Bimetallic Combinations for Dehalogenative Metalation Involving

Review pubs.acs.org/CR

Bimetallic Combinations for Dehalogenative Metalation Involving Organic Compounds David Tilly,† Floris Chevallier,† Florence Mongin,*,† and Philippe C. Gros*,‡,§ †

Equipe Chimie et Photonique Moléculaires, Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes 1, Bâtiment 10A, Case 1003, Campus de Beaulieu, Avenue du Général Leclerc, 35042 Rennes Cédex, France ‡ HECRIN, Université de Lorraine, SRSMC UMR 7565, Boulevard des Aiguillettes, 54506 Vandoeuvre-lès-Nancy, France § HECRIN, CNRS, SRSMC UMR 7565, Boulevard des Aiguillettes, 54506 Vandoeuvre-lès-Nancy, France Monometal magnesium- and zinc-based exchange reagents have since been developed.1n,7 The halogen/metal exchange has recently benefited from the use of bimetal species.8 Indeed, when properly chosen, the latter allowed chemists to achieve new efficient regioselective and/or chemoselective and/or enantioselective methods for the functionalization of organic compounds. Mixing two metallic reagents can lead to synergic CONTENTS combinations either because together they form new structures, as observed with turbo reagents or ate complexes, or because 1. Introduction A they act in a complementary way, as noted for metal−salt 2. Unimetallic Lithium−Lithium Reagents A mixtures. 3. Bimetallic Lithium−Magnesium Reagents B This review is not intended to describe exhaustively all the 3.1. Lithium Magnesates B progress made in the general halogen/metal exchange process 3.2. Turbo-Grignard Reagents J but will focus on the special reactivity exhibited in halogen/ 3.3. Mg−LiCl V metal exchange reactions when an alkali or alkaline earth metal 4. Bimetallic Metal−Manganese Reagents (Metal = compound is combined either with another alkali metal Lithium, Magnesium) X compound or with a compound containing a group 2 (Mg), 5. Bimetallic Metal−Copper Reagents (Metal = group 6 (Cr), group 7 (Mn), group 11 (Cu), group 12 (Zn), or Lithium, Magnesium) AA group 13 (In) element as acidic center. These combinations 6. Bimetallic Metal−Zinc Reagents (Metal = Lithium, represent the most developed in relation with the considered Magnesium) AF reaction. The review will be divided into six main sections [in 6.1. Lithium Zincates AF addition to the Introduction (section Introduction) and 6.2. Magnesium Zincates AL Conclusion (section 8)], depending on the metal considered. 6.3. Turbo-Zinc Reagents AL Generalities concerning the synthesis of the bimetal reagents 6.4. Zn−LiCl AN will be given throughout the document. 7. Miscellaneous AQ The structure of the reagents, a very important aspect, will 7.1. Lithium−Chromium Reagents AQ not be covered here since very comprehensive reviews have 7.2. Lithium−Indium Reagents AR appeared recently dealing with this topic.9 8. Conclusion AU Note that the formulas used (e.g., i-PrBu2MgLi) will refer to Author Information AU the overall compositions but do not necessarily reflect the Corresponding Authors AU stoichiometries of the actual species present in solution. Notes AU Biographies Acknowledgments References

AU AV AV

2. UNIMETALLIC LITHIUM−LITHIUM REAGENTS This category of reagents has at the moment only been used in the pyridine series. The bromine/lithium exchange of dibromopyridines using an alkyllithium is a selective process provided that very low temperatures (−78 to −100 °C) and coordinating solvents are used. Otherwise, many side reactions such as degradation of the formed lithio pyridines or side metalations occur. The first studies on 2,5-dibromopyridine by Parham and Piccirilli clearly established that the C-5 position could be lithiated selectively with BuLi in THF at −78 or −100 °C (Scheme 1, right).10 In contrast, Wang and co-workers reported that the control of the C-2 lithiation was more

1. INTRODUCTION The halogen/metal exchange is a general and powerful method for preparing functionalized compounds. This reaction has been originally developed using monometal lithium-based exchange agents.1 Its efficiency has been illustrated for the regioselective lithiation of dihalogenoarenes,2 benzyne generation,3 access to polybrominated biaryl compounds,4 chiral asymmetric exchange with the latter substrates,5 and polylithiation.6 © XXXX American Chemical Society

Received: July 11, 2013

A

dx.doi.org/10.1021/cr400367p | Chem. Rev. XXXX, XXX, XXX−XXX

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Scheme 1

Table 3. C-2 Lithiation of 2,3-Dibromopyridine and Reaction with Electrophiles

problematic.11 Due to the instability of 2-lithio-5-bromopyridine, careful attention to reaction temperature (−50 or −78 °C) and solvent (toluene) as well as dilution was needed to avoid C-2 to C-5 isomerization and degradation (Scheme 1, left). The unimetallic reagent TMSCH2Li−LiDMAE (LiDMAE = lithium 2-dimethylaminoethoxide),12 prepared by reacting 3 equiv of TMSCH2Li with 1 equiv of 2-dimethylaminoethanol in toluene has been reported to ensure efficient and C-2-selective lithiation under noncryogenic conditions (0 °C) in toluene.13 The effect of the aminoalkoxide on the C-2 selectivity is clearly shown in Table 1. The reaction was successfully applied to the

react with the solvent, resulting in reduced yields or alternative products. Ten years later, Screttas’ group reported the halogen/metal exchange of ω-lithium (halogenophenoxy)alkoxides.17 While no exchange of chlorine occurred with lithium naphthalenide, they found an impressive activation by adding Mg(O(CH2)2OEt)2 to the reaction medium, leading to good yields after carbonation (Table 4). In the same way, BuLi exchanged bromine only in the presence of the magnesium alkoxide (Table 5).

Table 1. Selectivity of Bromine/Lithium Exchange of 2,5Dibromopyridine

a

Table 4. Reaction of Alkyl and Aryl Halides with Lithium Metal and Carbonatation GC yields.

synthesis of a range of functional bromopyridines. The quenching step consumed reasonable amounts of electrophiles (20−50% excess), despite the use of 2 equiv of TMSCH2Li, and the condensation step could be realized efficiently at 0 or −20 °C in toluene (Table 2). Table 2. C-2 Lithiation of 2,5-Dibromopyridine and Reaction with Electrophiles

a

Formed after reaction of the organolithium with ethene formed upon THF decomposition.

3.1. Lithium Magnesates

The same reagent was later used to perform the selective exchange at C-2 of 2,3-dibromopyridine (Table 3).14 This was reported to be the first example of formation and stabilization of 2-lithio-3-bromopyridine under noncryogenic conditions.15

Since the pioneering work on lithium organomagnesates (R3MgLi) published by Wittig et al. in 1951,18 the synthetic usefulness of these reagents for halogen/metal exchange has been demonstrated only recently. Oshima and co-workers have reported numerous examples of successful halogen/metal exchange reactions on aromatic, heteroaromatic, and vinyl halides in a first communication in 200019 followed by an extended study in 2001.20 In the absence of sensitive substituents, Bu3MgLi [prepared from BuMgBr and BuLi (2 equiv)] was used at 0 or −78 °C (Tables 6 and 7). Oshima found an interesting reactivity of diarylmagnesates that could be transmetalated with TiCl4, leading to various biaryls in good yields. Due to the high reactivity of Bu3MgLi,

3. BIMETALLIC LITHIUM−MAGNESIUM REAGENTS Screttas and Steele investigated the effect of magnesium alkoxides on the reactivity of lithium reagents.16 The alkyllithium reagents trend to cleave THF is greatly diminished in the presence of magnesium 2-ethoxyethoxide, allowing the generation of organolithium reagents in THF under conditions not normally favorable to their stability. In the absence of magnesium 2-ethoxyethoxide, the alkyllithium reagents formed B


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promoting bromine/metal exchanges even at low temperature (−40 or −78 °C), biaryls bearing reactive functionalities could be obtained (Table 8).21

Table 5. Halogen/Lithium Exchange of Hydroxyalkoxy Aromatic Halides Using Activated BuLi

Table 8. Halogen/Metal Exchange of Aryl Halides with Bu3MgLi followed by TiCl4-Mediated Homocoupling

The tolerance of esters to Bu3MgLi was exploited for the synthesis of phthalides. Sensitive nitriles, amides, and esters were tolerated using the heteroleptic magnesate i-PrBu2MgLi [prepared from i-PrMgBr and BuLi (2 equiv)] at −78 °C (Scheme 2 and Table 9).20 The selectivity of the exchange was

Table 6. Halogen/Metal Exchange of Aryl Iodides with Bu3MgLi

Scheme 2

Table 9. Halogen/Metal Exchange of Sensitive Aryl Bromides with i-PrBu2MgLi Table 7. Halogen/Metal Exchange of Aryl Bromides with Bu3MgLi

a

a

In the presence of CuCN·2LiCl (30 mol %).

also investigated on dihalogenoarenes. In the case of 1,4diiodobenzene, the monomagnesation was favored using BuMe2MgLi thanks to a lower reactivity of methyl ligands leading to a slower second exchange (Table 10).20 In 2002, Schreiber and co-workers reported a very efficient procedure for the atroposelective synthesis of biaryl compounds libraries.22 The reaction was investigated in solution and on polystyrene beads. The authors found that iPr2Bu2MgLi was the best reagent, able to perform the exchange

In the presence of CuCN·2LiCl (30 mol %). C


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In 2004, Richey and co-workers investigated the effect of additives on the reaction of aromatic halides with Et2Mg. It was found that the addition of t-BuOLi, PhOK, or MeOK gave excellent exchange yields with aryl iodides and bromides, while limiting alkylation due to aryne formation was noted (Table 16). The formation of magnesates is postulated by the authors.31 Fused aromatic systems were also functionalized using magnesates. Ito and co-workers have reported efficient iodine/metal exchanges of iodoazulenes (Table 17).32 The same authors have reported efficient palladium-catalyzed crosscoupling of azulenyl magnesates with thienyl bromides (Table 18).33 The magnesates formed from electron-rich aryl bromides proved to be good partners for Kumada-type reaction, as reported by Lau and co-workers (Table 19).34 Gallou and co-workers at Novartis have developed another methodology using the in situ magnesate preparation. The bromoarenes were first mixed with i-PrMgCl, and BuLi was finally added. The exchange could be conducted at 0−5 °C, and the arylmagnesates were efficiently trapped by DMF to give the corresponding benzaldehydes. However, the reagent was not found compatible with nitriles and esters (Table 20).35 The monomagnesation of polyhalogenoarenes was applied by Balsells and co-workers for the preparation of t-butyl benzoates in excellent yields (Table 21).36 The selective monomagnesation using Bu3MgLi was also exploited recently by Gleiter for the preparation of building blocks for cyclophanes synthesis (Scheme 7).37 The monomagnesation of 4,4′-dibromobiphenyl was reported by Dolman and co-workers at Merck using 0.4 equiv of Bu3MgLi under inverse addition conditions (Table 22).38 Examining a similar topic, McCullough and co-workers have studied the monomagnesation of 2,7-dibromo-9,9-dioctylfluorene. Bu3MgLi was the most efficient reagent also for the monomagnesation of 2,7-dibromo-N-octylcarbazole, while iPrMgCl·LiCl was reactive enough for exchanging bromine in 2,5-dibromo-N-docecylpyrrole (Table 23). The metalated compounds were next involved in polymerization using Ni(dppp)Cl2 as catalyst.39 i-PrBu2MgLi was also used as a selective exchange agent for the preparation of monozincated 9,9-dioctylfluorene, which was next homopolymerized under palladium catalysis (Scheme 8).40 The halogen/metal exchange was performed at 0 °C on halogenopyridines and -thiophene, but Bu3MgLi had to be replaced by BuMe2MgLi to avoid side alkylations induced by an excess of butyl group in the magnesate (Table 24).20 In 2001, Iida et al. reported the monosubstitution of dibromobenzenes, dibromopyridines, and dibromothiophenes using Bu3MgLi (prepared from BuMgCl and BuLi). They found that it was possible to control the selectivity using 0.35 equiv of the reagent in a toluene−THF mixture. The selectivity was checked by quenching the arylmagnesates with DMF (Table 25).41 Mase and co-workers reported the usefulness of the monoformylation methodology for the synthesis of a muscarinic receptor antagonist.42 In 2003, Mongin and co-workers reported the first magnesation of bromoquinolines using Bu3MgLi (Table 26).43 The quinolyl magnesates have been involved in Kumada couplings with a range of aromatic and heteroaoromatic halides (Table 27).43b,44

Table 10. Selective Halogen/Metal Exchange of Aromatic Dihalides with Various Trialkylmagnesates

in solution and solid phase as well. The same reaction was later extended to the synthesis of pyridyl-aryl atropoisomers. In this case, the substrates were bound to polymer via the aryl group, and excellent diastereoselectivities were obtained (Table 11).23 Spring and co-workers have investigated the bromine/metal exchange on polystyrene beads using various metalating agents. While BuLi or i-PrMgCl gave poor efficiencies, i-PrBu2MgLi was found to give complete bromine removal and excellent yields upon trapping with ClPPh2 or i-Pr2SiHCl, regardless of beads size (Table 12). The corresponding functional resins were further used for Mitsunobu reactions and as traceless linker, respectively.24 Kato and co-workers have reported an efficient process for bromine/metal exchange of bromoarenes containing protondonating groups. The principle was to first react the substrate with Bu2Mg (0.5 equiv) followed by BuLi (1 equiv) in order to form a stable magnesio intermediate (Scheme 3). The reaction was used for the preparation of lactones from 2-bromobenzoic acid and appropriate electrophiles (Table 13). Other bromoarenes bearing base-sensitive functionalities were also magnesated selectively and reacted with aldehydes, giving the expected alcohols in good yields (Table 14).25 In 2003, Schlosser and co-workers used Bu3MgLi to promote a selective monodebromination of a tribromotrifluorobenzene. Only the bromine adjacent to fluorine was removed (Scheme 4).26 The magnesates could also be used in the presence of sensitive substituents. Schlosser and co-workers have reported the use of Bu3MgLi to promote selective magnesations in functional benzoic acids. The reagent was used to remove selectively one bromo atom ortho to a carboxylic acid. The selectivity was explained by the formation of an intermediate magnesium carboxylate. 27 The same reagent was also successfully used for selective exchange in a series of quinoline carboxylic acids (Scheme 5).28 Bu3MgLi was also found to be the reagent of choice for the synthesis of siloxane monomers, as reported by GuidaPitrasanta’s group. The product depicted in Scheme 6 was then successfully used in the synthesis of functional polysiloxanes.29 Jain and co-workers have studied the reaction of aryl halides bearing hydrogen-donating ortho-directing groups in order to investigate the competition between exchange and orthodeprotonation. The exchange was obtained chemoselectively using i-PrBu2MgLi, even when iodoindoles were reacted (Table 15).30 D


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Table 11. Atroposelective Synthesis of Biaryls via Magnesation−Cupration−Oxidation Sequence

was the best reagent, leading to functional picolines in good to excellent yields, provided that a 2 h contact time between the electrophile and the picolylmagnesate was applied (Table 28).47 In 2009, Sośn icki reported the bromine/magnesium exchange of 5-bromo-2-methoxypyridine using Bu3MgLi·

In 2004, Schlosser and co-workers reported a clean synthesis of functional isonicotic acids via a selective bromine45 or iodine/metal exchange using Bu3MgLi (Scheme 9).46 The bromine/magnesium exchange of 5-bromo-2-picoline has been investigated by Kii et al. They found that i-PrBu2MgLi E


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Table 12. Solid Phase Bromine/Metal Exchange

Scheme 5

Scheme 3

Scheme 6 Table 13. Preparation of Lactones Using Halogen/Metal Exchange of 2-Bromobenzoic Acid

Table 15. Chemoselective Halogen/Metal Exchange of Aryl Halides Bearing Hydrogen-Donating Substituents

Table 14. Halogen/Metal Exchange of Sensitive Aryl Bromides and Reaction with Benzaldehyde

Table 16. Effect of Additives on Halogen/Magnesium Exchange with Et2Mg Scheme 4

LiCl.48 In a following full paper in 2012, Struk and Sośnicki and compared the reactivity of Bu3MgLi, Bu3MgLi·LiCl, and iPrBu2MgLi·LiCl (Table 29). Since i-PrBu2MgLi·LiCl was found to be the most efficient reagent, it was used for the magnesation of other methoxypyridine isomers (Table 30).49 In 2004, Pedersen and co-workers reported the C-4 functionalization of fused pyrimidines under Barbier’s conditions using several organomagnesates. They have examined the effect of the nature of the organomagnesate and temperature, and the best results were obtained using Me2BuMgLi and Bu2PhMgLi (Table 31).50

In 2006, Turck and co-workers developed the first iodine/ magnesium exchange on sensitive 2-iododiazines using Bu3MgLi. For phenylpyridazine, a reverse addition was necessary to improve the electrophilic trapping step (Table 32).51 Lash and co-workers have reported the synthesis of carbaporphyrins that required the preparation of fulvene dialdehydes as key intermediates. The dialdehydes were F


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Table 17. Iodine/Magnesium Exchange of Iodoazulenes

Table 20. Halogen/Metal Exchange of Bromoarenes with Situ Generated Magnesate

Table 18. Halogen/Magnesium Exchange of Halogenoazulenes and Subsequent Cross-Coupling

Table 21. Mono-Halogen/Metal Exchange of Polyhalogenoarenes

Table 19. Kumada Coupling of Triarylmagnesates

Scheme 7

prepared by an iodine/metal exchange: only Bu3MgLi was able to promote the exchange, all attempts with BuLi or t-BuLi failing (Scheme 10).52 The possibility to coordinate several ligands to magnesium in magnesates was recently exploited for the preparation of chiral magnesates able to perform an efficient bromine/magnesium exchange of 2-bromopyridine and subsequently transfer chirality upon addition to a carbonyl compounds. Among several ligands investigated, (R,R)-TADDOL was found to be the most efficient. The (R,R)-TADDOLate)Bu2MgLi reagent was prepared by reacting lithium (R,R)-TADDOLate (1 equiv) successively with BuMgCl (1 equiv) and BuLi (1 equiv) (Scheme 11). A 0.5 equiv portion of the reagent allowed a

quantitative bromine/metal exchange and was used for the preparation of a range of chiral pyridyl alcohols (Table 33).53 The reaction was next extended to iodopyrazine and preparation of chiral pyrazinyl alcohols. In this case, 1 equiv of the magnesate was required. Despite moderate yields, very good enantiomeric excesses were obtained with electron-rich aldehydes (Table 34).54 The halogen/metal exchange by magnesates was also applied to alkenyl iodides (Table 35).20 In the case of alkenyl bromides, the exchange was slow and dehydrobomination as well as deprotonation led to significant amounts of magnesium acetylides (Table 36). To prevent such a side elimination G


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Table 22. Mono-Halogen/Metal Exchange of 4,4′Dibromobiphenyl

Table 25. Mono-Halogen/Metal Exchange of (Het)Aryl Dibromides and Subsequent Formylation

Table 23. Mono-Halogen/Metal Exchange of 2,7-Dibromo9,9-dioctylfluorene Table 26. Halogen/Metal Exchange of Bromoquinolines with Bu3MgLi and Reaction with Electrophiles

Scheme 8

Table 24. Halogen/Metal Exchange of Heteroaryl Halides with BuMe2MgLi Table 27. Cross-Coupling of Magnesated Quinolines

process, the acidic proton was replaced by a trialkylsilyl group (Table 37).20 In 2003, Sato and co-workers investigated the iodine/ magnesium exchange of 1,4-diiodo-1,3-alkadienes by i-Pr-tBu2MgLi. When vinyl aldehydes were used as electrophiles, it was possible to prepare polysubstituted phenols and styrenes via Heck couplings (Table 38).55 In 2001, Oshima and co-workers also investigated the alkylative magnesation of gem-dibromo silanes with organomagnesates. The methylation was found to be successful using Me3MgLi on a range of disilyl compounds. A subsequent dehydrobromination using 1,8-diazabicycloundec-7-ene afforded the corresponding disilylethenes (Table 39).56 When a monosilylated substrate was used (R2 = H), a 1,2-migration of one alkyl group of the magnesate was observed upon addition H


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Scheme 9

Table 30. Halogen/Metal Exchange of Methoxybromopyridines with i-PrBu2MgLi·LiCl

Table 28. Halogen/Metal Exchange of 5-Bromo-2-picoline

Table 29. Halogen/Metal Exchange of 2-Methoxy-5bromopyridine with Various Activated Trialkylmagnesates

Table 31. Iodine/Metal Exchange of Fused Thienopyrimidine

Table 32. Halogen/Metal Exchange of Iododiazines

of copper cyanide, as evidenced by quenching with MeOH (Scheme 12). It was possible to further functionalize the alkylated substrate by reaction with acyl chlorides (Table 40). The methodology was also efficient to perform conjugate addition to α,β-unsaturated ketones (Scheme 13).57 In 2002, Oshima successfully extended this reaction to gem-dibromocyclopropanes (Table 41).58 In 2004, Oshima and co-coworkers reported the synthesis of functional cyclopropanes via iodine/magnesium exchange of 3-

a

Trapping step performed at room temperature (rt). addition. cReaction performed in Et2O instead of THF.

b

Reverse

iodo-1-oxacyclopentanes. Several magnesium-containing reagents have been used, and i-PrMgBr and Bu3MgLi led to the product in excellent yields (Scheme 14).59 I


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Table 35. Halogen/Metal Exchange of Iodoalkenes with iPrBu2MgLi

Scheme 10

Scheme 11

Table 33. Halogen/Metal Exchange of 2-Bromopyridine with a Chiral Magnesate and Enantioselective Addition to Aldehydes

Table 36. Halogen/Metal Exchange of Bromoalkenes with iPrBu2MgLi and Side Dehydrobromination

Table 34. Halogen/Metal Exchange of 2-Iodopyrazine with a Chiral Magnesate and Enantioselective Addition to Aldehydes Table 37. Halogen/Metal Exchange of Halogenosilylalkenes with i-PrBu2MgLi

Fleming and co-workers have reported the use of the intermediate formation of a magnesate to promote iodine/ magnesium exchange at sp3 carbons in iodo alcohols (Table 42).60 3.2. Turbo-Grignard Reagents

activation of i-PrMgCl using several salts such as LiBF4, LiBr, LiClO4, and LiCl.62 LiCl was the most efficient when used in a stoichiometric amount, and it was found to give “ate-character” to the formed reagent. The i-PrMgCl·LiCl reagent was prepared by adding i-PrCl to a mixture of Mg turnings and

The halogen/metal exchange using nonactivated Grignard reagents has been reviewed by Knochel and co-workers in 20037b and 2006.61 In order to promote faster exchanges, especially bromine/magnesium ones, as well as reactions at lower temperatures, the same authors have investigated the J


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Table 38. Mono-Halogen/Metal Exchange of Diiodoalkadienes Using t-Bu2-i-PrMgLi

Scheme 13

Table 41. Alkylative Magnesation of gemDibromocyclopropanes and Reaction with Electrophiles

Table 39. Monomethylation of gem-Dibromo Disilanes and Formation of Disilylethenes

Scheme 12

Scheme 14 Table 40. Alkylation of gem-Dibromo Monosilanes and Reaction with Acyl Chlorides

from i-PrMgCl·LiCl to i-Pr2Mg·LiCl (Scheme 15). The obtained reagent was found to be highly reactive toward electron-rich aryl bromides provided that 10% of 1,4-dioxane was added to the mixture. When i-Pr was replaced by s-Bu in the reagent, s-Bu2Mg·LiCl was able to perform efficient exchange in THF without additive. When the same reagent was used in tetraglyme, it was possible to promote the double magnesation of diiodobenzene (Table 44). The arylmagnesiums were found to be reactive toward tetramethylthiuram disulfide, leading to aryl sulfides in good yields (Table 45).64 Chloramines are other possible electrophiles, allowing the preparation of arylamines in good yields (Table 46).65

LiCl in THF. The reagent was reacted efficiently with a range or aromatic and heteroaromatic bromides (Table 43). The effect of additives was later investigated theoretically and experimentally.63 It was shown that chelating additives like crown ethers or dioxane displaced the Schlenk equilibrium K


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Table 42. Iodine/Magnesium Exchange at sp3 Carbon via Intramolecular Magnesate Formation

Scheme 15

Table 44. Effect of Additives on Exchange with R2Mg·LiCl Reagents

Table 43. Bromine/Magnesium Exchange of (Het)Aryl Bromides with i-PrMgCl·LiCl and Reaction with Electrophiles a

The aryl Grignard was transmetalated with CuCN·2LiCl.

Table 45. Preparation of Aryl Sulfides by Reaction of Arylmagnesium with Tetramethylthiuram Disulfide

The aryl and heteroarylmagnesiums generated by i-PrMgCl· LiCl have been transmetalated with CuCl·LiCl, thus allowing oxidative cross-couplings with alkynyllithiums via cuprate formation (Table 47).66 In 2010, Knochel and co-workers reported a one-pot procedure to convert aryl and heteroaryl halides into the corresponding fluorinated products via a halogen/metal exchange using i-PrMgCl·LiCl and subsequent electrophilic

a

The aryl Grignard was transmetalated with CuCN·2LiCl. bProduct obtained after oxidative treatment (aq H2O2).

L


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Table 46. Preparation of Arylamines by Reaction of Arylmagnesiums with Chloramines

Table 48. Preparation of Aryl Fluorides by Reaction of (Het)Arylmagnesiums with N-Fluorobenzenesulfonimide

Table 47. Oxydative Coupling of Arylcoppers with Lithioalkynes

Table 49. Iodine/Magnesium Exchange from ElectronDeficient Aryl Iodides Using i-PrMgCl·LiCl toward the Preparation of Functionalized Arylboronic Esters

In 2012, McLaughlin and co-workers at Merck described the preparation of functionalized α-hydroxyacetophenones by halogen/magnesium exchange between haloaryl species and iPrMgCl·LiCl followed with transmetalation to the arylzinc reagent and Cu(I)-catalyzed reaction with acetoxyacetyl chloride. Subsequent cleavage of the acetate group to αhydroxyacetophenones was realized under acidic conditions (Table 50).69

fluorination with N-fluorobenzenesulfonimide (NFSI) (Table 48).67 In 2011, Chavant and co-workers reported an efficient process for the preparation of functionalized arylboronic esters derived from hexylene glycol and pinacol by iodine/magnesium exchange between i-PrMgCl·LiCl and electron-deficient aryl iodides and in situ quench by cyclic borate esters (Table 49).68 M


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predominant effect of inductive effects and formation of a hypervalent halogen complex. The order of the substituents effects (CO2-t-Bu < F = Cl < CF3 < CN) also shows that the mesomeric effect is negligible. The same experiments have been performed with heteroaryl bromides.72 At first, all derivatives were found to be much more reactive than bromobenzene. In the five-membered series (pyrroles, furans, thiophenes), the 2-bromo derivative was the most reactive compared with the 3-bromo isomer. In the pyridine series, 3- and 4-bromopyridines were found much more reactive than 2-bromopyridine. The most reactive substrates were 3,4-dibromofuran, 2-bromothiophene, 3,5dribromopyridine, and 2-bromothiazole. With these substrates, LiCl could be omitted from the reagent. The same authors have also quantified the leaving-group dependence on the rates of halogen/magnesium exchange. Using the competition experiments, they have determined that the increase of exchange rate is in the order ArCl < ArBr < ArI in 1:106:1011 ratio, whatever the substituents.73 The magnesation of aromatic and heteroaromatic iodides bearing hydroxyl groups was made possible using prior deprotonation by MeMgCl·LiCl followed by exchange with iPrMgCl (Table 52).74 Halogenobenzoic acids were also efficiently magnesated without protection of the carboxylic moiety using the double magnesation procedure (Table 53).75 The functional tolerance of i-PrMgCl·LiCl was illustrated in the preparation of boron−magnesium mixed reagents (Table 54).76 Triazenes have also been found to be tolerated by the turbo-Grignard (Table 55). The triazene moiety could be either removed by reaction with CH3I or Me3SiI to introduce iodine or used as an amine source for synthesis of carbazoles.77 The same methodology was used by Knochel’s group to prepare boronates via reaction of arylmagnesiums with B(Oi-Pr)3 (Table 56). The boronates were further doubly functionalized to give terphenyl derivatives (Scheme 17).78 The sulfur/magnesium exchange was investigated by Knochel and co-workers. The use of i-PrMgCl and subsequent addition to t-BuOLi allowed the formation of benzylic magnesium reagents from benzylic sulfides (Table 57). The actual reactive species was assumed to be the ArMg(O-tBu)ClLi magnesate, expected to be more reactive than the simple Grigrnard.79 Aromatic cyanohydrines were also selectively magnesated, leading to synthetic equivalents of carbonyl-containing aromatic Grignard compounds (Table 58). The reaction was used for the synthesis of a tricyclic ketone (Scheme 18).80 In 2009, Knochel and co-workers reported the preparation of polyfunctional indazoles by iodine/magnesium exchange on substituted 2-iodobenzyl chlorides with i-PrMgCl·LiCl, giving 2-chloromethylarylmagnesium chlorides that were transmetalated with ZnBr2·LiCl. The resulting functionalized 2chloromethylarylzinc reagents were further reacted with aryldiazonium tetrafluoroborates to form 2-aryl-2H-indazoles (Table 59).81 In 2012, Kobayashi described an efficient synthesis of substituted quinolines from the Boc amides of N-substituted 2-iodoanilines by iodine/magnesium exchange using 3.5 equiv of i-PrMgCl·LiCl, followed by intramolecular addition of the aryl anion to the carbonyl group, forming tetrahydroquinolines, and then rearomatization (Table 60).82 In 2008, Chen and co-workers reported the convertion of substituted aryl iodides into Grignard reagents using i-PrMgCl· LiCl. Subsequent one-pot transmetalation gave cuprates, which

Table 50. Halogen/Magnesium Exchange from Aryl Halides Using i-PrMgCl·LiCl for the Preparation of Functionalized α-Hydroxyacetophenones

In 2012, Togo and co-workers described a one-pot method consisting of halogen/magnesium exchange of aromatic halides (Br, I) bearing p-ester or nitrile groups using i-PrMgCl·LiCl, addition to aromatic or aliphatic aldehydes, and oxidation by treatment with 1,3-diiodo-5,5-dimethylhydantoin (DIH) and K2CO3 to prepare diaryl ketones, alkyl aryl ketones, and dialkyl ketones (Table 51).70 Table 51. Halogen/Magnesium Exchange of Aromatic Halides (Br, I) Bearing Ester or Nitrile Functions at the 4Position Using i-PrMgCl·LiCl

Knochel and co-workers have investigated the kinetics of bromine/magnesium exchange using i-PrMgCl·LiCl and especially the effect of substituents in bromobenzenes.71 The principle was to examine the competition between pairs of diversely substituted bromobenzenes (Scheme 16). From these experiments it appeared that electron-withdrawing substituents dramatically accelerated the exchange. The effect increased in the order para < meta ≪ ortho, in agreement with a Scheme 16a

a

FG = electron-donating and -withdrawing functional groups. N


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Table 52. Selective Exchange of Halogen in Halogenophenols

Table 53. Selective Exchange of Halogen in Halogenobenzoic Acids

a

The aryl Grignard was transmetalated with CuCN·2LiCl. bPalladiumcatalyzed cross-coupling after transmetalation with ZnCl2.

tion was obtained for the protonolysis, furnishing a monobromo alcohol (53% ee, 51% yield). The latter was converted into (R)-orphenadrine, an antihistaminic and anticholinergic drug (Scheme 22 and Tables 61 and 62).85 In 2009, Castle and co-workers reported an enantioselective total synthesis of (−)-acutumine with iodine/magnesium exchange on disubstituted iodocyclopentene using i-PrMgCl· LiCl in conjunction with 15-crown-5 as an important step, generating a Grignard reagent that was added to a Weinreb amide to form enones (Scheme 23).86 In 2011, Itakura and Harada reported a catalytic method for the enantioselective synthesis of functionalized diarylmethanols starting from aryl bromides and aldehydes. In the presence of (R)-3-(3,5-diphenylphenyl)BINOL (2 mol %) and titanium tetraisopropoxide, functionalized aryl Grignard reagents bearing a CF3, Br, and CN group at the meta and para positions, prepared in situ by bromine/magnesium exchange with iPrMgCl·LiCl, underwent addition to aldehydes to give the corresponding functionalized diarylmethanols in high enantioselectivities. Dibromobenzenes underwent selective monoexchange with i-PrMgCl·LiCl (Table 63).87 The turbo-Grignard i-PrMgCl·LiCl was also used to prepare alkenylmagnesium reagents in a stereoselective way (Table 64).88 The authors later applied the reaction to cyclic iodoalkenes bearing an alkoxy moiety (Table 65).89 In 2008, they reported the functionalization of 1,2-dibromocyclopentene by selective mono-bromine/magnesium exchange using i-PrMgCl·LiCl to afford the β-bromocyclopentenylmagnesium reagent, which could then be trapped with electrophiles (Table 66). By use of 2.4 equiv of turbo-Grignard reagent and a catalytic amount of

a The aryl Grignard was transmetalated with CuCN·2LiCl. bPalladiumcatalyzed cross-coupling after transmetalation with ZnCl2.

underwent an allylic substitution reaction to give mycophenolic acid analogs in moderate yields (Scheme 19).83 In 2008, Geng and co-workers reported nickel(II)-catalyzed polymerizations of fluorenyl Grignard reagent to form poly(9,9dioctylfluorene) with number-average molecular weights (Mn) up to 8.60 × 104. The sequence involved a selective iodine/ magnesium exchange by a turbo-Grignard reagent in the presence of a bromine substituent. LiCl promoted both the iodine/magnesium exchange and the polymerization (Scheme 20).84 In 2009, McCullough and co-workers reported similar polymerization, but from aromatic and heteroaromatic dibromo compounds, affording poly(9,9-dioctylfluorene) and poly(Ndodecylpyrrole) by halogen/magnesium exchange using either a Grignard reagent in the presence of a lithium salt (LiCl, LiOtBu) or a magnesium ate complex. Additives such as crown ethers and multidentate amines increased the rate of the halogen/magnesium exchange (Scheme 21).39 In 2009, Brückner and co-workers described asymmetric halogen/metal exchange reactions to desymmetrize prochiral bis(bromoaryl) alcohols using i-Pr2Mg in the presence of stoichiometric amounts of enantiopure lithium alkoxides or phenoxides. The desymmetrized arylmagnesium compounds were quenched with electrophiles. The best ee/yield combinaO


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Table 54. Iodine/Magnesium Exchange in the Presence of Boronates

Table 56. Halogen/Magnesium Exchange in the Presence of Triazenes and Reaction with B(O-i-Pr)3

Scheme 17

Table 57. Benzylmagnesium Generation from Intramolecular Sulfur/Magnesium Exchange

Table 55. Halogen/Magnesium Exchange in the Presence of Triazenes

trapped with various electrophiles. Also, transmetalation with CuCN·2LiCl or ZnCl2 allowed for coupling reactions. Several optically pure enol phosphates were prepared starting from readily available D-(+)-camphor derivatives (Table 68).91 In 2008, Knochel and co-workers reported the formation of sp3-hybridized Grignard reagents by iodine/magnesium exchange between i-Pr2Mg·LiCl or ClMg(CH2)5MgCl·2LiCl and functionalized primary alkyl iodides bearing oxygen or nitrogen atoms in the γ-position to the carbon−iodine bond. The resulting species were trapped with electrophiles (Table 69).92

Li2CuCl4 (2 mol %), its β-bromo substituent was substituted by the alkyl group of the magnesium reagent. The transformation could also be extended to 1,2-dibromonorbornadiene (Table 67).90 In 2010, Knochel and co-workers published α-magnesations of cyclic enol phosphates by halogen/magnesium exchange using i-PrMgCl·LiCl. The resulting magnesium reagents were P


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Table 58. Magnesation of Aromatic Cyanhydrines

Table 60. Functional Quinolines from Intramolecular Reaction of Arylmagnesium with Ketones

Scheme 19

Scheme 18

Table 59. Iodine/Magnesium Exchange from 2-Iodobenzyl Chlorides and Transmetalation to Zinc for the Preparation of Polyfunctional Indazoles Scheme 20

Scheme 21

Scheme 22

The functionalization of heteroaromatics using bimetal exchange agents has been considered as well. Knochel and co-workers investigated the bromine/magnesium exchange of bromopyrimidines (Table 71). The second bromine could be exchanged after introduction of a first electrophile. The methodology was found useful for the preparation of pharmaceuticals like oxypurinol or emivirine.94 Uracil derivatives were functionalized without protection.95 The principle is to protect the carbonyl groups via aromatizing magnesation (Table 72). Imidazoles were efficiently function-

In 2009, the same group described the stereoselective synthesis of functionalized cyclopropylmagnesium compounds by reaction of cyclopropyl bromides with i-PrMgCl·LiCl in THF−dioxane or s-Bu2Mg·LiCl. Bromine/magnesium exchange with complete retention of configuration was observed. Subsequent reactions with electrophiles provided polyfunctionalized cyclopropanes with excellent stereoselectivities (Table 70).93 Q


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Table 61. Bromine/Magnesium Exchange from α-(2Bromophenyl)ethanol and Subsequent Functionalization

a

Scheme 23

Trapping step after addition of CuCN·2LiCl (10 mol %).

Table 63. Br/Mg Exchange of Aryl Bromides for the Enantioselective Synthesis of Functionalized Diarylmethanols

Table 62. Desymmetrization of Prochiral Bis(bromoaryl) Alcohols Using i-Pr2Mg in the Presence of Stoichiometric Amounts of Enantiopure Lithium Alkoxides

Table 64. Stereoselective Generation of Alkenylmagnesiums and Reaction with Electrophiles

a

Only a catalytic amount of ligand (20 mol %) was used. bAddition of substrate in benzene. cUsing 2.0 equiv of BuLi relative to the ligand. d Using 2.2 equiv of i-Pr2Mg.

alized using the same methodology without protection of the free NH (Table 73).96 In 2009, Knochel and co-workers described the iodine/ magnesium exchange on different 4,5-dihydrobenzoindazoles using commercially available i-PrMgCl·LiCl at −30 °C. Trapping the magnesated species either directly with electrophiles or by cross-coupling after transmetalation with ZnCl2 or

CuCN·2LiCl furnished a range of substituted indazoles (Tables 74 and 75).97 R


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Table 65. Iodine/Magnesium Exchange of Alkoxyiodoalkenes and Reaction with Electrophiles

Table 68. Halogen/Magnesium Exchange of PhosphateBearing Halogenocycloalkenese

a

After transmetalation using CuCN·2LiCl (1 equiv). bAfter transmetalation using ZnCl2. cIn the presence of Pd(dba)2 (5 mol %). dIn the presence of Pd(OAc)2 (2 mol %) and S-Phos (4 mol %). e1-Bt = 1-benzotriazolyl.

Table 66. Monomagnesation of 1,2-Dibromocyclopentene and Reaction with Electrophiles

Table 69. Iodine/Magnesium Exchange of sp3-Hybridized Alkyl Iodides Followed by Electrophilic Trapping

a

After transmetalation using ZnCl2 (1 equiv). bIn the presence of Pd(dba)2 (5 mol %) and P(2-furyl)3 (7 mol %). cTrapping step performed in the presence of CuCN·2LiCl (20 mol %).

Table 67. Bromine/Magnesium Exchange of Dibromocycloalkenes with Various Alkylmagnesium Reagents and Reaction with Electrophiles

a The aryl Grignard was transmetalated with CuCN·2LiCl. cyclization to lactone.

b

After

In 2010, Carell and co-workers performed an iodine/ magnesium exchange on elaborated nucleosides using iPrMgCl·LiCl during syntheses of deazaguanosine-derived tRNA nucleosides PreQ0, PreQ1, and archaeosine. High tolerance toward functional groups such as esters and amides was observed, and the iodine/magnesium exchange reaction took place despite the presence of two negatively charged positions in the starting material after deprotonation with MeMgCl. The presence of LiCl was essential for enabling the transformation, as experiments with i-PrMgCl alone resulted in decomposition of the nucleoside (Scheme 24).98

a After transmetalation using ZnCl2 (1 equiv). bTrapping step performed in the presence of CuCN·2LiCl (20 mol %). cIn the presence of Pd(dba)2 (5 mol %) and P(2-furyl)3 (7 mol %).

S


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Table 70. Bromine/Magnesium Exchange on Cyclopropyl Bromides Using i-PrMgCl·LiCl or s-Bu2Mg·LiCl and Reactions with Electrophiles

Table 72. Selective Exchange of Halogen in Unprotected Halogenouracils

Table 73. Selective Exchange of Halogen in Iodoimidazoles with Free NH a

Trapping step performed in the presence of CuCN·2LiCl (5 mol %). The aryl Grignard was transmetalated with CuCN·2LiCl. cIn the presence of Pd(dba)2 (2 mol %) and P(2-furyl)3 (4 mol %). dIn the presence of Pd(OAc)2 (1 mol %) and S-Phos (1.5 mol %). b

Table 71. Halogen/Magnesium Exchange of Bromomethoxypyrimidines and Subsequent Functionalization

Table 74. Iodine/Magnesium Exchange from 1-Benzyl-3halo-4,5-dihydrobenzoindazoles Using i-PrMgCl·LiCl and Reactions with Electrophiles

a

The Grignard reagent was transmetalated with ZnCl2 before crosscoupling in the presence of Pd(dba)2 (5 mol %) and P(2-furyl)3 (10 mol %). bCuCN·2LiCl (1equiv) was added before the trapping step.

The turbo-Grignard was also found to be selective for monomagnesation of 3,5-dibromopyridine bearing a tosyloxy moiety at the C-2 position (Table 76). The sequential magnesation led to trisubstituted derivatives (Scheme 25).99 Dibromo- and tribromoquinolines were regioselectively functionalized, depending on the turbo-Grignard and conditions used (Table 77).100

In 2009, Duan and co-workers reported the magnesation of pyridine N-oxides using i-PrMgCl·LiCl via iodine or bromine/ magnesium exchange. The bromine adjacent to the pyridine Noxide can be regioselectively magnesated in the presence of T


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Table 75. Iodine/Magnesium Exchange from 2-Benzyl-3halo-4,5-dihydrobenzoindazoles Using i-PrMgCl·LiCl and Reactions with Electrophiles

Table 77. Selective Halogen/Metal Exchange of Polybromoquinolinesc

a

The quinolyl Grignard was transmetalated with CuCN·2LiCl. Pd(dba)2 (2 mol %) and P(2-furyl)3 (4 mol %) were used for the cross-coupling after transmetalation with ZnCl2. cMes = mesityl or 2,4,6-trimethylphenyl, TMEDA = N,N,N′,N′-tetramethylethylenediamine.

a

The Grignard reagent was transmetalated with ZnCl2 before crosscoupling in the presence of Pd(dba)2 (5 mol %) and P(2-furyl)3 (10 mol %). bCuCN·2LiCl (1 equiv) was added before the trapping step.

b

Scheme 24

Table 78. Halogen/Magnesium Exchange on Halopyridine N-Oxides Using i-PrMgCl·LiCl

Table 76. Selective Halogen/Metal Exchange of Tosyldibromopyridine

a

The pyridyl Grignard was transmetalated with CuCN·2LiCl (1 equiv).

Scheme 25

a

In the presence of CuI·2LiCl.

The arynes were efficiently trapped with furan to give the [4 + 2] Diels−Alder products in good yields (Table 79).102 In 2010, Wilkinson and co-workers at GlaxoSmithKline UK investigated the use of the LiCl−i-PrMgCl combination to perform mono-bromine/magnesium exchange on 2,6-dibromopyridine for the development of possible manufacturing routes

other halogens. This method was applied to the total synthesis of caerulomycins E and A (Table 78).101 The selective exchange allowed by i-PrMgCl·LiCl was used to generate 3,4-pyridynes using arylsulfonates as leaving groups. U


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Table 79. Generation of 3,4-Pyridines and Diels−Alder Trapping Step

Scheme 28

to EP1 antagonist GSK269984B. The efficiency of the halogen/ metal exchange using the commercially available reagent was less than reported by Knochel, affording the product in 66% yield after crystallization (Scheme 26).103 Knochel described an efficient iodine/magnesium exchange on 2,3,5-trisubstituted furans promoted by i-PrMgCl·LiCl (Scheme 27).104 Scheme 26 Table 80. Halogen/Magnesium Exchange Using i-PrMgCl· LiCl from Aryl Iodides or Bromides by Microscale React-IR Flow Cell

Scheme 27

In the course of studies directed toward the synthesis of dibenzothiophenes and related classes of heterocycles, Knochel and co-workers described in 2010 several bromine/magnesium or iodine/magnesium exchange reactions between functionalized aryl bromides or iodides and i-PrMgCl·LiCl followed with transmetalation with ZnCl2. Subsequent Negishi crosscoupling reactions with functionalized 1-chloro-2-iodobenzene derivatives afforded the polysubstituted biphenyls (Scheme 28).105 In 2012, Knochel and co-workers described the development of a microscale React-IR flow cell that was used for the preparation of functionalized arylmagnesium compounds from aryl iodides or bromides via LiCl-mediated halogen/magnesium exchange using i-PrMgCl·LiCl. Subsequent coupling with carbonyl compounds was realized under continuous flow conditions (Table 80).106

functionalization of aromatic and heteroaromatic halides was obtained (Table 81).107 Knochel and co-workers also transmetalated LiCl-activated arylmagnesium with diakylaluminum chlorides (Scheme 29).108 The formed arylaluminum reagents were involved in 1,4addition to cyclohex-2-enone (Scheme 30), cross-coupling reactions (Table 82), and acylation with acyl chorides (Scheme 31). LiCl-activated generated arylmagnesiums were next exploited for large-scale (15−20 mmol) synthesis of aromatic fluorides by reaction with (PhSO2)2NF as electrophilic fluorinating agent (Table 83).109

3.3. Mg−LiCl

Since the insertion of magnesium into a carbon−halogen bond is difficult to realize under mild conditions, the reaction was not applicable to the functionalization of sensitive substrates. Thus, methodologies have been developed to activate the metal. Knochel and co-workers have reported an efficient activation of magnesium by mixing with lithium chloride. LiCl can help in solubilization of organometallic species while cleaning the metal surface. Using such a Mg−LiCl combination, efficient V


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Table 81. Preparation of Functional Aromatic Compounds by Halogen/Magnesium Exchange Using Mg−LiCl and Reaction with Electrophiles

Scheme 29

Table 82. Palladium-Catalyzed Cross-Coupling of Arylaluminum Reagents with Aryl Halides

Scheme 30

A similar approach was reported by Beller and co-workers using N-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate (FTMP-BF4).110 The best yields were obtained using methoxyperfluorobutane as cosolvent (Table 84). The same group next developed an elegant domino Grignard−coupling− fluorination sequence, leading to a range of 2-arylfluoroarenes in good yields (Table 85).111 Beller and co-workers also used activated Grignard compounds for the preparation of aromatic and heteroaromatics nitriles via electrophilic cyanation of arylmagnesiums

with N-cyano-N-phenyl-4-methylbenzenesulfonamide (Table 86).112 W


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Scheme 31

Table 84. Preparation of Aryl Fluorides by Exchange with Mg−LiCl and Subsequent Electrophilic Fluorination Using F-TMP-BF4

Table 83. Preparation of Aryl Fluorides by Exchange with Mg−LiCl and Subsequent Electrophilic Fluorination Using (PhSO2)2NF

In 2011, Leermann et al. reported direct access to arylboronic acids by reaction of trimethylborate with (het)arylmagnesium generated using Mg/LiCl or occasionally iPrMgCl·LiCl (Table 87).113 In the same year, Knochel and co-workers reported a one-pot synthesis of di(hetero)arylboronates and their subsequent cross-coupling from several (het)aryl bromides (Table 88).114 The reaction was extended to the preparation of benzylic zinc reagents via transmetalation of the Grignard reagents using ZnCl2 (Table 89).107b,115 This magnesation−zincation procedure was applied successfully to the generation of functionalized aliphatic zinc halides (Table 90).116 Diorganozinc were next prepared using the same procedure made scalable up to 10−20 mmol for the synthesis of alcohols and carboxylic acids by reaction of aliphatic, benzyl, or arylzinc halides with aldehydes, ketones, or carbon dioxide (Table 91).117

4. BIMETALLIC METAL−MANGANESE REAGENTS (METAL = LITHIUM, MAGNESIUM) As previously reported in the case of reactions using cuprates or zincates (see the following chapters), gem-dibromocyclopropanes can successively react in THF with trialkylmanganates and electrophiles to afford 1,1-disubstituted cyclopropanes. The reaction mechanism proposed by Oshima and co-workers includes (i) halogen/metal exchange of the less hindered bromine due to the bulkiness of the manganese reagent, (ii) alkyl migration with bromide elimination (inversion on the

cyclopropane carbon), and (iii) reaction with the electrophile (retention of configuration) (Table 92).118 The reaction was then extended to substrates such as tertbutyl dibromoacetate and N,N-diethyldibromoacetamide (Table 93). From N,N-diethyldibromoacetamide, using successively (PhMe2Si)3MnLi and aldehydes led to α,β-unsaturated carboxamides, as shown in Scheme 32.118b,119 X


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Table 85. Preparation of 2-Arylfluoroarenes by Domino Grignard−Coupling−Fluorination Sequence

Table 86. Preparation of Aromatic Nitriles

Table 87. Preparation of Arylboronic Acids

a

a

i-PrMgCl·LiCl was used for bromine/magnesium exchange.

organomanganese halide, which then reacts with BuMgBr (2 equiv) to regenerate the manganate.118a,120 Stoichiometric (Table 94) and catalytic reactions are equally effective for the stereoselective formation of 1-trialkylsilyl-1-alkenes.118b,120b Using tri(cyclopropyl)manganates results in conjugated dienylsilanes due to an additional ring cleavage, as shown in Scheme 34. The reaction was extended to 2-alkoxy-1,1-dibromoalkanes and 2-alkoxy-1,1,1-tribromoalkanes to afford di- or trisubstituted alkenes (Table 95) and tri- or tetrasubstituted alkenes (Table 96), respectively, through mechanisms involving (i) bromine/metal exchanges, (ii) 1,2-alkyl migrations from manganese to carbon, and (iii) eliminations of metal and βalkoxy (Scheme 35).121 From substrates bearing a phenyl group, unexpected results were obtained. For example, (dibromomethyl)benzene reacts with Bu3MnMgBr to afford the corresponding styrene in a low 9% yield and with Ph3MnMgBr to furnish 1,1,2,2-tetraphenylethane in 76% yield (a reaction that could occur as depicted in Scheme 36). Finally,

The product was obtained as a mixture with 4-phenyltoluene (6%).

Unlike similar reactions using dibutylcuprate and tributylzincate, the reactions of dibromides such as gem-dibromocyclopropanes through manganates can take place using lithium or magnesium reagents in the presence of a catalytic amount of manganese halide. This possibility has been efficiently employed for the synthesis of (E)-alkenylsilanes according to the mechanism depicted in Scheme 33 (with BuMgBr): the elimination of manganese and β-H liberates BuMnH, able to generate low-valent Mn(0) species; the latter can insert into one of the C−Br bond of the substrate to give an Y


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Table 88. Preparation of Biaryls

Table 89. Preparation from Chlorides Using Mg−LiCl and then ZnCl2 and Functionalization of Benzylzincs

a

CuCN·2LiCl was added.

treatment of 1,2-bis(dibromomethyl)benzene with various magnesium arylmanganates provides the corresponding benzocyclobutanes (Table 97); the mechanism proposed includes (i) bromine/manganese exchanges, (ii) 1,2-migrations, and (iii) reductive elimination of Mn(0).120b Upon reaction with magnesium manganates, both bromo groups of 1,2-bis(bromomethyl)benzene are replaced, the first by phenyl or allyl depending on the manganate employed and the second by various substituents depending on the electrophilic trapping. Indeed, after bromine/manganese exchange, the species formed collapse to o-quinodimethane under 1,4elimination; after addition of a ligand from a second equivalent of manganate, electrophilic trapping becomes possible to furnish difunctionalized derivatives (Table 98). Using a higher-order magnesium manganate furnishes other derivatives also formed through o-quinodimethane (Scheme 37).120b From 1,1-dibromo-1-octene, only halogen/metal exchange is observed using magnesium tributylmanganate. In contrast, from 2iodobenzo[b]furan, the iodine/magnesium exchange is followed by 1,2-migration with concomitant ring-opening, leading to the (E)-alkene (Scheme 38).118c Oshima and co-workers also reported the treatment of 1,3dibromo- and 1,3-dichloropropene with trialkylmanganates followed by addition of an electrophile to provide homoallylic alcohols (Table 99). The proposed reaction mechanism includes (i) allylic halogen/manganate exchange, (ii) isomerization of the allylmanganate thus obtained, (iii) 1,2-alkyl group migration from manganese to an adjacent carbon under Z


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Table 90. Generation of Alkylzinc Reagents after Mg−LiClPromoted Exchange and Reaction with Electrophiles

Table 91. Generation of Arylzinc Reagents after Mg−LiClPromoted Exchange and Reaction with Carbonyl Electrophiles

a

The aryl Grignard was transmetalated with CuCN·2LiCl. bPd(OAc)2 (1.4%) and Ru-Phos (2.8%) were used for cross-coupling.

bromide elimination, and (iv) electrophilic trapping of the resulting allylic manganate.122 Hosomi and co-workers evidenced in 1997 a reaction in which bromine is replaced by manganese. Thus, ketones (or esters and amides) bearing substituents such as halogens (Br, I) as leaving groups at the position α to their CO group can be reduced to afford the corresponding ketone enolates then trapped by aldehydes. Nevertheless, the process suggested by the authors to explain the reductive generation of enolates is different from that of a halogen/metal exchange, with an oxidative addition of the substrate to the ate complex followed by a reductive elimination of the ligands on manganese (Scheme 39).123 The authors compared the reaction with previously described organocuprate-mediated generation of enolates from α-halogeno ketones reported by Posner and coworkers,124 and with Bu3MnLi-mediated partial reductive dimerization of cyclohexenone at β-position during 1,4-addition reactions described by Cahiez and co-workers.125 More recently, a study performed with iodomethyl sulfides showed a reaction mechanism dependent on the reaction temperature: halogen/metal exchange took place at very low temperature, as evidenced by interception with allyl bromides (Table 100), enones (Table 101), and aldehydes (in the presence of BF3· OEt2, Table 102), versus oxidative addition followed by βelimination or reductive elimination at higher temperature.126

a

The aryl Grignard was transmetalated with CuCN·2LiCl.

and organohalides (Cl, Br).127 In 1969, Whitesides et al. claimed that at least two reactions take place in the course of such reactions: the reaction leading to the coupling product and a reaction involving metal/halogen exchange between the organohalide and the cuprate, which competes with or precedes the coupling. In the case of alkyl halides, they proposed a mechanism (SN2 displacement at carbon) without significant metal/halogen exchange. In contrast, with aryl halides, they observed nonoxidative coupling and suggested a two-step mechanism including metal/halogen exchange (giving an arylmetallic reagent and an alkyl halide) and nucleophilic displacement of the halide by the arylmetallic reagent (Scheme 40).128

5. BIMETALLIC METAL−COPPER REAGENTS (METAL = LITHIUM, MAGNESIUM) Very early, “side” halogen/copper exchange was identified during the development of cross-couplings between cuprates AA


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Table 92. Reaction of gem-Dibromocyclopropanes with Manganates Followed by Electrophilic Trapping

Scheme 33

Table 94. Reaction of R3SiCHBr2 with (R′CH2)3MnM

Scheme 34

Table 93. Reaction of α-Halo Esters and Amides with Manganates Followed by Electrophilic Trapping

Table 95. Reaction of 2-Alkoxy-1,1-dibromoalkanes with R3MnM

Scheme 32

a

To rationalize the stereoselective dialkylation of gemdihalocyclopropanes observed in Et2O upon successive treatment by a dialkylcuprate and an alkyl halide, Hiyama and coworkers proposed in 1976 the following pathway: (i) halogen/ copper exchange at the less hindered halogen, (ii) 1,2-alkyl migration with halide elimination under inversion on the cyclopropane carbon, and (iii) second alkylation (with

Using 2 equiv of manganate.

retention of configuration) involving the organohalide (Table 103). Another possibility involving formation of a Cu(III) species followed by reductive elimination is presented as more unlikely.129 AB


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Table 96. Reaction of 2-Alkoxy-1,1,1-tribromoalkanes with R3MnM

Table 98. Reaction of 1,2-Bis(bromomethyl)benzene with Magnesium Triarylmanganates

Scheme 37

Reaction carried out at −42 °C. Low yields due to the competitive formation of PhCHCHBu (E/Z 87/13) in 43−50% yield. a

Scheme 38

Scheme 35

Table 99. Reaction of 1,3-Dihalopropenes with Trialkylmanganates

Scheme 36

Table 97. Reaction of 1,2-Bis(dibromomethyl)benzene with Magnesium Triarylmanganates

through SN2′ displacement (Table 104). From α-bromo-αmethyl-α-phenylacetonitrile, formation of the corresponding dimer (26% yield, probably through single electron transfer to the starting α-bromonitrile) and α,α-dimethyl-α-phenylacetonitrile (42% yield, through reductive elimination of the cuprate) was noted.130 Tanino et al. showed that 1,1-dibromoalkenes having an α,βunsaturated ester or an epoxide moiety can be involved in stereoselective halogen/metal exchanges followed by intra-

Halogen/metal exchange reactions of α-bromonitriles using Me2CuLi in THF were reported in 2005 by Fleming et al. After 1.5 h at 0 °C, addition of electrophiles such as allylic and propargyl bromides led to the functionalized compounds AC


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Scheme 39

Scheme 40

Table 103. Halogen/Metal Exchange from 1,1Dihalocyclopropanes Using Lithium Dialkylcuprates

Table 100. Reaction of Iodomethyl Sulfides with Bu3MnLi Followed by Trapping with Allyl Bromides

a

a

At −78 °C. bNo stereochemical assignment.

Table 104. Halogen/Metal Exchange from α-Bromonitriles using Me2CuLi

b

In the presence of CuCN (1 equiv). In the presence of CuCN (0.1 equiv).

Table 101. Reaction of Iodomethyl Sulfides with Bu3MnLi Followed by Trapping with Enones

Table 105. Reaction of 1,1-Dibromoalkenes with R2CuLi Followed by Electrophilic Trapping

Table 102. Reaction of Iodomethyl Sulfide with Bu3MnLi Followed by Trapping with Aldehydes

a

molecular reactions to afford five-, six-, and seven-membered carbocycles (Table 105).131 AD

Using 5 equiv of R2CuLi.


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In the course of the synthesis of 1,8-diphenylnaphthalene from 1,8-diiodonaphthalene, House and co-workers observed that the outcome of the reaction is dependent on the proportions of phenyllithium and CuBr used to prepare the copper reagent. The authors assumed that Ph2CuLi is formed using a 2:1 ratio and that the apparent stoichiometry Ph3CuLi2 is obtained using a 3:1 ratio. An excess of the former is capable of monoexchange when used in Et2O; subsequent hydrolysis and oxidation respectively furnishes 1-iodonaphthalene and 1iodo-8-phenylnaphthalene. The latter is more reactive, leading to the biscuprate, which can be either hydrolyzed to naphthalene or oxidized to 1,8-diphenylnaphthalene. The reaction has been extended to other substrates (Table 106).132

With the aim of developing a new method to get arylcuprates, Sakamoto and co-workers investigated the halogen/metal exchange of aromatic halides using lithium cuprates. The group identified Me2Cu(CN)Li2 as a reagent more efficient than Me2CuLi, Me2Cu(SCN)Li2, Me(PhC C)Cu(CN)Li2, and Me(2-thienyl)Cu(CN)Li2 when used in THF toward iodobenzenes, as demonstrated by subsequent interception with various electrophiles (Table 108).134 Table 108. Halogen/Metal Exchange from Aryl Iodides Using Me2Cu(CN)Li2

Table 106. Halogen/Metal Exchange from Aryl Iodides Using Lithium Cuprates

Some years later, Piazza and Knochel showed that sterically hindered lower-order organocuprates can be used for halogen/ copper exchange. (t-BuCH2)2CuLi (Neopent2CuLi) and above all (PhMe2CCH2)2CuLi (Neophyl2CuLi) chemoselectively reacted with different aryl iodides and an aryl bromide in THF to afford the corresponding aryl cuprates, which were trapped by different electrophiles. 2-Iodo-3-methyl-2-cyclohexenone was functionalized similarly (Table 109).135 Starting from polyiodides, successive halogen/copper exchange reactions have been performed in Et2O to selectively functionalize aromatic compounds, and a better tolerance toward functional group was noted using Neophyl2CuLi, which benefits from bad transferable groups (Table 110).135b,c The halogen/copper exchange was next extended to different five-membered heterocyclic series such as indoles (Table 111),135c,136 indazoles (Table 112),137 and imidazoles (Table 113).138 From 2,3-diiodoindole N-substituted by a phenylsulfonyl group and for 4,5-diiodoimidazoles N-substituted by a methoxymethyl or a tosyl group, a regioselective exchange at C2 was observed (explained by a precomplexation of the protected group to the exchange agent), allowing successive functionalizations at the 2- and 3-positions. That Neophyl2CuLi is compatible with sensitive functions has also been demonstrated in the case of formyl-containing aromatic substrates (Table 114).139 The same year, β-iodo-α,βunsaturated aldehydes,139 ketones,135c,140 and esters135c,141 have been involved in a similar halogen/copper exchange followed by trapping with various electrophiles such as halides (Table 115). The double bond configuration could be retained and competitive addition/elimination discarded, provided that low temperatures and short contact times are employed to carry out the reactions. The reaction could not be extended to β-iodo unsaturated carbonyl derivatives with a trans-configuration between the iodine and the carbonyl group due to favored addition/elimination in this case. Among the different electrophiles used to intercept the arylcuprates, we can cite allyl bromides, acid chlorides, enones, and alkyl iodides. In 2004, Knochel and co-workers showed that reactions with cyclic 2-iodoallylic acetates are also possible

Naso and co-workers documented in 1979 their studies on the reactivity of different heteroaromatics halides with Me2CuLi. Complete halogen replacement was observed from 2-iodobenzothiazole, 2-iodopyridine, and 4- and 5-iodobenzofurazan. The other halides as well as 3-iodopyridine were found to be less reactive (Table 107). Using Ph2CuLi instead of Me2CuLi with 2-iodobenzothiazole under similar reaction times led to a more rapid reaction; benzothiazole was obtained in high yield, together with iodobenzene and biphenyl.133 Table 107. Halogen/Metal Exchange from Heteroaryl Halides Using Me2CuLi

AE


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Table 109. Halogen/Metal Exchange from Halides Using (tBuCH2)2CuLi and (PhMe2CCH2)2CuLib

Table 110. Halogen/Metal Exchange from Aryl Polyiodides Using (t-BuCH2)2CuLi and (PhMe2CCH2)2CuLi

a Exchange performed in Et2O−THF and quenching after addition of NMP.

Table 111. Halogen/Metal Exchange from Indolyl Iodides Using (PhMe2CCH2)2CuLi

a Exchange performed in Et2O−THF using 2 equiv of exchange agent and quenching after addition of NMP. bNMP = N-methylpyrrolidinone.

and that the substitutions proceed stereoselectively (SN2) (Table 116).142 A magnesium cuprate coming from 1,5-bis(bromomagnesium)pentane (prepared by Grignard reaction from 1,5-dibromoethane) and CuCN·2LiCl was also reported in 2004 by Yang and Knochel for its ability to perform halogen/ metal exchange reactions on aryl iodides. It proved compatible with various functional groups, even when employed at room temperature. The method gives arylcuprates free of organic iodide through an elimination providing cyclopentane after the exchange reaction (Table 117).143

a c

6. BIMETALLIC METAL−ZINC REAGENTS (METAL = LITHIUM, MAGNESIUM)

Without DMAP. bTrapping performed using NMP as a cosolvent. Reaction performed using NMP as a cosolvent.

atom is in most cases predominantly exchanged using Bu3ZnLi (Table 118). Among the four possible mechanisms that have been proposed for the halogen/metal exchange reactions (a stepwise process initiated by a single electron transfer, a fourcentered process, formation of an ate complex, and an SN2 reaction), the authors rather considered the third or the fourth one, for which a linear transition state is possible (with strain relief due to elongation of the carbon−bromine bond), to explain the higher reactivity of the more hindered bromine

6.1. Lithium Zincates

Bromine/metal exchange of 1-bromo-1-chloroalkenes was published by Harada et al. in 1992 (Scheme 41). The reactions occur stereospecifically, with retention of configuration at the carbenoid carbon.144 The halogen/metal exchange of 1,1dibromoalkenes using different lithium trialkylzincates has been reported since 1988 by Harada et al. Under kinetically controlled conditions, the sterically more hindered bromine AF


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Table 112. Halogen/Metal Exchange from Indazolyl Iodides Using (PhMe2CCH2)2CuLi

Table 114. Halogen/Metal Exchange from FormylContaining Aryl Iodides Using (PhMe2CCH2)2CuLi

Table 113. Halogen/Metal Exchange from Imidazolyl Iodides Using (PhMe2CCH2)2CuLi

Table 115. Halogen/Metal Exchange from β-Iodo-α,βunsaturated Aldehydes and Ketones Using (PhMe2CCH2)2CuLi

a

Imidazole deprotection was observed in this case.

atom. Using BuLi for the same purpose led to a similar trend (suggesting similar mechanisms) but a lower level of selectivity.144 The authors observed that the 1-bromoalkenylzincates generated at −85 °C undergo intramolecular alkylation145 with inversion of configuration at the carbenoid carbon to give alkenes by warming to 0 °C (Table 119).146 An extension to the synthesis of 1,2-disubstituted cyclopropanes starting from the corresponding 2-substituted 1,1dibromocyclopropanes was documented by the same group in 1989. To favor the formation of the cis derivatives, it is worth performing the reactions by ZnCl2-mediated transmetalation of the corresponding lithium carbenoids, which are prepared stereoselectively, before treatment with an organolithium (2 equiv) (or even the dilithium alkoxide of ethylene glycol). The trans derivatives become major when the lithium carbenoids are

converted to chlorides and the latter treated with the lithium zincate (Table 120).147 Instead of hydrolysis, subsequent palladium(0)-catalyzed coupling reactions with acetyl chloride were also performed (Table 121).147 AG


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Table 116. Halogen/Metal Exchange from Aryl Halides Using (PhMe2CCH2)2CuLi Followed by Trapping with Cyclic 2-Iodoallylic Acetates

a

Table 118. Kinetically Controlled Halogen/Metal Exchange from 1,1-Dibromoalkenes Using Lithium Trialkylzincates

Halogen/metal exchange performed at rt for 0.5 h. The rest is starting material. bUsing BuLi, THF, −94 °C, 1.5 min. Using BuLi, THF−Et2O, −116 °C, 1.5 min.

a

Table 117. Halogen/Metal Exchange from Aryl Halides Using a Magnesium Cuprate

c

Table 119. Halogen/Metal Exchange from 1,1Dibromoalkenes Using Lithium Trialkylzincates Followed by Intramolecular Alkylation

Scheme 41

a 1

R CCH also formed. bUsing 2 equiv of zincate.

generated Zn compound undergoes a rearrangement to furnish the benzyl product then intercepted by different electrophiles (Table 123). From 3-iodobenzyl mesylate, the halogen/metal exchange is the only reaction observed using Bu3ZnLi under similar reaction conditions.149 The reaction scope was then extended; moreover, less reactive Me3ZnLi and magnesium zincates were identified as suitable reagents to carry out the reaction under Barbier’s conditions (Table 124).150

1,1-Dibromoalkanes are suitable substrates, too, for halogen/ metal exchange reaction with lithium trialkylzincates followed by intramolecular alkylation, as evidenced by subsequent hydrolysis or Pd-catalyzed interception (Table 122).148 Harada and co-workers documented in 1997 a strategy to convert 4-iodobenzyl mesylate into benzylzinc reagents. After halogen/metal exchange and subsequent 1,2-migration, the AH


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Table 120. Halogen/Metal Exchange from 1,1Dibromocyclopropanes Using Lithium Trialkylzincates

Table 122. Halogen/Metal Exchange from 1,1Dibromoalkanes Using Lithium Trialkylzincates Followed by Palladium-Catalyzed Coupling

a (i) BuLi (1 equiv), THF−hexane, −85 °C, 15 min; (ii) ZnCl2 (1 equiv) and RLi (2 equiv), −85 to 0 °C, 30 min; (iii) hydrolysis. b(i) BuLi (1 equiv), THF−hexane, −85 °C, 15 min; (ii) CF2ClCFCl2 (1 equiv), −85 °C, 30 min; (iii) R3ZnLi (1.3 equiv), −85 °C to rt, 30 min; (iv) hydrolysis.

Table 121. Halogen/Metal Exchange from 1,1Dibromocyclopropanes Using Lithium Trialkylzincates Followed by Palladium(0)-Catalyzed Coupling

a

After transmetalation to the Zn species using ZnCl2.

Table 123. Reaction of 4-Iodobenzyl Mesylate with Lithium Triorganozincates

(i) BuLi (1 equiv), THF−hexane, −85 °C; (ii) ZnCl2 (1 equiv) and RLi (1 equiv), −85 to rt; (iii) hydrolysis. b(i) BuLi (1 equiv), THF− hexane, −85 °C; (ii) CF2ClCFCl2 (1 equiv), −85 °C; (iii) R3ZnLi (1.3 equiv), −85 °C to rt; (iv) hydrolysis. a

In contrast to arylzincates bearing a leaving group at the para position, arylzincates (generated by exchange) bearing a leaving group at the ortho or meta position undergo homologation, but not through a pathway involving 1,2-migration. Those derived from 2-iodophenyl triflates and tosylate give 2-butylphenylzinc species through o-benzyne intermediates (Table 125). That derived from 3-iodophenyl triflate leads to a 3-butylphenylzinc species, maybe through the involvement of m-benzyne as intermediate in the reaction pathway (Scheme 42).151 In the aromatic series, Sakamoto and co-workers showed in 1994 that Me3ZnLi (methyl was chosen for its low transferability) can be used in THF for iodine/metal exchange. The method tolerates the presence of sensitive functions (ester, nitro), in contrast with the corresponding arylzinc iodides, which do not react with benzaldehyde, the generated lithium arylzincates can be converted to alcohols (Table 126).152 2And 3-iodo-1-phenylsulfonylindoles were similarly functionalized by the same group in 1995; improved yields were noted by carrying out the reaction in the presence of TMEDA (Table 127).153 Compared with butyl, phenyl, and methyl, tert-butyl

a

Yield of 45% using Bu3ZnMgCl.

was identified in 1997 by Kondo et al. as the most effective nontransfer group. t-Bu3ZnLi was thus evaluated as a halogen/ metal exchange reagent toward aryl iodides (Table 128), as well as primary and secondary alkyl iodides, functionalized or not (Table 129).154 It was also identified as effective for solid-phase halogen/metal exchange reactions on polystyrene (Table 130).155 The alkyl-ligation environment can change the reaction outcomes, as evidenced in 2002 by Uchiyama and co-workers on halogenated 1,2-disubstituted benzenes. For example, when Me3ZnLi is used for the halogen/metal exchange of 1-bromo-2iodobenzene, a subsequent elimination to benzyne is evidenced by cycloaddition using dienes (Table 131); in contrast, employing t-Bu3ZnLi leads to halogen/metal exchange without formation of benzyne, and the arylzincates can be trapped by benzaldehyde (Table 132).156 From o-haloiodobenzenes, AI


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Table 124. Reaction of 4-Iodobenzyl Mesylates and Phosphonates with Triorganozincates

Table 127. Halogen/Metal Exchange from Indolyl Iodides Using Me3ZnLi Followed by Electrophilic Trapping

a

Addition at −78 °C and then reaction at room temperature.

Table 128. Halogen/Metal Exchange from Aryl Iodides Using t-Bu3ZnLi Followed by Electrophilic Trapping a

Using 3 equiv of electrophile.

Table 125. Generation of Benzynes from Arylzincates

a Addition at −78 °C and then reaction at room temperature. bIn the presence of 2-ThCu(CN)Li. cUsing Me3ZnLi.

Table 129. Halogen/Metal Exchange from Alkyl Iodides Using t-Bu3ZnLi Followed by Electrophilic Trapping Scheme 42

Table 126. Halogen/Metal Exchange from Aryl Iodides Using Me3ZnLi Followed by Electrophilic Trapping

similarly performed using higher-order dilithium anisyltrimethylzincate (Scheme 43).156b The use of highly coordinated zincates, having a more anionic character than the previous ones, in halogen/metal exchange has been evaluated. Kondo and co-workers reported in 1996 iodine/zinc permutations followed by intramolecular cyclizations and observed different outcomes depending on the nature of the zincate. In particular, highly coordinated lithium zincates are capable of epoxide opening, with attack at the more substituted carbon, and of intramolecular carbometalation. In addition, unlike MeLi and Me3ZnLi, they are reactive in bromine/metal exchange reaction toward bromobenzene and derivatives (Table 134).134,157 In particular, the compatibility of t-Bu4ZnLi2 with functional groups attached to the substrate (CH2OH, CO2Me, OH, etc.) for halogen/metal exchange of different iodides (Table 135) and bromides (Table 136) was documented in 2006 by Uchiyama and co-workers.158 It is interesting to note that arylzincates prepared using both lowerand higher-order alkylzincate exchange agents can be oxidized

Addition at −78 °C and then reaction at room temperature. bIn the presence of catalytic Pd(PPh3)4. a

halogen/metal exchanges using Me2(PhMe2Si)ZnLi lead, after subsequent elimination, to benzynes. The latter were trapped in situ by silylzincation (Table 133). A carbozincation was AJ


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Table 130. Halogen/Metal Exchange of Immobilized Iodides Using t-Bu3ZnLi Followed by Electrophilic Trapping

Table 133. Generation of Benzynes from Arylzincates Followed by Silylzincation and Subsequent Electrophilic Trapping

a

After cleavage of the ester linkage. bCleavage using NaOMe at rt. Yield of 85% if the exchange is performed using t-Bu2PhZnLi (no PhI required). dAfter transmetalation with 2-ThCu(CN)Li at −20 °C. e Yield of 39% using (Me3SiCH2)2Cu(CN)Li2 and 10% using Me2Cu(CN)Li2. fCleavage using Et3N and MeOH at 100 °C. c

Table 131. Halogen/Metal Exchange from Aryl Iodides Using Me3ZnLi Followed by Elimination−Cycloaddition

a

Scheme 43

which showed that the more the pyridine coordinates to the zincate, the more the resultant zincate is stabilized. Starting from dibromopyridines led to mono- or bis-exchange, depending on the reaction conditions (Table 138).160 The halogen/zinc exchange of organohalides RX [R = Me, vinyl, ethynyl, CH(Cl)CH3, CH(CH3)CHCH2; X = Cl, Br, I] using organozincates Me2R′ZnLi·OMe2 (R′ = Me, Et, i-Pr, tBu) has been examined using (density functional theory) theoretical/computational studies by Nakamuraet al. The authors showed that the reactions go via a hypervalent halogen-type transition state and that the nature of the halogen affects its interaction energy; the transition state is more stabilized in the case of the electropositive iodine atom, allowing one to explain the increasing reactivity RCl < RBr < RI. For the different R′ groups, quite similar structures were obtained for the transition states involved in the exchange reactions, and the reactivity depends on the deformation energy of the zincate fragment (bulky ligands decrease the activation energy compared with smaller ones). Concerning the substrates, both the nature of the transition state (e.g., ethynyl is capable of polarizing the hypervalent bond effectively) and the relative structural changes (e.g., effective decrease in deformation energy for allyl iodide) have an impact on the activation energy. Besides the activation energy (kinetic condition), one has also to consider the thermodynamic aspect. On this side, the stabilities of the products can be estimated from the nature of the carbanions formed (e.g., the sp- or sp2hybridized carbanions are more stable).161 Highly coordinated t-Bu4ZnLi2 was recently used by Higashihara to control the access to head-to-tail regioregular poly(3-hexyl)thiophene and poly[3-(6-hydroxyhexyl)thiophene] from 2-bromo-3-hexyl-5-iodothiophene by halogen/metal exchange in THF at 0 °C for 2 h followed by nickelcatalyzed coupling-based polymerization. It is interesting to note that purification-free polymerization media of THF (even

Yield of 99% using either Me3ZnLi at rt or Me4ZnLi2 at −78 °C.

Table 132. Halogen/Metal Exchange from Aryl Iodides Using t-Bu3ZnLi Followed by Electrophilic Trapping

by VO(OEt)Cl2 to afford the corresponding cross-coupling compounds.159 Gros and co-workers studied the reactivity of lithium tri- and tetraalkyl zincates toward different bromopyridines. In these series, both Bu4ZnLi2 and Bu4ZnLi2·TMEDA were found to be better exchange agents than Bu3ZnLi, Bu3ZnLi·TMEDA, and tBu4ZnLi2·TMEDA; using toluene as solvent, the reaction of Bu4ZnLi2·TMEDA with 2- and 3-bromopyridine is achieved at room temperature in 1 h and 30 min, respectively, affording the corresponding iodides (Table 137). The efficiency of a substoichiometric amount of base to perform the reaction was rationalized by density functional theory calculations, AK


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Table 134. Halogen/Metal Exchange from Aromatic Halides Using Different Zincates

Table 135. Halogen/Metal Exchange from Iodides Bearing Functional Groups Using t-Bu4ZnLi2

a No electrophile. bYield of 50% (12:88) using Me2Cu(CN)Li2. cYield of 6% (78% ee)/62% (90% ee) using Me2Cu(CN)Li2 and 0%/73% (92% ee) using Me3Cu(CN)Li3. dElectrophile = PhCHO. e1-Acetyl-4bromobenzene was obtained in 50% yield. f4-Acetylbenzhydrol was obtained in 63% yield.

in the presence of 1000 ppm water) is suitable to perform the reactions.162 6.2. Magnesium Zincates

If lithium triorganozincates and dilithium tetraorganozincates can be prepared rather easily using the metathesis approach (from a Zn salt), the access to magnesium zincates using this way is complex, as exemplified by Hevia and co-workers for the reactions between ZnCl2 and variable amounts of t-BuMgCl. Nevertheless, the group published in 2010 its successful attempts to use [{Mg2Cl3(THF)6}+{Znt-Bu3}−], prepared from ZnCl2 and 3 equiv of t-BuMgCl, for the halogen/metal exchange of 4-iodotoluene (3 equiv) in THF. After stirring for 15 min at room temperature, the crystals of [{Mg2Cl3(THF)6}+{Zn(4-tolyl)3}−] isolated in 60% yield (after storage at −30 °C) show that the three tert-butyl groups of the magnesium trialkylzincate are successively involved in the reaction. Subsequent trapping with iodobenzene was found to be possible in the presence of PdCl2·dppf (2.5 mol %), affording the Suzuki cross-coupling product in 65−93% yield (Scheme 44).163 Magnesium zincates have also been used, in the presence of an iron or cobalt cocatalyst, for chlorine/metal exchange of aryl, heteroaryl, and also alkyl chlorides. To rationalize the results, Knochel and co-workers proposed an oxidative addition of the

a

In the presence of 2-ThCu(CN)Li. bA mixture was obtained using Me2CuCNLi2 under the same reaction conditions. cUsing 2 equiv of zincate. dUsing 0.55 equiv of zincate.

organic chloride to an in situ generated transition-metal catalyst, giving an organometallic. The latter then transfers its organo group to the Zn reagent, and the resulting organozinc can thus be trapped by electrophiles.164 6.3. Turbo-Zinc Reagents

Micouin and Knochel described in 1997 the acceleration of iodine/zinc exchange reactions using i-Pr2Zn prepared in situ from i-PrMgBr and ZnBr2. Compared with salt-free i-Pr2Zn, the bimetal reagent made of i-Pr2Zn and MgBr2 reacts almost 200 times faster to provide the corresponding mixed diorganozinc compounds. The latter were transmetalated with CuCN·2LiCl before trapping with allylic bromides (Table 139).165 In 2001, Marek and co-workers showed that dialkylzincs in the presence of LiBr are efficient to promote the intramolecular rearrangement of 1,1-diiodoalkanes with formation of Zn AL


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Table 136. Halogen/Metal Exchange from Bromides Bearing Functional Groups Using t-Bu4ZnLi2

Table 138. Halogen/Metal Exchange from Dibromopyridines Using Lithium Zincates

Table 137. Halogen/Metal Exchange from Bromopyridines Using Lithium Zincates

a

Yields estimated by NMR (the values in parentheses are yields after purification). bUsing I2 as electrophile. cUsing MeSSMe as electrophile. dUsing MeOD as electrophile. eUsing 4-MeOC6H4CHO as electrophile. fReaction performed under reflux for 12 h in the presence of PdCl2·2PPh3 (5 mol %) and PPh3 (10 mol %). gUsing PhSSPh as electrophile . hAdditional TMEDA (1 equiv) was used. iAdditional TMEDA (1.5 equiv) was used.

Scheme 44

Table 139. Halogen/Metal Exchange from Alkyl Iodides Using i-Pr2Zn·2MgBr2 and Trapping

a

Yields estimated by NMR (the values in parentheses are yields after purification). bDegradation was noted. cReaction performed under reflux for 12 h in the presence of PdCl2·2PPh3 (5 mol %) and PPh3 (10 mol %).

Scheme 45

carbenoid after halogen/metal exchange (Scheme 45). An activated form of R2Zn (as zincate) is proposed to rationalize the result observed.166 A large range of additives were later evaluated for their ability to catalyze the access to diarylzincs Ar2Zn by iodine/zinc exchange using R2Zn (i-Pr > Et > Me), and Li(acac) (acac = acetylacetonate) proved the best using 1:10 Et2O−NMP as

solvent. This additive was assumed to act as a ligand for ArZnR, allowing the second R group to react from the zincate (Scheme 46). The method was applied to the chemoselective AM


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Scheme 46

Table 141. Halogen/Metal Exchange from Heteroaryl Iodides Using i-Pr2Zn−Li(acac) and Trapping

functionalization of numerous aromatic (Table 140) and heteroaromatic (Table 141) compounds; various trappings were performed including transition-metal-catalyzed coupling reactions and intramolecular carbometalation.167 Table 140. Halogen/Metal Exchange from Aryl Iodides Using R2Zn−Li(acac) and Trapping

a b

After addition of Pd(dba)2 (2.5 mol %) and P(2-furyl)3 (5 mol %). After addition of CuCN·2LiCl (20 mol %).

achieved by using substituents (called “directed-insertion groups”) such as an ester, a ketone, an aryl sulfonate, an acetate, a triazene, or a carbamate, or even ring heteroatoms able to direct the reactions to the adjacent positions (Table 144).107b,169 For the 2,4-dibromo-1-substituted benzenes (substituent = OTs, OPiv, OAc, OBoc), using Mg−LiCl or Mg−LiCl−ZnCl2 led to an opposite regioselectivity for the bromo group at C4. This was rationalized by assuming that Zn insertion requires coordination, whereas easier magnesium insertion (due to a stronger reducing power) occurs at the less hindered site.107b To rationalize the acceleration of the oxidative addition of Zn dust into aryl halides (R−X) in the presence of LiCl, Knochel proposed Li+ZnRClX− as active species.168a Koszinowski and Böhrer detected the same anions after LiCl-mediated Zn insertion into various organic halides using anion-mode electrospray ionization mass spectrometry.170 In 2010, Liu et al. thermodynamically and kinetically confirmed the drastic acceleration of Zn insertion by LiCl for ethyl 2,4dibromobenzoate, but a much more moderate effect for 2,4dibromoanisole and -benzonitrile (Table 145) was observed. Using bromobenzene as substrate, the calculations performed proved in agreement with a facilitation of Zn insertion in the presence of LiCl (which seems to stabilize the Zn insertion

a

After addition of CuCN·2LiCl (20 mol %). bAfter addition of Pd(dba)2 (2.5 mol %) and P(2-furyl)3 (5 mol %). cAfter addition of CuCN·2LiCl (1 equiv). dIn the presence of Pd(PPh3)4 (3 mol %).

6.4. Zn−LiCl

The procedure for the direct insertion of Zn into organic halides has recently been simplified by Knochel and co-workers. The authors reported in 2006 a protocol using commercially available Zn dust in the presence of LiCl in THF for the reaction of aryl and heteroaryl iodides (Table 142), as well as activated aryl, heteroaryl, and alkenyl bromides (Table 143). The generated organozinc species can be titrated using iodine and trapped by a large range of electrophiles through transitionmetal-catalyzed reactions. Bis(functionalization) also proved possible.168 In 2007, Knochel and co-workers reported examples of regioselective direct Zn insertion on aryl and heteroaryl polybromides and polyiodides, as previously noted for halogen/metal exchange and deprotometalation. This was AN


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Table 142. Preparation from Iodides Using Zn−LiCl and Functionalization of Aryl- and Heteroarylzincs

a

After addition of CuCN·2LiCl (20 mol %). bAfter addition of CuCN·2LiCl (2 mol %). cUsing PEPPSI (pyridine-enhanced precatalyst preparation, stability, and initiation; see Table 82, 0.5 mol %). dAfter addition of CuCN·2LiCl (0.4 mol %). eUsing catalytic Pd(PPh3)4.

The good tolerance toward sensitive substrates led Knochel and co-workers to develop this chemistry in the pyrimidine172 (Table 146) and triazene173 (Table 147) series; further conversion of the triazene moiety to iodo was also demonstrated.173 In azinic series, metal insertion using Rieke Zn was similarly improved in the presence of 20 mol % of LiCl; the organometallics corresponding to 3-bromopyridine, 3bromoquinoline, and 4-bromoisoquinoline were trapped with recourse to palladium or copper catalysis (Table 148).174 The procedure for the direct insertion of Zn into organic halides has also been applied to the use of alkyl bromides including functionalized compounds. The generated alkylzinc species can be trapped by a large range of electrophiles through transition-metal-catalyzed reactions (Table 149).168a,b Inspired, the authors found an alternative of the Fischer indole synthesis using aryldiazonium salts and functionalized alkylzincs, prepared from the corresponding bromides using Zn dust, ZnBr2 (which is essential to ensure a selective reaction with the diazonium salt), and LiCl (Table 150).175 In 2007, the method was extended to the preparation of diand trisubstituted allylic Zn reagents starting from the corresponding chlorides. Interestingly, homocoupling products only form moderately using LiCl-mediated insertion of Zn dust, and subsequent trapping with iodine led to the expected derivatives in satisfying yields (Table 151). The addition of

Table 143. Preparation from Bromides Using Zn−LiCl and Functionalization of Aryl-, Heteroaryl-, and Alkenylzinc

a

After addition of CuCN·2LiCl (0.4 mol %). bUsing catalytic Pd(PPh3)4. cUsing PEPPSI (see Table 82, 0.5 mol %). dAfter addition of CuCN·2LiCl (20 mol %).

transition state sterically and electronically) and the generation of Li+ZnRClX− as active species. To explain the orthoselectivity observed in the presence of LiCl, they studied the impact of different functional groups on the five-membered Zn insertion transition state obtained and identified CO2Me as the best ortho-directing group.171 AO


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Table 144. Regioselective Preparation from Polybromides and Polyiodides Using Zn−LiCl and Functionalization of Aryl- and Heteroarylzincs

Table 145. Preparation from Dibromides Using either Zn or Zn−LiCl of Arylzincs

Table 146. Regioselective Preparation from Bromides and Iodides Using Zn−LiCl and Functionalization of Pyrimidylzincs

a

After addition of CuCN·2LiCl (0.5 equiv). bUsing Pd(dba)2 (5 mol %) and P(2-furyl)3 (10 mol %). cUsing Pd(PPh3)4 (5 mol %). dAfter addition of CuCN·2LiCl (20 mol %). eAfter addition of CuCN·2LiCl (1 equiv).

In 2008, the transposition of the method for the preparation of benzylic Zn chlorides was documented by the same group (Table 154). The protocol involving LiCl-mediated insertion of Zn dust to benzylic chlorides is much more efficient than that without LiCl and it tolerates functional groups (ester, nitrile, halogen and even ketone); it was for example successfully employed for a synthesis of papaverine.178 The method directly leading to diarylmethanes represents a good alternative to addition of organometallic reagents to benzaldehydes and subsequent reduction. A nickel-catalyzed coupling reaction with aryl halides and tosylates was reported in 2008 for the functionalization of the generated benzylic Zn compounds (Table 155).178b,179 It is also possible to employ palladiumbased PEPPSI for the same purpose (Table 156).168b

a

After addition of CuCN·2LiCl (20 mol %). bAfter addition of CuCN· 2LiCl (1 equiv). cUsing catalytic Pd(PPh3)4. dUsing Zn (2 equiv) and LiCl (2 equiv). eUsing catalytic Pd(dba)2 and P(2-furyl)3.

such Zn compounds to aldehydes and ketones proved both diastereoselective (anti isomers) and regioselective when performed at low temperature, affording homoallylic alcohols bearing quaternary centers (Table 152).176 In the presence of a silyl group at the 2-position of the allyl chloride in order to increase steric hindrance, the methodology was extended to the synthesis of syn-homoallylic alcohols (Table 153); it is possible to perform subsequent protodesilylation via a carbon to oxygen silyl migration promoted by sodium hydride in THF− HMPA.177 AP


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Table 147. Regioselective Preparation from Polybromides and Polyiodides Using Zn−LiCl and Functionalization of Triazene Arylzincs

Table 149. Preparation from Bromides Using Zn−LiCl and Functionalization of Alkylzincs

a

Using catalytic Pd(dba)2 (dba = dibenzylideneacetone) and S-Phos. After addition of CuCN·2LiCl (1 mol %). cUsing catalytic Pd(PPh3)4. dUsing catalytic PEPPSI (see Table 82).

b

Table 150. Fischer Indole Synthesis Using Alkylzincs

a

After addition of CuCN·2LiCl (3 mol %). bAfter addition of CuCN· 2LiCl (1 equiv). cUsing Pd(PPh3)4 (3 mol %).

Table 148. Preparation of 3-Azinylzinc Bromides and Subsequent Trapping

a

c c

Without Me3SiCl.

7. MISCELLANEOUS Other metal−alkali metal combinations than those presented above have been employed to perform halogen/metal exchange reactions. We will only describe briefly the use of lithium− chromium and lithium−indium reagents for which promising synthetic applications have been identified,180 but lithium− aluminum reagents have very recently emerged as powerful tools;181 for example, the direct insertion of aluminum to organohalides has been achieved successfully by employing either LiCl in the presence of catalytic TiCl4, BiCl3, InCl3, or PbCl2,182 or PbCl2.183

Using Pd(PPh3)4 (1 mol %). bAfter addition of CuI (10 mol %). ClSiMe3 was used for silylation.

7.1. Lithium−Chromium Reagents

Replacement of halogen by metal has been described from organic halides, by formal oxidative addition through two AQ


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Table 151. Preparation from Chlorides Using Zn−LiCl and Iodinolysis of Allylzincs

a

Table 153. Addition of Hindered Allylzincs to Aldehydes and Ketones

Yield of 72% (20 °C, 18 h) if Cl is replaced by OP(O)(OEt)2.

Table 152. Addition of the Generated Allylzincs to Aldehydes and Ketones

a

Yield based on the molarity of the Zn reagent.

formal two-electron reductant. The resulting enolates, which do not behave as simple lithium enolates, were selectively intercepted by a variety of electrophiles (Table 159).187 In the case of α-bromo esters, the enolates similarly obtained react with oxiranes to afford either γ-hydroxy esters or β-hydroxy esters as major products, respectively using AlEt3 and EtAlCl2 as Lewis acid (Table 160).188 7.2. Lithium−Indium Reagents

Chen and Knochel reported in 2008 the acceleration of indium insertion into organic iodides in the presence of LiCl. Indeed, after activation with 1,2-dibromoethane and chlorotrimethylsilane in THF, indium powder could be used for insertion into carbon−iodine bonds of activated aromatic halides, including heterocycles at temperatures between 30 and 50 °C for 20 min to 24 h. Subsequent iodolysis showed high yields, and palladium-catalyzed cross-coupling of the generated aryl indium(III) reagents led to biaryl compound satisfactorily, even in the presence of halides containing substituents (NH, OH) with acidic hydrogen atoms (Table 161).189 Papoian and Minehan documented in parallel halogen/indium exchange reactions on a large range of functionalized aryl iodides using the same reagent but DMF as solvent (Tables 162 and 163). In this case, the reagent is indium metal containing 0.1% Mg as anticaking agent. On the basis of several experiments, the authors concluded that the intermediate formed in the insertion reaction has an indium(II) or indium(III) oxidation state.190 The approach developed by Knochel and co-workers was extended in 2009 to the synthesis of benzylic indium(III) reagents from the corresponding chlorides or bromides. Their functionalization by palladium-catalyzed cross-coupling was improved by addition of a protic solvent and transmetalation of the indium reagent using i-PrMgCl·LiCl prior to the functionalization step. These precautions led to efficient trapping by aryl bromides and iodides (Table 164).191 Inspired by a study of Takai and Ikawa reporting the beneficial effect of indium(III) halides on the insertion of aluminum metal into allylic halides,192 the authors developed a room temperature

consecutive single electron transfers from a chromium(II) salt, and examples concern the use of a chromium−alkali metal reagent for this purpose.184 The formation of chromate(II) species such as Li2[CrX4] has been proposed to explain the reactivity change observed for reactions carried out in the presence of lithium halides.185 Hosomi and co-workers reported in 2001 their attempts to use chromium(III) reagents for the formal “two-electron” reduction of allyl (Table 157) and propargyl (Table 158) compounds. “Bu5CrLi2”, prepared from CrCl3 and BuLi (5 equiv), turned out to be a more powerful reagent than Bu3Cr and Bu4CrLi to react with 5-phenylpent-1-en-3-yl diethyl phosphate in THF at very low temperature. Extension to other allyl phosphates was found possible, as shown by subsequent trapping with a large range of electrophiles, but the replacement of phosphate by bromide or acetate led to lower yields.186 The same year, Hosomi and co-workers documented the conversion of carbonyl compounds, bearing a leaving group at the α-position, to the corresponding enolates upon treatment by a chromium(III) ate reagent, “Bu6CrLi3”, which behaves as a AR


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Table 154. Preparation from Chlorides Using Zn−LiCl and Functionalization of Benzylzincs

Table 155. Preparation from Chlorides Using Zn−LiCl and Nickel-Catalyzed Cross-Coupling of Benzylzincs

Table 156. Preparation from Chlorides Using Zn−LiCl and Palladium-Catalyzed Cross-Coupling of Benzylzincs

procedure for the conversion of functionalized aryl, heteroaryl, and alkyl bromides, as well as benzyl chlorides, to triorganoindiums through magnesium insertion in the presence

a

After addition of cat. CuCN·2LiCl. bUsing cat. Pd(PPh3)4. cAfter addition of CuCN·2LiCl (1 equiv). dAfter addition of Pd(OAc)2 (2.5 mol %) and S-Phos (5 mol %). eReaction at 40 °C. AS


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Table 157. Preparation Using “Bu5CrLi2” and Functionalization of Allyl Chromium Reagents

Table 160. Preparation Using “Bu6CrLi3” and Functionalization of Allyl Enolate Reagents

Table 161. Preparation from Iodides Using In−LiCl and Functionalization of Aryl- and Heteroarylindiums

a

Yield of 91% (83:17) using Bu4CrLi for 3 h and 61% (80:20) using Bu3Cr for 24 h. bSyn/anti 24/76. cSyn/anti 58/42.

Table 158. Preparation Using “Bu5CrLi2” and Functionalization of Propargyl Chromium Reagents

Table 159. Preparation Using “Bu6CrLi3” and Functionalization of Enolate Reagents

a

Using catalytic Pd(OAc)2 and SPhos, and 2:1 THF−NMP as solvent, reflux, 25 h. bUsing catalytic PdCl2·dppf, and 2:1 THF−NMP as solvent, 40 °C, 4 h.

Table 162. Preparation from Iodides Using In−LiCl and Cross-Coupling of Arylindiums

a

Reaction performed in the presence of HMPA. bReaction performed in the presence of NMP. c1,2-Adduct was also obtained in 38% yield.

of InCl3 and LiCl. The organometal species so generated were trapped by palladium-catalyzed cross-coupling.

a Due to competitive formation of R−R. bUsing PdCl2·2PPh3 instead of PdCl2·dppf.

193

AT


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It is worth noting that besides dehalogenative metalation,

Table 163. Preparation from Iodides Using In−LiCl and Interception with Acyl and Allylic Electrophiles of Arylindiums

other kinds of exchange using bimetal agents have also been described. Among them, we can cite the sulfoxide/magnesium exchange that has been extensively developed by Knochel and co-workers in the aromatic series194 including heterocycles.104,195 Even if there is a huge amount of work done in this field, the synergy exhibited by some bimetal combinations is still obscure and deserves further investigation from the structural and mechanistic points of view.

Table 164. Preparation from Halides Using In−LiCl and Functionalization of Benzylzincs

AUTHOR INFORMATION Corresponding Authors

*F.M.: phone, 33 223 236 931; fax, 33 223 236 955; e-mail, fl[email protected]. *P.C.G.: phone, 33 383 684 979; fax, 33 383 684 785; e-mail, [email protected]. Notes

The authors declare no competing financial interest. Biographies

David Tilly completed a Ph.D. in Organic Chemistry at Université du Maine (Le Mans, France) in 2004, working on directed lithiations (supervised by Prof. J. Mortier). He then worked as a postdoctoral research fellow on multistep syntheses of complex natural products (with Assoc. Prof. Williams, University of Queensland, Brisbane, Australia), development of novel anticancer drugs based on natural product scaffolds (with Assoc. Prof. Coster, ESKITIS, Brisbane, Australia), catalyzed C−H bond functionalizations (palladium a

catalysis, with Prof. Gevorgyan, University of Illinois, Chicago, IL; Without activation using i-PrMgCl·LiCl.

iron catalysis, with Dr. Crevisy, Université de Rennes, Rennes, France), development of asymmetric synergetic bimetallic ate combinations for organic synthesis (with Prof. F. Mongin, Université

8. CONCLUSION The aim of this review was to collect all of the bimetal-based methods for the dehalogenative metalation of organic compounds and to depict exhaustively the applicative potential of these methods.

de Rennes), design of novel radioimmunoconjugates of astatine-211, and boron cluster chemistry (with Prof. Deniaud, Université de Nantes, Nantes, France). AU


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Philippe C. Gros studied chemistry at the Universite of Lyon (Lyon, France) and obtained his Ph.D. in 1992. He then worked for two years as a postdoctoral fellow with the Isochem Company on phosgene derivative chemistry. In 1994 he entered the CNRS as “Chargé de Recherches” in the Laboratory of Pr. Paul Caubère at NancyUniversité (Lorraine, France). He received his Habilitation (HDR) in 2000 and was appointed “Directeur de Recherches” in 2006. His current research interests include the design of new metalating agents (organolithiums, ate complexes) for the regio- and enantioselective functionalization of heterocycles, structural and reaction mechanism investigation, transition-metal-catalyzed cross-couplings for ligand synthesis, and the building of photo- and electroactive organometallic materials for various applications including solar energy.

Floris Chevallier is an Associate Professor at the University of Rennes 1 (Rennes, France). He studied (organic) chemistry at the universities of Orléans and Nantes. He received his Ph.D. in 2004 under the supervision of Prof. Jean-Paul Quintard, where he worked on organotin chemistry. In 2005, he joined the group of Prof. Bernhard Breit at the Albert-Ludwigs-Universität Freiburg (Freiburg, Germany) as a postdoctoral researcher, where he focused on supramolecular catalysis. His current research interests include organometallic methodologies and molecular self-assemblies.

ACKNOWLEDGMENTS F.M. acknowledges the Institut Universitaire de France. F.M. and P.C.G. acknowledge the Agence Nationale pour la Recherche (grant ANR-BLAN-08-2-311886). REFERENCES (1) (a) Jones, R. G.; Gilman, H. Org. React. 1951, 6, 339. (b) Jones, R. G.; Gilman, H. Chem. Rev. 1954, 54, 835. (c) Gilman, H.; Gorsich, R. D. J. Am. Chem. Soc. 1956, 78, 2217. (d) Wakefield, B. J. The Chemistry of Organolithium Compounds; Pergamon Press: New York, 1974. (e) Bailey, W. F.; Patricia, J. J. J. Organomet. Chem. 1988, 352, 1. (f) Schlosser, M. In Organometallics in Synthesis: A Manual; Schlosser, M., Ed.; John Wiley & Sons: New York, 1994; p 1. (g) Boche, G.; Schimeczek, M.; Cioslowski, J.; Piskorz, P. Eur. J. Org. Chem. 1998, 1851. (h) Schlosser, M. In Organometallics in Synthesis: A Manual, 2nd ed.; Schlosser, M., Ed.; Wiley & Sons Ltd: West Sussex, UK, 2002; p 5. (i) Clayden, J. In Organolithiums: Selectivity for Synthesis; Pergamon: Oxford, UK, 2002; p 111. (j) Nájera, C.; Sansano, J. M.; Yus, M. Tetrahedron 2003, 59, 9255. (k) Sotomayor, N.; Lete, E. Curr. Org. Chem. 2003, 7, 275. (l) Leroux, F.; Schlosser, M.; Zohar, E.; Marek, I. In The Chemistry of Organolithium Compounds; Rappoport, Z., Marek, I., Eds.; Wiley: Chichester, UK, 2004; p 435. (m) Strohmann, C.; Schildbach, D. In The Chemistry of Organolithium Compounds; John Wiley & Sons: Chichester, UK, 2004; p 941. (n) Knochel, P. Handbook of Functionalized Organometallics: Applications in Synthesis; Wiley-VCH: Weinheim, Germany, 2005; Vol. 1. (o) Gribble, G. W. In Science of Synthesis; Georg Thieme Verlag: New York, 2006; p 357. (2) (a) Stanetty, P.; Krumpak, B.; Rodler, I. K. J. Chem. Res., Synop. 1995, 342. (b) Schlosser, M. Angew. Chem., Int. Ed. 2005, 44, 376. (c) Dąbrowski, M.; Kubicka, J.; Luliński, S.; Serwatowski, J. Tetrahedron 2005, 61, 6590. (d) Kurach, P.; Luliń s ki, S.; Serwatowski, J. Eur. J. Org. Chem. 2008, 3171. (3) (a) Gilman, H.; Gaj, B. J. J. Org. Chem. 1957, 22, 447. (b) Chen, L. S.; Chen, G. J.; Tamborski, C. J. Organomet. Chem. 1980, 193, 283. (c) Caster, K. C.; Keck, C. G.; Walls, R. D. J. Org. Chem. 2001, 66, 2932. (d) Leroux, F.; Schlosser, M. Angew. Chem., Int. Ed. 2002, 41, 4272. (e) Pellissier, H.; Santelli, M. Tetrahedron 2003, 59, 701.

Florence Mongin obtained her Ph.D. in Chemistry in 1994 from the University of Rouen (Rouen, France) under the supervision of Prof. Guy Queguiner. After a two-year stay at the Institute of Organic Chemistry of Lausanne (Lausanne, Switzerland) as a postdoctoral fellow with Prof. Manfred Schlosser, she returned to the University of Rouen as an Assistant Professor in 1997 (HDR in 2003). Besides research activities concerning the functionalization of heteroaromatic compounds using lithium and magnesium reagents and the synthesis of biologically active compounds, she got involved in catalysis studies, notably for the activation of C−F bonds, and the transition metal C− C bond formation using Grignard reagents in the presence of reactive functional groups. She has thus a strong expertise in the functionalization of aromatic and heterocyclic compounds, in the synthesis and use of metal bases, and in metal-catalyzed coupling reactions. She took up her present position in 2005 as Professor at the University of Rennes (Rennes, France) and was appointed Junior Member of the Institut Universitaire de France in 2009. Her present scientific interests include the functionalization of aromatic compounds with recourse to bimetallic bases. The synergies brought out by combining lithium and magnesium, lithium, and zinc; lithium and cadmium; lithium and copper; lithium and cobalt; and lithium and iron reagents have been evidenced in the course of the last eight years. Extensions to asymmetric synthesis are currently under investigation. AV


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