Palladium-Catalyzed Cyclization Reactions of Acetylene-Containing ...

FULL PAPERSLarissa B. Wolf et al.compared to the reduction of 35 was probably a result of thesteric bulk of the larger phenyl group. The reaction with the Nsprotectinggroup took significantly longer due to its strongerelectron-withdrawing properties and therefore more difficultformation of the N-sulfonyliminium ion. The long reactiontime was probably also the main reason for the lower yield.Despite the fact that extensive NOE-experiments were carriedout with product (R)-62, the configuration of the major isomercould not be unambiguously determined (Scheme 10).PhNPCO 2 Me(R)-37: P = Ts(R)-42: P = NsScheme 10.TFAEt 3 SiHCH 2 Cl 20 °C → rtStraightforward hydrogenation of the enamide functionusing Pd on carbon under a hydrogen atmosphere in thepresence of a catalytic amount of base led to 61 (major isomerappeared identical to the major isomer in the previousreactions on the basis of NMR data), albeit in a lower yieldand significantly lower selectivity (Scheme 11). In this reactiona small amount of ketone 63 was also isolated, but the yield wasnot determined. Without the base, the hydrolysis product 63was the only isolated product.PhScheme 11.Instead of the small hydride nucleophile, it was alsoattempted to introduce a larger nucleophile via the tertiaryN-sulfonyliminium ion using a cocktail of allyltrimethylsilane(10 equiv), trifluoroacetic acid (TFA, 5 equiv) and trifluoroaceticanhydride (TFAA, 5 equiv). The latter compound wasadded to trap traces of water that might be present in thereaction mixture. The allylated product 64 was obtained in amoderate yield and slightly contaminated with the hydrolysisproduct and the isomerized product 34. The formation of sideproducts is understandable, considering the difficulty ofnucleophilic attack on the tertiary iminium ion. [30] Unfortunately,the stereochemistry of both isomers could not beassigned.The enamide (R)-37 was subjected to the same conditions,but in this case only the product resulting from hydrolysis wasfound. Due to the lability of the enamides and the reluctancy ofthe tertiary iminium ions to undergo nucleophilic attack,further investigations were not carried out.PhNPCO 2 Me61: P = Ts (88%, 10:1)62: P = Ns (35%, 10:1)OPhPd/C, H 2N CO 2 Me EtOAc61 +base, rtTsHN CO 2 Me16 h(R)-37 (50%, 4.5:1)Ts63NTs(R)-33Scheme 12.CO 2 MeTFA, TFAASiMe 3CH 2 Cl 20 °C → rt, 3 hNTsCO 2 Me64 (21%, 1.6:1)ConclusionsIn this article, several types of palladium-catalyzed cyclizationreactions with different acetylene-containing amino acids aredetailed. Depending on the protection of the amine or thecarboxylic acid function, either the nitrogen or the oxygencould act as a nucleophile to form nitrogen- or oxygenheterocycles,respectively. In most cases, the yield of thecyclization(/coupling) reactions was satisfactory and the enantiopurityof the starting material was retained in the product.The nitrogen appeared a more useful and efficient nucleophilethan the oxygen atom, leading to a larger variety of cyclizationproducts. The cyclic enamides and enol ethers that wereformed in these reactions were generally not very stable andtherefore partially responsible for the moderate yields. A fewmethods to derivatize these products were investigated, butwere abandoned due to the reluctance of the resulting cationsto undergo further substitution.Experimental SectionGeneral InformationAll reactions were carried out under an inert atmosphere of dry nitrogen,unless stated otherwise. Standard syringe techniques were applied fortransfer of Lewis acids and dry solvents. Infrared (IR) spectra were obtainedfrom KBr pellets or neat, using a Bruker IFS 28FT spectrometer andwavelengths (n) are reported in cm 1 . Proton nuclear magnetic resonance( 1 H NMR) spectra were determined in CDCl 3 (unless stated otherwise)using a Bruker AC 200 (200 MHz) and a Bruker ARX 400 (400 MHz)spectrometer. The machines were also used for 13 C NMR (APT) spectra(50 MHz and 100 MHz) in CDCl 3 (unless stated otherwise). Chemical shifts(d) are given in ppm downfield from tetramethylsilane. Mass spectra andaccurate mass measurements were carried out using a JEOL JMS-SX/SX102A Tandem Mass Spectrometer, a Varian NIAT 711 or a VG MicromassZAB-HFQQ instrument. Elemental analysis were performed by Dornis u.Kolbe Mikroanalytisches Laboratorium, M¸lheim an der Ruhr, Germany.R f values were obtained by using thin layer chromatography (TLC) on silicagel-coated plastic sheets (Merck silica gel 60 F 254 ) with the indicated solvent(mixture). Chromatographic purification refers to flash column chromatography[31] using the indicated solvent (mixture) and Acros Organics silica gel(0.035 ± 0.070 mm). Melting and boiling points are uncorrected. Meltingpoints were determined with B¸chi melting point B-545. Dry THF and Et 2 Owere distilled from sodium benzophenone ketyl prior to use. Dry DMF,CH 2 Cl 2 and MeCN were distilled from CaH 2 and stored over MS 4 ä under adry nitrogen atmosphere. Triethylamine was dried from KOH pellets. Et 2 O,EtOAc, PE (60 ± 808C) were distilled prior to use. All commerciallyavailable reagents were used as received, unless indicated otherwise.(R)-2-(Toluene-4-sulfonylamino)pent-4-ynoic Acid (13)To a solution of (R)-11 (200 mg, 1.77 mmol) in H 2 O (15.0 mL), 1 M NaOH(1.80 mL, 1.80 mmol) and p-toluenesulfonyl chloride (47.2 mg, 2.47 mmol)were added. The reaction mixture was stirred at ambient temperature for16 h. The reaction mixture was kept at a basic pH by slowly adding 1 Maqueous NaOH. After the conversion was complete, the reaction mixturewas extracted with ether (3 10 mL), acidified with 1 M aqueous HCl andextracted with EtOAc (3 15 mL). The combined EtOAc layers were dried(MgSO 4 ) and concentrated. Purification of the crude product by flashchromatography (EtOAc, 5% AcOH) afforded (R)-13 as an amorphoussolid; yield: 390 mg (1.46 mmol, 83%); (R)-13: [a] D : ˆ 36.0 (c 1, CH 2 Cl 2 );1H NMR (400 MHz, CDCl 3 ): d ˆ 10.27 (s, 1H), 7.73 (d, J ˆ 8.3 Hz, 2H), 7.27(d, J ˆ 8.1 Hz, 2H), 5.75 (d, J ˆ 8.8 Hz, 1H), 4.16 ± 4.11 (m, 1H), 2.69 ± 2.6376 Adv. Synth. Catal. 2002, 344, 70±83