Nickel-catalyzed deaminative Sonogashira coupling of alkylpyridinium salts enabled by NN2 pincer ligand

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-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 synthesis, one-pot transformation, versatile late-stage derivatizations as well as the use of inexpensive 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.


Introduction
Alkynes are one of the most valuable functional groups in organic chemistry because they are not only served as versatile synthetic building blocks for diversi ed chemical transformations, but also common structural motifs in a wide range of natural products, bioactive molecules and organic materials [1][2][3] . For example, introduction of an alkyne into a drug molecule could provide remarkable bene ts in its biological activity, such as enhanced lipophilicity, bioavailability and metabolic stability (Fig. 1a). In addition to the widely used as functional tags in biochemistry for bioconjugation based on "alkyne-azide click chemistry" 4 , recent researches also indicated that alkynes have a privileged application in Raman imaging due to their unique and strong Raman scattering peaks in a cellular silent region that is free of interference from most endogenous molecules (Fig. 1b) [5][6][7][8][9] . Therefore, lots of efforts have been made to develop e cient methods for the construction of alkynes. Among these available transformations, the transition-metal-catalyzed Sonogashira coupling of aryl/vinyl electrophiles with terminal alkynes has proven to be one of the most powerful approaches for C(sp 2 )-C(sp) bond formation 10,11 . However, the incorporation of nonactivated, β-H-containing alkyl electrophiles in Sonogashira reaction to construct C(sp 3 )-C(sp) bond still remains a formidable challenge, presumably due to the following issues ( Fig. 1c): (1) the reluctance of alkyl electrophiles to undergo oxidative addition with a metal catalyst, (2) the propensity of the resulting alkylmetal intermediates to undergo intramolecular β-hydride elimination, (3) the poor nucleophilicity of the sp-hybridized carbon in alkynes, and (4) the low concentration of the transmetalating species generated in situ in reaction medium. Moreover, the facile cyclotrimerization and/or oligomerization of terminal alkynes under the catalysis of low-valent metal is another obstacle that renders such coupling a more intractable objective 12,13 . In a pioneering study, Fu and co-workers realized Pd/Cu-cocatalyzed Sonogashira coupling of nonactivated primary alkyl iodides and bromides by the use of a N-heterocyclic carbene (NHC) ligand 14 . Later on, a few elegant strategies for this transformation were developed based on the discovery of new catalytic systems including Pd/bisoxazoline-derived NHC ligand 15 , Ni/NN 2 pincer ligand 16,17 , Ni/pyridine bisoxazoline system 18 , and NHC pincer nickel(II) complex 19 (Fig. 1d). Despite these signi cant advances, the scope for alkyl-Sonogashira-type reactions is still relatively limited. Particularly, the electrophilic partners in such reactions are largely limited to alkyl halides 20 , and the need of copper(I) salt as cocatalyst might also cause some detrimental effects to the reaction, such as the undesired Glaser coupling of terminal alkynes and the complicated procedure in workup 21 . Thus, developing new approaches to access such coupling with more alternatives especially in copper-free conditions is highly important and appealing.
Alkyl amines are naturally abundant and readily available feedstock chemicals, and the prevalence of amino group in numerous bioactive molecules, pharmaceuticals and natural products provides expedient opportunities for late-stage functionalization and bioconjugation 22,23 . In this context, using alkyl amines as alkylating agents in organic synthesis would have many privileged advantages when compared to the traditional platforms using alkyl halides. However, such a promising transformation is still underexploited owing to the high bond dissociation energy of C(sp 3 )-N bond [24][25][26] . In a seminal work, Watson et al. demonstrated that pyridinium salts, also known as "Katritzky salts" which are easily formed from primary amines and pyrylium salt, could be used as alkyl radical precursors in cross-coupling with arylboronic acids 27 . Since then, many elegant approaches based on the utilization of these redox active amines for deaminative functionalization such as arylation [28][29][30] , borylation 31,32 , alkenylation 33 , allylation 34 , alkyl-Heck-type reaction 35,36 , carbonylation 37 , alkylation [38][39][40][41] , di uoromethylation 42 and C-heteroatom bondforming reactions [43][44][45] have been established. However, the deaminative alkynylation of alkyl amines to form C(sp 3 )-C(sp) bond still remains elusive. Although Gryko 46 and Han 47 have independently realized such transformation via photoredox or nickel-catalyzed reductive cross-coupling strategy recently, the need for tedious preparation of the corresponding alkynylating agents (e.g. alkynyl sulfones or bromides) limited their practical applicability and accessibility. In addition, the limited substrates scope and the use of largely excess reductants in both protocols further disfavored their utilizations in synthesis. Therefore, the direct coupling of terminal alkynes with alkylpyridinium salts in redox-neutral fashion for the synthesis of important alkynes would be highly desirable in terms of both atom-economy and practical application. To the best of our knowledge, however, such a straightforward and practical protocol has not been achieved.
Following our keen interest in nickel-catalyzed cross-coupling reactions 48,49 , herein, we report the rst general and e cient nickel-catalyzed Sonogashira coupling of alkylpyridinium salts via C-N bond activation under Cu-free conditions (Fig. 1e). The newly designed and readily accessible amide-type NN 2 pincer ligand (6-methyl-N-(quinolin-8-yl)picolinamide L4) was found to be crucial for this transformation, allowing the coupling to occur under mild reaction conditions with excellent yields and high functional group tolerance.

Results
Optimization study. Initially, the coupling of phenethylpyridinium salt 1a and phenylacetylene 2a was selected as the model reaction for optimization (Table 1). To realize such transformation, we envisaged that a pincer ligand might be feasible due to its strong and tridentate bonding mode to the metal center, thereby possibly stabilizing the alkylnickel intermediate 50 and suppressing the undesired Glaser coupling 51,52 . Thus, the ligands were rstly screened by using 10 mol% NiCl 2 (glyme) as catalyst, K 3 PO 4 as base in tetrahydrofuran (THF) at 80 o C. When pyridine bisoxazoline (pybox), the most e cient ligand in Liu's work 18 , was applied to this reaction, the desired product 3a was obtained in 4% yield and the main product was 1,4-diphenylbutadiyne derived from the homocoupling of 2a (entry 1). While the use of a more electron-rich and bulky 4,4′,4″-tritert-butyl terpyridine (ttbtpy) in this process, the yield of 3a was improved to 53% (entry 2). Much to our delight, the yields of 3a could be further improved to 87% and 83% respectively, when amide-type pincer ligand (e.g. N-(pyridin-2-ylmethyl)picolinamide (L1) or N-(quinolin-8-yl)picolinamide (L2)) was used (entries 3-4), though they were seldom used as ligands in transition metal-catalyzed cross-coupling reactions [53][54][55][56] . This discovery encouraged us to synthesize two new sterically more hindered methylated derivatives L3 and L4 as ligands. Gratifyingly, the yield was signi cantly improved to 96% by employing L4 (entry 6). The reasons for the high e ciency of L4 are still unclear at present, but probably related to its steric hindrance and rigidity. Screening of nickel catalysts revealed that Ni(acac) 2 was ineffective (entry 7), whereas the inexpensive, air-and moisture-stable NiCl 2 ·6H 2 O gave the best result (entry 8). Subsequently, the effect of base was examined. K 2 CO 3 resulted in a slightly diminished yield (entry 9). However, the reaction completely shut down by using Et 3 N, a frequently-used base in palladium-catalyzed Sonogashira coupling of aryl halides (entry 10) 11 . Lowering the amount of catalyst or reaction temperature led to a reduced yield in different extent (entries [11][12]. Control experiments indicated that NiCl 2 ·6H 2 O, L4 and K 3 PO 4 were all essential for achieving the transformation (entries 13-15) (For a detailed optimization study, see Supplementary Information).
Substrate scope. With the optimized coupling conditions in hand, the scope of alkynes was rst evaluated using 1a as the coupling partner. For some cases that the products were unseparated from the excess terminal alkynes, p-methoxylphenethylpyridinium salt 1b was used instead of 1a. As shown in Fig. 2, the arynes bearing both electron-donating and electron-withdrawing groups could participate in this transformation delivering the products (3b-3 k) in excellent yields. Various synthetically important functional groups including methoxyl, arylhalide, ester, acetyl, tri uoromethyl, formyl and free amino were all perfectly accommodated. Particularly noteworthy was that aryl chlorides and bromides, popular electrophilic partners in Sonogashira reactions 10 , remained inert under our optimized reaction conditions, highlighting the exquisite chemoselectivity of this transformation. Additionally, the presence of an ortho formyl did not hamper the reaction. Strikingly, terminal alkyne (2 l) containing a boronate ester group was also successfully engaged in this transformation with its C-B bond intact, thus allowing for further diversi cation. Heteroaromatic rings such as pyridine and thiophene that might deactivate a metal catalyst by coordination, and 1-ethynylcyclohexene could also smoothly undergo the transformation giving the corresponding products (3 m-3o) in excellent yields. More importantly, aliphatic alkynes (2p-2t) could also be coupled in high e ciency. The functional groups such as Cl, NHBoc, and OH were well tolerated, affording the products (3r-3t) in high to excellent yields with excellent selectivity. Finally, triisopropylsilyl-and trimethylsilyl-capped alkynes were also suitable substrates to obtain the products (3u-3v) in high yields.
Next, the generality of alkyl amines was evaluated as shown in Fig. 3. Various primary alkyl (1b-1 l) and benzylpyridinium salts (1 m-1o) were all suitable substrates for this transformation, and the desired products (4b-4o) could be obtained in high to excellent yields. However, the secondary alkylpyridinium salts (e.g. 1t) exhibited a dramatic drop in reaction e ciency (4t, 74%) under the optimized conditions. Then reoptimization of secondary alkylpyridinium salts was conducted by exploring various reaction parameters. Gratifyingly, 98% yield of 4t could be obtained by changing the solvent to DMF. Under the slightly modi ed conditions, diverse secondary alkylpyridinium salts underwent this coupling smoothly to give the desired products (4p-4w) in high to excellent yields. Similarly, good functional group tolerance was observed, as exempli ed by the well compatible with methoxyl, tri uoromethoxyl, bromide, indole NH, alkenyl, tert-amine, acetal, hydroxyl and chloride. More importantly, heterocyclic units such as thiophene (1f), pyridine (1 g), indole (1 h), tetrahydropyran (1 s) and piperidine (1t) which are prevalent in medicinally relevant molecules were competent substrates. In addition, benzylpyridinium salts especially electron-rich benzylic salts which are not suitable in Gryko's work 46 could be coupled with high e ciency (4 m-4n), emphasizing the robustness of our strategy in synthetic applications. It is worth noting that both cyclic (1p-1u) and acyclic secondary amines (1v-1w) could be readily applied to this protocol with high to excellent yields.
It is worth highlighting that this protocol was amenable to a one-pot transformation in which pyrylium salt, alkyl amine and the cross-coupling reagents were added simultaneously in a single step, and 78% yield of the product 3a could be obtained without further reoptimizing the reaction conditions (Fig. 4a).
Additionally, a gram-scale reaction was successfully performed using 1a and 2c under the optimized conditions producing 3c in 87% yield, exemplifying the practicability and scalability of this process (Fig. 4b).
Late-stage derivatizations. To further demonstrate the broad applicability of this method, late-stage functionalization of natural products and medicinally relevant molecules were conducted (Fig. 5). A series of pyridinium salts and alkynes derived from drugs and bioactive compounds underwent this transformation with good to excellent yields (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). This general protocol could be successfully applied for rapid construction of alkyne-labelled derivatives of biomolecules (5-9). The readily attached alkynyl group is expected to serve as a labeling tool to facilitate further chemical biology studies and as a handle for rapid entry to complex derivatives. Likewise, this versatile method can be also applied in the further functionalization of alkynyl-containing bioactive molecules or intermediates (10)(11)(12)(13)(14). Notably, the virtues of the current method were further illustrated by the successful coupling of two drug molecules for assembling their drug-like hybrids 15-20, highlighting the potential applications of this chemistry in the discovery of pharmaceutical candidates.
Mechanistic studies. To understand the reaction mechanism, a series of experiments were performed. When the radical trapping reagent TEMPO was added to the reaction mixture, only trace of 3a was obtained with the concurrent formation of TEMPO-adduct 21 in 16% yield (Fig. 6a). In addition, a radicalclock experiment was also conducted by employing cyclopropylmethyl pyridinium salt 1x. Instead of normal cross-coupling product 4x, a ring-opened product 22 was achieved in high yield (Fig. 6b). These results suggest that an alkyl radical may be involved in this transformation. To further elucidate the role of the nickel catalyst in this reaction, a Ni(II) complex Int-1 was synthesized by simple exposure of NiCl 2 ·6H 2 O and L4 in tetrahydrofuran at room temperature and characterized by X-ray crystallography.
Gratifyingly, a high yield of 3a was obtained when Int-1 was applied to this catalytic transformation (Fig. 6c). However, when Ni(cod) 2 was used as the catalyst, a remarkable decrease in e ciency was observed and only a moderate yield of 3a was achieved (Fig. 6d). These results indicate that Ni(II) complex Int-1 is likely involved as a competent catalytic species in this chemistry rather than a Ni(0) species.
Although a detailed mechanism awaits further studies, a plausible mechanism is depicted in Fig. 6e based on the reactions of Katritzky salts

Discussion
In summary, we have achieved a highly e cient and general Sonogashira coupling of alkylpyridinium salts by the development of a new Ni/NN 2 pincer ligand catalytic system. Notably, this is the rst time to realize the coupling of terminal alkynes with naturally abundant alkyl amines, extremely expanding the substrate scopes used in Sonogashira reactions. The virtues of this reaction are illustrated by the broad substrates scope, well functional group tolerance in both coupling partners as well as the e cient diversi cation of natural products and medicinally relevant molecules. Further mechanism investigation and application of this catalytic system for the cross-coupling with other electrophiles are currently ongoing in our laboratories.

Methods
General procedure for Sonogashira coupling of primary alkylpyridinium salts. In a nitrogen-lled glovebox, NiCl 2 ·6H 2 O (0.03 mmol, 7.1 mg), L4 (0.03 mmol, 7.9 mg), anhydrous K 3 PO 4 (0.39 mmol, 82.8 mg), primary alkylpyridinium salt (0.3 mmol) and tetrahydrofuran (1.5 mL) were successively added to an oven-dried sealable Schlenk tube (10.0 mL) followed by addition of terminal alkyne (0.45 mmol) via microliter syringe (If terminal alkyne is a solid, it was added before the solvent). Then the tube was securely sealed and taken outside the glovebox. And it was immersed into an oil bath preheated at 80 or short pad of silica gel. Then the lter cake was washed with dichloromethane or ethyl acetate. The resulting solution was concentrated under vacuum and the residue was puri ed by column chromatography on silica gel to afford the corresponding product.
General procedure for Sonogashira coupling of secondary alkylpyridinium salts. In a nitrogen-lled glovebox, NiCl 2 ·6H 2 O (0.03 mmol, 7.1 mg), L4 (0.03 mmol, 7.9 mg), anhydrous K 3 PO 4 (0.39 mmol, 82.8 mg), secondary alkylpyridinium salt (0.3 mmol) and N, N-dimethylformamide (1.5 mL) were successively added to an oven-dried sealable Schlenk tube (10.0 mL) followed by addition of phenylacetylene (0.45 mmol, 46.0 mg) via microliter syringe. Then the tube was securely sealed and taken outside the glovebox. And it was immersed into an oil bath preheated at 80 o C. After stirring for 24 h, the reaction mixture was cooled to room temperature and quenched with water. Then it was extracted with ethyl acetate or diethyl ether, washed with water and brine, and dried over anhydrous Na 2 SO 4 . The resulting solution was concentrated under vacuum and the residue was puri ed by column chromatography on silica gel to afford the corresponding product.

Data availability
Detailed experimental procedures and characterization of all new compounds can be found in the Supplementary Information. The authors declare that all the data supporting the ndings of this study are available within the article and Supplementary Information les, and are also available from the corresponding authors upon reasonable request. CCDC 2035475 (Int-1) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

Competing interests
The authors declare no competing interests.
Author contributions X.Z., and G.Z. conceived the idea and guided the project. X.Z., D.Q., C.J., and X.L. performed the experiments and analyzed the results. X.Z., X.L, and G.Z. wrote the manuscript.          Preliminary mechanistic studies. a Radical trap experiment. b Radical clock experiment. c Catalytic transformation using Int-1 as catalyst. d Catalytic transformation using Ni(cod)2 as catalyst. e Proposed reaction mechanism.
Page 23/24 Figure 6 Preliminary mechanistic studies. a Radical trap experiment. b Radical clock experiment. c Catalytic transformation using Int-1 as catalyst. d Catalytic transformation using Ni(cod)2 as catalyst. e Proposed reaction mechanism.
Supplementary Files