Aryl pyrrolidines

In the absence of organic solvents, Sc(OTf)3 catalysed the cycloaddition of aziridines to nitriles to produce substituted imidazolines in good to excellent yields at room temperature and in an air atmosphere. The reaction is believed to progress through a highly reactive cationic intermediate in which the aziridine nitrogen is coordinated to Sc(OTf)3.65 The phosphine-catalysed enantioselective 3 + 2-cycloaddition of buta-2,3-dienoates with arylimines yielded 2-aryl-3-pyrrolidines with 64% ee.66... 

The new method for asymmetric arylation was applicable to a host of aryl halides, to provide a diverse array of 2-arylpyrrolidines in good yield and 92% ee, regardless of the nature of the aryl bromide component. This sequence offers a number of advantages over existing methods, and represents the most convenient and practical synthesis of enantiopure 2-aryl pyrrolidines and 2,5-diarylpyrrolidines. 

Erhitzen von Anilinen und Tetrahydrofuran in der Dampfphase oder in flussiger Phase iiber Metalloxid-Katalysatoren wie Titan(IV)-/Molybdan(V)-oxid ergibt 1 -Aryl-pyrrolidine z. B. l-Phenyl-pyrrolidin (65%) ... 

Quinoxaline derivatives (36), and not the expected sydnones, were obtained from the Af-nitroso derivatives of 3-arylamino-l-aryl-pyrrolidine-2,5-diones (35). The precise nature of this rearrangement has not so far been determined.40 The derived quinoxaline-2,3-dicarboxylic acid mono-jV-arylamides (37) were obtained in 40-60% yield. The latter compounds were also made by the conventional reaction of quinoxaline 2,3-dicarboxylic anhydride and an amine.40... 

Scheme 1 Microwave-promoted synthesis of N-aryl pyrrolidines in neat water...

The pyrrolidine derivatives 129 were obtained with modest to excellent yields and good to excellent levels of diastereoselectivity (2,5-disubstituted 1-aryl pyrrolidines syn/anti > 20 1 2,3-disubstituted 1-aryl pyrrolidines syn/anti 9 1 to > 20 1). 

Codonopsinine and codonopsine are aryl pyrrolidines isolated from natural sources and exhibit hypotensive pharmacological activity. L-Threitol is the only carbohydrate used in the synthesis of these aryl pyrrolidines. 

Biocidal 2-aryl-l,3-diones and their enol esters showing acaricidal and pre-and postemergence herbicidal activity were reported since the mid-1970 s as exemplified by 3-hydroxy-2-arylindones from Union Carbide [1], 3-Aryl-pyrrolidine-... 

The Bayer research group described further heterocyclic diones (Fig. 9.5), which all belong to this chemical class 3-aryl-pyrrolidine-2,4-diones 5 [62, 63], 3-aryl-furan-2,4-diones 6 [64], 2 aryl-cyclopentan-l,3-diones 7 [65] 4-phenyl-[l,2]oxazin-3,5-diones 8 [66]. 

Hindered 1-aryl-pyrrolidines and -piperidines (271) have been prepared by a gas-phase, alumina-mediated reaction of primary aro-... 

Scheme 6.10 The Rh-diene-catalyzed one-pot synthesis of chiral 2-aryl pyrrolidine and piperidine derivatives and the corresponding deprotection of the tosyl group, as described by Lin s group [16],...

The initial objective in these early studies was the synthesis of the trans-substituted aryl pyrrolidines. Therefore, the Heck-Matsuda reactions were... 

Rodgers JD, Shepard SA, Argyrios G, Wang H, Storace L, Folmer B, Shao L, Zhu W, Glenn J (2010) N-(hetero)aryl-pyrrolidine derivatives of pyrazol-4-yl-pyrrolo[23-d]pyrimidines and pyrrol-3-ylpyrrolo[2,3-d]pyrimidines as janus kinase inhibitors. US2010/298334(A1)... 

Ney JE, Wolfe JP. Palladium-catalyzed s3mthesis of A-aryl pyrrolidines from y-(A-arylamino) alkenes evidence for chemoselective alkene insertion into Pd—N bonds. Angew. Chem. Int. Ed. 2004 43(27) 3605-3608. 

The first successful a-atylation of 2-lithio-N-Boc pyrrolidine, one of the most crucial extensions of the field due to its application to biologically active compounds, was reported by Dieter and Li. ° They showed that the reaction of 2-lithio-N-carbamates with aryl iodides in the presence of catalytic CuCN (10 mol%) and a Pd catalyst (5 mol%) afforded 2-aryl pyrrolidines initially in modest to good yields (Scheme 11.28). Although the use of ligands like dppf was shown to increase yields, this later method was limited to electron-rich aryl iodides. ... 

In peptide syntheses, where partial racemization of the chiral a-carbon centers is a serious problem, the application of 1-hydroxy-1 H-benzotriazole ( HBT") and DCC has been very successful in increasing yields and decreasing racemization (W. Kdnig, 1970 G.C. Windridge, 1971 H.R. Bosshard, 1973), l-(Acyloxy)-lif-benzotriazoles or l-acyl-17f-benzo-triazole 3-oxides are formed as reactive intermediates. If carboxylic or phosphoric esters are to be formed from the acids and alcohols using DCC, 4-(pyrrolidin-l -yl)pyridine ( PPY A. Hassner, 1978 K.M. Patel, 1979) and HBT are efficient catalysts even with tert-alkyl, choles-teryl, aryl, and other unreactive alcohols as well as with highly bulky or labile acids. 

When allene derivatives are treated with aryl halides in the presence of Pd(0), the aryl group is introduced to the central carbon by insertion of one of the allenic bonds to form the 7r-allylpalladium intermediate 271, which is attacked further by amine to give the allylic amine 272. A good ligand for the reaction is dppe[182]. Intramolecular reaction of the 7-aminoallene 273 affords the pyrrolidine derivative 274[183]. 

Aryl halides with a halogen activated by electron-withdrawing groups react with pyrrolidine enamines of cyclic ketones (68) to give the a-arylated ketones after hydrolysis. The enamine (28) with 2,4-dinitrochlorobenzene gave an excellent yield of 2(2,4-dinitrophenyl)cyclohexanone (88). The... 

The enamine (28) did not undergo C arylation with p-nitrochlorobenzene under these conditions, and at higher temperatures N arylation and subsequent eleavage with formation of N-(4-nitrophenyl) pyrrolidine takes place (68). 

Low yields of C-arylated ketones have also been obtained by reaction of pyrrolidine enamines with diaryl iodonium salts (68). 

Tertiary pyrrolines (49, = 1) and piperideines (49, = 2) (if R = H and the enamine can exist in the monomeric form or if R = aryl) evidently possess an endocyclic -double bond (79,155,156). The stretching frequency of the double bond can be lowered to 1620-1635 cm by conjugation with an aromatic substituent. The double bond of an analogous compound with aliphatic substituents in position 2 may occupy either the endo or the exo position. Lukes and co-workers (157) have shown that the majority of the five-membered-ring compounds, traditionally formulated with the double bond in a position, possess the structure of 2-alkylidene derivatives (50) with an exocyclic double bond, infrared absorption at 1627 cm . Only the 1,2-dimethyl derivative (51) is actually a J -pyrroline, absorbing at 1632 cm . For comparison, l,3,3-trimethyl-2-methylene pyrrolidine (52) with an unambiguous exocyclic double bond has been prepared (54). 

Protection of primary aryl amines as the triazene is accomplished by diazotiza-tion of the amine followed by reaction with pyrrolidine in aq. KOH. This group is stable to metalation of the aromatic ring by metal halogen exchange. The amine is recovered by reductive cleavage with Ni-Al alloy (aq. KOH, rt, 37-68% yield). ... 

The synthesis of 5-aminothiazoles via the reaction of isocyanate derivatives with aminomalononitrile p-toluenesulfonate (AMNT) has been investigated. It was found that AMNT 12 reacted with alkyl and aryl isothiocyanates in l-methyl-2-pyrrolidine (NMP) to furnish 5-amino-2-(alkylamino)-4-cyanothiazoles (13a) and 5-amino-2-(arylamino)-4-cyanothiazoles (13b-c) in 44-81 % yields. " ... 

Alternatively, hydration of the acetylenes in cold concentrated sulfuric acid, or with mercury(II) sulfate in formic acid, yields 1-aryl-3,4-dihydro-5//-2-benzazepin-5-ones which are isolated as their methylsulfonate salts.79 If, however, acetylene 4 is stirred with pyrrolidine at room temperature then cyclization is accompanied by amination to give 8-chloro-l-(2-chlorophenyl)-4-(pyrrolidin-l-yl)-3i/-2-benzazepine (5) in high yield. 

Optically active 2-allylpiperidines and -pyrrolidines arc obtained by treating hydroxylactams containing the l-[(S)-l-arylethyl]substituent as an auxiliary (see Appendix) with tin(IV) chloride and trimethyl(2-propenyl)silane46. Interestingly, the moderate diastereoselection when the aryl group is phenyl decreases when 2-chlorophenyl is used, whereas the sense of the stereoselectivity reverses for 2,6-dichlorophenyl or pentachlorophcnyl. These results are rationalized by application of molecular orbital theory and substrate conformational preferences46. 

The Michael additions of chiral cycloalkanone imines or enamines, derived from (FV l-l-phcnyl-ethanamine or (5)-2-(methoxymethyl)pyrrolidine, are highly diastereofacially selective reactions providing excellent routes to 2-substituted cycloalkanones. This is illustrated by the addition of the enamine of (S)-2-(methoxymethyl)pyrrolidine and cyclohexanone to 2-(aryl-methylene)-l,3-propanedioates to give, after hydrolysis, the (2 5,a.S )-oxodicstcrs in 35-76% yield with d.r. (2 S,aS)/(2 S,a/ ) 94 6- > 97 3 and 80-95% ee214. 

In a related study, the reaction of the enamine, l,2-dihydro-3-(2-methoxymethyl-l-pyrrolidin-yl)naphthalene [from 3,4-dihydro-2(l//)-naphthalenonc and (S)-2-(methoxymethyl)pyrrolidine] with 2-aryl-l-nitroethenes gave, after hydrolysis, an 83 17 to 95 5 mixture of the (3S,YR)- and (1/ ,1 T )-nitro ketones31. 

Campos, K.R., Klapers, A., Waldman, J.H., Dormer, P.G., Chen, C.Y. (2006) Enantioselective, Palladium-Catalyzed a-Arylation of N-Boc-pyrrolidine. Journal of the American Chemical Society, 128, 3538-3539. 

Other patent reports covering PDF inhibitors from structural classes different from those discussed above include hydrazides (43) [118], aryl-substituted pyrrolidines (44) [119], benzimidazoles (45, 46) [120-121], hydantoins (47) [122] and oxo-pyrrolidines (48) [123], A prodrug approach utilising PDF has been published by Pei, and patents have been published by NewBiotics, but in this case the compounds of interest are used as substrates rather than inhibitors (49) [124-126]. 

The drug discovery route to compound 1 started out with the expensive and poorly available boronic acid 2, which was coupled with aryl bromide 3 (Scheme 8.1). Hydrogenation of the resulting pyrrole 4 provided the racemic pyrrolidine 5. At... 

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... 

Scheme 8.11 Enantioselective coupling of N-Boc pyrrolidine with aryl bromide 3.

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