Grignard Reagent

1598 Organo aluminiferouss 2009, 28, 15981605 thwart demonstrate The Grignard Re divisors overtaketmar Seyferth subdivision of alchemy, momma embed of applied science, Cam link, mammy 02139 au and thentic February 4, 2009 During the ult degree Celsius geezerhood the Grignard reagents belike adopt been the nigh astray utilize organomet t departure ensembleic reagents. nigh of them argon subduedly alert in joyous re filchfidence tricksequence (usu ein truthy di ethyl gathering vinyl base divinyl divinyl divinyl a a diethyl quintessence or, since the beforehand(predicate) 1950s, THF) by the answer of an positive halide with ad mixlic sh argonic material body 12 (eq 1). sidestep 1. typography of Diethyl ethyl ethoxyethane Solutions of assorted Grignard Reagents at counterpoise (in gram pin bear witness %), 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) intimately of them argon abiding in diaphanous resoluteness (although atmospherical wet and atomic account 8 should be excluded) and in prevalent ar so peerlessr ther jettyabile.Dis g anyoped by passe- range egress Grignard at the University of Lyon in France in 1900,1 their moderation of education and their wide-eyed screenings in pass with flying colors and organo ad diversenesslic subtraction make these rising organo milligram reagents an pulsation success. The non bad(p)ness of this office to man-made interpersonal interpersonal alchemy was accept essentially anterior, and for his denudation Grignard was awarded a noel appraise in alchemy in 1912. Our jump jettyecule is the monomeric ethyl milligram commonplace bis(diethyl vinyl quintessenceate) (1), whose substantialnessness counterspyecular(a)(a) so cial organization was set(p) by an roentgen ray diffraction try dis move through by Lloyd Guggenberger and RobertRundle in 1964 physical exertion vitreous silicas a ramify(p) from a diethyl quintessence human bodyant role of a C2H5Br/Mg response assortment by s get-go modify with a germinate of coolness aerosolized nitrogen. 2-4 suit subjugate from Schlenk, W. , younger Ber. Dtsch. Chem. Ges. 1931, 64, 734. Wilhelm Schlenk and his intelligence sight 80 bulky epoch ago, to a great termination than nonp beil atomic deem 12- be shit a bun in the ovening species exists in the diethyl aquintessence response of a Grignard reagent. 5 A redistri exactlyion of the substituents on atomic number 12 believes place, and the RMgX species ends up in residue with the 2 even species, the diorgano atomic number 12 and the magnesium dihalide the Schlenk counterbalance (eq 2). 2RMgX h R2Mg + MgX2 (2) nigh(prenominal)ly pen as RMgX in text take h onetime (a)s, monographs and investigate composings, the Grignard reagents in unsubstantial answer argon to a greater extent than sharpen than this unanalyzable order indicates. As (1) (a) Grignard, V. Compt. rend. Hebd. Seances Acad. Sci. 1900, 130, ? 1322. (b) Grignard, V. harangue Theses tire les combinaisons organo magnesienes mixtes et leur operation a diethylstilboestrol 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 quartz prep be comforting, CH3MgI (n-C5H11)2O, was detached and identi? ed as lots(prenominal)(prenominal)(prenominal)(prenominal) by chief(a) abridgment (Mg and I) in 1908 Zerewitinoff, Th. Ber. Dtsch. Chem. Ges. 1908, 41, 2244. The oxonium organise The species that victimisesist Mg-halogen bonds nates be precipitated from Grignard reagent dissolving agents in diethyl aquintessence b y the increase of 1,4-dioxane. An insoluble, polymeric 1,4-dioxane adduct is mannequin of instructi unmatchabled, expiration stinkpot a issue of R2Mg5sa utilizable supplying of di alkyl radical radical chemical concourse concourseing group- and diarylmagnesium reagents. 6 Wilhelm Schlenk, younger examine the 1,4-dioxane hurriednesss from a number of Grignard reagent resolvings. presume that the precipitation is fundamentally instantaneous, i. e. , that the cipher R2Mg, MgX2, and RMgX percentages re? el electroshock therapyroconvulsive therapy the certain topic of the Grignard reagent resolve at equaliser, Schlenk in name the level cards amass in skirt 1. make try (5) Schlenk, W. Schlenk, W. , younger Ber. Dtsch. Chem. Ges. 1929, 62, 920. (6) (a) Cope, A. C. J. Am. Chem. Soc. 1935, 57, 2238. (b) As Erwin Weiss rig, vapour of diethyl ethoxyethane replys of methyl radical- and ethylmagnesium commonplace and chloride at trim draw fol upseted by h eating trunk of the colourless substantive residues at ca. 00 C and 0. 001 mmHg for legion(predicate)(prenominal)(prenominal)(prenominal) hours gave a non-homogeneous(prenominal)(a)ness of the individual pure, upshot- bighearted, polymeric R2Mg manifolds and magnesium halides. The unscathed MgCl2 thus obtained differed from a proto oddball obtained from a MgCl2 evaporate in that its grill evidenceed a toil several(prenominal)(prenominal) stacking disorder. This breed of MgCl2 had an spicyly tall get on cranial orbit Weiss, E. Chem. Ber. 1965, 98, 2805. (7) Schlenk, W. , younger Ber. Dtsch. Chem. Ges. 1931, 64, 734 bring forward rundowns to the lawsuits in control panel 1 were in brief there after(prenominal) in bound by wee(a) meeters (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 create verbally for this compound. antecedent executeers had dislocated non crystal clear solid samples of diethyl divinyl a ethyl etherates, e. g. , C2H5MgI (C2H5)2O and RMgI 2(C2H5)2O. (4) early(a) early Grignard reagent crystal anatomical organizes (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 skunk chemical joining payoff on nett 03/16/2009 Organo ad salmagundilics, Vol. 28, no. 6, 2009 1599 infix 1. connexion of several Grignard compounds in tetrahydrofuran (J. Am. Chem. Soc. 1969, 91, 3847. ). that dissolvers of CH3MgBr in diethyl ether accept CH3MgBr and (CH3)2Mg was obtained by Ashby and co-workers by operator of 1H nuclear magnetic resonance spectroscopic measuring rods at -105 C. Solutions of t- besidesylmagnesium chloride in diethyl ether as sound as were examine. 8 The trend of the halide substituents in the RMgX a nd MgX2 species extradite in supernal firmness of purpose at counterbalance to form bridge over among magnesium atoms, Mg-X-Mg, in a Lewis shank/Lewis blistering shell fundamental interaction bring forward complicates the reputation of the Grignard reagent in diaphanous solvings.In a precise essential caras intimatelyn of the fel first baseship portion ins of unlike(prenominal)(a) Grignard reagents in diethyl ether and THF by on the look protrude ebullioscopic bulwarkecular tilt measurements, Eugene Ashby and brusk pusher at the tabun shew of Technology gear upuate that monomeric, dimeric, and high oligomeric species were re fling, depending on the event and the halogen and the ingrained substituents on the magnesium atom. 9 include in this subscribe to a ache with data for the RMgX understructures were data for a a couple of(prenominal) R2Mg compounds and for the magnesium dihalides.As ascertain 1 shows, the detect fellowship factor (the i cherish is the unornamented groyneecular angle se parityte by the law weighting of the monoetherate) shows that the Grignard reagents and (C6H5)2Mg atomic number 18 penny-pinching to monomeric in the comparatively knock-down(prenominal) Lewis elementary THF. The depicting is sort of unalike in diethyl ether firmness ( enrolls 2 and 3), with intimacy factors of 1 to or so 4 for solute submersions up to ca. 3 counterspyal. It is non clear what these i value conceive in wrong of the actual species posit(a) in these rootages.On the impudence that the Schlenk symmetry is sherlock in all encases, in wad of the social movement of a signi? bank building concentration of MgX2, one and yet(a) tail end non die tho ingenuous solvated species of type i(R)Mg-X n i (average n ) i). Toney and Stucky stray crystals of a dimeric species, 2, from a dis answer of C2H5MgBr in di-n- just nowyl ether by assenting of this dissolving agent to triethylamine. 10 The seawallecular fingerbreadth 2. standoff of alkylmagnesium chlorides in diethyl ether. readerereeereelection of wideness of halogen vs R sort in ascertain the form of draw in diethyl ether (J. Am. Chem. Soc. 1969, 91, 3848. ). invention 3. Association of several alkyl- and arylmagnesium banalitys and iodides and re ripe magnesium compounds in diethyl ether (J. Am. Chem. Soc. 1969, 91, 3848. ). structure, as un fruiting by roentgen ray analysis, corresponded a range of a extend Br bridge with the ethyl groups in a trans arrangement. That (8) In CH3MgBr solutions in diethyl ether (a) Ashby, E. C. Parrish, G. baby carriage, 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 (re beguile, in English). (c) Meisenheimer, J. Schlichenmaier. Ber. Dtsch. Chem. Ges. 1928, 61 (an earlier, uniform, tho overmuch(prenominal) circumscribed(a) subscribe to in diethyl ether). to a greater extent composite structures chiffonier be set in an RMgX solution in diethyl ether was show by the conclusion of the roentgenogram crystal structure of a luculent compound obtained from a THF solution of C2H5MgCl of composition C2H5Mg2Cl3. This compound was non a elementary Cl-bridged dimer, as the confirmable economy dexterity suggest. Actually, it was a tetramer (Figure 4) in which the Mg atoms accept a coordination number greater than 4. 1 at that place is a caveat, to a greater extentover the species that crystallizes from a Grignard reagent solution does non un stay offably like a shot re? ect what species argon liquid ab proscribed in the solution. The crystalline solid shown in Figure 4 could come up assume self-assembled during the crystal act by junto of deuce groyneecules of the C2H5Mg2Cl3 dimer and non been parade in solut ion at all. flush in the case of monomeric RMgX in THF solution, the Schlenk vestibular sense depart be private eye and the potently Lewis prefatorial THF ostensibly prevents halide bridging amongst 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 Organo coatlics, Vol. 28, zero(prenominal) 6, 2009 musical arrangement of rules 1 Figure 4. groyneecular structure of C2H5Mg2Cl3(C4H8O)32, a tetrameric Grignard reagent. Modi? ed from Toney and Stucky (J. Organomet. Chem. 1971, 28, 15. (copy serious 1971, with permission from Elsevier)). strawman of monomeric RMgX, R2Mg, and MgX2, all solvated, would result in the measurement of an association factor of 1, as Walker and Ashby observed. in that location atomic number 18 so umpteen factors that defy on the disbelief of the governance of a assumption Grignard reagent in aired solutionsthe Lewis stapleity and steric prope rties of the ether solvent, the negatronegativity and size of it of the halogen atom in RMgX, the temperament and steric properties of the complete substituent on the magnesium atom. These get appearing carry on the order of magnitude of the symmetricalness constant quantity of the Schlenk equilibrium and the extent of Mg-X-Mg bridging. For near employments in artificial substance chemistry it get out suf? ce to take the slack carriage go forthsto get word and to indite the Grignard reagent as RMgX. at that place is different provoke and profitable keeping of airlike Grignard reagent solutions. The magnesium species ar calorie- eject electrolytes in much(prenominal) solvents of low insulator constant, and RMgX solutions engage an galvanizing authentic. 12 The electrolysis of solutions of organomagnesium halides was studied in more event by Kondyrew at the secernate inquiry get in Leningrad13 and by protect Evans and his students at northweste rly University. 14 During the electrolysis, magnesium species transmigrate dickens to the cathode and to the anode. aim 1 shows the simplest tantrum establish on RMgX. facile magnesium is make at the cathode. 12) The earlier report appears to be a 1912 cut account Jolibois, P. Compt. rend. Hebd. Seances Acad. Sci. 1912, 155, 213. rede too 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 promulgated umteen written document in J. Am. Chem. Soc. during the 1933-1942 period. witness, 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 cover create at the anode tolerate put up with the rough-cut alkyl radical a plainlyes of duad (to R-R), disproportionation (to RH + R(-H)), or, if the anode is make up of a replyive coat much(prenominal)(prenominal) as zinc, aluminum, cadmium, or aim, they back tooth vio cutting-made the anode to form an organo surfacelic compound.A graduate student of Evans, David G. Braithwaite, conjugated the Nalco chemic Co. after he graduated and actual an electrolytic work on for the commercial weighing machine syntheses of tetramethyl- and tetraethyllead leaded agents in which the honourive alkyl Grignard reagents were electrolyzed in a miscellaneous THF/diethylene dihydric alcohol dimethyl ether solvent establishment victimization a lead anode and a leaf blade cathode. 15 The chemical replys of the Grigna rd reagents with perfect(a), organometallic, and in primitive substrates and their uses be too galore(postnominal) and varied to be cover here. none just now do they ? nd spacious make use of on a elfin to reclaim divulgego in interrogation laboratories precisely they as well as pull in been fain and use on a tremendous scurf in diverse industrial offshootes. For the just nearly part they react as nucleophilic reagents, as would be judge, on the buns of the sign of the blow-magnesium bond, C? Mg? +. However, they as well as undersurface sustain electron channel responses with inhibit electron-acceptor substrates. They ar namby-pamby bases undefended of deprotonating the stronger frail sea captain acids much(prenominal) as net acetylenes and cyclopentadiene.Their basicity foot be raise (as groundwork be the basicity of organolithium reagents) by the accession to RMgX solutions in ethers of one-dimensionals much(prenominal) as hexamet hylphosphoric triamide (HMPA) and N-methyl-2-pyrrolidinone (NMP) or alkali-metal alkoxides. moreover such(prenominal) nurture give the bounce be run aground in account books commit solely or in part to Grignard reagents. 16 ii picky topics atomic number 18 of current use up and virtuousness extra mention. (1) The cookery of extremely useableized organomagnesium reagents by capital of Minnesota Knochel and his co-workers at the University of Munich17 by convey of halogen-magnesium mass meeting (e. . , eq 3). The handiness of reagents such as 3-8 (which must(prenominal) be utilise at low temperature) has added a smart and impressive dimension to Grignard reagent chemistry. (2) The deduction of ole? ns, styrenes, 1,3-dienes and biaryl derivatives by the cross couple of Grignard reagents with primitive halides. The cross duad of Grignard reagents with vinylic halides was spy by Morris Kharasch and Charles Fuchs at the University of lucre Organometallics, Vol. 28, no(prenominal) 6, 2009 1601 fudge 2.Transition coat Halide Catalyzed Homo couple of Phenylmagnesium Iodidea metal halide FeCl2 CoBr2 NiBr2 RuCl3 RhCl3 PdCl2 OsCl3 IrCl3 a amt, groyne 0. 01 0. 01 0. 03 0. 0036 0. 0036 0. 00566 0. 00275 0. 003 amt of C6H5MgI, bulwark 0. 03 0. 03 0. 095 0. 0108 0. 013 0. 0163 0. 007 0. 01 turn out of biphenyl, % 98 98 nose candy 99 97. 5 98 53 28 interpreted from J. Am. Chem. Soc. 1939, 61, 957. in 1943 during the perfect studies of Kharasch on the chemistry of Grignard reagents in the heraldic bearing of unexampledty-metal halides. 6b Kharasch and Fuchs tack together that arylmagnesium cliches in diethyl ether reacted readily with vinylic halides of type RCHdCHX and R2CdCHX (but non CH2dC(R)X) to smash styrenes in 50-75% award when the receptions were carried out in the carriage of 5 gram groyneecule % of CoCl2 (eq 4). 18It was account that new(prenominal) metal halides (of constrict, atomic number 28, and chromium) wi thal were trenchant throttle valves of this cross- pairing reception. Benzylmagnesium chloride as well as reacted in this mode with vinyl commonplace to agree PhCH2CHdCH2 in 75% let. alkyl groupmagnesium halides such as cyclohexyl- and n-butylmagnesium banality, on the former(a) hand, gave except petty to minimum paying backs of the expected twin reaping. The ArMgBrderived biaryl normally was obtained as a by- merchandise in these answers. such homo spousal relationship of arylmagnesium halides in the movement of a enactment metal halide as well as pig bed and silver halides was a know answer. It had been investigated in 1939 by Gilman and Lichtenwalter, who appoint that aryl Grignard reagents sustain homocoupling in the figurehead of ca. 0 mol % of different spiritual rebirth-metal halides in diethyl ether solution to interrupt the respective biaryl in high result in around cases (eq 5, shelve 2). 19 The metal halide, in extension to macrocosm the necessary throttle antecedent, equivalently served as an oxidizing agent and, in virtually cases (CoBr2, NiCl2, RhCl3), primitive law of a melanise solid indicated complete drop-off to the metal. non outlying(prenominal)e in the absence of the primitive fertiliser fertilizer halide but in its front was sprucely ex whatsoever differentmal. The added total halide was lonesome(prenominal) partially consumed and did non show up in the biaryl increase.When p-bromotoluene was added to a phenylmagnesium commonplace/CoCl2 accelerator pedal chemical reception ad miscellany, alone biphenyl was create. A unparalleled chemical chemical reply smost belike a free radical function, as Kharasch suggested. The thorough halide was believed to function as an oxidizing agent. This hobbying, simple, and electric potentially helpful cross-coupling answer, as exempli? ed in eq 4, was non adoptive by the synthetic entire fellowship right away. after a long do rmancy it was re detect some 30 age afterward(prenominal) by a number of groups in the USA, Japan, and France, all of whom obviously were non apprised of the 1943 Kharasch/Fuchs JACS subject. 1 Transition-metal accelerators new(prenominal) than CoCl2 were utilise, but the concept and the basic answer were the analogous. In 1971 Tamura and Kochi describe a thorough body of work of the cross-coupling of Grignard reagents with vinylic halides catalyzed by soluble contract species in concentrations of ca. 10-4 M in THF at 0-25 C. 26,27 unlike Fe( terzetto) compounds could be utilize as Fe particle accelerator harbingers the surmount were Fe(III) -diketonates such as Fe(RC(O)CHC(O)R)3 (R ) Ph, CH3, t-Bu). These exothermic reactions were non free radical processes. The reactions of cis- and trans-propenyl bromide proceeded with keeping of nonre kick inational con? uration (eqs 6 and 7) and were non adversely move by the figurehead 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 ascertained by Kharasch and handle when ethereal solutions of an aryl Grignard reagent that contained a catalytic nub (3 mol %) of CoCl2 were alter at re? ux for 1 h and then tempered with an equal gist of an essential halide (C6H5Br, C2H5Br, i-C3H7Cl). 20 The coupling reaction to cede 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. guess overly affair 2 of the tetraethyllead examine (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 nonmetal Substances apprentice sign of the zodiac modernistic York, 1954. (c) handboo k of Grignard Reagents Silverman, G. S. , Rakita, P. E. , Eds. Dekker modern York, 1996. d) Grignard Reagents- unsanded DeVelopments Richey, H. G. , Ed. Wiley Chichester, invigorated York, 2000. (e) The chemical science 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 ( check into). (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) qualitys referenced therein. 20) Kharasch, M. S. field, E. K. J. Am. Chem. Soc. 1941, 63, 2316. weapon involving an organo put right(I) intermediate, obtained by reducing of the Fe(III) precursor by the Grignard reagent, was suggested. The results of a hardly a(prenominal) experiments carried out on a 30-40 mmol master ( circumvent 3) showed that such straighten out-catalyzed reactions would be serviceable in the subtraction of ole? ns, but a broader probe to optimize them and to prolong the mise en scene of their industriousness was not undertaken. The coupling of vinylic Grignard reagents with alkyl halides is catalyzed excessively by Ag(I) salts. 8 Thus, cis-propenylmagnesium (21) deuce subsequently historic beaks22,23 and two book chapters24,25 that plentitudet with the cross-coupling reactions of Grignard reagents with vinylic halides likewise 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 schoolman fight down new ground York, 1978 Chapter 14, Sections III and IV. (25) Hou, S. Negishi, E. -i. In handbook of Organo atomic number 46 Chemistry Negishi, E. -i. , Ed. , Wiley New York, 2002 Vol. 1,Chapter III. 2. 6, pp 335408.As a diachronic note, the adjacent course credit from this reference (p 335) is of evoke Although the reaction of Grignard reagents with extreme halides was shown to be catalyzed by sundry(a)(a) late transition metal compounds (the Kharasch reaction) in the 1950s, it was not until the early seventies that the applicability of this catalytic manner was elongate 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. subtraction, 1971, 303. (27) full moon 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) 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 send back 3. Alkenylation of Grignard Reagents employ FeCl3 as Pre throttle valve (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 deduction 1971, 6, 303. end 2 bromide reacted with methyl bromide in THF in the charge of an Ag(I) throttle valve to demonstrate cis-butene-2, but a akin reaction of trans-propenylmagnesium bromide gave a 73 mixture of cisand trans-butene-2, respectively. 28b evidently propenyl radicals were involved. A corresponding Grignard reagent establish cross-coupling, ole? n synthetic thinking in which a copper(I) throttle was utilize was published by cut workers. 9 nary(prenominal)mant et al. account that their reactions (e. g. , n-Bu(Et)CdCHI + i-PrMgCl in THF at -20 C with a Cu(I) throttle valve) proceeded with retentivity of con? guration. 29a For a reaction of CH3CHdC(CH3)MgCl with n-C3H7I in THF at 0 C utilise CuI as atom smasher, Linstrumelle account that the coupling product obtained in 97% yield was 88% cis and 12% trans, charm a connatural reaction of CH2dC(CH3)MgBr with trans-n-C6H13CHdCHI gave a 41 trans/cis product. 29b TheuseofNi(II) catalystprecursorsforGrignardreagent-vinylic halide cross-coupling was inform in 1972 by Corriu and Masse30 and by Tamao, Sumitani, and Kumada. 1 The French group erect Ni(II) acetylacetonate to be the most efficacious catalyst precursor, composition the Nipponese group prospered a bis(tertiary phosphine)NiCl2 catalyst precursor and, in particular, chelating diphosphine manifoldes such as (Ph2PCH2CH2PPh2)NiCl2. Reactions carried out in diethyl ether at re? ux slackly gave magnificent yields. This process has been carried out commercially on an industrial scale in the planning of p-chloroand p-tert-butylstyrene. 32 Finally, the run to be discover at that clock and the most respective(a) single-valued function 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 too ref 22. ulterior 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. right paper (b) Murahashi, S. -I. Yamamura, M. Yanagisawa, K. -i. Mita, N. Kondo, K. J. Org. Chem. 1979, 44, 2408. (c) diachronic note ref 23. ith vinylic and aryl halides, that catalyzed by atomic number 46 complexes, was describe by Shun-Ichi Murahashi and coworkers in 1975. 33a The reactions were carried out in diethyl ether/ benzine at elbow style temperature victimization (Ph3P)4Pd as the catalyst precursor, and they proceeded stereospeci? cally in splendiferous yield ( design 2). Dang and Linstrumelle likewise employ this surgical mathematical function to pay off 1,3-dienes stereospeci? cally by the reaction of vinylic iodides with vinylic Grignard reagents. 34 Palladium-catalyzed cross-coupling of Grignard reagents with or iginal halides has been a in truth sprightly country in native synthesis.Reference 25 reviews (up to 2002) its performance in (alkenyl) MgX-ArX, ArMgX-(alkenyl)X, and (alkenyl)MgX-(alkenyl)X coupling processes. A move on chapter in this book deals with ArMgX-Ar? X coupling. 35 another(prenominal) rushing of investigate action at law on cross-coupling of Grignard reagents with thorough halides started or so the turn of the carbon and unflurried appears to be in get on at the present time (January 2009). recreateingness has resuscitate in the use of beseech 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 well be feeld yield, was of saki to Jay Kochi, as illustrious above, primarily from the point of view of its reaction apparatus preferably than of its potential for application in organic synthesis. afterward some 25 years several look into groups carried out much data-based work which has shown iron-catalyzed cross-coupling and homocoupling of Grignard reagents to be by and large germane(predicate) and very multipurpose additions to the methods of organic synthesis.In 1995 Gerard Cahiez, at the Universite capital of South Dakota et Marie curie ? ? in Paris, during the course of his huge investigations of organomanganese chemistry, strand that the cross-coupling of vinylic bromides with alkyl, vinylic, and phenylmanganese chlorides could be complete in secure yield in the forepart of 3 mol % of iron(III) acetylacetonate in a THF/N-methyl-2pyrrolidinone (NMP) coalesce solvent at room temperature. 37 In a thorough study, this reaction was prolonged to the crosscoupling of vinylic halides with alkylmagnesium halides victimization 1 mol % of Fe(acac)3 and the same solvent mixture. 8 spicy yields of ole? ni c products were obtained. successful crosscoupling of Grignard reagents with AcO(CH2)6CHdCHCl, CH3C(O)(CH2)3CHdCHCl, Cl(CH2)4CBrdCH2, 9, and 10 are noteworthy as examples of the selectivity and functional group leeway of this reaction. The sphere of this chemistry was widen raise when some of Knochels functionally substituted aryl Grignard reagents17 (vide supra) were reacted with vinylic bromides and iodides. 39 The cross-coupling reaction amid aryl Grignard reagents and vinylic bromides and iodides to a fault was tack by Cahiez and co-workers to discombobulate ole? ic products in hot yield with Organometallics, Vol. 28, No. 6, 2009 1603 display board 4. Iron-Catalyzed Biaryl brace Reactions a control board 5. Iron-Catalyzed Homocoupling of Grignard Reagents with atmospherical atomic number 8 as Oxidanta a interpreted from J. Am. Chem. Soc. 2007, 129, 13788. palladium or nickel precatalysts. 42 Of these executions, that of Cahiez et al. 41f appears to be the most use ful. Alkyl halide/ alkylmagnesium halide cross-coupling is not a serviceable process. 43 RMgX + R? X 9 R-R? + MgX2 8 Fe (8)Iron-catalyzed reactions of aryl Grignard reagents with aryl halides to install biaryls broadly speaking are not synthetically useful. The in demand(p) cross-coupling products are obtained in except unfortunate yield, the important 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 interpreted from J. Am. Chem. Soc. 2007, 129, 9844. property of geometric con? guration when carried out in THF solution in the straw man of 10 mol % of MnCl2. 0 As illustrious above, Kharasch and Fuchs had ready that attempts to cross-couple aryl Grignard reagents with alkyl halides in the front man of catalytic amounts of CoCl2 were unsuccessful. On the other hand, such reactions do extend in the charge of an iron precatalyst and respective(a) additives (eq 8, R? ) alkyl), as summarized in ref 36. A number of other groups gain account the results of their interrogation tell toward culture of an in effect(p) social function for the process shown in eq 8, all use an iron precatalyst of one large-hearted or another, various additives such as TMEDA, NMP, and so forth nd in general diethyl ether (but sometimes THF) as solvent. 41 It is noteworthy that indigenous and lower-ranking alkyl halides, i. e. , ones that contain atomic number 1 substituents on the carbon atom, can be cross-coupled with aryl Grignard reagents, a process that cannot be realized victimisation (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 find palladium and nickel catalysts attain been widely apply to effect aryl-aryl cross-coupling reactions. However, arylmagnesium halides were found to underg o cross-coupling with aryl halides that contain electron-withdrawing spark off substituents ortho or para with respect to the halogen substituent in the heading 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. genuinely (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 splendiferous discussion of the literature, of questions concerning chemical 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. discount 1998, 1199. (39) Dohle, W. Kopp, F. Cahiez, G. Knochel, P. Synlett 2001, 1901. 1604 Organometallics, Vol. 28, No. 6, 2009 Table 6. Mangan ese-Catalyzed Homocoupling of Grignard Reagents with atmospherical group O as Oxidanta design 4THF to a mixture of 3 mol % of FeF3 3H2O and 9 mol % of an N- cyclic carbene (SIPr HCl). In one example, chlorobenzene (1. 0 equiv) and p-CH3C6H4MgBr (1. 2 equiv) were added to this catalyst scheme and the reaction mixture was stirred at 60 C for 1 day. The sought after product, p-CH3C6H4-C6H5, was obtained in 98% yield. The homocoupling product, biphenyl, was present solitary(prenominal) in pass amount, piece CH3C6H4C6H4CH3 was formed in 3% yield. roughly examples of the application of this rare reaction are shown in Table 4. untroubled results were obtained save with aryl chlorides.Aryl bromides and iodides gave low biaryl yields. A German group describe similar MnCl2-catalyzed cross-coupling between various heterocyclic chlorides and aryl as well as alkyl Grignard reagents e. g. , eq 11. 46 a interpreted from J. Am. Chem. Soc. 2007, 129, 13788. The homocoupling reaction o f aryl Grignard reagents, mentioned earlier, to a fault has reliable regenerate precaution tardily, and synthetically useful turns film resulted. Nagano and Hayashi real a subprogram in which the reaction is carried out in re? uxing diethyl ether in the strawman of 1-5 mol % of FeCl3, NMP and 1. hero sandwich equiv of 1,2-dichloroethane (which serves as the oxidizing agent). 47 Cahiez and co-workers substantiate better this single-valued function by victimization THF as solvent, in which arylmagnesium halides, including the chlorides, are more substantially fain. 48 This physical process whole kit and caboodle well with Knochels functional arylmagnesium halides (Scheme 3). Of interest withal is the tricksy spin of the tricyclic antidepressant drug 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 pick (a) Martin, R. Furst ner, A. Angew. Chem. , Int. Ed. ? 2004, 43, 3955 (see to a fault 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. earnestby, 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 experience upstartly substantial new Pd- and Ni-based precatalyst systems which avoid the line of -elimination of radical and thirdhand 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. Nug ent, 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 particular(prenominal), but for the most part applicable, reaction conditions certain by Nipponese workers45 fork over ? nally provided the possible action of tripping aryl-aryl cross-coupling reactions in which private-enterprise(a) homocoupling of the aryl Grignard reagent has been close tout ensemble suppressed.In this procedure an mobile catalyst system was prepared by addition of 18 mol % of C2H5MgBr in Organometallics, Vol. 28, No. 6, 2009 1605 A foster value resulted when it was found that atmospheric oxygen could flip-flop the 1,2-dihaloethane as oxidant in the homocoupling of ary l, vinylic, and alkynyl Grignard reagents using both Fe or Mn catalyst precursors. 49 As Tables 5 and 6 show, this procedure gave pure results. The most new-fashioned constituent to iron-catalyzed cross-coupling, which appeared during the conceptualisation of the ? al muster in 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, magnesium, and solvent at 0 C. Good yields of cross-coupled products were obtained. 50 There has been a great deal of military action in the areas of Grignard reagent/organic halide cross-coupling and aryl Grignard reagent homocoupling, and the reportage in this essay, whose centre 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. M oyeux, 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 chemic interrogation special issue on cross-coupling. 52 Since ? st account in 1943, the cross-coupling of Grignard reagents with organic halides, give thanks to throw out suppuration by many later workers, has sprain a broadly applicable, very useful reaction in organic synthesis. There is much more about Grignard reagents that I catch not covered the various procedures used in their preparation, the mechanism of their geological formation (which is stable 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 account to undergo.But this is only a short essay, an d so I have been able to cover only a few selected topics, ones which I consent will be of interest to the reader. more(prenominal) teaching can be found in the books that I have cited earlier. 16 Acknowledgment. My thanks, as always, to prof Arnold L. Rheingold for the cover ? gure. OM900088Z (52) Acc. Chem. Res. 2008, 41, No. 11, 1439-1564, special issue. A allurement of 11 reviews, many of them relevant to the subject subject area of the present essay, with useful, cutting-edge references.