Synthesis of functionalized benzopyrans by sequential [3+3]-cyclization- Williamson reactions of 1,3-bis(trimethylsilyloxy)-7-chlorohepta-1,3-dienes

Article abstract of DOI:10.1016/j.tetlet.2004.12.009

Functionalized benzopyrans were regioselectively prepared by [3+3]-cyclization of 1,3-bis(trimethylsilyloxy)-7-chlorohepta-1,3-dienes with 3-silyloxy-2-eno-1-ones and subsequent intramolecular Williamson reactions of the salicylates thus formed.

Full text of DOI:10.1016/j.tetlet.2004.12.009

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 815–817
Synthesis of functionalized benzopyrans by sequential
[3+3]-cyclization—Williamson reactions of
1,3-bis(trimethylsilyloxy)-7-chlorohepta-1,3-dienes
Van Thi Hong Nguyen and Peter Langer*
Institut fu¨r Chemie und Biochemie der Ernst-Moritz-Arndt, Universita¨t Greifswald, Soldmannstr. 16, 17487 Greifswald, Germany
Received 20 November 2004; accepted 1 December 2004
Available online 18 December 2004
Abstract—Functionalized benzopyrans were regioselectively prepared by [3+3]-cyclization of 1,3-bis(trimethylsilyloxy)-7-chloro-
hepta-1,3-dienes with 3-silyloxy-2-eno-1-ones and subsequent intramolecular Williamson reactions of the salicylates thus formed.
Ó 2004 Elsevier Ltd. All rights reserved.
O
O
1,3-Bis-silyl enol ethers—electroneutral equivalents of
1,3-dicarbonyl dianions—represent versatile synthetic
building blocks in [3+2]-, [3+3]-, [4+2]- and [4+3]-cycli-
zations which provide a convenient access to a variety of
pharmacologically relevant ring systems.1–3 For exam-
ple, Chan and co-workers reported an efficient one-pot
synthesis of salicylates based on [3+3] cyclizations of
1,3-bis-silyl enol ethers with 3-silyloxyalk-2-en-1-ones
or 1,1,3,3-tetramethoxypropane.3,4 In all reactions re-
ported to date, mainly nonfunctionalized 1,3-bis-silyl
O
O
OEt
I
i
OEt
1
2
Cl
+
Cl
3 (86%)
ii
Me3SiO
O
Me3SiO
OSiMe3
OEt
5
enol ethers have been employed. Herein, we wish to
iii
OEt
report the synthesis and synthetic application of what
are, to the best of our knowledge, the first halide-substi-
tuted 1,3-bis-silyl enol ethers.6,7 The strategic placement
of the latent chloride functionality allowed a convenient
synthesis of functionalized benzopyrans by sequential
[3+3]-cyclization—Williamson reactions.
Cl
Cl
4 (91%)
5 (77%)
OMe OMe
OMe
iv
MeO
O
The reaction of the dianion of ethyl acetoacetate (1) with
1-iodo-3-chloropropane (2) afforded, following a known
procedure,8 ethyl 7-chloro-3-oxoheptanoate (3). Treat-
ment of the latter with Me3SiCl/NEt3 gave the silyl enol
ether 4 (Scheme 1). Deprotonation of 4 with LDAand
subsequent addition of Me3SiCl afforded the novel 1,3-
bis-silyl enol ether 5 in good yield. An intramolecular
6
Cl
OH
O
O
v
OEt
OEt
7 (42%)
8 (64%)
Keywords: Benzopyrans; Cyclizations; Ethers; Lewis acids; Silyl enol
ethers.
*
Scheme 1. Synthesis of 8. Reagents and conditions: i. (1) 2.3 LDA,
THF, 0 °C, 1 h; (2) 2, ꢀ78 ! 20 °C; ii. Me3SiCl, NEt3, toluene, 20 °C,
24 h; iii. (1) LDA, THF, ꢀ78 °C, 1 h, (2) Me3SiCl, 20 °C,
ꢀ78 ! 20 °C; iv. TiCl4, CH2Cl2, ꢀ78 ! 20 °C; v. NaH, TBAI, THF,
20 °C.
Corresponding author. At present address: Institut fur Chemie,
¨
Universita¨t Rostock, Albert-Einstein-Str. 3A, D-18051 Rostock,
Germany. Tel.: +49 3834 864461; fax: +49 3834 864373; e-mail:
peter.langer@uni-greifswald.de
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.12.009

816
V. T. H. Nguyen, P. Langer / Tetrahedron Letters 46 (2005) 815–817
nucleophilic substitution of the chloride group or elimi-
nation of hydrogen chloride was not observed. The
[3+3] cyclization of 5 with 1,1,3,3-tetramethoxypropane
(6), following the conditions reported by Chan,4 affor-
ded the salicylate 7 with very good chemoselectivity.
Treatment of a THF solution of 7 with sodium hydride
(NaH) in the presence of tetrabutylammonium iodide
(TBAI) afforded the benzopyran 8 in good yield.
Cl
OH
O
O
OSiMe3
5
EtO
i
9e
O
O
ii
10e (33%)
EtO
The [3+3] cyclization of 1,3-bis-silyl enol ether 5 with 3-
silyloxyalk-2-en-1-ones 9 was next studied. The reaction
of 5 with 9a–d, following the conditions reported by
Chan,4 afforded the salicylates 10a–d (Scheme 2). Salicyl-
ates 10a–d were transformed into the benzopyrans 11a–d
in good yields (Table 1).9,10
11e (70%)
Scheme 3. Synthesis of benzopyran 11e Reagents and conditions:
i. TiCl4, CH2Cl2, ꢀ78 ! 20 °C; ii. NaH, TBAI, THF, 20 °C.
The cyclization of 1,3-bis-silyl enol ether 5 with silyl enol
ether 9e, prepared from 2-(hydroxymethylidene)cyclo-
hexan-1-one, gave the salicylate 10e with very good
regioselectivity (Scheme 3). Treatment of 10e with
NaH/TBAI afforded the tricyclic benzopyran 11e.
Cl
Me3SiO
O
OH
O
5
The cyclization of 5 with 9f, available by silylation of 2-
acetylcyclohexanone, regioselectively afforded 10f
(Scheme 4). The latter was transformed into the tricyclic
benzopyran 11f.
OEt
i
9f
10f (34%)
The cyclization of 5 with 9g, prepared from 2-acetyltetra-
lone, regioselectively afforded 10g which was trans-
formed into the tetracyclic benzopyran 11g (Scheme 5).
ii
O
O
OEt
The TiCl4-mediated cyclization of 5 with 1,1-diacetyl-
cyclopropane (12), following our recently reported
11f (87%)
Scheme 4. Synthesis of benzopyran 11f Reagents and conditions:
i. TiCl4, CH2Cl2, ꢀ78 ! 20 °C; ii. NaH, TBAI, THF, 20 °C.
Me3SiO
R1
O
R3
Cl
R2
Me3SiO
OSiMe3
OEt
OH
R2
O
9a-d
OEt
Cl
i
R1
R3
Me3SiO
O
Cl
OH
O
5
5
OEt
O
O
10a-d
ii
i
OEt
9g
R1
R3
O
O
10g (37%)
R2
ii
OEt
11a-d
Scheme 2. Synthesis of benzopyrans 11a–d Reagents and conditions:
i. TiCl4, CH2Cl2, ꢀ78 ! 20 °C; ii NaH, TBAI, THF, 20 °C.
11g (88%)
Scheme 5. Synthesis of benzopyran 11g Reagents and conditions:
i. TiCl4, CH2Cl2, ꢀ78 ! 20 °C; ii. NaH, TBAI, THF, 20 °C.
Table 1. Products and yields
10,11
R1
R2
R3
% (10)a
% (11)a
a
b
c
Me
Me
Me
Et
H
Me
Me
Me
Et
46
52
43
42
70
90
82
65
methodology,11 regioselectively afforded the highly
functionalized salicylate 13 by a domino [3+3]-cycliza-
tion-homo-MichaelÕ reaction (Scheme 6). Salicylate 13
was transformed into the chlorinated benzopyran 14.
Me
Et
H
0
d
a Yields of isolated products.

V. T. H. Nguyen, P. Langer / Tetrahedron Letters 46 (2005) 815–817
817
Synth. Commun. 1985, 15, 217; (i) Schultz, A. G.; Dittami,
J. P. J. Org. Chem. 1983, 48, 2318; (j) Chatani, N.; Murai,
S.; Sonoda, N. J. Am. Chem. Soc. 1983, 105, 1370.
7. For bromo-substituted mono-silyl enol ethers, see: (a)
Marko, I. E.; Dumeunier, R.; Leclercq, C.; Leroy, B.;
Plancher, J.-M.; Mekhalfia, A.; Bayston, D. J. Synthesis
2002, 958; (b) Oku, A.; Miki, T.; Abe, M.; Ohira, M.;
Kamada, T. Bull. Chem. Soc. Jpn. 1999, 72, 511; (c) Rigby,
J. H.; Rege, S. D.; Sandanayaka, V. P.; Kirova, M. J. Org.
Chem. 1996, 61, 842.
O
O
Cl
Me3SiO
OSiMe3
OEt
OH
O
12
OEt
Cl
i
5
Cl
O
O
ii
13 (53%)
8. Lambert, P. H.; Vaultier, M.; Carrie, R. J. Org. Chem.
1985, 50, 5352.
OEt
9. General procedure: to a CH2Cl2 solution of 5 and 9 was
dropwise added TiCl4 at ꢀ78 °C under argon atmosphere.
The solution was stirred at ꢀ78 °C for 30 min and was
subsequently warmed to 20 °C within 18 h. To the solution
was added a saturated aqueous solution of NaHCO3. The
organic and the aqueous layer were separated and the
latter was extracted with ether. The combined organic
layers were dried (Na2SO4), filtered and the filtrate was
concentrated in vacuo. The residue was purified by
chromatography (silica gel, n-hexane–EtOAc 30/1). Syn-
thesis of 10a: starting with 5 (2.90 g, 8.2 mmol), 9a (1.42 g,
8.2 mmol), TiCl4 (1.55 g, 8.2 mmol) in CH2Cl2 (15 ml),
10a was isolated as a colourless oil (1.02 g, 46%). 1H NMR
(300 MHz, CDCl3): d = 1.42 (t, 3H, CH3CH2O), 2.00 (m,
2 H, CH2CH2CH2Cl), 2.25 (s, 3 H, CH3), 2.49 (s, 3 H,
CH3), 2.78 (t, 2 H, CH2CH2CH2Cl), 3.61 (t, 2 H,
CH2CH2CH2Cl), 4.42 (q, 2 H, CH3CH2O), 6.54 (s, 1 H,
CH), 11.76 (s, 1 H, OH). 13C NMR (75 MHz, CDCl3):
d = 14.2 (CH3), 19.8 (CH3), 23.6 (CH2), 23.9 (CH2), 31.8
(CH2), 45.3 (CH2), 61.4 (CH2), 109.7 (C), 124.8 (CH),
125.2 (C), 138.4 (C), 143.1 (C), 161.1 (C), 172.2 (C). MS
(EI, 70 eV): m/z = 272 (M+, 6), 271 (M+ + 1), 270 (M+,
21), 224 (20), 189 (100), 162 (25), 161 (23), 91 (10). IR
(KBr, cmꢀ1):
Cl
14 (77%)
Scheme 6. Synthesis of benzopyran 14 Reagents and conditions:
i. TiCl4 (2 equiv), CH2Cl2, ꢀ78 ! 20 °C; ii. NaH, TBAI, THF, 20 °C.
Acknowledgments
Financial support from the Ministry of Education of
Vietnam (scholarship for V.T.H.N.) and from the Deut-
sche Forschungsgemeinschaft is gratefully acknowl-
edged. We thank Ms. Esen Bellur for an experimental
contribution.
References and notes
1. For a review of domino reactions, see: (a) Tietze, L. F.;
Beifuss, U. Angew. Chem. 1993, 105, 137; Angew. Chem.,
Int. Ed. Engl. 1993, 32, 131; (b) Tietze, L. F. Chem. Rev.
1996, 96, 115.
2. (a) Chan, T.-H.; Brownbridge, P. J. Chem. Soc., Chem.
Commun. 1979, 578; (b) Molander, G. A.; Cameron, K. O.
J. Am. Chem. Soc. 1993, 115, 830.
~m ¼ 2977 (s), 2937 (s), 1938 (w), 1653 (s),
1563 (m), 1447 (s), 1396 (s), 1376 (s), 1349 (s), 1311 (s),
1273 (s), 1232 (s), 1175 (s), 1037 (s), 848 (s). UV–vis (nm):
kmax (1g e) = 215.8 (4.45), 253.4 (4.00), 315.7 (3.60).
HRMS (FT-ICR): calcd for C14H20O3Cl ([M+1]+):
271.11009; found: 271.10950. All new compounds gave
satisfactory spectroscopic data and correct elemental
analyses and/or high-resolution mass data.
3. For a review of 1,3-bis-silyl enol ethers, see: Langer, P.
Synthesis 2002, 441.
4. (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; for [3+3]
cyclizations of 1,3-bis-silyl enol ethers with 2-acetyl-1-
silyloxybut-1-en-3-one, see: (c) Dede, R.; Langer, P.
Tetrahedron Lett. 2004, 45, 9177 for sequential Ô[3+3]-
Cyclization—Suzuki-Cross-CouplingÕ reactions of 1,3-bis-
silyl enol ethers, see: (d) Nguyen, V. T. H.; Langer, P.
Tetrahedron Lett. 2004, in press.
10. General procedure: to a THF solution of 10 and of NaH
was added TBAI. The reaction mixture was stirred at
20 °C for 20 h. The mixture was directly purified by
column chromatography (silica gel, n-hexane–EtOAc 30/
1 ! 20/1). Synthesis of 11a: starting with 10a (59 mg,
0.22 mmol), NaH (8 mg, 0.33 mmol), n-Bu4NI (144 mg,
0.44 mmol), 11a was isolated as a colourless solid (36 mg,
70%). 1H NMR (300 MHz, CDCl3): d = 1.36 (t, 3 H,
CH3CH2O), 2.02 (m, 2 H, CH2), 2.16 (s, 3 H, CH3), 2.21
(s, 3 H, CH3), 2.59 (t, 2 H, CH2), 4.14 (t, 2 H, CH2), 4.38
(q, 2 H, CH3CH2O), 6.75 (s, 1 H, CH). 13C NMR
(75 MHz, CDCl3): d = 14.3 (CH3), 18.9 (CH3), 19.0 (CH3),
22.0 (CH2), 22.2 (CH2), 60.9 (CH2), 66.1 (CH2), 118.6 (C),
120.9 (C), 123.1 (CH), 133.1 (C), 138.6 (C), 151.9 (C),
168.7 (C). MS (EI, 70 eV): m/z = 235 (M++1, 12), 234
(M+, 87), 189 (100), 161 (31), 132 (20), 102.8, 77 (12). IR
5. For sequential reactions of alkenyl-substituted 1,3-bis-silyl
enol ethers, see: (a) Langer, P.; Eckardt, T.; Stoll, M. Org.
Lett. 2000, 2991; (b) Langer, P.; Eckardt, T.; Nehad, N.
´
R.; Saleh, X.; Karime, I.; Muller, P. Eur. J. Org. Chem.
2001, 3657.
¨
6. For chloro-substituted mono-silyl enol ethers, see: (a)
Fleming, F. F.; Shook, B. C.; Jiang, T.; Steward, O. W.
Tetrahedron 2003, 59, 737; (b) Hydrio, J.; van de Weghe,
P.; Collin, J. Synthesis 1997, 68; (c) Limat, D.; Schlosser,
M. Tetrahedron 1995, 51, 5799; (d) Masters, A. P.; Parvez,
M.; Sorensen, T. S.; Sun, F. J. Am. Chem. Soc. 1994, 116,
2804; (e) Stack, D. E.; Dawson, B. T.; Rieke, R. D. J. Am.
Chem. Soc. 1991, 113, 4672; (f) Hambly, G. F.; Chan, T.
H. Tetrahedron Lett. 1986, 27, 2563; (g) Chatani, N.; Fujii,
S.; Yamasaki, Y.; Murai, S.; Sonoda, N. J. Am. Chem.
Soc. 1986, 108, 7361; (h) Poirier, J.-M.; Hennequin, L.
(KBr, cmꢀ1): m ¼ 3414 (m), 2977 (s), 2938 (s), 1716 (s),
~
1612 (m), 1574 (m), 1457 (s), 1369 (m), 1303 (s), 1273 (s),
1151 (s), 1106 (s), 1056 (s), 959 (m). UV–vis (nm): kmax (1g
e) = 206.7 (4.48), 284.5 (3.34).
11. (a) Langer, P.; Bose, G. Angew. Chem. 2003, 115, 4165; .
Angew. Chem. Int. Ed. 2003, 42, 4033; (b) Bose, G.;
Nguyen, V. T. H.; Ullah, E.; Lahiri, S.; Go¨rls H.; Langer,
P. J. Org. Chem. 2004, in press.