D. Pournara et al. / Tetrahedron Letters 58 (2017) 2378–2380
2379
Scheme 1. Synthesis of ADT-OMe (1).
Fig. 2. 2,5-Bis(4-methoxyphenyl)-3,4-dimethylthiophene (3).
Conducting the reaction at 180 °C gave a complex reaction mix-
ture containing unreacted anethole, ADT-OMe, 1-methoxy-4-
propylbenzene (dihydroanethole), and dimer 3 (Entry 9). Increas-
ing the temperature to 200 °C afforded ADT-OMe in 32% yield
(Entry 10) with some dihydroanethole. These conditions were also
applied using the high boiling point solvent N-methyl-pyrrolidone
(NMP, Entry 11). The homogeneous solution and the absorption of
microwave irradiation by the highly polar solvent limits the micro-
wave effects on the reactants, resulting in a smoother tempera-
ture increase (Fig. 1) which may explain the lower yield in
contrast with solvent-free experiments. Reducing the sulfur equiv-
alents to 3 decreased the yield of 1 and enhanced by-product for-
mation (Entry 12). Therefore, the 1:4 anethole to sulfur ratio at
200 °C (200 W) for 10 min were so far the optimum reaction
conditions.
bath for 4 h. Compound 1 was isolated in very low yield (3%), along
with a complex mixture of non-identified by-products (Entry 2). To
7
avoid by-product formation which occurs below 180 °C, the
experiment was repeated by rapidly immersing the reaction mix-
ture in an oil bath that had been already heated to 200 °C. The mix-
ture melted almost immediately and ADT-OMe was afforded in
2
9% yield after 4 h (Entry 3).
1
2
Next, microwave irradiation was applied in a closed vessel
using DMF as the solvent at 140 °C; this resulted in the formation
of a complex mixture and the absence of ADT-OMe (Entry 4). Upon
increasing the temperature to 170 °C, a high internal pressure
developed and the experiment was stopped after 5 min. In this
case, anethole was completely consumed and ADT-OMe was iso-
lated in 12% yield (Entry 5).
For subsequent microwave assisted reactions, we opted to use
an open vessel setup equipped with a condenser to prevent the
development of internal pressure. As in Entry 3, the goal was to
minimize the time required to reach the final temperature. It is
worth noting that the reaction is exothermic at >150 °C. Polar
intermediates and/or transition states could act as molecular radi-
Additional experiments were performed by increasing the
power to 250 or 300 W (Entries 13–17), using temperatures
between 200 and 220 °C. Although the desired temperature was
reached in 75 s (instead of 150 s with 200 W) this rapid heating
favored the formation of dihydroanethole. Furthermore, the com-
bination of high power and 220 °C resulted in slightly lower yields
(30%) with a significant increase of anethole hydrogenation.
Shorter reaction times under these conditions resulted in a lower
ators, improving the absorption of microwave irradiation and
resulting in a steep rise in temperature.1
1,12
Moreover, the
1
observed exothermic effect might be due to an improvement of
reaction homogeneity since elemental sulfur melts at >150 °C.
The detailed data of the temperature increase was obtained from
the microwave reactor’s software and each T(t) diagram helped
to select the next possible reaction conditions (Fig. 1).
yield (Entry 16). In this case, the crude H NMR spectrum showed
a lower amount of dihydroanethole compared to the 10 min
entries, suggesting that its formation is favored as the reaction pro-
ceeds and is faster than the formation of 1.
In line with these results, a lower temperature (200 °C, 250 W)
was applied to afford ADT-OMe in 35% yield after 10 min
(Entry 17). Although the yield is comparable to entry 10, the
hydrogenated by-product was significantly present in the NMR
spectrum.
Moreover, to investigate the effect of allotropic forms of cyclo-
octasulfur, molten sulfur and hot anethole were mixed at ꢀ160 °C
in the microwave tube and the reaction performed at 200 °C
(200 W) for 10 min. However, compound 1 was obtained in 33%
yield and the crude reaction mixture had the same composition
as the other neat experiments (Entry 18).
Firstly, irradiation at 220 °C (200 W) for 10 min without solvent,
1
led to the full consumption of anethole, as illustrated by crude H
NMR spectroscopy. Traces of 2,5-bis(4-methoxyphenyl)-3,4-
dimethylthiophene (3), an anethole dimer by-product (Fig. 2 and
ESI), were observed and ADT-OMe was isolated in 18% yield (Entry
6
). The depicted dimer was first reported by Böttcher and co-
7
workers.
Increasing the reaction time to 20 min resulted in a viscous
solid mixture without an improved yield (Entry 7). Further
increases (240 °C) led to a decreased yield (Entry 8) suggesting that
a lower temperature at 200 W with a 10 min reaction time would
be suitable.
Finally, we endeavored to control the formation of polymeric
side-products. Anethole, like styrene, may generate radicals and
initiate self-polymerization at elevated temperatures. According
to the literature, thermal polymerization reactions can be con-
trolled using a stable radical mediator such as 2,2,6,6-tetram-
1
3
ethylpiperidin-1-yl)oxyl (TEMPO).
Thus, catalytic TEMPO
(
0.02 eq.) was added to the reaction mixture (Entry 19), using the
conditions in Entry 10 which afforded the highest yield with the
least side-products. In this case, neither the yield nor the T(t) dia-
gram were significantly affected (Fig. 1). However, when a higher
loading of TEMPO (0.1 eq.) was used (Entry 20), the T(t) curve
(Fig. 1) was similar to the curves of the 300 and 250 W experi-
ments, indicating that the addition of a stable radical probably
favors the formation of other reactive intermediates and helps
achieve the steep temperature increase using milder microwave
conditions. Under these conditions, a slight increase in yield
(
37%) was observed, while dihydroanethole formation was reduced
1
in comparison to Entry 17; based on the crude H NMR spectra
ESI). The formation of multiple undesired by-products was signif-
(
icantly restricted, although polymeric by-products, insoluble in
organic solvents, were not completely avoided.
Fig. 1. T(t) diagram of selected reaction conditions.
Pournara, Dimitra
