Synthesis of pyridine and isoquinoline derivatives by the palladium-catalyzed cyclization of olefinic ketone O-pentafluorobenzoyloximes

Article abstract of DOI:10.1246/cl.2001.526

Pyridines and isoquinolines are synthesized from olefinic ketone O-pentafluorobenzoyloximes by treatment with a catalytic amount of Pd(PPh₃)₄ in the presence of (n-Bu)₄NCl and triethylamine.

Full text of DOI:10.1246/cl.2001.526

526
Chemistry Letters 2001
Synthesis of Pyridine and Isoquinoline Derivatives by the Palladium-Catalyzed Cyclization of
Olefinic Ketone O-Pentafluorobenzoyloximes
Hironori Tsutsui and Koichi Narasaka*
Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033
(Received March 13, 2001; CL-010220)
Pyridines and isoquinolines are synthesized from olefinic
ketone O-pentafluorobenzoyloximes by treatment with a cat-
alytic amount of Pd(PPh3)4 in the presence of (n-Bu)4NCl and
triethylamine.
Recently, we have reported the oxidative addition of oxime
derivatives to palladium(0) complex to generate alkylidene-
aminopalladium(II) species.1,2 This process was applied to the
transformation of γ,δ-unsaturated ketone O-pentafluorobenzoyl-
oximes to pyrroles by the Heck-type cyclization, and the reac-
tion proceeded regardless of the E/Z stereochemistry of O-
pentafluorobenzoyloximes.
In order to prepare functionalized pyrroles, 3-methoxy-1-
phenyl-4-penten-1-one (E)-O-pentafluorobenzoyloxime (1a)3
was treated with a catalytic amount of Pd(PPh3)4 in the pres-
ence of triethylamine, and the reaction mixture was treated with
10 molar amounts of pyrrolidine.4 The desired methoxypyrrole
4a was obtained in 69% yield along with 7% yield of 6-endo
cyclized product, 2-phenylpyridine (3a). By contrast, when this
Heck-type reaction was carried out in the presence of 5 molar
amounts of (n-Bu)4NCl,5 pyridine 3a was obtained as a main
product in 58% yield (eq 1).6
amount of Pd(PPh3)4 (eq 3). This apparently means that the
cyclization does not occur via initial formation of π-allyl palla-
dium species. Murahashi et al. reported the synthesis of
pyridines from γ,δ-unsaturated ketone oximes or conjugated
dienyl ketone oximes by the palladium(II)-mediated reaction.6a
Accordingly, the cyclization of conjugated dienyl ketone oxime
8 was examined with a catalytic use of Pd(PPh3)4 in the pres-
As shown in Table 1, the palladium-catalyzed cyclization
of several β-methoxy γ,δ-unsaturated ketone O-pentafluoro-
benzoyloximes 1 was attempted in the presence of (n-Bu)4NCl.
Although mono 2-alkylated pyridine 3e was formed in poor
yield, disubstituted pyridines 3b–d were prepared in reasonable
yield with a small amount of pyrroles 4.7
To investigate the course of this formal 6-endo cyclization
were checked the following reactions. β-Methoxy group is
indispensable for the pyridine formation, because the reaction
of 5 bearing β-methyl group instead of β-methoxy group gave
only trisubstituted pyrrole 6 without forming 4-methyl-2-
phenylpyridine (eq 2). O-Methyloxime 7 was recovered under
the same reaction conditions even by using an equimolar
ence or absence of (n-Bu)4NCl, which yielded pyridine 3a in
61% and 38% yield, respectively (eq 4).8 On the whole, it is
concluded that the oxidative addition of O-pentafluorobenzoyl-
oxime 1a to Pd(PPh3)4 initially occurs, and the intramolecular
coordination of methoxy group to palladium(II) center directs
the cyclization to 6-endo mode and/or accelerates the elimina-
tion of methanol to give dienyl intermediate.
Thus, pyridines are prepared from β-methoxy γ,δ-un-
saturated ketone O-pentafluorobenzoyloximes by the 6-endo-
type cyclization. Although pyridines can be also prepared from
dienyl oxime derivatives as mentioned above, β-methoxy γ,δ-
unsaturated ketones are prepared very easily from silyl enol
ethers and α,β-unsaturated aldehyde dimethylacetals.9
Copyright © 2001 The Chemical Society of Japan

Chemistry Letters 2001
527
derivatives 10b–e were similarly prepared from o-allyl-ace-
tophenone derivatives 9 in moderate yield (entries 4–7).
References and Notes
1
2
H. Tsutsui and K. Narasaka, Chem. Lett., 1999, 45.
Recently, Uemura et al. have reported an example of
oxidative addition of cyclobutanone oximes to palladi-
um(0) complex. T. Nishimura and S. Uemura, J. Am.
Chem. Soc., 122, 12049 (2000).
3
In the synthesis of 2-methyl-5-phenylpyrrole,1 O-acetyl
and O-benzoyloximes are not so reactive under the palladi-
um-catalyzed cyclization conditions. For example, it takes
10 h to consume the O-benzoyl analogue and the pyrrole is
obtained in 35% yield, though the cyclization of O-penta-
fluorobenzoyloxime is complete only 1 h to give the pyr-
role in 86% yield.
4
5
Dihydropyrrole 2a did not isomerize to pyrrole 4a by treat-
ment of chlorotrimethylsilane,1 and 2a was decomposed.
It has been known that the addition of quaternary ammoni-
um halides causes dramatic influence on the reactivity of
the Heck reaction, see: B. C. Soderberg, “Transition Metal
Alkyl Complexes: Oxidative Addition and Insertion,” in
“Comprehensive Organometallic Chemistry II,” ed. by E.
W. Abel, F. G. A. Stone, and G. Wilkinson, Pergamon
Press, Oxford (1995), Vol. 12, Chap. 3.5, p. 259; S. Bräse
and A. de Meijere, “Palladium-Catalyzed Coupling of
Organyl Halides to Alkenes – The Heck Reaction,” in
“Metal-Catalyzed Cross Coupling Reactions,” ed. by P. J.
Stang and F. Diederich, John Wiley & Sons, New York
(1998), and references cited therein.
Then, we examined the possibility of 6-exo cyclization of
δ,ε-unsaturated ketone O-pentafluorobenzoyloximes by this
Heck-type cyclization. Such a cyclization, however, did not
proceed smoothly, when acyclic oxime such as ethyl 7-(O-
pentafluorobenzoyloxy)imino-7-phenyl-2-heptenoate was em-
ployed. On the contrary, O-pentafluorobenzoyloximes of o-
allylacetophenone derivatives10 cyclized to give isoquinoline
derivatives. That is, as shown in Table 2, o-allylacetophenone
O-pentafluorobenzoyloxime (9a)11 cyclized to 1,3-dimethyl-
isoquinoline (10a) by treatment with the palladium catalyst in
the presence of Et3N–LiCl or Et3N–(n-Bu)4NCl in 61% or 77%
yield, respectively (entries 1–3).12 Some other isoquinoline
6
7
Palladium-mediated and -catalyzed pyridine, quinoline,
and isoquinoline syntheses, see: a) T. Hosokawa, N.
Shimo, K. Maeda, A. Sonoda, and S.-I. Murahashi,
Tetrahedron Lett., 1976, 383. b) L. S. Hegedus, G. F.
Allen, J. J. Bozell, and E. L. Waterman, J. Am. Chem. Soc.,
100, 5800 (1978). c) A. Kasahara, T. Izumi, and O. Saito,
Chem. Ind., 1980, 666. d) C.-C. Yang, H.-M. Tai, and P.-J.
Sun, J. Chem. Soc., Perkin Trans. 1, 1997, 2843.
Though the formation of 3,4-dihydro-2H-pyrrole 2d was
1
confirmed by H NMR spectrum of the crude products
from 1d, 2d did not isomerize to 2-benzyl-3-methoxy-5-
phenylpyrrole (4d) with pyrrolidine.
8
9
The dienone oxime 8 did not form from 1a by treatment
with (n-Bu)4NCl and triethylamine in DMF at 80 °C.
T. Mukaiyama, Org. React., 28, 203 (1982); T.
Mukaiyama, S. Kobayashi, and M. Murakami, Chem. Lett.,
1984, 1759.
10 N. M. Kablaoui, F. A. Hicks, and S. L. Buchwald, J. Am.
Chem. Soc., 119, 4424 (1997).
11 The oxime 9a was easily prepared by the reaction of o-
allylacetophenone and hydroxylamine hydrochloride and
pyridine, and successively reacted with pentafluorobenzoyl
chloride and triethylamine.
12 In the isoquinoline formation from 9, it was afraid that the
reaction proceeded through the isomerization to o-vinyl-
acetophenone oximes and the successive 6-endo Heck-type
cyclization and/or 6π electrocyclization. Such processes,
however, can be excluded, because o-vinylacetophenone
O-pentafluorobenzoyloxime did not cyclized to isoquino-
line with and without Pd(PPh3)4.