The first 4-chloro-1,3-bis(trimethylsilyloxy)-1,3-diene and its application to the regioselective synthesis of chlorinated arenes

Article abstract of DOI:10.1016/j.tetlet.2008.01.139

Chlorinated phenols, benzophenones, and butenolides are prepared by various one-pot cyclization reactions of the first 4-chloro-1,3-bis(trimethylsilyloxy)-1,3-butadiene.

Full text of DOI:10.1016/j.tetlet.2008.01.139

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 2329–2332
The first 4-chloro-1,3-bis(trimethylsilyloxy)-1,3-diene and its
application to the regioselective synthesis of chlorinated arenes
Stefanie Reim a, Peter Langer a,b,
*
a Institut fu¨r Chemie, Universita¨t 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
Received 19 December 2007; accepted 23 January 2008
Available online 12 February 2008
Abstract
Chlorinated phenols, benzophenones, and butenolides are prepared by various one-pot cyclization reactions of the first 4-chloro-1,3-
bis(trimethylsilyloxy)-1,3-butadiene.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Arenes; Chlorinated products; Cyclizations; Silyl enol ethers
Functionalized chloroarenes are of considerable
pharmacological relevance1 and represent increasingly
important building blocks for transition metal-catalyzed
cross-coupling reactions.2 3-Chlorosalicylates and related
compounds are present in a variety of natural products.
This includes, for example, dihydronidulin.3 The spiro-
cyclic griseofulvin4 and epigriseofulvin5 have been reported
to show clastogenic, cytotoxic and antifungal activity.
Polyketide-derived xanthones,6 geodin7 and geodin-
hydrate-methyl ester8 show, for example, antibacterial
and antifungal activity. 7-Chloro-1-O-methylemodin has
been reported to exhibit antiviral activity.9 3-Chlorosali-
cylates and related compounds are also present in simple
arenes, acetophenones (longissiminone B), benzophenones
(chloroisosulochrin, pestalone) and diaryl ethers (methyl
chloroasterrate),10 falconensin B,11 natural chromones12
and in 7-chloro-8-hydroxy-6-methoxy-3-methyl-isochro-
man-1-one.13
the first synthesis of a chlorinated 1,3-bis(silyloxy)-1,3-
butadiene and synthetic applications of this useful building
block. The one-pot cyclizations reported herein provide a
convenient and regioselective approach to various sterically
encumbered, heavily substituted chlorinated products,
which are not readily available by other methods. Classic
syntheses of chloroarenes, based on direct chlorinations,
suffer from many drawbacks, such as low regioselectivities
and yields. In fact, the assembly of highly substituted and
functionalized arenes can be a difficult task.
O
O
Me3SiO
Cl
O
i
Cl
OMe
OMe
2 (93%)
1
ii
OR OR
RO
OR
OH
R1
O
1,3-Bis(trimethylsilyloxy)-1,3-butadienes (e.g., Chan’s
diene)14 represent important synthetic building blocks,
which have been used in formal [3+2], [3+3], [4+2] and
[4+3] cyclizations and various other transformations.15,16
Herein, we report what is, to the best of our knowledge,
R1
4a-e
Cl
Me3SiO OSiMe3
OMe
Cl
OMe
iii
3 (65%)
5a-e
R = Me, Et
Scheme 1. Synthesis of 5a–e. Reagents and conditions: (i) Me3SiCl, NEt3,
C6H6, 20 °C, 72 h; (ii) (1) LDA, THF, ꢀ78 °C, 1 h, (2) Me3SiCl,
ꢀ78 ? 20 °C; (iii) TiCl4, CH2Cl2, ꢀ78 ? 20 °C, 20 h.
*
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.2008.01.139

2330
S. Reim, P. Langer / Tetrahedron Letters 49 (2008) 2329–2332
Table 1
Noteworthy, product 7f was formed with very good regio-
Synthesis of 3-chlorosalicylates 5a–e
selectivity, which can be explained by TiCl4-mediated
isomerization of 6f, conjugate addition by the attack of car-
bon atom C-4 of 3 onto 6f and subsequent cyclization.16
The TiCl4-mediated reaction of 1,3-bis(silyloxy)-1,3-
diene 3 with 1,1-diacetylcyclopropane (8) afforded 3-chlo-
rosalicylate 9 (30%) containing a remote chloride function
(Scheme 3). The formation of the product can be explained
by means of a domino ‘[3+3]-cyclization-homo-Michael’
reaction.21
4, 5
R1
5a (%)
a
b
c
d
e
a
H
Me
CH(Me)2
(CH2)4Me
(CH2)6Me
30
35
36
52
30
Yields of isolated products.
The silylation of commercially available methyl 4-chlo-
roacetoacetate (1) gave 3-silyloxy-2-en-1-one 2 (Scheme
1). 4-Chloro-1-methoxy-1,3-bis(silyloxy)-1,3-butadiene (3)
was prepared by the deprotonation (LDA) of 2 at
ꢀ78 °C and subsequent addition of trimethylchlorosilane.
Noteworthy, the chloro group proved to be compatible
with the reaction conditions. Diene 3 can be stored at
ꢀ20 °C under inert atmosphere for several weeks. The
TiCl4-mediated cyclization of 4-chloro-1,3-bis(silyloxy)-
1,3-diene 3 with 1,1,3,3-tetramethoxypropane (4a) and
1,1,3,3-tetraethoxypropanes 4b–e,17 following a protocol
reported by Chan14 and by us,18 afforded 3-chlorosalicy-
lates 5a–e. During the optimization of the reaction, the
(high) concentration and the stoichiometry proved to be
important parameters.19 The Me3SiOTf-catalyzed20
(0.1 equiv) cyclization of 3 with 4a also afforded 5a, albeit,
in low yield (see Table 1).
The Me3SiOTf-catalyzed reaction of 1,3-bis(silyloxy)-
1,3-diene 3 with 3-formylchromone (10) afforded the
chlorinated 2,40-dihydroxybenzophenone 11 in 33% yield
(Scheme 4). The product is formed by a domino
‘Michael–retro-Michael–Mukaiyama-Aldol’ reaction.22
The TiCl4-mediated reaction of 1,3-bis(silyloxy)-1,3-
diene 3 with 1-methoxybut-1-en-3-one (12) afforded the
3-chlorosalicylate 13 (30%) (Scheme 5). The cyclization
proceeded by conjugate addition of carbon atom C-4 of 3
onto 12 and subsequent Mukaiyama-Aldol reaction.
The Me3SiOTf-catalyzed cyclization of 1,3-bis(silyloxy)-
1,3-diene 3 with oxalyl chloride (14) afforded the chlori-
nated c-alkylidenebutenolide 15 in 55% yield (Scheme 6).
Me3SiO OSiMe3
OH
O
Cl
Cl
OMe
TiCl4
i
OMe
3
The TiCl4-mediated [3+3] cyclization of 4-chloro-1,3-
bis(silyloxy)-1,3-diene 3 with 3-silyloxy-2-en-1-ones 6a–g,
prepared by silylation of the corresponding 1,3-diketones,
afforded 3-chlorosalicylates 7a–g (Scheme 2, Table 2). Dur-
ing the optimization, it proved again to be important to
carry out the reactions in a highly concentrated solution.19
O
O
Me
Me
Cl
+
Me
Me
8
9
Scheme 3. Synthesis of 9. Reagents and conditions: (i) TiCl4, CH2Cl2,
ꢀ78 ? 20 °C, 20 h.
Me3SiO OSiMe3
Cl
OH
O
Me3SiO OSiMe3
Cl
OMe
3
Cl
R1
OMe
i
OMe
O
O
O
OSiMe3
R3
3
Cl
R3
OMe
OH
i
O
O
H
1
+
R2
R
Cl
+
R2
OH
7a-g
6a-g
Cl
O
Scheme 2. Synthesis of 7a–g. Reagents and conditions: (i) TiCl4, CH2Cl2,
ꢀ78 ? 20 °C, 20 h.
11
10
Scheme 4. Synthesis of 11. Reagents and conditions: (i) (1) 10, Me3SiOTf
(0.3 equiv), 20 °C, 10 min; (ii) 3 (1.3 equiv), CH2Cl2, 0 ? 20 °C, 12 h; (3)
HCl (10%).
Table 2
Synthesis of 3-chlorosalicylates 7a–g
6, 7
R1
R2
R3
7a (%)
Me3SiO
Cl
OSiMe3
OMe
a
b
c
d
e
f
Me
Me
Me
Et
Me
Me
Me
Me
H
Cl
H
Et
H
Me
Me
Me
Et
Me
Ph
40
36
36
40
44
42
42b
OH
O
i
Cl
3
OMe
Me
MeO
+
O
Me
13
12
g
a
–(CH2)4–
Isolated yields.
Regioisomers.
Scheme 5. Synthesis of 13. Reagents and conditions: (i) TiCl4, CH2Cl2,
ꢀ78 ? 20 °C, 20 h.
b

S. Reim, P. Langer / Tetrahedron Letters 49 (2008) 2329–2332
2331
10. (a) Ahad, A. M.; Goto, Y.; Kiuchi, F.; Tsuda, Y.; Kondo, K.; Sato,
T. Chem. Pharm. Bull. 1991, 39, 1043; (b) Kim, Y.-J.; Nishida, H.;
Pang, C.-H.; Saito, T.; Shinichi, S.; Tonai-Kachi, H.; Yoshikawa, N.;
Vanvolkenburg, M. A.; Parkerf, J. C.; Kojima, Y. J. Antibiot. 2002,
55, 121; Longissiminone B: (c) Choudhary, M. I.; Azizuddin, M.;
Jalil, S.; Atta-ur-Rahman Phytochemistry 2005, 66, 2346; Chloro-
isosulochrin: (d) Shimada, A.; Takahashi, I.; Kawano, T.; Kimura, Y.
Z. Naturforsch., B: Chem. Sci. 2001, 56, 797; Pestalone: (e) Cueto, M.;
Jensen, P. R.; Kauffman, C.; Fenical, W.; Lobkovsky, E.; Clardy, J. J.
Nat. Prod. 2001, 64, 1444; (f) Iijima, D.; Tanaka, D.; Hamada, M.;
Ogamino, T.; Ishikawa, Y.; Nishiyama, S. Tetrahedron Lett. 2004, 45,
5469; Methyl chloroasterrate: (g) Hargreaves, J.; Park, J.-O.; Ghisal-
berti, E. L.; Sivasithamparam, K.; Skelton, B. W.; White, A. H. J.
Nat. Prod. 2002, 65, 7; (h) Lee, H. J.; Lee, J. H.; Hwang, B. Y.; Kim,
H. S.; Lee, J. J. J. Antibiot. 2002, 55, 552.
11. Falconensin B: Itabashi, T.; Nozawa, K.; Miyaji, M.; Udagawa, S.-i.;
Nakajima, S.; Kawai, K.-i. Chem. Pharm. Bull. 1992, 40, 3142.
12. Chromones: Kawamura, N.; Sawa, R.; Takahashi, Y.; Issiki, K.;
Sawa, T. J. Antibiot. 1995, 48, 435.
13. Hoeller, U.; Koening, G.; Wright, A. D. J. Nat. Prod. 1999, 62, 114.
14. (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.
Me3SiO OSiMe3
Cl
Cl
OMe
3
i
HO
OMe
O
Cl
O
O
O
+
Cl
O
15
14
Scheme 6. Synthesis of 15. Reagents and conditions: (i) Me3SiOTf
(0.3 equiv), CH2Cl2, ꢀ78 ? 20 °C, 20 h.
The formation of this product can be explained by the
attack of carbon atom C-4 of 3 onto 14 and subsequent
regioselective cyclization via the neighboured oxygen atom
of 3.23 The exocyclic double bond was formed with high
Z-diastereoselectivity (due to the steric influence of the
chlorine atom).
In conclusion, a variety of highly substituted chlorinated
arenes and hetarenes were regioselectively prepared by one-
pot cyclizations of the first 4-chloro-1,3-bis(trimethylsilyl-
oxy)-1,3-butadiene. The products are not readily available
by other methods.
15. For a review of 1,3-bis(trimethylsilyloxy)-1,3-dienes in general, see:
Langer, P. Synthesis 2002, 441.
16. For a review of [3+3] cyclizations, see: Feist, H.; Langer, P. Synthesis
2007, 327.
17. (a) Ruegg, R.; Lindlar, H.; Montavon, M.; Savey, G.; Schaeren, S. T.;
Schwieter, U.; Isler, O. Helv. Chim. Acta 1959, 42, 844; (b) Ruegg, R.;
Lindlar, H.; Montavon, M.; Savey, G.; Schaeren, S. T.; Schwieter, U.;
Isler, O. Helv. Chim. Acta 1959, 42, 859.
Acknowledgement
Financial support from the State of Mecklenburg-
Vorpommern is gratefully acknowledged.
18. Mamat, C.; Buttner, S.; Trabhardt, T.; Fischer, C.; Langer, P. J. Org.
¨
Chem. 2007, 72, 6273.
19. General procedure for the synthesis of salicylates 5 and 7: To a stirred
CH2Cl2 solution of 3 (1.0 equiv) was added 1,1,3,3-tetraalkoxypro-
pane 4a–e (0.5 equiv) or 3-(silyloxy)alk-2-en-1-one 6a–g (1.0 equiv) at
ꢀ78 °C under argon atmosphere. Subsequently, TiCl4 (1.0 equiv) was
dropwise added. The temperature of the reaction mixture was allowed
to rise to 20 °C during 20 h. The solution was poured into an aqueous
solution of HCl (10%). The organic layer was separated and the
aqueous layer was repeatedly extracted with CH2Cl2. The combined
organic layers were dried (Na2SO4) and filtered. The filtrate was
concentrated in vacuo and the residue was purified by chromato-
graphy (silica gel, n-heptane/EtOAc) to give salicylates 5 or 7. Methyl
3-chloro-2-hydroxybenzoate (5a): Starting with 3 (0.590 g, 2.0 mmol),
1,1,3,3-tetramethoxypropane (4a) (0.164 g, 1.0 mmol) and TiCl4
(0.22 mL, 2.0 mmol) in CH2Cl2 (2 mL), 5a was isolated after column
chromatography (silica gel, n-heptane/EtOAc = 20:1) as a yellow oil
(0.074 g, 36%). 1H NMR (300 MHz, CDCl3): d = 3.96 (s, 3H, OCH3),
6.83 (t, 3J = 8.0 Hz, 1H, CH), 7.54 (dd, 2J = 1.7 Hz, 3J = 6.3 Hz, 1H,
CH), 7.76 (dd, 2J = 1.7 Hz, 3J = 6.3 Hz, 1H, CH), 11.33 (s, 1H, OH).
13C NMR(75 MHz, CDCl3): d = 52.7 (OCH3), 113.6 (CAr), 119.2
(CH), 122.2 (CAr), 128.4, 135.8 (CH), 157.3 (COH), 170.3 (COOCH3).
IR (ATR, cmꢀ1): ~m ¼ 3090 (w), 2955 (w), 2926 (w), 2853 (w), 1732 (w),
1675 (s), 1607 (m), 1438 (s), 1322 (s), 1282 (m), 1252 (s), 1197 (s), 1176
(s), 1151 (s), 1073 (m). MS (GC–MS, 70 eV): m/z (%) = 188 ([M]+,
References and notes
1. Ro¨mpp Lexikon Naturstoffe; Steglich, W., Fugmann, B., Lang-
Fugmann, S., Eds.; Thieme: Stuttgart, 1997.
2. Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A., Diederich,
F., Eds.; Wiley-VCH: Weinheim, 2004.
3. Dihydronidulin: Finlay-Jones, P. F.; Sala, T.; Sargent, M. V. J. Chem.
Soc., Perkin Trans. 1 1981, 874.
4. Griseofulvin: (a) Osborne, C. S.; Leitner, I.; Hofbauer, B.; Fielding,
C. A.; Favre, B.; Ryder, N. S. Antimicrob. Agents Chemother. 2006,
50, 2234; (b) Takano, R.; Sugano, K.; Higashida, A.; Hayashi, Y.;
Machida, M.; Aso, Y.; Yamashita, S. Pharm. Res. 2006, 23, 1144; (c)
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Exp. Ther. 2006, 319, 277; (g) Albaugh, D.; Albert, G.; Bradford, P.;
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Meguro, S.; Akano, K. Chem. Pharm. Bull. 2000, 48, 1452.
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(b) Fujii, I.; Iijima, H.; Ebizuka, Y.; Sankawa, U. Chem. Pharm. Bull.
1983, 31, 337; (c) Katoh, T.; Ohmori, O.; Iwasaki, K.; Inoue, M.
Tetrahedron 2002, 58, 1289.
[
C
37Cl], 11), 186 ([M]+, [35Cl], 33), 156 (34), 154 (100). Anal. Calcd for
10H11ClO3 (214.65): C, 55.96; H, 5.17. Found: C, 55.72; H, 5.32.
Methyl 3-chloro-2-hydroxy-4,5,6-trimethylbenzoate (7a): Starting with
3 (0.442 g, 1.5 mmol), 3-methyl-4-(trimethylsilyloxy)pent-3-en-2-one
(6a) (0.279 g, 1.5 mmol) and TiCl4 (0.16 mL, 1.5 mmol) in CH2Cl2
(3 mL), 7a was isolated after column chromatography (silica gel,
n-heptane/EtOAc = 20:1) as a yellow oil (0.129 g, 38%). 1H NMR
(300 MHz, CDCl3): d = 2.17 (s, 3H, CH3), 2.38 (s, 6H, CH3), 3.95 (s,
3H, OCH3), 10.58 (s, 1H, OH). 13C NMR (75 MHz, CDCl3):
d = 16.4, 18.0, 18.9 (CH3), 52.3 (OCH3), 113.0, 119.9, 128.0, 135.8,
140.7 (CAr), 153.9 (COH), 171.5 (COOCH3). IR (ATR, cmꢀ1):
~m ¼ 2957 (w), 2922 (w), 2851 (w), 1732 (m), 1660 (m), 1593 (w), 1496
8. Geodinhydrate methyl ester: Hargreaves, J.; Park, J.-o.; Ghisalberti,
E. L.; Sivasithamparam, K.; Skelton, B. W.; White, A. H. J. Nat.
Prod. 2002, 65, 7.
9. 7-Chloro-1-O-methylemodin: (a) Cohen, P. A.; Towers, G. H. N.
Phytochemistry 1996, 42, 1325; (b) Shu, Y.-Z.; Arcuri, M.; Kozlowski,
M. R.; Wang, R. R.; Lam, K. S. J. Antibiot. 1994, 47, 1328; (c) Cohen,
P. A.; Hudson, J. B.; Towers, G. H. N. Experientia 1996, 52, 180.

2332
S. Reim, P. Langer / Tetrahedron Letters 49 (2008) 2329–2332
(w), 1439 (m), 1333 (m), 1314 (m), 1257 (s), 1232 (s), 1198 (s), 1160 (s),
21. Bose, G.; Nguyen, V. T. H.; Ullah, E.; Lahiri, S.; Go¨rls, H.; Langer,
1077 (s), 1010 (s). MS (GC–MS, 70 eV): m/z (%) = 230 ([M]+, [37Cl],
8), 228 ([M]+, [35Cl], 24), 198 (35), 197 (28), 196 (100). HRMS (EI):
calcd for C11H13ClO3 ([M]+, [35Cl]) 228.05477, found: 228.05463.
20. Sher, M.; Ahmed, Z.; Rashid, M. A.; Fischer, C.; Langer, P. J. Org.
Chem. 2007, 72, 6284.
P. J. Org. Chem. 2004, 69, 9128.
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2006, 3638.
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3204.