Allylic carbon-carbon double bond directed pd-catalyzed oxidative ortho -olefination of arenes

Article abstract of DOI:10.1021/ja300168m

Pd-catalyzed selective ortho-olefination of arenes assisted by an allylic C-C double bond at room temperature using O₂ as a terminal oxidant is described. A possible mechanism involving the initial coordination of allylic C=C bond to Pd followed by selective o-C-H bond metalation is proposed.

Full text of DOI:10.1021/ja300168m

Communication
pubs.acs.org/JACS
Allylic Carbon−Carbon Double Bond Directed Pd-Catalyzed
Oxidative ortho-Olefination of Arenes
Parthasarathy Gandeepan and Chien-Hong Cheng*
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan
S
* Supporting Information
To optimize the formation of 3a, we examined the reaction
under various conditions. Optimized reaction conditions were
found to include 1a (0.5 mmol) and 2a (1.5 mmol) in
dichloromethane (DCM, 3 mL) in the presence of Pd(OAc)2
(10 mol%) and TFA (8 equiv) at room temperature for 36 h
under 1 atm of O2. Under these conditions, the reaction gave
3a in 91% isolated yield (Table 1, entry 1). There are two
ABSTRACT: Pd-catalyzed selective ortho-olefination of
arenes assisted by an allylic C−C double bond at room
temperature using O2 as a terminal oxidant is described. A
possible mechanism involving the initial coordination of
allylic CC bond to Pd followed by selective o-C−H
bond metalation is proposed.
Table 1. Scope of Activated Alkenes 2 in the Pd-Catalyzed
Olefination of 1a
a
elective activation of C−H bonds catalyzed by transition metal
S
complexes has shown great potential for the construction of
value-added molecules through C−C or carbon−heteroatom
bond formation.1 This methodology is of interest for the chemical
and pharmaceutical industries, because it can significantly simplify
and shorten the synthetic route and also allow the utilization of
less expensive, more readily available, and environmentally benign
starting materials. In particular, oxidative cross-coupling between
arenes and olefins, commonly known as the Fujiwara−Moritani
reaction,2 is a powerful variant of the classical Mizoroki−Heck
reaction3 that avoids the need for the use of aryl halides and
reduces the generation of salt waste. In general, regioselectivity of
the Fujiwara−Moritani reaction can be achieved either through the
introduction of a directing group4 or by use of an external ligand.5
Such directors are usually N- or O-containing func-
tional groups. The search for new variants to assist selective
C−H bond functionalization is expected to extend the scope of
the synthetic application. Our ongoing interest in finding new
organic transformations through C−H bond activation6 prompts us
to examine the utilization of the CC bond as a director for
selective C−H functionalization reaction. Here, we report a Pd-
catalyzed regioselective ortho-olefination of arenes at ambient
temperature using molecular oxygen as the terminal oxidant. The
reaction appears to proceed unprecedentedly using the allylic CC
bond as the director for the C−H activation and functionalization.
Our investigation started with the reaction of styrene with
b
entry
2
product 3
yield, %
91
1
R = CO2n-Bu, 2a
R = CO2Et, 2b
R = CO2Me, 2c
R = CO2t-Bu, 2d
R = CO2C6H11, 2e
R = CO2CH2Ph, 2f
R = CO2H, 2g
2h
3a
3b
3c
3d
3e
3f
2
93
3
95
c
c
4
23 + (66)
43 + (49)
5
d
6
62
d
7
3g
3h
3i
64
d
8
63
d
9
2i
56
e
10
11
12
13
14
R = C(O)NH2, 2j
R = C(O)NMe2, 2k
R = C(O)NHCH2Ph, 2l
R = CN, 2m
3j
40 (73)
3k
3l
69
f
56
d
3m
3n
48
d
R = SO2Ph, 2n
67
butyl acrylate 2a using 10 mol% Pd(OAc)2 along with 1 equiv
of Ag2O in 1,2-dichloroethane (DCE) at 80 °C for 12 h. When
trifluoroacetic acid (TFA) was used as an additive, head-to-tail
homodimerization product styrene7 1a and olefination product
3a were observed in 37 and 18% yields, respectively (eq 1).
a
Unless otherwise mentioned, all reactions were carried out using 1a
(0.50 mmol), alkene 2 (1.5 mmol), Pd(OAc)2 (0.050 mmol), TFA
(4.0 mmol), and DCM (3.0 mL) at 25 °C in an O2 atmosphere for
36 h. Isolated yields. Yield of hydrolyzed product 3g. Reaction time
was 60 h. Reaction was carried out using 1a (1.0 mmol) and alkene 2j
(0.50 mmol), and the yield is calculated on the basis of 2j. 1.0 mmol
b
c
d
e
f
of alkene 2l was used.
phenyl groups in 1a, and the olefination appears to occur on an
ortho-carbon of the phenyl ring near the methyl group. The
Received: January 6, 2012
Published: March 20, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
a
Table 2. Scope of Alkene 1 in the Pd-Catalyzed Olefination with 2
a
Unless otherwise mentioned, all reactions were carried out using 1a (0.50 mmol), alkene 2 (1.5 mmol), Pd(OAc)2 (10 mol %), TFA (4.0 mmol),
b
c
and DCM (3.0 mL) at 25 °C in an O2 atmosphere for 36 h. Isolated yields. Reaction time was 60 h.
1
structure of 3a was confirmed by its H and 13C NMR and
mass data. As shown below, the structures of similar products
3g,l were further supported by NOE experiments and X-ray
structural determination, respectively. To our knowledge, this is
the first report of the use of allylic CC bond as a director for
the Pd-catalyzed C−H activation reaction.8
reaction was totally ineffective in the absence of TFA. However,
higher TFA concentration led to lower product yield of 3a.
When pure TFA was used as the solvent under an O2
atmosphere, 3a was obtained in 17% yield. The use of weaker
acids like AcOH and PivOH as additives instead of TFA totally
suppressed the formation of 3a. Of the oxidants tested, O2
appeared to be the best for this catalytic reaction. Other
oxidants such as Ag2O and Cu(OAc)2 are less effective,
affording 3a in 11 and 16% yield, respectively. In addition to
Pd(OAc)2, Pd sources such as PdCl2, PdCl2(PPh3)2, and
PdCl2(CH3CN)2 were also examined, but only PdCl2(CH3CN)2
The choice of solvent and oxidant is crucial for the success of
the present catalytic reaction. A series of solvents or solvent
combinations and oxidants were examined for the reaction of
1a with 2a (see Supporting Information). It appears that TFA
(8 equiv) in DCM gave the highest yield (91%) of 3a. The
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Journal of the American Chemical Society
Communication
showed catalytic activity, producing 3a in 16% yield; the others
were completely inactive.
Table 2, entry 21, we also examined the possibility of a butenylic
CC bond as a director for C−H bond activation with 2a.
However, we failed to observe any expected product 3sa.
Under the optimized reaction conditions, various electron-
deficient olefins (2b−n) also reacted with dimer 1a smoothly
to give the corresponding olefinated products in good to
excellent yields. Thus, ethyl (2b) and methyl acrylate (2c)
afforded the corresponding olefination products 3b,c in 93 and
95% yields, respectively. Similarly, tert-butyl and cyclohexyl
acrylate reacted efficiently with 1a to give 3d,e, but part of the
products underwent hydrolysis to give 3g. The reaction of
benzyl acrylate 2f with 1a also proceeded, although the
corresponding product 3f was obtained in slightly lower yield
(Table 2, entries 1−6). Interestingly, acrylic acid 2g also
underwent the same transformation to afford the corresponding
product 3g in 64% yield (entry 7). It is important to mention
that the reaction of 1a with α-substituted acrylates 2h,i
proceeded to form 3h,i (entries 8, 9) rather than the isomers
with structures similar to 3a−g. Unlike α-substituted acrylates,
β-substituted acrylate is not active for the transformation under
similar reaction conditions. In addition to acrylates, acrylamide
(2j), N,N-disubstituted acrylamide (2k), and N-benzyl
acrylamide (2l) also reacted smoothly with 1a to provide the
desired products 3j−l in moderate to good yields (entries 10−12).
The structure of 3l was further confirmed by X-ray diffraction.
Acrylonitrile 2m and phenyl vinyl sulfone 2n were also successfully
employed in this transformation to give the corresponding prod-
ucts 3m,n in 48 and 67% yields, respectively (entries 13, 14).
However, electronically neutral alkenes such as 1-hexene and
styrene are not suitable substrates for this transformation.
We next examine the scope of substrate 1 in the present
catalytic reaction. The results of these studies are shown in
Table 2. Substrates 1b−i were prepared byhomodimerization of
the corresponding substituted styrene.7c Under the optimized
reaction conditions shown in Table 1, these substrates
underwent olefination with acrylate 2a to give the correspond-
ing products 3 in good to excellent yields. The results indicate
that electron-donating substituents such as methyl, tert-butyl,
and methoxyl groups enhance the reactivity and increase the
product yields (entries 1, 2, 5, and 6); a less electron-donating
substituent appears to decrease the reactivity of the substrate,
but with a longer reaction time, high conversion and yield can
still be achieved (entries 3, 4 and 7, 8). For substrates with a
substituent at the meta position, olefination occurs only at the
less hindered ortho position. Presumably, the regioselectivity
was controlled by the steric effect of the meta substituent
(entries 6, 7). Substrates 1j−o without a methyl group on the
aliphatic chain also reacted efficiently with 2a to give the
expected olefination products in good yields (entries 9−14).
Interestingly, sterically hindered tri- and tetrasubstituted
alkenes 1p,q also drive the ortho-olefination reaction to give
the respective products 3pa,qc in good yields of 79 and 56%
(entries 15, 16). The reaction is not restricted to styrene
derivatives; it is also compatible with alkyl-substituted alkenes.
Thus, treatment of hex-2-enylbenzene (1r) with 2a afforded ortho-
olefination product 3ra in 82% yield (entry 17). The E:Z ratio of
the CC bond on substrate 1r does not change after the catalytic
reaction. In addition to acrylate 2a, acrylic amide 2k, acrylonitrile
2m, and vinyl sulfone 2n also react smoothly with 1,3-
diphenylpropene 1j to give 3jk−jn, respectively, in moderate to
good yield. The results in Tables 1 and 2 show clearly that it is the
allylic CC bond attached to an arene ring that activates the o-
C−H bond of the arene. Under the reaction conditions, a vinylic
CC bond does not activate the arene C−H bond. As shown in
To understand the mechanism of this catalytic reaction, we
first performed competition reactions using allylic substrates 1n
and 1o, 1j and 1r, and 1c and 1d with 2a. The results of these
three sets of reactions revealed that substrates 1c, 1n, and 1r,
with an electron-richer substituent on the allylic arene ring or
on the CC bond gave a higher product yield than 1o, 1j and
1d, respectively (Supporting Information). The observations
support the coordination of CC to Pd(II) and an
electrophilic C−H activation during the reaction (see proposed
mechanism, Scheme 2).9 Next, we examined possible D/H
exchange for the reaction of [d5]-1r with 2c under standard
reaction conditions. The reaction gave [d41]-3rc in 74% yield
with no D/H exchange, as indicated by its H NMR and mass
spectra (eq 2). This result ruled out the possibility of non-
regioselective C−H activation followed by ortho-selective olefin
insertion/reductive elimination. Finally, we measured the kinetic
isotopic effects (KIEs) of the catalytic reaction by carrying out
competition reaction inter- and intramolecularly. An intermolec-
ular KIE kH/kD = 1.63 was observed for the competition reaction
of 1j and deuterium-labeled [d5]-1j with 2a (Scheme 1). On the
Scheme 1. Isotope Effect for the Pd-Catalyzed Oxidative
Coupling of 1j with 2a
other hand, an intramolecular competition experiment of [d1]-1j
with 2a showed kH/kD = 3.7. The observed large difference in the
inter- and intramolecular KIE values implies that the coordination
of the CC bond occurs prior to C−H palladation in the
catalytic cycle.10 If palladation takes place before CC bond
coordination, similar KIE values for the inter- and intramolecular
competitions should be observed.10
Based on the experiment results and known transition metal
catalyzed C−H activation reactions,2−4,11 a possible mechanism
employing 1j and 1a as the substrates is proposed to account
for the present catalytic reaction (Scheme 2). The highly
electrophilic [Pd(TFA)]+ is expected to be generated in the
presence of TFA.2h,12 This cationic species should greatly
facilitate coordination of the CC bond and enhance
metalation of the aromatic C−H bond. Thus, coordination of
the CC bond in 1j and then the C−C π bond between the
ortho and ipso carbons to the Pd(II) center to give intermediate
A is expected.13 Subsequent cyclometalation forms Pd(II)
σ-aryl complex B. Insertion of activated olefin into the C−Pd
bond in intermediate B, followed by β-hydride elimination,
affords the corresponding product 3ja and H-Pd(TFA) species.
Oxidation by O2 regenerates the active Pd(II) species.11
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Journal of the American Chemical Society
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In conclusion, we have demonstrated an effective Pd-catalyzed
carbon−carbon double bond assisted selective o-C−H olefination
of arenes at room temperature using O2 as the oxidant. The
reaction appears to be the first example employing an allylic
alkenyl double bond as a directing group for C−H activation. In
addition, we have observed that a β-CC bond instead of an α-
CC bond is important to the o-C−H bond activation of arenes.
Further applications of this methodology to other coupling
partners and a detailed mechanistic investigation are in progress.
ASSOCIATED CONTENT
* Supporting Information
■
S
General experimental procedure and characterization details.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
chcheng@mx.nthu.edu.tw
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Science Council of Republic of China
(NSC-100-2119-M-007-002) for support of this research.
■
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