Pyrrolizines cycloadditions

Cycloaddition of the tetrahydropyrrolopyridine-2-carbaldehyde 153 with electron-depleted alkenes in the presence of a base leads to products, the 111 NMR spectra of which are consistent with their formulation as 154 rather than 155. In the case of the acrylonitrile adduct, the initially formed pyrrolizine reacts with another molecule of acrylonitrile to give a cyanoethyl-substituted derivative <1998CHE1418> (Scheme 43). 

Pyranopyrrolothiazoles can be prepared in a similar way to certain pyrano- and thiopyrano-pyrrolizines and pyrrolizinopyridines as discussed earlier. Thus, thiazolidine-4-carboxylic acid reacts with the aldehyde 179 to give a 2 1 mixture of 180 and 181 (Equation 16). This reaction is a 1,3-dipolar cycloaddition of the alkene to the 1,3-dipole formed from reaction of the amino acid amine with the aldehyde <1988T4953, 1990T2213>. The alkyne analogue of 179 is similarly converted into 182 (Equation 17). 

Cycl[3.2.2]azines may also be obtained by the cycloaddition of a bifunctional three-carbon unit to a 3//-pyrrolizine. Vinamidinium salts have been used for this purpose <1984CB1649>, although the reactions require the use of a strong base (sodium hydride) and extended reaction times. They appear to proceed via a stepwise mechanism, since intermediates (the conjugated enamines 354 and 355) have been isolated in certain cases (Scheme 94). 

Dipolar cycloadditions of 2-tert-butoxycarbonyl-1 -pyrroline A -oxide (627) with several chiral acrylamides (634a-f) (Scheme 2.276) followed by hydrogenolysis of cycloadducts (635) and (636) has been used in the synthesis of enantiopure tert-butyl (2RJ R)- and (2.S. 7a.S )-2-hydroxy-3-oxo-tetrahydro-l II -pyrrolizine-7a(5// )-carboxylates, useful intermediates for the synthesis of Gly-(s-cis)Pro dipeptide mimetic (790). 

The 1,2-dihydropyridines are also known to undergo [2 + 2] cycloadditions of the enamine double bond with alkynes (74JCS(P1)2496). The products of these reactions are azocine derivatives such as (259), which, after removal of the A-protecting group, have been used as intermediates in pyrrolizine synthesis (Scheme 47) (77JOC2903). 

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 ... 

Diphenylmethylene-3i/-pyrrolizine (36) underwent cycloaddition with DMAD to give 37, which could be reduced to 38.B0e... 

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... 

The only reaction reported between 3//-pyrrolizine (1) and a carbene (or carbenoid) is that involving n-butyllithium and dichloromethane.135 One of the products is formed by cycloaddition (Section III,B,6), one by ring opening (Section III,B,7), and the third according to Eq. (4). The latter two products are viewed as derived from the carbenoid 272, and the proposed route to indolizine (273) is shown in Eq. (4). 

The known cycloaddition reactions of 3H-pyrrolizines and of pyr-rolizinones involve only one double bond in the molecule azafulvenes and... 

Triazines are trimers of unstable imines and may serve as imine precursors. Treatment of trimer of A1-pyrrol ine with a trimethylsilylmethyl triflate gives trimethylsilylmethyl-imonium triflate which may be desilylated by cesium fluoride, providing an ylid suitable for 1,3-dipolar cycloaddition reactions and constmction of the hexahydro-pyrrolizine framework.386 This strategy has been applied to prepare trachelanthamidine, supinidine and isoretronecanol alkaloids.387... 

Intramolecular nitrilimine cycloadditions gave new pyrazolo[4,3-c]pyrrolizines 50 <04H(63)1423>. The syntheses of 5-substituted ethyl 3-oxo-2/7-pyrazolo[4,3-c]pyridlne-7-carboxylates 51 <04H(63)609> and 5//-pyrazolo[4,3-c]quinolines 52 <04H(63)1883> have been described. Ring-closure reactions of 3-arylhydrazonoalkyl-quinolin-2-ones gave rise to 1-aryl-pyrazolo[4,3-c]quinolin-2-ones <04JHC681>. 

Cycloaddition reactions of 3H-pyrrolizines involve only the 1,2-double bond azafulvenes and pyrrolizinimines can act as 87t-electron donors in the formation of a new ring linking C-3 to C-5. 

Azacyclazines (59) have been obtained by [8tu + 27t]cycloaddition of imino-3H-pyrrolizines (58) with DMAD <88H(27)1465>. 

Cycloaddition reactions have been carried out with Vilsmeier bases of pyrroles. Thus reaction of (180) with dimethylacetylene dicarboxylate gave pyrrolizines (181) and 3a-azaazulenes (182) in a non-concerted reaction <74JHC811>. In a closely related reaction, (183) was obtained from the Vilsmeier base with phenyl isocyanate <76H(4)i28i>. 

MO-LCAO-MNDO method allowed calculation of proton affinities and dipole moment <90Mi 8ii-02>. A MINDO/1 calculation on the ylide (13) predicted more ready addition of DMAD to position 6 than to position 2, thus rationalizing the proportion of pyrrolopyrimidines (14) and (15) formed in cycloaddition (Equation (1)) <86H(24)3473> (see also 8.11.9.2.2). In partly reduced systems, Molecular Orbital Package (MOPAC) heats of formation of pyrrolizine derivatives from pyrrolooxazinone (16) and alkynes <92JA593>, and deprotonation preference in pyrrolopyrazinedione (17) were calculated <79JA1885>. 

The [8 -I- 2] cycloaddition of 3-imino-3/f-pyrrolizine derivatives with DMAD has been also used to prepare 5-aza[2,2,3]cyclazines. Treatment of (538) with DMAD gave the dimethyl 4-cyano-3-methylthio-5-aza[2.2.3]cyclazine-6,7-dicarboxylate (539) in good yield. The 3-amino-5-aza-[2.2.3]cyclazine derivatives (541) have also been prepared from the corresponding l-amino-3-imino-377-pyrrolizine derivatives (540) (Equation (17)). 

The solvent dependence of this cycloaddition is remarkable. The formation of 5 requires an aprotic medium, whereas in a protic medium (e.g. CH3OH), the thieno[2,3-Z ]-5,6,7,7a-tetrahydro-l -pyrrolizine 10 is formed. As the rate of product formation is the same in both media, it is plausible that the same primary product 8 of a dipolar [2+2] cycloaddition is formed first. The reaction then proceeds to give 5 in the nonpolar medium and 10 via the ylide 9 in the polar medium [19]. 

Yebdri and Texier studied cycloaddition reactions of the well-known munch-none 153 (derived from proline and acetic anhydride) with methyl propiolate and methyl 3-phenylpropiolate to give mixtures of pyrrolizines 154 and 155, respectively (Fig. 4.55). 

Molteni G (2004) Synthesis of the new pyrazolo[4,3-c]pyrrolizine skeleton via intramolecular nitrilimine cycloaddition. Heterocycles 63 1423-1428 52. Padwa A, Hertzog DL et al (1994) Studies on the intramolecular cycloaddition reaction of mesoionics derived from the rhodium(II)-catalyzed cyclization of diazoimides. J Org Chem 59 1418-1427... 

Tominaga, Y, Y. Matsuoka, and A. Hosomi 1988. A new synthesis of 5-aza[2.2.3]cycla-zines by [8-r2]cycloaddition of 3-imino-3//-pyrrolizines with dimethyl acetylenedicar-boxylate. Heterocycles 27 (12) 2791-2793. 

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