Pyrrolidines Diels-Alder reactions

Intramolecular inverse electron-demand Diels-Alder reaction of iV-propargyl-2-(pyrimidin-2-yl)pyrrolidine provides an alternative route to pyridopyrrolizines. For example, heating of 130 to 170 °C in nitrobenzene affords the cyclized product with the loss of HCN <1992JOC3000> (Equation 9). The above reference includes molecular orbital (MO) calculations on relative reactivities in this series. 

In addition to the reaction of vinylcarbene complexes with alkynes, further synthetic procedures have been developed in which Fischer-type carbene complexes are used for the preparation of benzenes. Most of these transformations are likely to be mechanistically related to the Dbtz benzannulation reaction, and can be rationalized as sequences of alkyne-insertions, CO-insertions, and electrocycli-zations. A selection of examples is given in Table 2.18. Entry 4 in Table 2.18 is an example of the Diels-Alder reaction (with inverse electron demand) of an enamine with a pyran-2-ylidene complex (see also Section 2.2.7 and Figure 2.36). In this example the adduct initially formed eliminates both chromium hexacarbonyl ([4 -I- 2] cycloreversion) and pyrrolidine to yield a substituted benzene. 

For liquid-phase reactions it is known that they may be enhanced by applying higher pressures if the activation volumes are strongly negative, for example, with Diels-Alder reactions. At pressures up to 600 bar (6 x 10 Pa), Benito-Lopez et al. used fiber-based on-line UV-vis spectroscopy to monitor the nucleophilic aromatic substitution of l-fluoro-4-nitrobenzene with a ten-fold excess of pyrrolidine. ... 

Platts and Tomkinson reported a detailed quantitative study of the iminium ion catalysed Diels-Alder reaction between cyclopentadiene and cinnamaldehyde catalysed by trifluoromethyl pyrrolidine salt 182-HPFg [227]. This combination of secondary amine, co-acid and dienophile allowed the isolation and structural elucidation of the reactive iminium ion intermediate. As a result it was possible to... 

Similar reactivity and regioselectivity is observed with the parent system, 1,2,4-triazine (eq 2) Reduction of this process to a catalytic Diels-Alder reaction with in situ generation of the pyrrolidine enamine does... 

Nucleophilic additions were studied using the same TSIL with pyrrolidine and thiophenol as models. As with the Diels-Alder reaction above, the reaction gave the required adducts which were then transesterified to give the final products. Heck coupling catalyzed by a transition metal and the Stetter reaction, Scheme 30, to prepare 1,4-dicarbonyl compounds were also studied by the same group using similar TSILs. 

The iV-aminopyrrole - benzene ring methodology has been applied to a synthesis of the 9,10-dihydrophenanthrene juncusol (218) (81TL1775). Condensation of the tetralone (213) with pyrrolidine and reaction of the enamine with ethyl 3-methoxycarbonylazo-2-butenoate gave pyrrole (214). Diels-Alder reaction of (214) with methyl propiolate produced a 3 1 mixture of (215) and its isomer in 70% yield. Pure (215) was reduced selectively with DIBAL to the alcohol, reoxidized to aldehyde, and then treated with MCPBA to generate formate (216). Saponification to the phenol followed by O-methylation and lithium aluminum hydride reduction of the hindered ester afforded (217), an intermediate which had been converted previously to juncusol (Scheme 46). 

Pyrrolidines and pyrrolidinones can be synthesized on insoluble supports by intramolecular carbometallation of alkenes (Entry 1, Table 15.4) and by Ugi reaction of support-bound isonitriles with amines and 4-oxo acids (Entry 4, Table 15.4). In Entry 5 in Table 15.4, the pyrrolidinone ring is formed by intramolecular Diels-Alder reaction of a furan with a fumaric acid derivative. 2-Pyrrolidinones have also been prepared by treatment of resin-bound O-mesitylenesulfonyl cyclobutanone oximes with... 

Ethyl l,2,4-triazine-3-carboxylate (25) underwent a Diels-Alder reaction with ferf-butyl 4-(pyrrolidin-1 -yl)-1,2,3,4-tetrahydropyridine-1 -carboxylate (24) to give ethyl 6-ferf-butoxycarbonyl-5,6,7,8-tetrahydro-2,6-naphthyridine-l-carboxylate (26) as a minor product (CHC13, 20°C 8%).941... 

By using a sequence involving regio and diastereoselective reduction of the adducts (it only affects the carbonyl far away from the sulfinyl group, yielding y-oxygenated lactones), stereoselective AT-acyliminium addition, and retro Diels-Alder reactions as the main key steps, Koizumi et al. have synthesized chirally functionalized pyrrolidines [96, 97], pyrrolizidines [98], and indolizidines [98-100], depicted in Scheme 56. The milder conditions required for the evolution of the adducts derived from furan preserve the chirality of the substrates. 

A dihydro-derivative (4) of strobiline (M+ 193) was also obtained. In the mass spectrometer, the pyrrolidine ring is opened to give fragments of m/z 165 and 164 (base peak), followed by a retro-Diels-Alder reaction to give fragments of m/z 137 and 136, respectively. The location of the two additional hydrogen atoms was deduced from the relative u.v. extinctions of (3) and (4), which is consistent with the dihydro-y-pyrone skeleton in the latter compound. This was confirmed by 3H n.m.r. spectra that showed no vinylic protons. 

The generation of an 1,2-oxazine 4-1 by hetero Diels-Alder reaction is a transformation which opens a versatile array of highly functionalised acyclic and cyclic structures. Thus, pyrrolidine derivatives 4-2, amino alcohols 4-3 and aza sugars 4-4 are easily available from these cycloadducts. Cyclic dienes, e.g. 4-5 are converted into bicyclic adducts 4-6 representing straightforward intermediates for aminocyclitols 4-7 (Fig. 4-1). 

Cyclic nitrones generated by [4+ 2]-cycloaddition of nitroalkenes undergo various, synthetically very valuable reactions. Thus, Denmark et al. have developed an elegant access to different enantiopure, 3- and 3,4-substituted pyrrolidine derivatives by reductive ring contraction of the cyclic nitrone resulting from a hetero Diels-Alder reaction [389,390]. Upon reaction of -2-nitrostyrene 4-51 with the chiral enol ether 4-52 in the presence of the bulky Lewis acid MAPh (4-53), three diastereomeric cycloadducts 4-54, 4-55 and 4-56 were formed. Hydrogenolysis of the main product 4-54 yielded the desired pyrrolidine 4-57 in excellent optical purity and allowed nearly quantitative recovery of the chiral auxiliary (Fig. 4-12) [391]. It is noteworthy that the nature of the Lewis acid catalyst, especially its steric demand, decisively influences the stereochemical course of such cycloadditions [392]. 

The final series of five procedures presents optimized preparations of a variety of useful organic compounds. The first procedure in this group describes the preparation of 3-BROMO-2(H)-PYRAN-2-ONE, a heterodiene useful for (4+2] cycloaddition reactions. An optimized large scale preparation of 1,3,5-CYCLOOCTATRIENE, another diene useful for [4+2] cycloaddition, is detailed from the readily available 1,5-cyclooctadiene. Previously, the availability of this material has depended on the commercial availability of cyclooctatetraene at reasonable cost. A simple large scale procedure for the preparation of 3-PYRROLINE is then presented via initial alkylation of hexamethylenetetramine with (Z)-1,4-dichloro-2-butene. This material serves as an intermediate for the preparation of 2,5-disubstituted pyrroles and pyrrolidines via heteroatom-directed metalation and alkylation of suitable derivatives. The preparation of extremely acid- and base-sensitive materials by use of the retro Diels-Alder reaction is illustrated in the preparation of 2-CYCLOHEXENE-1.4-DIONE, a useful reactive dienophile and substrate for photochemical [2+2] cycloadditions. Functionalized ferrocene derivatives... 

When chiral thiocarbonyl S-oxides derived from (S)-proline, prepared from the appropriate l-(trimethylsilylalkylsulfonyl)-2-(alkoxymethyl)pyrrolidine, are subjected to Diels-Alder reaction with 2,3-dimcthyl-l,3-butadiene, the 2-substituted 2-[(2-alkoxymethyl-l-pyrrolidinyl)sul-fonyl]-3,6-dihydro-4.5-dimethyl-2/f-thiopyran 1-oxides 10A and 10B are formed as a mixture of diastereomers. Their ratio depends on the nature of the substituents R1 and R2 as well as on the reaction temperature. The diastereomeric excess values, determined by H NMR in the presence of Yb(tfc)3 or by HPLC, vary from 0 to 41 % 84. 

Pyridine annelation.1 1,2,4-Triazine can function as a reactive azadiene in Diels-Alder reactions with enamines, particularly pyrrolidine enamines, to form substituted pyridines. 

The parent pyrido[2,3-d]pyridazine has been used as an azadiene in inverse-electron-demand Diels-Alder reactions with pyrrolidin-l-ylalkenes. After the aromatization of the intermediate dihydroquinolines by elimination of pyrrolidine this represents a route to 6,7-disubstituted quinolines.155... 

---