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Synlett 2014; 25(6): 871-875
DOI: 10.1055/s-0033-1340835
DOI: 10.1055/s-0033-1340835
letter
Safe Generation and Direct Use of Diazoesters in Flow Chemistry
Further Information
Publication History
Received: 13 December 2013
Accepted after revision: 27 January 2014
Publication Date:
05 March 2014 (online)
Abstract
A safe and fast method for the production of β-hydroxy-α-diazoesters in continuous flow technology is described. The synthesis involves the formation of ethyl diazoacetate in situ and the addition to several aldehydes in a two-step continuous flow microreactor setup. Rhodium acetate catalyzes a subsequent 1,2-hydride shift to give access to β-keto esters in a three-step sequence.
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References and Notes
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- 23 General Procedure for the Two-Step Process: Glycine ethyl ester hydrochloride (1.12 g, 8 mmol) was dissolved in H2O (2.5 mL) and 5% sulfuric acid (0.76 mL, w/w) was added and a 4-mL syringe was equipped with the mixture. Next, NaNO2 (664 mg, 10 mmol) was dissolved in H2O (3.9 mL) and another 4-mL syringe was equipped with this solution. The two syringes were connected to a flow setup with a T-piece mixer and a 0.9-mL coil (PTFE, i.d. = 0.5 mm). 1,8-Diazabicycloundec-7-ene (596 μL, 4 mmol) was dissolved in dimethylsulfoxide (3.4 mL) and charged into a 4-mL syringe. Aldehyde (4 mmol) was dissolved in the required amount of DMSO to have a solution of exactly 4 mL volume. This mixture was charged into another 4-mL syringe. Both syringes were put to another syringe pump and connected with two T-pieces to the outlet of the first coil as well as to the inlet of the second coil. The second coil consisted of a 2-mL coil (PTFE, i.d. = 0.8 mm). The pumps were set to 4 mL/h and the entire setup ran for 28 min to reach the steady state. Afterwards, the product was collected for 20–30 min in NaHCO3 as quenching agent. Extraction was performed with CH2Cl2 (3 × 10 mL), the combined organic layers were washed with H2O thoroughly (3 × 10 mL) and dried over anhyd MgSO4. After evaporating the solvent in vacuo, the diazoalcohol was purified by column chromatography (hexane–EtOAc gradient, 100% hexane to 85% hexane). Ethyl 2-Diazo-3-hydroxy-3-phenylpropanoate (4a): obtained as a yellow thick oil; 363 mg (30 min collection time; 82% yield; 6.05 g, 115 min collection time, 72%). 1H NMR (400 MHz, CDCl3): δ = 7.57 (m, 5 H, ArH), 6.11 (d, J = 3.5 Hz, 1 H, CHOH), 4.47 (q, J = 7.5 Hz, 2 H, CH 2CH3), 3.26 (br s, 1 H, OH), 1.50 (t, J = 7.5 Hz, 3 H, CH2CH 3). 13C NMR (100 MHz, CDCl3): δ = 166.8, 139.2, 129.1, 128.6, 126.0, 69.2, 61.6, 15.0. MS (EI): m/z = 220.09 [M+]. Ethyl 3-(4-Bromophenyl)-2-diazo-3-hydroxypropanoate (4b): obtained as a yellow oil; 295 mg (20 min collection time; 74% yield). 1H NMR (400 MHz, CDCl3): δ = 7.79 (m, 2 H, ArH), 7.58 (m, 2 H, ArH), 6.15 (d, J = 3.5 Hz, 1 H, CHOH), 4.55 (q, J = 7.0 Hz, 2 H, CH 2CH3), 3.47 (br s, 1 H, CHOH), 1.58 (t, J = 7.5 Hz, 3 H, CH2CH 3). 13C NMR (100 MHz, CDCl3): δ = 166.8, 138.4, 132.5, 128.1, 122.8, 68.8, 61.8, 15.0. MS (EI): m/z = 297.98 [M+]. Ethyl 3-(2-Bromophenyl)-2-diazo-3-hydroxypropanoate (4c): obtained as a yellow oil; 421 mg (22 min collection time; 96% yield). 1H NMR (500 MHz, CDCl3): δ = 7.71 (dd, J = 8.0, 1.5 Hz, 1 H, ArH), 7.57 (dd, J = 8.0, 1.0 Hz, 1 H, ArH), 7.39 (td, J = 7.5, 1.5 Hz, 1 H, ArH), 7.20 (td, J = 8.0, 1.5 Hz, 1 H, ArH), 6.09 (s, 1 H, CHOH), 4.29 (m, 2 H, CH 2CH3), 3.34 (br s, 1 H, CHOH), 1.30 (t, J = 7.0 Hz, 3 H, CH2CH 3). 13C NMR (125 MHz, CDCl3): δ = 166.3, 137.7, 132.9, 127.8, 127.6, 121.6, 68.8, 61.3, 14.8. Ethyl 3-(3-Bromophenyl)-2-diazo-3-hydroxypropanoate (4d): obtained as a yellow oil; 362 mg (22 min collection time; 82% yield). 1H NMR (500 MHz, CDCl3): δ = 7.61 (m, 1 H, ArH), 7.46 (d, J = 8.0 Hz, 1 H, ArH), 7.35 (d, J = 8.0 Hz, 1 H, ArH), 7.26 (t, J = 7.5 Hz, 1 H, ArH), 5.87 (s, 1 H, CHOH), 4.28 (q, J = 7.0 Hz, 2 H, CH 2CH3), 3.09 (br s, 1 H, CHOH), 1.30 (t, J = 7.0 Hz, 3 H, CH2CH 3). 13C NMR (125 MHz, CDCl3): δ = 166.2, 141.1, 131.4, 130.5, 128.9, 124.5, 123.0, 68.1, 61.4, 14.5. Ethyl 2-Diazo-3-hydroxy-3-(p-tolyl)propanoate (4e): obtained as a yellow oil; 203 mg (17 min collection time; 77% yield). 1H NMR (500 MHz, CDCl3): δ = 7.31 (d, J = 8.0 Hz, 2 H, ArH), 7.19 (d, J = 8.0 Hz, 2 H, ArH), 5.88 (s, 1 H, CHOH), 4.27 (q, J = 7.0 Hz, 2 H, CH 2CH3), 3.12 (br s, 1 H, CHOH), 2.35 (s, 3 H, ArMe), 1.29 (t, J = 7.0 Hz, 3 H, CH2CH 3). 13C NMR (125 MHz, CDCl3): δ = 166.5, 138.2, 135.6, 129.4, 125.7, 68.7, 61.1, 21.1, 14.5. Ethyl 2-Diazo-3-(2-ethoxyphenyl)-3-hydroxypropanoate (4f): obtained as a yellow solid; 328 mg (22 min collection time; 85% yield). 1H NMR (500 MHz, CDCl3): δ = 7.44 (d, J = 7.5 Hz, 1 H, ArH), 7.28 (td, J = 8.0, 1.5 Hz, 1 H, ArH), 6.98 (dt, J = 7.5, 1 Hz, 1 H, ArH), 6.90 (d, J = 8.0 Hz, 1 H, ArH), 5.90 (d, J = 6.5 Hz, 1 H, CHOH), 4.25 (q, J = 7.0 Hz, 2 H, CO2CH 2CH3), 4.08 (m, 2 H, OCH 2CH3), 3.62 (br s, 1 H, CHOH), 1.42 (t, J = 7.0 Hz, 3 H, OCH2CH 3), 1.29 (t, J = 7.0 Hz, 3 H, CO2CH2CH 3). 13C NMR (125 MHz, CDCl3): δ = 166.5, 155.4, 129.3, 127.2, 127.2, 120.8, 111.2, 66.4, 63.7, 60.9, 14.8, 14.5. Ethyl 2-Diazo-3-(4-fluorophenyl)-3-hydroxypropanoate (4g): obtained as a yellow oil; 259.8 mg (20 min collection time; 1.09 mmol, 82%). 1H NMR (400 MHz, CDCl3): δ = 7.68 (m, 2 H, ArH), 7.35 (m, 2 H, ArH), 6.17 (d, J = 3.5 Hz, 1 H, CHOH), 4.55 (q, J = 7.0 Hz, 2 H, CH 2CH3), 3.36 (br s, 1 H, CHOH), 1.57 (t, J = 7.0 Hz, 3 H, CH2CH 3). 13C NMR (100 MHz, CDCl3): δ = 167.0, 163.5 (d, J = 234 Hz), 135.4, 128.2 (d, J = 9 Hz), 116.3 (d, J = 20 Hz), 68.8, 61.9, 15.1. MS (EI): m/z = 238.07 [M+]. Ethyl 2-Diazo-3-hydroxyoctanoate (4h): obtained as pale yellow oil; 188 mg (20 min collection time; 66% yield). 1H NMR (400 MHz, CDCl3): δ = 4.90 (dt, J = 4.5, 9.5 Hz, 1 H, CHOH), 4.47 (q, J = 7.0 Hz, 2 H, OCH 2CH3), 2.80 (br s, 1 H, CHOH), 1.86 (m, 2 H, CH 2CHOH), 1.53 (m, 9 H, CH 2CH 2CH 2CH 3), 1.12 (t, J = 7.0 Hz, 3 H, OCH2CH 3). 13C NMR (100 MHz, CDCl3): δ = 167.3, 67.3, 61.6, 34.5, 32.0, 25.8, 23.1, 15.1, 14.6. MS (EI): m/z = 214.14 [M+]. Ethyl 2-Diazo-3-(furan-2-yl)-3-hydroxypropanoate (4i): obtained as a yellow oil; 94 mg (15 min collection time; 45% yield). 1H NMR (400 MHz, CDCl3): δ = 7.49 (t, J = 0.8 Hz, 1 H, OCH=C), 6.46 (m, 2 H, CH=CH), 5.91 (d, J = 4.5 Hz, 1 H), 5.64 (d, J = 5.0 Hz, 1 H), 4.35 (q, J = 7.0 Hz, 2 H), 1.38 (t, J = 7.5 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ = 166.1, 143.4, 143.1, 110.7, 107.8, 63.9, 61.5, 14.7. MS (EI): m/z = 208.11 [M+]. Ethyl 3-(Bicyclo[2.2.1]hept-5-en-2-yl)-2-diazo-3-hydroxypropanoate (4j): obtained as a yellow oil; 238 mg (20 min collection time; 75% yield). MS (EI): m/z = 236.12 [M+]. General Procedure for the Three-Step Process: Syringes, pumps, reagents and flow setup were built the way as described for the two-step procedure. Rhodium acetate dimer (0.025 mmol, 11 mg) was dissolved in a H2O–DMSO (1:1; 10 mL) mixture. The solution was charged onto a 10-mL syringe and put on a third syringe pump which was calibrated on a flow rate of 16 mL/h to run through the third reactor (i.d. 0.8 mm, 1 mL). After the first two reactors had reached steady state, the third pump was started and collection commenced after another 4 min after the last reactor has reached steady state. The product was collected for 20–30 min in sat. NaHCO3 solution. Extraction was performed with CH2Cl2 (3 × 10 mL), the combined organic layers were washed with H2O (3 × 10 mL) and dried over anhyd MgSO4. After evaporating the solvent in vacuo, the β-keto ester was purified by column chromatography (hexane–EtOAc, 98:2). Ethyl 3-Oxo-3-phenylpropanoate (5a): obtained as a colourless oil; 187 mg (20 min collection time; 73% yield). Keto form: 1H NMR (400 MHz, CDCl3): δ = 7.88 (m, 2 H, ArH), 7.39 (m, 3 H, ArH), 4.14 (q, J = 7.0 Hz, 2 H, CH 2CH3), 3.92 (s, 2 H, OCCH2CO), 1.18 (t, J = 7.0 Hz, 3 H, CH 3CH2). 13C NMR (125 MHz, CDCl3): δ = 193.2, 168.1, 134.4, 129.4, 60.9, 40.6, 14.6. Enol form: 1H NMR (400 MHz, CDCl3): δ = 12.78 (s, 1 H, OH), 7.70 (m, 2 H, ArH), 7.53 (m, 2 H, ArH), 7.34 (m, 1 H, ArH), 5.60 (s, 1 H, C=CH), 4.19 (q, J = 7.0 Hz, 2 H, OCH 2CH3), 1.26 (t, J = 7.0 Hz, 3 H, OCH2CH 3). 13C NMR (100 MHz, CDCl3): δ = 173.8, 172.0, 134.0, 131.8, 126.6, 88.0, 60.9, 14.9. MS (EI): m/z = 192.07 [M+].
- 24 During the finalization of this manuscript, a similar report has been published: Maurya RA, Min K.-I, Kim D.-P. Green Chem. 2014; 16: 116
For selected reviews on diazo compounds, see:
For selected reviews on cyclopropanations using diazo compounds, see: