Synthesis and Reactivity of 3′,5′‐Dichloro‐1H‐spiro(quinazoline‐2,4′‐[1,2,6]thiadiazin)‐4(3H)‐ones

Abstract

A three‐step synthesis of 3′,5′‐dichloro‐1H‐spiro(quinazo‐line‐2,4′‐[1,2,6]thiadiazin)‐4(3H)‐ones starting from 3,4,4,5‐tetra‐chloro‐4H‐1,2,6‐thiadiazine is presented. The latter reacts with 2‐aminobenzonitriles to give 2‐[(3,5‐dichloro‐4H‐1,2,6‐thiadiazin‐4‐ylid‐ene)amino]benzonitriles, which affords, after hydration, the respective benzamides. Upon heating at reflux in EtOH or HFIP, the benzamides intramolecularly cyclize onto the thiadiazine C4 position to give 3′,5′‐dichloro‐1H‐spiro(quinazoline‐2,4′‐[1,2,6]thiadiazin)‐4(3H)‐ones. Single crystal X‐ray crystallography supports the structure of two analogues. The chloride displacement of these new spiroquinazolinones was demonstrated by Stille coupling, and by reaction with methoxide to afford both the mono and bis‐methoxy derivatives.

Synthesis of 2‐Cyanoquinazolin‐4‐ones from 3′,5′‐Dichloro‐1H‐spiro(quinazoline‐2,4′‐[1,2,6]thiadiazin)‐4(3H)‐ones

“…With the structure of quinazolinone 4 resolved, we investigated the reaction conditions that led to its formation. Early studies revealed that spirocycle 16 was stable under thermal conditions, and to Brønsted and Lewis acids and mild bases . Nevertheless, thermal treatment of spirocycle 16 in the presence of catalytic amounts of organic halides gave quinazolinone 4 : the two best reaction conditions being BnEt 3 NCl or BnEt 3 NI (10 mol%) in PhCl at 132 °C (Table , entries 2 and 7) that gave the product in 54 and 61% yields, respectively.…”

“…Early studies revealed that spirocycle 16 was stable under thermal conditions, and to Brønsted and Lewis acids and mild bases. [26] Nevertheless, thermal treatment of spirocycle 16 in the presence of catalytic amounts of organic halides gave quinazolinone 4: the two best reaction conditions being BnEt 3 NCl or BnEt 3 NI (10 mol%) in PhCl at 132°C ( Table 1, entries 2 and 7) that gave the product in 54 and 61% yields, respectively. The use of lower halide loadings or lower reaction temperatures led to longer reaction times and no improvement in the product yields.…”

“…Recently, we described the three‐step synthesis of spirocyclic 3′,5′‐dichloro‐1 H ‐spiro(quinazoline‐2,4′‐[1,2,6]thiadiazin)‐4(3 H )‐ones 15 starting from tetrachloro‐thiadiazine 7 (Scheme ) …”

“…[21] Our current interest in thiadiazines is focused on 3,4,4,5tetrachloro-4H-1,2,6-thiadiazine (7), which can be prepared from dichloromalononitrile and SCl 2 , [22] or from N-2,2-trichloro-2-cyanoacetimidoyl chloride and elemental sulfur. [23] Thiadiazine 7 is used to synthesize a plethora of aromatic 1,2,6thiadiazines such as 2-(3,5-dichloro-4H-1,2,6-thiadiazin-4ylidene)malononitrile (8), [24] N-aryl-3,5-dichloro-4H-1,2,6-thiadiazin-4-imines 9, [25] 3,5-dichloro-4H-1,2,6-thiadiazin-4-one (10), [24] and 3,5-dichloro-4H-1,2,6-thiadiazin-4-thione (11), [15] as well as in the synthesis of C4-saturated analogues such as 4,4-diamino-, [26] 4,4-dialkoxy-and 4,4-bis(alkylthio)-3,5-dichloro-4H-1,2,6thiadiazines 12, 13 and 14, respectively [15] (Scheme 3).…”

“…Recently, we described the three-step synthesis of spirocyclic 3',5'-dichloro-1H-spiro(quinazoline-2,4'-[1,2,6]thiadiazin)- Full Papers 4(3H)-ones 15 starting from tetrachloro-thiadiazine 7 (Scheme 4). [26] With spirocycles 15 in hand, we then studied the reactivity of parent spirocycle 16 (R = H) in the presence of various thiophiles: Ph 3 P and organic halides BnEt 3 NCl and BnEt 3 NI in the hope that cleavage of the thiadiazine would give the known 2-cyanoquinazolin-4(3H)-one (4) (Scheme 5). [7,14] NMR spectroscopic data on the sole product isolated from these studies did not match that reported in two independent literature sources.…”