Oxidative conversion of amines into benzoxazoles using hydrogen transfer catalysis

Article abstract of DOI:10.1016/j.tetlet.2009.08.042

Benzoxazoles are synthesised directly by oxidative condensation of primary and secondary amines with o-aminophenols under hydrogen transfer catalysis. The optimal system utilises 1 mol % of the Shvo catalyst, with dimethoxybenzoquinone as the hydrogen-acc

Full text of DOI:10.1016/j.tetlet.2009.08.042

Tetrahedron Letters 50 (2009) 6106–6109
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Oxidative conversion of amines into benzoxazoles using hydrogen
transfer catalysis
b
b
A. John Blacker a, Mohamed M. Farah a, Stephen P. Marsden a, , Ourida Saidi , Jonathan M. J. Williams
*
a School of Chemistry and Institute of Process Research and Development, University of Leeds, Leeds LS2 9JT, UK
b Department of Chemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 June 2009
Revised 29 July 2009
Accepted 14 August 2009
Available online 20 August 2009
Benzoxazoles are synthesised directly by oxidative condensation of primary and secondary amines with
o-aminophenols under hydrogen transfer catalysis. The optimal system utilises 1 mol % of the Shvo cat-
alyst, with dimethoxybenzoquinone as the hydrogen-accepting terminal oxidant.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Benzoxazole
Hydrogen transfer
Oxidation
Catalysis
Benzoxazoles occur in a diverse range of biologically active nat-
ural products1 and pharmaceutical targets,2 and as such, new
methods for the formation of these heterocycles are in constant
demand. Amongst the myriad synthetic approaches to benzoxaz-
oles,3–5 the use of stoichiometric oxidants to effect the aromatising
condensation of alcohols6 or aldehydes7 with 2-aminophenols has
been widely described. Catalytic oxidative processes have, by
contrast, been little studied,8 although there are reports of aerobic
oxidative formation of benzoxazoles using TEMPO derivatives,
copper nanoparticles and activated carbon.9 In this context, we
recently reported the use of homogeneous hydrogen transfer
catalysis for the oxidative formation of benzazoles from alcohols
or aldehydes according to Scheme 1, Path A.10 Thus, hydrogen
abstraction from an alcohol 1 by the catalyst gives an aldehyde 2,
which undergoes condensation with an ortho-heterosubstituted
aniline 3 to generate Schiff base 4. Alternatively, 4 may be accessed
directly from an aldehyde starting material. Subsequent hydrogen
abstraction from the ring-closed dihydrobenzazole 5 generates the
desired heterocycle 6.
In earlier work,10 we found that the combination of Ru(PPh3)3
(CO)H2/Xantphos together with crotononitrile as
a hydrogen
acceptor to mediate catalyst turnover was effective for the conver-
sion of alcohols into benzimidazoles, while the catalyst [CpIrI2]2
effected conversion of aldehydes into benzoxazoles and benzo-
Path A:
HX
[M catalyst]
H2 acceptor
3
H2N
R
R
R
OH
O
(- H2O)
Oxidation 1
[M catalyst]
1
2
8
HX
N
H2 acceptor
X
X
N
R
R
Path B:
NH2
N
H
Oxidation 2
R
[M] catalyst
4
5
6
H
2 acceptor
(- NH3)
HX
R
NH
Oxidation 1
X = O, S, NR
3
7
H2N
Scheme 1. Oxidative approaches to benzazoles by hydrogen transfer catalysis.
* Corresponding author. Tel.: +44 113 343 6425; fax: +44 113 343 6565.
E-mail address: s.p.marsden@leeds.ac.uk (S.P. Marsden).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.08.042

A. J. Blacker et al. / Tetrahedron Letters 50 (2009) 6106–6109
6107
Table 1
ure. This was particularly disappointing given the reports of
Watanabe8a and Huh8b that RuCl2(PPh3)3 catalysed the oxidative
condensation of 2-aminophenols and primary alcohols in moder-
ate yields, albeit at relatively high temperatures (180–215 °C).
However, given that the final hydrogen abstraction step in all the
above-mentioned reactions is effectively an amine dehydrogena-
tion, we wondered whether alkyl amines might themselves serve
as substrates for the direct oxidative formation of benzoxazoles.
Thus, hydrogen abstraction (e.g., from a primary amine 7) would
lead to the formation of a Schiff base 8 which upon transimination
with the ortho-heteroaniline 3 would generate the same interme-
diate Schiff base 4 for oxidative benzazole formation (Scheme 1,
Path B). Such use of an amine as the oxidation substrate for hetero-
cyclisation is, to our knowledge, unprecedented, and we report
herein the successful demonstration of this strategy for the conver-
sion of primary and secondary amines into benzoxazoles.
Optimisation of oxidative benzoxazole formation from amines
1% catalyst,
BnNH2
or
Bn2NH
HO
O
N
2 equiv. co-oxidant
Ph
+
mesitylene (0.5 M),
150 ºC, 24 h
H2N
9a
10a
Entry
Amine
Catalyst
Co-oxidant
Yield (%)
1a,b
2a,b
3b
BnNH2
BnNH2
BnNH2
BnNH2
BnNH2
BnNH2
Bn2NH
Bn2NH
Bn2NH
Bn2NH
Bn2NH
Bn2NH
Bn2NH
Bn2NH
Bn2NH
[CpIrI2]2
Shvo
None
None
0
0
0
Shvo
Shvo
Shvo
Shvo
None
4a,b
5
Styrene
DMBQ
DMBQ
None
DMBQ
None
0
43
31
0
43
0
0
5
66
46
20
27
6c
7
8
9
10
11
12
13d
14c
15
[CpIrI2]2
[CpIrI2]2
Shvo
Shvo
Shvo
Shvo
Shvo
none
Shvo
Crotononitrile
tBuCH@CH2
DMBQ
DMBQ
DMBQ
In our initial experiments, we examined the oxidative coupling
of benzylamine with ortho-aminophenol using two catalysts,
11
namely [CpIrI2]2
Ru2(CO)4(
and the Shvo catalyst {[(g
5-Ph4C4CO)]2H}-
l
-H)}.12 In the event, neither catalyst gave any
Air
benzoxazole when heated with the two reactants alone (Table 1,
entries 1–3).
a
b
c
Solvent = toluene, sealed tube.
Concentration = 4 M.
Reaction in toluene at reflux.
1 equiv of co-oxidant used.
Given the known ability of each of these catalysts to promote
hydrogen borrowing from amines,11,13 we reasoned that one possi-
ble explanation for the lack of reactivity might be an unfavourable
equilibrium between the amine and imine, leading to a low con-
centration of the latter for participation in the transimination.
We therefore investigated additives which might accept hydrogen
from the catalyst, and hence shift the equilibrium towards the
d
thiazoles without the need for an external hydrogen acceptor.
However, all of our attempts to form benzoxazoles by direct oxida-
tive condensation of alcohols with 2-aminophenols met with fail-
Table 2
Scope of the oxidative conversion of amines into benzoxazoles14
1% {[(η5-Ph4C4CO)]2H}Ru2(CO)4(μ-H)},
2 equiv. DMBQ
HO
O
N
R1
R1 NH2
+
R3
H2N
R3
mesitylene (c = 0.5 M)
R2
9
R2
10
150 oC, 24 h
7
Entry
1
Amine
R1
Aminophenol
R2
H
R3
H
Product
Yield (%)
43
7a
Ph
9a
10a
O
N
O
N
2
3
Bn2NH
Ph
9a
9a
H
H
H
H
10a
10b
66
70
O
N
7b
4-MeOC6H4
MeO
O
4
5
6
7c
7d
7e
4-MeC6H4
4-ClC6H4
2-thienyl
9a
9a
9a
H
H
H
H
H
H
10c
10d
10e
62
36
30
Me
Cl
N
O
N
O
S
N
O
7
8
7a
7b
Ph
9b
9b
H
H
Me
Me
10f
64
68
N
Me
O
N
MeO
4-MeOC6H4
10g
Me
(continued on next page)

6108
A. J. Blacker et al. / Tetrahedron Letters 50 (2009) 6106–6109
Table 2 (continued)
Entry
Amine
R1
Aminophenol
R2
H
R3
Product
Yield (%)
68
O
N
Me
9
7c
7b
7c
7a
4-MeC6H4
9b
Me
10h
Me
Cl
O
MeO
Me
10
11
12
4-MeOC6H4
4-MeC6H4
Ph
9c
9c
9d
H
Cl
Cl
H
10i
10j
10k
50
42
52
N
O
H
N
Cl
O
N
Me
Me
O
N
a
13
14
7f
ArCH2
9a
9a
H
H
H
H
10l
48
55
MeO
MeO
O
N
nC5H11
7g
C5H11
10m
a
Ar = 3,4-(MeO)2C6H3–.
imine. Styrene was found to be ineffective (entry 4), but 2,6-dim-
ethoxybenzoquinone (DMBQ)13b–d delivered moderate yields of
the desired benzoxazole in both mesitylene and toluene as sol-
vents (entries 5 and 6). We also considered the possibility that
the primary amine (benzylamine) might be more difficult to oxi-
dise than a more electron-rich secondary amine. The resulting N-
alkylbenzaldimine ought still to be able to participate in transimin-
ation and hence in benzoxazole formation. We therefore examined
the reactions using dibenzylamine as the substrate. In the absence
of a hydrogen accepting co-oxidant, no reaction was observed (en-
tries 7 and 9), but the addition of co-oxidants again proved effec-
tive, with DMBQ proving most efficient. The Shvo catalyst
appears more effective than [CpIrI2]2 in this transformation (en-
tries 8 and 12).
We next attempted to determine the role of the DMBQ. Use of a
single stoichiometric equivalent of DMBQ gave a much-reduced
yield of benzoxazole (entry 13), suggesting its involvement in both
oxidation steps. A control reaction in the absence of a catalyst
showed that DMBQ alone can mediate benzoxazole formation,
but this reaction returned only a low yield of product (entry 14),
demonstrating a significant role for the catalyst. Finally, we exam-
ined whether the formal dehydrogenation of the catalyst might be
mediated aerobically, to circumvent the need for the organic co-
oxidant. Again, this was successful but low yielding (entry 15).
Although we cannot comment further on the exact mode of action
of DMBQ, it is clear from these results that both catalyst and co-
oxidant are required for the most efficient transformation, and that
the latter has a role in both putative oxidation steps.
With an optimised protocol in hand, we next examined the
scope and limitations of the method with respect to both amine
and aminophenol reactants. The results are outlined in Table 2.
The reaction is effective for a range of primary benzylic and het-
erobenzylic amines. Higher yields are obtained for substrates bear-
ing electron-donating substituents (p-MeO–, p-Me) and lower
yields are obtained for the electron-poor p-chloro derivative (en-
tries 3 and 4 cf. entry 5). This is consistent with a mechanism
involving hydride abstraction with a resulting build-up of partial
positive charge at the benzylic carbon. Similarly, the presence of
an electronegative chlorine atom in the aminophenol gives lower
yields (entries 10 and 11) than the corresponding electronically
neutral (entries 3 and 4) or electron-rich (entries 8 and 9) variants.
Notably, the steric impediment presented by a methyl substituent
ortho to the amino function does not impact significantly upon the
efficiency of the process (entry 12). Finally, the reaction was found
to be general for simple (non-benzylic) substrates (entries 13 and
14). This is in contrast to our previously reported approach to
benzoxazoles commencing from aliphatic aldehydes, in which en-
amine-based pathways caused the formation of undesired 8-
hydroxyquinolines as the only observable products of the
reactions.10
In summary, we have developed a new oxidative approach to
benzoxazoles starting from primary amines as the source of the
C2-carbon,14 further broadening the scope of chemistry that can
be accomplished by hydrogen transfer from amines. The results
of further studies from our laboratories in the latter area will be
disclosed in due course.
Acknowledgement
We thank the EPSRC for funding through Grants EP/F038321/1
and EP/F0376431/1. SPM is a Royal Society Industry Fellow
(2008-10).
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a 100 mL Radley’s
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