Reflexiones sobre el fracaso del arbitraje recogido en la Ley nº 1/

Reaction of 2.1a with HMPA and DIBAL-H (Entry 1)

A flame-dried, 5 mL, round-bottomed flask, equipped with a stir bar and septum pierced with a nitrogen inlet needle was charged with toluene (0.3 mL) and cooled to 0 °C on an ice and water bath. HMPA (36 µL, 0.21 mmol, 6 equiv) and DIBAL-H (0.10 mL of a 1.0 M solution in toluene, 0.10 mmol, 3 equiv) were added sequentially and stirred for 30 min. Alkynoate 2.1a (15 mg, 0.034 mmol, 1 equiv), dissolved in toluene (0.2 mL), was added to the reaction in one portion via syringe and stirred for 5 h. A small aliquot was removed from the reaction, diluted with diethyl ether (2 mL) and washed with 1 M HCl, saturated NaHCO3, and brine (2 mL each),

dried over MgSO4, filtered and concentrated. Crude 1H NMR revealed a 10:1 mixture of alkene

characterized.43 Characterization was obtained from a sample obtained by a previous group member; the sample had a 6.1: 1, Z:E isomeric ratio.

Data for 2.21a.

1_{H NMR (400 MHz, CDCl} 3) 7.71-7.65 (m, 4 H), 7.44-7.34 (m, 6 H), 6.82 (dd, J = 15.6, 6.4 Hz, 1 H)*, 6.08 (dd, J = 11.6, 8.6 Hz, 1 H), 5.98 (dd, J = 15.6, 1.2 Hz, 1 H)*, 5.90 (dd, J = 11.6, 1.2 Hz, 1 H), 4.99-4.92 (m, 1 H), 4.73-4.69 (m, 2 H), 4.20 (t, J = 2.8, 2 H), 3.75 (s, 3 H)*, 3.69 (s, 3 H), 3.27 (s, 3 H), 2.37 (ddt, J = 14.8, 7.2, 2.8 Hz, 1 H), 2.27 (ddt, J = 14.8, 5.2, 2.8 Hz, 1 H), 1.05 (s, 9H)*, 1.04 (s, 9 H) ppm;

*discernable signal for E-2.21a

13_{C NMR (100 MHz, CDCl} 3) 206.7, 166.3, 150.4, 135.8, 129.7, 127.8, 127.7, 121.6, 99.7, 75.4, 64.9, 57.1, 51.5, 34.4, 27.0, 19.5 ppm; IR (thin film) 2931, 2858, 1961, 1725, 1429, 1196, 1109, 824, 703 cm-1; HRMS (FTMS + p ESI Full ms) [M + H]+ _{calcd for C} 27H35O4Si, 451.2299; found, 451.2280; TLC Rf = 0.65 (20% EtOAc in hexanes)

Silica gel, UV visible

Entry 2: A flame-dried, 10 mL, round-bottomed flask, equipped with a stir bar and septum pierced with a nitrogen inlet needle was charged with toluene (0.4 mL) and cooled to 0 °C on an ice and water bath. HMPA (29 µL, 0.17 mmol, 4 equiv) and DIBAL-H (0.14 mL of a 0.6 M solution in toluene, 0.082 mmol, 2 equiv) were added sequentially and stirred for 1 h. Alkynoate 2.1a (18 mg, 0.041 mmol, 1 equiv), dissolved in toluene (0.3 mL), was added to the reaction in one portion via syringe and stirred for 3 h. ClCH2BPin (11 mg, 0.062 mmol, 1.5

equiv), dissolved in toluene (0.2 mL), was added and stirred overnight at rt. The reaction was quenched with addition of 1 M HCl (3 mL) and diluted with Et2O. The organics were washed

with 1 M HCl, saturated NaHCO3, and brine (3 mL each), dried over MgSO4, filtered and

concentrated. The crude residue was purified by silica gel flash column chromatography (10% EtOAc in hexanes) to afford 6 mg of alkene 2.21a (33% yield) and 1 mg allylboronate 2.2a (4% yield) (a 7.8 : 1 molar ratio).

• When 2.6 equiv of ClCH2BPin were used, a crude 1H NMR taken 10 h after the boronate

addition revealed a 1.7:1 ratio of alkene 2.21a: boronate 2.2a. Stirring was continued; at 41 h, crude 1H NMR showed a 2.6:1 ratio of alkene 2.21a: boronate 2.2a (Entry 3). Data for 2.2a, see below.

Attempted reaction of ynoate 2.1b (Table 5, Entries 4, 5).

Entry 4: A flame-dried, 15 mL, round-bottomed flask equipped with a stir bar and septum was charged with THF (0.7 mL), and copper iodide (4 mg, 0.023 mmol, 0.1 equiv). The flask was cooled to -30 °C (dry ice and acetonitrile bath). Methyl lithium (14 µL of a 1.6 M solution in diethyl ether, 0.023 mmol, 0.1 equiv) was added and the solution stirred for 30 min. Toluene (1.6

mL) was added followed by sequential addition of HMPA (80 µL, 0.46 mmol, 2 equiv) and DIBAL-H (0.34 mL of a 1.0 M solution in hexanes, 0.34 mmol, 1.5 equiv). The reaction was stirred for 2 h. Alkynoate 2.1b (100 mg, 0.23 mmol, 1 equiv) was dissolved in toluene (1.1 mL) and added to the reaction in a single portion via syringe. The reaction stirred for 5 h. ClCH2BPin

(48 mg, 0.27 mmol, 1.2 equiv) was added and the reaction stirred overnight at rt. No change in the reaction was observed by TLC. The reaction was diluted with Et2O (5 mL), quenched with 1

M HCl (5 mL). The organic layer was separated and washed with 1 M HCl (2 x 5 mL), saturated NaHCO3 (5 mL), and brine (5 mL), dried over Na2SO4, filtered, and concentrated. The crude 1H

NMR showed ynoate 2.1b with signals consistent with literature values.68

Entry 5: Follows same procedure as described for entry 4 with THF (0.35 mL), copper iodide (2 mg, 0.012 mmol, 0.1 equiv), methyl lithium (8 µL of a 1.6 M solution in diethyl ether, 0.012 mmol, 0.1 equiv), toluene (0.8 mL), distilled HMPA (40 µL, 0.23 mmol, 2 equiv), DIBAL-H (0.17 mL of a 1.0 M solution in toluene, 0.17 mmol, 1.5 equiv), ynoate 2.1b (50 mg, 0.12 mmol, 1 equiv) dissolved in toluene (0.5 mL). After addition of ynoate 2.1b, no reaction had occurred after 5 h of stirring. ClCH2BPin was not added to this experiment. 1H NMR of the

crude residue showed ynoate 2.1b68 and no alkene 2.21b. Attempted 1,4-reduction of ynoate 2.1c (Table 5, Entry 6).

A flame-dried, 15 mL, round-bottomed flask equipped with a stir bar and septum was charged with THF (0.9 mL), and copper iodide (6 mg, 0.030 mmol, 0.1 equiv). The flask was cooled to -30 °C (cryocool and ethanol bath). Methyl lithium (19 µL of a 1.6 M solution in Et2O,

added followed by sequential addition of HMPA (0.10 mL, 0.59 mmol, 2 equiv) and DIBAL-H (0.34 mL of a 1.0 M solution in hexanes, 0.45 mmol, 1.5 equiv). The reaction was stirred for 2 h. Alkynoate 2.1c (50 mg, 0.30 mmol, 1 equiv) was dissolved in toluene (1.4 mL) and added to the reaction in a single portion via syringe. The reaction stirred at -20 °C for 5 h. An aliquot was taken from the reaction and concentrated. Crude NMR of this residue showed a 4:1 mixture of ynoate 2.1c: alkene 2.21c. Presence of alkene 2.21c was determined by 1H NMR signals at 6.3 and 5.8 ppm, which is consistent with literature values of this compound.71

• Allenyl-ynoate 2.1a was subjected to the same procedure which resulted in a complicated mixture as determined by TLC analysis (Entry 7).

Reaction of methyl 2-octynoate 2.1d (Table 5, Entries 8, 9).

A flame-dried, 10 mL, round-bottomed flask, equipped with a stir bar and septum was charged with THF (3.6 mL), and copper iodide (24 mg, 0.13 mmol, 0.4 equiv). The flask was cooled to -30 °C (cryocool and ethanol bath). Methyl lithium (80 µL of a 1.6 M solution in diethyl ether, 0.013 mmol, 0.4 equiv) was added and the solution stirred for 30 min. In a separate, 10 mL flask, toluene (1.3 mL) was cooled to -30 °C. 0.9 mL of the stirring CuMe solution (0.032 mmol, 0.1 equiv) was added followed by sequential addition of HMPA (0.17 mL, 0.97 mmol, 3 equiv) and DIBAL-H (1.28 mL of a 0.6 M solution in toluene, 0.64 mmol, 2 equiv). The reaction was stirred for 1 h. Alkynoate 2.1d (50 mg, 0.32 mmol, 1 equiv) was dissolved in toluene (0.4 mL) an added to the reaction in a single portion via syringe. The reaction stirred at -20 °C for 5 h until the ynoate was consumed, as evidenced by crude 1H NMR spectroscopy. ClCH2BPin (113 mg, 0.64 mmol, 2 equiv), dissolved in toluene (0.2 mL), was

added and stirred overnight. The reaction was quenched by 1 M HCl and diluted with diethyl ether. The organic layer was washed with 1 M HCl, saturated NaHCO3, and brine, dried over

MgSO4, filtered, and concentrated. Analysis by crude 1H NMR revealed a 1 : 1 mixture of alkene

2.21d (signals observed matched literature values)72 and allylboronate 2.2d (3.6:1, Z:E isomeric ratio). The crude mixture was purified by silica gel flash column chromatography (gradient of 10-20% diethyl ether in hexanes) to afford 7 mg of the Z-2.2d and 9 mg of the Z- and E-isomers of allylboronate 2.2d (1.4: 1 isomeric ratio) (35% yield overall).

• With freshly distilled ClCH2BPin, the crude 1H NMR showed 2.2d as the only product;

no alkene 2.21d was observed. Data for 2.2d. 1_{H NMR Z-isomer only: (600 MHz, CDCl} 3) 5.93 (t, J = 7.2 Hz, 1H), 3.70 (s, 3H), 2.48 (q, J = 7.2 Hz, 2H), 1.83 (s, 2H), 1.44-1.37 (m, 2H), 1.34-1.24 (m, 4H), 1.23 (s, 12H), 0.88 (t, J = 7.2 Hz, 3H) ppm; Z- and E-isomer: (400 MHz, CDCl3) 6.74 (t, J = 7.4 Hz, 1H)*, 5.93 (t, J = 7.4 Hz, 1H)**, 3.71 (s, 3H)*, 3.70 (s, 3H)**, 2.48 (q, J = 7.4 Hz, 2H)**, 2.14 (q, J = 7.4 Hz, 2H)*, 1.85 (s, 2H)*, 1.83 (s, 2H)**, 1.44-1.37 (m, 2H), 1.34-1.25 (m, 4H), 1.232 (s, 12H)**, 1.228 (s, 12H)*, 0.88 (m, 3 H) ppm; *E isomer, **Z isomer Impurities observed at 7.03, 3.65, 1.58 ppm. 13_{C NMR Z-isomer (150 MHz, CDCl} 3) 168.5, 143.9, 127.8, 83.4, 51.2, 31.7, 29.8, 29.3, 27.4, 24.9, 22.7, 14.2 ppm; HRMS (FTMS + p ESI Full ms)

IR (thin film)

2927, 2858, 1723, 1435, 1354, 1324, 1201, 1147 cm-1_;

TLC Rf = 0.45 (20% diethyl ether in hexanes)

Silica gel, UV visible, KMnO4

Allylboronate 2.2a. To a flame-dried, single-necked, round-bottomed flask, equipped with a stir bar and septum pierced with a nitrogen inlet needle, was added THF (1.2 mL) and copper iodide (8 mg, 0.040 mmol, 0.1 equiv) to form an off-white slurry. The flask was cooled to -30 °C using a cryocool/ethanol bath. Methyl lithium (0.025 mL of a 1.6 M solution in Et2O, 0.040 mmol, 0.1 equiv) was added and the solution

turned dark brown. The solution was stirred for 40 min. Toluene (1.7 mL) was added followed successively by HMPA (0.21 mL, 1.19 mmol, 3 equiv) and DIBAL-H (0.80 mL of a 1.0 M solution in toluene) and the black solution stirred for 2 h. Alkynoate 2.1a (174 mg, 0.40 mmol, 1 equiv) was dissolved in toluene (0.5 mL) and added to the reaction all at once via syringe. The temperature was warmed to -20 °C stirred for 3 h until all of the ynoate 2.1a had been consumed, determined by crude 1H NMR spectroscopy (shows formation of alkene 2.21a). Freshly distilled ClCH2BPin (141 mg, 0.80 mmol, 2 equiv), dissolved in toluene (0.4 mL), was added and stirred

overnight at rt. Over this time, the reaction solution went from black to translucent pale green. The reaction was quenched by the addition of 1 M HCl (10 mL). The mixture was transferred to a separatory funnel and diluted with Et2O (10 mL). The organic layer was separated and the

aqueous layer was extracted with Et2O (2 x 10 mL). The combined organics were washed with 1

M HCl (12 mL), saturated NaHCO3 (12 mL), and brine (12 mL), dried over MgSO4, filtered, and

concentrated using reduced pressure rotary evaporation. The crude material was purified by elution through a small silica column using 20% diethyl ether in hexanes to afford the title

compound 2.2 (183 mg, 78%) as a 1.6:1, Z:E isomeric ratio and as a colorless oil. The isomers were inseparable and taken on to the next step as a mixture. The characterization for the mixture is reported and the data matches previously reported data.43

Data for 2.2a.

1_{H NMR (400 MHz, CDCl} 3) 7.71-7.66 (m, 4H), 7.43-7.32 (m, 6H), 6.53 (d, J = 9.2 Hz, 1H)*, 5.74 (d, J = 8.8 Hz, 1H)**, 4.74-4.69 (m, 2H), 4.72-4.63 (m, 1H)**, 4.23-4.17 (m, 2H), 4.16-4.05 (m, 1H)*, 3.73 (s, 3H)*, 3.66 (s, 3H)**, 3.25 (s, 3H)**, 3.23 (s, 3H)*, 2.40-2.20 (m, 2H), 1.92-1.82 (m, 2H), 1.21 (s, 12H)**, 1.20 (s, 12H)*, 1.04 (s, 9H) ppm; *E isomer, **Z isomer TLC Rf = 0.48 (20% EtOAc in hexanes)

Silica gel, UV visible