Ruthenium-Catalyzed ROM-RCM of Cycloalkene-yne

Article abstract of DOI:10.1021/ol026696d

(Matrix Presented) ROM-RCM (ring-opening and ring-closing metatheses) of cycloalkene-yne was demonstrated using a second-generation ruthenium complex. When cycloalkene bearing the alkyne moiety at the C-1 position was reacted with a ruthenium-carbene complex under an atmosphere of ethylene, ROM-RCM proceeded smoothly to give bicyclic compound and/or dimeric compound in good yields.

Full text of DOI:10.1021/ol026696d

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3855-3858
Ruthenium-Catalyzed ROM−RCM of
Cycloalkene-yne
Miwako Mori,* Yuichi Kuzuba, Tsuyoshi Kitamura, and Yoshihiro Sato
Graduate School of Pharmaceutical Sciences, Hokkaido UniVersity,
Sapporo 060-0812, Japan
mori@pharm.hokudai.ac.jp
Received August 8, 2002
ABSTRACT
ROM−RCM (ring-opening and ring-closing metatheses) of cycloalkene-yne was demonstrated using a second-generation ruthenium complex.
When cycloalkene bearing the alkyne moiety at the C-1 position was reacted with a ruthenium−carbene complex under an atmosphere of
ethylene, ROM−RCM proceeded smoothly to give bicyclic compound and/or dimeric compound in good yields.
A metathesis reaction1 using a metal carbene complex is quite
interesting because multiple bonds are cleaved and, at the
same time, multiple bonds are formed. Enyne metathesis2-4
is particularly attractive. In the intramolecular enyne meta-
thesis, the double bond of an enyne is cleaved and the
alkylidene parts of alkene react with alkyne carbons to give
a cyclized compound having the diene moiety. We have
already reported enyne metathesis2 using Grubbs’ ruthenium
carbene complex 15 and the syntheses of natural products
using this method.
ROM-RCM6 of cycloalkene-yne under an atmosphere of
ethylene involves a cleavage of an olefinic bond in a
cycloalkene followed by formation of a new ring system.2k
Herein we report a ring skeletal reorganization of cycloalk-
ene-yne via ROM-RCM. Our initial strategy was envisioned
to act according to Scheme 1. Metathesis reaction of
cycloalkene-yne I, whose alkyne part is connected at the C-1
position of cycloalkene, would give triene II. If intra-
(1) For recent review on metathesis, see: (a) Grubbs, R. H.; Miller, S.
J. Acc. Chem. Res. 1995, 28, 446. (b) Schuster, M.; Blechert, S. Angew.
Chem., Int. Ed. Engl. 1997, 36, 2036. (c) Schmalz, H.-G. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 1833. (d) Fu¨rstner, A. Topics in Organometallic
Chemistry; Springer-Verlag: Berlin, 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, 3013. (i) Trnka,
T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
(2) (a) For reviews on enyne metathesis, see; Mori, M. Top. Organomet.
Chem. 1998, 1, 133. (b) Mori, M. J. Synth. Org. Chem. Jpn. 1998, 56, 115.
For reports from our laboratory, see: (c) Kinoshita, A.; Mori, M. Synlett
1994, 1020. (d) Kinoshita, A.; Mori, M. J. Org. Chem. 1996, 61, 8356. (e)
Kinoshita, A.; Mori, M. Heterocycles 1997, 46, 287. (f) Mori, M.;
Sakakibara, N.; Kinoshita, A. J. Org. Chem. 1998, 63, 6082. (g) Kinoshita,
A.; Sakakibara, N.; Mori, M. J. Am. Chem. Soc. 1997, 119, 12388. (h)
Kinoshita, A.; Sakakibara, N.; Mori, M. Tetrahedron 1999, 55, 8155. (i)
Mori, M.; Kitamura, T.; Sakakibara, N.; Sato, Y. Org. Lett. 2000, 2, 543.
(j) Mori, M.; Kitamura, T.; Sato, Y. Synthesis 2001, 654. (k) Kitamura, T.;
Mori, M. Org. Lett. 2001, 3, 1161. (l) Kitamura, T.; Sato, Y.; Mori, M.
Chem. Commun. 2001, 1258. (m) Mori, M.; Tonogaki, K.; Nishiguchi, N.
J. Org. Chem. 2002, 67, 224. (n) Saito, N.; Sato, Y.; Mori, M. Org. Lett.
2002, 4, 803. (o) Tonogaki, K.; Mori, M. Tetrahedron Lett. 2002, 43, 2235.
(p) Kitamura, T.; Sato, Y.; Mori, M. AdV. Synth. Catal. 2002, 344, 678.
(3) Ruthenium carbene systems, see: (a) Kim, S.-H.; Bowden, N.;
Grubbs, R. H. J. Am. Chem. Soc. 1994, 116, 10801. (b) Stragies, R.;
Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2518.
(c) Barrett, A. G. M.; Baugh, S. P. D.; Braddock, D. C.; Flack, K.; Gibson,
V. C.; Giles, M. R.; Marshall, E. L.; Procopiou, P. A.; White, A. J. P.;
Williams, D. J. J. Org. Chem. 1998, 63, 7893. (d) Hoye, R. T.; Donaldoson,
S. M.; Vos, T. Org. Lett. 1999, 1, 277. (e) Renaud, J.; Graf, C.-D.; Oberer,
L. Angew. Chem., Int. Ed. 2000, 39, 3101. (f) Stragies, R.; Voigtmann, U.;
Blechert, S. Tetrahedron Lett. 2000, 41, 5465. (g) Bentz, D.; Laschat, S.
Synthesis 2000, 1766. (h) Schramm, M. P.; Reddy, D. S.; Kozmin, S. A.
Angew. Chem., Int. Ed. 2001, 40, 4274. (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) Timmer, M. S. M.; Ovaa, H.; Filippov,
D. V.; van der Marel, G. A.; van Boom, J. H. Tetrahedron Lett. 2001, 42,
8231. (k) Yao, Q. Org. Lett. 2001, 3, 2069. (l) Smulik, J. A.; Giessert, A.
J.; Diver, S. T. Tetrahedron Lett. 2002, 43, 209. (m) Layton, M. E.; Morales,
C. A.; Shair, M. D. J. Am. Chem. Soc. 2002, 124, 773. (n) Poulsen, C. S.;
Madsen, R. J. Org. Chem. 2002, 67, 4441.
10.1021/ol026696d CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/04/2002

butane VI, which would then be converted into ruthenium-
carbene complex VII. This would react with ethylene
intermolecularly to afford triene II. On the other hand, if
complex VII can react with an alkene part of the diene
moiety intramolecularly, bicyclic compound III would be
obtained.
Scheme 1. Plan for ROM-RCM of Cycloalkene-yne
When a CH2Cl2 solution of cyclohexene-yne 2a and 10
mol % first-generation ruthenium carbene complex 1a5a was
stirred at room temperature for 18 h under an atmosphere of
ethylene, cross enyne metathesis2g product 3a was obtained
in 76% yield instead of the ring-opening metathesis product
(Scheme 2). Presumably, carbene complex VIII cannot react
with the cyclohexene moiety.
Scheme 2. Reaction of Cycloalkene-yne 2a Using 1a
molecular diene metathesis of II occurs, bicyclic compound
III would be formed. That is, the alkyne part of I would
react with the ruthenium-carbene complex to give ruthena-
cyclobutene IV, which would be converted into ruthenium-
carbene complex V by ring opening.7 Then, intramolecular
[2 + 2] cycloaddition would occur to afford ruthenacyclo-
On the other hand, when a toluene solution of 2a and 10
mol % second-generation ruthenium carbene complex 1b5b-e
was stirred at 80 °C for 16 h under an atmosphere of
ethylene, two ring-opening metathesis products were obtained
(Scheme 3). Surprisingly, 1H NMR and mass spectra revealed
that one is compound 4b having a 5,7-fused ring system,
not a 5,8-fused ring system, obtained in 46% yield. The
structure was confirmed by X-ray crystallographic analysis8
(Figure 1).
(4) For a review on cycloisomerization of enynes, see: (a) Trost, B. M.;
Krische, M. J. Synlett 1998, 1. For selected other examples, see: (b) Katz,
T. J.; Sivavec, T. M. J. Am. Chem. Soc. 1985, 107, 737. (c) Trost, B. M.;
Tanoury, G. J. J. Am. Chem. Soc. 1988, 110, 1636. (d) Mori, M.; Watanuki,
S. J. Chem. Soc., Chem. Commun. 1992, 1082. (e) Watanuki, S.; Ochifuji,
N.; Mori, M. Organometallics 1994, 13, 4129. (f) Chatani, N.; Morimoto,
T.; Muto, T.; Murai, S. J. Am. Chem. Soc. 1994, 116, 6049. (g) Fu¨rstner,
A.; Szillat, H.; Stelzer, F. J. Am. Chem. Soc. 2000, 122, 6785. (h) Fu¨rstner,
A.; Stelzer, F.; Szillat, H. J. Am. Chem. Soc. 2001, 123, 11863. (i)
Ackermann, L.; Bruneau, C.; Dixneuf, P. H. Synlett, 2001, 397. (j) Semeril,
D.; Cleran, M.; Bruneau, C.; Dixneuf, P. H. AdV. Synth. Catal. 2001, 343,
184.
(5) For 1a, see: (a) Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R.
H. Angew. Chem., Int. Ed. Engl. 1995, 34, 2039. For 1b, see: (b) Scholl,
M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953. For other
second-generation ruthenium catalysts, see: (c) Weskamp, T.; Schattenmann,
W. C.; Spiegler, M.; Herrmann, W. A. Angew. Chem., Int. Ed. 1998, 37,
2490. (d) Huang, J.; Stevens, E. D.; Nolan, S. P.; Peterson, J. L. J. Am.
Chem. Soc. 1999, 121, 2674. (e) Scholl, M.; Trnka, T. M.; Morgan, J. P.;
Grubbs, R. H. Tetrahedron Lett. 1999, 40, 2247.
The other is 16-membered ring compound 5a, which was
obtained in 4% yield (Table 1, run 1). At first, from the
1
coupling constant of Ha and Hb on a H NMR spectrum
(JHa-Hb ) 16.0 Hz), this compound was considered to be
trans-4a, and one set of peaks corresponding to trans-4a was
1
shown on H NMR and 13C NMR spectra. However, a MS
(6) For recent applications of ROM-RCM, see: (a) Zuercher, W. J.;
Hashimoto, M.; Grubbs, R. H. J. Am. Chem. Soc. 1996, 118, 6634. (b)
Chatani, N.; Furukawa, N.; Sakurai, H.; Murai, S. Organometallics 1996,
15, 901. (c) Fu¨rstner, A.; Szillat, H.; Gabor, B.; Mynott, R. J. Am. Chem.
Soc. 1998, 120, 8305. (d) Burke, S. D.; Quinn, K. J.; Chen, V. J. J. Org.
Chem. 1998, 63, 8626. (e) Adams, J. A.; Ford, J. G.; Stamatos, P. J.;
Hoveyda, A. H. J. Org. Chem. 1999, 64, 9690. (f) Voigtmann, U.; Blechert,
S. Synhesis 2000, 893. (g) Trost, B. M.; Doherty, G. A. J. Am. Chem. Soc.
2000, 122, 3801. (h) Ovaa, H.; Stragies, R.; van der Malel, G. A.; van
Boom, J. H.; Blechert, S. Chem. Commun. 2000, 1501. (i) Fu¨rstner, A.;
Szillat, H.; Stelzer, F. J. Am. Chem. Soc. 2000, 122, 6785. (j) Stragies, R.;
Blechert, S. J. Am. Chem. Soc. 2000, 122, 9584. (k) Voigtmann, U.; Blechert,
S. Org. Lett. 2000, 2, 3971 (l) Choi, T.-L.; Grubbs, R. H. Chem. Commun.
2001, 2648. (m) Ru¨ckert, A.; Eisele, D.; Blechert, S. Tetrahedron Lett. 2001,
42, 5245. (n) Banti, D.; North, M. Tetrahedron Lett. 2002, 43, 1561. (o)
Lee, C. W.; Choi, T.-L.; Grubbs, R. H. J. Am. Chem. Soc. 2002, 124, 3224.
(p) Minger, T. L.; Phillips, A. J. Tetrahedron Lett. 2002, 43, 5357 and
references therein.
spectrum of 5a (m/z 606 [M+]) indicated that it should be a
dimeric compound. Encouraged by this result, we found that
when a solution of 2a and 10 mol % 1b in CH2Cl2 was
refluxed under an atmosphere of ethylene for 24 h, the yields
were improved (run 2). Although an expected product 4a
was obtained under these reaction conditions (14% yield),
the main product was 5a (57%).9
Next, to determine whether dimeric compound 5a is
converted into fused 5,7- or 5,8-membered ring compounds
(8) Crystallographic data have been deposited with the Cambridge
Crystallographic Data Center as supplementary publication no. CCDC
193041.
(9) Reaction of 3a with 1b under Ar gas did not afford 5a or 4b, although
3a was completely consumed.
(7) If ROM-RCM proceeds from the cycloalkene part of I, a similar
reaction mechanism would be considered.
3856
Org. Lett., Vol. 4, No. 22, 2002

Scheme 3. Metathesis Reaction of Enyne 2a Using 1b
Scheme 4. Reaction of 5a with Ethylene in the Presence of
1b
10 mol % 1b was refluxed under an atmosphere of ethylene
for 2 h, the desired ROM-RCM product 4b was obtained
in 95% yield (Table 2, run 1). Even in the case of longer
reaction time (26 h), 4b was obtained in quantitative yield
(run 2). The use of 5 mol % 1b gave a similar result (run 3).
These results suggested that ring closure of VII to seven-
membered ring compound 4b proceeds easily and that 4b is
stable under these reaction conditions.
under the metathesis reaction conditions, a solution of 5a
and 20 mol % of 1b in toluene was stirred at 80 °C for 16
h under an atmosphere of ethylene. Interestingly, 4b, 4a, and
6a were obtained in 39, 9, and 21% yields, respectively
(Scheme 4). These results suggest that 5a reacted with
ethylene in the presence of ruthenium complex 1b to afford
6a. Since ring-closure to an eight-membered ring is difficult,
olefin migration10 followed by olefin metathesis would occur
to give fused 5,7-membered ring compound 4b.
Scheme 5. ROM-RCM of Cyclopenete-yne 2b Using 1b
Subsequently, ROM-RCM of cyclopentene-yne 2b was
investigated (Scheme 5). When a CH2Cl2 solution of 2b and
Furthermore, ROM-RCM of cycloheptene-yne 2c was
investigated (Scheme 6). When the reaction of 2c was carried
out in toluene at 80 °C for 21 h, 4b, dimeric compound 5c,
and isoindline derivative 811 were obtained in 36, 8, and 6%
yields, respectively, along with an inseparable mixture 9
(Table 3, run 1). GC-MS analysis showed that 9 is a mixture
(10) For examples, see: (a) Fu¨rstner, A.; Thiel, O. R.; Ackermann, L.;
Schanz, H.-J.; Nolan, S. P. J. Org. Chem. 2000, 65, 2204. (b) Alcaida, B.;
Almendros, P.; Alonso, J. M.; Aly, M. F. Org. Lett. 2001, 3, 3781. (c)
Cadot, C.; Dalko, P. I.; Cossy, J. Tetrahedron Lett. 2002, 43, 1839. (d)
Huang, J.; Hsung, R. P.; Rameshkumar, C.; Mulder, J. A.; Grebe, T. P
Org. Lett. 2002, 4, 2417 and references therein.
Figure 1. X-ray crystallographic analysis of 4b.
Org. Lett., Vol. 4, No. 22, 2002
3857

Scheme 6. Ring-Opening Metathesis of 2c
Scheme 7. Summary of ROM-RCM of Cycloalkene-yne
toluene gave 4b in moderate yield, bicyclic compound 4b
was obtained in all cases due to the easy formation of seven-
membered ring after isomerization of the double bond.
Although it is not clear why the dimerization occurred, these
results are very interesting.
of dihydropyrrole derivatives having different carbon lengths
and/or having an olefin at various positions in the substituent.
On the other hand, when a reaction was carried out in CH2Cl2
upon heating for 15 h, dimerization product 5c was obtained
in 58% yield along with a considerable amount of 9 (run 2).
In addition, when the reaction was quenched after the spot
of the starting material 2c disappeared on TLC (1 h), only
5c was obtained in 80% yield (run 3).
ROM-RCM of 5-, 6-, and 7-membered cycloalkene-ynes
2 was demonstrated. The results are summarized in Scheme
7. When the reaction was carried out in CH2Cl2, cyclopen-
tene-yne 2b gave fused 5,7-membered ring compound 4b,
but cycloheptene-yne 2c afforded dimeric compound 5c, both
in high yields. However, under similar reaction conditions,
cyclohexene-yne 2a gave 4b and dimeric compound 5a in
26 and 57% yields, respectively. Since the reaction of 2c in
Further studies on ROM-RCM of cycloalkene-yne and
mechanistic studies for this reaction are in progress.
Supporting Information Available: Typical procedures
and spectral data of 2a-c, 3a, 4a-b, 5a, 5c, and 6a. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL026696D
(11) Compound 8 was reported in the literature and was in agreement
with reported spectral data. See: Bottino, F.; Grazia, M. D.; Finocchiaro,
P.; Fronczek, F. R.; Mamo, A.; Pappalardo, S. J. Org. Chem. 1988, 53,
3521 and references therein.
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Org. Lett., Vol. 4, No. 22, 2002