Dihydropyrroles, preparation

A/ -Methoxycarbonyl-2-pyrroline undergoes Vilsmeier formylation and Friedel-Crafts acylation in the 3-position (82TL1201). In an attempt to prepare a chloropyrroline by chlorination of 2-pyrrolidone, the product (234) was obtained in 62% yield (8UOC4076). At pH 7, two molecules of 2,3-dihydropyrrole add together to give (235), thus exemplifying the dual characteristics of 2,3-dihydropyrroles as imines and enamines. The ability of pyrrolines to react with nucleophiles is central to their biosynthetic role. For example, addition of acetoacetic acid (possibly as its coenzyme A ester) to pyrroline is a key step in the biosynthesis of the alkaloid hygrine (236). 

Dihydropyrrole triflate 55, which was mentioned in Section 2.3.2, undergoes facile Stille couplings to yield, for example, 2-acylpyrrole derivative 116 after hydrolysis. Also prepared in these studies were the corresponding 2-vinyl (77%) and 2-phenyl (56%) derivatives [53, 81]. 

Singh and Han [60] have reported the preparation of another dihydropyrrole by using a N-Cbz derivative obtained by decarboxylative amidation (Scheme 9.27, results line 1) as starting material. N-Alkylation with allyl bromide followed by RCM (Grubbs II catalyst) furnished the dihydropyrrole in excellent yield (95%). Lee et al. have similarly transformed the amination product (Table 9.2, entry 21) into a variety of N-heterocycles [54]. 

Disubstituted dihydrofurans and dihydropyrans were prepared via allylic etherification [68] in a similar manner to dihydropyrroles (cf Section 9.4.6). Thus, diaste-reoisomeric ethers were generated by the reaction of cinnamyl tert-butyl carbonate with the copper alkoxide prepared from (Rj-l-octen-3-ol, depending on which enantiomer of the phosphoramidite ligand was used (Scheme 9.39). Good yields and excellent selectivities were obtained. RCM in a standard manner gave cis- and trans-dihydrofuran derivatives in good yield, and the same method was used for the preparation of dihydropyrans. 

Scheme 6.86 Typical 2-aryl-2,5-dihydropyrrole derivatives prepared with the asymmetric [3 + 2] cycloaddition between buta-2,3-dienoic acid ethyl ester and various DPP-protected (hetero)aromatic imines catalyzed by phosphinothiourea 75.

Dihydrooxazin-2,3-diones can be prepared by Baeyer-Villiger oxidation of dihydropyrrole-2,3-diones (Equation 51, Table 9). 

Although direct oxidation is sometimes possible (54CCC282), N- or S-oxides and dioxides are normally prepared by indirect routes. 3,6-Dihydro-l,2-oxazines can be reduced catalyti-cally to their tetrahydro derivatives, but zinc and acetic acid cause ring fission to 4-aminobut-3-enols which cyclize to dihydropyrroles (54MI22700). 

A variety of five-membered nitrogen heterocycles can be prepared efficiently by inter- or intramolecular addition/cyclizations of sulfonamide anions with alkynyliodonium salts. The intermolecular variant employs the combination of the amides 172 or anilides 174 with propynyl(phenyl)iodonium triflate (Scheme 65) [131,132]. The yield of dihydropyrroles 173 in this cyclization is extremely sensitive to the nature of the protective group P the tosyl group in 172 proved... 

Scheme 2 Rapid preparation of functionalized dihydropyrroles using RCM reaction...

This method provided an efficient access to cyclopentylamine-containing alkaloid skeleta. Similarly, by using 1-propynyl phenyliodonium triflate and various tosyl-amide anions, the preparation of dihydropyrroles and indoles was reported [72]. 

RCM reactions are most frequently employed in the synthesis of 2,5-dihydrofurans as well as dihydropyrrole derivatives . Likewise, RCM provides the most general approach to 3,6-dihydropyrans . In a specific example, dihydropyran 127 bearing a chiral oxacyclic diene can be constructed via enyne metathesis of the chiral ether 126 (Scheme 68) <2002T5627>. The analogous tetrahydropyridine derivatives are prepared by a similar RCM procedure . 

Not all heterocyclic methylene bases give spiropyrans (at least under the usual conditions). l,3,4,5,5-Pentamethyl-2-methylene-2,5-dihydropyrrole (69)77 did not condense with 5-nitrosalicylaldehyde to give any photochromic material.7 However, l-methyl-2-methylene-3,3,4,5-tetraphenyl-2,3-dihydropyrrole (70), prepared by reaction of methyllithium with 1 -methyl-3,3,4,5-tetraphenylcrotonolactam, did condense with 5-nitrosalicylaldehyde to give a product exhibiting reverse photo-chromism the unexposed form was red and the exposed form yellow. This behavior probably represents a trans to cis isomerization of the open form 7... 

The synthesis of )-A -BOC-2-hydroxymethyl-2,5-dihydropyrrole )-923 with ee up to 98% was achieved by its irreversible acetylation catalyzed by Pseudomonas fluorescens lipase (Scheme 179) <1998TA403>. Precursor ( )-922 for compound 923 can be easily prepared from commercially available pyrrole-2-carboxylic acid 921 by Birch reduction, followed by esterification and reduction according to literature procedure <1996JOC7664>. 

Preparation of Fused Vinylaziridines and Dihydropyrroles by Intramolecular 1,3-Dipolar Cycloaddition of Azidodienes... 

The ambident 1,3-dipolar 2-arylthiocarbamoyl imidazolium salts 859 are readily prepared from the corresponding carbenes and phenyl isothiocyanate as crystalline solids. Reaction of 859 with DMAD leads to the formation of spiro[imidazoline-2,3 -dihydrothiophenes] 860, indicating that 859 acts as a C-C-S dipole. In contrast, the reaction of 859 with ethyl propiolate proceeds slowly to form spiro [imidazoline-2,3 -dihydropyrroles] 861, indicating a C-C-N dipolar reaction being thermodynamically driven (Scheme 211) <2006CC1215>. 

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