The first examples of planar chiral organic benzimidazole derivatives

Article abstract of DOI:10.1055/s-2006-950432

The synthesis of a number of novel planar chiral benzimidazoles from [2.2]paracyclophane is reported. The key steps include a Buchwald-Hartwig amination of a sterically demanding inflate and the functionalisation of the C-2 bromide. Georg Thieme Verlag St

Full text of DOI:10.1055/s-2006-950432

LETTER
2625
The First Examples of Planar Chiral Organic Benzimidazole Derivatives
S
ynthesis of [2
e
.2](4,7)Be
t
nzimid
e
zoloparacy
r
clophanes B. Hitchcock, Andrew C. C. Hodgson, Gareth J. Rowlands*
Department of Chemistry, University of Sussex, Falmer, Brighton BN1 9QJ, UK
Fax +44(1273)677196; E-mail: g.rowlands@sussex.ac.uk
Received 13 July 2006
the preparation of a novel class of planar chiral benzimi-
dazole derivatives 2 (Figure 1) based on the [2.2]para-
cyclophane backbone, as this motif displays great
potential for a range of applications. Herein, we present
the synthesis and elaboration of the novel planar chiral
[2.2](4,7)benzimidazoloparacyclophane moiety 2.
Abstract: The synthesis of a number of novel planar chiral benz-
imidazoles from [2.2]paracyclophane is reported. The key steps
include a Buchwald–Hartwig amination of a sterically demanding
triflate and the functionalisation of the C-2 bromide.
Key words: planar chirality, heterocycles, cyclophanes, amination
Our initial goal was to devise a general synthesis of the
[2.2](4,7)benzimidazoloparacyclophane 2 moiety. Ideal-
ly, the route would be capable of furnishing enantiomeri-
cally pure derivatives without recourse to untested
resolution steps and the substituents on both C-2 and N-3
(benzimidazole 2 numbering; Figure 1) should be amena-
ble to late-stage modification to allow a range of com-
pounds to be easily accessed. As 4-monosubstituted
[2.2]paracyclophane derivatives are readily available in
enantiomerically pure form via either our own sulfoxide-
based methodology17 or classical resolution,13 they offer
an ideal starting point for any synthesis. With this caveat
in mind it should be noted that all the work carried out
in this communication was performed with racemic
material.
Substituted benzimidazoles are an important class of
heterocyclic compounds that have a broad range of chem-
ical and biological uses. They have shown diverse and sig-
nificant biological activity as anti-allergic,1 anti-viral,2
anti-tumour3 and anti-ulcerative4 agents. Their simple
elaboration, and the control this imparts on both their
steric and electronic properties, has resulted in their wide-
spread use as ligands;5 additionally benzimidazolium salts
have been employed as precursors to N-heterocyclic car-
bene ligands,6 heterazolium organocatalysts7 and as pre-
cursors to ground-state neutral organic electron donors.8
Benzimidazoles have also been incorporated into special-
ist materials.9
16
15
It is recognised that one of the main problems in the syn-
thesis of disubstituted [2.2]paracyclophane derivatives is
the regioselective incorporation of the second substituent.
We reasoned that selective introduction of a second amine
moiety could be achieved via the directed ortho-lithiation
of a 4-amino[2.2]paracyclophane derivative. It is known
that the directed metallation of [2.2]paracyclophane de-
rivatives can be highly problematic19,20 and all our studies
on amine-based directing groups bore this out; Bräse re-
cently reached a similar conclusion.21 As a result, a range
of ortho-directing groups known to work efficiently on
[2.2]paracyclophane were investigated. The most promis-
ing were the 4-N,N-diethylcarboxamide20 and the 4-N,N-
diethylcarbamate groups,22 which both furnished C-5
functionalised disubstituted derivatives in good yields.
Severe problems with the hydrolysis of the amide ulti-
mately led to the use of the carbamate as the directing
group.
11
10
14
R3
4
7
3
1
2
5
6
N
12
7
13
8
2
R2
9
6
3
N
1
5
4
R
1
2
Figure 1
[2.2]Paracyclophane 1 (R = H) and its derivatives are a
fascinating family of compounds (Figure 1).10 Their dis-
tinctive structure, comprised of two eclipsing aromatic
rings held in place by two ethyl bridges, imparts unique
electronic properties and permits the facile formation of
planar chiral compounds. These properties have led to
[2.2]paracyclophane derivatives being employed in the
synthesis of polymers,11 optoelectronic materials12 and
planar chiral auxiliaries, ligands and catalysts.13,14 Fur-
thermore, there are a limited number of reports of enantio-
merically pure [2.2]paracyclophane derivatives being
utilised to probe the effect of planar chirality on stereo-
controlled recognition processes in biological sys-
tems.15,16 We have an interest in the synthesis of
substituted [2.2]paracyclophanes17,18 and were attracted to
Having found a suitable directing group, our target be-
came the synthesis of the salicylic acid analogue 5
(Scheme 1). This compound contains suitable functional-
ity for the introduction of both the required nitrogen moi-
eties; the alcohol can be derivatised to allow Buchwald–
Hartwig amination,23 whilst the carboxylic acid can un-
dergo Curtius rearrangement to give N-1. To the best of
our knowledge, there are no reports of acid 5, which is sur-
prising considering its potential. The acid was prepared
from 4-bromo[2.2]paracyclophane 3 in four high-yielding
SYNLETT 2006, No. 16, pp 2625–2628
Advanced online publication: 22.09.2006
DOI: 10.1055/s-2006-950432; Art ID: D20006ST
© Georg Thieme Verlag Stuttgart · New York
0
4
.1
0
.2
0
0
6

2626
P. B. Hitchcock et al.
LETTER
Ar
NH
OH
OTf
Br
i, ii
O
O
iii, iv
vi
vii
O
O
O
NEt2
OR1
5 R1 = H
6 R1 = Me
OMe
OMe
3
4
7
8
9
Ar = 4-MeOC6H4 (78%)
Ar = 3-CF3C6H4 (48%)
v
10 Ar = 2-MeC6H4 (67%)
Scheme 1 Reagents and conditions: i. a) n-BuLi, THF, –78 °C; b) B(OMe)3; c) NMO, reflux. ii. ClC(O)NEt2, DMAP, toluene, 90 °C (65%
for two steps); iii. a) s-BuLi, TMEDA, THF, –78 °C; b) solid CO2; iv. 2 M aq HCl, toluene, 90 °C (81% for two steps); v. K2CO3, MeI, MeCN
(92%); vi. Tf2O, py, CH2Cl2, 0 °C (82%); vii. Pd2(dba)3 (5%), ( )-BINAP (7.5%), ArNH2, Cs2CO3, toluene, reflux, then dropwise addition of
7 in toluene.
steps (Scheme 1). First 3 was converted to 4-hy- methylaniline gave only 48% of 9 under the optimised
droxy[2.2]paracyclophane via formation of the boronic conditions with competitive hydrolysis of the triflate
ester and in situ oxidation using N-methyl morpholine N- accounting for the rest of the material. The sterically de-
oxide according to the procedure of Gotteland.24 The car- manding o-toluidine coupled to give the amine 10 in 67%
bamate 4 was then prepared under standard acylation con- yield. Neither 2,6-diisopropylaniline nor hexylamine fur-
ditions. Finally, directed ortho-lithiation with s-BuLi and nished the desired amines. In both cases only a mixture of
TMEDA followed by reaction with crushed solid CO2 and starting material and 6 were isolated. Presumably, the
subsequent acid hydrolysis gave the acid 5 in good yield. former is too sterically challenging whilst aliphatic
This reaction sequence is amenable to large-scale synthe- amines are notoriously poor coupling partners with ortho-
sis of intermediate 5; we regularly prepare the acid on a 5– substituted arenes.28
10 g scale. It was deemed prudent to install the substituted
amine at C-4 ([2.2]paracyclophane numbering or N-3 of
benzimidazole 2) prior to the Curtius rearrangement. To
this end the carboxylic acid was protected as the methyl
ester 6 and the hydroxyl group was converted to triflate 7
in good yield (Scheme 1).
Ar
Ar
NH
i, ii
N
O
O
N
H
OMe
There were few reports of palladium-mediated coupling
reactions of [2.2]paracyclophane-derived triflates25 and,
to our knowledge, only a limited number of palladium-
mediated aminations of [2.2]paracyclophane-based com-
pounds.15,26 At the outset of this project all examples, with
the exception of those of Rossen,27 employed 4-monosub-
stituted [2.2]paracyclophanes. Recently, Bräse reported
one example of the amination of a 4,5-disubstituted deriv-
ative analogous to those in this paper (vide infra).21 In all
but the latter example, a strong base, t-BuONa, which we
considered incompatible with our system, had been uti-
lised. Furthermore, triflate 7 is sterically congested, con-
taining two ortho substituents and one face of the aryl
system blocked by the lower ring of [2.2]paracyclophane,
thus rendering it a challenging example of the Buchwald–
Hartwig methodology. Initial attempts at coupling p-
methoxyaniline, employing the conditions of Buchwald,28
with Cs2CO3 as base and racemic BINAP as ligand, fur-
nished the desired product, 8, in moderate yield (50%),
along with unreacted starting material and considerable
quantities of phenol 6, the result of triflate hydrolysis.
This latter side-reaction could be minimised by the slow
dropwise addition of a solution of triflate 7 to the reaction
mixture already pre-heated to reflux. Under these opti-
mised conditions the yield rose to an excellent 78% on a
10 mmol (4.1g of 7) scale.29
8–10
11 Ar = 4-MeOC6H4 (55%; for 2 steps)
12 Ar = 3-CF3C6H4 (80%; for 2 steps)
13 Ar = 2-MeC6H4 (50%; for 2 steps)
iii
Ar
N
Br
N
14 Ar = 4-MeOC6H4 (85%)
15 Ar = 3-CF3C6H4 (68%)
16 Ar = 2-MeC6H4 (73%)
Scheme 2 Reagents and conditions: i. NaOH, H2O–EtOH, reflux;
ii. a) DPPA, Et3N, toluene, r.t.; b) reflux; iii. POBr3, toluene, reflux.
Having installed one amine unit, we then set about the in-
troduction of the second, which was to be achieved via
Curtius rearrangement. Simple base-promoted hydrolysis
of the esters followed by an expedient, ‘one-pot’ modifi-
cation of the Curtius rearrangement gave an isocyanate
that the adjacent aniline attacked to yield the imidazoli-
dinones 11–13 (Scheme 2). In order to enable the facile
introduction of a range of C-2 (benzimidazole num-
bering) substituents, we converted the carbonyl moiety to
a bromide by treatment with phosphorus(V) oxy-
bromide in toluene at reflux to cleanly give the desired
2-bromo[2.2](4,7)benzimidazoloparacyclophanes 14–16
(Scheme 2).30 The X-ray structure of bromide 14 is shown
in Figure 2.31
We then evaluated the generality of the amination reac-
tion. The reaction appears to be sensitive to the electronics
of the aniline employed; electron-poor m-trifluoro-
Synlett 2006, No. 16, 2625–2628 © Thieme Stuttgart · New York

LETTER
Synthesis of [2.2](4,7)Benzimidazoloparacyclophanes
2627
Under non-optimised conditions, 50% of the desired prod-
uct 20 was isolated.
Figure 2 ORTEP representation of molecular structure of 2-bromo-
benzimidazole 14 in the solid state.
Ar
Ar
Figure 3 ORTEP representation of molecular structure of one dia-
stereoisomer of alcohol 19 in the solid state.
N
N
Me
H
N
N
i
In conclusion we have devised an efficient synthesis of a
series of planar chiral benzimidazole derivatives based on
[2.2]paracyclophane. Judicious incorporation of bromide
functionality at C-2 permits the facile elaboration of the
basic backbone to be achieved at a late stage. Whilst the
present chemistry was performed with racemic material,
resolution of any one of the intermediates should be readi-
ly achievable. We are currently investigating the utility of
a number of these compounds in enantioselective cataly-
sis and the results will be reported in due course. Addi-
tionally, it should be noted that our route can be readily
modified to permit the simple preparation of a number of
ii
18
17
Ar
N
Br
iv
N
iii
Ph
OH
14
Ar
Ar
N
N
Ph
N
N
19
20
Scheme 3 Reagents and conditions: i. a) n-BuLi, THF, –78 °C; b)
H2O (89%); ii. a) n-BuLi, THF, –78 °C; b) MeI (42%); iii. a) n-BuLi, 4,5-disubstituted [2.2]paracyclophane derivatives, a sub-
THF, –78 °C; b) PhCHO (61%); iv. Pd(PPh3)4, K2CO3, PhB(OH)2, to-
luene, reflux (50%). Ar = 4-MeOC6H4.
stitution pattern that is often hard to obtain.
Acknowledgment
The 2-bromobenzimidazole derivative 14 is a versatile in-
termediate permitting access to a wide range of planar
chiral compounds. Scheme 3 gives an initial indication of
the possible functionality that can be appended at the 2-
position. Treatment with n-BuLi furnished the C-2 anion
and this was reacted with a range of electrophiles; simple
protonation by the addition of water gave the parent ben-
zimidazole derivative 17 in 89% yield. Alkylation with
methyl iodide furnished 18 in 42% yield; the main product
of this reaction results from protonation. Addition of the
anion to benzaldehyde gave rise to a 1:1 mixture of the
two possible diastereoisomeric alcohols 19 (61%), with
the remainder of the material being 17 again. These are
readily separated by column chromatography and the rel-
ative stereochemistry was determined by X-ray crystal-
lography (Figure 3).32 The competence of the bromide 14
in palladium-mediated couplings was evaluated by stan-
dard Suzuki–Miyaura reaction with phenylboronic acid
catalysed by tetrakis(triphenylphosphine)palladium(0).
We would like to thank Gordon Weingarten for useful discussions
and GlaxoSmithKline for a CASE award (to A.C.C.H.).
References and Notes
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Synlett 2006, No. 16, 2625–2628 © Thieme Stuttgart · New York

2628
P. B. Hitchcock et al.
LETTER
H. J.; Potenza, J. A. Inorg. Chem. 2004, 43, 1472.
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flash column chromatography (4% Et2O–PE → 8% Et2O–
PE) to afford 8 as a bright yellow crystalline solid (2.90 g,
78%); mp 174–176 °C. IR (CHCl3): 3336, 2947, 1680, 1574,
1514, 1461, 1439, 1415, 1240 cm–1. 1H NMR (300 MHz,
CDCl3): d = 8.61 (1 H, s, NH), 7.04 (1 H, dd, J = 7.8, 1.8 Hz,
H-15 or H-16), 6.88 (2 H, d, J = 8.4 Hz, MeOAr-H), 6.78 (2
H, d, J = 8.4 Hz, MeOAr-H), 6.61 (1 H, dd, J = 7.8, 1.5 Hz,
H-15 or H-16), 6.52–6.45 (3 H, m, H-12, H-13 and H-7 or H-
8), 6.39 (1 H, d, J = 7.8 Hz, H-7 or H-8), 3.85 (3 H, s, OMe),
3.71 (3 H, s, OMe), 3.63 (1 H, ddd, J = 12.6, 9.6, 2.4 Hz, H-
9), 3.12 (1 H, ddd, J = 12.0, 9.6, 2.1 Hz, H-10), 2.97–2.61 (5
H, m, 5 × CH2), 2.59–2.45 (1 H, m, CH2). 13C NMR (75
MHz, CDCl3): d = 170.3 (C=O), 154.8 (C), 144.0 (CH),
142.1 (C), 139.9 (C), 139.5 (CH), 138.7 (C), 137.6 (C),
133.5 (C), 133.4 (CH), 132.1 (CH), 130.9 (CH), 129.5 (CH),
127.8 (CH), 121.5 (C), 118.9 (CH), 114.8 (CH), 56.1 (CH3),
52.2 (CH3), 36.6 (CH2), 35.3 (CH2), 35.3 (CH2), 34.3 (CH2).
MS (EI): m/z = 387 [M]+, 355, 354 [M – CH3OH]+, 283, 268,
251, 236, 220, 208, 192. HRMS (EI): m/z calcd for
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C25H25NO3 (MH+): 388.1907; found: 388.1905.
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(30) 2-Bromo-3-(4-methoxyphenylamino)[2.2](4,7)benzimida-
zoloparacyclophane (14); Typical Procedure: A solution of
11 (0.41 g, 1.12 mmol) and phosphorus(V) oxybromide
(0.80 g, 2.80 mmol) in toluene (16 mL) was heated to reflux
for 5 h. The reaction mixture was cooled to r.t. and washed
with a sat. aq soln of NaHCO3 (25 mL). The organic layer
was separated and the aq layer extracted with CH2Cl2 (3 × 20
mL). The combined extracts were filtered to remove any
insoluble impurities, dried (MgSO4), concentrated and
purified by flash column chromatography (10% heptane–
Et2O→ 20% heptane–Et2O) to afford 14 as a white
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F. Tetrahedron: Asymmetry 1992, 3, 1387.
crystalline solid (0.41 g, 85%); mp 156–159 °C. IR (CHCl3):
3010, 2959, 2932, 2954, 1609, 1585, 1511, 1456, 1300,
1253, 1169 cm–1. 1H NMR (300 MHz, CDCl3): d = 7.65 (1
H, dd, J = 8.7, 2.4 Hz, H-2 or H-6 of MeOC6H4), 7.08 (1 H,
dd, J = 8.7, 2.7 Hz, H-2 or H-6 of MeOC6H4), 7.02 (1 H, dd,
J = 8.7, 2.4 Hz, H-3 or H-4 of MeOC6H4), 6.90 (1 H, dd,
J = 8.7, 3.0 Hz, H-3 or H-4 of MeOC6H4), 6.51 (1 H, d,
J = 7.5 Hz, H-5 or H-6), 6.39–6.41 (2 H, m, H-5 or H-6 and
pseudo-p N-1 or pseudo-p N-3), 6.28 (1 H, dd, J = 7.8, 1.5
Hz, pseudo-p N-1 or pseudo-p N-3), 6.22 (1 H, dd, J = 7.8,
1.8 Hz, pseudo-gem N-1 or pseudo-gem N-3), 6.05 (1 H, dd,
J = 7.8, 1.8 Hz, pseudo-gem N-1 or pseudo-gem N-3), 3.84
(3 H, s, OMe), 3.67–3.75 [1 H, m, (C-7)-CH2], 3.03 [1 H,
ddd, J = 14.4, 12.3, 4.2 Hz, (C-7)-CH2CH2], 2.96–2.71 (2 H,
m, CH2), 2.53–2.37 (1 H, m, CH2), 2.11 [1 H, ddd, J = 12.9,
9.6, 7.2 Hz, (C-4)-CH2]. 13C NMR (75 MHz, CDCl3):
d = 160.3 (C), 145.4 (C), 139.3 (C), 138.1 (C), 138.0 (C),
133.0 (CH), 132.0 (C), 131.8 (CH), 131.3 (CH), 129.7 (C),
129.6 (C), 129.5 (CH), 129.3 (C), 129.0 (CH), 128.7 (CH),
127.1 (CH), 125.4 (CH), 125.1 (C), 115.1 (CH), 114.7 (CH),
56.1 (CH3), 35.4 (CH2), 34.9 (CH2), 31.9 (CH2), 30.8 (CH2).
MS (EI): m/z = 435 [81M]+, 433 [79M]+, 330, 328, 297, 299,
249, 205. HRMS (EI): m/z calcd for C24H21N2OBr (79MH+):
433.0910; found: 433.0903.
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(31) CCDC 611020 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
at www.ccdc.cam.ac.uk/conts.retrieving.html [or from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 (1223)336033; e-mail:
deposit@ccdc.cam.ac.uk].
(32) CCDC 611019 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
at www.ccdc.cam.ac.uk/conts.retrieving.html [or from the
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 (1223)336033; e-mail:
deposit@ccdc.cam.ac.uk].
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(29) 4-(4-Methoxyphenylamino)[2.2]paracyclophan-5-yl
Carboxylic Acid Methyl Ester (8); Typical Procedure: A
solution of triflate 7 (4.00 g, 9.66 mmol) in toluene (20 mL)
was added dropwise over 1 h to a mixture of p-anisidine
(1.46 g, 11.59 mmol), tris(dibenzylideneacetone)dipalla-
dium(0) (0.44 g, 0.48 mmol), ( )-BINAP (0.45 g, 0.72
mmol) and Cs2CO3 (4.31 g, 13.23 mmol) in toluene (10 mL)
at reflux. The mixture was stirred at this temperature for a
further 12 h. The reaction was cooled to r.t., filtered through
celite and concentrated. The crude product was purified by
Synlett 2006, No. 16, 2625–2628 © Thieme Stuttgart · New York