Cyclic Thioanhydrides:  Linchpins for Multicomponent Coupling Reactions Based on the Reaction of Thioacids with Electron-Deficient Sulfonamides and Azides

Abstract

Reaction of cyclic thioanhydrides with amines affords amides functionalized with thioacids, which can be trapped in situ with electron-deficient azides or, preferably, 2,4-dinitrobenzenesulfonamides. In this manner the cyclic thioanhydride serves as a linchpin in a three-component coupling sequence. The use of thiomaleic anhydride and a bifunctional nucleophile extends the process to heterocycle synthesis, while a cyclic thioanhydride prepared from aspartic acid directly provides N-functionalized asparagine derivatives.

Dihydro-3-(triphenylphosphoranylidene)-2,5-thiophendione: a convenient synthon for the preparation of substituted 1,4-thiazepin-5-ones and piperidinones via the intermediacy of thioacids

“…By analogy with the chemistry of 2-(triphenylphosphanylidenesuccinic anhydride),44-51 we reasoned that treatment of monothiomaleic anhydride39,40,52,53 with triphenylphosphine would result in the formation of dihydro-3-(triphenylphosphoranylidene)-2,5-thiophendione 1 , and that this ylide would be stable, isolable, and a suitable partner for reaction with aldehydes to give substituted monothioitaconic anhydride derivatives. In the event, reaction of monothio maleic anhydride with triphenylphosphine in glacial acetic acid at room temperature provided the crystalline 1 in 86% yield (Scheme 1).…”

“…With a series of alkylidene monothiosuccinic anhydrides in hand, we turned our attention to tandem Michael addition – nucleophilic ring opening processes with suitably constituted mercapto amines, of the kind previously practiced on monothiomaleic anhydride,39,40 with subsequent trapping of the released thioacid by reaction with 2,4-dinitrobenzenesulfonamides 9-11,36. A series of reactions were conducted in which either 2-mercaptoaniline or 2-mercaptoethylamine were stirred in DMF at 0 °C overnight before the addition of cesium carbonate and a 2,4-dinitrobenzenesulfonamide leading, ultimately, to the isolation of a series of substituted 1,4-thiazepin-5-ones, or their benzo-fused analogues, as presented in Table 2.…”

Practical asymmetric access to carboxy-differentiated aspartate derivatives via 1,3-dipolar cycloaddition of a nitrone with (R)-4-ethyl-N-vinyloxazolidin-2-one

“…1 H NMR (400 MHz, CDCl 3 ) d 7.39-7.20 (m, 10H), 4.35-4.17 (m, 2H), 3.94 (dd, J = 9.9 Hz, 5.1 Hz, 1H), 3.84 (d, J = 13.5 Hz, 2H), 3.61 (s, 3H), 3.14-3.01 (m, 1H), 3.10 (s, 3H), 2.64-2.59 (m, 1H), 1.37 (t, J = 7.1 Hz, 3H). 13 C NMR (100 MHz, CDCl 3 ) 171. 9, 171.8, 139.3, 128.7, 128.2, 127.0, 61.0, 60.5, 57.8, 55.1, 32.7, 14.5 …”

“…12 Finally, N-Boc L-aspartic thioanhydride was shown to favor b-regioselective ring opening with anilines and L-glycosamines, despite moderate yields. 13 We have recently disclosed other promising precursors of aspartate derivatives which allow selective manipulations at the b-position: the N-dibenzylated aspartimides 4. 14 They were efficiently obtained by a high yielding two-step sequence: (i) solvent-free cycloaddition of nitrone 2 to N-vinyloxazolidin-2-one 1 and (ii) isoxazolidine ring opening via N-benzylation of the adducts 3 thus obtained (Scheme 1).…”

A simple method for the conversion of carboxylic acids into thioacids with Lawesson’s reagent

“…Another involves prior coupling of the carboxylic acid with either HSFmoc, HSTrt or HSTmob. Removal of the protecting group releases the target thioacid 8. Finally, Boc solid phase peptide synthesis (SPPS) with a thioester solid support can be applied to the preparation of large peptide thioacids 9.…”