Assembly of substituted 1H-benzimidazoles and 1,3-dihydrobenzimidazol-2- ones via CuI/L-proline catalyzed coupling of aqueous ammonia with 2-iodoacetanilides and 2-iodophenylcarbamates

Article abstract of DOI:10.1021/jo9017183

(Chemical Equation Presented) CuI/L-proline catalyzed coupling of aqueous ammonia with 2-iodoacetanilides and 2-iodophenylcarbamates affords the aryl amination products at room temperature, which undergo in situ additive cyclization under acidic conditions or heating to give substituted 1H-benzimidazoles and 1,3-dihydrobenzimidazol-2-ones, respectively. A wide range of functional groups including ketone, nitro, iodo, bromo, and ester are tolerated under these reaction conditions, providing these heterocycles with great diversity.

Full text of DOI:10.1021/jo9017183

pubs.acs.org/joc
and enzyme inhibition.4 For these reasons their synthesis has
Assembly of Substituted 1H-Benzimidazoles and
1,3-Dihydrobenzimidazol-2-ones via CuI/L-Proline
Catalyzed Coupling of Aqueous Ammonia with
2-Iodoacetanilides and 2-Iodophenylcarbamates
received considerable attention.5 The typical methods for
assembling these heterocycles are highly dependent on using
benzene-1,2-diamines as the key intermediates.6 Recently,
we have revealed that 1,2-disubstituted benzimidazoles7 and
N-substituted 1,3-dihydrobenzimidazol-2-ones8 could be
synthesized via a CuI/amino acid catalyzed coupling reac-
tion of primary amines with 2-haloacetanilides and 2-halo-
phenylcarbamates. Subsequent to this discovery, aqueous
ammonia was reported as a suitable coupling partner for
copper-catalyzed N-arylation.9,10 We envisaged that using
this new coupling partner we could elaborate substituted 1H-
benzimidazoles and 1,3-dihydrobenzimidazol-2-ones from
2-iodoacetanilides and 2-iodophenylcarbamates. The inves-
tigations thus undertaken are disclosed here.
As indicated in Table 1, we initiated our studies by screen-
ing suitable conditions for coupling aqueous ammonia with
2-iodophenylbenzamide. It was found that under the cata-
lysis of 10 mol % of CuI and 20 mol % of trans-4-hydroxy-L-
proline, this reaction took place in DMSO at room tempera-
ture to afford aniline 2a in 78% yield (entry 1). A similar
result was observed when ligand was changed to L-proline
(entry 2). The best yield was obtained by decreasing the
amount of NaOH (entry 3). Solvent plays a crucial role for
this coupling reaction, as is evident from DMF giving a
satisfactory yield, while a moderate yield was observed in the
case of NMP, and no coupling occurred when toluene,
dioxane, and methylene chloride were employed. Among
the bases we examined, NaOH gave the best result, although
Cs2CO3 and K2CO3 also worked for this coupling reaction
(compare entries 3, 9, and 10 in Table 1). Noteworthy is that
Xiaoqiong Diao,† Yuji Wang,† Yongwen Jiang,‡ and
Dawei Ma*,‡
†Department of Chemistry, Fudan University, Shanghai
200433, China, and ‡State Key Laboratory of Bioorganic and
Natural Products Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, China
madw@mail.sioc.ac.cn
Received August 7, 2009
CuI/L-proline catalyzed coupling of aqueous ammonia
with 2-iodoacetanilides and 2-iodophenylcarbamates
affords the aryl amination products at room temperature,
which undergo in situ additive cyclization under acidic
conditions or heating to give substituted 1H-benzimid-
azoles and 1,3-dihydrobenzimidazol-2-ones, respectively.
A wide range of functional groups including ketone,
nitro, iodo, bromo, and ester are tolerated under these
reaction conditions, providing these heterocycles with
great diversity.
(5) For recent examples, see: (a) Shen, M.; Driver, T. G. Org. Lett. 2008,
10, 3367. (b) Blacker, A. J.; Farah, M. M.; Hall, M. I.; Marsden, S. P.; Saidi,
Q.; Williams, J. M. J. Org. Lett. 2009, 11, 2039.
(6) For recent investigations, see: (a) Lim, H.-J.; Myung, D.; Lee, I. Y. C.;
Jung, M. J. Comb. Chem. 2008, 10, 501. (b) Charton, J.; Girault-Mizzi, S.;
Sergheraert, C. Chem. Pharm. Bull. 2005, 53, 492. (c) Du, L.-H.; Wang, Y.-G.
Synthesis 2007, 5, 675. (d) Chen, H.-Y.; Kulkarni, M. V.; Chen, C.-H.; Sun,
C.-M. Tetrahedron 2008, 64, 6387. (e) Zhang, P.; Terefenko, E. A.; McCo-
mas, C. C.; Mahaney, P. E.; Vu, A.; Trybulski, E.; Koury, E.; Johnston, G.;
Bray, J.; Deecher, D. Bioorg. Med. Chem. Lett. 2008, 18, 6067.
(7) Zou, B.; Yuan, Q.; Ma, D. Angew. Chem., Int. Ed. 2007, 46, 2598.
(8) Zou, B.; Yuan, Q.; Ma, D. Org. Lett. 2007, 9, 4291.
(9) (a) Kim, J.; Chang, S. Chem. Commun. 2008, 3052. (b) Xia, N.;
Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 337. (c) Jiang, L.; Lu, X.;
Zhang, H.; Jiang, Y.; Ma, D. J. Org. Chem. 2009, 74, 4542. (d) Xu, H.; Wolf,
C. Chem. Commun. 2009, 3035.
Substituted 1H-benzimidazoles and 1,3-dihydrobenzimi-
dazol-2-ones are pharmaceutically important heterocycles
that display a wide range of biological activities, such as
antitumor,1 antibacterial,2 δ-opioid receptor antagonism,3
(10) For other studies on copper-catalyzed N-arylation, see: (a) Ma, D.;
Zhang, Y.; Yao, J.; Wu, S.; Tao, F. J. Am. Chem. Soc. 1998, 120, 12459.
(b) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2001, 123, 7727. (c) Gujadhur, R. K.; Bates, C. G.; Venkataraman, D. Org.
Lett. 2001, 3, 4315. (d) Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am.
Chem. Soc. 2002, 124, 11684. (e) Ma, D.; Cai, Q.; Zhang, H. Org. Lett. 2003,
5, 2453. (f) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem.;
Eur. J. 2004, 10, 5607. (g) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005, 70,
5164. (h) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem.;Eur. J. 2006,
12, 3636. (i) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742.
(j) Kantam, M. L.; Yadav, J.; Laha, S.; Sreedhar, B.; Jha, S. Adv. Synth.
Catal. 2007, 349, 1938. (k) Ma, H.; Jiang, X. J. Org. Chem. 2007, 72, 8943.
(l) Chen, W.; Zhang, Y.; Zhu, L.; Lan, J.; Xie, R.; You, J. J. Am. Chem. Soc.
2007, 129, 13879. (m) Maheswaran, H.; Krishna, G. G.; Prasanth, K. L.;
Srinivas, V.; Chaitanya, G. K.; Bhanuprakash, K. Tetrahedron 2008, 64,
2471. (n) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450. (o) Liang, L.; Li, Z.;
Zhou, X. Org. Lett. 2009, 11, 3294. (p) Haldon, E.; Alvarez, E.; Nicasio,
M. C.; Perez, P. J. Organometallics 2009, 28, 3815. (q) Wang, D.; Ding, K.
Chem. Commun. 2009, 1891. (r) Xu, H.; Wolf, C. Chem. Commun. 2009, 1715.
(1) Kamal, A.; Kumar, P. P.; Sreekanth, K.; Seshadri, B. N.; Ramulu, P.
Bioorg. Med. Chem. Lett. 2008, 18, 2594.
(2) Hu, L.; Kully, M. L.; Boykin, D. W.; Abood, N. Bioorg. Med. Chem.
Lett. 2009, 19, 3374.
(3) (a) Balboni, G.; Guerrini, R.; Salvadori, S.; Bianchi, C.; Rizzi, D.;
Bryant, S. D.; Lazarus, L. H. J. Med. Chem. 2002, 45, 713. (b) Balboni, G.;
Fiorini, S.; Baldisserotto, A.; Trapella, C.; Sasaki, Y.; Ambo, A.; Marczak,
E. D.; Lazarus, L. H.; Salvadori, S. J. Med. Chem. 2008, 51, 5109.
(4) (a) Wittman, M. D.; Balasubramanian, B.; Stoffan, K.; Velaparthi,
U.; Liu, P.; Krishnanathan, S.; Carboni, J.; Li, A.; Greer, A.; Attar, R.;
Gottardis, M.; Chang, C.; Jacobson, B.; Sun, Y.; Hansel, S.; Zoeckler, M.;
Vyas, D. M. Bioorg. Med. Chem. Lett. 2007, 17, 947. (b) Schiffmann, R.;
Neugebauer, A.; Klein, C. D. J. Med. Chem. 2006, 49, 511. (c) Verma, R. P.
Bioorg. Med. Chem. 2005, 13, 1059. (d) Rangarajan, M.; Kim, J. S.; Sim, S. P.;
Liu, A.; Liu, L. F.; La Voie, E. J. Bioorg. Med. Chem. 2000, 8, 2591.
7974 J. Org. Chem. 2009, 74, 7974–7977
Published on Web 09/23/2009
DOI: 10.1021/jo9017183
r
2009 American Chemical Society

Diao et al.
JOCNote
TABLE 1. Coupling of Aqueous Ammonia and 2-Iodophenylbenzamide
under Different Conditionsa
TABLE 2. Synthesis of Benzimidazoles via Coupling of Aqueous Am-
monia and 2-Iodoacetanilidesa
entry
ligandb
base
solvent
yield (%)
1
2
A
B
B
A
A
A
A
A
B
B
B
B
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
Cs2CO3
K2CO3
K2CO3
NaOH
DMSO
DMSO
DMSO
DMF
78
82
91c
75
48
3c
4
5
6
7
8
NMP
toluene
dioxane
CH2Cl2
DMSO
DMSO
DMSO
DMSO
9
89d
32d
83e
63f
10
11
12
aReaction conditions: 1a (0.25 mmol), aqueous ammonia (0.375
mmol), CuI (0.025 mmol), ligand (0.05 mmol), base (0.75 mmol), slovent
(1 mL), rt. bA: trans-4-hydroxy-L-proline. B: L-proline. c0.375 mmol of
e
NaOH was used. d0.375 mmol of Cs2CO3 or K2CO3 was used. 0.75
mmol of K2CO3 was used. fNH4Cl was used to replace aqueous
ammonia.
in the case of K2CO3, 3 equiv of base was required to obtain a
satisfactory result (compare entries 10 and 11 in Table 1),
indicating that the base and its amount have great influence
to this reaction. Additionally, when NH4Cl was used as an
amine source a relatively low yield was observed.
After obtaining the optimized coupling reaction condi-
tions, we attempted to develop a one-pot procedure to
prepare 1H-benzimidazoles. Accordingly, after completion
of the coupling reaction of aqueous ammonia and 2-iodo-
phenylbenzamide, the reaction mixture was directly treated
with HOAc at 80 °C. We were pleased to find that the desired
2-phenylbenzimidazole 3a was isolated in 83% yield
(Table 2, entry 1). In view of this encouraging result, a
number of 2-iodoacetanilides were examined for this one-
pot process to explore it scope and limitation. It was found
that three 2-iodoacetanilides bearing electron-withdrawing
groups are suitable substrates for this process, delivering
the corresponding benzimidazoles in good yields (Table 2,
entries 2-4).
In the cases of methoxy substituted 2-iodoacetanilides as
the substrates, the coupling step worked well to give the
primary aryl amines. However, their conversion to benzimi-
dazoles did not take place by treatment with HOAc. After
some experiments, we discovered that this additive cycliza-
tion could be achieved by using 15% H2SO4 as the promoter
(Table 2, entries 5 and 6). This phenomena is inconsistent
with our observation in the synthesis of 1,2-disubstituted
benzimidazoles,7 although the reason is not clear.
Further investigations revealed that changing the substi-
tuents at the 2-position was possible by using different amides
(Table 2, entries 7-17). These substituents include aryl,
heteroaromatic, benzyl, simple alkyl, and functionalized
alkyl groups. Another notable character was that a wide
range of functional groups were found to be tolerated under
the reaction conditions. These groups include ketone, nitro,
iodo, bromo, and ester, which are ready for further trans-
formations to give more complicated benzimidazoles. When
compound 1i, a substrate with an additional iodo group at
aReaction conditions: 1a (0.25 mmol), aqueous ammonia (0.375
mmol), CuI (0.025 mmol), L-proline (0.05 mmol), NaOH (0.375 mmol),
DMSO (1 mL), rt, 3-7 h; then HOAc (3 mL), 50-80 °C, 3-12 h. b15%
H2SO4 (3 mL) was used for the condensative cyclization step.
the 4-position, was used, a double aryl amination product
was determined in the coupling step, and the desired product
3i was isolated in 61% yield (entry 9). However, only
monoaryl amination product was formed when a bromo
substituted 2-iodoacetanilide was used (Table 2, entry 16).
These results demonstrated that the regioselectivity between
two iodo groups (at the ortho-position of the amido group
and the other positions) is not so good, while the reactivity
difference between bromo and iodo groups is still significant
in the coupling step. It is notable that under the same
conditions 2-bromoacetanilide gave low yields of products.
More experimental studies are required to overcome this
drawback.
It was known that substituted 1H-benzimidazoles could
tautomerize (3 to 4, Scheme 1) and thereby give a mixture of
J. Org. Chem. Vol. 74, No. 20, 2009 7975

Diao et al.
JOCNote
SCHEME 1. Possible Courses for Formation of Two Regio-
isomers for 1H-Benzimidazoles
1H-benzimidazoles, which have different functional groups
such as ketone, ester, methoxy, bromo and iodo at the
aromatic ring, and aryl, simple, and functionalized alkyl
groups at the 2-position, could be elaborated from suitable
substrates. Additionally, by coupling of 2-halophenylcarba-
mates with aqueous ammonia at room temperature, and
subsequent intramolecular condensation at 130 °C, several
1,3-dihydrobenzimidazol-2-ones were constructed. These
two processes provide simple and reliable approaches for
assembly of the pharmaceutically important heterocycles,
and therefore may find applications in organic synthesis.
Experimental Section
General Procedure for the Synthesis of Substituted 1H-Benzi-
midazole. A Schlenk tube was charged with 2-iodoacetanilides
(0.25 mmol), CuI (5 mg, 0.025 mmol), L-proline (6 mg, 0.05
mmol), and NaOH (15 mg, 0.375 mmol). The tube was evac-
uated and backfilled with argon (3 times). Aqueous ammonia
(0.375 mmol) and 1 mL of DMSO was added into the tube. After
the reaction mixture was stirred at room temperature for 3-7 h,
3 mL of AcOH (in the cases of 1e and 1f as the substrates, 3 mL
of 15% H2SO4 was used) was added and the reaction mixture
was stirred at 50-80 °C for 3-12 h. The cooled reaction mixture
was partitioned between ethyl acetate and water. The organic
layer was washed with aqueous NaHCO3 and water, dried over
Na2SO4, and concentrated in vacuo. The residue was purified by
column chromatography on silica gel (eluting with 3:1 to 1:1
petroleum ether/ethyl acetate) to provide the desired product.
SCHEME 2. Assembly of 1,3-Dihydrobenzimidazol-2-ones 7
1
2-(4-Chlorophenyl)-6-nitro-1H-benzimidazole (3h): H NMR
(400 MHz, DMSO-d6) δ 13.70 (br s, 1H), 8.48 (s, 1H), 8.23 (d,
J = 8.4 Hz, 2H), 8.14 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.8 Hz,
1H), 7.69 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, DMSO-d6)
δ 155.0, 143.2 (2C), 136.1, 130.4, 129.6 (2C), 129.0 (2C), 128.8,
128.3, 118.5, 115.2; ESI-MS m/z 274.1 (M þ H)þ; ESI-HRMS
calcd for C13H9ClN3O2 (M þ H)þ requires m/z 274.0378, found
274.0389.
6-Fluoro-2-(furan-2-yl)-1H-benzimidazole (3l): mp 218-220 °C
(EtOAc/hexane); 1H NMR (500 MHz, DMSO-d6) δ 7.96 (s, 1H),
7.58 (dd, J = 5.0, 9.0 Hz, 1H), 7.38 (dd, J = 2.0, 9.5 Hz, 1H), 7.22
(d, J = 3.5 Hz, 1H), 7.09 (dt, J = 2.5, 9.5 Hz, 1H), 6.75 (dd, J =
2.0, 3.5 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 159.1 (d,
two regioisomers in some cases.5a,11 Indeed, a common
intermediate 5 might form in our additive cyclization step,
which might undergo dehydration from two possible direc-
tions (a and b) to afford regioisomers 3 and 4 (Scheme 1). On
the basis of this consideration, we checked the analytical data
of our products carefully. It was found that all products
(even for 3i) showed only one set of peaks in their 1H NMR
spectrum. However, this observation could not rule out the
possibility of the existence of two regioisomers because the
identical 1H NMR data were observed for two regioisomers
3e and 3f.
J
CF = 233.8 Hz), 145.6, 145.2, 139.9, 135.9, 116.0, 112.8, 111.2,
110.8, 110.6, 101.5; 19F NMR (376 MHz, DMSO-d6) δ -73.38;
ESI-MS m/z 203.1 (M þ H)þ; ESI-HRMS calcd for C11H8FN2O
(M þ H)þ requires m/z 203.0611, found 203.0615.
1
Methyl 2-n-propyl-1H-benzimidazole-6-carboxylate (3o): H
NMR (400 MHz, DMSO-d6) δ 8.09 (s, 1H), 7.79 (d, J = 8.4 Hz,
1H), 7.56 (d, J = 8.4 Hz, 1H), 3.86 (s, 3H), 2.83 (t, J = 7.6 Hz,
2H), 1.83-1.78 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H); 13C NMR
(125 MHz, DMSO-d6) δ 167.9, 157.8 (2C), 138.1, 124.1, 123.8,
116.7, 114.6, 52.1, 31.3, 21.5, 13.9; ESI-MS m/z 219.0 (M þ H)þ;
ESI-HRMS calcd for C12H15N2O2 (M þ H)þ requires
m/z 219.1128, found 219.1119.
General Procedure for the Synthesis of Substituted 1,3-Dihy-
drobenzimidazol-2-ones. A Schlenk tube was charged with 2-iodo-
phenylcarbamates 6 (0.25 mmol), CuI (5 mg, 0.025 mmol),
L-proline (6 mg, 0.05 mmol), and NaOH (15 mg, 0.375 mmol).
After the tube was evacuated and backfilled with argon (3 times),
aqueous ammonia (0.375 mmol) and 1 mL of DMSO were added
into the tube. The reaction mixture was stirred at room tempera-
ture for 3-7 h before it was heated at 130 °C for 3-12 h. The
cooled reaction mixture was partitioned between ethyl acetate and
water. The organic layer was washed with water and brine, dried
over Na2SO4, and concentrated in vacuo. The residue was purified
by column chromatography on silica gel (eluting with 3:1 to 1:1
petroleum ether/ethyl acetate) to provide the desired product.
After success in the elaboration of substituted 1H-benzi-
midazoles, we moved our attention to synthesize 1,3-di-
hydrobenzimidazol-2-ones via coupling of 2-iodophenyl-
carbamates 6 with aqueous ammonia. As depicted in
Scheme 2, it was found that the coupling step proceeded
smoothly at room temperature, and the resulting amines
were in situ converted into 1,3-dihydrobenzimidazol-2-ones
by heating at 130 °C. Four 1,3-dihydrobenzimidazol-2-ones
7a-d, which contain ketone, nitro, amido, and methyl
groups, were assembled to illustrate the generality of this
method.
In conclusion, a new method for assembling substituted
1H-benzimidazoles has been developed, which relied on a
one-pot coupling of 2-haloacetanilides with aqueous ammo-
nia and subsequent additive cyclization. A wide range of
(11) (a) Elguero, J.; Katritzky, A. R.; Denisko, O. V. Adv. Heterocycl.
Chem. 2000, 76, 1. (b) Zheng, N.; Buchwald, S. L. Org. Lett. 2007, 9, 4749.
7976 J. Org. Chem. Vol. 74, No. 20, 2009

Diao et al.
JOCNote
5-Acetyl-1H-benzimidazol-2(3H)-one (7a): 1H NMR (400
MHz, DMSO-d6) δ 11.04 (br s, 1H), 10.89 (br s, 1H), 7.66 (d,
J = 8.0 Hz, 1H), 7.46 (s, 1H), 7.01 (d, J = 8.4 Hz, 1H), 2.53 (s,
3H); 13C NMR (125 MHz, DMSO-d6) δ 197.0, 155.9, 134.5,
130.4, 130.1, 123.0, 108.34, 108.30, 26.8; ESI-MS m/z 177.1
(M þ H)þ; ESI-HRMS calcd for C9H9N2O2 (M þ H)þ requires
m/z 177.0988, found 177.1002.
4,6-Dimethyl-1H-benzimidazol-2(3H)-one (7d): 1H NMR (500
MHz, DMSO-d6) δ 10.49 (br s, 1H), 10.40 (br s, 1H), 6.52 (s, 1H),
6.50 (s, 1H), 2.19 (s, 3H), 2.17 (s, 3H); 13C NMR (125 MHz,
DMSO-d6) δ 156.1, 129.9, 129.7, 126.8, 122.7, 118.26, 107.1, 21.4,
16.5; ESI-MS m/z 163.0 (M þ H)þ; ESI-HRMS calcd for
C9H11N2O (M þ H)þ requires m/z 163.0793, found 163.0800.
2-Oxo-N-n-propyl-2,3-dihydro-1H-benzo[d]imidazole-5-carbo-
xamide (7c): H NMR (400 MHz, DMSO-d6) δ 10.84 (s, 1H),
Acknowledgment. The authors are grateful to the Chinese
Academy of Sciences, National Natural Science Foundation
of China (grant nos. 20621062 and 20872156) for their
financial support.
1
10.82 (s, 1H), 8.29-8.32 (m, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.43
(s, 1H), 6.94 (d, J = 8.0 Hz, 1H), 3.21-3.16 (m, 2H), 1.54-1.49
(m, 2H), 0.88 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, DMSO-
d6) δ 166.8, 156.0, 132.5, 129.8, 127.7, 120.8, 108.3, 108.2, 41.5,
22.9, 11.9; EI-MS m/z 219 (Mþ), 177, 161, 133; EI-HRMS calcd
for C11H14N3O2 (Mþ) requires m/z 219.1008, found m/z
219.1011.
Supporting Information Available: Copies of 1H NMR and
13C NMR spectra for all heterocycle products. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 20, 2009 7977