Pyrrolidine formation

Scheme 6. Proposed mechanism for copper-catalyzed carbenoid transfer to imines and competing pyrrolidine formation. [Adapted from (87).]...

The preparation of pyrrolidines has received extensive attention by synthetic chemists In recent years. In part due to the interesting biological activities exhibited by several polysubstituted pyrrolidines. Little attention has been given to one of the most conceptually simple ways of pyrrolidine formation a 1,3-dipolar cycloaddition of an azomethine yllde with an olefin. This Is not surprising since few methods exist for the preparation of nonstablllzed azomethine ylldes. " Sllyl-substituted amines of Type 1 represent conjunctive reagents which can be considered as the equivalent of nonstablllzed azomethine yllde. These reagents have recently been found to... 

Syntheses and photochemical behaviour of some azido-steroids have been described. Thermolytic and acid-catalysed reactions have also been studied and compared. Photolysis and thermolysis of azido-steroids led to alkyl migration products, endocyclic imines, and 1-2 hydrogen-transfer compounds, exocyclic imines giving ketones by hydrolysis. Pyrrolidine formation through a nitrene intermediate occurred only in the case of 6/3-azidopregnene. Mechanistic implications were fully discussed. 

The stereoselectivity of pyrrolidine formation by an overall 5-endo-trig process is greatly affected by a base. ... 

PYRROLIDINE FORMATION USING S-EJVDO-TRIG CYCLIZATIONS... 

Recently, the same catalyst enabled the formation of six-membered heterocycles in an unprecedented manner (Scheme 16.11). While pyrrolidine formation is usually a straightforward process in aminopalladation, the related six-membered ring formation is kinetically disfavored. Stahl and Lu [44] could show that, for Pd(DMS0)2(02CCF3)2 as catalyst, a series of different precursors could be cyclized to various heterocycles including morpholines, piperidines, piperazines, and piper-azidinones in good yields and within competitive reaction times. 

Scheme 16.16 Double palladium-catalyzed aminopaUadation of alkenes pyrrolidine formation.

Michael used a sequence of nucleopalladation followed by chlorination with N-chlorosucdnimide (NCS) as an alternative protocol for intramolecular aminochlorination. This protocol works with excellent selectivity, providing pyrrolidine formation from a metal-free chlorine source. In contrast, a cyclization attempt to a six-membered product led to product mixtures including a 3-chloro azepin. Azepin was the only product that was produced using N-bromosuccinimide (NBS)... 

The reaction has recently been developed further by use of the milder reagents PhIO and PhI(OAc)2, respectively, within the iodine(III)-mediated intramolecular pyrrolidine formation from alkenes. For example, the combined use of iodoso-benzene and trimethylsilyl triflate generates reaction conditions that enable an efficient aminooxygenation of urea precursors 61. Because of the acidic reaction conditions, the final carbon-heteroatom bond formation cannot proceed toward diamination, and aminooxygenation products 62 are obtained selectively. The free aminoalcohols are conveniently obtained by acidic cleavage of the cyclic carbamate [51]. 

An alternative process involves the combination of (diacetoxyiodo)benzene and trifluoroacetic acid (TFA). Under these conditions, the reaction of internal alkenes (63, with R preferentially phenyl) provides pyrrolidine formation products 64 [52]. These reactions are understood not to require proceeding through oxidation... 

The application of method (b) of 1,3-dipole generation allows asymmetric pyrrolidine formation initiated by chiral metal catalysts, as shown by the following examples. 

SCHEME 5 Enantioselective pyrrolidine formation from the Xiao group. 

Scheme 8.11 CuPFg-catalyzed pyrrolidines formation via radical aminohydroxylation of double bonds of unsaturated N-benzoyloxyamines.

Paderes and Chemler developed an intramolecular diastereoselective aminooxygenation of unactivated alkenes to pyrrolidines. Cu(EH)2/02 catalytic system could lead to 2,5-cis- and 2,5-fra s-pyrrolidines formation from a-substituted 4-pentenylsulfonamides in good to excellent yields and >20 1 selectivity. For P- and /-substituted 4-pentenylsulfonamides, Cu(OTf)2-bis(oxazoline) with O2 catalytic system could give higher diastereoselectivities. Furthermore, enantioselective desymmetrization could be achieved (up to 98% ee) with /l-allyl-4-pentenylsulfonamide [26] (Scheme 8.13). 

Jones et al. (67) also prepared a wide range of water soluble ammonium dithiocarbamate salts, [NH4][S2CNR2] (Fig. 5). They result from the iifitial reaction of the amine with concentrated aqueous ammonia in ethanol, followed by later addition of carbon disulfide at low temperatures. For example, diethanolamine, HN(CH2CH20H)2, forms a yellow precipitate in 65% yield. Castro et al. (68) studied the kinetics and mechanism of the reactions of piperidine, pyrrolidine, morpholine, and benzylamine (69) with carbon disulfide in ethanol (Fig. 6). They proceed via a dithiocarbamic acid intermediate (4), which in turn yields the dithiocarbamate anion (5) upon proton loss to the amine. While for pyrrolidine, formation of the dithiocarbamic acid is rate determining and proceeds to the dithiocarbamate irreversibly, for both morpholine and benzylamine, the transformation is reversible. Further, in these cases the ethoxide anion is found to catalyze the transformations. They have also determined that pyrrolidine is 200 times more nucleophilic toward carbon disulfide than piperidine, despite the later being only slightly more basic, a feature that may relate to the irreversible nature of the formation of pyrrolidine dithiocarbamate. 

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