Versatile synthesis of (Z)-1-alkylidene-1,3-dihydroisobenzofurans and 1H-isochromenes by palladium-catalyzed cycloisomerization of 2-alkynylbenzyl alcohols

Article abstract of DOI:10.1016/S0040-4020(03)01019-6

An easy synthesis of (Z)-1-alkylidene-1,3-dihydroisobenzofurans and 1H-isochromenes by palladium-catalyzed cycloisomerization of readily available 2-alkynylbenzyl alcohols under neutral conditions is reported. Reactions were carried out at 70-100°C in the

Full text of DOI:10.1016/S0040-4020(03)01019-6

Tetrahedron 59 (2003) 6251–6259
Versatile synthesis of (Z)-1-alkylidene-1,3-dihydroisobenzofurans
and 1H-isochromenes by palladium-catalyzed cycloisomerization
of 2-alkynylbenzyl alcohols
b
b
b
Bartolo Gabriele,a Giuseppe Salerno, Alessia Fazio and Rosina Pittelli
,
*
a
`
Dipartimento di Scienze Farmaceutiche, Universita della Calabria, 87036 Arcavacata di Rende, Cosenza, Italy
`
Dipartimento di Chimica, Universita della Calabria, 87036 Arcavacata di Rende, Cosenza, Italy
b
Received 7 April 2003; revised 29 May 2003; accepted 26 June 2003
Abstract—An easy synthesis of (Z)-1-alkylidene-1,3-dihydroisobenzofurans and 1H-isochromenes by palladium-catalyzed cyclo-
isomerization of readily available 2-alkynylbenzyl alcohols under neutral conditions is reported. Reactions were carried out at 70–1008C
in the presence of catalytic amounts (1–2%) of PdI2 in conjunction with 2 equiv. of KI for 1.5–24 h. The preference towards the 5-exo-dig
cyclization mode (leading to 1,3-dihydroisobenzofurans) or the 6-endo-dig cyclization mode (leading to isochromenes) turned out to be
dependent on the substitution pattern of the substrate as well as reaction conditions. In several cases, by properly adjusting the reaction
conditions, the same substrate could be selectively converted into either the dihydroisobenzofuran or the 1H-isochromene derivative.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
Palladium catalysis has recently acquired an increasing
ð1Þ
importance in the synthesis of heterocycles.1 Methods based
on annulation of acyclic substrates bearing suitably placed
nucleophilic and electrophilic functions are particularly
attractive, since they can regioselectively afford the
Cycloisomerization of 1 to 2 and 3 has been previously
reported to occur under basic conditions, with NaOH,4
heterocyclic ring with the desired substitution pattern
NaH4 or TBAF5 as the base. These reactions occurred with
under essentially neutral conditions. We have already
satisfactory yields only when R1 was an aryl group, leading
described several approaches to the Pd(II)-catalyzed
to 2 or 3 depending on the substitution pattern on R1,4 while
synthesis of heterocyclic derivatives starting from acetyl-
enic substrates, by a simple cycloisomerization approach2 as
well as by carbonylative cyclization reactions.3
with R1¼alkyl the final product 3 was obtained with yields
not higher than 10%.5 The PdI242-catalyzed methodology
reported in this work can be successfully applied to
substrates bearing R1¼alkyl or aryl. Moreover, it has been
found that not only the substitution pattern of the substrate,
but also reaction conditions can direct the catalytic process
towards the anti 5-exo-dig cyclization mode leading to 2 or
the 6-endo-dig cyclization mode leading to 3 (Scheme 1;
anionic iodide ligands are omitted for clarity).6
We now wish to report an extension of our Pd(II)-catalyzed
cycloisomerization methodology to readily available
2-alkynylbenzyl alcohols 1 for the synthesis of (Z)-1-
alkylidene-1,3-dihydroisobenzofurans and 1H-iso-
chromenes (2 and 3, respectively, Eq. (1)) under neutral
conditions.
2. Results and discussion
We started our investigation with 2-ethynylbenzyl alcohol
1a, readily available from (2-iodophenyl)methanol through
Pd/Cu-catalyzed coupling with ethynyltrimethylsilane to
give [2-(trimethylsilanyl)ethynylphenyl]methanol 1a0 fol-
lowed by deprotection. The reaction of 1a carried out under
Keywords: cycloisomerization; 1,3-dihydroisobenzofurans; isochromenes;
palladium.
*
Corresponding author. Tel.: þ39-0984-492130; fax.: þ39-0984-492044;
e-mail: b.gabriele@unical.it
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)01019-6

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B. Gabriele et al. / Tetrahedron 59 (2003) 6251–6259
Scheme 1.
in different solvents, such as 1,2-dimethoxyethane (DME),
1,4-dioxane, MeOH and MeCN (Table 1, entries 2–5). Low
yields of 4a were consistently obtained, the highest value
(17%) being observed in MeCN (entry 5). The yield could
not be improved even by decreasing substrate concentration
(entry 6) and reaction temperature (entry 7), or by changing
the counterion from iodide to chloride (entries 8 and 9).
Table 1. Reactions of 2-(ethynylphenyl)methanol 1a in different solvents in
the presence of PdI2 (0.01 equiv.) and KI (0.02 equiv.)
Entry
Solvent
Convn of 1a (%)a
Yield of 4a (%)b
1c
2
3
4
DMA
DME
100
100
100
98
100
82
95
100
100
Traces
14
6
4
17
9
10
Dioxane
MeOH
MeCN
MeCN
MeCN
MeCN
MeCN
5
A markedly different behavior was observed with substrates
bearing an internal rather than a terminal triple bond. Thus,
the reaction of (2-hex-1-ynylphenyl)methanol 1b carried
out in DMA at 808C for 2.5 h (substrate conc.¼2 mmol/mL
of DMA) in the presence of PdI2 (0.02 equiv.) and KI
(0.04 equiv.) afforded 3-butyl-1H-isochromene 3b in 20%
yield through a 6-endo-dig process (Scheme 1) at 85%
substrate conversion (Table 2, entry 1). The reaction was
then carried out in different solvents (entries 2–5); the best
results both in terms of yield and substrate conversion rate
were obtained in dioxane (entry 5). By using dioxane and
prolonging the reaction time to 3 h, substrate conversion
reached 100% and product GLC yield 70% (63% isolated,
entry 6 and Eq. (2)).
6d
7e
8f
9g
Traces
Traces
Unless otherwise noted, all reactions were carried out under nitrogen using
anhydrous solvents (2 mmol of 1a/mL of solvent, 3–5 mmol scale based on
1a) at 808C for 2 h.
a
Determined via GLC.
Based on starting 1a, by GLC.
Reaction time was 3 h.
Substrate concentration was 0.5 mmol/mL MeCN.
Reaction temperature was 708C.
The reaction was carried out with PdCl2 (0.01 equiv.) and KCl
b
c
d
e
f
(0.02 equiv.).
The reaction was carried out with (PhCN)2PdCl2 (0.01 equiv.).
g
Scheme 2.
conditions similar to those previously employed for the
synthesis of furans from (Z)-2-en-4-yn-1-ols2c,d [PdI2þ2
equiv. of KI as the catalyst with 1a/PdI2 molar ratio of 100
at 808C in N,N-dimethylacetamide (DMA) as the solvent,
substrate conc.¼2 mmol/mL of DMA] led after 3 h to the
formation of traces of a spiro derivative 4a together with
unidentified heavy products at total substrate conversion
(entry 1, Table 1).
Table 2. Synthesis of 3-butyl-1H-isochromene 3b by PdI2/KI-catalyzed
cycloisomerization of (2-hex-1-ynylphenyl)methanol 1b
Entry
Solvent
Convn of 1b (%)a
Yield of 3b (%)b
1
2
DMA
DME
85
77
20
26
Formation of 4a can be easily interpreted as occurring
through palladium-mediated 5-exo-dig cycloisomerization
to give the corresponding 1-methylene-1,3-dihydroiso-
benzofuran 2a in equilibrium with its isobenzofuran
tautomer 5a, followed by Diels–Alder cycloaddition
between 2a and 5a (Scheme 2, anionic iodide ligands are
omitted for clarity).
3
4
MeCN
MeOH
Dioxane
Dioxane
94
886
96
30
58
69
70 (63)
5
6c
100
Unless otherwise noted, all reactions were carried out under nitrogen using
anhydrous solvents (2 mmol of 1b/mL of solvent, 3–5 mmol scale based on
1b) at 808C for 2.5 h in the presence of PdI2 (0.02 equiv.) and KI
(0.04 equiv.).
a
Determined via GLC.
GLC yield (isolated yield) based on 1b.
Reaction time was 3 h.
b
In the attempt of minimizing substrate oligo- and/or
polymerization reactions, the reaction was also conducted
c

B. Gabriele et al. / Tetrahedron 59 (2003) 6251–6259
6253
triple bond, allowing the 5-exo-dig mechanism to compete
with the 6-endo-dig mechanism. Interestingly, working in
more dilute conditions resulted in higher selectivity towards
3d, even though reaction rate was decreased (entries 2 and
3). With 0.1 mmol of 1d per mL of dioxane, GLC yields of
3d and 2d were 78 and 19%, respectively (73 and 15%
isolated, entry 3 and Eq. (4)). On the other hand, a
completely selective reaction towards 2d was observed in
strongly polar solvents such as DMA or MeOH (entries 4
and 5). By working in MeOH for 2 h, 2d was obtained in
85% GLC yield (77% isolated, entry 5 and Eq. (4)).
ð2Þ
Only very low amounts of 3b (2–10%) were obtained using
PdCl2þ2KCl, (PhCN)2PdCl2, Pd(OAc)2, or Pd(acac)2 as the
catalysts under the same conditions. Thus the nature of the
Pd(II) counterion plays a fundamental role for the success of
the reaction. The reason iodide works much better than
chloride or acetate can be related to the greater ability of I2
to act as leaving group with respect to Cl2 or AcO2 in the
intramolecular nucleophilic attack step as well as to the
higher acidity of HI compared with HCl or AcOH, which
favors protonolysis of vinylpalladium intermediate to give
the final product (Scheme 1).
ð4Þ
1-Alkynylbenzyl alcohols with the triple bond substituted
with an alkyl group and bearing a secondary or a tertiary
alcoholic group turned out to be more reactive than those
bearing a primary alcoholic group. Thus, the reaction of
1-(2-hex-1-ynylphenyl)pentan-1-ol 1c, carried out in
dioxane at 808C with a substrate/KI/PdI2 molar ratio of
100/2/1 (substrate conc.¼2 mmol/mL of dioxane) required
2 h to achieve complete substrate conversion, affording 1,3-
dibutyl-1H-isochromene 3c in 84% GLC yield (74%
isolated, Eq. (3)). This result should be compared with
that reported in entry 6 (Table 2) for 1b.
Substrates 1e–g with the triple bond substituted with a
phenyl group were generally less reactive than the
corresponding 2-alkynylbenzyl alcohols 1b–d with the
triple bond substituted with an alkyl group. This is in
contrast to what we previously observed for PdI2/KI-
catalyzed cycloisomerization of (Z)-en-4-yn-1-ols and (Z)-
2-en-4-yne-1-thiols, where aryl conjugation to the triple
bond led to an increase of reactivity.2b–d It is conceivable
that extensive conjugation of the triple bond in 1e–g lowers
their coordination ability to Pd(II) thus leading to a decrease
of reactivity. Moreover, 1e–g showed a higher tendency
with respect to 1b–d to undergo 5-exo-dig cyclization. This
result is in agreement to what previously observed by other
Authors for the reaction carried out under basic conditions,4,5
and can be due to a combination of electronic and
stereoelectronic effects exerted by the phenyl group on the
triple bond. The reaction of (2-phenylethynylphenyl)metha-
nol 1e under the same conditions reported in entry 6
(Table 2) for 1b, but at 908C rather than 808C, led to a 52%
yield of a 1:1 mixture of (Z)-1-benzylidene-1,3-dihydroiso-
benzofuran 2e and 3-phenyl-1H-isochromene 3e at 80%
substrate conversion (Table 4, entry 1). As for 1d,
selectivity towards the isochromene derivative could be
improved by working in more dilute solution: with 0.5
rather than 2 mmol of 1e per mL of dioxane, after 24 h GLC
yields of 2e and 3e were 19% (15% isolated) and 45% (40%
isolated), respectively, at 90% substrate conversion (entry 2
and Eq. (5)). The reaction was also tested under the same
conditions in other solvents, in order to verify also the
ð3Þ
The higher reactivity for 1c with respect to 1b can be
ascribed to the steric assistance exerted by the alkyl group a
to the –OH, which tends to favor a conformation in which
the hydroxyl is closer to the triple bond (reactive rotamer
effect).7 This effect was even more important in the case of
3-(2-hex-1-ynylphenyl)pentan-3-ol 1d, bearing geminal
substitution a to the –OH group. The reaction of this
substrate under the same conditions employed for 1c led
after 1.5 h to a mixture of (Z)-1,1-diethyl-3-pentylidene-1,3-
dihydroisobenzofuran 2d and 3-butyl-1,1-diethyl-1H-iso-
chromene 3d in 35 and 49% yield, respectively, at total
substrate conversion (entry 1, Table 3). Clearly, gem-dialkyl
substitution causes the –OH group to be still closer to the
Table 3. PdI2/KI-catalyzed cycloisomerization reactions of 3-(2-hex-1-ynylphenyl)pentan-3-ol 1d in different solvents
Entry
Solvent
Substrate concn.a
t (h)
Convn of 1d (%)b
Yield of 2d (%)c
Yield of 3d (%)c
1
2
3
4
5
Dioxane
Dioxane
Dioxane
DMA
2
0.5
0.1
2
1.5
4
8
1.5
2
100
88
100
100
100
35
22
19 (15)
47
85 (77)
49
61
78 (73)
Traces
0
MeOH
2
All reactions were carried out under nitrogen using anhydrous solvents (3–5 mmol scale based on 1d) at 808C in the presence of PdI2 (0.01 equiv.) and KI
(0.02 equiv.).
a
mmol of 1d/mL of solvent.
Determined via GLC.
GLC yield (isolated yield) based on 1d.
b
c

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B. Gabriele et al. / Tetrahedron 59 (2003) 6251–6259
Table 4. Reactions of 2-(phenylethynylphenyl)methanol 1e in different
solvents in the presence of PdI2 (0.01 equiv.) and KI (0.02 equiv.)
50 at 808C for 10 h, 2e and 3e were obtained in 55 and 13%
GLC yields (49 and 9% isolated) at 95% substrate
conversion (entry 7 and Eq. (5)).
Entry Solvent
T
(8C) (h)
t
Convn of 1e Yield of 2e Yield of 3e
(%)b
(%)a
(%)b
1
Dioxane
Dioxane
MeCN
MeOH
DMA
90
90
90
90
90
80
80
3
24
3
3
3
80
90
41
100
62
57
95
26
19 (15)
12
26
45 (40)
8
23
13
8
13 (9)
2c
3
ð5Þ
4
5
36d
30
6
DMA
DMA
3
10
32
55 (49)
7e
As expected, secondary and tertiary 2-phenylethynylbenzyl
alcohols were more reactive than 1e and showed a higher
tendency towards the 5-exo-dig cyclization mode. The
results obtained with 1-(2-phenylethynylphenyl)pentan-1-ol
1f are shown in Table 5. Under the same conditions reported
in entry 2 (Table 4) for 1e, a mixture of 1-benzylidene-3-
butyl-1,3-dihydroisobenzofuran 2f (36% GLC yield) and
1-butyl-3-phenyl-1H-isochromene 3f (30% GLC yield) was
obtained at 78% substrate conversion (entry 1, Table 5).
Carrying out the reaction at 1008C rather than 908C, product
distribution changed in favor of 3f (GLC yields for 2f and 3f
after 4 h were 39 and 43%, respectively, at total substrate
conversion, entry 2). As usual, a higher selectivity for 3f
(48% GLC yield, 40% isolated, for 3f and 30% GLC yield,
27% isolated, for 2f) was obtained working in more dilute
solution (substrate concentration¼0.1 rather than 2 mmol
per mL of dioxane for 15 h, entry 3 and Eq. (6)). On the
Unless otherwise noted, all reactions were carried out under nitrogen using
anhydrous solvents (2 mmol of 1e/mL of solvent, 3–5 mmol scale based on
1e).
Determined via GLC.
a
b
GLC yield (isolated yield) based on 1e.
Substrate concentration was 0.5 mmol/mL of dioxane.
c
d
(E)-1-Benzylidene-1,3-dihydroisobenzofuran 2e0 was also formed in 10%
yield.
e
The reaction was carried out with 0.02 equiv. of PdI2 and 0.04 equiv. of
KI.
Scheme 3.
Table 5. Reactions of 1-(2-phenylethynylphenyl)pentan-1-ol 1f in different solvents in the presence of PdI2 (0.01 equiv.) and KI (0.02 equiv.)
Entry
Solvent
T (8C)
Substrate concn.a
t (h)
Convn of 1f (%)b
Yield of 2f (%)c
Yield of 3f (%)c
1
Dioxane
Dioxane
Dioxane
DMA
90
100
100
80
0.5
0.5
0.1
2
3
4
15
6
78
36
39
30 (27)
76 (70)
30
43
48 (40)
6 (4)
2c
3
100
100
100
4
All reactions were carried out under nitrogen using anhydrous solvents (3–5 mmol scale based on 1f).
mmol of 1f/mL of solvent.
a
b
Determined via GLC.
GLC yield (isolated yield) based on 1f.
c
possibility to shift the selectivity of the process towards the
formation of 2e. The results obtained in CH3CN, MeOH and
DMA are shown in entries 3–5. Indeed, in all these solvents,
2e turned out to be the main reaction product. The reaction
in CH3CN (entry 3) was somewhat slower than in MeOH
(entry 4) or DMA (entry 5). On the other hand, although
MeOH ensured a faster substrate conversion rate compared
with DMA, a mixture of stereoisomeric isobenzofurans 2e
and 2e0 was obtained in this solvent,† probably due to
reversible MeOH addition to the vinylethereal double bond
(Scheme 3). DMA was therefore the solvent of choice for
the subsequent experiments (entries 6 and 7), aimed at
achieving a good selectivity towards 2e with complete
substrate conversion. Working in this solvent at 808C rather
than 908C caused a slight decrement of reaction rate and a
significant enhancement of the 2e/3e ratio (from 2.3—entry
5, to 4.0—entry 6) With a substrate to catalyst molar ratio of
other hand, a selective reaction towards 2f was attained by
using DMA as solvent at 808C for 6 h with 2 mmol of 1f per
mL of DMA: under these conditions, 2f was obtained in
76% GLC yield (70% isolated), 3f being also formed in only
6% GLC yield (4% isolated) at total substrate conversion
(entry 4 and Eq. (6)).
ð6Þ
In the case of 3-(2-phenylethynylphenyl)pentan-3-ol 1g
(R1¼Ph, R2¼R3¼Et) bearing geminal substitution a to the
hydroxyl group, 5-exo-dig cyclization mode leading to
3-benzylidene-1,1-diethyl-1,3-dihydroisobenzofuran 2g
turned out to be the predominant pathway even working
in dioxane under dilute conditions. The best results in terms
of substrate conversion rate and product yields were
†
The E isomer 2e0 could not be isolated at the pure state from the reaction
mixture; however, the same hydrogenated product was obtained from
both 2e and 2e0 by catalytic hydrogenation of the reaction mixture, as
shown by GC–MS analysis, thus indicating geometric isomerism.

B. Gabriele et al. / Tetrahedron 59 (2003) 6251–6259
6255
obtained in MeOH under the same conditions reported in
entry 5 (Table 3) for 1d: after 2 h, GLC yield of 2g was as
high as 95% (89% isolated, Eq. (7)) at total substrate
conversion.
GC–MS apparatus. Microanalyses were performed at our
analytical laboratory. Unless otherwise noted, all reactions
were carried out under nitrogen using anhydrous solvents
and were monitored by TLC on silica gel 60 F254 or by GLC
using capillary columns with polymethylsiliconeþ5%
phenylsilicone as the stationary phase. Column chromato-
graphy was performed on silica gel 60 (70–230 mesh) or
neutral alumina 90 (70–230 mesh).
ð7Þ
Starting 2-alkynylbenzyl alcohols 1 and their precursors
were prepared as described below. All other materials were
commercially available and were used without further
purification.
3. Conclusion
4.2. Synthesis of 2-alkynylbenzyl alcohols
In conclusion, we have shown that cycloisomerization of
2-alkynylbenzyl alcohols 1 to (Z)-1-alkylidene-1,3-dihydro-
isobenzofurans 2 (through a 5-exo-dig mechanism) and/or
1H-isochromenes 3 (through a 6-endo-dig mechanism) can
be easily achieved under essentially neutral conditions by
means of a very simple catalytic system based on PdI422
anion. The selectivity of the process proved to be dependent
on the substitution pattern of the substrate and reaction
conditions, and in several cases it has been possible for the
same substrate to direct the process towards the selective
formation of either 2 or 3. In particular, on the basis of the
experimental results, the following generalizations can be
made: the 5-exo-dig cyclization mode tends to be favored by
(a) aryl rather than alkyl substitution on the triple bond; (b)
alkyl, and especially dialkyl substitution a to the hydroxyl
group; (c) a higher solvent polarity; (d) a higher substrate
concentration and (e) a lower reaction temperature. On the
other hand, the 6-endo-dig cyclization mode tends to be
favored by (a) alkyl rather than aryl substitution on the triple
bond; (b) a lower solvent polarity; (c) more dilute conditions
and (d) a higher reaction temperature.
2-Alkynylbenzyl alcohols bearing a primary alcoholic
group were prepared by Pd/Cu-catalyzed coupling between
(2-iodophenyl)methanol and the appropriate alk-1-yne.
Substrate 1a with terminal triple bond was obtained by
deprotection of the triple bond of (2-trimethylsilanyl-
ethynylphenyl)methanol 1a0 with KF/MeOH. Coupling
between an alk-1-yne and 2-bromobenzaldehyde followed
by addition of BuLi allowed a facile preparation of
substrates bearing a secondary alcoholic group. Substrates
bearing a tertiary alcoholic group were easily prepared by
coupling between an alk-1-yne and methyl 2-iodobenzoate
followed by Grignard reaction.
4.3. Coupling between (2-iodophenyl)methanol and
alk-1-ynes
To a stirred solution of (2-iodophenyl)methanol (10.0 g,
42.7 mmol) in anhydrous Et3N (420 mL) were added
Pd(PPh3)4 [2.0 g (1.73 mmol, R1¼SiMe3) or 4.0 g
(3.46 mmol, R1¼Bu, Ph)], CuI [650 mg (3.41 mmol,
R1¼SiMe3) or 1.3 g (6.83 mmol, R1¼Bu, Ph)], and
R1CuCH (52.0 mmol). The mixture was stirred for 1 h at
rt (R1¼SiMe3, Ph) or 608C (R1¼Bu), and then a saturated
solution of NH4Cl was added at rt followed by CH2Cl2.
Phases were separated, the aqueous layer was extracted
with CH2Cl2, and the combined organic layers were dried
over Na2SO4. After removal of the solvent by rotary
evaporation, the crude product was purified by column
chromatography on silica gel (1a0, CH2Cl2: pale yellow oil,
8.20 g, 94%; 1b, 98:2 hexane/AcOEt: pale yellow oil, 6.4 g,
80%; 1e, 7:3 hexane/AcOEt: pale yellow solid, 6.3 g, 71%)
followed in the case of 1e by repeated crystallization from
hexane.
Dihydroisobenzofurans and isochromenes are interesting
heterocyclic compounds. Dihydroisobenzofuran are useful
precursors of important heterocyclic derivatives,8 including
isobenzofurans9 and have also found application as
synthetic intermediates for the synthesis of biologically
active compounds.10 On the other hand, some isochromene
derivatives have showed interesting pharmacological
activity;11 moreover, isochromenes have found application
as synthetic intermediates12 and are potential precursors of
isochromanes, whose biological activity is well-known.13
The reaction reported in this work allows an easy
construction of both dihydroisobenzofuran and isochromene
rings starting from readily available substrates under mild
conditions.
4.4. Deprotection of 1a0 with KF/MeOH
To a stirred solution of 1a0 (5.56 g, 27.2 mmol) in MeOH
(143 mL) was added KF (5.65 g, 97.2 mmol). The mixture
was allowed to stir at rt for 3 h, and then it was diluted with
CH2Cl2 and quenched with water. Phases were separated,
the aqueous layer extracted with CH2Cl2 and the combined
organic layers dried over Na2SO4. After removal of the
solvent by rotary evaporation, the crude product was
purified by column chromatography on silica gel (6:4
hexane/AcOEt) followed by repeated crystallization from
hexane to give (2-ethynylphenyl)methanol 1a as a colorless
solid (2.6 g, 72%).
4. Experimental
4.1. General
1
Melting points are uncorrected. H NMR and 13C NMR
spectra were recorded at 300 MHz and 75 MHz,
respectively, with Me4Si as internal standard. Chemical
shifts and coupling constants (J) are given in ppm (d) and in
Hz, respectively. IR spectra were taken on a FT-IR
spectrometer. Mass spectra were obtained at 70 eV on a

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B. Gabriele et al. / Tetrahedron 59 (2003) 6251–6259
4.5. Coupling between 2-bromobenzaldehyde and alk-1-
ynes followed by addition of BuLi
(R1¼Bu) was a yellow oil (8.1 g, 96%); methyl 2-phenyl-
ethynylbenzoate (R1¼Ph) was a yellow oil, 8.8 g, 96%).
The method of Padwa4 and Dopico14 was employed. To a
stirred solution of 2-bromobenzaldehyde (10.0 g,
54.0 mmol) in anhydrous Et3N (164 mL) were added
Pd(OAc)2 (108 mg, 0.48 mmol), PPh3 (218 mg,
0.83 mmol), CuI (16 mg, 0.084 mmol) and R1CuCH
(80.0 mmol). After being stirred at 808C for 5 h, the mixture
was cooled, filtered and concentrated. Water was added to
the residue followed by Et2O. Phases were separated and the
aqueous layer was extracted with Et2O. The combined
organic layers were washed several times with H2O and
eventually dried over Na2SO4. After removal of the solvent
by rotary evaporation, the crude product was purified by
column chromatography on silica gel using as eluent 9:1
hexane/AcOEt (R1¼Bu: 8.6 g, 85%; R1¼Ph: 9.4 g, 84%).
Spectroscopic properties of aldehydes thus obtained agreed
with those reported.14
To a stirred solution of EtMgBr [78 mmol, prepared in
anhydrous Et2O (33 mL) from 1.9 g of Mg (78 mmol) and
8.8 g of EtBr (81 mmol)] was added dropwise a solution of
the alkynyl ester (37 mmol) in anhydrous benzene (17 mL)
with cooling. The mixture was then refluxed with stirring for
1 h. After cooling, a mixture of ice (85 g) and conc. HCl
(1.9 mL) was slowly added with external cooling, followed
by the addition of NH4Cl (2.86 g) and Et2O. Phases were
separated, and the organic layer was washed with water, 5%
NaHCO3, and water again. After drying over Na2SO4,
solvent was removed by rotary evaporation and the crude
product purified by column chromatography on silica gel
using as eluent 95:5 hexane–AcOEt: 1d was a pale yellow
oil (5.4 g, 60%), 1g was a yellow oil (7.1 g, 73%).
4.7. General procedure for cycloisomerization reactions
To a stirred solution of the aldehyde (45 mmol) in
anhydrous THF (450 mL) was added dropwise at 08C
18.0 mL of a 2 M solution of BuLi in pentane (36 mmol).
After being stirred at 08C for 2 h, the mixture was quenched
with ice-water and then with a 10% solution of HCl to
neutral pH. Phases were separated, and the aqueous layer
extracted with Et2O. The combined organic layers were
washed with H2O and brine, and then dried over Na2SO4.
After removal of the solvent by rotary evaporation, the
crude product was purified by column chromatography on
silica gel using as eluent 8:2 hexane/AcOEt: 1c was a pale
yellow oil (6.6 g, 60% with respect to starting aldehyde), 1f
was a yellow oil (7.1 g, 60% with respect to starting
aldehyde).
Reactions were carried out on a 3–5 mmol scale based on
2-alkynylbenzyl alcohol 1. Solvent, substrate: PdI2 molar
ratio, reaction temperature and time, yield of products 2, 3
and 4a are indicated in Tables 1–5. In a typical experiment,
PdI2 and KI (2 mol per mol of palladium) were added to a
solution of 1 in the suitable anhydrous solvent in a Schlenk
flask. The resulting mixture was stirred at the temperature
and for the time required to obtain a satisfactory conversion,
as shown by GLC and/or TLC analysis (Tables 1–5).
4.8. Separation of products
After removal of the reaction solvent by rotary evaporation,
products were isolated by column chromatography on silica
gel (2e and f, 3b–f, and 4a) or on neutral alumina under
nitrogen (2d, 2g; these products underwent decomposition
by using silica gel in the presence of air). Products 3d (pale
yellow oil), 2d (yellow oil) were eluted in this order using
hexane as eluent. Products 3e (colorless solid), 2e (colorless
solid) were eluted in this order using pure hexane as eluent.
Products 3f (yellow oil), 2f (yellow oil) were eluted in this
order using 9:1 hexane/AcOEt as eluent. 2g (colorless
solid) was eluted using 98:2 hexane/AcOEt. 3b (pale yellow
oil) was eluted using 98:2 hexane/AcOEt. 3c (pale yellow
oil) was eluted using 9:1 hexane/AcOEt. 4a (sticky
yellow oil) was eluted using 9:1 hexane/AcOEt.
4.6. Coupling between methyl 2-iodobenzoate and alk-1-
ynes followed by addition of EtMgBr
Methyl 2-iodobenzoate was prepared by Fischer esterifica-
tion of 2-iodobenzoic acid, according to the general
procedure described by Vogel.15 Thus, to a solution of
2-iodobenzoic acid (25 g, 0.1 mol) in MeOH (41 mL,
1.0 mol) was added 6.0 mL of conc. H2SO4. The mixture
was refluxed in air for 2.5 h, and then it was cooled, diluted
with H2O (200 mL) and extracted several times with CHCl3.
The combined organic layers were washed with H2O, 5%
NaHCO3 (2 times), H2O again, and brine (2 times), and
eventually dried over Na2SO4. Removal of the solvent by
rotary evaporation afforded crude methyl 2-iodobenzoate as
a colorless oil, which was sufficiently pure for the next step
(23.3 g, 89%). The method of Shi16 and Zhang17 was
employed for the coupling. To a stirred solution of the above
ester (10.2 g, 38.9 mmol) in anhydrous DMF (195 mL) were
added Pd(PPh3)2Cl2 (2.74 g, 3.9 mmol), CuI (742 mg,
3.9 mmol), (i-Pr)2NEt (21 mL) and R1CuCH (78 mmol).
The mixture was allowed to stir at rt for 18 h, and then sat.
NH4Cl (200 mL) and hexane (200 mL) were added and
phases separated. The aqueous layer was extracted with
hexane, and the combined organic layers were washed with
H2O and brine, and then dried over Na2SO4. After removal
of the solvent by rotary evaporation, the crude product was
purified by column chromatography on silica gel using as
eluent 9:1 hexane–AcOEt. Methyl 2-hex-1-ynylbenzoate
4.9. Characterization of substrates and products
All substrates and products were fully characterized by
spectroscopic techniques and elemental analysis. Com-
pounds 1a4,5,18 (mp¼66–678C), 1e4,5,19 (mp 72–738C), 2e4,5
(mp 100–1028C), 3e20 (mp 123–1258C), were characterized
by comparison with literature data. Characterization data for
new compounds and for compounds previously not fully
characterized are reported below.
4.9.1. (2-Trimethylsilanylethynylphenyl)methanol 1a0.5,19
Pale yellow oil. IR (neat) 3350 (m, br), 2959 (m), 2155 (m),
1480 (w), 1450 (w), 1249 (m), 1041 (m), 867 (s), 843 (s),
759 (m), 646 (w) cm21; 1H NMR (CDCl3) d 7.46–7.36 (m,
2H on phenyl ring, H-3þH-6), 7.29 (td, J¼7.6, 1.5 Hz, 1H,
H-4 or H-5), 7.19 (td, J¼7.6, 1.5 Hz, 1H, H-5 or H-4), 4.78

B. Gabriele et al. / Tetrahedron 59 (2003) 6251–6259
6257
(s, 2H, CH2), 0.26 (s, 9H, SiMe3); 13C NMR (CDCl3) d
143.3, 132.5, 129.0, 127.3, 127.1, 121.2, 102.8, 99.6, 63.9,
0.05; MS m/e 204 (35, Mþ), 189 (16) 171 (22), 145 (16), 131
(42), 129 (52), 128 (35), 115 (32), 75 (19), 73 (52), 61 (100).
Anal. calcd for C12H16OSi (FW 204.34): C, 70.53; H, 7.89.
Found C, 70.71; H, 7.87.
J¼7.8, 5.4 Hz, 1H, CHOH), 1.91–1.68 (m, 2H,
CHOHCH2), 1.56–1.24 (m, 4H, CH2CH2CH3), 0.86 (t,
J¼7.1, 3 Hz, Me); 13C NMR (CDCl3) d 147.0, 132.1, 131.4,
128.7, 128.4, 126.9, 125.4, 123.2, 120.5, 94.1, 87.3, 72.2,
38.1, 28.1, 22.6, 14.1; MS m/e 264 (17, Mþ), 221 (21), 208
(21), 207 (100), 179 (29), 178 (65), 176 (13), 152 (9). Anal.
calcd for C19H20O (FW 264.36): C, 86.32; H, 7.63. Found
C, 86.15; H, 7.64.
4.9.2. (2-Hex-1-ynylphenyl)methanol 1b.19 Pale yellow
oil. IR (neat) 3347 (m, br), 2956 (s), 2929 (s), 2871 (m),
1
2227 (w), 1452 (m), 1041 (m), 757 (m) cm21; H NMR
4.9.6. 3-(2-Phenylethynylphenyl)pentan-3-ol 1g. Yellow
oil. IR (neat) 3518 (m, br), 2967 (m), 2934 (m), 2877 (w),
2213 (vw), 1491 (m), 1442 (w), 1160 (m), 959 (m), 756 (s),
(CDCl3) d 7.42–7.36 (m, 2H on phenyl ring), 7.31–7.18 (m,
2H on phenyl ring), 4.79 (s, 2H, CH2), 2.45 (t, J¼6.9 Hz,
2H, CH2Cu), 1.67–1.55 (m, 2H, CH2CH2CH3), 1.55–1.42
(m, 2H, CH2CH2CH3), 0.95 (t, J¼7.3 Hz, 3H, Me); 13C
NMR (CDCl3) d 142.4, 131.9, 127.7, 127.0, 126.8, 122.0,
95.2, 78.1, 63.7, 30.7, 21.9, 19.0, 13.4; MS m/e 188 (27,
Mþ), 155 (32), 145 (71), 131 (46), 129 (35), 128 (41), 127
(23), 117 (49), 116 (26), 115 (100), 91 (54), 77 (25). Anal.
calcd for C13H16O (FW 188.27): C, 82.94; H, 8.57. Found
C, 83.14; H, 8.59.
1
690 (m) cm21; H NMR (CDCl3) d 7.63–7.46 (m, 4H on
phenyl ring), 7.39–7.28 (m, 4H on phenyl ring), 7.21 (td,
J¼7.3, 1.5 Hz, 1H on phenyl ring), 2.56–2.42 [m, 2H,
(CH3CHH)2COH], 2.04–1.88 [m, 2H, (CH3CHH)2COH],
0.79 [t, J¼7.3 Hz, 6H, (CH3CH2)2COH]; 13C NMR
(CDCl3) d 147.0, 134.4, 131.1, 128.45, 128.41, 128.2,
127.1, 126.3, 123.2, 119.4, 94.4, 89.7, 78.4, 33.1, 8.1; MS
m/e 264 (5, Mþ), 236 (19), 235 (100), 220 (9), 202 (6), 191
(7), 176 (5), 91 (3). Anal. calcd for C19H20O (FW 264.36):
C, 86.32; H, 7.63. Found C, 86.48; H, 7.61.
4.9.3. 1-(2-Hex-1-ynylphenyl)pentan-1-ol 1c. Pale yellow
oil. IR (neat) 3344 (m, br), 2955 (s), 2930 (s), 2870 (w),
2859 (w), 2228 (vw), 1465 (w), 1049 (m), 758 (m) cm21; 1H
NMR (CDCl3) d 7.45–7.40 (m, 1H on phenyl ring, H-3 or
H-6), 7.35 (dd, J¼7.3 1.5 Hz, 1H, H-6 or H-3), 7.25 (td,
J¼7.3, 1.5 Hz, 1H on phenyl ring, H-4 or H-5), 7.14 (td,
J¼7.3, 1.5 Hz, 1H on phenyl ring, H-5 or H-4), 5.08 (dd,
J¼7.3, 5.4 Hz, 1H, CHCH2), 2.43 (t, J¼6.8 Hz, 2H,
CH2Cu), 1.85–1.25 (m, 10H, CHCH2CH2CH2þuCCH2
CH2CH2CH3), 0.95 (t, J¼7.3 Hz, 3H, Me), 0.89 (t,
J¼6.8 Hz, 3H, Me); 13C NMR (CDCl3) d 146.8, 132.2,
127.9, 126.7, 125.3, 121.4, 95.3, 78.5, 72.4, 37.9, 30.9, 28.2,
22.6, 22.1, 19.2, 14.1, 13.6; MS m/e 244 (5, Mþ), 188 (16),
187 (100), 145 (16), 141 (13), 131 (17), 129 (11), 128 (11),
117 (25), 115 (27), 91 (10). Anal. calcd for C17H24O (FW
244.37): C, 83.55; H, 9.90. Found C, 83.78; H, 9.87.
4.9.7. (Z)-1,1-Diethyl-3-pentylidene-1,3-dihydroiso-
benzofuran 2d. Yellow oil. IR (neat) 2964 (s), 2930 (s),
2874 (m), 2853 (w), 1679 (m), 1463 (s), 1354 (w), 1296 (m),
1050 (m), 752 (s) cm21; 1H NMR (benzene-d6) d 7.27–7.22
(m, 1H on aromatic ring), 7.06–7.01 (m, 2H on aromatic
ring), 6.78–6.72 (m, 1H on aromatic ring), 4.94 (t,
J¼7.3 Hz, 1H, vCH), 2.54 (q, J¼7.3 Hz, 2H, CH2CHv),
1.94–1.80 (m, 2H, 2 OCCHHCH3), 1.76–1.37 (m, 6H, 2
OCCHHCH3þCH2CH2CH3), 0.95 (t, J¼7.3 Hz, 3H, CH2-
CH2CH3), 0.74 (t, J¼7.3 Hz, 6H, 2 OCCH2CH3); MS m/e
244 (13, Mþ), 216 (18), 215 (100), 201 (41), 173 (8), 159
(12), 157 (12), 145 (12), 128 (10), 115 (10), 91 (5), 57 (6).
Anal. calcd for C17H24O (FW 244.37): C, 83.55; H, 9.90.
Found C, 83.71; H, 9.87.
4.9.4. 3-(2-Hex-1-ynylphenyl)pentan-3-ol 1d. Pale yellow
oil. IR (neat) 3498 (m, br), 2961 (s), 2932 (s), 2874 (m),
2225 (vw), 1462 (m), 1159 (m), 959 (m), 758 (s) cm21; 1H
NMR (CDCl3) d 7.45 (dd, J¼7.6, 1.5 Hz, 1H on phenyl ring,
H-3 or H-6), 7.42 (dd, J¼7.6, 1.5 Hz, 1H on phenyl ring,
H-6 or H-3), 7.24 (td, J¼7.6, 1.5 Hz, 1H on phenyl ring, H-4
or H-5), 7.14 (td, J¼7.6, 1.5 Hz, 1H on phenyl ring, H-5 or
H-4), 2.44 (t, J¼7.1 Hz, 2H, CH2Cu), 2.37–2.23 [m, 2H,
(CH3CHH)2COH], 1.97–1.83 [m, 2H, (CH3CHH)2COH],
1.66–1.54 (m, 2H, CH2CH2CH3), 1.54–1.41 (m, 2H,
CH2CH2CH3), 0.95 (t, J¼7.3 Hz, 3H, CH2CH2CH3), 0.77
[t, J¼7.3 Hz, 6H, (CH3CH2)2COH]; 13C NMR (CDCl3) d
146.7, 134.6, 127.4, 126.9, 126.1, 120.3, 96.2, 80.8, 78.4,
32.8, 30.6, 22.1, 19.3, 13.6, 8.1; MS m/e 244 (1, Mþ), 216
(16), 215 (100), 201 (3), 172 (6), 159 (5), 157 (8), 141 (4),
129 (6), 128 (8), 115 (9), 91 (2), 57 (8). Anal. calcd for
C17H24O (FW 244.37): C, 83.55; H, 9.90. Found C, 83.64;
H, 9.92.
4.9.8. (Z)-1-Benzylidene-3-butyl-1,3-dihydroisobenzo-
furan 2f. Yellow oil. IR (neat) 2955 (m), 2929 (m), 2869
(m), 1655 (s), 1464 (m), 1365 (m), 1307 (w), 1049 (s), 809
1
(w), 761 (s), 693 (m), 517 (w) cm21; H NMR (CDCl3) d
7.78–7.72 (m, 2H on aromatic ring), 7.53–7.47 (m, 1H on
aromatic ring), 7.36–7.23 (m, 4H on aromatic ring), 7.22–
7.16 (m, 1H on aromatic ring), 7.16–7.09 (m, 1H on
aromatic ring), 5.88 (s, 1H, vCH), 5.60 (dd, J¼7.8, 3.9 Hz,
1H, OCH), 2.03–1.89 (m, 1H, CHHCH2CH2CH3), 1.82–
1.67 (m, 1H, CHHCH2CH2CH3), 1.57–1.29 (m, 4H,
CH2CH2CH3), 0.90 (t, J¼7.3 Hz, 3H, Me); 13C NMR
(CDCl3) d 155.5, 142.7, 136.7, 135.0, 128.6, 128.3, 128.1,
127.7, 125.1, 121.2, 119.9, 95.7, 86.1, 35.7, 27.1, 22.6,
14.0; MS m/e 264 (60, Mþ), 221 (17), 208 (20), 207 (100),
179 (15), 178 (40), 115 (11), 91 (7). Anal. calcd for
C19H20O (FW 264.36): C, 86.32; H, 7.63. Found C, 86.17;
H, 7.65.
4.9.9. (Z)-3-Benzylidene-1,1-diethyl-1,3-dihydroiso-
benzofuran 2g. Colorless solid, mp 61–628C. IR (KBr)
2960 (w), 1649 (m), 1462 (m), 1358 (w), 1096 (w), 1051
4.9.5. 1-(2-Phenylethynylphenyl)pentan-1-ol 1f. Yellow
oil. IR (neat) 3356 (m, br), 2955 (m), 2930 (m), 2869 (w),
2858 (w), 2215 (vw), 1493 (m), 1444 (w), 1047 (w), 1029
(w) 756 (s), 690 (m) cm21; 1H NMR (CDCl3) d 7.53–7.45
(m, 4H on phenyl ring), 7.36–7.27 (m, 4H on phenyl ring),
7.19 (td, J¼7.6, 1.5 Hz, 1H on phenyl ring), 5.21 (dd,
1
(m), 939 (s), 820 (m), 761 (s), 696 (s), 522 (m) cm21; H
NMR (benzene-d6) d 8.04–7.99 (m, 2H on aromatic ring),
7.39–7.31 (m, 2H on aromatic ring), 7.27–7.20 (m, 1H
on aromatic ring), 7.13–6.99 (m, 3H on aromatic ring),

6258
B. Gabriele et al. / Tetrahedron 59 (2003) 6251–6259
6.74–6.67 (m, 1H on aromatic ring), 5.96 (s, 1H, vCH),
1.93–1.79 (m, 2H, 2 CHHCH3), 1.67–1.53 (m, 2H, 2
CHHCH3), 0.68 (t, J¼7.3 Hz, 6H, 2 Me); 13C NMR
(benzene-d6) d 155.9, 144.4, 137.5, 136.6, 128.7, 128.4,
128.1, 125.4, 121.0, 120.0, 96.0, 94.7, 33.0, 7.8; MS m/e 264
(27, Mþ), 236 (19), 235 (100), 220 (6), 202 (4), 191 (7).
Anal. calcd for C19H20O (FW 264.36): C, 86.32; H, 7.63.
Found C, 86.46; H, 7.63.
NMR (CDCl3) d 7.78–7.71 (m, 2H on aromatic ring), 7.44–
7.26 (m, 3H on aromatic ring), 7.20 (td, J¼7.3, 1.5 Hz, 1H
on aromatic ring), 7.14 (td, J¼7.3, 1.5 Hz, 1H on aromatic
ring), 7.06 (distorted dd, J¼7.3, 1.5 Hz, 1H on aromatic
ring), 7.03–6.98 (m, 1H on aromatic ring), 6.39 (s, 1H,
vCH), 5.23 (dd, J¼8.8, 4.4 Hz, 1H, OCH), 2.15–1.99 (m,
1H, CHHCH2CH2CH3), 1.84–1.70 (m, 1H, CHHCH2CH2-
CH3), 1.70–1.27 (m, 4H, CH2CH2CH3), 0.91 (t, J¼7.3 Hz,
3H, Me); 13C NMR (CDCl3) d 151.6, 134.7, 131.7,
131.0, 128.6, 128.3, 127.7, 126.3, 125.0, 123.84,
123.78, 100.3, 78.2, 33.5, 27.6, 22.5, 14.1; MS m/e 264
(15, Mþ), 208 (16), 207 (100), 178 (22). Anal. calcd for
C19H20O (FW 264.36): C, 86.32; H, 7.63. Found C, 86.13;
H, 7.65.
4.9.10. 3-Butyl-1H-isochromene 3b.5 Pale yellow oil. IR
(neat) 2956 (s), 2929 (m), 2869 (w), 2859 (w), 1644 (s),
1488 (m), 1454 (m), 1392 (w), 1154 (m), 1025 (m), 799 (m),
750 (m) cm21; 1H NMR (acetone-d6) d 7.15 (tdt, J¼7.3, 1.7,
0.6 Hz, 1H on aromatic ring), 7.07 (td, J¼7.3, 1.5 Hz, 1H on
aromatic ring), 7.03–6.99 (m, 1H on aromatic ring), 6.91
(dd, J¼7.3, 1.5 Hz, 1H on aromatic ring), 5.69 (s, br, 1H,
vCH), 5.01 (s, 2H, OCH2), 2.17 (td, J¼7.4, 0.6 Hz, 2H,
CH2Cv), 1.58–1.47 (m, 2H, CH2CH2CH3), 1.43–1.29 (m,
2H, CH2CH2CH3), 0.91 (t, J¼7.3 Hz, 3H, Me); 13C NMR
(acetone-d6) d 159.6, 132.9, 128.7, 128.2, 126.4, 124.4,
123.0, 101.6, 69.1, 33.8, 30.0, 22.8, 14.1; MS m/e 188 (83,
Mþ), 187 (39), 146 (48), 145 (27), 131 (28), 117 (36), 115
(35), 104 (100), 103 (40), 91 (16), 77 (24). Anal. calcd for
C13H16O (FW 188.27): C, 82.94; H, 8.57. Found C, 83.08;
H, 8.60.
4.9.14. Spiro compound 4a. Sticky yellow oil. IR (neat)
1695 (m), 1487 (w), 1451 (w), 1354 (w), 1251 (w), 1108
(w), 1027 (m), 786 (s), 760 (s) cm21; 1H NMR (CD3OD) d
7.65–7.60 (m, 1H on phenyl ring), 7.54–7.10 (m, 6H on
phenyl ring), 7.10–7.03 (m, 1H on phenyl ring), 4.98 (s, 1H,
OCH), 4.90 (s, OCH2), 2.50 (s, 2H, CCH2C), 1.97 (s, 3H,
Me); MS m/e 264 (100, Mþ), 249 (47), 231 (45), 222 (18),
221 (20), 207 (22), 203 (22), 202 (19), 193 (22), 178 (42),
147 (23), 132 (39), 115 (55), 91 (41), 77 (21). Anal. calcd
for C18H16O2 (FW 264.32): C, 81.79; H, 6.10. Found C,
81.99; H, 6.08.
4.9.11. 1,3-Dibutyl-1H-isochromene 3c. Pale yellow oil.
IR (neat) 2955 (s), 2930 (s), 2869 (w), 2859 (w), 1648 (m),
1488 (w), 1465 (w), 1454 (m), 1381 (m), 1155 (m), 795 (m),
748 (m) cm21; 1H NMR (CDCl3) d 7.13 (td, J¼7.3, 1.5 Hz,
1H on aromatic ring), 7.06 (td, J¼7.3, 1.5 Hz, 1H on
aromatic ring), 6.92 (dd, J¼7.3, 1.5 Hz, 1H on aromatic
ring), 6.88 (dd, J¼7.3, 1.5 Hz, 1H on aromatic ring), 5.55 (s,
br, 1H, vCH), 5.04 (dd, J¼8.8, 4.9 Hz, 1H, OCH), 2.17 (td,
J¼7.6, 1.0 Hz, 2H, CH2C¼), 2.05–1.91 (m, 1H,
OCHCHH), 1.73–1.27 (m, 9H, OCHCHHþ2CH2CH2-
CH3), 0.92 (t, J¼7.3 Hz, 3 H, Me), 0.91 (t, J¼7.1 Hz, 3 H,
Me); 13C NMR (CDCl3) d 156.4, 131.2, 130.8, 127.6, 125.4,
123.8, 122.6, 99.9, 77.9, 33.8, 33.7, 29.1, 27.5, 22.6, 22.3,
14.0, 13.9; MS m/e 244 (10, Mþ), 188 (15), 187 (100), 115
(9). Anal. calcd for C17H24O (FW 244.37): C, 83.55; H,
9.90. Found C, 83.78; H, 9.91.
4.9.15. Methyl 2-hex-1-ynylbenzoate. Yellow oil. IR
(neat) 2955 (m), 2931 (m), 2229 (w), 1733 (s), 1484 (w),
1447 (w), 1432 (w), 1295 (m), 1250 (s), 1129 (m), 1083 (m),
757 (m) cm21; 1H NMR (CDCl3) d 7.86 (dd, J¼7.6, 1.5 Hz,
1H on phenyl ring, H-6), 7.49 (dd, J¼7.6, 1.5 Hz, 1H, H-3),
7.39 (td, J¼7.6, 1.5 Hz, 1H on phenyl ring, H-4 or H-5),
7.28 (td, J¼7.6, 1.5 Hz, 1H on phenyl ring, H-5 or H-4),
3.90 (s, 3H, CO2Me), 2.47 (t, J¼6.8 Hz, 2H, CH2Cu),
1.68–1.43 (m, 4H, CH2CH2CH3), 0.95 (t, J¼7.1 Hz, 3H,
CH2CH3); 13C NMR (CDCl3) d 167.0, 134.2, 132.0, 131.5,
130.1, 127.1, 124.5, 96.0, 79.3, 52.0, 30.8, 22.1, 19.5, 13.7;
MS m/e 216 (8, Mþ), 201 (12), 185 (10), 174 (100), 159
(38), 155 (15), 143 (16), 131 (16), 115 (26). Anal. calcd for
C14H16O2 (FW 216.28): C, 77.75; H, 7.46. Found C, 77.66;
H, 7.47.
4.9.12. 3-Butyl-1,1-diethyl-1H-isochromene 3d. Pale
yellow oil. IR (neat) 2963 (s), 2933 (s), 2875 (w), 1656
4.9.16. Methyl 2-phenylethynylbenzoate.21 Yellow oil. IR
(neat) 3061 (w), 2949 (w), 2217 (w), 1729 (s), 1493 (m),
1293 (s), 1252 (s), 1128 (m), 1078 (m), 756 (s), 691
(m) cm21; 1H NMR (CDCl3) d 7.96 (dd, J¼7.8, 1.5 Hz, 1H
on phenyl ring, H-6), 7.65–7.55 (m, 3H on phenyl ring),
7.45 (td, J¼7.6, 1.5 Hz, 1H on phenyl ring), 7.38–7.30 (m,
4H on phenyl ring), 3.94 (s, 3H, CO2Me); 13C NMR
(CDCl3) d 166.6, 133.9, 131.73, 131.68, 130.5, 128.5,
128.3, 127.9, 123.7, 123.3, 94.4, 88.3, 52.1; MS m/e 236
(100, Mþ), 221 (63), 207 (18), 205 (26), 193 (24), 177 (18),
176 (46), 165 (41), 151 (16), 150 (15), 122 (22), 105 (23), 88
(26), 77 (18). Anal. calcd for C16H12O2 (FW 236.27): C,
81.34; H, 5.12. Found C, 81.12; H, 5.11.
(m), 1455 (m), 1377 (m), 1149 (m), 791 (m), 748 (m) cm21
;
1H NMR (CDCl3) d 7.09 (td, J¼7.3, 1.5 Hz, 1H on aromatic
ring), 7.03 (td, J¼7.3, 2.0 Hz, 1H on aromatic ring), 6.88
(dd, J¼7.3, 1.5 Hz, 1H on aromatic ring), 6.84 (dd, J¼7.3,
2.0 Hz, 1H on aromatic ring), 5.38 (s, 1H, vCH), 2.14 (t,
J¼7.3 Hz, 2H, CH2Cv), 1.97–1.77 (m, 4H, 2 OCCH2-
CH3), 1.62–1.49 (m, 2H, CH2CH2CH3), 1.44–1.30 (m, 2H,
CH2CH2CH3), 0.92 (t, J¼7.3 Hz, 3H, CH2CH2CH3), 0.85
(t, J¼7.3 Hz, 6H, 2 OCCH2CH3); 13C NMR (CDCl3) d
156.1, 132.0, 131.9, 127.1, 125.2, 124.0, 122.9, 98.0, 83.9,
33.9, 31.8, 28.9, 22.4, 13.9, 8.1; MS m/e 244 (7, Mþ), 216
(17), 215 (100), 172 (4), 128 (6), 115 (6). Anal. calcd for
C17H24O (FW 244.37): C, 83.55; H, 9.90. Found C, 83.45;
H, 9.92.
References
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