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Synthesis 2023; 55(05): 821-825
DOI: 10.1055/a-1972-3819
DOI: 10.1055/a-1972-3819
paper
One-Step, Gram-Scale Synthesis of Caffeine-d 9 from Xanthine and CD3I
We would like to acknowledge the Natural Sciences and Engineering Research Council (NSERC) of Canada for funding through the Alliance Grant program (Grant ALLRP 566659-21).
Dedicated to Andrew T. B. Stuart, P.Eng., in recognition of his contributions to clean hydrogen and deuterium technologies.
Abstract
A one-step, gram-scale synthesis of caffeine-d 9 was achieved using xanthine and CD3I. The reaction proceeds at room temperature using dimsyl sodium as base and THF as solvent, and conducting the reaction on a 1-g scale gave caffeine and caffeine-d 9 in 77% and 86% yield, respectively, after recrystallization.
Publication History
Received: 07 September 2022
Accepted after revision: 04 November 2022
Accepted Manuscript online:
04 November 2022
Article published online:
29 November 2022
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References
- 1 Parente RM, Tarantino PM, Sippy BC, Burdock GA. Food Chem. Toxicol. 2022; 160: 112774
- 2 Nawrot P, Jordan S, Eastwood J, Rotstein J, Hugenholtz A, Feeley M. Food Addit. Contam. 2003; 20: 1
- 3 WHO Model List of Essential Medicines: 18th List, April 2013 (accessed Nov 11, 2022). World Health Organization; Geneva: 2013. https://apps.who.int/iris/handle/10665/93142
- 4 Kilicdag H, Daglioglu YK, Erdogan S, Zorludemir S. J. Matern.-Fetal Neonat. Med. 2014; 27: 1470
- 5 Eskelinen MH, Kivipelto M. J. Alzheimer’s Dis. 2010; 20: S167
- 6 Zarrabi Ahrabi N, Tabaie SM, Jahanshiri M. J. Sabzevar Uni. Med. Sci. 2021; 28: 663
- 7a Hanazawa T, Kamijo Y, Yoshizawa T, Usui K. Toxicol. Commun. 2021; 5: 97
- 7b Ribeiro JA, Sebastião AM. J. Alzheimer’s Dis. 2010; 20: S3
- 7c Kaplan GB, Greenblatt DJ, Ehrenberg BL, Goddard JE, Cotreau MM, Harmatz JS, Shader RI. J. Clin. Pharmacol. 1997; 37: 693
- 8a Sherman MM, Tarantino PM, Morrison DN, Lin CH, Parente RM, Sippy BC. Regul. Toxicol. Pharmacol. 2022; 133: 105194
- 8b Lelo A, Miners JO, Robson RA, Birkett DJ. Br. J. Clin. Pharmacol. 1986; 22: 183
- 9 Benchekroun Y, Dautraix S, Desage M, Brazier JL. Eur. J. Drug Metab. Pharmacokinet. 1997; 22: 127
- 10 Shao LM, Hewitt MC. Drug News Perspect. 2010; 23: 398
- 11a Cherrah Y, Falconnet JB, Desage M, Brazier JL, Zini R, Tillement JP. Biomed. Environ. Mass Spectrom. 1987; 14: 653
- 11b Cherrah Y, Zini R, Falconnet JB, Desage M, Tillement JP, Brazier JL. Biochem. Pharmacol. 1988; 37: 1311
- 11c Bechalany A, El Tayar N, Carrupt P.-A, Testa B, Falconnet J.-B, Cherrah Y, Benchekroun Y, Brazier J.-L. Helv. Chim. Acta 1989; 72: 472
- 12a Fischer E, Ach L. Ber. Dtsch. Chem. Ges. 1895; 28: 2473
- 12b Fischer E, Ach L. Ber. Dtsch. Chem. Ges. 1895; 28: 3135
- 13a Gepner B, Kreps L. Zh. Obshch. Khim. 1946; 16: 179
- 13b Bredereck H, Gotsmann U. Chem. Ber. 1962; 95: 1902
- 13c Bredereck H, von Schuh H.-G, Martini A. Chem. Ber. 1950; 83: 201
- 13d Falconnet JB, Brazier JL, Desage M. J. Labelled Compd. Radiopharm. 1986; 23: 267
- 14 Traube W. Ber. Dtsch. Chem. Ges. 1900; 33: 3035
- 15 Zajac MA, Zakrzewski AG, Kowal MG, Narayan S. Synth. Commun. 2003; 33: 3291
- 16a Fischer E. Ber. Dtsch. Chem. Ges. 1898; 31: 3266
- 16b Yamawaki J, Ando T, Hanafusa T. Chem. Lett. 1981; 1143
- 16c Biltz H, Damm P. Justus Liebigs Ann. Chem. 1917; 413: 186
- 16d González-Calderón D, González-Romero C, González-González CA, Fuentes-Benítes A. Educ. Quim. 2015; 26: 9
- 16e Pavia DL. J. Chem. Educ. 1973; 50: 791
- 16f Stanovnik B, Mirtič T, Koren B, Tišler M, Belčič B. Vestn. Slov. Kem. Drus. 1982; 29: 331
- 16g Nesterov VM, Kucherya LA, Zavalnyuk RG, Alibaeva TD. Khim. Farm. Zh. 1985; 19: 1389
- 17 Bier D, Hartmann R, Holschbach M. Rapid Commun. Mass Spectrom. 2013; 27: 885
- 18 The Merck Index: An Encyclopedia of Chemicals, Drugs, and Biologicals, 13th ed. O’Neil MJ. Merck & Co Inc; Whitehouse Station NJ:
- 19 There are significant hazards resulting from the thermal instability of the dimsyl anion, which has led to significant exothermic decomposition events and even reactor explosions at scale, see: Yang Q, Sheng M, Henkelis JJ, Tu S, Wiensch E, Zhang H, Zhang Y, Tucker C, Ejeh DE. Org. Process Res. Dev. 2019; 23: 2210
- 20 Dahl AC, Mealy MJ, Nielsen MA, Lyngso LO, Suteu C. Org. Process Res. Dev. 2008; 12: 429
- 21 A synthesis of caffeine-d 9 was reported by Falconnet et al. (see ref. 13d), in which 2 was reacted with CD3I (10.8 equiv) and NaOH in acetone/water, but no specific yield was reported. We repeated this procedure and produced 1-d 9 in 47% yield. In terms of CD3I stoichiometry and overall yield, this is less efficient than our developed method; however, given the hazards of dimsyl sodium (see ref. 19), this route may be better suited when conducting a caffeine-d 9 synthesis on a much larger scale.
- 22 Silverstein RM, Webster FX, Kiemle DJ, Bryce DL. Spectrometric Identification of Organic Compounds . Wiley; Hoboken NJ: 2015: 198
Given that theobromine (3) and theophylline (5) are naturally occurring desmethylcaffeine alkaloids also isolable from the hulls of cacao beans or tea, these have commonly served as synthetic precursors to caffeine, see: