Ruthenium-catalyzed olefin cross-metathesis tolerates a wide range of functional groups, including phosphine-boranes, sulfides, amines, phenols, and oxazolines. The high functional group tolerance allows for the use of an olefin as a linchpin for the synthesis of a variety of bi-, tri-, and tetradentate chiral ligands with a high degree of functional group diversity

Chatterjee, Arnab K.

Grubbs, Robert H.

Toste, F. Dean

Caltech Authors - Main

Pure Appl. Chem., Vol. 74, No. 1, pp. 7–10, 2002.
© 2002 IUPAC
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Functional group diversity by ruthenium-
catalyzed olefin cross-metathesis*
F. Dean Toste, Arnab K. Chatterjee, and Robert H. Grubbs‡
The Arnold and Mabel Beckman Laboratory of Chemical Synthesis, Division of
Chemistry and Chemical Engineering, California Institute of Technology, Pasadena,
California 91125, USA
Abstract: Ruthenium-catalyzed olefin cross-metathesis tolerates a wide range of functional
groups, including phosphine-boranes, sulfides, amines, phenols, and oxazolines. The high
functional group tolerance allows for the use of an olefin as a linchpin for the synthesis of a
variety of bi-, tri-, and tetradentate chiral ligands with a high degree of functional group
diversity.
The increasing necessity for the synthesis of diverse libraries of compounds demands the development
of methods that tolerate a wide range of functional groups. The formation of carbon–carbon bonds by
olefin metathesis [1] offers a powerful method for the creation of chemical diversity [2]. In particular,
olefin cross-metathesis (CM) can provide access to alkenes bearing a wide range of functional groups
[3]. However, the reaction has generally been limited to olefins in which functional groups that may
behave as ligands for the catalyst are absent. Herein are detailed our studies on the use of heteroatom
containing olefins in the cross-metathesis reaction and applications of this method to the generation of
a variety of 2-oxazolylphenol-derived tridentate chiral ligands.
The study was initiated by the observation that ruthenium catalyst 1 readily catalyzed the ring-
closing metathesis (RCM) of diallyl disulfide to afford cyclic disulfide 2 in 90% yield. This result is in
sharp contrast to the first-generation bis-phosphine catalyst [(PCy3)2Ru(CHPh)Cl2], which was shown
to be completely unreactive in this transformation [4]. This observation prompted us to explore the pos-
sibility that catalyst 1 may tolerate olefins bearing functional groups that were poor substrates for the
first-generation catalyst. To this end, allyl methyl sulfide was reacted with 5 mol% 1 to afford the dis-
ubstituted olefin 3 in 69% yield as a 6:1 mixture of E:Z olefin isomers [5].
*Lecture presented at the 11th IUPAC International Symposium on Organometallic Chemistry Directed Towards Organic
Synthesis (OMCOS-11), Taipei, Taiwan, 22–26 July 2001. Other presentations are presented in this issue, pp. 1–186.
‡Corresponding author
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The fact that catalyst 1 tolerates olefins substituted with an allylic sulfide suggested that other
functional groups that could behave as ligands for ruthenium might be viable substrates. In an extreme
case, the reaction of allyl diphenylphosphine with 5 mol% 1 failed to produce any of the desired cross-
metathesis adduct and returned terminal olefin unreacted. This problem was readily remedied by pro-
tection of the phosphine as its borane complex [6]. Catalyst 1 catalyzed the dimerization of borane
complexes of allyl diphenyl and dicyclohexylphosphine to produce bisphosphines 4a and 4b in 80%
(>95:5, E:Z) and 42% (13:1, E:Z) yield, respectively. 
Notably, catalyst 1 failed to dimerize borane-protected vinyl diphenylphosphine. Protected allyl
phosphines are not limited to simple dimerization reactions and may be employed as substrates for
cross-metathesis. For example, reaction of borane-protected allyl diphenylphosphine with 
4-nitrosytrene or 2-methylbutene-2-ol produces phosphines 5 and 6 in 71% and 63% yield, respective-
ly. In the case of 6, hydrogenation of the olefin and deprotection of the phosphine results in the forma-
tion of a P,O-bidentate ligand. Substitution of other oxidation states of phosphorus at the allylic posi-
tion is also tolerated [7]. For example, 5 mol% of 1 produces phosphine oxide 7 in 90% yield as a sin-
F. D. TOSTE et al.
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gle olefin isomer from the coupling of allyl diphenylphosphine oxide with 2-butene-1,4-diacetate.
Similarly, reaction of diethyl allylphosphonate with ethyl acrylate, catalyzed by 5 mol% 1, produces 8
in 87% yield with complete control of olefin geometry.
N-Allyl amines were also examined as partners in cross-metathesis reactions. It was found that
N-aryl-N-allyl amine readily participates in the reaction with 5-hexenyl acetate to produce amine 9 in
63% yield as a 3.3:1 mixture of trans:cis olefin isomers. This reaction stands in sharp contrast to
attempted reactions with Fmoc- and Boc-protected allyl amine, which failed to produce any of the
desired product and resulted primarily in conversion of the allyl amines into enamines [8]. 
The successful cross-metathesis of an unprotected N-allyl amine prompted us to examine the pos-
sibility of applying catalyst 1 for the preparation of a family of 2-oxazolylphenols [9]. Oxazoline 10
was prepared by zinc chloride-catalyzed [10] reaction of 2-cyanophenol with the amino alcohol derived
from allylglycine. We were pleased to find that 5 mol% 1 catalyzed the cross-metathesis of 10 to afford
a 64% yield of the dimer as a 5:1 mixture of trans:cis olefin isomers. The control of olefin geometry is
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irrelevant as the olefin was hydrogenated to afford 11, which may serve as salen-like ligand. Similarly,
oxazoline 12 (available from the Claisen rearrangement of the corresponding O-allyl aryl ether) is read-
ily dimerized with catalyst 1 to produce a 4:1 mixture of E:Z olefin isomers, which are subsequently
hydrogenated. The ability of catalyst 1 to tolerate 2-oxazolylphenol-substituted olefins is noteworthy
since it has been shown that Schiff-based ligands (sal) can serve as excellent ligands for related ruthe-
nium complexes [11]. Apparently, the exceptional reactivity of 1 toward olefins [12] exceeds its reac-
tivity towards this bidentate ligand. With these results in hand, we were able to prepare a small family
of potentially tridentate 2-oxazolylphenol ligands by the cross-metathesis of 10 with an olefin contain-
ing a functional group which could serve as the third coordinating group. For example, 5 mol% 1 cat-
alyzed the reaction of 10 with allyl methyl sulfide to produce 16, which after hydrogenation of the
olefin, may serve as a O,N,S-tridentate chiral ligand. Similarly, deprotection of the phosphine and
hydrogenation of the olefin are required to convert 17 into a O,N,P-tridentate chiral ligand. 
In conclusion, we have demonstrated that catalyst 1 tolerates functional groups that had been
detrimental to the catalytic activity of previous ruthenium metathesis catalysts. This increased scope
should further encourage the use of 1 and cross-metathesis as a method for creation of chemical diver-
sity. The ability of 1 to create structures with functional group diversity was demonstrated by the prepa-
ration of a small family of 2-oxazoylphenol chiral ligands.
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F. D. TOSTE et al.
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Functional group diversity by ruthenium-catalyzed olefin cross-metathesis

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Functional group diversity by ruthenium-catalyzed olefin cross-metathesis

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