Highly regioselective internal heck arylation of hydroxyalkyl vinyl ethers by aryl halides in water

Article abstract of DOI:10.1021/jo0705768

(Chemical Equation Presented) Highly regioselective and fast Pd(0)-catalyzed internal α-arylation of ethylene glycol vinyl ether with aryl halides was shown to be possible in water without the need for any halide scavengers or ionic liquid additives. This presents, to our knowledge, the first case of water being utilized in the selective arylation of electron-rich olefins. Resulting α-products were hydrolyzed and isolated as corresponding acetophenones in good to excellent yields when using aryl bromides and with good to moderate yields in the case of aryl iodides. Microwave irradiation was shown to be beneficial in activation of aryl chlorides toward the internal Heck arylation. The scope of the protocol was further increased to include different hydroxyalkyl vinyl ethers, these all giving selectively only branched α-products. Finally, the active role of the hydroxy group in directing the regioselectivity toward internal arylation of electron-rich olefins, even in nonpolar toluene, was revealed.

Full text of DOI:10.1021/jo0705768

Highly Regioselective Internal Heck Arylation of Hydroxyalkyl
Vinyl Ethers by Aryl Halides in Water
Riina K. Arvela,† Serena Pasquini,‡ and Mats Larhed*,†
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala Biomedical Center,
Uppsala UniVersity, P.O. Box 574, SE-751 23 Uppsala, Sweden, and Dipartimento Farmaco Chimico
Tecnologico, UniVersita` degli Studi di Siena, Via A. Moro, 53100 Siena, Italy
mats@orgfarm.uu.se
ReceiVed March 20, 2007
Highly regioselective and fast Pd(0)-catalyzed internal R-arylation of ethylene glycol vinyl ether with
aryl halides was shown to be possible in water without the need for any halide scavengers or ionic liquid
additives. This presents, to our knowledge, the first case of water being utilized in the selective arylation
of electron-rich olefins. Resulting R-products were hydrolyzed and isolated as corresponding acetophenones
in good to excellent yields when using aryl bromides and with good to moderate yields in the case of
aryl iodides. Microwave irradiation was shown to be beneficial in activation of aryl chlorides toward the
internal Heck arylation. The scope of the protocol was further increased to include different hydroxyalkyl
vinyl ethers, these all giving selectively only branched R-products. Finally, the active role of the hydroxy
group in directing the regioselectivity toward internal arylation of electron-rich olefins, even in nonpolar
toluene, was revealed.
Introduction
used in the reaction.7-9 It is today widely acknowledged that
electron-deficient olefins such as acrylates and acrylonitriles
generally give only terminal products (often referred to as
â-products), while electron-rich olefins tend to give mixtures
of internal R- and terminal â-products under standard Heck
reaction conditions.3
The first examples of Heck reaction, which is defined as a
Pd(0)-mediated coupling of an aryl or vinyl halide or sulfonate
ester with an alkene under the influence of base, were
independently reported by Heck and Nolley and Mizoroki et
al. in the early 1970s.1,2 Since then, it has gained more and
more interest among scientists and is today known as one of
the most versatile carbon-carbon coupling reactions.3-6 Espe-
cially interesting from an academic point of view has proven
to be the control of regioselectivity, which is affected by a
variety of different factors such as steric effects, electronic nature
of olefin and aryl counterparts, catalytic system, and solvent
Despite the initial problems relating to the use of acyclic
electron-rich olefins, a lot of effort has been put into studying
the regiocontrol of the Heck coupling in detail. The early work
by Andersson and Hallberg showed the beneficial effect of enol
triflates in vinylation of alkyl vinyl ethers, these giving both
better regiocontrol favoring the formation of branched products
and being superior in reaction rates compared to that of
corresponding enol iodides.10 Complete reversal of regioselec-
tivity, to give exclusively terminal â-products, was shown to
be possible by introducing Pd-coordinating amino or phosphine
† Uppsala University.
‡ Universita` degli Studi di Siena.
(1) Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320.
(2) Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 44,
581.
(3) Larhed, M.; Hallberg, A. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E., Ed.; Wiley-Interscience: New York,
2002; Vol. 1, p 1133.
(4) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009.
(5) Whitcombe, N. J.; Hii, K. K.; Gibson, S. E. Tetrahedron 2001, 57,
7449.
(7) von Schenck, H.; Åkermark, B.; Svensson, M. J. Am. Chem. Soc.
2003, 125, 3503.
(8) Deeth, R. J.; Smith, A.; Brown, J. M. J. Am. Chem. Soc. 2004, 126,
7144.
(9) Andappan, M. M. S.; Nilsson, P.; von Schenck, H.; Larhed, M. J.
Org. Chem. 2004, 69, 5212.
(6) Alonso, F.; Beletskaya, I. P.; Yus, M. Tetrahedron 2005, 61, 11771.
(10) Andersson, C. M.; Hallberg, A. J. Org. Chem. 1989, 54, 1502.
10.1021/jo0705768 CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/21/2007
6390
J. Org. Chem. 2007, 72, 6390-6396

Heck Arylation of Hydroxyalkyl Vinyl Ethers by Aryl Halides
SCHEME 1. Neutral vs Cationic Pathway in Arylation of Electron-Rich Olefins
groups to the vinyl ether.11-13 However, the major breakthrough
came from Cabri et al. who were the first to realize the influence
of both leaving group and phosphine ligand to the regioselec-
tivity of the Heck reaction. More precisely, they utilized a variety
of bidentate phosphine ligands, 1,3-bis(diphenylphosphino)-
propane (dppp) being especially advantageous, in conjunction
with triflates as leaving groups in highly regioselective internal
arylation of electron-rich olefins.14,15 Similar results were
obtained with aryl halides when thallium or silver salts were
used to scavenge halide ions from the solution.16 On the basis
of these findings, Cabri and co-workers proposed that the
reaction proceeds via a cationic pathway in which a charged
organopalladium intermediate is formed after dissociation of
an anionic ligand (Scheme 1).17,18 Dissociation of the neutral
ligand in the case of strongly Pd(II)-coordinating groups, such
as halide ions, results in a shift of the mechanism toward a
neutral pathway leading to mixtures of R- and â-products.19
Although the use of triflates and other sulfonate ester
derivatives has proven to be efficient in regioselective R-ary-
lation, they are rarely commercially available and often expen-
sive, thus limiting their applicability.20 Aryl halides, on the
contrary, are easily accessible and relatively cheap starting
materials for organic synthesis. In the early 21st century, both
Hallberg et al. and Xiao et al. reported methodologies for highly
regioselective R-arylation of electron-rich butyl vinyl ether with
aryl bromides in DMF-water mixtures or in ionic liquids
without the need for toxic thallium or expensive silver
additives.21-23 In these methods, the DMF-water-K2CO3
cocktail or imidazolium-based ionic liquids, [bmim][BF4] and
[bmim][PF6], were used as solvents to increase the polarity of
the reaction mixture to favor the formation of charged inter-
mediate. The applicability of ionic liquids as a sole solvent or
as an additive has further on been expanded to include the
arylation of a wide range of electron-rich olefins regioselectively
with aryl and heteroaryl halides.24-28 As further proof of this
concept, Jutand et al. reported very recently that [Pd(dppp)(S)-
Ph]+ (S ) solvent) is the most reactive complex formed in the
oxidative addition of PhI to the Pd(0)/dppp complex, its overall
role in directing the regioselectivity increasing at high ionic
strengths.29
In addition to finding faster, cheaper, and more operative
synthetic routes, there is also an ever-growing need for more
environmentally friendly ways to perform organic reactions. Use
of ionic liquids has in many cases been confirmed to be efficient,
but high costs, often laborious workup procedures, and lack of
long-range statistics relating to their possible toxicity and
biodegradability in nature have reduced somewhat their use in
industrial processes.30 Water, on the other hand, is nontoxic,
nonflammable, readily available, and inexpensive. Moreover,
because of its polar nature it is an excellent solvent, especially
suitable for microwave-assisted organic synthesis and is today
widely used in organic transformations as evidenced by increas-
ing numbers of reviews appearing in the literature every year.31,32
We herein report, to the best of our knowledge, the first ever
(11) Andersson, C. M.; Larsson, J.; Hallberg, A. J. Org. Chem. 1990,
55, 5757.
(12) Badone, D.; Guzzi, U. Tetrahedron Lett. 1993, 34, 3603.
(13) Stadler, A.; von Schenck, H.; Vallin, K. S. A.; Larhed, M.; Hallberg,
A. AdV. Synth. Catal. 2004, 346, 1773.
(14) Cabri, W.; Candiani, I.; Bedeschi, A.; Santi, R. J. Org. Chem. 1990,
55, 3654.
(15) Cabri, W.; Candiani, I.; Bedeschi, A.; Santi, R. J. Org. Chem. 1992,
57, 3558.
(16) Cabri, W.; Candiani, I.; Bedeschi, A.; Penco, S.; Santi, R. J. Org.
Chem. 1992, 57, 1481.
(17) Cabri, W.; Candiani, I. Acc. Chem. Res. 1995, 28, 2.
(18) For a recent mechanistic study on internal Heck arylation of electron-
rich olefins, see: Amatore, C.; Godin, B.; Jutand, A.; Lemaˆıtre, F.
Organometallics 2007, 26, 1757.
(19) For computational DFT calculations about R/â-selectivity under
neutral conditions, see: Datta, G. K.; von Schenk, H.; Hallberg, A.; Larhed,
M. J. Org. Chem. 2006, 71, 3896.
(21) Vallin, K. S. A.; Larhed, M.; Hallberg, A. J. Org. Chem. 2001, 66,
4340.
(22) Xu, L. J.; Chen, W. P.; Ross, J.; Xiao, J. L. Org. Lett. 2001, 3, 295.
(23) Vallin, K. S. A.; Emilsson, P.; Larhed, M.; Hallberg, A. J. Org.
Chem. 2002, 67, 6243.
(24) Mo, J.; Xu, L.; Xiao, J. J. Am. Chem. Soc. 2005, 127, 751.
(25) Pei, W.; Mo, J.; Xiao, J. L. J. Organomet. Chem. 2005, 690, 3546.
(26) Hyder, Z.; Mo, J.; Xiao, J. L. AdV. Synth. Catal. 2006, 348, 1699.
(27) Mo, J.; Xu, L. J.; Ruan, J. W.; Liu, S. F.; Xiao, J. L. Chem. Commun.
2006, 3591.
(28) Mo, J.; Liu, S. F.; Xiao, J. L. Tetrahedron 2005, 61, 9902.
(29) Amatore, C.; Godin, B.; Jutand, A.; Lemaˆıtre, F. Chem.-Eur. J.
2007, 13, 2002.
(30) Sheldon, R. A. Green Chem. 2005, 7, 267.
(31) For a few recent reviews about the use of aqueous media in carbon-
carbon bond formations, see: (a) Li, C.-J. Chem. ReV. 2005, 105, 3095.
(b) Beletskaya, I. P.; Cheprakov, A. V. In Handbook of Organopalladium
Chemistry for Organic Synthesis; Negishi, E., Ed.; Wiley-Interscience: New
York, 2002; Vol. 2, p 2957. (c) Genet, J. P.; Savignac, M. J. Organomet.
Chem. 1999, 576, 305.
(32) For a few general reviews, see: (a) Dallinger, D.; Kappe, C. O.
Chem. ReV. 2007, 107, 2563. (b) Leadbeater, N. E. Chem. Commun. 2005,
23, 2881. (c) Grieco, P. A. Organic Synthesis in Water, 1st ed.; Blackie
Academic & Professional: London, 1998.
(20) For a few recent examples, see: (a) Arefalk, A.; Larhed, M.;
Hallberg, A. J. Org. Chem. 2005, 70, 938. (b) Hansen, A. L.; Skrydstrup,
T. J. Org. Chem. 2005, 70, 5997. (c) Hansen, A. L.; Skrydstrup, T. Org.
Lett. 2005, 7, 5585. (d) Vallin, K. S. A.; Zhang, Q.; Larhed, M.; Curran,
D. P.; Hallberg, A. J. Org. Chem. 2003, 68, 6639. (e) Tu, T.; Hou, X.-L.;
Dai, L.-X. Org. Lett. 2003, 5, 3651.
J. Org. Chem, Vol. 72, No. 17, 2007 6391

Arvela et al.
TABLE 1. Reaction Development for Arylation of Ethylene Glycol
Vinyl Ether in Watera
methodology for highly selective, palladium-catalyzed internal
arylation of electron-rich olefins by aryl halides in water (eq
1). In addition, we discuss the unique nature of these olefins in
guiding the mechanism toward the cationic pathway, even in
nonpolar solvents such as toluene.
2a
(equiv)
K2CO3
(equiv)
T
(°C)
t
5ac
(%)
entry
(min)
3a/4ab
1
2
3
4
5
6
7
8
9
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
3.0
3.7
3.7
3.0
2.0
1.2
1.2
1.2
1.2
1.2
1.2
100
90
90
90
90
90
90
90
90
90
120
120
120
120
120
100
80
60
80
120
88:12
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
99:1
44d,e
74
70
75
74
69
73
71f
41f,g
41f
Results and Discussion
Reactions with Aryl Bromides and Iodides. In our previous
studies on the Heck arylation of electron-rich olefins, we focused
mainly on the use of triflates as leaving groups.33 However,
because of the problems relating to sulfonate esters, we were
keen to develop further our methodology utilizing aryl halides
in the DMF-water system21 and thus avoid the use of expensive
and laborious ionic liquids. As a starting point, we chose to
study a reaction between 4-bromoanisole (1a) and ethylene
glycol vinyl ether (2a), carrying a hydrophilic hydroxy group.
Reactions were run in water34 using K2CO3 as a base and a
catalytic system constructed of Pd(OAc)2 and dppp. Further-
more, all experiments were run under air using conventional
heating, and formed R-products were hydrolyzed and isolated
as 4′-methoxyacetophenone (5a). Results from the reaction
development are summarized in Table 1.
An initial coupling of 1a with olefin 2a (5.0 equiv), using
3.7 equiv of K2CO3, 2.5 mol % of Pd(OAc)2, and 5.0 mol % of
dppp in 1.0 mL of deionized water, gave full conversion after
2 h of heating at 100 °C, showing a promising R/â ratio of
88:12. However, analysis of the crude product revealed a major
loss of material, and disappointing 44% yield of 5a was recorded
by 1H NMR analysis35 (Table 1, entry 1). Decreasing the
temperature to 90 °C was noticed to be beneficial, giving 74%
isolated yield of 5a without any â-product formation (entry 2),
but further decrease of the temperature to 80 °C led to only
traces of product after 24 h of heating time. In addition to K2-
CO3, a few other bases, namely NEt3, KOAc, and KHCO3, were
tested in the protocol but neither of these superseded the results
obtained with K2CO3 (data not reported here).
10
a Constant in all experiments: 1a (0.50 mmol), Pd(OAc)2 (2.5 mol %),
dppp (5.0 mol %), H2O (1.0 mL). Hydrolysis of 3a was performed by
addition of concd HCl (aq). b Determined by 1H NMR and/or GC/MS.
c Isolated yield. Purity >95% by GC/MS. d Yield determined by comparing
to internal standard in 1H NMR analysis. e Major loss of material.
f Conversion of 1a to product(s) not complete. g Pd(OAc)2 (1.0 mol %),
dppp (2.0 mol %).
advantageous. In addition, the reaction proceeds cleanly in water,
without the need for heavy metal additives or inert atmosphere
and with no noticeable formation of dehalogenation products,
which sometimes has been reported in the literature to occur
when using aryl halides in aqueous media.21 Unfortunately, we
were not able to decrease either the amount of catalyst or the
amount of olefin (entries 9 and 10). It should also be noted that
omission of the bidentate ligand led to considerable decomposi-
tion of the starting material and changing it to monodentate PPh3
resulted in a loss of regioselectivity.
Having identified proper conditions (Table 1, entry 7), we
wanted to test the usefulness of our protocol by screening a
variety of substituted aryl bromides (Table 2). We soon
discovered that the amount of base becomes crucial when
moving from electron-donating to electron-withdrawing sub-
stituents on the organobromide; 4-bromobenzophenone (1h) is
far less reactive than 4-bromoanisole (1a) when using only a
slight excess of base (Table 2, compare entries 1 and 8, Method
A). In fact, only 8% yield of 5h was recorded after 80 min of
heating when using 1.2 equiv of K2CO3. Increasing the amount
of base to 3 equiv furnished an increase of the reaction rate,
giving full conversion and an excellent 99% isolated yield (entry
8, Method B). It is likely that the increase in basicity and ionic
strength of the reaction mixture with excess of base promotes
ionization and facilitates the olefin insertion step for this
electron-poor Pd-aryl intermediate.21
Additional adjustment of the reaction time and the amount
of base needed in the reaction (entries 3-8) provided 73%
isolated yield of 5a after only 80 min of heating at 90 °C using
1.2 equiv of base. The reaction time reported here is consider-
ably shorter than in most of the protocols available today for
the R-arylation of electron-rich olefins by organobromides (times
varying usually between 24 and 36 h),21,22,24-28 which combined
with the easy purification makes this methodology highly
Further screening demonstrated the applicability of our
aqueous methodology, and yields varying from good to excellent
were obtained with a diverse group of aryl bromides (Table 2,
entries 1-9). Method B, utilizing a large excess of base, was
shown to be more general altogether and absolutely necessary
when having electron-withdrawing groups on an aryl counter-
part.36 Reactions proceeded in a highly R-selective manner even
in the absence of an electron-rich aryl group capable of
(33) For a few recent examples, see: (a) Arefalk, A.; Wannberg, J.;
Larhed, M.; Hallberg, A. J. Org. Chem. 2006, 71, 1265. (b) References
20a,d. (c) Bengtson, A.; Larhed, M.; Hallberg, A. J. Org. Chem. 2002, 67,
5854.
(34) High-quality ultrapure Millipore water was used in all reactions.
However, regular tap water provides identical reaction outcome according
to GC/MS analysis.
1
(35) The H NMR integral of the methoxy group of 5a was compared
to integrals of a known amount of 2,3-dimethylnaphthalene used as an
internal standard.
(36) Interestingly, also after addition of extra amount of K2CO3 (Method
B), reactions with 2a appear to be homogeneous, not biphasic, at 90 °C.
6392 J. Org. Chem., Vol. 72, No. 17, 2007

Heck Arylation of Hydroxyalkyl Vinyl Ethers by Aryl Halides
TABLE 2. Internal Arylation of Ethylene Glycol Vinyl Ether with
Aryl Bromides and Iodides in Watera
stabilizing the cationic π-intermediate. The shift toward the
neutral pathway giving both internal and terminal products was
noticed only with 4-bromonitrobenzene, which gave a substantial
loss of material, some dehalogenation product, and a mixture
of R- and â-products.37 Two heteroaryl bromides were
also tested, but only 2-bromothiophene gave a synthetically
meaningful 73% isolated yield of ketone 5k (entries 10 and 11).
Finally, to prove the scalability of this methodology, the reaction
was scaled up to 100-fold using 4-bromoanisole as an aryl
substrate, giving an impressive 88% isolated yield of
4′-methoxyacetophenone 5a (entry 1). In addition to aryl
bromides, a few substituted aryl iodides were tested. This class
of arylpalladium precursors gave generally lower yields than
aryl bromides, with dehalogenation becoming a more serious
issue as moving toward electron-withdrawing substituents
on the benzene ring (entries 12-14). Despite this, reactions
with aryl iodides proceeded with full regiocontrol and represent
one of the few cases where aryl iodides have been used
successfully in regioselective internal arylation of electron-rich
olefins.16,24
Reactions with Aryl Chlorides. To our disappointment, aryl
chlorides showed no reactivity in our Pd(OAc)2/dppp-mediated
aqueous protocol. This is believed to be caused by an inadequate
activation of the strong Ar-Cl bond toward oxidative addition
by Pd(0)/dppp.4,5 In fact, only Xiao et al. have successfully used
aryl chlorides in the regioselective arylation of electron-rich
butyl vinyl ether, using [HNEt3][BF4] as an extra activator.38
However, only a handful of activated organochlorides were
arylated under somewhat harsh conditions, partly diminishing
the value of this discovery. We were, nevertheless, eager to find
a catalytic system to complete our methodology, and thus we
turned our attention to electron-rich, chelate-stabilized (dippp)2Pd-
(0) (dippp ) 1,3-bis(diisopropylphosphino)propane). This cata-
lyst, which can also be formed in situ from Pd(OAc)2 and dippp,
has been extensively used in, for example, carbonylation and
dechlorination of aryl chlorides.39 Indeed, by simply replacing
the earlier catalytic system by 5 mol % of (dippp)2Pd(0) we
managed to get 38% isolated yield from the reaction between
4-chloroacetophenone (1o) and olefin 2a after 80 min of heating
at 90 °C (Table 3, entry 1). The reaction proceeded with
excellent regioselectivity (99:1 R/â), giving some acetophenone
as a dehalogenated byproduct. Further improvement of the
reaction conditions was possible by pre-activating the catalytic
system at 50 °C followed by heating at 130 °C for 90 min with
high-density microwave irradiation;40,41 this gave an excellent
89% isolated yield of 5g with an R/â ratio of 94:6.
Encouraged by our success, we screened a few other aryl
chlorides with varying results using (dippp)2Pd(0) (Table 3).
When employing 4-chloroacetophenone (1o) and 2-chloronaph-
thalene (1p) (entries 1 and 2), good yields and regioselectivities
were obtained. However, in contrast to the outcome with aryl
bromides, unactivated aryl chlorides provided poor yields,
implying difficulties in the oxidative addition step (entries 3
a The reactions were performed on 0.50 mmol scale with 5.0 equiv of
2a, 2.5 mol % of Pd(OAc)2, 5.0 mol % of dppp, and 1.2-3.0 equiv of
K2CO3 in 1.0 mL of H2O by heating at 90 °C for 80 min. Hydrolysis of 3
was performed by addition of concd HCl (aq). b Determined by GC/MS.
c Method A: 1.2 equiv of K2CO3. Method B: 3.0 equiv of K2CO3. d Isolated
yield. Purity >95% by GC/MS. e Reaction was performed on 50 mmol scale.
f Conversion of 1 to product(s) not complete. g Substantial loss of material.
h Yield determined by comparing to internal standard in 1H NMR analysis.
i Reaction time of 120 min. j Formation of some dehalogenation product.
(37) Difficulties in using 4-nitrophenyl substrates have been previously
reported; see ref 33c.
(38) Mo, J.; Xiao, J. Angew. Chem., Int. Ed. 2006, 45, 4152.
(39) For a few examples, see: (a) Ben-David, Y.; Portnoy, M.; Milstein,
D. J. Am. Chem. Soc. 1989, 111, 8742. (b) Ben-David, Y.; Gozin, M.;
Portnoy, M.; Milstein, D. J. Mol. Catal. 1992, 73, 173. (c) Ben-David, Y.;
Portnoy, M.; Milstein, D. J. Chem. Soc., Chem. Commun. 1989, 1816. (d)
Portnoy, M.; Milstein, D. Organometallics 1993, 12, 1665.
(40) Larhed, M.; Moberg, C.; Hallberg, A. Acc. Chem. Res. 2002, 35,
717.
(41) Kappe, C. O. Angew. Chem., Int. Ed. 2004, 43, 6250.
J. Org. Chem, Vol. 72, No. 17, 2007 6393

Arvela et al.
TABLE 3. Internal Arylation of Ethylene Glycol Vinyl Ether with
Aryl Chlorides in Watera
TABLE 4. Arylation of Some Vinyl Ethers and Allyl Alcohol with
4-Bromoanisole in Watera
a The reactions were performed on 0.25 mmol scale with 5.0 equiv of
2a, 5.0 mol % of (dippp)2Pd, and 3.0 equiv of K2CO3 in 1.0 mL of H2O by
irradiating with microwaves at 130 °C for 90 min. Hydrolysis of 3 was
performed by addition of concd HCl (aq). b Determined by GC/MS.
c Isolated yield. Purity >95% by GC/MS. d Conventional heating at 90 °C
for 80 min. e Conversion of 1 to product(s) not complete. f Formation of
some dehalogenation product noticed. g 33% of benzophenone formed as a
byproduct.
a The reactions were performed on 0.50 mmol scale with 5.0 equiv of
olefin, 2.5 mol % of Pd(OAc)2, 5.0 mol % of dppp, and 3.0 equiv of K2CO3
in 1.0 mL of H2O by heating at 90 °C for 80 min. Hydrolysis of 3 was
performed by addition of concd HCl (aq). b Determined by GC/MS.
c Isolated yield. Purity >95% by GC/MS. d With 1.2 equiv of K2CO3.
e Reaction time of 6 h. f No product formation noticed. g nd ) not
determined. Reaction not complete even though amount of remaining starting
material was not verified. h Formed â-products were not isolated after the
reaction.
and 4). In the early 1990s, Milstein et al. reported their studies
about the Pd/dippp system in promoting the facile oxidative
addition of chlorobenzene to Pd(0).39d,42,43 The oxidative addition
step worked well in several solvents, and polar solvents provided
the fastest reaction rates. However, in a base-mediated terminal
Heck coupling, half of the catalytic species were deactivated
in each catalytic cycle because of formation of a stable
dichloride complex (dippp)PdCl2. In light of these results, it
might be that unactivated electron-rich aryl chlorides require a
higher catalyst concentration compared to more reactive electron-
poor analogues, explaining the incomplete conversion. On the
other hand, with electron-deficient 1s, the insertion of olefin
becomes rate-limiting, allowing formation of a significant
amount of dehalogenation product (entry 5). In addition, poorer
regiocontrol was noticed with 1s, which is likely to be caused
by the high reaction temperature and the inability of the electron-
deficient ArPd(dippp)Cl intermediate to release the chloride ion,
thus forcing the dippp ligand to hand over one of the metal
coordination sites for the incoming olefin (Scheme 1, neutral
reaction pathway).
Method B reported in Table 2, making a direct comparison
possible. Remarkably, all hydroxyalkyl vinyl ethers 2a-d were
arylated in water with 1a in highly regioselective manner and
without any byproduct formation (Table 4, entries 1-4). The
yields from the arylations of heavier olefins 2b-d were
moderate at best, and unfortunately, prolongation of the reaction
time to 6 h had only a slight positive effect on the yields (entries
2 and 3). For alkyl vinyl ethers lacking the hydroxy functional-
ity, the regioselectivity decreased gradually with elongated alkyl
chains (Table 4, entries 6 and 7). A similar regiochemical
outcome was obtained with ethylene glycol butyl vinyl ether
(2h) (entry 8). This can be explained by insolubility of 2f-h
in water, providing a two-phase reaction system with a nonpolar
organic layer as the probable arylation media. Moreover,
[2-(dimethylamino)ethoxy]ethane (2e) and allyl alcohol (2i)
showed no reactivity in the aqueous protocol (entries 5 and 9).44
Reactions in Toluene. In 2006, Mo and Xiao suggested a
hydrogen bond-induced regiocontrol and acceleration of the
reaction rate in R-arylation of electron-rich olefins by aryl
halides in ionic liquids or DMF.38 In this study, they proposed
Reactions with Different Olefins. To further explore the
scope of this highly selective internal Heck arylation, a few
additional examples of electron-rich olefins were screened.
Results from these experiments are summarized in Table 4.
Reactions were run using exactly the same conditions as in
that the HNEt3 ion from the additive [HNEt3]+[BF4]- was
+
capable of forming a hydrogen bond with the bromide ion in
(42) Portnoy, M.; Ben-David, Y.; Milstein, D. Organometallics 1993,
12, 4734.
(43) Portnoy, M.; Ben-David, Y.; Rousso, I.; Milstein, D. Organome-
tallics 1994, 13, 3465.
(44) Noncyclic, N-alkylated enamides have been reported to undergo
unselective arylation in water-DMF mixtures; see ref 21.
6394 J. Org. Chem., Vol. 72, No. 17, 2007

Heck Arylation of Hydroxyalkyl Vinyl Ethers by Aryl Halides
TABLE 5. Comparative Arylation of Ethylene Vinyl Glycol Ether
in Toluene or in Solventless Reactiona
group to the Pd(II) center leads to highly â-selective synthesis
of protected arylacetaldehydes from ethylene glycol vinyl ether
via terminal Heck arylation.45a,c While we have no definitive
answer what is behind the excellent R-selectivity in our case,
we suggest that the reaction proceeds via a pentacoordinate
π-complex (eq 2). This mechanistic suggestion is partly sup-
ported by Overman et al.’s proposition for asymmetric intramo-
lecular Heck reactions with aryl halides where axial olefin
coordination is essential for chiral discrimination.46,47 Here we
propose that the hydroxy group assists the dissociation of
bromide ion either via hydrogen bond formation or via a ligand
exhange-isomerization reaction sequence after the axial coor-
dination of the olefin to the ArPd(dppp)X complex, generating
the key cationic π-intermediate. The fact that olefins 2e and
2h, capable of binding to the Pd(II) complex via lone pair on
oxygen (weak coordination) or nitrogen (strong coordination)
atoms,13,48,49 failed in this aqueous regioselective internal Heck
protocol (Table 4, entries 5 and 8) points toward halide removal
via hydrogen bond formation. This hypothesis is further
strengthened by the large difference in reactivities of olefins
2a and 2d, both having an oxygen atom linked to vinyl ether
by a two-carbon spacer. As the efficiency of the halide removal
can be expected to be related to the length of the carbon tether
linking the double bond and OH-group moieties, the rate of the
overall reaction is anticipated to decrease with olefins 2b-d,
which was, in fact, shown to be the case in our preparative
experiments (Table 4). Finally, we believe that the same
mechanism prevails also in nonpolar toluene where internal
hydrogen bonding is further favored. However, as the ability
of toluene to promote the internal arylation gets weaker with
electron-poor aryl rings, the aqueous methodology is presumed
to be more general.
toluene
no solvent
entry ArX methodb product
R/âc
5 (%)d R/âc 5 (%)d
1
2
3
4
1a
1a
1c
1h
A
B
A
B
5a
5a
5c
5h
99:1
73:27
99:1
96:4
81
99:1
86
24e,f
88
62g
a The reactions were performed on 0.50 mmol scale with 5.0 equiv of
2a. Hydrolysis of 3 was performed by addition of concd HCl (aq). b Method
A: 1.2 equiv of K2CO3. Method B: 3.0 equiv of K2CO3. c Determined by
GC/MS. d Isolated yield. Purity >95% by GC/MS. e 2g used instead of 2a.
f Conversion of 1a to product(s) not complete. g 20% benzophenone formed
as a byproduct.
an oxidative addition intermediate, thus promoting the formation
of the cationic π-complex leading to internal arylation products.
To be able to conclude whether our results with hydroxyalkyl
vinyl ethers were based purely on the better solvation of these
olefins in alkaline water or whether the hydroxy group itself
could play an active role in the reaction mechanism, the
influence of nonpolar toluene on the outcome of the reaction
was investigated (Table 5). Much to our surprise, reactions in
toluene proceeded with excellent regioselectivities, and yields
comparable to those from the earlier reactions in aqueous media
were isolated in the case of 4-bromoanisole (1a) and 2-bro-
monaphthalene (1c) (Tables 2 and 5). A somewhat lower yield
and regioselectivity was recorded with electron-poor 4-bro-
mobenzophenone (1h); this gave also 20% of dehalogenation
product (benzophenone), implicating problems in the insertion
of the olefin. Additionally, 2a was successfully arylated with
1a without any cosolvent present, giving an excellent 86%
isolated yield of ketone 5a with no â-product formation. Finally,
a loss of selectivity as well as noticeable reduction of the
reaction rate in toluene was noticed when changing the olefin
2a to butyl vinyl ether 2g, lacking the OH functionality (Table
5, entry 2).
Reaction Pathway. Data from experiments in nonpolar
toluene together with the information gained from the reactions
in water with a variety of olefins clearly prove that the hydroxy
group has a major influence on the outcome of the reaction
(Tables 4 and 5). This can be seen in excellent regioselec-
tivities obtained with hydroxyvinyl ethers 2a-d as well as
faster reaction rates of ethylene glycol vinyl ether-mediated
reactions when compared to other olefins included in this
study. In fact, several researchers have noticed the increase in
selectivity of the reaction as a result of coordination of OH
group or similar functionality to the catalyst.11,12,45 Interestingly,
Santelli et al. have suggested that coordination of the hydroxy
Conclusion
We have demonstrated that aryl and heteroaryl bromides and
iodides can be efficiently converted to corresponding acetophe-
nones in high yields in water using ethylene glycol vinyl ether
as the olefin and potassium carbonate as the base. This
palladium(0)-catalyzed method is highly advantageous as no
heavy metal additives or ionic liquids are necessary, it proceeds
(45) For a few examples, see: (a) Kondolff, I.; Doucet, H.; Santelli, M.
Eur. J. Org. Chem. 2006, 765. (b) Oestreich, M.; Sempere-Culler, F.;
Machotta, A. B. Angew. Chem., Int. Ed. 2005, 44, 149. (c) Kondolff, I.;
Doucet, H.; Santelli, M. Synlett 2004, 1561. (d) Kang, S.-K.; Lee,
H.-W.; Jang, S.-B.; Kim, T.-H.; Pyun, S.-J. J. Org. Chem. 1996, 61, 2604.
(e) Kang, S.-K.; Jung, K.-Y.; Park, C.-H.; Namkoong, E.-Y.; Kim, T.-H.
Tetrahedron Lett. 1995, 36, 6287. (f) Jeffery, T. Tetrahedron Lett. 1993,
34, 1133. (g) Bernocchi, E.; Cacchi, S.; Ciattini, P. G.; Morera, E.; Ortar,
G. Tetrahedron Lett. 1992, 33, 3073.
(46) Ashimori, A.; Bachand, B.; Calter, M. A.; Govek, S. P.; Overman,
L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6488.
(47) Dounay, A. B.; Overman, L. E. Chem. ReV. 2003, 103, 2945.
(48) Nilsson, P.; Larhed, M.; Hallberg, A. J. Am. Chem. Soc. 2001, 123,
8217.
(49) Seligson, A. L.; Trogler, W. C. J. Am. Chem. Soc. 1991, 113,
2520.
J. Org. Chem, Vol. 72, No. 17, 2007 6395

Arvela et al.
Ether (Table 2, Entry 1). A mixture of 4-bromoanisole (9.35 g,
50 mmol), ethylene glycol vinyl ether (22.4 mL, 250 mmol), Pd-
(OAc)2 (0.28 g, 1.25 mmol), dppp (1.03 g, 2.5 mmol), K2CO3 (8.29
g, 60 mmol), and 100 mL of water was stirred in a 250-mL round-
bottom flask at 90 °C for 80 min under reflux. After cooling, 50
mL of ethyl acetate was added to the reaction mixture, which was
stirred for 5 min before analysis of the organic layer with GC/MS.
Thereafter, 25 mL of concentrated HCl (aq) was slowly added to
the mixture, followed by stirring at room temperature for 1 h.
Completion of hydrolysis was verified with GC/MS. Reaction was
worked up and purified as described above.
cleanly without any noticeable byproduct formation, avoids the
need for inert atmosphere, and allows for easy purification of
the products. Moreover, the reactions proceed faster than in most
of the protocols available in the literature today, and for the
first time, water can be utilized as a sole solvent in regioselective
internal Heck arylation of electron-rich olefins, making this
protocol more environmentally benign. Additionally, by using
microwave irradiation in conjunction with reactive (dippp)2Pd
catalyst, a limited number of aryl chlorides were transformed
into analogous aryl methyl ketones. Finally, the unique nature
of hydroxyalkyl vinyl ethers was demonstrated in directing the
mechanism toward the cationic pathway leading to internal
arylation products, even in the absence of a polar solvent
supporting the stabilization of charged intermediates.
General Experimental Procedure for Microwave-Assisted
Internal Heck Reactions Using Aryl Chlorides (Table 3). A
mixture of corresponding aryl chloride (0.25 mmol), (dippp)2Pd
(8.2 mg, 0.0125 mmol), K2CO3 (104 mg, 0.75 mmol), and 1.0 mL
of water was stirred in a sealed vessel suitable for microwave
experiments in a preheated oil bath at 50 °C for 15 min. Ethylene
glycol vinyl ether (112 µL, 1.25 mmol) was added, the vessel was
sealed, and the reaction mixture was irradiated with microwaves
at 130 °C for 90 min. Reactions were hydrolyzed, worked up, and
purified as previously described.
Experimental Section
General Experimental Procedure for Internal Heck Reactions
Using Aryl Bromides or Aryl Iodides (Tables 1, 2, and 4). A
mixture of corresponding aryl bromide or aryl iodide (0.50 mmol),
olefin (2.5 mmol), Pd(OAc)2 (2.8 mg, 0.0125 mmol), dppp (10.3
mg, 0.025 mmol), K2CO3 (83-207 mg, 0.60-1.5 mmol), and 1.0
mL of water was stirred in a sealed vessel (capable to withhold
elevated pressure) in a preheated oil bath at 90 °C for 80 min. After
cooling, 2.0 mL of ethyl acetate was added to the reaction mixture,
which was stirred for 5 min before analysis of the organic layer
with GC/MS. A quantity of 0.5 mL of concentrated HCl (aq) was
added to the mixture, followed by stirring at room temperature for
1-3 h. Completion of hydrolysis was verified with GC/MS. The
reaction was worked up by extraction with ethyl acetate and 10%
K2CO3 (aq). Products were purified by flash chromatography on
silica gel. Eluents: isohexane/ethyl acetate.
Acknowledgment. We gratefully acknowledge the financial
support from the Swedish Research Council and Knut and Alice
Wallenberg’s Foundation. We also thank Dr. Prasad Appuk-
kuttan, Gopal Datta, and Jonas Lindh for a critical review of
this article and Dr. Luke Odell for linguistic advice.
Supporting Information Available: Full details of experimental
procedures and spectroscopic data. This material is available free
of charge via the Internet at http://pubs.acs.org.
Experimental Procedure for Large-Scale Internal Heck
Reaction Using 4-Bromoanisole and Ethylene Glycol Vinyl
JO0705768
6396 J. Org. Chem., Vol. 72, No. 17, 2007