Letter pubs.acs.org/OrgLett
Cite This: Org. Lett. 2018, 20, 4601−4605
Preparation and Reactions of Mono- and Bis-Pivaloyloxyzinc Acetylides Carl Phillip Tüllmann, Yi-Hung Chen, Robin J. Schuster, and Paul Knochel* Department of Chemistry, Ludwig-Maximilian-Universität, Butenandtstraße 5-13, 81377 München, Germany
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S Supporting Information *
ABSTRACT: Mono-pivaloyloxyzinc acetylide and bis-pivaloyloxyzinc acetylide were selectively prepared from ethynylmagnesium bromide in quantitative yields. These zinc reagents readily underwent Negishi cross-couplings with (hetero)aryl iodides or bromides as well as subsequent Sonogashira cross-couplings. 1,3-Dipolar cycloadditions of these zinc acetylides with benzylic azides produced zincated and bis-zincated triazoles which were trapped with several electrophiles. An opposite regioselectivity compared to the Cu-catalyzed click-reactions was observed.
O
Scheme 1. Preparation of Mono-pivaloyloxyzinc Acetylide (1) and Bis-pivaloyloxyzinc Acetylide (2)
rganozinc reagents are important reagents in organic synthesis, since they tolerate a variety of functional groups and react with various electrophiles in the presence of an appropriate transition metal catalyst.1 Recently, we2 have reported the preparation of a new class of zinc organometallics with the general formula RZnX·Mg(OPiv)2·nLiCl (X = Cl, Br; abbreviated as RZnOPiv).3 The nature of the organic group R can be an aryl, heteroaryl, benzyl,4 alkynyl,5 allyl,6 or amide enolate zinc pivalate.7 The presence of Mg(OPiv)2 within these zinc reagents confers then enhanced air and moisture stability.3 For instance, alkynylzinc pivalates5 tolerate a broad range of functionalities and represent a reactive class of versatile Csp-centered nucleophiles that are stable for several hours when exposed to air. Herein, we wish to report the preparation and reactivity of two new alkynylzinc pivalates, namely mono-pivaloyloxyzinc acetylide (1) and bis-pivaloyloxyzinc acetylide (2), as storable solids with appreciable air and moisture stability (see Scheme 1). Such air-stable reagents are highly desirable organometallic building blocks, since the corresponding lithium or halogenomagnesium acetylides, which are widely used reagents for ethynylation,8 are highly air and moisture sensitive. Additionally, lithium acetylide is prone to undergo disproportionation to dilithium acetylide and acetylene in the absence of stabilizing agents above −25 °C.9 The zinc reagents 1 and 2 were conveniently prepared in almost quantitative yields from commercially available ethynylmagnesium bromide (3 see Scheme 1). Thus, the treatment of a solution of 3 with ZnCl2 in THF at −20 °C for 2 h, followed by the addition of a freshly © 2018 American Chemical Society
prepared solution of Mg(OPiv)23 at 25 °C for 20 min, produced, after evaporation of the solvent, a white-yellowish powder of mono-pivaloyloxyzinc acetylide (1) in 98% yield.10 Notably, the direct addition of Zn(OPiv)2 to 3 afforded a mixture of 1 and 2 in the ratio of 4:1. Bis-pivaloyloxyzinc acetylide (2) was prepared selectively by treating ethynylmagnesium bromide (3) with EtMgBr (1.1 equiv) at 50 °C for 12 h, followed by the addition of ZnCl2 (2.1 equiv) at −20 °C for 2 h and Mg(OPiv)2 (2.1 equiv) at 25 °C for 0.5 h. After solvent evaporation, 2 was obtained as a white powder in quantitative yield as indicated by a titration with iodine.11 A scale-up to 50 mmol was readily performed with the same yield. The resulting powders can be handled for a short time Received: June 18, 2018 Published: July 26, 2018 4601
DOI: 10.1021/acs.orglett.8b01892 Org. Lett. 2018, 20, 4601−4605
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Organic Letters on the benchtop and have a half-life time in air of about 5 h at 25 °C (see Table 1).
Furthermore, nonsymmetrical bis-arylated alkynes (6) were prepared in a one-pot reaction using, at first, the previously developed Negishi cross-coupling performed in the presence of 2% PdCl2(PPh3)2, followed by a Sonogashira cross-coupling15 using 10 mol % CuI and Et3N (2.0 equiv) at 25 °C for 12 h (see Table 3). The successive cross-coupling of 1 with 4a,
Table 1. Activity of Mono-pivaloyloxyzinc Acetylide (1) and Bis-pivaloyloxyzinc Acetylide (2) after Exposure to Air at 25 °C
Table 3. One-Pot Synthesis of Nonsymmetrical Bis-Arylated Acetylenes (6a−f)
a
Activity determined by titration with iodine.11
Mono-pivaloyloxyzinc acetylide (1) underwent Negishi cross-couplings12 with aryl iodides of type 4 leading to aryland heteroaryl-alkynes of type 5 (see Table 2). These reactions Table 2. Negishi Cross-Coupling Reactions between Monopivaloyloxyzinc Acetylide (1) and Various Aryl Iodides (4a− f)
a
Isolated yield.
followed by a Sonogashira coupling with the (hetero)aryl iodides (4c and 4f−i), resulted in the corresponding nonsymmetrical bis-arylated alkynes of type 6 in 74−90% yields (entries 1−4 in Table 3). Remarkably, this reaction tolerates sensitive functional groups such as ketones, esters, and nitro-arenes (entries 5 and 6 in Table 3) resulting in the desired alkynes (6e−f) in 65%−75% yields. Previously, we reported that alkynylzinc pivalates readily undergo 1,3-dipolar cycloadditions with retention of the carbon−zinc bond.5a Thus, we have performed coppercatalyzed regioselective azide−alkyne cycloadditions (CuAACs)16 with mono-pivaloyloxyzinc acetylide (1) with in situ generated benzyl azides (see Table 4). Only one regioisomeric cycloaddition product (7) was formed under the usual copper-catalyzed conditions (10% CuI in DMF at 25 °C for 6 h).17 To the best of our knowledge, this regioselectivity has not been observed in CuAACs to date and has only been realized by Fokin using a ruthenium catalyst.18 The heterocyclic zinc pivalate (7) was trapped with several electrophiles. Thus, the zinc reagent (7) underwent a smooth allylation when it was treated with allyl bromide leading to the corresponding 1,5-disubstitued 1,2,3-triazole (10a) in 49% yield (entry 1 in Table 4). Furthermore, a subsequent Negishi cross-coupling was performed with 2 mol % PdCl2(PPh3)2 at 50 °C for 12 h leading to the arylated
a
Isolated yield.
proceeded at 25 °C within 1 h in the presence of 1% Pd(PPh3)4 producing the desired ethynylated arenes. Electronrich aryl iodides (entries 1 and 2 in Table 2), electron-poor aryl iodides (entries 3−5 in Table 2), and 3-iodothiophene (4f, entry 6 in Table 2) gave the desired cross-coupling products (5a−f) in 76−98% yields.13 Thus, reagent 1 directly provided a range of terminal alkynes without the need of using a silyl protecting group as usually done to introduce an ethynyl moiety.14 4602
DOI: 10.1021/acs.orglett.8b01892 Org. Lett. 2018, 20, 4601−4605
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Organic Letters Table 4. Synthesis of 1,5-Disubstituted Triazoles (10a−d)
Table 5. Negishi Cross-Couplings Reactions between Zinc Pivalate 2 and Various Aryl Halides
a
Isolated yield. bReaction was treated with allyl bromide (8) (2.5 equiv). cReaction was performed with 2 mol % of PdCl2(PPh3)2 at 50 °C for 12 h. dReaction was treated with hydroxylamines benzoates (9a−b, 1.2 equiv).
triazole (10b) in 82% yield (entry 2 in Table 4).5a Notably, the addition of hydroxylamine benzoates (9a−b) gave the aminated 1,2,3-triazoles (10c−d) in 51%−74% yields (entries 3−4). Next, we have examined the Negishi cross-coupling of bispivaloyloxyzinc acetylide (2) with aryl and heteroaryl iodides or bromides. Due to the low solubility of 2 in THF, DMSO was the preferred solvent for these reactions. All cross-coupling reactions were completed within 3 h at 25 °C using 3 mol % Pd(dba)2 (dba = dibenzylideneacetone) and 6 mol % SPhos19 providing the desired bis-arylated alkynes (12a−f) in 74−98% yields (see Table 5). Both electron-rich aryl iodides (entries 1−3 in Table 5) and electron-poor aryl iodides (entries 4−6 in Table 5) smoothly underwent these cross-couplings. Encouraged by these results, we further tested the scope of this crosscoupling with various aryl bromides affording the desired bisarylated products of type 12 in 75−94% yield (entries 1 and 5−10 in Table 5) using 5 mol % Pd(dba)2 and 5 mol % XantPhos20 as ligand at 40 °C.21 Notably, the reaction was compatible with sensitive functional groups such as primary amines, nitriles, ketones, and esters. The bis-pivaloyloxyzinc acetylide (2) also underwent a [3 + 2]-cycloaddition in the presence of 10 mol % CuI leading to the 1,2-bis-zincated triazole (13) with two reactive zinc functionalities (see Scheme 2). After quenching with allyl bromide (3.0 equiv, 25 °C, 1 h), the triazole (14) was obtained in 66% yield.22 This bis-allylated triazole (14) underwent a ring-closing metathesis23 in the presence of 5 mol % Hoveyda−Grubbs catalyst (2nd generation)24 in DCM at 50 °C leading to the 1,2,3-triazole (15) in 82% yield. To the best of our knowledge, compounds 14 and 15 were not previously
a Isolated yield. bPerformed with 3 mol % Pd(dba)2 and 6 mol % SPhos. cPerformed with 5 mol % Pd(dba)2 and 5 mol % Xantphos.
synthesized and can be an interesting addition to the triazole class.25 In summary, we have reported the preparation of mono- and bis-pivaloyloxyzinc acetylide which display enhanced air and moisture stability. Monozinc acetylide pivalate (1) underwent Negishi cross-couplings to form (hetero)aryl alkynes. A subsequent Sonogashira cross-coupling led to the synthesis 4603
DOI: 10.1021/acs.orglett.8b01892 Org. Lett. 2018, 20, 4601−4605
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Organic Letters
Chung, C. K.; Dreher, S. D.; Kutchukian, P. S.; Peng, Z.; Davies, I. W.; Vachal, P.; Ellwart, M.; Manolikakes, S. M.; Knochel, P.; Nantermet, P. G. Angew. Chem., Int. Ed. 2016, 55, 13714. (d) Hammann, J. M.; Lutter, F. H.; Haas, D.; Knochel, P. Angew. Chem., Int. Ed. 2017, 56, 1082. (e) Stathakis, C.; Manolikakes, S. M.; Knochel, P. Org. Lett. 2013, 15, 1302. (f) Colombe, J. R.; Bernhardt, S.; Stathakis, C.; Buchwald, S. L.; Knochel, P. Org. Lett. 2013, 15, 5754. (g) Chen, Y.-H.; Graßl, S.; Knochel, P. Angew. Chem., Int. Ed. 2018, 57, 1108. (5) (a) Chen, Y.-H.; Tüllmann, C. P.; Ellwart, M.; Knochel, P. Angew. Chem., Int. Ed. 2017, 56, 9236. (b) Hammann, J. M.; Thomas, L.; Chen, Y.-H.; Haas, D.; Knochel, P. Org. Lett. 2017, 19, 3847. (6) Ellwart, M.; Knochel, P. Angew. Chem., Int. Ed. 2015, 54, 10662. (7) Chen, Y.-H.; Ellwart, M.; Toupalas, G.; Ebe, Y.; Knochel, P. Angew. Chem., Int. Ed. 2017, 56, 4612. (8) (a) Midland, M. M., Gallou, F. Lithium Acetylide; e-EROS Encyclopedia of Reagents for Organic Synthesis; 2006. (b) Rama Rao, A. V. Dilithium Acetylide; e-EROS Encyclopedia of Reagents for Organic Synthesis; 2001. (c) Midland, M. M. Ethynylmagnesium Bromide; e-EROS Encyclopedia of Reagents for Organic Synthesis; 2001. (d) Schmid, R.; Huesmann, P. L.; Johnson, W. S. J. Am. Chem. Soc. 1980, 102, 5122. (e) Stork, G.; Stryker, J. M. Tetrahedron Lett. 1983, 24, 4887. (f) Brummond, K. M.; Davis, M. M.; Huang, C. J. Org. Chem. 2009, 74, 8314. (g) Zhou, H.; Zhou, Q.; Zhou, Q.; Ni, L.; Chen, Q. RSC Adv. 2015, 5, 12161. (h) Burrows, L. C.; Jesikiewicz, L. T.; Lu, G.; Geib, S. J.; Liu, P.; Brummond, K. M. J. Am. Chem. Soc. 2017, 139, 15022. (9) (a) Beumel, O. F.; Harris, R. F. J. Org. Chem. 1963, 28, 2775. (b) Mortier, J.; Vaultier, M.; Carreaux, F.; Douin, J.-M. J. Org. Chem. 1998, 63, 3515. (10) See Supporting Information. (11) Krasovskiy, A.; Knochel, P. Synthesis 2006, 2006, 890. (12) (a) King, A. O.; Okudado, N.; Negishi, E.-i. J. Chem. Soc., Chem. Commun. 1977, 42, 1821. (b) King, A. O.; Negishi, E.-i. J. Org. Chem. 1978, 43, 358. (c) Negishi, E.-i. Angew. Chem., Int. Ed. 2011, 50, 6738. (d) Haas, D.; Hammann, J. M.; Greiner, R.; Knochel, P. ACS Catal. 2016, 6, 1540. (13) Aryl chlorides were found to be unreactive; aryl bromides gave mixtures of aryl alkynes and bis-arylated alkynes under various conditions. (14) (a) Severin, R.; Reimer, J.; Doye, S. J. Org. Chem. 2010, 75, 3518. (b) Kim, T.; Jeong, K. H.; Kim, Y.; Noh, T.; Choi, J.; Ham, J. Eur. J. Org. Chem. 2017, 2017, 2425. (c) Qiu, S.; Zhang, C.; Qiu, R.; Yin, G.; Huang, J. Adv. Synth. Catal. 2018, 360, 313. (15) (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 16, 4467. For recent reviews on Sonogashira reaction, see: (b) Chinchilla, R.; Nájera, C. Chem. Rev. 2007, 107, 874. (c) Chinchilla, R.; Nájera, C. Chem. Soc. Rev. 2011, 40, 5084. (16) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002, 41, 2596. (b) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002, 67, 3057. (17) The regioselectivity was confirmed by 1H NMR, 13C NMR, NOESY, HSQC, and HMBC. (18) (a) Hein, J. E.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1302. (b) Li, Y.; Qi, X.; Lan, Y. RSC Adv. 2015, 5, 49802. (19) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 4685. (20) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J. Organometallics 1995, 14, 3081. (21) Aryl chlorides were found to be unreactive under various conditions. (22) Differentiation of the two nucleophilic positions of triazole 13 could not be achieved. (23) Handbook of Metathesis, Vol. 2: Applications in Organic Synthesis, 2nd ed.; Grubbs, R. H., O’Leary, D. J., Eds.; Wiley: Weinheim, 2015. (24) (a) Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168. (b) Gessler, S.; Randl, S.; Blechert, S. Tetrahedron Lett. 2000, 41, 9973.
Scheme 2. Synthesis of 1,2,5-Trisubstituted Triazole 14 Followed by a Ring-Closing Metathesis to Benzotriazole Derivative 15
of asymmetric bis-arylated alkynes without employing silyl protection steps. Furthermore, reagent 1 underwent a coppercatalyzed azide−alkyne cycloaddition (CuAAC) which for the first time selectively led to 1,5-disubstituted 1,2,3-triazoles. Furthermore, bis-pivaloyloxyzinc acetylide (2) reacted in Negishi cross-couplings with aryl halides, obtaining symmetrical bis-arylated alkynes. In a performed CuAAC, both zinc−carbon bonds remained intact during the cycloaddition and could be subsequently engaged in an allylation to form 1,4,5-trisubstituted 1,2,3-triazoles. Further applications are currently underway in our laboratories.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01892. Experimental procedures, characterization data, and NMR spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Paul Knochel: 0000-0001-7913-4332 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the Deutsche Forschungsgemeinschaft (DFG) for financial support. We thank Albemarle (Germany) for the generous gift of chemicals.
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REFERENCES
(1) (a) Handbook of Functionalized Organometallics: Applications in Synthesis, 2nd ed.; Knochel, P., Ed.; Wiley: Weinheim, 2005. (b) Organometallics in Synthesis: Third Manual; Schlosser, M., Ed.; Wiley: Weinheim, 2013. (2) (a) Chen, Y.-H.; Ellwart, M.; Malakhov, V.; Knochel, P. Synthesis 2017, 49, 3215. (b) Manolikakes, S. M.; Ellwart, M.; Stathakis, C. I.; Knochel, P. Chem. - Eur. J. 2014, 20, 12289. (3) Hernán-Gómez, A.; Herd, E.; Hevia, E.; Kennedy, A. R.; Knochel, P.; Koszinowski, K.; Manolikakes, S. M.; Mulvey, R. E.; Schnegelsberg, C. Angew. Chem., Int. Ed. 2014, 53, 2706. (4) (a) Bernhardt, S.; Manolikakes, G.; Kunz, T.; Knochel, P. Angew. Chem., Int. Ed. 2011, 50, 9205. (b) Stathakis, C. I.; Bernhardt, S.; Quint, V.; Knochel, P. Angew. Chem., Int. Ed. 2012, 51, 9428. (c) Greshock, T. J.; Moore, K. P.; McClain, R. T.; Bellomo, A.; 4604
DOI: 10.1021/acs.orglett.8b01892 Org. Lett. 2018, 20, 4601−4605
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DOI: 10.1021/acs.orglett.8b01892 Org. Lett. 2018, 20, 4601−4605
