Scheme 2
Table 2. Ring-Closing Metathesis of 4 Using Catalyst 1b
1b
time
(h)
yielda
(%)
run
substrate
(mol %)
conditions
and 5 mol % of 1a6a in CH2Cl2 (0.03 M) was stirred at room
temperature for 24 h under ethylene gas3e,h,i (1 atm), the
desired pyrrolidine derivative 3, which has a dienamide
moiety, was produced in 10% yield along with the starting
material 2 in 35% yield.
1
2
3
4
5b
6
4a (R ) H)
5
5
5
10
10
10
toluene/80 °C
toluene/60 °C
CH2Cl2/reflux
CH2Cl2/reflux
CH2Cl2/reflux
CH2Cl2/reflux
20
20
27
6
5
6
22
19 (20)
36 (38)
85
82
61
Encouraged by this result, RCM of 2 was investigated
under various conditions (Table 1). A solution of 2 and 1a
4b (R ) Me)
a
b
The yield in parentheses is that of the recovered 4. The reaction
was carried out under Ar.
Table 1. Ring-Closing Metathesis of 2 Using 1a or 1b
tions (Table 2). The reactions of 4a and 5 mol % of 1b gave
poor results (runs 1-3). However, when reaction of 4a and
10 mol % of 1b in CH2Cl2 was carried out under reflux
condition for 6 h, the yield of 5a increased to 85% (run 4).8
The RCM of 4a also proceeded under argon (1 atm) to give
5a in 82% yield (run 5). Moreover, enyne metathesis of 4b
under the same conditions produced 5b in 61% yield (run
6).
run
catalyst
conditions
time
yield (%)
1
2
3
4b
1a
1b
1b
1b
CH2Cl2/reflux
CH2Cl2/reflux
toluene/80 °C
toluene/80 °C
24 h
4 h
15 min
30 min
7 (36)a
66
83
76
a The yield in parentheses is that of recovered 2. b The reaction was
carried out under Ar.
Next, we turned our attention to the synthesis of polycyclic
compounds using Diels-Alder reaction of the cyclized
product.
When a solution of 3 and dimethyl acetylenedicarboxylate
(DMAD) was stirred at 60 °C, indole derivatives 6a and 6b
were obtained in a total 53% yield in a ratio of 1.3 to 1 as
an inseparable mixture (Scheme 3, eq 1). It was thought that
in CH2Cl2 was refluxed for 4 h to give 3 in only 7% yield
(run 1). However, we were surprised to find that the use of
the second-generation Grubbs' catalyst 1b6b accelerated the
reaction rate and improved the yield of 3. Thus, when a
solution of 2 and 1b in CH2Cl2 was refluxed for 4 h, 3 was
obtained in 66% yield (run 2). Furthermore, the reaction of
2 in the presence of 1b in toluene was completed within 15
min at 80 °C to give 3 in 83% yield (run 3). It is noteworthy
that this ene-ynamide cyclization using 1b proceeded smoothly
under argon to afford 3 in 76% yield (run 4).7
Scheme 3
On the basis of the above results, the synthesis of a
piperidine derivative was investigated under various condi-
(2) For reviews on enyne metathesis, see: (a) Mori, M Topics in
Organometallic Chemistry; Fu¨rstner, A., Ed.; Springer-Verlag: Berlin,
Heidelberg, 1998; Vol. 1, p 133. (b) Mori, M. J. Synth. Org. Chem. Jpn.
1998, 56, 115. For recent applications, see: (c) Hoye, T. R.; Donaldson, S.
M.; Vos, T. J. Org. Lett. 1999, 1, 277. (d) Clark, J. S.; Hamelin, O. Angew.
Chem., Int. Ed. 2000, 39, 372. (e) Renaud, J.; Graf, C.-D.; Oberer, L. Angew.
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Am. Chem. Soc. 2000, 122, 6785. (g) Stragies, R.; Voigtmann, U.; Blechert,
S. Tetrahedron Lett. 2000, 41, 5465. (h) Bentz, D.; Laschat, S. Synthesis
2000, 1766. (i) 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. (j) Schramm, M. P.; Reddy, D. S.; Kozmin, S. A. Angew. Chem.,
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M. Tetrahedron 1999, 55, 8155. (g) Mori, M.; Kitamura, T.; Sakakibara,
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6b was formed via isomerization from 6a under the reaction
conditions. RCM of 2 was carried out under the same
conditions as those shown in Table 1 (run 3), and then a
solution of the crude product and DMAD in toluene was
heated at 60 °C without purification to give 6a as a sole
product in 80% yield (2 steps, from 2) (eq 2).9 Next, the
804
Org. Lett., Vol. 4, No. 5, 2002