A simple method for the α-oxygenation of aldehydes

Article abstract of DOI:10.1039/b418101h

A mild, efficient and general method for the chemospecific α-oxygenation of aldehydes is described. Treatment of a series of aldehydes with N-tert-butyl-O-benzoyl hydroxylamine hydrochloride gives the corresponding α-oxygenated carbonyl via a proposed per

Full text of DOI:10.1039/b418101h

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A simple method for the a-oxygenation of aldehydes
Cory S. Beshara,a Adrian Hall,b Robert L. Jenkins,a Teyrnon C. Jones,a Rachael T. Parry,a
Stephen P. Thomasa and Nicholas C. O. Tomkinson*a
Received (in Cambridge, UK) 2nd December 2004, Accepted 23rd December 2004
First published as an Advance Article on the web 24th January 2005
DOI: 10.1039/b418101h
In 1969 House described a five step synthetic protocol for the
A mild, efficient and general method for the chemospecific
a-oxygenation of aldehydes is described. Treatment of a series
of aldehydes with N-tert-butyl-O-benzoyl hydroxylamine
hydrochloride gives the corresponding a-oxygenated carbonyl
via a proposed pericyclic rearrangement process.
conversion of cyclohexanone 1, to a-acetoxycyclohexanone 6 as
outlined in Scheme 1.5 This process involved conversion to the
oxime 2, and then O-acylation followed by N-alkylation to give the
iminium ion 3. Rearrangement of this salt under basic conditions
gave the corresponding a-acetoxyimine 5, which was then
hydrolysed under aqueous acidic conditions to unmask the
a-acetoxycarbonyl 6. It was proposed that the key bond-forming
process involved conversion of the salt 3 to the enamine 4 followed
by a concerted pericyclic rearrangement.6 By consideration of the
recent elegant work within the literature involving enamine
intermediates7 we were intrigued whether we could develop a
one-pot method for the House synthesis.
There has been a recent explosion of interest in the use of metal-
free processes to carry out functional group manipulations and
transformations due to the accordant potential for academic,
industrial, economic and environmental benefit.1
a-Hydroxycarbonyl compounds represent important building
blocks for organic synthesis and correspond to a key functional
group present in a substantial number of important natural
products. A number of methods have been reported for the
preparation of this crucial functionality including the a-oxygena-
tion of enolates with electrophilic oxidising agents, and the
dihydroxylation or epoxidation of preformed enol ethers.2 More
recently, the aminoxylation of aldehydes3 and ketones4 has been
reported using nitrosobenzene, however the use of at least three
equivalents of the carbonyl compound, in conjunction with syringe
pump techniques, somewhat limits this innovative and attractive
piece of methodology.
Preparation of N-tert-butyl-O-benzoyl hydroxylamine 7 pro-
ceeded in one step by the reaction of tert-butylamine with
benzoylperoxide to give the proposed reagent.8 We initially
prepared the hydrochloride salt of 7 and investigated its reactivity
with both cyclohexanone 1 and isovaleraldehyde 8, at both room
temperature and 50 uC9 in water, and were delighted to discover
that with isovaleraldehyde the desired product 9 could be isolated
in 25% yield, showing that the proposed transformation was viable
(Scheme 2). We believe that this process proceeds via condensation
of the reagents to give an iminium ion, followed by conversion to
the enamine and rearrangement to give an a-benzoyloxy imine,
which is subsequently hydrolysed under the aqueous acidic
reaction conditions to give the observed product 9. No
a-functionalised carbonyl product was detected in the reaction of
cyclohexanone with only starting material being isolated from the
reaction mixture.
Herein, we report a simple method for the a-oxygenation of
carbonyl compounds under aerobic, aqueous acidic reaction
conditions. The reaction allows for complete control in chemo-
selectivity for aldehydes over ketones, and is applicable to the
transfer of a variety of acyl substituents.
Scheme 2
Encouraged by this initial result we went on to investigate the
effect of both the solvent and the nature of the acid involved in the
reaction in an attempt to optimise the transformation and
eventually adopted a solvent mixture of THF–H2O (9:1) and
HCl as the acid of choice for the reagent.{
Having established the best reaction conditions we then went on
to examine the applicability of the transformation (Table 1). The
transformation was effective for a range of simple aliphatic
aldehydes, with both valeraldehyde (entry 2) and decanal (entry 3)
giving the desired product in good yield. The reaction also worked
Scheme 1
*tomkinsonnc@cardiff.ac.uk
1478 | Chem. Commun., 2005, 1478–1480
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a
We were not able to detect any reaction product with acetone,
cyclohexanone, propiophenone or ethylacetoacetate under our
standard reaction conditions, and use of both acetone and
cyclohexanone as the reaction solvent (40 equivalents, 50 uC,
72 h) also led to no detectable products when treated with one
equivalent of the reagent, which indicated that 7?HCl is
chemospecific for aldehydes over ketones. This was further
supported by a competition experiment, where reaction of one
equivalent of both isovaleraldehyde 8 and cyclohexanone 1 in the
same flask, under our standard conditions for 16 hours, gave the
a-functionalised aldehyde product 9 in 73% isolated yield.
Finally, in an effort to determine if alternative groups could be
transferred within this reaction, we prepared N-tert-butyl-O-acetyl
hydroxylamine hydrochloride 10 and N-tert-butyl-O-pivaloyl
hydroxylamine hydrochloride 12. Reaction of these with isovaler-
aldehyde and cyclohexane carboxaldehyde, respectively, gave the
expected products 11 (72%) and 13 (64%) (Fig. 1), suggesting this
should be an effective method for the introduction of a variety of
acyl systems.
Table 1
Entry
Substrate
Product
Yield (%)
79
1
2
3
4
72
74
82
5
6
76
69
Fig. 1
7
67
In summary, we have developed an operationally simple and
effective method for the a-functionalisation of aldehydes that can
be carried out in the presence of both moisture and air, without the
need for purification of solvents or any specialist reaction
techniques. The N-tert-butyl-O-benzoyl hydroxylamine hydro-
chloride can be prepared in one step, is air stable and can be
stored at room temperature for prolonged periods of time without
loss of reactivity. The rearrangement is also effective for the
introduction of both aliphatic and aromatic acyl groups, greatly
adding to the utility of this procedure. We are currently
investigating whether this transformation is also applicable to the
formation of C–N and C–S bonds and will report on our findings
in due course.
8
9
a
endo/exo 9:1
endo/exo 1:1
9
9
1
1
62
61
All reactions were performed with 1 equivalent of reagent, 0.5 M
concentration, at 50 uC in a 9:1 mixture of THF and water except
entry 7 which was carried out at room temperature.
The authors wish to thank GlaxoSmithKline for a CASE
award, the EPSRC, Pfizer and The Leverhulme trust for financial
support, and Swansea HRMS service for analyses.
for rearrangement into tertiary centres with cyclohexane carbox-
aldehyde giving the desired product in 82% isolated yield (entry 4).
The reaction was also tolerant of a variety of functional groups,
for example, 4-pentenal (entry 5) and 3-phenylpropanal (entry 6)
both smoothly gave the desired product in good yield.
Interestingly, when phenylacetaldehyde was used as the substrate
for the procedure, the reaction was complete in just 45 minutes at
room temperature (entry 7), possibly due to the increased acidity
of the a-proton, accelerating enamine formation in the proposed
reaction sequence. We also discovered that treatment of a Diels–
Alder adduct as a 9:1 mixture of endo- and exo-isomers (entry 8)
gave the a-functionalised product in 62% isolated yield in an
identical ratio to the starting material. However, when the ratio of
the endo- and exo-isomers of the starting material was 1:1 (entry 9),
the endo–exo ratio of the products was once again 9:1, suggesting
that these two reactions proceed via the same intermediate.
Cory S. Beshara,a Adrian Hall,b Robert L. Jenkins,a Teyrnon C. Jones,a
Rachael T. Parry,a Stephen P. Thomasa and Nicholas C. O. Tomkinson*a
aSchool of Chemistry, Cardiff University, PO Box 912, Cardiff,
CF10 3TB, UK. E-mail: tomkinsonnc@cardiff.ac.uk;
Fax: +44 29 20874030; Tel: +44 29 20874068
bNeurology & GI Centre of Excellence for Drug Discovery,
GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Third
Avenue, Harlow, Essex, CM19 5AW, UK
Notes and references
{ Typical experimental procedure: to a solution of N-tert-butyl-O-benzoyl
hydroxylamine hydrochloride 7?HCl (0.25 g, 1.09 mmol) in a mixture of
THF and water (9:1 v/v, 2.2 mL) was added isovaleraldehyde 8 (92 mg,
1.09 mmol) and the resulting mixture was warmed to 50 uC for 14 h. The
reaction mixture was diluted with brine (15 mL) and extracted with ethyl
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acetate (4 6 15 mL). The combined extracts were washed with brine, dried
(MgSO4) and concentrated to give the crude product which was purified on
silica eluting with diethyl ether–light petroleum (15:85) to give 1-formyl-2-
methylpropyl benzoate 9 as a colourless oil (174 mg, 79%); IR (thin film)
2968, 1720, 1602, 1452, 1275 cm21; 1H NMR (400 MHz, CDCl3) d 9.57 (d,
1H, J 0.7 Hz, CHO), 8.03 (d, 2H, J 8.2 Hz, ArH), 7.53 (dd, 1H, J 8.2 &
8.2 Hz, ArH), 7.4 (dd, 2H, J 8.2 & 8.2 Hz, ArH), 5.0 (dd, 1H, J 4.5 &
0.7 Hz, CHOBz), 2.30–2.45 (m, 1H, CH(CH3)2), 1.06 (d, 3H, J 6.9 Hz,
CH3), 1.03 (d, 3H, J 6.9, CH3); 13C NMR (100 MHz, CDCl3) d 198.9,
199.2, 133.5, 129.8, 129.2, 128.4, 82.7, 29.3, 18.9, 17.3; m/z (APCI) 207 (M +
H); HRMS (found 207.1016; C12H14O3 requires 207.1016).
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5 H. O. House and F. A. Richey, J. Org. Chem., 1969, 34, 1430.
6 Similar rearrangements have been reported under basic reaction
conditions: A. J. Clark, Y. S. S. Al-Faiyz, D. Patel and
M. J. Broadhurst, Tetrahedron Lett., 2001, 42, 2007; A. J. Clark, Y. S.
S. Al-Faiyz, M. J. Broadhurst, D. Patel and J. L. Peacock, J. Chem. Soc.,
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Chem., 1983, 48, 2070; A. R. Katritzky, A. V. Chapman, M. J. Cook and
G. H. Millet, J. Chem. Soc., Perkin Trans. 1, 1980, 2743; V. J. Traynelis
and P. L. Pacini, J. Am. Chem. Soc., 1964, 86, 4917; V. J. Traynelis and
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7 B. List, Acc. Chem. Res., 2004, 37, 548; S. France, D. J. Geurin,
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2002, 58, 2481.
8 P. F. Alewood, I. C. Calder and R. L. Richardson, Synthesis, 1981, 121.
9 Heating the reaction mixture above this temperature for extended periods
of time resulted in decomposition of the reagent.
1 P. I. Dalko and L. Moisan, Angew. Chem. Int. Ed., 2004, 43, 5138.
2 B.-C. Chen, P. Zhou, F. A. Davies and E. Ciganek, Org. React., 2003, 62,
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1480 | Chem. Commun., 2005, 1478–1480
This journal is ß The Royal Society of Chemistry 2005