1,1-dibromo-1-alkenes as valuable partners in the copper-catalyzed direct alkynylation of azoles

Transcription

1 1,1-dibromo-1-alkenes as valuable partners in the copper-catalyzed direct alkynylation of azoles Pacheco Berciano Beatriz,, Sabrina Lebrequier, François Besselièvre,, Sandrine Piguel*,, Univ Paris-Sud, rsay, F UMR 176, Institut Curie/CRS, Bât , Centre Universitaire, rsay France Supporting information Table of contents: General Experimental Methods: S2 Experimental procedures and characterization data: S2 Copies of 1 H and 13 C MR spectra of compounds: S7 1

2 General Experimental Methods Commercially available reagents and solvents were used without further purification unless otherwise stated. LitBu (99.9% or 99% purity) was purchased from Aldrich or Alfa Aesar and used as supplied. Yields refer to isolated and purified products. Reactions were monitored by thin-layer chromatography carried out on silica gel plates (60F-254) visualized under UV light. Column chromatography was performed on silica gel 60, µm. Chemical shifts of 1 H MR and 13 C MR were reported in ppm (δ units) and residual non deuterated solvent was used as internal reference. 1 The following abbreviations were used to designate the multiplicities: s = singlet, d = doublet, t = triplet, bs = broad signal, m = multiplet. Experimental procedures and characterization data 1,1-dibromoalkenes 2 were synthesized using the Ramirez procedure starting from commercially available aldehydes. 2 General procedure as illustrated for the preparation of 1-(2,2-dibromovinyl)-4- phenylbenzene 2c: to a solution of 4-phenylbenzaldehyde (3 g, 16.5 mmol), carbon tetrabromide (7.1 g, 21.4 mmol) in dichloromethane (150 ml) at 0 C was added slowly a solution of PPh 3 (10.8 g, 41.2 mmol) in dichloromethane (70 ml). The reaction mixture was stirred until complete conversion of aldehyde before being concentrated. The resulting crude was purified by flash chromatography over Si 2 with 10% ethyl acetate in cyclohexane to afford the title compound 2c as a white solid (5.22 g, 94%). 1 H RM (300 MHz, CDCl 3 ) δ (m, 3H), 7.52 (s, 1H), (m, 6H). 13 C MR (75 MHz, CDCl 3 ) δ 89.5,127, 127.1, 127.7, 128.8, 128.9, 134.2, 136.5, 140.3, MS (electrospray) m/z (%) (50), (100), (50) [M+H] +. HRMS (ESI) calculated for C 14 H 10 Br 2 [M+H] , found [M+H] Compounds 2a, 3 2b, 3 2d, 4 2e, 5 2f, 6 2g, 6 2h, 2i, 7 2j, 8 2k 5 and 2l 9 showed satisfactory spectroscopic data in agreement with those reported in the literature. 1 Gottlieb, H.G.; Kotlyar, V.; udelman, A. MR chemical shifts of common laboratory solvents as trace impurities J. rg. Chem. 1997, 62, Ramirez, F.; Desai,.B.; Mc Kelvie,. J. Am. Chem. Soc. 1962, 84, Ueneshi, J.; Kawahama, R.; Yonemitsu,. J. rg. Chem. 1998, 63,

3 For compound 2m: to a solution of PPh 3 (15.5 g, 59.1 mmol) in dichloromethane (150 ml) at 0 C was added a solution of CBr 4 (10 g, 30.1 mmol) in dichloromethane (30 ml). Subsequently, a solution of the aldehyde (5.1 g, 24.5 mmol) and triethylamine (10 ml, 71.7 mmol) in dichloromethane (120 ml) was added dropwise. The reaction mixture was warmed up to room temperature overnight. The reaction mixture was concentrated under reduced pressure and the resulting crude was purified by flash chromatography over Si 2 with 2-3% ethyl acetate in cyclohexane to afford the title compound 2m as a yellow oil (6.5 g, 73%). 1 H RM (300 MHz, CDCl 3 ) δ 1.24 (t, J= 7.1 Hz, 6H), 3.57 (m, 4H), 5.49 (s, 1H), 7.47 (s, 1H), 7.51 (m, 4H). 13 C MR (75 MHz, CDCl 3 ) δ 15.2, 61.1, 89.7, 101.1, 126.7, 128.2, 135.2, 136.6, MS (electrospray) m/z (%) (50), (100), (50) [M-(C 4 H 10 )+H] +. HRMS (ESI) calculated for C 13 H 16 Br 2 2 [M+H] , found [M+H] substituted-oxazoles were prepared according to Van Leusen procedure. 10,11 Dimethyl-[4-(2-oxazol-5-yl-vinyl)-phenyl]-amine 1b: to a solution of 4- dimethylaminocinnamaldehyde (2.0 g, 11.4 mmol, 1 eq) and p- toluenesulfonylmethylisocyanide (TosMIC) (2.45 g, 12.5 mmol, 1.1 eq) in MeH (100 ml) was added potassium carbonate (3.2 g, 22.8 mmol, 2 eq). The reaction mixture was heated 2 hours in refluxing MeH. The solvent was removed under reduced pressure and the crude product was filtrated over silicagel (10-30% AcEt in cyclohexane) give 1.1 g (45 %) of a brownish solid. 1 H MR (300 MHz, CDCl 3 ) δ 3 (s, 6H), 6.7 (d, J = 15 Hz, 1H), 6.71 (m, 2H), 6.97 (s, 1H), 7.03 (d, J = 15 Hz, 1H), 7.37 (d, J = 9 Hz, 2H), 7.79 (s, 1H). 13 C MR (75 MHz, 4 Horibe, H.; Fukuda, Y.; Kondo, K.; kuno, H.; Murakami, Y.; Aoyama, T. Tetrahedron 2004, 60, Rao, M. L..; Jadhav, D..; Dasgupta, P. rg. Lett. 2010, 12, Shastin, A. V.; Korotchenko, V..; enajdenko, V. G.; Balenkova, E. S. Synthesis, 2001, Huh, D. H.; Jeong, J. S.; Lee, H. B. Ryu, H.; Kim, Y. G. Tetrahedron 2002, 58, Carpita, A.; Rossi, R.; Veracini, C. A. Tetrahedron 1985, 41, Moser, W. H.; Feltes, L. A.; Sun, L.; Giese, M. W.; Farrell, R. J. rg. Chem. 2006, 71, Van Leusen, A. M.; Hoogenboom, B. E.; Siderius, H. Tetrahedron Lett. 1972, 23, Besselièvre, F.; Mahuteau-Betzer, F.; Grierson, D. S.; Piguel, S. J. rg. Chem. 2008, 73,

4 CDCl 3 ) δ 40.4, 108.5, 112.3, 122.4, 124.4, 127.9, 130.6, 149.7, 150.6, MS (electrospray) m/z (%) (100) [M+H] +. 1-phenyl-1H-[1,2,4]triazole 12 and 9-benzyl-6-chloro-9H-purine 13 were prepared according procedures described in the literature. Typical direct alkynylation procedure: 5-Phenyl-2-phenylethynyl-oxazole 3a 3a A flame dried tube under argon was charged with 5-phenyloxazole (100.0 mg, 0.69 mmol, 1 eq), CuBr.SMe 2 (7.1 mg, mmol, 0.05 eq), DPEPhos (37.1 mg, mmol, 0.10 eq), tbuli (331.2 mg, 4.1 mmol, 6 eq). Then 2,2-dibromovinylbenzene (361.5 mg, 1.38 mmol, 2 eq) was diluted into dioxane (2 ml) and the solution was added to the medium. The tube was sealed with a Teflon cap and put in a pre-heated oil bath at 120 C for 2 hour. The reaction mixture was diluted with EtAc and water was added. This mixture was extracted with EtAc and the combined organic layers were put together and dried upon MgS 4. Solvents were removed under reduced pressure and the crude was purified by flash chromatography on silica gel using cyclohexane/etac (starting from 98/2) as a solvent mixture to afford the title compound 3a (117 mg, 70 %) as a white solid. For compounds 3a, 3b, 3d, 3e, 3f, 3g, 3h, 3i, 3l, 4, 5, 7, 8, 9, and 11, data were in good agreement with those described in the literature (4-phenylphenylethynyl)-5-phenyloxazole 3c 12 Cristau, H.-J; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem. Eur. J. 2004, 10, Lu, W.; Sengupta, S.; Petersen, J. L.; Akhmedov,. G.; Shi, X. J. rg. Chem. 2007, 72, Magdolen, P.; Zahradnik, P.; Foltinova, P. Arzneimittel-Forsch. 2000, 50, Besselièvre, F.; Piguel S. Angew. Chem. Int. Ed. 2009, 48,

5 After applying the typical direct alkynylation procedure on 100 mg of starting material, the product was purified by flash chromatography on silica gel using cyclohexane/etac (starting from 98/2) as a solvent mixture to afford the title compound 3c (133.5 mg, 60 %) as a light yellow solid. 1 H RM (300 MHz, CDCl 3 ) δ (m, 7H), (m, 6H), 7.70 (d, J=8.2 Hz, 2H). 13 C MR (75 MHz, CDCl 3 ) δ 78.0, 92.0, 119.5, 123.4, 124.5, 127.1, 127.2, 127.4, 128.0, 128.9, 129.0, 132.6, 133.6, 140.0, 142.7, 146.2, MS (electrospray) m/z (%) (100) [M+a] +. HRMS (ESI) calculated for C 23 H 16 [M+H] , found [M+H] furan-2ylethynyl-5-phenyloxazole 3j After applying the typical direct alkynylation procedure on 100 mg of starting material, the product was purified by flash chromatography on silica gel using cyclohexane/etac (starting from 98/2) as a solvent mixture to afford the title compound (92.5 mg, 61 %) as a brown solid. 1 H RM (300 MHz, CDCl 3 ) δ 6.48 (dd, J=3.4 Hz, J=1.8 Hz, 1H), 6.88 (d, J=3.4 Hz, 1H), (m, 5H), 7.69 (d, J=7.2 Hz, 2H). 13 C MR (75 MHz, CDCl 3 ) δ 81.7, 82, 111.4, 118.7, 123.5, 124.5, 127.2, 129.0, 129.1, 135.3, 145.3, 145.5, MS (electrospray) m/z (%) (100) [M+a] +, (20%) [M+H] +. HRMS (ESI) calculated for C 15 H 10 2 [M+H] , found [M+H] phenyl-2-thiophen-2-ylethynyloxazole 3k S After applying the typical direct alkynylation procedure on 100 mg of starting material, the product was purified by flash chromatography on silica gel using cyclohexane/etac (starting from 98/2) as a solvent mixture to afford the title compound (126.5 mg, 73 %) as a brown solid. 1 H RM (300 MHz, CDCl 3 ) δ 7.07 (dd, J=5.0 Hz, J=3.7 Hz, 1H), (m, 6H), 7.69 (d, J=7.1 Hz, 2H). 13 C MR (75 MHz, CDCl 3 ) δ 81.1, 85.6, 120.5, 123.4, 124.5, 127.3, 127.4, 129.0, 129.6, 134.6, 145.9, MS (electrospray) m/z (%) (100) [M+a] +. HRMS (ESI) calculated for C 15 H 10 S [M+H] , found [M+H]

6 2-(4-diethoxymethylphenylethynyl)-5-phenyloxazole 3m After applying the typical direct alkynylation procedure on 100 mg of starting material, the product was purified by flash chromatography on silica gel using cyclohexane/etac (starting from 98/2) as a solvent mixture to afford the title compound (133.5 mg, 55 %) as a light yellow oil. 1 H RM (300 MHz, CDCl 3 ) δ 1.25 (t, J=7.1 Hz, 6H), (m, 4H), 5.53 (s, 1H), (m, 4H), 7.52 (d, J=8.2 Hz, 2H), 7.63 (d, J=8.2 Hz, 2H), 7.7 (d, J=7.2 Hz, 2H). 13 C MR (75 MHz, CDCl 3 ) δ 15.1, 61, 77.4, 91.7, 100.7, 120.4, 123.2, 126.8, 127.2, 128.9, 131.9, 140.9, 145.9, 152. MS (electrospray) m/z (%) (100) [M+a] +. HRMS (ESI) calculated for C 22 H 21 3 [M+H] , found [M+H] Dimethyl-{4-[2-(2-phenylethynyl-oxazol-5-yl)-vinyl]-phenyl}-amine 8 After applying the typical direct alkynylation procedure on 100 mg of starting material with 15 mol% of DPEPhos and 15 mol% of CuBr.SMe 2, the product was purified by flash chromatography on silica gel using cyclohexane/etac (starting from 98/2) as a solvent mixture to afford the title compound (117 mg, 53 %) as a yellow solid. 1 H RM (300 MHz, CDCl 3 ) δ 3.00 (s, 6H), 6.67 (d, J=16.3 Hz, 1H), 6.70 (d, J= 8.6 Hz, 2H), 7.02 (s, 1H), 7.11 (d, J= 16.2 Hz,1H), (m, 5H), 7.62 (d, J=7.8 Hz, 2H). 13 C MR (75 MHz, CDCl 3 ) δ 40.3, 77.7, 91.9, 107.9, 112.2, 120.9, 124.2, 124.4, 128.0, 128.5, 129.7, 131.5, 132.1, 145.1, 150.6, MS (electrospray) m/z (%) (100) [M+H] +, (45%) [M+a] +. HRMS (ESI) calculated for C 21 H 19 2 [M+H] , found [M+H]

7 1-(2,2-dibromovinyl)-4-phenylbenzene 2c Br Br H 2c Br Br 2c

8 8 1-(2,2-Dibromo-vinyl)-4-diethoxymethyl-benzene 2m Br Br 2m Br Br 2m

9 Compound 1b H 3 C CH 3 1b H 3 C 1b CH

10 5-Phenyl-2-phenylethynyl-oxazole 3a 3a

11 11 2-aphthalen-1-ylethynyl-5-phenyl-oxazole 3b b

12 12 2-(4-phenylphenylethynyl)-5-phenyloxazole 3c c c

13 13 2-(3-Bromo-phenylethynyl)-5-phenyl-oxazole 3d Br 3d

14 14 2-(3,4-Dimethoxy-phenylethynyl)-5-phenyl-oxazole 3e e

15 2-(4-Fluoro-phenylethynyl)-5-phenyl-oxazole 3f F 3f

16 5-Phenyl-2-(4-trifluoromethyl-phenylethynyl)-oxazole 3g F F F 3g

17 5-Phenyl-2-(4-trifluoromethyl-phenylethynyl)-oxazole 3h 3h

18 4-(5-Phenyl-oxazol-2-ylethynyl)-benzonitrile 3i 3i

19 19 2-furan-2ylethynyl-5-phenyloxazole 3j j j

20 20 5-phenyl-2-thiophen-2-ylethynyloxazole 3k S 3k S 3k

21 5-Phenyl-2-(4-phenyl-but-3-en-1-ynyl)-oxazole 3l 3l

22 22 2-(4-diethoxymethylphenylethynyl)-5-phenyloxazole 3m CH 3 CH 3 3m CH 3 CH 3 3m

23 5-(3,4-Dimethoxy-phenyl)-2-phenylethynyl-oxazole

24 5-(4-itro-phenyl)-2-phenylethynyl-oxazole

25 25 Dimethyl-{4-[2-(2-phenylethynyl-oxazol-5-yl)-vinyl]-phenyl}-amine

26 2-Phenylethynyl-oxazole

27 2-Phenylethynyl-benzooxazole

28 2-Phenylethynyl-benzothiazole 9 S

29 1-Phenyl-5-phenylethynyl-1H-[1,2,4]triazole

30 9-Benzyl-6-chloro-8-phenylethynyl-9H-purine 11 Cl