A. T. Lindhardt, T. Skrydstrup et al.
General procedure for the butyl vinyl ether MH-coupling reactions: The
pyridyl tosylate (1 equiv), butyl vinyl ether (4.0 equiv), Cy2NMe
(3 equiv), DPPF or DPPP (0.05 equiv) and [PdACTHNUTRGENUG(N dba)2] (0.05 equiv) were
dissolved in dioxane (3 mL) and the sample vial was fitted with a Teflon
sealed screwcap and removed from the glovebox. The reaction mixture
was heated for the time stated below at 1008C. The crude reaction was
concentrated in vacuo and purified by column chromatography.
35 in 93 and 97% isolated yield, respectively (routes A and
B).[15c,19] Next, it was envisioned that the chloride in the 5-
position on 9 could be applied as an electrophile in addition-
al palladium-catalyzed transformations. Cu-free Sonoga-
shira-coupling reactions by conditions developed by Buch-
wald et al. were attempted (C).[20] Despite the somewhat
low yield obtained in the Sonogashira coupling with tert-
butyl acetylene a 61% yield of 35 could be isolated upon
coupling with the TIPS-protected acetylene. Both additional
MH (D) and Suzuki–Miyaura (E)-coupling reactions were
successful using conditions developed by Fu et al. providing
coupling yields ranging from 75–89% and 63–72%, respec-
tively, for the two reactions.[21,22] These results clearly indi-
cate the utility of 2-pyridyl tosylates as building blocks for
highly functionalized heteroaromatic compounds in few
steps.
2-(1-Butoxyvinyl)-5-(trifluoromethyl)pyridine (24): 5-(Trifluoromethyl)-2-
pyridinyl tosylate (95.2 mg, 0.30 mmol), butyl vinyl ether (155.3 mL,
1.20 mmol), Cy2NMe (191 mL, 0.90 mmol), DPPP (6.19 mg, 0.015 mmol)
and [PdACTHUNTGRNE(UGN dba)2] (8.6 mg, 0.015 mmol) were dissolved in dioxane (3 mL)
and reacted for 17 h at 1008C. The crude product was purified by flash
chromatography on silica gel using CH2Cl2/pentane 2:3 to afford the title
compound as
a
colorless oil (57.2 mg, 78%). 1H NMR (400 MHz,
CD3CN): d = 8.82 (d, 1H, J=0.8 Hz), 8.04 (dd, 1H, J=8.4, 0.8 Hz), 7.82
(d, 1H, J=8.4 Hz), 5.54 (d, 1H, J=2.0 Hz), 4.53 (d, 1H, J=2.0 Hz), 3.93
(t, 2H, J=6.4 Hz), 1.82–1.75 (m, 2H), 1.56–1.47 (m, 2H), 0.98 ppm (t,
3H, J=7.4 Hz); 13C NMR (100 MHz, CD3CN): d = 157.8, 157.0, 146.0
(q, J=4.4 Hz), 134.5 (q, J=3.6 Hz), 125.4 (q, J=32.6 Hz), 124.3 (q, J=
269.6 Hz), 118.8, 86.9, 68.2, 31.1, 19.5, 13.4 ppm; 19F NMR (376 MHz,
CD3CN): d = À63.3 ppm; HRMS (ESI): m/z: calcd for C12H14NOF3H:
246.1106, found: 246.1107 [M+H+].
Conclusions
In conclusion, we have successfully developed catalytic con-
ditions, which allow the use of heteroaromatic tosylates as
electrophiles in electron-rich MH-coupling reactions with
full regioselectivity. Both electron-rich enamides and vinyl
ethers could be applied as olefins without loss of reactivity.
Furthermore, changes in the heteroaromatic core of the to-
sylate to pyrimidines did not affect the overall catalytic ac-
tivity. Increased catalytic activity was observed when this
protocol was adapted in large-scale coupling reactions af-
fording full conversion using catalyst loadings of only
1 mol%. Finally, the stability of the formed N-acyl a-(2-pyr-
idyl)vinyl amines was established upon their application in a
variety of different palladium-catalyzed transformations.
Further work is now in progress to find suitable conditions
which may increase the scope of this methodology to in-
clude other heteroaromatic systems. This work will be re-
ported in due course.
Acknowledgements
We thank the Danish National Research Foundation, the Lundbeck
Foundation, the Carlsberg Foundation, the AstraZeneca group and
Aarhus University for generous financial support of this work.
[1] For some recent reviews on the Mizoroki–Heck reaction, see
[2] For a few papers on the topic of insertion and regioselectivity, see:
c) M. Ludwig, S. Stromberg, M. Svensson, B. Akermark, Organome-
of Organopalladium Chemistry for Organic Synthesis (Ed.: E. Ne-
gishi), Wiley, New York, 2002.
[4] a) K. S. A. Vallin, M. Larhed, K. Johansson, A. Hallberg, J. Org.
[5] a) S. Liu, N. Berry, N. Thomson, A. Pettman, Z. Hyder, J. Mo, J.
Experimental Section
General procedure for the N-vinyl acetamide MH-coupling reactions:
The pyridyl tosylate (1 equiv), N-vinyl acetamide (4.0 equiv), Cy2NMe
(3 equiv), DPPF or DPPP (0.05 equiv) and [PdACTHNUTRGENUG(N dba)2] (0.05 equiv) were
dissolved in dioxane (3 mL) and the sample vial was fitted with a Teflon
sealed screwcap and removed from the glovebox. The reaction mixture
was heated for the time stated below at 1008C. The crude reaction was
concentrated in vacuo and purified by column chromatography.
(N-(1-(5-Chloro-2-pyridinyl)vinyl)acetamide (9): 5-Chloro-2-pyridinyl to-
sylate (85.1 mg, 0.30 mmol), N-vinylacetamide (102.1 mg, 1.20 mmol),
Cy2NMe (191 mL, 0.90 mmol), DPPF (8.3 mg, 0.015 mmol), [PdACHTNUTRGNEUNG(dba)2]
[6] For some examples, see: a) Q. Shen, T. Ogata, J. F. Hartwig, J. Am.
[7] For some examples, see: a) A. S. Guram, A. O. King, J. G. Allen, X.
Wang, L. B. Schenkel, J. Chan, E. E. Bunel, M. M. Faul, R. D.
3358–3366; d) A. S. Guram, X. Wang, E. E. Bunel, M. M. Faul,
(8.6 mg, 0.015 mmol) were dissolved in dioxane (3 mL) and reacted for
17 h at 1008C. The crude product was purified by flash chromatography
on silica gel using EtOAc/pentane 3:7 to afford the title compound as
colorless crystals (51.7 mg, 88%). M.p. 84–858C; 1H NMR (400 MHz,
CD3CN): d = 8.94 (brs, 1H), 8.54 (dd, 1H, J=2.4, 1.2 Hz), 7.82–7.81 (m,
2H), 6.34 (s, 1H), 5.54 (d, J=1.2 Hz), 2.13 ppm (s, 3H); 13C NMR
(100 MHz, CD3CN): d = 169.5, 151.1, 146.9, 138.1, 137.2, 131.6, 120.8,
99.7, 24.2 ppm; HRMS (ESI): m/z: calcd for C9H9ClN2ONa: 219.0301,
found: 219.0299 [M+Na+].
5954
ꢀ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2009, 15, 5950 – 5955