Pyrrolizine-3-ones

Typical NMR data were compiled in CHEC-II(1996) <1996CHEC-II(8)2> for 3.77-pyrrolizine 1, its lithium salt, the pyrrolizin-3-one 2, and its regioisomer (pyrrolizin-2-one). More recently, Kissounko et al. <1998JOM(556)145> reported the H chemical shifts of the parent pyrrolizine anion and anion 21a as well as those of their silylated or stannylated derivatives 22-26. 

Unlike with sodium borohydride (see Section 11.01.5.2), pyrrolizin-3-one 2 reacts with lithium aluminohydride mainly as an amide. No conjugate addition occurs, and only the reductive lactam cleavage takes place to give stereoselectively the (Z)-allylie alcohol 77. Similarly, benzo-annulated pyrrolizin-3-one 17 gives the corresponding benzylic alcohol 78. The same reactivity was observed with organometallics such as methyllithium which gives exclusively the tertiary (Z)-allylic alcohol 79 (Scheme 7). 

Benzo-annulated pyrrolizin-3-ones 129 were synthesized in good yields from A-o-benzoylated pyrroles 128 by an intramolecular Heck reaction (Scheme 22) <2001JME4615>. 

As mentioned in CHEC-II(1996) <1996CHEC-II(8)16>, 3//-pyrrolizin-3-one 2 and many other substituted analogues were synthesized by FVP of Meldrum s acid derivatives 189 via the in. ( ////-generated pyrrol-2-ylmethylidene ketenes 190 which cyclize by an intramolecular A-acylation (Scheme 43) <1997J(P1)2195, 2000J(P1)3584>. 

Pyrrolizin-3-ones may also be obtained by FVP of 3-(pyrrol-2-yl)propenoate esters such as 62, 69, and 74. Also, benzo-annulated pyrrolizinone 17 was obtained by FVP of 2-(tf-methoxycarbonyl phenyl (pyrrole <1999J(P1)2047>. FVP of alcohols 77, 78, and 79 led to 3//-pyrrolyzine derivatives 1, 192, and 193, respectively, in good yields (66-95%). These transformations proceed by elimination of water and subsequent electrocyclization of the in situ-generated cumulene (Scheme 44) <1999J(P1)2049>. 

Pyrrolizin-3-ones 75 were synthesized in one step from 2-formylpyrrole derivatives 228 and hydrocinnamoyl chloride in the presence of 4-dimethylaminopyridine (DMAP) and T,iV-diisopropylethylamine (DIPEA), in low to moderate yields (Scheme 57) <2002TL3673>. 

FVP of the aza-bicyclic sulfone 236 at 700°C and 8xl0 2mbar resulted in 3//-pyrrolizin-3-one 237 <2004TL3889>. At same temperature and lower pressure, that is, 4 x 10-2 mbar, the same sulfone affords a mixture of 237 and vinyl pyrrole 238 in 44% and 27% yield, respectively. The latter was the only product obtained when the thermolysis of 236 was performed in a sealed tube in sulfolane. This result and others led Pinho e Melo et al. <2005JOC6629> to suggest the plausible eight-step mechanism shown in Scheme 61. 

Pyrrolizin-3-ones, 21 151 Pyrrolopyrrole pigments, 19 424 PYRUV 5-enoZ-Pyruvylshikimate synthase inhibitors, 13 300 Pyruvic acid... 

When treated with lithium diisopropylamide, the unsubstituted simple bicyclic y-lactam, hexa-hydro-3//-pyrrolizin-3-one (1), furnishes the corresponding enolate which reacts with (halo-methyl)benzenes to give the a-alkylation products with rather poor diastereoselectivity10. The major product 2 has cis configuration. Equilibration of the product with base gives a 72 28 mixture in favor of the frans-diastereomer10. 

Intramolecular condensation of either 2-formylpyrrole or 2-benzoylpyrrole with phenacyl bromide gave pyrrolizin-3-ones 52a39 and 52b,40 respectively. JV-Acylpyrroles presumably are intermediates. Similarly, 5-alkoxy-2-for-mylindoles (53) were converted to benzopyrrolizines (54) by treatment with methyl vinyl ketone in the presence of trimethylbenzylammonium hydroxide in dioxane 41 From diketone 55 a mixture of pyrrolizines [56a (25%) and 56b (11%)] was obtained.42... 

Acids 93a-d were cyclized to 3f/-pyrrolizin-3-ones in yields similar to those obtained for 92. Thus the parent (94a) could be obtained either from 93a or 93b 33 the synthesis of 94c was similar.64... 

Pyrrolizin-3-one (94a) is formed in 98% yield by flash thermolysis of 96, which was obtained from 2-formylpyrrole and Meldrum s acid. A possible ketene intermediate then reacts in an intramolecular acylation.66... 

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... 

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... 

McNab has reported 13C-NMR data for 3ff-pyrrolizin-3-one without assignment.66 Quaternary carbon signals are at 165.45 (presumably the carbonyl group)and at 136.75 nonquarternary signals occur at 138.06,121.82, 118.68,115.25, and 111.42 ppm. 

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... 

Not surprisingly, the anion derived from 3//-pyrrolizine is a stronger nucleophile than compound 1 itself. Thus the anion reacts with deuterium oxide to give 31//,32//-pyrrolizine, but attempts at further enrichment give mixed deuteriopyrrolizines.83,115 The anion reacts with ketones to give azafulvenes such as 248 and 268.43,115 It seems possible that the reported formation of the oxime of 3//-pyrrolizin-3-one (269) from 3//-pyrrolizine and... 

The frontier orbitals of 4-azaazulen-5-one (6) have been compared with those of pyrrolizin-3-one (9) (78CB2407). 

Infrared (IR) carbonyl frequencies of 4-azaazulenones 6 and 8, pyrrolizin-3-one (9), and partially hydrogenated derivatives have been discussed in terms of -interactions and ring size (61JOC4712 78CB2407). 

The thermal rearrangement of 1-substituted pyrroles to 2- (and 3-) substituted isomers by sequential [l,5]-shifts has been known and studied extensively <1966JA3671, 1976S0281, 1988J(P1)339>. It was also shown that pyrrol-2-yl)acrylate 16 and related compounds undergo concerted elimination of alcohols under flash vacuum pyrolysis (FVP) conditions to give pyrrolizin-3-one 18 by electrocyclization of an intermediate 17 (Scheme 7) <1997J(P1)2195>. 

The isomeric precursor 37 cyclizes efficiently under the same conditions to give the pyrrolizin-3-one 39 (via [1,5]-sigmatropic shift of the phenyl group, regiospecifically to the 5-position, followed by elimination of methanol to generate the ketene 38 and its electrocyclization to product 39) (Scheme 11) <2007ARK85>. 

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