The Chemo- and Regioselectivity of the Cyclization of Thiosemicarbazides with Haloacetic Acids and their Derivatives

A Microwave‐Assisted One‐Pot Three‐Step Metal‐Free [4+2] Annulation for the Sustainable Synthesis of Highly Substituted 1,2,4‐Triazines

“…An extensive literature search highlighted that the chemo-and regioselectivity of the cyclization of thiosemicarbazides with haloacetic acids and their derivatives, is strongly influenced by the presence of a base: K 2 CO 3 was shown to drive the formation of 1,2,4-triazine-3-thione, while six-membered heterocycles containing two N atoms and one S atom (1,3,4-thiadiazine) were formed in the absence of K 2 CO 3 . [22] In line with this report, addition of K 2 CO 3 during the second step of the one-pot oxidation/heterocyclization sequence, allowed to obtain the desired product 4 a in a good 66 % yield over two steps after only 20 minutes (Table 1, entry 7). Then, the use of sub-stoichiometric amount of iodine was also evaluated, revealing that 0.5 eq.…”

“…This is consistent with the poor reactivity of the thiol/thione group, which require to be alkylated or even oxidized to methyl sulfonyl group to undergo ammination. [25,26] Based on the available literature [22,27,28] and on our experimental observations, a plausible mechanism for this one-pot protocol is proposed in Scheme 3. The initial reaction of I 2 with methyl ketone 1 results in the formation of the α-iodo ketone A, which is converted to phenylglyoxal 2 via sequential iodination/Kornblum oxidation.…”

“…Based on the available literature [22,27,28] and on our experimental observations, a plausible mechanism for this one‐pot protocol is proposed in Scheme 3. The initial reaction of I 2 with methyl ketone 1 results in the formation of the α‐iodo ketone A, which is converted to phenylglyoxal 2 via sequential iodination/Kornblum oxidation.…”

“…Surprisingly, in the absence of any additive in the second step (step 2), this one‐pot reaction did not lead to the formation of 4 a (Table 1, entries 4–5) but to a complex mixture difficult to be characterized. An extensive literature search highlighted that the chemo‐ and regioselectivity of the cyclization of thiosemicarbazides with haloacetic acids and their derivatives, is strongly influenced by the presence of a base: K 2 CO 3 was shown to drive the formation of 1,2,4‐triazine‐3‐thione, while six‐membered heterocycles containing two N atoms and one S atom (1,3,4‐thiadiazine) were formed in the absence of K 2 CO 3 [22] . In line with this report, addition of K 2 CO 3 during the second step of the one‐pot oxidation/heterocyclization sequence, allowed to obtain the desired product 4 a in a good 66 % yield over two steps after only 20 minutes (Table 1, entry 7).…”