High temperature reactions aminocarbonylation

The scope of aminocarbonylations was extended by the works from various groups. For example, Skoda-Fbldes and Kollar studied the carbonylation reactions of ferrocene derivatives in the presence of Pd(OAc)2/PPh3 [126-128]. Ferrocene amides and novel ferrocene a-ketoamides were synthesized in good yields based on palladium-catalyzed aminocarbonylation or double carbonylation of iodofer-rocene at 40-50 bar of CO. The double-carbonylated products were favored at 40-60 °C and amides were produced almost exclusively at 100 °C, as the selectivity of the reaction with less sterically hindered secondary amines is highly dependent on the reaction temperature. Analogous aminocarbonylation reactions of l,l -diiodoferrocene led to I -iodo-ferrocenecarboxamides and I -iodo-ferro-ceneglyoxylic amide-type products. 

A Pd-catalyzed aminocarbonylation was performed above the boiling point of the solvent toluene up to 150 °C [44]. Two reaction products can be generated, an amide and an a-ketoamide, depending on the insertion of one or two equivalents of carbon monoxide. It was demonstrated that high-temperature microreactor operation favors the amide formation and high pressures lead to the a-ketoamide, according to prior literature experience with conventional technology. 

However, gas substrates such as carbon monoxide (CO) can be easily introduced in a packed-bed reactor. ThanesNano researchers reported aminocarbonylation of aryl halides with amines and CO gas at high pressure and high temperature under flow conditions, which afforded the corresponding amides in moderate-to-high yield (Scheme 7.24) [101]. In this paper, they described that reaction parameters (solvent, base, catalyst, pressure, temperature, and so on) were rapidly optimized in the reactions, which required less than 2 min. As a continuous study, the authors reported a double carbonylation reaction of iodobenzene to give a-ketoamides in a flow reactor [102]. 

Aminocarbonylation can also be carried out by use of CO and a silyl amide. Watanabe et al. reported the cobalt-catalyzed aminocarbonylation of epoxides [55]. Some silyl amides such as PhCH2NHSiMe3 and Et2NSiMe3 were applicable to the reaction to give the /i-siloxy amide in good yields, whereas high reaction temperature was required. The use of 4-(trimethylsilyl) morpholine was found to be crucial for a milder and more efficient carboami-nation here, the reaction proceeded at ambient temperature under 0.1 MPa of CO. However, N-(2-hydroxyalkyl)morpholines, a product without carbonyla-tion, were yielded as by-products (Scheme 18) [56]. 

Imidazole-2-carboxylates can be made by amidine cyclization (see Section 2.2.1 and Table 2.2.2), by reaction of an aminocarbonyl compound with thioxamate (see Section 4.1 and Scheme 4.1.6), and from 1-cyano-or 1-carbethoxy-substituted 4-amino-2-azabutadienes (see Section 3.2 and Scheme 3.2.3). An improved amidine cyclization treats trichloroacetonitrile with ami noacetaldehyde dimethyl acetal to give the amidine (5), which cyclizes with trifluoroacetic acid at room temperature to give 2-trichloromethylimidazole (Scheme 8.3.2). This is not purified, but converted immediately into ethyl imidazole-2-carboxylate or imidazole-2-carboxylic acid in high yields [10],... 

Jensen and coworkers employed a silicon microreactor (Figure 11.7) to perform aminocarbonylation reactions of aryl halides with morpholine [13]. The results show that carbonylation selectivity (mono- versus double carbonylation) depended on the reaction temperatures and CO pressures (Table 11.3). They also demonstrated that high-throughput screening of the optimal reaction conditions (temperature and pressure) could be performed with their system. 

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