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Synthesis of 1‑Cyanoalkynes and Their Ruthenium(II)-Catalyzed Cycloaddition with Organic Azides to Afford 4‑Cyano-1,2,3-triazoles Peiye Liu, Ronald J. Clark, and Lei Zhu* Department of Chemistry and Biochemistry, Florida State University, 95 Chieftan Way, Tallahassee, Florida 32306-4390, United States S Supporting Information *

ABSTRACT: A new method to convert terminal alkynes under relatively mild conditions to 1-cyanoalkynes using in situ formed cyanogen is described. 1-Cyanoalkynes have a higher reactivity than terminal alkynes in the ruthenium(II)-catalyzed regiospecific azide−alkyne cycloaddition to afford 4-cyano-1,2,3-triazoles. A mechanistic proposal different from the one that terminal alkynes adopt under the same reaction conditions is proposed. This work provides a new and convenient two-step sequence to prepare 4cyano-1,2,3-triazoles from terminal alkynes and organic azides.

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INTRODUCTION

RESULTS AND DISCUSSION As shown in Scheme 2, a base was required to deprotonate a terminal alkyne. The cyano source was (CN)2 from the disproportionation reaction of Cu(CN)2. The effects of base, cyanide source, and copper(II) salt in the transformation of phenylacetylene to 1-cyanophenylacetylene were investigated. (See Table S1 in the Supporting Information.) Copper(II) perchlorate, which was used to synthesize 1-iodoalkynes,19 was also effective in the formation of 1-cyanoalkynes. NaCN and diisopropylethylamine (DIPEA) worked best in delivering 1cyanophenylacetylene. A further increase of yield was achieved after raising the temperature from rt to 40 °C. The initially optimized conditions, however, did not deliver satisfactory yields in the conversion of other terminal alkynes, such as methyl 4-ethynylbenzoate. There were signs that the reagents, especially those pertaining to copper, lost their potencies during the reaction. Therefore, the inclusion of a ligand was studied to either increase the reactivity or the longevity of the copper-based reaction partner (Tables S2 and S3). 1-Methylimidazole or imidazole aided the conversions of both aliphatically and aromatically substituted terminal alkynes to 1-cyanoalkynes (Scheme 3).20 Compared to the existing terminal alkyne cyanation methods (Scheme 1), the current method offers lower reaction temperatures and, in most cases, shorter reaction times. This method is compatible with various functional groups such as ester (2f in Scheme 3), alkene (2g), aldehyde (2j), alkyl halide (2n), and alcohol (2o). The combination of copper(II) perchlorate and NaCN to produce an electrophilic cyano source is easier to handle and less expensive than those

1-Cyanoalkynes (aka propynenitriles) are building blocks in the syntheses of nitrile-containing bioactive molecules.1,2 They have also been used as hydrolytically stable electrophilic labels for tagging cysteines in bioconjugation chemistry.3,4 Included in Scheme 1 are published approaches to converting terminal alkynes to 1-cyanoalkynes.5−9 Although successful to various degrees, there are limitations, such as high temperature and costly reagents, that we wish to address in this work. We also report the ruthenium(II)-catalyzed azide−cyanoalkyne cycloaddition, which not only offers a regiospecific synthesis of 4cyano-1,2,3-triazoles but also suggests a different mechanistic pathway from that the terminal alkynes take in the related and thoroughly studied ruthenium(II)-catalyzed azide−alkyne cycloaddition (RuAAC).10 Uncatalyzed cycloaddition between 1-cyanoalkynes and azides was reported to afford a mixture of 4- and 5-cyano-1,2,3-triazoles (Scheme 1).11 The regiospecific synthesis of 4-cyano-1,2,3-triazoles can be done via aminecatalyzed condensation reaction between substituted phenyl or benzylic azides and benzoylacetonitrile (Scheme 1).12,13 A couple variants of the latter method where azides were produced in situ from either primary alcohols14,15 or boronic acids16 have also been developed. The current method tolerates a large variety of functionalized alkynes and azides, therefore providing access to a broader range of 4-cyano-1,2,3-triazoles than previously available. The current work was triggered by our previous observations on the rapid formation of 1-iodoalkynes from terminal alkynes using in situ generated electrophilic I2 from CuI2 (Scheme 2).17−19 Similarly, we postulated that in situ formed cyanogen, (CN)2, and Cu(I) from Cu(CN)2 would transform terminal alkynes to 1-cyanoalkynes. © XXXX American Chemical Society

Received: February 13, 2018 Published: April 9, 2018 A

DOI: 10.1021/acs.joc.8b00424 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 1. Formation of 1-Cyanoalkynes from Terminal Alkynes and Synthesis of 4-Cyano-1,2,3-triazoles

When the reaction temperature was raised to 60 °C, more 1cyanoalkynes and organic azides completed the RuAAC reaction (Scheme 6). The reactions involving benzylic type azides required as short as 3 h (e.g., 4b, 4m, 4n). Aliphatic 1cyanoalkynes needed more time (12 h, e.g., 4k, 4l, 4t) to reach a satisfactory yield. The lower reactivity of an aliphatic 1cyanoalkyne than the aromatic counterpart was corroborated by the observation that the aromatic 1-cyanoalkyne 2a outcompeted the aliphatic 1-cyanoalkyne 2l when both of the equal molar quantities were used in the cycloaddition with benzyl azide (Scheme S4). In addition to benzyl, primary aliphatic, and substituted phenyl azides, azidocyclohexane (a secondary aliphatic azide), 4-azidobiphenyl, 2-azidoanthracene (a polycyclic aromatic azide), were also amenable to this procedure to produce 4-cyanotriazole 4ab−4ad. Compounds 4ae and 4af that are derived from heteroaromatic azides were also prepared. Tertiary azides (t-butyl azide and 1-azidoadamantane) were inactive. At a higher temperature (e.g., 150 °C), the uncatalyzed thermal reaction took over to afford 5-cyano1,2,3-triazole instead as the only isolable isomer (Scheme S6, Figure S100). 2-Picolyl azide, which is highly reactive in copper(I)catalyzed azide−alkyne cycloaddition,24,25 failed to undergo ruthenium(II)-catalyzed cycloaddition with 1-cyanophenylacetylene (2a). This azide substrate that presumably chelates the ruthenium(II) center via the pyridyl nitrogen and the proximal N1 on the azido group (Scheme 7b, box), in fact, inhibited the reaction between benzyl azide and compound 2a (Schemes 7a,b). The reaction between 2a and benzyl azide, however, was not influenced by 2-picoline (Scheme 7c), while 4-picolyl azide (Schemes 7d,e), which is a regioisomer of 2-picolyl azide, did not provide inhibition and showed the normal reactivity under our reaction conditions to afford 4-cyanotriazole 4aa. These observations indicate that the association of the pyridyl group per se has no ill effect on the azide/1-cyanoalkyne cycloaddition reactivity. Rather, the coordinated binding (i.e., chelation) of ruthenium(II) with the pyridyl group and the azido’s proximal N1 provides a strong inhibitive effect on this reaction. The following observations offered clues for us to put together a mechanistic model: (1) 1-Cyanoalkyne is a better

Scheme 2. Iodination or Cyanation of Terminal Alkynes Using in Situ Produced Iodine or Cyanogen, (CN)2

previously used. One problem of this method that we have encountered is the production of the homocoupled diyne side products, which occasionally are difficult to separate from 1cyanoalkynes. The reactivity of 1-cyanoalkynes in ruthenium(II)-catalyzed azide−alkyne cycloaddition (RuAAC)21 was studied. 1Cyanophenylacetylene exhibited a higher reactivity than phenylacetylene in engaging benzyl azide under the RuAAC conditions (Scheme 4a).21 This elevated reactivity cannot be simply attributed to the electron-withdrawing ability of the cyano group, as 1-cyanoalkyne similarly outcompetes the electron-deficient 1-trifluoromethylalkyne and ethyl 3-phenylpropiolate in the RuAAC reactions (Schemes 4b,c). On the practical side, the higher reactivity of 1-cyanoalkynes over terminal alkynes makes it possible to synthesize 4-cyano-1,2,3triazoles from terminal alkynes without the rigorous purification of the 1-cyanoalkyne intermediates. One example is shown in Scheme 4d with a two-step yield of 71%. The Ru-catalyzed azide−cyanoalkyne cycloaddition exhibits a high functional group tolerance (Schemes 5 and 6). Aromatic azides are compatible without azide deactivation/decomposition that was observed in the RuAAC reactions involving terminal alkynes.21,22 Given enough time, the reactions involving aryl-substituted 1-cyanoalkynes can reach completion at rt to afford 4-cyano-1,2,3-triazoles with adequate yields (Scheme 5). 1,1-Dimethyl-3-cyanopropargyl alcohol was also reactive, having completed the reaction with benzyl azide in 14 h at rt (4f).23 The regiochemistry of the products was confirmed using single crystal X-ray crystallography (bold in Schemes 4−6; Figures S95−99). Benzyl, aliphatic, and aryl azides are all viable substrates, although some reactant pairs require up to 42 h to complete at rt (e.g., 4e in Scheme 5). B

DOI: 10.1021/acs.joc.8b00424 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 3. Substrate Scope of 1-Cyanoalkyne Formationa

Reagents and conditions: terminal alkyne 1 (0.2 mmol), Cu(ClO4)2·6H2O (0.8 mmol), NaCN (1.6 mmol), 1-methylimidazole (0.2 mmol), DIPEA (0.4 mmol), THF (2 mL), 40 °C, 18 h. bImidazole instead of 1-methylimidazole. cTerminal alkyne (0.2 mmol), Cu(ClO4)2·6H2O (1.2 mmol), NaCN (2.4 mmol), imidazole (0.3 mmol), DIPEA (0.6 mmol), THF (2 mL), 40 °C, 20 h. d1.0 mmol scale reaction. eTerminal alkyne (0.2 mmol), Cu(ClO4)2·6H2O (2.4 mmol), NaCN (4.8 mmol), imidazole (0.6 mmol), DIPEA (1.2 mmol), THF (2 mL), 40 °C, 18 h. a

N bond formation would need to be the result of the nucleophilic attack of the alkylated (proximal) nitrogen N1 of azide to the R-substituted alkynyl carbon C5 in III. After the formation of complex IV, 1-cyanoalkyne acts as a ligand to fill the vacated coordination site to give V.28 The reaction turns over to II upon the dissociation of the 4-cyanotriazole product (P) from V. The highlights of the proposed mechanism in Scheme 8 are the following: (a) 1-Cyanoalkyne binds ruthenium(II) stronger, and therefore earlier, than azide. The large quantity of 1cyanoalkyne at the beginning of the reaction traps the catalyst in the form of I, which explains the appearance of an induction period (Figure 1). (b) 1-Cyanoalkyne binds ruthenium(II) via σ-donation, which differs from the π-coordination of alkyne to ruthenium(II) in the RuAAC reactions.21,23 In addition to the similarity to the reported σ-coordination in nitrile/ruthenium(II) complexes,29,30 calculations also support the σ-coordination mode of 1-cyanoalkyne to ruthenium(II) over πcoordination.31 (c) The regiospecificity may necessitate the binding of azide via the distal N3 nitrogen in the regiochemistry-determining intermediate III, although the

substrate than terminal or electron-deficient internal alkynes in the RuAAC reactions (Scheme 4). (2) The reaction has induction and reaction phases (Figure 1); increasing the amount of 1-cyanoalkyne appears to saturate the ruthenium(II) catalyst in the induction phase (Figure 1a), while increasing the azide concentration shortens the induction phase (Figure 1b). Increasing the concentration of either 1-cyanoalkyne or azide accelerates the reaction phase. (3) The chelating 2-picolyl azide inhibits the cycloaddition (Scheme 7), and (4) the regiochemistry is specific; only 4-cyano-1,2,3-triazoles are formed. In the proposed mechanism (Scheme 8), the resting state of the catalyst is the off-cycle complex I, in which 1-cyanoalkyne replaces PPh3 in Cp*RuCl(PPh3)2. The favored σ-ligation of 1cyanoalkyne over azide to the ruthenium(II) center is supported by preliminary computational studies.26 One 1cyanoalkyne ligand departs to afford II, which allows an azide to bind to form complex III. This ternary complex of 1cyanoalkyne, azide, and the ruthenium(II) center undergoes two C−N bond formations to afford the 4-cyanotriazole-bound structure IV.27 To account for the regiochemistry, the first C− C

DOI: 10.1021/acs.joc.8b00424 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 4. Reactivity of 1-Cyanoalkyne in Ruthenium(II)-Catalyzed Azide−Alkyne Cycloadditiona

a

Bolded 4c was characterized via an X-ray single crystal structure (CCDC 1814329). [Ru] = Cp*RuCl(PPh3)2.

triazole products, the proximal N1 of the azido needs to attack C5 of 1-cyanoalkyne (Scheme 8). Therefore, if the azide forms a complex with the ruthenium(II) center prior to the CN bond formation, the coordinating atom is likely the distal N3 nitrogen, which is different from the previous two cases.21,32 Three major differences between the mechanism in Scheme 8 and the models of RuAAC21,23 will be addressed in an expanded mechanistic study: (1) The azide either is free from ruthenium(II) prior to the C−N bond formation, or as intermediate III (Scheme 8) uses the terminal (distal) N3 nitrogen of the azido to bind ruthenium(II), while in the RuAAC mechanism the carbon-bonded (proximal) nitrogen N1 associates with ruthenium(II). (2) 1-Cyanoalkyne binds ruthenium(II) via a σ dative bond, while in RuAAC, a π-bond between ruthenium(II) and alkyne is proposed. (3) 1Cyanoalkyne is the electrophile in the regioselectivitydetermining step (III to IV) to form the first C−N bond, while the alkyne is the nucleophile in the RuAAC models. The higher reactivity of an aromatic 1-cyanoalkyne than the aliphatic analogue may be explained by the higher electrophilicity of the former.

Scheme 5. 4-Cyano-1,2,3-triazoles Acquired from Reactions at Room Temperaturea

a

Reagents and conditions: azide/1-cyanoalkyne = 1:1, Cp*RuCl(PPh3)2 (2 mol %), 1,4-dioxane, rt. Bolded 4i was characterized via an X-ray single crystal structure (CCDC no. 1814327).

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CONCLUSION In summary, a convenient synthesis of 1-cyanoalkynes using in situ generated cyanogen is developed. 1-Cyanoalkynes have a high reactivity in the RuAAC reaction to afford 4-cyano-1,2,3triazoles as the only isomer. The structural variability of the two substituents is significantly expanded from the currently known cyano-1,2,3-triaole syntheses. The mechanistic differences between the current work and the previously reported RuAAC reaction are analyzed. This work provides a two-step sequence of preparing 4-cyano-1,2,3-triazoles from terminal alkynes.

intermolecular attack of the proximal N1 nitrogen of an unbound azide to the C5 of ruthenium(II)-bound 1cyanoalkyne could be a viable alternative. In the previously reported RuAAC reactions to produce 1,5-disubstituted triazoles, ruthenium(II) binds CC via a π-bond while to the azide via the proximal N1 position.10,21,23 In a subtly different RuAAC reaction in which σ-coordinated ruthenium acetylide is a substrate while azide still binds via the N1 nitrogen, 1,4-disubstituted triazoles are produced.32 In the current work where 1-cyanoalkyne binds ruthenium(II) through a σ-bond, to account for the 1,5-disubstitution of the D

DOI: 10.1021/acs.joc.8b00424 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 6. 4-Cyano-1,2,3-triazoles Acquired from Reactions at 60 °Ca

Reagents and conditions: azide (0.1 mmol), 1-cyanoalkyne (0.1 mmol), Cp*RuCl(PPh3)2 (0.002 mmol, 2 mol %), 1,4-dioxane (0.75 mL), 60 °C. Bolded 4o, 4r, and 4u were characterized via X-ray single crystal structures (CCDC nos. 1814331, 1814330, and 1814328, respectively).

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Aromatic azides were synthesized by diazotization of aniline derivatives. Other organic azides were synthesized by nucleophilic substitution of organic halides and NaN3.18 CAUTION! Low molecular weight organic azides and Cu(ClO4)2·6H2O are potentially explosive. Appropriate protective measures should always be applied when handling these chemicals. General Synthetic Procedures. Synthesis of 1-Cyanoalkyne. In a 15 mL cylindrical pressure vessel equipped with a magnetic stir bar, a terminal alkyne (0.2 mmol) was dissolved in THF (2 mL). To this mixture were added copper(II) perchlorate hexahydrate (296 mg, 0.8 mmol), 1-methylimidazole (16 μL, 0.2 mmol) or imidazole (14 mg, 0.2 mmol), sodium cyanide (78 mg, 1.6 mmol), and diisopropylethylamine (70 μL, 0.4 mmol) sequentially. The vessel was sealed before being placed in a preheated oil bath (40 °C). The heating was continued at 40 °C for 18 h. After cooling to rt, the reaction vessel was

EXPERIMENTAL SECTION

General Information. Reagents and solvents were purchased from various commercial sources without further purification unless otherwise stated. Cu(ClO4)2·6H2O was dried in a vacuum oven at 40 °C overnight before use. CAUTION! The vacuum oven needs to be cooled to rt before venting and opening. Tetrahydrofuran (THF), which was dried from a solvent purification system, was used in the reactions of 1-cyanoalkyne synthesis. Anhydrous 1,4-dioxane (99.8%), which was purchased from Sigma-Aldrich, was used in the RuAAC reactions. Column chromatography was performed using 40−63 μm silica gel as the stationary phase. 1H and 13C NMR spectra were recorded at 500 and 125 MHz, respectively. All chemical shifts were reported in δ units relative to tetramethylsilane. High-resolution mass spectra were obtained using electrospray ionization (ESI) or a directanalysis-in-real-time (DART) ion source with time-of-flight analyzers. E

DOI: 10.1021/acs.joc.8b00424 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Scheme 7. Reactivity Contrast of 2/4-Picolyl Azidesa

a Reagents and conditions: Compound 2a (0.1 mmol), Cp*RuCl(PPh3)2 (0.002 mmol), 1,4-dioxane 0.75 mL, Ar, 60 °C, 3 h with (a) benzyl azide (0.1 mmol); (b) 2-picolyl azide (0.1 mmol), benzyl azide (0.1 mmol); (c) 2-picoline (0.1 mmol), benzyl azide (0.1 mmol); (d) 4-picolyl azide (0.1 mmol); (e) 4-picolyl azide (0.1 mmol), benzyl azide (0.1 mmol). Conversion was determined from 1H NMR spectra.

Figure 1. Production of 4-cyano-1,2,3-triazole 4a over time based on 1H NMR. (a) [2a] = 133 (blue circles), 267 (orange squares), 400 (gray triangles), 533 (yellow crosses), or 667 mM (green diamonds), [benzyl azide] = 267 mM, [Cp*RuCl(PPh3)2] = 5.33 mM; (b) [2a] = 267 mM, [benzyl azide] = 267 (blue circles), 400 (orange, square), 533 (gray, triangles), or 800 (yellow crosses) mM, [Cp*RuCl(PPh3)2] = 5.33 mM. diisopropylethylamine (349 μL, 2.0 mmol) and a terminal alkyne (1.0 mmol) were added sequentially. The flask was sealed before placed in a preheated oil bath (40 °C). The heating was continued at 40 °C for 24 h. After the pressure flask was cooled to rt, it was opened and the reaction mixture was diluted with ethyl acetate or diethyl ether. The solution was washed by a 30% aqueous ammonia solution once, followed by saturated brine twice. The organic phase was separated, and dried over anhydrous Na2 SO 4, before being concentrated under reduced pressure. The residue was subjected to column chromatography to afford the pure 1-cyanoalkyne product. Ruthenium(II)-Catalyzed Azide−Cyanoalkyne Cycloaddition. Cp*RuCl(PPh3)2 (1.6 mg, 0.002 mmol) was added into a 15 mL

opened and the reaction mixture was diluted with ethyl acetate or diethyl ether (50 mL). The solution was washed by a 30% aqueous ammonia solution once, followed by saturated brine twice. The organic phase was separated and dried over anhydrous Na2SO4, before being concentrated under reduced pressure. The residue was subjected to column chromatography to afford the pure 1-cyanoalkyne product. Details specific to individual compounds are included in Synthetic Procedures and Characterization Data of Isolated Compounds. Synthesis of 1-Cyanoalkyne at the 1.0 mmol Scale. In a roundbottom pressure flask equipped with a magnetic stir bar, THF (10 mL), copper(II) perchlorate hexahydrate (1.5 g, 4.0 mmol), imidazole (68 mg, 1.0 mmol), sodium cyanide (392 mg, 8.0 mmol), F

DOI: 10.1021/acs.joc.8b00424 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry

Compound 2f. 1-Methylimidazole (16 μL, 0.2 mmol) was used as the ligand. Compound 2f was isolated as a white solid from a silica column eluted by hexanes/EtOAc (1:30) in 60% yield (22 mg). Rf = 0.15 (silica, hexanes/EtOAc = 1:20). 1H NMR (500 MHz, CDCl3): δ/ ppm 8.08 (d, J = 10.0 Hz, 2H), 7.69 (d, J = 10.0 Hz, 2H), 3.95 (s, 3H). This compound was reported.8 Compound 2g. 1-Methylimidazole (16 μL, 0.2 mmol) was used as the ligand. The reaction mixture was extracted with diethyl ether (50 mL). Compound 2g was isolated as a colorless oil from a silica column eluted by EtOAc/hexanes (1:60) in 80% yield (21 mg). Rf = 0.28 (silica, EtOAc/hexanes = 1:60). 1H NMR (500 MHz, CDCl3): δ/ppm 6.61 (m, 1H), 2.20−2.13 (m, 4H), 1.68−1.59 (m, 4H). This compound was reported.6 Compound 2h. 1-Methylimidazole (16 μL, 0.2 mmol) was used as the ligand. The reaction mixture was extracted with diethyl ether (50 mL). Compound 2h was isolated as a white solid from a silica column eluted by hexanes in 82% yield (24 mg). Rf = 0.35 (silica, EtOAc/ hexanes = 1:20). 1H NMR (500 MHz, CDCl3): δ/ppm 7.63 (dd, J = 9.0 Hz, 4JHF = 5.0 Hz, 2H), 7.12 (t, J = 9.0 Hz, 3JHF = 9.0 Hz, 2H). This compound was reported.33 Compound 2i. 1-Methylimidazole (16 μL, 0.2 mmol) was used as the ligand. Compound 2i was isolated as a yellow solid from a silica column eluted by EtOAc/hexanes (1:20) in 83% yield (42 mg). Rf = 0.70 (silica, EtOAc/hexanes = 1:10). 1H NMR (500 MHz, CDCl3): δ/ ppm 8.45 (d, J = 9.1 Hz, 1H), 8.33−8.28 (m, 3H), 8.25 (d, J = 9.9 Hz, 1H), 8.23 (d, J = 9.9 Hz, 1H), 8.15−8.08 (m, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 134.4, 133.6, 131.2, 130.9, 130.5, 130.2, 130.1, 127.0, 126.9, 126.9, 126.8, 124.4, 124.0, 123.9, 123.5, 110.6, 106.1, 83.2, 68.0. HRMS (ESI+) (m/z): [M + Na+] calcd for C19H9NNa, 274.0633; found, 274.0648. Procedure for Compounds 2j and 2q. In a 15 mL cylindrical pressure vessel equipped with a magnetic stir bar and THF (1 mL), copper(II) perchlorate hexahydrate (296 mg, 0.8 mmol), 1methylimidazole (16 μL, 0.2 mmol), sodium cyanide (78 mg, 1.6 mmol), and diisopropylethylamine (70 μL, 0.4 mmol) were added sequentially. Then the solution of a terminal alkyne (0.2 mmol) in THF (1 mL) was added into the reaction mixture. The vessel was sealed before being placed in a preheated oil bath (40 °C). The heating was continued at 40 °C for 18 h. After the reaction vessel was cooled to rt, the reaction mixture was diluted with ethyl acetate (50 mL). The solution was washed by a saturated basic brine (pH ∼ 10) once, followed by saturated brine twice. The organic phase was separated and dried over anhydrous Na2 SO 4 , before being concentrated under reduced pressure. Compound 2j. The compound was isolated as a yellow solid from a silica column eluted by EtOAc/hexanes (1:30) in 60% yield (18 mg). Rf = 0.40 (silica, EtOAc/hexanes = 1:10). 1H NMR (500 MHz, CDCl3): δ/ppm 10.07 (s, 1H), 7.94 (d, J = 5.0 Hz, 2H), 7.79 (d, J = 5.0 Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 191.0, 137.9, 134.2, 129.8, 123.3, 105.1, 81.3, 65.8. This compound was reported.9 Compound 2k. Imidazole (14 mg, 0.2 mmol) was used as the ligand. Compound 2k was isolated as a white solid from a silica column eluted by EtOAc/hexanes (1:60) in 98% yield (31 mg). Rf = 0.35 (silica, EtOAc/hexanes = 1:20). 1H NMR (500 MHz, CDCl3): δ/ ppm 7.56 (d, J = 5.0 Hz, 2H), 6.91 (d, J = 5.0 Hz, 2H), 3.85 (s, 3H). This compound was reported.8 Compound 2l. 1-Dodecyne (43 μL, 0.2 mmol), copper(II) perchlorate hexahydrate (445 mg, 1.2 mmol), imidazole (20 mg, 0.3 mmol), sodium cyanide (118 mg, 2.4 mmol), diisopropylethylamine (104 μL, 0.6 mmol), and THF (2 mL) were used in this reaction. The reaction time was 20 h, and the reaction mixture was extracted with diethyl ether. Compound 2l was isolated as a colorless oil from a silica column eluted by EtOAc/hexanes (1:40) in 78% yield (30 mg). Rf = 0.35 (silica, EtOAc/hexanes = 1:20). 1H NMR (500 MHz, CDCl3): δ/ ppm 2.35 (t, J = 7.5 Hz, 2H), 1.59 (quin, J = 7.5 Hz, 2H), 1.43−1.13 (m, 14H), 0.88 (t, J = 7.5 Hz, 3H). This compound was reported.8 Compound 2m. 1,7-Octadiyne (26 μL, 0.2 mmol), copper(II) perchlorate hexahydrate (889 mg, 2.4 mmol), imidazole (41 mg, 0.6 mmol), sodium cyanide (235 mg, 4.8 mmol), diisopropylethylamine (209 μL, 1.2 mmol), and THF (2 mL) were used in this reaction. The

Scheme 8. Proposed Mechanism

cylindrical pressure vessel equipped with a magnetic stir bar. A solution of 1-cyanoalkyne (0.1 mmol) and an organic azide (0.1 mmol) in anhydrous 1,4-dioxane (0.75 mL) was added. The vessel was purged with argon and sealed before placed in a preheated oil bath (60 °C), and the reaction was continued until completion as monitored by TLC. After the reaction vessel was cooled to rt, it was opened and the reaction mixture was diluted with ethyl acetate (50 mL). The solution was washed by saturated brine twice. The organic phase was separated, and dried over anhydrous Na2SO4, before being concentrated under reduced pressure. The residue was subjected to column chromatography to afford the pure 4-cyano-1,2,3-triazole product. Details specific to individual compounds are included in Synthetic Procedures and Characterization Data of Isolated Compounds. Synthetic Procedures and Characterization Data of Isolated Compounds. 1-Cyanoalkynes were synthesized using the general procedure shown in Synthesis of 1-Cyanoalkyne. Deviations from the general conditions are noted individually. Compound 2a. 1-Methylimidazole (16 μL, 0.2 mmol) was used as the ligand. The reaction mixture was extracted with diethyl ether (50 mL). Compound 2a was isolated as a white solid from a silica column eluted by hexanes in 79% yield (20 mg). Rf = 0.14 (silica, EtOAc/ hexanes = 1:60). 1H NMR (500 MHz, CDCl3): δ/ppm 7.62 (d, J = 8.0 Hz, 2H), 7.54 (t, J = 8.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 2H). This compound was reported.8 Compound 2b. 1-Methylimidazole (16 μL, 0.2 mmol) was used as the ligand. Compound 2b was isolated as a white solid from a silica column eluted by hexanes in 71% yield (20 mg). 1H NMR (500 MHz, CDCl3): δ/ppm 7.51 (d, J = 5.0 Hz, 2H), 7.22 (d, J = 5.0 Hz, 2H), 2.41 (s, 3H). This compound was reported.8 Compound 2c. 1-Methylimidazole (16 μL, 0.2 mmol) was used as the ligand. Compound 2c was isolated as a pale-yellow solid from a silica column eluted by EtOAc/hexanes (1:60) in 89% yield (37 mg). Rf = 0.14 (silica, EtOAc/hexanes = 1:60). 1H NMR (500 MHz, CDCl3): δ/ppm 7.57 (d, J = 10.0 Hz, 2H), 7.47 (d, J = 10.0 Hz, 2H). This compound was reported.8 Compound 2d. No ligand was used. Compound 2d was isolated as a white solid from a silica column eluted by EtOAc/hexanes (1:60) in 72% yield (23 mg). Rf = 0.10 (silica, hexanes). 1H NMR (500 MHz, CDCl3): δ/ppm 7.55 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H). This compound was reported.8 Compound 2e. No ligand was used. Compound 2e was isolated as a yellow solid from a silica column eluted by EtOAc/hexanes (1:40) in 85% yield (26 mg). Rf = 0.50 (silica, hexanes/EtOAc = 1:5). 1H NMR (500 MHz, CDCl3): δ/ppm 7.73 (s, 4H). This compound was reported.8 G

DOI: 10.1021/acs.joc.8b00424 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

column eluted by EtOAc/hexanes (1:60) in 57% yield (23 mg). Rf = 0.42 (silica, EtOAc/hexanes = 1:20). 1H NMR (500 MHz, CDCl3): δ/ ppm 7.69 (d, J = 8.6 Hz, 2H), 7.64 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 7.1 Hz, 2H), 7.48 (t, J = 7.5 Hz, 2H), 7.43−7.40 (m, 1H). This compound was reported.33 4-Cyano-1,2,3-triazoles were synthesized from the general procedure shown in subsection Ruthenium(II)-Catalyzed Azide−Cyanoalkyne Cycloaddition. Deviations from the general conditions are noted individually. Compound 4a. Compound 2a (0.4 mmol), benzyl azide (0.4 mmol), Cp*RuCl(PPh3)2 (6 mg, 0.008 mmol), and anhydrous 1,4dioxane (3 mL) were used in the reaction. The reaction was kept at rt. Compound 4a was isolated as a yellow oil from a silica column eluted by EtOAc/hexanes (1:5) in 92% yield (96 mg). Rf = 0.19 (silica, EtOAc/hexanes = 1:5). 1H NMR (500 MHz, CDCl3): δ/ppm 7.59− 7.50 (m, 3H), 7.35−7.31 (m, 5H), 7.10−7.07 (m, 2H), 5.56 (s, 2H). This compound was reported.11,12 Compound 4b. The compound was isolated as a yellow oil from a silica column eluted by EtOAc/hexanes (1:10) in 81% yield (27 mg). Rf = 0.32 (silica, EtOAc/hexanes = 1:5). 1H NMR (500 MHz, CDCl3): δ/ppm 7.66 (d, J = 10.0 Hz, 2H), 7.35−7.31 (m, 3H), 7.19 (d, J = 10.0 Hz, 2H), 7.09−7.07 (m, 2H), 5.54 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 142.9, 133.9, 133.0, 130.5, 129.4, 129.1, 127.4, 126.3, 122.3, 120.8, 111.8, 52.9. HRMS (ESI+) (m/z): [M + Na]+ calcd for C16H11BrN4Na, 361.0065; found, 302.0052. Compound 4c. For step 1, in a 15 mL cylindrical pressure vessel equipped with a magnetic stir bar, 1-ethynyl-4-nitrobenzene (29 mg, 0.2 mmol) was dissolved in THF (2 mL). To this mixture were added copper(II) perchlorate hexahydrate (296 mg, 0.8 mmol), 1methylimidazole (16 μL, 0.2 mmol), sodium cyanide (78 mg, 1.6 mmol), and diisopropylethylamine (70 μL, 0.4 mmol) sequentially. The vessel was sealed before placing in a preheated oil bath (40 °C), and the heating was continued at 40 °C for 18 h. After the reaction vessel was cooled to rt, the reaction mixture was diluted with ethyl acetate (50 mL). The solution was washed by a 30% aqueous ammonia solution once, followed by saturated brine twice. The organic phase was separated and dried over anhydrous Na2SO4, before being concentrated under reduced pressure. The residue was subjected to the next step without further purification. For step 2, Cp*RuCl(PPh3)2 (3 mg, 0.004 mmol) was added into a 15 mL cylindrical pressure vessel equipped with a magnetic stir bar. A solution of the residue in the previous step and azide 3a (33 mg, 0.2 mmol) in anhydrous 1,4-dioxane (1.5 mL) was added. The vessel was sealed before placing in a preheated oil bath (60 °C), and the reaction was continued for 6 h. After the reaction vessel was cooled to rt, the reaction mixture was diluted with ethyl acetate (50 mL). The solution was washed by a saturated brine twice. The organic phase was separated and dried over anhydrous Na2 SO 4 , before being concentrated under reduced pressure. Compound 4c was isolated as a brown solid from a silica column eluted by EtOAc/hexanes (1:2) in 71% yield (49 mg). Mp = 120−125 °C. Rf = 0.29 (silica, EtOAc/ hexanes = 1:2). 1H NMR (500 MHz, CDCl3): δ/ppm 8.46 (d, J = 10.0 Hz, 2H), 7.88 (d, J = 10.0 Hz, 2H), 7.28−7.25 (m, 2H), 6.99 (t, J = 7.5 Hz, 1H), 6.71 (d, J = 7.8 Hz, 2H), 4.77 (t, J = 5.0 Hz, 2H), 4.52 (t, J = 5.0 Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 157.1, 149.4, 142.8, 130.7, 129.8, 129.7, 124.8, 122.2, 121.0, 114.2, 111.4, 66.0, 48.8. HRMS (ESI+) (m/z): [M + Na]+ calcd for C17H13N5NaO3, 358.0916; found, 358.0933. Cambridge Crystallographic Data Centre deposition no. CCDC 1814329. Compound 4d. Compound 2a (51 mg, 0.4 mmol), 1-azidooctane (62 mg, 0.4 mmol), Cp*RuCl(PPh3)2 (6 mg, 0.008 mmol), and anhydrous 1,4-dioxane (3 mL) were used in the reaction. The reaction was kept at rt. Compound 4d was isolated as an oil from a silica column eluted by EtOAc/hexanes (1:10) in 79% yield (89 mg). Rf = 0.42 (silica, EtOAc/hexanes = 1:10). 1H NMR (500 MHz, CDCl3): δ/ ppm 7.59−7.57 (m, 3H), 7.47−7.44 (m, 2H), 4.35 (t, J = 7.5 Hz, 2H), 1.84 (quin, J = 7.5 Hz, 2H), 1.26−1.18 (m, 10H), 0.84 (t, J = 7.5 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 143.5, 131.2, 129.8, 128.8, 123.7, 120.2, 112.3, 49.2, 31.7, 29.9, 29.0, 28.8, 26.3, 22.6, 14.1.

reaction mixture was extracted with diethyl ether. Compound 2m was isolated as a colorless oil from a silica column eluted by EtOAc/ hexanes (1:5) in 71% yield (22 mg). Rf = 0.25 (silica, EtOAc/hexanes = 1:5). 1H NMR (500 MHz, CDCl3): δ/ppm 2.50−2.47 (m, 4H), 1.80−1.77 (m, 4H). This compound was reported.8 Compound 2n. 6-Chlorohex-1-yne (24 μL, 0.2 mmol), copper(II) perchlorate hexahydrate (445 mg, 1.2 mmol), imidazole (20 mg, 0.3 mmol), sodium cyanide (118 mg, 2.4 mmol), diisopropylethylamine (104 μL, 0.6 mmol), and THF (2 mL) were used in this reaction. The reaction time was 20 h, and the reaction mixture was extracted with diethyl ether. Compound 2n was isolated as a colorless oil from a silica column eluted by EtOAc/hexanes (1:20) in 75% yield (21 mg). Rf = 0.29 (silica, EtOAc/hexanes = 1:20). 1H NMR (500 MHz, CDCl3): δ/ ppm 3.56 (t, J = 7.5 Hz, 2H), 2.43 (t, J = 7.5 Hz, 2H), 1.92−1.86 (m, 2H), 1.81−1.75 (m, 2H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 105.3, 86.5, 55.9, 44.0, 31.3, 24.4, 18.4. This compound was reported.9 Compound 2o. In a round-bottom pressure flask equipped with a magnetic stir bar, THF (10 mL), copper(II) perchlorate hexahydrate (1482 mg, 4.0 mmol), imidazole (68 mg, 1.0 mmol), sodium cyanide (392 mg, 8.0 mmol), and diisopropylethylamine (349 μL, 2.0 mmol) were added sequentially. 2-Methyl-3-butyn-2-ol (97 μL, 1.0 mmol) was added into the reaction mixture. The vessel was sealed before placing in a preheated oil bath (40 °C). The heating was continued at 40 °C for 24 h. After the reaction vessel was opened at rt, the reaction mixture was diluted with diethyl ether (50 mL). The solution was washed by a 30% aqueous ammonia solution once, followed by saturated brine twice. The organic phase was separated and dried over anhydrous Na2SO4, before being concentrated under reduced pressure. Compound 2o was isolated as a yellow oil from a silica column eluted by EtOAc/hexanes (1:10) in 63% yield (69 mg). Rf = 0.32 (silica, EtOAc/hexanes = 1:5). 1H NMR (500 MHz, CDCl3): δ/ppm 2.87 (bs, 1H), 1.56 (s, 6H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 104.9, 89.0, 65.4, 56.7, 30.3. This compound was reported.7 Compound 2p. Ethynylcyclohexane (26 μL, 0.2 mmol), copper(II) perchlorate hexahydrate (445 mg, 1.2 mmol), imidazole (20 mg, 0.3 mmol), sodium cyanide (118 mg, 2.4 mmol), diisopropylethylamine (104 μL, 0.6 mmol), and THF (2 mL) were used in this reaction. The reaction time was 20 h, and the reaction mixture was extracted with diethyl ether. Compound 2p was isolated as a colorless oil from a silica column eluted by EtOAc/hexanes (1:40) in 58% yield (15 mg). Rf = 0.35 (silica, EtOAc/hexanes = 1:20). 1H NMR (500 MHz, CDCl3): δ/ppm 2.57−2.52 (m, 1H), 1.85−1.81 (m, 2H), 1.73− 1.67 (m, 2H), 1.56−1.50 (m, 3H), 1.39−1.32 (m, 3H). This compound was reported.6 Compound 2q. The procedure for compound 2j was applied. Compound 2q was isolated as a yellow solid from an alumina column eluted by EtOAc/hexanes (1:60) in 14% yield (5 mg). Rf = 0.47 (alumina, EtOAc/hexanes = 1:60). 1H NMR (500 MHz, CDCl3): δ/ ppm 7.45 (d, J = 10.0 Hz, 2H), 6.60 (d, J = 10.0 Hz, 2H), 3.04 (s, 6H). This compound was reported.34 Compound 2r. Imidazole (14 mg, 0.2 mmol) was used as the ligand. Compound 2r was isolated as a yellow solid from a silica column eluted by EtOAc/hexanes (1:20) in 84% yield (27.0 mg). Rf = 0.42 (silica, EtOAc/hexanes = 1:20). 1H NMR (500 MHz, CDCl3): δ/ ppm 7.68 (d, J = 10.0 Hz, 1H), 7.53−7.50 (m, 2H), 7.39−7.34 (m, 1H). This compound was reported.33 Compound 2s. Imidazole (14 mg, 0.2 mmol) was used as the ligand. Compound 2s was isolated as an off-white solid from a silica column eluted by EtOAc/hexanes (1:60) in 72% yield (23 mg). Rf = 0.44 (silica, EtOAc/hexanes = 1:20). 1H NMR (500 MHz, CDCl3): δ/ ppm 7.59 (t, J = 1.7 Hz, 1H), 7.53−7.50 (m, 2H), 7.37 (t, J = 7.5 Hz, 1H). This compound was reported.33 Compound 2t. Imidazole (14 mg, 0.2 mmol) was used as the ligand. Compound 2t was isolated as a yellow solid from a silica column eluted by EtOAc/hexanes (1:60) in 68% yield (27 mg). Rf = 0.45 (silica, EtOAc/hexanes = 1:20). 1H NMR (500 MHz, CDCl3): δ/ ppm 7.75 (d, J = 8.2 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H). This compound was reported.8 Compound 2u. Imidazole (14 mg, 0.2 mmol) was used as the ligand. Compound 2u was isolated as a yellow solid from a silica H

DOI: 10.1021/acs.joc.8b00424 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

0.87 (t, J = 7.5 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 145.1, 139.2, 134.6, 126.9, 120.7, 111.8, 96.7, 31.9, 29.5, 29.3, 29.3, 29.0, 28.9, 28.0, 23.4, 22.7, 14.2. HRMS (ESI+) (m/z): [M + H]+ calcd for C19H26IN4, 437.1202; found, 437.1190. Compound 4l. The compound was isolated as a yellow oil from a short silica column eluted by EtOAc in 86% yield (35 mg). This compound cannot be visualized on TLC with an UV lamp, I2, or KMnO4. 1H NMR (500 MHz, CDCl3): δ/ppm 7.50 (d, J = 10.0 Hz, 2H), 7.06 (d, J = 10.0 Hz, 2H), 5.48 (s, 2H), 2.67 (t, J = 7.5 Hz, 2H), 1.54−1.47 (m, 2H), 1.30−1.20 (m, 14H), 0.87 (t, J = 5.0 Hz, 3H). 13 C{1H} NMR (125 MHz, CDCl3): δ/ppm 144.5, 132.6, 129.1, 123.3, 120.8, 112.0, 52.0, 32.0, 29.6, 29.4, 29.4, 29.1, 29.1, 27.8, 23.2, 22.3, 14.3. HRMS (ESI+) (m/z): [M + H]+ calcd for C20H28BrN4, 403.1492; found, 403.1489. Compound 4m. The compound was isolated as a yellow oil from a silica column eluted by EtOAc/hexanes (1:5) in 86% yield (25 mg). Rf = 0.25 (silica, EtOAc/hexanes = 1:5). 1H NMR (500 MHz, CDCl3): δ/ppm 7.43 (d, J = 10.0 Hz, 2H), 7.28−7.25 (m, 3H), 7.20 (d, J = 5.0 Hz, 2H), 7.02−7.00 (m, 2H), 5.48 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 142.9, 137.9, 133.9, 130.4, 130.1, 129.3, 129.1, 127.4, 121.8, 120.8, 111.9, 52.9. HRMS (ESI+) (m/z): [M + Na]+ calcd for C16H11ClN4Na, 317.0570; found, 317.0587. Compound 4n. The compound was isolated as a yellow oil from a silica column eluted by EtOAc/hexanes (1:10) in 98% yield (29 mg). Rf = 0.19 (silica, EtOAc/hexanes = 1:5). 1H NMR (500 MHz, CDCl3): δ/ppm 7.10 (d, J = 10.0 Hz, 2H), 6.85 (d, J = 10.0 Hz, 2H), 5.98 (septet, J = 2.5 Hz, 1H), 5.45 (s, 2H), 3.79 (s, 3H), 2.23−2.18 (m, 2H), 2.11−2.07 (m, 2H), 1.72−1.62 (m, 4H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 159.8, 145.3, 136.1, 129.0, 126.2, 122.9, 119.5, 114.4, 112.3, 55.4, 52.4, 27.9, 25.6, 22.1, 21.1. HRMS (ESI+) (m/z): [M + Na]+ calcd for C17H18N4NaO, 317.1378; found, 317.1389. Compound 4o. The compound was isolated as a yellow solid from a silica column eluted by EtOAc/hexanes from 1:5 to 2:1 in 81% yield (37 mg). Mp = 70−75 °C. Rf = 0.24 (silica, EtOAc/hexanes = 1:1). 1H NMR (500 MHz, CDCl3): δ/ppm 7.59−7.57 (m, 3H), 7.51−7.48 (m, 2H), 4.52 (t, J = 5.0 Hz, 2H), 3.64 (t, J = 5.0 Hz, 2H), 2.14 (br, 1H), 2,12 (quin, J = 7.5 Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3): δ/ ppm 143.9, 131.3, 129.8, 128.9, 123.4, 120.2, 112.2, 58.7, 46.2, 32.1. HRMS (ESI+) (m/z): [M + H]+ calcd for C12H13N4O, 229.1089; found, 229.1092. Cambridge Crystallographic Data Centre deposition no. CCDC 1814331. Compound 4p. The compound was isolated as a pale-yellow oil from a silica column eluted by EtOAc/hexanes from 1:20 to 1:5 in 89% yield (28 mg). Rf = 0.24 (silica, EtOAc/hexanes = 1:5). 1H NMR (500 MHz, CDCl3): δ/ppm 7.32−7.24 (m, 6H), 6.93 (d, J = 10.0 Hz, 2H), 3.84 (s, 3H), 2.97 (sept, J = 7.0 Hz, 1H), 1.27 (d, J = 7.0 Hz, 6H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 161.6, 151.4, 143.1, 133.2, 130.6, 127.8, 125.1, 120.0, 115.4, 114.9, 112.6, 55.6, 34.0, 23.9. HRMS (ESI+) (m/z): [M + Na]+ calcd for C19H18N4NaO, 341.1378; found, 341.1366. Compound 4q. After the reaction, the reaction mixture was diluted with ethyl acetate (50 mL). The solution was washed by a HCl solution (pH = 2) twice. The organic phase was separated and dried over anhydrous Na2SO4, before being concentrated under reduced pressure. Compound 4q was isolated as a yellow solid from a silica column eluted by EtOAc/methanol (2:1) in a quantitative yield (46 mg). Rf = 0.44 (silica, EtOAc/methanol = 2:1). 1H NMR (500 MHz, (CD3)2SO): δ/ppm 7.69−7.67 (m, 2H), 7.61−7.58 (m, 3H), 4.70 (s, 2H), 3.43 (s, 1H). 13C{1H} NMR (125 MHz, (CD3)2SO): δ/ppm 167.0, 143.6, 131.0, 129.4, 129.0, 124.0, 118.3, 113.1, 53.2. HRMS (ESI+) (m/z): [M + H]+ calcd for C11H9N4O2, 229.0726; found, 229.0731. Compound 4r. The compound was isolated as a yellow solid from a silica column eluted by EtOAc/hexanes (1:5) in 87% yield (36 mg). Mp = 158−161 °C. Rf = 0.43 (silica, EtOAc/hexanes = 1:2). 1H NMR (500 MHz, CDCl3): δ/ppm 8.35−8.12 (m, 7H), 7.96 (d, J = 10.0 Hz, 1H), 7.58 (d, J = 10.0 Hz, 1H), 4.46−4.41 (m, 1H), 4.27−4.22 (m, 1H), 3.88−3.76 (m, 2H), 2.21 (t, J = 7.5 Hz, 2H), 2.03 (quin, J = 7.5 Hz, 2H), 1.01 (t, J = 7.5 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 171.8, 143.2, 133.5, 131.2, 130.6, 130.4, 129.8, 129.8, 127.4,

HRMS (ESI+) (m/z): [M + H]+ calcd for C17H23N4, 283.1923; found, 283.1919. Compound 4e. Compound 2a (51 mg, 0.4 mmol), 2-azidotoluene (53 mg, 0.4 mmol), Cp*RuCl(PPh3)2 (6 mg, 0.008 mmol), and anhydrous 1,4-dioxane (3 mL) were used in the reaction. The reaction was at rt. Compound 4e was isolated as an orange solid from a silica column eluted by EtOAc/hexanes (1:10) in 40% yield (41 mg). Mp = 135−139 °C. Rf = 0.39 (silica, EtOAc/hexane = 1:5). 1H NMR (500 MHz, CDCl3): δ/ppm 7.41−7.36 (m, 2H), 7.33−7.22 (m, 6H), 7.19− 7.18 (m, 1H), 1.89 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ/ ppm 144.0, 135.0, 134.5, 131.8, 131.2, 129.5, 128.4, 127.5, 127.4, 123.3, 119.6, 112.4, 17.6. HRMS (ESI+) (m/z): [M + H]+ calcd for C16H13N4, 261.1140; found, 261.1139. Compound 4f. The reaction was at rt. Compound 4f was isolated as a yellow oil from a silica column eluted by EtOAc/hexanes (1:5) in 76% yield (18 mg). Rf = 0.52 (silica, EtOAc/hexanes = 1:2). 1H NMR (500 MHz, CDCl3): δ/ppm 7.36−7.30 (m, 3H), 7.21−7.20 (m, 2H), 5.90 (s, 2H), 2.48 (s, 1H), 1.65 (s, 6H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 148.5, 135.3, 129.1, 128.7, 127.6, 118.1, 112.7, 69.6, 54.5, 30.7. HRMS (ESI+) (m/z): [M + H]+ calcd for C13H15N4O, 243.1240; found, 243.1234. Compound 4g. Compound 2b (22 mg, 0.15 mmol), benzyl azide (20 mg, 0.15 mmol), Cp*RuCl(PPh3)2 (2 mg, 0.003 mmol), and anhydrous 1,4-dioxane (1.5 mL) were used in the reaction. The reaction was kept at rt. Compound 4g was isolated as a yellow oil from a silica column eluted by EtOAc/hexanes (1:5) in 54% yield (22 mg). Rf = 0.20 (silica, EtOAc/hexanes = 1:5). 1H NMR (500 MHz, CDCl3): δ/ppm 7.34−7.31 (m, 5H), 7.24−7.22 (m, 2H), 7.11−7.09 (m, 2H), 5.54 (s, 2H), 2.44 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 144.2, 141.9, 134.2, 130.4, 129.2, 128.9, 128.9, 127.4, 120.4, 120.4, 112.3, 52.7, 21.6. HRMS (ESI+) (m/z): [M + Na]+ calcd for C17H14N4Na, 297.1116; found, 297.1132. Compound 4h. Compound 2f (28 mg, 0.15 mmol), benzyl azide (20 mg, 0.15 mmol), Cp*RuCl(PPh3)2 (2 mg, 0.003 mmol), and anhydrous 1,4-dioxane (1.5 mL) were used in the reaction. The reaction was kept at rt. Compound 4h was isolated as a yellow solid from a silica column eluted by EtOAc/hexanes (1:5) in 48% yield (23 mg). Rf = 0.43 (silica, EtOAc/hexanes = 1:2). 1H NMR (500 MHz, CDCl3): δ/ppm 8.17 (d, J = 10.0 Hz, 2H), 7.42 (d, J = 10.0 Hz, 2H), 7.35−7.29 (m, 3H), 7.07−7.05 (m, 2H), 5.57 (s, 2H), 3.97 (s, 3H). 13 C{1H} NMR (125 MHz, CDCl3): δ/ppm 165.8, 142.8, 133.7, 132.7, 130.6, 129.3, 129.1, 129.1, 127.6, 120.9, 111.7, 53.0, 52.7. HRMS (ESI +) (m/z): [M + Na]+ calcd for C18H14N4NaO2, 341.1014; found, 341.1026. Compound 4i. Compound 2c (39 mg, 0.19 mmol), 4-azidoanisole (28 mg, 0.19 mmol), Cp*RuCl(PPh3)2 (3.0 mg, 0.0038 mmol), and anhydrous 1,4-dioxane (1.5 mL) were used in the reaction. The reaction was kept at rt. Compound 4i was isolated as a white solid from a silica column eluted by EtOAc/hexanes from 1:10 to 1:5 in 69% yield (47 mg). Mp = 195−196 °C. Rf = 0.24 (silica, EtOAc/ hexanes = 1:5). 1H NMR (500 MHz, CDCl3): δ/ppm 7.58 (d, J = 10.0 Hz, 2H), 7.25−7.20 (m, 4H), 6.97 (d, J = 10.0 Hz, 2H), 3.86 (s, 3H). 13 C{1H} NMR (125 MHz, CDCl3): δ/ppm 161.0, 142.1, 132.9, 130.4, 127.9, 126.7, 125.9, 122.4, 120.5, 115.1, 112.1, 55.8. HRMS (ESI+) (m/z): [M + H]+ calcd for C16H12BrN4O, 355.0195; found, 355.0189. Cambridge Crystallographic Data Centre deposition no. CCDC 1814327. Compound 4j. The compound was isolated as a brown solid from a silica column eluted by EtOAc/hexanes (1:1) in 97% yield (29 mg). Rf = 0.39 (silica, EtOAc/hexanes = 1:2). 1H NMR (500 MHz, CDCl3): δ/ppm 7.74 (d, J = 10.0 Hz, 2H), 7.48 (d, J = 10.0 Hz, 2H), 7.23 (d, J = 10.0 Hz, 2H), 6.98 (d, J = 10.0 Hz, 2H), 3.87 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 161.3, 141.0, 133.2, 129.7, 128.0, 127.5, 126.7, 121.0, 117.6, 115.3, 115.0, 111.7, 55.9. HRMS (ESI+) (m/z): [M + H]+ calcd for C17H12N5O, 302.1042; found, 302.1041. Compound 4k. The compound was isolated as a red oil from a silica column eluted by EtOAc/hexanes (1:20) in 81% yield (36 mg). Rf = 0.53 (silica, EtOAc/hexanes = 1:10). 1H NMR (500 MHz, CDCl3): δ/ppm 7.94 (d, J = 8.4 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 2.81 (t, J = 7.5 Hz, 2H), 1.62−1.57 (m, 2H), 1.29−1.14 (m, 14H), I

DOI: 10.1021/acs.joc.8b00424 J. Org. Chem. XXXX, XXX, XXX−XXX

Article

The Journal of Organic Chemistry

HRMS (DART+) (m/z): [M + H]+ calcd for C17H14ClN4O, 325.0851; found, 325.0847. Compound 4z. 1-Cyanoalkyne 2m (16 mg, 0.1 mmol), 1(azidomethyl)-4-nitrobenzene (36 mg, 0.2 mmol), Cp*RuCl(PPh3)2 (3 mg, 0.004 mmol), and anhydrous 1,4-dioxane (0.75 mL) were used in this reaction. The crude product was washed by diethyl ether and was dried under a vacuum to afford the pure 4z as a yellow solid in 31% yield (16 mg). This compound cannot be visualized on TLC with an UV lamp, I2, or KMnO4. 1H NMR (500 MHz, (CD3)2SO): δ/ppm 8.20 (d, J = 8.8 Hz, 4H), 7.42 (d, J = 8.8 Hz, 4H), 5.83 (s, 4H), 2.83 (m, 4H), 1.39 (m, 4H). 13C{1H} NMR (125 MHz, (CD3)2SO): δ/ ppm 147.4, 145.0, 142.1, 128.7, 124.0, 119.1, 50.4, 26.5, 21.8. HRMS (ESI+) (m/z): [M + H]+ calcd for C24H21N10O4, 513.1742; found, 513.1745. Compound 4aa. The compound was isolated as a pale-yellow oil from an alumina column eluted with ethyl acetate in hexanes up to 80% (v/v) in 75% yield (20 mg). Rf = 0.50 (silica, EtOAc). 1H NMR (500 MHz, CDCl3): δ/ppm 8.60 (d, J = 6.1 Hz, 2H), 7.60−7.51 (m, 3H), 7.33−7.31 (m, 2H), 6.99 (d, J = 6.1 Hz, 2H), 5.57 (s, 2H). 13 C{1H} NMR (125 MHz, CDCl3): δ/ppm 150.8, 144.2, 142.9, 131.8, 129.9, 128.9, 123.0, 121.8, 120.8, 111.8, 51.4. HRMS (ESI+) (m/z): [M + H]+ calcd for C15H12N5, 262.1087; found, 262.1096. Compound 4b′. Cp*RuCl(PPh3)2 (6 mg, 0.008 mmol) was added into a 15 mL cylindrical pressure vessel equipped with a magnetic stir bar. A solution of 1-bromo-4-(3,3,3-trifluoro-1-propyn-1-yl)benzene35 (25 mg, 0.1 mmol) and benzyl azide (13 mg, 0.1 mmol) in anhydrous 1,4-dioxane (0.75 mL) was added. The vessel was purged with argon and sealed before placing in a preheated oil bath (60 °C), and the reaction was continued for 14 h. After the reaction vessel was cooled to rt, the reaction mixture was diluted with ethyl acetate (50 mL), which was washed by saturated brine twice. The organic phase was separated and dried over anhydrous Na2 SO 4 , before being concentrated under reduced pressure. Compound 4b′ was isolated as a pale-yellow oil from a silica column eluted by EtOAc/hexanes (1:10) in 84% yield (32 mg). Rf = 0.39 (silica, EtOAc/hexanes = 1:5). 1 H NMR (500 MHz, CDCl3): δ/ppm 7.59 (d, J = 5.0 Hz, 2H), 7.32− 7.27 (m, 3H), 7.03−7.00 (m, 4H), 5.42 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 136.9, 136.6, 136.4, 134.2, 132.4, 131.3, 129.2, 128.9, 127.6, 124.0, 123.5, 121.8, 119.7, 117.5, 52.6. HRMS (ESI+) (m/z): [M + H]+ calcd for C16H12BrF3N3, 382.0161; found, 382.0160. Compound 4ab. The compound was isolated as a colorless oil from a silica column eluted by EtOAc/hexanes (1:20 to 1:5) in 87% yield (22 mg). Rf = 0.35 (silica, EtOAc/hexanes = 1:5). 1H NMR (500 MHz, CDCl3): δ/ppm 7.62−7.57 (m, 3H), 7.44−7.40 (m, 2H), 4.22 (tt, J = 11.8, 4.0 Hz, 1H), 2.18−2.10 (m, 2H), 2.03−1.98 (m, 2H), 1.95−1.89 (m, 2H), 1.74−1.70 (m, 1H), 1.36−1.24 (m, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 142.9, 131.2, 129.8, 129.1, 123.9, 120.0, 112.4, 59.4, 33.5, 25.4, 24.9. HRMS (ESI+) (m/z): [M + H]+ calcd for C15H17N4, 253.1448; found, 253.1448. Compound 4ac. The compound was isolated as a pale-yellow solid from a silica column eluted by EtOAc/hexanes (1:20 to 1:5) in 95% yield (32 mg). Rf = 0.47 (silica, EtOAc/hexanes = 1:5). 1H NMR (500 MHz, CDCl3): δ/ppm 7.69 (d, J = 5.0 Hz, 2H), 7.62−7.60 (m, 2H) 7.48 (t, J = 7.2 Hz, 2H), 7.43−7.40 (m, 3H), 7.29−7.25 (m, 4H), 2.40 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 143.3, 143.2, 141.8, 139.3, 134.5, 130.3, 129.2, 129.0, 128.44, 128.39, 127.3, 125.5, 120.6, 120.5, 112.4, 21.7. HRMS (ESI+) (m/z): [M + H]+ calcd for C22H17N4, 337.1448; found, 337.1453. Compound 4ad. The compound was isolated as a yellow solid from a silica column eluted by EtOAc/hexanes (1:20 to 1:5) in 88% yield (32 mg). Rf = 0.33 (silica, EtOAc/hexanes = 1:5). 1H NMR (500 MHz, CDCl3): δ/ppm 8.49 (s, 1H), 8.45 (s, 1H), 8.12 (d, J = 1.4 Hz, 1H), 8.07−8.02 (m, 3H), 7.55 (d, J = 10.0 Hz, 2H), 7.31 (d, J = 8.3 Hz, 2H), 7.26 (dd, J = 10.4, 2.1 Hz, 1H), 7.21 (d, J = 8.0 Hz, 2H), 2.37 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 143.5, 141.9, 133.0, 132.6, 132.4, 130.9, 130.7, 130.5, 130.4, 129.0, 128.5, 128.4, 127.8, 127.1, 126.9, 126.8, 125.0, 121.8, 120.6, 120.6, 112.6, 21.8. HRMS (ESI+) (m/z): [M + H]+ calcd for C24H17N4, 361.1448; found, 361.1452.

127.1, 127.0, 126.9, 126.6, 125.1, 124.9, 124.2, 122.4, 122.4, 116.5, 112.0, 60.8, 48.6, 30.6, 24.8, 14.0. HRMS (ESI+) (m/z): [M + Na]+ calcd for C25H20N4NaO2, 431.1484; found, 431.1480. Cambridge Crystallographic Data Centre deposition no. CCDC 1814330. Compound 4s. The compound was isolated as a yellow oil from a silica column eluted by EtOAc/hexanes (1:5) in 76% yield (23 mg). Rf = 0.39 (silica, EtOAc/hexanes = 1:2). 1H NMR (500 MHz, CDCl3): δ/ppm 10.06 (s, 1H), 7.96 (d, J = 10.0 Hz, 2H), 7.55 (d, J = 10.0 Hz, 2H), 7.36 (t, J = 7.5 Hz, 1H), 7.07−7.05 (m, 1H), 6.93 (t, J = 2.5 Hz, 1H), 6.82−6.80 (m, 1H), 3.79 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 191.1, 160.7, 141.8, 137.7, 135.9, 130.8, 130.5, 129.7, 129.0, 121.2, 117.2, 116.4, 111.8, 111.1, 55.8. HRMS (ESI+) (m/z): [M + CH3OH + Na]+ calcd for C18H16N4NaO3, 359.1120; found, 359.1142. Compound 4t. The compound was isolated as a white solid from a silica column eluted by EtOAc/hexanes (1:1) in 93% yield (37 mg). Rf = 0.37 (silica, EtOAc/hexanes = 1:1). 1H NMR (500 MHz, CD3CN): δ/ppm 8.89 (s, 1H), 7.48 (s, 4H), 5.24 (s, 2H), 3.60 (t, J = 5.0 Hz, 2H), 2.85 (t, J = 7.5 Hz, 2H), 1.88−1.79 (m, 4H). 13C{1H} NMR (125 MHz, CD3CN): δ/ppm 164.2, 146.8, 138.1, 132.8, 122.5, 120.3, 117.4, 113.3, 52.0, 45.4, 32.4, 25.5, 23.0. HRMS (ESI+) (m/z): [M + Na]+ calcd for C15H15BrClN5NaO, 418.0046; found, 418.0058. Compound 4u. The compound was isolated as a yellow solid from a silica column eluted by EtOAc/hexanes in 87% yield (23 mg). Mp = 151−153 °C. Rf = 0.40 (silica, EtOAc/hexanes = 1:5). 1H NMR (500 MHz, CDCl3): δ/ppm 7.43−7.35 (m, 3H), 7.28−7.26 (m, 2H), 7.20− 7.13 (m, 4H), 2.35 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ/ ppm 143.1, 140.8, 132.9, 131.1, 130.4, 129.5, 129.0, 125.0, 123.5, 120.6, 112.3, 21.4. HRMS (ESI+) (m/z): [M + H]+ calcd for C16H13N4, 261.1135; found, 261.1133. Cambridge Crystallographic Data Centre deposition no. CCDC 1814328. Compound 4v. The compound was isolated as a colorless oil from a silica column eluted by EtOAc/hexanes (1:20) in 82% yield (29 mg). Rf = 0.45 (silica, EtOAc/hexanes = 1:5). 1H NMR (500 MHz, CDCl3): δ/ppm 7.88 (d, J = 8.0 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 4.36 (t, J = 7.5 Hz, 2H), 1.86 (quin, J = 7.5 Hz, 2H), 1.28−1.15 (m, 10H), 0.85 (t, J = 7.5 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 142.1, 133.3 (q, 2JC−F = 25 Hz), 129.5, 127.5, 126.9 (q, 3JC−F = 3.8 Hz), 123.5 (q, 1JC−F = 203 Hz), 120.7, 111.8, 49.5, 31.7, 30.0, 29.0, 28.8, 26.4, 22.7, 14.2. HRMS (ESI+) (m/z): [M + H]+ calcd for C18H22F3N4, 351.1791; found, 351.1784. Compound 4w. The compound was isolated as an off-white solid from a silica column eluted by EtOAc/hexanes from 1:5 to 1:1 in 84% yield (29 mg). Rf = 0.65 (silica, EtOAc/hexanes = 1:1). 1H NMR (500 MHz, CDCl3): δ/ppm 8.21 (d, J = 9.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 1H), 7.50 (t, J = 8.0 Hz, 1H), 7.30 (d, J = 9.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 2H), 5.66 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 148.3, 142.6, 140.4, 136.0, 132.0, 131.3, 128.9, 128.6, 127.2, 124.6, 124.6, 121.2, 111.3, 52.1. HRMS (ESI+) (m/z): [M + H]+ calcd for C16H11ClN5O2, 340.0596; found, 340.0600. Compound 4x. The compound was isolated as an off-white solid from a silica column eluted by EtOAc/hexanes (1:1) in 73% yield (27 mg). Rf = 0.50 (silica, EtOAc/hexanes = 1:1). 1H NMR (500 MHz, CDCl3): δ/ppm 7.79 (d, J = 10.0 Hz, 2H), 7.64 (d, J = 10.0 Hz, 2H), 7.62 (d, J = 10.0 Hz, 2H), 7.49 (t, J = 7.5 Hz, 2H), 7.43 (t, J = 7.5 Hz, 1H), 6.15 (t, J = 5.0 Hz, 1H), 5.04 (s, 2H), 3.31 (q, J = 6.7 Hz, 2H), 1.51 (quin, J = 7.5 Hz, 2H), 1.35−1.23 (m, 4H), 0.88 (t, J = 7.5 Hz, 3H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 164.2, 144.8, 144.7, 139.4, 129.5, 129.2, 128.6, 128.5, 127.3, 121.3, 120.4, 112.0, 51.7, 40.3, 29.1, 29.0, 22.4, 14.1. HRMS (ESI+) (m/z): [M + H]+ calcd for C22H24N5O, 374.1975; found, 374.1979. Compound 4y. The compound was isolated as a yellow oil from a silica column eluted by EtOAc/hexanes from 1:5 to 1:2 in 60% yield (20 mg). Rf = 0.42 (silica, EtOAc/hexanes = 1:2). 1H NMR (500 MHz, CDCl3): δ/ppm 7.58−7.51 (m, 2H), 7.36 (t, J = 8.0 Hz, 1H), 7.08 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 5.0 Hz, 2H), 6.72 (d, J = 5.0 Hz, 2H), 5.56 (d, J = 15.0 Hz, 1H), 5.24 (d, J = 15.0 Hz, 1H), 3.75 (s, 3H). 13 C{1H} NMR (125 MHz, CDCl3): δ/ppm 160.0, 140.8, 134.2, 132.9, 131.8, 130.6, 129.7, 127.6, 125.3, 123.2, 122.0, 114.3, 111.5, 55.4, 53.2. J

DOI: 10.1021/acs.joc.8b00424 J. Org. Chem. XXXX, XXX, XXX−XXX

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The Journal of Organic Chemistry Compound 4ae. The compound was isolated as a dark solid from a silica column eluted by EtOAc/hexanes (1:5 to 1:1) in 78% yield (30 mg). Rf = 0.28 (silica, EtOAc/hexanes = 1:2). 1H NMR (500 MHz, CDCl3): δ/ppm 7.96 (s, 1H), 7.54−7.44 (m, 5H), 7.36 (d, J = 9.0 Hz, 1H), 6.67 (dd, J = 9.0, 2.5 Hz, 1H), 6.49 (d, J = 2.4 Hz, 1H), 3.46 (q, J = 7.1 Hz, 4H), 1.24 (t, J = 7.1 Hz, 6H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 157.3, 157.1, 152.6, 145.1, 142.3, 131.2, 130.6, 129.6, 128.2, 123.9, 120.0, 114.9, 112.2, 110.1, 106.6, 97.3, 45.2, 12.5. HRMS (ESI+) (m/z): [M + H]+ calcd for C22H20N5O2, 386.1612; found, 386.1618. Compound 4af. The compound was isolated as an orange solid from a silica column eluted by EtOAc/hexanes (1:10 to 1:5) in 57% yield (17 mg). Rf = 0.13 (silica, EtOAc/hexanes = 1:5). 1H NMR (500 MHz, CDCl3): δ/ppm 8.22 (dd, J = 8.8, 1.1 Hz, 1H), 7.86−7.76 (m, 2H), 7.38−7.36 (m, 1H), 7.33−7.28 (m, 4H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 155.4, 149.3, 145.1, 131.2, 129.4, 128.9, 128.4, 127.7, 127.5, 124.6, 123.7, 120.4, 112.1. HRMS (DART+) (m/z): [M + H]+ calcd for C15H9N6S, 305.0604; found, 305.0608. Compound 4c′. The compound was isolated as a white solid from a silica column eluted by EtOAc/hexanes (1:100 to 1:25) in 54% yield (16 mg). Rf = 0.22 (silica, EtOAc/hexanes = 1:20). 1H NMR (500 MHz, CDCl3): δ/ppm 8.06−8.05 (d, J = 5.0 Hz, 2H), 7.52−7.44 (m, 3H), 2.51 (d, J = 5.0 Hz, 6H), 2.34 (s, 3H), 1.84 (s, 6H). 13C{1H} NMR (125 MHz, CDCl3): δ/ppm 153.8, 130.2, 129.2, 128.3, 126.9, 111.9, 104.4, 64.8, 42.0, 35.8, 29.8. HRMS (DART+) (m/z): [M + H]+ calcd for C19H21N4, 305.1761; found, 305.1769.

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Necrosis Factor-alpha Production with Antitumor Activity. Cancer Res. 2006, 66, 951−959. (2) Yamamoto, Y.; Asatani, T.; Kirai, N. Copper-Catalyzed Stereoselective Hydroarylation of 3-Aryl-2-propynenitriles with Arylboronic Acids. Adv. Synth. Catal. 2009, 351, 1243−1249. (3) Koniev, O.; Leriche, G.; Nothisen, M.; Remy, J. S.; Strub, J. M.; Schaeffer-Reiss, C.; Van Dorsselaer, A.; Baati, R.; Wagner, A. Selective Irreversible Chemical Tagging of Cysteine with 3-Arylpropiolonitriles. Bioconjugate Chem. 2014, 25, 202−206. (4) Kolodych, S.; Koniev, O.; Baatarkhuu, Z.; Bonnefoy, J. Y.; Debaene, F.; Cianferani, S.; Van Dorsselaer, A.; Wagner, A. CBTF: New Amine-to-thiol Coupling Reagent for Preparation of Antibody Conjugates with Increased Plasma Stability. Bioconjugate Chem. 2015, 26, 197−200. (5) Fen-Tair, L.; Ren-Tzong, W. A Novel Synthesis of Cyanoalkynes via Iodide-Catalyzed Cyanation of Terminal Acetylenes with Cuprous Cyanide. Tetrahedron Lett. 1993, 34, 5911−5914. (6) Okamoto, K.; Watanabe, M.; Sakata, N.; Murai, M.; Ohe, K. Copper-Catalyzed C-H Cyanation of Terminal Alkynes with Cyanogen Iodide. Org. Lett. 2013, 15, 5810−5813. (7) Li, Y. H.; Shi, D. F.; Zhu, P. Q.; Jin, H. X.; Li, S.; Mao, F.; Shi, W. Copper Mediated Oxidative Coupling between Terminal Alkynes and CuCN. Tetrahedron Lett. 2015, 56, 390−392. (8) Rong, G. W.; Mao, J. C.; Zheng, Y.; Yao, R. W.; Xu, X. F. CuCatalyzed Direct Cyanation of Terminal Alkynes with AMBN or AIBN as the Cyanation Reagent. Chem. Commun. 2015, 51, 13822− 13825. (9) Wang, H.; Mi, P.; Zhao, W.; Kumar, R.; Bi, X. Silver-Mediated Direct C−H Cyanation of Terminal Alkynes with N-Isocyanoiminotriphenylphosphorane. Org. Lett. 2017, 19, 5613−5616. (10) Johansson, J. R.; Beke-Somfai, T.; Stalsmeden, A. S.; Kann, N. Ruthenium-Catalyzed Azide Alkyne Cycloaddition Reaction: Scope, Mechanism, and Applications. Chem. Rev. 2016, 116, 14726−14768. (11) Rao, V. V. V. N. S. R.; Lingaiah, B. P. V.; Yadla, R.; Rao, P. S.; Ravikumar, K.; Swamy, G. Y. S. K.; Narsimulu, K. Synthesis of Fluorine Containing N-benzyl-1,2,3-triazoles and N-methyl-pyrazoles from Conjugated Alkynes. J. Heterocycl. Chem. 2006, 43, 673−679. (12) Danence, L. J. T.; Gao, Y.; Li, M.; Huang, Y.; Wang, J. Organocatalytic Enamide−Azide Cycloaddition Reactions: Regiospecific Synthesis of 1,4,5-Trisubstituted-1,2,3-Triazoles. Chem. - Eur. J. 2011, 17, 3584−3587. (13) Savegnago, L.; Sacramento, M. d.; Brod, L. M. P.; Fronza, M. G.; Seus, N.; Lenardao, E. J.; Paixao, M. W.; Alves, D. Phenylselanyl-1H1,2,3-triazole-4-carbonitriles: Synthesis, Antioxidant Properties and Use as Precursors to Highly Functionalized Tetrazoles. RSC Adv. 2016, 6, 8021−8031. (14) Jin, G.; Zhang, J.; Fu, D.; Wu, J.; Cao, S. One-Pot, ThreeComponent Synthesis of 1,4,5-Trisubstituted 1,2,3-Triazoles Starting from Primary Alcohols. Eur. J. Org. Chem. 2012, 2012, 5446−5449. (15) González-Calderón, D.; Santillán-Iniesta, I.; González-González, C. A.; Fuentes-Benítes, A.; González-Romero, C. A Novel and Facile Synthesis of 1,4,5-trisubstituted 1,2,3-triazoles from Benzylic Alcohols Through a One-pot, Three-component System. Tetrahedron Lett. 2015, 56, 514−516. (16) Zhang, J.; Jin, G.; Xiao, S.; Wu, J.; Cao, S. Novel Synthesis of 1,4,5-Trisubstituted 1,2,3-Triazoles via a One-Pot Three-Component Reaction of Boronic Acids, Azide, and Active Methylene Ketones. Tetrahedron 2013, 69, 2352−2356. (17) Brotherton, W. S.; Clark, R. J.; Zhu, L. Synthesis of 5-lodo-1,4disubstituted-1,2,3-triazoles Mediated by in Situ Generated Copper(I) Catalyst and Electrophilic Triiodide Ion. J. Org. Chem. 2012, 77, 6443−6455. (18) Barsoum, D. N.; Brassard, C. J.; Deeb, J. H. A.; Okashah, N.; Sreenath, K.; Simmons, J. T.; Zhu, L. Synthesis of 5-Iodo-1,2,3triazoles from Organic Azides and Terminal Alkynes: Ligand Acceleration Effect, Substrate Scope, and Mechanistic Insights. Synthesis 2013, 45, 2372−2386.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00424. X-ray single crystal structure of 4c (CIF) X-ray single crystal structure of 4i (CIF) X-ray single crystal structure of 4o (CIF) X-ray single crystal structure of 4r (CIF) X-ray single crystal structure of 4u (CIF) Experimental details and syntheses, 1H and 13C NMR spectra of new compounds, X-ray crystallography, Cartesian coordinates, and methods of monitoring reaction progress and of computational studies (PDF) X-ray single crystal structure of 4c′ (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Lei Zhu: 0000-0001-8962-3666 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the National Science Foundation (CHE1566011). The calculations were done while L.Z. was on sabbatical with Professor De-en Jiang at the University of California, Riverside. We thank the Mass Spectrometry Research and Education Center in the Department of Chemistry at the University of Florida for their support on HRMS experiments (NIH S10 OD021758-01A1).

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REFERENCES

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DOI: 10.1021/acs.joc.8b00424 J. Org. Chem. XXXX, XXX, XXX−XXX