Amidation-cyclization process

Several syntheses of thienobenzazepines have been reported in the literature however, they generally require the use of reagents and/or reaction conditions which present challenges on a preparative scale. In this manuscript we describe a new and efficient synthesis of the thieno[2,3-c]benzazepine tricycle that involves a key selective reduction-intramolecular amidation cyclization process and enables large-scale preparation of these important compounds. 

Acylation of norephedrine (56) with the acid chloride from benzoylglycolic acid leads to the amide (57), Reduction with lithium aluminum hydride serves both to reduce the amide to the amine and to remove the protecting group by reduction (58), Cyclization by means of sulfuric acid (probably via the benzylic carbonium ion) affords phenmetrazine (59), In a related process, alkylation of ephedrine itself (60) with ethylene oxide gives the diol, 61, (The secondary nature of the amine in 60 eliminates the complication of dialkylation and thus the need to go through the amide.) Cyclization as above affords phendimetra-zine (62), - Both these agents show activity related to the parent acyclic molecule that is, the agents are CNS stimulants... 

This application was performed on a lab-scale reactor and later in a miniplant-scale reactor. The reaction studied was the vapor phase catalytic amidation/cyclization step in a pesticide process. As shown in Figure 2, two reactions are taking place on the catalyst bed. 

Figure 2 Vapor phase catalytic amidation/cyclization reaction in a pesticide process monitored by on-line HPLC.

The absolute rate constants for a variety of cyclizafions have been measured. In particular, the rates of decarbonylafion of a variety of alkoxycarbonyl radicals have been obtained by LFP studies on PTOC oxalates." From these data, rate constants for the reduction of alkoxycarbonyl radicals with BusSnH and their 5-exo cyclizafions were determined. Whereas cyclizations were slightly faster than the analogous alkyl radical 5-exo cyclizations, their reactions with BusSnH were 10 times slower, indicating that cyclization processes should be synthetically useful. The rate constants for the cyclization of a number of variously substituted a-amide radicals have been determined together with their relative reactivities towards reduction using BusSnH (Scheme 16). Cyclizations of secondary-based radicals were found to be similar to the corresponding alkyl-substituted radicals. In addition, the rate constants were subject to minor electronic... 

Reviews including aspects of P-lactam chemistry are ketene-imine cycloaddition reactions <98CHE1222>, radical cyclization processes <98MI169>, combinatorial synthesis <98AJC875>, electrophilic cyclization of unsaturated amides <98T13681> and theoretical studies on the synthesis of P-lactams <98MI245>. 

A concise free radical cyclization process has been applied to the synthesis of new cyclopentanone-annulated azepines 204 from chiral vinylogous amides (Scheme 26). The free radical was generated from the phenylselenide group in 203 (made in turn by N-acylation of 202) using Bu3SnH and l,l -azobis(cyclohexanecarbonitrile) (ACN), as the initiator <2004SL1917>. 

Trost s synthesis138 of desethylibogamine (233) illustrates the application of a new approach to alkaloid synthesis, in which the two vital cyclization processes involve catalysis by palladium complexes protection of the nitrogen by formation of an amide, so often necessary in conventional syntheses, is here unnecessary. The first of the cyclization processes, (234)—>(235), results in a very neat formation of the isoquinuclidine ring system via a palladium-catalysed SN2 cyclization of the tryptamine derivative (234) (Scheme 24). 

This classification is illustrated in Scheme 260. Formation of the 1,2- (or 2,3-) bond via the activation of an amide or urea group is a versatile method to synthesize imidazoles. Many reagents, such as PPh3-CCl4, PCI5, or acids, etc., have been used for the cyclization process. 

The carbonyl unit involved in the cyclization process is not restricted to aldehydes and ketones. The carbonyl of acid derivatives, such as amides can also be utilized. One of the more important cyclodehydration reactions is applied to the formation of heterocychc systems via cyclization of p-aryl amides, in what is called the Bischler-Napieralski reaction In this reaction amides of the type 47 are... 

When hydantoins are treated with acetic anhydride, sodium hypochlorite, or nitiric acid, substitution takes place at the N-l position, followed by the formation of a 1,3-disubstituted hydantoin.1 Intramolecular processes yield only the amide cyclized products (102).255,256... 

Nicolaou further discovered that IBX can form heterocycles with certain N-aryl amides.10 The mechanism is postulated to be SET based and the aromatic ring plays an key role in the initial SET process (compounds that do not have the N-aryl moiety do not undergo the cyclization process). THF in the solvent system is also postulated to quench the reaction by providing the source of hydrogen atom transfer. The utility of this protocol is outlined below ... 

Finally, several palladium-catalyzed processes appear to occur by insertion of alkenes into palladium amides. Cyclizations of aminoalkenes in the presence of aryl halides to form P5nrolidines appear to occur by intramolecular insertion of alkenes into palladium amides. One example of the cyclizations of aminoalkenes in the presence of aryl halides is shown in Equation 9.89a. The relative stereochemistry of the aryl group and the nitrogen in the ring structure of the product indicates that syn addition of palladium and nitrogen occurred across the alkene. 

A gold catalysis-initiated cascade process toward the synthesis of electron-rich arene-fused hexahydroquinolizinones 131 was developed by Zhang and Liu in 2012 (Scheme 12.57) [62]. In this cascade reaction, a gold-catalyzed amide cyclization to a tethered C-C triple bond initiates a subsequent Frie del-Crafts type cyclization, followed by a Ferrier rearrangement. Synthetic utility of this... 

The free-standing films were made by casting DMAc solutions of the poly(amic acid)s onto a dust-free glass plate and vacuum drying at ambient temperature until tack-free. Films were cured under a dynamic nitrogen atmosphere at 30 C for 0.5 h and at 100,200, 300 C each for 1 h. In situ FTIR spectra (using a heated IR cell) confirmed the cyclization process. Disappearance of peaks at ca 1220 and 1544 cm were diagnostic for reaction of the amide and add residues while appearance of new peaks at ca 1365 and 1775 cm confirmed imide formation. 

Condensa.tlon, This term covers all processes, not previously iacluded ia other process definitions, where water or hydrogen chloride is eliminated ia a reaction involving the combination of two or more molecules. The important condensation reactions are nitrogen and sulfur heterocycle formation, amide formation from acid chlorides, formation of substituted diphenyl amines, and misceUaneous cyclizations. 

There are two important rhodium-catalyzed transformations that are broadly used in domino processes as the primary step. The first route is the formation of keto carbenoids by treatment of diazo keto compounds with Rh11 salts. This is then followed by the generation of a 1,3-dipole by an intramolecular cyclization of the keto carbenoid onto an oxygen atom of a neighboring keto group and an inter- or intramolecular 1,3-dipolar cycloaddition. A noteworthy point here is that the insertion can also take place onto carbonyl groups of aldehydes, esters, and amides. Moreover, cycloadditions of Rh-carbenes and ring chain isomerizations will also be discussed in this section. 

Piperidine derivatives 161 and 164 could be cyclized to hexahydropyridooxadiazines 162, 165 via a dehydrogenation process by six oxidation equivalents of Hg(n)-EDTA. However, in both reactions, side products were also formed. From 161, piperidone derivative 163 was obtained, whereas starting from the amide 164, pyridopyrimidine 166 was isolated via cyclization by the amide nitrogen instead of oxime oxygen (Scheme 21) <1999ZNB632>. 

---