7th International Electronic Conference on Synthetic Organic Chemistry (ECSOC-7), http://www.mdpi.net/ecsoc-7, 1-30 November 2003


[A017]

Jun-An Ma, and Dominique Cahard

 

UMR 6014 de l'IRCOF (Institut de Recherche en Chimie Organique Fine),Université de Rouen, 1 Rue Tesnière,F-76821 Mont Saint Aignan Cedex, France

 

E-mail:  majun_an68@yahoo.com, dominique.cahard@univ-rouen.fr

 

Abstract: The first phase-transfer catalyzed electrophilic trifluoromethylation is reported. Cyclic and acyclic b-ketoesters were efficiently trifluoromethylated with 5-trifluoromethyldibenzothiophenium tetrafluoroborate to afford the corresponding a-substituted a-trifluoromethyl b-ketoesters in good to excellent yields.

 


 

 

 

 

 

Keywords: Trifluoromethylation • Phase-Transfer catalysis • Fluorine Chemistry • b-ketoesters.

 

Organofluorine compounds have received considerable attention and become the focus of intense research efforts due to their fascinating potential of applications to the life science fields, agro-chemistry and to material science.[1,2,3] Among fluoroorganic compounds, trifluoromethyl substituted molecules have gained growing interest during the past decade.[4] The introduction of a trifluoromethyl group, with powerful electron-withdrawing ability can lead to significant changes in the physical, chemical and biological properties of trifluoromethylated compounds when compared with their nonfluorinated analogues.[1,5] Methods for the incorporation of the trifluoromethyl group into organic molecules may be considered as either nucleophilic, electrophilic, radical or carbene processes. Recently, nucleophilic, free radical or carbene trifluoromethylations have been extensively studied and utilized for preparation of trifluoromethylated compounds.[6,7] Electrophilic trifluoromethylation, however, has been relatively slowly developed. Yagupol’skii reported in 1984 the first electrophilic trifluoromethylating agents 1 which showed low reactivity (Figure 1).[8] The research work of Umemoto in the early 90's led to the development of highly reactive trifluoromethyl dibenzoheterocyclic salts, such as 2 and 3 (Figure 1).[9] However, there were until recently few reports of reactions where a trifluoromethyl group is introduced by electrophilic reagents into an organic molecule.[10] The introduction of the trifluoromethyl group is still a non-trivial exercise and new methods for direct trifluoromethylation are eagerly sought.

Figure 1. Electrophilic trifluoromethylating agents.

 

a-Substituted a-trifluoromethyl b-ketoesters are attractive compounds because they are regarded as nonenolizable b-ketoesters. In addition, since ketones are easily converted into other functional groups, a-substituted a-trifluoromethyl b-ketoesters would be versatile synthetic precursors of various a-trifluoromethyl carboxylic acid derivatives. As part of our research program toward the development of organofluorine compounds,[11] we report herein the first phase-transfer catalyzed electrophilic trifluoromethylation reaction of various b-ketoesters with commerically available 5-trifluoromethyldibenzothiophenium salt 2b under mild conditions.

 

To determine suitable reaction conditions for electrophilic trifluoromethylation of b-ketoesters, we initially employed indanone carboxylate 4a as a model compound and 5-trifluoromethyldibenzothiophenium tetrafluoroborate 2b as the electrophilic trifluoromethylating agent in the presence of 10 mol% of tetrabutylammonium iodide (n-Bu4NI) at room temperature.[12] Results of the phase-transfer catalyzed electrophilic trifluoromethylation in various solvents and optimization of the reaction conditions are listed in Table 1.

 

Table 1. Phase-transfer catalyzed electrophilic trifluoromethylation of 4a with 2b.

 

Entry

Solvent

n-Bu4NI (mol%)

Base

Time (h)

Yield (%)a

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Toluene

THF

CH2Cl2

CH3CN

DMF

CH3OH

DMF

DMF

DMF

DMF

DMF

DMF

DMF

DMF

10

10

10

10

10

10

5

5

1

5

5

5

5

5

K2CO3

K2CO3

K2CO3

K2CO3

K2CO3

K2CO3

K2CO3

K2CO3

K2CO3

Na2CO3

Cs2CO3

NaOH

KOH

CsOH.H2O

48

12

24

24

1

28

3

1

1

3

3

3

3

6

0 b

70

72

68

92

0 c

99

88

80

82

86

65

58

92

a Isolated yield. b Substrate 4a was recovered quantitatively. c Trifluoromethylating agent 2b decomposed (detected by TLC and 19F NMR).

 

Among the solvents tested, polar ones were effective for the reaction, and DMF[13] provided the best result, while no reaction occurred in toluene most likely because 5-trifluoromethyldibenzothiophenium tetrafluoroborate 2b is insoluble in this solvent (Table 1, entry 1). It is noteworthy that the reaction did not proceed in methanol in which trifluoromethylating agent 2b quickly decomposed. The amount of phase-transfer catalyst was reduced to 1 mol%, and slightly lower yield was obtained (Table 1, entry 9). K2CO3, Na2CO3, Cs2CO3 and CsOH.H2O were effective bases in this reaction while sodium and potassium hydroxides produced lower yields in trifluoromethylated compounds. As we expected, the reaction proceeded, but slowly and not completely without phase-transfer catalyst.

 

Table 2. Catalytic electrophilic trifluoromethylation of various b-ketoesters.

Entry

Substrate

Product

Yield (%)a

d (19F) (ppm) b

1

99

- 69.82

2

94

- 69.62

3

52 (34)

- 69.31

4

60 (28)

- 69.22

5

36 (60)

- 69.27

6

28 (52)

- 68.93

7c

97

- 69.49 / - 69.50

a Isolated yields. Values in parentheses are for the recovery of substrates. b Measured in CDCl3, relative to CFCl3. c Diastereomeric excess was measured by 19F NMR before isolation.

 

Optimal conditions were established for DMF as solvent at room temperature in the presence of 5 mol% phase-transfer catalyst, and various substrates were trifluoromethylated. As can be seen by the results summarized in Table 2, a-trifluoromethyl b-ketoesters were obtained in good to excellent yields (Table 2, entries 1-4). The reaction of cyclic and acyclic substrates 4e and 4f afforded trifluoromethylated products with relatively low yields (36% and 28%, respectively). Preliminary attempts to extend this reaction to stereoselective trifluoromethylation of b-ketoesters led to poor selectivity (4% de, Table 2, entry 7), probably due to trifluoromethylation being remote from the chiral centers.

 

In contrast to the effect of solvent on C- vs O-alkylation of ethyl acetoacetate with alkyl halides,[14] Matsuyama reported that C-alkylation of enolate ions of b-ketoesters with (p-chlorophenyl)ethylmethylsulfonium salt increased and O-alkylation decreased in higher polarity solvents.[15] However, it should be noted that in all our experiments, the reaction gave only C-trifluoromethylated products, and O-trifluoromethylated compounds were not detected (19F NMR and IR). Concerning the reaction mechanism, we can propose that the reaction proceeds via sulfurane intermediate 6 (Scheme 1). First the enolate ion attacks the cationic sulfur atom of the 5-trifluoromethyldibenzothiophenium salt to form S-O sulfurane intermediate 6. Cleavage of the S-O bond forms a tight ion pair, and the enolate attacks the trifluoromethyl group to yield the C-trifluoromethylated product..

 

Scheme 1. Proposed mechanism for the reaction of b-ketoesters with the trifluoromethylating agent 2b.

 

In summary, we have developed a very efficient and practical method presenting a remarkable rate acceleration for the preparation of a-substituted a-trifluoromethyl b-ketoesters using 5-trifluoromethyldibenzothiophenium tetrafluoroborate under mild phase-transfer conditions. Various b-ketoesters were trifluoromethylated in good to excellent yields. Extensions of this convenient trifluoromethylation process to other enolizable substrates, and to the corresponding asymmetric reaction are in progress.

 

Acknowledgment. The authors thank the French Ministry of Research for financial support.

 

References and notes

 

(1) For general applications of organofluorine compounds: Organofluorine Chemistry: Principles and Commercial Applications; Banks, R. E.; Smart, B. E.; Tatlow, J. C., Eds.; Plenum Press, New York, 1994.

(2) For the use of organofluorine compounds in medicinal and agrochemical science: (a) Biomedical Frontiers of Fluorine Chemistry; Ojima, I.; McCarthy, J. R.; Welch, J. T., Eds.; ACS Symposium Series 639; American Chemical Society: Washington, DC, 1996. (b) Organofluorine compounds in Medicinal Chemistry and Biomedical Applications; Filler, R.; Kobayashi, Y.; Yagupolskii, L.M., Eds.; Elsevier: Amsterdam, 1993. (c) Hudlicky, M.; Pavlath, A. E.; Chemistry of Organic Fluorine Compounds II: A Critical Review; ACS Monograph 187; American Chemical Society: Washington, DC, 1995. (d) Soloshonok, V. A.; Eds., Enantiocontrolled Synthesis of Fluoro-Organic Compounds: Stereochemical Challenges and Biomedicinal Targets; Wiley: New York, 1999.

(3) For the use of organofluorine compounds in materials chemistry: Asymmetric Fluoroorganic Chemistry; Synthesis, Applications, and Future Directions. Chapters 16-18; Ramachandran, P.V., Eds.; ACS Symposium Series 746; American Chemical Society: Washington, DC, 2000.

(4) (a) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48, 6555-6666. (b) Lin, P.; Jiang, J. Tetrahedron 2002, 56, 3635-3671.

(5) Welch, J. T. Tetrahedron 1987, 43, 3123-3197.

(6) Articles on free radical or carbene processes: (a) Miura, K.; Taniguchi, M.; Nozaki, K.; Oshima, K.; Utimoto, K. Tetrahedron Lett. 1990, 31, 6391-6394. (b) Miura, K.; Takeyama, Y.; Oshima, K.; Utimoto, K. Bull. Chem. Soc. Jpn. 1991, 64, 1542-1553. (c) Uneyama, K.; Kitagawa, K.; Tetrahedron Lett. 1991, 32, 375-378. (d) Uneyama, K.; Kanai, M.; Tetrahedron Lett. 1991, 32, 7425-7426. (e) Langlois, B. R.; Laurent, E.; Roidot, N. Tetrahedron Lett. 1992, 33, 1291-1294. (f) Iseki, K.; Nagai, T.; Kobayashi, Y. Tetrahedron Lett. 1993, 34, 2169-2170. (g) Chen, Q.–Y.; Li, Z.–T. J. Chem. Soc., Perkin Trans. I 1993, 645-648. (h) Chen, Q.–Y.; Duan, J.–X. Tetrahedron Lett. 1993, 34, 4241-4244. (i) Iseki, K.; Nagai, T.; Kobayashi, Y. Tetrahedron: Asymmetry 1994, 5, 961-974. (j) Kamigata, N.; Udodaira, K.; Shimizu, T. Phosphorus, Sulphur, and Silicon 1997, 129, 155-168. (k) Kirij, N. V.; Pasenok, S. V.; Yagupolskii, Y. L.; Tyrra, W.; Naumann, D. J. Fluorine Chem. 2000, 106, 217-221. (l) Billard, T.; Roques, N.; Langlois, B. R. Tetrahedron Lett. 2000, 41, 3069-3072. (m) Bertrand, F.; Pevere, V.; Quiclet-Sire, B.; Zard, S. Z. Org. Lett. 2001, 3, 1069-1071. (n) Zhang, X.; Qing, F.-L.; Peng, Y. J. Fluorine Chem. 2001, 108, 79-82.

(7) Recent articles for nucleophilic process: (a) Prakash, G. K. S.; Yudin, A. K. Chem. Rev. 1997, 97, 757-786. (b) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56, 7613-7632. (c) Billard, T.; Bruns, S.; Langlois, B. R. Org. Lett. 2000, 2, 2101-2103. (d) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Synlett. 2001, 77-78. (e) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Angew. Chem. Int. Ed. 2001, 40, 589-590. (f) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Org. Lett. 2001, 3, 2847-2850. (g) Singh, R. P.; Leitch, J. M.; Twamley, B.; Shreeve, J. M. J. Org. Chem. 2001, 66, 1436-1440. (h) Prakash, G. K. S.; Mandal, M. J. Am. Chem. Soc. 2002, 124, 6538-6539. (i) Motherwell, W.B.; Storey, L.J. Synlett. 2002, 646-648.

(8) Yagupol’skii, L. M.; Kondratenko, N. V.; Timofeeva, G. N. J. Org. Chem. USSR 1984, 20, 103-106.

(9) (a)Umemoto, T.; Ishihara, S. J. Am. Chem. Soc. 1993, 115, 2156-2164. (b) Umemoto, T.; Adachi, K. J. Org. Chem. 1994, 59, 5692-5699. (c) Umemoto, T. Chem. Rev. 1996, 96, 1757-1777. (d) Umemoto, T.; Ishihara, S. J. Fluorine Chem. 1998, 92, 181-187 and references therein.

(10) (a) Tamiaki, H.; Nagata, Y.; Tsudzuki, S. Eur. J. Org. Chem. 1999, 2471-2473. (b) Blazejewski, J.-C.; Wilmshurst, M. P. Popkin, M. D.; Wakselman, C.; Laurent, G.; Nonclercq, D.; Cleeren, A.; Ma, Y.; Seo, H.-S.; Leclercq, G. Bioorg. Med. Chem. 2003, 11, 335-345.

(11) (a) Cahard, D.; Audouard, C.; Plaquevent, J.–C.; Roques, N. Org. Lett. 2000, 2, 3699-3671. (b) Cahard, D.; Audouard, C.; Plaquevent, J.–C.; Roques, N. Tetrahedron Lett. 2001, 42, 1867-1869. (c) Mohar, B.; Baudoux, J.; Plaquevent, J.–C.; Cahard, D. Angew. Chem. Int. Ed. 2001, 40, 4214-4216.

(12) For electrophilic fluorination under phase-transfer conditions: Kim, D.Y.; Park, E.J. Org. Lett. 2002, 4, 545-547.

(13) Anhydrous and standard DMF give equal yields of trifluoromethylation.

(14) House, H. O. Modern Synthetic Reactions, 2nd , Benjamin, W. A. Ed.: Menlo Park, CA, 1972, 492-628.

(15) Umemura, K.; Matsuyama, H.; Watanabe, N.; Kobayashi, M.; Kamigata, N. J. Org. Chem. 1989, 54, 2374-2383.