Endo-selective pd-catalyzed silyl methyl heck reaction

Article abstract of DOI:10.1021/ja5104525

A palladium (Pd)-catalyzed endo-selective Heck reaction of iodomethylsilyl ethers of phenols and aliphatic alkenols has been developed. Mechanistic studies reveal that this silyl methyl Heck reaction operates via a hybrid Pd-radical process and that the silicon atom is crucial for the observed endo selectivity. The obtained allylic silyloxycycles were further oxidized into (Z)-alkenyldiols.

Full text of DOI:10.1021/ja5104525

Communication
pubs.acs.org/JACS
Endo-Selective Pd-Catalyzed Silyl Methyl Heck Reaction
Marvin Parasram, Viktor O. Iaroshenko, and Vladimir Gevorgyan*
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061, United States
S
* Supporting Information
radical cyclization, which is generally exo-selective.6 Conversely,
ABSTRACT: A palladium (Pd)-catalyzed endo-selective
Heck reaction of iodomethylsilyl ethers of phenols and
aliphatic alkenols has been developed. Mechanistic studies
reveal that this silyl methyl Heck reaction operates via a
hybrid Pd-radical process and that the silicon atom is
crucial for the observed endo selectivity. The obtained
allylic silyloxycycles were further oxidized into (Z)-
alkenyldiols.
in 1990, Koreeda reported that bromomethylsilyl tethered
homoallylic alcohols underwent endo radical cyclization over the
expected exo cyclization.7 Accordingly, we hypothesized that if
this unique endo-selectivity outcome would translate into a
Heck-type reaction, it would allow for a selective generation of
valuable (Z)-allylic silanes (Scheme 1, b).8
To this end, we first tested our hypothesis on a conforma-
tionally biased silyl-tethered vinylphenol 1a (Table 1). Gratify-
ingly, it was found that under the optimized conditions,9 1a
smoothly cyclized into 7-membered siloxycycle 2a in 79% yield
with delightfully high endo-selectivity (endo:exo = 33:1, Table 1,
entry 1). Next, the generality of this transformation was
examined. It was found that the regiochemical outcome was
not affected by electronic properties of substituents around the
arene ring (entries 2−8).10 Notably, this methodology enabled
the synthesis of medium size rings via 8-endo and 9-endo
cyclization generating 2i and 2j, respectively, in reasonable yields.
Moreover, this Heck reaction tolerates substitution at the
halomethyl moiety, as secondary bromomethylsilane 1k
produced aryl-substituted allylsilane 2k in good yield. However,
it was found that the regioselectivity of the cyclization is sensitive
to the substitution pattern of the pendent olefin. Hence,
cyclization of substrates possessing substituents at the α-position
produced endo products, 2l and 2m, selectively. In contrast,
substitution at the β-position of olefin reversed the regiose-
lectivity trend producing 2n and 2o, the products of the exo-trig
cyclization, exclusively (entries 14, 15).
he Mizoroki−Heck reaction is a fundamental synthetic
T
transformation that has been extensively used for synthesis
of valuable alkenes.1 Although Heck reaction of sp2 halides is well
established, the analogous reaction of sp3 halides, mainly due to a
premature β-hydride elimination problem, is much less
developed. In his seminal work, Fu solved this problem by
employing NHC ligands, which promote migratory insertion
over a competitive β-hydride elimination path (Scheme 1, a).2
Scheme 1. Intramolecular Alkyl Heck Reaction
After developing the silyl methyl Heck reaction of arene-
tethered substrates, we were eager to test this methodology on
more challenging systems such as aliphatic alkenols (Table 2).
The regiochemical outcome of their cyclization seemed more
ambiguous since (a) they are sterically unbiased and hence are
less predisposed to the endo cyclization; and (b) due to the
availability of alternative site for β-hydride elimination (vide
infra), the reaction could also lead to the formation of
homoallylic silane products. Indeed, the experiments revealed
that the Heck reaction of homoallylic alcohol 3a under the
optimized conditions resulted in formation of siloxycycle 4a with
high endo-selectivity (endo:exo = 50:1), albeit in moderate yield
(entry 1). Introduction of bulkier groups, such as nPent- (3b) and
Ph- (3c) at the α-position of the alcohol, led to an increase of
overall efficiency (entries 2, 3). Interestingly, substrates
possessing two geminal substituents at the α-position of the
tethered alcohols efficiently produced cyclic allylic silanes 4d and
4e. Remarkably, medium sized rings 4h and 4i were obtained via
8-endo-trig and 9-endo-trig cyclization in 85% and 44% yield,
Moreover, Alexanian3 reported an elegant alkyl Heck reaction
where a premature β-hydride elimination problem was sup-
pressed by redirecting reaction into a hybrid Pd-radical pathway.4
Both methods feature conventional exo-trig-cyclization pathway
(Scheme 1, a). While, methods for selective endo-trig-Heck
processes employing sp2 halides are scarcely reported,5 to the
best of our knowledge, there are no reports of an endo-selective
alkyl Heck reaction. Herein, we report an endo-selective silyl
methyl Heck reaction of iodomethylsilyl ethers of phenols and
aliphatic alkenols (Scheme 1, b). The use of the silyl tether allows
for selective endo cyclization without substrate bias and enables
post-modification of the obtained silyloxycycles. Moreover, by
design, the employed substrates do not have the issue of
premature β-hydride elimination.
Halomethylsilanes have been used as a tool for a formal
hydro−hydroxymethylation of allylic alcohols via a reductive
Received: October 10, 2014
© XXXX American Chemical Society
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Communication
Table 1. Scope of Benzene-Tethered Substrates
Table 2. Scope of Aliphatic Alkenols
a
b
c
Isolated yields. DABCO was used instead of iPr2NEt. Ag(OTf) was
d
not used as an additive. Major product shown, ratio of major product
to homoallylic side product is 7:1. Major product shown, ratio of
major product to homoallylic side product is 17:1. Reaction
performed at 130 °C. Major product shown, ratio of major product
e
f
g
h
to hydro-dehalogenation side product is 1:1. Major product shown,
ratio of major product to allylic side product is 3.5:1. Isomers were
separated.
a
b
c
Isolated yields. Reaction performed at 3.8 mmol scale. Reaction
d
performed at 120 °C. NMR ratio of product to hydro-dehalogenation
side product is 12:1. NMR ratio of product to hydro-dehalogenation
side product is 1.6:1. Reaction time = 36 h. Ag(OTf) was used as an
additive. Mixture of isomers.
cyclopropane ring opening occurs via a radical- or a Pd-mediated
β-C elimination process,13 the cyclization of phenyl-containing
substrate 5b was tested. If the Pd-mediated cyclization is
operative, then formation of a mixture of 7b and 8b would be
expected.13 However, reaction of 5b under the optimized
conditions produced 7b as the sole isomer, thus, strongly
supporting the radical cyclization pathway.12,14
e
f
g
h
respectively. Applying this methodology to naturally occurring
Isopulegol resulted in the formation of two endo products, from
which 4j was isolated as the major isomer.
Naturally, after establishing the scope of the silyl methyl Heck
reaction, we were eager to determine whether this trans-
formation proceeds via a classical Heck-type or a hybrid Pd-
radical mechanism.3,4 Our studies using radical traps such as
BHT and TEMPO3,11 were inconclusive.9 Therefore, the nature
of this cyclization was examined by a radical clock test.12 It was
found that 5a underwent smooth cyclization with a subsequent
ring opening of the cyclopropyl ring producing a 1:1 mixture of
dienes, 7a (8a) and 9a in 58% yield with no cyclopropyl-
containing product 6a detected (eq 1). In order to verify whether
Based on these preliminary mechanistic studies, the silyl
methyl Heck reaction is proposed to proceed via a hybrid-Pd-
radical process, introduced by Alexanian.3,15 A catalytic cycle is
depicted in Scheme 2. Oxidative addition of 3 followed by
B
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Journal of the American Chemical Society
Communication
Scheme 2. Hybrid Pd-Radical Catalytic Cycle
Scheme 3. Synthetic Utility of the Silyl Methyl Heck
a
Reaction
homolysis produces radical A and the Pd(I) species. In
cyclization of substrates possessing substituent(s) at the β-
position of the alkene (e.g., 1n,o), a 6-exo-trig cyclization
occurred, which subsequently leads to the products 2n,o.
However, with substrates possessing terminal double bond, A
undergoes selective endo-trig cyclization to produce cyclic alkyl
radical B. This regioselectivity trend could be attributed to the
combination of factors, including the elongated Si−C bond,6
slower relative rate of competitive exo cyclization,6c and favorable
stability of the endo transition state proposed for radical
cyclizations of halomethylsilanes.6c,7 Next, recombination of B
with Pd(I) produces alkylpalladium species C, which upon β-
hydride elimination produces reaction products 4. Apparently, C
has two alternative β-hydrogens, Hh and Ha, elimination of which
leads to homoallylic and allylic silanes, respectively. Although,
the origins of the observed selectivity at this point are not clearly
understood, it is apparent that sterics plays an important role
during the β-hydride elimination event,8 where increasing
substitution pattern favors allylic silane formation.
a
(i) 3 equiv MeLi, Et2O, 0 °C, 1 h. (ii) 1.1 equiv 1,1-
Dimethoxycyclohexane, 1.1 equiv BF3OEt2, DCM, −78 °C to rt, 1
h. (iii) 10 equiv 50% H2O2, 12 equiv KHCO3, 2 equiv KF, DMF, 70
i
°C, 12 h. (iv) 10 mol % Pd(OAc)2, 20 mol % L, 2.2 equiv Pr2NEt,
PhMe, 75 °C, 12 h. (v) 10 equiv BuOOH, 12 equiv KH, 5 equiv
TBAF, NMP, rt, 12 h.
t
methyl endo/exo cascade Heck cyclization. The obtained
siloxycycles were further functionalized via the intramolecular
Hosomi−Sakurai reaction to produce spiro benzofuran skeleton.
In addition, the obtained silyl ethers were oxidized to form (Z)-
allylic alcohols. We envision this protocol may become a useful
tool for a formal (Z)-hydroxymethylation of a broad range of
alkenols.
Finally, we turned our attention to the synthetic utility of
products obtained via this novel silyl methyl Heck reaction
(Scheme 3).16 Thus, ring opening of silyloxycycle 2a with MeLi,
produced 11 in 70% yield. Its subsequent intramolecular
Hosomi−Sakurai reaction with 1,1-dimethoxycyclohexane gen-
erated spiro benzofuran 12 in excellent yield (Scheme 3, a).17
Alternatively, 2a can be smoothly oxidized into (Z)-allylic
alcohol 10 in good yield, which highlights employment of
halomethylsilanes as a tool for a formal (Z)-hydroxymethylation
of alkenols.18 Next, we applied this methodology to a cascade
process, where a silyl methyl Heck reaction of dienol 1p
produced tricyclic compound 2p in excellent yield (Scheme 3, b).
Notably, due to the influence of the silicon atom in the first
cyclization event, this cascade reaction of 1p occurs via an endo/
exo cyclization protocol, whereas most carbon analogs produce
exo/exo cyclized products.19 Compound 2p was further oxidized
into indenediol 13 in good yield (Scheme 3, b). Lastly, silyl
methyl Heck reaction of vinyl steroid substrate 1q efficiently
underwent 7-endo-trig cyclization (Scheme 3, c), thus illustrating
usefulness of this methodology for a late stage modification of
complex molecules. Oxidation of silyl steroid 2q produced (Z)-
allylic alcohol 14 in good yield.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at http://
pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
vlad@uic.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank National Institutes of Health (GM-64444) and
National Science Foundation (CHE-1362541) for financial
support of this work.
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Journal of the American Chemical Society
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