[3+3] Cyclizations of 1,3-bis(silyl enol ether)s with 1,1-diacetylcyclopentane and 1,1-diacetylcyclopropane

Article abstract of DOI:10.1002/anie.200351263

Domino reactions of 1,3-bis(silyl enol ether)s with 1,1-diacetylcyclopentane and 1,1-diacetylcyclopropane (see scheme) allow a new and convenient one-pot synthesis of spiro[5.4]cyclodecenones, bicyclo[4.4.0]deca-1,4-dien-3-ones, and functionalized salicylates, which are versatile intermediates for the synthesis of pharmacologically relevant natural product analogues. MS = molecular sieves.

Full text of DOI:10.1002/anie.200351263

Angewandte
Chemie
Reactions of Bis(silyl enol ether)s
[3+3] Cyclizations of 1,3-Bis(silyl enol ether)s
with 1,1-Diacetylcyclopentane and 1,1-
Diacetylcyclopropane**
Peter Langer* and Gopal Bose
Domino reactions facilitate the rapid assembly of complex
products in a one-pot process.[1] Despite the simplicity of the
idea, domino cyclizations of 1,3-dicarbonyl dianions[2] with
dielectrophiles are relatively rare.[3] As a result of their high
negative charge density, ambident dianions are very reactive
compounds, and many side reactions can occur, such as
polymerization, decomposition, deprotonation, formation of
open-chain products, elimination, and single-electron-transfer
processes. Anumber of base-mediated cyclization reactions
of activated (symmetrical) 1,3,5-tricarbonyl compounds (e.g.
diethyl acetone-1,3-dicarboxylate) with enolizable 1,3-dicar-
bonyl derivatives have been reported.[4] In contrast, many side
reactions, such as deprotonation or reduction of the dielec-
trophile, can interfere with the direct cyclization of (unsym-
metrical) 1,3-dicarbonyl dianions with enolizable and non-
enolizable 1,3-diketones.[5] Asolution to this problem was
developed by Chan and co-workers. They reported the
synthesis of benzene derivatives and salicylic acid esters by
the Lewis acid mediated cyclization of acetals of b,b-
ketoaldehydes, b-ketocarboxylic acid esters, and b-ketocar-
boxylic acid chlorides (Scheme 1a), and of 3-silyloxyalk-2-en-
1-ones (Scheme 1b) with 1,3-bis(silyl enol ether)s. 1,3-Bis-
Scheme 1. Cyclizations of 1,3-bis(silyl enol ether)s reported by Chan
et al.[6b,8]
[*] Prof. Dr. P. Langer, Dr. G. Bose
Institut für Chemie und Biochemie
Ernst-Moritz-Arndt Universität Greifswald
Soldmannstr. 16, 17487 Greifswald (Germany)
Fax: (+49)3834-86-4373
E-mail: peter.langer@uni-greifswald.de
[**] This work was supported by the Deutsche Forschungsgemeinschaft
(Heisenberg Fellowship to P. L. and regular funding). We are
grateful to Dr. M. Noltemeyer for the X-ray crystal-structure analysis.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2003, 42, 4033 –4036
DOI: 10.1002/anie.200351263
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Communications
(silyl enol ether)s can be regarded as electroneutral 1,3-
dicarbonyl dianion equivalents.[6–8]
Herein, we report the first cyclizations, to the best of our
knowledge, of 1,3-bis(silyl enol ether)s with 1,1-diacetylcy-
clopentane and 1,1-diacetylcyclopropane. The reaction of 1,3-
bis(silyl enol ether)s with 1,1-diacetylcyclopentane afforded
spiro[5.4]cyclodecenones, which underwent a domino rear-
rangement upon treatment with trifluoroacetic acid (TFA).
This transformation provided efficient access to functional-
ized bicyclo[4.4.0]deca-1,4-dien-3-ones with an angular
methyl group. The products are of considerable pharmaco-
logical relevance and represent useful precursors for the
synthesis of steroids (e.g. corticoids) and terpene analogues.[9]
Furthermore, we report a novel [3+3] cyclization of 1,3-
bis(silyl enol ether)s with 1,1-diacetylcyclopropane, which
allows an efficient one-pot synthesis of salicylates that contain
a halogenated side chain. The strategic placement of the
latent functionality in these products makes them versatile
intermediates for the synthesis of natural product analogues
and electron-rich styrenes.[10]
The TiCl4-mediated cyclization of the bis(silyl enol ether)
1a (R1 = H, R2 = OEt) with 1,1-diacetylcyclopentane (2a)[11]
afforded the spiroannulated 3-hydroxycyclohex-5-en-1-one
3a in good yield (Scheme 2). The choice of Lewis acid, the
temperature (ꢀ78!208C), and the presence of molecular
sieves (4 Š) proved to be important parameters in the
optimization of this reaction. The reaction of 3a with TFA
gave 5a in high yield. The structure of 5a was established by
NMR spectroscopy (coupling constants, H,H COSY) and was
independently confirmed by X-ray crystal-structure analysis
(Figure 1).[12] The saturated six-membered ring has a distorted
chair conformation; the cyclohexadienone moiety is slightly
distorted from planarity. The formation of 5a can be
explained by an acid-catalyzed Wagner–Meerwein rearrange-
ment (Scheme 2).[13] The intermediacy of the spiro compound
4 is supported by the fact that 4 could be isolated when the
reaction was stopped after just 3 h. The structurally related
isomer 6 was not isolated from the reaction mixture.
Scheme 2. Cyclizations of 1,3-bis(silyl enol ether)s 1 with 1,1-diacetyl-
cyclopentane (2a); a) 1. TiCl4 (2.0 equiv), CH2Cl2, molecular sieves
(4 Š), ꢀ78!208C, 2. H+, H2O; b) TFA, CH2Cl2, 72 h.
The 1,3-bis(silyl enol ether)s 1b and 1c, derived from
acetylacetone and ethyl 3-oxohexanoate, respectively, were
also used successfully as starting materials. The reaction of 2a
with 1b and 1c gave the spiro compounds 3b and 3c, which
were transformed into the bicyclo[4.4.0]deca-1,4-dien-3-ones
5b and 5c in the presence of TFA(Table 1).
The reaction of the bis(silyl enol ether)s 1a and 1b with
2,2-diacetylindane (2b) afforded the spiro compounds 3d and
3e, respectively, in good yields (Scheme 3). Treatment of 3d
and 3e with TFAafforded the interesting tricyclic products
5d and 5e, respectively, which can be regarded as 9,9a-
dihydroanthracenes. The products were formed via inter-
Table 1: Synthesis of 3a–c and 5a–c.
Entry
R1
R2
Yields [%][a]
3
5
Figure 1. ORTEP plot of 5a. Non-hydrogen atoms are represented by
thermal ellipsoids of 50% probability. Selected bond lengths [Š] and
angles [8]: O1-C2 1.227(2), C1-C9 1.345(2), C1-C2 1.473(2), C3-C4
1.335(3), C4-C10 1.509(2), C5-C6 1.520(3), C6-C7 1.517(3), C7-C8
1.532(2); C9-C1-C2 122.16(15), C1-C2-C3 122.52(17), C4-C3-C2
123.21(17), C6-C5-C10 113.67(14), C6-C7-C8 110.96(15).
a
b
c
H
H
Et
OEt
Me
OEt
78
97
95
88
67
41[b]
[a] Yields of isolated products. [b] Diastereomeric mixture (4:1, assign-
ment unclear).
4034
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Angewandte
Chemie
Table 2: Synthesis of 7a–d.
1
7
X
R1
R2
Yield of 7 [%][a]
d
d
b
c
a
b
c
Cl
Br
Cl
Cl
H
H
H
Et
OMe
OMe
Me
82
80
68
40
d
OEt
[a] Yields of isolated products.
The spiro[5.2]cyclooctenone E could be isolated in up to 55%
yield when only a small amount of TiCl4 (0.5–0.7 equiv) was
used. The use of larger quantities of the Lewis acid resulted in
the formation of significant amounts of 7a. The reaction of 2c
with the bis(silyl enol ether)s 1b and 1c afforded the
functionalized salicylates 7c and 7d in good yields (Table 2).
Further studies related to the scope and limitations of the
cyclization reactions presented herein and their application in
organic synthesis are in progress.
Scheme 3. Cyclizations of 1,3-bis(silyl enol ether)s 1 with 2,2-diacetylin-
dane (2b); a) 1. TiCl4 (2.0 equiv), CH2Cl2, molecular sieves (4 Š),
ꢀ78!208C, 2. H+, H2O; b) TFA, CH2Cl2, 72 h.
Experimental Section
Typical procedure for 3: 3a: TiCl4 (0.22 mL, 2.0 mmol) was added
dropwise at ꢀ788C under an argon atmosphere to a stirred solution of
2a (0.154 g, 1.0 mmol) and 1a (0.415 g, 1.5 mmol) in CH2Cl2 (100 mL)
in the presence of molecular sieves (4 Š; 1.0 g). The reaction mixture
was allowed to warm to 208C over 6 h, was stirred for an additional
6 h at 208C, and was then filtered. The filtrate was poured into an
aqueous solution of HCl (10%, 100 mL). The organic layer was
collected, and the aqueous layer was extracted with CH2Cl2 (3 ”
100 mL). The combined organic layers were dried (Na2SO4) and
filtered, and the filtrate was concentrated in vacuo. The residue was
purified by column chromatography (silica gel; hexane/ethyl acetate
3:2) to give 3a (0.208 g, 78%) as colorless crystals; m.p. 107–1088C;
Rf = 0.35 (hexane/ethyl acetate 1:1); IR (KBr): n˜ = 3410 s, 2966 s, 1724
s, 1663 s, 1619 s, 1470 m, 1385 s, 1342 s, 1237 s, 1205 s, 1089 s, 1026 cmꢀ1
m; 1H NMR (CDCl3, 300 MHz): d = 4.29 (q, 2H, J = 7.2 Hz; OCH2),
2.64 (br, 2H; CH2), 2.16 (br, 2H; CH2), 1.98 (s, 3H; CH3), 1.88 (br,
1H; OH), 1.76 (brs, 6H; CH2), 1.32 (t, 3H, J = 7.2 Hz; CH3),
1.26 ppm (s, 3H; CH3); 13C NMR (CDCl3, 75 MHz): d = 194.2, 167.5,
164.6, 131.7 (C), 75.7 (C-OH), 61.5 (CH2), 56.4 (C), 50.0, 33.5, 33.5,
28.5, 28.5 (CH2), 25.1, 18.0, 14.4 ppm (CH3); MS (EI, 70 eV): m/z (%):
266 (M+, 9), 220 (52), 162 (100); elemental analysis: calcd for
C15H22O4: C 67.64, H 8.32; found: C 67.38, H 8.45. All compounds
were characterized by spectroscopic methods and gave correct
elemental analyses and/or high-resolution mass spectra.
mediate D and reside in the thermodynamically more stable
enol tautomeric form as a result of conjugation of the enol
with the aryl ring.
An unexpected cyclization was observed in the reaction of
the silyl enol ether 1d with 1,1-diacetylcyclopropane (2c)[11] in
the presence of TiCl4 (Scheme 4).[14] The functionalized
salicylic ester 7a, which contains a chloro-substituted side
Typical procedure for 5: 5a: TFA(0.4 mL, 5.2 mmol) was added
dropwise at 208C to a stirred solution of 3a (0.134 g, 0.5 mmol) in
CH2Cl2 (0.4 mL) and the mixture was stirred until all the starting
material had disappeared (72 h; monitored by TLC). The solvent and
TFAwere then removed in vacuo, and the residue was purified by
column chromatography (silica gel; hexane/ethyl acetate 3:2) to give
5a (0.120 g, 96%) as colorless crystals; m.p. 79–808C; Rf = 0.30
(hexane/ethyl acetate 3:2); IR (KBr): n˜ = 2941 s, 1730 s, 1658 s, 1630
Scheme 4. Cyclizations of 1,3-bis(silyl enol ether)s 1 with 1,1-diacetyl-
cyclopropane (2c); a) 1. TiX4 (X=Cl, Br; 2.0 equiv), CH2Cl2, molecular
sieves (4 Š), ꢀ78!208C, 2. H+, H2O.
1
m, 1447 m, 1390 m, 1324 w, 1265 s, 1245 s, 1050 cmꢀ1 m; H NMR
4
¼
(CDCl3, 300 MHz): d = 6.14 (q, 1H, J = 1.2 Hz; C CH), 4.33 (q, 2H,
J = 7.2 Hz; OCH2), 2.47–2.41 (m, 2H; CH2), 2.12–1.98 (m, 2H; CH2),
2.01 (d, 3H, 4J = 1.2 Hz; CH3), 1.78–1.71 (m, 2H; CH2), 1.44–1.37 (m,
2H; CH2), 1.36 (s, 3H; CH3), 1.34 ppm (t, 3H J = 7.2 Hz; CH3);
13C NMR (CDCl3, 75 MHz): d = 182.0, 167.2, 166.0, 163.8, 131.1 (C),
126.3 (CH), 61.3 (CH2), 43.2 (C), 37.6, 29.8, 28.1 (CH2), 22.6 (CH3),
21.2 (CH2), 19.0, 14.2 ppm (CH3); MS (EI, 70 eV): m/z (%): 248 (M+,
71), 233 (46), 203 (72), 178 (100); elemental analysis: calcd for
C15H20O3: C 72.55, H 8.11; found: C 72.59, H 8.39.
chain, was isolated in 82% yield. The use of TiBr4 (in place of
TiCl4) resulted in the formation of the bromo-substituted
salicylate 7b in 80% yield (Table 2).
The formation of 7a can be explained by a TiCl4-mediated
cyclization with formation of the intermediate E. Asubse-
quent TiCl4-mediated cyclopropylcarbinyl!homoallyl rear-
rangement[14] and elimination of water afforded product 7a.
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Typical procedure for 7: 7a: Compound 2c (0.136 g, 1.1 mmol)
bridge CB21EZ, UK; fax: (+ 44)1223-336-033; or deposit@
ccdc.cam.ac.uk).
[13] For acid-mediated dienone–phenol rearrangements, see: B.
Hagenbruch, S. Hünig, Chem. Ber. 1983, 116, 3884.
[14] “Carbocyclic Three-Membered Ring Compounds”: Methods
Org. Chem. (Houben-Weyl) 4th ed. 1952–, Vol. E17, 1996.
was treated with 1d (0.421 g, 1.6 mmol) in the presence of TiCl4
(0.22 mL, 2.0 mmol), as described for the synthesis of 3. Chromatog-
raphy: silica gel; hexane/ethyl acetate 4:1. Compound 7a (0.251 g,
82%) was obtained as colorless crystals; m.p. 73–748C; Rf = 0.53
(hexane/ethyl acetate 4:1); IR (KBr): n˜ = 3026 m, 2906 s, 1657 s, 1601
m, 1574 m, 1468 m, 1437 s, 1355 s, 1239 s, 1151 m, 1072 m, 804 cmꢀ1 s;
1H NMR (CDCl3, 300 MHz): d = 10.68 (s, 1H; OH), 6.70 (s, 1H;
ArH), 3.95 (s, 3H; OCH3), 3.51–3.46 (m, 2H; CH2Cl), 3.12–3.06 (m,
2H; CH2), 2.48 (s, 3H; CH3), 2.32 ppm (s, 3H; CH3); 13C NMR
(CDCl3, 75 MHz): d = 171.8, 160.3, 144.2, 139.0, 127.1, 117.2, 111.9,
52.1, 42.2, 33.0, 21.0, 18.5 ppm; MS (EI, 70 eV): m/z (%): 244.5
([M+2]+, 15), 242.5 (M+, 47), 212.5 (41), 210.4 (93), 161.4 (100);
elemental analysis: calcd for C12H15O3Cl: C 59.39, H 6.22; found: C
59.56 H 6.50.
Received: February 24, 2003
Revised: June 3, 2003 [Z51263]
Keywords: cyclizations · cyclopropanes · rearrangements ·
.
silyl enol ethers · spiro compounds
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bridge Crystallographic Data Centre, 12, Union Road, Cam-
4036
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