Table 1: Glyoxylation/Stephens–Castro synthesis of ynediones 3, 4, and 5.[a]
The sequence proceeds smoothly in ethereal sol-
vents (THF, DME, or 1,4-dioxane), thus making it
possible to perform the glyoxylation step in a wide
temperature range. The reaction with electron-rich
indoles and 7-azaindoles gives derivatives functional-
ized in the 3-position exclusively (compounds 3a–k).
Generally, pyrroles give 2-substituted regioisomers
without noticeable amounts of the 3-substituted iso-
mers (compounds 4a–e). Expectedly, when the sub-
strate has a bulky substituent on the nitrogen atom of
the pyrrole ring, the 3-position is functionalized (com-
pound 4 f). To our great delight, other important
heterocycles like pyrazole (compound 5a), thiophene
(compounds 5b and 5c), and furan (compound 5d)
could be converted to ynediones, although the glyox-
ylation of these heterocycles to glyoxylyl chlorides has
never been described. Interestingly, there is a method
describing a direct carboxylation of 1,3,5-trisubstituted
pyrazoles with oxalyl chloride.[15] However, with 1-
methyl-1H-pyrazole we observed no decarbonylation
but instead formation of compound 5a. A further
advantage of the described Lewis acid free method is
the possibility of reacting substrates that are not
compatible with Lewis-acid-mediated Friedel–Crafts
conditions and (compound 5d). Surprising, however,
was the observation that thiophenes turned out to be
excellent substrates for the described sequence. The
more electron-rich 2-methylfuran gave a lower yield of
ynedione 5d along with a by-product resulting from the
condensation of two furan molecules with one molecule
of oxalyl chloride in 14% yield.
Furthermore, the electron-rich hydrocarbon azu-
lene could be functionalized as well (compound 5e).[16]
Aryl acetylenes bearing electron-neutral (compounds
3a, 3g,h, 3j,k, 4a–f, and 5a–e), electron-donating
(compound 3b), or electron-withdrawing (compounds
3c,d) substituents can be carried through the sequence
without difficulties. Also heteroaryl (compound 3e) as
well as TIPS-substituted acetylenes (compound 3 f) can
be coupled efficiently. However, an alkyl acetylene
gave a very poor yield (compound 3i). In all cases, no
decarbonylative products were observed. The products
were easily isolated by flash chromatography and were
usually obtained in analytically pure form as stable
compounds.
Product
Yield [%][b]
(method[c])
Product
Yield [%][b]
(method[c])
66 (A)
68 (A)
73 (A)
64 (A)
74 (A)
67 (A)
60 (A)
60 (A)
43 (A)
74 (A)
77[d] (C)
44 (C)
57 (A)
35 (A)
47 (D)
53 (E)
2 (A)
62 (B)
59 (B)
66 (E)
38 (F)
33 (A)
[a] Reactions were performed in ethereal solvents [c(1)=0.2m] using 5.00 mmol
of substrate 1. Abbreviations: Ph=phenyl, Me=methyl, TIPS=triisopropylsilyl,
Bu=butyl, Bn=benzyl, PMB=p-methoxybenzyl, Bzh=benzhydryl. [b] All yields
refer to isolated and purified compounds. [c] Method A: THF, 08C to RT, 4 h;
method B: DME, 08C to 1008C, 2 h; method C: THF, 08C to 508C, 4 h;
method D: DME, 08C to 1008C, 24 h; method E: 1,4-dioxane, RT to 1008C, 4 h;
method F: 1,4-dioxane, RT to 1008C, 24 h. [d] According to method A, 33% of 4e
could be obtained.
The reactivity of the glyoxylation of p nucleophiles
can be estimated by considering the nucleophilicity
parameters N of the (hetero)aryl substrate as deter-
mined by Mayr et al. for some reference nucleo-
philes.[17] The nucleophilicity parameters of the
employed (hetero)arenes range from approximately
1.26 to 6.66, spanning five orders of magnitude (see
Table S8 in the Supporting Information).
active metal. Neither chelating ligands nor phosphanes are
Azoles, furans, and thiophenes are of paramount impor-
required.
The structures of the obtained ynediones 3, 4, and 5 were
unambiguously supported by NMR spectroscopy, mass spec-
trometry, and combustion analysis, and later by an X-ray
structure analysis of compound 3a (Figure 1).
tance in the synthesis of products relevant for medicinal
chemistry and material science as well as in the synthesis of
natural products. Therefore, the described mild and easy-to-
perform one-pot functionalization of these prevalent classes
of heterocycles opens up remarkable possibilities for their
Angew. Chem. Int. Ed. 2011, 50, 2966 –2969
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim