Supporting Information

Transcription

1 Supporting Information Unconventional Passerini Reaction towards α-aminoxyamides Ajay L. Chandgude, Alexander Dömling* Department of Drug Design, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The etherlands Homepage:

2 Contents General Information... 3 Experimental Procedures and Spectral Data... 4 Procedure for the synthesis of -hydroxylamines and acylation/ sulfonylation... 1 Reference MR spectra and SFC-MS Chromatograms... 13

3 General Information Reagents were available from commercial suppliers (Sigma Aldrich, ABCR, Acros and AK Scientific) and used without any purification unless otherwise noted. Thin layer chromatography was performed on Fluka precoated silica gel plates (.2 mm thick, particle size 25 µm). Flash chromatography was performed on a Teledyne ISC Combiflash Rf, using RediSep Rf ormal-phase Silica Flash Columns (Silica Gel 6 Å, 23-4 mesh) and on a Reveleris X2 Flash Chromatography, using Grace Reveleris Silica flash cartridges (12 grams). All ultrasonic irradiation reactions were carried out in a Sonicor SC Ultrasonic Table Top Cleaner with 22/24V, frequency of 5/6 Hz and 25 Amps. uclear magnetic resonance spectra were recorded on a Bruker Avance 5 spectrometer. Chemical shifts for 1 H MR were reported relative to TMS (δ ppm) and coupling constants were in hertz (Hz). The following abbreviations were used for spin multiplicity: s = singlet, d = doublet, t = triplet, dt = double triplet, ddd = doublet of double doublet, and m = multiplet. Chemical shifts for 13 C MR reported in ppm relative to the solvent peak (CDCl 3 δ ppm). Mass spectra were measured on a Waters Investigator Supercritical Fluid Chromatograph with a 31 MS Detector (ESI) using a solvent system of methanol and C 2 on a Viridis silica gel column ( mm, 5 µm particle size) and reported as (m/z). High resolution mass spectra were recorded using a LTQ-rbitrap-XL (Thermo Fisher Scientific; ESI pos. mode) at a resolution of 6@m/z4.

4 Experimental Procedures and Spectral Data General procedure for the synthesis of α-aminoxy amides: A 1 ml tube was charged with aldehyde (1. mmol) and isocyanide (1. mmol) and HS/HBT/-hydroxamic acids (2 mmol) or HPI (1.5 mmol) with THF (1 ml). The mixture was sonicated in the water bath of an ultrasonic cleaner (frequency of 5/6 Hz, 22/24V, 25 Amps) at room temperature till completion of the reaction (monitored by TLC). The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography using EtAc hexane as eluent. Spectral Data 2-((2,5-dioxopyrrolidin-1-yl)oxy)-3-methyl--phenethylbutanamide (4a) btained from.5 mmol reaction as a colorless liquid, yield: 154 mg (97%); 1 H MR (5 MHz, CDCl 3 ) δ (m, 2H), 7.19 (t, J = 7.3, 1H), 7.14 (d, J = 7.2, 2H), 4.16 (d, J = 8.2, 1H), (m, 2H), 3.38 (s, 1H), 2.74 (td, J = 6.8, 2.5, 2H), 2.59 (s, 4H), (m, 1H), 1.6 (d, J = 6.6, 3H),.97 (d, J = 6.8, 3H). 13 C MR (126 MHz, CDCl 3 ) δ 17.8, 155.3, 139.8, 129., 128.2, 126.1, 72.2, 48.2, 37.2, 32.2, 25.5, 18.5, MS (ESI) m/z calculated [M+H] + : ; found [M+H] + : HRMS (ESI) m/z calculated [M+H] + : ; found [M+H] + : benzyl-2-cyclohexyl-2-((2,5-dioxopyrrolidin-1-yl)oxy)acetamide (4b) btained from 1 mmol reaction as a white solid, yield: 296 mg (86%); 1 H MR (5 MHz, CDCl 3 ) δ (m, 2H), 7.2 (t, J = 7.3, 1H), 7.13 (d, J = 7.5, 2H), 4.64 (s, 2H), 4.36 (br s, 1H), 3.68 (d, J = 4.4, 1H), 2.71 (s, 4H), 2.1 (d, J = 12.4, 1H), (m, 5H), (m, 2H), (m, 1H), (m, 2H). 13 C MR (126 MHz, CDCl 3 ) δ 17.8, 156.7, 139.5, 128.3, 126.7, 126.6, 71.8, 5.4, 41.5, 28.8, 28.5, 26.3, 25.9, 25.7, MS (ESI) m/z calculated [M+H] + : 345.4; found [M+H] + : HRMS (ESI) m/z calculated [M+H] + : ; found [M+H] + :

5 -benzyl-2-((2,5-dioxopyrrolidin-1-yl)oxy)-3-methylbutanamide (4c) H btained from 1 mmol reaction as a white viscus liquid, yield: 276 mg (91%); 1 H MR (5 MHz, CDCl 3 ) δ 7.28 (t, J = 7.5, 2H), 7.19 (t, J = 7.3, 1H), 7.13 (d, J = 7.5, 2H), 4.65 (s, 2H), 4.31 (d, J = 7.9, 1H), 3.87 (s, 1H), 2.71 (s, 4H), (m, 1H), 1.1 (d, J = 6.6, 3H), 1.3 (d, J = 6.8, 3H). 13 C MR (126 MHz, CDCl 3 ) δ 17.8, 156.8, 139.5, 128.3, 126.7, 126.6, 72.6, 5.3, 32.3, 25.6, MS (ESI) m/z calculated [M+H] + : 35.34; found [M+H] + : HRMS (ESI) m/z calculated [M+H] + : ; found [M+H] + : cyclohexyl-2-((1,3-dioxoisoindolin-2-yl)oxy)-4-phenylbutanamide (4d) btained from.5 mmol reaction as a colorless liquid, yield: 147 mg (72%); 1 H MR (5 MHz, CDCl 3 ) δ 7.86 (d, J = 3.1, 2H), (m, 2H), (m, 6H), 4.64 (brs, 1H), 3.44 (brs, 1H), 2.88 (brs, 2H), (m, 2H), 1.41 (brs, 5H), 1.9 (brs, 5H). 13 C MR (126 MHz, CDCl 3 ) δ 163.9, 153.6, 141.1, 134.5, 129.4, 128.6, 128.5, 126.1, 123.6, 66., 54.7, 36.5, 33.8, 31.2, 25.5, MS (ESI) m/z calculated [M+H] + : 47.47; found [M+H] + : HRMS (ESI) m/z calculated [M+H] + : ; found [M+H] + : benzyl-2-cyclohexyl-2-((1,3-dioxoisoindolin-2-yl)oxy)acetamide (4e) H btained from.5 mmol reaction as a colorless liquid, yield: 165 mg (84%); 1 H MR (5 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), (m, 3H), 6.99 (d, J = 7.2, 2H), 4.65 (s, 2H), (m, 1H), 3.64 (d, J = 6., 1H), 2.15 (d, J = 12.4, 1H), (m, 2H), (m, 2H), 1.68 (d, J = 12.5, 1H), (m, 5H). 13 C MR (126 MHz, CDCl 3 ) δ 163.6, 157.2, 139.3, 134.5, 129.3, 128.1, 126.6, 126.4, 123.7, 72., 5.3, 41.7, 28.9, 28.5, 26.3, 25.9, MS (ESI) m/z calculated [M+H] + : ; found [M+H] + : HRMS (ESI) m/z calculated [M+H] + : ; found [M+H] + : ((1,3-dioxoisoindolin-2-yl)oxy)-3,3-dimethyl--phenethylbutanamide (4f)

6 H btained from.5 mmol reaction as a colorless liquid, yield: 119 mg (63%); 1 H MR (5 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), (m, 3H), 6.99 (d, J = 6.5, 2H), 4.25 (s, 1H), (m, 2H), (m, 2H), 1.91 (s, 1H), 1.9 (s, 9H). 13 C MR (126 MHz, CDCl 3 ) δ 163.3, 155.2, 139.5, 134.4, 129.3, 128.9, 128.8, 128.1, 126., 123.6, 74.3, 49.4, 37.2, 35.7, 26., MS (ESI) m/z calculated [M+H] + : ; found [M+H] + : HRMS (ESI) m/z calculated [M+H] + : ; found [M+H] + : methyl 2-(2-((1,3-dioxoisoindolin-2-yl)oxy)-3-phenylpropanamido)-3-methylbutanoate (4g) btained from.5 mmol reaction as a colorless liquid, yield: 15 mg (71%) as a mixture of diastereomers (1:1.14); 1 H MR (5 MHz, CDCl 3 ) δ (m, 4H), (m, 4H), 7.38 (t, J = 9., 4H), (m, 4H), 7.24 (t, J = 7.5, 2H), 4.82 (s, 1H), 4.7 (t, J = 7., 1H), 4.15 (s, 1H), 3.91 (s, 1H), 3.62 (s, 3H), 3.55 (s, 3H), (m, 3H), (m, 2H), 3.3 (s, 1H), (m, 1H), (m, 1H),.66 (brs, 3H),.47 (brs, 6H),.36 (brs, 3H). 13 C MR (126 MHz, CDCl 3 ) δ 171.6, 171.6, 163.5, 163.5, 158.4, 136.1, 136., 134.7, 134.5, 129.8, 129.7, 129.7, 129.4, 128.7, 128.6, 127., 127., 123.8, 123.6, 69.4, 68.9, 64.1, 63.8, 52., 51.9, 4.9, 4.2, 31.5, 31.3, 19.2, MS (ESI) m/z calculated [M+H] + : ; found [M+H] + : HRMS (ESI) m/z calculated [M+H] + : ; found [M+H] + : benzyl-2-((1,3-dioxoisoindolin-2-yl)oxy)-4-phenylbutanamide (4h) btained from 1 mmol reaction as a colorless liquid, yield: 314 mg (76%); 1 H MR (5 MHz, CDCl 3 ) δ (m, 4H), (m, 5H), (m, 3H), 6.96 (d, J = 7., 2H), 4.72 (d, J = 5.8, 1H), 4.56 (s, 2H), 3.18 (d, J = 4.7, 1H), (m, 2H), (m, 2H). 13 C MR (126 MHz, CDCl 3 ) δ 163.5, 157.4, 14.9, 139.1, 134.6, 129.3, 128.6, 128.5, 128.2, 126.5, 126.1, 123.8, 66.6, 5.1, 35.9, MS (ESI) m/z calculated [M+H] + : ; found [M+H] + : HRMS (ESI) m/z calculated [M+H] + : ; found [M+H] + :

7 Cl -(4-chlorobenzyl)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-methylbutanamide (4i) btained from.5 mmol reaction as a colorless liquid, yield: 174 mg (9%); 1 H MR (5 MHz, CDCl 3 ) δ 7.86 (dd, J = 5.2, 3.1, 2H), 7.78 (dd, J = 5.2, 3.1, 2H), 7.1 (d, J = 8.1, 2H), 6.93 (d, J = 8., 2H), 4.62 (s, 2H), 4.37 (t, J = 7.2, 1H), 3.7 (d, J = 5.8, 1H), (m, 1H), 1.16 (d, J = 6.6, 3H), 1.9 (d, J = 6.7, 3H). 13 C MR (126 MHz, CDCl 3 ) δ 163.5, 157.4, 137.7, 134.6, 132.2, 129.2, 128.3, 127.9, 123.7, 73., 49.7, 32.6, MS (ESI) m/z calculated [M+H] + : ; found [M+H] + : HRMS (ESI) m/z calculated [M+H] + : ; found [M+H] + : H -benzyl-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-phenylpropanamide (4j) btained from 4 mmol reaction as a white solid, yield: 121 mg (76%); 1 H MR (5 MHz, CDCl 3 ) δ 7.84 (d, J = 3., 2H), 7.74 (d, J = 2.8, 2H), 7.37 (d, J = 7.1, 2H), 7.29 (t, J = 7.2, 2H), (m, 1H), 7.8 (d, J = 6.8, 3H), 6.85 (d, J = 6.2, 2H), 4.9 (brs, 1H), 4.29 (d, J = 16.1, 1H), 4.8 (d, J = 16.1, 1H), 3.32 (brs, 1H), (m, 2H). 13 C MR (126 MHz, CDCl 3 ) δ 163.4, 156.3, 139., 135.8, 134.5, 129.8, 129.3, 128.7, 128.1, 127.1, 126.5, 126.4, 123.8, 68.7, 49.9, 41.. MS (ESI) m/z calculated [M+H] + : 41.43; found [M+H] + : HRMS (ESI) m/z calculated [M+H] + : ; found [M+H] + : ((1,3-dioxoisoindolin-2-yl)oxy)--phenethyl-2-phenylacetamide (4k) btained from.5 mmol reaction as a colourless liquid, yield: 98 mg (49%); 1 H MR (5 MHz, CDCl 3 ) δ 7.84 (d, J = 3., 2H), 7.77 (dd, J = 4.6, 3.2, 2H), 7.41 (t, J = 8.1, 2H), (m, 2H), 7.7 (brs, 3H), 6.88 (brs, 2H), 5.63 (s, 1H), (m, 2H), 2.52 (t, J = 6.7, 2H). 13 C MR (126 MHz, CDCl 3 ) δ 168.2, 164.7, 138.5, 135.6, 134.5, 133.6, 129.8, 129., 128.8, 128.8, 128.7, 128.6, 127.3, 126.6, 123.7, 75.9, 4.3, MS (ESI) m/z calculated [M+H] + : 41.43; found [M+H] + : HRMS (ESI) m/z calculated [M+H] + : ; found [M+H] + :

8 -benzyl-2-(4-chlorophenyl)-2-((1,3-dioxoisoindolin-2-yl)oxy)acetamide (4l) btained from.5 mmol reaction as a white solid, yield: 19 mg (52%); 1 H MR (5 MHz, CDCl 3 ) δ 7.86 (d, J = 2.8, 2H), (m, 2H), 7.6 (d, J = 8.1, 2H), 7.4 (d, J = 8.1, 2H), (m, 4H), 6.9 (d, J = 6.1, 2H), 5.79 (s, 1H), 4.57 (d, J = 15.8, 1H), 4.47 (d, J = 15.9, 1H). 13 C MR (126 MHz, CDCl 3 ) δ 163.4, 156.1, 138.7, 135.8, 135.2, 134.7, 134.5, 129.2, 129.1, 128.2, 127.9, 126.5, 123.9, 69.2, 5.. MS (ESI) m/z calculated [M+H] + : ; found [M+H] + : HRMS (ESI) m/z calculated [M+H] + : ; found [M+H] + : benzyl-2-((1,3-dioxoisoindolin-2-yl)oxy)-2-(2-nitrophenyl)acetamide (4m) H 2 btained from.5 mmol reaction as a brown solid, yield: 156 mg (72%); 1 H MR (5 MHz, CDCl 3 ) δ 8.15 (dd, J = 33.5, 7.7, 2H), (m, 7H), 7.55 (t, J = 7.4, 1H), (m, 3H), 7.3 (d, J = 6.4, 2H), 6.53 (s, 1H), 4.77 (s, 2H). 13 C MR (126 MHz, CDCl 3 ) δ 163.2, 154.4, 147.5, 138.9, 134.7, 134.2, 133.6, 129.4, 129.2, 129.1, 128.2, 126.8, 126.6, 125.3, 123.8, 66.1, 5.9. MS (ESI) m/z calculated [M+H] + : 432.4; found [M+H] + : HRMS (ESI) m/z calculated [M+H] + : ; found [M+H] + : (2,2-diethoxyethyl)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-methylbutanamide (4o) btained from.5 mmol reaction as a colorless liquid, yield: 143 mg (76%); 1 H MR (5 MHz, CDCl 3 ) δ 7.86 (dd, 2H), (m, 2H), (m, 2H), 3.82 (d, J = 2.2, 1H), 3.73 H (dd, J = 12.5, 5.6, 1H), (m, 2H), (m, 1H), (m, 2H), (m, 1H), (m, 12H). 13 C MR (126 MHz, CDCl 3 ) δ 163.1, 158.5, 134.4, 129.3, 123.6, 12., 72.6, 63.5, 63.1, 5.4, 31.9, 18.5, 18.2, 15.1, MS (ESI) m/z calculated [M+H] + : ; found [M+H] + : HRMS (ESI) m/z calculated [M+H] + : ; found [M+H] + : methyl (4p) 2-(2-((1,3-dioxoisoindolin-2-yl)oxy)-3-methylbutanamido)-3-methylbutanoate

9 H btained from.5 mmol reaction as a colorless liquid, yield: 86 mg (46%) as a mixture of diastereomers (1:1.5); 1 H MR (5 MHz, CDCl 3 ) δ (m, 4H), 7.78 (dd, J = 5.4, 3.1, 4H), 4.37 (d, J = 4., 1H), 4.27 (d, J = 4., 2H), 4.13 (d, J = 8.6, 1H), 3.67 (s, 3H), 3.62 (s, 3H), 3.25 (s, 1H), 3.3 (s, 1H), (m, 2H), (m, 2H), (m, 13H),.73 (dd, J = 15.3, 5.8, 6H),.49 (s, 6H). 13 C MR (126 MHz, CDCl 3 ) δ 171.9, 171.9, 171.7, 163.7, 163.6, 163.6, 163.6, 159.5, 134.7, 134.4, 129.4, 129.4, 123.6, 123.6, 73.8, 73.8, 64.6, 64.3, 64.2, 52., 51.9, 32.7, 32.7, 31.8, 31.8, 31.5, 31.2, 31.2, 19.3, 19.2, 18.5, 18.5, 18.5, MS (ESI) m/z calculated [M+H] + : 377.4; found [M+H] + : HRMS (ESI) m/z calculated [M+H] + : ; found [M+H] + : cyclohexyl-2-((1,3-dioxoisoindolin-2-yl)oxy)--phenethylacetamide (4q) H btained from 1 mmol reaction as a colorless liquid, yield: 316 mg (78%); 1 H MR (5 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), (m, 3H), 6.99 (d, J = 6.8, 2H), (m, 1H), (m, 2H), 2.73 (d, J = 5.3, 1H), (m, 2H), 2.9 (d, J = 12.5, 1H), (m, 5H), (m, 2H), (m, 1H), (m, 2H). 13 C MR (126 MHz, CDCl 3 ) δ 163.3, 156.1, 139.6, 134.4, 129.2, 128.9, 128.1, 126., 123.6, 71.5, 48.8, 41.5, 37.2, 28.9, 28.4, 26.3, 25.9, MS (ESI) m/z calculated [M+H] + : 47.47; found [M+H] + : HRMS (ESI) m/z calculated [M+H] + : ; found [M+H] + : ((1,3-dioxoisoindolin-2-yl)oxy)-3-methyl--phenethylbutanamide (4r) H btained from 1 mmol reaction as a colorless liquid, yield: 324 mg (89%); 1 H MR (5 MHz, CDCl 3 ) δ (m, 2H), (m, 2H), (m, 3H), 7. (d, J = 6.9, 2H), (m, 1H), (m, 2H), (m, 3H), (m, 1H), 1.9 (d, J = 6.5, 3H), 1. (d, J = 6.8, 3H). 13 C MR (126 MHz, CDCl 3 ) δ 163.3, 156.1, 139.6, 134.4, 129.2, 128.9, 128.2, 126.1, 123.7, 72.2, 48.8, 37.2, 32.3, 18.5, MS (ESI) m/z calculated [M+H] + : ; found [M+H] + : HRMS (ESI) m/z calculated [M+H] + : ; found [M+H] + :

10 Procedure for the synthesis of -hydroxylamines and acylation/ sulfonylation Procedure for the synthesis of -benzyl-3-phenyl-2- (pivalamidooxy)propanamide (6) 1 To a solution of 4j (2 mg,.5 mmol) in 5 ml of methanol was added 2 µl of hydrazine hydrate. This mixture was stirred at room temperature over 5 h, at the end of which the solvent was removed and dissolved the residue in 15 ml of DCM and washed it with 3% ahc 3 aqueous solution. The organic layer was dried over anhydrous MgS 4, and then concentrated to afford colorless oil which was subjected to the next step without further purification. To the solution of above crude product in 2 ml of DCM/H 2 (3:1) was added 27 mg of K 2 C 3 (3 equivalent), and followed by 61 µl of pivaloyl chloride (.5 mmol) at C. The resulting mixture was stirred for 12 h, and then 1 ml of DCM added to it and organic layer was separated and after washed with brine dried over anhydrous MgS 4. The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography using EtAc hexane as eluent to afford 6. -benzyl-3-phenyl-2-(pivalamidooxy)propanamide (6)

11 H H btained as a white solid, yield: 126 mg (71%); 1 H MR (5 MHz, CDCl 3 ) δ (m, 4H), (m, 2H), (m, 3H), 7.21 (d, J = 7.3, 2H), 6.76 (s, 1H), 4.48 (dd, J = 14.7, 6., 1H), (m, 2H), 3.27 (dd, J = 13.9, 4.1, 1H), 2.95 (dd, J = 13.9, 8.2, 1H), 1.26 (s, 9H). 13 C MR (126 MHz, CDCl 3 ) δ 176., 172.2, 137.9, 136.6, 132.1, 129.6, 128.9, 128.7, 127.8, 127.6, 127.1, 73., 43.2, 4.9, 27.5, 27.1, 27.. MS (ESI) m/z calculated [M+H] + : ; found [M+H] + : Synthesis of -benzyl-2-((4-methylphenylsulfonamido)oxy)-3 phenylpropanamide (7) To a solution of 4j (2 mg,.5 mmol) in 5 ml of methanol was added 2 µl of hydrazine hydrate. This mixture was stirred at room temperature over 5 h, at the end of which the solvent was removed and dissolved the residue in 15 ml of DCM and washed it with 3% ahc 3 aqueous solution. The organic layer was dried over anhydrous MgS 4, and then concentrated to afford colorless oil which was subjected to the next step without further purification. To the solution of above crude product in 2 ml of DCM/H 2 (3:1) was added 27 mg of K 2 C 3 (3 equivalent), and followed by 8 mg of p-tscl (.5 mmol) at C. The resulting mixture was stirred for 12 h, and then 1 ml of DCM added to it and organic layer was separated and after washed with brine dried over anhydrous MgS 4. The solvent was removed under reduced pressure and the residue was purified by silica gel flash chromatography using EtAc hexane as eluent to afford 7. -benzyl-2-((4-methylphenylsulfonamido)oxy)-3-phenylpropanamide (7) btained as a white solid, yield: 135 mg (64%); 1 H MR (5 MHz, CDCl 3 ) δ 7.78 (d, J = 8.2, 2H), 7.34 (d, J = 8.1, 2H), (m, 4H), (m, 4H), 7.18 (d, J = 7.1, 2H), 6.87 (brs, 1H), 5.87 (s, 1H), 4.45 (dd, J = 14.8,

12 6.1, 1H), (m, 2H), 3.24 (dd, J = 13.9, 4., 1H), 2.93 (dd, J = 13.9, 8.2, 1H), 2.44 (s, 3H). 13 C MR (126 MHz, CDCl 3 ) δ 172.6, 144.6, 137.8, 136.8, 133.1, 13., 129.6, 128.7, 128.7, 128.4, 128.2, 127.8, 127.5, 127., 72.9, 43.1, 4.9, MS (ESI) m/z calculated [M+H] + : ; found [M+H] + : Reference 1. D. W. Zhang, Z. Luo, G. J. Liu and L. H. Weng, Tetrahedron, 29, 65,

13 MR spectra and SFC-MS Chromatograms 2-((2,5-dioxopyrrolidin-1-yl)oxy)-3-methyl--phenethylbutanamide (4a)

14 -benzyl-2-cyclohexyl-2-((2,5-dioxopyrrolidin-1-yl)oxy)acetamide (4b)

15 -benzyl-2-((2,5-dioxopyrrolidin-1-yl)oxy)-3-methylbutanamide (4c)

16 -cyclohexyl-2-((1,3-dioxoisoindolin-2-yl)oxy)-4-phenylbutanamide (4d) H H

17 -benzyl-2-cyclohexyl-2-((1,3-dioxoisoindolin-2-yl)oxy)acetamide (4e) H E+5 1E+5 1E+5 1E+5 1E+5 2E+5 2E+5 2E+5 2E+5 2E+5 2E+5 2E+5 2E+5 H

18 2-((1,3-dioxoisoindolin-2-yl)oxy)-3,3-dimethyl--phenethylbutanamide (4f) H H 3 C H H 3 C

19 methyl 2-(2-((1,3-dioxoisoindolin-2-yl)oxy)-3-phenylpropanamido)-3-methylbutanoate (4g) H C H 3 H 3 C H C H 3 H 3 C

20 -benzyl-2-((1,3-dioxoisoindolin-2-yl)oxy)-4-phenylbutanamide (4h) H E+5 1E+5 1E+5 H

21 -(4-chlorobenzyl)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-methylbutanamide (4i) H Cl H Cl

22 -benzyl-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-phenylpropanamide (4j) H E+5 H

23 2-((1,3-dioxoisoindolin-2-yl)oxy)--phenethyl-2-phenylacetamide (4k) H H

24 -benzyl-2-(4-chlorophenyl)-2-((1,3-dioxoisoindolin-2-yl)oxy)acetamide (4l) H Cl H Cl

25 -benzyl-2-((1,3-dioxoisoindolin-2-yl)oxy)-2-(2-nitrophenyl)acetamide (4m) H H + -

26 -(2,2-diethoxyethyl)-2-((1,3-dioxoisoindolin-2-yl)oxy)-3-methylbutanamide (4o) H 3 C H E H 3 C H

27 methyl 2-(2-((1,3-dioxoisoindolin-2-yl)oxy)-3-methylbutanamido)-3-methylbutanoate (4p) H C H 3 C H H C H 3 C H 3

28 2-cyclohexyl-2-((1,3-dioxoisoindolin-2-yl)oxy)--phenethylacetamide (4q) H C H 3 C H H

29 2-((1,3-dioxoisoindolin-2-yl)oxy)-3-methyl--phenethylbutanamide (4r) E+5 1E+5 1E+5 2E+5 2E+5 2E+5 2E+5 2E+5 3E+5 3E+5 3E+5 3E+5 3E+5 H H

30 -benzyl-3-phenyl-2-(pivalamidooxy)propanamide (6) H H H

31 H H

32 -benzyl-2-((4-methylphenylsulfonamido)oxy)-3-phenylpropanamide (7) H H S H H S

33