Synthesis of homophthalates by [3+3] cyclocondensation reactions of 1,3-bis(silyloxy)-1,3-butadienes with silylated methyl 3,5-dioxohexanoate

Article abstract of DOI:10.5560/ZNB.2013-3020

Homophthalates were prepared by formal [3+3] cyclocondensation of 1,3-bis(silyl enol ethers) with silylated methyl 3,5-dioxohexanoate.

Full text of DOI:10.5560/ZNB.2013-3020

Synthesis of Homophthalates by [3 + 3] Cyclocondensation
Reactions of 1,3-Bis(silyloxy)-1,3-butadienes with Silylated Methyl
3,5-Dioxohexanoate
Jennifer Hefnera, Alexander Villingera and Peter Langera,b
a
Institut fu¨r Chemie, Universita¨t Rostock, Albert-Einstein-Str. 3a, 18059 Rostock, Germany
Leibniz-Institut fu¨r Katalyse an der Universita¨t Rostock e. V., Albert-Einstein-Str. 29a, 18059
b
Rostock, Germany
Reprint requests to Prof. Dr. Peter Langer. E-mail: peter.langer@uni-rostock.de
Z. Naturforsch. 2013, 68b, 831 – 835 / DOI: 10.5560/ZNB.2013-3020
Received January 21, 2013
Homophthalates were prepared by formal [3 + 3] cyclocondensation of 1,3-bis(silyl enol ethers)
with silylated methyl 3,5-dioxohexanoate.
Key words: Homophthalates, Cyclizations, Silyl Enol Ethers, Regioselectivity
O
Introduction
OH
O
OH
O
OMe
Homophthalates (Fig. 1) are of considerable rel-
evance to the synthesis of natural products [1].
Lunularic acid (6-(4-hydroxyphenethyl)salicylic acid;
Fig. 1) plays an important role in the regulation of
the growth of plants [2]. Homophthalates also repre-
sent versatile synthetic building blocks. For example,
Arai et al. reported the condensation of 3-methoxy-
homophthalic acid with anisol to give an isocuma-
HO
OH
Homophthalic acid
Lunularic acid
Fig. 1. Homophthalic acid and lunularic acid.
rine which was transformed by catalytic hydrogena- Results and Discussion
tion and reaction with boron tribromide into lunularic
acid [3]. Another example is the synthesis of sclerin
Methyl 3,5-dioxohexanoate (2) was prepared by
from methyl 3-oxopentanoate via a dimethyl homoph- reaction of dehydracetic acid (1) with magnesium
thalate [4]. Sclerin is a natural product isolated from methanolate in 89% yield (Scheme 1) [12]. Silylation
the fungus Sclerotinia libertiana and is known to act as of 2 resulted in the formation of silyl enol ether 3 (77%
a phytohormon [5]. Homophthalates were earlier pre- yield) which exists as a mixture of three isomers which
pared by cyclization of 1,3-bis(silyl enol ethers) [6 – 9] were not structurally assigned. The 6 theoretically pos-
with trimethylorthoacetate, acetyl chloride or acetic sible regioisomers and E/Z-isomers are depicted in
anhydride [4 – 10]. The reaction follows a 2 : 1 sto- Scheme 2. 1,3-Diketones are more readily enolized
ichiometry and proceeds by condensation to give an than β-ketoesters. Therefore, we believe that isomers
open-chain adduct and by subsequent formal [3+3] cy- E and F are not present, although we do not have an
clocondensation. Homophthalates are also available by experimental proof. Detailed NMR experiments were
[4 + 2] cycloaddition of 1,3-bis(silyl enol ethers) with not possible, due to the unstable nature of the prod-
dimethyl allene-1,3-dicarboxylate [11]. Herein, we re- uct. However, the exact structure of the isomers is pre-
port a stepwise synthesis of homophthalates by formal sumably not relevant for the subsequent cyclization re-
[3 + 3] cyclocondensation of 1,3-bis(silyl enol ethers) action, because it is known that the silyl groups and
with silylated 3,5-dioxoesters.
double bond configurations can be interconverted un-
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832
J. Hefner et al. · Synthesis of Homophthalates
Scheme 1. Synthesis of 3.
O
O
Me3SiO
O
O
Table 1. Synthesis of 5a – c and iso-5a – c.
4, 5
R
5 (%) a
45
20
41
iso-5 (%) a
Me3SiO
OMe
OMe
a
b
c
H
Me
Et
0
10
0
A
B
SiMe3
O
a
SiMe3
O O
Yields of isolated products.
O
O
OMe
OMe
other isomer, containing the ester groups located para
to each other was not observed. The structure of 5a
(isomer A) was established by a 1H,1H-NOESY exper-
O
C
D
1
iment (Scheme 4). A H,1H-NOESY correlation was
O
OSiMe3
SiMe3
O
O
O
observed between the methyl group (δ = 2.30 ppm)
and the aromatic protons (δ = 6.54 ppm and δ =
6.77 ppm). The methylene group (δ = 3.84 ppm) only
showed a correlation with the aromatic proton resonat-
ing at δ = 6.54 ppm. The NOE correlations expected
for isomer B were not observed.
OMe
E
F
O
OMe
Scheme 2. Possible isomers of 3.
der the conditions of TiCl4-mediated [3+3] cyclization
reactions with 1,3-bis(silyl enol ethers) [10].
The structure was independently confirmed by an
X-ray crystal structure analysis (Fig. 2). Both intra-
The TiCl4-mediated formal [3 + 3] cyclization of 3 and intermolecular hydrogen bonds are observed.
with 1,3-bis(silyl enol ether) 4a, prepared from methyl The intramolecular distances are d(O(3)–H···O(1) =
˚
˚
acetoacetate, resulted in the formation of homophtha- 1.79(2) A and d(O(3)···O(1)) = 2.565(1) A. The inter-
˚
late 5a in 45% yield (Scheme 3, Table 1). The best molecular distances are d(O(3)–H···O(3)* = 2.853 A
˚
yield was obtained when 1.0 equiv. of 3, 1.5 equiv. of and d(O(3)···O(3)*) = 3.022 A (* = neighboring
4a and 1.1 equiv. of TiCl4 were employed, and when molecule). Between the benzene rings π-stacking in-
˚
the reaction was carried out in a highly concentrated teractions are observed with dmin(center) = 3.690 A.
solution (c(3) = 0.4 mol L−1). The reaction proceeded
The cyclization of 1,3-bis(silyl enol ether) 4b with
with excellent regioselectivity. Only the regioisomer 3 afforded a separable mixture of the regioisomers 5b
containing a homophthalate structure with both ester (20%) and iso-5b (10%). The structures were estab-
1
1
groups located ortho to each other was obtained. The lished by H,1H-NOESY und H,13C-HMBC experi-
Scheme 3. Synthesis of 5a – c and iso-5a – c.
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J. Hefner et al. · Synthesis of Homophthalates
833
ing the methylene group ortho to the methoxycarbonyl
group, are shifted downfield by 0.2 ppm as compared
to the regioisomer in which the methylene group is lo-
cated para to the methoxycarbonyl group.
The regioselective formation of homophthalates 5a–
c can be explained by the assumption that the more
nucleophilic terminal carbon atom of the diene under-
takes an attack onto the sterically less hindered lateral
keto group of 3 (and not onto the more hindered cen-
tral keto group). In addition, a chelation control (inter-
action of the Lewis acid TiCl4 with the ester groups of
both substrates) may also play a role.
Scheme 4. Observed NOESY correlations of 5a (isomer A)
and expected correlations of iso-5a (isomer B).
Experimental Section
Synthesis of 3
Compound 2 (1.0 equiv.) was dissolved in pentane (2 mL
per mmol), and triethylamine (1.3 equiv.) was added under
argon atmosphere. After stirring for 30 min, trimethylsilyl
chloride (1.5 equiv.) was dropwise added. The mixture was
stirred for 3 days at room temperature. The mixture was
filtered under argon atmosphere, and the filtrate was con-
centrated in vacuo. Starting with 2 (2.372 g, 15.0 mmol),
triethylamine (1.973 g, 19.5 mmol) and Me3SiCl (2.444 g,
22.5 mmol) in pentane (30 mL), 3 was isolated as an orange
oil (2.67 g, 77%). The compound exists as a mixture of three
isomers (see Scheme 2) which were not structurally assigned.
The exact configuration is irrelevant for the cyclization reac-
tion. Therefore, the 1H NMR signals are given with the over-
all integration. The compound is unstable and has to be used
directly after its preparation. – 1H NMR (250 MHz, CDCl3):
δ = 0.28, 0.28, 0.29 (3× s, 9H, Si(CH3)3), 2.14, 2.28, 2.20
(3× s, 3H, CH3), 3.34, 3.39 (3× s, 2H, CH2, partial signal
overlap), 3.65, 3.72, 3.74 (3 × s, 3H, OCH3), 5.25 (3 × s,
1H, CH, signal overlap).
Fig. 2. ORTEP plot of 5a (displacement ellipsoids at the 50%
probability level; H atoms as spheres with arbitrary radii).
Scheme 5. Diagnostic NOESY correlations (double headed
arrow) and HMBC correlations (single headed arrow) of 5b
(left) and iso-5b (right).
1
ments (Scheme 5). A diagnostic H,1H-NOESY cor-
General procedure for the synthesis of homophthalates 5a–c
relation is observed for 5b between the methyl group
located at carbon C-3 and the methylene group. For 5b,
To a CH2Cl2 solution of 3 was added 4 and, subsequently,
TiCl4 at −78 ◦C. The temperature of the solution was al-
lowed to warm to 20 ◦C during 14 h with stirring. To the so-
lution was added hydrochloric acid (10%, 20 mL), and the
organic and the aqueous layer were separated. The latter was
extracted with CH2Cl2 (3 × 20 mL). The combined organic
layers were dried (Na2SO4), filtered, and the filtrate was con-
centrated in vacuo. The residue was purifed by chromatogra-
phy (silica gel, n-heptane, EtOAc).
a
1H,13C-HMBC correlation was observed between
carbon atom C-1 (13C: δ = 109.0 ppm) and the methy-
lene group (1H: δ = 3.81 ppm). For iso-5b, a 1H,13C-
HMBC correlation was observed between carbon atom
C-1 (13C: δ = 110.6 ppm) and the methyl group lo-
cated at carbon C-6 (1H: δ = 2.48 ppm).
The cyclization of diene 4c with 3 afforded homoph-
thalate 5c in 41% yield. The structure of the prod-
uct was established based on the comparison of the
1H NMR chemical shifts of the methylene protons of
5a, 5b, 5c and iso-5b. This comparison suggests that
Methyl 6-(2-methoxy-2-oxoethyl)-4-methyl-salicylate (5a)
Starting with 3 (0.230 g, 1.00 mmol), 4a (0.391 g,
1.50 mmol) and TiCl4 (0.12 mL, 1.10 mmol) in CH2Cl2
the methylene protons of the homophthalates, contain- (2.5 mL), 5a was isolated as a colorless solid (0.164 g, 45%);
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J. Hefner et al. · Synthesis of Homophthalates
m. p. 79 – 81 ◦C. – Rf = 0.39 (heptane-EtOAc 1 : 1). – 1H OCH3), 6.58 (s, 1H, Ar), 11.70 (s, 1H, OH). – 13C NMR
NMR (300 MHz, CDCl3): δ = 2.30 (s, 3H, CH3), 3.69 (s, (125.8 MHz, CDCl3): δ = 11.5, 23.8 (CH3), 39.3 (CH2),
3H, CH2COOCH3), 3.84 (s, 2H, CH2), 3.87 (s, 3H, OCH3) 52.0, 52.1 (OCH3), 110.6 (C-1), 123.2 (C-3), 124.4 (CHAr),
6.54 (s, 1H, H-5), 6.77 (s, 1H, H-3), 11.22 (s, 1H, OH). – 137.9, 138.8 (CAr), 161.2 (CArOH), 171.2 (CH2COOCH3),
13C NMR (75.5 MHz, CDCl3): δ = 21.5 (CH3), 42.5 (CH2), 172.5 (COOCH3).
51.8 (OCH3), 109.4 (C-1), 117.7, 125.3 (CHAr), 136.0 (C-6),
Methyl 3-ethyl-6-(2-methoxy-2-oxoethyl)-4-methyl-
salicylate (5c)
145.7 (C-4), 163.1 (CArOH), 171.0 (CH2COOCH3), 172.0
(COOCH3). – IR (ATR, cm−1): ν = 3100 (w), 2951 (w),
˜
1737 (s), 1657 (s), 1437 (s), 1164 (m), 733 (m). – MS (GC,
70 eV): m/z (%) = 238 (42) [M]+, 206 (52), 178 (86), 174
(43), 163 (100), 119 (42). – HRMS (EI, 70 eV): m/z (%)
= 238.08419 (calcd. 238.08358 for C12H14O5, [M]+). –
Anal. for C12H14O5(238.24): calcd. C 60.50, H 5.92; found
C 61.13, H 5.96.
Starting with 3 (0.230 g, 1.00 mmol), 4c (0.433 g,
1.50 mmol) and TiCl4 (0.12 mL, 1.10 mmol) in CH2Cl2
(2.5 mL), 5c was isolated as a colorless solid (0.108 g, 41%);
m. p. 101 – 103 ◦C. – Rf = 0.38 (heptane-EtOAc 1 : 1). – 1H
NMR (250 MHz, CDCl3): δ = 1.11 (t, 3J = 7.5 Hz, 3H,
CH2CH3), 2.30 (s, 3H, CH3), 2.68 (q, 3J = 7.1 Hz, 2H,
CH2CH3), 3.68 (s, 3H, CH2COOCH3), 3.80 (s, 2H, CH2),
3.86 (s, 3H, OCH3), 6.52 (s, 1H, Ar), 11.56 (s, 1H, OH). –
13C NMR (75.5 MHz, CDCl3): δ = 12.9, 19.4 (CH3), 19.5
Methyl 6-(2-methoxy-2-oxoethyl)-3,4-dimethyl-salicylate
(5b)
Starting with 3 (0.230 g, 1.00 mmol), 4b (0.433 g, (CH2CH3), 42.5 (CH2), 51.8, 51.8 (OCH3), 109.2 (CAr),
1.50 mmol) and TiCl4 (0.12 mL, 1.10 mmol) in CH2Cl2 125.8 (CHAr), 130.5, 132.8, 143.1 (CAr), 161.1 (CArOH),
(2.5 mL), 5b (0.051 g, 20%) and iso-5b (0.035 g, 10%) 171.6, 172.3 (COO). – IR (ATR, cm−1): ν = 2959 (m), 1739
˜
were isolated as colorless solids; m. p. 100 – 102 ◦C. – Rf = (s), 1648 (m), 1436 (s), 1168 (m), 759 (m). – MS (GC,
0.37 (heptane-EtOAc 1 : 1). – 1H NMR (500 MHz, CDCl3): 70 eV): m/z (%) = 266 (44) [M]+, 234 (60), 206 (28), 174
δ = 2.16 (s, 3H, C3-CH3), 2.27 (s, 3H, C4-CH3), 3.68 (100), 146 (27). – HRMS (EI, 70 eV): m/z (%) = 266.11480
(s, 3H, CH2COOCH3), 3.81 (s, 2H, CH2), 3.87 (s, 3H, (calcd. 266.11488 for C14H18O5, [M]+).
OCH3), 6.54 (s, 1H, Ar), 11.60 (s, 1H, OH). – 13C NMR
Crystal structure determination of 5a
(75.5 MHz, CDCl3): δ = 11.5 (C3-CH3), 20.4 (C4-CH3),
42.5 (CH2), 51.8, 51.8 (OCH3), 109.0 (C-1), 124.6 (C-3),
Suitable single crystals of 5a were obtained from
125.4 (CHAr), 132.6 (C-6), 143.8 (C-4), 161.2 (CArOH),
dichloromethane. Intensity data were collected on a Bruker
171.6 (CH2COOCH3), 172.3 (COOCH3). – IR (ATR, cm−1):
X8Apex Diffractometer with CCD camera (graphite-
˜
ν = 3024 (w), 2943 (w), 1731 (s), 1654 (m), 1429 (m),
˚
monochromatized MoKα radiation, λ = 0.71073 A). Crys-
1135 (m), 771 (m). – MS (GC, 70 eV): m/z (%) = 252 (46)
[M]+, 220 (100), 192 (55), 160 (49), 133 (26). – HRMS
(EI, 70 eV): m/z (%) = 252.09970 (calcd. 252.09923 for
C13H16O5, [M]+). – Anal. for C13H16O5(252.26): calcd. C
61.90, H 6.39; found C 61.40, H 6.38.
tal data: Monoclinic space group P21/c, a = 7.57◦76(2),
˚
b = 20.1852(5), c = 8.1722(2) A, β = 112.8560(10) , Z =
4; wR2 = 0.1069 for 161 refined parameters and 3326
unique data; largest diff. peak/hole: 0.38/−0.21 e A−3. Pro-
˚
grams used: Data analysis and space group determination:
XPREP [13]; structure solution and refinement: SHELXS/L-
97 [14, 15].
Methyl 4-(2-methoxy-2-oxoethyl)-3,6-dimethyl-salicylate
(iso-5b)
CCDC 929422 contains the supplementary crystallo-
1
Rf = 0.43 (heptane-EtOAc 1 : 1). – H NMR (500 MHz, graphic data for this paper. These data can be obtained free
CDCl3): δ = 2.17 (s, 3H, C3-CH3), 2.48 (s, 3H, C6-CH3), of charge from The Cambridge Crystallographic Data Centre
3.61 (s, 2H, CH2), 3.69 (s, 3H, CH2COOCH3), 3.94 (s, 3H, via www.ccdc.cam.ac.uk/data request/cif.
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J. Hefner et al. · Synthesis of Homophthalates
835
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