One-pot synthesis of 2-aminobenzimidazoles using 2-chloro-1,3- dimethylimidazolinium chloride (DMC)

Article abstract of DOI:10.1016/j.tetlet.2010.07.177

2-Chloro-1,3-dimethylimidazolinium chloride (DMC or DMC-Cl) has been found to effectively and rapidly generate 2-aminobenzimidazoles from 1,2-diaminoarenes and isothiocyanates in moderate to good yields at room temperature in a one-pot operation.

Full text of DOI:10.1016/j.tetlet.2010.07.177

Tetrahedron Letters 51 (2010) 5319–5321
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Tetrahedron Letters
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One-pot synthesis of 2-aminobenzimidazoles using
2-chloro-1,3-dimethylimidazolinium chloride (DMC)
Gerald D. Artman III, Catherine F. Solovay, Christopher M. Adams, Brian Diaz, Martin Dimitroff,
Takeru Ehara, Danlin Gu, Fupeng Ma, Donglei Liu, Bridget R. Miller, Teresa E. Pick, Daniel J. Poon,
David Ryckman, David A. Siesel, Brady S. Stillwell, Tyson Swiftney, Jonathan P. van Dyck,
*
Chun Zhang, Nan Ji
Global Discovery Chemistry, Novartis Institutes for BioMedical Research, 250 Massachusetts Avenue, Cambridge, MA 02139, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Chloro-1,3-dimethylimidazolinium chloride (DMC or DMC-Cl) has been found to effectively and rapidly
generate 2-aminobenzimidazoles from 1,2-diaminoarenes and isothiocyanates in moderate to good
yields at room temperature in a one-pot operation.
Received 28 June 2010
Revised 29 July 2010
Accepted 31 July 2010
Available online 6 August 2010
Ó 2010 Elsevier Ltd. All rights reserved.
2-Aminobenzimidazole is an important chemotype for drug dis-
covery programs in the pharmaceutical industry.1 For instance, our
drug discovery program targeting RAF kinase is based on a 2-ami-
nobenzimidazole core (cf. 5).1a Our initial approach toward this
ring system was enabled through a common disconnection as de-
scribed in Scheme 1. Exposure of the 1,2-diaminoarene 1 to the
commercially available isothiocyanate 2 affords the intermediate
thiourea 3. Cyclization of the tethered amino group onto the thio-
urea to form the 2-aminobenzimidazole can be achieved using a
variety of reagents. These include metal-based reagents such as
CuI2 or simple exposure to iodomethane.3,4 As in the case of benz-
imidazole 5, introduction of iodomethane to the intermediate thio-
urea 3 provides the activated intermediate 4, which is more
amenable to cyclization. Attack of the tethered aniline nitrogen
and loss of methanethiol affords the desired product 5.
Despite the variety of conditions described to prepare 2-amino-
benzimidazoles,4,5 there are drawbacks associated with many of
them. For example, the use of metals salts in large amounts often
results in tedious workup procedures to ensure complete removal
of the metals from the final product. In addition, cyclization using
iodomethane can require long reaction times (>24 h) for acceptable
yields. Finally, iodomethane in large quantities can present a haz-
ard in accidental exposure to this toxic chemical.
colorless solid that is soluble in a variety of organic solvents
(CH3CN, DCE, CH2Cl2, etc.) with reduced toxicity. Isobe and Ishika-
Br
S
N
NH
2
N
N
MeHNOC
MeHNOC
O
O
NH2
1
NH
NH
MeI
Br
Br
S
S
N
H
3
NH
N
N
-MeSH
MeHNOC
O
N
H
4
Not satisfied with the current conditions to achieve this key ring
closure, we have continued to explore alternative conditions that
are more amenable for scale-up of compounds like benzimidazole
5 as well as reducing the toxicity of the reagents employed. To this
end, we were drawn to a recent paper by Isobe and Ishikawa
describing the dehydrating capabilities of 2-chloro-1,3-dimethy-
limidazolinium chloride (DMC or DMC-Cl, 6).6,7 DMC (6) is a stable,
Br
N
N
N
NH
MeHNOC
O
5
* Corresponding author. Tel.: +1 617 871 7366; fax: +1 617 871 7044.
E-mail address: nan.ji@novartis.com (N. Ji).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.177

5320
G. D. Artman et al. / Tetrahedron Letters 51 (2010) 5319–5321
benzimidazole 13 in 87% yield (entry 5). In addition, it was noticed
Cl
N
Cl
that under these conditions, the reaction was completed in less
than 15 min. Based on this encouraging result, it was then found
that the reaction could be carried out in dichloromethane at room
temperature (entry 6): the formation of the benzimidazole was
achieved in less than 5 min and in 86% yield. Furthermore, we
found that the isolation of the desired product was readily
achieved through basic aqueous workup to remove much of the
residual 1,3-dimethylthioimidazilone. The resulting crude product
was purified either by silica gel flash chromatography using a 0–
100% EtOAc–heptane gradient or through trituration from MeOH.
Finally, we recognized that a one-pot procedure may be possible
by performing the thiourea formation in CH2Cl2 rather than the
MeOH/THF mixture previously employed. To this end, we repeated
the synthesis of 13 using a one-pot procedure. Much to our delight,
the one-pot synthesis (entry 7) gave similar yield to the previous
two-step sequence (entries 5 and 6). Two things are worth noting:
(1) in the first step of the one-pot procedure, dithiourea is a likely
side-product (especially on a large scale), which can be minimized
by slow addition of the isothiocyanate; (2) since DMC-induced
cyclization is quite exothermic, an ice-water bath and portion-wise
addition of DMC are recommended for large-scale reactions.
To demonstrate the versatility of these reaction conditions, a
series of commercially available isothiocyanates were screened un-
der the one-pot DMC conditions.8,9 Exposure of compound 1 to the
isothiocyanates listed in Table 2 resulted in the rapid formation of
the desired benzimidazoles with moderate to good isolated yields.
The electronic nature of the arene ring seems important: electron-
withdrawing substituents such as fluorine (entries a–e) or cyano
(entry g) led to higher yields, whereas more electron-rich aromat-
N
N
Cl
S
6
N
S
Ph
Ph
N
H
N
H
triethylamine
CH2Cl2, rt, 4h
Ph
N
NH
Ph
7
8
S
Ph
N
86%
N
N
N
Ph
9
10
Scheme 2.
wa have described many uses of DMC (6), but it was the formation
of carbodiimides from thioureas that made this reagent particu-
larly interesting to our synthetic needs (Scheme 2). Isobe and Ishik-
awa reported that the exposure of a thiourea-like 7 to DMC (6) and
triethylamine in CH2Cl2 results in the formation of the activated
intermediate 8.6a This then transforms to the carbodiimide 9 in
good yield, producing the water-soluble 1,3-dimethylthioimidazi-
lone (10) as the main byproduct. In light of this finding and the
similarities between intermediates 4 and 8, we decided to explore
the application of DMC (6) in the formation of 2-aminobenzimi-
dazoles from 1,2-diaminoarenes and isothiocyanates.8
To test the application of DMC (6), we tried to prepare the benz-
imidazole 13 from the 1,2-diaminoarene 1 (vide supra) and the
commercially available 3-(trifluoromethyl)phenyl isothiocyanate
(11) under a variety of known conditions (Table 1). Using EDC (en-
try 1), CuI (entry 2) or FeCl3/pyridine to facilitate cyclization re-
sulted in no or little conversion at room temperature. These
conditions only provided reasonable yields after the reaction mix-
tures were heated at 80 °C for several hours. FeCl3/MeOH (entry 4)
provided the best yield but it required an extended reaction time
(15 h) at room temperature. However, exposure of thiourea 12 to
DMC (6) and DIPEA in refluxing MeCN readily afforded the desired
Table 2
Scope of DMC (6) conditions in one-pot operation with commercially available
isothiocyanates
O
N
NH
CH2Cl2, rt;
1
+
SCN-Ar
N
N
DMC, DIPEA
NH
Ar
O
14
Table 1
Comparison of reported benzimidazole formation conditions to DMC (6)
Entry
a
Ar
Yield (%)
57
F3C
NCS
NH
NH
F
F
O
N
11
1
b
c
76
71
S
N
CF3
H
MeHNOC
NH
12
F
F
F
F
d
69
See Table
Below
CF3
O
N
N
O
N
F
NH
e
f
70
37
13
O
O
Entry
Conditions
Results (%)
1
2
3
4
5
6
7
EDC, CH3CN, 80 °C
CuI, DIPEA MeCN, PhMe, 80 °C
FeCl3, MeOH, 80 °C
24
50
45
61
87
86
84
g
61
49
FeCl3, MeOH, rt
CN
DMC (6) DIPEA, MeCN, reflux
DMC (6) DIPEA, CH2Cl2, rt
One-pot in CH2Cl2
h

G. D. Artman et al. / Tetrahedron Letters 51 (2010) 5319–5321
5321
8. Dimitroff, M.; Miller, B. R.; Stillwell, B. S.; Siesel, D. A.; Swiftney, T.; Diaz, B.; Gu,
D.; van Dyck, J. P.; Ryckman, D.; Poon, D. J.; Pick, T. E. U. S. 2007/0049622.
9. General procedure: To a flame-dried 50 mL round-bottomed flask, compound 1
(1 mmol) was dissolved in DCM (10 mL). In a separate flask, the isothiocyanate
(1.2 mmol) was dissolved in DCM (5 mL) and slowly added to the flask
containing compound 1 over 10 min via a syringe at room temperature. The
reaction mixture was stirred and reaction progress was monitored by TLC or
LCMS. Once this step was determined to be complete, DIPEA (2 mmol) was
added in a single portion via a syringe followed by DMC (6, 1.5 mmol). The
reaction was then stirred for 5 min and then checked by TLC or LCMS. Once the
reaction was determined to be complete (ꢀ5–10 min), the reaction mixture was
poured into a 1:2 aqueous solution of concentrated ammonium hydroxide/
water (20 mL). The layers were separated and the aqueous layer was extracted
CH2Cl2 (2 Â 20 mL). The combined organic extracts were dried over Na2SO4,
filtered, and dried. The resulting crude product was purified by silica gel
chromatography using a Teledyne ISCO CombiFlash Rf instrument (0–100%
EtOAc:heptane) to provide 14. The purity of all the final compounds was greater
than 98% by LC–MS and HPLC analysis. 1H NMR data of 14a–h are listed here:
compound 14a: 1H NMR (400 MHz, CDCl3) d ppm 8.38 (d, J = 5.6 Hz, 1H), 8.08 (d,
J = 4.6 Hz, 1H), 7.59 (d, J = 2.0 Hz, 1H), 7.52 (dd, J = 8.8 Hz, J = 4.6 Hz, 2H), 7.20 (d,
J = 1.8 Hz, 1H), 7.08–6.93 (m, 4H), 6.75 (dd, J = 8.3 Hz, J = 2.0 Hz, 1H), 3.45 (s, 3H),
3.02 (d, J = 5.1 Hz, 3H); compound 14b: 1H NMR (400 MHz, CDCl3) d ppm 8.40 (d,
J = 5.6 Hz, 1H), 8.08 (d, J = 4.8 Hz, 1H), 7.61 (d, J = 2.5 Hz, 1H), 7.49 (d, J = 10.9 Hz,
1H), 7.29–7.20 (m, 3H), 7.11 (d, J = 8.59 Hz, 1H), 7.06 (dd, J = 5.6 Hz, 2.5 Hz, 1H),
6.83 (dd, J = 8.2 Hz, 1.9 Hz, 1H), 6.76–6.67 (m, 1H), 3.58 (s, 3H), 3.02 (d,
J = 5.3 Hz, 3H); compound 14c: 1H NMR (400 MHz, CDCl3) d ppm 8.38 (d,
J = 5.6 Hz, 1H), 8.15 (br s, 1H), 8.01 (d, J = 5.3 Hz, 1H), 7.59 (s, 1H), 7.34 (d,
J = 9.6 Hz, 1H), 7.30 (d, J = 2.0 Hz, 1H), 7.21–7.03 (m, 3H), 7.00 (dd, J = 5.7 Hz,
2.4 Hz, 2H), 3.75 (s, 3H), 3.00 (d, J = 5.3 Hz, 3H); compound 14d: 1H NMR
(400 MHz, CDCl3) d ppm 8.40 (d, J = 5.6 Hz, 1H), 8.08 (d, J = 4.9 Hz, 1H), 7.67–
7.57 (m, 1H), 7.53 (d, J = 2.3 Hz, 1H), 7.22 (d, J = 2.0 Hz, 1H), 7.20–7.11 (m, 2H),
7.10–6.99 (m, 2H), 6.85 (dd, J = 8.5 Hz, 2.2 Hz, 1H), 3.59 (s, 3H), 3.00 (d,
J = 5.1 Hz, 3H); compound 14e: 1H NMR (400 MHz, CDCl3) d ppm 8.37 (d,
J = 5.3 Hz, 1H), 8.01 (br s, 2H), 7.63–7.51 (m, 1H), 7.43–7.24 (m, 3H), 7.12–7.03
(m, 1H), 7.00 (d, J = 4.8 Hz, 1H), 6.93–6.80 (m, 1H), 3.79 (br s, 3H), 3.00 (d,
J = 5.1 Hz, 3H); compound 14f: 1H NMR (400 MHz, DMSO-d6) d ppm 8.91 (s, 1H),
8.76 (d, J = 4.8 Hz, 1H), 8.48 (d, J = 6.0 Hz, 1H), 7.61 (d, J = 2.0 Hz, 1H), 7.24 (dd,
J = 8.5 Hz, 2.2 Hz, 1H), 7.19 (d, J = 2.2 Hz, 1H), 7.14 (dd, J = 5.7 Hz, 2.7 Hz, 1H),
6.91–6.85 (m, 2H), 5.98 (s, 2H), 3.72 (s, 3H), 2.77 (d, J = 4.9 Hz, 3H); compound
14g: 1H NMR (400 MHz, DMSO-d6) d ppm 9.63 (s, 1H), 8.77 (d, J = 5.1 Hz, 1H),
8.49 (d, J = 5.6 Hz, 1H), 7.78 (d, J = 9.1 Hz, 2H), 7.50 (d, J = 8.6 Hz, 1H), 7.33 (dd,
J = 7.8 Hz, 2.5 Hz, 2H), 7.15 (dd, J = 5.7 Hz, 2.7 Hz, 1H), 6.97 (dd, J = 8.6 Hz,
J = 2.3 Hz, 1H), 3.80 (s, 3H), 2.77 (d, J = 5.1 Hz, 3H); compound 14h: 1H NMR
(400 MHz, CDCl3) d ppm 11.43 (br s, 1H), 8.42 (d, J = 5.6 Hz, 1H), 8.04 (br s, 1H),
7.61 (d, J = 9.1 Hz, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.34 (m, 2H), 7.20–7.10 (m, 3H),
7.08 (dd, J = 5.6 Hz, 2.5 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 3.87 (s, 3H), 2.97 (d,
J = 5.1 Hz, 3H).
ics such as the benzodioxole (entry f), phenyl (entry h) resulted in
lower yields.
In conclusion, we have found DMC (6) to be an effective, less
toxic reagent for the preparation of 2-aminobenzimidazoles from
1,2-diaminoarenes and isothiocyanates using a room temperature,
one-pot procedure. These conditions will allow other chemists to
rapidly access this heterocyclic ring system.
Acknowledgments
We would like to thank Savithri Ramurthy, Paul A. Renhowe,
and Baoqing Gong for their many helpful discussions regarding this
heterocyclic system.
References and notes
1. (a) Ramurthy, S.; Subramanian, S.; Aikawa, M.; Amiri, P.; Costales, A.; Dove, J.;
Fong, S.; Jansen, J. M.; Levine, B.; Ma, S.; McBride, C. M.; Michaelian, J.; Pick, T.;
Poon, D. J.; Girish, S.; Shafer, C. M.; Stuart, D.; Sung, L.; Renhowe, P. A. J. Med.
Chem. 2008, 51, 7049–7052; (b) Beaulieu, C.; Wang, Z.; Denis, D.; Greig, G.;
Lamontagne, S.; O’Neill, G.; Slipetz, D.; Wang, J. Bioorg. Med. Chem. Lett. 2004, 14,
3159–3199; (c) Kling, A.; Backfisch, G.; Delzer, J.; Geneste, H.; Graef, C.;
Hornberger, W.; Lange, U.; Lauterbach, A.; Seitz, W.; Subkowski, T. Bioorg. Med.
Chem. 2003, 11, 1319–1341.
2. Wang, X.; Zhang, L.; Zu, Y.; Krishnamurthy, D.; Senanayake, C. H. Tetrahedron
Lett. 2004, 45, 7167–7170.
3. Omar, A.-M. M. E. Synthesis 1974, 41–42.
4. For additional conditions to prepare benzimidazoles via this approach, see: (a)
Cee, J.; Downing, N. S. Tetrahedron Lett. 2006, 47, 3747–3750; (b) Perkins, J. L.;
Zartman, A. E.; Meissner, R. S. Tetrahedron Lett. 1999, 40, 1103–1106; (c) Heinelt,
U.; Schultheis, D.; Jager, S.; Lindenmaier, M.; Pollex, A.; Beckmann, H. S. G.
Tetrahedron 2004, 60, 9883–9888; (d) Omar, A.-M. M. E.; Habib, N. S.; Aboulwafa,
O. M. Synthesis 1977, 864–865.
5. (a) For re examples of formation of 2-aminobenzimidazoles via coupling of 2-
halobenzimidazoles and anilines, please see: (a) Aso, K.; Mochizuki, M.; Kojima,
T.; Kobayashi, K.; Pratt, S. A.; Gyorkos, A. C.; Corrette, C. P.; Cho, S. Y. PCT Int.
Appl. 2008, WO 2008051533.; (b) Hooper, M. W.; Utsunomiya, M.; Hartwig, J. F.
J. Org. Chem. 2003, 68, 2861.
6. (a) Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64, 6984–6988; (b) Isobe, T.;
Ishikawa, T. J. Org. Chem. 1999, 64, 6989–6992; (c) Isobe, T.; Ishikawa, T. J. Org.
Chem. 1999, 64, 5832–5835.
7. 2-Chloro-1,3-dimethylimidazolinium chloride is commercially available from
several
vendors.
We
purchased
our
supply
of
2-chloro-1,3-
dimethylimidazolinium from Sigma–Aldrich, St. Louis, MO.