Amides substituted pyrrolidines

Lithium ( )- or (Z)-5-alkenylamides are converted regio- and stereoselectively in a 5-exo-fng-cyclization of an intermediate amide radical to substituted pyrrolidines [84]. 

Aziridines can add to carbon—carbon multiple bonds. Elevated temperature and alkali metal catalysis are required in the case of nonpolarized double bonds (193—195). On the other hand, the addition of aziridines onto the conjugated polarized double or triple bonds of a,p-unsaturated nitriles (196—199), ketones (197,200), esters (201—205), amides (197), sulfones (206—209), or quinones (210—212) in a Michael addition-type reaction frequendy proceeds even at room temperature without a catalyst. The adducts obtained from the reaction of aziridines with a,p-unsaturated ketones, eg, 4-aziridinyl-2-butanone [503-12-8] from 3-buten-2-one, can be converted to 1,3-substituted pyrrolidines by subsequent ring opening with acyl chlorides and alkaline cyclization (213). 

Pyrrolidines. The Grignard reagent 2, obtained from 3-bromopropylamine protected as the stabase adduct with 1, reacts with the N-methoxy-N-methyl amides 3 (11, 201-202) to form an intermediate ketone that cyclizes to an imine on liberation of the free primary amino group. Reduction of the imine results in a 2-substituted pyrrolidine (4). 

The cyclization of unsaturated amines and amides leading to 2,4-substituted pyrrolidines, mediated by mercury(II)222-223 or silver(I)217 salts, as well as the cyclization of imines by phenylse-lenenyl bromide254 proceeded with low or no diastereoselectivity, e.g., formation of 1-3. 

Another strategy for the formation of /V-acyliminium ions as substrates for 2-aza-Cope rearrangements consists of the intramolecular cyclization of carboxylic amides of type 17. The Cope products are cyclized to afford substituted pyrrolidines, e.g., 20 and 21964. 

Peepuloidin, C14H19O5N (mp 149°) was shown to be an amide of pyrrolidine and a highly substituted cinnamic acid. Spectral data indicated structure XC and this was confirmed by permanganate oxidation to... 

Numerous 2-substituted pyrrolidine organocatalysts have been prepared from L-proline and its derivatives, and have been proven to be highly efficient for many asymmetric reactions. Representative organocatalysts have been selected and categorised on the basis of the 2-substituted group that includes di- and tri-amine (la-m), dithioacetal (2a-f), guanidine (2g-i), sulfonamide (3a-j), amide and thioamide (3k-n), urea (4a and 4e), thiourea (4b-d, f-j) and heterocycles such as tetrazole (5a,b), triazole (5c-g), imidazole (5h-j) and benzoimidazole (5k) (Figure 9.1). 

Of the several syntheses available for the phenothiazine ring system, perhaps the simplest is the sulfuration reaction. This consists of treating the corresponding diphenylamine with a mixture of sulfur and iodine to afford directly the desired heterocycle. Since the proton on the nitrogen of the resultant molecule is but weakly acidic, strong bases are required to form the corresponding anion in order to carry out subsequent alkylation reactions. In practice such diverse bases as ethylmagnesium bromide, sodium amide, and sodium hydride have all been used. Alkylation with (chloroethyl)diethylamine affords diethazine (1), a compound that exhibits both antihista-minic and antiParkinsonian activity. Substitution of w-(2-chloroethyl)pyrrolidine in this sequence leads to pyrathiazine (2), an antihistamine of moderate potency. 

They have developed direct asymmetric synthesis of quaternary carbon centers via addition-elimination process. The reactions of chiral nitroenamines with zinc enolates of a-substituted-8-lactones afford a,a-disubstituted-6-lactones with a high ee through addition-elimination process, in which (5)-(+)-2-(methoxy methy l)pyrrolidine (SMP) is used as a chiral leaving group (Eq. 4.96).119 Application of this method to other substrates such as a-substituted ketones, esters, and amides has failed to yield high ee. 

Chemical degradations have allowed the identification of both extremities of peripentadenine, hexanoic acid (present as an amide) and 2-hydroxy-6-meth-ylacetophenone. 13C NMR showed that the rest of the molecule included two nitrogen atoms, six methylenes, and one methine arranged in a (3-propylami-no)-l-pyrrolidine unit substituted at C-2. This formula was definitively proved by chemical degradations as well as by two total syntheses. As noted before in the cases of hygrine and of the ruspolinone alkaloids, peripentadenine is optically inactive. 

Two transformations should be discussed in more detail (1) presence of the amino group in 275 was utilized for the synthesis of the fused isoquinolinium salt 276 bearing the bicyclic heterocycle as an A-substituent <2003JHC1041> (2) selective nucleophilic substitution of 277 with pyrrolidine was reported <2001ZOR604> to yield only substitution on the phenyl substituent without formation of an amide from the ester group 278. 

The carboxylic group of 6-aryl-2-methylthiopyrido[2,3- s1pyrimidine-7-carboxylic acid 563 was amidated with (i )-2-(aminomethyl)-l-( /t-butoxycarbonyl)pyrrolidine 564, followed by sulfide oxidation of the resulting amide 565 and reaction with 4-morpholinoaniline to give the substituted pyridopyrimidine 566 as a kinase inhibitor (Scheme 26) <2005W02005090344>. 

Aminyl radicals also can be generated via electrochemical oxidation of amide bases or O-substituted hydroxylamines. Suginome has studied radical cyclizations involving oxidations of lithium alkenylamides as a route to ccs-l-methyl-2,5-disubstituted pyrrolidines (85TL6085). Electrolysis of lithium alkenylamide 17a, generated from the amine and butyllithium at - 78°C, led to the formation of 18a, exclusively cis, in 52% yield (Scheme 4). The reactions require 0.25 M UC104 in THF HMPA (30 1) as the supporting electrolyte. A variety of 2-substituted amines were studied. 

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