Achieving vinylic selectivity in Mizoroki-heck reaction of cyclic olefins

Article abstract of DOI:10.1002/chem.201204427

In Heck reactions of cyclic olefins, the products usually have aryl groups that end up at the allylic and/or homoallylic position. We herein report new selectivity that adds aryl groups to the vinylic position. Cyclic olefins of various ring size worked well. The desired isomers were produced by palladium-hydride-catalyzed isomerization of the initial products. Thus, a specific catalyst must be used so that it can perform two jobs under one set of reaction conditions. Copyright

Full text of DOI:10.1002/chem.201204427

DOI: 10.1002/chem.201204427
Achieving Vinylic Selectivity in Mizoroki–Heck Reaction of Cyclic Olefins
Xiaojin Wu, Yunpeng Lu, Hajime Hirao, and Jianrong (Steve) Zhou*[a]
Abstract: In Heck reactions of cyclic olefins, the products usually have aryl groups
that end up at the allylic and/or homoallylic position. We herein report new selec-
Keywords: arylation · Heck reac-
tivity that adds aryl groups to the vinylic position. Cyclic olefins of various ring
tion · isomerization · olefins · vinyl-
size worked well. The desired isomers were produced by palladium–hydride-cata-
ic selectivity
lyzed isomerization of the initial products. Thus, a specific catalyst must be used so
that it can perform two jobs under one set of reaction conditions.
Introduction
The Pd-catalyzed arylation and vinylation of olefins (Mizor-
oki–Heck reaction) is commonly used today to prepare
pharmaceutically active ingredients, agrochemicals, and
functional materials.[1] Aryl insertion into acyclic olefins
leads to conjugated isomers or vinylic selectivity [Scheme 1,
Eq. (1)]. However, in reactions of cyclic olefins, aryl groups
usually end up at the allylic and/or homoallylic positions in
products due to facile b-hydride elimination in the syn rela-
tionship with Pd centers [Scheme 1, Eq. (2)].[2] In fact, the
(homo)allylic selectivity of cyclic olefins has been the basis
for the development of asymmetric Heck reactions.[3]
Recently, Gaunt et al. reported Cu-catalyzed arylation of
cyclohexene using Ph2IOTf (OTf=trifluoromethanesulfo-
nate) electrophiles, but the vinylic selectivity was only 4:1;
some diarylation byproduct was also formed [Scheme 1,
Eq. (3)].[4] In a special example, Heck–Matsuda reaction of
aryldiazonium salts gave predominantly conjugated Heck
products, but the reaction was limited to reactive cyclopen-
tene, and aryldiazonium electrophiles of other anions led to
lower vinylic selectivity [Scheme 1, Eq. (4)].[5]
Herein, we report a general method that can selectively
produce conjugated Heck adducts between aryl triflates and
cyclic olefins [Scheme 1, Eq. (5)]. The ratio of the conjugat-
Scheme 1. Overview of Heck reactions of cyclic olefins and our new
results. CuTC=copper(I) thiophene-2-carboxyl.
ed isomer versus other nonconjugated isomers combined
(vinylic selectivity) is >20:1 in most cases.
1-Arylcycloolefins are commonly used as intermediates in
the synthesis of bioactive natural products[6] and pharma-
ceutically active compounds.[7] Often, they have been assem-
bled through couplings of alkenyl (pseudo)halides or
alkenyl–metal reagents.[8] Our new Heck reaction avoids the
use of these preactivated reagents.
Results and Discussion
Conjugated Heck products are the most stable isomers
(DFT calculation): It is generally believed that 1-arylcyclo-
AHCTUNGTREGoNNNU lefins are more stable than nonconjugated isomers. Howev-
er, there were controversial reports in the literature with
regard to the relative stability of these isomers.[2a,b] Thus, we
decided to reevaluate the relative stability by using DFT cal-
culations. Our results confirmed that 1-phenylcyclohexene
was indeed more stable than two nonconjugated isomers by
[a] X. Wu, Dr. Y. Lu, Prof. Dr. H. Hirao, Prof. Dr. J. (S.) Zhou
Division of Chemistry and Biological Chemistry
School of Physical and Mathematical Sciences
Nanyang Technological University
21 Nanyang Link, Singapore 637371
Fax : (+65)67911961
E-mail: jrzhou@ntu.edu.sg
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201204427.
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FULL PAPER
wald ligands, and N-heterocyclic carbenes gave poor yield
and selectivity.
We also found that [Pd
ACHTUNGTNER(NUNG hfacac)2] (hfacac=hexafluoroace-
tylacetonate) was a much better palladium source than
[Pd
[Pd
N
ACHTUNGRTENN(UNG OAc)2, and
Figure 1. Relative stability of isomers of phenylcyclohexene and phenyl-
cyclopentene using the B3LYP method with 6-31G(d,p) basis set.
AHCTUNGTRENNUNG
approximately 4 kcalmolÀ1 (Figure 1). A similar trend can
be found in the series of cyclopentene. We also determined
that electronic perturbation by the presence of p-methoxy
or p-ester on the aryl ring has little effect on the relative
stability (see the Supporting Information).
The proper choice of solvent and base also proved critical.
Li2CO3 was the most suitable base (Table 2, entry 1). N-
Table 2. Effect of bases in the model Heck reaction.
Catalyst discovery: Initially, we used p-tert-butylphenyl trif-
ACHTUNGTRENNUNGlate and cyclohexene as model substrates in search for a
Entry
Base
Conv. [%]
Yield [%]
Selectivity
1
2
3
4
Li2CO3
Na2CO3
K2CO3
100
88
25
93
69
13
3
23:1
4:1
1:4
1:2
1:1
1:23
2:1
21:1
8:1
10:1
–
selective catalyst. Cyclohexene is a difficult olefin substrate
in Heck reactions. After many experiments, we found that
the use of the simple 1,3-bis(diphenylphosphino)propane
(dppp) ligand can indeed give the desired arylation product
in 93% yield and 23:1 vinylic selectivity.
A sampling of bisphosphanes is listed in Table 1. Ligands
such as 1,2-bis(diphenylphosphino)ethane (dppe), 1,1’-bis(di-
phenylphosphino)ferrocene (dppf), and dnpf gave poor re-
sults. Dnpf is a dppf analogue that carries di(1-naphthyl)-
LiOAc
21
5
6
Et3N
iPr2NEt
100
66
45
9
7
8
9
10
11
Cy2NMe
53
24
83
56
73
0
N-Me-morpholine
2,6-lutidine
proton sponge
DABCO
100
100
100
1
Table 1. Effect of ligands in the model Heck reaction.
Methylmorpholine can also be used, but the yield
was slightly lower. Other trialkylamines such as
Et3N, iPr2NEt, and Cy2NMe can donate hydride to
Pd and led to a significant amount of reduction by-
product, tert-butylbenzene.[12] 1,4-Diazabicyclo-
AHCTUNGTREGUN[NN 2.2.2]octane (DABCO) inhibited the catalysis
owing to its strong coordination ability to Pd cen-
ters.
Veratrole (1,2-dimethoxybenzene) was found to
be the best solvent (Table 3, entry 1). It is an aro-
matic ether with a boiling point of 2068C and it is
relatively cheap (approximately US$100 per kg in
2012, according to the Aldrich catalogue). The re-
sults in other aromatic solvents such toluene and
anisole were much worse. Notably, in some coordi-
nating solvents such as THF, 1,2-dimethoxyethane
(DME), and triglyme, the selectivity was good (15–
20:1) despite moderate conversion.
Entry
Ligand[a]
Bite angle [8][b]
Conv. [%]
Yield [%]
Selectivity
1
2
3
4
dppbz
dppe
dppp
BINAP
dppb
83
86
91
93
94
23
16
100
48
8
18
14
93
41
0
0
2
0
0
3:1
2:1
23:1
1:24
–
–
1:6
–
5
6
7
8
9
10
11
dpppent
dppf
dnpf
dippf
DPEphos
Xantphos
99
99
103
104
104
108
2
19
8
6
8
–
1:6
1:11
2
3
16
[a] dppbz=1,2-bis(diphenylphosphino)benzene; dppb=1,4-bis(diphenylphosphino)bu-
tane; dpppent=1,5-bis(diphenylphosphino)pentane; dippf=1,1’-bis(diisopropylphos-
phino)ferrocene; DPEphos=bis[(2-diphenylphosphino)phenyl] ether; Xantphos=4,5-
bis(diphenylphosphino)-9,9-dimethylxanthene. [b] Natural bite angle.
Table 3. Effect of solvent in the model Heck reaction.
Entry
Solvent
Conv. [%]
Yield [%]
Selectivity
phosphino groups, which we developed for a-selective Heck
reaction of terminal olefins.[9] From the data provided in
Table 1, we can see an intriguing trend in the reactivity and
natural bite angles of the bisphosphanes.[10] In the ligand
series, the optimal activity peaked with dppp (918) and 2,2’-
1
2
3
4
5
6
7
8
9
veratrole
toluene
anisole
THF
dioxane
DME
diglyme
triglyme
100
6
6
37
23
39
22
51
11
93
6
3
31
14
34
15
43
3
23:1
4:1
3:1
16:1
10:1
21:1
4:1
15:1
1:2
bis(diphenylphosphino)-1,1’-binaphthyl
(BINAP;
938).
Other ligands with larger or smaller bite angles showed
much worse results (see below for mechanistic insight).
Common bulky monophosphanes such as PCy3, PtBu3 Buch-
dimethylacetamide
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J. (S.) Zhou et al.
Figure 2. Scope of organic triflates in the Heck reaction of cyclohexene.
Figure 3. Heck reaction of aryl and vinyl triflates with cyclopentene.
Scope of the reaction and synthetic applications: Next, we
examined the scope of aryl triflates in the Heck
reaction of cyclohexene. In most cases, the reactions pro-
ceeded smoothly to give the conjugated products in >20:1
selectivity (Figure 2). The catalyst can tolerate electronic
variation on aryl rings; sensitive functional groups such as
ketone, aldehyde, and free alcohol can be present. For in-
stance, 3-estrone triflate coupled smoothly in 24:1 selectivi-
ty. The minor isomers were removed by routine flash chro-
matography. Some heteroaryl and vinyl electrophiles also
worked well.
We also examined other cyclic olefins (Figures 3 and 4).
The PdACHTUNGTRENNUNG(dppp) catalyst could be directly applied to cyclopen-
tene, cycloheptene, and cyclooctene. In all cases, good yield
and excellent vinylic selectivity were obtained. Various aryl
triflates with electronic and steric perturbation worked well.
Notably, methoxy and nitrile groups can be present at the
ortho position, both of which can potentially chelate on the
Pd catalyst. Some nitrogen- and sulfur-containing heteroaryl
triflates and vinyl triflates also coupled smoothly.
To demonstrate synthetic utility, we applied the Heck con-
ditions to a short synthesis of a substituted olefin, which was
en route to synthesis of a nonsteroidal androgen receptor
antagonist (Scheme 2). The latter showed promising activity
Figure 4. Heck reaction of large-ring olefins.
in reducing hair loss in animal models.[13] In the reported
synthesis, classic transformations were used including addi-
tion of an organolithium reagent to a cyclic ketone and sub-
sequent acidic dehydration. By comparison, our Heck
method displayed excellent tolerance of sensitive functional
groups and can avoid the use of strongly basic and acidic
conditions.
The PdACTHNURGTNE(NUG dppp) catalyst can also be applied to the coupling
of 1,3-cyclohexadiene (Scheme 3). The reaction did not stop
at the monoarylation stage. Instead, symmetrical 1,4-diaryl-
AHCTUNGTREGaNNUN ted products were preferentially formed because the
second arylation was even faster. Use of a different base,
nBu2NMe, was necessary to obtain the diarylation products.
The unsymmetrical products can be obtained by first aryl
Scheme 2. Synthesis of a drug candidate.
coupling
with
enone
tosylhydrozones
(Barluenga
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Vinylic Selectivity
FULL PAPER
Scheme 4. Oxidative addition of aryl triflate.
tions was a coupling product of aryl–methyl (approximately
60% yield). It was formed by methyl exchange between Pd
À
centers to form [(L)Pd(Me)(Ph)] and subsequent C C re-
ductive elimination. Biaryl was also detected, but in small
amounts (<10% yield).
Next, we turned our attention to olefin insertion, and we
initially suspected that the insertion step might be slow on
dppf and dppe complexes. Treatment of [(dppp)Pd(Ph)I]
with cyclohexene (5 equiv) in the presence of AgOTf gave
78% yield of the Heck products after 1 h at 1208C
(SchACTHUNRTGNEUNGeme 5a). Notably, the vinylic selectivity changed over
time and increased to 42:1 after 12 h.
Scheme 3. Heck products of cyclic dienes.
method),[14] followed by a second arylation through our
Heck procedure.
The 1,4-diarylcyclohexadiene products can be easily oxi-
dized to give substituted p-terphenyls in almost quantitative
yield (Scheme 3). Some synthetic p-terphenyls were used to
construct electronic devices,[15] and others exhibited very in-
teresting biological activity such as induction of apoptosis of
cancer cells.[16] To access these compounds, sequential cou-
plings of bifunctional reagents were often used.[17] Our short
sequence (Scheme 3) can avoid the use of bifunctional cou-
pling reagents, which sometimes require multiple-step prep-
aration.
Scheme 5. Stoichiometric insertion of cyclohexene into [(dppp)Pd(Ph)I]
in the presence of AgOTf.
Similar treatment of dppf complexes with AgOTf and
cyclohexene, however, only gave 8% combined yield of
three Heck isomers at 1208C (Scheme 5b). To our surprise,
PPh3 was formed in good yield (60%). This side reaction
was very fast even at RT. Presumably, the Pd–phenyl and
P(Ph)2 group underwent facile reductive elimination. Subse-
Mechanistic study—Bite-angle effect of bisphosphanes and
olefin insertion: During our search for an active catalyst, we
noticed a striking trend in catalytic activity and natural bite
angles of the bisphosphanes (Table 1). For instance, in the
presence of dppp (natural bite angle of dppp: 918), the yield
of the Heck product was 93%. When other ligands such as
dppe (868) and dppf (998) were used, very poor yields result-
ed. We were intrigued to find at which step the dppe and
dppf catalysts had problems in the catalytic cycle.
0
+
À
quent reinsertion of (L)Pd into the Fc [P(Ph)3] bond gave
PPh3.
Treatment of the dppe complex (Scheme 5c) led to slow
formation of three Heck isomers in 10% combined yield at
1208C. In this case, neither PPh3 nor other organic deriva-
tives were detected by GC. It is possible that relatively fast
We first examined the step of oxidative addition. A model
aryl triflate was stirred at different temperatures in the pres-
ence of a bisphosphane and [(tmeda)Pd(Me)2] (tmeda=
À
reductive elimination between Pd phenyl and P(Ph)2 group
N,N,N’,N’-tetramethylethylenediamine). The latter is
a
occurred, but no subsequent reinsertion of Pd0 into the
+
known Pd0 precursor (Scheme 4). To our surprise, oxidative
addition of dppe and dppf complexes occurred at 808C, but
that of the dppp complex actually needed a higher tempera-
ture (1208C)! The main organic product in all three reac-
C [P(Ph)3] bond took place to produce PPh3.
À
We also conducted DFT calculations on the cyclohexene
À
insertion into the Pd phenyl bond in the cationic complexes
of three bisphosphanes above. We found that in the main
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J. (S.) Zhou et al.
pathway, the insertion barriers for the three complexes were
quite similar (ꢀ16 kcalmolÀ1).
In conclusion, dppf and dppe catalysts failed to catalyze
the insertion of cyclic olefins because of other side reactions,
which were faster than olefin insertion.
Reaction pathway: Next, we added 3-phenylcyclohexene
(1 equiv; >99% isomeric purity) to an active Heck reaction
of an aryl triflate to probe product isomerization (Table 4).
From the active Heck reaction, vinylic selectivity kept
changing over the first 6 h. After the first 2 h, the conjugat-
ed isomer became predominant. For example, the selectivity
was 1:7 after 0.5 h, but improved to 16:1 after 2 h.
Table 4. Isomerization of added 3-phenylcycohexene in an active Heck
reaction.
Figure 5. Reaction pathway leading to conjugated isomers of Heck
reaction.
This can also help to explain why the Heck reaction
needed a weak base, Li2CO3, and why many other bases
failed (Table 2). To ensure fast isomerization of products,
[(dppp)Pd(H)]+ must exist in an appreciable concentra-
tion.[18] A strong base will quickly remove the hydride spe-
cies and prevent product isomerization. On the other hand,
a relatively weak base can establish an acid–base equilibri-
um between the Heck catalyst (dppp)Pd0 and the isomeriza-
tion catalyst [(dppp)Pd(H)]+.
Time [h]
Yield [%]
Selectivity a
Selectivity b
0
0.5
1
1.5
2
6
18
48
0
5
7
–
1:7
1:2
<1:100
1:3
1.4:1
17:1
25:1
25:1
25:1
25:1
9
5:1
22
27
46
89
16:1
25:1
26:1
26:1
Conclusion
We have realized new selectivity in a Heck reaction that
gave arylation at the vinylic position of cyclic olefins. In
most cases, the isomeric purity of products was >95%. This
new method can replace some cross-coupling procedures
that need to use cycloalkenyl halides or metallic reagents.
Our mechanistic study revealed that the desired products
were formed by isomerization of initial Heck isomers. Thus,
a special set of conditions must be used to ensure the palla-
dium catalyst can exist in two states under one condition:
(dppp)Pd0 for the Heck catalytic cycle and [(dppp)Pd(H)]+
for product isomerization. Extension of the scope to aryl
halides is ongoing.
In the same pot, isomerization of added 3-phenylcyclo-
hexene was almost complete after the first 2 h and gave
vinylic selectivity of 25:1 (Table 4). A trace amount of an-
other isomer, 4-phenylcyclohexene, was also detected. The
result of the added olefin indicated that the isomerization
was a bimolecular event. It was catalyzed by the hydride
catalyst [(dppp)Pd(H)]+, which can fully dissociate from
olefins.
Therefore, the Heck reaction produced nonconjugated
isomer 3-arylcyclohexene first (Figure 5). After olefin inser-
tion, the first alkyl–Pd intermediate has the benzylic hydro-
gen in a position anti to the Pd center, which cannot under-
go fast elimination to give 1-arylcyclohexene directly. Thus,
3-phenylcyclohexene undergoes Pd–hydride-catalyzed iso-
merization to eventually give 1-arylcyclohexene.
Experimental Section
Typical procedure: In an argon-filled glovebox, a dry 10 mL Schlenk tube
that contained a magnetic stirrer bar was charged with [PdACHTUNGTRENNUNG(hfacac)2]
Palladium hydride and choice of solvent and base: The un-
derstanding of the essential role of [(dppp)Pd(H)]+ catalyst
can help to explain some empirical observations. During cat-
alyst discovery, we noticed that high selectivity was obtained
only in some ether solvents such as veratrole and 1,2-di-
(10 mg, 0.02 mmol), dppp (12 mg, 0.03 mmol), and dry veratrole
(2.5 mL). After stirring at RT for 10 min, phenyl triflate (113 mg,
0.5 mmol), cyclohexene (82 mg, 1.0 mmol), and Li2CO3 (74 mg, 1.0 mmol)
were added sequentially. The Schlenk tube was capped tightly and the
mixture was heated with vigorous stirring in an oil bath at 1208C for
48 h. The product was directly purified by flash chromatography
(hexane) as a colorless oil (75 mg, 95%). The conjugated selectivity in
the reaction mixture was determined to be 20:1 by GC. Similar results
ACHTUNGTRENNUNGmethoxyethane (Table 3). The ether solvents might play an
active role in coordinating to [(dppp)Pd(H)]+ and shuttling
it between olefin isomers for product isomerization.
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Vinylic Selectivity
FULL PAPER
were obtained using a Schlenk manifold and standard synthetic opera-
tion.
1-Phenylcyclohexene: 1H NMR (400 MHz, CDCl3): d=7.37 (d, J=
7.6 Hz, 2H), 7.31–7.27 (m, 2H), 7.22–7.18 (m, 1H), 6.12–6.10 (m, 1H),
2.42–2.39 (m, 2H), 2.23–2.18 (m, 2H), 1.81–1.75 (m, 2H), 1.68–1.62 ppm
(m, 2H); 13C NMR (100 MHz, CDCl3): d=142.7, 136.6, 128.2, 126.5,
[1] For reviews, see: a) R. F. Heck, Acc. Chem. Res. 1979, 12, 146;
b) I. P. Beletskaya, A. V. Cheprakov, Chem. Rev. 2000, 100, 3009;
c) K. C. Nicolaou, P. G. Bulger, D. Sarlah, Angew. Chem. 2005, 117,
4516; Angew. Chem. Int. Ed. 2005, 44, 4442; d) S. Brꢁse, A. de Mei-
jere in Metal-Catalyzed Cross-coupling Reactions (Eds.: A. de Mei-
jere, F. Diederich), Wiley-VCH, Weinheim, 2004, pp. 217; e) G.
Zeni, R. C. Larock, Chem. Rev. 2006, 106, 4644.
124.9, 124.7, 27.4, 25.9, 23.1, 22.2 ppm; GCMS (EI): m/z calcd for C12H14
:
158.2; found: 158.1.
[2] For examples, see: a) C. G. Hartung, K. Kçhler, M. Beller, Org.
Lett. 1999, 1, 709; b) L. Djakovitch, M. Wagner, C. G. Hartung, M.
Beller, K. Koehler, J. Mol. Catal. A: Chem. 2004, 219, 121; c) R. C.
Larock, B. E. Baker, Tetrahedron Lett. 1988, 29, 905; d) M. Ohff, A.
Ohff, D. Milstein, Chem. Commun. 1999, 357; e) O. Loiseleur, M.
Hayashi, N. Schmees, A. Pfaltz, Synthesis 1997, 1338; f) K. Kikuka-
wa, K. Nagira, F. Wada, T. Matsuda, Tetrahedron 1981, 37, 31; g) S.
Brꢁse, M. Schroen, Angew. Chem. 1999, 111, 1139; Angew. Chem.
Int. Ed. 1999, 38, 1071.
[3] For reviews on asymmetric Heck reaction of cyclic olefins, see: a) O.
Loiseleur, M. Hayashi, M. Keenan, N. Schmees, A. Pfaltz, J. Orga-
nomet. Chem. 1999, 576, 16; b) L. F. Tietze, H. Ila, H. P. Bell, Chem.
Rev. 2004, 104, 3453; c) D. McCartney, P. J. Guiry, Chem. Soc. Rev.
2011, 40, 5122.
1-(p-Cyano-m-trifluoromethylphenyl)cyclohexene: In an argon-filled
glovebox, [Pd(hfacac)2] (10 mol%, 0.05 mmol, 26 mg), dppp (15 mol%,
ACHTUNGTRENNUNG
0.075 mmol, 31 mg), and dry veratrole (2.5 mL) were added to a dry
10 mL Schlenk tube that contained a magnetic stirrer bar. After stirring
at RT for 10 min, p-cyano-m-trifluoromethylphenyl triflate (160 mg,
0.5 mmol), PhNHMe (1.0 mmol, 107 mg), and cyclohexene (2.5 mmol,
205 mg) were added sequentially. The Schlenk tube was capped tightly
and the mixture was heated with vigorous stirring in an oil bath at 1208C
for 72 h. The product was directly purified by flash chromatography (1:10
ethyl acetate/hexane) as a colorless oil (121 mg, 96%). The conjugated
selectivity in the reaction mixture was determined to be 24:1 by GC. Use
of 4% Pd catalyst and Li2CO3 (2 equiv) led to poor conjugated selectivi-
ty. 1H NMR (400 MHz, CDCl3): d=7.75 (m, 2H), 7.64–7.62 (dd, J=8.1,
1.6 Hz, 1H), 6.38–6.35 (m, 1H), 2.43–2.38 (m, 2H), 2.31–2.25 (m, 2H),
1.85–1.79 ppm (m, 2H), 1.72–1.66 (m, 2H); 13C NMR (100 MHz, CDCl3):
[4] R. J. Phipps, L. McMurray, S. Ritter, H. A. Duong, M. J. Gaunt, J.
Am. Chem. Soc. 2012, 134, 10773.
[5] E. Artuso, M. Barbero, I. Degani, S. Dughera, R. Fochi, Tetrahedron
2006, 62, 3146.
d-147.4, 134.7, 134.5, 132.7 (q, J
(C,F)=4.7 Hz), 122.6 (q, J
ACHTUNGTRENN(UNG C,F)=32.3 Hz), 130.4, 128.0, 123.0 (q,
J
N
(C,F)=273.8 Hz), 115.9, 107.2, 26.9, 26.0,
22.6, 21.6 ppm; 19F NMR (376 MHz, CDCl3): d=À61.95 ppm; GCMS
(EI): m/z calcd for C14H12F3N: 251.1; found: 251.1.
[6] For examples, see: a) T. Nishimata, Y. Sato, M. Mori, J. Org. Chem.
2004, 69, 1837; b) L. V. White, B. D. Schwartz, M. G. Banwell, A. C.
Willis, J. Org. Chem. 2011, 76, 6250; c) M. G. Banwell, J. E. Harvey,
D. C. R. Hockless, A. W. Wu, J. Org. Chem. 2000, 65, 4241; d) H. Ta-
nimoto, R. Saito, N. Chida, Tetrahedron Lett. 2008, 49, 358.
[7] For examples, see: a) L. K. Thalꢂn, D. Zhao, J.-B. Sortais, J. Paet-
zold, C. Hoben, J.-E. Bꢁckvall, Chem. Eur. J. 2009, 15, 3403;
b) D. D. Dixon, D. Sethumadhavan, T. Benneche, A. R. Banaag,
M. A. Tius, G. A. Thakur, A. Bowman, J. T. Wood, A. Makriyannis,
J. Med. Chem. 2010, 53, 5656; c) A. Yanagisawa, K. Nishimura, K.
Ando, T. Nezu, A. Maki, S. Kato, W. Tamaki, E. Imai, S.-i. Mohri,
Org. Process Res. Dev. 2010, 14, 1182; d) N. Handler, G. Brunhofer,
C. Studenik, K. Leisser, W. Jaeger, S. Parth, T. Erker, Bioorg. Med.
Chem. 2007, 15, 6109.
1-(m-Anisyl)-4-(p-tert-butylphenyl)cyclohexa-1,3-diene: In an argon-
filled glovebox, [PdACHTUNGTRENNUNG(hfacac)2] (10 mg, 0.02 mmol), dppp (12 mg,
0.03 mmol), and dry veratrole (2.5 mL) were added to a dry 10 mL
Schlenk tube that contained a magnetic stirrer bar. After stirring at RT
for 10 min, p-tert-butylphenyl triflate (0.5 mmol, 141 mg), 1-(m-anisyl)-
ACHTUNGTRENNUNGcyclohexadiene (0.75 mmol, 140 mg), and nBu2NMe (1.0 mmol, 143 mg)
were added sequentially. The Schlenk tube was capped tightly and the
mixture was heated with vigorous stirring in an oil bath at 1208C for
36 h. The product was directly purified by flash chromatography (1:10
ethyl acetate/hexane) as a white solid (143 mg, 90%). The compound
was prone to oxidation by air during chromatography. 1H NMR
(400 MHz, CDCl3): d=7.45 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.0 Hz, 2H),
7.28–7.23 (m, 1H), 7.10 (d, J=7.6 Hz, 1H), 7.03 (s, 1H), 6.81–6.78 (m,
1H), 6.53–6.49 (m, 2H), 3.83 (s, 3H), 2.75 (pseudosinglet, 4H), 1.33 ppm
(s, 9H); 13C NMR (100 MHz, CDCl3): d=159.8, 150.3, 142.4, 137.7, 136.1,
135.4, 129.4, 125.4, 124.7, 122.1, 120.9, 117.6, 112.4, 110.6, 55.3, 34.6, 31.3,
26.3, 26.1 ppm; GCMS (EI): m/z calcd for C23H26O: 318.2; found: 318.2.
[8] For examples, see: a) V. J. Olsson, K. J. Szabꢃ, Angew. Chem. 2007,
119, 7015; Angew. Chem. Int. Ed. 2007, 46, 6891; b) A. Kondoh, T. F.
Jamison, Chem. Commun. 2010, 46, 907; c) A. F. Littke, C. Dai,
G. C. Fu, J. Am. Chem. Soc. 2000, 122, 4020.
1-(m-Anisyl)-4-(p-tert-butylphenyl)benzene: Under argon, 1-(m-anisyl)-
4-(p-tert-butylphenyl)cyclohexa-1,3-diene (0.50 mmol, 159 mg), CuCl2
(1.0 mmol, 134 mg), and dry benzene (2 mL) were added to a dry 10 mL
Schlenk tube that contained a magnetic stirrer bar. The reaction mixture
was stirred at 1008C for 5 h until completion. The product was purified
by flash chromatography (1:10 ethyl acetate/hexane) as a white solid
(149 mg, 94%). 1H NMR (400 MHz, CDCl3): d=7.67–7.66 (m, 4H), 7.59
(d, J=8.4 Hz, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.37 (pseudotriplet, J=
7.9 Hz, 1H), 7.24–7.22 (m, 1H), 7.17 (pseudotriplet, J=2.0 Hz, 1H),
6.92–6.89 (m, 1H), 3.88 (s, 3H), 1.38 ppm (s, 9H); 13C NMR (100 MHz,
CDCl3): d=160.0, 150.4, 142.3, 140.2, 139.7, 137.8, 129.8, 127.5, 127.3,
126.9, 126.7, 125.8, 119.6, 112.8, 55.3, 34.6, 31.4 ppm; GCMS (EI): m/z
calcd for C23H24O: 316.2; found: 316.2.
[9] We recently reported an a-selective Heck reaction of both aliphatic
olefins and substituted styrenes by using a Pd/DNPF catalyst: a) L.
Qin, X. Ren, Y. Lu, Y. Li, J. Zhou, Angew. Chem. Int. Ed. 2012, 51,
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2013, 19, 3504—3511.
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sow), Z. Freixa, P. W. N. M. van Leeuwen, Chem. Soc. Rev. 2009, 38,
1099; b) Z. Freixa, P. W. N. M. van Leeuwen, Dalton Trans. 2003,
1890.
[11] C. Amatore, A. Jutand, Coord. Chem. Rev. 1998, 178–180, 511.
[12] For examples of Pd-catalyzed reduction of aryl triflates by trialkyl-
AHCTUNGERTGaNNUN mines, see: W. Cabri, I. Candiani, S. DeBernardinis, F. Francalanci,
S. Penco, R. Santo, J. Org. Chem. 1991, 56, 5796.
[13] J. J. Li, D. M. Iula, M. N. Nguyen, L.-Y. Hu, D. Dettling, T. R. John-
son, D. Y. Du, V. Shanmugasundaram, J. A. Van Camp, Z. Wang,
W. G. Harter, W.-S. Yue, M. L. Boys, K. J. Wade, E. M. Drummond,
B. M. Samas, B. A. Lefker, G. S. Hoge, M. J. Lovdahl, J. Asbill, M.
Carroll, M. A. Meade, S. M. Ciotti, T. Krieger-Burke, J. Med. Chem.
2008, 51, 7010.
Acknowledgements
We thank the Singapore National Research Foundation (NRF-RF2008-
10) and Nanyang Technological University for financial support, and
Johnson-Matthey for a gift of palladium.
[14] J. Barluenga, M. Tomꢄs-Gamasa, F. Aznar, C. Valdꢂs, Adv. Synth.
Catal. 2010, 352, 3235.
[15] For examples, see: a) F. Maya, J. M. Tour, Tetrahedron 2004, 60, 81;
b) M. Modjewski, S. V. Lindeman, R. Rathore, Org. Lett. 2009, 11,
4656.
Chem. Eur. J. 2013, 19, 6014 – 6020
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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J. (S.) Zhou et al.
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Simoni, S. Grimaudo, C. Di, V. Abbadessa, N. Gebbia, M. Tolomeo,
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[18] For a recent example of Pd-hydride-catalyzed isomerization of ole-
fins, see: D. Gauthier, A. T. Lindhardt, E. P. K. Olsen, J. Overgaard,
T. Skrydstrup, J. Am. Chem. Soc. 2010, 132, 7998.
[17] For some examples of sequential couplings to make para-terphenyls,
see: a) J. M. Antelo Miguez, L. A. Adrio, A. Sousa-Pedrares, J. M.
Received: December 12, 2012
Published online: March 7, 2013
6020
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ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2013, 19, 6014 – 6020