Microwave-assisted one step high-throughput synthesis of benzimidazoles

Article abstract of DOI:10.1016/j.tetlet.2006.02.127

One-pot synthesis of benzimidazoles from diamines and carboxylic acids was developed under microwave irradiation condition, which provided a practical and efficient method for high-throughput synthesis of this important class of heterocyclic compounds.

Full text of DOI:10.1016/j.tetlet.2006.02.127

Tetrahedron Letters 47 (2006) 2883–2886
Microwave-assisted one step high-throughput synthesis
of benzimidazoles
Shou-Yuan Lin, Yuko Isome, Ethan Stewart, Ji-Feng Liu,* Daniel Yohannes
and Libing Yu
ArQule, Inc., 19 Presidential Way, Woburn, MA 01801, USA
Received 8 February 2006; revised 20 February 2006; accepted 21 February 2006
Available online 9 March 2006
Abstract—One-pot synthesis of benzimidazoles from diamines and carboxylic acids was developed under microwave irradiation
condition, which provided a practical and efficient method for high-throughput synthesis of this important class of heterocyclic
compounds.
Ó 2006 Elsevier Ltd. All rights reserved.
Microwave-assisted organic synthesis (MAOS) contin-
ues to affect synthetic chemistry significantly by enabling
rapid, reproducible, and scalable chemistry develop-
ment.1 Numerous reactions including condensations,
cycloadditions, heterocycle formations, and metal cata-
lyzed cross-coupling have been explored under micro-
wave conditions, some of which have been applied
to medicinal chemistry and total syntheses of natural
products.2 MAOS can facilitate the discovery of new
reactions and reduce cycle time in optimization of
reactions. In addition, it serves to expand chemical space
in compound library synthesis.
N
N
H
N
O
Cl
N
Benzimidazole Core
N
N
NPY1 Receptor Antagonist
N
N
O
O
NH
S
N
As it relates to our efforts to develop efficient and robust
methodologies and processes for high-throughput syn-
thesis of pharmacologically interesting libraries for drug
discovery,3 the exploration of microwave chemistry to
access heterocyclic compounds has been of particular
interest to us. Herein, we report a microwave-assisted
approach for the synthesis of benzimidazoles in one
pot from readily available starting materials.
NH2
CO2H
Thrombin Inhibitor
Figure 1. Biologically relevant benzimidazoles.
scope of accessible benzimidazoles has been to sequence
the reduction of nitroanilines and condensation with
aldehydes in one-pot reactions.6 However, many
approaches for the synthesis of benzimidazoles continue
to utilize the condensation reactions of arylenediamines
with carboxyl equivalents such as carboxylic acids, carb-
oxylic acid esters, lactones, anhydrides, and aldehydes.7
These reactions require harsh dehydration conditions
such as strong mineral acids, which have limited the
viability of many starting materials. We envisioned that
microwave irradiation could enhance this chemistry and
expand the chemistry scope.
Benzimidazole has been an important pharmacophore
and privileged structure in medicinal chemistry
(Fig. 1),4 encompassing a diverse range of biological
activities including antiarrhythmic, antiulcer, anthelmin-
tical, inotropic, antihistamine, antifungal, antiviral, and
cytotoxicity.5 A recent advancement, which expands the
*
Corresponding author. Tel.: +1 781 994 0446; fax: +1 781 994
0678; e-mail addresses: jifeng.liu@yahoo.com; jliu@arqule.com
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.127

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S.-Y. Lin et al. / Tetrahedron Letters 47 (2006) 2883–2886
Table 1. Optimization of microwave-assisted benzimidazole formation
Table 2. Evaluation of diamines 1 and carboxylic acids 2
R2
R2
R3CO2H
HO2C
R1
R2
R1
R2
H
N
NH
N
NH2
NH2
2
R3
2a
N
P(OPh)3, μW, 220 oC
10 min
NH2
N
conditions
4
1
3
1a
Entry Diamines, 1
Acids, 2
Yielda of
4 (%)
Temp (°C)
Reaction time (min)
3a (%)
180
200
220
10
10
10
68
79
100 (78)
NH2
2a
1
100 (58)
100 (49)
MeO
NH2
a The conversions are determined by HPLC (ELSD) from LC–MS
results of the reaction mixture. In parentheses, isolated yields by
preparative TLC. The purities of the isolated products were deter-
mined by HPLC or/and 1H NMRs.
H
N
Ph
2
3
2a
NH2
NH2
N
Initial efforts focused on optimizing microwave condi-
tions for the formation of 3 employing our ‘standard’
microwave conditions (Table 1).3a Although reaction
of benzene-1,2-diamine (1a, 1.0 equiv) with benzoic acid
(2a, 1.0 equiv) in the presence of P(OPh)3 (1.2 equiv) in
pyridine under microwave irradiation at 180 °C success-
fully generated desired product 3, the reaction could not
go to completion even at 200 °C for 10 min. However,
microwave irradiation of the reaction mixture at
220 °C for 10 min triggered the effective amidation–
cyclization reaction, which resulted in formation of the
desired product 3 in 100% conversion with 78% isolated
yield. It was noted that pyridine was a better solvent for
a broad range of diamines and carboxylic acids with a
variety of functional groups than others such as glacial
acetic acid, hydrochloric acid, sulfuric acid, and poly-
phosphoric acid.
2a
2a
100 (32)
N
NH2
NH2
4b
5
82 (55)
NH2
1a
1a
100 (86)
CO2H
F
CO2H
F
6
7
89 (58)
78 (58)
CO2H
1a
1a
1a
MeO
CO2H
CO2H
8
9
100 (67)
100 (58)
Our preliminary success prompted an evaluation of the
reaction scope aimed at achieving the ultimate goal of
applying this method to high-throughput synthesis.
The optimized conditions above were applied to various
diamines 1 and carboxylic acids 2, as shown in Table 2.8
Aliphatic diamines and aromatic diamines as well as
heterocyclic diamines (entries 1–4) generally provided
good to excellent conversion (82–100%) with moderate
to good isolated yields (32–58%). It is noteworthy that
heteroaromatic diamine (entry 3) also worked well
under this set of conditions. In addition, an aliphatic
cyclohexyl diamine (a mixture of cis/trans, entry 4)
underwent the effective cyclization to elaborate the hexa-
hydrobenzimidazole products. These microwave results
demonstrated a broad range of diamines applicable to
this chemistry.
N
a The conversions are determined by HPLC (ELSD) from LC–MS
results of the reaction mixture. In parentheses, isolated yields by
preparative TLC. These yields were not optimized. The purities of
the isolated products were determined by HPLC or/and 1H NMRs.
b cis/trans Mixture purchased from Aldrich.
selected diamines included aliphatic (cis and trans cyclo-
hexyl diamines), aromatic (both plain and mono-substi-
tuted) as well as heterocyclic diamines. The selected
carboxylic acids included aliphatic, aromatic, and het-
erocyclic acids. The library synthesis was performed
on a solution-phase high-throughput automated synthe-
sis platform integrated with a microwave station.10
These compounds were then purified on an in-house
high-throughput purification platform by reverse-phase
HPLC with mass-triggered fraction collection,11 quanti-
fied by weight, and characterized by LC/MS to confirm
the synthesis of the desired compounds and to establish
purity. Table 3 shows the results in purities and yields of
all products in the combinatorial crossing of the two
components using given reaction condition.
The carboxylic acid component of this reaction was also
examined (entries 5–9) under the conditions. Aliphatic
(entry 5), aromatic (entries 6–8), and heterocyclic carb-
oxylic acids (entry 9) all worked well, providing overall
conversions from 78% to 100% with corresponding iso-
lated yields ranging from 58% to 86%.
To further explore the scope of the conditions, synthesis
of a small library of 42 compounds was carried out with
a crossing of six diamines and seven acids (Table 3). The

S.-Y. Lin et al. / Tetrahedron Letters 47 (2006) 2883–2886
2885
Table 3. Small library synthesis
R2
R2
R3CO2H
R1
R2
R1
R2
NH
N
2
R3
N
P(OPh)3, μW, 220 oC
10 min
NH2
4
1
2
1
NH2
NH2
NH2
N
NH2
NH2
NH2
NH2
NH2
NH2
NH
NH2
NH2
racemates
56a (100, 100)
43 (100, 100)
71 (74, 84)
43 (92, 100)
50 (100, 100)
32 (100, 100)
CO2H
CO2H
72 (100, 100)
57 (82, 100)
83 (100, 100)
36 (100, 100)
14 (100, 100)
68 (100, 100)
31 (86, 81)
65 (100, 100)
38 (63, 100)
66 (100, 100)
25 (100, 100)
41 (100, 100)
65 (100, 100)
25 (100, 100)
46 (50, 86)
43 (100, 100)
65 (100, 100)
30 (100, 100)
51 (100, 100)
40 (100, 100)
72 (100, 100)
39 (100, 100)
67 (100, 100)
42 (100, 100)
36 (67, 79)
OH
59 (50, 100)
98 (100, 100)
35b (100, 100)
94 (74, 100)
68 (76, 100)
CO2H
O
84 (100, 100)
53 (92, 100)
74 (100, 100)
73 (100, 100)
OH
CO2H
S
16 (100, 100)
49 (100, 100)
N
CO2H
CO2H
a Isolated yields by preparative HPLC. In parentheses are the UV214 nm and ELSD purity determined by HPLC.
b See Ref. 9.
(d) Raheem, I. T.; Goodman, S. N.; Jacobsen, E. N. J.
Am. Chem. Soc. 2004, 126, 706; (e) Baran, P. S.; O’Malley,
D. P.; Zografos, A. L. Angew. Chem., Int. Ed. 2004, 43,
2674; (f) Hughes, R. A.; Thompson, S. P.; Alcaraz, L.;
Moody, C. J. Chem. Commun. 2004, 946; (g) Wolkenberg,
S. E.; Wisnoski, D. D.; Leister, W. H.; Wang, Y.; Zhao,
In summary, a microwave-assisted one-pot synthesis of
benzimidazoles from readily available starting materials
has been developed. The broad chemistry scope and
efficiency have been demonstrated through successful
syntheses of a diverse set of benzimidazoles. The further
application of this microwave methodology for the
synthesis of other heterocycles will be described in due
course.
´
Z.; Lindsley, C. W. Org. Lett. 2004, 6, 1453; (h) Lepine,
R.; Zhu, J. Org. Lett. 2005, 7, 2981; (i) Geske, G. D.;
Wezeman, R. J.; Siegel, A. P.; Blackwell, H. E. J. Am.
Chem. Soc. 2005, 127, 12762; (j) Liu, J.-F.; Ye, P.; Zhang,
B.-L.; Bi, G.; Sargent, K.; Yu, L.; Yohannes, D.; Baldino,
C. M. J. Org. Chem. 2005, 70, 6339; (k) Liu, J.-F.; Ye, P.;
Sprague, K.; Sargent, K.; Yohannes, D.; Baldino, C. M.;
Wilson, C. J.; Ng, S.-C. Org. Lett. 2005, 7, 3363; (l) Liu,
J.-F.; Kaselj, M.; Isome, Y.; Chapnick, J.; Zhang, B.; Bi,
G.; Yohannes, D.; Yu, L.; Baldino, C. M. J. Org. Chem.
2005, 70, 10488.
References and notes
1. For recent reviews of microwave-assisted organic synthesis
(MAOS), see: (a) Kappe, C. O.; Dallinger, D. Nat. Rev.
Drug. Discovery 2006, 5, 55; (b) Shipe, W. D.; Wolken-
berg, S. E.; Lindsley, C. W. Drug Discovery Today:
Tech. 2005, 2, 155; (c) Leadbeater, N. E. Chem. Commun.
2005, 2881; (d) Kappe, C. O. Angew. Chem., Int. Ed. 2004,
43, 6250; (e) Lidstro¨m, P.; Tierney, J.; Wathey, B.;
Westman, J. Tetrahedron 2001, 57, 9225; (f) Perreux, L.;
Loupy, A. Tetrahedron 2001, 57, 9199, and references cited
therein.
2. For recent applications of microwave technology in
natural product syntheses, see: (a) Baxendale, I. R.; Ley,
S. V.; Piutti, C. Angew. Chem., Int. Ed. 2002, 41, 2194; (b)
Kang, Y.; Mei, Y.; Du, Y.; Jin, Z. Org. Lett. 2003, 5, 4481;
(c) Grainger, R. S.; Patel, A. Chem. Commun. 2003, 1072;
3. (a) Liu, J.-F.; Lee, J.; Dalton, A. M.; Bi, G.; Yu, L.;
Baldino, C. M.; McElory, E.; Brown, M. Tetrahedron
Lett. 2005, 46, 1241; (b) Liu, J.-F.; Wilson, C. J.; Ye, P.;
Sprague, K.; Sargent, K.; Si, Y.; Beletsky, G.; Yohannes,
D.; Ng, S.-C. Biorg. Med. Chem. Lett. 2006, 16, 686; (c)
Liu, J.-F.; Kaselj, M.; Isome, Y.; Ye, P.; Sargent, K.;
Sprague, K.; Cherrak, D.; Wilson, C. J.; Si, Y.; Yohannes,
D.; Ng, S.-C. J. Comb. Chem. 2006, 8, 7.
4. (a) Preston, P. N. In The Chemistry of Heterocyclic
Compounds, Benzimidazoles and Congeneric Tricyclic
Compounds; John Wiley & Son: New York, 1980; Vol.

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S.-Y. Lin et al. / Tetrahedron Letters 47 (2006) 2883–2886
40, Part 2; Chapter 10; According to Evans, a privileged
245 lmol) were charged. The sealed vial was irradiated
in the microwave for 10 min at 220 °C. The pressure
reading at this temperature was 8.1 bar. After cooling, the
reaction mixture was concentrated in vacuo and the
residue was purified by preparative TLC (CH2Cl2/MeOH,
20/1) to give the desired product 4 (Table 2, entry 5):
2-propyl-1H-benzimidazole; 27.5 mg (86%); 1H NMR
(CDCl3, 400 MHz) d 0.98 (t, J = 7.6 Hz, 3H), 1.91 (m,
2H), 2.96 (t, J = 7.6 Hz, 2H), 7.21–7.60 (dd, J = 3.2,
6.0 Hz, 2H), 7.56 (dd, J = 3.2, 6.0 Hz, 2H), 10.9 (br s, 1H);
13C NMR (CDCl3, 100 MHz) d 14.2, 22.1, 31.6, 115.0,
122.5, 138.9, 155.9; HRMS calcd for (C17H16N2O2+H)
161.1073, found 161.1076.
structure is ‘a single molecular framework able to provide
ligands for diverse receptors’, see: (b) Evans, B. E.; Rittle,
K. E.; Bock, M. G.; DiPardo, R. M.; Freidinger, R. M.;
Whitter, W. L.; Lundell, G. F.; Veber, D. F.; Anderson, P.
S.; Chang, R. S. L.; Lotti, V. J.; Cerino, D. J.; Chen, T. B.;
Kling, P. J.; Kunkel, K. A.; Springer, J. P.; Hirshfield, J. J.
Med. Chem. 1988, 31, 2235.
5. Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev.
2003, 103, 893, and references cited therein.
6. Yang, D.; Fokas, D.; Li, J.; Yu, L.; Baldino, C. M.
Synthesis 2005, 47.
7. For reviews on the chemistry of benzimidazoles, see: (a)
Wright, J. B. Chem. Rev. 1951, 48, 397; (b) Preston, P. N.
Chem. Rev. 1974, 74, 279; (c) Gray, D. N. J. Heterocycl.
Chem. 1970, 7, 947; (d) Hudkins, R. L. Heterocycles 1995,
41, 1045; (e) Brain, C. T.; Brunton, S. A. Tetrahedron Lett.
2002, 43, 1893; (f) Brain, C. T.; Steer, J. T. J. Org. Chem.
2003, 68, 6814; (g) Howarth, J.; Hanlon, K. Tetrahedron
Lett. 2001, 42, 751; (h) Hendrickson, J. B.; Hussoin, S. M.
J. Org. Chem. 1989, 54, 1144.
8. General reaction procedure for the synthesis of benz-
imidazoles from acids and diamines are described in Table
2: In a conical-bottomed Smith Process vial, 0.5 mL of
butyric acid in anhydrous pyridine (0.4 M, 200 lmol),
0.5 mL of 1,2-phenylenediamine in anhydrous pyridine
(0.4 M, 200 lmol), and triphenyl phosphite (70 lL,
9. 1H NMR (CD3OD, 400 MHz) d 1.37–1.43 (m, 2H), 1.51–
1.57 (m, 2H), 1.85–1.88 (m, 2H), 2.24–2.27 (m, 2H), 3.18–
3.21 (m, 2H), 7.16 (dd, J = 4.0, 4.8 Hz, 1H), 7.64 (dd
J = 3.6, 1.2 Hz, 1H), 7.68 (dd, J = 4.8, 1.2 Hz, 1H); 13C
NMR (CD3OD, 100 MHz) d 26.3, 31.8, 70.2, 129.5, 131.6,
132.3, 133.2, 163.8; HRMS calcd for (C11H14N2S+H)
207.0951, found 207.0952.
10. We employed a Biotage Smith SynthesizerTM integrated
into the ArQule AMAPTM high-throughput chemistry
platform.
11. (a) Kyranos, J. N.; Cai, H.; Zhang, B.; Goetzinger, W. K.
Curr. Opin. Drug Discovery Dev. 2001, 4, 719; (b)
Goetzinger, W.; Zhang, X.; Bi, G.; Towle, M.; Cherrak,
D.; Kyranos, J. N. Int. J. Mass. Spectrom. 2004, 238, 153.