A-Methyl pyrrolidine

Roberts and Laine [25] describe a process for electrochemically transferring oxygen with the scheme shown as Fig. 11. Air or other oxygen-containing gas is drawn into the left side of the vessel. The solution contains an organic solvent such A-methyl pyrrolidine with a supporting electrolyte as tetrabutyl ammonium tetrafluroborate. The carrier, one of the two Schiflf bases shown as Fig. 12, is dissolved to about 3 volume percent. 

Figure 8-69. CIS sub-2-(xm column. Column temperature, 30°C injection volume, 1 (xL flow rate, 0.7mL/min wavelength, 225 nm. Mobile phase 80% A/20% B (isocratic). A, pH 11.4 [4mM A-methyl pyrrolidine] B, acetonitrile.

When 2,4(1//,3//)-quinazolinedione reacts with phosphoryl chloride in the presence of excess of iV-alkyl cyclic amines, mixtures of 2,4-dichloroquinazolines, and 4-chloro-2-(A-alkyl-co-chloro-alkylamino)quinazolines (120) result. Bulky amines favor dichloride formation. Almost exclusive formation of 2-aminated product results from A-methyl pyrrolidine, indicating that either 4-oxo-... 

Variations of these reaction conditions have remained the most frequent method for the synthesis of 6-fluoropurines since these early publications [12,25,102-108]. A development of the conditions was the use of A-methyl pyrrolidine instead of condensing gaseous trimethylamine which led to a simplification of the reaction procedure [35]. Alternatively, a silver fluoride mediated reaction was used to great effect to convert a AJ-norbomyl-6-chloropurine to the corresponding A-norbomyl-6-fluoropurine in good yield (71 %) [109]. 

An alternative approach was elaborated by the functionalization of poly (dimethylsiloxane) [10-12], polystyrene [13, 14], and poly (ethylene oxide) [15]. The first two polymers were prepared in such a way that two CH2OH end groups were introduced, whereas commercial poly (ethylene glycol) has two CH2OH end groups anyway. These end groups were quantitatively tosylated by means of tosyl chloride and 4-dimethylamino pyridine. The resulting tosylates were, in turn, reacted with A-methyl pyrrolidine (Formula 13.2). 

In 1931 Winterfeld and Kneuer, as a result of their observation that jS-lupinane can be obtained from lupanine, and the formation of 2-methyl-pyrrolidine by the oxidation of sparteine, combined these two features in a partial formula (II) for lupanine, which could be developed in various ways depending on the mode of attachment of the methylpyrrolidine residue. In view, however, of Ing s demonstration of the relationship of anagyrine, CJ5H20ON2, to Z-lupanine, CJ5H24ON2, and d-sparteine, C15H28N2, it was elearly neeessary to consider formul for lupanine derivable from the two alternati-ves, which Ing had proposed for anagyrine and which are shown below as (III) and (IV) with the formul for lupanine derived from them (V) by Ing and (VI) by Clemo and Raper. Sparteine would be represented by (V) or (VI) with the change CO CH2. 

In 1878, Hofmann reported that treatment of D-l-bromo-2-propylpiperidine (3) with hot sulfuric acid gave rise to a tertiary amine 4, D-octahydroindolizine. In the ensuing decade, Loffler and Freytag extended the reaction to simple secondary amines and found it to be a general way to synthesize pyrrolidines as exemplified by transformation of N-bromo-A-methyl-2-butylaminylpyridine 5 to nicotine (6). The Hofmann-Loffler-Freytag reaction is sometimes referred to as Loffler s method, Hofmann-Loffler reaction, Loffler-Hofmann reaction, as well as Loffler-Freytag reaction. 

Treatment of the pyrrolidine derivative 130 with sodium hydride followed by A-methyl piperazine afforded pyrrolidino[l,2-a]quinolinone 4-carboxy-late 131 (93JPR397) (Scheme 25). 

Chemical Name 3-(10,11-Dihydro-5H-dibenzo[a,dlcyclohepten-5-ylidene)-1-ethyl-2-methyl-pyrrolidine... 

As another extension of this process, Davies et al. have developed highly regio-, diastereo- and enantioselective C-H insertions of methyl aryldiazoace-tates into cyclic A-Boc-protected amines catalysed by rhodium(II) S)-N- p-dodecylphenyl)sulfonylprolinate. The best results were obtained in the case of the C-H insertion of methyl aryldiazoacetates into A-Boc-pyrrolidine, which gave, in all cases, a diastereoselectivity and an enantioselectivity greater than 90% de and 90% ee respectively (Scheme 10.77). The synthetic utility of this method was demonstrated by means of a two-step asymmetric synthesis of a novel class of C2-symmetric amines. 

Scheme 10.77 Rh-catalysed intermolecular C-H insertions of methyl aryldiazoacetates into A-Boc-pyrrolidines with sulfonamide ligand.

A Knoevenagel condensation/Michael addition sequence has been reported by Barbas III and coworkers (Scheme 2.70) [158] using benzaldehyde, diethyl malonate, and acetone in the presence of the chiral amine (S)-l-(2-pyrrolidinyl-methyl)-pyrrolidine (2-301). As the final product the substituted malonate 2-302 was isolated in 52% yield with 49% ee. 

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>. 

Cadmium, copper, and silver have been determined by an ammonium pyrrolidine dithiocarbamate chelation, followed by a methyl isobutyl ketone extraction of the metal chelate from the aqueous phase [677], and finally followed by graphite furnace atomic absorption spectrometry. The detection limits of this technique for 1% absorption were 0.03 pmol/1 (copper), 2 nmol/1 (cadmium), and 2 nmol/1 (silver). 

Ferrero, J.L., Thomas, S.B., Marsh, K.C., Rodrigues, A.D., Uchic, J.T. and Buko, A.M. (2002) Implication of P450-metabolite complex formation in the nonlinear pharmacokinetics and metabolic fate of ( )-(l R, 3R )-3-phenyl-l-[(l, 2, 3, 4 -tetrahydro-5, 6 -methylene-dioxy-l -naphthalenyl) methyl] pyrrolidine methanesulfonate (ABT-200) in dogs. Drug Metabolism and Disposition, 30 (10), 1094-1101. 

On the other hand, the method of Mukaiyama can be succesfully applied to silyl enol ethers of acetic and propionic acid derivatives. For example, perfect stereochemical control is attained in the reaction of silyl enol ether of 5-ethyl propanethioate with several aldehydes including aromatic, aliphatic and a,j5-unsaturated aldehydes, with syir.anti ratios of 100 0 and an ee >98%, provided that a polar solvent, such as propionitrile, and the "slow addition procedure " are used. Thus, a typical experimental procedure is as follows [32e] to a solution of tin(II) triflate (0.08 mmol, 20 mol%) in propionitrile (1 ml) was added (5)-l-methyl-2-[(iV-l-naphthylamino)methyl]pyrrolidine (97b. 0.088 mmol) in propionitrile (1 ml). The mixture was cooled at -78 °C, then a mixture of silyl enol ether of 5-ethyl propanethioate (99, 0.44 mmol) and an aldehyde (0.4 mmol) was slowly added to this solution over a period of 3 h, and the mixture stirred for a further 2 h. After work-up the aldol adduct was isolated as the corresponding trimethylsilyl ether. Most probably the catalytic cycle is that shown in Scheme 9.30. 

Figure 3.3 Dynamic bis-salicylaldimine Ztf + complexafion identifies an oligo d(A T) DNA ligand. Right The selected A-methyl 2-aminoethyl pyrrolidine based bis-salicylaldimine complex 1 (hypothetical), which binds to oligo d(A T) DNA.

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