Ring closing metathesis may be used in the formation of small ring bicycloalkenes from monocyclic diene precursors

Grubbs, Robert H.

Morehead, Andrew, Jr.

English

Caltech Authors - Main

 ButMe2SiO (   )m
(   )n
Cl2(PCy3)2RuCHPh
CH2Cl2, RT or reflux
OSiMe2But
(1)
1a–g 2a–g
(   )m
(   )n
Formation of bridged bicycloalkenes via ring closing metathesis
Andrew Morehead, Jr. and Robert Grubbs*
The Arnold and Mabel Beckman Laboratory of Chemical Synthesis, Division of Chemistry and Chemical Engineering, California
Institute of Technology, Pasadena, California 91125, USA
Ring closing metathesis may be used in the formation of
small ring bicycloalkenes from monocyclic diene pre-
cursors.
Ring closing metathesis (RCM), catalyzed by transition metal
carbenes, has recently become an established method for the
conversion of dienes to cyclic olefins.1 While many applica-
tions of RCM have been reported,2 only a few have involved the
formation of bridged bicyclic compounds. The reported exam-
ples all involved macrocyclization (ring sizes > 12 atoms)
except one, which involved the formation of a seven-membered
ring leading to a bicyclo[9.5.1]alkene ring system.3 Since small
ring bridged bicycloalkanes and heterocycles are ubiquitous in
natural products, the application of RCM in ring closures of this
type would potentially lead to greatly broadened utility of this
method.
A series of monocyclic diene substrates was synthesized† and
the ring closure promoted by the well-defined ruthenium
benzylidene complex4 was examined [eqn. (1)].‡ The results of
the cyclization reactions are summarized in Table 1.
The ring closure of five-, six- and seven-membered rings to
form [3.x.1], [4.x.1] and [5.x.1] bicycloalkenes is a relatively
facile process (entries 1, 2, 5, 6 and 8), while ring closure of
eight-membered rings to give bicyclo[5.x.1]alkenes does not
occur (entries 3, 9 and 10). Variation of the reaction tem-
perature, concentration of the diene and catalyst type (Mo
catalyst5) had no influence on the formation of the eight-
membered rings, as starting material and oligomers were the
only products isolated. 
Formation of the bicyclo-[3.2.1]- and -[3.3.1]-alkenes when
the six-membered ring is being closed is extremely facile
(entries 1 and 6). In general, as the ring closure becomes slower,
other processes such as dimerization may start to compete.
Lower concentration disfavors the intermolecular coupling
relative to the intramolecular ring closure, and allows clean
formation of the products. Raising the temperature to that of
refluxing CH2Cl2 was necessary only when the substrate was
sterically hindered (entries 4 and 5) or the cyclization was very
slow (entry 8).
The enthalpies of ring closure (including formation of
ethylene) were calculated using the MM2 forcefield and are
included in Table 1.6 In general, if the calculated enthalpy is less
than ca. 10 kcal mol21, the ring closure should be favorable due
to the entropy gain from the generation of ethylene. An
interesting comparision may be made between entry 5 and entry
3, both of which are calculated to have DH ≈ 13 kcal mol21.
For substrate 1 (entry 5), the kinetic favorability of ring closure
for five-membered rings, coupled with the loss of ethylene to
the atmosphere, drives the reaction to completion. Note that at
higher concentrations (entry 4), the yield is much lower, as a
result of a significant amount of polymer being formed,
suggesting that endothermic ring closures are possible if the
concentration is kept below the critical concentration for
polymerization. In the case of the eight-membered ring (entry
3), although the same loss of ethylene would occur, the ring
closure is sufficently slow as to be non-competitive with
polymerization. Linderman et al. have recently reported the use
of removable But3Sn groups to overcome the entropic barrier
allowing formation of eight-membered rings,7 a strategy that
could potentially be applied here. The molecular mechanics also
suggest that the silyl-protected alcohol plays a small role in the
cyclization by decreasing the enthalpy of the ring flip to the bis-
axial conformer needed for the ring closure by ca. 1 kcal mol21
relative to the unprotected alcohol.
In conclusion, a number of small ring bridged bicycloalkenes
have been synthesized from monocyclic dienes, demonstrating
the power of ring closing metathesis to form carbocycles that
contain a significant amount of strain.
A. T. M. acknowledges a postdoctoral fellowship from the
National Institutes of Health (USA). We also thank Professor
Dennis Dougherty for the use of the SGI Power Impact
workstation and the software packages used for the calculations
referred to in this paper.
Table 1 Conversion and ethalpies for ring closure of monocyclic dienes
DHa/
Entry Substrate n m Conc./m [Ru] (mol%) T/°C Yield (%) kcal mol21
1 1a 0 1 0.050 5 RT 87 1.2
2 1b 0 2 0.005 5 RT ( > 95 Conv.)b 6.9
3 1c 0 3 0.005 10 Reflux Oligo 13.1
4 1d 1 0 0.050 5 Reflux 41 13.3
5 1d 1 0 0.005 10 Reflux 84 13.3
6 1e 1 1 0.050 5 RT 95 1.7
7 1f 1 2 0.050 5 RT Trace 10.0
8 1f 1 2 0.005 10 Reflux 96 10.0
9 1g 1 3 0.050 5 RT Oligo 17.5
10 1g 1 3 0.005 10 Reflux Oligo 17.5
a MM2 Calculations. b Conversion by NMR spectroscopy.
Chem. Commun., 1998 275
Footnotes and References
* E-mail: rhg@cco.caltech.edu
† The substrates were synthesized by addition of the appropriate Grignard
reagent to 3-vinylcyclohexanone or cyclopentanone, and protection of the
tertiary alcohol with the tert-butyldimethylsilyl group. The cis and trans
isomers could be separated for the six- membered ring substrates, but not the
five-membered ring substrates. The five-membered ring substrates were
cyclized as mixtures and the product separated from the uncyclized trans
diene by chromatography.
‡ Typical experiment procedure for 1-(tert-butyldimethylsilyloxy)-
bicyclo[3.3.1]non-6-ene (2e). The silyl ether protected diene 1e (630 mg,
2.25 mmol) was dissolved in 45 ml CH2Cl2 and treated with [Cl2(Cy-
3P)2RuCHPh (ref. 5) 92.4 mg, 0.11 mmol, 0.05 equiv.]. The initial red
solution rapidly turned light brown, was stirred for 4 h, and the solvent was
removed. The brown oil was purified by filtration through silica gel using
hexane as the eluent to give a clear oil (540 mg, 2.14 mmol, 95%): dH (300
MHz, CDCl3) 0.08 (s, 6 H), 0.86 (s, 9 H), 1.34–1.38 (m, 2 H), 1.45–1.86 (m,
6 H), 2.13–2.32 (m, 2 H), 2.56–2.60 (m, 1 H), 5.52–5.57 (m, 1 H), 5.69–5.74
(m, 1 H); dC (75 MHz, CDCl3) 21.7, 17.9, 19.7, 25.8, 28.1, 34.2, 41.0, 42.4,
42.7, 71.9, 127.8, 129.0; n(film)/cm21 3023, 2930, 2855, 1472, 1253, 1112,
1013, 835.
1 For recent reviews of RCM see: R. H. Grubbs, S. J. Miller and G. C. Fu,
Acc. Chem. Res., 1995, 28, 446; H.-G. Schmalz, Angew. Chem., Int. Ed.
Engl., 1995, 34, 1833.
2 For selected examples see: S. F. Martin, Y. Liao, Y. Wong and T. Rein,
Tetrahedron Lett., 1994, 35, 691; B. C. Borer, S. Deerenberg,
H. Beiraugel and U. K. Pandit, Tetrahedron Lett., 1994, 35, 3191;
A. F. Houri, Z. Xu, D. A. Cogan and A. H. Hoveyda, J. Am. Chem. Soc.,
1995, 117, 2943; J. S. Clark and J. G. Kettle, Tetrahedron Lett., 1997, 38,
123 and 127; A. Fu¨rstner and K. Langemann, J. Org. Chem., 1996, 61,
8746; A. Kinoshita and M. Mori, J. Org. Chem. 1996, 61, 8356;
K. C. Nicolaou, Y. He, D. Vourloumis, H. Valberg and Z. Yang, Angew.
Chem., Int. Ed. Engl., 1996, 35, 2399.
3 M. D. E. Forbes, J. T. Patton, T. L. Myers, H. D. Maynard, D. W. Smith,
Jr., G. R. Schulz and K. B. Wagener, J. Am. Chem. Soc., 1992, 114,
10 978.
4 P. Schwab, R. H. Grubbs and J. W. Ziller, J. Am. Chem. Soc., 1996, 118,
100.
5 R. R. Schrock, J. S. Murdzek, G. C. Bazan, J. Robbins, M. DiMare and
M. O’Regan, J. Am. Chem. Soc., 1990, 112, 3875.
6 The molecular mechanics calculations were performed using the MM2
forcefield as implemented in the SPARTAN (ver. 4.1.1, Wavefunction,
Inc., 18401 Von Karman Ave., #370, Irvine, CA, 92715 USA, © 1995
Wavefunction, Inc.) and MACROMODEL (F. Mohamadi, N. G. J.
Richards, W. C. Guida, R. Liskamp, M. Lipton, C. Caufield, G. Chang,
T. Hendrickson and W. C. Still, J. Comput. Chem., 1990, 11, 440, ver.
3.5a, Dept. of Chemistry, Columbia University, NY, 10027) software
packages.
7 R. J. Linderman, J. Siedlecki, S. A. OANeill and H. Sun, J. Am. Chem.
Soc., 1997, 119, 6919.
Received in Corvallis, OR, USA, 25th August 1997; 7/06200A
276 Chem. Commun., 1998


Formation of bridged bicycloalkenes via ring closing metathesis

Andrew Morehead Jr.

Robert Grubbs

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For recent reviews of RCM see:

of Chemistry,

The molecular mechanics calculations were performed using the MM2 forcefield as implemented in the SPARTAN (ver. 4.1.1, Wavefunction, Inc., 18401 Von Karman Ave.,

http://authors.library.caltech.edu/28751/1/MORcc98.pdf

Formation of bridged bicycloalkenes via ring closing metathesis

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