Pyrrolidine, ruthenium-catalyzed

From the results presented here, one could get the impression that such allenes with hydroxyl groups in the substituents will always form heterocydes in the presence of transition metal catalysts, but in the presence of other substrates even allenylcarbinols can react to give different products. Examples are the rhodium-catalyzed reaction of allenylcarbinol 78 and phenylacetylene 79 to 80 [42], the palladium-catalyzed reaction of 81 and pyrrolidine 82 to 83 [43] and the ruthenium-catalyzed reaction of 78 and 79 to 84, an isomer of the rhodium-catalyzed reaction of the same substrates mentioned above [44] (Scheme 15.19). 

Since the Lewis acid-promoted reactions of the oxidized products with nucleophiles give the corresponding N-acyl-a-substituted amines efficiently, the present reactions provide a versatile method for selective C-H activation and C-C bond formation at the a-position of amides [138]. Typically, TiCl4-promoted reaction of a-t-butyldioxypyrrolidine 66, which can be obtained by the ruthenium-catalyzed oxidation of l-(methoxycarbonyl)pyrrolidine with f-BuOOH, with a silyl enol ether gave keto amide 67 (81%), while the similar reaction with less reactive 1,3-diene gave a-substituted amide 68 (Eq. 3.80). 

An even better nucleophile is nitrogen. The incompatibility of basic amines for almost every one of these reactions catalyzed by these coordinatively unsaturated Ru complexes led us to examine sulfonamides and carboxamides. However, no productive results ensued. A basic amino group was also examined to verify its incompatibility. In contrast to that expectation, cyclization proceeded without problems as summarized in Equation 1.70 [61]. A Lewis acid was required as a cocatalyst. For formation of pyrrolidines, titanium tetrachloride proved most efficacious whereas for formation of piperidines, methylaluminum dichloride proved best. In principle, any nucleophile, such as carbon, that satisfactorily reacts in ruthenium-catalyzed allylic alkylations should function here also. 

Trost, B.M., Pinkerton, A.B. and Kremzow, D. (2000) A ruthenium-catalyzed pyrrolidine and piperidine synthesis, Journal of the American Chemical Society, 122 12007-12008. 

Scheme 9.21 Ruthenium-catalyzed functionalization of a C(sp )—H bond in pyrrolidine 58.

The ruthenium-catalyzed oxidation of l-(methoxycarbonyl)pyrrolidine with t-BuOOH gives 2-(t-butyldioxy)-l-(methoxycarbonyl)pyrrolidine (48) in 60% yield (Eq. (7.63)). 

Scheme 3.25 Ruthenium catalyzed decarboxylative arylation at sp carbon centers in pyrrolidine and piperidine heterocydes, as described by Sames and coworkers [42].

The most recent example of pyrrolidine synthesis by C-H functionalization was illustrated in 2014, when Che and coworkers demonstrated the synthesis of pseu-doheliotridane, a simple pyrrolidine alkaloid, by employing a ruthenium-catalyzed C-H insertion reaction (Scheme 16.44) [89]. Although diazocarbonyl compounds are generally required as the precursor of the metal carbenoid intermediate, they utilized an alkyl diazomethane as the carbene source. To this end, tosylhydrazone 192 was reacted with [Ru(TTP)(CO)] (TTP tetra(p-tolyl)porphyrin) (1 mol%) and KjCOj, which generated ruthenium carbene 193 in situ, followed by C-H insertion to produce pseudohehotridane in 95% yield with high diastereoselectivity. 

Che and co-workers developed a catalytic r-selective aziridination of aromatic /V-arylirnincs with ethyl diazoacetate catalyzed by a ruthenium(ll) porphyrin complex (Scheme 75).364 The corresponding pyrrolidines were isolated as minor byproducts. 

In addition to copper and rhodium catalysts commonly used in the generation of metal carbene complexes, other transition metals have also been explored in the diazo decomposition and subsequent ylide generation.Che and co-workers have recently studied ruthenium porphyrin-catalyzed diazo decomposition and demonstrated a three-component coupling reaction of a-diazo ester with a series of iV-benzylidene imines and alkenes to form functionalized pyrrolidines in excellent diastereoselectivities (Scheme 20). ... 

The results show that a number of ruthenium carbonyl complexes are effective for the catalytic carbonylation of secondary cyclic amines at mild conditions. Exclusive formation of N-formylamines occurs, and no isocyanates or coupling products such as ureas or oxamides have been detected. Noncyclic secondary and primary amines and pyridine (a tertiary amine) are not effectively carbonylated. There appears to be a general increase in the reactivity of the amines with increasing basicity (20) pyrrolidine (pKa at 25°C = 11.27 > piperidine (11.12) > hexa-methyleneimine (11.07) > morpholine (8.39). Brackman (13) has stressed the importance of high basicity and the stereochemistry of the amines showing high reactivity in copper-catalyzed systems. The latter factor manifests itself in the reluctance of the amines to occupy more than two coordination sites on the cupric ion. In some of the hydridocar-bonyl systems, low activity must also result in part from the low catalyst solubility (Table I). 

Schinkel M, Wang L, Bielefeld K, Ackermann L (2014) Ruthenium(II)-catalyzed C(sp )-H a-alkylation of pyrrolidines. Org Lett 16 1876-1879... 

Nishibayashi and Sakata recently described the Ru-catalyzed [3+2] cycloaddition of ethynylcyclopropanes bearing two carboxy groups at the homopropargyUc position with aldehydes and aldimines to afford 2-ethynyltetrahydrofurans and pyrrolidines (Scheme 52) [179]. The proposed mechanism requires the formation of the ruthenium allenylidene species II by isomerization of the initially formed vinylidene I. Nucleophilic attack of species II to the aldehyde or aldimine, which are activated by BF3-OEt2, would afford allenylidene III. Final nucleophilic attack on the Cy by the oxygen or nitrogen followed by tautomerization of the vinylidene... 

They present the advantage of being cost-eflfective and are easily prepared as their formation does not involve the formation of residual products. Different series of liquid crystalline have been isolated from the reaction of nitric, hydrochloric formic, and tetrafiuoroboric acids with the corresponding alkylimidazoles, pyrrolidines, pyr-idines, or alkylamines. Those based on the imidazolium cation induce a specific stereoselectivity for the catalyzed Diels-Alder condensation reaction of cyclopentadiene and diethyl maleate [2,15]. [The protonated Hiinig base, [NHEt(i-Pr)2][CF3C02], is reported to be an efficient medium for the nitration of arenes. Ohno and Yoshiwaza demonstrated for PILs prepared by neutralization of 1-alkylimidazoles the synergic effect between protonated alkyUmidazoles and palladium, rhodium, or ruthenium catalysts observed in reactions where the presence of a proton is essential for good performance [16]. 

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