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Chemistry Letters Vol.38, No.7 (2009)
Catalytic Cyclization of Alkenyl N,O-Acetals by Fe(OTf)3
Kimihiro Komeyama,ꢀ Ryoichi Igawa, Takayuki Morimoto, and Ken Takakiꢀ
Department of Chemistry and Chemical Engineering, Graduate School of Engineering, Hiroshima University,
1-4-1 Kagamiyama, Higashi-Hiroshima 739-8527
(Received May 13, 2009; CL-090470; E-mail: kkome@hiroshima-u.ac.jp)
Fe(OTf)3, was found to be a good catalyst for the cyclization
of alkenyl N,O-acetals to give various nitrogen-containing
heterocycles in high yields.
Table 1. Screening of catalyst
O
O
O
10 mol% cat.
+
N
N
N
1,4-dioxane
70 °C
OH
1a
2a
2a'
Nitrogen-containing heterocycles are widely distributed in
nature and a lot of these compounds display important biological
and pharmaceutical activities. Although the heterocycles have
been prepared by various methods,1 development of more effi-
cient and convenient approaches to the synthesis of the function-
alized heterocycles under mild conditions is still desired. For the
sophisticated procedure, N-acyliminium ion is a useful synthetic
intermediate due to its highly electrophilic character, which
allows the intramolecular addition of various ꢀ- and ꢁ-nucleo-
philes to afford numerous heterocycles.2 However, there is no
catalytic example of iminium ion cyclization. Herein, we would
like to report a catalytic cyclization of alkenyl N,O-acetals by
Fe(OTf)3 to provide an easy access to nitrogen-containing
heterocycles (eq 1).
Total yield/%a
Entry
Catalyst
Sc(OTf)3
TfOH
Time/h
Conv./%a
[2a/2a0]a
1
2
3
4
5
6
7
8
9
3
3
3
48
3
3
8
3
27
27
3
32 [75/25]
46 [72/28]
36 [86/14]
35 [77/23]
0 [—]
0 [—]
0 [—]
73 [77/23]
68 [81/19]
71 [80/20]
70 [76/24]
34
96
62
79
3
96
92b
100
Cu(OTf)2
.
(CuOTf)2 C6H6
AgOTf
PdCl2
PtCl2
Fe(OTf)3
Fe(OTf)2
92
100
100
10 CpFe(CO)2OTf
11 Bi(OTf)3
PG
R1
R2
PG
aDetermined by NMR. Olefin isomerization occured.
b
N
iron catalyst
( )n
N
OX
R3
( )n
ð1Þ
R2
R1
R3
With optimal conditions in hand, the cyclization of several
alkenyl N,O-acetals was investigated as summarized in
Table 2.4 2,2-Disubstituted olefin was a good coupling partner
for the N,O-acetal moiety, giving rise to heterocycles 2b as a mix-
ture of three regioisomers in 94% yield, even at room temperature
(Entry 1).5 Similarly, high reactivity was observed in the case of
1,2,2-trisubstituted substrates, 1c and 1d (Entries 2 and 3). Acy-
clic N,O-acetal function also participated in the cyclization
(Entry 3). The cyclization of internal olefins such as 1e and 1f fa-
vored the formation of azacyclohexenes, and thus, neither the 5-
membered ring from 1e nor the 7-membered one from 1f was de-
tected (Entries 4 and 5). In contrast, cyclization of N,O-acetal
with a terminal 4-pentenyl moiety such as 1g and 1h constructed
only azacycloheptene skeletons in good yields (Entries 6 and 7).6
For several plausible mechanisms in the cyclization, the imi-
nium ion could be a key intermediate because its generation has
been well known to occur the ꢂ-fragmentation of N,O-acetal
with typical Lewis acid other than iron.7 However, useful imini-
OX = OH, OAc, OMe
PG = protecting group
We first investigated catalytic activities of various transi-
tion-metal complexes and Brønsted acid in the cyclization of
2-(but-3-enyl)-3-hydroxyisoindolin-1-one (1a) as a model sub-
strate (Table 1). Treatment of 1a with 10 mol % of Sc(OTf)3
afforded the azacyclohexene 2a and its isomer 2a0 in 24 and
8% yields, respectively (Entry 1). Although Sc(OTf)3 showed
a good mass balance, the reaction was not catalytic even with ad-
ditional stirring due to a loss of activity. Similar phenomena
.
were observed with AlCl3 and BF3 OEt2 catalysts. With TfOH,
CuOTf, and Cu(OTf)2 catalysts, most of 1a was consumed with-
out decreasing the catalyst activity, but a low mass balance was
found because of oligomerization of 1a (Entries 2–4). In strong
contrast, AgOTf did not initiate the reaction (Entry 5). PdCl2 af-
forded a complex mixture (Entry 6). Use of PtCl2 caused olefin
isomerization of 1a to give a mixture of (E)-and (Z)-2-(but-2-en-
yl)-3-hydroxyisoindolin-1-one in 28% yield without cyclization
(Entry 7). Further screening revealed that employment of
Fe(OTf)3 catalyst improved the product yield to 73% NMR yield
(Entry 8), from which the pure product was obtained by column
chromatography in 63% yield with the same isomer ratio
(2a:2a0 = 76:24). Other iron triflates, Fe(OTf)2, and CpFe(CO)2-
OTf were also effective for the cyclization, but they needed
longer reaction time to complete the reaction (Entries 9 and
10). Similar catalytic activity was observed by Bi(OTf)3 (Entry
11). 1,4-Dioxane, 1,2-dichloroethane, and 1,2-dimethoxyethane
were suitable solvents, whereas toluene decreased the reaction
rate.3
.
um ion generators such as BF3 OEt2, Sc(OTf)3, and TfOH did
not display high catalytic performance in the present cyclization.
To gain further information of the iron-catalyzed mechanism, a
reaction of alkenyl N,O-acetals 1g and Bi(OTf)3 (0.3 equiv),
which possesses similar catalytic activity to the iron and
is diamagnetic, was monitored by 1H NMR (Scheme 1 and
Figure S110). An acetal proton (Ha) of the alkenyl N,O-acetal
1g appeared at 5.72 ppm as a doublet signal (J ¼ 11:9 Hz) in
the absence of the catalyst. In contrast, treatment of 1g with Bi-
(OTf)3 resulted in a disappearance of the coupling between Ha
and OH, and low-field shifts of Ha as well as all olefinic protons
Copyright Ó 2009 The Chemical Society of Japan
Komeyama, Kimihiro
