Palladium(II)-catalyzed intramolecular addition of arylboronic acids to ketones

Article abstract of DOI:10.1016/j.tet.2008.05.056

A palladium(II)-catalyzed intramolecular addition of arylboronic acids to ketones was developed. Compared to Pd(OAc)₂ catalysis system, cationic palladium complex with dppp as the ligand has higher catalytic activity and efficiency for wider sc

Full text of DOI:10.1016/j.tet.2008.05.056

Tetrahedron 64 (2008) 7324–7330
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Palladium(II)-catalyzed intramolecular addition of arylboronic acids to ketones
*
Guixia Liu, Xiyan Lu
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 April 2008
Received in revised form 8 May 2008
Accepted 13 May 2008
Available online 16 May 2008
A palladium(II)-catalyzed intramolecular addition of arylboronic acids to ketones was developed. Com-
pared to Pd(OAc)2 catalysis system, cationic palladium complex with dppp as the ligand has higher
catalytic activity and efficiency for wider scope of substrates. From this reaction, the normal addition
product or the dehydrated product could be selectively furnished as controlled by additives. Highly
optically active cyclic tertiary alcohols (up to 96% ee) can be obtained by using chiral cationic palladium
complex as the catalyst.
Keywords:
Ó 2008 Elsevier Ltd. All rights reserved.
Cationic palladium complex
Arylboronic acid
Intramolecular addition
Ketones
Benzocycloalkanols
1. Introduction
groups.8 Also, there are some reports about the use of palladium as
the catalyst for the addition of arylboron compounds to aldehydes,2
Transition metal-catalyzed Grignard-type reactions of arylboron
compounds with carbonyl groups provide powerful and versatile
approaches toward C–C bond formation and the synthesis of al-
cohols.1–3 Several features of the chemistry make it attractive in-
cluding the availability and stability of the substrates, the wide
functional group tolerance as well as the potential application to
asymmetric synthesis.4 Much progress have been seen in the
addition of arylboron compounds to aldehydes1,2 and activated
ketones.3,2d However, the successful examples of targeting simple
ketones as substrates are quite limited, as is anticipated by the
lesser reactivity of ketones toward the nucleophilic addition. Only
recently, rhodium-catalyzed addition of arylboron compounds to
simple ketones was achieved by Miura’s group.5,6
In contrast, the corresponding reactions catalyzed by palladium
are even rarer. In these reactions, aryl-transition metal complexes
generated via transmetalation of arylboron compounds are reactive
species as nucleophiles. Generally, compared to arylrhodium spe-
cies, arylpalladium species are relatively less nucleophilic and have
been involved mainly in the electrophilic reactions, such as carbon–
carbon coupling reactions and the reaction with alcohols and
amines.7 Although it is uncommon for the arylpalladium species
to act as nucleophiles, some examples of the direct insertion of
carbon–heteroatom multiple bonds into arylpalladium inter-
mediates have been reported by Yamamoto, Larock, and other
activated ketones,2d and nitriles.9
Enantioselective addition of arylboronic acids to ketones is
a straightforward strategy for the construction of optically active
tertiary alcohols.10 After the success on Rh-catalyzed asymmetric
addition of arylboronic acids to activated ketones,3b–d we demon-
strated the chiral cationic palladium-catalyzed highly enantio-
selective intramolecular addition of arylboronic acids to ketones,
which provided a convenient synthesis of optically active benzo-
cycloalkanols (Eq. 1).11
R2 OH
*
[{Pd((R)-binap)(μ-OH)}2]2+(TfO-)2
B(OH)2
O
(2.5 mol%)
R1
R1
ð1Þ
Amberlite IRA-400(OH)
(1.5 equiv)
R2
2
toluene, 40 °C
1
In the process of our study on the intramolecular addition of
arylboronic acids to ketones, we found that both neutral and
cationic palladium complexes could catalyze this reaction and the
cationic palladium complexes exhibit higher reactivity and
efficiency (Scheme 1). Meanwhile, with the cationic palladium
complex as the catalyst, either the normal addition product 2 or the
dehydrated product 3 could be selectively furnished by the choice
of additives (Scheme 1).
We report herein the full details of the development of palla-
dium(II)-catalyzed intramolecular addition of arylboronic acids to
ketones. We wish to present the effect of different kinds of palla-
dium(II) catalysts and a full account of the scope and limitations of
this reaction.
* Corresponding author. Tel.: þ86 21 54925158; fax: þ86 21 64166128.
E-mail address: xylu@mail.sioc.ac.cn (X. Lu).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.05.056

G. Liu, X. Lu / Tetrahedron 64 (2008) 7324–7330
7325
Pd(OAc)2
conditions.14 K3PO4 seemed to be the most suitable base, while
KOAc decreased the yield and KF required longer reaction time.
Lowering the temperature led to the prolonged reaction time and
the mixture of 2a and 3a (Table 1, entry 8). The combination of
K3PO4 (2 equiv) and H2O (2 equiv) resulted the desired rate
enhancement and good yield (87%, Table 1, entry 9).
The effect of different palladium catalyst was investigated as
demonstrated in Table 2. With KF as additive, we screened two
other neutral palladium compounds PdCl2(CH3CN)2 and PdCl2. In
the case of PdCl2(CH3CN)2, longer reaction time was required (Table
2, entry 2). The yield was low while PdCl2 was used as catalyst
(Table 2, entry 3). In the further study, we found the ligand bpy was
not necessary. Without bpy, Pd(OAc)2 alone could catalyze the
intramolecular addition well (Table 2, entry 4). No trace of addition
product would be obtained in the absence of palladium catalyst
(Table 2, entry 5).
R2 OH
or [dpppPd( H2O)2]2+(OTf-)2
(5 mol%)
R1
K3PO4 /H2O (2 equiv)
dioxane
B(OH)2
O
2
R1
R2
R2
[dpppPd( H2O)2]2+(OTf-)2
(5 mol%)
1
R1
dioxane
3
Scheme 1. Cationic palladium complex catalyzed addition of arylboronic acids to
ketones.
2. Results and discussion
On the basis of the above investigation, the optimal conditions
for this neutral palladium-catalyzed intramolecular addition re-
action are as follows: 5 mol % of Pd(OAc)2, 2 equiv of K3PO4, and
H2O (2 equiv) in dioxane at 100 ꢀC.
Consequently, a variety of substrates with different substituents
on the ketone carbonyl was investigated to define the scope and
limitation of this Pd(OAc)2 catalyzed intramolecular addition.
Compounds 1a–h were easily prepared starting from the appro-
2.1. Neutral palladium(II)-catalyzed intramolecular addition
of arylboronic acids to ketones
The intramolecular addition of arylboronic acids to ketones
was initially studied using Pd(OAc)2/bpy as the catalyst, which is
effective for other palladium(II)-catalyzed reactions developed by
our group.12 Firstly, efforts were focused on optimizing the reaction
conditions. The representative results are summarized in Table 1. In
the presence of 5 mol % of Pd(OAc)2 and 6 mol % of bpy, substrate 1a
reacted in various solvents at 100 ꢀC to give the dehydrated product
benzofuran (3a) in moderate to low yields (25–66%, Table 1, entries
1–5) along with the deboronated aryl ketone 4a, which is the main
side product. Moderate yield of 3a was observed in dioxane, though
the reaction required 4 to 5 days to reach completion. Additives are
well known to play an important role in the transmetalation be-
tween boron and palladium.13 Therefore, we examined the base
effect on this intramolecular addition reaction. Various bases such
as KOAc, KF, and K3PO4 could increase the reaction rate (Table 1,
entries 6, 7, and 9). Interestingly, the product was changed to the
normal product dihydrobenzofuranol (2a), which was stable
enough not to dehydrate to benzofuran under these basic
priate
After coupling of
a
-bromoketones and 2-iodophenol as shown in Scheme 2.
-bromoketones with 2-iodophenol, and sub-
a
sequent acetalization with ethylene glycol, 5 was obtained. Lith-
iation of 5 with n-BuLi at ꢁ78 ꢀC, quenching with trimethyl borate,
Table 2
Effect of neutral palladium(II) complexes as catalysts
OH
neutral palladium complex
(5 mol%)
B(OH)2
Ph
Ph
K3PO4 (2 equiv)
H2O (2 equiv)
dioxane, 100 °C
O
O
O
1a
2a
Entry
Catalyst
Time (h)
Yielda (%)
1b
2b
3b
4
Pd(OAc)2/bpy
PdCl2(CH3CN)2
PdCl2
Pd(OAc)2
None
18
72
12
5
73
71
57
90
Table 1
Effect of solvents and additives on the intramolecular addition of arylboronic acids
to ketonesa
Ph
5
12
None
OH
Pd(OAc)2 (5 mol%)
bpy (6 mol%)
B(OH)2
Ph
a
Isolated yields.
+
Ph
b
KF (2 equiv) was used as the additive.
Additive
solvent, 100 °C
O
O
O
O
3a
1a
2a
O
I
R2
I
1) K2CO3
Br
Ph
R1
R1
O
+
2) ethylene glycol
O
O
R2
OH
O
O
4a
5
Entry
Solvent
Additive (equiv)
Time (h)
Yieldb (%)
1) n-BuLi, B(OMe)3
B(OH)2
-78 °C
2a
3a
4a
O
2) H2SO4,MeOH
rt
1
2
3
4
5
6
HOAc/THF/H2O (1:1:0.3)
Dioxane/H2O (10:1)
Dioxane
DMSO
Toluene
Dioxane
Dioxane
Dioxane
Dioxane
None
None
None
None
None
KOAc (2)
KF (2)
108
72
108
12
12
12
18
72
5
d
d
d
d
d
41
73
58
72
87
25
41
66
62
50
d
d
15
d
d
46
38
12
31
50
51
10
13
10
5
O
R1
R2
1
R1
R2
R1
R2
7
8c
9
KF (2)
1a
Ph
H
H
H
H
1e
1f
4-CF3C6H4
2-furyl
H
H
H
K3PO4 (2)
K3PO4 (2),
H2O (2)
4-MeOC6H4
1b
1c
1d
10
Dioxane
5
2-MeOC6H4
4-ClC6H4
CH3
1g
1h
a
All reactions were carried out with 1a (0.2 mmol), Pd(OAc)2 (5 mol %), and bpy
(6 mol %) at 100 ꢀC.
-(CH2)4-
b
Isolated yields.
Reaction at 80 ꢀC.
c
Scheme 2. Synthesis of substituted arylboronic acids.

7326
G. Liu, X. Lu / Tetrahedron 64 (2008) 7324–7330
Table 3
Table 4
Reactions of arylboronic acids bearing different kinds of ketonesa
Reactions of arylboronic acids bearing different substituents on the aryl ringa
R1
Entry
Substrate
Product
Yieldb (%)
HO
B(OH)2
Pd(OAc)2 (5 mol%)
O
O
K3PO4/H2O (2 equiv )
dioxane
R2
Ph
B(OH)2
O
O
R1
HO
100 °C
O
R2
2
1
1
79
Ph
O
Entry
1
R1
R2
2
Yieldb (%)
1i
2i
1
2
3
4
1a
1b
1c
1d
1e
1f
Ph
H
H
H
H
H
H
H
2a
2b
2c
2d
2e
2f
90
93
91
94
79
62
60
79
B(OH)2
OH
Ph
4-MeOC6H4
2-MeOC6H4
4-ClC6H4
4-CF3C6H4
2-Furyl
Ph
2
3
91
82
MeO
Cl
O
O
5
MeO
Cl
O
6
2j
1j
7c
8c
1g
1h
CH3
–(CH2)4–
2g
2hd
B(OH)2
OH
Ph
a
Unless otherwise indicated, all reactions were performed at 100 ꢀC using the
substrate (0.2 mmol), K3PO4 (2 equiv), H2O (2 equiv), and Pd(OAc)2 (5 mol %) in di-
oxane (2 mL) under N2.
Ph
O
O
O
b
Isolated yield.
H2O (0.1 mL) was added.
The stereochemistry of 2h was determined by NOESY spectra as cis.
2k
1k
c
d
B(OH)2
OH
Ph
Ph
Ph
4c
5d
6
90
40
O
O
and then hydrolysis to remove the acetal group gave the resulting
boronic acids 1a–h.
O
2l
1l
With various phenylboronic acids bearing different ketones in
hand, we explored the reaction scope and the results are presented
in Table 3. The intramolecular arylations of either electron-donat-
ing or electron-withdrawing aromatic ketones proceeded smoothly
to afford the corresponding dihydrobenzofuranol in moderate to
good yields (79–94%, Table 3, entries 1–5). When ortho-substituted-
phenyl ketone 1c was subjected to the reaction conditions, good
yield (91%) of 2c was achieved (Table 3, entry 3). The reaction
conditions were also compatible with heteroaromatic, aliphatic,
and cyclic ketones, which resulted in moderate yields (60–79%,
Table 3, entries 6–8). Thus, neither electronic nor steric effects of
ketones appeared to play a major role on the reactivity of
substrates.
HO Ph
B(OH)2
O
O
O
1m
2m
B(OH)2
Ph
None
d
d
O
1n
B(OH)2
O
O
7
None
Ph
Encouraged by the excellent results obtained above, we then
investigated the effect of substituents on the aromatic ring of bo-
ronic acids. The starting materials 1i–l were prepared according to
the procedure for the substrates 1a–h. 1-Naphthylboronic acid (1i)
gave the corresponding product 2i in a moderate yield of 79% (Table
4, entry 1). The reaction for OMe, Cl, CH3 substituted arylboronic
acids (1j–l) led to good yields (82–91%) of the desired products 2j–l
(Table 4, entries 2–4).
1o
a
Reactions were carried out at 100 ꢀC using the substrate (0.2 mmol), K3PO4
(2 equiv), H2O (2 equiv), and Pd(OAc)2 (5 mol %) in dioxane (2 mL) under N2.
b
Isolated yield.
c
H2O (0.1 mL) was added.
KF (2 equiv) was used as the additive.
d
Series of dihydrobenzofuranol derivatives having been readily
obtained, we decided to investigate the possibility of synthesizing
other type of cycloalkanols. The substrates 1m and 1n were pre-
pared according to our previously reported procedure11 and 1o was
prepared from (2-phenyl-1,3-dioxolan-2-yl)-methanol as shown in
Scheme 3.
yield was low (40%, Table 4, entry 5), for compound 1m was easily
transformed to 1-phenyl-propenone. To our disappointment, sub-
strates 1n and 1o did not afford the desired products under opti-
mized conditions.
From the structure of the substrates, it was found that the only
difference of the neighboring atom of arylboronic acid between 1a–
m and 1n–o was the change of oxygen to carbon atom. This results
reflects that the neighboring oxygen in the substrates have a pro-
nounced effect on the success of this Pd(OAc)2 catalyzed intra-
molecular addition.
Br
Br
NaH
O
O
O
O
+
HO
O
Br
Ph
Ph
5o
A plausible explanation for this role of oxygen atom is shown in
Scheme 4. The arylpalladium intermediate 6, formed by the
transmetalation of Pd(OAc)2 with substrate 1, could partition into
two competitive pathways: (i) protonolysis to generate the
deboronated aryl ketone 4 (pathway-I) or (ii) addition to intra-
molecular ketones to yield the desired product 2 (pathway-II). As
a hypothesis, the neighboring oxygen atom seemed to be helpful for
the addition step (pathway-II), accounting for its ability to co-
ordinate to the palladium atom (mode A)15 or its electron-donation
character (mode B) to increase the nucleophilicity of the arylpal-
ladium species.16 The coordination of the oxygen to the palladium
B(OH)2
1) n-BuLi, B(OMe)3
O
2) H2SO4,MeOH
O
Ph
1o
Scheme 3. Synthesis of substituted arylboronic acids.
Under standard reaction conditions, substrate 1m only gave
a trace of desired product. When KF was used as the additive,
successful cyclization of compound 1m occurred to afford six-
membered ring product 2m, a derivative of chroman. However, the

G. Liu, X. Lu / Tetrahedron 64 (2008) 7324–7330
7327
atom could stabilize the species 6 and bring the carbonyl group
nearer to the metal atom. All of these could facilitate the addition of
arylpalladium species 6 to ketones.
the catalyst under the same condition, almost five days were re-
quired (Table 1, entry 3). With K3PO4 (2 equiv) and H2O (2 equiv) as
additives, dihydrobenzofuranol (2a) could be obtained selectively
in high yield (85%, Table 5, entry 2). The presence of K3PO4 and H2O
is critical for the formation of dihydrobenzofuranol. Without K3PO4
and H2O, only dihydrobenzofuran was formed (Table 5, compare
entries 1 and 2, 3 and 4, 7 and 8, 10 and 11). A prolonged reaction
time would favor the formation of dihydrobenzofuran (Table 5,
compare entries 8 and 9). Thus, 80 ꢀC seemed to be the most
suitable temperature. Even at room temperature, 1a could afford
the addition product in moderate yield within a couple of hours
(Table 5, entries 10 and 11). A slightly lower yield was observed
when [Pd(dppe)(H2O)2]2þ(TfOꢁ)2 (5 mol %) was used as the catalyst
(Table 5, entry 6).
PdOAc
O
I
O
R1
R1
[H]
R2
R2
1
4
6
II
Pd(OAc)2
R2 OPd
2
R1
K3PO4
H2O
The scope and generality of the intramolecular addition was
examined using [Pd(dppp)(H2O)2]2þ(OTfꢁ)2 (7) as the catalyst.
Under condition A (5 mol % of 7, 2 equiv of K3PO4, and 2 equiv of
H2O in dioxane at 80 ꢀC), all substrates in hand could react
smoothly to give the corresponding cycloalkanols in moderate to
good yield (66–94%, Table 6). By using this method, derivatives of
dihydrobenzofuranol (2a–l), indanol (2n), chromanol (2m), and
isochromanol (2o) could be obtained. Especially, 2n and 2o, which
could not be formed in Pd(OAc)2 catalysis system, were obtained in
good yields (83% and 82%, Table 6).
δ−
PdOAc
PdOAc
R1
R1
R2
R2
( )n
O
O
O
B
A
O
Scheme 4. Role of oxygen atom in this reaction.
Thus, by utilizing Pd(OAc)2 as the catalyst, intramolecular ad-
dition of arylboronic acids to ketones could be achieved. However,
the substrates were limited to those having a neighboring oxygen
atom in the arylboronic acid and the catalytic system need to be
improved.
Table 6
2.2. Cationic palladium complex [Pd(dppp)(H2O)2]2D(TfOL
(7) as the catalyst
)
2
[Pd(dppp)(H2O)2]2þ(OTfꢁ)2 (7) catalyzed intramolecular addition of arylboronic
acids to ketones under condition Aa
R2 OH
B(OH)2
With the aim of improving the efficiency and generality of this
intramolecular reaction, we turned our efforts to other palladium
catalysts. Among kinds of Pd(II) catalysts, cationic Pd(II) complexes
have great advantages over analogous neutral ones mainly in two
dimensions: (1) vacant coordination site for substrates or reagents
and (2) stronger Lewis acidity. Cationic palladium complexes have
exhibited high reactivity in many kinds of reactions.17
7 (5 mol%)
O
R1
R1
K3PO4/H2O(2 equiv)
dioxane, 80 °C
R2
1
2
condition
A
MeO
OH
OH
OH
O
OMe
Initially, cationic palladium complex [Pd(dppp)(H2O)2]2þ(TfOꢁ)2
(7)18 was chosen as the catalyst to examine the intramolecular 1,2-
addition of 1a (Table 5). To our delight, upon heating at 100 ꢀC for
5 h in the presence of 5 mol % of 7 in dioxane, 1a underwent ad-
dition smoothly to afford dihydrobenzofuran (3a) in extremely high
yield (quantitative, Table 5, entry 1). In contrast, with Pd(OAc)2 as
O
O
2a, 91%
2d, 90%
2b, 94%
2c, 89%
2f, 79%
OH
OH
OH
O
O
O
Cl
CF3
O
O
Table 5
Optimization of reaction conditions with [Pd(dppp)(H2O)2]2þ(OTfꢁ
catalysta
)
2
(7) as the
2e, 68%
Ph
HO
OH
HO
OH
Ph
B(OH)2
Ph
7 (5 mol%)
Ph
O
O
Additive
dioxane
O
O
O
O
3a
1a
2a
2g, 66%
2h, 82%b
2i, 88%
OH
OH
OH
Entry
Additive (2 equiv)
Temp (ꢀC)
Time (h)
Yielda (%)
Cl
2a
3a
O
O
O
MeO
1
2
3
4
d
100
100
80
80
80
80
60
60
60
25
25
5
5
5
1
1.5
2
5
1
5
d
85
d
91
65
85
d
94
d
12
78
100
d
K3PO4, H2O
d
96
d
2j, 91%b
2k, 91%
2l, 75%b
K3PO4, H2O
K3PO4, H2O
K3PO4, H2O
d
5b
6c
7
24
d
Ph
OH
Ph
OH
O
Ph
OH
95
d
O
8
9
10
11
K3PO4, H2O
K3PO4, H2O
d
95
82
d
7
7
2n, 83%c
2o, 82%
2m, 88%
K3PO4, H2O
a
b
c
a
Cited yields are of materials isolated by silica gel chromatography.
H2O (0.1 mL) was added.
KF (1 equiv) was added as additive.
Isolated yield.
b
c
Using 2.5 mol % of 7 as catalyst.
Using 5 mol % of [Pd(dppe)(H2O)2]2þ(OTfꢁ)2 as catalyst.

7328
G. Liu, X. Lu / Tetrahedron 64 (2008) 7324–7330
Table 7
The proposed catalytic cycle is shown in Scheme 5. It has been
demonstrated that interconversion exists between aquo compound
[Pd(dppp)(H2O)2]2þ(OTfꢁ)2 (7) catalyzed intramolecular addition of arylboronic
acids to ketones under condition Ba
7 and the corresponding binuclear m
-hydroxo complex 70, which is
R2
a dimeric form of the mono-hydroxo complex 8.19 An equivalent
amount of HOTf and H2O should be generated when complex 8 was
formed. The Pd hydroxo complex 8 was supposed to be the active
catalytic species, which enable smooth transmetalation with the
substrate 1 without any assistance of additive bases. Two features
of intermediate 8 maybe accounted for its feasible transmetalation:
cationic nature of the transition metal complex4d,20 and the exis-
tence of the hydroxo ligand.4a,21 After transmetalation, owing to the
vacant coordination site on the cationic palladium complex, the
intramolecular ketone easily coordinated to the palladium center to
give intermediate 10. High Lewis acidity of palladium center in
cationic species 10 may activate the carbonyl group by coordination
resulting in very smooth intramolecular 1,2-addition to produce
intermediate 11.4a,18,21 While in Pd(OAc)2 catalysis system, the
analogous intermediate 6 (Scheme 4) needs the neighboring oxy-
gen atom to assist the addition. The subsequent fast hydrolysis of
11 would afford product 2 and regenerate the catalytic active in-
termediate 8. In most cases, the product 2 could dehydrate to
produce 3 catalyzed by HOTf formed in situ as described above.
Indeed, a control experiment showed that 5 mol % of HOTf in
dioxane at room temperature did catalyze the dehydrate of 2a to
produce 3a. Otherwise, if a base was added to neutralize the HOTf,
product 2 could be isolated after reaction.
7 (5 mol%)
B(OH)2
O
R1
dioxane
R1
R2
80 °C
condition
B
1
3
OMe
Ph
OMe
O
O
3b, 95%
O
3c, 98%
3a, 96%
Cl
CF3
O
O
3f, 98%
O
3d, 96%
O
3e, quant
Ph
Ph
O
O
O
MeO
H
3h, 53%
2+
3j, 91%
P
P
OH2
OH2
P
P
P
P
O
3i, 88%
Pd
Pd
Pd
2TfO-
-H2O
O
2TfO-
H
-TfOH
7'
7
Ph
Ph
Ph
Cl
P
P
OH
TfO-
Pd
8
O
O
3k, quant
Cat. HOTf
-H2O
ArB(OH)2
1
2
3
3n, 83%
3l, 96%
a
Cited yields are of material isolated by silica gel chromatography.
P
P
H
O
R2
OPd
On the other hand, in the presence of 5 mol % of 7, in dioxane at
P
P
B(OH)2
R1
Pd
80 ꢀC (condition B) most substrates afforded the dehydrated
products selectively in good to excellent yields (82% to quantitative,
Table 7), though 1,2,3,4-tetrahydro-dibenzofuran (3h) was formed
only in moderate yield (53%, Table 7). In case of 1m and 1o, poor
selectivity was observed. Substrate 1m gave 43% yield of 3m along
with 53% yield of 2m (Eq. 2). When 1o was subjected to condition B,
no trace of dehydrated product was afforded and 2o was produced
in 88% of yield (Eq. 3). Interestingly, when 10 mol % of Yb(OTf)3 was
added under the condition B, substrate 1m offered the dehydrated
product 3m selectively in high yield (96%) (Eq. 4).
Ar
9
11
P
Pd
P
O
Ph
Scheme 5. Proposed catalytic cycle of the reaction.
10
Cationic palladium 7 has been demonstrated to be an efficient
catalyst for the intramolecular addition of arylboronic acids to
ketones. It can catalyze this addition reaction smoothly without the
assistance of a base in transmetalation step and a neighboring
oxygen atom in addition step, which indicated great advantages
over Pd(OAc)2 catalysis system.
Ph
Ph
OH
B(OH)2
O
O
Condition B
Ph
ð2Þ
ð3Þ
ð4Þ
+
O
O
1m
2m: 53%
3m: 43%
Ph
OH
B(OH)2
O
2.3. Asymmetric version
O
Condition B
O
Ph
Ph
Having developed successful protocols for the intramolecular
addition of arylboronic acid to ketones, we turned our efforts to-
ward the asymmetric version. The attempts at using Pd(OAc)2
combined with chiral ligands to induce enantioselectivity were
unsuccessful (Table 8, entries 1 and 2). Our attention was then fo-
cused on the easily prepared chiral cationic palladium complexes
12 and 13. Unfortunately, with the catalyst 12 under the optimized
reaction conditions, 2a was formed in high yield (89%) with
1o
2o: 88%
Ph
O
7 (5 mol%)
B(OH)2
O
O
Yb(OTf )2 (10 mol%)
dioxane, 80 °C
2h
1m
3m: 96%

G. Liu, X. Lu / Tetrahedron 64 (2008) 7324–7330
7329
Table 8
HO
R1
R2
B(OH)2
( )n
R
R1
R2
*
cat. 13 (2.5 mol%)
Optimization of asymmetric reaction conditions
( )n
Amberlite IRA-400(OH)
cat.
OH
Ph
R
B(OH)2
X
X
(1.5 equiv)
(5 mol%Pd)
O
toluene, 40 °C
Ph
additive
solvent
X = O or C
O
O
2a
n = 1 or 2
O
1a
Scheme 6. Asymmetric intramolecular addition of arylboronic acids to ketones.
O
O
catalysis system, cationic palladium complex 7 have higher cata-
lytic activity and efficiency for wider scope of substrates. With
using 7 as the catalyst, different products, the normal addition
product 2 or the dehydrated product 3, could be furnished
selectively as controlled by additives. Though the combination of
chiral ligands and Pd(OAc)2 could not induce the enantio-
selectivity, highly optically active cyclic tertiary alcohols (up to 96%
ee) can be obtained by using chiral cationic palladium complex as
the catalyst.
L*:
OH
OH
PPh2
PPh2
N
N
Ph
Ph
L1
L2: (R)-BINOL
L3: (R)-BINAP
H
O
cat.
2+
OH2
OH2
P
P
P
P
P
P
-
-
.
.
Pd
2TfO
*
2TfO
Pd
Pd
*
*
O
H
12
13
P
P
= (R)-BINAP
*
4. Experimental section
4.1. General
Entry
Catalyst
Solvent
Additivea
Temp/time
(ꢀC/h)
Yieldb
(eec) (%)
1d
2d
3
4
5
6
7
8
9
10
11
12e
13d
Pd(OAc)2/L1
Pd(OAc)2/L2
12
13
13
13
13
13
13
13
13
13
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
CH2Cl2
MeOH
DMF
THF
Toluene
Toluene
Toluene
A
A
A
A
B
B
B
B
B
B
B
B
B
100/5
100/5
80/1
80/1
80/2
40/72
40/5.5
40/5.5
40/-
74 (0)
88 (0)
89 (7)
All reactions were carried out in dry solvents under a nitrogen
atmosphere unless otherwise noted. All solvents were dried and
distilled before use according to the standard methods. The prog-
ress of all reactions was monitored by thin layer chromatography to
ensure that the reactions had reached completion.
77 (28)
85 (82)
83 (92)
81 (85)
53 (20)
None
94 (90)
85 (92)
75 (88)
44 (78)
40/9
4.2. Representative procedure for the Pd(OAc)2 catalyzed
intramolecular addition of arylboronic acids to ketones to
furnish cycloalkanols
40/12
40/41
40/96
Pd(OTf)2/L3
a
Additive: A: K3PO4 (2 equiv), H2O (2 equiv); B: Amberlite IRA-400 (OH)
Under nitrogen, K3PO4 (113 mg, 2 equiv) was added to a mixture
of 1a (73.7 mg, 0.288 mmol), Pd(OAc)2 (3.4 mg, 5 mol %), and water
(11 mL, 2 equiv) in dioxane (2.9 mL). The reaction mixture was
stirred at 100 ꢀC for 5 h. After the reaction was completed as
monitored by TLC, the reaction mixture was quenched with H2O
and the aqueous layer was extracted with EtOAc (3ꢂ20 mL). The
organic layers were dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified by flash column chro-
matography (petroleum ether/EtOAc, 8:1) to obtain the product 2a
(55 mg, 90%).
(1.5 equiv).
b
Isolated yield.
c
Determined by HPLC analysis using a Chiralcel OD column.
Chiral ligand (6 mol %) was used.
H2O (2 equiv) was added.
d
e
extremely low ee (7%, Table 8, entry 3). When chiral Pd complex 13
was used instead of 12, a slight improvement in the ee value was
observed (28%, Table 8, entry 4). To our delight, while employing
anion exchange resin (Amberlite IRA-400 (OH)) as the additive, we
effectively furnished the cyclization product 2a in good yield with
high enantiomeric excess (85% yield, 82% ee; Table 8, entry 5). The
screening of different temperature and solvents showed that the
reaction proceeded smoothly at 40 ꢀC in less polar solvents such as
CH2Cl2, THF, and dioxane with high yield and ee value (Table 8,
entries 6–11). In contrast, the results were much worse in polar
solvents such as DMF and MeOH (Table 8, entries 8 and 9). Per-
forming the reaction in DMF completely inhibited the desired
intramolecular addition (Table 8, entries 9). Finally, the best result
was provided in toluene at 40 ꢀC (85% yield, 91% ee; Table 8, entry
11). Addition of 2 equiv of H2O led to lower yield and longer
reaction time as shown in entry 12. Other catalyst such as Pd(OTf)2/
BINAP could not give the equally good result (Table 8, entry 13).
Under the optimized asymmetric reaction conditions, avariety of
substrates including various aromatic, heteroaromatic, and aliphatic
ketones could be used to afford the optically active tertiary alcohols
in good to excellent yield and enantioselectivity (Scheme 6).11
4.2.1. 3-Phenyl-3-hydroxy-2,3-dihydrobenzofuran (2a)22
Oil; 1H NMR (300 MHz, CDCl3)
d 7.51–6.91 (m, 9H), 4.67 and 4.49
(AB q, J¼10.2 Hz, 2H), 2.54 (br s, 1H). 13C NMR (75 MHz, CDCl3)
d
160.5, 142.5, 132.1, 130.6, 128.2, 127.5, 126.0, 124.4, 121.4, 110.7,
86.0, 82.5. IR (oil)
(Mþ, 100), 194, 77.
n
3437 (br), 3061, 1600 cmꢁ1. MS (m/z, EI): 212
4.3. Representative procedure for [Pd(dppp)(H2O)2]2D(OTfL
)
2
(7) catalyzed intramolecular addition of arylboronic acids to
ketones under condition A to yield cycloalkanols
Under nitrogen, K3PO4 (128.1 mg, 0.6 mmol) was added to
a mixture of 1a (76.6 mg, 0.3 mmol), 7 (12.6 mg, 0.015 mmol), and
water (11 mL, 0.6 mmol) in dioxane (3 mL). The reaction mixture
was stirred at 80 ꢀC for 1 h. After the reaction was completed as
monitored by TLC, the reaction mixture was quenched with H2O
and the aqueous layer was extracted with EtOAc (3ꢂ20 mL). The
organic layers were dried over Na2SO4 and concentrated under
reduced pressure. The residue was purified by flash chromato-
graphy (petroleum ether/EtOAc, 8:1) to obtain the product 2a
(58 mg, 91%).
3. Conclusion
We have developed a palladium(II)-catalyzed intramolecular
addition of arylboronic acids to ketones. Compared to Pd(OAc)2

7330
G. Liu, X. Lu / Tetrahedron 64 (2008) 7324–7330
4.4. Representative procedure for [Pd(dppp)(H2O)2]2D(OTfL
(7) catalyzed intramolecular addition of arylboronic acids to
ketones under condition B to yield the dehydrated products of
cycloalkanols
)
2
2. For Ni or Pd-catalyzed addition of arylboron compounds to aldehydes, see: (a)
Takahashi, G.; Shirakawa, E.; Tsuchimoto, T.; Kawakami, Y. Chem. Commun.
2005, 1459; (b) Yamamoto, T.; Ohta, T.; Ito, Y. Org. Lett. 2005, 7, 4153; (c) Suzuki,
K.; Arao, T.; Ishii, S.; Maeda, Y.; Kondo, K.; Aoyama, T. Tetrahedron Lett. 2006, 47,
5789; (d) He, P.; Lu, Y.; Dong, C.-G.; Hu, Q.-S. Org. Lett. 2007, 9, 343.
3. For Rh-catalyzed addition of arylboron compounds to activated ketones, see:
(a) Matsuda, T.; Makino, M.; Murakami, M. Org. Lett. 2004, 6, 1257; (b) Shintani,
R.; Inoue, M.; Hayashi, T. Angew. Chem., Int. Ed. 2006, 45, 3353; (c) Toullec, P. Y.;
Jagt, R. B. C.; de Vries, J. G.; Feringa, B. L.; Minnaard, A. J. Org. Lett. 2006, 8, 2715;
(d) Martina, S. L. X.; Jagt, R. B. C.; de Vries, J. G.; Feringa, B. L.; Minnaard, A. J.
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K.; Shibata, T. Comprehensive Asymmetric Catalysis; Jacobsen, E. N., Pfaltz, A.,
Yamamoto, H., Eds.; Springer: Berlin, 2004; Suppl. 1, pp 95–106; (c) Boronic
Acids: Preparation and Applications in Organic Synthesis and Medicine; Hall, D. G.,
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Under nitrogen, a mixture of 1a (51.3 mg, 0.2 mmol) and
[Pddppp(H2O)2]2þ(TfOꢁ)2 (4.1 mg, 5 mol %) was stirred in dioxane
(2 mL) at 80 ꢀC for 5 h. After cooling, the reaction mixture was
concentrated under reduced pressure. The residue was purified by
flash chromatography (petroleum ether/EtOAc, 20:1) to obtain the
product 3a (37 mg, 95%).
4.4.1. 3-Phenylbenzofuran (3a)23
1H NMR (300 MHz, CDCl3)
d
7.86–7.28 (m, 10H). IR (oil)
n 3057,
5. Ueura, K.; Miyamura, S.; Satoh, T.; Miura, M. J. Organomet. Chem. 2006, 691,
2821.
3025, 747, 697 cmꢁ1. MS (m/z, EI): 194 (Mþ, 100), 166, 83.
6. For selected examples of Rh-catalyzed addition of other organometallic
reagents to simple ketones, see: (a) Takezawa, A.; Yamaguchi, K.; Ohmura, T.;
Yamamoto, Y.; Miyaura, N. Synlett 2002, 1733; (b) Oi, S.; Moro, M.; Fukuhara, H.;
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4.5. Representative procedure for asymmetric cyclization of
1a catalyzed by 13 to furnish the optically active
cycloalkanols11
Under nitrogen, Amberlite IRA(OH) (1.5 equiv) was added to
a solution of 1a (51.2 mg, 0.2 mmol), 13 (9.0 mg, 2.5 mol %) in tol-
uene (2 mL). The reaction mixture was stirred at 40 ꢀC for 12 h.
After the reaction was completed as monitored by TLC, the reaction
mixture was quenched with 1 N NaOH (8 mL) and the aqueous
layer was extracted with EtOAc (3ꢂ15 mL). The organic layers were
dried over Na2SO4 and concentrated under reduced pressure. The
residue was purified by flash column chromatography (petroleum
ether/EtOAc, 8:1) to obtain the product 2a (36 mg, 85%). The ee
value was determined by chiral HPLC using a Chiralcel OD-H col-
Kamijo, S.; Sasaki, Y.; Kanazawa, C.; Schu¨beler, T.; Yamamoto, Y. Angew. Chem.,
Int. Ed. 2005, 44, 7718.
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2005, 14, 211 and references therein.
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nedouche, J. Org. Biomol. Chem. 2007, 5, 873.
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20
[
a]
ꢁ114.5 (c 1.00, CHCl3).
D
Acknowledgements
14. The additive base is necessary to prevent the product for further dehydration to
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We thank the Major State Basic Research Program
(2006CB806105). We also thank the National Natural Sciences
Foundation of China (20423001, 20732005) and the Chinese
Academy of Sciences for the financial support.
16. Zhao, L.; Lu, X.; Xu, W. J. Org. Chem. 2005, 70, 4059.
Supplementary data
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Experimental procedure, characterization data, and copies of
1H and 13C NMR spectra for new compounds are provided. Sup-
plementary data associated with this article can be found in the
online version, at doi:10.1016/j.tet.2008.05.056.
References and notes
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