Arisawa et al.
TABLE 1. Synthesis of 1,2-Dihydroquinoline (2) from 1
SCHEME 1. Synthesis of 2, 4, and 5 from 1
entry
substrate
[Ru]
yield (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
B
B
B
A
B
A
B
B
A
B
B
B
93
100
90
95
74
90
87
100
90
100
95
Nonmetathetic catalytic activity has recently been identified,
and has increased the utility of these catalysts beyond meta-
thesis.8
10
11
12
1j
1k
1l
We have been investigating the feasibility of using metathesis
to prepare heterocyclic compounds and its application to the
synthesis of bioactive natural products.9 Recently, we found that
N-allyl-o-vinylaniline (1) gave 1,2-dihydroquinoline (2) by
normal RCM, and developed silyl enol ether-ene metathesis
for the novel synthesis of 4-silyloxy-1,2-dihydroquinoline, and
thus demonstrated a convenient entry to quinolines and 1,2,3,4-
tetrahydroquinolines.9f,k We also found a novel selective isomer-
ization of terminal olefins and a cycloisomerization of 1,6-
dienes, using ruthenium carbene catalyst and silyl enol ether,
which represented a new synthetic route to a series of substituted
indoles (4) and 3-methylene-2,3-dihydroindoles (5).9h,l We now
report our systematic studies on RCM, effective isomerization
followed by RCM, and cycloisomerization of 1, including the
scope and limitations of these reactions. Substituted 2, 4, and
5, which are useful synthons for biologically active natural
products, were selectively synthesized from 1 with catalyst
B by slightly changing the reaction conditions (Scheme 1).
Cycloisomerization of 1 efficiently gives 2,3-disubstituted in-
dole, and 5. We also report an unambiguous characterization
of intervenient ruthenium hydride complex with N-heterocyclic
carbene (NHC) ligand, which is generated from B and vinyl-
oxytrimethylsilane (6a) and the actual active species for these
nonmetathetic reactions, isomerization of a terminal olefin, and
100
cycloisomerization of an R,ω-diene. Olefin isomerization of
Grubbs catalyst has been reported and has been exploited
recently in a deprotection of allyl ethers and amines. Unfortu-
nately, the ruthenium species derived from the decomposition
of the Grubbs catalyst (B) responsible for this reactivity has
been unclear.10
Results
RCM of 1 to Substituted 1,2-Dihydroquinoline (2). The
reaction of 1a-l with A or B (5 mol %) in refluxing CH2Cl2
for 1 h gave the corresponding 1,2-dihydroquinolines (2a-l)
via RCM in good to excellent yields (Table 1) regardless of
the substituents (methoxy, chloro, or methyl) on the aromatic
ring. 1,2-Dihydroquinolines could be readily converted to
quinolines or 1,2,3,4-tetrahydroquinolines. In addition, the
substituent on nitrogen is not limited to a p-toluenesulfonyl
group. Acetyl, benzyl, and tert-butoxycarbonyl derivatives also
gave the corresponding 1,2-dihydroquinolines.9k With this
method, an anti-malarial compound, (+)-(S)-angustureine, was
synthesized efficiently and the absolute configuration of natural
angustureine was established to be (-)-(R)-enantiomer.9m
Isomerization and Subsequent RCM of 1 to Substituted
Indole 4. On the basis of our finding of silyl enol ether-ene
ring-closing metathesis, we applied this reaction to a cross
metathesis. The reaction of terminal olefin 7 with B exclusively
gave the dimeric compounds 9, which is the homo cross
metathesis product of 7 (Table 2, entry1).
(8) (a) Alcaide, B.; Almendros, P. Chem. Eur. J. 2003, 9, 1259-1262.
(b) Schmidt, B. Eur. J. Org. Chem. 2004, 9, 1865-1880.
(9) (a) Arisawa, M.; Takezawa, E.; Nishida, A.; Mori, M.; Nakagawa,
M. Synlett 1997, 1179-1180. (b) Nakagawa, M.; Uchida, H.; Torisawa,
Y.; Nishida, A. J. Synth. Org. Chem. Jpn. 1999, 57, 1004-1005. (c)
Arisawa, M.; Kato, C.; Kaneko, H.; Nishida, A.; Nakagawa, M. J. Chem.
Soc., Perkin Trans. 1 2000, 1873-1876. (d) Arisawa, M.; Kaneko, H.;
Nishida, A.; Yamaguchi, K.; Nakagawa, M. Synlett 2000, 841-843. (e)
Arisawa, M.; Takahashi, M.; Takezawa, E.; Yamaguchi, T.; Torisawa, Y.;
Nishida, A.; Nakagawa, M. Chem. Pharm. Bull. 2000, 48, 1593-1596. (f)
Arisawa, M.; Theeraladanon, C.; Nishida, A.; Nakagawa, M. Tetrahedron
Lett. 2001, 42, 8029-8033. (g) Arisawa, M.; Kaneko, H,; Nishida, A.;
Nakagawa, M. J. Chem. Soc., Perkin Trans. 1 2002, 959-964. (h) Arisawa,
M.; Terada, Y.; Nakagawa, M.; Nishida, A. Angew. Chem., Int. Ed. 2002,
41, 4732-4734. (i) Nagata, T.; Nakagawa, M.; Nishida, A. J. Am. Chem.
Soc. 2003, 125, 7484-7485. (j) Ono, K.; Nakagawa, M.; Nishida, A. Angew.
Chem., Int. Ed. 2004, 43, 2020-2023. (k) Theeraladanon, C.; Arisawa, M.;
Nishida, A.; Nakagawa, M. Tetrahedron 2004, 60, 3017-3035. (l) Terada,
Y.; Arisawa, M.; Nishida, A. Angew. Chem., Int. Ed. 2004, 43, 4063-
4067. (m) Theeraladanon, C.; Arisawa, M.; Nakagawa, M.; Nishida, A.
Tetrahedron: Asymmetry 2005, 16, 827-831. (n) Arisawa, M.; Theeral-
adanon, C.; Nishida, A. Heterocycles 2005, 66, 683-688. (o) Arisawa, M.;
Terada, Y.; Theeraladanon, C.; Takahashi, K.; Nakagawa, M.; Nishida, A.
J. Organomet. Chem. 2005, 690, 5398-5406.
However, when the reaction of 7 with 6a was carried out,
the isomerization product 8 was unexpectedly obtained in 74%
(10) (a) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan,
S. P. J. Org. Chem. 2000, 65, 2204-2207. (b) Alcaide, B.; Almendros, P.;
Alonso, J. M.; Aly, M. F. Org. Lett. 2001, 3, 3781-3784. (c) Fu¨rstner, A.;
Ackermann, L.; Gabor, B.; Goddard, R.; Lehmann, C. W.; Mynott, R.;
Stelzer, F.; Thiel, O. R. Chem. Eur. J. 2001, 7, 3236-3253. (d) Sutton, A.
E.; Seigal, B. A.; Finnegan, D. F.; Snapper, M. L. J. Am. Chem. Soc. 2002,
124, 13390-13391. (e) Bourgeois, D.; Pancrazi, A.; Nolan, S. P.; Prunet,
J. J. Organomet. Chem. 2002, 643-644, 247-252. (f) Cadot, C.; Dalko,
P. I.; Cossy, J. Tetrahedron Lett. 2002, 43, 1839-1841. (g) Alcaide, B.;
Almendros, P.; Alonso, J. M. Chem. Eur. J. 2003, 9, 5793-5799. (h)
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4256 J. Org. Chem., Vol. 71, No. 11, 2006