Ruthenium-catalysed conversion of oxime ethers into nitriles

Article abstract of DOI:10.1016/j.tetlet.2007.09.028

The conversion of oxime ethers into nitriles has been achieved under neutral conditions using Ru(CO)(PPh₃)₃H₂ and the bidentate ligand Xantphos as the catalyst.

Full text of DOI:10.1016/j.tetlet.2007.09.028

Tetrahedron Letters 48 (2007) 7761–7763
Ruthenium-catalysed conversion of oxime ethers into nitriles
Naveen Anand,a Nathan A. Owston,a Alexandra J. Parker,b
Paul A. Slatforda and Jonathan M. J. Williamsa,*
aDepartment of Chemistry, University of Bath Claverton Down, Bath BA2 7AY, UK
bProcess Research and Development, AstraZeneca, Avlon Works, Severn Road, Hallen, Bristol BS10 7ZE, UK
Received 10 August 2007; revised 31 August 2007; accepted 4 September 2007
Available online 8 September 2007
Abstract—The conversion of oxime ethers into nitriles has been achieved under neutral conditions using Ru(CO)(PPh3)3H2 and the
bidentate ligand Xantphos as the catalyst.
Ó 2007 Elsevier Ltd. All rights reserved.
Standard methods for the conversion of oximes into
nitriles involve dehydrating agents such as trifluoro-
acetic anhydride, thionyl chloride,1 or pivaloyl chlo-
ride.2 Oxime ethers can undergo elimination to give
nitriles when treated with strong bases.2 There are a
few reports of transition metal catalysed reactions of
oximes leading to either the corresponding nitrile3 or
the amide,4 depending on the choice of catalyst.
Recently, we have shown that the combination of
Ru(CO)(PPh3)3H2 with dppe leads to the highly selec-
tive re-arrangement of oximes into amides.5 In this
Letter, we report that a closely related catalyst is effec-
tive for the conversion of oxime ethers to nitriles under
neutral conditions (Scheme 1). Iridium catalysts have
previously been used for the ring cleavage of cyclobuta-
none oxime ethers to give nitriles, but we are unaware of
any other reports of metal catalysed conversion of
oxime ethers into nitriles.6
In preliminary experiments, oxime ether 1 was treated
with Ru(CO)(PPh3)3H2 and several bidentate phosphine
ligands and heated to reflux in toluene for 14 h with
moderate conversion into nitrile 2 (Scheme 2). With
the exception of Xantphos 3,7 all the other phosphine li-
gands examined hindered the progress of the reaction.
We have previously noted the reactivity of Ru/Xantphos
combinations in other processes,8 although for oxime to
amide re-arrangement, dppe was found to be a better li-
gand than Xantphos.
We therefore decided to proceed with the reaction using
Xantphos as an additive, although the reaction in the
OMe
N
1 mol% Ru(CO)(PPh3)3H2
1 mol% ligand
Ar CN
Ar
H
Toluene, reflux 14 h
Ar = p-MeOC6H4
2
1
Ru(PPh3)3(CO)H2
OH
Ligand Conv. (%)
dppe
N
3
60
3
R
CONH2
4
O
rearrangement
(ref 5)
dppf
dppe
dppb
none
6
R
H
PPh2
PPh2
25
13
46
Xantphos 3
Ru(PPh3)3(CO)H2
Xantphos
OMe
N
R
CN
elimination
(this study)
R
H
O
PPh2
PPh2
Scheme 1. Reactions of oximes and oxime ethers.
DPE-Phos 4
*
Scheme 2. Phosphine screen for the elimination of oxime ether to
nitrile.
Corresponding author. Tel.: +44 1225 383 942; fax: +44 1225 386
231; e-mail: j.m.j.williams@bath.ac.uk
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.09.028

7762
N. Anand et al. / Tetrahedron Letters 48 (2007) 7761–7763
Table 1. Yields of nitriles from the corresponding oxime ether
cat. Ru(CO)(PPh3)3H2
OMe
H
N
cat. Xantphos
Entry
Product
Catalysta (%)
Yieldb (%)
R
CN
R
Toluene, reflux 24 h
CN
1
3.5
98 (81)
Scheme 3. Conversion of oxime ethers into nitriles.
MeO
CN
absence of this ligand was almost as effective. Using
2.5 mol % of catalyst demonstrated that toluene was a
convenient solvent affording 63% conversion to nitrile
2 after 6 h. The use of DMF as solvent afforded the same
conversion, whilst a lower conversion of 37% was
obtained in 1,4-dioxane. No reaction was observed in
isopropanol or acetonitrile, although these reactions
were performed at a lower temperature (80 °C vs
111 °C). The conversion was dependent on the catalyst
loading with the reaction (in toluene for 24 h) proceed-
ing to 71% with 1 mol % of catalyst, 89% with
2.5 mol %, 98% with 3.5 mol % and 100% with
5 mol %. The addition of acid (EtCO2H or TsOHÆH2O)
as a co-catalyst (1 equiv with respect to ruthenium)
resulted in no reaction, whilst the use of base (Cs2CO3,
2
3
3.5
3.5
89 (80)
94
Me2N
CN
Me
CN
Me
4
3.5
98 (83)
CN
5
6
7
8
5.0
3.5
5.0
5.0
99 (80)c
NC
F
CN
t
KOH or BuOK) reduced reactivity.
96
Alternative oxime ethers were readily prepared in good
yields from the corresponding aldehyde and O-meth-
ylhydroxylamine hydrochloride using the literature pro-
cedures.9 We then examined the conversion of these
oxime ethers into nitriles using either 3.5 or 5 mol %
of Ru(CO)(PPh3)3H2/Xantphos in toluene at reflux for
24 h. All reactions were run at 0.5 M in substrate.10
We were pleased to find that the majority of oxime
ethers were cleanly converted into nitriles with good
conversions and with good isolated yields (Scheme 3
and Table 1). The reaction was successful when there
were electron-donating substituents (entries 1 and 2),
as well as for other p-substituted aryl groups. The pres-
ence of an o-substituent did not appear to compromise
reactivity (entry 4). The process did not require an aryl
group, as evidenced by the success of the reaction of
the oxime ether derived from octanal (entry 11). The
considerably lower conversion obtained with the p-nitro
substituted oxime (entry 8) may be due to electronic
effects, although since the aliphatic substrate was reac-
tive, it is possible that the catalyst is being deactivated
by the nitro group.11 It is also likely that the lower reac-
tivity of the pyridyl-containing substrate (entry 9) is due
to inhibition of the catalyst by co-ordination.
CN
95
CN
28
O2N
N
CN
9
5.0
73
CN
10
11
5.0
3.5
99 (85)
C7H15ACN
100 (83)
a Ru(CO)(PPh3)3H2/Xantphos.
b Conversion, with isolated yield in parentheses.
c The starting material was the p-NC-substituted oxime ether.
OBn 5 mol% Ru(CO)(PPh3)3H2
N
5 mol% Xantphos
Ph CN
Ph
Ph
H
Toluene, reflux 24 h
7
5
Whilst the use of the O-methylhydroxylamine-derived
oxime ethers is convenient, we also wished to determine
whether alternative oxime ethers would undergo conver-
sion into nitriles, and therefore examined the reactions
of oxime ethers 5 and 6, derived from O-benzylhydr-
oxylamine and O-t-butylhydroxylamine, respectively
(Scheme 4). In both cases, these reactions provided the
corresponding nitriles, although a slightly lower conver-
sion was observed for the reaction with oxime ether 5,
perhaps because of the easier oxidation of the liberated
benzyl alcohol, which may result in carbonylation and
de-activation of the catalyst.12
74% conversion
O
t-Bu 5 mol% Ru(CO)(PPh3)3H2
5 mol% Xantphos
N
Ph CN
H
Toluene, reflux 24 h
7
6
98% conversion
Scheme 4. Reactions with O-benzyl and O-t-butyl oximes.
provides in these reactions. We assume that the elimina-
tion of alcohol is facilitated by N-co-ordination of the
oxime ether to the ruthenium catalyst to give a nitrile
complex which then dissociates.6
We are currently investigating the nature of the catalyst,
and the reasons for the benefits that the bidentate ligand

N. Anand et al. / Tetrahedron Letters 48 (2007) 7761–7763
7763
5. Owston, N. A.; Parker, A. J.; Williams, J. M. J. Org. Lett.
2007, 9, 3599–3601.
In summary, oxime ethers can be converted into nitriles
using a similar catalyst combination to one that is effec-
tive for the conversion of the parent oximes into amides.
6. Nishimura, T.; Yoshinaka, T.; Nishiguchi, Y.; Maeda, Y.;
Uemura, S. Org. Lett. 2005, 7, 2425–2427; The conversion
of a ruthenium complex into the ruthenium nitrile
complex on treatment with an oxime ether has been
reported: Kendrick Geno, M. J.; Dawson, J. H. Inorg.
Chem. 1984, 23, 509–510.
Acknowledgements
We wish to thank the Royal Society for a Visiting
Fellowship (to N.A.), the Higher Education Dept.,
Govt. of Jammu and Kashmir, India, as well as Astra-
Zeneca and the EPSRC for further funding.
7. Freixa, Z.; van Leeuwen, P. W. N. M. Dalton Trans. 2003,
1890–1901.
8. (a) Slatford, P. A.; Whittlesey, M. K.; Williams, J. M. J.
Tetrahedron Lett. 2006, 47, 6787–6789; (b) Pridmore, S. J.;
Slatford, P. A.; Williams, J. M. J. Tetrahedron Lett. 2007,
48, 5111–5114; (c) Pridmore, S. J.; Slatford, P. A.; Daniel,
A.; Whittlesey, M. K.; Williams, J. M. J. Tetrahedron Lett.
2007, 48, 5115–5120.
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