Synthesis of α-chloroaldoxime O-methanesulfonates and their use in the synthesis of functionalized benzimidazoles

Article abstract of DOI:10.1021/jo8023544

Three different α-chloroaldoxime O-methanesulfonates were synthesized to investigate their chemical properties. The compounds were found to be stable and were able to be stored at ambient temperature without any precautions. The reactions with anilines we

Full text of DOI:10.1021/jo8023544

SCHEME 1. Synthesis of r-Chloroaldoxime
O-Methanesufonates
Synthesis of r-Chloroaldoxime
O-Methanesulfonates and Their Use in the
Synthesis of Functionalized Benzimidazoles
Yuhei Yamamoto,* Hiroo Mizuno, Takayuki Tsuritani, and
Toshiaki Mase
Process Research, Preclinical DeVelopment, Banyu
Pharmaceutical Co., Ltd., 3 Okubo, Tsukuba,
Ibaraki, 300-2611, Japan
compounds,2 and only one synthetic application had appeared in
the literature, that is to synthesize 1,4,2-dithiazolium salt.3 This is
plausibly due to the lack of general information of the chemical
properties (stability, reactivity, etc.) of these compounds. We
envisioned that further study of this class of compound would make
us realize the full potential of this class of compounds, and thus
lead to a discovery of new chemistry. We report herein a practical
method to access R-chloroaldoxime O-methanesulfonate 1a-c
(Scheme 1), and the first extensive studies on the reactivity toward
anilines, with an aim to obtain benzimidazoles.4,5
yuhei_yamamoto@merck.com
ReceiVed October 21, 2008
Three different R-chloroaldoxime O-methanesulfonates
were synthesized to investigate their chemical properties. The
compounds were found to be stable and were able to be
stored at ambient temperature without any precautions. The
reactions with anilines were investigated, and it was found
that an additive is required to activate the sulfonate. TMEDA
was found to be the most efficient additive, and various
benzimidazoles were synthesized through the reaction.
R-Chloroaldoxime O-methanesulfonates bearing a phenyl
group (1a), a cyclohexyl group (1b), and a propyl group (1c)
were synthesized from the corresponding aldoxime (Scheme 1).
All of the compounds were stable through aqueous workup, and
were able to be purified through silica gel column chromatog-
raphy. R-Chlorobenzaldoxime O-methanesufonate 1a was
obtained as a white crystalline solid, where R-chlorocyclohex-
anecarboxaldoxime O-methanesufonate 1b and R-chlorobuty-
laldoxime O-methanesufonate 1c were obtained as colorless oils.
Importantly, all of the compounds were stable for more than a
month at ambient temperature without any precautions.
The reaction between R-chlorobenzaldoxime O-methane-
sulfonate 1a and p-methoxyaniline 5a was selected as a model
reaction to investigate the best reaction conditions (Table 1).
In this reaction, 5-methoxy-2-phenyl-1H-benzimidazole 7aa is
expected to be obtained through nitrene precursor 6.6 We first
conducted the reaction in the presence of TEA, but no reaction
occurred even at elevated temperature (entry 1). Deprotonation
Synthesis of new reagents and their application to synthesis
of functionalized heterocycles are of great interest in organic
synthesis, as such motifs are ubiquitous in both natural products
and biologically active pharmaceutical agents. Development of
such reagents is extremely important, not only because it
provides a more practical pathway to highly functionalized
heterocycles, but also because it could enable one to synthesize
new heterocycles that are difficult to synthesize by conventional
methodologies. We became particularly interested in the syn-
thesis of R-chloro oxime O-sulfonates 1 and their chemical
properties, since these compounds should allow one to easily
synthesize O-sulfonyl oximes 2 which are frequently used for
the synthesis of aza-heterocycles (eq 1).1 Despite the significant
synthetic potential of these compounds, less attention has been
received. Few examples exist for the synthesis of these
(3) (a) Florence, S.; Chan, Y.; Sammes, M. P. J. Chem. Soc., Chem. Commun.
1985, 899–906. (b) Florence, S.; Chan, Y.; Sammes, M. P. J. Chem. Soc., Perkin
Trans. I 1988, 899–906.
(4) Partridge, M. W.; Turner, H. A. J. Chem. Soc. 1958, 2086–2092. Also
see ref 1h.
(5) For recent studies on the synthesis of benzimidazoles, see: (a) Evindar,
G.; Batey, R. A. Org. Lett. 2003, 5, 133–136. (b) Zou, B.; Yuan, Q.; Ma, D.
Angew. Chem., Int. Ed. 2007, 46, 2598–2601. (c) Zheng, N.; Anderson, K. W.;
Huang, X.; Nguyen, H. N.; Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46,
7509–7512. (d) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
1932–1934. (e) Shen, M.; Driver, T. G. Org. Lett. 2008, 10, 3367–3370. (f)
Yang, D.; Fu, H.; Hu, L.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2008, 73, 7841–
7844.
(6) (a) Grenda, V. J.; Joens, R. E.; Gal, G.; Sletzinger, M. J. Org. Chem.
1965, 30, 259–261. (b) Sauer, J.; Mayer, K. K. Tetrahedron Lett. 1968, 9, 325–
330. (c) Garapon, J.; Sillion, B.; Bonnier, J. M. Tetrahedron Lett. 1970, 11,
4905–4908. (d) Houghton, P. G.; Pipe, D. F.; Rees, C. W. J. Chem. Soc., Perkin
Trans. I 1985, 1471–1479. (e) Ichikawa, M.; Hisano, T. Chem. Pharm. Bull.
1982, 30, 2996–3003. (f) Ramsden, C. A.; Rose, H. L. J. Chem. Soc., Perkin
Trans. I 1995, 615–617. (g) Ramsden, C. A.; Rose, H. L. J. Chem. Soc., Perkin
Trans. I 1997, 2319–2327, and references cited therein.
(1) For review, see: (a) Narasaka, K.; Kitamura, M. Eur. J. Org. Chem. 2005,
4505–4519. For recent advances in this area, see: (b) Feng, L.; Kumar, D.;
Kerwin, S. M. J. Org. Chem. 2003, 68, 2234–2242. (c) Zaman, S.; Kitamura,
M.; Abell, A. D. Org. Lett. 2005, 7, 609–611. (d) Szczepankiewicz, B. G.; Rohde,
J. J.; Kurukulasuriya, R. Org. Lett. 2005, 7, 1833–1835. (e) Sadaoka, K.; Mihara,
J.; Ichikawa, J. Chem. Commun. 2005, 4684–4686. (f) Wahyuningshih, T. D.;
Pchalek, K.; Kumar, N.; Black, D. StC. Tetrahedron 2006, 62, 6343–6348. (g)
Counceller, C. M.; Eichman, C. C.; Wray, B. C.; Stambuli, J. P. Org. Lett. 2008,
10, 1021–1023. (h) Yamamoto, Y.; Tsuritani, T.; Mase, T. Tetrahedron Lett.
2008, 49, 876–878. (i) Liu, S.; Liebeskind, L. S. J. Am. Chem. Soc. 2008, 130,
6918–6919.
(2) (a) Truce, W. E.; Naik, A. R. Can. J. Chem. 1966, 44, 297–305. (b)
Rajagopalan, P.; Talaty, C. N. Tetrahedron Lett. 1966, 19, 2101–2108.
1394 J. Org. Chem. 2009, 74, 1394–1396
10.1021/jo8023544 CCC: $40.75 2009 American Chemical Society
Published on Web 12/31/2008

TABLE 1. Optimization of Reaction Conditions
TABLE 2. Synthesis of Various Benzimidazoles
entry additive (equiv) base (equiv) solvent temp, °C yield,a
%
1
2
3
4
5
6
7
8
TEA (2.2)
NaH (2.2)
TEA (2.1)
DMF
DMF
DMF
DMF
85
85
50
50
rt
<5
<5
18
36
72
76
96
92
87
63
87
55
DMAP (1.1)
imidazole (1.1) TEA (2.1)
Me2NEt (2.1) DMF
TMEDA (2.1) DMF
TMEDA (2.1) DMF
TMEDA (1.2) DMF
TMEDA (2.1) THF
TMEDA (2.1) MeCN
TMEDA (2.1) CHCl3
TMEDA (2.1) toluene
rt
50
50
50
50
50
50
9
10
11
12
a HPLC yield.
FIGURE 1. Plausible reactive intermediates.
of aniline with NaH was also not effective (entry 2), and gave a
complex mixture at 85 °C. We next turned our attention to
activating the chloride 1a, and soon found that the activation is
possible by employing imidazole (entry 3) or DMAP (entry 4) to
the reaction. The intermediate 8 (Figure 1)7 formed immediately
after the addition of the additives to the chloride 1a, and slowly
reacted with the aniline 5a to give benzimidazole 7aa, albeit in
low yield. Further exploration revealed that the activation is also
possible by an addition of a less sterically hindered base such as
Me2NEt or TMEDA,8 which dramatically increased the yield.
TMEDA was chosen for further investigation because of the
volatility of Me2NEt at higher temperature. DMF, THF, and CHCl3
(entries 7, 9, and 11) were found to be suitable solvents for the
reaction, but solvents such as MeCN and toluene (entries 10 and
12) resulted in low yield due to low conversion.
Having established optimized reaction conditions, reactions
of three R-chloroaldoxime O-methanesulfonates 1a-c with
various anilines were investigated (Table 2). The reactions were
conducted in THF in the presence of 2.1 equiv of TMEDA,
and were stirred at 50 °C overnight. Among the three R-chlo-
roaldoxime O-methanesulfonates 1a-c, the reactivity of R-chlo-
rocyclohexanecarboxaldoxime O-methanesulfonate 1b was the
lowest (entry 5 vs entries 1 and 10, entry 6 vs entries 2 and
11), which is plausibly due to the bulkiness of the cyclohexyl
group. The reaction was also sensitive to the steric bulk at the
ortho position of anilines (entry 2 vs 3), and reaction with
anilines possessing ortho substituents resulted in low yield
(entries 3, 14, and 15). Reaction with 4-substituted anilines
generally gave the corresponding benzimidazoles in good yields,
and functional groups such as ester (entry 4), MeS (entries 8
and 12), benzyloxy (entry 9), fluoro (entry 13), and iodo (entry
16) were all tolerated under these reaction conditions.
be stable, and thus required activation to react with anilines.
TMEDA was found to be the best additive for the activation,
and the reactions with various anilines were conducted to obtain
numerous 2-substitued benzimidazoles. Further utilization of the
R-chloroaldoxime O-methanesulfonates for the synthesis of
heterocycles is currently under investigation in our laboratories.
In summary, we have synthesized three different R-chloro-
aldoxime O-methanesulfonates to investigate the chemical
properties of these compounds. The compounds were found to
Experimental Section
General Procedures for Synthesis of r-Chloroaldoxime O-
Methanesulfonates (1a-c) from Their Corresponding Oximes:
Representative Procedure for the Synthesis of 1a. To a 500 mL
round-bottomed flask was added benzaldoxime (25 g, 206 mmol),
(7) Not isolated, but determined by LCMS.
(8) In this case, no intermediates were observed by LCMS.
J. Org. Chem. Vol. 74, No. 3, 2009 1395

DMF (25 mL), THF (188 mL), and CHCl3 (188 mL). A portion of
NCS (2.89 g, 21.7 mmol, 0.105 equiv) was added to the mixture,
and the mixture was stirred vigorously. After confirming the start
of the reaction by the rise in temperature (mixture becomes a blue
solution), the remaining NCS (26.0 g, 195.3 mmol) was added in
small portions while keeping the temperature around 40-45 °C.
The reaction mixture was stirred for 1 h and was then quenched
with water (188 mL). The aqueous layer was discarded and the
organic layer was washed with water (188 mL). The organic layer
was dried over Na2SO4, then concentrated under reduced pressure.
To the residue was added EtOAc (960 mL), and the resulting
solution was cooled to 0 °C. TEA (63.2 mL, 453 mmol, 2.2 equiv)
was added to the solution, and the mixture was stirred at the same
temperature for 10 min to give a white slurry. MsCl (26.0 g, 227
mmol, 1.1 equiv) was added, slowly over 10 min, to the mixture,
and the mixture was warmed to room temperature. The mixture
was stirred at room temperature for 1 h, and the crystal was filtered
off. The filtrate was washed with H2O (2 × 160 mL), dried over
Na2SO4, and concentrated under reduced pressure, then isolated as
a crystal from EtOAc.
bottomed flask was added p-anisidine (369 mg, 3 mmol), R-chlo-
robenzaldoxime O-methanesulfonate 1a (841 mg, 3.6 mmol), THF
(3.7 mL), and TMEDA (0.95 mL, 6.3 mmol). The solution was
warmed to 50 °C and then stirred for 15 h. The mixture was
quenched with water and extracted with EtOAc. The aqueous layer
was discarded and the organic layer was dried over Na2SO4 and
evaporated. The residue was purified through a SiO2 column to
give benzimidazole 7aa as a white crystal (585 mg, 87% yield).
5-Methoxy-2-phenyl-1H-benzimidazole (7aa) Mixture of Tau-
tomers. Isolated as a white crystal (87% yield, mp 149-150 °C):
TLC Rf 0.36 (EtOAc/hexanes, 1:1); FTIR (neat) υmax 3055, 2931,
1
1631, 1456, 1404, 1269, 1159, 702 cm-1; H NMR (400 MHz,
DMSO-d6) δ 12.7 (s, 0.45H), 12.7 (s, 0.55H), 7.24-7.54 (m, 4H),
7.18 (br s, 0.45H), 6.98 (br s, 0.55H), 6.80-6.86 (m, 1H), 3.80 (s,
1.65H), 3.78 (s, 1.35H); 13C NMR (100 MHz, DMSO-d6) δ 156.3,
155.6, 151.6, 150.5, 144.8, 138.5, 135.8, 130.5, 129.6, 129.0, 126.3,
120.0, 112.4, 111.7, 111.3, 101.5, 94.6, 55.6; HRMS m/z calcd for
C14H12N2O 224.0950, found 224.0952.
r-Chlorobenzaldoxime O-Methanesulfonate (1a). Isolated as
a crystal from EtOAc: 37.5 g (78% yield, 2 steps, mp 112-113 °C);
TLC Rf 0.62 (EtOAc/hexanes, 1:4); FTIR (neat) υmax 3050, 1560, 1377,
1319, 1259, 1180, 1155, 969, 892, 813, 771, 688, 598 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.94 (m, 1H), 7.57 (m, 2H), 7.48 (m, 2H), 3.28
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 148.5,132.5, 129.8, 128.2,
127.5, 36.3. Anal. Calcd for C8H8ClNO3S: C, 41.12; H, 3.45; N, 5.99.
Found: C, 41.27; H, 3.42; N, 5.88.
Acknowledgment. We thank Dr James Michael McNamara
(MRL) for helpful discussions and Dr Hirokazu Ohsawa (Banyu)
for HRMS measurements.
Supporting Information Available: Experimental proce-
dures, characterization data, and 1H, 13C NMR spectra of these
synthesized compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
General Procedures for Synthesis of Benzimidazoles from
Aniline and r-Chloroaldoxime O-Methanesulfonates: Repre-
sentative Procedure for the Synthesis of 7aa. To a 50 mL round-
JO8023544
1396 J. Org. Chem. Vol. 74, No. 3, 2009