Phenylacetylenespotlight Spotlight 473 Compiled by Marcin Konrad Kowalski

1484██ SPOTLIGHT

SYNLETT Phenylacetylenespotlight Spotlight 473 Compiled by Marcin Konrad Kowalski

This feature focuses on a reagent chosen by a postgradu- Marcin Konrad Kowalski was born in Opoczno, Poland, in 1989. He ate, highlighting the uses and obtained his B.Sc. (2011) and M.Sc. (2013) in organic chemistry preparation of the reagent in and synthesis from the University of Łódź, Poland. Currently, he is pursuing his Ph.D. in synthetic organic chemistry under the supervi- current research sion of Professor Dr. Grzegorz Mlostoń at the same university. His research is focused on the synthesis of β-lactams and other heterocycles which are functionalized with fluoroalkyl groups. Department of Organic and Applied Chemistry, Faculty of Chemis- try, University of Łódź, 91-403 Łódź, Poland E-mail: [email protected] Dedicated to Professor Dr. Grzegorz Mlostoń, Dr. Emilia Obijalska, and my family.

Introduction actions, 1,3-dipolar cycloaddition reactions, diverse tran- sition-metal-supported coupling reactions, and in Phenylacetylene (1-phenylethyne, 1-phenylacetylene) is a nucleophilic additions. terminal alkyne which under standard conditions is a light O O yellow liquid with a characteristic odor. It can be conve- P Me OMe niently prepared via the reaction of benzaldehyde with the OMe O N2 Bestmann–Ohira reagent in the presence of a base at room Ph P O Bestmann–Ohira Cl OEt O temperature.1a Other methods applied for its preparation reagent 1. LDA, OEt Ph H consists in the treatment of acetophenone with lithium di- K2CO3, MeOH, r.t., 4 h 2. LDA (2 equiv), aq HCl Ph Me isopropylamide (LDA) and diethyl chlorophosphate.1b H Phenylacetylene is widely applied as a versatile building Scheme 1 block, for example in Kinugasa reactions, Diels–Alder re- Abstracts

(A) Phenylacetylene is widely explored as a model acetylenic sub- Ph CuOTf⋅Tol (10 mol%) Ph Ph –O + Ph Ph Ph strate in Kinugasa reactions. Saito et al. described an enantioselec- N ligand (12 mol%) N N + + tive version of this reaction which was performed in the presence of MeCN, Cy2NH (1 equiv) 2 Ph Ph O Ph O chiral oxazoline ligands. The reported diastereo- and enantioselec- H 0 °C, 44 h O tivities were satisfactory, but chemical yields were rather low. In an- 67–71% yield Me cis/trans = 93:7 other paper, the applications of modified bis(oxazoline) ligands N 95% ee were reported, and in this case the desired β-lactams were obtained O O in high chemical yields. In addition, better diastereo- and enantio- N N selectivities were observed.3

ligand

(B) Cyclic, achiral, and enantiopure nitrones were used in reactions R R Ph H H with phenylacetylene under Kinugasa reaction conditions. In both Ph CuI, Et3N cases only one diastereoisomer of the desired β-lactam was isolated + + N N 4 – MeCN, 24 h in low to moderate yield. O O H This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. R = H, OBn cis 20–65% yield

– (C) Analogous reactions with diverse nitrones in the presence of cat- O + Bn Ph InBr3 (25 mol%) HO Bn N N alytic amounts of indium tribromide (InBr3) and a tertiary amine led i-Pr2EtN (25 mol%) 5 + to N-hydroxypropargyl amines in moderate to good yields. R CH2Cl2, 40 °C, 24 h R H Ph R = Alk, Ar 40–81% yield

SYNLETT 2014, 25, 1484–1485 Advanced online publication: 12.05.20140936-52141437-2096 DOI: 10.1055/s-0033-1339082; Art ID: st-2014-v0480-v © Georg Thieme Verlag Stuttgart · New York SPOTLIGHT M. K. Kowalski 1485

(D) In a three-component reaction, performed in the presence of a Ph 2 3 O R R catalytic amount of Ni(II)-Y zeolite, phenylacetylene reacted with H NiII-Y N + N + 2 R3 aldehydes and secondary amines yielding β-ynamines in high to ex- R1 H R neat, 80 °C 6 4–10 h R1 cellent yields. H Ph R1 = Alk, Ar R2 = Alk, Ar, R3 = Alk 81–98% yield

(E) 1,3-Dipolar cycloadditions of aryl- and alkylazides with phenyl- I Ph acetylene, carried out in the presence of copper(II) salts, sodium io- R R Cu(II) salt, NaI N Ph N dide, and a base, led to 5-iodo-1,2,3-triazoles formed as the main or RN3 + + Ph Et3N, THF, r.t. N exclusive products. However, the formation of 4-unsubstituted N N N H 1,2,3-triazoles as side-products was observed in reactions carried out R = Alk, Ar 1a 1b in the presence of copper(II) chlorate(VII).7 1a/1b from 4:1 to 1:0 70–97% yield

(F) Heterocyclization of gem-dibromovinylphenols followed by Ph Sonogashira reaction of the initially formed 2-bromobenzofurane Br Br with phenylacetylene gave 2-phenylethynyl-substituted benzofurans Ph CuI (0.15 mmol) OH in high yield.8 Upon optimizing the reaction conditions, copper(I) io- DABCO (0.30 mmol) + O dide, DABCO, and cesium carbonate were used in a one-pot proce- Cs2CO3 (2 mmol) TBAF⋅3H O (1 mmol), DMF dure. H 2 100–140 °C R R R = 4-MeO, 3-Cl, 3-Me 31–90% yield

(G) In a microwave assisted, palladium-catalyzed tandem reaction, O Ph O phenylacetylene and 2-bromobenzamide were used for the efficient PdCl2(MeCN)2 (5 mol%) 9 NH2 BINAP (5 mol%) preparation of isoindolinone derivatives. + NH DBU, DMF Br MW 120 °C, 30 min H Ph 89% yield

(H) The nucleophilic addition of phenylacetylene to isatin deriva- Ph O Ph HO 1 CuI (5 mol%) tives was achieved under copper-mediated C–H bond activation R R1 10 DBU (20 mol%) conditions. O + O PhMe, N2 atm N N 2 H 25 °C, 5 min R R2

R1 = H, F, Cl, Br 94–98% yield R2 = Me, Bn

(I) 2-Substituted, optically active tetrahydroquinolines were ob- O gold catalyst (0.4 mol%) Ph 1 chiral phosphoric acid (0.8 mol%) tained in high chemical yields and with high enantiomeric excess via R R1 H 4-MeOC6H4NH2 (4.0 mol%) the reaction of 2-aminobenzaldehydes with phenylacetylene under + 11 2 EtO2C CO2Et asymmetric cooperative triple catalysis. R NH2 R2 N Ph H H R1 = H, Br, Cl MeN Me H 89–92% yield R2 = H, Cl 97–99% ee 1 2 R –R = OCH2O (2.5 equiv) 4 Å MS, CHCl3, 60 °C, 32 h

References

(1) (a) Möller, S.; Liepold, B.; Bestmann, H. J. Synlett 1996, (6) Namitharan, K.; Pitchumani, K. Eur. J. Org. Chem. 2010, This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. 521. (b) Negishi, E.; King, A. O.; Klima, W. L. J. Org. 411. Chem. 1980, 40, 2526. (7) Brotherton, W. S.; Clark, R. J.; Zhu, L. J. Org. Chem. 2012, (2) Saito, T.; Kikuchi, T.; Tanabe, H.; Yahiro, J.; Otani, T. 77, 6443. Tetrahedron Lett. 2009, 50, 4969. (8) Liu, J.; Zhang, N.; Yue, Y.; Wang, D.; Zhang, Y.; Zhang, X.; (3) Chen, J.-H.; Liao, S.-H.; Sun, X.-L.; Shen, Q.; Tang, Y. Zhuo, K. RSC Adv. 2013, 3, 3865. Tetrahedron 2012, 68, 5042. (9) Hellal, M.; Cuny, G. D. Tetrahedron Lett. 2011, 52, 5508. (4) Grzeszczyk, B.; Poławska, K.; Shaker, S.; Stecko, Y.; (10) Chouhan, M.; Senwar, K. R.; Kumar, K.; Sharma, R.; Nair, Mames, M. A.; Woźnicka, M.; Chmielewski, M.; Furman, V. A. Synthesis 2014, 46, 195. B. Tetrahedron 2012, 68, 10633. (11) Patil, N. T.; Raut, V. S.; Tella, R. B. Chem. Commun. 2013, (5) Ji, D.-M.; Xu, M.-H. Tetrahedron Lett. 2009, 50, 2952. 49, 570.