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

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Palladium-Catalyzed Cyclization Reactions of Acetylene-Containing Amino AcidsFULL PAPERSimprovement of the yield to 64%, but again significantracemization occurred (entry 12). Inversely, the use of LiCldid not result in any improvement (entry 13). Conducting thereaction under ligandless conditions with only Pd(OAc) 2present resulted in a disappointing yield of only 12%.Finally, without a Pd-catalyst present, the cyclization alsoproceeded to afford product 32 in a yield of 25% (entry 15). Inthe literature, several examples of such types of cyclizationswithout using a transition metal catalyst have been published.Examples include the cyclization of acetylenic amines (neat at180 ± 200 8C), [19] the cyclization of acetylenic amides usingTBAFas the base at 80 8C [20] and the cyclization of amides usingNaOEt in refluxing EtOH [21] to provide the correspondingcyclic enamides. Presumably, the base acts to generate a morenucleophilic nitrogen anion, and then gives rise to a cycloisomerization.However, in order to obtain acceptable yields inour reactions the cyclizations have to be enhanced throughpalladium(II) activation of the triple bond.Not shown in Table 3 are cyclizations that were carried outwith several other protecting groups at the nitrogen atomunder the standard conditions. Precursors activated as anamide (e.g., acetyl) or a carbamate (Boc, CO 2 Me) weresubjected to these conditions, but all of them failed to givethe desired cyclized product. Apart from the tosyl group, only anosyl-protected compound gave cyclized material under theoptimized conditions albeit in the very lowyield of 8%.A similar set of reactions was carried out using theenantiopure homologous precursors (R)-19 and (R)-20 ofwhich the results are summarized in Table 4. A satisfactoryyield of the five-membered ring (R)-33 containing an exocyclicdouble bond was obtained upon subjection of (R)-19 to thestandard conditions in THF at 60 8C (entries 1 and 2). In bothcases, no (partial) racemization was observed during theTable 4.HN CO 2 MeP(R)-19(R)-2010% ofcatalystbaseTHF, 60 °CN CO 2 MeTs(R)-33: P = Ts(R)-35: P = Nsentry reactant catalyst base12345678910111213141919191919191919191919192020Pd(PPh 3 ) 4Pd(OAc) 2 /2PPh 3Pd(OAc) 2 /2PPh 3 /5PhIPd(OAc) 2 /dppePd(OAc) 2 /dppbPd(OAc) 2 /xantphosPd(OAc) 2 /2P(o-tol) 3Pd 2 (dba) 3 /2PPh 3PdCl 2 (MeCN) 2Pd(PPh 3 ) 4Pd(OAc) 2 /2PPh 3Pd(OAc) 2 /2PPh 3Pd(OAc) 2 /2PPh 3 /5PhIK 2 CO 3K 2 CO 3K 2 CO 3K 2 CO 3K 2 CO 3K 2 CO 3K 2 CO 3K 2 CO 3Et 3 N [b]Et 3 N [b]Cs 2 CO 3K 2 CO 3K 2 CO 3K 2 CO 3time(h)111111.511571510.5N CO 2 MeP(R)-34: P = Tsproduct33333333343434333334333535yield(%) [a]64 [c]74 [c]907470 [d]60 [d]4354098%) was determined by chiral HPLC (Chiralpak OD; eluent:20% IPA/heptane).[d] Isolated as a mixture of 33:34; 1:8 (entry 5), 33:34; 1:10 (entry 6).reaction, the products were shown to have completely retainedtheir enantiopurity with the aid of chiral HPLC. When 5 equivof iodobenzene were added during the reaction, the yieldimproved to 90% (entry 3). A possible explanation is that theiodobenzene reacts with the Pd(0)-catalyst to in situ generatean organopalladium(II) catalyst that is more reactive towardsthe triple bond. As long as there is no TBAC present, reductiveelimination to form the corresponding phenyl-substitutedcross-coupled product does not occur (see also the mechanisticdiscussion).By changing the catalyst or the ligands, comparable yieldswere obtained; remarkably, when dppb, xantphos and P(o-tol) 3were used as the ligands, the isomerized enamide (R)-34 wasobtained after column chromatography (entries 5 ± 7). However,from 1 H NMR data of the crude product it was apparentthat the isomerization took place during column chromatography.Analogous to previous examples, the combination of aPd(II) catalyst with Et 3 N as a base did not give any product(entry 9). With Cs 2 CO 3 as the base, (R)-33 was formed in asmall amount (entry 11). Without a metal catalyst, the cyclizedproduct was found in 12% (entry 12), which is in line with theresults described in Table 3. Finally, the homopropargylglycinederivative (R)-20 containing the more easily removable Nsprotectinggroup cyclized in satisfactory yields to (R)-35(entries 13 and 14). As before, the addition of iodobenzeneresulted in an improved yield (difference between entries 13and 14).Similar Pd-catalyzed cyclizations were also carried out in thepresence of aryl halides and vinyl triflates to introduce anorganic substituent in the cyclization step (Table 5). Theenantiomerically pure Ts- and Ns-protected amino acids (R)-19 and (R)-20, respectively, were subjected to 10 mol % of aPd(0) catalyst, TBAC (1 equiv), an aryl halide or a vinyl triflate(5 equiv) and K 2 CO 3 (5 equiv). When the reaction was carriedout in DMF and iodobenzene was added as the aryl halide,beside (R)-37, a small amount of the undesired non-arylatedcyclized product (R)-33 was found. In MeCN, however, thecross-coupled product (R)-37 was selectively formed in 74%(entry 2) without detectable racemization. Coupling with p-nitroiodobenzene and p-iodoanisole resulted in the crosscoupledproducts (R)-38 and (R)-39 in reasonable yields.Reaction with the less reactive p-bromoanisole resulted in thesame product albeit in a significantly lower yield of 22%(entry 5). The range of coupling reagents was extended to vinyltriflates (viz. 26 and 36), [22] which resulted in the coupledproducts (R)-40 and (R)-41 (entries 6 and 7). Changing fromthe Ts to the Ns-protecting/activating group resulted in a highyield and excellent selectivity using standard conditions inMeCN at a lower temperature (entry 8). On the other hand,poor selectivity was observed when the solvent or the ligandswere changed. Apparently, the CC-bond formation throughreductive elimination is slower with these ligands.The double bond geometry of (R)-37 was unambiguouslyproven by 1 H NMR NOE studies which clearly showed the(E)-configuration. Figure 1 summarizes the NOE-enhancementsof the different protons. Especially the enhancement ofthe aromatic protons upon irradiation of the vinylic proton wasdiagnostic for proving the (E)-geometry.Adv. Synth. Catal. 2002, 344, 70±83 73
FULL PAPERSLarissa B. Wolf et al.Table 5.HNPentryreactantCO 2 Me(R)-19(R)-20RX10% ofcatalystRX, TBACK 2 CO 3MeCN, TR+N CO 2 Me N CO 2 MePPAB(R)-37-41: P = Ts (R)-33: P = Ts(R)-42: P = Ns (R)-35: P = NscatalystT(°C)time(h)ratio [a]A:Bproductproduct1 19 PhI Pd(PPh 3 ) 4 80 [d] 1 83:17 37 53 >992 19 PhI Pd(PPh 3 ) 4 82 2.5 100:0 37 743 19 p-NO 2 C 6 H 4 I Pd(PPh 3 ) 4 82 0.6 100:0 38 59 954 19 p-MeOC 6 H 4 I Pd(PPh 3 ) 4 82 2 100:0 39 58 975 19 p-MeOC 6 H 4 Br Pd(PPh 3 ) 4 82 2 100:0 39 226 19 26 Pd(PPh 3 ) 4 82 1 100:0 40 55 >997 1936Bu OTfPd(PPh 3 ) 4 82 1 100:0 41 138 20 PhI Pd(PPh 3 ) 4 60 1.5 100:0 42 80 >999 20 PhI Pd(OAc) 2 /2PPh 3 60 1 100:0 42 6210 20 PhI Pd(OAc) 2 /2PPh 3 60 [e] 3.5 91:9 42 5711 20 PhI Pd(OAc) 2 /dppe 60 [e] 0.5 66:33 42 1712 20 PhI Pd(OAc) 2 /dppb 60 4 93:7 42 5913 20 PhI Pd(OAc) 2 /xantphos 60 2 25:75 42 19[a] In entries 1 and 10-13, the products were isolated as mixtures of which theratio was determined on the basis of 1 H NMR spectra of the crude mixtures.[b] Isolated yield after column chromatography.[c] The ee was determined by chiral HPLC (Chiralpak OD; eluent: 20%IPA/heptane)[d] The reaction was carried out in DMF.[e] The reaction was carried out in THF.7.6%7.8% HH3.1%PhHN CO 2 Me9.3% H Ts6.5%(R)-37Figure 1. 1 H NMR NOE data of enamide (R)-37.yield [b] ee [c](%) (%)Both the TBS-protected and the unprotected amino alcoholswere subjected to the aforementioned amidopalladation conditionsof which the results are summarized in Table 6. Aminoalcohol (R)-43 cyclized in a 5-endo fashion to the fivememberedenamide in a lowyield (entry 1). When thehomologous alcohol (S)-44 was subjected to similar conditions,the yield of the cyclized product improved to 55% (entry 2). Apossible explanation for the increase of yield is the stability ofthe product; the endocyclic enamide readily decomposedunder the reaction conditions and during work-up. Underligandless conditions [Pd 2 (dba) 3 ] even higher yields wereobtained (entry 3). Furthermore, using the TBS-protectedamino alcohols (R)-45 and (S)-46 (entries 4 and 5) somewhathigher yields were obtained. Surprisingly, the best result wasobtained at room temperature (entry 6); although the reactionwas rather slow, the yield (90%) was excellent. This might be aresult of the fact that the formed enamide is more stable atroom temperature than at 60 8C.The cyclization/coupling reaction of the unprotected alcohol(S)-44 with iodobenzene did only result in trace amounts of thecyclized product. In contrast, the TBS-protected alcohol (S)-46reacted in high yield (82%) to the desired product (S)-52(entry 8). When this reaction was carried out at room temperatureunder the same conditions, cyclization did occur, but noCC-coupling took place and the only product that was isolatedwas the cyclic product (S)-50 (entry 9). Apparently, at thistemperature protonolysis of the intermediate organopalladiumintermediate is faster than reductive elimination.At first sight, there is no significant difference between thecyclizations of the amino esters and the amino alcohols. It isclear that the reactions with the protected alcohols proceed inhigher yields than the unprotected ones. Furthermore, from thelatter cyclizations it is apparent that the alcohol itself is notsufficiently nucleophilic to effect cyclization. This might be dueto the fact that the alcohol is not deprotonated under the mildlybasic conditions, which is the case for the correspondingcarboxylic acids.The mechanism of the oxypalladation reactions follows whatis known from literature experiments and is already mentionedIn order to study the influence of the ester group on theamidopalladation reactions, the enantiopure amino acids wereconverted into the corresponding (protected) amino alcohols(Scheme 6). The Ts-protected amino acids (R)-13 and (S)-14were reduced with LiAlH 4 (4 equiv) following a literatureprocedure. [23] The resulting alcohols (R)-43 and (S)-44 werewithout further purification protected using TBSCl (1.2 equiv)and imidazole (2.5 equiv) in DMF [24] to give (R)-45 and (S)-46in good overall yields without loss of enantiopurity.( ) n( ) nHN CO 2 H THF, rt HN CH 2 OHTsTs(R)-13: n = 1(S)-14: n = 2Scheme 6.LiAlH 4(R)-43: n = 1(S)-44: n = 2TBSClimidazoleDMF, 35 °C2.5 hHNTs( ) nCH 2 OTBS(R)-45: n = 1 (80%)(S)-46: n = 2 (90%)Table 6.10 mol%( ) of catalystnPhHN RX, base NNNTHF, TTs OR Ts OR Ts OR Ts OR43-46 47: R = H48: R = TBSentryreactant1 (R)-432 (S)-443 (S)-444 (R)-455 (S)-466 (S)-467 (S)-448 (S)-469 (S)-46RXcatalystbasePd 2 (dba) 3 K 2 CO 3PhI Pd(PPh 3 ) 4 K 2 CO 3 /TBACPd(OAc) 2 /2PPh 3 K 2 CO 3Pd 2 (dba) 3 K 2 CO 3Pd(PPh 3 ) 4 K 2 CO 3Pd(PPh 3 ) 4 K 2 CO 3Pd(PPh 3 ) 4 K 2 CO 3PhIPhIPd 2 (dba) 3Pd(PPh 3 ) 4K 2 CO 3 /TBACK 2 CO 3 /TBAC[a] Isolated yield after column chromatography.[b] The reaction was carried out in DMF.49: R = H50: R = TBST(°C)6060 [b]6080 [b]60rt6060rttime(h)73.51.54.52548165.54851: R = H52: R = TBS(R)-47(S)-49(S)-49(R)-48(S)-50(S)-50(S)-51(S)-52(S)-50yield(%) [a]165578287490
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