A Practical Approach to Semicarbazone and Hydrazone Derivatives via Imino-isocyanates

Abstract

Isocyanates have a broad spectrum of uses and they are used in the production of many products including polyurethane polymers, coatings, adhesives, paints and foams. While isocyanates are widely studied and well represented in the literature, nitrogen substituted isocyanates are quite rare.Amino and imino-isocyanates are examples of nitrogen substituted isocyanates. Previous work within the group studied the reactivity of these intermediates in the alkene aminocarbonylation reaction, and used hydrazones and hydrazides as precursors of nitrogen substituted isocyanates.From there, a second reaction pathway was studied. This involved the reactivity of hydrazones with nucleophiles to develop a simple exchange reaction. In this work, the substitution reactivity involving imino-isocyanates will be presented. This will include the scope of nucleophiles and hydrazones as well as a discussion on the formation of the imino-isocyanates. This reactivity allows for the facile formation of a variety of hydrazones with the flexibility to start from common hydrazone precursors.iii

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

“…It should be highlighted that carbazones are typically excellent N -isocyanate precursors: easier to synthesize, stable, often crystalline yet in general more prone than amino-isocyanates to react with nucleophilic amines. 6 …”

“…This encouraged us to investigate the generation and reactivity of N -isocyanate precursors with simple nucleophiles. Gratifyingly, the substitution reactions proceeded efficiently under stoichiometric conditions using both hydrazones 6 and hydrazides 7 as blocked N -isocyanates ( Scheme 1 ). A comparison of the conditions below establishes that imino-isocyanates react more readily than amino-isocyanates.…”

A Cascade Synthesis of Aminohydantoins Using In Situ‐Generated N‐Substituted Isocyanates

“…Recently, we reported that amphoteric amino‐ and imino‐isocyanates can be formed in situ under mild conditions and engage in high‐yielding alkene cycloadditions6a–c and nucleophilic additions,6d,e despite their known tendency to dimerize or oligomerize 7. 8 Hydrazones6b–d and hydrazides6a,e are bench‐stable, convenient “blocked” N ‐substituted isocyanate precursors9 that form the desired isocyanates via an equilibrium induced under mild conditions, and then react with nucleophiles such as amines, alcohols, and thiols 6d–e. Using this reactivity, we developed a cascade substitution/hydroamination sequence allowing rapid assembly of saturated nitrogen heterocycles from hydrazide starting materials 6e.…”

“…To our knowledge, there have been no examples of cascade reactions involving either imino‐isocyanates (CNNCO) or amido‐isocyanates [C(O)NNCO] reported to date, and we felt that this extension would significantly broaden the applicability of this approach to aminohydantoins. Thus we first investigated the ability of imino‐isocyanates to engage in cascade reactions, building on our recent report on their substitution reactivity 6d. We were pleased that several hydrazones used as imino‐isocyanate precursors afforded the desired aminohydantoins in the presence of N ‐methyl glycine ethyl ester (Table 2).…”

N-Isocyanates, N-Isothiocyanates and Their Masked/Blocked Derivatives: Synthesis and Reactivity

“…Related reactivity of hydrazone derivatives was studied in detail by Beauchemin and co-workers (Equation 11), 33 who looked at the ability of a variety of substrates and nucleophiles to undergo similar reactions. Notably, this work showed that substitution is possible at room temperature using amines and iminoisocyanate precursors with suitable leaving groups (e.g., LG = OPh).…”