Copper(II) acetate/oxygen-mediated nucleophilic addition and intramolecular C-H activation/C-N or C-C bond formation: One-pot synthesis of benzimidazoles or quinazolines

Article abstract of DOI:10.1002/adsc.201000469

Diarylcarbodiimides or benzylphenylcarbodiimides are converted to 1,2-disubstituted benzimidazoles or 1,2-disustituted quinazolines via addition/intramolecular C-H bond activation/C-N or C-C bond forming reaction using copper(II) acetate/oxygen [Cu(OAc)₂/O₂] as the oxidant at 100°C in one-pot cascade procedure. Copyright

Full text of DOI:10.1002/adsc.201000469

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DOI: 10.1002/adsc.201000469
Copper(II) Acetate/Oxygen-Mediated Nucleophilic Addition and
À
À
À
Intramolecular C H Activation/C N or C C Bond Formation:
One-Pot Synthesis of Benzimidazoles or Quinazolines
Hua-Feng He,a Zhi-Jing Wang,a and Weiliang Baoa,*
a
Department of Chemistry, Xixi Campus, Zhejiang University, Hangzhou, Zhejiang 310028, Peopleꢀs Republic of China
Fax : (+86)-571-8827-3814; e-mail: wlbao@css.zju.edu.cn
Received: June 17, 2010; Revised: September 3, 2010; Published online: November 12, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000469.
Abstract: Diarylcarbodiimides or benzylphenylcar-
bodiimides are converted to 1,2-disubstituted benz-
ACHTUNGTRENNUNGimidazoles or 1,2-disustituted quinazolines via addi-
À
tion/intramolecular C H bond activation/C-N or
C C bond forming reaction using copper(II) ace-
À
tate/oxygen [Cu
(OAc)2/O2] as the oxidant at 1008C
in one-pot cascade procedure.
À
Keywords: carbodiimides; cascade reactions; C H
activation; copper(II)acetate catalysis; cyclization;
one-pot reaction
Figure 1.
In recent years, a new and novel synthetic method-
À
À
ology – C H activation/C H functionalization has at-
tracted considerable attention for its efficiency and
Benzoxazoles are a group of compounds that possess atom economy.[9] Ruthenium-,[10] rhodium-,[11] and pal-
biological and pharmaceutical activities.[1] Many bio- ladium-based[12] catalysts have been extensively ap-
À
À
logically and medicinally active substances, even some plied to effect either C C or C Het (Het=hetero-
À
hormones that play important roles in the regulation
atom) bond formation by replacement of a C H
of physiological activities in organism, are based on bond. Compared to these methods, employing copper
these structures. Benzimidazoles and quinazolines are as the catalyst[13] is particularly more attractive due to
two particularly attractive series in the benzoxazole its low cost and low toxicity. Very recently, Buchwald
family, for both of the scaffolds are broadly present in and co-workers reported a CuACTHNUTRGNE(UNG OAc)2-catalyzed syn-
bioactive compounds and medicines.[2] For example, a thesis of benzimidazoles from amines through a C H
À
[14]
À
number of 2-piperazinylbenzimidazoles (A) exhibit activation/C N bond coupling process.
Our group
anti-inflammatory[3b] and antihistaminic activities;[3a] had reported the synthesis of benzimidazoles from o-
some 2-phenoxylbenzimidazoles (B) are claimed to halocarbodiimides through a one-pot cascade reacti-
be antivirally active.[4] Compound (C) is used as
on.[15a] Encouraged by these results, we envisaged that
ACHTUNGTRENNUNG
potent H4R (the human histamine H4 receptor) benzimidazole and its derivatives might be synthe-
ligand,[5] 2-(arylamino)-4(3H)-quinazolinone (D) is an sized directly from the reaction of diphenylcarbodi-
inhibitor of the enzyme aldose reductase,[6] which pre-
vents the onset of diabetic complications (Figure 1). activation/C H functionalization cascade process cat-
imides with different nucleophiles via addition/C H
À
À
Although some methods for the syntheses of these alyzed by CuACTHNUGRTNEUNG(OAc)2/O2 in a one-pot procedure.
two types of compounds and their derivatives have Herein, as a part of our continuing efforts, we wish to
been developed,[2f,g,h,k,l,7,8] they still suffer from the lim- disclose this efficient and facile reaction.
itations of difficultly available starting materials, trou-
blesome procedures or low reactant diversity. So it is
highly desirable to search for more convenient and ef- the possibility of nucleophilic addition and C H acti-
Firstly, the reaction of bis(p-methylphenyl)carbodi-
AHCTUNGTRENNUNG
À
ficient approaches.
vative cyclization in a cascade procedure. Because
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Table 1. Optimization of the initial screening results.
Entry
Cu catalyst
Oxidant
Solvent
T [oC]
Yield [%][a]
1[b]
2[c]
3[d]
4[e]
5
6
7
8
9
10
11[f]
12
13
14[g]
15[h]
Cu
Cu
Cu
–
Cu
Cu
Cu
Cu
Cu
Cu
CuBr2
CuO
Cu
Cu
Cu
N
Cu
Cu
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
O2
G
xylene
xylene
xylene
xylene
xylene
xylene
toluene
DMSO
DMSO+HOAc
DMF
toluene
toluene
toluene
toluene
toluene
130
130
130
130
100
80
100
100
100
100
100
100
100
100
100
61
43
79
–
63
33
87
75
47
50
–
40
–
63
69
[a]
Isolated yield based on carbodiimide.
[b]
[c]
[d]
[e]
[f]
1.0 equivalent of Cu
1.0 equivalent of Cu
1.0 equivalent of CuAHCTUNGTRENNUNG
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
No catalyst was added.
Unless otherwise noted, the dosage of Cu catalyst was 0.1 equiv.
[g]
[h]
0.05 equivalents of Cu
ACHTUNGRTEN(NUNG OAc)2 were used.
0.5 equivalents of Cu(OAc)2 were used.
AHCTUNGTRENNUNG
both Cu
G
G
With the optimized conditions in hand, we next ex-
amount)/O2 (terminal oxidant) systems were good ox- plored the scope and generality of the process. Ac-
idant systems,[15b] at the begining the reaction was cording to the experiment, electron-donating groups
conducted in the presence of CuACTHNUTRGENNUG(OAc)2ACHTUNGTNER(NUGN 1 equiv.) on the carbodiimide promote this conversion and
under air in xylene at 1308C. To our delight, the ex- electron-withdrawing groups affect this protocol
pected product 3a was obtained in 61% yield (Table 2, entries 1–10). High yields were obtained
(Table 1, entry 1). The yield was lower when the same when the electron-donating substituents are in the 4-
reaction was conducted under an N2 atmosphere position of the diarylcarbodiimide (Table 2, entry 1).
(Table 1, entry 2). Then the CuACHTUNRTGENUNG(OAc)2(catalytic)/O2 When the substituents are in the 2- and 3-positions of
system was applied and the result was even better the diarylcarbodiimides (Table 2, entries 2 and 3),
(Table 1, entry 3). Without the Cu2+ catalyst, no prod- comparatively lower yields were obtained. Maybe this
uct was obtained (Table 1, entry 4). So both CuACTHNUTRGNEUNG(OAc)2 is due to the steric hindrance. Theoretically, two iso-
and O2 are useful in this reaction. Temperature meric products should be formed if the methyl was
should affect this reaction greatly. When the tempera- placed at the 3-position. Nevertheless, only product
ture was lowered, the yield declined (Table 1, entry 5 3b was obtained (Table 2, entry 2). In comparison,
and 6). Different solvents were screened also and tol- when bis(m-chlorophenyl)carbodiimide was used,
uene was found to be the best one (Table 1, entries 7– both the two corresponding products were obtained,
10). Subsequently some copper sources were screened with the ratio of 3h/3i=1.7/1 (Table 2, entry 8). The
and Cu
catalyst was also examined. The change of the dosage stituents makes this method particularly appealing,
of Cu(OAc)2 resulted in a decline of the yield. So we since these substituents can be used for further syn-
chose Cu(OAc)2 (0.1 equiv.) as the catalyst, O2 as the thetic manipulations (Table 2, entries 7 and 8). For N-
terminal oxidant in toluene at 1008C as the optimized [(phenylimino)methylene]-4-(trifluoromethoxy)benz-
ACHTUNGTRENNUNG(OAc)2 was chosen as the best. The dosage of ability to incorporate the whole range of halogen sub-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
conditions.
ACHTUNGTRENeNUNG namine, the corresponding two products were also
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Copper(II) Acetate/Oxygen-Mediated Nucleophilic Addition and Intramolecular C H Activation
[a]
À
À
Table 2. CuACHTUNGTRENNUNG(OAc)2-catalyzed synthesis of benzimidazoles through C H activation/C N bond forming of arylcarbodiimides.
Entry
R1
R2
Product
Yield [%][b]
1
2
3
4
5
6
7
p-Me
m-Me
o-Me
p-OMe
H
p-Me
m-Me
o-Me
p-OMe
H
3a
3b[c]
3c
3d
3e
3f
87
78
67
38
72
52
53
p-OCF3
p-Cl
p-OCF3
p-Cl
3g
8
m-Cl
m-Cl
p-CF3
H
36[d], 21[e]
9
p-CF3
p-OCF3
3j
47
10
59[f], 11[g]
11
3m
69
[a]
Reaction conditions: arylcarbodiimide (0.5 mmol), piperidine (1.0 equiv.) and CuACTHNUTRGNEUNG(OAc)2 (0.1 equiv.) in toluene under
oxygen for 20 h.
[b]
[c]
[d]
[e]
[f]
Isolated yield based on carbodiimide.
Only 0.36 mmol bis-(p-methylphenyl)carbodiimide was used.
The yield for 3h.
The yield for 3i.
The yield for 3k.
[g]
The yield for 3l.
obtained with the ratio of 3k/3l=6/1 (Table 2, cleophiles as well (Table 3, entries 6–8). But the reac-
entry 10). After the addition had taken place, two ni- tion times for aromatic amines and O-nucleophiles
trogen atoms on the carbodiimide may become anion- were longer and the yields were relatively lower. Ac-
ic, but the one without the CF3O group on the ben- cording to the experiments, the lower yields of aro-
zene should be more active. When the di-1-naphthyl- matic amines and O-nucleophiles might due to their
carbodiimide was used, the corresponding product weaker nucleophilicities. Even when heated to 1008C
(3m) was also obtained (Table 2, entry 11). Unfortu- for 24 h, the nucleophilic addition of aromatic amines
nately, when we used aliphatic carbodiimides, no cor- and O-nucleophiles still did not go to completion, in
responding product was obtained. This may be due to contrast, the addition of aliphilic amines was complet-
the instability of the addition intermediate.
ed quickly.
We also explored whether our protocol was viable
Unexpectedly, when we used benzyl-p-methylcarbo-
for the reaction between arylcarbodiimides and other diimide and piperidine to explore the reaction, prod-
N-nucleophiles and the corresponding products were uct 4a with fluorescent properties was obtained as the
prepared in moderate to good yields (Table 3, en- dominant product instead of the expected benzimida-
tries 1–5). The reaction was successful for the O-nu- zole. To our delight, after characterization with NMR,
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Table 3. The one-pot synthesis of 1, 2-disubstituted benzimidazoles with other nucleophiles.[a]
Entry
1
Carbodiimide
NuH
Product
Yield [%][b]
1a
1a
(Et)2NH
2b’
2c’
3h
69
84
2[3c]
3o
3p
3
1a
2d’
65
4
5
1a
1a
2e’
2f’
3q
3r
55
62
6
1a
1a
2g’
2h’
3s
3t
56
54
7[d]
8
9
1a
1c
2i’
2j’
3u
3v
57
65
(Et)2NH
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Copper(II) Acetate/Oxygen-Mediated Nucleophilic Addition and Intramolecular C H Activation
Table 3. (Continued)
Entry
Carbodiimide
NuH
Product
Yield [%][b]
45
10
1j
(Et)2NH
2k’
3w
[a]
Reaction conditions: arylcarbodiimide (0.5 mmol), nucleophiles (1.0 equiv.) and Cu
oxygen for 20 h.
Isolated yield based on carbodiimide.
0.25 mmol bis(p-methylphenyl)carbodiimide was used.
0.25 mmol bis(p-methylphenyl)carbodiimide was used.
ACHTUNGERTN(NUNG OAc)2 (0.1 equiv.) in toluene under
[b]
[c]
[d]
IR and MS, the unanticipated product 4a was shown ring. Studies on the exact mechanism and further re-
to be a quinazoline derivative. As far as we know, the search works are underway.
À
intramolecular cyclization between a phenyl ring and
In conclusion, an efficient copper-catalyzed C H
À
À
the methylene of a benzyl group via Cu
alyzed C H bond activation had not been reported synthesize benzimidazoles and quinazolines in
before. Encouraged by this result, the scope of this re- medium to good yields directly from arylcarbodi-
(OAc)2/O2 cat- activation/C N or C C bond-forming approach to
À
action was explored. As shown in Table 4, electron-
ACHTUNGTRENiNGNU mides has been developed. A number of N-substitut-
donating groups accelerate this process in contrast to ed 2-aminobenzimidazoles, 2-alkoxylbenzimidazoles
the electron-withdrawing groups (Table 4, entries 1– and 4-aryl-2-aminoquinazolines, which might possess
4). When other amines were used, the corresponding biological and pharmaceutical activities, were smooth-
products could also be obtained (Table 4, entry 5).
Currently, we are not sure of the mechanistic
course for the cyclization process. One thing to be
ly synthesized via this process.
sure is that there is a nucleophilic addition process Experimental Section
À
before the activation of the aromatic C H bond. Ac-
cording to the literature[16] and the observations in Representative Procedure for the Synthesis of 1,2-
our reaction, a plausible mechanism was proposed Disubstituted Benzimidazoles
(Scheme 1). In the course of the formation of five-
To an oven-dried Schlenk tube charged with a magnetic stir
bar, bis(p-methylphenyl)carbodiimide (0.5 mmol), piperidine
(1.0 equiv.) and CuACHTNUGTRNEUNG(OAc)2 (0.1 equiv.) were added. The
À
membered rings, a Cu N adduct maybe formed, with
copper either in oxidation state II or III[13]. In the for-
mation of the six-membered rings, the oxidation of
the methylene carbon would be a key step to com-
plete the electrophilic substitution of the benzene
Schlenk tube was capped with a Teflon screwcap, and then
evacuated and backfilled with O2 (with an O2 balloon).
Then 2 mL toluene were added as the solvent. The reaction
system was stirred for 20 h at 1008C. The reaction was moni-
tored by TLC. The reaction mixture was directly passed
through Celite and rinsed with an additional 30 mL of Et2O.
The combined filtrate was concentrated and purified by
column chromatography to give the corresponding pured
product (petroleum ether/ethyl acetate, v/v=10/1–8/1).
Representative Procedure with Aromatic Amines and
O-Nucleophiles
To an oven-dried Schlenk tube charged with a magnetic stir
bar arylcarbodiimide (0.5 mmol) and nucleophiles
(1.0 equiv.) were added. The Schlenk tube was capped with
a Teflon screwcap, and then evacuated and backfilled with
O2 (with an O2 balloon). Then 2 mL toluene were added as
the solvent. The reaction system was stirred for 24 h at
1008C. Then under the protection of oxygen, the reaction
was monitored to detect when the nucleophilic addition was
completed. After the addition process, CuACTHNURTGNENG(U OAc)2 (0.1 equiv)
was added, then the reaction was stirred at 1008C for anoth-
er 20 h. The reaction was monitored by TLC. The reaction
mixture was directly passed through Celite and rinsed with
Scheme 1. The plausible mechanism of the cyclization pro-
cess.
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À
À
Table 4. CuACHTUNGTRENNUNG(OAc)2-catalyzed synthesis of quinazolines through C H activation/C N bond forming of benzylarylcarbodiimi-
des.[a]
Entry
1
R1
R2
R3
R4
Product
Yield [%][b]
p-methyl
phenyl
-(CH2)5-
4a
4b
4c
69
2
3
H
phenyl
phenyl
-(CH2)5-
-(CH2)5-
58
53
p-Cl
4
H
p-cyanophenyl
-(CH2)5-
4d
4e
45
5
p-methyl
phenyl
C2H5
C2H5
78[c]
[a]
Reaction conditions: aryl carbodiimide (0.5 mmol), nucleophiles (1.0 equiv.) and Cu
oxygen for 20 h.
Isolated yield based on carbodiimide.
ACHTUNGERTN(NUNG OAc)2 (0.1 equiv.) in toluene under
[b]
[c]
Only 0.25 mmol benzylcarbodiimide was used.
an additional 30 mL of Et2O. The combined filtrate was con-
dine (1.0 equiv.) and CuACTHNGUTERN(UNG OAc)2 (0.1 equiv.) were added. The
centrated and purified by column chromatography to give
the corresponding pured product (petroleum ether/ethyl
acetate, v/v=25/1–20/1).
Schlenk tube was capped with a Teflon screwcap, and then
evacuated and backfilled with O2 (with an O2 balloon).
Then 2 mL toluene were added as the solvent. The reaction
system was stirred for 20 h at 1008C. The reaction was moni-
tored by TLC. The reaction mixture was directly passed
through Celite and rinsed with an additional 30 mL of Et2O.
The combined filtrate was concentrated and purified by
column chromatography to give the corresponding pured
product (petroleum ether/ethyl acetate, v/v=30/1–25/1).
Representative Procedure for the Synthesis of 1,2-
Disubstituted Quinazolines
To an oven-dried Schlenk tube charged with a magnetic stir
bar p-methylphenylbenzylcarbodiimide (0.5 mmol), piperi-
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Copper(II) Acetate/Oxygen-Mediated Nucleophilic Addition and Intramolecular C H Activation
[6] R. A. Smits, H. D. Lim, A. Hanzer, O. P. Zuiderveld, E.
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This work was financially supported by the Natural Science
Foundation of China (No. 21072168).
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