Palladium-catalyzed Heck arylations of allyl alcohols in ionic liquids: Remarkable base effect on the selectivity

Article abstract of DOI:10.1021/jo070005f

Pd-catalyzed Heck arylation of allyl alcohols in tetraalkylammonium ionic liquids (ILs) can be made highly selective toward the formation of either aromatic carbonyl compounds or aromatic conjugated alcohols by carefully choosing both the IL and the base.

Full text of DOI:10.1021/jo070005f

Palladium-Catalyzed Heck Arylations of Allyl Alcohols in Ionic
Liquids: Remarkable Base Effect on the Selectivity
Vincenzo Calo`,† Angelo Nacci,*,‡ Antonio Monopoli,§ and Valentina Ferola‡
CNR - ICCOM, Department of Chemistry, UniVersity of Bari, Via Orabona 4, 70126-Bari, Italy,
Department of Chemistry, UniVersity of Bari, Via Orabona 4, 70126-Bari, Italy, and Laboratory for
Repressione frodi alimentari, Via CaVedone, 18, 41100-Modena, Italy
nacci@chimica.uniba.it
ReceiVed January 2, 2007
Pd-catalyzed Heck arylation of allyl alcohols in tetraalkylammonium ionic liquids (ILs) can be made
highly selective toward the formation of either aromatic carbonyl compounds or aromatic conjugated
alcohols by carefully choosing both the IL and the base.
SCHEME 1. General Trend in the Heck Arylation of Allyl
Alcohols
Introduction
The palladium-catalyzed Heck arylation of olefins is one of
the most powerful methods for the formation of C-C bonds.1
This process is generally applied to electron-deficient alkenes;
otherwise, reactions are sluggish and mixtures of regioisomeric
olefins are formed, thus making the method of only limited
synthetic utility. When allyl alcohols are used as substrates, the
problem with the selectivity is further complicated by the
formation of carbonyl products via isomerization of the initially
formed arylated allyl alcohols, so much that four arylated
products can be obtained (Scheme 1).2
The regioselectivity of the insertion is mainly controlled by
steric factors; indeed, with terminal alkenols (R1 ) H), the
addition of the aryl moiety usually occurs on the unsubstituted
carbon of the double bond with few exceptions.3 With internal
olefins (R1 * H) also other factors can play a role such as the
coordination properties of the hydroxyl group or the effect of
the base,4,5 and selectivity seems to be quite unpredictable
depending on the reaction conditions.
† CNR - ICCOM, University of Bari.
‡ University of Bari.
§ Laboratory for Repressione frodi alimentari.
(1) For general reviews on the Heck reaction see: (a) Phan, N. T. S.;
Van Der Sluys, M.; Jones, C. W. AdV. Synth. Catal. 2006, 348, 609-679.
(b) Alonso, F.; Beletskaya, I. P.; Yus, M. Tetrahedron 2005, 61, 11771-
11835. (c) Beletskaya, I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009.
For reviews on the Heck reaction in ionic liquids see: (d) Calo`, V.; Nacci,
A.; Monopoli, A. Eur. J. Org. Chem. 2006, 3791-3802. (e) Welton, T.;
Smith, P. J. AdV. Organomet. Chem. 2004, 51, 251-284. (f) Wasserscheid,
P. In Transition Metals for Organic Synthesis 2nd ed.; Beller, M. Bolm, C.
Ed.; Wiley-VCH Verlag GmbH & Co: Weinheim, Germany, 2004; Vol.
2.
(2) For papers and reviews on the Heck arylation of allyl alcohols see:
(a) Barbero, M.; Cadamuro, S.; Dughera, S. Synthesis 2006, 20, 3443-
3452. (b) Masllorens, J.; Bouquillon, S.; Roglans, A.; Henin, F.; Muzart, J.
J. Organomet. Chem. 2005, 690, 3822-3826. (c) Berthiol, F.; Doucet, H.;
Santelli, M. Eur. J. Org. Chem. 2005, 7, 1367-1377. (d) Muzart, J.
Tetrahedron 2005, 61, 4179-4212 and references cited therein.
(3) See for example (a) Mo, J.; Xu, L.; Ruan, J.; Liu, S.; Xiao, J. Chem.
Commun. 2006, 34, 3591-3593. (b) Pei, W.; Mo, J.; Xiao, J. J. Organomet.
Chem. 2005, 690, 3546-3551.
10.1021/jo070005f CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/03/2007
2596
J. Org. Chem. 2007, 72, 2596-2601

Palladium-Catalyzed Heck Arylations of Allyl Alcohols
TABLE 1. Base Effect on the Heck Arylation of 1-Octen-3-ol
Much less studied is the isomerization process, which impedes
the arylated allylic alcohols to be isolated. Indeed, only few
examples have been reported showing the substitution of allylic
alcohols by aryl halides occurring without the isomerization of
the double bond. In these cases, special additives such as silver
salts,6 cesium carbonate,7 or unusual substrates such as aryl
triflates8 and hypervalent iodonium salts4 proved to be necessary.
Because of the synthetic importance of both conjugated aromatic
alcohols and the corresponding carbonyl compounds, the
development of a method which allows to control the isomer-
ization process would be of significant utility.
In a program aimed at developing powerful catalytic methods
in ionic liquids (ILs),9 we disclosed that highly efficient Heck
olefinations of aryl halides can be accomplished in tetraalkyl-
ammonium ILs, obviating the need for toxic solvents and labile
phosphane ligands.1d,10 In particular, some ILs such as tetrabu-
tylammonium bromide (TBAB) and tetrabutylammonium ac-
etate (TBAA) proved to be exceptionally able to stabilize
colloidal palladium nanoparticles that in these media act as very
active and selective catalysts for the C-C couplings. As an
example, the Heck arylation of cinnamates11 can be performed
in a high stereoselective manner thanks to the aptitude of TBAA
to rapidly neutralize the Pd-H species responsible for the E/Z
isomerization.
a
Catalyzed by Pd(OAc)2
convnb yieldsc ratio (%)b
run
X
IL
base
T [˚C] t/h
(%)
(%) 1a/1b/1c/1d
1
2
3
4
5
6
7
8
9
I
TBAB NaHCO3 110
2.5 >99
89
92
91
85
90
93
45
49
90
92
93
90
90
94
85
0/0/97/3
0/0/94/6
0/0/94/6
0/0/95/5
0/0/94/6
0/0/94/6
0/0/95/5
0/0/95/5
48/9/43/0
56/10/34/0
65/10/25/0
85/4/11/0
86/3/11/0
90/6/4/0
83/5/11/0
I
I
I
TBAB K2CO3
TBAB Bu3N
110
110
1
>99
1.5 >99
3.5 >99
TBAB NaOAc 110
Br TBAB NaHCO3 130
Br TBAB K2CO3
Br TBAB Bu3N
Br TBAB NaOAc 130
Br TBAB TBAA
3
1
12
12
>99
>99
55
130
130
62
90
90
90
90
80
70
60
50
80
70
60
rt
0.7 >99
0.5 >99
0.5 >99
0.5 >99
0.5 >99
0.5 >99
1.5 >99
10d Br TBAB TBAA
11e Br TBAB TBAA
12 Br TBAA TBAA
13 Br TBAA TBAA
14 Br TBAA TBAA
15 Br TBAA TBAA
16 Br TBAA TBAA
17
18
19
20
14
1
2
1.5
2.5
<1
>99
>99
96
I
I
I
I
TBAA TBAA
TBAA TBAA
TBAA TBAA
TBAA TBAA
93
90
89
85
85/5/10/0
85/11/4/0
80/12/8/0
65/16/19/0
93
a General reaction conditions: IL (1 g), halobenzene (1.2 mmol), allyl
alcohol (1 mmol), Pd(OAc)2 (1.2 mol %); base (2 mmol or 1 g of TBAA
Results presented below fall again in line with this hypothesis,
showing that a comparable control on the selectivity can also
be reached with allyl alcohols, avoiding the need for aryl triflates
or toxic and costly inorganic additives.
when it was used as both base and IL), TBAA/TBAB ) 1:1.5 (mmol ratio).
1
b Conversions and product ratios evaluated by H NMR. c Isolated overall
yields. d TBAA/TBAB ) 1.5:1 (mmol ratio). e TBAA/TBAB ) 4:1 (mmol
ratio).
Results and Discussion
Recently, we reported12 an efficient Heck arylation of allyl
alcohols carried out in molten TBAB catalyzed by a Pd-
benzothiazole-carbene complex using NaHCO3 as base. Reac-
tions followed the usual pathway of the Heck coupling with
allyl alcohols, affording arylated aldehydes and ketones with a
regioselectivity R/â depending on the steric hindrance around
the double bond. Only trace amounts of the arylated allyl
alcohols were obtained with that catalytic system.
as catalyst in place of the Pd-carbene complex, as the former
provided, in TBAB, a similar product distribution. Reaction
conditions were optimized to process 1 mmol of alkenol in 1 g
of IL with 1.2 mol % of catalyst, performing the process by
heating the catalyst source in the molten IL in the presence of
reagents, so that Pd-nanocolloids were formed. Reaction times
were carefully regulated to avoid the formation of byproducts
coming from both the bis-arylation and the aldol condensation
processes. Since it was reported5 that a slight difference in the
strength of bases used can have a striking effect on the
regioselectivity, we started investigations evaluating a possible
base effect on this process. Inspections were started on a
monosubstituted olefin such as 1-octen-3-ol, using iodo- and
bromo-benzene as arylating agents (Table 1).
Following on from this previous work, we decided to study
deeply factors affecting the selectivity of these reactions.
Preliminary experiments showed that Pd(OAc)2 could be used
(4) Kang, S.-K.; Lee, H.-W.; Jang, S.-B.; Kim, T.-H.; Pyun, S.-J. J. Org.
Chem. 1996, 61, 2604-2605.
(5) Berthiol, F.; Doucet, H.; Santelli, M. Tetrahedron 2006, 62, 4372-
4383.
(6) Jeffery, T. Tetrahedron Lett. 1991, 32, 2121-2124.
(7) Grasa, G. A.; Singh, R.; Stevens, E. D.; Nolan, S. P. J. Organomet.
Chem. 2003, 687, 269-279.
(8) Bernocchi, E.; Cacchi, S.; Ciattini, P.G.; Morera, E.; Ortar, G.
Tetrahedron Lett. 1992, 33, 3073-3076.
As expected from a monosubstituted olefin, because of steric
reasons, reactions were regioselective with respect to the
addition of the aromatic group, affording predominantly to the
â-substituted products 1a and 1c. Quite surprising, instead, was
the influence of bases on both the catalyst activity and the
isomerization process. Indeed, in TBAB as solvent, almost all
the bases used, of both organic and inorganic nature, behaved
similarly leading to a mixture of the sole arylated carbonyl
compounds where the â-substituted product 1c clearly prevailed
(Table 1, runs 1-8). Under these conditions, reaction temper-
atures could not be lowered below 110 and 130 °C for
iodobenzene and bromobenzene, respectively. Moreover, among
the bases used, Bu3N and NaOAc were the less efficient (Table
1, runs 7-8).
(9) For reviews on ionic liquids, see: (a) Zhang, C. Z. AdV. Catal. 2006,
49, 153-237. (b) Wilkes, J. S. J. Mol. Catal. A: Chem. 2004, 214, 11-
17. (c) Welton, T. Coord. Chem. ReV. 2004, 248, 2459-2477. (d) Ionic
Liquids in Synthesis; Wasserscheid, P., Welton, T., Eds.; Wiley-VCH:
Weinheim, Germany, 2003. (e) Dupont, J.; de Souza, R. F.; Suarez, P. A.
Z. Chem. ReV. 2002, 102, 3667-3692. (f) Olivier-Bourbigou, H.; Magna,
L. J. Mol. Catal. A: Chem. 2002, 182 183, 419-437. (g) Zhao, D.; Wu,
M.; Kou, Y.; Min, E. Catal. Today 2002, 74, 157-189. (h) Wasserscheid,
P.; Keim, W. Angew. Chem., Int. Ed. 2000, 39, 3772-3789. (i) Welton, T.
Chem. ReV. 1999, 99, 2071-2084.
(10) Calo`, V.; Nacci, A.; Monopoli, A. J. Organomet. Chem., 2005, 690,
5458-5466.
(11) Calo`, V.; Nacci, A.; Monopoli, A.; Laera, S.; Cioffi, N. J. Org.
Chem. 2003, 68, 29292-2933.
On the contrary, with TBAA as base, bromobenzene was
rapidly reacted (0.7 h) at 90 °C and selectivity markedly changed
affording an almost equimolecular mixture of the allyl alcohols
(12) Calo`, V.; Nacci, A.; Monopoli, A.; Spinelli, M. Eur. J. Org. Chem.,
2003, 1382-1385.
J. Org. Chem, Vol. 72, No. 7, 2007 2597

Calo`
Undoubtedly, as it is often postulated in the literature,4,8,13,14
the coordination effect exerted by the hydroxyl group is a key
factor in explaining the high catalyst activity and selectivity in
the Heck arylation of allyl alcohols. However, to elucidate the
extraordinary IL effect observed in our reactions, also the
following factors must be taken into account: (1) the large
quantity of acetate anions in the reaction medium, (2) their weak
ligand nature which may lead to the switching from the neutral
to cationic mechanism, and (3) their enhanced basicity in the
tetraalkylammonium ionic liquid.
On the basis of these assumptions, our results can be
reasonably explained with the reaction mechanism depicted in
Scheme 2. After the oxidative addition, the Ar-Pd-X species
can undergo the two reaction pathways a and b depending on
the nature of the ligand (X) bonded to palladium. When TBAB
is used as solvent, and a conventional base such as NaHCO3 is
employed (catalytic method A), ligand X will be Br- or I- (path
a).
TABLE 2. Solvent Effect in the Heck Arylation of 1-Octen-3-ol
a
Catalyzed by Pd(OAc)2
run
solvent
T [˚C] convnb (%) t (h) ratio (%)b 1a/1b/ 1c/1d
1c TBAA
70
90
90
90
90
90
90
>99
98
94
89
81
0.5
2
2
2
6
90/6/4/0
2
3
4
5
6
7
DMAc
DMF
toluene
51/7/15/0d
72/8/15/0e
60/12/13/0f
58/5/28/0g
NMP
[bmim][BF4]h
[bupy][BF4]i
a General reaction conditions: solvent (1 mL), halobenzene (1.2 mmol),
allyl alcohol (1 mmol), Pd(OAc)2 (1.2 mol %); TBAA (2 mmol) stirred at
90 °C under inert atmosphere. b Conversions and product ratios evaluated
by 1H NMR. c For comparison, run 14 of Table 1 has been inserted. d 27%
of 1a′ was formed. e 5% of 1a′ was formed. f 15% of 1a′ was formed. g 9%
of 1a′ was formed. h [bmim][BF4] ) 1-butyl-3-methyl imidazolium tet-
rafluoroborate. i [bupy][BF4] ) N-butyl pyridinium tetrafluoroborate.
Under these conditions, the coordination sphere of palladium
would probably be filled by halide ions so that coordination of
the starting alkenol, which affords the π-complex C, would be
decelerated by the slow deligation of one of these ligands.15
This could be the reason for the higher reaction temperatures
required by the catalytic method A (110 ÷ 130 °C).
1a and b (overall yield 57%) and the carbonyl compound 1c
(43%, Table 1, run 9).
To verify the dependence of selectivity on the concentration
of that base, we gradually increased the TBAA/TBAB ratio,
observing thus a corresponding enhancement of the selectivity
in favor of the allyl alcohols 1a and b (Table 1, runs 9-11).
Subsequently, we replaced completely TBAB with TBAA
by using this latter as both base and reaction medium. Under
these conditions, we observed a twofold effect: (1) an extraor-
dinary increase of the catalyst activity and (2) an almost
complete inversion of selectivity in favor of the arylated allyl
alcohols 1a and b (Table 1, runs 12-20).
The first effect was evidenced by the request of much more
milder reaction conditions; indeed, bromobenzene was reacted
at 60 °C (Table 1, run 15) and iodobenzene was activated even
at room temperature, although with minor selectivity (Table 1,
run 20). As a consequence of the second effect, the amount of
the carbonyl product 1c was reduced to a percentage lower than
5% (Table 1, runs 14 and 18). Moreover, reactions carried out
in TBAA were highly stereoselective, being the conjugated
aromatic alcohol 1a formed all times in high stereoisomeric ratio
(E/Z ratio ) ca. 98:2).
Then, for steric reasons, the migratory insertion of the aryl
group occurs predominantly to the â-position of the alkenol
giving the σ-complex D, while the addition of the aryl moiety
to the R-position occurs to a minor extent (complex E). As the
syn â-elimination can take place on both the sides of the carbon
bonded to the metal, a mixture of arylated allyl alcohols and
arylated carbonyl compounds is expected to be formed by action
of the base. However, as in these cases where the Pd-H
readdition-elimination mechanism can operate, the thermody-
namically favored R/â-substituted carbonyl compounds are
solely observed.
When TBAA is used as the reaction medium, halogen ion
X- initially bonded to palladium is presumably replaced by
acetate (path b), which readily dissociates facilitating the
coordination of the starting alkenol and giving the cationic
complex F. This could be the key factor explaining the high
catalytic activity displayed by palladium in TBAA, which allows
the metal to activate iodo- and bromoarenes at such low reaction
temperatures (rt and 60 °C, respectively).
For comparison, the same reaction experiments carried out
by using TBAA as base were executed in the common organic
solvents. Results given in Table 2 showed that reactions carried
out in molecular solvents were slower and occurred with both
minor conversions and selectivity. In addition, they required
higher reaction temperatures (not lower than 90 °C) and
furnished variable amounts of the byproduct (E)-1-phenyloct-
1-en-3-one (1a′) coming from the oxidation of 1a (Table 2, runs
1-5). At the same time, also the other two different classes of
ILs were tested (viz., an imidazolium and a pyridinium-based
IL), but in both cases reactions did not occur at all (Table 2,
runs 6-7).
Migratory insertion on the double bond occurring on F can
give the two σ-complexes G and I. In this case, the insertion
of the aryl group to the â-position (complex G) is favored by
steric reasons as well as by the formation of a chelate structure,
which is reported4,8,14 to be responsible for the high selectivity
toward the conjugated allyl alcohol. Indeed, this form impedes
the hydrogen atom (Hc) on the carbon bearing the hydroxyl
group to reach the syn-relationship with palladium. As a
consequence, the extraction of the benzylic hydrogen atom (Ha)
should be the one and only pathway for the â-elimination.
Finally, because acetate ion is more basic in TBAA,16 it is
To gain further insights on the TBAA effect, we extended
investigations to other monosubstituted allyl alcohols by varying
the substituents on both the substrate and the aromatic ring of
the aryl halide. Table 3 summarizes the results clearly showing
how the two catalytic systems A and B, on the basis of the two
different ILs TBAB and TBAA, display an opposite selectivity
affording predominantly the arylated carbonyl compounds and
the conjugated allyl alcohols, respectively.
(13) Heck, R. F. Org. React. 1982, 27, 345.
(14) Jeffery, T. Tetrahedron Lett. 1993, 34, 1133-1136.
(15) As already reported by us (see refs 1d, 10-12), in the presence of
TBAB or TBAA, the Ar-Pd-X species could be stabilized by interaction
with the tetraalkylammonium salt affording more stable anionic complexes
+
+
such as [ArPdX2]- NR4 or [ArPdX3]2- 2NR4 (where X ) Br or AcO)
depending on the free coordination sites on palladium. Indeed, if the reaction
occurs on the nanoparticle surface, the number of coordination sites of Pd
is smaller than four because of the linkage of the Pd atom to the metal
bulk.
2598 J. Org. Chem., Vol. 72, No. 7, 2007

Palladium-Catalyzed Heck Arylations of Allyl Alcohols
TABLE 3. Effect of the Substituents in Heck Arylation of Monosubstituted Allyl Alcoholsa
run
R1
R2
Ar
X
catalyst systemb
T [˚C]
t (h)
yields (%)c
product number
ratioc a/b/c/d
1
2
3
4
5
6
7
8
9
10
11
12
13
H
H
H
H
H
H
H
H
H
CH3
H
H
H
H
H
H
H
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
Br
Br
I
I
I
A
B
A
B
B
B
A
B
A
B
A
B
B
130
70
110
50
50
50
130
70
130
70
130
70
100
2
0.5
1
0.5
2.5
3
3
0.5
4
0.8
1
4
90
87
90
84
90
92
90
89
85
92
87
10d
60
2c, d
2a, b
2c, d
2a, b
1a, b, c
3a
4c, d
4a, b, c
5c, d
5a, b, c
6c, d
0/0/85/15
64/36/0/0
0/0/87/13
64/36/0/0
80/11/9/0
100/0/0/0
0/0/94/6
86/6/8/0
0/0/94/6
82/9/9/0
0/0/95/5
80/6/14/0
80/5/15/0
n-C5H11
CH3
I
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C5H11
4-CH3C6H4
4-CH3C6H4
Br
Br
Br
Br
Br
Br
Br
4-CH3OC6H4
4-CH3OC6H4
4-CH3COC6H4
4-CH3COC6H4
4-CH3COC6H4
6a, b, c
6a, b, c
5
a Reaction conditions: mixtures of aryl halides (1.5 mmol) and allyl alcohols (1 mmol) were stirred at the reaction temperature in the presence of the
catalyst system (1.2 mol % of Pd) in molten TBAX (X ) Br- or AcO-). b A: Pd(OAc)2 (0.012 mmol) heated at 110 ÷ 130 °C in molten TBAB (1 g) until
a dark suspension of Pd-nanocolloids is obtained; then, NaHCO3 (2 mmol) and reagents (alkenol and ArX 1 and 1.2 mmol, respectively) are added. B:
Pd(OAc)2 (0.012 mmol), alkenol (1 mmol), and ArX (1.2 mmol) are added to TBAA (1 g) and the mixture is heated at the reaction temperature for the
1
reaction times. c Evaluated by H NMR. d Conversion 30%.
SCHEME 2. The Reaction Mechanism
presumable to expect a further accelerating effect by means of
a rapid neutralization of the Pd-H species occurring intramo-
lecularly on the π-complex H.11
As in this case where the Pd-H readdition-elimination
mechanism can be completely ruled out, the formation of small
amounts of carbonyl product in the reactions carried out in
TBAA can be explained by admitting that the two reaction
pathways a and b can operate simultaneously. The greater the
contribution of truly cationic form of palladium complex inter-
mediate (path b) is, that is, the poorer the coordination ability
of ligand X, the higher the relative yield of allyl alcohol is.
A direct evidence of this hypothesis can be found comparing
selectivity in the reactions carried out in the presence of variable
TBAB/TBAA ratios (Table 1, runs 9-12). The greater the
amount of TBAB in the reaction medium is, that is, the higher
the presence of a good ligand for Pd such as Br-, the higher
the proportion of carbonyl products is and vice versa. Also, the
selectivity in favor of the carbonyl products observed by using
(16) Because of the tetrahedral structure of the tetraalkylammonium
cation of TBAA, the positive charge on the nitrogen atom was shielded by
the bulky butyl chains, and as a consequence, the more naked acetate anions
proved to be more basic than in water.
J. Org. Chem, Vol. 72, No. 7, 2007 2599

Calo`
a
TABLE 4. Heck Arylation of Disubstituted Allyl Alcohols Catalyzed by Pd(OAc)2
run
R1
R2
R3
Ar
X
catalytic systemb
T [˚C]
t (h)
yields (%)c
product number
ratioc a/b/c/d
1
2
3
4
5
6
7
8
9
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C6H5
C6H5
C6H5
C6H5
4-CH3COC6 H4
4-CH3COC6 H4
4-CH3OC6H 4
4-CH3OC6H 4
C6H5
Br
Br
I
A
B
A
B
A
B
A
B
A
B
A
B
130
80
110
80
130
100
130
80
130
70
6
0.5
5
0.5
1
6
6
1.5
1
0.5
2
8
90
92
89
87
90
20d
78
87
90
88
90
85
7b, c, d
7a, b
7b, c, d
7a, b
8c, d
8a, b
9b, c, d
9a, b
10c, d
10a, c
11c, d
11a, b
0/3/47/50
7/93/0/0
0/5/46/49
4/96/0/0
0/0/40/60
10/90/0/0
0/5/45/50
6/94/0/0
0/0//95/5
43/0/21/0e
0/0/69/31
54/26/0/0f
I
Br
Br
Br
Br
Br
Br
Br
Br
CH3
CH3
H
10
11
12
H
CH3
CH3
C6H5
C6H5
C6H5
130
80
H
a Reaction conditions: the same as Table 3. b A: Pd(OAc)2 (0.012 mmol) heated at 110 ÷ 130 °C in molten TBAB (1 g) until a dark suspension of
Pd-nanocolloids is obtained; then, NaHCO3 (2 mmol) and reagents (alkenol and ArX 1 and 1.2 mmol, respectively) are added. B: Pd(OAc)2 (0.012 mmol),
alkenol (1 mmol), and ArX (1.2 mmol) are added to TBAA (1 g) and the mixture is heated at the reaction temperature for the reaction times. c Evaluated
1
by H NMR. d Conversion 25%. e 36% of the byproduct 10a′ was formed. f 20% of the byproduct 11b′ was formed.
SCHEME 3. Directive Effects of Substituents on the Double
Bond of Cinnamic Alcohol
sodium acetate (Table 1, run 8) is explainable with these
assumptions because of the low solubility of this base in TBAB.
Most of the experimental evidence reported in this paper support
the mechanism depicted in Scheme 2:
(1) The addition of the aryl moiety to the R-position
(complexes I and J) occurs to a major extent in TBAA (ranging
from 3% to 36%, see Tables 1-2) than in TBAB, where the
R-product is obtained at a maximum of 6%. This strongly
confirms that in TBAA the cationic mechanism operating as
the coordination of the alkenol by the cationic complex should
cause the polarization of the π system, resulting in a more
longer reaction times (Table 3, runs 12-13). This is in contrast
directed migration of the aryl residue to the slightly more
with the outcome of the analogous reactions carried out in
electrophilic R-position.17
TBAB (Table 1, run 1 and Table 3, runs 7, 9, 11) and the typical
scale reactivity of aryl halides in the Heck reactions (electron
(2) The variable amounts of the R-arylated allyl alcohols
obtained in TBAA seem to be predictable on the basis of the
poor > neutral > electron rich), but it is in complete agreement
structure of the starting alkenol. As can be seen in Table 3, the
percentages of the R-arylated alcohols gradually decrease
starting from 36%, in the case of the allyl alcohol (Table 3, run
4), to 11% for 1-octen-3-ol (Table 3, run 5), until 0% for
3-methyl-1-buten-3-ol (Table 3, run 6). This is in agreement
with the acidity scale of the starting allyl alcohols (primary >
secondary > tertiary) and falls in line with the hypothesis that
the starting alkenol can be partially deprotonated by acetate,
affording the corresponding alcoholate anion which, by enhanc-
ing the electron-rich character of the double bond, would favor
addition to the R-position.
(3) Results in Table 3 show also that in TBAA as reaction
medium, both neutral and electron-rich aryl halides proved to
be more active than the corresponding electron-poor substrates.
In fact, under the same conditions, bromobenzene (Table 1, run
14), p-bromotoluene (Table 3, run 8), and p-bromoanisole (Table
3, run 10) are completely converted in less than 1 h, while
p-bromoacetophenone required higher reaction temperatures and
with a cationic mechanism.17
(4) Further evidence supporting our hypothesis arises from
the outcome of the Heck arylation of disubstituted alcohols
(Table 4). Noteworthy is the high R-selectivity of the reaction
in TBAA on the cinnamic alcohol with respect to the analogous
process in TBAB (Table 4, runs 1-8). Indeed, because of its
nature of primary alcohol, a sensible amount of alcoholate anion
is expected to be formed by the action of the base. It appears
evident in this case that directive effects of both the phenyl
group and the alcoholate moiety add together to favor almost
exclusively the formation of the R-allyl alcohol (Scheme 3).
The opposite trend of the selectivity toward either the arylated
allyl alcohols (method B) or the carbonyl compounds (method
A) was confirmed also with disubstituted olefins (Table 4).
Results also confirm the opposite influence on the catalyst
activity displayed by substituents on the aryl halides in the two
catalytic systems. Indeed, an electron-poor aryl halide such as
p-bromoacetophenone behaved as an activated aryl agent with
method A and as a deactivated one with method B (Table 4,
runs 5-6). Of course, an electron-rich aryl halide such as
p-bromoanisole behaved in the opposite manner (Table 4, runs
7-8).
(17) The formation of a cationic complex intermediate is usually invoked
by many authors to explain the enhancement of R-regioselectivity observed
in the Heck arylation of unsymmetrical olefins, especially the electron-rich
one. The cationic complex can be generated either by means of the assistance
of halide scavengers (thallium(I) or silver(I) salts) or by spontaneous
dissociation of good leaving groups such as the triflate. See, for example:
de Meijere, A.; Meyer, F. E. Angew. Chem., Int. Ed. Engl. 1994, 33, 2379-
2411. Mo, J.; Xu, L.; Xiao, J. J. Am. Chem. Soc. 2005, 127, 751-760.
Excluding cinnamic alcohol, with disubstituted olefins bearing
an alkyl chain on the double bond, the selectivity is complicated
by the formation of arylated products coming from the
2600 J. Org. Chem., Vol. 72, No. 7, 2007

Palladium-Catalyzed Heck Arylations of Allyl Alcohols
SCHEME 4. Selectivity Displayed by 1,1- and
1,2-Disubstituted Alkenols in TBAA
[bmim]- and [bupy]-based ILs are poor reaction media (Table
2, runs 6-7).1d,10,11 However, in the case of reactions in TBAA
(method B) at low temperatures, the formation of nanocolloids
as catalyst reservoir has not been ascertained, and works are in
progress to evaluate also the catalyst recycling.
(3) Finally, by using TBAA as the IL (method B), a very
active Pd-cationic complex operates allowing the reactions to
occur at so mild conditions to activate bromoarenes and
iodoarenes at 60 °C and room temperature, respectively. This
also constitutes, to our knowledge, an unprecedented result in
the Heck couplings under phosphane-free conditions.
Experimental Section
â-elimination occurring on the side of the alkyl chain. Two
model examples are shown in Table 4: (1) the Heck phenylation
of 2-methylprop-2-en-1-ol, a 1,1-disubstituted olefin, that in
TBAA furnished, besides the expected â-arylated products 10a
and 10c, also the terminal alkenol 10a′ (Scheme 4 and Table 4,
run 10) and (2) the arylation of crotyl alcohol, a 1,2-disubstituted
olefin, that afforded in TBAA the expected R- and â-substituted
allyl alcohols 11a and 11b together with the byproduct 11b′
(Table 4, run 12). The same reactions carried out with method
A occurred without side products (Table 4, runs 9 and 11).
General Procedure for the Heck Arylation of Allyl Alcohols
in Molten Tetraalkyammonium Salt (Catalyst Systems A and
B). In a 25-mL round-bottom flask, equipped with a magnetic bar,
tetraalkylammonium salt (TBAB or TBAA) (1 g), Pd(OAc)2, (2.7
mg, 0.012 mmol), alkenol (1 mmol), base (only in method A, 2
mmol), and aryl halide (1.2 mmol) were placed. In the case of using
molecular solvents, a three-necked flask connected with a nitrogen
line was used to create the inert atmosphere. For reactions carried
out at room temperature (method B), TBAA (1 g), Pd(OAc)2, and
iodobenzene were added together and the mixture was melted at
ca. 70 °C. Then, under vigorous stirring, the mixture was cooled
at room temperature and the allyl alcohol was added.
Conclusions
All the reaction mixtures were heated under stirring at the
reaction temperature and were monitored by glc (gas liquid
chromatography) for a maximum of 8 h. Then, after cooling to
room temperature, reaction mixture was washed with diluite HCl
to remove most of both the tetraalkyammonium salt and the
trialkylammine deriving from the IL decomposition. After the
solvent removal, in vacuo, the reaction mixture was examined via
1H NMR to evaluate the product ratio (see Supporting Information).
Next, the whole reaction mixture was poured on a short pad of
silica gel to get the overall yields reported in tables 1-3 and 4.
In summary, our results proved to be of particular interest
for the following reasons:
(1) The outcome of the arylation of allyl alcohols can be
highly controlled by the catalytic systems A and B which are
both highly selective. Aryl-substituted carbonyl compounds and
the corresponding R,â-unsatured alcohols can be obtained by
simply choosing the appropriate reaction medium and the base
(TBAB/NaHCO3 or TBAA, respectively). To our knowledge,
this is the first case in the literature in which a so high selectivity
can be reached on such substrates without using phosphane
ligands, special arylating agents (e.g., triflates), and toxic or
expensive additives (thallium and silver salts).
(2) Protocols A and B proved to be very simple and useful
and do not require special care such as the inert atmosphere or
particular manipulations; both reagents and catalyst source are
mixed together in the IL, assuring this latter the almost
immediate formation of the catalytically active species. In
addition, the nature of surfactant of the tetraalkylammonium
IL allows the stabilization of the Pd nanoparticles that constitute
a reservoir of catalyst. This could be also the reason for which
Acknowledgment. This work was in part financially sup-
ported by Ministero dell’Universita` e della Ricerca Scientifica
e Tecnologica, Rome, and the University of Bari (National
Project: “Stereoselezione in Sintesi Organica: “Metodologie
ed Applicazioni”).
Supporting Information Available: General methods, experi-
mental details, characterization data of the unknown compounds,
and NMR spectra of reaction mixtures. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO070005F
J. Org. Chem, Vol. 72, No. 7, 2007 2601