Direct evidence for a ruthenium(IV) oxo complex-mediated oxidation of a hydroxamic acid in the presence of phosphine oxide donors

Article abstract of DOI:10.1039/b106338n

Ruthenium(II) complexes can be used to oxidise N-Boc hydroxylamine in the presence of tert-butylhydroperoxide to the corresponding nitroso dienophile, which is trapped using cyclohexa-1,3-diene as the hetero-Diels-Alder adduct; direct evidence has been obtained for the intervention of a triphenylphosphine oxide-stabilised ruthenium(IV) oxo-complex as the catalytically active species.

Full text of DOI:10.1039/b106338n

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Direct evidence for a ruthenium(IV) oxo complex-mediated oxidation
of a hydroxamic acid in the presence of phosphine oxide donors
Kevin R. Flower,a Andrew P. Lightfoot,b Hayley Wana and Andrew Whiting*a
a UMIST, Department of Chemistry, PO Box 88, Manchester, UK M60 1QD.
E-mail: a.whiting@umist.ac.uk
b GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Third Avenue, Harlow, Essex, UK
CM19 5AW
Received (in Cambridge, UK) 17th July 2001, Accepted 6th August 2001
First published as an Advance Article on the web 3rd September 2001
peroxide oxidants), [RuCl2(PPh3)4] and tBuOOH was found to
be highly effective as shown by the screening results reported in
Table 1, entries 1–3. Having established that [RuCl2(PPh3)4]
clearly catalysed the in situ oxidation of 1, we investigated the
probable mechanism for this process. Since it is well known9
that triphenylphosphine dissociates from the [RuCl2(PPh3)4]
complex in solution, we expected that the dissociated phosphine
would be immediately oxidised by tert-butylhydroperoxide
(TBHP) to give triphenylphosphine oxide. Indeed, 31P NMR
studies showed that not only is free triphenylphosphine
oxidised, but after 10 min exposure to the TBHP, all
triphenylphosphine had been oxidised, which suggests that the
[RuCl2(PPh3)4] is a pre-catalyst. From these results, it was
hypothesised that catalytic activity was the result of a
ruthenium(II)–(IV) couple, where the ruthenium(IV) species was
stabilised by the presence of triphenylphosphine oxide ligands.
Further support for this hypothesis was obtained by subsequent
experiments, as reported in Table 1.
Entry 10 (Table 1) shows that TBHP alone gives a slow
background oxidation of 1, providing only 30% yield of adduct
over 4 d, compared with 60% yield in 30 min using 10 mol%
[RuCl2(PPh3)4] (entry 8, Table 1). Ruthenium(III) chloride
(entry 9, Table 1) displays little more than background, i.e.
TBHP-derived activity, even in the presence of OPPh3. In
contrast, RuO2 dissolves slowly in DCM in the presence of
OPPh3 and accomplishes a slow oxidation of the hydroxamic
acid 1 in the absence of TBHP (19% over 4 d) when used
stoichiometrically (entry 11, Table 1). However, when the
RuO2 + OPPh3 mixture is used catalytically with 3 equiv. of
TBHP, only slight enhancement over the background (TBHP-
derived) reaction occurs (compare entries 11 and 12, Table 1).
This shows that although a RuO2-derived complex can effect
the oxidation of 1 (entry 12, Table 1), it is not responsible for
the catalytic activity observed in, for example, entry 8 (Table 1).
It is therefore likely that a mixed ruthenium(IV) oxo-chloride
complex stabilised by a phosphine oxide is responsible for the
observed catalytic activity, as outlined in Scheme 1.
Ruthenium(II) complexes can be used to oxidise N-Boc
hydroxylamine in the presence of tert-butylhydroperoxide to
the corresponding nitroso dienophile, which is trapped using
cyclohexa-1,3-diene as the hetero-Diels–Alder adduct; direct
evidence has been obtained for the intervention of a
triphenylphosphine oxide-stabilised ruthenium(IV
complex as the catalytically active species.
) oxo-
The use of acyl nitroso compounds as efficient hetero
dienophiles in the [4+2]-cycloaddition reaction with conjugated
1,3-dienes, to produce 3,6-dihydro-1,2-oxazines have been
studied since the 1940s.1 These types of hetero Diels–Alder
reactions have been used as powerful synthetic tools in the
formation of natural products such as polyhydroxylated alka-
loids and their derivatives.2–5
The formation of acyl nitroso dienophiles is usually achieved
via an in situ oxidation of a hydroxamic acid6 and the unstable
dienophiles (liable to dimerisation) are usually trapped by
reaction with a diene via a hetero-Diels–Alder reaction.7 Apart
from the common periodate oxidation of hydroxamic acids, the
only other oxidants reported are Swern and lead(IV) oxide-based
oxidants.8 In this communication, we report a new ruthen-
ium(IV)-based method for the in situ generation of an acyl
nitroso dienophile, identified from a combinatorial screening
approach.†
A diversity-based screening strategy was used to search for
new in situ oxidation methods for the generation of the Boc-
nitroso dienophile 2 for use in a subsequent hetero-Diels–Alder
cycloaddition with cyclohexadiene to produce adduct 3 [eqn.
(1)]. Of several metal complex–oxidant combinations screened
(i.e. including complexes derived from manganese, chromium,
osmium, ruthenium, titanium and vanadium and various
(1)
Table 1 Reaction conditions and yields for the in-situ generation of 2 and trapping as 4
Entry
Catalyst/mol%
Solvent
tBuOOH/mol%
Temp./°C
Time/°C
Yield of 3a(%)
1
2
3
4
5
6
7
8
9
RuCl2(PPh)4 (10)
RuCl2(PPh)4 (10)
RuCl2(PPh)4 (10)
RuCl2(PPh)4 (10)
RuCl2(PPh)4 (10)
RuCl2(PPh)4 (0.1)
RuCl2(PPh)4 (1.0)
RuCl2(PPh)4 (10)
RuCl3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeOHc
CH2Cl2
CH2Cl2
MeOHc
0
100
100
300
500
300
300
300
300
300
0
rt
278
rt
rt
rt
rt
rt
rt
rt
rt
rt
72
8
0
25
57
69
43d
39
54
60
20
30
19
38
24
72
72
48
18
0.5
144
96
96
72
10
11
12
None
RuCl2(PPh)4 (100) + OPPh3 (400)b
RuO2 (10) + OPPh3 (40)
300
rt
a Isolated yields after silica gel chromatography. b No RuO2 solubility until addition of OPPh3. c MeOH was used due to the insolubility of both RuCl3 and
RuO2 in CH2Cl2. d Effervescence during addition of TBHP.
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Chem. Commun., 2001, 1812–1813
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b106338n

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complex 6, the opportunity to carry out an asymmetric version
of this reaction is a real possibility; we are actively pursuing
this.
We thank EPSRC and GlaxoSmithKline for an industrial
CASE studentship (to HW) (Ref. no. 9931546X).
Notes and references
† Typical procedure: A solution of [RuCl2(PPh3)4] (92 mg, 0.075 mmol) in
DCM (10 ml), N-Boc hydroxamic acid 1 (100 mg, 0.751 mmol) and
cyclohexa-1,3-diene (0.08 ml, 0.751 mmol) was treated with TBHP (slow,
dropwise addition) (5–6 M solution in decane) (0.42 ml, 2.250 mmol). After
30 min, the reaction mixture was washed H2O (10 ml) (23) and brine (10
ml), dried (MgSO4) and evaporated to give the crude cycloadduct as a
brown oil (279 mg). Purification by silica gel chromatography (hexane–
ethyl acetate, 6+1 as the eluent) gave cycloadduct 312 as a pale yellow oil
(100 mg, 63%).
1 G. W. Kirby, Chem. Soc. Rev., 1977, 6, 1.
2 O. Wichterle, Coll. Czech. Chem. Commun., 1947, 12, 292.
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Scheme 1
From the data presented, it is evident that the PPh3 ligands of
[RuCl2(PPh3)4] are oxidised to OPPh3 to give compound 4,
which is then further oxidised to give 5 by TBHP. The presence
of an oxo-ligand is inferred from the unprecedented oxidation of
the hydroxamic acid, facilitated by RuO2 in the presence of
OPPh3 (note: hydrated RuO2 is known to catalytically decom-
pose H2O2, fully crystalline RuO2 does not10). The oxo-
chloride-containing complex 5 then oxidises the hydroxamic
acid 1 to give 6, which contains an N-bound nitroso ligand.
Evidence to support the presence of an N-bound nitroso ligand
comes from the recent report11 which clearly demonstrated this
bonding mode in ruthenium complexes. The N-bound nitroso
complex 6 then undergoes the cycloaddition reaction with
cyclohexadiene to give adduct 3 and regenerate 4. If the
cycloaddition does take place directly on the N-bound nitroso
7 G. W. Kirby and J. G. Sweeny, J. Chem. Soc., Chem. Commun., 1973,
704.
8 L. H. Dao, J. M. Dust, D. Mackay and K. N. Watson, Can. J. Chem.,
1979, 57, 1712.
9 (a) R. H. Crabtree, Chem. Commun., 1999, 1611; (b) T. A. Stephenson
and G. Wilkinson, J. Inorg. Nucl. Chem., 1966, 28, 945.
10 ‘The Chemistry of Ruthenium’, eds. E. A. Seddon and K. R. Seddon,
Elsevier, Oxford, 1984.
11 J.-L. Liang, J.-S. Huang, Z.-Y. Zhou, K.-K. Cheung and C.-M. Che,
Chem. Eur. J., 2001, 7, 2306.
12 D. Zhang, C. Süling and M. J. Miller, J. Org. Chem., 1998, 63, 885.
Chem. Commun., 2001, 1812–1813
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