Potassium hydroxide/dimethyl sulfoxide promoted intramolecular cyclization for the synthesis of benzimidazol-2-ones

Article abstract of DOI:10.1021/ol2008878

A new protocol for intramolecular N-arylations of ureas to form benzimidazol-2-ones has been developed. The cyclization reaction occurs in the presence of KOH and DMSO at close to ambient temperature. Under these conditions the yields are high and a wide

Full text of DOI:10.1021/ol2008878

ORGANIC
LETTERS
2011
Vol. 13, No. 11
2876–2879
Potassium Hydroxide/Dimethyl Sulfoxide
Promoted Intramolecular Cyclization for
the Synthesis of Benzimidazol-2-ones
Astrid Beyer, Christine M. M. Reucher, and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1,
D-52074 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received April 5, 2011
ABSTRACT
A new protocol for intramolecular N-arylations of ureas to form benzimidazol-2-ones has been developed. The cyclization reaction occurs in the
presence of KOH and DMSO at close to ambient temperature. Under these conditions the yields are high and a wide range of functional groups are
tolerated.
Benzimidazol-2-ones are important heterocycles with an
embedded cyclic urea scaffold that is a core element of
many pharmaceutically relevant compounds. They can
exhibit a wide range of biological activities including, for
example, inhibitions of the respiratory syncytial virus
(RSV) fusion1 and the non-nucleoside reverse transcrip-
tase (NNRT).2 Furthermore, benzimidazol-2-one deriva-
tives play important roles as progesterone receptor
antagonists,3 in the selective inhibition of farnesyltransfer-
ase (FTase),4 and the activation of Kþ channels.5 Chal-
lenged by the demand, various synthetic approaches to-
ward those interesting compounds have been developed,
most of them using benzene-1,2-diamines as key inter-
mediates. Their subsequent cyclization to form the imida-
zolone core then requires the use of phosgene,6 tripho-
sgene,7 or carbonyldiimidazole (CDI).8 To avoid the use of
such toxic substances and the often harsh reaction condi-
tions, alternative protocols have been introduced giving
(6) For selected examples, see: (a) Monforte, A.-M.; Logoteta, P.; De
Luca, L.; Iraci, N.; Ferro, S.; Maga, G.; De Clercq, E.; Pannecouque, C.;
Chimirri, A. Bioorg. Med. Chem. 2010, 18, 1702. (b) Monforte, A.-M.;
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Zadjura, L.; Marino, A.; Dando, S.; D’Arienzo, C.; Kadow, K. F.;
Cianci, C. W.; Li, Z.; Clarke, J.; Genovesi, E. V.; Medina, I.; Lamb, L.;
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Chem. Lett. 2007, 17, 895.
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Galicia, T.; Hutchins, C.; Frost, D.; Rosenberg, S. H.; Sham, H. L.
Bioorg. Med. Chem. Lett. 2005, 15, 2918.
(7) For selected examples, see: (a) Poulain, R.; Horvath, D.; Bonnet,
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B.; Eckhoff, C.; Chapelain, B.; Bodinier, M.-C.; Deprez, B. J. Med.
Chem. 2001, 44, 3378. (b) Gustin, D. J.; Sehon, C. A.; Wei, J.; Cai, H.;
Meduna, S. P.; Khatuya, H.; Sun, S.; Gu, Y.; Jiang, W.; Thurmond,
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1687.
(8) For selected examples, see: (a) Hammach, A.; Barbosa, A.;
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Liu, P.; Qian, K. C.; Ralph, M.; Sarko, C.; Soleymanzadeh, F.; Moss, N.
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r
10.1021/ol2008878
Published on Web 05/02/2011
2011 American Chemical Society

access to imidazo[4,5-b]pyridine-2-ones9 or benzimidazol-
2-ones10 by palladium or copper catalysis.11 In these
reactions the formations of the cyclic urea units occur
either by metal-catalyzed N-arylation or coupling of am-
monia with 2-iodoacetanilides followed by acid-catalyzed
cyclization.12 Also here, elevated temperatures (>80 °C)
and additional activation modes such as microwave irra-
diation were required. We now developed a transition-
metal-free base-promoted intramolecular N-arylation of
ureas to form benzimidazol-2-ones.13ꢀ16 Noteworthy, it
utilizes simple KOH in DMSO, takes place at close to
ambient temperature, and is applicable to a wide range of
substrates. The results of our studies are described herein.
Initially, the reaction conditions were optimized by
examining the conversion of 1-benzyl-1-(2-iodophenyl)-
3- phenylurea (1a), synthesized by a transition-metal-free
two-step procedure from 2-iodoaniline,17 into 1-benzyl-3-
phenyl-1,3-dihydro-benzoimidazole-2-one (2a) (Table 1).
80 °C resulted in complete decomposition of the starting
material (entry 1). At room temperature the cyclization
was slow, and after the standard 24 h reaction time product
2a was isolated in only 67% yield. It required an additional
20 h to reach a yield of 84% (Table 1, entries 3 and 4,
respectively). The use of 2 equiv of KOH proved essential.
Decreasing the amount of the base to 1 equiv led to a
significant reduction in yield (entry 6).
Encouraged by these results, various phenyl ureas were
synthesized and submitted to the KOHꢀDMSO mixture
to determine the scope and the limitations of the cycliza-
tion method. Table 2 shows the data.
Pleasingly, a wide variety of products were accessible
under the optimized reaction conditions, and commonly
good to excellent yields were achieved. As demonstrated
for the synthesis of benzimidazol-2-one 2a the product
could be obtained not only by starting from iodo-substi-
tuted phenyl urea 1a but also through cyclizations of the
analogous bromo, chloro, and fluoro derivatives 1bꢀd,
respectively (Table 2, entries 1ꢀ3). Compared to the
conversion of 1a transformations of the latter halo phenyl
ureas were less effective, but nevertheless yields of up to
79% were achieved here as well. Attempts to cyclize less
substituted urea 1e (where R2 = H) remained unsuccess-
ful, and after 24 h the entire amount of starting material
was recovered (Table 2, entry 4).18 This result showed that
an N,N,N0-trisubstitution of the urea core in 2 was critical
for the cyclization (Table 2, entry 4). With respect to the
N-substituent R2 we were pleased to find that both alkyl
(methyl, entries 10 and 16) and benzyl groups were toler-
ated. The latter could have additional aryl substituents
which appeared to have no significant influence on the
cyclization toward the corresponding benzimidazol-2-ones
2 (entries 9, 11, 12). Substrates with additional chloro or
bromo substituents (R1) at the 4-position of the 2-halo-
phenyl moiety showed reactivity differences, but in all
cases the products were formed well reaching a yield of
93% in the synthesis of chloro-substituted 2i (Table 2,
entry 13). Comparing the cyclization results of 2-iodo
derivatives 1a (R1 = H), 1n (R1 = Cl), and 1p (R1 = Br)
revealed that the latter process was the most difficult
one leading to product 2j in only 78% yield (Table 2,
entry 15). Variations of the N0-aryl (R3) indicated that
substituents in the para position had almost no effect on
the product yield (Table 2, entries 5ꢀ8, 19). One excep-
tion is nothworthy: The cyclization of p-methoxy-sub-
stituted 1h provided the corresponding product 2d in
Table 1. Optimization of the Reaction Conditions
entry
KOH (equiv)
t °C, 24 h
yield %a
1
2
3
4
5
6
2.0
2.0
2.0
2.0
2.0
1.0
80
40
rt
decomp.
89 (98)b
67
rt
84c
40
40
88d
23
a After column chromatography; use of 0.234 mmol of 1a. b In
parentheses, yield from a reaction with 0.700 mmol of 1a. c Reaction
time: 44 h. d Reaction time: 6 h.
To our delight, the reaction proceeded well, and in the
presence of 2 equiv of KOH in DMSO at 40 °C a smooth
cyclization occurred providing the product in up to 98%
yield(Table1, entry 2). Attemptstoperformthe reaction at
(10) Barbero, N.; Carril, M.; SanMartin, R.; Domı
hedron 2008, 64, 7283.
(11) For Pd-catalyzed reactions, see: (a) Xu, X.-J.; Zong, Y.-X.
Tetrahedron Lett. 2007, 48, 129. (b) Benedı, C.; Bravo, F.; Uriz, P.;
´
nguez, E. Tetra-
´
ꢀ
ꢀ
Fernandez, E.; Claver, C.; Castillon, S. Tetrahedron Lett. 2003, 44, 6073.
For Cu-catalyzed reactions, see: (c) Li, Z.; Sun, H.; Jiang, H.; Liu, H.
Org. Lett. 2008, 10, 3263. (d) Zou, B.; Yuan, Q.; Ma, D. Org. Lett. 2007,
9, 4291. For a general review, see: (e) Sadig, J. E. R.; Willis, M. C.
Synthesis 2011, 1.
(16) Great care was taken to avoid the presence of trace metals in the
reaction mixture. Those measures included the transition-metal-free
synthesis of the starting materials, reagent transfers with plastic spatulas,
and the use of new glassware for the cyclization reactions. Such precautions
appeared advisable in light of the recent reports on trace metal effects on
cross-coupling reactions. For examples, see: (a) Buchwald, S. L.; Bolm, C.
Angew. Chem., Int. Ed. 2009, 48, 5586. (b) Larsson, P.-F.; Correa, A.;
Carril, M.; Norrby, P.-O.; Bolm, C. Angew. Chem., Int. Ed. 2009, 48, 5691.
(c) Leadbeater, N. E. Nature Chem. 2010, 2, 1007.
(12) Diao, X.; Wang, Y.; Jiang, Y.; Ma, D. J. Org. Chem. 2009, 74,
7974.
(13) For a review on KOHꢀDMSO mixtures as “superbases”, see:
Trofimov, B. A. Sulfur Rep. 1992, 74, 207.
(14) For an interesting early observation, see: Heaney, H.; Ley, S. V.
J. Chem. Soc., Perkin Trans. 1 1973, 499.
(17) Clayden, J.; Turner, H.; Pickworth, M.; Adler, T. Org. Lett.
2005, 7, 3147.
(15) (a) For an initial study on the use of KOHꢀDMSO mixtures,
ꢀ
see: Yuan, Y.; Thome, I.; Kim, S. H.; Chen, D.; Beyer, A.; Bonnamour,
J.; Zuidema, E.; Chang, S.; Bolm, C. Adv. Synth. Catal. 2010, 352, 2892.
(18) Also attempted cyclizations of 1e with 3 or 4 equiv of KOH (at
40 °C) remained unsuccessful. At 100 °C (using 2 equiv of KOH) only
traces of 2b were detected after 22.5 h.
ꢀ
(b) For a related study, see: Cano, R.; Ramon, D. J.; Yus, M. J. Org.
Chem. 2011, 76, 654.
Org. Lett., Vol. 13, No. 11, 2011
2877

Table 2. Scope of the Intramolecular N-Arylation of Phenyl Ureas
a After column chromatography; using 0.234 mmol of starting material. b At 60 °C.
99% yield, which was the best result of the entire study.
When R3 had an ortho substituent, as in compounds 1r
and 1s (entries 17 and 18), the yields were lower (66 and
79%, respectively). If R3 was cyclohexyl, no cyclization
occurred, and only hydrolysis of the starting material
was observed.
2878
Org. Lett., Vol. 13, No. 11, 2011

To add synthetic value and demonstrate the usefullness
of the obtained fully substituted benzimidazol-2-ones we
decided to investigate debenzylation reactions. To our
surprise, hydrogenation with Pd(OH)2/C proved inapplic-
able, and when 2a was used as a test substrate only arene
reduction of the benzyl group was observed.19 After nume-
rous attempts a recently described protocol by Rombouts20
led to success. Thus, treatment of 2a with triflourmethane
sulfonic acid (TfOH) in toluene under microwave irradia-
tion afforded debenzylated urea 2b in almost quantitative
yield (Scheme 1).
(F > Cl > Br) for a standard SNAr mechanism.21
A
reaction via an aryne intermediate would require the
generation of a carbanion.22 In order to evaluate this
reaction path, we attempted to obtain the identical
species as for a reaction with 1a starting from isomeric
1-benzyl-1-(3-iodophenyl)-3-phenylurea (1u) (Table 2,
entry 20). When this compound was submitted to the
KOHꢀDMSO mixture, however, no cyclization was
observed and the starting material remained unreactive.
Although not entirely conclusive, this result indicates
that arynes do not play a central role in the cyclization.
Currently, we assume that short-lived radical intermedi-
ates are formed,22 and subsequent studies shall be direc-
ted toward their detection.
In summary, we have developed a new protocol for the
synthesis of substituted benzimidazol-2-ones. The intra-
molecular cyclization is promoted by KOH in DMSO at
nearly ambient temperature. Various aryl halides show
satisfying reactivities, and the protocol proved promising
for the formation of synthetically relevant nitrogen-con-
taining heterocycles.
Scheme 1. Microwave-Promoted Debenzylation of 2a
Acknowledgment. We are grateful to the Fonds der
Chemischen Industrie for financial support.
Finally, we wondered about the cyclization mechanism.
As indicated by the yields of 2a starting from 1aꢀd the
aryl halide reactivity did not follow the expected order
Supporting Information Available. Experimental pro-
cedures, full charakterization of new products, and copies
of NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(19) Even at 70 bar of hydrogen pressure (RT, 22 h) formation of 3a
was not observed, and the yield of 1-(cyclohexylmethyl)-3-phenyl-1,3-
dihydrobenzoimidazol-2-one was only 32%.
´
(20) Rombouts, F.; Franken, D.; Martınez-Lamenca, C.; Braeken,
M.; Zavattaro, C.; Chen, J.; Trabanco, A. A. Tetrahedron Lett. 2010, 51,
4815.
(21) For a review, see: Bunnett, J. F.; Zahler, R. E. Chem. Rev. 1951,
49, 273.
(22) Huisgen, R.; Sauer, J. Angew. Chem. 1960, 3, 91.
(23) (a) Bunnett, J. F. Acc. Chem. Res. 1987, 11, 413. (b) For a recent
overview on metal-free arylations under basic conditions involving
radical anions, see: Yanagisawa, S.; Itami, K. ChemCatChem 2011,
DOI: 10.1002/cctc.201000431.
Org. Lett., Vol. 13, No. 11, 2011
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