Palladium-catalyzed [1,3]-O-to-C rearrangement of pyrans toward functionalized cyclohexanones

Article abstract of DOI:10.1021/ol102213s

Functionalized cyclohexanones are prepared from cyclic enol ethers via a Pd-catalyzed [1,3]-O-to-C rearrangement reaction. α-Arylketones are generated with excellent diastereocontrol when basic phosphine ligands are used. In contrast, a Lewis acid is requ

Full text of DOI:10.1021/ol102213s

ORGANIC
LETTERS
2010
Vol. 12, No. 21
4832-4835
Palladium-Catalyzed [1,3]-O-to-C
Rearrangement of Pyrans toward
Functionalized Cyclohexanones
Julien C. R. Brioche,† Thomas A. Barker,† David J. Whatrup,‡ Michael D. Barker,§
and Joseph P. A. Harrity*,§
Department of Chemistry, UniVersity of Sheffield, Brook Hill, Sheffield, S3 7HF,
United Kingdom, GlaxoSmithKline, Tonbridge, Kent, TN11 9AN, United Kingdom, and
GlaxoSmithKline Research and DeVelopment, Gunnels Wood Road, SteVenage,
Hertfordshire, SG1 2NY, United Kingdom
j.harrity@sheffield.ac.uk
Received August 25, 2010
ABSTRACT
Functionalized cyclohexanones are prepared from cyclic enol ethers via a Pd-catalyzed [1,3]-O-to-C rearrangement reaction. r-Arylketones are
generated with excellent diastereocontrol when basic phosphine ligands are used. In contrast, a Lewis acid is required to promote the
rearrangement of the alkyl-substituted enol ether systems.
[1,3]-Oxygen-to-carbon rearrangement processes represent
a potentially powerful strategy for synthesis, and have been
widely employed since the pioneering studies of Ferrier.1
The significant majority of these approaches have involved
the use of acetal functionality as a prelude to an oxocarbe-
nium ion intermediate. Accordingly, O-based heterocycles
are commonly generated by this technique. In an effort to
uncover alternative carbocation stabilizing motifs that pro-
mote O-to-C rearrangements, we have been exploring the
potential of transition metal complexes and have demon-
strated that the hexacarbonyldicobalt alkyne cluster can
perform effectively in this manner, allowing access to a broad
range of functionalized carbocycles.2-4 A significant draw-
back to this methodology, however, is the requirement of
stochiometric Lewis acid and cobalt carbonyl complex.
Therefore, we have turned our attention to exploring the
potential of an analogous but catalytic [1,3]-O-to-C rear-
(2) (a) Carbery, D. R.; Miller, N. D.; Harrity, J. P. A. Chem. Commun.
2002, 1546. (b) Carbery, D. R.; Reignier, S.; Myatt, J. W.; Miller, N. D.;
Harrity, J. P. A. Angew. Chem., Int. Ed. 2002, 41, 2584. (c) Carbery, D. R.;
Reignier, S.; Miller, N. D.; Adams, H.; Harrity, J. P. A. J. Org. Chem.
2003, 68, 4392. (d) Meek, S. J.; Pradaux, F.; Demont, E. H.; Harrity, J. P. A.
Org. Lett. 2006, 8, 5597. (e) Meek, S. J.; Pradaux, F.; Demont, E. H.;
Harrity, J. P. A. J. Org. Chem. 2007, 72, 3467. (f) Meek, S. J.; Demont,
E. H.; Harrity, J. P. A. Tetrahedron Lett. 2007, 48, 4165
(3) For an elegant application of this chemistry in the synthesis of
hydrolytically stable glycoside mimics see: Deleuze, A.; Menozzi, C.;
.
† University of Sheffield.
Sollogoub, M.; Sinay¨, P. Angew. Chem., Int. Ed. 2004, 43, 6680.
‡ GlaxoSmithKline, Tonbridge.
(4) For examples of thermal rearrangements via non-stabilized enolates
see: (a) Letsinger, R. L.; Lansbury, P. T. J. Am. Chem. Soc. 1959, 81, 935.
(b) Morrow, G. W.; Wang, S.; Swenton, J. S. Tetrahedron Lett. 1988, 29,
3441. (c) Swenton, J. S.; Bradin, D.; Gates, B. D. J. Org. Chem. 1991, 56,
§ GlaxoSmithKline, Stevenage.
(1) (a) Ferrier, R. J. J. Chem. Soc., Perkin Trans. 1 1979, 1455. (b) For
an overview of [1,3]-O-to-C rearrangement reactions see: Meek, S. J.;
Harrity, J. P. A. Tetrahedron 2007, 63, 3081.
6156
.
10.1021/ol102213s  2010 American Chemical Society
Published on Web 10/01/2010

rangement to access cyclic ketones, and report our initial
observations herein.
Trost has shown that Pd-enolates do not isomerize on the
time scale of allylic alkylation.9 Moreover, we opted to
prepare E- and Z-allyl ethers to establish whether these
stereoisomers would converge to a single E-olefin substituted
cyclohexanone via rapid syn-:anti-isomerization of the Pd-π-
allyl complex.10
The required phosphonium salts were prepared by using
a protocol originally developed by Ley, and by analogy to
the method reported in our Co-mediated rearrangement study
(Scheme 1).2,11 Specifically, addition of a vinyl aluminum
Surprisingly little precedent for such a catalytic transfor-
mation can be found in the literature. Nonetheless, Trost and
Tsuji independently demonstrated that furan-based enol
ethers can be transformed to cyclopentanones in good yield,
in the presence of a low-valent palladium source.5 This
concept was later used by Langer in an intramolecular variant
in order to access bicyclo[3.2.1]octan-8-ones.6 Notably, all
of these examples exploited the intermediacy of a stabilized
enolate by appending electron-withdrawing substituents on
the enol ether moiety.
We wanted to investigate the rearrangement of nonstabi-
lized pyran enol ethers such as 2 (RE/Z ) aryl, alkyl) into
2,3-substituted cyclohexanones 3 using substoichiometric
quantities of a transition metal catalyst (Figure 1). A key
Scheme 1. Synthesis of Enol Ether Precursors
species generated from DibalH and terminal alkyne12 allowed
us to access E-pyranyl ether substrates. Alternatively, alkyl-
ation with preformed alkynylaluminum species, followed by
hydrogenation provided Z-pyranyl ether substrates. Finally,
a terminal alkene substrate was prepared in three steps
following a literature procedure.13 The Wittig salts 7-9 could
be prepared on multigram scale and in high yield by
treatment of the respective pyranyl ethers with triph-
enylphosphonium tetrafluoroborate.
Figure 1. Pd-catalyzed O-to-C rearrangement.
step in this process is the intramolecular Pd-catalyzed allylic
alkylation (AA) of a ketone enolate, which is generated in
situ. The regio- and diastereoselective Pd-catalyzed AA of
ketone enolates remains a challenging transformation, and
is often restricted to stabilized ketone enolates or substrates
bearing a single point of enolization.7 An alternative approach
employs functional groups that act as a masked enolate.8 In
our approach, we wished to exploit a cyclic enol ether as a
masked ketone enolate that would be generated after Pd-
promoted ionization of an allyl ether. As highlighted in
Figure 1, one would expect the stereochemistry of the enol
ether alkene moieties to play a role in determining the
diastereoselectivity of cyclohexanone product formation, as
The subsequent Wittig reaction was next investigated by
using a range of aromatic and aliphatic aldehydes (Table 1).
Table 1. Scope of the Wittig Reaction
(5) (a) Trost, B. M.; Runge, T. A.; Jungheim, L. N. J. Am. Chem. Soc.
1980, 102, 2840. (b) Trost, B. M.; Runge, T. A. J. Am. Chem. Soc. 1981,
103, 2485. (c) Trost, B. M.; Runge, T. A. J. Am. Chem. Soc. 1981, 103,
7550. (d) Trost, B. M.; Runge, T. A. J. Am. Chem. Soc. 1981, 103, 7559.
(e) Tsuji, J.; Kobayashi, Y.; Kataoka, H.; Takahashi, T. Tetrahedron Lett.
1980, 21, 1475.
(6) (a) Langer, P.; Holtz, E. Angew. Chem., Int. Ed. 2000, 39, 3086. (b)
Langer, P.; Holtz, E.; Saleh, N. N. R. Chem.sEur. J. 2002, 8, 917.
(7) (a) Trost, B. M.; Schroeder, G. M. J. Am. Chem. Soc. 1999, 121,
6759. (b) Braun, M.; Laicher, F.; Meier, T. Angew. Chem., Int. Ed. 2000,
39, 3494. (c) Trost, B. M.; Schroeder, G. M.; Kristensen, J. Angew. Chem.,
Int. Ed. 2002, 41, 3492. (d) Zheng, W.-H.; Zheng, B.-H.; Zhang, Y.; Hou,
X.-L. J. Am. Chem. Soc. 2007, 129, 7718. (e) Braun, M.; Meier, T.; Laicher,
F.; Meletis, P.; Fidan, M. AdV. Synth. Catal. 2008, 350, 303.
(8) (a) Behenna, D. C.; Stoltz, B. J. Am. Chem. Soc. 2004, 126, 15044.
(b) Burger, E. C.; Tunge, J. A. Org. Lett. 2004, 6, 4113. (c) Trost, B. M.;
Xu, J. J. Am. Chem. Soc. 2005, 127, 17180. (d) Burns, A. C.; Forsyth, C.
Org. Lett. 2008, 10, 97. (e) Petrova, K. V.; Mohr, J. T.; Stoltz, B. M. Org.
Lett. 2009, 11, 293.
a Yield of isolated product. b Refers to enol ether stereochemistry.
Org. Lett., Vol. 12, No. 21, 2010
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Table 2. Optimization of the Rearrangement with Aryl Enol Ether Substrates
entry
catalyst (mol %)
Pd(PPh3)4 (15)
Pd(PPh3)4 (15)
Pd(PPh3)4 (15)
additive (mol %)
conditions
yielda (trans:cis)b
1
2
3
4c
5
6
7
toluene, 55 °C, 20 h
toluene, 110 °C, 20 h
toluene, 55 °C, 5 h
toluene, 55 °C, 20 h
MeCN, 55 °C, 20 h
MeCN, 55 °C, 20 h
MeCN, 55 °C, 20 h
0% (-)
Zn(OTf)2 (50)
Et2AlCl (50)
Et2AlCl (100)
Et2AlCl (50)
27% (>95:5)
40% (>95:5)
0% (-)
Pd(PPh3)4 (10)
Pd(PPh3)4 (10)
Pd(OAc)2 (10) PBun3 (60)
60% (4:1)
55% (70%)d (2:1)
82% (>95:5)
a Yield of isolated product. b Refers to stereochemistry of the cyclohexanone 2,3-substituents. c Compound 19 isolated in 47% yield. d Reaction performed
over 48 h.
In all cases, the pyran enol ethers were obtained in moderate
to good yield with generally high E:Z ratios.
as an efficient ligand system, providing trans-cyclohexanone
18 in high yield with good diastereocontrol.
The optimized conditions were applied to freshly prepared
aryl enol ether substrates (Table 3). Electron-rich (entry 1)
With the required pyran-based enol ethers in hand, we
turned our attention to the rearrangement transformation; our
results are outlined in Table 2. We first tried Pd(PPh3)4, which
has been reported by Trost to catalyze similar transforma-
tions,5 but only trace amounts (<5%) of 18 were observed
(entry 1). We next decided to employ Lewis acids in an
attempt to promote the ionization step. A preliminary
screening study highlighted Zn(OTf)2 and Et2AlCl as po-
tentially useful promoters, providing 18 in 27% and 40%
yields, respectively (entries 2 and 3). At this stage, we
decided to confirm that the Lewis acid did not itself mediate
the O-to-C rearrangement in a similar manner to that reported
by Rovis;14 only Claisen product 19 was isolated in this case
in 47% yield (entry 4). We envisaged that the ionization step
could be further facilitated by the use of a polar solvent.
Indeed, when the reaction was carried out in MeCN we were
delighted to isolate 18 in improved yield (entry 5). This
observation was surprising given that the Lewis basic solvent
would be expected to attenuate the effects of the Lewis acid.
Accordingly, we conducted the rearrangement in the absence
of Lewis acid and were pleased to find that cyclohexanone
18 was isolated in good yield as a 1:2 cis:trans mixture,
within the same reaction time (entry 6). Finally, we explored
Table 3. Pd-Catalyzed O-to-C Rearrangement of Aryl Enol
Ethers
a Yield of isolated product. b Refers to stereochemistry of the cyclo-
c
hexanone 2,3-substituents. 100% PBun employed in this case.
3
the use of more electron-rich phosphines and identified PBun
3
and electron-deficient (entry 2) aryl enol ethers were found
to rearrange into their corresponding cyclohexanones in
moderate to good yield with excellent trans-diastereoselec-
tivity. The chemistry could also be extended to provide R-3-
pyridyl-substituted cyclohexanones (entry 3). As we ex-
pected, pyran enol ether 14 and 15 gave the corresponding
cyclohexanones having E-stereochemistry at the alkene
moiety in good yield and excellent trans-diastereoselectivity
(entries 4 and 5). Finally, terminal alkene-substituted enol
ether 16 was also found to rearrange to trans-cyclohexanone
24 selectively and in very good yield (entry 6).
(9) Trost, B. M.; Xu, J.; Schmidt, T. J. Am. Chem. Soc. 2009, 131,
18343.
(10) (a) Ogasawara, M.; Takizawa, K.-I.; Hayashi, T. Organometallics
2002, 21, 4853. (b) Solin, N.; Szabo`, K. J. Organometallics 2001, 20, 5464,
and references cited therein.
(11) (a) Ley, S. V.; Lygo, B.; Organ, H. M.; Wonnacott, A. Tetrahedron
1985, 41, 3825. (b) Ley, S. V.; Brown, D. S. Tetrahedron Lett. 1988, 29,
4869. (c) Brown, D. S.; Bruno, M.; Davenport, R. J.; Ley, S. V. Tetrahedron
1989, 45, 4293. (d) Ley, S. V.; Humphries, A. C.; Eick, H.; Downham, R.;
Ross, A. R.; Boyce, R. J.; Pavey, J. B. J.; Pietruszka, J. J. Chem. Soc.,
Perkin Trans. 1 1998, 3907.
(12) Elzner, S.; Maas, S.; Engel, S.; Kunz, H. Synthesis 2004, 2153.
and references cited therein.
(13) Sasmal, K. P.; Maier, M. E. Org. Lett. 2002, 4, 1271.
(14) (a) Nasveschuk, C. G.; Rovis, T. Angew. Chem., Int. Ed. 2005, 44,
3264. (b) Nasveschuk, C. G.; Rovis, T. Org. Lett. 2005, 7, 2173.
Surprisingly, attempts to perform the [1,3]-rearrangement
of alkyl-substituted enol ether 17 failed to furnish any of
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Org. Lett., Vol. 12, No. 21, 2010

the desired cyclohexanone product 25, but gave complex
mixtures that appeared to consist of acyclic polyolefinic
material (Scheme 2). The formation of such material could
outcome of the [1,3] rearrangement reactions of aryl-
substituted enol ethers 10-16 and substrate 25 is also
noteworthy. Indeed, we had anticipated from our reaction
design in Figure 1 that enol ether stereochemistry would be
transmitted through to the cyclohexanone product whereby
the E-enol ethers would provide cis-2,3-disubstituted-cyclo-
hexanones, rather than the trans products obtained. While
we are not at present able to provide a detailed stereochem-
ical rationale for these reactions, it appears that product
epimerization is at least partially responsible for the diaste-
reocontrol observed in the reactions highlighted in Table 3.18
In summary, we have developed a Pd-catalyzed O-to-C
rearrangement to access cyclohexanones from pyran enol
ethers under mild conditions. The transformation was found
to proceed in the presence of electron-rich phosphine ligands.
The rearrangement of aromatic pyran enol ethers with
Pd(OAc)2/PBun3 as catalyst in MeCN seems to be a general
method and usually gives the cyclohexanone products in high
yield with excellent levels of trans-selectivity. Alternative
ligand systems are necessary when employing aliphatic enol
ether substrates, and studies are underway to improve the
diastereoselectivity of these particular processes.
Scheme 2.
Rearrangement of Aliphatic Enol Ethersa
a DavePhos ) 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphe-
nyl.
be explained by the higher basicity of the in situ generated
enolate (pKa ≈ 25),15 which could enhance an elimination
of the Pd-π-allyl complex intermediate.16 We therefore
performed a further optimization study for these substrates
and found that the combination of arylphosphine ligands and
Lewis acid promoter allowed the cyclohexanone to be
isolated in high yield, albeit with disappointing levels of
diastereocontrol.17 The requirement of a Lewis acid in this
case is intriguing and it may be that this serves to both
activate the pyran ring as well as decrease the basicity of
the in situ generated enolate. The difference in stereochemical
Acknowledgment. The authors are grateful to the EPSRC,
GlaxoSmithKline, and the University of Sheffield for finan-
cial support and Johnson-Matthey for the loan of palladium
salts.
Supporting Information Available: Full experimental
details for the syntheses reported. This material is available
free of charge via the Internet at http://pubs.acs.org.
(15) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456.
(16) For studies on the mechanism of elimination reactions of Pd π-allyl
complexes towards 1,3-dienes see: Takacs, J. M.; Lawson, E. C.; Clement,
F. J. Am. Chem. Soc. 1997, 119, 5956.
OL102213S
(17) The diastereomers of 25 could not be separated thereby preventing
a clear assignment of the identity of the major stereoisomer in this
mixture.
(18) Subjection of a 1.2:1 diastereomeric mixture of trans- and cis-18
to the rearrangement conditions (10% Pd(OAc)2, 60% PBun , MeCN, 55
3
°C, 18 h) resulted in epimerization to a 5:1 mixture of trans:cis 18.
Org. Lett., Vol. 12, No. 21, 2010
4835