Chelation-control in the formal [3+3] cyclization of 1,3-bis-(silyloxy)-1,3-butadienes with 1-hydroxy-5-silyloxy-hex-4-en-3-ones. One-pot synthesis of 3-aryl-3,4-dihydroisocoumarins

Article abstract of DOI:10.1016/j.tet.2010.01.019

The [3+3] cyclization of 1,3-bis(silyloxy)-1,3-butadienes with 1-hydroxy-5-silyloxy-hex-4-en-3-ones resulted in the one-pot formation of 3-aryl-3,4-dihydroisocoumarins. The reactions proceeded by regioselective cyclization to give 6-(2-aryl-2-chloroethyl)

Full text of DOI:10.1016/j.tet.2010.01.019

Tetrahedron 66 (2010) 1874–1884
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Chelation-control in the formal [3þ3] cyclization of 1,3-bis-(silyloxy)-1,3-
butadienes with 1-hydroxy-5-silyloxy-hex-4-en-3-ones. One-pot synthesis
of 3-aryl-3,4-dihydroisocoumarins
,
,
b
,
,
Ihsan Ullah a b, Muhammad Sher a c, Rasheed Ahmad Khera a, Asad Ali a b, Muhammad Farooq Ibad a,
Alexander Villinger a, Christine Fischer b, Peter Langer a
,b,
*
a
¨
Institut fu¨r Chemie, Universitat Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Leibniz-Institut fu¨r Katalyse e. V. an der Universita¨t Rostock, Albert-Einstein-Str. 29a, 18059 Rostock, Germany
c Department of Chemistry, Allama Iqbal Open University, Islamabad, Pakistan
a r t i c l e i n f o
a b s t r a c t
Article history:
The [3þ3] cyclization of 1,3-bis(silyloxy)-1,3-butadienes with 1-hydroxy-5-silyloxy-hex-4-en-3-ones
resulted in the one-pot formation of 3-aryl-3,4-dihydroisocoumarins. The reactions proceeded by re-
gioselective cyclization to give 6-(2-aryl-2-chloroethyl)salicylates, which underwent a silica gel-medi-
ated lactonization. The cyclizations of protected 1-amino-5-silyloxy-hex-4-en-3-ones proved to be not
regioselective.
Received 21 October 2009
Received in revised form 30 December 2009
Accepted 5 January 2010
Available online 11 January 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Arenes
Cyclizations
Isocoumarins
Regioselectivity
Silyl enol ethers
1. Introduction
Formal [3þ3] cyclization reactions3,4 of 1,3-bis(trimethylsilyloxy)-
1,3-butadienes5 with 3-silyloxy-2-en-1-ones provide a versatile
3-Aryl-3,4-dihydroisocoumarins (3-aryl-isochroman-1-ones)
constitute a pharmacologically important chemical entity, which
occurs in several natural products. This includes, for example,
thunberginol C, D, and E and hydrangenol.1a–c Pharmacological
activities of these natural products include promotion of the adi-
pogenesis of murine 3T3-L1 cells,1a and show antiproliferative
activity against mouse splenocytes1b and activity against human
gastric cancer cell lines.1c Other 3-aryl-3,4-dihydroisocoumarins1d
show antifungal activity,1e inhibition of rat basophilic leukaemia
RBL-2H3 cells,1f antiproliferative activity against C57/BL6 mouse
splenocytes,1b antiallergic activity,1g induction of steroidogenes-
is,1h phagocytic activity,1i immunomodulatory activity on spleen
lymphocyte proliferation (activated by lipopolysaccharide, con-
canavalin A and phytohaemagglutinin in mice) 1j and antimicrobial
activity.1k–m,2 In a number of natural products, one of the hydroxyl
groups of the 3-aryl-3,4-dihydroisocoumarin core structure is
glycosylated; this includes, for example, (ꢀ)-hydrangenol 40-O-
glucoside1i and phyllodulcin 8-O-glucoside.1a,1l
method for the synthesis of various functionalized arenes and
hetarenes. However, this method is mainly limited to cyclizations of
3-silyloxy-2-en-1-ones derived from symmetrical 1,3-diketones.
Cyclizations of unsymmetrical derivatives mostly proceed with low
regioselectivity. Exceptions are 3-aryl-3-silyloxy-2-en-1-ones pre-
pared from aroylacetones, which usually react with very good
regioselectivity. For example, dibenzo[b,d]pyran-6-ones have been
prepared by [3þ3] cyclizations of 3-aryl-3-silyloxy-2-en-1-ones and
subsequent lactonization.6 Recently, we have reported7 a one-pot
synthesis of 3-aryl-3,4-dihydroisocoumarins by domino8 ‘[3þ3] cy-
clization/lactonization’ reactions of 1,3-bis(silyloxy)-1,3-butadienes
with 1-hydroxy-5-silyloxy-hex-4-en-3-ones. The regioselectivity of
these reactions is controlled by chelation effects. Herein, we report
full details and a comprehensive study of the scope.
2. Results and discussion
The reaction of the dianion of acetylacetone (1) with aldehydes
2a–h afforded, following a known procedure,9 condensation prod-
ucts 3a–h (Scheme 1, Table 1). The NEt3-mediated reaction of 3a–h
with Me3SiCl resulted in chemoselective formation of 1-aryl-1-
* Corresponding author. Tel.: þ49 381 4986410; fax: þ49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.01.019

I. Ullah et al. / Tetrahedron 66 (2010) 1874–1884
1875
O
O
5a, readily available from methyl acetoacetate, afforded 6-(2-phe-
nyl-2-chloroethyl)salicylate 6a (Scheme 2). The cyclization pro-
ceeded with excellent regioselectivity. The formation of the other
regioisomer, 4-(2-phenyl-2-chloroethyl)salicylate, was not ob-
served. The moderate yield of 6a (52%) can be explained by prac-
tical problems during the chromatographic purification.
The regioselective formation of product 6a might be explained by
chelation-control. The reaction of TiCl4 with 4a gave intermediate A
and hydrogen chloride. The chelation of Ti(IV) by the hydroxyl and
the carbonyl group facilitates the conjugate addition of the (most
reactive) terminal carbon atom of 5a to A to give intermediate B,
which underwent a cyclization to give intermediate C. The reaction
of HCl with the carbon atom attached to the phenyl group resulted in
nucleophilic substitution and formation of intermediate D, which
underwent aromatization to give intermediate E. Product 6a is
formed upon aqueous work-up. Interestingly, the presence of the free
hydroxy group of 4a is important to achieve a high degree of regio-
selectivity. The presence of a methoxy rather than a hydroxyl group
resulted in the formation of a mixture of regioisomers.
O
i
O
O
OH
+
Me
Me
R
2a-h
Me
R
1
3a-h
ii
Me3SiO
Me
O
OH
R
4a-h
Scheme 1. Synthesis of 1-aryl-1-hydroxy-5-silyloxy-hex-4-en-3-ones 4a–h: i: 1) 1, 2.5
LDA, THF, 1 h, 0 ꢁC; 2) 2a–h, ꢀ78/20 ꢁC, 14 h; 3) NaHCO3, H2O; ii: NEt3, Me3SiCl,
CH2Cl2, 20 ꢁC, 14 h.
Table 1
Synthesis of 1-hydroxy-5-silyloxy-hex-4-en-3-ones 4a–h
3,4
R
% (3)a
% (4)a
a
b
c
d
e
f
Ph
2-FC6H4
70
56
65
63
66
74
60
45
86
83
80
90
92
95
88
78
2,3-(MeO)2C6H3
3-MeC6H4
4-MeC6H4
4-EtC6H4
4-ClC6H4
3-Pyridyl
Stirring of a solution of 6a in wet THF in the presence of silica gel
afforded 3-phenyl-3,4-dihydroisocoumarin 7a in 69% yield
(Scheme 3). The formation of 7a can be explained by acid-mediated
hydrolysis of the chloride to give intermediate F and subsequent
lactonisation.
g
h
a
Yields of isolated products.
hydroxy-5-silyloxy-hex-4-en-3-ones 4a–h. A silylation of the hy-
droxy group was not observed.
OH
O
OH
O
The TiCl4-mediated [3þ3] cyclization of 1-phenyl-1-hydroxy-5-
OMe
Cl
i
O
silyloxy-hex-4-en-3-one 4a with 1,3-bis(silyloxy)-1,3-butadiene
Me
Me
Ph
Me3SiO
OSiMe3
OMe
Ph
OH
O
6a
7a (69%)
OMe
Cl
TiCl4
5a
OH
O
+
Me
i
Me3SiO
Me
O
OH
Ph
OMe
OH
Ph
6a (52%)
Me
Ph
4a
F
TiO
HCl,
H2O
2
Scheme 3. Synthesis of 7a: i: SiO2, wet THF, 14 h.
TiCl4
HCl
The [3þ3] cyclization of 4a with 1,3-bis(silyloxy)-1,3-butadiene
5b afforded 6b, which was transformed into lactone 7b by stirring in
the presence of wet silica gel for 14 h (Scheme 4, Table 2). The [3þ3]
cyclization of 4a with 1,3-bis(silyloxy)-1,3-butadienes 5c–f, con-
taining an alkyl group attached to carbon atom C4, directly afforded
the 3-phenyl-3,4-dihydroisocoumarins 7c–f. The formation of
7b–d can be explained by [3þ3] cyclization and subsequent hydro-
lysis and lactonization during the aqueous work-up and/or silica
gel chromatography. The cyclization of 4a with 1,3-bis(silyloxy)-
1,3-butadienes 5g,i–k resulted in the formation of 6-(2-phenyl-
2-chloroethyl)salicylates 6g,i–k. The cyclization of various 1,3-
bis(silyloxy)-1,3-butadienes with 4b–h, containing phenyl groups
with electron-withdrawing or -donating substituents, directly
TiCl2(OH)2
OH
O
TiCl3
O
OMe
Me3SiO
Me
O
Me
Ph
Ph
Cl
A
E
5a
Me3SiCl
O
O
O
O
OMe
Cl2
Me3SiO
Ti
OMe
TiCl2OH
Cl
O
O
Me
Me
Me3SiO
OH
O
Ph
R2
OR1
Cl
Ph
B
D
Me3SiO
R2
OSiMe3
OR1
Me
(Me3Si)2O
HCl
Ar
6a-af
TiCl4
5a-p
O
O
O
+
i
Me3SiO
Me
O
OH
Ar
OH
O
OMe
TiCl2
O
R2
O
Me
4a-h
Me
Ar
Ph
C
7a-af
Scheme 2. Possible mechanism of the formation of 6a: i: 1) TiCl4, CH2Cl2, ꢀ78/20 ꢁC,
Scheme 4. Synthesis of 6a–af and 7a–af: i: 1) TiCl4, CH2Cl2, ꢀ78/20 ꢁC, 14 h; 2)
14 h; 2) NaHCO3, H2O.
NaHCO3, H2O; 3) silica gel chromatography (EtOAc /heptanes).

1876
I. Ullah et al. / Tetrahedron 66 (2010) 1874–1884
Table 2
Synthesis of 6-(2-aryl-2-chloroethyl)salicylates 6a–af and 3-aryl-3,4-dihy-
droisocoumarins 7a–af
4
5
6,7
R1
R2
Ar
% (6)a
% (7)a
a
a
a
a
a
a
a
a
a
a
a
b
b
c
a
b
c
d
e
f
g
h
i
j
k
l
m
l
m
a
m
c
d
a
b
n
g
h
o
j
a
b
c
d
p
a
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
p
q
r
s
t
u
v
w
x
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
H
Me
Et
nHex
nNon
nDec
Allyl
(CH2)2CH]CH2
OMe
H
H
H
Me
H
Me
H
Me
Et
nHex
H
Me
nBu
Allyl
(CH2)2CH]CH2
(CH2)2Ph
H
H
Me
Et
nHex
Cl
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
52
35
0
0
0
0
33
0
44
37
40
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
28
0
69b
48c
33
57
53
54
0
42
0
0
Ph
Ph
Ph
Figure 1. Ortep plot of 7l (50% probability level); the position of the OH-proton was
calculated from the difference map and refined freely.
iPr
0
Bn
Et
Bn
Et
Me
Et
2-FC6H4
2-FC6H4
2,3-(MeO)2C6H3
2,3-(MeO)2C6H3
3-MeC6H4
3-MeC6H4
3-MeC6H4
3-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-EtC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
3-Pyridyl
50
46
38
35
42
45
54
58
41
43
62
35
38
40
48
55
50
53
55
0
c
d
d
d
d
e
e
e
e
e
e
f
g
g
g
g
g
h
Me
Me
Me
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
y
z
aa
ab
ac
ad
ae
af
37
a
b
c
Yields of isolated products.
Prepared from 6a.
Prepared from 6b.
Figure 2. Ortep plot of 7o (50% probability level); the position of the OH-proton was
calculated from the difference map and refined freely.
ether 11 (Scheme 5). The TiCl4-mediated cyclization of 11 with 5a
and 5j afforded products 12a and 12b, respectively. Products 12a
and 12b were both formed as unseparable mixtures of regioisomers
with a ratio of 0.49/0.51 and 0.47/0.53, respectively. Due to the rigid
nature of the carbamate moiety, different rotamers are possible. For
12b, the rotamers could be detected at low temperature (263 K).
For one regioisomer, the ratio of the two rotamers was 0.53/0.47.
For the other one the ratio was 0.62/0.38 (see Experimental sec-
tion). The low regioselectivity might be explained by the fact that
the amino group contains no free hydrogen atom.
In conclusion, we have reported a convenient synthesis of 3-aryl-
3,4-dihydroisocoumarins by domino ‘[3þ3] cyclization/lactonization’
reactions of 1,3-bis(silyloxy)-1,3-butadienes with 1-hydroxy-5-sily-
loxy-4-en-3-ones. These reactions proceed by regioselective [3þ3]
cyclization to give 6-(2-aryl-2-chloroethyl)salicylates and sub-
sequent silica gel-mediated lactonization.
afforded 3-aryl-3,4-dihydroisocoumarines 7l–af (except for the
reaction of 4g with 5p which gave 6ae).
The silica gel chromatography generally proved to be important
for the hydrolysis and lactonization to occur. In most reactions the
direct formation of 2,3-dihydroisocoumarines was observed. The
formation of products 6 mainly occurred when the phenyl-
substituted silyl enol ether 4a was employed. In this series, the
choice of the 1,3-bis(silyloxy)-1,3-butadiene seems to have a sig-
nificant influence on the product distribution. On the other hand,
different products were obtained for reactions of one and the same
1,3-bis(silyloxy)-1,3-butadiene with different silyl enol ethers 4. It
was mentioned above that products 6 can be transformed into
lactones 7 by stirring in the presence of wet silica gel. This result
suggests that the quality and nature of the silica gel and of the
solvent employed for the chromatographic purification also have
an influence on the product distribution. In addition, the individual
handling of each reaction may play a role. This includes, for ex-
ample, the time required for the aqueous work-up or the prepa-
ration of the crude material for chromatography (concentration of
a solution of the crude product in the presence of silica gel and
addition of the solid residue on the top of the column or, alterna-
tively, direct addition of the oily crude product by syringe without
silica gel). In addition, the quality of the Lewis acid should have
some influence (an older charge of TiCl4 may be partly hydrolyzed
and contains HCl).
The structures of all products were confirmed by spectroscopic
methods. The structures of 7l, 7o, 7q and 7af were independently
confirmed by X-ray crystal structure analyses (Figs. 1–4).10
The ethyl chloroformate-mediated reaction of 1,3-bis(silyl enol
ether) 8, readily available from acetylacetone, with imine 9 afforded
condensation product 10, which was transformed into silyl enol
Figure 3. Ortep plot of 7q (50% probability level); the position of the OH-proton was
calculated from the difference map and refined freely.

I. Ullah et al. / Tetrahedron 66 (2010) 1874–1884
1877
1.91 mmol), 1-hydroxy-1-phenyl-5-(trimethylsilyloxy)hex-4-en-3-
one 4a (530 mg, 1.91 mmol) and TiCl4 (0.21 mL, 1.91 mmol), 6a was
isolated after column chromatography (silica gel, n-heptane/
EtOAc¼24/1) as a colourless oil (304 mg, 52%). 1H NMR (300 MHz,
CDCl3):
d
¼2.22 (s, 3H, CH3), 3.61 (m, 2H, CH2), 3.93 (s, 3H, OCH3),
5.02 (m, 1H, CH), 6.41 (s, 1H, HAr), 6.72 (s, 1H, HAr), 7.29–7.35 (m, 5H,
Ph), 11.23 (s, 1H, OH); 13C NMR (75 MHz, CDCl3):
d
¼21.5 (CH3), 46.7
(CH2), 52.3 (OCH3), 64.1 (CH), 109.5 (CAr), 117.3, 125.9, 126.9 (2CHAr),
128.3 (CHAr), 128.5 (2CHAr), 139.4, 141.6, 145.3, 163.0 (CAr), 171.3
~
(C]O); IR (neat):
n
¼2955 (w), 1653 (s), 1568 (m), 1452 (s), 1317 (s),
1261 (s), 1207 (s), 1092 (s), 955 (m), 855 (m), 728 (s), 691 (s) cmꢀ1
;
Figure 4. Ortep plot of 7af (50% probability level); the position of the OH-proton was
calculated from the difference map and refined freely.
GC–MS (EI, 70 eV): m/z (%)¼306 (Mþ, 37Cl, 13), 304 (Mþ, 35Cl, 35),
268 (32), 237 (86), 208 (24), 179 (100), 165 (31), 125 (45), 119 (21),
89 (15), 77 (13); HRMS (EI): calcd for C17H17ClO3 ([M]þ, [35Cl]):
304.08715; found: 304.08607.
Me
CO2Et
Ph
Me3SiO
OSiMe3
+
NMe
HO
Me
O
N
i
Me
Ph
3.1.3. Methyl 6-(2-chloro-2-phenylethyl)-2-hydroxy-3,4-dimethyl-
benzoate (6b). Starting with 1,3-bis(silyl enol ether) 5b (600 mg,
2.18 mmol), 1-hydroxy-1-phenyl-5-(trimethylsilyloxy)hex-4-en-3-
one 4a (608 mg, 2.18 mmol) and TiCl4 (0.24 mL, 2.18 mmol), 6b was
isolated after column chromatography (silica gel, n-heptane/
EtOAc¼24/1) as a light yellow oil (243 mg, 35%). 1H NMR (300 MHz,
10
8
9
ii
Me
OH
O
CO2Et
Ph
Me3SiO
Me
O
N
OR
CDCl3):
d
¼2.14 (s, 3H, CH3), 2.19 (s, 3H, CH3), 3.58 (m, 2H, CH2), 3.93
(s, 3H, OCH3), 5.01 (m, 1H, CH), 6.42 (s, 1H, HAr), 7.31–7.35 (m, 5H,
Me
11
Ph), 11.61 (s, 1H, OH); 13C NMR (75 MHz, CDCl3):
46.7 (CH2), 52.3 (OCH3), 64.3 (CH), 108.7, 124.1 (CAr), 126.0 (CHAr),
d
¼11.5, 20.3 (CH3),
CO2Et
TiCl4
iii
Ph
N
Me
+
126.9 (2CHAr), 128.5 (3CHAr), 136.0, 141.8, 143.4, 161.0 (CAr), 171.9
Me3SiO
OSiMe3
OR
~
(C]O); IR (neat):
n
¼2927 (m), 2862 (w), 1670 (s), 1629 (m), 1435
OH
O
(w), 1220 (s), 1126 (m), 1041 (w), 970 (s), 901 (s), 810 (s) cmꢀ1; GC–
MS (EI, 70 eV): m/z (%)¼320 (Mþ, 37Cl, 11), 318 (Mþ, 35Cl, 33), 282
(10), 251 (43), 250 (76), 222 (10), 194 (14), 193 (100), 179 (10), 178
(14), 161 (11), 133 (28), 125 (18), 91 (10), 77 (10); HRMS (EI): calcd
for C18H19ClO3 ([M]þ, [35Cl]): 318.10172; found: 318.10196.
OR
Me
CO2Et
5a,j
Ph
N
Me
12a (R = Me), 37%
3.1.4. Methyl-3-allyl-6-(2-chloro-2-phenylethyl)-2-hydroxy-4-
methylbenzoate (6g). Starting with 1,3-bis(silyl enol ether) 5g
(600 mg, 1.99 mmol), 1-hydroxy-1-phenyl-5-(trimethylsilyloxy)-
hex-4-en-3-one 4a (555 mg, 1.99 mmol) and TiCl4 (0.21 mL,
1.99 mmol), 6g was isolated after column chromatography (silica
gel, n-heptane/EtOAc¼24/1) as a slight yellow oil (226 mg, 33%). 1H
12b (R = Et), 42%
Scheme 5. Synthesis of 12a,b: i: 1) ClCO2Et, CH2Cl2, 20 ꢁC, 14 h, 2) EtOAc, cold H2O; ii:
NEt3, Me3SiCl, C6H6, 20 ꢁC, 72 h; iii: 1) TiCl4, CH2Cl2, ꢀ78/20 ꢁC, 14 h; 2) NaHCO3, H2O.
3. Experimental section
3.1. General comments
NMR (300 MHz, CDCl3):
d
¼2.04 (s, 3H, CH3), 3.41 (d, 2H, J¼2.5 Hz,
CH2), 3.57 (m, 2H, CH2), 3.94 (s, 3H, OCH3), 4.98–5.03 (m, 3H,
CH,]CH2), 5.91 (m, 1H, ]CH), 6.43 (s, 1H, HAr), 7.24–7.34 (m, 5H,
All solvents were dried by standard methods and all reactions
were carried out under an inert atmosphere. For 1H and 13C NMR
spectra the deuterated solvents indicated were used. Mass spec-
trometric data (MS) were obtained by electron ionization (EI,
70 eV), chemical ionization (CI, isobutane) or electrospray ioniza-
tion (ESI). For preparative scale chromatography silica gel 60
(0.063–0.200 mm, 70–230 mesh) was used.
Ph), 11.59 (s, 1H, OH); 13C NMR (75 MHz, CDCl3):
d¼19.4 (CH3), 30.0,
46.5 (CH2), 52.1 (OCH3), 64.0 (CH), 108.8 (CAr), 114.3 (]CH2), 125.2
(CAr), 126.1 (CHAr), 126.7 (2CHAr), 128.0 (CHAr), 128.5 (2CHAr), 135.1
(]CH), 136.7, 141.5, 143.6, 160.7 (CAr), 171.6 (C]O); IR (neat):
~
n
¼2920 (m), 2856 (w),1665 (s),1625 (m),1414 (w),1290 (s),1246 (s),
1159 (s),1115 (m),1038 (w), 806 (s), 750 (s), 717 (s) cmꢀ1; GC–MS (EI,
70 eV): m/z (%)¼346 (Mþ, 37Cl, 15), 344 (Mþ, 35Cl, 43), 308 (26), 276
(67), 261 (39), 219 (100), 178 (15), 159 (22), 91 (23). Anal. Calcd (%)
for C20H21ClO3 (344.83): C 69.66, H 6.14; found: C 69.61, H 6.41.
3.1.1. General procedure for the synthesis of 1-hydroxy-2,4-benzo-
dioates (6a–af) and 3-aryl-3,4-dihydroisocoumarins (7c–af). To
a CH2Cl2 solution (2 mL/1.0 mmol of 5) of 5 (1.0 equiv) was added 4
(1.0 equiv) and subsequently TiCl4 (1.0 equiv) at ꢀ78 ꢁC under ar-
gon atmosphere. The temperature of the solution was allowed to
warm to 20 ꢁC during 14 h with stirring. To the reaction mixture
was added saturated aqueous NaHCO3 solution (10 mL) and the
organic and the aqueous layers were separated. The later was
extracted with Et2O (3ꢂ20 mL). The combined organic layers were
dried (Na2SO4), filtered and the filtrate was concentrated in vacuo.
The residue was purified by chromatography (silica gel, n-heptane/
EtOAc¼24/1) to give product 6 or 7.
3.1.5. Methyl 6-(2-chloro-2-phenylethyl)-2-hydroxy-3-methoxy-4-
methylbenzoate(6i). Starting with 1,3-bis(silyl enol ether) 5i (700 mg,
2.40 mmol), 1-hydroxy-1-phenyl-5-(trimethylsilyloxy)hex-4-en-3-
one 4a (670 mg, 2.40 mmol) and TiCl4 (0.26 mL, 2.40 mmol), 6i was
isolated after column chromatography (silica gel, n-heptane/EtOAc¼
24/1) as a slight yellow oil (350 mg, 44%). 1H NMR (300 MHz, CDCl3):
d
¼2.07 (s, 3H, CH3), 3.43 (m, 2H, CH2), 3.70 (s, 3H, OCH3), 3.80 (s, 3H,
OCH3), 4.87 (m, 1H, CH), 6.28 (s, 1H, HAr), 7.12–7.21 (m, 5H, Ph), 11.24
(s, 1H, OH); 13C NMR (75 MHz, CDCl3):
d
¼16.0 (CH3), 46.4 (CH2), 52.4,
59.8 (OCH3), 64.2 (CH), 110.5 (CAr), 125.9 (CHAr), 126.9 (2CHAr), 128.2
(CHAr), 128.4 (2CHAr), 133.8, 137.2, 141.6, 145.7, 156.3 (CAr), 171.4
~
3.1.2. Methyl-2-(2-chloro-2-phenylethyl)-6-hydroxy-4-methyl-
benzoate (6a). Starting with 1,3-bis(silyl enol ether) 5a (500 mg,
(C]O); IR (neat):
n
¼2953 (w), 1658 (s), 1440 (m), 1309 (w), 1252 (s),
1199 (m), 1007 (m), 805 (w), 696 (s) cmꢀ1; GC–MS (EI, 70 eV): m/z

1878
I. Ullah et al. / Tetrahedron 66 (2010) 1874–1884
(%)¼336 (Mþ, 37Cl, 2), 334 (Mþ, 35Cl, 6), 284 (59), 266 (100), 208 (27),
251 (20), 236 (30), 165 (23), 77 (20); HRMS (EI): calcd for C18H19ClO4
([M]þ, [35Cl]): 334.09674; found: 334.09664.
1.73 mmol), 1-hydroxy-1-phenyl-5-(trimethylsilyloxy)hex-4-en-
3-one 4a (482 mg, 1.73 mmol) and TiCl4 (0.19 mL, 1.73 mmol), 7c
was isolated after column chromatography (silica gel, n-heptane/
EtOAc¼23/2) as a white solid (161 mg, 33%), mp¼116–117 ꢁC. 1H
3.1.6. Ethyl-2-(2-chloro-2-phenylethyl)-6-hydroxy-4-methyl-
benzoate (6j). Starting with 1,3-bis(silyl enol ether) 5j (600 mg,
2.18 mmol), 1-hydroxy-1-phenyl-5-(trimethylsilyloxy)hex-4-en-3-
one 4a (610 mg, 2.18 mmol) and TiCl4 (0.24 mL, 2.18 mmol), 6j was
isolated after column chromatography (silica gel, n-heptane/
EtOAc¼24/1) as a slight yellow oil (257 mg, 37%).1H NMR (300 MHz,
NMR (300 MHz, CDCl3):
d
¼1.13 (t, 3H, J¼7.4 Hz, CH3), 2.33 (s, 3H,
CH3), 2.70 (q, 2H, J¼7.4 Hz, CH2), 3.02 (dd, 1H, J¼16.4, 3.6 Hz, CH2),
3.23 (dd, 1H, J¼16.4, 12.0 Hz, CH2), 5.53 (dd, 1H, J¼12.0, 3.6 Hz, CH),
6.54 (s, 1H, HAr), 7.36–7.46 (m, 5H, Ph), 11.21 (s, 1H, OH); 13C NMR
(75 MHz, CDCl3):
80.8 (CH), 105.8 (CAr), 119.6 (CHAr), 126.1 (2CHAr), 128.3 (CHAr),
d
¼13.1 (CH3), 19.0 (CH2), 19.9 (CH3), 35.0 (CH2),
CDCl3):
d
¼1.36 (t, 3H, J¼7.1 Hz, CH3), 2.15 (s, 3H, CH3), 3.55 (dd, 1H,
128.7 (2CHAr), 129.7, 135.6, 138.2, 145.3, 160.1 (CAr), 170.2 (C]O); IR
~
J¼13.2, 6.8 Hz, CH2), 3.75 (dd, 1H, J¼13.2, 7.3 Hz, CH2), 4.41 (q, 2H,
J¼7.1 Hz, OCH2), 5.03 (dd, 1H, J¼13.2, 7.0 Hz, CH), 6.27 (s, 1H, HAr),
6.68 (s, 1H, HAr), 7.27–7.30 (m, 5H, Ph), 11.45 (s, 1H, OH); 13C NMR
(KBr):
n
¼3067 (w), 2964 (w), 2873 (w), 1660 (m), 1623 (m), 1571
(w), 1497 (m), 1415 (m), 1349 (m), 1281 (m), 1239 (s), 1162 (s), 1107
(m), 1029 (m), 976 (m), 917 (m), 854 (m), 801 (s), 754 (s), 693 (s)
cmꢀ1; GC–MS (EI, 70 eV): m/z (%)¼282 (Mþ, 61), 265 (21), 264
(100), 250 (10), 249 (53), 221 (10), 191 (8), 178 (19), 91 (8), 77 (12).
Anal. Calcd (%) for C18H18O3 (282.45): C 76.57, H 6.43; found: C
76.21, H 6.21.
(75 MHz, CDCl3):
(CH), 109.5 (CAr), 117.2 (CHAr), 125.7 (CHAr), 127.0 (2CHAr), 128.2
d
¼14.0, 21.3 (CH3), 46.3 (CH2), 61.8 (OCH2), 63.7
(CHAr), 128.3 (2CHAr), 139.2,141.2, 145.0, 163.0 (CAr), 170.9 (C]O); IR
~
(neat):
n
¼2980 (w), 1654 (s), 1620 (m), 1570 (w), 1452 (m), 1314 (s),
1258 (s), 1212 (s), 1095 (s), 1014 (w), 852 (w), 738 (m), 696 (s) cmꢀ1
;
GC–MS (EI, 70 eV): m/z (%)¼320 (Mþ, 37Cl, 9), 318 (Mþ, 35Cl, 27), 282
(28), 237 (79), 208 (27), 165 (100), 125 (29), 91 (12), 77 (10); HRMS
(EI): calcd for C18H19ClO3 ([M]þ, [35Cl]): 318.10230; found: 318.10172.
3.1.10. 7-Hexyl-8-hydroxy-6-methyl-3-phenyl-3,4-dihydro-isochro-
man-1-one (7d). Starting with 1,3-bis(silyl enol ether) 5d (600 mg,
1.74 mmol), 1-hydroxy-1-phenyl-5-(trimethylsilyloxy)hex-4-en-
3-one 4a (485 mg, 1.74 mmol) and TiCl4 (0.19 mL, 1.74 mmol), 7d
was isolated after column chromatography (silica gel, n-heptane/
EtOAc¼23/2) as a colourless solid (336 mg, 57%), mp¼69–71 ꢁC. 1H
3.1.7. Isopropyl-2-(2-chloro-2-phenylethyl)-6-hydroxy-4-methyl-
benzoate (6k). Starting with 1,3-bis(silyl enol ether) 5k (600 mg,
2.07 mmol), 1-hydroxy-1-phenyl-5-(trimethylsilyloxy)hex-4-en-3-
one 4a (576 mg, 2.07 mmol) and TiCl4 (0.22 mL, 2.07 mmol), 6k was
isolated after column chromatography (silica gel, n-heptane/
EtOAc¼24/1) as a slight yellow oil (275 mg, 40%). 1H NMR
NMR (300 MHz, CDCl3):
d
¼0.70 (t, 3H, J¼6.9 Hz, CH3),1.08–1.36 (m,
8H, 4CH2), 2.15 (s, 3H, CH3), 2.48 (t, 2H, J¼7.1 Hz, CH2), 2.84 (dd,1H,
J¼16.2, 3.4 Hz, CH2), 3.05 (dd,1H, J¼16.3, 12.3 Hz, CH2), 5.36 (dd,1H,
J¼12.3, 3.4 Hz, CH), 6.36 (s,1H, CHAr), 7.18–7.29 (m, 5H, Ph), 11.04 (s,
(300 MHz, CDCl3):
d
¼1.37 (d, 6H, J¼6.3 Hz, (CH3)2), 2.11 (s, 3H, CH3),
1H, OH); 13C NMR (75 MHz, CDCl3):
d
¼15.3, 21.3 (CH3), 23.8, 27.0,
3.48 (dd, 1H, J¼13.0, 7.5 Hz, CH2), 3.87 (dd, 1H, J¼13.0, 6.8 Hz, CH2),
5.04 (dd,1H, J¼13.0, 6.8 Hz, CH), 5.32–5.40 (m, 1H, OCH), 6.16 (s, 1H,
HAr), 6.66 (s, 1H, HAr), 7.24–7.30 (m, 5H, Ph), 11.45 (s, 1H, OH); 13C
30.0, 30.7, 32.9, 36.2 (CH2), 82.0 (CH),106.9 (CAr),120.7 (CHAr),127.2
(2CHAr), 129.8 (CAr), 129.9 (3CHAr), 136.8, 139.4, 146.7, 161.5 (CAr),
~
171.4 (C]O); IR (KBr):
n
¼3061 (w), 2921 (m), 2855 (m), 1658 (s),
NMR (75 MHz, CDCl3):
(OCH), 109.5 (CAr), 117.2, 125.8 (CHAr), 127.3 (2CHAr), 128.2 (CHAr),
d
¼21.3, 21.9 (CH3), 46.1 (CH2), 63.6 (CH), 70.1
1623 (s), 1573 (w), 1497 (w), 1450 (m), 1353 (m), 1243 (s), 1155 (s),
1085 (m),1057 (m),1013 (m), 927 (w), 860 (m), 804 (s), 751 (m), 699
(s), 604 (m), 537 (w) cmꢀ1; GC–MS (EI, 70 eV): m/z (%)¼338 (Mþ,
45), 320 (38), 321 (9), 305 (10), 291 (13), 251 (22), 250 (100), 249
(73), 179 (7), 178 (24); HRMS (EI): calcd for C22H26O3 [M]þ:
338.18765; found: 338.18805.
128.3 (2CHAr), 139.1, 141.0, 144.8, 163.1 (CAr), 170.5 (C]O); IR (neat):
~
n
¼2981 (w), 1650 (s), 1618 (m), 1571 (w), 1452 (m), 1367 (m), 1310
(m), 1259 (s), 1214 (s), 1090 (s), 1041 (w), 1090 (s), 909 (w), 852 (m),
738 (m), 695 (s) cmꢀ1; GC–MS (EI, 70 eV): m/z (%)¼334 (Mþ, 37Cl, 9),
332 (Mþ, 35Cl, 27), 296 (15), 254 (25), 237 (92), 208 (28), 179 (19),
165 (100), 125 (64), 91 (17); HRMS (EI): calcd for C19H21ClO3 ([M]þ,
3.1.11. 8-Hydroxy-6-methyl-7-nonyl-3-phenyl-3,4-dihydro-isochro-
man-1-one (7e). Starting with 1,3-bis(silyl enol ether) 5e (600 mg,
1.55 mmol), 1-hydroxy-1-phenyl-5-(trimethylsilyloxy)hex-4-en-3-
one 4a (430 mg, 1.55 mmol) and TiCl4 (0.17 mL, 1.55 mmol), 7e was
isolated after column chromatography (silica gel, n-heptane/
EtOAc¼23/2) as a yellow solid (311 mg, 53%), mp¼142–144 ꢁC. 1H
[
35Cl]): 332.11759; found: 332.11734.
3.1.8. Methyl-3-chloro-6-(2-chloro-2-(4-chlorophenyl)ethyl)-2-hy-
droxy-4-methylbenzoate (6ae). Starting with 1,3-bis(silyl enol
ether) 5p (600 mg, 2.03 mmol), 1-(4-chlorophenyl)-1-hydroxy-5-
(trimethylsilyloxy)hex-4-en-3-one 4g (636 mg, 2.03 mmol) and
TiCl4 (0.22 mL, 2.03 mmol), 6ae was isolated after column chro-
matography (silica gel, n-heptane/EtOAc¼24/1) as an orange solid
NMR (250 MHz, CDCl3):
d
¼0.81 (t, 3H, J¼7.3 Hz, CH3), 1.15–1.48 (m,
14H, 7CH2), 2.25 (s, 3H, CH3), 2.58 (t, 2H, J¼7.2 Hz, CH2), 2.95 (dd,
1H, J¼16.3, 3.4 Hz, CH2), 3.17 (dd, 1H, J¼16.3, 12.3 Hz, CH2), 5.47 (dd,
1H, J¼12.3, 3.4 Hz, CH), 6.47 (s, 1H, HAr), 7.28–7.39 (m, 5H, Ph), 11.14
(212 mg, 28%), mp¼135–137 ꢁC. 1H NMR (300 MHz, CDCl3):
¼2.25
d
(s, 3H, CH3), 3.49 (m, 2H, CH2), 3.90 (s, 3H, OCH3), 4.89 (m, 1H, CH),
(s, 1H, OH); 13C NMR (62 MHz, CDCl3):
d
¼14.0 20.1 (CH3), 22.6, 25.8,
6.40 (s, 1H, HAr), 7.19 (d, 2H, J¼8.5 Hz, 2HAr), 7.25 (d, 2H, J¼8.5 Hz,
27.2, 28.8, 29.3, 29.5, 29.9, 31.8, 35.0 (CH2), 80.8 (CH), 105.7 (CAr),
2HAr), 11.76 (s, 1H, OH); 13C NMR (75 MHz, CDCl3):
46.4 (CH2), 52.8 (OCH3), 62.8 (CH), 110.4, 121.9 (CAr), 126.0 (CHAr),
d
¼20.6 (CH3),
119.5 (CHAr), 126.0 (2CHAr), 128.6 (CAr), 128.7 (3CHAr), 135.5, 138.2,
~
145.5, 160.3 (CAr), 170.2 (C]O); IR (KBr):
n
¼2921 (m), 2852 (m),
128.3 (2CHAr), 128.7 (2CHAr), 134.2, 136.8, 139.8, 143.1, 158.5 (CAr),
1659 (m), 1623 (m), 1573 (w), 1502 (w), 1450 (m), 1354 (m), 1269
(m), 1240 (s), 1155 (s), 1086 (m), 1029 (m), 915 (w), 843 (m), 804
(m), 751 (m), 699 (m), 609 (m), 538 (w) cmꢀ1; GC–MS (EI, 70 eV):
m/z (%)¼380 (Mþ, 41), 363 (12), 362 (44), 291 (23), 251 (24), 250
(100), 249 (75), 178 (20); HRMS (EI): calcd for C20H20O3 [M]þ:
380.23460; found: 330.23488.
~
171.0 (C]O); IR (KBr):
n
¼2953 (w), 2848 (w), 1728 (w), 1655 (s),
1607 (m), 1549 (m), 1492 (m), 1434 (s), 1391 (m), 1307 (m), 1263 (s),
1213 (s),1091 (m),1065 (m),1013 (m), 956 (m), 870 (m), 804 (s), 769
(m), 722 (m), 651 (m), 579 (m) cmꢀ1; GC–MS (EI, 70 eV): m/z
(%)¼376 (Mþ, 37Cl, 5), 374 (Mþ, 37Cl35Cl, 16), 372 (Mþ, 35Cl, 16), 338
(10), 336 (13), 307 (19), 306 (32), 305 (27), 304 (40), 215 (32), 214
(12), 213 (100), 178 (12), 161 (17), 159 (27), 153 (16); HRMS (EI):
calcd for C17H15Cl3O3 ([M]þ, [35Cl]): 372.00813; found: 372.00788.
3.1.12. 7-Decyl-8-hydroxy-6-methyl-3-phenyl-3,4-dihydro-isochro-
man-1-one (7f). Starting with 1,3-bis(silyl enol ether) 5f (700 mg,
1.74 mmol), 1-hydroxy-1-phenyl-5-(trimethylsilyloxy)hex-4-en-3-
one 4a (485 mg, 1.74 mmol) and TiCl4 (0.19 mL, 1.74 mmol), 7f was
isolated after column chromatography (silica gel, n-heptane/
3.1.9. 7-Ethyl-8-hydroxy-6-methyl-3-phenyl-3,4-dihydro-isochro-
man-1-one (7c). Starting with 1,3-bis(silyl enol ether) 5c (500 mg,

I. Ullah et al. / Tetrahedron 66 (2010) 1874–1884
1879
EtOAc¼23/2) as a colourless solid (372 mg, 54%), mp¼127–128 ꢁC.
(0.22 mL, 2.07 mmol), 7m was isolated after column chromatog-
raphy (silica gel, n-heptane/EtOAc¼23/2) as a slight yellow solid
1H NMR (300 MHz, CDCl3):
d¼0.88 (t, 3H, J¼7.1 Hz, CH3), 1.22–1.38
(m, 16H, 8CH2), 2.32 (s, 3H, CH3), 2.65 (t, 2H, J¼8.2 Hz, CH2), 3.02
(dd,1H, J¼16.5, 3.2 Hz, CH2), 3.23 (dd,1H, J¼16.5,12.3 Hz, CH2), 5.54
(dd, 1H, J¼12.3, 3.2 Hz, CH), 6.51 (s, 1H, HAr), 7.25–7.46 (m, 5H, Ph),
(272 mg, 46%), mp¼126–128 ꢁC. 1H NMR (250 MHz, CDCl3):
¼2.11
d
(s, 3H, CH3), 2.22 (s, 3H, CH3), 2.99 (dd, 1H, J¼16.3, 3.8 Hz, CH2), 3.13
(dd, 1H, J¼16.3, 11.5 Hz, CH2), 5.77 (dd, 1H, J¼11.5, 3.8 Hz, CH), 6.49
(s, 1H, HAr), 6.97–7.05 (m, 1H, HAr), 7.11–7.17 (m, 1H, HAr), 7.23–7.32
(m, 1H, HAr), 7.49–7.56 (m, 1H, HAr), 11.11 (s, 1H, OH); 19F-NMR
11.21 (s, 1H, OH); 13C NMR (75 MHz, CDCl3):
d
¼14.1 (CH3), 20.1
(CH3), 22.6, 25.9, 27.3, 28.8, 29.3, 29.5, 29.6, 29.9, 31.8, 35.1 (CH2),
80.8 (CH), 105.7 (CAr), 119.5 (CHAr), 126.0 (2CHAr), 128.5 (CAr), 128.6
(3CHAr), 135.5, 138.2, 145.5, 160.3 (CAr), 170.2 (C]O); IR (KBr):
~
(282 MHz, CDCl3):
d
¼ꢀ118.8; 13C NMR (75 MHz, CDCl3):
¼11.1,
d
20.7 (CH3), 34.0 (JF,C¼1.0 Hz, CH2), 75.1 (JF,C¼3.3 Hz, CH), 105.9 (CAr),
115.5 (JF,C¼21.5 Hz), 119.3 (CHAr), 123.6 (CAr), 124.5 (JF,C¼3.5 Hz,
CHAr), 125.7 (JF,C¼12.5 Hz, CAr), 127.5 (JF,C¼3.1 Hz), 130.1
(JF,C¼8.7 Hz), (CHAr), 135.4, 146.2, 159.5 (JF,C¼247.3 Hz), 160.2 (CAr),
~
n
¼2920 (m), 2856 (w), 1665 (s), 1625 (m), 1414 (w), 1290 (s), 1246
(s), 1159 (s), 1115 (m), 1038 (w), 806 (s), 750 (s), 717 (s) cmꢀ; GC–MS
(EI, 70 eV): m/z (%)¼394 (Mþ, 67), 306 (46), 291 (18), 264 (100), 249
(15), 192 (19), 91 (11); HRMS (EI): calcd for C26H34O3 [M]þ:
394.17200; found: 394.17167.
170.1 (C]O); IR (KBr):
n
¼3049 (w), 2911 (w), 1650 (m), 1615 (m),
1573 (m),1496 (m),1451 (m),1408 (m),1351 (m),1266 (m),1240 (s),
1208 (m), 1152 (s), 1098 (s), 1034 (m), 915 (m), 831 (m), 795 (s), 744
(s), 680 (m), 607 (m), 542 (m) cmꢀ1; GC–MS (EI, 70 eV): m/z
(%)¼286 (Mþ, 58), 269 (18), 268 (100), 253 (19), 240 (18), 225 (14),
197 (19), 196 (14), 177 (7), 162 (9), 91 (10); HRMS (EI): calcd for
C17H15FO3 [M]þ: 286.09997; found: 286.10011. Anal. Calcd (%) for
C17H15FO3 (286.100): C 71.32, H 5.28; found: C 70.89, H 4.92.
3.1.13. 7-(But-3-enyl)-8-hydroxy-6-methyl-3-phenyl-3,4-dihydro-
isochroman-1-one (7h). Starting with 1,3-bis(silyl enol ether) 5h
(600 mg, 1.90 mmol), 1-hydroxy-1-phenyl-5-(trimethylsilyloxy)-
hex-4-en-3-one 4a (528 mg, 1.90 mmol) and TiCl4 (0.20 mL,
1.90 mmol), 7h was isolated after column chromatography (silica
gel, n-heptane/EtOAc¼23/2) as a yellow solid (251 mg, 43%),
mp¼86–87 ꢁC. 1H NMR (300 MHz, CDCl3):
d
¼2.20 (q, 2H, J¼8.2 Hz,
3.1.16. 3-(2,3-Dimethoxyphenyl)-8-hydroxy-6-methyl-3,4-dihydro-
isochroman-1-one (7n). Starting with 1,3-bis(silyl enol ether) 5l
(600 mg, 1.78 mmol), 1-(2,3-dimethoxyphenyl)-1-hydroxy-5-(tri-
methylsilyloxy)hex-4-en-3-one 4c (602 mg, 1.78 mmol) and TiCl4
(0.19 mL, 1.78 mmol), 7n was isolated after column chromatogra-
phy (silica gel, n-heptane/EtOAc¼23/2) as a yellow solid (212 mg,
CH2), 2.26 (s, 3H, CH3), 2.69 (t, 2H, J¼7.4, CH2), 2.95 (dd, 1H, J¼16.4,
3.2 Hz, CH2), 3.17 (dd, 1H, J¼16.4, 12.0 Hz, CH2), 4.88–5.02 (m,
2H,]CH2), 5.47 (dd, 1H, J¼12.0, 3.2 Hz, CH), 5.78–5.90 (m, 1H,
]CH), 6.48 (s, 1H, HAr), 7.26–7.40 (m, 5H, Ph), 11.16 (s, 1H, OH); 13
C
NMR (75 MHz, CDCl3):
(CH), 105.8 (CAr), 114.7 (]CH2), 119.6 (CHAr), 126.1 (2CHAr), 127.4
d
¼20.2 (CH3), 25.4, 32.8, 35.0 (CH2), 80.8
38%), mp¼142–144 ꢁC. 1H NMR (250 MHz, CDCl3):
¼2.26 (s, 3H,
d
(CAr), 128.7 (3CHAr), 135.9, 138.2 (CAr), 138.3 (]CH), 145.6, 160.4
CH3), 2.96 (dd,1H, J¼16.4, 3.4 Hz, CH2), 3.15 (dd,1H, J¼16.4, 11.9 Hz,
CH2), 3.79 (s, 3H, OCH3), 3.81 (s, 3H, OCH3), 5.81 (dd, 1H, J¼11.9,
3.4 Hz, CH), 6.47 (s, 1H, HAr), 6.66 (s, 1H, HAr), 6.82–6.89 (m, 1H,
J¼5.8, 3.8 Hz, HAr), 7.00–7.08 (d, 2H, J¼5.8, 3.8 Hz, HAr), 10.87 (s, 1H,
~
(CAr), 170.2 (C]O); IR (KBr):
n
¼3062 (w), 2940 (w), 1659 (s), 1622
(m), 1573 (m), 1537 (w), 1496 (m), 1415 (m), 1350 (m), 1287 (m),
1238 (s), 1162 (s), 1058 (m), 1006 (m), 908 (m), 843 (m), 800 (s), 755
(s), 697 (s), 586 (m) cmꢀ1; GC–MS (EI, 70 eV): m/z (%)¼308 (Mþ, 19),
268 (6), 267 (28), 250 (19), 249 (100), 178 (13). Anal. Calcd (%) for
C20H20O3 (308.141): C 77.90, H 6.54; found: C 77.64, H 6.86; HRMS
(EI): calcd for C20H20O3 [M]þ: 308.14128; found: 308.14097.
OH); 13C NMR (75 MHz, CDCl3):
(OCH3), 76.2 (CH), 106.0 (CAr), 112.6, 116.4, 118.5, 119.1, 124.4 (CHAr),
d
¼22.0 (CH3), 34.5 (CH2), 55.8, 61.0
131.9, 135.2, 139.5, 146.0, 152.5, 162.2 (CAr), 170.0 (C]O); IR (KBr):
~
n
¼2939 (w), 2837 (w), 1714 (s), 1670 (m), 1627 (m), 1579 (m), 1482
(m), 1358 (m), 1313 (m), 1266 (m), 1231 (s), 1145 (s), 1086 (m), 1002
(m), 907 (w), 799 (m), 745 (m), 696 (s), 620 (w), 580 (m) cmꢀ1; MS
(EI, 70 eV): m/z (%)¼314 (Mþ, 100), 296 (61), 281 (12), 268 (13), 253
(32), 225 (16), 165 (5), 148 (15) 91 (8). Anal. Calcd (%) for C18H18O5
(314.11): C 68.78, H 5.77; found: C 68.51, H 6.02.
3.1.14. 3-(2-Fluorophenyl)-8-hydroxy-6-methyl-3,4-dihydro-isochro-
man-1-one (7l). Starting with 1,3-bis(silyl enol ether) 5l (600 mg,
1.78 mmol), 1-(2-fluorophenyl)-1-hydroxy-5-(trimethylsilyloxy)-
hex-4-en-3-one 4b (527 mg, 1.78 mmol) and TiCl4 (0.19 mL,
1.78 mmol), 7l was isolated after column chromatography (silica
gel, n-heptane/EtOAc¼23/2) as a colourless solid (241 mg, 50%),
3.1.17. 3-(2,3-Dimethoxyphenyl)-8-hydroxy-6,7-dimethyl-3,4-dihy-
dro-isochroman-1-one (7o). Starting with 1,3-bis(silyl enol ether)
5m (600 mg, 2.07 mmol), 1-(2,3-dimethoxyphenyl)-1-hydroxy-5-
(trimethylsilyloxy)hex-4-en-3-one 4c (700 mg, 2.07 mmol) and
TiCl4 (0.22 mL, 2.07 mmol), 7o was isolated after column chroma-
tography (silica gel, n-heptane/EtOAc¼23/2) as a yellow solid
mp¼144–146 ꢁC. 1H NMR (250 MHz, CDCl3):
¼2.27 (s, 3H, CH3),
d
3.03 (dd, 1H, J¼16.5, 4.0 Hz, CH2), 3.16 (dd, 1H, J¼16.5, 11.7 Hz, CH2),
5.79 (dd, 1H, J¼11.7, 4.0 Hz, CH), 6.49 (s, 1H, HAr), 6.67 (s, 1H, HAr),
6.98–7.06 (m, 1H, HAr), 7.11–7.17 (m, 1H, HAr), 7.24–7.33 (m, 1H, HAr),
7.48–7.55 (m, 1H, HAr), 10.78 (s, 1H, OH); 19F-NMR (282 MHz,
CDCl3):
d
¼ꢀ118.7; 13C NMR (75 MHz, CDCl3):
d
¼21.0 (CH3), 33.2
(237 mg, 35%), mp¼141–142 ꢁC. 1H NMR (250 MHz, CDCl3):
¼2.11
d
(JF,C¼1.5 Hz, CH2), 73.9 (JF,C¼3.2 Hz, CH), 104.7 (CAr), 114.6
(JF,C¼21.1 Hz), 115.6, 118.2, 123.5 (JF,C¼3.6 Hz), (CHAr), 124.5
(JF,C¼12.4 Hz, CAr), 126.5 (JF,C¼3.2 Hz), 129.2 (JF,C¼8.3 Hz), (CHAr),
137.8, 147.1, 158.5 (JF,C¼247.5 Hz), 161.2 (CAr), 168.5 (C]O); IR (KBr):
~
(s, 3H, CH3), 2.22 (s, 3H, CH3), 2.94 (dd, 1H, J¼16.4, 3.5 Hz, CH2), 3.10
(dd, 1H, J¼16.3, 12.0 Hz, CH2), 3.79 (s, 3H, OCH3), 3.81 (s, 3H, OCH3),
5.80 (dd, 1H, J¼12.0, 3.5 Hz, CH), 6.47 (s, 1H, HAr), 6.82–6.89 (m, 1H,
J¼5.8, 3.8 Hz, HAr), 7.00–7.08 (d, 2H, J¼5.8, 3.8 Hz, HAr), 11.20 (s, 1H,
n
¼3073 (w), 2962 (w), 2909 (w), 1667 (s), 1630 (m), 1575 (m), 1492
OH); 13C NMR (75 MHz, CDCl3):
61.0 (OCH3), 76.3 (CH), 105.6 (CAr), 112.5, 118.5, 119.3 (CHAr), 123.4
d
¼11.0, 20.7 (CH3), 34.3 (CH2), 55.8,
(m), 1455 (m), 1366 (m), 1324 (m), 1273 (m), 1230 (s), 1205 (s), 1160
(m), 1088 (m), 1058 (s), 980 (m), 912 (m), 869 (m), 796 (s), 743 (s),
693 (s), 609 (m), 555 (w) cmꢀ1; GC–MS (EI, 70 eV): m/z (%)¼273
(16), 272 (Mþ, 91), 255 (17), 254 (100), 198 (12), 197 (25), 196 (10),
183 (33), 148 (25), 91 (18); HRMS (EI): calcd for C16H13FO3 [M]þ:
272.08432; found: 272.08445. Anal. Calcd (%) for C16H13FO3
(272.084): C 70.58, H 4.81; found: C 70.19, H 4.62.
(CAr), 124.4 (CHAr), 132.1, 136.0, 146.0, 152.4, 160.2 (CAr), 170.5
~
(C]O); IR (KBr):
n
¼3008 (w), 2923 (w), 2829 (w),1665 (s),1627 (m),
1587 (m), 1481 (m), 1416 (m), 1274 (s), 1223 (m), 1158 (m), 1084 (s),
1004 (s), 940 (m), 867 (m), 797 (s), 747 (s), 657 (m), 602 (m), 547 (m)
cmꢀ1; GC–MS (EI, 70 eV): m/z (%)¼328 (Mþ, 91), 311 (20), 310 (100),
295 (25), 280 (9), 279 (19), 267 (18), 239 (8), 91 (10); HRMS (EI):
calcd for C19H20O5 [M]þ: 328.13053; found: 328.13083. Anal. Calcd
(%) for C19H20O5 (328.131): C 69.50, H 6.14; found: C 68.51, H 6.17.
3.1.15. 3-(2-Fluorophenyl)-8-hydroxy-6,7-dimethyl-3,4-dihydro-iso-
chroman-1-one (7m). Starting with 1,3-bis(silyl enol ether) 5m
(600 mg, 2.07 mmol), 1-(2-fluorophenyl)-1-hydroxy-5-(trime-
thylsilyloxy)hex-4-en-3-one 4b (613 mg, 2.07 mmol) and TiCl4
3.1.18. 8-Hydroxy-6-methyl-3-(m-tolyl)-3,4-dihydro-isochroman-1-
one (7p). Starting with 1,3-bis(silyl enol ether) 5a (600 mg,

1880
I. Ullah et al. / Tetrahedron 66 (2010) 1874–1884
2.30 mmol), 1-hydroxy-1-(m-tolyl)-5-(trimethylsilyloxy)hex-4-en-
3-one 4d (672 mg, 2.30 mmol) and TiCl4 (0.25 mL, 2.30 mmol), 7p
was isolated after column chromatography (silica gel, n-heptane/
EtOAc¼23/2) as a yellow solid (260 mg, 42%), mp¼142–144 ꢁC. 1H
2.48 (t, 2H, J¼6.2 Hz, CH2), 2.83 (dd, 1H, J¼16.2, 3.2 Hz, CH2), 3.05
(dd, 1H, J¼16.2, 12.4 Hz, CH2), 5.33 (dd, 1H, J¼12.4, 3.2 Hz, CH),
6.36 (s, 1H, HAr), 6.99–7.16 (m, 4H, HAr), 11.04 (s, 1H, OH); 13C NMR
(75 MHz, CDCl3):
32.9, 36.3 (CH2), 82.1 (CH), 106.9 (CAr), 120.7, 124.2, 127.9, 129.6
d
¼13.5, 21.3, 22.6 (CH3), 23.8, 27.0, 30.0, 30.8,
NMR (300 MHz, CDCl3):
d
¼2.26 (s, 3H, CH3), 2.31 (s, 3H, CH3), 2.96
(dd, 1H, J¼16.7, 3.4 Hz, CH2), 3.18 (dd, 1H, J¼16.7, 12.0 Hz, CH2), 5.43
(dd, 1H, J¼12.0, 3.4 Hz, CH), 6.47 (s, 1H, HAr), 6.66 (s, 1H, HAr), 7.09–
7.25 (m, 4H, HAr), 10.84 (s, 1H, OH); 13C NMR (75 MHz, CDCl3):
(CHAr), 129.7 (CAr), 130.6 (CHAr), 136.9, 139.4, 139.6, 146.6, 161.5
~
(CAr), 171.5 (C]O); IR (KBr):
n
¼2922 (m), 2855 (w), 1661 (s), 1622
(m), 1573 (w), 1512 (w), 1435 (m), 1354 (m), 1292 (m), 1244 (s),
1162 (s), 1078 (m), 1013 (m), 972 (w), 909 (w), 842 (m), 788 (s),
700 (m), 605 (m) cmꢀ1; GC–MS (EI, 70 eV): m/z (%)¼352 (Mþ, 59),
335 (10), 334 (57), 319 (12), 265 (26), 264 (100), 263 (74), 249 (17),
192 (14), 191 (13); HRMS (EI): calcd for C23H28O3 [M]þ: 352.20330;
found: 352.20368.
d
¼21.4, 22.0 (CH3), 35.2 (CH2), 80.8 (CH), 105.9 (CAr), 116.5, 119.1,
123.1, 126.7, 128.6, 129.5 (CHAr), 138.0, 138.5, 139.1, 147.9, 162.2 (CAr),
~
169.7 (C]O); IR (KBr):
n
¼2921 (w), 1660 (m), 1631 (m), 1582 (s),
1486 (w), 1349 (m), 1274 (m), 1158 (m), 1092 (m), 976 (m), 847 (m),
698 (s) cmꢀ1; GC–MS (EI, 70 eV): m/z (%)¼268 (Mþ, 100), 250 (60),
249 (18), 222 (75), 194 (10), 179 (33), 178 (22), 148 (27), 91 (29).
Anal. Calcd (%) for C17H16O3 (268.31): C 76.10, H 6.01; found: C
75.98, H 6.32.
3.1.22. 8-Hydroxy-6-methyl-3-p-tolyl-3,4-dihydro-isochroman-1-
one (7t). Starting with 1,3-bis(silyl enol ether) 5a (600 mg,
2.30 mmol), 1-hydroxy-1-(p-tolyl)-5-(trimethylsilyloxy)hex-4-en-
3-one 4e (672 mg, 2.30 mmol) and TiCl4 (0.25 mL, 2.30 mmol), 7t
was isolated after column chromatography (silica gel, n-heptane/
EtOAc¼23/2) as a light yellow solid (252 mg, 41%), mp¼111–113 ꢁC.
3.1.19. 8-Hydroxy-6,7-dimethyl-3-(m-tolyl)-3,4-dihydro-isochro-
man-1-one (7q). Starting with 1,3-bis(silyl enol ether) 5m (600 mg,
2.07 mmol), 1-hydroxy-1-(m-tolyl)-5-(trimethylsilyloxy)-hex-4-
en-3-one 4d (605 mg, 2.07 mmol) and TiCl4 (0.22 mL, 2.07 mmol),
7q was isolated after column chromatography (silica gel, n-hep-
tane/EtOAc¼23/2) as a yellow solid (262 mg, 45%), mp¼146–
1H NMR (300 MHz, CDCl3):
d
¼2.34 (s, 3H, CH3), 2.38 (s, 3H, CH3),
3.04 (dd,1H, J¼16.4, 3.2 Hz, CH2), 3.25 (dd,1H, J¼16.4,12.2 Hz, CH2),
5.51 (dd, 1H, J¼12.2, 3.2 Hz, CH), 6.56 (s, 1H, HAr), 6.73 (s, 1H, HAr),
7.22 (d, 2H, J¼8.0 Hz, HAr), 7.33 (d, 2H, J¼8.0 Hz, HAr), 10.95 (s, 1H,
148 ꢁC. 1H NMR (300 MHz, CDCl3):
CH3), 2.25 (s, 3H, CH3), 2.89 (dd, 1H, J¼16.3, 3.3 Hz, CH2), 3.11 (dd,
1H, J¼16.3, 12.0 Hz, CH2), 5.36 (dd, 1H, J¼12.0, 3.3 Hz, CH), 6.42 (s,
1H, HAr), 7.03 (m, 4H, HAr), 11.12 (s, 1H, OH); 13C NMR (75 MHz,
d
¼2.05 (s, 3H, CH3), 2.17 (s, 3H,
OH); 13C NMR (75 MHz, CDCl3):
d¼21.1, 22.0 (CH3), 35.1 (CH2), 80.7
(CH), 105.9 (CAr), 116.5, 119.1 (CHAr), 127.9 (2CHAr), 129.6 (2CHAr),
~
135.1, 138.7, 139.1, 147.9, 162.2 (CAr), 169.8 (C]O); IR (KBr):
n
¼2919
CDCl3):
d
¼11.0, 20.7, 21.4 (CH3), 35.0 (CH2), 80.9 (CH), 105.6 (CAr),
(w), 1660 (s), 1628 (s), 1578 (m), 1516 (w), 1349 (m), 1268 (m), 1230
(s), 1202 (s), 1157 (m), 1095 (s), 1058 (s), 975 (m), 854 (s), 814 (s),
732 (m), 695 (s) cmꢀ1; EIMS (EI, 70 eV): m/z (%)¼268 (Mþ, 100), 250
(75), 222 (78),179 (23), 148 (17) 91 (15). Anal. Calcd (%) for C17H16O3
(268.31): C 76.10, H 6.01; found: C 75.98, H 6.32.
119.2, 123.1, 126.7, 128.5, 129.4 (CHAr), 135.6, 138.1, 138.4, 139.9,
~
146.0, 160.0 (CAr), 170.2 (C]O); IR (KBr):
n
¼2918 (w), 2859 (w),
1659 (m), 1573 (m), 1445(m), 1349 (m), 1270 (m), 1197 (m), 1097
(m), 1019 (m), 955 (m), 861 (s), 800 (m), 758 (s), 712 (s), 610 (m),
564 (m) cmꢀ1; MS (EI, 70 eV): m/z (%)¼282 (Mþ, 75), 265 (20), 264
(100), 263 (18), 249 (45), 236 (30), 221 (14), 193 (15), 178 (15), 162
(9), 91 (16). Anal. Calcd (%) for C18H18O3 (282.12): C 76.57, H 6.43;
found: C 76.54, H 6.44.
3.1.23. 8-Hydroxy-6,7-dimethyl-3-(p-tolyl)-3,4-dihydro-isochro-
man-1-one (7u). Starting with 1,3-bis(silyl enol ether) 5b (600 mg,
2.18 mmol), 1-hydroxy-1-p-tolyl-5-(trimethylsilyloxy)hex-4-en-3-
one 4e (640 mg, 2.18 mmol) and TiCl4 (0.24 mL, 2.18 mmol), 7u was
isolated after column chromatography (silica gel, n-heptane/
EtOAc¼23/2) as an orange solid (265 mg, 43%), mp¼107–109 ꢁC. 1H
3.1.20. 7-Ethyl-8-hydroxy-6-methyl-3-(m-tolyl)-3,4-dihydro-iso-
chroman-1-one (7r). Starting with 1,3-bis(silyl enol ether) 5c
(600 mg, 2.07 mmol), 1-hydroxy-1-(m-tolyl)-5-(trimethylsilyloxy)-
hex-4-en-3-one 4d (605 mg, 2.07 mmol) and TiCl4 (0.22 mL,
2.07 mmol), 7r was isolated after column chromatography (silica
gel, n-heptane/EtOAc¼23/2) as a yellow solid (296 mg, 54%),
NMR (300 MHz, CDCl3):
d
¼2.16 (s, 3H, CH3), 2.28 (s, 3H, CH3), 2.36
(s, 3H, CH3), 2.99 (dd, 1H, J¼16.1, 3.2 Hz, CH2), 3.21 (dd, 1H, J¼16.1,
12.1 Hz, CH2), 5.49 (dd, 1H, J¼12.1, 3.2 Hz, CH), 6.54 (s, 1H, HAr), 7.20
(d, 2H, J¼7.9 Hz, HAr), 7.32 (d, 2H, J¼7.9 Hz, HAr), 11.26 (s, 1H, OH);
mp¼121–123 ꢁC.1H NMR (300 MHz, CDCl3):
d
¼1.06 (t, 3H, J¼7.5 Hz,
13C NMR (75 MHz, CDCl3):
d
¼11.0, 20.7, 21.1 (CH3), 34.8 (CH2), 80.8
CH3), 2.26 (s, 3H, CH3), 2.31 (s, 3H, CH3), 2.63 (q, 2H, J¼7.5 Hz, CH2),
2.93 (dd, 1H, J¼16.4, 3.3 Hz, CH2), 3.15 (dd, 1H, J¼16.4, 12.4 Hz, CH2),
5.42 (dd, 1H, J¼12.4, 3.3 Hz, CH), 6.46 (s, 1H, HAr), 7.09–7.22 (m, 4H,
(CH), 105.6 (CAr), 119.2 (CHAr), 123.4 (CAr), 126.1 (2CHAr), 129.3
(2CHAr), 135.2, 135.6, 138.6, 146.0, 160.1 (CAr), 170.3 (C]O); IR (KBr):
~
n
¼2920 (w), 1662 (s), 1575 (w), 1517 (m), 1449 (m), 1367 (m), 1276
HAr), 11.14 (s, 1H, OH); 13C NMR (75 MHz, CDCl3):
(CH2), 19.9, 21.4 (CH3), 35.0 (CH2), 80.9 (CH), 105.8 (CAr), 119.5, 123.1,
d
¼13.1 (CH3), 19.0
(s), 1254 (s), 1160 (s), 1098 (m), 1017 (m), 965 (w), 859 (m), 809 (s),
750 (s), 695 (m) cmꢀ1; GC–MS (EI, 70 eV): m/z (%)¼282 (Mþ, 65),
264 (100), 249 (34), 236 (24), 221 (15), 193 (16), 178 (20), 165 (8), 91
(21), 77 (9); HRMS (EI): calcd for C18H18O3 [M]þ: 282.12505; found:
282.12562.
126.7,128.5,129.4 (CHAr),129.7,135.7,138.2,138.4,145.2,160.2 (CAr),
~
170.2 (C]O); IR(KBr):
n
¼2963(w), 2870 (w),1660(s),1624(m),1572
(w), 1504 (w), 1442 (m), 1415 (m), 1349 (m), 1283 (m), 1238 (s), 1160
(s),1107 (m),1064 (m),1033 (m), 977 (m), 912 (m), 858 (w), 805 (m),
755 (s), 706 (s), 611 (m), 573 (s) cmꢀ1; GC–MS (EI, 70 eV): m/z
(%)¼296 (Mþ, 60), 279 (21), 278 (100), 264 (11), 263 (56), 235 (9),192
(9), 191 (9), 91 (8); HRMS (EI): calcd for C19H20O3 [M]þ: 296.14070;
found: 296.14101.
3.1.24. 7-Butyl-8-hydroxy-6-methyl-3-(p-tolyl)-3,4-dihydro-isochro-
man-1-one (7v). Starting with 1,3-bis(silyl enol ether) 5n (700 mg,
2.21 mmol), 1-hydroxy-1-(p-tolyl)-5-(trimethylsilyloxy)hex-4-en-
3-one 4e (646 mg, 2.21 mmol) and TiCl4 (0.24 mL, 2.21 mmol), 7v
was isolated after column chromatography (silica gel, n-heptane/
EtOAc¼23/2) as a yellow solid (444 mg, 62%), mp¼83–84 ꢁC. 1H
3.1.21. 7-Hexyl-8-hydroxy-6-methyl-3-(m-tolyl)-3,4-dihydro-iso-
chroman-1-one (7s). Starting with 1,3-bis(silyl enol ether) 5d
(600 mg, 1.74 mmol), 1-hydroxy-1-(m-tolyl)-5-(trimethylsilyloxy)-
hex-4-en-3-one 4d (510 mg, 1.74 mmol) and TiCl4 (0.19 mL,
1.74 mmol), 7s was isolated after column chromatography (silica
gel, n-heptane/EtOAc¼23/2) as a slight yellow solid (356 mg, 58%),
NMR (300 MHz, CDCl3):
d
¼0.92 (t, 3H, J¼7.1 Hz, CH3), 1.36–1.47 (m,
4H, 2CH2), 2.30 (s, 3H, CH3), 2.34 (s, 3H, CH3), 2.63 (t, 2H, J¼8.1 Hz,
CH2), 2.97 (dd,1H, J¼16.5, 3.2 Hz, CH2), 3.20 (dd,1H, J¼16.5, 12.1 Hz,
CH2), 5.48 (dd, 1H, J¼12.1, 3.2 Hz, CH), 6.51 (s, 1H, HAr), 7.26 (d, 2H,
J¼8.0 Hz, HAr), 7.31 (d, 2H, J¼8.0 Hz, HAr), 11.21 (s, 1H, OH); 13C NMR
mp¼71–73 ꢁC. 1H NMR (300 MHz, CDCl3):
d
¼0.72 (t, 3H, J¼6.9 Hz,
(75 MHz, CDCl3):
(CH2), 80.8 (CH), 105.8 (CAr), 119.5 (CHAr), 126.1 (2CHAr), 128.5 (CAr),
d
¼14.0 (CH3), 20.1, 21.2 (CH3), 23.0, 25.6, 31.0, 35.0
CH3), 1.08–1.36 (m, 8H, 4CH2), 2.15 (s, 3H, CH3), 2.21 (s, 3H, CH3),

I. Ullah et al. / Tetrahedron 66 (2010) 1874–1884
1881
129.3 (2CHAr), 135.3, 135.7, 138.6, 145.5, 160.3 (CAr), 170.3 (C]O); IR
(%)¼372 (Mþ, 20), 281 (20), 264 (19), 263 (100), 192 (9),191 (7), 91
(11), 77 (3). Anal. Calcd (%) for C25H26O3 (372.17): C 80.80, H 6.78;
found: C 80.72, H 6.53.
~
(KBr):
n
¼2920 (m), 2856 (w), 1665 (s), 1625 (m), 1414 (w), 1290 (s),
1246 (s), 1159 (s), 1115 (m), 1038 (w), 806 (s), 750 (s), 717 (s) cmꢀ1
;
GC–MS (EI, 70 eV): m/z (%)¼324 (Mþ, 67), 306 (46), 291 (18), 264
(100), 249 (15), 192 (19), 91 (11); HRMS (EI): calcd for C21H24O3
[M]þ: 324.17200; found: 324.17117.
3.1.28. 3-(4-Ethylphenyl)-8-hydroxy-6-methyl-3,4-dihydro-isochro-
man-1-one (7z). Starting with 1,3-bis(silyl enol ether) 5j (600 mg,
2.18 mmol), 1-(4-ethylphenyl)-1-hydroxy-5-(trimethylsilyloxy)hex-
4-en-3-one 4f (668 mg, 2.18 mmol) and TiCl4 (0.24 mL, 2.18 mmol),
7z was isolated after column chromatography (silica gel, n-heptane/
EtOAc¼23/2) as a yellow solid (295 mg, 48%), mp¼103–104 ꢁC. 1H
3.1.25. 7-Allyl-8-hydroxy-6-methyl-3-(p-tolyl)-3,4-dihydro-isochro-
man-1-one (7w). Starting with 1,3-bis(silyl enol ether) 5g (600 mg,
1.99 mmol), 1-hydroxy-1-(p-tolyl)-5-(trimethylsilyloxy)hex-4-en-
3-one 4e (582 mg, 1.99 mmol) and TiCl4 (0.22 mL, 1.99 mmol), 7w
was isolated after column chromatography (silica gel, n-heptane/
EtOAc¼23/2) as a yellow solid (215 mg, 35%), mp¼93–94 ꢁC. 1H
NMR (300 MHz, CDCl3):
d
¼1.24 (t, 3H, J¼7.6 Hz, CH3), 2.34 (s, 3H,
CH3), 2.67 (q, 2H, J¼7.6 Hz, CH2), 3.04 (dd, 1H, J¼16.6, 3.2 Hz, CH2),
3.21 (dd, 1H, J¼16.6, 12.1 Hz, CH2), 5.51 (dd, 1H, J¼12.1, 3.2 Hz, CH),
6.55 (s, 1H, HAr), 6.73 (s, 1H, HAr), 7.21 (d, 2H, J¼8.1 Hz, HAr), 7.36 (d,
2H, J¼8.1 Hz, HAr), 10.93 (s, 1H, OH); 13C NMR (75 MHz, CDCl3):
NMR (300 MHz, CDCl3):
d
¼2.29 (s, 3H, CH3), 2.35 (s, 3H, CH3), 2.99
(dd, 1H, J¼16.6, 3.3 Hz, CH2), 3.21 (dd, 1H, J¼16.6, 12.0 Hz, CH2), 3.42
(d, 2H, J¼5.9 Hz, CH2), 4.81–5.11 (m, 2H, CH2), 5.49 (dd, 1H, J¼12.0,
3.3 Hz, CH), 5.84–5.97 (m, 1H, CH), 6.54 (s, 1H, HAr), 7.19 (d, 2H,
J¼8.1 Hz, HAr), 7.31 (d, 2H, J¼8.1 Hz, HAr), 11.25 (s, 1H, OH); 13C NMR
d
¼15.5, 22.1 (CH3), 28.6, 35.1 (CH2), 80.7 (CH),106.0 (CAr),116.5,119.1
(CHAr), 126.2 (2CHAr), 128.2 (2CHAr), 135.3, 139.1, 145.1, 147.9, 162.2
~
(CAr),169.8 (C]O); IR (KBr):
n
¼2966 (w),1660 (s),1576 (m),1497 (w),
(75 MHz, CDCl3):
105.9 (CAr), 114.8 (]CH2), 119.6 (CHAr), 123.3 (CAr), 125.0 (2CHAr),
129.6 (2CHAr), 135.1 (]CH), 135.2, 136.5, 138.6, 146.3, 160.1 (CAr),
d
¼20.1, 21.2 (CH3), 29.8, 34.9 (CH2), 80.8 (CH),
1347 (m), 1279 (m), 1201 (s), 1058 (s), 1008 (w), 913 (w), 829 (s), 769
(w), 700 (s) cmꢀ1; GC–MS (EI, 70 eV): m/z (%)¼282 (Mþ, 100), 265
(15), 264 (92), 236 (28), 221 (62), 178 (11) 148 (17), 91 (10), 77 (4).
Anal. Calcd (%) for C18H18O3 (282.45): C 76.57, H 6.43; found: C 76.46,
H 6.12.
~
n
170.2 (C]O); IR (KBr): ¼3061 (w), 2904 (w), 1659 (s), 1432 (m),
1352 (m), 1271 (s), 1239 (s), 1153 (s), 1070 (m), 1008 (m), 912 (m),
824 (s) 756 (s), 720 (m) cmꢀ1; GC–MS (EI, 70 eV): m/z (%)¼308 (Mþ,
100), 290 (82), 275 (86), 247 (28), 203 (19), 173 (14), 115 (21), 91
(22); HRMS (EI): calcd for C20H20O3 [M]þ: 308.14070; found:
308.14130.
3.1.29. 3-(4-Chlorophenyl)-8-hydroxy-6-methyl-3,4-dihydro-iso-
chroman-1-one (7aa). Starting with 1,3-bis(silyl enol ether) 5a
(600 mg, 2.30 mmol), 1-(4-chlorophenyl)-1-hydroxy-5-(trime-
thylsilyloxy)hex-4-en-3-one 4g (720 mg, 2.30 mmol) and TiCl4
(0.25 mL, 2.30 mmol), 7aa was isolated after column chromatog-
raphy (silica gel, n-heptane/EtOAc¼23/2) as a colourless solid
3.1.26. 7-(But-3-enyl)-8-hydroxy-6-methyl-3-(p-tolyl)-3,4-dihydro-
isochroman-1-one (7x). Starting with 1,3-bis(silyl enol ether) 5h
(600 mg,1.90 mmol), 1-hydroxy-1-p-tolyl-5-(trimethylsilyloxy)hex-
4-en-3-one 4e (555 mg, 1.90 mmol) and TiCl4 (0.20 mL, 1.90 mmol),
7x was isolated after column chromatography (silica gel, n-heptane/
EtOAc¼23/2) as a light orange solid (234 mg, 38%), mp¼98–99 ꢁC.
(365 mg, 55%), mp¼115–116 ꢁC. 1H NMR (300 MHz, CDCl3):
¼2.34
d
(s, 3H, CH3), 3.04 (dd, 1H, J¼16.4, 3.6 Hz, CH2), 3.21 (dd, 1H, J¼16.4,
11.8 Hz, CH2), 5.53 (dd, 1H, J¼11.8, 3.6 Hz, CH), 6.56 (s, 1H, HAr), 6.74
(s, 1H, HAr), 7.38–7.40 (m, 4H, HAr), 10.85 (s, 1H, OH); 13C NMR
1H NMR (300 MHz, CDCl3):
d
¼2.31 (s, 3H, CH3), 2.35 (s, 3H, CH3),
(75 MHz, CDCl3):
116.7, 119.1 (CHAr), 127.4 (2CHAr), 128.9 (2CHAr), 134.6, 136.6, 138.6,
d
¼22.0 (CH3), 35.1 (CH2), 79.8 (CH), 105.8 (CAr),
2.75 (t, 2H, J¼7.7 Hz, CH2), 2.96 (dd,1H, J¼16.6, 3.3 Hz, CH2), 3.19 (dd,
1H, J¼16.6, 12.2 Hz, CH2), 4.95–5.07 (m, 2H, CH2), 5.46 (dd, 1H,
J¼12.2, 3.3 Hz, CH2), 5.85–5.96 (m, 1H, ]CH), 6.53 (s, 1H, HAr), 7.20
(d, 2H, J¼8.0 Hz, HAr), 7.31 (d, 2H, J¼8.0 Hz, HAr), 11.25 (s, 1H, OH);
~
148.2, 162.2 (CAr), 169.4 (C]O); IR (KBr):
n
¼3070 (w), 2959 (w),
1673 (s), 1577 (m), 1491 (m), 1409 (m), 1360 (m), 1276 (m), 1229 (s),
1160 (m), 1085 (s), 1010 (m), 968 (w), 914 (m), 839 (s), 797 (s), 730
(s), 692 (s) cmꢀ1; GC–MS (EI, 70 eV): m/z (%)¼290 (Mþ, 37Cl, 26),
288 (Mþ, 35Cl, 87), 270 (100), 242 (45), 207 (21), 179 (39), 148 (26),
91 (12); HRMS (EI): calcd for C16H13ClO3 ([M]þ, [35Cl]): 288.06442;
found: 288.064851.
13C NMR (75 MHz, CDCl3):
80.9 (CH–O), 105.9 (CAr), 114.6 (]CH2), 119.6 (CHAr), 126.5 (2CHAr),
d
¼20.3, 21.2 (CH3), 26.0, 32.8, 35.0 (CH2),
127.4 (CAr), 129.4 (2CHAr), 135.3, 136.1 (CAr), 138.4 (]CH), 138.6,
~
145.6, 160.4 (CAr),170.3 (C]O); IR (KBr):
n
¼3079 (w), 2953 (w),1656
(s), 1573 (w), 1514 (m), 1444 (m), 1350 (m), 1241 (s), 1158 (s), 1072
(m), 1017 (m), 906 (m), 815 (s), 745 (s), 652 (w), 599 (m), 526 (m)
cmꢀ1; GC–MS (EI, 70 eV): m/z (%)¼322 (Mþ, 19), 304 (3), 281 (15),
264 (19), 263 (100), 192 (9), 191 (7), 91 (4), 77 (2); HRMS (EI): calcd
for C21H22O3 [Mþ]: 322.15635; found: 322.15602.
3.1.30. 3-(4-Chlorophenyl)-8-hydroxy-6,7-dimethyl-3,4-dihydro-iso-
chroman-1-one (7ab). Starting with 1,3-bis(silyl enol ether) 5b
(500 mg, 1.82 mmol), 1-(4-chlorophenyl)-1-hydroxy-5-(trimethyl-
silyloxy)hex-4-en-3-one 4g (570 mg, 1.82 mmol) and TiCl4
(0.20 mL, 1.82 mmol), 7ab was isolated after column chromatogra-
phy (silica gel, n-heptane/EtOAc¼23/2) as a white solid (275 mg,
3.1.27. 8-Hydroxy-6-methyl-7-phenethyl-3-(p-tolyl)-3,4-dihydro-
isochroman-1-one (7y). Starting with 1,3-bis(silyl enol ether) 5o
(600 mg, 1.64 mmol), 1-hydroxy-1-p-tolyl-5-(trimethylsilyloxy)-
hex-4-en-3-one 4e (480 mg, 1.64 mmol) and TiCl4 (0.18 mL,
1.64 mmol), 7y was isolated after column chromatography (silica
gel, n-heptane/EtOAc¼23/2) as a colourless solid (245 mg, 40%),
50%), mp¼125–126 ꢁC. 1H NMR (300 MHz, CDCl3):
¼2.17 (s, 3H,
d
CH3), 2.29 (s, 3H, CH3), 3.04 (dd, 1H, J¼16.3, 3.5 Hz, CH2), 3.18 (dd,
1H, J¼16.3,11.8 Hz, CH2), 5.51 (dd,1H, J¼11.8, 3.5 Hz, CH), 6.55 (s,1H,
HAr), 7.37–7.39 (m, 4H, HAr), 11.18 (s, 1H, OH); 13C NMR (75 MHz,
CDCl3):
d
¼11.1, 20.7 (CH3), 34.9 (CH2), 80.0 (CH), 105.4 (CAr), 119.3
mp¼151–152 ꢁC. 1H NMR (300 MHz, CDCl3):
d
¼2.19 (s, 3H, CH3),
(CHAr), 123.7 (CAr), 127.4 (2CHAr), 128.9 (2CHAr), 134.5, 135.1, 136.7,
~
2.36 (s, 3H, CH3), 2.81 (t, 2H, J¼4.5 Hz, CH2), 2.93 (t, 2H, J¼4.5 Hz,
CH2), 2.99 (dd, 1H, J¼16.6, 3.2 Hz, CH2), 3.22 (dd, IH, J¼16.6, 12.2 Hz,
CH2), 5.49 (dd, 1H, J¼12.2, 3.2 Hz CH), 6.51 (s, 1H, HAr), 7.19–7.34 (m,
146.2,160.2 (CAr),169.9 (C]O); IR (KBr):
n
¼3152 (w), 2920 (w),1651
(s), 1623 (m), 1574 (w), 1491 (m), 1354 (m), 1273 (m), 1215 (m), 1160
(s), 1074 (s), 964 (m), 872 (m), 815 (s), 718 (m) cmꢀ1; GC–MS (EI,
70 eV): m/z (%)¼304 (Mþ, 37Cl,17), 302 (Mþ, 35Cl, 52), 284 (100), 269
(17), 256 (15), 249 (26), 241 (11), 193 (12), 178 (24), 165 (8), 91 (13),
77 (12); HRMS (EI): calcd for C17H15ClO3 ([M]þ, [35Cl]): 302.07042;
found: 302.070344.
9H, HAr), 11.30 (s, 1H, OH); 13C NMR (75 MHz, CDCl3):
d¼20.1, 21.2
(CH3), 28.4, 34.9, 35.0 (CH2), 80.8 (CH), 105.9 (CAr), 119.6, 125.9
(CHAr), 126.1 (2CHAr), 127.3 (CAr), 128.3 (2CHAr), 128.5 (2CHAr), 129.4
(2CHAr), 135.3, 136.2, 138.7, 142.2, 145.7, 160.4 (CAr), 170.3 (C]O); IR
~
(KBr):
n
¼3027 (w), 2953 (w), 1663 (s), 1573 (w), 1516 (m), 1449 (m),
1361 (m), 1288 (s), 1247 (s), 1160 (s), 1081 (m), 1016 (m), 968 (w),
3.1.31. 3-(4-Chlorophenyl)-7-ethyl-8-hydroxy-6-methyl-3,4-dihy-
dro-isochroman-1-one (7ac). Starting with 1,3-bis(silyl enol ether)
918 (w), 858 (m), 751 (s), 694 (s) cmꢀ1; GC–MS (EI, 70 eV): m/z

1882
I. Ullah et al. / Tetrahedron 66 (2010) 1874–1884
5c (600 mg, 2.07 mmol), 1-(4-chlorophenyl)-1-hydroxy-5-(trime-
thylsilyloxy)hex-4-en-3-one 4g (648 mg, 2.07 mmol) and TiCl4
(0.22 mL, 2.07 mmol), 7ac was isolated after column chromatog-
raphy (silica gel, n-heptane/EtOAc¼23/2) as a brownish solid
temperature for 6–14 h. After completion of the reaction (TLC
control), THF was removed in vacuo. The residue was purified
by chromatography (silica gel, heptane/ethyl acetate¼23/2) to
give 7.
(347 mg, 53%), mp¼110–112 ꢁC. 1H NMR (300 MHz, CDCl3):
¼1.06
d
(t, 3H, J¼7.4 Hz, CH3), 2.26 (s, 3H, CH3), 2.63 (q, 2H, J¼7.4 Hz, CH2),
2.94 (dd, 1H, J¼16.4, 3.2 Hz, CH2), 3.11 (dd, 1H, J¼16.4, 12.0 Hz, CH2),
5.44 (dd, 1H, J¼12.0, 3.2 Hz, CH), 6.47 (s, 1H, HAr), 7.31–7.33 (m, 4H,
3.1.35. 8-Hydroxy-6-methyl-3-phenyl-3,4-dihydro-isochroman-1-
one (7a). Starting with 6a (190 mg, 0.62 mmol) and silica gel
(Merck silica gel 60, 0.063–0.200 mm, 70–230 mesh, 1.5 g), 7a was
isolated after column chromatography (silica gel, n-heptane/
EtOAc¼23/2) as a white solid (110 mg, 69%), mp¼125–126 ꢁC. 1H
HAr), 11.07 (s, 1H, OH). 13C NMR (75 MHz, CDCl3):
(CH2), 18.9 (CH3), 33.9 (CH2), 79.0 (CH), 104.6 (CAr), 118.6 (CHAr),
d
¼12.0 (CH3), 18.0
126.4 (2CHAr), 127.9 (2CHAr), 128.9, 133.5, 134.2, 135.7, 144.4, 159.2
NMR (300 MHz, CDCl3):
d
¼2.34 (s, 3H, CH3), 3.07 (dd, 1H, J¼16.5,
~
(CAr), 168.9 (C]O); IR (KBr):
n
¼2930 (m), 2871 (w), 1658 (s), 1620
3.3 Hz, CH2), 3.27 (dd,1H, J¼16.5,12.0 Hz, CH2), 5.56 (dd,1H, J¼12.0,
(m), 1493 (m), 1417 (m), 1359 (m), 1274 (m), 1236 (s), 1151 (s), 1062
(m), 1012 (m), 917 (m), 802 (s), 747 (s), 682 (m), 606 (s) cmꢀ1; GC–
MS (EI, 70 eV): m/z (%)¼318 (Mþ, 37Cl, 15), 316 (Mþ, 35Cl, 49), 300
(34), 299 (22), 298 (100), 285 (14), 283 (44), 191 (11), 91 (11); HRMS
3.3 Hz, CH), 6.56 (s, 1H, HAr), 6.74 (s, 1H, HAr), 7.39–7.45 (m, 5H, Ph),
10.92 (s, 1H, OH); 13C NMR (75 MHz, CDCl3):
d¼22.0 (CH3), 35.2
(CH2), 80.7 (CH), 105.9 (CAr), 116.5, 119.1 (CHAr), 126.1 (2CHAr), 128.7
(CHAr),128.8 (2CHAr),138.0,139.0,148.1,162.2 (CAr),169.7 (C]O); IR
(EI): calcd for C18H17ClO3 ([M]þ,
316.08635.
[
35Cl]): 316.08607; found:
(KBr):
n
¼3089 (w), 1652 (s), 1455 (m), 1277 (m), 1097 (s), 1060 (s),
~
912 (w), 845 (s), 798 (s), 699 (s) cmꢀ1; GC–MS (EI, 70 eV): m/z
(%)¼254 (Mþ, 100), 236 (69), 208 (61), 179 (40), 165 (51), 148 (31),
91 (28), 77 (22). Anal. Calcd (%) for C16H14O3 (254.28): C 75.57, H
5.55; found: C 75.11, H 5.56.
3.1.32. 3-(4-Chlorophenyl)-7-hexyl-8-hydroxy-6-methyl-3,4-dihy-
dro-isochroman-1-one (7ad). Starting with 1,3-bis(silyl enol ether)
5d (600 mg, 1.74 mmol), 1-(4-chlorophenyl)-1-hydroxy-5-(trime-
thylsilyloxy)hex-4-en-3-one 4g (545 mg, 1.74 mmol) and TiCl4
(0.19 mL, 1.74 mmol), 7ad was isolated after column chromatogra-
phy (silica gel, n-heptane/EtOAc¼23/2) as a viscous orange oil
3.1.36. 8-Hydroxy-6,7-dimethyl-3-phenyl-3,4-dihydro-isochroman-
1-one (7b). Starting with 6b (160 mg, 0.50 mmol) and silica gel
(Merck silica gel 60, 0.063–0.200 mm, 70–230 mesh, 1.5 g), 7b was
isolated after column chromatography (silica gel, n-heptane/
EtOAc¼23/2) as a light yellow solid (65 mg, 48%), mp¼99–100 ꢁC.
(357 mg, 55%). 1H NMR (300 MHz, CDCl3):
d
¼0.72 (t, 3H, J¼6.9 Hz,
CH3), 1.08–1.35 (m, 8H, 4CH2), 2.15 (s, 3H, CH3), 2.48 (t, 2H, J¼7.1 Hz,
CH2), 2.84 (dd, 1H, J¼16.2, 3.4, CH2), 3.01 (dd, 1H, J¼16.2, 12.0 Hz,
CH2), 5.34 (dd, 1H, J¼12.0, 3.4 Hz, CH), 6.36 (s, 1H, HAr), 7.20–7.22
1H NMR (300 MHz, CDCl3):
d
¼2.18 (s, 3H, CH3), 2.25 (s, 3H, CH3),
3.04 (dd, 1H, J¼16.3, 3.4 Hz, CH2), 3.24 (dd, 1H, J¼16.3, 12.2 Hz,
(m, 4H, HAr), 10.97 (s, 1H, OH); 13C NMR (62 MHz, CDCl3):
d¼15.2,
CH2), 5.54 (dd, 1H, J¼12.2, 3.4 Hz, CH), 6.56 (s, 1H, HAr), 7.37–7.43
21.3 (CH3), 23.8, 27.0, 29.9, 30.7, 32.9, 36.2 (CH2), 81.2 (CH), 106.8
(m, 5H, HAr), 11.23 (s, 1H, OH); 13C NMR (75 MHz, CDCl3):
d
¼11.5,
(CAr), 120.7 (CHAr), 128.6 (2CHAr), 129.9 (CAr), 130.1 (2CHAr), 135.7,
20.7 (CH3), 35.0 (CH2), 80.9 (CH), 104.4 (CAr), 119.2 (CHAr), 126.1
~
136.4, 138.0, 146.9, 161.6 (CAr), 171.1 (C]O); IR (neat):
n
¼3197 (w),
(2CHAr), 128.2 (CHAr), 128.7 (2CHAr), 129.4, 136.7, 142.2, 145.4,
~
2924 (m), 2853 (m), 1934 (w),1747 (w),1662 (s), 1620 (m),1573 (w),
1492 (m), 1434 (m), 1346 (m), 1272 (m), 1156 (s), 1073 (m), 1010 (s),
874 (w), 818 (s), 747 (m), 639 (m), 539 (m) cmꢀ1; GC–MS (EI, 70 eV):
m/z (%)¼374 (Mþ, 37Cl, 8), 372 (Mþ, 35Cl, 43), 356 (14), 354 (41), 339
(12), 325 (11), 286 (35), 285 (42), 284 (100), 283 (63), 249 (8), 192
(13), 191 (15), 177 (8); HRMS (EI): calcd for C22H25ClO3 ([M]þ,
160.3 (CAr), 168.9 (C]O); IR (KBr):
n
¼2919 (w), 1657 (s), 1573 (m),
1510 (w), 1356 (m), 1272 (m), 1226 (s), 1165 (m), 1097 (s), 1059 (s),
973 (m), 849 (s), 810 (s), 697 (s) cmꢀ1; GC–MS (EI, 70 eV): m/z
(%)¼268 (Mþ, 60), 250 (100), 222 (28), 179 (23), 91 (21), 77 (14).
Anal. Calcd (%) for C17H16O3 (268.31): C 76.10, H 6.01; found: C
75.81, H 6.22.
[
35Cl]): 372.89523; found: 372.63828.
3.1.37. Methyl-4-(2-(ethoxycarbonyl(methyl)amino)-2-phenyl-
ethyl)-2-hydroxy-6-methylbenzoate and methyl-2-(2-(ethoxycar-
bonyl(methyl)amino)-2-phenylethyl)-6-hydroxy-4-methylbenzoate
(12a). Starting with 1,3-bis(silyl enol ether) 5a (600 mg,
2.30 mmol), ethyl methyl(3-oxo-1-phenyl-5-(trimethylsilyloxy)hex-
4-enyl)carbamate 11 (835 mg, 2.30 mmol) and TiCl4 (0.25 mL,
2.30 mmol), 12a was isolated after column chromatography (silica
gel, n-heptane/EtOAc¼23/2) as a slight orange oil (316 mg, 37%)
a two different regioisomers in a ratio of 0.51 (II):0.49 (I). 1H NMR
3.1.33. 8-Hydroxy-6-methyl-3-(pyrid-4-yl)-3,4-dihydro-isochroman-
1-one (7af). Starting with 1,3-bis(silyl enol ether) 5a (600 mg,
2.30 mmol), 1-hydroxy-1-(pyridin-3-yl)-5-(trimethylsilyloxy)hex-
4-en-3-one 4h (643 mg, 2.30 mmol) and TiCl4 (0.25 mL, 2.30 mmol),
7af was isolated after column chromatography (silica gel, n-heptane/
EtOAc¼23/2) as a slight yellow solid (216 mg, 37%), mp¼124–126 ꢁC.
1H NMR (250 MHz, CDCl3):
d
¼2.28 (s, 3H, CH3), 3.02 (dd, 1H, J¼16.6,
3.8 Hz, CH2), 3.20 (dd, 1H, J¼16.6, 12.2 Hz, CH2), 5.54 (dd, 1H, J¼12.2,
3.8 Hz, CH), 6.51 (s, 1H, HAr), 6.68 (s, 1H, HAr), 7.30 (dd (br),1H, J¼7.9,
4.9 Hz, HPyrid), 7.77 (dt (br),1H, J¼7.9, 1.9 Hz, HPyrid), 8.56 (dd (br),1H,
J¼4.9, 1.6 Hz, HPyrid), 8.61 (d (br), 1H, J¼1.6 Hz, HPyrid), 10.73 (s, 1H,
(500 MHz, CDCl3, 300 K):
d
¼0.93–1.12 (br, 3H(II), H-12(II)); 1.16 (t,
3J¼7.3 Hz, 3H(I), H-12(I)); 2.25 (s, 3H(II), H-10(II)); 2.49 (s, 3H(I), H-10(I));
2.63 (s, 3H(I), 3H(II), H-9(I,II)); 3.03–3.11 (m), 3.20 (dd, 2J¼14.2 Hz,
OH); 13C NMR (75 MHz, CDCl3):
105.7 (CAr), 116.8, 119.2 (CHAr), 123.7 (CHPyrid), 133.8 (CAr), 133.9
d
¼22.0 (CH3), 34.8 (CH2), 78.3 (CH),
3J¼5.7 Hz), (2H(I) or H(II), 1H(I) or H(II), H-7(I), H-7(II)); 3.78 (s, 3H(II)
,
H-13(II)); 3.91 (s, 3H(I), H-13(I)); 3.86 (br), 4.04 (br), (2H(I), 2H(II), 1H(I)
(CHPyrid), 138.3 (CPyrid), 147.6 (CHPyrid), 148.3 (CAr), 150.1 (CHPyrid),
or H(II), H-11(I), H-11(II), H-7(I) or H-7(II)); 5.50–5.76 (br, 1H(I), 1H(II),
162.3 (CAr), 169.2 (C]O); IR (KBr):
n
¼3145 (br w), 2919 (w), 1659 (s),
H-8(I,II)); 6.45 (d, 4J¼1.5 Hz), 6.61 (br), (1H(I), 1H(II), H-4(I,II)); 6.69 (br),
~
1578 (m), 1495 (m), 1417 (m), 1349 (m), 1269 (s), 1202 (s), 1157 (m),
1096 (m), 975 (m), 886 (m), 814 (s), 781 (m), 695 (s) cmꢀ1; GC–MS
(EI, 70 eV): m/z (%)¼255 (Mþ, 100), 210 (93), 180 (73), 148 (52), 91
(17), 77 (6). Anal. Calcd (%) for C15H13NO3 (255.09): C 70.58, H 5.13, N
5.49; found: C 69.53, H 5.32, N 5.02.
6.71 (d, 4J¼1.5 Hz), (1H(I), 1H(II), H-6(I,II)); 7.25–7.38 (br, 5H(I), 5H(II)
,
Ph(I,II)); 11.28 (s, 1H(II), OH(II)); 13C NMR (125 MHz, CDCl3, 300 K):
d
¼14.1, 14.5 (C-12(I,II)); 21.5 (C-10(II)); 24.0 (C-10(I)); 28.8, 29.2 (br) (C-
9(I,II)); 36.4, 36.7 (C-7(I,II)); 51.9, 52.1 (C-13(I,II)); 58.0, 58.9 (C-8(I,II));
61.1, 61.3 (C-11(I,II)); 109.3 (C-2(II)); 110.4 (C-2(I)); 115.8 (C-6(I)); 116.9
(C-6(II)); 123.7 (C-4(I)); 124.5 (br, C-4(II)); 127.3, 127.3, 127.5, 128.4
(o-Ph(I,II), p-Ph(I,II)); 139.4, 140.1 (br) (i-Ph(I,II)); 141.1 (C-3(I,II)); 145.3
(C-5(I,II)); 156.6 (NCOO(I,II)); 162.8, 163.1 (C-1(I,II)); 171.5, 172.0
~
3.1.34. Typical procedure for the synthesis of 3-aryl-3,4-dihy-
droisocoumarins 7a,b from 6a,b. To
a THF solution of 6a,b
(0.62 mmol) silica gel (Merck silica gel 60, 0.063–0.200 mm, 70–230
mesh, 1.5 g) was added and the mixture was stirred at room
(COO(I,II)); IR (neat):
n
¼3029 (w), 2978 (w), 1688 (s), 1657 (s), 1619
(m), 1570 (m), 1438 (m), 1360 (m), 1314 (s), 1261 (s), 1133 (m), 1048

I. Ullah et al. / Tetrahedron 66 (2010) 1874–1884
1883
(m), 943 (m), 881 (w), 804 (m), 698 (s), 582 (m), 528 (w) cmꢀ1; EIMS
(EI, 70 eV): m/z (%)¼371 (Mþ, 2), 340 (9), 270 (8), 269 (35), 268 (19),
238 (10), 237 (55), 236 (23),194 (14),193 (76),192 (100),179 (18),165
(41), 164 (53), 148 (86), 135(66), 120 (87), 91 (32), 77 (18), 42 (85);
HRMS (ESI-TOF): calcd for C42H50N2NaO10 [2MþNa]þ: 765.33577;
found: 765.33613.
H-14(I)); 2.25 (s, 3H(IIB), H-10(IIB)); 2.29 (s, 3H(IIA), H-10(IIA)); 2.49 (s),
2.50 (s), (3H(I), H-10(I)); 2.58 (s, 3H(IIA), H-9(IIA)); 2.59 (s, 3H(IIB), H-
9(IIB)); 2.61 (s), 2.62 (s), (3H(I), H-9(I)); 2.96 (dd, J¼12.9 Hz, J¼12.0 Hz,
2H(II), H-7(II)); 3.00–3.10 (m, 1H(I), 1H(II), H-7(I), H-7(II)); 3.20 (ddd,
2J¼14.0 Hz, 3J¼9.8 Hz, 3J¼5.0 Hz, 2H(I), H-7(I)); 3.67–3.85 (m, 2H(II), H-
11(II)); 3.68–4.07 (m, 3H(I), 1H(II), H-7(I), H-7(II), H-11(I)); 4.18–4.34 (m,
2H(II), H-13(II)); 4.35–4.41 (m, 2H(I), H-13(I)); 5.63 (dd, 3J¼11.5 Hz,
3J¼2.8 Hz), 5.67 (dd, 3J¼10.8 Hz, 3J¼5.0 Hz), 5.75–5.79 (m), (1H(I)
,
OH
O
OH
O
13
Me
1
1H(II), H-8(I), H-8(II)); 6.42 (d, 4J¼1.5 Hz, 1H(IIB), H-4(IIB)); 6.43 (d,
4J¼1.5 Hz, 1H(IIA), H-4(IIA));6.58(brs), 6.66(brs), (1H(I), H-4(I));6.68(br
s, 1H(IIB), H-6(IIB)); 6.70 (br s, 1H(IIA), H-6(IIA)); 6.69 (br s), 6.72 (br s),
13
Me
1
2
2
6
6
O
O
3
3
10 Me
Me10
5
7
8
5
7
8
4
4
(1H(I), H-6(I)); 7.26–7.38 (m, 5H(I), 5H(II), Ph); 11.56 (s), 11.58 (s), (1H(I)
OH(I)); 11.65 (s, 1H(IIB), OH(IIB)); 11.66 (s, 1H(IIA), OH(IIA)); 13C NMR
(125 MHz, CDCl3, 263 K):
¼13.5 (C-14(IIB)); 13.6 (C-14(IIA)); 14.0
,
9Me
Me9
N
N
d
O
O
11
O
11
O
(C-12(IIA)); 14.1, 14.1 (C-14(I)); 14.4, 14.5, 14.6 (C-12(I), C-12(IIB)); 21.5
(C-10(IIB)); 21.6 (C-10(IIA)); 24.3, 24.4 (C-10(I)); 28.5, 28.6 (C-9(I)); 28.9
(C-9(IIA)); 29.1 (C-9(IIB)); 36.0, 36.0, 36.1 (C-7(I), C-7(IIB)); 36.3 (C-7(IIA));
57.5, 57.6 (C-8(I)); 58.1 (C-8(IIB)); 58.2 (C-8(IIA)); 61.0 (C-11(IIB)); 61.1
(C-11(IIA)); 61.3, 61.3 (C-11(I)); 61.5, 61.6 (C-13(I)); 61.6 (C-13(IIA)); 61.7
(C-13(IIB)); 108.9 (C-2(IIA)); 109.4 (C-2(IIB)); 110.2, 110.3 (C-2(I)); 115.7,
115.8(C-6(I));116.8(C-6(IIB));116.9(C-6(IIA));123.6,123.7(C-4(I));124.2
(C-4(IIB)); 124.6 (C-4(IIA)); 127.1, 127.2, 127.2, 127.4, 127.4, 127.5, 127.5,
127.5 (o-Ph(I,II), p-Ph(I,II)); 128.3, 128.4, 128.4, 128.5 (m-Ph(I,II)); 139.2
(i-Ph(IIA)); 139.6 (i-Ph(IIB)); 139.6, 139.9 (i-Ph(I)); 140.8 (C-3(IIB)); 140.9
(C-3(IIA)); 141.2, 141.3 (C-3(I)); 144.6 (C-5(IIB)); 144.9, 145.1 (C-5(I));
145.3 (C-5(IIA)); 156.3 (NCOO(IIB)); 156.5 (NCOO(IIA)); 156.7, 156.8
(NCOO(I)); 162.7, 162.8 (C-1(I)); 163.1 (C-1(IIB)); 163.2 (C-1(IIA)); 171.3
~
12Me
Me12
12a
I
II
I / II = 0.49 / 0.51
OH
O
OH
O
13
1
13
14
1
2
2
O
Me14
6
6
O
10
Me
3
3
10 Me
5
7
7
8
5
Me
4
4
9Me
Me9
8
N
N
O
O
11
O
11
O
(COO(IIB)); 171.4 (COO(IIA)); 171.6, 171.7 (COO(I)); IR (neat):
n
¼3029 (w),
12
12
Me
Me
2978 (w), 1690 (s), 1652 (s), 1618 (m), 1570 (m), 1445 (m), 1397 (m),
1311 (s),1259 (s),1171 (m),1095 (m), 1003 (m), 946 (w), 863 (w), 803
(m), 698 (s), 581 (m) cmꢀ1; EIMS (EI, 70 eV): m/z (%)¼385 (Mþ, 3), 340
(7), 283 (15), 282 (13), 266 (10), 238 (10), 237 (40), 236 (26), 194 (14),
193 (63), 192 (100), 165 (45), 148 (71), 120 (79), 91 (26), 77 (15), 42
(85); HRMS (ESI-TOF): calcd for C22H26NO5 [M-H]þ: 384.18165;
found: 384.18236.
II
I
12b
IIA (0.62) : IIB (0.38)
IA (0.53) : IB (0.47)
I / II = 0.47 / 0.53
A and B (Rotamers at 263 K)
3.1.38. Ethyl-4-(2-(ethoxycarbonyl(methyl)amino)-2-phenylethyl)-2-
hydroxy-6-methylbenzoate and ethyl-2-(2-(ethoxycarbonyl(methyl)-
amino)-2-phenylethyl)-6-hydroxy-4-methylbenzoate (12b). Starting
with 1,3-bis(silyl enol ether) 5j (600 mg, 2.18 mmol), ethyl methyl(3-
oxo-1-phenyl-5-(trimethylsilyloxy)hex-4-enyl)carbamate 11 (792 mg,
2.18 mmol) and TiCl4 (0.24 mL, 2.18 mmol), 12b was isolated after
column chromatography (silica gel, n-heptane/EtOAc¼23/2) as a
slight orange oil (353 mg, 42%). 1H NMR (500 MHz, CDCl3, 300 K):
Acknowledgements
Financial support by the State of Pakistan (HEC scholarship for
I.U.), by the DAAD (scholarship for M.F.I. And A.A.) and by the
Friedrich-Irmgard-Harms-Stiftung (scholarship for A.A.) is grate-
fully acknowledged.
d
¼0.93–1.10 (br m, 6H(II), H-12(II), H-14(II)); 1.16 (t, 3J¼7.3 Hz, 3H(I),
References and notes
H-12(I)); 1.40 (t, 3J¼7.3 Hz, 3H(I), H-14(I)); 2.25 (s, 3H(II), H-10(II)); 2.50
(s, 3H(I), H-10(I)); 2.61 (s, 3H(II), H-9(II)); 2.63 (s, 3H(I), H-9(I)); 3.14–2.99
(m), 3.21 (dd, 2J7a,7b¼14.2 Hz, 3J7,8¼6.0 Hz), (H-7(I,II)); 3.71–4.08 (br m,
1. (a) Zhang, H.; Matsuda, H.; Kumahara, A.; Ito, Y.; Nakamura, S.; Yoshikawa, M.
Bioorg. Med. Chem. Lett. 2007, 17, 4972; (b) Shimoda, H.; Matsuda, H.; Yamahara,
J.; Yoshikawa, M. Biol. Pharm. Bull. 1998, 21, 809; (c) Patnam, R.; Chang, F.-R.;
Chen, C.-Y.; Kuo, R.-Y.; Lee, Y.-H.; Wu, Y.-C. J. Nat. Prod. 2001, 64, 948; (d) Yasuda,
T.; Kayaba, S.; Takahashi, K.; Nakazawa, T.; Ohsawa, K. J. Nat. Prod. 2004, 67,
1604; (e) Nozawa, K.; Yamada, M.; Tsuda, Y.; Kawai, K.-I.; Nakajima, S. Chem.
Pharm. Bull. 1981, 29, 2689; (f) Wang, Q.; Matsuda, H.; Matsuhira, K.; Nakamura,
S.; Yuan, D.; Yoshikawa, M. Biol. Pharm. Bull. 2007, 30, 388; (g) Matsuda, H.;
Shimoda, H.; Yamahara, J.; Yoshikawa, M. Biol. Pharm. Bull. 1999, 22, 870; (h)
Kawamura, M.; Kagata, M.; Masaki, E.; Nishi, H. Pharmacol. Toxicol. (Copenhagen)
2002, 90, 106; (i) Umehara, K.; Matsumoto, M.; Nakamura, M.; Miyase, T.; Kur-
oyanagi, M.; Noguchi, H. Chem. Pharm. Bull. 2000, 48, 566; (j) Matsuda, H.; Shi-
moda, H.; Yamahara, J.; Yoshikawa, M. Bioorg. Med. Chem. Lett. 1998, 8, 215; (k)
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Miki, A.; Yamahara, J.; Murakami, N. Chem. Pharm. Bull. 1996, 44, 1440; (l) Yosh-
ikawa, M.; Harada, E.; Naitoh, Y.; Inoue, K.; Matsuda, H.; Shimoda, H.; Yamahara, J.;
Murakami, N. Chem. Pharm. Bull. 1994, 42, 2225; (m) Yoshikawa, M.; Uchida, E.;
Chatani, N.; Kobayashi, H.; Naitoh, Y. Chem. Pharm. Bull. 1992, 40, 3352.
2. (a) Hashimoto, T.; Tori, M.; Asakawa, Y. Phytochemistry 1987, 26, 3323; (b)
Matsuda, H.; Shimoda, H.; Yoshikawa, M. Bioorg. Med. Chem. 1999, 7, 1445.
3. (a) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980, 102, 3534; (b) Brown-
bridge, P.; Chan, T.-H.; Brook, M. A.; Kang, G. J. Can. J. Chem. 1983, 61, 688.
4. For a review of [3þ3] cyclizations, see: Feist, H.; Langer, P. Synthesis 2007, 327.
5. For a review of 1,3-bis(silyl enol ethers), see: Langer, P. Synthesis 2002, 441.
6. (a) Nguyen, V. T. H.; Langer, P. Tetrahedron Lett. 2005, 46, 1013; (b) Hussain, I.;
Nguyen, V. T. H.; Yawer, M. A.; Dang, T. T.; Fischer, C.; Reinke, H.; Langer, P. J. Org.
Chem. 2007, 72, 6255.
3H(I), 3H(II), H-11(I), H-7(I), OCH2(II), H-7(II)); 4.22–4.35 (m, 2H(II)
,
OCH2(II)); 4.40 (q, 2H(I), H-13(I)); 5.60–5.78 (br m, 1H(I), 1H(II), H-
8(I,II));6.44(d, 4J4,6¼1.5 Hz, 1H(II), H-4(II));6.61(br,1H(I), H-4(I));6.70(br,
1H(II), H-6(II)); 6.71 (br, 1H(I), H-6(I)); 7.25–7.39 (m, 5H(I), 5H(II), Ph(I,II));
11.36 (s,1H(I), OH(I)); 11.45 (s,1H(II), OH(II)); 13C NMR (125 MHz, CDCl3,
300 K):
d¼13.7, 14.2, 14.5 (C-12(I,II), C-14(I,II)); 21.5 (C-10(II)); 24.1 (C-
10(I)); 28.8 (C-9(I)); 29.1 (br), 29.3 (br), (C-9(II)); 36.2, 36.4, 36.5 (br),
(C-7(I,II)); 58.0 (C-8(I)); 58.7 (C-8(II)); 61.3 (C-11(I)); 61.4 (C-13(I)); 61.1,
61.6 (br), (C-11(II), C-13(II)); 109.3 (br),109.7 (br), (C-2(II)); 110.6 (C-2(I));
115.8 (C-6(I)); 117.0 (br, C-6(II)); 123.7 (C-4(I)); 124.2 (br), 124.7 (br),
(C-4(II)); 128.5, 127.5, 127.4, 127.4 (o-Ph(I,II), m-Ph(I,II), p-Ph(I,II)); 139.5
(i-Ph(I)); 140.0 (br),140.2 (br), (i-Ph(II)); 141.1 (br, C-3(II)); 141.2 (C-3(I));
145.1 (C-5(I)); 144.5 (br), 145.3 (br), (C-5(II)); 156.6 (br), 156.8 (br),
(NCOO(I,II)); 162.9 (C-1(I)); 163.3 (br, C-1(II)); 171.3, 171.6 (COO(I,II)); 1H
NMR (500 MHz, CDCl3, 263 K, ratios of rotamers 0.53 (IA):0.47 (IB)
and 0.62 (IIA):0.38 (IIB)):
d
¼0.92 (t, 3J¼7.3 Hz, 3H(IIA), H-12(IIA)); 0.99
(t, 3J¼7.3 Hz, 3H(IIA), H-14(IIA)); 1.00 (t, 3J¼7.3 Hz, 3H(IIB)), 1.06 (t,
3J¼7.3 Hz, 3H(IIB)), (H-12(IIB), H-14(IIB)); 1.14 (t, 3J¼7.3 Hz), 1.16 (t,
3J¼7.3 Hz), (3H(I), H-12(I)); 1.39 (t, 3J¼7.3 Hz),1.41 (t, 3J¼7.3 Hz), (3H(I),

1884
I. Ullah et al. / Tetrahedron 66 (2010) 1874–1884
7. Sher, M.; Ali, A.; Reinke, H.; Langer, P. Tetrahedron Lett. 2008, 49, 5400.
8. For reviews of domino reactions, see: (a) Tietze, L. F.; Beifuss, U. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 131; Angew. Chem. 1993, 105, 137; (b) Tietze, L. F. Chem.
Rev. 1996, 96, 115.
10. CCDC 756025-756028 contain all crystallographic details of this publication
and is available free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html or
can be ordered from the following address: Cambridge Crystallographic Data
Centre, 12 Union Road, GB-Cambridge CB21EZ; Fax: (þ44) 1223-336-033; or
deposit@ccdc.cam.ac.uk.
9. Weiler, L. J. Am. Chem. Soc. 1970, 92, 6702.