Palladium-Catalyzed Three-Component coupling reactions: 1,1 -Difunctionalization of activated alkenes

Article abstract of DOI:10.1002/ejoc.200801245

A three-component coupling reaction was developed to access 3,3-oxyarylpropionate derivatives. Each of the three reaction components can be varied, allowing the modular synthesis of a range of important chiral building blocks. Wiley-VCH Verlag GmbH & Co, KGaA.

Full text of DOI:10.1002/ejoc.200801245

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200801245
Palladium-Catalyzed Three-Component Coupling Reactions:
1,1-Difunctionalization of Activated Alkenes
Arantxa Rodriguez[a] and Wesley J. Moran*[a]
Keywords: Palladium / C–C coupling / C–H activation / Iodine / Heck reaction
A three-component coupling reaction was developed to ac-
cess 3,3-oxyarylpropionate derivatives. Each of the three re-
action components can be varied, allowing the modular syn-
thesis of a range of important chiral building blocks.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
details a related transformation that does not require the
use of stoichiometric organometallic reagents, as arenes are
coupled directly.
Introduction
Palladium-catalyzed oxidative functionalization of ole-
fins is a powerful technique for synthesis;[1] transformations
such as 1,2-diamination,[2] 1,2-aminooxygenation,[3] 1,2-di-
carbonylation[4] and 1,2-dioxygenation[5] of alkenes have
been reported. We were intrigued by the oxidative Heck-
type coupling reactions of benzenes with olefins[6] and won-
dered if the Heck intermediates could be captured and func-
tionalized (Scheme 1). It is known that the β-hydride elimi-
nation step is very fast and reversible and this could lead to
a relatively long-lived benzylic palladium(II) intermediate,
which could be functionalized.[7] Such three-component
coupling reactions are of interest because of the potential
for reduction in the number of synthetic steps required to
make target molecules.[8] Indeed, similar reactivity was
demonstrated by Yoshida and coworkers and, more re-
cently, by Sanford and coworkers, whereby aryl stannanes
were coupled with terminal olefins with concomitant for-
mation of a C–Cl bond under Pd catalysis.[9] This report
Results and Discussion
Our initial studies began with the Pd-catalyzed reaction
of benzene with methyl acrylate in the presence of iodo-
benzene diacetate and acetic acid open to air (Scheme 2).
We were pleased to discover that under our initial condi-
tions two intriguing products were obtained in a 1:1 ratio.
The first product was desired 1,1-aryloxygenated com-
pound 1 and the second was 1,2-dioxygenated species 2. We
set out to optimize the formation of 1 and to determine the
scope of the transformation.
Scheme 2. Oxidative functionalization of methyl acrylate.
Removal of acetic acid from the reaction mixture led to
complete consumption of the acrylate and formation of
product 1 in a modest 31% yield with no other isolable
compounds identified (Table 1, Entry 1). Performing the re-
action in acetic acid with one equivalent of NaOAc and no
benzene led to the selective formation of product 2 in an
excellent 95% yield (Table 1, Entry 2). Running the reaction
in acetic anhydride led to no reaction (Table 1, Entry 3),
whereas the use of DMF or MeCN as solvent provided the
Heck product methyl cinnamate (3) in 85 and 14%, respec-
tively (Table 1, Entries 4 and 5). In the presence of
Pd(acac)2 the reaction was somewhat more efficient, provid-
ing a 38% yield of 1 (Table 1, Entry 6). Utilizing 3-NO2-
C6H4I(OAc)2 as oxidant instead of PhI(OAc)2 led to an ap-
preciable increase in yield, providing a 63% isolated yield
Scheme 1. Heck reaction mechanism and proposed capture and
functionalization of Heck intermediate.
[a] Department of Chemical & Biological Sciences, University of
Huddersfield
Huddersfield HD1 3DH, UK
Fax: +44-1484-472182
E-mail: w.j.moran@hud.ac.uk
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2009, 1313–1316
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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A. Rodriguez, W. J. Moran
SHORT COMMUNICATION
of 1 (Table 1, Entry 7). The cationic Pd source Pd(MeCN)4- Table 2. Substrate scope for the three-component coupling reac-
tion.
(BF4)2 provided a mixture of products 1 and 2 (Table 1,
Entry 8). The reaction did not occur with the use of other
late-transition-metal sources such as PtCl2 (Table 1, En-
try 9) or with Lewis acids.[10] Running the reaction without
either a Pd source or the iodinane oxidant led to no conver-
sion to product 1 (or 2 or 3).
Entry
Arene
R
RЈ
Yield[a] / %
1
2
3
4
5
6
7
8
benzene
toluene
p-xylene
Me
Me
Me
Me
Me
tBu
Bn
Me
nBu
tBu
Et
H
H
H
H
H
H
H
Me
63
72[b]
25
bromobenzene
chlorobenzene
benzene
46[c]
55[d]
65
Table 1. Optimization studies for Pd-catalyzed coupling reactions.[a]
benzene
benzene
benzene
benzene
benzene
benzene
43
61[e,f]
67[e,f]
57[f]
51[f]
20[e,f]
Entry
Catalyst
Solvent
Oxidant
Yield[b] / % (1/2/3)
9
Me
Me
Et
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(acac)2
Pd(acac)2
PhH
AcOH
Ac2O
DMF
MeCN
PhH
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
31:0:0
0:95:0
0:0:0
0:0:85
0:0:14
38:0:0
63:0:5
30:30:0
0:0:0
10
11
12
2[c]
3
nBu
CH2CO2nBu
4[d]
5
6
7
8
[a] Isolated yields. [b] o/m/p, 1:4:4. [c] o/m/p, 1:2.8:1.6. [d] o/m/p,
1:2.2:2.1. [e] PhI(OAc)2 was used in place of 3-NO2C6H4I(OAc)2.
[f] Mixture of diastereomers (generally less than 2.5:1).
PhI(OAc)2
PhH
3-NO2C6H4I(OAc)2
PhI(OAc)2
Pd(MeCN)4(BF4)2 PhH
PtCl2 PhH
9
PhI(OAc)2
[a] Methyl acrylate, benzene, catalyst (5 mol-%), oxidant (2 equiv.),
solvent, air. [b] Isolated yields. [c] No benzene, NaOAc (1 equiv.).
[d] Reaction run at 153 °C.
The third component of the coupling reaction, that is,
the ester, can also be varied. 3-NO2C6H4I(O2CBn)2 pro-
vided the corresponding ester upon reaction with methyl
acrylate, and 3-NO2C6H4I(O2CCy)2 furnished the cyclo-
hexyl ester (Scheme 4).[14] Importantly, only IIII dicarboxyl-
ates were found to be successful in this process. For exam-
ple, iodobenzene dichloride (PhICl2) leads only to the 1,2-
dichlorinated product with no benzene incorporation,
whereas iodosobenzene (PhIO) and [hydroxy(tosyloxy)-
iodo]benzene [PhI(OH)OTs] lead to no conversion of acryl-
ate.
Under the optimized conditions (i.e. those in Table 1, En-
try 7) a range of different arenes and acrylate derivatives
were found to be successful in the reaction (Scheme 3,
Table 2).[11] Toluene reacted efficiently with methyl acrylate
to provide the desired product as a mixture of regioisomers
(Table 2, Entry 2). p-Xylene was found to react sluggishly
with methyl acrylate to provide only a modest yield of cou-
pled product; possibly palladation is hindered by sterics
(Table 2, Entry 3). Bromobenzene and chlorobenzene re-
acted smoothly to generate the aldol-type products in 46
and 55% yield, respectively (Table 2, Entries 4 and 5). tert-
Butyl acrylate was found to react with benzene with similar
efficiency to that of methyl acrylate, providing a 65% yield
(Table 2, Entry 6). Benzyl acrylate was a less-effective sub-
strate, as the Heck product was isolated alongside the aldol
compound (Table 2, Entry 7). The methacrylates (Table 2,
Entries 8–10) were converted into product more efficiently
by the less-reactive oxidant PhI(OAc)2 than were the acryl-
ates, furnishing up to 67% yield of the aldol-type prod-
ucts.[12] Increasing the size of the alkene α-substituent from
a methyl to an ethyl group resulted in a slight drop in yield,
providing a reasonable 51% yield of product (Table 2, En-
try 11). Dibutyl itaconate was somewhat less successful in
the reaction, supplying a modest 20% yield with PhI-
(OAc)2 as oxidant (Table 2, Entry 12), whereas with the 3-
nitrobenzene-derived oxidant only the Heck coupled prod-
uct was produced. Interestingly, reaction of methyl 2-phen-
ylacrylate furnished none of the coupled products but in-
stead resulted in epoxidation of the alkene.[13]
Scheme 4. (a) Use of a benzoic acid derived iodinane. (b) Use of a
cyclohexane carboxylic acid derived iodinane.
The mechanism of this transformation is proposed to
proceed through electrophilic attack on PdII by the arene
followed by Heck-type addition to the alkene in a similar
fashion to that proposed by Fujiwara.[6f] This Heck inter-
mediate then undergoes β-hydride elimination, and the re-
sulting Pd-H species readds to place the Pd at the benzylic
site. This elimination and readdition of Pd-H is very fast
and reversible and is a common process in palladium chem-
istry.[7] Oxidation of PdII to PdIV by the hypervalent iodine
reagent followed by displacement with acetate with inver-
sion of configuration or reductive elimination could then
provide the observed products (Scheme 5).[15,16] The use of
Dess–Martin periodinane as oxidant resulted in an insepa-
Scheme 3. Reaction scope under optimized conditions.
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Eur. J. Org. Chem. 2009, 1313–1316

Palladium-Catalyzed Three-Component Coupling Reactions
rable 1:1.5 ratio of the AcO– and 2-IC6H4CO2 incorpo-
–
Experimental Section
rated products. This suggests that hypervalent iodine plays
General Procedure:
A flask was charged with an alkene
a key role in the final C–O bond formation.
(0.58 mmol), Pd(acac)2 (9 mg, 0.029 mmol), the iodinane
(1.45 mmol) and an arene (1 mL) and heated at reflux for 12 h open
to air. The volatiles were removed in vacuo, and the mixture was
purified by flash chromatography [silica gel; petroleum ether (40–
60)/EtOAc, 20:1] to give the corresponding product.
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental procedures and characterization data for all
new compounds.
Acknowledgments
Scheme 5. Postulated mechanism for three-component coupling.
We thank the University of Huddersfield for funding.
In order to rule out the possibility of a simple conjugate
addition reaction of acetic acid or acetate to the Heck inter-
mediate, ethyl cinnamate was subjected to a range of condi-
tions (Scheme 6, Table 3). Heating ethyl cinnamate with five
equivalents of either NaOAc or AcOH in benzene resulted
in complete recovery of the starting material (Table 3, En-
tries 1 and 2). Likewise, Pd(acac)2 did not catalyze the con-
jugate addition of either NaOAc or AcOH (Table 3, En-
tries 3 and 4).[17] Interestingly, subjecting ethyl cinnamate to
the coupling reaction conditions also led to complete recov-
ery of the starting material (Table 3, Entry 5). These results
clearly indicate that conjugate addition to the cinnamate
intermediate does not occur, which therefore supports the
mechanism proposed.
[1] For an excellent review on PdII-catalyzed reactions involving
oxidants, see: E. M. Beccalli, G. Broggini, M. Martinelli, S.
Sottocornola, Chem. Rev. 2007, 107, 5318.
[2] a) K. Muniz, C. H. Hovelmann, J. Streuff, J. Am. Chem. Soc.
2008, 130, 763; b) J. Streuff, C. H. Hovelmann, M. Nieger, K.
Muniz, J. Am. Chem. Soc. 2005, 127, 14586.
[3] a) L. V. Desai, M. S. Sanford, Angew. Chem. 2007, 119, 5839;
Angew. Chem. Int. Ed. 2007, 46, 5737; b) G. Liu, S. S. Stahl, J.
Am. Chem. Soc. 2006, 128, 7179; c) E. J. Alexanian, C. Lee,
E. J. Sorensen, J. Am. Chem. Soc. 2005, 127, 7690.
[4] M. Hayashi, H. Takezaki, Y. Hashimoto, K. Takaoki, K.
Saigo, Tetrahedron Lett. 1998, 39, 7529.
[5] a) Y. Li, D. Song, V. M. Dong, J. Am. Chem. Soc. 2008, 130,
2962; b) Y. Zhang, M. S. Sigman, J. Am. Chem. Soc. 2007, 129,
3076.
[6] a) M. Tani, S. Sakaguchi, Y. Ishii, J. Org. Chem. 2004, 69, 1221;
b) T. Yokota, M. Tani, S. Sakaguchi, Y. Ishii, J. Am. Chem.
Soc. 2003, 125, 1476; c) M. Dams, D. E. De Vos, S. Celen, P. A.
Jacobs, Angew. Chem. Int. Ed. 2003, 42, 3512; Angew. Chem.
2003, 115, 3636; d) M. D. K. Boele, G. P. F. van Strijdonck,
A. H. M. de Vries, P. C. J. Kamer, J. G. de Vries, P. W. N. M.
van Leeuwen, J. Am. Chem. Soc. 2002, 124, 1586; e) C. Jia, T.
Kitamura, Y. Fujiwara, Acc. Chem. Res. 2001, 34, 633; f) C.
Jia, W. Lu, T. Kitamura, Y. Fujiwara, Org. Lett. 1999, 1, 2097;
g) Y. Fujiwara, I. Moritani, S. Danno, R. Asano, S. Teranishi,
J. Am. Chem. Soc. 1969, 91, 7166.
Scheme 6. Conjugate addition to cinnamate?
Table 3. Mechanistic investigations.
[7] M. Portnoy, D. Milstein, Organometallics 1994, 13, 600.
[8] For examples of sequential coupling reactions involving C–H
functionalization, see: a) B.-J. Li, S.-L. Tian, Z. Fang, Z.-J. Shi,
Angew. Chem. Int. Ed. 2008, 47, 1115; Angew. Chem. 2008, 120,
1131; b) L. Ackermann, A. Althammer, Angew. Chem. Int. Ed.
2007, 46, 1627; Angew. Chem. 2007, 119, 1652; c) C.-G. Dong,
Q.-S. Hu, Angew. Chem. Int. Ed. 2006, 45, 2289; Angew. Chem.
2006, 118, 2347.
Entry Conditions
Conversion / %
1
2
3
NaOAc (5 equiv.), PhH, 80 °C, 15 h
0
0
0
AcOH (5 equiv.), PhH, 80 °C, 15 h
Pd(acac)2 (5 mol-%), NaOAc (2 equiv.), PhH,
80 °C, 15 h
4
5
Pd(acac)2 (5 mol-%), AcOH (2 equiv.), PhH,
80 °C, 15 h
Pd(acac)2 (5 mol-%), PhI(OAc)2 (2 equiv.),
PhH, 80 °C, 15 h
0
0
[9] a) Y. Tamaru, M. Hojo, S.-I. Kawamura, Z.-I. Yoshida, J. Org.
Chem. 1986, 51, 4089; b) D. Kalyani, M. S. Sanford, J. Am.
Chem. Soc. 2008, 130, 2150.
[10] The reaction was also unsuccessful with AuCl3, (Ph3P)2NiCl2,
CuI and BF3·OEt2.
[11] The reactions can be performed with just one equivalent of
oxidant; however, sometimes they stall; the addition of an ex-
cess amount of oxidant prevents this from happening.
[12] Interestingly, 3-NO2C6H4I(OAc)2 provided no improvement in
yields for these substrates.
[13] The enantioselective organocatalytic epoxidation of α,β-unsat-
urated aldehydes with the use of hypervalent iodine reagents
has recently been reported: S. Lee, D. W. C. MacMillan, Tetra-
hedron 2006, 62, 11413.
[14] P. J. Stang, M. Boehshar, H. Wingert, T. Kitamura, J. Am.
Chem. Soc. 1988, 110, 3272.
[15] A number of other mechanisms could be proposed; however,
experimentation appears to rule out a Heck-type process fol-
Conclusions
In summary, we developed a Pd-catalyzed three-compo-
nent coupling reaction to access aldol-type products. This
process uses cheap, readily available starting materials and
is straightforward to carry out. We have shown that each of
the three components of the reaction can be varied and that
the reaction efficiency is dependent on the oxidant utilized.
Current work is focused on expanding the scope of this
transformation and delineating the mechanism.
Eur. J. Org. Chem. 2009, 1313–1316
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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A. Rodriguez, W. J. Moran
SHORT COMMUNICATION
lowed by conjugate addition of acetate (all attempts to add
acetate to ethyl cinnamate were unsuccessful), and the addition
of radical inhibitors does not affect the outcome of the reac-
tion, ruling out a radical pathway.
X. Tong, M. Beller, M. K. Tse, J. Am. Chem. Soc. 2007, 129,
4906.
[17] For the Pd-catalyzed conjugate addition of acetic acid to en-
ones, see: T. Hosokawa, T. Shinohara, Y. Ooka, S.-I. Mura-
hashi, Chem. Lett. 1989, 2001.
[16] Displacement of PdIV by acetate with inversion of configura-
tion has been proposed: a) L. L. Welbes, T. W. Lyons, K. A.
Cychosz, M. S. Sanford, J. Am. Chem. Soc. 2007, 129, 5836; b)
Received: December 16, 2008
Published Online: January 22, 2009
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Eur. J. Org. Chem. 2009, 1313–1316