Pyrrolidine, lithiation

The enantioselectivity is due to the retention of the chiral sparteine in the lithiated reagent. The adducts have been used to synthesize a number of pyrrolidine and piperidine derivatives. 

We became interested in a disconnection between the pyrrolidine and the aryl group (Approach D) as the most convergent method for enantioselective construction of 12 [10]. Although (-)-sparteine mediated enantioselective lithiation of N-Boc pyrrolidine 19 is well established by Beak [11], arylation of the resulting chiral... 

The key to the success of the synthesis was the development of a novel method for enantioselective formation of a-arylpyrrolidines. In this method, (-)-sparteine-mediated, enantioselective lithiation of N-Boc-pyrrolidine 19 was followed by an in situ transmetallation to zinc and Pd-catalyzed coupling reaction with aryl bromide 3, which afforded 2-arylpyrrolidine in 63% isolated yield and 92% ee. Notably, the acidic aniline NH2 group was tolerated under the coupling reaction conditions. 

Compound 145 on lithiation <1999SM(102)987> and subsequent reaction with carbon dioxide afforded compound 146. Sandmeyer reaction of 2-bromodi thieno[3,2-A2, 3 -with copper(l)cyanide in hot iV-methyl pyrrolidine (NMP) gave the corresponding nitrile 148 which was then converted to the tetrazole 149 with a mixture of sodium azide and ammonium chloride in NMP in low overall yield (Scheme 14) <2001JMC1625>. 

Nucleophilic addition of lithiated sulfones to nitrones made it possible to develop new stereoselective approaches to the synthesis of pyrrolidine-N -oxides based on a reverse-Cope-type elimination. One method is based on the reaction of lithiated sulfones with nitrones (386) (Scheme 2.168) (625). 

Pyrrolo[l,2- ][l,2]oxazines are a class of compounds with very few references regarding synthesis and reactivity. An interesting preparation has been described by intramolecular cyclization of IV-hydroxy pyrrolidines carrying a methoxyallene substituent at C-2 (242, Scheme 32). These compounds were obtained by addition of a lithiated allene to chiral cyclic nitrones 241. Cyclization occurred spontaneously after some days at relatively high dilution (0.05 M). Compounds 243 (obtained with excellent diastereoselectivity) can be submitted to further elaboration of the double bond or to hydrogenolysis of the N-O bond to form chiral pyrrolidine derivatives (Section 11.11.6.1) <2003EJ01153>. 

The nucleophilic addition of lithiated methoxyallene to N-tosylimines delivers tosylamides 174. Treatment of the latter with AgN03 leads cleanly to dihydropyrroles 175, which under acidic conditions provide pyrrolidin-3-ones 176. Another example is the reaction of 177 to 178 (Scheme 15.55) [113]. 

Aminomethylferrocene 338, this time without further methoxy substituents, also lithi-ates diastereoselectively (Scheme 150) , and similar results may be obtained with simple chiral pyrrolidines. Treatment of 322 with the binaphthylamine 337 yields 338. Lithiation generates a 9 1 mixture of diastereoisomeric organoUthiums, which give the phosphine 339 (Scheme 150) Attempts to obtain reversed planar diastereoselectivity by using silylation to block the more reactive lithiation site failed. 

A particular case for the generation of a y-substimted organolithium compound, derived from an imine, was used for the synthesis of 2-substituted pyrrolidines. DTBB-catalyzed (5%) lithiation of y-chloro imines 196 yielded, after hydrolysis, 2-substituted pyrrolidines 198, including nomicotine (R = H, R = 3-pyridyl). The corresponding y-nitrogenated organolithium intermediate 197 was probably involved (Scheme 68). ... 

The synthesis of oxygen- and nitrogen-containing heterocyclic compounds by anionic cyclization of unsaturated organolithium compounds has been reviewed recently. " Broka and Shen reported the first intramolecular reaction of an unstabilized a-amino-organolithium compound using reductive lithiation of an A,5-acetal derived from a homoaUylic secondary amine (Scheme 21). Just one example was reported treatment with lithium naphthalenide gave the pyrrolidine product, predominantly as the cis isomer. 

Astonishingly enough, enantioenriched lithiated cyclooctene oxides 142, originating from (—)-sparteine-mediated lithiation of 124 by i-BuLi/(—)-sparteine (11), could be trapped by external electrophiles, resulting in substituted epoxides 143 (equation 31) ° . Again, the use of i-PrLi furnished better enantioselectivities (approx. 90 10). Lithiated epoxides, derived from tetrahydrofurans and A-Boc-pyrrolidines, undergo an interesting elimination reaction . ... 

A synthesis of optically active trihydroxyindolizidines, developed by Majewski and coworkers, is based on the lithiated pyrrolidine . A second asymmetric lithiation/substi-tution in the 5-position is possible, but the yields are usually not high. The problem lies in the slow interconversion of the pre-complexes ( )- and (Z)-152 (equation 35) directed lithiation is only possible in ( )-152. 

The asymmetric lithiation/substitution of Af-Boc-Af-(3-chloropropyl)-2-alkenylamines 395 by w-BuLi/(—)-sparteine (11) provides (5 )-Af-Boc-2-(alken-l-yl)pyrrolidines 397 via the allyllithium-sparteine complexes 396 (equation 106) . Similarly, the piperidine corresponding to 397 was obtained from the Af-(4-chlorobutyl)amine. Intramolecular epoxide openings gave rise to enantioenriched pyrrolidinols. Beak and coworkers conclude from further experiments that an asymmetric deprotonation takes place, but it is followed by a rapid epimerization a kinetic resolution in favour of the observed stereoisomer concludes the cyclization step. 

The Sparteine Method 42 was applied successfully to generate chiral a-lithiated pyrrolidine when using the Boc-protected (tcrt-butoxycarbonyl)pyrrolidine and sec-butyllithium/sparteine as an asymmetric deprotonating agent in diethyl ether at — 78 °C. Alkylation, silylation, stanny-lation and methylation occurred with good yield (70-75%) and high selectivity (95% ee)53. 

Pyrrolidine readily forms an IV-nitroso derivative. This can be lithiated in the 2-position, and subsequent reaction with electrophiles and deprotection yields 2-substituted pyrrolidines (780S(58)l 13), as illustrated in Scheme 54. The transformation of tetrahydrothiophene 1,1-dioxide (238) into its 2-bromo derivative (239) is similar in principle. This involves deprotonation with ethylmagnesium bromide followed by electrophilic attack by bromine. Sodium ethoxide treatment of (239) gives buta-1,3-diene in 74% yield (80LA1540). 

Lithiation of pyrrolidine, H26(CH2)3NH, in hexane produces a white insoluble powder, (H2(5(CH LNLi ]n (21,150). This is assumed to have an extensive ladder structure (Section III,A Fig. 26c) compare the cyclized-ladder structure of crystalline [H2C(CH2)5NLi]6 (164). However, if lithiation is carried out in the presence of the ligands PMDETA or TMEDA, crystalline complexes are isolated [H2C(CH2)3- JLi]3-PMDETA 2 (59) (21,150) and [H2C(CH2)3tiLi]2-TMEDA 2 (60)... 

The synthesis of polysubstituted pyrrolidines has been achieved344 in a diastereo-selective and enantioselective manner via the zinca-ene-allene cyclization. In an extension of this work,345 the zinca-ene-allene reaction of polysubstituted enynes lithiated on the propargylic position has been used to prepare polysubstituted... 

N-Nitroso pyrrolidine 92 can be lithiated just with LDA. Double benzylation gives principally the trans isomer of 93 after reduction.61... 

To assess the effect of intramolecular chelation in this class of organolithium, Gawley also made 157 and treated it under similar conditions.57 In THF alone, the MEM-protected 158 has greater chemical stability than 155, and is configurationally stable up to about -60 °C. Like the lithiated Boc-pyrrolidine 138 (but unlike the lithiated /V-methyl pyrrolidines 155) TMEDA tends to decrease its configurational stability and a direct comparison between MEM protected 158 and 155 in the presence of TMEDA shows that the MEM group also... 

Much more successful in a pyrrolidine synthesis was the use of a stereochemically defined organolithium 362 formed by tin-lithium exchange from an almost enantiomerically pure stannane 361, itself a product of Beak s sparteine lithiation chemistry. Despite the high temperature (20 °C) required for tin-lithium exchange in hexane-ether, it is nonetheless possible to carry out a stereospecific cyclisation via an organolithium which is configurationally stable, even at 20 °C, on the timescale of the cyclisation.169 The cyclisation proceeds with retention and gives the alkaloid pseudoheliotridane 363 in 87% yield and with no loss of enantiomeric excess. 

Other aminations of more substituted arene complexes allow the regiospedfic synthesis of polysubstituted aromatics. For example, p-fluoroanisoletricarbonylchromium complex can first be lithiated and quenched with chloroformate to give 33b (R = OMe, R = CChMe). After substitution of the fluoride by pyrrolidine, complex 31 is obtained in 89 % yield (Scheme 18) [29]. 

The venom of the fire ant, Solenopsis punctaticeps, contains several 2,5-dialkyl-pyrrolidines and -pyrrolines their structures have been settled by combined g.c-m.s., and confirmed by syntheses employing the Hofmann-Loffler reaction on the corresponding primary amines.7 A new synthesis of 2,5-dialkyl-pyrrolidines via lithiated iV-nitrosopyrrolidine and two stages of alkylation, followed by removal of the nitroso-group, should be applicable to the synthesis of the venom components. The major products are trans in stereochemistry.8... 

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