Synthesis of benzazoles by hydrogen-transfer catalysis

Article abstract of DOI:10.1021/ol900557u

Transition-metal-catalyzed hydrogen-transfer reactions have been used for the conversion of alcohols into benzimidazoles and aldehydes into benzoxazoles and benzothiazoles.

Full text of DOI:10.1021/ol900557u

ORGANIC
LETTERS
2009
Vol. 11, No. 9
2039-2042
Synthesis of Benzazoles by
Hydrogen-Transfer Catalysis
A. John Blacker,*,† Mohamed M. Farah,† Michael I. Hall,‡ Stephen P. Marsden,*,†
Ourida Saidi,‡ and Jonathan M. J. Williams*,‡
School of Chemistry and Institute of Process Research and DeVelopment, UniVersity of
Leeds, Leeds LS2 9JT, U.K., and Department of Chemistry, UniVersity of Bath,
ClaVerton Down, Bath BA2 7AY, U.K.
j.blacker@leeds.ac.uk; s.p.marsden@leeds.ac.uk; j.m.j.williams@bath.ac.uk
Received March 18, 2009
ABSTRACT
Transition-metal-catalyzed hydrogen-transfer reactions have been used for the conversion of alcohols into benzimidazoles and aldehydes into
benzoxazoles and benzothiazoles.
Transition-metal-catalyzed hydrogen-transfer reactions
have been widely used for the oxidation of a range of
organic substrates.1 In particular, the oxidation of alcohols
to carbonyl compounds by hydrogen transfer to a suitable
acceptor represents a useful alternative to other oxidation
reactions.2 The use of hydrogen transfer for the oxidation
of aldehydes3 and amines4 has also been reported.
Additionally, oxidation reactions in the absence of a
hydrogen acceptor have been achieved in the presence of
ruthenium catalysts for the conversion of primary alcohols
into esters5 or amides,6 as well as the conversion of
secondary alcohols into ketones.7
We wanted to explore oxidation reactions where aroma-
tization could act as a driving force for loss of hydrogen.
Herein, we report the first examples of catalytic hydrogen-
transfer reactions for the formation of benzimidazoles,
benzoxazoles, and benzothiazoles. These heteroaromatic
systems are commonly encountered groups in natural prod-
ucts,8 pharmaceuticals,9 agrochemicals,10 and other effect
chemicals, and new methods for their preparation are in
frequent demand.
(5) (a) Ichikawa, N.; Sato, S.; Takahashi, R.; Sodesawa, T.; Inui, K. J.
Mol. Catal. A: Chem. 2004, 212, 197. (b) Zhao, J.; Hartwig, J. F.
Organometallics 2005, 24, 2441.
(6) (a) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317,
790. (b) Nordstrøm, L. U.; Vogt, H.; Madsen, R. J. Am. Chem. Soc. 2008,
130, 17672. (c) Zweifel, T.; Naubron, J-V.; Gru¨tzmacher, H. Angew. Chem.,
Int. Ed. 2009, 41, 559.
(7) Adair, G. R. A.; Williams, J. M. J. Tetrahedron Lett. 2005, 46, 8233.
(8) For examples, see: (a) Ueki, M.; Ueno, K.; Miyadoh, S.; Abe, K.;
Shibata, K.; Taniguchi, M.; Oi, S. J. Antibiot. 1993, 46, 1089. (b) Kusumi,
T.; Ooi, T.; Wa¨lchli, M. R.; Kakisawa, H. J. Am. Chem. Soc. 1998, 110,
2954. (c) Chaney, M. O.; Demarco, P. V.; Jones, N. D.; Occolowitz, J. L.
J. Am. Chem. Soc. 1974, 96, 1932.
(9) Battershill, A. J.; Scott, L. J. Drugs 2006, 66, 51. For some recent
examples of pharmaceutical candidates, see: (a) Yoshida, S.; Watanabe,
T.; Sato, Y. Bioorg. Med. Chem. 2007, 15, 3515. (b) Wang, B.; Vernier,
J.-M.; Rao, S.; Chung, J.; Anderson, J. J.; Brodkin, J. D.; Jiang, X.; Gardner,
M. F.; Yang, X.; Munoz, B. Bioorg. Med. Chem. 2004, 12, 17. (c) Gong,
B.; Hong, F.; Kohm, C.; Bonham, L.; Klein, P. Bioorg. Med. Chem. Lett.
2004, 14, 1455. (d) Ott, G. R.; Asakawa, N.; Lu, Z.; Anand, R.; Liu, R.-
Q.; Covington, M. B.; Vaddi, K.; Qian, M.; Newton, R. C.; Christ, D. D.;
Trzaskos, J. M.; Duan, J. J.-W. Bioorg. Med. Chem. Lett. 2008, 18, 1577.
(e) Ishida, T.; Suzuki, T.; Hirashima, S.; Mizutani, K.; Yoshida, A.; Ando,
I.; Ikeda, S.; Adachi, T.; Hashimoto, H. Bioorg. Med. Chem. Lett. 2006,
16, 1859. (f) Falco, J. L.; Pique, M.; Gonza, M.; Buira, I.; Mendez, E.;
Terencio, J.; Perez, C.; Princep, M.; Palomer, A.; Guglietta, A. Eur. J. Med.
Chem. 2006, 41, 985.
† University of Leeds.
‡ University of Bath.
(1) (a) Backvall, J.-E., Ed. Modern Oxidation Methods; Wiley-VCH:
Weinheim, 2004. (b) Samec, J. S. M.; Ba¨ckvall, J.-E.; Andersson, P. G.;
Brandt, P. Chem. Soc. ReV. 2006, 35, 237.
(2) (a) Zassinovich, G.; Mestroni, G.; Gladiali, S. Chem. ReV. 1992,
92, 1051. (b) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999, 10,
2045. (c) Gladiali, S.; Alberico, E. Chem. Soc. ReV. 2006, 35, 226.
(3) Murahashi, S.-I.; Naota, T.; Ito, K.; Maeda, Y.; Taki, H. J. Org.
Chem. 1987, 52, 4319.
(4) Choi, H.; Doyle, M. P. Chem. Commun. 2007, 745. (a) Samec,
(10) Fungicidal Agents. Kirk-Othmer Encyclopedia of Chemical Tech-
nology; Wiley: New York, 1980; Vol. 11, pp 490-498.
´
J. S. M.; Ell, A. H.; Ba¨ckvall, J.-E. Chem.sEur. J. 2005, 11, 2327.
10.1021/ol900557u CCC: $40.75
Published on Web 04/08/2009
 2009 American Chemical Society

The proposed reaction pathway is described in Scheme 1.
Starting from alcohol 1, catalytic hydrogen transfer to an
Table 2. Benzimidazoles Prepared in Scheme 3
Scheme 1
.
Conversion of Alcohols or Aldehydes into
Benzazoles
appropriate acceptor via “Oxidation 1” would lead to the
formation of aldehyde 2. Alternatively, aldehyde 2 could be
used directly as the substrate. In either case, condensation of 2
with an ortho-heterosubstituted aniline 3 generates an intermedi-
ate imine 4, which would be in equilibrium with dihydroben-
zazole 5. A second hydrogen-transfer process from 5 then
provides a route to benzazole 6 via “Oxidation 2”.
Two of us (J.M.J.W./M.I.H.) have recently reported the
use of Ru(PPh3)3(CO)H2 in combination with the bidentate
ligand Xantphos 711 for the oxidation of alcohols by
hydrogen transfer.12 We therefore chose to use this catalyst
for our initial investigations. 4-Methylbenzyl alcohol 1a was
reacted with o-aminoaniline 8 in the presence of ruthenium
catalyst and crotononitrile 9, which led to the formation of
benzimidazole 10a, as shown in Table 1.
Table 1. Catalyst Optimization for the Formation of
Benzimidazole 10a
a Conditions: alcohol (1.0 mmol), o-aminoaniline (1.2 mmol), croto-
nonitrile (2.2 mmol), piperidinium acetate (15 mol %).
entry
catalyst (2.5 mol %)a
additiveb
none
5 mol % of A
10 mol % of A
10 mol % of B
15 mol % of B
20 mol % of B
none
conversion (%)
1
2
3
4
5
6
7
8
Ru(PPh3)3(CO)H2
Ru(PPh3)3(CO)H2
Ru(PPh3)3(CO)H2
Ru(PPh3)3(CO)H2
Ru(PPh3)3(CO)H2
Ru(PPh3)3(CO)H2
48
97
6
75
98
98
0
In the absence of any further additive, we were pleased
to observe a reasonable conversion into product (Table 1,
entry 1). However, the addition of either 5 mol % of p-TsOH
(entry 2) or piperidinium acetate (entries 4-6) provided an
improved conversion. We believe that p-TsOH reacts with
the ruthenium dihydride to form a ditosylate and that
c
[Ru(p-cymene)Cl2]2 dppe
d
[Cp*IrCl2]2
none
0
a Entries 7 and 8 were run at 1.25 mol % of the catalyst dimer (i.e.,
2.5 mol % in Ru or Ir). b Additive A is p-TsOH. Additive B is piperidinium
acetate. c Acetone was used as the acceptor in place of 9. d Styrene was
used as the acceptor in place of 9
(11) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M. Organometallics 1995, 14, 3081.
2040
Org. Lett., Vol. 11, No. 9, 2009

piperidinium acetate may promote addition of o-aminoaniline
8 to the intermediate aldehyde by temporary iminium ion
formation.
combination led to a complex mixture of products from
which benzoxazole 12a could not be isolated. The iridium
complex [Cp*IrI2]2 (SCRAM catalyst) has previously been
shown by one of us (A.J.B.) to be effective for the
racemization of R-branched amines via temporary oxidation
to an achiral imine,15 and we therefore examined the use of
this catalyst for benzoxazole formation. Although no reaction
took place between benzyl alcohol and o-aminophenol 11a,
we were pleased to find that by starting at the aldehyde
oxidation state, the reaction of benzaldehyde 2a with 11a
led to the formation of benzoxazole 12a using [Cp*IrI2]2
under a range of conditions (Table 3).
The use of [Ru(p-cymene)Cl2]2/dppe with acetone as an
acceptor13 and the use of [Cp*IrCl2]2 (Cp* ) pentamethyl-
cyclopentadienyl) with styrene as the acceptor14 gave no
formation of product, and therefore, the conditions identified
in entry 5, Table 1, were used for further reactions. A range
of alcohols 1 was converted into the corresponding benz-
imidazoles 10 as shown in Table 2. The benzimidazole
product precipitated from the reaction mixture upon cooling.
Benzylic alcohols were converted into benzimidazoles in
good yield including electron-rich (entries 3 and 4) and
electron-deficient (entry 5) substrates, although the o-methyl-
substituted benzyl alcohol gave a lower isolated yield (entry
6). The 2-thienyl and 2-furyl substrates (entries 7 and 8) were
also found to be effective, as were nonbenzylic substrates
(entries 9 and 10). The reaction is not limited to simple
o-aminoanilines, with heterocyclization also being effected
upon 2,3-diaminophenazine in good yield (entry 11).
Table 4. Acceptorless Oxidation of Aldehydes to Benzoxazoles
Table 3. Ir-Catalyzed Conversion of Benzaldehyde into
2-Phenylbenzoxazole
entry
reaction conditionsa
80 °C
80 °C, styrene (1.5 equiv)
80 °C, MeCO2H (1.0 equiv)
reflux
conversionb (%)
1
2
3
4
5
6
7
8
9
15
12
13
52
100
50
17
17
<5
reflux, c ) 5 M
reflux, styrene (1.5 equiv)
reflux, [Cp*IrCl2]2 as catalyst
reflux, 0.1 mol % of [Cp*IrI2]2
reflux, no catalyst
a Conditions: benzaldehyde (1.0 mmol), o-aminophenol (1.0 mmol),
toluene, c ) 0.5 M, 24 h. b Conversion determined by NMR ratio of Schiff
base to benzoxazole product.
We next examined the formation of benzoxazoles. How-
ever, the reaction of benzyl alcohol or benzaldehyde with
o-aminophenol 11a using the Ru(PPh3)3(CO)H2/Xantphos
(12) (a) Slatford, P. A.; Whittlesey, M. K.; Williams, J. M. J. Tetrahedron
Lett. 2006, 47, 6787. (b) Hall, M. I.; Pridmore, S. J.; Williams, J. M. J.
AdV. Synth. Catal. 2008, 350, 1975. (c) Owston, N. A.; Parker, A. J.;
Williams, J. M. J. Chem. Commun. 2008, 624.
a Conditions: aldehyde (1.0 mmol), o-aminophenol (1.2 mmol),
[Cp*IrI2]2 (1 mol %), PhMe (0.2 cm3), 111 °C, 24 h.
(13) Hamid, M. H. S. A.; Williams, J. M. J. Chem. Commun. 2007,
725.
(14) Owston, N. A.; Parker, A. J.; Williams, J. M. J. Org. Lett. 2007, 9,
73.
At 80 °C, only small amounts of product were formed
(entries 1-3); however, when the reaction was performed
(15) (a) Blacker, A. J.; Stirling, M. J. WO2004046059, Avecia Phar-
maceuticals Ltd., 2004. (b) Blacker, A. J.; Stirling, M. J.; Page, M. I. Org.
Proc. Res. DeV. 2007, 11, 642. (c) Stirling, M.; Blacker, J.; Page, M. I.
Tetrahedron Lett. 2007, 48, 1247.
(16) Nakajima, T.; Inada, T.; Igarishi, T.; Sekioka, T.; Shimizu, I. Bull.
Chem. Soc. Jpn. 2006, 79, 1941.
Org. Lett., Vol. 11, No. 9, 2009
2041

at reflux, a higher conversion was obtained (entries 4-6),
and quantitative conversion was observed when the reaction
was carried out at the higher concentration of 5 M (entry 5).
Notably, the reactions were equally effective in the presence
or absence of styrene as a sacrificial hydrogen acceptor
(entries 1 and 4 versus entries 2 and 6). This suggests that
the aromatizing oxidation is ultimately mediated by loss of
hydrogen gas from an intermediate (di)hydridoiridium com-
plex. The liberation of hydrogen has previously been
observed accompanying the oxidative self-dimerization of
primary amines by [Cp*IrI2]2.15b
Finally, the reaction conditions used for benzoxazole
synthesis were also successfully applied to the synthesis of
a benzothiazole. Thus, p-tolualdehyde 2b and o-aminothiophe-
nol 13 underwent oxidative cyclization to generate ben-
zothiazole 14 (Scheme 2).
Scheme 2. Formation of a Benzothiazole
The diiodide [Cp*IrI2]2 was found to be a superior catalyst
to the corresponding dichloride [Cp*IrCl2]2 (entry 7), as
expected from their known relative effectiveness as catalysts
for amine oxidation.13 Conversion was too slow to be
synthetically useful at a 0.1 mol % catalyst loading (entry
8). Finally, as a control we verified that in the absence of
catalyst essentially no product was formed (entry 9).
In summary, ruthenium-catalyzed hydrogen-transfer reac-
tions have been used for the conversion of alcohols into
benzimidazoles using crotononitrile as a hydride acceptor,
while iridium-catalyzed acceptorless oxidation has been used
for the highly atom economic conversion of aldehydes into
benzoxazoles and benzothiazoles.
We then applied these reaction conditions to the conversion
of a range of aldehydes 2 into benzoxazoles 12 (Table 4).
Good isolated yields were obtained in the majority of
cases. Benzaldehyde (entry 1) and electron-rich benzal-
dehydes (entries 2 and 3) were good substrates, although
the electron-deficient p-cyanobenzaldehyde (entry 4) and
aliphatic aldehyde (entry 7) only gave moderate yields,
consistent with a mechanism involving a hydride abstrac-
tion with associated buildup of partial cation character.
The use of heterocyclic aldehydes (entries 5 and 6) and
substituted o-aminophenols (entries 8-11) was successful
in all cases. Enolizable aliphatic aldehydes were not
suitable substrates, however, giving rise instead to hy-
droxyquinoline derivatives via enamine condensation/
cyclization pathways.16
Acknowledgment. We thank the EPSRC for funding
through Grant No. EP/F038321/1 and Piramal Healthcare
for further support.
Supporting Information Available: Details of experi-
mental procedures and characterization data are provided.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL900557U
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Org. Lett., Vol. 11, No. 9, 2009