Carbometalation and Heterometalation of Carbon‐Carbon Multiple‐Bonds Using Group‐13 Heavy Metals: Carbogallation, Carboindation, Heterogallation, and Heteroindation

Abstract Organogallium and ‐indium compounds are useful reagents in organic synthesis because of their moderate stability, efficient reactivity and high chemoselectivity. Carbogallation and ‐indation of a carbon‐carbon multiple bond achieves the simultaneous formation of carbon‐carbon and carbon‐metal bonds. Heterogallation and ‐indation construct carbon‐heteroatom and carbon‐metal bonds. Therefore, these reaction systems represent a significant synthetic method for organogalliums and ‐indiums. Many chemists have attempted to apply various types of unsaturated compounds such as alkynes, alkenes, and allenes to these reaction systems. This minireview provides an overview of carboindation and ‐gallation as well as heteroindation and ‐gallation.


Introduction
Carbometalation of a carbon-carbon multiple-bond is an important and powerful method for the synthesis of organometallic compounds because organometallics are produced by the formation of a new carbon-carbon bond. [1] There are many types of transition metal-catalyzed carbometalations, and most of them occur in a syn-addition fashion. Transition metal catalyst-free carbometalation is also an attractive reaction because toxic and expensive transition metals are not required. In several reports, highly reactive organometallic compounds such as organolithiums and Grignard reagents have been added directly to alkynes and alkenes. However, the high nucleophilicity of the organometallics that were used led to a lack of functional group tolerance. On the other hand, carbometalation using group-13 heavy metal species such as organogalliums and -indiums is a diverse reaction system with high chemoselectivity. This is because the Ga(III) and In(III) centers possess moderate Lewis acidity and high π-electron affinity that is caused by the large ionic radius, which leads to a compatibility with functional groups and to the activation of carbon-carbon multiple bonds, respectively. [2] Moderate reactivity of organogalliums and -indiums enables chemoselective reactions, and the organometallics produced by carbometalation are applicable to sequential reactions. [1,3] Carboindation via a radical mechanism is possible due to the stability of low-valent indium species. Therefore, the importance of carbogallation and carboindation has increased because of their usability and diversity. This review focuses on stoichiometric carbogallation and carboindation to synthesize organogalliums and organoindiums, respectively, and the application of these organometallic compounds to organic synthesis. Many excellent catalytic reactions, in which the catalytic cycle involves carbogallation and -indation, have been reported. In these cases, organogalliums and indium species are generated as transient intermediates, but are not afforded as final products. Therefore, the catalytic reactions are excluded in this review. [2] Additionally, heterometalation of carbon-carbon multiple bonds (heterogallation and heteroindation) is described. This is the reaction wherein new carbon-hetero atom bonds and new carbon-metal bonds are formed via the addition of hetero and metal atoms to the multiple bond.

Carbogallation with Organogalliums
The first carbogallation of alkynes was reported by Yamaguchi. [4] Treatment of alkynyltrimethylsilane with GaCl 3 in the presence of a catalytic amount of pyridine 2 gave dimeric product 4 after a workup with D 2 O, and two deuterium atoms were introduced at an exo-methylene moiety of 4, which suggested the possibility of a generation of 3 via carbogallation (Scheme 1a). The addition of pyridine 2 prevented origomerization of 4. The reaction mechanism is shown in Scheme 1b. Transmetalation between 5 and GaCl 3 produces alkynylgallium 6, and then carbogallation between two alkynylgallium 6 yields digallium compound 8.
Yorimitsu and Oshima disclosed carbogallation of alkynes using allylic galliums generated by retro-allylation (Scheme 7a). [11] Allylic gallium 36 was produced by retroallylation between homoallyl alkoxide 41 and GaCl 3 , and then reacted with alkyne 35 to give product 37 after quenching with an aqueous solution of HCl. Quenching with DCl instead of HCl afforded di-and monodeuterated products (37-d 2 and (E)-37d 1 ). Based on a DCl-quenching experiment, a syn-addition mechanism was proposed (Scheme 7b). Allylgallation of alkyne 35 with 36 proceeds via a six-membered transition state to give     1,2-Bis(arylimino)acenaphthene (bian) ligands have attracted much attention. The synthesis of (dpp-bian)GaÀ Ga(dppbian) complex 41 and reversible carbogallation of alkynes with 41 was reported (Scheme 8). [12] When treatment of a solution of 41 with acetylene or phenylacetylene was carried out, the GaÀ NÀ C fragment was added to the alkynes to provide carboncarbon and carbon-gallium bonds and to give alkenyl gallium 42 or 43, respectively. These organogalliums were identified by single-crystal X-ray analysis. The carbogallation was reversible, and the equilibrium between 43 and 41 + phenyl acetylene was studied by 1 H NMR spectroscopy.
Carbogallation of a carbon-carbon double bond was established using allylgallium species. Araki reported a regioselective allylgallation of cyclopropenes (Scheme 9). [13] The reaction of the allylic gallium with cyclopropene 44 bearing a hydroxyalkyl group on the C 1 carbon gave cyclopropylgallium products 47 and 48. The structure of 47 was revealed by X-ray diffraction analysis. Therefore, the coordination of the hydroxy group to a Ga atom in the allylic gallium was classified as anti-Markovnikov regioselectivity (TS 45 and TS 46).

Carbogallation of Gallium Trihalide-Activated Carbon-Carbon Multiple-Bond
A reaction of silyl acetylene with GaCl 3 and nucleophilic arenes was carried out, followed by treatment with MeLi to gave alkenyldimethylgallium 52 (Scheme 10a). [14] π-Complex 53 was formed from GaCl 3 and vinyl tert-butyldimethylsilane and identified at À 78°C via NMR spectroscopy (Scheme 10b). Carbogallation proceeds via the regioselective nucleophilic attack of an arene at the β-carbon atom of a silyl group to give zwitterion intermediate 54. Finally, a proton abstract and ligand exchange by MeLi produce alkenylgallium 52. In the absence of nucleophilic arenes, ethynylsilane 55 was trimerized via alkenylgallation caused by GaCl 3 (Scheme 11a). [15] The reaction of GaCl 3 with 3 equivalents of 55 in CH 2 Cl 2 and methylcyclohexane at À 78°C gave trienyl cation 56. Interestingly, the cation intermediate 56 was identified by 1 H and 13 C NMR spectroscopies. MeMgBr in Et 2 O was then added to the solution of 56 to Scheme 6. Plausible reaction mechanism for carbogallation using silyl enolates and GaCl 3 .
Scheme 8. Synthesis of (dpp-bian)GaÀ Ga(dpp-bian) complex by carbogallation. produce alkenylgallium 57. Proposed mechanism is shown in Scheme 11b. The reaction is initiated with the activation of 55 by GaCl 3 , and then the nucleophilic addition of another 55 gives alkenyl cation 59. The cation 59 is converted to trienyl cation 56 by the addition of 55. Finally, the treatment of MeMgBr produces trienylgallium compound 57.
Silyl allene 60 also underwent carbogallation with GaCl 3 and p-xylene (Scheme 12). [16] In this case, however, an intramolecular proton transfer in zwitterion alkylgallium species 61, which was formed by the carbogallation, occurred to give alkenylsilane 62 and GaCl 3 , so a stable organogallium product was not obtained.
We reported the regio-and stereoselective anti-carbogallation of alkynes using GaBr 3 and silyl ketene acetals (Scheme 13). [17] Alkyne 63 was treated with GaBr 3 and silyl ketene acetal 64 to give dialkenylgallium 65 (Scheme 13a). The structure of 65 was determined by X-ray diffraction analysis after complexation with pyridine (65·pyridine). That result suggested carbogallation occurred as shown in Scheme 13b. The interaction between GaBr 3 and a carbon-carbon triple bond of alkyne 63 causes the regioselective nucleophilic attack of 64 from the opposite site of GaBr 3 to provide monoalkenylgallium 64 and Me 3 SiBr.
Synthesized alkenylgalliums were directly applied to Pdcatalyzed cross-coupling with aryl iodides (Scheme 14). Various types of functional groups were compatible with alkenylgalliums, and 4-acetyliodobenzene, 2-iodopyridine as well as iodobenzene smoothly coupled with alkenylgalliums (65 or 66) to give the corresponding trisubstituted alkene products (67, 68, and 69). The use of phosphine ligands for a Pd-catalyst is not necessary to the cross-coupling of organogalliums (and organoindiums) in highly-coordinative solvents such as DMF perhaps because the solvents could work as efficient ligands.
The developed process for trisubstituted alkene synthesis via carbogallation/cross-coupling was employed for the first total synthesis of nodosol 75 (Scheme 15). The key synthetic intermediate, diene 72, was regio-and stereoselectively prepared by carbogallation of enyne 70 followed by crosscoupling using 4-bromoiodobenzene.

Heterogallation of Carbon-Carbon Multiple-Bonds
Zheng and Yang demonstrated the first synthesis and characterization of pyrazolato gallium dichlorides and its application to azagallation of alkynes. [20] When pyrazolato gallium dichloride 88 was mixed with silyl acetylene, azagallation of the carbon-carbon triple-bond gave pyrazolato alkenylgallium 89 (Scheme 18a). The reaction mechanism remains unclear, but the more reactive three-coordinated gallium species 91 is proposed (Scheme 18b). The gallium center of 91 activates silyl acetylene by π-coordination, and the intramolecular nucleophilic attack by a β-nitrogen of the Ga atom causes azagallation.
Uhl synthesized Ga/P complex 93 with the geminal arrangement of coordinatively unsaturated Ga and P atoms. [21] When 93 was mixed with alkyne 94, phosphagallation of a carbon-carbon triple bond occurred to give five-membered heterocycle 95 involving P and Ga atoms (Scheme 19). The terminal C atom of alkyne 94 has its relatively high negative partial charge to bind to the electropositive Ga atom, and the relatively positive internal C atom binds to the electronegative P atom.
The regioselectivity depended on the structures of alkynols and allylic indiums (Scheme 21a). The reaction using sterically hindered alkynol 105 and allylic indium 106 showed perfect regioselectivity. A proposed reaction mechanism is shown in Scheme 21b. A hydroxy group coordinates to an indium atom of allylic indium 97. The allyl group on the coordinated indium atom adds to the terminal carbon of alkynol 96 and the indium adds to the inner carbon. [23] Yamamoto [24] and Ranu [25] independently reported the carboindation of unactivated alkynes using allylic indiums (Scheme 22). In contrast to the DMF solvent conditions, aromatic alkyne 111 and aliphatic alkyne 114 without a directing group such as a hydroxy group smoothly underwent carboindation using an allylic indium under THF solvent conditions to give dienes 113 and 115, respectively (Scheme 22a and 22b). Quenching with DCl/D 2 O afforded an E/Z mixture of deuterated diene product 115 (Scheme 22b). Therefore, the carboindation of an alkyne with an allylic indium proceeds via syn-addition fashion (116) to produce alkenyindium 117, which undergoes E-Z isomerization (Scheme 22c).
Carboindation of alkynes using benzylic indiums was also reported by Yamamoto (Scheme 23). [24b] The benzylindation of aromatic alkyne 111 occurred in an anti-addition manner (Scheme 23a), while that of aliphatic alkyne 114 took place in a nonstereoselective fashion (Scheme 23b). As in the case of allylindation, syn-addition followed by E-Z isomerization occurred. The produced alkenylindium 122 coupled with benzyl iodide in the presence of a palladium catalyst to give threecomponent coupling product 123 in 49 % yield (Scheme 23c).
Intramolecular cyclizations of alkynes bearing an allylic bromide moiety via allylindation were reported. Salter discovered that In(0) mediated the cyclization of 123 to give cyclic compound 124 (Scheme 24a). [26] The allylic indium moiety of 125, which generated by the reaction of allylic bromide 123 with In(0), adds to an intramolecular carbon-carbon triple bond in a syn fashion, giving alkenylindium 126, regio-and stereo-Scheme 20. Carboindation of a carbon-carbon triple-bond nearby a hydroxy group.

Scheme 21.
Regioselectivity and plausible mechanism for carboindation of alkynols with allylic indiums. selectively (Scheme 24b). Actually, the use of D 2 O instead of H 2 O stereoselectively gave deuterated product 124-d. Lee reported an improved intramolecular cyclization system (Scheme 24c). [27] The cyclization of 127 in DMF smoothly proceeded without an H 2 O co-solvent, and the addition of KI was a key factor. The produced alkenylindium 128 was successfully coupled with an aryl iodide or I 2 .
Araki and Butsugan discovered the stereodivergent allylindation of cyclopropene derivatives (Scheme 25). [28] In a reaction of cyclopropene 131 with allylic indium 132, the allylic indium was added preferentially from the anti-face of the acetoxymethyl group (TS 133) to avoid steric repulsion with the acetoxymethyl group, and the allylic group was introduced to the substituted carbon of the cyclopropene double bond to give product 134. In contrast, the stereoselectivity of allylindation into cyclopropene 135 was reversed to that of acetate 131, although the regioselectivity was not changed. This result suggested that the coordination of the hydroxy group to an allylic indium species led to allylindation from the cis face of the hydroxymethyl group (TS136).
The generated cyclopropylindiums were applicable to further transformations (Scheme 26). [29] The treatment of generated cyclopropylindium 139 by I 2 and LiCl afforded iodo cyclopropane derivative 140. In addition, cyclopropylindium 139 coupled with allyl iodide to give diallyl propane 141 in the presence of an excess amount of Et 3 Al, in which a kind of cyclopropylindium ate-complex generated by the reaction of 139 with Et 3 Al would be an active nucleophile.
Interestingly, the allylindation of cyclopropene 142 bearing a hydroxyalkyl group at a 1-position as well as at a 2-position took place with the opposite regioselectivity in the reaction of 135 (Scheme 27a). [30] The coordination of a hydroxy group hanging on the 2-position to an indium center of 142 in TS143 caused a drastic change in the regioselectivity. The X-ray crystal structure of cyclopropylindium 146 synthesized by allylindation of cyclopropene 145 bearing 2-hydroxyethyl and ester groups at the C 1 and C 2 carbons, respectively (Scheme 26b).
Other strained olefins underwent carboindation with allylic indium reagents. Allylindation of norbornenol 147 regio-and stereoselectively proceeded to give allylated product 148, and the allylic group was installed exclusively from the exo face (Scheme 28). [31] Therefore, the hydroxy group of 147 acts as a director to lead the carboallylation on the exo face (TS 149).
The reaction of methylenecyclopropane 151 with allylic indium species 138 exclusively gave deuterated cyclopropane 152 after carrying out a 1 M DCl/D 2 O quench (Scheme 29). [32] Regio-and setereoselective allylindation occurred owing to the coordination of a hydroxyl of 151 to an indium center (TS153).
Araki and Butsugan developed carboindation of allenols using an allylic indium species. [33,34] The regio-and stereoselective addition of prenylindium species 156 to an allene moiety of allenol 155 proceeded to afford product 157 (Scheme 30a). O-protected allenols were not applicable to this carboindation system, which suggested the importance of an hydroxy group for effective carboallylation. A plausible reaction mechanism is shown in Scheme 30b. The carboindation regioand stereoselectively proceeds through hydroxyl-chelated bicyclic transition state TS158 to give alkenylindium 159, and 159 was protonated by an internal hydroxy group to afford indium alkoxide 160.

Carboindation of Indium Trihalide-Activated Carbon-Carbon Multiple-Bond
We reported the carboindation of alkynes using InBr 3 and silyl ketene acetals. [35] When alkyne 161 was treated with InBr 3  The treatment with I 2 gave iodinated β,γ-unsaturated ester 166, and Pd-catalyzed cross-coupling of the synthesized alkenylindium with iodobenzene in a one-pot manner gave coupling product 167 (Scheme 33). In both reactions, the configuration of the corresponding alkenylindium was retained.

Carboindation via Radical Mechanism
Takemoto discovered indium-mediated reductive radical cyclization of alkynes bearing an iodoalkane moiety by using a lowvalent indium species (Scheme 35). Treatment of alkyne 194 with In(0) and I 2 promoted 5-exo cyclic carboindation to give alkenylindium 195 (Scheme 37a). [39] The generated alkenylindium 195 was coupled with iodobenzene in the presence of a Pd catalyst to give an E/Z isomer mixture 196. A proposed mechanism is illustrated in Scheme 37b. The single electron transfer (SET) from a low-valent indium iodide species, which is generated from In(0) and I 2 , to 194 provides alkyl radical 197. The radical 197 then undergoes a radical cyclization to produce alkenyl radical 198, and then the radical reductively combines with an indium cation ( + InX 2 ) to give the E/Z-mixture of alkenylindium 195. Alkene 199 with an iodoalkyl moiety was also applicable to this reductive radical cyclization, and stable alkylindium 200 was isolated (Scheme 37c). [40] The alkylindium 200 underwent oxidation by H 2 O 2 to give the corresponding primary alcohol 201.
A reductive radical cyclization of iodoarene bearing an alkynylamide moiety by using In(0)/pyridinium tribromide (PyHBr 3 ) occurred regio-and stereoselectively to produce 3alkylideneoxindoles 203 (Scheme 38a). [41] In the reaction mechanism (Scheme 38b), either InBr generated from In(0) or InBr 2 generated from PyHBr 3 could mediate the radical carboindation of iodoarene 202, and the coordination of the amide group to an indium atom led to the high stereoselectivity. 202 underwent SET from a low-valent indium species to afford sp 2 -σ radical 205. The radical 205 produces alkenyl radical 206 via radical cyclization, and then the radical exclusively gives an Eisomer of alkenykindium 203 due to the strong coordination of the amido moiety to the indium center. The generated alkenylindium 203 was applied to Pd-catalyzed cross-coupling with 4-iodo toluene.
Shibata and Baba established the carboindation of alkynes and allenes via indium hydride-mediated radical cyclization. Enyne 210 underwent cyclization in the presence of HInCl 2 , which was generated from InCl 3 and Et 3 SiH, to give exomethylene compound 212 through alkenylindium 211 (Scheme 40a). [43] A proposed mechanism is shown in Scheme 40b. Transmetalation between InCl 3 and Et 3 SiH gives HInCl 2 , and then the Et 3 B/O 2 system generates a dichloroindium radical (·InCl 2 ) from HInCl 2 . The indium radical adds to an alkyne moiety of 210 to produce alkenyl radical 213. Alkyl radical 214 is produced by the 5-exo cyclization of 213, and then abstracts a hydrogen atom from HInCl 2 to give alkenylindium 211.
Carboindation of allenes by radical cyclization was also developed (Scheme 41a). [44] When allenene 215 was treated with In(OMe)Cl 2 and PhSiH 3 , carboindation of an allene moiety and 5-exo cyclization proceeded to give alkenylindium 216. In this case, an indium radical selectively adds to a central carbon of an allene moiety to provide allylic radical 218 (Scheme 41b). The 5-exo cyclyzation of 218 followed by the hydrogen abstraction of alkyl radical 219 from HInCl 2 affords alkenylindium 216. Then, Pd-catalyzed cross-coupling of the alkenyl indium 216 with an iodoarene successfully proceeds to yield 217.
A reaction mechanism of the oxyindation was revealed by both experimental and theoretical studies. When the reaction of 222 with InI 3 was carried out at room temperature, zwitterion intermediate 224 with a new carbon-indium and carbon-carbon bonds was obtained and identified by X-ray diffraction analysis (Scheme 43a). Zwitterion 224 was heated at 50°C, and then elimination of MeI occurred to give isocoumarin 225 bearing a carbon-indium bond at the 4-position (Scheme 43b). Based on experimental results, the details of the reaction mechanism were examined using theoretical calculation (Scheme 44), which showed that the activation energy of 5-exo cyclization is much smaller than that of the elimination of MeI so that 5-exo cyclization is reversible. Eventually, selective production of the thermodynamically stable 6-membered zwitterion 224 produced a remarkable level of 6-endo selectivity.
Alkenyl indium 229 was synthesized by the oxyindation of 222 using InBr 3 and applied to Pd-catalyzed cross-coupling with iodobenzene or benzoic chloride in a one-pot manner to afford 4-substituted isocoumarin 230 or 231, respectively (Scheme 45).
The formal total synthesis of oosponol was demonstrated by the present oxyindation (Scheme 46). Alkenylindium 234 was synthesized via the oxyindation of 233 with InBr 3 , and then a one-pot process for the Pd-catalyzed cross-coupling of 2- (acetyloxy)acetyl chloride provided a key isocoumarin precursor, 235, for Oosponol. [47] Carbonyl-ene-yne compounds are also applicable to oxyindation with indium trihalides to give 2-pyrones bearing a carbon-indium bond (Scheme 47). [48] The oxyindation of 236 using InI 3 produced tetrasubstituted metalated isocumarin 237. Subsequently, the coupling reaction of 237 with either an aryl iodide or an aroyl chloride in the presence of a palladium catalyst led to 2-pyrones 238 or 239 bearing four different substituents, respectively. Tetrasubstituted 2-pyrones 240 and 241 exhibited an aggregation-induced emission (AIE) in the solid state (Scheme 48). It is noted that 240 and 241 exhibit greater quantum yields than triphenylated 2-pyrone 242. [49] Gomez-Bengoa and Sestelo reported that cyclic oxyindation of lithium o-phenylethynylphenoxide 243 with InCl 3 proceeded to give alkenylindium 244 (Scheme 49). [50] In this case, the πcoordination of an alkyne moiety to InCl 3 followed by endocyclization induced by the nucleophilic attack of a lithium alkoxide moiety occurs (TS245). Organoindium 244 underwent Pd-catalyzed cross-coupling with 4-iodotoluene to afford benzo [b]furan 246. The discovery of oxyindation provided important insight into the reaction mechanism of the In-catalyzed hydroalkoxylation of o-alkynylphenol derivatives.

Conclusions and Outlook
We briefly summarized the history of carbogallation and -indation, and heterogallation and -indation of carbon-carbon multiple bonds. Carbogallation is divided into two main systems that are the addition of organogallium species and the addition of an external nucleophile to a gallium-activated alkyne. In the former system, allylgalliums, alkynylgalliums, and gallium enolates were used as organogallium species. In the latter, a gallium trihalide activates a carbon-carbon multiple-bond of alkynes, allenes, and alkenyl ethers, and carbogallation is then completed by the nucleophilic addition of various carbon nucleophiles. On the other hand, there are three types of carboindation. Two types are the same as carbogallation. A third type includes a radical pathway, which gives it broader diversity than carbogallation. A third type of carboindation involves a radical mechanism due to the stability of low-valent indium species. A few types of fascinating azagallation and oxyindation have been established. The moderate reactivity and stability of organogallium and -indium has resulted in high levels of compatibility with functional groups. Carbogallation, carboindation, heterogallation, and heteroindation are powerful tools available for the synthesis of highly functinalized organometallic compounds, and further development of this field of study will be extremely useful as more sophisticated organic syntheses are required in the near future.