Synthesis of 1-Cyanoalkynes and Their Ruthenium(II)-Catalyzed

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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 J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00424 • Publication Date (Web): 09 Apr 2018 Downloaded from http://pubs.acs.org on April 9, 2018

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The Journal of Organic Chemistry

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, FL 32306-4390

KEYWORDS. Cyanoalkyne, azide, cyanotriazole, cycloaddition, copper, ruthenium

ABSTRACT. A new method to convert terminal alkynes under relatively mild conditions to 1cyanoalkynes using in situ formed cyanogen is described. 1-Cyanoalkynes have 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 that the terminal alkynes adopt under the same reaction conditions is proposed. This work provides a new and convenient two-step sequence to prepare 4-cyano-1,2,3-triazoles from terminal alkynes and organic azides.

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Introduction 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 4-cyano-1,2,3-triazoles, but 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 amine-catalyzed 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 4cyano-1,2,3-triazoles than previously available. The current work was triggered by our previous observations on the rapid formation of 1iodoalkynes from terminal alkynes using in situ generated electrophilic I2 from CuI2 (Scheme 2).1719

Similarly, we postulated that in situ formed cyanogen - (CN)2 - and Cu(I) from Cu(CN)2 would

transform terminal alkynes to 1-cyanoalkynes.


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Scheme 1. Formation of 1-cyanoalkynes from terminal alkynes, and synthesis of 4-cyano-1,2,3triazoles

Scheme 2. Iodination or cyanation of terminal alkynes using in situ produced iodine or cyanogen – (CN)2

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


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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 1-cyanophenylacetylene. 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 copperbased reaction partner (Tables S2-3). 1-Methylimidazole or imidazole aided the conversions of both aliphatically and aromatically substituted terminal alkynes to 1-cyanoalkynes (Scheme 3).20


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Scheme 3. The substrate scope of 1-cyanoalkyne formationa

a. 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; b. imidazole instead of 1-methylimidazole; c. terminal 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; d. 1.0 mmol scale reaction; e. terminal 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.


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Comparing 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 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 1-cyanoalkynes.

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.


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The reactivity of 1-cyanoalkynes in ruthenium(II)-catalyzed azide-alkyne cycloaddition (RuAAC)21

was

studied.

1-Cyanophenylacetylene

exhibited

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 2-step yield of 71%.

Scheme 5. 4-Cyano-1,2,3-triazoles acquired from reactions at rta

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 1814327).


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The Ru-catalyzed azide-cyanoalkyne cycloaddition exhibits high functional group tolerance (Schemes 5-6). 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-1,2,3triazoles 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. Also see 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). When the reaction temperature was raised to 60 °C, more 1-cyanoalkynes 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 1-cyanoalkynes needed more time (12 h, e.g., 4k, 4l, 4t) to reach a satisfactory yield. The lower reactivity of an aliphatic 1-cyanoalkyne than the aromatic counterpart was corroborated by the observation that the aromatic 1-cyanoalkyne 2a outcompeted the aliphatic 1-cyanoalkyne 2l when both of equal molar quantity 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, azidoanthracene (a polycyclic aromatic azide), were also amenable to this procedure to produce 4cyanotriazole 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-cyano-1,2,3triazole instead as the only isolable isomer (Scheme S6, Figure S100).


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Scheme 6. 4-Cyano-1,2,3-triazoles acquired from reactions at 60 °Ca 2

R

(2 mol%)

CN

3

o 1,4-dioxane, 60 C

R' N3 NC

Br

R

NC

Cp*RuCl(PPh3)2

+

N

I N

N

N

N CN

CN N

N

N

N

CN

CN Ph

4

N R'

N

N

N

N

O

4b, 3 h, 81%

Br

N 4k, 12 h, 81%

4l, 12 h, 86%

4j,14 h, 97%

Cl CN

CN Ph

N

N

HO

N

N

N

N

N

CN

N N

4o, 6 h, 80%

4n, 3 h, 98%

HOOC

N

O

OHC

EtO

O N

N N

4q, 6 h, quant.

N

N

N

N

N

Cl

Ph

CN

N H

CN

4u, 12 h, 87%

F3C

CN

O 2N

4v, 14 h, 82%

N N N

N N

CN

Cl

Ph NO2 N N

N N N

CN N N N

N CN

N N

4z, 100 h, NC 31%

O 2N

N

N

Cl 4y, 16 h, 60%

CN

4x, 42h, 73%

4w, 6h, 84% CN

O

N N N

O

N

N N

CN

4t, 12 h, 93%

4s, 6 h, 75%

nOct N N N

N

Br

CN

4r, 6 h, 87%

N

N O

CN

CN

4p, 6 h, 89%

H N

O

N

N

N

CN

4m,3 h, 86% N

N

N

O

4ab, 18 h, 87%

CN N

O

O N

4ac, 12 h, 95%

4ae, 12 h, 78%

Ph

N N CN

N S N

N

N N

Ph

CN 4af, 24 h, 57%

4ad, 12 h, 88%

a. 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 1814331, 1814330, and 1814328, respectively).


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Scheme 7. The reactivity contrast of 2/4-picolyl azidesa

+

(a)

N3

N

Ph

CN

Ph

N

N

Ph

2a

4a

CN

100% conversion

N

(b)

+ N3

+ Ph

N3

N

Ph

N

Cp*

N

CN Ph

N

CN

N

4a

2a

Ru

Cl N

2% conversion

N

(c)

+

+ N3

N

Ph

CN

Ph

N

Ph

2a

N

N

4a

CN

100% conversion

N (d)

+ N3

N N N

N CN

Ph 2a

(e)

N

4aa

+ N3

+ N3

CN

Ph

CN

100% conversion 75% isolated yield

Ph

N N N

N

2a 4aa

Ph

CN

N N N

+ 4a

CN

Ph

ratio = 1.4 : 1; 100% conversion

a. Reagents and conditions: Compound 2a (0.1 mmol), Cp*RuCl(PPh3)2 (0.002 mmol), 1,4dioxane 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.

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


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azide and compound 2a (Schemes 7a,b). The reaction between 2a and benzyl azide however was not influenced by 2-picoline (Scheme 7c), while a regioisomer of 2-picolyl azide, 4-picolyl azide (Schemes 7d,e) 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.

Figure 1. The 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.

The following observations offered clues for us to put together a mechanistic model: 1) 1cyanoalkyne is a better substrate than terminal or electron-deficient internal alkynes in the RuAAC


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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.

Scheme 8. A proposed mechanism Cp*

N N N R'

CN

Cl

Ru NCCCR

II

R P

R

V

Cp* Cl

Ru

N

NCCCR

C

'N 3

RCCCN

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

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Cp* Cl

Cp*

R N N N

R'

Cl

Ru

NCCCR

III

NCCCR I

Ru 3N

N C C4 C5 R

2N 1N

R'

RC

CC

N

Cp* IV

Ru Cl

N

R C

4

5

1

N R' 3N N2

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


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studies.26 One 1-cyanoalkyne ligand departs to afford II, which allows an azide to bind to form complex III. This ternary complex of 1-cyanoalkyne, 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-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 4cyanotriazole 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 1-cyanoalkyne 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 π-coordination.31 (c) The regiospecificity may necessitate the binding of azide via the distal N3 nitrogen in the regiochemistry-determining intermediate III, although the intermolecular attack of the proximal N1 nitrogen of an unbound azide to the C5 of ruthenium(II)-bound 1-cyanoalkyne 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


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of the 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 Comparing to the models of RuAAC,21,23 there are three major differences that 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 in 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 is reported to bind 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) 1-cyanoalkyne is the electrophile in the regioselectivity-determining 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 1cyanoalkyne than the aliphatic analog may be explained by the higher electrophlicity of the former.

Conclusion In summary, a convenient synthesis of 1-cyanoalkynes using in situ generated cyanogen is developed. 1-Cyanoalkynes have 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.


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Experimental Section 1. 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 need to be cooled to rt before venting and opening. Tetrahydrofuran (THF) dried from a solvent purification system was used in the reactions of 1-cyanoalkyne synthesis. Anhydrous 1,4-dioxane (99.8%) 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 MHz 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 direct-analysis-in-real-time (DART) ion source with time-of-flight analyzers. 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. 2. General synthetic procedures 2-1. 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, 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) were added sequentially. The vessel was sealed before placed in a pre-heated oil bath (40 °C). The heating was continued at 40 °C for 18 h. After cooling to rt, the reaction vessel was opened and the reaction mixture was diluted with ethyl acetate or diethyl ether (50 mL). The


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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 Section 3. 2-2. Synthesis of 1-cyanoalkyne at the 1.0 mmol scale. In a round-bottom 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), diisopropylethylamine (349 µL, 2.0 mmol) and a terminal alkyne (1.0 mmol) were added sequentially. The flask was sealed before placed in a pre-heated 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 Na2SO4, before being concentrated under reduced pressure. The residue was subjected to column chromatography to afford the pure 1-cyanoalkyne product. 2-3. Ruthenium(II)-catalyzed azide-cyanoalkyne cycloaddition. Cp*RuCl(PPh3)2 (1.6 mg, 0.002 mmol) was added into a 15-mL 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 pre-heated 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.


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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 Section 3. 3. Synthetic procedures and characterization data of isolated compounds 1-Cyanoalkynes were synthesized using the general procedure shown in Subsection 2-1. 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); 1

H 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


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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). 1H NMR (500 MHz, CDCl3) δ/ppm 7.73 (s, 4H). Rf = 0.50 (silica, hexanes/EtOAc =1:5). This compound was reported.8 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). 1

H 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,

3

JHF = 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); 13

C{1H} NMR (125 MHz, CDCl3) δ/ppm 134.4, 133.6, 131.2, 130.9, 130.5, 130.2, 130.1, 127.0,


18

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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. The 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), 1-methylimidazole (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 placed in a pre-heated 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 saturated basic brine (pH ~ 10) once, followed by saturated brine twice. The organic phase was separated, and dried over anhydrous Na2SO4, before being concentrated under reduced pressure. Compound 2j 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


19


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(104 µL, 0.6 mmol), and THF (2 mL) was 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) was used in this reaction. The 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 (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) was 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, 77.4, 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


20

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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 pre-heated 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 (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) was 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). 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, 2H); Rf = 0.35 (silica, EtOAc/hexanes = 1:20). 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


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= 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) 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 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) 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 (t, J = 7.5 Hz, 1H); This compound was reported.33 4-Cyano-1,2,3-triazoles were synthesized from the general procedure shown in Subsection 2-3. 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 1,4-dioxane (3 mL) was 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


22

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Compound 4b 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. 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, copper(II) perchlorate hexahydrate (296 mg, 0.8 mmol), 1-methylimidazole (16 µL, 0.2 mmol), sodium cyanide (78 mg, 1.6 mmol), and diisopropylethylamine (70 µL, 0.4 mmol) were added sequentially. The vessel was sealed before placed in a pre-heated 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. 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 placed in a pre-heated 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 saturated brine twice. The organic phase was separated, and dried over anhydrous Na2SO4, before being concentrated under reduced pressure. Compound 4c was isolated as a brown


23


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solid from a silica column eluted by EtOAc/hexanes (1:2) in 71% yield (49 mg). m.p. = 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) was 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; 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 (6.4 mg, 0.008 mmol) and anhydrous 1,4-dioxane (3 mL) was 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). m.p. = 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);

13

C{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.


24

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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 (2.4 mg, 0.003 mmol) and anhydrous 1,4-dioxane (1.5 mL) was 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 (2.4 mg, 0.003 mmol) and anhydrous 1,4-dioxane (1.5 mL) was 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), 7.357.29 (m, 3H), 7.07-7.05 (m, 2H), 5.57 (s, 2H), 3.97 (s, 3H); 13C{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.


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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) was 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). m.p. = 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 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 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), 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 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 UV lamp, I2, or KMnO4. 1H


26

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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); 13C{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 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);

13

C{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 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 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). m.p. = 70-75 °C; Rf = 0.24 (silica, EtOAc/hexanes = 1:1); 1

H 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+)


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(m/z): [M+H]+ calcd for C12H13N4O, 229.1089; found 229.1092. Cambridge Crystallographic Data Centre deposition No. CCDC 1814331. Compound 4p 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 was isolated as a yellow solid from a silica column eluted by EtOAc/hexanes (1:5) in 87% yield (36 mg). m.p. = 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), 3.21(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, 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


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C25H20N4NaO2, 431.1484; found 431.1480. Cambridge Crystallographic Data Centre deposition No. CCDC 1814330. Compound 4s 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), 7.077.05 (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 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 was isolated as a yellow solid from a silica column eluted by EtOAc/hexanes in 87% yield (23 mg). m.p. = 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); 13

C{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 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)


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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), 1.28-1.25 (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 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 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 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,


30

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3H);

13


127.6, 125.3, 123.2, 122.0, 114.3, 111.5, 55.4, 53.2; 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) was used in this reaction. The crude product was washed by diethyl ether and was dried under vacuum to afford the pure 4z as a yellow solid in 31% yield (16 mg). This compound cannot be visualized on TLC with 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 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); 13C{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-1propyn-1-yl)benzene35 (25 mg, 0.1 mmol) and benzyl azide (13 mg, 0.1 mmol) in anhydrous 1,4dioxane (0.75 mL) was added. The vessel was purged with argon and sealed before placing in a pre-heated 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


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saturated brine twice. The organic phase was separated, and dried over anhydrous Na2SO4, 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); 1H 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 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 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 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),


32

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2.37 (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 C24H17N4, 361.1448; found 361.1452. Compound 4ae 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 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);

13


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’ was isolated as a white solid from a silica column eluted by 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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Corresponding Author *Email: [email protected] ACKNOWLEDGMENT This work was supported by the National Science Foundation (CHE1566011). The calculations were done while LZ was on sabbatical with Prof. De-en Jiang at Univ. of California, Riverside. We thank the Mass Spectrometry Research and Education Center in Department of Chemistry, University of Florida for their support on HRMS experiments (NIH S10 OD021758-01A1).

Supporting Information. 1H and 13C NMR spectra of new compounds; .cif files of X-ray single crystal structures; methods of monitoring reaction progress and of computational studies. The Supporting Information is available free of charge on the ACS Publications website.

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Kuang, G.-C.; Michaels, H. A.; Simmons, J. T.; Clark, R. J.; Zhu, L. Chelation-

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The coordination of 2-butynenitrile to ruthenium(II) is ~ 6 kcal/mol favored over

methylazide based on computation. See details in the Supporting Information. (27)

In IV, the coordination with ruthenium(II) via the cyano group is favored over the

1,2,3-triazolyl group as shown by computation – see the Supporting Information. (28)

In V, the coordination with ruthenium(II) via the cyano group is favored over the

1,2,3-triazolyl group as shown by computation – see the Supporting Information. (29)

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The σ-bonding via the nitrogen of cyano group in 2-butynenitrile is favored over

the π-bonding via the C≡C bond by 0.7 kcal/mol. (32)

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M.-L.; Blanchard, N.; Evano, G. Practical Methods for the Synthesis of Trifluoromethylated Alkynes: Oxidative Trifluoromethylation of Copper Acetylides and Alkynes. Adv. Synth. Catal. 2014, 356, 2051-2060.


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Graphical Abstract


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Synthesis of 1-Cyanoalkynes and Their Ruthenium(II)-Catalyzed

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