Transition-metal-free synthesis of benzimidazoles mediated by KOH/DMSO

Article abstract of DOI:10.1021/ol403414v

Benzimidazoles are prepared by intramolecular N-arylations of amidines mediated by potassium hydroxide in DMSO at 120 °C. In this manner, diversely substituted products have been obtained in moderate to very good yields.

Full text of DOI:10.1021/ol403414v

Letter
pubs.acs.org/OrgLett
Transition-Metal-Free Synthesis of Benzimidazoles Mediated by
KOH/DMSO
Hannah Baars, Astrid Beyer, Stefanie V. Kohlhepp, and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, D-52074 Aachen, Germany
S
* Supporting Information
ABSTRACT: Benzimidazoles are prepared by intramolecular
N-arylations of amidines mediated by potassium hydroxide in
DMSO at 120 °C. In this manner, diversely substituted
products have been obtained in moderate to very good yields.
ross-coupling reactions are important transformations in
organic synthesis, which are commonly catalyzed by
(Scheme 1 and Table 1, entry 1). To our delight, increasing the
reaction temperature had a positive effect on the cyclization
C
metals such as Pd, Cu, Fe, or Ni.1 Recently, we reported
analogous C−N, C−O, C−S, and C−C bond-forming
processes that occurred in the absence of transition metals.2,3
In general, such protocols are of great synthetic interest because
they allow trace-metal impurities to be avoided in the final
products.
Table 1. Optimization of the Reaction Conditions
Benzimidazoles can reveal important bioactivities,4 and
several strategies for their synthesis have been developed.
Commonly, they are prepared from 1,2-diaminoarenes by
condensations with carboxylic acids under harsh dehydrating
conditions5 or oxidative couplings with aldehydes.6 Under
milder reaction conditions benzimidazoles can be accessed
from amidines by metal-catalyzed intramolecular C−N cross-
couplings.7 Considering our previous findings,2 we hypothe-
sized that the latter transformations could also be promoted by
a strong base under transition metal-free conditions.8 Here, we
report on the realization of this concept.
a
temp time yield
entry
X
1
base (equiv)
solvent
(°C)
(h)
(%)
1
I
ba KOH (2.0)
ba KOH (2.0)
ba KOH (2.0)
ba KOH (2.0)
bb KOH (2.0)
bc KOH (2.0)
bd KOH (2.0)
bb KOH (2.0)
bb KOH (2.0)
bb KOH (1.0)
bb KOH (2.0)
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
toluene
60
80
24
24
24
24
24
24
24
16
2
9
2
I
61
82
89
96
67
97
93
86
70
96
s.m.
3
I
100
120
120
120
120
120
120
120
120
120
4
I
5
Br
Cl
F
6
7
8
Br
Br
Br
Br
Br
9
At the outset, amidine 1aa with a free NH2 group was chosen
as substrate, and we attempted to cyclize it in the superbasic
medium consisting of KOH and DMSO (Scheme 1).9−11
10
11
12
16
16
24
b
bb K2CO3 (2.0)/
DMEDA (0.1)
13
Br
bb K2CO3 (2.0)/
MeCN
120
24
s.m.
Scheme 1. First Attempts for the Intramolecular N-Arylation
of Amidines
DMEDA (0.1)
a
b
After column chromatography. Use of KOH with a purity of
>99.99%; s.m. = starting material.
(Table 1, entries 1−4), and performing the same trans-
formation at 120 °C led to 2b in 89% yield. The product
formation was also affected when the iodo substituent of 1ba
was changed to a bromo, chloro, or fluoro group (Table 1,
entries 5−7). While chloro-substituted 1bc gave 2b in a lower
yield (67%, Table 1, entry 6), bromo- and fluoro-substituted
amidines 1bb and 1bd performed better leading to 2b in 96%
Unfortunately, however, no conversion of 1aa was observed, at
40 °C or 100 °C after 24 h. Assuming that the nucleophilicity
of the resulting anion was too low for the cyclization to occur,
N-phenyl-substituted amidine 1ba was subjected to the KOH/
DMSO mixture next. As expected, 1ba showed a higher
reactivity, affording benzimidazole 2b in 9% yield at 60 °C
Received: November 25, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol403414v | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Scope of the Intramolecular N-Arylation for the Synthesis of Benzimidazoles
a
After column chromatography.
and 97% yield, respectively. These observations are important
with respect to the mechanism (see discussion below) because
the results are inconsistent with a typical nucleophilic
substitution reaction where the leaving group ability of the
halide commonly shows a clear trend (F > Cl > Br > I).12
Further optimization studies revealed that the reaction time
could be shortened from 24 to 16 h and even 2 h providing
product 2b in 93% and 86%, respectively (Table 1, entries 8
and 9). The use of 2 equiv of KOH was crucial for complete
conversion. When only 1 equiv was used, the product yield was
lower (70%, Table 1, entry 10). To ensure that the base quality
did not affect the cyclization yield, the commonly used KOH
providing indazoles,2e this protocol was applied here using
1bb as starting material. Unfortunately, no conversion
occurred, and the attempt was unsuccessful in both toluene
and acetonitrile (Table 1, entries 12 and 13).
Next, the substrate scope was investigated (Table 2). Varying
the substituent on the amidine nitrogen had a significant effect
on the product yield. While benzyl-substituted 1c gave
benzimidazole 2c in only 28% yield (Table 2, entry 1), p-
methoxyphenyl-bearing 1d cyclized well to provide 2d in 89%
yield (Table 2, entry 2). Reactions of alkyl-substituted amidines
1e and 1f proved to be less efficient leading to the
corresponding products 2e and 2f in 73% and 65% yield,
respectively (Table 2, entries 3 and 4). Using amidine with
electron-donating substituents on the arene core afforded
benzimidazoles in high yields (Table 2, entries 5 and 6). The
presence of an additional halo substituent slightly decreased the
amidine conversion giving products with yields ranging from
58% to 83% (Table 2, entries 7−13). The moderate yield of 2m
(Grussing, 85%) was substituted by a sample with a purity of
̈
>99.99% (from Acros Organics). Also in this case, the yield of
2b was 96% (Table 1, entry 11) indicating that this factor was
irrelevant here.
Finally, as we have recently found a mild cyclization of N-
tosyl hydrazones upon treatment with K2CO3/DMEDA
B
dx.doi.org/10.1021/ol403414v | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(58%, Table 2, entry 11) might be due to side reactions taking
place at the iodo-substituted sites of both substrate 1m and
product 2m. The steric hindrance induced by the o-chloro
group of amidine 1o can be responsible for the relatively low
yield of 2o (69%, Table 2, entry 13).
bearing 1w the fluoro group was substituted. In Br/Cl-
containing 1x the bromo moiety served as leaving group.
From these data a reactivity order of F > I > Br > Cl can be
deduced.
To evaluate if the reaction proceeded via an aryne
intermediate as proposed by Xiang, Wang, and co-workers,8
two substrates with halo substituents in the meta-position were
examined (Scheme 4). For both fluoro-substituted compound
Finally, R2 of the amidine was varied from methyl and
cycloalkyl to aryl. In general, those substrates (1p−u) cyclized
well, providing the corresponding benzimidazoles in high yields
(Table 2, entries 14−19). Three points are noteworthy in the
context: First, steric bulk did not significantly affect the reaction
as revealed by the high yield in the formation of 2r (Table 2,
entry 16). Second, for unknown reasons, halo-substituted
amidines 1s and 1t gave the corresponding products in only
36% and 27% yield, respectively (Table 2, entries 17 and 18).
Third, also hetaryl 1u cyclized well to provide thiophenyl-
substituted benzimidazole in remarkable 91% yield (Table 2,
entry 19).
Scheme 4. Control Experiment: Aryne Mechanism
To gain a deeper mechanistic understanding, inter- and
intramolecular competition experiments were performed. Using
a mixture of halo-substituted amidines 1ba-bd in “one pot”
(Scheme 2) confirmed the aforementioned observation that the
1y and bromo-bearing amidine 1z no conversion was observed,
which makes an aryne mechanism in these cases unlikely. The
result with dihalo-substituted amidine 1o can be interpreted in
the same manner. There, cyclization to give 2o occurred
although aryne formation can be excluded (Table 2, entry 13).
Taking all results into account, we consider an SRN1
mechanism and the involvement of short living radicals as
most likely for the iodo-containing aryl halides.3d,14,15 In
contrast, the fluoro-, bromo-, and chloro-substituted com-
pounds seem to react through a typical SNAr mechanism.
In summary, a new protocol for the synthesis of
benzimidazoles starting from amidines has been developed.
The cyclization is mediated by KOH in DMSO at 120 °C.
Various functional groups are tolerated giving access to a wide
range of substituted benzimidazoles.
Scheme 2. Intermolecular Competition Experiments
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, full characterization of new products,
and copies of NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
reactivity order was inconsistent with a typical SNAr
mechanism.13 While iodo- and fluoro-substituted amidines
1ba and 1bd showed the same level of conversion, bromo-
substituted amidine 1bb reacted surprisingly slow under these
conditions, and its conversion was even lower than that of
chloro-substituted 1bc.
■
S
Intramolecular competition experiments were performed
with substrates 1v−x having two different halo groups in the
ortho-positions of the reacting moiety (Scheme 3). Interest-
ingly, in all three cases high product ratios were observed (as
determined by GC−MS). In both F/I-substituted 1v and F/Br-
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: carsten.bolm@oc.rwth-aachen.de.
Notes
The authors declare no competing financial interest.
Scheme 3. Intramolecular Competition Experiments
ACKNOWLEDGMENTS
■
We thank Lena Henkel (RWTH Aachen University) for various
synthetic contributions. H.B. acknowledges support by the
Deutsche Forschungsgemeinschaft through the International
Research Training Group Seleca (IGRK 1628).
REFERENCES
■
(1) Metal-Catalyzed Cross-Coupling Reactions, 2nd. ed.; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, 2004.
́
(2) (a) 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. (b) Beyer, A.; Reucher, C. M. M.; Bolm, C. Org. Lett.
2011, 13, 2876. (c) Thome,
(d) Beyer, A.; Buendia, J.; Bolm, C. Org. Lett. 2012, 14, 3948.
(e) Thome, I.; Besson, C.; Kleine, T.; Bolm, C. Angew. Chem., Int. Ed.
2013, 52, 7509.
́
I.; Bolm, C. Org. Lett. 2012, 14, 1892.
́
C
dx.doi.org/10.1021/ol403414v | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(3) For additional stimulating examples, see: (a) Yanagisawa, S.;
Ueda, K.; Taniguchi, T.; Itami, K. Org. Lett. 2008, 10, 4673. (b) Sun,
C. L.; Li, H.; Yu, D.-G.; Yu, M.; Zhou, X.; Lu, X.-Y.; Huang, K.; Zheng,
Z.-B.; Shi, J. Nat. Chem. 2010, 2, 1044. (c) Yanagisawa, T.; Itami, K.
ChemCatChem. 2011, 3, 827. (d) Studer, A.; Curran, D. P. Angew.
Chem., Int. Ed. 2011, 50, 5018. (e) Shirakawa, E.; Hayashi, T. Chem.
Kranz, M.; Tuttle, T.; Murphy, J. A. Chem. Sci. 2013, DOI: 10.1039/
C3SC52315B.
Lett. 2012, 41, 130. (f) Buden
Lett. 2013, 15, 1174.
́
, M. E.; Guastvino, J. F.; Rossi, R. A. Org.
(4) (a) Alamgir, M.; Black, D. S. C.; Kumar, N. Top. Heterocycl. Chem.
2007, 9, 87. (b) Bansal, Y.; Silakari, O. Bioorg. Med. Chem. 2012, 20,
6208. (c) Narasimhan, B.; Sharma, D.; Kumar, P. Med. Chem. Res.
2012, 21, 269. (d) Shah, K.; Chhabra, S.; Shrivastava, S. K.; Mishra, P.
Med. Chem. Res. 2013, 22, 5077.
(5) For selected examples, see: (a) Preston, P. N. In The Chemistry of
Heterocyclic Compounds; Weissberger, A., Taylor, E. C., Eds.; John
Wiley & Sons: New York, 1981; Vol. 40: Benzimidazoles and
Cogeneric Tricyclic Compounds p 6. (b) Lin, S.-Y.; Isome, Y.; Stewart,
E.; Liu, J.-F.; Yohannes, D.; Yu, L. Tetrahedron Lett. 2006, 47, 2883.
(6) For selected examples, see: (a) Chari, M. A.; Shobha, D.; Sasaki,
T. Tetrahedron Lett. 2011, 52, 5575. (b) Bahrami, K.; Khodaei, M. M.;
Naali, F. Synlett 2009, 569. (c) Sharghi, H.; Aberi, M.; Doroodmand,
M. M. Adv. Synth. Catal. 2008, 350, 2380.
(7) (a) Zheng, N.; Anderson, K. W.; Huang, X.; Nguyen, H. N.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46, 7509. (b) Zou, B.;
Yuan, Q.; Ma, D. Angew. Chem., Int. Ed. 2007, 46, 2598. (c) Evindar,
G.; Batey, R. A. Org. Lett. 2003, 5, 133. (d) Brain, C. T.; Brunton, S. A.
Tetrahedron Lett. 2002, 43, 1893. (e) Brain, C. T.; Steer, J. T. J. Org.
Chem. 2003, 68, 6814. (f) Peng, J.; Ye, M.; Zong, C.; Hu, F.; Feng, L.;
Wang, X.; Wang, Y.; Chen, C. J. Org. Chem. 2011, 76, 716. (g) Brasche,
G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 1932. (h) Xiao,
Q.; Wang, W.; Liu, G.; Meng, F.; Chen, J.; Yang, Z.; Shi, Z. Chem.
Eur. J. 2009, 15, 7292. (i) Wray, B. C.; Stambuli, J. P. Org. Lett. 2010,
12, 4576. (j) Deng, X.; Mani, N. S. Eur. J. Org. Chem. 2010, 680.
(k) Saha, P.; Ramana, T.; Purkait, N.; Ali, M. A.; Paul, R.;
Punniyamurthy, T. J. Org. Chem. 2009, 74, 8719. (l) Sadig, J. E. R.;
Foster, R.; Wakenhut, F.; Willis, M. C. J. Org. Chem. 2012, 77, 9473.
(8) During our studies, a potassium tert-butoxide-promoted
benzimidazole synthesis starting from 2-iodoanilines and nitriles was
reported. See: Xiang, S.-K.; Tan, W.; Zhang, D.-X.; Tian, X.-L.; Feng,
C.; Wang, B.-Q.; Zhao, K.-Q.; Hu, P.; Yang, H. Org. Biomol. Chem.
2013, 11, 7271.
(9) For a review on KOH/DMSO mixtures as “superbases”, see:
Trofimov, B. A. Sulfur Rep. 1992, 74, 207.
(10) For selected recent synthetic applications of the KOH/DMSO
́
system, see: (a) Cano, R.; Ramon, D. J.; Yus, M. J. Org. Chem. 2011,
76, 654. (b) Fang, Y.; Zheng, Y.; Wang, Z. Eur. J. Org. Chem. 2012,
1495. (c) Joshi, M.; Patel, M.; Tiwari, R.; Verma, A. K. J. Org. Chem.
2012, 77, 5633.
(11) 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
metal impurities affecting 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. (d) Thome,
2012, 41, 979.
́
I.; Nijs, A.; Bolm, C. Chem. Soc. Rev.
(12) For a review, see: Bunnett, J. F.; Zahler, R. E. Chem. Rev. 1951,
49, 273.
(13) Similar observations were made in KOH/DMSO-mediated
formations of benzimidazol-2-ones (ref 3a).
(14) For nucleophilic substitution reactions involving electron
transfer, see: (a) Bunnett, J. F. Acc. Chem. Res. 1978, 11, 413.
(b) Rossi, R. A.; Pierini, A. B.; Penenory, A. B. Chem. Rev. 2003, 103,
́
̃ ̃
71.
(15) For an electron-transfer reaction initiated by KO-t-Bu, see:
Zhou, S.; Anderson, G. M.; Mondal, B.; Doni, E.; Ironmonger, V.;
D
dx.doi.org/10.1021/ol403414v | Org. Lett. XXXX, XXX, XXX−XXX