Stereoretentive Olefin Metathesis Made Easy: In Situ Generation of Highly Selective Ruthenium Catalysts from Commercial Starting Materials

Article abstract of DOI:10.1021/acs.orglett.8b02943

The in situ preparation of highly stereoretentive ruthenium-based metathesis catalysts is reported. This approach completely avoids the isolation of intermediates and air-sensitive catalysts, thus allowing for the rapid access and evaluation of numerous dithiolate Ru catalysts. A procedure was established to perform cross-metathesis reactions without the use of a glovebox, and on a small scale even Schlenk techniques are not required. Consequently, the chemistry displayed in this report is available to every practicing organic chemist and presents a powerful approach for the identification of new stereoretentive catalysts.

Full text of DOI:10.1021/acs.orglett.8b02943

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Stereoretentive Olefin Metathesis Made Easy: In Situ Generation of
Highly Selective Ruthenium Catalysts from Commercial Starting
Materials
†
†
‡
§
†
́
̂
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Daniel S. Muller, Idriss Curbet, Yann Raoul, Jerome Le Notre, Olivier Basle,
̈
and Marc Mauduit*,†
†
́
Univ Rennes, Ecole Nationale Superieure de Chimie de Rennes, CNRS, ISCR UMR 6226, F-35000 Rennes, France
‡
̀
OLEON SAS, Venette BP 20609, Compiegne 60206 Cedex, France
§
̀
PIVERT SAS, Rue les Rives de l’Oise CS50149, Compiegne 60201 Cedex, France
S
* Supporting Information
ABSTRACT: The in situ preparation of highly stereo-
retentive ruthenium-based metathesis catalysts is reported.
This approach completely avoids the isolation of intermediates
and air-sensitive catalysts, thus allowing for the rapid access
and evaluation of numerous dithiolate Ru catalysts. A
procedure was established to perform cross-metathesis
reactions without the use of a glovebox, and on a small scale
even Schlenk techniques are not required. Consequently, the
chemistry displayed in this report is available to every
practicing organic chemist and presents a powerful approach
for the identification of new stereoretentive catalysts.
atalytic methods for the synthesis of olefins with high
stereochemical purity are in high demand, particularly if
2)5 or zinc dithiolate (3)6 salt is prepared from the
C
commercially available dithiols by deprotonation with either
NaOtBu or Zn(OAc)2 in the presence of ethylenediamine.
Second, commercially available Hoveyda−Grubbs catalyst Ru-
3 is reacted with 1, 2 or 3a to give, after filtration in a glovebox,
the corresponding air-sensitive dithiolate catalysts.6,10
̀
these transformations produce less waste vis-a-vis established
stoichiometric procedures.1,2 Recently, a number of efficient Z-
selective Ru-based metathesis catalysts have been reported by
Grubbs and Jensen.3,4 These catalysts transform terminal
alkenes to Z-alkenes with high stereoselectivity. In 2013,
Hoveyda et al. reported the first highly stereoretentive
ruthenium dithiolate catalysts Ru-1 and Ru-2.5 Two years
later, the more robust dichloro-substituted catalyst S2-Ru-3
was identified by the same group.6 These catalysts allow for the
transformation of E- or Z-olefins with high retention of the
original stereochemical information (Scheme 1b, eq 1).2d The
great functional group tolerance of ruthenium dithiolate
catalysts combined with the high stereochemical purities
obtained for the products has given rise to a remarkable
research activity in this area over the past five years.7
Independent investigations by Hoveyda and Grubbs highlight
the importance of electronic and steric properties of the NHC
and dithiolate ligand for the efficiency of ruthenium dithiolate
catalysts.6,7e,f,8 The origins of stereoretentive mechanism have
been recently elucidated by computational studies by Liu and
Houk.9 Given the many advantages of stereoretentive
dithiolate ruthenium catalysts, important progress would be
made if this class of catalyst could be made available to every
organic chemist in any desired quantity.
Stimulated by our recent involvement in the field of
stereoselective and stereoretentive metathesis catalysts,7c,11
we became interested in the development of a highly practical
and easily accessible stereoretentive metathesis catalyst. Due to
our strong background in copper-catalyzed reactions,12 where
the catalyst is often generated in situ by mixing the
corresponding ligand and the Cu salt, we wondered if a
related process would be possible for the in situ generation of
dithiolate catalysts (Scheme 1b). We surmised that the right
choice of a base to deprotonate dithiol 4 might allow for the
efficient in situ generation of catalyst S2Ru-3 while generating
only side products that do not perturb the catalytic activity of
the metathesis catalyst. Furthermore, we speculated that
solutions of the in situ generated catalyst might be stable
enough to tolerate semi-inert conditions (argon-flushed vials),
hence allowing for the reaction to be carried out outside of a
glovebox without the use of Schlenk equipment. If such a
simple and practical procedure could be implemented, the
benefits of ruthenium dithiolate catalysts would be available to
the entire organic synthetic community.
Currently Ru-1, Ru-2, and S2Ru-3 are synthesized via a two-
step procedure, requiring manipulation in the glovebox
(Scheme 1a).5,6 First, the corresponding disodium (1 and
Received: September 14, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02943
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Previous Work by Hoveyda et al. and This Work
Table 1. Screening of Ruthenium Dichloride Precursors for
the in Situ Generation of Ru-Dithiolate Catalysts
a
b
c
[Ru] precursor
(x equiv)
catalyst
(5 mol %)
conv
yield
d
entry
(%)
(%)
Z/E
e
1
S2Ru-3
81
60
70
13
55
15
57
35
45
16
37
52
38
59
48
63
55
73
62
66
58
62
74
72
52
61
nd
48
nd
51
25
35
nd
35
37
26
41
34
49
48
61
53
55
45
55
64
96:4
>98:2
>98:2
nd
56:44
nd
20:80
26:74
17:83
nd
>98:2
>98:2
>98:2
>98:2
94:6
96:4
98:2
95:5
98:2
86:14
62:38
>98:2
>98:2
2
3
Ru-3 (0.5)
Ru-3 (0.5)
Ru-4 (0.5)
Ru-5 (0.5)
Ru-6 (0.5)
Ru-7 (0.5)
Ru-8 (0.5)
Ru-9 (0.5)
Ru-10 (0.5)
Ru-11 (0.5)
Ru-12 (0.5)
Ru-13 (0.5)
Ru-14 (0.5)
Ru-15 (0.5)
Ru-16 (0.5)
Ru-17 (0.5)
Ru-18 (0.5)
Ru-3 (0.66)
Ru-3 (0.85)
Ru-3 (0.1)
Ru-3 (0.66)
Ru-3 (0.66)
IS-S2-Ru-3
IS-S2-Ru-3
IS-S2-Ru-4
IS-S2-Ru-3
IS-S2-Ru-6
IS-S2-Ru-7
IS-S2-Ru-8
IS-S2-Ru-9
IS-S2-Ru-10
IS-S2-Ru-11
IS-S2-Ru-12
IS-S2-Ru-13
IS-S2-Ru-14
IS-S2-Ru-15
IS-S2-Ru-16
IS-S2-Ru-17
IS-S2-Ru-18
IS-S2-Ru-3
IS-S2-Ru-3
IS-S2-Ru-3
IS-S2-Ru-3
IS-S2-Ru-3
f
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
With these goals in mind, we started out by evaluating
several bases for the in situ generation of metal dithiolates
(Scheme 2). Subsequently, we added Ru-3 to the metal
Scheme 2. Scouting Studies: Identification of Et2Zn for
Efficient Synthesis of S2Ru-3
g
22
23
gh
,
a
b
e
Reactions performed in argon flushed vials on a 0.4 mmol scale.
c
d
Determined by GC. Isolated yield. Determined by 1H NMR.
f
Result obtained by Hoveyda and co-workers (see ref 6). Reaction
carried out in a glovebox with degassed solvents. nd = not determined.
g
h
With 6 mol % of (IS)-S2-Ru-3. Addition of catalyst in four equal
portions (1.5 mol % after each hour).
(entry 3). We took advantage of the simple in situ synthesis of
ruthenium dithiolate catalysts to survey the efficiency of
numerous, mostly commercially available catalysts for the CM
of 5 and 6 (Figure 1 and Table 1).
Phosphine-based catalysts afforded 7 either in poor yield or
with poor stereochemical purity (Table 1, entries 4−10).
Exposing 14-electron Piers complex (Ru-11) to our in situ
procedure and cross-metathesis reaction furnished 7 with
excellent stereoselectivity (Table 1, entry 11). Importantly, no
study concerning 14-electron ruthenium dithiolate catalysts
was reported in the literature.8a Attempts to isolate the
corresponding dithiolate catalyst, however, failed, very likely
due to the lack of stability of the corresponding complex.
Nevertheless, we were encouraged by this result, as the in situ
strategy allowed for the identification of a previously unknown
catalyst. Precursors of the Hoveyda-type catalysts (Ru-16),
including the well-known Grela (Ru-12 and Ru-14) and
Blechert (Ru-13 and Ru-15) derivatives as well as our in house
developed catalysts (Ru-17 and Ru-18),15 afford the CM
dithiolate solutions to generate in situ (IS) S2Ru-3. The
catalyst solution was immediately subjected to the cross-
metathesis (CM) of cis-butenediol 5 and 1-dodecene 6.
The outcome of our scouting studies clearly showed the
challenge of our in situ approach. n-BuLi, NaHMDS, and
KHMDS gave completely inefficient CM, probably due to
incomplete formation of (IS)-S2Ru-3 or generation of
deleterious byproducts.13 In stark contrast, Et2Zn allowed for
synthesis of allylic alcohol 7 with excellent stereoretention
(>98:2 Z-selectivity).14 Importantly, excess zinc dithiolate 8
and generated ZnCl2 had only a modest effect on the reaction
outcome compared to the isolated catalyst (Table 1, entries 1
and 2). Carrying out the same reaction in the glovebox gave
slightly increased yields with identical stereochemical purity
B
DOI: 10.1021/acs.orglett.8b02943
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Scope of the Stereoretentive Metathesis
a
Reaction
Figure 1. Ru-based metathesis catalysts used in this study.
product 7 in modest to good yields with constantly high
stereochemical puritiy (Table 1, entries 12−18). Further
optimization showed that a minimum of 1.5 equiv of dithiolate
zinc reagent 2 has to be added to the catalyst precursor in
order to afford high levels of stereoselectivity (Table 1, entries
19−21). We were aware of the fact that terminal alkenes such
as alkene 6 resulted in catalyst decomposition.6 Indeed,
portionwise addition of catalyst (IS)-S2-Ru-3 resulted in an
approximate 10% increase in product yield (Table 1, entries 22
and 23). With the optimized conditions (Table 1, entry 23) in
hand, we started exploring the scope of the reaction (Scheme
3).
The great variety of products which were obtained attests to
the robustness of the in situ generated catalyst (IS)-S2-Ru-3.
Even in the presence of 3% of Zn dithiolate and 6% of ZnCl2
which are likely to react with some of the functional groups,
the in situ generated catalyst still afforded useful synthetic
yields which are in most instances similar to the ones obtained
with the isolated catalyst S2Ru-3 and in some cases even higher
(e.g., 14 and 20).6 Noteworthy is the tolerance toward
sensitive functional groups such as bromides 10 and aldehydes
11. Bromide 10 was also prepared on larger scale (4.5 mmol)
with continuous addition of only two mole percent of catalyst
over 2 h with a syringe pump. We were pleased to observe a
significantly higher turn over number of 21 compared to the
portion wise addition (TON of 12). Acidic functional groups
such as carboxylic acid 12 or phenol 15 perform particularly
well. Diester 16 was synthesized in 53% yield, comparing
favorably to a recent four-step synthesis thereof (23% overall
yield).16 Sterically hindered alkenes (leading to products 17
and 18) reacted with excellent levels of selectivity, albeit in
slightly lower yields. The cross-metathesis of styrenes was
a
See the SI for details.
strongly dependent on its electronic properties. While the
reaction with styrene was poor yielding (19), electron poor 4-
(trifluoromethyl)styrene afforded 20 in good yield and high
levels of Z-selectivity. The cross-metathesis with cis-diacetoxy-
2-butene yielded 21 in good yields and high selectivity.7h,17 In
terms of limitations we noticed a significant drop in yield for
allyl ether 22 and disubstituted alkenes such as (R) limonene
23.
Next, we tested in situ generated catalysts for stereoretentive
ring-closing metathesis (Scheme 3b). After a preliminary
screening of catalysts (see the Supporting Information (SI))
C
DOI: 10.1021/acs.orglett.8b02943
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
we found in situ generated (IS)-S2-Ru-16 to give macrocyle 25
with excellent selectivity and 70% yield. We also tested a
selection of in situ generated Ru dithiolate catalysts for the self-
metathesis of Z- and E-methyl 9-octadecenoate (26) to
produce 9-octadecene (27) and dimethyl 9-octadecenedioate
(28) (Scheme 3c and SI). For the reaction with (Z)-26 (99%
purity) the equilibrium (26/27/28 = 50:25:25) was achieved
with only 100 ppm of (IS)-S2-Ru-15 with excellent stereo-
chemical purity (Z/E > 99:1). Carrying out the self-metathesis
reaction with technical grade methyl oleate 85% purity (Radia
7072) demonstrated the robustness of the in situ protocol
described herein.18 Within only 2 h, the equilibrium was
achieved with high stereochemical purity of the components
(Z/E = 98:2). The self-metathesis of (E)-methyl 9-
octadecenoate ((E)-26) proceeded smoothly with excellent
stereoretention in the presence of catalyst (IS)-S2-Ru-3
(Scheme 3c).
In conclusion, we have developed a highly practical in situ
protocol for the generation of stereoretentive Ru-based
metathesis catalysts. These catalysts perform very well, often
delivering the products in similar yields and selectivity
compared to the isolated catalysts. Furthermore, the in situ
protocol allowed for the rapid evaluation of a great number of
dichlororuthenium precursors. This enabled the identification
of a previously unknown ruthenium ditholate catalyst derived
from the Piers catalyst Ru-11. Our findings concerning the
evaluation of new ligands leading to stereoretentive Ru
catalysts using the in situ method described herein will be
reported in due course.
REFERENCES
■
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ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02943.
Optimization reactions, experimental procedures, and
characterization data (1H NMR, 13C NMR, GC traces)
(PDF)
(8) (a) Mikus, M. S.; Torker, S.; Xu, C.; Li, B.; Hoveyda, A. H.
Organometallics 2016, 35, 3878−3892. (b) Montgomery, T. P.;
Grandner, J. M.; Houk, K. N.; Grubbs, R. H. Organometallics 2017,
36, 3940−3953.
(9) Grandner, J. M.; Shao, H.; Grubbs, R. H.; Liu, P.; Houk, K. N. J.
Org. Chem. 2017, 82, 10595−10600.
(10) Hoveyda reported that reactions with S2Ru-3 can be stopped
by addition of technical grade ether (wet ether); see ref 6. Our results
concerning the RCM of 24 showed that the catalyst degrades in the
presence of air. Reactions carried out with nondegassed THF gave in
the presence of 10 mol % of catalyst conversions < 2%.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: marc.mauduit@ensc-rennes.fr.
ORCID
́
(11) Dumas, A.; Tarrieu, R.; Vives, T.; Roisnel, T.; Dorcet, V.; Basle,
O.; Mauduit, M. ACS Catal. 2018, 8, 3257−3262.
́
Olivier Basle: 0000-0002-4551-473X
Marc Mauduit: 0000-0002-7080-9708
(12) For recent contributions of our group in the field of Cu-
catalyzed reactions, see: (a) Tarrieu, R.; Dumas, A.; Thongpaen, J.;
Notes
́
́
Vives, T.; Roisnel, T.; Dorcet, V.; Crevisy, C.; Basle, O.; Mauduit, M.
The authors declare no competing financial interest.
J. Org. Chem. 2017, 82, 1880−1887. (b) Drissi-Amraoui, S.; Schmid,
́
́
T. E.; Lauberteaux, J.; Crevisy, C.; Basle, O.; de Figueiredo, R. M.;
Halbert, S.; Gerard, H.; Mauduit, M.; Campagne, J.-M. Adv. Synth.
Catal. 2016, 358, 2519−2540. (c) Drissi-Amraoui, S.; Morin, M. S.
T.; Crevisy, C.; Basle, O.; Marcia de Figueiredo, R.; Mauduit, M.;
Campagne, J.-M. Angew. Chem., Int. Ed. 2015, 54, 11830−11834.
(13) Hoveyda reported poor yields of S2Ru-3 when the disodium
dithiolate salt was used for its synthesis (ref 6).
(14) The complete deprotonation of dithiol 4 by Et2Zn was
confirmed by H NMR analysis (see the SI).
ACKNOWLEDGMENTS
́
■
This work was supported by the FASO (grant to D.S.M. and
́
́
́
I.C.; Z-SELECT) and the Region Bretagne (SAD 2016 N°
9639 − RZSELECT; grant to O.B. and D.S.M.). O.B. and
́
M.M. acknowledge the Ecole Nationale Superieure de Chimie
de Rennes (ENSCR) and the Centre National de la Recherche
Scientifique (CNRS) for financial support. Umicore AG & Co
is acknowledged for a generous gift of M1 and M2 ruthenium
complexes.
1
(15) For a recent account covering the contributions of this group in
the field of Ru-catalyzed metathesis reactions, see: Schmid, T. E.;
D
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́
́
Dumas, A.; Colombel-Rouen, S.; Crevisy, C.; Basle, O.; Mauduit, M.
Synlett 2017, 28, 773−798.
(16) Chiarucci, M.; Locritani, M.; Cera, G.; Bandini, M. Beilstein J.
Org. Chem. 2011, 7, 1198−1204.
(17) Hence, a hydrogen bond is not required as recently discussed
by Hoveyda (ref 7h). For an excellent review concerning the allylic
chalcogen effect in metathesis, see: Chiarucci, M.; Locritani, M.; Cera,
G.; Bandini, M. Beilstein J. Org. Chem. 2011, 7, 1198−1204.
(18) We recently reported on the self-metathesis of Radia on large
scale: Allard, J.; Curbet, I.; Chollet, G.; Tripoteau, F.; Sambou, S.;
́
́
Caijo, F.; Raoul, Y.; Crevisy, C.; Basle, O.; Mauduit, M. Chem. - Eur. J.
2017, 23, 12729−12734.
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