An Expedient Synthesis of Pyrrole Derivatives by Reaction of Lithiated Methoxyallenes with Imines

Abstract

Addition of lithiated methoxyallene 2 to imines provided the expected allenyl amines in good yield. These could be cyclized with base or with silver nitrate to a variety of 2,5-dihydropyrrole derivatives. Selected examples describe their conversion to pyrrolidin-3-ones or 3-methoxypyrroles. Most importantly, this [3+2] cyclization method could also be applied to the synthesis of 2,5-disubstituted derivatives such as 26-28 and also to the preparation of the enantiopure compound 23.Syntheses of pyrrole derivatives are of great importance due to their presence in numerous biologically active compounds. 2 Therefore, many routes leading to this class of heterocycles have been developed. 3 In addition, certain electron-rich pyrrole derivatives are of interest because of their redox behaviour and their ability to provide polypyrroles. 4 Lithiated methoxyallene 2 is an extremely valuable building block for the synthesis of oxygen and nitrogen heterocycles. 5 With carbonyl compounds it provides furan derivatives after cyclization, 6 whereas its reaction with nitrones leads to 1,2-oxazines. 7 Surprisingly, no additions to simple imines have been reported, 8 which should furnish pyrrole derivatives. A recent publication describing reactions of 2 with SAMP-hydrazones providing enantiopure 3-methoxy-2,5-dihydropyrrole derivatives 9 prompts us to report our results with various imines. 10 Lithiated methoxyallene 2 was generated by the standard procedure employing n-butyllithium at -40°C, and after addition of N-tosylimine 1 11 followed by aqueous workup and purification the primary adduct 3 was obtained in 67% yield (Scheme 1). This intermediate could be hydrolyzed with acid to afford an a,ß-unsaturated ketone 10 or, more interestingly, converted into a-amino ester 4 by ozonolysis. 12In analogy to the behaviour of the carbonyl adducts 6 cyclization of 3 employing 0.15 equivalents of potassium tert-butoxide in DMSO furnished the desired pyrrole derivative 6 in 84% yield. Since an excess of base converts 6 into 5, the isomerization 3AE6 is better performed by using of 0.27 equivalents of silver nitrate in acetone 13 which gave a yield of 93%. 14 Cyclization of 3 and elimination of toluene sulfinate from intermediate 6 proceeded by use of 1.5 equivalents of KOtBu and furnished 3-methoxy-2-phenylpyrrole (5) in 71% yield. This compound was also formed by heating the primarily obtained lithium salt of 3 in DMSO. An obvious subsequent transformation of 2,5-dihydropyrrole derivative 6 is the hydrolysis of its enol ether moiety; treatment of 6 with 2N aqueous sulfuric acid provided pyrrolidinone 7 in 96% yield. Analogous experiments were successfully performed with N-tosyl imines derived from pivalaldehyde and cinnamyl aldehyde. Having established that highly reactive imines such as 1 behave similarly to carbonyl compounds, we studied less reactive N-aryl and N-alkyl imines. Scheme 2 presents selected examples of the additions of 2 to readily available imines 8, 10, 12, 15, and 17. Cyclization either with silver nitrate or under basic ...

Silver and platinum-catalysed addition of O–H and N–H bonds to allenes

“…Fürstner et al have used this methodology in several syntheses of natural products containing furan-derivatives, such as amphidinolide X and Y (Scheme 18a), 21 and more recently 40 Leiodolide B (Scheme 18b). 22 In their elegant approach, they use the transfer of chirality from the corresponding allenes as a relay to obtain the desired stereochemistry in the highly substituted tetrahydrofurans in the early stages of the syntheses.…”

“…40 This chiral counterion strategy has also been employed in gold chemistry, and high enantioselectivities (up to 99% ee) have been obtained in the intramolecular hydroxylation and hydroamination of allenes. 33 In reported examples, chiral silver salts of Binol-equivalents of silver were needed in the more challenging …”

“…Many metals have been studied in these reactions and some reviews have already covered this reactivity with different type of 40 unsaturated compounds. 1 The purpose of this review is to give a state-of-the-art account of the reaction on allenic systems using silver and platinum complexes with oxygen and nitrogen nucleophiles from the first examples to the latest features of this useful transformation.…”

“…35 Very recently, Wan et al have reported the silver-catalysed cyclisation of allenyl-tosylamides containing an acyloxy group for the synthesis of vinyloxazoles (Scheme 24). 29 In this case the nucleophile is in β-position, and instead of the 5-endo cyclisation, the 5-exo is favoured with attack of the amidic oxygen onto the 40 central carbon of the allene. Although this type of attack to the central carbon is less common, the elimination of both, the sulfonyl and the acyloxy group, favour the formation of the 5-memebered ring in this case, to generate the final product.…”

“…In the presence of silver salts, the endo cyclisation with attack to the terminal carbon of the distal double bond is preferred with α-and β-amino allenes, 40 while γ-and δ-amino allenes favour the exo-attack to the terminal carbon of the proximal double bond. In the same year, Reissig et al 40 reported the synthesis of α-60 aminoallenes by reaction of methoxyallenes and imines, and then submitted them to reaction with AgNO 3 in acetone.…”