Synthesis of Benzimidazole-Substituted Arylboronic Acids via Aerobic Oxidation of 1,2-Arylenediamines and Formyl-Substituted Aryl MIDA Boronates using Potassium Iodide as a Catalyst

Article abstract of DOI:10.1002/adsc.201500302

A highly efficient protocol for the synthesis of benzimidazole-substituted arylboronic acids was developed via aerobic oxidative cyclization of 1,2-aryldiamines and formyl-substituted aryl MIDA (N-methyliminodiacetic acid) boronates using potassium iodide as a nucleophilic catalyst. Furthermore, a one-pot protocol for the synthesis of benzimidazole-substituted arylboronic acids from 1,2-phenylenediamines and formyl-substituted arylboronic acids was developed without the isolation of any intermediates. The resulting boronic acids were further subjected to Suzuki-Miyaura coupling reactions without isolation, leading to diaryl-substituted benzimidazoles with only one separation step.

Full text of DOI:10.1002/adsc.201500302

UPDATES
DOI: 10.1002/adsc.201500302
Synthesis of Benzimidazole-Substituted Arylboronic Acids via
Aerobic Oxidation of 1,2-Arylenediamines and Formyl-Substitut-
ed Aryl MIDA Boronates using Potassium Iodide as a Catalyst
Ye-Sol Leea and Cheol-Hong Cheona,*
a
Department of Chemistry, Korea University, 145 Anam-ro, Seongbuk-gu, Seoul 136701, Republic of Korea
Fax: (+82)-2-3290-3121; phone: (+82)-2-3290-3147; e-mail: cheon@korea.ac.kr
Received: March 27, 2015; Revised: June 3, 2015; Published online: September 10, 2015
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500302.
Abstract: A highly efficient protocol for the synthe-
sis of benzimidazole-substituted arylboronic acids
was developed via aerobic oxidative cyclization of
1,2-aryldiamines and formyl-substituted aryl MIDA
(N-methyliminodiacetic acid) boronates using po-
tassium iodide as a nucleophilic catalyst. Further-
more, a one-pot protocol for the synthesis of benz-
imidazole-substituted arylboronic acids from 1,2-
phenylenediamines and formyl-substituted arylbor-
onic acids was developed without the isolation of
any intermediates. The resulting boronic acids were
further subjected to Suzuki–Miyaura coupling reac-
tions without isolation, leading to diaryl-substituted
benzimidazoles with only one separation step.
Keywords: aerobic oxidative cyclization; benzimida-
zole-substituted boronic acids; iodides; N-methyli-
minodiacetic acid (MIDA); MIDA boronates;
Suzuki–Miyaura coupling reaction
Figure 1. Selected therapeutically active agents and impor-
tant compounds in materials science that contain 2-arylben-
zimidazole moieties. In previous syntheses of these com-
pounds, benzimidazole-substituted arylboronic acids 3 were
utilized as key intermediates.[2,3]
Benzimidazole is considered to be an important scaf- the resulting materials,[4] it is highly beneficial to be
fold that is found in a variety of biologically and ther- able to rapidly synthesize a variety of benzimidazole
apeutically important natural and pharmaceutical derivatives from key intermediates. Among the vari-
products.[1] For example, various 2-arylbenzimidazoles ous intermediates used in the diverse syntheses of de-
carrying substituents at either the meta- or para-posi- rivatives derived from benzimidazoles, benzimidazole-
tion of the aryl group have been extensively investi- substituted arylboronic acids 3 are often utilized as
gated as potential candidates for antagonists and/or key intermediates in the reported syntheses of the
inhibitors in several pharmaceutical applications.[2] In compounds shown in Figure 1.[2,3]
addition, benzimidazole moieties are frequently used
Conventionally, boronic acids 3 are prepared via
in materials science, particularly in organic light-emit- the subsequent incorporation of a boronic acid func-
ting diodes (OLEDs), as acceptor units in novel push- tionality from the corresponding halides in pre-gener-
pull fluorescent materials and/or as precursors for ated benzimidazole scaffolds by either electrophilic
novel monoanionic cyclometalating ligands in iridium borylation of trialkyl boronates or metal-catalyzed
complexes (Figure 1).[3]
borylation with a diboron reagent (Scheme 1a).[2,3]
To maximize positive screening results for libraries However, these methods generally display poor func-
of compounds bearing benzimidazole scaffolds and/or tional group tolerance and often require multi-step
fully investigate the structure-property relationship of synthetic sequences. On the other hand, direct cou-
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Ye-Sol Lee and Cheol-Hong Cheon
sis of 3 through direct oxidative condensation of 1,2-
arylenediamines and formyl-substituted aryl MIDA
boronates[6,7,8] under aerobic oxidation conditions
using KI as a nucleophilic catalyst[9] (Scheme 1c). A
one-pot protocol for the synthesis of 3 was further de-
veloped from 1,2-arylenediamines with formylarylbor-
onic acids without isolation of the MIDA boronates.
Furthermore, a sequential one-pot protocol for aero-
bic oxidative cyclization followed by a Suzuki–
Miyaura coupling reaction of the resulting MIDA bor-
onates was developed, which allows us to prepare
benzimidazole-containing triaromatic products with-
out the isolation of any intermediates.
Since the Molander group reported that even tri-
fluoroborate is not completely stable under their oxi-
dative condensation conditions and observed the for-
mation of 2-arylbenzimidazoles via protodeborona-
tion of a trifluoroborate moiety,[5] our initial concern
was the vulnerability of a boronic acid functionality
under oxidative cyclization conditions.[10] In order to
overcome the vulnerability of a boronic acid function-
ality under oxidative cyclization conditions, we
needed to develop even milder reaction conditions
for this transformation than those[5] developed by the
Molander group.
Very recently, our group developed a new protocol
for the synthesis of benzimidazoles from 1,2-arylene-
diamines and aldehydes via aerobic oxidative cycliza-
tion in wet organic solvents in an open flask without
the aid of any metal catalysts/additives.[9] Considering
the mildness of those reaction conditions (i.e., no
metals, no additives, and in an open flask), we envis-
aged that this protocol might be applicable to the syn-
thesis of 3 by direct oxidative cyclization from 1,2-ar-
yldiamines with aldehydes bearing boronic acid moi-
eties without any side-reactions, such as protodeboro-
nation of the boronic acid functionality.[10,11]
Scheme 1. (a) Conventional synthetic routes for 3. (b) Previ-
ous example of direct coupling protocol for the synthesis of
benzimiazole-substituted trifluoroborates (3-BF3K).[5] (c)
One-pot protocol for 3 (this work).
With this expectation, 1,2-phenylenediamine 1a and
pling of 1,2-aryldiamines with an aldehyde carrying 4-formylphenylboronic acid 2a were subjected to
a boronic acid functionality is an attractive alternative aerobic oxidation conditions for the synthesis of the
to conventional methods for the synthesis of 3. How- benzimidazoles[9] developed by our group (Table 1).
ever, there has been only one example of the synthe- However, the expected boronic acid 3a was not ob-
sis of 3 via direct oxidative condensation of 1,2-ary- tained; instead, benzodiazaborole 4 was exclusively
lenediamines and aldehydes bearing boronic acid formed via reaction of 1a with the boronic acid
functionalities; the Molander group reported the syn- moiety in 2a rather than the aldehyde functionality
thesis of benzimidazole-substituted potassium trifluor- (entry 1). This result implies that the ortho-aryldia-
oborates via condensation of 1,2-aryldiamines with mine could react with either a boronic acid function-
formyl-substituted aryltrifluoroborates as boronic acid ality or an aldehyde functionality, and the reaction of
surrogates under an oxygen atmosphere in the pres- 1a toward the boronic acid functionality would be
ence of KHF2 as a catalyst (Scheme 1b).[5]
faster than that toward the aldehyde functionality.[12]
However, considering the importance and versatili- Thus, it was expected that boronic acid 3a could not
ty of 3 as intermediates in diverse syntheses of benz- be prepared under such conditions without impeding
imidazole derivatives, we strongly feel that the devel- the reaction of 1a toward the boronic acid functionali-
opment of a more general synthetic method for 3 via ty in 2a.
direct oxidative condensation between 1,2-aryldi-
Since a decrease in the Lewis acidity of the boron
amines and aldehydes carrying boronic acid function- atom in a boronic acid is generally known to enhance
alities is highly desired. Herein, we report the synthe- the stability of the boronic acid,[10] the corresponding
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Synthesis of Benzimidazole-Substituted Arylboronic Acids via Aerobic Oxidation
Table 1. Reaction of 1a with 2a under aerobic oxidative cyc-
lization conditions in wet DMF.
MIDA, while the hydrolyzed boronic acid 2a affords
4 via the reaction of 1a with the boronic acid func-
tionality in 2a. This result led us to conclude that the
formation of 4 is unavoidable in wet DMF even with
MIDA boronates 2, and a new aerobic oxidative cycli-
zation protocol should be developed under anhydrous
conditions.
During our previous study,[9] we found that iodide
could act as an efficient catalyst for the synthesis of
benzimidazoles in dry solvents, and developed a novel
protocol for the synthesis of benzimidazoles under an-
hydrous conditions via aerobic oxidative cyclization
using iodide as a nucleophilic catalyst.[9,13,14] Thus, we
decided to explore the possibility of the formation of
3a-MIDA from 1a with 2a-MIDA using KI as a nucle-
ophilic catalyst. When the reaction was performed in
the presence of a stoichiometric amount of KI under
anhydrous conditions, gratifyingly, aerobic oxidative
cyclization smoothly occurred to afford 3a-MIDA in
an excellent yield without the formation of 4. Further-
[a]
Yields were determined by 1H NMR analysis of the
crude mixture using CH3NO2 as an internal standard.
Isolated yields of 3a-MIDA and 4, respectively.
[b]
pinacol boronate 2a-pin was subjected to the aerobic more, a catalytic amount of iodide was sufficient to
oxidative cyclization conditions (entry 2). However, yield 3a-MIDA without any loss of its efficiency
even with 2a-pin, 4 was still exclusively obtained and (Scheme 3).
no formation of benzimidazole 3a-pin was observed.
With this result in hand, a one-pot protocol for the
Rehybridization of the boron center from sp2 to sp3 synthesis of 3a from boronic acid 2a with 1a was fur-
via complexation with a ligand is known to further de- ther developed. Here 2a-MIDA, prepared in situ from
crease the Lewis acidity of the boron atom, and thus 2a and MIDA by simple dehydration in the presence
increase the stability of the corresponding boronic of molecular sieves,[15] was subjected to KI-catalyzed
acid.[5,7,11] Accordingly, an sp3-hybridized MIDA (N- aerobic oxidative cyclization with 1a to generate 3a-
methyliminodiacetic acid) boronate 2a-MIDA was MIDA. Subsequent removal of the MIDA moiety
tested in this transformation. To our delight, the de-
sired benzimidazole, 3a-MIDA, was observed in 60%
yield along with 4 in a moderate yield (entry 3).
Although 2a-MIDA provides benzimidazole 3a-
MIDA, the concomitant formation of 4 was rather un-
expected because MIDA boronates are generally be-
lieved to be stable.[7,11] Thus, we further investigated
how 4 was generated from the reaction of 2a-MIDA
with 1a under aerobic oxidative cyclization conditions
in wet DMF. When 2a-MIDA was subjected to the re-
action conditions in wet DMF in the absence of 1a,
surprisingly, 2a-MIDA underwent partial hydrolysis to
generate the parent boronic acid 2a in a 30% yield
(Scheme 2). Under such circumstances, the reaction
of 1a with 2a-MIDA provides benzimidazole 3a- zation using KI as a nucleophilic catalyst
Scheme 3. Synthesis of 3a-MIDA via aerobic oxidative cycli-
Scheme 2. Rationale for the formation of 4 from 2a-MIDA.
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Table 2. Substrate scope.
Scheme 4. One-pot protocol for synthesis of 3a from 2a.
from 3a-MIDA under aqueous basic conditions[7] af-
forded the desired boronic acid 3a in an excellent
yield over three steps in the same flask without isola-
tion of any intermediates (Scheme 4).
Under these optimized reaction conditions, the sub-
strate scope of this transformation was investigated
(Table 2). First, the effect of a substituent on 1,2-phe-
nylenediamines 1 was explored (entries 1–5 and 6–
10). Substituents on 1 had little effect on the synthesis
of 3; 1 bearing either electron-donating or electron-
withdrawing substituents provided the desired prod-
ucts 3 in excellent yields regardless of the electronic
nature of the substituent.[16] Next, the effect of the po-
sition of the boronic acid moiety in the aldehydes 2
was investigated (entries 1, 6, and 11). The relative
position of the boronic acid moiety to the aldehyde
functionality influences this transformation. Benzalde-
hydes bearing the boronic acid moiety at the para-
and meta-positions provided the corresponding benz-
imidazoles 3 in high yields (entries 1 and 6), whereas
ortho-formylphenylboronic acid provided the desired
benzimidazole 3k in a moderate yield (entry 11).[17] N-
Substituted ortho-aryldiamines were also applicable
to this protocol. When N-phenyl-1,2-phenylenedi-
amine was subjected to the optimized reaction condi-
tions, the corresponding boronic acid 3n was obtained
in an excellent yield (entries 14). Furthermore, this
transformation could be performed on a gram scale
and the desired boronic acid 3a was obtained without
[a]
Isolated yield of 3.
Numbers in parentheses represent the isolated yields of
3-MIDA.
Isolated yield after oxidation of the boronic acid moiety
in 3k into a phenolic hydroxy group.
Boronic acids (3l and 3m) and their MIDA boronates are
unstable and decomposed during purification.
10 mmol scale reaction.
[b]
[c]
[d]
[e]
any loss of efficiency (entry 15). However, the exten- and cross-coupling reactions leading to benzimida-
sion of this one-pot protocol to the preparation of zole-bearing triaromatic products without isolating
benzimidazole-substituted heteroarylboronic acids any intermediates. When 2a-MIDA, prepared by con-
was not successful (entries 12 and 13). Although the densation of 2a with MIDA, was subjected to KI-cata-
formation of the corresponding boronic acids and the lyzed aerobic oxidative cyclization with N-phenyl 1,2-
MIDA boronates from formyl-substituted heteroaryl- phenylenediamine, the corresponding benzimidazole
boronic acids was observed in the reaction mixture, 3n-MIDA was obtained. Then, 3n-MIDA was directly
surprisingly, these boronic acids (3l and 3m) and even subjected to the Suzuki–Miyaura reaction condi-
the MIDA boronates (3l-MIDA and 3m-MIDA) are tions[18] developed by the Burke group without isola-
unstable, and gradually decomposed during the purifi- tion. To our delight, this generated diaryl-substituted
cation procedure.
benzimidazole 5 in good yield over three steps with
In order to further demonstrate the synthetic utility only one separation step[19] even though the cross-cou-
of this protocol, we attempted to develop a one-pot pling reaction was not completely optimized
sequential protocol via aerobic oxidative cyclization (Scheme 5).
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Synthesis of Benzimidazole-Substituted Arylboronic Acids via Aerobic Oxidation
lowed to stir at 1208C under an argon atmosphere, and
monitored by TLC. After 2 was completely converted into
2-MIDA, the reaction mixture was cooled down to room
temperature. To the above reaction mixture were added 1,2-
aryldiamine (1, 0.55 mmol; 1.1 equiv.) and potassium iodide
(0.10 mmol, 0.20 equiv.) in one portion. The reaction mix-
ture was exposed to air, and allowed to stir at 808C in an
open flask until 2-MIDA was completely consumed. On the
complete consumption of 2-MIDA, the reaction mixture was
cooled to room temperature and 3.0 mL of NaOH (1.0N,
3.0 mmol, 6.0 equiv.) were added to the above reaction mix-
ture. The reaction mixture was stirred at room temperature.
After the complete consumption of 3-MIDA, the reaction
mixture was diluted with water (5.0 mL), was extracted with
CH2Cl2 to remove the remaining 1,2-aryldiamine 1 and
other organic impurities. The combined basic aqueous layer
was filtered to remove the residual 4Š molecular sieves.
The filtrate was further acidified with 1N HCl until the pH
of the solution became 6–7, where the desired product was
precipitated. The precipitate was collected by filtration to
provide the desired boronic acid 3.
Scheme 5. Sequential aerobic oxidative cyclization/cross-
coupling reactions of MIDA boronates
This sequential one-pot protocol was further ap-
plied to the cross-coupling reactions of benzimida-
zole-substituted heteroarylboronic acids, which turned
out to be unstable, and thus, not able to be isolated in
analytically pure forms. When MIDA boronates, pre-
pared via aerobic oxidative cyclization of N-phenyl-
1,2-phenylenediamine and either formyl thienyl or
furyl MIDA boronate, were subjected to cross-cou-
pling reaction with aryl bromide, the desired coupling
products 6 were obtained in good yields over three
steps with only one separation step.
In conclusion, we have developed a highly efficient
method for the synthesis of benzimidazole-substituted
arylboronic acids through metal-free aerobic oxida-
tive condensation of 1,2-arylenediamines and the
MIDA boronate of formylarylboronic acid in the
presence of KI as a nucleophilic catalyst. Further-
more, we developed a simple one-pot protocol for the
synthesis of benzimidazole-substituted arylboronic
acids through the following sequence: MIDA boro-
nate formation, aerobic oxidative cyclization using
KI, and subsequent removal of the MIDA moiety.
Various types of aromatic aldehydes with boronic acid
functionalities were applicable to this protocol, and
the desired boronic acids were obtained in high
yields. In addition, we successfully demonstrated the
utility of this protocol for the direct application of the
resulting boronic acids to Suzuki–Miyaura coupling
reaction without the isolation of any intermediates.
For the preparation of 3-MIDA, after the complete con-
sumption of 2-MIDA, the reaction mixture was concentrat-
ed under reduced pressure and the crude product was fur-
ther purified by solid column chromatography on silica gel
to afford the corresponding benzimidazole 3-MIDA.
Acknowledgements
This work was supported by a National Research Foundation
of Korea (NRF) grant funded by the Korean Government
(NRF-2013R1A1A1008434 and NRF-20100020209). We are
also thankful for financial support from another NRF grant
(NRF-2014M2A84021398).
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Experimental Section
General Procedure
To a solution of formyl-substituted arylboronic acid (2,
0.50 mmol; 1.0 equiv.) in DMF (4.0 mL) were added N-
methyliminodiacetic acid (MIDA, 1.5 mmol; 3.0 equiv.) and
200 mg of 4Š molecular sieves. The reaction mixture was al-
[5] G. A. Molander, K. Ajayi, Org. Lett. 2012, 14, 4242.
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[6] For the seminal report on MIDA boronates, see: E. P.
Gillis, M. D. Burke, J. Am. Chem. Soc. 2007, 129, 6716.
[7] For a review on the use of MIDA boronates, see: E. P.
Gillis, M. D. Burke, Aldrichimica Acta 2009, 42, 17.
[8] For a recent example of the use of MIDA, see: E. M.
Woerly, J. Roy, M. D. Burke, Nat. Chem. 2014, 6, 484,
and references cited therein.
[9] Y.-S. Lee, Y.-H. Cho, S. Lee, J.-K. Bin, J. Yang, G.
Chae, C.-H. Cheon, Tetrahedron 2015, 71, 532.
[10] For recent reviews on the reactivity and stability of bor-
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Chem. Soc. Rev. 2014, 43, 412; b) D. G. Hall, (Ed.),
Boronic Acids, Wiley-VCH, Weinheim, 2005, Chapter
1, pp 1–85.
[11] For recent examples of metal-free thermal protode-
boronation of boronic acids, see: a) C.-Y. Lee, S.-J.
Ahn, C.-H. Cheon, J. Org. Chem. 2013, 78, 12154; b) S.-
J. Ahn, C.-Y. Lee, N.-K. Kim, C.-H. Cheon, J. Org.
Chem. 2014, 79, 7277.
[12] Since 1,2-arylenediamines are known to form strong
complexes with a boronic acid functionality, they have
been utilized as a protection group for a boronic acid,
see: G. Kaupp, M. R. Naimi-Jamal, V. Stepanenko,
Chem. Eur. J. 2003, 9, 4156.
[13] Iodide accelerates aerobic oxidative cyclization for the
synthesis of benzimidazoles by facilitating cyclization
of imines via converting the disfavored 5-endo-trig cy-
clization of an imine into the favored 5-exo-tet cycliza-
tion of a tetrahedral intermediate through addition of
iodide to the imine. For a general guideline on intramo-
lecular cyclization, see Baldwinꢁs rule: a) J. E. Baldwin,
J. Chem. Soc. Chem. Commun. 1976, 734; b) C. D.
Johnson, Acc. Chem. Res. 1993, 26, 476.
[14] For our original demonstration of nucleophile-cata-
lyzed metal-free aerobic oxidative cyclization of imines
in the synthesis of benzo-fused azoles, see: Y.-H. Cho,
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2012, 354, 2992.
[15] For a detailed procedure of the preparation of MIDA
boronates via simple condensation in the presence of
molecular sieves, see: S.-J. Ahn, C.-Y. Lee, C.-H.
Cheon, Adv. Synth. Catal. 2014, 356, 1767.
[16] The actual yields of both 3 and 3-MIDA should be
higher than the reported values in Table 2. Since some
of 3 and 3-MIDA derivatives displayed poor solubili-
ties, it was difficult to isolate them in analytically pure
forms, which often led to lower isolation yields of the
desired products.
[17] Due to the high solubility of 3k in water, we encoun-
tered difficulty in isolating 3k during aqueous work-up.
Thus, we determined the yield of 3k after oxidation of
the boronic acid moiety in 3k into a phenolic hydroxy
group.
[18] For the slow-release cross-coupling procedure, see:
D. M. Knapp, E. P. Gillis, M. D. Burke, J. Am. Chem.
Soc. 2009, 131, 6961.
[19] DMF used as the solvent in aerobic oxidation turned
out to have a harmful effect on the cross-coupling reac-
tion. Thus, DMF was removed by evaporation prior to
the cross-coupling reaction.
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