Cu(II)-Catalyzed CN Coupling of (Hetero)Aryl Halides and N

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Article Cu(II)-Catalyzed C-N Coupling of (Hetero)aryl Halides and N-Nucleophiles Promoted by α-Benzoin Oxime

Chunling Yuan *, Lei Zhang and Yingdai Zhao

Department of Medicinal Chemistry, Pharmacy School, Jinzhou Medical University, Jinzhou 121001, China; [email protected] (L.Z.); [email protected] (Y.Z.) * Correspondence: [email protected]; Tel.: +86-0416-4673440

Received: 29 October 2019; Accepted: 16 November 2019; Published: 18 November 2019

Abstract: We ﬁrst reported the new application of a translate metal chelating ligand α-benzoin oxime for improving Cu-catalyzed C-N coupling reactions. The system could catalyse coupling reactions of (hetero)aryl halides with a wide of nucleophiles (e.g., azoles, piperidine, pyrrolidine and amino acids) in moderate to excellent yields. The protocol allows rapid access to the most common scaﬀolds found in FDA-approved pharmaceuticals.

Keywords: α-Benzoin oxime; Copper catalyst; (Hetero)aryl halides; N-Nucleophiles; C-N Coupling

1. Introduction N-Arylated compounds are ubiquitous synthons in numerous natural products and functional molecules [1,2]. Particularly, their most important function is as structural fragment for FDA-approved pharmaceuticals (Figure1), for example, antibacterial agents (Ofloxacin [ 3] and Pipemidic acid [4]), antidiabetic drug (Repaglinide [5]), nonsteroidal anti-inflammatory drug (Celecoxib [6]), antihypertensive drug (Prazosin [7]), etc. Although C-N bond-formation reactions between (hetero)aryl halides and N-nucleophiles are well known, including the SNAr reactions [8], classical Ullmann-type coupling reactions [9–11], and Buchwald-Hartwig reactions [12–14]. Amongst Pd-catalyzed C-N coupling reaction has been confirmed as a very useful method to build aromatic amines or arylazoles [15–18]. However, considering to the cost and toxicity of both palladium catalyst and auxiliary phosphine ligands, the arylation of N-nucleophiles with (hetero)aryl halides to form new C-N bonds still remains a significant opportunity. In recent years, Cu-catalyzed Ullmann-type couplings have attracted more and more attention due to the inexpensive catalyst and low toxicity. Although many commercially available or novel designed ligands have been developed for promoting copper-catalyzed couplings of aryl halides with N-nucleophiles, few of them are effective with less inactivated heterocyclic aryl chlorides. Besides, an easy-removal catalyst system is also very important for the environment.

Molecules 2019, 24, 4177; doi:10.3390/molecules24224177 www.mdpi.com/journal/molecules Molecules 2019, 24, 4177 2 of 12 Molecules 2019, 24, x 2 of 12

FigureFigure 1. Chemical 1. Chemical structures structures of of selected selected pharmaceuticalspharmaceuticals containing containing the the N-arylatedN-arylated core. core.

DuringDuring the the past past few few years, years, Ma Ma and and co-workers co-workers have have reported reported that that the the oxalic oxalic diamide diamide ligands ligands are powerfulare powerful ligands ligands for for the the copper-catalyzedcopper-catalyzed couplings couplings [19–21]. [19–21 In]. the In presence the presence of ligands, of ligands,the reaction temperature and catalyst loading could be significantly decreased while the yields were the reaction temperature and catalyst loading could be significantly decreased while the yields increased [22–24]. Following these studies, a number of bidentate ligands were reported for the were increased [22–24]. Following these studies, a number of bidentate ligands were reported for the synthesis of N-arylated compounds. synthesisOn of Nthe-arylated other hand, compounds. α-benzoin oxime (BO) is a common ligand, which is usually applied to Oninspect the otherand measure hand, α copper,-benzoin molyb oximedenum, (BO) and is a tungsten common [25,26], ligand, and which also is as usually a chelating applied agent to for inspect and measureextracting copper, antimony, molybdenum, vanadium, andtungsten tungsten [27]. [ 25However,,26], and alsothe use as a of chelating BO in agentimproving for extracting the antimony,Cu-catalyzed vanadium, Ullmann tungsten style reactions [27]. However, is never the reported. use of Herein, BO in improvingit was found the that Cu-catalyzed BO could be used Ullmann stylein reactions the direct is couplings never reported. of the (hetero)aryl Herein, it washalides found withthat N-nucleophiles. BO could be The used reaction in the allowed direct couplingsrapid of theaccess (hetero)aryl to N-arylated halides compounds, with N-nucleophiles. the most Thecommo reactionn scaffolds allowed found rapid in access FDA-approved to N-arylated compounds,pharmaceuticals. the most These common reactions scaff oldswere foundoccurred in FDA-approvedat mild temperature pharmaceuticals. (80 °C), with Theseemploying reactions (hetero)aryl halides, nucleophiles (e.g., azoles, piperidine, pyrrolidine and amino acids) and were occurred at mild temperature (80 ◦C), with employing (hetero)aryl halides, nucleophiles (e.g., inexpensive catalysts, and affording high yields. Importantly, this process was general with respect azoles, piperidine, pyrrolidine and amino acids) and inexpensive catalysts, and affording high yields. to both the (hetero)aryl halides and nucleophiles, including the use of secondary amines and amino Importantly,acids. this process was general with respect to both the (hetero)aryl halides and nucleophiles, including the use of secondary amines and amino acids. 2. Results and Discussions 2. Results and Discussions To initiate our studies, 2-bromoanisole was treated with pyrrole in the presence of 0.28 mol CuI Toin DMF. initiate Regrettably, our studies, coupling 2-bromoanisole product 3a was was obtained treated within 12% pyrrole yield, along in the with presence unreacted of 0.28 starting mol CuI in DMF.material Regrettably, (Table 1, couplingentry 1). The product use of 3aCuwas powder obtained and Cu(OTf) in 12%2 yield,as catalyst along in DMF with delivered unreacted 3a starting in materiallow yields (Table (entries1, entry 2, 1).3). Consistently, The use of Cu Cu(II) powder gluconate and and Cu(OTf) Cu2(OH)2 as2CO catalyst3 did not in provide DMF deliveredthe desired 3a in product (entries 4, 5), only a trace of 3a was observed. In the event, 10 mol% Cu(OAc)2 enabled the low yields (entries 2, 3). Consistently, Cu(II) gluconate and Cu2(OH)2CO3 did not provide the desired coupling of 2-bromoanisole and pyrrole to provide the desired product in 53% yield (entry 6). product (entries 4, 5), only a trace of 3a was observed. In the event, 10 mol% Cu(OAc)2 enabled the Attempts to improve the yield through changing the base were successful, with K3PO4 proving to be coupling of 2-bromoanisole and pyrrole to provide the desired product in 53% yield (entry 6). Attempts optimal in terms of yield (entries 6–11). Furthermore, with dioxane, toluene, DCE, H2O as solvents to improve(entries the 12–16), yield the through yield was changing lower than the basethat in were DMF. successful, Fortunately, with DMSO K3PO gave4 proving significantly to be optimalbetter in termsresults, of yield and (entries 3a was 6–11). obtained Furthermore, in a much-improved with dioxane, 90% yield. toluene, Meanwhile, DCE, H 2loweringO as solvents the temperature (entries 12–16), the yieldto 60 was °C lowerdecreased than the that yield in DMF.and led Fortunately, incomplete DMSO conversion gave (entry significantly 17). A bettersignificant results, amount and 3aof was obtainedcoupling in a much-improvedproduct was observed 90% yield.when using Meanwhile, BO as loweringligand, comparing the temperature with the tocorresponding 60 ◦C decreased the yieldcontrol and experiments led incomplete (entries conversion 12 and 18). (entry The scalab 17). Aility significant of this protocol amount was of also coupling tested productthrough was observedsynthesis when of usingthe 3a BOon a as 4.4 ligand, g scale comparing (entry 19). Additionally, with the corresponding the BO-promoted control C-N experiments reaction was (entries also 12 and 18).carried The out scalability under air, of 3a this was protocol obtained was in also61% testedyield, throughindicating synthesis that this ofcatalytic the 3a systemon a 4.4 was g scale (entry 19). Additionally, the BO-promoted C-N reaction was also carried out under air, 3a was obtained in 61% yield, indicating that this catalytic system was sensitive with air (entry 20). Finally, we checked other ligands (including N,N-, N,O-, O,O-type bidentate ligands) that were applied in Cu-catalyzed MoleculesMolecules2019, 201924, 4177, 24, x 3 of 123 of 12 Molecules 2019, 24, x 3 of 12 sensitive with air (entry 20). Finally, we checked other ligands (including N,N-, N,O-, O,O-type N-arylationbidentatesensitive reactions, ligands)with air andthat (entry discoveredwere 20). applied Finally, that in we onlyCu-catalyzed checkedL3 and other L4N-arylation couldligands furnish (includingreactions,3a in andN moderate,N -,discovered N,O-, yieldsO,O that-type under standardonlybidentate condition.L3 and ligands) L4 could It was that furnish reasoned were 3a applied in that moderate thesein Cu-catalyzed yields reported under ligands N standard-arylation may condition. bereactions, effective It and was when discoveredreasoned chelating that that with Cu(I).theseonly reported L3 and L4 ligands could may furnish be effective 3a in moderate when chelating yields under with standardCu(I). condition. It was reasoned that these reported ligands may be effective when chelating with Cu(I). TableTable 1. 1.Identification Identification ofof reaction condition condition a. a. Table 1. Identification of reaction condition a. OMe OMe HO Cu cources (10 mol%) N Br OMe BO (10 mol%) OMeN HO HN Cu cources (10 mol%) N Br+ BO (10 mol%) N HN Base (2 equiv.) + o OH Solvent,Base (2 Ar, equiv.) 80 C 3a BO o OH Solvent, Ar, 80 C 3a BO Entry Cu Sources Base Solvent Yield (%) b 1 CuI K2CO 3 DMF 12 2 1Cu powder CuI KKCO2CO3 DMFDMF 1215 1 CuI 2 K2CO3 3 DMF 12 3 2Cu(OTf) Cu powder2 KKCO2CO3 DMFDMF 1522 2 Cu powder 2 K2CO3 3 DMF 15 4 3Cu(II) glucona Cu(OTf)t e KKCO2CO3 DMFDMF 22Trace 3 Cu(OTf)2 2 2 K2CO3 3 DMF 22 5 4Cu Cu(II)2(OH)2 gluconateCO3 KKCO2CO3 DMFDMF TraceTrace 4 Cu(II) gluconat e 2 K2CO3 3 DMF Trace 6 Cu(OAc)2 K2CO3 DMF 53 5 5Cu Cu2(OH)2(OH)2CO2CO3 3 K2COK2CO3 3 DMFDMF TraceTrace 7 Cu(OAc)2 Cs2CO3 DMF 60 6 6Cu(OAc) Cu(OAc)2 2 K2COK2CO3 3 DMFDMF 53 53 8 Cu(OAc)2 K3PO4 DMF 72 7 7Cu(OAc) Cu(OAc)2 2 Cs2CsCO2CO3 3 DMFDMF 60 60 9 Cu(OAc)2 NaHCO3 DMF 0 c 8 8Cu(OAc) Cu(OAc)2 2 K3POK3PO4 4 DMFDMF 72 72 10 Cu(OAc)2 Et3N DMF c 0 c 9 9Cu(OAc) Cu(OAc)2 2 NaHCONaHCO3 3 DMFDMF 0 0 c 11 Cu(OAc)2 t-BuOK DMF Tracec 10 10Cu(OAc) Cu(OAc)2 2 Et3EtN3N DMFDMF 0 0 c 12 Cu(OAc)2 K3PO4 DMSO 90 11 11Cu(OAc) Cu(OAc)2 2 t-BuOKt-BuOK DMFDMF TraceTrace 13 Cu(OAc)2 K3PO4 Dioxane 43 12 12Cu(OAc) Cu(OAc)2 2 K3KPO3PO44 DMSO DMSO 90 90 14 Cu(OAc)2 K3PO4 DCE Trace 13 13Cu(OAc) Cu(OAc)2 2 K3KPO3PO44 Dioxane Dioxane 43 43 15 Cu(OAc)2 K3PO4 Toluene 0 c 14 14Cu(OAc) Cu(OAc)2 2 K3KPO3PO44 DCE DCE TraceTrace 16 Cu(OAc)2 K3 PO4 H2O c 0 c 15 15Cu(OAc) Cu(OAc)2 2 K3KPO3PO44 Toluene Toluene 0 0 c d 17 Cu(OAc)2 K3PO4 3 DMSO c70 c 16 16Cu(OAc) Cu(OAc)2 2 K3KPO3 P4O4 H2OH2O 0 0 e 18 Cu(OAc)2 DMSO 15d d 17 17Cu(OAc) Cu(OAc)2 K KPO3PO4 DMSO3 DMSO 70 70 2 3 4 f 19 Cu(OAc)2 DMSO 90e e 18 18Cu(OAc) Cu(OAc)2 2 K3PO4 DMSODMSO 15 15 f f 19 19 Cu(OAc)Cu(OAc)2 2 K3PO4 DMSODMSO 90 90 g 20 Cu(OAc)2 K3PO4 DMSOO O 61 O O O H OEt N O COOH Me H OH N N N N N OEt N H COOH Me OH N L1 HL2 NL3 N NL4 N L5 traceL1 traceL2 42%L3 55%L4 0%L5 trace 55% a Reaction conditions: 2-Bromoanisoletrace (2.81 mmol),42% pyrrole (3.37 mmol), Cu source (0.28 0%mmol), BO b (0.28a Reaction mmol), conditions: solvent (4 mL),2-Bromoanisole base (5.62 mmol),(2.81 mmol), under pyrrole Ar, at 80 (3.37 °C, mmol),unless otherwiseCu source noted(0.28 mmol),for 8 h. BO a c d e ReactionIsolated conditions: yield with 2-Bromoanisole column chromatography. (2.81 mmol), pyrrole Almost (3.37 no reaction mmol),Cu was source observed (0.28 by mmol), TLC.BO 60 (0.28 °C. mmol), b (0.28 mmol), solvent (4 mL), base (5.62 mmol), under Ar, at 80 °C, unless otherwiseb noted for 8 h. solvent (4 mL), basef (5.62 mmol), under Ar, at 80 ◦C, unless otherwiseg noted for 8 h. Isolated yield with column Without BO. The loading of 2-bromoanisole wasc 28.1 mmol. The reaction was carried outd under e chromatography.Isolated yieldc Almost with nocolumn reaction chromatography. was observed by TLC.Almostd 60 noC. reactione Without was BO. observedf The loading by TLC. of 2-bromoanisole 60 °C. air. Red bond indicated cleavage bond; blue bond indicated◦ formed bond; and BO was α-benzoin was 28.1Without mmol. gBO.The f The reaction loading was of carried 2-bromoanisole out under air.was Red 28.1 bond mmol. indicated g The reaction cleavage was bond; carried blue bondout under indicated formedoxime.air. bond; Red and bond BO indicated was α-benzoin cleavage oxime. bond; blue bond indicated formed bond; and BO was α-benzoin oxime. With optimized conditions in hand, we set out to evaluate the scope of (hetero)aryl halides that With optimized conditions in hand, we set out to evaluate the scope of (hetero)aryl halides wouldWith participate optimized in conditionsthis transformation in hand, we (Table set out 2). to Theevaluate reaction the scope tolerated of (hetero)aryl a diverse halides array thatof that would participate in this transformation (Table2). The reaction tolerated a diverse array of functionalwould participate groups on inthe this (hetero) transformationaryl halides, (Tableincluding 2). methoxyThe reaction (3a), aldehydetolerated (a3c ),diverse carboxyl array (3d ),of functionalaminofunctional groups(3e), ketonegroups on the (on3f), (hetero)arylthe ester (hetero) (3g, aryl3h halides,), halides,cyano including(3i including). Electronic methoxymethoxy properties ( (3a3a),), aldehydeof aldehyde the (hetero)aryl (3c (),3c carboxyl), carboxyl halides (3d ), ( 3d), aminowereamino (3e ),evaluated ketone(3e), ketone (by3f ),introducing ( ester3f), ester (3g ,( 3g3helectron-withdrawi, ),3h cyano), cyano (3i ().3i). Electronic ngElectronic and electron-donating properties of of the thegroups (hetero)aryl (hetero)aryl on the halides aryl halides weremoiety. evaluatedwere evaluatedAlthough by introducing electron-poorby introducing electron-withdrawing (hetero)aryl electron-withdrawi halides ( ande.g.ng, electron-donating3cand, 3d electron-donating, 3i) underwent groups coupling groups on thefasteron arylthe than aryl moiety. Althoughelectronmoiety. electron-poor richAlthough ones electron-poor( (hetero)aryl3a, 3e), the (hetero)aryl halidesdesired (e.g.,products halides3c, 3d ( e.g.were, 3i, 3c) underwent, successfully3d, 3i) underwent coupling obtained coupling faster in allfaster than cases. electronthan rich onesUnfortunately,electron (3a , rich3e), chlorobenzene theones desired(3a, 3e), products couldn’tthe desired provide were products successfully the product were obtained3bsuccessfully. By changing in allobtained cases. which in Unfortunately,heteroaryl all cases. chlorobenzeneUnfortunately, couldn’t chlorobenzene provide thecouldn’t product provide3b. the By product changing 3b which. By changing heteroaryl which chlorides heteroaryl were employed, couplings were smoothly proceeded, although the yield was decreased. A more sterically encumbered 2-methylimidazole also reacted without incidents (3l, 3n). Molecules 2019, 24, x 4 of 12 Molecules 2019, 24, 4177 4 of 12

chlorides were employed, couplings were smoothly proceeded, although the yield was decreased. A more Tablesterically 2. C-N encumbered Coupling 2-meth reactionsylimid of substitutedazole also reac arylted compounds without incidents with pyrrole (3l, 3n or). azoles a,b.

Y X Cu(OAc)2 (10 mol%) BO (10 mol%) Y N Heteroaryl R + Heteroaryl-NH Z R K3PO4 (2 equiv.) Z Y, Z = CH or N DMSO, Ar, 80 oC X=Br or Cl

OMe CO2H NH2 N N N OHC N N N N N

3a: X=Br, 88% 3b: X=Br, 94% 3c: X=Br, 95% 3d: X=Br, 96% 3e: X=Br, 85% Molecules 2019, 24, x 4 of 12 N X=Cl, 0% N CN N EtO C N N N N N chlorides were employed, couplings2 were Nsmoothly proceeded, although the Nyield was decreased. A more stericallyO encumbered 2-methylimidazole also reacted without incidents (3l, 3n). MeO2C 3j Me 3f: X=Br, 90% 3g: X=Br, 91% 3h: X=Br, 93% 3i: X=Br, 98% : X=Cl, 84% Y X Cu(OAc) (10 mol%) N 2 N N N N N N N BO (10N mol%)N N NY N Heteroaryl R + Heteroaryl-NH Z R Me K3PO4 (2N equiv.) N MeZ Y, Z = CH or N DMSO, Ar, 80 oC 3k: X=X=Cl,Br or 88% Cl 3l: X=Cl, 85% 3m: X=Cl, 83% 3n: X=Cl, 80% OMe a CO2H NH2 N Reactions conducted on (hetero)aryl halides (2.81 mmol), pyrrole or azoles (3.37 mmol), Cu(OAc)2 (0.28 mmol), N N OHC N N b N BO (0.28 mmol), K3PO4 (5.62 mmol), DMSO (4 mL) under ArN at 80 ◦C for 8~10N h. Isolated yield with column chromatography.Table 3. C-N Coupling reactions of substituted aryl compounds with amines a,b 3a: X=Br, 88% 3b: X=Br, 94% 3c: X=Br, 95% 3d: X=Br, 96% 3e: X=Br, 85% X=Cl, 0% In order to exploreN the feasibility of this approach,N cyclic secondaryCN amines (piperidine and N EtO C N Cu(OAc) (10 mol%)N N N N pyrrolidine), acyclic secondaryY X 2 amine (diethylamine),N 2 aliphatic primary amineN (ethanolamine) were BO (10 mol%) Y NRR' O R + NHRR' WZ R examined to achieve the desired coupling (TableMeO2C 3). First, the reactionsWZ were carried out by using K3PO4 (2 equiv.) 3j Me 3f: X=Br, 90% 3g: X=Br, 91% 3h: X=Br, 93% 3i: X=Br, 98% : X=Cl, 84% 2-chloropyridine as startingW, Y, Z = CH material. or N To our delight,DMSO, Ar, 80 theoC corresponding coupling product 4a and 4b X=Br or Cl were obtained in 87%N and 88% yield, respectively. We alsoN attempted the couplingN of 4-chloropyridine N N N N N N N N N to form 4c and 4d. In both cases, the products were obtained inOMe good yields.OMe Both electron-rich N N N (4g) and electron-poorN N (4i) arylN bromidesN Me participatedN N equally well inN theMe reaction. The reaction was 3k: X=Cl, 88% eﬀective in the presence of unprotected3l: X=Cl, 85%N polar functional3m:N X=Cl, 83% groups such3n: X=Cl, as alcohol.80% It was encouraged that the ethanolamine4a: X=Cl, 87% substitute4b: X=Cl, could88% 4c provide: X=Cl, 85%4l in4d 90%: X=Cl, yield; 86% the4g: X=Br, lower 80% yield4h: wasX=Br, due82% to incomplete conversion of the starting material. H N a,bN Table 3. C-N CouplinN g reactionsN N of substituN tedN aryl compoundsNEt with2 amines OH

N O N a,b OHCTable 3. C-NOHC Coupling reactions of substitutedN aryl compounds with2 amines . 4i: X=Br, 89% 4j: X=Br, 90% 4e: X=Cl, 88% 4f: X=Cl, 87% 4k: X=Br, 92% 4l: X=Br, 90% Y X Cu(OAc)2 (10 mol%) BO (10 mol%) Y NRR' R + NHRR' WZ R WZ K3PO4 (2 equiv.) W, Y, Z = CH or N DMSO, Ar, 80 oC X=Br or Cl

In order to explore the feasibility of this approach, cyclic secondaryOMe aminesOMe (piperidine and N N N N N pyrrolidine),N acyclicN secondary amine (diethylaminN e), aliphatic primary amine (ethanolamine) were examined to achieve the desired couplingN (Table 3).N First, the reactions were carried out by using 2-chloropyridine4a: X=Cl, 87%as starting4b: X=Cl, material. 88% 4c To: X=Cl, our 85% delight,4d: the X=Cl, corresponding 86% 4g: X=Br, coupling80% 4h: X=Br,product 82% 4a and 4b

were obtained in 87% and 88% yield, respectively. We also attempted the Hcoupling of N N 4-chloropyridine to form 4c andN 4d. In bothN cases,N theN productsN were obtainedNEt2 in good yields.OH Both electron-rich (4g) and electron-poor (4i) aryl bromides participated equally well in the reaction. The OHC N N O2N reaction was effectiveOHC in the presence of unprotected polar functional groups such as alcohol. It was 4i: X=Br, 89% 4j: X=Br, 90% 4e: X=Cl, 88% 4f: X=Cl, 87% 4k: X=Br, 92% 4l: X=Br, 90%

a Reactions conducted on (hetero)aryl halides (2.81 mmol), amines (3.37 mmol), Cu(OAc)2 (0.28 mmol), b BO (0.28 mmol), K3PO4 (5.62 mmol), DMSO (4 mL) under Ar at 80 ◦C for 8 h. Isolated yield with column chromatography.

In order to explore the feasibility of this approach, cyclic secondary amines (piperidine and pyrrolidine), acyclic secondary amine (diethylamine), aliphatic primary amine (ethanolamine) were examined to achieve the desired coupling (Table 3). First, the reactions were carried out by using 2-chloropyridine as starting material. To our delight, the corresponding coupling product 4a and 4b were obtained in 87% and 88% yield, respectively. We also attempted the coupling of 4-chloropyridine to form 4c and 4d. In both cases, the products were obtained in good yields. Both electron-rich (4g) and electron-poor (4i) aryl bromides participated equally well in the reaction. The reaction was effective in the presence of unprotected polar functional groups such as alcohol. It was Molecules 2019, 24, 4177 5 of 12

Although N-heterocycle electrophiles were the primary focus of this study, amino acids-based electrophiles were also evaluated (Table4). Amino acids underwent coupling to a ﬀord corresponding products in moderate yields. Although the yields were modest, it was noted that these reactions were conducted under the conditions developed for the 2-bromoanisole with minimal reoptimization. Substrates bearing either electron-withdrawing (5b) or electron-donating groups (5c) on the (hetero)aryl halidesMolecules coupled 2019, 24 with, x high yields. Introduction of an ester group into amino acid was also5 of tolerated 12 (5a). Finally, we were pleased to ﬁnd that our method was not limited to 2-chloropyrimidine. Using encouraged that the ethanolamine substitute could provide 4l in 90% yield; the lower yield was due 2-chloropyrimidineto incomplete conversion as the substrate of the starting led to material. the formation of 5e, 5f in 86%, 87% yield, respectively.

a,b TableTable 4. C-N 4. C-N Coupling Coupling reactions reactions of of substituted substituted ar arylyl compounds compounds with with amino amino acids/esters acids/esters a,b. .

Y X Cu(OAc)2 (10 mol%) Y NHR1 R + Amino Acid/Ester BO (10 mol%) Z R K3PO4 (2 equiv.) Z Y, Z = C H o r N o X=Br or Cl DMSO, Ar, 80 C

O iPr O O O O OtBu O H iPr N Me MeS NH OH OH OH OH OH HN NH N NH N NH O2N N N 5a: X=Br, 90% 5b: X=Br, 92% 5c: X=Br, 88% 5d: X=Br, 90% 5e: X=Cl, 86% 5f: X=Cl, 87%

a Reactions conducted on (hetero)aryl halides (2.81 mmol), amino acids/esters (3.37 mmol), Cu(OAc)2 (0.28 mmol), BO b 0.28 mmol), K3PO4 (5.62 mmol), DMSO (4 mL) under Ar at 80 ◦C for 8 h. Isolated yield with column chromatography. a Reactions conducted on (hetero)aryl halides (2.81 mmol), amino acids/esters (3.37 mmol), Cu(OAc)2 (0.28 mmol), BO 0.28 mmol), K3PO4 (5.62 mmol), DMSO (4 mL) under Ar at 80 oC for 8 h. b Isolated Theyield ligand with BO column has chromatography. been reported to be used as a metal chelating agent [28], which is a typical N,O-ligand. Thus, it was believed that the Cu-catalyzed couplings could process in a homogeneous manner dueAlthough to the N formation-heterocycle of electrophiles Cu-benzoinoxime were the complex. primary Herein,focus of itthis was study, proposed amino thatacids-based the possible mechanismelectrophiles for the were couplings also evaluated might run (Table via a prototypical 4). Amino Cuacids (I)/ Cuunderwent (III) catalytic coupling cycle. to [29 ]afford As shown corresponding products in moderate yields. Although the yields were modest, it was noted that in Figure2, the catalytic cycle initiated from a Cu complex ( A). Then, coordinated copper species (B) these reactions were conducted under the conditions developed for the 2-bromoanisole with wereminimal produced reoptimization. via oxidative Substrates addition bearing of an ArX either and electron-withdrawingA. Ligand exchange (5b was) or subsequently electron-donating occurred betweengroupsA and(5c) onN-heterocycles the (hetero)aryl to halides form intermediate coupled withC, highwhich yields. could Introduction be converted of an ester to D groupin the into presence of base.amino The acidN-arylazole was also tolerated was obtained (5a). Finally, by ﬁnal we were reductive pleased elimination to find that of ourD method. was not limited to 2-chloropyrimidine. Using 2-chloropyrimidine as the substrate led to the formation of 5e, 5f in 86%, 87% yield, respectively. The ligand BO has been reported to be used as a metal chelating agent [28], which is a typical N,O-ligand. Thus, it was believed that the Cu-catalyzed couplings could process in a homogeneous manner due to the formation of Cu-benzoinoxime complex. Herein, it was proposed that the possible mechanism for the couplings might run via a prototypical Cu (I)/Cu (III) catalytic cycle. [29] As shown in Figure 2, the catalytic cycle initiated from a Cu complex (A). Then, coordinated copper species (B) were produced via oxidative addition of an ArX and A. Ligand exchange was subsequently occurred between A and N-heterocycles to form intermediate C, which could be converted to D in the presence of base. The N-arylazole was obtained by final reductive elimination of D. Molecules 2019, 24, 4177 6 of 12 Molecules 2019, 24, x 6 of 12

OH Ar-N-Het Ph N ArX Cu Ph O H A

OH OH Ph Ph N Ar N Ar Cu Cu N-Het O X Ph O Ph H H D B

B-HX OH NH-Het Ph N Ar Cu X B Ph O NH-Het H C FigureFigure 2. Proposed 2. Proposed mechanism mechanism for the for couplings the couplings of (hetero)aryl of (hetero)aryl halides withhalidesN-containing with N-containing heterocycles. NH-Hetheterocycles. represented NH-Het N-hetero represented nucleophiles; N-hetero Xnucleophiles; was bromine X was or chloride.bromine or chloride.

3. Materials3. Materials and and Methods Methods All ofAll the of starting the starting materials, materials, reagents, reagents, and solventsand solvents are commerciallyare commercially available available and and used used without furtherwithout purification. further purification. Melting points Melting were points determined were determined with a X-4 with apparatus a X-4 apparatus (Beijing (Beijing Taike Instrument Taike Instrument Co., Ltd., Beijing, China) and were uncorrected. The nuclear magnetic resonance (NMR) Co., Ltd., Beijing, China) and were uncorrected. The nuclear magnetic resonance (NMR) spectra were spectra were recorded on a Bruker (Bruker Technology Co., Ltd., Karlsruhe, Germany) 400 MHz recorded on a Bruker (Bruker Technology Co., Ltd., Karlsruhe, Germany) 400 MHz spectrometer in spectrometer in CDCl3 or DMSO-d6 using tetramethylsilane (TMS) as an internal standard. CDClElectrospray3 or DMSO- ionizationd6 using tetramethylsilanemass spectrometry (TMS)(MS (ESI)) as ananalyses internal were standard. recorded Electrospray in an Agilent ionization 1100 massSeries spectrometry MSD Trap (MS SL (ESI)) (Santa analyses Clara, wereCA, recordedUSA). The in reactions an Agilent were 1100 monitored Series MSD by Trapthin-layer SL (Santa Clara,chromatography CA, USA). The (TLC: reactions HG/T2354-92, were monitored GF254), and by thin-layercompounds chromatography were visualized on (TLC: TLC HGwith/T2354-92, UV GF254),light and (Gongyi compounds Yuhua Instrument were visualized Co., Ltd, on Zhengzhou, TLC with China). UV light (Gongyi Yuhua Instrument Co., Ltd, Zhengzhou, China). General Procedure for Catalytic Experiments. General ProcedureTo a solution for Catalytic of (hetero)aryl Experiments halide (2.81 mmol), N-nucleophile (3.37 mmol), BO (0.28 mmol), ToK3PO a solution4 (5.62 mmol) of (hetero)aryl in DMSO (4 halidemL), were (2.81 added mmol), Cu(OAc)N-nucleophile2 (0.28 mmol). (3.37 The mmol), flask was BO evacuated (0.28 mmol), and backfilled with argon for three times. The resulting suspension was heated in a 80 °C oil bath K PO (5.62 mmol) in DMSO (4 mL), were added Cu(OAc) (0.28 mmol). The flask was evacuated 3 with4 stirring for the indicated time. The reactor was cooled to 2r.t., the flask was opened to air and the and backfilled with argon for three times. The resulting suspension was heated in a 80 C oil bath reaction mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL × 3),◦ and withorganic stirring layer for the was indicated washed time.with Thewater reactor (20 mL was × cooled2) and toonce r.t., with the flaskbrine was (25 openedmL), dried to air over and the reaction mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL 3), and organic magnesium sulfate and concentrated in vacuo. The product was purified by column chromatography× layeron was silica washed gel using with petroleum water (20 ether mL and2) ethyl and acetate once with as eluent. brine (25 mL), dried over magnesium sulfate × and concentrated in vacuo. The product was purified by column chromatography on silica gel using 1-(2-Methoxyphenyl)-1H-pyrrole (3a) [30]: colorless oil (0.43 g, 88%). 1H-NMR (400 MHz, CDCl3) δ (ppm): petroleum7.30–7.23 ether (2H, and m), ethyl7.03–6.98 acetate (4H, asm), eluent. 6.30 (2H, t, J = 2.2 Hz), 3.82 (3H, s). MS (ESI) m/z: 174.11 [M + H]+, see supplementary material. 1 1-(2-Methoxyphenyl)-1H-pyrrole (3a) [30]: colorless oil (0.43 g, 88%). H-NMR (400 MHz, CDCl3) δ (ppm): 7.30–7.23 (2H, m), 7.03–6.98 (4H, m), 6.30 (2H, t, J = 2.2 Hz), 3.82 (3H, s). MS (ESI) m/z: 174.11 [M + H]+, see Supplementary Materials.

Molecules 2019, 24, 4177 7 of 12

1 1-Phenyl-1H-pyrrole (3b) [31]: white solid (0.38 g, 94%). m.p. 60–62 C. H-NMR (400 MHz, CDCl3) δ (ppm): 7.43–7.37 (4H, m), 7.25–7.21 (1H, m), 7.08 (2H, t, J = 2.2 Hz), 6.34 (2H, t, J = 2.2 Hz). MS (ESI) m/z: 144.04 [M + H]+.

1 3-(1H-Pyrazol-1-yl)benzaldehyde (3c) [32]: oﬀ white solid (0.46 g, 95%), m.p. 28–30 ◦C. H-NMR (400 MHz, CDCl3) δ (ppm): 10.08 (1H, s), 8.19 (1H, t, J = 1.8 Hz), 8.05–8.02 (2H, m), 7.81–7.76 (2H, m), 7.64 (1H, t, J = 7.9 Hz), 6.52 (1H, t, J = 2.1 Hz). MS (ESI) m/z: 173.08 [M + H]+.

1 2-(1H-Pyrazol-1-yl)benzoic acid (3d) [33]: white solid (0.51 g, 96%), m.p. 128–129 ◦C. H-NMR (400 MHz, CDCl3) δ (ppm): 11.40 (1H, br), 8.05–8.02 (1H, dd, J = 7.8 Hz, 1.2 Hz), 7.76–7.74 (2H, m), 7.62–7.58 (1H, m), 7.49–7.40 (2H, m), 6.48 (1H, s). MS (ESI) m/z: 189.06 [M + H]+.

1 2-(1H-Pyrazol-1-yl)aniline (3e) [34]: brown oil (0.38 g, 85%). H-NMR (400 MHz, CDCl3) δ (ppm): 7.74–7.71 (2H, m), 7.19–7.13 (2H, m), 6.85–6.76 (2H, m), 6.44 (1H, t, J = 2.0 Hz), 4.63 (2H, br). MS (ESI) m/z: 160.09 [M + H]+.

1 1-(4-(1H-Pyrazol-1-yl)phenyl)ethan-1-one (3f) [35]: yellow oil (0.47 g, 90%). H-NMR (400 MHz, CDCl3) δ (ppm): 8.08–8.06 (2H, m), 8.02 (1H, d, J = 2.5 Hz), 7.83–7.81 (2H, m), 7.78 (1H, d, J = 1.4 Hz), 6.53 (1H, t, J = 2.0 Hz), 2.63 (3H, s). MS (ESI) m/z: 187.09 [M + H]+.

1 Ethyl 3-(1H-pyrazol-1-yl)benzoate (3g) [36]: yellow liquid (0.55 g, 91%). H-NMR (400 MHz, CDCl3) δ (ppm): 8.31 (1H, t, J = 1.8 Hz), 7.99 (1H, d, J = 2.4 Hz), 7.97–7.93 (2H, m), 7.74 (1H, d, J = 1.6 Hz), 7.53 (1H, t, J = 8.0 Hz), 6.49 (1H, t, J = 2.0 Hz), 4.44–4.38 (2H, q, J = 14.3 Hz, 7.2 Hz), 1.41 (3H, t, J = 7.1 Hz). MS (ESI) m/z: 217.10 [M + H]+.

1 Methyl 4-(1H-pyrazol-1-yl)benzoate (3h) [37]: white solid (0.53 g, 93%), m.p. 103–105 ◦C. H-NMR (400 MHz, CDCl3) δ (ppm): 8.15–8.12 (2H, m), 8.00 (1H, d, J = 2.4 Hz), 7.80–7.77 (2H, m), 7.76 (1H, d, J = 1.4 Hz), 6.51 (1H, t, J = 2.1 Hz), 3.93 (3H, s). MS (ESI) m/z: 203.11 [M + H]+.

1 2-(1H-Pyrazol-1-yl)benzonitrile (3i) [38]: yellow oil (0.47 g, 98%). H-NMR (400 MHz, CDCl3) δ (ppm): 8.15 (1H, d, J = 2.5 Hz), 7.81–7.79 (3H, m), 7.77 (1H, d, J = 1.3 Hz), 7.72–7.68 (1H, m), 6.55 (1H, t, J = 2.1 Hz). MS (ESI) m/z: 170.07 [M + H]+.

1 2-(1H-Pyrrol-1-yl)pyridine (3j) [39]: colorless oil (0.34 g, 84%). H-NMR (400 MHz, CDCl3) δ (ppm): 8.43–8.42 (1H, m), 7.75–7.71 (1H, m), 7.52 (2H, t, J = 2.3 Hz), 7.32 (1H, d, J = 8.3 Hz), 7.11–7.08 (1H, m), 6.36 (2H, t, J = 2.3 Hz). MS (ESI) m/z: 145.04 [M + H]+.

1 2-(1H-Imidazol-1-yl)pyridine (3k) [40]: white solid (0.36 g, 88%), m.p. 40–41 ◦C. H-NMR (400 MHz, CDCl3) δ (ppm): 8.50–8.48 (1H, m), 8.35 (1H, s), 7.85–7.80 (1H, m), 7.65 (1H, t, J = 1.3 Hz), 7.37–7.35 (1H, m), 7.27–7.23 (1H, m), 7.20 (1H, s). MS (ESI) m/z: 146.08 [M + H]+.

1 2-(2-Methyl-1H-imidazol-1-yl)pyridine (3l) [41]: colorless oil (0.38 g, 85%). H-NMR (400 MHz, CDCl3) δ (ppm): 8.56–8.54 (1H, m), 7.86–7.82 (1H, m), 7.32–7.29 (2H, m), 7.28 (1H, d, J = 1.5 Hz), 7.02 (1H, d, J = 1.5 Hz), 7.02 (1H, d, J = 1.4 Hz), 2.59 (3H, s). MS (ESI) m/z: 160.09 [M + H]+.

1 2-(1H-Imidazol-1-yl)pyrimidine (3m) [42]: white solid (0.34 g, 83%), m.p. 120–122 ◦C. H-NMR (400 MHz, CDCl3) δ (ppm): 8.71 (2H, d, J = 4.8 Hz), 8.64 (1H, s), 7.90 (1H, s), 7.21 (1H, t, J = 4.8 Hz), 7.18 (1H, s). MS (ESI) m/z: 147.06 [M + H]+.

1 2-(2-Methyl-1H-imidazol-1-yl)pyrimidine (3n) [43]: white solid (0.36 g, 80%), m.p. 90–92 ◦C. H-NMR (400 MHz, CDCl3) δ (ppm): 8.72 (2H, d, J = 4.8 Hz), 7.86 (1H, d, J = 1.4 Hz), 7.18 (1H, t, J = 4.8 Hz), 6.97 (1H, d, J = 1.3 Hz), 2.82 (3H, s). MS (ESI) m/z: 161.10 [M + H]+.

1 2-(Piperidin-1-yl)pyridine (4a) [44]: colorless oil (0.40 g, 87%). H-NMR (400 MHz, CDCl3) δ (ppm): 8.16–8.15 (1H, m), 7.44–7.39 (1H, m), 6.63 (1H, d, J = 8.6 Hz), 6.54–6.51 (1H, m), 3.52 (4H, d, J = 4.9 Hz), 1.62 (6H, s). MS (ESI) m/z: 163.13 [M + H]+. Molecules 2019, 24, 4177 8 of 12

1 2-(Pyrrolidin-1-yl)pyridine (4b) [45]: colorless oil (0.37 g, 88%). H-NMR (400 MHz, CDCl3) δ (ppm): 8.16–8.14 (1H, m), 7.44–7.39 (1H, m), 6.51–6.48 (1H, m), 6.35 (1H, d, J = 8.5 Hz), 3.46–3.43 (4H, m), 2.02–1.98 (4H, m). MS (ESI) m/z: 149.12 [M + H]+.

1 4-(Piperidin-1-yl)pyridine (4c) [46]: colorless oil (0.39 g, 85%). H-NMR (400 MHz, CDCl3) δ (ppm): 8.22–8.20 (2H, q, J = 5.1 Hz, 1.6 Hz), 6.62–6.61 (2H, q, J = 5.1 Hz, 1.6 Hz), 3.31 (4H, d, J = 4.9 Hz), 1.63 (6H, s). MS (ESI) m/z: 163.13 [M + H]+.

1 4-(Pyrrolidin-1-yl)pyridine (4d) [44]: colorless oil (0.36 g, 86%). H-NMR (400 MHz, CDCl3) δ (ppm): 8.18 (2H, d, J = 4.9 Hz), 6.36 (2H, d, J = 4.9 Hz), 3.30–3.27 (4H, m), 2.03–1.99 (4H, m). MS (ESI) m/z: 149.09 [M + H]+.

1 2-(Pyrrolidin-1-yl)pyrimidine (4e) [47]: colorless oil (0.37 g, 88%). H-NMR (400 MHz, CDCl3) δ (ppm): 8.32 (2H, d, J = 4.8 Hz), 6.45 (1H, t, J = 4.8 Hz), 3.59–3.56 (4H, m), 2.02–1.98 (4H, m). MS (ESI) m/z: 150.11 [M + H]+.

1 2-(Piperidin-1-yl)pyrimidine (4f)[47]: colorless oil (0.40 g, 87%). H-NMR (400 MHz, CDCl3) δ (ppm): 8.30 (2H, t, J = 5.6 Hz), 6.42 (1H, t, J = 5.6 Hz), 3.81–3.78 (4H, m), 1.72–1.59 (6H, m). MS (ESI) m/z: 164.14 [M + H]+.

1 1-(2-Methoxyphenyl)pyrrolidine (4g) [48]: colorless oil (0.40 g, 80%). H-NMR (400 MHz, CDCl3) δ (ppm): 6.90–6.81 (4H, m), 3.83 (3H, s), 3.30–3.27 (4H, m), 1.95–1.91 (4H, m). MS (ESI) m/z: 178.16 [M + H]+.

1 1-(2-Methoxyphenyl)piperidine (4h) [49]: colorless oil (0.44 g, 82%). H-NMR (400 MHz, CDCl3) δ (ppm): 6.99–6.84 (4H, m), 3.86 (3H, s), 2.99–2.97 (4H, m), 1.78–1.54 (6H, m). MS (ESI) m/z: 192.17 [M + H]+.

1 4-(Pyrrolidin-1-yl)benzaldehyde (4i) [50]: white solid (0.44 g, 89%), m.p. 83–85 ◦C. H-NMR (400 MHz, CDCl3) δ (ppm): 9.72 (1H, s), 7.73 (2H, d, J = 8.8 Hz), 6.58 (2H, d, J = 8.8 Hz), 3.40–3.37 (4H, m), 2.08–2.02 (4H, m). MS (ESI) m/z: 176.13 [M + H]+.

1 4-(Piperidin-1-yl)benzaldehyde (4j) [51]: white solid (0.48 g, 90%). m.p. 63–64 ◦C. H-NMR (400 MHz, CDCl3) δ (ppm): 9.75 (1H, s), 7.75–7.71 (2H, m), 6.91 (2H, d, J = 8.9 Hz), 3.41–3.40 (4H, m), 1.68 (6H, s). MS (ESI) m/z: 190.16 [M + H]+.

1 N,N-Diethylaniline (4k)[52]: yellow liquid (0.39 g, 92%). H-NMR (400 MHz, CDCl3) δ (ppm): 7.23–7.18 (2H, m), 6.69–6.61 (3H, m), 3.37–3.32 (4H, q, J = 14.1 Hz, 7.0 Hz), 1.15 (6H, t, J = 7.1 Hz). MS (ESI) m/z: 150.12 [M + H]+.

1 2-((4-Nitrophenyl)amino)ethan-1-ol (4l) [53]: yellow solid (0.46 g, 90%). m.p. 110–111 ◦C. H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.05 (2H, d, J = 9.2 Hz), 7.35 (1H, t, J = 5.0 Hz), 6.73 (2H, d, J = 9.2 Hz), 4.86 (1H, t, J = 5.4 Hz), 3.65–3.61 (2H, q, J = 11.2 Hz, 5.6 Hz), 3.31–3.27 (2H, q, J = 11.4 Hz, 5.7 Hz). MS (ESI) m/z: 183.08 [M + H]+.

1 tert-Butyl phenyl-D-valinate (5a) [54]: white solid (0.63 g, 90%), m.p. 64–66 ◦C. H-NMR (400 MHz, CDCl3) δ (ppm): 7.17–7.13 (2H, m), 6.72–6.69 (1H, m), 6.64–6.62 (2H, m), 4.12 (1H, br), 3.75 (1H, d, J = 5.3 Hz), 2.15–2.04 (1H, m), 1.42 (9H, s), 1.05–1.01 (6H, m). MS (ESI) m/z: 250.16 [M + H]+.

1 (4-Nitrophenyl)glycine (5b) [55]: brown solid (0.51 g, 92%), 224–226 ◦C. H-NMR (400 MHz, DMSO-d6) δ (ppm): 8.02 (2H, d, J = 9.0 Hz), 7.44 (1H, t, J = 5.6 Hz), 6.66 (2H, d, J = 9.1 Hz), 3.98 (2H, d, J = 6.0 Hz). MS (ESI) m/z: 197.08 [M + H]+.

.1 Phenyl-D-phenylalanine (5c) [56]: white solid (0.60 g, 88%), m.p. 173–176 ◦C H-NMR (400 MHz, CDCl3) δ (ppm): 7.33–7.17 (7H, m), 6.80 (1H, t, J = 7.3 Hz), 6.62 (2H, d, J = 7.8 Hz), 4.32 (1H, t, J = 5.8 Hz), 3.30–3.10 (2H, m). MS (ESI) m/z: 242.11 [M + H]+.

1 Phenyl-L-alanine (5d) [57]: white solid (0.42 g, 90%), m.p. 133–135 ◦C. H-NMR (400 MHz, DMSO-d6) δ (ppm): 7.06 (2H, t, J = 7.8 Hz), 6.56–6.53 (3H, m), 3.95–3.89 (1H, q, J = 14.0 Hz, 7.0 Hz), 1.37 (3H, d, J = 7.0 Hz). MS (ESI) m/z: 166.07 [M + H]+. Molecules 2019, 24, 4177 9 of 12

1 Pyrimidin-2-yl-D-valine (5e): white solid (0.47 g, 86%), 113–115 ◦C. H-NMR (400 MHz, CDCl3) δ (ppm): 11.24 (1H, br), 8.25 (2H, s), 7.22 (1H, d, J = 8.1 Hz), 6.55 (1H, t, J = 4.9 Hz), 4.62–4.59 (1H, q, J = 13.1 Hz, 5.0 Hz), 2.37–2.29 (1H, m), 1.06 (6H, t, J = 7.2 Hz). MS (ESI) m/z: 196.16 [M + H]+, 218.11 [M + H]+. 13 C-NMR (100 MHz, CDCl3) δ (ppm): 176.0, 161.2, 110.4, 59.4, 31.0, 18.9, 18.2. 1 Pyrimidin-2-ylmethionine (5f): white solid (0.56 g, 87%). H-NMR (400 MHz, CDCl3) δ (ppm): 13.32 (1H, br), 8.29 (2H, br), 7.92 (1H, d, J = 6.6 Hz), 6.62 (1H, t, J = 4.9 Hz), 4.88–4.84 (1H, q, J = 12.2 Hz, 6.1 Hz), 2.70–2.64 (2H, m), 2.37–2.22 (2H, m), 2.11 (3H, s). MS (ESI) m/z: 228.13 [M + H]+. 13 C-NMR (100 MHz, CDCl3) δ (ppm): 175.8, 160.3, 110.3, 53.7, 31.9, 30.0, 15.4.

4. Conclusions In summary, a highly effective coupling reaction has been developed for the preparation of N-aryl compounds. This transformation occurs with good to excellent yields. A variety of substituted (hetero)aryl halides can be used as electrophiles, and azoles, piperidine, pyrrolidine, and amino acids, etc. function as nucleophiles. The key to this discovery was the identification of benzoin oxime ligand that can promote the (hetero)aryl halides to the corresponding N-arylation compounds. Efforts to apply our Cu-based system to other catalytic reactions and to expand the scope of the N-nucleophiles to other classes of nucleophiles are currently underway in our laboratory.

Supplementary Materials: The following are available online at http://www.mdpi.com/1420-3049/24/22/4177/s1. Copies of 1H NMR and MS for known compounds and copies of 13C NMR for new compounds. Author Contributions: Conceptualization, C.Y.; Methodology, C.Y. and L.Z.; Software, C.Y.; Formal Analysis, Y.Z. and L.Z.; Writing-Original Draft Preparation, C.Y.; Writing-Review and Editing, C.Y. and Y.Z.; Project Administration, C.Y. Funding: This research was funded by Liaoning Provincial Natural Science Foundation of China, grant number “2019-BS-102”; College Students Innovation Training Program of Liaoning Province, grant number “201910160017” and “The APC was funded by Liaoning Provincial Natural Science Foundation of China”. Conﬂicts of Interest: The authors declare no conﬂict of interest.

References

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Sample Availability: Samples of the compounds are not available from the authors.

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