Aromatic amination/imination approach to chiral benzimidazoles

Article abstract of DOI:10.1021/jo016251n

The powerful Buchwald-Hartwig amination was utilized for the construction of the benzimidazole nucleus with the substituted nitrogen atom bearing a chiral substituent. A successive amination/imination was followed by an acid-catalyzed ring closure step to give the benzimidazole ring. The products were deprotonated and acylated at the C2 position and could be alkylated on nitrogen to give chiral benzimidazolium salts.

Full text of DOI:10.1021/jo016251n

1708
J . Org. Chem. 2002, 67, 1708-1711
resort to direct N-alkylation of an unsubstituted benz-
imidazole.4 Synthetic strategies that utilize intermediate
o-nitroanilines have evolved to include the synthesis of
benzimidazoles on solid support.5-11 Benzimidazoles have
been used as antifungals,12,13 antibacterials,12,14,15 anti-
helminthics,16 5-HT receptor antagonists,17,18 and throm-
bin receptor antagonists.19,20 A weakness in the current
preparations of benzimidazoles, identified in our own
synthetic studies directed toward chiral benzimidazolium
salts, is the incorporation of chiral substitution on the
nitrogen atom.
The starting point for the construction of the benzimi-
dazoles are the 2-bromoanilines, which were prepared by
amination of 1,2-dibromobenzene, as previously re-
ported.21 To install the second amine required the use of
an ammonia equivalent, and benzophenone imine22 was
chosen for this purpose. Benzophenone imine was coupled
to three 2-bromoanilines 1A-C, each with chiral substi-
tution on the position R to nitrogen (Scheme 1). The
intermediate iminoanilines 2 were purified and subjected
to transimination using the R-effect nucleophile hydroxyl-
amine to provide the respective unprotected anilines 3.
Since Buchwald’s original report using benzophenone
imine as an ammonia equivalent, other ammonia equiva-
lents for palladium-catalyzed amination have been
developed.23-29 Excellent yields of the 2-aminoanilines 3
are obtained using this two-step procedure.
Ar om a tic Am in a tion /Im in a tion Ap p r oa ch to
Ch ir a l Ben zim id a zoles
Felix M. Rivas, Anthony J . Giessert, and
Steven T. Diver*
Department of Chemistry, University at Buffalo, the State
University of New York, Buffalo, New York 14260-3000
diver@nsm.buffalo.edu
Received October 30, 2001
Abstr a ct: The powerful Buchwald-Hartwig amination was
utilized for the construction of the benzimidazole nucleus
with the substituted nitrogen atom bearing a chiral sub-
stituent. A successive amination/imination was followed by
an acid-catalyzed ring closure step to give the benzimidazole
ring. The products were deprotonated and acylated at the
C2 position and could be alkylated on nitrogen to give chiral
benzimidazolium salts.
Many of the most utilized methods for benzimidazole
synthesis employ the intermediacy of N-substituted 1,2-
benzenediamines, which can be subsequently cyclized in
a number of ways.1 However, the introduction of chiral
centers in the nitrogen side chain of N-substituted 1,2-
benzenediamines is difficult, although a paper describing
the solid-phase preparation of chiral 2-aminobenzimida-
zoles has recently appeared.2 Here we describe a novel
approach to the synthesis of chirality-bearing N-substi-
tuted 1,2-benzenediamines using Pd-catalyzed amination
and imination (eq 1). The mildness of the procedure
allows for the direct introduction of R-chiral primary
amines. The second coupling utilizes benzophenone imine
as precursor to the unsubstituted nitrogen of the azole
ring system. The products can then be cyclized to afford
benzimidazoles by using literature methods. The unique
chiral benzimidazole products can be acylated or quat-
ernized with alkyl halides.
(4) Racemic achiral benzimidazoles can be prepared by alkylation
of benzimidazole. See: Simonov, A. M.; Pozharskii, A. F. Zh. Obshch.
Khim. 1964, 34, 1572-1574.
(5) Mazurov, A. Bioorg. Med. Chem. Lett. 2000, 10, 67-70.
(6) Tumelty, D.; Cao, K.; Holmes, C. P. Org. Lett. 2001, 3, 83-86.
(7) Tumelty, D.; Schwarz, M. K.; Needels, M. C. Tetrahedron Lett.
1998, 39, 7467-7470.
(8) Mayer, J . P.; Lewis, G. S.; McGee, C.; Bankaitis-Davis, D.
Tetrahedron Lett. 1998, 39, 6655-6658.
(9) Huang, W.; Scarborough, R. M. Tetrahedron Lett. 1999, 40,
2665-2668.
(10) Smith, J . M.; Krchnak, V. Tetrahedron Lett. 1999, 40, 7633-
7636.
(11) Kilburn, J . P.; Lau, J .; J ones, R. C. F. Tetrahedron Lett. 2000,
41, 5419-5421.
(12) Kucukbay, H.; Durmaz, R.; Guven, M.; Gunal, S. Arzneim.-
Forsch. 2001, 51, 420-424.
(13) Kawato, H. C.; Nakayama, K.; Inagaki, H.; Ohta, T. Org. Lett.
2001, 3, 3451-3454.
(14) Weidner-Wells, M. A.; Ohemeng, K. A.; Nguyen, V. N.; Fraga-
Spano, S.; Macielag, M. J .; Werblood, H. M.; Foleno, B. D.; Webb, G.
C.; Barrett, J . F.; Hlasta, D. J . Bioorg. Med. Chem. Lett. 2001, 11,
1545-1548.
Interest in benzimidazoles can be attributed to their
diverse biological properties.3 For this reason, substituted
benzimidazoles have attracted considerable recent syn-
thetic attention. The most popular strategies for their
synthesis utilize o-nitroanilines as intermediates1 or
(15) Kennedy, G.; Viziano, M.; Winders, J . A.; Cavallini, P.; Gevi,
M.; Micheli, F.; Rodegher, P.; Seneci, P.; Zumerle, A. Bioorg. Med.
Chem. Lett. 2000, 10, 1751-1754.
(16) Navarrete-Vazquez, G.; Cedillo, R.; Hernandez-Campos, A.;
Yepez, L.; Hernandez-Luis, F.; Valdez, J .; Morales, R.; Cortes, R.;
Hernandez, M.; Castillo, R. Bioorg. Med. Chem. Lett. 2001, 11, 187-
190.
(1) General reviews of benzimidazole synthesis: (a) Grimmett, M.
R. In Comprehensive Heterocyclic Chemistry II; Shinkai, I., Ed.;
Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds-in-chief; Perga-
mon: Oxford, 1996; Vol. 3, chapter 3.02. (b) Grimmett, M. R. In
Comprehensive Heterocyclic Chemistry; Potts, K. T., Ed.; Katritzky, A.
R., Rees, C. W., Eds-in-chief; Pergamon: Oxford, 1984; Vol. 4, chapter
4.08. (c) Preston, P. N. In Benzimidazoles and Congeneric Tricyclic
Compounds. Part I; Preston, P. N., Ed.; The Chemistry of Heterocyclic
Compounds, J ohn Wiley and Sons: New York, 1981; Vol. 1. (d) Preston,
P. N. Chem. Rev. 1974, 74, 4, 279-314. (e) Pozharskii, A. F.;
Garnovskii, A. D.; Simonov, A. M. Russ. Chem. Rev. 1966, 35, 122-
144. (f) Wright, J . B. Chem. Rev. 1951, 48, 397-537.
(17) Lopez-Rodriguez, M. L.; Benhamu, B.; Viso, A.; Murcia, M.;
Pardo, L. Tetrahedron 2001, 57, 6745-6749.
(18) Lopez-Rodriguez, M. L.; Benhamu, B.; Ayala, D.; Rominguera,
J . L.; Murcia, M.; Ramos, J . A.; Viso, A. Tetrahedron 2000, 56, 3245-
3253.
(19) Chackalamannil, S.; Xia, Y.; Clasby, M.; Greenlee, W.; Doller,
D.; Eagen, K.; Tsai, H. S.; Asberom, T.; Lin, Y.; Czarniecki, M.; Ahn,
H. S.; Foster, C.; Boykow, G. Abstr. Pap. Am. Chem. Soc. 2001, 221,
U60.
(20) Chackalamannil, S.; Doller, D.; Eagen, K.; Czamiecki, M.; Ahn,
H. S.; Foster, C. J .; Boykow, G. Bioorg. Med. Chem. Lett. 2001, 11,
2851-2853.
(2) Lee, J . B.; Doucette, A.; Wilson, N. S.; Lord, J . Tetrahedron Lett.
2001, 42, 2635-2638.
(21) Rivas, F. M.; Riaz, U.; Diver, S. T. Tetrahedron: Asymmetry
2000, 11, 1703-1707.
(3) Spasov, A. A.; Yozhitsa, I. N.; Bugaeva, L. I.; Anisimova, V. A.
Pharm. Chem. J . 1999, 33, 232-243.
(22) Wolfe, J . P.; Ahman, J .; Sadighi, J . P.; Singer, R. A.; Buchwald,
S. L. Tetrahedron Lett. 1997, 38, 6367-6370.
10.1021/jo016251n CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/06/2002

Notes
J . Org. Chem., Vol. 67, No. 5, 2002 1709
Sch em e 1. Im in a tion /Tr a n sim in a tion
together for 0.5 h before the reactants were introduced,
which were then heated in a sealed reaction vessel. With
1 mol % Pd-atom (n ) 0.5), a 58% conversion was
achieved with ligand 4, but only after 28 h reaction time
(entry 1). The reaction is about 10 times faster using 4
mol % Pd-atom (n ) 2, entry 2). The mixed donor ligand
5 was also effective in catalyzing the coupling in eq 3,
but like BINAP, it proved most effective at higher
palladium loadings. Short reaction time (0.5 h, entry 5)
was realized at 80 °C when 6.8 mol % Pd atom was used.
The synthesis of benzimidazoles bearing a chiral sub-
stituent on nitrogen is summarized in Table 2. The
Ta ble 2. Rin g Syn th esis of N-Ch ir a l Ben zim id a zoles
The monosubstituted 1,2 benzenediamines 3 bear a
chiral substituent. Due to the possibility of racemization
during and after the Pd-catalyzed coupling reaction, the
enantiomeric excesses of 2 were analyzed by HPLC. The
imination of Scheme 1 requires rather high catalyst
loadings which is probably necessary due to the steric
bulk of the substituted ortho nitrogen substituent and
the electron rich nature of the aromatic ring. Buchwald
has reported the use of low catalyst loadings for the
coupling to less-hindered aromatic halides,22 and further
improvement in the imination of Scheme 1 might be
possible using other phosphine donors. The phenylgly-
cinol-derived aniline required higher reaction tempera-
tures for the coupling using BINAP as the diphosphine
ligand. The latter conditions had previously been found
to be suitable for the synthesis of hindered 1,2-phenylene
diamines;21 however, the extreme temperatures were not
necessary for iminations to form 2A and 2B.
entry diamine
reagents
product R3
yield
1
2
3
4
5
6
7
3A
3A
3A
3A
3B
3C
3C
(MeO)3CH, TsOH (cat.) 6A
H
91% (99% ee)
(MeO)3CCH3, HCl
(MeO)3CPh, HCl
CNBr, EtOH
7A
8A
9A
CH3 98% (99% ee)
Ph 97% (99% ee)
NH2 89% (99% ee)
H
H
(MeO)3CH, TsOH (cat.) 10B
(MeO)3CH, TsOH (cat.) 11C
88% (98% ee)
90%
(MeO)3CCH3, HCl
12C
CH3 86%
In general, higher catalyst loadings (4 mol % Pd atom)
were needed to drive the imination to completion; how-
ever, we examined the effect of catalyst loading on the
coupling of 1A with benzophenone imine to see if the
reaction could function at lower catalyst loadings (Table 1).
sequence constitutes a ring synthesis of the benzimida-
zole nucleus from the substituted 1,2-benzenediamine.
The cyclization reactions were carried out using excess
of the required ortho ester.30,31 In some cases, the reaction
could be catalyzed by p-TsOH; however, in the more
demanding cyclizations using (EtO)3CCH3 and (EtO)3-
CPh, the use of 1 equiv of hydrochloric acid proved
necessary. Basicification and extractive workup then
provided the benzimidazole free bases. Purification of the
benzimidazoles was possible through chromatography or
recrystallization.
Ta ble 1. Effect of Ca ta lyst Loa d in g
From Table 2 it is evident that a variety of substitution
patterns can be introduced on the N-chiral benzimidazole.
Using commercially available orthoformate or ortho
esters, proton, methyl, or phenyl could be introduced in
the C2 position. Cyclization using cyanogen bromide was
used to form the 2-amino-substituted benzimidazole 9A.32
The cyclizations proceed without racemization, a process
that could have occurred through azolium species. In the
first five entries, the enantiomeric excess was checked
against authentically prepared racemates, synthesized
starting from commercially available racemic R-methyl-
benzylamine. The optical activities of compounds 11C
and 12C were established by optical rotation. Although
entry
n
ligand solvent temp, C° time, h % conversion
1
2
3
4
5
0.5
2.0
0.07
1.0
3.4
4
4
5
5
5
toluene
toluene
DME
DME
DME
110
110
80
80
80
28
2.5
19.5
28
58
100
<1
31
0.5
100
(26) Bolm, C.; Hildebrand, J . P. Tetrahedron Lett. 1998, 39, 5731-
5734.
(27) Lim, C. W.; Lee, S.-G. Tetrahedron 2000, 56, 5131-5136.
(28) Lee, S.; J orgensen, M.; Hartwig, J . F. Org. Lett. 2001, 3, 2729-
2732.
(29) Huang, X.; Buchwald, S. L. Org. Lett. 2001, 3, 3417-3419.
(30) Montgomery, J . A.; Temple, C. J . Org. Chem. 1960, 25, 395-
399.
(31) Schipper, E.; Day, A. R. J . Am. Chem. Soc. 1951, 73, 5672-
5675.
(32) Bashir, M.; Kingston, D. G. I.; Carman, R. J .; Vantassell, R.
L.; Wilkins, T. D. Heterocycles 1987, 26, 2877-2886.
In each of the iminations of Table 1, the palladium
precatalyst and the donor ligand 4 or 5 were heated
(23) Mann, G.; Hartwig, J . F.; Driver, M. S.; Fernandez-Rivas, C.
J . Am. Chem. Soc. 1998, 120, 827-828.
(24) J aime-Figueroa, S.; Liu, Y.; Muchowski, J . M.; Putman, D. G.
Tetrahedron Lett. 1998, 39, 1313-1316.
(25) Hori, K.; Mori, M. J . Am. Chem. Soc. 1998, 120, 7651-7652.

1710 J . Org. Chem., Vol. 67, No. 5, 2002
Notes
11C was not prepared as its racemate for authentication
of enantiomeric purity, its HPLC trace showed a single
peak.
in the cyclization step or in subsequent functionalization
at the C2 position.
The chiral benzimidazoles could be further function-
alized by acylation. For instance, benzimidazole 6A was
deprotonated with BuLi and benzoylated with methyl
benzoate (eq 5).33,34 Addition of the metalated benzimi-
dazole to the electrophile at -78 °C gave variable yields.
Similar results were observed by Davies et al. in the low-
temperature acylation of 2-lithioimidazoles.33 To improve
the yields, the C2 metalated benzimidazole was precooled
to -95 °C before the dropwise introduction of the elec-
trophile. In this way, consistent results were obtained.
As expected, the enantiomeric excess of the chiral center
present in the side chain was not diminished under
strongly basic conditions.
Exp er im en ta l Section
Gen er a l. Reactions were conducted under an argon atmo-
sphere in oven-dried, sealable Schlenk or pressure tubes equipped
with a threaded Teflon plug and magnetic stirbar. Column
chromatography was carried out on Merck silica gel 60 (230-
400 mesh). H NMR spectra were recorded at 500 MHz and 13C
1
NMR spectra at 125 MHz in CDCl3. Optical rotations were
measured using the sodium D line in a thermostated cell held
at 25 °C. Enantiomeric and diastereomeric excesses were
determined by HPLC using a Chiralcel OD-H column, 2-pro-
panol/hexane, at the indicated ratio and rate, and UV-254 unless
stated otherwise. Melting points are uncorrected. Elemental
analyses were performed by Atlantic Microlabs Inc., Norcross,
GA. Toluene was distilled from CaH2 immediately prior to use.
Tetrahydrofuran (THF) and ethylene glycol dimethyl ether
(DME) was distilled from sodium benzophenone ketyl prior to
use. Pd2dba3 and (()-BINAP were purchased from Strem
Chemical Company. Sodium tert-butoxide was purchased from
Aldrich Chemical Co. and transferred inside a drybox to small
vials that were then stored in a desiccator filled with anhydrous
calcium sulfate and weighed in the air. Methyl benzoate was
dried with Na2SO4 and fractionally distilled prior to use. (R)-
(-)-1-Amino-1-phenyl-2-methoxyethane was prepared as re-
ported.37 1-(N,N-Dimethylamino)-1′-(dicyclohexylphosphino)-
biphenyl 5 was prepared as reported.38 (2-Bromophenyl)-(S)-1-
phenylethylamine, (2-bromophenyl)-(S)-1-cyclohexylethylamine,
and (2-bromophenyl)-(R)-2-methoxy-1-phenylethylamine were
prepared according to the literature.36 All other reagents were
purchased from Aldrich Chemical company and used without
additional purification.
Due in part to the current interest in room-tempera-
ture ionic liquids35 and our long standing interest in
chiral benzimidazolium salts, we elaborated the chiral
benzimidazoles into N-alkyl benzimidazolium salts (eq
6). The approach in eq 6 offers a complementary strategy
Gen er a l P r oced u r e for t h e Im in a t ion of (2-Br om o-
p h en yl)a m in es: N-[(S)-1-P h en yleth yl]-N′-(d ip h en ylm eth -
ylen e)-1,2-ben zen ed ia m in e 2A. An oven-dried pressure tube
equipped with magnetic stirbar and rubber septum was cooled
under argon. The pressure tube was charged with 70.9 mg of
Pd2dba3 (0.0774 mmol, 2.0 mol %), 96.4 mg of rac-BINAP (0.155
mmol, 4.0 mol %), and toluene (15.0 mL). The rubber septum
was replaced with a Teflon screwcap, and the mixture was
heated at 110 °C in an oil bath for 30 min. The solution was
then allowed to cool to room temperature, and 844 µL of
benzophenone imine (5.03 mmol, 1.30 equiv), 1.07 g of 1A (3.87
mmol, 1.00 equiv), and 483.4 mg of sodium tert-butoxide (5.03
mmol, 1.30 equiv) were added. The pressure tube was sealed
and heated in an oil bath at 110 °C with stirring for 2.5 h. The
solution was then allowed to cool to room temperature, diluted
to the direct synthesis of benzimidazolium salts reported
from these laboratories36 and is an efficient way to
introduce simple alkyl groups. Butyl iodide alkylation
provided the quaternary salt 14A in 98% yield. Counte-
rion exchange on 14A using excess NH4BF4 proved
inefficient, giving mixtures of the iodide and tetrafluo-
roborate salts which are distinguishable by TLC. How-
ever, treatment of iodide 14A with AgBF4 in CH3CN gave
a high yield of the desired tetrafluoroborate 14B, which
was obtained as a solid, mp 126-127 °C. Similar alky-
lations of long chain normal alkyl iodides is expected to
give similar results and may result in salts with lower
melting points. Further studies are in progress.
In conclusion, an efficient synthesis of benzimidazoles
that bear chiral substituents on the nitrogen atom has
been achieved using an amination/imination/ring syn-
thesis approach. The methods used for the synthesis of
the benzimidazoles do not result in racemization of the
chirality in the side chain at nitrogen. The incorporation
of substitution at the C2 position may be accomplished
with diethyl ether, filtered through
a pad of Celite, and
concentrated in vacuo (rotatory evaporator) to give a crude dark
brown-black oil which was purified by flash chromatography
(gradient elution with 10% CH2Cl2/hexane to 50% CH2Cl2/
hexane) to provide 1.44 g of 2A (99%) as a yellow oil. Analytical
1
TLC (50% CH2Cl2/hexane) Rf 0.14. H NMR (500 MHz, CDCl3)
7.84 (d, J ) 7.5 Hz, 2 H), 7.50-7.32 (m, 5 H), 7.31-7.28 (m, 5
H), 7.23-7.15 (m, 3 H), 6.70 (t, J ) 7.5 Hz, 1 H), 6.36 (d, J ) 7.5
Hz, 1 H), 6.26 (t, J ) 7.5 Hz, 1 H), 6.13 (d, J ) 7.5 Hz, 1 H),
4.86 (s, 1 H), 4.55 (m, 1 H), 1.54 (d, J ) 6.5 Hz, 3 H); 13C NMR
(125 MHz, CDCl3) δ 168.0, 145.7, 141.3, 139.9, 136.7, 136.4,
130.5, 129.4, 129.1, 128.8, 128.5, 128.1, 128.1, 126.7, 125.8, 125.0,
119.2, 116.1, 111.3, 53.7, 25.4; FT-IR (film, NaCl) 3402, 1593
cm-1; High-resolution MS (EI+, m/z) molecular ion calcd for
C
27H24N2 376.1939, found 376.1935; error 1.1 ppm. Enantiomeric
excess determination by HPLC (0.50 mL/min, 10% 2-propanol/
hexane, tR ) 8.0 (S) and 9.6 (R) min) indicated 99% ee.
Gen er a l P r oced u r e22 for th e Tr a n sim in a tion : N-[(S)-1-
P h en yleth yl]-1,2-ben zen ed ia m in e 3A. To a 50 mL round-
bottom flask equipped with a magnetic stirbar were added 504.0
mg of 2A (1.339 mmol, 1.0 equiv), methanol (30.0 mL), 263.3
mg of sodium acetate (3.210 mmol, 2.4 equiv), and 167.5 mg of
(33) Davies, D. H.; Hall, J .; Smith, E. H. J . Chem. Soc., Perkin Trans.
1 1991, 2691-2698.
(34) Ohta, S.; Hayakawa, S.; Moriwaki, H.; Harada, S.; Okamoto,
M. Chem. Pharm. Bull. 1986, 34, 4916-4926.
(35) Welton, T. Chem. Rev. 1999, 99, 9, 2071-2083.
(36) Rivas, F. M.; Riaz, U.; Giessert, A.; Smulik, J . A.; Diver, S. T.
Org. Lett. 2001, 3, 2673-2676.
(37) Smith, A. B.; Yager, K. M.; Taylor, C. M. J . Am. Chem. Soc.
1995, 117, 10879-10888.
(38) Old, D. W.; Wolfe, J . P.; Buchwald, S. L. J . Am. Chem. Soc.
1998, 120, 9722-9723.

Notes
J . Org. Chem., Vol. 67, No. 5, 2002 1711
hydroxylamine hydrochloride (2.410 mmol, 1.8 equiv). The
resulting solution was then stirred at room temperature for 1
h. The solution was partitioned between 0.1 M NaOH and CH2-
Cl2, and the organic layer was dried over Na2SO4, filtered, and
concentrated in vacuo (rotatory evaporator). The resulting oil
was purified by flash chromatography (elution with 6:1 hexane/
ethyl acetate, then 4:1 hexane/ethyl acetate) to yield 268.8 mg
of 3A (95%) as a colorless oil that turned light red upon standing
in solution or neat. Analytical TLC (30% hexane/ethyl acetate)
and the combined organic layers were dried with Na2SO4,
filtrated, and concentrated in vacuo (rotatory evaporator).
Purification by flash chromatography (gradient elution with CH2-
Cl2 to 5% MeOH/CH2Cl2) provided 200.3 mg of 9A (89%) as a
white solid, mp 97 °C (lit.4 120-122 °C for racemic 9A).
Analytical TLC (10% methanol/CH2Cl2) Rf 0.32. 1H NMR (500
MHz, CDCl3) δ 7.42 (d, J ) 7.5 Hz, 1 H), 7.39-7.30 (m, 5 H),
7.12 (t, J ) 7.5 Hz, 1 H), 7.07 (d, J ) 7.5 Hz, 1 H), 7.01 (t, J )
7.5 Hz, 1 H), 5.61 (q, J ) 7.0 Hz, 1H), 4.69 (br s, 2 H), 1.90 (d,
J ) 7.0 Hz, 3 H); 13C NMR (125 MHz, CDCl3, ppm) δ 153.4,
141.9, 139.0, 133.8, 129.1, 128.2, 126.5, 121.4, 119.6, 116.5, 108.6,
52.2, 17.5; FT-IR (film, NaCl) 3451, 3314, 1644, 1537 cm-1; High-
resolution MS (EI+,m/z) molecular ion calcd for C15H15N3 237.1266
found, 237.1269; error ) 1.3 ppm. Enantiomeric excess deter-
1
Rf 0.21. H NMR (500 MHz, CDCl3) δ 7.37 (d, J ) 7.5 Hz, 2 H),
7.31 (t, J ) 7.5 Hz, 2 H), 7.22 (t, J ) 7.5 Hz, 1 H), 6.72 (dd, J )
7.5, 1.3 Hz, 1 H), 6.66 (td, J ) 7.5, 1.3 Hz, 1 H), 6.61 (td, J )
7.5, 1.0 Hz, 1 H), 6.42 (d, J ) 7.5 Hz, 1 H), 4.49 (q, J ) 6.5 Hz,
1 H), 3.75 (br s, 1 H), 3.37 (br s, 2 H), 1.55 (d, J ) 6.5 Hz, 3 H);
13C NMR (125 MHz, CDCl3) δ 145.2, 136.9, 133.8, 128.6, 126.8,
125.9, 120.7, 118.4, 116.6, 113.1, 53.5, 25.2; FT-IR (film, NaCl)
3392, 3328, 741, 701 cm-1; High-resolution MS (EI+, m/z)
molecular ion calcd for C14H16N2 212.1313, found 212.1312; error
0.5 ppm. Enantiomeric excess determination by HPLC (0.50 mL/
min, 25% 2-propanol/hexane, tR ) 21.2 (S) and 27.2 (R) min)
indicated 99% ee.
mination by HPLC (1.00 mL/min, 5.0% 2-propanol/hexane, tR
30.6 (R) and 40.5 (S) min) indicated 99% ee.
)
1-[(S)-1-P h en ylet h yl]-3-b u t yl-1H -b en zim id a zoliu m io-
d id e 14A. Into an oven-dried 10 mL round-bottom flask
equipped with magnetic stirbar, reflux condenser, and rubber
septum was added 195.1 mg of 10B (0.854 mmol 1.0 equiv) and
3.0 mL of 1-iodobutane, and the resulting solution was heated
to 100 °C for 1.5 h. After cooling to room temperature, 9 mL of
hexane was added, and the resulting solution was separated
from the precipitate by decantation. The resulting yellow solid
was filtered through a plug of silica gel (elution 5% MeOH in
CH2Cl2) to provide a pale yellow solid that was recrystallized
from toluene/CH3CN and dried under vacumm (1 mmHg) at 30
°C over P2O5 to provide 345.8 mg of 14A (98%) as white crystals,
mp 185-186 °C. Analytical TLC (5% MeOH in CH2Cl2) Rf 0.29.
1H NMR (500 MHz, CDCl3) δ 11.18 (s, 1H), 7.82 (m, 2H), 7.69
(m, 2 H), 4.78 (app t, J app ) 7.5 Hz, 2 H), 4.70 (quin, 1 H), 2.13-
2.02 (m, 3 H), 1.90-1.79 (m, 5 H), 1.66 (m, 2 H), 1.47 (app sex,
J app ) 7.5 Hz, 2 H), 1.34-1.02 (m, 6 H), 1.00 (t, J ) 7.5 Hz, 3
H); 13C NMR (125 MHz, CDCl3) δ 140.9, 131.2, 130.9, 127.2,
127.1, 113.9, 113.2, 61.0, 47.3, 42.6, 31.4, 29.7, 29.1, 25.5, 25.4,
25.3, 19.6, 18.2, 13.5; FT-IR (KBr) 1556 cm-1; Low resolution
FAB-MS molecular ion calcd for C19H29N2(-I) 285.2, found 285.2.
Anal. Calcd. for C19H29IN2: C, 55.34%; H, 7.09%; N, 6.79%, found
C, 55.20%; H, 7.11%; N 6.65%. [R]25D) + 3.6 (c ) 0.50, CH2Cl2).
Gen er a l P r oced u r e for th e Syn th esis of Ben zim id a zole
Meth od A: 1-[(S)-1-P h en yleth yl]-1H-ben zim id a zole 6A. To
a 15 mL round-bottom flask equipped with magnetic stirbar was
added 194.8 mg of 3A (0.918 mmol, 1.0 equiv), 10.0 mL of triethyl
orthoformate, and 17.5 mg of p-toluenesulfonic acid monohydrate
(0.0918 mmol, 0.10 equiv), and the resulting solution was stirred
for 8 h. The solution was then diluted with ethyl acetate and
washed with NaHCO3. The aqueous layer was back-extracted
with ethyl acetate, and the combined organic layers were dried
over Na2SO4, filtered, and concentrated in vacuo (rotatory
evaporator) to give a brown oil. Purification by flash chroma-
tography (elution with 1% MeOH/CH2Cl2) provided 185 mg of
6A (91%) as a white solid, mp 151-152 °C (lit.38 114-115 °C
for racemic 6A). Analytical TLC (5% methanol/CH2Cl2) Rf 0.26.
1H NMR (500 MHz, CDCl3) δ 8.08 (s, 1 H), 7.82 (d, J ) 8.0 Hz,
1 H), 7.35-7.22 (m, 4 H), 7.19 (m, 4 H), 5.62 (q, J ) 7.0 Hz, 1
H), 2.00 (d, J ) 7.0 Hz, 3 H); 13C NMR (125 MHz, CDCl3, ppm)
δ 144.1, 140.9, 140.6, 133.6, 128.9, 128.0, 125.9, 122.8, 122.2,
120.4, 110.6, 55.2, 21.6; FT-IR (KBr) 1615, 1479 cm-1; High-
resolution MS (EI+, m/z) molecular ion calcd for C15H14N2
222.1157, found 222.1156; error 0.5 ppm. Anal. Calcd for
C15H14N2: C, 81.05%; H, 6.35%; N, 12.60%, found C, 80.90%;
H, 6.44%; N 12.62%. Enantiomeric excess determination by
HPLC (0.50 mL/min, 10% 2-propanol/hexane, tR ) 24.0 (S) and
32.4 (R) min) indicated 99% ee.
Gen er a l P r oced u r e for th e Syn th esis of Ben zim id a zole
Meth od B: 2-Meth yl-1-[(S)-1-p h en yleth yl]-1H-ben zim id a -
zole 7A. To a 10 mL round-bottom flask equipped with magnetic
stirbar were added 197.9 mg of 3A (0.932 mmol, 1.0 equiv), 5.0
mL of triethyl orthoacetate, and 80 µL of 12.1 N HCl (0.968
mmol, 1.0 equiv), and the resulting solution was stirred for 45
min. The solution was then diluted with CH2Cl2 and washed
with saturated NaHCO3. The aqueous layer was back-extracted
with CH2Cl2, and the combined organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo (rotatory evapora-
tor). Purification by flash chromatography (gradient elution with
1:2 ethyl acetate/hexane to ethyl acetate) provided 215.1 mg of
7A (98%) as a white solid, mp 78-79 °C. Analytical TLC (5%
methanol/CH2Cl2) Rf 0.31. 1H NMR (500 MHz, CDCl3) δ 7.70
(d, J ) 8.5 Hz, 1 H), 7.35-7.27 (m, 3 H), 7.21-7.16 (m, 3 H),
7.09-7.02 (m, 2 H), 5.76 (q, J ) 7.0 Hz, 1 H), 2.58 (s, 3 H), 1.97
(d, J ) 7.0 Hz, 3 H); 13C NMR (125 MHz, CDCl3, ppm) δ 151.5,
142.9, 139.5, 134.1, 128.8, 127.7, 126.2, 121.8, 121.6, 119.2, 111.0,
53.4, 18.7, 15.0; FT-IR (film, NaCl) 1613, 1516 cm-1; High-
resolution MS (EI+, m/z) molecular ion calcd for C16H16N2
236.1313, found 236.1314; error 0.4 ppm. Anal. Calcd for
1-[(S)-1-P h en yleth yl]-3-bu tyl-1H-ben zim id a zoliu m Tet-
r a flu or obor a te 14B. Into a plastic vial capped with a septum
were added 249.8 mg of 14A (0.606 mmol, 1.0 equiv) and 2.5
mL of dry acetonitrile. To the resulting solution was added 119.1
mg of AgBF4 (0.606 mmol, 1.0 equiv) in one portion. The
resulting yellow precipitate was filtered, and the resulting clear
solution was concentrated in vacuo (rotatory evaporator). Puri-
fication by flash chromatography using a 1.5 in. plug of silica
gel (elution 1% MeOH in CH2Cl2) followed by drying under
vacuum (1 mmHg) at 30 °C over P2O5 provided 195.6 mg of 14B
(87%) as a white solid, mp 126-127 °C. Analytical TLC (5%
MeOH in CH2Cl2) Rf 0.39. 1H NMR (500 MHz, CDCl3) δ 9.56 (s,
1 H), 7.78 (m, 2 H), 7.67 (m, 2 H), 4.60-4.51 (m, 3 H), 1.99 (app
quin, 3 H), 1.89-1.74 (m, 5 H), 1.66 (m, 2 H), 1.42 (app sex, J app
) 7.5 Hz, 2 H), 1.32-1.07 (m, 5 H), 1.04-0.96 (m, 4 H); 13C NMR
(125 MHz, CDCl3) δ 140.7, 131.4, 131.2, 127.2, 127.1, 113.9,
113.3, 61.3, 47.6, 42.5, 31.3, 29.7, 29.2, 25.6, 25.5, 25.4, 19.6,
17.5, 13.4; FT-IR (KBr) 1556, 1082 cm-1; Low resolution FAB-
MS molecular ion calcd. for C19H29N2(-I) 285.2, found 285.2.
Anal. Calcd for C19H29BF4N2: C, 61.30%; H, 7.85%; N, 7.53%,
found C, 61.37%; H, 7.83%; N 7.51%. [R]25 ) -8.3 (c ) 3.50,
D
CH2Cl2).
Ack n ow led gm en t. The authors thank the National
Science Foundation (Career CHE-92434) and Wyeth-
Ayerst for financial support of this work. F.M.R grate-
fully acknowledges the Ford Foundation for a predoc-
toral fellowship.
C
16H16N2: C, 81.32%; H, 6.82%; N, 11.85%, found C, 81.10%;
H, 6.73%; N 11.88%. Enantiomeric excess determination by
HPLC (0.50 mL/min, 20% 2-propanol/hexane, tR ) 14.4 (S) and
25.7 (R) min) indicated 99% ee.
2-Am in o-1-[(S)-1-p h en yleth yl]-1H-ben zim id a zole 9A. To
a 15 mL round-bottom flask were added 202.4 mg of 3A (0.953
mmol, 1.0 equiv), ethanol (11.0 mL), and 158.9 mg of BrCN (1.50
mmol, 1.5 equiv). The reaction mixture was stirred overnight,
diluted with 30 mL of CH2Cl2, and treated with saturated Na2-
CO3. The aqueous layer was back-extracted with fresh CH2Cl2,
Su p p or tin g In for m a tion Ava ila ble: Detailed experi-
mental procedures and characterization data for compounds
2B, 2C, 3B, 3C, 8A, 10B, 11C, 12C, and 13 are available as
Supporting Information. This information is available free of
charge via the Internet at http://pubs.acs.org.
J O016251N