SOMOphilic alkyne vs radical-polar crossover approaches: The full story of the azido-alkynylation of alkenes

We report the detailed background for the discovery and development of the synthesis of homopropargylic azides by the azido-alkynylation of alkenes. Initially, a strategy involving SOMOphilic alkynes was adopted, but only resulted in a 29% yield of the desired product. By switching to a radical-polar crossover approach and after optimization, a high yield (72%) of the homopropargylic azide was reached. Full insights are given about the factors that were essential for the success of the optimization process.


General methods
All reactions were carried out under air unless stated otherwise.Reactions requiring heating were carried out using DrySyn heating block.For flash chromatography, distilled technical grade solvents were used.THF, toluene, Et2O and CH2Cl2 were dried by passage over activated alumina under nitrogen atmosphere (H2O content <10 ppm, Karl-Fischer titration).Solvents were degassed by bubbling with a balloon of argon.All chemicals were purchased from Acros, Aldrich, Combi-blocks, Fluka, Fluorochem, Merck, TCI or VWR and used as such unless stated otherwise.
High-resolution mass spectrometric measurements were performed by the mass spectrometry service of ISIC at the EPFL.Electrospray-ionisation HRMS data were acquired on a Q-Tof Ultima mass spectrometer (Waters) or a Q-Tof 6530 Accurate mass spectrometer (Agilent) operated in the positive ionization mode and fitted with a standard Z-spray ion source equipped with the Lock-Spray interface.Data from the Lock-Spray were used to calculate a correction factor for the mass scale and provide accurate mass information of the analyte.Data were processed using the MassLynx 4.1 software.Atmospheric pressure photo-ionisation (APPI) HRMS measurements were done on a LTQOrbitrap Elite instrument (Thermofisher) operated in the positive ionization mode.
Reactions under "blue LEDs irradiation" (440 nm, 40 W) were performed in test tubes (14 mL, soda-lime glass, wall thickness = 0.8 mm) which were placed at the center of a crystallization flask.On this flask were attached the blue LEDs (RUBAN LED 5MÈTRES -60LED/M -3528 BLEU -IP65 with Transformateur pour Ruban LED 24W/2A/12V, bought directly on RubanLED.com).The distance between the LEDs and the test tubes was approximatively 3

S3
cm.Long irradiation resulted in temperature increasing up to 35 °C during overnight reactions.Reactions using "Kessil lamp" of 467 nm or 440 nm used the corresponding models PR160L-467 or PRL160L-440.

Picture of the photochemistry set-up
The Kessil lamp was placed diagonally at a distance of ≈4 cm from the top of the reaction vessel (test tube or round-bottom flask).The latter was immersed in a bath of ice and salt (-20 °C) contained in a Dewar.For the optimized conditions the lamp intensity was set at 50% (22 W).

Synthesis of Alkenes
General procedure A: Following a reported procedure, 1 an oven dried round-bottom flask charged with methyltriphenylphosphonium bromide (1.79 g, 5.00 mmol, 1.25 equiv) and potassium tertbutoxide (584 mg, 5.20 mmol, 1.30 equiv) was evacuated and backfilled with N2.Dry THF (11 mL) was added and the mixture was stirred at rt for 30 min.A solution of aldehyde (4.00 mmol, 1 equiv) in dry THF (5 mL) was added dropwise over 5 min and the reaction was stirred at rt under N2 until full conversion was observed by TLC.The reaction was quenched with 35 mL of a sat.sol. of NH4Cl and the mixture was extracted with 3 × 40 mL of Et2O or EtOAc.The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo.The crude product was purified by column chromatography to obtain alkene 1.

Synthesis of potassium trifluoroborate salts
General note: It is known that carbons linked to the boron atom are difficult to be observed by 13   C NMR due to a broadening of the signal caused by the quadrupole moment of 11 B nuclei.This implies that the two carbons of the alkyne (in alkynyl-BF3K) are too broad to be properly visible. 6Therefore, they are not listed in the characterization data.

General procedure B:
Following a reported procedure, 7 , 8 an oven-dried round-bottom flask (PFA), charged with alkyne (1.0 equiv) if solid, was evacuated and backfilled with N2 (3×).Then, alkyne (if liquid) and dry THF (0.3 M) were added.The mixture was cooled to −78 °C and a solution of n-BuLi (2.5 M, 1.0 equiv) in hexane was added dropwise under N2.The reaction was stirred at −78 °C for 1 h and B(Oi-Pr)3 (1.5 equiv) was added quickly.The reaction was stirred 10 min at −78 °C then 2 h at rt.The mixture was cooled to 0 °C and a saturated solution of KHF2 (6.0 equiv) in water (40% of THF volume + additional 40% to rinse the remaining solid) was added.The reaction was stirred at rt open to air for 2 h then concentrated in vacuo.The wet solid obtained was further dried by co-evaporation with toluene (3×).To the dry solid was added acetone (≈50 mL) and the resulting mixture was placed on a rotary evaporator and rotated rapidly at atmospheric pressure with the bath set at 45 °C for 15 minutes.The flask was removed and the mixture carefully filtered taking care to leave the insoluble material (KHF2) in the reaction flask.Acetone was once again added and the process (heating for 15 min then collection of the liquid) was repeated 2 more times.The combined acetone filtrates were concentrated in vacuo to approximately 1/3 of the initial volume.Et2O (≈60 mL) was added causing a white solid to precipitate.The mixture was cooled to 0 °C for 10 min then filtered.The solid obtained was washed with Et2O and dried in vacuo to afford the desired potassium alkynyltrifluoroborate 5.
Note: This purification procedure usually affords the pure desired product.If it is not the case a more classical recrystallization from acetone/Et2O can be performed.

Annexes
The synthesis of all the compounds listed in this section as well as their corresponding characterization data were taken from previous publications of our group. 8,11,12,13,14f.Following an adapted version of a reported procedure, 15 NaIO4 (18.1 g, 84.7 mmol, 1.05 equiv) and 2-iodobenzoic acid (15) (20.0 g, 80.6 mmol, 1.00 equiv) were suspended in a mixture of AcOH (36 mL) and water (84 mL).The mixture was vigorously stirred and refluxed for 4 h.The reaction mixture was then diluted with cold water (100 mL) and allowed to cool to room temperature protected from light.The crude product was collected by filtration, washed on the filter with cold water (3 × 50 mL) and cold acetone (3 × 50 mL), and air-dried in the dark overnight to give the pure 1-hydroxy-1,2-benziodoxol-3-(1H)-one (HOBX, 16) (20.0 g, 75.7 mmol, 94%) as a white solid.

1-Azido-2-tosyl-1,2-dihydro-3H-1λ 3 -benzo[d][1,2]iodazol-3-one (Ts-ABZ, 3):
Caution: Even though Ts-ABZ has a much safer safety profile than the most commonly used azidobenziodoxolone (ABX) care has to be taken when preparing it. 20The synthesis and filtration were carried out behind a blast shield wearing anti cut gloves (HyFlex 11-541) below regular nitrile gloves.The scale described in the procedure below was the largest scale the reaction was carried on.To synthesize larger amount of the reagent we performed the reaction in multiple batches in parallel and filtered them individually.Ts-ABZ batches were stored in plastic containers and kept in the fridge at 4 °C.During the course of this project this synthesis was performed 34 times without incident with an average yield of 86%.
An oven dried round-bottom flask charged with methyltriphenylphosphonium bromide (6.7 g, 19 mmol, 1.25 equiv) and potassium tert-butoxide (2.2 g, 20 mmol, 1.30 equiv) was evacuated and backfilled with N2.Dry THF (45 mL) was added and the mixture was stirred at rt for 30 min.A solution of crude aldehyde 28 previously prepared in dry THF (15 mL) was added dropwise over 5 min and the reaction was stirred at rt under N2 for 1 h.The reaction was quenched with 60 mL of a sat.sol. of NH4Cl and the mixture was extracted with 3 × 60 mL of EtOAc.The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated in vacuo.The crude product was loaded on celite and purified by column chromatography (pentane) to afford 1-(allyloxy)-2-vinylbenzene (29) (1.78 g, 11.1 mmol, 74% over 2 steps) as a colorless oil.

S23
This process was repeated 2 more times.Solvents were removed in vacuo.The obtained solid was dissolved in the minimum amount of hot acetone and precipitation of the desired product was performed by addition of diethyl ether.The mixture was cooled down to 0 °C, filtered off, washed with diethyl ether (3 × 20 mL) and dried in vacuo to afford potassium (3-(4chlorophenyl)-3-hydroxyprop-1-yn-1-yl)trifluoroborate (34) (1.64 g, 6.02 mmol, 80%) as a white solid.

Potassium ethynyltrifluoroborate (5e):
Compound 5e was synthesized following a reported procedure. 40An oven-dried round-bottom flask (PFA) was evacuated and backfilled with N2 (3×).Then, a solution of ethynylmagnesium bromide (32) (30.0 mL, 15.0 mmol, 0.5 M, 1.0 equiv) in THF and dry THF (30 mL) were added.The solution was cooled to −78 °C and B(OMe)3 (2.5 mL, 22 mmol, 1.5 equiv) was added quickly under N2.The reaction was stirred 1 h at −78 °C then 1.5 h at −20 °C.A saturated solution of KHF2 (7.03 g, 90.0 mmol, 6.0 equiv) in water (20 mL + additional 20 mL to rinse the remaining solid) was added.The reaction was stirred at rt open air for 2 h then concentrated in vacuo.The wet solid obtained was further dried by co-evaporation with acetone.To the dry solid was added acetone (≈30 mL) and the resulting mixture was placed on a rotary evaporator and rotated rapidly at atmospheric pressure with the bath set at 45 °C for 15 minutes.The flask S24 was removed and the mixture carefully filtered taking care to leave the insoluble material in the reaction flask.Acetone was once again added and the process (heating for 15 min then collection of the liquid) was repeated 2 more times.The combined acetone filtrates were concentrated in vacuo to approximately 1/3 of the initial volume.Et2O (≈30 mL) was added causing a white solid to precipitate.The mixture was cooled to 0 °C for 10 min then filtered.The solid obtained was washed with Et2O and dried in vacuo to afford potassium ethynyltrifluoroborate (5e) (1.17 g, 8.86 mmol, 59%) as a white solid. 1 H NMR (400 MHz, acetone-d6) δ 1.67 (d, J = 5.4 Hz, 1H, C≡CH). 13C NMR (101 MHz, acetone-d6) not observed. 19F NMR (376 MHz, acetone-d6) δ -135.5.Spectroscopic data was consistent with the values reported in the literature. 8

Potassium trifluoro(prop-1-yn-1-yl)borate (5m):
Compound 5m was synthesized following a reported procedure. 8An oven-dried round-bottom flask (PFA) was evacuated and backfilled with N2 (3×).Then, a solution of 1propynylmagnesium bromide (38) (15 mL, 7.5 mmol, 0.5 M, 1.0 equiv) in THF and dry THF (15 mL) were added.The solution was cooled to −78 °C and B(OMe)3 (1.25 mL, 11.3 mmol, 1.5 equiv) was added quickly under N2.The reaction was stirred 1 h at −78 °C then 1.5 h at −20 °C.A saturated solution of KHF2 (3.5 g, 45 mmol, 6.0 equiv) in water (10 mL + additional 10 mL to rinse the remaining solid) was added.The reaction was stirred at rt open air for 2 h then concentrated in vacuo.The wet solid obtained was further dried by co-evaporation with acetone.To the dry solid was added acetone (≈30 mL) and the resulting mixture was placed on a rotary evaporator and rotated rapidly at atmospheric pressure with the bath set at 45 °C for 15 minutes.The flask was removed and the mixture carefully filtered taking care to leave the insoluble material in the reaction flask.Acetone was once again added and the process (heating for 15 min then collection of the liquid) was repeated 2 more times.The combined acetone filtrates were concentrated in vacuo to approximately 1/3 of the initial volume.Et2O (≈30 mL) was added causing a white solid to precipitate.The mixture was cooled to 0 °C for 10 min then filtered.The solid obtained was washed with Et2O and dried in vacuo to afford potassium trifluoro(prop-1-yn-1-yl)borate (5m) (0.95 g, 6.5 mmol, 87%) as a white solid. 1 H NMR (400 MHz, acetone-d6) δ 1.64 -1.58 (m, 3H, CH3). 13C NMR (101 MHz, acetone-d6) δ 4.0. 19F NMR (376 MHz, acetone-d6) δ -134.7.Spectroscopic data was consistent with the values reported in the literature. 8

Scope of the azido-alkynylation previously reported by our group
General Note: We observed that the homopropargylic azides synthetized in this work tend to slowly decompose even when stored in the fridge at 4 °C
Note: Commercially available liquid alkenes were eluted through a short plug of basic Al2O3 before use.DME was sparged with argon for 0.5 h before use.Cooling was performed using a Dewar filled with a mixture of ice and salt.We did not observe significant rise in temperature after 1.5 h (which is enough in most cases to reach full conversion).In the case of longer reactions, the cold bath was replaced with a new one after 1.5 h.For further details on the photochemistry set-up see Figure S1.