Pyrrolidinopyridine

Acylation of mesoionic pyrido[l,2-u]pyrimidin-4-ones 150 with aroyl chlorides in the presence of NEts yielded 2-aroyloxy-4//-pyrido[l,2-u]pyrimidin-4-ones 178 (96JHC663). None of the esters 178 could be rearranged to the 2-hydroxy-3-aroyl derivatives 179. The hydroxy group of 9-hydroxy-2-methyl-3- 2-[4-(6-fluoro-l,2-benzisoxazol-3-yl)-l-piperidinyl] ethyl -6,7,8,9-tetrahydro-4//-pyrido[l, 2-u]pyrimidin-4-one was acylated with hexadecanoic acid in CH2CI2 in the presence of dicyclohexylcarbodi-imide and 4-pyrrolidinopyridine at room temperature for 3 days in 80% yield (97MIP7). 

However, the reaction always led to some overreduction of the pyridine ring. Reduction with BH /THF was unsuccessful. However, NaBH /BF2 Et20 proved to be an excellent reagent for the reduction step, resulting in the formation of the desired polymer. The polymer was shown by UV and NMR spectroscopy to be 67% functionalized primarily with 4-pyrrolidinopyridine moieties by UV and NMR spectroscopy according to these data no starting polymer is present anymore, and the nature of the remaining 23% of functionalization is unknown. 

Pyrrolidinopyridine based polymers react faster with benzyl chloride than low molecular weight analogs. The polymer synthesized by cyclopolymerization of N-4-pyridyl bis(methacrylimide)... 

Figure 1. Absorbance at 400 nm vs. time for the poly(4-pyrrolidi-nopyridine) and 4-pyrrolidinopyridine catalyzed hydrolysis of p-nitrophenylacetate at pH 8.5.

Intramolecular aldol reaction of 137 takes place in the presence of 4-pyrrolidinopyridine (Scheme 7-41), providing 138a and 138b as a mixture (11 1), from which the desired compound 138a can be obtained as the major component. The thus formed C-7 hydroxyl group is then protected by TrocCl... 

Cycloaddition of 3,6-bis(trifluoromethyl)-l,2,4,5-tetrazine 321 with l-methyl(acetyl)-l,2,5,6-tetrahydro-4-pyrrolidinopyridine 322 led to the formation of A -methyl(acetyl)pyridopyridazine 323 (Equation 26) <1994H(38)1845>. 

Cyclopeptides.1 Cyclization of polypeptides under conditions of high dilution usually proceeds in low yield. A new method involves cyclization of co-peptide-pentafluorophenyl esters in dioxane in the presence of 4-pyrrolidinopyridine and an alcohol (ethanol or f-butyl alcohol). p-Nitrophenyl esters can also be employed, but separation of p-nitrophenol from product is more difficult than that of pen-tafluorophenol. 

Benzylamino)acetonitrile, 29 4-Pyrrolidinopyridine, 262 Triphenylphosphine-2,2 -Dipyridyl disulfide, 332 Zinc iodide, 350 Lactonization (see also Enol lactonization)... 

Kawabata et al. found that peptides 24a-c containing a 4-pyrrolidinopyridine (PPY) unit afford selectivity factors in the range 5.6-7.6 in the kinetic resolution of the N-acylated amino alcohol roc-26 with iso-butyric anhydride (Scheme 12.12) [30]. In further studies by Miller et al. the octapeptide 27 was identified as even more enantioselective [31], As shown in Scheme 12.13, selectivity factors as high as 51 were achieved. 

The peptide catalysts 53a-e incorporating a 4-pyrrolidinopyridine moiety were tested in the desymmetrization of cyclohexane meso-1,2- and meso-1,3-diols by Ka-wabata et al. (Scheme 13.26) [42]. As summarized in Scheme 13.26, enantiomeric excesses were up to 65% and chemical yields were in the range 40-77%. (Application of the Kawabata catalysts to the kinetic resolution of racemic alcohols is discussed in Section 12.1.)... 

Basic investigations on conditions for coupling by use of butyric acid and dextran confirm that the imidazolide is formed within 2 h. The reaction at room temperature for 17 h results in butyrate content of 92% of the acid applied. Only 0.25% N is found in the product. The solvent has a pronounced influence for dextran the solvent of choice is the mixture formamide/DMF/CH2Cl2 [189]. 4-Pyrrolidinopyridine is used as catalyst in this process. 

D1methylam1nopyr1d1ne was obtained from Scherlng AG, D-1000 Berlin, Germany. 4-Pyrrolidinopyridine, which is equally well suited as a catalyst in this reaction may be purchased from Ega-Chem1e, D-7924 Steinheim, Germany. 

A mixture consisting of the Step 7 product (0.74 mmol), 4-pyrrolidinopyridine (0.09 mmol), and 927 jxl n-butyl chloroformate dissolved in 6 ml pyridine was stirred 2 days at ambient temperature, then concentrated. The residue was dissolved in CH2C12, washed with a 10% solution of citric acid and with water, dried with Na2S04, and concentrated. The residue was purified by chromatography using CH2Cl2/methyl alcohol, 20 1, and 470 mg of product isolated as a slightly yellow amorphous foam. 

This procedure has been used by Roush and Blizzard [33] in the synthesis of the macrocyclic mycotoxin verrucarin J (55). Thus, seco acid 54 was treated with 2 equiv of pivaloyl chloride and 3 equiv of triethylamine in dichloromethane (0.01 M) and the resultant mixed anhydride was treated in situ with 4-pyrrolidinopyridine (4-PP) to effect the ring closure at 23 °C. Verrucarin J (55) was obtained in up to 60% yield (Scheme 17). The mixed pivalic anhydride method has also been applied, e.g. to the synthesis of verrucarin B [34] and 4-epiverrucarin A [35] as the key cyclization step. 

Sometimes the /3-lactam precursors are constructed using DCC in the protection of the carboxylic acid group by reacting it with benzylhydroxylamine. N-tosyllactams are obtained similarly using DCC and 4-pyrrolidinopyridine to effect ring closure. 

Ar O = 2,6-di-f-butylphenoxide acac = acetylacetonate bppy = 4-(l-butylpentyl)pyridine cup = cupferron dippe = l,2-bis(diisopropylphosphino)ethane dppe = l,2-bis(diphe-nylphosphino)ethane fee = face-centered cubic = CH(Cp3)2 hep = hexagonal close-packed hexone = methyl isobutyl ketone OEP = octaethylporphyrinogen phen = phenanthroline py = 4-pyrrolidinopyridine tritox = (f-Bu)3CO tbp = BU3PO4 TPP = tetraphenyl-porphyrino-gen trmpe = tris(dimethylphosphinomethyl)ethane. 

Esterification. DCC has been satisfactory only for esterification of phenols and thiophenols because of variable yields. However, if 4-dimethylaminopyridine (3, 118-119 5, 26) or 4-pyrrolidinopyridine (this volume) is added as catalyst, alcohols and thiols are csterified readily at rm temperature in satisfactory yields. Sterically... 

Review. A new method suitable for large-scale preparation of DMAP (1) is shown in equation (I), The related reagent 4-pyrrolidinopyridine (2 4,416) can be obtained in this way by use of N-formylpyrrolidine in place of DMF. 

Related catalysts. Hassner et al. have prepared a number of substituted derivatives of pyridine, pyridazine, and quinoline, but only a few are useful acylation catalysts. Of these, 4-pyrrolidinopyridine (2) and l,l,3,3-tetramethyl-4-(4-pyri-dyl)guanidine (3) are most effective. 

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