Mannich-type cyclizations

Hozien et al. in their pubhcation [149] studied the Mannich-type cyclization of 5-aminopyrazoles with formaldehyde and diverse amines. It was shown that treatment of 5-aminopyrazoles with primary aliphatic amines and formaldehyde in the ethanol under the ambient temperature gave 1,3,5-trisubstituted tetrahydropyrazolo... 

An intramolecular Mannich-type cyclization of l,3-dimethyl-6-(2-aminophenylthio)uracil (120) has been utilized for the synthesis of 5, 6-dihydropyrimido[4,5-b][ 1,5]benzothiazepine-2,4( 1H,3//)-diones (121) this synthesis was realized by reaction of 120 with an excess of formaldehyde, benzaldehyde, or p-nitro- or p-methoxybenzaldehyde in chloroform in the presence of a catalytic amount of p-toluenesulfonic acid under reflux for 4-10 hours. The thiazepine cyclization using aliphatic aldehydes other than formaldehyde did not give satisfactory results. In these cases the reaction resulted in the formation of a dimeric product that probably... 

Chiral imines have been shown to undergo intramolecular Mannich reaction to give the tetrasubstituted 4-pipeiidones <05JACS8398> (Scheme 65). A Mannich-type cyclization of... 

As mentioned previously, there are many Mannich-type cyclizations of acetals that undoubtedly occur via enol ether intermediates and afford -amino acetal products. A prototypical example is presented in Scheme 12. In this sequence, due to Wenkert, the iminium ion precursor is formed by semihydrogenation of a nicotinic ester salt. ... 

Most ir-nucleophiles employed in iminium ion cyclizations have a predetennined postcyclization destiny. For example, aromatic terminators will rearomatize, organosilanes will eliminate silicon through anticipated pathways and acetals and enol ethers will produce carbonyl compounds. However, the cyclizations of simple alkenes have supplied products that are the formal results of eliminations, additions and Wagner-Meerwein rearrangements. Almost exclusively Mannich-type cyclizations of unsaturated amines have been employed to prepare piperidines. 

In less than 10 years, organosilanes have emerged as an unusually versatile class of nucleophiles for terminating Mannich-type cyclizations. Their utility derives from the ability of the silicon substituent to control the regioselectivity of bond formation and dictate the postcyclization destiny of the carbenium ion intermediate produced upon cyclization. The characteristics of silicon that are responsible for this exceptional control have been discussed in several recent reviews. ... 

Mannich-type cyclizations of vinylsilanes have found considerable application in the area of alkaloid total synthesis. Cyclizations that occur in the exocyclic mode with respect to the vinylsilane nucleophile have been widely employed to assemble 3-alkylidenepiperidine substructures with high stereocontrol. Overman and coworkers have made extensive use of the acid-promoted conversion of bicyclic oxazolidines to alkylideneindolizidines in their total syntheses of pumiliotoxin A alkaloids (Scheme 36). - " - An illustration of the mild nature of iminium ion-vinylsilane cyclizations is provided in the conversion of (101) to (102), the penultimate precursor of (-i-)-pumiliotoxin A. This conversion was accomplished in 71% yield by heating (101) at 80 C in a methanolic pyridine-pyridinium tosylate buffer (pH 4.5). More strongly acidic conditions had to be avoided since they led to competitive solvolysis of the allylic benzyl ether functionality of the pumiliotoxin A side chain. To the limits of detection by high... 

A number of Mannich-type cyclizations that proceed in an exocyclic mode with respect to the allylsi-lane terminator have been reported. In this way, five-, six-, seven- and eight-membered azacycles are accessed in good yields. In keeping with Baldwin s suggestion concerning ring closure aptitudes, the iminium ion derived from amine (113) could not be cyclized (Scheme 41). 

In several instances, Mannich-type cyclizations can be carried out expeditiously under photochemical conditions. The photochemistry of iminium ions is dominated by pathways in which the excited state im-inium ion serves as a one-electron acceptor. The photophysical and photochemical ramifications of such single-electron transfer (SET) processes as applied to excited state iminium ions have been expertly reviewed. In short, one-electron transfer to excited state iminium ions occurs rapidly from one of several electron donors electron rich alkenes, aromatic hydrocarbons, alcohols and ethers. Alternatively, an excited state donor, usually aromatic, can transfer an electron to a ground state iminium ion to afford the same reactive intermediates. Scheme 46 adumbrates the two pathways that have found most application in intramolecular cyclizations. Simple alkenes and aromatic hydrocarbons will typically suffer addition processes (pathway A). However, alkenic and aromatic systems with allylic or benzylic groups more electrofugal than hydrogen e.g. silicon, tin) commonly undergo elimination reactions (pathway B) to generate the reactive radical pair. 

For further details regarding this Mannich type cyclization, see D.A. Heerding, C.Y. Hong, N. Kado, G.C. Look, and L.E. Overman, J. Org. Chem., 58,... 

Many of the methods used for the preparation of 1,3,5-oxadiazines also apply to the 1,3,5-thiadiazines. Similar to the oxygen analogs, the starting Wnitroguanidine can be treated with formaldehyde, but in the presence of sodium sulfide to afford the Mannich-type cyclization product 4-nitroimino-l,3,5-thiadiazines (Section 9.09.9.1.2). Primary amines react with carbon disulfide under basic conditions to form dithiocarbamate salts which react with 2 equiv of formaldehyde and a second primary amine to furnish tetrahydro-2//-l,3,5-thiadiazine-2-thiones (Section 9.09.9.1.3). 

General synthetic methodologies involving Mannich-type cyclization reactions as the key step have been developed for the synthesis of the 2-nitroimino-l,3,5-triazinanes 9 [14—18, 22-26] and the 4-nitroimino-l,3,5-oxadiazinanes 10 [19-22, 26, 27] (Schemes 29.2.3.1 and 29.2.3.2). These methodologies allow the introduc-... 

Optically active trifluoromethyl-substituted tetrahydroimidazo[l, 5-c] quinazoline derivatives 44 were synthesized by Zhao and coworkers via a diastereo- and enantioselective Mannich-type cyclization cascade reaction of a-aryl isocyanoacetates and trifluoromethyl-substituted cyclic ketimines, using a multihydrogen-bonding donor squaramide/AgOAc cooperative catalytic system in THF at 0°C (Scheme 30) (140L4566). The products were obtained in 76—99% yield with a diastereomeric ratio of greater than 15 1 and 58-98% enantiomeric excess. 

C-l,4-addition/Mannich-type cyclization through respective intermediates 303 and 304. This finding invoked historical perspectives from Prelog s work in 1949 [139] and the enamine work of Stork et al. in the 1950s [140]. With the latter case, a distinct contrast could be generalized whereby cycloadditions of a,(3-unsaturated carbonyl systems with enamines mostiy led to carbo-[3+3] cycloaddition [138], and those with enaminones, or vinylogous amides, almost exclusively proceeded down the pathway of an aza-[3+3] cycloaddition. 

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