Review

Applications of Acceptorless Dehydrogenation and Related Transformations in Chemical Synthesis

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Science  19 Jul 2013:
Vol. 341, Issue 6143, 1229712
DOI: 10.1126/science.1229712

Structured Abstract

Background

Acceptorless dehydrogenation (AD) reactions can result not only in simple removal of hydrogen gas from various substrates but also, importantly, in surprisingly efficient and environmentally benign (“green”) synthetic methodologies when intermediates resulting from the initial dehydrogenation process undergo further reactions.

Advances

Traditionally, dehydrogenation/oxidation reactions of organic compounds have been performed using stoichiometric amounts of inorganic oxidants, in addition to employing various additives, cocatalysts, and catalytic systems that result in generation of copious stoichiometric, often toxic, waste. Catalytic transfer hydrogenation methods, in which stoichiometric amounts of sacrificial organic acceptor compounds are used, also generate stoichiometric amounts of organic waste. Recent developments in catalysis by metal complexes have resulted in acceptorless dehydrogenation reactions that release hydrogen gas and in related reactions in which dehydrogenation is followed by in situ consumption of the generated hydrogen equivalents and no net hydrogen gas is liberated. These reactions circumvent the need for conventional oxidants or sacrificial acceptors and provide an assortment of applications in organic synthesis, including several methods based on further reactivity of the dehydrogenated intermediate compounds. Moreover, the evolved hydrogen gas is valuable in itself.

Outlook

Further development of new ADs for green, efficient chemical synthesis is expected to be greatly influenced by fundamental organometallic chemistry as a basis for catalyst design. Such processes are highly desirable and are expected to gradually displace elaborate conventional laboratory and industrial synthetic methods. They may also provide opportunities for hydrogen storage cycles, because the dehydrogenation reactions can be reversed under hydrogen pressure using the same catalyst. In general, AD and related dehydrogenative coupling reactions have the potential for redirecting synthetic strategies to the use of sustainable resources, devoid of toxic reagents and deleterious side reactions, with no waste generation.

Embedded Image

Dehydrogenation strategies in organic synthesis. (A) Successive AD with release of hydrogen gas. The catalyst liberates H2 from both starting compound and intermediate, exemplified by dehydrogenative coupling of primary alcohols with amines to form amides. (B) AD with H2 and water release. A dehydrogenated intermediate couples with nucleophiles, exemplified by dehydrogenative coupling of alcohols with amines (liberating water) to form imines that can be isolated or carried on to products such as pyrazines. (C) Borrowing hydrogen. The catalyst dehydrogenates the substrate and formally transfers the H atoms to an unsaturated intermediate, exemplified by coupling of ammonia or amines with alcohols to form new amines, liberating water, but not H2. (D) Coupling of redox pairs. Dehydrogenation generates an electrophile and a nucleophile that react to form C−C bonds. Neither H2 nor water is evolved.

Setting Hydrogen Free

Oxidation of organic compounds has traditionally been considered to involve the transfer of hydrogen atoms in the molecular framework to an oxidant such as O2, peroxide, or a metal oxide complex. Gunanathan and Milstein (p. 1229712) review the ongoing development of an alternative process, in which a catalyst coaxes the H atoms to depart on their own in the form of H2. These acceptorless dehydrogenations are appealing because they generate so little waste. In one class of reactions, the liberated H2 gas is actively expelled from the reaction mixture and collected for potential use elsewhere. In another class, the H atoms return to the source molecule after it has undergone an intermediate transformation in their absence.

Abstract

Conventional oxidations of organic compounds formally transfer hydrogen atoms from the substrate to an acceptor molecule such as oxygen, a metal oxide, or a sacrificial olefin. In acceptorless dehydrogenation (AD) reactions, catalytic scission of C−H, N−H, and/or O−H bonds liberates hydrogen gas with no need for a stoichiometric oxidant, thereby providing efficient, nonpolluting activation of substrates. In addition, the hydrogen gas is valuable in itself as a high-energy, clean fuel. Here, we review AD reactions selectively catalyzed by transition metal complexes, as well as related transformations that rely on intermediates derived from reversible dehydrogenation. We delineate the methodologies evolving from this recent concept and highlight the effect of these reactions on chemical synthesis.

Anticipation of fossil fuel depletion and growing environmental concerns urge chemists and chemical industries to search for alternative raw materials and for atom-economical, environmentally benign synthetic methods. In this context, acceptorless dehydrogenation (AD) reactions, in which hydrogen is liberated and new bonds prospectively generated by further reactions of the dehydrogenated products, are emerging as a powerful approach, circumventing the need for stoichiometric oxidants or prefunctionalization of substrates.

Removal of hydrogen atoms from adjacent atomic centers of a hydrogen-rich organic molecule is in most cases a thermodynamically unfavorable process. Thus, dehydrogenation of organic compounds often requires stoichiometric or excess molar amounts of oxidants such as oxygen, peroxides, iodates, and metal oxides (Fig. 1A) or sacrificial hydrogen acceptors (Fig. 1B), leading to wasteful by-product generation. In the more atom-economical AD reaction, molecular hydrogen must be effectively removed from the reaction mixture to drive the equilibrium toward the products (Fig. 1C). Alternatively, the liberated hydrogen can also be used in situ to hydrogenate unsaturated intermediates generated from a condensation reaction.

Fig. 1 Classes of dehydrogenation reaction.

(A) Dehydrogenation/oxidation by conventional oxidants. (B) Hydrogen-transfer reactions. Liberated hydrogen binds to a sacrificial acceptor molecule. (C) AD. Dehydrogenation leads to liberation of hydrogen gas, which is removed from the reaction mixture under reflux conditions or by vacuum.

Our group has developed a class of AD reactions in which the catalyst dehydrogenates both the starting compound and an intermediate compound, leading to the net-oxidized product with liberation of two equivalents of hydrogen (Fig. 2A). Reactions have also been developed in which both liberation of hydrogen and elimination of water take place (Fig. 2B). In a related class of reactions, termed the “borrowing hydrogen” approach, the catalyst hydrogenates an intermediate using the hydrogen removed from the starting compound. This method is also called “hydrogen autotransfer” (Fig. 2C); it does not involve net hydrogen evolution, and the overall process is redox neutral. Dehydrogenation reactions can also couple a redox pair such as an alcohol and an alkene, to provide products of formal alcohol C−H functionalization; upon alcohol dehydrogenation (in the presence of catalytic base), the generated metal hydride intermediate adds to the alkene to give a nucleophilic metal alkyl, followed by reaction of the latter with the intermediate keto compound to form a C–C bond (Fig. 2D). AD reactions provide environmentally benign synthetic methodologies for the preparation of an assortment of useful products, in addition to the generation of valuable hydrogen gas. For example, amines and amides, which are traditionally prepared by multistep processes using stoichiometric amounts of activating reagents, can be obtained in a single synthetic step from alcohols with minimal waste by means of AD.

Fig. 2 Dehydrogenation strategies in organic synthesis, exemplified by reactions of alcohols.

(A) Successive AD with release of hydrogen gas. The catalyst liberates H2 (the sole by-product) from both starting compound and intermediate generated by reaction with a nucleophilic substrate. “Catalyst-H2” indicates formal abstraction of two hydrogen atoms by the catalyst. (B) AD with hydrogen and water release. An intermediate formed by dehydrogenation of the starting compound can couple with nucleophiles; the resulting products can be isolated or can undergo further addition or cyclization reactions with or without further H2 liberation. (C) Borrowing hydrogen. The catalyst dehydrogenates the substrate at the outset and formally transfers the H atoms to an unsaturated intermediate. Hydrogen gas is not evolved, and the reaction often involves elimination of water as a by-product. (D) Coupling of redox pairs. The catalyst dehydrogenates the substrate to generate an electrophile and metal-hydride; addition of the latter to an unsaturated substrate forms a nucleophilic metal alkyl that reacts with the electrophile to form a C–C bond. Neither hydrogen gas nor water are produced.

Because X−H bonds (X = C, O, or N) are ubiquitous among organic molecules, selective AD followed by further tandem functionalization can provide a diverse stream of products. This strategy has been achieved mostly as a result of advancement in the field of catalysis by transition metal complexes. Dehydrogenation reactions classified by the substrates and catalysts have been reviewed (13). Here, we highlight AD reactions catalyzed by soluble transition metal complexes from the perspective of the strategies outlined in Fig. 2, with particular emphasis on selective coupling reactions leading to useful products efficiently and atom-economically.

Precursors to Modern AD

In organic synthesis, the oxidation/dehydrogenation is carried out using conventional methods, which use stoichiometric amounts or excess of inorganic oxidants such as chromium(IV) reagents (4), pressurized oxygen (5), or peroxides, in addition to employing various additives, cocatalysts, and catalytic systems combined with metal complexes and TEMPO (2,2,6,6-tetramethylpiperidinyl-1-oxy) that result in stoichiometric waste generation, which is undesirable environmentally and economically (6). In addition, pressurized oxygen and peroxides pose explosion hazards. To circumvent these problems, dehydrogenation methods without use of conventional oxidants were developed. Early investigations of AD emanated from heterogeneous catalysis. Dehydrogenation of linear primary alcohols resulted in β-branched primary alcohols as a result of condensation of the intermediate aldehydes followed by dehydration and hydrogenation, as reported in the late 1800s by Guerbet, much before hydrogen-transfer reactions were reported (7). The simple hydrogen-transfer reaction has its origin in the Oppenauer oxidation of secondary alcohols to ketones in the presence of acetone, mediated by aluminum tert-butoxide (8) and later catalyzed by transition metal complexes. Hydrogen transfer using alkanes as the hydrogen source is much more difficult due to the generally unreactive C−H bonds. In 1979, Crabtree achieved stoichiometric dehydrogenation of alkanes using a cationic iridium(III) metal complex (9) in the presence of a hydrogen acceptor. Pioneering examples of catalytic alkane hydrogen-transfer reactions by soluble complexes were independently reported by Felkin and colleagues (10) and Crabtree and colleagues (11).

Alkane Dehydrogenation

In pioneering work, Aoki and Crabtree reported AD of cyclooctane using [IrH2(O2CCF2CF3)(PCy3)] as catalyst, which gave 36 turnovers to cyclooctene under reflux conditions (12). Stability of the applied homogeneous catalysts at higher temperatures, which is essential for these reactions, severely limited scope and efficiency. However, an efficient AD reaction was achieved by Xu et al. (13) using the Ir(PCP) pincer complex 1a (Fig. 3A). Later, the sterically less-crowded complex 1b developed by Liu and Goldman provided close to 1000 turnovers in AD of cyclooctane; linear alkanes were also dehydrogenated (14). The high thermal stability of pincer complexes, coupled with the effectiveness of iridium complexes in C−H activation, resulted in catalysts 1a and 1b being the most effective complexes for AD of alkanes.

Fig. 3 Examples of dehydrogenation.

(A) Dehydrogenation of an alkane catalyzed by iridium pincer complexes. (B) Dehydrogenation of primary and secondary alcohols by conventional oxidants. (C) Dehydrogenation of secondary alcohols by well-defined ruthenium and iridium complexes. (D and E) Dehydrogenation of primary alcohols. (D) Synthesis of aldehydes. (E) Synthesis of aldehydes and ketones in water solution.

Alcohol Dehydrogenation

Traditionally, alcohol oxidations are primarily performed using toxic strong oxidants such as periodates or chromium oxides, which generate toxic stoichiometric waste (4, 6). Greener alternatives have also been developed (15). For example, a method of TEMPO-catalyzed dehydrogenation of alcohols with sodium hypochlorite has been developed and commonly used in both small- and large-scale applications (Fig. 3B). However, the method suffers from the need for a stoichiometric amount of sodium hypochlorite, the need for a cocatalyst [e.g., 10 mole percent (mol %) NaBr] in addition to the use of chlorinated solvents, and the equivalent amount of sodium chloride produced for every molecule of alcohol dehydrogenated (16). In contrast, several examples of oxidant-free catalytic AD of secondary alcohols to the corresponding ketones were reported (Fig. 3C) in which hydrogen gas is the only by-product. Early examples required the presence of an acid as a hydride ion acceptor (1720). The ruthenium PNP [2,6-bis-(di-tert-butylphosphinomethyl)pyridine] pincer complex 2, reported by our group, catalyzes the dehydrogenation of secondary alcohols using low catalyst loading, demonstrating the potential of pincer complexes in the dehydrogenation of alcohols (21). However, complex 2 required activation by a base. The modified catalysts 3a and 3b can catalyze the reaction under neutral conditions using low loading of 0.1 mol % (22). The iridium complexes 4 (23) and 5 (24) also catalyze this reaction. The catalytic activity of 5 is comparable to that of ruthenium complex 3b, whereas complex 4 shows higher efficiency. In addition to the synthetic potential, the dehydrogenation of secondary alcohols to ketones is also of interest from the point of view of hydrogen production from simple and biorenewable alcohols. Combining the ruthenium precursor [RuH2(CO)(PPh3)3] [used earlier for this reaction (20)] with PNP-type pincer ligands was shown to be highly effective in hydrogen production from iso-propanol (25).

AD of primary alcohols to yield the corresponding aldehydes (Fig. 3, D and E) is less common, as often ruthenium complexes are deactivated by decarbonylation of the aldehydes. Synthesis of aldehydes from alcohols was reported recently by Fujita and Yamaguchi (26) using the iridium catalyst 6a. The modified water-soluble catalyst 6b catalyzes the dehydrogenation of both secondary and primary alcohols in water. This catalyst family operates by a mechanism involving metal-ligand cooperation (27, 28).

Dehydrogenative Coupling of Alcohols to Form Esters

Esterification is one of the most important fundamental reactions in synthetic organic chemistry, with applications in the production of an assortment of fine chemicals ranging from fragrances to pharmaceuticals. Elaborating on the dehydrogenation of secondary alcohols catalyzed by complex 2, rational design of the pincer complexes 7-9, based on metal-ligand cooperation involving aromatization-dearomatization sequences of the pyridine-based ligand (see Fig. 5G), resulted in the direct catalytic dehydrogenative coupling of primary alcohols to esters with high efficiency (Fig. 4A) (29). The aromatic, coordinatively saturated complexes 7 and 8 require the presence of a catalytic amount of a base, for in situ generation of the corresponding dearomatized complexes by deprotonation, which are the actual catalysts. Installing a hemilabile amine arm, which can play an important role in the catalytic cycle by opening a coordination site, resulted in precatalyst 8. Treatment with a base affords unsaturated, dearomatized complex 9, an excellent catalyst for dehydrogenative coupling of alcohols to form esters with liberation of H2 under neutral conditions. Only traces of aldehydes are formed.

Fig. 4 Direct synthesis of esters from alcohols.

(A) Synthesis of esters by dehydrogenative coupling of primary alcohols. These reactions are catalyzed by the rationally designed dearomatized, unsaturated PNN pincer complex 9, and its precursor 8, as well as the less reactive PNP complex 7. (B to F) Application of alcohol dehydrogenative coupling reactions under acceptorless conditions. (B) Synthesis of esters from cross-coupled primary and secondary alcohols. (C) Synthesis of mixed esters by transesterification of esters using secondary alcohols. (D) Synthesis of lactones from diols. (E) Synthesis of polyesters from diols. (F) Synthesis of carboxylic acid salts from alcohols using water.

This catalytic reaction provides an efficient, atom-economical, environmentally friendly pathway for the synthesis of esters. It can be carried out in a solvent or with neat liquid reagents. Previous examples of dehydrogenative coupling of alcohols to esters were considerably less efficient (3032). Shvo’s catalyst provided benzyl benzoate and pentyl pentanoate from the corresponding neat alcohols at 137° to 145°C, although yields and reaction times were not reported (31). Murahashi demonstrated dehydrogenative coupling of various alcohols to esters using RuH2(PPh3)3 (2 mol %) in refluxing mesitylene (180°C) for 24 hours (32). The acridine catalyst 10 prepared by our group also catalyzes this transformation in the presence of a catalytic amount of base in refluxing solvent or under neat conditions (33). Complexes 3a and 3b (22), as well as the PNS [2-((tert-butylthio)methyl)-6-((di-tert-butylphosphino)methyl)pyridine] pincer ruthenium complex [(PNS)RuHCl(CO)] (34), analogous to complex 8, and the iridium complex 5 (24) also catalyze the dehydrogenative esterification of alcohols. Catalytic conversion of ethanol, a biorenewable alcohol, to ethyl acetate and molecular hydrogen is of particular interest because ethyl acetate is a widely used industrial bulk chemical. In this context, further fine-tuning of steric and electronic factors of the pincer backbone (35, 36) and screening of known pincer complexes (37) provided efficient catalysts.

Dehydrogenative cross-coupling of primary with secondary alcohols to form mixed esters was achieved for an assortment of primary and secondary alcohols, in a molar ratio of 1/2.5, using the bipyridine-based, dearomatized catalyst 12 (Fig. 4B) (38). In general, transesterification (ester to ester transformation) is not an atom-economical process, because it produces, in addition to the desired ester, an equivalent amount of alcohol. Our group has developed a distinct mode of transesterification, in which hydrogen gas is formed as a by-product, rather than alcohols, upon reaction of esters with secondary alcohols catalyzed by complex 9 (Fig. 4C). When symmetrical esters (i.e., having the same R groups) are used, both the acyl and alkoxy fragments of the substrate ester are incorporated into the product ester with liberation of hydrogen (39). This cross-selectivity is a result of slower dehydrogenation of the secondary alcohol to the corresponding ketone as compared with the dehydrogenative coupling of the primary alcohol to ester. Diols can undergo an intramolecular reaction to provide the corresponding lactones with hydrogen liberation (22) with complex 3b as catalyst (Fig. 4D).

Currently practiced methods for the synthesis of polyesters are generally not atom-economical and not environmentally benign. They are normally based on carboxylic acid derivatives, prepared using toxic reagents and generating toxic by-products and salts; subsequent polycondensation with diols also generates salt waste, which can be challenging to remove from viscous polymer solutions, often resulting in low conversion and poor polymer properties. By using the in situ–generated complex 9 (from commercially available complex 8) as a catalyst, Robertson and colleagues have demonstrated a remarkable process (40) for the synthesis of polyesters from diols (Fig. 4E). Efficient removal of the generated hydrogen was achieved by performing the polymerization reaction under reduced pressure, resulting in formation of high-molecular-weight polyesters.

Very recently, primary alcohols were oxidized by our group to the corresponding carboxylic acid salts using water as the terminal oxidant, with liberation of hydrogen (41). The precatalyst 11 was used for the in situ generation of catalyst 12 (Fig. 4F), which catalyzes this transformation under acceptorless conditions. Interestingly, water plays the role of both oxygen donor and reaction medium. Complex 9 is also known to stoichiometrically split water, by consecutive thermal H2 and light-induced O2 generation (42).

Dehydrogenative Coupling of Alcohols with Amines to Form Amides

Intermolecular dehydrogenative coupling of alcohols with amines is the most atom-economical method for amide synthesis (43). However, this catalytic reaction was difficult to envision, since hemiaminal formation was expected to follow alcohol dehydrogenation. Subsequent spontaneous water elimination would then form an imine that could undergo hydrogenation with the liberated H2 to yield a secondary amine (from primary amine reagents). We discovered that this transformation (44) could indeed be catalyzed by the dearomatized pincer complex 9 (Fig. 5A). A range of alcohols reacted with alkyl and aryl amines and diamines to produce amides with liberation of hydrogen under low catalyst loading (0.1 mol %). Moreover, the reactions are selective toward the primary amine functionality under these conditions. Following this discovery, a number of catalytic systems were reported for this transformation with various ruthenium precursors in combination with carbene and/or phosphine ligands, although these systems required higher loading of metal complex and ligands in addition to the need for substoichiometric amounts of base; selected examples (4547) are given in Fig. 5B.

Fig. 5 Direct synthesis of amides from alcohols and amines.

(A) Discovery of dehydrogenative coupling of alcohols with amines to form amides with liberation of hydrogen, catalyzed by the pincer complex 9. (B) Selected examples of other catalytic systems developed later for the same transformation. (C to F) Applications of catalyst 9 in acceptorless dehydrogenative coupling processes involving amines. (C) Synthesis of amides from esters and amines. (D) Synthesis of a chiral amide from (S)-2-amino-3-phenylpropan-1-ol and benzylamine. (E) Synthesis of cyclic dipeptides from β-amino-alcohols. (F) Synthesis of polyamides from diols and diamines. (G) Metal-ligand cooperation by facile aromatization and dearomatization sequences (highlighted in blue). The dearomatized ligand participates in various bond activation and reversible bond-formation reactions and plays a key role in catalysis.

Synthesis of amides from esters and amines is also a potentially attractive method. Complex 9 efficiently catalyzes this transformation (Fig. 5C) with liberation of H2 under neutral conditions (48). Similar to the alcohol acylation process (Fig. 4C), both the acyl and alkoxo fragments of the symmetrical esters are incorporated in the amide product. One outcome of this reaction is that ethyl acetate, a cheap and abundant ester, can be used as a convenient, atom-economical acetylation agent of amines, producing hydrogen as the only by-product; this is clearly advantageous over the commonly employed acetylation agents. Amino alcohols also participate in the acylation of amines. Gratifyingly, chiral amino-alcohols react with retention of configuration (Fig. 5D), a likely attribute of the neutral reaction conditions (49). As complex 9 catalyzes the amidation of amines using amino-alcohols, we reasoned that use of amino-alcohols alone might result in formation of linear or cyclic peptides. Indeed, complex 9 catalyzes the conversion of various amino-alcohols (bearing substituents larger than methyl α to the amine group) to the corresponding cyclic dipeptides (diketopiperazines) as the only products in very good yields with liberation of H2 (Fig. 5E). In the case of alaninol, oligopeptides were formed. Using catalyst 9, we have also developed the catalytic synthesis of polyamides (50) from diols and diamines. Before we published this work, Zeng and Guan reported (51) the direct polyamidation reaction using the now commercially available catalyst 9. Optimization studies by them revealed the need for polar solvents for successful polymerization of diols and diamines, anisole being a suitable polar solvent, resulting in high number-average molecular weights (Mn) of the polyamides (3.2 kD in toluene versus 13.8 kD in anisole). Mn of the polyamides were further improved (22.6 kD) by the addition of small amounts of dimethyl sulfoxide. Polymers bearing secondary amine groups in the backbone, potentially useful for gene delivery, were obtained by Zeng and Guan (51), with no need for a wasteful protection-deprotection sequence, due to the selectivity of 9 toward the amidation of primary amine groups (Fig. 5F).

Ru-pincer complexes (7 to 12) developed by our group are believed to operate by a mode of metal-ligand cooperation (Fig. 5G) involving aromatization-dearomatization of the pincer ligand (52, 53). Dearomatized pincer complexes can activate primary alcohols, yielding the corresponding saturated hydrido alkoxo complexes, with aromatization. The mechanism of further dehydrogenation of the alkoxy ligand, which could follow β-hydride elimination, remains unclear at this stage (54). However, esterification and amidation reactions likely proceed through hemiacetal and hemiaminal intermediates, respectively, formed by nucleophilic attack by the alcohol or amine on an intermediate aldehyde that is either coordinated to the metal or free in solution (55, 56). Catalyst 9, and its bipyridine analog 12, also effectively catalyze under mild conditions the hydrogenolysis reactions of esters to alcohols (57), amides to alcohols and amines (58), and the hydrogenation of the CO2-derived organic carbonates and formates as mild, green, two-step routes to methanol (when dimethyl carbonate or methyl formate are used) (59). Methyl carbamates and urea derivatives were also hydrogenated to alcohols and amines under mild conditions (60). Density functional theory (DFT) calculations carried out by other groups on our amidation reaction (55, 56) and on the microscopic reverse, hydrogenation of amides (61), further support the involvement of suggested intermediates.

Dehydrogenative Coupling with Concomitant Condensation Reactions

The acridine pincer ruthenium catalyst 10 catalyzes the conversion of alcohols to acetals in very good yields, liberating hydrogen and water (Fig. 6A) (33, 62). The reaction proceeds via enol-ether intermediates, which upon further alcohol addition yield acetals. The recently developed ruthenium complex 14 also catalyzes this transformation (63).

Fig. 6 Acceptorless dehydrogenative coupling reactions that proceed with loss of water.

(A) Direct synthesis of acetals from alcohols. (B) Synthesis of imines from alcohols and amines. (C) Synthesis of pyrazines from amino-alcohols. (D) Synthesis of pyrroles from diols and amines. (E) Three-component synthesis of pyrroles. (F) Synthesis of pyrroles from alcohols and amino-alcohols.

The RuPNP pincer complex 15 catalyzes the dehydrogenative coupling of alcohols with amines, unexpectedly leading to imine products (Fig. 6B) rather than to amides, as catalyzed by the analogous RuPNN complex 9 [PNN is (2-(di-tert-butylphosphinomethyl)-6-diethylaminomethyl)pyridine] (64). It is possible that in the case of complex 15, intermediate aldehyde dissociates from the metal complex, forming free hemiaminal in solution, whereas in the case of 9, a coordinated aldehyde is attacked by the amine and no free hemiaminal is involved. The reason for the discrepancy might be a lack of the hemilabile amine “arm” and higher steric hindrance in 15. The free hemiaminal eliminates water, providing a method for the synthesis of imines, with no subsequent hydrogenation to the corresponding amines. DFT calculations on imine formation catalyzed by 15 are in line with the observed selectivity (65). An analogous RuPNP catalyst with amine-based pincer “arms” (66), a Ru-carbene complex (67), and an OsPOP [POP is 4,6-bis(diisopropylphosphino)dibenzofuran] complex (68) were also later reported to catalyze this transformation. Using amino alcohols, complex 15 catalyzes formation of pyrazines (Fig. 6C). Apparently, the reaction proceeds through a cyclic-diimine intermediate, which undergoes further dehydrogenation to provide the aromatic pyrazines (49). Dehydrogenative coupling of diols and amines can lead to pyrroles. Thus, reaction of 2,5-hexandiol and alkylamines catalyzed by complex 13 in the presence of sodium formate resulted in formation of N-alkyl-2,5-dimethylpyrroles in a dehydrogenative Paal-Knorr pyrrole synthesis (Fig. 6D) (46). Very recently, synthetic approaches to pyrroles were reported, based on alcohol dehydrogenation, imine formation, and base-promoted condensation. Thus, Ru3(CO)12 with an added diphosphine and a base catalyzes the reaction of 1,2 diols with amines and ketones, resulting in a variety of functionalized pyrroles (Fig. 6E) (69). The IrPNP complex 16, developed by Michlik and Kempe, in the presence of base catalyzes the dehydrogenative coupling of β-amino-alcohols with secondary alcohols to form pyrroles; the proposed mechanism involves ketimine formation from the ketone and amino-alcohol, followed by Ir-catalyzed dehydrogenation and base-promoted condensation to result in elegant synthesis of pyrroles in very good yields with diverse substituents (Fig. 6F) (70). This reaction is also efficiently catalyzed by the bipyridine-based RuPNN complex 11, following a similar mechanism, as reported by our group very recently (71).

Alkane Metathesis

Combining alkane dehydrogenation and the borrowing approach, Goldman, Brookhart and co-workers achieved alkane metathesis in a three-step tandem sequence using two different catalysts (72). The iridium complex (17) dehydrogenates alkanes in the first step to produce the respective alkenes, which are converted into either longer or shorter alkenes by the Mo-based Schrock metathesis catalyst (18) in the second step. The hydrogen obtained in the first step hydrogenates the alkenes, thus providing a near thermodynamically neutral process (Fig. 7). Although the terminal alkene is the kinetic dehydrogenation product, isomerization of the double bond along the chain and then cross metathesis of the isomerized products lead to a broad distribution of hydrocarbons.

Fig. 7 Alkane metathesis via borrowing methodology.

(A) General strategy. Catalytic C–H activation is coupled with catalytic olefin metathesis for net alkane metathesis. (B) Metathesis of n-hexane by 17a or 17b and 18.

Alkylation of Amines by Borrowing Hydrogen Methodology

The limited reactivity of alcohols toward nucleophiles can be readily overcome upon dehydrogenation to the corresponding carbonyl compounds, which are amenable to nucleophilic addition reactions (Fig. 2) (73). Nitrogen-containing compounds, ranging from primary amines to heterocycles, were obtained using the metal-catalyzed, alcohol-borrowing hydrogen pathway (Fig. 8) (74). In pioneering work, Grigg et al. reported that [RhH(PPh3)4] catalyzed N-alkylation of amines by alcohols (Fig. 8C) (75). Murahashi et al. and Tsuji et al. reported catalysis by ruthenium complexes for the preparation of a range of secondary and tertiary amines (76), including indoles (Fig. 8E) (77). Selective synthesis of primary amines from ammonia and electrophiles is a challenging task, because the primary amine intermediate is more nucleophilic than ammonia, and it undergoes competing alkylation reactions when conventional alkylating reagents such as alkyl halides are used, resulting in a mixture of products. Alkylation of amines by the borrowing hydrogen pathway can circumvent this problem, and selectivity could be reached by a suitable choice of ligands and catalyst design. For example, primary amines were selectively synthesized by our group from primary alcohols and ammonia, using the acridine-derived ruthenium pincer complex 10 under mild conditions and low catalyst loading (Fig. 8A); selectivity in this case is enhanced by the steric bulk around the metal center, lending preference to ammonia coordination. Reactions can also be performed using water as reaction medium, resulting in enhanced selectivity (78). Recently, 10 was also used as a catalyst for the preparation of diamines from the diols derived from vegetable oils (79). Secondary alcohols could also be employed using different ligands and metal precursors (80, 81). Secondary and tertiary amines were selectively obtained from ammonium salts (Fig. 8B) and primary alcohols using an iridium complex by Fujita and colleagues (82, 83) and Eary and Clausen (84). Beller and co-workers developed phosphine ligands that, in combination with Ru(0), were effective catalysts for the synthesis of tertiary amines (Fig. 8D) (85). In general, ruthenium and iridium complexes were found to be good catalysts for alkylation of amines as well as amides (86). Whereas reaction of ammonia and primary amines with carbonyl compounds proceeds by imine intermediates, use of secondary amines leads to the formation of iminium ion intermediate. Both imine and iminium ion intermediates are hydrogenated by the catalyst using the hydrogen obtained from starting alcohols to deliver the primary or secondary and tertiary amines, respectively.

Fig. 8 Alkylation of amines using alcohols.

Products targeted include (A) primary amines, (B) secondary amines, (C and D) tertiary amines, and (E) heterocycles, all with very good selectivities.

Williams and co-workers have demonstrated that borrowing hydrogen tactics can be applied in alkylation processes often used in the synthesis of drugs (Fig. 9A); on the laboratory scale, they obtained various pharmaceuticals employing alcohols in place of conventional alkyl halides (87). Berliner reported the synthesis of PF 03463275, a GlyT1 inhibitor developed for the treatment of schizophrenia, by applying the borrowing-hydrogen methodology on a multikilogram scale (88), with (Cp*IrCl2)2 as catalyst (Fig. 9B). The strategic advantage of the borrowing hydrogen methodology was also applied in the synthesis of natural products such as noranabasamine (89), isolated from the dart frog (Fig. 9C). A combination of RuHCl(CO)(PPh3)3 and xantphos ligand was used by Beller and co-workers for the selective diamination of isosorbide, which is obtained from d-glucose (81). The versatility of the alkylation of amines by borrowing-hydrogen methodology allowed the preparation of primary, secondary, and tertiary amines from alcohols, including biomass-derived alcohols (3, 85). Because the methodology is already being adopted in large-scale synthesis and tolerates various functional groups, it is well on its way to displacing the conventional alkylation reactions in organic synthesis that rely on alkyl halides.

Fig. 9 Application of the borrowing hydrogen methodology.

(A) Laboratory synthesis of various pharmaceuticals. (B) Demonstration on multi-Kg scale. (C) Application in total synthesis of a natural product.

Alcohols as a Source of Electrophiles and Nucleophiles

Construction of C−C bonds through the borrowing-hydrogen concept has been achieved using two different approaches, in which the alcohols are modified to manifest either electrophilic or nucleophilic reactivity. Upon alcohol dehydrogenation, the generated carbonyl compounds can act as electrophiles and undergo coupling reactions with nucleophiles to generate unsaturated intermediates; further hydrogenation by using hydrogen borrowed from the alcohols in the first step provides the product of the net redox-neutral tandem process (Fig. 10A). In contrast, dehydrogenation of secondary alcohols in the presence of a base can turn the resulting electrophilic carbonyl compounds into nucleophilic enolates, which can react with electrophiles through the β-carbon center (Fig. 10B). Like amine alkylation by borrowing-hydrogen methods (C−N bond formation), several different types of carbon nucleophiles can be used for C−C bond formation by this strategy. Grigg reported early examples of C−C bond formation through borrowing hydrogen in which aryl acetonitriles were alkylated by primary alcohols using ruthenium and rhodium catalysts and a stoichiometric base (90); other metal catalysts and nucleophiles were employed later (91). Williams and co-workers devised efficient alkylation methods of carbon nucleophiles catalyzed by ruthenium and iridium complexes using low catalyst loading. For example, an active methylene compound was alkylated (92) by benzyl alcohol using RuH2(CO)(PPh3)3 and xantphos ligand in very good yield (Fig. 10C). Recently, oxindole was also alkylated by the borrowing-hydrogen method (93). Use of [Ir(cod)Cl]2 + PPh3 allowed Obora and Ishii to perform such reactions without an additional base at elevated temperature (94). The borrowing-hydrogen approach can also be applied to the Wittig reaction in which the alcohol functions as a surrogate to aldehydes (Fig. 10D) (95). Amine products can also be obtained from the aza-Wittig reaction (96). β-alkylation of alcohols was achieved using iridium and ruthenium catalysts (Fig. 10, E and F) (97, 98). In addition, upon dehydrogenation, amines can also give rise to electrophilic reactivity and can undergo self-coupling or coupling reactions with other amines (74).

Fig. 10 C−C bond formation using alcohols as sources of electrophiles and nucleophiles.

(A) Borrowing hydrogen strategy for C−C bond formation, in which the alcohol transformed into an electrophilic intermediate. (B) Borrowing hydrogen strategy for β-alkylation, in which the alcohol is transformed into a nucleophilic intermediate. (C and D) Typical examples of the strategy shown in (A). (E and F) Typical examples of the strategy shown in (B). (G) A nucleophilic intermediate is generated from the alkene: enantioselective C−H functionalization of primary alcohols.

Unlike the borrowing-hydrogen strategies described in Fig. 10, A and B, C−C coupling can also be achieved without using preformed nucleophiles. Bower and Krische developed reactions that involve alcohols and partially unsaturated substrates such as alkenes, dienes, alkynes, and allenes (99), which result in products of formal alcohol α-C−H functionalization (Fig. 2D). This strategy involves alcohol dehydrogenation to generate a metal-hydride intermediate that adds to the unsaturated substrate, generating a nucleophilic intermediate capable of aldehyde addition reactions. Very recently, Krische and co-workers also uncovered an alternative mechanism for such C−C bond formation (100). Excellent stereoselectivities were achieved in several transformations; for example, a catalyst generated in situ from RuH2(CO)(PPh3)3, a diphosphine and a chiral acid catalyzes anti-diastereoselective and enantioselective C−H crotylation of primary alcohols (Fig. 10G) (101).

Outlook

AD is a rapidly growing area, propelled by the profound influence of fundamental organometallic chemistry, in part based on metal-ligand cooperation. This has led to reactions such as the dehydrogenative coupling of amines with alcohols to form amides, peptides, and polyamides under neutral conditions with liberation of hydrogen gas and no waste generation. The related dehydrogenation reactions that do not evolve hydrogen gas—namely the borrowing-hydrogen methodology and the coupling of redox pairs via intermediate generation of nucleophiles and electrophiles—allow construction of both C−N and C−C bonds from alcohols and provide efficient, atom-economical access to an assortment of useful products. The strides made thus far exemplify the power of dehydrogenation as an activation tactic by generation of more reactive unsaturated intermediate compounds, which can then couple in situ with other substrates and provide effective catalytic processes under mild, environmentally benign conditions. As AD is increasingly applied in transformations of complex and biorenewable molecules, we feel that many additional useful applications are bound to unfold.

References and Notes

  1. Acknowledgments: Supported by the European Research Council (ERC) under the FP7 framework (no. 246837) and by the Kimmel Center for Molecular Design. C.G. thanks the Department of Science and Technology and NISER, and he is a Ramanujan Fellow. D.M. is the Israel Matz Professorial Chair of Organic Chemistry.
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