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Synthetic Access to Functionalized Dipolarophiles of Lewis Basic Complexant Scaffolds through Sonogashira Cross-Coupling Sauradip Chaudhuri, and Jesse Dwayne Carrick J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01446 • Publication Date (Web): 17 Jul 2018 Downloaded from http://pubs.acs.org on July 17, 2018

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The Journal of Organic Chemistry

Synthetic Access to Functionalized Dipolarophiles of Lewis Basic Complexant Scaffolds through Sonogashira Cross-Coupling Sauradip Chaudhuri and Jesse D. Carrick* Department of Chemistry, Tennessee Technological University, 55 University Drive, Cookeville, TN 38505-0001 The authors dedicate this work in memory of TTU Professor Emeritus Scott H. Northrup (1951-2018)

Supporting Information Placeholder

ABSTRACT: Soft-Lewis basic complexants that facilitate Pd(dppf)Cl2 (5 mol%), CuI (5 mol%), selective removal of discrete ions resident in spent nuclear R1 R1 TEA (3 equiv) fuel can decrease repository volume and radiotoxicity and N R2 (1.5 equiv), N N N Br are of significant interest. Optimization of chelation efficacy N R2 N o N is predicated on modular access to synthons to rapidly evalMTBE, 55 C, 16 h N 41 examples (31-96%) uate structure-activity relationships. The following work R1 R1 R1 = H, F, CH3, OCH3 R2 = alkyl, aryl, heteroaryl highlights efficient access to functionalized synthons for use as potential dipolarophiles in subsequent cycloaddition processes via Sonogashira coupling of 3-(6-Bromo-pyridin-2-yl)-[1,2,4]triazine scaffolds. The forty-one examples explored during method development evaluated electrophile and nucleophile diversity affording the desired coupled products in 31–96% isolated yield. Method optimization, substrate scope, a scale-up reaction, and downstream product functionalization are reported herein. INTRODUCTION The Sonogashira coupling reaction1 has been widely employed in contemporary organic synthesis towards the pursuit of terrestrial and oceanic natural products,2 heterocycles,3 and materials.4 The overall mild reaction conditions, chemoselectivity, and wide substrate scope enhance the applicability of the transformation. Exploration of advanced scaffolds for liquidliquid separations processes in the areas of spent nuclear fuel (SNF)5 remediation and recovery of critical materials6 necessitates the continuous development of modular synthetic methods to expand the competency, selectivity, and efficiency of complexant scaffolds beyond simple functional group interconversions towards more efficacious species. Research in this laboratory has focused on the preparation of soft-Lewis basic complexant synthons for the formation of previously unexplored constructs based on the pyridinyl-1,2,4-triazine motif for use in minor-actinide separations from SNF. Recently, we disclosed procedures to afford a variety of functionalized scaffolds with applications in liquid-liquid separations7 including 3-(6-bromo-pyridin-2-yl)-5,6-diaryl-[1,2,4]triazines for utilization in Suzuki-Miyaura cross-coupling8 as well as Pdcatalyzed diamination.9 Current focus areas include the development of synthons for dipolar cycloaddition reactions leading to the formation of unsymmetric complexant scaffolds. The alkynyl moiety can be a participant in the Huisgen cycloaddition10 leading to the formation of 1,2,3-triazoles,11 in addition to related processes, which facilitate access to 1,2pyrazoles.12 Pursuit of the aforementioned cycloadducts is centered on foundational access to the requisite Sonogashira coupling product through Pd-catalysis. A systematic approach to optimize the transformation for the desired application was pursued which varied critical parameters (Table 1).

Table 1. Sonogashira Coupling Method Development Catalyst, Ligand Base, Additive, Ph

N N

Ph

N N

Br

1

Solvent (0.25 M), Temp (oC), 16 h

Ph

N

Ph

N

N N

2

entry

catalyst

ligand

base

additive

solvent

temp (°C)

conv (%)a

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Pd2(dba)3 Pd(dba)2 Pd(dba)2 Pd(cod)Cl2 Pd(OAc)2 Pd(PPh3)2Cl2 Pd(MeCN)2Cl2 Pd(OAc)2 Pd(dppf)2Cl2 Pd(dppf)2Cl2 Pd(dppf)2Cl2 Pd(dppf)2Cl2 Pd(dppf)2Cl2 Pd(dppf)2Cl2 Pd(dppf)2Cl2

--------CyPF-tBu ----RuPhos -----------------------------------------

TEA TEA TEA TEA TEA TEA TEA TEA TEA TEA TEA DBU ----TEA -----

CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI CuI --------CuI

CPME CPME CPME CPME CPME CPME CPME CPME CPME MTBE MTBE MTBE MTBE MTBE MTBE

80 80 80 80 80 80 80 80 80 55 55 55 55 55 55

74b 83b 34b 71b 71b 40b 70b 79b 87b 88b 99c (78)d 99c (51)d 0c 0c 0c

5 mol% catalyst, 10 mol% ligand (entries 3 and 5), 5 mol% CuI, in cyclopentyl methyl ether (CPME) or methyl tert-butyl ether (MTBE) as solvent. aConversion determined from integration of select resonances in the 1H NMR spectrum without internal standard. b1.05 equiv of 4methylphenylacetylene used. c1.50 equiv of 4-methylphenylacetylene used. d isolated, purified yield. CyPF-tBu = 1-dicyclohexylphosphino-2-di-t-butylphosphinoethylferrocene

RESULTS AND DISCUSSION Initial definition of reaction conditions began with the evaluation of Pd2(dba)3 and Pd(dba)2 entries 1 and 2, with 3-(6bromo-pyridin-2-yl)-5,6-diphenyl-[1,2,4]triazine,13 1-ethynyl4-methylbenzene, copper iodide, and triethylamine which resulted in 74% and 83% conversion, respectively. Evaluation of Pd(dba)2 with CyPF-tBu which Hartwig14 has demonstrated for amination was successful in our hands with an amination

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reaction15 of the same scaffold (1), but resulted in poor performance in the current context (entry 3). The change in nucleophile in this transformation is postulated to have a marked impact on desired product formation under these conditions. A commonly employed catalyst for the Sonogashira coupling, Pd(PPh3)Cl2 (entry 6), was moderately successful.16 Screening of additional Pd(II) salts, entries 7−9 validated Pd(dppf)Cl2 as the most potent catalyst system. Alternative ethereal solvents were explored, including 1,4-dioxane, 2-methylTHF, THF, and MTBE. MTBE facilitated the formation of the desired product 2 in marginally higher conversion, but with a better impurity profile (entry 10). An increase in the alkyne loading from 1.05 equiv relative to 1 (entry 10) to 1.50 equiv (entry 11) afforded quantitative formation of 2 and good isolated yield. Base optimization with DBU (entry 12), DABCO, DIPEA, or diisopropylamine, in addition to the assessment of alternative copper salts, including copper acetate, proved unfruitful. As part of due diligence, the appropriate control experiments were performed highlighted by entries 13−15 and resulted in no conversion. With a preliminary set of reaction conditions defined for 4-methylphenyl acetylene, we set out to evaluate the alkyne scope with 1 (Table 2). Table 2. Alkyne Reaction Scopea

Ph Ph

N N

N N

Br

1

Pd(dppf)Cl2 (5 mol%), CuI (5 mol%), TEA (3 equiv) R (1.5 equiv), MTBE, 55 oC, 16 h

Entry

Ph

1 2

3 4 5 6 7 8

5 2 6 7 8

R' = H R' = CH3 R' = OCH3 R' = CN R' = Br

N

Ph

N

Ph

N

Ph

N

Ph

N

Ph

N

Ph

N

11

Ph

N

12

Ph

N

Ph

N

Ph

N

Ph

N

Ph

N

Ph

N

Ph

N

Ph

N

13

16

Ph

N

Ph

N

Ph a

N

R b

N

3 (76) 4 (91) n

3n=5 4n=7

N N R'

5 2 6 7 8

(63)c (77)c (63) (50) (54)

9 (75)

N N

N

10 (51)

N

11 (31)c

N N N N N

12 (74) Si(iPr)3

N

13 (55) Si(CH3)2tBu

N

H N

N

14

15

N

Ph

N N Yield

N

9

10

N

Product

N

Ph

Ph

N

O

14 (73)

O N N

15 (61) O

Ph

16 (59)

N

OH

N Ph

Reaction Conditions: 3-(6-Bromo-pyridin-2-yl)-5,6-diphenyl-[1,2,4]triazine (0.13 mmol), Pd(dppf)Cl2 (0.007 mmol), CuI (0.007 mmol), TEA (0.39 mmol), Alkyne (0.20 mmol), slurried in MTBE (0.25 M), and heated for 16 h. bIsolated, purified yield over one synthetic step, c Average yield from 2 experiments.

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Table 2 describes the utility of various alkynes with different electronic properties and functional groups towards the expansion of synthetic derivatives of 1. Aliphatic alkynes such as octyne and decyne (entries 1−2) afforded the desired products 3 and 4 in good to excellent yield, respectively. Phenylacetylene (entry 3) and related derivatives (entries 4−8) provided functionalized products in a consistent yield range with electron-donating substituents methyl (2), tert-butyl (9), and methoxy (6) affording the highest yields. Deactivating substitutents including nitrile and bromo- (entries 7–8) proved competent nucleophiles in this transformation.17 Constitutional isomers of 4-methylphenylacetylene, including the 3-methyl (entry 10) and 2-methyl congeners were explored in the context of this work with the former providing the desired product (10) in a lower yield and the latter affording no conversion presumably due to steric interference during the catalytic cycle. A heteroaromatic alkyne in the case of 2-ethynylpyridine afforded the lowest isolated yield of any substrate and alkyne combination screened (entry 11). Silylated acetylenes were successful, with the triisopropylsilyl- (12) and tertbutyldimethylsilylacetylene (13) derivatives which provide access to synthetic equivalents to coupling with acetylene.18 More electron-rich amines in the case of BOC protected propargylamine (entry 14) yielded the desired product in good isolated yield and proved superior to propargylamine, which was unsuccessful presumably due to poisoning of the catalytic system. Benzylpropargyl ether afforded 15 in 61% yield. Similar to above, attempted coupling with 4-pentyn-1-ol was unsuccessful, whereas 1-phenylprop-2-yn-ol provided the desired coupling product in 59% yield (entry 16). The alkyne scope with 1 affords numerous opportunities for further exploration of these functionalized synthons in the context of dipolarophiles for cycloaddition reactions with relevant dipoles. As process-relevant diluents for liquid-liquid separations of the minor-actinides from SNF continue to advance towards more efficient systems it is often desirable to enhance the nonpolarity of resident Lewis basic complexant scaffolds. Pursuant to the aforementioned, we sought to investigate the utility of the proposed method for the development of more nonpolar complexant synthons (Table 3). The input materials required to execute this series of examples, with the exception of 3-(6-bromo-pyridin-2-yl)-5,6-bis-(4-fluoro-phenyl)-[1,2,4] triazine, have previously been disclosed by us.19 Thus, 3-(6bromo-pyridin-2-yl)-5,5,8,8-tetra-methyl-5,6,7,8-tetrahydrobenzo[1,2,4]triazine (entries 1–2), 3-(6-bromo-pyridin-2-yl)5,6-bis-[4-(3,3-dimethyl-butyl)-phenyl]-[1,2,4] triazine (entries 3, 5, 7, and 9), as well as the butyl derivative (entries 2, 4, 6, 8, and 10) afforded the desired coupling products in (37– 96%) isolated yield with the electron-rich example 21 affording the highest yield of any substrate and alkyne combination evaluated. Incorporation of the prepared complexants in downstream processes will provide fundamental guidance on important structure-activity relationships for effective separation systems involving polydentate, soft-Lewis basic moieties. Alternative aromatic scaffolds were also attempted to ascertain the impact of different electronic combinations in the transformation (Table 4). Utilization of decyne with 3-(6bromo-pyridin-2-yl)-5,6-di-p-tolyl-[1,2,4]triazine (entry 2) afforded the highest isolated yield. The electron-withdrawing 4,4’-difluorosubstituent with phenylacetylenes (entries 3−5), as well as octyne (entry 7), resulted in satisfactory performance. Complexant scaffolds bearing the 3,3’-dimethoxy1,2,4-triazinyl moiety have demonstrated efficacy in the separation of the minor actinide Am3+ from the neutron-poisoning


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Table 3. Diversified Complexant Scaffoldsa

N N

N N

Br

Pd(dppf)Cl2 (5 mol%), CuI (5 mol%), TEA (3 equiv) R (1.5 equiv),

1 2

N

MTBE, 55 C, 16 h

N

N

N

N N

R N

Yieldb

Product

N

N

Br

N

MTBE, 55 C, 16 h

N N

N

O

Ph

N

N

R

29 R = H 30 R = F 31 R = OCH3

H3CO

N

29 (78) 30 (73) 31 (52)

N

20 (45)

N

N

N

F

N

27 (62) 28 (90)

N

F 3 4 5

N

4

R2 = alkyl, aryl

27 R = 4-MePh 28 R = (CH2)7CH3

19 (67)e

N

R

32 (80)c

6

N

F

N

N N F

H3CO

N

5

21 (96)

N

F

N

N

R2

Yieldb

N N

3

N N

Product

1 2

R

N R1

Entry

N

N

o

R1 = F, CH3, OCH3

R1

17 (37) 18 (73)

N 17 R = F 18 R = OCH3

Pd(dppf)Cl2 (5 mol%), CuI (5 mol%), R1 TEA (3 equiv) 2 (1.5 equiv), R

R1

o

Entry

Table 4. Diversified Ar Complexant Scaffoldsa

N

7

N

33 (78)

N N

5

F

N

OCH3

N

6

22 (80)

N

N

8 9

N N

N 7 N

N

N

N N

N

24 (65) Si(iPr)3

N 9

N N

R

N N

Si(CH3)2tBu

25 (55)

donating functionality were screened leading to the examples highlighted in Table 5. Table 5 outlines the efficacy of the developed method for acetyl, formyl, cyano-, and methyl bromopyridine substrates with yields ranging from 40−84%. Interestingly, it was observed that the oxidative addition into the heterocycle C-Br bond occurred preferentially to self-reaction or oligomerizaTable 5. Pyridine Substrate Scopea,b R

10

34 R = F 35 R = OCH3

a Reaction Conditions: 3-(6-Bromo-pyridin-2-yl)-[1,2,4]triazinyl scaffold (0.13 mmol), Pd(dppf)Cl2 (0.007 mmol), CuI (0.007 mmol), TEA (0.39 mmol), Alkyne (0.20 mmol), slurried in MTBE (0.25 M), and heated for 16 h. bIsolated, purified yield over one synthetic step, c Average yield from 2 experiments.

8 N

N

OCH3

23 (58)

N

34 (55) 35 (58)

N

N

N

26 (67)

N

Br

Pd(dppf)Cl2 (5 mol%), CuI (5 mol%), TEA (3 equiv) R (1.5 equiv),

lanthanides20 which preclude incorporation into advanced fuels for nuclear reactors through the partition and transmutation strategy.21 Entries 8−9 with 1-ethynyl-4-flouro- as well as 1-ethynyl-4-methoxybenzene resulted in the production of 34 and 35 in 55% and 58% yield, respectively. Interested in evaluating the suitability of standard functionalized bromopyridines for the method scope beyond pyridinyl-1,2,4triazines, a series of substrates with electron-withdrawing and

O

N R

MTBE, 55 oC, 16 h

R = CH3, EWD

a Reaction Conditions: 3-(6-Bromo-pyridin-2-yl)-[1,2,4]triazinyl scaffold (0.13 mmol), Pd(dppf)Cl2 (0.007 mmol), CuI (0.007 mmol), TEA (0.39 mmol), Alkyne (0.20 mmol), slurried in MTBE (0.25 M), and heated for 16 h. bIsolated, purified yield over one synthetic step, c Average yield from 2 experiments.

R

O

N

NC

N H

36 (84)

N 38 (58)

37 (56) O H

N

N 40 (40)

39 (57)

N O

41 (40)

Br

Br

a

Reaction Conditions: 6-bromopyridine derivative (0.13 mmol), Pd(dppf)Cl2 (0.007 mmol), CuI (0.007 mmol, 5 mol%), TEA (0.39 mmol), Alkyne (0.20 mmol), slurried in MTBE (0.25 M), and heated for 16 h. bIsolated, purified yield over one synthetic step.


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tion of the 1-ethynyl-4-bromobenzene nucleophile in the cases of 39 and 41. Homocoupled Glaser22 products, a potential byproduct of the Sonogashira coupling, were not observed in the aforementioned cases or, with product 8. The modest yields were attributed more to instability during chromatographic purification and less to unwanted side reactions. The 1,2,4-triazinyl-moiety appears to bear little influence on the selective oxidative addition into the C-Br bond of the pyridinyl moiety based on the outcome of these competition experiments other than to potentially enhance the electrophilicity of this position. Products 8, 39, and 41 afford strategic opportunities for additional functionalization. A tenfold scale-up experiment over initial screening pursuant to the conditions outlined in Table 1 for 16 above was executed and produced similar results to the development scale experiment (Scheme 1). Downstream functionalization of prepared synthons was also attempted (Scheme 2). SuzukiMiyaura cross-coupling of 8 and potassium 3,3-dimethylbutyl trifluoroborate23 afforded the derivatized product 42. Pdcatalyzed amination of 8 was also successful, but purification accelerated decomposition of aminated analogues of 42. Scheme 1. Tenfold Scale-Up Experiment Pd(dppf)Cl2 (5 mol%), CuI (5 mol%), TEA (3 equiv) R (1.5 equiv),

Ph

N

Ph

N

N

1 o

MTBE, 55 C, 16 h

N

OH

16 Ph

1.3 mmol scale 56.1%

Scheme 2. Suzuki-Miyaura Cross-Coupling

8

Pd(OAc)2 (5 mol%), RuPhos (10 mol%) R3BF3K (2.1 equiv), Cs2CO3 (3 equiv) Tol:H2O (4:1), 115 oC, 16 h, (27%)

Ph

N

Ph

N

N N

42

CONCLUSION In summary, we have described a synthetic method to access Sonogashira coupling products of a variety of functionalized 3-(6-bromo-pyridin-2-yl)-[1,2,4]triazine scaffolds leading to the formation of 41 examples in 31−96% isolated yield. The method is moderately scalable and allows entry into numerous structurally diverse possibilities. Additionally, these experiments have highlighted the selectivity of oxidative addition at the C-Br bond of the pyridinyl scaffold preferentially to the CBr bond of 1-ethynyl-4-bromobenzene. Access to these diversified synthons will afford opportunities to prepare advanced, unsymmetric complexants with alternative heterocycle constructs for potential use in liquid-liquid separations of SNF or in the area of polyconjugated materials. Studies towards these synthetic goals are ongoing in our laboratory and will be reported in due course. EXPERIMENTAL SECTION General Methods. All reagents were purchased from U.S. chemical suppliers, stored according to published protocols, and used as received unless indicated otherwise. All experiments were performed in oven- or flame-dried glassware. Reaction progress was monitored using thin-layer chromatography on glass-backed silica gel plates and/or 1H NMR analysis of crude reaction mixtures. Rf values for compounds that resulted in a concentrically observed spot on normal phase

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silica gel are reported using the conditions listed. All reported yields listed are for pure compounds and corrected for residual solvent, if applicable, from 1H NMR spectroscopy unless otherwise indicated. Melting points are for a single experiment and are uncorrected. All 1H and 13C NMR data was acquired from a 500 MHz multinuclear spectrometer with broad-band N2 cryoprobe. Chemical shifts are reported using the δ scale and are referenced to the residual solvent signal: CDCl3 (δ 7.26), C6D6 (7.16) for 1H NMR and CDCl3 (δ 77.15), C6D6 (128.06) for 13C NMR. 13C NMR spectra were corrected for ringdown using linear back prediction. Splittings are reported as follows: (s) = singlet, (d) = doublet, (pent) = pentet, (t) = triplet, (dd) = doublet of doublets, (dt) = doublet of triplets, (br) = broad, and (m) = multiplet. Infrared spectral data was acquired from the (form) listed. High resolution mass spectrometry (HRMS) data was obtained utilizing electron impact ionization (EI) with a magnetic sector (EBE trisector), double focusing-geometry mass analyzer. For an experimental procedure towards the preparation of 3(6-bromo-pyridin-2-yl)-5,6-diphenyl-[1,2,4]triazine used for the construction of 2–16 please see reference 8(a). The synthons required for 17–18 and 27–28 also appear in reference 8(a). For the bis-3,3’-dimethylbutyl- and bis-butyl functionalized scaffolds used with 19−26, as well as scaffolds used to afford 32 and 34–35, please see reference 15. Preparation of starting material for products 29−31; 33. 3-(6-bromopyridin-2-yl)-5,6-bis-(4-fluoro-phenyl)-[1,2,4] triazine. For a general procedure for the formation of 6bromo-pyridinyl-2-yl hydrazonamide please refer to reference 8(a). A 25 mL round bottom flask equipped with a magnetic stir bar was charged with the requisite hydrazonamide (0.200 g, 0.93 mmol, 1.00 equiv) in anhydrous DMF (6.0 mL, 0.11 M). To the resulting slurry was added 4,4’-difluorobenzil (0.229 g, 0.93 mmol, 1.00 equiv) in one portion followed by heating at 66 °C for 18 hours. Afterwards, the mixture was cooled to ambient temperature, absorbed on silica gel, and purified using automated flash-column chromatography. Rf = 0.65, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.272 g, 69%; greenish yellow-colored solid; melting point = 180.5–182.7 °C; 1H NMR (500 MHz, CDCl3): δ = 8.63 (d, J = 7.6 Hz, 1H), 7.79 (t, J = 7.8 Hz, 1H), 7.75−7.68 (m, 3H), 7.66−7.62 (m, 2H), 7.15−7.06 (m, 4H); 13 C NMR (125 MHz, CDCl3): δ = 165.4 (d, J = 76.9 Hz), 163.4 (d, J = 76.9 Hz), 163.1, 159.8, 155.6, 155.1, 153.8, 143.1, 139.4, 132.4 (d, J = 8.3 Hz), 131.7 132.4 (d, J = 8.3 Hz), 131.4 (d, J = 3.8 Hz), 131.2 (d, J = 3.1 Hz), 130.4, 123.1, 116.3 (d, J = 9.8 Hz), 116.2 (d, J = 9.3 Hz); IR (ATR-CDCl3): ῡmax = 3073, 2973, 2934, 1601, 1575, 1557, 1512, 1376, 1359, 1226, 1158, 839, 797, 742 cm−1; HRMS (EI): m/z: [M]+ Calcd for C20H11BrF2N4 424.0135; Found: 424.0128. General Procedure for Pd-Catalyzed Sonogashira Reaction of 3-(6-bromo-pyridin-2-yl)-[1,2,4]triazinyl Scaffolds: To an 8 mL reaction vial equipped with a magnetic stir bar at ambient temperature was charged Pd(dppf)Cl2 (5 mol%), CuI (5 mol%), TEA (3 equiv), the requisite alkyne (1.5 equiv) in anhydrous MTBE (0.25 M). The resulting slurry was heated at 55 °C for the time indicated upon which time the crude reaction mixture was concentrated under reduced pressure at ambient temperature to remove the TEA. The resulting darkbrown residue was partitioned between EtOAc (5 mL) and water (2 mL). The organic layer was separated and the aqueous layer was back-extracted with two additional 5 mL portions of EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, and then concentrated to afford


4

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the crude mixture which was absorbed on silica gel and purified using automated flash column chromatography under the discrete conditions for each described compound to afford the pure compound in the listed yield. 5,6-Diphenyl-3-(6-p-tolylethynyl-pyridin-2-yl)-[1,2,4]triazine (2). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6-diphenyl-[1,2,4] triazine and 1-ethynyl-4-methyl-benzene, Rf = 0.25, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0418 g, 76%; peach-colored solid; melting point = 209.0–211.4 °C; 1H NMR (500 MHz, CDCl3): δ = 8.61 (d, J = 7.8 Hz, 1H), 7.92 (br-t, J = 7.8 Hz, 1H), 7.75−7.69 (m, 3H), 7.65 (d, J = 7.7 Hz, 2H), 7.54 (d, J = 7.8 Hz, 2H), 7.48−7.34 (m, 6H), 7.19 (d, J = 7.8 Hz, 2H), 2.39 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 160.5, 156.6, 156.4, 153.4, 144.6, 139.5, 137.3, 135.7, 135.4, 132.2, 130.9, 130.2, 129.9, 129.7, 129.3, 129.0, 128.8, 128.7, 123.1, 119.3, 90.5, 88.4, 21.7; IR (ATRCDCl3): ῡmax = 3054, 3028, 2238, 1578, 1512, 1564, 1360, 822, 813, 775, 697, 533 cm−1; HRMS (EI): m/z: [M]+ Calcd for C29H20N4 424.1688; Found: 424.1690. 3-(6-Oct-1-ynyl-pyridin-2-yl)-5,6-diphenyl-[1,2,4]triazine (3). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6-diphenyl-[1,2,4] triazine and 1-octyne, Rf = 0.62, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0413 g, 76%; offwhite solid; melting point = 117.3–119.8 °C; 1H NMR (500 MHz, CDCl3): δ = 8.54 (dd, J = 7.9 Hz, 0.9 Hz, 1H), 7.84 (t, J = 7.9 Hz, 1H), 7.71−7.67 (m, 2H), 7.64−7.60 (m, 2H), 7.54 (dd, J = 7.8, 0.9 Hz, 1H), 7.44−7.31 (m, 6H), 2.46 (t, J = 7.2 Hz, 2H), 1.64 (t, J = 7.2 Hz, 2H), 1.51−1.43 (m, 2H), 1.37−1.26 (m, 4H), 0.93−0.85 (m, 3H); 13C NMR (125 MHz, CDCl3): δ = 160.6, 156.5, 156.3, 153.2, 144.9, 137.1, 135.7, 135.4, 130.8, 130.2, 129.9, 129.7, 128.7, 128.6, 128.57, 122.8, 92.3, 80.6, 31.5, 28.8, 28.4, 22.6, 19.6, 14.2; IR (ATRCDCl3): ῡmax = 3061, 3029, 2925, 2856, 2229, 1579, 1564, 1412, 1357, 1178, 811, 775, 701, 694 cm−1; HRMS (EI): m/z: [M]+ Calcd for C28H26N4 418.2157; Found 418.2144. 3-(6-Dec-1-ynyl-pyridin-2-yl)-5,6-diphenyl-[1,2,4]triazine (4). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6-diphenyl-[1,2,4] triazine and 1-decyne, Rf = 0.48, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0455g, 78%; brown solid; melting point = 101.1–104.2 °C; 1H NMR (500 MHz, CDCl3): δ = 8.55 (dd, J = 7.9, 0.8 Hz, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.73−7.68 (m, 2H), 7.66−7.61 (m, 2H), 7.55 (dd, J = 7.9, 0.8 Hz, 1H), 7.47−7.33 (m, 6H), 2.47 (t, J = 7.2 Hz, 2H), 1.66 (pent, J = 7.2 Hz, 2H), 1.51−1.43 (m, 2H), 1.37−1.24 (m, 8H), 0.92−0.86 (m, 3H); 13C NMR (125 MHz, CDCl3): δ = 160.6, 156.6, 156.4, 153.3, 145.0, 137.8, 135.7, 135.5, 130.9, 130.2, 129.9, 129.7, 128.8, 128.7, 128.6, 122.8, 92.3, 80.6, 32.0, 29.3, 29.28, 29.21, 28.5, 22.8, 19.6, 14.2; IR (ATR-CDCl3): ῡmax = 3058, 2923, 2858, 2229, 1579, 1564, 1454, 1445, 1356, 812, 769, 694 cm−1; HRMS (EI): m/z: [M]+ Calcd for C30H30N4 446.2470; Found 446.2486. 5,6-Diphenyl-3-(6-phenylethynyl-pyridin-2-yl)-[1,2,4] triazine (5). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6-diphenyl[1,2,4]triazine and ethynylbenzene, Rf = 0.55, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0413 g, 77%; brown solid; melting point = 208.5– 213.8 °C; 1H NMR (500 MHz, CDCl3): δ = 8.64 (d, J = 7.5 Hz, 1H), 7.94 (br-t, J = 7.5 Hz, 1H), 7.76−7.69 (m, 3H), 7.67−7.62 (m, 4H), 7.49−7.35 (m, 9H); 13C NMR (125 MHz, CDCl3): δ = 160.5. 156.7, 156.4, 153.5, 144.4, 137.5, 135.7,

135.4, 132.3, 131.0, 130.2, 130.0, 129.7, 129.2, 129.1, 128.8, 128.7, 128.5, 123.4, 122.4, 90.2, 88.9; IR (ATR-CDCl3): ῡmax = 3052, 2234, 1577, 1562, 1492, 1411, 1358, 812, 775, 749, 695, 533 cm−1; HRMS (EI): m/z: [M]+ Calcd for C28H18N4 410.1531; Found 410.1537. 3-[6-(4-Methoxy-phenylethynyl)-pyridin-2-yl]-5,6-diphenyl[1,2,4]triazine (6). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6diphenyl-[1,2,4]triazine and 1-ethynyl-4-methoxybenzene, Rf = 0.25, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0360 g, 63%; off-white; melting point = 199.6–201.5 °C; 1H NMR (500 MHz, CDCl3): δ = 8.61 (d, J = 7.9 Hz, 1H), 7.92 (br-t, J = 7.9 Hz, 1H), 7.73 (br-d, J = 7.8 Hz, 2H), 7.69 (br-d, J = 7.7 Hz, 1H), 7.65 (br-d, J = 7.8 Hz, 2H), 7.60 (br-d, J = 8.0 Hz, 2H), 7.49−7.33 (m, 6H), 6.91 (d, J = 8.0 Hz, 2H), 3.85 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 160.5, 160.4, 156.7, 156.5, 153.4, 144.7, 137.4, 135.7, 135.5, 133.9, 131.0, 130.3, 130.0, 129.8, 128.9, 128.8, 128.7, 123.0, 114.5, 90.7, 87.9, 55.5; IR (ATR-CDCl3): ῡmax = 3073, 2906, 2839, 2210, 1605, 1575, 1564, 1511, 1358, 1243, 826, 776, 701, 695 cm−1; HRMS (EI): m/z: [M]+ Calcd for C29H20N4O 440.1637; Found 440.1633. 4-[6-(5,6-Diphenyl-[1,2,4]triazin-3-yl)-pyridin-2-ylethynyl] -benzonitrile (7). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6-diphenyl[1,2,4]triazine and 4-ethynylbenzonitrile, Rf = 0.15, 33% EtOAc:hexanes; neutral alumina; eluent, EtOAc/hexanes (gradient); isolated yield 0.0281 g, 50%; brown solid; melting point = 216.5–220.6 °C; 1H NMR (500 MHz, CDCl3): δ = 8.69 (d, J = 7.9 Hz, 1H), 7.98 (t, J = 7.9 Hz, 1H), 7.79−7.60 (m, 9H), 7.50−7.34 (m, 6H); 13C NMR (125 MHz, CDCl3): δ = 160.3, 156.8, 156.5, 153.8, 143.5, 137.6, 135.6, 135.3, 132.7, 132.3, 131.1, 130.2, 130.1, 129.7, 129.3, 128.8, 128.7, 127.3, 124.0, 118.5, 112.5, 92.7, 87.9; IR (ATR-CDCl3): ῡmax = 3066, 2921, 2228, 1601, 1578, 1566, 1503, 1495, 1359, 816, 772, 736, 724, 698 cm−1; HRMS (EI): m/z: [M]+ Calcd for C29H17N5 435.1484; Found 435.1487. 3-[6-(4-Bromo-phenylethynyl)-pyridin-2-yl]-5,6-diphenyl[1,2,4]triazine (8). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6diphenyl-[1,2,4]triazine and 1-bromo-4-ethynylbenzene, Rf = 0.48, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0341 g, 54%; brown solid; melting point = 221.0–223.0 °C; 1H NMR (500 MHz, CDCl3): δ = 8.66 (br-d, J = 6.5 Hz, 1H), 7.98 (br-s, 1H), 7.77−7.68 (m, 3H), 7.65 (brd, J = 7.7 Hz, 1H), 7.53 (br-s, 4H), 7.48−7.34 (m, 6H); 13C NMR (125 MHz, CDCl3): δ = 160.1, 156.8, 156.5, 153.3, 143.7, 137.9, 135.6, 135.3, 133.8, 131.9, 131.0, 130.3, 130.0, 129.7, 129.2, 128.8, 128.7, 123.8, 123.6, 121.2, 90.0, 89.5; IR (ATR-CDCl3): ῡmax = 3054, 1577, 1564, 1488, 1360, 1009, 826, 776, 698 cm−1; HRMS (EI): m/z: [M]+ Calcd for C28H17BrN4 488.0637; Found 488.0628. 3-[6-(4-tert-Butyl-phenylethynyl)-pyridin-2-yl]-5,6diphenyl-[1,2,4]triazine (9). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6diphenyl-[1,2,4]triazine and 1-tert-butyl-4-ethynylbenzene, Rf = 0.39, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0452 g, 75%; off-white solid; melting point = 173.1–176.4 °C; 1H NMR (500 MHz, CDCl3): δ = 8.61 (d, J = 7.9 Hz, 1H), 7.92 (t, J = 7.9 Hz, 1H), 7.75−7.69 (m, 3H), 7.67−7.63 (m, 2H), 7.61−7.57 (m, 2H), 7.47−7.34 (m, 8H), 1.34 (s, 9H); 13C NMR (125 MHz, CDCl3): δ = 160.6, 156.7, 156.4, 153.5, 152.5, 144.7, 137.3, 135.7, 135.5, 132.1, 131.0, 130.2, 130.0, 129.7, 129.0, 128.8, 128.7, 125.6,


5


123.1, 119.4, 90.5, 88.5, 35.0, 31.3; IR (ATR-CDCl3): ῡmax = 3062, 2963, 2866, 2213, 1580, 1564, 1493, 1443, 1358, 831, 813, 765, 695 cm−1; HRMS (EI): m/z: [M]+ Calcd for C32H26N4 466.2157; Found: 466.2151. 5,6-Diphenyl-3-(6-m-tolylethynyl-pyridin-2-yl)-[1,2,4] triazine (10). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6-diphenyl[1,2,4]triazine and 1-ethynyl-3-methyl-benzene, Rf = 0.40, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0280 g, 51%; brown solid; melting point = 183.7–186.1 °C; 1H NMR (500 MHz, CDCl3): δ = 8.62 (d, J = 7.9 Hz, 1H), 7.92 (t, J = 8.0 Hz, 1H), 7.74−7.68 (m, 3H), 7.66−7.62 (m, 2H), 7.46−7.33 (m, 8H), 7.28−7.23 (m, 1H), 7.21−7.17 (m, 1H), 2.37 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 160.5, 156.7, 156.4, 153.5, 144.5, 138.2, 137.4, 135.7, 135.4, 132.8, 131.0, 130.2, 130.1, 130.0, 129.7, 129.4, 129.1, 128.8, 128.7, 128.4, 123.2, 122.2, 90.5, 85.6, 21.4; IR (ATR-CDCl3): ῡmax = 3056, 3031, 2920, 2852, 2217, 1600, 1578, 1563, 1487, 1357, 812, 774, 690 cm−1; HRMS (EI): m/z: [M]+ Calcd for C29H20N4 424.1688; Found 424.1677. 5,6-Diphenyl-3-(6-pyridin-2-ylethynyl-pyridin-2-yl)[1,2,4]triazine (11). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6diphenyl-[1,2,4]triazine and 2-ethynylpyridine, Rf = 0.10, 50% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0166 g, 31%; brown solid; melting point = 227.5– 231.5 °C; 1H NMR (500 MHz, CDCl3): δ = 8.71−8.63 (br-m, 2H), 7.96 (br-t, J = 7.8 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.76−7.67 (m, 4H), 7.65 (d, J = 7.6 Hz, 2H), 7.48−7.35 (m, 6H), 7.34−7.28 (br-m, 1H); 13C NMR (125 MHz, CDCl3): δ = 160.4, 156.7, 156.4, 153.6, 150.2, 143.6, 142.8, 137.5, 136.5, 135.7, 135.4, 131.0, 130.2, 130.0, 129.7, 129.66, 128.8, 128.7, 128.1, 123.9, 123.6, 88.6, 88.2; IR (ATR-CDCl3): ῡmax = 3057, 1580, 1564, 1507, 1390, 766, 634 cm−1; HRMS (EI): m/z: [M]+ Calcd for C27H17N5 411.1484; Found 411.1468. 5,6-Diphenyl-3-{6-[(triisopropylsilanyl)-ethynyl]-pyridin-2yl}-[1,2,4]triazine (12). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6diphenyl-[1,2,4]triazine and ethynyltriisopropylsilane, Rf = 0.72, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0473 g, 74%; yellow solid; melting point = 137.4–142.2 °C; 1H NMR (500 MHz, CDCl3): δ = 8.61 (d, J = 7.5 Hz, 1H), 7.91 (br-t, J = 7.5 Hz, 1H), 7.73 (d, J = 7.7 Hz, 2H), 7.67 (d, J = 7.6 Hz, 1H), 7.47−7.34 (m, 6H), 1.23−1.11 (m, 21H); 13C NMR (125 MHz, CDCl3): δ = 160.3, 156.7, 156.4, 153.1, 144.1, 137.5, 135.6, 135.4, 131.0, 130.2, 130.0, 129.7, 128.8, 128.7, 123.6, 105.4, 94.0, 18.8, 11.4; IR (ATRCDCl3): ῡmax = 3063, 2941, 2863, 1577, 1486, 1445, 1377, 838, 770, 698, 662 cm−1; HRMS (EI): m/z: [M]+ Calcd for C31H34N4Si 490.2553; Found 490.2535. 3-{6-[(tert-Butyl-dimethyl-silanyl)-ethynyl]-pyridin-2-yl}5,6-diphenyl-[1,2,4]triazine (13). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2yl)-5,6-diphenyl-[1,2,4]triazine and tert-butylethynyldimethylsilane, Rf = 0.57, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0319 g, 55%; yellow solid; melting point = 201.2–203.1 °C; 1H NMR (500 MHz, CDCl3): δ = 8.60 (dd, J = 7.9, 0.6 Hz, 1H), 7.89 (t, J = 7.9 Hz, 1H), 7.73−7.67 (m, 2H), 7.66−7.61 (m, 3H), 7.48−7.34 (m, 6H), 1.03 (s, 9H), 0.23 (s, 6H); 13C NMR (125 MHz, CDCl3): δ = 160.5, 156.6, 156.4, 153.4, 144.2, 137.2, 135.7, 135.4, 131.0, 130.2, 130.0, 129.7, 129.5, 128.8, 128.7, 123.5, 104.5, 94.6, 23.4, 16.9, −4.58; IR (ATR-CDCl3): ῡmax = 3052, 2926, 2854, 1576, 1566, 1409, 1357, 916, 843, 814, 772, 699, 533 cm−1;

Page 6 of 11

HRMS (EI): m/z: [M−CH3]+ Calcd for C28H28N4Si 448.2083; Found 433.1865. {3-[6-(5,6-Diphenyl-[1,2,4]triazin-3-yl)-pyridin-2-yl]-prop2-ynyl}-carbamic acid tert-butyl ester (14). Prepared according to the general procedure discussed above with 3-(6-bromopyridin-2-yl)-5,6-diphenyl-[1,2,4]triazine and prop-2-ynylcarbamic acid tert-butyl ester, Rf = 0.12, 33% EtOAc:hexanes; neutral alumina; eluent, EtOAc/hexanes (gradient); isolated yield 0.0441 g, 73%; yellow solid; melting point = 82.8–86.5 °C; 1H NMR (500 MHz, CDCl3): δ = 8.61 (d, J = 7.9 Hz, 1H), 7.89 (t, J = 7.9 Hz, 1H), 7.72−7.68 (m, 2H), 7.65−7.62 (m, 2H), 7.59 (d, J = 7.9 Hz, 1H), 7.49−7.33 (m, 6H), 4.85 (br-s, 1H), 4.22 (s, 2H), 1.48 (s, 9H); 13C NMR (125 MHz, CDCl3): δ = 160.4, 156.7, 156.1, 153.5, 143.7, 137.4, 135.7, 135.4, 131.0, 130.2, 130.0, 129.7, 128.8, 128.7, 123.5, 85.6, 82.7, 31.3, 28.5; IR (ATR-CDCl3): ῡmax = 3400, 3059, 2976, 2928, 1717, 1579, 1565, 1501, 1357, 1241, 1161, 770, 696 cm−1; HRMS (EI): m/z: [M−C4H8]+ Calcd for C28H25N5O2 463.2008; Found 407.1369. 3-[6-(3-Benzyloxy-prop-1-ynyl)-pyridin-2-yl]-5,6-diphenyl[1,2,4]triazine (15). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6diphenyl-[1,2,4]triazine and prop-2-ynyloxymethyl-benzene, Rf = 0.20, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0359 g, 61%; brown solid; melting point = 139.0–141.6 °C; 1H NMR (500 MHz, CDCl3): δ = 8.63 (dd, J = 8.0, 0.6 Hz, 1H), 7.91 (t, J = 7.9 Hz, 1H), 7.72−7.69 (m, 2H), 7.65−7.63 (m, 3H), 7.48−7.28 (m, 11H), 4.72 (s, 2H), 4.47 (s, 2H); 13C NMR (125 MHz, CDCl3): δ = 160.4, 156.7, 156.4, 153.5, 143.7, 137.6, 137.4, 135.7, 135.4, 131.0, 130.2, 130.0, 129.7, 129.0, 128.8, 128.7, 128.6, 128.3, 128.1, 123.6, 86.3, 85.9, 72.1, 58.0; IR (ATR-CDCl3): ῡmax = 3043, 2857, 2236, 1579, 1562, 1414, 1353, 1092, 734, 692, 532 cm−1; HRMS (EI): m/z: [M]+ Calcd for C30H22N4O 454.1794; Found 454.1795. 3-[6-(5,6-Diphenyl-[1,2,4]triazin-3-yl)-pyridin-2-yl]-1phenyl-prop-2-yn-1-ol (16). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6diphenyl-[1,2,4]triazine and 1-phenyl-prop-2-yn-1-ol, Rf = 0.37, 50% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0336 g, 59%; brown solid; melting point = 183.6–187.3 °C; 1H NMR (500 MHz, CDCl3): δ = 8.63 (d, J = 7.9 Hz, 1H), 7.91 (t, J = 7.9 Hz, 1H), 7.73−7.68 (m, 2H), 7.67−7.61 (m, 5H), 7.47−7.32 (m, 9H), 5.77 (s, 1H); 13C NMR (125 MHz, CDCl3): δ = 160.3, 156.7, 156.4, 153.5, 143.6, 140.1, 137.4, 135.6, 135.4, 131.0, 130.2, 130.0, 129.7, 129.0, 128.8, 128.8, 128.7, 128.65, 127.0, 123.7, 89.7, 85.9, 65.1; IR (ATR-CDCl3): ῡmax = 3400, 3030, 2923, 2227, 1579, 1563, 1491, 1412, 1392, 1358, 769, 739, 696 cm−1; HRMS (EI): m/z: [M]+ Calcd for C29H20N4O 440.1637; Found 440.1651. 3-[6-(4-Fluoro-phenylethynyl)-pyridin-2-yl]-5,5,8,8tetramethyl-5,6,7,8-tetrahydro-benzo[1,2,4]triazine (17). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-benzo[1,2,4]triazine and 1-ethynyl-4-fluoro-benzene, RF = 0.48, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0187 g, 37%; yellow solid; melting point = 62.3–65.5 °C; 1H NMR (500 MHz, CDCl3): δ = 8.37 (dd, J = 7.9, 0.8 Hz, 1H), 7.85 (t, J = 7.9 Hz, 1H), 7.62 (dd, J = 7.8, 0.8 Hz, 1H), 7.61−7.57 (m, 2H), 7.09−7.01 (m, 2H), 1.88−1.81 (m, 4H), 1.48 (s, 6H), 1.42 (s, 6H); 13C NMR (125 MHz, CDCl3): δ = 164.4, 164.0, 163.0 (J = 249.7 Hz), 160.6, 154.4, 143.9, 137.5, 134.19 (J = 8.9 Hz), 128.4, 122.9, 118.6 (J = 4.1 Hz), 115.9 (J = 21.8 Hz), 88.8, 88.6, 37.4, 36.6, 33.8,


6

Page 7 of 11 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


33.5, 29.8, 29.3; IR (ATR-CDCl3): ῡmax = 3060, 2962, 2928, 2865, 2217, 1600, 1579, 1565, 1507, 1455, 1222, 835, 812, 741, 530 cm−1; HRMS (EI): m/z: [M]+ Calcd for C24H23FN4 386.1907; Found 386.1916. 3-[6-(4-Methoxy-phenylethynyl)-pyridin-2-yl]-5,5,8,8tetramethyl-5,6,7,8-tetrahydro-benzo[1,2,4]triazine (18). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-benzo[1,2,4]triazine and 1-ethynyl-4-methoxy-benzene, Rf = 0.15, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0379 g, 73%; green-yellow solid; melting point = 100.3–101.6 °C; 1H NMR (500 MHz, CDCl3): δ = 8.33 (d, J = 7.9, 0.8 Hz, 1H), 7.82 (t, J = 7.7 Hz, 1H), 7.60 (d, J = 7.9, 0.8 Hz, 1H), 7.56−7.53 (m, 2H), 6.89−6.85 (m, 2H0, 3.81 (s, 3H), 1.87−1.79 (m, 4H), 1.47 (s, 6H), 1.41 (s, 6H); 13C NMR (125 MHz, CDCl3): δ = 164.3, 163.2, 160.7, 160.2, 154.3, 144.4, 137.0, 133.7, 128.2, 122.5, 114.5, 114.1, 90.0, 88.0, 55.4, 37.3, 36.6, 33.8, 33.4, 29.8, 29.3; IR (ATRCDCl3): ῡmax = 3062, 2961, 2919, 2864, 2213, 1605, 1565, 1579, 1510, 1455, 1245, 1163, 831, 813, 728, 536 cm−1; HRMS (EI): m/z: [M]+ Calcd for C25H26N4O 398.2107; Found 398.2105. 3-[6-(3-Benzyloxy-prop-1-ynyl)-pyridin-2-yl]-5,6-bis-[4(3,3-dimethyl-butyl)-phenyl]-[1,2,4]triazine (19). Prepared according to the general procedure discussed above with 3-(6bromo-pyridin-2-yl)-5,6-bis-[4-(3,3-dimethyl-butyl)-phenyl][1,2,4]triazine and prop-2-ynyloxymethyl-benzene, Rf = 0.36, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0546 g, 67%; white solid; melting point = 174.6– 176.3 °C; 1H NMR (500 MHz, CDCl3): δ = 8.60 (dd, J = 8.0, 0.8 Hz, 1H), 7.89 (t, J = 7.8 Hz, 1H), 7.66−7.63 (m, 2H), 7.62 (dd, J = 7.8, 0.8 Hz, 1H0, 7.58−7.55 (m, 2H), 7.43−7.39 (m, 2H), 7.38−7.34 (m, 2H), 7.33−7.28 (m, 1H), 7.21 (d, J = 8.2 Hz, 2H0, 7.17 (d, J = 8.2 Hz, 2H), 4.72 (s, 2H), 4.47 (s, 2H), 2.64−2.56 (m, 4H), 1.54−1.46 (m, 4H), 0.97 (s, 9H), 0.95 (s, 9H); 13C NMR (125 MHz, CDCl3): δ = 160.1, 156.5, 156.2, 153.7, 147.1, 145.8, 143.7, 137.6, 137.3, 133.1, 132.8, 130.2, 129.6, 128.8, 128.77, 128.7, 128.6, 128.3, 128.0, 123.5, 86.1, 86.0, 72.1, 58.0; IR (ATR-CDCl3): ῡmax = 3062, 3029, 2951, 2864, 1610, 1565, 1579, 1492, 1459, 1356, 1079, 751, 700, 548 cm−1; HRMS (EI): m/z: [M−CH3]+ Calcd for C42H46N4O 622.3642; Found 607.3426. 5,6-Bis-(4-butyl-phenyl)-3-[6-(4-fluoro-phenylethynyl)pyridin-2-yl]-[1,2,4]triazine (20). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2yl)-5,6-bis-(4-butyl-phenyl)-[1,2,4]triazine and 1-ethynyl-4fluoro-benzene, Rf = 0.55, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0315 g, 45%; beige solid; melting point = 166.0–168.0 °C; 1H NMR (500 MHz, CDCl3): δ = 8.62 (dd, J = 8.0, 0.9 Hz, 1H), 7.92 (t, J = 7.9 Hz, 1H0, 7.67 (dd, J = 7.9, 0.9 Hz, 1H), 7.66−7.61 (m, 4H), 7.58−7.55 (m, 2H), 7.22−7.19 (m, 2H), 7.18−7.15 (m, 2H), 7.10−7.05 (m, 2H), 2.68−2.61 (m, 4H), 1.67−1.56 (m, 4H), 1.42−1.29 (m, 4H), 0.94 (t, J = 7.5 Hz, 3H), 0.92 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ = 163.1 (J = 252.0 Hz), 160.2, 156.6, 156.3, 153.8, 146.4, 145.1, 144.2, 137.3, 134.3 (J = 9.0 Hz), 133.1, 132.9, 130.1, 129.6, 128.9, 128.8, 128.75, 123.3, 118.6 (J = 3.6 Hz), 115.9 (J = 22.0 Hz), 88.9, 88.7, 35.7, 35.6, 33.4, 33.36, 22.5, 22.4, 14.1, 14.0; IR (ATRCDCl3): ῡmax = 3032, 2958, 2928, 2856, 2236, 1609, 1579, 1566, 1507, 1354, 1276, 836, 816, 607, 527 cm−1; HRMS (EI): m/z: [M]+ Calcd for C36H33FN4 540.2689; Found 540.2689. 3-[6-(4-tert-Butyl-phenylethynyl)-pyridin-2-yl]-5,6-bis-[4(3,3-dimethyl-butyl)-phenyl]-[1,2,4]triazine (21). Prepared

according to the general procedure discussed above with 3-(6bromo-pyridin-2-yl)-5,6-bis-[4-(3,3-dimethyl-butyl)-phenyl][1,2,4]triazine and 1-tert-butyl-4-ethynyl-benzene, RF = 0.70, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0793 g, 96%; white solid; melting point = 192.0– 194.0 °C; 1H NMR (500 MHz, CDCl3): δ = 8.59 (dd, J = 8.0, 0.9 Hz, 1H), 7.91 (t, J = 7.9 Hz, 1H), 7.69 (dd, J = 7.9, 0.9 Hz, 1H), 7.68−7.64 (m, 2H), 7.61−7.55 (m, 4H), 7.42−7.38 (m, 2H), 7.23−7.20 (m, 2H), 7.19−7.16 (m, 2H), 2.65−2.57 (m, 4H), 1.55−1.47 (m, 4H), 1.34 (s, 9H), 0.97 (s, 9H), 0.96 (s, 9H); 13C NMR (125 MHz, CDCl3): δ = 160.2, 156.5, 156.2, 153.7, 152.5, 147.1, 145.8, 144.6, 137.2, 133.1, 132.9, 132.1, 130.2, 129.6, 128.9, 128.8, 128.7, 125.6, 123.0, 119.5, 90.4, 88.5, 46.0, 45.99, 35.0, 31.4, 31.3, 30.8, 29.49, 29.48; IR (ATR-CDCl3): ῡmax = 3032, 2952, 2864, 2214, 1609, 1579, 1492, 1454, 1408, 1358, 832, 560 cm−1; HRMS (EI): m/z: [M]+ Calcd for C44H50N4 634.4035; Found 634.4027. 5,6-Bis-(4-butyl-phenyl)-3-(6-cyclohexylethynyl-pyridin-2yl)-[1,2,4]triazine (22). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6bis-(4-butyl-phenyl)-[1,2,4]triazine and ethynylcyclohexane, Rf = 0.62, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0551 g, 80%; brown solid; melting point = 126.0–128.0 °C; 1H NMR (500 MHz, CDCl3): δ = 8.53 (d, J = 7.9 Hz, 1H), 7.84 (t, J = 7.9 Hz, 1H), 7.64 (d, J = 8.2 Hz, 2H), 7.57−7.53 (m, 3H), 7.20 (d, J = 8.2 Hz, 2H), 7.16 (d, J = 8.2 Hz, 2H), 2.68−2.61 (m, 4H), 1.98−1.91 (br-m, 2H0, 1.83−1.75 (br-m, 2H), 1.66−1.58 (m, 9H), 1.42−1.30 (m, 7H), 0.94 (t J = 7.4 Hz, 3H), 0.92 (t, J = 7.4 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ = 160.3, 156.4, 155.2, 153.4, 146.3, 145.0, 144.98, 137.1, 133.2, 132.9, 130.1, 129.5, 128.8, 128.76, 128.7, 122.7, 95.9, 80.6, 35.7, 35.6, 33.4, 3.37, 32.4, 29.9, 26.0, 25.2, 22.5, 22.4, 14.1, 14.05; IR (ATR-CDCl3): ῡmax = 3031, 2956, 2922, 2850, 226, 1608, 1579, 1566, 1405, 1350, 807, 732, 604 cm−1; HRMS (EI): m/z: [M]+ Calcd for C36H40N4 528.3253; Found: 528.3253. 3-(6-Cyclohexylethynyl-pyridin-2-yl)-5,6-bis-[4-(3,3dimethyl-butyl)-phenyl]-[1,2,4]triazine (23). Prepared according to the general procedure discussed above with 3-(6-bromopyridin-2-yl)-5,6-bis-[4-(3,3-dimethyl-butyl)-phenyl][1,2,4]triazine and ethynyl-cyclohexane, Rf = 0.70, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0441 g, 58%; white solid; melting point = 214.1–216.5 °C; 1H NMR (500 MHz, CDCl3): δ = 8.52 (dd, J = 7.9, 0.8 Hz, 1H), 7.83 (t, J = 7.9 Hz, 1H), 7.66−7.62 (m, 2H), 7.58−7.53 (m, 3H), 7.22−7.19 (m, 2H), 7.18−7.15 (m, 2H), 2.68−2.54 (m, 5H), 1.98−1.91 (br-m, 2H), 1.83−1.75 (m, 2H), 1.63−1.55 (br-m, 4H), 1.54−1.46 (m, 4H), 1.39−1.32 (br-m, 2H), 0.97 (s, 9H), 0.96 (s, 9H); 13C NMR (125 MHz, CDCl3): δ = 160.3, 156.4, 156.1, 153.4, 147.0, 145.7, 145.0, 137.1, 133.1. 132.9, 130.2, 130.16, 129.6, 128.8, 128.6, 122.7, 95.9, 80.6, 46.0, 45.98, 32.4, 31.4, 31.3, 30.75, 30.7X (overlaps with 30.75); IR (ATR-CDCl3): ῡmax = 3032, 2950, 2931, 2861, 2230, 1609, 1581, 1566, 1490, 1451, 1355, 1363, 820, 804, 731, 602 cm−1; HRMS (EI): m/z: [M]+ Calcd for C40H48N4 584.3879; Found 584.3881. 5,6-Bis-(4-butyl-phenyl)-3-{6-[(triisopropylsilanyl)ethynyl]-pyridin-2-yl}-[1,2,4]triazine (24). Prepared according to the general procedure discussed above with 3-(6-bromopyridin-2-yl)-5,6-bis-(4-butyl-phenyl)-[1,2,4]triazine and ethynyltriisopropylsilane, Rf = 0.75, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0509 g, 65%; brown oil; 1H NMR (500 MHz, CDCl3): δ = 8.57 (dd, J = 8.0, 0.9 Hz, 1H), 7.86 (t, J = 7.9 Hz, 1H), 7.66−7.62 (m,


7


3H), 7.58−7.55 (m, 2H), 7.20 (d, J = 7.9 Hz, 2H), 7.17 (d, J = 7.9 Hz, 2H), 2.68−2.60 (m, 4H), 1.67−1.55 (m, 4H), 1.42−1.29 (m, 4H), 1.22−1.13 (m, 21H), 0.93 (J = 7.5 Hz, 3H), 0.92 (t, J = 7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ = 160.2, 156.4, 156.2, 153.6, 146.4, 145.1, 144.3, 137.1, 133.1, 132.9, 130.1, 129.7, 129.5, 128.8, 128.7, 123.4, 106.0, 92.8, 35.7, 35.6, 33.4, 33.36, 22.5, 22.4, 18.8, 14.1, 14.0, 11.5; IR (ATR-CDCl3): ῡmax = 3032, 2955, 2929, 2863, 2050, 1609, 1578, 1566, 1489, 1462, 1379, 882, 845, 676, 661, 561 cm−1; HRMS (EI): m/z: [M]+ Calcd for C39H50N4Si 602.3805; Found 602.3807. 3-{6-[(tert-Butyl-dimethyl-silanyl)-ethynyl]-pyridin-2-yl}5,6-bis-[4-(3,3-dimethyl-butyl)-phenyl]-[1,2,4]triazine (25). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6-bis-[4-(3,3’-dimethylbutyl)-phenyl]-[1,2,4]triazine and tert-butyl-ethynyldimethylsilane, Rf = 0.48, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0443 g, 55%; white solid; melting point = 192.0–194.0 °C; 1H NMR (500 MHz, CDCl3): δ = 8.57 (dd, J = 7.9, 0.8 Hz, 1H), 7.86 (t, J = 7.9 Hz, 1H0, 7.66−7.63 (m, 2H), 7.62 (dd, J = 7.9, 0.9 Hz, 1H), 7.58−7.54 (m, 2H), 7.22−7.19 (m, 2H), 7.18−7.15 (m, 2H), 2.64−2.55 (m, 4H), 1.53−1.47 (m, 4H), 1.03 (s, 9H), 0.97 (s, 9H), 0.95 (s, 9H0, 0.22 (s, 6H); 13C NMR (125 MHz, CDCl3): δ = 160.2, 156.4, 155.2, 153.6, 153.6X (overlaps with 153.6), 147.1, 145.8, 144.1, 137.1, 133.1, 132.8, 130.2, 129.6, 129.2, 128.8, 128.7, 123.4, 104.6, 94.4, 46.0, 45.97, 31.4, 31.3, 30.75, 30.7X (overlaps with 30.75), 29.48, 29.47, 26.3, 16.9, −4.6; IR (ATR-CDCl3): ῡmax = 2953, 2900, 2861, 1609, 1578, 1567, 1493, 1468, 1351, 1248, 917, 851, 824, 781 cm−1; HRMS (EI): m/z: [M]+ Calcd for C40H52N4Si 616.3961; Found 616.3965. 5,6-Bis-(4-butyl-phenyl)-3-(6-dec-1-ynyl-pyridin-2-yl)[1,2,4]triazine (26). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6-bis(4-butyl-phenyl)-[1,2,4]triazine and 1-decyne, Rf = 0.75, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0486 g, 67%; dark brown oil; 1H NMR (500 MHz, CDCl3): δ = 8.55 (d, J = 7.9 Hz, 1H), 7.87 (t, J = 7.9 Hz, 1H), 7.66 (d, J = 8.2 Hz, 2H0, 7.58−7.54 (m, 2H), 7.22−7.18 (m, 2H), 7.17−7.14 (m, 2H), 2.68−2.60 (m, 4H), 2.47 (t, J = 7.2 Hz, 2H), 1.69−1.56 (m, 6H), 1.50−1.43 (m, 2H), 1.41−1.24 (m, 12H), 0.94 (t, J = 7.5 Hz, 3H), 0.92 (t, J = 7.5 Hz, 3H), 0.89 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ = 160.0, 156.5, 156.2, 153.2, 146.3, 145.1, 144.6, 137.5, 133.1, 132.9, 130.2, 129.6, 128.8, 128.7, 122.8, 93.1, 80.3, 35.7, 35.6, 33.43, 33.4, 32.0, 29.33, 29.3, 29.2, 28.4, 22.8, 22.5, 22.4, 19.7, 14.2; IR (ATR-CDCl3): ῡmax = 3058, 3031, 2954, 2926, 2855, 2228, 1609, 1580, 1565, 1455, 1489, 1379, 1357, 829, 806, 737, 549 cm−1; HRMS (EI): m/z: [M]+ Calcd for C38H46N4 558.3722; Found 558.3722. 5,6-Di-p-tolyl-3-(6-p-tolylethynyl-pyridin-2-yl)-[1,2,4] triazine (27). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6-di-p-tolyl[1,2,4]triazine and 1-ethynyl-4-methylbenzene, Rf = 0.60, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0338 g, 62%; yellow solid; melting point = 184.8– 186.2 °C; 1H NMR (500 MHz, CDCl3): δ = 8.59 (d, J = 7.9 Hz, 1H), 7.91 (t, J = 7.9 Hz, 1H), 7.69 (d, J = 7.5 Hz, 1H), 7.64 (d, J = 7.9 Hz, 2H), 7.57−7.52 (m, 4H), 7.23−7.13 (m, 6H), 2.40 (s, 3H), 2.38 (s, 6H); 13C NMR (125 MHz, CDCl3): δ = 160.3, 156.5, 153.7, 144.5, 151.4, 140.1, 139.4, 137.3, 133.0, 132.8, 132.2, 130.2, 129.6, 129.5, 129.4, 129.3, 128.8, 123.1, 119.4, 90.4, 88.5, 21.8, 21.7, 21.6; IR (ATR-CDCl3): ῡmax = 3031, 2920, 2856, 2230, 1608, 1578, 1565, 1488, 1357,

Page 8 of 11

817, 800, 527 cm−1; HRMS (EI): m/z: [M]+ Calcd for C31H24N4 452.2001; Found 452.2015. 3-(6-Dec-1-ynyl-pyridin-2-yl)-5,6-di-p-tolyl-[1,2,4]triazine (28). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6-di-p-tolyl-[1,2,4] triazine and 1-decyne, Rf = 0.55, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0556 g, 90%; brown solid; melting point = 89.6–91.6 °C; 1H NMR (500 MHz, CDCl3): δ = 8.52 (d, J = 7.8 Hz, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.64−7.61 (m, 2H), 7.56−7.52 (m, 3H), 7.19 (d, J = 8.1 Hz, 2H), 7.15 (d, J = 8.1 Hz, 2H), 2.46 (t, J = 7.3 Hz, 2H), 2.39 (s, 3H), 2.37 (s, 3H), 1.69 (pent, J = 7.3 Hz, 2H), 1.50−1.42 (m, 2H), 1.37−1.23 (m, 8H), 0.92−0.85 (m, 3H); 13 C NMR (125 MHz, CDCl3): δ = 160.3, 156.4, 156.1, 153.4, 144.9, 141.3, 140.0, 137.1, 133.0, 132.8, 130.1, 129.53, 129.48, 129.3, 128.5, 122.7, 92.2, 80.6, 32.0, 29.32, 29.28, 29.2, 28.5, 22.8, 21.63, 21.55, 19.6, 14.2; IR (ATR-CDCl3): ῡmax = 3056, 3030, 2920, 2852, 2230, 1610, 1578, 1563, 1491, 1458, 1356, 820, 802, 723, 533 cm−1; HRMS (EI): m/z: [M]+ Calcd for C30H30N4 446.2470; Found: 446.2451. 5,6-Bis-(4-fluoro-phenyl)-3-(6-phenylethynyl-pyridin-2-yl)[1,2,4]triazine (29). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6-bis(4-fluoro-phenyl)-[1,2,4]triazine and ethynylbenzene, Rf = 0.39, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.041 g, 79%; brown solid; melting point = 156.9–159.8 °C; 1H NMR (500 MHz, CDCl3): δ = 8.60 (dd, J = 8.0, 0.8 Hz, 1H), 7.93 (t, J = 7.8 Hz, 1H), 7.75−7.68 (m, 3H), 7.66−7.61 (m, 4H), 7.41−7.34 (m, 3H), 7.14−7.03 (m, 4H); 13C NMR (125 MHz, CDCl3): δ = 165.3 (J = 76.8 Hz), 163.2 (J = 72.9 Hz), 160.5, 155.5, 155.1, 153.2, 144.4, 137.4, 132.4 (J = 9.0 Hz), 132.2, 131.6 (J = 9.0 Hz), 131.5 (J = 2.7 Hz), 131.3 (J = 3.5 Hz), 129.20, 129.15, 128.5, 123.3, 116.2 (J = 11.7 Hz), 116.0 (J = 11.9 Hz), 90.2, 88.8; IR (ATR-CDCl3): ῡmax = 3063, 2237, 1601, 1579, 1564, 1492, 1357, 1229, 1160, 911, 841, 725, 686, 558, 536, 517 cm−1; HRMS (EI): m/z: [M]+ Calcd for C28H16F2N4 446.1343; Found 446.1358. 5,6-Bis-(4-fluoro-phenyl)-3-[6-(4-fluoro-phenylethynyl)pyridin-2-yl]-[1,2,4]triazine (30). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2yl)-5,6-bis-(4-fluoro-phenyl)-[1,2,4]triazine and 1-ethynyl-4fluoro-benzene, Rf = 0.48, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0443 g, 73%; beige solid; melting point = 180.6–183.5 °C; 1H NMR (500 MHz, C6D6): δ = 8.61 (d, J = 7.9 Hz, 1H), 7.39−7.34 (m, 2H), 7.31−7.29 (m, 3H), 7.21−7.12 (m, 3H), 6.70−6.64 (m, 2H), 6.62−6.52 (m, 4H); 13C NMR (125 MHz, C6D6): δ = 165.3 (J = 269.2 Hz), 163.9 (J = 356.1 Hz), 162.7 (J = 378.5 Hz), 161.1, 155.3, 154.7, 154.2, 144.6, 137.0, 134.4 (J = 33.4 Hz), 132.8 (J = 34.5 Hz), 132.0 (J = 34.3 Hz), 128.7, 128.4, 128.2, 123.5, 118.8 (J = 13.6 Hz), 116.0 (J = 11.1 Hz), 115.8 (J = 10.0 Hz), 115.6, 89.5, 89.1; IR (ATR-CDCl3): ῡmax = 3068, 2236, 1601, 1578, 1563, 1505, 1358, 1225, 1159, 832, 815, 536, 526 cm−1; HRMS (EI): m/z: [M]+ Calcd for C28H15F3N4 464.1249; Found 464.1235. 5,6-Bis-(4-fluoro-phenyl)-3-[6-(4-methoxy-phenyl-ethynyl)pyridin-2-yl]-[1,2,4]triazine (31). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2yl)-5,6-bis-(4-fluoro-phenyl)-[1,2,4]triazine and 1-ethynyl-4methoxybenzene, Rf = 0.42, 33% EtOAc:hexanes; neutral alumina; eluent, EtOAc/hexanes (gradient); isolated yield 0.0320 g, 52%; yellow solid; melting point = 185.1–186.5 °C; 1 H NMR (500 MHz, CDCl3): δ = 8.59 (d, J = 8.0 Hz, 1H), 7.92 (t, J = 7.8 Hz, 1H), 7.77−7.72 (m, 2H), 7.70 (d, J = 7.8


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Hz, 1H), 7.67−7.61 (m, 2H), 7.60−7.57 (m, 2H), 7.15−7.06 (m, 4H), 6.93−6.89 (m, 2H), 3.86 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 165.3 (J = 76.4 Hz), 163.3 (J = 73.6 Hz), 160.6, 160.5, 133.9, 132.5 (J = 8.9 Hz), 131.7 (J = 8.9 Hz), 131.6 (J = 3.1 Hz), 131.4 (J = 3.3 Hz), 129.0, 123.0, 116.3 (J = 48.8 Hz), 116.1 (J = 48.6 Hz), 114.4, 114.3, 90.7, 87.9, 55.5; IR (ATR-CDCl3): ῡmax = 3050, 2209, 1601, 1577, 1559, 1510, 1487, 1354, 1225, 1155, 834, 829, 810, 552, 547, 527 cm−1; HRMS (EI): m/z: [M]+ Calcd for C29H18F2N4O 476.1449; Found 476.1444. 3-[6-(4-Fluoro-phenylethynyl)-pyridin-2-yl]-5,6-bis-(4methoxy-phenyl)-[1,2,4]triazine (32). Prepared according to the general procedure discussed above with 3-(6-bromopyridin-2-yl)-5,6-bis-(4-methoxy-phenyl)-[1,2,4]triazine and 1-ethynyl-4-fluoro-benzene, Rf = 0.10, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0500 g, 79%; brown solid; melting point = 173.6–178.0 °C; 1H NMR (500 MHz, CDCl3): δ = 8.60 (dd, J = 7.9, 0.5 Hz, 1H), 7.92 (t, J = 7.9 Hz, 1H), 7.77−7.73 (m, 2H), 7.68 (dd, J = 7.9, 0.5 Hz, 1H), 7.66−7.61 (m, 4H), 7.10−7.05 (m, 2H), 6.95−6.91 (m, 2H), 6.90−6.87 (m, 2H), 3.86 (s, 3H), 3.85 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 164.1, 162.1, 161.6 (J = 121.0 Hz), 159.9, 155.9, 155.5, 153.8, 144.2, 137.3, 134.3, 134.2, 131.9, 131.1, 128.8, 128.1 (J = 2.9 Hz), 123.2, 118.7 (J = 3.6 Hz), 115.9 (J = 21.8 Hz), 114.4, 114.2, 88.9, 88.8, 55.54, 55.50; IR (ATR-CDCl3): ῡmax = 3070, 2235, 1607, 1577, 1566, 1508, 1490, 1355, 1252, 1177, 832, 527 cm−1; HRMS (EI): m/z: [M]+ Calcd for C30H21FN4O2 488.1649; Found 488.1635. 5,6-Bis-(4-fluoro-phenyl)-3-(6-oct-1-ynyl-pyridin-2-yl)[1,2,4]triazine (33). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6-bis(4-fluoro-phenyl)-[1,2,4]triazine and 1-octyne, Rf = 0.38, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0460 g, 78%; brown amorphous; 1H NMR (500 MHz, CDCl3): δ = 8.54 (d, J = 7.9 Hz, 1H), 7.82 (d, J = 7.9 Hz, 1H), 7.74−7.71 (m, 2H), 7.65−7.61 (m, 2H), 7.56 (d, J = 7.9 Hz, 1H), 7.14−7.09 (m, 2H), 7.08−7.05 (m, 2H), 2.47 (t, J = 7.2 Hz, 2H), 1.66 (pent, J = 7.4 Hz, 2H), 1.52−1.44 (m, 2H), 1.38−1.29 (m, 4H), 0.91 (t, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ = 165.3 (J = 75.7 Hz), 163.3 (J = 73.5 Hz), 160.6, 155.4, 155.2, 153.0, 145.0, 137.3, 132.4 (J = 9.1 Hz), 131.7 (J = 9.1 Hz), 131.6 (J = 2.7 Hz), 131.4 (J = 3.8 Hz), 128.9, 122.8, 116.2 (J = 15.2 Hz), 116.1 (J = 14.2 Hz), 116.0, 92.5, 80.5, 31.5, 28.9, 28.4, 22.7, 19.6, 14.2; IR (ATRCDCl3): ῡmax = 3066, 2958, 2924, 2856, 2227, 1597, 1580, 1509, 1491, 1356, 1225, 1157, 861, 844, 813, 805, 541 cm−1; HRMS (EI): m/z: [M]+ Calcd for C28H24F2N4 454.1969; Found 454.1954. 3-[6-(4-Fluoro-phenylethynyl)-pyridin-2-yl]-5,6-bis-(3methoxy-phenyl)-[1,2,4]triazine (34). Prepared according to the general procedure discussed above with 3-(6-bromopyridin-2-yl)-5,6-bis-(3-methoxy-phenyl)-[1,2,4]triazine and 1-ethynyl-4-fluoro-benzene, RF = 0.18, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0352 g, 55%; brown solid; melting point = 189.0–192.7 °C; 1H NMR (500 MHz, CDCl3): δ = 8.65 (d, J = 7.7 Hz, 1H), 7.94 (br-t, J = 7.7 Hz, 1H), 7.72−7.68 (m, 1H), 7.63 (dd, J = 8.5, 5.4 Hz, 2H), 7.31−7.24 (m, 5H), 7.15 (d, J = 7.4 Hz, 1H), 7.08 (br-t, J = 8.5 Hz, 2H), 7.01−6.97 (m, 2H), 3.77 (s, 3H), 3.73 (s, 3H); 13 C NMR (125 MHz, CDCl3): δ = 163.0 (J = 250.0 Hz), 160.5, 159.9, 159.8, 156.6, 156.3, 153.5, 144.2, 137.5, 136.9, 136.6, 134.3, 134.26, 129.8 (J = 2.8 Hz), 129.0, 123.4, 122.7, 122.3, 118.6 (J = 3.6 Hz), 117.2, 116.3, 115.9 (J = 22.3 Hz), 115.9, 115.1, 114.6, 89.2, 88.6, 55.54, 55.50; IR (ATR-CDCl3): ῡmax

= 3068, 2938, 2225, 1599, 1577, 1562, 1508, 1354, 1227, 1036, 839, 811, 708 cm−1; HRMS (EI): m/z: [M]+ Calcd for C30H21FN4O2 488.1649; Found 488.1640. 5,6-Bis-(3-methoxy-phenyl)-3-[6-(4-methoxy-phenylethynyl)-pyridin-2-yl]-[1,2,4]triazine (35). Prepared according to the general procedure discussed above with 3-(6-bromopyridin-2-yl)-5,6-bis-(3-methoxy-phenyl)-[1,2,4]triazine and 1-ethynyl-4-methoxy-benzene, Rf = 0.10, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0375 g, 58%; brown solid; melting point = 145.0–147.0 °C; 1H NMR (500 MHz, CDCl3): δ = 8.59 (d, J = 7.9 Hz, 1H), 7.91 (t, J = 7.9 Hz, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.61−7.55 (m, 3H), 7.31−7.23 (m, 5H), 7.14 (d, J = 7.7 Hz, 1H), 7.01−6.96 (m, 2H), 6.92−6.87 (m, 2H), 3.84 (s, 3H), 3.77 (s, 3H), 3.73 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 160.6, 160.4, 159.9, 159.8, 156.5, 156.3, 153.4, 144.7, 137.3, 137.0, 136.7, 133.9, 129.8, 129.75, 128.9, 123.0, 122.7, 122.3, 117.3, 116.3, 115.0, 114.5, 114.5X (overlaps with 114.5), 114.2, 90.5, 88.0, 55.50, 55.49, 55.48,; IR (ATR-CDCl3): ῡmax = 3068, 2938, 2834, 2220, 1603, 1576, 1563, 1510, 1352, 1228, 811, 805, 537, cm−1; HRMS (EI): m/z: [M]+ Calcd for C31H24N4O3 500.1848; Found: 500.1832. 1-(6-p-Tolylethynyl-pyridin-2-yl)-ethanone (36). Prepared according to the general procedure discussed above with substrate 1-(6-bromo-pyridin-2-yl)-ethanone and 1-ethynyl-4methylbenzene, Rf = 0.69, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0495 g, 84%; beige solid; melting point = 111.3–112.4 °C; 1H NMR (500 MHz, CDCl3): δ = 7.96 (br-d, J = 7.6 Hz, 1H), 7.81 (br-t, J = 7.6 Hz, 1H), 7.67 (br-d, J = 7.6 Hz, 1H), 7.52 (d, J = 7.8 Hz, 2H), 7.19 (d, J = 7.8 Hz, 2H), 2.77 (s, 3H), 2.39 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 200.0, 154.0, 143.2, 139.7, 137.1, 132.2, 130.6, 129.4, 120.6, 119.0, 90.3, 87.8, 26.0, 21.8; IR (ATRCDCl3): ῡmax = 2923, 2206, 1700, 1574, 1561, 1358, 815, 603 cm−1; HRMS (EI): m/z: [M]+ Calcd for C16H13NO 235.0997; Found: 235.0991. 6-p-Tolylethynyl-pyridine-2-carbaldehyde (37). Prepared according to the general procedure discussed above with 6bromo-pyridine-2-carbaldehyde and 1-ethynyl-4-methyl benzene, Rf = 0.68, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0333 g, 56%; brown solid; melting point = 116.7–120.3 °C; 1H NMR (500 MHz, CDCl3): δ = 10.10 (s, 1H), 7.91−7.85 (m, 2H), 7.73 (dd, J = 7.5, 1.5 Hz, 1H), 7.54−7.51 (m, 2H), 7.19 (d, J = 7.8 Hz, 2H), 2.39 (s, 3H); 13 C NMR (125 MHz, CDCl3): δ = 193.2, 153.1, 144.5, 140.0, 137.5, 132.3, 131.3, 129.4, 120.3, 118.7, 91.3, 87.2, 21.8; IR (ATR-CDCl3): ῡmax = 3064, 2833, 2210, 1712, 1701, 1577, 1510, 1212, 819, 801, 529 cm−1; HRMS (EI): m/z: [M]+ Calcd for C15H11NO 221.0841; Found 221.0834. 6-p-Tolylethynyl-pyridine-2-carbonitrile (38). Prepared according to the general procedure discussed above with 6bromo-pyridine-2-carbonitrile and 1-ethynyl-4-methylbenzene, Rf = 0.50, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0342 g, 58%; brown solid; melting point = 155.4–158.3 °C; 1H NMR (500 MHz, CDCl3): δ = 7.81 (t, J = 7.8 Hz, 1H), 7.69 (dd, J = 8.1, 0.9 Hz, 1H), 7.62 (dd, J = 7.8, 0.9 Hz, 1H), 7.51 (d, J = 8.1 Hz, 2H), 7.19 (d, J = 8.1 Hz, 2H), 2.39 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 145.5, 140.3, 137.4, 134.3, 132.3, 130.2, 128.5, 120.1, 118.3, 116.8, 92.4, 86.7, 21.8; IR (ATR-CDCl3): ῡmax = 3051, 2205, 1578, 1550, 1449, 988, 817, 534 cm−1; HRMS (EI): m/z: [M]+ Calcd for C15H10N2 218.0844; Found 218.0852.


9


2-(4-Bromo-phenylethynyl)-6-methyl-pyridine (39). Prepared according to the general procedure discussed above with 2-bromo-pyridine-3-carbaldehyde and 1-bromo-4-ethynylbenzene, Rf = 0.63, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0448 g, 57%; white solid; melting point = 107.9–111.4 °C; 1H NMR (500 MHz, CDCl3): δ = 7.58 (t, J = 8.1 Hz, 1H), 7.52−7.43 (m, 4H), 7.36 (d, J = 7.8 Hz, 1H), 7.13 (d, J = 7.8 Hz, 1H), 2.60 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 159.3, 142.5, 136.6, 133.6, 131.8, 124.6, 123.4, 123.0, 121.5, 90.0, 87.8, 24.8; IR (ATRCDCl3): ῡmax = 2920, 1576, 1563, 1485, 1444, 1394, 1009, 827, 816, 792, 521 cm−1; HRMS (EI): m/z: [M]+ Calcd for C14H10BrN 270.9997; Found 270.9987. 2-p-Tolylethynyl-pyridine-3-carbaldehyde (40). Prepared according to the general procedure discussed above with 2bromo-pyridine-3-carbaldehyde and 1-ethynyl-4methylbenzene, Rf = 0.43, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); isolated yield 0.0240 g, 40%; brown solid; melting point = 92.5–94.9 °C; 1H NMR (500 MHz, CDCl3): δ = 10.65 (s, 1H), 8.80 (dd, J = 4.7, 1.8 Hz, 1H), 8.19 (dd, J = 8.0, 1.8 Hz, 1H), 7.53 (d, J = 8.1 Hz, 2H), 7.38 (dd, J = 8.0, 4.7 Hz, 1H0, 7.20 (d, J = 8.1 Hz, 2H), 2.39 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 191.0, 154.6, 146.4, 140.5, 134.9, 132.2, 131.8, 129.5, 123.1, 118.3, 96.7, 84.4, 21.8; IR (ATR-CDCl3): ῡmax = 3040, 2214, 1689, 1574, 1558, 1426, 1256, 810, 790, 758, 516 cm−1; HRMS (EI): m/z: [M]+ Calcd for C15H11NO 221.0841; Found 221.0840. 1-[6-(4-Bromo-phenylethynyl)-pyridin-2-yl]-ethanone (41). Prepared according to the general procedure discussed above with 1-(6-bromo-pyridin-2-yl)-ethanone and 1-bromo-4ethynyl-benzene: Rf = 0.70, 33% EtOAc:hexanes; neutral alumina; eluent, EtOAc/hexanes (gradient); isolated yield 0.0300 g, 40%; white solid; melting point = 112.4–114.3 °C; 1 H NMR (500 MHz, CDCl3): δ = 7.99 (d, J = 7.8 Hz, 1H), 7.83 (t, J = 7.8 Hz, 1H), 7.68 (d, J = 7.8 Hz, 1H), 7.55−7.51 (m, 2H), 7.50−7.45 (m, 2H), 2.77 (s, 3H); 13C NMR (125 MHz, CDCl3): δ = 199.8, 154.0, 142.7, 137.2, 133.6, 131.9, 130.7, 123.8, 121.1, 120.9, 89.3, 88.7, 26.0; IR (ATR-CDCl3): ῡmax = 2206, 1694, 1572, 1557, 1482, 1445, 823, 812, 608, 514, cm−1; HRMS (EI): m/z: [M]+ Calcd for C15H10BrNO 298.9946; Found 298.9941. 3-{6-[4-(3,3-Dimethyl-butyl)-phenylethynyl]-pyridin-2-yl}5,6-diphenyl-[1,2,4]triazine (42). An 8 mL reaction vial equipped with a magnetic stirring bar at ambient temperature was charged 9 (0.050 g, 0.102 mmol, 1.00 equiv), Pd(OAc)2 (0.001 g, 0.005 mmol, 1.00 equiv), RuPhos (0.005 g, 0.001 mmol, 1.00 equiv), and Cs2CO3 (0.098 g, 0.300 mmol, 3.00 equiv). The mixture was slurried in toluene:H2O (4:1) (0.2 M) and heated to 115 °C for 16 h. Subsequent the crude material was absorbed on normal phase silica gel and purified using automated flash column chromatography to afford the title compound (0.0134 g, 27%): Rf = 0.45, 33% EtOAc:hexanes; eluent, EtOAc/hexanes (gradient); yellow solid; melting point = 199.0–200.4 °C; 1H NMR (500 MHz, CDCl3): δ = 8.61 (dd, J = 8.1, 0.9 Hz, 1H), 7.92 (t, J = 7.8 Hz, 1H), 7.74−7.69 (m, 3H), 7.66−7.63 (m, 2H), 7.57−7.54 (m, 2H), 7.48−7.35 (m, 6H), 7.21−7.18 (m, 2H), 2.62−2.57 (m, 2H), 1.54−1.48 (m, 2H), 0.97 (s, 9H); 13C NMR (125 MHz, CDCl3): δ = 160.6, 156.6, 156.5, 153.5, 145.1, 144.6, 137.3, 135.7, 135.4, 132.3, 130.9, 130.2, 129.9, 129.7, 129.0, 128.8, 128.7, 128.6, 123.1, 119.5, 90.6, 88.4, 46.2, 31.5, 30.7, 29.5; IR (ATR-CDCl3): ῡmax = 3057, 2952, 2869, 2204, 1577, 1564, 1492, 1358, 812, 771, 693 cm−1; HRMS (EI): m/z: [M]+ Calcd for C34H30N4 494.2470; Found 494.2485.

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ASSOCIATED CONTENT Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: Copies of 1H and 13C NMR spectra as well as purification chromatograms for all compounds. (PDF) AUTHOR INFORMATION Corresponding Author * Email: [email protected]

Notes The authors declare no competing interest.

ACKNOWLEDGMENTS Financial support for this work was provided by an award from the U.S. Department of Energy, Basic Energy Sciences, Separations Program Award: DE-SC0018033. An award from the National Science Foundation Major Research Instrumentation Program (1531870) is gratefully acknowledged for the acquisition of the University’s 500 MHz multinuclear NMR spectrometer with broad-band N2 cryoprobe. The authors would like to thank Dr. Qiaoli Liang, The University of Alabama, for acquisition of HRMS data. Jacob W. Cleveland and Ai Lin Chin are acknowledged for the preparation of the requisite scaffolds leading to the production of 27−31 and 33. REFERENCES (1) (a) Chinchilla, R.; Nájera, C. Recent Advances in Sonogashira Reactions. Chem. Soc. Rev. 2011, 40, 5084–5121. (b) Li, P.; Wang, L.; Wang, M.; You, F. Gold (I) Iodide Catalyzed Sonogashira Reactions. Eur. J. Org. Chem. 2008, 14, 5946–5951. (2) Wang, D.; Gao, S. Sonogashira Coupling in Natural Prodcut Synthesis. Org. Chem. Front. 2014, 1, 556–566. (3) For a recent review see: (a) Chinchilla, R.; Nájera, C. The Sonogashira Reaction: A Booming Methodology in Synthetic Organic Chemistry. Chem. Rev. 2007, 107, 874–922. For examples incorporating 2-bromopyridines as substrates see: (b) Hebenbrock, M.; Stegemann, L.; Koesters, J.; Doltsinis, N. L.; Mueller, J.; Strassert, C. A. Phosphorescent Pt(II) Complexes Bearing a Monoanionic C^N^N Luminophore and Tunable Ancillary Ligands. Dalton Trans. 2017, 46, 3160–3169. (c) Alagille, D.; Baldwin, R. M.; Wroblewski, J. T.; Grajkowska, E.; Tamagnan, G. E. Functionalization at Position 3 of the Phenyl Ring of the Potent mGluR5 Noncompetitive Antagonists MPEP. Biorg. Med. Chem. Lett. 2005, 15, 945–949. (d) Saleh, S.; Picquet, M.; Meunier, P.; Hierso, J.-C. A Straightforward Copper-Free Palladium Methodology for the Selective Alkynylation of a Wide Variety of S-, O-, and N-based Mono- and Diheterocyclic Bromides and Chlorides. Tetrahedron 2009, 65, 7146–7150. (e) Liu, M.; Ye, M.; Xue, Y.; Yin, G.; Wang, D.; Huang, J. Sonogashira Coupling Catalyzed by the Cu(Xantphos)I-Pd(OAc)2 System. Tetrahedron Lett. 2016, 57, 3137–3139. (f) Shirakawa, E.; Kitabata, T.; Otsuka, H.; Tsuchimoto, T. A Simple Catalyst System for the Palladium-catalyzed Coupling of Aryl Halides with Terminal Alkynes. Tetrahedron 2005, 61, 9878–9885. For examples describing other heterocycles see: (g) Galenko, A. V.; Shakirova, F. M.; Galenko, E. E.; Novikov, M. S.; Khlebnikov, A. F. Fe(II)/Au(I) Relay Catalyzed Propargylisoxazole to Pyridine Isomerization: Access to 6-Halonicotinates. J. Org.


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