Pyridinyl directed alkenylation with olefins via Rh(III)-catalyzed C-C bond cleavage of secondary arylmethanols

Article abstract of DOI:10.1021/ja205228y

Novel C-C bond cleavage of secondary alcohols through Rh(III)-catalyzed β-carbon elimination directed by a pyridinyl group is reported. A five-membered rhodacycle is proposed as a key intermediate, which undergoes further alkenylation with various olefins. This novel transformation shows high efficiency along with excellent selectivity in mild conditions. A wide range of functionalities are compatible. This study offers a new strategy to carry out C-C bond activation.

Full text of DOI:10.1021/ja205228y

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Pyridinyl Directed Alkenylation with Olefins via Rh(III)-Catalyzed CÀC
Bond Cleavage of Secondary Arylmethanols
Hu Li,† Yang Li,† Xi-Sha Zhang,† Kang Chen,† Xin Wang,† and Zhang-Jie Shi*,†,‡
†Beijing National Laboratory of Molecular Sciences and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of
Ministry of Education, College of Chemistry and Green Chemistry Center, Peking University, Beijing 100871, China
‡State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
S Supporting Information
b
Table 1. Rh(III)-Catalyzed Alkenylation of 1a by Cross-Cou-
pling with Different Alkenes through CÀC Bond Cleavagea
ABSTRACT: Novel CÀC bond cleavage of secondary
alcohols through Rh(III)-catalyzed β-carbon elimination
directed by a pyridinyl group is reported. A five-membered
rhodacycle is proposed as a key intermediate, which under-
goes further alkenylation with various olefins. This novel
transformation shows high efficiency along with excellent
selectivity in mild conditions. A wide range of functionalities
are compatible. This study offers a new strategy to carry out
CÀC bond activation.
ransition-metal-catalyzed CÀC bond cleavage has attracted
T
much attention and emerged as a tremendous challenge in
recent years.1 Typically, in order to facilitate CÀC bond cleavage,
two basic strategies are employed. One is to use strained three- or
four-membered-ring compounds, which undergo oxidative cy-
clometalation, forming more stable metallacyclic complexes, to
release ring strain.2 On the other hand, for the reaction of unstrained
molecules, special driving forces for CÀC bond cleavage are
required to generate stable intermediates.3,4 For example, tertiary
alcohols have been successfully applied as substrates for catalytic
selective CÀC bond cleavage via β-carbon elimination, forming
an organometallic intermediate and a ketone.5 In comparison,
catalytic CÀC bond cleavage of secondary alcohols has rarely
been reported.6,7 Herein we demonstrate an unprecedented
strategy to facilitate Rh(III)-catalyzed selective CÀC bond
activation of secondary alcohols directed by a pyridinyl group
followed by CÀC bond formation.
The major challenge remaining in cleaving the CÀC bond
adjacent to the hydroxyl group of secondary alcohols is to avoid
hydrogen transfer, which is the typical transformation of second-
ary alcohols in the presence/absence of external oxidants (Scheme 1,
path a).8 In our design, a proper substrate for CÀC bond cleavage
should satisfy geometrical requirements by generating a
a Reactions conducted with 0.25 mmol of alcohol substrate 1a, 2.5 mol %
of [Cp*RhCl2]2 as catalyst, 1.2 equiv of alkene, 1.2 equiv of Ag2CO3, and
1.0 mL of EtOH as solvent unless otherwise noted; isolated yields
are given. b Reaction performed on 1.0 mmol scale. c Reaction ran for 3 h.
d Reaction ran for 12 h. e E/Z = 6.7:1.
Scheme 1. Rational Design To Form a CÀM Intermediate
through β-Carbon Elimination
thermodynamically favorable metallacyclic complex as the key
intermediate, which has also been demonstrated in CÀH
activation.9 The generated organometallic intermediates can
potentially facilitate sequential functionalizations, such as olefi-
nation (Scheme 1, path b). This strategy offers a new concept for
CÀC bond activation.
Received: June 7, 2011
Published: August 30, 2011
r
2011 American Chemical Society
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|

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Table 2. Rh(III)-Catalyzed Alkenylation of Various Alcohols 1 by Cross-Coupling with Styrene through CÀC Bond Cleavagea
a Reactions conducted with 0.25 mmol of alcohol substrate 1, 2.5 mol % of [Cp*RhCl2]2 as catalyst, 1.2 equiv of styrene, 1.2 equiv of Ag2CO3, and 1.0 mL of
EtOH as solvent unless otherwise noted. Isolated yields are given. b 3.0 equiv each of styrene and Ag2CO3 were used. c Reaction ran for 5 h. d Reaction ran for 4 h.
With this idea in mind, we initiated our study by examining the
reactivity of 1-phenyl-(4-methyl-2-(pyridin-2-yl))benzyl alcohol
(1a) with styrene (2a). After a series of screening, we found that
employing [Cp*RhCl2]2 (Cp* = η5-pentamethylcyclopentadie-
nyl) as the catalyst, Ag2CO3 as the oxidant, and EtOH as the
solventafforded the desired alkenylatedproduct3ain 92%isolated
yield, along with 95% NMR yield of benzaldehyde (eq 1).10
Under the optimized conditions in hand, we explored the
substrate scope of olefins (Table 1). Reaction with styrene
provided satisfactory results, even on a larger scale (3a). Styrene
bearing methyl substituents at different positions on the phenyl
ring afforded good yields (3bÀe). However, sterically hindered
2,4,6-trimethylstyrene inhibited this transformation (3f). More-
over, both electron-rich (3gÀi) and electron-deficient styrene
derivatives (3jÀm) were excellent coupling partners. Notably,
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Scheme 2. Plausible Mechanism for Rh(III)-Catalyzed CÀC
Bond Cleavage/Alkenylation of 1a with Olefins
Scheme 3. Competition of Rh(III)-Catalyzed CÀC Bond
Cleavage versus CÀH Activation
captured by cleaving the C-C bond of 1a using stoichiometric
[Cp*RhCl2]2, which also showed excellent catalytic activity.14
On the other hand, since 2-m-tolylpyridine (8) was detected
occasionally as a byproduct of the reaction of 1a, a pathway via
sequential protonation of rhodacycle 6/Rh-catalyzed CÀH
alkenylation of 8 could also be considered (path B). This
hypothesis was supported by a deuterium labeling experiment
(eq 2), where partially deuterium labeled product 4h-d4 was
generated from CÀD cleavage, as shown in path B.14
halogen substituents were well tolerated (3k,l), providing op-
portunities for further functionalization. In addition, 2-
vinylnaphthalene also showed excellent reactivity (3n). Last,
2,3,4,5,6-pentafluorostyrene was tested, and the desired product
was obtained albeit in lower yield (3o). Notably, aliphatic
terminal alkenes, e.g., vinylcyclohexane and 1-octene, both
reacted smoothly under this condition, affording double-bond-
migrated products in high yields (3p,q), the result of β-hydride
elimination from the other site, lacking π-conjugation from the
phenyl ring of styrene substrates.
To distinguish the two pathways, a competition experiment was
done, treating of 1 equiv each of alcohol 1a, 2-phenylpyridine (9),and
styrene in one pot under the standard reaction conditions, as shown
in Scheme 3.14 The results evidenced that alkenylation from CÀC
cleavage was much faster than from direct CÀH activation. Thus,
path A was proposed to be more facile than path B in Scheme 2.
Finally, “dual activation” of secondary alcohol 1h was achieved
by sequential CÀC bond cleavage/CÀH activation by stepwise
addition of styrene (2a) and 4-methylstyrene (2b) in one pot
under mild conditions, with good efficiency and outstanding
selectivity (eq 3). This unique activity highlights the potential
utility of this CÀC cleavage in postsynthetic elaboration of
complex natural products. Thus, rationally designed alcohol
substrates and their alkenylated products can serve as versatile
synthetic intermediates.
The substrate scope of alcohols was further investigated (Table 2).
To our satisfaction, both electron-donating and -withdrawing groups
on the phenyl ring of 1 showed moderate to good compatibility
(entries 1À3). Again, halogen groups were tolerated (entry 2). Most
importantly and interestingly, a secondary or tertiary alcohol motif at
a nonchelating position remained intact in the reaction (entries 4
and 5), which exhibited exclusive selectivity controlled by the
pyridinyl directing group. Furthermore, by simply adjusting the
excess of styrene and oxidant, secondary alcohol substrates with a
para or no substituent on the phenyl ring provided mono- and
dialkenylated products selectively in good yields at 70 °C within 1 h
(entries 6 and 7), showing better controllable selectivity than direct
CÀH activation.9d A pyrazolyl group could also be used to direct this
Rh(III)-catalyzed CÀC bond cleavage reaction (entry 8).11,12
A variety of aliphatic-substituted secondary alcohols other than
diarylmethanols were examined to test the reactivity. To our delight,
secondary alcohols bearing both aryl and aliphatic groups under-
went β-C elimination and further alkenylation smoothly, generating
aliphatic aldehydes as the byproducts (Table 2, entry 9, 1j,k).
Tertiary alcohols also exhibited good reactivity under these
conditions (entry 10); however, primary alcohols were not suitable
for this sequence of CÀC bond cleavage/formation (entry 11).
Based on previous studies, the reaction pathway shown in
Scheme 2 was proposed. After the initial coordination of Rh(III)
catalyst with N and O atoms of 1a, Ag2CO3 might act as a base to
facilitate the deprotonation process,13 promoting β-C elimination to
release benzaldehyde and generate five-membered rhodacycle 6,
which further undergoes alkene insertion and β-H elimination to
produce the final alkenylated product 3 and Rh(I) species.9d The
latter was subsequently oxidized by Ag(I) to regenerate Rh(III)
species (path A). In fact, a five-membered rhodacyclic complex was
In summary, we have developed an unprecedented Rh(III)-
catalyzed CÀC bond cleavage reaction of secondary diaryl-
methanols with the assistance of a pyridinyl group through
β-C elimination. The formed five-membered rhodacycle under-
goes alkenylation through coupling with a variety of terminal
alkenes. The pyridinyl group is essential to control the selec-
tivity of CÀC bond cleavage via chelation assistance. This novel
strategy provides a mild and efficient method for “inert” CÀC
bond activation, showcasing the viability of late-stage modifica-
tion of complex molecules toward a diversity-oriented synthesis.
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Further studies to find other substrates and investigate alternative
transformations are underway.
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures and
b
spectral data for alcohol substrates, alkenylated products, mechan-
istic study experiments, and rhodacyclic intermediate. This material
is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
zshi@pku.edu.cn
’ ACKNOWLEDGMENT
Support of this work by NSFC (Nos. 20672006, 20821062,
20832002, 20925207, 21002001, and GZ419) and the “973”
Project from the MOST of China (2009CB825300) is gratefully
acknowledged. H.L. thanks Zhi-Quan Lei for assistance in the
preparation of alcohol substrates.
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(10) For condition screening table and more detailed explanations,
see Supporting Information.
(11) The ketone from oxidation of1i was detected as the main byproduct.
(12) Other directing groups such as acetamide did not work; using a
phenyl group instead of a pyridinyl group also afforded no CÀC cleavage
products. These resulted in oxidation of the starting alcohol substrates to
the corresponding ketones.
(13) O-Silylated substrates, e.g., O-TBS-substituted 1a, did not react
in the standard conditions.
(14) For experimental details, see Supporting Information.
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