Synthesis of 3-aryl-3,4-dihydroisocoumarins by regioselective domino '[3+3] cyclization/lactonization' reactions of 1,3-bis-(silyloxy)-1,3-butadienes with 1-hydroxy-5-silyloxy-4-en-3-ones

Article abstract of DOI:10.1016/j.tetlet.2008.07.014

The [3+3] cyclization of 1,3-bis(silyloxy)-1,3-butadienes with 1-hydroxy-5-silyloxy-4-en-3-ones afforded 6-(2-aryl-2-chloroethyl)salicylates, which were transformed into 3-aryl-3,4-dihydroisocoumarins by silica gel-mediated lactonization.

Full text of DOI:10.1016/j.tetlet.2008.07.014

Tetrahedron Letters 49 (2008) 5400–5402
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 3-aryl-3,4-dihydroisocoumarins by regioselective domino
‘[3+3] cyclization/lactonization’ reactions of 1,3-bis-(silyloxy)-1,3-butadienes
with 1-hydroxy-5-silyloxy-4-en-3-ones
Muhammad Sher a,b, Asad Ali a,b, Helmut Reinke a, Peter Langer a,b,
*
a Institut für Chemie, Universität Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
b Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Straße 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:
The [3+3] cyclization of 1,3-bis(silyloxy)-1,3-butadienes with 1-hydroxy-5-silyloxy-4-en-3-ones afforded
6-(2-aryl-2-chloroethyl)salicylates, which were transformed into 3-aryl-3,4-dihydroisocoumarins by sil-
ica gel-mediated lactonization.
Received 22 May 2008
Revised 25 June 2008
Accepted 1 July 2008
Available online 4 July 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Arenes
Cyclizations
Regioselectivity
Silyl enol ethers
3-Aryl-3,4-dihydroisocoumarins
(3-aryl-isochroman-1-ones)
antiallergic activity,7 induction of steroidogenesis,8 phagocytic
activity,9 immunomodulatory activity on spleen lymphocyte
proliferation (activated by lipopolysaccharide, concanavalin A,
and phytohemagglutinin in mice),10 and antimicrobial activity.11
In a number of natural products, one of the hydroxyl groups of
the 3-aryl-3,4-dihydroisocoumarin core structure is glycosyl-
ated;12 this includes, for example, (ꢀ)-hydrangenol 40-O-glucoside9
and phyllodulcin 8-O-glucoside.1a,11a
are of considerable pharmacological relevance and occur in many
natural products. For example, the natural products thunberginol
C, D, and E (Chart 1) and related natural products have been
reported to promote the adipogenesis of murine 3T3-L1 cells1a
and show antiproliferative activity against mouse splenocytes.1b
Hydrangenol exhibits cytotoxic activity against human gastric
cancer cell lines and human nasopharyngeal carcinoma cell lines.2
Related natural products3 have been reported to show antifungal
activity,4 inhibition of rat basophilic leukemia RBL-2H3 cells,5
antiproliferative activity against C57/BL6 mouse splenocytes,6
Chan and coworkers were the first to report13 the TiCl4-medi-
ated [3+3] cyclization14 of 1,3-bis(trimethylsilyloxy)-1,3-butadi-
enes15 with 3-silyloxy-2-en-1-ones, which allows a convenient
synthesis of salicylates. In recent years, we studied the application
of this reaction to the synthesis of various functionalized arenes.
Recently, we reported the synthesis of dibenzo[b,d]pyran-6-
ones based on a [3+3] cyclization/lactonization strategy.16 Herein,
we report what are, to the best of our knowledge, the first
domino17 ‘[3+3] cyclization/lactonization’ reactions of 1,3-bis-
(silyloxy)-1,3-butadienes with 1-hydroxy-5-silyloxy-4-en-3-ones.
These reactions proceed with very good regioselectivity and pro-
vide a convenient approach to 3-aryl-3,4-dihydroisocoumarins,
which are not readily available by other methods.
The reaction of the dianion of acetylacetone (1) with aldehydes
2a–c afforded, following a known procedure,18 condensation prod-
ucts 3a–c (Scheme 1, Table 1). The NEt3-mediated reaction of 3a–c
with Me3SiCl resulted in chemoselective formation of 1-aryl-1-
hydroxy-5-silyloxy-4-en-3-ones 4a–c. Notably, a silylation of the
hydroxy group was not observed.
OH
O
O
R2
R1
OH
Hydrangenol (R1 = H, R2 = H)
Thunberginol C (R1 = OH, R2 = H)
Thunberginol D (R1 = OH, R2 = OH)
Chart 1. 3-Aryl-3,4-dihydroisocoumarins in nature.
* Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.07.014

M. Sher et al. / Tetrahedron Letters 49 (2008) 5400–5402
5401
O
O
Me3SiO
O
OSiMe3
OMe
i
O
O
OH
OH
O
+
Me
Me
R
Me
ii
R
OMe
Cl
TiCl4
i
2a-c
5a
+
1
3a-c
Me
Me3SiO
Me
O
OH
Ph
Me3SiO
Me
O
OH
Ph
6a
R
4a
4a-c
TiO
HCl,
H2O
2
TiCl4
HCl
Scheme 1. Synthesis of 1-aryl-1-hydroxy-5-silyloxy-4-en-3-ones 4a–c: Reagents
and conditions: (i) (1) 1, 2.5 LDA, THF, 1 h, 0 °C; (2) 2a–c, ꢀ78?20 °C, 14 h; (3)
NaHCO3, H2O; (ii) NEt3, Me3SiCl, CH2Cl2, 20 °C, 14 h.
TiCl2(OH)2
OH
O
TiCl3
O
OMe
Table 1
Me3SiO
Me
O
Synthesis of 1-hydroxy-5-silyloxy-4-en-3-ones 4a–c
Me
a
a
Ph
3,4
R
%
%
Ph
E
Cl
A
a
b
c
Ph
4-MeC6H4
4-ClC6H4
70
66
60
86
92
88
5a
Me3SiCl
a
Yields of isolated products.
O
O
O
O
OMe
Cl2
Me3SiO
The TiCl4-mediated [3+3] cyclization of 4a with 1,3-bis(silyl
Ti
OMe
TiCl2OH
Cl
enol ether) 5a, readily available from methyl acetoacetate,13 affor-
ded the novel 6-(2-phenyl-2-chloroethyl)salicylate 6a (Scheme 2).
The best yield was obtained when the reaction was carried out in a
highly concentrated solution.19 Notably, the cyclization proceeded
with excellent regioselectivity. In fact, the formation of the regio-
isomeric 4-(2-phenyl-2-chloroethyl)salicylate was not observed.
The formation of product 6a might be explained by reaction of
TiCl4 with 4a to give intermediate A and hydrogen chloride. The
conjugate addition of the (most reactive) terminal carbon atom
of 5a to A afforded 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. The latter underwent aromatiza-
tion to give intermediate E. Product 6a is formed upon aqueous
work-up. Interestingly, the presence of the free hydroxy group of
4a seems to be important to achieve a high degree of regioselectiv-
ity. The presence of a methoxy rather than a hydroxyl group
resulted in the formation of a mixture of regioisomers.
O
O
Me
Me
Me3SiO
Ph
Ph
B
D
HCl
(Me3Si)2O
O
O
O
OMe
TiCl2
O
Me
Ph
C
Scheme 2. Possible mechanism of the formation of 6a: Reagents and conditions: (i)
(1) TiCl4, CH2Cl2, ꢀ78?20 °C, 14 h; (2) NaHCO3, H2O.
Stirring of a solution of 6a in wet THF in the presence of silica
gel afforded the 3-phenyl-3,4-dihydroisocoumarin 7a in 69%
yield (Scheme 3, Table 2).20 The formation of 7a can be explained
by acid-mediated hydrolysis of the chloride and subsequent
lactonization.
Me3SiO
R2
OSiMe3
OR1
OH
O
OR1
Cl
5a-j
TiCl4
i
Me
+
O
Me3SiO
Me
OH
The [3+3] cyclization of 4a with 1,3-bis(silyloxy)-1,3-butadi-
enes 5b–d, containing an alkyl group attached to carbon atom
C4, directly afforded the 3-phenyl-3,4-dihydroisocoumarins 7b–
d. The formation of 7b–d can be explained by [3+3] cyclization
to give 6-(2-phenyl-2-chloroethyl)salicylates, which subsequently
hydrolyzed and underwent a lactonization during the aqueous
work-up or silica gel chromatography. This process can be
regarded as a domino ‘[3+3] cyclization/lactonization’ reaction.
The cyclization of 4a with 1,3-bis(silyloxy)-1,3-butadienes 5e,f
resulted in the formation of 6-(2-phenyl-2-chloroethyl)salicylates
6e,f, which were transformed, by treatment with silica gel, into
the 3-phenyl-3,4-dihydroisocoumarins 7e,f. The cyclization of 4a
with 1,3-bis(silyloxy)-1,3-butadienes 5g,h afforded the ethyl and
isopropyl salicylates 6g,h. Notably, the SiO2-mediated lactoniza-
tion proved to be unsuccessful for these substrates. The cyclization
of 4b with 5a,b,e,i directly afforded the 3-(4-tolyl)-3,4-
dihydroisocoumarins 7i–l. The reaction of 4b with 5j gave the
benzyl salicylate 6m, which could not be transformed into 7m.
Ar
Ar
6a-o
4a-c
TiCl4
i
ii
OH
O
R2
O
Me
Ar
7a-o
Scheme 3. Synthesis of 6a–o and 7a–o: Reagents and conditions: (i) (1) TiCl4,
CH2Cl2, ꢀ78?20 °C, 14 h; (2) NaHCO3, H2O; (ii) SiO2, wet THF, 14 h.
The cyclization of 5a with 4c directly afforded the 3-(4-chloro-
phenyl)-3,4-dihydroisocoumarin 7n. The reaction of 4c with 5j
gave the benzyl salicylate 6o; its transformation into 7o proved
to be unsuccessful.

5402
M. Sher et al. / Tetrahedron Letters 49 (2008) 5400–5402
Table 2
References and notes
Synthesis of 6-(2-aryl-2-chloroethyl)salicylates 6a–o and 3-aryl-3,4-dihydroiso-
coumarins 7a–o
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.
2. Patnam, R.; Chang, F.-R.; Chen, C.-Y.; Kuo, R.-Y.; Lee, Y.-H.; Wu, Y.-C. J. Nat. Prod.
2001, 64, 948.
3. Yasuda, T.; Kayaba, S.; Takahashi, K.; Nakazawa, T.; Ohsawa, K. J. Nat. Prod.
2004, 67, 1604.
4. Nozawa, K.; Yamada, M.; Tsuda, Y.; Kawai, K.-I.; Nakajima, S. Chem. Pharm. Bull.
1981, 29, 2689.
5. Wang, Q.; Matsuda, H.; Matsuhira, K.; Nakamura, S.; Yuan, D.; Yoshikawa, M.
Biol. Pharm. Bull. 2007, 30, 388.
6. Shimoda, H.; Matsuda, H.; Yamahara, J.; Yoshikawa, M. Biol. Pharm. Bull. 1998,
21, 809.
7. Matsuda, H.; Shimoda, H.; Yamahara, J.; Yoshikawa, M. Biol. Pharm. Bull. 1999,
22, 870.
8. Kawamura, M.; Kagata, M.; Masaki, E.; Nishi, H. Pharmacol. Toxicol.
(Copenhagen) 2002, 90, 106.
4
5
6,7
R1
R2
Ar
% (6)a
% (7)a
a
a
a
a
a
a
a
a
b
b
b
b
b
c
a
b
c
d
e
f
g
h
a
b
i
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
Me
Me
Me
Me
Me
Me
Et
H
Me
Et
nDec
Allyl
OMe
H
H
H
Me
nBu
Allyl
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
52
0
0
69
48
33
54
55
66
0
0
33
44
37
40
0
0
0
0
32
0
iPr
0
Me
Me
Me
Me
Bn
41
43
62
35
0
e
j
a
j
Me
Bn
H
H
55
0
9. Umehara, K.; Matsumoto, M.; Nakamura, M.; Miyase, T.; Kuroyanagi, M.;
Noguchi, H. Chem. Pharm. Bull. 2000, 48, 566.
c
34
10. Matsuda, H.; Shimoda, H.; Yamahara, J.; Yoshikawa, M. Bioorg. Med. Chem. Lett.
1998, 8, 215.
a
Yields of isolated products.
11. (a) Yoshikawa, M.; Matsuda, H.; Shimoda, H.; Shimada, H.; Harada, E. Chem.
Pharm. Bull. 1996, 44, 1440; (b) Yoshikawa, M.; Harada, E.; Naitoh, Y.; Inoue, K.;
Matsuda, H. Chem. Pharm. Bull. 1994, 42, 2225; (c) Yoshikawa, M.; Uchida, E.;
Chatani, N.; Kobayashi, H.; Naitoh, Y. Chem. Pharm. Bull. 1992, 40, 3352.
12. (a) Tori, M.; Asakawa, Y. Phytochemistry 1987, 26, 3323; (b) Matsuda, H.;
Shimoda, H.; Yoshikawa, M. Bioorg. Med. Chem. 1999, 7, 1445.
13. (a) Chan, T.-H.; Brownbridge, P. J. Am. Chem. Soc. 1980, 102, 3534; (b)
Brownbridge, P.; Chan, T.-H.; Brook, M. A.; Kang, G. J. Can. J. Chem. 1983, 61, 688.
14. For a review of [3+3] cyclizations, see: Feist, H.; Langer, P. Synthesis 2007, 327.
15. For a review of 1,3-bis(silyl enol ethers), see: Langer, P. Synthesis 2002, 441.
16. (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.
17. For reviews of domino reactions, see: (a) Tietze, L. F.; Beifuss, U. Angew. Chem.,
Int. Ed. Engl. 1993, 32, 131; Tietze, L. F.; Beifuss, U. Angew. Chem. 1993, 105, 137;
(b) Tietze, L. F. Chem. Rev. 1996, 96, 115.
18. Weiler, L. J. Am. Chem. Soc. 1970, 92, 6702.
19. Typical procedure: synthesis of methyl 4-methyl-6-(2-phenyl-2-chloroethyl)-
salicylate (6a): To a CH2Cl2 solution (5 mL) of 5a (500 mg, 1.91 mmol) and 4a
(490 mg, 2.07 mmol) was dropwise added TiCl4 (0.22 mL, 2.07 mmol) at
ꢀ78 °C. The reaction mixture was allowed to warm to 20 °C during 6–12 h.
After stirring for additional 2–6 h at 20 °C, a saturated aqueous solution of
NaHCO3 (20 mL) was added. The organic and the aqueous layers were
separated and the latter was extracted with diethyl ether (3 ꢁ 25 mL). The
combined organic layers were dried (NaSO4), filtered, and the filtrate was
concentrated in vacuo. The residue was purified by chromatography (silica gel,
heptane/ethyl acetate) to give 6a as a colorless solid (302 mg, 52%). 1H NMR
(300 MHz, CDCl3): d = 2.22 (s, 3H, CH3), 3.61 (dd, 2H, J = 7.4, 2.9 Hz, CH2), 3.93
(s, 3H, OCH3), 5.02 (dd, 1H, J = 7.4, 6.2 Hz), 6.41 (s, 1H, ArH), 6.72 (s, 1H, ArH),
7.29–7.35 (m, 5H, Ph), 11.23 (s, 1H, OH). 13C NMR (75 MHz, CDCl3): d = 21.5
(CH3), 46.7 (CH2), 52.3 (OCH3), 64.1 (CH), 109.5 (C), 117.3, 125.9, 126.9, 128.3,
~
Figure 1. Ortep plot of 6a (50% probability level); the position of the OH-proton
was calculated from the difference map and refined freely.
128.5 (CHAr), 139.4, 141.6, 145.3, 163.0, 171.3 (C). IR (KBr):
m ¼ 2955 (w), 1653
(s), 1568 (m), 1452 (s), 1317 (s), 1261 (s), 1207 (s), 1092 (s), 955 (m), 855 (m)
728 (s), 691 (s) cmꢀ1. GC–MS (EI, 70 eV): m/z (%) = 304 (M+, 35Cl, 35), 306 (M+,
37Cl, 13), 268 (32), 237 (86), 208 (24), 179 (100), 165 (31), 125 (45), 119 (21),
89 (15), 77 (13). HRMS (EI): calcd for C17H17O3Cl [M]+: 304.087148; found:
304.08607.
The structures of all products were confirmed by spectroscopic
methods. The structure of 6a was independently confirmed by
X-ray crystal structure analysis (Fig. 1).21
20. Typical procedure: synthesis of 8-hydroxy-6-methyl-3-phenylisochroman-1-one
(7a): To a THF solution of 6a (190 mg, 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 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 acetate) to give 7a as a colorless
solid (110 mg, 69%). 1H NMR (300 MHz, CDCl3): d = 2.34 (s, 3H, CH3), 3.07 (dd,
1H, J = 16.5, 3.3 Hz, CH2), 3.27 (dd, 1H, J = 16.3, 3.3 Hz, CH2), 5.56 (dd, 1H,
J = 12.0, 3.3 Hz), 6.56 (s, 1H, ArH), 6.74 (s, 1H, ArH), 7.39–7.45 (m, 5H, Ph),
10.92 (s, 1H, OH). 13C NMR (75 MHz, CDCl3): d = 22.0 (CH3), 35.2 (CH2), 80.7
(CH), 105.9 (C), 116.5, 119.1, 126.1, 128.7, 128.8 (CHAr), 138.0, 139.0, 148.1,
~
In conclusion, we have reported a convenient synthesis of
3-aryl-3,4-dihydroisocoumarins by domino ‘[3+3] cyclization/
lactonization’ reactions of 1,3-bis(silyloxy)-1,3-butadienes with
1-hydroxy-5-silyloxy-4-en-3-ones. These reactions proceed by
regioselective [3+3] cyclization to give 6-(2-aryl-2-chloroethyl)-
salicylates and subsequent silica gel-mediated lactonization. Under
the reaction conditions, a smooth lactonization is observed for
methyl, but not for ethyl, isopropyl, and benzyl salicylates. We
are currently studying the preparative scope of our methodology
and applications to the synthesis of pharmacologically active nat-
ural products and their analogues.
1662.2, 169.7 (C). IR (KBr):
m ¼ 3089 (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
(%) = 254 (M+, 100), 236 (69), 208 (61), 179 (40), 165 (51), 148 (31), 91 (28), 77
(22). Elemental Anal. Calcd for C16H14O3 (254.28): C, 75.57; H, 5.55. Found: C,
75.11; H, 5.56.
Acknowledgement
21. CCDC 689390 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: (+44)1223-336-033; or
deposit@ccdc.cam.ac.uk.
Financial support by the Friedrich-Irmgard-Harms-Stiftung
(scholarship for A.A.) is gratefully acknowledged.