A Sequentially Copper-Catalyzed Alkyne Carboxylation–Propargylation–Azide Cycloaddition (CuACPAC) Synthesis of 1,2,3-Triazolylmethyl Arylpropiolates

Dedicated to Prof. Dr. Günter Szeimies on the occasion of his 80^th birthday.

Abstract

Concatenation of copper-catalyzed alkyne carboxylation–alkylation and copper-catalyzed alkyne–azide cycloaddition gives a novel sequentially copper-catalyzed alkyne carboxylation–propargylation–azide cycloaddition (CuACPAC) process furnishing 1,2,3-triazolylmethyl arylpropiolates via a consecutive four-component synthesis. The CuACPAC can be expanded to a five-component synthesis of 1,2,3-triazolylmethyl 3-amino arylacrylates by a concluding Michael addition in the same pot.

Copper-catalyzed carbon–heteroatom and carbon–carbon bond-forming reactions have experienced an impressive renaissance in the past decade, inevitably in competition to well-established palladium-catalyzed methodologies.[1] In particular, the copper-catalyzed alkyne–azide cycloaddition (CuAAC)[2] has received utmost attention and application in rapid regioselective syntheses of 1,2,3-triazoles in all fields of molecular sciences. The highly modular nature makes CuAAC particularly attractive for proposing new transition-metal-catalyzed multicomponent reactions (MCR)[3] and an impressive new branch of MCR is currently rapidly evolving.[4] Multicomponent reactions represent a reactivity-based concept,[5] where the reaction sequences are performed as domino, sequential, or consecutive processes in a one-pot fashion, in a strict sense all transformations are carried out in the same reaction vessel, excluding intermediate workup, filtration of byproducts, or solvent exchange by evaporation. The advantages of one-pot methodologies over traditional multistep synthesis lie in the economy and ecological efficacy that can be achieved.[6] In addition, the modular aspect of one-pot reactions also makes them applicable to combinatorial and parallel synthesis[7] for rapid lead identification and exploration of structural space in the search for new drug candidates. Our approach to novel consecutive and sequential MCR commences with alkyne activation by transition-metal-catalyzed C–C bond formation.[8]

Recently, we reported consecutive three-component syntheses of 2,6-disubstituted pyrimid-4(3H)-ones and 1,5-disubstituted 3-hydroxy pyrazoles initiated by copper-catalyzed carboxylation of terminal alkynes.[9] We developed direct carboxylations of alkynes with carbon dioxide furnishing propiolic acids[10] [11] to give methyl propiolates that, in turn, acting as three-carbon building blocks containing a Michael system, were susceptible to generate the pyrimid-4(3H)-ones and 3-hydroxy pyrazoles efficiently by Michael addition cyclocondensation with amidinium salts and hydrazines, respectively.

Herein, we communicate a copper-catalyzed carboxylative alkynylation to generate propioliates that can be directly transformed into 1,2,3-triazolyl methyl propiolates by CuAAC in a one-pot fashion. This consecutive four-component reaction can be considered as a sequential copper-catalyzed process[12] that can be further extended to a consecutive five-component reaction by a concluding Michael addition with secondary amines furnishing 1,2,3-triazolyl methyl 3-amino acrylates.

Propargylation–CuAAC sequences have been only rarely reported to date. Furanonyl-substituted amino acid ligated 1,2,3-triazolylmethyl esters may be accessed either in a three- or four-component fashion by propargylation of the carboxylate followed by CuAAC in a consecutive one-pot reaction.[13] Propargylation of benzanellated thiopyrimidones also sets the stage for CuAAC in the consecutive three-component synthesis of 1,2,3-triazol-4-yl-methylthio-3-arylquinazolin-4(3H)-ones.[14] In a similar fashion hydroxyl xanthen-11-one derivatives can be transformed by phenolate propargylation and subsequent CuAAC into a domino three-component reaction to give xanthene–triazole–quinoline conjugates.[15] Propargyl amides as transient intermediates are formed in consecutive four-component syntheses of indole-3-glyoxyl-methyl 1,2,3-triazoles by glyoxylation of propargylamine,[16] or in a chemoenzymatic three-component synthesis of amide methyl-substituted 1,2,3-triazoles,[17] initiated by CAL-B-catalyzed aminolysis of methyl esters with propargylamine. In both cases the concluding CuAAC furnishes the target structures in a one-pot fashion.

Prior to developing the one-pot synthesis of 1,2,3-triazolyl methyl propiolates by sequential copper(I)-catalyzed carboxylative alkynylation–CuAAC of terminal alkynes, we first set out to identify the optimal conditions for the CuAAC step. As a model reaction, propargyl 3-phenylpropiolate (3a),[18] synthesized by copper-catalyzed carboxylation of phenylacetylene (1a) followed by propargylation with propargyl bromide (2) according to our previously published protocol,[9] was reacted with benzyl azide (4a) to give (1-benzyl-1H-1,2,3-triazol-4-yl)methyl 3-phenylpropiolate (5a, Scheme [1]).

For compatibility with the preceding alkyne carboxylation, DMF was chosen as solvent and 5 mol% of Cu(PPh₃)₂NO₃ was employed as the catalyst. While a reaction temperature of 80 °C gave complete conversion of 3a within one hour giving rise to the desired CuAAC product 5a in 58% yield, the isolation of a 30% yield of 1-benzyl-4-phenyltriazole indicated that 3a obviously underwent decarboxylative decomposition under these conditions.

However, lowering the temperature to 50 °C gave full conversion of 3a after 90 minutes and furnished the triazole 5a in 87% yield after chromatography. The byproduct 1-benzyl-4-phenyltriazole was not detected. Lowering catalyst loading to 2.5 mol% revealed that the conversion at 50 °C was not complete after four hours. With the optimal catalyst loading of 5 mol%, a reaction temperature of 50 °C, and a reaction time of 90 minutes the stage was set for concatenating the alkyne–carboxylation and the CuAAC to a novel sequentially copper-catalyzed consecutive four-component process.

After performing the copper(I)-catalyzed carboxylation of terminal alkynes 1 under our previously published conditions,[9] propargyl bromide (2) was added to the reaction mixture and, after 45 minutes, the resulting propargyl propiolate was directly treated with alkyl or aryl azides 4 to furnish 1,2,3-triazolyl methyl propiolates 5 in moderate to good yields (Scheme [2]).[19] The title compounds 5 are thus prepared in a one-pot reaction, forming four new bonds with a yield per bond-forming step of 73–89%.

1,2,3-Triazolyl methyl propiolates 5 still contain a propiolate functionality that is well suited for a five-component reaction. Therefore, a concluding Michael addition with secondary amines was illustrated in five examples. Upon sequential copper-catalyzed alkyne carboxylation–propargylation–azide cycloaddition (CuACPAC) of phenylacetylene (1a) or p-tolylacetylene (1b) and benzyl azide (4a) the subsequent concluding Michael addition of secondary amines 6 furnished triazolylmethyl aminoacrylates 7 in good yields (Scheme [3]).[20]

The occurrence of single sets of carbon resonances excludes the presence of E/Z-isomer mixtures and the E-configuration was unambiguously established by 2D NOESY spectra of the triazolylmethyl aminoacrylates 7 showing that the acrylate α-protons only gave cross peaks to the α-amino methylene and methyl protons but not to the 3-aryl ortho protons. In addition the assigned E configuration resulting from a syn addition of the cyclic secondary amines 6 is in excellent agreement with preparative and kinetic findings for amine additions to alkyl 3-aryl propiolates.[21]

Taking into account that six new bonds are being formed in this consecutive one-pot process a yield per bond forming step of 87–91% can be estimated. In this preliminary study heteroalicyclic secondary amines clearly react faster than acyclic derivatives.

In conclusion, both the four-component one-pot synthesis of 1,2,3-triazolylmethyl propiolates 5 and the five-component one-pot synthesis of triazolylmethylamino acrylates 7 are novel representatives of sequentially copper-catalyzed consecutive multicomponent processes that proceed under mild reaction conditions with a reasonably broad scope of two and three points of diversity. Further studies directed to explore further sequentially copper-catalyzed processes and their application for accessing functional chromophores are currently under way.

Acknowledgment

The authors cordially thank the Fonds der Chemischen Industrie for financial support.

• References and Notes

• 1a Kunz K, Scholz U, Ganzer D. Synlett 2003; 2428
  Thieme Connect
• 1b Monnier F, Taillefer M. Angew. Chem. Int. Ed. 2009; 48: 6954
  Search in Google Scholar
• 1c Beletskaya IP, Ananikov VP. Chem. Rev. 2011; 111: 1596
  CrossrefPubMedSearch in Google Scholar
• 1d Rao H, Fu H. Synlett 2011; 745
  Thieme Connect
• 1e Liu Y, Wan J.-P. Chem. Asian J. 2012; 7: 1488
  CrossrefPubMedSearch in Google Scholar
• 1f Liu T, Fu H. Synthesis 2012; 44: 2805
  Thieme ConnectSearch in Google Scholar

For leading reviews, see:
• 2a Bock VD, Hiemstra H, van Maarseveen JH. Eur. J. Org. Chem. 2006; 51
• 2b Meldal M, Tornoe CW. Chem. Rev. 2008; 108: 2952
  Search in Google Scholar
• 2c Hänni KD, Leigh DA. Chem. Soc. Rev. 2010; 39: 1240
  CrossrefSearch in Google Scholar
• 2d Kappe CO, Van der Eycken E. Chem. Soc. Rev. 2010; 39: 1280
  CrossrefPubMedSearch in Google Scholar
• 2e Hein JE, Fokin VV. Chem. Soc. Rev. 2010; 39: 1302
  Search in Google Scholar
• 2f Liang L, Astruc D. Coord. Chem. Rev. 2011; 255: 2933
  CrossrefSearch in Google Scholar
• 3a Balme G, Bossharth E, Monteiro N. Eur. J. Org. Chem. 2003; 4101
• 3b D’Souza DM, Müller TJ. J. Chem. Soc. Rev. 2007; 36: 1095
  CrossrefPubMedSearch in Google Scholar
• 3c Kirsch SF. Synthesis 2008; 3183
  Thieme Connect
• 3d Arndtsen BA. Chem. Eur. J. 2009; 15: 302
  CrossrefSearch in Google Scholar
• 3e Abbiati G, Rossi E. Beilstein J. Org. Chem. 2014; 10: 481
  CrossrefPubMedSearch in Google Scholar
• 4 For the first review on multicomponent syntheses based upon CuAAC, see: Hassan S, Müller TJ. J. Adv. Synth. Catal. 2015; 357: 617
  CrossrefSearch in Google Scholar
• 5 Müller TJ. J. Multicomponent Reactions 1. General Discussion and Reactions Involving a Carbonyl Compound as Electrophilic Component. In Science of Synthesis. Vol. 1. Müller TJ. J. Thieme; Stuttgart: 2014: 5
  Search in Google Scholar
• 6 Tietze LF. Chem. Rev. 1996; 96: 115
  CrossrefPubMedSearch in Google Scholar

For seminal reviews, see:
• 7a Ugi I, Dömling A, Werner B. J. Heterocycl. Chem. 2000; 37: 647
  CrossrefSearch in Google Scholar
• 7b Weber L, Illgen K, Almstetter M. Synlett 1999; 366
  Thieme Connect

For reviews on alkynes as reactive modules in sequential syntheses of heterocycles, see:
• 8a Cacchi S. J. Organomet. Chem. 1999; 576: 42
  Search in Google Scholar
• 8b Willy B, Müller TJ. J. Curr. Org. Chem. 2009; 13: 1777
  CrossrefSearch in Google Scholar
• 8c Müller TJ. J. Top. Heterocycl. Chem. 2010; 25: 25
  Search in Google Scholar
• 8d Müller TJ. J. Synthesis 2012; 44: 159
  Thieme ConnectSearch in Google Scholar
• 8e Abbiati G, Arcadi A, Marinelli F, Rossi E. Synthesis 2014; 46: 687
  Thieme ConnectSearch in Google Scholar
• 8f Yamamoto Y. Chem. Soc. Rev. 2014; 43: 1575
  Search in Google Scholar
• 9 Schreiner E, Braun S, Kwasnitschka C, Frank W, Müller TJ. J. Adv. Synth. Catal. 2014; 356: 3135
  CrossrefSearch in Google Scholar
• 10 Fukue Y, Oi S, Inoue Y. J. Chem. Soc., Chem. Commun. 1994; 2091
• 11a Yu D, Zhang Y. Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 20184
  CrossrefPubMedSearch in Google Scholar
• 11b Gooßen LJ, Rodríguez N, Manjolinho F, Lange PP. Adv. Synth. Catal. 2010; 352: 2913
  CrossrefSearch in Google Scholar
• 11c Inamoto K, Asano N, Kobayashi K, Yonemoto M, Kondo Y. Org. Biomol. Chem. 2012; 10: 1514
  CrossrefSearch in Google Scholar
• 11d Zhang W.-Z, Li W.-J, Zhang X, Zhou H, Lu X.-B. Org. Lett. 2010; 12: 4748
  Search in Google Scholar
• 11e Manjolinho F, Arndt M, Gooßen K, Gooßen LJ. ACS Catal. 2012; 2: 2014
  CrossrefSearch in Google Scholar
• 11f Yu B, Diao Z.-F, Guo C.-X, Zhong C.-L, He L.-N, Zhao Y.-N, Song Q.-W, Liu A.-H, Wang J.-Q. Green Chem. 2013; 15: 2401
  CrossrefSearch in Google Scholar

For reviews on tandem and sequential catalysis, see:
• 12a Wasilke J.-C, Obrey SJ, Baker RT, Bazan GC. Chem. Rev. 2005; 105: 1001
  CrossrefPubMedSearch in Google Scholar
• 12b Ajamian A, Gleason JL. Angew. Chem. Int. Ed. 2004; 43: 3754
  CrossrefSearch in Google Scholar
• 12c Fogg DE, de Santos EN. Coord. Chem. Rev. 2004; 248: 2365
  CrossrefSearch in Google Scholar
• 13 Tan Y.-H, Li J.-X, Xue F.-L, Qi J, Wang Z.-Y. Tetrahedron 2012; 68: 2827
  CrossrefSearch in Google Scholar
• 14 Koohshari M, Dabiri M, Salehi P, Bahramnejad M. Synth. Commun. 2012; 42: 2415
  CrossrefSearch in Google Scholar
• 15 Singh H, Nand B, Sindhu J, Khurana JM, Sharmab C, Aneja KR. J. Braz. Chem. Soc. 2014; 25: 1178
  Search in Google Scholar
• 16 Stefani HA, Vasconcelos SN. S, Souza FB, Manarin F, Zukerman-Schpector J. Tetrahedron Lett. 2013; 54: 5821
  CrossrefSearch in Google Scholar
• 17 Hassan S, Tschersich R, Müller TJ. J. Tetrahedron Lett. 2013; 54: 4641
  CrossrefSearch in Google Scholar
• 18 Witulski B, Zimmermann A. Synlett 2002; 1855
  Thieme Connect
• 19 Typical Procedure for the Synthesis of Compound 5a In a flame-dried Schlenk tube under nitrogen, Cs₂CO₃ (889 mg, 2.73 mmol), Cu(PPh₃)₂NO₃ (63 mg, 10 μmol), and phenanthroline (18 mg, 10 μmol) were dissolved in dry DMF (4.1 mL), and the mixture was stirred for 10 min at r.t. A balloon filled with CO₂ under ambient pressure was placed on the tube. Then, phenylacetylene (1a; 0.15 mL, 1.36 mmol) was added to the reaction mixture, and the suspension was stirred at 50 °C for 6 h. After the addition of propargyl bromide (2; 174 μL, 1.63 mmol of an 80% solution in toluene) the suspension was stirred at 50 °C for 45 min before benzyl azide (4a; 200 mg, 1.50 mmol) was added. The reaction mixture was stirred at 50 °C for 1 h. After workup and flash chromatography on silica gel (EtOAc–hexane, 1:3), compound 5a (278 mg, 64%) was obtained analytically pure as a yellow solid; mp 83–85 °C. ¹H NMR (300 MHz, CDCl₃): δ = 5.27 (s, 2 H), 5.45 (s, 2 H), 7.19–7.93 (m, 8 H), 7.46 (m, 1 H), 7.48 (m, 1 H), 7.51 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 54.4 (CH₂), 59.0 (CH₂), 80.3 (C_quat), 87.3 (C_quat), 119.4 (C_quat), 124.0 (CH), 128.3 (CH), 128.7 (CH), 129.0 (CH), 129.3 (CH), 130.9 (CH), 133.1 (CH), 134.3 (C_quat), 142.4 (C_quat), 153.9 (C_quat). MS (EI⁺): m/z (%) = 317 (2) [M]⁺, 129 (45) [C₉H₅CO⁺], 91 (100) [C₆H₅CH₂ ⁺]. Anal. Calcd for C₁₉H₁₅N₃O₂ (317.4): C, 71.91; H, 4.76; N, 13.24. Found: C, 72.11; H, 4.83, N, 13.14.
• 20 Typical Procedure for the Synthesis of Compound 7e In a flame-dried Schlenk tube under nitrogen, Cs₂CO₃ (889 mg, 2.73 mmol), Cu(PPh₃)₂NO₃ (63 mg, 10 μmol), and phenanthroline (18 mg, 10 µmol) were dissolved in dry DMF (4.1 mL), and the mixture was stirred for 10 min at r.t. A balloon filled with CO₂ under ambient pressure was placed on the tube. Then, phenylacetylene (1a; 0.15 mL, 1.36 mmol) was added to the reaction mixture, and the suspension was stirred at 50 °C for 6 h. After the addition of propargyl bromide (2; 174 μL, 1.63 mmol of an 80% solution in toluene) the suspension was stirred at 50 °C for 45 min before benzyl azide (4a; 200 mg, 1.50 mmol) was added. The reaction mixture was stirred at 50 °C for 1 h. Then, methyl benzylamine (6e; 182 mg, 1.50 mmol) was added, and the suspension was stirred at 50 °C for 16 h. After workup and flash chromatography on silica gel (EtOAc–hexane, 1:1), compound 7e (311 mg, 52%) was obtained analytically pure as a yellow resin. ¹H NMR (300 MHz, CDCl₃): δ = 2.81 (s, 3 H), 4.17 (br, 2 H), 4.91 (s, 1 H), 5.01 (s, 2 H), 5.46 (s, 2 H), 7.20–7.40 (m, 16 H). ¹³C NMR (75 MHz, CDCl₃): δ = 38.0 (CH₃), 54.2 (CH₂), 55.7 (CH₂), 56.3 (CH₂), 87.0 (CH), 123.2 (CH), 126.9 (CH), 127.5 (CH), 128.2 (CH), 128.4 (CH), 128.4 (CH), 128.8 (CH), 128.8 (CH), 128.8 (CH), 129.0 (CH), 134.7 (C_quat), 136.2 (C_quat), 137.3 (C_quat), 144.7 (C_quat), 164.1 (C_quat), 167.4 (C_quat). MS (ESI⁺): m/z = 439 [M + H]⁺. HRMS (ESI⁺): m/z calcd for [C₂₇H₂₆N₄O₂ + H]⁺: 439.2134; found: 439.2129.
• 21 Sharaf SM, El-Sadany SK, Hamed EA, Youssef A.-HA. Can. J. Chem. 1991; 69: 1445
  CrossrefSearch in Google Scholar

• References and Notes

• 1a Kunz K, Scholz U, Ganzer D. Synlett 2003; 2428
  Thieme Connect
• 1b Monnier F, Taillefer M. Angew. Chem. Int. Ed. 2009; 48: 6954
  Search in Google Scholar
• 1c Beletskaya IP, Ananikov VP. Chem. Rev. 2011; 111: 1596
  CrossrefPubMedSearch in Google Scholar
• 1d Rao H, Fu H. Synlett 2011; 745
  Thieme Connect
• 1e Liu Y, Wan J.-P. Chem. Asian J. 2012; 7: 1488
  CrossrefPubMedSearch in Google Scholar
• 1f Liu T, Fu H. Synthesis 2012; 44: 2805
  Thieme ConnectSearch in Google Scholar

For leading reviews, see:
• 2a Bock VD, Hiemstra H, van Maarseveen JH. Eur. J. Org. Chem. 2006; 51
• 2b Meldal M, Tornoe CW. Chem. Rev. 2008; 108: 2952
  Search in Google Scholar
• 2c Hänni KD, Leigh DA. Chem. Soc. Rev. 2010; 39: 1240
  CrossrefSearch in Google Scholar
• 2d Kappe CO, Van der Eycken E. Chem. Soc. Rev. 2010; 39: 1280
  CrossrefPubMedSearch in Google Scholar
• 2e Hein JE, Fokin VV. Chem. Soc. Rev. 2010; 39: 1302
  Search in Google Scholar
• 2f Liang L, Astruc D. Coord. Chem. Rev. 2011; 255: 2933
  CrossrefSearch in Google Scholar
• 3a Balme G, Bossharth E, Monteiro N. Eur. J. Org. Chem. 2003; 4101
• 3b D’Souza DM, Müller TJ. J. Chem. Soc. Rev. 2007; 36: 1095
  CrossrefPubMedSearch in Google Scholar
• 3c Kirsch SF. Synthesis 2008; 3183
  Thieme Connect
• 3d Arndtsen BA. Chem. Eur. J. 2009; 15: 302
  CrossrefSearch in Google Scholar
• 3e Abbiati G, Rossi E. Beilstein J. Org. Chem. 2014; 10: 481
  CrossrefPubMedSearch in Google Scholar
• 4 For the first review on multicomponent syntheses based upon CuAAC, see: Hassan S, Müller TJ. J. Adv. Synth. Catal. 2015; 357: 617
  CrossrefSearch in Google Scholar
• 5 Müller TJ. J. Multicomponent Reactions 1. General Discussion and Reactions Involving a Carbonyl Compound as Electrophilic Component. In Science of Synthesis. Vol. 1. Müller TJ. J. Thieme; Stuttgart: 2014: 5
  Search in Google Scholar
• 6 Tietze LF. Chem. Rev. 1996; 96: 115
  CrossrefPubMedSearch in Google Scholar

For seminal reviews, see:
• 7a Ugi I, Dömling A, Werner B. J. Heterocycl. Chem. 2000; 37: 647
  CrossrefSearch in Google Scholar
• 7b Weber L, Illgen K, Almstetter M. Synlett 1999; 366
  Thieme Connect

For reviews on alkynes as reactive modules in sequential syntheses of heterocycles, see:
• 8a Cacchi S. J. Organomet. Chem. 1999; 576: 42
  Search in Google Scholar
• 8b Willy B, Müller TJ. J. Curr. Org. Chem. 2009; 13: 1777
  CrossrefSearch in Google Scholar
• 8c Müller TJ. J. Top. Heterocycl. Chem. 2010; 25: 25
  Search in Google Scholar
• 8d Müller TJ. J. Synthesis 2012; 44: 159
  Thieme ConnectSearch in Google Scholar
• 8e Abbiati G, Arcadi A, Marinelli F, Rossi E. Synthesis 2014; 46: 687
  Thieme ConnectSearch in Google Scholar
• 8f Yamamoto Y. Chem. Soc. Rev. 2014; 43: 1575
  Search in Google Scholar
• 9 Schreiner E, Braun S, Kwasnitschka C, Frank W, Müller TJ. J. Adv. Synth. Catal. 2014; 356: 3135
  CrossrefSearch in Google Scholar
• 10 Fukue Y, Oi S, Inoue Y. J. Chem. Soc., Chem. Commun. 1994; 2091
• 11a Yu D, Zhang Y. Proc. Natl. Acad. Sci. U.S.A. 2010; 107: 20184
  CrossrefPubMedSearch in Google Scholar
• 11b Gooßen LJ, Rodríguez N, Manjolinho F, Lange PP. Adv. Synth. Catal. 2010; 352: 2913
  CrossrefSearch in Google Scholar
• 11c Inamoto K, Asano N, Kobayashi K, Yonemoto M, Kondo Y. Org. Biomol. Chem. 2012; 10: 1514
  CrossrefSearch in Google Scholar
• 11d Zhang W.-Z, Li W.-J, Zhang X, Zhou H, Lu X.-B. Org. Lett. 2010; 12: 4748
  Search in Google Scholar
• 11e Manjolinho F, Arndt M, Gooßen K, Gooßen LJ. ACS Catal. 2012; 2: 2014
  CrossrefSearch in Google Scholar
• 11f Yu B, Diao Z.-F, Guo C.-X, Zhong C.-L, He L.-N, Zhao Y.-N, Song Q.-W, Liu A.-H, Wang J.-Q. Green Chem. 2013; 15: 2401
  CrossrefSearch in Google Scholar

For reviews on tandem and sequential catalysis, see:
• 12a Wasilke J.-C, Obrey SJ, Baker RT, Bazan GC. Chem. Rev. 2005; 105: 1001
  CrossrefPubMedSearch in Google Scholar
• 12b Ajamian A, Gleason JL. Angew. Chem. Int. Ed. 2004; 43: 3754
  CrossrefSearch in Google Scholar
• 12c Fogg DE, de Santos EN. Coord. Chem. Rev. 2004; 248: 2365
  CrossrefSearch in Google Scholar
• 13 Tan Y.-H, Li J.-X, Xue F.-L, Qi J, Wang Z.-Y. Tetrahedron 2012; 68: 2827
  CrossrefSearch in Google Scholar
• 14 Koohshari M, Dabiri M, Salehi P, Bahramnejad M. Synth. Commun. 2012; 42: 2415
  CrossrefSearch in Google Scholar
• 15 Singh H, Nand B, Sindhu J, Khurana JM, Sharmab C, Aneja KR. J. Braz. Chem. Soc. 2014; 25: 1178
  Search in Google Scholar
• 16 Stefani HA, Vasconcelos SN. S, Souza FB, Manarin F, Zukerman-Schpector J. Tetrahedron Lett. 2013; 54: 5821
  CrossrefSearch in Google Scholar
• 17 Hassan S, Tschersich R, Müller TJ. J. Tetrahedron Lett. 2013; 54: 4641
  CrossrefSearch in Google Scholar
• 18 Witulski B, Zimmermann A. Synlett 2002; 1855
  Thieme Connect
• 19 Typical Procedure for the Synthesis of Compound 5a In a flame-dried Schlenk tube under nitrogen, Cs₂CO₃ (889 mg, 2.73 mmol), Cu(PPh₃)₂NO₃ (63 mg, 10 μmol), and phenanthroline (18 mg, 10 μmol) were dissolved in dry DMF (4.1 mL), and the mixture was stirred for 10 min at r.t. A balloon filled with CO₂ under ambient pressure was placed on the tube. Then, phenylacetylene (1a; 0.15 mL, 1.36 mmol) was added to the reaction mixture, and the suspension was stirred at 50 °C for 6 h. After the addition of propargyl bromide (2; 174 μL, 1.63 mmol of an 80% solution in toluene) the suspension was stirred at 50 °C for 45 min before benzyl azide (4a; 200 mg, 1.50 mmol) was added. The reaction mixture was stirred at 50 °C for 1 h. After workup and flash chromatography on silica gel (EtOAc–hexane, 1:3), compound 5a (278 mg, 64%) was obtained analytically pure as a yellow solid; mp 83–85 °C. ¹H NMR (300 MHz, CDCl₃): δ = 5.27 (s, 2 H), 5.45 (s, 2 H), 7.19–7.93 (m, 8 H), 7.46 (m, 1 H), 7.48 (m, 1 H), 7.51 (s, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 54.4 (CH₂), 59.0 (CH₂), 80.3 (C_quat), 87.3 (C_quat), 119.4 (C_quat), 124.0 (CH), 128.3 (CH), 128.7 (CH), 129.0 (CH), 129.3 (CH), 130.9 (CH), 133.1 (CH), 134.3 (C_quat), 142.4 (C_quat), 153.9 (C_quat). MS (EI⁺): m/z (%) = 317 (2) [M]⁺, 129 (45) [C₉H₅CO⁺], 91 (100) [C₆H₅CH₂ ⁺]. Anal. Calcd for C₁₉H₁₅N₃O₂ (317.4): C, 71.91; H, 4.76; N, 13.24. Found: C, 72.11; H, 4.83, N, 13.14.
• 20 Typical Procedure for the Synthesis of Compound 7e In a flame-dried Schlenk tube under nitrogen, Cs₂CO₃ (889 mg, 2.73 mmol), Cu(PPh₃)₂NO₃ (63 mg, 10 μmol), and phenanthroline (18 mg, 10 µmol) were dissolved in dry DMF (4.1 mL), and the mixture was stirred for 10 min at r.t. A balloon filled with CO₂ under ambient pressure was placed on the tube. Then, phenylacetylene (1a; 0.15 mL, 1.36 mmol) was added to the reaction mixture, and the suspension was stirred at 50 °C for 6 h. After the addition of propargyl bromide (2; 174 μL, 1.63 mmol of an 80% solution in toluene) the suspension was stirred at 50 °C for 45 min before benzyl azide (4a; 200 mg, 1.50 mmol) was added. The reaction mixture was stirred at 50 °C for 1 h. Then, methyl benzylamine (6e; 182 mg, 1.50 mmol) was added, and the suspension was stirred at 50 °C for 16 h. After workup and flash chromatography on silica gel (EtOAc–hexane, 1:1), compound 7e (311 mg, 52%) was obtained analytically pure as a yellow resin. ¹H NMR (300 MHz, CDCl₃): δ = 2.81 (s, 3 H), 4.17 (br, 2 H), 4.91 (s, 1 H), 5.01 (s, 2 H), 5.46 (s, 2 H), 7.20–7.40 (m, 16 H). ¹³C NMR (75 MHz, CDCl₃): δ = 38.0 (CH₃), 54.2 (CH₂), 55.7 (CH₂), 56.3 (CH₂), 87.0 (CH), 123.2 (CH), 126.9 (CH), 127.5 (CH), 128.2 (CH), 128.4 (CH), 128.4 (CH), 128.8 (CH), 128.8 (CH), 128.8 (CH), 129.0 (CH), 134.7 (C_quat), 136.2 (C_quat), 137.3 (C_quat), 144.7 (C_quat), 164.1 (C_quat), 167.4 (C_quat). MS (ESI⁺): m/z = 439 [M + H]⁺. HRMS (ESI⁺): m/z calcd for [C₂₇H₂₆N₄O₂ + H]⁺: 439.2134; found: 439.2129.
• 21 Sharaf SM, El-Sadany SK, Hamed EA, Youssef A.-HA. Can. J. Chem. 1991; 69: 1445
  CrossrefSearch in Google Scholar

• Supplementary Material