Over the past few years, N-heterocyclic carbene (NHC)
dioxane) was filtered and suspended in an aqueous 1 M NaOH
ligands have received a great deal of attention due to their
2
solution. The aqueous phase was extracted twice with CH
2 2
Cl
1,22
superior stability and electronic properties.
This led to the
and, after evaporation of the combined CH Cl phases, the
2
2
so-called Grubbs’ second generation catalyst, several variants
1
quinoline was obtained in good yield (typically 5–10% lower
than GC yields).
3
of which have been synthesized (Scheme 3). The results are
summarized in Table 2.
3 2
The replacement of a PCy ligand by H -IMes clearly
References
improves catalytic activity. The first generation Grubbs’ cat-
alyst reached 74% conversion after 1 h, while the second
generation gave complete conversion. This may implicate that
the s-donating character of the ligands influence the activity
w Although the order of the steps could theoretically be reversed, i.e.
first a condensation reaction between the amine and the ketone to form
an imine, followed by the catalytic oxidation and cross-aldol reaction,
this is not observed. The reaction of 1 with acetophenone in basic
media (KOH, dioxane, 80 1C, 1 h) gave no imine formation. This is not
really unexpected, since imine formation using ketones proceeds very
slowly and is typically performed in acidic media. To further illustrate
this, the reaction of 1 with acetophenone using a catalytic amount of
formic acid (dioxane, 80 1C, 1 h) does not produce detectable amounts
of imine either.
of the catalyst. Phosphines and H -IMes are both good s-
2
donors, but the superior donor capacity of the latter has been
attributed to be the cause of increased catalytic activity for
2
several catalytic systems.
1
Variation of the NHC ligand through replacement of one
Mes group by an aliphatic group decreased the conversion.
The bulkiness of the amino side group seems to play an
important role, which is evidenced in the series methyl
o cyclohexyl E n-octyl o Mes, where the complex with the
bulkiest group shows the highest quinoline yield.
1 G. Jones, in Comprehensive Heterocyclic Chemistry, ed. A. R.
Katritzky and C. W. Rees, Pergamon, New York, 5th edn, 1984,
vol. 2, pp. 395–524.
2
M. Arisawa, Y. Terada, C. Theeraladanon, K. Takahashi, M.
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To assess the scope of this reaction, a series of ketones was
screened with 4 and 8. The results are shown in Table 3.
From these results, it is obvious that the second generation
Grubbs’ catalyst outperformed the first. For all ketone
substrates, a higher yield was obtained for catalyst 8
compared to catalyst 4. Substrates with strong electron
3
4
5
6
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withdrawing groups, such as NO , inhibit the reaction. When
2
two a-protons are available in an asymmetric ketone, two
quinolines will be formed, as illustrated by 2-heptanone and
4
2
3
-heptanone.
8
In summary, we have shown that Grubbs’ second genera-
2
tion catalyst and its analogues are efficient catalysts for the
oxidative cyclization of 1 with ketones to give quinolines. The
second generation catalyst 8 proved to be a superior catalyst,
even surpassing the first generation catalyst, which had been
the best catalyst to date.
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1
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1
Experimental
The general experimental procedure for quinoline synthesis is
as follows: A mixture of ketone (2 mmol), 1 (1 mmol),
KOH (1 mmol) and Ru catalyst (0.01 mmol) in 3 mL dioxane
was placed in a 7 mL screw-capped vial and allowed to react at
1
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6
2
8
0 1C for 1 h. To remove the catalyst and inorganic salts, the
reaction mixture was filtered through a short silica gel column
ethyl acetate). Unless otherwise stated, yields were deter-
mined by GC. Isolation of the quinoline, as described by
1
1
9
(
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9
,10
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Cho and co-workers,
proved to be problematic: the quino-
1
9 S. Chang, L. Jones, C. M. Wang, L. M. Henling and R. H. Grubbs,
line could not be separated from the unreacted ketone. To
isolate the quinoline, the resulting solution was concentrated
and passed through a second silica gel column (ethyl acetate/
hexane 1 : 4). The solvent was evaporated and the resulting
product was dissolved again in ethyl acetate. The pale yellow
precipitate that formed upon addition of HCl (4 M solution in
1
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3
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2
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1
574 | New J. Chem., 2007, 31, 1572–1574
This journal is ꢀc the Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2007