The Effect of HMPA on the Reactivity of Epoxides, Aziridines, and Alkyl Halides with Organolithium Reagents Hans J. Reich,* Aaron W. Sanders, Adam T. Fiedler, and Martin J. Bevan Department of Chemistry, UniVersity of Wisconsin, Madison, Wisconsin 53706 Received May 15, 2002 The reaction of epoxides with nucleophiles is a widely used and effective method for the synthesis of alcohols. 1 Related reactions with N-activated aziridines provide access to amines. Simple alkyl, 2 vinyl-, or alkynyllithium 3 reagents and ketone 4,5a or ester enolates 6 work poorly, but more nucleophilic carboxylate dianions, meta- loenamines, 4 and stabilized organolithium reagents such as meta- lated dithianes give generally clean reactions and high yields. 7 Because of their relatively low reactivity, it is frequently advanta- geous to either activate epoxides by addition of a Lewis acid like boron trifluoride etherate 3,8 or activate the nucleophile by addition of lithium-complexing reagents such as HMPA or DMPU. 7b,9 We report here some observations on the latter reaction of interest to synthetic chemists. Figure 1 shows the results of a kinetic study of the effect of HMPA on the rate of reaction of three bis-thio substituted organolithium reagents, 1, 2, and 3, with methyloxirane, N-tosyl- 2-methylaziridine, and primary alkyl halides. 10 The reactivity order of 1:2:3 in THF was 1:29:5 for the epoxide and 1:16:3 for the aziridine. On addition of HMPA, the three lithium reagents showed wildly different rate effects, as did the electro- philes. With 1 as the nucleophile, the rate increase on addition of >10 equiv of HMPA was 8000 for the epoxide, 800 000 for the aziridine, and ca. 140 000 000 for BuCl. For 2, the rate decreased by a factor of 350 for the epoxide (after an initial small increase), but increased by 40× for the aziridine and 380× for BuCl. For 3, the rate decreased by >2500 for the epoxide and 15× for the aziridine, but stayed constant for the reaction with allyl chloride, BuBr, and BuI. Thus, the indiscriminate use of cosolvents for organolithium reactions without mechanistic understanding can be counterproductive - HMPA can act as a potent catalyst or inhibitor depending both on the structure of RLi and on the nature of the electrophile. How can we rationalize these behaviors? S N 2 reactions involving strongly contact ion-paired organolithium reagents exhibit the “product-separated ion pair” problem - the cation is unable to intimately follow the charge. 11a When the monomeric contact ion pair (CIP) of RLi is the nucleophile in a backside S N 2 attack (such as on an epoxide in Scheme 1), the developing negative charge on oxygen cannot be stabilized by the lithium counterion because a least-motion pathway results in the Li + separated from the oxyanion. Extensive ab initio calculations on the reaction of LiH, MeLi, 11a,b and cuprate species 11c with oxirane and alkyl halides have defined the strong requirement for catalysis by lithium and the ion separation problems of backside S N 2 displacements by a CIP. Separated ion pairs (SIPs) should be inherently favored as reactants in such reactions. 12 The key to understanding our data is the dual role played by HMPA. Strong complexation to lithium weakens the C-Li interac- tion and increases the fraction of SIP present, with a great enhancement of nucleophilic reactivity. 13 However, the Li + -HMPA complexes are much weaker Lewis acids than THF solvates, so any lithium assistance to departure of the leaving group is reduced or eliminated. 14 We have developed NMR techniques that allow reliable assess- ment of RLi ion pair status in the presence of HMPA. 15a Application to the lithium reagents 1, 2, and 3 led to the data in Figure 2. 15b,c Qualitatively, 1 is a strong CIP, with little ion pair separation until 2 equiv of HMPA have been added, and incomplete separation even at 10 equiv of HMPA. Reagent 2 is a weak CIP in THF, with substantial formation of SIP even before 1 equiv of HMPA was added. In contrast, 3 is ca. 80% SIP in THF at -78 °C. Our working hypothesis is that these reactions involve nucleo- philic attack of the organolithium SIP on the electrophile. The differences in behavior can be rationalized by competition between the ease of formation of the SIP (3 . 2 . 1, see Figure 2), the inherent nucleophilicity of the separated anions (1 . 2 . 3, as indicated by the relative reactivities at high HMPA equivalents, * To whom correspondence should be addressed. E-mail: reich@chem.wisc.edu. Figure 1. Effect of HMPA on rates of reaction of (a) methyloxirane, (b) N-tosyl-2-methylaziridine, and (c) BuCl, BuI, and/or allyl chloride with 1, 2, and 3 in THF at -78 °C(k2 is the second-order rate constant in M -1 s -1 ). 10 Scheme 1 Published on Web 00/00/0000 10.1021/ja026915q CCC: $22.00 © xxxx American Chemical Society J. AM. CHEM. SOC. XXXX, XXX, 9 A PAGE EST: 2