Regioselective synthesis of phthalans via Cu(OTf)2-catalyzed 5-exo-dig intramolecular hydroalkoxylation of 2-(ethynyl)benzyl alcohols

Article abstract of DOI:10.1016/j.tetlet.2010.07.030

An efficient, regioselective Cu(OTf)₂-catalyzed 5-exo-dig intramolecular hydroalkoxylation of 2-(ethynyl)benzyl alcohol, which provides a concise access to functionalized phthalan in high yields has been developed. A wide range of substrates po

Full text of DOI:10.1016/j.tetlet.2010.07.030

Tetrahedron Letters 51 (2010) 4767–4771
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Regioselective synthesis of phthalans via Cu(OTf)2-catalyzed 5-exo-dig
intramolecular hydroalkoxylation of 2-(ethynyl)benzyl alcohols
*
Chandrasekaran Praveen, Chandran Iyyappan, Paramasivan Thirumalai Perumal
Organic Chemistry Division, Central Leather Research Institute, Adyar, Chennai 600 020, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient, regioselective Cu(OTf)2-catalyzed 5-exo-dig intramolecular hydroalkoxylation of 2-(ethy-
nyl)benzyl alcohol, which provides a concise access to functionalized phthalan in high yields has been
developed. A wide range of substrates possessing terminal, internal, and heteroaromatic alkynes can
be efficiently transformed into the targeted phthalans. Substrates with primary, secondary, and tertiary
benzyl alcohols also proceed well to produce the corresponding phthalans in good yields. Irrespective of
the nature of the substrates, the cyclization follows highly selective 5-exo-dig regiochemistry when
regioselectivity is an issue.
Received 4 June 2010
Revised 1 July 2010
Accepted 6 July 2010
Available online 8 July 2010
Keywords:
2-(Ethynyl)benzyl alcohol
Cu(OTf)2
Ó 2010 Elsevier Ltd. All rights reserved.
5-exo-dig regiochemistry
Phthalan
Phthalans (1,3-dihydroisobenzofurans) have drawn consider-
able interest in organic chemistry, not only as useful building
blocks1 but also as key structural units in several natural prod-
ucts2 and biologically active compounds.3 For example, pestacin
1 (Fig. 1) isolated from the endophytic bacteria, Pestalotiopsis
microspora exhibits potent antioxidant and antimycotic activi-
ties.2e,f Escitalopram 2 is an antidepressant of the selective sero-
tonin reuptake inhibitor class.3a Molecule 3 (RPR 225,370) is a
farnesyl transferase inhibitor with good cellular potency.3c Com-
pound 4 is a representative of a group of molecules, possessing
isobenzylidene ring system, proven to be a potential tyrosine ki-
nase inhibitor.3d
the stoichiometric use of hazardous reagents such as NaH,5m
NaOH,5m nBu4NF,5d Hg(OAc)2,5g I2,5b and metallic sodium.5q In the
context of our ongoing studies on heterocyclic constructions,6 the
possibility of regioisomeric cyclization of 2-(ethynyl)benzyl alco-
hol leading to phthalan appeared attractive from the viewpoint
of devising a regioselective synthetic route (phthalan vs isochrom-
ene). Herein, we describe Cu(OTf)2-catalyzed 5-exo-dig cycloiso-
merization of 2-(ethynylbenzyl) alcohols, leading to phthalan
derivatives. We started our investigation with 2-(phenyleth-
ynyl)benzyl alcohol 1a which was prepared from the Sonogashira
coupling of 2-iodobenzyl alcohol and phenyl acetylene (Scheme
1).7
While many synthetic routes for phthalans exist, they are still
limited by the acidic/basic reaction conditions or narrow applica-
bility to substrates.4 On the other hand, cycloisomerization of
2-(ethynyl)benzyl alcohol offers opportunities for constructing
oxygenated heterocycles and has attracted considerable attention
in recent years.5 This transformation relies on the catalytic activa-
tion of the C–C triple bond followed by the nucleophilic attack of
the tethered hydroxyl function. Although these reactions have
been extensively studied by a number of research groups,5 the re-
sults in most cases offer no regioselectivity and lead to the forma-
tion of either isochromenes,5a,h,j or both isochromenes and
phthalans.5b,d,e Moreover, most of these protocols suffer the lim-
ited use of pricey catalysts such as CpRuCl(PPh3)2,5a La[N(Si-
Me3)2]3,5i,o Py-Pd-NHC,5f and hydridoiridium(III) complexes5h or
F
HO
OH
NMe2
O
O
OH
Me
NC
Escitalopram 2
Pestacin 1
H
NH
O
O
O
COOMe
Ph
O
MeO
(Z)-3-(isobenzofuran-3(1H)-ylidene)
indolin-2-one 4
RPR 225,370 3
* Corresponding author. Tel.:+91 44 24911329; fax: +91 44 24911539.
E-mail address: ptperumal@gmail.com (P.T. Perumal).
Figure 1. Biologically active compounds containing isobenzofuran scaffold.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.030

4768
C. Praveen et al. / Tetrahedron Letters 51 (2010) 4767–4771
Catalyst
+
O
OH
O
Toluene, N2, reflux
1a
2a'
3a
Scheme 1. Screening of different Lewis acids for the cyclization of model substrate 1a.
(Table 2).11 The reaction appears to be general and works well
regardless of the nature of the substituents on the triple bond ter-
minus. However, alkynes possessing electron-rich groups enhance
the cyclization and generally higher yields are obtained at a shorter
reaction time (entries 2–4). The presence of substituent at the ben-
zylic position did have deleterious effects on the cyclization; pri-
mary alcohols underwent cyclization significantly (entries 1–4,
8–10, and 13–15) in terms of shorter reaction times and higher
yields, than the secondary alcohols (entries 5, 11, and 12), which
in turn react efficiently than their tertiary counterparts (entries 6
and 7). The copper-catalyzed cyclization of substrate 1l is particu-
larly noteworthy of these functionalities, only the hydroxyl group
reacts to afford phthalan 2l in a good yield, leaving the amine
group intact. Our method also finds application in a more complex
heteroaromatic synthesis as well. For example, the piperanol-de-
rived substrate 1i gave an excellent yield of the product 2i under
the same reaction conditions.11 It is noteworthy to mention that
substrates possessing heteroaromatic motif like pyridine 1n and
pyrazine 1o tolerated well under our reaction conditions (entries
14 and 15). A preparative scale-catalytic reaction was performed
for the reaction of 2j–2m in benzene-d6, since these compounds
readily underwent decomposition in CDCl3 solvent.12 The Z-config-
uration of phthalan was assigned from the comparison of the
chemical shifts of the vinylic protons with those reported for sim-
ilar compounds.5d The (Z)-stereochemistry of phthalan 2i has been
assigned using a 1-D NOE experiment. Selective irradiation of the
vinylic proton effected the enhancement of the signals of C4–H
(9.1%) and ortho-phenyl proton (16.7%), respectively. Irradiation
of C4–H effected the enhancement of vinylic proton (7.5%) and no
enhancement of ortho-phenyl proton. This observation confirmed
that the vinylic proton is cis to C4–H, thus the compound 2i is Z-
configured. Similarly, for compound 2c, irradiation of vinylic pro-
ton effected the enhancement of both C4–H (11.5%) and ortho-phe-
nyl proton (22.4%). Irradiation of C4–H proton however effected the
enhancement of vinylic proton (8.7%) and no enhancement of the
ortho-phenyl proton. These facts confirmed the cis relationship of
the vinylic proton and C4–H, thus favoring the Z-configuration (
Fig. 2). The stereochemistry of the other phthalan is assigned by
analogy to 2i and 2c.
Table 1
Screening of carbophilic Lewis acids for the cyclization of 1aa
Entry Catalyst (5 mol %)
Regioisomeric ratio (%)
Yieldb (%)
Phthalan (2a0) Isochromene (3a)
1
2
3
4
5
6
AuBr3
In(OTf)3
PtCl2
Zn(OTf)2
NiBr2
Cu(OTf)2
35
55
100
51
44
100
65
45
—
49
66
–
70
75
20
70
25
95
a
Crude 1H NMR yield obtained in CDCl3 solvent.
All reactions were carried out in 20 min.
b
CDCl3 or
O
O
Silica Gel
2a
Scheme 2. Isomerization of 2a0–2a.
2a'
Treatment of 1a with 5 mol % of AuBr3 in toluene8 at reflux tem-
perature for 20 min resulted in the formation of the expected iso-
chromene 3a and phthalan 2a0 in 35:65 ratio and with 20% of the
starting material remains unconsumed, as evidenced by crude 1H
NMR analysis (Table 1, entry 1). In order to improve the formation
of the targeted phthalan exclusively, we screened different carbo-
philic Lewis acids. The results revealed that the use of In(OTf)3 led
to the product formation in 75% yield, with equal amount of phtha-
9
lan 2a0 and isochromene 3a (entry 2). In contrast, the use of PtCl2
resulted in slower reactions and decreased yields of 2a0 because of
the incomplete conversion and partial decomposition of the sub-
strate (entry 3). The conversion of 1a was also catalyzed by
Zn(OTf)2, although a mixture of both regioisomers was obtained
(entry 4). The use of NiBr2 resulted in a poor yield of products (en-
10
try 5). Finally, treatment of 1a with 5 mol % of Cu(OTf)2 in tolu-
In IR spectra, a peak observed at 1620–1650 cmꢀ1 for all com-
pounds revealed the presence of an ether linkage. In 1H NMR spec-
tra, all products exhibited a sharp singlet between dH 4.75 (for
unsubstituted olefins) and 6.43 ppm (for substituted olefins) and
indicated the presence of vinylic proton. In 13C NMR spectra, a peak
at dc 120–125 ppm ascertained the presence of olefinic carbon,
characteristic of the exocyclic alkylidene carbon of isobenzofuran.
All these findings confirmed the formation of phthalans.
The reason for the exclusive formation of the five-membered
ring over their six-member counter part was not clear. However,
a tentative mechanism, on the basis of the obtained results is pro-
posed (Scheme 3), according to which a six-membered transition
state 4 was formed via a bidentate complexation of [Cu] with the
ene at reflux temperature led to the regioselective 5-exo-dig
cyclization within 1 h to give the corresponding phthalan 2a0 in a
quantitative yield (entry 6). Although, the reaction yielded the de-
sired phthalan 2a0 in an excellent yield, the stereochemistry of the
product was not fixed. Crude 1H NMR analysis indicated the forma-
tion of both the
Z (@CH, dH = 5.95 ppm) and the E (@CH,
dH = 6.49 ppm) isomers in 88:12 ratios. However, when the NMR
spectrum of the same mixture was recorded after 6 h it revealed
the formation of only the Z-isomer. Our attempts at separating
the two isomers on a silica gel column led to the Z-isomer exclu-
sively. These observations confirmed the isomerization of the min-
or E-isomer to the thermodynamically more stable Z-isomer 2a,
under CDCl3 or silica gel condition (Scheme 2).
Encouraged by the high regioselectivity and excellent yield, we
next set out to examine the scope of the reaction, by treating var-
ious substituted 2-(ethynyl)benzyl alcohols with Cu(OTf)2 and ob-
tained the corresponding phthalans 2a–2o in high yields
hydroxyl group and a-carbon of the alkyne of 1. As a consequence,
a partial depletion of electron density at the b-carbon of the
acetylene function drives the nucleophilic attack of the pendant
hydroxyl group toward the b-carbon leading to the five-membered

C. Praveen et al. / Tetrahedron Letters 51 (2010) 4767–4771
4769
Table 2
Copper(II)-catalyzed synthesis of phthalans via cycloisomerisation of 2-(ethynyl)benzyl alcoholsa
Entry
2-(Ethynyl)benzyl alcohol (1)
Phthalan (2)b
Time (min)
Yield (%)c
1
20
92
95
O
OH
2a
1a
OMe
OMe
2
3
4
20
45
45
O
OH
2b
1b
Me
Me
94
95
O
OH
2c
1c
Me
Me
O
OH
2d
1d
O
5
6
7
8
30
3.5
40
25
88
76
79
OH
Bu
2e
Bu
1e
Bu
Bu
O
OH
Et
Et
Et
1f
Et
2f
O
OH
Et
1g
Et
Et
Et
2g
Me
O
O
Me
86
85
O
OH
1h
2h
O
O
O
O
9
30
25
O
OH
2i
1i
10
85d
O
OH
2j
1j
(continued on next page)

4770
C. Praveen et al. / Tetrahedron Letters 51 (2010) 4767–4771
Table 2 (continued)
Entry
2-(Ethynyl)benzyl alcohol (1)
Phthalan (2)b
Time (min)
40
Yield (%)c
O
OH
11
12
75d
Me
Me
2k
1k
O
OH
30
40
77d
NH2
NH2
2l
1l
MeO
MeO
13
14
87d
O
OH
2m
1m
N
N
35
55
75
78
O
2n
N
OH
1n
N
N
N
15
O
OH
2o
1o
d
The reaction was carried out in benzene-d6 solvent at 65 °C.
a
All reactions were carried out at 110 °C in toluene using 5 mol % of Cu(OTf)2 under nitrogen atmosphere.
b
All products were characterized by IR, 1H NMR, 13C NMR, and mass spectroscopy.
c
Isolated yield.
Substrates possessing tertiary, secondary, and primary benzyl alco-
hols and alkynes having hydrogen, alkyl, aromatic, and heteroaro-
matic groups can be used in this procedure. For reasons that are
not clear, this Cu(II)-catalyzed protocol affords only the five-mem-
bered oxygenated heterocycle. We are in the process of examining
the relationship between the regioselectivity and the Lewis acidity
of Cu(OTf)2. DFT computational studies are now being evaluated to
reason out the predominant formation of phthalans over isochrom-
enes. Biological activity of the synthesized compounds is underway
in our laboratory and will be reported in due course.
7.6%
16.7%
9.1 %
H
8.7%
H
Me
H
H
11.5%
H
22.4%
H
O
O
O
H
H
O
5.3%
2i
2c
Acknowledgment
Figure 2. 1-D NOE enhancement of compounds 2i and 2c.
One of the authors, C.P. thanks the Council of Scientific and
Industrial Research, New Delhi, India, for the research fellowship.
intermediate 5. Subsequent protodecupration of 5 results in the
formation of phthalan 2.
Supplementary data
In summary, we have developed an effective Cu-catalyzed intra-
molecular hydroalkoxylation of various 2-(ethynyl) benzyl alcohols
leading to the regioselective synthesis of substituted phthalans.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.07.030.
-
R
δ−
R
R
R
[Cu]
δ+
[Cu]
[Cu]
+
..
O
O
H
OH
-
OH
[Cu]
2
1
5
4
Scheme 3. Plausible mechanism for the formation of isobenzofuran 2.

C. Praveen et al. / Tetrahedron Letters 51 (2010) 4767–4771
4771
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11. Representative procedure for the synthesis of (Z)-5-benzylidene-5,7-dihydro-
furo[30,40:4,5]benzo[1,2-d][1,3]dioxole (2i): To a degassed solution of (5-(2-
phenylethynyl)benzo[d][1,3]dioxol-6-yl)methanol (1i, 252 mg, 1.0 mmol) in
drytoluene(1 mL)under N2 wasadded Cu(OTf)2 (18.08 mg, 0.018 mmol)and the
reaction mixture was stirred at 110 °C for 30 min. After completion of the
reaction as indicated by TLC, the reaction mixture was concentrated under
reduced pressure and was purified by column chromatography over silica gel
(100–200 mesh) to afford the pure product of 2i in 85% (214 mg) yield as a pale
yellow solid; mp 132–134 °C; IR (KBr) 2898, 1733, 1632, 1481, 1367, 1291, 1152,
1035, 860, 757 cmꢀ1 1HNMR(500 MHz, CDCl3):dH 5.11(s, 2H, –OCH2Ar);5.93(s,
.
2H, –OCH2O–); 6.36 (s, 1H, @CH); 6.60 (s, 1H, C8–H); 6.62 (s, 1H, C4–H); 7.32–7.38
(m, 3H, Ar-H); 7.69 (d, 2H, J = 6.8 Hz, Ar-H). 13C NMR (125 MHz, CDCl3): dC 69.0,
101.0, 101.4, 104.6, 105.2, 121.5, 124.8, 126.3, 128.4, 128.7, 134.2, 146.1, 147.5,
152.7. MS (EI): m/z = 253 [M+H]+. Anal. Calcd for C16H12O3: C, 76.18; H, 4.79.
Found: C, 75.99; H, 4.85.
12. Representative procedure for the intramolecular hydroalkoxylation of 2m in
C6D6: To an NMR tube equipped with a screw cap containing benzene-d6
(0.50 mL) under argon, 2-(2-(2-methoxyphenyl)ethynyl)phenylmethanol (1m,
50.0 mg, 0.21 mmol) and Cu(OTf)2 (3.79 mg, 0.0105 mmol) were added. The
resulting mixture was heated at 65 °C and monitored by NMR until the starting
material had been consumed. At completion of the reaction, this reaction
mixture was filtered through a small plug of silica gel to remove the catalyst.
The crude product was purified by silica gel column chromatography
(petroleum ether/AcOEt 9.5:0.5) to afford the pure product of (Z)-1-(2-
methoxy-benzylidene)-1,3-dihydro-isobenzofuran 2m in 87% (43 mg) yield
as a brown oil. IR (neat): 3308, 2938, 2189, 1635, 1427, 1327, 1200, 1076,
878 cmꢀ1 1H NMR (500 MHz, benzene-d6): dH 3.25 (s, 3H, –OCH3); 4.92 (s, 2H,
.
–OCH2Ar); 6.48–7.05 (m, 8H, Ar-H); 7.92–7.93 (m, 1H, Ar-H). 13C NMR
(125 MHz, benzene-d6): 54.8, 68.5, 107.0, 111.2, 120.4, 123.7, 123.8, 126.2,
128.3, 128.5, 128.8, 129.4, 129.6, 132.6, 151.4, 157.6. MS (EI): m/z = 239
[M+H]+. Anal. Calcd for C16H14O2: C, 80.65; H, 5.92. Found: C, 80.85; H, 5.86.