Although there are a number of reports on the synthesis
of various nitrogen heterocyclic compounds via the RCEM
reaction, to the best of our knowledge, no publications have
Table 1. RCEM Reaction of 6aa
8
appeared concerning the use of enyne substrates containing
9
a basic or nucleophilic N atom. It is also noteworthy that
with terminal alkynes ethylene was usually required to
1
0
increase the reaction rate and the yield of the reaction.
Herein, we report a simple method for the preparation of
a series of new pyrrolidine derivatives by RCM reaction of
enynes containing a basic or nucleophilic N atom in the
absence of ethylene gas.
i
catalyst
(mol %)
Ti(O Pr)
4
time
(h)
yield
b
entry
(mol %)
(%)
1
2
3
2 (5.0)
2 (5.0)
1 (5.0)
1 (3.0)
20
-
3
3
15
15
90
91
84
52
-
We first synthesized several enyne substrates in fine yields
from commercially available chiral amino acids, following
c
4
-
a
Reaction conditions: 6a (1 mmol), CH2Cl2 (20 mL). b Isolated yield.
11,12
literature procedures (Scheme 1).
Enyne 6a was used to
c
3
1% starting material was recovered.
catalyst loading was reduced to 3 mol %, the yield deceased
significantly and the starting material was not completely
consumed (Table 1, entry 4).
Scheme 1. Synthesis of Enyne Substrates
Considering that catalyst 2 is more expensive than catalyst
1
, the latter was employed to assess the scope of the RCEM
reaction. The results are presented in Table 2. Enynes
containing ester, indole, etc. afforded the pyrrolidines, nearly
always, in good yields.
To further extend the scope of this reaction, we tried some
other substrates with substituents on the alkene or alkyne
bond (Table 3, entries 1-3). With enynes 6i and 6j, the
reactions went smoothly and good yields were obtained.
However, when substrate 6k was subjected to the same
reaction conditions, a large amount of starting material was
recovered because of the steric effect. Substrate 6l, which
contains a sulfur atom, gave no reaction under the same
conditions. This may be due to the fact that the sulfur atom
is a stronger electron donor, therefore causing the alkylidene
ruthenium carbene to coordinate with the sulfur atom. This
determine the optimum reaction conditions, and the results
are presented in Table 1.
The RCEM reaction occurred successfully, with or without
i
Ti(O Pr)
4
, and the desired product was obtained in almost
the same yields (Table 1, entries 1 and 2). The result indicates
that the Lewis acid does not play any substantive role in
1
4
results in the deactivation of the catalyst. However, when
i
this enyne RCM reaction. We previously reported that with
40 mol % of Ti(O Pr) was added to the reaction system,
4
i
the assistance of the Lewis acid Ti(O Pr)
4
, diallylamines
the reaction occurred successfully in 68% yield (Table 3,
1
3
containing a basic or nucleophilic N atom can successfully
entry 4). Also, we tried an enyne with a less basic N atom,
and the same good result was obtained (Table 3, entry 5).
There are at least two possible pathways for the RCEM
13
undergo the RCM reaction. Otherwise, the RCM reaction
of such dienes is very difficult.14 When we subjected 6a to
the less active and cheaper catalyst 1 in the absence of the
Lewis acid, almost the same result was obtained except that
a longer reaction time was needed (Table 1, entry 3). If the
1
5
reaction. In some cases, it was proven that the alkylidene
15a,e,g,h
ruthenium carbene reacts with the alkene first,
whereas
in others, the ruthenium carbene first coordinates with the
1
5b,f,i
alkyne.
It can be seen from the literature that the RCM
(8) Kim, Y. J.; Lee, D. Org. Lett. 2004, 6, 4351 and references cited
reaction of dienes containing a basic or nucleophilic N atom
therein.
1
6
is difficult to achieve.
(
9) Gracias, V.; Gasiecki, A. F.; Djuric, S. W. Tetrahedron Lett. 2005,
4
6, 9049.
(
10) Mori, M.; Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998, 63,
(
15) (a) Lippstreu, J. J.; Straub, B. F. J. Am. Chem. Soc. 2005, 127, 7444.
b) Vedrenne, E.; Royer, F.; Oble, J.; Ka ¨ı m, L. E.; Grimaud, L. Synlett
005, 2379. (c) Galan, B. R.; Giessert, A. J.; Keister, J. B.; Diver, S. T. J.
6
082.
(
2
(11) (a) Mancilla, T.; Carrillo, L.; Zamudio-Rivera, L. S.; Beltran, H. I.;
Farfan, N. Org. Prep. Proced. Int. 2002, 34, 87. (b) Mancilla, T.; Carrillo,
L.; Zamudio-Rivera, L. S.; Beltran, H. I.; Farfan, N. Org. Prep. Proced.
Int. 2001, 33, 341. (c) Stoianova, D. S.; Hanson, P. R. Org. Lett. 2000, 2,
Am. Chem. Soc. 2005, 127, 5762. (d) Lee, H.-Y.; Kim, H. Y.; Tae, H.;
Kim, B. G.; Lee, J. Org. Lett. 2003, 5, 3439. (e) Schramm, M. P.; Reddy,
D. S.; Kozmin, S. A. Angew. Chem., Int. Ed. 2001, 40, 4274. (f) Kitamura,
T.; Sato, Y.; Mori, M. Chem. Commun. 2001, 1258. (g) Hoye, T. R.;
Donaldson, S. M.; Vos, T. J. Org. Lett. 1999, 1, 277. (h) Stragies, R.;
Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. 1997, 36, 2518. (i)
Miwako, M.; Kinoshita, A. Synlett 1994, 1020.
1
769.
(12) Cho, J. H.; Kim, B. M. Tetrahedron Lett. 2002, 43, 1273.
13) (a) Yang, Q.; Xiao, W.-J.; Yu, Z. Org. Lett. 2005, 7, 871. (b) Taber,
(
D. Organic Chemistry Highlights, October 17, 2005. Please see: http://
www.organic-chemistry.org/Highlights/2005/17october.shtm. (c) Yang, Q.;
Li, X.-Y.; Wu, H.; Xiao, W.-J. Tetrahedron Lett. 2006, 47, 3893. (d) Guo,
Y.-C.; Mele, G.; Martina, F.; Margapoti, E.; Vasapollo, G.; Xiao, W.-J. J.
Organomet. Chem. 2006, 691, 5383.
(16) (a) Dieltiens, N.; Stevens, C. V.; Vos, D. D.; Allaert, B.; Drozdzak,
R.; Verpoort, F. Tetrahedron Lett. 2004, 45, 8995. (b) Clercq, B. D.;
Verpoort, F. Tetrahedron Lett. 2001, 42, 8959. (c) Briot, A.; Bujard, M.;
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(d) Furstner, A.; Thiel, O. R.; Ackermann, L.; Schanz, H.-J.; Nolan, S. P.
J. Org. Chem. 2000, 65, 2204.
(14) Smulik, J. A.; Giessert, A. J.; Diver, S. T. Tetrahedron Lett. 2002,
4
3, 209.
770
Org. Lett., Vol. 9, No. 5, 2007