Regioselective synthesis of functionalized resorcins by cyclization of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3,3-dimethoxypentanoyl chloride

Article abstract of DOI:10.1055/s-2008-1072675

Functionalized resorcins are regioselectively prepared by cyclization of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with 3,3-dimethoxypentanoyl chloride. The regioselectivity is controlled by the type of Lewis acid employed. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1072675

1050
LETTER
Regioselective Synthesis of Functionalized Resorcins by Cyclization of 1,3-
Bis(trimethylsilyloxy)-1,3-butadienes with 3,3-Dimethoxypentanoyl Chloride
R
egioselective Synthes
u
is of Functio
h
nalized Reso
a
rcins mmad Sher,a,b Peter Langer*a,b
a
Institut für Chemie, Universität Rostock, Albert Einstein Str. 3a, 18059 Rostock, Germany
E-mail: peter.langer@uni-rostock.de
b
Leibniz-Institut für Katalyse e. V. an der Universität Rostock, Albert Einstein Str. 29a, 18059 Rostock, Germany
Received 3 December 2007
Table 1).13 The best yields were obtained when 0.5 equiv-
alents of TMSOTf were employed. The yield decreased
when the amount of TMSOTf was reduced. The use of
more Lewis acid (1.0 equiv) did not result in an increase
of the yield. The formation of the products can be ex-
plained by regioselective attack of the terminal carbon
atom of the 5a–l onto the acetal and subsequent attack
from the central carbon onto the acid chloride.
Abstract: Functionalized resorcins are regioselectively prepared
by cyclization of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with
3,3-dimethoxypentanoyl chloride. The regioselectivity is controlled
by the type of Lewis acid employed.
Key words: arenes, cyclizations, regioselectivity, silyl enol ethers
A great variety of pharmacologically important natural
products are biosynthetically derived from poly(b-
oxo)carboxylic acids (polyketides).1 Harris and cowork-
ers reported the biomimetic synthesis of various 1,3,5,7-
tetracarbonyl compounds and their higher homologues
based on condensations of 1,3-dicarbonyl dianions or
1,3,5-tricarbonyl trianions with esters and diesters, Wein-
reb amides, and salts of b-keto esters.2 These products are
unstable and rapidly undergo an intramolecular aldol con-
densation to give polyhydroxylated arenes present in
many poylyketide-derived natural products. 1,3-Bis(tri-
methylsilyloxy)-1,3-butadienes can be regarded as elec-
troneutral equivalents of 1,3-dicarbonyl dianions (masked
dianions).3,4 Chan and coworkers were the first to report
the reaction of 1-methoxy-1,3-bis(trimethylsiloxy)-1,3-
butadiene with acetyl chloride.5 Salicylates were prepared
by Lewis acid mediated [5+1] cyclization of 1-methoxy-
1,3,5-tris(trimethylsiloxy)-1,3,5-hexatriene with acid
chlorides and imidazolides.6 We reported on the reaction
of 1,3-bis(trimethylsilyloxy)-1,3-butadienes with various
acid chlorides.7,8 g-Alkylidenebutenolides are available
by cyclization of 1,3-bis(silyl enol ethers) with oxalyl
chloride9 and phthaloyl chloride.10 Recently, we reported
the synthesis of new 1,3,5,7-tetracarbonyl compounds by
condensation of 1,3-bis(trimethylsilyloxy)-1,3-buta-
dienes with methyl malonyl chloride.11 Herein, we report
an efficient synthetic approach to functionalized resorcins
based on what are, to the best of our knowledge, the first
formal [3+3] cyclizations of 1,3-bis(silyl enol ethers) with
3,3-dimethoxypentanoyl chloride.12
OMe
O
O
O
i
MeO
Et
OMe
Et
OMe
2
75%
ii
1
OMe
O
OMe
O
iii
MeO
Et
MeO
Et
OH
Cl
4
85%
3 62%
Scheme 1 Synthesis of 4. Reagents and conditions: (i) HC(OMe)3
(6.0 equiv), Amberlite IR 120+; (ii) NaOH, H2O, 12 h, 20 °C; (iii)
(COCl)2, C6H6, 2 h, reflux.
OMe
O
MeO
Et
OH
O
Cl
R1
Et
TMSOTf
(0.5 equiv)
OR2
4
TMSO
R1
OTMS
OR2
i
OH
+
6a–l
5a–l
+ TMSOTf
– TMSOMe
– TMSOMe
TMSO
O
O
O
R1
R1
OR2
OTf–
+
TMS
OR2
OTMS
Et
3,3-Dimethoxypentanoyl chloride was prepared in three
steps as shown in Scheme 1. The TMSOTf-catalyzed re-
action of 4 with 1,3-bis(trimethylsilyloxy)-1,3-butadienes
5a–l, prepared from the corresponding b-keto esters,3 af-
forded the 6-hydroxysalicylates 6a–l (Scheme 2,
Et
– TMSCl
– TfOH
MeO
MeO
Cl
O
B
A
Scheme 2 Synthesis of 6a–l. Reagents and conditions: (i) TMSOTf
(0.5 equiv), CH2Cl2, –78 °C to 20 °C.
SYNLETT 2008, No. 7, pp 1050–1052
x
x.
x
x.
2
0
0
8
Advanced online publication: 28.03.2008
DOI: 10.1055/s-2008-1072675; Art ID: D38707ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Regioselective Synthesis of Functionalized Resorcins
1051
Table 2 Synthesis of 7a–i
Table 1 Synthesis of 6a–l
5
7
R1
R2
Yield of 7 (%)a
5, 6
a
b
c
R1
R2
Yield of 6 (%)a
5a
5b
5d
5e
5f
7a
7b
7c
7d
7e
7f
7g
7h
7i
H
Me
61
40
34
40
65
66
52
57
53
H
Me
43
47
56
52
38
35
60
40
40
50
36
34
H
Et
H
Et
H
CH2Ph
(CH2)2OMe
Me
H
i-Pr
CH2Ph
(CH2)2OMe
Me
H
d
e
H
Me
i-Bu
n-Hex
n-Hept
n-Oct
H
5h
5m
5n
5o
Me
f
Me
Et
Me
g
h
i
Et
Me
i-Bu
n-Pr
n-Bu
Bn
MeO
Me
Et
Me
a Yields of isolated products.
j
Et
k
l
Me
In conclusion, functionalized resorcins were prepared by
cyclization of 1,3-bis(trimethylsilyloxy)-1,3-butadienes
with 3,3-dimethoxypentanoyl chloride. The regioselectiv-
ity depends on the type of Lewis acid employed. The re-
gioselectivity might be explained based on the HSAB
principle. The acid chloride is selectively activated by the
‘hard’ Lewis acid TiCl4. In contrast, TMSOTf is known to
readily activate ketals and acetals, but not ketones and al-
dehydes.7,15 On the other hand, acid chlorides are readily
activated by TMSOTf.3,7,9 The observed selectivity in fa-
vor of the activation of the ketal (rather than the acid chlo-
ride) might again be explained based on the HSAB
principle.
Me
a Yields of isolated products.
The TiCl4-mediated reaction of 4 with 1,3-bis(trimethyl-
silyloxy)-1,3-butadienes 5 afforded the 4-hydroxysalicy-
lates 7a–i (Scheme 3, Table 2).14 The formation of
products 7 can be explained by regioselective attack of the
terminal carbon atom of the 1,3-bis(trimethylsilyloxy)-
1,3-butadiene onto the acid chloride and subsequent at-
tack of the central carbon atom onto the acetal.
O
OMe
OMe
Acknowledgment
OH
O
Cl
Et
TiCl4
(1.0 equiv)
R1
Financial support by the State of Mecklenburg-Vorpommern is gra-
tefully acknowledged.
4
5
OR2
TMSO
R1
OTMS
i
HO
Et
+
OR2
References and Notes
7a–i
(1) (a) Staunton, J.; Weissman, K. J. Nat. Prod. Rep. 2001, 18,
380. (b) Koskinen, A. M. P.; Karisalmi, K. Chem. Soc. Rev.
2005, 34, 677. (c) Römpp-Lexikon Naturstoffe; Fugmann,
B., Ed.; Thieme: Stuttgart / New York, 1997.
(2) For a review, see: (a) Harris, T. M.; Harris, C. M.
Tetrahedron 1977, 33, 2159. See also: (b) Murray, T. P.;
Harris, T. M. J. Am. Chem. Soc. 1972, 94, 8253. (c) Harris,
C. M.; Roberson, J. S.; Harris, T. M. J. Am. Chem. Soc. 1976,
98, 5380. (d) Harris, T. M.; Hay, J. V. J. Am. Chem. Soc.
1977, 99, 1631. (e) Hubbard, J. S.; Harris, T. M.
Tetrahedron Lett. 1978, 47, 4601. (f) Sandifer, R. M.;
Bhattacharya, A. K.; Harris, T. M. J. Org. Chem. 1981, 46,
2260. (g) Gilbreath, S. G.; Harris, C. M.; Harris, T. M. J. Am.
Chem. Soc. 1988, 110, 6172.
+ TiCl4
– TMSCl
– HCl
+ H2O
– TiOCl2
– HCl
TMSO
R1
O
OH
O
OR2
R1
OR2
Cl3TiO
MeO
MeO
Cl3TiO
Et
Et
E
C
HCl
HCl
– MeOH
– TMSOMe
OH
O
(3) For a review of 1,3-bis(silyl enol ethers), see: Langer, P.
R1
OR2
Synthesis 2002, 441.
(4) For a review of formal [3+3] cyclizations of 1,3-bis(silyl
enol ethers), see: Feist, H.; Langer, P. Synthesis 2007, 327.
(5) Chan, T.-H.; Brownbridge, P. J. Chem. Soc., Chem.
Commun. 1979, 578.
(6) (a) Chan, T.-H.; Stössel, D. J. Org. Chem. 1988, 53, 4901.
(b) Chan, T.-H.; Stössel, D. J. Org. Chem. 1986, 51, 2423.
Et
OMe
Cl3TiO
D
Scheme 3 Synthesis of 7a–i. Reagents and conditions: (i) 1) TiCl4
(1.0 equiv), CH2Cl2, –78 °C to 20 °C; 2) H2O.
Synlett 2008, No. 7, 1050–1052 © Thieme Stuttgart · New York

1052
M. Sher, P. Langer
LETTER
OH). 13C NMR (75 MHz, CDCl3): d = 14.4 (CH3), 29.2
(CH2), 52.7 (OCH3), 97.7 (C), 107.8 (CH), 154.6,164.5,
169.8 (C). IR (KBr): 3427 (s), 2960 (s), 1670 (s), 1571 (s),
1377 (m), 1257 (s), 1103 (s), 1040 (m), 949 (m), 846 (s)799
(s), 738 (s), 613 (s), 531 (m) cm–1. GC-MS (EI, 70 eV): m/z
(%) = 196.0(35) [M+], 164.0(100), 136.0(21), 121.0(27).
Anal. Calcd for C10H12O4 (196.07): C, 61.22; H, 6.16.
Found: C, 61.32; H, 6.11.
(7) Langer, P.; Krummel, T. Chem. Eur. J. 2001, 7, 1720.
(8) Rahn, T.; Nguyen, V. T. H.; Dang, T. H. T.; Ahmed, Z.;
Lalk, M.; Fischer, C.; Spannenberg, A.; Langer, P. J. Org.
Chem. 2007, 72, 1957.
(9) For a review of cyclizations of silyl enol ethers with oxalyl
chloride, see: Langer, P. Synlett 2006, 3369.
(10) Albrecht, U.; Nguyen, V. T. H.; Langer, P. Synthesis 2006,
1111.
(11) Reim, S.; Nguyen, V. T. H.; Albrecht, U.; Langer, P.
Tetrahedron Lett. 2005, 46, 8423.
(14) Typical Procedure for the Synthesis of 7a–i
To a CH2Cl2 solution (5 mL) of 1,3-bis(trimethylsilyloxy)-1-
methoxy-1,3-butadiene (500 mg, 1.91 mmol) and of 4 (385
mg, 2.11 mmol) was added dropwise TiCl4 (0.21 mL, 1.91
mmol) at –78 °C. The reaction mixture was allowed to warm
to 20 °C during 6–12 h. After stirring for additional 2–6 h at
20 °C, a sat. aq solution of NaHCO3 (20 mL) was added. The
organic and the aqueous layers were separated and the latter
was extracted with Et2O (3 × 25 mL). The combined organic
layers were dried (NaSO4), filtered and the filtrate was
concentrated in vacuo. The residue was purified by
chromatography (SiO2, heptane–EtOAc) to give 7a as a
yellow solid (230 mg, 61%). 1H NMR (300 MHz, CDCl3):
d = 1.30 (t, 3 H, J = 7.5 Hz, CH3), 3.28 (q, 2 H, J = 7.5 Hz,
CH2), 4.01 (s, 3 H, OCH3), 6.08 (s, 1 H, CHAr), 6.78 (s, 1 H,
CHAr), 12.06 (s, 1 H, OH). 13C NMR (75 MHz, CDCl3):
d = 14.8 (CH3), 28.8 (CH2), 52.7 (OCH3), 110.5, 116.0,
155.0, 166.0, 167.6, 170.5, 179.9. IR (KBr): 3427 (s), 2960
(s), 1670 (s), 1571 (s), 1377 (m), 1257 (s), 1103 (s), 1040
(m), 949 (m), 846 (s), 799 (s), 738 (s), 613 (s), 531 (m)
cm–1. GC-MS (EI, 70 eV): m/z (%) = 196.0(37) [M+],
164.0(100), 136.0(26), 121.0(27). HRMS (EI): m/z calcd for
C10H12O4 [M]+: 196.072572; found: 196.07301.
(12) (a) Some years ago, an isolated example of the cyclization of
a protected b-keto ester was reported, see ref. 12b. In the
case of 2, this reaction failed to give the desired product
(formation of a complex mixture). An isolated reaction of a
1,3-dioxolan-protected b-keto acid chloride was also
reported by Chan and Chaly. However, in our hands, the use
of the dioxolan group proved to be disadvantageous in order
to isolate the desired product in pure form. (b) Chan, T. H.;
Chaly, T. Tetrahedron Lett. 1982, 23, 2935.
(13) Typical Procedure for the Synthesis of 6a-l
To a CH2Cl2 solution (8 mL) of 1,3-bis(trimethylsilyloxy)-1-
methoxy-1,3-butadiene (5a, 860 mg, 3.32 mmol) and of 4
(660 mg, 3.65 mmol) was dropwise added TMSOTf (0.3
mL, 1.66 mmol, 0.5 equiv) at –78 °C. The reaction mixture
was allowed to warm to 20 °C during 6–12 h. After stirring
for additional 2–6 h at 20 °C, HCl (10%, 25 mL) was added.
The organic and the aqueous layers were separated and the
latter was extracted with CH2Cl2 (3 × 20 mL). The combined
organic layers were dried (NaSO4), filtered, and the filtrate
was concentrated in vacuo. The residue was purified by
chromatography (SiO2, heptanes–EtOAc) to give 6a as
yellow solid (280 mg, 43%). 1H NMR (300 MHz, CDCl3):
d = 1.13 (t, 3 H, J = 7.6 Hz, CH3), 2.48 (q, 2 H, J = 7.5 Hz,
CH2), 3.99 (s, 3 H, OCH3), 6.28 (s, 2 H, CHAr), 9.54 (s, 2 H,
(15) Murata, S.; Suzuki, M.; Noyori, R. J. Am. Chem. Soc. 1980,
102, 3248.
Synlett 2008, No. 7, 1050–1052 © Thieme Stuttgart · New York

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