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DOI: 10.1055/s-0031-1290317
Three-Step Synthesis of (Thio)xanthene and Dibenzothiepine/Dibenzoxepine by an Intramolecular Mizoroki-Heck Reaction of Diaryl (Thio)Ethers
Publication History
Publication Date:
25 January 2012 (online)
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Abstract
We present a novel three-step protocol for preparing xanthene/thioxanthene and dibenzothiepine/dibenzoxepine from readily available starting materials. The Mizoroki-Heck cyclization as the final step was optimized to afford full conversion of the corresponding diaryl (thio)ethers and furthermore to achieve reasonably good selectivity between the 6-exo and the 7-endo products.
Key words
fused-ring systems - Heck reaction - heterocycles - palladium - sulfur
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References and Notes
Synthesis of 2-(2-Bromophenylsulfanyl)benzaldehyde (5a): 2-Fluorobenzaldehyde (3;
2.0 g, 16 mmol), 2-bromo-thiophenol (4a;
3.0 g, 16 mmol) and anhyd K2CO3 (3.29 g, 23.8
mmol) were dissolved in MeCN (10 mL) and stirred at 100 ˚C
for 30 min under MW conditions. The crude reaction mixture was evaporated
onto Celite and purified using column chromatography on silica gel
(eluent: heptane → 30% EtOAc in heptane). The
title compound was obtained as a colorless solid (3.97 g, 84%); R
f
0.61
(EtOAc-heptane, 1:2); mp 49-50 ˚C. ¹H
NMR (600 MHz, CDCl3): δ = 10.39 (s,
1 H), 7.95 (dd, J = 7.6, 1.7
Hz, 1 H), 7.66 (dd, J = 7.9,
1.3 Hz, 1 H), 7.48-7.51 (m, 1 H), 7.43 (m, 1 H), 7.24-7.28
(m, 1 H), 7.14-7.21 (m, 3 H). ¹³C
NMR (151 MHz, CDCl3): δ = 191.8, 138.8,
135.7, 134.6, 134.4, 133.6, 133.3, 131.8, 131.6, 129.3, 128.4, 127.5,
126.4. GC-MS: m/z = 392 [M+]. Anal.
Calcd for C13H9BrOS: C, 53.26; H, 3.09. Found:
C, 53.22; H, 3.05.
Synthesis of 2-(2-Bromophenoxy)benzaldehyde (5b):
2-Fluorobenzaldehyde (3; 2.0 g, 16 mmol), 2-bromophenol (4b; 2.8 g, 16 mmol), and anhyd K2CO3 (3.29
g, 23.8 mmol) were dissolved in anhyd DMF (20 mL) and the mixture
was refluxed for 2 h. The mixture was then diluted with EtOAc (30
mL) and brine (100 mL); the layers were separated and the aqueous
layer was extracted with EtOAc (3 × 30 mL). The combined
organic layers were washed with 2 M aq NaOH (2 × 20 mL)
and H2O (20 mL), dried with MgSO4, filtered,
concentrated in vacuo onto Celite, and purified using column chromatography
on silica gel (eluent: heptane → 30% EtOAc in
heptane). Compound 5b was obtained as a
pale-yellow solid (3.19 g, 71%); R
f
0.60 (EtOAc-heptane, 1:2);
mp 62-63 ˚C. ¹H NMR (600 MHz,
CDCl3): δ = 10.60 (s, 1 H), 7.96 (dd, J = 7.8, 1.6 Hz, 1 H), 7.66-7.70
(m, 1 H), 7.50 (m, 1 H), 7.32-7.37 (m, 1 H), 7.19 (td, J = 7.7, 0.8 Hz, 1 H), 7.10
(m, 2 H), 6.74 (d, J = 8.4 Hz,
1 H). ¹³C NMR (151 MHz, CDCl3): δ = 189.2,
159.4, 152.5, 135.7, 134.2, 129.0, 128.6, 126.3, 126.1, 123.3, 121.7,
116.9, 115.5. GC-MS:
m/z = 276 [M+].
Anal. Calcd for C13H9BrO2: C, 56.34;
H, 3.27. Found: C, 56.39; H, 3.25.
Synthesis
of 2-Bromophenyl-2-vinylphenylsulfane (6a): Methyltriphenylphosphonium
iodide (3.31 g, 8.19 mmol) was dissolved in anhyd THF (50 mL) and
the solution was cooled to 0 ˚C under an argon atmosphere. t-BuOK (1.15 g, 10.2 mmol) was added
by which the solution turned yellow and after stirring for 10 min,
compound 5a (2.00 g, 6.82 mmol) was added
and the mixture was allowed to reach r.t. and stirred for 1.5 h.
The crude mixture was concentrated in vacuo directly onto Celite
and purified using column chromatography on silica gel (eluent:
heptane → 30% EtOAc in heptane). Compound 6a was obtained as a yellow solid (1.98
g, 100%); R
f
0.77 (EtOAc-heptane,
1:2); mp 58-59 ˚C. ¹H NMR
(600 MHz, CDCl3): δ = 7.69 (dd, J = 7.9, 1.2 Hz, 1 H), 7.53
(dd, J = 7.9, 1.3 Hz, 1 H),
7.48 (dd, J = 7.7, 1.3 Hz, 1
H), 7.42 (m, 1 H), 7.29 (td, J = 7.6,
1.4 Hz, 1 H), 7.18 (dd, J = 17.4,
11.0 Hz, 1 H), 7.07-7.10 (m, 1 H), 6.97 (td, J = 7.6, 1.5 Hz, 1 H), 6.63
(dd, J = 8.0, 1.5 Hz, 1 H),
5.73 (dd, J = 17.4, 0.9 Hz,
1 H), 5.29 (dd, J = 11.0, 0.9
Hz, 1 H). ¹³C NMR (151 MHz, CDCl3): δ = 141.3,
138.9, 136.0, 134.4, 132.8, 130.3, 129.7, 128.9, 128.2, 127.7, 126.5,
126.4, 121.6, 116.7. GC-MS: m/z = 290 [M+].
Anal. Calcd for C14H11BrS: C, 57.74; H, 3.81.
Found: C, 53.72; H, 3.85.
Synthesis
of 1-Bromo-2-(2-vinylphenoxy)benzene (6b): Methyltriphenylphosphonium
iodide (5.51 g, 13.6 mmol) was dissolved in anhyd THF (50 mL) and
the solution was cooled to 0 ˚C under an argon atmosphere. t-BuOK (1.64 g, 14.6 mmol) was added
by which the solution turned yellow and after stirring for 10 min,
compound 5b (2.7 g, 9.7 mmol) was added
and the mixture was allowed to reach r.t. and subsequently stirred
for 1 h. The crude mixture was concentrated in vacuo directly onto
Celite and purified using column chromatography on silica gel (eluent:
heptane → 30% EtOAc in heptane). Compound 6b was obtained as a pale-yellow oil (2.49
g, 93%); R
f
0.76
(EtOAc-heptane, 1:2). ¹H NMR (600 MHz,
CDCl3): δ = 7.62 (m, 2 H), 7.18-7.23 (m,
2 H), 7.14 (t, J = 7.4 Hz, 1
H), 6.93-7.04 (m, 2 H), 6.82 (dd, J = 8.1,
0.8 Hz, 1 H), 6.76 (dd, J = 8.2,
1.4 Hz, 1 H), 5.81 (dd, J = 17.7,
1.1 Hz, 1 H), 5.30 (dd, J = 11.1,
1.1 Hz, 1 H). ¹³C NMR (151 MHz, CDCl3): δ = 154.2,
153.2, 133.7, 130.7, 129.3, 129.0, 128.6, 126.8, 124.3, 124.3, 119.2,
118.9, 115.7, 113.7. GC-MS: m/z = 274 [M+].
Anal. Calcd for C14H11BrO: C, 61.11; H, 4.03.
Found: C, 61.20; H, 4.02.
Synthesis
of Thioxanthene (1a) and Dibenzothiepine
(2a; Entry 1, Table 1): A microwave vial was purged with anhyd dioxane
(2.0 mL) and then compound 6a (0.29 g,
1.0 mmol), DavePhos (29.5 mg, 0.075 mmol), Pd2(dba)3 (22.9
mg, 0.0250 mmol), and t-BuONa (144 mg,
1.50 mmol) were added to this vial under a flow of argon and finally
the tube was capped. The mixture was heated for 30 min at 180 ˚C under
MW conditions for full conversion of starting material. Judged from
LC-MS and GC-MS, the reaction mixture contained
a 30:70 ratio of 1a/2a and it was concentrated in vacuo directly
onto Celite and purified using column chromatography on silica gel
(eluent: heptane → 30% EtOAc in heptane). Compounds 1a (59 mg, 28%) and 2a (124 mg, 59%) were obtained
as colorless oils and the characterization data were in accordance
with the literature data.4i,m
Synthesis
of Xanthene (1b)/Xanthone (7) and Dibenzoxepine (2b; Entry 1, Table 2):
The procedure described above for preparing compounds 1a and 2a was followed
using anhyd toluene (2.0 mL), compound 6b (0.150
g, 0.545 mmol), DavePhos (12.9 mg, 0.0327 mmol), Pd2
(dba)3 (9.98
mg, 0.0109 mmol), and t-BuONa (78.6 mg, 0.818
mmol). The mixture was heated for 30 min at 180 ˚C under
MW conditions. Judged from LC-MS and GC-MS, the
reaction mixture contained a 1:1 ratio of 1b/2b and it was concentrated in vacuo directly
onto Celite and purified using column chromatography on silica gel
(eluent: heptane → 30% EtOAc in heptane). Compound 2b was isolated as a colorless solid (47
mg, 44%). During workup compound 1b underwent
conversion into xanthone (7), which was
isolated as a colorless solid (44 mg, 41%). Characterization
data of 2b and 7 were
in accordance with the literature data.¹0