Grignard Reagent

1598 Organo surfacelics 2009, 28, 15981605 CoVer Essay The Grignard Reagents Dietmar Seyferth Department of Chemistry, mum Institute of Technology, Cambridge, Massachusetts 02139 ReceiVed February 4, 2009 During the past c years the Grignard reagents credibly discombobulate been the most widely employ organometallic reagents. close to of them argon easily prep bed in di vinyl lively reply (normally diethyl ethoxyethane or, since the early 1950s, THF) by the reception of an thoroughgoing halide with metallic atomic number 12 (eq 1). defer 1. Composition of Diethyl Ether Solutions of sundry(a) Grignard Reagents at Equilibrium (in mol %), 2RMgX h R2Mg + MgX2a RX in RX + Mg reacn CH3I C2H5I C2H5Br C2H5Cl n-C3H7I n-C3H7Br n-C3H7Cl C6H5I C6H5Br a RMgX 87. 0 43. 0 41. 0 15. 0 24. 0 24. 0 17. 0 38. 0 30. 0 R2Mg ) MgX2 6. 5 28. 5 29. 5 42. 5 38. 0 38. 0 41. 5 31. 0 35. 0 RX + Mg f RMgX (X ) Cl, Br, I) (1) Most of them are stable in quintessenceeal settlement (although atmospher ic moisture and type O should be excluded) and in general are quite reactive.Discover by Victor Grignard at the University of Lyon in France in 1900,1 their ease of pre paration and their big applications in constitutive(a) and organometallic synthesis made these new organo milligram reagents an instant success. The importance of this contri besidesion to artificial chemistry was recognized very(prenominal) early, and for his discovery Grignard was awarded a n oneel Prize in Chemistry in 1912. Our cover molecule is the monomeric ethylmagnesium bromide bis(diethyl diethyl aetherate) (1), whose solid-state molecular construction was determined by an X-ray diffraction study by Lloyd Guggenberger and RobertRundle in 1964 using crystallisations insulate from a diethyl ether solution of a C2H5Br/Mg answer multifariousness by slow modify with a stream of cold gaseous nitrogen. 2-4 Adapted from Schlenk, W. , Jr. Ber. Dtsch. Chem. Ges. 1931, 64, 734. Wilhelm Schlenk and his male child detect 80 years ago, more than one magnesium-containing species exists in the diethyl ether solution of a Grignard reagent. 5 A redistri preciselyion of the substituents on magnesium takes place, and the RMgX species ends up in sense of balance with the two symmetrical species, the diorganomagnesium and the magnesium dihalide the Schlenk Equilibrium (eq 2). 2RMgX h R2Mg + MgX2 (2) Generally written as RMgX in textbooks, monographs and research written document, the Grignard reagents in supernal solution are more complicated than this simple formula indicates. As (1) (a) Grignard, V. Compt. rend. Hebd. Seances Acad. Sci. 1900, 130, ? 1322. (b) Grignard, V. Dissertation Theses sur les combinaisons organo magnesienes mixtes et leur application a des syntheses, University of Lyon, Lyon, France, 1901. (2) (a) Guggenberger, L. J. Rundle, R. E. J. Am. Chem. Soc. 1964, 86, 5344. (b) Guggenberger, L. J. Rundle, R. E. J. Am. Chem. Soc. 1968, 90, 5375. 3) A lucid solid, CH 3MgI (n-C5H11)2O, was isolated and identi? ed as such(prenominal)(prenominal) by elemental compendium (Mg and I) in 1908 Zerewitinoff, Th. Ber. Dtsch. Chem. Ges. 1908, 41, 2244. The oxonium structure The species that contain Mg-halogen bonds tolerate be precipitated from Grignard reagent solutions in diethyl ether by the humanitarian of 1,4-dioxane. An insoluble, polymeric 1,4-dioxane adduct is formed, leaving behind a solution of R2Mg5sa reusable preparation of dialkyl- and diarylmagnesium reagents. 6 Wilhelm Schlenk, Jr. analyzed the 1,4-dioxane precipitations from a number of Grignard reagent solutions. Assuming that the precipitation is essentially instantaneous, i. e. , that the calculated R2Mg, MgX2, and RMgX percentages re? electroshock therapy the actual composition of the Grignard reagent solution at symmetricalness, Schlenk inform the compositions collected in tabulate 1. Direct evidence (5) Schlenk, W. Schlenk, W. , Jr. Ber. Dtsch. Chem. Ges. 1929, 62, 920. (6) (a) Cope, A. C. J. Am. Chem. Soc. 1935, 57, 2238. (b) As Erwin Weiss ensnare, evaporation of diethyl ether solutions of methyl- and ethylmagnesium bromide and chloride at reduced pressure followed by heating of the pallid solid residues at ca. 00 C and 0. 001 mmHg for several hours gave a mixture of the several(prenominal)(prenominal) pure, firmness-free, polymeric R2Mg compounds and magnesium halides. The solid MgCl2 thus obtained differed from a sample obtained from a MgCl2 melt in that its lattice showed a strong stacking disorder. This form of MgCl2 had an highly high surface area Weiss, E. Chem. Ber. 1965, 98, 2805. (7) Schlenk, W. , Jr. Ber. Dtsch. Chem. Ges. 1931, 64, 734 Further concomitants to the examples in Table 1 were soon thereafter reported by separate workers (a) zero(prenominal)ler, C. R. Hilmer, F. B. J. Am. Chem. Soc. 1932, 54, 2503. (b) Johnson, G. O. Adkins, H. J. Am. Chem. Soc. 1932, 54, 1943. (c) Cope, A. C. J. Am. Chem. Soc. 1934, 56, 1578. was writt en for this compound. Earlier workers had isolated non see-through solid samples of etherates, e. g. , C2H5MgI (C2H5)2O and RMgI 2(C2H5)2O. (4) Other early Grignard reagent crystal structures (a) Stucky, G. D. Rundle, R. E. J. Am. Chem. Soc. 1964, 86, 4825 (C6H5MgBr 2Et2O). (b) Vallino, M. J. Organomet. Chem. 1969, 20, 1 (CH3MgBr 3THF). . 10. 1021/om900088z CCC $40. 75 ? 2009 Ameri evict Chemical Society proceeds on Web 03/16/2009 Organometallics, Vol. 28, No. 6, 2009 1599 Figure 1.Association of several Grignard compounds in tetrahydrofuran (J. Am. Chem. Soc. 1969, 91, 3847. ). that solutions of CH3MgBr in diethyl ether contain CH3MgBr and (CH3)2Mg was obtained by Ashby and co-workers by means of 1H proton magnetic resonance spectroscopic measurements at -105 C. Solutions of t-butylmagnesium chloride in diethyl ether alike were studied. 8 The intention of the halide substituents in the RMgX and MgX2 species generate in supernal solution at equilibrium to form bridges sur rounded by magnesium atoms, Mg-X-Mg, in a Lewis launch/Lewis acid type interaction further complicates the nature of the Grignard reagent in vaporous solvents.In a very thorough study of the connector factors of different Grignard reagents in diethyl ether and THF by ca refereeul ebullioscopic molecular tilt measurements, Eugene Ashby and Frank pram at the Georgia Institute of Technology found that monomeric, dimeric, and higher oligomeric species were present, depending on the solvent and the halogen and the organic substituents on the magnesium atom. 9 Included in this study a spacious with data for the RMgX solutions were data for a few R2Mg compounds and for the magnesium dihalides.As Figure 1 shows, the observed sleeper factor (the i hold dear is the apparent molecular weight divided by the formula weight of the monoetherate) shows that the Grignard reagents and (C6H5)2Mg are close to monomeric in the relatively strong Lewis basic THF. The control is quite different in diethyl ether solution (Figures 2 and 3), with association factors of 1 to nearly 4 for solute concentrations up to ca. 3 molal. It is non hit what these i values mean in terms of the actual species present in these solutions.On the assumption that the Schlenk equilibrium is operative in all cases, in view of the movement of a signi? cant concentration of MgX2, one cannot dribble moreover simple solvated species of type i(R)Mg-X n i (average n ) i). Toney and Stucky isolated crystals of a dimeric species, 2, from a solution of C2H5MgBr in di-n-butyl ether by addition of this solution to triethylamine. 10 The molecular Figure 2. Association of alkylmagnesium chlorides in diethyl ether. notification of importance of halogen vs R group in determining the form of association in diethyl ether (J. Am. Chem. Soc. 1969, 91, 3848. ).Figure 3. Association of several alkyl- and arylmagnesium bromides and iodides and related magnesium compounds in diethyl ether (J. Am. Chem. Soc. 1969, 91, 3848. ). structure, as determined by X-ray analysis, contained a copy Br bridge with the ethyl groups in a trans arrangement. That (8) In CH3MgBr solutions in diethyl ether (a) Ashby, E. C. Parrish, G. Walker, F. Chem. Commun. 1969, 1464. (b) (CH3)3CMgCl solutions in diethyl ether at-26 C Parris, G. Ashby, E. C. J. Am. Chem. Soc. 1971, 93, 1206. (9) (a) Walker, F. W. Ashby, E. C. J. Am. Chem. Soc. 1969, 91, 3845. (b) Ashby, E. C. Bull. Soc.Chim. Fr. 1972, 2133 (review, in English). (c) Meisenheimer, J. Schlichenmaier. Ber. Dtsch. Chem. Ges. 1928, 61 (an earlier, same, but more limited study in diethyl ether). more complicated structures can be present in an RMgX solution in diethyl ether was exhibit by the determination of the X-ray crystal structure of a coherent compound obtained from a THF solution of C2H5MgCl of composition C2H5Mg2Cl3. This compound was not a simple Cl-bridged dimer, as the empirical formula might suggest. Actually, it was a tetramer (Figure 4) in w hich the Mg atoms have a coordination number greater than 4. 1 on that point is a caveat, however the species that crystallizes from a Grignard reagent solution does not necessarily this instant re? ect what species are swimming around in the solution. The crystalline solid shown in Figure 4 could well have self-assembled during the crystal process by combination of two molecules of the C2H5Mg2Cl3 dimer and not been present in solution at all. Even in the case of monomeric RMgX in THF solution, the Schlenk equilibrium will be operative and the strongly Lewis basic THF apparently prevents halide bridging between Mg atoms.Consequently, the (10) Toney, J. Stucky, G. D. Chem. Commun. 1967, 1168. (11) Toney, J. Stucky, G. D. J. Organomet. Chem. 1971, 28, 5. 1600 Organometallics, Vol. 28, No. 6, 2009 Scheme 1 Figure 4. Molecular structure of C2H5Mg2Cl3(C4H8O)32, a tetrameric Grignard reagent. Modi? ed from Toney and Stucky (J. Organomet. Chem. 1971, 28, 15. (copyright 1971, with permi ssion from Elsevier)). aim of monomeric RMgX, R2Mg, and MgX2, all solvated, would result in the measurement of an association factor of 1, as Walker and Ashby observed.There are so many factors that bear on the question of the constitution of a given(p) Grignard reagent in ethereal solutionsthe Lewis basicity and steric properties of the ether solvent, the electronegativity and size of the halogen atom in RMgX, the nature and steric properties of the organic substituent on the magnesium atom. These will affect the magnitude of the equilibrium constant of the Schlenk equilibrium and the extent of Mg-X-Mg bridging. For most applications in synthetic chemistry it will suf? ce to take the easy way exposesto visit and to write the Grignard reagent as RMgX.There is an different amuseing and usable property of ethereal Grignard reagent solutions. The magnesium species are weak electrolytes in such solvents of low dielectric constant, and RMgX solutions conduct an electric true. 12 The electrolysis of solutions of organomagnesium halides was studied in approximately flesh show up by Kondyrew at the State Research Institute in Leningrad13 and by Ward Evans and his students at Northwestern University. 14 During the electrolysis, magnesium species migrate both to the cathode and to the anode. Scheme 1 shows the simplest picture based on RMgX. Metallic magnesium is formed at the cathode. 12) The earliest report appears to be a 1912 french paper Jolibois, P. Compt. rend. Hebd. Seances Acad. Sci. 1912, 155, 213. See excessively Nelson, ? J. M. Evans, W. V. J. Am. Chem. Soc. 1917, 39, 82. (13) (a) Kondyrew, N. W. Ber. Dtsch. Chem. Ges. 1925, 58, 459. (b) Kondyrew, N. W. Manojew, D. P. Ber. Dtsch. Chem. Ges. 1925, 58, 464. (c) Kondyrew, N. W. Ber. Dtsch. Chem. Ges. 1928, 61, 208. (d) Kondyrew, N. W. Ssusi, A. K. Ber. Dtsch. Chem. Ges. 1929, 62, 1856. (14) The Evans group published many papers in J. Am. Chem. Soc. during the 1933-1942 period. See, for example (a) Evans, W. V. Lee, F.H. J. Am. Chem. Soc. 1934, 56, 654. (b) Evans, W. V. Field, E. J. Am. Chem. Soc. 1936, 58, 720. (c) Evans, W. V. Braithwaite, D. J. Am. Chem. Soc. 1939, 61, 898. (d) Evans, W. V. Braithwaite, D. Field, E. J. Am. Chem. Soc. 1940, 62, 534. (e) Evans, W. V. Pearson, R. J. Am. Chem. Soc. 1942, 64, 2865. The alkyl infrastructures formed at the anode can put up with the usual alkyl radical processes of coupling (to R-R), disproportionation (to RH + R(-H)), or, if the anode is composed of a reactive metal such as zinc, aluminum, cadmium, or lead, they can attempt the anode to form an organometallic compound.A graduate student of Evans, David G. Braithwaite, joined the Nalco Chemical Co. after he graduated and developed an electrolytic process for the commercial ordered series syntheses of tetramethyl- and tetraethyllead antiknock agents in which the respective alkyl Grignard reagents were electrolyzed in a mixed THF/diethylene glycol dimethyl ether solvent ashes using a lead anode and a steel cathode. 15 The reactions of the Grignard reagents with organic, organometallic, and inorganic substrates and their applications are too numerous and varied to be covered here.Not wholly do they ? nd coarse use on a small to moderate get over in research laboratories but they also have been prepared and utilized on a large scale in diverse industrial processes. For the most part they react as nucleophilic reagents, as would be expected, on the basis of the polarity of the carbon-magnesium bond, C? Mg? +. However, they also can change electron transfer reactions with appropriate electron-acceptor substrates. They are weak bases capable of deprotonating the stronger weak organic acids such as net acetylenes and cyclopentadiene.Their basicity can be enhanced (as can be the basicity of organolithium reagents) by the addition to RMgX solutions in ethers of additives such as hexamethylphosphoric triamide (HMPA) and N-methyl-2-pyrrolidinone (NMP) or alkali-metal alkoxides. All such schooling can be found in books devoted solely or in part to Grignard reagents. 16 Two spare topics are of current interest and merit special mention. (1) The preparation of highly running(a)ized organomagnesium reagents by capital of Minnesota Knochel and his co-workers at the University of Munich17 by means of halogen-magnesium exchange (e. . , eq 3). The availability of reagents such as 3-8 (which must be utilized at low temperature) has added a new and spectacular dimension to Grignard reagent chemistry. (2) The synthesis of ole? ns, styrenes, 1,3-dienes and biaryl derivatives by the crosscoupling of Grignard reagents with organic halides. The crosscoupling of Grignard reagents with vinylic halides was discovered by Morris Kharasch and Charles Fuchs at the University of Chicago Organometallics, Vol. 28, No. 6, 2009 1601 Table 2.Transition Metal Halide Catalyzed Homocoupling of Phenylmagnesium Iodidea metal halide FeCl2 CoBr2 NiBr2 RuCl3 RhC l3 PdCl2 OsCl3 IrCl3 a amt, mol 0. 01 0. 01 0. 03 0. 0036 0. 0036 0. 00566 0. 00275 0. 003 amt of C6H5MgI, mol 0. 03 0. 03 0. 095 0. 0108 0. 013 0. 0163 0. 007 0. 01 show of biphenyl, % 98 98 100 99 97. 5 98 53 28 taken from J. Am. Chem. Soc. 1939, 61, 957. in 1943 during the classic studies of Kharasch on the chemistry of Grignard reagents in the presence of transition-metal halides. 6b Kharasch and Fuchs found that arylmagnesium bromides in diethyl ether reacted readily with vinylic halides of type RCHdCHX and R2CdCHX (but not CH2dC(R)X) to give styrenes in 50-75% yield when the reactions were carried out in the presence of 5 mol % of CoCl2 (eq 4). 18It was reported that an different(prenominal) metal halides (of put right, nickel, and chromium) also were effective throttles of this cross-coupling reaction. Benzylmagnesium chloride also reacted in this manner with vinyl bromide to give PhCH2CHdCH2 in 75% yield.Alkylmagnesium halides such as cyclohexyl- and n-butylmagnesium br omide, on the other hand, gave only small to negligible yields of the expected coupling product. The ArMgBrderived biaryl usually was obtained as a byproduct in these reactions. Such homocoupling of arylmagnesium halides in the presence of a transition metal halide as well as papal bull and silver halides was a known reaction. It had been investigated in 1939 by Gilman and Lichtenwalter, who found that aryl Grignard reagents undergo homocoupling in the presence of ca. 0 mol % of conglomerate transition-metal halides in diethyl ether solution to give the respective biaryl in high yield in most cases (eq 5, Table 2). 19 The metal halide, in addition to be the needed gun precursor, also served as an oxidizing agent and, in nearly cases (CoBr2, NiCl2, RhCl3), formation of a black solid indicated complete reduction to the metal. not occur in the absence of the organic halide but in its presence was vigorously exothermic. The added organic halide was only partially consumed and did no t show up in the biaryl product.When p-bromotoluene was added to a phenylmagnesium bromide/CoCl2 catalyst reaction mixture, only biphenyl was formed. A remarkable reaction smost likely a free radical process, as Kharasch suggested. The organic halide was believed to function as an oxidizing agent. This interesting, simple, and potentially useful cross-coupling reaction, as exempli? ed in eq 4, was not adopted by the synthetic organic community right away. afterwards a long dormancy it was rediscovered around 30 years later by a number of groups in the USA, Japan, and France, all of whom apparently were not aware of the 1943 Kharasch/Fuchs JACS paper. 1 Transition-metal catalysts other than CoCl2 were used, but the concept and the basic reaction were the same. In 1971 Tamura and Kochi reported a thorough study of the cross-coupling of Grignard reagents with vinylic halides catalyzed by soluble iron species in concentrations of ca. 10-4 M in THF at 0-25 C. 26,27 Various Fe(III) comp ounds could be used as Fe catalyst precursors the best were Fe(III) -diketonates such as Fe(RC(O)CHC(O)R)3 (R ) Ph, CH3, t-Bu). These exothermic reactions were not free radical processes. The reactions of cis- and trans-propenyl bromide proceeded with retention of geometric con? uration (eqs 6 and 7) and were not adversely affected by the presence of 0. 4 M styrene. A ArMgBr + RCHdCHX 9 ArCHdCHR + MgBrX 8 (X ) Cl, Br) CoCl2 5 mol % (4) 2ArMgX + MXn f Ar-Ar + MgX2 + MXn-2 (5) A novel catalytic process for such ArMgX to Ar-Ar coupling was discovered by Kharasch and Fields when ethereal solutions of an aryl Grignard reagent that contained a catalytic amount (3 mol %) of CoCl2 were heated at re? ux for 1 h and then treated with an equivalent amount of an organic halide (C6H5Br, C2H5Br, i-C3H7Cl). 20 The coupling reaction to give Ar-Ar did (15) (a) Bott, L.L. Hydrocarbon Process. Petrol. Re? ner 1965, 44, 115. (b) Guccione, E. Chem. Eng. 1965, (June 21), 102. See also Part 2 of the tetra ethyllead essay (c) Seyferth, D. Organometallics 2003, 22, 5154 (pages 5172-5174). (16) (a) Krause, E. von Grosse, A. Die Chemie der metall-organischen Verbindungen Gebruder Borntrager Berlin, 1937 pp 14-61, 110-114. ? ? (b) Kharasch, M. S. Reinmuth, O. Grignard Reactions of Nonmetallic Substances Prentice foyer New York, 1954. (c) Handbook of Grignard Reagents Silverman, G. S. , Rakita, P. E. , Eds. Dekker New York, 1996. d) Grignard Reagents-New DeVelopments Richey, H. G. , Ed. Wiley Chichester, New York, 2000. (e) The Chemistry of Organomagnesium Compounds Rappaport, Z. , Marek, L. , Eds. Wiley-VCH Weinheim, Germany, 2008. (17) Knochel, P. Dohle, W. Gommermann, N. Kneisel, F. F. Kopp, F. Korn, T. Sapountzis, J. Vu, V. A. Angew. Chem. , Int. Ed. 2003, 42, 4302 (review). (18) Kharasch, M. S. Fuchs, C. F. J. Am. Chem. Soc. 1943, 65, 504. (19) Gilman, H. Lichtenwalter, M. J. Am. Chem. Soc. 1939, 61, 957. and earlier (back to 1914) references cited therein. 20) Kharasch , M. S. Fields, E. K. J. Am. Chem. Soc. 1941, 63, 2316. mechanics involving an organoiron(I) intermediate, obtained by reduction of the Fe(III) precursor by the Grignard reagent, was suggested. The results of a few experiments carried out on a 30-40 mmol scale (Table 3) showed that such iron-catalyzed reactions would be useful in the synthesis of ole? ns, but a broader study to optimize them and to broaden the field of their application was not undertaken. The coupling of vinylic Grignard reagents with alkyl halides is catalyzed also by Ag(I) salts. 8 Thus, cis-propenylmagnesium (21) Two later historical broadsheets22,23 and two book chapters24,25 that dealt with the cross-coupling reactions of Grignard reagents with vinylic halides also did not cite the Kharasch/Fuchs paper. (22) Tamao, K. J. Organomet. Chem. 2002, 653, 27. (23) Murahashi, S. -I. J. Organomet. Chem. 2002, 653, 27. (24) Kochi, J. K. Organometallic Mechanisms and Catalysis Academic Press New York, 1978 Chapter 14, Sections III and IV. (25) Hou, S. Negishi, E. -i. In Handbook of Organopalladium Chemistry Negishi, E. -i. , Ed. , Wiley New York, 2002 Vol. 1,Chapter III. 2. 6, pp 335408.As a historical note, the following character from this reference (p 335) is of interest Although the reaction of Grignard reagents with organic halides was shown to be catalyzed by various late transition metal compounds (the Kharasch reaction) in the 1950s, it was not until the early seventies that the applicability of this catalytic method was extended to the cross-coupling involving alkenyl and aryl halides catalyzed by Ag, Fe and other late transition metals. (26) (a) Kochi, J. Tamura, M. J. Am. Chem. Soc. 1971, 93, 1487. (b) Tamura, M. Kochi, J. Synthesis, 1971, 303. (27) Full papers (a) Neumann, S.M. Kochi, J. K. J. Org. Chem. 1975, 40, 599. (b) Smith, R. S. Kochi, J. K. J. Org. Chem. 1976, 41, 502. (c) Reviews ref 24. (d) Kochi, J. K. J. Organomet. Chem. 2002, 653, 11 (historical note). (28) (a) Wh itesides, G. M. Casey, C. P. J. Am. Chem. Soc. 1966, 88, 4541. (b) Tamura, M. Kochi, J. J. Am. Chem. Soc. 1971, 93, 1483. 1602 Organometallics, Vol. 28, No. 6, 2009 Table 3. Alkenylation of Grignard Reagents using FeCl3 as Precatalyst (in THF)a R MgBr (amt, mmol) n-C6H13MgBr (40) CH2dCH(CH2)4MgBr (36) n-C6H13MgBr (40) a 1 R2Br (amt, mmol) CH2dCHBr (204) CH2dCHBr (102) CH3CHdCHBr (355)FeCl3 (amt, mmol) 0. 05 0. 05 0. 10 reacn temp, C 0 25 25 product (yield, %) n-C6H13CHdCH2 (83) CH2dCH(CH2)4CHdCH2 (64) n-C6H13CHdCHCH3 (67) (53/47 cis/trans mixture) Taken from Synthesis 1971, 6, 303. Scheme 2 bromide reacted with methyl bromide in THF in the presence of an Ag(I) catalyst to give cis-butene-2, but a same reaction of trans-propenylmagnesium bromide gave a 73 mixture of cisand trans-butene-2, respectively. 28b ostensibly propenyl radicals were involved. A similar Grignard reagent based cross-coupling, ole? n synthesis in which a copper(I) catalyst was used was published by french wo rkers. 9 Normant et al. reported that their reactions (e. g. , n-Bu(Et)CdCHI + i-PrMgCl in THF at -20 C with a Cu(I) catalyst) proceeded with retention of con? guration. 29a For a reaction of CH3CHdC(CH3)MgCl with n-C3H7I in THF at 0 C using CuI as catalyst, Linstrumelle reported that the coupling product obtained in 97% yield was 88% cis and 12% trans, plot of ground a similar reaction of CH2dC(CH3)MgBr with trans-n-C6H13CHdCHI gave a 41 trans/cis product. 29b TheuseofNi(II)catalystprecursorsforGrignardreagent-vinylic halide cross-coupling was reported in 1972 by Corriu and Masse30 and by Tamao, Sumitani, and Kumada. 1 The French group found Ni(II) acetylacetonate to be the most effective catalyst precursor, while the Japanese group favored a bis(tertiary phosphine)NiCl2 catalyst precursor and, curiously, chelating diphosphine complexes such as (Ph2PCH2CH2PPh2)NiCl2. Reactions carried out in diethyl ether at re? ux slackly gave excellent yields. This military operation has been carried out commercially on an industrial scale in the preparation of p-chloroand p-tert-butylstyrene. 32 Finally, the last to be discovered at that time and the most versatile functioning for the cross-coupling of Grignard reagents (29) (a) Normant, J. F. Commercon, A. Cahiez, G. Villieras, J. Compt. ? rend. Hebd. Seances Acad. Sci. , Ser. C 1974, 278, 967. (b) Derguini? Boumechal, F. Linstrumelle, G. Tetrahedron Lett. 1976, 3225. (30) Corriu, R. J. P. Masse, J. P. J. Chem. Soc. , Chem. Commun. 1972, 144. (31) (a) Tamao, K. Sumitani, K. Kumada, M. J. Am. Chem. Soc. 1972, 94, 1375. (b) See also ref 22. Later work (c) Tamao, K. Kiso, Y. Sumitani, K. Kumada, M. J. Am. Chem. Soc. 1972, 94, 9268. (d) Kiso, Y. Tamao, K. Kumada, M. J. Organomet. Chem. 1973, 50, C12. (e) Kiso, Y. Tamao, K. Miyake, N. Yamamoto, K. Kumada, M. Tetrahedron Lett. 974, (No. 1), 3. (f) Tamao, K. Sumitani, K. Kiso, Y. Zembayashi, M. Fujioka, A. Kodama, S. Nakajima, I. Minato, A. Kumada, M. Bull. Chem. Soc. Jpn. 1976, 49, 1958. (g) Tamao, K. Kodama, S. Nakajima, I. Kumada, M. Minato, A. Suzuki, K. Tetrahedron 1982, 38, 3347. (32) Banno, T. Hayakawa Umeno, M. J. Organomet. Chem. 2002, 653, 288. (33) (a) Yamamura, M. Moritani, I. Murahashi, S. -I. J. Organomet. Chem. 1975, 91, C39. Full paper (b) Murahashi, S. -I. Yamamura, M. Yanagisawa, K. -i. Mita, N. Kondo, K. J. Org. Chem. 1979, 44, 2408. (c) Historical note ref 23. ith vinylic and aryl halides, that catalyzed by palladium complexes, was reported by Shun-Ichi Murahashi and coworkers in 1975. 33a The reactions were carried out in diethyl ether/benzene at room temperature using (Ph3P)4Pd as the catalyst precursor, and they proceeded stereospeci? cally in excellent yield (Scheme 2). Dang and Linstrumelle also used this procedure to prepare 1,3-dienes stereospeci? cally by the reaction of vinylic iodides with vinylic Grignard reagents. 34 Palladium-catalyzed cross-coupling of Grignard reagents with organic halides has been a very active area in organic synthesis.Reference 25 reviews (up to 2002) its application in (alkenyl) MgX-ArX, ArMgX-(alkenyl)X, and (alkenyl)MgX-(alkenyl)X coupling processes. A further chapter in this book deals with ArMgX-Ar? X coupling. 35 Another surge of research activity on cross-coupling of Grignard reagents with organic halides started around the turn of the century and still appears to be in progress at the present time (January 2009). Interest has revived in the use of iron complexes as precatalysts for the cross- and homocoupling of Grignard reagents,36 since iron complexes are cheaper than those of palladium and are nontoxic.The iron-catalyzed cross-coupling of organomagnesium bromides with vinylic bromides, although it produced ole? ns in upright yield, was of interest to Jay Kochi, as mention above, primarily from the point of view of its reaction mechanism rather than of its potential for application in organic synthesis. After some 25 years sever al research groups carried out frequently experimental work which has shown iron-catalyzed cross-coupling and homocoupling of Grignard reagents to be broadly applicable and very useful additions to the methods of organic synthesis.In 1995 Gerard Cahiez, at the Universite Pierre et Marie Curie ? ? in Paris, during the course of his extensive investigations of organomanganese chemistry, found that the cross-coupling of vinylic bromides with alkyl, vinylic, and phenylmanganese chlorides could be effected in good yield in the presence of 3 mol % of iron(III) acetylacetonate in a THF/N-methyl-2pyrrolidinone (NMP) mixed solvent at room temperature. 37 In a thorough study, this reaction was extended to the crosscoupling of vinylic halides with alkylmagnesium halides using 1 mol % of Fe(acac)3 and the same solvent mixture. 8 High yields of ole? nic products were obtained. Successful crosscoupling of Grignard reagents with AcO(CH2)6CHdCHCl, CH3C(O)(CH2)3CHdCHCl, Cl(CH2)4CBrdCH2, 9, and 10 a re noteworthy as examples of the selectivity and functional group tolerance of this reaction. The scope of this chemistry was extended further when some of Knochels functionally substituted aryl Grignard reagents17 (vide supra) were reacted with vinylic bromides and iodides. 39 The cross-coupling reaction between aryl Grignard reagents and vinylic bromides and iodides also was found by Cahiez and co-workers to give ole? ic products in good yield with Organometallics, Vol. 28, No. 6, 2009 1603 Table 4. Iron-Catalyzed Biaryl Coupling Reactions a Table 5. Iron-Catalyzed Homocoupling of Grignard Reagents with Atmospheric Oxygen as Oxidanta a Taken from J. Am. Chem. Soc. 2007, 129, 13788. palladium or nickel precatalysts. 42 Of these procedures, that of Cahiez et al. 41f appears to be the most useful. Alkyl halide/ alkylmagnesium halide cross-coupling is not a practical process. 43 RMgX + R? X 9 R-R? + MgX2 8 Fe (8)Iron-catalyzed reactions of aryl Grignard reagents with aryl halides to g ive biaryls generally are not synthetically useful. The desired cross-coupling products are obtained in only poor yield, the main product being the homocoupled biaryl derived from the aryl Grignard reagent (eq 9) (recall the Gilman/ Lichtenwalter and Kharasch/Fields reactions, vide supra). ArMgX + Ar? X f Ar-Ar? + (low yield) (major Ar-Ar product) (9) a Taken from J. Am. Chem. Soc. 2007, 129, 9844. retention of geometric con? guration when carried out in THF solution in the presence of 10 mol % of MnCl2. 0 As noted above, Kharasch and Fuchs had found that attempts to cross-couple aryl Grignard reagents with alkyl halides in the presence of catalytic amounts of CoCl2 were unsuccessful. On the other hand, such reactions do occur in the presence of an iron precatalyst and various additives (eq 8, R? ) alkyl), as summarized in ref 36. A number of other groups have reported the results of their research directed toward development of an effective procedure for the process shown in eq 8 , all using an iron precatalyst of one kind or another, various additives such as TMEDA, NMP, etc. nd generally diethyl ether (but sometimes THF) as solvent. 41 It is noteworthy that simple and secondary alkyl halides, i. e. , ones that contain hydrogen substituents on the carbon atom, can be cross-coupled with aryl Grignard reagents, a process that cannot be realized using (34) Dang, H. P. Linstrumelle, G. Tetrahedron Lett. 1978, 191. (35) Anastasia, L. Negishi, E. -i. Chapter II. 2. 5, pp 311-344, in ref 25. (To date palladium and nickel catalysts have been widely used to effect aryl-aryl cross-coupling reactions. However, arylmagnesium halides were found to undergo cross-coupling with aryl halides that contain electron-withdrawing activating substituents ortho or para with respect to the halogen substituent in the presence of 10 mol % of manganese(II) chloride (eq 10). 44 Cyclohexyl and 2-methylpropenyl Grignard reagents reacted with such substituted halobenzenes in a similar manner. Very (36) (a) Cahiez, G. Duplais, C. Iron-Catalyzed Reactions of Grignard Reagents, Chapter 13, pp 594-630 in ref 16e. (b) Furstner, A. Leitner, ? A. Mendez, M. Kraus, H. J. Am.Chem. Soc. 2002, 124, 13856 (a long ? paper that brings an excellent discussion of the literature, of questions concerning mechanism, and original results). (c) Sherry, B. D. Furstner, ? A. Acc. Chem. Res. 2008, 41, 1500. (37) Cahiez, G. Marquis, S. Tetrahedron Lett. 1996, 37, 1773. (38) Cahiez, G. Avedissian, H. Synthesis 1998, 1199. (39) Dohle, W. Kopp, F. Cahiez, G. Knochel, P. Synlett 2001, 1901. 1604 Organometallics, Vol. 28, No. 6, 2009 Table 6. Manganese-Catalyzed Homocoupling of Grignard Reagents with Atmospheric Oxygen as Oxidanta Scheme 4THF to a mixture of 3 mol % of FeF3 3H2O and 9 mol % of an N-heterocyclic carbene (SIPr HCl). In one example, chlorobenzene (1. 0 equiv) and p-CH3C6H4MgBr (1. 2 equiv) were added to this catalyst system and the reaction mixture was stirred at 60 C for 1 day. The desired product, p-CH3C6H4-C6H5, was obtained in 98% yield. The homocoupling product, biphenyl, was present only in trace amount, while CH3C6H4C6H4CH3 was formed in 3% yield. few examples of the application of this remarkable reaction are shown in Table 4. true results were obtained only with aryl chlorides.Aryl bromides and iodides gave low biaryl yields. A German group reported similar MnCl2-catalyzed cross-coupling between various heterocyclic chlorides and aryl as well as alkyl Grignard reagents e. g. , eq 11. 46 a Taken from J. Am. Chem. Soc. 2007, 129, 13788. The homocoupling reaction of aryl Grignard reagents, mentioned earlier, also has reliable renewed attention recently, and synthetically useful procedures have resulted. Nagano and Hayashi developed a procedure in which the reaction is carried out in re? uxing diethyl ether in the presence of 1-5 mol % of FeCl3, NMP and 1. molar equiv of 1,2-dichloroethane (which serves as the oxidant). 47 Cahiez and co -workers have improved this procedure by using THF as solvent, in which arylmagnesium halides, including the chlorides, are more easily prepared. 48 This procedure works well with Knochels functional arylmagnesium halides (Scheme 3). Of interest also is the clever construction of the tricyclic system 11 by intramolecular homocoupling (Scheme 4). (40) (a) Cahiez, G. Gager, O. Lecomte, F. Org. Lett. 2008, 10, 5255. (b) Alami, M. Ramiandrasoa, P. Cahiez, G. Synlett 1998, 325. 41) A selection (a) Martin, R. Furstner, A. Angew. Chem. , Int. Ed. ? 2004, 43, 3955 (see also ref 36b and references cited therein). (b) Nagano, T. Hayashi, T. Org. Lett. 2004, 6, 1297. (c) Bedford, R. B. Bruce, D. W. Frost, R. M. Goodby, J. W. Hird, M. Chem. Commun. 2004, 2822. (d) Nakamura, N. Matsuo, K. Ito, S. Nakamura, E. J. Am. Chem. Soc. 2004, 126, 3686. (e) Bedford, R. B. Bruce, D. W. Frost, R. M. Hird, M. Chem. Commun. 2005, 4161. (f) Cahiez, G. Habiak, V. Duplais, C. Moyeux, A. Angew. Chem. , Int. Ed. 2007, 46, 4364. g) Cahiez, G. Duplais, C. Moyeux, A. Org. Lett. 2007, 9, 3253. (h) Guerinot, A. Reymond, S. Cossy, J. Angew. ? Chem. , Int. Ed. 2007, 46, 6521. (42) However, Terao and Kambe have recently developed new Pd- and Ni-based precatalyst systems which avoid the problem of -elimination of firsthand and secondary alkyl groups Terao, J. Kambe, M. Acc. Chem. Res. 2008, 41, 1545. (43) (a) Tamura, M. Kochi, J. J. Organomet. Chem. 1971, 31, 289. (b) Rollick, K. L. Nugent, W. A. Kochi, J. K. J. Organomet. Chem. 1982, 225, 279. (44) Cahiez, G. Lepifre, F. Ramiandrasoa, P. Synthesis 1999, 2138. (45) Hatakeyama, T. Nakamura, M. J. Am. Chem. Soc. 2007, 129, 9844. (46) Rueping, M. Ieawsuwan, W. Synlett 2007, 247. (47) Nagano, T. Hiyama, T. Org. Lett. 2005, 7, 491. (48) Cahiez, G. Chaboche, C. Mahuteau-Betzer, F. Org. Lett. 2005, 7, 1943. Scheme 3 special, but generally applicable, reaction conditions developed by Japanese workers45 have ? nally provided the possibility of swell aryl-aryl cross-coupling reactions in which competitive homocoupling of the aryl Grignard reagent has been almost completely suppressed.In this procedure an active catalyst system was prepared by addition of 18 mol % of C2H5MgBr in Organometallics, Vol. 28, No. 6, 2009 1605 A further improvement resulted when it was found that atmospheric oxygen could replace the 1,2-dihaloethane as oxidant in the homocoupling of aryl, vinylic, and alkynyl Grignard reagents using either Fe or Mn catalyst precursors. 49 As Tables 5 and 6 show, this procedure gave excellent results. The most recent contribution to iron-catalyzed cross-coupling, which appeared during the preparation of the ? al draft of this paper, involves application of the old one-pot Barbier procedure in which FeCl3 served as precatalyst and stoichiometric amounts of magnesium turnings and TMEDA additive were used. A mixture of an alkyl and an aryl bromide was added to the mixture of precatalyst, TMEDA, ma gnesium, and solvent at 0 C. Good yields of cross-coupled products were obtained. 50 There has been a great deal of activity in the areas of Grignard reagent/organic halide cross-coupling and aryl Grignard reagent homocoupling, and the coverage in this essay, whose focus is on the historical aspects, is far from exhaustive.Attention is called to the 2005 review by Frisch and Beller51 and especially (49) Cahiez, G. Moyeux, A. Buendia, J. Duplais, C. J. Am. Chem. Soc. 2007, 129, 13789. (50) Czaplik, W. M. Mayer, M. von Wangelin, A. J. Angew. Chem. , Int. Ed. 2009, 48, 607. (51) Frisch, A. C. Beller, M. Angew. Chem. , Int. Ed. 2005, 44, 674. to the recent Accounts of Chemical Research special issue on cross-coupling. 52 Since ? st reported in 1943, the cross-coupling of Grignard reagents with organic halides, thanks to further development by many later workers, has become a broadly applicable, very useful reaction in organic synthesis. There is much more round Grignard reagents that I have not covered the various procedures used in their preparation, the mechanism of their formation (which is still controversial), the more complex organomagnesium compounds such as bis(cyclopentadienyl)magnesium, magnesium butadiene, and magnesium anthracene, and the many kinds of reactions that Grignard reagents have been reported to undergo.But this is only a short essay, and so I have been able to cover only a few selected topics, ones which I hope will be of interest to the reader. More information can be found in the books that I have cited earlier. 16 Acknowledgment. My thanks, as always, to Professor Arnold L. Rheingold for the cover ? gure. OM900088Z (52) Acc. Chem. Res. 2008, 41, No. 11, 1439-1564, special issue. A collection of 11 reviews, many of them relevant to the subject function of the present essay, with useful, up-to-date references.