Cu-Catalyzed Decarboxylative Borylation

A simple method for the conversion of carboxylic acids to boronic esters via redox-active esters (RAEs) is reported using copper catalysis. The scope of this transformation is broad, and compared with the known protocols available, it represents the most inexpensive, rapid, and operationally simple option. In addition to a full exploration of the scope, a kinetic study was performed to elucidate substrate and reagent concentration dependences.

TLC was performed on 0.25 mm E. Merck silica plates (60F-254), using short-wave UV light as the visualizing agent, and cerium ammonium molybdate (CAM) or KMnO 4 and heat as developing agents.
The following abbreviations were used to explain multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad. Column chromatography was performed using E. Merck silica gel (60, particle size 0.043-0.063 mm). High-resolution mass spectra (HRMS) were recorded on Waters LC with G2-XS TOF mass spectrometer by electrospray ionization time of flight reflectron experiments. GCMS (EI) was recorded on Agilent 7820A GC systems and 5975 Series MSD. Melting points were recorded on a Fisher-Johns 12-144 melting point apparatus and are uncorrected.

Handling of Cu Catalysts
All Cu catalysts were handled open to air on the bench top, and the bottles were neither flame dried nor stored under inert atmosphere.

General Procedure A
Redox-active esters were prepared according to the previously reported procedure 1,2 . In short, a round-bottom flask or culture tube equipped with a stir bar was charged with carboxylic acid (1.0 equiv), N-hydroxy-phthalimide (1.1 equiv) and DMAP (0 -0.1 equiv). Dichloromethane was added (0.1 -0.5 M) followed by DIC (1.1 equiv), and the mixture was allowed to stir vigorously for 0.5 -2 hours. The mixture was filtered (over Celite, SiO 2 , or through a fritted funnel) and rinsed with additional CH 2 Cl 2 /Et 2 O. The solvent was removed under reduced pressure, and purification by column chromatography (and recrystallization, if necessary) afforded the corresponding redox-active ester.

5.
For cases that the borylation product is close to B 2 pin 2 on TLC and difficult to separate: upon completion, the reaction mixture was diluted with EtOAc and bubbled with air until green color was observed (typically < 3 min). Excess B 2 pin 2 could be consumed this way.
6. For cases that the borylation product is close to phthalimide (PhthH) on TLC and difficult to separate: upon completion, the reaction mixture was diluted with EtOAc and washed with NH 4 Cl followed by K 2 CO 3 (10% aq). PhthH could be washed away by K 2 CO 3 .      Do I need to run the reaction in glovebox?

Answer:
We do not set up or run the reaction in glovebox. A glovebox is not necessary for this reaction. We do evacuate the air from the tube via vacuum manifold though.

Question 2:
How sensitive is this reaction to water and air?

Answer:
Addition of ~30 equivalents of H 2 O resulted in <5% drop in yield. Running the reaction under air without inert atmosphere resulted in ~20% drop in yield.

Why do you need 15 equivalents of LiOH•H 2 O?
Answer: The solubility of LiOH•H 2 O in organic solvent is limited. So 15 equivalents is necessary to increase the actually effective amounts of LiOH•H 2 O.

Question 4:
Can I use LiOH instead of LiOH•H 2 O?

Answer:
LiOH resulted in similar yield (within 5% difference) as long as LiOH was also grinded to floppy powder prior to use.

Question 5:
Is MgCl 2 essential for this reaction?

Answer:
Without MgCl 2 , the yield dropped to <20%. However, instead of MgCl 2 , many other metal salts also

Question 6:
How do I purify my products?

Answer:
The pinacol alkylboronate esters are not stable on preparative TLC due to possible oxidation of C-B bond or hydrolytic cleavage of pinacol esters. In all cases shown in this paper, we purify the products by flash column chromatography with gradient elution. For products that were very unstable on silica gel, deactivated silica gel (35 wt% H 2 O) could be used as suggested in reference 5.
Two major impurities, namely B 2 pin 2 and phthalimide (PhthH), could be removed by methods shown below: a. Upon completion, the reaction mixture was diluted with EtOAc and bubbled with air. Observing of green color (typically < 2 min) indicated complete consumption of excess B 2 pin 2 .
b. Upon completion, the reaction mixture was diluted with EtOAc and washed with NH 4 Cl followed by K 2 CO 3 (10% aq) for three times. PhthH could be washed away by K 2 CO 3 .

Question 7:
Are the Bpin products volatile?

Answer:
Most of products reported in this study are not volatile except the radical clock products 43 and 44.
You can use pentane and Et 2 O for workup and column chromatography and keep the temperature of rotavapor water bath below 30 °C.

Question 8:
Sometimes emulsion formed during the workup. What should I do? Answer: After addition of NH 4 Cl solution, shake the reaction tube vigorously until getting a clear biphasic solution. Intermittent introduce of air (oxygen) could help break the metal aggregates. If lighter color was observed but emulsion still existed, add more H 2 O or brine and shake again.

Question 9:
I'm working on small scales, and the general procedure requires relatively high concentration (0.14 M). Can I dilute the reaction?

Answer:
The reaction can be diluted to 0.07 M by the addition of more solvent, thus diluting all reaction components, obtaining essentially the same yield, although the reaction will take a little longer to completion. Further dilution will cause decrease in yield.

Question 10:
Is this reaction exothermic? Does that affect the yield?

Answer:
The reaction became exothermic when brown color was observed. We didn't observe any appreciable ill effect to the yield though.

Question 11:
Dose longer reaction time cause decrease in yield?

Answer:
We left the reaction running overnight sometimes and no significant decrease of yield was observed.

Question 12:
Does the base-sensitive group survive under current base conditions?

Answer:
Base-sensitive functional groups such as ketone, ester, lactone, amide, free phenol, epoxide and carbamates such as Boc and Fmoc are all tolerated in this method.

Question 13:
How's the color changing during the transformation and which color indicates the completion of this reaction?

Answer:
Color change of this reaction was recorded graphically. The observation of dark brown color (4'08'') indicated the completion of the reaction.

Answer:
Substrates containing alkyl or aryl halogens (Br or I) gave lower yields due to competing S32 protodehalogenation and borylation of halogens. Tertiary and amino acid substrates are in general not working well in this method. Please see 'Unsuccessful or Challenging Substrates' section for the problematic examples we've tried.

Question 15:
Could external ligand on copper improve the yield?

Answer:
We've screened common nitrogen, phosphine and acac-type ligands and no appreciable improvement was observed.

Question 16:
Is a rigorous stirring rate required to maintain high yields? Does it have any effect on the yield?

Answer:
Rigorous stirring rate is not necessary. Stirring control experiments have been done under stir rates of 200, 400, 600, 800, 1000 and 1200 rpm on substrate 11. All entries gave essentially the same yield of product (<5% difference).

Question 17:
This is a heterogeneous reaction. Does the yield drop in a larger scale?

Answer:
We obtained similar yield when scaling up the reaction to 1 gram scale. Larger scale was not tested.
We believe that it is very important to use well-grinded powder of LiOH•H 2 O, MgCl 2 and Cu(acac) 2 for scale up.

Experimental Procedures and Characterization Data for Redox-Active Esters
Compound S26
Purification by flash column chromatography (silica
Purification by flash column chromatography (silica
Spectroscopic data are in accordance with that reported in the literature. 5
Purification by flash column chromatography (silica Compound 20
Purification by flash column chromatography (silica
Physical state: colorless oil. Spectroscopic data are in accordance with that reported in the literature. 5
Physical state: colorless oil. Spectroscopic data are in accordance with that reported in the literature. 6 Compound 25
Purification by flash column chromatography (silica, 5
Purification by flash column chromatography (silica ppm. The carbon directly attached to the boron atom was not detected due to quadrupolar broadening.
Spectroscopic data are in accordance with that reported in the literature. 5
Purification Spectroscopic data are in accordance with that reported in the literature. 6 Compound 36
Spectroscopic data are in accordance with that reported in the literature. 5 Compound 37

methyl)cyclohexyl)methyl)carbamate
Following General Procedure B on 0.123 mmol scale with redox-active ester S19 in dioxane/DMF Spectroscopic data are in accordance with that reported in the literature. 5 Compound 40
Purification by flash column chromatography (silica Spectroscopic data are in accordance with that reported in the literature. 5 Compound 42