Benzimidazole nitrogen-directed, regiocontrolled, lithiation of ferrocenyl- and phenyl-N-n-butylbenzimidazoles

Article abstract of DOI:10.1021/jo061639+

2-Ferrocenyl- and 2-phenyl-N-n-butylbenzimidazoles were synthesized to evaluate the influence of the benzimidazole functional group upon their directed lithiation. The regiochemistry of lithiation was studied, as well as the effect of stabilization of the

Full text of DOI:10.1021/jo061639+

Benzimidazole Nitrogen-Directed, Regiocontrolled, Lithiation of
Ferrocenyl- and Phenyl-N-n-butylbenzimidazoles
†
†
†
‡
Damien H e´ rault, Karel Aelvoet, Alexandrea J. Blatch, Abdullah Al-Majid,
§
,†
Christian A. Smethurst, and Andrew Whiting*
Department of Chemistry, Durham UniVersity, Sciences Laboratories, South Road, Durham DH1 3LE,
U.K., Chemistry Department, College of Science, King Saud UniVersity, PO Box 2455, Riyadh 11451,
Saudi Arabia, and GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Third AVenue, Harlow,
Essex, CM19 5AW, U.K.
Andy.whiting@durham.ac.uk
ReceiVed August 7, 2006
2
-Ferrocenyl- and 2-phenyl-N-n-butylbenzimidazoles were synthesized to evaluate the influence of the
benzimidazole functional group upon their directed lithiation. The regiochemistry of lithiation was studied,
as well as the effect of stabilization of the lithiated species by diamine coordination using tetramethyl-
ethylenediamine and (-)-sparteine. The lithiations were followed by reaction with a variety of electrophiles
to give the disubstituted 2-ferrocenyl- and 2-phenyl-N-n-butylbenzimidazoles compounds. This study
showed that despite a simple n-butyl function on the benzimidazole, directed lithiation was readily achieved
with high regiocontrol on the ferrocenyl and phenyl groups. (-)-Sparteine failed to provide asymmetric
induction in the ferrocene system, and its inefficiency is explained by intramolecular coordination of the
lithiated species by the benzimidazole nitrogen, which is preferred over sparteine coordination.
5
Introduction
frequently used are functionals such as amides, carboxylic
6
7
8
9
10
acids, amines, imidazoles, imidazolines, methoxyls, and
oxazolines. In ferrocene systems, there are numerous directing
groups used to provide ring substitution in an enantioselective
The lithiation of phenyl and ferrocenyl groups is very
common in the synthesis of di- or trisubstituted aromatic
11
1
-3
4
compounds
or chiral planar ferrocene derivatives. In par-
1
2
13
manner, including ferrocene chiral acetals, oxazolines,
ticular, for the regioselective lithiation of, for example, mono-
substituted phenyl and ferrocene derivatives, the directing groups
(
(
(
6) Mortier, J.; Vaultier, M. C. R. Acad. Sci. Paris 1998, 1, 465-478.
7) Lauer, M.; Wulff, G. J. Organomet. Chem. 1983, 256, 1-9.
8) (a) Molina, P.; Aller, E.; Lorenzo, A.; Foces-Foces, C.; Llamas Saiz,
*
To whom correspondence should be addressed. Tel: +44-191-334-2081.
Fax: +44-191-384-4737.
†
A. L. Tetrahedron 1996, 52, 13671-13680. (b) Demuth, T. P.; Lever,
D. C.; Gorgos, L. M.; Hogan, C. M.; Chu, J. J. Org. Chem. 1992, 57, 2963-
Department of Chemistry, Durham University.
Chemistry Department, King Saud University.
GlaxoSmithKline Pharmaceuticals, Essex.
‡
§
2965.
(
1) Slocum, D. W.; Shelton, P.; Moran, K. M. Synthesis 2005, 20, 3477-
498.
2) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem.,
(9) (a) Houlihan, W. J.; Parrino, V. A. J. Org. Chem. 1982, 47, 5177-
3
5180. (b) Houlihan, W. J.; Parrino, V. A. Heterocycl. Chem. 1981, 18,
(
1549-1550.
Int. Ed. 2004, 43, 2206-2225.
(10) Nguyen, T.-H.; Castanet, A.-S.; Mortier, J. Org. Lett. 2006, 8, 765-
(
3) Snieckus, V. Chem. ReV. 1990, 90, 879-933.
768.
(4) Balavoine, G. G. A.; Daran, J.-C.; Iftime, G.; Manoury, E.; Moreau-
(11) Meyers, A. I.; Mihelich, E. D. J. Org. Chem. 1975, 40, 3158-
3159.
Bossuet, C. J. Organomet. Chem. 1998, 567, 191-198.
5) Alo, B. I.; Kandil, A.; Patil, P. A.; Sharp, M. J.; Siddiqui, M. A.;
Snieckus, V. J. Org. Chem. 1991, 56, 3763-3768.
(
(12) Riant, O.; Samuel, O.; Kagan, H. B. J. Am. Chem. Soc. 1993, 115,
5835-5836.
1
0.1021/jo061639+ CCC: $37.00 © 2007 American Chemical Society
Published on Web 12/07/2006
J. Org. Chem. 2007, 72, 71-75
71

H e´ rault et al.
SCHEME 1. Synthesis of Boronic Acid Derivatives by
Directed Lithiation
trolled metalation could be accomplished across the biaryl ring
system, as opposed to alpha to nitrogen, i.e., on the benzimi-
dazole benzene ring. In this paper, we report the successful
application of the strategy, the conditions for the optimization
of the lithiation of these two systems, and the results obtained
with the different electrophiles.
Results and Discussion
First, we synthesized 1 and 3. In the case of the ferrocene
23
derivative, we applied Beaulieu’s method involving oxidative
coupling between the (N-n-butylamine)aniline and the ferrocene
carboxaldehyde in the presence of Oxone. The preparation of
the N-n-butylaniline precursor (7) was realized in two steps, as
shown in Scheme 2, involving aromatic nucleophilic substitution
of n-butylamine on 2-bromonitrobenzene, followed by hydro-
genation of the nitro-function, as reported. After coupling with
the ferrocene carboxaldehyde, the substituted ferrocene 1 was
obtained in an overall yield of 63% (Scheme 2). 3 can also be
prepared by a similar route or by using more conventional
polyphosphoric acid-catalyzed cyclocondensation methods;24
however, for this study it was readily prepared by N-alkylation
of the commercial 2-phenylbenzimidazole in 88% (eq 1).25 With
amines, sulfoxides,15 imidazolines,16 and oxazaphospholodine-
1
4
24
oxides.17 To synthesize chiral planar ferrocene systems, external
chiral auxiliaries were generally employed to induce enanti-
oselectivity. Because diamines, such as TMEDA, are often
1
employed to stabilize the product of directed lithiation, enan-
tioselective lithiation can also be effected by directed enanti-
oselective deprotonation using chiral diamines, (-)-sparteine
being a most efficient auxiliary for the ortho-lithiation of
ferrocene carboxamides.18 In addition, amide anions can be used
to temporarily protect aromatic aldehydes via formation of the
19
aldehyde-amide adduct, and both (S)-(+)-1-(2-pyrrolidinyl-
2
0
21
methyl)pyrrolidine and chiral cyclohexanediamines have
provided temporary protection with concomitant ortho-lithiation
of a ferrocene carboxaldehyde and a benzaldehyde chromium
tricarbonyl complex.
access to both benzimidazoles 1 and 3 achieved, the lithiation
of these systems was examined with the aim of synthesizing
the chiral planar 1,2-ferrocene and ortho-disubstituted benzene
derivatives as typified by the boronic acid derivatives 2 and 4,
respectively. To achieve the synthesis of systems related to the
ferrocene system 2, the direct lithiation of 1 was attempted by
We are interested in the synthesis of amino-boronic acid
compounds which have potential as bifunctional and organic
catalysts.22 In particular, we focused our attention on the
preparation of 2-(2-boronoferrocenyl)-N-n-butylbenzimidazole
(
2) and 2-(2-boronophenyl)-N-n-butylbenzimidazole (4a), which
we argued would be available via the directed lithiation of
-ferrocenyl-N-n-butylbenzimidazole (1) and 2-phenyl-N-n-
butylbenzimidazole (3) (Scheme 1), assuming that regiocon-
17
the method of Snieckus et al. (eq 2). Treatment with 1.3 equiv
of n-butyllithium and 1.3 equiv of (-)-sparteine was used to
form the lithiated ferrocene, followed by quenching with excess
electrophile. With the use of trimethylborate as the electrophile,
2 was obtained in an inadequate 23% yield and with no
asymmetric induction (zero rotation by optical rotation).
2
(
13) (a) Pickett, T. E.; Richards, C. J. Tetrahedron Lett. 2001, 42, 3767-
3
769. (b) Pickett, T. E.; Roca, F. X.; Richards, C. J. J. Org. Chem. 2003,
6
8, 2592-2599. (c) Manoury, E.; Fossey, J. S.; A ¨ı t-Haddou, H.; Daran,
J-C.; Balavoine, G. G. A. Organometallics 2000, 19, 3736-3739. (d) Salter,
R.; Pickett, T. E.; Richards, C. J. Tetrahedron: Asymmetry 1998, 9, 4239-
4
247.
(14) (a) Anderson, J. C.; Blake, A. J.; Arnall-Culliford, J. C. Org. Biomol.
Chem. 2003, 1, 3586-3591. (b) Steurer, M.; Tiedl, K.; Wang, Y.;
Weissensteiner, W. Chem. Commun. 2005, 4929-4931.
(
15) Priego, J.; Manche n˜ o, O.; Cabrera, S.; Carretero, J. C. Chem.
Commun. 2001, 2026-2027.
(
16) Peters, R.; Fischer, D. F. Org. Lett. 2005, 7, 4137-4140.
(17) Vinci, D.; Mateus, N.; Wu, X.; Hancock, F.; Steiner, A.; Xiao, J.
Org. Lett. 2006, 8, 215-218.
To confirm the inefficiency of (-)-sparteine to direct asym-
metric induction in competition with the benzimidazole, 2-(2-
bromoferrocenyl)-N-n-butylbenzimidazole (9a) was synthesized
directly using both TMEDA-n-BuLi (Table 1, entry 4) and (-)-
sparteine-n-BuLi (entry 3) in 41 and 47% yields, respectively.
Chiral HPLC analysis again showed the absence of any
(
18) (a) Tsukazaki, M.; Tinkl, M.; Roglans, A.; Chapell, B. J.; Taylor,
N. J.; Snieckus, V. J. Am. Chem. Soc. 1996, 118, 685-686. (b) Metallinos,
C.; Szillat, H.; Taylor, N. J.; Snieckus, V. AdV. Synth. Catal. 2003, 345,
3
70-382.
(
19) (a) Comins, D. L.; Brown, J. D.; Mantlo, N. B. Tetrahedron Lett.
1
982, 23, 3979-3982. (b) Comins, D. L.; Brown, J. D. J. Org. Chem. 1984,
4
9, 1078-1083.
(20) Iftime, G.; Daran, J.-C.; Manoury, E.; Balavoine, G. G. A. Angew.
Chem., Int. Ed. 1998, 37, 1698-1701.
21) Alexakis, A.; Kanger, T.; Mangeney, P.; Rose-Munch, F.; Perrotey,
A.; Rose, E. Tetrahedron: Asymmetry 1995, 6, 2135-2138.
22) (a) Giles, R. L.; Howard, J. A. K.; Patrick, L. G. F.; Probert, M. R.;
(23) Beaulieu, P. L.; Hach e´ , B.; von Moos, E. Synthesis 2003, 11, 1683-
1692.
(24) Blatch, A. J.; Botsanov, A.; Chetina, O.; Howard, J. A. K.; Patrick,
L. G. F.; Smethurst, C. A.; Whiting, A. Org. Biomol. Chem., in press
(available from http://www.rsc.org/publishing/journals/ob/ as an advance
article).
(25) Stibrany, R. T.; Schulz, D. N.; Kacher, S.; Patil, A. O.; Baugh,
L. S.; Rucker, S. P.; Zushma, S.; Berluche, E.; Sissano, J. A. Macromol-
ecules 2003, 36, 8584-8586.
(
(
Smith, G. E.; Whiting, A. J. Organomet. Chem. 2003, 680, 257-262. (b)
Coghlan, S. W.; Giles, R. L.; Howard, J. A. K.; Patrick, L. G. F.; Probert,
M. R.; Smith, G. E.; Whiting, A. J. Organomet. Chem. 2005, 690, 4784-
4
793. (c) Arnold, K.; Davies, B.; Giles, R. L.; Grosjean, C.; Smith, G. E.;
Whiting, A. AdV. Synth. Catal. 2006, 348, 813-820.
72 J. Org. Chem., Vol. 72, No. 1, 2007

Ferrocenyl- and Phenyl-N-n-butylbenzimidazoles
SCHEME 2. Synthesis of 2-Ferrocenyl-N-n-butylbenzimidazole (1)
TABLE 1. Lithiation of 2-(Ferrocenyl)-N-n-butyl-benzimidazole
TABLE 2. Lithiation of 2-(Phenyl)-N-n-butyl-benzimidazole (3)
(1)
BuLi
entry E+ (equiv) (equiv) solvent T (°C)
E (product)
yield (%)
BuLi
(equiv)
diamine
(1.3 equiv)
E
yield ee
entry
E+
solvent (product) (%) (%)
1
2
3
B(O-iPr)
3
(2) t-(1.5)
Et
2
O
-78 (RBO)
3
-boroxine 65
1
2
3
4
5
6
B(OMe)
B(OMe)
3
n-(1.3) (-)-sparteine Et
t-(1.5) THF
n-(1.3) (-)-sparteine Et
2
O
B(OH)
B(OH)
Br-9a
Br-9a
Br-9a
2
-2
-2
23
87
47
41
85
25
0
0
4b
B(O- iPr)
3
(2) t-(1.5)
(3) n-(2)
THF
THF
-78 (RBO)
3
-boroxine 67
3
2
4b
(BrCCl
(BrCCl
(BrCCl
2
2
2
)
)
)
2
2
2
2
O
O
B(O- iPr)
3
-25 mixture of ester/ ND
n-(1.3) TMEDA
t-(1.5)
Et
2
acid
THF
THF
4
5
6
7
8
9
0
DMF (8)
DMF (8)
DMF (8)
n-(1.5)
n-(1.5)
n-(2)
THF
THF
THF
THF
THF
THF
THF
THF
THF
-78 CHO 10a
-42 CHO 10a
-25 CHO 10a
-78 Br 10b
-42 Br 10b
-25 Br 10b
-25 Br 10b
-42 TMS 10c
-25 mixture
SM
31
87
SM
ND (32 )
5 (64 )
9 (55 )
87
ND
TMSCl
t-(1.5)
TMS-9b
asymmetric induction in the latter case. Indeed, further studies
showed that the addition of a diamine was not required during
the lithiation. In addition, lithiation of 1 with 1.5 equiv of t-BuLi
followed by quenching with either trimethylborate or 1,2-
dibromotetrachloroethane gave the boronic acid 2 and the
bromide 9a in yields of 87 and 85%, respectively. This proved
the ability of a simple N-alkyl-substituted benzimidazole group
to direct the lithiation onto the neighboring ring of a biaryl
system and to stabilize the resulting lithiated intermediate
without any external diamine additive; i.e., the lack of asym-
metric induction is presumably a direct result of the preferred
metalation reaction being an intramolecular delivery of a
benzimidazole-n-butyllithium species which does not require
sparteine. With the use of the same conditions as those for the
bromination of ferrocene 1, the corresponding TMS derivative
(BrCCl
(BrCCl
(BrCCl
2
2
2
)
)
)
2
2
2
(2) n-(1.5)
(2) n-(1.5)
(2) n-(2)
n-(2)
a
a
a
1
Br
2
(2)
11 TMSCl (2)
n-(2)
n-(2)
12
TMSCl (2)
a
1
Percentage of 10b in the crude product was determined by H NMR,
on the basis of the relative integrations of the CH2N groups.
and TMSCl. First, the DMF quenched reaction (Table 2, entries
4
4
-6) was carried out at -78 °C using 1.5 equiv of n-BuLi (entry
). However, only starting material 3 was observed; hence, the
reaction temperature was increased to -42 °C to promote the
lithiation and subsequent reaction with DMF (entry 5). In this
case, 31% of the benzaldehyde derivative 10a was isolated.
Raising the temperature again to -25 °C gave a further increase
in yield to 87% (entry 6) of the corresponding aldehyde 10a. It
is also interesting to note that the percentage of side products
observed in the crude NMR also decreased with increasing
temperature.
(
2
Table 1, entry 6) was also isolated, albeit only with a yield of
5%.
The lithiation of benzimidazole 2 was also realized according
8
to the method of Demuth and Molina/Foces-Foces using
different electrophiles, as outlined in eq 3 and Table 2. In this
case, the conditions were optimized in a manner which depended
upon the type of electrophile used. First, lithiation of benzimi-
For the bromination of 3 to give 10b (Table 2, entries 7-10),
the initial reaction was carried out at -78 °C using 1.5 equiv
of n-BuLi; however, only starting material 3 was recovered
(
8
entry 7). When the temperature was increased to -42 °C (entry
), complete conversion of 3 was achieved; however, separation
of the starting material and product 10b was difficult due to
their similar retention times. With the use of 2 equiv of n-BuLi
at -25 °C (entry 9), the conversion of 3 was improved to an
estimated 67%; however, again due to separation problems, only
5
% of 10b was isolated after silica gel chromatography. A
marginal improvement in yield to 9% was possible using Br2
as the electrophile (entry 10), though the conversion was lower
(55%). In contrast, the lithiation of benzimidazole 3 and reaction
with TMSCl gave the corresponding trimethylsilyl compound
10c in a much more straightforward manner (Table 2, entries
11 and 12). Carrying out the reaction at -25 °C using 2 equiv
of n-BuLi (entry 12), followed by quenching with TMSCl, gave
dazole 3 was developed for the synthesis of the boronic acid
derivative 4. It was found that the efficiency of the lithiation
did not depend upon the solvent, since under the same reaction
conditions (temperature, equivalents, and type of lithiating
agent), the yields were similar in diethyl ether or THF, i.e., 65
and 67%, respectively (Table 2, entries 1 and 2). Thus, the
preferred conditions involved THF at -78 °C with 1.5 equiv
of t-BuLi, which gave the pure single regioisomer boroxine 4b.
When the reaction was run at -25 °C using 2 equiv of n-BuLi,
a mixture of compounds (Table 2, entry 3) was clearly indicated
1
a crude product which by H NMR also showed the presence
of a major side product. This side product may well be the ortho-
trimethylsilylated derivative 11a; however, it could not be
isolated in a pure state. The directed metalation was substantially
improved to give regioselective trimethylsilylation when the
reaction was carried out at a lower temperature (-42 °C),
resulting in 87% yield of 10c (entry 11).
1
11
by H NMR. Indeed, this was reinforced by B NMR which
showed three peaks at 8, 19, and 33 ppm, corresponding to the
intramolecular chelated derivative,24 the boroxine 4b, and the
boronic acid 4a, respectively.
Conclusions
It was also interesting to investigate the same reaction using
different electrophiles, i.e., DMF, 1,2-dibromotetrachloroethane,
It is clear that neighboring group electron-donor systems
attached to nitrogen functions such as N-Boc, for example,5
J. Org. Chem, Vol. 72, No. 1, 2007 73

H e´ rault et al.
(
1
1
m, 1H). 13C NMR (CDCl
09.1, 118.6, 121.2, 121.6, 127.7 (2C), 128.2 (2C), 128.6, 129.8,
34.6, 142.1, 152.6. IR (neat, cm ): 3157, 2978, 2905, 1453, 1314.
3
, 100 MHz): δ 12.4, 18.7, 30.7, 43.4,
-1
+
HRMS (ES+): C17
51.1542. Anal. Calcd for C17
Found C, 80.25; H, 7.21; N, 11.16.
-(2-Boronoferrocenyl)-N-n-butylbenzimidazole (2). Method
H
19
N
2
m/z calcd 251.1543 (M + H ), found
2
18 2
H N
: C, 81.56; H, 7.25; N, 11.19.
2
A: To a solution of (-)-sparteine (1.19 mL, 5.2 mmol) in dry
diethyl ether (20 mL) under argon stirred at -78 °C was added
n-butyllithium (3.25 mL of a 1.6 M solution in hexane, 5.2 mmol).
The resulting solution was stirred for 30 min. Then, a solution of
1
(1.43 g, 3.9 mmol) in diethyl ether (15 mL) was added and the
mixture was stirred at -78 °C, followed by addition of trimeth-
ylborate (0.894 mL, 7.98 mmol). After 30 min, the mixture was
warmed to room temperature, quenched with saturated NH
solution (10 mL), and extracted with diethyl ether (3 × 15 mL).
The combined organic extracts were washed with H
mL) and brine (3 × 15 mL), dried, evaporated, and purified by
silica gel chromatography (hexane, hexane/ethyl acetate, ethyl
acetate, ethyl acetate/methanol, methanol, gradient elution) to give
4
Cl
assist the directed lithiation and subsequent stabilization of the
aryl lithium. The present study shows that N-alkyl benzimidazole
systems alone can direct metalation with reasonable-to-good
facility, even with a simple alkyl group attached to nitrogen.
However, the subsequent reaction with an external electrophile
does vary in efficiency and it is therefore necessary to optimize
reaction conditions to reflect this. From the results presented
here, it is clear that directed metalation of biaryl-benzimidazole
systems is not necessarily completely regioselective; however,
with a suitable choice of reaction conditions, lithiated species
such as 12 or 13 do predominate over 11b or 14, respectively.
Overall, this directed metalation is a useful way to rapidly
functionalize biaryl-benzimidazole systems, and although the
enantioselective metalation is not possible on the ferrocene
system 1 by sparteine-directed metalation, the resulting racemic
products, such as 2, could be subjected to resolution as a route
to novel axially chiral catalysts and ligands.
2
O (3 × 15
a solid which was recrystallized from acetonitrile/water to give 2
1
(
341 mg, 23%) as orange needles. Mp: 143-145 °C. H NMR
(CDCl , 400 MHz): δ 0.93 (t, 3H, J ) 6.8 Hz), 1.41 (hextet, 2H,
3
J ) 6.8, 14.8 Hz), 1.75-1.90 (m, 2H), 4.09 (s, 5H), 4.14-4.21
(m, 1H), 4.32-4.40 (m, 1H), 4.59 (s br, 1H), 4.79 (s br, 1H), 4.88
(
s br, 1H), 7.12-7.28 (m, 3H), 7.60-7.70 (m, 1H), 9.80 (s br, 2H).
1
3
C NMR (CDCl
3
, 100 MHz): δ 13.8, 20.3, 32.2, 44.8, 70.7, 71.6,
7
3.1, 76.4, 78.0, 109.5, 118.5, 122.6, 122.7, 135.4, 140.8, 154.6.
11
-1
B NMR (CDCl
3
, 128 MHz): δ 29.6. IR (neat, cm ): 3323, 2954,
2
924, 2361, 1518, 1398, 1289. MS (ES+, m/z, %): 403.1 (M +
+
H , 100), 346.9 (15), 232.0 (15). Anal. Calcd for C21
2 2
H23BFeN O :
C, 62.73; H, 5.77; N, 6.97. Found C, 62.33; H, 5.81; N, 6.76.
Method B: To a solution of 1 (100 mg, 0.28 mmol) in dry THF
2 mL) under argon stirred at -78 °C was added tert-butyllithium
0.279 mL of a 1.5 M solution in pentane, 0.418 mmol). The
(
(
resulting solution was stirred for 2 h followed by the addition of
trimethylborate (0.062 mL, 0.56 mmol). After 1 h, the mixture was
warmed to room temperature and stirred for 2 h, the reaction was
Experimental Section
2-Ferrocenyl-N-n-butylbenzimidazole (1). To a solution of
2-(N-n-butylamine)aniline (7) (1.0 g, 6 mmol) in DMF/water (15
4
quenched with saturated NH Cl solution (2 mL), and the product
mL:0.5 mL) was added the ferrocene carboxaldehyde (1.30 g, 6
mmol) and Oxone (2.43 g, 4 mmol). The reaction mixture was
stirred at room temperature overnight, quenched with a saturated
was extracted with diethyl ether (3 × 5 mL). The combined organic
extracts were washed with brine (3 × 5 mL), dried, evaporated,
and purified by silica gel chromatography as in the previous
experiment to give 2 (98 mg, 87%) as orange needles.
2-(2-Bromoferrocenyl)-N-n-butylbenzimidazole (9a). Method
A: To a solution of (-)-sparteine (0.083 mL, 0.36 mmol) in dry
THF (2 mL) under argon stirred at -78 °C was added n-
butyllithium (0.226 mL of a 1.6 M solution in hexane, 0.36 mmol).
The resulting solution was stirred for 30 min. Then, a solution of
1 (100 mg, 0.28 mmol) in THF (2 mL) was added, and the mixture
was stirred at -78 °C. After 1 h, a solution of dibromotetrachlo-
roethane (181 mg, 0.56 mmol) in THF (2 mL) was added. After
30 min, the mixture was warmed to room temperature, the reaction
solution of K
mL), dried, evaporated, and purified by silica gel chromatography
ethyl acetate/hexane, 1:9 as eluent) to give 1 (1.43 g, 66%) as
2
CO
3
(5 mL), extracted with ethyl acetate (3 × 15
(
1
3
orange needles. Mp: 73-74°C. H NMR (CDCl , 400 MHz): δ
0
1
1
.98 (t, 3H, J ) 7.2 Hz), 1.46 (sextet, 2H, J ) 7.2, 14.8 Hz), 1.81-
.89 (m, 2H), 4.12 (s, 5H), 4.32-4.37 (m, 2H), 4.40 (t, 2H, J )
.6 Hz), 4.85 (t, 2H, J ) 2.0 Hz), 7.15-7.21 (m, 2H), 7.23-7.28
(
m, 1H), 7.65-7.72 (m, 1H). 13C NMR (CDCl
3
, 100 MHz): δ 13.9,
2
1
1
0.4, 32.4, 44.3, 69.1, 69.7, 70.0, 74.2, 109.1, 119.1, 121.9, 122.0,
-1
36.0, 143.2, 152.9. IR (KBr, cm ): 3088, 2957, 2927, 2860, 2905,
54
535, 1459, 1428, 1363, 742. HRMS (ES+): C21
H
23
N
2
Fe m/z
was quenched with saturated NH Cl solution (2 mL), and the
4
+
calcd 357.1252 (M + H ), found 357.1255
-Phenyl-N-n-butylbenzimidazole (3). Sodium hydride (300 mg
of 60% oil suspension, 7.5 mmol) was washed with dry hexane (3
10 mL) and dissolved in anhydrous DMF (25 mL) under argon.
-Phenyl-1H-benzimidazole (8) (971 mg, 5.0 mmol) was added and
product was extracted with diethyl ether (3 × 5 mL). The combined
2
organic extracts were washed with H
2
O (3 × 5 mL) and brine (3
× 5 mL), dried, evaporated, and purified by silica gel chromatog-
raphy (hexane/ethyl acetate, 8:2 as eluent) to give 9a (57 mg, 47%)
as brown-green solid. Mp: 92-93 °C. Enantiomeric ratio ) 1,
×
2
stirred for 10 min at room temperature. The n-butylbromide (0.54
mL, 5.0 mmol) was added dropwise over 15 min, and the reaction
mixture was heated to reflux. After 6 h, ethanol (0.5 mL) was added
to quench the reaction and the mixture was stirred for an extra 10
min at room temperature. The solvent was evaporated, and the
mixture was redissolved in diethyl ether (20 mL), washed with 20%
Chiralcel OD, hexane/isopropanol: 95/5, 1 mL/min, λ ) 254 nm,
1
8.35 min, 9.62 min. H NMR (CDCl
3
, 400 MHz): δ 0.71 (t, 3H,
J ) 7.2 Hz), 1.07 (hextet, 2H, J ) 7.6, 14.4 Hz), 1.49-1.58 (m,
2H), 3.90-3.98 (m, 1H), 4.00-4.09 (m, 1H), 4.26 (s br, 1H), 4.41
(s br, 1H), 4.43 (s, 5H), 4.59 (s br, 1H), 7.15-7.32 (m, 3H), 7.81-
7.85 (m, 1H). 13C NMR (CDCl
, 100 MHz): δ 13.5, 19.8, 31.5,
3
NaOH (3 × 10 mL), dried, and evaporated to give 3 (1.10 g, 88%)
44.1, 67.3, 69.4, 70.1, 71.2, 72.9, 79.4, 109.7, 120.2, 121.9, 122.4,
1
-1
as a dark yellow oil. H NMR (CDCl
3
, 400 MHz): δ 0.69 (t, 3H,
135.5, 143.1, 149.8. IR (neat, cm ): 3104, 2938, 2874, 1541, 1451,
+
+
J ) 7.2 Hz), 1.09 (hextet, 2H, J ) 7.6 Hz), 1.62 (quintet, 2H, J )
.6 Hz), 4.04 (t, 2H, J ) 7.2 Hz), 7.14-7.16 (m, 2H), 7.24-7.26
m, 1H), 7.34-7.36 (m, 3H), 7.55-7.57 (m, 2H) and 7.70-7.73
1241. MS (ES+, m/z, %): 437.0 (M + H , 100), 439.0 (M + H
+ 2), 346.9 (25), 232.0 (20). Anal. Calcd for C21 21BrFeN : C,
57.70; H, 4.84; N, 6.41. Found C, 57.75; H, 4.91; N, 6.10.
7
(
H
2
74 J. Org. Chem., Vol. 72, No. 1, 2007

Ferrocenyl- and Phenyl-N-n-butylbenzimidazoles
Method B: To a solution of 1 (100 mg, 0.28 mmol) in dry THF
mmol) was added dropwise. The reaction mixture was stirred 1 h
(
2 mL) under argon stirred at -78 °C was added tert-butyllithium
at -25 °C and then was allowed to warm to room temperature
overnight, quenched with a saturated solution of NH Cl (10 mL),
4
(0.279 mL of a 1.5 M solution in pentane, 0.418 mmol). The
resulting solution was stirred for 2 h. Then a solution of 1,2-
dibromotetrachloroethane (181 mg, 0.56 mmol) in dry THF (2 mL)
was added, and the mixture was stirred at -78 °C. After 1 h, the
mixture was warmed to room temperature and stirred over 2 h, the
and extracted with diethyl ether (3 × 7 mL). The combined organic
extracts were dried, evaporated, and purified by silica gel chroma-
tography (hexane/ethyl acetate, 9:1, then ethyl acetate as eluent)
1
to give 10a (179 mg, 87%) as a yellow thick oil. H NMR (CDCl
3
,
reaction was quenched with saturated NH
4
Cl solution (2 mL), and
400 MHz): δ 0.69 (t, 3H, J ) 7.6 Hz), 1.08 (hextet, 2H, J ) 7.2
Hz), 1.61 (quintet, 2H, J ) 7.6 Hz), 4.01 (t, 2H, J ) 7.6 Hz),
7.24-7.31 (m, 2H), 7.37-7.40 (m, 1H), 7.53 (d, 1H, J ) 7.6 Hz),
7.60 (t, 1H, J ) 7.6 Hz), 7.67 (t, 1H, J ) 7.6 Hz), 7.76 (dd, 1H,
the product was extracted with diethyl ether (3 × 5 mL). The
combined organic extracts were washed with brine (3 × 5 mL),
dried, evaporated, and purified as in the previous experiment to
give 9a (103 mg, 85%) as a brown-green solid.
1
3
J ) 6.6, 2 Hz), 8.04 (d, 1H, J ) 7.6 Hz), 9.88 (1H, s). C NMR
(CDCl , 100 MHz): δ 12.4, 18.8, 30.6, 43.4, 109.2, 119.2, 121.6,
122.2, 127.6, 129.3, 130.0, 132.3, 132.5, 134.0, 134.6, 142.1, 149.0,
2-(2-Trimethylsilylferrocenyl)-N-n-butylbenzimidazole (9b).
3
To a solution of 1 (200 mg, 0.56 mmol) in dry THF (8 mL) under
argon stirred at -78 °C was added tert-butyllithium (0.56 mL of a
-1
189.9. IR (neat, cm ): 3059, 2957, 2930, 2870, 1693, 1453, 1385,
1329, 743. HRMS (ES+): C18 O m/z calcd 279.1492 (M +
H ), found 279.1494. Anal. Calcd for C18 O: C, 77.67; H,
1.5 M solution in pentane, 0.84 mmol). The resulting solution was
19 2
H N
+
stirred for 3.5 h. Then, trimethylsilylchloride (0.15 mL, 1.12 mmol)
18 2
H N
was added dropwise, and the mixture was stirred at -78 °C. After
6.52; N, 10.06. Found C, 76.56; H, 6.82; N, 9.63.
2
h, the mixture was gradually warmed to room temperature and
2-(2-Bromophenyl)-N-n-butylbenzimidazole (10b). To a solu-
tion of 3 (307 mg, 1.23 mmol) in dry THF (10 mL) under argon
stirred at -25 °C was added dropwise n-butyllithium (1.54 mL of
a 1.6 M solution in hexane, 2.46 mmol) over 20 min. After the
solution was stirred for 3 h at -25 °C, a solution of 1,2-
dibromotetrachloroethane (0.800 g, 2.46 mmol) in dry THF (1.5
mL) was added dropwise. The reaction mixture was stirred 1 h at
-25 °C, allowed to warm to room temperature overnight, quenched
stirred for 15 h. The reaction was then quenched with saturated
NH
Cl solution (9 mL) and extracted with diethyl ether (3 × 10
mL). The combined organic extracts were washed with water (2 ×
0 mL) and brine (2 × 10 mL), dried, evaporated, and purified by
silica gel chromatography (hexane/ethyl acetate, 2:1 as eluent) to
4
1
1
3
give 9b (92 mg, 25%) as a red oil. H NMR (CDCl , 400 MHz):
δ 0.21 (s, 9H), 0.93 (t, 3H, J ) 7.2 Hz), 1.36 (hextet, 2H, J ) 7.2,
1
4
4.8 Hz), 1.62-1.84 (m, 2H), 3.96-4.05 (m, 1H), 4.34 (s, 5H),
.36 (dd, 1H, J ) 1.2, 2.4 Hz), 4.37-4.47 (m, 1H), 4.53 (t, 1H, J
4
with a saturated solution of NH Cl (10 mL), and extracted with
diethyl ether (3 × 7 mL). The combined organic extracts were dried,
evaporated, and purified by silica gel chromatography (hexane/ethyl
acetate, 9:1, then ethyl acetate as eluent) to give 10b (20 mg, 5%)
as a red thick oil. All spectroscopic and analytical properties were
)
2.4 Hz), 4.62 (dd, 1H J ) 1.2, 2.4 Hz), 7.20-7.27 (m, 2H),
13
7
3
.29-7.34 (m, 1H), 7.71-7.80 (m, 1H). C NMR (CDCl , 100
MHz): δ 0.0, 13.1, 19.6, 31.4, 43.4, 69.3, 70.6, 71.7, 74.1, 74.7,
-
1
24
108.6, 119.0, 120.9, 121.2, 130.8, 146.6, 151.9. IR (KBr, cm ):
identical to those reported in the literature.
2
C
958, 2926, 2852, 1531, 1457, 1243, 838, 743. HRMS (ES+):
2-(2-Trimethylsilanylphenyl)-N-n-butylbenzimidazole (10c).
To a solution of 3 (393 mg, 1.57 mmol) in dry THF (13 mL) under
argon stirred at -42 °C was added dropwise n-butyllithium (1.96
mL of a 1.6 M solution in hexane, 3.136 mmol) over 30 min. After
the solution was stirred for 2 h at -42 °C, anhydrous TMSCl (0.397
mL, 3.14 mmol) was added dropwise. The reaction mixture was
stirred 1 h at -42 °C, allowed to warm to room temperature
54
+
24 31 2
H N FeSi m/z calcd 429.1646 (M + H ), found 429.1647.
2-(N-n-Butylbenzimidazole)phenylboroxine (4b). To a solution
of 3 (338 mg, 1.35 mmol) in dry THF (14 mL) under argon stirred
at -78 °C was added dropwise tert-butyllithium (1.35 mL of a 1.5
M solution in pentane, 2.02 mmol) over 40 min. After the solution
was stirred for 2 h at -78 °C, triisopropylborate (0.63 mL, 2.69
mmol) was added dropwise. The reaction mixture was stirred 1 h
at -78 °C and then was allowed to warm to room temperature
overnight. The reaction mixture was quenched with a 10% solution
of NaOH (8 mL) and neutralized to a pH of 7 with a 10% solution
of HCl. After evaporation of the THF, a precipitate was formed
and removed by filtration. The resulting solid was purified by
chromatography on aluminum oxide (ethyl acetate, then acetonitrile
4
overnight, quenched with a saturated solution of NH Cl (10 mL),
and extracted with diethyl ether (3 × 10 mL). The combined organic
extracts were dried, evaporated, and purified by silica gel chroma-
tography (hexane/ethyl acetate, 9:1, then ethyl acetate as eluent)
1
to give 10c (438 mg, 87%) as a yellow thick oil. H NMR (CDCl
3
,
400 MHz): δ 0.00 (s, 9H), 0.85 (t, 3H, J ) 7.6 Hz), 1.28 (hextet,
2H, J ) 8 Hz), 1.72 (quintet, 2H, J ) 7.2 Hz), 3.94 (t, 2H, J ) 7.6
24
and acetonitrile/methanol, 9:1, as eluent) giving the boroxine 4b
Hz), 7.26-7.32 (m, 2H), 7.37-7.49 (m, 4H), 7.69-7.72 (m, 1H),
1
13
(
(
248 mg, 67%) as a white powder. Mp: 238-239 °C. H NMR
7.78-7.82 (m, 1H). C NMR (CDCl
3
, 100 MHz): δ 0.00 (3C),
CDCl
3
, 400 MHz): δ 0.77 (t, 9H, J ) 7.2 Hz), 1.21 (hextet, 6H,
13.6, 20.5, 32.2, 44.7, 110.3, 120.4, 122.4, 122.9, 128.7, 129.1,
130.1, 135.0, 135.4, 136.5, 141.9, 143.2, 154.8. IR (neat, cm ):
-
1
J ) 8 Hz), 1.60 (quintet, 6H, J ) 7.6 Hz), 3.96 (t, 6H, J ) 7.2
Hz), 7.02 (d, 3H, J ) 8 Hz), 7.09-7.19 (m, 12H), 7.27-7.30 (m,
3051, 2955, 2896, 2872, 1454, 1385, 1328, 835, 750. HRMS
H), 7.53-7.55 (m, 6H). 13C NMR (CDCl
(ES+): C20
Anal. Calcd for C20
73.17; H, 7.70; N, 8.59.
H
N
Si m/z calcd 323.1938 (M + H ), found 323.1940.
+
3
2
1
1
1
3
, 100 MHz): δ 13.6,
27
2
0.1, 31.5, 44.5, 109.7, 117.3, 122.3, 122.9, 124.5, 127.6, 130.1,
26 2
H N Si: C, 74.48; H, 8.12; N, 8.69. Found C,
11
3
32.2, 132.4, 135.6, 136.6, 149.1 (br), 155.2. B NMR (CDCl ,
28 MHz): δ 18.0. IR (neat, cm ): 3055, 2957, 2931, 2869, 1459,
433, 1397, 1358, 1297, 737. HRMS (ES+): C51 m/z
-1
Acknowledgment. We thank the EPSRC for a research grant
(GR/T22759/01) and both the EPSRC and GlaxoSmithKline
Pharmaceuticals for a CASE award (to A.R.B.).
52 6 3 3
H N O B
+
calcd 829.4364 (M + H ), found 829.4375. Anal. Calcd for
C H B N O
51 51 3 6 3
: C, 73.94; H, 6.21; N, 10.14. Found C, 72.26; H,
6
.10; N, 9.86.
Supporting Information Available: General experimental
2-(N-n-Butylbenzimidazole)benzaldehyde (10a). To a solution
1
13
methods and H and C NMR spectra for compounds 1 and 9b.
This material is available free of charge via the Internet at
http://pubs.acs.org.
of 3 (186 mg, 0.74 mmol) in dry THF (7 mL) under argon stirred
at -25 °C was added dropwise n-butyllithium (0.927 mL of a 1.6
M solution in hexane, 1.483 mmol) over 20 min. After the solution
was stirred for 3 h at -25 °C, anhydrous DMF (0.459 mL, 5.93
JO061639+
J. Org. Chem, Vol. 72, No. 1, 2007 75