ARTICLE https://doi.org/10.1038/s41467-021-25222-1 OPEN Nickel-catalyzed deaminative Sonogashira coupling of alkylpyridinium salts enabled by NN2 pincer ligand ✉ ✉ Xingjie Zhang 1 ,DiQi1,2, Chenchen Jiao1,2, Xiaopan Liu1 & Guisheng Zhang 1 Alkynes are amongst the most valuable functional groups in organic chemistry and widely used in chemical biology, pharmacy, and materials science. However, the preparation of alkyl- 1234567890():,; substituted alkynes still remains elusive. Here, we show a nickel-catalyzed deaminative Sonogashira coupling of alkylpyridinium salts. Key to the success of this coupling is the development of an easily accessible and bench-stable amide-type pincer ligand. This ligand allows naturally abundant alkyl amines as alkylating agents in Sonogashira reactions, and produces diverse alkynes in excellent yields under mild conditions. Salient merits of this chemistry include broad substrate scope and functional group tolerance, gram-scale synth- esis, one-pot transformation, versatile late-stage derivatizations as well as the use of inex- pensive pre-catalyst and readily available substrates. The high efficiency and strong practicability bode well for the widespread applications of this strategy in constructing functional molecules, materials, and fine chemicals. 1 Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, School of Chemistry and Chemical Engineering, Henan ✉ Normal University, Xinxiang, Henan, China. 2These authors contributed equally: Di Qi, Chenchen Jiao. email: [email protected]; [email protected] NATURE COMMUNICATIONS | (2021) 12:4904 | https://doi.org/10.1038/s41467-021-25222-1 | www.nature.com/naturecommunications 1 ARTICLE NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-25222-1 lkynes are one of the most valuable functional groups in β-hydride elimination, (3) the poor nucleophilicity of the sp- organic chemistry because they are not only served as hybridized carbon in alkynes, and (4) the low concentration of A fi versatile synthetic building blocks for diversi ed chemical the transmetalating species generated in situ in the reaction transformations, but also common structural motifs in a wide medium. Moreover, the facile cyclotrimerization and/or oligo- range of natural products, bioactive molecules and organic merization of terminal alkynes under the catalysis of low-valent materials1–3. For example, the introduction of an alkyne into a metal is another obstacle that renders such coupling a more drug molecule could provide remarkable benefits in its biological intractable objective12,13. In a pioneering study, Fu and co- activity, such as enhanced lipophilicity, bioavailability, and workers realized Pd/Cu-cocatalyzed Sonogashira coupling of metabolic stability (Fig. 1a). In addition to the widely used as nonactivated primary alkyl iodides and bromides by the use of an functional tags in biochemistry for bioconjugation based on N-heterocyclic carbene (NHC) ligand14. Later on, a few elegant “alkyne-azide click chemistry”4, recent researches also indicated strategies for this transformation were developed based on the that alkynes have a privileged application in Raman imaging due discovery of different catalytic systems including Pd/bisoxazoline- 15 16,17 to their unique and strong Raman scattering peaks in a cellular derived NHC ligand , Ni/NN2 pincer ligand , Ni/pyridine silent region that is free of interference from most endogenous bisoxazoline (pybox) system18, and NHC pincer nickel(II) molecules (Fig. 1b)5–9. Therefore, lots of efforts have been made complex19 (Fig. 1d). Furthermore, Lalic et al. discovered an to develop efficient methods for the construction of alkynes. excellent protocol of photoinduced copper-catalyzed alkylation of Among these available transformations, the transition-metal- terminal alkyne with alkyl iodides as the alkyl source20. More catalyzed Sonogashira coupling of aryl/vinyl electrophiles with recently, Wang and co-workers further expanded the scope of terminal alkynes has proven to be one of the most powerful alkyl to the cheap and easily accessible carboxylic acid derivatives approaches for C(sp2)–C(sp) bond formation10,11. However, the by the utilization of redox-active esters21. Despite these significant incorporation of nonactivated, β-H-containing alkyl electrophiles advances, the scope for alkyl-Sonogashira-type reactions is still in Sonogashira reaction to construct C(sp3)–C(sp) bond still relatively limited. Particularly, the electrophilic partners in such remains a formidable challenge, presumably due to the following reactions are largely limited to alkyl halides22, and the need of issues (Fig. 1c): (1) the reluctance of alkyl electrophiles to undergo copper(I) salt as cocatalyst might also cause some detrimental oxidative addition with a metal catalyst, (2) the propensity of the effects to the reaction, such as the undesired Glaser coupling of resulting alkylmetal intermediates to undergo intramolecular terminal alkynes and the complicated procedure in workup23. a Representative alkynyl-containing drugs O d State-of-the-art catalytic systems for Sonogashira coupling of nonactivated alkyl electrophiles Limited to alkyl halides Me Pd or Ni catalyst O 3 O Alkyl X + R Alkyl R Required Cu co-catalyst OH Me HO Cu co-catalyst Me o o Alkyl = 1 , 2 , X = I, Br, Cl Moderate to good yields OH O HN OH F3C O H Cl [( -allyl)PdCl]2 O Ni(cod)2 O + NMe2 H H Me HO + 2 adamantyl HO N O H N Ni Cl OH O OH HO N Cl O O ethynylestradiol efavirenz dynemicin A alfaprostol N N NMe2 N N b Important applications of alkynes in bioconjugation and molecular imaging O adamantyl Hu (2009) Liu (2013) Fu (2003) Biomolecules HN N Click N HO O N + Biomolecules O bioconjugation N N3 alkyne-tag Raman imaging OH O O NMe2 NMe c Challenges in Sonogashira coupling of nonactivated alkyl electrophiles N Cl 2 -H elimination olefins Pd Cl N facile N Ni Cl N Ni Cl N Cl Pd transition-metal [M] undesired Alkyl X N N iPr Alkyl [M] X O Cl NMe oxidative addition transmetalation 2 N difficult unfavourable O Hu (2015) Li (2018) R Alkyl R Glorius (2006) weak nucleophile targeted e This work: deaminative Sonogashira coupling of alkyl amines catalyzed by nickel and amide-type pincer ligand (L4) New ligand Air-stable and inexpensive Ni(II) precatalyst Ph O Excellent yields and mild reaction conditions activation Ni/L4 Alkyl NH Alkyl N Ph + R Alkyl R 2 catalysis N Broad substrate scope and functional group tolerance H o o o BF >60 examples N N Alkyl = 1 , 2 , 3 , benzyl Ph 4 Scalable and one-pot transformation Sonogashira coupling up to 98% isolated yield Katritzky salts Cu-free Me L4 Easily accessible and bench-stable amide-type NN2 pincer ligand Readily available feedstocks High value-add chemicals Widespread application for late-stage functionalization, bioconjugation and molecular imaging e.g. CH3 R O N O Me N N Biomolecules N Me N Biomolecules NH2 N CN RO N CN N Me N O + Biomolecules Biomolecules N Me O N O Biomolecules H2N O OR OR Biomolecules Me Me CH3 Me O Tags for Raman imaging, fluorescence Me R = H, 51%, d.r. > 95:5 ; imaging or bioconjugation 90%, d.r. > 95:5 R = Ac, 88%, d.r. 10:1 from Alogliptin and Vitamin E from Alogliptin and Adenosine Fig. 1 Significances and strategies for Sonogashira coupling of nonactivated alkyl electrophiles. a Representative alkynyl-containing drugs (ethynylestradiol, hormone drug for estrogen medication; efavirenz, an antiretroviral drug for HIV/AIDS; dynemicin A, an antitumor drug for cancer treatments; alfaprostol, a veterinary drug for breeding control). b Important applications of alkynes in bioconjugation and molecular imaging. c Challenges in Sonogashira coupling of nonactivated alkyl electrophiles. d State-of-the-art catalytic systems for Sonogashira coupling of nonactivated alkyl electrophiles. e This work: deaminative Sonogashira coupling of alkyl amines catalyzed by nickel and amide-type pincer ligand (L4). 2 NATURE COMMUNICATIONS | (2021) 12:4904 | https://doi.org/10.1038/s41467-021-25222-1 | www.nature.com/naturecommunications NATURE COMMUNICATIONS | https://doi.org/10.1038/s41467-021-25222-1 ARTICLE Thus, developing simple approaches to access such coupling with with triisopropylsilyl (TIPS)-substituted bromoethyne to achieve more alternatives especially in copper-free conditions is highly the challenging C(sp3)–C(sp) bond64. Nevertheless, these methods important and appealing. rely mainly upon the use of preformed and activated alkynyl Alkyl amines are naturally abundant and readily available sulfones or bromides as alkynylating reagents. In addition, the feedstock chemicals, and the prevalence of amino groups in limited substrate scope and the utilization of largely excess numerous bioactive molecules, pharmaceuticals, and natural reductants (e.g. zinc flake) further disfavored their wide appli- products provide expedient opportunities for late-stage functio- cations in organic synthesis. Therefore, the direct coupling of nalization and bioconjugation24,25. In this context, using alkyl terminal alkynes with alkylpyridinium salts in a redox-neutral amines as alkylating agents in organic synthesis would have many fashion for the synthesis of important alkynes would be highly privileged advantages when compared to the traditional platforms desirable in terms of both atom-economy and practical applica- using alkyl halides. However, such a promising transformation