Skip to main content
NCBI home page
JACS Au logoLink to JACS Au
. 2022 Jul 25;2(8):1929–1934. doi: 10.1021/jacsau.2c00320

Nickel-Catalyzed Stereoselective Alkenylation of Ketones Mediated by Hydrazine

Shumei Xia †,‡, Dawei Cao †,§, Huiying Zeng §, Liang-Nian He ‡,*, Chao-Jun Li †,*
PMCID: PMC9400169  PMID: 36032538

Abstract

graphic file with name au2c00320_0009.jpg

The direct conversion of naturally abundant carbonyl compounds provides a powerful platform for the efficient synthesis of valuable chemicals. In particular, the conversion of ketones to alkenes is a commonly encountered chemical transformation, often achieved via the multistep Shapiro reaction with tosylhydrazone and over stoichiometric organolithium or Grignard reagent. Herein, we report an earth abundant nickel-catalyzed alkenylation of naturally abundant methylene ketones to afford a wide range of alkene derivatives, mediated by hydrazine. The protocol features a broad substrate scope (including alkyl ketones, aryl ketones, and aldehydes), good functional group compatibility, mild reaction conditions, water tolerance, and only environmentally friendly N2, H2, and H2O as theoretical byproducts. Moreover, gram-scale synthesis with good yield and generation of pharmaceutical intermediates highlighted its practical applicability.

Keywords: alkenylation, ketones, hydrazone, hydrazine, nickel catalysis

1. Introduction

Alkenes are basic constitutional units, which are prevalent in natural products, pharmaceuticals, and common organic molecules. In addition, alkenes act as versatile intermediates in chemical transformations.1 Consequently, efficient methods toward facile synthesis of alkenes have long been a core pursuit in synthetic chemistry.2 The carbonyl olefination has emerged as a powerful tool due to the easy availability and synthetic versatility of carbonyl compounds. Seminal discoveries include the Wittig reaction,3 Homer–Wittig reaction,4 Tebbe–Petasis olefination,5 Peterson olefination6 and Julia–Lythgoe olefination,7 among others. In comparison to these classical Wittig-type reaction mechanisms involving the carbon-chain elongation, the direct alkenylation of aldehydes/ketones to deliver alkenes has received considerably less attention.

As early as in 1969, pioneered by Shapiro’s work,8 a reliable strategy based on a base-induced tosylhydrazone reaction realized the conversion of ketones to alkenes. Despite its remarkable importance, the requirement of an air-sensitive strong base (e.g., BuLi) resulted in a limited substrate scope and was accompanied by the formation of equivalent metal wastes (Scheme 1a). To pursuit a more maneuverable and general alkenylation process, Fernandes and co-workers demonstrated an elegant method allowing access to alkenes from ketones via oxo-rhenium catalysis with pentanol as the reducing agent (Scheme 1b).9 More recently, a rhodium-catalyzed deoxygenation of ketones with B2pin2 to deliver alkenes has been established by Zhao and co-workers (Scheme 1c),10 in which a boron enolate intermediate was proven to be the key for success. However, the existing alkenylation strategies are relatively scarce and still have limitations for large scale synthesis and application due to the requirement of stoichiometric amounts of air/moisture-sensitive organometallic reagents, high temperature,9 or noble metal catalyst.11 Hence, a sustainable and practical strategy, using an inexpensive and ubiquitous first row transition-metal catalyzed system, to access high valued alkenes from naturally prevailing ketones (aldehydes) remains highly desirable and challenging.

Scheme 1. Strategies for Deoxygenation of Aldehydes and Ketones.

Scheme 1

Open in a new tab

Hydrazine, acting as an ideal mediator for the in situ hydrazone formation via its condensation with ketones/aldehydes, plays an important role in various organic transformations because of the inherent advantages of being readily available in large quantities and inexpensive as well as easy to handle (note: the hydrate form).12 The classical Wolff–Kishner (WK) reduction mediated by hydrazine enables direct reduction of C=O bonds for facile preparation of methylene derivatives.13 Inspired by the WK reduction, our group made significant progress in the development of umpolung aldehydes/ketones that act as carbanion equivalents in the catalytic addition reactions,14 cross-couplings,15 homocouplings,16 and carboxylation with carbon dioxide.17 In view of the significance of olefin structural motifs in chemical products and chemical transformations, we contemplated the feasibility of utilizing N2H4 as both the mediator and the reductant to realize the direct alkenylation to facilitate efficient synthesis of alkenes from carbonyl compounds.

Herein, we describe a distinct strategy for the efficient preparation of alkenes via a nickel-catalyzed direct alkenylation of naturally rich ketones mediated by hydrazine (Scheme 1d), by successfully inhibiting the competing WK reduction, deoxygenative homocoupling reaction and direct coupling of hydrazones. The highlights of this novel olefination strategy are the following: (a) inexpensive and first-row abundant nickel catalyst; (b) broad substrate scope (aryl ketones and alkyl ketones, common in renewable feedstocks); (c) good functional group tolerance with high chem- and stereoselectivity; (d) low cost hydrazine as both key mediator and reductant; (e) only N2, H2, and H2O as environmentally benign side (theoretical) products, and (f) synthetic demonstration of pharmaceutical intermediates.

2. Results and Discussion

2.1. Optimization of the Reaction Conditions

Initially, hydrazone 2h, generated from 1-phenylbutan-1-one (1h), was chosen as the model substrate to explore the reaction conditions (Table 1). Inspired by ours and other group’s recent achievements in the carbonyl conversions,16,18 we evaluated various reaction factors including different nickel catalysts, ligands (phosphine- and carbene-based ligands), solvents, and temperatures (see SI for more details). The target product (E)-1-butenylbenzene (3h) was obtained in 32% yield with excellent stereoselectivity under a NiCl2/IPr·HCl catalytic system mediated by hydrazine with DBU as the base at 100 °C (Table 1, entry 1), together with butylbenzene, octane-4,5-diyldibenzene, and azines as side products. Based on this promising result, various nickel catalysts with different ligands such as Ni(DME)Cl2, Ni(dppe)Cl2, Ni(dmpe)Cl2, Ni(PCy3)2Cl2, and Ni(Py)4Cl2 were examined and all gave comparable results, while Ni(PPh3)2Cl2 afforded a 62% yield of product 3h (Table 1, entries 2–7). Bases were subsequently investigated, considering their key role in the hydrazone deprotonation process according to our previous work.16 Parallel experiments demonstrated that 1,5,7-triazabicyclo[4,4,0]dec-5-ene (TBD), a relatively strong base, provided a higher yield than triethylenediamine (DABCO), Et3N, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (Table 1, entries 8–10), while inorganic bases like KOH and t-BuOK lowered the product yield, possibly due to their poor solubility in the reaction system (Table 1, entries 11–12). To our delight, increasing the amount of THF to 1.5 mL efficiently facilitated the desired transformation to give an optimal yield of product 3h, while no further improvement was observed with more THF (Table 1, entries 13 and 14). Decreasing THF amount to 0.5 mL led to a significant drop in yield, due to the competing Wolff–Kishner reduction (Table 1, entry 15). Moreover, the transformation could also be performed for 16 h or under air atmosphere to give 63% and 40% yield of the desired product, respectively (Table 1, entries 16 and 17). Besides, no or only 15% yield of the alkenylation product was detected in the control experiments, demonstrating the indispensability of Ni catalyst/ligand and base (Table 1, entries 18–20).

Table 1. Optimization of the Reaction Conditionsa,b.

2.1.

entry catalyst ligand base solvent (mL) 3h yield (%)c
1 NiCl2 IPr·HCl DBU 1 32
2 Ni(DME)Cl2 IPr·HCl DBU 1 33
3 Ni(dppe)Cl2 IPr·HCl DBU 1 15
4 Ni(dmpe)Cl2 IPr·HCl DBU 1 31
5 Ni(PCy3)2Cl2 IPr·HCl DBU 1 45
6 Ni(Py)4Cl2 IPr·HCl DBU 1 n.p.
7 Ni(PPh3)2Cl2 IPr·HCl DBU 1 62
8 Ni(PPh3)2Cl2 IPr·HCl TBD 1 73
9 Ni(PPh3)2Cl2 IPr·HCl Et3N 1 15
10 Ni(PPh3)2Cl2 IPr·HCl DABCO 1 trace
11 Ni(PPh3)2Cl2 IPr·HCl KOH 1 8
12 Ni(PPh3)2Cl2 IPr·HCl tBuOK 1 trace
13 Ni(PPh3)2Cl2 IPr·HCl TBD 1.5 90 (85)
14 Ni(PPh3)2Cl2 IPr·HCl TBD 2 88
15 Ni(PPh3)2Cl2 IPr·HCl TBD 0.5 72
16d Ni(PPh3)2Cl2 IPr·HCl TBD 1.5 63
17e Ni(PPh3)2Cl2 IPr·HCl TBD 1.5 40
18 - IPr·HCl TBD 1.5 n.p.
19 Ni(PPh3)2Cl2 - TBD 1.5 15
20 Ni(PPh3)2Cl2 IPr·HCl - 1.5 n.p.
Open in a new tab
a

Main byproducts:a

b

General conditions: 2 h (0.2 mmol), catalyst (0.04 mmol, 20 mol %), ligand (0.04 mmol, 20 mol %), base (0.2 mmol, 1 equiv), and solvent (x mL) at 100 °C for 24 h under an argon atmosphere; isolated yields in brackets. n.p.: no product.

c

Yields were determined by 1H NMR with dibromomethane as internal standard.

d

16 h.

e

Air atmosphere.

2.2. Scope of the Alkenylation Reaction

With the optimized conditions identified, the scope of carbonyl compounds for the direct alkenylation was subsequently investigated. As shown in Table 2, for various aryl alkyl ketones, the alkenylation delivered (E)-alkenes as the main product, as confirmed by 1H NMR and GC-MS analysis, with high stereoselectivity (generally E/Z > 90/10). Propiophenones bearing both electron-donating (MeO-, 3,4-dimethoxy-) and electron-withdrawing (Cl-) groups all proceeded smoothly to afford the corresponding (E)-alkenes 3a–3f. The desired product 3g could also be obtained in 70% yield when a substrate containing a protected phenolic hydroxyl group was tested. Aryl alkyl ketones with different chain lengths or branched chains were suitable substrates, providing the olefination products 3h–3l in high yields. Notably, various polycyclic/heterocyclic (e.g., indene, naphthalene, dioxole, pyridine, thiophene) aryl alkyl ketones, as important motifs of pharmaceuticals, underwent the alkenylation efficiently in our system (3m–3q). Unfortunately, for the 4-phenyl-3-buten-2-one substrate, only a trace yield of the desired product 3r was detected by GC-MS, probably due to the rapid competing formation of azines under high temperature. To our delight, regardless of the carbonyl group locating at the α- or the β-site, arylbenzyl/dibenzyl and aryl phenethyl ketones all worked well with moderate to excellent yields (3s–3ac). Among them, when the aromatic ring contains a substituent, mixed products were obtained. This protocol also worked well for the alkenylation of benzocyclic ketones: for example, benzo five-, six-, and seven-membered cyclic ketones could react smoothly to give the corresponding products 3ad–3af in excellent yields. Moreover, naphthocyclohexanone, benzoheterocyclic ketone, and substituted benzocyclic ketones were also applicable in this transformation to generate the desired products 3ag–3ak. It is worth noting that when the substituted benzo five-membered cyclic ketones were used as substrates, mixed products were also obtained during the reaction process. In addition, aryl methyl ketones containing electron-donating (MeO–, PhO–, 3,4-dimethoxy–, Ph−) and electron-withdrawing (Br–, CF3−) groups all worked well to give the desired products 3al–3ar, albeit with lower efficiency. Alkyl aldehydes such as phenyl acetaldehyde and phenylpropyl aldehyde were also investigated, affording the desired products 3as–3at in trace and 18% yields. 5-Nonanone and cycloheptanone were also viable substrates 3au–3av; however, several double-bond migration isomers were detected by GC-MS with 5-nonanone as the substrate. Furthermore, piperitone and carvone, as common ketones in medicines and fragrances, were converted into the corresponding olefin products 3aw–3ax by the present nickel-catalyzed alkylenation system, albeit in low yield mainly due to the competing WK reduction products, homocoupling products, ketones, and azines.

Table 2. Substrate Scope of the Alkenylation Reactiona.

2.2.

2.2.

Open in a new tab
a

General conditions: 2 (0.2 mmol), Ni(PPh3)2Cl2 (0.04 mmol, 20 mol %), IPr·HCl (0.04 mmol, 20 mol %), TBD (0.2 mmol, 1 equiv), and THF (1.5 mL) at 100 °C for 24 h under an argon atmosphere; isolated yields.

b

Detected by GC-MS.

2.3. Application

To explore the practicality of the current protocol, a gram-scale experiment of 2a, generated from propiophenone (1a), was performed, and the alkenylation product 3a was obtained in 65% yield by prolonging the reaction time to 36 h (Scheme 2a). LY223982, a potent and selective antagonist of leukotriene B4, has been selected for clinical trials in human.19 To evaluate the synthetic potentials of the present alkenylation reaction, alkene 9 was successfully synthesized under standard reaction conditions, which can be used as a precursor for the synthesis of LY223982 (Scheme 2b). These results exemplified the utility and generality of our protocol in the late-stage synthesis and modification of complex molecules.

Scheme 2. Applications of the Alkenylation Reaction.

Scheme 2

Open in a new tab

2.4. Mechanistic Investigation

To shed light on the mechanism of this alkenylation chemistry, we performed several control experiments (Scheme 3). When deuterated hydrazones (d-2aa and d-2aa′) were subjected to the standard reaction conditions, similar deuterium incorporation at the 1-, 2-, and 3-positions of the corresponding alkene d-3aa was observed by 1H NMR spectroscopic analysis, indicating the facile H/D exchanges of N–H with C–H bond of ketone (Scheme 3a). Furthermore, the isomerization experiments of cis-alkene 3s was explored under the standard reaction conditions, and no 3s-(E) was detected (Scheme 3b), indicating that the alkenylation process directly forms trans-alkenes without involving an isomerization of cis-alkene and further demonstrating the excellent stereoselectivity of the system.

Scheme 3. Mechanistic Study.

Scheme 3

Open in a new tab

Based on our previous works12,14,16 and the above experimental results, a plausible reaction mechanism is depicted in Scheme 4. Initially, the potential coordination between the active nickel species A with hydrazone anion formed in situ from hydrazone with base affords nickel complex B. It is worth mentioning that complex B undergoes the deprotonation with the assistance of base to deliver the nickel hydrazine carbanion complex C, instead of directly releasing N2 from intermediate B as reported in the previous work.16 The intramolecular cyclization of complex C delivers a nickel pyrazole ring complex D, followed by extrusion release of N2 and H2 to afford the desired alkene derivatives 3, and regenerates the active catalyst A. The formation of complex D rationalizes the generation of double-bond migration olefin isomers.

Scheme 4. Proposed Mechanism.

Scheme 4

Open in a new tab

3. Conclusions

In conclusion, we have established a simple and clean stereoselective alkenylation reaction of carbonyl compounds mediated by hydrazine and catalyzed by commercially available nickel catalyst as a sustainable protocol to access alkenes derivatives. Notably, prominent features of the strategy include broad substrate scope, earth-abundant metal catalyst, high chem- and stereoselectivity, only N2, H2, and H2O as environmentally benign side products, and synthesis of a commercial pharmaceutical precursor for LY223982. This inexpensive Ni-catalyzed system offers an efficient and reliable alkenylation to access versatile alkenes, as well as a novel avenue for the conversion and utilization of naturally rich ketones in organic synthesis

4. Methods

4.1. General Experimental Procedure

In a glovebox, a flame-dried reaction tube (10 cm3) equipped with a magnetic stir bar was charged with Ni(PPh3)2Cl2 (26.2 mg, 0.04 mmol, 20 mol %), IPr·HCl (17.0 mg, 0.04 mmol, 20 mol %), TBD (27.8 mg, 0.2 mmol), substrates (0.2 mmol), and THF (1.5 mL) before being sealed with a rubber septum. The tube was placed in a preheated oil bath at 100 °C, and the mixture was stirred under an argon atmosphere for 24 h. The reaction mixture was cooled to room temperature and concentrated; the NMR yield was determined by 1H NMR using dibromomethane as an internal standard. The residue was purified by preparative TLC on silica gel eluting with hexane: EtOAc (200:1–2:1) to afford the products. (Note: For obtaining products’ E/Z ratios, after the reaction, the mixture was cooled to room temperature and concentrated; then quantitative dibromomethane was added into the mixture as an internal standard, and the E/Z ratio was determined by 1H NMR. In addition, for products whose E/Z ratio cannot be obtained by 1H NMR, it is necessary to further determine the E/Z ratio by GC-MS using n-dodecane as the internal standard.)

Acknowledgments

We thank NSERC, CFI, FQRNT, and Canada Research Chair (to C.J.L.). S.X. is grateful for support from China Scholarship Council and National Natural Science Foundation of China (21975135, 22005154). D.C. is grateful for support from Lanzhou University. We would like to thank Dr. Ruofei Cheng (McGill University, Canada) for reproducing the results presented for substrate 1e in Table 2.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacsau.2c00320.

  • Experimental procedures, characterization data of products, and calculation details (PDF)

Author Contributions

∥ (S.X. and D.C.) These authors contributed equally.

The authors declare no competing financial interest.

Supplementary Material

au2c00320_si_001.pdf (4.3MB, pdf)

References

  1. a Beller M.; Seayad J.; Tillack A.; Jiao H. Catalytic Markovnikov and anti-Markovnikov Functionalization of Alkenes and Alkynes: Recent Developments and Trends. Angew. Chem., Int. Ed. 2004, 43 (26), 3368–3398. 10.1002/anie.200300616. [DOI] [PubMed] [Google Scholar]; b Dong Z.; Ren Z.; Thompson S. J.; Xu Y.; Dong G. Transition-Metal-Catalyzed C–H Alkylation Using Alkenes. Chem. Rev. 2017, 117 (13), 9333–9403. 10.1021/acs.chemrev.6b00574. [DOI] [PubMed] [Google Scholar]
  2. a Guo X.; Wang J.; Li C.-J. An Olefination via Ruthenium-Catalyzed Decarbonylative Addition of Aldehydes to Terminal Alkynes. J. Am. Chem. Soc. 2009, 131 (42), 15092–15093. 10.1021/ja906265a. [DOI] [PubMed] [Google Scholar]; b Hoveyda A. H.; Zhugralin A. R. The Remarkable Metal-Catalysed Olefin Metathesis Reaction. Nature 2007, 450 (7167), 243–251. 10.1038/nature06351. [DOI] [PubMed] [Google Scholar]; c Ludwig J. R.; Zimmerman P. M.; Gianino J. B.; Schindler C. S. Iron(III)-Catalysed Carbonyl–Olefin Metathesis. Nature 2016, 533 (7603), 374–379. 10.1038/nature17432. [DOI] [PubMed] [Google Scholar]; d Takemoto S.; Shibata E.; Nakajima M.; Yumoto Y.; Shimamoto M.; Matsuzaka H. Ruthenium-Sulfonamide-Catalyzed Direct Dehydrative Condensation of Benzylic C–H Bonds with Aromatic Aldehydes. J. Am. Chem. Soc. 2016, 138 (45), 14836–14839. 10.1021/jacs.6b08863. [DOI] [PubMed] [Google Scholar]
  3. Maryanoff B. E.; Reitz A. B. The Wittig Olefination Reaction and Modifications Involving Phosphoryl-Stabilized Carbanions. Stereochemistry, Mechanism, and Selected Synthetic Aspects. Chem. Rev. 1989, 89 (4), 863–927. 10.1021/cr00094a007. [DOI] [Google Scholar]
  4. Wadsworth W. S.; Emmons W. D. The Utility of Phosphonate Carbanions in Olefin Synthesis. J. Am. Chem. Soc. 1961, 83 (7), 1733–1738. 10.1021/ja01468a042. [DOI] [Google Scholar]
  5. Tebbe F. N.; Parshall G. W.; Reddy G. S. Olefin Homologation with Titanium Methylene Compounds. J. Am. Chem. Soc. 1978, 100 (11), 3611–3613. 10.1021/ja00479a061. [DOI] [Google Scholar]
  6. a Peterson D. J. Carbonyl Olefination Reaction using Silyl-Substituted Organometallic Compounds. J. Org. Chem. 1968, 33 (2), 780–784. 10.1021/jo01266a061. [DOI] [Google Scholar]; b Staden L. F. v.; Gravestock D.; Ager D. J. New Developments in the Peterson Olefination Reaction. Chem. Soc. Rev. 2002, 31 (3), 195–200. 10.1039/a908402i. [DOI] [PubMed] [Google Scholar]
  7. Baudin J. B.; Hareau G.; Julia S. A.; Ruel O. A Direct Synthesis of Olefins by Reaction of Carbonyl Compounds with Lithio Derivatives of 2-[alkyl- or (2′-alkenyl)- or Benzyl-Sulfonyl]-Benzothiazoles. Tetrahedron Lett. 1991, 32 (9), 1175–1178. 10.1016/S0040-4039(00)92037-9. [DOI] [Google Scholar]
  8. a Adlington R. M.; Barrett A. G. M. Recent Applications of the Shapiro Reaction. Acc. Chem. Res. 1983, 16 (2), 55–59. 10.1021/ar00086a004. [DOI] [Google Scholar]; b Maruoka K.; Oishi M.; Yamamoto H. The Catalytic Shapiro Reaction. J. Am. Chem. Soc. 1996, 118 (9), 2289–2290. 10.1021/ja951422p. [DOI] [Google Scholar]
  9. Bernardo J. R.; Fernandes A. C. Deoxygenation of Carbonyl Compounds using an Alcohol as an Efficient Reducing Agent Catalyzed by Oxo-rhenium Complexes. Green Chem. 2016, 18 (9), 2675–2681. 10.1039/C5GC02777B. [DOI] [Google Scholar]
  10. Tao L.; Guo X.; Li J.; Li R.; Lin Z.; Zhao W. Rhodium-Catalyzed Deoxygenation and Borylation of Ketones: A Combined Experimental and Theoretical Investigation. J. Am. Chem. Soc. 2020, 142 (42), 18118–18127. 10.1021/jacs.0c07854. [DOI] [PubMed] [Google Scholar]
  11. a Korstanje T. J.; de Waard E. F.; Jastrzebski J. T. B. H.; Klein Gebbink R. J. M. Rhenium-Catalyzed Dehydration of Nonbenzylic and Terpene Alcohols to Olefins. ACS Catal. 2012, 2 (10), 2173–2181. 10.1021/cs300455w. [DOI] [Google Scholar]; b Mahdi T.; Stephan D. W. Facile Protocol for Catalytic Frustrated Lewis Pair Hydrogenation and Reductive Deoxygenation of Ketones and Aldehydes. Angew. Chem., Int. Ed. 2015, 54 (29), 8511–8514. 10.1002/anie.201503087. [DOI] [PubMed] [Google Scholar]; c Yang Z.; Zhu X.; Yang S.; Cheng W.; Zhang X.; Yang Z.-h. Iridium-Catalysed Reductive Deoxygenation of Ketones with Formic Acid as Traceless Hydride Donor. Adv. Synth. Catal. 2020, 362 (23), 5496–5505. 10.1002/adsc.202000821. [DOI] [Google Scholar]; d Sousa S. C. A.; Fernandes T. A.; Fernandes A. C. Highly Efficient Deoxygenation of Aryl Ketones to Arylalkanes Catalyzed by Dioxidomolybdenum Complexes. Eur. J. Org. Chem. 2016, 2016 (18), 3109–3112. 10.1002/ejoc.201600441. [DOI] [Google Scholar]; e Fernandes T. A.; Bernardo J. R.; Fernandes A. C. Direct Reductive Deoxygenation of Aryl Ketones Catalyzed by Oxo-Rhenium Complexes. ChemCatChem. 2015, 7 (7), 1177–1183. 10.1002/cctc.201402909. [DOI] [Google Scholar]; f Guyon C.; Baron M.; Lemaire M.; Popowycz L.; Métay E. Commutative Reduction of Aromatic Ketones to Arylmethylenes/Alcohols by Hypophosphites Catalyzed by Pd/C under Biphasic Conditions. Tetrahedron 2014, 70 (12), 2088–2095. 10.1016/j.tet.2014.02.014. [DOI] [Google Scholar]
  12. a Cao D.; Chen Z.; Lv L.; Zeng H.; Peng Y.; Li C.-J. Light-Driven Metal-Free Direct Deoxygenation of Alcohols under Mild Conditions. iScience 2020, 23 (8), 101419. 10.1016/j.isci.2020.101419. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Furst A.; Berlo R. C.; Hooton S. Hydrazine as a Reducing Agent for Organic Compounds (Catalytic Hydrazine Reductions). Chem. Rev. 1965, 65 (1), 51–68. 10.1021/cr60233a002. [DOI] [Google Scholar]
  13. Wolff L. Methode zum Ersatz des Sauerstoffatoms der Ketone und Aldehyde durch Wasserstoff. Justus Liebigs Ann. Chem. 1912, 394 (1), 86–108. 10.1002/jlac.19123940107. [DOI] [Google Scholar]
  14. a Chen N.; Dai X.-J.; Wang H.; Li C.-J. Umpolung Addition of Aldehydes to Aryl Imines. Angew. Chem., Int. Ed. 2017, 56 (22), 6260–6263. 10.1002/anie.201610578. [DOI] [PubMed] [Google Scholar]; b Kang H.; Li C.-J. Ruthenium(ii)-Catalyzed Regioselective 1,6-Conjugate Addition of Umpolung Aldehydes as Carbanion Equivalents. Chem. Sci. 2021, 13 (1), 118–122. 10.1039/D1SC03732C. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Li C.-C.; Kan J.; Qiu Z.; Li J.; Lv L.; Li C.-J. Synergistic Relay Reactions To Achieve Redox-Neutral α-Alkylations of Olefinic Alcohols with Ruthenium(II) Catalysis. Angew. Chem., Int. Ed. 2020, 59 (11), 4544–4549. 10.1002/anie.201915218. [DOI] [PubMed] [Google Scholar]; d Lv L.; Li C.-J. Ruthenium Catalyzed β-selective Alkylation of Vinylpyridines with Aldehydes/Ketones via N2H4 Mediated Deoxygenative Couplings. Chem. Sci. 2021, 12 (8), 2870–2875. 10.1039/D0SC06586B. [DOI] [PMC free article] [PubMed] [Google Scholar]; e Lv L.; Yu L.; Qiu Z.; Li C.-J. Switch in Selectivity for Formal Hydroalkylation of 1,3-Dienes and Enynes with Simple Hydrazones. Angew. Chem., Int. Ed. 2020, 59 (16), 6466–6472. 10.1002/anie.201915875. [DOI] [PubMed] [Google Scholar]; f Yu L.; Lv L.; Qiu Z.; Chen Z.; Tan Z.; Liang Y.-F.; Li C.-J. Palladium-Catalyzed Formal Hydroalkylation of Aryl-Substituted Alkynes with Hydrazones. Angew. Chem., Int. Ed. 2020, 59 (33), 14009–14013. 10.1002/anie.202005132. [DOI] [PubMed] [Google Scholar]; g Dai X.-J.; Li C.-C.; Li C.-J. Carbonyl Umpolung as an Organometallic Reagent Surrogate. Chem. Soc. Rev. 2021, 50 (19), 10733–10742. 10.1039/D1CS00418B. [DOI] [PubMed] [Google Scholar]; h Li C.-J.; Huang J.; Dai X.-J.; Wang H.; Chen N.; Wei W.; Zeng H.; Tang J.; Li C.; Zhu D.; Lv L. An Old Dog with New Tricks: Enjoin Wolff–Kishner Reduction for Alcohol Deoxygenation and C–C Bond Formations. Synlett 2019, 30 (13), 1508–1524. 10.1055/s-0037-1611853. [DOI] [Google Scholar]; i Wang H.; Dai X.-J.; Li C.-J. Aldehydes as Alkyl Carbanion Equivalents for Additions to Carbonyl Compounds. Nat. Chem. 2017, 9 (4), 374–378. 10.1038/nchem.2677. [DOI] [PubMed] [Google Scholar]
  15. a Lv L.; Zhu D.; Tang J.; Qiu Z.; Li C.-C.; Gao J.; Li C.-J. Cross-Coupling of Phenol Derivatives with Umpolung Aldehydes Catalyzed by Nickel. ACS Catal. 2018, 8 (5), 4622–4627. 10.1021/acscatal.8b01224. [DOI] [Google Scholar]; b Tang J.; Lv L.; Dai X.-J.; Li C.-C.; Li L.; Li C.-J. Nickel-Catalyzed Cross-Coupling of Aldehydes with Aryl Halides via Hydrazone Intermediates. Chem. Commun. 2018, 54 (14), 1750–1753. 10.1039/C7CC09290C. [DOI] [PubMed] [Google Scholar]; c Zhu D.; Lv L.; Qiu Z.; Li C.-J. Nickel-Catalyzed Cross-Coupling of Umpolung Carbonyls and Alkyl Halides. J. Org. Chem. 2019, 84 (10), 6312–6322. 10.1021/acs.joc.9b00649. [DOI] [PubMed] [Google Scholar]; d Cao D.; Pan P.; Zeng H.; Li C.-J. Umpolung Cross-Coupling of Polyfluoroarenes with Hydrazones via Activation of C–F Bonds. Chem. Commun. 2019, 55 (63), 9323–9326. 10.1039/C9CC04299G. [DOI] [PubMed] [Google Scholar]
  16. Cao D.; Li C.-C.; Zeng H.; Peng Y.; Li C.-J. C(sp3)–C(sp3) Bond Formation via Nickel-Catalyzed Deoxygenative Homo-coupling of Aldehydes/Ketones Mediated by Hydrazine. Nat. Commun. 2021, 12 (1), 3729. 10.1038/s41467-021-23971-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Yan S.-S.; Zhu L.; Ye J.-H.; Zhang Z.; Huang H.; Zeng H.; Li C.-J.; Lan Y.; Yu D.-G. Ruthenium-Catalyzed Umpolung Carboxylation of Hydrazones with CO2. Chem. Sci. 2018, 9 (21), 4873–4878. 10.1039/C8SC01299G. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. a Lv L.; Zhu D.; Li C.-J. Direct Dehydrogenative Alkyl Heck-Couplings of Vinylarenes with Umpolung Aldehydes Catalyzed by Nickel. Nat. Commun. 2019, 10 (1), 715. 10.1038/s41467-019-08631-1. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Lv L.; Zhu D.; Qiu Z.; Li J.; Li C.-J. Nickel-Catalyzed Regioselective Hydrobenzylation of 1,3-Dienes with Hydrazones. ACS Catal. 2019, 9 (10), 9199–9205. 10.1021/acscatal.9b02483. [DOI] [Google Scholar]; c Wang S.; König B. Catalytic Generation of Carbanions through Carbonyl Umpolung. Angew. Chem. Int. Ed. 2021, 60 (40), 21624–21634. 10.1002/anie.202105469. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Gapinski D. M.; Mallett B. E.; Froelich L. L.; Jackson W. T. Benzophenone Dicarboxylic Acid Antagonists of Leukotriene B4. 2. Structure-Activity Relationships of the Lipophilic Side Chain. J. Med. Chem. 1990, 33 (10), 2807–2813. 10.1021/jm00172a020. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

au2c00320_si_001.pdf (4.3MB, pdf)

Articles from JACS Au are provided here courtesy of American Chemical Society

RESOURCES