Iridium-catalyzed conversion of alcohols into amides via oximes

Article abstract of DOI:10.1021/ol062549u

(Chemical Equation Presented) The iridium catalyst [Ir(Cp*)Cl ₂]₂ is effective for the rearrangement of oximes to furnish amides. The reaction has been combined with catalytic transfer hydrogenation between an alcohol and alkene to allow the conversion of alcohols into amides in a one-pot process.

Full text of DOI:10.1021/ol062549u

ORGANIC
LETTERS
2007
Vol. 9, No. 1
73-75
Iridium-Catalyzed Conversion of
Alcohols into Amides via Oximes
Nathan A. Owston,† Alexandra J. Parker,‡ and Jonathan M. J. Williams*,†
Department of Chemistry, UniVersity of Bath, ClaVerton Down, Bath BA2 7AY, U.K.,
and Process Research and DeVelopment, AstraZeneca, AVlon Works, SeVern Road,
Hallen, Bristol BS10 7ZE, U.K.
j.m.j.williams@bath.ac.uk
Received October 17, 2006
ABSTRACT
The iridium catalyst [Ir(Cp*)Cl2]2 is effective for the rearrangement of oximes to furnish amides. The reaction has been combined with catalytic
transfer hydrogenation between an alcohol and alkene to allow the conversion of alcohols into amides in a one-pot process.
Transition metal catalyzed transfer hydrogenation reactions
have been used successfully for the interconversion of alco-
hols and carbonyl compounds.1 Some catalysts also allow for
the reduction of alkenes2 or imines3 using an alcohol as the
stoichiometric reducing agent. Research from this group4 and
from others5 has demonstrated that iridium and ruthenium
catalysts can be used for the conversion of alcohols into
amines, according to the pathway outlined in Scheme 1. The
reduced to the corresponding amine without any overall
change in oxidation state. This “borrowing hydrogen”
strategy has also been applied to the synthesis of C-C bonds
from alcohols via the aldehyde and alkene.6
We were interested in the possibility of converting alcohols
into hydroxylamines using this catalytic pathway, although
it is known that oximes are less amenable to reduction than
are the equivalent imines.7 We were unable to identify a cata-
lyst that was able to reduce benzaldehyde oxime with isopro-
panol. However, the iridium catalyst [Ir(Cp*)Cl2]2 gave an
unusual rearrangement reaction leading to the corresponding
amide. Neither alcohol nor base was required for the rearrange-
ment reaction to be effective. Yamaguchi and co-workers have
Scheme 1. C-N Bond Formation from Alcohols
(1) Palmer, M. J.; Wills, M. Tetrahedron: Asymmetry 1999, 10, 2045-
2061.
(2) Sakaguchi, S.; Yamaga, T.; Ishii, Y. J. Org. Chem. 2001, 66, 4710-
4712.
(3) Uematsu, N.; Fujii, A.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1996, 118, 4916-4917.
(4) (a) Cami-Kobeci, G.; Williams, J. M. J. Chem. Commun. 2004, 1072.
(b) Cami-Kobeci, G.; Slatford, P. A.; Whittlesey, M. K.; Williams, J. M. J.
Bioorg. Med. Chem. 2005, 15, 535-537.
(5) Fujita, K.; Li, Z.; Ozeki, N.; Yamaguchi, R. Tetrahedron Lett. 2003,
44, 2687.
(6) (a) Edwards, M. G.; Williams, J. M. J. Angew. Chem., Int. Ed. 2002,
41, 4740-4743. (b) Edwards, M. G.; Jazzar, R. F. R.; Paine, B. M.:
Shermer, D. J.; Whittlesey, M. K.; Williams, J. M. J.; Edney, D. D. Chem.
Commun. 2004, 90-91.
(7) Jnaneshwara, G. K.; Sudalai, A.; Deshpande, V. H. J. Chem. Res.,
Synop. 1998, 160-161.
alcohol is oxidized into an aldehyde, which then undergoes
simple imine formation in situ. These intermediates are
† University of Bath.
‡ AstraZeneca.
10.1021/ol062549u CCC: $37.00
© 2007 American Chemical Society
Published on Web 12/06/2006

previously used this catalyst for a range of transfer hydro-
genation reactions.8 Transition metal complexes have been
reported to dehydrate oximes to the corresponding nitriles,9
but the only report of a catalytic rearrangement into amides
required high temperatures (5 mol % RhCl(PPh3)3, 150 °C).10
We developed a standard set of conditions that was
successful for the conversion of a range of oximes into the
corresponding amides. Thus, treatment of oximes with [Ir-
(Cp*)Cl2]2 in toluene provided the amides exceptionally
cleanly upon heating at reflux for 4-16 h. The isolated yields
of the amides after simple purification were consistently
excellent (Table 1). Either the (E)- or (Z)- isomer of the
Scheme 2. Mechanistic Proposal for the Rearrangement
mechanisms could be conceived for this process, with one
option being that outlined in Scheme 2, where initial
displacement of a chloride by oxime allows the iridium to
remove the oxygen and the hydride, followed by replacing
them in the isomeric form prior to the release of amide.
Since iridium complexes are known to be good catalysts
for transfer hydrogenation reactions of alcohols and carbonyl
compounds,8 we investigated the use of alcohols as starting
materials. We reasoned that in the presence of a suitable
hydrogen acceptor, an alcohol would be transformed into
an aldehyde which could be converted in situ to the
corresponding oxime and then further transformed into an
amide. This would then provide a one pot conversion of
alcohols into amides, where the iridium complex would fulfill
a dual role, acting as a catalyst in the two key steps. The
total conversion of benzyl alcohol to benzaldehyde was
readily achieved employing styrene (in slight excess) as the
sacrificial acceptor, using [Ir(Cp*)Cl2]2 as the catalyst in
toluene at reflux over 24 h (Scheme 3). We chose to use an
Table 1. Ir-Catalyzed Rearrangement of Oximes into Amides
entrya
Rb
t (h)
yield (%)c
1
2
3
4
5
6
7
8
9
Z-Ph
E-Ph
6
6
6
6
8
8
4
4
12
16
91
92
90
92
88
85
97
94
82
78
Z-(4-MeO)C6H4
E-(4-MeO)C6H4
(2,4-Cl)C6H3
(4-O2N)C6H4
C3H7
C6H5CHdCH
2-furyl
3-pyridyl
10d
a Conditions: oxime (1.0 mmol), [Ir(Cp*)Cl2]2 (2.5 mol %), PhMe (2
cm3); 111 °C. b Unless specified, oximes are commercially available as
mixed E/Z isomers. c Isolated yields after recrystallization or column
chromatography. d DMF as solvent; 111 °C.
Scheme 3. Optimized Oxidation Conditions
oxime could be used,11 although the interconversion of the
(Z)-isomer into the (E)-isomer was more rapid than the
rearrangement into the amide. Commercially available
oximes are usually a mixture of the (E)- and (Z)-isomers,
which were successfully employed for entries 5-10. Aro-
matic, aliphatic, and heteroaromatic oximes were all viable
substrates for this rearrangement process.
From a mechanistic standpoint, it was interesting to
observe that O-alkylated oximes were inert to reaction, as
were oximes derived from ketones. This suggested that the
presence of both a hydrogen and a hydroxyl group was
required for the transformation. In addition, nitrones were
also resistant to rearrangement. Benzonitrile was inert to
hydrolysis under these reaction conditions, suggesting that
the reaction does not proceed via a free nitrile. Several
alkene as the oxidant to avoid having an additional carbonyl
compound present that would cause complications in the
oxime-forming step, although transfer hydrogenation reac-
tions employing alkenes in this manner have remained
Scheme 4. Novel Strategy for Converting Alcohols into
Amides
(8) (a) Review: Fujita, K.; Yamaguchi, R. Synlett 2005, 560-571. (b)
Suzuki, T.; Morita, K.; Tsuchida, M.; Hiroi, K. J. Org. Chem. 2003, 68,
1601-1602.
(9) (a) Ishihara, K.; Furuya, Y.; Yamamoto, H. Angew. Chem., Int. Ed.
2002, 41, 2983-2986. (b) Yang, S. H.; Chang, S. Org. Lett. 2001, 3, 4209-
4211.
(10) Park, S.; Choi, Y.; Han, H.; Yang, S. H.; Chang, S. Chem. Commun.
2003, 1936-1937.
(11) For examples, see: (a) Albrecht, M. R.; Crabtree, R. H.; Mata, J.;
Peris, E. Chem. Commun. 2002, 32. (b) Tani, K.; Iseki, A.; Yamagata, T.
Chem. Commun. 1999, 1821. (c) Hillier, A. C.; Lee, H. M.; Stevens, E. D.;
Nolan, S. P. Organometallics 2001, 20, 4246.
74
Org. Lett., Vol. 9, No. 1, 2007

and a related process in which amides can be formed via
aldehydes13 using stoichiometric manganese(IV) oxide.
The amides formed from alcohols are identified in Table
2, along with the isolated yields and time required for the
oxidation step. These reactions were successful for a range
of benzylic alcohols, although those with electron-withdraw-
ing groups gave rise to more sluggish oxidations and lower
yields. The reaction proved to be unsuccessful for aliphatic
alcohols, as no oxidation to the aldehyde was observed under
the conditions employed. Further studies into metal-mediated
oxidations of this type are ongoing.
In summary, we have identified a novel iridium-catalyzed
rearrangement of oximes into amides, which has also been
used in a sequential process that permits the conversion of
alcohols into amides in good yield and with minimal
purification.14 Further studies into this and other metal-
mediated tandem and sequential reactions will be reported
in due course.
Table 2. One-Pot Synthesis of Amides from Alcohols
entrya
R
t1 (h)
yield (%)b
1
2
3
4
5
6
7
8
9
Ph
24
24
24
30
30
24
24
36
36
87
90
84
79
83
91
90
48
56
(4-Me)C6H4
(4-F)C6H4
(4-Br)C6H4
(4-Cl)C6H4
(4-MeO)C6H4
(4-BnO)C6H4
(4-O2N)C6H4
(4-F3C)C6H4
a Conditions: alcohol (1.0 mmol), [Ir(Cp*)Cl2]2 (2.5 mol %), PhMe (2
mL); 111 °C. b Isolated yields after recrystallization or column chroma-
tography.
Acknowledgment. We thank the EPSRC and AstraZen-
eca for funding a studentship (to N.A.O.).
comparatively poorly developed.11 Styrene is a convenient
oxidant as it is cheap and benign, and both itself and the
reduced product (ethylbenzene) can be removed by simple
evaporation.
Supporting Information Available: Details of experi-
mental procedures and characterization data. This material
is available free of charge via the Internet at http://pubs.acs.org.
OL062549U
We established the procedure shown in Scheme 4 for the
conversion of alcohols into amides. The alcohol was oxidized
into the corresponding aldehyde using the iridium catalyst
in the presence of base over 24-36 h. Hydroxylamine
hydrochloride was added to the reaction mixture, and the
reaction was heated at reflux to allow the oxime to form
and then undergo rearrangement into the amide, which was
isolated in moderate to excellent yield. Kanno and Taylor
have reported a tandem oxidation/oxime-forming process12
(13) Foot, S. J.; Kanno, H; Giblin, G. M. P.; Taylor, R. J. K. Synthesis
2003, 1055-1064.
(14) Representative Procedure for Formation of Amides from Al-
cohols via a Sequential Process. To an oven-dried, nitrogen-purged Schlenk
tube charged with [Ir(Cp*)Cl2]2 (0.025 mmol) and cesium carbonate (16.4
mg, 0.05 mmol) were added alcohol (1 mmol), styrene (172 µL, 1.5 mmol),
and degassed anhydrous toluene (2 cm3) via syringe, and the mixture was
heated at reflux. The reaction was allowed to cool to room temperature
and hydroxylamine hydrochloride (36.2 mg, 1 mmol) added. The vessel
was flushed with nitrogen and the mixture further refluxed for 16 h. The
reaction was allowed to cool to room temperature, diluted with dichlo-
romethane, and filtered through a short plug of silica gel, and the solvent
was removed in vacuo. The crude product was purified by column
chromatography on silica gel or recrystallization from suitable solvent
(12) Kanno, H.; Taylor, R. J. K. Synlett 2002, 1287-1290.
Org. Lett., Vol. 9, No. 1, 2007
75