3H-Pyrrolizin

Das bei der Thermolyse von 7-Azido-3-phenylthio-, 7-Azido-3-silyloxy- oder 7-Azido-3-(l-ethoxy-ethoxy)-l,3-heptadien entstehende Nitren geht eine intramolekulare (doppel-te) Cycloaddition ein unter Bildung von 1-Phenylthio- (50-62%), l-(tert.-Butyl-dimeihyl-silyloxy)- (39%) bzw. I-(2-Ethoxy-ethoxy)-5,6,7,7a-tetrahydro-3H-pyrrolizin (55%) ne-ben anderen Produkten2 ... 

Cyclazines (229) are stable aromatic compounds, the synthesis of which may involve indolizines, 3H-pyrrolizines or pyridines. Their chemistry has been investigated extensively. 

A base-catalyzed cyclization of esters 57 gave a mixture of 3H-pyrrolizine esters (58a and 58b).14,43 The isomers were separated and the dependence of the ratio of isomer 58a to isomer 58b on the conditions of cyclization has been investigated.44 Generally the isomer with the electron-attracting group in the pyrrole ring seems to be the more stable isomer (see Section III). 

Reaction of 2-acylpyrroles with a series of allylphosphoranes gave 3H-pyrrolizines. A proposed mechanism is based on the observation that 2-formylpyrrole (105a) and phosphorane 106 (R1 = H, R2 = Ph) gave pyrryl-butadiene 107, which could not be cyclized70 (see Scheme 7). Rules governing the composition of mixtures (108 and 109) are treated in Section III. 

A direct synthesis of 3H-pyrrolizin-3-one derivatives has been effected. Reaction of 2-benzoylpyrrole with ylides 148 gave the 3H-pyrrolizin-3-one 149 9 ,92 analogous reaction of 2-formyl pyrroles could be achieved with... 

From 2-acylpyrroles and keteniminophosphorane (151), 3H-pyrrolizin-3-imines (152) are obtained in 20-50% yield.91,95... 

Cycloaddition reactions have been carried out with corresponding bases of Vilsmeier salts of pyrroles. Thus reaction of 153 with dimethyl acetylenedicar-boxylate gave pyrrolizines 154 and 3a-azaazulenes 155 in a nonsynchronous reaction. The structure of 3H-pyrrolizine 154a was proved by X-ray analysis.96 In a closely related reaction, pyrrolizinones 156 and 157 were obtained from the corresponding Vilsmeier salts with phenyl isocyanate.97 Reaction of 2-p-nitrobenzoylindolin-3-one (158) with methyl acetoacetate gave the benzopyrrolizinone (159).5 7... 

Influences of substituents on the positions of isomeric equilibria that have been calculated116 by the HMO route do not agree with experimental findings (see Section III,B,1). A correlation of the acidity of 3H-pyrrolizine(l)with the difference in HMO delocalization energies between the pyrrolizine anion and the neutral molecule has been attempted but showed limited success.115... 

Protonation of 3H-pyrrolizine (1) takes place at positions 2 and 5, yielding the immonium salts 193 and 194, respectively, in approximately equal amounts (see Section III,B,4). From HMO calculations, however, 193 is more stable than the cross-conjugated isomer 194.116... 

UV/Visible Spectra of Substituted 3H-Pyrrolizin-3-ones and Related Derivatives... 

The H-NMR shifts and coupling constants for unsubstituted and substituted 3H-pyrrolizines have been grouped in Table VI.125-127 The spectral data for 3//-pyrrolizin-3-ones are in Table VII, and those of lH-pyrrolizin-1-ones and related compounds in Table VIII. There are no examples of pure... 

The most common feature of the few published spectra for 3H-pyrrolizines is a strong M + or (M — 1)+ peak. The only series of similar compounds where data are available are the ketones 208a-e.122,123 All show loss of the group R and of the group RCO either may give the base peak. Phenylthiopyrrolizine 209 has its base peak M+ and substantial peaks at 180 (M — SH) and at 104 (M - C6HsS).90... 

The recorded fragmentation peaks for 3H-pyrrolizin-3-one (94a)66121 are due to loss of CO and then of HCN. A series of 2-substituted pyrrolizin-3-ones (95a-d) shows fragmentations similar to those of the acylpyrrolizines with loss... 

Okamura and Katz have determined the pKa of 3H-pyrrolizine by measuring the rate of exchange of its protons with 5 M D20 in dimethyl-formamide containing 1 M triethylamine.115 The value of 29 seems surprisingly high compared with those of indene (18.2), cyclopentadiene (15), and fluorene (22.8). 

The l-amino-3H-pyrrolizines are potentially tautomeric. Whereas the 1-isopropylamino derivative 227 is reported to have the 3-imino structure, the 1-benzyl derivative is said to favor the 3-amino form (228).67... 

Protonation of lH-pyrrolizin-l-ones appears to take place on oxygen (see Sections III,A,2 and III,A,4). The other derivative of type 258 is the Vilsmeier formylation intermediate from l-chloro-3H-pyrrolizine, the perchlorate... 

Vilsmeier formylation has attracted much attention as a route to cyclazines (see Section III,B,6). Jessep and Leaver have obtained the Vilsmeier salt 263 from 1 by using dimethylformamide and phosphoryl chloride at — 65°C, but the formylpyrrolizine was very unstable, and a second Vilsmeier reaction has not been achieved.128 The salt 263 could be converted to the 3,5-bisaldehyde equivalent 264a by treatment with dimethylthioformamide and acetic anhydride. Flitsch et al. prepared l-chloro-3H-pyrrolizine and treated it in situ at — 60°C with the Vilsmeier reagent to obtain the chloro derivative 259 of compound 263. 7 They also obtained the bis(dimethylaminomethylene) derivative 264b and, at room temperature, the tris(dimethylaminomethylene) derivative 265, which was hydrolyzed to give the dialdehyde 266. Reactions... 

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