One-Pot Synthesis of Aza-Diketopiperazines Enabled by Controlled Reactivity of N-Isocyanate Precursors

Abstract

A one-pot sequence for the synthesis of aza-diketopiperazines is reported, involving carbazate acylation with chloroacetyl chloride, SN2 with a primary amine, N-isocyanate formation, and cyclization. Nitrogen-substituted isocyanates (N-isocyanates) are a rare class of amphoteric isocyanate with high, but severely underdeveloped synthetic potential. This approach highlights that βN-acyl carbazates can act as blocked (masked) N-isocyanates, thus allowing a challenging intermolecular SN2 reaction of a primary amine to proceed while the N-isocyanate is "protected", and then cyclization once it is unmasked. Control experiments show that the alternate pathway--N-isocyanate substitution and then cyclization by an intramolecular SN2 reaction--is not operating.

Cascade reactions of nitrogen-substituted isocyanates: a new tool in heterocyclic chemistry

“…Indeed, cyclization using the proximal nitrogen (αN) would yield the 5-membered amino-hydantoin, while cyclization using the distal nitrogen (βN) would yield the 6-membered aza-diketopiperazine. 13 We tested the reaction with a proline ester, and were pleased to observe complete selectivity for amino-hydantoin formation (eqn (3)). 12 After this initial result, we decided to further explore this reactivity using N -benzyl carbazate and several amino-esters ( Table 3 ).…”

Rhodium‐Catalyzed Oxidative Coupling Reaction of Isocyanides with Alcohols or Amines and Molecular Oxygen as Oxygen Source: Synthesis of Carbamates and Ureas

“…On the basis of the above experimental results together with related reports, a possible mechanism for the reaction is proposed (Scheme ). Initially, Rh(PPh 3 ) 3 Cl undergoes an insertion reaction with α‐diazocarbonyl compound L1 to give Rh‐carbene A .…”

“…Intermediate B is oxidized by O 2 (from air), and this is followed by homolysis of the O–O bond to give intermediate E . Finally, intermediate E reacts with alcohols or amines to give the desired products 2 or 3 (Scheme ) …”

Oxa–diketopiperazines: Access and Conformational Analysis of Potential Turn Inducers

“…In similar fashion, a focus on original 1,2,5‐oxadiazine‐3,6‐diones (1,2,5‐Oxd), which can be considered as oxa‐diketopiperazines (oxa‐DKPs) is presented here. While aza‐DKPs were recently studied, synthetic access to oxa‐DKPs is poorly described. Geffken et al.…”

“…[6] In similar fashion, a focus on original 1,2,5-oxadiazine-3,6-diones (1,2,, which can be considered as oxa-diketopiperazines (oxa-DKPs) is presented here. While aza-DKPs were recently studied, [7] synthetic access to oxa-DKPs is poorly described. Geffken et al briefly reported the double addition of N,Ndialkylhydroxamic amino acids on carbonyldiimidazole afford-ing a poorly functionnalized collection of oxa-DKPs in good yields (Scheme 1, a).…”