Copper-catalyzed synthesis of allenylboronic acids. Access to sterically encumbered homopropargylic alcohols and amines by propargylboration

Synthesis and application of allenylboronic acids is presented. The successful synthetic applications are based on the possibility of the versatile transformations of the unprotected B(OH)2 group in situ under the propargylboration conditions.


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Comparision of the 1 H NMR spectra of 1a obtained after the toluene extraction in procedure A and after purification using procedure B. Spectrum i) below is the 1 H NMR spectrum of 1a (in wet toluene-d8, 500 MHz) purified by the above method. Peak "d" belongs to the unprotected B(OH)2 group. The spectrum does not display any peaks arising from boronic esters or boroxine. Spectrum ii) shows the 1 H NMR spectrum of 1a obtained by extraction of the reaction mixture as described in "Procedure A for the synthesis of allenylboronic acids" above.
Comparision of the 1 H NMR spectrum of the purified (spectrum i) and extracted (spectrum ii) sample of 1a reveals that the extracted sample is sufficiently pure and contains the B(OH)2 form of 1a. This also means that under the extractive purification procedure the glycol ester of B(OH)2 is completely hydrolyzed. As mentioned in the main text, all the reactions (Table 3 -4) were carried out with extracted allenylboronic acids, such as 1a (spectrum ii). 7 Synthesis of allenyl boronate 1a-Bpin followed by oxidative hydrolysis to allenylboronic acid 1a A vial was charged with mesitylcopper(I) (0.03 mmol, 5.5 mg), trimethyl phosphite (0.06 mmol, 7.8 μL), 3 Å molecular sieves, and MeOH (2.5 mL). This reaction mixture was stirred for 20 minutes at room temperature. Then a MeOH solution (0.45 ml) of propargylic carbonate 4a (0.30 mmol, 74 mg), naphthalene (internal standard, 0.3 mmol 38 mg) and bis(pinacolato)diboron 5b (0.45 mmol, 114 mg) was added dropwise to the reaction mixture via syringe at -10 °C. Subsequently, this reaction mixture was stirred at -10 °C for 24 hours. Then the reaction mixture was filtered through a 0.45 μm syringe PTFE filter and transferred to 3 ml degassed HCl solution (0.5 M).
The resulting slurry was extracted with 1.5 mL toluene and washed once with 1.5 mL phosphate buffer-NaCl solution (prepared from 100 mL commercial phosphate buffer solution (pH = 7) by addition of 10 g NaCl). The toluene solution was placed in a roundbottom flask and the solvent was removed. The resulting oil was dissolved in 2.5 mL degassed THF:H2O (8:2) under Ar, which was followed by addition of NaIO4 (0.9 mmol, 192 mg). When the NaIO4 had dissolved completely (5 minutes), 0.18 mL 0.5 M HCl was added dropwise. The mixture was stirred at room temperature for two hours, after which it was extracted with 2 mL of degassed toluene. The organic layer was washed with 2 mL degassed phosphate buffer-NaCl solution and 2 mL degassed brine, and then dried in vacuo.
The resulting solids were then dissolved in 1 mL degassed toluene-d8 and sampled for 1 H NMR analysis. This procedure yielded 63% of 1a.

Synthesis of allenyl boronate 1a-Bnep
A vial was charged with mesitylcopper(I) (0.03 mmol, 5.5 mg), trimethyl phosphite (0.06 mmol, 7.8 μL), 3 Å molecular sieves, and MeOH (2.5 mL). This reaction mixture was stirred for 20 minutes at room temperature. Then a MeOH solution (0.45 ml) of propargylic carbonate 4a (0.30 mmol, 74 mg) and bis(neopentyl glycolato)diboron 5c (0.45 mmol, 102 mg) was added dropwise to the reaction mixture via syringe at -10 °C. Subsequently, this reaction mixture was stirred at -10 °C for 24 hours. Then, the reaction mixture was filtered through a 0.45 μm syringe PTFE filter and transferred to 3 ml degassed HCl solution (0.5 M). The resulting slurry was extracted with 1.5 mL toluene and washed once with 1.5 mL phosphate buffer-NaCl solution (prepared from 100 mL commercial phosphate buffer solution (pH = 7) by addition of 10 g NaCl). The toluene layer was dried by passing through an IST phase separator ® (Biotage) and the solvent was removed, affording a colorless oil (71 mg) of 1a-Bnep and 4a in a 8 : 2 mass ratio, calculated from 1 H NMR analysis. We attempted to purify 1a-Bnep by silica gel chromatography but these attempts were fuitless because of decomposition of 1a-Bnep in the presence of silica gel. NMR data for 1a-Bnep. 1

Procedure C for reaction of allenylboronic acids with aldehyde, ketones, imines and indole
A vial was charged with the corresponding aldehyde, ketone, imine or indole (0.15 mmol), 3 Å molecular sieves and toluene (0.5 ml). This solution was stirred for 1 min, then the allenylboronic acid (0.10 mmol, obtained by procedure A) in a toluene (0.5 ml) was added to the reaction mixture via syringe. The final reaction mixture was stirred at room temperature. Completion of the reaction was checked by 1 H NMR. After a full conversion, the reaction mixture was diluted with diethyl ether (1 mL) under air. The precipitate was filtered off through a short silica pad (about 1 cm in a Pasteur-pipette) using ethyl acetate/hexane (1:1) as an eluent. Then, the solvent was removed and the residue was purified by a rapid silica gel chromatography.

Explanation of the A-level alert in the checkif file of 6g-ester
The checkif file (6g_ester_checkif.pdf) reports an A-level alert stating that "Structure Contains Solvent these voids are part of the unit cell. The largest residual density that was found in these void channels is 0.75 e/Å 3 . Partial occupation of these channels by disordered solvent molecules is a possible explanation for this residual density. Since the residual density is low, these channels are largely empty. In conclusion, the voids do not effect the accuracy of the structural parameters determined from the X-ray data. The Flack parameter is x = -0.01 (2), thus the absolute configuration of 6g-ester can be unambiguously assigned as R.
Crystal packing structure of 6g-ester (5x5 unit cells) showing the void channels.

Esterification of boronic acid 1b with EtOH
We stated in the main text that " ... the enantioselective version of the reaction starts with monoor diesterification of allenyl boronic acid 1b with EtOH." In Figure 2 below we present experimental data supporting this statement.
The 1 H NMR spectrum of 1b toluene-d8 (Figure 2i) shows a characteristic peak "a" (4.16 ppm), which belongs to the free (unesterified) B(OH)2 group. The sample was obtained by extraction (see preparation above) and therefore it contains (non-deuterated) toluene. One hour after reacting 0.1 mmol of 1b with 0.2 mmol of EtOH in the presence of MS (3 Å) in degassed toluene, the 1 H NMR spectrum of this reaction mixture was monitored by 1 H NMR ( Figure   2ii). In spectrum ii) the peak "a" of the free B(OH)2 group at 4.16 ppm does not appear any more indicating the

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Spectrum for 1c: 1 H NMR (500 MHz,. The sample was obtained by extraction of the crude mixture with tol-d8. Naphtalene was used as internal standard.
Spectrum for 1d: 1 H NMR (500 MHz, tol-d8). The sample was obtained by extraction of the crude mixture with tol-d8. Naphtalene was used as internal standard.   1 H NMR (500 MHz,. The sample was obtained by extraction of the crude mixture with tol-d8. Naphtalene was used as internal standard. Spectrum for 1f: 1 H NMR (500 MHz, tol-d8). The sample was obtained by extraction of the crude mixture with tol-d8. Naphtalene was used as internal standard.