Synthetic Access to Functionalized Dipolarophiles of Lewis Basic

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Article Cite This: J. Org. Chem. 2018, 83, 10261−10271

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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, Tennessee 38505-0001, United States

J. Org. Chem. 2018.83:10261-10271. Downloaded from pubs.acs.org by KAOHSIUNG MEDICAL UNIV on 09/08/18. For personal use only.

S Supporting Information *

ABSTRACT: Soft Lewis basic complexants that facilitate selective removal of discrete ions resident in spent nuclear fuel can decrease repository volume and radiotoxicity and are of significant interest. Optimization of chelation efficacy is predicated on modular access to synthons to rapidly evaluate structure−activity relationships. The following work 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 41 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.

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INTRODUCTION

The Sonogashira coupling reaction1 has been widely employed in contemporary organic synthesis toward 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 liquid−liquid separations processes in the areas of spent nuclear fuel (SNF)5 remediation and recovery of critical materials6 necessitates the continuous development of synthetic methods to expand the competency, selectivity, and efficiency of complexant scaffolds beyond simple functional group interconversions toward 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-1,2,4triazine 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 separations,7 including 3-(6-bromo-pyridin-2-yl)-5,6-diaryl[1,2,4]triazines for utilization in Suzuki−Miyaura crosscoupling8 as well as Pd-catalyzed diamination.9 Current focus areas include the development of synthons for dipolar cycloaddition reactions, eventually leading to the formation of unsymmetric complexant scaffolds. The alkynyl moiety can be a participant in the Huisgen cycloaddition,10 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). © 2018 American Chemical Society

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-(6-bromo-pyridin-2-yl)-5,6-diphenyl-[1,2,4]triazine,13 1ethynyl-4-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 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, 2methyl THF, 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 1-ethynyl-4Received: June 7, 2018 Published: July 17, 2018 10261

DOI: 10.1021/acs.joc.8b01446 J. Org. Chem. 2018, 83, 10261−10271

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The Journal of Organic Chemistry Table 1. Sonogashira Coupling Method Developmenta

entry

catalyst

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

ligand

CyPF-tBu RuPhos

base

additive

solvent

temp (°C)

conv (%)b

TEA TEA TEA TEA TEA TEA TEA TEA TEA TEA TEA DBU

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

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

TEA CuI

a

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. bConversion determined from integration of select resonances in the 1H NMR spectrum without internal standard. c1.05 equiv of 1ethynyl-4-methylbenzene used. d1.50 equiv of 4-methylphenylacetylene used. eIsolated, purified yield. CyPF-tBu = 1-dicyclohexylphosphino-2-di-tbutylphosphinoethylferrocene

methylbenzene, we set out to evaluate the alkyne scope with 1 (Table 2). Table 2 describes the utility of various alkynes with different electronic properties and functional groups toward the expansion of synthetic derivatives of 1. Aliphatic alkynes such as octyne and decyne (entries 1 and 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 substituents including nitrile and bromo- (entries 7−8) proved competent nucleophiles in this transformation.17 Constitutional isomers of 1-ethynyl-4-methylbenzene , 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 tert-butyldimethylsilylacetylene (13) derivatives which provide access to synthetic equivalents to direct coupling with acetylene.18 More electron-rich amines in the case of BOC-protected propargylamine (entry 14) provided 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-2yn-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 toward more efficient systems, it is often desirable to enhance the nonpolarity of resident Lewis basic complexant scaffolds. Pursuant to the aforementioned, we investigated 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-(6bromo-pyridin-2-yl)-5,6-bis(4-fluoro-phenyl)-[1,2,4]triazine, have previously been disclosed by us.19 Thus, 3-(6-bromopyridin-2-yl)-5,5,8,8-tetra-methyl-5,6,7,8-tetrahydro-benzo[1,2,4]triazine (entries 1 and 2), 3-(6-bromo-pyridin-2-yl)-5,6bis-[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′-dimethoxy-1,2,4triazinyl moiety have demonstrated efficacy in the separation of the minor actinide Am3+ from the neutron-poisoning lanthanides20 which preclude incorporation into advanced fuels for nuclear reactors through the partition and trans10262

DOI: 10.1021/acs.joc.8b01446 J. Org. Chem. 2018, 83, 10261−10271

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The Journal of Organic Chemistry Table 2. Alkyne Reaction Scopea

Table 3. Diversified Complexant Scaffoldsa

a

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 two experiments.

mutation strategy.21 Entries 8 and 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. Due to interest 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 -donating functionality was 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 oligomerization 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-

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 two experiments.

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. 10263

DOI: 10.1021/acs.joc.8b01446 J. Org. Chem. 2018, 83, 10261−10271

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The Journal of Organic Chemistry Table 4. Diversified Ar Complexant Scaffoldsa

A 10-fold 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 Scheme 1. Tenfold Scale-Up Experiment

Scheme 2. Suzuki−Miyaura Cross-Coupling

prepared synthons was also attempted (Scheme 2). Suzuki− Miyaura 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.

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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 highlighted the selectivity of oxidative addition at the C−Br bond of the pyridinyl scaffold preferentially to the C−Br 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 toward these synthetic goals are ongoing in our laboratory and will be reported in due course.

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 two experiments.

Table 5. Pyridine Substrate Scopea,b

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EXPERIMENTAL SECTION

General Methods. All reagents were purchased from United States 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 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 were 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

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.

Products 8, 39, and 41 afford strategic opportunities for additional functionalization. 10264

DOI: 10.1021/acs.joc.8b01446 J. Org. Chem. 2018, 83, 10261−10271

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The Journal of Organic Chemistry

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-(6bromo-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%; off-white 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 (ATR-CDCl3): v̅max = 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): v̅max = 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): v̅max = 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)-5,6-diphenyl-[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): v̅max = 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,

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 toward the preparation of 3-(6bromo-pyridin-2-yl)-5,6-diphenyl-[1,2,4]triazine used for the construction of 2−16, please see ref 8a. Synthetic procedures for the starting materials required for 17, 18, 27, and 28 also appear in ref 8a. For the bis-3,3′-dimethylbutyl and bis-butyl functionalized scaffolds used with 19−26, as well as scaffolds used to afford 32, 34, and 35, please see ref 15. Preparation of Starting Material for Products 29−31 and 33. 3-(6-Bromopyridin-2-yl)-5,6-bis(4-fluoro-phenyl)-[1,2,4]triazine. For a general procedure for the formation of 6-bromopyridinyl-2-yl hydrazonamide please refer to ref 8a. A 25 mL roundbottom 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 h. Afterward, 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); 13C 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): v̅max = 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), and 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 residual solvent. The resulting dark-brown residue was partitioned between EtOAc (5 mL) and water (2 mL) to remove TEA. 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 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-4methyl-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 (ATR-CDCl3): v̅max = 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. 10265

DOI: 10.1021/acs.joc.8b01446 J. Org. Chem. 2018, 83, 10261−10271

Article

The Journal of Organic Chemistry 124.0, 118.5, 112.5, 92.7, 87.9; IR (ATR-CDCl3): v̅max = 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)-5,6-diphenyl-[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 (br-d, 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): v̅max = 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]-5,6-diphenyl[1,2,4]triazine (9). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6-diphenyl-[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, 123.1, 119.4, 90.5, 88.5, 35.0, 31.3; IR (ATR-CDCl3): v̅max = 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 1ethynyl-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): v̅max = 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)-5,6-diphenyl-[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): v̅max = 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-2-yl}[1,2,4]triazine (12). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6-diphenyl-[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 (ATR-CDCl3): v̅max = 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-2-yl)-5,6-diphenyl-[1,2,4]triazine and tert-butylethynyldimethyl-silane, 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): v̅max = 3052, 2926, 2854, 1576, 1566, 1409, 1357, 916, 843, 814, 772, 699, 533 cm−1; 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]-prop-2-ynyl}carbamic Acid tert-Butyl Ester (14). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6diphenyl-[1,2,4]triazine and prop-2-ynyl-carbamic 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): v̅max = 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)-5,6-diphenyl-[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): v̅max = 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]-1-phenylprop-2-yn-1-ol (16). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6-diphenyl-[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); 13 C 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): v̅max = 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]-5,5,8,8-tetramethyl5,6,7,8-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-tetra-hydro-benzo[1,2,4]triazine and 1ethynyl-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, 10266

DOI: 10.1021/acs.joc.8b01446 J. Org. Chem. 2018, 83, 10261−10271

Article

The Journal of Organic Chemistry 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, 33.5, 29.8, 29.3; IR (ATR-CDCl3): v̅max = 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]-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-benzo[1,2,4]triazine (18). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2yl)-5,5,8,8-tetramethyl-5,6,7,8-tetra-hydro-benzo[1,2,4]triazine and 1ethynyl-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 (ATR-CDCl3): v̅max = 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-(6-bromo-pyridin-2-yl)-5,6bis-[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): v̅max = 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-2yl]-[1,2,4]triazine (20). 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-ethynyl-4-fluoro-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 (ATR-CDCl3): v̅max = 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-(6-bromo-pyridin-2-yl)-5,6bis-[4-(3,3-dimethyl-butyl)-phenyl]-[1,2,4]triazine and 1-tert-butyl-4ethynyl-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): v̅max = 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-2-yl)[1,2,4]triazine (22). 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 ethynylcyclohexane, R f = 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): v̅max = 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-(3,3-dimethylbutyl)-phenyl]-[1,2,4]triazine (23). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-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): v̅max = 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-bromo-pyridin-2-yl)-5,6-bis(4butyl-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, 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): v̅max = 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-bromopyridin-2-yl)-5,6-bis-[4-(3,3′-dimethyl-butyl)-phenyl]-[1,2,4]triazine and tert-butyl-ethynyldimethyl-silane, 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, 10267

DOI: 10.1021/acs.joc.8b01446 J. Org. Chem. 2018, 83, 10261−10271

Article

The Journal of Organic Chemistry

5,6-Bis(4-fluoro-phenyl)-3-[6-(4-fluoro-phenylethynyl)-pyridin-2yl]-[1,2,4]triazine (30). 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-ethynyl-4-fluoro-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): v̅max = 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-2-yl)-5,6-bis(4fluoro-phenyl)-[1,2,4]triazine and 1-ethynyl-4-methoxybenzene, 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; 1H 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 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): v̅max = 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(4-methoxyphenyl)-[1,2,4]triazine (32). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6-bis(4methoxy-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): v̅max = 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; 1 H 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): v̅max = 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(3-methoxyphenyl)-[1,2,4]triazine (34). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6-bis(3-

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): v̅max = 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): v̅max = 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 1ethynyl-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): v̅max = 3031, 2920, 2856, 2230, 1608, 1578, 1565, 1488, 1357, 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); 13C 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 (ATRCDCl3): v̅max = 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); 13 C 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): v̅max = 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. 10268

DOI: 10.1021/acs.joc.8b01446 J. Org. Chem. 2018, 83, 10261−10271

Article

The Journal of Organic Chemistry

pyridine-3-carbaldehyde and 1-bromo-4-ethynyl-benzene, 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); 13 C 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 (ATR-CDCl3): v̅max = 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 2-bromo-pyridine3-carbaldehyde and 1-ethynyl-4-methylbenzene, 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): v̅max = 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-(6bromo-pyridin-2-yl)-ethanone and 1-bromo-4-ethynyl-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; 1H 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): v̅max = 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). In 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. Subsequently, 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): v̅max = 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.

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); 13C 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): v̅max = 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-phenyl-ethynyl)pyridin-2-yl]-[1,2,4]triazine (35). Prepared according to the general procedure discussed above with 3-(6-bromo-pyridin-2-yl)-5,6-bis(3methoxy-phenyl)-[1,2,4]triazine and 1-ethynyl-4-methoxy-benzene, Rf = 0.10, 33% EtOAc:hex-anes; 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): v̅max = 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-(6bromo-pyridin-2-yl)-ethanone and 1-ethynyl-4-methylbenzene, 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); 13 C 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): v̅max = 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 6-bromo-pyridine2-carbaldehyde and 1-ethynyl-4-methylbenzene, 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); 13C 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): v̅max = 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 6-bromo-pyridine-2carbonitrile and 1-ethynyl-4-methyl-benzene, 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): v̅max = 3051, 2205, 1578, 1550, 1449, 988, 817, 534 cm−1; HRMS (EI): m/z: [M]+ Calcd for C15H10N2 218.0844; Found 218.0852. 2-(4-Bromo-phenylethynyl)-6-methyl-pyridine (39). Prepared according to the general procedure discussed above with 2-bromo-

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DOI: 10.1021/acs.joc.8b01446 J. Org. Chem. 2018, 83, 10261−10271

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Sauradip Chaudhuri: 0000-0003-3578-5293 Jesse D. Carrick: 0000-0002-0663-2426 Notes

The authors declare no competing financial interest.

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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.

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DEDICATION The authors dedicate this work in memory of TTU Professor Emeritus Scott H. Northrup (1951−2018). REFERENCES

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