Synthesis of cyclic dienamide using ruthenium-catalyzed ring-closing metathesis of ene-ynamide.

Article abstract of DOI:10.1021/ol017298y

[reaction: see text] Ring-closing metathesis of ene-ynamide using the second-generation Grubbs' catalyst produced nitrogen-containing heterocycles, which have dienamide moieties, in high yields. Diels-Alder reaction of the cyclized product and dienophile

Full text of DOI:10.1021/ol017298y

ORGANIC
LETTERS
2002
Vol. 4, No. 5
803-805
Synthesis of Cyclic Dienamide Using
Ruthenium-Catalyzed Ring-Closing
Metathesis of Ene-Ynamide
Nozomi Saito, Yukako Sato, and Miwako Mori*
Graduate School of Pharmaceutical Sciences, Hokkaido UniVersity,
Sapporo 060-0812, Japan
mori@pharm.hokudai.ac.jp
Received December 25, 2001
ABSTRACT
Ring-closing metathesis of ene-ynamide using the second-generation Grubbs' catalyst produced nitrogen-containing heterocycles, which have
dienamide moieties, in high yields. Diels−Alder reaction of the cyclized product and dienophile proceeded smoothly to afford a bi- or tricyclic
compound.
A transition metal catalyzed metathesis reaction is recognized
as one of the most powerful and useful methodologies in
synthetic organic chemistry.1 Ring-closing metathesis (RCM)
is widely used for the synthesis of complex cyclic com-
pounds, including natural products. An intramolecular enyne
metathesis is a particularly interesting reaction, because the
double bond of the enyne is cleaved and the alkylidene part
of the olefin migrates to the alkyne carbon to afford a
cyclized product that has a diene moiety.2 We have recently
developed enyne metathesis using a Grubbs' ruthenium
catalyst 1 and have reported some applications, including
natural product synthesis, using this reaction.3
Herein we report the synthesis of cyclic dienamide using
ruthenium-catalyzed RCM. As shown in Scheme 1, enyne
Scheme 1
(1) For recent reviews on metathesis, see: (a) Grubbs, R. H.; Miller, S.
J.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446. (b) Schmalz, H.-G. Angew.
Chem., Int. Ed. Engl. 1995, 34, 1833. (c) Schuster, M.; Blechert, S. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2036. (d) Topics in Organometallic
Chemistry; Fu¨rstner, A., Ed.; Springer-Verlag: Berlin, Heidelberg, 1998;
Vol. 1. (e) Grubbs, R. H.; Chang. S. Tetrahedron 1998, 54, 4413. (f)
Armstrong, S. K. J. Chem. Soc., Perkin Trans. 1 1998, 371. (g) Phillips,
A. J.; Abell, A. D. Aldrichimica Acta 1999, 32, 75. (h) Fu¨rstner, A. Angew.
Chem., Int. Ed. 2000, 39, 3012. (i) Trnka, T. M.; Grubbs, R. H. Acc. Chem.
Res. 2001, 34, 18. (j) Shrock, R. R. Tetrahedron 1999, 55, 8141. (k)
Hoveyda, A. H.; Schrock, R. R. Chem. Eur. J. 2001, 7, 945. (l) Weskamp,
T.; Schattenmann, W. C.; Spiegler, M.; Herrmann, W. A. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 2490. (m) Huang, J.; Stevens, E. D.; Nolan, S. P.;
Petersen, J. L. J. Am. Chem. Soc. 1999, 121, 2674. (n) Ackermann, L.;
Fu¨rstner, A.; Weskamp, T.; Kohl, F. J.; Herrmann, W. A. Tetrahedron Lett.
1999, 40, 4787.
metathesis of the substrate i having an ynamide moiety4
would give the cyclized product ii, which has an electron-
donating group on the diene part (i.e., dienamide part). It is
expected that the dienamide moiety could be used for a
further carbon-carbon bond-forming reaction, such as the
Diels-Alder reaction.5
To examine the feasibility of this approach, RCM of ene-
ynamide 2 was attempted (Scheme 2). When a solution of 2
10.1021/ol017298y CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/05/2002

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.
Chem., Int. Ed. 2000, 39, 3101. (f) Fu¨rstner, A.; Szillat, H.; Stelzer, F. J.
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.,
Int. Ed. 2001, 40, 4274. (k) Timmer, M. S. M.; Ovaa, H.; Filippov, D. V.;
Van der Marel, G. A.; Van Boom, J. H. Tetrahedron Lett. 2001, 42, 8231.
(3) (a) Kinoshita, A.; Mori, M. Synlett 1994, 1020. (b) Kinoshita, A.;
Mori, M. J. Org. Chem. 1996, 61, 8356. (c) Kinoshita, A.; Mori, M.
Heterocycles 1997, 46, 287. (d) Kinoshita, A.; Sakakibara, N.; Mori, M. J.
Am. Chem. Soc. 1997, 119, 12388. (e) Mori, M.; Sakakibara, N.; Kinoshita,
A. J. Org. Chem. 1998, 63, 6082. (f) Kinoshita, A.; Sakakibara, N.; Mori,
M. Tetrahedron 1999, 55, 8155. (g) Mori, M.; Kitamura, T.; Sakakibara,
N.; Sato, Y. Org. Lett. 2000, 2, 543. (h) Kitamura, T.; Mori, M. Org. Lett.
2001, 3, 1161. (i) Mori, M.; Kitamura, T.; Sato, Y. Synthesis 2001, 654. (j)
Kitamura, T.; Sato, Y.; Mori, M. Chem. Commun. 2001, 1258.
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

reaction of the crude product, which was obtained from RCM
of 2, and N-phenylmaleimide was attempted (eq 3). The
reaction proceeded smoothly in toluene at room temperature,
and the tricyclic compound 7 was produced in 68% yield (2
steps, from 2).
In a manner similar to that of indole derivative synthesis,
preparation of quinoline derivative was examined (Scheme
4). When a toluene solution of the crude product, which was
of isolated 5a and DMAD in toluene gave only 8b, which
would have been isomerized from 8a, in 71% yield as a sole
product (eq 5).10
These results indicate that nitrogen-heterocycles having
dienamide moieties (i.e., cyclic dienamides) can easily be
synthesized by using ruthenium-catalyzed ring-closing me-
tathesis of ene-ynamide. It was also demonstrated that the
dienamides are suitable substrates to prepare indole and
quinoline derivatives via Diels-Alder reaction. Further
studies along these lines are in progress.
Acknowledgment. N.S. acknowledges the Japan Society
Scheme 4
for the Promotion of Sciences for financial support.
Supporting Information Available: Experimental pro-
cedures and spectral data for the synthesis of substrates 2
and 4; spectral data of cyclized products 3 and 5 and Diels-
Alder products 6-8; typical procedures for RCM. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL017298Y
(6) (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew.
Chem., Int. Ed. Engl. 1995, 34, 2039. (b) Scholl, M.; Ding, S.; Lee, C. W.;
Grubbs, R. H. Org. Lett. 1999, 1, 953.
(7) When ene-ynamide was used as the substrate, the enyne metathesis
of terminal alkyne proceeded smoothly under argon for the first time (cf.
ref 3e). Recently, RCM of electron-rich terminal alkynes using 1 without
ethylene gas has been reported (refs 2d and 2k). We continued to examine
the reaction under ethylene gas, since the yield of the cyclized product that
was obtained from the reaction under ethylene gas is greater than that of
the cyclized product obtained from the reaction under argon.
obtained from the RCM of 5a, and DMAD was heated at
100 °C for 12 h, the quinoline derivative 8a was obtained
in 57% yield (2 steps, from 4a) (eq 4). However, the reaction
(4) For a recent review on the chemistry of ynamines and ynamides,
see: (a) Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.; Rameshkumar, C.;
Wei, L.-L. Tetrahedron 2001, 57, 7575 and references therein. For recent
examples of nitrogen-heterocycles synthesis by cyclization of ynamide using
transition metals, see: (b) Witulski, B.; Stengel, T. Angew. Chem., Int. Ed.
1998, 37, 489. (c) Witulski, B.; Stengel, T. Angew. Chem., Int. Ed. Engl.
1999, 38, 2426. (d) Witulski, B.; Go¨ssmann, M. Chem. Commun. 1999,
1879. (e) Rainier, J. D.; Imbriglio, J. E. Org. Lett. 1999, 1, 2037. (f) Rainier,
J. D.; Imbriglio, J. E. J. Org. Chem. 2000, 65, 7272. (g) Witulski, B.;
Stengel, T. Ferna´ndez-Herna´ndez, J. M. Chem. Commun. 2000, 1965.
(5) For reviews on Diels-Alder reaction of dienamide, see: (a) Petrzilka,
M.; Grayson, J. I. Synthesis 1981, 753 and references therein. (b) Campbell,
A. L.; Lenz, G. R. Synthesis 1987, 421 and references therein. For recent
examples of preparation and reaction of dienamides, see: (c) Gauvry, N.;
Huet, F. J. Org. Chem. 2001, 66, 583 and references therein.
(8) For precedence of solvent effect on the reactivity of the second-
generation Ru-carbene complex, see: Fu¨rstner, A.; Thiel, O. R.; Ackermann,
L.; Schanz, H.-J.; Nolan, S. P. J. Org. Chem. 2000, 65, 2204
(9) Synthesis of 6a (Scheme 3, eq 2). A solution of 2 (55 mg, 0.22
mmol) and 1b (10 mg, 0.012 mmol) in degassed toluene (7 mL) was refluxed
for 30 min under ethylene gas (1 atm). After the reaction mixture cooled to
room temperature, the atmosphere of ethylene gas was replaced by argon
gas. To this solution was added DMAD (0.14 mL, 1.2 mmol), and the
resulting mixture was stirred at 60 °C for 12 h. After evaporation of the
solvent, the residue was purified by silica gel flash column chromatography
(hexane/AcOEt 3:1) to give 6a (69 mg, 80%, 2 steps) as a colorless oil.
(10) The reason the reaction of the isolated product 3 or 5a gave
isomerization products of the double bond 6b or 8b is not clear.
Org. Lett., Vol. 4, No. 5, 2002
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