Hydrogen-bonding-promoted oxidative addition and regioselective arylation of olefins with aryl chlorides

Article abstract of DOI:10.1021/ja1081926

The first, general, and highly efficient catalytic system that allows a wide range of activated and unactivated aryl chlorides to couple regioselectively with olefins has been developed. The Heck arylation reaction is likely to be controlled by the oxidative addition of ArCl to Pd(0). Hence, an electron-rich diphosphine, 4-MeO-dppp, was introduced to facilitate the catalysis. Solvent choice is critical, however; only sluggish arylation is observed in DMF or DMSO, whereas the reaction proceeds well in ethylene glycol at 0.1-1 mol % catalyst loadings, displaying excellent regioselectivity. Mechanistic evidence supports that the arylation is turnover-limited by the oxidative addition step and, most importantly, that the oxidative addition is accelerated by ethylene glycol, most likely via hydrogen bonding to the chloride at the transition state as shown by DFT calculations. Ethylene glycol thus plays a double role in the arylation, facilitating oxidative addition and promoting the subsequent dissociation of chloride from Pd(II) to give a cationic Pd(II)-olefin species, which is key to the regioselectivity observed.

Full text of DOI:10.1021/ja1081926

Published on Web 10/28/2010
Hydrogen-Bonding-Promoted Oxidative Addition and
Regioselective Arylation of Olefins with Aryl Chlorides
Jiwu Ruan, Jonathan A. Iggo, Neil G. Berry, and Jianliang Xiao*
Department of Chemistry, UniVersity of LiVerpool, LiVerpool L69 7ZD, U.K.
Received September 10, 2010; E-mail: j.xiao@liv.ac.uk
Abstract: The first, general, and highly efficient catalytic system that allows a wide range of activated and
unactivated aryl chlorides to couple regioselectively with olefins has been developed. The Heck arylation
reaction is likely to be controlled by the oxidative addition of ArCl to Pd(0). Hence, an electron-rich
diphosphine, 4-MeO-dppp, was introduced to facilitate the catalysis. Solvent choice is critical, however;
only sluggish arylation is observed in DMF or DMSO, whereas the reaction proceeds well in ethylene glycol
at 0.1-1 mol % catalyst loadings, displaying excellent regioselectivity. Mechanistic evidence supports that
the arylation is turnover-limited by the oxidative addition step and, most importantly, that the oxidative
addition is accelerated by ethylene glycol, most likely via hydrogen bonding to the chloride at the transition
state as shown by DFT calculations. Ethylene glycol thus plays a double role in the arylation, facilitating
oxidative addition and promoting the subsequent dissociation of chloride from Pd(II) to give a cationic
Pd(II)-olefin species, which is key to the regioselectivity observed.
include palladium complexes bearing electron-rich phosphines,3a,4
N-heterocyclic carbenes,5 palladacycles,5n,6 palladium pincer
Introduction
complexes,6k,7 and palladium nanoparticles.1c,8 However, these
catalysts can only effectively be applied to neutral or activated
olefins, such as styrene and acrylates. When used for electron-
The palladium-catalyzed Heck arylation of olefins with aryl
halides is one of the most important tools for constructing sp2
C-C bonds in synthetic chemistry1 and is probably one of the
most frequently applied Pd-catalyzed coupling reactions in the
fine chemical and pharmaceutical industries.2 In the vast
majority of reported Heck reactions, aryl bromides and iodides
are used as substrates, for which very good reactivities and
regioselectivities have been demonstrated in the last three
decades or so.1,2
(3) For reviews of Heck reaction of aryl chlorides, see: (a) Fu, G. C. Acc.
Chem. Res. 2008, 41, 1555. (b) Bedford, R. B.; Cazin, C. S. J.; Holder,
D. Coord. Chem. ReV. 2004, 248, 2283. (c) Littke, A. F.; Fu, G. C.
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Aryl chlorides are the cheapest and most widely available
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9
10.1021/ja1081926  2010 American Chemical Society
J. AM. CHEM. SOC. 2010, 132, 16689–16699 16689

A R T I C L E S
Ruan et al.
Scheme 2. The Two Competing Pathways in the Heck Reaction
Scheme 1. Examples of Heck Arylation of Enol Ethers with Aryl
Chlorides in the Literature4a,8a,9,10
in Scheme 2.12,13 The neutral pathway (pathway A, Scheme 2)
produces the ꢀ product and features the dissociation of a neutral
ligand from PdII. In contrast, the ionic pathway (pathway B),
involving halide dissociation instead, yields the R product.
Considering the electrophilic nature of cationic PdII, pathway
B is expected to favor electron-rich olefins.14 Indeed, in
competition reactions involving both electron-rich and -deficient
olefins, the former preferentially undergoes arylation when the
reaction follows the ionic pathway.15,16 A modified mechanism
has recently been proposed by Amatore, Jutand, and co-workers,
who showed that the electron-rich isobutyl vinyl ether reacts
with [Pd(dppp)(Ph)X] (X ) I, OAc) via the cationic species,
[Pd(Ph)(dppp)(solvent)]+, affording both R and ꢀ products.17
Their kinetic study led to the suggestion that the succeeding
Pd-olefin intermediate, [Pd(Ph)(dppp)(olefin)]+, undergoes
reversible 1,2- as well as 2,1-insertion, resulting in R arylation
when the concentration of coordinating anions is low but ꢀ
product when the anion is abundant.17b
rich or deactivated olefins, such as enol ethers and enamides,
they are generally less active and, without exception, give rise
to a mixture of R- and ꢀ-arylated products, in which the ꢀ isomer
usually dominates (Scheme 1). In 2001, Fu first reported the
Pd-P(t-Bu)3 catalyzed Heck arylation of n-butyl vinyl ether
by 4-chloroacetophenone, affording a 91/9 mixture of ꢀ- and
R-arylated products in 82% yield.4a Using a Pd-HPAd2 (Ad )
adamantyl) catalyst, Studer and co-workers later obtained a
mixture of regioisomers having a ꢀ/R ratio of 74/26 in the
arylation with 4-chlorotoluene.9 In 2006, Larhed and co-workers
applied microwave heating to the arylation of n-butyl vinyl ether
with various aryl chlorides by Pd-P(t-Bu)3, obtaining mixtures
of ꢀ- and R-arylated products in moderate yields.10 More
recently, Calo` and Nacci et al. used Pd nanoparticles to catalyze
the arylation with chlorobenzene in ionic liquids, but a low yield
of 25% of a mixture of products was observed (Scheme 1).8a
In view of the importance of R-arylated products in chemical
and particularly bioactive compound synthesis,11 access to these
olefins in high yield from cheap aryl chlorides would be an
important extension of the Heck reaction.
The R regioselectivity along the ionic pathway is probably a
result of the electron-rich olefin being polarized upon coordina-
tion to the cationic Pd(II) center, which renders the R carbon
positively charged and hence more susceptible to attack by the
migrating aryl moiety, as highlighted by the resonance structures
shown in Scheme 3 for a vinyl ether.18 DFT calculations have
provided more insight into the mechanism19 and show that when
following pathway B, electron-rich olefins indeed tend to afford
the R-arylated olefin, and this is driven primarily by electrostatic
and frontier orbital interactions.19a Thereotical studies also
revealed how an electron-rich olefin is polarized by Pd(II). Thus,
2,3-dihydrofuran coordinates to a Pd(II)-P^N complex almost
The origin of regioselectivity in the Heck reaction may be
accounted for by two competing reaction pathways, as illustrated
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16690 J. AM. CHEM. SOC. VOL. 132, NO. 46, 2010

Heck Arylation of Olefins with Aryl Chlorides
A R T I C L E S
Scheme 3. Resonance Structures of the Cationic Pd(II)
High regioselectivity has also been observed by changing the
reaction medium. In the past few years, we have shown that R
regiocontrol in the coupling of aryl bromides with electron-
rich olefins can be readily achieved by using imidazolium ionic
liquids as solvents.15,27 Under these conditions, we believe that
the formation of the key cationic PdII species in pathway B is
favored, thus enhancing selectivity for the R product. Ionic
liquids are entirely composed of ions;28 hence, electrostatic
interactions would favor the generation of a PdII-olefin cation
and a halide anion (Scheme 2, pathway B). Consistent with this
view, Amatore and Jutand have shown that a high ionic strength
favors R arylation.17 This method, alongside those reported by
Hallberg and Larhed,29,30 Calo´,31 and Alper,32 enables a highly
regioselective Heck reaction without the use of halide scavengers
or triflates.33,34 However, none of these methods are known to
allow for efficient and selective R arylation of olefins with aryl
chlorides.
We recently reported that by using the Pd-dppp catalyst and
a hydrogen bond donor additive, such as [HNEt3][BF4], regi-
oselective R arylation of olefins with aryl bromides can be
effected in a common solvent, such as DMF.35 The hydrogen
bond donor is essential, probably promoting the dissociation of
bromide from [Pd(dppp)(Ph)Br] and thus the formation of the
cationic Pd-olefin intermediate in Scheme 2. We were delighted
to find that under these conditions, the benchmark electron-
rich olefin n-butyl vinyl ether can be R arylated, for the first
time, with aryl chlorides (Scheme 4a).35 A similar reaction of
aryl chlorides was also demonstrated in neat water by Larhed
and co-workers36 using an electron-rich alkyl diphosphine, 1,3-
bis(diisopropylphosphino)propane (dippp) (Scheme 4b).4g How-
ever, these two catalytic systems only work for a few activated
aryl chlorides, i.e., those bearing electon-withdrawing substit-
uents. For those that are unactivated, i.e., electron-neutral or
-rich, the catalysts were ineffective. The inefficiency of dppp
may be a result of its inability to promote the oxidiative addition
of ArCl to Pd(0), while that of dippp probably stems from the
formation of catalytically inactive [Pd(dippp)Cl2].4g,36 In addi-
Intermediate
exclusively through only one of the two olefinic carbons, the
C4 atom, supporting the representations in Scheme 3.20
Extensive studies have been carried out of how to control the
regioselectivity and promote R arylation.10,15,16,21-24 The work of
Hallberg and Larhed,21 Cabri,16,22 and other researchers23 revealed
that high R/ꢀ regioselectivity could be obtained under Pd-dppp
(dppp )1,3-bis(diphenylphosphino)propane) catalysis by employ-
ing aryl triflates or by adding stoichiometric silver or thallium salts
when aryl iodides and bromides are chosen. Silver and thallium
salts act as halide scavengers, thereby promoting pathway B.
Similarly, the lability of the Pd-OTf bond facilitates the formation
of the cationic PdII-olefin species, thus leading to regioselective
production of the branched product.25 It is also apparent from
Scheme 2 that a monodentate phosphine ligand would make
pathway A more likely, whereas a bidentante ligand such as dppp
would promote pathway B. These tactics have also been widely
exploited in effecting enantioselective Heck reactions, where the
ionic pathway is generally believed to give high enantio-
selectivities.1h,26
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J.; Este´vez, J. C.; Este´vez, R. J.; Castedo, L. Tetrahedron Lett. 2002,
43, 5141. (e) Ludwig, M.; Stro¨mberg, S.; Svensson, M.; Åkermark,
B. Organometallics 1999, 18, 970.
(24) For other examples of regioselective Heck reaction of electron-rich
olefins, see: (a) Calo`, V.; Nacci, A.; Monopoli, A.; Ferola, V. J. Org.
Chem. 2007, 72, 2596. (b) Fall, Y.; Berthiol, F.; Doucet, H.; Santelli,
M. Synthesis 2007, 1683. (c) Calo`, V.; Nacci, A.; Monopoli, A. Eur.
J. Org. Chem. 2006, 3791. (d) Svennebring, A.; Nilsson, P.; Larhed,
M. J. Org. Chem. 2004, 69, 3345. (e) Bouquillon, S.; Ganchegui, B.;
Estrine, B.; He´nin, F.; Muzart, J. J. Organomet. Chem. 2001, 634,
153.
(29) Vallin, K. S. A.; Emilsson, P.; Larhed, M.; Hallberg, A. J. Org. Chem.
2002, 67, 6243.
(30) The arylation can also be performed in a DMF-water mixture: Vallin,
K. S. A.; Larhed, M.; Hallberg, A. J. Org. Chem. 2001, 66, 4340.
This paper also shows that the regioselective Heck reaction is feasible
by using a mixture of DMF and MeOH.
(31) Calo´, V.; Nacci, A.; Monopoli, A.; Detomaso, A.; Iliade, P. Organo-
metallics 2003, 22, 4193.
(25) (a) Jutand, A. Eur. J. Inorg. Chem. 2003, 2017. (b) Brown, J. M.;
Hii, K. K. Angew. Chem., Int. Ed. 1996, 35, 657. (c) Jutand, A.;
Mosleh, A. Organometallics 1995, 14, 1810.
(32) Park, S. B.; Alper, H. Chem. Commun. 2004, 1306.
(33) For ꢀ arylation in ionic liquid, see ref 24c and references therein.
(34) Opposite regioselectivities have been observed when the reaction is
run in poly(ethylene glycol): Chandrasekhar, S.; Narsihmulu, Ch.;
Sultana, S. S.; Reddy, N. R. Org. Lett. 2002, 4, 4399.
(26) Intramolecular coordination of an olefin may facilitate the dissociation
of a halide anion from palladium to form the cationic palladium
intermediate (Scheme 2): Ashimori, A.; Bachand, B.; Calter, M. A.;
Govek, S. P.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998,
120, 6488.
(35) Mo, J.; Xiao, J. Angew. Chem., Int. Ed. 2006, 45, 4152.
(36) Arvela, R. K.; Pasquini, S.; Larhed, M. J. Org. Chem. 2007, 72, 6390.
9
J. AM. CHEM. SOC. VOL. 132, NO. 46, 2010 16691

A R T I C L E S
Ruan et al.
Scheme 4. R-Arylation of Enol Ethers with Aryl Chlorides Reported in the Literature35,36
Scheme 5. Possible Effect of EG on the Formation of the Key
Cationic Pd(II) Species
which the Heck reaction of ArBr with vinyl ethers leads to
mixtures of R- and ꢀ-arylation products.15,16,22
These studies point to a strategy for addressing the issue of
aryl chlorides in R selective arylation. First, an electron rich
ligand is necessary, since the overall Heck reaction is almost
certainly turnover-limited by the oxidative addition of ArCl to
Pd(0).3,44,45 Second, the ligand should be bidentate, and third
the reaction medium should be highly ionizing. The latter two
conditions are necessary in order to channel the arylation into
the ionic pathway, without which the arylation would stop at
the [Pd(dppp)(Ph)Cl] intermediate or yield both regioiosmers,17b
even if the oxidative addition occurred. Bearing in mind the
success with dppp in controlling the R regioselectivity in
arylation with ArBr, an electron-rich, dppp-like ligand would
be a good starting point. We report herein that by combining
such a diphosphine with palladium in EG, a wide range of aryl
chlorides can indeed be coupled with electron-rich olefins, in a
highly R-regioselective manner.
tion, like most other alkyl phosphines which are usually liquid-
and air-sensitive, dippp is not easy to handle. Apart from these
two catalytic systems, no other catalyst is known to be effective
for R-selective Heck reaction of ArCl.
More recently, we disclosed that when carried out in alcohols
such as ethylene glycol (EG),37 the arylation of electron-rich olefins
with aryl bromides catalyzed by Pd-dppp is fast, affording up to
1.5 × 104 h-1 turnover frequency (TOF) and 3.8 × 105 turnover
number (TON),37d and exclusively R-regioselective.37,38 The
promoting effect of the protic solvent can be attributed, as in
the case of the [HNEt3][BF4],35 to the equilibrium shown in
Scheme 5 being shifted by hydrogen bonding to favor the
cationic Pd(II) complex,39,40 Since the Heck reaction of ArX
(X ) I, Br, OTf) is likely to be turnover-limited by the olefin
insertion step when proceeding via the pathway B,4f,17 a higher
equilibrium concentration of the Pd-olefin cation is expected
to give rise to a faster overall rate.
Results and Discussion
Identification of Catalytic System. We started the investiga-
tion by examining the coupling of a deactivated aryl chloride,
4-chloroanisole 1c, with n-butyl vinyl ether 2a. Since palladium
in combination with dppp in EG has been shown to be highly
effective for various ArBr coupling with 2a,37 we initially
focused on exploring conditions using this readily available
ligand. The results are given in Table 1. As can be seen, when
performed in EG with Pd(OAc)2-dppp (4 mol % Pd) as catalyst
and using Et3N as base for 24 h, the arylation afforded 3c in
35% yield following acidic hydrolysis of the Heck product
(Table 1, entry 1); a similar yield was obtained with Cy2NMe,
and no ꢀ-arylated product was detected by NMR in the reaction.
Surprisingly, the yield increased significantly, up to 85%, when
an inorganic base was used (entries 2-6), with the best yield
being observed with KOH (entry 4). This is remarkable, as few
arylphosphines are known to be able to effect the Heck reaction
of an electron-rich aryl chloride, such as 1c.3 In sharp contrast,
when other solvents (entries 7-13) or ligands (entries 15-26),
regardless of being mono or bidentate, were used, much lower
Alcohols are known to act as receptors for halide anions,41
and EG is a particularly good hydrogen bond donor, as judged
by its high ETN value of 0.790.40,42 An illuminating example is
that tetraalkylammonium halides show no ionic association when
dissolved in ethylene glycol. In contrast, there is evidence for
ionic association for such salts in acetonitrile and DMF,43 in
(37) (a) Hyder, Z.; Ruan, J.; Xiao, J. Chem.sEur. J. 2008, 14, 5555. (b)
Xu, D.; Liu, Z.; Tang, W.; Xu, L.; Hyder, Z.; Xiao, J. Tetrahedron
Lett. 2008, 49, 6104. (c) McConville, M.; Blacker, J.; Xiao, J. Synthesis
2010, 349. (d) Liu, M.; Hyder, Z.; Sun, Y.; Tang, W.; Xu, L.; Xiao,
J. Org. Biomol. Chem. 2010, 8, 2012.
(38) (a) He, T.; Tao, X.; Wu, X.; Cai, L.; Pikeb, V. W. Synthesis 2008,
887. Using alcohol as additives, see: (b) Ohrai, K.; Kondo, K.;
Sodeoka, M.; Shibasaki, M. J. Am. Chem. Soc. 1994, 116, 11737.
(39) EG may hydrogen bond to the halide anions via only one of its
hydroxyl groups (see the section on DFT calculations); but chelation
is also possible: Barcza, L.; Pope, M. T. J. Phys. Chem. 1974, 78,
168.
(40) Ethylene glycol is an excellent hydrogen bond donor: Reichardt, C.
SolVents and SolVent Effects in Organic Chemistry, 3rd ed.; Wiley-
VCH: Weinheim, 2003.
(41) (a) Smith, D. K. Org. Biomol. Chem. 2003, 1, 3874. (b) Llinares, J. M.;
Powell, D.; Bowman-James, K. Coord. Chem. ReV. 2003, 240, 57.
(c) Aullo´n, G.; Bellamy, D.; Brammer, L.; Bruton, E. A.; Orpen, A. G.
Chem. Commun. 1998, 653.
(44) (a) Barrios-Landeros, F.; Carrow, B. P.; Hartwig, J. F. J. Am. Chem.
Soc. 2009, 131, 8141. (b) Barrios-Landeros, F.; Hartwig, J. F. J. Am.
Chem. Soc. 2005, 127, 6944. (c) Hills, I. D.; Netherton, M. R.; Fu,
G. C. Angew. Chem., Int. Ed. 2003, 42, 5749. (d) Herrmann, W. A.;
¨
Broꢀmer, C.; Priermeier, T.; Ofele, K. J. Organomet. Chem. 1994,
(42) The hydrogen bonding equilibria of alcohols and other hydrogen bond
donors with Cl- have been measured. For instance, methanol interacts
with Cl-, forming a 1:1 complex with an association constant K of
6.5 in sulfolane at 30 °C. In the case of phenol, a better hydrogen
bond donor, K increased to 160. See: Lam, S. Y.; Louis, C.; Benoit,
R. L. J. Am. Chem. Soc. 1976, 98, 1156.
481, 97. (e) Portnoy, M.; Milstein, D. Organometallics 1993, 12, 1665.
(45) For DFT studies, see: (a) Surawatanawong, P.; Fan, Y.; Hall, M. B.
J. Organomet. Chem. 2008, 693, 1552. (b) Ahlquist, M.; Norrby, P.-
O. Organometallics 2007, 26, 550. (c) Lam, K. C.; Marder, T. B.;
Lin, Z. Organometallics 2007, 26, 758. (d) Ahlquist, M.; Fristrup, P.;
Tanner, D.; Norrby, P.-O. Organometallics 2006, 25, 2066. (e) Kozuch,
S.; Amatore, C.; Jutand, A.; Shaik, S. Organometallics 2005, 24, 2319.
(f) Senn, H. M.; Ziegler, T. Organometallics 2004, 23, 2980.
(43) DeSieno, R. P.; Greco, P. W.; Mamajek, R. C. J. Phys. Chem. 1971,
75, 1722.
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Heck Arylation of Olefins with Aryl Chlorides
A R T I C L E S
Table 1. Screening Conditions for Heck Arylation of n-Butyl Vinyl Ether (2a) with 4-Chloroanisole (1c)a
a Reaction conditions: 1) 1c (1 mmol), 2a (3 mmol), Pd(OAc)2 (4 mol %), ligand (6 mol %), base (1.5 mmol), solvent (4 mL), 145 °C or reflux,
c
24 h; 2) 3 M HCl, r.t., 1 h. b Isolated yields of ketone. HBD ) 1.5 equiv of [H2NiPr2][BF4]. d 12 mol % ligand used. e 8% linear product and 30%
anisole formed. f 8 mol % ligand used.
yields were recorded, showing the importance of both EG and
a dppp type ligand to successful arylation with ArCl. In
particular, the hydrogen bond donor [H2NiPr2][BF4], which we
had previously shown to be highly effective for ArBr,35 led to
a yield of only ca. 10% in DMF with ArCl (entry 11), and
although Fu’s PtBu3 afforded 3c in 45% yield in EG, significant
Figure 1. Dppp and its derivatives used in this study.
dechlorination was observed (entry 18). As may be expected,
no reaction occurred without ligand (entry 14).
The screening above indicates that Pd-dppp in EG affords
loading of 1 mol % when 4-MeO-dppp was used as ligand, with
no ꢀ product detected by NMR. Consistent with oxidative
the most promising catalyst for the arylation with ArCl. At 4
addition being rate-determining, the electron-deficient 4-CF3-
mol % Pd, however, the catalyst loading is too high and the
dppp led to insignificant yields. The lower yield with 3,5-
reaction time tends to be long. We therefore decided to vary
DiMeO-dppp may be electronic or steric in origin. In the case
of ArBr substrates, where oxidative addition is less likely to
the electronic property of dppp in the hope to accelerate the
oxidative addition of 1c to Pd-dppp, a step most likely limiting
control the turnover, both experiment and computation have
the arylation turnover as aforementioned. Figure 1 shows the
shown that electron-deficient ligands actually accelerate the
new ligands synthesized by following similar literature
arylation.46,47 It is worth noting that the viability of 4-MeO-
procedures.21b
dppp is manifested only when EG is present. Thus, when the
With these ligands in hand, we undertook further screening,
quickly establishing that the more electron-rich dppp analogues
are indeed more effective in enabling the palladium-catalyzed
coupling of 1c and 2a (Table 2). Most delightfully, a high
(46) von Schenck, H.; Åkermark, B.; Svensson, M. Organometallics 2002,
21, 2248.
(47) Liu, S.; Saidi, O.; Berry, N.; Ruan, J.; Pettman, A.; Thomson, N.;
isolated yield of 88% was obtained in 10 h at a palladium
Xiao, J. Lett. Org. Chem. 2009, 6, 60.
9
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A R T I C L E S
Ruan et al.
Table 2. Heck Arylation of 2a with 1c Using dppp-type Ligandsa
r Arylation with ArCl in EG. Using 4-MeO-dppp as ligand
for palladium and the conditions shown in Table 2 (entry 7),
we then extended the arylation to aryl chlorides 1a-z. The
results are shown in Table 3. As can be seen, the reactions
afforded good to excellent yields of ketones 3a-z, tolerating
activated, unactivated, para-, meta- as well as ortho-substituted
aryl chlorides, with all the reactions giving the R-arylation
products. We note that none of the previous catalysts are known
to be capable of dealing with aryl chlorides of this diversity in
the regioselective Heck arylation.3-10,35,36 Of particular note is
that we encountered no problem with aryl chlorides bearing very
electron-rich substituents (entries 20-22), and those bearing
very electron-deficient groups also led to good yields (entries 5
and 10). Of further interest is the reaction of 3- and 4-chlo-
robenzoic acid with 2a, affording the corresponding acetyl
benzoic acid in decent yield (entries 7 and 14). To the best of
our knowledge, this is the first time a carboxylic acid halide
entry
Pd(OAc)2 (mol %)
ligand
reaction time (h)
yield (%)b
1
2
3
4
5
6
7
8
4
4
4
4
1
1
1
1
4-CF3-dppp
dppp
4-MeO-dppp
3,5-DiMeO-dppp
4-CF3-dppp
dppp
24
24
24
24
10
10
10
10
5
85
90
90
<2
40
88
70
4-MeO-dppp
3,5-DiMeO-dppp
a Reaction conditions: (1) 1c (1 mmol), 2a (3 mmol), Pd(OAc)2:
ligand ) 1:1.5, KOH (1.5 mmol), EG (4 mL), 145 °C; (2) 3 M HCl,
r.t., 1 h. b Isolated yields of ketone.
solvent was switched to DMF or DMSO, the desired ketone
product could hardly be detected under conditions otherwise
identical to those employed for entry 7 (Table 2), showing that
the ligand and solvent are both critical to successful arylation.
Table 3. Heck Coupling of ArCl 1a-z with 2aa
a Reaction conditions: (1) 1 (1 mmol), 2a (3 mmol), Pd(OAc)2 (1 mol %), 4-MeO-dppp (1.5 mol %), KOH (1.5 mmol), ethylene glycol (4 mL), 145
°C, 10 h; (2) 3 M HCl, r.t., 1 h. b Isolated yields of ketones. c 16 h reaction time. d 2.5 equiv of KOH used as base. e 1.5 equiv of Et3N used as base.
f 2a (4 mmol), Pd(OAc)2 (2 mol %), 4-MeO-dppp (3 mol %), 16 h.
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Heck Arylation of Olefins with Aryl Chlorides
A R T I C L E S
Table 5. Heck Coupling of ArCl 1c and 1t with Olefins 2f-ha
Table 4. Heck Coupling of ArCl 1c and 1t with Olefins 2b-ea
a Reaction conditions: 1 (1 mmol), 2 (3 mmol), Pd(OAc)2 (2 mol %),
4-MeO-dppp (3 mol %), KOH (1.5 mmol), ethylene glycol (4 mL), 145
°C, 10 h. b Isolated yields. c Products were obtained after hydrolysis
with 3 M HCl at r.t. for 1 h.
substrate has been shown to be viable in the Heck arylation
reaction of aryl chlorides. The dichloride substrate 1z also
coupled, furnishing a diketone product when 2 mol % catalyst
and 4 equiv olefin were used (entry 26). In the reactions with
ArCl that contains the base-sensitive acetyl, formyl, or nitrile
group (entries 8-10, 15-16), NEt3 was shown to be a better
base than KOH; the latter led to side reactions being observed
and consequently lower yields of products.
a Reaction conditions: 1 (1 mmol), 2f or 2g (1.5 mmol), or 2h (3
mmol), Pd(OAc)2 (2 mol %), 4-MeO-dppp (3 mol %), KOH (1.5
mmol), ethylene glycol (4 mL), 145 °C, 10 h. b Isolated yields of both
isomers, which were separated except for 12a,b and 13a,b which were
isolated as mixtures.
With the success in n-butyl vinyl ether 2a, we then turned
our attention to other electron-rich olefins 2b-e. These olefins
have been R arylated with ArBr previously;15,16,21b,23b,c,35,37a,48
but none is known to couple with an ArCl. To demonstrate the
viability of the catalytic system, two typical electron-rich ArCl
1c and 1t were selected to couple with 2b-e. As can be seen
from the results shown in Table 4, all the reactions afforded
good yields of the R-arylation products. In comparison with 2a,
however, these four olefins led to slightly lower yields, probably
due to increased steric bulk in the olefins. In addition, N-
vinylacetamide failed to give any detectable arylation product,
probably due to decomposition of the substrate under the
reaction conditions. In contrast, it undergoes successful R
arylation with aryl bromides and tosylates, as shown by
Skrydstrup and others.11c,23a,b,49
To expand further the scope of the catalysis, unactivated
olefins, i.e., olefins without a heteroatom adjacent to the CdC
double bond, were explored next. The olefins 2f-h were chosen
and tested against the chlorides 1c and 1t. As shown in Table
5, all the olefins were arylated. With the relatively more electron-
rich 2h, R-arylated homoallylic alcohols were predominately
produced. The regioselectivity is similar to that observed when
the homoallylic alcohol was arylated with ArBr in an ionic
liquid-DMSO mixture.27a In contrast, the styrenes 2f and 2g
gave rise to a mixture of regioisomers, with the R/ꢀ ratio varying
with the electronic properties of both the olefin and aryl chloride.
In particular, when 4-methoxystyrene 2g was coupled with
4-chloroanisole 1c, the products were obtained in a surprising
R/ꢀ ratio of 90/10 (entry 3), providing a convenient means for
(48) Andappan, M. M. S.; Nilsson, P.; von Schenck, H.; Larhed, M. J.
Org. Chem. 2004, 69, 5212.
(49) Gøgsig, T. M.; Lindhardt, A. T.; Dekhane, M.; Grouleff, J.; Skrydstrup,
T. Chem.sEur. J. 2009, 15, 5950.
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A R T I C L E S
Ruan et al.
Table 6. Heck Arylation of 2a with 1 at Low Catalyst Loadinga
Table 7. Effects of Chloride Anion on the Heck Arylation of 2a with
1c,ia
b
)
entry
R
NBu4Cl (mmol)
initial rate (× 10-7 M·s-1
1
2
3
4
OCH3
OCH3
CHO
CHO
none
1
none
1
7.4
8.0
225
244
a Reaction conditions: (1) 1c or 1i (1 mmol), 2a (3 mmol), Pd(OAc)2
(1 mol %), 4-MeO-dppp (1.5 mol %), Et3N (1.5 mmol), NBu4Cl (0 or 1
mmol), EG (4 mL), 145 °C; (2) 3 M HCl, r.t., 1 h. b The initial rates
were based on conversions <10%.
chloride anion did not inhibit the reaction, which in fact went
slightly faster in the presence of the chloride salt,51 indirectly
supporting the assertion above. In sharp contrast, the arylation
with aryl bromides and iodides in nonprotic solvents, such as
DMF and imidazolium ionic liquids, is dramatically retarded
when halide anion is added.35,22b In these later cases, the
arylation is probably controlled by the olefin insertion step and
hence is expected to suffer from halide coordination, which
decreases the concentration of the Pd-olefin cation.4f,15,17 In
kinetic studies of [Pd(dppp)(Ph)X] reacting with isobutyl vinyl
ether in DMF, the reaction rate is also found to be inversely
proportional to the concentration of added iodide ion.17b
In EG, the equilibrium in Scheme 5 lies probably far to the
right, favoring the cationic Pd-olefin intermediate.37a Chloride
anions, when added, are likely to be well solvated by the
medium, via hydrogen bonding with EG molecules, and hence
have little effect on the equilibrium.40-42 As mentioned previ-
ously, the ions of tetraalkylammonium halides are not associated
in EG, due to EG hydrogen bonding with the halide anions.43
The strength of interaction of halide anions with EG may be
further judged from the standard molar Gibbs free energy of
transporting single chloride anions from water to EG, ∆G )
9.0 kJ/mol. For comparison, chloride ion transfer to DMSO and
DMF costs ∆G ) 40.3 and 48.3 kJ/mol, respectively, indicating,
unsurprisingly, much less favorable interactions of chloride
anions with these two solvents.52
a Reaction conditions: (1) 1 (1 mmol), 2a (3 mmol), Pd(OAc)2 (0.1
mol %), 4-MeO-dppp (0.15 mol %), base (1.5 mmol), EG (4 mL), 145
°C, 48 h; (2) 3 M HCl, r.t., 1 h. TON was calculated according to the
conversion of ArX (no other products were detected).
synthesizing 1,1-diarylalkene derivatives, which are useful
precursors for the synthesis of biologically active compounds.50
No (Z)-configured olefins were detected for all the ꢀ-arylation
products. We note that with all the existing literature methods,
it is the ꢀ-arylation products that are normally afforded when
styrenes are arylated.1,3 The high R selectivity observed in the
case of 1c and 2g may stem from an increased nucleophilicity
at the migrating Ar group and an increased positive charge at
the R carbon of the styrene in the cationic Pd-olefin intermedi-
ate (Scheme 2).
From a practical viewpoint, it is highly desirable to minimize
catalyst loading, although in the Heck reaction of aryl chlorides,
rarely can one employ <1 mol % palladium for reactions using
electron-rich olefins or unactivated aryl chlorides.4a,e,5c,g,i,6b,c,e,7a
With this in mind, we examined the Heck arylation of n-butyl
vinyl ether (2a) with chlorobenzene derivatives under a lower
catalyst loading. As shown in Table 6, TON up to 1000 can be
achieved by using 0.1 mol % Pd(OAc)2 in EG. To the best of
our knowledge, this is the highest TON ever obtained for the
Heck arylation of electron-rich olefins with aryl chloride
substrates, showing the potential of the current catalytic system
for industrial applications.
We next studied the effect of olefin concentration on the initial
rate of Heck arylation of 2a with 1c. The results are summarized
in Table 8. As can be seen, the reaction rates remained
essentially the same when the concentration of olefin was varied,
suggesting that the olefin insertion step is unlikely to dictate
the turnover rate of the arylation cycle. Note that the initial rates
in Table 8 are different from those in Table 7 due to the bases
used being different.
Mechanistic Observations. As aforementioned, the arylation
under question is likely to be rate-limited by the oxidative
addition of ArCl to Pd(0). To gain more insight into the arylation
mechanism in EG, several experiments were carried out. We
first examined the effect of chloride anion on the Heck arylation
of n-butyl vinyl ether (2a) with 4-substituted chlorobenzenes
(1c,i). If oxidative addition is the turnover-determining step,
introduction of halide anions into the reaction should have an
insignificant effect on the arylation rate, unless a subsequent
step in the catalytic cycle has an energy barrier close to the
oxidative addtion. As shown in Table 7, in both cases the added
To probe further the mechanism, we studied the effect of
para substituents of ArCl on the arylation of 2a with ArCl (1).
Based on the initial rate measurements, a Hammett plot using
the σ constants is obtained, revealing a positive F value of 2.1
(Figure 2). This indicates the building up of negative charge at
the transition state and thus is consistent with an oxidative
addition-, rather than olefin insertion-, controlled reaction,
(50) (a) Barda, D. A.; Wang, Z.-Q.; Britton, T. C.; Henry, S. S.; Jagdmann,
G. E.; Coleman, D. S.; Johnson, M. P.; Andis, S. L.; Schoepp, D. D.
Bioorg. Med. Chem. Lett. 2004, 14, 3099. (b) Faul, M. M.; Ratz, A. M.;
Sullivan, K. A.; Trankle, W. G.; Winneroski, L. L. J. Org. Chem.
2001, 66, 5772. (c) Nussbaumer, P.; Dorfstatter, G.; Grassberger,
M. A.; Leitner, I.; Meingassner, J. G.; Thirring, K.; Stutz, A. J. Med.
Chem. 1993, 36, 2115. (d) Waespe, H. K. Eur. Pat. Appl. EP0278915
(A2), 1988.
(51) Chloride anion additives are known to accelerate the Heck reaction
catalyzed by Pd-PPh3; see: Amatore, C.; Azzabi, M.; Jutand, A. J. Am.
Chem. Soc. 1991, 113, 8375.
(52) Marcus, Y. Pure Appl. Chem. 1983, 55, 977.
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16696 J. AM. CHEM. SOC. VOL. 132, NO. 46, 2010

Heck Arylation of Olefins with Aryl Chlorides
A R T I C L E S
Table 8. Effect of Olefin Concentration on the Initial Rate of Heck
Arylation of 2a with 1ca
Scheme 6. Oxidative Addition of PhCl to Pd(0) in EG
b
)
entry
olefin (equiv)
initial rate (× 10-6 M·s-1
1
2
3
4
1
2
3
4
8.0
8.3
8.4
8.0
Scheme 7. Catalytic Homocoupling of ArCl in EG
a Reaction conditions: (1) 1c (1 mmol), 2a (1-4 mmol), Pd(OAc)2 (1
mol %), 4-MeO-dppp (1.5 mol %), KOH (1.5 mmol), EG (4 mL), 145
°C; (2) 3 M HCl, r.t., 1 h. b The initial rates were based on conversions
<10%.
consistent with an initial oxidative addition reaction to give
[PdCl(Ph)(dppp)], which disproportionates, yielding [PdCl2-
(dppp)] and [Pd(Ph)2(dppp)] as shown in Scheme 6; the latter
then gives rise to the biphenyl and Pd(0)-dppp, which can react
again with PhCl. However, catalytically inactive [PdCl2(dppp)]
is produced in each catalytic cycle, limiting the maximum
biphenyl yield to ca. 0.2 mmol, i.e., 20% [active palladium
avaliable ) 0.1 mmol × (1 + 1/2 + 1/4 + 1/8 + ...)]. Similar
reactions have been previously observed when heating
[PdCl(Ph)(dippp)].4f In contrast, little biphenyl was detected
when the reaction of Scheme 6 was carried out in DMF or
DMSO under the same conditions, indicative of no or little
oxidative addition taking place in these solvents. In a related
study by Herrmann, heating Pd(dba)2 and dppp in neat chlo-
robenzene at 140 °C only led to a very low yield of
[PdCl(Ph)(dppp)].44d
The reaction in Scheme 6 becomes catalytic when performed
in the presence of base. Thus, when 4-chloroanisole or 4-chlo-
rotoluene was subjected to homocoupling in EG with K2CO3
added, the corresponding biaryl was isolated in ca. 60-70%
yield (Scheme 7).56 Most likely, reduction of [PdCl2(dppp)] with
EG occurs in the presence of K2CO3, which neutralizes the HCl
formed. These results suggest that oxidative addition of ArCl
to palladium occurs readily in EG but do not explain how.
Figure 2. Plot of log(kX/kH) vs Hammett substituent constant σ for the
arylation of 2a with ArCl (see the Supporting Information for experimental
details).
probably with a concerted or a SNAr-type transition state.1b,45,53,54
Judging from Scheme 3, one would actually expect the olefin
insertion to benefit from electron-donating substituents on the
migrating aryl moiety.19a This F value is significantly smaller
than that (5.2) determined by Milstein44e using Pd-dippp in
dioxane and the σ- constant but is similar to those measured
for ArI55 and ArOTf;25c this may suggest an easier oxidative
addition step in EG.1b
The investigations above are in agreement with the arylation
with ArCl being controlled by the oxidative addition of ArCl.
The success of the current catalytic system may then be traced
to the use of an electron-rich ligand, 4-MeO-dppp. However,
ligands are not the decisive factor in the success of our catalytic
system. As mentioned above, without EG as solvent, neither
Pd-dppp nor Pd-4-MeO-dppp afforded a significant amount of
product. This raises questions of fundamental importance: is
the oxidative addition of ArCl to Pd(0) accelerated by EG and,
if so, how?
In order to discover if choice of solvent might affect the
oxidative addition step, we reacted Pd(dba)2 (0.1 mmol) with
chlorobenzene (1.0 mmol) in the presence of dppp (0.11 mmol)
in EG. The major product identified by NMR was [PdCl2(dppp)]
and biphenyl (ca. 22% yield) (Scheme 6). This result is
DFT Calculations. To gain further insight into the oxidative
addition step, we carried out DFT calculations by using B3LYP
functional57 on the reaction of [Pd(dppp)] with PhCl, assuming
that the Pd(0) species is in situ generated from Pd(OAc)2 and
dppp.58 The transition state of the reaction in vacuo was located
and is shown in Figure 3 (TS1). This appears to be a concerted
transition state,1b,45,54 with Pd interacting with both Cipso and
Cl, and resembles those calculated for aryl halides using different
Pd(0)-diphosphine complexes.45a,c,e,f An interesting feature of
these transition states is the large angle between the planes
45a,c,e,f
defined by PdPP and PdXCipso,
this case.
which is 59.98° in the
A similar calculation was then conducted for the reaction in
methanol, using the PCM continuum solvation model.59 Com-
paring the calculated structures in vacuo and in MeOH shows
(53) For the mechanism of classical SNAr reactions, see: (a) Smith, M. B.;
March, J. AdVanced Organic Chemistry, 6th ed.; Wiley-Interscience:
Hoboken, NJ, 2007; Chapter 13. (b) Buncel, E.; Dust, J. M.; Terrier,
F. Chem. ReV. 1995, 95, 2261.
(56) The homocoupling of aryl bromides or iodides in 3-pentanol by
palladium catalysis has recently been reported, but it is inefficient for
aryl chlorides: Zeng, M.; Du, Y.; Shao, L.; Qi, C.; Zhang, X. J. Org.
Chem. 2010, 75, 2005.
(54) Concerted mechanism has also be suggested: (a) Jakt, M.; Johannissen,
L.; Rzepa, H. S.; Widdowson, D. A.; Wilhelm, R. J. Chem. Soc.,
Perkin Trans. 2 2002, 576. (b) Sundermann, A.; Uzan, O.; Martin.,
J. M. L. Chem.sEur. J. 2001, 7, 1703. (c) Amatore, C.; Pflu¨ger, F.
Organometallics 1990, 9, 2276 In this mechanism, charge separation
at the transition state appears to be moderate.
(57) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. J.
Phys. Chem. 1994, 98, 11623.
(58) Generation of Pd(0)-diphosphine from Pd(0)-bisdiphosphine can be
an energy-cost process: Shaw, B. L.; Perera, S. D. Chem. Commun.
1998, 1863. Also see ref 45f.
(55) Fauvarque, J.-F.; Pflu¨ger, F.; Troupel, M. J. Organomet. Chem. 1981,
208, 419.
(59) Tomasi, J.; Mennucci, B.; Cammi, R. Chem. ReV. 2005, 105, 2999.
(60) http://www.chemcraftprog.com/.
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J. AM. CHEM. SOC. VOL. 132, NO. 46, 2010 16697

A R T I C L E S
Ruan et al.
stabilizing the transition state than is captured by the continuum
solvation model.
The DFT studies thus established that the oxidative addition
of ArCl to Pd(0) is indeed facilitated in an alcohol medium,
and this can be traced to hydrogen bonding between the alcohol
and the departing chloride, which lowers the energy barrier of
the trasnsition state. Although oxidative addition reactions
proceeding via the SN2 mechanism are known to be promoted
by polar aprotic solvents,44c,61 which function to solvate the
leaving anions,62 we are not aware of examples of oxidative
addition of organohalides that are accelerated by hydrogen bond
donors. However, solvents of this nature have long been known
to “exert an electrophilic pull on the departing anions in much
the same way that heavy metal ions (Ag+, Hg2+) catalyze
nucleophilic substitution reactions of haloalkanes”.40 Indeed, as
indicated earlier, numerous examples are known of O-H· · ·Cl-
hydrogen bonding,41 including O-H· · ·Cl-M interactions,
where the chloride bonds to a metal,41c resembling the TS
involving EG above. In the classic SNAr reaction that bears
similarities to the concerted mechanism under question, sug-
gestions have been made of N-H hydrogen bonding to fluoride,
facilitating its leaving.63 Furthermore, H · · ·Cl hydrogen bonding
has been exploited to facilitate C-Cl bond breaking in sto-
ichiometric,64 organo-catalytic,65 and enzymatic reactions.66
Figure 3. Calculated transition state for the oxidative addition of PhCl to
[Pd(dppp)]: TS1 in vacuo; TS2 with one explicit ethylene glycol molecule.
Carbon, gray; hydrogen, white; phosphorus, orange; palladium, dark blue;
chlorine, green; oxygen, red. Molecules rendered using Chemcraft.60
a root-mean-square deviation of only 0.218 Å in bond distances
between the two structures (all atoms). The main difference
between the two structures is the angle between the planes
defined by PdPP and PdClCipso increasing from 59.98° in vacuo
to 72.55° in MeOH, reflecting possible interactions of the
departing chloride with the medium. The Pd-Cipso distance
shortened to 2.091 Å while the Cipso-Cl and Pd-Cl distances
elongated to 2.143 Å and 2.784 Å, respectively. Most interest-
ingly, the energy of the transition state in methanol is signifi-
cantly lower. Indeed, the transition state in this polar protic
solvent is 7.16 kcal/mol lower in energy than the analogous
transition state in vacuo. A much longer Cipso-Cl and Pd-Cl
distance at the transition state was found by Ziegler for the
Conclusion
We have developed the first, general, and highly efficient
catalytic system that allows a wide range of activated and
unactivated aryl chlorides to couple, R-regioselectively, with
electron-rich olefins. Further advantages of the protocol include
a ligand that is easy to synthesize and handle, and an
inexpensive, readily available solvent of low toxicity. While
the Heck reaction has been extensively studied for over four
decades, R arylation of electron-rich olefins with aryl chlorides
remained largely elusive until now. The efficacy of the current
catalysis arises from the use of an electron-rich diphosphine
ligand 4-MeO-dppp and an alcohol solvent EG, with the latter
playing the more important role. Experimental and computa-
tional studies provide evidence which indicates that the arylation
is controlled by the oxidative addition step and that the success
of our system is due to acceleration of this step by a specific
hydrogen bonding interaction between a solvent molecule and
the chloride of ArCl at the transition state.
EG also plays a second role in the regioselective arylation,
viz. promotion of the dissociation of chloride anions from the
[PdCl(Ar)(dppp)] to give the [Pd(Ar)(olefin)(dppp)]+ intermedi-
ate. Without the formation of this cationic Pd(II) species, the
arylation is expected to give rise to a mixture of R- and
ꢀ-arylation products, at a slow rate. Most likely, this promotion
stems from the strong ionizing power of EG and its ability to
oxidative addition of PhCl to [Pd(dmpe)] (dmpe
)
Me2PCH2CH2PMe2) in THF, indicating a dissociative process
in the reaction.45f
In line with Ziegler’s results45f and the Hammett plot (Figure
2), significant charge separation was found at the transition state.
The calculated atomic charges on the PhCl moiety are -0.42
in vacuo and -0.49 in MeOH, while the partial atomic charges
on the chloride atom are -0.29 (vacuum) and -0.38 (methanol).
In comparison, the charge on the chloride at the ground state is
almost zero (-0.009). With the significant negative charge
developed at the chloride, solvents capable of hydrogen bonding
with the chloride are expected to stabilize the transition state.
A further calculation indeed shows that EG interacts with
the chloride, significantly lowering the energy barrier by 13.03
kal/mol relative to that in vacuo. The calculation was carried
out by introducing one EG molecule. As can be seen from Figure
3 (TS2), the chloride atom bonds to one of the hydroxyl groups
of EG through the hydrogen atom, displaying a Cl · · ·H distance
of 2.30 Å. This is significantly shorter than the sum (2.95 Å)
of van der Waals radii of H and Cl, falling in the category of
“short” H · · ·Cl interactions.41c As with the results above,
shortening of the Pd-Cipso distance and elongation of the
Cipso-Cl and Pd-Cl were also observed. The PdClCipso plane
becomes closer to being perpendicular to that of PdPP; this
minimizes steric interactions with the dppp phenyl rings. The
energy barrier with one EG involved is considerably lower than
that obtained with the continuous MeOH medium, suggesting
that hydrogen bonding may play a more important role in
(61) Rendina, L. M.; Puddephatt, R. J. Chem. ReV. 1997, 97, 1735.
(62) Hayaki, S.; Yokogawa, D.; Sato, H.; Sakaki, S. Chem. Phys. Lett.
2008, 458, 329.
(63) (a) Crampton, M. R. In Organic Reaction Mechanisms-2004; Knipe,
A. C., Ed.; Wiley: Chichester, U.K., 2008, Chapter 5. (b) Forlani, L.
J. Phys. Org. Chem. 1999, 12, 417.
(64) Stanger, K. J.; Lee, J.-J.; Smith, B. D. J. Org. Chem. 2007, 72, 9663.
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2008, 130, 7198. (b) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.;
Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404. (c) Almerindo,
G. I.; Pliego, J. R., Jr. Chem. Phys. Lett. 2006, 423, 459. (d) Pliego,
J. R., Jr. J. Mol. Catal. A: Chem. 2005, 239, 228.
(66) (a) Soriano, A.; Silla, E.; Tun˜o´n, I.; Ruiz-Lo´pez, M. F. J. Am. Chem.
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16698 J. AM. CHEM. SOC. VOL. 132, NO. 46, 2010

Heck Arylation of Olefins with Aryl Chlorides
A R T I C L E S
dedicated to Professor Richard Heck on the occasion of his, together
with Professors Ei-ichi Negishi and Akira Suzuki, winning of the
2010 Nobel Prize in Chemistry, which was announced while the
manuscript was being refereed.
solvate the resulting chloride anions through hydrogen bonding
(Scheme 5). Given the ample evidence recorded in the
literature,40-42 showing that alcohols hydrogen bond to chlorides
as free ions or when bonded to metal or carbon atoms, it is
surprising that hydrogen bonding has not previously been
intentionally exploited to facilitate metal-catalyzed reactions of
organohalides and the derivatives, including the Heck arylation
studied in this contribution.
Supporting Information Available: Experimental procedures
and characterization data of products. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the EPSRC (EP/F000316 and EP/
C005643/1) for support and dedicate this paper to Professor Albert
S. C. Chan on the occasion of his 60th birthday. This paper is also
JA1081926
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