Synlett 2020; 31(05): 512-516
DOI: 10.1055/s-0039-1690818
letter
© Georg Thieme Verlag Stuttgart · New York

General Route to Purin-2-ylmagnesium Halides by Metal–Halogen Exchange in Dichloromethane

Silvia Gazzola
,
Malcolm R. Gordon
,
Stephen D. Lindell
We thank the European Commission for Marie Curie Fellowships for S. Gazzola and M. Gordon (FP7-PEOPLE-2012-ITN, Project: ECHONET ‘Expanding Capability in Heterocyclic Organic Synthesis’ No. 316379).
Further Information

Publication History

Received: 28 November 2019

Accepted after revision: 20 January 2020

Publication Date:
10 February 2020 (online)


Abstract

Treatment of a solution of a 9-alkyl- or 9-aryl-2-iodopurine in dichloromethane with an ethereal solution of ethylmagnesium bromide at –5 °C generates the corresponding purin-2-ylmagnesium bromide, which reacts with aldehydes to give the corresponding 2-(hydroxyalkyl)purines in yields of 53–84%. The purin-2-yl Grignard reagents show good functional-group tolerance to ester and nitro groups, and the method permits the synthesis of the previously unknown 6-unsubstituted 2-magnesiopurines for the first time. Performing the same procedure in THF as solvent resulted either in extensive decomposition or rapid isomerization to give purin-8-ylmagnesium halides.

Supporting Information

 
  • References and Notes

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  • 16 (6-Chloro-9-isopropyl-9H-purin-2-yl)(2-furyl)methanol (4c) Pale-yellow oil; yield: 228 mg (78%). 1H NMR (400 MHz, CDCl3): δ = 1.64 (d, J = 6.6 Hz, 6 H), 4.39 (br s, 1 H), 4.91 (sept, J = 6.8 Hz, 1 H), 5.95 (d, J = 7.3 Hz, 1 H), 6.31 (br s, 2 H), 7.34 (br s, 1 H), 8.18 (s, 1 H). 13C NMR (150 MHz, CDCl3): δ = 22.6 (q), 48.3 (d), 69.9 (d), 108.2 (d), 110.5 (d), 131.2 (s), 142.8 (d), 143.4 (d), 151.3 (s), 151.7 (s), 154.1 (s), 161.7 (s). HRMS (ESI/QTOF): m/z [M + H]+ calcd for C13H14ClN4O2: 293.0805; found: 293.0807. [9-(4-Methylphenyl)-9H-purin-2-yl](phenyl)methanol (5a) Pale-yellow solid; yield: 218 mg (69%); mp 145–148 °C. 1H NMR (400 MHz, CDCl3): δ = 2.48 (s, 3 H), 4.88 (d, J = 6.4 Hz, 1 H), 5.99 (d, J = 6.4 Hz, 1 H), 7.26 (m, 1 H), 7.31 (m, 2 H), 7.40 (dd, J = 8.6, 0.6 Hz, 2 H), 7.53 (m, 2 H), 7.58 (m, 2 H), 8.32 (s, 1 H), 9.18 (s, 1 H). 13C NMR (150 MHz, CDCl3): δ = 21.3 (q), 75.8 (d), 123.4 (d), 126.8 (d), 127.8 (d), 128.5 (d), 130.7 (d), 131.7 (s), 133.5 (s), 138.9 (s), 142.8 (s), 144.7 (d), 149.1 (d), 151.3 (s), 165.0 (s). HRMS (ESI/QTOF): m/z [M + H]+ calcd for C19H20N4O: 317.1402; found: 317.1388. Methyl 4-{hydroxy[9-(4-methylphenyl)-9H-purin-2-yl]methyl}benzoate (5b) Pale-yellow solid; yield: 217 mg (58%); mp 144–146 °C. 1H NMR (600 MHz, CDCl3): δ = 2.48 (s, 3 H), 3.88 (s, 3 H), 5.01 (d, J = 6.0 Hz, 1 H), 6.02 (d, J = 5.5 Hz, 1 H), 7.41 (d, J = 8.1 Hz, 2 H), 7.55 (d, J = 8.3 Hz, 2 H), 7.65 (d, J = 8.3 Hz, 2 H), 7.99 (d, J = 8.4 Hz, 2 H), 7.53 (m, 2 H), 8.33 (s, 1 H), 9.17 (s, 1 H). 13C NMR (150 MHz, CDCl3): δ = 21.3 (q), 52.2 (q), 75.3 (d), 123.4 (d), 126.8 (d), 129.6 (s), 129.8 (d), 130.7 (d), 131.6 (s), 133.7 (s), 139.1 (s), 144.9 (d), 147.7 (s), 149.1 (d), 151.5 (s), 164.2 (s), 167.1 (s). HRMS (ESI/QTOF): m/z [M + H]+ calcd for C21H19N4O3: 375.1457; found: 375.1450. 1,3-Benzodioxol-5-yl[9-(4-methylphenyl)-9H-purin-2-yl]methanol (5c) Pale-yellow oil; yield: 173 mg (48%). 1H NMR (600 MHz, CDCl3): δ = 2.47 (s, 3 H), 4.86 (d, J = 6.1 Hz, 1 H), 5.89 (m, 3 H), 6.75 (d, J = 8.0 Hz, 1 H), 6.96 (d, J = 1.5 Hz, 1 H), 7.01 (dd, J = 8.1, 1.4 Hz, 1 H), 7.40 (d, J = 8.1 Hz, 2 H), 7.57 (d, J = 8.3 Hz, 2 H), 8.32 (s, 1 H), 9.17 (s, 1 H). 13C NMR (150 MHz, CDCl3): δ = 21.3 (q), 75.5 (d), 101.1 (t), 107.3 (d), 108.2 (d), 120.4 (d), 123.4 (d), 130.6 (d), 131.7 (s), 133.5 (s), 136.8 (s), 138.9 (s), 144.7 (d), 147.2 (s), 147.8 (s), 149.2 (d), 151.3 (s), 164.9 (s). HRMS (ESI/QTOF): m/z [M + H]+ calcd for C20H17N4O3: 361.1301; found: 361.1286. 2-(Benzyloxy)-1-[9-(4-methylphenyl)-9H-purin-2-yl]ethanol (5d) Pale-yellow oil; yield: 191 mg (53%). 1H NMR (600 MHz, CDCl3): δ = 2.46 (s, 3 H), 3.92 (dd, J = 10.1, 5.0 Hz, 1 H), 4.02 (dd, J = 10.1, 3.2 Hz, 1 H), 4.35 (br s, 1 H), 4.53 (d, J = 12.3 Hz, 1 H), 4.60 (d, J = 12.4 Hz, 1 H), 5.11 (m, 1 H), 7.21 (m, 5 H), 7.36 (d, J = 7.9 Hz, 2 H), 7.54 (d, J = 8.3 Hz, 2 H), 8.33 (s, 1 H), 9.19 (s, 1 H). 13C NMR (150 MHz, CDCl3): δ = 21.3 (q), 73.5 (t), 73.6 (d), 74.1 (t), 123.4 (d), 127.6 (d), 127.7 (d), 128.3 (d), 130.6 (d), 131.7 (s), 133.6 (s), 138.3 (s), 138.8 (s), 144.6 (d), 148.8 (d), 151.4 (s), 163.4 (s). HRMS (ESI/QTOF): m/z [M + H]+ calcd for C21H21N4O2: 361.1665; found: 361.1635. The 1H NMR and 13 C NMR spectra for compounds 4a, 4b, and 4d were identical to those reported previously in the literature.7a