Coupling of Primary Alcohols - American Chemical Society

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Ketone Synthesis by a Nickel-Catalyzed Dehydrogenative Cross-Coupling of Primary Alcohols Thomas Verheyen, Lars van Turnhout, Jaya Kishore Vandavasi, Eric S Isbrandt, Wim M. De Borggraeve, and Stephen G. Newman J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.9b03280 • Publication Date (Web): 15 Apr 2019 Downloaded from http://pubs.acs.org on April 15, 2019

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Journal of the American Chemical Society

Ketone Synthesis by a Nickel-Catalyzed Dehydrogenative CrossCoupling of Primary Alcohols Thomas Verheyen,†,‡ Lars van Turnhout,†,# Jaya Kishore Vandavasi,†,# Eric S. Isbrandt,† Wim M. De Borggraeve,‡ Stephen G. Newman*,† †Centre

for Catalysis Research and Innovation, Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, Ontario, Canada, K1N 6N5 ‡Molecular Design and Synthesis, Department of Chemistry, KU Leuven, 3001 Leuven, Belgium

Supporting Information Placeholder ABSTRACT: An intermolecular coupling of primary alcohols and organotriflates has been developed to provide ketones by the action of a Ni(0) catalyst. This oxidative transformation is proposed to occur by the union of three distinct catalytic cycles. Two competitive oxidation processes generate aldehyde in situ via hydrogen transfer oxidation or (pseudo)dehalogenation pathways. As aldehyde forms, a Ni-catalyzed carbonyl-Heck process enables formation of the key carbon–carbon bond. The utility of this rare alcohol to ketone transformation is demonstrated through the synthesis of diverse complex and bioactive molecules.

Net oxidation and reduction reactions are also possible if a sacrificial hydrogen acceptor or donor is incorporated into the reaction. For instance, pioneering work by Krische and Scheme 1. Classical C-C bond formation strategy and recent redox neutral reports a) Classical redox manipulation to enable C-C bond formation OH R

activation by oxidation

Ar

In organic synthesis, it is undesirable to carry out redox reactions that do not actively contribute to the formation of the desired molecular scaffold.1 Nonetheless, the adjustment of oxidation state is often necessary to prepare the desired functionality that enables the key complexitybuilding steps to take place. For instance, the addition of Grignard reagents to aldehydes is among the most important C–C bond forming reactions available. However, the aldehyde component often needs to be synthesized by oxidation of a more abundant alcohol precursor (Scheme 1a). Furthermore, the Grignard reagent must be prepared by reduction of an organohalide with stoichiometric Mg. Subsequent manipulation of the product may also be required. For instance, another oxidation is required if a ketone product is desired, culminating in 3 redox steps required for one desirable C—C bond formation.2 This classical route relies on well-established and reliable transformations, but exhibits poor efficiency due to the step count and stoichiometric waste products generated.3 The incorporation of oxidation state-manipulating and complexity-building steps into a single catalytic cycle is a powerful strategy for overcoming the poor step economy of some classical synthetic sequences. For instance, borrowing hydrogen and related hydrogen transfer strategies are becoming increasingly common to enable redox-neutral transformations to take place between two reaction partners that are unreactive in their native oxidation state.4

O

[O]

M (e.g. Mg)

X

activation by reduction

R

OH R

Ar

O

[O]

Ar

R

Ar

MX

b) Krische and co-workers: Redox-triggered carbonyl allylation OH

OH

Ru +

Ar

Ar via O R

catalytically generated electrophile

[Ru]

+

catalytically generated nucleophile

c) This work: Redox-triggered cross-coupling OH R via O R

Ni +

Ar

OTf

catalytically generated electrophile

O

acetone (5 equiv) (mild oxidant) +

Ar

[Ni]

R

Ar

catalytically generated nucleophile

co-workers showed that redox-triggered carbonyl allylation can be achieved via reaction between a catalytically-generated nucleophile/electrophile pair (Scheme 1b), and the oxidation state of the starting material and product could be manipulated by the inclusion or exclusion of a mild reducing agent such as isopropanol.5 Recently, these reactions were expanded to engage organohalides as pro-nucleophiles in catalytic Grignardlike reactions by the Krische and Weix groups in net

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reductive transformations,6 highlighting the diversity of this strategy. In contrast to achievements in Ru, Ir, and Rh catalysis, the incorporation of hydrogen transfer and other oxidation state-manipulating strategies into Pd(0)- and Ni(0)catalyzed cross-coupling reactions is rare.6b, 7 This is in large part due to the nature of the coupling partners used, which cannot be readily generated by mild oxidants or reductants. In a unique demonstration of aldehydes as cross-coupling partners, our lab recently demonstrated an efficient Nicatalyzed coupling to form ketones.8 This transformation is proposed to occur by a Heck-type mechanism with the aldehyde acting as an olefin surrogate in the catalytic cycle. While useful, there are a number of deficiencies with the use of aldehydes. In addition to being relatively expensive and unstable, aldehydes are prone to aldol and Tishchenko-type side reactions.9 In contrast, simple primary alcohols are abundant, inexpensive, stable precursors; however, their direct use in C-C bond forming cross-coupling reactions is rare.10 Inspired by recent efforts in borrowing hydrogen and related chemistry, we sought to utilize primary alcohols as cross-coupling partners in catalytic ketone synthesis. Herein, we present how this can be accomplished in a Nicatalyzed process. The transformation is proposed to occur by multiple oxidation state-manipulating steps, ultimately using acetone and a slight excess of the triflate coupling partner as terminal hydrogen acceptors for the oxidative transformation. We began by investigating the reaction of benzyl alcohol 1 with phenyltriflate 2. The combination of Ni(cod)2 (10 mol%) and 1,1,1-tris(diphenylphosphinomethyl)ethane (Triphos, 12 mol%) as the catalyst, tetramethylpiperidine (TMP, 2 equiv) as the base, and acetone (5 equiv) as a hydrogen acceptor enabled formation of ketone 3 in 93% yield at 130 °C (Table 1, entry 1). As observed in several other Ni-catalyzed Heck-type reactions, the use of organo(pseudo)halides with a non-coordinating triflate group was critical.11 Traditional organohalides provided only traces of product (entry 2) and alternative pseudohalides provided only moderate yields (entries 3, 4). Acetone was conveniently the most effective hydrogen acceptor of those studied; for instance, use of cyclohexanone (entry 5) and 2-decanone (entry 6) resulted in significantly reduced yields. The reaction temperature can be reduced to 110 °C (entry 7) with almost no decrease in yield, though 130 °C was later found to be more generally effective for challenging substrates (Scheme S2). Equimolar amounts of organotriflate can be used (entry 8) albeit with a decrease in yield. The use of the multidentate ligand Triphos12 was particularly important. Structurally similar dppp provided low yields (entry 9), while Xantphos, dcypp, BINAP, S-Phos and PPh3 gave only traces of product (entry 10). Similarly, TMP and its more expensive pentamethyl analog (PMP, entry 11) were particularly effective, though alternative inorganic and organic bases still gave appreciable amounts of product (entry 12, 13). Most Ni(II) salts were found to be ineffective with the exception of Ni(OTf)2, which gave reasonable amounts of product and allowed reaction set-up without the need of a glovebox (entry 14). With optimized reaction conditions in hand, the reaction of phenyltriflate was explored with a variety of coupling

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partners (Scheme 2). Different alcohols were used to make benzophenone derivatives that were electron-neutral (45), electron-rich (6-8), and electron poor (9, 10), along with double coupling to provide bis-ketone 11. Similar tolerance was observe for variation of the organotriflate, with electron-neutral (12, 13), electron-rich (14, 15), electronpoor (16, 17), and sterically hindered (18) substrates readily participating. High yields were also observed in the presence of an aryl chloride (19), unprotected amide (20) and estrone backbone (21). Heterocycle-bearing alcohols could also be used to make heterocyclic compounds with pyridine (22), unprotected indole (23), furan (24), and thiophene (25) substituents in good yield. Table 1: Optimization of the Ni-Catalyzed Coupling of alcohols with Organotriflatesa standard conditions OH TfO + 2 (1.5 equiv)

1

Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14c

Ni(cod)2 (10 mol%) Triphos (12 mol%) TMP (2 equiv) Acetone (5 equiv) PhMe, 20 h, 130 °C

Deviation from standard reaction conditions None PhCl, PhBr or PhI instead of PhOTf ArOMs instead of ArOTf ArONf instead of ArOTf Cyclohexanone instead of acetone 2-Decanone instead of acetone Temperature = 110 °C 1.1 equiv ArOTf Ligand = dppp Ligand = Xantphos, dcypp, BINAP, S-Phos, PPh3 Base = PMP Base = K2CO3 Base = NEt3 Ni(OTf)2 instead of Ni(cod)2

O

3

% Yield 93 (91)b trace 30 67 44 86 90 62 23 trace 90 64 76 75 (67)b

aReactions

run at 0.2 M concentration on 0.1 mmol scale. Yield determined by GC-FID of the crude mixture with 1,3,5trimethoxybenzene as internal standard. bReaction run on 0.3 mmol scale; isolated yield. cReaction run on 0.3 mmol scale outside of a glovebox.

Heterocycle-bearing organotriflates were also well tolerated, enabling preparation of quinoline (26), pyridine (27), quinoxaline (28) and benzothiazole (29) containing products. A robustness screen confirmed this generality (Scheme S3). Notably, many of these corresponding alcohol precursors to organotriflates are more readily available than the analagous organohalides. Next, in contrast to the previously demonstrated carbonyl-Heck reaction,8a aliphatic alcohols were found to be excellent coupling partners. For instance, -primary ketones with aliphatic chains (30, 31) could be prepared in good yields. Products bearing -secondary alkyl substituent were similarly effective, including cyclohexyl (32), cyclopropyl (33), acyclic (34) and cyclobutyl (35) ketones. -Tertiary ketone 36 could be synthesized from 1-adamantanemethanol, though the steric hinderance necessitated the use of elevated temperatures and catalyst loading. Finally an chiral ketone could be prepared from the corresponding


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Journal of the American Chemical Society Scheme 2. Reaction scope Ni(cod)2 (10 mol%) Triphos (12 mol%) TMP (2 equiv)

OH +

OTf

Ar

alcohol

O Ar

PhMe, 20 h, 130 oC Acetone (5 equiv)

organotriflate

ketone

Diarylketone products O

O O

O

O Ph

Ph

6: 96%

O

O Ph

Ph

OMe

CF3

OMe

14: 86%

16: 70%

15: 90%

O

22: 73% O Ph

24: 81%

N

26: 74%

Cl

30: 72% MeO

O

O

Ph

Ph

Ph

35: 84%

34: 69%

33: 69%d

O

O Ph

29: 64%

Ph

32: 78%

31: 75%

N

28: 43%

O Ph

Ph Ph

S

Ph

N

27: 81%

O

25: 93% O

N

Ph N

d

O

Ph

O

Ph

O

23: 88%

O

O

O

O S

Ph

Ph

HN

21: 90%

Aliphatic products

O

N

H

20: 91%

19: 71%

H

H

N H

Cl

18: 83%

17: 88%

Heterocyclic products O Ph

Ph O

Ph

Ph

12: 80%c O

O

O

O Ph

Ph

11: 76%b

10: 81%

O

Ph

Ph O

9: 91%

O

Ph

Ph

13: 75%

8: 88%

O

O

F3C

F

7: 70%

O

Ph Ph Ph

Ph

Ph

OMe

MeO

O

O

O

O

Ph

Ph

5: 90%, 68%a

4: 83%

O

36: 56%

e

37: 32%, 91:9 e.r.

Bioactive molecule synthesis & derivatization Cl O Cl

O

Ph

O Boc

N H

O O

Photoactive Tyr derivative 38: 60%f, 97:3 e.r.

Cl

O

O

O

O

Idebenone derivative 39: 62%d,f

HO

N

7

OMe

O N

F O

F

Clofoctol derivative 40: 62%

41 (4-F): 69% (Melperone) 42 (3-F): 66% 43 (2-F): 76%

Haloperidol 44: 37%

General reaction conditions: alcohol (0.30 mmol), organotriflate (0.45 mmol), TMP (0.6 mmol), Acetone (1.5 mmol), Triphos (12 mol%), Ni(cod)2 (10 mol%) in toluene (1.5 mL), 130 °C for 22h. aNi(OTf)2 (10 mol%), set-up outside of glovebox. bOrganotriflate (0.90 mmol), TMP (1.2 mmol), Acetone (3.0 mmol). cReaction on 3.0 mmol scale. d140 °C. eNi(cod)2 (20 mol%), Triphos (24 mol%) and 140 °C. fReaction on 0.2 mmol scale.

enantiopure alcohol starting material with minimal erosion of enantiopurity (37). Due to the functional group tolerance of this oxidative process and the availability of primary alcohols and phenols, this method is highly applicable to the derivatization of bioactive molecules. For instance, photoactive protected tyrosine derivative 38 was prepared, maintaining the epimerizable sterocenter.13 The Alzheimer’s therapeutic idebenone and antibacterial agent clofoctyl could also be readily converted to novel ketone analogues 39 and 40. Lastly, melperone 41 and haloperidol 44 are two important ketone-containing antipsychotic therapeutics which are traditionally formed from paraselective Friedel-Crafts reactions of fluorobenzene and the corresponding acid chloride.14 These molecules can be efficiently prepared by Ni-catalyzed oxidative coupling without limitations on the substitution patterns available.15,16

We next sought to uncover the nature of the oxidation step in the reaction.17 An experiment was carried out between 4Methylbenzyl alcohol 45, 1.5 equivalents of organotriflate 46, and 5 equivalents of 2-dodecanone, allowing the fate of these reaction components to be tracked (Scheme 3a). A 72% NMR yield of ketone 47 was observed, along with two reduction side-products, biaryl 48a (50%) and dodecanol 48b (20%), providing a nearly closed redox balance suggestive of two distinct oxidative pathways. Coupling with the deuterated alcohol analogue provided substantial deuterium incorporation in both reduction side-products (Scheme S8). Catalytic oxidation of alcohols is known both with sacrificial ketones (Oppenauer oxidation)18 and sacrificial organo(pseudo)halides,19 both of which could produce an aldehyde in situ along with the observed reduction products. Indeed, aldehyde intermediates can be observed, particularly when quenching reactions before completion. For instance, when monitoring the reaction of 49 by NMR, aldehyde 50 could be observed throughout,



albeit in low concentration (Scheme 3b). Aldehyde 50 was also a viable starting material in the reaction, though yields were generally low with significant quantities of the Tishchenko (52) and aldol (53) products being formed (Scheme 3c and Scheme S10). Gradual formation and consumption of aldehyde in situ may thus explain the high efficiency and scope of this oxidative coupling reaction in comparison to redox neutral carbonyl-Heck, particularly with aliphatic alcohols.8a, 20 With this information in mind, a plausible mechanistic pathway is proposed (Scheme 4). The Ni(0) catalyst I first reacts with organotriflate to form oxidative addition intermediate II. This species can react with the alcohol starting material to form alkoxide III via Oxidation Cycle 1.19a, 21 -Hydride elimination produces aldehyde and nickel hydride IV, which can undergo reductive elimination to form I and reduced organotriflate. Alternatively, arylnickel II can react with aldehyde if present via insertion to form alkoxide V. -Hydride elimination produces the ketone product and Ni-hydride VI. Such species are known Scheme 3. Mechanistic information A) Identifying redox balance

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hydride can reduce the acetone additive via complex VII and undergo substitution with alcohol starting material to form VIII (Oxidation Cycle 2).23 -Hydride elimination provides aldehyde and regenerates metal hydride VI. In conclusion, a Ni-catalyzed oxidative coupling of alcohols and organotriflates has been demonstrated. This reaction relies on catalytic formation of two reactive species: an arylNi nucleophile and an aldehyde electrophile. These intermediates react via a carbonyl Heck-type pathway, forming ketone products. This oxidative reaction, enabled by the use of acetone and a small excess of organotriflate coupling partner, demonstrates a new interface between cross-coupling reactions with dehydrogenative activation. In contrast to redox-neutral reactions with stoichiometric aldehydes, no decomposition and dimerization side reactions were observed, likely due to the slow in situ formation of the reactive aldehyde intermediate. We anticipate the incorporation of mild oxidation state manipulating steps into diverse transition metal-catalyzed coupling reactions has much unrealized potential for efficient chemical synthesis. Scheme 4. Plausible catalytic cycle

O

(5 equiv) C8H17 OH Ni(cod)2 (10 mol%) Triphos (12 mol%) ArOTf 46 (1.5 equiv) TMP (2 equiv) PhMe, 20 h, 130 °C

45

reduction

oxidation O



Ar

H + Ar 48a 50%

47: 72%

Ar = 4-PhC6H4

O

OH C8H17 48b 20%

R ArH OH

B) Observation of aldehyde as a reaction intermediate

Ph

OH 49

Ni(cod)2 (10 mol%) Triphos (12 mol%) ArOTf 46 (1.5 equiv) Acetone (5 equiv) TMP (2 equiv) PhMe (0.2 M), 20 h, 130 °C

Ar

Ph

R

51: 85% after 20 h

[Ni]

Ar

[Ni] IV H

III

Ar O R

oxidation cycle 1

ketone product

triflate counterion omitted for clarity

Ar

R

sideproducts

O

O

O

aldehyde intermediate

base•HOTf

H

Ar

ArOTf

base•HOTf

[Ni] I

Ar

[Ni] II

R OH base

Ph

O 50 up to 18% observed

O O

productive cycle

base

R

[Ni] V O

[Ni] VI H [Ni] VII

oxidation cycle 2

O

Ar

R

[Ni]

Ni

O Ph

H 50

+ PhOTf

various conditions

31

+

Ph

O 52 O

29-44% +

Ph

OH

H

53

VIII

O R

AUTHOR INFORMATION Corresponding Author

H

Ph

R

O

R

aldehyde side-reactions O

R

O

OH

C) Challenges with aldehyde as a reactant

Ar

Ph

to undergo slow reductive elimination to regenerate Ni(0), which is proposed to be rate determining in other Nicatalyzed Heck-type reactions.11a, 22 Alternatively, the

[email protected]

Author Contributions #These

authors contributed equally to this work.


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Journal of the American Chemical Society

Supporting Information Experimental procedures, optimization tables, troubleshooting, robustness screen, characterization of organic molecules, mechanistic studies. This material is available free of charge via the Internet at http://pubs.acs.org.

ACKNOWLEDGEMENT Financial support for this work was provided by the University of Ottawa, the National Science and Engineering Research Council of Canada (NSERC), the Canada Research Chair program. The Canadian Foundation for Innovation (CFI) and the Ontario Ministry of Research, Innovation, & Science are thanked for essential infrastructure. T.V. thanks FWOvlaanderen for the FWO-SB PhD fellowship received. E.S.I. thanks NSERC for a graduate fellowship.

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G. A High-Throughput Approach to Discovery: Heck-Type Reactivity with Aldehydes. Synlett 2018, 29, 2081-2086. (9) (a) Hoshimoto, Y.; Ohashi, M.; Ogoshi, S. Nickel-Catalyzed Selective Conversion of Two Different Aldehydes to CrossCoupled Esters. J. Am. Chem. Soc. 2011, 133, 4668-4671. (b) Hoshimoto, Y.; Ohashi, M.; Ogoshi, S. Catalytic Transformation of Aldehydes with Nickel Complexes through eta(2) Coordination and Oxidative Cyclization. Accounts Chem. Res. 2015, 48, 17461755. (c) Bernhard, Y.; Thomson, B.; Ferey, V.; Sauthier, M. Nickel-Catalyzed alpha-Allylation of Aldehydes and Tandem Aldol Condensation/Allylation Reaction with Allylic Alcohols. Angew. Chem., Int. Ed. 2017, 56, 7460-7464. (10) (a) Maekawa, T.; Sekizawa, H.; Itami, K. Controlled AlcoholCarbonyl Interconversion by Nickel Catalysis. Angew. Chem., Int. Ed. 2011, 50, 7022-7026. (b) Twilton, J.; Christensen, M.; DiRocco, D. A.; Ruck, R. T.; Davies, I. W.; MacMillan, D. W. C. Selective Hydrogen Atom Abstraction through Induced Bond Polarization: Direct alpha-Arylation of Alcohols through Photoredox, HAT, and Nickel Catalysis. Angew. Chem., Int. Ed. 2018, 57, 5369-5373. (c) Berini, C.; Navarro, O. Ni-Catalysed, Domino Synthesis of Tertiary Alcohols from Secondary Alcohols. Chem. Commun. 2012, 48, 1538-1540. (11) (a) Gogsig, T. M.; Kleimark, J.; Lill, S. O. N.; Korsager, S.; Lindhardt, A. T.; Norrby, P. O.; Skrydstrup, T. Mild and Efficient Nickel-Catalyzed Heck Reactions with Electron-Rich Olefins. J. Am. Chem. Soc. 2012, 134, 443-452. (b) Tasker, S. Z.; Gutierrez, A. C.; Jamison, T. F. Nickel-Catalyzed Mizoroki-Heck Reaction of Aryl Sulfonates and Chlorides with Electronically Unbiased Terminal Olefins: High Selectivity for Branched Products. Angew. Chem., Int. Ed. 2014, 53, 1858-1861. (c) Matsubara, R.; Gutierrez, A. C.; Jamison, T. F. Nickel-Catalyzed Heck-Type Reactions of Benzyl Chlorides and Simple Olefins. J. Am. Chem. Soc. 2011, 133, 19020-19023. (12) Triphos is a precedented but rare ligand for Ni chemistry. For examples see: (a) Petuker, A.; Mebs, S.; Schuth, N.; Gerschel, P.; Reback, M. L.; Mallick, B.; van Gastel, M.; Haumann, M.; Apfel, U. P. Spontaneous Si-C Bond Cleavage in (Triphos(Si))-Nickel Complexes. Dalton Trans. 2017, 46, 907-917. (b) Kandiah, M.; McGrady, G. S.; Decken, A.; Sirsch, P. (Triphos)Ni(eta(2)-BH4) : An Unusual Nickel(I) Borohydride Complex. Inorg. Chem. 2005, 44, 8650-8652. (13) Kauer, J. C.; Ericksonviitanen, S.; Wolfe, H. R.; Degrado, W. F. Para-Benozyl-L-Phenylalanine, a New Photoreactive AminoAcid - Photolabeling of Calmodulin With a Synthetic CalmodulinBinding Peptide. J. Biol. Chem. 1986, 261, 695-700. (14) Janssen, P. A. J.; Vandewesteringh, C.; Jageneau, A. H. M.; Demoen, P. J. A.; Hermans, B. K. F.; Vandaele, G. H. P.; Schellekens, K. H. L.; Vandereycken, C. A. M.; Niemegeers, C. J. E. Chemistry and Pharmacology of CNS Depressants Related to 4(4-Hydroxy-4-Phenylpiperidino)Butyrophenone .1. Synthesis and Screening Data in Mice. J. Med. Chem 1959, 1, 281-297. (15) The first SAR studies on these meta and ortho isomers showed promising results. Leyva-Perez, A.; Cabrero-Antonino, J. R.; Rubio-Marques, P.; Al-Resayes, S. I.; Corma, A. Synthesis of the ortho/meta/para Isomers of Relevant Pharmaceutical Compounds by Coupling a Sonogashira Reaction with a Regioselective Hydration. ACS Catal. 2014, 4, 722-731. (16) For recent methods to make aryl ketones without the regioselectivity challenges associated with Friedel-Crafts reactions, see: (a) Serratore, N. A.; Anderson, C. B.; Frost, G. B.; Hoang, T. G.; Underwood, S. J.; Gemmel, P. M.; Hardy, M. A.; Douglas, C. J. Integrating Metal-Catalyzed C-H and C-O Functionalization To Achieve Sterically Controlled Regioselectivity in Arene Acylation. J. Am. Chem. Soc. 2018, 140, 10025-10033. (b) Ruan, J. W.; Saidi, O.; Iggo, J. A.; Xiao, J. L. Direct Acylation of Aryl Bromides with Aldehydes by Palladium Catalysis. J. Am. Chem. Soc. 2008, 130, 10510-10511. (c) Zhang, X. H.; MacMillan, D. W. C. Direct Aldehyde C-H Arylation and

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Alkylation via the Combination of Nickel, Hydrogen Atom Transfer, and Photoredox Catalysis. J. Am. Chem. Soc. 2017, 139, 11353-11356. (d) Weires, N. A.; Baker, E. L.; Garg, N. K. NickelCatalysed Suzuki-Miyaura Coupling of Amides. Nat. Chem. 2016, 8, 75-79. (e) Ben Halima, T.; Zhang, W. Y.; Yalaoui, I.; Hong, X.; Yang, Y. F.; Houk, K. N.; Newman, S. G. Palladium-Catalyzed Suzuki-Miyaura Coupling of Aryl Esters. J. Am. Chem. Soc. 2017, 139, 1311-1318. (17) The role of acetone and triflate as oxidant was investigated by changing respective ratios. The results are shown in table S3. (18) (a) Chorghade, R.; Battilocchio, C.; Hawkins, J. M.; Ley, S. V. Sustainable Flow Oppenauer Oxidation of Secondary Benzylic Alcohols with a Heterogeneous Zirconia Catalyst. Org. Lett. 2013, 15, 5698-5701. (b) Manzini, S.; Urbina-Blanco, C. A.; Nolan, S. P. Chemoselective Oxidation of Secondary Alcohols Using a Ruthenium Phenylindenyl Complex. Organometallics 2013, 32, 660-664. (c) Wang, Q. F.; Du, W. M.; Liu, T. T.; Chai, H. N.; Yu, Z. K. Ruthenium(II)-NNN Complex Catalyzed Oppenauer-Type Oxidation of Secondary Alcohols. Tetrahedron Lett. 2014, 55, 1585-1588. (d) Nicklaus, C. M.; Phua, P. H.; Buntara, T.; Noel, S.; Heeres, H. J.; de Vries, J. G. Ruthenium 1,1 'Bis(diphenylphosphino)ferrocene-Catalysed Oppenauer Oxidation of Alcohols and Lactonisation of alpha,omega-Diols using Methyl Isobutyl Ketone as Oxidant. Adv. Synth. Catal. 2013, 355, 28392844. (e) Labes, R.; Battilocchio, C.; Mateos, C.; Cumming, G. R.; de Frutos, O.; Rincon, J. A.; Binder, K.; Ley, S. V. Chemoselective Continuous Ru-Catalyzed Hydrogen-Transfer Oppenauer-Type Oxidation of Secondary Alcohols. Org. Process Res. Dev. 2017, 21, 1419-1422. (19) (a) Desmarets, C.; Kuhl, S.; Schneider, R.; Fort, Y. Nickel(0)/Imidazolium Chloride Catalyzed Reduction of Aryl Halides. Organometallics 2002, 21, 1554-1559. (b) Desmarets, C.; Schneider, R.; Fort, Y. Nickel (0)/Dihydroimidazol-2-Ylidene Complex Catalyzed Coupling of Aryl Chlorides and Amines. J. Org. Chem. 2002, 67, 3029-3036. (c) Berini, C.; Brayton, D. F.; Mocka, C.; Navarro, O. Homogeneous, Anaerobic (N-Heterocyclic Carbene)-Pd or -Ni Catalyzed Oxidation of Secondary Alcohols at Mild Temperatures. Org. Lett. 2009, 11, 4244-4247. (d) Bei, X. H.; Hagemeyer, A.; Volpe, A.; Saxton, R.; Turner, H.; Guram, A. S. Productive Chloroarene C-Cl Bond Activation: Palladium/Phosphine-Catalyzed Methods for P-Oxidation of Alcohols and Hydrodechlorination of Chloroarenes. J. Org. Chem. 2004, 69, 8626-8633. (e) Berini, C.; Winkelmann, O. H.; Otten, J.; Vicic, D. A.; Navarro, O. Rapid and Selective Catalytic Oxidation of Secondary Alcohols at Room Temperature by Using (NHeterocyclic Carbene)-Ni-0 Systems. Chem.-Eur. J. 2010, 16, 6857-6860. (f) Navarro, O.; Kaur, H.; Mahjoor, P.; Nolan, S. P. Cross-Coupling and Dehalogenation Reactions Catalyzed by (Nheterocyclic carbene)Pd(allyl)Cl Complexes. J. Org. Chem. 2004, 69, 3173-3180. (20) For additional experiments on dimerization of aldehyde see scheme S10. (21) Similar oxidation mechanism are well established in the borrowing hydrogen and related literature. (a) Tang, G.; Cheng, C. H. Synthesis of alpha-Hydroxy Carboxylic Acids via a Nickel(II)Catalyzed Hydrogen Transfer Process. Adv. Synth. Catal. 2011, 353, 1918-1922. (b) Whittaker, A. M.; Dong, V. M. NickelCatalyzed Dehydrogenative Cross-Coupling: Direct Transformation of Aldehydes into Esters and Amides. Angew. Chem., Int. Ed. 2015, 54, 1312-1315. (22) Lin, B. L.; Liu, L.; Fu, Y.; Luo, S. W.; Chen, Q.; Guo, Q. X. Comparing Nickel- and Palladium-Catalyzed Heck Reactions. Organometallics 2004, 23, 2114-2123. (23) (a) Kozuch, S.; Lee, S. E.; Shaik, S. Theoretical Analysis of the Catalytic Cycle of a Nickel Cross-Coupling Process: Application of the Energetic Span Model. Organometallics 2009, 28, 1303-1308. (b) Tschaen, B. A.; Schmink, J. R.; Molender, G. A. Pd-Catalyzed Aldehyde to Ester Conversion: A Hydrogen


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Journal of the American Chemical Society Transfer Approach. Org. Lett. 2013, 15, 500-503. (c) Krug, C.; Hartwig, J. F. Direct Observation of Aldehyde Insertion into Rhodium-Aryl and -Alkoxide Complexes. J. Am. Chem. Soc. 2002, 124, 1674-1679. (d) Blum, Y.; Shvo, Y. Catalytically Reactive Ruthenium Intermediates in the Homogeneous Oxidation of Alcohols to Esters. Isr. J. Chem. 1984, 24, 144-148. (e) Nakai, K.; Yoshida, Y.; Kurahashi, T.; Matsubara, S. Nickel-Catalyzed

Redox-Economical Coupling of Alcohols and Alkynes to Form Allylic Alcohols. J. Am. Chem. Soc. 2014, 136, 7797-7800. (f) Eberhardt, N. A.; Wellala, N. P. N.; Li, Y.; Krause, J. A.; Guan, H. Dehydrogenative Coupling of Aldehydes with Alcohols Catalyzed by a Nickel Hydride Complex. Organometallics 2019, 38, 14681478.


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oxidation then BrMg R' then oxidation

Page 8 of 8

multistep synthesis by stoichiometric oxidation state manipulation

common route

OH R

O Ni catalyst TfO R' H2 acceptor direct route

R

>40 examples R'

up to 96% yield

integration of crosscoupling reactivity with catalytic oxidation


8

Coupling of Primary Alcohols - American Chemical Society

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