Asmic Isocyanide‐Nitrile Isomerization‐Alkylations

Abstract

Anisylsulfanylmethylisocyanide, Asmic, is a versatile building block whose alkylations provide a range of substituted isocyanides. The anisylsulfanyl group plays a critical role in the sequenced deprotonation‐alkylation and the subsequent sulfanyl‐lithium exchange. Complexation of the anisylsulfanyl group to BuLi in the presence of TMEDA affords a lithiated isocyanide whose alkylations generate trisubstituted isocyanides. In the absence of TMEDA, BuLi triggers cyanide expulsion to afford a transient carbene; reorientation of cyanide with attack at the carbene affords a lithiated nitrile whose alkylations afford quaternary nitriles. The complexation‐induced isocyanide‐nitrile rearrangement is exceptionally facile, occurring within 5 min at –78 °C. Detailed mechanistic and computational analyses identify the importance of chelation in the bifurcating mechanism: internal chelation favors cyanide extrusion to form a carbene whereas chelating agents favor arylsulfanyl‐lithium exchange to generate a lithiated isocyanide. The combined experimental and computational analyses reveal a new mechanism for isocyanide‐nitrile isomerization which provides valuable insight for rapidly assembling substituted isocyanides.

Dearomatization of aromatic asmic isocyanides to complex cyclohexadienes

“…3 ) 21 . The addition of BuLi to sulfur-substituted isocyanides such as 19a generates electron-rich sulfuranides 20a 22 which, in the presence of TMEDA, intercept electrophiles at the isocyanide-bearing carbon to afford trisubstituted isocyanides such as 21 21 . Speculating that lithium salts might promote scission of the weak isocyanocarbon–sulfur bond, analogous to halogen–lithium exchange reactions 23 , led to the inclusion of lithium chloride which completely suppressed the formation of 21a ( 21 , R = Bn) to provide 22a in 42% yield (Fig.…”

“…Prior calculations on the sulfur–lithium exchange of dialkylAsmic provided the starting point for computationally probing the influence of chelation 22 . Specifically, the importance of HMTETA to sequester the lithium cation was incorporated into the energetics for the complexation and transfer of the alkyl group from MeLi (as a computational surrogate for BuLi with fewer rotatable bonds) to sulfur (Fig.…”

Stability, atomic charges, bond‐order analysis, and the directionality of lone‐electron pairs on nitriles and isocyanides

“…Nitriles and isocyanides are two classes of important nitrogen-containing compounds with multiple bonds, which will conjugate with other functional groups to form complex delocalization π bonds and multifunctional compounds containing intrinsic physical properties and interesting chemical reactivity. [1][2][3][4][5][6][7] Over the past decade, the :C N and C N: functional groups have been extensively investigated for their unique properties and reactivity of varied organic and biological compounds such as proteins and transition metal complexes. [8] The simplest nitrile, HCN, is a widespread small molecule in interstellar space [9][10][11] and plays a significant role in prebiotic chemistry.…”

Asmic Isocyanide [3 + 2] Cascade to Dihydrooxazoles and Dihydroimidazoles

“…Central to the success of Asmic (1b) as a powerful isocyanide building block is the anisylsulfanyl moiety (Scheme 2); the anisylsulfanyl moiety facilitates deprotonation− alkylation 1b → 4 and the sulfur−lithium exchange−alkylation (4 → 5). 10 Electrophilic trapping is successful for a range of electrophiles, providing trisubstituted isocyanides 5 that are otherwise challenging to access. azole 6a (Figure 1).…”