A general method for the α-acyloxylation of carbonyl compounds

Article abstract of DOI:10.1021/ol052474e

(Chemical Equation Presented) A simple, one-pot method for the α-acyloxylation of carbonyl compounds that proceeds at room temperature in the presence of both moisture and air has been developed. Treatment of a variety of aldehydes and both cyclic and acy

Full text of DOI:10.1021/ol052474e

ORGANIC
LETTERS
2005
Vol. 7, No. 25
5729-5732
A General Method for the
r
-Acyloxylation of Carbonyl Compounds
Cory S. Beshara,† Adrian Hall,‡ Robert L. Jenkins,† Kerri L. Jones,†
Teyrnon C. Jones,† Niall M. Killeen,† Paul H. Taylor,† Stephen P. Thomas,† and
Nicholas C. O. Tomkinson*,†
School of Chemistry, Main Building, Cardiff UniVersity, Park Place, Cardiff CF10
3AT, U.K., and Neurology & GI Centre of Excellence for Drug DiscoVery,
GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Third AVenue,
Harlow, Essex CM19 5AW, U.K.
tomkinsonnc@cardiff.ac.uk
Received October 12, 2005
ABSTRACT
A simple, one-pot method for the
and air has been developed. Treatment of a variety of aldehydes and both cyclic and acyclic ketones with N-methyl-O-benzoylhydroxylamine
hydrochloride provides the -functionalized product in 69 92% isolated yield. The transformation is tolerant of a wide range of functional
groups and, significantly, is regiospecific in the discrimination of secondary over primary centers in the case of nonsymmetrical substrates.
r-acyloxylation of carbonyl compounds that proceeds at room temperature in the presence of both moisture
r
−
At the heart of synthetic chemistry is the drive to develop
novel, cleaner, more efficient, and selective transformations.
To this end, 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 potential for
academic, industrial, economic, and environmental benefit.1
Herein, we report a simple and practical method for the
R-functionalization of carbonyl compounds that proceeds via
a proposed concerted pericyclic rearrangement.
The R-hydroxy carbonyl functionality represents a sig-
nificant building block in organic synthesis and is present
in a substantial number of both naturally occurring and
synthetic biologically significant molecules. This importance
is reflected in the extensive synthetic research directed toward
introducing this group in a chemo- regio-, stereo-, and
enantioselective manner. Particularly noteworthy among
these contributions are the R-oxygenation of enolates with
electrophilic oxidizing agents, and the dihydroxylation or
epoxidation of preformed enol ethers.2 More recently, there
have been major advances in the area which allow the
aminooxylation of aldehydes3 and ketones.4 Treatment of an
excess of the substrate carbonyl species with nitrosobenzene
in the presence of a catalytic amount of proline delivers the
R-aminooxylated species in excellent yield and ee. Unmask-
ing of the hydroxyl functionality is then accomplished under
reductive conditions. Advances continue to be made in this
area5 toward the ultimate goal of using just 1 equiv of
substrate carbonyl and oxidant to make a truly practical
procedure.6
(2) Chen, B.-C.; Zhou, P.; Davies, F. A.; Ciganek, E. Org. React. 2003,
62, 1.
(3) (a) Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2003, 125, 10808; (b) Zhong, G. Angew. Chem., Int. Ed.
2003, 42, 4247; (c) Hayashi, Y.; Yamaguchi, J.; Hibino K.; Shoji, M.
Tetrahedron Lett. 2003, 44, 8293.
(4) (a) Bøgevig, A.; Sunde´n, H.; Co´rdova, A. Angew. Chem., Int.
Ed. 2004, 43, 1109. (b) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Shoji,
M. Angew. Chem., Int. Ed. 2004, 43, 1112. (c) Co´rdova, A.; Sunde´n,
H.; Bøgevig, A.; Johannson, M.; Himo, F. Chem. Eur. J. 2004, 10,
3673.
(5) (a) Suji, P. M.; Hiroshi, I.; Blackmond, D. G. Angew. Chem., Int.
Ed. 2004, 43, 3317. (b) Iwamura, H.; Mathew, S. P.; Blackmond, D. G. J.
Am. Chem. Soc. 2004, 126, 11770. Iwamura, H.; Wells, D. H., Jr.; Mathew,
S. P.; Klussmann, M.; Armstrong, A.; Blackmond, D. G. J. Am. Chem.
Soc. 2004, 126, 16312. (c) Iwamura, H.; Wells, D. H., Jr.; Mathew, S. P.;
Klussmann, M.; Armstrong, A.; Blackmond, D. G. J. Am. Chem. Soc. 2004,
126, 16312.
† Cardiff University.
‡ GlaxoSmithKline.
(1) (a) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2004, 43, 5138.
(b) Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726. (c)
Groger, H.; Wilken, J. Angew. Chem., Int. Ed. 2001, 40, 529.
10.1021/ol052474e CCC: $30.25
© 2005 American Chemical Society
Published on Web 11/10/2005

Scheme 1
Scheme 2
We have recently described a direct method for the
chemospecific R-functionalization of aldehydes using N-tert-
butyl-O-benzoylhydroxylamine hydrochloride (1) (Scheme
1).7 However, we found 1 to be ineffective for the analogous
transformation with ketones. Although this permits useful
chemoselectivity, we sought to develop a more general
reagent that would permit the transformation of both alde-
hydes and ketones. We rationalized that the hindered nature
of the nitrogen lone pair in 1 rendered the reagent too
sterically encumbered to form the proposed iminium ion and
subsequent enamine (2) intermediates. Therefore, we rea-
soned that reduction in the size of the nitrogen substituent
would provide a system that avoided this deficiency. Herein,
we report that a series of N-methyl-O-acylhydroxylamines
(9-12) can be used for the effective R-acyloxylation of both
aldehydes and ketones.
O-benzoylhydroxylamine hydrochloride 10 crystallized di-
rectly from the reaction mixture and could therefore be iso-
lated by a simple filtration, providing a practical and acces-
sible route to significant quantities of the reagent.12 Acetyl
9, pivaloyl 11, and 4-methoxyphenyl 12 systems were also
prepared in an analogous manner providing a series of com-
pounds with which to investigate the R-oxygenation reaction.
We initially examined the reaction between cyclohexanone
and N-methyl-O-benzoylhydroxylamine hydrochloride (10)
at room temperature using water as the solvent and were
delighted to discover that the desired product 13 could be
isolated from the reaction mixture in 80% yield after
purification by column chromatography.
The origin of our investigation lay in a report by House,
who showed that cyclohexanone could be converted to
2-acetoxycyclohexanone via a five-step protocol.8 This
sequence was shortened to three steps by Coates in 19829
and was elegantly used in the preparation of fumagillol by
Sorensen and co-workers.10 Both of these sequences proposed
a [3,3] sigmatropic rearrangement in the key bond-forming
sequence under basic reaction conditions. More recently,
Lobo has described the R-oxyacylation of enehydroxylamines
by a proposed sigmatropic rearrangement, once again under
basic reaction conditions.11
Scheme 3
Preparation of the reagent commenced with protection of
commercially available N-methylhydroxylamine hydrochlo-
ride (3) as its N-tert-butylcarbamate 4 (97%), followed by
acylation of the product with benzoyl chloride under standard
conditions to give 6. Removal of the protecting group with
hydrochloric acid in dioxane gave the desired reagent 10 in
88% overall yield for the three steps (Scheme 2). It is
particularly noteworthy that both of the synthetic intermedi-
ates 4 and 6 were purified by distillation, and the N-methyl-
We believe this reaction proceeds via condensation of the
reagents to give the iminium ion 14, which is then converted
into the enamine 15 under aqueous acidic reaction conditions.
Concerted pericyclic rearrangement provides the R-benzoy-
loxy imine 16, which is hydrolyzed in situ to give the
observed product 13 (Scheme 3).13 Having established that
(6) (a) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Hibino, K.; Shoji, M. J.
Org. Chem. 2004, 69, 5966. (b) Merino, P.; Tejero, T. Angew. Chem., Int.
Ed. 2004, 43, 2995.
(12) This reaction sequence has been carried out successfully on a 25 g
scale and the resulting salts 9-12 were all bench stable throughout the
course of this investigation.
(13) Clark and co-workers have reported a base catalyzed rearrangement
of N-alkyl-O-acylhydroxamic acids to deliver 2-acyloxyamides, see: (a)
Clark, A. J.; Al-Faiyz, Y. S. S.; Broadhurst, M. J.; Patel, D.; Peacock, J. L.
J. Chem. Soc., Perkin Trans. 1 2000, 1117. (b) Al-Faiyz, Y. S. S.; Clark,
A. J.; Filik, R. P.; Peacock, J. L.; Thomas, G. H. Tetrahedron Lett. 1998,
39, 1269.
(7) Beshara, C. S.; Hall, A.; Jenkins, R. L.; Jones, T. C.; Parry, R. T.;
Thomas, S. P.; Tomkinson, N. C. O. Chem. Commun. 2005, 1478.
(8) House, H. O.; Forrest, A. R. J. Org. Chem. 1969, 34, 1340.
(9) Cummins, C. H.; Coates, R. M. J. Org. Chem. 1983, 48, 2070.
(10) Vosburg, D. A.; Weiler, S.; Sorensen, E. Chirality 2003, 15, 156.
(11) (a) Reis, L. V.; Lobo, A. M.; Prabhakar, S. Tetrahedron Lett. 1994,
35, 5977. (b) Reis, L. V.; Lobo, A. M.; Prabhakar, S.; Duarte, M. P. Eur.
J. Org. Chem. 2003, 1, 190.
5730
Org. Lett., Vol. 7, No. 25, 2005

Table 1. Scope of Transformation
a DMSO, rt, 4-24 h, 1 equiv of 10. b DMSO, 50 °C, 24 h, 1 equiv of 10. c DMSO, 50 °C, 48 h, 1.5 equiv of 10. d DMSO, 50 °C, 48 h, 2 equiv of 10.
it was indeed possible to carry out the proposed rearrange-
ment on ketone substrates, we went on to explore the scope
of this novel transformation.
Although the reaction was effective when water was used
as the solvent, consistently higher yields and cleaner
transformations were observed using dimethyl sulfoxide
which we adopted in our standard protocol.14 The results
obtained are outlined in Table 1. The reaction was effective
for the functionalization of five- (73%, entry 1), six- (80%)
and seven-membered rings (69%, entry 3). It was also
possible to functionalize acyclic systems, although the
reaction was sluggish at room temperature with this class of
ketone. Convenient rates were achieved by warming the
reaction mixture to 50 °C. For example, pentan-3-one (entry
4) and heptan-4-one (entry 5) gave R-benzoylated products
in 74% and 90% isolated yields, respectively. Aldehydes
were also efficient substrates for rearrangement into both
secondary (entry 6) and tertiary (entry 7) centers, which
suggested that this reaction should be effective for a wide
variety of carbonyl-containing compounds.
We next went on to examine the functional group tolerance
of the transformation. The reaction was tolerant of ethers,
tetrahydropyran-4-one giving the expected product in 79%
yield (entry 8) as well as hydrolytically sensitive function-
alities including cyclic acetals (70%, entry 10) and esters
(75%, entry 13). The nonoxidizing nature of the reagent
(14) The reaction is effective in both polar and nonpolar solvents with
the R-functionalised product being isolated as the major product in each
case, however, reactions are cleaner and faster in DMSO. Representative
yields for the reaction of cyclohexanone with 10 at room temperature for
24 h: CHCl3 (76%), THF (80%), THF/H2O (9/1) (62%), DMSO (80%).
1H NMR spectra of crude reaction mixtures in these solvents are contained
in the Supporting Information.
Org. Lett., Vol. 7, No. 25, 2005
5731

means that sulfides can also be used effectively within this
transformation (75%, entry 9). Amides (entry 11) and
sulfonamides (entry 12) also remain unaffected under the
reaction conditions. Interestingly, the reaction tended to give
the thermodynamically more stable product, for example,
treatment of 4-tertbutyl cyclohexanone with 1 equiv of 10
gave the cis-substituted product in 76% isolated yield (entry
15), with no indication of the trans-diastereoisomer detected
Table 2. Reaction of Nonsymmetrical Substrates
1
in the H NMR of the crude reaction mixture. Use of the
less sterically encumbered 4-methyl cyclohexanone, however,
led to a 1:1 mixture of diastereoisomers being observed for
the product (entry 14).
The reaction was also effective in the presence of a variety
of aromatic systems. Although these reactions were slow
under our standard reaction conditions for acyclic ketones,
addition of 1.5 equiv of the reagent 10 led to good yields
with propiophenone (69%, entry 16), electron-rich aromatics
(92%, entry 17), and electron-deficient aromatics (82%, entry
18). Of particular note is the fact that this transformation is
also tolerant of the presence of a free hydroxyl group with
4-hydroxypropiophenone giving the expected product in 85%
isolated yield (entry 19), greatly adding to the potential of
this intriguing transformation.
Having shown that the procedure was effective for a
variety of carbonyl compounds and established the range of
the reaction profile, we then went on to investigate if the
rearrangement was also tolerant of alternative acyl substit-
uents (Scheme 4).
a DMSO, 50 °C, 24 h, 1 equiv of 10.
complete regiospecificity was observed for the secondary
center, highlighting the utility of this transformation. With
the aliphatic substrates 4-methylpentan-2-one (entry 1) and
5-hexen-2-one (entry 2) the products were isolated in 73%
and 81% yield, respectively. This specificity was also the
case for the aromatic substrates (entry 3 83% and entry 4
83%). A limitation to the procedure was that we were unable
to bring about reaction at primary centers; for example, both
acetone and acetophenone gave no indication of the desired
R-functionalized product after prolonged reaction times (50
°C, up to 72 h). We are unable to explain this lack of
reactivity at present, but such regiospecificity may be
exploited to great effect with nonsymmetrical substrates.
In summary, we have described the synthesis of a new
family of reagents for the R-functionalization of aldehyde
and ketone substrates. The reagents are simple to prepare,
with intermediates being purified by distillation and the final
compound crystallizing directly from the reaction mixture.
The reactions are operationally simple and can be conducted
at either room temperature or warming to 50 °C in the
presence of both moisture and air without the need for any
specialized reaction techniques and equipment or purification
of solvents. Particularly useful is the fact that the reaction is
tolerant of a wide variety of functional groups and that the
reaction does not work for primary centers, providing a
regiospecific method for the functionalization of nonsym-
metrical substrates. We are currently investigating the
development of a catalytic asymmetric variant of this
procedure and will report our findings shortly.
Scheme 4
The reactivity profile of the alternative reagents 9, 11, and
12 turned out to be similar to the standard benzoyl reagent
10, with the compounds working effectively with both cyclic
and acyclic carbonyl compounds (Scheme 4). These results
suggest that the reaction is not only effective for the reaction
of a broad spectrum of carbonyl compounds, but is also
capable of delivering the acyl group of choice.
Finally, we examined the reaction of a series of nonsym-
metrical substrates with the reagent 10 (Table 2). In each
case, when distinguishing primary from secondary centers,
Acknowledgment. We thank the EPSRC for a research
fellowship (N.C.O.T.), GlaxoSmithKline and the Leverhulme
Trust (F/00 407/X) for financial support, and the Mass
Spectrometry Service, Swansea, for high-resolution spectra.
Supporting Information Available: Analytical data and
experimental details for preparation of the reagents 9-12
and R-functionalized products. This material is available free
of charge via the Internet at http://pubs.acs.org.
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Org. Lett., Vol. 7, No. 25, 2005