4
anticipate that this type of electron delocalisation also influences
the reactivity of the carbon–palladium bond in I.
In summary, we have detailed reaction conditions that facilitate
the rather tricky Sonogashira alkynylation of 4,6-dichloro-2-
2 and text for yields); d
H
(400 MHz, CDCl
3
) 5.45 (d, 1H, J = 1.6 Hz),
4
3
3
5
7
.18 (d, 1H, J = 1.6 Hz), 3.39 (q, 4H, J = 7.1 Hz), 1.23 (t, 6H, J =
.1 Hz); d
C
(100 MHz, CDCl
) 1726 (C=O), 1585 (C=C), 1531; LRCI m/z 202 (MH , 100),
, 60); HRCI m/z exact mass calc. for C H NO Cl (MH ):
3
) 160.6, 134.6, 127.7 93.6, 82.3, 42.7, 12.5;
+
m
max (CH
2
Cl
2
+
+
218 (M + NH
4
9
13
2
pyrone 8. Side-reactions of 8 with Et
can be suppressed by careful selection of the palladium cata-
lyst/precatalyst source. The dba ligands from Pd(dba) clearly
3
N are a problem that
202.06348. Found: 202.06344. Further characterisation data can be found
in the Electronic Supplementary Information.
It was established that use of a catalyst system of either Pd(OAc)
¶
2 3
/PPh
2
(
1 : 3) or Pd(OAc) , the so-called ligand-free conditions, proved ineffective
2
hinder the cross-coupling reactions of 8. This outcome appears to
in cross-coupling 8 with several terminal acetylenes under a variety of
conditions (solvent, base and temperature, including changes in global Pd
concentration).
be more convoluted than the simple situation where dba ligates and
22
3 n
lowers the concentration of (PPh ) Pd(0) in the catalytic cycle,
and potentially hints at a secondary role for this ligand. The high
1 For reviews in the area, see: G. P. McGlacken and I. J. S. Fairlamb, Nat.
Prod. Rep., 2005, 22, 369; J. M. Dickinson, Nat. Prod. Rep., 1993, 10,
regioselectivity seen at the 6-position in 8 shows that a certain
7
1.
1
3
degree of caution is required when using C NMR chemical shifts
to predict the reactivity of halogenated 2-pyrones. It is of particular
note that cross-coupling at the 4-position in 8 is not observed.
The fact that dialkynylation is possible suggests that the 4-chloro
substituent is more activated in the mono-alkynylated products
2
L. R. Marrison, J. M. Dickinson and I. J. S. Fairlamb, Bioorg. Med.
Chem. Lett., 2002, 12, 3509; L. R. Marrison, J. M. Dickinson, R.
Ahmed and I. J. S. Fairlamb, Tetrahedron Lett., 2002, 43, 8853; I. J. S.
Fairlamb, F.-J. Lu and J.-P. Schmidt, Synthesis, 2003, 2564.
I. J. S. Fairlamb, L. R. Marrison, J. M. Dickinson, F.-J. Lu and J.-P.
Schmidt, Bioorg. Med. Chem., 2004, 12, 4285.
3
9
relative to 8 (under the described reaction conditions). In due
4 J. C. Collings, A. C. Parsons, L. Porr e` s, A. Beeby, A. S. Batsanov,
J. A. K. Howard, D. P. Lydon, P. J. Low, I. J. S. Fairlamb and T. B.
Marder, Chem. Commun., 2005, 2666.
course, the biological effects and fluoresecence properties of the
novel cross-coupled products will be reported.
We are grateful to the Royal Society for funding a university
research fellowship and for providing a generous equipment grant
5
I. J. S. Fairlamb, J. M. Lynam, I. E. Taylor and A. C. Whitwood,
Organometallics, 2004, 23, 4964.
6 I. J. S. Fairlamb, S. M. Syv
a¨ nne and A. C. Whitwood, Synlett, 2003,
1
693.
(
to I. J. S. F.). We thank Professor Todd B. Marder (Durham, UK)
7
I. J. S. Fairlamb, A.-K. Duhme-Klair, J. M. Lynam, B. E. Moulton,
C. T. O’Brien, P. Sawle, J. Hammad and R. Motterlini, Bioorg. Med.
Chem. Lett., 2006, 16, 995.
I. J. S. Fairlamb, A. F. Lee, F. Loe-Mie, E. H. Niemel a¨ , C. T. O’Brien
and A. C. Whitwood, Tetrahedron, 2005, 61, 9827.
and Dr Jean-Cyrille Hierso (Dijon, France) for discussions and
acknowledge Johnson Matthey for a loan of PdCl .
2
8
Notes and references
9 M. Biagetti, F. Bellina, A. Carpita and R. Rossi, Tetrahedron Lett.,
2
003, 44, 607; F. Bellina, A. Carpita, L. Mannocci and R. Rossi,
1
1
13
‡
Quantitative H NOE (500 MHz) and H– C HMBC experiments
Eur. J. Org. Chem., 2004, 2610.
confirm the C6-substitution pattern. The regiochemistry was also con-
10 V. N. Kalinin, O. S. Shilova, D. S. Okladnoy and H. Schmidhammer,
Mendeleev Commun., 1996, 244.
9
firmed by an independent synthesis of 6-(2-phenylethynyl)-2-pyrone;
the spectroscopic data for 4-(2-phenylethynyl)-2-pyrone were used for
comparison purposes.
8
11 W. S. Kim, H. J. Kim and C. G. Cho, Tetrahedron Lett., 2002, 43,
9015.
§
General procedure for Sonogashira cross-coupling: to a degassed solution
containing 8 (0.38 mmol, 1 equiv.) and the terminal acetylene (0.42 mmol,
.1 equiv) in dry toluene (2 mL) under a nitrogen atmosphere, was
added Et N (0.16 ml, 1.15 mmol, 3 equiv.), followed by Pd(PPh Cl
1.3 mg, 1.9 lmol, 5 mol%) and CuI (0.2 mg, 1.1 lmol, 3 mol%). The
12 W. S. Kim, H. J. Kim and C. G. Cho, J. Am. Chem. Soc., 2003, 125,
1428.
13 J. H. Lee, J. S. Park and C. G. Cho, Org. Lett., 2002, 4, 1171.
14 K. M. Ryu, A. K. Gupta, J. W. Han, C. H. Oh and C. G. Cho, Synlett,
2004, 2197.
15 J. H. Lee and C. G. Cho, Tetrahedron Lett., 2003, 44, 65.
16 F. Bellina, M. Biagetti, A. Carpita and R. Rossi, Tetrahedron, 2001, 57,
2857.
17 M. Biagetti, F. Bellina, A. Carpita, S. Viel, L. Mannina and R. Rossi,
Eur. J. Org. Chem., 2002, 1063.
18 X. Shi, W. S. Leal, Z. Liu, E. Schrader and J. Meinwald, Tetrahedron
Lett., 1995, 36, 71; W. S. Leal, X. Shi, D. Liang, C. Schal and J.
Meinwald, Proc. Natl. Acad. Sci. U. S. A., 1995, 92, 1033.
19 K. Afarinkia, M. J. Bearpark and A. Ndibwami, J. Org. Chem., 2003,
1
3
3
)
2
2
(
◦
solution was allowed to stir for 21 h at 25 C. After this time, the
mixture was concentrated in vacuo and the resultant oil purified by column
chromatography on silica-gel using hexane–ethyl acetate mixtures (9 : 1
to 7 : 3), which gave the cross-coupled products as crystalline solids or
viscous oils. Representative data: 4-chloro-6-(phenylethynyl)-2-pyrone (9a)
was isolated as a yellow crystalline solid. Mp 97–98 C; d
CDCl
◦
H
(400 MHz,
4
3
) 7.52 (m, 3H), 7.40 (m, 2H), 6.51 (d, 1H, J = 1.7 Hz) 6.41
4
C 3
(
1
d, 1H, J = 1.7 Hz); d
(400 MHz, CDCl
) 160.6, 144.3, 138.4, 132.0,
Cl
) 2210 (C≡C),
28.6, 121.0, 120.5, 117.5, 112.0, 95.9, 81.3; mmax (CH
2
2
+
1
NH
728 (C=O), 1618 (C=C), 1531; LRCI m/z 231 (MH , 100), 248 (M +
68, 7158.
20 We refer to Pd(PPh
+
+
2
4
, 73); HRCI m/z exact mass calc. for C13
H
11NO
2
Cl (M + NH
4
):
3
)
2
-g -dba as a precatalyst species, as dba dissocia-
2
48.04785. Found: 248.04780. 4,6-Dichloro-2-pyrone (8) was prepared
tion is required prior to oxidative addition with 8.
21 I. J. S. Fairlamb and C. T. O’Brien, unpublished results.
22 C. Amatore and A. Jutand, Coord. Chem. Rev., 1998, 178–180, 511 and
refs. cited therein; I. J. S. Fairlamb, A. R. Kapdi and A. F. Lee, Org.
Lett., 2004, 6, 4435.
according to the procedure described by Afarinkia et al. in 65% yield
19
◦
◦
as a pale white solid. Mp 44–46 C, lit. 43–45 C; d
H
(400 MHz, CDCl
.31 (s, 2H); LRCI m/z 164 (M , 55), 129 (M − Cl, 100). 4-Chloro-6-(N-
diethylamino)-2-pyrone (12) was isolated as a viscous oil (see Tables 1 and
3
)
+
+
6
1
216 | Org. Biomol. Chem., 2006, 4, 1213–1216
This journal is © The Royal Society of Chemistry 2006