Catalytic transformation of functionalized carboxylic acids using multifunctional rhenium complexes

Carboxylic acids (CAs) are one of the most ubiquitous and important chemical feedstocks available from biorenewable resources, CO2, and the petrochemical industry. Unfortunately, chemoselective catalytic transformations of CHnCO2H (n = 1–3) groups into other functionalities remain a significant challenge. Herein, we report rheniumV complexes as extremely effective precatalysts for this purpose. Compared to previously reported heterogeneous and homogeneous catalysts derived from high- or low-valent metals, the present method involves a α-C–H bond functionalization, a hydrogenation, and a hydrogenolysis, which affords functionalized alcohols with a wide substrate scope and high chemoselectivity under relatively mild reaction conditions. The results represent an important step toward a paradigm shift from ‘low-valent’ to ‘high-valent’ metal complexes by exploring a new portfolio of selective functional group transformations of highly oxygenated organic substrates, as well as toward the exploitation of CAs as a valuable biorenewable feedstock.

robustness and inertness of the catalyst toward many different FGs is of crucial importance, while new concepts for the selective activation of CH n CO 2 H groups (n = 1-3) in CAs must be developed. High-valent (d 0 -d 2 ) 30 transition metals may represent more promising prospectives than their low-valent analogues, considering that the former are less susceptible to oxidative addition and π-back donation than the latter. Therefore, we have developed molecular single-active-site rhenium V complexes (Fig. 1b) that selectively hydrogenate and/or functionalize a wide range of functionalized CAs. The majority of high-valent Re complexes have thus far been used for oxidation 31 and deoxydehydration 31,32 , rather than for FGT of CA (α-C-H functionalization 15 and hydrogenation 23,33 ).

Results
Catalytic hydrogenation of functionalized CAs. We recently reported a systematic study on the nature of cationic mononuclear Ru II carboxylates as catalyst precursors for the self-induced hydrogenation of CAs 18 . Simultaneously, a similar hydrogenation mechanism involving cobalt(II)-triphos catalysts (triphos: CH 3 C[CH 2 PPh 2 ] 3 ) was proposed by Elsevier and Bruin 19 . Subsequently, we extended the putative hydrogenation mechanism to high-valent metal catalysts 34 , as the originally proposed mechanism seemed to involve acid-base cooperative catalysis rather than a redox-based catalytic cycle.
Initially, we evaluated a series of commercially available high-valent Re catalyst precursors. Treatment of a toluene solution of 3-phenylpropanoic acid (CA-a) with catalytic amounts of (CH 3 Table 1, entry 1 and  Supplementary Table 1). In contrast, the cationic Re species from each of the latter four complexes (2 mol% each), formed upon treatment with Na[B(C 6 H 5 ) 4 ] (10 mol%) ([Re] 0 = 2.5 mM), afforded 3-phenylpropan-1-ol (AL-a) in 14-62% and 3-phenylpropyl 3-phenylpropanoate (ES-a) in 5-11% (entry 2 and Supplementary Table 1). The highest yield of AL-a (72%) was obtained using Re-c (entry 3). Encouraged by these results, we used several  35 and bidentate diphosphine ligands (entries 4-7). The best results were observed for Cl 3 Re V O[Ph 2 P(CH 2 ) 2 PPh 2 ] 35 (Re-a), which furnished AL-a in >98% yield (entry 4) together with negligible amounts of ES-a (~1%). This result stands in sharp contrast to many homogeneous and heterogeneous catalysts, which induce undesirable CA esterification and deoxygenation with the generated alcohols [36][37][38] . The exclusive formation of AL-a suggests that undesirable over-reductions (e.g. dearomatic hydrogenation and hydrogenolysis) of AL-a, and/or decarboxylation of CA-a, are prevented. This high FG tolerance surpasses that of Mo(CO) 6 -Rh/Al 2 O 3 (P H2 = ~10 MPa, 150 °C), in which benzene rings of the CAs are hydrogenated 39 . Moreover, the low-valent Re 0 carbonyl cluster Re 2 (CO) 10 is unable to catalyze the hydrogenation of n-C 14 H 29 CO 2 H in dimethoxyethane at 170 °C, even at P H2 = ~10 MPa 39 . Similarly, non-oxo complexes of Re III exhibited low to negligible catalytic activity (entries 8 and 9).
Molecular Re VII and Re V species are able to catalyze the hydrogenation of sulfoxides, which affords dialkyl sulfides as the major product 33 . Surprisingly, the hydrogenation of CA with Re-b was barely inhibited by sulfur-containing CAs or thiophene (TH) derivatives such as CA-u,x and CA-7 (Supplementary Table 8). For example, 4-(thien-2-yl)-substituted CA-u was hydrogenated with Re-b to give AL-u in 99% yield; hydrogenation of CA-x proceeded almost quantitatively even at milder P H2 (P H2 = 1 MPa, 180 °C, 12 h). In many cases, sulfur-containing substances poison precious metal hydrogenation catalysts. However, Re-b was not deactivated by benzothiophene or dibutylsufide (30 mol%), affording AL-a in 99% in both cases (P H2 = 4 MPa, 160 °C, 24 h). Even in the presence of a mixture of dibenzothiophene derivatives (TH-a-c), which are detrimental to conventional hydro-desulfurization catalysts 28,29 , no negative effects were observed at P H2 = 4 MPa ( Fig. 3b; Supplementary Table 9). In contrast, TH slightly decreases the hydrogenation rate of the bimetallic catalyst OsO 4 -Re 2 O 7 , although over-reduction of the hydrocarbon was diminished 40 .
Compared to the selective formation of AL-4 from furan-2-carboxylic acid (CA-4), the π-extended derivative CA-11a showed intriguing reactivity upon reaction with Re-b and H 2 ( Fig. 3c; Supplementary Table 10). CA-11a underwent either full hydrogenation of all non-aryl unsaturated bonds to afford AL-11b, or chemoselective reduction, i.e., a carbonyl hydrogenation to afford AL-11a or an α,β-ene hydrogenation to furnish CA-11b. Even hydrodeoxygenation (HDO), which is uncommon for Re complex catalysts, was achieved by varying the reaction parameters: hydrogenolysis of the different C-O bonds of the reaction intermediates AL-11a and AL-11b afforded FR-11 and alcoholic phenol AL-11c, respectively. To the best of our knowledge, this represents the first example of a directed, catalytic CA hydrogenation and subsequent hydrogenolysis in one pot using molecular catalysts.
Catalytic α-C-H bond functionalization of CAs. So far, Re-a and Re-b have provided the best catalytic results for the hydrogenation of a broad variety of CAs under relatively mild conditions. However, as previously discussed, Re-a induces the epimerization of N-protected amino acids such as CA-r-t (P H2 = 4 MPa, 160 °C). This result suggests that a catalyst derived from Re-a easily deprotonates the α-C-H moiety of these CAs, while the racemization may occur before or during the hydrogenation. Indeed, decreasing P H2 (1 → 0.1 MPa) under otherwise identical conditions resulted in the apparent full recovery of CA-a, i.e., a recovery most likely due to a very fast α-C-H deprotonation-protonation sequence. Likewise, replacing H 2 with D 2 [Re-b (2 mol%), K[B(C 6 H 5 ) 4 ] (10 mol%), P D2 = 0.1 MPa, 180 °C] did not introduce deuterium on the carbonyl carbons; instead, in the absence of a solvent, the α-CH 2 group of CA-a underwent fast H/D exchange to generate CA-a-d n (n = 1, 2), whereby 98% of the α-CH 2 moieties of CA-a were deuterated (Fig. 4a, top) (Fig. 4a, middle). In comparison, a combination of Ru II 2 Cl 2 (μ-Cl) 2 (μ-OH 2 )(Ph 2 P(CH 2 ) 4 PPh 2 ) 2 (2 mol%) and Na(acetylacetonate) (10 mol%), which is an effective catalyst system for CA hydrogenation (P H2 = 2-6 MPa, 160 °C) 18 , resulted in 0% deuteration of CA-a under milder conditions (P D2 = 0.1 MPa, 180 °C). The hydrogenation of aldehyde AD-a (P D2 = 0.9 MPa) afforded AL-a-d 1 in quantitative yield, while C2 was not deuterated (Fig. 4a, bottom). Even with the much higher acidity of the α-C-H of aldehydes (pK a = ~16 in H 2 O) than that of carboxylates (pK a 34-40 in DMSO), enolization of the aldehyde was prevented. Methyl 3-phenylpropionate underwent neither C2 deuteration nor hydrogenation (α-C-H of esters: pK a = ~30 in DMSO), and full recovery of the ester was achieved under similar reaction conditions (P D2 = 0.9 MPa, 180 °C, 12 h).
Treating CA-a with acid anhydrides (AAs) in the presence of catalytic Re-b and KOAc, and in the absence of H 2 and a solvent, afforded unsymmetrical ketones (KEs) KE-a-c in acceptable yields ( Fig. 4b; Supplementary  Table 12). In the absence of Re-b under otherwise identical conditions, KE-a was obtained in substoichiometric amounts (24%) relative to KOAc (30 mol%). This result highlights an important advantage of the method presented herein over previously reported strategies to synthesize methyl or phenyl ketones based on MeLi or PhLi, followed by aqueous workup 45 , or on ArB(OH) 2 /AAs and Pd catalysts 26 , which produce stoichiometric amounts of salts. The Dakin-West conditions (stoichiometric base in AA) 46 are useful mainly for the synthesis of methyl ketones from amino acids and α-arylacetic acids, but catalytic base only promote the catalytic formation of KE-a from CA-a 47 . In contrast, the present method opens a new route to the catalytic synthesis of KEs from two different CAs without generating any salt waste, albeit that one of the CAs must be converted to the AAs via dehydration before the reaction. Most likely, α-C-H deprotonation of CA-a and subsequent addition of the resulting enolate to the AA generates an intermediate β-ketoacid, which could undergo rapid decarboxylation to afford KE-a-c.
The deprotonation of the α-C-H moiety of CA-a with Re-b proceeds hence even in the absence of H 2 . However, decarboxylation frequently occurs before the deprotonative functionalization of the α-C-H groups of CAs when using low-valent transition metal catalysts [24][25][26][27] or slightly basic reagents in buffered solutions 48 . For example, the intramolecular aldol cyclization of CA-12 in AcOH using an excess of NaOAc (4.4 equiv relative to CA-12) exclusively promoted the decarboxylative dehydration (path a, Fig. 4c) 48 . The latter involves β-hydroxycarboxylic acid intermediate I, which generates FR-12 upon elimination of the CO 2 H group. In contrast, Re complexes induce a double α-C-H deprotonation via the following fast reaction sequence: 1) α-C-H deprotonation of CA-12, 2) enolate addition, and 3) α-C-H deprotonation of I (path b). Using multifunctional Re V complexes, the formation of CA-11a prevails over that of FR-12 (Fig. 4c) Table 13).

Discussion
To verify the potential involvement of high-valent Re species in the catalytic cycle, several control experiments were carried out using CA-a and CA-11a. Initially, solutions of the resting state of the catalysts, generated by the treatment of Re-a or Re-b with K[BPh 4 ] during the hydrogenation of CA-a (P H2 = 1.5 MPa, 180 °C), were prepared separately, and the samples were analyzed directly by electrospray ionization-mass spectrometry (ESI-MS) ( Supplementary Figs. 1-3). In both cases, [(PP) 2 Re V H 4 ] + , which does not contain the oxygen atom of the original Re = O group anymore (Fig. 5a) 49 . This result suggests that these four hydrides are magnetically equivalent, and that they are coupled to four magnetically equivalent phosphorus atoms. This conclusion is supported by the presence of only one intensive, sharp 31 P{ 1 H} NMR singlet at 47.9 ppm. The structure should thus adopt C 2 -symmetry, wherein the four hydrides should be located in more apical than equatorial positions on the Re center, as the latter should be occupied by the four phosphorus atoms 49 . In contrast, the ESI-MS spectrum obtained from the solution of Re-a exhibited a set of unknown signals. One of these signals could represent [(PP) 2 Re II (OCO(CH 2 ) 2 Ph)] + (m/z Calcd: 1132.2872, Found: 1132.2894), which was not observed for the sample prepared from Re-b. This clearly suggests that Re-b is structurally more robust than Re-a, and consequently affords [(PP) 2 Re V H 4 ] + more efficiently.
Accordingly, Re-b should decompose slightly during the hydrogenation to form [(PP) 2 Re V H 4 ] + under concomitant release of chiraphos and the generation of phosphine-free Re species. Re black and/or Re nanoparticle are easily obtained from dehydrative reduction/decomposition of heterogeneous, high-valent Re-oxo species in the hydrogenation of CAs at 150-250 °C (P H2 = ~20 MPa) 50 . Therefore, a mercury test 51,52 was carried out, in which Hg(0) (338 mol%) was added during the hydrogenation of CA-11a with Re-b and KOAc (20 mol%) ([Re-b] 0 = 5.0 mM in PhCF 3 , P H2 = 6 MPa, 160 °C, 168 h) to examine a potential catalysis by Re nanoparticles. However, the addition of Hg did not affect the catalytic activity of the hydrogenation or the hydrogenolysis (AL-11b: 33%; AL-11c: 63%; cf. Fig. 3c).
When H 2 O (100, 200, or 500 mol% with respect to CA-a) was added prior to starting the hydrogenation of CA-a with Re-b, the reaction rate for the formation of AL-a (99% after 12 h) observed in the absence of such a pre-addition of H 2 O was considerably retarded (AL-a: 71%, 59%, and 34%, respectively). However, the integrity of the catalysis was sustained, and extending the reaction time to 24 h increased the yield of AL-a significantly (96%, 97%, and 50%, respectively) (Fig. 5c). This result implies that Re = O species should only play a peripheral role in the catalysis, considering that H 2 O should shift the reaction equilibrium from a ReH 2 species to a Re = O structure (Fig. 5d) 50,53 . All control experiments suggest that the mononuclear Re species [(PP)Re V (η 1 -H) 4 ] + represents an important precursor (albeit presumably outside the catalytic cycle) that subsequently affords the cationic mononuclear Re-carboxylate [(PP)Re V (η 1 -H) 3 (OCO(CH 2 ) 2 Ph)] + upon reaction with CA-a (Fig. 6a) in an initial critical point of the catalytic cycle. This interpretation is consistent with our previous observations, which identified the related cationic metal carboxylate [(PP)Ru II (OCO(CH 2 ) 2 Ph)] + as the key intermediate in a catalytic cycle involving the "CA-self-induced hydrogenation of CA" 18 . However, at this point, a catalytic involvement of [(PP)Re III (η 1 -H)(η 2 -H 2 )(OCO(CH 2 ) 2 Ph)] + (Fig. 6a), which could also be derived from [(PP)Re III (η 1 -H) 2 ] + in the presence or absence of η 2 -H 2 coordination, cannot be ruled out with certainty.
In contrast, a treatment of catalytic Re-b (6 mol%) with KOAc ( Fig. 6). Therein, the detected [(PP)Re V Cl(OCO(CH 2 ) 2 Ph) 3 ] + should not be a catalytically active species for the H-D exchange, considering that deuterium was not incorporated in the three carboxylates. In sharp contrast, when Re-a was used instead of Re-b under otherwise identical conditions (P D2 = 0.1 MPa), [(PP)Re V Cl(OCO(CH 2 ) 2 Ph) 3 ] + was not detected (PP = dppe), and the typical separation pattern of the MS signals corresponding to Re complexes was barely observed, which suggests ready decomposition of the Re complexes at 180 °C to Re black or  Fig. 7). In a similar fashion, the use of Re-a under comparable conditions (in the absence of H 2 ) in the Dakin-West reaction resulted only in a significant detachment of dppe from the Re center ( Supplementary Fig. 8). Indeed, deuteration at the α-position of CA-a hardly proceeded (deuteration: ~3%) using Re-a at P D2 = 0.1 MPa, whereas at P D2 = 1.0 MPa ([Re-a] 0 = 5 mM in toluene, 180 °C, 36 h), AL-a-d 3-4 (>95%) was obtained as the major product (deuteration: C1 = 85%, C2 = ~92%). To summarize the behavior of Re-a: in the absence of H 2 or at low H 2 pressure (P H2 ~0.1 MPa), a 1:1 Re-dppe complexation in Re-a is rather unstable at 160-180 °C, while a good yield of [(dppe) 2 Re V H 4 ] + is obtained at higher H 2 pressure (e.g. P H2 = 1.0 MPa). These experiments lead to the provisional conclusion that an H-D exchange reaction of CA-a should -at least partially -involve a "CA-self-induced deprotonation of CA" promoted by an intramolecular hydrogen transfer in [(PP) Re III L(OCO(CH 2 ) 2 Ph) 2 ] (Fig. 6b). However, a definite conclusion, excluding e.g. hitherto unobserved catalytically active species, should require further detailed experiments and analyses.
In conclusion, the use of Re V (=O)-diphosphine complexes provides a novel operationally simple concept for the selective activation and functionalization of CH n CO 2 H groups (n = 1-3). This method combines an unprecedented substrate scope with outstanding functional group compatibility. Furthermore, sulfur components, i.e., poisons for conventional low-valent transition metal hydrogenation catalysts, do not affect the catalytic performance. High-valent transition metal complexes have traditionally been underestimated in the context of the hydrogenation of CAs, hydrogenolysis of alcohols, C-H bond functionalization, and hydrogenation of compounds with more reactive unsaturated bonds (e.g. C=C and C=O) 33 . Our results represent an important step toward the development of new catalyst systems for carbon 54 and hydrogen management 55 , that allow the formation of asymmetric carbon-carbon bonds and hydrogenations using biomass-derived renewable feedstocks. Rhenium is one of the rarest elements in the Earth's crust, and a commercial price of Re source we used to synthesize different Re complexes is more expensive than, or comparable to, that of a Ru source, from which our previous Ru complexes were prepared 18 , and is ca. one forth that of rhodium-and iridium sources used for CA hydrogenation 36 . Since Co(BF 4 ) 2 used by Elsevier/Bruin 19 is much economical, an effort to lower a Re load in hydrogenation is ongoing research in our laboratory.

Methods
Representative hydrogenation of CA-a with Re-b. 3-Phenylpropanoic acid (CA-a) (0.5 mmol, 75.0 mg), KBPh 4 (0.05 mmol, 17.9 mg), ReOCl 3 [(S,S)-Chiraphos] (Re-b) (0.01 mmol, 7.3 mg) and a magnetic stirring bar, were placed in a dried glass tube that was inserted in an autoclave, which was purged with Ar gas several times. Anhydrous THF (4.0 mL) was added under a continuous flow of Ar, and the autoclave was purged five times with H 2 (1 MPa). The autoclave was pressurized with H 2 (P H2 = 2 MPa) at 25 °C and heated to 160 °C, where the mixture was stirred (500 rpm) for 24 h. Then, the autoclave was cooled to 0 °C, before the reaction mixture was transferred to a 100 mL round bottom flask containing CHCl 3 . The mixture was concentrated (~30 mmHg, 40 °C), and the residue was dissolved in CDCl 3 and analyzed by 1 H NMR spectroscopy. Yields of 3-phenyl-1-propanol (AL-a) (93%) and 1-(3-phenylpropyl)-3-phenylpropanoate (ES-a) (~1%) were calculated based on the integration ratio of their signals relative to the internal standard mesitylene and by GC-MS analysis, respectively.