Oxidative condensations to form benzimidazole-substituted potassium organotrifluoroborates

Article abstract of DOI:10.1021/ol301956p

A library of benzimidazole-substituted potassium organotrifluoroborates was prepared via the condensation of various potassium formyl-substituted aryl- and heteroaryltrifluoroborates with aromatic 1,2-diamines under oxidative conditions. The efficient Suzuki-Miyaura cross-coupling of products thus formed to various aryl and heteroaryl bromides was achieved in good yields. The method allows the facile preparation of benzimidazole-containing triaromatic products in two steps from simple potassium formyl substituted aryl- or heteroaryltrifluoroborates.

Full text of DOI:10.1021/ol301956p

ORGANIC
LETTERS
2012
Vol. 14, No. 16
4242–4245
Oxidative Condensations To Form
Benzimidazole-Substituted Potassium
Organotrifluoroborates
Gary A. Molander* and Kehinde Ajayi
Roy and Diana Vagelos Laboratories, Department of Chemistry, University
of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States
gmolandr@sas.upenn.edu
Received July 14, 2012
ABSTRACT
A library of benzimidazole-substituted potassium organotrifluoroborates was prepared via the condensation of various potassium formyl-
substituted aryl- and heteroaryltrifluoroborates with aromatic 1,2-diamines under oxidative conditions. The efficient SuzukiÀMiyaura cross-
coupling of products thus formed to various aryl and heteroaryl bromides was achieved in good yields. The method allows the facile preparation of
benzimidazole-containing triaromatic products in two steps from simple potassium formyl substituted aryl- or heteroaryltrifluoroborates.
Over the past several decades, organoboron compounds
have proven to be supremely useful synthetic intermediates
for a wide variety of chemical processes. Boronic acids and
esters, in particular, are well suited for the formation of
carbonÀcarbon bonds.1 However, traditional organoboron
compounds suffer from various vulnerabilities that place
real limits on their strategic usefulness for the construc-
tion of complex molecules.2 Organotrifluoroborates
have emerged as robust boronic acid surrogates that do
not suffer from many of those vulnerabilities.3 We there-
fore envision organotrifluoroborates continuing to be of
service in enabling the synthesis of much more complex
organoboron compounds for use in medicinal chemistry,
total synthesis, and organic materials discovery.
materials science. Benzimidazoles, in particular, have been
identified as one of a handful of “privileged scaffolds”4
found in a variety of natural and pharmaceutical
products.5 Employing privileged scaffolds in combinator-
ial syntheses would presumably maximize positive screen-
ing results for the resulting libraries. We have previously
demonstrated the usefulness of the trifluoroborate group
for synthesizing substituted triazole3b and oxazoline3e
heterocycles. The robustness of the trifluoroborate group
(4) (a) Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Curr. Opin.
Chem. Biol. 2010, 14, 1–15. (b) DeSimone, R. W.; Currie, K. S.; Mitchell,
S. A.; Darrow, J. W.; Pippin, D. A. Comb. Chem. High Throughput
Screening 2004, 7, 473–493.
(5) Biologically active 2-aryl-(1H)-benzimidazoles: (a) Wang, P.;
Zheng, G.-j.; Wang, Y.-p.; Wei, H.-g.; Xiang, W.-s. Tetrahedron 2012,
68, 2509–2512. (b) Dasari, M.; Lee, S.; Sy, J.; Kim, D.; Lee, S.; Brown,
M.; Davis, M.; Murthy, N. Org. Lett. 2010, 12, 3300–3303. (c) Simard,
J. R.; Grutter, C.; Pawar, V.; Aust, B.; Wolf, A.; Rabiller, M.; Wulfert,
S.; Robubi, A.; Kluter, S.; Ottmann, C.; Rauh, D. J. Am. Chem. Soc.
2009, 131, 18478–18488. (d) RodriguezÀRodriguez, C.; Sanchez de
Groot, N.; Rimola, A.; Alvarez-Larena, A.; Lloveras, V.; Vidal-Gancedo,
J.; Ventura, S.; Vendrell, J.; Sodupe, M.; Gonzalez-Duarte, P. J. Am.
Chem. Soc. 2009, 131, 1436–1451. (e) Charton, J.; Girault-Mizzi, S.;
Debreu-Fontaine, M.-A.; Foufelle, F.; Hainault, I.; Bizot-Espiard,
J.-G.; Caignard, D.-H.; Sergheraert, C. Bioorg. Med. Chem. 2006, 14,
4490–4518. (f) Ismail, M. A.; Batista-Parra, A.; Miao, Y.; Wilson, W. D.;
Wenzler, T.; Brun, R.; Boykin, D. W. Bioorg. Med. Chem. 2005, 13, 6718–
6726. (g) Goker, H.; Boykin, D. W.; Yildiz, S. Bioorg. Med. Chem. 2005,
13, 1707–1714. (h) Katz, B. A.; Spencer, J. R.; Elrod, K.; Luong, C.;
Mackman, R. L.; Rice, M.; Sprengeler, P. A.; Allen, D.; Janc, J. J. Am.
Chem. Soc. 2002, 124, 11657–11668.
Heterocycles are among the most important subtypes
of organic molecules in the realm of both biomedical and
(1) Recent reviews: (a) Suzuki, A. Angew. Chem., Int. Ed. 2011, 50,
6722–6737. (b) Wu, X.-F.; Anbarasan, P.; Neumann, H.; Beller, M.
Angew. Chem., Int. Ed. 2010, 49, 9047–9050.
(2) Hall, D. G., Ed. Boronic Acids; Wiley-VCH Verlag GmbH & Co,
KGaA: Weinheim, Baden-W€urttemberg, 2005; Chapter 1, pp 1À85.
(3) (a) Molander, G. A.; Ham, J. Org. Lett. 2006, 8, 2767–2770.
(b) Molander, G. A.; Ellis, N. Acc. Chem. Res. 2007, 40, 275–286.
(c) Molander, G. A.; Cooper, D. J. J. Org. Chem. 2007, 72, 3558–3560.
(d) Molander, G. A.; Cooper, D. J. J. Org. Chem. 2008, 73, 3885–3891.
(e) Molander, G. A.; Febo-Ayala, W.; Jean-Gerard, L. Org. Lett. 2009,
11, 3830–3833. (f) Kim, D.-S.; Ham, J. Org. Lett. 2010, 12, 1092–1095.
(g) Bolla, K.; Kim, T.; Song, J. H.; Lee, S.; Ham, J. Tetrahedron 2011, 67,
5556–5563.
r
10.1021/ol301956p
Published on Web 08/08/2012
2012 American Chemical Society

was anticipated to render it suitable for the rapid synthesis
of a diverse library of 2-substituted benzimidazoles.
Though many modern methods exist for the synthesis of
benzimidazoles,6 we elected to initiate these studies with a
method that allows maximal availability and variability in
the starting materials. Benzimidazoles substituted at the
2-position are typically constructed by condensation of
aryl 1,2-diamines with either aldehydes in the presence of
an oxidant (eq 1) or carboxylic acids in the presence of an
acid. We elected to use aldehydes as our starting materials
because of the greater variety of commercially available
derivatives. A mechanistic study showedthat the oxidant is
essential for an efficient reaction; in the absence of oxidant,
a competing redox process results in the formation of 1,2-
disubstituted derivatives.7 Furthermore, for our particular
study, the formation of 1,2-disubstituted benzimidazole 3
would prevent isolation of the desired 1H-benzimidazole
2a, as organotrifluoroborates are not easily separatedfrom
one another (eq 1). Therefore, it was imperative to find an
effective oxidant for the process that would tolerate the
trifluoroborate group.
Table 1. Oxidative Condensation of Formyl-Substituted
Potassium Aryl and Heteroaryltrifluoroborates with
3,4-Toluenediamine
Toward that end, we began our investigation by surveying
the literature for oxidants known to promote the desired
condensation. All of the commonly utilized oxidants, in-
cluding I2,8a CAN,8b 1,4-benzoquinone,8c PhI(OAc)2,8d and
FeCl3,8e failed to yield any of the desired trifluoroborate 2a,
with the protodeboronated benzimidazole 4 being the
major product. Use of bisulfite reagents9 gave a low
yield of the desired product after prolonged heating.
We eventually found that the best results came with the
use of molecular oxygen as an oxidant. Catalysis with
aqueous KHF2 allowed the reaction to be completed
at a reduced temperature, which seemed to be necessary
for preservation of the CÀB bond. The choice of solvent
turned out to be crucial for success; a 1:1 EtOH/CH3CN
solvent mixture provided the optimal environment.
An increase in the solvent ratio caused an unacceptable
increase in the rate of protodeboronation, while a
decrease in the ratio greatly retarded the reaction,
necessitating higher temperatures and reducing the
yield.
(6) Modern benzimidazole syntheses: (a) Brasche, G.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2008, 47, 1932–1934. (b) Chen, Y.-X.;
Qian, L.-F.; Zhang, W.; Han, B. Angew. Chem., Int. Ed. 2008, 47, 9330–
9333. (c) Shen, M.; Driver, T. G. Org. Lett. 2008, 10, 3367–3370.
(d) Sharghi, H.; Aberi, M.; Doroodmand, M. M. Adv. Synth. Catal.
2008, 350, 2380–2390. (e) Blacker, A. J.; Farah, M. M.; Hall, M. I.;
Marsden, S. P.; Saidi, O.; Williams, J. M. J. Org. Lett. 2009, 11, 2039–
2042. (f) Yamamoto, Y.; Mizuno, H.; Tsuritani, T.; Mase, T. J. Org.
Chem. 2009, 74, 1394–1396. (g) Deng, X.; McAllister, H.; Mani, N. S.
J. Org. Chem. 2009, 74, 5742–5745. (h) Diao, X.; Wang, Y.; Jiang, Y.;
Ma, D. J. Org. Chem. 2009, 74, 7974–7977. (i) Xiao, Q.; Wang, W.-H.;
Liu, G.; Meng, F.-K.; Chen, J.-H.; Yang, Z.; Shi, Z.-J. Chem.;Eur. J.
2009, 15, 7292–7296. (j) Shiraishi, Y.; Sugano, Y.; Tanaka, S.; Hirai, T.
Angew. Chem., Int. Ed. 2010, 49, 1656–1660. (k) Kim, Y.; Kumar, M. R.;
Park, N.; Heo, Y.; Lee, S. J. Org. Chem. 2011, 76, 9577–9583. (l) Fu, S.;
Jiang, H.; Deng, Y.; Zeng, W. Adv. Synth. Catal. 2011, 353, 2795–2804.
(7) Smith, J. G.; Ho, I. Tetrahedron Lett. 1971, 12, 3541–3544.
(8) (a) Lin, C.; Lai, P.-T.; Liao, S. K-S.; Hung, W.-T.; Yang, W.-B.;
Fang, J.-M. J. Org. Chem. 2008, 73, 3848–3853. (b) Bahrami, K.;
Khodaei, M. M.; Naali, F. J. Org. Chem. 2008, 73, 6835–6837.
(c) Henary, M. M.; Wu, Y.; Cody, J.; Sumalekshmy, S.; Li, J.; Mandal,
S.; Fahrni, C. J. J. Org. Chem. 2007, 72, 4784–4797. (d) Aakeroy, C. B.;
Fasulo, M.; Schultheiss, N.; Desper, J.; Moore, C. J. Am. Chem. Soc.
2007, 129, 13772–13773. (e) Singh, M. P.; Sasmal, S.; Lu, W.; Chatterjee,
M. N. Synthesis 2000, 1380–1390.
(9) (a) Ridley, H. F.; Spickett, R. G. W.; Timmis, G. M. J. Hetero-
cycl. Chem. 1965, 2, 453–456. (b) Arienti, K. L.; Brumark, A.; Axe, F. U.;
McClure, K.; Lee, A.; Blevitt, J.; Neff, D. K.; Huang, L.; Crawford, S.;
Pandit, C. R.; Karlsson, L.; Breitenbucher, J. G. J. Med. Chem. 2005, 48,
1873–1885.
Org. Lett., Vol. 14, No. 16, 2012
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Table 2. Oxidative Condensation of Potassium 4-Formyl Phe-
nyltrifluoroborate with Functionalized 1,2-Diaminobenzenes
Table 3. Cross-Couplings of Aryl and Heteroaryl Bromides
with Benzimidazole-Substituted Aryl and
Heteroaryltrifluoroborates
are increased in all such cases relative to 3,4-diaminoto-
luene (entry 1). Mildly deactivated diamines, such as those
with halide substituents, react fully within 24 h (entries 2, 3,
and 4), while the phenylcarbonyl-substituted diamine
completely reacts only after 36 h at 60 °C (entry 6). The
nitro-substituted diamine does not react fully under the
reaction conditions, even after 96 h (entry 5). The reaction
with 4-methoxy-1,2-diaminobenzene goes to completion
after 7 h, but oxidative side reactions with the diamine
lowered the yield considerably (entry 7).
To prepare benzimidazole derivatives for SuzukiÀ
Miyaura cross-couplings, boronates are usually incorpo-
rated by electrophilic borylation with a trialkyl borate,10
or by metal-catalyzed borylation with a diboron reagent.11
Both methods suffer from functional group tolerance
issues, limiting the complexity that can be incorporated.
The method shown herein is unique in that it obviates
the need for such subsequent functionalization, allowing a
more convergent synthesis.
a Yield determined by 1H NMR.
With the development of optimal conditions for oxidative
condensation, we then examined the effect of substitutions
on the aldehyde moiety. The results of those studies are
shown in Table 1. Electron-neutral (entries 1 and 2) and
electron-poor (entries 3, 4, and 7) benzaldehyde derivatives
performed well under the reaction conditions, as well as
some heterocyclic aldehydes (entries 5 and 6). On the other
hand, electron-rich aldehydes proved too reactive under
the reaction conditions to prevent formation of 1,2-disub-
stituted benzimidazoles, even at temperatures as low as
À20 °C. In addition, the reaction is somewhat sensitive to
the amount of oxygen introduced; too much oxygen
oxidizes the trifluoroborate group to an alcohol under
thereactionconditions, oftengiving phenolic side products
in up to 15% yields by 1H NMR. The phenol derivatives,
when formed, could not be separated from the desired
benzimidazoles in most cases, presumably because of the
unexpectedly high degree of similarity in physical proper-
ties. A protocol that involves bubbling O2 into the reaction
mixture for 20 s before stirring under positive O2 pressure
gave the optimal results.
The benzimidazole-containing trifluoroborates so ob-
tained were then subjected to cross-coupling condi-
tions. Using a modified version of the conditions that
were previously developed for the cross-coupling of
(10) Blatch, A. J.; Chetina, O. V.; Howard, J. A. K.; Patrick, L. G. F.;
Smethurst, C. A.; Whiting, A. Org. Biomol. Chem. 2006, 4, 3297–
3302.
(11) Wu, C.-H.; Chien, C.-H.; Hsu, F.-M.; Shih, P.-I.; Shu, C.-F.
J. Mater. Chem. 2009, 19, 1464–1470.
We then examined the effect of substitutions on the aro-
matic diamine moiety (Table 2). Electron-poor diamines
successfully couple to aldehydes, though the reaction times
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Org. Lett., Vol. 14, No. 16, 2012

with organic halides (Table 3). Electron-rich aryl (entries 1
and 3), electron-poor aryl (entries 2 and 4), and heteroaryl
halides (entries 3 and 6) underwent cross-coupling in good
to excellent yields.
Table 4. Sequential Oxidative Condensation/Cross-Coupling of
Formyl-Substituted Potassium Aryl- and Heteroaryltrifluoroborates
Finally, we thought it would be advantageous to be able
to carry out the oxidative condensation and the cross-
coupling reactions without having to isolate any inter-
mediates, especially in cases where an analytically pure
intermediate is difficult to obtain. The described sequence
is shown in Table 4. Operationally, after the oxidative
condensation was carried out to generate the benzimida-
zole, the crude reaction mixture was concentrated and
triturated with Et2O to remove most of the organic by-
products. The cross-coupling was then effected directly
on the crude organotrifluoroborate by the addition of the
aryl halide and catalyst system. In this manner, one can
quicklyobtainpharmaceuticallyrelevant,5 elaboratedben-
zimidazoles from electron-rich aromatic aldehydes (entries
1, 2, and 6) and heteroaryl aldehydes (entries 3À6) in good
overall yields.
In conclusion, a series of 2-substituted potassium (1H)-
benzimidazoletrifluoroborates were prepared by conden-
sation of the corresponding aldehyde with aromatic 1,2-
diamines under oxidative conditions. When followed with
functionalization methods such as SuzukiÀMiyaura cou-
pling, the power of the trifluoroborate group in enabling
the synthesis of libraries of complex molecules is particu-
larly evident.
Acknowledgment. We acknowledge Lauren Kennedy
(University of Pennsylvania) for the preparation of
some starting materials. Dr. Rakesh Kohli (University
of Pennsylvania) is acknowledged for obtaining HRMS
data. We thank Frontier Scientific for providing the
boronic acids that were utilized to prepare the organotri-
fluoroborates, and we are grateful to Johnson-Matthey
for providing the palladium catalysts. This work was
supported by the NIH (R01 GM081376), to whom we
are also grateful.
heteroaryltrifluoroborates with heteroaryl halides,12 we
were able to couple unprotected benzimidazole derivatives
Supporting Information Available. Experimental pro-
cedures and spectroscopic data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(12) Molander, G. A.; Canturk, B.; Kennedy, L. E. J. Org. Chem.
2009, 74, 973–980.
The authors declare no competing financial interest.
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