Regioselective control in the palladium-catalyzed isomerization of methylenecyclopropylcarbinols using acetic acid as a reagent

Article abstract of DOI:10.1055/s-2007-973871

Tuning the regioselectivity of the Pd-catalyzed isomerization of methylenecyclopropylcarbinols in acetic acid is achieved by a subtle choice of the ligand and/or solvent. When dioxane is used as the solvent, penta-2,4-dien-1-ols are formed, whereas when A

Full text of DOI:10.1055/s-2007-973871

LETTER
909
Regioselective Control in the Palladium-Catalyzed Isomerization of
Methylenecyclopropylcarbinols Using Acetic Acid as a Reagent
P
alladium-Catalyze
d
I
i
n
ation of Methylene
S
cyclopropylca
h
rbinols i,* Bao-Yu Wang, Li-Xiong Shao
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, P. R. of China
Fax +86(21)64166128; E-mail: Mshi@mail.sioc.ac.cn
Received 8 December 2006
Table 1 Isomerization of 2-(Phenylmethylene)cyclopropylcarbinol
(E)-1a by a Variety of Catalysts in the Presence of Acetic Acid in
Dioxane
Abstract: Tuning the regioselectivity of the Pd-catalyzed isomer-
ization of methylenecyclopropylcarbinols in acetic acid is achieved
by a subtle choice of the ligand and/or solvent. When dioxane is
used as the solvent, penta-2,4-dien-1-ols are formed, whereas when
AsPh3 is used as the ligand and toluene is used as the solvent, pent-
4-enals are formed. A plausible reaction mechanism is discussed on
the basis of the control experiments.
OH
catalyst
AcOH
+
Ph
OH
dioxane, r.t.
Ph
2a
(E)-1a
Key words: regioselectivity, palladium-catalyzed isomerization,
methylenecyclopropylcarbinols, acetic acid
Entrya Catalyst
Time (h)
Yield (%)b
2a (E,E:Z,E)c
1
2
3
4
5
6
Pd(PPh3)4
Pd(OAc)2
PdCl2(PPh3)2
Pd(dba)2
12
90 (93:7)
50 (93:7)d
n.r.d
Methylenecyclopropanes (MCPs) are highly strained but
readily accessible molecules that serve as useful building
blocks in organic synthesis. MCPs undergo a variety of
ring-opening reactions because the relief of ring strain
provides a potent thermodynamic driving force.1 Transi-
tion-metal-catalyzed reactions (such as Pd, Rh, Ru, and
Pt) of MCPs with various reactants have attracted much
attention.2 Recently, we reported Pd-catalyzed isomeriza-
tion of MCPs in the presence of acetic acid at 80 °C in tol-
uene to give the corresponding 1-substituted or 1,1-
disubstituted dienes in good to excellent yields.3 This re-
sult prompted us further to examine the Pd-catalyzed
isomerization of another type of MCPs, methylenecyclo-
propylcarbinols 1 bearing an additional hydroxymethyl
group.4 During this examination, we found that the regio-
selectivity of this isomerization can be easily tuned by a
subtle choice of the ligand and/or solvent. Namely, when
dioxane is used as the solvent, penta-2,4-dien-1-ols5 are
formed in high yields, whereas when AsPh3 is used as the
ligand and toluene is used as the solvent, pent-4-enals6 are
formed in good yields. A plausible reaction mechanism is
discussed on the basis of the control experiments.
11
13
12
12
12
n.r.
Ru3(CO)12
NiCl2(dppe)
n.r.
n.r.
a Reaction conditions: (E)-1a (0.4 mmol), AcOH (0.16 mmol),
catalyst (0.02 mmol), dioxane (2.0 mL).
b Isolated yields.
c Determined by analysis of 1H NMR spectroscopic data.
d PPh3 (0.16 mmol) was added.
conditions (Table 1, entry 2). PdCl2(PPh3)2, Pd(dba)2,
Ru3(CO)12 and NiCl2(dppe) did not catalyze this reaction
(Table 1, entries 3–6). The best reaction conditions for
this transformation are to carry out the reaction in the
presence of acetic acid (0.4 equiv) and Pd(PPh3)4 (5
mol%) in dioxane at room temperature. Under these opti-
mized conditions, we next examined a variety of methyl-
enecyclopropylcarbinols (E)-1 for this transformation.
The results are summarized in Table 2. The corresponding
isomerized products (E,E)-penta-2,4-dien-1-ols 2 were
obtained in high yields within 11–15 hours as major iso-
mers in most cases (Table 2).
The isomerization of 2-(phenylmethylene)cyclopropyl-
carbinol (E)-1a (0.4 mmol) was first carried out in the
presence of acetic acid (0.16 mmol, 0.4 equiv) with
various transition-metal catalysts (0.02 mmol) at room
temperature in a variety of solvents to screen the best
reaction conditions.7 We found that Pd(PPh3)4 can effec-
tively catalyze the isomerization of (E)-1a to give (E,E)-
5-phenylpenta-2,4-dien-1-ol (2a) in high yield as a major
isomer (E,E:Z,E = 93:7) in 1,4-dioxane (Table 1, entry 1).
Pd(OAc)2 is not as effective as Pd(PPh3)4 under identical
Interestingly, when 2-(phenylmethylene)cyclopropyl-
carbinol (E)-1a (0.4 mmol) was treated with Pd(PPh3)4
(0.02 mmol) in the presence of acetic acid (0.4 mmol, 1.0
equiv) at 80 °C in toluene, (E)-5-phenylpent-4-enal (3a)
was obtained in 62% yield along with a trace of 2a (Table
3, entry 1). Pd(dba)2, Pd(PPh3)4, and Ru3(CO)12 can also
catalyze this isomerization under identical conditions, but
give 3a in lower yields (Table 3, entries 2–4). On the other
hand, PdCl2(MeCN)2, RuCl2(PPh3)4, NiCl2(dppe), and
SYNLETT 2007, No. 6, pp 0909–0912
0
3.
0
4.
2
0
0
7
Advanced online publication: 26.03.2007
DOI: 10.1055/s-2007-973871; Art ID: U14706ST
© Georg Thieme Verlag Stuttgart · New York

910
M. Shi et al.
LETTER
Table 2 Pd-Catalyzed Isomerization of a Variety of Methylene-
Table 4 Ligand Screening for the Pd-Catalyzed Isomerization of
cyclopropylcarbinols (E)-1 in Dioxane in the Presence of Acetic Acid 2-(Phenylmethylene)cyclopropylcarbinol (E)-1a in the Presence of
Acetic Acid in Toluene
OH
Pd(PPh3)4
OH
+
O
R
OH
AcOH
+
Pd(PPh3)4, Ligand
toluene, 80 °C
dioxane, r.t.
R
AcOH
2
Ph
H
(E)-1
Ph
3a
(E)-1a
Entrya (E)-1 (R)
Time (h)
Yield (%)b
2 (E,E:Z,E)c
Entrya
Ligand
Time (h)
Yield (%)b
3a
1
2
3
4
5
6
7
8
9
(E)-1a (Ph)
12
11
11
15
11
12
12
12
12
2a, 90 (93:7)
2b, 86 (96:4)
2c, 84 (98:2)
2d, 91 (94:6)
2e, 92 (98:2)
2f, 87 (96:4)
2g, 91 (98:2)
2h, 93 (96:4)
2i, 90 (94:6)
1
2
–
3
2
63
83
81
62
58
55
50
40
40
20
59c
19
(E)-1b (4-FC6H4)
(E)-1c (4-ClC6H4)
AsPh3
TFP
3
2
(E)-1d (2-ClC6H4)
4
PPh3
2
(E)-1e (4-BrC6H4)
5
PBu3
6
(E)-1f (4-MeC6H4)
(E)-1g (4-MeOC6H4)
(E)-1h [3,4,5-(MeO)3C6H2]
(E)-1i (PhCH2CH2)
6
DPE-Phos
dppp
3
7
12
12
4
8
dppb
9
bipyridine
P(OPh)3
a Reaction conditions: (E)-1 (0.4 mmol), AcOH (0.16 mmol),
Pd(PPh3)4 (0.02 mmol), dioxane (2.0 mL).
b Isolated yields.
10
11
12
18
15
15
c Determined by analysis of 1H NMR spectroscopic data.
Pd(dba)2 + AsPh3
Pd(OAc)2 + AsPh3
a Reaction conditions: (E)-1a (0.4 mmol), AcOH (0.4 mmol),
Pd(PPh3)4 (0.02 mmol), ligand (0.16 mmol), toluene (2.0 mL).
b Isolated yields.
Table 3 Isomerization of 2-(Phenylmethylene)cyclopropylcarbinol
(E)-1a in a Variety of Catalysts in the Presence of Acetic Acid in
Toluene
c Compound 3a was obtained with a small amount of dba.
O
OH
catalyst
To improve the yield of 3a, the isomerization of 2-(phen-
ylmethylene)cyclopropylcarbinol [(E)-1a] was carried
out in the presence of acetic acid and Pd(PPh3)4 with
various ligands and a variety of solvents. As can be seen
from Table 4, 3a was obtained in good yield with AsPh3
or TFP [tri(2-furyl)phosphine] as a ligand in toluene.7
Considering the stability and cost of these two ligands, we
next carried out this transformation in the presence of ace-
tic acid (1.0 equiv), Pd(PPh3)4 (5 mol%) and AsPh3 (0.4
equiv) in toluene at 80 °C. The results are summarized in
Table 5. The corresponding pent-4-enals 3 were obtained
in moderate to high yields within 1.5–12 hours for a vari-
ety of methylenecyclopropylcarbinols (E)-1 along with a
trace of penta-2,4-dien-1-ols 2 (Table 5). Using alkyl-
idenecyclopropylcarbinol (E)-1i as the substrate, the
corresponding product 3i can be also obtained in 30%
yield though in moderate conversion (Table 5, entry 8).
+
AcOH
Ph
H
toluene, 80 °C
3a
Ph
(E)-1a
Entrya
Catalyst
Time (h)
Yield (%)b
3a
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(dba)2
2
10
10
10
24
24
24
24
62c
30
RuCl2(PPh3)4
Ru3(CO)12
25
5
PdCl2(MeCN)2
PdCl2(PPh3)2
NiCl2(dppe)
Ni(acac)2
n.r.
n.r.
n.r.
n.r.
Their structures are determined by spectroscopic data, mi-
croanalyses and HRMS. The control experiment indicated
that 3a is not derived from the Pd(0)-catalyzed isomeriza-
tion of 2a under the standard conditions (Scheme 1).
a Reaction conditions: (E)-1a (0.4 mmol), AcOH (0.4 mmol), catalyst
(0.02 mmol), toluene (2.0 mL).
b Isolated yields.
c PPh3 (0.16 mmol) was added.
The mechanism of this highly regioselective Pd-catalyzed
isomerization of methylenecyclopropylcarbinols (E)-1
has not been unequivocally established, but one plausible
Ni(acac)2 did not catalyze this isomerization under identi-
cal conditions (Table 3, entries 5–8).
Synlett 2007, No. 6, 909–912 © Thieme Stuttgart · New York

LETTER
Palladium-Catalyzed Isomerization of Methylenecyclopropylcarbinols
911
Table 5 Pd-Catalyzed Isomerization of a Variety of Methylene-
cyclopropylcarbinols (E)-1 in Toluene in the Presence of Acetic Acid
OH
(E)-1
O
Pd(PPh3)4, AsPh3
R
AcOH
(E)-1
+
+
2
trace
R
H
toluene, 80 °C
3
AcOH
Pd(0)
AcOPdH
OH
Entrya (E)-1 (R)
Time (h) Yield (%)b
3
R
PdOAc
1
2
3
4
5
6
7
8
(E)-1a (Ph)
2
3a, 83
3b, 79
3c, 78
3d, 75
3f, 66
3g, 90
3h, 70
3i, 30c
A
(E)-1b (4-FC6H4)
2
Ha
Hb
rearrangement
(E)-1c (4-ClC6H4)
1.5
1.5
5
OH
PdOAc
(E)-1d (2-ClC6H4)
(E)-1f (4-MeC6H4)
(E)-1g (4-MeOC6H4)
(E)-1h [3,4,5-(MeO)3C6H2]
(E)-1i (PhCH2CH2)
R
B
path b
path a
3
Ha
O
Hb
5
R
OH
R
12
2
3
a Reaction conditions: (E)-1 (0.4 mmol), AcOH (0.4 mmol),
Pd(PPh3)4 (0.02 mmol), AsPh3 (0.16 mmol).
b Isolated yields.
Scheme 2 Proposed mechanism
c The mixture was stirred at 65 °C and the starting material was recov-
ered in 30% yield.
Pd(PPh3)4
no reaction
AcOH
+
dioxane, r.t.
Ph
(E)-4a
O
Pd(PPh3)4, AsPh3
toluene, 80 °C
OH AcOH
+
Ph
H
Ph
2a
3a
Scheme 3 Palladium-catalyzed isomerization of MCP (E)-4a in the
presence of acetic acid in dioxane
Scheme 1 Control experiment. Reaction conditions: 2a (0.2 mmol),
AcOH (0.2 mmol), Pd(PPh3)4 (0.01 mmol), AsPh3 (0.08 mmol),
toluene (1.0 mL).
strate under identical conditions. This may be due to that
the hydroxyl group in intermediate B can coordinate to Pd
center to stabilize this key species and therefore, provide
a thermodynamic driving force for this Pd-catalyzed reac-
tion.
explanation is proposed in Scheme 2 based on the previ-
ous investigations1,3,8,9 and above experimental observa-
tions. The initial step of this isomerization reaction is the
hydropalladation of the double bond in methylenecyclo-
propylcarbinols (E)-1 with the hydridopalladium species
(H–Pd–OAc), generated from Pd0 catalyst and acetic acid,
to form the cyclopropylcarbinylpalladium complex A.
The cyclopropylcarbinylpalladium to homoallylpalladi-
um rearrangement leads to the formation of the species B.
The subsequent b-hydride elimination (Pd–H) produces
either product 2 (path a: via Pd–Ha elimination) or product
3 (path b: via Pd–Hb elimination) in two different orienta-
tions. The precoordinative solvent dioxane or the AsPh3
ligand might be able to stabilize the reaction intermediate
A or B to give the corresponding product 2 or 3 in good
yield.
In conclusion, we have disclosed a highly regioselective
Pd-catalyzed isomerization of methylenecyclopropyl-
carbinols (E)-1 in the presence of acetic acid. By a subtle
choice of ligand and/or solvent, the corresponding penta-
2,4-dien-1-ols 2 and pent-4-enals 3 can be obtained in
good to excellent yields. The mechanism has been dis-
cussed on the basis of the experimental observations and
the control experiments. Further mechanistic investiga-
tions will be carried out by deuterium labeling experi-
ments as well as DFT calculations. Efforts are in progress
to elucidate the mechanistic details of this reaction and to
disclose its scope and limitations.
The control experiment shown in Scheme 3 suggests that
the hydroxy group in 2-(arylmethylene)cyclopropyl-
carbinols 1 is important in this palladium-catalyzed
isomerization of 2-(arylmethylene)cyclopropylcarbinols
1 because no reaction occurred using MCP (E)-4a as sub-
Acknowledgment
We thank the Shanghai Municipal Committee of Science and Tech-
nology (04JC14083, 06XD14005), Chinese Academy of Sciences
(KGCX2-210-01), and the National Natural Science Foundation of
China for financial support (20472096, 203900502, and 20672127).
Synlett 2007, No. 6, 909–912 © Thieme Stuttgart · New York

912
M. Shi et al.
LETTER
(4) For the preparation of methylenecyclopropylcarbinols:
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