Oxidative Carbon - Carbon Bond Formation via Allyldimethylsilyl Enol Ethers

Article abstract of DOI:10.1021/ol902400q

"Chemical Equation Presented" A method for the oxidative alkylation of ketones through intramolecular allyl-group transfer within preformed allyldimethylsilyl enol ethers is reported. A number of examples are detailed, including a study into the effects o

Full text of DOI:10.1021/ol902400q

ORGANIC
LETTERS
2009
Vol. 11, No. 23
5550-5553
Oxidative Carbon-Carbon Bond
Formation via Allyldimethylsilyl Enol
Ethers
Leah C. Konkol, Brian T. Jones, and Regan J. Thomson*
Department of Chemistry, Northwestern UniVersity, 2145 Sheridan Road,
EVanston, Illinois 60208
r-thomson@northwestern.edu
Received October 18, 2009
ABSTRACT
A method for the oxidative alkylation of ketones through intramolecular allyl-group transfer within preformed allyldimethylsilyl enol ethers is
reported. A number of examples are detailed, including a study into the effects of resident sterocenters within cyclic enol ethers.
Ceric ammonium nitrate (CAN) is a powerful single electron
oxidant that has significant demonstrated utility in promoting
a wide range of useful synthetic transformations.1 Our interest
in CAN as a reagent stemmed from an initial desire to
elaborate the synthetic potential of silyl bis-enol ethers, an
area we have been actively developing.2 While the 1,4-
diketone adducts derived from silyl bis-enol ether oxidation
are of significant value for synthesis, we wished to extend
this general reactivity to other species and herein report the
development of an intramolecular oxidative allylation from
allylsilyl enol ethers.
allyltrimethylsilane in the presence of CAN.5,6 The scope
of these transformations is limited to enolizable 1,3-dicar-
bonyls since the first step of the reaction pathway is most
likely oxidation of the enol tautomer to an intermediate
radical cation. We speculated that exposure of an allyldim-
ethylsilyl enol ether (i.e., 1) to CAN might induce intramo-
lecular bond formation via radical-cation 2, which would
collapse to produce cyclic intermediate 3 (Figure 1). Si-C
and Si-O bond cleavage, along with a second single electron
oxidation would then produce the desired adduct 4.7 Related
examples of intermolecular allylation of ꢀ-carbonyl imines,8
and one example of a vinylogous amide9 have been reported.
Moeller and co-workers have shown that intramolecular
We were drawn to the work published by the groups of
Hwu3 and Flowers,4 who have each shown that 1,3-
dicarbonyl species undergo effective oxidative allylation with
(5) Phenols have been shown to undergo a related oxidative allylation,
see: Sabot, C.; Commare, B.; Duceppe, M.-A.; Nahi, S.; Gue´rard, K. C.;
(1) For a comprehensive recent review, see: Nair, V.; Deepthi, A. Chem.
ReV. 2007, 107, 1862–1891.
Canesi, S. Synlett 2008, 2008, 3226–3230.
(6) Hirao and coworkers have reported that oxidative allylation of 1,3-
dicarbonyl compounds with allylsilanes can be achieved using VO(OEt)Cl2
as the oxidant, see: Hirao, T.; Sakaguchi, M.; Ishikawa, T.; Ikeda, I. Synth.
(2) (a) Clift, M. D.; Taylor, C. N.; Thomson, R. J. Org. Lett. 2007, 9,
4667–4669. (b) Avetta, C. T.; Konkol, L. C.; Taylor, C. N.; Dugan, K. C.;
Stern, C. L.; Thomson, R. J. Org. Lett. 2008, 10, 5621–5624. (c) Clift,
M. D.; Thomson, R. J. J. Am. Chem. Soc. 2009, 131, 14579–14583. See,
also: (d) Schmittel, M.; Burghart, A.; Malisch, W.; Reising, J.; Sollner, R.
J. Org. Chem. 1998, 63, 396–400. (e) Schmittel, M.; Haeuseler, A. J.
Organomet. Chem. 2002, 661, 169–179.
Commun. 1995, 25, 2579–2585
.
(7) The exact timing of the process from intermediate 3 onwards is
unclear. It seems likely that cleavage of the Si-C bond preceeds the second
oxidation and Si-O bond cleavage. X in Figure 1 is most likely nitrate,
although it is known that cleavage of Si-C bonds in radical cations is
accelerated by nucleophilic solvents such as acetonitrile, see: Dinnocenzo,
J. P.; Farid, S.; Goodman, J. L.; Gould, I. R.; Mattes, S. L.; Todd, W. P.
J. Am. Chem. Soc. 2002, 111, 8973–8975.
(3) Hwu, J. R.; Chen, C. N.; Shiao, S.-S. J. Org. Chem. 2002, 60, 856–
862.
(4) (a) Zhang, Y.; Raines, A. J.; Flowers, R. A. Org. Lett. 2003, 5, 2363–
2365. (b) Devery, J. J., III; Mohanta, P. K.; Casey, B. M.; Flowers, R. A.,
II Synlett 2009, 2009, 1490–1494.
(8) Zhang, Y.; Raines, A. J.; Flowers, R. A., II J. Org. Chem. 2004, 69,
6267–6272.
10.1021/ol902400q CCC: $xxxx
Published on Web 11/04/2009
 2009 American Chemical Society

allylation of enol ethers with allylsilanes is possible when
the silane is part of the ketone (i.e., linked through the carbon
backbone rather than the enol oxygen such as in our
system).10 MacMillan and co-workers have elegantly dem-
onstrated the power of their SOMO activation strategy by
developing an enantioselective allylation of aldehydes using
organocatalysis.11 Against this background, the method for
intramolecular allylation of unactivated ketones (i.e., not 1,3
dicarbonyls) that we report herein expands the scope of
compounds that may be accessed through oxidative coupling.
NaHCO3 at -30 °C provided only 39% yield of 6b (Table
1, entry 5), but when conducted at -40 °C gave an enhanced
52% yield (Table 1, entry 6). Unlike for the simple allyl
system (i.e., 5a), replacing NaHCO3 with 2,6-di-t-butylpy-
ridine led to a further improvement in yield to 83% (Table
1, entry 7). Under these conditions the benzyloxy substituted
silyl ether 5c (R ) CH2OBn)9 gave 62% yield of the desired
allylated ketone 6c (R ) CH2OBn), indicating that func-
tionalized allyl fragments may be employed with this
chemistry.
Table 1. Initial Development of the Oxidative Allylationa
Figure 1. Proposed intramolecular oxidative allylation.
entry
R
base
temp (°C) yield (%)b
We began our study by preparing the allyldimethylsilyl
ether derived from tetralone (i.e., 5a, R ) H), since such
ketones had proved exceptional in our prior work on silyl
bis-enol ether oxidative coupling. Preparation of the substrate
was trivial and involved the addition of commercially
available chloro allyldimethylsilane to the lithium enolate
of tetralone.12 Exposure of 5a (R ) H) to the standard set
of conditions known to promote oxidative coupling of enol
silanes led to formation of the desired material in 51% yield
(Table 1, entry 1). Conducting the reaction at a lower
temperature (-30 °C) increased the yield to 57% (Table 1,
entry 2), while use of 2,6-di-t-butylpyridine (DTBP) afforded
a 46% yield of 6a (R ) H). The addition of a base is required
in these reactions to minimize decomposition of the acid-
sensitive enol ether; exposure of 5a (R ) H) to CAN in the
absence of a base gave exclusively tetralone (Table 1, entry
4). We investigated the use of other oxidants known to
promote enol silane coupling, such as Ag2O and Cu(OTf)2/
Cu2O, but these provided none of the desired product. At
this juncture, we prepared the allyldimethylsilyl enol ethers
of several other ketones, but were disappointed to obtain
generally low yields. We speculated that the general lack of
scope might be due to the poor nucleophilicity of the allyl
group. If intramolecular C-C bond formation from the initial
radical-cation (akin to 2 f 3 in Figure 1) is slow, then
unproductive Si-O bond cleavage may compete and lead
to diminished yields. Allylsilanes possessing electron-releas-
ing substituents at C2 are known to be more nucleophilic
than unsubstituted systems,13 so we investigated the meth-
allylsilyl enol ether 5b (R ) Me).11 Exposure of 5b to CAN/
1
2
3
4
5
6
7
8
H (5a)
H (5a)
H (5a)
H (5a)
Me (5b)
Me (5b)
Me (5b)
NaHCO3
NaHCO3
2,6-di-t-BuPy
none
NaHCO3
NaHCO3
2,6-di-t-BuPy
0
-30
-30
-30
-30
-40
-40
-40
51
57
46
0
47
52
83
62
CH2OBn (5c) 2,6-di-t-BuPy
a 5 (1.0 mmol), 0.1 M MeCN. b Isolated yield after chromatography.
Given the limited results obtained with the simple al-
lyldimethylsilyl enol ether when we attempted to use ketones
other than tetralone, we wished to conduct an analysis of
ketone scope for the 2-substituted allylsilanes (Table 2,
prepared in 59-99% yield from the corresponding ketones,
see Supporting Information). In general, the 2-substituted
allylsilanes gave good yields of the allylated material on
exposure to CAN/DTBP (Table 2, entries 1 and 2). When
2-methyltetralone was used as the ketone substrate, the
oxidative allylation procedure led to smooth generation of a
quaternary stereocenter in good yield (Table 2, entry 3).
Acyclic R-aryl substituted ketones also proved to be suitable
substrates for the reaction. For example, the allylsilanes (R
) Me or CH2OBn) derived from propiophenone, gave 81%
and 59% yields of the respective allylated adduct (Table 2,
entry 4). The 2-acetylfuran derived system also performed
well in the reaction (Table 2, entry 5).
Surprisingly, the oxidative allylation of carvone afforded
low levels of diastereoselectivity, which stood in contrast to
what we have observed in our ketone-ketone cross-
coupling.2b The locked bicyclic enol silane derived from
trans-decalone, however, produced a 3:1 mixture favoring
of the axial product 8j (43% isolated yield of single
(9) Chandra, A.; Pigza, J. A.; Han, J.-S.; Mutnick, D.; Johnston, J. N.
J. Am. Chem. Soc. 2009, 131, 3470–3471. Narasaka and coworkers reported
two examples of an alkene adding to a vinylogous amide under the action
of CAN, see: Narasaka, K.; Okauchi, T.; Tanaka, K.; Murakami, M. Chem.
Lett. 1992, 2099–2102.
(10) Hudson, C. M.; Marzabadi, M. R.; Moeller, K. D.; New, D. G.
J. Am. Chem. Soc. 1991, 113, 7372–7385.
(13) For a systematic analysis and discussion of such relative nucleo-
philicities, see: Mayr, H.; Bug, T.; Gotta, M. F.; Hering, N.; Irrgang, B.;
Janker, B.; Kempf, B.; Loos, R.; Ofial, A. R.; Remennikov, G.; Schimmel,
H. J. Am. Chem. Soc. 2001, 123, 9500–9512.
(11) Beeson, T. D.; Mastracchio, A.; Hong, J. B.; Ashton, K.; MacMillan,
D. W. C. Science 2007, 316, 582–585.
(12) See Supporting Information for full experimental details.
Org. Lett., Vol. 11, No. 23, 2009
5551

cally favored 1,3-syn isomer. Independent synthesis of the
1,3-anti isomer,15 and its subsequent exposure to the reaction
conditions confirmed that significant isomerization was
occurring (9:1 anti:syn f 1:5 anti:syn after 24 h at -25 °C).
In light of this result, we assessed the diastereoselectivity as
a function of reaction time (Figure 3). Typical reaction times
for the oxidative allylation of 7l were about 24 h and afforded
a 5:1 ratio of syn to anti isomers. Quenching the reaction
after just 3 h, however, revealed a modest preference for
the anti diastereomer indicating that kinetic axial alkylation
was occurring to a significant extent, but the extended
reaction times required for all the starting material to be
consumed allowed for significant product isomerization. In
light of these details, the poor diastereoselectivity of the
carvone-derived allyl silanes (7c and 7d) may be attributed
to an internal competition between axial addition leading to
the syn isomer and allylation anti to the isopropenyl
substituent. In this instance there appears to be no bias for
one stereochemical course over the other.16
Table 2. Ketone Scope of the Oxidative Allylationa
Figure 3. Product stereochemistry with respect to reaction time.
The diminished yields for saturated systems (i.e., entries
6 and 8, Table 2) relative to aryl and unsaturated derive
systems, is most likely a consequence of slower oxidation
of the less electron-rich nonconjugated π-system and sub-
sequent generation of a less stable initially formed radical-
cation intermediate. We probed this issue by conducting an
experiment where an equimolar ratio of 7k and 7l were
exposed to only enough CAN to oxidize one substrate
completely. Our hypothesis regarding the different reactivity
proved correct: only the unsaturated derivative 7k underwent
oxidative allylation to form 8k, and the corresponding adduct
of the saturated derivative 7l was not observed (eq 1, Figure
4).
Crossover experiments were conducted to determine
whether the reaction was proceeding solely through intramo-
lecular delivery of the allyl fragment (Figure 4). Accordingly,
a 1:1 mixture of the allylsilanes 5a and 7a, each of which
performed well on their own, was exposed to the oxidation
conditions and the product mixture analyzed (eq 2, Figure
4). Only the products of intramolecular delivery were
a Standard conditions for oxidative allylation: 7, CAN (2.0 equiv), 2,6-
di-t-BuPy (4.0 equiv), 0.1 M MeCN, -25 °C, 0.5-24 h. b Isolated yield
b
after chromatography. Determined by H NMR spectroscopy. d Isolated
1
yield of single isomer.
diastereomer, Table 2, entry 6). We also wished to determine
the effect a more remote stereocenter at C4 would have on
the facial selectivity. To probe this issue, the enol allylsilanes
of 4-t-Bu-cyclohexenone and of 4-t-Bu-cyclohexanone were
prepared and exposed to conditions for effecting oxidative
bond formation. Allylation of the cyclohexenone derivative
proceeded in 76% yield as a 20:1 mixture of diastereomers,
favoring the 1,3-anti isomer 8k (Table 2, entry 6). The
corresponding saturated derivative gave a slightly diminished
yield (52%), but favored the syn isomer 8l (5:1 syn to anti).
At first glance the preferential formation of the 1,3-syn
isomer 8l from t-Bu-cyclohexanone derivative 7l (Table 2,
entry 7) was surprising, given the results for 7k (Table 2,
entry 6) and the well documented preference for axial
alkylation in similar systems.14 We suspected that under the
mildly basic reaction conditions, the less stable 1,3-anti
isomer would undergo epimerization to the thermodynami-
(14) (a) Corey, E. J.; Sneen, R. A. J. Am. Chem. Soc. 1956, 78, 6269–
6278. (b) Velluz, L.; Valls, J.; Nomine´, G. Angew. Chem., Int. Ed 1965, 4,
181–200. (c) Evans, D. A. In Asymmetric Synthesis, Vol 3; Morrison, J. D.,
Ed.; Academic Press: Orlando, FL; 1984; p 2.
(15) Prepared by a modification of the procedure for axial alkylation
reported by: Lightner, D. A.; Bouman, T. D.; Vincent Crist, B.; Rodgers,
S. L.; Knobeloch, M. A.; Jones, A. M. J. Am. Chem. Soc. 1987, 109, 6248–
6259.
(16) Resubjection of the 1:1 mixture of diastereomers of 8c to the
reaction conditions led to equilibration to the favored anti isomer.
5552
Org. Lett., Vol. 11, No. 23, 2009

nucleophile. In the event, exposure of the TMS-enol ether
of 4-t-Bu-cyclohexanone (i.e., 9) to CAN/DTBP in the
presence of one equivalent of allylsilane 10 gave little of
the desired adduct 8l. By increasing the amount of allylsilane
used to ten equivalents, a chemically efficient allylation could
be achieved (57% yield), albeit as a 1.5:1 mixture of
diastereomers. The necessary use of excess silane negates
this alternative as a possible fragment coupling for advanced
precursors, and serves to highlight the utility of the intramo-
lecular allylation in the context of complex molecule
synthesis.
To summarize, we have successfully expanded the scope
of silicon-tethered oxidative carbon-carbon bond formation
to allow for allylation of ketones. The reaction was shown
to be compatible with aryl ketones, enones, and saturated
systems. This new method for allylation offers an additional
synthetic tool for chemists for cases where direct enolate
alkylation, Claisen rearrangement or palladium-catalyzed
methods are insufficient to achieve construction of the desired
molecule.
Acknowledgment. This work was supported by the
NationalInstitutesofHealth(NIH/NIGMS1R01GM085322),
Northwestern University (NU), and the NU Intergrated
Molecular Structure and Education Research Center
(DMR0114235 and CHE9871268).
Figure 4. Experiments to gain insight into the reaction process.
Supporting Information Available: Experimental pro-
cedures and spectral data. This material is available free of
charge via the Internet at http://pubs.acs.org.
observed. We also investigated whether intermolecular
oxidative allylation could be achieved when using an external
OL902400Q
Org. Lett., Vol. 11, No. 23, 2009
5553