A General and Mild Copper-Catalyzed Arylation of Diethyl Malonate

Transcription

1 A General and Mild Copper-Catalyzed Arylation of Diethyl Malonate 1 Edward J. Hennessy and Stephen L. Buchwald Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA Supporting Information General Considerations: All reactions were carried out in oven-dried glassware that was cooled under argon. THF was purchased from J. T. Baker in a CYCLE-TAINER solvent delivery keg, which was vigorously purged with argon for two hours and further purified by passing through two packed columns of neutral alumina under argon pressure. Copper (I) iodide (98%) was purchased from Strem Chemical Company. Cesium carbonate was purchased from both Chemetall and Strem, and the bulk of the reagent was stored under nitrogen in a Vacuum Atmospheres glovebox. Small portions (5-10 g) were removed from the glovebox as needed and stored in a benchtop dessicator in glass vials. 2-Phenylphenol was purchased from Fluka and was recrystallized from hexanes prior to use. Diethyl malonate was purchased from Alfa Aesar and was used without further purification. 4-Iodoaniline (Table 1, Entry 16) was purchased from Aldrich and was recrystallized from hexanes prior to use. 4-Iodoacetanilide (Table 1, Entry 15) was prepared by treatment of a CH 2 Cl 2 solution of 4-iodoaniline with acetyl chloride in the presence of triethylamine. All other aryl iodides were obtained from commercial sources and were used as received. Thin layer chromatography was performed using EM Science silica gel 60 F 254 plates; after development, the plates were stained using a solution prepared from 2 g KMnO 4 and 12g Na 2 CO 3 in 200 ml H 2 O. Column chromatography was done using either Silicycle or EM Science silica gel ( mesh). Melting points were obtained using a Mel- Temp apparatus (Laboratory Devices) and are uncorrected. IR spectra for all previously unreported compounds were obtained by placing the neat sample on the DiComp probe of an ASI ReactIR 1000 instrument. Elemental analyses were performed by Atlantic Microlabs, Inc.,

2 2 Norcross, GA. 1 H NMR and 13 C NMR were obtained using a Varian 300 MHz spectrometer, with chemical shifts referenced to residual protons in the deuterated solvent. Gas chromatographic analysis was performed on a Hewlett Packard 6890 instrument equipped with a FID detector and a Hewlett Packard HP-1 (10 m x 0.2 mm i.d.) capillary column. Mass spectra were obtained using a Hewlett Packard Model G1800B GCD. All yields reported in Table 1 refer to isolated yields (average of two runs) of products estimated to be >95% pure as determined by 1 H NMR and GC analysis. The yields reported below may differ from those in Table 1, as they refer to the isolated yields of the single runs whose products were submitted for elemental analysis. In addition to 1 H NMR 1 and 13 C NMR, all previously unreported compounds were further characterized by elemental analysis and IR. Those compounds described in the literature were positively identified by comparing their 1 H NMR spectra to previously reported data. 2 General Procedure for Malonate Arylation: An oven-dried Schlenk tube equipped with a magnetic stirbar and a Teflon stopcock was evacuated while hot and allowed to cool under argon. The tube was charged sequentially with CuI (9.6 mg, 5.0 mol %), 2-phenylphenol (17.1 mg, 10.0 mol %), Cs 2 CO 3 (0.490 g, 1.50 mmol), and the aryl iodide (1.00 mmol), if a solid. The tube was evacuated and backfilled with argon (3 times), and the Teflon stopcock was replaced with a rubber septum. The aryl iodide (if a liquid) was added volumetrically (1.00 mmol), followed by diethyl malonate (304 µl, 2.00 mmol) and anhydrous THF (1.0 ml). The septum was replaced by the Teflon stopcock under a positive pressure of argon, and the sealed tube was placed in an oil bath preheated to 70 C. After the designated time period, the reaction was allowed to cool to room temperature and was then partitioned between ethyl acetate (20 ml) and saturated aqueous NH 4 Cl (10 ml). The organic portion was dried (Na 2 SO 4 ), filtered through a plug of Celite, and concentrated on a rotary evaporator. The material thus obtained was purified by silica gel chromatography to give the product α-aryl malonate.

3 3 Diethyl (3,5-dimethylphenyl) malonate (Table 1, Entry 2): Reaction time 27 h; silica gel chromatography (60:40 toluene:ch 2 Cl 2 ; R f = 0.29) afforded a colorless oil (96%). 1 H NMR (CDCl 3 ) δ 1.28 (t, J = 7.2 Hz, 6H), 2.32 (s, 6H), 4.22 (m, 4H), 4.55 (s, H), 6.98 (s, 1H), 7.01 (s, 2H). 13 C NMR (CDCl 3 ) δ 14.14, 21.39, 57.93, 61.83, , , , , Calc. For C 15 H 20 O 4 : C 68.16, H 7.63; Found: C 68.45, H IR (neat) ν (cm -1 ) 1733, Diethyl (2-isopropylphenyl) malonate (Table 1, Entry 4): Reaction time 31 h, using 10 mol% CuI and 15 mol% 2-phenylphenol; silica gel chromatography (80:20 hexanes:ethyl acetate; R f = 0.43) afforded a pale yellow oil (86%). 1 H NMR (CDCl 3 ) δ 1.26 (d, J = 6.9 Hz, 6H), 1.27 (t, J = 7.2 Hz, 6H), 3.13 (septet, J = 6.9 Hz, 1H), 4.23 (m, 4H), 5.01 (s, 1H), (m, 5H aromatic). 13 C NMR (CDCl 3 ) δ 14.19, 23.87, 29.49, 53.69, 61.91, , , , , , , Calc. For C 16 H 22 O 4 : C 69.04, H 7.97; Found: C 69.25, H IR (neat) ν (cm -1 ) 1733, Diethyl (3-pyridyl) malonate (Table 1, Entry 6): Reaction time 26.5 h; GC analysis indicated that in this time the reaction had gone to only 90% conversion. Silica gel chromatography (1:1 hexanes:ethyl acetate; R f = 0.27) afforded a pale yellow oil (71%). Note: chromatography and analysis should be performed as quickly as possible following reaction workup, as the product slowly decomposes. 1 H NMR (CDCl 3 ) δ 1.28 (t, J = 7.2 Hz, 6H), 4.24 (m, 4H), 4.63 (s, 1H), 7.33 (m, 1H aromatic), 7.86 (m, 1H aromatic), 8.59 (m, 2H aromatic). 13 C NMR (CDCl 3 ) δ 14.10, 55.57, 62.33, , , , , , Calc. For C 12 H 15 NO 4 : C 60.75, H 6.37; Found: C 60.51, H IR (neat) ν (cm -1 ) Diethyl (3-trifluoromethylphenyl) malonate (Table 1, Entry 7): Reaction time 24 h; silica gel chromatography (1:1:0.03 toluene:hexanes:acetone; R f = 0.39) afforded a colorless oil (88%). 1 H NMR (CDCl 3 ) δ 1.28 (t, J = 7.2 Hz, 6H), 4.24 (m, 4H), 4.67 (s, H), (m, 5H aromatic). 13 C NMR (CDCl 3 ) δ 14.01, 57.74, 62.23, (q, J = Hz), (q, J = 3.8

4 4 Hz), (q, J = 3.9 Hz), , (q, J = 32.4 Hz), , , Calc. For C 14 H 15 O 4 F 3 : C 55.26, H 4.97, F 18.73; Found: C 55.56, H 4.96, F IR (neat) ν (cm -1 ) Diethyl (2,4-dimethoxyphenyl) malonate (Table 1, Entry 8): Reaction time 30 h; silica gel chromatography (75:25 hexanes:ethyl acetate; R f = 0.38) afforded a pale yellow solid (91%), mp = C. 1 H NMR (CDCl 3 ) δ 1.27 (t, J = 7.2 Hz, 6H), (s, 3H), (s, 3H), 4.22 (dq, J = 2.1Hz, 7.2 Hz, 4H), 5.02 (s, H), (dt, J = 2.4 Hz, 8.1 Hz, 2H aromatic), 7.26 (d, J = 8.1 Hz, 1H aromatic). 13 C NMR (CDCl 3 ) δ 14.21, 50.73, 55.48, 55.75, 61.66, 98.70, , , , , , Calc. For C 15 H 20 O 6 : C 60.80, H 6.80; Found: C 60.86, H IR (neat) ν (cm -1 ) 1513, 1725, Diethyl (3-fluorophenyl) malonate (Table 1, Entry 9): Reaction time 24 h; silica gel chromatography (1:1:0.03 toluene:hexanes:acetone; R f = 0.38) afforded a colorless oil (89%). 1 H NMR (CDCl 3 ) δ 1.28 (t, J = 7.2 Hz, 6H), 4.23 (dq, J = 3.3 Hz, 7.2 Hz, 4H), 4.61 (s, 1H), (m, 1H aromatic), (m, 2H aromatic), (m, 1H aromatic). 13 C NMR (CDCl 3 ) δ 14.14, 57.70, 62.16, (d, J = 21.3 Hz), (d, J = 22.7 Hz), (d, J = 3.0 Hz), (d, J = 8.4 Hz), (d, J = 8.1 Hz), (d, J = Hz), Calc. For C 13 H 15 O 4 F: C 61.41, H 5.95, F 7.47; Found: C 61.18, H 5.91, F IR (neat) ν (cm -1 ) Diethyl (3-nitrophenyl) malonate (Table 1, Entry 10): Reaction time 24 h; silica gel chromatography (80:20 hexanes:ethyl acetate; R f = 0.26) afforded a pale yellow oil (83%). 1 H NMR (CDCl 3 ) δ 1.29 (t, J = 7.2 Hz, 6H), 4.25 (m, 4H), 4.73 (s, 1H), 7.57 (m, 1H aromatic), 7.79 (m, 1H aromatic), 8.22 (m, 1H aromatic), 8.31 (m, 1H aromatic). 13 C NMR (CDCl 3 ) δ 14.12, 57.49, 62.50, , , , , , , Calc. For C 13 H 15 NO 6 : C 55.51, H 5.38; Found: C 55.56, H IR (neat) ν (cm -1 ) 1530, Diethyl (3-carboethoxyphenyl) malonate (Table 1, Entry 12): Reaction time 24 h; silica gel chromatography (7:3 hexanes:diethyl ether; R f = 0.34) afforded a colorless oil (86%).

5 5 1 H NMR (CDCl 3 ) δ 1.28 (t, J = 7.2 Hz, 6H), 1.40 (t, J = 7.2 Hz, 3H), 4.23 (dq, J = 3.0 Hz, 7.2 Hz, 4H), 4.38 (q, J = 7.2 Hz, 2H), 4.68 (s, 1H), 7.46 (m, 1H aromatic), 7.65 (m, 1H aromatic), (m, 2H aromatic). 13 C NMR (CDCl 3 ) δ 14.09, 14.42, 57.81, 61.19, 62.08, , , , , , , , Calc. For C 16 H 20 O 6 : C 62.33, H 6.54; Found: C 62.12, H IR (neat) ν (cm -1 ) Diethyl (4-hydroxyphenyl) malonate (Table 1, Entry 13): Reaction time 29 h, using 3 equivalents of diethyl malonate and 3.5 equivalents of cesium carbonate; silica gel chromatography (65:35 hexanes:ethyl acetate; R f = 0.30) afforded a colorless oil which crystallized upon standing (76%), mp = ºC. 1 H NMR (CDCl 3 ) δ 1.27 (t, J = 7.2 Hz, 6H), 4.22 (m, 4H), 4.56 (s, 1H), 5.71 (s, 1H, chemical shift dependent upon NMR sample concentration), 6.76 (AB, J AB = 2.1 Hz, 8.4 Hz, 2H aromatic), 7.24 (AB, J AB = 2.1 Hz, 8.4 Hz, 2H aromatic). 13 C NMR (CDCl 3 ) δ 14.19, 57.35, 62.12, , , , , Calc. For C 13 H 16 O 5 : C 61.90, H 6.39; Found: C 61.84, H IR (neat) ν (cm -1 ) 1519, 1698, 1737, Diethyl (3-cyanophenyl) malonate (Table 1, Entry 14): Reaction time 24 h; silica gel chromatography (80:20 hexanes:ethyl acetate;r f = 0.29) afforded a colorless oil (61%). 1 H NMR (CDCl 3 ) δ 1.28 (t, J = 7.2 Hz, 6H), 4.24 (m, 4H), 4.64 (s, 1H), (m, 1H aromatic), (m, 1H aromatic), (m, 1H aromatic). 13 C NMR (CDCl 3 ) δ 14.04, 57.34, 62.35, , , , , , , , Calc. For C 14 H 15 NO 4 : C 64.36, H 5.79; Found C 64.19, H IR (neat) ν (cm -1 ) 1731, Diethyl (4-(N-acetyl)-aminophenyl) malonate (Table 1, Entry 15): Reaction time 29 h, using 3 equivalents of diethyl malonate and 2.5 equivalents of cesium carbonate; silica gel chromatography (crude product loaded onto column as solution in CH 2 Cl 2, column eluted with diethyl ether; R f = 0.24) afforded a colorless solid (78%), mp = C. 1 H NMR (CDCl 3 ) δ 1.26 (t, J = 7.2 Hz, 6H), 2.15 (s, 3H), 4.21 (m, 4H), 4.58 (s, 1H), 7.31 (s, 1H, chemical shift

6 6 dependent upon NMR sample concentration), 7.33 (AB, J AB = 7.2 Hz, 2H aromatic), 7.48 (AB, J AB = 7.2 Hz, 2H aromatic). 13 C NMR (CDCl 3 ) δ 14.21, 16.60, 57.56, 62.08, , , , , , Calc. For C 15 H 19 NO 5 : C 61.42, H 6.53; Found: C 61.39, H IR (neat) ν (cm -1 ) 1663, 1725, 1744, 3263, Diethyl (4-aminophenyl) malonate (Table 1, Entry 16): Reaction time 29 h; silica gel chromatography (3:1 ether:hexanes;r f = 0.30) afforded a pale yellow oil (69%). Note: chromatography and analysis should be performed as quickly as possible following reaction workup, as the product slowly decomposes. 1 H NMR (CDCl 3 ) δ 1.26 (t, J = 7.2 Hz, 6H), 3.70 (s, 2H, chemical shift depends on NMR sample concentration), 4.21 (m, 4H), 4.50 (s, 1H), 6.67 (AB, J AB = 2.1 Hz, 6.5 Hz, 2H aromatic), 7.19 (AB, J AB = 2.1 Hz, 6.5 Hz). 13 C NMR (CDCl 3 ) δ 14.17, 57.30, 61.77, , , , , Calc. For C 13 H 17 NO 4 : C 62.14, H 6.82; Found C 62.17, H IR (neat) ν (cm -1 ) 1519, 1625, 1723, 3228, 3379, References (1) The methylene protons of the diester ethyl group are diasterotopic, and thus the 1 H NMR signal is a doublet of quartets. When clearly resolved, the coupling constant is given for this splitting. Otherwise, it is reported as a multiplet. (2) a) Table 1, Entries 1 and 11: Djakovitch, L.; Kohler, K. J. Organomet. Chem. 2000, 606, 101. (b) Table 1, Entries 3 and 5: Guanti, G.; Narisano, E.; Podgorski, T.; Thea, S.; Williams, A. Tetrahedron 1990, 46, 7081.