Cystothiazole A by Microwave-Assisted Olefin Cross-Metathesis
of MeOH (5 mL) at the same temperature, and the mixture was
poured into cold 1 HCl (20 mL). The aqueous phase was ex-
Experimental Section
General: All reactions were performed under argon in anhydrous
tracted with Et
were dried with MgSO
2
O (3ϫ 20 mL), and the combined organic phases
. Evaporation of the solvent gave the crude
solvents (CH
Et O were distilled from sodium/benzophenone). TLC was per-
formed on Merck 60F254 silica gel plates and visualized with a UV
lamp (254 nm) and a KMnO /K CO /AcOH solution in H O fol-
2 2 2
Cl and toluene were distilled from CaH , THF and
4
2
aldehyde (330 mg) which was dissolved in THF (5 mL) and added
dropwise to a cooled (0 °C) solution of methylenetriphenylphos-
4
2
3
2
phorane [prepared from Ph
tBuOK (390 mg, 3.4 mmol) at 0 °C in THF (10 mL)]. After 1 h at
°C, the reaction was quenched with saturated aqueous NH Cl
20 mL), and the aqueous phase was extracted with Et O (3ϫ
, evap-
3
PCH Br (1.23 g, 3.4 mmol) and
3
lowed by heating. Flash chromatography was performed with
Merck Geduran Si60 silica gel (40–63 µ). Optical rotations were
determined with a Perkin–Elmer 343 polarimeter. Infrared (IR)
spectra were recorded with a Bruker TENSOR
trometer, and wavenumbers are indicated in cm . H NMR spectra
were recorded with a Bruker AVANCE 400 spectrometer at
0
4
(
2
TM
27 (IRFT) spec-
20 mL). Drying of the combined organic phases with MgSO
4
–1 1
oration of the solvent and purification of the residue by flash
chromatography (SiO ; pentane Ǟ 5% Et O in pentane) gave 9
200 mg, 53%) as a yellow oil. H NMR (CDCl , 400 MHz): δ =
2
2
400 MHz, and data are reported as follows: chemical shift in ppm
1
(
3
relative to the residual solvent peak, multiplicity (s = singlet, d =
doublet, t = triplet, q = quartet, quint = quintet, sext = sextet, sept
6
1
.96 (s, 1 H), 6.56 (dd, J = 10.8 and 17.5 Hz, 1 H), 6.00 (dd, J =
.2 and 17.5 Hz, 1 H), 5.32 (dd, J = 1.2 and 10.8 Hz, 1 H) ppm.
C NMR (CDCl , 100 MHz): δ = 154.6 (s), 136.1 (s), 128.6 (d),
3
=
septet, m = multiplet or overlap of non-equivalent resonances),
13
13
integral. C NMR spectra were recorded with a Bruker AVANCE
00 spectrometer at 100 MHz, and data are reported as follows:
1
1
C
18.4 (d), 117.8 (t) ppm. IR: ν˜ = 3100, 1629, 1489, 1435, 1396,
4
–1
309, 1005, 981, 917, 843, 763 cm . HRMS (ESI): calcd. for
chemical shift in ppm relative to the residual solvent peak, multi-
plicity with respect to proton (deduced from DEPT experiments, s
BrNS [M + H]+ 191.9299; found 191.9297.
5
H
5
Methyl 7-(2-Bromothiazol-4-yl)-3,5-dimethoxy-4-methylhepta-2,6-
dienoate (10): A solution of 9 (23 mg, 0.12 mmol) in CH Cl
0.5 mL) was added in 5 portions (5ϫ 0.1 mL) to a solution of 2
25 mg, 0.12 mmol) and GII (17 mg, 20%) in CH Cl (0.6 mL), and
=
C
q
, d = CH, t = CH
impact (MS) were recorded with a Hewlett–Packard tandem
890A/5971 GC-MS (70 eV) instrument. High-resolution mass
2 3
, q = CH ). Mass spectra with electronic
2
2
(
(
5
2
2
spectra (HRMS) were recorded by the Groupe de Spectrométrie de
Masse de l’Université Pierre et Marie Curie (Paris).
the mixture was irradiated for 1 h after each addition (400 W,
00 °C with cooling). Another portion of GII (9 mg, 10%) was then
1
4
-Bromo-2Ј-isopropyl-2,4Ј-bithiazole (7):[8] To a solution of 6
206 mg, 1 mmol) in Et O (5 mL) was added tBuLi (1.3 mL, 1.5
in pentane, 2.1 mmol) dropwise at –78 °C. After 15 min at –78 °C,
Bu SnCl (326 mg, 1 mmol) was added slowly, and the mixture was
stirred at room temp. for 1.5 h. The reaction was quenched with
O (5 mL), and the aqueous phase was extracted with Et O (3ϫ
mL). Drying of the combined organic phases and evaporation of
the solvent gave the crude stannane which was dissolved in toluene
added, and the mixture was irradiated for further 30 min before the
solvent was evaporated. Purification of the residue by flash
(
2
chromatography (SiO
a colourless viscous oil. [α]
CDCl , 400 MHz): δ = 6.92 (s, 1 H), 6.40 (d, J = 16.0 Hz, 1 H),
.31 (dd, J = 7.0 and 16 Hz, 1 H), 4.89 (s, 1 H), 4.06 (dq, J = 7.0
and 7.5 Hz, 1 H), 3.73 (tapp, J = 7.5 Hz, 1 H), 3.59 (s, 3 H), 3.53
2 2
; Et O/hexane, 1:3) gave 10 (25 mg, 55%) as
3
20
3
= +120.3 (c = 0.8, CHCl ). H NMR
1
D
(
3
H
2
2
6
5
s, 3 H), 3.24 (s, 3 H), 1.12 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR
(
(
(
10 mL) and treated with 5 (243 mg, 1 mmol) and Pd(PPh
58 mg, 0.05 mmol). After refluxing for 16 h, H O (10 mL) was
O (3ϫ
0 mL). Drying of the combined organic phases, evaporation of the
solvent and purification of the residue by flash chromatography
SiO ; hexane Ǟ 5% Et O in hexane) gave 7 (225 mg, 78%) as a
white solid. H NMR (CDCl , 400 MHz): δ = 7.82 (s, 1 H), 7.15
s, 1 H), 3.29 (sept, J = 7 Hz, 1 H), 1.37 (d, J = 7 Hz, 6 H) ppm.
3 4
)
CDCl
3
, 100 MHz): δ = 176.5 (s), 167.6 (s), 154.0 (s), 135.7 (s),
(
2
1
5
1
32.9 (d), 124.0 (d), 117.7 (d), 91.1 (d), 84.0 (d), 57.1 (q), 55.5 (q),
added, and the aqueous phase was extracted with Et
2
0.8 (q), 39.9 (d), 14.1 (q) ppm. IR: ν˜ = 2924, 1709, 1623, 1436,
1
–1
382, 1147, 1094, 1011 cm . HRMS (ESI): calcd. for
NaS [M + Na]+ 398.0032; found 398.0033.
C
14
H
18BrNO
Cystothiazole A (1).[1a] From 2: A solution of 3 (11 mg, 0.047 mmol)
in CD Cl (0.5 mL) was added in 5 portions (5ϫ 0.1 mL) to a
solution of 2 (10 mg, 0.047 mmol) and GII (8 mg, 20%) in CD Cl
0.2 mL), and the mixture was irradiated for 1 h after each addition
400 W, 100 °C with cooling). Another portion of GII (4 mg, 10%)
4
(
2
2
1
3
2
2
(
2
2
2Ј-Isopropyl-4-vinyl-2,4Ј-bithiazole (3): To a solution of bromide 7
(
(
(250 mg, 0.86 mmol) and PdCl
2
(PPh (30 mg, 0.04 mmol) in diox-
3 2
)
ane (5 mL) was added tributyl(vinyl)tin (317 mg, 1 mmol) drop-
wise, and the mixture was stirred at 100 °C for 20 h. After dilution
was then added, and the mixture was irradiated for further 30 min
before the solvent was evaporated. Purification of the residue by
with Et
5 mL), dried with MgSO
residue by flash chromatography (SiO
ane) gave 3 (180 mg, 89%) as a yellow oil. 1H NMR (CDCl
2
O (80 mL), the organic phase was washed with H
and concentrated. Purification of the
; hexane Ǟ 5% Et O in hex-
2
O (2ϫ
2 2
flash chromatography (SiO ; Et O/hexane, 1:2) gave 1 (5 mg, 25%)
1
4
as a colourless viscous oil. From 10: A solution of 10 (8 mg,
2
2
0
5
.02 mmol), stannane 11 (8 mg, 0.02 mmol) and Pd(PPh
%) in toluene (0.2 mL) was stirred at 110 °C for 16 h. Evaporation
3 4
) (1.2 mg,
3
,
4
1
00 MHz): δ = 7.80 (s, 1 H), 7.05 (s, 1 H), 6.68 (dd, J = 10.8 and
7 Hz, 1 H), 6.05 (dd, J = 1.5 and 17.0 Hz, 1 H), 5.32 (dd, J = 1.5
of the solvent and purification of the residue by preparative TLC
SiO ; Et O/hexane, 1:2) gave 1 (7 mg, 83%) as a colourless viscous
(
2
2
and 10.8 Hz, 1 H), 3.31 (sept, J = 7 Hz, 1 H), 1.37 (d, J = 7 Hz, 6
H) ppm. 13C NMR (CDCl
, 100 MHz): δ = 178.7 (s), 162.8 (s),
55.0 (s), 148.6 (s), 129.9 (d), 116.7 (t), 115.6 (d), 115.1 (d), 33.4
d), 23.2 (2ϫ q) ppm. IR: ν˜ = 3098, 2964, 2330, 1628, 1537, 1497,
20
1
oil. [α]
7.78 (s, 1 H), 7.02 (s, 1 H), 6.50 (d, J = 15.8 Hz, 1 H), 6.34 (dd,
J = 7.8 and 15.8 Hz, 1 H), 4.89 (s, 1 H), 4.11 (dq, J = 7.0 and
.8 Hz, 1 H), 3.74 (tapp, J = 7.8 Hz, 1 H), 3.59 (s, 3 H), 3.53 (s, 3
H), 3.30 (sept, J = 7.0 Hz, 1 H), 3.26 (s, 3 H), 1.37 (d, J = 7.0 Hz,
D 3 3
= +110 (c = 0.5, CHCl ). H NMR (CDCl , 400 MHz): δ
3
=
1
(
7
–1
1441, 1383, 1311, 1178, 1036, 983, 914, 796, 762 cm . HRMS
+
(ESI): calcd. for C11
H
12
N
2
NaS
2
[M + Na] 259.0334; found
13
6
3
H), 1.14 (d, J = 7.0 Hz, 3 H) ppm. C NMR (CDCl , 100 MHz):
259.0330.
δ = 178.6 (s), 176.7 (s), 167.7 (s), 162.6 (s), 154.3 (s), 148.6 (s), 131.6
(d), 125.5 (d), 115.0 (d), 114.9 (d), 91.1 (d), 84.4 (d), 57.0 (q), 55.5
(q), 50.8 (q), 39.8 (d), 33.3 (d), 23.1 (2q), 14.1 (q) ppm. IR: ν˜ =
2-Bromo-4-vinylthiazole (9): To a solution of 8 (472 mg, 2 mmol) in
THF/CH
tion in CH
2
Cl
2
(1:1, 30 mL) was added DIBAL-H (6 mL, 1 solu-
, 6 mmol) dropwise to maintain the temperature Ͻ
–
1
2
Cl
2
3105, 2968, 1710, 1624, 1150, 1086 cm . HRMS (ESI): calcd. for
–70 °C. After 5 h at –78 °C, the reaction was quenched by addition
C
20
H
26
N
2
O
4
NaS
2
[M + Na]+ 445.1226; found 445.1216.
Eur. J. Org. Chem. 2008, 2701–2704
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2703