A facile synthesis of 1,3-dihydroisobenzofurans using iodocylization of 2-vinylbenzyl alcohols

Article abstract of DOI:10.3987/COM-07-11244

An efficient route for the preparation of 1,3-dihydroisobenzofurans based on the iodine-mediated cyclization of 2-vinylbenzyl alcohols, which can be prepared feasibly by reactions of 2-vinylphenyllithiums with carbonyl compounds, is reported. Substitution reactions of the iodo moiety of the resulting 1-(iodomethyl)-1,3-dihydroisobenzofurans with tributyltin hydride and sodium thiolates are also described.

Full text of DOI:10.3987/COM-07-11244

HETEROCYCLES, Vol. 75, No. 3, 2008
599
HETEROCYCLES, Vol. 75, No. 3, 2008, pp. 599 - 609. © The Japan Institute of Heterocyclic Chemistry
Received, 15th October, 2007, Accepted, 21st November, 2007, Published online, 22nd November, 2007. COM-07-11244
A FACILE SYNTHESIS OF 1,3-DIHYDROISOBENZOFURANS USING
IODOCYLIZATION OF 2-VINYLBENZYL ALCOHOLS
Kazuhiro Kobayashi,* Kazuaki Shikata, Shuhei Fukamachi, and Hisatoshi
Konishi
Department of Materials Science, Faculty of Engineering, Tottori University,
4-101 Koyama-minami, Tottori 680-8552, Japan
Abstract - An efficient route for the preparation of 1,3-dihydroisobenzofurans
based on the iodine-mediated cyclization of 2-vinylbenzyl alcohols, which can be
prepared feasibly by reactions of 2-vinylphenyllithiums with carbonyl compounds,
is reported. Substitution reactions of the iodo moiety of the resulting
1-(iodomethyl)-1,3-dihydroisobenzofurans with tributyltin hydride and sodium
thiolates are also described.
Iodocyclization is one of the most useful operations in organic synthesis. Recently, it has been reported
to be very effective in the synthesis of benzene-fused heterocyclic compounds from appropriate
o-substituted styrene derivatives.1 In this paper, we wish to report a simple approach to
1,3-dihydroisobenzofuran (phthalane) derivatives, which involves the conversion of 2-vinylbenzyl
alcohols (2) to 1-(iodomethyl)-1,3-dihydroisobenzofurans (3) on treatment with iodine in the presence of
potassium t-butoxide. 1,3-Dihydroisobenzofuran derivatives are of biological interest.2 Moreover, a
natural product having this system has recently been isolated from the nature.3 A few methods for the
preparation of this class of molecules have been reported.4 However, these suffer from limited generality
and troublesome preparation of the precursors. We also report on substitution reactions of the iodo
moiety of 3 with tributyltin hydride and sodium thiolates.
The synthesis of 1,3-dihydroisobenzofurans was conducted as shown in Scheme 1. The starting
2-vinylbenzyl alcohols (2) were obtained by reactions of 2-vinylphenyllithium derivatives, generated
from 2-bromostyrene derivatives 1 by bromine-lithium exchange with butyllithium in diethyl ether at 0 ˚C,
with carbonyl compounds in fair yields, as summarized in Table 1. These alcohols were
subsequently transformed into the corresponding 1-(iodomethyl)-1,3-dihydroisobenzofurans (3) in
generally good yields on treatment with iodine in the presence of potassium t-butoxide at 0 ˚C in toluene.
These results are also listed in Table 1. Entry 11 shows that, when compound (2k) carring a methoxy
substituent on benzene ring was used, the corresponding desired product 3k was obtained in somewhat

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HETEROCYCLES, Vol. 75, No. 3, 2008
lower yield from a complicated mixture of products. The use of sodium hydrogencarbonate in place of
potassium t-butoxide gave rather intractable mixture of products, from which only lower yields of the
desired products were isolated. Unfortunately, however, we have no explicit explanation for these.
R1
Br
R1
R1
CH2I
R2
R2
R2
I2 ,t-BuOK
1) n-BuLi, Et2O, 0 ˚C
2) R3COR4, 0 ˚C
O
toluene, 0 ˚C
OH
R3 R4
R4
R3
3
1
2
R1
Me
R2
n-Bu3SnH, C6H6, rt
O
R4
R3
4
Scheme 1
Table 1. Preparation of 1,3-Dihydroisobenzofuran Derivatives (3) and (4), via 2
Entry
o-Bromostyrene 1
1a (R1 = Ph, R2 = H)
1a
R3COR4
2 (Yield/%)a) 3 (Yield/%)a) 4 (Yield/%)a)
1
2
3
4
5
6
7
8
9
cyclopentanone
cyclohexanone
benzaldehyde
acetone
cyclopentanone
cyclohexanone
acetone
cyclopentanone
cyclohexanone
cyclooctanone
cyclohexanone
2a (57)
2b (67)
2c (61)
2d (63)
2e (64)
2f (61)
2g (64)
2h (63)
2i (64)
2j (65)
2k (61)
3a (88)
3b (72)
3c (70)b),c)
3d (72)
3e (66)
3f (70)
3g (79)
3h (73)
3i (70)
4a (60)
4b (56)
4c (72)c),d)
4d (60)
4e (63)
4f (73)
4g (71)
4h (61)
4i (68)
4j (58)
e)
1b (R1 = 4-ClC6H4, R2 = H)
1b
1b
1b
1c (R1 = Me, R2 = H)
1c
1c
1c
10
11
3j (78)
3k (49)
1d (R1 = Me, R2 = OMe)
a) Isolated yields. b) An inseparable mixture of diastereomers (ca. 3:1). c) Stereochemistry of each isomer
was not determined yet. d) A separable mixture of diastereomers (ca. 3:1). e) The reduction of 3k was not
carried out.
We then proceeded to study the replacement of iodine of 1-iodomethyl-1,3-dihydroisobenzofurans (3)
with hydrogen. The compound (3) were treated with tributyltin hydride in benzene at room temperature.
The reactions were completed within 2 h to give the corresponding 1-methyl derivatives (4) in fair to
good yields, as summarized in Table 1.
We next proceeded to explore the nucleophilic substitution of 3 with sodium thiolates. The procedure is
outlined in Scheme 2. The reactions were conducted in DMF at the temperature indicated in the Table 2,
in which reaction times and yields of the products were also summarized. Phenylmethanethiolate (entries

HETEROCYCLES, Vol. 75, No. 3, 2008
601
1 and 3), 2-hydroxyethanethiolate (entry 4), and benzenethiolate (entry 6) reacted smoothly with 3 at
room temperature to give the corresponding sulfenylated 1,3-dihydroisobenzofurans (5) in fair yields. It
was also found that heterocyclic thiols, such as pyridine-2-thiol and 4,6-dimethylpirimidine-2-thiol, could
be successfully employed in this substitution reaction, but elevated reaction temperatures were required
for satisfactory production of the desired products (5b), (5e), and (5g) (entries 2, 5, and 7).
CH2SR5
R1
R2
NaSR5, DMF, rt – 90 ˚C
O
3
R4
R3
5
Scheme 2
Table 2. Reactions of 3 with Sodium Thiolates
Entry
3
3b
3f
3g
3g
3h
3i
R5 in NaSR5
Bn
4,6-dimethylpyrimidin-2-yl
Temp
rt
90 ˚C
rt
Time/h
Product (Yield/%)a)
5a (70)
5b (51)
1
2
3
4
5
6
7
4
7
2
20
18
24
9
Bn
(CH2)2OH
pyridin-2-yl
5c (60)
5d (67)
5e (48)
5f (64)
5g (51)
rt
65 ˚C
rt
70 ˚C
Ph
4,6-dimethylpyrimidin-2-yl
3k
a) Isolated yields.
In conclusion, the present study has led to the development of a novel and convenient method for the
preparation of 1,1,4,4-tetrasubstituted 1,3-dihydroisobenzofurans. The present method has advantages
over the previous methods of 1,3-dihydroisobenzofuran synthesis: simple manipulations as well as the
ready availability of the starting materials. Applications of the present procedure to the preparation of
related heterocycle systems are presently under investigation and will be reported at a later date.
EXPERIMENTAL
The melting points were determined on a Laboratory Devices MEL-TEMP II melting-point apparatus and
1
are uncorrected. The IR spectra were recorded on a Shimadzu FTIR-8300 spectrometer. H NMR spectra
were determined using SiMe4 as an internal reference in CDCl3 with a JEOL ECP500 FT NMR
spectrometer operating at 500 MHz or a JEOL LA400 FT NMR spectrometer operating at 400 MHz.
Low-resolution mass spectra (EI) were recorded on a JEOL AUTOMASS 20 spectrometer.
Low-resolution mass spectra (CI) were recorded on a JEOL JMS AX505 HA spectrometer. Thin-layer
chromatography (TLC) was carried out using Merck Kieselgel 60 PF254. Column chromatography was

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performed using Merck Kieselgel 60 (0.063–0.200 mm). All of the solvents used were dried over the
appropriate drying agents and distilled under argon prior to use.
Starting
Materials
1-Bromo-2-(1-phenylethenyl)benzene
(1a),5
1-bromo-2-[1-(4-
chlorophenyl)ethenyl]benzene (1b),1d and 1-bromo-2-(methylethenyl)benzene (1c)6 were prepared by
appropriated reported methods. All other chemicals used in this study were commercially available.
Typical Procedure for the Preparation of 2-Vinylbenzyl Alcohol Derivatives (2).
1-[2-(2-Phenylethenyl)phenyl]cyclopentanol (2a): To a stirred solution of 1a (0.96 g, 3.7 mmol) in Et2O
(10 mL) at 0 ˚C was added dropwise n-BuLi (1.6 M in hexane; 3.7 mmol); the mixture was stirred for 1 h
at the same temperature. Cyclopentanone (0.31 g, 3.7 mmol) was added and stirring was continued for an
additional 30 min. The reaction was quenched by adding saturated aqueous NH4Cl (15 mL) and extracted
with Et2O three times (10 mL each). The combined extracts were washed with brine and dried over
anhydrous Na2SO4, and the solvent was evaporated. The residue was purified by preparative TLC on
silica gel to give 2a (0.56 g, 57%); a yellow oil; Rf 0.24 (1:9 AcOEt–hexane); IR (neat) 3570, 3458, 1612
cm–1; 1H NMR (400 MHz) δ 1.65–1.82 (4H, m), 1.88 (1H, s), 1.95–1.97 (4H, m), 5.27 (1H, d, J = 1.1 Hz),
5.89 (1H, d, J = 1.1 Hz), 7.14 (1H, dd, J = 7.7, 1.8 Hz), 7.24–7.34 (7H, m), 7.50 (1H, dd, J = 8.0, 1.4 Hz).
Anal. Calcd for C19H20O: C, 86.32; H, 7.63. Found: C, 86.05; H, 7.63.
1-[2-(2-Phenylethenyl)phenyl]cyclohexanol (2b): a yellow oil; Rf 0.39 (1:9 AcOEt–hexane); IR (neat)
1
3572, 3466, 1612 cm–1; H NMR (500 MHz) δ 1.11–1.20 (1H, m), 1.46–1.88 (9H, m), 1.98 (1H, s), 5.19
(1H, s), 5.83 (1H, s), 7.08 (1H, d, J = 7.3 Hz), 7.21–7.35 (7H, m), 7.50 (1H, d, J = 8.2 Hz). Anal. Calcd
for C20H22O: C, 86.29; H, 7.97. Found: C, 86.24; H, 7.84.
{2-[2-(4-Chlorophenyl)ethenyl]phenyl}phenylmethanol (2c): a pale-yellow oil; Rf 0.33 (1:7
Et2O–hexane); IR (neat) 3404, 1601 cm–1; 1H NMR (500 MHz) δ 1.93 (1H, d, J = 3.7 Hz), 5.17 (1H, d, J
= 1.4 Hz), 5.789 (1H, d, J = 1.4 Hz), 5.790 (1H, d, J = 3.7 Hz),7.16–7.25 (10H, m), 7.31 (1H, td, J = 7.8,
1.4 Hz), 7.39 (1H, td, J = 7.8, 1.4 Hz), 7.53 (1H, dd, J = 7.8, 1.4 Hz). Anal. Calcd for C21H17ClO: C,
78.62; H, 5.34. Found: C, 78.71; H, 5.50.
2-[2-(4-Chlorophenyl)ethenyl]phenylpropan-2-ol (2d): a pale-yellow oil; Rf 0.22 (1:3 Et2O–hexane); IR
(neat) 3568, 3412, 1614 cm–1; 1H NMR (500 MHz) δ 1.49 (6H, s), 2.14 (1H, s), 5.22 (1H, d, J = 0.9 Hz),
5.84 (1H, d, J = 0.9 Hz), 7.07 (1H, dd, J = 7.8, 1.4 Hz), 7.23 (2H, d, J = 9.2 Hz), 7.24 (2H, d, J = 9.2 Hz),
7.26 (1H, ddd, J = 7.8, 7.3, 1.4 Hz), 7.34 (1H, ddd, J = 7.8, 7.3, 1.4 Hz), 7.50 (1H, dd, J = 7.8, 1.4 Hz).
Anal. Calcd for C17H17ClO: C, 74.86; H, 6.28. Found: C, 74.90; H, 6.21.
1-[2-(4-Chlorophenyl)ethenyl]phenylcycopentanol (2e):
a
pale-yellow oil; Rf 0.40 (1:2
1
CH2Cl2–hexane); IR (neat) 3576, 3458, 1614 cm–1; H NMR (500 MHz) δ 1.65–1.72 (2H, m), 1.78–1.86
(3H, m), 1.91–1.98 (4H, m), 5.27 (1H, s), 5.87 (1H, s), 7.10 (1H, d, J = 7.8 Hz), 7.23–7.29 (5H, m), 7.33
(1H, dd, J = 7.8, 7.3 Hz), 7.49 (1H, d, J = 7.8 Hz). Anal. Calcd for C19H19ClO: C, 76.37; H, 6.41. Found:
C, 76.21; H, 6.80.

HETEROCYCLES, Vol. 75, No. 3, 2008
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1-[2-(4-Chlorophenyl)ethenyl]phenylcycohexanol (2f): a pale-yellow oil; Rf 0.40 (1:2 Et2O–hexane); IR
1
(neat) 3580, 3468, 1612 cm–1; H NMR (500 MHz) δ 1.16–1.20 (1H, m), 1.47–1.52 (2H, m), 1.61–1.74
(5H, m), 1.80–1.87 (2H, m), 1.88 (1H, s), 5.18 (1H, d, J = 0.9 Hz), 5.81 (1H, d, J = 0.9 Hz), 7.04 (1H, dd,
J = 7.8, 1.4 Hz), 7.22–7.30 (5H, m), 7.34 (1H, ddd, J = 7.8, 7.3, 1.4 Hz), 7.49 (1H, d, J = 8.2 Hz). Anal.
Calcd for C20H21ClO: C, 76.79; H, 6.77. Found: C, 76.76; H, 6.84.
2-[2-(1-Methylethenyl)phenyl]propan-2-ol (2g): a yellow oil; Rf 0.25 (1:10 AcOEt–hexane); IR (neat)
1
3566, 3452, 1635 cm–1; H NMR (500 MHz) δ 1.62 (6H, s), 2.17 (3H, d, J = 1.4 Hz), 2.97 (1H, s), 4.89
(1H, d, J = 0.9 Hz), 5.21 (1H, qd, J = 1.4, 0.9 Hz), 7.01 (1H, dd, J = 7.8, 1.4 Hz), 7.18 (1H, ddd, J = 7.8,
7.3, 1.4 Hz), 7.23 (1H, ddd, J = 7.8, 7.3, 1.4 Hz), 7.36 (1H, dd, J = 7.8, 1.4 Hz). Anal. Calcd for C12H16O:
C, 81.77; H, 9.15. Found: C, 81.75; H, 9.24.
1-[2-(1-Methylethenyl)phenyl]cyclopentanol (2h): a white solid; mp 42–44 ˚C (hexane); IR (KBr) 3560,
3452, 1634 cm–1; 1H NMR (500 MHz) δ 1.75–1.82 (2H, m), 1.90–1.99 (2H, m), 2.02–2.12 (4H, m), 2.18
(3H, s), 2.56 (1H, s), 4.92 (1H, d, J = 1.4 Hz), 5.22 (1H, d, J = 1.4 Hz), 7.05 (1H, dd, J = 7.8, 1.4 Hz),
7.18–7.24 (2H, m), 7.37 (1H, dd, J = 7.8, 1.4 Hz). Anal. Calcd for C14H18O: C, 83.12; H, 8.97. Found: C,
82.84; H, 9.13.
1-[2-(1-Methylethenyl)phenyl]cyclohexanol (2i): a yellow oil; Rf 0.40 (1:5 AcOEt–hexane); IR (neat)
3568, 3454, 1633 cm–1; 1H NMR (500 MHz) δ 1.21–1.30 (1H, m), 1.55–1.60 (2H, m), 1.71–1.93 (7H. m),
2.18 (3H, t, J = 1.4 Hz), 2.70 (1H, s), 4.85 (1H, quint, J = 1.4 Hz), 5.16 (1H, q, J = 1.4 Hz), 7.00 (1H, dd,
J = 7.3, 1.8 Hz), 7.17 (1H, td, J = 7.3, 1.4 Hz), 7.23 (1H, ddd, J = 7.8, 7.3, 1.8 Hz), 7.36 (1H, dd, J = 7.8,
1.4 Hz). Anal. Calcd for C15H20O: C, 83.28; H, 9.32. Found: C, 82.98; H, 9.46.
1-[2-(1-Methylethenyl)phenyl]cyclooctanol (2j): a yellow oil; Rf 0.30 (1:2 CH2Cl2–hexane); IR (neat)
3501, 3385, 1636 cm–1; 1H NMR (500 MHz) δ 1.35–1.40 (1H, m), 1.48–2.10 (13H, m), 2.18 (3H, s), 2.83
(1H, s), 4.84 (1H, d, J = 1.8 Hz), 5.17 (1H, d, J = 1.8 Hz), 7.00 (1H, dd, J = 7.3, 1.8 Hz), 7.18 (1H, td, J =
7.3, 1.4 Hz), 7.22 (1H, ddd, J = 7.8, 7.3, 1.8 Hz), 7.33 (1H, dd, J = 7.8, 1.4 Hz). Anal. Calcd for C17H24O:
C, 83.55; H, 9.90. Found: C, 83.41; H, 10.01.
1-[4-Methoxy-2-(1-methylethenyl)phenyl]cyclohexanol (2k):
a
colorless oil; Rf 0.33 (1:9
1
EtOAc–hexane); IR (neat) 3564, 1634, 1605 cm–1; H NMR (500 MHz) δ 1.19–1.28 (1H, m), 1.54–1.59
(2H, m), 1.69–1.90 (7H, m), 2.18 (3H, s), 2.59 (1H, s), 3.79 (3H, s), 4.87 (1H, s), 5.16 (1H, s), 6.54 (1H,
d, J = 2.8 Hz), 6.78 (1H, dd, J = 8.7, 2.8 Hz), 7.29 (1H, d, J = 8.7 Hz). Anal. Calcd for C16H22O2: C,
78.01; H, 9.00. Found: C, 77.85; H, 9.14.
Typical Procedure for the Preparation of 1-(Iodomethyl)-1,3-dihydroisobenzofuran Derivatives (3)
3’-Iodomethyl-3’-phenyl-3’H-spiro[cyclopentane-1,1’-(1’,3’-dihydroisobenzofuran)] (3a): To a
stirred solution of 2a (0.31 g, 1.2 mmol) in toluene (15 mL) containing t-BuOK (0.40 g, 3.6 mmol) at 0
˚C was added I2 (0.96 g, 3.6 mmol) in several portions; stirring was continued for 15 min. Ten percent
aqueous Na2S2O3 was added until the color of iodine disappeared, and the organic materials were

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HETEROCYCLES, Vol. 75, No. 3, 2008
extracted with Et2O three times (10 mL each). The combined extracts were washed with saturated
aqueous NH4Cl and then brine, and dried over anhydrous Na2SO4. Evaporation of the solvent gave a
residue, which was purified by preparative TLC on silica gel (1:9 CH2Cl2–hexane) to give 3a (0.41g,
1
88%); a pale-yellow solid; mp 109–114 ˚C (hexane–Et2O); IR (KBr) 1040 cm–1; H NMR (500 MHz) δ
1.68–1.81 (1H, m), 1.83–1.85 (2H, m), 1.93–2.09 (4H, m), 2.37–2.41 (1H, m), 3.76 (1H, d, J = 11.0 Hz),
3.83 (1H, d, J = 11.0 Hz), 7.14 (1H, d, J = 7.3 Hz), 7.25 (1H, t, J = 7.3 Hz), 7.31–7.36 (5H, m), 7.58 (2H,
d, J = 7.3 Hz); MS (EI) m/z 390 (M+, 0.2), 263 (1.1), 249 (100). Anal. Calcd for C19H19IO: C, 58.47; H,
4.91. Found: C, 58.42; H, 4.89.
3’-Iodomethyl-3’-phenyl-3’H-spiro[cyclohexane-1,1’-(1’,3’-dihydroisobenzofuran)]
(3b):
a
1
pale-yellow solid; mp 88–90 ˚C (hexane–Et2O); IR (KBr) 1040 cm–1; H NMR (500 MHz) δ 1.47–1.65
(5H, m), 1.73–1.99 (4H, m), 2.10–2.13 (1H, m), 3.72 (1H, d, J = 10.5 Hz), 3.85 (1H, d, J = 10.5 Hz), 7.10
(1H, dd, J = 7.3, 2.2 Hz), 7.25 (1H, t, J = 7.3 Hz), 7.31–7.35 (5H, m), 7.62 (2H, d, J = 7.8 Hz); MS (EI)
m/z 404 (M+, 1.2), 263 (100). Anal. Calcd for C20H21IO: C, 59.42; H, 5.24. Found: C, 59.27; H, 4.96.
1-(4-Chlorophenyl)-1-iodomethyl-3-phenyl-1,3-dihydroisobenzofuran
(3c):
a
mixture
of
diastereoisomers (ca. 3:1); a pale-yellow solid; mp 109–114 ˚C; IR (KBr) 1601, 1092 cm–1; 1H NMR (500
MHz) δ 3.87 (0.75H, d, J = 11.0 Hz), 3.88 (0.25H, d, J = 11.0 Hz), 3.91 (0.75H, d, J = 11.0Hz), 3.93
(0.25H, d, J = 11.0 Hz), 6.02 (0.25H, s), 6.40 (0.75H, s), 6.93 (0.25H, d, J = 7.8 Hz), 7.03 (0.75H, dd, J =
7.8, 0.9 Hz), 7.16–7.18 (1.5H, m), 7.28–7.42 (7.5H, m), 7.46–7.58 (3H, m); MS (EI) m/z 446 (M+, 0.02),
305 (100). Anal. Calcd for C21H16ClIO: C, 56.46; H, 3.61. Found: C, 56.15; H, 3.61.
1-(4-Chlorophenyl)-1-iodomethyl-3,3-dimethyl-1,3-dihydroisobenzofuran (3d): a pale-yellow solid;
1
mp 108–110 ˚C (hexane–Et2O); IR (KBr) 1069 cm–1; H NMR (500 MHz) δ 1.40 (3H, s), 1.72 (3H, s),
3.71 (1H, d, J = 11.0 Hz), 3.79 (1H, d, J = 11.0 Hz), 7.11–7.14 (1H, m), 7.30 (2H, d, J = 8.7 Hz),
7.35–7.39 (3H, m), 7.53 (2H, d, J = 8.7 Hz); MS (EI) m/z 398 (M+, 0.19), 257 (100). Anal. Calcd for
C17H16ClIO: C, 51.22; H, 4.05. Found: C, 51.08; H, 4.27.
3’-(4-Chlorophenyl)-3’-iodomethyl-3’H-spiro[cyclopentane-1,1’-(1’,3’-dihydroisobenzofuran)] (3e):
1
a white solid; mp 91–92 ˚C (hexane–Et2O); IR (KBr disk) 1091 cm–1; H NMR (500 MHz) δ 1.67–1.73
(1H, m), 1.80–2.08 (6H, m), 2.33–2.39 (1H, m), 3.71 (1H, d, J = 10.5 Hz), 3.78 (1H, d, J = 10.5 Hz), 7.15
(1H, dd, J = 7.8, 0.9 Hz), 7.30 (2H, d, J = 8.7 Hz), 7.31–7.38 (3H, m), 7.50 (2H, d, J = 8.7 Hz); MS (EI)
m/z 424 (M+, 0.29), 283 (100). Anal. Calcd for C19H18ClIO: C, 53.73; H, 4.27. Found: C, 53.70; H, 4.18.
3’-(4-Chlorophenyl)-3’-iodomethyl-3’H-spiro[cyclohexane-1,1’-(1’,3’-dihydroisobenzofuran)] (3f): a
pale-yellow solid; mp 110–111 ˚C (hexane–Et2O); IR (KBr) 1089 cm–1; 1H NMR (500 MHz) δ 1.31–1.40
(1H, m), 1.47–1.55 (2H, m), 1.62–1.66 (1H, m), 1.72–2.00 (5H, m), 2.07–2.09 (1H, m), 3.67 (1H, d, J =
11.0 Hz), 3.80 (1H, d, J = 11.0 Hz), 7.11–7.13 (1H, m), 7.29 (2H, d, J = 8.7 Hz), 7.34–7.36 (3H, m), 7.55
(2H, d, J = 8.7 Hz); MS (EI) m/z 438 (M+, 2.1), 297 (100). Anal. Calcd for C20H20ClIO: C, 54.75; H, 4.59.
Found: C, 54.63; H, 4.61.

HETEROCYCLES, Vol. 75, No. 3, 2008
605
1-Iodomethyl-1,3,3-trimethyl-1,3-dihydroisobenzofuran (3g):
a
yellow oil; Rf 0.40 (1:1
AcOEt–hexane); IR (neat) 1067 cm–1; 1H NMR (500 MHz) δ 1.52 (3H, s), 1.61 (3H, s), 1.69 (3H, s), 3.48
(1H, d, J = 10.5 Hz), 3.51 (1H, d, J = 10.5 Hz), 7.11 (1H, d, J = 7.3 Hz), 7.16 (1H, dd, J = 6.9, 1.4 Hz),
7.30 (1H, td, J = 7.3, 1.4 Hz), 7.33 (1H, ddd, J = 7.3, 6.9, 1.4 Hz); MS (EI) m/z 302 (M+, 0.01), 287 (14),
161 (100). Anal. Calcd for C12H15IO: C, 47.70; H, 5.00. Found: C, 47.61; H, 5.01.
3’-Iodomethyl-3’-methyl-3’H-spiro[cyclopentane-1,1’-(1’,3’-dihydroisobenzofuran)] (3h): a yellow
oil; Rf 0.42 (1:2 CH2Cl2–hexane); IR (neat) 1032 cm–1; 1H NMR (500 MHz) δ 1.67 (3H, s), 1.79–2.05 (7H,
m), 2.19–2.33 (1H, m), 3.49 (2H, s), 7.12 (1H, dd, J = 7.3, 1.4 Hz), 7.14 (1H, d, J = 7.3 Hz), 7.29 (1H, td,
J = 7.3, 0.9 Hz), 7.33 (1H, td, J = 7.3, 1.4 Hz); MS (EI) m/z 328 (M+, 1.3), 299 (9.8), 187 (100). Anal.
Calcd for C14H17IO: C, 51.24; H, 5.22. Found: C, 51.21; H, 5.50.
3’-Iodomethyl-3’-methyl-3’H-spiro[cyclohexane-1,1’-(1’,3’-dihydroisobenzofuran)] (3i): a yellow
1
oil; Rf 0.29 (1:10 CH2Cl2–hexane); IR (neat) 1034 cm–1; H NMR (500 MHz) δ 1.30–1.38 (1H, m),
1.61–1.87 (11H, m including s at 1.67), 1.91–1.95 (1H, m), 3.47 (1H, d, J = 10.5 Hz), 3.50 (1H, d, J =
10.5 Hz), 7.11 (1H, dd, J = 7.8, 1.4 Hz), 7.17 (1H, dd, J = 6.9, 1.4 Hz), 7.27–7.33 (2H, m); MS (EI) m/z
342 (M+, 6.7), 299 (32), 201 (100). Anal. Calcd for C15H19IO: C, 52.65; H, 5.60. Found: C, 52.48; H, 5.62.
3’-Iodomethyl-3’-methyl-3’H-spiro[cyclooctane-1,1’-(1’,3’-dihydroisobenzofuran)]
(3j):
a
pale-yellow oil; Rf 0.57 (1:2 CH2Cl2–hexane); IR (neat) 1032 cm–1; 1H NMR (500 MHz) δ 1.56–1.61 (2H,
m), 1.66 (3H, s), 1.68–1.86 (9H, m), 1.96–2.06 (2H, m), 2.10–2.16 (1H, m), 3.46 (1H, d, J = 10.5 Hz),
3.49 (1H, d, J = 10.5 Hz), 7.16–7.18 (2H, m), 7.27–7.32 (2H, m); MS (CI) m/z 371 [(M+1)+, 100]. Anal.
Calcd for C17H23IO: C, 55.14; H, 6.26. Found: C, 54.87; H, 6.47.
3’-Iodomethyl-5-methoxy-3’-methyl-3’H-spiro[cyclohexane-1,1’-(1’,3’-dihydroisobenzofuran)] (3k):
a white solid; mp 81–83 ˚C (hexane–Et2O); IR (KBr) 1614, 1032 cm–1; 1H NMR (500 MHz) δ 1.30–1.33
(1H, m), 1.57–1.91 (12H, m including s at 1.66), 3.46 (1H, d, J = 11.0 Hz), 3.48 (1H, d, J = 11.0 Hz),
3.82 (3H, s), 6.69 (1H, d, J = 2.3 Hz), 6.85 (1H, dd, J = 8.2, 2.3 Hz), 7.01 (1H, d, J = 8.2 Hz); MS (EI)
m/z 372 (M+, 11) and 329 (100). Anal. Calcd for C16H21IO: C, 51.63; H, 5.69. Found: C, 51.43; H, 6.01.
Typical Procedure for the Preparation of 1-Methyl-1,3-dihydroisobenzofuran Derivatives (4)
3’-Methyl-3’-phenyl-3’H-spiro[cyclopentane-1,1’-(1’,3’-dihydroisobenzofuran)] (4a): A solution of
3a (0.20 g, 0.52 mmol) in benzene (5 mL) containing n-Bu3SnH (0.30 g, 1.0 mmol) was stirred at rt for 2
h. The solvent was evaporated and the residue was purified by preparative TLC on silica gel to give 4a
1
(82 mg, 60%); a colorless oil; Rf 0.42 (1:15 THF–hexane); IR (neat) 1072 cm–1; H NMR (400 MHz) δ
1.82–2.14 (11H, m including s at 1.85), 7.13–7.31 (7H, m), 7.49 (2H, d, J = 7.3 Hz); MS (EI) m/z 264
(M+, 10), 249 (100). Anal. Calcd for C19H20O: C, 86.32; H, 7.63. Found: C, 86.29; H, 7.70.
3’-Methyl-3’-phenyl-3’H-spiro[cyclohexane-1,1’-(1’,3’-dihydroisobenzofuran)] (4b): a colorless oil;
1
Rf 0.51 (1:10 THF–hexane); IR (neat) 1057 cm–1; H NMR (500 MHz) δ 1.32–1.43 (1H, m), 1.57–1.97
(12H, m including s at 1.84), 7.10–7.12 (1H, m), 7.20 (1H, t, J = 7.3 Hz), 7.23–7.27 (3H, m), 7.30 (2H,
dd, J = 7.8, 7.3 Hz), 7.57 (2H, d, J = 7.8 Hz); MS (EI) m/z 278 (M+, 30), 263 (73), 235 (100). Anal.

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Calcd for C20H22O: C, 86.29; H, 7.97. Found: C, 86.27; H, 8.11.
1-(4-Chlorophenyl)-1-methyl-3-phenyl-1,3-dihydroisobenzofuran (4c): a major diastereomer: a
1
colorless solid; mp 90–92 ˚C (hexane–Et2O); IR (KBr) 1094 cm–1; H NMR (500 MHz) δ 1.83 (3H, s),
6.20 (1H, s), 6.95 (1H, dd, J = 7.3, 0.9 Hz), 7.09 (1H, d, J = 7.3 Hz), 7.16–7.30 (9H, m), 7.42 (2H, d, J =
8.7 Hz); MS (EI) m/z 320 (M+, 1.2), 305 (100). Anal. Calcd for C21H17ClO: C, 78.62; H, 5.34. Found: C,
78.79; H, 5.67. A minor diastereomer: a colorless solid; mp 68–72 ˚C (hexane–Et2O); IR (KBr) 1094
cm–1; 1H NMR (500 MHz) δ 1.99 (3H, s), 6.07 (1H, s), 6.92 (1H, d, J = 7.3 Hz), 7.22–7.39 (10H, m), 7.48
(2H, d, J = 8.7 Hz); MS (EI) m/z 320 (M+, 1.6), 305 (100). Anal. Calcd for C21H17ClO: C, 78.62; H, 5.34.
Found: C, 78.38; H, 4.98.
1-(4-Chlorophenyl)-1,3,3-trimethyl-1,3-dihydroisobenzofuran (4d):7 a pale-yellow oil; Rf 0.43 (1:10
1
CH2Cl2–hexane); IR (neat) 1096 cm–1; H NMR (500 MHz) δ 1.47 (3H, s), 1.61 (3H, s), 1.84 (3H, s),
7.11–7.13 (1H, m), 7.21–7.22 (1H, m), 7.27 (2H, d, J = 8.7 Hz), 7.29–7.32 (2H, m), 7.46 (2H, d, J = 8.7 Hz).
3’-(4-Chlorophenyl)-3’-methyl-3’H-spiro[cyclopentane-1,1’-(1’,3’-dihydroisobenzofuran)] (4e): a
colorless oil; Rf 0.70 (1:9 EtOAc–hexane); IR (neat) 1090 cm–1; 1H NMR (500 MHz) δ 1.77–1.87 (6H, m
including s at 1.82), 1.91–2.04 (4H, m), 2.09–2.17 (1H, m), 7.14 (2H, d, J = 8.7 Hz), 7.25–7.32 (4H, m),
7.42 (2H, d, J = 8.7 Hz); MS (EI) m/z 298 (M+, 10), 283 (100). Anal. Calcd for C19H19ClO: C, 76.37; H,
6.41. Found: C, 76.10; H, 6.21.
3’-(4-Chlorophenyl)-3’-methyl-3’H-spiro[cyclohexane-1,1’-(1’,3’-dihydroisobenzofuran)] (4f):
a
pale-yellow oil; Rf 0.61 (1:10 THF–hexane); IR (neat) 1094 cm–1; 1H NMR (500 MHz) δ 1.32–1.41 (1H,
m), 1.59–1.92 (12H, m including s at 1.82), 7.10–7.13 (1H, m), 7.19–7.23 (1H, m), 7.25–7.29 (4H, m),
7.49 (2H, d, J = 8.7 Hz); MS (EI) m/z 312 (M+, 46), 297 (71), 269 (100). Anal. Calcd for C20H21ClO: C,
76.79; H, 6.77. Found: C, 76.77; H, 6.87.
1,1,3,3-Tetramethyl-1,3-dihydroisobenzofuran (4g):4a,8
a
pale-yellow liquid; Rf 0.22 (1:2
CH2Cl2–hexane). The spectral data for this product were identical to those reported previously.4a
3’,3’-Dimethyl-3’H-spiro[cyclopentane-1,1’-(1’,3’-dihydroisobenzofuran)] (4h): a white solid; mp
42–43 ˚C (hexane–CHCl3); IR (KBr) 1038 cm–1; 1H NMR (500 MHz) δ 1.50 (6H, s), 1.79–2.06 (8H, m),
7.08 (1H, dd, J = 6.9, 1.8 Hz), 7.11 (1H, dd, J = 6.9, 1.4 Hz), 7.24–7.29 (2H, m); MS (EI) m/z 202 (M+,
22), 187 (54), 173 (100). Anal. Calcd for C14H18O: C, 83.12; H, 8.97. Found: C, 83.07; H, 9.15.
3’,3’-Dimethyl-3’H-spiro[cyclohexane-1,1’-(1’,3’-dihydroisobenzofuran)] (4i):4a,8
a
pale-yellow
liquid; Rf 0.34 (1:2 CH2Cl2–hexane). The spectral data for this product were identical to those reported
previously.4a
3’,3’-Dimethyl-3’H-spiro[cyclooctane-1,1’-(1’,3’-dihydroisobenzofuran)] (4j): a colorless oil; Rf 0.29
1
(1:9 CHCl3–hexane); IR (neat) 1051 cm–1; H NMR (500 MHz) δ 1.49 (6H, s), 1.54–1.61 (2H, m),
1.69–1.79 (8H, m), 1.85–1.90 (2H, m), 2.01–2.06 (2H, m), 7.09 (1H, dd, J = 6.9, 1.4 Hz), 7.16 (1H, dd, J

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= 6.9, 1.4 Hz), 7.23–7.29 (2H, m); MS (EI) m/z 244 (M+, 13), 173 (100). Calcd for C17H24O: C, 83.55; H,
9.90. Found: C, 83.46; H, 10.05.
Typical Procedure for the Preparation of 1-Sulfenylmethyl-1,3-dihydrobenzofuran Derivatives (5)
3’-Benzylthiomethyl-3’-phenyl-3’H-spiro[cyclohexane-1,1’-(1’,3’-dihydroisobenzofuran)] (5a): To a
stirred suspension of NaH (60% in oil; 23 mg, 0.58 mmol) in DMF (4 mL) at 0 ˚C was added dropwise
BnSH (72 mg, 0.58 mmol). After 10 min, a solution of 3b (0.21 g, 0.53 mmol) in DMF (2 mL) was added
and the mixture was stirred for at the same temperature for an additional 4 h. Saturated aqueous NH4Cl
(20 mL) was added and the mixture was extracted with Et2O three times (15 mL each). The combined
extracts were washed with water twice and then brine once, dried over anhydrous Na2SO4, and evaporated.
The residue was purified by preparative TLC on silica gel to give 5a (0.15 g, 70%); a colorless oil; Rf 0.27
1
(1:5 C6H6–hexane); IR (neat) 1040 cm–1; H NMR (500 MHz) δ 1.33–1.63 (4H, m), 1.75–2.05 (6H, m),
3.03 (1H, d, J = 13.7 Hz), 3.16 (1H, d, J = 13.7 Hz), 3.64 (1H, d, J = 13.3 Hz), 3.72 (1H, d, J = 13.3 Hz),
7.09–7.11 (1H, m), 7.19–7.36 (11H, m), 7.59 (2H, d, J = 8.2 Hz); MS (EI) m/z 400 (M+, 0.04), 262 (100).
Anal. Calcd for C27H28OS: C, 80.96; H, 7.05. Found: C, 81.04; H, 7.15.
3’-(4-Chlorophenyl)-3’-(4,6-dimethylpyrimidin-2-yl)thiomethyl-3’H-spiro[cyclohexane-1,1’-(1’,3’-di
hydroisobenzofuran)] (5b): a white solid; mp 152–153 ˚C (hexane–Et2O); IR (KBr) 1088 cm–1; 1H NMR
(500 MHz) δ 1.25–1.36 (1H, m), 1.47–1.87 (8H, m), 2.02–2.06 (1H, m), 2.34 (6H, s), 3.96 (1H, d, J =
13.7 Hz), 4.07 (1H, d, J = 13.7 Hz), 6.61 (1H, s), 7.07 (1H, d, J = 6.9 Hz), 7.21–7.29 (4H, m), 7.45 (1H,
dd, J = 7.8, 0.9 Hz), 7.63 (2H, d, J = 8.7 Hz); MS (EI) m/z 450 (M+, 0.63), 297 (100). Anal. Calcd for
C26H27ClN2OS: C, 69.24; H, 6.03; N, 6.21. Found: C, 68.90; H, 6.02; N, 6.08.
1-Benzylthiomethyl-1,3,3-trimethyl-1,3-dihydroisobenzofuran (5c): a colorless oil; Rf 0.28 (1:10
AcOEt–hexane); IR (neat) 1060 cm–1; 1H NMR (500 MHz) δ 1.51 (3H, s), 1.56 (3H, s), 1.57 (3H, s), 2.81
(2H, s), 3.71 (1H, d, J = 13.3 Hz), 3.74 (1H, d, J = 13.3 Hz), 7.10 (2H, dd, J = 7.8, 1.4 Hz), 7.19–7.32
(7H, m); MS (EI) m/z 298 (M+, 0.11), 283 (0.47), 161 (100). Anal. Calcd for C19H22OS: C, 76.46; H, 7.43.
Found: C, 76.77; H, 7.49.
2-(1,3,3-Trimethyl-1,3-dihydroisobenzofuran-1-yl)methylthioethanol (5d): a colorless oil; Rf 0.19 (1:3
AcOEt–hexane); IR (neat) 1063 cm–1; 1H NMR (500 MHz) δ 1.52 (3H, s), 1.59 (3H, s), 1.62 (3H, s), 2.70
(1H, dt, J = 14.2, 5.5 Hz), 2.80 (1H, dt, J = 14.2, 6.0 Hz), 2.95–3.01 (3H, m), 3.71–3.74 (2H, m),
7.09–7.12 (2H, m), 7.27–7.33 (2H, m); MS (EI) m/z 252 (M+, 0.02), 237 (0.18), 191 (0.33), 173 (0.75),
161 (100). Anal. Calcd for C14H20O2S: C, 66.63; H, 7.99. Found: C, 66.48; H, 7.83.
3’-Methyl-3’-(pyrydin-2-yl)thiomethyl-3’H-spiro[cyclopentane-1,1’-(1’,3’-dihydroisobenzofuran)]
(5e): a yellow oil; Rf 0.67 (1:7 CH2Cl2–hexane); IR (neat) 1061 cm–1; 1H NMR (500 MHz) δ 1.61 (3H, s),
1.73–1.96 (6H, m), 2.00–2.05 (1H, m), 2.11–2.17 (1H, m), 3.70 (1H, d, J = 13.3 Hz), 3.74 (1H, d, J =
13.3 Hz), 6.92 (1H, ddd, J = 7.3, 5.0, 0.9 Hz), 7.10–7.13 (2H, m), 7.16 (1H, d, J = 7.3 Hz), 7.20 (1H, td, J

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= 7.3, 1.4 Hz), 7.27 (1H, td, J = 7.3, 1.4 Hz), 7.39 (1H, ddd, J = 8.2, 7.3, 0.9 Hz), 8.38 (1H, ddd, J = 7.3,
5.0, 0.9 Hz); MS (EI) m/z 311 (M+, 0.55), 270 (2.8), 191 (3.3), 227 (6.1), 187 (100). Anal. Calcd for
C19H21NOS: C, 73.27; H, 6.80; N, 4.50. Found: C, 73.19; H, 6.98; N, 4.48.
3’-Methyl-3’-phenylthiomethyl-3’H-spiro[cyclohexane-1,1’-(1’,3’-dihydroisobenzofuran)] (5f): a
1
pale-yellow oil; Rf 0.19 (1:10 CH2Cl2–hexane); IR (neat) 1059 cm–1; H NMR (500 MHz) δ 1.27–1.36
(1H, m), 1.61 (3H, s), 1.62–1.83 (8H, m), 1.90–1.92 (1H, m), 3.36 (1H, d, J = 12.8 Hz), 3.39 (1H, d, J =
12.8 Hz), 7.10–7.15 (3H, m), 7.20–7.33 (6H, m); MS (EI) m/z 324 (M+, 0.12), 201 (100). Anal. Calcd for
C21H24OS: C, 77.73; H, 7.46. Found: C, 77.49; H, 7.30.
5-Methoxy-3’-methyl-3’-(4,6-dimethylpirimidin-2-yl)thiomethyl-3’H-spiro[cyclohexane-1,1’-(1’,3’-d
ihydroisobenzofuran)] (5g): a white solid; mp 102–103 ˚C (hexane–Et2O); IR (KBr) 1614, 1045 cm–1;
1H NMR (500 MHz) δ 1.25–1.34 (1H, m), 1.58–1.70 (10H, m including s at 1.62), 1.74–1.79 (1H, m),
1.93–1.98 (1H, m), 2.34 (6H, s), 3.67 (1H, d, J = 13.7 Hz), 3.73 (3H, s), 3.77 (1H, d, J = 13.7 Hz), 6.61
(1H, s), 6.74 (1H, d, J = 2.3 Hz), 6.77 (1H, dd, J = 8.2, 2.3 Hz), 6.97 (1H, d, J = 8.2 Hz);MS (CI) m/z 385
[(M+1)+, 100]. Anal. Calcd for C22H28N2O2S: C, 68.72; H, 7.34; N, 7.29. Found: C, 68.69; H, 7.38; N,
7.09.
ACKNOWLEDGEMENTS
We gratefully acknowledge Mrs. Miyuki Tanmatsu of this Faculty for determining mass spectra and
performing combustion analyses.
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