Synthesis of dichloroindium hydride and exploration of its reactivity with organic functional groups . Tandem , selective and partial reductions of halo-nitriles

Methods for the in situ generation of dichloroindium hydride (HInCl 2) via the reduction of InCl 3 with various reducing agents, such as tributyltin h ydride (tributylstannane; Bu 3SnH), diisobutylaluminum hydride (DIBAL-H), triethylsilan e (Et3SiH), lithium aminoborohydride (LAB), and sodium borohydride (NaBH 4), in various solvents are reviewed and compared. T he use of the InCl 3/NaBH4 system in addition to forming HInCl 2, also generated borane that was trapped as BH3-tetrahydrofuran (THF). Carefully controlling the a ctivity of these reducing agents allows for the selective and/or partial reduction o f multi-functionalized compounds containing nitriles and halogens.


Introduction
The use of metal-mediated reactions has played an important role in the development and advancement of organic chemistry with far reaching effects spanning novel laboratory techniques to vital industrial applications.Among the many uses of metals, metal hydride reductions of functional groups are among the most common and useful chemical transformations.Traditional and commonly used metal hydrides like sodium borohydride (NaBH 4 ) 1 and lithium aluminum hydride (LiAlH 4 ) 2 form an integral part of the modern organic chemist's toolbox.While both hydrides are used extensively, the ability of LiAlH 4 to reduce most functional groups limits its use in the reduction of multifunctional compounds when selective reduction is desired.Conversely, NaBH 4 is a mild reducing agent with limited abilities in the reduction of many functional groups such as nitriles and carboxylic acids.Sodium borohydride is known to selectively reduce ketones and aldehydes in the presence of other functional groups.Many alternatives have recently been developed to safely and selectively reduce several functional groups at will. 3 Among these alternatives, a variety of Group 13 metal hydride derivatives have been developed over the years, some of which are extensively utilized. 4ndium has recently garnered attention in metal-mediated reactions due in part to the relatively low oxidation potentials of the most common oxidation states of indium: In + (0.14 V) and In 3+ (0.44 V). 5 These oxidation potentials tend to produce favorable reaction conditions for the synthesis of organoindium compounds under ambient conditions.Indium hydride reagents (LiInH 4 , LiPhInH 3 , and LiPh 2 InH 2 ) were first prepared from InCl 3 and LiH by Wiberg and Schmidt 6 and were later explored by Butsugan and coworkers who further demonstrated their ability to reduce a variety of functional groups including aldehydes, ketones, esters, and halides. 7Subsequently, other indium hydride reagents have been developed.In the next section, we give an overview of the generation of dichloroindium hydride (HInCl 2 ) and its application to various reductions in organic synthesis.

Preparation of Dichloroindium Hydride (HInCl 2 )
2.1 Generation of HInCl 2 using Bu 3 SnH Dichloroindium hydride was first prepared by Baba and coworkers by the reduction of InCl 3 with tributyltin hydride (tributylstannane; Bu 3 SnH) (Scheme 1). 8Scheme 1. Generation of dichloroindium hydride. 8e in situ generated HInCl 2 arising from the reduction of InCl 3 with Bu 3 SnH was able to reduce a variety of functionalities including aldehydes, ketones and alkyl halides. 8Interestingly, the InCl 3 /Bu 3 SnH system was found to effect stereoselective reductive aldol reactions affording both syn and anti selectivity depending on the solvent used (Scheme 2). 9Scheme 2. Selective reductive aldol reactions of α,β-unsaturated ketones. 9e use of anhydrous THF favored the anti product (syn:anti 5:95), while the use of methanol or H 2 O/THF favored the syn derivative (syn:anti 99:1 and 95:5 respectively).Additionally, acid chlorides have been partially reduced to the corresponding aldehyde in the presence of triphenylphosphine (PPh 3 ) along with HInCl 2 generated using a catalytic amount of InCl 3 and one equivalent of Bu 3 SnH (Scheme 3).The catalytic cycle proposed by Baba and coworkers proceeds via the coordination of PPh 3 to InCl 3 followed by a hydride transfer from the Bu 3 SnH to the InCl 3 to generate HInCl 2 , which then reduces the acid chloride to the corresponding aldehyde and regenerates the InCl 3 . 10ichloroindium hydride was also found to be an efficient radical initiator catalyzing the reduction of organic halides (     The proposed catalytic cycle for the reduction of organic halides suggests a radical dehalogenation mechanism wherein the In-H bond is cleaved to allow formation of the indium radical, which then reacts with organic halides (Scheme 4).11a More recently, this system has been effectively used in the generation of allylic indium through the hydroindation of 1,3-dienes that react with carbonyl or imine compounds in a onepot reaction sequence.11b For example, 1,4-diphenyl-1,3-butadiene underwent hydroindation and upon the addition of an aliphatic aldehyde, 3-phenylpropanal, gave the allylated product in 88% yield.11b However, because of the toxicity of Bu 3 SnH, alternative reducing agents should be considered to obtain HInCl 2 .

Generation of HInCl 2 using DIBAL-H
Oshima and coworkers developed an alternative method of generating HInCl 2 using diisobutylaluminum hydride (DIBAL-H) as the hydride source to reduce InCl 3 (Scheme 5). 12ichloroindium hydride was produced and used along with triethylborane (Et 3 B) to carry out the hydroindation of a variety of alkynes to the corresponding (Z)-alkenes (Table 2). 12Scheme 5. Generation of HInCl 2 with DIBAL-H. 12hima suggests that the addition of Et 3 B promotes the reaction by acting as a radical initiator that facilitates the radical addition of HInCl 2 across the carbon-carbon triple bond.Additionally, HInCl 2 and Et 3 B in the presence of dioxygen were found to promote radical cyclizations via the generation of an ethyl radical, which then reacts with HInCl 2 to provide an indium-centred radical •InCl 2 . 13The generated •InCl 2 then reacts with iodine to form the radical intermediate 2 which subsequently cyclizes to afford 3 followed by a hydrogen atom abstraction from HInCl 2 to regenerate •InCl 2 and afford the final product 4 (Scheme 6).
Proposed catalytic cycle of the radical cyclizations of halo acetals. 13emoselective reductions of alkyl bromides and carbonyl functionalities using HInCl 2 were also explored. 13Interestingly, alkyl bromides were found to undergo exclusive reduction in the presence of ester and ketone functionalities, but aldehydes were found to undergo reduction faster than alkyl bromides. 13

Generation of HInCl 2 using silanes
Mixtures of silanes and InCl 3 have also been used to carry out a variety of reductions.The combination of chlorodimethylsilane and InCl 3 was first used to catalyze the reductive Friedel-Crafts alkylation of various aromatics with carbonyl compounds (Scheme 7). 14Scheme 7. Friedel-Crafts alkylation with aromatic carbonyl compounds. 14bsequently, reductive deoxygenation of aryl ketones was achieved using chlorodimethylsilane and InCl 3 (Scheme 8). 15heme 8. Reductive deoxygenation of various ketones. 15is mixture of chlorodiphenylsilane and InCl 3 has also been shown to bring about analogous reductive deoxygenations of a variety of secondary and tertiary alcohols (Scheme 9). 16heme 9. Reduction of various alcohols. 16dditionally, the system was found to give high chemoselectivity for hydroxyl groups in the presence of other functional groups, such as esters, as exemplified by the selective deoxygenation of hydroxy-esters (Scheme 10). 16 Scheme 10.Direct chemoselective reduction of alcohols by Ph 2 SiHCl/InCl 3 . 16 was proposed that InCl 3 acts as a Lewis acid that loosely coordinates to oxygen to accelerate the deoxygenation of the resulting intermediate by promoting a hydride transfer from silane. 16While the generation of HInCl 2 was not reported in these earlier studies, the in situ formation of HInCl 2 may also explain the observed reductions.Later studies of InCl 3 with other silanes including triethylsilane (Et 3 SiH), have proposed the in situ generation of HInCl 2 and its use in reductive aldol reactions (Scheme 11). 17Scheme 11.Diastereoselective aldol reactions. 17terestingly, InBr 3 was also found to undergo a similar reduction in the presence of Et 3 SiH to generate HInBr 2 which was used in a variety of diastereoselective reductive aldol reductions. 17echanistically, it was suggested that HInX 2 is generated by the slow transmetallation of InX 3 with Et 3 SiH which then undergoes a 1,4-addtion to the enone to afford the indium enolate 1. Subsequent reaction of 1 with 2 via a Zimmerman-Traxler six-membered cyclic transition state ultimately affords the product 4. 17 Scheme 12. Plausible mechanistic cycle. 17rther exploration of the InCl 3 /Et 3 SiH system revealed its ability to reduce alkyl bromides in addition to the intramolecular cyclization of enynes via the hydroindation of alkynes. 18The proposed mechanism proceeds via the formation of the vinyl radical which cyclizes to the alkene product.For example, diethyl allylpropargylmalonate afforded the cyclized exo-methylene compound in a 53% yield (eq. 1, Scheme 13).18a Additionally, Baba and coworkers have also demonstrated the inter-and intramolecular radical coupling of ene-ynes and halo-alkenes using the InCl 3 /MeONa/Ph 2 SiH 2 system.18b For example, iodobenzene and acrylonitrile gave the coupled 3-phenylpropanenitrile product in a 60% yield (eq. 2, Scheme 13).18b The versatility of the InCl 3 /Et 3 SiH system to generate HInCl 2 has also been extended to the reduction of organic azides to the corresponding amines in a highly chemoselective fashion (Scheme 14). 19dditionally, γ-azidonitriles cyclize to afford pyrrolidin-2-imines (Scheme 15). 19The authors propose the γ-azidonitriles undergo a radical cyclization similar to that of the aforementioned cyclization of enynes.
More recently, the chemoselective reductive amination of carbonyl compounds has also been demonstrated by Yang and coworkers using the InCl 3 /Et 3 SiH system (Scheme 16). 20Scheme 16.Reductive amination of aldehydes and ketones with various amine salts. 20e system can be applied to a variety of cyclic, acyclic, aromatic and aliphatic amines in the presence of functionalities such as esters, hydroxyls, carboxylic acids and olefins.NMR and ESI-MS were used to help elucidate a mechanism and found the existence of a stable methanolcoordinated indium(III) species which they postulate to be responsible for the generation of indium hydride (Scheme 17). 20M e O H ) x -1 Scheme 17. Proposed mechanism for the InCl 3 /Et 3 SiH/MeOH system-promoted reductive amination. 20kai and coworkers have further explored the scope of the reductive capabilities of indium hydride with various carbonyl compounds.Tertiary amides were directly reduced to the corresponding tertiary amines using InBr 3 /Et 3 SiH (Scheme 18). 21heme 18. Reduction of amides to amines. 21terestingly, the reduction of carboxylic acids to primary alcohols or deoxygenation to diphenylmethanes using a similar system with the addition of an aromatic compound has recently been reported. 22Aromatic carboxylic acids with the addition of aromatic compounds were fully reduced to the corresponding diphenylmethanes using this system.Sakai and coworkers also describe an efficient method for directly converting carboxylic acids into the corresponding primary alcohols using InBr 3 and tetramethyldisiloxane (TMDS) (Scheme 19). 22cheme 19.Synthesis of primary alcohols from aliphatic carboxylic acids. 22

Generation of HInCl 2 using NaBH 4
Although HInCl 2 has great potential as a mild reducing agent, some of the methods previously used for its synthesis utilize less than ideal conditions and reagents.The InCl 3 /NaBH 4 reagent system has received significant attention due to the simple and convenient in situ preparation of HInCl 2 . 23NaBH 4 is less expensive and a less toxic than Bu 3 SnH originally used to prepare HInCl 2 . 8Dichloroindium hydride was first generated with NaBH 4 by Baba and coworkers when exploring alternative hydride sources to the tin hydride originally used (Scheme 20). 23Scheme 20.HInCl 2 reduction of halides. 23is new system was also used in the representative intramolecular cyclization of 1-allyloxy-2-iodobenzene which afforded 3-methyl-2,3-dihydrobenzofuran in 62% yield (Scheme 21). 23heme 21.Intramolecular cyclization of 1-allyloxy-2-iodobenzene. 23presentative InCl 3 /NaBH 4 intermolecular radical additions were also demonstrated using iodobenzene and electron-deficient olefins (Scheme 22). 23heme 22. Radical addition of iodobenzene to electron-deficient olefins. 23n subsequent work, Ranu and coworkers used the InCl 3/ NaBH 4 system to generate HInCl 2 and chemoselectively reduced conjugated alkenes (Scheme 23).24,25 Scheme 23.Reduction of carbon-carbon double bond of conjugated alkenes.24 This system was shown to reduce selectively a variety of conjugated alkenes such as, α,αdicyano olefins, α,β-unsaturated nitriles, cyanoesters, cyanophosphonate and dicarboxylic esters. Interengly, the attempted reduction of chalcones produced a mixture of saturated ketones and alcohols when quenched with H 2 O and exclusively saturated alcohols when quenched with MeOH.24 Similarly, Ranu and coworkers also found that the InCl 3 /NaBH 4 system selectively reduces α,β-carbon-carbon double bond in α,β:γ,δ-unsaturated diaryl ketones, dicarboxylic esters, cyano esters and dicyano compounds (Scheme 24).26 Scheme 24. Setive reduction of α,β-carbon-carbon double bonds.26 Ranu and coworkers have also demonstrated the ability of the InCl 3 /NaBH 4 system to synthesize (E)-alkenes through the stereoselective reduction of vic-dibromides (eq. 1, Scheme 25), 27 as well as the selective reduction of 2,3-epoxybromides to the corresponding allylic alcohols (eq.2, Scheme 25).28 Interesting reactions using alkynes have also been developed using the InCl 3 /NaBH 4 system, including the dimerization of terminal alkynes to enynes (eq.3, Scheme 25).29 Others have continued to explore the InCl 3 /NaBH 4 system and its reaction with alkynes.Pan and coworkers have been able to stereoselectively synthesize (E)-2-arylvinylphosphonates through the hydroindation and subsequent hydrolysis of aryl alkyl phosphonates (Scheme 26).30 They were able to expand this methodology to the coupling of terminal alkynes with aryl halides to give disubstituted (E)-alkenes.31 Although a considerable number of studies have examined the InCl 3 /NaBH 4 system, few have reported on the significant influence that solvent can have on reaction rates and yields of reductions.23,31 For example, Baba and coworkers report that alkyl halides were reduced efficiently (up to 78% reduction) using a catalytic amount of InCl 3 along with one equivalent of NaBH 4 in MeCN (Table 3, entry 4).However, the same reaction is low yielding in THF (only 15% reduction) under otherwise similar reaction conditions (Table 3, entry 5).23 Similar solvent effects were observed by others working with HInCl 2 .31 Scheme 25. Dierization of terminal alkynes to enynes.29 Scheme 26.Synthesis of (E)-2-arylvinylphosphonates using the InCl 3 /NaBH 4 system. 30nce previous reports had not elucidated the origin of these solvent effects, we decided to explore the InCl 3 /NaBH 4 reagent system further by monitoring the boron species formed during the reaction via 11 B NMR spectroscopy.32 Consequently, we reacted a 1:1 molar ratio of InCl 3 to NaBH 4 in both THF and MeCN and analyzed the supernatant solution by 11 B NMR spectroscopy to probe the identity of the boron species formed in situ (Scheme 27).32 B NMR spectral analysis of InCl 3 /NaBH 4 in THF (Scheme 27, equation 1) revealed the formation of a borane-tetrahydrofuran complex (BH 3 •THF).33 When the same reaction was run in MeCN (Scheme 27, equation 2), a significantly different 11 B NMR spectrum was observed. A 2 species was observed, which we believe is the result of the reduction of the MeCN solvent by borane.
We suggest that the poor reduction of alkyl halides using a catalytic amount of InCl 3 along with one equivalent of NaBH 4 in THF that was previously reported 23 is likely to have been due to the inhibition of the catalytic cycle by the in situ generated BH 3 •THF.Consequently, when a stoichiometric amount of InCl 3 was used along with three equivalents of NaBH 4 , (3-bromopropyl)benzene was fully reduced to n-propylbenzene with an isolated yield of 80%, indicating that BH 3 •THF or the solvent THF has little effect on stoichiometric reductions involving HInCl 2 .Based on the 11 B NMR spectral data, we postulated that the InCl 3 /NaBH 4 system in THF should reduce nitriles efficiently.After some optimization we found that 1 equivalent of InCl 3 and 3 equivalents of NaBH 4 in THF was the optimum ratio to reduce aromatic, heteroaromatic, and aliphatic nitriles the corresponding primary amine (Scheme 28). 32Scheme 28.InCl 3 /NaBH 4 reduction of aromatic, heteroaromatic and aliphatic nitriles to primary amines. 32e InCl 3 /NaBH 4 system was able to reduce a variety of aromatic nitriles, including aromatic nitriles with electron-donating groups in good to excellent yields (70-99%).A variety of halogen-substituted aromatic nitriles were also reduced using this simple procedure.Although the reduction of benzyl and aliphatic nitriles is typically more challenging due to the acidity of the α-hydrogens, which tend to be deprotonated under some reaction conditions, 34 the InCl 3 /NaBH 4 system in THF readily reduced these substrates to their corresponding primary amine in good to excellent yields.Nitriles containing heteroaromatic rings, such as thiopheneacetonitriles, were also nicely reduced using this system.

Generation of HInCl 2 using lithium aminoborohydride (LAB)
We have recently explored alternative methods of producing HInCl 2 by the reduction of InCl 3 using LAB reagents previously discovered in our laboratory. 35The experiments were carried out by reacting one to three equivalents of anhydrous InCl 3 with one to three equivalents of lithium dimethylaminoborohydride (MeLAB) in THF for 1 h at 25 °C.The reactions were then evaluated by obtaining the 11 B NMR spectrum of the supernatant solution under an inert atmosphere.It was discovered that the ratio of InCl 3 to MeLAB played a significant role in the formation of the reducing species (Table 4). 32hen an excess of MeLAB was used (Table 4, entries 1 and 2), the reaction mixture quickly turned dark grey and precipitated colloidal indium metal which aggregated to form a shiny indium nugget.From the weight of the indium metal, it was deduced that indium metal was formed essentially quantitatively in these reactions.Our results indicate that two equivalents of MeLAB reagent were sufficient to fully reduce InCl 3 to indium metal in a quantitative manner (Table 4, entry 2).However, when two or more equivalents of InCl 3 were used and one equivalent of MeLAB was added slowly over 5 minutes (Table 4, entries 4 and 5), little or no indium metal was generated and only a slight browning of the reaction mixture was observed.11 B NMR spectroscopy revealed the complete disappearance of the MeLAB quartet at δ -15 ppm and the appearance of a corresponding aminoborane [BH 2 N(CH 3 ) 2 ] n complex that we believe to be a dimmer, with a triplet at δ 5 ppm. 32t was also found that the HInCl 2 produced using the MeLAB/InCl 3 reagent system possesses similar reductive capabilities to that of HInCl 2 prepared via other methods.For example, we were able to reduce aliphatic halides like (3-bromopropyl)benzene to n-propylbenzene in 77% yield (Scheme 29). 32a Reactions were carried out on 1 mmol scale in 10 mL of solvent.
Scheme 29.Carbon-bromine bond reduction using InCl 3 /MeLAB. 32 2.6.Tandem, selective and partial reduction of halides and nitriles using HInCl 2 As discussed above, dichloroindium hydride can be synthesized by a variety of methods.The method and the reaction conditions utilized can have a profound effect on the reaction outcome.We suggest that these dramatic differences can in part be explained by the reaction of byproducts generated during the synthesis of HInCl 2 .This allows for the customization of the reductive capabilities depending on the method used to prepare HInCl 2 (Scheme 30).

Selective reduction of halides in the presence of nitriles.
We next turned our attention to the selective reduction of halides in the presence of nitriles using the InCl 3 /NaBH 4 system.The main obstacle envisioned for this reaction was the selective scavenging of BH 3 •THF from the mixture of HInCl 2 and BH 3 •THF.Attempts were made to capture the generated borane with tetramethylethylenediamine (TMEDA), which is known to readily complex with BH 3 to form (BH 3 ) 2 •TMEDA. 36However, TMEDA also tightly complexed HInCl 2 and prevented it from reducing carbon-halogen bonds.This result prompted us to revisit the MeLAB/InCl 3 system which previously reduced (3-bromopropyl) benzene to the corresponding n-propylbenzene in 77% yield.We anticipated that this system would give selective reductions of carbon-halogen bonds in the presence of nitriles (Scheme 33).Scheme 33.Generation of HInCl 2 with MeLAB.
As noted earlier, MeCN was found to be an excellent borane scavenger and generated only HInCl 2 from the InCl 3 /NaBH 4 system.This property of MeCN along with the ability of HInCl 2 to reduce halides was utilized to selectively reduce 4-(bromomethyl)benzonitrile and 4-(chloromethyl)benzonitrile to p-tolunitrile in an isolated yield of 98% and 68%, respectively (Scheme 35).Scheme 35.Selective reduction using InCl 3 /NaBH 4 /MeCN.

Tandem, selective, and partial reduction of halo-nitriles using DIBAL-H and InCl 3 .
Lastly, generation of HInCl 2 using DIBAL-H was also explored and utilized to selectively reduce halides in the presence of nitriles.As previously mentioned, Oshima and coworkers demonstrated the generation of HInCl 2 using InCl 3 /DIBAL-H.We were able to utilize HInCl 2 generated via Oshima's procedure to selectively reduce 4-(bromomethyl)benzonitrile and 4-(chloromethyl)benzonitrile to p-tolunitrile in isolated yields of 85% and 74%, respectively (Scheme 36).Scheme 36.Selective reduction using InCl 3 /DIBAL-H.
It is well established that DIBAL-H can partially reduce nitriles to aldehydes. 37Interestingly, DIBAL-H selectively and partially reduces 4-(bromomethyl)benzonitrile and 4-(chloromethyl)benzonitrile to the corresponding aldehydes in very good yields (Scheme 37).Scheme 37. Selective partial reductions using DIBAL-H.Sequential addition of two equivalents of DIBAL-H followed by addition of InCl 3 afforded an efficient tandem reduction reaction of halo nitriles.The first equivalent of DIBAL-H partially reduced the nitrile functionality while the second equivalent of DIBAL-H, in conjunction with InCl 3 , reduced the carbon-halogen bond.This was exemplified by the tandem reduction of 4-(bromomethyl)benzonitrile and 4-(chloromethyl)benzonitrile to 4-methylbenzaldehye in 67% and 63%, respectively (Scheme 38).

Conclusions
Generation of HInCl 2 using a variety of hydride sources, such as: Bu 3 SnH, Et 3 SiH, NaBH 4 , DIBAL-H, and MeLAB, is comparatively reviewed.The methods of HInCl 2 generation and the reaction by-products allowed for tailoring of the systems towards tandem, selective and partial reductions of halo nitriles.The InCl 3 /NaBH 4 /THF system was found to efficiently reduce both nitriles and carbon-halogen bonds in a tandem fashion utilizing both HInCl 2 and BH 3 •THF.In comparison, the InCl 3 /NaBH 4 /MeCN system, in which acetonitrile scavenges the in situ generated borane and affords the selective reduction of the carbon-halogen bond in halo nitriles.Similarly, the InCl 3 /MeLAB and the InCl 3 /DIBAL-H systems were also found to selectively reduce the carbon-halogen bond in halo nitriles, while DIBAL-H alone selectively reduced halo nitriles to the corresponding halo aldehyde.The sequential addition of two equivalents of DIBAL-H followed by the addition of an equivalent of InCl 3 allowed the partial reduction of halo nitriles to halo imines and subsequent reduction of the carbon-halogen bond to afford the corresponding aldehyde in a one-pot procedure.

Table of Contents
Tandem, selective, and partial reduction of nitriles and halides using HInCl 2 2.6.1 Tandem reductions using HInCl 2 and BH 3 •THF