Ortho- and para-substituted Hoveyda-Grubbs carbenes. An improved synthesis of highly efficient metathesis initiators

Article abstract of DOI:10.1021/jo049222w

A novel highly efficient and general route to various 3- and 5-substituted 2-alkoxystyrenes, required for the preparation of Hoveyda-Grubbs catalysts, is described.

Full text of DOI:10.1021/jo049222w

rone.6 Despite lower initiation activities, the use of cata-
lysts 3 and 4 was proved to be advantageous in many
cases, particularly in reactions of electron-deficient ole-
fins.7
Or th o- a n d P a r a -Su bstitu ted
Hoveyd a -Gr u bbs Ca r ben es. An Im p r oved
Syn th esis of High ly Efficien t Meta th esis
In itia tor s†
Recently, Wakamatsu and Blechert8 have shown that
the complex 5, substituted ortho to the chelating isopro-
poxy ligand, initiates dramatically faster than the parent
catalyst 3, while retaining the excellent air and moisture
stability. Our group has recently introduced the stable
5-nitro-substituted analogue 6, which was shown to
exhibit impressive activity in ring-closing (RCM), cross
(CM), and enyne metathesis.10 As a result, this highly
active catalyst has found a successful application in
target-oriented syntheses.10c-e The higher activity of 5
may be the result of faster initiation of the catalytic cycle
as a result of a more facile release of the sterically
demanding phenyl-substituted benzylidene.9,10 Similarly,
the electron-withdrawing NO2 para to the ligating i-PrO
in 6 would weaken O f Ru chelation and facilitate faster
initiation of the catalytic cycle.10
Robert Bujok,‡ Michal Bieniek,‡ Marek Masnyk,‡
Anna Michrowska,‡ Agata Sarosiek,‡,§
Halszka Ste¸powska,‡ Dieter Arlt,*,|, and Karol Grela*,‡
Institute of Organic Chemistry, Polish Academy of Sciences,
Kasprzaka 44/ 52, Warsaw, 01-224, Poland,
LIGAND Chemie GmbH, Papenhauser Str. 10,
Lemgo, D-32657, Germany, Institut fu¨r Organische Chemie
der Universita¨t zu Ko¨ln, Greinstr. 4, 50939 Ko¨ln, Germany
prof.arlt@t-online.de; grela@icho.edu.pl
Received May 9, 2004
Abstr a ct: A novel highly efficient and general route to
various 3- and 5-substituted 2-alkoxystyrenes, required for
the preparation of Hoveyda-Grubbs catalysts, is described.
Over the past few years, the olefin metathesis has been
applied with increased frequency in organic chemistry.
The tremendous success of this transformation is largely
due to discovery of active, well-defined first-generation
((PCy3)2Cl2RudCHPh, 1) and second-generation (2) ru-
thenium alkylidene complexes, which combine high cata-
lytic activity with almost ideal functional group toler-
ance.1 The chromatography-stable phosphane-free com-
plex 3, described by Hoveyda et al.,2-4 initiates more
slowly than the highly active Grubbs' benzylidene 2.5
Recently, we have described the similarly stable and
reusable catalyst 4, prepared from an inexpensive R-asa-
To explore the synthetic potential of 5 and 6 and to
study structure-activity relationships in Hoveyda-type
complexes 5-8 (Scheme 2), a simple and general syn-
thetic route to various 3- and 5-substituted 2-alkoxysty-
renes was required.11 The described preparation of
5-nitro-2-isopropoxystyrene, a substrate for 6, consists
of alkylation of the commercially available 2-hydroxy-5-
nitrobenzaldehyde followed by Wittig reaction (49%
overall yield).10 The latter transformation is not practical
for larger scale operations as it requires column chro-
matography to remove the triphenyl phosphine oxide
(6) (a) Grela, K.; Kim, M. Eur. J . Org. Chem. 2003, 963-966. (b)
For an unique activity of a catalyst derived from 4 in living polymer-
ization of diynes, see: Krause, J . O.; Zarka, M. T.; Anders, U.;
Weberskirch, R.; Nuyken, O.; Buchmeiser, M. R. Angew. Chem., Int.
Ed. 2003, 42, 5965-5969.
† This work was presented at the Congress of Chemistry Lecturers-
Chemiedozententagung 2004, Dortmund, Germany, March, 7-10, 2004.
‡ Institute of Organic Chemistry, PAS.
§ Current address: Pharmaceutic Institute, Rydygiera 8, 01-793,
Warsaw, Poland.
(7) (a) Randl, S.; Gessler, S.; Wakamatsu, H.; Blechert, S. Synlett
2001, 430-432. For activation of Grubbs’ carbene 2 towards acrylo
nitrile, either via structural modifications or addition of CuCl, see: (b)
Love, J . A.; Morgan, J . P.; Trnka, T. M.; Grubbs, R. H. Angew. Chem.,
Int. Ed. 2002, 41, 4035-4037. (c) Rivard, M.; Blechert, S. Eur. J . Org.
Chem. 2003, 2225-2228. (d) Imhof, S.; Randl, S.; Blechert, S. Chem.
Commun. 2001, 1692-1693. (e) Grela, K.; Michrowska, A.; Bieniek,
M.; Kim, M.; Klajn, R. Tetrahedron 2003, 59, 4525-4531.
(8) (a) Wakamatsu, H.; Blechert, S. Angew. Chem., Int. Ed. 2002,
41, 2403-2405. (b) For an improved synthesis of 5, see: Dunne, A.
M.; Mix, S.; Blechert, S. Tetrahedron Lett. 2003, 44, 2733-2736.
(9) Extensive studies described in ref 8 suggest that a steric bulk
adjacent to the chelating isopropoxy moiety is the crucial factor
securing the unusually high activity of 5.
(10) (a) Grela, K.; Harutyunyan, S.; Michrowska, A. Angew. Chem.,
Int. Ed. 2002, 41, 4038-4040. (b) Harutyunyan, S.; Michrowska, A.;
Grela, K. A Highly Active Ruthenium (Pre)catalyst for Metathesis
Reactions. In Catalysts for Fine Chemical Synthesis; Roberts, S., Ed.;
Wiley-Interscience: New York, 2004; Vol. 3, in press. For applications
of 6 in target-oriented synthesis, see the following. (c) (-)-Securinine:
Honda, T.; Namiki, H.; Kaneda, K.; Mizutani, H. Org. Lett. 2004, 6,
87-89. (d) (+)-Viroallosecurinine: Honda, T.; Namiki, H.; Watanabe,
M.; Mizutani, H. Tetrahedron Lett. 2004, 45, 5211-5213. (e) An
artificial photosynthesis model: Ostrowski, S.; Mikus, A. Mol. Diversity
2003, 6, 315-321.
| LIGAND Chemie GmbH.
Ko¨ln University.
(1) Pertinent reviews: (a) Schrock, R. R.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2003, 42, 4592-4633. (b) Trnka, T. M.; Grubbs, R. H.
Acc. Chem. Res. 2001, 34, 18-29. (c) Forstner, A. Angew. Chem., Int.
Ed. 2000, 39, 3012-3043. (d) Grubbs, R. H.; Chang, S. Tetrahedron
1998, 54, 4413-4450. (e) Schuster, M.; Blechert, S. Angew. Chem., Int.
Ed. Engl. 1997, 36, 2037-2056. (f) Dragutan, V.; Dragutan, I.; Balaban,
A. T. Platinum Met. Rev. 2001, 45, 155-163.
(2) (a) Kingsbury, J . S.; Harrity, J . P. A.; Bonitatebus, P. J .; Hoveyda,
A. H. J . Am. Chem. Soc. 1999, 121, 791-799. (b) Garber, S. B.;
Kingsbury, J . S.; Gray, B. L.; Hoveyda, A. H. J . Am. Chem. Soc. 2000,
122, 8168-8179. (c) For
a short review on these catalysts, see:
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, 1-16.
(3) For syntheses of supported variants of 2, see inter alia: ref 2b
and (a) Kingsbury, J . S.; Garber, S. B.; Giftos, J . M.; Gray, B. L.;
Okamoto, M. M.; Farrer, R. A.; Fourkas, J . T.; Hoveyda, A. H. Angew.
Chem., Int. Ed. 2001, 40, 4251-4255. (b) Grela, K.; Tryznowski, M.;
Bieniek, M. Tetrahedron Lett. 2002, 43, 9055-9059. (c) Connon, S. J .;
Dunne, A. M.; Blechert, S. Angew. Chem., Int. Ed. 2002, 41, 3835-
3838. (d) Dowden, J .; Savovic, J . Chem. Commun. 2001, 37-38. (e)
Yao, Q. Angew. Chem., Int. Ed. 2000, 39, 3896-3898. (f) Yao, Q.; Zhang,
Y. Angew. Chem., Int. Ed. 2003, 42, 3395-3398. (g) Connon, S. J .;
Blechert, S. Bioorg. Med. Chem. Lett. 2002, 12, 1873-1876. (h) Yao,
Q.; Zhang, Y. J . Am. Chem. Soc. 2004, 12, 74-75. (i) Yao, Q.; Motta,
A. R. Tetrahedron Lett. 2004, 45, 2447-2451.
(11) (a) For a recent application of Ru catalysts derived from 5-nitro-
2-isopropoxystyrene in polymer chemistry, see: Krause, J . O.; Nuyken,
O.; Buchmeiser, M. R. Chem. Eur. J . 2004, 10, 2029-2035. (b) Recently,
the concept of steric and electronic activation has been utilized by
Hoveyda et al. in a preparation of chiral ruthenium complexes for
asymmetric metathesis: Van Veldhuizen, J . J .; Gillingham, D. G.;
Garber, S. B.; Kataoka, O.; Hoveyda, A. H. J . Am. Chem. Soc. 2003,
125, 12502-12508.
(4) Catalysts 1-3 are commercially available from Aldrich Chemical
Co.
(5) For a comparison of relative initiation rates of 2 and 3, see: refs
6, 8a,b, and 10.
10.1021/jo049222w CCC: $27.50 © 2004 American Chemical Society
Published on Web 08/27/2004
6894
J . Org. Chem. 2004, 69, 6894-6896

SCHEME 1. F a m ily of Mod er n Ru th en iu m
Ca ta lysts for Alk en e Meta th esisa
SCHEME 3. P r ep a r a tion of Ca ta lysts 5 a n d 6
P r ecu r sor sa
a
Cy ) cyclohexyl; Mes ) 2,4,6-trimethyl phenyl
a
SCHEME 2. Selected Oth er Or th o- a n d
Isolated yields. Reagents: (a) Cs2CO3 (cat.), K2CO3, allyl
bromide, DMF, 40 °C, 1 day or NaOH, K2CO3, allyl bromide,
acetone-water, 45 °C, 1 day; (b) 195 °C, 6 h; (c) RhCl3‚3H2O (cat.),
p-TsOH‚H2O (cat.), 90% aq EtOH, reflux, 5 h; (d) K2CO3, Cs2CO3
(cat.), i-PrI, DMF, 40 °C, 1-2 days.
P a r a -Su bstitu ted Hoveyd a -Gr u bbs Ca r ben es
The isomerization of 10a to 11a was then tested. From
many isomerization protocols known,14 the reaction
catalyzed by 3 mol % rhodium trichloride/p-TsOH‚H2O
in 90% aqueous EtOH gave the best results in terms of
both selectivity and yield.15 Finally, the alkylation of 11a
was carried out with i-PrI in DMF, using K2CO3 and a
catalytic amount of Cs2CO3, yielding the catalyst 5
precursor 12a in 88% yield after a final chromatographic
purification (Scheme 3). The styrene 12b, a precursor for
the highly active NO2-substituted catalyst10 6 can be
obtained with similar efficiency using the same protocol.
(13) (a) For a review on Claisen rearrangement, see: Rhoadas, S.
J .; Raulis, N. R. Org. React. 1975, 22, 1-252. For a similar Claisen
rearrangement-isomerization protocol of phenol allyl ethers applied
in total syntheses, see: (b) Baxendale, I. R.; Lee, A.-L.; Ley, S. V. J .
Chem. Soc., Perkin Trans. 1 2002, 1850-1857. (c) Nguyen Van, T.;
Debenedetti, S.; De Kimpe, N. Tetrahedron Lett. 2003, 44, 4199-4201.
(d) De Koning, C. B.; Green, I. R.; Michael, J . P.; Oliveira, J . R.
Tetrahedron 2001, 57, 9623-9634.
byproduct. Similarly, the optimized preparation of a
starting material for 5 consists of five steps, starting from
2-hydroxybiphenylsodium salt (Kolbe-Schmitt reaction,
alkylation with 12 equiv of i-PrBr, LAH reduction, MnO2
oxidation, and Wittig olefination) and gives the required
2-isopropoxy-3-phenylstyrene with 16% overall yield.8b
Therefore, we were encouraged to develop a more step-
and atom-economic method that minimizes the use of
large amounts of solvents and expensive reagents.
(14) Several homogeneous and supported catalysts for a C-C double
bond isomerization are known, including: (a) RhCl3‚nH2O and poly-
styrene-supported RhCl3: Setty-Fichman, M.; Blum. J .; Sasson, Y.
Tetrahedron Lett. 1994, 35, 781-784. (b) Felkin’s iridium catalyst:
Baudry, D.; Ephritikhine, M.; Felkin, H. J . Chem. Soc., Chem.
Commun. 1978, 694-695. (c) Polymer-supported: Wilkinson’s catalyst,
[(COD)IrCl]2 and 2-tert-butylimino-2-diethylamino-1,3-dimethyl per-
hydro-1,3,2-diazaphosphorine (PS-BEMP); see ref 13a. (d) RuClH(CO)-
(PPh3)3: Krompiec, S.; Kuznik, N.; Bieg, T.; Adamus, B.; Majnusz, J .;
Grymel, M. Polish J . Chem. 2000, 74, 1197-1200. Krompiec, S.;
Pigulla, M.; Szczepankiewicz, W.; Bieg, T.; Kuznik, N.; Leszczynska-
Sejda, K.; Kubicki, M.; Borowiak, T. Tetrahedron Lett. 2001, 42, 7095-
7098. (e) For recent examples of aryl-allyls isomerization using t-BuOK,
see: ref 13c,d. (f) For a RuClH(CO)(PPh3)3 isomerization of structurally
related 2-isopropoxyallylbenzenes, see: van Otterlo, W. A. L.; Pathak,
R.; de Koning, C. B. Synlett 2003, 1859-1861.
Herewith, we present a general route to various 3- and
5-substituted Hoveyda-type complexes 3-8, including the
highly reactive 5 and 6, which rely on solvent-free Claisen
rearrangement and catalytic C-C double bond isomer-
ization as key steps.12
Our synthesis of 58 begins from inexpensive 2-hydroxy-
biphenyl 8a , which is readily allylated using allyl bro-
mide and solid K2CO3 to give the aryl ether 9a in 93%
yield (Scheme 3). The crude product 9a was then sub-
jected to a rearrangement.13 The Claisen rearrangement
was achieved by heating neat 9a at 190-195 °C. The
reaction proceeded smoothly to give 10a in 86% yield.
(15) In addition to the expected 11a (96% of yield) a small amount
of the byproduct 11a ′ (4% of yield) has been obtained.
(12) See Supporting Information for experimental details.
J . Org. Chem, Vol. 69, No. 20, 2004 6895

SCHEME 4. P r ep a r a tion of Ca ta lysts 3, 7a , a n d 8
P r ecu r sor sa
SCHEME 5. P r ep a r a tion of Ca ta lysts 3-6, 7a ,
a n d 8a
a
Isolated yields. Reagents: (a) 2, CuCl, CH2Cl2, 40-45 °C, 45-
60 min. bTwo equivalents of 12a was used.
with 2 in CH2Cl2 at 40-45 °C in the presence of CuCl as
a phosphane scavenger gave catalysts 3-8 in good to
excellent yields (Scheme 5). In the case of ortho-
substituted catalyst 5, 2 equiv of styrene 12a was
required to achieve good yield. It was also observed that
more electron-rich catalysts (Scheme 5, reactions 12d f
3, 12c f 7a , and 13 f 4) can be obtained in higher yields
as compared with sterically or electronically altered 5,
6, and 8. Complexes 3-8 displayed the expected activities
in a set of benchmark metathesis reactions, and their
analytical data are in full agreement with those pub-
lished in the literature.2,6,8,10,18
a
Isolated yields. Reagents: (a) K2CO3, Cs2CO3 (cat.), allyl
bromide, DMF, 65-70 °C, 5 h or NaOH, K2CO3, allyl bromide,
acetone-water, 45 °C, 1 day; (b) 195 °C, 6 h; (c) K2CO3, Cs2CO3
(cat.), i-PrI, DMF, 40 °C, 1-2 days or NaOH, K2CO3, i-PrI or
Me2SO4, acetone-water, 45 °C, 20 h; (d) RhCl3‚3H2O (cat.),
p-TsOH‚H2O (cat.), 90% aq EtOH, reflux, 5 h. b2-Allylphenol (10d )
c
was used as received from Fluka AG. Ruthenium isomerization
conditions: CH2dCHOTMS, 2 (cat.), CH2Cl2, 35 °C, 24 h (66%).
d10b was used as a substrate.
In summary, we have developed an efficient and
general synthetic route, based on a solvent-free Claisen
rearrangement and catalytic isomerization, which allows
various catalyst precursors to be readily prepared in
multigram quantities. This protocol can be used in
preparation of highly active ortho- and para-substituted
catalysts 5 and 6 and their chiral analogues, as well as
parent Hoveyda-Grubbs carbene 3 and other sys-
tems.11,21
However, the electron-poor aryl-ether 9b was substan-
tially less prone to rearrangement (Scheme 3).16,17
To show the general applicability of our Claisen rear-
rangement-isomerization procedure, other representa-
tive styrenes 12c-e, precursors for the benzylidene-
modified (7a , 8) and supported (7b)18 catalysts, were
prepared (Scheme 4). In this case, isomerizations of aryl
ethers (11c-e) also proceeded smoothly, with even higher
trans selectivity.
Nishida and co-workers recently reported that several
substrates can be isomerized using a catalyst formed in
situ from Grubbs’ benzylidene 2 and vinyloxytrimethyl-
silane.19 We have checked that this system can be used
for isomerization of the 2-isopropoxy-allylbenzene 11d
(Scheme 4).20
Having the required precursors in hand we attempted
the catalyst preparation, using the standard ligand
exchange-metathesis procedure.2b Treatment of 12a -e
Ack n ow led gm en t. Financial support was provided
by the State Committee of Scientific Research (Grant 4
T09A 136 22). M.B. thanks the IOC PAS for a predoc-
toral fellowship.
Su p p or tin g In for m a tion Ava ila ble: Full experimental
procedures, characterization data, and 1H and 13C NMR
spectra of 12a -e. This material is available free of charge via
the Internet at http://pubs.acs.org.
J O049222W
(16) For safety reasons, Claisen rearrangement of the NO2-bearing
9b was carried out in a 1:1 w/w mixture with diphenyl ether, which
can be then separated by a simple biphasic extraction and recycled.
(17) Claisen rearrangement of this substrate is known to give
moderate yields: White, W., N.; Gwyn, D.; Schlitt, R.; Girard, C.; Fife,
W. J . Am. Chem. Soc. 1958, 80, 3271-3277 (o-dichloro benzene, 6 h,
59%).
(20) (a) For a recent example of ruthenium isomerization catalyst
formed in situ from 1, 2-propanol, and NaOH, see: Schmidt, B. Chem.
Commun. 2004, 742-743. For reviews on olefin isomerization caused
by ruthenium metathesis catalysts, see: (b) Schmidt, B. Eur. J . Org.
Chem. 2004, 1865-1880. (c) Alcaide, B.; Almendros, P. Chem. Eur. J .
2003, 9, 1259-1262.
(21) (a) Recently, another example of an o-substituted Hoveyda-type
catalyst has been described: Zaja, M.; Connon, S. J .; Dunne, A. M.;
Rivard, M.; Buschmann, N.; J iricek, J .; Blechert, S. Tetrahedron 2003,
59, 6545-6558. (b) The high activity of this catalyst has been proved:
Synlett 2004, 667-670.
(18) The bromo-substituted styrene 12c constitutes
a
valuable
starting material for preparation of a PS-DES-supported catalyst 7b;
cf. ref 3b.
(19) Arisawa, M.; Terada, Y.; Nakagawa, M.; Nishida, A. Angew.
Chem., Int. Ed. 2002, 41, 4732-4734. (b)
6896 J . Org. Chem., Vol. 69, No. 20, 2004