Regioselective pyrrolins

The regioselectivity observed in these reactions can be correlated with the resonance structure shown in Fig. 2. The reaction with electron-rich or electron-poor alkynes leads to intermediates which are the expected on the basis of polarity matching. In Fig. 2 is represented the reaction with an ynone leading to a metalacycle intermediate (formal [4C+2S] cycloadduct) which produces the final products after a reductive elimination and subsequent isomerisation. Also, these reactions can proceed under photochemical conditions. Thus, Campos, Rodriguez et al. reported the cycloaddition reactions of iminocarbene complexes and alkynes [57,58], alkenes [57] and heteroatom-containing double bonds to give 2Ff-pyrrole, 1-pyrroline and triazoline derivatives, respectively [59]. 

Independent work by Schmid93 and by Padwa94 on the photochemistry of 2H-azirines has shown that irradiation of such systems leads in the first instance to the formation of nitrile ylids (nitrilium betaines). Subsequent 1,3-addition to a variety of dipolarophiles affords five-membered heterocycles. These additions take place in a stereospecific and regioselective manner thus, irradiation of the diphenyl-2f/-azirine 117 in the presence of dimethyl maleate leads to the formation of the two isomeric 1-pyrrolines... 

The intramolecular photochemistry of 9-[2-(7V-substituted aminomethyl)-l-naph-thyl]phenanthrenes has also been studied101 (equation 40). The pyrroline derivatives are obtained by the addition of the N—H to the C-9 carbon atom of phenanthrene ring. Reasonable yields for the highly regioselective products are obtained by irradiation in benzene solution. 

Cyclohydrocarbonylation of unsymmetrical amidodiene 29 catalyzed by Rh-BIPHEPHOS complex yielded dehydropiperidine aldehyde 31 as the sole product (Scheme S). The fact that no pyrroline was formed indicates that this reaction was extremely chemo- and regioselective so that the hydroformylation took place at the homoallylic olefin moiety exclusively, yielding the linear aldehyde intermediate 30. 

This above result was only obtained with maleimide as the dipolarophile. With dimethyl fumarate and fumaronitrile, A2-pyrrolines are obtained, probably because of the acidity of the hydrogen atoms a- to ester and nitrile functionalities. Reaction with alkynes produces pyrrole derivatives in good to excellent yields and with aromatic aldehydes leads regioselectively to oxazolidines in moderate yields.263... 

The regioselectivity of the 1,3-dipolar cycloadditions of azides to alkenes is usually difficult to predict due to the similar energies for the transition states which involve either the HOMO (dipole) or the LUMO (dipole). The results of a study which utilized 5-alkoxy-3-pyrrolin-2-ones as dipolar-ophiles in reactions with a variety of aryl azides seemed to reflect this problem the results suggested that the low regioselectivity observed was due to the frontier molecular orbital interactions between dipole and dipolarophile, and not any steric hindrance offered by the 5-alkoxy function <84H(22)2363>. 

Changing the position of the electron-withdrawing group (either an amide or ester) to the C-3 of pyrrole allowed access via regioselective reductive alkylations to the corresponding 4-alkyl-2-pyrrolines 924 (Equation 224) and 925 (Equation 225) in good yields <1998TL3075>. Reduction of 3-substituted pyrroles was more difficult to achieve than that of the 2-substituted isomers. 

Dipolar cycloadditions. Nitrones such as 1 combine with alkenes to form isoxazolidines. Tufariello has employed these 1,3-dipolar cycloadditionS as key steps in the synthesis of several alkaloids. Monosubstituted olefins react with nitrones regioselectively to afford 5-substituted iSoxazolidines thus addition of 2 to 1-pyrroline-l-oxide produces the cycioadduct 3, which serves as an intermediate in a total synthesis of elaeocarpine (4). ... 

The intermediate bicyclic vinyl dihydro triazoles were generally not isolated, as they are unstable. By thermal decomposition, the vinylaziridines were converted to regioisomeric bicyclic pyrrolines 1 and/or 2, with different substitution patterns, depending on the nature of the substituents. Under the same conditions a 1,5-homodienyl shift can take place to give a monocyclic pyrroline 3. Nucleophilic displacement by iodide ion, however, regioselectively cleaves the C-N bond of the aziridine ring, giving 2 exclusively. 

Regioselectivity in a ring closure by internal nucleophilic attack is often puzzling. While the substituent appears to make the difference in equation (57) a similar reaction of a diethynylketone with aryl amines leads to both 5- and 6-rings, i.e. oxo-A -pyrrolines and pyridones - -. The question that arises most frequently here is illustrated by the choice given in equation (58). 

Newer investigations deal with the conversion of a-ketoalkynes to highly functionalized 3,5-substituted 5-hydroxy-3-pyrrolin-2-ones in a regioselective synthesis with KCN catalyzed by tetracyanonickelate(O) formed in situ from the system Ni(CN)2/CO/KCN in alkaline aqueous medium. This study is based on the catalytic hydrocyanation of alkynes in the presence of Ni(CN)4" introduced by Funabiki and co-workers [66]. 

Two new syntheses of racemic mesembrine have been described. In the first, outlined in Scheme 1, an improved synthesis of the penultimate 2-pyrroline (8) was achieved annelation of this afforded ( )-mesembrine (9). The second (Scheme 2) incorporates a regioselective borohydride imide reduction. Investigations on the biosynthesis of mesembrine alkaloids have revealed that a stereospecific protonation occurs at C-7 [see formula (9)] as one of the late stages. ... 

The final example in this section is classed as a 1,3-dipolar addition, as this is the key step in the reaction, although actual formation of the pyrrolizidine ring is by an intramolecular alkylation process. Tufariello and Tette showed that A -pyrroline-N-oxide added regioselectively in a 1,3-dipolar fashion to the dipolarophile to give an isoxazolidine (95) in 80% yield [Eq. (27)]. The pyrrolizidine ring was then formed by hydrogenolysis of the methanesulfonate derivative of 95 in 95% yield. The dehydration and reduction steps were not so efficient, and a mixture of reduction products was obtained. Half of this mixture was ( )-supinidine (96) and the remainder consisted of fully reduced isomeric 1-hydroxymethylpyrrolizidines. 

When reacted with 1-aryl-3,3,3-trifluoropropynes, azomethine ylide 14, generated from the aziridine, provides pyrrolines in high yield, with no regioselectivity. These cycloadducts can be converted into the corresponding pyrroles or pyrrolidines.102... 

The regioselective functionalization of A -pyrrolines at the 2-position by metalation of the derived r-butylformamidine (21) is shown in Scheme 27. Metalation at the 2-position of a pyrrole having an ortho director at the 3-position is readily achieved. Functionalization of a pyrrole at the 3-position by ortho metalation of a 2-substituted derivative is more problematic, with a mixture of 3- and 5-substituted... 

The buUdness of the substituent on the amide nitrogen virtually does not have any effect on the regioselectivity, but it exerts a marked effect on the cyclic/acychc ratio of the products. The effect of the bulky N-substituents is particularly pronounced in the trityl derivative (R=Tr, n=l), since no formation of pyridone 136 was observed. A mixture of open chain linear aldehyde and pyrrolin-2-one 137 was obtained. 

Condensation of addehydes with N-acyl-V -alkylhydrazines affords an incipient azomethineimine capable of cycloaddition to suitable double bonds. The value of the synthesis is indicated by reactions in Scheme 16. Reaction with benzaldehyde shows a marked regioselectivity. Other interesting dipolar additions are shown in Scheme 17. The interm iacy of a diazacyclopenta-dienone in the decomposition of (59) is clearly shown by the trapping experiments. Also reported are adducts of tetracyanoethylene with 3,6-dialkyl-azepines and the Cope rearrangement of the pyrroline oxide (60) to give... 

Maleimides (pyrrole-2,5-diones) can be converted into 3-pyrrolin-2-ones and 5-hydroxy-3-pyrrohn-2-ones by complete or partial reduction of one of the imide carbonyls, respectively. In the case of unsymmetrical substrates, the reaction requires a regioselective reduction of one of the two carbonyls there has been success in this area although some substrates prove to be problematic (1994TL9135,1999TA4469). Nucleophihc additions to maleimides by carbon-based nucleophilics also provide access to 3-pyrrolin-2-ones. 

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