Synthesis and reactions of 2-chloro-1,3-bis(trimethylsilyloxy)-1,3-butadienes

Article abstract of DOI:10.1016/j.tetlet.2008.05.151

The reaction of 2-chloro-1,3-bis(trimethylsilyloxy)-1,3-butadienes with various electrophiles allows a convenient synthesis of chlorinated molecules which are not readily available by other methods.

Full text of DOI:10.1016/j.tetlet.2008.05.151

Tetrahedron Letters 49 (2008) 4901–4904
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Tetrahedron Letters
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Synthesis and reactions of 2-chloro-1,3-bis(trimethylsilyloxy)-1,3-butadienes
Stefanie Reim a, Muhammad Adeel a, Ibrar Hussain a, Mirza A. Yawer a, Zafar Ahmed a,b
,
Alexander Villinger 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-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:
The reaction of 2-chloro-1,3-bis(trimethylsilyloxy)-1,3-butadienes with various electrophiles allows a
convenient synthesis of chlorinated molecules which are not readily available by other methods.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 5 May 2008
Revised 27 May 2008
Accepted 30 May 2008
Available online 5 June 2008
Keywords:
Cyclizations
Regioselectivity
Organochlorine compounds
Silyl enol ethers
Chlorinated molecules are of considerable pharmacological rel-
evance and occur in a number of natural products.1 In fact, arenes
and hetarenes containing a chloride group often show a better
pharmacological activity compared to their non-halogenated ana-
logues.2 Chlorinated arenes and hetarenes also represent versatile
building blocks in transition metal-catalyzed cross coupling reac-
tions.3 However, the direct chlorination of arenes, hetarenes and
open-chained molecules often suffers from several drawbacks,
such as low regioselectivity or multiple chlorination. An alternative
strategy for the regioselective synthesis of organochlorine com-
pounds relies on the use of appropriate chlorine-containing build-
ing blocks in condensation and cyclization reactions. For example,
Manzanares and co-workers reported the synthesis of a 4-chloro-
phenol by [4+2] cycloaddition of a chlorinated thiophene with
dimethyl acetylenedicarboxylate.4
oxy)-1,3-butadienes 3a,b were prepared by deprotonation (LDA)
of 2a,b at ꢀ78 °C and subsequent addition of trimethylchlorosi-
lane. It is noteworthy that the chloride group proved to be compat-
ible with the reaction conditions.
3-Chloro-2,4-bis(silyloxy)-1,3-pentadiene (3c) and 2-chloro-1-
phenyl-1,3-bis(silyloxy)-1,3-butadiene (3d) were prepared by
reaction of an ether solution of 1c and 1d, respectively, with
2.0 equiv of trimethylsilyl-trifluoromethanesulfonate (Me3SiOTf)
and triethylamine (Scheme 2). This method of silylation was first
developed by Simchen and Krägeloh.6b Dienes 3a–d can be stored
at ꢀ20 °C under inert atmosphere for several weeks.
The reaction of 3a with benzoyl chloride, following our recently
reported protocol,9 afforded methyl 2-chloro-5-phenyl-3,5-dioxo-
pentanoate (4) in 82% yield (Scheme 3). The best yields were
1,3-Bis(trimethylsilyloxy)-1,3-butadienes (e.g., Chan’s diene)5,6
represent important synthetic building blocks, which have been
used in formal [3+2], [3+3], [4+2] and [4+3] cyclizations and other
transformations.7 Herein, we report the synthesis and synthetic
application of 2-chloro-1,3-bis(silyloxy)-1,3-butadienes.8 Their
reaction with various electrophiles provides a convenient and reg-
ioselective approach to a variety of organochlorine compounds,
which are not readily available by other methods.
Me3SiO
O
O
O
i
OR
OR
Cl
Cl
1a,b
2a (R = Me): 69%
2b (R = Et): 90%
Me3SiO OSiMe3
ii
The reaction of commercially available methyl and ethyl 2-chlo-
roacetoacetate (1a,b) with Me3SiCl and triethylamine afforded silyl
enol ethers 2a,b (Scheme 1). The 2-chloro-1-alkoxy-1,3-bis(silyl-
OR
Cl
3a (R = Me): 82%
3b (R = Et): 95%
* Corresponding author. Tel.: +49 381 4986410; fax: +49 381 4986412.
E-mail address: peter.langer@uni-rostock.de (P. Langer).
Scheme 1. Synthesis of dienes 3a,b. Reagents and conditions: (i) Me3SiCl, NEt3,
benzene, 20 °C, 48 h; (ii) (1) LDA, THF, ꢀ78 °C, 1 h, (2) Me3SiCl, ꢀ78?20 °C, 14h.
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.05.151

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S. Reim et al. / Tetrahedron Letters 49 (2008) 4901–4904
The TiCl4-mediated cyclization of 3b with epibromohydrin, fol-
O
O
Me3SiO OSiMe3
lowing our recently reported protocol,11 afforded the halogenated
2-alkylidenetetrahydrofuran 7 (Scheme 6). The exocyclic double
bond was again formed with excellent Z-diastereoselectivity.
The Me3SiOTf-catalyzed condensation of 3b with 1-chloro-2,2-
dimethoxyethane gave ethyl 2,6-dichloro-5-methoxy-3-oxohex-
anoate (8) in good yield as a 1:1 mixture of diastereomers (Scheme
7). The DBU-mediated cyclization12 of 8 afforded the Z-configured
4-methoxy-2-alkylidenetetrahydrofuran 9. Noteworthy, this prod-
uct is not available by direct halogenation.13
i
R
R
Cl
1c,d
Cl
3c (R = Me): 95%
3d (R = Ph): 83%
Scheme 2. Synthesis of dienes 3c,d. Reagents and conditions: (i) Me3SiOTf, NEt3,
Et2O, 0?20 °C, 4 h.
The Me3SiOTf-mediated condensation of 3b with 3-cyanochro-
mone (10) gave product 11 by regioselective attack of the terminal
obtained when the reactions were carried out in the absence of
Lewis acid. It is noteworthy that products such as 4 are not
available by direct chlorination of 3,5-dioxoalkanoates, due to the
formation of a mixture of regioisomers.
The Me3SiOTf-catalyzed condensation of 3a with methyl
malonyl chloride afforded dimethyl 2-chloro-3,5-dioxopimelate
(5) (Scheme 4). The synthesis of 5 by direct chlorination of
dimethyl 3,5-dioxopimelate is not possible, due to the formation
of regioisomers and multiple chlorination.
Me3SiO OSiMe3
OEt
O
OEt
Cl
i
Cl
3b
The Me3SiOTf-catalyzed cyclization10 of 2-chloro-1,3-bis(silyl-
oxy)-1,3-butadienes 3a, 3c, and 3d with oxalyl chloride afforded
O
Br
O
+
Br
7 (47%)
the novel chlorinated
c-alkylidenebutenolides 6a–c (Scheme 5).
The exocyclic double bond of all products was formed with excel-
lent Z-diastereoselectivity (due to thermodynamic reasons). Prod-
ucts 6a–c are not readily available by other methods.
Scheme 6. Synthesis of 2-alkylidenetetrahydrofuran 7. Reagents and conditions: (i)
TiCl4 (2.0 equiv), 4 Å MS, CH2Cl2, ꢀ78?20 °C, Z/E (7) > 98:2.
Me3SiO OSiMe3
OMe O
O
i
Me3SiO
OSiMe3
OMe
Cl
OEt
3b
OMe
OEt
Cl
O
O
O
Cl
i
Cl
8 (72%)
Ph
OMe
3a
Cl
Cl
4 (82%)
ii
OMe
O
+
O
Ph
Cl
OEt
MeO
Scheme 3. Synthesis of 4. Reagents and conditions: (i) CH2Cl2, ꢀ78?20 °C.
Cl
O
9 (73%)
Me3SiO
OSiMe3
OMe
Scheme 7. Synthesis of 2-alkylidenetetrahydrofuran 9. Reagents and conditions: (i)
Me3SiOTf (0.5 equiv), CH2Cl2, ꢀ78?20 °C, dr (8) = 1:1; (ii) DBU (2.0 equiv), THF,
20 °C, Z/E (9) > 98:2.
O
O
O
O
i
Cl
O
MeO
OMe
3a
Cl
5 (57%)
O
Me3SiO
OSiMe3
OEt
MeO
Cl
Scheme 4. Synthesis of 5. Reagents and conditions: (i) Me3SiOTf (0.2 equiv), CH2Cl2,
ꢀ78?20 °C.
O
O
Cl
3b
CN
i
O
O
+
O
OEt
CN
Me3SiO
OSiMe3
R
Cl
11
O
O
O
O
ii
O
O
Cl
3a,c,d
Cl
10
HO
i
Cl
R
O
O
N
OEt
+
Cl
12 (58%, based on 10)
Cl
O
6a (R = OMe): 47%
6b (R = Me): 52%
6c (R = Ph): 50%
Scheme 8. Synthesis of 1-azaxanthone 12. Reagents and conditions: (i) (1) 10,
Me3SiOTf, 1 h, 20 °C; (2) 3b, CH2Cl2, 0?20 °C, 12 h; (3) HCl (10%); (ii) (1) NEt3, EtOH,
20 °C, 12 h, (2) HCl (1 M).
Scheme 5. Synthesis of butenolides 6a–c. Reagents and conditions: (i) Me3SiOTf
(0.3 equiv), CH2Cl2, ꢀ78?20 °C, 14 h, Z/E (6a–c) > 98:2.

S. Reim et al. / Tetrahedron Letters 49 (2008) 4901–4904
4903
formation of a regioisomeric mixture. The structure of 13a was
independently confirmed by X-ray crystal structure analysis
(Fig. 1).16
Me3SiO
OSiMe3
OEt
HO
Cl
The hetero-Diels–Alder reaction17 of 1,3-bis(silyloxy)-1,3-buta-
dienes 3b with phenylsulfonylcyanide afforded the chlorinated 2-
(arylsulfonyl)pyridine 14 (Scheme 11).18 This type of product is
again not available by direct chlorination.
CO2Me
CO2Me
Cl
3b
+
i
H
MeO2C
CO2Me
OH
In conclusion, we reported the synthesis of 2-chloro-1,3-bis(tri-
methylsilyloxy)-1,3-butadienes and their reaction with various
electrophiles. These reactions provide a regioselective approach
to a variety of chlorinated carba- and heterocycles and of chlori-
nated tri- and tetracarbonyl compounds. The products are not
available by direct chlorination reactions. The preparative scope
of the methodology is currently being studied.
13a (64%)
H
Scheme 9. Synthesis of homophthalate 13a. Reagents and conditions: (i) (1) neat,
40 °C, 14 h; (2) HNEt3F, EtOH.
Me3SiO
OSiMe3
Me
HO
Cl
Acknowledgement
CO2Me
CO2Me
Cl
3c
+
i
Financial support by the State of Pakistan (HEC scholarship for
I.H. and M.A.Y.) and by the State of Mecklenburg-Vorpommern is
gratefully acknowledged.
H
MeO2C
CO2Me
Me
13b (42%)
H
References and notes
Scheme 10. Synthesis of homophthalate 13b. Reagents and conditions: (i) (1) neat,
40 °C, 14 h; (2) HNEt3F, EtOH.
1. For pharmacologically active chlorinated natural products and drugs:
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) Xue, C.; Li, T.; Deng, Z.; Fu, H.; Lin, W. Pharmazie
2006, 61, 1041; (d) Phelps, J. B.; Hoffman, W. P.; Lee, C.; Murphy, G. P.; Garriott,
M. L. Mutat. Res. 2004, 561, 153; (e) Rosefort, C.; Fauth, E.; Zankl, H. Mutagenesis
2004, 19, 277; (f) Kinobe, R. T.; Dercho, R. A.; Vlahakis, J. Z.; Brien, J. F.; Szarek,
W. A.; Nakatsu, K. J. Pharmacol. Exp. Ther. 2006, 319, 277; (g) Albaugh, D.; Albert,
G.; Bradford, P.; Cotter, V.; Froyd, J. J. Antibiot. 1998, 51, 317; Dihydronidulin:
(h) Finlay-Jones, P. F.; Sala, T.; Sargent, M. V. J. Chem. Soc., Perkin Trans. 1981, 1,
874.
2. For an example from our laboratory, see: (a) Albrecht, U.; Lalk, M.; Langer, P.
Bioorg. Med. Chem. 2005, 13, 1531; (b) Nguyen, V. D.; Wolf, C.; Mäder, U.; Lalk,
M.; Langer, P.; Lindequist, U.; Hecker, M.; Antelmann, H. Proteomics 2007, 7,
1391.
3. de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions; Wiley-
VCH: Weinheim, 2004.
4. Corral, C.; Lissavetzky, J.; Manzanares, I. Synthesis 1997, 29.
Figure 1. Crystal structure of 13a.
5. For a review of 1,3-bis(silyl enol ethers), see: Langer, P. Synthesis 2002, 441.
6. (a) Chan, T.-H.; Brownbridge, P. J. Chem. Soc., Chem. Commun. 1979, 578; (b)
Krägeloh, K.; Simchen, G. Synthesis 1981, 30.
7. For a review of [3+3] cyclizations, see: Feist, H.; Langer, P. Synthesis 2007, 327.
8. For the synthesis and reactions of a 4-chloro-1,3-bis(trimethylsilyloxy)-1,3-
butadiene, see: (a) Reim, S.; Langer, P. Tetrahedron Lett. 2008, 49, 2329. For an
isolated example of a 2-chloro-1,3-bis(trimethylsilyloxy)-1,3-butadiene, see:
(b) Savard, J.; Brassard, P. Tetrahedron Lett. 1979, 20, 4911. For [3+3]
cyclizations of 1,3-bis(silyloxy)-1,3-dienes with 2-chloro-3-silyloxy-2-en-1-
ones, see: (c) Yawer, M. A.; Hussain, I.; Reim, S.; Ahmed, Z.; Ullah, E.; Iqbal, I.;
Fischer, C.; Reinke, H.; Görls, H.; Langer, P. Tetrahedron 2007, 63, 12562.
9. Rahn, T.; Nguyen, V. T. H.; Dang, T. H. T.; Ahmed, Z.; Methling, K.; Lalk, M.;
Fischer, C.; Spannenberg, A.; Langer, P. J. Org. Chem. 2007, 72, 1957.
10. Langer, P.; Stoll, M.; Schneider, S. Chem. Eur. J. 2000, 6, 3204.
11. Langer, P.; Armbrust, H.; Eckardt, T.; Magull, J. Chem. Eur. J. 2002, 8, 1443.
12. (a) Bellur, E.; Görls, H.; Langer, P. Eur. J. Org. Chem. 2005, 2074. See also: (b)
Langer, P.; Krummel, T. Chem. Eur. J. 2001, 7, 1720.
13. The synthesis of a difluoro-(furan-2-yl)acetate by a different approach has
been recently reported: (a) Eto, H.; Kanwko, Y.; Sakamoto, T. Chem. Pharm. Bull.
2000, 48, 982; (b) Murakami, S.; Kim, S.; Ishii, H.; Fuchigami, T. Synlett 2004,
815.
14. (a) Langer, P.; Appel, B. Tetrahedron Lett. 2003, 5133; (b) Rashid, M. A.; Rasool,
N.; Appel, B.; Adeel, M.; Karapetyan, V.; Mkrtchyan, S.; Reinke, H.; Fischer, C.;
Langer, P. Tetrahedron 2008, 64, 5416.
carbon atom of the diene onto carbon atom C-2 of the cyanochro-
mone and subsequent hydrolysis upon aqueous work-up. Treat-
ment of an ethanol solution of crude 11 with triethylamine
afforded the novel chlorinated 1-azaxanthone 12 (Scheme 8). This
type of product is again not available by direct chlorination. The
transformation of A into 12 can be explained by a domino ‘retro-
Michael/nitrile-addition/heterocyclization’ reaction.14
The [4+2] cycloaddition15 of 1,3-bis(trimethylsiloxy)-1,3-buta-
diene 3b with dimethyl allene-1,3-dicarboxylate afforded the
novel chlorinated 2,4-dihydroxy-homophthalate 13a in good yield
and with very good regioselectivity (Scheme 9). The cycloaddition
of dimethyl allene-1,3-dicarboxylate with 3c gave the homophtha-
late 13b (Scheme 10). Products 13a,b are not available by direct
halogenation of the corresponding homophthalate because of the
15. Langer, P.; Kracke, B. Tetrahedron Lett. 2000, 41, 4545.
Me3SiO
OSiMe3
OEt
16. CCDC-684862 (13a) contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
17. Emmrich, T.; Reinke, H.; Langer, P. Synthesis 2006, 2551.
18. Synthesis of 3-chloro-2-phenylsulfonyl-4-hydroxypyridine 14: To the
phenylsulfonyl cyanide (0.167 g, 1.0 mmol) was added dropwise 3b (0.617 g,
2.0 mmol) at ꢀ78 °C. The mixture stirred at 45 °C for 48 h. To the mixture was
added an aqueous solution of ammonium chloride (1 M, 20 mL) and the
organic and the aqueous layer were separated. The latter was extracted with
CH2Cl2 (3 ꢁ 20 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/EtOAc) to give 14 as a yellow viscous oil
OH
N
Cl
i
Cl
Ph
S
OEt
3b
O
O
Ph
C N
S
+
14 (56%)
O
O
Scheme 11. Synthesis of pyridine 14. Reagents and conditions: (i) (1) neat, 45 °C,
48 h; (2) NH4Cl, H2O.

4904
S. Reim et al. / Tetrahedron Letters 49 (2008) 4901–4904
(0.175 g, 56%). 1H NMR (250 MHz, CDCl3): d 1.22 (t, 3J = 7.1 Hz, 3H, OCH2CH3),
(CPh), 153.6 (COHHeter), 159.9, 160.4 (CHeter). IR (neat, cmꢀ1): v ¼ 3312 (w),
1731 (br, w), 1608 (m), 1417 (m), 1385 (m), 1347 (m), 1304 (m), 1251 (m),
1159 (m), 1093 (s), 1076 (s), 840 (s), 725 (s), 592 (s). HRMS (ESI): calcd for
C
C
~
4.27 (q, 3J = 7.1 Hz, 2 H, OCH2CH3), 7.19 (br s, 1H, OHHeter), 7.44–7.49 (m, 2H,
CHPh), 7.52 (m, 1H, CHPh), 7.55 (s, 1H, CHHeter), 7.96 (dd, 3J = 8.4 Hz, 4J = 1.5 Hz,
2H, CHPh). 13C NMR (75 MHz, CDCl3): d 14.2 (OCH2CH3Heter), 64.1 (OCH2CH3),
105.6 (CHHeter), 106.9 (CHeter), 128.9 (2CHPh), 129.0 (2CHPh), 133.8 (CHPh), 138.4
13H13ClNO4S ([M+H]+, 35Cl): 314.02483; found: 314.02486. Calcd for
13H12ClNO4SNa ([M+Na]+, 35Cl): 336.006433; found: 336.00678.