Synthesis and structure of bifunctional N-alkylbenzimidazole phenylboronate derivatives

Article abstract of DOI:10.1039/b607127a

N-Methyl and N-n-butyl-2-(2-boronophenyl)benzimidazoles are accessed from the corresponding mono-N-alkyl-ortho-phenylenediamines, either using a polyphosphoric acid-mediated cyclisation with ortho-bromobenzoic acid, or preferably using an Oxone-mediated c

Full text of DOI:10.1039/b607127a

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis and structure of bifunctional N-alkylbenzimidazole phenylboronate
derivatives
Alexandrea J. Blatch,a Olga V. Chetina,a Judith A. K. Howard,a Leonard G. F. Patrick,a
Christian A. Smethurstb and Andrew Whiting*a
Received 19th May 2006, Accepted 7th July 2006
First published as an Advance Article on the web 26th July 2006
DOI: 10.1039/b607127a
N-Methyl and N-n-butyl-2-(2-boronophenyl)benzimidazoles are accessed from the corresponding
mono-N-alkyl-ortho-phenylenediamines, either using a polyphosphoric acid-mediated cyclisation with
ortho-bromobenzoic acid, or preferably using an OxoneTM-mediated cyclisation of the corresponding
aldehyde, followed by a lithium-exchange and borylation sequence. The resulting boronic acids show
unusual physical and chemical properties, as shown by 11B NMR and X-ray crystallography.
the preparation of N-alkyl derivatives. Initially, we examined the
synthesis of N-methyl analogue 2b, as outlined in Scheme 1.
Introduction
There are many examples of polyfunctional catalysts which
do not contain transition or lanthanide metals,1 including
organocatalysts.2 Some of the earliest reported examples of non-
transition metal containing systems are based on organoboron
bifunctional systems, reported as early as the 1950s, and are
effective catalysts for the hydrolysis of chloroalcohols.3 It was
suggested that such systems promoted the hydrolysis of chloroal-
cohols through the cooperative interaction of both the amine and
boronic acid functionalities,3 hence amino boronate-containing
systems of general structure 1 are of general interest as bifunctional
catalysts, which are perhaps closely related to organic catalysts
if they are chemically stable organoboronate derivatives. In
addition, there is increasing interest in the use of bifunctional
aminoboronate analogues as selective binding agents and sensors
for polyfunctional molecules, such as carbohydrates, and hydroxy
acids.4 As part of a programme aimed at investigating the potential
of such systems, we have examined the synthesis, structure and
physical properties of several classes of such aminoboronates
and recently applied certain systems in direct amide formation,5
and herein report our recent studies on N-alkylbenzimidazole
boronate derivatives of type 2.
Scheme 1 Synthesis of N-methylbenzimidazolephenylboronic acid (2b)
and pinacol ester 6.
Results and discussion
Hence, condensation of N-methyl-1,2-phenylenediamine 4 and
2-bromobenzoic acid 3 in polyphosphoric6 acid gave 2-(2-
bromophenyl)-N-methylbenzimidazole 5 in 53% yield. Attempts
to improve this conversion using either P2O5 or microwave tech-
niques failed to improve this reaction. Lithium–halogen exchange,
followed by trans-metallation and aqueous work-up produced a
compound which was assigned the overall formula of boronic acid
derivative 2b in 78% yield, due to its similarity to data reported
by Letsinger.7 However, the 11B NMR spectrum of this compound
Benzimidazole phenylboronic acid 2a has been reported by
Letsinger3 as an effective catalyst for chlorohydrin hydrolysis,
however, its low solubility in organic solvents led us to investigate
aDepartment of Chemistry, Durham University, Science Laboratories, South
Road, Durham, UK DH1 3LE. E-mail: andy.whiting@durham.ac.uk;
Tel: +44 (191) 334 2081
bDiscovery Research Systems Chemistry, GlaxoSmithKline Pharmaceuti-
cals, Stevenage, Hertfordshire, UK SG1 2NY
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 3297–3302 | 3297
©

View Article Online
was not as expected for a free boronic acid (vide infra), appearing as
a very broad signal d 15.5, i.e. as drawn in structure (I) (Scheme 1).
Confirmation of the formation of a compound which behaved as
boronic acid 2b was readily obtained by formation of the pinacol
ester as a crystalline solid in 69% yield. This compound exhibited
an 11B NMR shift at d 29.7, showing that it exists as shown in
diagram 6, i.e. without N–B interaction (vide infra). The poor
solubility of what appeared to be boronic acid 2b in organic
solvents led us to attempt to prepare a derivative which would
be expected to have improved solubility in organic solvents, i.e.
the N-butyl analogue 2c. Hence, this synthesis of this compound
was attempted, initially using a similar approach to that outlined
in Scheme 1, i.e. as outlined in Scheme 2.
which is typical of a boronate ‘ate’-complex.11 Since method A
(Scheme 2) resulted in the formation of the ‘ate’-complex of 2c, the
preparation of the free boronic acid 2c was examined in a similar
way to that of the ‘ate’-complex, but using a final acidification
step of the reaction mixture to pH 7 (method B). The material
recovered by this method showed a 11B NMR (CD3CN–D2O)
spectrum which contained peaks at d 12.5, 19.7 and 32.8 for the
intramolecular N–B chelate (III), boroxine (II) and free amino
boronic (I) acid, respectively,11 as shown in Scheme 3. Mass
spectrometric data (ES+) obtained for this material confirmed the
boronic acid 2a due to signals observed at m/z 295.2 (MH+) and
317.2 (MNa+), but also revealed the existence of a dimer at m/z
553.4 (2M–2OH) which may either be due to fragmentation of
the boroxine trimer (II) during analysis, or it may also be due to
the presence of a dimer which is implicated as the intermediate
in the formation of boroxine (II) from free boronate (I) (Scheme 3).
The corresponding N-methyl derivative 2b behaves similarly in
terms of mass spectrometric analysis, however, its 11B NMR
spectrum (vide supra) was quite different, showing a single broad
peak at d 15.5. This suggests that interconversion between each
of the different possible forms is relatively fast on the NMR
timescale, however, the intramolecular chelate version, i.e. form
(II) Scheme 1, predominates, explaining the observed chemical
shift. Hence, the N-n-butyl group versus N-methyl group in 2b
versus 2c has the effect of seemingly slowing interconversion
between each of the different possible species present in solution,
i.e. between species (I), (II) and (III) (Scheme 3) in the case of the
N-n-butyl system 2c.
Scheme 2 Synthesis of N-n-butylbenzimidazolephenylboronic acid (2c)
and derivatives.
The synthesis of boronic acid derivative 2c started with prepa-
ration of N-n-butyl-1,2-phenylenediamine 9, which was prepared
over two steps in essentially quantitative yield (Scheme 2). This was
followed by exposure to the polyphosphoric acid-mediated cycli-
sation with ortho-bromobenzoic acid 3. This was an exceptionally
capricious reaction, which after a lengthy work up and purification
procedure could provide the required benzimidazole 10 in up to
38% yield. All attempts to find an improved method of preparing
the benzimidazole 10 from diamine 9 using polyphosphoric acid
failed. Hence, further alternatives were sought.
There are many alternative approaches for the formation
of benzimidazoles from diamines,8 with perhaps the simplest
involving the coupling of 1,2-phenylenediamines with aldehydes,
rather than carboxylic acids, but carried out under oxidising
conditions. Initial attempted reactions of the phenylenediamine
9 with benzaldehyde 11 in refluxing NMP or DMF in air9 failed
to provide any of the desired benzimidazole 10, however, addition
of 0.6 equivalents of OxoneTM to this type of reaction was more
successful,10 especially when carried out in DMF–water mixture,
which resulted in the clean formation of benzimidazole 10 in 69%
yield (Scheme 2).
The preparation of the boronate 2c was then performed accor-
ding to Scheme 2, via lithium–halogen exchange of bromide 10,
followed by quenching with triisopropyl borate. After quenching
with aqueous sodium hydroxide (method A), boronate 2c was
isolated in quantitative yield as a white precipitate as the sodium
hydroxide complex, as evidenced by a 11B NMR shift of d 2.9,
Scheme 3 Equilibrium between the various forms of the N-n-butyl-
benzimidazolephenylboronic acid 2c.
The interesting behaviour exhibited by boronates 2b and 2c
is consistent with other amino boronate complexes which are
capable of intramolecular N–B bonding.12 Since the 11B NMR
signal for the free boronate of 2c, i.e. form (I), appears at d
32.8, and yet it is in equilibrium with signals at d 12.5 and 19.7
indicates that pH 7 is slightly below the isoelectric point for N-n-
butylbenzimidazolephenylboronic acid system 2c.13 In an attempt
to further probe the structural behaviour of 2c, crystallisation was
attempted, but this proved extremely difficult. This was largely
due to (a) its poor solubility in most solvents and (b) presumably
the fact that in solution, it exists in several possible equilibrium
species (see Scheme 3). However, of the numerous solvent systems
tested, the most successful was found to be a mixture of DMF
and chloroform, recrystallisation from which was encouraged by
3298 | Org. Biomol. Chem., 2006, 4, 3297–3302
This journal is
The Royal Society of Chemistry 2006
©

View Article Online
temperature cycling. In addition, this crystallisation had to be
performed on a sample of boronate 2c which had first been
acidified to pH <5 with dilute HCl and then re-precipitated
from neutral solution. This method yielded, concomitantly, single
crystals of four very different habits, which could represent
different forms of the boronate 2c (Scheme 3). Unfortunately, only
one crystal was suitable for single crystal X-ray diffraction analysis,
which revealed the structure of the boroxine trimer (II) (Fig. 1) and
hence, also confirmed the chemical connectivity of the monomeric
form of boronic acid 2c. The molecule 2c (II) contains a puckered
1,3,5-boroxine (B3O3) ring, in which the B(1), B(2) and B(3) atoms
(II) in having two of the ligands C–N-chelating, while the third
one remains C-monodentate. This indicates that tetrahedrisation
of boron atoms becomes progressively more difficult, obviously
due to steric overcrowding. Nevertheless, the difficulty is not
unsurmountable, since two boroxines are known to have all boron
atoms 4-coordinate.5a,15a
The strength of the N: → B donor–acceptor interaction is
highly variable. In 218 known adducts of the N: → B(OR)2R
type (R = organic group), the B–N distances range from 1.56
14
˚
˚
to 1.98 A; those in 2c (II) (see Table 1) are ca. 0.1 A from
the lower limit. Toyota et al.15c suggested a method to quantify
‘tetrahedral character’ (TCH), of a boron atom by the average
angle h between the covalent bonds, as h can vary from 120◦ for
planar–trigonal coordination to 109.5◦ for the tetrahedral; hence
TCH = (120◦ − h)/(120◦–109.5◦). TCH shows better correlation
with the stability of adducts than the B–N distance.15c By this
estimate, B(2) and B(3) have TCH of 48 and 53%, respectively,
showing the relative lability of the N → B bonds. Indeed, in
solution, this compound shows a single 11B NMR resonance at d =
19, which indicates fluxional behaviour (on the NMR timescale)
with all three nitrogen ligands, which rapidly switch between boron
chelation and decomplexation.
˚
deviate from the O3 plane by 0.04, 0.36 and −0.34 A, respectively.
The B(1) atom has planar–trigonal geometry, its plane is inclined
by 14◦ to the adjacent benzene ring. The B(2) and B(3) atoms are 4-
coordinate through additional intramolecular N → B donations.
These require planarisation of the ligands, wherein the dihedral
angle between the benzimidazole and benzene planes is reduced
to 7◦, against 81◦ in the monodentate ligand bonded to B(1).
In the latter ligand, the “unsupported” benzimidazole moiety is
intensely librating (or statically disordered) within its own plane,
and besides the n-butyl side-chain is conformationally disordered.
Summary and conclusions
The requirements for cooperative bifunctional binding of sub-
strates using aminoboronate systems are essentially similar to the
requirements for catalytic effects.3–5 It is becoming clear that seem-
ingly minor changes in the structure of the aminoboronate system
can have profound effects on the physical, and subsequently, the
chemical properties of such compounds. In the present case, a
seemingly minor substitution (methyl versus n-butyl in 2b and 2c,
respectively) results in subtle changes in the dynamics of the B–N
chelation, as evidenced by 11B NMR. Both these benzimidazoles
also show very different physical and chemical behaviour to, for
example, ortho-benzylaminoboronic acid derivatives, where B–N
chelation can be switched on and off by using simple steric effects,5d
which results in the latter systems being efficient direct amide
formation catalysts, whereas the present systems are unreactive.
However, the aminoboronate systems 2 discussed herein are active
catalysts for chloroalcohol hydrolysis,3 and are therefore likely to
have other catalytic applications which directly correlate with their
unique chemical and structural properties. Further reports on the
application of these systems for novel catalytic applications will be
reported in due course.
Fig. 1 Molecular structure of 2c (II) (Scheme 3) (50% thermal ellipsoids,
H atoms are omitted for clarity).
A survey of the November 2005 release of the Cambridge Struc-
tural Database,14 revealed 29 neutral (rather than anionic) borox-
ines (RBO)3 where R = alkyl or aryl. Of these, 12 contain only
planar–trigonal boron atoms and 13 combine one 4-coordinate
atom with two 3-coordinate, but only two compounds have two
out of three borons 4-coordinate, namely (Me2NXC6H4BO)3,
15a
15b
=
where X = CH2 or CH N. These compounds resemble 2c
◦
˚
Table 1 Selected bond distances (A) and angles ( ) in 2c (II) (Scheme 3)
Bond
Distance (angle)
Bond
Distance (angle)
B(3)–O(1)
B(2)–O(3)
B(2)–C(117)
B(2)–N(101)
B(1)–O(1)
1.480(4)
1.417(4)
1.634(4)
1.666(4)
1.358(4)
1.586(4)
118.2(2)
115.2(2)
113.8(3)
115.9(3)
94.1(2)
B(2)–O(2)
B(3)–O(3)
1.458(4)
1.416(4)
1.630(5)
1.641(4)
1.358(4)
122.1(3)
119.5(3)
114.3(2)
116.3(3)
112.7(2)
94.6(2)
B(3)–C(217)
B(3)–N(201)
B(1)–O(2)
O(1)B(1)O(2)
O(2)B(1)C(17)
O(1)B(3)O(3)
O(3)B(3)C(217)
O(1)B(3)C(217)
N(201)B(3)C(217)
B(1)–C(17)
O(1)B(1)C(17)
O(2)B(2)O(3)
O(2)B(2)C(117)
O(3)B(2)C(117)
N(101)B(2)C(117)
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 3297–3302 | 3299
©

View Article Online
dropwise over 1.5 h. The resulting suspension was then stirred for
a further 2 h at −72 ◦C. A solution of triisopropylborate (23.5 ml
in 250 ml of dry diethyl ether) was then added dropwise over 0.5 h.
After stirring at −78 ◦C for further 0.5 h the solution was allowed
to warm to room temperature overnight. 5% Aqueous sodium
hydroxide (300 ml) was then added and the layers separated.
The pH of the aqueous phase was then adjusted to pH 1–2
with concentrated HCl. The aqueous phase was then washed
with diethyl ether (3 × 50 ml). The aqueous phase was then
adjusted to pH 7–8 with 5% sodium hydroxide, saturated with
salt and extracted with chloroform (3 × 100 ml). Evaporation
gave N-methyl-2-(2-boronophenyl)benzimidazole 2b as a cream
Experimental
All starting materials were obtained commercially from Aldrich,
Lancaster or Fluka and were used as received or prepared by
known methods, unless otherwise stated. Solvents were also
used as received or dried by known methods, unless otherwise
stated. In the case of DCM and toluene this involved refluxing
over calcium hydride under argon and in the case of ether and
THF involved refluxing over sodium and benzophenone under
argon. Purification by column chromatography was performed
˚
using Lancaster silica gel with pore size 60 A. TLC was carried
out using Merck aluminium-backed or plastic-backed pre-coated
plates. TLC plates were analysed by UV at 254 and 365 nm,
and visualisation was performed using standard solutions of 4-
anisaldehyde, vanillin or phosphomolybdic acid. NMR spectra
were recorded at 200, 300 or 400 MHz using a Varian Mercury
200 MHz spectrometer, Varian Unity 300 MHz spectrometer or
a Brucker 400 MHz spectrometer, respectively, unless otherwise
stated. Electrospray (ES) mass spectra were recorded using a Mi-
cromass LCT spectrometer. Infrared spectra were obtained using
FT1600 series spectrometer. Ultra-violet spectra were measured
using a Unicam UV-Vis UV2 spectrometer. Melting points were
measured with an Electrothermal apparatus and were uncorrected.
Evaporations were carried out at 20 mm Hg using a Bu¨chi rotary
evaporator and water bath, followed by evaporation to dryness
under vacuum (<2 mm Hg). Chloroform used in the preparation
of the phosphoryl compounds was Aldrich HPLC grade 99.9%
stabilised with amylenes.
◦
solid (4.8 g, 78%); mp. 218 dec C; mmax(nujol)/cm−1 1734, 1596,
1532, 1491, 1433, 1370, 1325, 1296, 1279, 1256, 1239, 1174, 1135,
1118, 1063, 749; kmax(MeCN)/nm 208.0 (e/dm3mol−1cm−1 49610),
244.0 (15620); dH (400 MHz, CDCl3) 3.16 (3H, s, CH3N), 7.00–
7.08 (1H, m, Ar–H), 7.18–7.24 (2H, m, Ar–H), 7.26–7.32 (2H, m,
Ar–H), 7.38–7.48 (2H, m, Ar–H), 7.55–7.60 (1H, m, Ar–H); dC
(100 MHz, CDCl3) 30.8, 109.5, 117.2, 122.2, 122.7, 124.0, 125.0,
127.9, 130.1, 131.4, 132.4, 132.6, 136.0, 137.0, 155.6; dB (96 MHz,
CDCl3) 15.5 (br s); m/z (ES+) inter alia 253 (100%, M + H), 469
(65%, 2M + H–2OH); HRMS (ES+) found (M + H) 253.1172,
C14H14N2O2B requires 253.1148.
N-Methyl-2-(2-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-
2-yl)phenyl)benzimidazole (6)
N-Methyl-2-(2-boronophenyl)benzimidazole 2b (1.0 g; 3.97 mmol)
was added to a solution of pinacol (0.45 g; 3.97 mmol in 25 ml
of diethyl ether) and the resulting suspension stirred at room
temperature overnight. The desired boronic acid ester 6 was then
isolated by filtration as white solid (0.92 g; 69%); mp. 169 ◦C;
mmax(nujol)/cm−1 1603, 1523, 1353, 1143, 1090, 1045, 859, 749, 658;
kmax(MeCN)/nm 208.0 (e/dm3mol−1cm−1 79890), 244.0 (18140);
dH(400 MHz, CDCl3) 1.12 (12H, s, 4 × CH3C), 3.67 (3H, s, CH3N),
7.27–7.40 (3H, m, ArH), 7.44–7.56 (3H, m, ArH), 7.76–7.79 (1H,
m, ArH); dC (100 MHz, CDCl3) 24.9, 31.3, 83.8, 109.5, 119.7,
122.1, 122.5, 129.2, 130.3, 134.9, 135.7, 136.2, 142.8, 155.2; dB
(96 MHz, (CD3)2SO) 29.7 (br s); m/z (EI+) inter alia 333 (M–H,
100), 334 (M+, 44); found C, 71.65; H, 6.95; N, 8.22; C20H23BN2O2
requires C, 71.87; H, 6.94; N, 8.38%.
N-Methyl-2-(2-bromophenyl)benzimidazole (5)
N-Methylphenylene-1,2-diamine 4 (12.0 g, 0.10 mmol), 2-
bromobenzoic acid 3 (19.9 g, 0.01 mmol) and polyphosphoric
acid (60.0 g) were mixed into a paste and heated to 175 ◦C under
argon for 4 h. The reaction solution was then poured into ice-water
(400 ml) and the pH adjusted to 10–11 with ammonium hydroxide.
The resulting sticky solid was then dissolved in ethanol (50 ml) and
reprecipitated with dilute ammonium hydroxide at pH 10–11 to
yield pale purple needles (23.7 g). The needles were then removed
by filtration and purified by dissolving in ethyl acetate passing
through a short dry silica gel column (toluene–ethyl acetate, 9 : 1,
as eluent), to give N-methyl-2-(2-bromophenyl)benzimidazole 5
as a pale cream solid (15.2 g, 53%); mp 116 ◦C; mmax(nujol)/cm−1
inter alia 752, 782, 1023, 1240, 1281, 1327, 1434, 1523, 1560, 1598,
1612 cm−1; kmax(EtOH)/nm 206.0 (e/dm3mol−1cm−1 59180), 256.0
(9470), 278.0 (12370), 284.0 (11940); dH(400 MHz, CDCl3) 3.66
(3H, s, CH3N), 7.30–7.43 (4H, m, ArH), 7.46 (1H, td, J 7.4 and 1.4,
ArH), 7.54 (dd, 1H, J 7.6 and 1.6, ArH), 7.71 (dd, 1H, J 8.0 and
0.8, ArH), 7.84 (dd, 1H, J 7.1 and 1.6, ArH); dC(100 MHz, CDCl3)
31.1, 109.9, 120.4, 122.7, 123.2, 124.1, 127.8, 131.7, 132.4, 132.7,
1-Butylamino-2-nitrobenzene (8)16
2-Bromonitrobenzene 7 (20.0 g; 0.099 mol) and n-butylamine
(36 ml; 0.366 mol) were dissolved in DMSO (100 ml) and heated
to 80 ◦C and stirred overnight. The reaction solution was then
allowed to cool to room temperature before the addition of water
(300 ml). The resulting solution was then extracted with DCM
(3 × 150 ml). The combined extracts were then washed with brine
(3 × 100 ml) and dried over MgSO4. Filtration and evaporation
gave nitrophenylamine 816 as a yellow oil in quantitative yield,
which was used for the following step without further purification;
mmax(neat)/cm−1 inter alia 3381, 3084, 1618, 1572, 1510, 1419,
1354, 1263, 2333, 1159, 1038, 861, 742; kmax(EtOH)/nm 208.3
(e/dm3mol−1cm−1 9550), 230.0 (21990), 260.8 (5580), 283.9 (7660);
dH (400 MHz, CDCl3) 0.97 (3H, t, J 7.2, CH2CH3), 1.47 (2H, sex-
tet, J 7.4, CH2CH2CH3), 1.71 (2H, quintet, J 7.3, CH2CH2CH2),
3.28 (2H, m,CH2NH), 6.60 (1H, ddd, J 8.5, 6.8, 1.3, Ar–H), 6.83
•
133.1, 135.7, 143.0, 152.8; m/z (EI+) inter alia 288 (94%, M+ 81Br),
•
286 (96, M+ 79Br), 207 (100), 206 (75); found C, 59.04; H, 3.87; N,
9.78; C14H11N2Br requires C, 58.56; H, 3.86; N 9.76%.
N-Methyl-2-(2-boronophenyl)benzimidazole (2b)
t-Butyllithium (29 ml, 1.69 M in hexanes, 48.8 mmol) and dry
diethyl ether (162 ml) were placed in a flask and cooled to
−78 ◦C. A solution of N-methyl-2-(2-bromophenyl)benzimidazole
5 (7.0 g, 24.4 mmol in 315 ml of dry diethyl ether) was then added
3300 | Org. Biomol. Chem., 2006, 4, 3297–3302
This journal is
The Royal Society of Chemistry 2006
©

View Article Online
(1H, ddd, J 8.8, 0.8 and 0.4, Ar–H), 7.41 (1H, dddd, J 8.8, 6.8, 1.6
and 0.8), 8.04 (1H, br s, N–H), 8.14 (1H, ddd, J 8.4, 1.6 and 0.4);
dC (100 MHz, CDCl3) 14.0, 20.5, 31.2, 42.9, 114.0, 115.2, 127.1,
131.9, 136.4, 145.9. m/z (ES+) inter alia 217 (100, M + Na), 195
(M + H); HRMS (ES+) found: (M + Na) 217.0962, C10H14N2O2
requires 217.0953.
Synthesis of the 2-(2-bromophenyl)-N-n-butyl-benzimidazole (10)18
A solution of 9 (4.977 g, 30.40 mmol) in DMF (50 ml) and
H2O (1.6 ml), was treated with 2-bromobenzaldehyde 11 (3.52 ml,
30.4 mmol) and OxoneTM (11.008 g, 18.2 mmol). After stirring at
room temperature for 12 h, the reaction was carefully quenched
by the addition of an aqueous solution of K2CO3 (0.04 M,
310 ml). The resulting suspension was extracted with ethyl acetate
(3 × 150 ml) and the combined organic extracts dried (MgSO4)
and evaporated. The resulting residue was purified by silica
gel chromatography (hexane–ethyl acetate, gradient elution) to
provide 1018 as a viscous pale brown oil (6.936 g, 69%), which was
identical to that prepared in the previous experiment.
N-n-Butyl-1,2-phenylenediamine (9)16
1-n-Butylamino-2-nitrobenzene 8 (20 g; 0.10 mol) and Pd/C
catalyst (2 g 10% Pd/C; 1.88 mmol) were placed in methanol
and stirred under hydrogen for 3 h. The reaction was maintained
at room temperature by the use of an ice-water bath. The resulting
solution was the filtered through a short silica gel column to
remove the catalyst, to give a clear colourless solution which
turned brown upon standing. Evaporation gave the diamine 916
as a viscous brown liquid, which was used for the following step
without further purification; dH (400 MHz, CDCl3) 0.99 (3H, t, J
7.4, CH3CH2), 1.48 (2H, hextet, J 7.4, CH2CH2CH3), 1.68 (2H,
quintet, J 7.3, CH2CH2CH2), 3.12, (2H, t, J 7, CH2N), 3.37 (3H,
br s, N–H), 6.66–6.76 (3H, m, Ar–H), 6.85 (1H, td, J 7.4 and 1.8,
Ar–H); dC (100 MHz, CDCl3) 14.3, 20.7, 32.0, 44.3, 112.0, 116.7,
118.7, 121.0, 134.3, 138.2.
Synthesis of the 2-(2-boronophenyl)-N-n-butyl-benzimidazole
sodium hydroxide salt of 2c
A solution of ◦benzimidazole 10 (0.223 g, 0.677 mmol) in ether
(7 ml) at −78 C under argon was treated with t-BuLi (1.69 ml,
0.52 M in pentane, 0.879 mmol) over a period of 15 min. The
resultant solution was stirred at −78 ◦C for 1 h, treated with
B(OiPr)3 (0.355 ml, 1.54 mmol) and the solution stirred for 48 h
during which it was allowed to warm slowly from −78 ◦C to
room temperature. NaOH (20% w/v, 7 ml) was then added, and
the mixture was stirred at room temperature for 1 h. The yellow
precipitate that formed, was filtered, washed with ether and dried
to give 2c·NaOH as a white solid (0.161 g, 100%); mp 147.7–
148.9 ◦C; kmax (EtOH)/nm 225sh, 245sh, 252sh, 297sh and 316
(e/dm3 mol−1 cm−1 15 015, 9 610, 8 408, 10 811 and 13 513); mmax
(KBr)/cm−1 inter alia 3418 (amine), 3044 (Ar), 2959 (CH), 2931
(CH), 2873 (CH), 1455, 1397 (CH), 1284 (benzimidazole), 1204,
1173, 1059 (benzimidazole), 959, 897, 866 and 745; dH (400 MHz,
CD3CN–D2O, 3 : 1) 0.71 (t, J 7.4 Hz, 3 H, CH3), 1.14 (hextet,
J 7.5 Hz, 2 H, CH3CH2CH2), 1.64 (quintet, J 7.5 Hz, 2 H,
NCH2CH2), 3.99 (m, 2 H, NCH2CH2), 7.25–7.32 (m, 4 H, ArH),
7.39–7.43 (m, 1 H, ArH), 7.54–7.57 (m, 1 H, ArH), 7.64–7.66 (m, 1
H, ArH) and 7.70 (d, J 7.2 Hz, 1 H, ArH); dC (400 MHz, CD3CN–
D2O, 3 : 1) 10.2, 16.7, 28.3, 41.6, 108.5, 115.3, 119.9, 120.0, 122.7,
126.2, 126.5, 129.0, 129.7, 131.9 and 159.0; dB (128 MHz, D2O)
2.9; m/z ES (−) 309.5 (M–Na, 22%), 293.5 (M–NaOH, 100%);
m/z ES (+) 611.4 (2M–Na–2OH, 35%), 317.2 (M–OH, 100%);
HMRS ES (+) found 295.1627, C17H20O2N2B requires 295.1630.
2-(2-Bromophenyl)-N-butylbenzimidazole (10)17
N-Butyl-1,2-phenylenediamine 9 (20 g; 0.122 mol) and 2-
bromobenzoic acid 3 (26.8 g; 0.133 mol) were mixed into PPA
(80 g), placed under an atmosphere of argon and heated to 180 ◦C
for 6 h. This resulted in the formation of a black solution which
was poured into ice-water (ca. 500 ml) whilst hot. The resulting
water–tar mixture solution was then adjusted to alkaline pH by
the addition of dilute ammonium hydroxide and further ice. The
aqueous phase was then extracted with DCM (1 × 300 ml). Sodium
chloride was then added to the remaining aqueous phase and
the solution was further extracted with DCM (2 × 200 ml). The
combined extracts were then washed with ammonium hydroxide
(10% v/v) containing a trace of ethanol and dried over MgSO4.
Evaporation gave a viscous black oil (28.7 g) which was purified
by passing through a short dry silica gel column (diethyl ether as
eluant) to give 2-(2-bromophenyl)-N-n-butylbenzimidazole 1017 as
a viscous brown oil (14.2 g; 35%); mmax/cm−1 inter alia 3661 (amine),
3391 (amine), 3059 (Ar), 2958 (CH), 2931 (CH), 2871 (CH),
1613 (Ar), 1599 (Ar), 1453, 1393 (CH), 1281 (benzimidazole),
1243 (benzimidazole), 1026 (benzimidazole) and 706 (ArBr); dH
(400 MHz, CDCl3) 0.71 (t, J 7.4 Hz, 3 H, CH3), 1.11 (hextet,
J 7.5 Hz, 2 H, CH3CH2CH2), 1.61 (quintet, J 7.5 Hz, 2 H,
CH2CH2CH2), 3.98 (t, J 7.2 Hz, 2 H, NCH2CH2), 7.25–7.46 (m, 6
H, ArH), 7.64–7.66 (m, 1 H, ArH) and 7.76–7.80 (m, 1 H, ArH);
dC (100 MHz, CDCl3) 13.5 (CH3), 20.0 (CH2), 31.5 (CH2), 44.4
(CH2), 110.2 (Ar), 120.2 (Ar), 122.4 (Ar), 123.0 (Ar), 124.0 (Ar),
127.4 (Ar), 131.4 (Ar), 132.4 (Ar), 132.9 (Ar), 134.4 (Ar), 145.6
(Ar) and 152.3 (Ar); m/z EI (+) inter alia 206.0 (M–CH2CHCH2Br,
91%), 284.7 (M–CH2CHCH2, 56%), 286.7 (M–CH2CHCH2, 56%),
327.8 (MH, 100%) and 329.8 (MH, 99%); m/z EI (+) 327.8 (M–H,
95.57%) 329.8 (M–H, 89.07%); HRMS (ES+) C17H17N2Br requires
328.2487 and 330.2467.
Synthesis of the 2-(2-boronophenyl)-N-n-butyl-benzimidazole (2c)
A solution of 10 (0.369 g, 1.12 mmol) in diethyl ether (3 ml) at
◦
−78 C under argon, was treated with n-BuLi (0.896 ml, 2.5 M
in pentane, 2.24 mmol) over 30 min, and the resultant solution
stirred for 1 h. B(OiPr)3 (0.52 ml, 2 × 1.12 mmol) was added and
the solution stirred for 4 h at −78 ◦C and allowed to warm to room
temperature. The solution was quenched with aqueous NaOH
(10% w/v, 2 ml), and stirred at room temperature for 15 min. The
pH of the solution was adjusted to pH 7 with aqueous HCl (10%
w/v) and the resulting precipitate was filtered, washed (diethyl
ether) and dried to give 2c as a white solid (0.261 g, 79%); mp
235.6–239.9 ◦C; mmax (KBr)/cm−1 inter alia 3439 (amine), 3049
(Ar), 2957 (CH), 2930 (CH), 2872 (CH), 1636, 1616 (Ar), 1524,
1461, 1360, 1300 (ArB(OH)2), 1171, 1007 (boroxine) and 953; dH
(400 MHz, CD3CN–D2O, 3 : 1) 0.90 (t, J 7 Hz, 3 H, CH3), 1.40
(hextet, J 7.5 Hz, 2 H, CH2), 1.90 (quintet, J 8 Hz, 2 H, CH2), 4.55
This journal is
The Royal Society of Chemistry 2006
Org. Biomol. Chem., 2006, 4, 3297–3302 | 3301
©

View Article Online
(t, J 7 Hz, 2 H, NCH2), 7.41–7.51 (m, 4 H, Ar), 7.64–7.67 (m, 2 H,
Ar) and 7.79–7.83 (m, 2 H, Ar); dC (400 MHz, CD3CN–D2O, 3 : 1)
12.7, 19.3, 31.0, 44.3, 111.3, 114.4, 116.4, 123.0, 123.5, 124.4, 127.5,
129.3, 130.16, 131.0, 133.1, 136.1 and 159; dB (128 MHz, CD3CN–
D2O, 3 : 1) 12.5, 19.7 and 32.8; m/z ES (+) 553.4 (2M–2OH, 100%),
317.2 (47) and 295.2 (25); HRMS (ES+) found m/z 295.1627
[M + H], C17H20N2O2B requires m/z 295.1618.
Morrison, J. Am. Chem. Soc., 1963, 85, 2227; (c) R. L. Letsinger and
A. J. Wysocki, J. Org. Chem., 1963, 28, 3199; (d) R. L. Letsinger and S.
Dandegaonker, J. Am. Chem. Soc., 1959, 81, 498.
4 (a) C. W. Gray and T. A. Houston, J. Org. Chem., 2002, 67, 5426;
(b) M. Yamamoto, M. Takeuchi, S. Shinkai, F. T. Tani and Y. Naruta,
J. Chem. Soc., Perkin Trans. 2, 2000, 9; (c) M. Bielecki, H. Eggert and
J. C. Norrild, J. Chem. Soc., Perkin Trans. 2, 1999, 449; (d) B. Appleton
and T. D. Gibson, Sens. Actuators, B, 2000, 65, 302.
5 (a) R. L. Giles, J. A. K. Howard, L. G. F. Patrick, M. R. Probert,
G. E. Smith and A. Whiting, J. Organomet. Chem., 2003, 680, 257;
(b) S. W. Coghlan, R. L. Giles, J. A. K. Howard, M. R. Probert, G. E.
Smith and A. Whiting, J. Organomet. Chem., 2005, 690, 4784; (c) A. S.
Batsanov, R. L. Giles, M. R. Probert, G. E. Smith and A. Whiting, Acta
Crystallogr., Sect. E, 2006, 62, o466; (d) K. Arnold, B. Davies, R. L.
Giles, C. Grosjean, G. E. Smith and A. Whiting, Adv. Synth. Catal.,
2006, 348, 813.
6 (a) J. C. Craig, N. N. Ekwuribe, C. C. Fu and K. A. M. Walker, Synth.
Commun., 1981, 303; (b) E. Alcade, I. Dinares, L. Perez-Garcia and T.
Roca, Synthesis, 1992, 395.
7 R. L. Letsinger and D. B. MacLean, J. Am. Chem. Soc., 1963, 85, 2230.
8 (a) M. R. Grimmet, in Comprehensive Organic Chemistry: The Syn-
thesis and Reactions of Organic Compounds, vol. 4, ed. D. Barton,
W. D. Ollis and P. G. Sammes, Pergamon Press, Oxford, 1979, p. 395;
(b) M. R. Grimmet, in Comprehensive Heterocyclic Chemistry, vol. 5,
ed. A. R. Katritzky and C. W. Rees, Pergamon Press, Oxford, 1984, p.
457.
9 (a) A. Harizi and H. Zantour, Synth. Commun., 2002, 32, 387; (b) M. T.
Bilodeau and A. M. Cunningham, J. Org. Chem., 1998, 63, 2800; (c) H.
Akamatsu, K. Fukase and S. Kusumoto, J. Comb. Chem., 2002, 4, 475;
(d) K. Nagata, T. Itoh, H. Ishikawa and A. Ohsawa, Heterocycles, 2003,
61, 93; (e) D. Yang, D. Fokas, J. Li, L. Yu and C. M. Baldino, Synthesis,
2005, 1, 47.
X-Ray crystallography†
The diffraction experiment for (II) (Scheme 3) was carried out on
a 3-circle Bruker diffractometer with a SMART 6 K CCD area
¯
detector, using graphite-monochromated Mo Ka radiation (k =
˚
0.71073 A) and a Cryostream (Oxford Cryosystems) open-flow N2
cryostat. The structure was solved by direct methods and refined
by full-matrix least squares against F2 of all reflections, using
SHELXTL software.18 Refining high-ADP atoms of the uncoordi-
nated benzimidazole group in two split positions gave no improve-
ment. Crystal data: C51H51B3N6O3, M = 828.41, T = 120 K,
triclinic, space group P1 (No. 2), a = 11.223(2), b = 13.252(3),
◦
˚
c = 16.734(3) A, a = 75.48(3), b = 73.58(3), c = 70.65(3) , U =
3
−3
−1
˚
2218.3(8) A , Z = 2, Dc = 1.240 g cm , l = 0.08 mm , 14759
reflections with 2h ≤ 50◦, Rint = 0.070, wR(F2) = 0.130 (7766
unique data), R(F) = 0.058 [3854 data with I ≥ 2r(I)].
10 P. L. Beaulieu, B. Hache´ and E. von Moos, Synthesis, 2003, 11, 1683.
11 H. No¨th and B. Wrackmeyer, Nuclear Magnetic Resonance Spec-
troscopy of Boron Compounds, Springer-Verlag, Berlin, 1978, p. 14.
12 (a) L. I. Bosch, T. M. Fyles and T. D. James, Tetrahedron, 2004, 60,
11175; (b) M. Yamamoto, M. Takeuchi and S. Shinkai, Tetrahedron,
1998, 54, 3125; (c) S. Shinkai and M. Takeuchi, Bull. Chem. Soc. Jpn.,
2005, 78, 40; (d) L. Zhu, S. H. Shabbir, M. Gray, V. M. Lynch, S. Sorey
and E. V. Anslyn, J. Am. Chem. Soc., 2006, 128, 1222.
Acknowledgements
We thank both EPSRC and GlaxoSmithKline Pharmaceuticals
for a CASE award (to ARB), and Dr A. S. Batsanov (Durham
University) for assistance with crystal data.
13 D. Voet and J. G. Voet, Biochemistry, 2nd edn, John Wiley and Sons,
1997, p. 56.
References
14 F. H. Allen and R. Taylor, Chem. Soc. Rev., 2004, 463.
15 (a) J. C. Norrid and I. Sotofte, J. Chem. Soc., Perkin Trans. 2, 2002,
303; (b) P. D. Robinson, M. P. Grozniak and L. Yi, Acta Crystallogr.,
1 (a) C. Mocquet and S. Warriner, SYNLETT, 2004, 2, 356; (b) B. M.
Nugent, R. A. Yoder and J. N. Johnston, J. Am. Chem. Soc., 2004, 126,
3418.
2 (a) P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2001, 40, 3726;
(b) P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2004, 43, 5138.
3 (a) R. L. Letsinger, S. Dandegaonker, W. J. Vullo and J. D. Morrison,
J. Am. Chem. Soc., 1963, 85, 2223; (b) R. L. Letsinger and J. D.
¯
Sect. C, 1996, 52, 2826; (c) S. Toyota and M. Oki, Bull. Chem. Soc.
Jpn., 1992, 65, 1832.
16 (a) J. Beger, G. Wagner, E. Uhlig and U. Dinjus, J. Prakt. Chem., 1983,
325, 708; (b) S. M. Chiacchiera, J. O. Singh, J. D. Anunziata and J. J.
Silber, J. Chem. Soc., Perkin Trans. 2, 1988, 1585; (c) B. W. Ashton
and H. Suschitzky, J. Chem. Soc., 1957, 4559; (d) J. T. Ralph, Synth.
Commun., 1989, 19, 1381.
17 K. R. Reddy and G. G. Krishna, Tetrahedron Lett., 2005, 46, 661.
18 SHELXTL, version 6.12, Bruker AXS, Madison, Wisconsin, USA.
† CCDC reference number 608045. For crystallographic data in CIF
format see DOI: 10.1039/b607127a
3302 | Org. Biomol. Chem., 2006, 4, 3297–3302
This journal is
The Royal Society of Chemistry 2006
©