Pyrrolidine, addition

Heating pyrrole with pyrrolidinocyclohexene gives the 2-substituted pyrrole 121, which forms the azafulvene 122 by elimination of pyrrolidine. Addition of a second molecule of the enamine leads to the spiro compound 123 (equation 53)74. 

In acetonitrile all reactions of pyrrolidine addition exhibited AV values between -15 and -17cm3mol-1.262 However, upon decreasing the solvent polarity, AV became markedly more negative and a good correlation with the solvent parameter qv (i.e. the pressure derivative of q, the polarisability of the solvent) could be demonstrated. It was concluded that the addition of pyrrolidine followed a two-step process with a polar transition state leading to a zwitterionic intermediate. Addition of / ara-substituted anilines to a similar Fischer carbene complex in acetonitrile was characterised by more negative values of AV (-21 to -27cm3mol-1) than those for addition of pyrrolidine. 263 Second-order rate constants for the addition reaction exhibited an excellent correlation with the basicity of the aniline derivatives used. The trend in activation volumes could be correlated with an early or late transition state for the fast and slow addition reactions, respectively Scheme 12. 

An area that has been subject to more investigation is the non-metal or organocatalytic coupling of esters and amines. Numerous catalysts such as l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and l,5,7-triazabicyclo[4.4.0]-dec-5-ene (TBD) have shown significant potential in this area. However, the drawback of these methods is that slightly higher catalytic loadings of 20 and 30 mol% were required respectively. DBU has been employed as a catalyst for several transformations prior to its use in the aminolysis of esters." This method is only applicable in the case of methyl esters and has only been tested with benzylamine, aniline and pyrrolidine. Additionally, these catalysed reactions still required reaction times of up to 48 hours to reach a maximum of 90% conversion (in most cases, the conversions were lower). 

In addition to their antiknock properties, organic lead compounds possess bactericidal properties and motor fuels with lead are known to inhibit bacterial growth during storage in contact with water. With the disappearance of lead-based compounds, it is necessary to incorporate biocides from the cyclic imine family, (piperidine, pyrrolidine, hexamethyleneimine), alkylpropylene diamines or imidazolines (Figure 9.2). 

Aldehydes take part in the cycloaddition to give the methylenetetrahydrofuran 178 by the co-catalysis of Pd and Sn compounds[115]. A similar product 180 is obtained by the reaction of the allyl acetate 179, which has a tributyltin group instead of a TMS group, with aldehydesfl 16]. The pyrrolidine derivative 182 is formed by the addition of the tosylimine 181 to 154[117]. 

In aqueous solution, azetidine (p/sTa 11.29) is slightly more basic than pyrrolidine and larger-ring cyclic amines and appreciably more basic than aziridine. It forms an addition compound (m.p. - 9 to -6 °C) with trimethylboron which is more stable than that formed by pyrrolidine (50JA2926, 64HC(l9-2)885). Azetidinium salts are well known (Section 5.09.2.2.7). 

Steroidal A -dienamines are formed with a high degree of selectivity in the presence of 17- or 20-ketones. Preparation of morpholine and pyrrolidine enamines is achieved by azeotropic removal of water with or without a catalyst. Pyrrolidine enamines are also formed efficiently by addition of the base to the hot solution of the ketone in methanol followed by immediate cooling. ... 

Normally, phenylhydrazine reacts with the enol form of 1,1,1-trifluorometh-ylpentane-2,4-dione to give 5-methyl-l-phenyl-3-tnfluoromethylpyrazole as the major product. However, the use of pyrrolidine as a transient carbonyl-blocking group can completely reverse the regiochemistry of the addition and leads to 3-methyl-l-phenyl-5-trifluoromethylpyrazole [102] (equation 88)... 

It was, however, found 22) that when the pyrrolidine enamine of cyclohexanone was allowed to react with an excess of -nitrostyrene, a bis adduct (46), made up of one molecule of the enamine and two molecules of olefin, was obtained in addition to the monoadduct. That the bis adduct is not derived from the monoadduct was shown by the latter s failure to react with (9-nitrostyrene. Therefore, this adduct must be formed by the addition of the olefin to the dipolar intermediate (47), as shown in the following scheme. 

Interestingly the pyrrolidine enamine of 3-t-butylcyclohexanone (41) consists of a 3 2 mixture of A and A isomers (79 and 80). The preference for the A isomer in this case is due to the relief of two of the four skew butane interactions, which are present in the isomer. The A isomer, owever, contains two additional interactions, i.e., one modified skew utane interaction 0.4 kcal/mole (42) and one interaction between c C-2 vinylic hydrogen atom and the ethyl portion of the t-butyl group hich is pointed toward it. 

The enamines derived from cyclic ketones give the normal alkylated products, although there is some evidence that unstable cycloadducts are initially formed (55b). Thus the enamine (28) derived from cyclohexanone and pyrrolidine on reaction with acrylonitrile, acrylate esters, or phenyl vinyl sulfone gave the 2-alkylated cyclohexanones (63) on hydrolysis of the intermediates (31,32,55,56). These additions are sensitive to the polarity of the solvent. Thus (28) in benzene or dioxane gave an 80% yield of the... 

The addition of ethyl acrylate to 1,2-dimethyl- -piperideine 163), l-methyl-2-ethyl-zJ -piperideine 164), and 1,2-dimethyl- -pyrrolidine 216,217) occurs, yielding both possible enamine structures (138 and 139, n=I,2). 

It is interesting to see that the addition of methyl acrylate to the pyrrolidine enamine derivative of 2-methylcyelohexanone in benzene gave equal amounts of 2-methyl-2-carbomethoxyethyl and 2-methyl-6-earbomethoxy-ethylcyclohexanone even though the less substituted double-bond isomer predominates in the starting enamine (199,200,237). In contrast, the methylation of the same enamine mixture led only to 2,6-dimethyleyclo-... 

Dicarbomethoxyacetylene has also been added to the pyrrolidine enamine derivative of acetylacetone, demonstrating a new synthesis of phthalic esters (345). A 3-acylpyridine synthesis was achieved by the addition of an acetylenic aldehyde to the vinylogous amide derived from ammonia and dihydroresorcinol (346). 

Design of chiral catalysis and asymmetric autocatalysis for diphenyl-(l-methyl-pyrrolidin-2-yl) methanol-catalyzed enantioselective additions of organozinc reagents 97YGK994. 

Another pathway for the aromatization of the cr -adducts was found in the reactions of 3-pyrrolidino-l,2,4-triazine 4-oxide 81 with amines. Thus the treatment of 1,2,4-triazine 4-oxide 81 with ammonia leads to 5-amino-1,2,4-triazine 4-oxides 54—products of the telesubstitution reaction. In this case the cr -adduct 82 formed by the addition of ammonia at position 5 of the heterocycle undergoes a [l,5]sigmatropic shift resulting in 3,4-dihydro-1,2,4-triazine 83, which loses a molecule of pyrrolidine to yield the product 54. This mechanism was supported by the isolation of the key intermediates for the first time in such reactions—the products of the sigmatropic shift in the open-chain tautomeric form of tiiazahexa-triene 84. The structure of the latter was established by NMR spectroscopy and X-ray analysis. In spite of its open-chain character, 84 can be easily aromatized by refluxing in ethanol to form the same product 54 (99TL6099). 

Substituted TMMs also participate smoothly in imine cycloaddition to generate more structurally elaborate pyrrolidines. The regioselectivity of these reactions is similar to that of olefin addition, although subsequent isomerization of the initial adduct is often observed. For example, the cyano system produced the thermody-... 

Formal oxidation of pyrrolidine to the succinimide stage affords a series of compounds used as anticonvulsant agents for treatment of seizures in petit mal epilepsy. Knoevnagel condensation of benzaldehyde with ethyl cyanoacetate affords the unsaturated ester, 9. Conjugate addition of cyanide ion leads to the di-nitrile ester (10). Hydrolysis in mineral acid affords the succinic acid (11), presumably by decarboxylation of the intermediate tricarboxyllie acid. Lactamization with methylamine gives phensuximide (12). ... 

The net effect of the Stork reaction is the Michael addition of a ketone to an cn/3-unsaturated carbonyl compound. For example, cyclohexanone reacts with the. cyclic amine pyrrolidine to yield an enamine further reaction with an enone such as 3-buten-2-one yields a Michael adduct and aqueous hydrolysis completes the sequence to provide a 1,5-diketone (Figure 23.8). 

As well as the disubstituted C2-symmelrie pyrrolidines E and F, the monosubstituted (f> )-2-(mcthoxymethyl)pyrrolidine G can be used as chiral auxiliary for the diastereoselecti ve addition of organomctallic reagents to a-oxo amides16. As with the phenylglyoxylic acid derivatives derived from amines E and F. methyllithium or methylmagnesium bromide in diethyl ether preferentially attack the (,S)-mms-conformer 11 (R = ( 6H5), leading to predominant formation of the (2 S)-diastercomer by Re-side attack. 

The first reports on enantioselective addition reactions of achiral organometallic reagents, modified by aprotic chiral additives, described the addition of Grignard reagents to prostereogenic carbonyl compounds in the presence of ( + )-(/ ,/J)-2,3-dimethoxybutane (l)4 5, (-)-tetrahydro-2-methylfuran (2)6, (-)-l-[(tetrahydro-2-furanyl)methyl]pyrrolidine (3)7 or (-)-sparteine (4)8. The enantioselectivity, however, was poor (0-22% ee). 

After 19 hours, no reaction between the zinc chelate 2 and benzaldehyde can be detected at 20 °C. However, 10 mol % of the zinc chelate effectively catalyzes theenantioselective addition of diethylzinc to aromatic aldehydes. The predominant formation of the S-configurated products, effected by this conformationally unambiguous catalyst, can be explained by a six-mem-bered cyclic transition state assembly17. The fact that the zinc chelate formed from ligand M is an equally effective catalyst clearly demonstrates that activation of the aldehyde moiety does not occur as a consequence of hydrogen bond formation between the ammonium proton of the pyrrolidine unit and the aldehydic oxygen. 

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