst.[a]
Reuse
number
Yield [%] using
Pd/C[b]
Yield [%] using acid-treat-
ed Pd/C[c]
0
1
2
3
4
5
90
87
90
89
90
89
88
89
87
82[d]
75[d]
–
[a]
Applied to the synthesis of 12 using butylamine 16.
Pd/C simply recovered after filtration and washing with
solvents.
Pd/C treated with HCl and further washed, see text and
Experimental Section for details.
Scheme 5. Comparison of reactivity between N-aryl and N-
alkyl secondary amines.
[b]
[c]
[d]
Some starting material was detected in the GC/MS.
tion of the aminal H and final Pd-mediated aromati-
zation give the 1,2 disubstituted benzimidazole I. This
picture justifies the formation of the by-products
using amine 28–30 and the clean assembly of disubsti-
tuted benzimidazoles from N-alkyl-o-phenylenedi-
AHCTUNGTREGaNNUN mine without formation of monosubstituted benzimi-
dazoles or dialkylphenylenediamines. Finally, the ef-
fective possibility to reuse Pd/C was investigated with
the aim of improving the overall process performance.
Simple filtration, washing with CH2Cl2 and MeOH
and further drying of the catalyst, gave a product that
retains its catalytic activity (at least for four times)
but with loss of efficiency (Table 6). However, wash-
ing the solid with aqueous 1M HCl,[35] followed by
water, THF to remove water and drying under
vacuum, gave a product that could be employed sev-
eral times (we experimented 5 times) with the same
results as those of the new one.[36] The reaction per-
formance of the catalyst showed a TON=90 (calcu-
lated on a 10-mmol scale) that, although far from op-
timized activity, could be considered overall good and
encouraging for a further application on a large scale.
Scheme 6. Possible pathways for the hydrogen transfer syn-
thesis of benzimidazoles from primary amines.
Conclusions
In conclusion, the use of primary amines as suitable
addition by the other arylamine group with formation substrates for the heterogeneous catalyzed prepara-
of cyclic aminal C that is immediately oxidized to 2- tion of 2-substituted benzimidazoles or benzoxazoles
substituted benzimidazole D. When a group promot- and 1,2-disubstituted benzimidazoles via an hydrogen
ing the imine-enamine equilibrium is located in transfer approach was investigated. The experiments
a proper position (such as the aryl moieties present in carried out allowed us also to outline a possible mech-
amines 28–30 at R1) the formation of enamine E anism path for the process and for the other reactions
occurs at the expense of cyclization intermediate B.
that may occur during the transformation. The versa-
À
Enamine E is probably reduced by the Pd-(H H) tility of the method was demonstrated by the prepara-
complex to amine F. Thus, the intramolecular cyclisa- tion of disubstituted benzimidazoles and suggests that
tion is stopped and the ortho-NH2 can intermolecular- the couple Pd/C–MW could be successfully utilized
ly add to another imine to give the product G. Forma- for other hydrogen transfer-based reactions.
8
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A General Approach to Substituted Benzimidazoles and Benzoxazoles
90 min at 1708C (max internal pressure 300 psi). After cool-
Experimental Section
ing, the crude reaction mixture was filtered through a pad of
celite inside a syringe equipped with a sintered set (frit).
The filter was washed with MeOH and the collected solvent
dried over dry MgSO4 and further removed under vacuum.
Purification by flash chromatography (petroleum ether 40–
60/EtOAc 6:4) gave product 33 as a pale yellow oil; yield:
142 mg (76%). 1H NMR (400 MHz, CDCl3): d=7.53 (m,
2H), 7.18 (m, 2H), 2.80 (s, 2H), 1.04 (s, 9H); 13C NMR
(100 MHz, CDCl3): d=153.1 (2C), 137.8, 122.1 (2C), 115.6,
43.5, 32.1, 29.8; ES/MS: m/z=189 [M+H]+; GC/MS
(70 eV): m/z (%)=189 (100%); 132 (100%); Rt =18.54 min;
General Remarks
All reagents and solvents were used as purchased from com-
mercial suppliers without further purification except toluene
that was distilled from sodium. The reactions were carried
out in oven-dried or flamed vessels (vials) and performed
under nitrogen. Flash column chromatography was per-
formed with Merck silica gel 60, 0.040–0.063 mm (230–400
mesh). Merck aluminum-backed plates pre-coated with
silica gel 60 (UV254) were used for TLC and were visual-
ized by staining with a solution of KMnO4. Proton nuclear
magnetic resonance (1H NMR) spectra were recorded at
278C. Proton chemical shifts are expressed in parts per mil-
lion (ppm, d scale) and are referred to the residual hydrogen
in the solvent (CHCl3, 7.27 ppm; CD2HOD, 3.31 ppm,
CHD2SOCD3, 2.50 ppm). Data are represented as follows:
chemical shift, multiplicity (s=singlet, d=doublet, t=trip-
let, q=quartet, sex=sextet, h=septet, m=multiplet and/or
multiple resonances, br s=broad singlet), coupling constant
(J) in Hertz and integration. Carbon nuclear magnetic reso-
nance spectra (13C NMR) were recorded at 278C. Carbon
chemical shifts are expressed in parts per million (ppm, d
scale) and are referenced to the carbon resonances of the
+
HR-MS (ESI): m/z=189.1389, calcd. for C12H17N2 :
189.1392.
2-(3,4-Dimethoxybenzyl)-1H-benzo[d]imidazole (38): Pu-
rification by flash chromatography (petroleum ether 40–60/
EtOAc 6:4) gave 38 as a yellow oil; yield: 177 mg (66%)
1H NMR (400 MHz, CDCl3): d=9.10 (bs, 1H), 7.48 (m,
2H), 7.17 (m, 2H), 6.69–6.63 (m, 3H), 4.12 (s, 2H), 3.72 (s,
3H), 3.61 (s, 3H); 13C NMR (100 MHz, CDCl3): d=154.5,
149.1, 148.1, 128.9, 122.3, 121.1, 114.8, 112.2, 111.5, 58.0
(2C), 35.4; ES/MS: m/z=291 [M+Na]+; 269 [M+H]+; GC/
MS (70 eV): m/z (%=268 (100%); 253 (30%); Rt =
26.73 min; HR-MS (ESI): m/z=269.1292, calcd. for
+
C16H17N2O2 : 269.1290.
NMR solvent (CDCl3,
d 77.0 ppm, CD3OD, 49.1 ppm,
6-Carboxymethyl-2-benzyl-1H-benzo[d]imidazole
(42):
DMSO-d6, 39.5 ppm). Mass spectroscopy data of the prod-
ucts were collected on GC/MS or LC-MS ESI mass spec-
trometers. GC conditions: ion trap detector equipped with
a 30 m OV-101 capillary column, splitting injector at 3008C,
method: 40–608C 58/min, 60–1608C 28C/min, 160–2008C
18C/min. LC/MS conditions: ES ionization after passage
through a C-18, 35ꢂ5 mm, 3 m column, elution: mixture A
(99.9% water, 0.1% HCOOH); mixture B (99.9% acetoni-
trile, 0.1% HCOOH): 0–6.0 min, 95% mixture A; 6.0–
9.0 min 95- 0% mixture A; 9.0–15 min 0–95% mixture A,
flow 1.0 mLminÀ1, T=408C. Reactions carried out under
MW dielectric heating were performed with a microwave
oven (Discover from CEM) under monomode irradiation in
a 10-mL sealed vial. The internal temperature was moni-
tored through an internal IR sensor and the maximal inter-
nal pressure monitored and maintained under the value of
300 psi. Pd/C (10 wt%) was purchased from Sigma–Aldrich
and wet with 50 wt% water.[27] Compounds 1, 3, 4, 10, 11,
15, 16, 17–22, 23–32, 55–56 and 65 are commercially avail-
able. Compounds 53, 57, and 58 were prepared following re-
ported procedures.[30] Products 9,[36] 12,[37]13,[38] 34,[38] 35,[19]
36,[20] 37,[39] 39,[20] 40,[20] 41,[29c] 43,[29c] 44,[38] 48a,[40] 48b,[41]
48c,[42] 48d,[43] 59,[37] and 60[29c] have been previously de-
Purification by flash chromatography (petroleum ether 40–
60/EtOAc 6:4) gave 42 as a colourless oil; yield: 188 mg
1
(70%). H NMR (400 MHz, CDCl3): d=8.19 (s, 1H), 7.89
(d, J=8.8 Hz, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.20 (m, 6H),
4.21 (s, 2H), 3.87 (s, 3H); 13C NMR (100 MHz, CDCl3): d=
167.7, 156.2, 141.7, 129.0 (2C), 128.4 (2C), 127.3 (2C), 124.4,
124.1, 117.2, 114.4, 52.1, 35.6; ES/MS: m/z=267 [M+H]+;
GC/MS (70 eV): m/z (%)=266 (100%), 235 (10%); Rt =
27.467 min; HR-MS (ESI): m/z=267.1130, calcd. for
+
C16H15N2O2 : 267.1134.
2-Benzyl-6-methyl-1H-benzo[d]imidazole (45): Purifica-
tion by flash chromatography (petroleum ether 40–60/
EtOAc 6:4) gave 45 as a yellow oil; yield: 183 mg (82%).
1H NMR (400 MHz, CDCl3): d=10.91 (bs, 1H), 7.36 (d, J=
8 Hz, 1H), 7.14 (s, 5H), 7.01 (d, J=8 Hz, 1H), 4.13 (s, 2H),
2.40 (s, 3H); 13C NMR (100 MHz, CDCl3): d=153.6, 139.2,
138.0, 136.6, 132.3, 128.9, 128.8 (2C), 127.0 (2C), 124.0,
119.7, 114.6, 35.2, 21.6; ES/MS: m/z=223 [M+H]+; GC/MS
(70 eV): m/z (%)=223 (100%); 222 (30%); Rt =24.132 min;
+
HR-MS (ESI): m/z=223.1232, calcd. for C15H15N2 :
223.1235.
2-Benzyl-5,6-dimethyl-1H-benzo[d]imidazole (46): Purifi-
cation by flash chromatography (petroleum ether 40–60/
EtOAc 6:4) gave 46 as a yellow oil; yield: 190 mg (80%).
1H NMR (400 MHz, CDCl3): d=9.32 (bs, 1H), 7.24 (s, 2H),
7.16 (s, 5H), 4.13 (s, 2H), 2.30 (s, 6H); 13C NMR (100 MHz,
CDCl3): d=153.5, 138.0, 136.6, 136.4, 132.3, 130.6, 128.9,
128.7 (2C), 127.0 (2C), 122.5, 114,3, 35.2, 21.6, 21.1; ES/MS:
m/z=237 [M+H]+; GC/MS (70 eV): m/z (%)=237 (100%);
91 (5%); Rt =25.387 min; HR-MS (ESI): m/z=237.1389,
1
scribed and showed H NMR data in agreement with litera-
ture values (see the Supporting Information).
2-Neopentyl-1H-benzo[d]imidazole (33); General
Procedure
+
A 10-mL vial for MW equipped with a magnetic stirrer was
charged with Pd/C (10% wt wet with 50% of water, 212 mg,
0.1 mmol) under nitrogen. Dry toluene (2 mL), o-phenylene-
diamine 3 (108 mg, 1 mmol), 3,3-dimethylbutylamine 24
(121.4 mg, 1.2 mmol), crotonitrile 4 (147.4 mg, 2.2 mmol)
and acetic acid (5 mL, 0.1 mmol) were subsequently added.
The mixture was stirred under MW dielectric heating for
calcd. for C16H17N2 : 237.1392.
2-Propylbenzo[d]oxazole (48a); General Procedure
A 10-mL vial for MW equipped with a magnetic stirrer was
charged with Pd/C (10% wt wet with 50% of water, 106 mg,
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0.05 mmol) under nitrogen. EtOH (2 mL), 47 (109 mg,
1 mmol), 15 (50 mL, 0.5 mmol), were subsequently added.
The mixture was stirred under MW dielectric heating for
90 min at 1708C (max internal pressure 300 psi). After cool-
ing, the crude reaction mixture was filtered through a pad of
celite inside a syringe equipped with a sintered set (frit).
The filter was washed with MeOH and the collected solvent
dried over dry MgSO4 and further removed under vacuum.
Purification by flash chromatography (petroleum ether 40–
60/EtOAc 8:2) gave 48a as a brown oil; yield: 37 mg (46%).
GC/MS (70 eV): m/z (%)=162 (100%); 146 (25%); 133
(100%); Rt =13.14 min; 1H NMR (400 MHz, CDCl3): d=
7.64 (m, 1H), 7.45 (m, 1H), 7.26 (m, 2H), 2.88 (t, J=7.2 Hz,
2H), 1.90 (sex, J=7.6 Hz, 2H), 1.02 (t, J=7.6 Hz, 3H);
13C NMR (100 MHz, CDCl3): d=167.1; 150.6; 141.3; 124.0
(2C); 119.4; 110.3; 30.5; 20.3; 13.9; HR-MS (ESI): m/z=
184.0741, calcd. for C10H11NONa+: 184.0738.
118.3, 109.8, 43.6, 25.7, 22.8, 18.4, 9.1; ES/MS: m/z=225
[M+Na]+, 203 [M+H]+; GC/MS (70 eV): m/z (%)=202
(100%), 187 (100%), 159 (25%), 145 (30%); Rt =
18.179 min; HR-MS (ESI): m/z=203.1546, calcd. for
+
C13H19N2 : 203.1548.
2-Ethyl-1-propyl-1H-benzo[d]imidazole (63): After flash
cromatography (CH2Cl2/MeOH 95:5), compound 63 was ob-
tained as a yellow oil; yield: 173 mg (92%). 1H NMR
(400 MHz, CDCl3):d=7.39 (m, 2H), 7.24 (m, 2H), 4.16 (m
2H), 3.15 (m, 2H), 1.90 (m, 2H), 1.56 (m, 3H), 1.02–0.90
(m, 3H); 13C NMR (100 MHz, CDCl3): d=157.9, 140.7,
133.7, 122.1, 121.1, 120.1, 106.6, 47.2, 20.1, 18.5, 10.3, 9.5;
ES/MS: m/z=189 [M+H]+; GC/MS (70 eV): m/z (%)=189
(100%), 173 (30%), 159 (30%), 145 (30%); Rt =18.277 min;
+
HR-MS (ESI): m/z=189.1393, calcd. for C12H17N2 :
189.1392.
1-Decyl-2-ethyl-1H-benzo[d]imidazole (64): After flash
cromatography (petroleum ether 40–60/EtOAc 6:4), com-
pound 64 was isolated as a yellow oil; yield: 264 mg (92%).
1H NMR (400 MHz, CDCl3): d=7.72 (m, 1H), 7.23 (m,
3H), 4.06 (t, J=7.6 Hz, 2H), 2.88 (q, J=7.6 Hz, 2H), 1.77
(m, 2H), 1.46 (m, 3H), 1.23 (m, 13H), 0.85 (t, J=6.4 Hz,
3H); 13C NMR (100 MHz, CDCl3): d=155.7, 146.0, 136.3,
122.1, 121.9, 119.1, 109.3, 43.8, 31.9, 29.9, 29.6, 29.5, 29.3,
28.6, 27.8, 27.0, 22.7, 14.1, 12.0; ES/MS: m/z=287 [M+H]+;
GC/MS (70 eV): m/z (%)=287 (100%), 257 (50%); Rt =
24.928 min; HR-MS (ESI): m/z=287.2485, calcd. for
2-Benzyl-1-phenethyl-1H-benzo[d]imidazole (52);
General Procedure for the Synthesis of Disubstituted
Imidazoles
A 10-mL MW vial with magnetic stirrer was charged with
Pd/C (10% wt, 50% wt water, 212 mg 0,1 mmol) under ni-
trogen. Dry toluene (2 mL), N-1-phenethylbenzene-1,2-dia-
mine 28 (212 mg, 1 mmol), phenethylamine 3 (151 mL,
1.2 mmol), crotonitrile 4 (145 mL, 2.2 mmol) and acetic acid
(5 mL, 0.1 mmol) were subsequently added. The mixture was
stirred under MW dielectric heating for 90 min at 1708C.
The crude reaction mixture was filtered through a frit and
washed with MeOH. The solvent was removed under
vacuum and after purification by column cromatography
(petroleum ether 40–60/EtOAc 6:4), 52 was obtained as
a yellow oil; yield: 238 mg (73%). 1H NMR (400 MHz,
CDCl3): d=7.76 (m, 1H), 7.26 (m, 9H), 7.16 (d, J=6 Hz,
2H), 6.92 (d, J=6 Hz, 2H), 4.16 (t, J=7.6 Hz, 2H), 3.94 (s,
2H), 2.78 (t, J=7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d=153.2, 142.7, 137.8, 136.4, 136.1, 135.1, 128.9 (2C), 128.6
(2C), 128.4 (2C), 127.0 (2C), 126.4, 122.4, 122.0, 116.7,
109.4, 45.8, 35.6, 34.4; ES/MS: m/z=313 [M+H]+; GC/MS
(70 eV): m/z (%)=312 (100%); 207 (100%); 91 (40%); 65
(20%); Rt =28.149 min; HR-MS (ESI): m/z=314.1742,
+
C19H31N2 : 287.2487..
Dealkylation of Trioctylamine
A 10-mL vial for MW equipped with a magnetic stirrer was
charged with Pd/C (10% wt wet with 50% wt of water,
106 mg, 0.05 mmol) under nitrogen. Dry toluene (2 mL), o-
phenylenediamine 3 (108 mg, 1 mmol), trioctylamine 24
(325 mg, 0.9 mmol) and crotonitrile 4 (147.4 mg, 2.2 mmol)
were subsequently added. The mixture was stirred under
MW dielectric heating for 90 min at 1708C (max internal
pressure 300 psi). After cooling, the crude reaction mixture
was filtered through a pad of celite inside a syringe
equipped with a sintered set and the solid washed on the
filter with Et2O. The solvent was carefully removed and the
residue dissolved in dry MeOH (2 mL) and passed through
an SCX cartridge (prepacked 6 mL tube). The column was
washed several times with dry MeOH (8 mL) and dried
under vacuum suction. The column was eluted with a solu-
tion of NH3 in MeOH (10 mL of a 2M solution, 20 mmol);
the solvent was carefully evaporated to give dioctylamine
14; yield: 168 mg (76%). The product showed a GC/MS pro-
file and 1H NMR data in agreement with those of a commer-
cial sample.
+
calcd. for C22H21N2 : 314.1738.
2-Benzyl-1-propyl-1H-benzo[d]imidazole (61): Purifica-
tion by flash cromatography (petroleum ether 40–60/EtOAc
6:4), gave compound 61 as a yellow oil; yield: 213 mg
1
(85%). H NMR (400 MHz, CDCl3): d=7.76 (d, 1H), 7.26
(m, 7H), 4.31 (s, 2H), 3.93 (t, J=7 Hz, 2H), 1.57 (sex, J=
7 Hz 2H), 0.83 (t, J=7 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=152.9, 136.6, 135.2, 128.8, 128.5 (2C), 128.3
(2C), 127.0, 122.3, 122.0, 119.5, 109.54, 45.6, 34.5, 22.8, 11.4;
ES/MS: m/z=251 [M+H]+; GC/MS (70 eV): m/z (%)=250
(100%), 235 (25%), 207 (25%), 91 (25%), 132 (90%); Rt =
23.687 min; HR-MS (ESI): m/z=251.1546, calcd. for
General Procedure for Recycling the Catalyst
+
C17H19N2 : 251.1548.
After reaction, the mixture was passed through a syringe
equipped with a frit and Pd/C was washed with CH2Cl2 (3ꢂ
10 mL), MeOH (3ꢂ10 mL) and diethyl ether (2ꢂ10 mL).
Then the bottom of the syringe was closed and 1 mM aque-
ous HCl (3 mL) was added. After 10 min, the solvent was
drained, and the residue washed with H2O ( 3ꢂ10 mL) mL,
MeOH (3ꢂ10 mL) and dry THF (3ꢂ10 mL). The Pd/C was
dried under vacuum suction and removed from the syringe.
2-Isopropyl-1-propyl-1H-benzo[d]imidazole (62): After
flash cromatography (CH2Cl2/MeOH 95:5), compound 62
1
was obtained as a yellow oil; yield: 153 mg (76%). H NMR
(400 MHz, CDCl3): d=7.81 (m, 1H), 7.33–7.24 (m, 3H),
4.10 (t, J=6.8 Hz, 2H), 3.22 (m), 1.85 (sex, J=6.8 Hz, 2H),
1.48 (d, J=6.4 Hz, 6H), 0.98 (t, J=6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3): d=165.6, 145.1, 131.6, 122.1, 120.0,
10
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ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A General Approach to Substituted Benzimidazoles and Benzoxazoles
The catalyst (5% of overall weight loss) was wet with water
and used a second time.
[11] R. Rossi, F. Bellina, Tetrahedron 2009, 65, 10269–10310.
[12] a) M. Yus, F. Alonso, P. Rienta Acc. Chem. Res. 2011,
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c) J. M. J. Williams, M. H. S. A. Hamid, P. A. Slatford,
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Acknowledgements
[13] a) S. Bꢃhn, S. Imm, L. Neubert, M. Zhang, H. Neu-
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This work was financially supported by MIUR (Rome)
within the PRIN 2009 Project n 2009RMW3Z5 006 and
FIRB Project
n
RBFR08TTWW. Chemessentia-Chemo
(Novara) is also acknowledged for a gift of Pd/C.
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12
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Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

FULL PAPERS
A General Approach to Substituted Benzimidazoles and
Benzoxazoles via Heterogeneous Palladium-Catalyzed
Hydrogen-Transfer with Primary Amines
13
Adv. Synth. Catal. 2012, 354, 1 – 13
Marianna Pizzetti, Elisa De Luca, Elena Petricci,
Andrea Porcheddu, Maurizio Taddei*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
13
ÞÞ
These are not the final page numbers!