A novel synthesis of 2-functionalized benzofurans by palladium-catalyzed cycloisomerization of 2-(1-hydroxyprop-2-ynyl)phenols followed by acid-catalyzed allylic isomerization or allylic nucleophilic substitution

Article abstract of DOI:10.1021/jo801444n

(Chemical Equation Presented) A novel two-step synthesis of 2-hydroxymethylbenzofurans 3 and 2-alkoxymethylbenzofurans 4-6, based on palladium-catalyzed cycloisomerization of 2-(1-hydroxyprop-2-ynyl)phenols 1 under basic conditions to give 2-methylene-2,3-dihydrobenzofuran-3-ols 2, followed by acid-catalyzed isomerization or allylic nucleophilic substitution with alcohols as nucleophiles, is reported. Cycloisomerization reactions leading to 2 (80-98% yields) were carried out at 40°C in MeOH as the solvent, in the presence of a base and catalytic amounts of PdX₂ + 2KX (X = Cl, I). Isomerization reactions of 2 readily occurred at 25-60 °C in DME as the solvent, with H₂SO₄ as the proton source, to give 2-hydroxymethylbenzofurans 3 in 65-90% yields. In a similar manner, allylic nucleophilic substitution reactions of 2 with ROH as nucleophiles [carried out at 25-40°C in ROH (R = Me) or ROH-DME mixtures (R = Bu, Bn) in the presence of H₂SO₄] afforded 2-alkoxymethylbenzofurans 4, 5, and 6 (R = Me, Bu, and Bn, respectively), in 65-98% yields.

Full text of DOI:10.1021/jo801444n

A Novel Synthesis of 2-Functionalized Benzofurans by
Palladium-Catalyzed Cycloisomerization of
2-(1-Hydroxyprop-2-ynyl)phenols Followed by Acid-Catalyzed
Allylic Isomerization or Allylic Nucleophilic Substitution
Bartolo Gabriele,*,† Raffaella Mancuso,‡ and Giuseppe Salerno‡
Dipartimento di Scienze Farmaceutiche, UniVersita` della Calabria, 87036 ArcaVacata di Rende, Cosenza, Italy,
and Dipartimento di Chimica, UniVersita` della Calabria, 87036 ArcaVacata di Rende, Cosenza, Italy
b.gabriele@unical.it
ReceiVed July 1, 2008
A novel two-step synthesis of 2-hydroxymethylbenzofurans 3 and 2-alkoxymethylbenzofurans 4-6, based
on palladium-catalyzed cycloisomerization of 2-(1-hydroxyprop-2-ynyl)phenols 1 under basic conditions
to give 2-methylene-2,3-dihydrobenzofuran-3-ols 2, followed by acid-catalyzed isomerization or allylic
nucleophilic substitution with alcohols as nucleophiles, is reported. Cycloisomerization reactions leading
to 2 (80-98% yields) were carried out at 40 °C in MeOH as the solvent, in the presence of a base and
catalytic amounts of PdX2 + 2KX (X ) Cl, I). Isomerization reactions of 2 readily occurred at 25-60
°C in DME as the solvent, with H2SO4 as the proton source, to give 2-hydroxymethylbenzofurans 3 in
65-90% yields. In a similar manner, allylic nucleophilic substitution reactions of 2 with ROH as
nucleophiles [carried out at 25-40 °C in ROH (R ) Me) or ROH-DME mixtures (R ) Bu, Bn) in the
presence of H2SO4] afforded 2-alkoxymethylbenzofurans 4, 5, and 6 (R ) Me, Bu, and Bn, respectively),
in 65-98% yields.
SCHEME 1
Introduction
Benzofurans represent a very important class of heterocyclic
compounds. The benzofuran core is present in many biologically
active products, displaying a wide range of pharmacological
activities, including anti-HIV, anticancer, and antimicrobial
activity.1 The importance of benzofurans justifies the continuous
efforts directed toward the development of new, selective, and
efficient syntheses of these heterocycles. In particular, during
the last years, several approaches to benzofurans by heteroan-
nulation of acyclic precursors have appeared in the literature.2
In this work, we report a novel method for the synthesis of
functionalized benzofurans, 2-hydroxymethylbenzofurans 3 and
2-alkoxymethylbenzofurans 4-6 (R ) Me, Bu, Bn, respectively)
based on palladium-catalyzed cycloisomerization of 2-(1-
hydroxyprop-2-ynyl)phenols 1 to give 2-methylene-2,3-dihy-
drobenzofuran-3-ols 2 followed by acid-catalyzed isomerization
or allylic nucleophilic substitution using alcohols as nucleo-
philes, according to Scheme 1.
† Dipartimento di Scienze Farmaceutiche.
‡ Dipartimento di Chimica.
7336 J. Org. Chem. 2008, 73, 7336–7341
10.1021/jo801444n CCC: $40.75 2008 American Chemical Society
Published on Web 08/26/2008

Synthesis of 2-Functionalized Benzofurans
TABLE 1. Cycloisomerization Reactions of 2-(1-Hydroxy-1-methylprop-2-ynyl)phenol 1a under Different Conditionsa
entry
metal catalyst
base
none
morpholine
morpholine
morpholine
none
1a/base/metal molar ratio
solvent
conversion of 1ab(%)
yield of 2ac(%)
1
2
3
4
5
6
7
8
PdI2 + 2KI
PdI2 + 2KI
PdI2 + 2KI
PdI2 + 2KI
Pd(PPh3)4
Pd(dba)2
none
none
PdCl2 + 2KCl
PdCl2 + 2KCl
CuCl2
CuCl2
AuCl
PdCl2 + 2KCl
PdCl2 + 2KCl
PdCl2 + 2KCl
PdCl2 + 2KCl
PdCl2 + 2KCl
PdCl2 + 2KCl
PdCl2 + 2KCl
PdCl2 + 2KCl
100/0/1
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DME
<10
86
91
100
100
97
<10
24
tracesd
70
74
98
49
100/10/1
100/30/1
100/100/1
100/0/1
none
none
100/0/1
51
<5d
<5d
86
morpholine
morpholine
morpholine
morpholine
morpholine
morpholine
Et2NH
(i-Pr)2NH
(i-Pr)2NEt
K2CO3
100/10/0
100/10/1
100/100/1
100/10/1
100/100/1
100/10/1
100/10/1
100/10/1
100/10/1
100/10/1
100/10/1
100/10/1
100/10/1
100/10/1
9
100
100
70
10
11
12
13
14
15
16
17
18
19
20
21
79
47
41
61
74
71
86
42
68
100
100
100
100
100
100
100
32
morpholine
morpholine
morpholine
morpholine
69
dioxane
MeCN
DMA
15d
10
100
72
a Unless otherwise noted, all reactions were carried out with a substrate concentration of 0.22 mmol of 1a/mL of solvent (3 mmol scale based on 1a)
at 40 °C for 2 h. b Based on starting 1a, by GLC. c Based on starting 1a. d Partial decomposition of the substrate with formation of unidentified products
was observed under these conditions.
Results and Discussion
substrate was initially allowed to react in MeOH at 40 °C for
2 h in the presence of catalytic amounts of PdI2 (1 mol %) in
conjunction with 2 equiv of KI.3 No reaction occurred under
these conditions, as shown in Table 1, entry 1. However, the
same reaction, carried out in the presence of 10 mol % of a
base such as morpholine, did afford the desired 5-membered
cycloisomerization product, 3-methyl-2-methylene-2,3-dihy-
drobenzofuran-3-ol 2a, in 70% yield at 86% substrate conversion
(Table 1, entry 2). With 30 mol % of morpholine, the substrate
conversion and product yield after 2 h were 91% and 74%,
respectively (Table 1, entry 3). With an equimolar amount of
morpholine with respect to 1a, substrate conversion rate and
product yield reached 100% and 98%, respectively (entry 4,
Table 1). These results suggest that deprotonation of the phenolic
hydroxyl group is necessary for the reaction to occur. Either
5-exo-dig intramolecular nucleophilic attack to the triple bond
coordinated to the metal center or triple bond insertion into the
Pd-O bond of a phenoxypalladium intermediate, followed by
protonolysis, may occur (Scheme 2; anionic ligands are omitted
for clarity). In any case, no formation of the 6-membered
The first experiments were carried out with 2-(1-hydroxy-1-
methylprop-2-ynyl)phenol 1a (R1 ) Me, R2 ) R3 ) H), easily
obtained by ethynylation of 2-hydroxyacetophenone. This
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J. Org. Chem. Vol. 73, No. 18, 2008 7337

Gabriele et al.
SCHEME 2
product, corresponding to 6-endo-dig cyclization, could be
detected in the reaction mixture.
An alternative mechanism would involve the base-promoted
reduction of Pd(II) to Pd(0) followed by oxidative addition of
the phenolic -OH group to Pd(0), triple bond insertion, and
reductive elimination (Scheme 3).
To test the likelihood of this mechanism, 1a was reacted in
MeOH at 40 °C for 2 h but in the absence of PdI2, KI, and
morpholine and in the presence of a Pd(0) catalyst, such as
Pd(PPh3)4 or Pd(dba)2. Under these conditions, the formation
of 2a was observed, even though in significantly lower yields
(49-51%, entries 5 and 6) with respect to the yield obtained
with the PdI2/KI/morpholine system (98%, entry 4). These
results show that the mechanism starting with Pd(0) (Scheme
3) may also be at work under the reaction conditions of entries
2-4. In any case, in the absence of the metal catalyst, the
SCHEME 3
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reaction occurred to a very limited extent, either in the absence
(entry 7) or in the presence of the base (entry 8).
Interestingly, the use of PdCl2 + 2KCl rather than PdI2 +
2KI led to better results in the presence of a catalytic rather
than a stoichiometric amount of morpholine (Table 1, entries 9
and 10). The catalytic activity of CuCl2 and AuCl in this reaction
was also tested; however, less satisfying results with respect to
PdX2 + 2KX were obtained, as shown in Table 1, entries
11-13. The influence of the nature of the base and of the solvent
on the reaction rate and product yield was also studied. Under
the same conditions as those of entry 9 (Table 1), the use of
acyclic secondary (entries 14 and 15) or tertiary amines (entry
16) as well as of an inorganic base such as K2CO3 (entry 17)
led to poorer results with respect to morpholine (entry 9). On
the other hand, with morpholine as the base, the use of aprotic
solvents such as 1,2-dimethoxyethane (DME), dioxane, aceto-
nitrile, or N,N-dimethylacetamide (DMA) (entries 18-21) led
to less satisfactory results with respect to MeOH (entry 9).
The cycloisomerization reaction was then generalized to other
2-(1-hydroxyprop-2-ynyl)phenols 1b-g, bearing different sub-
stituents at the benzylic position and on the aromatic ring. The
results obtained are reported in Table 2. As can be seen, high
yields in the corresponding 2-methylene-2,3-dihydrobenzofuran-
3-ols 2b-g were consistently obtained by employing the
conditions previously optimized for 1a with PdI2 + 2KI or PdCl2
+ 2KCl as catalysts.
With a simple and convenient method for the preparation of
2-methylene-2,3-dihydrobenzofuran-3-ols 2 in hand, we next
tried to synthesize 2-hydroxymethylbenzofurans 3 by acid-
catalyzed allylic isomerization of 2. The key intermediate of
the process was clearly expected to be the allyl cation I (ensuing
7338 J. Org. Chem. Vol. 73, No. 18, 2008

Synthesis of 2-Functionalized Benzofurans
TABLE 2. Synthesis of 2-Methylene-2,3-dihydrobenzofuran-3-ols 2b-g by Pd-Catalyzed Cycloisomerization of
2-(1-Hydroxyprop-2-ynyl)phenols 1b-ga
entry
metal catalyst
1
R1
R2
R3
1/morpholine/metal molar ratio
2
yield of 2b (%)
1
2
3
4
5
6
7
8
PdI2 + 2KI
PdCl2 + 2KCl
PdI2 + 2KI
PdCl2 + 2KCl
PdI2 + 2KI
PdCl2 + 2KCl
PdI2 + 2KI
PdCl2 + 2KCl
PdI2 + 2KI
PdCl2 + 2KCl
PdI2 + 2KI
PdCl2 + 2KCl
1b
1b
1c
1c
1d
1d
1e
1e
1f
H
H
Ph
Ph
H
H
H
H
H
Cl
Cl
Cl
Cl
H
H
H
H
H
H
H
H
H
H
OMe
OMe
100/100/1
100/10/1
100/100/1
100/10/1
100/100/1
100/10/1
100/100/1
100/10/1
100/100/1
100/10/1
100/100/1
100/10/1
2b
2b
2c
2c
2d
2d
2e
2e
2f
82
85
96
86
88
85
86
84
82
80
88
82
H
Me
Me
H
H
H
9
OMe
OMe
H
10
11
12
1f
1g
1g
2f
2g
2g
H
H
a All reactions were carried out in MeOH (substrate concentration ) 0.22 mmol of 1/mL of solvent, 3 mmol scale based on 1) at 40 °C for 2 h.
Substrate conversion was quantitative in all cases. b Based on starting 1.
SCHEME 4
SCHEME 5
TABLE 3. Synthesis of 2-Hydroxymethylbenzofurans 3a-g by
Acid-Catalyzed Allylic Isomerization of
2-Methylene-2,3-dihydrobenzofuran-3-ols 2a-ga
TABLE 4. Synthesis of 2-Methoxymethylbenzofurans 4a-g by
Acid-Catalyzed Allylic Nucleophilic Substitution of
2-Methylene-2,3-dihydrobenzofuran-3-ols 2a-g with MeOHa
entry
2
R1
R2
R3
T (°C)
3
yield of 3b (%)
1
2
3
4
5
6
7
2a
2b
2c
2d
2e
2f
Me
H
Ph
H
Me
H
H
H
H
H
Cl
Cl
OMe
H
H
H
H
H
H
H
OMe
25
40
40
60
40
40
40
3a
3b
3c
3d
3e
3f
83
85
89
65
90
81
86
entry
1c
2
3
4
2
R1
R2
R3
4
yield of 4b (%)
2a
2a
2b
2c
2d
2d
2d
2e
2f
Me
Me
H
Ph
H
H
H
Me
H
H
H
H
H
H
Cl
Cl
Cl
Cl
OMe
H
H
H
H
H
H
H
H
H
4a
4a
4b
4c
4d
4d
4d
4e
4f
78
80
78
93
15d
25f
65
98
87
70
2g
3g
a All reactions were carried out in a 9:1 mixture of DME-H2SO4 (0.2
M in H2O) (substrate concentration ) 0.22 mmol of 2/mL of solvent,
0.6 mmol scale based on 2) for 15 h. Substrate conversion was
quantitative in all cases. b Based on starting 2.
5
6e
c e
,
7
8
9
H
OMe
10
2g
4g
from protonation of the -OH group followed by elimination
of water), which then would convert into 3 by nucleophilic
attack by water to the exocyclic carbon with aromatization and
loss of proton (Scheme 4).
a Unless otherwise noted, all reactions were carried out in a 9:1
mixture of MeOH-H2SO4 (0.02 M in H2O) (substrate concentration )
0.22 mmol of 2/mL of solvent, 0.6 mmol scale based on 2) at room
temperature for 15 h. Unless otherwise noted, substrate conversion was
quantitative. b Based on starting 2. c The reaction was carried out using
a 1:9 mixture of 0.2 M H2SO4-MeOH (substrate concentration ) 0.22
mmol of 2/mL of solvent). d Substrate conversion was 25%. e Reaction
temperature was 40 °C. f Substrate conversion was 40%.
We indeed found that in DME as the solvent in the presence
of dilute H2SO4 at 25-60 °C, dihydrobenzofuranols 2a-g were
readily converted into the corresponding 2-hydroxymethylben-
zofurans 3a-g in good to high yields (65-90%, Table 3).
The allyl cation I, obtained from 2 under acidic conditions
(Scheme 4), could also be easily trapped by other oxygen
nucleophiles such as alcohols (Scheme 5). Thus, under condi-
tions similar to those of entry 1 (Table 3), but using MeOH as
cosolvent and with a lower concentration of H2SO4, 2-meth-
oxymethylbenzofurans 4 were selectively obtained in 70-98%
yields (Table 4, entries 2-4 and 8-10). In the case of 2d, a
higher temperature and a higher concentration of H2SO4 were
necessary in order to attain an acceptable reaction rate and a
good product yield (Table 4, entry 7).
In addition to methanol, other nucleophilic alcohols, such as
1-butanol or benzyl alcohol (Scheme 4, R ) Bu or Bn,
J. Org. Chem. Vol. 73, No. 18, 2008 7339

Gabriele et al.
TABLE 5. 5. Synthesis of 2-Alkoxymethylbenzofurans 5a-g and
6a-g by Acid-Catalyzed Allylic Nucleophilic Substitution of
2-Methylene-2,3-dihydrobenzofuran-3-ols 2a-g with Primary
Alcoholsa
respectively) could be used to give the corresponding 2-alkoxym-
ethylbenzofurans 5 and 6 in good to excellent yields (69-95%),
as exemplified by the results reported in Table 5.4 DME was
the solvent of choice for these reactions in the presence of a
5-fold excess of ROH with respect to starting 2-methylene-2,3-
dihydrobenzofuran-3-ols 2.
Conclusions
entry
2
R1
2a Me
2b
2e Me Cl
R2
R3
R
product yield of productb (%)
In conclusion, we have shown that a simple catalytic system,
consisting of PdX2 in conjunction with 2 equiv of KX (X )
Cl, I) and in the presence of a base such as morpholine, is an
excellent catalyst for the conversion of 2-(1-hydroxyprop-2-
ynyl)phenols 1 into 2-methylene-2,3-dihydrobenzofuran-3-ols
2 in high to excellent yields (80-98%).5 With PdI2 + 2KI as
the catalyst, the use of a stoichiometric rather than catalytic
amount of base led to better results in terms of reaction rate
and product yield. On the other hand, the use of PdCl2 + 2KCl
led to better results in the presence of a catalytic rather than a
stoichiometric amount of base. The 2-methylene-2,3-dihy-
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
H
H
Bu
Bu
Bu
Bu
Bn
Bn
Bn
Bn
5a
5b
5e
5f
95
80
83
76
81
71
88
69
H
2f
2a Me
2b
2e Me Cl
2f OMe
H
OMe
H
6a
6b
6e
6f
H
H
H
a All reactions were carried out in the presence of a 5-fold excess of
ROH with respect to 2, in a 9:1 mixture of DME-H2SO4 (0.02 M in
DME) (substrate concentration ) 0.22 mmol of 2/mL of solvent, 0.6
mmol scale based on 2) at room temperature for 15 h. Substrate
conversion was quantitative in all cases. b Based on starting 2.
(3) We have recently shown that PdI2 in conjunction with an excess of KI is
an excellent catalyst for the heterocyclization of several acetylenic substrates
bearing a suitably placed nucleophilic group. See ref 2r, ii, yy and: (a) Gabriele,
B.; Mancuso, R.; Salerno, G.; Lupinacci, E.; Ruffolo, G.; Costa, M. J. Org.
Chem. 2008, 73, 4971–4977. (b) Gabriele, B.; Mancuso, R.; Salerno, G.; Plastina,
P. J. Org. Chem. 2008, 73, 756–759. (c) Plastina, P.; Gabriele, B.; Salerno, G.
Synthesis 2007, 3083–3087. (d) Gabriele, B.; Mancuso, R.; Salerno, G.; Ruffolo,
G.; Plastina, P. J. Org. Chem. 2007, 72, 6873–6877. (e) Gabriele, B.; Plastina,
P.; Salerno, G.; Mancuso, R.; Costa, M. Org. Lett. 2007, 9, 3319–3322. (f)
Gabriele, B.; Salerno, G. PdI2. In e-EROS, Electronic Encyclopedia of Reagents
for Organic Synthesis; Crich, D., Ed.; Wiley-Interscience: New York, 2006. (g)
Gabriele, B.; Plastina, P.; Salerno, G.; Mancuso, R. Synthesis 2006, 4247–4251.
(h) Gabriele, B.; Salerno, G.; Fazio, A.; Veltri, L. AdV. Synth. Catal. 2006, 348,
2212–2222. (i) Gabriele, B.; Salerno, G.; Veltri, L.; Mancuso, R.; Li, Z.; Crispini,
A.; Bellusci, A. J. Org. Chem. 2006, 71, 7895–7898. (j) Bacchi, A.; Costa, M.;
Della Ca`, N.; Gabriele, B.; Salerno, G.; Cassoni, S. J. Org. Chem. 2005, 70,
4971–4979. (k) Gabriele, B.; Plastina, P.; Salerno, G.; Costa, M. Synlett 2005,
935–938. (l) Gabriele, B.; Salerno, G.; Costa, M. Synlett 2004, 2468–2483. (m)
Gabriele, B.; Salerno, G.; Costa, M.; Chiusoli, G. P. Curr. Org. Chem. 2004, 8,
919–946. (n) Gabriele, B.; Salerno, G.; Plastina, P. Lett. Org. Chem. 2004, 1,
134–136. (o) Costa, M.; Della Ca`, N.; Gabriele, B.; Massera, C.; Salerno, G.;
Soliani, M. J. Org. Chem. 2004, 69, 2469–2477. (p) Gabriele, B.; Salerno, G.;
Plastina, P.; Costa, M.; Crispini, A. AdV. Synth. Catal. 2004, 346, 351–358. (q)
Bacchi, A.; Costa, M.; Della Ca`, N.; Fabbricatore, M.; Fazio, A.; Gabriele, B.;
Nasi, C.; Salerno, G. Eur. J. Org. Chem. 2004, 57, 4–585. (r) Gabriele, B.;
Salerno, G.; Costa, M.; Chiusoli, G. P. J. Organomet. Chem. 2003, 687, 219–
228. (s) Gabriele, B.; Salerno, G.; Fazio, A. J. Org. Chem. 2003, 68, 7853–
7861. (t) Chiusoli, G. P.; Costa, M.; Cucchia, L.; Gabriele, B.; Salerno, G.; Veltri,
L. J. Mol. Catal. A: Chem. 2003, 204, 133–142. (u) Gabriele, B.; Salerno, G.;
Fazio, A.; Pittelli, R. Tetrahedron 2003, 59, 6251–6259. (v) Bacchi, A.; Costa,
M.; Gabriele, B.; Pelizzi, G.; Salerno, G. J. Org. Chem. 2002, 67, 4450–4457.
(w) Gabriele, B.; Salerno, G.; Fazio, A.; Campana, F. B. Chem. Commun. 2002,
1408–1409. (x) Gabriele, B.; Salerno, G.; Veltri, L.; Costa, M.; Massera, C.
Eur. J. Org. Chem. 2001, 460, 7–4613. (y) Gabriele, B.; Salerno, G.; Fazio, A.;
Bossio, M. R. Tetrahedron Lett. 2001, 42, 1339–1341. (z) Gabriele, B.; Salerno,
G.; Fazio, A. Org. Lett. 2000, 2, 351–352. (aa) Gabriele, B.; Salerno, G.; De
Pascali, F.; Costa, M.; Chiusoli, G. P. J. Organomet. Chem. 2000, 593, 409–
415. (bb) Gabriele, B.; Salerno, G.; De Pascali, F.; Costa, M.; Chiusoli, G. P. J.
Org. Chem. 1999, 64, 7693–7699. (cc) Gabriele, B.; Salerno, G.; Lauria, E. J.
Org. Chem. 1999, 64, 7687–7692. (dd) Chiusoli, G. P.; Costa, M.; Gabriele, B.;
Salerno, G. J. Mol. Catal. A: Chem. 1999, 143, 297–310. (ee) Bacchi, A.;
Chiusoli, G. P.; Costa, M.; Sani, C.; Gabriele, B.; Salerno, G. J. Organomet.
Chem. 1998, 562, 35–43. (ff) Gabriele, B.; Salerno, G.; De Pascali, F.; Tomasi
Sciano`, G.; Costa, M.; Chiusoli, G. P. Tetrahedron Lett. 1997, 38, 6877–6880.
(gg) Bacchi, A.; Chiusoli, G. P.; Gabriele, B.; Righi, C.; Salerno, G. Chem.
Commun. 1997, 1209–1210. (hh) Gabriele, B.; Salerno, G. Chem. Commun. 1997,
1083–1084. (ii) Gabriele, B.; Salerno, G.; De Pascali, F.; Costa, M.; Chiusoli,
G. P. J. Chem. Soc., Perkin Trans. 1 1997, 147–154. (jj) Bonardi, A.; Costa,
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Chem. Commun. 1994, 1429–1430.
drobenzofuran-3-ols 2 thus obtained could be efficiently con-
verted into functionalized benzofurans by acid-promoted allylic
isomerization (with formation of 2-hydroxymethylbenzofurans
3 in 65-90% yields) or allylic nucleophilic substitution with
primary alcohols as nucleophiles (with formation of 2-alkoxym-
ethylbenzofurans 4-6 in 65-98% yields). The methodology
here reported allows an easy entry to both 2,3-dihydrobenzofuran
and benzofuran derivatives starting from readily available
starting materials.
Experimental Section
Starting 2-(1-hydroxyprop-2-ynyl)phenols 1 were prepared as we
already described.2ii,3b,6 Typical procedures for the synthesis of
2-methylene-2,3-dihydrobenzofuran-3-ols 2, 2-hydroxymethylben-
zofurans 3, and 2-alkoxymethylbenzofurans 4-6 are given below.
Typical Procedure for the Synthesis of 2-Methylene-2,3-
dihydrobenzofuran-3-ols 2 in the Presence of PdI2+2KI. We
report here as a typical procedure the preparation of 3-methyl-2-
methylene-2,3-dihydrobenzofuran-3-ol 2a (Table 1, entry 4). Details
for the preparation of all the other 2-methylene-2,3-dihydrobenzo-
furan-3-ols 2b-g can be found in the Supporting Information. In
a typical experiment, PdI2 (10.5 mg, 2.92 × 10-2 mmol), KI (9.7
mg, 5.84 × 10-2 mmol), and morpholine (253.0 mg, 2.90 mmol)
were added under nitrogen to a solution of 1a (470.0 mg, 2.90
mmol) in anhydrous MeOH (13.2 mL) in a Schlenk flask. The
resulting mixture was stirred under nitrogen at 40 °C for 2 h. Solvent
was evaporated and the crude product purified by column chro-
matography on silica gel using 80:20 hexane-AcOEt as eluent to
(5) To our knowledge, this is the first method reported in the literature of
catalytic conversion of 2-(1-hydroxyprop-2-ynyl)phenols into 2-methylene-2,3-
dihydrobenzofuran-3-ols. The cyclization of 4-hydroxy-4-(2-hydroxyphenyl)pent-
2-ynoic acid ethyl ester (obtained by in situ HgCl2-promoted deprotection of
the corresponding methylthiomethyl ether) by classical intramolecular conjugate
addition to give a mixture of (3-hydroxy-3-methyl-3H-benzofuran-2-ylidene)
acetic acid ethyl ester (15%) and hydroxy-(3-methylbenzofuran-2-yl)acetic acid
ethyl ester (68%) was reported some years ago. Pflieger, D.; Muckensturm, B.
Tetrahedron 1989, 45, 2031–2040.
(6) We report here the correct GC-MS data for 2-(1-hydroxyprop-2-
ynyl)phenol 1b and 2-(1-hydroxyprop-2-ynyl)-4-methoxyphenol 1f, which were
inadvertently reported incorrect in refs 2ii and 3b: MS (EI, 70 eV) for 1b, m/z
) 148 (4) [M+], 130 (25), 121 (3), 103 (11), 102 (100), 91 (8), 77 (19), 76 (26),
75 (12), 74 (10), 65 (14), 63 (14), 53 (11), 51 (16), 50 (11); for 1f, m/z ) 178
(13) [M+], 161 (13), 160 (87), 145 (7), 132 (21), 118 (16), 117 (41), 103 (30),
102 (43), 89 (100), 77 (22), 63 (59), 62 (23), 53 (33), 51 (22).
(4) The methodology could not be applied to alcohols of low nucleophilicity,
such as isopropyl alcohol (R ) i-Pr) or tert-butylalcohol (R ) t-Bu), or to phenols
(R ) Ar); in these cases, the GLC, GLC-MS, and TLC analyses of the reaction
crudes showed that substrates 2 preferentially underwent decomposition, with
formation of small amounts of the desired products, which, however, owing to
the complexity of the mixture, could not be isolated at the pure state.
7340 J. Org. Chem. Vol. 73, No. 18, 2008

Synthesis of 2-Functionalized Benzofurans
give 2a as a yellow solid: mp 67-68 °C (462.2 mg, 98%); IR (KBr)
ν 3338 (s, br), 1673 (m), 1619 (m), 1595 (m), 1496 (s), 1460 (m),
1439 (m), 1324 (w), 1287 (m), 1175 (m), 1092 (w), 1036 (s), 930
(m), 847 (m), 804 (w), 756 (m) cm-1; 1H NMR (300 MHz, CDCl3)
δ 7.33 (ddd, J ) 7.5, 1.4, 0.6, 1 H), 7.24 (distorted ddd, J ) 8.1,
7.5, 1.4, 1 H), 7.00 (td, J ) 7.5, 0.9, 1 H), 6.89 (ddd, J ) 8.1, 0.9,
0.6, 1 H), 4.77 (distorted d, J ) 2.9, 1 H), 4.62 (distorted d, J )
2.9, 1 H), 2.68 (s, br, 1 H), 1.61 (s, 3 H); 13C NMR (75 MHz,
CDCl3) δ 168.3, 156.1, 131.6, 130.1, 123.7, 122.4, 110.1, 86.3,
75.8, 28.4; GC-MS m/z ) 162 (40) [M+], 161 (12), 148 (19), 147
(100), 145 (25), 121 (13), 115 (17), 91 (51), 77 (16), 65 (12). Anal.
Calcd for C10H10O2 (162.19): C, 74.06; H, 6.21. Found: C, 74.15;
H, 6.19.
Typical Procedure for the Synthesis of 2-Methylene-2,3-
dihydrobenzofuran-3-ols 2 in the Presence of PdCl2 + 2KCl.
We report here as a typical procedure the preparation of 3-methyl-
2-methylene-2,3-dihydrobenzofuran-3-ol 2a (Table 1, entry 9).
Details for the preparation of all the other 2-methylene-2,3-
dihydrobenzofuran-3-ols 2b-g can be found in the Supporting
Information. In a typical experiment, PdCl2 (5.1 mg, 2.88 × 10-2
mmol), KCl (4.3 mg, 5.77 × 10-2 mmol), and morpholine (25.3
mg, 0.29 mmol) were added under nitrogen to a solution of 1a
(470.0 mg, 2.90 mmol) in anhydrous MeOH (13.2 mL) in a Schlenk
flask. The resulting mixture was stirred under nitrogen at 40 °C
for 2 h. Solvent was evaporated and the crude product purified by
column chromatography on silica gel using 80:20 hexane-AcOEt
as the eluent to give 2a as a yellow solid: mp 67-68 °C (405.1
mg, 86%).
Typical Procedure for the Synthesis of 2-Hydroxymethyl-
benzofurans 3. We report here as a typical procedure the
preparation of (3-methylbenzofuran-2-yl)methanol 3a (Table 3,
entry 1). Details for the preparation of all the other 2-hydroxym-
ethylbenzofurans 3b-g can be found in the Supporting Information.
In a typical experiment, a mixture of 2a (103.5 mg, 0.64 mmol)
and H2SO4 (0.2 M in H2O, 290 µL) in DME (2.6 mL) was stirred
under nitrogen at room temperature for 15 h. After evaporation of
the solvent, the residue was purified by column chromatography
on silica gel using 95:5 hexane-acetone as eluent to give pure 3a
as a yellow solid: mp 84-85 °C (lit.7 mp 83-84 °C) (86.1 mg,
83%); IR (KBr) ν 3231 (s, br), 1451 (s), 1426 (w), 1337 (w), 1271
(m), 1224 (m), 1177 (w), 1104 (w), 1004 (s), 942 (w), 849 (m),
748 (s), 692 (m) cm-1; 1H NMR (300 MHz, CDCl3) δ 7.50-7.45
(m, 1 H), 7.43-7.38 (m, 1 H), 7.31-7.18 (m, 2 H), 4.72 (s, 2 H),
2.22 (s, 3 H), 2.16 (s, br, 1 H); 13C NMR (75 MHz, CDCl3) δ
154.2, 151.2, 129.7, 124.5, 122.3, 119.6, 112.9, 111.1, 55.8, 7.8;
GC-MS m/z ) 162 (91) [M+], 161 (55), 147 (45), 146 (12), 145
(100), 131 (11), 119 (11), 115 (39), 105 (23), 103 (15), 91 (28), 77
(17), 63 (11), 51 (17). Anal. Calcd for C10H10O2 (162.19): C, 74.06;
H, 6.21. Found: C, 74.15; H, 6.19.
Typical Procedure for the Synthesis of 2-Methoxymethyl-
benzofurans 4. We report here as a typical procedure the
preparation of 2-methoxymethyl-3-methylbenzofuran 4a (Table 4,
entry 2). Details for the preparation of all the other 2-hydroxym-
ethylbenzofurans 4b-g can be found in the Supporting Information.
In a typical experiment, a mixture of 2a (103.5 mg, 0.64 mmol)
and H2SO4 (0.02 M in H2O, 290 µL) in MeOH (2.6 mL) was stirred
under nitrogen at room temperature for 15 h. After evaporation of
the solvent, the residue was purified by column chromatography
on silica gel using 95:5 hexane-acetone as eluent to give pure 4a
as a yellow oil (90.4 mg, 80%): IR (film) ν 2923 (w), 1454 (s),
1246 (w), 1188 (w), 1085 (s), 961 (w), 852 (w), 748 (s) cm-1; 1H
NMR (300 MHz, CDCl3) δ 7.52-7.48 (m, 1 H), 7.47-7.42 (m, 1
H), 7.33-7.20 (m, 2 H), 4.56 (s, 2 H), 3.42 (s, 3 H), 2.28 (s, 3 H);
13C NMR (75 MHz, CDCl3) δ 154.4, 149.2, 129.6, 124.6, 122.3,
119.5, 114.4, 111.2, 64.7, 58.1, 8.0; GC-MS m/z ) 176 (68) [M+],
175 (16), 161 (13), 146 (24), 145 (100), 144 (12), 115 (41), 91
(11), 77 (11). Anal. Calcd for C11H12O2 (176.21): C, 74.98; H, 6.86.
Found: C, 75.12; H, 6.85.
Typical Procedure for the Synthesis of 2-Butoxymethylben-
zofurans 5. We report here as a typical procedure the preparation
of 2-butoxymethyl-3-methylbenzofuran 5a (Table 5, entry 1).
Details for the preparation of all the other 2-butoxymethylbenzo-
furans 5b, 5e, and 5f can be found in the Supporting Information.
In a typical experiment, a mixture of 2a (103.5 mg, 0.64 mmol),
H2SO4 (0.02 M in DME, 290 µL), and BuOH (237.0 mg, 3.20
mmol) in DME (2.6 mL) was stirred under nitrogen at room
temperature for 15 h. After evaporation of the solvent, the residue
was purified by column chromatography on silica gel using 95:5
hexane-acetone as eluent to give pure 5a as a yellow oil (133.0
mg, 95%): IR (film) ν 2962 (s), 2923 (m), 2864 (m), 1459 (m),
1
1239 (w), 1092 (s), 853 (w), 751 (s) cm-1; H NMR (500 MHz,
CDCl3) δ 7.48-7.45 (m, 1 H), 7.44-7.41 (m, 1 H), 7.27-7.24
(m, 1 H), 7.22-7.18 (m, 1 H), 4.57 (s, 2 H), 3.50 (t, J ) 6.6, 2 H),
2.24 (s, 3 H), 1.62-1.55 (m, 2 H), 1.41-1.33 (m, 2 H), 0.90 (t, J
) 7.4, 3 H); 13C NMR (126 MHz, CDCl3) δ 154.3, 149.8, 129.7,
124.4, 122.2, 119.4, 114.0, 111.2, 70.3, 63.2, 31.7, 19.3, 13.9, 7.9;
GC-MS m/z ) 218 (37) [M+], 161 (15), 147 (13), 146 (29), 145
(100), 131 (29), 115 (24), 91 (11), 77 (7). Anal. Calcd for C14H18O2
(218.29): C, 77.07; H, 8.31. Found: C, 77.18; H, 8.29.
Typical Procedure for the Synthesis of 2-Benzyloxymethyl-
benzofurans 6. We report here as a typical procedure the
preparation of 2-benzyloxymethyl-3-methylbenzofuran 6a (Table
5, entry 5). Details for the preparation of all the other 2-benzy-
loxymethylbenzofurans 6b, 6e, and 6f can be found in the
Supporting Information. In a typical experiment, a mixture of 2a
(103.5 mg, 0.64 mmol), H2SO4 (0.02 M in DME, 290 µL), and
BnOH (346.0 mg, 3.20 mmol) in DME (2.6 mL) was stirred under
nitrogen at room temperature for 15 h. After evaporation of the
solvent, the residue was purified by column chromatography on
silica gel using 95:5 hexane-acetone as eluent to give pure 6a as
a yellow oil (130.2 mg, 81%): IR (film) ν 1447 (m), 1238 (w),
1
1071 (s), 853 (w), 743 (s), 698 (m) cm-1; H NMR (500 MHz,
CDCl3) δ 7.49-7.46 (m, 1 H), 7.45-7.43 (m, 1 H), 7.38-7.31
(m, 4 H), 7.29-7.24 (m, 2 H), 7.23-7.19 (m, 1 H), 4.61 (s, 2 H),
4.57 (s, 2 H), 2.20 (s, 3 H); 13C NMR (126 MHz, CDCl3) δ 154.4,
149.4, 137.9, 129.7, 128.4, 127.9, 127.7, 124.5, 122.3, 119.5, 114.5,
111.2, 72.0, 62.2, 7.9; GC-MS m/z 252 (41) [M+], 161 (57), 146
(81), 145 (100), 144 (28), 133 (24), 132 (31), 131 (94), 115 (67),
105 (49), 92 (51), 91 (68), 77 (48), 65 (42), 63 (22), 51 (42), 50
(20). Anal. Calcd for C17H16O2 (252.12): C, 80.93; H, 6.39. Found:
C, 81.03; H, 6.37.
Acknowledgment. This work was supported by the Ministero
dell’Universita` e della Ricerca (Progetto di Ricerca di Interesse
Nazionale PRIN 2006031888).
Supporting Information Available: General experimental
methods, general procedure for the synthesis of 2-methylene-
2,3-dihydrobenzofuran-3-ols 2 in the presence of PdI2 + 2KI,
general procedure for the synthesis of 2-methylene-2,3-dihy-
drobenzofuran-3-ols 2 in the presence of PdCl2 + 2KCl, general
procedure for the synthesis of 2-hydroxymethylbenzofurans 3,
general procedure for the synthesis of 2-methoxymethylbenzo-
furans 4, general procedure for the synthesis of 2-butoxymeth-
ylbenzofurans 5, general procedure for the synthesis of 2-ben-
zyloxymethylbenzofurans 6, characterization data and copies
1
of H and 13C NMR spectra for all products. This material is
available free of charge via the Internet at http://pubs.acs.org.
(7) Baciocchi, E.; Clementi, S.; Sebastiani, V. J. Chem. Soc., Perkin Trans.
2 1974, 1882–1884.
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