M.A. Fox et al. / Journal of Fluorine Chemistry 143 (2012) 148–154
153
3.2.4.2. With thiophenol 4. 2,3,5,6-Tetrafluoro-4-pyridinecarboni-
trile 2c (0.5 g, 2.84 mmol), thiophenol 4 (0.31 g, 2.84 mmol),
sodium hydrogen carbonate (0.48 g, 5.68 mmol) and acetonitrile
(100 mL) were stirred at rt for 12 d and, after purification by
column chromatography on silica gel (4:1 n-hexane/ethyl acetate),
lithium diisopropylamide (1.3 mL, 2.34 mmol, 1.8 M) were added
to dry THF (200 mL) under argon at À78 8C. The reaction mixture
was stirred for 1 h before warming to rt and stirring for 17 h. The
reaction mixture was concentrated, poured into water (30 mL),
extracted with dichloromethane (3Â 50 mL) and dried (MgSO4).
The solvent was evaporated to dryness to yield the crude product
as a yellow oil (0.28 g) which consisted of one major component.
Purification by column chromatography on silica gel using n-
hexane/ethyl acetate (4:1) as elutant followed by recrystallisation
from ethyl acetate gave 3-amino-5-ethoxycarbonylmethylsulfanyl-
4,7-difluoro-thieno[2,3-c]pyridine-2-carboxylic acid ethyl ether 16
(50 mg, 23%) as a yellow solid; mp 110.2–111.5 8C; (found: [M+H]+
377.0435. C14H14N2O4F2S2 requires: [M+H]+, 377.0436); dF À71.35
gave
2,5-difluoro-3,6-bis(phenylsulfanyl)isonicotinonitrile
10a
(0.63 g, 63%) as a yellow solid; mp 84.2–85.0 8C; (found: C, 60.6;
H, 2.9; N, 7.8. C18H10F2N2S2 requires: C, 60.8; H, 2.8; N, 7.9%); dF
À62.61 (1F, d, 5JFF 27.1, F-2), À117.95 (1F, d, 5JFF 29.3, F-5);
dH 7.55
(2H, m, ArH), 7.45 (5H, m, ArH), 7.32 (3H, m, ArH); m/z (EI+) 356
([M]+, 97%), 109 (76), 77 (100).
3.2.4.3. With ethyl 2-mercaptoacetate 11. 2,3,5,6-Tetrafluoropyr-
idine-4-carbonitrile 2c (1.0 g, 5.68 mmol), sodium methoxide
(0.61 g, 11.36 mmol), ethyl 2-mercaptoacetate 11 (0.68 g,
5.68 mmol) and tetrahydrofuran (100 mL) were heated at reflux
for 4 h to yield the crude product as a yellow oil (0.83 g).
Purification by column chromatography on silica gel (1:1 n-
hexane/ethyl acetate followed by 4:1 n-hexane/ethyl acetate) gave
a mixture of ethyl[(4-cyano-2,5,6-trifluoropyridin-3-yl)sulfanyl]ace-
tate 12 and ethyl[(4-cyano-3,5,6-trifluoropyridin-2-yl)sulfanyl]ace-
tate 13 (0.55 g, 35%) as a yellow oil and in the ratio 5:1; 12: dF
À63.03 (1F, dd, 3JFF 29.3, 4JFF 11.3, F-6), À81.75 (1F, dd, 5JFF 22.6, 4JFF
(1F, d, 5JFF 31.6, F-7), À137.26 (1F, d, 5JFF 31.6, F-4);
dH 6.20 (2H, br s,
NH2), 4.37 (2H, q, 3JHH 7.2, CH2CH3), 4.22 (2H, q, 3JHH 7.2, CH2CH3),
3.95 (2H, s, SCH2), 1.39 (3H, t, 3JHH 6.8, CH2CH3), 1.28 (3H, t, 3JHH 7.2,
CH2CH3);
7), 150.2 (dd, 1JCF 251.9, 4JCF 5.6, C-4), 145.6 (s, C-3), 134.2 (dd, 2JCF
d
C 169.2 (s, C55O), 164.7 (s, C55O), 152.5 (d, 1JCF 238.0, C-
3
2
3
22.5, JCF 13.4, C-5), 131.1 (s, C-2), 130.5 (dd, JCF 14.3, JCF 7.1, C-
2
7a), 118.9 (d, JCF 41.4, C-3a), 62.1 (s, CH2CH3), 61.5 (s, CH2CH3),
32.7 (s, SCH2), 14.6 (s, CH2CH3), 14.3 (s, CH2CH3); m/z (EI+) 376
([M]+, 58%), 331 (16), 303 (100), 257 (42).
3
5
11.3, F-2), À135.46 (1F, dd, JFF 27.1, JFF 20.3, F-5); m/z (EI+) 276
3.3. NMR calculations
([M]+, 66%), 203 (100); 13: dF À85.95 (1F, dd, 5JFF 31.6, 3JFF 22.6, F-
5
4
3
6), À116.45 (1F, dd, JFF 31.6, JFF 4.5, F-3), À137.61 (1F, dd, JFF
22.6, 4JFF 4.5, F-5); m/z (EI+) 276 ([M]+, 4%), 203 (16); and (4-cyano-
6-ethoxycarbonylmethylsulfanyl-2,5-difluoro-pyridin-3-ylsulfanyl)-
acetic acid ethyl ester 14 (0.30 g, 29%); dF À64.35 (1F, d, 5JFF 29.3, F-
2), À118.85 (1F, d, 5JFF 29.1, F-5); 12–14 were used in subsequent
reactions without further purification.
All ab initio/DFT computations were carried out with the
Gaussian 09 package. Optimisation of these geometries without
symmetry constraints were carried out at the MP2/6-31G* level of
theory. Calculated 19F NMR shifts at the GIAO-B3LYP/6-311G* level
were obtained from these MP2-optimised geometries using the
d
(
19F) = 168.8 À
s(
19F) scale.
3.2.5. Synthesis of ethyl 3-amino-4,5,7-trifluorothieno[2,3-
c]pyridine-2-carboxylate 15
Acknowledgements
The mixture of 12 and 13 (5:1) (0.08 g, 0.29 mmol) obtained
above was added to a solution of lithium diisopropylamide
(0.32 mL, 0.58 mmol. 1.8 M) in dry tetrahydrofuran (200 mL) at
À78 8C and stirred for 2 h. The reaction mixture was warmed to rt
and stirred for 2 d, concentrated, poured into water (30 mL),
extracted with dichloromethane (3Â 50 mL) and dried (MgSO4).
The solvent was evaporated to dryness to yield a brown/yellow
solid (0.12 g) consisting of one major component. Purification by
preparative TLC on silica gel (4:1 n-hexane/ethyl acetate) gave
ethyl 3-amino-4,5,7-trifluorothieno[2,3-c]pyridine-2-carboxylate 15
(0.07 g, 88%) as a yellow solid; (found: C, 43.7; H, 2.5; N, 10.2.
We thank GlaxoSmithKline and EPSRC for an Industrial CASE
Fellowship.
References
[1] (a) R.D. Chambers, C.R. Sargent, Adv. Heterocycl. Chem. 28 (1981) 1–71;
(b) G.M. Brooke, J. Fluorine Chem. 86 (1997) 1–76;
(c) M.J. Silvester, Adv. Heterocycl. Chem. 59 (1994) 1–37;
(d) R.D. Chambers, Fluorine in Organic Chemistry, Blackwell, Oxford, 2004.
[2] P. Cornago, C. Escolastico, M.D. Santa Maria, R.M. Claramunt, C. Fernandez-
Castano, C. Foces-Foces, J.P. Fayet, J. Elguero, Tetrahedron 52 (1996) 11075–
11094.
[3] R.D. Chambers, P.R. Hoskin, G. Sandford, D.S. Yufit, J.A.K. Howard, J. Chem. Soc.,
Perkin Trans. 1 (2001) 2788–2795.
[4] (a) R.D. Chambers, P.R. Hoskin, A.M. Kenwright, P. Richmond, G. Sandford, D.S.
Yufit, J.A.K. Howard, Org. Biomol. Chem. 1 (2003) 2137–2147;
(b) R.D. Chambers, A. Khalil, P. Richmond, G. Sandford, D.S. Yufit, J.A.K. Howard, J.
Fluorine Chem. 125 (2004) 715–720;
(c) G. Sandford, Highly functionalised heterocycles and macrocycles from penta-
fluoropyridine in fluorine containing synthons, in: V.A. Soloshonok (Ed.), ACS
Symposium Series 911, ACS, Washington D.C., 2004, pp. 248–261.
[5] C.A. Hargreaves, G. Sandford, B.G. Davis, Polyfluoro-pyridyl glycosyl donors in
fluorinated synthons, in: V.A. Soloshonok (Ed.), ACS Symposium Series 949, ACS,
Washington D.C., 2007, pp. 323–336.
C
10H7F3N2O2S requires: C, 43.5; H, 2.5; N, 10.1%); mp 104.1–
105.6 8C; dF À71.69 (1F, dd, 5JFF 29.3, 4JFF 11.3, F-7), À100.52 (1F, dd,
3JFF 20.3, 4JFF 13.5, F-5), À158.14 (1F, dd, 5JFF 31.6, 3JFF 20.3, F-4); dH
6.13 (2H, br s, NH2), 4.32 (2H, q, 3JHH 7.0, CH2), 1.33 (3H, t, 3JHH 7.0,
CH3); d
C 163.2 (s, C55O), 147.9 (ddd, 1JCF 245.2, 2JCF 13.4, 3JCF 2.4, C-
5), 144.6 (m, C-3), 143.4 (ddm, 1JCF 239.9, 3JCF 13.4, C-7), 137.5 (ddd,
1JCF 257.2, 2JCF 27.3, 4JCF 7.2, C-4), 131.7 (ddd, 2JCF 12.1, 3JCF 7.2, 3JCF
2.4, C-3a), 117.9 (dd, 2JCF 39.3, 3JCF 4.3, C-7a), 103.6 (s, C-2), 60.4 (s,
CH2), 13.3 (s, CH3); m/z (EI+) 276 ([M]+, 50%), 230 (100).
Crystal data for 15: C10H7F3N2O2S, M = 276.24, monoclinic,
[6] (a) G. Sandford, R. Slater, D.S. Yufit, J.A.K. Howard, A. Vong, J. Org. Chem. 70 (2005)
7208–7216;
˚
space group C2/c, a = 20.319(1), b = 4.8461(2), c = 21.909(1) A,
3
˚
(b) A. Baron, G. Sandford, R. Slater, D.S. Yufit, J.A.K. Howard, A. Vong, J. Org. Chem.
70 (2005) 9377–9381;
(c) G. Sandford, C.A. Hargreaves, R. Slater, D.S. Yufit, J.A.K. Howard, A. Vong,
Tetrahedron 63 (2007) 5204–5211;
(d) G. Pattison, G. Sandford, D.S. Yufit, J.A.K. Howard, J.A. Christopher, D.D. Miller,
J. Org. Chem. 74 (2009) 5533–5540;
(e) G. Pattison, G. Sandford, D.S. Yufit, J.A.K. Howard, J.A. Christopher, D.D. Miller,
Tetrahedron 65 (2009) 8844–8850;
b
= 91.134(2)8, U = 2156.9(2) A , F(0 0 0) = 1120, Z = 8, Dc =
1.701 mg mÀ3 = 0.338 mmÀ1. 11,148 reflections were collected
, m
yielding 3000 unique data (Rmerg = 0.083). Final wR2(F2) = 0.1274
for all data (191 refined parameters), conventional R1(F) = 0.0490
for 2431 reflections with I ꢀ 2s, GOF = 1.003.
(f) M.W. Cartwright, L. Convery, T. Kraynck, G. Sandford, D.S. Yufit, J.A.K. Howard,
J.A. Christopher, D.D. Miller, Tetrahedron 66 (2010) 519–529;
(g) M.R. Cargill, K.E. Linton, G. Sandford, D.S. Yufit, J.A.K. Howard, Tetrahedron 66
(2010) 2356–2362;
3.2.6. Synthesis of 3-amino-5-ethoxycarbonylmethylsulfanyl-4,7-
difluoro-thieno[2,3-c]pyridine-2-carboxylic acid ethyl ether 16
(4-Cyano-6-ethoxycarbonylmethylsulfanyl-2,5-difluoro-pyri-
din-3-ylsulfanyl)-acetic acid ethyl ester 14 (0.22 g, 0.59 mmol) and
(h) M.W. Cartwright, E.L. Parks, G. Pattison, R. Slater, G. Sandford, I. Wilson, D.S.