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. Author manuscript; available in PMC: 2025 Aug 21.
Published in final edited form as: ACS Catal. 2025 May 2;15(10):8274–8283. doi: 10.1021/acscatal.5c01994

Formate-Mediated C-C Coupling of Aryl/Vinyl Halides and Triflates: Carbonyl Arylation and Reductive Cross-Coupling

Yu-Hsiang Chang 1, Yoon Cho 1, Weijia Shen 1, Michael J Krische 1
PMCID: PMC12366644  NIHMSID: NIHMS2097171  PMID: 40843079

Abstract

Catalytic methods for the intermolecular formate-mediated C-C coupling of Csp2-X pronucleophiles beyond reductive Heck reactions (alkene hydroarylations) are catalogued. These methods include transfer hydrogenative reductive couplings of aryl/vinyl halides or triflates to carbonyl compounds (Grignard/NHK-type reactions), as well as reductive cross-couplings of two aryl/vinyl halide or triflate partners. These studies demonstrate that reactions traditionally associated with discrete Csp2 carbanions can be rendered catalytic and free from premetalated reagents or metallic reductants using sodium or potassium formate - abundant, low molecular weight sources of hydrogen.

Keywords: Green Chemistry, Hydrogen Transfer, Formic Acid, C-C Coupling, Reduction

Graphical Abstract

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1. Introduction and Scope of Review

The formation of C-C bonds mediated by preformed carbanions has played a central role in chemical synthesis since the inception of organic chemistry. Milestones include Frankland’s preparation of diethylzinc (1849)1–3 and subsequent work on organozinc reagents by Wanklyn4,5 and Butlerov6,7 (and other Kazan chemists),8,9 as well as the discovery of organomagnesium reagents (Grignard reagents),10,11 organolithium12,13 and organocopper reagents.14 The ability to prepare non-stabilized carbanions revolutionized the chemistry of carbonyl addition15 and unlocked the field of metal-catalyzed cross-coupling.16 Despite their utility, stoichiometric carbanions (and the zero-valent metals from which they derive) are often hazardous, display poor functional group compatibility, and generate metallic byproducts that complicate product isolation. These issues pose challenges vis-á-vis large volume chemical manufacture. As demonstrated by the Fischer-Tropsch reaction (1922)17,18 and alkene hydroformylation (1938),19 completely atom-efficient reductive C-C bond formation can be achieved via hydrogenation, yet the concept of exploiting hydrogenation and transfer hydrogenation for reductive C-C couplings to carbonyl and imine partners were not systematically investigated until work from the present author’s laboratory.15,20 Rather, metal-catalyzed reductive couplings to carbonyl compounds are mediated by zero-valent metals (Mn°, Zn°) or organometallic reagents (ZnEt2, BEt3).21 This includes the Nozaki-Hiyama-Kishi reaction, which employs stoichiometric quantities of chromium(II) as the terminal reductant.22,23 Similarly, the majority of metal-catalyzed “cross-electrophile reductive couplings” of two organic halides are mediated by zero-valent metals.24,25

Due to its many uses spanning the agricultural, textile and chemical manufacturing industries, and use as a deicing agent, formic acid is produced on immense scale (>106 tons/year).26 Like hydrogen and 2-propanol, formic acid and its salts are inexpensive, low molecular weight hydrogen transfer agents that are commonly used for the reduction of C=X (X = O, NR) π-bonds.27 Intermolecular metal-catalyzed reductive C-C couplings mediated by formic acid and its salts are highly uncommon and were first reported in the context of reductive Heck reactions (hydroarylations),28,29 as initially reported by Cacchi (1983).28a Formate-mediated reductive couplings of π-unsaturated pronucleophiles with carbonyl compounds (and related 2-propanol mediated processes) were subsequently developed in the Krische laboratory (2008),30 as described in the review literature.15,20,31

In the current monograph, recently developed intermolecular metal-catalyzed carbonyl and cross-electrophile reductive C-C couplings of Csp2-X pronucleophiles mediated by formate are surveyed (Figure 1).32–35 The former processes represent the first intermolecular transfer hydrogenative Grignard-NHK-type couplings of Csp2-X pronucleophiles to carbonyl compounds.33,34 Similarly, formate-mediated cross-coupling of distinct aryl/vinyl halide or triflate partners represent the first use of an abundant feedstock reductant in arylative reductive coupling.35

Figure 1.

Figure 1.

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Common reducing agents and formate-mediated catalytic C-C couplings of Csp2-X pronucleophiles described in this review.

The current monograph catalogs formate-mediated reductive cross C-C couplings of Csp2-X pronucleophiles beyond Heck-type reactions28,29 and the carbonylation of Csp2-X bonds to form aldehydes.36 Reductive homo-couplings are not covered.37 Two distinct classes of formate-mediated reductive C-C couplings are surveyed: (a) intermolecular carbonyl reductive couplings of Csp2-X pronucleophiles32–34 and (b) cross-electrophile reductive couplings of aryl/vinyl halide or triflate partners.35 The use of formate as reductant in these processes is significant, as hydrogenation and transfer hydrogenation are used in large scale chemical manufacturing more than any other type of reaction (14% of GMP reactions38a) with patent analyses suggesting a trend toward even broader use.38b Thus, once fully developed, transfer hydrogenative variants of Grignard-NHK-type couplings and arylative reductive cross-couplings should be far more scalable than their metal-mediated counterparts.39,40 Reductive couplings of this type are also remarkable from a mechanistic standpoint, as formate-mediated hydrogenolyses of Csp2-X bonds is longstanding41 and such pathways must be suppressed for reductive C-C coupling to prevail. More broadly, the processes described herein (along with other work from our laboratory15,20,31) demonstrate that reactions traditionally associated with discrete carbanions can be rendered catalytic and free from premetalated reagents or metallic reductants using inexpensive, green hydrogen transfer agents.

2. Reductive Coupling of Csp2X Pronucleophiles to Carbonyl Compounds

The rhodium complex assembled from Rh(acac)(CO)2 and tBu2PMe catalyzes the formate-mediated reductive coupling of aryl iodides with aldehydes to form products of carbonyl addition (Scheme 1).32a These processes are highly chemoselective and occur in the presence of lower halides and diverse functional groups. The collective data are consistent with the indicated catalytic cycle. Oxidative addition of the aryl iodide to rhodium(I) provide an aryllrhodium(III) species,42 which upon migratory insertion of aldehyde into the carbon-rhodium bond43 forms a rhodium(III) alkoxide. As established by deuterium labelling studies (not shown), reversible β-hydride elimination does not occur at the stage of the rhodium(III) alkoxide. Additionally, exposure of ketones to the reaction conditions results in only trace quantities of carbonyl reductive product. Substitution of iodide by formate followed by decarboxylation provides an alkoxyrhodium(III) hydride, which upon O-H reductive elimination44 releases product. Optimal yields require use of cesium carbonate (and not lower alkali metal carbonates), suggesting the high polarizability of cesium ion facilitates certain steps in the reaction mechanism.45

Scheme 1.

Scheme 1.

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Rhodium-catalyzed reductive aldehyde arylation mediated by formate.

In related formate-mediated reductive couplings of 2-bromopropene to aldehydes, branched or linear alkyl ketones were formed in a ligand-dependent manner via successive carbonyl vinylation-redox isomerization (Scheme 2).32b Whereas Rh(acac)(CO)2-tBu2PMe catalyst system delivered the anticipated branched adducts, reactions conducted using PPh3, a less strongly coordinating ligand, led to formation of linear propyl ketones. In the latter case, dissociation of PPh3 creates a vacant coordination site at the metal center, triggering β-hydride elimination to form a transient allene. The allene likely does not leave the coordination sphere due to rapid hydrometallation to generate an allylrhodium nucleophile, which upon carbonyl addition-redox isomerization provides the linear ketone. Thus, from a common set of reactants, one can access the branched or linear ketones through a ligand-dependent partitioning of regioisomers. This method enables direct conversion of aldehydes to ketones,46 bypassing the multi-step sequences involving the addition of premetalated reagents to Weinreb or morpholine amides.47

Scheme 2.

Scheme 2.

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Regiodivergent rhodium-catalyzed reductive coupling-redox isomerization of vinyl bromide with aldehydes mediated by formate.

In a significant expansion in scope, tandem rhodium-catalyzed reductive coupling-redox isomerization mediated by formate was applied to the reaction of cyclic vinyl triflates to form cycloalkyl ketones (Scheme 3).32c A series of deuterium labelling experiments were conducted to corroborate the proposed mechanism. Reaction of the indicated aldehyde that is deuterated at the formyl position results in deuterium transfer to the β-carbon of the product with high fidelity (>95% 2H). Similarly, reaction of the allylic alcohol incorporating deuterium at the allylic carbinol methine results in deuterium transfer to the β-carbon of the product with high fidelity (>95% 2H). Finally, reaction of the non-deuterated aldehyde using NaO2D does not result in deuterium incorporation. The collective data are consistent with a mechanism involving vinyl triflate-aldehyde reductive coupling to form a transient allylic alcohol that isomerizes to form the ketone.

Scheme 3.

Scheme 3.

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Rhodium-catalyzed reductive coupling-redox isomerization of cyclic vinyl triflates with aldehydes mediated by formate.

3. Reductive Cross-Coupling of Two Csp2X Partners

Metal-catalyzed cross-couplings16 are among the most broadly utilized methods in the discovery and manufacture of small-molecule drugs.48 As conventional cross-couplings require premetalated reagents, which most often derive from halides, efforts to develop direct reductive cross-couplings of halide partners have been put forth, however, metallic reductants (Zn, Mn) are typically required.24,25 Initial efforts using heterogeneous palladium catalysts in combination with formate gave the first glimmer of hope that a “transfer hydrogenative” cross-electrophile reductive coupling was possible, but these processes required high temperatures, superstoichiometric loadings of an iodide additive (Bu4NI) and provided low yields of the targeted products (not shown).35a High-throughput experimentation (HTE) accompanied by keen interpretation of the mechanistic data implicated intervention of PdI-iodide dimers,49 ultimately enabled development of an efficient homogenous catalytic process for formate-mediated aryl halide reductive cross-coupling (Scheme 4).35c Remarkably, these reactions display orthogonality with respect to Buchwald-Hartwig and Suzuki couplings, as anilines and pinacol boronates are tolerated. Additionally, the conditions are effective for 2-pyridyl systems, which are known to be especially challenging coupling partners.50

Scheme 4.

Scheme 4.

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Palladium-catalyzed reductive cross-coupling of aryl halides mediated by formate (Bu4N⊕ omitted from the catalytic cycle for clarity).

The collective experimental and computational data corroborate a catalytic mechanism wherein the PdI precatalyst, [Pd(I)(PtBu3)]2, is converted to the dianionic species, [Pd2I4][NBu4]2, from which aryl halide oxidative addition is more facile. Under reducing conditions, PdII salts are converted to the PdI complex [Pd(I)(PtBu3)]2 (Scheme 4, eq. 1). However, [Pd2I6][NBu4]2 can be crystallized from reaction mixtures using [Pd(I)(PtBu3)]2 as the precatalyst (Scheme 4, eq. 4),51 and [Pd(I)(PtBu3)]2 is converted to [Pd2I4][NBu4]2 upon exposure to Bu4NI (Scheme 4, eq. 5). Finally, Pd(OAc)2 and [Pd2I6][NBu4]2 and competent precatalysts in the absence of PtBu3 (Scheme 4, eq. 2, 3). The monoarylpalladium species obtained via oxidative addition engage in rapid and reversible Pd-to-Pd transmetalation52 to form homo- and heteroaryl iodide-bridged diarylpalladium dimers. The hetero-diarylpalladium dimers are calculated to be more stable than the homodimers.35c Additionally, computational35c and experimental53 data suggest they have lower barriers to reductive elimination. These two effects conspire to promote high levels of cross-selectivity.

Remarkably, related PdI-catalyzed reductive cross-couplings of aryl iodides with cyclic vinyl triflates occur with cine-substitution (Scheme 5).35b,54 In these reactions, exposure of the PdII precatalyst, Pd(OAc)2, to sodium formate in the presence of Bu4NI delivers the dianionic iodide-bridged PdI dimer, [Pd2I4][NBu4]2. The formation of [Pd2I4][NBu4]2 in this manner is corroborated by 31P NMR studies in which Pd(OAc)2 or [Pd2I6][NBu4]2 are cleanly converted to the well-established PdI complex [Pd(I)(tBu3P)]2 without formation of phosphine oxide and other oxidized phosphine species (e.g. tBu3PX2).55 These data suggest formate reduces palladium(II) faster than phosphine in the presence of iodide, which stabilizes such dimeric palladium(I) complexes.56 Oxidative addition of aryl iodide to [Pd2I4][NBu4]2 followed by dimer dissociation forms anionic T-shaped arylpalladium(II) complex57 that engages in vinyl triflate carbopalladation to form a palladium(IV) carbene.58 Carbopalladation of the trisubstituted vinyl triflate may be facilitated by the fact that the anionic arylpalladium(II) complex is more electron rich and can bind the olefin more strongly due to enhanced π-backbonding.59 Indeed, Hartwig has demonstrated that such anionic T-shaped arylpalladium(II) complexes react at faster rates than neutral tBu3P-ligated complexes,57 accounting for the enhanced efficiency of so-called “Jeffrey conditions” in Heck arylations that entail challenging carbopalladations.60 Finally, consistent with the results of deuterium labelling, β-hydride elimination-C-H reductive elimination from the palladium(IV) carbene provides the product of cine-selective reductive cross-coupling.

Scheme 5.

Scheme 5.

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cine-Selective palladium-catalyzed reductive cross-coupling of aryl iodides with cyclic vinyl triflates mediated by formate.

Recently, the scope of the cine-selective palladium-catalyzed reductive cross-coupling of aryl iodides was extended to acyclic vinyl halide partners (Scheme 6).35d Again, the active dianionic palladium(I) dimer, [Pd2I4][NBu4]2, is generated in situ from Pd(OAc)2, Bu4NI and formate, as described above. Reductive coupling of aryl iodides with the linear halide β-chlorostyrene resulted in formation of the branched adducts. Conversely, reductive coupling of aryl iodides with the branched halide α-bromostyrene resulted in formation of an analogous set of linear adducts. In all cases, complete levels of cine-selectivity were observed. Remarkably, pinacol boronates are tolerated, demonstrating orthogonality with respect to Suzuki coupling. Deuterium labelling studies again provide strong corroborative evidence for the intervention of PdIV carbenoid intermediates (not shown).

Scheme 6.

Scheme 6.

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cine-Selective palladium-catalyzed reductive cross-coupling of aryl iodides with acyclic vinyl halides mediated by formate.

4. Conclusion and Outlook

Preformed carbanions have unlocked vast volumes of chemical space, yet many issues complicate their use in large-scale chemical manufacturing. In contrast, hydrogenation and transfer hydrogenation are among the largest volume applications of metal catalysis.38,40 Catalytic reductive C-C couplings that occur through the addition, transfer or redistribution of hydrogen allow transient organometallic species to serve as surrogates to stoichiometric carbanions, unlocking greener and safer variants of classical carbanionic C-C bond formations. Like hydroformylation19 and the parent Fischer-Tropsch reaction,17,18 the majority of hydrogen-mediated C-C couplings have exploited π-unsaturated partners.15,20,31 Here, the first formate-mediated reductive C-C couplings of aryl/vinyl halides or triflates to carbonyl compounds (transfer hydrogenative Grignard/NHK-type reactions), and the first reductive cross-couplings of two aryl or vinyl halide (or triflate) partners (transfer hydrogenative cross-electrophile reductive couplings) are summarized. These proof-of-concept studies raise numerous possibilities for further advances, including the development of catalysts capable of activating Csp3-X pronucleophiles (methyl halides and higher alkyl halides) as alkyl anion equivalents in formate-mediated carbonyl addition and Csp3-Csp2 reductive cross-coupling, as well as the development of base-metal catalysts for formate-mediated reductive C-C coupling. It is the authors’ hope that the present monograph will accelerate progress toward the development of these and other C-C bond forming processes in which metal-catalyzed hydrogenation and transfer hydrogenation supplant the use of premetalated reagents or metallic reductants.

ACKNOWLEDGMENTS

The Robert A. Welch Foundation (F-0038) and the NIH-NIGMS (R35 GM155947) are acknowledged for partial support of this research.

Footnotes

The authors declare no competing financial interest.

References

  • (1).(a) Frankland E Isolation of Organic Radicals. Ann 1849, 71, 171–213. [Google Scholar]; (b) Frankland E On the Isolation of Organic Radicals. J. Chem. Soc 1850, 2, 263–296. [Google Scholar]
  • (2).For a historical review, see:; Seyferth D Alkyls Zinc, Frankland Edward, and the Beginnings of Main-Group Organometallic Chemistry. Organometallics 2001, 20, 2940–2955. [Google Scholar]
  • (3).For a historical review, see:; Thayer JS Historical Origins of Organometallic Chemistry. J. Chem. Educ 1969, 46, 764–765. [Google Scholar]
  • (4).Wanklyn JA Ueber die Bildung der Propionsäure aus Kohlensäure und eine Aethylverbindung. Ann. Chem. Pharm 1858, 107, 125–128. [Google Scholar]
  • (5).For a historical review, see:; Seyferth D Alkyl and Aryl Derivatives of the Alkali Metals: Useful Synthetic Reagents as Strong Bases and Potent Nucleophiles. 1. Conversion of Organic Halides to Organoalkali-Metal Compounds. Organometallics 2006, 25, 2–24. [Google Scholar]
  • (6).Butlerov A Studien über die Einfachsten Verbindungen der Organischen Chemie. Z. Chem. Pharm, 1863, 6, 484–497. [Google Scholar]
  • (7).Butlerov AZ Sur l’Alcool Pseudobuylique Tertiare ou Alcool Méthylique triméthylé Bull. Soc. Chim. Fr 1864, 2, 106–116. [Google Scholar]
  • (8).Lewis DE The Beginnings of Synthetic Organic Chemistry: Zinc Alkyls and The Kazan’s School. Bull. Hist. Chem 2002, 27, 37–42. [Google Scholar]
  • (9).Reformatsky S Neue Synthese Zweiatomiger Einbasischer Säuren aus den Ketonen. Ber. Dtsch. Chem. Ges 1887, 20, 1210–1211. [Google Scholar]
  • (10).Grignard V Sur Quelques Nouvelles Combinaisons Organométalliques du Magnèsium et Leur Application à des Synthèses d’alcools et d’hydrocarbures. C. R. Acad. Sci 1900, 130, 1322–1325. [Google Scholar]
  • (11).Also, see:; Barbier P Synthèse du Diéthylhepténol. Compt. Rend 1899, 128, 110–111. [Google Scholar]
  • (12).Schlenk W; Holtz J Über die Einfachsten Metallorganischen Alkaliverbindungen. Ber. Dtsch. Chem. Ges 1917, 50, 262–274. [Google Scholar]
  • (13).Ziegler K; Colonius H Untersuchungen über Alkali-Organische Verbindungen. V. Eine Bequeme Synthese Einfacher Lithiumalkyle. Liebigs Ann. Chem 1930, 479, 135–149. [Google Scholar]
  • (14).Gilman H; Jones RG; Woods LA The Preparation of Methylcopper and some Observations on the Decomposition of Organocopper Compounds. J. Org. Chem 1952, 17, 1630–1634. [Google Scholar]
  • (15).Nguyen KD; Park BY; Luong T; Sato H; Garza VJ; Krische MJ Metal Catalyzed Reductive Coupling of Olefin-Derived Nucleophiles: Reinventing Carbonyl Addition. Science 2016, 354, 300 (aah5133) and references cited therein. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (16).Johansson Seechurn CCC; Kitching MO; Colacot TJ; Snieckus V Palladium-Catalyzed Cross-Coupling: A Historical Contextual Perspective to the 2010 Nobel Prize. Angew. Chem. Int. Ed 2012, 51, 5062–5085. [DOI] [PubMed] [Google Scholar]
  • (17).Fischer F; Tropsch H Process for the Synthesis of Alcohols and Other Oxygen-Compounds via Catalytic Reduction of Carbon Monoxide, DRP 411216, Nov 3, 1922. [Google Scholar]
  • (18).Fischer F; Tropsch H Process for the Synthesis of Long Chain Hydrocarbons from Carbon Monoxide and Hydrogen in a Catalytic Method, DRP 484337, Jul 22, 1925. [Google Scholar]
  • (19).Roelen O (to Chemische Verwertungsgesellschaft Oberhausen m.b.H.) German Patent DE 849548, 1938/1952; U.S. Patent 2327066, 1943; Chem. Abstr 1944, 38, 3631. [Google Scholar]
  • (20).For selected reviews on metal-catalyzed C-C coupling via hydrogenation, transfer hydrogenation and hydrogen auto-transfer, see:; (a) Ngai M-Y; Kong J-R; Krische MJ Hydrogen-Mediated C-C Bond Formation – A Broad New Concept in Catalytic C-C Coupling. J. Org. Chem 2007, 72, 1063–1072. [DOI] [PubMed] [Google Scholar]; (b) Iida H; Krische MJ Catalytic Reductive Coupling of Alkenes and Alkynes to Carbonyl Compounds and Imines Mediated by Hydrogen. Top. Curr. Chem 2007, 279, 77–104. [Google Scholar]; (c) Patman RL; Bower JF; Kim IS; Krische MJ Formation of C-C Bonds via Catalytic Hydrogenation and Transfer Hydrogenation: Vinylation, Allylation and Enolate Addition. Aldrichim. Acta 2008, 41, 95–104. [PMC free article] [PubMed] [Google Scholar]; (d) Shibahara F; Krische MJ Formation of C-C Bonds via Ruthenium Catalyzed Transfer Hydrogenation: Carbonyl Addition from the Alcohol or Aldehyde Oxidation Level. Chem. Lett 2008, 37, 1102–1107. [DOI] [PMC free article] [PubMed] [Google Scholar]; (e) Bower JF; Kim IS; Patman RL; Krische MJ Catalytic Carbonyl Addition through Transfer Hydrogenation: A Departure from Preformed Organometallic Reagents. Angew. Chem. Int. Ed 2009, 48, 34–46. [DOI] [PMC free article] [PubMed] [Google Scholar]; (f) Bower JF; Krische MJ Formation of C-C Bonds via Iridium Catalyzed Hydrogenation and Transfer Hydrogenation. Top. Organomet. Chem 2011, 34, 107–138. [DOI] [PMC free article] [PubMed] [Google Scholar]; (g) Hassan A; Krische MJ Unlocking Hydrogenation for C-C Bond Formation: A Brief Overview of Enantioselective Methods. Org. Proc. Res. Devel 2011, 15, 1236–1242. [DOI] [PMC free article] [PubMed] [Google Scholar]; (h) Moran J; Krische MJ Formation of C-C Bonds via Ruthenium Catalyzed Transfer Hydrogenation. Pure Appl. Chem 2012, 84, 1729–1739. [DOI] [PMC free article] [PubMed] [Google Scholar]; (i) Ketcham JM; Shin I; Montgomery TP; Krische MJ Catalytic Enantioselective C-H Functionalization of Alcohols by Redox-Triggered Carbonyl Addition: Borrowing Hydrogen, Returning Carbon. Angew. Chem. Int. Ed 2014, 53, 9142–9150. [DOI] [PMC free article] [PubMed] [Google Scholar]; (j) Perez F; Oda S; Geary LM; Krische MJ Ruthenium Catalyzed Transfer Hydrogenation for C-C Bond Formation: Hydrohydroxyalkylation and Hydroaminoalkylation via Reactant Redox Pairs. Top. Curr. Chem 2016, 374, 365–387. [DOI] [PMC free article] [PubMed] [Google Scholar]; (k) Schwartz LA; Krische MJ Hydrogen-Mediated C–C Bond Formation: Stereo- and Site-Selective Chemical Synthesis Beyond Stoichiometric Organometallic Reagents. Isr. J. Chem 2018, 58, 45–51. [Google Scholar]; (l) Santana CG; Krische MJ From Hydrogenation to Transfer Hydrogenation to Hydrogen Auto-Transfer in Enantioselective Metal-Catalyzed Carbonyl Reductive Coupling: Past, Present and Future. ACS Catal 2021, 11, 5572–5585. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (21).For selected reviews on metal-catalyzed carbonyl reductive C-C coupling mediated by ZnEt2, BEt3, and zero-valent metals, see:; (a) Tamaru Y Novel Catalytic Reactions Involving π-Allylpalladium and -Nickel as the Key Intermediates: Umpolung and β-Decarbopalladation of π-Allylpalladium and Nickel-Catalyzed Homoallylation of Carbonyl Compounds with 1,3-Dienes. J. Organomet. Chem 1999, 576, 215–223. [Google Scholar]; (b) Montgomery J Nickel-Catalyzed Reductive Cyclizations and Couplings. Angew. Chem. Int. Ed 2004, 43, 3890–3908. [DOI] [PubMed] [Google Scholar]; (c) Krische MJ; Jang H-Y Metal Catalyzed Reductive Cyclization (C=C, C≡C, C=O Bonds) In Comprehensive Organometallic Chemistry III; Mingos M, Crabtree R, Eds. Elsevier: Oxford, 2006, Vol. 10, pp 493–536. [Google Scholar]; (d) Metal Catalyzed Reductive C-C Bond Formation; Krische M, Eds.; Topics in Current Chemistry 279; Springer-Verlag; Berlin Heidelberg: Germany, 2007. [Google Scholar]; (e) Jeganmohan M; Cheng C-H Cobalt- and Nickel-Catalyzed Regio- and Stereoselective Reductive Coupling of Alkynes, Allenes, and Alkenes with Alkenes. Chem. Eur. J 2008, 14, 10876–10886. [DOI] [PubMed] [Google Scholar]; (f) Moragas T; Correa A; Martin R Metal-Catalyzed Reductive Coupling Reactions of Organic Halides with Carbonyl-Type Compounds. Chem. Eur. J 2014, 20, 8242–8258. [DOI] [PubMed] [Google Scholar]
  • (22).(a) Okude Y; Hirano S; Hiyama T; Nozaki H Grignard-type Carbonyl Addition of Allyl Halides by Means of Chromous Salt. A Chemospecific Synthesis of Homoallyl Alcohols. J. Am. Chem. Soc 1977, 99, 3179–3181. [Google Scholar]; (b) Takai K; Tagashira M; Kuroda T; Oshima K; Utimoto K; Nozaki H Reactions of Alkenylchromium Reagents Prepared from Alkenyl Trifluoromethanesulfonates (Triflates) with Chromium(II) Chloride under Nickel Catalysis. J. Am. Chem. Soc 1986, 108, 6048–6050. [DOI] [PubMed] [Google Scholar]; (c) Jin H; Uenishi J; Christ WJ; Kishi Y Catalytic Effect of Nickel(II) Chloride and Palladium(II) Acetate on Chromium(II)-Mediated Coupling Reaction of Iodo Olefins with Aldehydes. J. Am. Chem. Soc 1986, 108, 5644–5646. [Google Scholar]
  • (23).For selected reviews on the Nozaki-Hiyama-Kishi reaction, see:; (a) Hargaden GC; Guiry PJ The Development of the Asymmetric Nozaki–Hiyama–Kishi Reaction. Adv. Synth. Catal 2007, 349, 2407–2424. [Google Scholar]; (b) Tian Q; Zhang G Recent Advances in the Asymmetric Nozaki–Hiyama–Kishi Reaction. Synthesis 2016, 48, 4038–4049. [Google Scholar]; (c) Gil A; Albericio F; Àlvarez M Role of the Nozaki–Hiyama–Takai–Kishi Reaction in the Synthesis of Natural Products. Chem. Rev 2017, 117, 8420–8446. [DOI] [PubMed] [Google Scholar]
  • (24).For selected reviews on the cross coupling of organic halides employing zero-valent metals as terminal reductants, see:; (a) Gosmini C; Moncomble A Cobalt-Catalyzed Cross-Coupling Reactions of Aryl Halides. Isr. J. Chem 2010, 50, 568–576. [Google Scholar]; (b) Knappke CEI; Grupe S; Gärtner D; Corpet M; Gosmini C; Jacobi von Wangelin A Reductive Cross-Coupling Reactions between Two Electrophiles. Chem. Eur. J 2014, 20, 6828–6842. [DOI] [PubMed] [Google Scholar]; (c) Everson DA; Weix DJ Cross-Electrophile Coupling: Principles of Reactivity and Selectivity. J. Org. Chem 2014, 79, 4793–4798. [DOI] [PMC free article] [PubMed] [Google Scholar]; (d) Gu Jun; Wang X; Xue W; Gong H Nickel-Catalyzed Reductive Coupling of Alkyl Halides with Other Electrophiles: Concept and Mechanistic Considerations. Org. Chem. Front 2015, 2, 1411–1421. [Google Scholar]; (e) Wang X; Dai Y; Gong H Nickel-Catalyzed Reductive Couplings. Top. Curr. Chem 2016, 374, 1–29. [DOI] [PubMed] [Google Scholar]; (f) Richmond E; Moran J Recent Advances in Nickel Catalysis Enabled by Stoichiometric Metallic Reducing Agents. Synthesis 2018, 50, 499–513. [Google Scholar]; (g) Poremba KE; Dibrell SE; Reisman SE Nickel-Catalyzed Enantioselective Reductive Cross-Coupling Reactions. ACS Catal 2020, 10, 8237–8246. [DOI] [PMC free article] [PubMed] [Google Scholar]; (h) Jin Y; Wang C Nickel-Catalyzed Asymmetric Cross-Electrophile Coupling Reactions. Synlett 2020, 31, 1843–1850. [Google Scholar]; (i) Pang X; Peng X; Shu X-Z Reductive Cross-Coupling of Vinyl Electrophiles. Synthesis 2020, 52, 3751–3763. [Google Scholar]; (j) Charboneau DJ; Hazari N; Huang H; Uehling MR; Zultanski SL Homogeneous Organic Electron Donors in Nickel Catalyzed Reductive Transformations. J. Org. Chem 2022, 87, 7589–7609. [DOI] [PMC free article] [PubMed] [Google Scholar]; (k) Ehehalt LE; Beleh OM; Priest IC; Mouat JM; Olszewski AK; Ahern BN; Cruz AR; Chi BK; Castro AJ; Kang K; Wang J Weix DJ Cross-Electrophile Coupling: Principles, Methods, and Applications in Synthesis. Chem. Rev 2024, 124, 13397–13569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (25).Certain non-metallic reductants for the cross coupling of organic halides have proven effective, but are relatively expensive (TDAE, ref. a-c) or generate mass-intensive byproducts (strained diols, ref. d):; (a) Anka-Lufford LL; Huihui KMM; Gower NJ; Ackerman LKG; Weix DJ Nickel-Catalyzed Cross-Electrophile Coupling with Organic Reductants in Non-Amide Solvents. Chem. Eur. J 2016, 22, 11564–11567. [DOI] [PubMed] [Google Scholar]; (b) Shu W; García-Domínguez A; Quirós MT; Mondal R; Cárdenas DJ; Nevado C Ni-Catalyzed Reductive Dicarbofunctionalization of Nonactivated Alkenes: Scope and Mechanistic Insights. J. Am. Chem. Soc 2019, 141, 13812–13821. [DOI] [PubMed] [Google Scholar]; (c) Charboneau DJ; Huang H; Barth EL; Germe CC; Hazari N; Mercado BQ; Uehling MR; Zultanski SL Tunable and Practical Homogeneous Organic Reductants for Cross-Electrophile Coupling. J. Am. Chem. Soc 2021, 143, 21024–21036. [DOI] [PMC free article] [PubMed] [Google Scholar]; (d) Ishida N; Masuda Y; Sun F; Kamae Y; Murakami M A Strained Vicinal Diol as a Reductant for Coupling of Organyl Halides. Chem. Lett 2019, 48, 1042–1045. [Google Scholar]
  • (26).Hietala J, Vuori A, Johnsson P, Pollari I, Reutemann W; Kieczka H Formic Acid. In Ullmann’s Encyclopedia of Industrial Chemistry; Wiley: New York, 2016; pp 1–22. [Google Scholar]
  • (27).For selected reviews encompassing formate-mediated transfer hydrogenation of C=X (X = O, NR) π-bonds, see:; (a) Johnstone RAW; Wilby AH; Entwistle ID Heterogeneous Catalytic Transfer Hydrogenation and Its Relation to Other Methods for Reduction of Organic Compounds. Chem. Rev 1985, 85, 129–170. [Google Scholar]; (b) Clapham SE; Hadzovic A; Morris RH Mechanisms of the H2-Hydrogenation and Transfer Hydrogenation of Polar Bonds Catalyzed by Ruthenium Hydride Complexes. Coord. Chem. Rev 2004, 248, 2201–2237. [Google Scholar]; (c) Wang D; Astruc D The Golden Age of Transfer Hydrogenation. Chem. Rev 2015, 115, 6621–6686. [DOI] [PubMed] [Google Scholar]; (d) Farrar-Tobar RA; Tin S; de Vries JG Selective Transfer Hydrogenation of α,β-Unsaturated Carbonyl Compounds. Top. Organomet. Chem 2019, 63, 193–224. [Google Scholar]; (e) Wei Y; Liang Y; Luo R; Ouyang L Recent Advances of Cp*Ir Complexes for Transfer Hydrogenation: Focus on Formic Acid/Formate as Hydrogen Donors. Org. Biomol Chem 2023, 21, 7484–7497. [DOI] [PubMed] [Google Scholar]
  • (28).For Cacchi’s seminal work on formic acid-mediated reductive Heck reactions of alkenes and alkynes and subsequent work by other researchers, see:; (a) Cacchi S; Arcadi A Palladium-Catalyzed Conjugate Addition Type Reaction of Aryl Iodides with α,β-Unsaturated Ketones. J. Org. Chem 1983, 48, 4236–4240. [Google Scholar]; (b) Cacchi S; Felici M; Pietroni B The Palladium-Catalyzed Reaction of Aryl Iodides with Mono and Disbustituted Acetylenes: New Synthesis of Trisubstituted Alkenes. Tetrahedron Lett 1984, 25, 3137–3140. [Google Scholar]; (c) A One-Pot Palladium-Catalyzed Synthesis of β,β-Diaryl Ketones and Aldehydes from Aryl Iodides and α,β-Unsaturated Carbonyl Compounds. Cacchi S; Palmieri G Synthesis 1984, 575–577. [Google Scholar]; (d) Cacchi S; La Torre F; Palmieri G The Palladium-Catalyzed Conjugate Addition Type Reaction of Aryl Iodides with α,β-Unsaturated Aldehydes. J. Organomet. Chem 1984, 268, C48–C51. [Google Scholar]; (e) Arcadi A; Cacchi S; Marinelli F The Palladium-Catalyzed Reductive Addition of Aryl Iodides to Propargyl Alcohols: A Route to γ,γ-Diaryl Allylic Alcohols. Tetrahedron 1985, 41, 5121–5131. [Google Scholar]; (f) Arcadi A; Cacchi S; Marinelli F Palladium-Catalyzed Reductive Addition of Aryl Iodides to Aryl- and (Alkylethynyl)silanes. A Stereo- and Regioselective Route to Functionalized 2,2-Disubstituted Vinylsilanes. Tetrahedron Letters 1986, 27, 6397–6400. [Google Scholar]; (g) Arcadi A; Marinelli F; Cacchi S Reaction of Aryl Iodides with Hindered α,β,γ,δ-Dienones in the Presence of the [Pd(OAc)2(PPh3)2]-Trialkylammonium Formate Reagent. J. Organomet. Chem 1986, 312, C27–C32. [Google Scholar]; (h) Arcadi A; Cacchi S; Ianelli S; Marinelli F; Nardelli M The Palladium-Catalyzed Reductive Addition of Aryl Iodides to Carbon-Carbon Triple Bonds: A Structural Study on 1,2,3-Triphenyl-2-propen-1-ol, the Product of syn-Addition. Gazz. Chim. Ital 1986, 116, 725–729. [Google Scholar]; (i) Arcadi A; Bernocchi E; Burini A; Cacchi S; Marinelli F; Pietroni B The Palladium-Tributylammonium Formate Reagent in the Stereoselective Hydrogenation, and Stereo- and Regioselective Hydroarylation of Alkyl 4-Hydroxy-2-alkynoates: A Route to Substituted Butenolides. Tetrahedron 1988, 44, 481–490. [Google Scholar]; (j) Arcadi A; Cacchi S; Marinelli F; Misiti D The Reaction of Alkyl 4-Hydroxy-2-alkynoates and 4-Hydroxy-2-alkyn-1-ones with Palladium-Tributylammonium Formate and with Tributylamine. Preparation of 1,4-Dicarbonyl Compounds. Tetrahedron Lett 1988, 29, 1457–1460. [Google Scholar]; (k) Arcadi A; Marinelli F; Bernocchi E; Cacchi S; Ortar G Palladium-Catalyzed Preparation of exo-Eryl Derivatives of the Norbornane Skeleton. J Organomet. Chem 1989, 368, 249–256. [Google Scholar]; (l) Arcadi A; Bernocchi E; Burini A; Cacchi S; Marinelli F; Pietroni B Palladium-Catalyzed Stereoselective Hydrovinylation of Disubstituted Acetylenes: Preparation of Functionalized 1,2,4-Trisubstituted-1,3-Dienes. Tetrahedron Lett 1989, 30, 3465–3468. [Google Scholar]; (m) Brunner H; Kramler K Asymmetric Catalysis. 72. Enantioselective Hydroarylation of Norbornene and Norbornadiene with Palladium(II) Acetate/Phosphine Catalysts. Synthesis 1991, 1121–1124. [Google Scholar]; (n) Hay LA; Koenig TM; Ginah FO; Copp JD; Mitchell D Palladium-Catalyzed Hydroarylation of Propiolamides. A Regio- and Stereocontrolled Method for Preparing 3,3-Diarylacrylamides. J. Org. Chem 1998, 63, 5050–5058. [Google Scholar]; (o) Arcadi A; Cacchi S; Fabrizi G; Marinelli F; Verdecchia M 4-Aryl- and 4-Vinyl-2,2-Dialkyl-3-chromenes from Tertiary 3-(o-Bromophenyl)propynols via a Palladium-Catalyzed Hydroarylation/Hydrovinylation–Cyclization Sequence 4-Substituted Chromenes from 3-(o-Bromophenyl)propynols. Synlett 2005, 909–915. [Google Scholar]; (p) Vijayan A; Jumaila CU; Baiju TV; Radhakrishnan KV Palladium-Catalyzed Cross-Coupling of Aryl Iodides with Heterobicyclic Olefins: Access to Hydroarylated and Heteroannulated Motifs. ChemistrySelect 2017, 2, 5913–5916. [Google Scholar]; (q) Gurak JA Jr.; Engle KM Practical Intermolecular Hydroarylation of Diverse Alkenes via Reductive Heck Coupling. ACS Catal 2018, 8, 8987–8992. [DOI] [PMC free article] [PubMed] [Google Scholar]; (r) Oxtoby LJ; Li Z-Q; Tran VT; Erbay TG; Deng R; Liu P; Engle KM A Transient-Directing-Group Strategy Enables Enantioselective Reductive Heck Hydroarylation of Alkenes. Angew. Chem. Int. Ed 2020, 59, 8885–8890. [DOI] [PMC free article] [PubMed] [Google Scholar]; (s) Guo T; Ding Y; Zhou L; Xu H; Loh T-P; Wu X Palladium-Catalyzed anti-Michael Reductive Heck Reaction of α,β-Unsaturated Esters. ACS Catal 2020, 10, 7262–7268. [Google Scholar]
  • (29).For reviews on the reductive Heck reactions of alkenes and alkynes (hydroarylation), see:; (a) Chacchi S The Palladium-Catalyzed Hydroarylation and Hydrovinylation of Carbon-Carbon Multiple Bonds: New Perspectives in Organic Synthesis. Pure Appl. Chem 1990, 62, 713–722. [Google Scholar]; (b) Yamamoto Y Heterocycles via Transition-Metal-Catalyzed Hydroarylation of Alkynes. Chem. Soc. Rev 2014, 43, 1575–1600. [DOI] [PubMed] [Google Scholar]; (c) Ghosh T Reductive Heck Reaction: An Emerging Alternative in Natural Product Synthesis. ChemistrySelect 2019, 4, 4747–4755. [Google Scholar]; (d) Oxtoby LJ; Gurak JA Jr.; Wisniewski SR; Eastgate MD; Engle KM Palladium-Catalyzed Reductive Heck Coupling of Alkenes. Trends Chem 2019, 1, 572–687. [DOI] [PMC free article] [PubMed] [Google Scholar]; (e) Pang X; Peng X; Shu X-Z Reductive Cross-Coupling of Vinyl Electrophiles. Synthesis 2020, 52, 3751–3763. [Google Scholar]; (f) Xie J-Q; Liang R-X; Jia Y-X Recent Advances of Catalytic Enantioselective Heck Reactions and Reductive-Heck Reactions. Chin. J. Chem 2021, 39, 710–728. [Google Scholar]; (g) De Angelis M; Lazzetti A; Serraiocco A; Ciogli A Asymmetric Hydroarylation Reactions Catalyzed by Transition Metals: Last 10 Years in a Mini Review. Catalysts 2022, 12, 1289–1315. [Google Scholar]
  • (30).(a) Shibahara F; Bower JF; Krische MJ Ruthenium Catalyzed C-C Bond Forming Transfer Hydrogenation: Carbonyl Allylation from the Alcohol or Aldehyde Oxidation Level Employing Acyclic 1,3-Dienes as Surrogates to Preformed Allyl Metal Reagents. J. Am. Chem. Soc 2008, 130, 6338–6339. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Leung JC; Patman RL; Sam B; Krische MJ Alkyne-Aldehyde Reductive C-C Coupling via Ruthenium Catalyzed Transfer Hydrogenation: Regio- and Stereoselective Carbonyl Vinylation to Form Trisubstituted Allylic Alcohols in the Absence of Vinylmetal Reagents,” Leung, J. C.; Patman, R. L.; Sam, B.; Krische, M. J. Chem. Eur. J 2011, 17, 12437–12443. [DOI] [PMC free article] [PubMed] [Google Scholar]; (c) Bausch CC; Patman RL; Breit B; Krische MJ Divergent Regioselectivity in the Synthesis of Trisubstituted Allylic Alcohols by Nickel- and Ruthenium-Catalyzed Alkyne Hydroxymethylation with Formaldehyde. Angew. Chem. Int. Ed 2011, 50, 5687–5690. [DOI] [PubMed] [Google Scholar]; (d) Geary LM; Woo SK; Leung JC; Krische MJ Diastereo- and Enantioselective Iridium Catalyzed Carbonyl Propargylation from the Alcohol or Aldehyde Oxidation Level: 1,3-Enynes as Allenylmetal Equivalents. Angew. Chem. Int. Ed 2012, 51, 2972–2976. [DOI] [PubMed] [Google Scholar]; (e) Spinello BJ; Wu J; Cho Y; Krische MJ Direct Conversion of Primary Alcohols and Butadiene to Branched Ketones via Merged Transfer Hydrogenative Carbonyl Addition-Redox Isomerization Catalyzed by Rhodium. J. Am. Chem. Soc 2021, 143, 13507–13512. [DOI] [PMC free article] [PubMed] [Google Scholar]; (f) Saludares C; Ortiz E; Santana CG; Spinello BJ; Krische MJ Asymmetric Ruthenium-Catalyzed Carbonyl Allylations by Gaseous Allene via Hydrogen Auto-Transfer: 1º vs 2º Alcohol Dehydrogenation for Streamlined Polyketide Construction. ACS Catal 2023, 13, 1662–1668. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (31).For a review encompassing examples of formate-mediated carbonyl reductive couplings of π-unsaturated partners, see:; Holmes M; Schwartz LA; Krische MJ Intermolecular Metal-Catalyzed Reductive Coupling of Dienes, Allenes and Enynes with Carbonyl Compounds and Imines. Chem. Rev 2018, 118, 6026–6052. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (32).For intermolecular formate-mediated reductive couplings of Csp2-X pronucleophiles to carbonyl compounds, see:; (a) Swyka RA; Zhang W; Richardson J; Ruble JC; Krische MJ Rhodium-Catalyzed Aldehyde Arylation via Formate-Mediated Transfer Hydrogenation: Beyond Metallic Reductants in Grignard-NHK-Type Addition. J. Am. Chem. Soc 2019, 141, 1828–1832. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Swyka RA; Shuler WG; Spinello BJ; Zhang W; Lan C; Krische MJ Conversion of Aldehydes to Branched or Linear Ketones via Regiodivergent Rhodium-Catalyzed Vinyl Bromide Reductive Coupling-Redox Isomerization Mediated by Formate. J. Am. Chem. Soc 2019, 141, 6864–6868. [DOI] [PMC free article] [PubMed] [Google Scholar]; (c) Shuler WG; Swyka RA; Schempp TT; Spinello BJ; Krische MJ Vinyl Triflate-Aldehyde Reductive Coupling-Redox Isomerization Mediated by Formate: Rhodium-Catalyzed Ketone Synthesis in the Absence of Stoichiometric Metals. Chem. Eur. J 2019, 25, 12517–12520. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (33).Following the work described in ref. 32a (2019), an intermolecular sec-phenethyl alcohol-mediated reductive couplings of Csp2-X pronucleophiles to carbonyl compounds has been described:; Isbrandt ES; Nasim A; Zhao K; Newman SG Catalytic Aldehyde and Alcohol Arylation Reactions Facilitated by a 1,5-Diaza-3,7-diphosphacyclooctane Ligand. J. Am. Chem. Soc 2021, 143, 14646–14656. [DOI] [PubMed] [Google Scholar]
  • (34).Reductive cyclizations of Csp2-X pronucleophiles onto carbonyl electrophiles mediated by formic acid (ref. d), alcohols (ref. a, b) or hydrogen (ref. c) have been described:; (a) Quan LG; Lamrani M; Yamamoto Y Intramolecular Nucleophilic Addition of Aryl Bromides to Ketones Catalyzed by Palladium. J. Am. Chem. Soc 2000, 122, 4827–4828. [Google Scholar]; (b) Jia Y-X; Katayev D; Kündig E P Synthesis of 3-Hydroxyoxindoles by Pd-Catalysed Intramolecular Nucleophilic Addition of Aryl Halides to α-Ketoamides. Chem. Commun 2010, 46, 130–132. [DOI] [PubMed] [Google Scholar]; (c) Shin I; Ramgren SD; Krische MJ Palladium Catalyzed Reductive Cyclization of N-Acyl ortho-Bromoanilides to Form 3-Hydroxy-2-Oxindoles: A Hydrogen-Mediated Grignard Addition. Tetrahedron 2015, 71, 5776–5780. [DOI] [PMC free article] [PubMed] [Google Scholar]; (d) Dong M; Tong X Pd(0)-Catalyzed Asymmetric Intramolecular Grignard-Type Reaction of Vinyl Iodide-Carbonyl. Chem. Eur. J 2024, 30, e202400236. [DOI] [PubMed] [Google Scholar]
  • (35).For formate-mediated reductive cross couplings of aryl and vinyl halides or triflates, see:; (a) Schwartz LA; Spielmann K; Swyka RA; Xiang M; Krische MJ Formate-Mediated Cross-Electrophile Reductive Coupling of Aryl Iodides and Bromopyridines. Isr. J. Chem 2020, 60, 298–301. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Chang Y-H; Shen W; Shezaf JZ; Ortiz E; Krische MJ Palladium(I)-Iodide-Catalyzed Deoxygenative Heck Reaction of Vinyl Triflates: A Formate-Mediated Cross-Electrophile Reductive Coupling with cine-Substitution. J. Am. Chem. Soc 2023, 145, 22890–22895. [DOI] [PMC free article] [PubMed] [Google Scholar]; (c) Cho Y; Chang Y-H; Quirion KP; Strong ZH; Dubey ZJ; Nguyen N; Lee S; Taylor NS; Hoover JM; White NA; Liu P; Krische MJ Aryl Halide Cross-Coupling via Formate-Mediated Transfer Hydrogenation. Nature Chem 2025, 17, DOI: 10.1038/s41557-024-01729-0. [DOI] [PMC free article] [PubMed] [Google Scholar]; (d) Santana CG; Teoh YS; Evarts MM; Shezaf JZ; Krische MJ Formate-Mediated Reductive Cross-Coupling of Vinyl Halides with Aryl Iodides: cine-Substitution via Palladium(I)-Catalysis. Org. Lett 2024, 26, 7055–7059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (36).For selected reviews on the reductive carbonylation of aryl halides, see:; (a) Brennführer A; Neumann H; Beller M Palladium-Catalyzed Carbonylation Reactions of Aryl Halides and Related Compounds. Angew. Chem. Int. Ed 2009, 48, 4114–4133. [DOI] [PubMed] [Google Scholar]; (b) Gautam P; Bhanage BM Recent Advances in the Transition Metal Catalyzed Carbonylation of Alkynes, Arenes and Aryl Halides Using CO Surrogates. Catal. Sci. Technol 2015, 5, 4663–4702. [Google Scholar]
  • (37).For related formate-mediated reductive homo-couplings of aryl halides, see:; (a) Mukhopadhyay S; Rothenberg G; Gitis D; Wiener H; Sasson Y Kinetics and Mechanism of Heterogeneous Palladium-Catalyzed Coupling Reactions of Chloroaryls in Water. J. Chem. Soc., Perkin Trans 2 1999, 2481–2484. [Google Scholar]; (b) Abiraj K; Srinivasa GR; Gowda DC Facile Synthesis of Symmetrical Functionalized Biaryls from Aryl Halides Catalyzed by Commercial Zinc Dust Using Ammonium Formate. Tetrahedron Lett 2004, 45, 2081–2084. [Google Scholar]; (c) Abiraj K; Srinivasa GR; Gowda DC Novel and Efficient Synthesis of Symmetrical Functionalized Biaryls Using Zinc and Triethylammonium Formate. Synlett 2004, 5, 0877–0879. [Google Scholar]
  • (38).(a) Carey JS; Laffan D; Thomson C; Williams MT Analysis of The Reactions Used for The Preparation of Drug Candidate Molecules. Org. Biomol. Chem 2006, 4, 2337–2347. [DOI] [PubMed] [Google Scholar]; (b) Stoffels MA; Klauck FJR; Hamadi T; Glorius F; Leker J Technology Trends of Catalysts in Hydrogenation Reactions: A Patent Landscape Analysis. Adv. Synth. Catal 2020, 362, 1258–1274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (39).For a discussion on the characteristics of a scalable reaction, see:; Rossen K Greening Organic Chemistry with Process Chemistry. J. Org. Chem 2019, 84, 4580–4582 and references cited therein. [DOI] [PubMed] [Google Scholar]
  • (40).For selected reviews on enantioselective hydrogenation and transfer hydrogenation in the synthesis of pharmaceutical ingredients, see:; (a) Hawkins JM; Watson TJN Asymmetric Catalysis in the Pharmaceutical Industry. Angew. Chem. Int. Ed 2004, 43, 3224–3228. [DOI] [PubMed] [Google Scholar]; (b) Thommen M Homogeneous Asymmetric Hydrogenation: Mature and Fit for Early Stage Drug Development. Spec. Chem. Mag 2005, 25, 26–28. [Google Scholar]; (c) Thayer AM Chiral Catalysis. Chem. Eng. News 2005, 83, 40–58. [Google Scholar]; (d) Farina V; Reeves JT; Senanayake CH; Song JJ Asymmetric Synthesis of Active Pharmaceutical Ingredients. Chem. Rev 2006, 106, 2734–2793. [DOI] [PubMed] [Google Scholar]; (e) Carey JS; Laffan D; Thomson C; Williams MT Analysis of The Reactions Used for The Preparation of Drug Candidate Molecules. Org. Biomol. Chem 2006, 4, 2337–2347. [DOI] [PubMed] [Google Scholar]; (f) Ager DJ; de Vries AHM; de Vries JG Asymmetric Homogeneous Hydrogenations at Scale. Chem. Soc. Rev 2012, 41, 3340–3380. [DOI] [PubMed] [Google Scholar]; (g) Etayo P; Vidal-Ferran A Rhodium-Catalyzed Asymmetric Hydrogenation as a Valuable Synthetic Tool for The Preparation of Chiral Drugs. Chem. Soc. Rev 2013, 42, 728–754. [DOI] [PubMed] [Google Scholar]; (h) Hayler JD; Leahy DK; Simmons EM A Pharmaceutical Industry Perspective on Sustainable Metal Catalysis. Organometallics 2019, 38, 36–46. [Google Scholar]; (i) Biosca M; Dieguez M; Zanotti-Gerosa A Asymmetric Hydrogenation in Industry. Adv. Catal 2021, 68, 241–283. [Google Scholar]
  • (41).For reviews on metal-catalyzed hydrogenolysis of Csp2-X bonds, see:; (a) Pinder AR The Hydrogenolysis of Organic Halides. Synthesis 1980, 425–452. [Google Scholar]; (b) Urbano FJ; Marinas JM Hydrogenolysis of Organohalogen Compounds over Palladium Supported Catalysts. J. Mol. Catal. A Chem 2001, 173, 329–345. [Google Scholar]; (c) Alonso F; Beletskaya IP; Yus M Metal-Mediated Reductive Hydrodehalogenation of Organic Halides. Chem. Rev 2002, 102, 4009–4092. [DOI] [PubMed] [Google Scholar]
  • (42).For oxidative addition of aryl halides to monophosphine- (ref. a-d) and bisphosphine-ligated (ref. e,f) rhodium(I) complexes, see:; (a) Jiao Y; Brennessel WW; Jones WD Oxidative Addition of Chlorohydrocarbons to a Rhodium Tris(pyrazolyl)borate Complex. Organometallics 2015, 34, 1552‒1566. [Google Scholar]; (b) Townsend NS; Chaplin AB; Abu Naser M; Thompson AL; Rees NH; Macgregor SA; Weller AS Reactivity of the Latent 12-Electron Fragment [Rh(PiBu3)2]+ with Aryl Bromides: Aryl‒Br and Phosphine Ligand C‒H Activation. Chem. Eur. J 2010, 16, 8376‒8389. [DOI] [PubMed] [Google Scholar]; (c) Chen S; Li Y; Zhao J; Li X Chelation-Assisted Carbon-Halogen Bond Activation by a Rhodium(I) Complex. Inorg. Chem 2009, 48, 1198‒1206. [DOI] [PubMed] [Google Scholar]; (d) Douglas TM; Chaplin AB; Weller AS Dihydrogen Loss from a 14-Electron Rhodium(III) Bis-Phosphine Dihydride to Give a Rhodium(I) Complex That Undergoes Oxidative Addition with Aryl Chlorides. Organometallics 2008, 27, 2918‒2921. [Google Scholar]; (e) Pike SD; Weller AS C–Cl Activation of the Weakly Coordinating Anion [B(3,5-Cl2C6H3)4]– at a Rh(I) Centre in Solution and the Solid-State Dalton Trans 2013, 42, 12832‒12835. [DOI] [PubMed] [Google Scholar]; (f) Koenig A; Fischer C; Alberico E; Selle C; Drexler H-J; Baumann W; Heller D Oxidative Addition of Aryl Halides to Cationic Bis(phosphane)rhodium Complexes: Application in C–C Bond Formation. Eur. J. Inorg. Chem 2017, 2040‒2047. [Google Scholar]
  • (43).For migratory insertion of aldehyde C=O π-bonds into aryl-rhodium σ-bonds and the reverse process (β-aryl elimination), see:; (a) Krug C; Hartwig JF Direct Observation of Aldehyde Insertion into Rhodium–Aryl and –Alkoxide Complexes. J. Am. Chem. Soc 2002, 124, 1674‒1679. [DOI] [PubMed] [Google Scholar]; (b) Zhao P; Incarvito CD; Hartwig JF Direct Observation of β-Aryl Eliminations from Rh(I) Alkoxides. J. Am. Chem. Soc 2006, 124, 3124‒3125. [DOI] [PubMed] [Google Scholar]
  • (44).For O-H reductive elimination of group 9 alkoxides, see:; (a) Milstein D Carbon-Hydrogen vs. Oxygen-Hydrogen Reductive Elimination of Methanol from a Metal Complex. Which is a More Likely Process? J. Am. Chem. Soc 1986, 108, 3525‒3526. [Google Scholar]; (b) Glueck DS; Winslow LJN; Bergman RG Iridium Alkoxide and Amide Hydride Complexes. Synthesis, Reactivity, and the Mechanism of Oxygen-Hydrogen and Nitrogen-Hydrogen Reductive Elimination Organometallics 1991, 10, 1462‒1479. [Google Scholar]; (c) Blum O; Milstein D Direct Observation of O‒H Reductive Elimination from IrIII Complexes Angew. Chem. Int Ed 1995, 34, 229‒231. [Google Scholar]
  • (45).For cesium-ion effects in catalysis, see:; Jung W-O; Mai BK; Yoo M; Shields WJ; Zbieg JR; Stivala CE; Liu P; Krische MJ Kinetic, ESI-CID-MS and Computational Studies of π-Allyliridium C,O-Benzoate-Catalyzed Allylic Amination: Understanding the Effect of Cesium Ion. ACS Catal 2022, 12, 3660–3668 and references cited therein. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (46).Spinello BJ; Ortiz E; Evarts MM; Strong ZH; Krische MJ Intermolecular Metal-Catalyzed C‒C Coupling of Unactivated Alcohols or Aldehydes for Convergent Ketone Construction beyond Premetalated Reagents. ACS Catal 2023, 13, 10976–10987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (47).For selected reviews on the synthesis of ketones from Weinreb amides, see:; (a) Balasubramaniam S; Aidhen IS The Growing Synthetic Utility of the Weinreb Amide. Synthesis 2008, 3707–3738. [Google Scholar]; (b) Nowak M Weinreb Amides. Synlett 2015, 26, 561–562. [Google Scholar]
  • (48).Analysis of >9 million patents reveals that cross-coupling is the foremost method for C-C bond formation in medicinal chemistry:; Schneider N; Lowe DM; Sayle RA; Tarselli MA; Landrum GA Big Data from Pharmaceutical Patents: A Computational Analysis of Medicinal Chemists’ Bread and Butter. J. Med. Chem 2016, 59, 4385–4402. [DOI] [PubMed] [Google Scholar]
  • (49).A moderately efficient π-crotylpalladium(II) chloride complex was identified by high-throughput experimentation. Closely related complexes were known to form halide-bridged PdI-dimers:; Hruszkewycz DP; Balcells D; Guard LM; Hazari N; Tilset M Insight into the Efficiency of Cinnamyl-Supported Precatalysts for the Suzuki–Miyaura Reaction: Observation of Pd(I) Dimers with Bridging Allyl Ligands during Catalysis. J. Am. Chem. Soc 2014, 136, 7300–7316. [DOI] [PubMed] [Google Scholar]
  • (50).(a) Billingsley KL; Buchwald SL A General and Efficient Method for the Suzuki-Miyaura Coupling of 2-Pyridyl Nucleophiles. Angew. Chem. Int. Ed 2008, 47, 4695–4698. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Dick GR; Woerlyl EM; Burke MD A General Solution for the 2-Pyridyl Problem. Angew. Chem. Int. Ed 2012, 51, 2667–2672. [DOI] [PMC free article] [PubMed] [Google Scholar]; (c) Cook XAF; de Gombert A; McKnight J; Pantaine LRE; Willis MC The 2-Pyridyl Problem: Challenging Nucleophiles in Cross-Coupling Arylations. Angew. Chem. Int. Ed 2021, 60, 11068–11091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (51).The bimetallic palladium complex [Pd2I6][NBu4]2 has previously been prepared:; (a) Chan S; Lee S-M; Lin Z; Wong W-T Syntheses, Structures and Reactivities of [Os6Pd(CO)18(bipy)] and [{(bipy)Pd}2Os3(CO)12]: Crystal and Molecular Structures of [{(bipy)Pd}2(μ-H)(μ-CO)][H3Os4(CO)12] and [(C4H9)4N]2[Pd2I6]. J. Organomet. Chem 1996, 510, 219–231. [Google Scholar]; (b) Linnenberg O; Mayerl L; Monakhov KY The Heck Reaction as a Tool to Expand Polyoxovanadates towards Thiol-Sensitive Organic–Inorganic Hybrid Fluorescent Switches. Dalton Trans 2018, 47, 14402–14407. [DOI] [PubMed] [Google Scholar]
  • (52).For Pd-to-Pd transmetalation, see:; (a) Wang D; Izawa Y; Stahl SS Pd-Catalyzed Aerobic Oxidative Coupling of Arenes: Evidence for Transmetalation between Two Pd(II)-Aryl Intermediates. J. Am. Chem. Soc 2014, 136, 9914–9917. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Pérez-Iglesias M; Lozano-Lavilla O; Casares JA [Cu(C6Cl2F3)(tht)]4: An Extremely Efficient Catalyst for the Aryl Scrambling between Palladium Complexes. Organometallics 2019, 38, 739–742. [Google Scholar]; (c) Lin Z; Oliveira JCA; Scheremetjew A; Ackermann L Palladium-Catalyzed Electrooxidative Double C–H Arylation. J. Am. Chem. Soc 2024, 146, 228–239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (53).Shekhar S; Hartwig JF Distinct Electronic Effects on Reductive Eliminations of Symmetrical and Unsymmetrical bis-Aryl Platinum Complexes. J. Am. Chem. Soc 2004, 126, 13016–13027. [DOI] [PubMed] [Google Scholar]
  • (54).For selected reviews on cine-substitution, see:; (a) Suwiński J; Świerczek K Cine- and Tele-Substitution Reactions. Tetrahedron 2001, 57, 1639–1662. [Google Scholar]; (b) Peng Y; Li W-DZ Cine Substitution and the Cu Effect in Stille Cross-Coupling Reactions: Mechanistic Perspectives and Synthetic Utility. Eur. J. Org. Chem 2010, 2010, 6703–6718. [Google Scholar]; (c) Suwiński J Cine- and Tele-Substitution Reactions: Review of Work from 2002–2016. Arkivoc 2017, 402–435. [Google Scholar]
  • (55).Johansson Seechurn CCC; Sperger T; Scrase TG; Schoenebeck F; Colacot TJ Understanding the Unusual Reduction Mechanism of Pd(II) to Pd(I): Uncovering Hidden Species and Implications in Catalytic Cross-Coupling Reactions. J. Am. Chem. Soc 2017, 139, 5194–5200. [DOI] [PubMed] [Google Scholar]
  • (56).Calculations suggest the iodide-bridged palladium(I) dimers are considerably more stable than the bromide-bridged dimers:; (a) Bonney KJ; Proutiere F; Schoenebeck F Dinuclear Pd(I) Complexes–Solely Precatalysts? Demonstration of Direct Reactivity of a Pd(I) Dimer with an Aryl Iodide. Chem. Sci 2013, 4, 4434–4439. [Google Scholar]; (b) Kalvet I; Bonney KJ; Schoenebeck F Kinetic and Computational Studies on Pd(I) Dimer-Mediated Halogen Exchange of Aryl Iodides. J. Org. Chem 2014, 79, 12041–12046. [DOI] [PubMed] [Google Scholar]
  • (57).Carrow BP; Hartwig JF Ligandless, Anionic, Arylpalladium Halide Intermediates in the Heck Reaction. J. Am. Chem. Soc 2010, 132, 79–81. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • (58).PdIVI2 carbenes have been characterized by single crystal X-ray diffraction and display a square planar geometry, see:; (a) Kablitz H-J; Kallweit R; Wilke G Dicyclooctatetraen-Hafnium und Derivate. J. Organomet. Chem 1972, 37, C49–C50. [Google Scholar]; (b) Herrmann WA; Goossen LJ; Spiegler M Functionalized Imidazoline-2-ylidene Complexes of Rhodium and Palladium. J. Organomet. Chem 1997, 547, 357–366. [Google Scholar]; (c) Bildstein B; Malaun M; Kopacka H; Ongania K-H; Wurst K Imidazoline-2-ylidene Metal Complexes with Pendant Ferrocenyl Substituents. J. Organomet. Chem 1998, 552, 45–61. [Google Scholar]; (d) Xu L; Chen W; Bickley JF; Steiner A; Xiao J Fluoroalkylated N-heterocyclic Carbene Complexes of Palladium. J. Organomet. Chem 2000, 598, 409–416. [Google Scholar]; (e) Buron C; Stelzig L; Guerret O; Gornitzka H; Romanenko V; Bertrand G Synthesis and Structure of 1,2,4-Triazol-2-ium-5-ylidene Complexes of Hg(II), Pd(II), Ni(II), Ni(0), Rh(I) and Ir(I). J. Organomet. Chem 2002, 664, 70–76. [Google Scholar]; (f) Albrecht M; Stoeckli-Evans H Catalytically Active Palladium Pyridylidene Complexes: Pyridinium Ionic Liquids as N-Heterocyclic Carbene Precursors. Chem. Commun 2005, 4705–4707. [DOI] [PubMed] [Google Scholar]; (g) Anisimova TB; Guedes da Silva MFC; Kukushkin VY; Pombeiro AJL; Luzyanin KV Metal-Mediated Coupling of Amino Acid Esters with Isocyanides Leading to New Chiral Acyclic Aminocarbene Complexes. Dalton Trans 2014, 43, 15861–15871. [DOI] [PubMed] [Google Scholar]; (h) Chernenko AY; Astakhov AV; Kutyrev VV; Gordeev EG; Burykina JV; Minyaev ME; Khrustalev VN; Chernyshev VM; Ananikov VP Stabilization of the Pd–NHC Framework with 1,2,4-Triazol-5-ylidene Ligands toward Decomposition in Alkaline Media. Inorg. Chem. Front 2021, 8, 3382–3401. [Google Scholar]
  • (59).(a) Dewar MJS A Review of the π-Complex Theory. Bull. Soc. Chim. Fr 1951, C71–C79. [Google Scholar]; (b) Chatt J; Duncanson LA Olefin Co-ordination Compounds. Part III. Infra-red Spectra and Structure: Attempted Preparation of Acetylene Complexes. J. Chem. Soc 1953, 2939–2947. [Google Scholar]; (c) Dewar MJS; Ford GP Relationship between Olefinic π Complexes and Three-Membered Rings. J. Am. Chem. Soc 1979, 101, 783–791. [Google Scholar]
  • (60).(a) Jeffrey T Palladium-Catalysed Vinylation of Organic Halides under Solid-Liquid Phase Transfer Conditions. J. Chem. Soc. Chem. Comm 1984, 1287–1289. [Google Scholar]; (b) Jeffrey T Highly Stereospecific Palladium-Catalysed Vinylation of Vinylic Halides under Solid-Liquid Phase Transfer Conditions. Tetrahedron Lett 1985, 26, 2667–2670. [Google Scholar]; (c) Jeffrey T On the Efficiency of Tetraalkylammonium Salts in Heck Type Reactions. Tetrahedron 1996, 52, 10113–10130. [Google Scholar]

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