Silanol: A traceless directing group for Pd-catalyzed o -alkenylation of phenols

Article abstract of DOI:10.1021/ja204924j

A silanol-directed, Pd(II)-catalyzed C-H alkenylation of phenols is reported. This work features silanol, as a novel traceless directing group, and a directed o-C-H alkenylation of phenols. This new method allows for efficient synthesis of diverse alkenylated phenols, including an estrone derivative.

Full text of DOI:10.1021/ja204924j

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pubs.acs.org/JACS
Silanol: A Traceless Directing Group for Pd-Catalyzed o-Alkenylation
of Phenols
Chunhui Huang, Buddhadeb Chattopadhyay, and Vladimir Gevorgyan*
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061, United States
S Supporting Information
b
reactivity of the reaction.9 We were intrigued by the possibility to
develop a method that would employ an easily remov-
ABSTRACT: A silanol-directed, Pd(II)-catalyzed CÀH
alkenylation of phenols is reported. This work features
silanol, as a novel traceless directing group, and a directed
o-CÀH alkenylation of phenols. This new method allows
for efficient synthesis of diverse alkenylated phenols, includ-
ing an estrone derivative.
able directing group at the phenol, which would allow for a
general synthesis of alkenylated phenols.10,11 Recently, we re-
ported a traceless/modifiable silicon-tethered directing group12
(PyDipSi) for ortho-acyloxylation and halogenation of arenes.13
Hence, we envisioned that employment of a temporary silicon-
tethered directing group for phenols might be beneficial as it can
efficiently be removed under mild conditions. In a recent report,
Yu disclosed an elegant hydroxyl-directed ortho-CÀH alkenyla-
tion of β-phenethylalcohols en route to alkenylaed arenes
and/or benzopyrans (eq 4).14,15 Inspired by the successful alco-
hol-directed CÀH functionalization reactions14,15 and efficient
silicon-tethered directing group employment in CÀH func-
tionalizations,13 we hypothesized that silanol may serve as an
ideal easily removable directing group for CÀH alkenylation of
phenols.16
rtho-Alkenyl phenols are important building blocks for
o
synthetic organic chemistry.1 Traditionally, these synthons
can be assembled via a combined Claisen rearrangement of
O-allylphenols to C-allylphenols followed by a transition metal-
catalyzed double bond isomerization process (eq 1).2 This
method is not general, as the Claisen rearrangement may
produce a mixture of ortho- and para-allylphenols. Besides, the
stereoselectivity of the isomerization step is ambiguous. Another
common route to ortho-alkenyl phenols involves consecutive
ortho-halogenation/Mizoroki-Heck cross-coupling reaction3
with alkenes (eq 2). The requisite of extra ortho-prefunctionali-
zation step and concomitant overbromination byproducts sig-
nificantly limits the wide application of this approach.4 More
directly, orhto-alkenylation reaction of phenols with terminal
alkynes can be promoted by a Lewis acid, such as SnCl4.5 An
obvious drawback of this method is an employment of stoichio-
metric amounts6 of a toxic tin reagent. Herein, we wish to report
a silanol group-directed Pd-catalyzed ortho CÀH alkenylation of
phenols to produce diverse ortho-alkenyl derivatives in good to
high yields (eq 3).
To test this hypothesis, silanol17 1a (1 equiv) was treated with
butyl acrylate (2a, 2 equiv) under the conditions employing
amino acid-derived ligand developed by Yu14 (10 mol % Pd-
(OAc)2, 20 mol % (+)menthyl(O2C)-Leu-OH (L1), 1 equiv
Li2CO3, 4 equiv AgOAc, in C6F6 at 100 °C). To our delight, the
desired ortho-alkenylated product 3a was formed in 52% NMR
yield (Table 1, entry 1). Solvent optimization indicated PhCF3 to
be similarly efficient (entry 2), whereas employment of other
solvents, such as toluene, dioxane, THF, t-AmylOH, and DMF
gave poor yields. Finally, switching to DCE improved the yield of
the reaction (78% NMR yield, entry 7).
Next, the removal of the silanol directing group was examined.
Expectedly, desilylation of 3a with TBAF proceeded unevent-
fully, producing the unprotected phenol 4a in 84% yield (eq 5) or
in 66% yield over two steps. It deserves mentioning that better
efficiency was achieved by carrying out two steps, CÀH alkeny-
lation/desilylation, in semi-one-pot fashion18 (Table 2, entry 1).
Transition metal-catalyzed directed CÀH7 alkenylaton8
reactions have emerged as attractive alternative to the
MizorokiÀHeck reaction. A directing group is usually intro-
duced to control the regioselectivity as well as to enhance the
Received: May 28, 2011
Published: July 18, 2011
r
2011 American Chemical Society
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|

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Table 1. Solvent Screening for Silanol-Directed
Alkenylationa
Table 2. Phenol Scope for Silanol-Directed Alkenylation
entry
solvent (0.1 M)
conversion,%b
yield, %c
1
2
3
4
5
6
7
8
C6F6
77
79
43
18
4
52
50
24
<3
<3
<3
78
0
PhCF3
PhMe
dioxane
THF
t-AmylOH
DCE
26
90
55
DMF
a 1a/2a = 1: 2, L1 = (+)menthyl(O2C)-Leu-OH. b Consumption of
starting material 1a measured by GC/MS. c 1H NMR yield.
After developing the semi-one-pot procedure for the Pd-
catalyzed silanol-directed CÀH alkenylation/deprotection se-
quence, the scope of this new method was investigated. Table 2
summarizes olefinations of various phenol-derived silanols with
butyl acrylate (2a) to produce the corresponding 2-hydroxy
butyl cinnamates 4. It was found that diverse alkyl-, methoxy-,
trifluoromethoxy-, chloro-, and fluoro-substituents (entries 1À5,
8À11) were tolerated well under these reaction conditions.
Moreover, 5-indanol and tetrahydro-2-naphthol reacted
smoothly to afford the olefinated phenols in good to excellent
yields (entries 6 and 7). Notably, meta-substituted substrates
(entries 2À4) reacted regioselectively at the sterically less
hindered CÀH site. In general, electron-rich phenols gave better
yields of the olefinated products compared to their electron-
deficient counterparts. Remarkably, in contrast to most of the
reported CÀH alkenylation reactions,19 this Pd(II)-catalyzed
olefination reaction is monoselective. Most likely, the bulky tert-
butyl groups at the silanol moiety prevent orientation of the
silanol directing group toward the less hindered CÀH site, thus,
effectively stopping the reaction at the monoalkenylation stage.
Next, we turned our attention to the scope of olefins. It was
found that a wide range of electron-deficient alkenes could be
successfully employed in this transformation (Table 3). Thus,
vinylsulfonate 2b and vinylsulfone 2c readily reacted with silanol
1e to give the olefinated products in very good yields (entries 1,
2). Acrolein (2d) and alkyl vinyl ketones 2e and 2f are also
capable reactants in this olefination reaction (entries 3À5).
Moreover, styrene and its derivatives, smoothly reacted with 1e
to give (E)-2-styrylphenols 4qÀ4t in reasonable yields (entries
6À9). 1,1-Disubstituted acrylate 2k reacted with 1e to give
expected product 4u,20 along with its isomer 4v in 45% and
39% NMR yields, respectively.9b
1
a Isolated yield. b The yield was measured by H NMR analysis using
CH2Br2 as internal standard.
benzofuranone from a simple phenol featuring a CÀH activation
strategy.
Finally, an application of this novel alkenylation methodology
on the olefination of a more complex substrate estrone was
tested. Thus, the corresponding silanol 7 underwent a smooth
alkenylation/desilylation reaction sequence to produce the ole-
finated estrone 8 as a single regioisomer in 89% yield (eq 7).21
This example showcases the viability of employment of this
Furthermore, the reaction of 1e with diethyl maleate (2l)
under the standard reaction conditions produced alkenylated
product 5, which upon desilylation/cyclization, led to the
formation of lactone 6 in 58% yield (eq 6).20 It should be
mentioned that this example represents the first synthesis of a
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Table 3. Alkene Scope for Silanol-Directed Alkenylation
alkenylation method was further demonstrated in the efficient
synthesis of benzofuranone and alkenylated estrone derivative.
’ ASSOCIATED CONTENT
S
Supporting Information. Detailed experimental proce-
b
dures and characterization data for all new compounds. This
material is available free of charge via the Internet at http://pubs.
acs.org.
’ AUTHOR INFORMATION
Corresponding Author
vlad@uic.edu
’ ACKNOWLEDGMENT
We thank the National Institutes of Health (GM-64444) for
financial support of this work.
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