Recent Advances in Catalysis Using Organoborane-Mediated Hydride Abstraction

C–H functionalization is widely regarded as an important area in the development of synthetic methodology, enabling the design of more time-and atom-efficient syntheses. The ability of electron-deficient organoboranes to mediate hydride abstraction from  -amino C–H bonds is therefore of great interest, as the reactive iminium and hy-dridoborate moieties generated are able to participate in a range of synthetically useful transformations. In this review, we cover the recent advances made in organoborane-mediated hydride abstraction, and focus on the catalytic applications of electron-deficient boranes in  - or  - functionalization,  ,  -difunctionalization, and the dehydrogenation of amines.


Introduction
Organoboranes are widely used as reagents and building blocks in synthetic chemistry. For example, hydroboranes and borohydrides are often used in reduction chemistry, whereas boronic acids are commonly employed in crosscoupling processes. 1,2 The use of organoboranes as catalysts has also received significant attention whereby the interaction of the Lewis acidic boron atom with a pair of nonbonding electrons or -electron pairs is employed to activate the substrate. [3][4][5] Recent attention has focused on more electron-deficient organoboranes, such as B(C 6 F 5 ) 3 , in catalysis. These more Lewis acidic species can also interact with (C-H) bonds, resulting in hydride abstraction and the formation of a formal carbocation and a borohydride counterion. [6][7][8] When the C-H-bearing substrate is a cyclohexadiene, Wheland-type intermediates are formed, [9][10][11][12] and when dihydropyridines are used, pyridinium salts form (Scheme 1a). 13,14 The most explored reactions of this type are those that involve organoborane-mediated hydride abstraction from -amino C-H bonds, during which iminium borohydride salts 4 are generated (Scheme 1b).
Organoborane-mediated hydride abstraction has been exploited in a variety of reactions that generate iminium salts in situ directly from the corresponding alkyl amines and include organoborane-catalyzed amine-based transfer hydrogenation and dehydrogenation, racemization and isomerization, -functionalization, -functionalization, dual ,-functionalization, and C-N bond cleavage. In this review, we include new developments in organoboranecatalyzed processes involving organoborane-mediated hydride abstraction in amines that have been disclosed since our previous review. 6,[15][16][17] New reactions herein include examples that generate complex amine products via cooperative organoborane-metal catalysis, incorporate hydride shuttles, lead to multifunctionalizations, and allow dehydrogenation of liquid organic hydrogen carriers. We will

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proposed reaction mechanism is initiated by conversion of 10 into borate ion pair 11 in the presence of trityl alcohol or water. Ligand exchange in 11 with alkynyl silane 6 generates trimethylsilanol (12) and alkynyl borate 13. Subsequent transmetalation generates an alkynyl copper intermediate 16 in addition to B(C 6 F 5 ) 3 , which abstracts a hydride from the -N position within amine 5 to generate the iminium hydridoborate ion pair 17. Addition of the alkynyl copper intermediate 16 to the iminium ion produces Npropargylamine 7, while the hydridoborate ion reacts with trityl alcohol 19 to regenerate 11 and complete the catalytic cycle. Impressively, this approach enabled the derivatization of a wide range of N-protected bioactive molecules, such as the antidepressants fluoxetine (cf. 7a) and duloxetine (cf. 7c). The protocol tolerated a range of functional groups, such as protected alcohols, amides, esters, and halogens. For amine substrates with multiple sites of potential hydride abstraction, the regioselectivity of propargylation was attributed to the rapid consumption of short-lived CH 2 iminium ions (derived from B(C 6 F 5 ) 3 -mediated hydride abstraction at N-Me sites) before isomerization to lower energy iminium ions can occur. Furthermore, through employing chiral PyBOX ligand 9b, a variety of N-propargylamines (e.g., 7b) could be accessed with high levels of enantiocontrol (up to 94% ee).
In 2022, Wang and co-workers reported the -furylation of N-methyl-substituted tertiary amines using a borane/gold(I) co-catalytic system (Scheme 3). 19 It was found that a range of tertiary N-methylamines 20 and -alkynylenones 21 could be converted into substituted furans 22 in the presence of B(C 6 F 5 ) 3 and AuCl(PPh 3 ) catalysts. -Furylation occurred regioselectively at N-methyl groups in the presence of N-benzyl groups. The mechanism was proposed to proceed via B(C 6 F 5 ) 3 -mediated -amino hydride abstraction to form an iminium hydridoborate ion 23 with concurrent gold-promoted cycloisomerization of alkynylenone 21 to produce an [Au]-associated furyl 1,3-dipole 24. Borohydride reduction of the furyl cation forms furyl species 25, which then adds to the iminium ion 26 to produce the observed -amino furylation product 22, whilst regenerating the borane and gold catalysts. The procedure could be applied to a range of compounds, including bioactive compounds such as butenafine to yield derivative 22a. The reaction showed good functional group tolerance, including protected alcohols 22b, ethers 22c, trifluoromethyl groups, and halogens. When the iminium ions contained -protons, enamine intermediates were formed and engaged the aurated furans in [3+2] cycloadditions resulting in -and -functionalization (see Section 4).
In 2022, Maulide and co-workers reported the stereoselective synthesis of a variety of azabicyclic structures 36 from enamines 34 (derived from N-heterocycles) and Michael acceptors 35 (Scheme 5). 22 Initially, the two substrates, enamine 34 and Michael acceptor 35, react to form iminium 37. A mixture of B(2,6-F 2 C 6 H 3 ) 3 and the corresponding tetrabutylammonium borohydride salt effectively isomerizes iminium ion 38 to form iminium 41 via a sequence of hydride donation to form 39 followed by hydride abstraction. A similar isomerization was also proposed by Oestreich in the ,′-H silylation of tertiary amines described below (see Scheme 9). Interestingly, the Lewis acid B(2,6-F 2 C 6 H 3 ) 3 is significantly less electron-deficient than B(C 6 F 5 ) 3 , which is almost exclusively used in organoborane-

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mediated hydride abstraction with amines. Other organoboranes, including B(C 6 F 5 ) 3 , BMes(2,6-F 2 C 6 H 3 ) 2 and BPh 3 , failed to yield the desired products, whilst B(2,4,6-F 3 C 6 H 2 ) 3 gave yields of <10%. With the iminium in the correct position, cyclization occurs to give the desired aza-bicycles 36 as single diastereomers in most cases. The reaction tolerated a range of substituents on the Michael acceptor 35 and enamine 34, including different heterocycles (e.g., 36a), ethers, halides and protected alcohols. Nitro or trifluoromethyl ketones could also act as the electron-withdrawing group in 35. Acyclic enamines were amenable to the method, forming highly substituted monocyclic piperidines. Additionally, it was shown that the process could be telescoped from the aldehyde and amine corresponding to the enamine. Impressively, an enantioselective variant was also reported, whereby an enantioselective organocatalyzed Michael addition yielded enantioenriched aldehyde 44 prior to formation of iminium 45. Lewis acid/borohydride catalysis enabled the formation of azabicyclic products (e.g., 36c) with very high enantioselectivity.

-Functionalization of Amines
Our previous review covered organoborane-catalyzed -functionalization of amines, describing reactions such as -silylation, -alkylation, and -deuteration. 6 These reactions occur when the iminium species formed upon hydride abstraction undergoes deprotonation at the -position, yielding reactive enamines. These enamines are capable of acting as nucleophiles, which, if an appropriate electrophile is available, can lead to -functionalization. In this review, we cover new -functionalizations with isatins and Michael acceptors, as well as -silylation.
Yang, Ma and co-workers reported the -functionalization of pyrrolidines 46 with isatins 47 to give substituted pyrrolidines 48 (Scheme 6). 23 The catalytic cycle proceeds via B(C 6 F 5 ) 3 -mediated abstraction of the -N C(sp 3 )-H hydride on pyrrolidine 46. The -proton of the resultant iminium 49 is then removed to form enamine 50 and ammonium borohydride salt 51. Enamine 50 attacks the isatin 47 to form a new C-C bond in 52. Elimination of water then forms unsaturated species 53. Reduction of the iminium moiety in 53 with the hydride from the borohydride counterion forms -functionalized product 48 and regenerates the B(C 6 F 5 ) 3 catalyst. The reaction demonstrated good stereoselectivity and tolerated various functional groups such as halides, nitro groups (e.g., 48a), N-branched alkenes and alkynes (e.g., 48b). The use of diethyl ketomalonate rather than isatin 47 furnished product 48c, where water was not eliminated. It was also possible to dehydrogenate the pyrrolidine products 48 to form pyrroles in situ (see Section 5).
In 2021, Wasa and co-workers studied the application of B(C 6 F 5 ) 3

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or 57 (Scheme 7). 24 The reaction proceeds via B(C 6 F 5 ) 3 -mediated abstraction of the -N C(sp 3 )-H hydride yielding iminium borohydride 59, before deprotonation by a base (e.g., 54 or 56) to give enamine 61. This then undergoes nucleophilic attack on the B(C 6 F 5 ) 3 -activated Michael acceptor 62 forming enolate 63, before reduction by the protonated base and hydridoborate yields the product 56 (path i). Alternatively, enolate 63 can tautomerize to form alternative product 57, with the protonated base/hydridoborate instead reducing the Michael acceptor 55 to yield alkane 58 (path ii). The method showed exceptional functional group tolerance, with examples including ethers, secondary amines, and protected alcohols. Excitingly, the method could also be used to derivatize bioactive compounds, including silyl-protected raloxifene and risperidone to give products 56a and 57a, respectively.
In the same paper, 24 the Wasa group also reported an enantioselective variation of the reaction, using a B(C 6 F 5 ) 3 /Sc(OTf) 3 /PyBOX catalytic system to enable enantioselective C-C bond formation between N-alkylamines and Michael acceptors (Scheme 8). As with the racemic version, the reaction proceeds through B(C 6 F 5 ) 3 -mediated abstraction of the -N C(sp 3 )-H hydride to give iminium borohydride 59. Mechanistic studies suggest that in the next step the borohydride reduces one equivalent of the Michael acceptor, yielding boron enolate 68. Interestingly, kinetic and NMR spectroscopic studies suggest that the rate-limiting step is the proton transfer from the -position to the N-position of the enamine, yielding intermediate 69. This inter-

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mediate then protonates the boron enolate, giving 67 as a by-product, and freeing up the enamine to undergo nucleophilic attack on the Sc-bound Michael acceptor 70, forming enolate 71. Due to the chiral scandium complex, attack selectively occurs on the Michael acceptor. Product 66 can then form by intramolecular proton transfer, whilst product 65 forms upon reduction by a protonated base and the borohydride. As with the racemic version, the reaction showed exceptional functional group tolerance, with examples including trifluoromethyl groups (e.g., 65a), ketones, and protected alcohols. Additionally, bioactive molecules were also derivatized ( cf. 66a and 66b).
In 2021, Oestreich and co-workers reported a B(C 6 F 5 ) 3catalyzed ,′-H silylation of tertiary amines 72, yielding sila analogues of piperidines 74 (Scheme 9). 25 The mechanism proceeds through B(C 6 F 5 ) 3 -mediated abstraction of the -N C(sp 3 )-H hydride in 72, to give iminium borohydride 75, before deprotonation by another equivalent of the amine 72 yields enamine 76 and ammonium borohydride 77. The ammonium borohydride then eliminates H 2 to reform the active B(C 6 F 5 ) 3 catalyst and amine 72. The B(C 6 F 5 ) 3 catalysis can also activate the Si-H bond (cf. 78), creating an Si electrophile that can be attacked by enamine 76 to form a C-Si bond. The resulting iminium 79 can then undergo borohydride-induced tautomerization to give iminium 80, which can be deprotonated by another equivalent of 72 to yield enamine 81 and ammonium borohydride 77. The enamine 81 then proceeds through further B(C 6 F 5 ) 3 -mediated C-Si bond formation, as before, to yield the desired product 74, with the ammonium borohydride 77 evolving H 2 to reform the active catalyst B(C 6 F 5 ) 3 . The reaction tolerated functional groups on the amine starting material such as unprotected phenols (e.g., 74a), halogens, and trifluoromethyl groups, and the silane could also be varied to give unsymmetric silanes (e.g., 74b) and substituted diarylsilanes (e.g., 74c).

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The reaction is proposed to proceed through B(C 6 F 5 ) 3mediated abstraction of the -N C(sp 3 )-H hydride to yield iminium borohydride 85. This can then be deprotonated by a base (e.g., amines 82 or 88) to yield enamine 87, which undergoes nucleophilic addition to the 3H-indol-3-one 83 to give zwitterionic intermediate 88. This can then accept a proton from 86, before borohydride reduction to yield the desired product 84, as well as reforming B(C 6 F 5 ) 3 . Functional group tolerance was demonstrated with ethers (e.g., 84a) and halogens (e.g., 84b), as was various substitution patterns around the aromatic rings. Additionally, the reaction was demonstrated to work with N-butyl-N,N-diethylamine to give amine 84c.

,-Difunctionalization of Amines
,-Difunctionalization of amines facilitated by organoborane-mediated hydride abstraction had not been reported at the time of our previous review, 6 and represents a new reaction class. Here the enamine can participate in cycloaddition reactions resulting in ,-difunctionalization. In this section we will look at how this is leveraged to form cyclobutenes, furan-fused cyclopentenes, and alkyl-aminofunctionalized quinolines.

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tions could also be applied to the derivatization of bioactive compounds, such as in the formation of paroxetine derivative 97d.
In 2022, He, Fan and co-workers reported an ,-functionalization strategy involving anilines 102 and benzo[c]isoxazoles 103 followed by a C-N bond cleavage to furnish functionalized quinoline derivatives 104 (Scheme 13). 28 The catalytic cycle proceeds via B(C 6 F 5 ) 3 , 104a), trifluoromethyl, nitro, ether and thioether groups. The saturated heterocycle in 102 was varied to allow for pyrrolidines, piperidines, azepanes (e.g., 104b), and even azocanes and azonanes to all be used in the protocol. Acyclic examples such as diethylaniline and dipropylaniline were used to furnish quinoline 112 and 3-methylquinoline respectively. When ethyl 1-phenylpiperidine-4-carboxylate was used, a further intermolecular condensation of the secondary amine and ester group delivered product 113 with a lactam moiety.

Dehydrogenation of Amines
In our previous review, 6 we observed how hydride abstraction had been utilized in the dehydrogenation of a variety of benzofused N-heterocycles, 29 as well as the dehydrogenative coupling of indoles with silanes and boranes. These reactions are believed to proceed via an acceptorless dehydrogenation pathway, where an ammonium borohydride intermediate (generated after hydride abstraction and iminium tautomerization) undergoes an acid-base reaction to evolve H 2 . We have also seen a few examples of H 2 evolution in several of the examples described above. Here, we look at the dehydrogenation of -functionalized pyrrolidines, and how the dehydrogenation of tetrahydroquinolines has been utilized for hydrogen storage and purification.
In the report from Yang, Ma and co-workers described in Section 3 on the -functionalization of pyrrolidines 46 with isatins 47, a pyrrolidine acceptorless dehydrogenation process was also reported. 23 The products of the aforementioned -functionalization of pyrrolidines 48 were converted into pyrroles 114 (Scheme 14). Simply increasing the temperature of the standard -functionalization conditions led to the formation of pyrroles. The authors proposed that the mechanism proceeds through B(C 6 F 5 ) 3 -mediated hydride abstraction on product 48 (as formed above in Scheme 6) to form iminium species 115. Isomerization of 115 into 117 (or 116) creates an acidic proton that reacts with the borohydride counterion, causing aromatization, loss of H 2 and reformation of B(C 6 F 5 ) 3 . Functional group tolerance was demonstrated for the two-step procedure with nitro groups (e.g., 114a), halogens, alkenes (e.g., 114b), and ethers (e.g., 114c).
Ogoshi, Hoshimoto and co-workers have reported an organoborane-catalyzed dehydrogenation applied to the purification of molecular hydrogen (Scheme 15). 30

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A selection of organoboranes was shown to mediate the dehydrogenation of tetrahydroquinoline 118 to form quinoline 119 in high yield. Organoborane derivatives based on (2,6-dichlorophenyl)bis(2,6-difluorophenyl)borane (e.g., 120-122), were shown to be optimal for the dehydrogenation of 118, with the brominated derivative 120 performing across both dehydrogenation and hydrogenation steps (see below). Whilst no mechanism for the dehydrogenation was proposed, it is likely that the reaction proceeds in a manner analogous to the acceptorless dehydrogenations encountered above (e.g., Scheme 13, conversion of 102 into 106) and in our previous review. 6 The ability of organoboranes to mediate dehydrogenation via hydride abstraction was applied to the purification of hydrogen from gaseous mixtures via a hydrogenation-dehydrogenation sequence. Hydrogen was removed from a mixture of H 2 , CO and CO 2 and incorporated into tetrahydroquinoline 118 via frustrated Lewis pair hydrogenation of quinoline 119. 31 Tetrahydroquinoline 118 was easily removed from the gas mixture, and separately dehydrogenated with borane 120, concurrently form-ing high purity H 2 gas. Interestingly, the ubiquitous B(C 6 F 5 ) 3 borane performed significantly worse in the initial hydrogenation step due to competing reactions with the H 2 /CO/CO 2 mixture, as well as in the dehydrogenation step (88% vs 18% of 119).

Summary and Future Prospects
In this review update, we have covered the recent advances made in organoborane-mediated hydride abstraction. We have shown that various Lewis acidic borane catalysts are able to mediate hydride abstraction from -amino C-H bonds to yield a reactive iminium cation and a hydridoborate anion. These have been demonstrated to participate in a range of synthetically useful transformations, including -or -functionalization, ,-difunctionalization, and the dehydrogenation of amines. It has become clear that further investigations are needed around the structure and electronic properties of the organoborane catalyst, as subtle changes play an important role in catalyst performance, as underscored by the work of Maulide, 22 Wang, 27 and Ogoshi and Hoshimoto 30 described above. The repurposing of common amine starting materials for novel transformations is an important area in synthetic chemistry and we envision that further development in the area of orga-