Cobalt-, copper-and chromium–catalyzed carbon-carbon coupling reactions using a broad spectrum of Grignard reagents as reaction partners

The cobalt, copper and chromium catalyzed cross-coupling reaction of various Grignard reagents with electrophilic substrates is a powerful technique for the construction of carbon–carbon bonds, enabling the preparation of a wide variety of organic compounds that are employed in the pharmaceutical industry, as agricultural compounds, and for forming organic electronic materials. This review highlights major developments in carbon-carbon cross-coupling reactions catalyzed by cobalt, copper and chromium complexes over the past decade.


Introduction
9][20][21][22][23][24] In addition to this, the development of broadly applicable, more environmental friendly and economical catalysts is a worthy target in catalytic crosscoupling reactions. 25,26rignard reagents were discovered, by Victor Grignard at the University of Lyon in 1900, and for this significant finding Grignard was awarded the Nobel Prize in Chemistry in 1912.[27][28][29][30] Most of the Grignard reagents are prepared by the reaction of an organic halide with magnesium in ether solution under an inert atmosphere.27 During the past century, Grignard reagents have been the most widely used organometallic reagents.[31][32][33][34][35][36] They remain desirable coupling partners owing to their stability and ease of preparation, with many representatives being commercially available.37,38 Chromium is among the most abundant elements on earth.21 Interestingly, it has recently proven to be an ideal alternative to palladium and nickel in cross-coupling reactions.In 1919, Hein described the formation of bis(arene)chromium species by reaction of a Grignard reagent with chromium(III) chloride.39 From the middle of the 20th century, cobalt catalyzed carbon-carbon bond-forming reactions have received considerable attention. In 193, Kharasch demonstrated the first example of cobalt catalyzed alkenylation of aromatic Grignard reagents by employing catalytic amounts of cobalt chloride and a stoichiometric amount of aromatic or aliphatic halides, affording good yields of homocoupling products.40 Copper-catalyzed coupling reactions had been demonstrated several years before Pd and Ni-catalyzed reactions to form carbon-carbon bonds: in 1971, Kochi and Tamura carried out the coupling reaction of Grignard reagents and alkyl halides using alkylcopper(I) species.[41][42][43]

Metal Catalyzed C-C Cross-coupling Reactions Using Various Grignard Reagents
In this review, we classify the metal catalyzed cross-coupling reactions according to the metal present in the catalyst.Therefore, three major categories are discussed: the cobalt-catalyzed, the copper-catalyzed and the chromium-catalyzed reactions.Scheme 1. Cross coupling reaction of arylbromide substrates with n-octylmagnesium bromide using CoCl 2.
In 2008, Hayashi et al. designed an efficient protocol for C(sp 2 )-C(sp 2 ) coupling via cross-coupling reaction of alkenyl triflates with aryl and alkenyl Grignard reagents at low temperatures using a low cobalt loading catalyst and triphenylphosphine as free ligand to produce the corresponding alkenylarenes.Arylmagnesium bromides 4 cross-coupled with 1-octen-2-yl triflate (5) at 0 o C within 3 h to provide the desired products in high yields (6a-d) (Scheme 2).The reaction is compatible with aromatic Grignard reagents bearing electrondonating or electron withdrawing groups.Unactivated alkyl halides are often inactive substrates for metal catalyzed cross-coupling reactions because of their reluctance to undergo oxidative addition.In addition, metal alkyl intermediates are prone to induce unproductive β-hydrogen eliminations. 31,47In 2009, Cahiez and his group developed a novel method to construct carbon-carbon bonds by chemoselective cobalt catalyzed cross-coupling of the functionalized nonactivated secondary alkyl bromide 7 with phenylmagnesium bromide 8 in the presence of TMEDA under mild reaction conditions to produce the cross-coupled products 9 (Scheme 3).Building upon this protocol, various functionalized primary alkyl bromides 10 were cross-coupled smoothly with arylmagnesium bromides 11 using CoCl 2 /TMEDA (1:1) as an efficient catalyst system to afford the corresponding products 12 in excellent yields (Scheme 4).A wide range of sensitive groups such as acetate, ester, and ketone are fully tolerated in this coupling reaction. 48

Br OEt
0][51] Hence, the development of straightforward and selective methods for the preparation of biaryls has attracted much attention in recent years.3][54] Nevertheless, the ease of formation of Grignard reagents often indicates the likelihood of side reactions such as homocoupling to form undesired symmetrical biaryl compounds. 55Nakamura and coworkers have designed a practical and selective method to form the wanted unsymmetrical biaryls in excellent yields (Ar 1 -Ar 2 ) 15 with formation of much lower amounts of the homocoupling byproducts such as biphenyl ( 16) and 4,4'-dimethylbiphenyl (17) via cross-coupling reactions between phenyl halides 13 and aryl Grignard reagents 14 catalyzed by cobalt(II) fluoride tetrahydrate in combination with an imidazolium chloride salt as an effective preligand. 560 Scheme 4. Cross-coupling of aryl Grignard reagents with functionalized primary alkyl bromides.21. 57 The catalytic activity of various cobalt complexes such as Co(OAc) 2, Co(acac) 3 , CoCl(PPh 3 ) 3 , and CoCl 2 (PPh 3 ) 2 was carefully investigated under optimal reaction conditions, the results in terms of catalyst loading and product yield of (S)-20 are summarized in Scheme 6. C-glycosides are prominent carbohydrate analogues with applications as efficacious pharmaceutical compounds. 58In 2012, Cossy and coworkers designed an efficient diastereoselective cobalt catalyzed crosscoupling reaction of aryl Grignard reagents 23 and 1-bromoglycosides 22 to give an array of C-aryl glycosides with α selectivity (e.g.24) in synthetically useful yields.1-Bromoglycoside as the electrophilic substrate reacted smoothly with various aryl Grignard reagents at either 0 o C or room temperature using Co(acac) 3 as a catalyst with the aid of tetramethylethylenediamine (TMEDA) (Scheme 7).Strikingly, aryl Grignard reagents with electron donating or electron withdrawing groups provided the coupling products in good yields with a higher α/β ratio (> 9:1) (entries 1-5).The use of a bulkier Grignard reagent furnished the product in about 37% yield (entry 6), the lower yield possibly being due to steric hindrance. 59he Kumada cross-coupling reaction has become a powerful synthetic tool for the synthesis of carboncarbon bonds, and recent advances have expanded the scope of this reaction to include tertiary alkyl Grignard reagents to give branched alkanes with quaternary carbon centers. 60However, the use of tertiary alkyl Grignard reagents as nucleophiles in cross-couplings often affords low yields due to steric hindrance, facile βhydrogen elimination and ease of isomerization of the tertiary metal alkyls. 1,61In 2013, Kambe and his group demonstrated an efficient protocol for the coupling reaction of tertiary alkyl Grignard reagents and various alkyl halides in the presence of the mixed catalyst system including 2 mol% of CoCl 2 , 4 mol% LiI and of isoprene as a ligand precursor to generate a wide spectrum of important organic molecules containing quaternary carbon centers.Accordingly, alkyl bromides 26 carrying an arene, olefin, alkyne, trifluoromethyl, ether, and amide groups cross-coupled effectively with tert-butylmagnesium chloride 27 to produce the corresponding coupled products in good to excellent yields without occurring side products arising from the isomerization of the t-Bu group (Scheme 8, 28a-g).Knochel and coworkers designed a novel catalyst system for fast and selective cross-coupling reaction of N-heteroaryl halides 29 and arylmagnesium reagents 30 using cobalt chloride in combination with an isoquinoline ligand.Moreover, the use of methyl tert-butyl ether as a co-solvent can minimize the formation of homocoupling byproducts.Interestingly, good yields of the selective coupled products 31 were obtained through cobalt catalyzed C-C coupling reaction of bromo-or chloro-substituted pyridines, pyrimidines and triazines with electron rich Grignard reagents (Scheme 9).In this way, even polyfunctional pyridine, pyrimidine and triazine derivatives cross-coupled with sterically hindered aryl Grignard reagents selectively. 63n 2014, Zhong et al. developed an efficient protocol for asymmetric cross-coupling of functionalized racemic α-bromo ester substrates 32 with phenyl Grignard reagents 8 in THF at −80 o C within 5 h, catalyzed by 10 mol % of CoI 2 and 12 mol % of bisoxazoline ligand 33 to produce a variety of chiral α-arylalkanoic esters 34 in excellent enantioselectivity and yield.Building upon this protocol, α-bromopropanoic and α-bromobutyric acid esters with various OR groups (R = methyl, ethyl, isopropyl, cyclopentyl or benzyl) were coupled efficiently with phenylmagnesium bromide to provide enantioselectivities ranging from 83 to 95% ee and yields in the 89−95% range (Scheme 10). 64In 2015, Cossy and coworkers extended their protocol to couple 4-iodopiperidine 37 with alkenyl Grignard reagents 38, catalyzed by CoCl 2 with the aid of (R,R)-tetramethylcyclohexanediamine (TMCD) in THF.The corresponding coupled products 39 were obtained in moderate yields (52-55%) when reaction of different alkenylmagnesium bromides with N-Boc-4-iodopiperidine in the temperature range between 0 o C and room temperature (entries 1-3, Scheme 12).On the other hand, lowering the temperature to -10 o C resulted in a significant improvement in the yield of the desired product (entry 4). 66

RO
Page 116 In the same year, Časar et al. made a significant contribution to the development of coupling reactions of Grignard reagent with allylic and vinylic bromides by virtue of the use of a CoBr 2 /sarcosine catalyst system in THF at a low temperature.Consequently, phenyl and benzyl Grignard reagents were efficiently coupled with allylic 40a and alkenyl 40b bromides to generate a diverse array of the corresponding coupled products 41a,b in good to excellent yields (Scheme 13).However, vinyl bromides afford slightly higher yields (entries 4-6) compared to cross-coupling reactions with allyl bromides (entries 1-3). 67R)-ar-Curcumene and 4,7-dimethyl-1-tetralone have been found in nature, and they have significant biological activity. 68In 2015, Bian et al. reported the first cobalt-catalyzed asymmetric Kumada cross-coupling reaction in the synthesis of (R)-ar-curcumene, (R)-4,7-dimethylltetralone, and their enantiomers.Racemic αbromopropanoate (rac-32) reacted with p-tolylmagnesium bromide catalyzed by CoI 2 and (S,S)-2,2′-Isopropylidene-bis(4-phenyl-2-oxazoline) ligand to generate chiral α-arylcarboxylic ester 42, which was reduced by diisobutylaluminum hydride to give chiral primary alcohol 43.In turn, the primary alcohol was converted into primary bromide 44 with the help of triphenylphosphine and carbon tetrabromide.The desired terminal alkene (R)-45 was obtained via CuI catalyzed cross-coupling (S)-44 with vinylmagnesium bromide.The oxidation of (R)-45 by Dess-Martin reagent led to the formation of the chiral aldehyde (R)-46 which is an advantageous building block in the synthesis of (R)-ar-curcumene and (R)-4,7-dimethyl-1-tetralone.The reaction of aldehyde (R)-46 with iso-propyltriphenylphosphonium iodide at low temperature afforded the desired (R)-ar-curcumene 47 in 79% yield, whereas the oxidation of aldehyde (R)-46 with Ag 2 O gave carboxylic acid (R)-48 which was transformed into (R)-4,7-dimethyl-1-tetralone 49. 69age 117 The use of aryl chlorides as electrophilic substrates in cross-coupling reactions proved to be difficult, while their low cost and better availability compared to their iodo and bromo analogues makes them a highly attractive substrate class. 71 Scheme 16.Cross-coupling of aryl chlorides with Grignard reagents catalyzed by cobalt-silylene complex.

Copper catalyzed cross-coupling reactions
In recent years, copper reagents have emerged as applicable and powerful catalysts for cross-coupling reactions to construct C-C bonds. 73The use of catalytic copper complexes in C-C bond formation had actually been demonstrated several years before the discovery of palladium and nickel as effective catalysts for these transformations.In 1971, Kochi et al. reported the first examples of copper-catalyzed cross-coupling reactions of Grignard reagents with alkyl halides. 74However, during the last decade numerous methods have been developed for the formation of carbon-carbon bonds using copper-catalyzed cross-couplings of Grignard reagents with various electrophilic substrates, as will be discussed here.
In 2007, Kambe and his group reported a method for constructing C-C bonds by the copper-catalyzed cross-coupling reaction of Grignard reagents and non-activated alkyl fluorides with the aid of 1-phenylpropyne as an additive under mild reaction conditions.Normally, alkyl fluorides were considered to be no suitable coupling partners in cross-couplings because of their low reactivity for oxidative addition. 75In this optimized cross-coupling methodology, n-nonyl fluoride 56 reacted with Grignard reagents 57 in the presence of catalytic amounts of CuCl 2 (0.02 mmol) and 1-phenylpropyne in THF under reflux for 6 h, leading to crosscoupled products 58 in yields greater than 98% yield (Scheme 17 Cahiez et al. successfully prepared a broad spectrum of functionalized internal alkynes 61 by coupling alkyl Grignard reagents 59 with alkynyl halides 60 using CuCl 2 with σ-donor ligands like N-methylpyrrolidone (NMP) as an effective catalyst system at low temperatures in THF.Primary alkyl (Scheme 18, entries 1-2) and cyclic or acyclic secondary alkyl Grignard reagents (entries 3,4) coupled with 1-bromo-1-heptyne to afford the corresponding coupling products in good to excellent yields.Using this protocol, the catalyst system was also used to effect the coupling reaction of functionalized Grignard reagents with alkynyl bromides under mild reaction conditions, giving the desired products in satisfactory yields (entries 5-7  As a rule, C(sp 3 )-C(sp 3 ) cross-coupling is difficult owing to competing side reactions such as homocoupling, dehalogenation and β-elimination. 1,78,79In 2012, Liu and coworkers developed a mixed catalyst system including CuI/ TMEDA/ LiOMe for the coupling reaction of functionalized nonactivated secondary alkyl halides or tosylates 62 with different chain lengths and cyclohexylmagnesium bromide 63 at 0 o C within 24 h, © ARKAT USA, Inc generating the desired products in synthetically useful yields (Scheme 19, 64a-f).This coupling methodology tolerates a broad range of functional groups like hydroxyl, methoxy, trifluoromethyl and ester, although these functional groups are normally incompatible with Grignard reagents.In 2012, Hu et al. designed a protocol to prepare a large array of organic compounds 67 by coupling a functionalized alkyl halide or tosylate 65 with a secondary or tertiary alkyl Grignard reagent 66 using 3 mol% CuCl as an efficient catalyst at room temperature.Electrophilic substrates containing ester, amide and carboxylic acid groups were fully tolerated (Scheme 20, entries 1-3).In this work, ether and thioether substrates were efficiently coupled in good yields (entries 4,5), likewise 6-bromohexanenitrile reacted smoothly with Grignard reagent under the same reaction conditions (entry 6).Heterocyclic substrates revealed exceptional reactivity, yielding the corresponding coupled products in good yields (entries 7-10). 81lthough the yields are similar, the coupling reaction is faster and more efficient in this case, compared to the previous cobalt catalyzed coupling tertiary alkyl Grignard reagents with alkyl halides developed by Kambe et al. as shown in scheme 8.
Kambe et al. have continued their efforts to develop the efficiency of copper catalysts in C-C coupling reactions.They carried out coupling of unactivated secondary alkyl iodides 68 with alkyl Grignard reagents 69 with loadings of the CuI catalyst as low as 1 mol% in the presence of 1,3-butadiene as an effective additive under mild reaction conditions.2-Iodooctane and 4-iodoheptane coupled with n-BuMgCl to give alkyl-alkyl coupled products in very good yields (Scheme 21, entries 2, 3) Homoallylic iodides as substrates produced acceptable yields (entries 4, 6).In contrast, the sterically hindered 2,4-dimethylpent-3-yl iodide generated poor yields of the corresponding coupling products (entries 8-9). 82RKAT USA, Inc CuI (1 mol%) Recently, the copper-catalyzed reactions of allylic electrophiles with allyl Grignard reagents have seen impressive progress.In 2013, Feringa and coworkers reported the first copper-catalyzed enantioselective allyl−allyl coupling reaction of allyl bromides 71 and an allyl Grignard reagent 72 with the presence of phosphoramidite as efficient ligand (L 1 ) to afford a variety of the chiral 1,5-dienes 73 in good yields and high enantioselectivity.Nevertheless, the chiral 1,5-diene structures have served as building blocks for the chemical synthesis of complex natural products, including many terpenes.Several allylic substrates bearing various functional groups including protected alcohols, amines and alkenes coupled efficiently with allylmagnesium bromide to furnish the cross-coupled products in good yields with excellent enantioselectivities (Scheme 22, 73a-g). 83n 2014, Shi et al. designed a novel oxidative copper catalyzed C-C coupling reaction of alkynyl Grignard reagents 74 with alkyl and alkenyl Grignard reagents 75 by using di-tert-butyldiaziridinone as an oxidant under mild reaction conditions.Remarkably, this oxidative coupling reaction was effective for C(sp)-C(sp 2 ) and C(sp)-C(sp 3 ) bond formations in the presence of 2 mol% of CuBr•SMe 2 and 1.1 equiv of di-tert-butyldiaziridinone at room temperature for 3 h to afford the corresponding coupled products in good yields (Scheme 23, 76a-i).

Chromium catalyzed cross-coupling reactions using various Grignard reagents
Cross-coupling reactions using chromium catalysts have rarely been investigated.Recently, the attention of researchers has been drawn towards the use of chromium salts in cross-couplings owing to their low cost and commercial availability, showing their ability to catalyze cross-couplings of C-X and C-H bonds with Grignard reagents. 21In the last decade, Knochel and his group in pioneering studies have successfully developed chromium as a powerful catalyst for C-C bond formation via cross-coupling reactions.
In 2007, Oshima and co-workers reported the chromium-catalyzed arylmagnesiation of alkynes 77 using pivalic acid as co-catalyst.They found that aryl Grignard reagents added across the triple bond, forming the Knochel et al. have made distinguished contributions to the development of a wide spectrum of chromium-mediated catalytic reactions to be used efficiently in cross-coupling reactions of a variety of Grignard reagents with various electrophilic substrates.In 2013, he and his group designed a method to construct C(sp 2 )-C(sp 2 ) bonds (82, 84) by fast cross-coupling reaction of the functionalized Grignard reagents bearing sensitive functionalities like ester, methoxy or halogens 81 with N-heterocyclic halides 80 or 2chlorobenzophenone 83 using CrCl 2 as an efficient catalyst at room temperature within 15 min.Phenylmagnesium bromide coupled smoothly with 2-bromo-3-(but-3-en-1-yl)pyridine, resulting in the 2,3disubstituted pyridine in 95% yield (entry 1, Scheme 25), and cross-coupling of 4-(N,N-dimethylamino)phenylmagnesium bromide with 4-chloroquinoline gave the desired product in good yield (entry 2).Similarly, the Grignard reagent containing a CF 3 group reacted with 2-bromo-3-chloropyridine to afford the product in 76% yield (entry 3).The sensitive ester-substituted Grignard reagent in entry 4 reacted with 2-chloro-5fluoropyridine providing the expected product in a moderate yield. 86Compared to the cobalt catalyzed arylation of N-heterocyclic halides by Grignard reagents previously illustrated in scheme 9, Knochel has successfully replaced cobalt chloride and isoquinoline ligand as catalyst system by equally efficient chromium chloride to give comparable results.Knochel and coworkers have considerably extended the scope of chromium catalyzed C-C coupling reactions with Grignard reagents as coupling partners.8][89] In 2014, Knochel et al. reported a novel chromium catalyzed direct arylation of pyridines and aryloxazolines by aryl Grignard reagents and 2,3dichlorobutane (DCB) as an oxidant at room temperature.Direct arylation via activation of a C-H bond was efficiently accomplished by treatment of benzo[h]quinoline (85) with ArMgBr 86 catalyzed by CrCl 2 and DCB to give the arylated heterocycle 87a in 95% yield (Scheme 27).Electron rich or -deficient Grignard reagents reacted effectively with benzo[h]quinoline, furnishing relatively high yields of products 87b-f.2-(2-Trimethylsilylphenyl)oxazoline (88) has also been successfully coupled with various Grignard reagents providing the oxazoline ortho-arylated at the phenyl ring (89a-c) in 72-91 % yields (Scheme 28). 90Compared to the previous methods developed by Knochel Knochel and colleagues have continued to improve and extend chromium-mediated cross-coupling reactions involving functionalized Grignard reagents and substrates.They have reported selective coupling reactions of dichloropyridines 90 with a range of functionalized aryl Grignard reagents using CrCl 2 as the catalyst at room temperature leading to 2-arylated products 91.In this optimized cross-coupling protocol, 2,5dichloropyridine reacted selectively with a Grignard reagent within 15 minutes to form the product in 87% Page 129 © ARKAT USA, Inc yield (Scheme 29, entry 1).Similarly, 2,4-dichloro-3-methylpyridine coupled with phenylmagnesium bromide giving the cross-coupled product in good yield (entry 2).The reaction was also tolerant of steric hindrance: reaction of 2,4-dichloro-3-(1,3-dioxolan-2-yl)pyridine with a Grignard reagent afforded the expected product in moderate yield (entry 3).Electron-rich and electron-deficient Grignard reagents smoothly underwent coupling reactions with dichlorinated pyridines to provide the coupled products in satisfactory yields (entries 4-6). 91Noteworthy, under the same cross-coupling conditions mentioned in the scheme 25, Knochel has demonstrated that the highly efficient regioselective coupling between dichlorinated pyridines and quinolines with aromatic Grignard reagents can be easily achieved using chromium salts.In accordance with a postulated mechanism, the selectivity is mainly attributed to pyridine-ring nitrogen which directs the attack of the phenyl-chromium intermediates into the proximal C-Cl bond.Aryl ethers are considered one of the most attractive substrates in cross-coupling reactions in terms of availability, economics, and safety. 92,93However, it is difficult to replace aryl ether groups in coupling reactions because of the robust nature of the C(aryl)-O bonds. 13In 2015, Zeng et al. reported the first chromium catalyzed cross-coupling reactions of aryl ethers 92 with aryl Grignard reagents, giving excellent yields of functionalized aromatic aldehydes 93.Both electron-rich and electron-deficient aryl ethers furnished the ortho-arylated aromatic aldehydes in good to excellent yields (62-98 %) (Scheme 30, 93a-k).The electronic properties of electron-donating and electron-withdrawing groups on the Grignard reagents had little influence on the reaction: substituents like methoxy, fluoride, chloride, trifluoromethyl and amino were well tolerated in this coupling reaction (95a-k).
Scheme 30.Chromium catalyzed cross-coupling of aryl ethers with various aryl Grignard reagents.
In 2016, Knochel et al. demonstrated an efficient method for C(sp 2 )-C(sp 3 ) bond formation via chromium catalyzed cross-coupling reactions of chloroquinolines 96 with Grignard reagents 97 under mild reaction conditions within 15 minutes.However, 2-chloroquinoline underwent a rapid coupling reaction with phenethylmagnesium and ethylmagnesium bromides using CrCl 3 as a catalyst in THF to produce the coupled products in good yields (Scheme 31, entries 1, 2).Under the same reaction conditions, 2-chloro-4-methylquinoline cross-coupled effectively with phenethylmagnesium and 2-(cyclohexyl)ethylmagnesium bromide, leading to alkylated quinolines in 82 and 79% yields respectively (entries 3, 4).Regioselective cross-coupling was achieved by treatment of 2,6-dichloroquinolines with various primary alkylmagnesium bromides, generating the 2-alkylated-6-chloroquinolines in very high yields (entries 5, 6).A surge of activity in the direct activation of C-H bonds has been witnessed in the last 20 years.In 2018, Zeng and coworkers have developed a chromium-catalyzed para-selective formation of quaternary carbon centers by direct alkylation of benzamide derivatives 99 using Grignard reagent 100, in the presence of CrCl 3 with bromotrimethylsilane (TMSBr) as an efficient catalyst system at room temperature, to form alkylated benzamides 101 in good yields.Trimethylsilyl bromide may facilitate the formation of tert-butyl radicals and a trimethylsilyl-Cr intermediate through reaction with t-BuMgBr and low-valent Cr species in the catalytic cycle.The benzamide derivatives containing an ortho-methyl, benzyl, methoxy, ethoxy or phenoxymethyl substituent coupled with t-BuMgBr, generating acceptable yields of the corresponding para-t-butylated compounds 101a-f (Scheme 32).Steric effects arising from meta-substitution of the benzamides did not exert much influence on the site selectivity of alkylation and product yields (101g-i). 96n the same year, Zeng et al.Grignard reagent affording the selectively coupled products in good yields, while keeping the other C(aryl)-O bonds in the reaction system intact (Scheme 33, 104a-f). 97

Conclusions
The metal catalyzed cross-coupling reactions provide one of the most straightforward protocols for carboncarbon bond construction.These transformations are typically catalyzed by expensive and rare palladium and nickel complexes.Recently, the use of the abundant and inexpensive transition metals cobalt, copper and chromium in developing cost-effective synthetic strategies has attracted much attention.Grignard reagents remain desirable coupling partners owing to the ease of their preparation, and many of them are commercially available.Considerable effort has been devoted to developing novel and efficient methods using cobalt, copper and chromium-catalysts for the C-C coupling reaction of various organic halide substrates and related electrophiles with functionalized Grignard reagents, and significant achievements in this area have emerged during the past decade.This review highlights recent advances of carbon-carbon bond formation via cobalt, copper and chromium-catalyzed cross-coupling reactions of Grignard reagents with various electrophilic substrates to produce a wide variety of organic compounds.

Scheme 5 .
Scheme 5. Cross-coupling of chlorobenzene/ bromobenzene with p-tolMgBr using CoF 2 catalyst in the presence of an imidazolium chloride salt.

Scheme 9 .
Scheme 9. Scope of Co-catalyzed cross-coupling reactions utilizing isoquinoline as a ligand.
reported a novel methodology for C-C bond formation via chromiumcatalyzed regioselective cross-coupling reaction of aryl 2-pyridyl ethers 102 with phenylmagnesium bromide 103.The 2-pyridyl moiety played a crucial role in the cleavage of the C(aryl)-OPy bond to couple with the © ARKAT USA, Inc

62 © ARKAT USA, Inc
a large variety of Grignard reagents and electrophilic substrates.In 2017, Cossy et al. have developed a protocol for the cross-coupling reaction of α-bromoamides 50 with aryl Grignard reagents 51 using CoCl 2 and Xantphos as an efficient catalyst system under mild reaction conditions.(Scheme15, entries 1-6) Electron rich and electron poor Grignard reagents reacted efficiently with α-bromo amides with 10 mol % catalyst loading of CoCl 2 and Xantphos as ligand, furnishing α-aryl amides 52 in relatively good yields.On the other hand, the reaction was extremely sensitive to steric hindrance, as in the case of 2-MeC 6 H 4 MgBr (Scheme 15, entry 7). 70cheme Ph 95 Scheme 13.CoBr 2 / Sarcosine-catalyzed carbon-carbon cross-coupling of allyl and alkenyl bromides with phenyl or benzyl Grignard reagents.The scope of cobalt-catalyzed cross-coupling reactions has been considerably expanded by including © ARKAT USA, Inc Scheme 14. Synthesis of (R)-ar-curcumene and (R)-4,7-dimethyl-l-tetralone.15.Cobalt catalyzed cross-coupling of α-bromo amides with aryl Grignard reagents.© ARKAT USA, Inc In 2018, Sun and coworkers have synthesized a powerful Co(III) hydride supported by a N-heterocyclic silylene ligand as a promising catalyst, which was successfully employed in cross-coupling of aryl chlorides 53 with aryl Grignard reagents 54.Very good yields of coupled products were obtained at 50 ).76 Scheme 17. Cross-coupling reaction of n-nonyl fluoride with Grignard reagents. ).77 Cross-coupling reaction of unactivated secondary alkyl iodides with alkyl Grignard reagents.