Cascade reactions: Sequential homobimetallic catalysis leading to benzofurans and β,γ-unsaturated esters

Article abstract of DOI:10.1002/adsc.200606037

The concatenation between a Pd(0)-promoted deallylation catalytic cycle and a Pd(II)-promoted heterocyclization catalytic cycle (an example of what we have named "sequential homobimetallic catalysis") has been shown to occur starting from 1-(2-allyloxyphenyl)-2-yn-1-ols 1 to afford 2-benzofuran-2- ylacetic esters 2 and β,γ-unsaturated esters in high yields under carbonylative conditions. In view of the conceptual as well as the synthetic importance of the process, the mechanistic aspects and the synthetic scope of the reaction have been investigated in detail. All the experimental evidence is in agreement with the sequential homobimetallic mechanism, and the reaction has proven to be of general synthetic applicability.

Full text of DOI:10.1002/adsc.200606037

FULL PAPERS
DOI: 10.1002/adsc.200606037
Cascade Reactions: Sequential Homobimetallic Catalysis Leading
to Benzofurans and b,g-Unsaturated Esters
Bartolo Gabriele,a,* Raffaella Mancuso,b Giuseppe Salerno,b and Mirco Costac
a
Dipartimento di Scienze Farmaceutiche, Università della Calabria, 87036 Arcavacata di Rende (Cosenza), Italy
Fax : (+39)-0984-492-044; e-mail: b.gabriele@unical.it
Dipartimento di Chimica, Università della Calabria, 87036 Arcavacata di Rende (Cosenza), Italy
Dipartimento di Chimica Organica e Industriale, Università di Parma, 43100 Parma, Italy
b
c
Received: February 1, 2006; Accepted: April 15, 2006
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: The concatenation between a Pd(0)-pro- of the process, the mechanistic aspects and the syn-
moted deallylation catalytic cycle and a Pd(II)-pro- thetic scope of the reaction have been investigated in
moted heterocyclization catalytic cycle (an example detail. All the experimental evidence is in agreement
of what we have named “sequential homobimetallic with the sequential homobimetallic mechanism, and
catalysis”) has been shown to occur starting from 1- the reaction has proven to be of general synthetic
(2-allyloxyphenyl)-2-yn-1-ols 1 to afford 2-benzofur- applicability.
an-2-ylacetic esters 2 and b,g-unsaturated esters in
high yields under carbonylative conditions. In view Keywords: benzofurans; carbonylation; palladium;
of the conceptual as well as the synthetic importance sequential catalysis; b,g-unsaturated esters
Introduction
catalysis”), is represented by the Pd(0)-catalyzed deal-
lylation/Pd(II)-catalyzed carbonylative heterocycliza-
The concatenation between different catalytic cycles, tion reaction of 1-(2-allyloxyphenyl)-2-yn-1-ols 1 lead-
in which the product of the first cycle becomes the ing to benzofuran derivatives 2, which has recently
substrate of the second cycle and so on (sequential or been communicated by us [Eq. (1)].[2]
tandem catalysis, Figure 1) is rather frequent in bio-
logical systems, where a substrate can be subsequently
transformed into the final product through a sequence
of biosynthetic steps catalyzed by different enzymes,
but it is not so commonly observed in chemical sys-
tems.
Compared to the huge number of examples of
single catalytic processes promoted by an organome-
tallic catalyst, relatively few examples of sequential
catalytic cycles promoted by different metal systems
(sequential heterobimetallic catalysis) have appeared
in the literature.[1] However, to the best of our knowl-
edge, the first example of a concatenation of different
catalytic cycles promoted by the same metal, but in
different oxidation states (“sequential homobimetallic
In this process, the first catalytic cycle (consisting of
deallylation of 1, with simultaneous allylic carbonyla-
tion) is promoted by a Pd(0) complex, and affords a
product (the free phenol 3) that acts as the substrate
of the second catalytic cycle (consisting of a carbony-
lative heterocyclization leading to 2), promoted by a
Pd(II) species (Scheme 1).
We now report a complete account on this kind of
reactivity. In view of the conceptual as well as the
Figure 1. Sequential catalysis.
Adv. Synth. Catal. 2006, 348, 1101 – 1109
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1101

Bartolo Gabriele et al.
FULL PAPERS
Scheme 1. Sequential homobimetallic catalysis leading to
benzofurans 2.
synthetic importance of the process,[3,4] the mechanis-
tic aspects and the synthetic scope of the reaction
have been investigated in detail.
Scheme 3.
Scheme 4.
Results and Discussion
Our investigations were initially focused on the possi-
bility to synthesize benzofuran-2-acetic esters (an im-
portant class of benzofuran derivatives, with impor-
tant biological activity)[4] in one step starting from 2-
(1-hydroxyalk-2-ynyl)phenols 3, through the PdI2-cat-
alyzed heterocyclization-alkoxycarbonylation-reduc-
tion sequence shown in Scheme 2.
termediate (Scheme 2). Free phenols 3, however, with
This mechanistic hypothesis was based on our pre- R2 =alkyl, were, according to the literature, difficult
vious studies on the PdI2-catalyzed carbonylation re- to obtain in the pure state owing to their instability
actions leading to heterocycles.[5] In particular, we and tendency to polymerize.[7] This was confirmed by
have reported several examples of exo-dig type heter- our attempts to prepare 2-(1-hydroxyhept-2-ynyl)phe-
ocyclization-alkoxycarbonylation processes catalyzed nol (R1 =H, R2 =Bu), which were unsuccessful. One
by PdI2 in conjunction with an excess of KI under oxi- possibility to bypass this inconvenience was to protect
À
dative conditions, with oxygen as the oxidant, as ex- the phenolic OH group with a suitable function, re-
emplified in Scheme 3.
movable in situ under the reaction conditions. Our
On the other hand, we have also recently showed choice fell on the allyl group, potentially removable
À
À
that an H Pd I species is able to promote the reduc- through oxidative addition to Pd(0) followed by
tion of an allylic alcohol function through the forma- cleavage by HI and carbonylation (Scheme 5).
tion of a p-allyl complex, with elimination of water,
We therefore needed the presence of both a Pd(0)
catalyst, able to promote the deallylation-carbonyla-
followed by protonolysis, according to Scheme 4.[6]
We therefore reasoned that the PdI2/KI-catalyzed tion cycle, and a Pd(II) catalyst (PdI42À), able to pro-
carbonylation of 2-(1-hydroxyalk-2-ynyl)phenols 3, mote the heterocyclization-methoxycarbonylation-re-
carried out in the absence of oxygen, could directly duction cycle, i.e., a sequential catalysis in which a
afford benzofurans 2 through initial heterocyclization- suitable Pd(0) complex catalyzed the formation of the
alkoxycarbonylation followed by the reduction by substrate undergoing the subsequent reaction, cata-
À
À
H Pd I of the allyl alcohol moiety of the resulting in- lyzed by PdI2 (sequential homobimetallic catalysis).
The model substrate we used to test this possibility
was 1-(2-allyloxyphenyl)hept-2-yn-1-ol (1a; R1 =H,
Scheme 2.
Scheme 5.
1102
www.asc.wiley-vch.de
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 1101 – 1109

Sequential Homobimetallic Catalysis
FULL PAPERS
R2 =Bu), which was initially reacted in MeOH at
1008C under 15 atm of CO in the presence of
PdACHTREUNG(PPh3)4 (1 mol%), PdI2 (1 mol%) and KI (KI:PdI2
molar ratio=10). After 5 h, 2-benzofuran-2-ylhexano-
ic acid methyl ester (2a) was indeed formed in 32%
GLC yield at ca. 50% substrate conversion, thus con-
firming the validity of our hypotheses [Eq. (2) and
Table 1, entry 1].
ally leading to the benzofuran are depicted in
The GLC and GC/MS analysis of the reaction Scheme 6.
crude showed the formation of but-3-enoic acid
In agreement with our hypotheses, the reaction car-
methyl ester as co-product, in agreement with ried out in the absence of PdACHTRE(UNG PPh3)4 led to the forma-
Scheme 1. The two sequential catalytic cycles eventu- tion of only small amounts of 2a (3%), while the
Table 1. Reactions of 1-(2-allyloxyphenyl)hept-2-yn-1-ol (1a) with CO (15 atm) in MeOH at 1008C in the presence of Pd cat-
alysts.[a]
Entry Pd
(PPh3)4:PdI2:KI:Ligand:1a Ligand
H2O:PdI2
Conv. of 1a Yield of 2a Yield of 4a Yield of 5a
Molar Ratio
Molar Ratio [%][b]
[%][c]
[%][b]
[%][b]
1
2
3
4
5
6
7
0.5:0.5:10:0:100
0:1:10:0:100
1:0:0:0:100
0:1:10:4:100
0:1:10:5:100
0:1:10:3:100
0:1:10:2:100
-
-
-
0
0
0
50
80
30
44
62
49
100
95
100
20
32
3
60
2
PPh3
PPh3
PPh3
PPh3
200
200
200
200
200
200
200
200
200
33
30
22
10
5
11
8
2
2
traces
4
71
52
66
8
4
6
80:1:10:1:100
9
PPh
3
0:1:10:0:100
-
10
11
12
13
14
15
16
17
0:1:10:4:100
0:1:10:3:100
0:1:10:4:100
0:1:10:4:100
0:1:10:4:100
0:1:10:2:100
0:1:10:1:100
0:1:10:4:100
PBu3
PBu3
PCy3
T
U
dppe
dppe
P
15
4
60
65
0
20
10
100
100
4820
0
0
21
2
2
traces
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
1000
0
G
G
E
7
4
4
2
0
820
4
2
65
20
12
85
60
50
85
180:1:10:4:100
P
85
19
20
21
22
23
24
25
26
27
0:1:10:4:100
P
100
100
90
100
100
100
100
40
49
52
52
56
38traces
71
100
100 3
100
62
60
0
0:1:10:4:100
0:1:10:4:100
0:1:10:2:100
0:1:10:4:100
0:1:10:8:100
0:1:10:4:100
0:1:10:4:100
0:1:2:4:100
AsPh3
SbPh3
bipy
bipy
bipy
40
3
3
phen
85
A
25
20
46
32
29
17
59
98(91)
882
7
traces
traces
1
PPh3
280:1:100:4:100
PPh
3
29
30
31
0:1:200:4:100
0:1:100:4:100
0:1:10:4:100
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
-
8
32[d] 0:1:100:4 :100
33[d,e] 0:1:100:4:100
34[d,e] 0:1:100:4:100
35[d,e] 0:1:100:0:100
200
200
0
200
85
2
[a]
Unless otherwise noted, all reactions were carried out in MeOH (0.22 mmol of 1a/mL of MeOH, 2 mmol scale based on
1a) under 15 atm (at 258C) of CO for 5 h.
[b] Based on starting 1a, by GLC.
[c]
GLC yield (isolated yield) based on 1a.
[d] The reaction was carried out under 30 atm (at 258C) of CO.
[e]
Reaction time was 15 h.
Adv. Synth. Catal. 2006, 348, 1101 – 1109
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
1103

Bartolo Gabriele et al.
FULL PAPERS
mation of unidentified heavy product (entry 3). This
result proves that, in the absence of the Pd(II) cata-
lyst, the free phenol intermediate does not undergo
the heterocylization reaction, and goes through de-
composition instead.
Interestingly, we have found that a PPh3-stabilized
Pd(0) complex could be formed in situ directly from
PdI2 and PPh3 working in MeOH in the presence of
small amounts of H2O. In fact, under these conditions,
À
À
formation of an I Pd CO2H species (from the reac-
tion between PdI2, CO and H2O)[9] occurs, whose de-
carboxylation[10] affords H Pd I in equilibrium with
Pd(0) and HI (Scheme 7).
À
À
Scheme 7.
Actually, the use of PdI2 (1 mol%) in conjunction
with 10 equivs. of KI, 4 equivs. of PPh3 and 200
equivs. of H2O (at 1008C and under 15 atm of CO, as
in the previous experiments) led to a 33% yield of 2a
together with a 2% yield of 4a at 44% substrate con-
version (entry 4). The use of a higher amount of PPh3
Scheme 6. Sequential homobimetallic catalysis leading to
benzofurans 2: the two sequential cycles.
main reaction product turned out to be 1-allyloxy-(1- led to similar results (entry 5). On the other hand, the
methoxyhept-2-ynyl)benzene (4a), still bearing the al- use of a lower amount of PPh3 led to less satisfactory
lyloxy group (60% yield, deriving from etherification results, as shown by entries 6–8. In the absence of
of the alcoholic function of 1a, entry 2) [Eq. (3)]. 4- PPh3, the yields of 2a, 4a and 5a were 11, 66 and 6%,
respectively (entry 9). This means that the presence of
PPh3 is essential for stabilizing the Pd(0) complex, re-
sponsible for the initial deallylation reaction. We next
tested the effect of the nature of other ligands on the
reaction. The results obtained, reported in entries 10–
26, clearly indicate PPh3 as the ligand of choice. The
results obtained by changing the KI:PdI2 and
H2O:PdI2 ratio with 4 mol of PPh3 per mol of PdI2
are shown in entries 27–31. The optimal molar ratio
was found to be H2O:KI:PdI2 =200:100:1 (substrate
conversion=52% after 5 h, yields of 2a, 4a and 5a=
46, 1 and 0%, respectively, entry 28). It is interesting
to note that, according to the fact that the presence of
H2O is necessary to generate the Pd(0) species re-
sponsible for in situ deallylation, the reaction carried
(2-Allyloxyphenyl)-2-butylbuta-2,3-dienoic acid methyl out in the absence of water afforded 4a as the main
ester (5a) (2%, from Tsuji-type carbonylation[8] of product (17%) with only traces of 2a (entry 31). The
the propargylic function of 1a) was also detected in effect of rising the CO pressure from 15 to 30 atm
the reaction mixture under these conditions. This was also tested. As can be seen by comparing the re-
result confirms that practically no deallylation occur- sults reported in entries 28and 32, working with
red in the absence of the Pd(0) catalyst.
On the other hand, when the reaction was carried conversion rate and product selectivity.
out in the presence of Pd(PPh3)4 alone, partial de- The next experiments were aimed at achieving
composition of the substrate was observed with for- complete substrate conversion in order to maximize
PCO =30 atm had a beneficial effect both on substrate
AHCTREUNG
1104
www.asc.wiley-vch.de
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 1101 – 1109

Sequential Homobimetallic Catalysis
FULL PAPERS
the yield of 2a. Under the optimized conditions found (entries 50–53) or even alkynyl substituent (entry 54)
before (PdI2:KI:PPh3:H2O:1a=1:100:4:200:100, T= could be present at the benzylic position. Finally, p-
1008C, PCO =30 atm, 1a concentration=0.22 mmol donors (entries 55–60) as well as electron-withdrawing
per mL of anhydrous MeOH), the conversion of 1a (entries 61 and 62) groups could be present on the ar-
reached 100% after 15 h, benzofuran 2a being ob- omatic ring.
tained in a GLC yield as high as 98% [91% isolated,
Interestingly, in the case of substrates 1e and 1f,
Eq. (4) and entry 33]. To further confirm our mecha- bearing a methyl group at the benzylic position,
enyne by-products 6e and 6f (ensuing from deallyla-
tion and dehydration of the tertiary alcoholic group)
could be isolated after 15 h reaction time. These com-
pounds proved to be possible intermediates in the for-
mation of benzofurans 2, as shown by the results ob-
tained by prolonging the reaction time to 24 h (en-
tries 41 and 43, to be compared with entries 40 and
42, respectively). In the case of substrate 1f, rising the
nistic hypotheses, the same reaction was carried out CO pressure from 30 to 60 atm also had a beneficial
in the absence of water: 2a was obtained in only 8%
effect on product selectivity (entries 44 and 45, to be
yield, while the main reaction product was the methyl compared with entries 42 and 43, respectively). That
ether 4a (83% yield; the allene 5a was also formed in enynes 6e and 6f could also afford 2e and 2f is con-
2% yield, entry 34). Similar results were observed
when the reaction was carried out in the presence of
water but in the absence of PPh3 (entry 35).
Our methodology could be successfully applied to a
variety of differently substituted substrates, as shown
in Eq. (5) and Table 2. All the tested substrates af-
ceivable, since the dienic intermediates ensuing from
heterocyclization-alkoxycarbonylation can easily un-
À
À
dergo reduction by H Pd I (Scheme 8).
Scheme 8.
In the case of substrates 1g and 1i (bearing an alkyl
forded the corresponding benzofurans in good to ex- or phenyl substituent at the benzylic position and
cellent isolated yields (62–91%), working under 30– with the triple bond conjugated with a phenyl group),
90 atm of CO. Thus, the triple bond could also be ter- an undesired methoxylation by-reaction, with forma-
minal (entries 36 and 37) or substituted with a very tion of 2-methyoxymethylbenzofurans 7g and 7i, re-
bulky alkyl group (entries 38, 42–45) or conjugated spectively, was observed (entries 46–48, 51 and 52).
with a phenyl group (entries 39, 46–49, 51–53, 56, 58,
This by-reaction results from methanol attack on
60, 62).[11] An additional alkyl (entries 40–49), phenyl the allylic carbocation (stabilized by the alkyl or
Adv. Synth. Catal. 2006, 348, 1101 – 1109
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
1105

Bartolo Gabriele et al.
Table 2. Reactions of 1-(2-allyloxyphenyl)-2-yn-1-ols 1 with CO in MeOH at 1008C in the presence of PdI2-KI-H2O.[a]
FULL PAPERS
Entry
1
R1
R2
R3
R4
R5
PCO [atm]
Time [h]
Yield of 2 [%][b]
36
37
38
39
40
41
42
43
44
45
46
47
48[i]
49[i]
50
51
52[i]
53[i]
54
55
56
57
58
59
60
61
62
1b
1b
1c
1d
1e
1e
1f
1f
1f
1f
1g
1g
1g
1g
1h
1i
1i
1i
1j
1k
1l
1m
1n
1o
1p
1q
1r
H
H
H
H
H
H
t-Bu
Ph
Bu
Bu
t-Bu
t-Bu
t-Bu
t-Bu
Ph
Ph
Ph
Ph
Bu
Ph
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
OMe
Cl
Cl
30
60
30
30
30
30
30
30
60
60
30
60
60
90
30
30
60
90
30
30
30
30
30
30
30
30
30
15
15
15
15
15
24
15
24
15
24
15
15
15
15
15
15
24
24
15
15
15
15
15
15
15
15
15
70
70
8
0
2
8
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
1-hexynyl
H
H
H
H
H
H
H
H
62[c]
8
3
62[d]
74[e]
79[f]
8
0
55[g]
70[h]
75[j]
81
74
63[k]
73[l]
81
Ph
Ph
H
H
H
H
Bu
Bu
Ph
Bu
Ph
Bu
Ph
Bu
Ph
80
84
82
80
62
87
71
8
H
OMe
OMe
H
H
H
H
H
H
8
H
79
[a]
Unless otherwise noted, all reactions were carried out in MeOH (0.22 mmol of 1 per mL of MeOH, 2 mmol scale based
on 1) in the presence of PdI2 (1 mol%), KI, PPh3, and H2O (PdI2:KI:PPh3:H2O molar ratio=1:100:4:200) at 1008C. Sub-
strate conversion was quantitative in all cases.
[b] Isolated yield based on starting 1.
[c]
The reaction also led to the formation of 2-(1-methylenehept-2-ynyl)phenol (6e) (20%).
[d] The reaction also led to the formation of 2-(4,4-dimethyl-1-methylenepent-2-ynyl)phenol (6f) (17%).
[e]
The reaction also led to the formation of 6f (6%).
[f] The reaction also led to the formation of 6f (2%).
[g]
The reaction also led to the formation of 2-(methoxyphenylmethyl)-3-methylbenzofuran 7g (26%).
[h] The reaction also led to the formation of 7g (14%).
[i]
The KI:PdI2 molar ratio was 200.
[j] The reaction also led to the formation of 7g (9%).
[k] The reaction also led to the formation of 2-(methoxyphenylmethyl)-3-phenylbenzofuran 7i (21%).
[l] The reaction also led to the formation of 7i (7%).
phenyl R1 group and by conjugation with the R2
phenyl group) ensuing from HI-promoted elimination
of water from the vinylpalladium intermediate, as
shown in Scheme 9.
The methoxylation by-reaction could be easily cur-
tailed by working at higher CO pressures (which
favor the CO insertion at the level of the vinylpalladi- Scheme 9.
1106
www.asc.wiley-vch.de
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 1101 – 1109

Sequential Homobimetallic Catalysis
FULL PAPERS
spectra were recorded at 258C on a Bruker DPX Avance
300 spectrometer in CDCl3 solutions at 300 MHz and
75 MHz, respectively, with Me4Si as internal standard.
Chemical shifts (d) and coupling constants (J) are given in
ppm and in Hz, respectively. IR spectra were taken with a
Perkin–Elmer Paragon 1000 PC FT-IR spectrometer. Mass
spectra were obtained using a Shimadzu QP-2010 GC-MS
apparatus at 70 eV ionization voltage. Microanalyses were
carried out with a Carlo Erba Elemental Analyzer Model
1106. All reactions were analyzed by TLC on silica gel 60
F254 and by GLC using a Shimadzu GC-2010 gas chromato-
graph and capillary columns with polymethylsilicone + 5%
phenylsilicone as the stationary phase (HP-5). Column chro-
matography was performed on silica gel 60 (Merck, 70–230
mesh). Evaporation refers to the removal of solvent under
reduced pressure.
um intermediate) and by rising the KI:PdI2 molar
ratio (which, on the other hand, increases the concen-
tration of iodide anions, thus making the formation of
the allylic carbocation less favored), as shown by en-
tries 47–49 (to be compared with entry 46) and 52 and
53 (to be compared with entry 51).
The nature of the allylic protecting group could
also be changed, as shown by the results obtained
with
1-[2-(3-phenylallyloxy)phenyl]hept-2-yn-1-ol
(1a’), which, under the usual conditions, afforded 2a
in 83% yield. As expected on the basis of the sequen-
tial mechanism, the reaction also led to the formation
of 4-phenylbut-3-enoic acid methyl ester (70% yield),
together with small amounts of (3-methoxypropenyl)-
benzene (by direct MeOH attack on the phenyallyl-
palladium complex) [12%, Eq. (6)]. Thus, the present
Substrates were prepared, purified and characterized as
described in the Supporting Information. Characterization
data for products 2a–2r, 4a, 5a, 6e, 6f, 7g, and 7i can also be
found in the Supporting Information.
General Procedure for Carbonylation of 1-(2-Allyl-
oxyphenyl)-2-yn-1-ols 1a–r to Benzofuran-2-acetic
Esters 2a–r and Separation of Products (Tables 1 and
2, entries 33, 36–39, 41, 45, 49, 50, 53–62)
A 250 mL stainless steel autoclave was charged with PdI2
(7.2 mg, 2.0·10À2 mmol), KI (332.0 mg, 2.0 mmol), PPh3
(21.0 mg, 8.0·10À2 mmol) and a solution of 1 (2.0 mmol) in
anhydrous MeOH (9.1 mL). Water (72 mL, 4.0 mmol) was
then added, and the autoclave was sealed, purged at room
temperature several times with CO with stirring (10 atm)
and eventually pressurized at 30 atm (1a, 1a’, 1c–e, 1h, 1j–r),
60 atm (1b, 1f), or 90 atm (1g, 1i). After stirring at 1008C
for 15 h (1a, 1a’, 1b–d, 1g, 1h, 1j–r) or 24 h (1e, 1f, 1i), the
autoclave was cooled and degassed. The solvent was evapo-
rated and products were purified by column chromatogra-
phy on silica gel: 2a (1:1 hexane-CH2Cl2, colorless oil,
449.5 mg, 91%); 2b (8:2 hexane-AcOEt, yellow oil,
265.8mg, 70%); 2c (8:2 hexane-AcOEt, pale yellow solid,
mp 60–618C, 395.4 mg, 80%); 2d (8:2 hexane-acetone,
yellow oil, 438.1 mg, 82%); 2e (9:1 hexane-AcOEt, pale
yellow oil, 431.2 mg, 83%); 2f (8:2 hexane-AcOEt, yellow
oil, 416.8mg, 80%); 2g (9:1 hexane-AcOEt, yellow oil,
453.4 mg, 81%); 2h (95:5 hexane-AcOEt, pale yellow oil,
478.1 mg, 74%); 2i (8:2 hexane-AcOEt, yellow oil,
555.8mg, 81%); 2j (9:1 hexane-acetone, yellow oil,
520.6 mg, 80%); 2k (8:2 hexane-AcOEt, yellow oil,
463.7 mg, 84%); 2l (8:2 hexane-AcOEt, yellow oil,
486.6 mg, 82%); 2m (8:2 hexane-AcOEt, yellow oil,
440.9 mg, 80%); 2n (8:2 hexane-AcOEt, yellow oil,
368.3 mg, 62%); 2o (8:2 hexane-AcOEt, yellow oil,
481.5 mg, 87%); 2p (8:2 hexane-AcOEt, yellow oil,
419.3 mg, 71%); 2q (7:3 hexane-AcOEt, pale yellow oil,
493.2 mg, 88%); 2r (8:2 hexane-acetone, yellow oil,
476.8mg, 79%).
methodology can permit one to couple the heterocyc-
lization-carbonylation of the 1-oxy-(2-hydroxy-2-
ynyl)benzene moiety of the substrate with the substit-
utive carbonylation of the allyloxy moiety of the same
substrate, thus achieving two synthetically important
goals in the same catalytic process.
Conclusions
In conclusion, we have shown that two different com-
plexes of palladium, with palladium in different oxi-
dation states, may efficiently catalyze two catalytic
cycles in ordered sequence (“sequential homobimetal-
lic catalysis”). Thus, the concatenation of a Pd(0)-cat-
alyzed carbonylative deallylation catalytic cycle with
a Pd(II)-catalyzed carbonylative heterocyclization cat-
alytic cycle has allowed to obtain benzofuran-2-acetic
esters and b,g-unsaturated esters simultaneously in
one step starting from the same substrate, easily pre-
pared from commercially available products through
a few simple synthetic steps.
Experimental Section
General Remarks
Melting points were determined with a Reichert Thermovar
apparatus and are uncorrected. 1H NMR and 13C NMR
Adv. Synth. Catal. 2006, 348, 1101 – 1109
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
1107

Bartolo Gabriele et al.
FULL PAPERS
hexane-AcOEt as eluent. Order of elution: 2f (yellow oil,
323.2 mg, 62%), 6f (yellow oil, 67.4 mg, 17%).
Carbonylation of 1-(2-Allyloxyphenyl)-hept-2-yn-1-ol
1a to a Mixture of 2-Benzofuran-2-ylhexanoic Acid
Methyl Ester (2a), 1-Allyloxy-(1-methoxyhept-2-
ynyl)benzene (4a), and 4-(2-Allyloxyphenyl)-2-
butylbuta-2,3-dienoic Acid Methyl Ester (5a) and
Separation of Products (Table 1, entry 7)
Carbonylation of 2-(2-Allyloxyphenyl)-4-phenylbut-
3-yn-2-ol (1g) to a Mixture of (3-methylbenzofuran-
2-yl)phenylacetic Acid Methyl Ester (2g) and
2-(Methoxyphenylmethyl)-3-methylbenzofuran (7g)
and Separation of Products (Table 2, entry 46)
A 250 mL stainless steel autoclave was charged with PdI2
(7.2 mg, 2.0·10À2 mmol), KI (33.5 mg, 0.2 mmol), PPh3
(10.5 mg, 4.0·10À2 mmol) and a solution of 1a (489.0 mg,
2.0 mmol) in anhydrous MeOH (9.1 mL). Water (72 mL,
4.0 mmol) was then added, and the autoclave was sealed,
purged at room temperature several times with CO with
stirring (10 atm) and eventually pressurized at 15 atm. After
stirring at 1008C for 5 h, the autoclave was cooled and de-
gassed. The solvent was evaporated and products were puri-
fied by column chromatography on silica gel using 6:4
hexane-CH2Cl2 as eluent. Order of elution: 2a (yellow oil,
49.6 mg, 10%), 4a (yellow oil, 367.2 mg, 71%), 5a (yellow
oil, 45.8mg, 8%).
A 250 mL stainless steel autoclave was charged with PdI2
(7.2 mg, 2.0·10À2 mmol), KI (332.0 mg, 2.0 mmol), PPh3
(21.0 mg, 8.0·10À2 mmol) and a solution of 1g (556.5 mg,
2.0 mmol) in anhydrous MeOH (9.1 mL). Water (72 mL,
4.0 mmol) was then added, and the autoclave was sealed,
purged at room temperature several times with CO with
stirring (10 atm) and eventually pressurized at 30 atm. After
stirring at 1008C for 15 h, the autoclave was cooled and de-
gassed. The solvent was evaporated and products were puri-
fied by column chromatography on silica gel using 9:1
hexane-AcOEt as eluent. Order of elution: 7g (yellow oil,
132.3 mg, 26%), 2g (yellow oil, 307.7 mg, 55%).
Carbonylation of 2-(2-Allyloxyphenyl)-oct-3-yn-2-ol
(1e) to a Mixture of 2-(3-Methylbenzofuran-2-yl)-
hexanoic Acid Methyl Ester (2e) and 2-(1-Methyl-
enehept-2-ynyl)phenol (6e) and Separation of Products
(Table 2, entry 40)
Carbonylation of 1-(2-Allyloxyphenyl)-1,3-di-
phenylprop-2-yn-1-ol (1i) to a Mixture of
Phenyl-(3-phenylbenzofuran-2-yl)acetic Acid Methyl
Ester (2i) and 2-(Methoxyphenylmethyl)-3-methyl-
benzofuran (7i) and Separation of Products (Table 2,
entry 51)
A 250 mL stainless steel autoclave was charged with PdI2
(7.2 mg, 2.0·10À2 mmol), KI (332.0 mg, 2.0 mmol), PPh3
(21.0 mg, 8.0·10À2 mmol) and a solution of 1e (516.5 mg,
2.0 mmol) in anhydrous MeOH (9.1 mL). Water (72 mL,
4.0 mmol) was then added, and the autoclave was sealed,
purged at room temperature several times with CO with
stirring (10 atm) and eventually pressurized at 30 atm. After
stirring at 1008C for 15 h, the autoclave was cooled and de-
gassed. The solvent was evaporated and products were puri-
fied by column chromatography on silica gel using 9:1
hexane-AcOEt as eluent. Order of elution: 6e (yellow oil,
80.5 mg, 20%), 2e (yellow oil, 323.6 mg, 62%).
A 250 mL stainless steel autoclave was charged with PdI2
(7.2 mg, 2.0·10À2 mmol), KI (332.0 mg, 2.0 mmol), PPh3
(21.0 mg, 8.0·10À2 mmol) and a solution of 1i (680.5 mg,
2.0 mmol) in anhydrous MeOH (9.1 mL). Water (72 mL,
4.0 mmol) was then added, and the autoclave was sealed,
purged at room temperature several times with CO with
stirring (10 atm) and eventually pressurized at 30 atm. After
stirring at 1008C for 15 h, the autoclave was cooled and de-
gassed. The solvent was evaporated and products were puri-
fied by column chromatography on silica gel using 95:5
hexane-AcOEt as eluent. Order of elution: 7i (yellow oil,
132.6 mg, 21%), 2i (yellow oil, 430.1 mg, 63%).
Carbonylation of 2-(2-Allyloxyphenyl)-5,5-
dimethylhex-3-yn-2-ol (1f) to a Mixture of
3,3-Dimethyl-2-(3-methylbenzofuran-2-yl)butanoic
Acid Methyl Ester (2f) and 2-(4,4-Dimethyl-1-
methylenepent-2-ynyl)phenol (6f) and Separation of
Products (Table 2, entry 42)
References
[1] For recent excellent reviews, see: a) J.-C. Wasilke, S. J.
Obrey, R. T. Baker, G. C. Bazan, Chem. Rev. 2005, 105,
1001–1020; b) J. M. Lee, J. Na, H. Han, S. Chang,
Chem. Soc., Rev. 2004, 33, 302–312; c) D. E. Fogg,
E. N. dos Santos, Coord. Chem. Rev. 2004, 248, 2365–
2379; see also: d) Multimetallic Catalysis in Organic
Synthesis, (Eds.: M. Shibasaki, Y. Yamamoto), Wiley-
VCH: Weinheim, 2004, pp 46–48.
A 250 mL stainless steel autoclave was charged with PdI2
(7.2 mg, 2.0·10À2 mmol), KI (332.0 mg, 2.0 mmol), PPh3
(21.0 mg, 8.0·10À2 mmol) and a solution of 1f (516.5 mg,
2.0 mmol) in anhydrous MeOH (9.1 mL). Water (72 mL,
4.0 mmol) was then added, and the autoclave was sealed,
purged at room temperature several times with CO with
stirring (10 atm) and eventually pressurized at 30 atm. After
stirring at 1008C for 15 h, the autoclave was cooled and de-
gassed. The solvent was evaporated and products were puri-
fied by column chromatography on silica gel using 8:2
[2] B. Gabriele, R. Mancuso, G. Salerno, L. Veltri, Chem.
Commun. 2005, 271–273.
[3] The synthesis of 2-substituted 3-allylbenzofurans start-
ing from 2-alkynyl-1-allyloxybenzenes through a se-
quence of steps involving oxidative addition of the sub-
1108
www.asc.wiley-vch.de
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2006, 348, 1101 – 1109

Sequential Homobimetallic Catalysis
FULL PAPERS
strate to Pd(0) to give a p-allyl palladium species fol-
lowed by heteroannulation has been reported: a) N.
Monteiro, G. Balme, Synlett 1998, 746–747; b) S.
Cacchi, G. Fabrizi, L. Moro, Synlett 1998, 741–745.
[4] Benzofurans are a very important class of heterocyclic
molecules, which may display a wide range of biologi-
cal activity. In particular, benzofuranacetic derivatives
are known to exhibit a marked pesticidal, insecticidal,
and acaricidal activity: T. N. Wheeler, (Union Carbide
Corp., USA), US Patent 4,431,650, 1977; Chem. Abstr.
1984, 101, 54903u.
[5] For recent reviews on PdI2-catalyzed carbonylation re-
actions leading to heterocyclic derivatives, see: a) B.
Gabriele, G. Salerno, M. Costa, Synlett 2004, 2468–
2483; b) B. Gabriele, G. Salerno, M. Costa, G. P. Chiu-
soli, Curr. Org. Chem. 2004, 8, 919–946; c) B. Gabriele,
G. Salerno, M. Costa, G. P. Chiusoli, J. Organomet.
Chem. 2003, 687, 219–228; for other very recent exam-
ples, see: d) B. Gabriele, P. Plastina, G. Salerno, M.
Costa, Synlett 2005, 935–938; e) A. Bacchi, M. Costa,
N. Della Cà, B. Gabriele, G. Salerno, S. Cassoni, J. Org.
Chem. 2005, 70, 4971–4979.
[6] G. P. Chiusoli, M. Costa, L. Cucchia, B. Gabriele, G.
Salerno, L. Veltri, J. Mol. Catal. A: Chem. 2003, 204,
133–142.
[7] D. Pflieger, B. Muckensturm, Tetrahedron Lett. 1990,
31, 2299–2300.
[8] J. Tsuji, T. Mandai, J. Organomet. Chem. 1993, 451, 15–
21 and references cited therein.
[9] B. Gabriele, L. Veltri, G. Salerno, M. Costa, G. P. Chiu-
soli, Eur. J. Org. Chem. 2003, 1722–1728and referen-
ces cited therein.
ample, ref.[7] and a) R. Bertani, G. Cavinato, L. Tonio-
lo, G. Vasapollo, J. Mol. Catal. 1993, 84, 165–176;
b) V. V. Grushin Chem. Rev. 1996, 96, 2011–2033.
[11] In contrast to 1a, 2-(1-hydroxyprop-2-ynyl)phenol (3b)
and 2-(1-hydroxy-3-phenylprop-2-ynyl)phenol (3d),
bearing a triple bond terminal or conjugated with a
phenyl group, respectively, were sufficiently stable to
be prepared in the pure state, according to the litera-
ture.[12,13] These substrates, as expected, afforded the
corresponding benzofurans 2 working in the absence of
PPh3 and H2O. Thus, under the same conditions of
entry 37, but in the absence of PPh3 and H2O, 3b led to
2b in 40% yield at total substrate conversion. On the
other hand, under the same conditions of entry 39, but
in the absence of PPh3 and H2O, 3d gave 2d in 61%
yield after 3 h at total substrate conversion. From a
practical point of view, however, the procedure em-
ploying unprotected 3b and 3d is less convenient than
that employing the corresponding protected substrates
1b and 1d, since a considerable higher excess of the
corresponding alkynylmagnesium reagents is necessary
for carbonyl alkynylation (see Supporting Information
for details) and also in view of the higher yields of 2b
and 2d obtained when starting from 1b (70%, entry 37)
or 1d (82%, entry 39) respectively, rather than from 3b
or 3d (40% and 61%, respectively, as we have seen).
[12] A. Mann, C. Muller, E. Tyrrel, J. Chem. Soc., Perkin
Trans. 1 1998, 1427–1438.
[13] a) C. M. Brennan, D. C. Johnson, P. D. McDonnell, J.
Chem. Soc., Perkin Trans. 2 1989, 957–962; b) T. T.
Jong, S.-J. Leu, J. Chem. Soc., Perkin Trans. 1 1990,
423–424.
À
À
[10] Decarboxylation of X Pd CO2H complexes to give
À
À
X Pd H species is a well-known process: see, for ex-
Adv. Synth. Catal. 2006, 348, 1101 – 1109
ꢀ 2006 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
1109