Grignard Reagent

1598 Organometallics 2009, 28, 1598–1605 CoVer Essay The Grignard Reagents Dietmar Seyferth Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 ReceiVed February 4, 2009 During the elapsed 100 years the Grignard reagents probably own been the most widely used organovocal reagents. Most of them are enlightenedly fitted in supramundane key (usually diethyl ether or, past the forthcoming 1950s, THF) by the counteraction of an fundamental halide succeeding a suitableness vocal magnesium (eq 1). Ttalented 1. Compromise of Diethyl Ether Solutions of Multitudinous Grignard Reagents at Makeefficacy (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 steady in supramundane key (although supernal dampness and oxygen should be surrounding) and in public are entirely counteractive. Disdressed by Victor Grignard at the University of Lyon in France in 1900,1 their quiet of making-ready and their generic contacts in fundamental and organovocal mould made these new organomagnesium reagents an trice luck. The avail of this assistance to synthetic chemistry was repopular very forthcoming, and for his disruption Grignard was awarded a Nobel Prize in Chemistry in 1912. Our screen monad is the monomeric ethylmagnesium bromide bis(diethyl etherate) (1), whose valid-state molecular edifice was robust by an X-ray diffraction examine by Lloyd Guggenberger and Robert Rundle in 1964 using crystals ununnatural from a diethyl ether key of a C2H5Br/Mg counteraction commutation by inert composure succeeding a suitableness a popular of deliberate gaseous nitrogen. 2-4 Adapted from: Schlenk, W. , Jr. Ber. Dtsch. Chem. Ges. 1931, 64, 734. Wilhelm Schlenk and his son disdressed 80 years ago, over than one magnesium-containing record exists in the diethyl ether key of a Grignard reagent. 5 A redistribution of the substituents on magnesium receives locate, and the RMgX record ends up in makeefficacy succeeding a suitableness the two shapely record, the diorganomagnesium and the magnesium dihalide: the “Schlenk Equilibrium” (eq 2). 2RMgX h R2Mg + MgX2 (2) Generally written as “RMgX” in textbooks, monographs and investigation monographs, the Grignard reagents in supramundane key are over entangled than this lowly mouldula indicates. As (1) (a) Grignard, V. Compt. disintegrate. Hebd. Seances Acad. Sci. 1900, 130, ? 1322. (b) Grignard, V. Dissertation “Theses sur les combinaisons organo` magnesienes mixtes et leur contact 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 effulgent valid, CH3MgI · (n-C5H11)2O, was ununnatural and identi? ed as such by elemental dissection (Mg and I) in 1908: Zerewitinoff, Th. Ber. Dtsch. Chem. Ges. 1908, 41, 2244. The oxonium edifice The record that comprise Mg-halogen fetters can be precipitated from Grignard revicar keys in diethyl ether by the conjunction of 1,4-dioxane. An insoluble, polymeric 1,4-dioxane adduct is moulded, leaving succeeding a key of R2Mg5sa adapted making-ready of dialkyl- and diarylmagnesium reagents. 6 Wilhelm Schlenk, Jr. analyzed the 1,4-dioxane residuums from a sum of Grignard revicar keys. Assuming that the residuum is essentially triceaneous, i. e. , that the adapted R2Mg, MgX2, and RMgX percentages re? ect the plain compromise of the Grignard revicar key at makeweight, Schlenk reputed the compromises attentive in Ttalented 1. Direct illustration (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 plant, evaporation of diethyl ether keys of methyl- and ethylmagnesium bromide and chloride at moderation hurry followed by heating of the colorless valid residues at ca. 00 °C and 0. 001 mmHg for multitudinous hours gave a commutation of the appertaining unspotted, solvent-free, polymeric R2Mg coalescences and magnesium halides. The valid MgCl2 thus obtained differed from a pattern obtained from a MgCl2 colliquate in that its lattice semblanceed a brawny stacking selfreliance. This mould of MgCl2 had an extremely justifitalented habit area: Weiss, E. Chem. Ber. 1965, 98, 2805. (7) Schlenk, W. , Jr. Ber. Dtsch. Chem. Ges. 1931, 64, 734 Elevate conjunctions to the illustrations in Ttalented 1 were before-hanker theresucceeding reputed by other fruiters: (a) Noller, 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 written for this coalescence. Precedent fruiters had ununnatural noneffulgent valid patterns of etherates, e. g. , C2H5MgI · (C2H5)2O and RMgI · 2(C2H5)2O. (4) Other forthcoming Grignard revicar crystal edifices: (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 American Chemical Society Publication on Web 03/16/2009 Organometallics, Vol. 28, No. 6, 2009 1599 Figure 1. Association of multitudinous Grignard coalescences in tetrahydrofuran (J. Am. Chem. Soc. 1969, 91, 3847. ). that keys of “CH3MgBr” in diethyl ether comprise CH3MgBr and (CH3)2Mg was obtained by Ashby and co-workers by instrument of 1H NMR spectroscopic bignesss at -105 °C. Solutions of “t-butylmagnesium chloride” in diethyl ether to-boot were elaborate. 8 The sequence of the halide substituents in the RMgX and MgX2 record concede in supramundane key at makeefficacy to mould bridges among magnesium motes, Mg-X-Mg, in a Lewis base/Lewis fine archearchepattern interaction elevate complicates the character of the Grignard revicar in supramundane solvents. In a very entire examine of the denomination elements of multitudinous Grignard reagents in diethyl ether and THF by cautious ebullioscopic molecular efficacy bignesss, Eugene Ashby and Frank Walker at the Georgia Institute of Technology plant that monomeric, dimeric, and justifiableer oligomeric record were concede, depending on the solvent and the halogen and the fundamental substituents on the magnesium mote. 9 Included in this examine concurrently succeeding a suitableness axioms for the “RMgX” keys were axioms for a few R2Mg coalescences and for the magnesium dihalides. As Figure 1 semblances, the observed denomination element (the i appraise is the indubittalented molecular efficacy separated by the mouldula efficacy of the monoetherate) semblances that the Grignard reagents and (C6H5)2Mg are plug to monomeric in the relatively brawny Lewis basic THF. The draw is entirely irrelative in diethyl ether key (Figures 2 and 3), succeeding a suitableness denomination elements of 1 to nforthcoming 4 for solute circumspections up to ca. 3 molal. It is not manifest what these i appraises moderation in stipulations of the plain record concede in these keys. On the selfreliance that the Schlenk makeefficacy is efficacious in all circumstances, in purpose of the intersequence of a signi? cant circumspection of MgX2, one cannot forebode singly lowly solvated record of archearchepattern i(R)Mg-X] n [ i (medium n ) i). Toney and Stucky ununnatural crystals of a dimeric record, 2, from a key of “C2H5MgBr” in di-n-butyl ether by conjunction of this key to triethylamine. 10 The molecular Figure 2. Denomination of alkylmagnesium chlorides in diethyl ether. Demonstration of avail of halogen vs R assemblage in determining the mould of denomination in diethyl ether (J. Am. Chem. Soc. 1969, 91, 3848. ). Figure 3. Denomination of multitudinous alkyl- and arylmagnesium bromides and iodides and connected magnesium coalescences in diethyl ether (J. Am. Chem. Soc. 1969, 91, 3848. ). edifice, as robust by X-ray dissection, compriseed a inclose Br bridge succeeding a suitableness the ethyl assemblages in a trans provision. That (8) In “CH3MgBr” keys in diethyl ether: (a) Ashby, E. C. ; Parrish, G. ; Walker, F. Chem. Commun. 1969, 1464. (b) “(CH3)3CMgCl” keys 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 precedent, harmonious, but over scant examine in diethyl ether). over entangled edifices can be concede in an “RMgX” key in diethyl ether was demonstrated by the vill of the X-ray crystal edifice of a effulgent coalescence obtained from a THF key of “C2H5MgCl” of compromise C2H5Mg2Cl3. This coalescence was not a lowly Cl-bridged dimer, as the tentative mouldula movablesualness recommend. Actually, it was a tetramer (Figure 4) in which the Mg motes own a coordination sum largeer than 4. 1 Tinsufficient is a caveat, however: the record that crystallizes from a Grignard revicar key does not necessarily undeviatingly re? ect what record are swimming environing in the key. The effulgent valid semblancen in Figure 4 could courteous-behaved-behaved own self-assembled during the immutability habit by collocation of two monads of the C2H5Mg2Cl3 dimer and not been concede in key at all. Even in the circumstance of monomeric “RMgX” in THF key, the Schlenk makeefficacy accomplish be efficacious and the brawnyly Lewis basic THF indubitablely prevents halide bridging among Mg motes. 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 edifice of [C2H5Mg2Cl3(C4H8O)3]2, a tetrameric Grignard reagent. Modi? ed from Toney and Stucky (J. Organomet. Chem. 1971, 28, 15. (copycorrect 1971, succeeding a suitableness leave from Elsevier)). intersequence of monomeric RMgX, R2Mg, and MgX2, all solvated, would upshot in the bigness of an denomination element of 1, as Walker and Ashby observed. Tinsufficient are so multifarious elements that submit-to on the scrutiny of the character of a ardent Grignard revicar in supramundane keysthe Lewis basicity and steric properties of the ether solvent, the electronegativity and bigness of the halogen mote in RMgX, the character and steric properties of the fundamental substituent on the magnesium mote. These accomplish desire the largeerity of the makeefficacy true of the Schlenk makeefficacy and the size of Mg-X-Mg bridging. For most contacts in synthetic chemistry it accomplish suf? ce to receive the unconstrained way outsto honor and to transcribe the Grignard revicar as RMgX. Tinsufficient is another thrilling and adapted gear of supramundane Grignard revicar keys. The magnesium record are wishy-washy electrolytes in such solvents of low dielectric true, and “RMgX” keys convoy an electric popular. 12 The electrolysis of keys of organomagnesium halides was elaborate in some sundericular by Kondyrew at the State Investigation Institute in Leningrad13 and by Ward Evans and his tyros at Northwestern University. 14 During the electrolysis, magnesium record proceed twain to the cathode and to the anode. Scheme 1 semblances the lowlyst draw inveterate on RMgX. Vocal magnesium is moulded at the cathode. 12) The primitive tidings appears to be a 1912 French monograph: Jolibois, P. Compt. disintegrate. Hebd. Seances Acad. Sci. 1912, 155, 213. See to-boot: 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 assemblage published multifarious monographs in J. Am. Chem. Soc. during the 1933-1942 limit. See, for illustration: (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 fundamentals moulded at the anode can bear the general alkyl fundamental habites of coupling (to R-R), disproportionation (to RH + R(-H)), or, if the anode is collected of a counterfree metal such as zinc, aluminum, cadmium, or bring, they can onslaught the anode to mould an organovocal coalescence. A disequalize tyro of Evans, David G. Braithwaite, attached the Nalco Chemical Co. succeeding he disequalized and plain an electrolytic habit for the commerciallayer syntheses of tetramethyl- and tetraethylbring antiknock vicars in which the appertaining alkyl Grignard reagents were electrolyzed in a qualified THF/diethylene glycol dimethyl ether solvent way using a bring anode and a steel cathode. 15 The counteractions of the Grignard reagents succeeding a suitableness fundamental, organometallic, and infundamental substrates and their contacts are too vaporous and multifarious to be dressed insufficient. Not singly do they ? nd enlightened use on a paltry to limited layer in investigation laboratories but they to-boot own been fitted and utilized on a enlightened layer in sundry industrial habites. For the most sunder they counteract as nucleophilic reagents, as would be forebodeed, on the cause of the polarity of the carbon-magnesium fetter, C? --Mg? +. However, they to-boot can bear electron transport counteractions succeeding a suitableness embezzle electron-acceptor substrates. They are wishy-washy bases captalented of deprotonating the brawnyer wishy-washy fundamental fines such as final acetylenes and cyclopentadiene. Their basicity can be enhanced (as can be the basicity of organolithium reagents) by the conjunction to RMgX keys in ethers of implieds such as hexamethylphosphoric triamide (HMPA) and N-methyl-2-pyrrolidinone (NMP) or alkali-metal alkoxides. All such notice can be plant in bodys consecrated merely or in sunder to Grignard reagents. 16 Two eespecific topics are of popular concern and worth eespecific communication. (1) The making-ready of justifiablely exercisealized organomagnesium reagents by Paul Knochel and his co-workers at the University of Munich17 by instrument of halogen-magnesium substitute (e. . , eq 3). The availability of reagents such as 3-8 (which must be utilized at low atmosphere) has adventitious a new and spectacular measurement to Grignard revicar chemistry. (2) The mould of ole? ns, styrenes, 1,3-dienes and biaryl derivatives by the crosscoupling of Grignard reagents succeeding a suitableness fundamental halides. The crosscoupling of Grignard reagents succeeding a suitableness vinylic halides was disdressed by Morris Kharasch and Charles Fuchs at the University of Chicago Organometallics, Vol. 28, No. 6, 2009 1601 Ttalented 2. Transition Metal Halide Catalyzed Homocoupling of Phenylmagnesium Iodidea metal halide FeCl2 CoBr2 NiBr2 RuCl3 RhCl3 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 concede of biphenyl, % 98 98 100 99 97. 5 98 53 28 Taken from: J. Am. Chem. Soc. 1939, 61, 957. in 1943 during the fashiontalented studies of Kharasch on the chemistry of Grignard reagents in the intersequence of transition-metal halides. 6b Kharasch and Fuchs plant that arylmagnesium bromides in diethyl ether counteracted laydly succeeding a suitableness vinylic halides of archearchepattern RCHdCHX and R2CdCHX (but not CH2dC(R)X) to concede styrenes in 50-75% concede when the counteractions were carried out in the intersequence of 5 mol % of CoCl2 (eq 4). 18It was reputed that other metal halides (of sinewy, nickel, and chromium) to-boot were movablesual catalysts of this cross-coupling counteraction. Benzylmagnesium chloride to-boot counteracted in this habit succeeding a suitableness vinyl bromide to concede PhCH2CHdCH2 in 75% concede. Alkylmagnesium halides such as cyclohexyl- and n-butylmagnesium bromide, on the other influence, gave singly “paltry to negligible” concedes of the forebodeed coupling fruit. The ArMgBrconservative biaryl generally was obtained as a byfruit in these counteractions. Such homocoupling of arylmagnesium halides in the intersequence of a transition metal halide as courteous-behaved-behaved as copper and silver halides was a public counteraction. It had been investigated in 1939 by Gilman and Lichtenwalter, who plant that aryl Grignard reagents bear homocoupling in the intersequence of ca. 0 mol % of multitudinous transition-metal halides in diethyl ether key to concede the appertaining biaryl in justifitalented concede in most circumstances (eq 5, Ttalented 2). 19 The metal halide, in conjunction to nature the needed catalyst cause, to-boot served as an oxidizing vicar and, in some circumstances (CoBr2, NiCl2, RhCl3), mouldation of a ebon valid implied entire contraction to the metal. not supervene in the insufficiency of the fundamental halide but in its intersequence was vigorously exothermic. The adventitious fundamental halide was singly sunderially consumed and did not semblance up in the biaryl fruit. When p-bromotoluene was adventitious to a phenylmagnesium bromide/CoCl2 catalyst counteraction commutation, singly biphenyl was moulded. A distinguished counteraction! smost likely a bounteous fundamental habit, as Kharasch recommended. The fundamental halide was believed to exercise as an oxidizing vicar. This thrilling, lowly, and hypothetically adapted cross-coupling counteraction, as exempli? ed in eq 4, was not adopted by the synthetic fundamental commonity correct loose. Succeeding a hanker repose it was redisdressed some 30 years succeeding by a sum of assemblages in the USA, Japan, and France, all of whom indubitablely were not informed of the 1943 Kharasch/Fuchs JACS monograph. 1 Transition-metal catalysts other than CoCl2 were used, but the concept and the basic counteraction were the selfsame. In 1971 Tamura and Kochi reputed a entire examine of the cross-coupling of Grignard reagents succeeding a suitableness vinylic halides catalyzed by divisible sinewy record in circumspections of ca. 10-4 M in THF at 0-25 °C. 26,27 Multitudinous Fe(III) coalescences could be used as Fe catalyst causes; the best were Fe(III) -diketonates such as Fe(RC(O)CHC(O)R)3 (R ) Ph, CH3, t-Bu). These exothermic counteractions were not bounteous fundamental habites. The counteractions of cis- and trans-propenyl bromide proceeded succeeding a suitableness dissatisfaction of geometric con? uration (eqs 6 and 7) and were not adversely desireed by the intersequence 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 fantastic catalytic habit for such ArMgX to Ar-Ar coupling was disdressed by Kharasch and Fields when supramundane keys of an aryl Grignard revicar that compriseed a catalytic aggregate (3 mol %) of CoCl2 were heated at re? ux for 1 h and then treated succeeding a suitableness an equiponderant aggregate of an fundamental halide (C6H5Br, C2H5Br, i-C3H7Cl). 20 The coupling counteraction to concede 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 to-boot Sunder 2 of the tetraethylbring 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 Nonvocal Substances; Prentice Hall: New York, 1954. (c) Handbody 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 precedent (tail to 1914) allusions mentiond therein. 20) Kharasch, M. S. ; Fields, E. K. J. Am. Chem. Soc. 1941, 63, 2316. arrangement involving an organoiron(I) interposed, obtained by contraction of the Fe(III) cause by the Grignard reagent, was recommended. The upshots of a few experiments carried out on a 30-40 mmol layer (Ttalented 3) semblanceed that such sinewy-catalyzed counteractions would be adapted in the mould of ole? ns, but a genericer examine to optimize them and to genericen the occasion of their contact was not undertaken. The coupling of vinylic Grignard reagents succeeding a suitableness alkyl halides is catalyzed to-boot by Ag(I) salts. 8 Thus, cis-propenylmagnesium (21) Two succeeding “unvarnished stationary n esss”22,23 and two body sections24,25 that tradet succeeding a suitableness the cross-coupling counteractions of Grignard reagents succeeding a suitableness vinylic halides to-boot did not mention the Kharasch/Fuchs monograph. (22) Tamao, K. J. Organomet. Chem. 2002, 653, 27. (23) Murahashi, S. -I. J. Organomet. Chem. 2002, 653, 27. (24) Kochi, J. K. Organovocal Mechanisms and Catalysis; Academic Press: New York, 1978; Section 14, Sections III and IV. (25) Hou, S. ; Negishi, E. -i. In Handbody of Organofortress Chemistry; Negishi, E. -i. , Ed. , Wiley: New York, 2002; Vol. 1,Chapter III. 2. 6, pp 335408. As a unvarnished stationary n ess, the subjoined citation from this allusion (p 335) is of concern: “Although the counteraction of Grignard reagents succeeding a suitableness fundamental halides was semblancen to be catalyzed by multitudinous deceased transition metal coalescences (the Kharasch counteraction) in the 1950s, it was not until the forthcoming 1970s that the applicability of this catalytic way was protracted to the cross-coupling involving alkenyl and aryl halides catalyzed by Ag, Fe and other deceased 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 monographs: (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 (unvarnished stationary n ess). (28) (a) Whitesides, 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 Ttalented 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 fruit (yield, %) n-C6H13CHdCH2 (83) CH2dCH(CH2)4CHdCH2 (64) n-C6H13CHdCHCH3 (67) (53/47 cis/trans commutation) Taken from: Mould 1971, 6, 303. Scheme 2 bromide counteracted succeeding a suitableness methyl bromide in THF in the intersequence of an Ag(I) catalyst to concede cis-butene-2, but a harmonious counteraction of trans-propenylmagnesium bromide gave a 7:3 commutation of cisand trans-butene-2, appertainingly. 28b Passtalented propenyl fundamentals were implicated. A harmonious Grignard revicar inveterate cross-coupling, ole? n mould in which a copper(I) catalyst was used was published by French fruiters. 9 Normant et al. reputed that their counteractions (e. g. , n-Bu(Et)CdCHI + i-PrMgCl in THF at -20 °C succeeding a suitableness a Cu(I) catalyst) proceeded succeeding a suitableness dissatisfaction of con? guration. 29a For a counteraction of CH3CHdC(CH3)MgCl succeeding a suitableness n-C3H7I in THF at 0 °C using CuI as catalyst, Linstrumelle reputed that the coupling fruit obtained in 97% concede was 88% cis and 12% trans, suitableness a harmonious counteraction of CH2dC(CH3)MgBr succeeding a suitableness trans-n-C6H13CHdCHI gave a 4:1 trans/cis fruit. 29b TheuseofNi(II)catalystprecursorsforGrignardreagent-vinylic halide cross-coupling was reputed in 1972 by Corriu and Masse30 and by Tamao, Sumitani, and Kumada. 1 The French assemblage plant Ni(II) acetylacetonate to be the most movablesual catalyst cause, suitableness the Japanese assemblage favored a bis(tertiary phosphine)NiCl2 catalyst cause and, extraordinaryly, chelating diphosphine multifoldes such as (Ph2PCH2CH2PPh2)NiCl2. Reactions carried out in diethyl ether at re? ux publicly gave justifitalented concedes. This act has been carried out commercially on an industrial layer in the making-ready of p-chloroand p-tert-butylstyrene. 32 Finally, the definite to be disdressed at that duration and the most ready act for the cross-coupling of Grignard reagents (29) (a) Normant, J. F. Commercon, A. ; Cahiez, G. ; Villieras, J. Compt. ? disintegrate. 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 to-boot ref 22. Succeeding fruit: (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 monograph: (b) Murahashi, S. -I. ; Yamamura, M. ; Yanagisawa, K. -i. ; Mita, N. ; Kondo, K. J. Org. Chem. 1979, 44, 2408. (c) Unvarnished stationary n ess: ref 23. ith vinylic and aryl halides, that catalyzed by fortress multifoldes, was reputed by Shun-Ichi Murahashi and coworkers in 1975. 33a The counteractions were carried out in diethyl ether/benzene at capacity atmosphere using (Ph3P)4Pd as the catalyst cause, and they proceeded stereospeci? cally in justifitalented concede (Scheme 2). Dang and Linstrumelle to-boot used this act to lay 1,3-dienes stereospeci? cally by the counteraction of vinylic iodides succeeding a suitableness vinylic Grignard reagents. 34 Palladium-catalyzed cross-coupling of Grignard reagents succeeding a suitableness fundamental halides has been a very free area in fundamental mould. Reference 25 criticisms (up to 2002) its contact in (alkenyl) MgX-ArX, ArMgX-(alkenyl)X, and (alkenyl)MgX-(alkenyl)X coupling habites. A elevate section in this body trades succeeding a suitableness ArMgX-Ar? X coupling. 35 Another surge of investigation earnestness on cross-coupling of Grignard reagents succeeding a suitableness fundamental halides launched environing the diverge of the age and stationary appears to be in journey at the concede duration (January 2009). Concern has reinvigorated in the use of sinewy multifoldes as precatalysts for the cross- and homocoupling of Grignard reagents,36 past sinewy multifoldes are cheaper than those of fortress and are nontoxic. The sinewy-catalyzed cross-coupling of organomagnesium bromides succeeding a suitableness vinylic bromides, although it manufactured ole? ns in amitalented concede, was of concern to Jay Kochi, as stationary n essd over, primarily from the top of purpose of its counteraction arrangement rather than of its possible for contact in fundamental mould. Succeeding some 25 years multitudinous investigation assemblages carried out fur tentative fruit which has semblancen sinewy-catalyzed cross-coupling and homocoupling of Grignard reagents to be genericly conducive and very adapted conjunctions to the ways of fundamental mould. In 1995 Gerard Cahiez, at the Universite Pierre et Marie Curie ? ? in Paris, during the sequence of his enlightened investigations of organomanganese chemistry, plant that the cross-coupling of vinylic bromides succeeding a suitableness alkyl, vinylic, and phenylmanganese chlorides could be movablesed in amitalented concede in the intersequence of 3 mol % of sinewy(III) acetylacetonate in a THF/N-methyl-2pyrrolidinone (NMP) qualified solvent at capacity atmosphere. 37 In a entire examine, this counteraction was protracted to the crosscoupling of vinylic halides succeeding a suitableness alkylmagnesium halides using 1 mol % of Fe(acac)3 and the selfselfcorresponding solvent commutation. 8 Justifitalented concedes of ole? nic fruits were obtained. Successful crosscoupling of Grignard reagents succeeding a suitableness AcO(CH2)6CHdCHCl, CH3C(O)(CH2)3CHdCHCl, Cl(CH2)4CBrdCH2, 9, and 10 are stationary n essworthy as illustrations of the selectivity and exerciseal assemblage tolerance of this counteraction. The occasion of this chemistry was protracted elevate when some of Knochel’s exerciseally substituted aryl Grignard reagents17 (vide supra) were counteracted succeeding a suitableness vinylic bromides and iodides. 39 The cross-coupling counteraction among aryl Grignard reagents and vinylic bromides and iodides to-boot was plant by Cahiez and co-workers to concede ole? ic fruits in amitalented concede succeeding a suitableness Organometallics, Vol. 28, No. 6, 2009 1603 Ttalented 4. Iron-Catalyzed Biaryl Coupling Reactions a Ttalented 5. Iron-Catalyzed Homocoupling of Grignard Reagents succeeding a suitableness Supernal Oxygen as Oxidanta a Taken from: J. Am. Chem. Soc. 2007, 129, 13788. fortress or nickel precatalysts. 42 Of these acts, that of Cahiez et al. 41f appears to be the most adapted. Alkyl halide/ alkylmagnesium halide cross-coupling is not a skilled habit. 43 RMgX + R? X 9 R-R? + MgX2 8 [Fe] (8) Iron-catalyzed counteractions of aryl Grignard reagents succeeding a suitableness aryl halides to concede biaryls publicly are not accumulatively adapted. The desired cross-coupling fruits are obtained in singly insufficient concede, the main fruit nature the homocoupled biaryl conservative from the aryl Grignard revicar (eq 9) (resumption the Gilman/ Lichtenwalter and Kharasch/Fields counteractions, vide supra). ArMgX + Ar? X f Ar-Ar? + (low concede) (greater Ar-Ar fruit) (9) a Taken from: J. Am. Chem. Soc. 2007, 129, 9844. dissatisfaction of geometric con? guration when carried out in THF key in the intersequence of 10 mol % of MnCl2. 0 As stationary n essd over, Kharasch and Fuchs had plant that attempts to cross-couple aryl Grignard reagents succeeding a suitableness alkyl halides in the intersequence of catalytic aggregates of CoCl2 were vain. On the other influence, such counteractions do supervene in the intersequence of an sinewy precatalyst and multitudinous implieds (eq 8, R? ) alkyl), as summarized in ref 36. A sum of other assemblages own reputed the upshots of their investigation directed inland harvest of an movablesual act for the habit semblancen in eq 8, all using an sinewy precatalyst of one bark or another, multitudinous implieds such as TMEDA, NMP, etc. nd publicly diethyl ether (but rarely THF) as solvent. 41 It is stationary n essworthy that earliest and inferior alkyl halides, i. e. , ones that comprise hydrogen substituents on the carbon mote, can be cross-coupled succeeding a suitableness aryl Grignard reagents, a habit that cannot be realized using (34) Dang, H. P. ; Linstrumelle, G. Tetrahedron Lett. 1978, 191. (35) Anastasia, L. ; Negishi, E. -i. Section II. 2. 5, pp 311-344, in ref 25. (To age fortress and nickel catalysts own been widely used to movables aryl-aryl cross-coupling counteractions. However, arylmagnesium halides were plant to bear cross-coupling succeeding a suitableness aryl halides that comprise electron-withdrawing activating substituents ortho or para succeeding a suitableness honor to the halogen substituent in the intersequence of 10 mol % of manganese(II) chloride (eq 10). 44 Cyclohexyl and 2-methylpropenyl Grignard reagents counteracted succeeding a suitableness such substituted halobenzenes in a harmonious habit. Very (36) (a) Cahiez, G. ; Duplais, C. “Iron-Catalyzed Reactions of Grignard Reagents”, Section 13, pp 594-630 in ref 16e. (b) Furstner, A. ; Leitner, ? A. ; Mendez, M. ; Kraus, H. J. Am. Chem. Soc. 2002, 124, 13856 (a hanker ? monograph that brings an justifitalented argument of the lore, of scrutinys relative-to arrangement, and principal upshots). (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. Mould 1998, 1199. (39) Dohle, W. ; Kopp, F. ; Cahiez, G. ; Knochel, P. Synlett 2001, 1901. 1604 Organometallics, Vol. 28, No. 6, 2009 Ttalented 6. Manganese-Catalyzed Homocoupling of Grignard Reagents succeeding a suitableness Supernal Oxygen as Oxidanta Scheme 4 THF to a commutation of 3 mol % of FeF3 · 3H2O and 9 mol % of an N-heterocyclic carbene (SIPr · HCl). In one illustration, chlorobenzene (1. 0 equiv) and p-CH3C6H4MgBr (1. 2 equiv) were adventitious to this catalyst way and the counteraction commutation was enlivened at 60 °C for 1 day. The desired fruit, p-CH3C6H4-C6H5, was obtained in 98% concede. The homocoupling fruit, biphenyl, was concede singly in follow aggregate, suitableness CH3C6H4C6H4CH3 was moulded in 3% concede. Some illustrations of the contact of this distinguished counteraction are semblancen in Ttalented 4. Amitalented upshots were obtained singly succeeding a suitableness aryl chlorides. Aryl bromides and iodides gave low biaryl concedes. A German assemblage reputed harmonious MnCl2-catalyzed cross-coupling among multitudinous heterocyclic chlorides and aryl as courteous-behaved-behaved as alkyl Grignard reagents: e. g. , eq 11. 46 a Taken from: J. Am. Chem. Soc. 2007, 129, 13788. The homocoupling counteraction of aryl Grignard reagents, communicationed precedent, to-boot has accepted untarnished circumspection of-late, and accumulatively adapted acts own upshoted. Nagano and Hayashi plain a act in which the counteraction is carried out in re? uxing diethyl ether in the intersequence 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 own improved this act by using THF as solvent, in which arylmagnesium halides, including the chlorides, are over enlightenedly fitted. 48 This act fruits courteous-behaved-behaved succeeding a suitableness Knochel’s exerciseal arylmagnesium halides (Scheme 3). Of concern to-boot is the ingenious composition of the tricyclic way 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 to-boot ref 36b and allusions mentiond 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 own of-late plain new Pd- and Ni-inveterate precatalyst ways which forsake the quantity of -elimination of earliest and inferior alkyl assemblages: 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. Mould 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 especial, but publicly conducive, counteraction stipulations plain by Japanese fruiters45 own ? nally granted the possibility of clear aryl-aryl cross-coupling counteractions in which competitive homocoupling of the aryl Grignard revicar has been almost entirely muttering. In this act an free catalyst way was fitted by conjunction of 18 mol % of C2H5MgBr in Organometallics, Vol. 28, No. 6, 2009 1605 A elevate progress upshoted when it was plant that supernal oxygen could relocate the 1,2-dihaloethane as oxidant in the homocoupling of aryl, vinylic, and alkynyl Grignard reagents using either Fe or Mn catalyst causes. 49 As Tables 5 and 6 semblance, this act gave justifitalented upshots. The most new-fangled assistance to sinewy-catalyzed cross-coupling, which appeared during the making-ready of the ? al draw of this monograph, involves contact of the old one-pot Barbier act in which FeCl3 served as precatalyst and stoichiometric aggregates of magnesium divergeings and TMEDA implied were used. A commutation of an alkyl and an aryl bromide was adventitious to the commutation of precatalyst, TMEDA, magnesium, and solvent at 0 °C. Amitalented concedes of cross-coupled fruits were obtained. 50 Tinsufficient has been a large trade of earnestness in the areas of Grignard reagent/fundamental halide cross-coupling and aryl Grignard revicar homocoupling, and the screenage in this essay, whose centre is on the unvarnished aspects, is far from wasting. Attention is denominated to the 2005 repurpose by Frisch and Beller51 and extraordinaryly (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 new-fangled Accounts of Chemical Investigation eespecific progeny on cross-coupling. 52 Past ? st reputed in 1943, the cross-coupling of Grignard reagents succeeding a suitableness fundamental halides, benediction to elevate harvest by multifarious succeeding fruiters, has beseem a genericly conducive, very adapted counteraction in fundamental mould. Tinsufficient is fur over environing Grignard reagents that I own not dressed: the multitudinous acts used in their making-ready, the arrangement of their mouldation (which is stationary controversial), the over multifold organomagnesium coalescences such as bis(cyclopentadienyl)magnesium, magnesium butadiene, and magnesium anthracene, and the multifarious barks of counteractions that Grignard reagents own been reputed to bear. But this is singly a insufficient essay, and so I own been talented to screen singly a few clarified topics, ones which I desire accomplish be of concern to the reader. Over notice can be plant in the bodys that I own mentiond precedent. 16 Acknowledgment. My benediction, as constantly, to Professor Arnold L. Rheingold for the screen ? gure. OM900088Z (52) Acc. Chem. Res. 2008, 41, No. 11, 1439-1564, eespecific progeny. A assembly of 11 criticisms, multifarious of them pertinent to the subject subject of the concede essay, succeeding a suitableness adapted, up-to-age allusions.