ORDER
REPRINTS
318
MOGHADDAM AND GHAFFARZADEH
active compounds such as pesticides (4,5), and anti-inflammatory (4,7), antiulcer
(8), agents.
Although the classical Willgerodt-Kindler reaction of aldehydes and ke-
tones provides useful routes to these compounds, a severe reaction condition
(high temperature ∼200◦C) and a long refluxing time in the order of hours is
required (9). We (10,11) and others (12,13) have demonstrated the efficiency of
microwave irradiation, especially the focused system for promoting organic re-
actions. In the present work, the preparation of thioamides via the Willgerodt-
Kindler reaction and their hydrolysis to the corresponding carboxylic acids was
investigated. Strauss et al. reported (14) the synthesis of phenylacetamide upon
microwave heating using a microwave batch reactor (MBR). During the course
of our investigation, a paper appeared on the Kindler-modification of aryl alkyl
ketones under microwave irradiation with a domestic multi-mode oven (15). How-
ever, for the ketones, some further improvements were observed due to the use
of a focused microwave digester (monomode system), instead of a domestic mi-
crowave oven. The reaction conditions were optimized by examining the different
parameters such as time of irradiation, power of irradiation, the ratio of sulfur
to secondary amine, and starting material. Morpholine as a cheap and technically
available secondary amine was found to be most suitable. After performing several
experiments, the best molar ratio was found to be substrate: sulfur: morpholine
(1:2.5:3).
In a typical procedure, aldehyde or ketone (0.01 mol) was mixed with sulfur
(0.025 mol) and morpholine (0.03 mol) in a closed Teflon vessel (∼20 mL) and
subjected to microwave irradiation (16) for four min. After conventional work-
up, excellent yields of thioamides were obtained. For hydrolysis to corresponding
carboxylic acids, the isolated thioamide (0.01 mol) was mixed with 5 mL of NaOH
solution (15%) in a Teflon flask (∼20 mL) and irradiated for one min.
Tables 1 and 2 show our results. Compared to results obtained with multi-
mode domestic ovens, those achieved from monomode system by our method are
clearly better (e.g., Table 1, entry 3, 85% versus 55%). We also examined the reac-
tion of aldehydes, which, in general, produced excellent yields of thiomorpholides
and their hydrolyzed products. To the best of our knowledge, the case of aldehydes
has not studied yet by this methodology. The method has been applied to aromatic
as well as aliphatic and α,β-unsaturated aldehydes (Table 2, entry 6,7). In conclu-
sion, we have developed a rapid, mild, and high-yielding method for preparation
and hydrolysis of thioamides by microwave activation. Further investigations of
this reaction are now in progress in our laboratory.
EXPERIMENTAL
All products were known and identified either by their IR, NMR, or their
physical data according to the literature (15,17,18).