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

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Palladium-Catalyzed Cyclization Reactions of Acetylene-Containing Amino AcidsFULL PAPERSthe literature, several other successful examples of this type ofreaction involving oxygen nucleophiles are known. [6]Analogously, these types of Pd-catalyzed coupling/cyclizationreactions can also be carried out with nitrogen nucleophiles.[7] For example, tosylated carbamates, [8] tosylatedamides [9] and sulfonamides [10] are known to react with arylhalides and vinyl triflates to give the corresponding crosscoupledtosylated oxazolidinones, tosylated lactams andsulfonylated piperidines, respectively, all containing an (E)-configured double bond.Inversely, in the group of Hiemstra acetylene-substitutedlactams and oxazolidinones (viz. 7) were cyclized under similarconditions to afford the corresponding bicyclic (Z)-substitutedenamides (Scheme 4). [11] A plausible reaction mechanism thatexplains these contradictary results involves the intermediate8, in which palladium(II) coordinates to the carbamate nitrogenatom before the nitrogen-carbon bond is formed. Thisintramolecular activation of the triple bond is then followed bynucleophilic attack of the nitrogen from within the coordinationsphere of palladium to initially give the bicyclic species 9.Reductive elimination of Pd(0) finally gives rise to the (Z)-configured olefin 10.OOScheme 4.OONHNPdL Ph8The precedence of these literature examples, combined withthe relatively facile biocatalytic access to enantiomericallypure acetylene-containing amino acids developed in our groupin collaboration with DSM (Geleen, The Netherlands) [12]inspired us to use these trifunctional amino acids [13] in similarPd-catalyzed reactions. Logically, these amino acids ± containingboth an oxygen and a nitrogen nucleophile ± might uponsuitable protection give access to a variety of enantiomericallypure substituted lactones, as well as to the correspondingnitrogen heterocycles. [14]Results and Discussion7Pd(PPh 3 ) 4 ,TBAC, PhIK 2 CO 3 , MeCNreflux, 3 hIn order to obtain the cyclization precursors, the enantiomericallypure amino acids 11 and 12 [12] were protected withdifferent protecting groups. In case of the oxypalladationprecursors, the nitrogen atom was protected according toliterature procedures [15] involving either tosylation or acylationin an aqueous medium or irradiation in a microwave in thepresence of phthalic anhydride. [16] In all cases, the N-protectedamino acids 13 ± 16 were obtained in good yields without loss ofOOOON−Pd(0)Ph10 (60%)NPdL L9PhHHP 1NP( ) nCO 2 H(R)-13: (83%)n = 1, P = Ts, P 1 = H(S)-14: (73%)n = 2, P = Ts, P 1 = H(R)-15: (83%)n = 1, P = Boc, P 1 =H(S)-16: (91%)n = 1, P = P 1 = Phthrac-17: (91%)n = 2, P = P 1 = Phtha or b or cH 2 N( ) nCO 2 H(S/R)-11: n = 1(S/R)-12: n = 2d, eHNPCO 2 Meenantiopurity according to chiral HPLC analysis (Scheme 5).Additionally, rac-12 was converted to racemic phthalimide 17.Conversely, the enantiomerically pure amidopalladationprecursors 18 ± 20 were obtained by esterification using thionylchloride (2 equiv) in MeOH at reflux temperature andsubjection of the crude residue to Et 3 N (5 equiv) and p-toluenesulfonyl chloride (TsCl, 2 equiv) or p-nitrobenzenesulfonylchloride (NsCl, 2 equiv) in CH 2 Cl 2 . Alternatively, thecrude esterified residue was dissolved in pyridine and treatedwith TsCl or NsCl to give the same products in similar yields.The palladium-catalyzed cyclizations with the carboxylicacid as the nucleophile are shown in Table 1. Subjection of theN-protected amino acids 13 ± 17 to a mixture of 10 mol % of aPd(II) catalyst and 15 mol % of Et 3 N in various solvents atdifferent temperatures led to five- and six-membered lactones.The tosylamide (R)-13 was cyclized in a satisfactory yield of66% at 70 8C (entry 1). Changing the catalyst to Pd(OAc) 2 ledto a much faster reaction at room temperature in the same yield(66%, entry 2). A single attempt to use an inorganic base(K 2 CO 3 ) appeared fatal to the reaction (entry 3). Subjection of( ) n(S)-18: (94%)n = 1, P = Ts(R)-19: (72%)n = 2, P = Ts(R)-20: (59%)n = 2, P = NsScheme 5. Reagents and conditions: 13, 14 ! 15, 16 (a) TsCl(1.4 equiv), 1 M NaOH (1.1 equiv), rt, 16 h; 13 ! 17 (b) di-tertbutyldicarbonate (1.1 equiv), NaHCO 3 (2 equiv), dioxane/H 2 O,reflux, 4 h; 13, 14 ! 18, 19 (c) phthalic anhydride (1 equiv), H 2 O,microwave (600 W, 5 min); (d) SOCl 2 (2 equiv), MeOH, reflux;(e) TsCl or NsCl (2 equiv), Et 3 N (5 equiv), CH 2 Cl 2 , rt, 16 h.Table 1.( ) n 10% of catalyst( ) nP 1 P 1ON CO 2 H base, solvent , TNPP O13-17 21-25T timeentry substrate catalyst base solvent product(°C) (h)1 (R)-13 Pd(MeCN) 2 Cl 2 Et 3 N THF 70 16 (R)-212 (R)-13 Pd(OAc) 2 Et 3 N THF rt 1 (R)-213 (R)-13 Pd(MeCN) 2 Cl 2 K 2 CO 3 DMF 80 64 (R)-15 Pd(OAc) 2 Et 3 N THF rt 2 (R)-225 (S)-16 Pd(OAc) 2 Et 3 N THF rt 1.5 (S)-236 rac-14 Pd(MeCN) 2 Cl 2 Et 3 N MeCN 60 16 rac-247 rac-17 Pd(OAc) 2 Et 3 N THF 60 5 rac-25[a] Isolated yields after column chromatography.[b] ee >97% according to 1 H NMR using Eu(hfc) 3 as the shift reagent in CDCl 3 .yield(%) [a]6666 [b]06342 [b]3224Adv. Synth. Catal. 2002, 344, 70±83 71
FULL PAPERSLarissa B. Wolf et al.the Boc-protected acid 15 to similar conditions resulted atroom temperature in 22 in 63% (entry 4). Likewise, thephthalimide-protected amino acid 16 cyclized in a lower yield.In contrast with the five-membered rings, the six-memberedlactones 24 and 25 were obtained in somewhat disappointingyields (entries 6 and 7), which is probably due to the lowertendency of Pd to react in a 6-exo-fashion. [4d,6f] The ee of 21 and23 was determined via 1 H NMR experiments using a chiralshift reagent [Eu(hfc) 3 in CDCl 3 ] showing an ee higher than97%, which led us to conclude that virtually no racemizationoccurred in these cyclization reactions.In addition to these reactions, other cyclization reactionswere carried out in the presence of various aryl halides or avinyl triflate to introduce an organic substituent in thecyclization step, which are summarized in Table 2. The generalreaction conditions involved 10 mol % of a Pd(0) catalyst,Et 3 N (5 equiv), tetrabutylammonium chloride (TBAC,2 equiv) and the aryl halide (2 equiv) in MeCN at 608C.When tosylamide (R)-13 was reacted under these conditionsneither cyclization nor introduction of the aryl group wasobserved. Although the starting material had disappeared,amidopalladation could be excluded on the basis of NMRanalysis. More gratifyingly, the Boc-protected amino acid (R)-15 reacted under similar conditions to the cross-coupledlactone (R)-27 in a moderate yield of 44%, without detectableracemization. The phthalimide-protected amino acid (S)-16was treated with iodobenzene and p-iodoanisole to afford thelactams 28 and 29, respectively, in similar yields (entries 3 ± 6).Unfortunately, in all these cases complete racemizationoccurred at the temperature required for cyclization. Apparently,the phthalimide protecting group renders the a-protonof the amino acid sufficiently acidic to be prone to racemizationunder the slightly basic reaction conditions. No cyclizationoccurred with p-nitroiodobenzene (entry 7), which was probablydue to the decreased reactivity of the organopalladiumintermediate. Treatment of (S)-16 with vinyl triflate 26 [17]afforded 30, albeit in only 23% (entry 8). Furthermore, inanalogy with the aforementioned oxypalladation reactions,Table 2.R10% of catalyst( ) nRX, Et 3 N( )nP 1P ON CO 2 HTBAC1NMeCN, 60 °CPP O13, 15-17 27-31entry123456789substrate(R)-13(R)-15(S)-16(S)-16(S)-16(S)-16(S)-16(S)-16rac-17catalystRXtime (h)Pd(PPh 3 ) 4 PhI 2Pd(OAc) 2 /2PPh 3 PhI 5Pd(OAc) 2 /2PPh 3 PhI 6Pd(PPh 3 ) 4 PhI 5Pd(OAc) 2 /2PPh 3 PhI 5Pd(PPh 3 ) 2 Cl 2 PhI 5Pd(PPh 3 ) 4 p-MeOC 6 H 4 I 24Pd(PPh 3 ) 4 p-NO 2 C 6 H 4 I 16Pd(PPh 3 ) 4 t Bu OTf1626product(R)-2728282829044 [b]43411841023[a] Isolated yields after column chromatography.[b] The geometry of the (E)-double bond was proven via 1 H NMR NOE experiments.3031yield(%) [a]31formation of a six-membered lactone appeared difficult asindicated by the relatively lowyield of 31 (31%, entry 9).In summary, the yields of the cross-coupling reactions turnedout to be somewhat disappointing; this could either be due to alower reactivity of the amino acids towards oxypalladationreactions compared to −regular× carboxylic acids, but on theother hand also to the relative instability of the enol esters thatare formed. The fact that analysis by TLC always showedcomplete conversion and no starting material was recovered inthese reactions seems to support the latter hypothesis.The Pd-catalyzed cyclizations with the enantiopure propargylglycine-derivedprecursor (S)-18 are shown in Table 3.The anticipated five-membered endocyclic enamide (S)-32was formed in 76% yield using 10 mol % of Pd(PPh 3 ) 4 and5 equiv of K 2 CO 3 in DMF at 80 8C (entry 1). Unfortunately,partial racemization occurred under these conditions leadingto an enantiopurity of the product of only 33%. To circumventthe undesired racemization, catalyst, solvent, reaction temperatureand the base were varied. By changing the solvent fromDMF to THF and the catalyst from Pd(PPh 3 ) 4 to Pd(OAc) 2 /2PPh 3 , the ee increased from 91% at 60 8C (entry 2) to >99% at40 8C (entry 3), albeit that the yield dropped to 48%. Adding asmaller amount of base, i.e., one equiv instead of five equiv,resulted in a dramatic lowering of the yield (18%), while stillpartial racemization was observed (entry 5). Changing the baseto the less basic salt NaHCO 3 did not improve the yield either(entry 6). When using the organic base Et 3 N, no cyclizationproduct was observed at all (entry 7). In addition, the influenceof different ligands was studied. Several combinations ofcatalysts and ligands with different bite angles [18] werescreened, but none of these combinations had a dramaticinfluence on the yield or the reaction time. The chloridesources were also varied to study their effect on the yield andthe reaction rate at 40 8C. The use of TBAC led to anTable 3.HN CO 2 MeTs(S)-18entry123456789101112131415catalyst10% of catalystbase (5 equiv)solvent, TPd(PPh 3 ) 4Pd(OAc) 2 /2PPh 3Pd(OAc) 2 /2PPh 3Pd(PPh 3 ) 4Pd(OAc) 2 /2PPh 3Pd(OAc) 2 /2PPh 3Pd(OAc) 2 /2PPh 3Pd(OAc) 2 /xantphosPd 2 (dba) 3 /xantphosPd(OAc) 2 /dppePd(OAc) 2 /dppbPd(OAc) 2 /2PPh 3 /TBACPd(OAc) 2 /2PPh 3 /LiClPd(OAc) 2baseK 2 CO 3K 2 CO 3K 2 CO 3K 2 CO 3K 2 CO 3cNaHCO 3Et 3 NK 2 CO 3K 2 CO 3K 2 CO 3K 2 CO 3K 2 CO 3K 2 CO 3K 2 CO 3K 2 CO 3N CO 2 MeTs(S)-32solventDMFTHFTHFTHFTHFTHFTHFTHFTHFTHFTHFTHFTHFDMFTHFT(°C)806040406060606060606040406080time(h)3.544848242424325421244855.5OPPh 2 PPh 2xantphosyield(%) [a]76654836181806664444064261225ee(%) [b]3391>99[a] Isolated yields after column chromatography.[b] The ee was determined by chiral HPLC (Chiralpak OD; eluent: 20% IPA/heptane).[c] One instead of five equiv of base was added.84618972 Adv. Synth. Catal. 2002, 344, 70±83
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