Unexpected results of enyne metathesis using a ruthenium complex containing an N-heterocyclic carbene ligand

Article abstract of DOI:10.1039/b101453f

Metathesis of enyne having 1,1-substituted alkene, carried out with the new generation of a ruthenium carbene complex containing an N-heterocyclic carbene ligand, gave five- and six-membered cyclic compounds in high yield.

Full text of DOI:10.1039/b101453f

Unexpected results of enyne metathesis using a ruthenium complex
containing an N-heterocyclic carbene ligand
Tsuyoshi Kitamura, Yoshihiro Sato and Miwako Mori*
Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
Received (in Cambridge, UK) 14th February 2001, Accepted 24th May 2001
First published as an Advance Article on the web 20th June 2001
Metathesis of enyne having 1,1-substituted alkene, carried
out with the new generation of a ruthenium carbene complex
containing an N-heterocyclic carbene ligand, gave five- and
six-membered cyclic compounds in high yield.
the novel ruthenium carbene complex 1b or 1c for enyne
metathesis.†
When a toluene solution of enyne 2c was warmed in the
presence of 5 mol% of 1b at 80 °C for 5 h, two metathesis
products, 3c and 4c, were obtained in 85% yields along with
compound 5c in 5% yield (Scheme 2). Compounds 3c and 4c
were obtained as a mixture of two inseparable isomers, and they
could be isolated by iterative chromatography on silica gel.
Compound 3c has a five-membered ring, which is usually
formed by the reaction of enyne having a mono-substituted
alkene and 1a.3a On the other hand, the 1H NMR spectrum of 4c
is similar to that of 3c, and other spectral data such as 13C NMR,
HMQC, HMBC and mass spectra supported this structure. This
compound should be produced by C–C bond formation between
the disubstituted alkene carbon (C7) and the outside alkyne
carbon (C2), and the methylene carbon of the alkene migrates to
the inside alkyne carbon (C3).
Compound 5c is formed by reductive elimination from
ruthenacyclobutane III as shown in Scheme 2. When ruthenium
carbene complex 1c was used for this reaction, the same
compounds 3c and 4c were each obtained in 32% yield, along
with a small amount of 5c. This indicates that the six-membered
ring 4c was formed from 1,6-ene-yne using ruthenium carbene
complex 1b or 1c.
A possible reaction course is shown in Scheme 3. It is thought
that there are two pathways in the reaction of the alkyne part of
the enyne with the methylidene ruthenium carbene complex.5 If
the reaction proceeds through path A, ruthenium carbene
complex II would be formed.
Intramolecular [2 + 2]cycloaddition affords III. Thus, a
smaller ring-sized product is formed (five-membered ring).
However, when ruthenium metal of the carbene complex bonds
to the outside carbon of alkyne, ruthenacycle IV would be
formed and would be converted into ruthenium carbene
complex V by ring opening. Then the ruthenium carbene
complex reacts intramolecularly with the alkene part to give
ruthenacyclobutane VI, which affords a six-membered ring
compound.6
In recent synthetic organic chemistry, transition metals play an
important role and enable bond cleavage of multiple bonds,
such as a double bond or triple bond. A metathesis reaction1
using a metal carbene complex is quite interesting because
multiple bonds are cleaved and, at the same time, a multiple
bond is formed. Enyne metathesis2,3 is particularly attractive,
since the double bond of enyne is cleaved and the alkylidene
part of the alkene migrates to the alkyne carbon to give a
cyclized compound. However, in this reaction, the substituents
on the alkyne or the alkene are important. It has been shown that
the reaction rate of an enyne having a terminal alkyne is slow
because the generated diene moiety coordinates to the ruthe-
nium carbene complex.3a On the other hand, the effect of the
substituent on the alkene is also important. In the case of an
enyne having a mono- or 1,2-disubstituted alkene, the met-
athesis reaction proceeded smoothly and the desired product
was obtained.3a
However, when enyne 2b (R3
= Me) having 1,1-di-
substituted alkene was treated in a similar manner, no cyclized
product was obtained and the starting material was recovered
(Scheme 1). This means that ruthenium carbene complex i
formed by the reaction of the alkyne part of enyne and 1a4a does
not react intramolecularly with a 1,1-disubstituted alkene.
Recently, a new generation of ruthenium carbene complexes
containing N-heterocyclic carbene ligands was reported.4b,c The
reactivity of these complexes is greater than that of 1a, and the
metathesis of an olefin having a 1,1-disubstituted alkene
proceeded smoothly using 1b or 1c to give a cyclized product
having tri- or tetra-substituted olefin. Thus, we decided to use
Various enynes were treated with 1b in a similar manner, and
the results are shown in Table 1. In all cases, enyne metathesis
Scheme 1 Ruthenium-catalyzed intramolecular enyne metathesis.
Scheme 2 Reaction of 2c with ruthenium catalyst 1.
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Chem. Commun., 2001, 1258–1259
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b101453f

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Although the reason why the reaction of enyne 2a with 1a
gave only 3a,3a but enyne 2b reacts with 1b or 1c gave 3b and
4b is not clear, the results are quite interesting.
Further studies of enyne metathesis using 1b or 1c are in
progress.
Notes and references
† Typical procedure for the metathesis reaction of 2d. To a solution of 2d
(34.2 mg, 115 mmol) in toluene (3.8 ml, 0.03 M) was added 1b (4.9 mg, 5.8
mmol, 5 mol%), and the solution was heated at 80 °C for 6 h. After the
solvent was removed, the residue was purified three times by flash column
chromatography on silica gel (C6H12–C6H6–AcOEt 8+1+2) to yield 3d
(17.1 mg, 58 mmol, 50%), and 4d (13.3 mg, 46 mmol, 39%) as colorless oils,
respectively.
Selected spectral data for 3d and 4d. 3-Acetoxymethyl-4-isopropenyl-
cyclopent-3-ene-1,1-dicarboxylic acid dimethyl ester (3d). n/(neat) 1740,
1636, 1603, 1230 cm21; dH(270 MHz, CDCl3) 1.86 (s, 3 H), 2.06 (s, 3 H),
3.15 (s, 2 H), 3.18 (m, 2 H), 3.75 (s, 6 H), 4.73 (s, 2 H), 4.81 (s, 1 H), 5.02
(s, 1 H); dC(67.8 MHz, CDCl3) 20.9 (CH3), 21.9 (CH3), 42.7 (CH2), 43.5
(CH2), 52.9 (CH3 3 2), 57.0 (C), 60.8 (CH2), 116.0 (CH2), 129.3 (C), 139.2
(C), 139.8 (C), 170.9 (C), 172.3 (C 3 2); LRMS m/z 296 (M+), 236, 204,
191, 177, 145, 131, 117; HRMS calcd for C15H20O6 (M+) 296.1260, found
296.1251. 3-Acetoxymethyl-4-methyl-5-methylenecyclohex-3-ene-1,1-di-
Scheme 3 Two possible reaction pathways for enyne metathesis.
products 3 and 4 were obtained as an inseparable mixture of two
isomers. In some cases, we could isolate each pure compound
after iterative of flash column chromatography on silica gel. In
each case, a small amount of 5 was produced. Although all
spectral data supported the structures of compounds 4, the
structure of a derivative of 4b was further confirmed by X-ray
crystallographic analysis.7
carboxylic acid dimethyl ester (4d). n/(neat) 1738, 1640, 1610, 1230 cm21
;
dH(270 MHz, CDCl3) 1.85 (s, 3 H), 2.08 (s, 3 H), 2.73 (s, 2 H), 2.88 (s, 2
H), 3.70 (s, 6 H), 4.71 (s, 2 H), 4.99 (s, 1 H), 5.13 (s, 1 H); dH(67.8 MHz,
CDCl3) 13.7 (CH3), 20.9 (CH3), 34.2 (CH2), 37.2 (CH2), 52.7 (CH3 3 2),
53.8 (C), 64.6 (CH2), 112.8 (CH2), 127.9 (C), 131.1 (C), 140.6 (C), 171.0
(C), 171.1 (C 3 2); LRMS m/z 296 (M+), 254, 236, 223, 204, 177, 163, 117;
HRMS calcd for C15H20O6 (M+) 296.1260, found 296.1258.
Table 1 Enyne metathesis using 1ba
Run Substrate
1
Conditions
Products, yieldb
80 °C 6 h
1 For recent reviews on metathesis, see R. H. Grubbs and S. J. Miller, Acc.
Chem. Res., 1995, 28, 446; M. Schuster and S. Blechert, Angew. Chem.,
Int. Ed. Engl., 1997, 36, 2036; H.-G. Schmalz, Angew. Chem., Int. Ed.
Engl., 1995, 34, 1833; A. Fürstner, Topics in Organometallic Chemistry,
Vol. 1, Springer-Verlag, Berlin, Heidelberg, 1998; R. H. Grubbs and S.
Chang, Tetrahedron, 1998, 54, 4413; S. K. Armstrong, J. Chem. Soc.,
Perkin Trans. 1, 1998, 371; A. J. Phillips and A. D. Abell, Aldrichimica
Acta, 1999, 32, 75; A. Fürstner, Angew. Chem., Int. Ed., 2000, 39,
3013.
E = CO2Me
2
80 °C 15 h
2 For a review on enyne metathesis, see M. Mori, Top. Organomet. Chem.,
1998, 1, 133; for recent applications, see; R. T. Hoye, S. M. Donaldoson
and T. Vos, Org. Lett., 1999, 1, 277; A. G. M. Barrett, S. P. D. Baugh,
D. C. Braddock, K. Flack, V. C. Gibson, M. R. Giles, E. L. Marshall, P. A.
Procopiou, A. J. P. White and D. J. Williams, J. Org. Chem., 1998, 63,
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39, 310; A. Fürstner, H. Szillat and F. Stelzer, J. Am. Chem. Soc., 2000,
122, 6785; R. Stragies, U. Voigtmann and S. Blechert, Tetrahedron Lett.,
2000, 41, 5465; D. Bentz and S. Laschat, Synthesis, 2000, 1766.
3 (a) A. Kinoshita and M. Mori, Synlett, 1994, 1020; (b) A. Kinoshita and
M. Mori, J. Org. Chem., 1996, 61, 8356; (c) A. Kinoshita and M. Mori,
Heterocycles, 1997, 46, 287; (d) M. Mori, N. Sakakibara and A.
Kinoshita, J. Org. Chem., 1998, 63, 6082; (e) A. Kinoshita, N. Sakakibara
and M. Mori, J. Am. Chem. Soc., 1997, 119, 12 388; (f) A. Kinoshita, N.
Sakakibara and M. Mori, Tetrahedron, 1999, 55, 8155; (g) M. Mori, T.
Kitamura, N. Sakakibara and Y. Sato, Org. Lett., 2000, 2, 543.
4 For 1a, see (a) P. Schwab, M. B. France, J. W. Ziller and R. H. Grubbs,
Angew. Chem., Int. Ed. Engl., 1995, 34, 2039; for 1b see (b) T. Weskamp,
W. C. Schattenmann, M. Spiegler and W. A. Herrmann, Angew. Chem.,
Int. Ed., 1998, 37, 2490; (c) J. Huang, E. D. Stevens, S. P. Nolan and J. L.
Peterson, J. Am. Chem. Soc., 1999, 121, 2674; (d) M. Scholl, T. M. Trnka,
J. P. Morgan and R. H. Grubbs, Tetrahedron Lett., 1999, 40, 2247; for 1c
see (e) M. Scholl, S. Ding, C. W. Lee and R. H. Grubbs, Org. Lett., 1999,
1, 953.
3
4
80 °C 24 h
80 °C 6 h
5
6
50 °C 3 h
5 If this reaction proceeds by the reaction of the methylene carbene
complex and the olefin part of the enyne, a similar reaction pathway is
described.
6 In the synthesis of an eight-membered ring compound using ruthenium
catalyst 1a, we considered the same possibility, but no other products
were observed. See ref. 3g.
50 °C 24 h
7 Treatment of compound 4d with K2CO3 in MeOH followed by Dess–
Martin oxidation (D. B. Dess and J. C. Martin, J. Org. Chem., 1983, 48,
4156) afforded an aldehyde, which was converted into 2,4-di-
nitrophenylhydrazone, whose X-ray crystallography shows that a six-
membered ring is formed. CCDC 161214. See http://www.rsc.org/
suppdata/cc/b1/b101453f/ for crystallographic data in CIF or other
format.
Si = TBDMS
a All reactions were carried out using 1b (5 mol%) in toluene. b All yields
were calculated from H NMR spectra after isolation as a mixture of two
isomers. c 10 mol% of 1b was used.
1
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