Chloro-substituted Hoveyda-Grubbs ruthenium carbene: Investigation of electronic effects

Article abstract of DOI:10.1016/j.jorganchem.2007.04.017

A series of applications of cross and ring-closing metathesis has been made to investigate the application profile of the chloro-substituted Hoveyda-Grubbs ruthenium carbene in order to evaluate electronic effects resulting from the introduction of a chlorine atom para to the isopropoxy moiety of its parent catalyst.

Full text of DOI:10.1016/j.jorganchem.2007.04.017

Journal of Organometallic Chemistry 692 (2007) 3574–3576
www.elsevier.com/locate/jorganchem
Note
Chloro-substituted Hoveyda–Grubbs ruthenium carbene:
Investigation of electronic effects
*
Roberta Ettari , Nicola Micale
Dipartimento Farmaco-Chimico, University of Messina, Viale Annunziata, 98168 Messina, Italy
Received 12 March 2007; received in revised form 11 April 2007; accepted 11 April 2007
Available online 21 April 2007
Abstract
A series of applications of cross and ring-closing metathesis has been made to investigate the application profile of the chloro-substi-
tuted Hoveyda–Grubbs ruthenium carbene in order to evaluate electronic effects resulting from the introduction of a chlorine atom para
to the isopropoxy moiety of its parent catalyst.
Ó 2007 Elsevier B.V. All rights reserved.
Keywords: Cross metathesis; Ring-closing metathesis; Electronic effects; Chloro-substituted Hoveyda–Grubbs catalyst
1. Introduction
introduced by Hoveyda [5], this catalyst proved to initialize
slower than 2, probably as a result of steric (large isoprop-
oxy group) and electronic factors (iPrO ! Ru chelation)
[6].
Over the last decade, olefin metathesis reactions have
emerged as a powerful tool for the formation of carbon–
carbon bonds in chemistry [1].
Several studies have been made by Blechert et al. [7] on
the influence of various substituents other than hydrogen
ortho or para to the isopropoxy group. Since the decrease
of electron density at the oxygen atom of the iPrO group
results in an increase of the catalytic activity [6,7], the intro-
duction of an electron withdrawing group (EWG) could
weaken the iPrO ! Ru chelation and thus facilitate the ini-
tiation of the catalytic cycle. With regard to the effect of the
introduction of an halogen atom in para to the bulky
group, the fluoro-analogue 4 (Fig. 1) was compared with
its precursor 3 in a series of ring-closing metathesis
(RCM) by showing that the introduction of a fluorine atom
led to a less efficient catalyst but faster than 3 [7].
In order to evaluate the reactivity of the bromo-ana-
logue 5 (Fig. 1), Grela et al. [8] tested metal-carbenes 3
and 5 in some model reactions showing that the reactivity
patterns of complexes 3 and 5 were in general similar, with
the latter system visibly less reactive.
The ruthenium carbene complexes introduced by Grubbs
and co-workers are undoubtedly the most popular and ver-
satile catalysts for these reactions. Despite its limited ther-
mal stability, the first generation Grubbs alkylidene 1
proved to be an efficient catalyst in particular for metathesis
of terminal olefins [2], whereas all second generation N-het-
erocyclic carbene (NHC) ruthenium complexes, e.g. 2–3,
showed higher reactivity towards a broad range of elec-
tron-deficient substrates (Fig. 1) [3]. These imidazolidinylid-
ene-based systems possess greater electron density at the
metal center as the imidazolidinylidene ligand acts as a
strong r donor and has almost no p acceptor properties.
The stability of bimetallic, bridged-chloride Ru-carbene
complexes can be critically dependent on the presence of
steric bulk in the ligand environment surrounding the
metal center [4]. Despite the promising application profile
observed in reactions of the phosphine-free catalyst 3,
The aim of our paper is to report an investigation on the
application profile of the chloro-substituted complex 6 [9]
(Fig. 1) in order to complete the studies on electronic effects
*
Corresponding author. Tel.: +39 090 6766466; fax: +39 090 355613.
E-mail address: rettari@pharma.unime.it (R. Ettari).
0022-328X/$ - see front matter Ó 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jorganchem.2007.04.017

R. Ettari, N. Micale / Journal of Organometallic Chemistry 692 (2007) 3574–3576
3575
stirring. The corresponding CM products 8a–c were iso-
lated, by flash column chromatography, exclusively as the
E-isomers, whereas 8d was obtained as a mixture of iso-
mers Z/E in a 3:1 ratio (Table 1). In these reactions catalyst
6 gave excellent yields with very reactive olefins 7a–b, as
catalysts 2 and 3, whereas with less reactive olefins 7c–d
it exhibited higher activity than that of complex 2, as
expected, and slightly lower than that of complex 3.
For the coupling of styrene with olefins 7e–f, we sought
to employ microwave (MW) irradiation as an energy
source to promote CM. A few studies of microwave
assisted metathesis have been reported, but most refer to
RCM [10]. Therefore, a mixture of styrene (2.5 equiv.), ole-
fin (7e or 7f) (1 equiv.) and metal-carbene complex (2, 3 or
6) in dry CH2Cl2 was stirred under MW irradiation at
100 °C for 30 min. The crude was purified by flash column
chromatography to afford the CM product in good yields
with excellent stereoselectivity towards the E-isomer for
both compounds 8e and 8f (Table 1).
N
N
N
N
Mes Mes
Mes
PCy3
Ru
Mes
Cl
Cl
Cl
Cl
Ru
Ru
O
Cl
Cl
Ph
PCy3
Ph
PCy3
R
1
2
3 R = H
4 R = F
5 R = Br
6 R = Cl
Fig. 1. Ruthenium carbene complexes for olefin metathesis (Cy = cyclo-
hexyl and Mes = C6H2-2,4,6-Me3).
previously reported [7,8], with the purpose to give a final
complete picture of the influence of all halogen atoms
introduced in para to the iPrO group of Hoveyda–Grubbs
second generation catalyst.
An identical cross-coupling, using 1.9 equiv. of sty-
rene, 1 equiv. of CM partner 7e–f, 5 mol% of catalyst
2, in CH2Cl2 at 40 °C for 15 h, proceeds in 25% yield
for 8e and 63% for 8f [11]. These data clearly demon-
strate the potential of microwave irradiation to both
improve the yields and reduce the reaction times of
CM reactions.
The obtained results point out that the chloro-substi-
tuted complex 6 shows a catalytic efficiency towards CM
undoubtedly better than that of Grubbs catalyst 2 and
almost comparable, sometimes lower, than that of parent
catalyst 3.
2. Results and discussion
The reactivity of the chloro-substituted complex 6 in
cross metathesis (CM) reactions was compared with that
of second generation Grubbs catalyst 2 and Hoveyda–
Grubbs catalyst 3 in a series of CM with electron-deficient
substrates.
Test reactions between allylbenzene (2.5 equiv.), olefins
7a–d (1 equiv.) and ruthenium complexes 2, 3 or 6
(2.5 mol%) were performed under argon, in refluxing dry
CH2Cl2 for 5–12 h. Under these conditions, we observed
the initial formation of a small amount of homodimer of
allylbenzene which decreased significantly after prolonged
The activity of the complex 6 in RCM reactions has
been briefly explored, as shown in Table 2.
Table 1
Cross metathesis reactionsa
Entry
a
Olefin
CM-partner 7
Product 8b
Conditions
Catalyst
Yield %c
E/Z
E
2.5 mol% of catalyst CH2Cl2, D, 12 h
2
3
6
2
3
6
2
3
6
2
3
6
2
3
6
2
3
6
99
99
99
99
99
99
43
71
62
51
67
59
30
65
45
99
99
99
COCH3
Ph
COCH3
Ph
b
c
d
e
f
2.5 mol% of catalyst CH2Cl2, D, 12 h
E
E
COOCH3
SO2Ph
Ph
Ph
Ph
COOCH3
Ph
Ph
Ph
Ph
Ph
2.5 mol% of catalyst CH2Cl2, D, 12 h
SO2Ph
CN
2.5 mol% of catalyst CH2Cl2, D, 5 h
Z/E
3:1d
CN
O
N
5 mol% of catalyst CH2Cl2, MW, 100 °C, 30 min
5 mol% of catalyst CH2Cl2, MW, 100 °C, 30 min
E
E
N
O
Ph
Ph
COOH
COOH
a
All reactions were carried out by reacting 2.5 equiv. of allylbenzene or styrene and 1 equiv. of 7.
b
c
The analytical and spectroscopic data are in agreement with those reported in literature: 8a [13], 8b [14], 8c [6], 8d [15], 8e [16], 8f [17].
Isolated yields of analytically pure compounds.
Ratio determined by 1H NMR spectroscopy.
d

3576
R. Ettari, N. Micale / Journal of Organometallic Chemistry 692 (2007) 3574–3576
Table 2
Ring-closing metathesis reactions
Entry
a
Substrate 9
Product 10a
Conditions
Yields %b
3
6
Ts
N
Ts
N
3 mol% of catalyst CH2Cl2, rt, 2 h
99
99
b
c
a
5 mol% of catalyst CH2Cl2, rt, 2 h
5 mol% of catalyst CH2Cl2, rt, 2 h
99
85
99
49
Ts
N
Ts
N
N
Ts
N
Ts
The analytical and spectroscopic data are in agreement with those reported in literature: 10a [18], 10b [19], 10c [20].
b
Determined by 1H NMR.
[3] (a) M. Scholl, T.M. Trnka, J.P. Morgan, R.H. Grubbs, Tetrahedron
Lett. 40 (1999) 2247;
(b) C.W. Bielawsky, R.H. Grubbs, Angew. Chem. 112 (2000) 3025.
[4] E.L. Dias, R.H. Grubbs, Organometallics 17 (1998) 2758.
[5] (a) S.B. Garber, J.S. Kingsbury, B.L. Gray, A.H. Hoveyda, J. Am.
Chem. Soc. 122 (2000) 8168;
Metal-carbene complex (3 or 6) (3–5 mol%) was added
to a 0.01 M solution of the diene 9 in dry CH2Cl2 and
the reaction mixture was stirred under argon for 2 h at
room temperature. After this time it was possible to appre-
ciate the conversion of the substrate 9a–c into the cyclized
product 10a–c in good yields (Table 2).
In these reactions catalysts 3 and 6 proved to be equipo-
tent to promote cyclization of unsaturated amines 9a–b by
RCM and only for RCM of 9c the parent catalyst 3 showed
efficacy higher than the chloro-derivative 6.
To sum up we can affirm that the chloro-analogue 6, such
as the fluoro and the bromo-substituted complexes 4–5 [7,8]
are slightly less efficient than Hoveyda–Grubbs catalyst 3 in
terms of yields, both in CM and RCM reactions. However,
it has been reported [12] that the presence of both electron
withdrawing (e.g. NO2) and donating (e.g. OMe) groups
exerts similar effects on the catalytic efficiency of the Hov-
eyda-type chiral ruthenium carbene complexes showing that
the effects of these electron modifications are actually far
from being comprehensively clarified.
(b) A.H. Hoveyda, D.G. Gillingham, J.J. Van Veldhuizen, O.
Kataoka, S.B. Garber, J.S. Kingsbury, J.P.A. Harrity, Org. Biomol.
Chem. 2 (2004) 1.
[6] A. Michrowska, R. Bujok, S. Harutyunyan, V. Sashuk, G. Dolgonos,
K. Grela, J. Am. Chem. Soc. 126 (2004) 9318.
[7] M. Zaja, S.J. Connon, A.M. Dunne, M. Rivard, N. Buschmann, J.
Jiricek, S. Blechert, Tetrahedron 59 (2003) 6545.
[8] A. Michrowska, M. Bieniek, M. Kim, R. Klajn, K. Grela, Tetrahe-
dron 59 (2003) 4525.
[9] Chloro-substituted complex 6 has been purchased by Zannan Pharma
Ltd., Shanghai, China; Zhan, Z.-Y. WO2007003135, 2007.
[10] F.C. Bargiggia, W.V. Murray, J. Org. Chem. 70 (2005) 9636.
[11] T.-L. Choi, A.K. Chatterjiee, R.H. Grubbs, Angew. Chem., Int. Ed.
40 (2001) 1277.
[12] J.J. Van Veldhuizen, D.G. Gillinghan, S.B. Garber, O. Kataoka, A.
Hoveyda, J. Am. Chem. Soc. 125 (2003) 12502.
[13] S. Chang, J. Yoon, M. Brookhart, J. Am. Chem. Soc. 116 (1994)
1869.
[14] P. Muller, P. Polleux, Helv. Chem. Acta 81 (1998) 317.
[15] S. Inaba, H. Matsumoto, R.D. Rieke, J. Org. Chem. 49 (1984)
2093.
References
[16] G.B. Gill, G. Pattenden, G.S.J. Reynolds, J. Chem. Soc., Perkin
Trans. 1 (1994) 369.
[17] T. Kim, C. Huh, B. Lee, I. Lee, J. Chem. Soc., Perkin. Trans. 2
(1995) 2257.
[18] A. Furstner, L.A. Ackermann, Chem. Commun. (1999) 95.
¨
[19] H. Clavier, N. Audic, J.-C. Guillemin, M. Mauduit, J. Organomet.
Chem. 690 (2005) 3585.
[1] (a) R.H. Grubbs (Ed.), Handbook of Metathesis, vol. 3, Wiley-VCH
Verlag GmbH & Co., Weinheim, 2003;
(b) R.H. Grubbs, Tetrahedron 60 (2004) 7117;
(c) K.C. Nicolaou, P.G. Bulger, D. Sarlah, Angew. Chem., Int. Ed.
44 (2005) 4490.
[2] (a) P. Schwab, R.H. Grubbs, J.W. Ziller, J. Am. Chem. Soc. 118
(1996) 100;
[20] M.S. Visser, N.M. Heron, M.T. Didiuk, J.F. Sagal, A.H. Hoveyda,
J. Am. Chem. Soc. 118 (1996) 4291.
(b) A. Furstner, Angew. Chem., Int. Ed. 39 (2000) 3012;
¨
(c) T.M. Trnka, R.H. Grubbs, Acc. Chem. Res. 34 (2001) 18.