Heterocycles from substituted amides. VII Oxazoles from 2‐isocyanoacetamides

Abstract

Certain heretofore unknown tertiary α‐isocyanacetanilides 1 are reported for the first time, prepared by methods necessarily different from those employed to prepare the previously cited aliphatic α‐isocyano‐acetamides 2. Like 2, 1 has been shown to readily undergo dialkylation with alkyl halides. Moreover, 1 also gives rise to oxazole and oxazoline derivatives upon reaction with acyl halides and aldehydes, respectively, resembling the similarly activated α‐isocyano esters and sulfones. Further, in a demonstrable ring‐chain tautomeric equilibration, apparently restricted to tertiary amides, 1 readily cyclizes, providing the only known synthesis of 5‐amino‐2,4‐unsubstituted oxazoles 3. In other examples 4‐chloro and 4‐alkyl‐5‐amino‐oxazoles are produced. The materials and reactions are characterized, and compared with previous related studies.

Oxazole chemistry. A review of recent advances

“…Attempted chlorination of the a-isocyanoacetanilide 134 leads to the novel 4-chloro-5-aminooxazole 135 (59).…”

“…Thermolysis of a-isocyanoacetamides 136 results in the establishment of an equilibrium between 136 and the 5aminooxazoles 138 favoring the heterocycle (98:2). This observation has lead Chupp and co-workers (59) to propose a mechanism involving a 1,5-dipolar electrocyclization of the carbonylnitrile ylide 137 (34) which is derived from Isonitriles afford the pseudothioureas 140 by an a-addition when combined with sulfenamides of the type 139 (60). Isocyanoacetanilides 141, on the other hand, are transformed into 2-alkylthio-5-aminooxazoles 144 when allowed to react with 139.…”

“…The 5-aminooxazoles 138 prepared by thermolysis of the a-isocyanoacetamides 136 as described above (59) react with isocyanates to give the 5-aminooxazole-4-carboxamides 153 when R3 = H. Thus electrophilic substitution by isocyanates occurs exclusively at the 4-position in 138, R3 = H. When 138 is substituted at the 4-position with an alkyl group, electrophilic substitution occurs at the 2-position to afford the 5-aminooxazole-2-carboxamides 154 (61). This process occurs with greater difficulty, however.…”

Parallel Synthesis of Arrays of Amino-Acid-Derived Isocyanoamides Useful As Starting Materials in IMCR

“…Including the current approach, now four complementary synthetic pathways are available to access this important starting material class. ,, Current evaluation of this isocyanide class for use in new IMCR is ongoing in our laboratory. We are also investigating the broad use of the described compound class in the synthesis of 1-alkyl-4-carboxamidoimidazoles, 2,3,4-trisubstituted pyrroles, isoxazolinopyrroles, macrocycles, lennoxamine-type natural products, silver catalyzed imidazolidines and oxazoles, oxazolines, spiroimidazolones, 10b, peptides, 1 H -imidazole-2-thiones, 2,4-bis(arylthio)-5-[ N -alkyl- N -phenylamino]oxazoles,9b α-keto esters, mesoionic 3-alkyl-2-(arylthio)-1,3-diazolium-4-olates, 2-aminoimidazoles, optically active threo-β-hydroxyamino acids, 2-imidazolin-5-ones, 5-amino oxazoles,9a or 1-oxo-1,2-dihydroisoquinoline-3-carboxylic acid derivatives . This class of isocyanides will provide the foundation of focused and general libraries for use in the discovery of biologically active compounds.…”

Ugi/Robinson–Gabriel reactions directed toward the synthesis of 2,4,5-trisubstituted oxazoles

“…6 Thanks to the merits of their useful properties and widespread distribution in nature, methodologies to develop the oxazole core structure have attracted a great deal of attention over the years. 7–9 Among the developed methodologies is the well-known Robinson–Gabriel oxazole synthesis which involves intra-molecular cyclization of an amide carbonyl onto a ketone group embedded in an N -acyl α-aminoketone 6 with ensuing the elimination of water. 10,11 To continue our research theme of developing robust methodologies with high user uptake in the pharmaceutical sector, it was envisioned that the application of 2,4-dimethoxybenzylamine 1 in the Ugi reaction, previously exploited by Sheehan et al, 12 in combination with arylglyoxal 3 and supporting reagents would enable oxazole synthesis in one single second step through acid mediated deprotection of the 2,4-dimethoxybenzyl protecting group followed by concomitant cyclodehydration (i.e., the Robinson–Gabriel reaction), Scheme 1.…”