TBDPS and Br-TBDPS protecting groups as efficient aryl group donors in Pd-catalyzed arylation of phenols and anilines

Article abstract of DOI:10.1021/ja904791y

(Chemical Equation Presented) It is shown that the TBDPS protecting group can serve as an efficient phenyl group donor for o-bromophenols via Pd-catalyzed C-H arylation followed by a routine TBAF deprotection of the resulting silacycles. Employment of the newly designed Br-TBDPS protecting group in the same sequence allows for a facile introduction of a phenyl group at the ortho position of phenols and anilines. Alternatively, switching desilylation to oxidation in the last step allows the conversion of forming silacycles into valuable o-biphenols.

Full text of DOI:10.1021/ja904791y

Published on Web 07/15/2009
TBDPS and Br-TBDPS Protecting Groups as Efficient Aryl Group Donors
in Pd-Catalyzed Arylation of Phenols and Anilines
Chunhui Huang and Vladimir Gevorgyan*
Department of Chemistry, UniVersity of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061
Received June 11, 2009; E-mail: vlad@uic.edu
Table 1. Arylation of TBDPS-Protected o-Bromophenols (Mode
Aryl-aryl bond formation is an important process because of
A)a b
,
the unique pharmaceutical features and wide applications of biaryls
in material science.1 Traditionally, aryl-aryl bonds are made via
cross-coupling reactions between aryl halide (or equivalent) and
arylmetal components.2 Recently, a number of excellent transition-
metal-catalyzed direct C-H arylation methodologies have
emerged.3 However, these methods are not without boundaries.
Thus, intermolecular versions often suffer from low reactivity and/
or regioselectivity, which in some cases can be circumvented by
the introduction of a directing group,3k,4 including a removable
directing group.5 Intramolecular arylations, although much less
problematic,3a,d,6 lead by default to cyclic biaryl products. To the
best of our knowledge, there are no reports of the employment of
easily removable tethers in the synthesis of biaryls via the C-H
arylation motif.7 Herein, we report that the common TBDPS
protecting group can serVe as an efficient aryl group donor for
o-bromophenols via Pd-catalyzed intramolecular arylation followed
by a deprotection step (mode A, eq 1). Moreover, it was found
a See the Supporting Information for the detailed procedure. b Isolated
that the newly designed Br-TBDPS protecting group is an eVen
yields are given, with NMR yields (against CH2Br2 as an internal
standard)
3-dioxolan-2-yl.
in
parentheses.
c TMDO
)
4,4,5,5-tetramethyl-1,
more efficient aryl group donor for simple phenols and anilines
(mode B). Employing this temporary silicon tether motif is
beneficial not only because of the ease of its deprotection but also
because it provides easy access to deuteriated biaryls and biphenols
(eq 1).
Next, the substrate scope was studied (Table 1). Gratifyingly, it
was found that this method is quite general, as diverse substrates
possessing MeO, Cl, F, NO2, and CHO groups were perfectly
tolerated under these reaction conditions and produced the corre-
sponding oxasilacycles 2 in good to high yields. The yields were
normally higher with electron-rich substrates and somewhat lower
with electron-deficient arenes. As expected, highly sterically
congested 1i was less efficient in this reaction.
Inspired by a successful employment of the TBDPS group as a
tether and, at the same time, a donor of an aryl group to
o-bromophenols, we aimed at the design of a silyl tether that would
allow for arylation of simple phenols (mode B). To this end, we
synthesized a Br-TBDPS group16 and tested it in the Pd-catalyzed
arylation of phenols (Table 2). We were pleased to find that the
O-Br-TBDPS-protected phenol (3a) underwent a nearly quantitative
transformation into silacycle 2a under the same reaction conditions
(Table 2, entry 1). Likewise, O-Br-TBDPS-protected 1- and
2-naphthols were cleanly converted into the corresponding cycliza-
tion products. O-TBS-protected resorcinol reacted highly regiose-
lectively to give oxasilacycle 4d in very high yield. Moreover, our
initial experiments demonstrated that N-Br-TBDPS-protected anilines
also can undergo the Pd-catalyzed intramolecular arylation to give
azasilacycle 4e in good yield!17,18
The temporary silicon connection method, coined by Stork,8 has
been widely used for rendering intermolecular reactions intramo-
lecular, often resulting in superior regio- and stereoselectivities for
these processes.9 Thus, we reasoned that employing a suitable easily
introducible and removable silicon tether may improve the reactivity
and regioselectivity of Pd-catalyzed intermolecular C-H arylation
reactions (see above). For these studies, we chose phenol, inter-
molecular arylation of which is a challenging task.10 Initially, as a
removable tether, we chose the tert-butyldiphenylsilyl (TBDPS)
protecting group, which, since its invention by Hanessian,11 has
enjoyed extensive use in synthesis.12 We hypothesized that if
efficient conditions for intramolecular arylation of silicon-tethered
phenyl groups are found, this process would provide a convenient
route to ortho-arylated phenols.10,13 Accordingly, we examined the
Pd-catalyzed intramolecular arylation of TBDPS-protected o-
halophenols 1. Screening of several sets of standard conditions
showed that a modified Fagnou’s protocol3d,14 was the most efficient
method for arylation of o-bromophenol 1a.15,16
Naturally, after the development of efficient intramolecular C-H
arylations of silicon-tethered o-bromophenols, phenols, and aniline,
we performed deprotection of the silicon tether. The standard TBAF
deprotection protocol proved successful on oxasilacycles 2 and
azasilacycle 4e to produce arylated phenols 5a and 5k and aniline
6 in very high to quantitative yields (eq 2). Moreover, treatment of
9
10844 J. AM. CHEM. SOC. 2009, 131, 10844–10845
10.1021/ja904791y CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Arylation of Br-TBDPS-Protected Phenols (Mode B)a
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In summary, two methods for the Pd-catalyzed arylation of
phenols and anilines that employ removable silicon tethers have
been developed. It has been shown that the TBDPS protecting group
can serve as a convenient aryl group donor for o-bromophenols
via an intramolecular arylation/deprotection sequence. It has also
been shown that the newly designed Br-TBDPS group can serve
as an even more efficient aryl group donor for simple phenols and
anilines. Remarkably, switching desilylation to oxidation in the last
step allows the conversion of the forming silacycles into valuable
o-biphenols.
Acknowledgment. This work was supported by the National
Institutes of Health (Grant GM-64444).
(14) Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2007, 129,
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(15) Iodo- and chlorophenols were less efficient, whereas the corresponding
triflates were not stable under these conditions at all.
Supporting Information Available: Experimental data. This ma-
terial is available free of charge via the Internet at http://pubs.acs.org.
(16) See the Supporting Information for details.
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to an alternative five-membered silacycle) was not observed.
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