A versatile synthesis of substituted benzimidazolium salts by an amination/ ring closure sequence

Article abstract of DOI:10.1021/ol016254m

(Equation presented) A new method to produce benzimidazolium salts based on a successive Buchwald-Hartwig amination and ring closure is reported. A variety of different benzimidazolium salts can be prepared using this procedure. Amines that bear an α-chir

Full text of DOI:10.1021/ol016254m

ORGANIC
LETTERS
2001
Vol. 3, No. 17
2673-2676
A Versatile Synthesis of Substituted
Benzimidazolium Salts by an Amination/
Ring Closure Sequence
Felix M. Rivas, Uzma Riaz, Anthony Giessert, Jason A. Smulik, 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 June 8, 2001
ABSTRACT
A new method to produce benzimidazolium salts based on a successive Buchwald−Hartwig amination and ring closure is reported. A variety
of different benzimidazolium salts can be prepared using this procedure. Amines that bear an r-chiral group undergo the reaction to furnish
chiral benzimidazolium salts. The salts that lack a C2 substituent on the heterocycle are readily deprotonated to give nucleophilic carbenes.
There remain fundamental questions about the factors which
most affect the reactivity of N-heterocyclic carbenes.1
Nonetheless, applications of these carbenes as ligands in the
general area of metal-based catalysis have become well-
known.2 The basis for the enhanced reactivity of metal
catalysts using the N-heterocyclic carbene is based on the
ligand’s σ donicity.3 Our interest in benzimidazole carbenes
and in N-heterocyclic carbenes in general stems from
questions concerning the nucleophilicity of the carbenes
themselves. To begin to address nucleophilicity, a method
was needed that could produce a range of carbenes in order
to probe electronic and structural issues. Knowledge of
nucleophilicity is expected to aid further organometallic
catalyst design and to facilitate applications of the carbenes
as nucleophilic catalysts.
(1) Recent review: Arduengo, A. J. Acc. Chem. Res. 1999, 32 (11), 913-
921.
N-Heterocyclic carbenes can be generated by deprotonation
of the corresponding azolium salts.4 Our experience with
benzimidazole carbenes led us to adopt this direct approach
(2) (a) Herrmann, W. A.; Kocher, C. Angew. Chem., Int. Ed. Engl. 1997,
36, 2162-2187. (b) Bourissou, D.; Guerret, O.; Gabbaie, F. P.; Bertrand,
G. Chem. ReV. 2000, 100, 39-91. (c) Weskamp, T.; Schattenmann, W. C.;
Spiegler, M.; Herrmann, W. A. Angew. Chem., Int. Ed. 1998, 37, 2490-
2493. (d) Weskamp, T.; Kohl, F. J.; Hieringer, W.; Gleich, D.; Herrmann,
W. A. Angew. Chem., Int. Ed. 1999, 38, 2416-2419. (e) Scholl, M.; Trnka,
T. M.; Morgan, J. P.; Grubbs, R. H. Tetrahedron Lett. 1999, 40, 2247-
2250. (f) Jafarpour, L.; Nolan, S. P. Organometallics 2000, 19, 2055-
2057. (g) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan,
S. P. J. Org. Chem. 2000, 65, 2204-2207. (h) Ackermann, L.; Fu¨rstner,
A.; Weskamp, T.; Kohl, F. J.; Herrmann, W. A. Tetrahedron Lett. 1999,
40, 4787-4790. (i) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402-
3415. (j) Lee, H. M.; Smith, D. C., Jr.; He, Z.; Stevens, E. D.; Yi, C. S.;
Nolan, S. P. Organometallics 2001, 20, 794-797. (k) Fu¨rstner, A.; Leitner,
A. Synlett 2001, 290-292. (l) Huang, J.; Grasa, G.; Nolan, S. P. Org. Lett.
1999, 1, 1307-1309. (m) Fu¨rstner, A.; Krause, H. AdV. Synth. Catal. 2001,
343, 343-350. (n) Enders, D.; Gielen, H. J. Organomet. Chem. 2001, 617-
618, 70-80. (o) Enders, D.; Gielen, H.; Raabe, G.; Runsink, J.; Teles, J.
H. Chem. Ber. 1996, 129, 1483-1488. (p) Lee, H. M.; Jiang, T.; Stevens,
E. D.; Nolan, S. P. Organometallics 2001, 20, 1255-1258.
(3) Enthalpy of binding to metals and chalcogens has been measured by
calorimetry: (a) Huang, J.; Stevens, E. D.; Nolan, S. P.; Petersen, J. L. J.
Am. Chem. Soc. 1999, 121, 2674-2678. (b) Huang, J.; Schanz, H.-J.;
Stevens, E. D.; Nolan, S. P.; Capps, K. B.; Bauer, A.; Hoff, C. D. Inorg.
Chem. 2000, 39, 1042-1045. (c) Huang, J.; Jafarpour, L.; Hillier, A. C.;
Stevens, E. D.; Nolan, S. P. Organometallics 2001, 20, 2878-2882.
(4) An alternative approach involves desulfurization of the thiourea: (a)
Kuhn, N.; Kratz, T. Synthesis 1993, 561-562. (b) Denk, M. K.; Thadani,
A.; Hatano, K.; Lough, A. J. Angew. Chem., Int. Ed. Engl. 1997, 36, 2607-
2609. (c) Hahn, F. E.; Wittenbecher, L.; Van, D. L.; Fro¨hlich, R. Angew.
Chem., Int. Ed. 2000, 39, 541-544. (d) Kuhn, N.; Niquet, E.; Steimann,
M.; Walker, I. Z. Naturforsch. B 1999, 54, 1181-1187. (e) Karkhanis, D.
W.; Field, L. Phos., Sulfur 1985, 22, 49-57. (f) Arduengo, A. J.; Goerlich,
J. R.; Krafczyk, R.; Marshall, W. J. Angew. Chem., Int. Ed. 1998, 37, 1963-
1965. (g) Faust, R.; Go¨belt, B. Chem. Commun. 2000, 919-920.
10.1021/ol016254m CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/20/2001

using benzimidazolium salts as the carbene precursors.
However, the literature methods for the synthesis of benz-
imidazolium salts have generally focused on N-alkylation
reactions which are limited to reactive halides and are
inappropriate for introduction of chiral substituents. In this
report, we provide a new method for the synthesis of
benzimidazolium salts containing a wide variety of substitu-
tion patterns (eq 1). The effectiveness of the method allows
for the generation of benzimidazolium salts which bear C2
substituents as well.
zene. This process has proven versatile for simultaneous and
stepwise introduction of amines resulting in symmetrical or
unsymmetrical 1,2-benzenediamines, respectively. To il-
lustrate the flexibility of our approach, monobromoanilines
were chosen as starting materials, available through a
controlled monoamination reaction (Scheme 1). Each reaction
Scheme 1. Preparation of Chiral Monobromoanilines
Our approach to carbene synthesis requires the availability
of the azolium precursors. Chiral N-substituted imidazolium
salts have been synthesized by a three-component condensa-
tion, a method that is suitable for the incorporation of R-chiral
primary amines into the imidazolium ring.5 The Grubbs
group has prepared dihydroimidazole carbenes in situ from
the dihydroimidazolium salts6 used in the preparation of the
highly active ruthenium carbene metathesis catalyst.7 Im-
portantly, the Grubbs paper7a also reported ruthenium
complexes made from the corresponding chiral dihydroimi-
dazolium salt produced through chiral diamine amination
with bromoarenes.6b Despite these advances, to the best of
our knowledge, there is no available method for introducing
chiral, nonracemic substituents on the nitrogen atoms of the
benzimidazolium nucleus.8 Recent developments in the
Buchwald-Hartwig reaction have facilitated the mild intro-
duction of chiral amines onto aromatic rings.9 The palladium-
catalyzed amination is also suitable for preparing polyanilines
including 1,2-benzenediamines, indicating a tolerance for
electron-rich aromatic halides.10
a) 1.0-2.0 mol % Pd2dba3, 2.0-6.0 mol % BINAP, 1.2-1.5
eq. NaOt-Bu, 1.0-1.2 eq. amine; Specific conditions: b) 95 °C,
48 h; c) 110 °C, 14 h; d) 80 °C, 48 h.
was optimized with respect to temperature and time. In the
case of 1 and 2, enantiomeric excess determinations indicated
that no racemization was occurring competitively with C-N
bond formation. The major byproducts in most cases were
the corresponding aniline (via reduction) and the correspond-
ing symmetrical dianiline. The competing reduction of
sterically hindered bromoarenes is thought to occur as a result
of intermediate palladium hydrides. It has been shown that
bulky phosphines and chelating diphosphines such as BINAP
are effective in suppressing the â-elimination pathway
leading to Pd-H, the pathway that also leads to racemization
of R-chiral primary amines.11 The diphosphine BINAP
proved to be the most versatile ligand in the couplings of
Scheme 1.
Our synthetic approach toward N-substituted benzimida-
zolium ions relies on Pd-catalyzed amination of dibromoben-
Benzimidazolium salts were constructed by a second
amination and a subsequent ring closure step (Table 1). In
the amination of 1 with R-methylbenzylamine, optimized
reaction conditions have already been reported.10c Careful
attention to reaction conditions proved critical in order to
suppress epimerization (entries 1 and 2) which was assayed
by 1H NMR and hplc. The cyclization step can be conducted
with one equivalent of the appropriate strong acid (HCl in
entries 1,3-5; HClO4 in entry 2). Typically, the salt
precipitated from the cooled solution. Counterion exchange
proved beneficial for the isolation of 10, the BPh4 salt
obtained by treating the crude chloride salt with NaBPh4 in
CH3CN. All of the salts in Table 1 are new compounds and
were characterized by spectral and elemental analyses.12
The present work was prompted by a need to generate
benzimidazole carbenes from the prepared benzimidazolium
(5) (a) Herrmann, W. A.; Goossen, L. J.; Ko¨cher, C.; Artus, G. R. J.
Angew. Chem., Int. Ed. Engl. 1996, 35, 2805-2807. (b) Herrmann, W. A.;
Goossen, L. J.; Artus, G. R. J.; Ko¨cher, C. Organometallics, 1997, 16,
2472-2477. (c) Arduengo, A. J. U.S. Patent 5,077,414, 1991. (d) Gridnev,
A. A.; Mihaltseva, I. M. Synth. Commun. 1994, 24, 1547-1555. (e)
Arduengo, A. J.; Krafczyk, R.; Schmutzler, R. Tetrahedron, 1999, 55,
14523-14534.
(6) (a) Saba, S.; Brescia, A.; Kaloustian, M. K. Tetrahedron Lett. 1991,
32, 5031-5034. (b) Cabanal-Duvillard, I.; Mangeney, P. Tetrahedron Lett.
1999, 40, 3877-3880.
(7) (a) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953-956. (b) Sanford, M. S.; Ulman, M.; Grubbs, R. H. J. Am. Chem.
Soc. 2001, 123, 749-750.
(8) Direct alkylation of benzimidazole is possible but produces a mixture
of enantiomers and diastereomers. Preparation of N-sec-phenethylbenzimi-
dazole: Simonov, A. M.; Pozharskii, A. F. Zh. Obshch. Khim. 1964, 34,
1572-1574.
(9) (a) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc.
1996, 118, 7215-7216. (b) Driver, M. S.; Hartwig, J. F. J. Am. Chem.
Soc. 1996, 118, 7217-7218. Reviews: (c) Wolfe, J. P.; Wagaw, S.;
Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31, 805-818. (d)
Hartwig, J. F. Angew. Chem., Int. Ed. 1998, 37, 2046-2047. (e) Yang, B.
H.; Buchwald, S. L. J. Organomet. Chem. 1999, 576, 125-146.
(10) (a) Witulski, B.; Senft, S.; Thum, A. Synlett 1998, 504-506. (b)
Beletskaya, I. P.; Bessmertnykh, A. G.; Guilard, R. Tetrahedron Lett. 1999,
40, 6393-6397. (c) Rivas, F. M.; Riaz, U.; Diver, S. T. Tetrahedron:
Asymmetry 2000, 11, 1703-1707.
(11) Mechanistic work on the â-elimination pathway: (a) Hartwig, J.
F.; Richards, S.; Baranano, D.; Paul, F. J. Am. Chem. Soc. 1996, 118, 3626-
3633. (b) Wagaw, S.; Rennels, R. A.; Buchwald, S. L. J. Am. Chem. Soc.
1997, 119, 8451-8458.
2674
Org. Lett., Vol. 3, No. 17, 2001

Scheme 2. Soluble Benzimidazolium Salts via Anion
Table 1. Benzimidazolium Salts by Amination/Ring Closure
Exchange
in Scheme 2, and one example appears in entry 4 of Table
1. For example, the ion pair 26 proved to be highly soluble
in common organic solvents (CH2Cl2, CHCl3, THF, CH3-
CN, EtOAc, acetone) and was more easily handled on the
benchtop than the hygroscopic chloride salts which became
gels on exposure to the atmosphere.15
Other chiral substituents in addition to R-methylbenzyl-
amine could be used in the reaction sequence. For instance,
phenylglycinol-derived monobromide 3 was coupled to
BuNH2 and acetylated to give a mixture of amide rotamers
that were cyclized with 1 equiv of HCl in toluene to give
salt 30 (Scheme 3). The main side reaction in the coupling
step was reduction of bromide 3.
salts of Table 1; however, the scope of the bisamination/
ring closure encompasses C-2 substituted benzimidazolium
salts.13 By a slight modification, a variety of R groups can
be introduced into the C-2 position by acylation of diamine
A with an acid chloride (Table 2). In this case, ring closure
Scheme 3. Introduction of Additional Chiral Substitution
Table 2. C-2-Substituted Benzimidazolium Salts
conditions: (a) 4 mol % Pd2dba3, 8 mol % (() BINAP
Benzimidazolium salts are precursors to nucleophilic
carbenes by deprotonation. The downfield carbene carbon
chemical shift is diagnostic.4b,c,16 For dihydroimidazole
carbenes, Wanzlick carbenes I (Scheme 4) and imidazole
carbenes II, the chemical shift is quite different, ca. 238 and
215 ppm, respectively.4b,16c Benzimidazole carbenes display
a carbene chemical shift intermediate between the afore-
mentioned carbenes, although it has been suggested that
benzimidazole carbenes are more like saturated carbenes.16a
Deprotonation of salt 26 (KOt-Bu, THF) produces carbene
31 (eq 4), which displays a 13C chemical shift of 224.0 ppm
is accomplished by reaction of B with 1 equiv of the desired
acid to provide the salts 19-24.
Solubility and handling of the prepared benzimidazolium
salts in organic solvents can be improved by counterion
exchange.14 Three examples of the ion exchange are provided
(15) Compound 5 is not soluble in THF or ethyl acetate; 5 is soluble in
CH3CN, CHCl3, and CH2Cl2.
(16) (a) Hahn, F. E.; Wittenbecher, L.; Boese, R.; Bla¨ser, D. Chem. Eur.
J. 1999, 5, 1931-1935. (b) Liu, Y.; Lindner, P. E.; Lemal, D. M. J. Am.
Chem. Soc. 1999, 121, 10626-10627. (c) Arduengo, A. J.; Dias, R. H. V.;
Harlow, R. L.; Kline, M. J. Am. Chem. Soc. 1992, 114, 5530-5534.
(17) The nucleophilicity of 35 is akin to an enamine; however, the
aromatic resonance contributor probably enhances the nucleophilicity of
the enamine terminal carbon atom. (a) For relevant study reporting the
methylation of an enamine similar to 35, see: Bourson, J. Bull. Soc. Chim.
Fr. 1971, 3541-3547. (b) Study of an imidazole-2-methylidene: Arduengo,
A. J.; Davidson, F.; Dias, H. V. R.; Goerlich, J. R.; Khasnis, D.; Marshall,
W. J.; Prakasha, T. K. J. Am. Chem. Soc. 1997, 119, 12742-12749.
(12) For the benzimidazolium salts in Table 1, the chemical shift of the
C2 proton was diagnostic: ca. 12 ppm for the chloride salts. 5 displays a
chemical shift of 12.52 ppm (CDCl3) for the C2 proton; the perchlorate
salt, 9.93 ppm; the Ph4B salt, 7.03 ppm.
(13) Phase transfer-catalyzed allylation of the benzophenone imine of
glycine tert-butyl ester using catalyst 19 gave a 92% yield of monoallylated
product of 31% ee. Further studies are in progress.
(14) Use of AgPF6: Shi, Z.; Thummel, R. P. Tetrahedron Lett. 1994,
35, 33-36.
Org. Lett., Vol. 3, No. 17, 2001
2675

Scheme 4. Carbene Families
Scheme 5. Alkylation of Carbene 31 with MeI
method is suitable for the preparation of C2-substituted salts
and benzimidazolium salts that bear chiral substituents on
either one or both of the nitrogen atoms. The salts could be
deprotonated to generate the benzimidazole carbenes. A more
detailed investigation of the nucleophilicities of benzimida-
zole carbenes derived from the new C2-unsubstituted benz-
imidazolium salts will be reported in due course.
in d8-THF. This value is consonant with related nucleophilic
carbenes. Like Wanzlick carbenes, the benzimidazole car-
benes of type III have a widened N-C-N bond angle and
show a tendency to dimerize, chemical behavior that has been
independently studied by Hahn4c and Liu.16b Beyond dimer-
ization, it has not been shown how the structural differences
of the benzimidazole carbene will influence reactivity.16
Initial studies of the nucleophilicity of carbene 31 led to
a surprising result. Generation of the benzimidazole carbene
using 1.0 equiv of KOt-Bu in THF and filtration of the salts
produced the free carbene. Alkylation with an excess of
iodomethane gave the C2-ethylated benzimidazolium salt 32
along with ca. 0.5 equiv of C-2 protio salt 33, recovered as
its iodide (Scheme 5). A likely interpretation of this result
is that the intermediate salt 34 was deprotonated by un-
alkylated carbene to give betaine 35 which underwent
alkylation by the excess MeI.17 Further alkylation studies
are in progress.
Acknowledgment. The authors thank the donors of the
Petroleum Research Fund, administered by the American
Chemical Society (33298G1), the National Science Founda-
tion (CHE-0092434), and SUNY-Buffalo for financial sup-
port of this work. F.M.R and J.A.S gratefully acknowledge
the Ford Foundation and the National Institutes of Health
(F31GM20439), respectively, for predoctoral fellowships.
Supporting Information Available: Experimental pro-
cedures for the synthesis of salts and characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
In summary, a versatile method for the synthesis of a
variety of benzimidazolium salts has been detailed. The
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Org. Lett., Vol. 3, No. 17, 2001