Regioselective synthesis of 5-chlorosalicylates by one-pot cyclization of 1,3-bis(trimethylsilyloxy)buta-1,3-dienes with 2-chloro-3-ethoxy-2-alken-1-ones

Article abstract of DOI:10.1055/s-0030-1258488

A variety of 5-chlorosalicylates were prepared by regioselective one-pot cyclizations of 1,3-bis(trimethylsilyloxy)buta-1,3-dienes with novel 2-chloro-3-ethoxy-2-alken-1-ones. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258488

LETTER
1963
Regioselective Synthesis of 5-Chlorosalicylates by One-Pot Cyclization of 1,3-
Bis(trimethylsilyloxy)buta-1,3-dienes with 2-Chloro-3-ethoxy-2-alken-1-ones
S
ynthesisof 5-Chl
l
orosali
u
Aiyelaagbe,c Emmanuel T. Akintayo,d Christine Fischer,b Peter Langer*a,b
a
Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
Fax +49(381)4986412; E-mail: peter.langer@uni-rostock.de
Leibniz-Institut für Katalyse an der Universität Rostock e.V., Albert Einstein Str. 29a, 18059 Rostock, Germany
Department of Chemistry, University of Ibadan, Ibadan 200284, Nigeria
b
c
d
Department of Chemistry, University of Ado-Ekiti, P.M.B 5363, Ado-Ekiti, Nigeria
Received 11 March 2010
1,3-bis(trimethylsilyloxy)buta-1,3-diene with dimethyl
Abstract: A variety of 5-chlorosalicylates were prepared by regio-
selective one-pot cyclizations of 1,3-bis(trimethylsilyloxy)buta-
1,3-dienes with novel 2-chloro-3-ethoxy-2-alken-1-ones.
acetylenedicarboxylate.5
1,3-Bis(trimethylsilyloxy)buta-1,3-dienes represent im-
portant synthetic building blocks which have been used in
various cyclocondensation reactions.6,7 Chlorinated are-
nes and heteroarenes have been prepared by cyclization of
1,3-bis(silyloxy)buta-1,3-dienes with 3-silyloxy-2-en-1-
ones8 and by cyclization of 2-chloro- and 4-chloro-1,3-
bis(silyloxy)buta-1,3-dienes with various electro-
philes.9,10 Herein, we report the synthesis of highly substi-
tuted 5-chlorosalicylates by what are, to the best of our
knowledge, the first one-pot cyclizations of 1,3-bis-(tri-
methylsilyloxy)buta-1,3-dienes with novel 2-chloro-3-
ethoxy-2-alken-1-ones. The reactions proceed with excel-
lent regioselectivity and provide a convenient access to 5-
chlorosalicylates, which are not readily available by other
methods.
Key words: organochlorine compounds, cyclizations, silyl enol
ethers, arenes
Aryl chlorides are of great importance as lead structures in
medicinal chemistry. Chlorinated molecules occur in var-
ious pharmacologically important natural products. This
includes, for example, chlorinated dibenzo[b,e][1,4]diox-
epin-11-ones.1 5-Chlorosalicylates occur, for example, in
the natural product chloratranorin (Figure 1).1 Last but not
least, chloroarenes are of increasing relevance as synthetic
building blocks for transition-metal-catalyzed cross-cou-
pling reactions.2
OH
O
The reaction of a-chloroketones 1a–f with triethyl ortho-
formate and acetic anhydride afforded the novel 2-chloro-
3-ethoxy-2-alken-1-ones 2a–f in 41–81% yields
(Scheme 1, Table 1).11,12 The yields of aryl-substituted
derivatives 2a–e were considerably higher than the yield
of 2f. The chloro group proved to be compatible with the
reaction conditions.
Me
O
OH
O
OMe
OHC
HO
Me
Me
Cl
Figure 1 Chloratranorin
O
O
Cl
Classic syntheses of functionalized aryl chlorides rely on
the chlorination of arenes which often proceed with low
ortho/para regioselectivities and in low yields. An alter-
native strategy relies on the application of a building
block strategy and employment of chlorinated substrates
in cyclization reactions. Brassard and coworkers reported
the synthesis of a chlorinated anthraquinone by [4+2] cy-
cloaddition of 2-chloro-1-methoxy-1,3-bis(trimethylsilyl-
oxy)buta-1,3-diene with a 2-chloronaphthoquinone.3 In
addition, the synthesis of a chlorinated phenol by [4+2]
cycloaddition of a chlorinated thiophene with dimethyl
acetylenedicarboxylate has been reported.4 We have re-
ported the [4+2] cycloaddition of 2-chloro-1-methoxy-
i
R
Cl
R
OEt
1a–f
2a–f
Scheme 1 Synthesis of 2a–f. Reagents and conditions: 1a–f (1.0
equiv), HC(OEt)3 (3.0 equiv), Ac2O (3.0 equiv), reflux, 15 h; all pro-
ducts were prepared as mixtures of E/Z-isomers.
The TiCl4-mediated reaction of 2-chloro-3-ethoxy-2-alk-
en-1-ones 2a–f with 1,3-bis(silyloxy)buta-1,3-dienes 3a-
d, which are available from the corresponding b-keto
esters in two steps,6 afforded the novel 5-chlorosalicylates
4a–q in moderate yields (Scheme 2, Table 2).13,14 During
the optimization, it proved to be important to carry out the
reactions in a highly concentrated solution (0.5 M solution
of 2a–f). 6-Aryl-5-chlorosalicylates 4a–p can be regarded
as chlorinated biphenyls. The chloro group again proved
to be compatible with the reaction conditions. All reac-
SYNLETT 2010, No. 13, pp 1963–1965
x
x
.x
x
.2
0
1
0
Advanced online publication: 09.07.2010
DOI: 10.1055/s-0030-1258488; Art ID: D06610ST
© Georg Thieme Verlag Stuttgart · New York

1964
O. Fatunsin et al.
LETTER
Table 1 Synthesis of 2a–f
Table 2 Synthesis of 4a–q
1, 2
a
R
Yield of 2 (%)a
2
a
a
a
a
b
b
b
b
c
3
a
b
c
4
a
b
c
R1
R2
Yield of 4 (%)a
Ph
76
68
81
70
60
41
H
Ph
45
44
46
45
42
40
47
49
51
44
b
4-FC6H4
4-ClC6H4
2,4-Cl2C6H3
2,4-F2C6H3
Me
Me
Et
Ph
c
Ph
d
d
a
b
c
d
e
n-Bu
H
Ph
e
4-FC6H4
4-FC6H4
4-FC6H4
4-FC6H4
4-ClC6H4
4-ClC6H4
f
f
Me
Et
a Yields of isolated products.
g
h
i
d
c
n-Bu
Et
tions proceeded with very good regioselectivity in favor
of the products containing substituent R3 located ortho to
the ester group. The other regioisomers, containing sub-
stituent R3 located para to the ester group, were not
formed (inspection of the crude product). The moderate
yields can be explained by hydrolysis and oxidative
dimerization of the diene and loss of material during the
chromatographic purification.
c
d
a
c
j
n-Bu
H
d
d
d
e
k
l
2,4-Cl2C6H3 44
2,4-Cl2C6H3 45
2,4-Cl2C6H3 47
Et
d
a
c
m
n
o
p
q
n-Bu
H
2,4-F2C6H3
2,4-F2C6H3
2,4-F2C6H3
Me
50
49
45
45
OSiMe3
OMe
Me3SiO
R1
e
Et
OH
O
e
d
c
n-Bu
Et
TiCl4
R1
3a–d
CH2Cl2
OMe
f
+
–78 to 20 °C
12 h
R2
O
a Yields of isolated products.
Cl
4a–q
R2
EtO
Cl
2a–f
References and Notes
Scheme 2 Synthesis of 4a–q
(1) (a) Sala, T.; Sargent, M. V. J. Chem. Soc., Perkin Trans. 1
1981, 849. (b) Birkbeck, A. A.; Sargent, M. V.; Elix, J. A.
Aust. J. Chem. 1990, 43, 419. (c) Mahandru, M. M.;
Tajbakhsh, A. J. Chem. Soc., Perkin Trans. 1 1983, 413.
(d) Elix, J. A.; Jenie, U. A.; Arvidsson, L.; Joergensen,
P. M.; James, P. W. Aust. J. Chem. 1986, 39, 719.
(e) Nielsen, J.; Nielsen, P. H.; Frisvad, J. C. Phytochemistry
1999, 50, 263.
(2) (a) Harkal, S.; Kumar, K.; Michalik, D.; Zapf, A.; Jackstell,
R.; Rataboul, F.; Riermeier, T.; Monsees, A.; Beller, M.
Tetrahedron Lett. 2005, 46, 3237; and references cited
therein. (b) Harkal, S.; Rataboul, F.; Zapf, A.; Fuhrmann, C.;
Riermeier, T. H.; Monsees, A.; Beller, M. Adv. Synth. Catal.
2004, 346, 1742. (c) Metal-Catalyzed Cross-Coupling
Reactions; de Meijere, A.; Diederich, F., Eds.; Wiley-VCH:
Weinheim, 2004.
In conclusion, we have reported the synthesis of a variety
of highly substituted 5-chlorosalicylates by one-pot cy-
clizations of 1,3-bis(trimethylsilyloxy)buta-1,3-dienes
with 2-chloro-3-ethoxy-2-alken-1-ones. The reactions
proceed with very good regioselectivity. The products are
not readily available by other methods. The scope and ap-
plications of this methodology are currently being studied.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
(3) Savard, J.; Brassard, P. Tetrahedron Lett. 1979, 20, 4911.
(4) Corral, C.; Lissavetzky, J.; Manzanares, I. Synthesis 1997,
29.
(5) Abid, O.-u. R.; Ibad, M. F.; Nawaz, M.; Adeel, M.; Rama,
N. H.; Villinger, A.; Langer, P. Tetrahedron Lett. 2010, 51,
657.
Financial support by the State of Mecklenburg-Vorpommern (scho-
larship for M. S.) and by the DAAD (scholarship for S.-M. T. T.) is
gratefully acknowledged.
(6) (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.
Synlett 2010, No. 13, 1963–1965 © Thieme Stuttgart · New York

LETTER
Synthesis of 5-Chlorosalicylates
1965
(7) For a review of 1,3-bis(trimethylsilyloxy)-1,3-dienes in
general, see: (a) For a review of [3+3] cyclizations, see:
Langer, P. Synthesis 2002, 441. (b) Feist, H.; Langer, P.
Synthesis 2007, 327.
(8) 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) Reim, S.; Hussain, I.; Adeel, M.; Yawer, M. A.; Villinger,
A.; Langer, P. Tetrahedron Lett. 2008, 49, 4901.
(10) (a) Reim, S.; Langer, P. Tetrahedron Lett. 2008, 49, 2329.
(b) Wolf, V.; Adeel, M.; Reim, S.; Villinger, A.; Fischer, C.;
Langer, P. Eur. J. Org. Chem. 2009, 5854.
(11) General Procedure for the Synthesis of 2a–f
To a solution of 1a–f (1 equiv) in Ac2O (3 equiv) was added
triethyl orthoformate (3 equiv). The mixture was heated for
15 h at 140 °C. The mixture was dried in vacuo and was
purified by chromatography (silica gel, heptanes–EtOAc) to
give 2a–f.
(12) 2-Chloro-3-ethoxy-1-phenylprop-2-en-1-one (2a)
A mixture of 1a (2.00 g, 12.9 mmol), triethyl orthoformate
(6.5 mL, 38.8 mmol) and Ac2O (3.7 mL, 38.8 mmol), was
refluxed for 15 h at 140 °C, and the resultant mixture was
purified by chromatography (silica gel, n-heptane–EtOAc)
to give 2a as a brownish oil (2.10 g, 76%). 1H NMR (300
MHz, CDCl3): d = 1.32 (t, 3J = 7.1 Hz, 3 H, OCH2CH3), 4.10
(q, 3J = 7.1 Hz, 2 H, OCH2CH3), 7.37–7.44 (m, 4 H, CH,
CHAr), 7.52–7.55 (m, 2 H, CHAr). 13C NMR (75 MHz,
CDCl3): d = 15.3 (CH3), 66.0 (OCH2), 113.8 (CCl), 128.7
(2 × CHAr), 128.8 (2 × CHAr), 134.0 (CHAr), 138.2 (CAr),
160.5 (CH), 189.5 (CO). IR (neat): 3368 (w), 3062 (w), 2980
(w), 2935 (w), 1747 (m), 1691 (s), 1596 (m), 1449 (m), 1372
(m), 1216 (s), 1181 (m), 1085 (m), 1000 (m), 965 (m), 846
(m), 754 (m), 686 (s), 640 (m), 600 (m), 561 (m) cm–1. Anal.
Calcd for C11H11O2Cl: C, 62.66; H, 5.22. Found: C, 62.85;
H, 5.03.
(13) General Procedure for the Synthesis of 4a–q
To a CH2Cl2 solution (2 mL/1.0 mmol of 2a–f) of 2a–f was
added 3a–d (1.1 mmol) and, subsequently, TiCl4 (1.1 mmol)
at –78 °C. The temperature of the solution was allowed to
warm to 20 °C over 12 h with stirring. HCl (10%, 20 mL)
was added to the solution, and the organic and the aqueous
layers 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, heptanes–EtOAc) to give 4a–q.
(14) Methyl 6-Chloro-3-hydroxybiphenyl-2-carboxylate (4a)
Starting with 2a (316 mg, 1.5 mmol) and 3a (430 mg, 1.65
mmol), 4a was isolated after chromatography (silica gel, n-
heptane–EtOAc) as a yellowish oil (177 mg, 45%). 1H NMR
(300 MHz, CDCl3): d = 3.32 (s, 3 H, OCH3), 6.92 (d, 3J = 8.9
Hz, 1 H, CHAr), 7.05–7.08 (m, 2 H, CHAr), 7.27–7.35 (m, 3
H, CHAr), 7.42 (d, 3J = 8.9 Hz, 1 H, CHAr), 10.65 (s, 1 H,
OH). 13C NMR (75 MHz, CDCl3): d = 51.0 (OCH3), 113.1
(CCOOCH3), 117.4 (CHAr), 124.0 (CCl), 126.2 (CHAr),
126.6 (2 × CHAr), 127.5 (2 × CHAr), 134.1 (CHAr), 138.7,
140.8 (CAr), 159.2 (COH), 169.6 (CO). IR (neat): 3058 (w),
3025 (w), 2951 (w), 2925 (w), 2852 (w), 1739 (w), 1666 (s),
1593 (m), 1499 (w), 1435 (s), 1334 (m), 1289 (m), 1206 (s),
1135 (m), 1093 (m), 1027 (w), 1000 (w), 963 (m), 825 (m),
770 (m), 748 (s), 698 (s), 690 (s), 635 (m), 610 (m), 573 (m)
cm–1. GC-MS (EI, 70 eV): m/z (%) = 262 (35Cl, 68) [M]+,
230 (100), 202 (63), 168 (11), 139 (81), 113 (6), 87 (7), 69
(8). HRMS (EI): m/z calcd for C14H11O335Cl [M]+:
262.03912; found: 262.03916.
Synlett 2010, No. 13, 1963–1965 © Thieme Stuttgart · New York

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