TiCl4-promoted intramolecular cyclization of 4-methoxy-5-arylethyl-1,3-dioxolan-2-ones: an expedient method to prepare 2-tetralones

Article abstract of DOI:10.1016/j.tetlet.2009.03.185

DABCO is a very effective catalyst in the formation of 4-methoxy-5-arylethyl-1,3-dioxolan-2-ones 12 from the corresponding α-carbonatoaldehyde. Intramolecular cyclization of cyclic carbonates 12 promoted by TiCl₄ affords 2-tetralones 13 contain

Full text of DOI:10.1016/j.tetlet.2009.03.185

Tetrahedron Letters 50 (2009) 2831–2834
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Tetrahedron Letters
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TiCl4-promoted intramolecular cyclization of 4-methoxy-5-arylethyl-1,3-
dioxolan-2-ones: an expedient method to prepare 2-tetralones
*
Yung-Son Hon , Rammohan Devulapally
Department of Chemistry and Biochemistry, National Chung Cheng University, Chia-Yi 62102, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
DABCO is a very effective catalyst in the formation of 4-methoxy-5-arylethyl-1,3-dioxolan-2-ones 12
Received 12 February 2009
Revised 24 March 2009
Accepted 27 March 2009
Available online 1 April 2009
from the corresponding
moted by TiCl4 affords 2-tetralones 13 containing a variety of substituents in high yields.
Ó 2009 Elsevier Ltd. All rights reserved.
a-carbonatoaldehyde. Intramolecular cyclization of cyclic carbonates 12 pro-
Keywords:
2-Tetralone
Friedel–Crafts reaction
DABCO
Cyclic carbonates
2-Tetralones A are important precursors in the synthesis of bio-
logically active compounds and natural products.1,2 In comparison
with 1-tetralones, 2-tetralones often are less stable, more expen-
sive, and more difficult to be synthesized. Synthetic methods for
generating 2-tetralones are categorized as direct building of tetra-
lines, transformations in a pre-formed tetralinic ring or naphtha-
lene precursor, and ring-expansion of 1-indanone exo-methylene
derivatives.1 Among them, the most efficient method is to build
2-tetralone via a direct intramolecular cyclization, such as Rh(II)-
O
Me
Y
R
S
O
Y
O
Cl
3
H2C=CH2, AlCl3
4
N2
IPh
Y
R
Y
Rh+2
Y
O
O
O
Cu+
R = H, CO2Me, SMe
2
1
a
-diazocarbonyl 1,3 intramolecular
A
catalyzed decomposition of
cyclization of iodonium ylides 2 with CuCl,4 the Friedel–Crafts
acylation–cycloalkylation sequence from the reaction of acyl chlo-
ride 3 and simple alkene,5 or Pummerer rearrangement–mediated
cyclization of aryl b-ketosulfoxides 4 (Fig. 1).6 We previously re-
ported that DABCO is an excellent catalyst in the formation of 4-
Figure 1. Typical methods used to prepare 2-tetralone A from the intramolecular
cyclization of compounds 1–4.
OH
TiCl4, Ar-X, -78oC to rt
when X is a medium
electron donating group
O
ArX
methoxy-5-alkyl-1,3-dioxolan-2-one 5 from the corresponding
carbonatoaldehyde. In the presence of TiCl4, compound 5 is useful
to prepare either -diarylethanol 6 or -arylmethyl alkyl ketones
a-
R
O
6
ArX
O
a,a
a
R
O
TiCl4, Ar-X', -78oC to rt
when X' is a strong
electron donating group
5
7 depending on the electron richness of the aryl nucleophiles.
Compound 5 can be considered as a synthetic equivalent of either
synthon I or II (Fig. 2).7 Following this line of work, we are inter-
ested in the intramolecular aromatic electrophilic substitution of
cyclic carbonates tethered with an aryl group. Herein, we report
our results of 2-tetralone formation from 4-methoxy-5-arylethyl-
1,3-dioxolan-2-ones promoted by TiCl4.
OMe
ArX'
R
7
OH
O
Synthon-I
Synthon-II
R
R
Figure 2. Cyclic carbonate 5 is a synthetic equivalent of either synthon-I or II
depending on the electron richness of the aromatic nucleophiles.
The allyl methyl carbonates (11a–k) were prepared in modest
to good yields by the one-pot reaction of methyl chloroformate
with allyloxylmagnesium bromides, which were prepared in situ
by either the reaction of vinylmagnesium bromide (9) with
aryl-substituted aldehydes (8a–b and 8d–k)8 or the reaction of
* Corresponding author. Tel.: +886 5 2720411x66412; fax: +886 5 2721040.
E-mail address: cheysh@ccu.edu.tw (Y.-S. Hon).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.03.185

2832
Y.-S. Hon, R. Devulapally / Tetrahedron Letters 50 (2009) 2831–2834
3-phenylpropylmagnesium bromide (10) with acrolein (8c). When
the methyl allyl carbonates 11 in CH2Cl2 were sequentially treated
intramolecular cyclization
when n = 2
2-tetralone (13b)
ene-diol
rearrange-
ment
TiCl3
with O3 and Ph3P, the corresponding
a-carbonatoaldehyde inter-
H
( )n
Ph
O
Ph ( )n
12a
12b
12c
Ph ( )n
TiCl4
no
mediates were formed. When 0.2 equiv of DABCO (1,4-diazabicy-
clo[2.2.2]octane) was added to this solution of crude aldehydes
in MeOH and the mixture was stirred for 8 h, the cyclic carbonates
12 were formed as a mixture of two diastereomers in excellent
yields (Scheme 1).7,9 In general, the syn-isomer was the major
and less polar product. The relative stereochemistry of the two dia-
stereomers was confirmed using the 2D-NOESY technique. The C-4
protons of the syn- and anti-isomers have well-separated chemical
shifts, and the latter one usually appears more downfield. The syn-
and anti-ratio are easily determined by 1H NMR integration. Both
diastereomers are separable by silica gel column chromatography.
However, their separation was not needed because both isomers
yielded the same product in this study.
When the diluted solution (about 0.05 M) of benzyl-substituted
cyclic carbonate 12a in CH2Cl2 was treated with 2 equiv of TiCl4,
benzyl hydroxymethyl ketone 13a00 was formed in 27% yield. The
3-phenylpropyl-substituted analogue 12c also produced hydroxy-
methyl ketone 13c00 in 55% yield (Eq. 1). Interestingly, under similar
conditions 2-phenylethyl-substituted cyclic carbonate 12b pro-
duced 2-tetralone 13b in 83% yield and no hydroxymethyl ketone
13b00 was isolated (Eq. 1). These results indicate that the intramo-
lecular cyclization is applicable only to six-membered ring forma-
tion and not to five- or seven-membered ring formation.
O
O
O
cyclization
when n = 1
or n = 3
MeO
CO2
Cl
HO
n = 1 12a-1
n = 2 12b-1
n = 3 12c-1
H
n = 1 12a'
n = 3 12c'
n = 1 13a"
n = 3 13c"
Figure 3. The reaction pathway of the intermediates 12a-1, 12b-1, and 12c-1
depends on the spacer length (i.e., n value).
Table 1
The formation of 2-tetralones from the intramolecular cyclization of 2-arylethyl-
substituted cyclic carbonates 12b–k promoted by TiCl4
Entry
Carbonate
TiCl4 (equiv)
Time (h)
Product
Yield (%)
1
2
3
4
5
6
7
8
12b
12b
12b
12d
12e
12f
12g
12h
12i
1
8
7
5
4
4
4
5
5
5
5
5
5
13b
13b
13b
13d
13e
13f
13g
13h
13i
46
57
83
69
75
73
65
63
32a
58
89
88
1.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
4.0
2.0
2.0
9
10
11
12
12i
12j
12k
13i
13j
13k
a
7-Chloro-1,2,3,4-tetrahydronaphthalene-1,2-diol (13i0) was isolated in 23% as a
mixture of cis- and trans-isomers.
Ph ( )n
TiCl4, 0.05 M in
CH2Cl2
O
( )n
O
+
Ph
O
-78 oC to rt, 5 h
MeO
( )n
a 2-methoxy- or 4-methoxy-substituent produced the correspond-
ing 2-tetralones in good yields (entries 4 and 6). The phenyl group
with a 3-methoxy substituent generated only 6-methoxy-2-tetra-
lone (13e) in good yield; the other regioisomer (8-methoxy-2-tetra-
lone) was not formed (entry 5). We next studied the phenyl group
with the chlorine deactivating group. The phenyl group with a 2-
chloro- or 4-chloro-substituent produced the corresponding 2-tet-
ralones in good yields (entries 7 and 8). With the 4-chloro-phenyl
compound 12i, we obtained not only 2-tetralone 13i but also 7-
chloro-1,2,3,4-tetrahydronaphthalene-1,2-diol (13i0) (entry 9).
When the reaction mixture was treated with 4 equiv of TiCl4, the
yield of 2-tetralone 13i increased to 58% (entry 10). Presumably,
the precursor of compound 13i0 is convertible to 2-tetralone 13i by
theextraamountof TiCl4. Whenwe replacedthearylgroupof2-aryl-
ethyl-substituted cyclic carbonate with 2-naphthyl and 1-naphthyl,
we obtained 1,2-dihydrophenanthren-3(4H)-one (13j) and 3,4-
dihydrophenanthren-2(1H)-one (13k) in 89% and 88% yields,
respectively (entries 11 and 12). In the intermolecular reaction, we
found that the electron richness of the aromatic compound is crucial
to the success of its reaction with cyclic carbonate 5.7 Interestingly,
O
O
ð1Þ
OH
(syn/anti)
n = 1 12a (2.2/1)
n = 2 12b (2.7/1)
n = 3 12c (5.0/1)
n = 1 13a" 27%
n = 2 13b" 0%
n = 3 13c" 55%
n = 1 13a 0%
n = 2 13b 83%
n = 3 13c 0%
The cyclic carbonates 12a–c were treated with TiCl4 to generate
the oxonium intermediates 12a-1–12c-1, respectively (Fig. 3).
Among them, only intermediate 12b-1 underwent cyclization to
give 2-tetralone (13b). The other two intermediates (12a-1 and
12c-1) were decomposed by water during workup to produce the
a-hydroxyaldehydes, which then underwent ene-diol rearrange-
ment to give the corresponding
a
-hydroxymethyl ketones (13a00
and 13c00), respectively (Fig. 3).10
To determine the optimal condition for 2-tetralone formation,
compound 12b was treated with different amounts of TiCl4 at
ꢀ78 °C. We found that 2 mol equiv of TiCl4 produced the best yield
of the desired product (Table 1, entries 1–3).11 Using this optimized
condition, we tested a variety of the 2-arylethyl-substituted cyclic
carbonates (Eq. 2); Table 1 lists out the results. Phenyl groups with
b, c
H2C=CHCHO
8c
Ar ( )n
Ar ( )n
d, e, f
O
a, c
O
Ar(CH2)nCHO
MeO
O
O
O
MeO
(syn/anti)
Ar = Ph
Ar = Ph
Ar = Ph
n = 1 12a 77% (2.2/1)
n = 2 12b 92% (2.7/1)
n = 3 12c 88% (5.0/1)
Ar = Ph
Ar = Ph
n = 1 8a
n = 2 8b
Ar = Ph
Ar = Ph
Ar = Ph
n = 1 11a 51%
n = 2 11b 56%
n = 3 11c 39%
Ar = 2-MeOPh n = 2 12d 83% (4.0/1)
Ar = 3-MeOPh n = 2 12e 87% (3.3/1)
Ar = 4-MeOPh n = 2 12f 79% (2.8/1)
Ar = 2-ClPh
Ar = 3-ClPh
Ar = 4-ClPh
Ar = 2-MeOPh n = 2 8d
Ar = 3-MeOPh n = 2 8e
Ar = 4-MeOPh n = 2 8f
Ar = 2-ClPh
Ar = 3-ClPh
Ar = 4-ClPh
Ar = 2-MeOPh n = 2 11d 61%
Ar = 3-MeOPh n = 2 11e 64%
Ar = 4-MeOPh n = 2 11f 62%
Ar = 2-ClPh
Ar = 3-ClPh
Ar = 4-ClPh
n = 2 12g 92% (2.7/1)
n = 2 12h 88% (3.0/1)
n = 2 12i 86% (2.9/1)
n = 2 8g
n = 2 8h
n = 2 8i
n = 2 11g 55%
n = 2 11h 54%
n = 2 11i 55%
Ar = 2-Naph n = 2 12j 78% (5.0/1)
Ar = 1-Naph n = 2 12k 75% (3.3/1)
Ar = 2-Naph n = 2 8j
Ar = 1-Naph n = 2 8k
Ar = 2-Naph n = 2 11j 63%
Ar = 1-Naph n = 2 11k 68%
Scheme 1. Reagents and conditions: (a) H2C@CHMgBr (9), THF, 0 °C, 1 h; (b) Ph(CH2)3MgBr (10), THF, 0 °C, 1 h; (c) ClCO2Me, 0 °C to rt, 5 h; (d) O3, CH2Cl2, ꢀ78 °C; (e) Ph3P,
ꢀ78 °C to rt, 5 h; (f) DABCO (0.2 equiv), MeOH, rt, 8 h.

Y.-S. Hon, R. Devulapally / Tetrahedron Letters 50 (2009) 2831–2834
2833
the results given in Table 1 indicate that the deactivated chloro-
R1
Y
R1
Y
phenyl group can still be used to form 2-tetralone. This property will
make this methodology more versatile and useful in the preparation
of 2-tetralone with a variety of substituents.
R2
O
c, d, e
R2
a, b
CHO
O
R1
MeO
R1
YR1 = CHMe; R2 = H 11l 47%
YR1 = CHPh; R2 = H 11m 50%
YR1 = CH2; R2 = Me 11n 63%
YR1 = CH2; R2 = Ph 11o 57%
2 equiv. TiCl4,
0.05 M in CH2Cl2,
-78 oC to rt
YR1 = CHMe; R2 = H 8l
YR1 = CHPh; R2 = H 8m
YR1 = CH2; R2 = Me 8n
YR1 = CH2; R2 = Ph 8o
R2
R3
R2
R3
O
O
MeO
R4
YR1 = O;
R2 = H 11p 47%
YR1 = O;
R2 = H 8p
O
O
R4
R1
Y
R1 = R2 = R3 = R4 = H
12b
R1 = R2 = R3 = R4 = H
13b
R1
O
R
R
R
R
R
1 = OMe; R2 = R3 = R4 = H 12d
2 = OMe; R1 = R3 = R4 = H 12e
3 = OMe; R1 = R3 = R4 = H 12f
1 = Cl; R2 = R3 = R4 = H
2 = Cl; R1 = R3 = R4 = H
R
R
R
R
R
1 = OMe; R2 = R3 = R4 = H 13d
2 = OMe; R1 = R3 = R4 = H 13e
3 = OMe; R1 = R3 = R4 = H 13f
1 = Cl; R2 = R3 = R4 = H
2 = Cl; R1 = R3 = R4 = H
R2
O
ð2Þ
Y
R2
O
f
OH
12g
12h
12i
13g
13h
13i
13p'
O
O
OH
MeO
R3 = Cl; R1 = R3 = R4 = H
R3 = Cl; R1 = R3 = R4 = H
YR1 = CHMe; R2 = H 13l 77%
YR1 = CHPh; R2 = H 13m 84%
YR1 = CH2; R2 = Me 13n 74%
YR1 = CH2; R2 = Ph 13o 75%
YR1 = CHMe; R2 = H 12l 85% (3/3/1)
YR1 = CHPh; R2 = H 12m 82% (2.7/1)
YR1 = CH2; R2 = Me 12n 85% (1/1)
YR1 = CH2; R2 = Ph 12o 79% (7.7/1)
R2, R3
R1, R2
=
=
R1 = R4 = H 12j
R3 = R4 = H 12k
R3, R4
R1, R2
=
=
R1 = R2 = H 13j
R3 = R4 = H 13k
YR1 = O; R2 = H
13p 0%
YR1 = O;
R2 = H 12p 86% (6.2/1)
We next turned our attention to the possibility of function-
alizing the C-3 and C-4 positions of 2-tetralone. The cyclic car-
bonates (12l–o) were prepared from aryl-substituted aldehydes
(8l–o) following the method described above. They were treated
with TiCl4 to produce 4-methyl-2-tertralone (13l), 4-phenyl-2-
tetralone (13m), and 3-methyl-2-tetralone (13n), respectively,
in excellent yields (Scheme 2). 2-Tetralone 13m is an important
compound in the synthesis of 4-phenyl-2-amidotetralins as a
melatonin-receptor agent.12 The cyclic carbonate 12o contains
two phenyl groups. When it was treated with TiCl4, we ob-
tained 3-phenyl-2-tetralone (13o) exclusively in 75% yield. This
result indicates that only the 3-phenyl group participates in the
Friedel–Crafts reaction because the reaction favors six-mem-
bered ring formation instead of five-membered ring formation.
We also prepared phenoxymethyl-substituted cyclic carbonate
12p following our standard protocol. When it was treated with
TiCl4, chroman-3,4-diol (13p0) was isolated in 52% yield as a
mixture of two diastereomers; no chroman-3-one (13p) was
observed.
Scheme 2. Reagents and conditions: (a) H2C@CHMgBr (9), THF, 0 °C, 1 h; (b)
ClCO2Me, 0 °C to rt, 5 h; (c) O3, CH2Cl2, ꢀ78 °C; (d) Ph3P, ꢀ78 °C to rt, 5 h; (e) DABCO
(0.2 equiv), MeOH, rt, 8 h; (f) TiCl4, (2 equiv), CH2Cl2 (0.05 M), ꢀ78 °C to rt, 3–5 h.
intermediate C. The benzylic methoxy group of C is removed with
the help of the second equivalent of TiCl4 to generate intermediate
D or F-1. Intermediate D then undergoes deprotonation to give 2-
tetralone 13. In contrast, intermediate F-1 is quenched by water to
produce diol 13p0.
In summary, the arylethyl-substituted cyclic carbonate 12
can be prepared using a very straightforward method, and it
can be considered as a synthetic equivalent of synthon-III to
synthesize the 2-tetralone derivatives (Fig. 4). Further studies
are in progress to determine the applicability of this method
to ring annulation with heteroaromatic rings and natural prod-
uct synthesis.
Acknowledgments
Figure 4 describes the rationale for the formation of compounds
13 and 13p0 from cyclic carbonate 12. The cyclic carbonate 12 is
decomposed by the first equivalent of TiCl4 to give oxonium inter-
mediate B, which undergoes the Friedel–Crafts reaction to produce
We are grateful to the National Science Council, National
Chung Cheng University, and Academia Sinica for financial
support.
- HCl
+ H2O
O
O
O
H2O
Cl
Cl
13p'
OTiCl3
OTiCl3
O
13p
F-2
F-1
When YR2= O, X = R1 = H
TiCl4
MeOTiCl3
R2
Y
R2
Y
R2
R2
Aromatic
X
When Y = CH
R1
O
X
Electrophilic
Substitution
R1
X
X
R1
R1
H
Y
TiCl4
TiCl4
Cl
MeO
OTiCl3
OTiCl3
OTiCl3
MeOTiCl3
CO2
O
D
O
OMe
Cl
OMe
B
C
12
R1
R2
R1
R2
X
X
R2
O
X
R1
OTiCl3
X
R2
R1
O
H2O
-HCl
O
MeO
E
13
O
O
synthon-III
12
Figure 4. The plausible mechanism for the formation of 2-tetralone 13 or chroman-3,4-diol (13p0) from the reaction of cyclic carbonate 12 with TiCl4. The arylethyl-
substituted cyclic carbonate 12 can be considered as a synthetic equivalent of synthon-III.

2834
Y.-S. Hon, R. Devulapally / Tetrahedron Letters 50 (2009) 2831–2834
the reaction mixture was warmed slowly to room temperature and was stirred
References and notes
at room temperature for 3 h. The reaction mixture was concentrated to give the
crude residue. To a solution of the crude residue in MeOH (6 mL) was added
DABCO (44.8 mg, 0.4 mmol) and the reaction mixture was stirred at room
temperature for 8 h. The reaction mixture was concentrated to give the crude
residue which was purified by silica gel column chromatography to give the
carbonate 12c-syn (354.5 mg, 1.50 mmol) and 12c-anti (70.9 mg, 0.30 mmol) in
88% yield.
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9. General procedure for the preparation of cyclic carbonate (12c): A two-necked
flask fitted with a glass tube to admit ozone, a CaCl2 drying tube, and a
magnetic stirring bar was charged with alkene 11c (479.2 mg, 2.0 mmol) in
CH2Cl2 (10 mL). The flask was cooled to ꢀ78 °C and O3 was bubbled through
the solution. When the solution turned blue, ozone addition was stopped and
N2 was passed through the solution until the blue color was discharged. To the
resulting ozonide in CH2Cl2 was added Ph3P (419.7 mg, 1.6 mmol) at ꢀ78 °C,
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11. General procedure for the preparation of 2-tetralone (13b): To a solution of 4-
methoxy-5-phenethyl-1,3-dioxolan-2-one (12b) (62 mg, 0.29 mmol) in 5 mL of
CH2Cl2, TiCl4 (0.58 mmol, 0.58 mL, 1 M in CH2Cl2) was added dropwise at
ꢀ78 °C over a period of 5 min. The reaction mixture was warmed slowly to rt in
a period of 5 h. The reaction mixture was quenched with saturated aqueous
NaHCO3 and was extracted with CH2Cl2. The organic layer was dried over
MgSO4, concentrated, and chromatographed on silica gel column to give 2-
teralone (13b, 35.2 mg) as a pale yellow oil in 83% yield. TLC Rf = 0.57 (hexane/
EtOAc = 6:1); 1H NMR (CDCl3, 400 MHz) d 2.53–2.57 (t, J = 6.6 Hz, 2H), 3.05–
3.08 (t, J = 6.6 Hz, 2H), 3.59 (s, 2H), 7.12–7.23 (m, 4H); 13C NMR (CDCl3,
100 MHz) d 28.3 (2°), 38.1 (2°), 45.0 (2°), 126.8 (3°), 126.8 (3°), 127.5 (3°), 128.2
(3°), 133.2 (4°), 136.7 (4°), 210.6 (4°); IR (KBr, neat) 3023, 2952, 2849, 1716,
1456, 1238, 749 cmꢀ1; MS m/z (relative intensity): 147 (M++1, 1), 146 (M+, 71),
117 (28), 104 (100), 103 (15), 91 (14), 78 (12); HRMS calcd for C10H10O:
146.0732. Found: 146.0731.
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