A novel synthetic route to ethyl 3-substituted-trans-2,3-difluoro-2-acrylates and their reactions with nucleophiles

Article abstract of DOI:10.1016/S0040-4039(00)01517-3

Reaction of a variety of trans-1-trimethylsilyl-1,2-difluoroalkenes with ethyl chloroformate in the presence of potassium fluoride gave the corresponding ethyl 3-substituted-trans-2,3-difluoro-2-acrylates in good yields, which reacted with a variety of nucleophiles such as hydrazine hydrate, amidines and thiourea etc. in the presence of bases to afford the corresponding 4-fluoropyrazole, 5-fluoropyrimidine and 5-fluoro-2-uracil derivatives in good yields. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01517-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8545–8548
A novel synthetic route to ethyl
3-substituted-trans-2,3-difluoro-2-acrylates and their
reactions with nucleophiles
Qisheng Zhang and Long Lu*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, PR China
Received 28 June 2000; revised 24 August 2000; accepted 7 September 2000
Abstract
Reaction of a variety of trans-1-trimethylsilyl-1,2-difluoroalkenes with ethyl chloroformate in the
presence of potassium fluoride gave the corresponding ethyl 3-substituted-trans-2,3-difluoro-2-acrylates in
good yields, which reacted with a variety of nucleophiles such as hydrazine hydrate, amidines and
thiourea etc. in the presence of bases to afford the corresponding 4-fluoropyrazole, 5-fluoropyrimidine and
5-fluoro-2-uracil derivatives in good yields. © 2000 Elsevier Science Ltd. All rights reserved.
Much attention has been given to fluorinated organic compounds both in a theoretical and in
a practical sense owing to the characteristic features of fluorine.1 The introduction of fluorine
into organic compounds often leads to enhanced biological activity. The preparation of alkenes
fluorinated at selected positions is an important synthetic objective in this area.2,3 Recently,
stereoselective incorporation of a vinylic fluorine into bioactive organic molecules has been
shown to increase biological potency compared with their non-fluorinated parent compounds.4–7
However, methodology for introducing the 1,2-difluoroethylene unit (ꢀCFꢁCFꢀ) stereoselec-
tively into organic compounds has not received much attention,8–12 Recently, Burton described
the preparation and palladium/CuI catalyzed stereospecific cross-coupling reaction of 1,2-
difluorovinylstannanes with aryl iodides and vinyl halides.13 We now report a novel synthetic
route to a variety of ethyl 3-substituted-trans-2,3-difluoro-2-acrylates and their reactions with
nucleophiles.
A modified literature procedure11 was utilized to prepare trans-(2-alkyl- or 2-aryl-1,2-
difluoroethenyl)trimethylsilanes. Trifluorovinyltrimethylsilane, prepared from trimethylsilyl
chloride, chlorotrifluoroethylene and n-butyl lithium in THF, reacted with a variety of lithium
reagents to afford the corresponding addition–elimination products (trans>98%) (Scheme 1).
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01517-3

8546
Scheme 1. R=n-Bu, sec-Bu, n-C5H11, n-C6H13, n-C8H17, Ph, p-MeOPh
Hiyama reported the fluoride ion-catalyzed generation and carbonyl addition of trans-2-sub-
stituted 1,2-difluoroethenyl carbanions from the corresponding trans-(2-substituted 1,2-
difluoroethenyl)silanes.14 In place of aldehydes, ethyl chloroformate reacted with trans-(2-alkyl-
or 2-aryl-1,2-difluoroethenyl)trimethylsilanes in the presence of dry potassium fluoride (1.5–2.0
equiv.) in DMF at 80°C to afford the corresponding esters stereospecifically in good yields.
Table 1 summarizes our preliminary results.
Table 1
Preparation of ethyl 3-substituted-trans-2,3-difluoro-2-acrylates
Entry
R
Yield(%)a
1
2
3
4
5
6
7
sec-Bu
n-Bu
Ph
p-MeOPh
n-C5H11
n-C6H13
n-C8H17
62
66
72
81
67
76
71
a Isolated yields based on the corresponding silanes.
As a,b-unsaturated esters, ethyl 3-substituted-trans-2,3-difluoro-2-acrylates can undergo
Michael addition reactions with nucleophiles such as thiophenol, sodium azide etc. followed by
elimination of the b-fluorine to give addition–elimination products.15 Consequently, a new
synthetic route to monofluorinated heterocyclic compounds could be envisaged if reagents with
two nucleophilic centers were employed.
Hydrazine monohydrate was selected first to react with ethyl 3-substituted-trans-2,3-difluoro-
2-acrylates. In the presence of triethylamine, ethyl trans-2,3-difluoro-2-heptenoate reacted with
a small excess of hydrazine monohydrate in ethanol at room temperature. The reaction was
monitored by TLC and 19F NMR. After the starting material disappeared, the reaction mixture
was worked up and purified on a silica gel column to give the corresponding 3-hydroxy-4-fluoro-
5-pentylpyrazole in a yield of 80%. The structure was confirmed by 1H NMR, 19F NMR, IR and
HRMS. Table 2 summarizes the preliminary results.
Similarly, treatment of ethyl 3-substituted-trans-2,3-difluoro-2-acrylates with acetamidine
hydrochloride and benzamidine hydrochloride, respectively, in the presence of potassium
carbonate in 1,4-dioxane afforded the corresponding 5-fluoropyrimidine derivatives in good
yield. The preliminary results are listed in Table 3.

8547
Table 2
Preparation of 4-fluoropyrazole derivatives
Entry
R
Yield(%)a
1
2
3
4
sec-Bu
n-Bu
n-C5H11
n-C8H17
76
75
80
78
a Isolated yield based on ethyl 3-substituted-trans-2,3-difluoro-2-acrylates.
Table 3
Synthesis of 5-fluoropyrimidine derivatives
Entry
R
R%
Yield(%)a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
sec-Bu
n-C5H11
n-C6H13
Ph
p-MeOPh
n-C8H17
sec-Bu
n-Bu
n-C5H11
n-C6H13
Ph
p-MeOPh
n-C8H17
sec-Bu
CH3
CH3
CH3
CH3
CH3
CH3
CH3
Ph
Ph
Ph
Ph
Ph
87
85
76
71
92
89
84
89
91
83
88
81
89
93
Ph
Ph
a Isolated yields based on ethyl 3-substituted-trans-2,3-difluoro-2-acrylates.
When thiourea was employed in the above reaction, the corresponding 6-n-butyl-5-fluoro-2-
thiouracil was obtained in 68% yield (Scheme 2).

8548
Scheme 2.
In conclusion, we have developed a new and convenient method for the synthesis of ethyl
3-substituted-trans-2,3-difluoro-2-acrylates, which can further react with a variety of nucleo-
philes such as hydrazine hydrate, amidines and thiourea etc. to afford the corresponding
4-fluoropyrazole, 5-fluoropyrimidine and 5-fluoro-2-uracil derivatives in good yield.
Acknowledgements
We thank the National Natural Science Foundation of China (Grant Number 29825104 and
29632003) and the Chinese Academy of Sciences for financial support of this work.
References
1. (a) In Biochemical Aspects of Fluorine Chemistry; Filler, R.; Kobayashi, Y., Eds.; Elsevier Biomedical Press and
Kodansha Ltd: Tokyo, 1982. (b) Welch, J. T. Tetrahedron 1987, 43, 3123. (c) In Selective Fluorination in Organic
and Bioorganic Chemistry; Welch, J. T., Ed.; ACS Symposium Series, 1991; No. 456.
2. (a) Sun, W. C.; Ng, C. S.; Prestwich, G. D. J. Org. Chem. 1992, 57, 132 and references cited therein. (b) Masnyk,
M.; Fried, J.; Roelofs, W. Tetrahedron Lett. 1989, 30, 3243. (c) Kwok, P. Y.; Muellner, F. W.; Chen, C. K.;
Fried, J. J. Am. Chem. Soc. 1987, 109, 3684.
3. (a) Briggs, G. C.; Cayley, G. R.; Dawson, G. W.; Griffiths, D. C.; Macaulay, E. D. M.; Pickett, J. A.; Pile, M.
M.; Wadhams, L. J.; Woodcock, C. M. Pestic. Sci. 1986, 17, 441. (b) Buist, P. H.; Findlay, J. M.; Leger, G.; Pon,
R. A. Tetrahedron 1987, 28, 3891.
4. (a) Camps, F.; Coll, J.; Fabrias, G.; Guerrero, A. Tetrahedron 1984, 40, 2871. (b) Camps, F.; Fabrias, G.;
Guerrero, A. Tetrahedron Lett. 1986, 42, 3623.
5. (a) Taguchi, T.; Takigawa, T.; Kobayashi, Y.; Tanaka, Y.; Jubiz, W.; Briggo, R. G. Chem. Pharm. Bull. 1987,
37, 1666. (b) Ducep, J.-B.; Nave, J. F.; Zimmermann, P. R. Bioorg. Med. Chem. 1994, 2, 213.
6. (a) McCarthy, J. R.; Mattews, D. P.; Stemerick, D. M.; Huber, E. W.; Bey, P.; Lippert, B. J.; Snyder, R. D.;
Sunkara, P. S. J. Am. Chem. Soc. 1991, 113, 7439 and references cited therein. (b) Mattews, D. P.; Miller, S. C.;
Jarri, E. T.; Sabol, J. S.; McCarthy, J. R. Tetrahedron Lett. 1993, 34, 3057.
7. (a) Eddarir, S.; Francesch, C.; Mestdagh, H.; Rolando, C. Tetrahedron Lett. 1990, 31, 4449. (b) Eddarir, S.;
Mestdagh, H.; Rolando, C. Tetrahedron Lett. 1991, 32, 69.
8. (a) Normant, J. F. J. Organomet. Chem. 1990, 400, 19 and references cited therein. (b) Tellier, F.; Sauvetre, R.;
Normant, J.-F. J. Organomet. Chem. 1989, 364, 17.
9. (a) Xue, L.; Lu, L.; Pederson, S.; Liu, Q.; Narske, R.; Burton, D. J. Tetrahedron Lett. 1996, 37, 1921. (b) Xue,
L.; Lu, L.; Pederson, S.; Liu, Q.; Narske, R.; Burton, D. J. J. Org. Chem. 1997, 62, 1064.
10. (a) Asato, A. E.; Liu, R. S. H. Tetrahedron Lett. 1986, 27, 3337. (b) Bildstein, S.; Ducep, J.-B.; Jacob, D.;
Zimmermann, P. R. Tetrahedron Lett. 1996, 37, 4941.
11. Martinet, P.; Sauvetre, R.; Normant, J. F. Bull. Soc. Chim. Fr. 1990, 86.
12. Kuroboshi, M.; Yamada, N.; Takebe, Y.; Hiyama, T. Tetrahedron Lett. 1995, 36, 6271.
13. Lu, L; Burton, D. J. Tetrahedron Lett. 1997, 38, 7673 and references cited therein.
14. Fujita, M.; Obayashi, M.; Hiyama, T. Tetrahedron 1988, 44, 4135.
15. Zhang, Q. S.; Lu, L., to be published.
.