Organocatalytic Doubly Annulative Approach to 3,4-Dihydrocoumarins Bearing a Fused Pyrrolidine Scaffold. Dorota Kowalczyk, and Łukasz Albrecht*

Size: px

Start display at page:

Download "Organocatalytic Doubly Annulative Approach to 3,4-Dihydrocoumarins Bearing a Fused Pyrrolidine Scaffold. Dorota Kowalczyk, and Łukasz Albrecht*"

Tracy Mosley
5 years ago
Views:

1 Organocatalytic Doubly Annulative Approach to 3,4-Dihydrocoumarins Bearing a Fused Pyrrolidine Scaffold Dorota Kowalczyk, and Łukasz Albrecht* Institute of Organic Chemistry, Chemistry Department, Lodz University of Technology Żeromskiego 116, Łódź, Poland lukasz.albrecht@p.lodz.pl Supporting Information 1. General methods S2 2. Screening results S3 3. X-ray data for diethyl (3R,3aS,9bR)-3-(4-methoxyphenyl)-8-nitro-4-oxo-1,3a,4,9btetrahydrochromeno[4,3-b]pyrrole-2,2(3H)-dicarboxylate 3s S5 4. NMR data S7 5. HPLC traces S31

2 1. General methods NMR spectra were acquired on the instrument, running at 700 MHz for 1 H and 176 MHz for 13 C, respectively. Chemical shifts (δ) are reported in ppm relative to residual solvent signals (CDCl 3: 7.26 ppm for 1 H NMR, ppm for 13 C NMR). Mass spectra were recorded on a spectrometer (qtof) using electrospray (ES+) ionization. Optical rotations were measured on a polarimeter and [ ] D values are given in deg cm g -1 dm -1 ; concentration c is listed in g (100 ml) -1. Analytical thin layer chromatography (TLC) was performed using pre-coated aluminum-backed plates and visualized by ultraviolet irradiation or I 2 stain. The enantiomeric ratio (er) of the products was determined by chiral stationary phase HPLC. Unless otherwise noted, analytical grade solvents and commercially available reagents were used without further purification. For flash chromatography (FC) silica gel (Silica gel 60, mesh) was used. Diethyl 2-hydroxyarylideneaminomalonates 1 and diethyl β,γ-unsaturated-α-ketophosphonates 2 were prepared according to literature procedures. 1 Cinchona-alkaloid-derived catalysts 4a,b,h 2 and 4c 3 were synthesized following the literature procedures. 1 (a) Tian, L.; Xu, G.-Q.; Li, Y.-H.; Liang, Y.-M.; Xu, P.-F. Chem. Commun. 2014, 50, (b) Evans, D. A.; Johnson, J. S.; Olhava, E. J. J. Am. Chem. Soc. 2000, 122, (a) Yang, W.; Du, D.-M. Org. Lett. 2010, 12, (b) Vakulya, B.; Varga, S.; Csámpai, A.; Soós, T. Org. Lett. 2005, 7, Liu, X.; Li, H.; Deng, L. Org. Lett. 2005, 7, 167. S2

3 2. Screening results 2.1. Catalyst screening a a Reactions performed on 0.1 mmol scale using 1a (1 equiv) and 2a (1 equiv) in 0.2 ml of the solvent. Isolated yields are given. Diastereomeric ratios (dr) as determined by 1 H NMR of a crude reaction mixture. Enantiomeric ratios (er) as determined by a chiral stationary phase HPLC. S3

4 2.2. Reaction conditions screening a Entry Solvent T [ C] Yield [%] b dr c er d 1 CH 2Cl 2 rt 69 >20:1 89:11 2 CHCl 3 rt 65 >20:1 80:20 3 ClCH 2CH 2Cl rt 66 >20:1 85:15 4 Toluene rt 53 >20:1 74:26 5 THF rt 42 >20:1 71:29 6 1,4-Dioxane rt 65 >20:1 76:24 7 (CH 3CH 2) 2O rt 66 >20:1 76:24 8 CH 3CN rt 67 >20:1 87:13 9 benzene rt 60 >20:1 82:18 10 CH 2Cl >20:1 91:9 11 CH 2Cl >20:1 85:15 12 CH 2Cl >20:1 91:9 13 CH 2Cl >20:1 90:10 14 CH 2Cl >20:1 93:7 15 CH 2Cl >20:1 94:6 16 e CH 2Cl >20:1 91:9 17 f CH 2Cl >20:1 90:10 18 g CH 2Cl >20:1 97:3 19 h CH 2Cl >20:1 90:10 20 i CH 2Cl >20:1 98:2 a Reactions performed on 0.1 mmol scale using 1a (1 equiv) and 2a (1 equiv) in 0.2 ml of the solvent. b Isolated yields are given. c Determined by 1 H NMR of a crude reaction mixture. d Determined by a chiral stationary phase HPLC. e Reaction was performed in 0.4 ml of CH2Cl2. f Reaction was performed in 0.1 ml of CH2Cl2. g Reaction was performed using 4e (10 mol%). h Reaction was performed using 4e (5 mol%). i Reaction was performed using 4e (10 mol%) with the addition of extra portion of 2a (1 equiv) after 4h. S4

5 3. X-ray data for diethyl (3R,3aS,9bR)-3-(4-methoxyphenyl)-8-nitro-4-oxo-1,3a,4,9btetrahydrochromeno[4,3-b]pyrrole-2,2(3H)-dicarboxylate 3s Formula C 24H 24N 2O 9, orthorhombic, space group P , Z = 4, cell constants a = (10) Å, b = (3) Å, c = (5) Å, V = (8) Å 3. The data was collected on a Bruker Smart Apex2 diffractometer at 100 K using Incoatec IµS Cu-K α (λ = Å) as a source of radiation. The integration of the data yielded a total of reflections to a θ angle of , of which 4787 were independent (R int = 2.12%,) and 4786 were greater than 2σ(F 2 ). The final anisotropic full-matrix leastsquares refinement on F 2 with 323 variables converged at R 1 = 2.81%, for the observed data and wr 2 = 7.34% for all data. Hydrogen atom connected to nitrogen atom in pyrrole ring was located in the difference Fourier map and allowed to refine freely in isotropic model. The rest of hydrogen atoms were placed in calculated positions and refined isotropically by using a riding model. The goodness-offit was The absolute configuration of 3s was determined from anomalous scattering, by calculating the Flack parameter: 0.03(2) from 2016 selected quotients (Parsons' method) and Hooft parameter: 0.017(19). CCDC contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via S5

6 An asymmetric unit of X crystal structure. Atomic displacement ellipsoids draw with 50% probability level. Hydrogens atoms are shown as fixed-size spheres for better clarity. S6

7 4. NMR data 3a Diethyl (3R,3aS,9bR)-8-nitro-4-oxo-3-phenyl-1,3a,4,9b-tetrahydrochromeno[4,3-b]pyrrole- 2,2(3H)-dicarboxylate (Scheme 3) 1 H NMR 13 C NMR S7

8 3b Diethyl (3R,3aS,9bR)-8-bromo-4-oxo-3-phenyl-1,3a,4,9b-tetrahydrochromeno[4,3-b]pyrrole- 2,2(3H)-dicarboxylate (Scheme 3) 1 H NMR 13 C NMR S8

9 3c Diethyl (3R,3aS,9bR)-8-chloro-4-oxo-3-phenyl-1,3a,4,9b-tetrahydrochromeno[4,3-b]pyrrole- 2,2(3H)-dicarboxylate (Scheme 3) 1 H NMR 13 C NMR S9

10 3d Diethyl (3R,3aS,9bR)-4-oxo-3-phenyl-1,3a,4,9b-tetrahydrochromeno[4,3-b]pyrrole-2,2(3H)- dicarboxylate (Scheme 3) 1 H NMR 13 C NMR S10

11 3e Diethyl (3R,3aS,9bR)-6-methyl-4-oxo-3-phenyl-1,3a,4,9b-tetrahydrochromeno[4,3-b]pyrrole- 2,2(3H)-dicarboxylate (Scheme 3) 1 H NMR 13 C NMR S11

12 3f Diethyl (3R,3aS,9bR)-8-metoxy-4-oxo-3-phenyl-1,3a,4,9b-tetrahydrochromeno[4,3-b]pyrrole- 2,2(3H)-dicarboxylate (Scheme 3) 1 H NMR 13 C NMR S12

13 3g Diethyl (3R,3aS,9bR)-6,8-dichloro-4-oxo-3-phenyl-1,3a,4,9b-tetrahydrochromeno[4,3-b]pyrrole- 2,2(3H)-dicarboxylate (Scheme 3) 1 H NMR 13 C NMR S13

14 3h Diethyl (3R,3aS,9bR)-8-fluoro-6-methyl-4-oxo-3-phenyl-1,3a,4,9b-tetrahydrochromeno[4,3- b]pyrrole-2,2(3h)-dicarboxylate (Scheme 3) 1 H NMR 13 C NMR S14

15 3i Diethyl (3R,3aS,9bR)-4-oxo-3-phenyl-1,3a,4,9b-tetrahydro-2H-benzo[g]chromeno[4,3-b]pyrrole- 2,2(3H)-dicarboxylate (Scheme 3) 1 H NMR 13 C NMR S15

16 3j Diethyl (3R,3aS,9bR)-3-(4-trifluoromethylphenyl)-8-nitro-4-oxo-1,3a,4,9btetrahydrochromeno[4,3-b]pyrrole-2,2(3H)-dicarboxylate (Table 2, entry 2) 1 H NMR 13 C NMR S16

17 3k Diethyl (3R,3aS,9bR)-3-(4-cyanophenyl)-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3- b]pyrrole-2,2(3h)-dicarboxylate (Table 2, entry 3) 1 H NMR 13 C NMR S17

18 3l Diethyl (3R,3aS,9bR)-3-(4-nitrophenyl)-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3- b]pyrrole-2,2(3h)-dicarboxylate (Table 2, entry 4) 1 H NMR 13 C NMR S18

19 3m Diethyl (3R,3aS,9bR)-3-(4-bromophenyl)-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3- b]pyrrole-2,2(3h)-dicarboxylate (Table 2, entry 5) 1 H NMR 13 C NMR S19

20 3n Diethyl (3R,3aS,9bR)-3-(4-chlorophenyl)-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3- b]pyrrole-2,2(3h)-dicarboxylate (Table 2, entry 6) 1 H NMR 13 C NMR S20

21 3o Diethyl (3R,3aS,9bR)-3-(3-chlorophenyl)-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3- b]pyrrole-2,2(3h)-dicarboxylate (Table 2, entry 7) 1 H NMR 13 C NMR S21

22 3p Diethyl (3R,3aS,9bR)-3-(2-chlorophenyl)-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3- b]pyrrole-2,2(3h)-dicarboxylate (Table 2, entry 8) 1 H NMR 13 C NMR S22

23 3q Diethyl (3R,3aS,9bR)-3-(4-methylphenyl)-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3- b]pyrrole-2,2(3h)-dicarboxylate (Table 2, entry 9) 1 H NMR 13 C NMR S23

24 3r Diethyl (3R,3aS,9bR)-3-(4-methoxyphenyl)-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3- b]pyrrole-2,2(3h)-dicarboxylate (Table 2, entry 10) 1 H NMR 13 C NMR S24

25 3s Diethyl (3R,3aS,9bR)-3-(4-methoxyphenyl)-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3- b]pyrrole-2,2(3h)-dicarboxylate (Table 2, entry 11) 1 H NMR 13 C NMR S25

26 3t Diethyl (3R,3aS,9bR)-3-naphtyl-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3-b]pyrrole- 2,2(3H)-dicarboxylate (Table 2, entry 12) 1 H NMR 13 C NMR S26

27 3u Diethyl (3R,3aS,9bR)-3-(1,3-benzodioxol-5-yl)-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3- b]pyrrole-2,2(3h)-dicarboxylate (Table 2, entry 13) 1 H NMR 13 C NMR S27

28 3v Diethyl (3R,3aS,9bR)-3-(furan-2-yl)-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3-b]pyrrole- 2,2(3H)-dicarboxylate (Table 2, entry 14) 1 H NMR 13 C NMR S28

29 3w Diethyl (3R,3aS,9bR)-3-ethyl-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3-b]pyrrole- 2,2(3H)-dicarboxylate (Table 2, entry 15) 1 H NMR 13 C NMR S29

30 3x Diethyl (3R,3aS,9bR)-3-hexyl-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3-b]pyrrole- 2,2(3H)-dicarboxylate (Table 2, entry 16) 1 H NMR 13 C NMR S30

31 5. HPLC traces 3a Diethyl (3R,3aS,9bR)-8-nitro-4-oxo-3-phenyl-1,3a,4,9b-tetrahydrochromeno[4,3-b]pyrrole- 2,2(3H)-dicarboxylate (Scheme 3) Racemic sample Enantiomerically enriched sample S31

32 3b Diethyl (3R,3aS,9bR)-8-bromo-4-oxo-3-phenyl-1,3a,4,9b-tetrahydrochromeno[4,3-b]pyrrole- 2,2(3H)-dicarboxylate (Scheme 3) Racemic sample Enantiomerically enriched sample S32

33 3c Diethyl (3R,3aS,9bR)-8-chloro-4-oxo-3-phenyl-1,3a,4,9b-tetrahydrochromeno[4,3-b]pyrrole- 2,2(3H)-dicarboxylate (Scheme 3) Racemic sample Enantiomerically enriched sample S33

34 3d Diethyl (3R,3aS,9bR)-4-oxo-3-phenyl-1,3a,4,9b-tetrahydrochromeno[4,3-b]pyrrole-2,2(3H)- dicarboxylate (Scheme 3) Racemic sample Enantiomerically enriched sample S34

35 3e Diethyl (3R,3aS,9bR)-6-methyl-4-oxo-3-phenyl-1,3a,4,9b-tetrahydrochromeno[4,3-b]pyrrole- 2,2(3H)-dicarboxylate (Scheme 3) Racemic sample Enantiomerically enriched sample S35

36 3f Diethyl (3R,3aS,9bR)-8-metoxy-4-oxo-3-phenyl-1,3a,4,9b-tetrahydrochromeno[4,3-b]pyrrole- 2,2(3H)-dicarboxylate (Scheme 3) Racemic sample Enantiomerically enriched sample S36

37 3g Diethyl (3R,3aS,9bR)-6,8-dichloro-4-oxo-3-phenyl-1,3a,4,9b-tetrahydrochromeno[4,3-b]pyrrole- 2,2(3H)-dicarboxylate (Scheme 3) Racemic sample Enantiomerically enriched sample S37

38 3h Diethyl (3R,3aS,9bR)-8-fluoro-6-methyl-4-oxo-3-phenyl-1,3a,4,9b-tetrahydrochromeno[4,3- b]pyrrole-2,2(3h)-dicarboxylate (Scheme 3) Racemic sample Enantiomerically enriched sample S38

39 3i Diethyl (3R,3aS,9bR)-4-oxo-3-phenyl-1,3a,4,9b-tetrahydro-2H-benzo[g]chromeno[4,3-b]pyrrole- 2,2(3H)-dicarboxylate (Scheme 3) Racemic sample Enantiomerically enriched sample S39

40 3j Diethyl (3R,3aS,9bR)-3-(4-trifluoromethylphenyl)-8-nitro-4-oxo-1,3a,4,9btetrahydrochromeno[4,3-b]pyrrole-2,2(3H)-dicarboxylate (Table 2, entry 2) Racemic sample Enantiomerically enriched sample S40

41 3k Diethyl (3R,3aS,9bR)-3-(4-cyanophenyl)-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3- b]pyrrole-2,2(3h)-dicarboxylate (Table 2, entry 3) Racemic sample Enantiomerically enriched sample S41

42 3l Diethyl (3R,3aS,9bR)-3-(4-nitrophenyl)-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3- b]pyrrole-2,2(3h)-dicarboxylate (Table 2, entry 4) Racemic sample Enantiomerically enriched sample S42

43 3m Diethyl (3R,3aS,9bR)-3-(4-bromophenyl)-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3- b]pyrrole-2,2(3h)-dicarboxylate (Table 2, entry 5) Racemic sample Enantiomerically enriched sample S43

44 3n Diethyl (3R,3aS,9bR)-3-(4-chlorophenyl)-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3- b]pyrrole-2,2(3h)-dicarboxylate (Table 2, entry 6) Racemic sample Enantiomerically enriched sample S44

45 3o Diethyl (3R,3aS,9bR)-3-(3-chlorophenyl)-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3- b]pyrrole-2,2(3h)-dicarboxylate (Table 2, entry 7) Racemic sample Enantiomerically enriched sample S45

46 3p Diethyl (3R,3aS,9bR)-3-(2-chlorophenyl)-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3- b]pyrrole-2,2(3h)-dicarboxylate (Table 2, entry 8) Racemic sample Enantiomerically enriched sample S46

47 3q Diethyl (3R,3aS,9bR)-3-(4-methylphenyl)-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3- b]pyrrole-2,2(3h)-dicarboxylate (Table 2, entry 9) Racemic sample Enantiomerically enriched sample S47

48 3r Diethyl (3R,3aS,9bR)-3-(4-methoxyphenyl)-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3- b]pyrrole-2,2(3h)-dicarboxylate (Table 2, entry 10) Racemic sample Enantiomerically enriched sample S48

49 3s Diethyl (3R,3aS,9bR)-3-(4-methoxyphenyl)-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3- b]pyrrole-2,2(3h)-dicarboxylate (Table 2, entry 11) Racemic sample Enantiomerically enriched sample S49

50 3t Diethyl (3R,3aS,9bR)-3-naphtyl-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3-b]pyrrole- 2,2(3H)-dicarboxylate (Table 2, entry 12) Racemic sample Enantiomerically enriched sample S50

51 3u Diethyl (3R,3aS,9bR)-3-(1,3-benzodioxol-5-yl)-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3- b]pyrrole-2,2(3h)-dicarboxylate (Table 2, entry 13) Racemic sample Enantiomerically enriched sample S51

52 3v Diethyl (3R,3aS,9bR)-3-(furan-2-yl)-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3-b]pyrrole- 2,2(3H)-dicarboxylate (Table 2, entry 14) Racemic sample Enantiomerically enriched sample S52

53 3w Diethyl (3R,3aS,9bR)-3-ethyl-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3-b]pyrrole- 2,2(3H)-dicarboxylate (Table 2, entry 15) Racemic sample Enantiomerically enriched sample S53

54 3x Diethyl (3R,3aS,9bR)-3-hexyl-8-nitro-4-oxo-1,3a,4,9b-tetrahydrochromeno[4,3-b]pyrrole- 2,2(3H)-dicarboxylate (Table 2, entry 16) Racemic sample Enantiomerically enriched sample S54

Enantioselective Conjugate Addition of 3-Fluoro-Oxindoles to. Vinyl Sulfone: An Organocatalytic Access to Chiral. 3-Fluoro-3-Substituted Oxindoles

Enantioselective Conjugate Addition of 3-Fluoro-Oxindoles to Vinyl Sulfone: An Organocatalytic Access to Chiral 3-Fluoro-3-Substituted Oxindoles Xiaowei Dou and Yixin Lu * Department of Chemistry & Medicinal