Cyclizations of N-acyliminium ions.

Converting carbon dioxide into carbamato derivatives.

Properties and Synthetic Utility of N-Substituted Benzotriazoles.

Novel monomers of the general formula ##STR1## where b is 0 or 1, a is 1, 2, 3 or 4, R 2 is a monovalent alkyl radical and R is an organic radical. The novel monomers may be employed to produce novel copolymers useful as hydrogel, soft non-hydrogel and/or rigid gas permeable contact lens materials.

Novel vinyl carbonate and vinyl carbamate contact lens material monomers

Regioselective synthesis of β-ketoesters from lithium enolates and methyl cyanoformate

A new reagent for the selective, high-yield N-dealkylation of tertiary amines: improved syntheses of naltrexone and nalbuphine

Individual diastereomeric 1,2-oxaphosphetanes have been directly observed in the Wittig olefination reaction by use of high-field NMR spectroscopy at low temperature, permitting detailed evaluation of these intermediates. Reactions of benzaldehyde with ylide 4 and with ylide 11 were monitored over time to gain the first intimate kinetic perspective of the Wittig reaction. Complete kinetic data are presented, along with the specifics of our analysis. In a number of instances, the reaction of nonstabilized phosphorus ylides with aldehydes showed a noncorrespondence between the relative proportion of cisand trans-oxaphosphetanes at low temperature (prior to significant alkene formation) and the final proportion of Z and E alkenes, resulting in an exaggerated production of E alkene (a phenomenon termed 'stereochemical drift\" for convenience). Thus, there was a measure of thermodynamic control in these reactions. For triaryl ylide 4, equilibration readily occurred with the aromatic aldehyde, benzaldehyde, in the presence of lithium salt. The shift to the more stable trans isomer (6a, R = Ph) with 4 and benzaldehyde was found to be concentration dependent, presumably because of competitive sequestration of lithium cation by the THF solvent. Such stereochemical drift also occurs in the absence of lithium if the trans-oxaphosphetane contaminates the cis isomer to a significant extent, reflecting an interaction of some kind between the two different oxaphosphetanes during their decomposition (a process termed \"diastereomeric synergism\"). In the case of trialkyl ylide 11, both an aromatic and an aliphatic aldehyde, benzaldehyde and pivaldehyde, showed drift to the trans-oxaphosphetane (6a and 6d, R = n-Bu); in fact, the E alkene became nearly the exclusive product ( Z / E = 8:92 and 1:99, respectively). The above-mentioned rate studies, entailing low-temperature ' 8 , I3C, and/or \"P NMR spectroscopic measurements, indicate that the equilibration of cisto truns-oxaphosphetane arises from a larger rate of reversion of the cis-oxaphosphetane to ylide and aldehyde. Crossover experiments involving deprotonation of diastereomerically pure P-hydroxyphosphonium salts 7a and Sa (R = Ph), followed by the addition of 4-chlorobenzaldehyde, supported our overall viewpoint, as did a double-label crossover experiment. A single-crystal X-ray analysis of threo salt 8a (R = Ph) was performed to unambiguously confirm the stereochemistry. Low-temperature 31P NMR investigations of semistabilized and stabilized phosphorus ylides are also described. Unfortunately, these latter studies did not offer any direct evidence for the existence of oxaphosphetane or betaine intermediates. A general discussion of the Wittig reaction mechanism is presented. Since its inception about 30 years ago, the Wittig reaction for olefination of aldehyde and ketone functionalities using phosphorus ylides has assumed a key position in the armamentarium of organic chemists.] Although considerable mechanistic discussion on the Wittig reaction has transpired, intimate mechanistic details still remain to be elucidated.2 The most useful tool for probing the Wittig reaction process probably is stereochemistry. Originally, little attention was paid to stereochemistry since several olefins were obtained as Z / E mixtures, suggesting that the reaction might not be generally stereo~elective.~ However, it was soon discovered that the type of ylide and the exact reaction conditions play key roles in determining reaction stereochemistry.' For example, nonstabilized phosphorus ylides react with aldehydes to give largely 2 alkenes, except under special condition^,^,^ and stabilized ylides give predominantly E alkenes, but semistabilized ylides generally give a mixture of Z / E alkenes with a ratio around 5050. From a historical perspective, the Wittig reaction has become widely recognized and applied because of (1) the ease of obtaining carbon-carbon double bonds in a predictable location and (2) the high stereoselectivity available in the preparation of less thermodynamically stable Z alkenes with lithium salt-free, nonstabilized ylides. Several proposed mechanisms for the Wittig reaction have attracted interest.* All of these seek to answer two key questions: (1) what intermediates predominate as the reaction proceeds from ylide and carbonyl compound to alkenes and phosphine oxide and (2) what mechanistic factors govern the resulting stereochemistry. In a classical formulation of the reaction, a phosphorus ylide combines with an aldehyde or unsymmetrical ketone to afford two ' McNeil Pharmaceutical. *The Pennsylvania State University. dipolar betaine intermediates, which collapse to Z and E alkenes and phosphine oxide via very transient oxaphosphetane species (Figure l).Ibqk However, the pioneering NMR studies of Vedejs' group in the 1970's indicated that 1,2-oxaphosphetanes can be reasonably persistent and that they should be considered as more important intermediates than betaines.2d,6 Whether oxaphosphetanes are formed directly, or via betaines, is still unknown. To rationalize stereochemical data, Bestmann has suggested that oxaphosphetane intermediates, presumably cis rich at the outset, can open to zwitterions (Figure l), which are free to rotate to the thermodynamically more stable threo isomers before decomposing to product^.^^^^.^ The loss of the initial stereochemistry (1) For general reviews of the Wittig reaction or selected aspects of it, see: (a) Gosney, I . ; Rowley, A. G. In Organophosphorus Reagents in Organic Synthesis; Cadogan, J. I . G., Ed.; Academic Press: New York, 1979; pp 7-153. (b) Schlosser, M. Top. Sfereochem. 1970, 5, 1. (c) Bestmann, H. J. Pure Appl. Chem. 1980, 52, 771. (d) Trippett, S. Quart. Reu. 1963, 17, 406. (e) Trippett, S . Pure Appl. Chem. 1964, 9, 255. (0 Maercker, A. Org. React. 1965, 14,270. (g) LeBigot, Y . ; Delmas, M.; Gaset, A. InJ Chim. 1984, 251, 123. (h) Bergelson, L. D.; Shemyakin, M. M. Angew. Chem., Inf . Ed. Engl. 1964, 3, 250. (i) Bestmann, H. J. Pure Appl. Cbem. 1979, 51, 515. (2) (a) Schlosser, M.; Schaub, B. J . Am. Chem. SOC. 1982, 104, 5821. (b) Reference I C and references cited therein. (c) Bestmann, H. J. Bull. Soc. Chim. Belg. 1981, 90, 519. (d) Vedejs, E.; Meier, G. P.; Snoble, K. A. J. J . Am. Chem. SOC. 1981, 103, 2823. (e) Olah, G. A,; Krishnamurthy, V. V. Ibid. 1982, 104, 3987. (f) McEwen, W. E.; Beaver, B. D.; Cooney, J. V. Pbosphorus Sulfur 1985, 25, 255. (3) Wittig, G.; Schollkopf, U. Chem. Ber. 1954, 87, 1318. (4) (a) Schlosser, M.; Christmann, K. F. Jusfus Liebigs Ann. Chem. 1967, 708, I . (b) Schlosser, M.; Muller, G.; Christmann, K. F. Angew. Chem., Int. Ed. Engl. 1966, 5, 667. (5) Maryanoff, B. E.; Reitz, A. B.; Duhl-Emswiler, B. A. J . Am. Chem. Soc. 1985, 107, 217 and references cited therein. (6) (a) Vedejs, E.; Snoble, K. A. J. J . Am. Cbem. SOC. 1973, 95, 5778. (b) Vedejs, E.; Snoble, K. A. J.; Fuchs, P. L. J . Org. Cbem. 1973, 38, 1178. 0002-7863/86/1508-7664$01.50/0

Stereochemistry and mechanism of the Wittig reaction. Diasteromeric reaction intermediates and analysis of the reaction course.

Protection by acylation in the selective alkylation of heterocycles

Deprotonation of benzocyclobutenols 6 in the presence of aromatic aldehydes affords benzopyranols 7 in high yield. In the key step of this process, an o-tolualdehyde anion generated by the known ring-opening of benzocyclobutenoxides adds to the aldehyde to give 7 which is easily oxidized to 3-substituted 3,4-dihydroisocoumarins 8 including intermediates in some natural product syntheses. For example, reaction of 6-methoxybenzocyclobutenol (1) with LTMP and p-anisaldehyde gave in 96% yield the benzopyranol 16, which subsequently was converted to (±)-hydrangenol (17). Similar treatment of 1 with LDA and isovanillin benzyl ether afforded the benzopyranol 19 (87% yield) which already has been converted to (±)-phyllodulcin (21). Finally, reaction of 5,6-(methylenedioxy)-benzocyclobutenol (10) with LTMP and the aldehyde 26 (from treatment of hydrastinine with ClCO 2 -Me) followed by methanolysis produced the acetal 28 in 96% yield. The overall yield was 65% for the five-step synthesis of the alkaloid (±)-peshawarine (24) from 10 and 26. Extension of the process to aliphatic aldehydes was illustrated by the preparation of 32 from benzocyclobutenol and isobutyraldehyde in 69% overall yield after oxidation with PCC

Roy A. Olofson

Papers

A new reagent for the selective, high-yield N-dealkylation of tertiary amines: improved syntheses of naltrexone and nalbuphine

Stereochemistry and mechanism of the Wittig reaction. Diasteromeric reaction intermediates and analysis of the reaction course.

Protection by acylation in the selective alkylation of heterocycles

Reaction of Benzocyclobutene Oxides with Aldehydes: Synthesis of Peshawarine and Other 3,4-Dihydroisocoumarins

Efficient and convenient synthesis of fluoroformates and carbamoyl fluorides