Smart cleavage reactions: The synthesis of benzimidazoles and benzothiazoles from polymer-bound esters

Article abstract of DOI:10.1016/j.tetlet.2003.10.168

The preparation of an array of benzimidazoles and benzothiazoles from polymer-bound esters is described. Polymer-bound esters were treated with 2-aminothiophenols or 1,2-phenylenediamines in the presence of a Lewis acid to afford the corresponding benzothiazole or benzimidazole cleavage products. The reaction of 2-aminophenols with the polymer-bound esters failed to give the desired benzoxazole products using this procedure.

Full text of DOI:10.1016/j.tetlet.2003.10.168

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 313–316
Smart cleavage reactions: the synthesis of benzimidazoles and
benzothiazoles from polymer-bound estersq
Hana Matsushita, Sang-Hyeup Lee, Meyoungju Joung, Bruce Clapham* and
Kim D. Janda*
Department of Chemistry, The Scripps Research Institute and The Skaggs Institute for Chemical Biology,
10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Received 8 October 2003; revised 27 October 2003; accepted 28 October 2003
Abstract—The preparation of an array of benzimidazoles and benzothiazoles from polymer-bound esters is described. Polymer-
bound esters were treated with 2-aminothiophenols or 1,2-phenylenediamines in the presence of a Lewis acid to afford the corre-
sponding benzothiazole or benzimidazole cleavage products. The reaction of 2-aminophenols with the polymer-bound esters failed
to give the desired benzoxazole products using this procedure.
Ó 2003 Elsevier Ltd. All rights reserved.
1. Introduction
nothiophenol 2 was reacted with polymer-bound oxa-
zole 1 in the presence of AlMe3. In this instance, instead
of the anticipated amide product 3, the cyclo-dehydrated
benzothiazole 4 was isolated as the major product from
this reaction (Fig. 1).
Combinatorial chemistry is now the accepted method of
choice for the preparation of chemical libraries for
screening in drug discovery programs.1 Solid-phase
synthesis2 is especially useful in library production since
large numbers of compounds can be generated using
only a few separate reactions during a Ôsplit-and-mixÕ
synthesis.3 The choice of linker for the library scaffold to
the polymer support is critical for successful library
production,4 and a number of groups have devised ele-
gant methods that enable additional diversity to be
incorporated into the products during the cleavage
reaction. For example, Ley and later Morphy demon-
strated that polymer-bound esters could be cleaved from
the resin by reaction with an amine in the presence of
Lewis acid to provide the corresponding amide prod-
ucts.5 We have utilized this cleavage methodology to
produce amide-functionalized oxazole,6 indole,7 and
imidazolone8 libraries that were prepared from polymer-
bound a-diazo-b-ketoesters as key intermediates.9 We
investigated the use of a diverse selection of amine
building blocks in this cleavage/diversification reaction
and an interesting observation was made when 2-ami-
Although there are several reports for the direct con-
version of esters into the corresponding benzimidazoles
and benzothiazoles, these reactions required extremely
harsh conditions and often the products were isolated in
poor yields.10 However, there have been two reports
whereby this transformation was performed under
milder, Lewis acid promoted conditions; this corrobo-
rated our observation of the fully dehydrated benzo-
thiazole product 4, rather than the expected amide 3.11
Accordingly, we set out to extend the application of this
reaction toward its use as a diversity-building cleavage
reaction from the solid support. Reported herein are our
findings from these investigations.
The first set of reactions was performed in order to
establish the effect of the type of Lewis acid and the ratio
of amino substrate 7 to Lewis acid upon the success of
SH
SH
O
O
N
NH2
S
N
N
N
O
N
H
2
Keywords: Solid-phase; Cleavage; Lewis acid; Heterocycles.
q
Supplementary data associated with this article can be found, in the
R1
R2
R1
R2
R1
R2
AlMe3
O
1
O
3
O
4
(Not isolated)
online version, at doi:10.1016/j.tetlet.2003.10.168.
* Corresponding authors. Tel.: +1-858-784-2519; fax: +1-858-784-
2595; e-mail: bclapham@scripps.edu; kdjanda@scripps.edu
Figure 1. Unexpected formation of a benzothiazole cleavage product.
0040-4039/$ - see front matter Ó 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.10.168

314
H. Matsushita et al. / Tetrahedron Letters 45 (2004) 313–316
the reaction. In order to expedite this study, benzyl
benzoate 5 was used as a model solution-phase analogue
of a hydroxymethyl JandaJel12 resin-supported ester 6,13
(Scheme 1, Table 1).
Et2AlCl was used at a substrate/reagent ratio (ester/
amine/Lewis acid) of 1:4:2, the desired benzimidazole 9a
was formed in 86% yield (Table 1, entry 3 vs 1). Con-
versely, when X ¼ S or NMe, AlMe3 gave better results,
and when the reagents were combined in a ratio of 1:4:4
(ester/amino substrate/Lewis acid), the desired N-methyl
benzimidazole 9b (X ¼ NMe) and benzylthiazole 9d
(X ¼ S) products were formed in 89% and 62% yield,
respectively (Table 1, entries 5 and 11). Despite
numerous attempts, when 2-aminophenol (X ¼ O) was
used in the reaction, only the corresponding amide
8c was isolated. However, we note that these amides
8c could be subsequently converted into the corre-
sponding benzoxazole 9d (X ¼ O) by p-toluenesulfonic
acid-catalyzed azeotropic removal of water from boiling
toluene (data not shown).14
Four amines 7 were tested in this reaction, 1,2-phenyl-
enediamine (X ¼ NH), N-methyl-1,2-phenylene diamine
(X ¼ NMe), 2-aminophenol (X ¼ O) and 2-aminothio-
phenol (X ¼ S). Of the Lewis acids examined, trimethyl-
aluminum (AlMe3) and diethylaluminum chloride
(Et2AlCl) provided the best results, whereas aluminum
chloride (AlCl3) was rejected early in this study since it
only gave complex mixtures of cleaved compounds with
poor mass recovery. More precisely, when X ¼ NH,
Et2AlCl was found to be superior to AlMe3, and when
With these results in hand, the next series of experiments
involved the conversion of a hydroxymethyl JandaJel-
bound benzoate ester 6 into the corresponding cleavage
products 8 and 9 (Scheme 1, Table 2). In a similar
fashion to the solution-phase study, 1,2-phenylene-
diamine 7 (X ¼ NH) gave the best yield of product 9a
when used in conjunction with Et2AlCl at an amino
substrate/Lewis acid ratio of 2:1 (entries 1 and 2). In
addition, increasing the excess of this amino substrate/
Lewis acid complex over the polymer-bound ester 6 gave
O
XH
H
O
X
X
N
O
NH2
5
+
7
(a)
O
N
H
O
8a X= NH
8b X= NMe
8c X= O
9a X= NH
9b X= NMe
9c X= O
6
8d X= S
9d X= S
Scheme 1. Reagents and conditions: (a) Lewis acid, toluene, reflux,
24 h.
Table 1. Solution-phase investigation of Lewis acid for the heterocycle formation reaction
Entry
Amine 7
Lewis acid
Product
X
Equivalent
Equivalent
(%)
(%)
1
NH
NH
NH
NMe
NMe
NMe
NMe
O
3
2
4
8
4
4
8
5
4
5
4
4
7
AlMe3
AlMe3
Et2AlCl
AlMe3
AlMe3
Et2AlCl
Et2AlCl
AlMe3
AlMe3
Et2AlCl
AlMe3
Et2AlCl
AlCl3
1.5
2
8a (48)
8a (0)
8a (0)
8b (0)
8b (0)
8b (0)
8b (0)
8c (99)
8c (34)
8c (86)
8d (0)
8d (0)
8d (0)
9a (36)
9a (60)
9a (86)
9b (68)
9b (89)
9b (72)
9b (85)
9c (0)
2
3
2
4
4
5
4
6
4
7
4
8
5
9
O
2
9c (0)
9c (0)
10
11
12
13
O
4
S
4
9d (62)
9d (29)
9d (0)
S
4
S
6
Table 2. Solid-phase synthesis of benzimidazoles, benzothiazoles and hydroxylamides from polymer-bound ester 6
Entry
Amine
Lewis acid
Product
X
Equivalent
Equivalent
(%)a
(%)a
1
NH
NH
NMe
NMe
O
4
8
Et2AlCl
Et2AlCl
AlMe3
2
4
4
4
4
8
4
4
4
4
4
8a (0)
8a (0)
8b (0)
8b (0)
8c (23)
8c (47)
8c (33)
8c (50)
8d (0)
8d (0)
8d (0)
9a (77)
9a (99)
9b (93)
9b (86)
9c (0)
2
3
4
4
4
Et2AlCl
Et2AlCl
Et2AlCl
AlMe3
5
5
6
O
10
8
9c (8)
9c (0)
9c (0)
7
O
8
O
4
AlMe3
AlMe3
9
S
4
9d (50)
9d (50)
9d (17)
10
11
S
8
AlMe3
Et2AlCl
S
8
a Yield of pure product based upon initial hydroxyl loading of resin used to prepare 6.

H. Matsushita et al. / Tetrahedron Letters 45 (2004) 313–316
315
improved yields (Table 2, entry 2 vs 1) whereby the
H
X
desired product 9a was isolated from the resin in nearly
quantitative yield after purification by preparative TLC
(based upon initial loading of hydroxymethyl JandaJel
as estimated by DMT titration).15 The cases where
X ¼ NMe and S also mirrored the results observed in the
solution-phase model study whereby the polymer-bound
ester 6 was treated with a four-fold excess of a 1:1
mixture of the amino substrate/Lewis acid (AlMe3)
complex, the corresponding N-methyl benzimidazole 9b
(X ¼ NMe) and benzothiazole 9d (X ¼ S) products were
obtained in 93% and 50% yields, respectively, after
purification by preparative TLC (Table 2, entries 3 and
9). We also note that the direct conversion of the poly-
mer-bound esters 6 into the desired benzoxazole prod-
ucts 9c (X ¼ O) was not feasible; by using a large excess
of reagent mixture, we were able to isolate the benz-
oxazole 9c in only 8% yield, (Table 2, entry 6); however,
the major products from all reactions performed using
the 2-aminophenol 7 (X ¼ O) were the hydroxyl amides
8c.
X
O
O
a
R
+
O
R
N
N
H
R
12
10
11
(X = NH, NMe, S, O)
Scheme 2. Reagents and conditions: (a) A: 7 (X ¼ NH) (8 equiv),
Et2AlCl (4 equiv), toluene, reflux, 24 h. B: 7 (X ¼ NMe, S, O) (4 equiv),
AlMe3 (4 equiv), toluene, reflux, 24 h.
bicarbonate and the mixture was then filtered through
Celiteâ to provide a mixture of both the cleavage
products 8 or 9 and the unreacted amines 7, which re-
quired separation by chromatography. Although this
methodology provides cleavage products that are con-
taminated with unreacted reagents, we feel that given
the many recent developments for the high throughput
purification of libraries using automated, preparative-
HPLC16 that the preparation of larger libraries of ben-
zothiazoles and benzimidazoles is a viable option. The
final aspect of our study was to establish the effect of
different ester groups upon the outcome of the reaction.
In this case, a series of diverse polymer-bound esters 10
were prepared by reaction of an acid chloride with the
hydroxymethyl JandaJel resin (data not shown). Ten
different Rgroups were selected to include electron-rich
and electron-deficient aryls, pyridyls and straight
chained or bulky alkyls to examine the general appli-
cability of this protocol. Each polymer-bound ester 10
was reacted with the series of amines 7 (X ¼ NH, NMe,
S, O) to provide the small pilot library of benzimidazoles
(X ¼ NH, NMe), benzothiazoles (X ¼ S) 12 and hydro-
xyl amides (X ¼ O) 11 (Scheme 2, Table 3).
In our earlier work preparing amide cleavage products
using this Lewis acid-promoted amidation chemistry,
mixed bed ion-exchange resins were utilized to sequester
excessively used amine reagents from the reaction mix-
ture to yield essentially pure cleavage products. How-
ever, the use of ion exchange resins to purify the above
heterocycle cleavage products gave unreliable results
and often the heterocyclic products 9 were isolated in
poor yields. In these cases we assume the cleaved
products were retained by the ion-exchange resin along
with the excessively used amine reagents and we attrib-
uted this to the slightly basic nature of the cleavage
products 9. Because of these drawbacks, after reaction
had been allowed to proceed for the appropriate time,
the reagents were quenched with aqueous sodium
As can be seen from Table 3, most of the desired
products were obtained in modest to good yields. From
Table 3. Solid-phase synthesis of an array of benzimidazoles 12, benzothiazoles 12 and hydroxyl amides 11
a
a
Entry
X
RCond.
Yieldb
Entry
X
RCond.
Yieldb
11
12
11
12
1
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
S
4-MeOPh
4-MePh
n-Pentyl
4-CF3–Ph
Cyclohexyl
Benzyl
A
A
A
A
A
A
A
A
A
A
B
B
B
B
B
B
B
B
B
B
––
––
––
––
58
––
––
––
––
––
––
––
––
––
––
––
––
––
––
––
42
63
99
33
––
42
58
98
71
21
46
––
71
71
54
63
50
75
75
46
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
NMe
NMe
NMe
NMe
NMe
NMe
NMe
NMe
NMe
NMe
O
4-MeOPh
4-MePh
n-Pentyl
4-CF3–Ph
Cyclohexyl
Benzyl
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
B
––
––
––
––
28
––
––
––
––
––
50
37
75
58
42
58
––
42
67
46
63
63
58
99
71
83
71
83
75
31
––
––
––
––
––
––
––
––
––
––
2
3
4
5
6
7
Styryl
Styryl
8
4-Pyridyl
3-Pyridyl
2-Pyridyl
4-MeOPh
4-MePh
n-Pentyl
4-CF3–Ph
Cyclohexyl
Benzyl
4-Pyridyl
3-Pyridyl
2-Pyridyl
4-MeOPh
4-MePh
n-Pentyl
4-CF3–Ph
Cyclohexyl
Benzyl
9
10
11
12
13
14
15
16
17
18
19
20
S
O
S
O
S
O
S
O
S
O
S
Styryl
O
Styryl
S
4-Pyridyl
3-Pyridyl
2-Pyridyl
O
4-Pyridyl
3-Pyridyl
2-Pyridyl
S
O
S
O
a A: 7 (X ¼ NH) (8 equiv), Et2AlCl (4 equiv), toluene, reflux, 24 h. B: 7 (X ¼ NMe, S, O) (4 equiv), AlMe3 (4 equiv), toluene, reflux, 24 h.
b Yield based upon original hydroxyl loading of resin used to prepare 10.

316
H. Matsushita et al. / Tetrahedron Letters 45 (2004) 313–316
2. (a) Solid Phase Organic Synthesis; Czarnik, A. W., Ed.;
John Wiley & Sons: New York, 2001; (b) Solid Phase
Organic Synthesis; Burgess, K., Ed.; John Wiley & Sons:
New York, 2000.
3. Furka, A.; Bennett, W. D. Comb. Chem. High Throughput
Screen. 1999, 2, 105.
4. Guillier, F.; Orain, D.; Bradley, M. Chem. Rev. 2000, 100,
2091.
5. (a) Ley, S. V.; Mynett, D. M.; Koot, W.-J. Synlett 1995,
1017; (b) Barn, D. R.; Morphy, J. R.; Rees, D. C.
Tetrahedron Lett. 1996, 37, 3213.
these results, it is apparent that the nature of the R
group of 10 does not have a dramatic effect on the
outcome of the yield of the cleavage products 11 or 12.
When R ¼ aryl, few differences between the yields of
cleavage products were observed when R ¼ electron-rich
versus electron-deficient aryl groups and good yields
were also observed when R ¼ alkyl. However, when
R ¼ cyclohexyl less satisfactory results were observed. In
these cases (entries 5 and 25), the intermediate amino
amide product 11 was isolated as either sole product or
as a mixture with the desired product 12. This result was
attributed to the steric bulk of the cyclohexyl group.
6. Clapham, B.; Spanka, C.; Janda, K. D. Org. Lett. 2001, 3,
2173.
7. Lee, S.-H.; Clapham, B.; Koch, G.; Zimmermann, J.;
Janda, K. D. J. Comb. Chem. 2003, 5, 188.
8. Lee, S.-H.; Clapham, B.; Koch, G.; Zimmermann, J.;
Janda, K. D. Org. Lett. 2003, 5, 511.
2. Conclusion
9. Clapham, B.; Lee, S.-H.; Koch, G.; Zimmermann, J.;
Janda, K. D. Tetrahedron Lett. 2002, 43, 5407.
10. Alcalde, E.; Dinares, I.; Perez-Garcia, L.; Roca, T.
Synthesis 1992, 395, This paper reports the reaction
between 4-pyridylacetic methyl ester with 1,2-phenylene-
diamine, the desired benzimidazole product was obtained
after heating to 170–180 °C in the presence of polyphos-
phoric acid for 4.5 h.
In summary, the chemistry developed herein constitutes
a simple and robust method for the conversion of
polymer-bound esters into the corresponding benz-
imidazole and benzothiazole cleavage products by
reaction with 1,2-phenylenediamines and 2-aminothio-
phenols in the presence of a Lewis acid. In the cases
where 2-aminophenols were employed, the amidation
products were obtained rather than the desired benz-
oxazoles. Further investigations of novel cleavage
strategies are currently being performed in our labora-
tories and will be reported in due course.
11. (a) Hudkins, R. L. Heterocycles 1995, 41, 1045; (b)
Busacca, C. A.; Dong, Y.; Spinelli, E. M. Tetrahedron
Lett. 1996, 37, 2935.
12. JandaJelTM resins are available from Aldrich Chemical
Company. For further discussion of the JandaJelTM resins
see: (a) Toy, P. H.; Reger, T. S.; Janda, K. D. Aldrichim.
Acta 2000, 33, 87; (b) Toy, P. H.; Reger, T. S.; Garibay, P.;
Garno, J. C.; Malikayil Liu, G.; Janda, K. D. J. Comb.
Chem. 2001, 3, 117; (c) Toy, P. H.; Janda, K. D.
Tetrahedron Lett. 1999, 40, 6329; For recent applica-
3. Supplementary data
€
tions see: (d) Brummer, O.; Clapham, B.; Janda, K. D.
General experimental procedures and full characteriza-
tion of all compounds is included. The Supplementary
data is available online with the paper on ScienceDirect.
Tetrahedron Lett. 2001, 42, 2257; (e) Clapham, B.; Cho,
C.-W.; Janda, K. D. J. Org. Chem. 2001, 66, 868.
13. Representative procedure: A solution of trimethylalumi-
num chloride in toluene (2.0 M, 600 lL, 1.2 mmol) was
added to a stirred solution of N-methyl-1,2-phenylenedi-
amine (147 mg, 1.2 mmol) 7 (X ¼ NMe) in toluene (2 mL)
cooled to 0 °C under an atmosphere of argon. After
stirring for 10 min, the resulting solution was allowed to
warm up to room temperature and stirred additional 1 h
during, which time a fine white suspension had formed.
This suspension was then added to a suspension of resin-
bound benzoyl ester 6 (250 mg, 0.3 mmol) in toluene
(3 mL) and the resulting mixture was heated to reflux for
24 h. After cooling to room temperature, a saturated
aqueous solution of NaHCO3 (1 mL) was slowly added
and the mixture was stirred for further 10 min, filtered
through a pad of Celiteâ and concentrated under reduced
pressure. The crude product was then purified by chro-
matography (gradient elution, 50% toluene/ethyl acetate
to 75% toluene ethyl acetate) to give N-methyl-2-phenyl-
benzimidazole 9 (58.9 mg, 93%) as a white solid.
Acknowledgements
We gratefully acknowledge financial support from The
Scripps Research Institute, The Skaggs Institute for
Chemical Biology and Novartis Pharma AG Switzer-
land.
References and Notes
1. (a) Bunin, B. A. The Combinatorial Index; Academic:
London, 1998; (b) Obrecht, D.; Villalgordo, J. M. Solid-
Supported Combinatorial and Parallel Synthesis of Small-
Molecular-Weight Compound Libraries; Elsevier, 1998; (c)
In Combinatorial Chemistry: Synthesis, Analysis, Screen-
ing; Jung, G., Ed.; Wiley-VCH: Weinheim, 1999; (d)
Combinatorial Chemistry and Molecular Diversity in Drug
Discovery; Gordon, E. M., Kerwin, J. F., Jr. Eds.; John
Wiley & Sons: New York, 1998.
14. Soucy, F.; Grenier, L.; Behnke, M. L.; Destree, A. T.;
McCormack, T. A.; Adams, J.; Plamondon, L. J. Am.
Chem. Soc. 1999, 121, 9967.
15. Reddy, M. P.; Voelker, P. J. J. Peptide Protein Res. 1988,
31, 345.
16. Kassel, D. B. Chem. Rev. 2001, 101, 255.