Organocatalytic, enantioselective synthesis of benzoxaboroles via Wittig/oxa-Michael reaction Cascade of α-formyl boronic acids

An enantioselective synthesis of 3-substituted benzoxaboroles has been developed using organocatalysts with good to excellent enantioselectivities (up to 99%). The resulting benzoxaboroles were converted to the chiral β-hydroxy ketones without affecting the enantioselectivity.

1. The starting materials (2a-u) were also prepared according to the reported procedure in ref.
2. The starting material 2-formyl phenylboronic acid derivatives were also purchased from Sigma Aldrich.
For experimental data of (thiourea and squramide catalysts) see: ref.
The organic layer was extracted with EtOAc (10 mL x 3) and dried over anhydrous Na 2 SO 4 and the residue was purified by flash column chromatography on silica gel using EtOAc / hexanes as an eluent to give the corresponding product 4.

Procedure for deborylation-phenylation of compound 3c:
To a solution of 3c (1equiv. 0.1 mmol) and bromobenzene (1.1equiv. o.11 mmol) in dry 1,4dioxane was taken and degassing the reaction mixture with N 2 gas up to 1 hour. Under N 2 atmosphere Pd(PPh 3 ) 4 ( 0.02equiv.) and K 2 CO 3 ( 2 equiv.) was then added. The reaction mixture was heated at 80°C . After completion of substrate 3c (monitored by TLC), the reaction mixture was pass through a plug of silica gel and purified by column chromatography by using hexane/EtOAc as eluent. The obtained product 5 was characterised as follows. (5)

Procedure for deborylation-protonation of compound 3c:
In a 2 mL round bottom flask substrate 3c (1 euqiv., 0.14 mmol) and AgNO 3 (0.1equiv., 0.014 mmol) in 2 mL (EtOH: H 2 O = 1:1 ) as a solvent and Et 3 N (0.1equiv., 0.014) was taken, followed by stirring the reaction mixture up to 1 hour. Then organic layer extracted with EtOAc (3x10 mL) and brine water also added during extraction and the residue obtained purified by column chromatography by hexane/EtOAc as eluent. The obtained product 6 was characterised as follows.
Caution: On keeping the reaction in longer time, there is a possibility of decrease of % ee of the product due to racemization (6)

Procedure for deborylation-(O-allylation) of compound 3c:
In a 5 mL round bottom flask substrate 3c (1 euqiv., 0.084 mmol) and Cu(OAc) 2 (2 equiv., 0.168 mmol) in 1 mL allyl alcohol as a solvent and Et 3 N (4 equiv., 0.336 mmol) was taken, followed by stirring the reaction mixture up to 9 hour under room temperature. Then organic layer extracted with EtOAc (3x10 mL) and brine water also added during extraction and the residue obtained purified by column chromatography by hexane/EtOAc as eluent. The obtained product 7 was characterised as follows.
Caution: On keeping the reaction in longer time, there is a possibility of decrease of % ee of the product due to racemization. (7) Synthetic Procedure for olefination of 3c 8 :

Synthetic procedure for selective reduction of compound 3c:
To a solution of 3c (1equiv., 0.1 mmol) in dry MeOH was taken and stirring the reaction mixture at -5°C to -10°C, then NaBH 4 (1.1equiv., 0.11 mmol) was added. After 15 minutes the reaction mixture passed through over silica gel and send for 1 H NMR to record the dr. The reaction mixture was purified on column chromatography using hexane/EtOAc as an eluent and the obtained product 9 was characterized as follows.

Procedure for oxidative deborylation of compound 9:
To a solution of compound 9 (1 equiv., 0.1 mmol) and in dry 1,4-dioxane was taken and degassing the reaction mixture with N 2 gas up to 1 hour, then under N 2 atmosphere Pd(PPh 3 ) 4 (0.02 equiv.) and K 2 CO 3 (0.2 equiv.) was added. The reaction mixture was heated at 80°C . After completion of substrate 9 (monitored by TLC), the reaction mixture was passed through a plug of silica gel and purified by column chromatography by using hexane/EtOAc as eluent. The obtained product 10 was characterised as follows:

Procedure for synthesis of methyl acetal of compound 4c:
In a 2 mL round bottom flask substrate 4c was taken (1 euqiv., 0.034 mmol) and acetaldehyde (1.2 equiv., 0.04 mmol) in 1 mL CH 2 Cl 2 and then p-TSA (0.2 equiv., 0.007 mmol) was added and stirred the reaction mixture up to 30 minutes and then reaction mixture passed through over silica gel, send for 1 H NMR to record the dr. The reaction mixture purified on column chromatography using hexane/EtOAc as an eluent and the obtained product was characterized as follows.

Procedure for synthesis of phenyl acetal of compound 4c:
In a 2 mL round bottom flask substrate 4c was taken (1 euqiv., 0.05 mmol) and benzaldehyde dimethyl acetal (1.2 equiv., 0.06 mmol) in 1 mL CH 2 Cl 2 and then p-TSA (0.2 equiv., 0.01 mmol) was added and stirred the reaction mixture up to 2 hours. After completion (monitored by TLC) reaction mixture passed through over silica gel, send for 1 H NMR to record the dr.
Then the reaction mixture was purified on column chromatography using hexane/EtOAc as an eluent and the obtained product was characterized as follows.
Caution: On keeping the reaction in longer time there is a possibility of decrease of % ee in the product due to racemization. The following ALERTS were generated. Each ALERT has the format test-name_ALERT_alert-type_alert-level. Click on the hyperlinks for more details of the test.