Cascade reactions: A new synthesis of 2-benzofuran-2-ylacetamides by sequential Pd(0)-catalyzed deallylation-Pd(II)-catalyzed aminocarbonylative heterocyclization of 1-(2-allyloxyaryl)-2-yn-1-ols

Article abstract of DOI:10.1021/jo701956k

(Chemical Equation Presented) A general and efficient synthesis of 2-benzofuran-2-ylacetamides 5 starting from 1-(2-allyloxyaryl)-2-yn-l-ols 1, amines 4, and CO, in the presence of catalytic amounts of PdI₂ in conjunction with PPh₃ and KI, has been developed based on the "sequential homobimetallic catalysis" concept, that is, a process in which two different complexes of the same metal, but in two different oxidation states, promote two catalytic cycles in sequence. The first cycle corresponds to a Pd(0)-catalyzed aminodeallylation of 1 with formation of the free phenol 2, which then undergoes Pd(II)-catalyzed aminocarbonylative heterocyclization to give the final product 5.

Full text of DOI:10.1021/jo701956k

Cascade Reactions: A New Synthesis of
2-Benzofuran-2-ylacetamides by Sequential Pd(0)-Catalyzed
Deallylation-Pd(II)-Catalyzed Aminocarbonylative
Heterocyclization of 1-(2-Allyloxyaryl)-2-yn-1-ols
Bartolo Gabriele,*,† Raffaella Mancuso,‡ Giuseppe Salerno,‡ and Mirco Costa§
Dipartimento di Scienze Farmaceutiche and Dipartimento di Chimica, UniVersita` della Calabria,
87036 ArcaVacata di Rende (Cosenza), Italy, and Dipartimento di Chimica Organica e Industriale,
UniVersita` di Parma, 43100 Parma, Italy
b.gabriele@unical.it
ReceiVed September 5, 2007
A general and efficient synthesis of 2-benzofuran-2-ylacetamides 5 starting from 1-(2-allyloxyaryl)-2-
yn-1-ols 1, amines 4, and CO, in the presence of catalytic amounts of PdI2 in conjunction with PPh3 and
KI, has been developed based on the “sequential homobimetallic catalysis” concept, that is, a process in
which two different complexes of the same metal, but in two different oxidation states, promote two
catalytic cycles in sequence. The first cycle corresponds to a Pd(0)-catalyzed aminodeallylation of 1
with formation of the free phenol 2, which then undergoes Pd(II)-catalyzed aminocarbonylative
heterocyclization to give the final product 5.
Introduction
phenols 2, with R2 ) alkyl, were known to be unstable and
therefore difficult to obtain at the pure state.2 On the other
hand, the use of isolable phenols 2 (with R2 ) H or aryl) led
to the corresponding benzofurans 3 in lower yields with re-
spect to the sequential procedure starting from O-allyl phe-
nols 1.
We have recently described the first example of “se-
quential homobimetallic catalysis”, that is, a process in
which two different complexes of the same metal, but in two
different oxidation states, promote two catalytic cycles in
sequence.1 Thus, 1-(2-allyloxyaryl)-2-yn-1-ols 1 were selec-
tively converted into 2-benzofuran-2-ylacetic esters 3 through
Pd(0)-catalyzed carbonylative deallylation to give â,γ-unsatur-
ated esters and the free phenols 2, followed by in situ PdI2-
catalyzed cyclization-alkoxycarbonylation of the latter to
give 3, as depicted in Scheme 1 (unreactive ligands are omit-
ted for clarity). The possibility to obtain free phenols 2 in
situ, by deallylation of 1, was particularly important, since
(3) Benzofuran-2-ylacetamides are an interesting class of compounds.
Recently, some 2-benzofuran-2-ylacetamide derivatives have shown inter-
esting anticonvulsant activity: Kohn, H. K.; Sawhney, N.; LeGall, P.;
Conley, J. D.; Robertson, D. W.; Leander, J. D. J. Med. Chem. 1990, 33,
919-926.
(4) To the best of our knowledge, no general methodology for the
synthesis of 2-benzofuran-2-ylacetamides by annulation of acyclic precursors
has been reported thus far. The classical syntheses of 2-benzofuran-2-
ylacetamides are based on amination of benzofuran-2-ylacetyl chorides
(obtained from the corresponding acids): (a) Foster, R. T.; Robertson, A.;
Healy, T. V. J. Chem. Soc. 1939, 1594-1601. (b) Dean, F. M.; Halewood,
P.; Mongkolsuk, S.; Robertson, A.; Whalley, W. B. J. Chem. Soc. 1953,
1250-1261 and on rearrangement of 2-diazoacetylbenzofurans in the
presence of ammonia: (c) McGookin, A.; Roberston, A.; Whalley, W. J.
Chem. Soc. 1940, 787-795. (d) Wagner, R. B.; Tome, J. M. J. Am. Chem.
Soc. 1950, 72, 3477-3478. (e) Trofimov, F. A.; Mukhanove, T. I.; Grinov,
A. N. Chem. Heterocycl. Compd. (N.Y., NY, U.S.) 1973, 9, 552-554.
† Dipartimento di Scienze Farmaceutiche, Universita` della Calabria.
‡ Dipartimento di Chimica, Universita` della Calabria.
§ Universita` di Parma.
(1) (a) Gabriele, B.; Mancuso, R.; Salerno, G.; Costa, M. AdV. Synth.
Catal. 2006, 348, 1101-1109. (b) Gabriele, B.; Mancuso, R.; Salerno, G.;
Veltri, L. Chem. Commun. 2005, 271-273.
(2) Pflieger, D.; Muckensturm, B. Tetrahedron Lett. 1990, 31, 2299-
2300.
10.1021/jo701956k CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/01/2007
9278
J. Org. Chem. 2007, 72, 9278-9282

Synthesis of 2-Benzofuran-2-ylacetamides
SCHEME 1
200 equiv of KI, 4 equiv of PPh3, and 200 equiv of H2O. The
presence of water was necessary to generate in situ the Pd(0)
species promoting the deallylation cycle, according to Scheme
2. On the other hand, ligands PPh3 and I- were needed to
stabilize the Pd(0) species (catalyst of the first cycle) and the
Pd(II) species (catalyst of the second cycle), respectively.
To expand the synthetic scope of the reaction, we have
investigated the possibility to use amines 4 as the nucleophiles
for the direct synthesis of the corresponding 2-benzofuran-2-
ylacetamides 5,3,4 according to eq 1.
Results and Discussion
We first tested the reactivity of 1-(2-allyloxyphenyl)hept-2-
yn-1-ol 1a (R1 ) R3 ) R4 ) R5 ) H, R2 ) Bu) in the presence
of 2 equiv of morpholine 4a under conditions similar to those
employed for the synthesis of benzofuranacetic esters 3, namely,
anhydrous MeOH as the solvent (1a concentration ) 0.22 mmol/
mL of MeOH) at 100 °C under 30 atm of CO in the presence
of PdI2 in conjunction with KI, PPh3, and H2O (PdI2/KI/PPh3/
1a/4a/H2O molar ratio ) 1:10:4:100:200:200). We found that,
in agreement with the higher nucleophilicity of morpholine with
respect to methanol, the substrate conversion rate was signifi-
cantly higher with respect to the analogous reaction carried out
in the absence of morpholine,1 and thus 1a conversion was
quantitative after only 1 h reaction time. According to our
hypotheses, the reaction led to the formation of 2-benzofuran-
2-yl-1-morpholin-4-ylhexan-1-one 5aa in 40% GLC yield (Table
1, entry 1).
SCHEME 2
SCHEME 3
The GLC-MS analysis of the reaction crude also suggested
the presence in the reaction mixture of the deallylated substrate,
that is, the free phenol 2a (R1 ) R3 ) R4 ) R5 ) H, R2 ) Bu,
ca. 30%), which, however, according to its instability,2 could
not be isolated at the pure state from the reaction crude. The
formation of unidentified heavy compounds was detected by
TLC analysis (these materials were chromatographically im-
mobile) and accounted for the remaining part of the converted
substrate. Interestingly, an equimolar amount of 4-allylmorpho-
line 6a with respect to 1a was detected in the reaction mixture,
thus showing that in this case the π-allylpalladium intermediate
of the first cycle directly undergoes external nucleophilic attack
by 4a (eq 2 and Scheme 3, to be compared with Scheme 1).5
As shown by the results reported in entry 2, the presence of
PPh3 was essential for the reaction to occur; in fact, the substrate
1a remained unconverted working in the absence of PPh3. This
is in agreement with what we already observed in the formation
Reactions were carried out in MeOH at 100 °C under 30-
90 atm of carbon monoxide in the presence of catalytic amounts
of PdI2 (1 mol % with respect to 1) in conjunction with 100-
J. Org. Chem, Vol. 72, No. 24, 2007 9279

Gabriele et al.
TABLE 1. Reactions of 1-(2-Allyloxyphenyl)hept-2-yn-1-ol 1a with CO and Morpholine 4a in the Presence of the PdI2-KI-PPh3 Catalytic
Systema
PdI2/KI/PPh3/1a/4a/H2O
T
(°C)
PCO
(atm)
time
(h)
yield of
entry
molar ratio
solvent
5aab (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
1:10:4:100:200:200
1:10:0:100:200:200
1:10:4:100:200:0
1:100:4:100:200:0
1:200:4:100:200:0
1:10:4:100:200:0
1:100:4:100:200:0
1:100:4:100:200:0
1:10:4:100:200:0
1:10:4:100:200:0
1:10:4:100:200:0
1:10:4:100:200:0
1:10:4:100:200:0
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
dioxane
DME
100
100
100
100
100
80
100
100
100
100
100
100
100
30
30
30
30
30
30
15
60
30
30
30
30
30
1
1
1
1
1
1
1
1
15
15
15
15
15
40
0c
40
42
50
10
30
38
69
25
16
25
42
DMA
MeCN
a All reactions were carried out with a substrate concentration of 0.22 mmol of 1a/mL of solvent (2 mmol scale based on 1a). Unless otherwise noted,
substrate conversion was quantitative. b GLC yield based on starting 1a. c Substrate conversion was 0%.
TABLE 2. Synthesis of 2-Benzofuran-2-ylacetamides 5aa-ja Starting from 1-(2-Allyloxyaryl)-2-yn-1-ols 1, Morpholine 4a, and CO, in the
Presence of the PdI2-KI-PPh3 Catalytic Systema
yield of 5b
entry
1
R1
R2
R3
R4
R5
5
(%)
14
15
16
17c
18d
19
20
21
22
23
24
25
1a
1b
1c
1c
1c
1d
1e
1f
H
H
H
H
Bu
Ph
t-Bu
t-Bu
t-Bu
Bu
Bu
Bu
Bu
Bu
H
H
H
H
H
H
H
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
5aa
5ba
5ca
5ca
5ca
5da
5ea
5fa
5ga
5ha
5ia
87
66
46
60
27
65
66
80
80
80
65
80
H
Me
Ph
H
H
H
1g
1h
1i
OMe
H
H
H
H
H
H
OMe
OMe
Cl
H
H
Ph
Bu
1j
H
5ja
a Unless otherwise noted, all reactions were carried out in anhydrous MeOH (0.22 mmol of 1/mL of MeOH, 2 mmol scale based on 1) in the presence
of PdI2, KI, PPh3, and morpholine 4a (PdI2/KI/PPh3/1/4 molar ratio ) 1:200:4:100:200) at 100 °C and under 30 atm of CO for 15 h. Substrate conversion
was quantitative in all cases. b Isolated yield based on starting 1a. c The reaction was carried out with a KI/PdI2 molar ratio of 100. d The reaction was
carried out with a KI/PdI2 molar ratio of 10.
of benzofuran-2-acetic esters1 and confirms the role played by
PPh3 in stabilizing the Pd(0) species promoting the deallylation
cycle. On the contrary, the presence of H2O in the present
process turned out to be unnecessary for promoting the
formation of Pd(0), as shown by comparing entry 3 with entry
1. This effect must be ascribed to the presence of the amine,
whose partial oxidative carbonylation may be responsible for
the in situ formation of Pd(0) from PdI2 and CO.6 The effect
on the yield of 5aa of the KI/PdI2 molar ratio, reaction
temperature, and carbon monoxide pressure was also tested
(entries 4-8). A significantly higher selectivity toward 5aa was
observed by increasing the KI/PdI2 ratio to 200 (entry 5).
The detection of intermediate 2a in the reaction mixture
after 1 h also suggested the possibility to improve the yield of
5aa by simply increasing the reaction time. Indeed, under
the same conditions of entry 3, but after 15 h, the yield of 5aa
reached 69% (entry 9). The reaction was much slower in aprotic
solvents, such as 1,4-dioxane, 1,2-dimethoxyethane (DME),
N,N-dimethylacetamide (DMA), or acetonitrile, as shown by
the results reported in entries 10-13. On the other hand, by
carrying out the reaction under the same conditions as those in
entry 9, but with a KI/PdI2 molar ratio of 200, the GLC yield
of 5aa was as high as 93% (87% isolated, Table 2, entry 14,
and eq 3).
(5) Although there could be the possibility that deallylation occurred by
direct nucleophilic attack by morpholine 4a on the allyl group of 1a with
formation of 2a and 6a, we have verified that this was not the case. In fact,
1a remained unconverted when it was reacted with 4a in MeOH under
nitrogen at 100 °C for 15 h. This confirms that deallylation is indeed Pd-
catalyzed according to Scheme 2.
The generality of the process was then verified by varying
the nature of substituents R1 (at the benzylic position), R2 (on
(6) For a recent monograph on oxidative carbonylations, see: Gabriele,
B.; Salerno, G.; Costa, M. Top. Organomet. Chem. 2006, 18, 239-272.
9280 J. Org. Chem., Vol. 72, No. 24, 2007

Synthesis of 2-Benzofuran-2-ylacetamides
TABLE 3. Synthesis of 2-Benzofuran-2-ylacetamides 5ab-ai Starting from 1-(2-Allyloxyphenyl)hept-2-yn-1-ol 1a, Amines 4, and CO, in the
Presence of the PdI2-KI-PPh3 Catalytic Systema
PdI2/KI/PPh3/1a/4
time
(h)
yield of
entry
molar ratio
solvent
4
R6R7NH
5
5b (%)
26
27
28
29
30
31
32
33
34
35
36
37
38
39
1:200:4:100:200
1:200:4:100:200
1:100:4:100:200
1:200:4:100:200
1:200:4:100:200
1:100:4:50:100
1:200:4:100:200
1:100:4:50:100
1:200:4:100:200
1:100:4:50:100
1:200:4:100:200
1:100:4:50:100
1:200:4:100:200
1:100:4:50:100
MeOH
MeOH
MeOH
MeOH
MeOH
MeCN
MeOH
MeCN
MeOH
MeCN
MeOH
MeCN
MeOH
MeCN
4b
4c
4c
4d
4e
4e
4f
piperidine
Bu2NH
Bu2NH
Et2NH
PhNHMe
PhNHMe
BuNH2
BuNH2
BnNH2
BnNH2
t-BuNH2
t-BuNH2
PhNH2
15
15
15
15
15
24
15
24
15
24
15
24
15
24
5ab
5ac
5ac
5ad
5ae
5ae
5af
5af
5ag
5ag
5ah
5ah
5ai
65
46
66
62
61c
70
35d
71
4f
4g
4g
4h
4h
4i
22e
62
26f
68
10g
68
4h
PhNH2
5ai
a Unless otherwise noted, all reactions were carried out with a substrate concentration of 0.22 mmol of 1a/mL of solvent (2 mmol scale based on 1) in
the presence of PdI2, KI, PPh3, and R6R7NH 4 at 100 °C and under 30 atm of CO. Substrate conversion was quantitative in all cases. b Isolated yield based
on starting 1. c The reaction also led to the formation of 2-benzofuran-2-ylhexanoic acid methyl ester 3a in 24% isolated yield. d The reaction also led to the
formation of 3a in 36% isolated yield. e The reaction also led to the formation of 3a in 42% isolated yield. f The reaction also led to the formation of 3a in
41% isolated yield. g The reaction also led to the formation of 3a in 67% isolated yield.
the triple bond), and R3-R5 (on the aromatic ring) (eq 3). The
results are shown in Table 2, entries 15-25. As can be seen,
good isolated yields in the corresponding 2-benzofuran-2-
ylacetamides 5aa-ja were consistently obtained.7 In the case
of 1-(2-allyloxyphenyl)-4,4-dimethylpent-2-yn-1-ol 1c, the prod-
uct selectivity was higher working with a KI/PdI2 molar ratio
of 100 (entry 17) rather than 200 (entry 16).
Conclusions
In conclusion, we have reported a new and convenient method
for the synthesis of important heterocyclic derivatives, such as
2-benzofuran-2-ylacetamides 5, starting from readily available
1-(2-allyloxyaryl)-2-yn-1-ols 1, amines 4, and CO. Carbonyla-
tion reactions are carried out under relatively mild conditions
in the presence of a PdI2-based catalytic system. The generality
of the process has been verified by varying the nature of the
substrate 1 as well as the nature of the amine 4. Mechanistically,
the process is an example of “sequential homobimetallic
catalysis”: a PPh3-stablized Pd(0) complex (generated in situ
under the reaction conditions) catalyzes the deallylation of 1,
The effect of the nature of the amine was also tested, using
1a as the model substrate (eq 4). Cyclic and acyclic dialky-
lamines (such as piperidine 4b, dibutylamine 4c, and diethy-
lamine 4d) behaved similarly to morpholine, as shown by Table
3, entries 26-29. On the other hand, less nucleophilic secondary
amines (such as N-methylaniline 4e) and primary amines (such
as butylamine 4f, benzylamine 4g, tert-butylamine 4h, and
aniline 4i), led, under the usual conditions (in MeOH as the
solvent), to mixtures of the corresponding 2-benzofuran-2-
ylacetamides 5ae-ai and 2-benzofuran-2-ylhexanoic acid meth-
yl ester 3a, because of the competition between the amine and
MeOH as the nucleophile (entries 30, 32, 34, 36, 38). We
accordingly carried out the reactions in a non-nucleophilic
solvent such as MeCN. To compensate for the lower reactivity
in this latter solvent as compared with MeOH (Table 1, entries
9 and 13), carbonylations were performed with a substrate-to-
catalyst ratio of 50 rather than 100 for 24 h. Under these
conditions, 2-benzofuran-2-ylacetamides 5ae-ai were selec-
tively obtained in good isolated yields (entries 31, 33, 35,
37, 39).
with formation of the free phenol 2, which then acts as the
substrate in a second catalytic cycle, consisting of a PdI4
catalyzed aminocarbonylative heterocyclization of 2 to give the
final product 5.
2-
-
Experimental Section
Preparation of Substrates. Substrates were prepared as de-
scribed in the literature.1 2-Benzofuran-2-ylhexanoic acid methyl
ester 3a was characterized by comparison with literature data.1
General Procedure for the Synthesis of 2-Benzofuran-2-
ylacetamides 5 (Tables 1-3). A 250-mL stainless steel auto-
clave was charged with PdI2 (8.0 or 16.0 mg, 2.22 × 10-2 or 4.44
× 10-2 mmol), KI (370.0 or 740.0 mg, 2.23 or 4.46 mmol), PPh3
(23.3 or 46.5 mg, 8.88 × 10-2 or 1.77 × 10-1 mmol), and a solution
of 1 (2.22 mmol) in anhydrous MeOH or MeCN (10.1 mL).
Anhydrous 4 (4.44 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 being
stirred at 100 °C for the required time, the autoclave was cooled
and degassed. The solvent was evaporated, and products were
purified by column chromatography on silica gel: 5aa (9:1 hexane/
(7) It is worth noting that unprotected 2-(1-hydroxy-3-phenylprop-2-
ynyl)phenol 2b was sufficiently stable during the purification procedure
to be isolated at the pure state.1a However, its carbonylation reaction,
carried out under the same conditions as those in entry 15 (Table 2), but
in the absence of PPh3, led to the corresponding 2-benzofuran-2-ylaceta-
mide 5ba in only 34% isolated yield. See the Experimental Section for
details.
J. Org. Chem, Vol. 72, No. 24, 2007 9281

Gabriele et al.
acetone, pale yellow oil, 580 mg, 87%); 5ba (9:2 hexane/AcOEt,
yellow solid, mp 127-128 °C, 470 mg, 66%); 5ca (95:5 hexane/
acetone, colorless solid, mp 108-109 °C, 400 mg, 60%); 5da (9:1
hexane/acetone, colorless oil, 455 mg, 65%); 5ea (8:2 hexane/
acetone, yellow solid, mp 96-97 °C, 550 mg, 66%); 5fa (8:2
hexane/acetone, yellow oil, 590 mg, 80%); 5ga (9:1 hexane/acetone,
yellow oil, 586 mg, 80%); 5ha (9:1 hexane/acetone, pale yellow
oil, 588 mg, 80%); 5ia (8:2 hexane/acetone, yellow solid. The
product thus obtained could be further purified by dissolving it in
MeOH followed by crystallization with hexane, to give a colorless
solid, mp 114-116 °C, 506 mg, 65%); 5ja (8:2 hexane/acetone,
yellow solid, mp 61-63 °C, 595 mg, 80%); 5ab (9:1 hexane/
acetone, yellow solid, 52-53 °C, 430 mg, 65%); 5ac (9:1 hexane/
acetone, yellow oil, 501 mg, 66%); 5ad (9:1 hexane/Et2O, yellow
oil, 395 mg, 62%); 5ae (8:2 hexane/AcOEt, yellow oil, 500 mg,
70%); 5af (8:2 hexane/Et2O, yellow solid, mp 61-62 °C, 451 mg,
71%); 5ag (8:2 hexane/acetone, yellow solid, mp 68-69 °C, 443
mg, 62%); 5ah (8:2 hexane/AcOEt, yellow solid, mp 95-96 °C,
435 mg, 68%); 5ai (9:1 hexane/acetone, yellow solid, mp 118-
120 °C, 465 mg, 68%).
stainless steel autoclave was charged with PdI2 (8.0 mg, 2.22 ×
10-2 mmol), KI (737.4 mg, 4.44 mmol), and a solution of 2b (497.4
mg, 2.22 mmol) in anhydrous MeOH (10.1 mL). Anhydrous
morpholine 4a (386.9 mg, 4.44 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 being stirred at 100 °C for 15 h, the autoclave was cooled
and degassed. The solvent was evaporated, and the product 5ba
was purified by column chromatography on silica gel (9:1 hexane/
AcOEt, yellow solid, mp 127-128 °C, 242 mg, 34%).
Acknowledgment. This work was supported by the Minis-
tero dell’Universita` e della Ricerca (Progetto di Ricerca di
Interesse Nazionale PRIN 2006031888).
Supporting Information Available: General experimental
methods, characterization data, and copy of 1H and 13C NMR
spectra for all products. This material is available free of charge
via the Internet at http://pubs.acs.org.
Carbonylation of 2-(1-Hydroxyphenylprop-2-ynyl)phenol
2b to 2-Benzofuran-2-ylacetamide 5ba (Note 7). A 250-mL
JO701956K
9282 J. Org. Chem., Vol. 72, No. 24, 2007