Additions of nucleophiles to 2-formyl-1-naphthamides 4We started by treating the aldehydes 4 with a range of simpleorganolithium and Grignard reagents in THF at 78 C asshown in Scheme 4 and Table 2: methyllithium (entry 1), butyllithium(entry 2), octynyllithium (entry 7), phenyllithium(entry 10); and methylmagnesium bromide (entry 12), butylmagnesiumchloride (entry 13), phenylmagnesium bromide(entry 17), allylmagnesium bromide (entry 18). The reactionsgave moderate to excellent yields of the alcohols 11–15 but withselectivities varying greatly, from 140:1 syn to >99:1 anti.The additions have one simple overriding feature: all theGrignard reagents add with syn-selectivity, and (apart fromPhLi and octynyllithium) the organolithiums add with antiselectivity.Other than this, the trends are much less distinct.Phenyl and butyl additions are more selective than allyl additions,with the methyl additions lying in between. Selectivityalso varies with the N-substituents R 1 and R 2 : generally,but by no means always, the Ni-Pr 2 aldehyde 4d reacts withslightly higher selectivity than the NEt 2 aldehyde 4c. TheN(CHPr 2 ) 2 aldehyde 4e underwent the most anti-selective (withMeLi, entry 1) and the most syn-selective (with PhMgBr, entry17) reactions of all, but its reactions with BuLi (entry 2)and BuMgBr (entry 13) were notably unselective, and gavesignificant amounts of the reduction product 16e. Our firstconclusion, therefore, is that the reactions of 4 are controlledScheme 2 Synthesis of aldehydes 4 (i) s-BuLi, THF, 78 C; (ii)Me 2 NCHO, 78 C.Table 1 Synthesis of aldehydes 4Entry R 1 R 2 Startingmaterial Product Yield (%)1234a Plus 5 (65%).MeEti-PrCH(n-Pr) 2t-BuEti-PrCH(n-Pr) 23b3c3d3e4b4c4d4e33 a7882 2859 or 44 2Scheme 3 Synthesis of 4a; (i) NBS, (PhCO 2 ) 2 , CCl 4 , (60%); (ii) 2-nitropropane,NaOEt, EtOH, (62%); (iii) HOCH 2 CH 2 OH, p-TsOH, PhH,(91%); (iv) 1. t-BuLi × 2, 2. ClCONMe 2 ; (v) p-TsOH, AcMe (83% over2 steps).Table 2 Additions of nucleophiles to aldehydes 4From 4c From 4d From 4eEntryReagentAdditives(equiv.)Product,yield a (%)Ratio banti:synProduct,yield a (%)Ratio banti:synProduct,yield a (%)Ratio banti:syn12345678910111213141516171819202122232425MeLi—n-BuLi—HMPA (4)BF 3 OEt 2 (1) dBF 3 OEt 2 (2) dMe 3 Al (0.1)OctynylLi—Me 3 Al (0.1)i-Bu 2 AlH (1)PhLi—HMPA (4)MeMgBr—n-BuMgCl—HMPA (4)MgBr 2 (1) dZnBr 2 (1) dPhMgBr—AllylMgBr—MeTi(Oi-Pr) 3 —n-BuTi(Oi-Pr) 3 —OctynylTi(Oi-Pr) 3 —PhTi(Oi-Pr) 3 —AllylTi(Oi-Pr) 3 —gMeTiCl 3iMeTiCl 311c 9471:2912c 5685:1512c 6366:3412c 6757:4312c 4943:57————————14c 5219:8114c — e 27:7311c 9125:7512c 7214:8612c 6838:6212c 8343:5712c 7437:6314c 8114:8615c 9742:5811c 7098:212c 6474:2613c 7695:514c 9711:8915c 9271:2911c 48 12 h 6:9418 h —11d 9080:2012d 8385:1512d 6573:2712d 4148:5212d 5945:5512d 5694:613d 9020:8013d 6693:713d 50 >99:114d 9534:6614d — e 33:6711d 6623:7712d 5715:8512d 6232:6812d 6150:5012d 8932:6814d 713:9715d 9440:6011d 99 300:112d 63 125:113d 52 125:114d 9685:1515d 100 77:2811d 41 13 h 65:3523 h —11e 9912e 91 6 c——————————12e 33 33 c, f———14e 90—11e 59——————>99:149:51——————————34:66———1:140—>99:1——————a Isolated yield of mixture. b Determined by analytical HPLC. c Yield of reduction product 16. d CH 2 Cl 2 in the absence of THF. e Product notisolated. f n-BuMgBr used. g Reagent formed in situ from MeMgBr TiCl 4 . h Yield of pinacol product 17. i Reagent formed in situ fromMeLi TiCl 4 .1364 J. Chem. Soc., Perkin Trans. 1, 2000, 1363–1378
Fig. 1 Conformation of aldehyde 4.Scheme 4principally by the nature of the metal and are influenced relativelylittle by the size of R 1 and R 2 .In contrast with the reactions of aldehydes 4 the reactions ofketones 2 all proceed with the same stereochemical sense 1because all reagents attack 2 from the less hindered face (syn tothe amide CO) of its s-cis conformation. For aldehyde 4, boths-cis and s-trans conformations are accessible (Fig. 1), and 4may present either face of its electrophilic carbonyl group to anincoming reagent simply by rotation about the Ar–CHO bond.The effect of the metal on the stereoselectivity of the reactioncould be a result of the degree of chelation by the metalbetween the amide and the aldehyde carbonyl groups, whichwould affect the Ar–CHO torsional angle in the transitionstate. 33 This being so, additives which promote or dissuade chelationshould influence the selectivity accordingly. We added tothe reactions of BuLi, PhLi and BuMgCl four equiv. of HMPA(entries 3, 11, 14, Table 2) in an attempt to prevent amide–aldehyde chelation: in all cases selectivity decreased, becomingmore syn-selective from BuLi and more anti-selective from PhLiand BuMgCl. We also repeated the reactions of BuLi andBuMgCl in CH 2 Cl 2 in the presence of Lewis acids: BF 3 OEt 2(1 or 2 equiv., entries 4 and 5) to discourage chelation andMgBr 2 and ZnBr 2 (entries 15, 16) to encourage it. Again, the onlyeffect was that the selectivity, in whichever direction, decreased.Organoaluminium reagents can exhibit high levels of stereoselectivityin their additions to aldehydes. 22 Additionally, trimethylaluminiumhas been shown to be capable of formingfive-membered chelates with epoxyalcohol derivatives, increasingtheir reactivity and controlling the regioselectivity of theirreactions. 34 We therefore briefly investigated the effect oforganoaluminium reagents on the stereoselectivity of additionsto chiral aldehydes. In the presence of one equivalent ofDIBAL-H, octynyllithium gave the alcohol 13d solely as itsanti-diastereoisomer (entry 9). 35 The reaction was (unsurprisingly)accompanied by a significant amount of reduction toalcohol 16d and behaved unpredictably, with 16d sometimesbeing the sole product. 36 No reaction was observed whenDIBAL-H was replaced with trimethylaluminium. However, inthe presence of catalytic quantities (0.1 equiv.) of trimethylaluminium,reactivity was restored, the anti diastereoisomerbeing produced (entry 8) with slightly lower stereoselectivitythan with stoichiometric DIBAL-H. The same enhanced antistereoselectivitywas observed when BuLi was added to 4d inthe presence of catalytic trimethylaluminium (entry 6).Trialkylaluminiums cannot usually be used as Lewis acids inthe presence of organolithiums because of the rapid formationof ate-complexes. However, Maruoka and co-workers 34 haveshown that Me 3 Al leads to an enhancement of the reactivity ofepoxy-alcohol derivatives towards organolithiums which cannotbe ascribed to ate complex formation: catalytic quantitiesof Me 3 Al are essential. DIBAL-H–trialkylaluminium complexeshave moreover been used to control the selectivity ofadditions of vinyllithiums to chiral aldehydes. 37 We thereforepropose that these are reactions of organolithiums catalysed(and increased in selectivity) by coordination of R 3 Al to thealdehyde oxygen, and that the presence of excess Me 3 Al leads tothe formation of less reactive ate complexes. The highly selectiveformation of the anti diastereoisomer suggests that chelationbetween the amide and aldehyde carbonyl groups is notinvolved.As an alternative to the use of additives, we next turnedto reagents designed respectively to avoid and to promotechelation during stereoselective reactions. Alkyltitanium triisopropoxides,whose reactions with α-alkoxyaldehydes proceedvia non-chelated transition states, 15,38,39 were made bytreating MeLi, BuLi, octynyllithium, phenyllithium andallylmagnesium bromide with ClTi(Oi-Pr) 3 . The outcomes oftheir reactions with 4 are shown in entries 19–23 of Table 2.Apart from one case, the reactions went in the same sense asmost of the organolithium reactions—they were anti-selective—but with much higher levels of stereocontrol than even theMe 3 Al-catalysed reactions (entries 6, 8 and 9). MeTi(Oi-Pr) 3was the most selective of all, reacting with 4c, 4d and 4e with50:1, 300:1 and >99:1 selectivity respectively (entry 19), withthe octynylTi(Oi-Pr) 3 performing almost as well (entry 21: theoctynyltitanium species reacts with selectivity opposite to thatof octynyllithium). BuTi(Oi-Pr) 3 reacted selectively with theNi-Pr 2 aldehyde 4d, though the selectivity with the NEt 2 aldehyde4c was less good (entry 20). The allyl reagent (entry 23),as before, was less selective, and the PhTi(Oi-Pr) 3 (entry 22)exhibited a bizarre switch from anti-selectivity with 4d to synselectivitywith 4c [PhLi had also proved unusually syn-selective(entry 7)].The alkyltitanium triisopropoxide reactions demonstrate thatthe key to good anti-selectivity in the addition to 2-formyl-1-naphthamides is to avoid chelation. In fact, the results obtainedJ. Chem. Soc., Perkin Trans. 1, 2000, 1363–1378 1365
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