Ligand‐Controlled Diastereoselective Cobalt‐Catalysed Hydroalkynylation of Terminal Alkynes to E‐ or Z‐1,3‐Enynes

Abstract A diastereoselective hydroalkynylation of terminal alkynes to form the head‐to‐head dimerization products by two different cobalt‐phosphine catalyst system is reported. The use of the bidentate ligand dppp and additional triphenylphosphine led to the selective formation of the (E)‐1,3‐enynes (E:Z>99:1) in good to excellent yields, while the tridentate ligand TriPhos led to the corresponding (Z)‐1,3‐enynes in moderate to good yields with excellent stereoselectivities (up to E:Z=1:99). Both pre‐catalysts are easy to handle, because of their stability under atmospheric conditions. The optimized reaction conditions were identified by the Design of Experiments (DoE) approach, which has not been used before in cobalt‐catalysed reaction optimisation. DoE decreased the number of required reactions to a minimum.

bis(diphenylphosphinoethyl)phenylphosphine (1.60 g, 3.00 mmol, 1.00 equiv.) dissolved in THF (30.0 mL) was added slowly and the resulting dark red suspension was stirred for 16 h. Within the addition the suspension solidified for a short period of time. The solvent was removed under reduced pressure and the residue washed with n-pentane and diethyl ether. The precatalyst was dried in vacuo and isolated as a red-brown amorphous solid (2.25 g, 3.00 mmol, quant.). The catalyst was used without further purification.
The resulting dark suspension was shortly heated to approximately 80 °C, whereas a color change from dark blue/green to green appeared. The resulting solution was cooled to 0 °C and the corresponding alkyne (1.00 equiv.) was added. The reaction mixture was stirred until complete conversion was determined via GC/MS and TLC. The mixture was diluted with CH2Cl2 and filtered over a short plug of silica gel (eluent: n-pentane:CH2Cl2 = 3:1 or CH2Cl2, depending on the polarity of the substrate). The solvent was removed under reduced pressure. The crude product was purified via column chromatography (n-pentane:CH2Cl2 or n-pentane:ethyl acetate).

General Procedure 2:
Under Argon atmosphere [CoBr2(TriPhos)] (10 mol%), zinc dust (20 mol%) and zinc iodide (46 mol%) were added to a predried reaction vessel. The solids were dried 10 min in vacuo. The catalyst system was dissolved in dry acetonitrile (0.67 mL•mmol -1 ) and the resulting dark red suspension was heated to 37 °C and stirred for 15 min. Then the corresponding alkyne (1.00 equiv.) was added at 37 °C. The reaction mixture was stirred until complete conversion was determined via GC/MS and TLC. The mixture was diluted with CH2Cl2 and filtered over a short plug of silica gel (eluent: n-pentane:CH2Cl2 = 3:1 or CH2Cl2, depending on the polarity of the substrate). The solvent was removed under reduced pressure. The crude product was purified via column chromatography (n-pentane:CH2Cl2 or n-pentane:ethyl acetate).

General Procedure 3:
Under Argon atmosphere [CoBr2(TriPhos)] (10 mol%), zinc dust (20 mol%) and zinc iodide (46 mol%) were added to a predried reaction vessel. The solids were dried 10 min in vacuo. The catalyst system was dissolved in dry acetonitrile (0.67 mL•mmol -1 ) and the resulting dark red suspension was heated to 37 °C and stirred for 15 min. Then the corresponding alkyne (1.00 equiv.) was added at 0 °C. The reaction mixture was stirred 1 h at 0 °C. Afterwards the mixture was stirred at ambient temperature until complete conversion was determined via GC/MS and TLC. The mixture was diluted with CH2Cl2 and filtered over a short plug of silica gel (eluent: n-pentane:CH2Cl2 = 3:1 or CH2Cl2, depending on the polarity of the substrate). The solvent was removed under reduced pressure. The crude product was purified via column chromatography (n-pentane:CH2Cl2 or n-pentane:ethyl acetate).

Determination of categorical parameters
[b] Only cyclotrimerization product could be observed. [a] All reactions were carried out on a 0.5 mmol scale using phenylacetylene as test substrate in 0.5 mL MeCN. For all reactions 5 mol% CoBr2(dppp), 10 mol% zinc dust and 0.55 equiv. additive were used. The yields were determined via GC/FID using (1.0 M in CH2Cl2, 0.5 mL, 0.5 mmol, 1.00 equiv.) as internal standard. The internal standard was added after 16 h reaction time.
[b] 4-Fluorophenylacetylene was used. The reaction mixture was quenched after 1 h reaction time.

Reaction Optimization for the E-selective hydroalkynylation of terminal alkynes using Design of Experiments
A D-optimal screening design was generated by using JMP 13 software package by SAS (version 13.

General Procedure 4:
Under Argon atmosphere all solids were added into a pre-dried reaction vessel. The solids were dried in vacuo for 15 min. Afterwards the catalyst system was dissolved in acetonitrile (0.33 -2.50 mL) using standard single use syringes. The mixture was shortly heated up to approximately 80 °C. whereas a color-change from dark blue/green to dark green appeared. The resulting solution was cooled to the desired temperature and the test substrate (4-fluorophenylacetylene) was added (60.0 µL, 500 µmol, 1.00 equiv., via Eppendorf TM pipette) to the catalyst system. After the desired reaction time, mesitylene (1.0 M in CH2Cl2, 0.5 mL, 500 µmol, 1.00 equiv., via syringe) and hexafluorobenzene (57.7 µL, 500 µmol, 1.00 equiv., via Eppendorf TM pipette) were added. The yield of the product was determined via GC/FID and 19 F NMR spectroscopy.

Prediction Profiler
The results of the screening design were verified by k-fold cross validation (k = 5).
The higher p-value of the linear terms (substrate concentration and triphenylphosphine equivalents) could be a result of inaccuracies of the scale weighing small amounts of triphenylphosphine and inexact voluminal of the solvent using single-use syringes.

Reaction Optimization for the Synthesis of Z-1,3-Enynes
Determination of categorical parameters  [a] All reactions were carried out on a 0.5 mmol scale using (4-fluorophenyl)acetylene as test substrate in 0.5 mL acetonitrile. For all reactions 5 mol% [CoBr2(TriPhos)], 10 mol% zinc dust and 10 mol% Lewis acid were used. The yields were determined via GC/FID using (1.0 M in CH2Cl2, 0.5 mL, 0.5 mmol, 1.00 equiv.) as internal standard. The internal standard was added after 16 h reaction time.
[b] ZnI2 (50 mol%) were used.  [a] All reactions were carried out on a 0.5 mmol scale using (4-fluorophenyl)acetylene as test substrate in 0.5 mL acetonitrile. The yields were determined via GC/FID using (1.0 M in CH2Cl2, 0.5 mL, 0.5 mmol, 1.00 equiv.) as internal standard. The internal standard was added after 16 h reaction.

Reaction Optimization for the Z-selective hydroalkynylation of terminal alkynes using Design of Experiments
A D-optimal screening design was generated by using JMP 13 software package by SAS (version 13.2.1, SAS Institute Inc, Cary, NC, © 2016). The generated design considered all linear and quadratic terms of the numerical parameters. After running all initial experiments, the screening design was extended to consider possible cross interactions and to expand the zinc iodide equivalents from 4 -60 mol to 4 -100 mol%. In this case no cross interaction had a low p-value. In total the design consisted of 30 reactions, excluding two verified outliers. For the lack of fit value six experiments were replicated. At last three experiments were run to verify the predicted optimum and reaction time.
Under Argon atmosphere all solids were added into a pre-dried reaction vessel. The solids were dried in vacuo for 15 min. Afterwards the catalyst system was dissolved in acetonitrile (0.33 -2.50 mL) using standard single use syringes. The mixture was stirred 15 min at 37 °C. The suspension was cooled or heated to the desired temperature and the test substrate (4fluorophenylacetylene) was added via Eppendorf TM pipette (60.0 µL, 500 µmol, 1.00 equiv.) to the catalyst system. After the corresponding reaction time mesitylene (1.0 M in CH2Cl2, 0.5 mL, 500 µmol, 1.00 equiv., via syringe) and hexafluorobenzene (57.7 µL, 500 µmol, 1.00 equiv., via Eppendorf TM pipette) were added. The yield of the product was determined via GC/FID and 19 F NMR spectroscopy.