The doping effect of fluorinated aromatic hydrocarbon solvents on the performance of common olefin metathesis catalysts: Application in the preparation of biologically active compounds

Article abstract of DOI:10.1039/b816567j

Aromatic fluorinated hydrocarbons, used as solvents for olefin metathesis reactions, catalysed by standard commercially available Ru precatalysts, allow substantially higher yields to be obtained, especially of challenging substrates, including natural an

Full text of DOI:10.1039/b816567j

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The doping effect of fluorinated aromatic hydrocarbon solvents
on the performance of common olefin metathesis catalysts: application
in the preparation of biologically active compoundsw
Cezary Samoj$owicz,a Micha$ Bieniek,a Andrzej Zarecki,a Renat Kadyrovb and Karol Grela*a
Received (in Cambridge, UK) 22nd September 2008, Accepted 7th October 2008
First published as an Advance Article on the web 22nd October 2008
DOI: 10.1039/b816567j
Aromatic fluorinated hydrocarbons, used as solvents for olefin
metathesis reactions, catalysed by standard commercially avail-
able Ru precatalysts, allow substantially higher yields to be
obtained, especially of challenging substrates, including natural
and biologically active compounds.
industrial processes and fulfil the recent guidelines of green
chemistry.5
Besides the evolutionary improvement of catalyst structures,3
research aimed at finding new reaction conditions that allow
more optimal use of standard commercially available catalysts
can be considered as a complementary approach.6 During a
recent profiling study of a set of commercially available Ru
catalysts, we noted that the rate of olefin metathesis of some
simple dienes was significantly enhanced when fluorinated
aromatic hydrocarbons (FAH), such as perfluorotoluene and
perfluorobenzene, were used as reaction media.7 Fluorine-
containing aromatic hydrocarbons PhCF3 and C6F6 have been
used previously as solvents in some metathesis reactions,8 but no
enhancements in metathesis rate were reported in these cases.9
Therefore, in the current study, we decided to explore the
applicability and the generality of this unexpected activating
effect in the metathesis of selected ‘‘challenging’’ olefins,
including natural-like substrates. To gain an insight into this
new activating effect, a set of comparative metathesis experi-
ments catalysed by commercially available Ru initiators was
attempted in ‘‘classical’’ metathesis solvents (toluene and
1,2-dichloroethane) and in FAH under otherwise identical
conditions (catalyst loading, time, concentration and
temperature).z
Recent decades have seen burgeoning interest in olefin meta-
thesis, as witnessed by the rapidly growing number of elegant
applications.1 Using this tool, chemists can now efficiently
synthesize an impressive range of molecules that only a decade
ago required significantly longer and more tedious routes. The
development of efficient and selective catalysts 1–3 is the key to
the widespread application of olefin metathesis in organic
synthesis.1
In more advanced applications of olefin metathesis, espe-
cially in the total synthesis of natural and biologically active
compounds, commercially available Ru catalysts 1–3 do not
always lead to satisfactory conversions.2 To solve this limita-
tion, a lot of research effort has been directed to designing
improved catalysts that might allow for better results in
‘‘difficult’’ cases.3 A recently published total synthesis of
largazole, a natural product exhibiting broad anti-cancer
activity, represents a convincing example, where improved
catalysts were used to counteract the low potency of commer-
cially available initiators for this substrate.4 Another limita-
tion of commercially available initiators applied to total
synthesis is that relatively high loadings of catalysts (up to
25–40 mol%) are often required, resulting in the sub-optimal
use of this powerful methodology.2,5 Nowadays, it is desirable
to use expensive and potentially toxic heavy metal-based
catalysts more efficiently in order to reduce the costs of
The formation of tetrasubstituted double bonds typically
requires high catalyst loadings, and even then doesn’t lead to
quantitative yields.10 It is believed that di(methylallyl)malonate
(s1) is a very challenging model substrate for Ru catalysts,
giving 1b and 3b in only 17 and 6% yield, respectively
(5 mol%, CH2Cl2, 30 1C, 96 h).10a Catalyst 1c, applied at a
higher temperature, was reported to give only 47% of the
product (5 mol%, toluene, 80 1C, 24 h; GC yield).10b Therefore,
we selected this reaction as the first trial in our study. As a
result, we found that the observed activating effect was of a
quite general nature, as all the catalysts tested lead to higher
yields in FAH compared to ‘‘classical’’ conditions (Scheme 1).
The activity increase was quite substantial, as in the most
pronounced case of 3b, it was possible to increase the reaction
yield 18-fold, simply by changing the solvent from 1,2-dichloro-
ethane to perfluorotoluene. Encouraged by these results, we
attempted to test FAH in the metathesis of selected natural or
biologically active substrates (Scheme 2). Diene s2, a derivative
of (ꢀ)-isopulegol, a monoterpenic alcohol that is widely em-
ployed in the flavour and perfume industry,11 was chosen as a
representative challenging substrate. The ring-closing metathesis
(RCM) of s2, where a tetrasubstituted double bond is formed,
lead to incomplete conversion in 1,2-dichloroethane, while the
a Institute of Organic Chemistry, Polish Academy of Sciences,
Kasprzaka 44/52, 01-224 Warsaw, Poland.
E-mail: klgrela@gmail.com; Fax: +49 22-632-66-81
b Evonik Degussa GmbH, Rodenbacher Chaussee 4, 63457
Hanau-Wolfgang, Germany. E-mail: renat.kadyrov@evonik.com;
Fax: +49 6181-59-78710
w Electronic supplementary information (ESI) available: Experimental
procedures for the preparation of the starting materials, RCM and
CM in FAH, and the characterisation of the products. See DOI:
10.1039/b816567j
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with 1b. Importantly, applying perfluorotoluene as the solvent
allowed an increase in yield to 50%. Again, the activating
effect of the FAHs was observed for all the catalysts tested.
CM reactions have gained increased importance in the
synthesis of natural and biologically active products in recent
years.13 Therefore, the CM reactions of two advanced sub-
strates (Scheme 4) were selected to reveal the potential utility
of FAH solvents in target-oriented synthesis.
The functionalisation of steroid cores by olefin CM has
become an important tool in the pharmaceutical industry.
Recently, we reported the synthesis of new 17b-hydroxysteroid
dehydrogenase type 1 inhibitors—drug candidates in estradiol-
dependent diseases such as breast cancer or endometriosis—
via the CM of allylestrone with various acrylic acid
derivatives.15 Kotora et al. have published a study on the
perfluoroalkylation of some steroid derivatives through CM
reactions with (perfluoroalkyl)propenes.16a We decided to test
the potential of FAHs in similar reactions, because fluorine-
containing compounds are popular targets in the pharmaceu-
tical industry.16b The CM of functionalised alkenes and
fluorinated olefins has previously been studied by Blechert
et al.8a When (perfluorobutyl)ethylene was used as both the
CM partner and solvent, it was found that a,a,a-trifluoro-
toluene could be used as an additive to overcome the insolubility
of the Ru catalysts in the reaction medium.8a However, no
enhancement in the metathesis rate of 3b was reported in
connection with use of this co-solvent. To look more closely at
this phenomenon, we executed a CM reaction between
3b-pent-4-enoyloxy-17,17-ethylenedioxy-5-androstene (s5)17 and
(perfluorohexyl)ethylene in two solvents, 1,2-dichloroethane
and perfluorobenzene, under otherwise identical conditions
(Scheme 4). Importantly, it was found that in the latter
medium, CM proceeded in a much more productive and
selective fashion, while in the ‘‘classical’’ solvent, the reaction
suffered from low conversion and selectivity, with the
unwanted homo-cross metathesis product, p50, being formed
in large quantities (Scheme 4). Finally, to determine the scope
of the enabling effect of FAHs with respect to structural
variations in substrates, we tested the CM reaction of acid
s6, a distant relative of the fluoroquinolone antibacterial
agent moxifloxacin,18 with 3,3-dimethyl-1-butene (Scheme 4).
Modification at the terminal vinyl positions, leading to the
corresponding tert-butyl-substituted alkenes, can be proble-
matic in some cases.19 Therefore, we were pleased to find that
our new conditions allowed a much higher yield to be obtained
in this case.
Scheme 1 Model RCM reaction. Conditions: 2 mol% of catalyst,
C[s1] = 0.02 M, 70 1C, 3 h; nd = not determined. Yields calculated
by GC.
Scheme 2 RCM of (ꢀ)-isopulegol (s2) and Vitamin D2 (s3) deriva-
a
tives. Isolated yields after column chromatography. Conversions
1
calculated by H NMR are in parentheses; nd = not determined.
use of perfluorotoluene provided quantitative conversion under
otherwise identical conditions (loading, temperature, time).
Pentaene s3, derived from 7,8-dihydroxy-7,8-dihydrovitamin
D2,12a was tested by us previously and considered to be rather
problematic under ‘‘classical’’ conditions.12b Therefore, we
were pleased to find that in the case of this polyfunctional
substrate, the use of FAH also lead to much improved results
(Scheme 2).
Next, we tested cross-metathesis (CM), the second most
popular variant of olefin metathesis.13 To estimate the poten-
tial of our newly developed conditions, we focused only on the
most demanding cases, such as the CM of substituted or
electron deficient alkenes.13 The results presented in
Scheme 3 show that in 1,2-dichloroethane, the commercially
available Ru catalysts were not potent in CM between gemin-
ally disubstituted14 s4 and (Z)-1,4-diacetoxy-2-butene. In
1,2-dichloroethane, the highest yield (27%) was obtained
In accordance with assumptions made by the groups of
Furstner,10b Ledoux,20 Blechert9c and Collins,9d we think that
¨
the formation of p–p complexes between N-mesityl groups of
the NHC ligand that is present in second generation Ru
catalysts and the FAH solvent molecules plays a role in the
observed catalyst activity enhancement. Although the exact
nature of the observed effect is not yet clear,21 we foresee its
practical importance as a method for the in situ activation of
commercial metathesis catalysts.y We expect that this techni-
que will find applications in the synthesis of advanced natural
and biologically active compounds, where any increase in yield
is of high importance, especially when the metathesis step is
applied at a late stage of a total synthesis. Detailed studies on
Scheme 3 Model CM reaction. Conditions: C[s4] = 0.02 M, 5 mol%
of catalyst, 70 1C, 3 h. Yields calculated by GC.
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a
Scheme 4 The CM of substrates s5 and s6. Isolated yields after column chromatography; conversions calculated by 1H NMR are shown in
parentheses. 1,2-Dichloroethane was used as a co-solvent to increase the solubility of s6 in the reaction medium; nd = not determined.
b
the nature and scope of the activating effect of FAHs are
ongoing in our laboratory, and will be published in due course.
C. S. thanks the Foundation for Polish Science (‘‘Ventures’’
Programme) for financial support.
(c) J. C. Conrad, D. Amoroso, P. Czechura, G. P. A. Yap and
D. E. Fogg, Organometallics, 2003, 22, 3634.
9 (a) For the activation of fluorous Ru catalysts in aliphatic fluorous
media, see: R. Corrae da Costa and J. A. Gladysz, Chem.
Commun., 2006, 2619; (b) R. Corrae da Costa and J. A. Gladysz,
Adv. Synth. Catal., 2007, 349, 243; During preparation of this
manuscript, two significant reports on the observed promoting
effect of C6F6 in olefin metathesis have appeared: (c) D. Rost,
M. Porta, S. Gessler and S. Blechert, Tetrahedron Lett., 2008, 49,
5968; and (d) A. Grandbois and S. K. Collins, Chem.–Eur. J.,
2008, 14, 9323.
Notes and references
z Solvents used in comparative experiments were distilled from CaH2
and stored under argon. A representative procedure for the the CM
reaction of s5: To a solution of s5 (132.7 mg, 0.32 mmol) and
(perfluorohexyl)ethylene (1.1 g, 3.2 mmol) in deoxygenated anhydrous
hexafluorobenzene (6.5 ml) was added 2b as a solid (0.016 mmol,
5 mol%). The resulting mixture was stirred under argon at 60 1C for
20 h. The solvent was removed under reduced pressure.y The crude
product was purified by flash chromatography, yielding product p5 as
a colourless solid (210.6 mg, 0.287 mmol).
10 (a) T. Ritter, A. Hejl, A. G. Wenzel, T. W. Funk and R. H. Grubbs,
Organometallics, 2006, 25, 5740; (b) A. Furstner, L. Ackermann,
¨
B. Gabor, R. Goddard, C. W. Lehmann, R. Mynott, F. Stelzer and
O. R. Thiel, Chem.–Eur. J., 2001, 7, 3236.
11 The Chemistry of Fragrances, ed. D. H. Pybus and C. S. Sell, Royal
Society of Chemistry, Cambridge, UK, 1999.
12 (a) H. T. Toh and W. H. Okamura, J. Org. Chem., 1983, 48, 1414;
(b) A. Zarecki and K. Grela, unpublished results.
y It should be noted that the expensive fluorinated solvents can be fully
recovered by distillation after reactions and reused.
13 For a review, see: S. J. Connon and S. Blechert, Angew. Chem., Int.
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1 R. H. Grubbs, Handbook of Metathesis, Wiley-VCH, Weinheim,
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6284 | Chem. Commun., 2008, 6282–6284