Safe Generation and Direct Use of Diazoesters in Flow Chemistry

Simon T. R. Müller; Daniel Smith; Paul Hellier; Thomas Wirth

doi:10.1055/s-0033-1340835

Synlett, Table of Contents

Synlett 2014; 25(6): 871-875
DOI: 10.1055/s-0033-1340835

letter

Safe Generation and Direct Use of Diazoesters in Flow Chemistry

Simon T. R. Müller

^aCardiff University, School of Chemistry, Park Place, Cardiff CF10 3AT, UK Fax: +44(29)20876968 Email: wirth@cf.ac.uk

,

Daniel Smith

^aCardiff University, School of Chemistry, Park Place, Cardiff CF10 3AT, UK Fax: +44(29)20876968 Email: wirth@cf.ac.uk

,

Paul Hellier

^bInstitut de Recherche Pierre Fabre, 81603 Gaillac, France

,

Thomas Wirth*

^aCardiff University, School of Chemistry, Park Place, Cardiff CF10 3AT, UK Fax: +44(29)20876968 Email: wirth@cf.ac.uk

› Author Affiliations

Abstract

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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.

Key words

addition - aldehydes - diazo compounds - flow chemistry - rhodium

Full Text

References

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