Synthesis of dichloromethyl-substituted salicylates and pyran-4-ones by cyclocondensation of 1,3-bis(silyloxy)-1,3-butadienes with 1,1-dimethoxy-4,4-dichlorobut-1-en-3-one: control of the C,C- and C,O-regioselectivity by the choice of Lewis acid

Article abstract of DOI:10.1016/j.tet.2009.09.016

The TiCl₄-mediated formal [3+3] cyclocondensation of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 1,1-dimethoxy-4,4-dichlorobut-1-en-3-one afforded a variety of functionalized 6-dichloromethyl-4-methoxysalicylates with very good regioselectiv

Full text of DOI:10.1016/j.tet.2009.09.016

Tetrahedron 65 (2009) 9271–9279
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of dichloromethyl-substituted salicylates and pyran-4-ones
by cyclocondensation of 1,3-bis(silyloxy)-1,3-butadienes with
1,1-dimethoxy-4,4-dichlorobut-1-en-3-one: control of the
C,C- and C,O-regioselectivity by the choice of Lewis acid
Vahuni Karapetyan a, Satenik Mkrtchyan a, Gagik Ghazaryan a, Alexander Villinger a,
,b,
Christine Fischer b, Peter Langer a
*
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
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 June 2009
Received in revised form 27 August 2009
Accepted 3 September 2009
Available online 9 September 2009
The TiCl4-mediated formal [3þ3] cyclocondensation of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with
1,1-dimethoxy-4,4-dichlorobut-1-en-3-one afforded a variety of functionalized 6-dichloromethyl-4-
methoxysalicylates with very good regioselectivity. Some of the products were transformed into 6-
formyl-4-methoxysalicylates. The employment of Me3SiOTf instead of TiCl4 resulted in a change of the
regioselectivity and in the formation of functionalized 2-(dichloromethyl)pyran-4-ones.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
cyclization of 1,3-bis(silyloxy)-1,3-butadienes with 1,1-dimethoxy-
4,4,4-trifluorobut-1-en-3-one is influenced by the choice of the Lewis
The dichloromethyl group is of interest as a precursor of alde-
hydes. Dichloromethyl-substituted arenes are of potential relevance
in the field of medicinal chemistry. To date, however, only moderate
pharmacological activities have been reported.1–3 Dichloromethyl-
substituted arenes have been previously prepared by chlorination of
the corresponding aldehydes using various chlorination agents.4
Despite its great utility, this approach suffers from the fact that the
required starting materials, functionalized aromatic aldehydes, are
not always readily available. An alternative synthesis of dichloro-
methyl-substituted arenes and hetarenes is based on direct nucleo-
acid.10 Recently, wehave reported thesynthesis of 6-formylsalicylates
based on the cyclization of 1,3-bis(silyloxy)-1,3-butadienes with
1-ethoxy-4,4-dichorobut-1-en-3-one.11 Herein, we report, for the
first time, the synthesis of 6-dichloromethyl-4-methoxysalicylates by
TiCl4-mediatedcyclocondensationof1,3-bis(silyloxy)-1,3-butadienes
with 1,1-dimethoxy-4,4-dichlorobut-1-en-3-one. The products can
be transformed into 6-formyl-4-methoxysalicylates. In addition, we
have found that 2-(dichloromethyl)pyran-4-ones were formed when
Me3SiOTf instead of TiCl4 was employed. The products reported
herein have not been previously prepared and are not readily avail-
able by other methods.
philic substitution reactions of nitroarenes with chloroform.5
A
drawbackof thismethodistheformationofregioisomericmixturesin
some cases. An alternative strategy is based on the application of
suitable CHCl2-containing substrates in cyclocondensation reactions
(‘building block approach’). Such reactions have only scarcely been
reported to date. Chan and Stossel reported the synthesis of a 6-
dichloromethyl-4-hydroxysalicylate by formal [5þ1] cyclization of
1-methoxy-1,3,5-tris(silyloxy)-1,3,5-hexatriene with dichloroacetyl
chloride.6 Recently, we have reported7 a new approach to 6-(tri-
fluoromethyl)salicylates by formal [3þ3] cyclizations8 of 1,3-bis(si-
lyloxy)-1,3-butadienes9 with 1-ethoxy-4,4,4-trifluorobut-1-en-3-
ones. In addition, it was found that the product distribution of the
2. Results and discussion
The synthesis of 1,1-dimethoxy-4,4-dichlorobut-1-en-3-one (1)
has, to the best of our knowledge, not yet been reported.12 It was
prepared, in analogy to the procedure reported for the synthesis
of 1,1-diethoxy-4,4,4-trifluorobut-1-en-3-one,13 by reaction of
dichloroacetic anhydride with 1,1,1-trimethoxyethane (Scheme 1).
O
O
OMe O
Cl2HC
O
+
CHCl2
i
CHCl2
MeO
CH3C(OMe)3
1 (67%)
* Corresponding author. Fax: þ49 381 4986412.
Scheme 1. Synthesis of 1. Conditions: i, pyridine, CH2Cl2, 20 ꢀC, 12 h.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.016

9272
V. Karapetyan et al. / Tetrahedron 65 (2009) 9271–9279
1,3-Bis(silyloxy)-1,3-butadienes 2a–o were prepared according to the
literature from the corresponding
-ketoesters in two steps.14–16
Me3SiO OSiMe3
R1
b
OR2
OH
O
R1
2a-h
The TiCl4-mediated reaction of 1 with 1,3-bis(silyloxy)-1,3-
butadiene 2a afforded 6-dichloromethyl-4-methoxysalicylate 3a in
47% yield (Scheme 2). The best yield was obtained when the solution
was slowly warmed from ꢁ78 ꢀC to 20 ꢀC, when the reaction was
carried out in a highly concentrated solution, and when an excess
(2.0 equiv) of 2a was employed.
i
OR2
OMeO
+
MeO
CHCl2
MeO
CHCl2
3a-h
1
R1
ii
OH
O
OR2
MeO
Me3SiO
OSiMe3
O
OH
O
4a-d
TiCl4
CH2Cl2
OEt
Scheme 3. Synthesis of 3a–h and 4a–d. Conditions: i, TiCl4, CH2Cl2, ꢁ78 to 20 ꢀC; ii, (1)
OEt
CHCl2
3a (47%)
2a
NaOMe, MeOH, 20 ꢀC, 24 h, (2) HCl, H2O.
MeO
O
_
78 to 20 °C
18 h
MeO
+
MeO
CHCl2
The reaction of 1 with 1,3-bis(silyloxy)-1,3-butadiene 2i, car-
ried out in the presence of Me3SiOTf (1.0 equiv) instead of TiCl4,
resulted in the formation of 2-(dichloromethyl)pyran-4-one 5a
(Scheme 4).
1a
TiCl3(OH)
TiCl4
_
O
O
The formation of the corresponding salicylate was not observed.
The formation of 5a presumably proceeds by formation of allylic
cation F (Scheme 4). The attack of the terminal carbon atom of 2i
onto F gave intermediate G. Now two possible pathways can be
discussed. Path A: The direct cyclization of intermediate G (via the
oxygen atom derived from 1) afforded intermediate H, which was
subsequently transformed into 5a during the aqueous work-up.
Alternatively, mechanism path B can be envisaged: the elimination
of Me3SiOTf from G gave I. The latter underwent elimination of
Me3SiOMe, to give intermediate J, and subsequent cyclization by
attack of the oxygen atom (derived from 2i) to give intermediate K.
The elimination of silanol (before or during the aqueous work-up)
resulted in the formation of pyran-4-one 5a.
TiCl4
MeO
O
OEt
+
OTiCl3
CHCl2
MeO
CHCl2
MeO
E
A
2a
Me3SiCl
Me3SiO
Me3SiCl
Me3SiO
O
Me3SiO
OEt
OEt
_
+
TiCl3
TiCl4
Cl
MeO
MeO
O
O
CHCl2
CHCl2
MeO
The Me3SiOTf-mediated cyclization of 1 with 1,3-bis(silyloxy)-
1,3-butadienes 2a–d and 2i–o afforded the functionalized 2-
(dichloromethyl)pyran-4-ones 5a–k (Scheme 5, Table 2). The yields
of the esters 5c–k are higher than the yields of the ketones 5a,b.
B
D
Me3SiOMe
Me3SiCl
O
Me3SiCl
Me3SiO
OEt
This can be explained by the higher nucleophilicity of b-ketoester-
TiCl3
O
derived 1,3-bis(silyloxy)-1,3-butadienes compared to those derived
from 1,3-diketones. The best yield was obtained for product 5c,
which is derived from the simple diene 2a. The structures of all
products were confirmed by spectroscopic methods. The structures
of 5g and 5i were independently confirmed by X-ray crystal
structure analyses (Figs. 3 and 4).18
MeO
MeO
CHCl2
C
Scheme 2. Possible mechanism of the formation of 3a.
The change of the regioselectivity depending on the type of
Lewis acid employed might be explained based on mechanism path
B. The nucleophilicity of the silyl enol ether moiety of intermediate
G is higher than the nucleophilicity of the titanium enolate moiety
of intermediate B (due to the high oxophilicity of titanium).
Therefore, the elimination of Me3SiCl from intermediate B and
formation of C is faster than the formation of a pyranone by
O-cyclization of the titanium enolate. In contrast, the O-cyclization
of the silyl enol ether moiety of intermediate G is relatively fast.
However, a (reversible) O-cyclization of intermediate B cannot be
ruled out. Therefore, the regioselective formation of salicylates 3
might be explained also by the assumption that the aromatization
of intermediate E (by elimination of TiCl3OH) is more rapid than the
The formation of 3a can be explained by reaction of 1a with TiCl4
to give allylic cation A. The attack of the terminal carbon atom of 2a
onto A afforded intermediate B and extrusion of Me3SiCl gave C.
The elimination of Me3SiOMe (intermediate D) and subsequent
cyclization gave intermediate E (Scheme 2). The elimination of
TiCl3OH (before or during the aqueous work-up) and aromatization
resulted in the formation of product 3a. Product 3a, containing the
CHCl2 group located ortho to the ester group, was formed with
excellent regioselectivity. The formation of the other regioisomer,
containing the CHCl2 group located para to the ester group, was not
observed. The moderate yield can be explained by TiCl4-mediated
oxidative dimerization of the diene. This type of process has been
previously reported.17
The TiCl4-mediated reaction of 1 with 1,3-bis(silyloxy)-1,3-buta-
dienes 2a–h afforded the 6-dichloromethyl-4-methoxysalicylates
3a–h in moderate yields (Scheme 3, Table 1). The yields also depend
on the type of diene employed. However, no clear trend was ob-
served. The reaction of 3d,e,g,h with NaOMe–MeOH and subsequent
addition of hydrochloric acid afforded the 6-formylsalicylates 4a–d in
good yields. The structures of all products were confirmed by spec-
troscopic methods. The structures of 3e and 4b were independently
confirmed by X-ray crystal structure analyses (Figs. 1 and 2).18
aromatization of intermediates
Me3SiOH).
H and K (by elimination of
It is important to note that the Me3SiOTf-mediated formation of
CHCl2-substituted pyran-4-ones was generally observed for all di-
enes employed. This result is in contrast to the Me3SiOTf-mediated
synthesis of CF3-substituted pyran-4-ones, which were formed
only for 1,3-bis(trimethylsilyloxy)-1,3-butadienes containing no
substituent located at carbon atom C-4.7 For substituted dienes, the
formation of cyclohexenones was observed. This is illustrated
by the reactions shown in Scheme 6. The Me3SiOTf-mediated

V. Karapetyan et al. / Tetrahedron 65 (2009) 9271–9279
9273
Table 1
Synthesis of 6-dichloromethylsalicylates 3a–h and 6-formylsalicylates 4a–d
a
2, 3
4
1,3-Bis(silyloxy)-1,3-butadienes (2)
6-Dichloromethylsalicylates (3)
%
(3)
6-Formylsalicylates (4)
%
a (4)
OH
O
Me3SiO
OSiMe3
OEt
a
OEt
45
48
32
48
53
46
52
MeO
OH
CHCl2
O(CH2)2OMe
O
O
OSiMe3
Me3SiO
b
c
d
e
f
O(CH2)2OMe
MeO
CHCl2
OH
OH
OH
OH
Me3SiO
Me
OSiMe3
OMe
Me
OMe
CHCl2
O
MeO
OH
OH
O
OSiMe3
OMe
Me3SiO
Et
Et
Et
a
70
77
OMe
CHCl2
O
OMe
MeO
MeO
CHO
O
Me3SiO
nPr
OSiMe3
OMe
nPr
nPr
OMe
CHCl2
O
b
OMe
CHO
MeO
MeO
Me3SiO
nBu
OSiMe3
OMe
nBu
OMe
CHCl2
O
MeO
OH
OH
O
Me3SiO
OSiMe3
OMe
OMe
CHCl2
g
c
81
72
OMe
CHO
MeO
MeO
OH
O
OH
O
Me3SiO
Ph(CH2)3
OSiMe3
OMe
Ph(CH2)3
MeO
Ph(CH2)3
MeO
OMe
CHCl2
h
d
43
OMe
CHO
a
Yields of isolated products.
Figure 1. ORTEP plot of 3e (50% probability level).
cyclization of 2d with 1 afforded pyran-4-one 5i, while the cycli-
zation of 2d with 6 gave under identical conditions the cyclohex-
anone 7. The latter did not undergo aromatization under the
conditions employed because of the low stability of a cation located
next to the CF3 group. The different regioselectivity of the formation
Figure 2. ORTEP plot of 4b (50% probability level).
of 5i and 7 might be explained by the lower nucleophilicity of the
CF3- compared to the CHCl2-substituted silyl enol ether. In addition,
the steric influence of the dichloromethyl group (which should be

9274
V. Karapetyan et al. / Tetrahedron 65 (2009) 9271–9279
Table 2
O
Me3SiO OSiMe3
Synthesis of 2-(dichloromethyl)pyran-4-ones 5a–k
Me
Me3SiOTf
CH2Cl2
a
Me
2
1,3-Bis(silyloxy)-1,3-
butadienes (2)
5
2-(Dichloromethyl)-
pyran-4-ones (5)
% (5)
2i
O
MeO
O
_
78 to 20 °C
18 h
O
+
O
CHCl2
MeO
CHCl2
Me3SiOTf
SiMe3
Me3SiO
Me3SiO
Me3SiO
Me3SiO
Me3SiO
Me3SiO
OSiMe3
Me
5a
1
i
a
21
25
61
47
35
30
35
35
33
O
Me3SiOH
Cl2HC
O
O
Me
Ph
O
OSiMe3
Ph
Me
O
j
b
c
d
e
f
Me3SiO
_
MeO
O
OTf
+
O
Cl2HC
Cl2HC
Cl2HC
Cl2HC
Cl2HC
O
MeO
MeO
MeO
CHCl2
CHCl2
O
F
H
OSiMe3
OEt
O
a
k
l
path A
2i
Me3SiOTf
O
OEt
Me3SiO
Me3SiO
O
Me
OSiMe3
_
+
SiMe3
O
OTf
MeO
MeO
O
Oi-Pr
O
O
Oi-Pr
Oi-Bu
OBn
CHCl2
G
Me3SiOTf
O
OSiMe3
path B
O
O
Oi-Bu
O
O
Me3SiO
Me
Me
SiMe3
O
O
OSiMe3
OBn
MeO
MeO
m
b
c
O
CHCl2
O
CHCl2
I
O
5a
Me3SiOTf
Me3SiOMe
Me
O
Me3SiOH
OSiMe3
Me3SiO
g
h
i
O
O(CH2)2OMe
O
O
Cl2HC
O
O(CH2)2OMe
O
Me
O
OSiMe3
+
OSiMe3
OMe
Me3SiO
Me
Me
SiMe3
O
_
O
O
OTf
OSiMe3
CHCl2
Me3SiOTf
O
CHCl2
MeO
Cl2HC
O
O
OMe
OMe
K
J
5a
Me3SiO
Et
OSiMe3
OMe
Scheme 4. Possible mechanisms of the formation of 5a.
Et
d
n
Cl2HC
O
O
O
O
Me3SiO
R1
OSiMe3
R2
R2
nHept
Me3SiO
nHept
OSiMe3
OMe
O
j
30
25
R1
O
2a-d,i-o
i
OMe O
Cl2HC
Cl2HC
O
O
OEt
CHCl2
MeO
CHCl2
1
5a-k
n
Oct
O
Me3SiO
nOct
OSiMe3
OMe
o
k
Scheme 5. Synthesis of 5a–k. Conditions: i, Me3SiOTf, CH2Cl2, ꢁ78 to 20 ꢀC.
O
OMe
higher than that of the trifluoromethyl group) may play a role
(steric interaction with the ester group).
a
Yields of isolated products.
(dichloromethyl)pyran-4-ones. A different regioselectivity was ob-
served for CHCl2 compared to CF3-substituted substrates.
3. Conclusions
In conclusion, we have reported the TiCl4-mediated formal [3þ3]
cyclocondensation of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with
1,1-dimethoxy-4,4-dichlorobut-1-en-3-one. These reactions allow
for convenient synthesis of a variety of functionalized 6-dichlor-
omethyl-4-(methoxy)salicylates with very good regioselectivity.
The employment of Me3SiOTf instead of TiCl4 resulted in a change of
the regioselectivity and in the formation of functionalized 2-
4. Experimental section
4.1. General comments
All solvents were dried by standard methods and all reactions
were carried out under an inert atmosphere. For 1H and 13C NMR

V. Karapetyan et al. / Tetrahedron 65 (2009) 9271–9279
9275
dichloroacetic anhydride instead of dichloroacetic chloride was
employed. Starting with methyl orthoacetate (1.202 g, 10.0 mmol),
dichloroacetyl anhydride (4.800 g, 20.0 mmol) and dry pyridine
(1.820 g, 23.0 mmol) in CH2Cl2 (15 mL), 1 was obtained as a col-
ourless solid (1.33 g, 67%). 1H NMR (250 MHz, CDCl3):
d
¼3.87 (s, 3H,
OCH3), 3.91 (s, 3H, OCH3), 5.02 (s, 1H, CCH), 5.89 (s, 1H, CHCl2). 13
NMR (75.5 MHz, CDCl3):
¼55.3, 57.3 (OCH3), 70.8 (CHC), 73.1
(CHCl2), 171.2 (CO), 183.8 (CO(CH3)2). IR (ATR, cmꢁ1):
C
d
~
n
¼3120 (w),
3002 (w), 1731 (w), 1664 (m), 1531 (s), 1477 (s), 1427 (s), 1306 (s),
1275 (s), 1178 (m), 1137 (m), 1047 (s), 1014 (s), 937 (w), 719 (s). MS
(EI, 70 eV): m/z (%)¼198 (Mþ, 0.2), 135 (5), 115 (100), 89 (11), 69
(32), 47 (9). HRMS (EI): Calculated for C6H8O3Cl2 (Mþ) 197.98450,
found 197.98401.
4.2. General procedure for the synthesis of 3a–h
Figure 3. ORTEP plot of 5g (50% probability level).
To a CH2Cl2 solution (4.0 mL) of 1 (2.0 mmol) and of 1,3-bis(silyl
enol ether) 2 (4.0 mmol) was added TiCl4 (2.0 mmol) at ꢁ78 ꢀC
under argon atmosphere. The temperature of the solution was
allowed to rise to 20 ꢀC during 20 h. The solution was poured into
an aqueous solution of HCl (10%). The organic and the aqueous
layers were separated and the latter was extracted (3ꢂ30 mL) with
CH2Cl2. The combined organic layers were dried (Na2SO4), filtered
and the filtrate was concentrated in vacuo. The residue was purified
by column chromatography (silica gel, heptane–EtOAc¼15:1).
4.2.1. 2-Dichloromethyl-6-hydroxy-4-methoxy-benzoic acid ethyl
ester (3a). Starting with 1 (0.400 g, 2.0 mmol), 1-ethoxy-1,3-
bis(trimethylsilyloxy)buta-1,3-diene 2a (1.098 g, 4.0 mmol) and
TiCl4 (0.379 g, 2.0 mmol) in CH2Cl2 (4.0 mL), 3a was obtained as
a
colourless solid (0.251 g, 45%); mp¼65–66 ꢀC. 1H NMR
(300 MHz, CDCl3):
d
¼1.48 (t, 3J¼7.1 Hz, 3H, OCH2CH3), 3.86 (s, 3H,
OCH3), 4.48 (q, 3J¼7.1 Hz, 2H, OCH2CH3), 6.49 (d, 4J¼2.6 Hz, 1H,
CHAr), 7.22 (d, 4J¼2.6 Hz, 1H, CHAr), 7.76 (s, 1H, CHCl2), 11.65 (s,
1H, OH). 13C NMR (75.5 MHz, CDCl3):
d
¼14.0 (OCH2CH3), 55.6
(OCH3), 62.4 (OCH2CH3), 68.9 (CHCl2), 102.0 (CAr), 102.2, 109.5
(CHAr), 143.1, 164.3, 164.9 (CAr), 169.7 (C]O). IR (ATR, cmꢁ1):
Figure 4. ORTEP plot of 5i (50% probability level).
~
n
¼3075 (w), 2982 (w), 1656 (s), 1615 (s), 1574 (m), 1463 (w), 1434
O
O
Me3SiO
Et
OSiMe3
OMe
(m), 1366 (s), 1327 (m), 1249 (s), 1205 (s), 1160 (s), 1109 (m), 1014
(s), 954 (m), 852 (s), 760 (s), 738 (s), 683 (m). MS (EI, 70 eV): m/z
(%)¼278 (Mþ, 27), 232 (100), 197 (12), 179 (43), 126 (7), 95 (4).
HRMS (EI): Calculated for C11H12O4Cl2 (Mþ) 278.01072, found
278.01059.
OMe
2d
Et
i
OMe O
O
CHCl2
MeO
CHCl2
1
5i
4.2.2. 2-Dichloromethyl-6-hydroxy-4-methoxy-benzoicacid2-methoxy-
ethyl ester (3b). Starting with 1 (0.400 g, 2.0 mmol), 1-(2-methoxy-
ethoxy)-1,3-bis(trimethylsilyloxy)-buta-1,3-diene 2b (1.218 g,
4.0 mmol) and TiCl4 (0.379 g, 2.0 mmol) in CH2Cl2 (4.0 mL), 3b was
obtained as a colourless oil (0.277 g, 48%). 1H NMR (300 MHz, CDCl3):
Me3SiO
Et
OSiMe3
OMe
O
O
2d
Et
i
OMe
CF3
d
¼3.45 (s, 3H, CH2OCH3), 3.74 (m, 3J¼4.6 Hz, 2H, CH2OCH3), 3.84 (s, 3H,
OMe O
OCH3), 4.49–4.53 (m, 2H, OCH2CH2), 6.47 (d, 4J¼2.6 Hz, 1H, CHAr), 7.21
MeO
MeO
CF3
OH
(d, 4J¼2.6 Hz, 1H, CHAr), 7.82 (s, 1H, CHCl2), 11.26 (s, 1H, OH). 13C NMR
6
7
(75.5 MHz, CDCl3):
d¼55.6 (OCH3), 59.0 (OCH3), 64.7 (OCH2CH2), 69.0
Scheme 6. Different regioselectivity of the cyclization of 2d with 1 and 6. Conditions: i,
Me3SiOTf, CH2Cl2, ꢁ78 to 20 ꢀC.
(CHCl2), 69.7 (COOCH2), 102.1 (CAr), 102.2, 109.5 (CHAr), 143.6, 164.3,
164.4 (CAr), 169.2 (C]O). IR (ATR, cmꢁ1): ¼3072 (w), 2893 (w), 1715
~
n
(w),1657 (m),1615 (s),1574 (m),1436 (w),1368 (m),1323 (m),1242 (s),
1200(s),1158(s),1114 (s),1045(s), 954 (m), 842(w), 726(s), 621 (m). MS
(EI, 70 eV): m/z (%)¼308 (Mþ, 15), 232 (100), 198 (10), 169 (21), 135 (8),
59 (31). HRMS (EI): Calculated for C12H14O5Cl2 (Mþ) 308.02128, found
308.02119.
spectra the deuterated solvents indicated were used. Mass spec-
trometric (MS) data 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. 1,3-Bis(silyloxy)-1,3-
butadienes 2a–o were prepared according to the literature from the
4.2.3. 6-Dichloromethyl-2-hydroxy-4-methoxy-3-methyl-benzoic acid
methyl ester (3c). Starting with 1 (0.400 g, 2.0 mmol), 1-methoxy-
1,3-bis(trimethylsilyloxy)penta-1,3-diene 2c (1.096 g, 4.0 mmol) and
TiCl4 (0.379 g, 2.0 mmol) in CH2Cl2 (4.0 mL), 3c was obtained as
corresponding b
-ketoesters in two steps.14–16
4.1.1. 1,1-Dichloro-4,4-dimethoxy-but-3-en-2-one (1). Product
was prepared following
1
a
known procedure.13 However,
a colourless solid (0.118 g, 32%). 1H NMR (250 MHz, CDCl3):
d¼2.11 (s,

9276
V. Karapetyan et al. / Tetrahedron 65 (2009) 9271–9279
3H, CArCH3), 3.95 (s, 3H, OCH3), 4.01 (s, 3H, OCH3), 7.21 (s, 1H, CHAr),
3.44 (m, 2H, CArCH2), 3.95 (s, 3H, OCH3), 4.01 (s, 3H, OCH3), 4.94–
5.06 (m, 2H, CH2CHCH2), 5.86–5.99 (m, 1H, CH2CHCH2), 7.23 (s, 1H,
CHAr), 7.77 (s, 1H, CHCl2), 11.54 (s, 1H, OH). 13C NMR (62.9 MHz,
7.76 (s, 1H, CHCl2), 11.54 (s, 1H, OH). 13C NMR (62.8 MHz, CDCl3):
d
¼52.8 (OCH3), 55.0 (OCH3), 69.5 (CHCl2), 102.2 (CAr), 103.5 (CHAr),
115.6, 140.3, 161.0, 161.8 (CAr), 170.4 (C]O). IR (ATR, cmꢁ1):
CDCl3):
d
¼27.1 (CArCH2), 52.8 (OCH3), 55.8 (OCH3), 69.4 (CHCl2),
~
n
¼3079
(w), 2954 (w), 1722 (w), 1662 (s), 1574 (m), 1506 (w), 1436 (m), 1402
(m), 1373 (w) 1279 (s), 1226 (m), 1194 (m), 1157 (s), 1125 (br s), 994
(s), 930 (w), 789 (s), 717 (s), 667 (m). MS (EI, 70 eV): m/z (%)¼278
(Mþ, 36), 246 (64), 210 (100), 183 (19), 149 (5), 77 (15). HRMS (EI):
Calculated for C11H12O4Cl2 (Mþ) 278.01072, found 278.01045.
102.5 (CAr), 103.8 (CHAr), 114.8 (CH2CH), 117.2 (CAr), 135.2 (CH2CH),
141.0, 160.9, 161.6 (CAr), 170.3 (C]O). IR (ATR, cmꢁ1):
n
¼3078 (w),
~
2955 (w), 1788 (w), 1720 (w), 1659 (s), 1605 (m), 1510 (w), 1403 (m),
1360 (w), 1276 (s), 1195 (s), 1153 (s), 1133 (s), 999 (m), 912 (m), 724
(s), 630 (m). MS (EI, 70 eV): m/z (%)¼304 (Mþ, 40), 269 (29), 236
(100), 203 (13), 173 (59), 115 (12), 77 (14). HRMS (EI): Calculated for
C13H14O4Cl2 (Mþ) 304.02637, found 304.02625.
4.2.4. 6-Dichloromethyl-3-ethyl-2-hydroxy-4-methoxy-benzoic acid
methyl ester (3d). Starting with 1 (0.400 g, 2.0 mmol), 1-methoxy-
1,3-bis(trimethylsilyloxy)hexa-1,3-diene 2d (1.152 g, 4.0 mmol) and
TiCl4 (0.379 g, 2.0 mmol) in CH2Cl2 (4.0 mL), 3d was obtained as
a colourless solid (0.281 g, 48%); mp¼63–65 ꢀC. 1H NMR (300 MHz,
4.2.8. 6-Dichloromethyl-2-hydroxy-4-methoxy-3-(3-phenyl-propyl)-
benzoic acid methyl ester (3h). Starting with 1 (0.400 g, 2.0 mmol),
(7-methoxy-5,7-bis(trimethylsilyloxy)-hepta-4,6-dienyl)benzene 2h
(1.515 g, 4.0 mmol) and TiCl4 (0.379 g, 2.0 mmol) in CH2Cl2 (4.0 mL),
3h was obtained as a colourless oil (0.329 g, 43%). 1H NMR (300 MHz,
CDCl3):
d
¼1.08 (t, 3J¼7.5 Hz, 3H, CH2CH3), 2.68 (q, 3J¼7.5 Hz, 2H,
CH2CH3), 3.94 (s, 3H, OCH3), 4.01 (s, 3H, OCH3), 7.21 (s, 1H, CHAr),
7.76 (s, 1H, CHCl2), 11.48 (s, 1H, OH). 13C NMR (75.5 MHz, CDCl3):
CDCl3):
4.02 (s, 3H, OCH3), 4.10 (s, 3H, OCH3), 7.28–7.38 (m, 6H, CHAr), 7.87 (s,
1H, CHCl2), 11.62 (s, 1H, OH). 13C NMR (62.9 MHz, CDCl3):
d¼1.89–2.00 (m, 2H, CArCH2CH2), 2.76–2.86 (m, 4H, CArCH2),
d
¼12.9 (CH2CH3), 16.4 (CH2CH3), 52.8 (OCH3), 55.7 (OCH3), 69.6
(CHCl2), 102.4 (CAr), 103.7 (CHAr), 121.6, 140.4, 160.8, 161.6 (CAr),
d¼22.9,
170.4 (C]O). IR (ATR, cmꢁ1):
n
¼3083 (w), 2956 (w), 2851 (w), 1659
29.8, 35.9 (CH2CH2CH2), 52.7 (OCH3), 55.7 (OCH3), 69.5 (CHCl2), 102.4
~
(s), 1603 (m), 1569 (w), 1437 (m), 1406 (m), 1275 (s), 1218 (s), 1154
(s), 1129 (s), 1001 (s), 943 (w), 849 (w), 724 (s), 587 (m). MS (EI,
70 eV): m/z (%)¼292 (Mþ, 23), 260 (20), 224 (100), 206 (10), 161
(16), 125 (2), 77 (7). HRMS (EI): Calculated for C12H14O4Cl2 (Mþ)
292.02637, found 292.02654.
(CAr), 103.6 (CHAr), 119.8 (CAr), 125.5, 128.1, 128.3 (CHAr), 140.5, 142.6,
161.0, 161.7 (CAr),170.4 (C]O). IR (ATR, cmꢁ1):
n
¼3025 (w), 2939 (w),
~
1934 (w), 1804 (w), 1703 (w), 1661 (m), 1605(m), 1496 (w), 1405 (m),
1359 (w), 1280 (s), 1226 (m), 1157 (s), 1116 (s), 1002 (m), 843 (w), 733
(m), 699 (m). MS (EI, 70 eV): m/z (%)¼382 (Mþ, 40), 347 (14), 314 (7),
245 (32), 210 (100), 176 (16), 91 (31). HRMS (EI): Calculated for
C19H20O4Cl2 (Mþ) 382.07332, found 382.07328.
4.2.5. 6-Dichloromethyl-2-hydroxy-4-methoxy-3-propyl-benzoic
acid methyl ester (3e). Starting with 1 (0.400 g, 2.0 mmol), 1-
methoxy-1,3-bis(trimethylsilyloxy)hepta-1,3-diene 2e (1.098 g,
4.0 mmol) and TiCl4 (0.379 g, 2.0 mmol) in CH2Cl2 (4.0 mL), 3e was
obtained as a yellow solid (0.325 g, 53%); mp¼68–71 ꢀC. 1H NMR
4.3. General procedure for the synthesis of 4a–d
To
a methanol (10 mL) solution of sodium methanolate
(250 MHz, CDCl3):
d
¼0.94 (t, 3J¼7.4 Hz, 3H, CH2CH3), 1.43–1.61 (m,
(3.0 mmol) was added 3 (1.0 mmol) under argon atmosphere and the
solution was stirred for 24 h at room temperature. The solution was
poured into an aqueous solution of HCl (10%). The organic and the
aqueous layers were separated and the latter was extracted
(3ꢂ30 mL) with CH2Cl2. The combined organic layers were dried
(Na2SO4), filtered and the filtrate was concentrated in vacuo. The
residue was purified by column chromatography (silica gel, heptane–
EtOAc¼15:1).
2H, CH2CH3), 2.60–2.66 (m, 2H, CArCH2), 3.92 (s, 3H, OCH3), 4.01 (s,
3H, OCH3), 7.20 (s,1H, CHAr), 7.75 (s,1H, CHCl2),11.49 (s,1H, OH). 13
NMR (75.5 MHz, CDCl3):
C
d¼14.2 (CH2CH3), 21.7, 25.0 (CH2CH2), 52.8
(OCH3), 55.7 (OCH3), 69.6 (CHCl2), 102.4 (CAr), 103.7 (CHAr), 120.2,
140.4, 161.0, 161.8 (CAr), 170.5 (C]O). IR (ATR, cmꢁ1):
n
¼3083 (w),
~
2959 (m), 2899 (w), 1715 (w), 1652 (s), 1602 (m), 1511 (w), 1435 (w),
1270 (s), 1193 (m), 1132 (m), 994 (m), 729 (s), 601 (w). MS (EI,
70 eV): m/z (%)¼306 (Mþ, 40), 274 (32), 238 (100), 210 (40), 175
(15), 111 (15), 69 (32). HRMS (EI): Calculated for C13H16O4Cl2 (Mþ)
306.04202, found 306.04150.
4.3.1. 3-Ethyl-6-formyl-2-hydroxy-4-methoxy-benzoic acid methyl
ester (4a). Starting with 3d (0.295 g, 1.0 mmol), NaOMe (0.165 g,
3.0 mmol) in dry MeOH (10 mL), 4a was obtained as a colourless
solid (0.167 g, 70%); mp¼57–58 ꢀC. 1H NMR (300 MHz, CDCl3):
4.2.6. 3-Butyl-6-dichloromethyl-2-hydroxy-4-methoxy-benzoic acid
methyl ester (3f). Starting with 1 (0.400 g, 2.0 mmol), 1-methoxy-
1,3-bis(trimethylsilyloxy)octa-1,3-diene 2f (1.212 g, 4.0 mmol) and
TiCl4 (0.379 g, 2.0 mmol) in CH2Cl2 (4.0 mL), 3f was obtained as
a colourless solid (0.294 g, 46%); mp¼91–92 ꢀC. 1H NMR (250 MHz,
d
¼1.09 (t, 3J¼7.5 Hz, 3H, CH2CH3), 2.71 (q, 3J¼7.5 Hz, 2H, CH2CH3),
3.91 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 6.93 (s, 1H, CHAr), 10.47 (s, 1H,
CHO), 11.27 (s, 1H, OH). 13C NMR (75.5 MHz, CDCl3):
d¼12.8
(CH2CH3), 16.6 (CH2CH3), 52.7 (OCH3), 55.9 (OCH3), 103.2 (CHAr),
CDCl3):
d
¼0.92 (t, 3J¼7.2 Hz, 3H, CH2CH3), 1.30–1.39 (m, 2H, CH2),
105.3, 125.0, 137.5, 161.0, 161.6 (CAr), 170.4 (C]O), 192.2 (CHO). IR
(ATR, cmꢁ1):
n
¼2961 (w), 2875 (w), 1662 (s), 1596 (m), 1570 (m),
~
1.40–1.52 (m, 2H, CH2), 2.63–2.68 (m, 2H, CArCH2), 3.94 (s, 3H,
OCH3), 4.01 (s, 3H, OCH3), 7.21 (s, 1H, CHAr), 7.76 (s, 1H, CHCl2), 11.48
1503 (w), 1437 (m), 1390 (m), 1346 (m), 1276 (s), 1251 (s), 1196 (m),
1155 (s),1131 (s),1058 (m),1003 (m), 957 (m), 944 (m), 806 (m), 729
(m). MS (EI, 70 eV): m/z (%)¼238 (Mþ, 65), 209 (41), 191 (26), 179
(100), 150 (63), 135 (31), 107 (16), 77 (29). HRMS (EI): Calculated for
C12H14O5 (Mþ) 238.08358, found 238.08340.
(s,1H, OH). 13C NMR (75.5 MHz, CDCl3):
d
¼14.0 (CH2CH3), 22.7, 22.8,
30.7 (CH2), 52.7 (OCH3), 55.7 (OCH3), 69.6 (CHCl2), 102.3 (CAr), 103.7
(CHAr), 120.4, 140.3, 161.0, 161.7 (CAr), 170.4 (C]O). IR (ATR, cmꢁ1):
~
n
¼3080 (w), 2925 (m), 1657 (s), 1605 (m), 1573 (w), 1435 (m), 1404
(m), 1287 (s), 1270 (s), 1190 (m), 1138 (s), 1077 (m), 1004 (s), 991 (s),
851 (m), 725 (s), 644 (m). MS (EI, 70 eV): m/z (%)¼320 (Mþ, 35), 277
(22), 245 (65), 210 (100), 179 (12), 145 (5), 89 (8). HRMS (EI): Cal-
culated for C14H18O4Cl2 (Mþ) 320.05767, found 320.05768.
4.3.2. 6-Formyl-2-hydroxy-4-methoxy-3-propyl-benzoic acid methyl
ester (4b). Starting with 3e (0.306 g, 1.0 mmol), NaOMe (0.165 g,
3.0 mmol) in dry MeOH (10 mL), 4b was obtained as a colourless
solid (0.194 g, 77%); mp¼72–73 ꢀC. 1H NMR (250 MHz, CDCl3):
4.2.7. 3-Allyl-6-dichloromethyl-2-hydroxy-4-methoxy-benzoic acid
methyl ester (3g). Starting with 1 (0.400 g, 2.0 mmol), 1-methoxy-
1,3-bis(trimethylsilyloxy)hepta-1,3,6-triene 2g (1.204 g, 4.0 mmol)
and TiCl4 (0.379 g, 2.0 mmol) in CH2Cl2 (4.0 mL), 3g was obtained as
d
¼0.93 (t, 3J¼7.4 Hz, 3H, CH2CH3), 1.46–1.58 (m, 2H, CH2CH3), 2.63–
2.68 (m, 2H, CArCH2), 3.89 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 6.92 (s,
1H, CHAr), 10.47 (s, 1H, CHO), 11.27 (s, 1H, OH). 13C NMR (75.5 MHz,
CDCl3):
d
¼14.1 (CH2CH3), 21.6, 25.1 (CH2CH2), 52.7 (OCH3), 55.8
a colourless oil (0.316 g, 52%). 1H NMR (300 MHz, CDCl3):
d¼3.41–
(OCH3), 103.1 (CHAr), 105.2, 123.6, 137.6, 161.2, 161.8 (CAr), 170.4

V. Karapetyan et al. / Tetrahedron 65 (2009) 9271–9279
9277
(C]O), 192.2 (CHO). IR (ATR, cmꢁ1):
n
¼2924 (w), 2867 (w), 1686
69 (17). HRMS (EI): Calculated for C9H8O3Cl2 (Mþ) 233.98450, found
233.98491.
~
(m),1660 (s),1570 (m),1503 (w),1435 (m), 1386 (m),1346 (m),1298
(s), 1285 (s), 1217 (s), 1135 (s), 1077 (m), 1036 (w), 999 (w), 951 (w),
875 (w), 795 (m), 754 (s), 610 (m). MS (EI, 70 eV): m/z (%)¼252 (Mþ,
66), 223 (52), 193 (100), 177 (42), 135 (18), 105 (17), 77 (28). HRMS
(EI): Calculated for C13H16O5 (Mþ) 252.09923, found 252.09915.
4.4.2. 2-Dichloromethyl-6-(2-oxo-2-phenyl-ethyl)-pyran-4-one
(5b). Starting with 1 (0.400 g, 2.0 mmol), (1,3-bis(trimethylsilyloxy)-
buta-1,3-dienyl)benzene 2j (1.224 g, 4.0 mmol) and TMSOTf
(0.488 g, 2.2 mmol) in CH2Cl2 (20 mL), 5b was obtained as a colour-
less solid (0.148 g, 25%); mp¼76–77 ꢀC. 1H NMR (300 MHz, CDCl3):
4.3.3. 3-Allyl-6-formyl-2-hydroxy-4-methoxy-benzoic acid methyl
ester (4c). Starting with 3g (0.304 g, 1.0 mmol), NaOMe (0.165 g,
3.0 mmol) in dry MeOH (10 mL), 4c was obtained as a colourless
solid (0.202 g, 81%); mp¼54–55 ꢀC. 1H NMR (300 MHz, CDCl3):
d
¼4.25 (s, 2H, CH2), 6.29 (d, 4J¼2.2 Hz, 1H, CHCO), 6.31 (s,1H, CHCl2),
6.53 (d, 4J¼2.2 Hz, 1H, CHCO), 7.49–7.54 (m, 2H, CHAr), 7.64 (ddd,
3J¼7.4 Hz, 3J¼6.2 Hz, 4J¼2.0 Hz, 1H, CHAr), 7.97–8.00 (m, 2H, CHAr).
d
¼3.44–3.47 (m, 2H, CArCH2), 3.91 (s, 3H, OCH3), 3.99 (s, 3H, OCH3),
13C NMR (62.9 MHz, CDCl3):
d¼43.2 (CH2CO), 65.2 (CHCl2), 113.0,
4.95–5.04 (m, 2H, CH2CHCH2), 5.85–5.98 (m, 1H, CH2CH), 6.94 (s,
117.2 (CHCO), 128.4, 129.0, 134.2 (CHAr), 135.5 (CAr), 161.3, 162.4
1H, CHAr), 10.49 (s, 1H, CHO), 11.32 (s, 1H, OH). 13C NMR (75.5 MHz,
(OCCH), 178.6 (C]O), 192.2 (CArCO). IR (ATR, cmꢁ1):
n
¼3076 (w),
~
CDCl3):
d
¼27.2 (CArCH2), 52.8 (OCH3), 56.0 (OCH3), 103.2 (CHAr),
2979 (m), 2662 (w), 2476 (w), 1668 (s), 1632 (s), 1609 (m), 1449 (w),
1392 (s), 1338 (m), 1299 (m), 1217 (m), 1196 (m), 1149 (m), 1078 (w),
978 (m), 964 (m), 923 (s), 879 (m), 824 (w), 767 (s), 734 (s), 690 (s),
666 (m), 587 (m). MS (EI, 70 eV): m/z (%)¼297 (Mþ, 6), 218 (32), 192
(15), 176 (100), 94 (32), 78 (8). HRMS (EI): Calculated for C14H11O3Cl2
((MþH)þ) 297.00798, found 297.0079.
105.4 (CAr), 115.1 (CH2CH), 120.6 (CAr), 134.9, (CH2CH), 138.1, 161.1,
161.7 (CAr), 170.3 (C]O), 192.2 (CHO). IR (ATR, cmꢁ1):
n
¼3077 (w),
~
2946 (w), 2845 (w), 1661 (s), 1602 (w), 1570 (s), 1504 (w), 1435 (m),
1408 (m), 1344 (m), 1284 (s), 1212 (s), 1158 (s), 1131 (s), 1035 (m),
995 (s), 910 (m), 876 (m), 797 (s), 750 (s), 631 (m). MS (EI, 70 eV):
m/z (%)¼250 (Mþ, 75), 222 (61), 191 (100), 175 (74), 147 (12), 119
(24), 91 (41). HRMS (EI): Calculated for C13H14O5 (Mþ) 250.08358,
found 250.08381.
4.4.3. (6-Dichloromethyl-4-oxo-4H-pyran-2-yl)-acetic acid ethyl ester
(5c). Starting with 1 (0.400 g, 2.0 mmol), 1-ethoxy-1,3-bis(trimethyl-
silyloxy)buta-1,3-diene 2a (1.096 g, 4.0 mmol) and TMSOTf (0.488 g,
2.2 mmol) in CH2Cl2 (20 mL), 5c was obtained as an orange oil (0.321 g,
4.3.4. 6-Formyl-2-hydroxy-4-methoxy-3-(3-phenyl-propyl)-benzoic
acid methyl ester (4d). Starting with 3h (0.153 g, 0.4 mmol), NaOMe
(0.083 g, 1.5 mmol) in dry MeOH (5 mL), 4d was obtained as a col-
ourless solid (0.110 g, 72%); mp¼65–67 ꢀC. 1H NMR (300 MHz,
61%). 1H NMR (300 MHz, CDCl3):
d
¼1.27 (t, 3J¼7.2 Hz, 3H, OCH2CH3),
3.59 (s, 2H, CCH2C), 4.21 (q, 3J¼7.2 Hz, 2H, OCH2CH3), 6.27 (d, 4J¼2.1 Hz,
1H, CHCO), 6.33 (s, 1H, CHCl2), 6.51 (d, 4J¼2.1 Hz, 1H, CHCO). 13C NMR
CDCl3):
d
¼1.80–1.90 (m, 2H, CArCH2CH2), 2.65–2.79 (m, 4H, CArCH2),
(75.5 MHz, CDCl3):
d
¼14.1 (OCH2CH3), 39.4 (CH2CO), 62.0 (OCH2CH3),
3.89 (s, 3H, OCH3), 3.99 (s, 3H, OCH3), 6.93 (s, 1H, CHAr), 7.15–7.26
65.1 (CHCl2),112.9,116.6 (CHCO),161.2,161.5 (OCCH),166.7 (COO),178.7
(m, 5H, CHAr), 10.48 (s, 1H, CHO), 11.31 (s, 1H, OH). 13C NMR
(C]O). IR (ATR, cmꢁ1):
n
¼3078 (w), 2983 (w), 1734 (s), 1659 (s), 1627
~
(62.9 MHz, CDCl3):
d
¼23.1, 29.7, 35.9 (CH2CH2CH2), 52.7 (OCH3),
(s), 1465 (w), 1393 (s), 1331 (w), 1250 (m), 1162 (m), 1026 (m), 975 (w),
928 (s), 873 (m), 760 (s), 734 (s), 621 (m), 590 (w). MS (EI, 70 eV): m/z
(%)¼264 (Mþ, 56),192 (80),157 (53),128 (100),109 (17), 69 (56). HRMS
(EI): Calculated for C10H10O4Cl2 (Mþ) 263.99507, found 263.99509.
55.8 (OCH3), 103.1 (CHAr), 105.2, 123.2 (CAr), 125.6, 128.1, 128.3
(CHAr), 137.7, 142.5, 161.2, 161.7 (CAr), 170.4 (C]O), 192.2 (CHO). IR
(ATR, cmꢁ1):
¼2937 (w), 2856 (w), 1746 (w), 1657 (s), 1569 (m),
~
n
1494 (w), 1438 (m), 1387 (m), 1341 (m), 1294 (s), 1273 (s), 1255 (s),
1200 (s), 1146 (s), 1107 (s), 1000 (s), 948 (m), 846 (m), 804 (m), 746
(s), 699 (s). MS (EI, 70 eV): m/z (%)¼328 (Mþ, 2), 269 (19), 224 (100),
192 (99), 164 (18), 105 (16), 77 (17). HRMS (EI): Calculated for
C19H20O5 (Mþ) 328.13053, found 328.13059.
4.4.4. (6-Dichloromethyl-4-oxo-4H-pyran-2-yl)-acetic acid isopropyl
ester (5d). Starting with 1 (0.400 g, 2.0 mmol), 1-isopropyloxy-1,3-
bis(trimethylsilyloxy)buta-1,3-diene 2k (1.114 g, 4.0 mmol) and
TMSOTf (0.488 g, 2.2 mmol) in CH2Cl2 (20 mL), 5d was obtained as
an orange oil (0.262 g, 47%). 1H NMR (300 MHz, CDCl3):
d
¼1.24 (d,
3J¼6.3 Hz, 6H, OCH(CH3)2), 3.56 (s, 2H, CCH2C), 5.01–5.10 (m,
3J¼6.3 Hz, 1H, OCH(CH3)2), 6.26 (d, 4J¼2.2 Hz, 1H, CHCO), 6.33 (s,
1H, CHCl2), 6.51 (d, 4J¼2.2 Hz, 1H, CHCO). 13C NMR (75.5 MHz,
4.4. General procedure for the synthesis of 5a–k
To a CH2Cl2 solution (10 mL) of 1 (1.0 mmol) was added 2
(2.0 mmol) and, subsequently, Me3SiOTf (0.244 g, 1.1 mmol) at
ꢁ78 ꢀC. The temperature of the solution was allowed to warm to
20 ꢀC during 12–14 h with stirring. To the solution was added
hydrochloric acid (10%, 10 mL) and the organic and the aqueous
layers were separated. The latter was extracted with CH2Cl2
(3ꢂ30 mL). The combined organic layers were dried (Na2SO4), fil-
tered and the filtrate was concentrated in vacuo. The residue was
purified by chromatography (silica gel, heptane–EtOAc¼15:1).
CDCl3):
d
¼21.6 (CH(CH3)2), 39.7 (CH2CO), 65.1 (CHCl2), 69.9
(COOCH), 112.7, 116.4 (CHCO), 161.3, 161.8 (OCCH), 166.2 (COO),
178.9 (C]O). IR (ATR, cmꢁ1):
n
¼3079 (w), 2982 (w), 1730 (m), 1659
~
(s), 1627 (m), 1454 (w), 1394 (s), 1321 (m), 1258 (m), 1172 (m), 1101
(s), 996 (m), 928 (s), 873 (m), 761 (m), 680 (w), 621 (m). MS (EI,
70 eV): m/z¼278 (Mþ, 11), 219 (14), 192 (27), 163 (11), 128 (12), 69
(15), 43 (100). HRMS (EI): Calculated for C11H12O4Cl2 (Mþ)
278.01072, found 278.01083.
4.4.5. (6-Dichloromethyl-4-oxo-4H-pyran-2-yl)-acetic acid isobutyl
ester (5e). Starting with 1 (0.400 g, 2.0 mmol), 1-isobutoxy-1,3-
bis(trimethylsilyloxy)buta-1,3-diene 2l (1.202 g, 4.0 mmol) and
TMSOTf (0.488 g, 2.2 mmol) in CH2Cl2 (20 mL), 5e was obtained as
4.4.1. 2-Dichloromethyl-6-(2-oxopropyl)-pyran-4-one (5a). Starting
with 1 (0.400 g, 2.0 mmol), 2,4-bis(trimethylsilyloxy)-penta-1,3-
diene 2i (0.978 g, 4.0 mmol) and TMSOTf (0.488 g, 2.2 mmol) in
CH2Cl2 (20 mL), 5a was obtained as a brownish viscous oil (0.099 g,
an orange oil (0.205 g, 35%). 1H NMR (250 MHz, CDCl3):
d
¼0.85 (d,
1
21%). H NMR (300 MHz, CDCl3):
d
¼2.30 (s, 3H, CH3), 3.68 (s, 2H,
3J¼6.8 Hz, 6H, CH(CH3)2), 1.80–1.96 (m, 3J¼6.8 Hz, 1H, CH(CH3)2),
3.58 (s, 2H, CCH2C), 3.88 (d, 3J¼6.7 Hz, 2H, OCH2CH), 6.25 (d,
4J¼2.2 Hz, 1H, CHCO), 6.36 (s, 1H, CHCl2), 6.48 (d, 4J¼2.2 Hz, 1H,
CH2), 6.24 (d, 4J¼2.1 Hz, 1H, CHCO), 6.32 (s, 1H, CHCl2), 6.52 (d,
4J¼2.1 Hz, 1H, CHCO). 13C NMR (62.9 MHz, CDCl3):
¼30.0 (CH3),
d
47.8 (CH2CO), 65.2 (CHCl2), 112.9, 116.9 (CHCO), 161.3, 161.9 (OCCH),
CHCO). 13C NMR (62.9 MHz, CDCl3):
d
¼18.8 (CH(CH3)2), 27.4
178.7 (CHC]O), 200.1 (CH2CO). IR (ATR, cmꢁ1):
n
¼3078 (w), 2922
(CH(CH3)2), 39.2 (CH2CO), 65.0 (CHCl2), 71.8 (COOCH2), 112.7, 116.4
~
(w), 1725 (m), 1656 (s), 1603 (m), 1394 (m), 1314 (m), 1213 (w), 1156
(s), 975 (w), 928 (s), 873 (m), 761 (s), 741 (s), 655 (m), 621 (w). MS
(EI, 70 eV): m/z (%)¼234 (Mþ, 1), 192 (100), 157 (27), 128 (7), 109 (8),
(CHCO), 161.3, 161.7 (OCCH), 166.7 (COO), 178.8 (C]O). IR (ATR,
cmꢁ1):
n
¼3080 (w), 2962 (w), 1736 (m), 1660 (s), 1629 (m), 1469
~
(w),1393 (s),1321 (w), 1246 (br m),1163 (s),1104 (w), 1005 (m), 928

9278
V. Karapetyan et al. / Tetrahedron 65 (2009) 9271–9279
(s), 874 (m), 761 (s), 683 (w), 622 (m). MS (EI, 70 eV): m/z¼292 (Mþ,
41), 237 (77), 192 (55), 163 (15), 128 (30), 99 (11), 69 (28), 57 (100),
41 (60). HRMS (EI): Calculated for C12H14O4Cl2 (Mþ) 292.02637,
found 292.02661.
1108 (m), 1015 (m), 978 (m), 907 (w), 850 (m), 788 (m), 758 (s), 671
(w), 637 (m). MS (EI, 70 eV): m/z (%)¼278 (Mþ, 21), 242 (99), 210
(100), 184 (21), 169 (51), 143 (21), 101 (11), 69 (24). HRMS (EI):
Calculated for C11H12O4Cl2 (Mþ) 278.01157, found 278.01148.
4.4.6. (6-Dichloromethyl-4-oxo-4H-pyran-2-yl)-acetic acid benzyl
ester (5f). Starting with 1 (0.400 g, 2.0 mmol), (1,3-bis(trimethyl-
silyloxy)buta-1,3-dienyloxymethyl)benzene 2m (1.344 g, 4.0 mmol)
and TMSOTf (0.488 g, 2.2 mmol) in CH2Cl2 (20 mL), 5f was obtained
4.4.10. (6-Dichloromethyl-3-heptyl-4-oxo-4H-pyran-2-yl)-acetic
acid ethyl ester (5j). Starting with 1 (0.400 g, 2.0 mmol), 1-ethoxy-
1,3-bis(trimethylsilyloxy)undeca-1,3-diene 2n (1.492 g, 4.0 mmol)
and TMSOTf (0.488 g, 2.2 mmol) in CH2Cl2 (20 mL), 5j was obtained
as an orange oil (0.197 g, 30%). 1H NMR (300 MHz, CDCl3):
d
¼3.64 (s,
as an orange oil (0.217 g, 30%). 1H NMR (300 MHz, CDCl3):
d
¼0.86 (t,
2H, CCH2C), 5.19 (s, 2H, OCH2C), 6.26 (s,1H, CHCl2), 6.29 (d, 4J¼2.1 Hz,
3J¼6.8 Hz, 3H, CH2CH3), 1.27 (t, 3J¼7.1 Hz, 3H, OCH2CH3), 1.29–1.46
(m, 10H, (CH2)5CH3), 2.36–2.41 (m, 2H, CCH2CH2), 3.68 (s, 2H,
CCH2C), 4.21 (q, 3J¼7.1 Hz, 2H, OCH2CH3), 6.31 (s, 1H, CHCl2), 6.57 (s,
1H, CHCO), 6.52 (d, 4J¼2.1 Hz,1H, CHCO), 7.33–7.38 (m, 5H, CHAr).13
C
NMR (75.5 MHz, CDCl3):
d
¼39.3 (CH2CO), 65.0 (CHCl2), 67.8
(CArCH2O), 112.9, 116.9 (CHCO), 128.5, 128.7 (CHAr), 134.1 (CAr), 161.3,
1H, CHCO). 13C NMR (75.5 MHz, CDCl3):
24.7, 28.4, 29.1, 29.6, 31.7 ((CH2)6CH3), 37.3 (CH2CO), 62.0
d
¼14.0, 14.1 (CH3), 22.6,
161.4 (OCCH),166.5 (COO),178.9 (C]O). IR (ATR, cmꢁ1):
¼3066 (w),
~
n
3004 (w), 1738 (m), 1659 (s), 1605 (br m), 1455 (w), 1395 (m), 1321
(w),1256 (m),1210 (m),1159 (s),1142 (s),1000 (m), 929 (m), 874 (m),
730 (s), 696 (s), 646 (w), 620 (m). MS (EI, 70 eV): m/z (%)¼326 (Mþ, 3),
219 (2), 192 (15), 158 (3), 91 (100), 65 (8). HRMS (EI): Calculated for
C15H12O4Cl2 (Mþ) 326.01072, found 326.01085.
(OCH2CH3), 65.2 (CHCl2), 111.6 (CHCO), 128.4 (CCH2CH2), 157.8,
160.4 (OC), 167.3 (COO), 179.0 (C]O). IR (ATR, cmꢁ1):
n
¼2926 (w),
~
2855 (w), 1739 (s), 1645 (s), 1464 (w), 1418 (m), 1267 (m), 1175 (s),
1107 (m), 1025 (m), 867 (w), 763 (s), 676 (m), 637 (w). MS (EI,
70 eV): m/z (%)¼362 (Mþ, 2), 316 (15), 275 (100), 241 (34), 206 (24),
155 (14), 91 (6). HRMS (EI): Calculated for C17H24O4Cl2 (Mþ)
362.10462, found 362.10426.
4.4.7. (6-Dichloromethyl-4-oxo-4H-pyran-2-yl)-acetic acid 2-methoxy-
ethyl ester (5g). Starting with 1 (0.400 g, 2.0 mmol), 1-(2-methoxy-
ethoxy)-1,3-bis(trimethylsilyloxy)buta-1,3-diene 2b (1.216 g, 4.0 mmol)
and TMSOTf(0.488 g, 2.2 mmol)inCH2Cl2 (20 mL), 5g was obtained as
a colourless solid (0.206 g, 35%); mp¼60–61 ꢀC. 1H NMR (300 MHz,
4.4.11. (6-Dichloromethyl-3-octyl-4-oxo-4H-pyran-2-yl)-acetic acid
ethyl ester (5k). Starting with 1 (0.400 g, 2.0 mmol), 1-ethoxy-1,3-
bis-trimethylsilanyloxy-dodeca-1,3-diene 2o (1.548 g, 4.0 mmol)
and TMSOTf (0.488 g, 2.2 mmol) in CH2Cl2 (20 mL), 5k was
obtained as an orange oil (0.188 g, 25%). 1H NMR (300 MHz, CDCl3):
CDCl3):
d
¼3.32 (s, 3H, OCH3), 3.54–3.57 (m, 2H, CH2OCH3), 3.61 (s, 2H,
CCH2C), 4.25–4.28 (m, 2H, COCH2), 6.25 (d, 4J¼2.1 Hz,1H, CHCO), 6.34
(s, 1H, CHCl2), 6.48 (d, 4J¼2.1 Hz, 1H, CHCO). 13C NMR (62.9 MHz,
d
¼0.86 (t, 3J¼6.8 Hz, 3H, CH2CH3), 1.27 (t, 3J¼7.2 Hz, 3H, OCH2CH3),
CDCl3):
d
¼39.0 (CH2CO), 58.8 (OCH3), 64.7 (OCH2CH2), 65.0 (CHCl2),
1.28–1.61 (m, 12H, (CH2)6CH3), 2.36–2.41 (m, 2H, CCH2CH2), 3.67 (s,
2H, CCH2C), 4.21 (q, 3J¼7.2 Hz, 2H, OCH2CH3), 6.30 (s, 1H, CHCl2),
69.9 (COOCH2), 112.9, 116.5 (CHCO), 161.2 (OCCH), 166.7 (COO), 178.5
(C]O). IR (ATR, cmꢁ1):
n
¼3085 (w), 3006 (w), 2888 (w),1732 (s),1653
6.50 (s, 1H, CHCO). 13C NMR (75.5 MHz, CDCl3):
d
¼14.0, 14.1 (CH3),
~
(s), 1617 (s), 1419 (w), 1400 (s), 1366 (m), 1280 (s), 1229 (m), 1181 (m),
1124 (s),1098 (m),1032 (s), 993 (m), 933 (s), 894 (s), 856(s), 759 (s), 733
(s), 625 (m). MS (EI, 70 eV): m/z¼294 (Mþ, 12), 228 (59), 192 (51), 158
(30), 128 (34), 99 (12), 69 (33), 45 (100). HRMS (EI): Calculated for
C11H12O5Cl2 (Mþ) 294.00563, found 294.05227.
22.6, 24.7, 28.4, 29.2, 29.4, 29.7, 31.8 ((CH2)7CH3), 37.3 (CH2CO), 61.9
(OCH2CH3), 65.3 (CHCl2), 111.7 (CHCO), 128.4 (CCH2CH2), 157.5,
160.3 (OC), 167.4 (COO), 178.7 (C]O). IR (ATR, cmꢁ1):
n
¼2925 (m),
~
2854 (w), 1740 (m), 1656 (s), 1602 (m), 1463 (w), 1415 (m), 1323 (w),
1252 (m), 1176 (s), 1107 (m), 1027 (m), 911 (w), 848 (w), 762 (s), 672
(w). MS (EI, 70 eV): m/z (%)¼376 (Mþ, 5), 330 (19), 289 (100), 278
(33), 255 (18), 206 (23), 177 (12), 155 (12), 69 (20). HRMS (EI):
Calculated for C18H26O4Cl2 (Mþ) 376.12027, found 376.12002.
4.4.8. (6-Dichloromethyl-3-methyl-4-oxo-4H-pyran-2-yl)-acetic acid
methyl ester (5h). Starting with 1 (0.400 g, 2.0 mmol), 1-methoxy-
1,3-bis(trimethylsilyloxy)penta-1,3-diene 2c (1.096 g, 4.0 mmol)
and TMSOTf (0.488 g, 2.2 mmol) in CH2Cl2 (20 mL), 5h was
obtained as an orange oil (0.184 g, 35%). 1H NMR (300 MHz, CDCl3):
Acknowledgements
d
¼1.95 (s, 3H, CCH3), 3.70 (s, 2H, CCH2C), 3.74 (s, 3H, OCH3), 6.33 (s,
Financial support from the State of Mecklenburg-Vorpommern
(scholarships for V.K., G.G. and for S.M.) is gratefully acknowledged.
1H, CHCl2), 6.54 (s, 1H, CHCO). 13C NMR (62.9 MHz, CDCl3):
d
¼9.8
(CCH3), 37.3 (CH2CO), 52.8 (OCH3), 65.1 (CHCl2), 111.2 (CHCO), 124.3
(CCH3), 157.4, 160.6 (OC), 167.5 (COO), 179.3 (C]O). IR (ATR, cmꢁ1):
~
n
¼3084 (w), 3002 (w), 1740 (m), 1656 (s), 1605 (m), 1411 (m), 1381
References and notes
(m),1322 (m),1271 (m),1204 (m),1155 (s), 1092 (m),1044 (w),1006
(m), 909 (w), 868 (w), 758 (s), 729 (s), 619 (m). MS (EI, 70 eV): m/z
(%)¼264 (Mþ, 92), 233 (25), 196 (100), 155 (86), 142 (58), 83 (4), 69
(34), 53 (27). HRMS (EI): Calculated for C10H10O4Cl2 (Mþ)
263.99507, found 263.99455.
1. Medwid, J. B.; Paul, R.; Baker, J. S.; Brockman, J. A.; Du, M. T.; Hallett, W. A.;
Hanifin, J. W.; Hardy, R. A., Jr.; Tarrant, M. E.; Torley, L. W.; Wrenn, S. J. Med.
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6. Chan, T. H.; Stossel, D. J. Org. Chem. 1986, 51, 2423.
4.4.9. (6-Dichloromethyl-3-ethyl-4-oxo-4H-pyran-2-yl)-acetic acid
methyl ester (5i). Starting with 1 (0.400 g, 2.0 mmol), 1-methoxy-
1,3-bis(trimethylsilyloxy)hexa-1,3-diene 2d (1.152 g, 4.0 mmol) and
TMSOTf (0.488 g, 2.2 mmol) in CH2Cl2 (20 mL), 5i was obtained as
a colourless solid (0.183 g, 33%); mp¼64–65 ꢀC. 1H NMR (250 MHz,
7. Mamat, C.; Pundt, T.; Dang, T. H. T.; Klassen, R.; Reinke, H.; Ko¨ckerling, M.;
Langer, P. Eur. J. Org. Chem. 2008, 492.
CDCl3):
d
¼1.00 (t, 3J¼7.5 Hz, 3H, CH2CH3), 2.37 (q, 3J¼7.5 Hz, 2H,
8. For a review of [3þ3] cyclizations of 1,3-bis(silyl enol ethers) see: Feist, H.;
Langer, P. Synthesis 2007, 327.
CH2CH3), 3.65 (s, 2H, CCH2C), 3.70 (s, 3H, OCH3), 6.32 (s, 1H, CHCl2),
9. For a review of 1,3-bis(silyl enol ethers) in general, see: Langer, P. Synthesis
2002, 441.
10. (a) Lubbe, M.; Bunescu, A.; Villinger, A.; Langer, P. Synlett 2008, 1862; (b)
Bunescu, A.; Reimann, S.; Lubbe, M.; Spannenberg, A.; Langer, P. J. Org. Chem.
2009, 74, 5002.
6.47 (s, 1H, CHCO). 13C NMR (62.9 MHz, CDCl3):
17.9 (CH2CH3), 36.8 (CH2CO), 52.6 (OCH3), 65.1 (CHCl2), 111.7
d
¼12.6 (CH2CH3),
(CHCO), 129.4 (CCH2CH3), 157.0, 160.2 (OC), 167.7 (COO), 178.3
(C]O). IR (ATR, cmꢁ1):
n
¼2995 (w), 2959 (w), 1739 (s), 1654 (s),
~
11. (a) Lubbe, M.; Mamat, C.; Langer, P. Synlett 2008, 1684; (b) Karapetyan, V.;
Mkrtchyan, S.; Lubbe, M.; Villinger, A.; Langer, P. Tetrahedron 2009, 65, 6211.
1601 (s), 1461 (w), 1415 (s), 1289 (w), 1263 (s), 1186 (m), 1131 (m),

V. Karapetyan et al. / Tetrahedron 65 (2009) 9271–9279
9279
12. For 1,1-diethoxy-4,4-dichlorobut-1-en-3-one, see: Scharf, H. D.; Sporrer, E.
Synthesis 1975, 733.
17. (a) Brownbridge, P.; Chan, T. H.; Brook, M. A.; Kang, G. . Can. J. Chem. 1983, 61,
688; (b) Hirai, K.; Ojima, I. Tetrahedron Lett. 1983, 24, 785.
13. (a) Hojo, M.; Masuda, R.; Okada, E. Synthesis 1986,1013; See also: (b) Effenberger,
F.; Maier, R.; Schoenwaelder, K.-H.; Ziegler, T. Chem. Ber. 1982, 115, 2766.
14. Chan, T. H.; Brownbridge, P. J. Am. Chem. Soc. 1980, 102, 3534.
15. Molander, G. A.; Cameron, K. O. J. Am. Chem. Soc. 1993, 115, 830.
16. Nguyen, V. T. H.; Bellur, E.; Appel, B.; Langer, P. Synthesis 2006, 2865.
18. CCDC-746023, 746024, 746025, and 746026 contains 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.