A convenient ring formation of 3-aryl-2,2-dialkyl-2,3-dihydrobenzofurans from phenols and 2-aryl-2,2-dialkylacetaldehydes

Article abstract of DOI:10.1016/j.tet.2004.01.077

A new and simple route for the preparation of 3-aryl-2,2-dialkyl-2,3- dihydrobenzofurans from phenols is described. In the presence of an acid catalyst phenols react with 2-aryl-2,2-dialkylacetaldehydes, prepared in good yield from 2-arylacetonitriles in 2 steps, to give 3-aryl-2,2-dialkyl-2,3- dihydrobenzofurans. Electron-donating substituents were required on the phenols in order to give 3-aryl-2,2-dialkyl-2,3-dihydrobenzofurans in good yield.

Full text of DOI:10.1016/j.tet.2004.01.077

Tetrahedron 60 (2004) 2843–2849
A convenient ring formation of
3-aryl-2,2-dialkyl-2,3-dihydrobenzofurans from phenols and
2-aryl-2,2-dialkylacetaldehydes
*
Makoto Yamashita, Yujirou Ono and Hiroyuki Tawada
Chemical Development Laboratories, Takeda Chemical Industries, Ltd, 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan
Received 3 December 2003; accepted 19 January 2004
Abstract—A new and simple route for the preparation of 3-aryl-2,2-dialkyl-2,3-dihydrobenzofurans from phenols is described. In the
presence of an acid catalyst phenols react with 2-aryl-2,2-dialkylacetaldehydes, prepared in good yield from 2-arylacetonitriles in 2 steps, to
give 3-aryl-2,2-dialkyl-2,3-dihydrobenzofurans. Electron-donating substituents were required on the phenols in order to give 3-aryl-2,2-
dialkyl-2,3-dihydrobenzofurans in good yield.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
for the preparation of 3-aryl-2,2-dialkyl-2,3-dihydrobenzo-
furans.
2,3-Dihydrobenzofuran derivatives are useful as key
intermediates in the synthesis of a variety of biologically
active compounds.1 For example, 2,3-dihydrobenzofurans
were developed for the treatment of traumatic and
ishchemic central nervous system (CNS) injury,1a and 2,3-
dihydro-5-benzofuranamines are said to be useful in treating
arteriosclerosis, hepatopathy, and cerebrovascular disease.1c
2. Results and discussion
2.1. Preliminary studies for the preparation of 2,2,4,6,7-
pentamethyl-3-(4-methylphenyl)-2,3-dihydrobenzo-
furan (1)
Two synthetic methods2c,e were investigated for the
preparation of dihydrobenzofuran 1, as shown in
Scheme 1. In method A, the propiophenone derivative 34
was reacted with 2,3,5-trimethylphenol (2) in the presence
of CF3SO3H to afford the desired dihydrobenzofuran in low
yield. Method B, involving the reaction of phenol 2 with the
alcohol derivative 4, prepared from 2-bromo-40-methyliso-
butyrophenone (5)5 (see Section 4), in the presence of AlCl3
gave the desired dihydrobenzofuran 1 in moderate yield.
In our laboratories, we have required a facile and efficient
synthesis of 3-aryl-2,2-dialkyl-2,3-dihydrobenzofurans to
support one of our drug development programs. Although
various methods for the preparation of 3-unsubstituted-2,2-
dialkyl-2,3-dihydrobenzofurans have been reported,2 there
are only a few reports of the synthesis of 3-aryl-2,2-dialkyl-
2,3-dihydrobenzofurans,1a,3 and none of them are suitable
for large scale manufacture. In this paper we wish to
describe a new simple, economical, and practical process
Scheme 1.
Keywords: 2,3-Dihydrobenzofurans; Phenols; Aldehydes; Wagner–Meerwein rearrangement.
*
Corresponding author. Tel.: þ81-6-6300-6797; fax: þ81-6-6300-6251; e-mail address: yamashita_makoto@takeda.co.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.01.077

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M. Yamashita et al. / Tetrahedron 60 (2004) 2843–2849
However, as neither of these processes were sufficiently
high yielding for our purpose, we decided to investigate a
new approach, using an intramolecular cyclization reaction
of alcohol derivative 7, to synthesize dihydrobenzofuran 1
(Scheme 2). Intermediate 7 was prepared from phenol 2 by
alkylation with 55 in the presence of potassium carbonate to
give 2-methyl-1-(4-methylphenyl)-2-(2,3,5-trimethyl-
phenoxy)propan-1-one (6) in 87% yield. Subsequent
reduction of 6 with NaBH4 in MeOH gave 2-methyl-1-(4-
methylphenyl)-2-(2,3,5-trimethylphenoxy)propan-1-ol (7)
in quantitative yield. The cyclization reaction of 7 was
then performed using 0.1 equiv. of CF3SO3H in refluxing
toluene for 1 h to afford the dihydrobenzofuran 1 in 74%
yield.
synthetic method, as shown in Scheme 4. Treatment of
4-methylbenzylcyanide (9) with MeI7 (4 equiv.) in the
presence of t-BuONa (4 equiv.) gave 2-methyl-2-(4-methyl-
phenyl)propionitrile (10) in 98% yield, and subsequent
reduction8 of 10 with DIBAH (1.3 equiv.) gave aldehyde 8
in 95% yield.
Scheme 4.
We considered that the reaction mechanism for the
formation of phenol 2 and aldehyde 8 from 7 is similar to
the Wagner–Meerwein rearrangement9 shown in Scheme 5.
Treatment of 7 with CF3SO3H in toluene at room
temperature initially cleaves the ether bond and leads to
the formation of 2 and cation 12, which then undergoes
Wagner–Meerwein type rearrangement to form aldehyde 8.
2.2. Exploration of a new convenient ring formation of
3-aryl-2,2-dialkyl-2,3-dihydrobenzofurans from phenols
and 2-aryl-2,2-dialkylacetaldehydes
The identification of phenol 2 and aldehyde 8 as
intermediates in the cyclization reaction prompted us to
explore a new ring formation of 3-aryl-2,2-dialkyl-2,3-
dihydrobenzofurans. According to this result, it should be
Scheme 2.
Scheme 3.
When the cyclization reaction was carried out at room
temperature, 1 was only obtained in low yield and two
unknown products were formed. When the reaction mixture
was refluxed for a further hour the dihydrobenzofuran 1 was
obtained. Isolated the two unknown products by silica gel
column chromatography suggested their structures to be
phenol 2 and 2-methyl-2-(4-methylphenyl)propanal (8),
from 1H NMR and Mass spectrometry {1H NMR
(CDCl3); CHO for 9.47 ppm, MS (EI); m/e¼162 (Mþ)}
(Scheme 3).
possible to obtain dihydrobenzofuran 1 by reaction of
phenol 2 with aldehyde 8 in the presence of an acid catalyst.
When phenol 2 was reacted with aldehyde 8 in the presence
of a catalytic amount of CF3SO3H in refluxing toluene,
dihydrobenzofuran 1 was obtained in 75% yield. Various
acids were evaluated in this reaction (eg. AlCl3, BF3/Et2O,
TiCl4, SnCl4, ZnCl2, H2SO4, MeSO3H, PPA, p-TsOH,
CF3SO3H), but CF3SO3H was found to be superior to the
others in terms of yield. The reaction was carried out with
other phenols and aldehydes to investigate the scope of this
new method for the preparation of 3-aryl-2,2-dialkyl-2,3-
dihydrobenzofurans, and phenols 2, 14a–c and aldehydes 8,
15a–c were examined (Scheme 6, Table 1). Reaction of
2,3,5-trimethylphenol (2) and p-cresol (14a) with aldehydes
8, 15a–c afforded dihydrobenzofurans 1, 16–22 in good
yield (entry 1–8). However, reaction of phenol (14b) and
The aldehyde structure was confirmed by comparison with
the spectral data of an authentic sample, which was prepared
by Schaffner’s method.6 Aldehyde 8 was obtained by
oxidation of the corresponding alcohol prepared in two
steps, and we also synthesized aldehyde 8 by an alternative

M. Yamashita et al. / Tetrahedron 60 (2004) 2843–2849
2845
Scheme 5.
p-chlorophenol (14c) with aldehydes 8, 15a–c gave
dihydrobenzofurans 23–30 in low yield (entry 9–16).
2 with 1-phenylcyclopropanecarbaldehyde (31) afforde0d
4,6,7-trimethyl-3-phenyl-3H-spiro-[1-benzofuran-2,1 -
cyclopropane] (32) in good yield (Scheme 7).
These results indicate that although electron-donating
substituents are required on the phenols for good conver-
sion, the substituents on the aldehydes have little effect on
the reaction, and therefore a variety of 2-aryl-2,2-dialkyl-
acetaldehydes may be used. For example, reaction of phenol
Scheme 7.
The proposed reaction mechanism for this process is shown
in Scheme 8. In the presence of CF3SO3H, phenol 2 and
aldehyde 8 initially form 34, which after protonation
followed by dehydration, leads to cation 36, which then
Scheme 6.
Table 1. Reactiona of phenols and 2-aryl-2,2-dialkylacetaldehydes
Entry
Phenols
R2
Aldehydes
(R)
Temperature
Time
(h)
Products
(yield %)
R1
R3
R4
(8C)
1
2
3
4
5
6
7
8
2
2
2
2
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
H
H
H
H
Cl
Cl
Cl
Cl
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
8
CH3
OCH3
H
110
110
110
110
110
25
25
25
110
25
25
25
110
110
25
1
1
1
1
2
17
15
17
1
15
15
17
2
1
75b
15a
15b
15c
8
15a
15b
15c
8
15a
15b
15c
8
15a
15b
15c
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
77b
90b
85b
52b
60b
62b
65b
11c
6c
Cl
14a
14a
14a
14a
14b
14b
14b
14b
14c
14c
14c
14c
CH3
OCH3
H
Cl
9
CH3
OCH3
H
10
11
12
13
14
15
16
8c
Cl
32c
8c
CH3
OCH3
H
2
15
17
11c
7c
Cl
25
13c
a
Reaction conditions: 1.0 equiv. of phenols, 1.0 equiv. of aldehydes, 0.1 equiv. (entry 1–5) or 0.5 equiv. (entry 6–16) of CF3SO3H, toluene was used as
solvent.
Isolated yield.
Not isolated yield but HPLC analyses. The structure of 23–30 was just assigned by LC-Ms.
b
c

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M. Yamashita et al. / Tetrahedron 60 (2004) 2843–2849
Scheme 8.
undergoes Wagner–Meerwein type rearrangement and
cyclization to form the desired product 1.
(wavelength 230 nm); column, YMC-Pack ODS-A302
(4.6 mm i.d.£150 mm); mobile phase, 0.02 M KH2PO4
aqueous solution/MeCN (20/80); flow rate, 1.0 ml/min;
column temperature, 25 8C. All compounds were judged to
1
be of greater than 95% purity based upon H NMR and
3. Conclusions
HPLC analysis. Elemental analysis and mass spectra were
carried out by Takeda Analytical Research Laboratories,
Ltd.
We have developed a new and convenient ring formation
reaction for the synthesis of 3-aryl-2,2-dialkyl-2,3-dihydro-
benzofurans using phenols and 2-aryl-2,2-dialkylacetalde-
hydes, and its reaction mechanism was elucidated. The ease
and utility of this method indicates that it may be applicable
to the industrial manufacture of 3-aryl-2,2-dialkyl-2,3-
dihydrobenzohurans, and investigations are in progress.
4.1.1. 2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-
dihydrobenzofuran (1). (Scheme 1, Method A). A solution
of phenol 2 (1.36 g, 10 mmol), 40,2-dimethylpropiophenone
(3)4 (1.62 g, 10 mmol) and CF3SO3H (3.73 g, 25 mmol) in
toluene (13.6 ml) was refluxed for 3 h. The reaction mixture
was cooled to room temperature, and aqueous NaOH (6 M,
10 ml) was added. The organic layer was separated, washed
with water, dried over sodium sulfate and concentrated. The
residue was chromatographed on silica gel (AcOEt/
n-hexane¼1/19) to afford 1 (0.21 g, 8%) as a white
crystalline powder. Mp 119–120 8C. IR (cm21, KBr)
4. Experimental
4.1. General
Melting points were recorded on a Bu¨chi B-540 micro
melting apparatus and were uncorrected. IR spectra were
recorded on a Horiba FT-210 spectrophotometer. NMR
spectra were run at 300 MHz on a Bruker DPX-300
spectrometer. Chemical shifts are reported as d values
using tetramethylsilane as an internal standard and the
coupling constants (J) are given in Hz. The following
abbreviations are used: s¼singlet, d¼doublet, t¼triplet,
m¼multiplet, br¼broad. All column chromatography was
performed on Merck Silica gel 60 (0.063–0.200 mm). The
HPLC data in Table 1 was obtained under the following
conditions: detector, ultraviolet absorption photometer
1
1457, 1511, 1589, 3436; H NMR (300 MHz, CDCl3) d
1.02 (3H, s), 1.49 (3H, s), 1.83 (3H, s), 2.14 (3H, s), 2.23
(3H, s), 2.30 (3H, s), 4.09 (1H, s), 6.48 (1H, s), 6.5–7.1 (4H,
m). 13C NMR (300 MHz, CDCl3) d 11.5, 18.1, 19.3, 20.9,
24.8, 29.8, 57.5, 88.5, 115.4, 123.0, 126.2, 128.4, 128.8,
132.0, 136.0, 136.7, 137.3, 157.3. Anal. calcd for C20H24O
(280.40): C, 85.67, H, 8.63. Found: C, 85.67, H, 8.74.
4.1.2. 2-Bromo-2-methyl-1-(4-methylphenyl)propan-1-ol
(4). A solution of 2-bromo-40-methylisobutyrophenone (5)5
(5.0 g, 20.7 mmol) in MeOH (50 ml) was cooled to 10 8C,

M. Yamashita et al. / Tetrahedron 60 (2004) 2843–2849
2847
and NaBH4 (0.24 g, 6.3 mmol) was added and stirred for
4 h. To the reaction mixture was added aqueous HCl (1 M,
8 ml) and the solvent was evaporated in vacuo. The residue
was diluted with ethyl acetate and water, the organic layer
was separated, washed with water, dried over sodium sulfate
and concentrated. The residue was chromatographed on
silica gel (AcOEt/n-hexane¼1/19) to afford 4 (4.2 g, 84%)
and concentrated in vacuo to afford 7 (25.4 g) quantitatively
as a colorless oil. The product was subsequently used
without further purification. IR (cm21, neat) 1128, 1298,
1
2981, 3558; H NMR (300 MHz, CDCl3) d 1.11 (3H, s),
1.22 (3H, s), 2.13 (3H, s), 2.22 (3H, s), 2.25 (3H, s), 2.34
(3H, s), 3.38 (1H, bs), 4.87 (1H, s), 6.72 (1H, s), 6.74 (1H, s),
7.13 (2H, d, J¼8.3 Hz), 7.34 (2H, d, J¼8.3 Hz). 13C NMR
(300 MHz, CDCl3) d 13.2, 20.3, 20.7, 21.0, 21.1, 22.8, 80.5,
84.2, 121.6, 126.0, 127.8, 128.4, 134.9, 136.7, 137.2, 137.9,
152.7. Anal. calcd for C20H26O2 (298.42): C, 80.50, H, 8.78.
Found: C, 80.71, H, 8.65; MS (CI): m/z 299 (MþH)þ.
1
as a colorless oil. IR (cm21, neat) 1101, 1384, 3540; H
NMR (300 MHz, CDCl3) d 1.68 (3H, s), 1.73 (3H, s), 2.33
(3H, s), 2.77 (1H, bs), 4.77 (1H, s), 7.14 (2H, d, J¼8.0 Hz),
7.27 (2H, d, J¼8.1 Hz). 13C NMR (300 MHz, CDCl3) d
21.0, 27.3, 31.6, 74.8, 81.9, 127.7, 128.4, 134.9, 137.8; MS
(EI): m/z 242 (Mþ); HRMS (EI) calcd for C11H15BrO (Mþ)
242.0306. Found: 242.0281.
4.1.6. 2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-
dihydrobenzofuran (1). (Scheme 2). A solution of 7
(25.4 g, 85 mmol) and CF3SO3H (1.28 g, 8.5 mmol) in
toluene (127 ml) was refluxed for 1 h. The reaction mixture
was cooled to 50 8C before aqueous NaOH (1 M, 76 ml) was
added and then the mixture was stirred at 35 8C for 30 min.
The organic layer was separated and washed with water
and concentrated in vacuo. The residue was diluted with
2-propanol (76 ml) and heated to 60 8C, and water (76 ml)
was added dropwise at the same temperature. The mixture
was cooled to room temperature and stirred for 1 h. The
precipitate was filtered, washed with 2-propanol/H2O (1:1)
twice and dried in vacuo at 50 8C to afford 1 (17.6 g, 74.0%
based on 6) as a white crystalline powder. The spectral data
(IR, NMR) were identical with these of the sample that was
prepared by using method A (Scheme 1). Mp 119–120 8C.
Anal. calcd for C20H24O (280.40): C, 85.67, H, 8.63. Found:
C, 85.54, H, 8.79.
4.1.3. 2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-
dihydrobenzofuran (1). (Scheme 1, Method B). A solution
of 2 (0.28 g, 2 mmol) and 4 (0.5 g, 2 mmol) in dichloro-
methane (5 ml) was cooled to 5 8C, and AlCl3 (0.27 g,
2 mmol) was added. The mixture was stirred at room
temperature for 20 h and diluted with toluene and aqueous
HCl (6 M). The organic layer was separated, washed with
water, dried over sodium sulfate and concentrated. The
residue was chromatographed on silica gel (AcOEt/
n-hexane¼1/19) to afford 1 (0.3 g, 52%) as a white
crystalline powder. The spectral data (IR, NMR) were
identical with these of the sample that was prepared by
using method A (Scheme 1). Mp 118–119 8C. Anal. calcd
for C20H24O (280.40): C, 85.67, H, 8.63. Found: C, 85.84,
H, 8.65.
4.1.4. 2-Methyl-1-(4-methylphenyl)-2-(2,3,5-trimethyl-
phenoxy)propan-1-one (6). A suspension of phenol 2
(13.6 g, 100 mmol) and K2CO3 (27.6 g, 200 mmol) in
DMSO (68 ml) was warmed to 35 8C, and 55 (42.2 g in
68 ml of DMSO, 175 mmol) was added and stirred for 24 h.
MeOH (95 ml) and water (95 ml) were added to the reaction
mixture, which was stirred at 40 8C for 1 h. The precipitate
was filtered, washed with MeOH/H2O (1:1) twice to give the
crude product. The crude cake was dissolved in refluxing
MeOH (204 ml), and then water (68 ml) was added and it
was cooled to 40 8C. After stirring at 40 8C for 1 h, the
precipitate was collected by filtration, washed with
MeOH/H2O (3:1) and water, and dried in vacuo at 50 8C
to afford 6 (25.8 g, 87.0% based on 2) as a white crystalline
powder. Mp 115–117 8C. IR (cm21, KBr) 1141, 1604,
4.1.7. Reaction of (7) with CF3SO3H at room tempera-
ture. A solution of 7 (1.0 g) and CF3SO3H (0.05 g) in
toluene (6 ml) was stirred at room temperature for 1 h. The
reaction mixture was diluted with aqueous NaHCO3 and
separated. The organic layer was washed with water, dried
over sodium sulfate and concentrated in vacuo. The residue
was chromatographed on silica gel (AcOEt/n-hexane¼1/19)
to afford phenol 2 (305 mg) as a white crystalline powder,
aldehyde 8 (353 mg) as a colorless oil, and benzofuran 1
(169 mg) as a white crystalline powder.
4.2. General procedure for the preparation of 2-aryl-2,2-
dialkylacetaldehydes
4.2.1. 2-Methyl-2-(4-methylphenyl)propanal (8). A sol-
ution of t-BuONa (19.9 g, 207 mmol) in 1-methyl-2-
pyrrolidone/THF (1:1, 68 ml) was cooled to 5 8C, and a
solution of 4-methylbenzylcyanide (9) (6.8 g, 52 mmol) and
methyl iodide (12.9 ml, 207 mmol) was added maintaining
the reaction temperature below 10 8C. After the mixture was
stirred for 1 h, diluted with aqueous HCl (3 M) and toluene,
the organic layer was separated, washed with aqueous
NaHCO3 and brine, dried over sodium sulfate and
concentrated in vacuo to afford 2-methyl-2-(4-methyl-
phenyl)propionitrile (10) (8.1 g, 98%) as a red-brown oil,
which was used in the next reaction without further
1
1664, 2985; H NMR (300 MHz, CDCl3) d 1.65 (6H, s),
2.05 (3H, s), 2.18 (3H, s), 2.20 (3H, s), 2.34 (3H, s), 6.18
(1H, s), 6.54 (1H, s), 7.18 (2H, d, J¼8.3 Hz), 8.23 (2H, d,
J¼8.3 Hz). 13C NMR (300 MHz, CDCl3) d 12.0, 20.0, 20.9,
21.5, 25.9, 84.7, 115.3, 124.2, 124.4, 129.0, 130.1, 132.1,
134.9, 137.7, 143.4, 153.2, 202.4. Anal. calcd for C20H24O2
(296.40): C, 81.04, H, 8.16. Found: C, 80.74, H, 7.90.
4.1.5. 2-Methyl-1-(4-methylphenyl)-2-(2,3,5-trimethyl-
phenoxy)propan-1-ol (7). To a suspension of 6 (25.2 g,
85 mmol) in MeOH (252 ml) was added NaBH4 (2.6 g,
69 mmol), and the mixture was stirred at 35 8C for 3 h under
nitrogen gas purge. The reaction mixture was cooled to
15 8C and adjusted to pH 7 at 20 8C with aqueous HCl
(1 M), and the whole was concentrated in vacuo. The
residue was diluted with toluene and water, the organic layer
was separated, washed with water, dried over sodium sulfate
1
purification. IR (cm21, neat) 815, 1513, 2235, 2981; H
NMR (300 MHz, CDCl3) d 1.70 (6H, s), 2.35 (3H, s), 7.17–
7.22 (2H, m), 7.33–7.37 (2H, m). 13C NMR (300 MHz,
CDCl3) d 20.7, 29.0, 36.6, 124.5, 124.8, 129.4, 137.4, 138.4;
MS (EI): m/z 159 (Mþ). A solution of 10 (8.1 g, 51 mmol) in
toluene (81 ml) was cooled to 250 8C, and DIBAH (1.5 M

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M. Yamashita et al. / Tetrahedron 60 (2004) 2843–2849
in toluene, 42 ml, 63 mmol) was added dropwise maintain-
ing the reaction temperature below 240 8C and stirred for
1 h. Aqueous HCl (6 M) was added to the reaction mixture,
which was stirred at room temperature for 30 min. The
organic layer was separated, washed with aqueous HCl
(2 M), aqueous NaHCO3 and brine successively, dried over
sodium sulfate and concentrated in vacuo. The residue was
chromatographed on silica gel (AcOEt/n-hexane¼1/19) to
neat) 1514, 1728, 2973; 1H NMR (300 MHz, CDCl3) d 1.44
(6H, s), 2.33 (3H, s), 7.14–7.24 (4H, m), 9.47 (1H, s). 13C
NMR (300 MHz, CDCl3) d 20.8, 22.3, 49.9, 126.5, 129.4,
136.8, 138.0, 202.1; MS (EI): m/z 162 (Mþ); HRMS (EI)
calcd for C11H14O (Mþ) 162.1045. Found: 162.1034.
concentrated. The residue was chromatographed on silica
gel (AcOEt/n-hexane¼1/39) to afford 1 (1.3 g, 75%) as a
white crystalline powder. The spectral data (IR, NMR) were
identical with these of the sample that was prepared by
using method A (Scheme 1). Mp 118–120 8C. Anal. calcd
for C20H24O (280.40): C, 85.67, H, 8.63. Found: C, 85.67,
H, 8.72; MS (EI): m/z 280 (Mþ).
afford 8 (7.8 g, 93% based on 9) as a colorless oil. IR (cm21
,
The following compounds were obtained according to the
general procedure.
4.3.2. 2,2,4,6,7-Pentamethyl-3-(4-methoxylphenyl)-2,3-
dihydrobenzofuran (16). Yield 77%, white crystalline
powder. Mp 105–106 8C. IR (cm21, KBr) 825, 1088, 1248,
1
1510, 2974; H NMR (300 MHz, CDCl3) d 1.02 (3H, s),
The following compounds were obtained according to the
general procedure.
1.48 (3H, s), 1.84 (3H, s), 2.14 (3H, s), 2.23 (3H, s), 3.76
(3H, s), 4.07 (1H, s), 6.48 (1H, s), 6.5–7.2 (4H, m). 13C
NMR (300 MHz, CDCl3) d 11.5, 18.0, 19.3, 24.8, 29.7,
55.0, 57.1, 88.5, 113.4, 115.4, 123.0, 126.3, 129.5, 131.9,
132.5, 136.7, 157.2, 158.2. Anal. calcd for C20H24O2
(296.40): C, 81.04, H, 8.16. Found: C, 80.81, H, 7.92; MS
(EI): m/z 296 (Mþ).
4.2.2. 2-Methyl-2-(4-methoxyphenyl)propanal (15a).
Yield 72%, colorless oil. IR (cm21, neat) 1254, 1514,
1
1724, 2971; H NMR (300 MHz, CDCl3) d 1.43 (6H, s),
3.80 (3H, s), 6.88–6.93 (2H, m), 7.17–7.22 (2H, m), 9.44
(1H, s). 13C NMR (300 MHz, CDCl3) d 22.4, 49.6, 55.1,
114.1, 127.7, 132.9, 158.6, 202.0. Anal. calcd for C11H14O2
(178.23): C, 74.13, H, 7.92. Found: C, 73.77, H, 7.99; MS
(EI): m/z 178 (Mþ).
4.3.3. 2,2,4,6,7-Pentamethyl-3-phenyl-2,3-dihydrobenzo-
furan (17). Yield 90%, white crystalline powder. Mp 89–
1
91 8C. IR (cm21, KBr) 698, 1090, 1456, 2979; H NMR
(300 MHz, CDCl3) d 1.02 (3H, s), 1.50 (3H, s), 1.83 (3H, s),
2.14 (3H, s), 2.23 (3H, s), 4.12 (1H, s), 6.48 (1H, s), 6.5–7.3
(5H, m). 13C NMR (300 MHz, CDCl3) d 11.6, 18.0, 19.3,
24.8, 29.8, 57.9, 88.5, 115.5, 123.0, 126.1, 126.5, 128.1,
128.6, 132.0, 136.9, 140.4, 157.4. Anal. calcd for C19H22O
(266.38): C, 85.67, H, 8.32. Found: C, 85.52, H, 8.19; MS
(EI): m/z 266 (Mþ).
4.2.3. 2-Methyl-2-phenylpropanal (15b). Yield 70%,
1
colorless oil. IR (cm21, neat) 1448, 1496, 1722, 2981; H
NMR (300 MHz, CDCl3) d 1.46 (6H, s), 7.25–7.30 (3H, m),
7.35–7.40 (2H, m), 9.49 (1H, s). 13C NMR (300 MHz,
CDCl3) d 22.3, 50.3, 125.2, 126.5, 127.1, 128.4, 128.7,
141.1, 202.0; MS (EI): m/z 148 (Mþ); HRMS (EI) calcd for
C10H12O (Mþ) 148.0888. Found: 148.0878.
4.3.4. 2,2,4,6,7-Pentamethyl-3-(4-chlorophenyl)-2,3-
dihydrobenzofuran (18). Yield 85%, white crystalline
powder. Mp 110–112 8C. IR (cm21, KBr) 831, 1084, 1489,
2976; 1H NMR (300 MHz, CDCl3) d 1.02 (3H, s), 1.49 (3H,
s), 1.83 (3H, s), 2.13 (3H, s), 2.23 (3H, s), 4.08 (1H, s), 6.48
(1H, s), 6.5–7.3 (4H, m). 13C NMR (300 MHz, CDCl3) d
11.5, 18.0, 19.3, 24.8, 29.7, 57.2, 88.3, 115.6, 123.1, 125.7,
128.3, 129.9, 131.8, 132.3, 137.2, 139.0, 157.3. Anal. calcd
for C19H21OCl (300.82): C, 75.86, H, 7.04, Cl, 11.79.
Found: C, 75.82, H, 6.99, Cl, 11.66; MS (EI): m/z 300 (Mþ).
4.2.4. 2-Methyl-2-(4-chlorophenyl)propanal (15c). Yield
87%, colorless oil. IR (cm21, neat) 1105, 1495, 1724, 2976;
1H NMR (300 MHz, CDCl3) d 1.45 (6H, s), 7.18–7.23 (2H,
m), 7.32–7.36 (2H, m), 9.47 (1H, s). 13C NMR (300 MHz,
CDCl3) d 22.4, 49.9, 128.0, 128.8, 133.1, 139.6, 201.4; MS
(EI): m/z 182 (Mþ); HRMS (EI) calcd for C10H11ClO (Mþ)
182.0499. Found: 182.0481.
4.2.5. 1-Phenylcyclopropanecarbaldehyde (31). Yield
90%, colorless oil. IR (cm21, neat) 1446, 1498, 1711,
1
2823; H NMR (300 MHz, CDCl3) d 1.37–1.41 (2H, m),
4.3.5. 2,2,5-Trimethyl-3-(4-methylphenyl)-2,3-dihydro-
benzofuran (19). Yield 52%, colorless oil. IR (cm21
,
1.54–1.58 (2H, m), 7.29–7.36 (5H, m), 9.28 (1H, s). 13C
NMR (300 MHz, CDCl3) d 16.0, 37.3, 127.5, 128.5, 129.9,
137.4, 200.8; MS (EI): m/z 146 (Mþ); HRMS (EI) calcd for
C10H10O (Mþ) 146.0732. Found: 146.0726.
neat) 1251, 1491, 2974; 1H NMR (300 MHz, CDCl3) d 0.96
(3H, s), 1.56 (3H, s), 2.24 (3H, s), 2.33 (3H, s), 4.26 (1H, s),
6.71 (1H, d, J¼8.1 Hz), 6.83 (1H, s), 6.95–6.99 (3H, m),
7.07–7.15 (2H, m). 13C NMR (300 MHz, CDCl3) d 20.7,
20.9, 24.0, 28.8, 58.1, 89.7, 109.2, 126.3, 128.7, 128.8,
128.9, 129.5, 130.3, 130.6, 136.5, 136.7, 156.8; MS (EI):
m/z 252 (Mþ); HRMS (EI) calcd for C18H20O (Mþ)
252.1514. Found: 252.1511.
4.3. General procedure for the preparation of 3-aryl-2,2-
dialkyl-2,3-dihydrobenzofurans using phenols and
2-aryl-2,2-dialkylacetaldehydes
4.3.1. 2,2,4,6,7-Pentamethyl-3-(4-methylphenyl)-2,3-
dihydrobenzofuran (1). (Scheme 6). A suspension of
phenol 2 (0.84 g, 6.2 mmol), aldehyde 8 (1.0 g, 6.2 mmol)
and CF3SO3H (0.09 g, 0.62 mmol) in toluene (6.2 ml) was
refluxed for 1 h. The reaction mixture was cooled to room
temperature, and aqueous NaOH (1 M) was added before it
was stirred for 30 min. The organic layer was separated,
washed with water, dried over sodium sulfate and
4.3.6. 2,2,5-Trimethyl-3-(4-methoxyphenyl)-2,3-
dihydrobenzofuran (20). Yield 60%, pale yellow oil. IR
(cm21, neat) 1250, 1491, 1512, 2974; 1H NMR (300 MHz,
CDCl3) d 0.96 (3H, s), 1.55 (3H, s), 2.25 (3H, s), 3.79 (3H,
s), 4.25 (1H, s), 6.71 (1H, d, J¼8.1 Hz), 6.82–6.86 (3H, m),
6.95–7.02 (3H, m). 13C NMR (300 MHz, CDCl3) d 20.7,
24.0, 28.7, 55.1, 57.7, 89.8, 109.2, 113.6, 126.2, 128.7,

M. Yamashita et al. / Tetrahedron 60 (2004) 2843–2849
2849
129.5, 129.8, 130.7, 131.8, 156.7, 158.6; MS (EI): m/z 268
(Mþ); HRMS (EI) calcd for C18H20O2 (Mþ) 268.1463.
Found: 268.1443.
References and notes
1. (a) Ohkawa, S.; Fukatsu, K.; Miki, S.; Hashimoto, T.;
Sakamoto, J.; Doi, T.; Nagai, Y.; Aono, T. J. Med. Chem.
1997, 40, 559–573. (b) Semple, J.E. US Patent 4881967, 1989.
(c) Aono, T.; Ohkawa, S.; Doi, T. EP Patent 483772, 1992.
(d) Ohkawa, S.; Hashimoto, T.; Fukatsu, K. WO Patent 98/
08842, 1998.
4.3.7. 2,2,5-Trimethyl-3-phenyl-2,3-dihydrobenzofuran
(21). Yield 62%, pale yellow oil. IR (cm21, neat) 1252,
1
1491, 2974; H NMR (300 MHz, CDCl3) d 0.96 (3H, s),
1.57 (3H, s), 2.24 (3H, s), 4.29 (1H, s), 6.71 (1H, d,
J¼8.1 Hz), 6.84 (1H, s), 7.07–7.10 (2H, m), 7.24–7.30
(4H, m). 13C NMR (300 MHz, CDCl3) d 20.7, 24.0, 28.8,
58.5, 89.7, 109.3, 126.3, 126.9, 128.2, 128.8, 128.9, 129.5,
130.3, 130.4, 139.8, 156.8; MS (EI): m/z 238 (Mþ); HRMS
(EI) calcd for C17H18O (Mþ) 238.1358. Found: 238.1353.
2. (a) Choudhury, P. K.; Almena, J.; Foubelo, F.; Yus, M.
Tetrahedron 1997, 53, 17373–17382. (b) Kim, M. K.; Ryu,
K. E. Heterocycles 1995, 41, 219–224. (c) Martini, C. J.;
Franke, W. N.; Singerman, M. G. J. Org. Chem. 1970, 35,
2904–2907. (d) Larock, R. C.; Berrios-Pena, N.; Narayanan, K.
J. Org. Chem. 1990, 55, 3447–3450. (e) Carpino, L. A.; Shroff,
H.; Triolo, S. A.; Mansour, E. M. E.; Wenschuh, H.; Albericio,
F. Tetrahedron Lett. 1993, 34, 7829–7832. (f) Arduini, A.;
Ungaro, R. Synthesis 1984, 11, 950–953. (g) Hurd, D. J. Am.
Chem. Soc. 1958, 80, 4711–4713. (h) Bartz, R.; Miller, R. F.;
Adams, R. J. Am. Chem. Soc. 1935, 57, 371–376.
4.3.8. 2,2,5-Trimethyl-3-(4-chlorophenyl)-2,3-dihydro-
benzofuran (22). Yield 65%, colorless oil. IR (cm21
,
neat) 1093, 1252, 1491, 2976; 1H NMR (300 MHz, CDCl3)
d 0.96 (3H, s), 1.55 (3H, s), 2.24 (3H, s), 4.25 (1H, s), 6.72
(1H, d, J¼8.1 Hz), 6.81 (1H, s), 6.96–7.03 (3H, m), 7.25–
7.28 (2H, m). 13C NMR (300 MHz, CDCl3) d 20.7, 24.0,
28.8, 57.9, 89.5, 109.4, 126.1, 128.4, 129.1, 129.6, 129.7,
129.9, 130.2, 132.8, 138.4, 156.8; MS (EI): m/z 272 (Mþ);
HRMS (EI) calcd for C17H17ClO (Mþ) 272.0968. Found:
272.0944.
3. (a) Tomioka, H.; Nakanishi, K.; Izawa, Y. J. Chem. Soc. Perkin
Trans. 1 1991, 2, 465–470. (b) Nishinaga, A.; Iwasaki, H.;
Shimizu, T.; Toyoda, Y.; Matsuura, T. J. Org. Chem. 1986, 51,
2257–2266.
4. Fountain, K. R.; Heinze, P.; Sherwood, M.; Maddex, D.;
Gerhardt, G.; Can, J. Chem. 1980, 58, 1198–1205.
5. Borowitz, I. J.; Firstenberg, S.; Borowitz, G. B.; Schuessler, D.
J. Amer. Chem. Soc. 1972, 94, 1623–1628.
4.3.9. 4,6,7-Trimethyl-3-phenyl-3H-spiro[1-benzofuran-
2,10-cyclopropane] (32). Yield 73%, pale yellow oil. IR
(cm21, neat) 698, 1084, 1296, 1450, 2939; 1H NMR
(300 MHz, CDCl3) d 2.01–2.05 (1H, m), 2.15 (3H, s), 2.18
(3H, s), 2.24 (3H, s), 2.46–2.53 (1H, m), 2.76–2.85 (2H,
m), 3.92–3.95 (1H, m), 6.55 (1H, s), 7.17–7.42 (3H, m),
7.57–7.60 (2H, m). 13C NMR (300 MHz, CDCl3) d 11.7,
17.9, 19.2, 23.2, 35.1, 49.0, 90.9, 116.1, 123.0, 124.7, 127.3,
127.4, 128.1, 128.3, 128.9, 131.2, 137.1, 142.4, 158.7. Anal.
calcd for C19H20O (264.36): C, 86.32, H, 7.63. Found: C,
86.18, H, 7.86; MS (EI): m/z 264 (Mþ).
6. Kuntzel, H.; Wolf, H.; Schaffner, K. Helv. Chim. Acta. 1971,
54, 868–897.
7. Cope, C. A.; Foster, T. T.; Towle, H. P. J. Amer. Chem. Soc.
1949, 71, 3929–3934.
8. Kametani, T.; Toya, T.; Tsubuki, M.; Kawai, K.; Honda, T.
Chem. Pharm. Bull. 1986, 34, 3169–3174.
9. (a) Paquette, A. L.; Waylole, L.; Jendralla, H.; Cottrell, E. C.
J. Am. Chem. Soc. 1986, 108, 3739–3744. (b) Smith, A. B.;
Wexler, A. B.; Tu, C. Y.; Konopelski, P. J. J. Am. Chem. Soc.
1985, 107, 1308–1320. (c) Huffman, J. W.; Browder, L. E.
J. Org. Chem. 1962, 27, 3208–3211.
Acknowledgements
We thank Kokichi Yoshida, Dr. Kiminori Tomimatsu and
Dr. Shigenori Ohkawa for helpful discussions.