Solid-supported cross metathesis and the role of the homodimerization of the non-immobilized olefin

Article abstract of DOI:10.1021/jo7025433

(Chemical Equation Presented) We have prepared immobilized olefins as models for the cross metathesis using different olefin partners in the presence of second generation Grubbs and Hoveyda-Grubbs precatalysts. We have demonstrated that solid-phase cross metathesis is strongly dependent on the degree of homodimerization of the non-immobilized olefin and the reactivity of such a homodimer. As in the homogeneous phase, the Hoveyda-Grubbs precatalyst was better for immobilized α,β-unsaturated carbonyl compounds.

Full text of DOI:10.1021/jo7025433

Solid-Supported Cross Metathesis and the Role of
the Homodimerization of the Non-immobilized
Olefin
Andre´s A. Poeylaut-Palena, Sebastia´n A. Testero, and
Ernesto G. Mata*
FIGURE 1. Grubbs and Hoveyda-Grubbs precatalysts.
Instituto de Qu´ımica Rosario, Facultad de Ciencias Bioqu´ımicas
y Farmace´uticas, UniVersidad Nacional de Rosario-CONICET,
Suipacha 531, S2002LRK Rosario, Argentina
The site isolation on the polymeric matrix makes homodimer-
ization of the immobilized olefin a considerably less favorable
process. (ii) The olefin that remains in solution can be added
in excess in order to drive the reaction to completion (its homo-
dimer can be eliminated easily by simple filtration, avoiding
time-consuming separation techniques). (iii) Automation can be
easily accomplished.
mata@iquios.goV.ar
ReceiVed NoVember 27, 2007
Despite its enormous potential, few example of alkene cross
metathesis on solid phase can be found in the literature.3,4 The
increase in activity from the first generation Grubbs precatalyst
(1) (Figure 1) to those of the second generation (2 and 3) further
improves the importance of an efficient application of alkene
cross metathesis to a solid support.5
Herein, we wish to report a study on the solid-supported olefin
cross metathesis by different ruthenium carbene complexes in
order to contribute to the understanding of the reaction under
the particular environment of the solid-phase chemistry.
We prepared three Wang resin-immobilized olefins (4a-c)
that were employed as models for the cross metathesis using
different olefin partners (5) (Scheme 1). These non-immobilized
olefin partners were chosen by taking into account the olefin
classification recently reported by Grubbs et al. that established
a rule for olefin cross metathesis selectivity.2 Type-I olefins are
those that undergo fast homodimerization; type-II go through a
slow homodimerization; type-III do not undergo homodimer-
ization, and type-IV are spectators to CM. Which olefin belongs
to which category depends on the catalyst used. In the case of
having one of the olefins immobilized, such as in solid-phase
metathesis, this classification could be useful to understand the
behavior of the olefin partner.
Under our optimized conditions, the resin (4a-c) was heated
to reflux in DCM for 20 h with excess olefin (5) and the
corresponding ruthenium carbene complex. The amount of the
precatalyst was kept to a minimum (5 mol %) in order to reduce
the formation of ruthenium metal byproducts to get both a less
ruthenium-contaminated resin and a less contaminated product.
The resin was resubjected to the same reaction conditions to
ensure the formation of the coupled product (7, 10, 12) which
was then released from the resin with 10% TFA/DCM.
We have prepared immobilized olefins as models for the
cross metathesis using different olefin partners in the
presence of second generation Grubbs and Hoveyda-Grubbs
precatalysts. We have demonstrated that solid-phase cross
metathesis is strongly dependent on the degree of homo-
dimerization of the non-immobilized olefin and the reactivity
of such a homodimer. As in the homogeneous phase, the
Hoveyda-Grubbs precatalyst was better for immobilized
R,â-unsaturated carbonyl compounds.
The emergence of structurally well-defined catalysts has
established the olefin metathesis as an outstanding tool for
modern organic and polymer synthesis.1 Particularly, cross
metathesis (CM) represents an interesting alternative to more
traditional carbon-carbon bond forming reactions. In addition
to the mild reaction conditions, functional group tolerance, high
activity, and stability of modern olefin metathesis precatalysts,
CM requires little synthetic labor in the preparation of starting
material. Alkenes are readily available materials compared to
vinyl stannanes, vinyl halides, and boronates, which are usually
required in more classical transition metal cross-coupling
reactions (e.g. Stille, Heck, and Suzuki). Furthermore, CM is
especially useful in stepwise syntheses since it allows the use
of functionalized olefin substrates and since functional groups
can take part in subsequent reactions avoiding the employment
of protecting groups.
(2) A great improvement in olefin cross metathesis selectivity has been
achieved through the recent advances in catalyst design and the development
of empirical models for predicting the outcome of cross metathesis reactions.
See: Chatterjee, A. K.; Choi, T.; Sanders, D. P.; Grubbs, R. H. J. Am.
Chem. Soc. 2003, 125, 11360.
(3) For previous reports on cross metathesis of polymer-supported olefins
under first generation Grubbs catalyst, see: (a) Schuster, M.; Pernerstorfer,
J.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1996, 35, 1979. (b) Breed, P.
G.; Ramsden, J. A.; Brown, J. M. Can. J. Chem. 2001, 79, 1049.
(4) For previous reports on cross metathesis of polymer-supported olefins
under second generation Grubbs catalyst, see: (a) Chang, S.; Na, Y.; Shin,
H. J.; Choi, E.; Jeong, L. S. Tetrahedron Lett. 2002, 43, 7445. (b) Testero,
S. A.; Mata, E. G. Org. Lett. 2006, 8, 4783. (c) Garner, A. L.; Koide, K.
Org. Lett. 2007, 9, 5235.
However, application of alkene cross metathesis in synthetic
chemistry is far behind its ring-closing counterpart, mainly due
to the difficulty of avoiding the formation of unwanted
homodimeric products.2 In contrast, immobilization of one of
the olefin substrates has a series of potential advantages: (i)
(1) (a) Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. (b) Connon,
S. J.; Blechert, S. Angew. Chem., Int. Ed. 2003, 42, 1900. (c) Fu¨rstner, A.
Angew. Chem., Int. Ed. 2000, 39, 3012. (d) Hoveyda, A. H.; Gillingham,
D. G.; Van Veldhuizen, J. J.; Kataoka, O.; Garber, S. B.; Kingsbury, J. S.;
Harrity, J. P. A. Org. Biomol. Chem. 2004, 2, 8. (e) Nicolaou, K. C.; Burger,
P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4490. (f) Giessert, A.
J.; Diver, S. T. Org. Lett. 2005, 7, 351.
(5) Straub, B. F. Angew. Chem., Int. Ed. 2005, 44, 5974.
10.1021/jo7025433 CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/08/2008
2024
J. Org. Chem. 2008, 73, 2024-2027

SCHEME 1. Solid-Phase Olefin Cross Metathesis
due to the rapid formation of the essentially inactive dimer 6b.
Very efficient CM was achieved using 4-vinylbenzyl chloride
(5c) (80%) (entry 3). In this case, it can be concluded that the
active monomer contributes largely to the formation of the CM
product (11c), given that homodimerization is slow (20 h) and
the homodimer gave lower reaction yield (58%) (entry 9). In
the middle range was 4-phenyl-1-butene (5d) in which both
monomer 5d and homodimer 6d gave CM product in moderate
yields (entries 4 and 10).
On the other hand, when a prototypical “type-II” olefin was
used [e.g., crotonic acid (5e)], the coupling product (11e) was
obtained in a quantitative manner (entry 5). Although crotonic
acid is an electron-deficient olefin, reaction was favored by the
forced conditions (reflux, large excess of olefin), while homo-
dimerization was negligible. Resin-supported cross metathesis
is then an alternative to Horner-Wadsworth-Emmons for the
solid-phase synthesis of cinnamic acid derivatives.7 In the case
of using 2-bromostyrene (5f), another type-II olefin, CM product
11f was obtained in lower (although still acceptable) yield (43%)
(entry 6). The extra steric hindrance of the bromine atom can
be the reason for the lower yield by affecting the approach to
the polymer matrix.
Different acrylate derivatives were obtained by cross meta-
thesis when commercially available acryloyl Wang resin (4c)
was used as immobilized starting material (Scheme 1 and Table
1). While the role of the non-immobilized homodimers was
essentially the same as that of the resin 4b, reaction of resin 4c
with type-I and type-II olefins was not very successful in the
presence of second-generation Grubbs precatalyst 2. Yields of
the CM products 13 ranged from 11 to 35% (entries 11-14).
However, the use of the newly developed Hoveyda-Grubbs
precatalyst 3 (Figure 1)8 substantially increases the yields of
the CM products. In the case of type-I non-immobilized olefins,
such as allyl benzene (5a), 4-vinylbenzyl chloride (5c), and
4-phenyl-1-butene (5d) yields were increased 2-fold or more
(entries 11-13). Precatalyst 3 has been reported as the best
catalyst for R,â-unsaturated carbonyl compounds,9 and when
that olefin is also an immobilized one, the advantage of this
precatalyst seems to be even more clear.
In summary, we report a study in order to establish guidelines
for the solid-supported olefin cross metathesis by ruthenium
carbene complexes. Thus, it can be concluded that homodimer-
ization of the non-immobilized olefin plays a key role in solid-
phase CM. Very high yields were obtained when a type-I, easily
homodimerizable olefin, was used, as long as that homodimer
was also very reactive. Type-II olefins usually gave high yields
since homodimerization was slow. Type-I olefins, which
undergo fast homodimerization to generate an unreactive dimer,
generally afforded low CM yields. As in the homogeneous
phase, the Hoveyda-Grubbs precatalyst (3) has distinctive
properties for CM involving R,â-unsaturated carbonyl com-
pounds. We hope that this study could lead to a more general
Esterification with diazomethane followed by flash chromatog-
raphy afforded desired products (8, 11, 13) (Scheme 1). Initial
attempts with immobilized pentenoic acid (4a) gave disappoint-
ing results. Reaction of type-I olefins, such as allyl benzene
(5a) or 4-vinylbenzyl chloride (5c) in the presence of second
generation Grubbs precatalyst (2),6 afforded after cleavage from
the resin and subsequent esterification a mixture of desired
product (8a or 8c), with 4-octenedioic acid dimethyl ester (9).
We envisioned that a more rigid system such as resin 4b could
avoid those site-site interactions. Thus, when a similar synthetic
sequence was applied to the coupling between resin 4b and allyl
benzene (5a), the expected product, methyl 4-(3-phenyl-pro-
penyl)benzoate (11a), was obtained in excellent isolated yield
(86%) with no trace of the corresponding intra-site byproduct
(Table 1, entry 1). On the other hand and considering that the
non-immobilized olefin 5a was added in excess, formation of
the homodimer in the reaction media can influence the reaction
output. Under the optimized conditions, CM of olefin 5a in the
absence of the solid-supported olefin 4b gave the corresponding
homodimer (E)-1,6-diphenylhex-3-ene (6a) in very high yield
in just 15 min. As expected, when the homodimer 6a was
submitted to the CM with resin 4a, product 11a was isolated in
a yield similar to that obtained when using olefin 5a (compare
entries 1 and 7). It was clear that the homodimer 6a was the
reactive olefin in both cases.
Surprisingly, 4-methyl styrene (5b), which can be considered
as a type-I olefin according to Grubbs classification, gave only
31% yield of the CM product (11b) under similar reaction
conditions (entry 2). Explanation can be found in the formation
of the corresponding homodimer (6b). While 6b was obtained
in homogeneous phase in 2 h, it was unreactive to resin 4b
under our solid-phase conditions (entry 8). Even though
4-methyl styrene (5b) is very reactive, reaction was low yielding
(7) Reaction of Wang resin-bound 4-formyl benzoate with triethyl-
phosphonoacetate gave, after releasing from the resin and esterification,
the cinnamic acid derivative 11e in almost quantitative yield.
(8) (a) Kingsbury, J. S.; Harrity, J. P. A.; Bonitatebus, P. J., Jr.; Hoveyda,
A. H. J. Am. Chem. Soc. 1999, 121, 791. (b) Garber, S. B.; Kingsbury, J.
S.; Gray, B. L.; Hoveyda, A. H. J. Am. Chem. Soc. 2000, 122, 8168. (c)
Gillingham, D. G.; Kataoka, O.; Garber, S. B.; Hoveyda, A. H. J. Am. Chem.
Soc. 2004, 126, 12288.
(9) (a) Silva, F. A.; Gouverneur, V. Tetrahedron Lett. 2005, 46, 8705.
(b) Randl, S.; Gessler, S.; Wakamatsu, H.; Blechert, S. Synlett 2001, 430.
(c) Dewi, P.; Randl, S.; Blechert, S. Tetrahedron Lett. 2005, 46, 577. (d)
Ref 1d.
(6) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
J. Org. Chem, Vol. 73, No. 5, 2008 2025

TABLE 1. Solid-Phase Olefin Cross Metathesis by Ruthenium Carbene Complexes
a Overall isolated yield after flash column chromatography. b No reaction, starting material recovered.
mL) and diisopropylcarbodiimide (575 µL, 3.7 mmol, 5.0 equiv)
application of solid-supported olefin cross metathesis to the
generation of libraries of complex organic structures.
was added. The mixture was stirred for 30 min at room temperature
and transferred via cannula to Wang resin (677.2 mg, 1.1 mmol/g,
0.74 mmol), which was previously washed with anhydrous DMF
(5.0 mL). Dimethylaminopyridine (91.0 mg, 0.7 mmol, 1.0 equiv)
was added, and the reaction was magnetically stirred for 16 h. The
resin was washed with DMF (3 × 10 mL), MeOH (3 × 10 mL),
and DCM (3 × 10 mL) and dried under high vacuum. To determine
Experimental Section
General Procedure for the Solid-Phase Immobilization of
Olefins. As a representative procedure, vinylbenzoic acid (551.0
mg, 3.7 mmol, 5.0 equiv) was dissolved in anhydrous DMF (10
2026 J. Org. Chem., Vol. 73, No. 5, 2008

the vinylbenzoic acid loading, resin 4b (151.3 mg, 0.96 mmol/g,
0.14 mmol) was treated with 10% TFA in DCM and the acid was
in turn esterified with diazomethane to obtain methyl vinylbenzoate
(20.1 mg, 0.12 mmol, 0.78 mmol/g) in 85% yield.
General Procedure for the Obtention of the Homodimeric
Olefins (6a-d). As a representative procedure, the monomeric
olefin 5b (700.3 mg, 5.9 mmol) was dissolved in anhydrous
DCM (10.0 mL) and precatalyst 2 (25.0 mg, 0.5 mol %) was added.
The reaction was refluxed to starting material consumption
monitored by TLC (see the reaction times in Table 1). Solvent was
evaporated under reduced pressure to give a crude product, which
was purified flash column chromatography (hexane-DCM) to
General Procedure for the Solid-Phase Cross Metathesis by
Ruthenium Carbene Complexes. As a representative procedure,
resin-bound olefin 4b (192.3 mg, 0.15 mmol) was suspended in
anhydrous DCM (10 mL) and the non-immobilized olefin 5a (100
µL, 0.75 mmol, 5.0 equiv) was added via syringe under a nitrogen
atmosphere. Grubbs second generation catalyst 2 (6.4 mg, 7.5 µmol,
5 mol %) was added, and the flask was fitted with a condenser and
refluxed for 20 h, after which the resin was filtered, washed with
DCM (3 × 4 mL), MeOH (3 × 4 mL), and DCM (1 × 4 mL), and
dried under high vacuum. The resin was resubjected to the same
reaction conditions. Resin-bound olefin 10a (205.4 mg, 0.15 mmol)
was treated with 5 mL of 10% TFA in DCM for 1 h. The mixture
was filtered, and the filtrate was evaporated under reduced pressure
to give the crude product. This crude material was dissolved in
DCM and treated with diazomethane at 0 °C for 30 min. The solvent
was evaporated under reduced pressure, and the crude material was
purified by flash column chromatography (hexane-AcOEt) to
provide 6b (615.6 mg, 2.96 mmol) in 100% yield: IR νmax (cm-1
)
3019, 2912, 972, 822; 1H NMR (CDCl3, 300 MHz) δ 7.40 (d, J )
8.1 Hz, 4H), 7.15 (d, J ) 8.1 Hz, 4H), 7.03 (s, 2H, vinylic), 2.35
(s, 6H, CH3); 13C NMR (CDCl3, 75 MHz) δ 137.1, 134.6, 129.2,
127.5, 126.2, 21.1; HRMS m/z 209.1333 [(M + H+); calcd for
C16H17 209.1330].
Acknowledgment. Financial support from Consejo Nacional
de Investigaciones Cient´ıficas y Te´cnicas (CONICET), Agencia
Nacional de Promocio´n Cient´ıfica y Tecnolo´gica (ANPCyT),
and Universidad Nacional de Rosario from Argentina is
gratefully acknowledged. A.A.P.P. and S.A.T. thank ANPCyT
and CONICET for fellowships.
provide 11a (32.5 mg, 0.13 mmol) in 86% yield: IR νmax (cm-1
)
3027, 2950, 1720 (CO), 1605, 1279; 1H NMR (CDCl3, 300 MHz)
δ 7.95 (d, J ) 6.1 Hz, 2H, ArH), 7.40-7.22 (m, 7H, ArH), 6.6-
6.4 (m, 2H, H5-6), 3.90 (s, 3H, CH3O), 3.57 (d, J ) 4.9 Hz, 2H,
H7); 13C NMR (CDCl3, 75 MHz) δ 166.8, 141.9, 139.5, 132.1,
130.1, 129.8, 128.6, 128.5, 126.2, 126.0, 125.9, 51.9, 39.3; HRMS
m/z 253.1232 [(M + H+); calcd for C17H17O2 253.1229].
Supporting Information Available: Spectroscopic data, 1H
NMR and 13C NMR spectra of new compounds. This material is
available free of change via the Internet at http://pubs.acs.org.
JO7025433
J. Org. Chem, Vol. 73, No. 5, 2008 2027