Chemistry Letters Vol.37, No.7 (2008)
795
ed. Chemical yield of 8a was slightly improved up to 72% when
the reaction was carried out at rt, though the starting compound 6
was not consumed and was recovered it in 6% yield after 168 h
of reaction at rt (Entry 2). We anticipated that the real catalyst
.
may be iron(III) species derived from Fe(BF4)2 6H2O by the
aerobic oxidation during performance of the reaction process.5
Strong Lewis acids, Fe(NO3)3, Fe2(SO4)3, and FeCl3, cata-
lyzed the alkylation of 6, but the results were not satisfactory
(Entires 4–6). The catalytic activity was significantly dependent
on the anionic part of the iron(III) salts: K3Fe(CN)6, Fe3O4, and
FeO(OH) showed no catalytic activity (Entries 7–9). To our de-
light, the desired alkylation product was obtained when iron(III)
perchlorate [Fe(ClO4)3] was used as a catalyst and, in particular,
alumina-supported iron(III) perchlorate [Fe(ClO4)3–Al2O3]3
afforded dialkylated pyrrole 8a and trialkylated pyrrole 9a in
65% and 24% yields, respectively (Entries 11).
Scheme 1.
Choice of the solvent is very important: the reaction pro-
ceeded smoothly in CH3CN, hexane, or CH2Cl2, while desired
product 8a was obtained in poor yield when the reaction was
conducted in MeOH (Entry 16), and no reaction took place in
H2O (Entry 17). Monoalkylated product 7a13 was also obtained
in 18% yield when the reaction was carried out in MeOH
(Entry 16). The best yield of 8a (80%) was recorded when the
reaction was carried out without solvent at 60 ꢁC (Entry 13).
These results were completely different from those of iron
salt-catalyzed alkylation of indole that we previously reported;
alkylation product was obtained in good yield in MeOH or
H2O when indole was subjected to the reaction with 2a using
In summary, we demonstrated the very simple alkylation of
pyrrole derivatives with vinyl ketone in the presence of two
.
types of iron salts; Fe(BF4)2 6H2O and Fe(ClO4)3–Al2O3
worked as efficient catalysts to give dialkylation products. The
results looked very similar to those of the reaction of indole
which we previously reported. However, details of the reaction
profile were different from that of alkylation of indole,7 because
alkylation of indole with vinyl ketone took place in water while
no reaction occurred with pyrrole. Although the reaction mech-
anism is still unclear, the alkylation products were obtained in
moderate to good yield under very mild reaction conditions:
the reaction proceeds very smoothly at rt or 60 ꢁC and requires
no tedious argon atmospheric conditions. Further investigation
of the scope and limitations of this iron salt-catalyzed reaction
will make it even more valuable.
7
.
Fe(ClO4)3–Al2O3 or Fe(BF4)2 6H2O as catalyst. We previous-
ly demonstrated that an ionic liquid solvent such as [bmim]-
[TFSI] gave better results than those in CH3CN solvent for the
alkylation of indole.7 Although alkylation of pyrrole 6 also
proceeded very smoothly in the [bmim][TFSI] solvent system,
unfortunately, it was quite difficult to extract product 8a from
the ionic liquid solution.
This work was supported by a Grant-in-Aid for Scientific
Research from The Ministry of Education, Culture, Sports,
Science and Technology of Japan.
The reaction was completely inhibited by addition of
1.0 equiv of TEMPO (Entry 18). On the contrary, no inhibition
was observed when 1.0 equiv (vs. pyrrole 6) of 1,6-di-t-butyl-
phenol (BHT) was added to the reaction (Entry 19). It was also
found that the reaction was completely inhibited by addition of a
base: no reaction took place when the reaction was conducted in
the presence of 1.0 equiv of 2,6-lutidine (Entry 20). From these
results, we are assuming that the mild Lewis acid property of
iron salt might contribute to the present iron salt-catalyzed alkyl-
ation of pyrrole.
The reaction conditions having thus been optimized, we
next demonstrated alkylation of 2-acetylpyrrole with three types
of vinyl ketones, 2b, 2c, and 2d (Scheme 1). 3,4-Dialkylated
pyrrole 8b was obtained in 52% yield when vinyl ketone 2b
reacted with 6. To our delight, dialkylated product 8c was ob-
tained in better yield (78%) for the reaction of 2c (Scheme 1,
right).12 On the other hand, interesting regiospecific alkylation
was recorded when 1.5 equiv of 2d was used as an acceptor
(Scheme 1, left): the only product obtained was a monoalkylated
compound and 4-alkylated pyrrole derivative 10 was obtained
as the sole product in 50% yield.12 Because no reaction took
place when 4-methylpent-3-en-2-one was allowed to react with
pyrrole 6, we are assuming that the result of present alkylation
was significantly influenced by the steric bulkiness of the reac-
tion center.
References and Notes
1
For recent reviews see: a) C. Bolm, J. Legros, J. L. Paih, L. Zani, Chem. Rev.
¨
2
H. Ohara, K. Kudo, T. Itoh, M. Nakamura, E. Nakamura, Heterocycles 2000,
52, 505.
3
4
c) T. Itoh, H. Uehara, K. Kawai, S. Hayase, H. Ohara, M. Oyama, in Analyt-
ical Mechanistic and Synthetic Organic Electrochemistry- 6th International
M. Baizer Award Symposium in Honor of Dennis H. Evans and Masao
Tokuda, ed. by J. Lessard, P. Hapiot and I. Nishiguchi, The Electrochemical
Society, Inc. USA, 2004, pp. 9–12. ISBN 1-56677-423-3.
H. Uehara, S. Nomura, S. Hayase, M. Kawatsura, T. Itoh, Electrochemistry
2006, 74, 635.
5
6
7
M. Kawatsura, Y. Komatsu, M. Yamamoto, S. Hayase, T. Itoh, Tetrahedron
T. Itoh, H. Uehara, K. Ogiso, S. Nomura, S. Hayase, M. Kawatsura, Chem.
8
9
M. Kawatsura, Y. Higuchi, S. Hayase, M. Nanjo, T. Itoh, Synlett 2008, 1009.
A preliminary result of this study was reported: T. Itoh, Abstracts of Papers,
231st ACS National Meeting, Atlanta, GA, United States, March 26–30,
2006, IEC-313.
10 The Friedel–Crafts type alkylation of pyrrole using heteropoly acid was
11 Unfortunatelly, no reaction took place when ethyl acrylate or acrylonitrile
was used as acceptor.
12 Supporting Information that is available electronically on the CSJ-Journal
Kawatsura, Motoi
