Synthesis of functionalized 4-chlorophenols and 1,4-dihydroquinones by [3+3] cyclization of 1,3-bis-silyl enol ethers with 2-chloro- and 2-acyloxy-3-(silyloxy)alk-2-en-1-ones

Article abstract of DOI:10.1016/j.tetlet.2005.11.077

Functionalized 4-chlorophenols and 1,4-dihydroquinones were prepared by [3+3] cyclization of 1,3-bis-silyl enol ethers with 2-chloro- and 2-acyloxy-3-(silyloxy)alk-2-en-1-ones.

Full text of DOI:10.1016/j.tetlet.2005.11.077

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 417–419
Synthesis of functionalized 4-chlorophenols and
1,4-dihydroquinones by [3+3] cyclization of 1,3-bis-silyl enol
ethers with 2-chloro- and 2-acyloxy-3-(silyloxy)alk-2-en-1-ones
Zafar Ahmeda,b and Peter Langera,b,
*
aInstitut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
bLeibniz-Institut fu¨r Organische Katalyse an der Universita¨t Rostock e. V. (IfOK), Albert-Einstein-Str. 29a, 18059 Rostock, Germany
Received 24 October 2005; revised 15 November 2005; accepted 16 November 2005
Available online 2 December 2005
Abstract—Functionalized 4-chlorophenols and 1,4-dihydroquinones were prepared by [3+3] cyclization of 1,3-bis-silyl enol ethers
with 2-chloro- and 2-acyloxy-3-(silyloxy)alk-2-en-1-ones.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1,4-Dihydroquinones and 4-chlorophenols occur in a
number of natural products, for example, in the natural
product belamcandol A.1–3 They have found many tech-
nical and medicinal applications and represent impor-
tant synthetic building blocks. 2-Alkoxycarbonyl- and
2-acyl-1,4-dihydroquinones also occur in natural prod-
ucts, for example, in methoxymicareic acid (Chart 1);4
2-alkoxycarbonyl- and 2-acyl-4-chlorophenols are
found, for example, in the natural product chloratrano-
rin (Chart 2).1 Some years ago, Chan and co-workers re-
ported an elegant approach to salicylates based on [3+3]
cyclizations5,6 of 1,3-bis-silyl enol ethers;7 the latter can
be regarded as electroneutral equivalents of 1,3-dicar-
bonyl dianions. Herein, we report the synthesis of func-
tionalized 4-chlorophenols and 1,4-dihydroquinones by
what are, to the best of our knowledge, the first [3+3]
cyclizations of 1,3-bis-silyl enol ethers with novel 2-
OMe
O
OH
O
OH
Hept
Hept
HO
O
OMe
Chart 1. Methoxymicareic acid.
OH
O
Me
O
OH
Cl
O
OMe
Me
OHC
HO
Me
Chart 2. Chloratranorin.
chloro-
and
2-acyloxy-3-(silyloxy)alk-2-en-1-ones,
respectively. These transformations are of synthetic use-
fulness, since they offer a convenient approach to mono-
protected 1,4-dihydroquinones without the need of
regioselective protective group manipulations. Likewise,
the functionalized 4-chlorophenols prepared are not
readily available by other methods, since the classic
approach, based on aromatic chlorinations, suffers from
low regioselectivities and yields.
2-Chloro-1,3-diketones, such as 1a, are readily available
by reaction of 1,3-diketones with N-chlorosuccinimide
(NCS).8 The reaction of 1a with sodium acetate affor-
ded, following a known procedure,9 2-acetoxypentane-
2,4-dione (2a). The reaction of 1a with Me3SiCl/NEt3
afforded 2-chloro-3-(silyloxy)alk-2-en-1-one 3a.10 Like-
wise, the novel 2-acetoxy-3-(silyloxy)alk-2-en-1-one 4a
was prepared from 2a. The TiCl4 mediated [3+3] cycli-
zation of 3a with 1,3-bis-silyl enol ether 5a afforded
the desired 4-chlorosalicylate 6a without extrusion of
the chloride group (Scheme 1). The cyclization of 5a
with 2-acetoxy-3-(silyloxy)alk-2-en-1-one 4a was equally
successful and gave the desired 4-acetoxysalicylate 7a
Keywords: Cyclization; Dihydroquinones; Phenols; Silyl enol ethers.
*
Corresponding author. Tel.: +49 381 498 6410; fax: +49 381 498
6412; e-mail: peter.langer@uni-rostock.de
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.077

418
Z. Ahmed, P. Langer / Tetrahedron Letters 47 (2006) 417–419
O
O
Me3SiO OSiMe3
O
O
i
R1
R2
O
OH
OAc
Cl
5a,b,d-f
R1
R3
i
R2
1a
2a (92%)
Me3SiO
R3
O
R4
R4
OR5
ii
ii
OR5
4a-d
7a-j
Me SiO
O
3
Me SiO
O
3
Scheme 3. Synthesis of 7a–j. Reagents and conditions: (i) TiCl4,
CH2Cl2, ꢀ78!20 ꢁC, 20 h.
Cl
3a (76%)
OAc
4a (78%)
from ethyl 3-oxopentanoate and ethyl 3-oxohexanoate,
gave the 4-chlorosalicylates 6d and 6e. The cyclization
of 5a and 5e with 3b, prepared from 4-chloroheptane-
3,5-dione (1b), afforded 6f and 6g. The cyclization of
5d with 3c, prepared from 3-chlorobenzoylacetone
(1c), resulted in regioselective formation of 6h.
Me SiO OSiMe
3
3
5a
iii
5a
iii
OMe
5a
OH
Cl
O
OH
O
OMe
OMe
The reaction of 2-acetoxy-3-(silyloxy)alk-2-en-1-one 4a
with 1,3-bis-silyl enol ether 5b afforded the 2-acetyl-4-
(acetoxy)phenol 7b (Scheme 3 and Table 2). The cycliza-
tion of 4a with 5d and 5e gave the methyl- and ethyl-
substituted 4-(acetoxy)salicylates 7c and 7d. The cycliza-
tion of 4a with 5f, prepared from methyl 4-(meth-
oxy)acetoacetate, afforded the salicylate 7e containing
one free and two orthogonally protected hydroxyl
groups. The cyclization of 5a,d with 4b, prepared from
4-(acetoxy)heptane-3,5-dione (2b), gave the 4-(acet-
oxy)salicylates 7f,g. The cyclization of 5d with 4c, pre-
pared from 3-(acetoxy)benzoylacetone (2c), resulted in
regioselective formation of 7h. The cyclization of 1,3-
bis-silyl enol ethers 5a,e with 3-(benzoyloxy)acetylace-
tone (4d) afforded the O-benzoyl-protected 1,4-dihydro-
quinones 7i,j.
OAc
6a (62%)
7a (52%)
Scheme 1. Synthesis of 5a. Reagents and conditions: (i) NaOAc,
DMSO, 3 h, 20 ꢁC; (ii) Me3SiCl, NEt3, C6H6, 20 ꢁC, 3 d; (iii) TiCl4,
CH2Cl2, ꢀ78!20 ꢁC, 20 h.
Me SiO
3
OSiMe
3
1
R
2
R
OH
O
R
1
3
5a-e
i
R
2
R
Me SiO
3
O
4
R
4
3
R
R
Cl
Cl
3a-c
6a-h
First results indicate that 1,4-dihydroquinones 7 can be
readily deprotected and oxidized to the corresponding
functionalized 1,4-quinones. The free hydroxy group
can be functionalized by Suzuki reaction via the corre-
sponding enol triflates.
Scheme 2. Synthesis of 6a–h. Reagents and conditions: (i) TiCl4,
CH2Cl2, ꢀ78!20 ꢁC, 20 h.
without extrusion of the acetoxy group or cleavage of
the acetyl group.
We have reported a new approach to the functionalized
4-chlorophenols and 1,4-dihydroquinones based on
[3+3] cyclizations of 1,3-bis-silyl enol ethers with novel
2-chloro- and 2-acyloxy-3-(silyloxy)alk-2-en-1-ones.
The reaction of 2-chloro-3-(silyloxy)alk-2-en-1-one 3a
with 5b and 5c, prepared from acetylacetone and benz-
oylacetone, afforded the 2-acetyl- and 2-benzoyl-4-
chlorophenols 6b and 6c, respectively (Scheme 2 and
Table 1). The cyclization of 3a with 5d and 5e, prepared
Table 2. Products and yields
7
R1
R2
R3
R4
R5
Yield (%)a
a
b
c
d
e
f
H
H
Me
Et
OMe
H
Me
H
Et
H
Et
OMe
Me
Me
Me
Me
Me
Me
Et
Et
Ph
Ph
Me
Me
Me
Me
Me
Me
Me
Et
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Ac
Bz
Bz
52
55
55
54
50
51
73
43
37
55
46
Table 1. Products and yields
6
R1
R2
R3
R4
Yield (%)a
OEt
OEt
OMe
OMe
OEt
OMe
OEt
OMe
OEt
a
b
c
d
e
f
H
H
H
Me
Et
H
Et
Me
OMe
Me
Ph
OEt
OEt
OMe
OEt
OEt
Me
Me
Me
Me
Me
Et
Me
Me
Me
Me
Me
Et
62
50
44
55
56
52
54
51
g
h
i
Et
Me
Me
Me
Me
j
g
h
Et
Ph
Et
Me
k
a Isolated yields.
a Isolated yields.

Z. Ahmed, P. Langer / Tetrahedron Letters 47 (2006) 417–419
419
Currently, we study the preparative scope and synthetic
applications of these transformations.
(EI, 70 eV): calcd for C13H16O6 (M+): 268.0941; found:
268.0942.
General procedure for the synthesis of 4-chloro- and 4-
hydroxysalicylates: To a CH2Cl2 solution (15 mL) of
1,3-bis-silyl enol ether 5 (7.67 mmol) and 3-(silyl-
oxy)alk-2-en-1-one 3 or 4 (7.67 mmol) was added TiCl4
(7.67 mmol) at ꢀ78 ꢁC under argon atmosphere. The
temperature of the reaction mixture was allowed to rise
to 20 ꢁC during 20 h and, subsequently, a saturated
aqueous solution of NaHCO3 (20 mL) was added. The
organic layer was separated and extracted with diethyl
ether (3 · 30 mL). The combined organic layers were
dried (Na2SO4), filtered and the filtrate was concen-
trated in vacuo. The residue was purified by column
chromatography (silica gel, n-heptane/EtOAc).
Acknowledgements
Financial support by the state of Mecklenburg-Vor-
pommern (scholarship for Z.A. and Landesfor-
schungsschwerpunkt ÔNeue Wirkstoffe und Screening-
verfahrenÕ) is gratefully acknowledged.
References and notes
1. Ro¨mpp Lexikon Naturstoffe; Steglich, W., Fugmann, B.,
Lang-Fugmann, S., Eds.; Thieme: Stuttgart, 1997.
2. For belamcandol A, see: (a) Fukuyama, Y.; Okino, J.;
Kodama, M. Chem. Pharm. Bull. 1991, 39, 1877; (b)
Marner, F.-J.; Horper, W. Helv. Chim. Acta 1992, 75,
1557; (c) Oshima, R.; Yamauchi, Y.; Watanabe, C.;
Kumanotani, J. J. Org. Chem. 1985, 50, 2613; (d)
Budzikiewicz, H.; Scholl, H.; Neuenhaus, W.; Pulverer,
G.; Korth, H. Z. Naturforsch. B 1980, 35, 909.
3. (a) Jinno, S.; Hata, K.; Shimidzu, N.; Okita, T. J. Antibiot.
1998, 51, 508; (b) Jinno, S.; Okita, T. Chem. Pharm. Bull.
1998, 46, 1688; (c) Papendorf, O.; Koenig, G. M.; Wright,
A. D. Phytochemistry 1998, 49, 2383.
Compound 6a: Starting with 5a (2.00 g, 7.67 mmol), 3a
(1.58 g, 7.67 mmol) and TiCl4 (0.85 mL, 7.67 mmol), 6a
was isolated as a colourless solid (1.01 g, 62%), mp 59–
1
60 ꢁC; H NMR (250 MHz, CDCl3): d = 2.35 (s, 3H,
CH3), 2.60 (s, 3H, CH3) 3.96 (s, 3H, OCH3), 6.76 (s,
1H, ArH), 10.83 (s, 1H, OH); 13C NMR (75 MHz,
CDCl3): d = 19.90, 21.90, 52.36 (CH3), 111.96 (C),
117.41 (CH), 126.82, 137.92, 143.63, 159.98, 171.39
~
(C); IR (KBr): m ¼ 3426 ðwÞ, 3000 (w), 2952 (s), 2874
(m), 1663 (s), 1603 (s), 1564 (s), 1449 (s), 1381 (m),
1358 (s), 1310 (s), 1229 (s), 1190 (s), 1104 (m), 943 (m)
cmꢀ1; MS (EI, 70 eV): m/z (%): 214 (M+, 88), 184
(100), 154 (61), 91 (64); elemental analysis: calcd (%)
for C10H11O3Cl (214.65): C 55.95, H 5.16; found: C
55.97, H 5.12. All compounds were characterized by
spectroscopic methods and gave correct elemental ana-
lyses and/ or high resolution mass data.
4. Methoxymicareic acid: Elix, J. A.; Jones, A. J.; Lajide, L.;
Coppins, B. J.; James, P. W. Aust. J. Chem. 1984, 37,
2349.
5. (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; (c) Molander,
G. A.; Cameron, K. O. J. Am. Chem. Soc. 1993, 115, 830.
6. For [3+3] cyclizations from our laboratory, see: (a) Dede,
R.; Langer, P. Tetrahedron Lett. 2004, 45, 9177; (b) Bose,
G.; Nguyen, V. T. H.; Ullah, E.; Lahiri, S.; Go¨rls, H.;
Langer, P. J. Org. Chem. 2004, 69, 9128; (c) Nguyen, V. T.
H.; Langer, P. Tetrahedron Lett. 2005, 46, 815; (d)
Nguyen, V. T. H.; Langer, P. Tetrahedron Lett. 2005, 46,
1013; (e) Nguyen, V. T. H.; Bellur, E.; Appel, B.; Langer,
P. Synthesis, in press.
Compound 7e: Starting with 5f (600 mg, 2.06 mmol), 4a
(476 mg, 2.06 mmol) and TiCl4 (0.22 mL, 2.06 mmol), 7e
was isolated as a colourless solid (263 mg, 50%), mp 68–
1
72 ꢁC; H NMR (250 MHz, CDCl3): d = 2.10 (s, 3H,
CH3), 2.25 (s, 3H, CH3), 2.33 (s, 3H, CH3), 3.83 (s,
3H, OCH3), 3.94 (s, 3H, OCH3), 11.16 (s, 1H, OH);
13C NMR (75 MHz, CDCl3): d = 10.86, 15.42, 20.76,
52.71, 60.66 (CH3), 111.62, 127.23, 131.57, 140.88,
145.31, 154.41, 169.54, 172.19 (C); IR (KBr):
7. For a review of 1,3-bis-silyl enol ethers, see: Langer, P.
Synthesis 2002, 441.
8. Roshchupkina, G. I.; Gatilov, Y. V.; Rybalova, T. V.;
Reznikov, V. A. Eur. J. Org. Chem. 2004, 1765.
9. Valgimigli, L.; Brigati, G.; Pedulli, G. F.; Dilabio, G. A.;
Mastragostino, M.; Arbizzani, C.; Pratt, D. A. Chem. Eur.
J. 2003, 9, 4997.
~
m ¼ 3501ðwÞ, 3009 (w), 2960 (w), 2937 (w), 1753 (s),
1660 (s), 1440 (s), 1352 (s), 1214 (s), 1071 (m), 1041
(m), 806 (m) cmꢀ1; GC-MS (EI, 70 eV): m/z (%): 268
(M+, 10), 226 (17), 194 (100), 165 (38), 67 (46); HRMS
10. Tius, M. A.; Kwoka, C. K.; Gu, X. Q.; Zhao, C. Synth.
Commun. 1994, 24, 871.