Synthesis of benzylic mono(α,α-difluoromethylphosphonates) and benzylic bis(α,α-difluoromethylphosphonates) via electrophilic fluorination

Tetrahedron Letters

Volumn 37, Issue 45, 1996, Pages 8089-8092

  Taylor, Scott D ^a   Dinaut, A Nicole ^a   Thadani, Avinash N ^a   Huang, Zheng ^b  

^a UNIVERSITY OF TORONTO   (Canada)

^b MERCK FROSST CENTRE FOR THERAPEUTIC RESEARCH   (Canada)

Author keywords

[No Author keywords available]

Indexed keywords

ORGANOFLUORINE DERIVATIVE; PHOSPHONIC ACID DERIVATIVE;

ARTICLE; DRUG SYNTHESIS; FLUORINATION; REACTION ANALYSIS; TECHNIQUE;

EID: 0030569370     PISSN: 00404039     EISSN: None     Source Type: Journal    
DOI: 10.1016/0040-4039(96)01847-3     Document Type: Article

References (20)

1. 1 (a) Ide, R.; Maegawa, H.; Kikkawa, R.; Shigetta, Y.; Kashiwagi, A. Biochem. Biophys. Res. Commun. 1994, 201, 77.
2. (b) Weiner, J. R.; Hurteau, J. A.; Kerns, B. J.; Whitaker, R. S.; Conaway, M. R.; Berchuck, A.; Bast, R. C. Am. J. Obstet. Gynecol., 1994, 170, 1171.
3. 2. (a) Brugge, J. S. Science 1993, 260, 918.
4. (b) See Kole, K. H.; Smyth, M. S.; Russ, P. L.; Burke, T. R. Biochem. J 1995, 311, 1025 and ref. therein.
5. 3 (a) Burke, T. R.; Kole, H. K.; Roller, P. P. Biochem. Biophys. Res. Commun. 1994, 204, 129.
6. (b) Kole, H. K.; Akamatsu, M.; Ye, B.; Yan, X.; Barford, D.; Roller, P. P.; Burke, T. R. Biochem. Biophys. Res. Commun. 1995, 209, 817.
7. 4. (a) Montserat, J.; Chen, L.; Lawrence, D. S.; Zhang, Z-Y J. Biol. Chem. 1996, 271, 7868.
8. (b) Desmarais, S.; Govindarajan, A.; Ramachandran, C; Zamboni, R.; Abdullah, K; Huang, Z. FASEB J. 1995, 9, A1347.
9. 5. Smyth, M. S.; Ford, H. Jr.; Burke, T.R. Jr. Tetrahedron. Lett 1992, 33, 4137. These workers also attempted to synthesize similar benzylic α,α-difluoromethylphosphonates (entries 1 and 6 in Table 1 protected with t-butyl groups) by converting the α-monofluorophosphonates, obtained by DAST fluorination of the α-hydroxy phosphonates, to the difluorophosphonates using NFBS but were unsuccessful.
10. 6. Friedman, L.; Fishel, D. L; Shechter, D. J. Org. Chem. 1965, 30, 1453.
11. 7. Burdett, K. A. Synthesis 1991, 441.
12. 31P NMR analysis of the crude reaction mixtures showed a multitude of peaks. We also considered synthesizing the bis(α-ketophosphonates) by converting naphthalenedicarboxaldehydes into bis(α-hydroxyphosphonates) followed by oxidation to the desired ketones (see ref. 5). However, this approach was not taken due to the potential difficulties in obtaining all of the various isomers of naphthalenedicarboxaldehyde.
13. 9. Differding, E.; Duthaler, R. O.; Kreiger, A.; Ruegg, G. M.; Schmit, C. Synlett 1991, 395.
14. 10. The benzylic phosphonates were either purchased or could be readily prepared in high yields by reacting trimethyl phosphite with benzylic halides (Arbuzov reaction).
15. 11. Successful fluorinations were also performed using KDA and KHMDS, however, NaHMDS consistently gave the highest yields. LDA also worked but much more poorly than the other bases.
16. 12. We also synthesized entries 1, 6 and 7 in Table 1 using the DAST procedure (reference 5) from the corresponding α-ketophosphonates. However, in our hands, yields ranged from 32-50 % and purification required several columns.
17. 13 While this work was in progress Burton and Qui reported the synthesis of a series of benzylic α,α-difluoromethylphosphonates via CuCl-promoted coupling of (diethylphosphonyl)difluoromethylcadmium reagent with aryl iodides. See Qui, W.; Burton, D.J. Tetrahedron Lett. 1996, 57, 2745.
18. 14. The bis(bromomethyl)naphthalenes were prepared by photochemical bromination of isomers of dimethylnaphthalene See Futamara, S.; Zong, Z-M. Bull. Chem. Soc. Jpn. 1992, 65, 345.
19. +] 444.051. found 444.051.
20. 16. We were unable to obtain the para-phenyl derivative or the 1,4-naphthyl derivative using this procedure. Only unidentified polymeric products were obtained. While this work was in progress. Burton and Qui reported the synthesis of the paraphenyl derivative in 75 % yield by CuCl promoted coupling of para-diiodobenzene with (diethylphosphonyl)difluoromethylcadmium reagent. See reference 13.