Activated Hoveyda-Grubbs Olefin Metathesis Catalysts Derived from a Large Scale Produced Pharmaceutical Intermediate – Sildenafil Aldehyde

Article abstract of DOI:10.1002/adsc.202100669

Two EWG-activated Hoveyda-Grubbs-type ruthenium complexes (Sil-II and Sil-II’) were obtained, characterized, and screened in a set of olefin metathesis reactions. These catalysts were conveniently synthesized from a commercially available pharmaceutical building block – Sildenafil aldehyde – in two steps only. Stability and catalytic activity tests disclosed that the bulkier NHC-ligand bearing catalyst Sil-II’ is visibly more stable and productive than its smaller NHC-analogue Sil-II. Good application profile of catalyst Sil-II’ was confirmed in a set of diverse metathesis reactions including ring-closing metathesis (RCM) and cross-metathesis (CM) of complex polyfunctional substrates of medicinal chemistry interest, including a challenging macrocyclization of the Pacritinib precursor. Compatibility of the new catalyst with various green solvents was checked and metathesis of Sildenafil and Tadalafil-based substrates was successfully conducted in acetone. The mechanism of Sil-II’ initiation has been investigated through kinetic experiments unveiling that the decrease of the steric hindrance of the chelating alkoxy moiety (from iPrO to EtO) favors the interchange initiation pathway over the typical dissociation pathway for other popular 2^nd generation Hoveyda-Grubbs catalysts. (Figure presented.).

Full text of DOI:10.1002/adsc.202100669

Title: Activated Hoveyda-Grubbs Olefin Metathesis Catalysts Derived
from a Large Scale Produced Pharmaceutical Intermediate—
Sildenafil Aldehyde
Authors: Louis Monsigny, Jakub Piątkowski, Damian Trzybiński,
Krzysztof Wozniak, Tomasz Nienałtowski, Anna
Kajetanowicz, and Karol Grela
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content of this Accepted Article.
To be cited as: Adv. Synth. Catal. 10.1002/adsc.202100669
Link to VoR: https://doi.org/10.1002/adsc.202100669

Advanced Synthesis & Catalysis
10.1002/adsc.202100669
RESEARCH ARTICLE
DOI: 10.1002/adsc.202100669
Activated Hoveyda-Grubbs Olefin Metathesis Catalysts Derived
from a Large Scale Produced Pharmaceutical Intermediate—
Sildenafil Aldehyde
a
a
a
a
Louis Monsigny, Jakub Piątkowski, Damian Trzybiński, Krzysztof Woźniak, To-
a,b
a,
a,
masz Nienałtowski, Anna Kajetanowicz, * and Karol Grela *
a
Biological and Chemical Research Centre, Faculty of Chemistry, University of Warsaw, Żwirki i Wigury Street 101,
0
[
2-089 Warsaw, Poland
Karol Grela: karol.grela@gmail.com, Anna Kajetanowicz: a.kajetanowicz@uw.edu.pl]
Polpharma SA Pharmaceutical Works, Pelplinska 19, 83-200 Starogard Gdanski, Poland
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Two EWG-activated Hoveyda-Grubbs-type ruthe- of the Pacritinib precursor. Compatibility of the new catalyst
nium complexes (Sil-II and Sil-II') were obtained, character- with various green solvents was checked and metathesis of
ized, and screened in a set of olefin metathesis reactions. Sildenafil and Tadalafil-based substrates was successfully
These catalysts were conveniently synthesized from a com- conducted in acetone. The mechanism of Sil-II' initiation has
mercially available pharmaceutical building block—Sildena- been investigated through kinetic experiments unveiling that
fil aldehyde—in two steps only. Stability and catalytic activity the decrease of the steric hindrance of the chelating alkoxy
tests disclosed that the bulkier NHC-ligand bearing catalyst moiety (from iPrO to EtO) favors the interchange initiation
Sil-II' is visibly more stable and productive than its smaller pathway over the typical dissociation pathway for other pop-
nd
NHC-analogue Sil-II. Good application profile of catalyst Sil- ular 2 generation Hoveyda-Grubbs catalysts.
II' was confirmed in a set of diverse metathesis reactions in-
cluding ring-closing metathesis (RCM) and cross-metathesis Keywords: Catalysis, Olefin metathesis, Electron withdraw-
(
CM) of complex polyfunctional substrates of medicinal ing group (EWG), Ruthenium catalysts, N-heterocyclic car-
chemistry interest, including a challenging macrocyclization
bene ligands (NHC), Mechanism
Gru-I in solution and a quite high catalyst loading typ-
ically used are the limitations of this system. Succes-
sive enhancement of the catalysis activity and stability
has been achieved, firstly, with the introduction of N-
heterocyclic carbene (NHC) ligands such as SIMes
(1,3-bis-(2,4,6-trimethylphenyl)-2-imidazolidinyli-
dene) or SIPr (1,3-bis-(2,6-triisopropylphenyl)-2-im-
idazolidinylidene) leading to the so called 2nd genera-
Introduction
The formation of carbon-carbon bonds is a crucial re-
[1]
action in organic chemistry. Among numerous meth-
ods for the creation of C–C bonds,[2] olefin metathesis
[3]
appears to be a peculiarly important tool. Signifi-
cantly, the catalytic olefin metathesis reaction can di-
rectly transform a set of already existing C-C double
bonds (e.g. in a diene) into valuable product (e.g. a cy-
cloalkene) with high precision and selectivity under
mild conditions.[ Since the development of relatively
air stable ruthenium based Grubbs’ catalyst
tion
Grubbs-type
catalysts
(NHC)(PCy
3
)(Cl)
2
Ru=CHPh (Gru-II, and Gru-II',
[7]
Figure 1). Another noteworthy improvement in the
field of olefin metathesis catalyst was the development
of ruthenium-indenylidene complexes (such as Ind-I
and Ind-II, Figure 1) which are readily obtained from
4]
[5]
(
PCy
3
)
2
(Cl) Ru=CHPh (Gru-I, Figure 1), this meth-
2
odology became broadly employed in organic chemis-
try, particularly in target oriented synthesis, prepara-
tion of polymers, and industrial transformation of re-
[RuCl
2
(PPh ) ] and 1,1-diphenylpropargyl alcohol and
3
3
are resistant to harsh conditions such as high tempera-
[8]
ture. Next milestone was reached when Hoveyda re-
ported on the first phosphine-free Ru complex bearing
a bidentate 2-alkoxybenzylidene ligand [(SIMes)(2-
[6]
newable materials. Despite the high tolerance toward
organic functions and the plethora of applications re-
ported with this catalyst, a relatively low stability of
isopropoxy-κ-O-benzylidene)RuCl ] (Hov-II, Fig-
2
[9]
ure 1). Subsequently, the introduction of electron
1
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Advanced Synthesis & Catalysis
10.1002/adsc.202100669
withdrawing group (EWG) in the chelating benzyli-
dene moiety of Hoveyda-Grubbs type complexes led
to a further increase of the activity and stability of such
obtained catalysts enabling the decrease of the catalyst
loading concomitantly with an increase in application
Figure 1b). These complexes have been obtained
within only two simple steps from commercially avail-
able aldehyde 1, a popular precursor in Sildenafil (Vi-
[19]
agra™; Figure 1) production.
[10]
[11]
[12]
scope.
In this regard, Grela,
Zhan,
and
Mauduit[ developed several activated derivatives of Results and Discussion
13]
Hov-II, that were substituted in the chelating benzyli-
dene fragment with electron withdrawing groups such
as NO (Gre), SO NMe (Zha), and NHC(O)CF
Mau; Figure 1). Despite their usually higher activity
Synthesis of the new EWG-activated Hoveyda-
2
2
2
3
Grubbs type catalysts. Sildenafil (commercialized,
among others, as Viagra™ by Pfizer or Maxigra™ by
Polpharma) is a worldwide known inhibitor of phos-
pho-diesterase(V) used in a treatment for erectile dys-
(
[14]
and some promising applications, the synthesis of
such catalysts require more synthetic steps as com-
[15]
[19c]
[20]
pared to the parental unsubstituted Hov-II complex.
function
and pulmonary arterial hypertension.
Consequently, finding a commercially available build-
ing block that can be used in the synthesis of a EWG-
activated benzylidene ligand is of high interest, as it
shall lead to the significant reduction of synthetic and
purification steps en route to an activated Hoveyda-
Grubbs type catalyst.[ Furthermore, if such building
block is a part of the already existing large-scale in-
dustrial process, either as an intermediates or a side-
product, its alternative way of utilization is welcomed,
as it goes along with the recent policies of Circular
Economy,[ as well as with the general principles of
green chemistry.[
As an indication of the importance of this drug on the
market, Viagra™ generated over 1 billion of US dol-
[21-22]
lars worldwide for Pfizer in 2017.
The so-called
Sildenafil aldehyde (1, Figure 1b), is a crucial interme-
diate in the convergent synthesis of this active pharma-
16]
[19a, 19b]
ceutical ingredient (API).
We realized that the same building block, widely
available since it is used in a large-scale global manu-
facturing of Sildenafil, can be utilized as the precursor
of choice in the synthesis of some new EWG-activated
Hoveyda-Grubbs type catalysts (coded as Sil-II and
Sil-II', Figure 1b). Indeed, the EWG sulfonamide
group in 1 is located in the required position, para to
the ether fragment, exactly like in the other EWG-ac-
tivated catalysts (Figure 1a). In addition, the presence
of ethyl ether fragment in 1, which is smaller than iso-
propyl ether (typically present in Hoveyda-Grubbs cat-
alysts) shall activate the envisaged complex in metath-
esis by further destabilizing the catalyst resting
17]
18]
[23]
state.
Figure 1. a) Selected NHC ligands ruthenium catalysts for
olefin metathesis. b) New complex Sil derived from phar-
maceutical building-block 1. Cy = cyclohexyl.
Scheme 1. Synthesis of complexes Sil-II and Sil-II' from 1
as a common precursor.
Herein, we described the synthesis and the charac-
nd
terization of two new Hoveyda-Grubbs type 2 gener-
ation olefin metathesis catalysts bearing a 2-ethoxy-5-
To reduce this hypothesis to reality, two com-
plexes of general structure Sil-II and Sil-II' (with
sulfonamide-benzylidene ligand (Sil-II and Sil-II',
2
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Advanced Synthesis & Catalysis
10.1002/adsc.202100669
SIMes and SIPr NHC ligands) were obtained from al-
dehyde 1 within only two simple synthetic steps, con-
sisting of Wittig olefination reaction and ligand ex-
change. As illustrated in Scheme 1, styrene derivative
a parameter characterizing the geometry of coordina-
tion centers of this type[27] is 0.32 and 0.26 for Sil-II
and Sil-II’ respectively. Therefore, the Ru(II) center,
in both cases, adopts the symmetry closest to distorted
square pyramid. Of interest, the reduction of the steric
bulk on the alkoxy moiety in Sil-II does not affect the
Ru‒O bond length when compared to the one of Hov-
II and Gre-II (Table 1). The value of this parameter is
2.269(5), 2.2562(10) and 2.2581(13) / 2.2869(12) Å
for Sil-II, Hov-II and Gre-II, respectively. On the
other hand, the corresponding bond within Sil-II’ is
noticeably shorter (2.2472(18) Å). In this case, the dis-
tance between the Ru and O atoms is comparable to
the one reported for Gre-II’ (2.244(2) Å) and slightly
longer than in Hov-II’ (2.2357(6) / 2.2490(6) Å). The
values of Ru‒C(NHC) bond length for Sil-II and Sil-
II’ are 1.981(7) and 1.973(3) Å, respectively and are
similar to those noted for the most of SIMes or SIPr-
based complexes compared in this study (Table 1). The
only noteworthy difference is the Ru‒C(NHC) bond of
both Sil-II and Sil-II’ being noticeably shorter than the
one reported for Mau-II’ complex (1.9911(13) Å).
Comparison of the Ru=C(benzylidene) bond length in
Sil-II and in Sil-II’ (1.816(7) and 1.829(3) Å respec-
tively) underline that the difference between them do
not exceed a three-sigma criterion, and these men-
tioned values are in good agreement with those ob-
served for other discussed derivatives (Table 1). The
values of the Ru‒Cl bond lengths in Sil-II (2.322(2)
and 2.329(2) Å) as well as the one of Sil-II’ (2.3335(7)
and 2.3307(7) Å) do not differ from those reported for
the vast majority of compared SIMes and SIPr com-
plexes.
2
was obtained in good yield (71%) via the reaction of
aldehyde 1 with ethyl(triphenyl)phosphonium bro-
mide (1.4 equiv.) and potassium tert-pentoxide
(
1.5 equiv.) at 0 °C in THF for 20 h. The SIMes-bear-
ing complex Sil-II was then obtained in good yield
82%) as a green microcrystalline solid via a stoichio-
(
metric metathesis reaction of 2 (1 equiv.) with the sec-
ond-generation ruthenium-indenylidene complex Ind-
[24]
II (1 equiv.) in the presence of CuCl (1.5 equiv.) as
phosphine scavenger.
A similar synthetic approach has been attempted
for the preparation of the SIPr analogue, Sil-II'. Un-
fortunately, the use of the corresponding indenylidene
complex (Ind-II’, SIPr analogue of Ind-II) as a sub-
strate did not provide a satisfying yield (<50%). There-
fore, Sil-II' was conveniently synthesized from the in
situ prepared second generation Grubbs complex Gru-
II' (Scheme 1). The addition of the styrene derivatives
2
(1.0 equiv.) and CuCl (2.2 equiv.) followed by a sim-
ple column chromatography under atmospheric condi-
tions and re-crystallization from a mixture of DCM
and heptane gave the desired complex Sil-II' as a
green microcrystalline solid (61% of yield). The re-
quired ruthenium source (Gru-II') was prepared one
pot from Gru-I and a free carbene (SIPr) made in situ
via deprotonation of the corresponding chloride salt
.
(
SIPr HCl) with hexamethyldisilazane lithium salt in
toluene (LiHMDS). Of note, Sil-II' has been isolated
as an ethyl acetate solvate (with one molecule of
EtOAc) as confirmed by NMR, FTIR, and elemental
analysis. For the sake of clarity, the solvation is omit-
ted in the manuscript, however it was taken into ac-
count during the calculation of yields and catalyst
loading.
When analyzing the geometrical features of the
first coordination sphere, special attention should be
paid primarily on the Cl1‒Ru‒Cl2 and the C(NHC)‒
Ru‒O valence angles, which can be considered as de-
scriptors of the accessibility of the metallic center dur-
ing the catalytic reaction. Of interest, the value of the
Cl1‒Ru‒Cl2 in Sil-II and Sil-II’ (respectively
X-ray solid-state structures. Crystals of the ruthe-
nium complexes Sil-II and Sil-II' suitable for diffrac-
tometric measurements were obtained via liquid-to-
liquid diff usion of heptane into concentrated DCM so-
lutions of complexes. The structure of both derivatives
was unambiguously confirmed by single-crystal X-
Ray diffraction analysis (Figure 2). The investigated
systems crystallize in monoclinic C2/c (Sil-II) and or-
thorhombic Pbca (Sil-II’) space group with one mole-
cule of given compound in the asymmetric unit of the
crystal lattice. In case of Sil-II’, the independent part
of the unit cell contains also a molecule of heptane.
The values of selected parameters describing the ge-
ometry of both compounds are reported in Table 1
158.32(9) and 157.25(2)°) are higher than those of the
other complexes reported in Table 1. While the
C(NHC)‒Ru‒O angle value of Sil-II (177(4)°) is sim-
ilar to those reported for Hov-II and Gre-II, the values
of these angles of all SIPr-based complexes reported
in Table 1 are noticeably lower. These angles are rang-
ing from 171.09(4) to 172.91(9)° and the highest value
was observed for the Sil-II’.
Structural differences beyond the geometry of the
coordination center of Sil-II and Sil-II’ become more
pronounced after respective alignment of their mole-
cules. The superimposition of Sil-II and Sil-II’ de-
picted in Figure 3 reveals that the molecular skeletons
of these complexes exhibit different degree of deflec-
tion of the NHC relative to the plane of alkoxybenzyl-
idene ligand. This feature was already highlighted by
[
9,
along with those of other selected ruthenium SIMes
2
5]
[13, 26]
and SIPr-based complexes.
The crystallo-
graphic data and refinement details as well as a full set
of bond lengths and values of valence and torsion an-
gles for Sil-II and Sil-II’ are given in Tables S11‒S17
(
ESI).
As expected, the Ru-atom of both analyzed com-
plexes is penta-coordinated. The value of τ , which is
5
3
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Advanced Synthesis & Catalysis
10.1002/adsc.202100669
the different values of the O‒Ru‒C(NHC) valence an-
gle (Table 1) and can also be described by the value of
the angle between mean-planes of the NHC five-
4
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Advanced Synthesis & Catalysis
10.1002/adsc.202100669
Figure 2. Molecular structure of Sil-II and Sil-II' complexes with crystallographic atom numbering. Displacement ellipsoids
are drawn at the 50% probability level. The hydrogen atoms and minor component of disordered 4-methylpiperazine-1-
sulfonyl moiety are omitted for clarity.
Table 1. Selected bond lengths [Å] and angles [°] for the Ru‐ based complexes Sil, Gre, Hov (SIMes and SIPr) and Mau-
II'.
SIMes Complexes
Sil-II
Hov-II[9]
Gre-II a) [25]
Ru‒O
Ru‒Cl1
Ru‒Cl2
2.269(5)
2.322(2)
2.329(2)
1.981(7)
1.816(7)
158.32(9)
177.4(3)
2.2562(10)
2.3279(4)
2.3380(4)
1.9791(15)
1.8286(15)
156.251(15)
176.06(5)
2.2581(13)/2.2869(12)
2.3429(5) / 2.3330(5)
2.3272(5)/ 2.3299(5)
1.9827(18)/ 1.9790(19)
1.8286(19)/ 1.8251(19)
157.88(2) / 157.880(18)
175.80(6) / 178.45(7)
Ru‒C(NHC)
Ru=C(benzylidene)
Cl1‒Ru‒Cl2
C(NHC)‒Ru‒O
SIPr Complexes
Hov-II' a) [26a]
NG-II'[26b]
2.244(2)
Mau-II'[13]
2.3002(10)
2.3293(4)
2.3358(4)
1.9911(13)
1.8266(14)
153.478(14)
171.09(4)
Sil-II'
Ru‒O
Ru‒Cl1
Ru‒Cl2
2.2472(18)
2.3335(7)
2.3307(7)
1.973(3)
1.829(3)
157.25(2)
172.91(9)
2.2357(6)/2.2490(6)
2.3283(2)/2.3298(2)
2.3480(2)/2.3407(2)
1.9789(8) /1.9782(8)
1.8322(8)/1.8307(8)
156.858(9)/155.881(8)
171.58(3)/171.88(3)
2.3326(9)/
2.3238(9)
1.985(3)
1.828(3)
156.79(3)
172.48(11)
Ru‒C(NHC)
Ru=C(benzylidene)
Cl1‒Ru‒Cl2
C(NHC)‒Ru‒O
a) Crystals of these compounds contain two crystallographically independent molecules of given complex.
Figure 3. Superimposed molecules of Sil-II and Sil-II’. The hydrogen atoms are omitted for clarity.
5
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Advanced Synthesis & Catalysis
10.1002/adsc.202100669
membered ring and the phenyl ring of the benzyl-
idene unit. These moieties in Sil-II and Sil-II’ are in-
Notably, the latter complex reached only 12% of de-
composition after twice-prolonged time (14 days in so-
clined to themselves by the angle of 161.4(3) and
lution). In comparison, after 14 days in CD
2
Cl at room
2
1
52.2(10) °, respectively. The substitution of the NHC
temperature, Gre-II (orange) and Zha-II (red) as well
as Hov-II (purple) remained untouched (<5% of de-
composition after 15 days). In contrast, the sensitivity
of Gru-II (black) in solution is much more pro-
nounced and led to the complete decomposition after
8 days within these conditions. The order of stability
is thus as followed: Gre-II ≈ Zha-II ≈ Hov-II> Sil-II'
> Sil-II > Gru-II. Of note, the SIPr analogue, Sil-II'
could also be stored as a solid under argon for
3 months at room temperature without considerable
loss (98% of the complex remaining).
moiety by the 2,6-disopropylphenyl groups (for SIPr
in Sil-II’) results in noticeable twisting of this ancil-
lary ligand on C2‒C3 bond. Moreover, the investi-
gated compounds differ in the spatial orientation of the
substituents attached to the NHC. Indeed, the mean-
planes of the aromatic rings defined by the C4‒C10
and the C13‒C18 atoms are inclined to the mean-plane
of the five-membered ring by the angles of 88.4(3) and
89.5(3) ° for Sil-II, and 80.43(10) and 79.65(10) ° for
Sil-II’. Finally, the 4-methylpiperazine-1-sulfonyl
groups in Sil-II and Sil-II’ are flipped on the opposite
side of their alkoxybenzylidene units as depicted in the
side view of Figure 3. In Sil-II, this functional group
is additionally disordered.
Catalytic activity studies. The catalytic activity
of Sil complexes was first tested in the ring closing
metathesis (RCM) reaction of a standard model sub-
strate, diethyl(diallyl)malonate (3a)[ at 0.1 mol%
catalyst loading (Figure 5). This well-known bench-
mark reaction unveiled that Sil-II initiated the reaction
more quickly than the commercial Zha-II and Hov-II
28]
Thermodynamic stability assessment. Despite their
structural similarity, the two Sil catalysts were found
to visibly differ in stability. Even during their prepara-
tions, it was easy to observe that Sil-II (SIMes com-
plex) is sensitive towards air and moisture and its iso-
lation in good yield requires a work-up under inert at-
mosphere as well as the use of a dry degassed solvent.
In contrast, the SIPr variant, Sil-II', could be isolated
in air. The aforementioned difference in stability was
not only observed during the synthesis and work-up
process, but was also independently confirmed in sta-
catalysts reaching 28% of conversion of 3a within
29]
5
2
min (krel(Sil-II) = 1.67)[ in dichloromethane at
0 °C while after the same period of reaction time,
complexes Hov-II and Zha-II led to 7 and 14% con-
version, respectively within the same reaction condi-
tions (krel(Hov-II) = 0.44 and krel(Zha-II) = 1.02). In
contrast, nitro-substituted complex Gre-II exhibited a
higher initiation rate for this reaction leading to a 38%
conversion of 3a within 5 min (krel(Gre-II) = 2.59).
The relative rates of the RCM of 3a were calculated
with respect to the initial rate of RCM catalyzed by Sil-
II' and led to krel(Sil-II') = 1.0, krel(Hov-II) = 0.44,
bility tests conducted in dry degassed CD
sealed NMR tube at 20 °C (Figure 4).
2
Cl in a
2
krel(Zha-II) = 1.02, and krel(Gre-II) = 2.59.
Thus, the order of the initiation rate of the reaction of
RCM of compound 3a is: Gre-II > Sil-II > Sil-
II' ≈ Zha-II > Hov-II. Of note, this trend of reactivity
[
30]
follows the respective Hammett constants σ as pos-
tulated by Blechert and co-workers[ with values of
31]
[
σ
σ
p,m(-NO
p,m(-SO
2
) > σp,m(-SO
) > σp,m(-H). ((σ
2
(N-methylpiperazinyl) 32]
≈
2
NMe
2
p
; σ
m
) = (0.78; 0.71),
, -SO NMe and
(0.65; 0.51) and (0.00; 0.00) for -NO
H respectively.
2
2
2
-
It is noteworthy that Sil-II exhibits a higher initiation
rate than Zha-II catalyst, while the electronic proper-
ties (i.e. Hammett parameters) of their sulfonamide
EWGs shall be similar. Such results are in accordance
with the previous observations by Plenio et al. who
demonstrated that the reduction of the steric bulk at the
alkoxy moiety of the benzylidene ligand increased the
initiation rate of RCM reactions.[ Furthermore, the
low stability of such alkoxy sterically unhindered com-
plex is evenly in agreement with the literature.[
Figure 4. Curve of the stability of the catalysts in degassed
DCM monitored by H NMR Hov-II (purple), Zha-II (red),
Sil-II' (green) and Sil-II (blue), Gre-II (orange) and Gru-
II (black). Lines are visual aid only.
1
33
]
11b, 23, 33]
More than 20% of Sil-II decomposed within 7 days,
while the SIPr complex Sil-II' exhibited only a small
amount of decomposition after the same period of time.
Importantly, increasing the bulk of the NHC in Sil
(
from SIMes to SIPr) seems to compensate the lack of
6
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Advanced Synthesis & Catalysis
10.1002/adsc.202100669
stability as well as the acceleration of activation rate of
these catalysts since Sil-II' exhibit a similar kinit to
Zha-II catalyst (krel(Zha-II) = 1.02). Albeit the initia-
tion rates of these complexes are similar, the conver-
sion of the RCM of 3a catalyzed by Sil-II' surpassed
the one promoted by Zha-II catalyst after 10 min of
reaction and reached completion after 60 min (vs
This lower stability of the active complex induces an
early inflexion point of the curve (c.a. 15 min) and
consequently a longer reaction time to reach comple-
tion.
Similar picture has been obtained for another
[28]
benchmark reaction —RCM of N,N-diallyltosyla-
mide (3b) in DCM (0.1 M) using catalyst loading of
0
.1 mol%, underlining the same order of relative initi-
90 min for Zha-II). In contrast, the Sil-II, exhibiting a
ation rates for Hov-II', Mau-II', Sil-II' and Gre-II'
which were 0.1, 0.4, 1.0 and 1.5 respectively (vs 0.2,
0.3, 1.0 and 1.9 respectively, noted for RCM of 3a,
(see ESI, Scheme S9).
higher initiation rate than Sil-II' and Zha-II, did not
reach completion and led to a maximum conversion of
72%. Thus, the model RCM reaction results reflect the
Because the above experiments witnessed that the
SIMes bearing catalyst Sil-II is visibly inferior to its
SIPr analogue Sil-II' in terms of productivity and sta-
bility, for further studies we decided to focus on the
latter.
respective stability picture of these complexes.
Figure 5. Plot of the reaction conversion in function of time
for RCM of DEDAM (3a) (0.1 M) with commercially avail-
able SIMes-bearing catalysts and Sil (SIMes and SIPr)
(
0.1 mol %) in DCM at 20 °C: Hov-II (blue), Zha-II (pur-
ple), Sil-II' (green) and Sil-II (orange) and Gre-II (red).
Conversion determined by NMR spectroscopy and con-
firmed by GC. Lines are visual aid only.
Figure 6. Plot of the reaction conversion in function of time
for RCM of DEDAM (3a) (0.1 M) with commercially avail-
able SIPr-bearing catalysts and Sil-II' (0.1 mol %) in DCM
at 20 °C: Hov-II' (purple), Mau-II' (green), Sil-II' (orange)
and Gre-II' (red). Conversion determined by NMR spec-
troscopy and confirmed by GC. Lines are visual aid only.
In order to have a proper comparison, the RCM
reaction of 3a was repeated with the SIPr-bearing
Hoveyda-Grubbs catalysts under the same conditions
(
i.e. 0.1 mol% catalyst and 0.1 M 3a in DCM at 20 °C;
Scope and limitation study. The application profile
of the more robust Sil-II' catalyst was evaluated with
a set of diene derivatives 3a-3h under mild conditions
(Ru loading of only 0.1 mol%, ambient temperature,
2 h of reaction time; Scheme 2). The relatively struc-
turally undemanding 5- and 6-membered carbo- and
heterocycles 4a-4f featuring di- and trisubstituted C–
C double bonds were formed in good to quantitative
yields at 20 °C. Gratifyingly, the spirocyclic anthrone
derivative (4g) was formed in high yield (97%). Fur-
thermore, the more densely functionalized barbituric
acid derivative 4h was formed in high yield under sim-
ilar mild conditions (Scheme 2).
Figure 6). Again, the order of reactivity of the SIPr cat-
alysts followed the trend of the Hammett parameters,
namely Gre-II' > Sil-II' > Mau-II' > Hov-II' with rel-
ative initiation rate of 1.9, 1.0, 0.3 and 0.2 respectively
(
σ
p
= 0.12, σ
m
= 0.30 for -NHC(O)CF substituent). Of
3
note, while Sil-II' reached full conversion at the same
time than the SIMes-bearing Gre-II, the SIPr deriva-
tive Gre-II' exhibited a higher productivity, reaching
full conversion within 40 min (vs 60 min for Gre-II
and Sil-II'). This behavior can be surprising since the
initiation rate of Gre-II is higher than its SIPr ana-
logue (krel 2.59 and 1.9 respectively). Nevertheless,
this difference in activity can be explained by the
lower stability of the active species (i.e. methylidene
complex) generated from Gre-II compared to Gre-II'.
Next, the application profile of Sil-II' has been probed
in the cross‐ metathesis (CM) reaction (Scheme 3). To
7
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Advanced Synthesis & Catalysis
10.1002/adsc.202100669
do so, we started with a benchmark CM reaction[28] be-
In this report, the cross-coupling between 13 and
14 was achieved with a relatively high loading
(5 mol%) of Gre-II at 30 °C within 3 h to yield to
tween allylbenzene (5) and (Z)-1,4-diacetoxybutene
(
6) in DCM at 20 °C. Within 1 h, alkene 5 was com-
[36]
pletely transformed into the corresponding CM prod-
uct 7, which has been isolated with 85% yield and E/Z
ratio of 76/24. It is noteworthy that isomerization of
allylbenzene 5 to the corresponding styrene was not
compound 15 in 72%.
Relying on the observed high stability of SIPr-
based Sil-II’ and its longevity in reaction mixture (vide
infra), the CM of the indole 13 and the sulfonamide 14
was undertaken with only 0.2 mol% of Sil-II’ at ambi-
ent temperature (20 °C). Satisfyingly, even such mild
reaction conditions allowed the isolation of the prod-
uct 15 in a good yield of 85% within 15 h (Scheme 3).
The encouraging results obtained so far with Sil-II’ led
us to approach even more complex polyfunctional
products relevant to the pharmaceutical industry. To
that aim, N,N-diallylsulfonamide derivative of
Sildenafil 16 was subjected to RCM in DCM
(Scheme 4). Despite the high level of functionalization
of this molecule and the presence of the acidic proton
of the pyrazolopyrimidinone moiety, the RCM of
diene 16 reached completion within 0.5 h at 20 °C in
the presence of only 0.5 mol% of Sil-II’. Of note,
product 17 was found to be slightly soluble in cold
DCM. Therefore, filtration of the cooled reaction mix-
ture (0 °C) and the subsequent washing of the resulting
solid with cold DCM enabled the isolation of the de-
sired product (92%) with a low content of Ru contam-
ination of 9.3 ppm.
[34]
observed during the reaction. Next, electron defi-
cient CM partners, such as α,β‐ unsaturated ester (9),
ketone (11),[ and sulfonamide (14) were tested.
35]
[36]
These compounds are known to be challenging part-
[37]
ners in CM reactions (Type II and III olefins) be-
cause the C–C double bond in these compounds is less
reactive in metathesis due to the conjugation with the
EWG-group.[
37-38]
Nevertheless, the reaction of termi-
nal alkene 8 with 9 and 11 occurred in the presence of
.5 mol% of Sil-II' in DCM within only 2 h at 20 °C
0
to afford the corresponding α,β‐ unsaturated carbonyl
compounds 10 and 12 with good yields (78 and 84%,
respectively). This attainment led us to consider even
more challenging vinyl sulfonamide 14 as a partner in
CM reaction with indole derivative 13, which has been
[36]
previously reported as the key step in the synthesis
of a naratriptan derivative 15.[
39]
Next, the precursor of Pacritinib 18 was selected
as a more challenging substrate for the RCM reaction.
Pacritinib is of particular interest because of potential
pharmaceutical applications for the treatment of
myelofibrosis and lymphoma. From a chemical point
of view, compound 18 is a rather problematic substrate
for RCM mainly due to the presence of chelating sites,
such as basic nitrogen atoms present on the amino-py-
rimidine fragment that are able to “arrest” the catalyst
in the form of a stable chelate. Moreover, 18 possesses
two labile O-allyl fragments that create the risk of C–
[37, 40]
C double bond isomerization (shift).
Therefore,
the RCM macrocyclization of this diene shall be con-
sidered as a rather challenging transformation. The
group of Williams in 2011 reported the RCM of diene
1
8 (1 mM) in acidic conditions (aqueous HCl, pH ≈
Scheme 2. RCM reactions of model dienes catalyzed by Sil-
II’ (isolated yields of analytically pure substances).
2.0-2.2) in DCM using 10 mol% of Gru-II as the cat-
[41]
alyst. Under such conditions, the RCM reaction at
0-45 °C afforded product 19 in 74% with an E/Z ratio
of 85/15.
4
Scheme 3. Model CM reactions catalyzed by Sil-II' at ambient temperature (isolated yields of analytically pure substances).
TBDMS = tert-butyldimethylsilyl.
8
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Advanced Synthesis & Catalysis
10.1002/adsc.202100669
Scheme 4. Metathesis reactions of APIs 16, 18 and 20 catalyzed by Sil-II' (isolated yields of analytically pure substances)
and the solid-state structure of the 17.
In 2017, Hoveyda and co-workers disclosed the
Assessing the practicability: Applicability in non-
degassed solvent and Ru removal after the reaction.
Until now, all experiments have been conducted in dry
and degassed DCM (3 ppm of water), under protective
atmosphere. However, one of the key features of Ru
metathesis catalysts is there uses under air and in not
strictly dry solvents, which can be beneficial in practi-
cal industrial setups. To further investigate the ap-
plicability of Sil-II' in such non-perfect conditions, we
attempted RCM of 3a in a non-dry and non-degassed
DCM (the water content in the solvent was 265 ppm
according to Karl Fisher titration). Under such condi-
tions 0.5 mol% of Sil-II' reached 95% of conversion
after 3 h. In the case of Gre-II' and Hov-II', the RCM
reaction of 3a led to full conversion (>99%). Interest-
ingly, the SIMes bearing Gre-II led to only 69% of
conversion after 3 h (Scheme 5). This result demon-
strated the generally higher stability of the SIPr cata-
lysts during the metathesis reaction.
preparation of Pacritinib precursor 19 using an E-se-
[42]
lective molybdenum-based metathesis catalyst. In
this reaction, the boryl-protected diene (20 mM in dry
toluene) was treated at 22 °C with 10 mol% of the cat-
alyst to yield the Pacritinib precursor 19 (73%) with
the E/Z ratio of 92/8. Despite the high selectivity of
this reaction, the protection of the NH group with a
tert-butoxycarbonyle group (Boc) of the pyrimidine
moiety was required to reach an acceptable yield (34%
yield of 19 in the case of the nonprotected derivative)
which force additional synthetic steps to obtain the tar-
get molecule Pacritinib.
[44]
Based on the above reports, the macrocyclization
of compound 18 (2 mM in DCM) was undertaken in
the presence of triflic acid (4 equiv.) to protonate the
basic nitrogen sites present in the substrate. Remarka-
bly, with Sil-II' catalyst, the full conversion was
reached after 3 h of reflux (45 °C), using a relatively
low catalyst loading of 3×1 mol% (the catalyst was
added portion wise during the reaction). The macrocy-
cle 19 was isolated in 73% yield (E/Z = 76/24) after a
We also attempted to check if the new complex,
Sil-II', leads to similar Ru contamination levels as
other catalysts of the Hoveyda-Grubbs family. To do
so, samples of crude product 4a obtained in the above
test reactions were used to determine such Ru contam-
ination (Scheme 5). Of note, in contrast to product 17
which could be filtered off the reaction mixture, the
purification of the oily product 4a is more challenging
and required the addition of Ru scavenger such as iso-
basic work-up with saturated Na
2
CO and column
3
chromatography on silica gel (Scheme 4).
The final example of a polyfunctional molecule of
pharmaceutical interest used in this study was a Tada-
lafil derivative.[
19a]
Tadalafil is a potent inhibitor of
phosphodiesterase(V) used as the same purpose than
Sildenafil (treatment of erectile dysfunction) and com-
[45]
cyanide 22. Therefore, the crude reaction mixtures
of scheme 5 were stirred with commercial scavenger
22 and silica gel in DCM at ambient temperature for
30 min and then filtered. After this simple phase sepa-
[43]
mercialized as Cialis™ by Lilly Eli & Company. In
contrast to Sildenafil-related diene 16, N-allyl Tadala-
fil derivative 20 proved to be more reluctant in metath-
esis. Nevertheless, with 1 mol% of Sil-II', the une-
ventful CM reaction between 20 and (Z)-1,4-diace-
toxybutene (6, 5 equiv.) occurred at 20 °C to afford the
expected product 21 in 68% yield with a relatively
high E/Z ratio of 95/5.
[46]
ration procedure, the content of Ru was measured
by ICP-MS, showing similar levels (24-66 ppm) of
trace Ru contamination in 4a for all Hoveyda-Grubbs
catalysts tested.
9
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Advanced Synthesis & Catalysis
10.1002/adsc.202100669
itated during the reaction allowing the isolation of an-
alytically pure product 17 in 94% yield within a simple
filtration without any cooling required. Of high inter-
est, this simple filtration led the recovery of product 17
with a very low ruthenium contamination content of
only 3.9 ppm (vs 9.3 with DCM).
Scheme 5. RCM of 3a catalyzed by selected SIPr-bearing
catalysts in non-dried and non-degassed DCM (265 ppm of
water) and purification of 4a from spend catalyst traces. n.d.
=
non-determined
Use in green solvents. As pointed out recently by
Sherwood, the use of chlorinated solvents soon will be
banned (or are already prohibited) and the society of
chemists must adapt to.[ Therefore, we decided to in-
vestigate the application profile of Sil-II' in greener
and more sustainable solvents than DCM. A set of en-
vironmentally friendly solvents, composed of 2-me-
thyltetrahydrofuran (2-MeTHF), cyclopentyl methyl
ether (CPME), anisole, ethyl acetate (AcOEt), dime-
thyl carbonate (DMC) and acetone, has been selected
according to the CHEM21 selection guide of sol-
vents.[ The activity of Sil-II' in these beforehand
dried and distilled solvents has been checked using the
model RCM reaction of 3a under the same conditions
as used previously, namely 1 mmol of 3a (0.1 M),
47]
Figure 7. Plot of the reaction conversion in function of time
for RCM of 3a (0.1 M) in different solvents catalyzed by
Sil-II' (0.1 mol %) at 20 °C: 2-MeTHF (black), CPME (pur-
ple), AcOEt (blue), anisole (green), DMC (orange), and ac-
etone (red). Conversion determined by H NMR spectros-
copy and confirmed by GC. Lines are visual aid only.
48]
1
0
.1 mol% of the catalyst at 20 °C under inert atmos-
phere, and the results are depicted in Figure 7. Surpris-
ingly, the ethereal solvents such as 2-MeTHF, CPME,
or anisole were found to be deleterious for the RCM of
The second complex substrate of medicinal
chemistry context, N-allyl Tadalafil derivative 20 was
also almost completely insoluble in acetone. In con-
trast to substrate 16, no metathesis was observed in the
presence of 1 mol% of Sil-II' at room temperature.
Heating the reaction mixture to reflux (c.a. 60 °C) led
to the complete dissolution of the substrate and the CM
reaction with 5 equiv. of (Z)-1,4-diacetoxybutene (6)
within 3 h afforded product 21 in 73% yield (E/Z ratio:
92/8; comparing with 68% of yield in DCM, see
Scheme 4).
3
a with a relative initiation rate of krel(2-MeTHF) =
0
.03, krel(CPME) = 0.24 and krel(anisole) = 0.34 (with
respect to the initiation of the reaction in DCM which
-5
-1
was 4.8.10 mol·s ). Surprisingly, the use of AcOEt
also decreased the efficiency of Sil-II', resulting in a
slow initiation comparable to CPME (krel(AcOEt) =
0.28). Nevertheless, the other carbonyl group-contain-
ing solvents such as DMC or acetone offered higher
initiation rate than the ethereal solvents and AcOEt
with relative initiation rate of krel(DMC) = 0.84 and
k
rel(acetone) = 1.19.
For further studies acetone was selected, as it al-
lowed to achieve both high initiation rate and good
overall productivity. To provide cogent evidence for
the applicability of the new catalyst in this solvent, the
RCM reaction of Sildenafil derivative 16 was under-
taken. While diene 16 proved to be poorly soluble in
acetone, the RCM reaction uneventfully occurred at
2
0 °C in the presence of 0.5 mol% of Sil-II' giving
product 17 in 94% of yield (Scheme 6). The only dif-
ference between this reaction and the RCM previously
made in DCM is the longer reaction time (2 h, 94% of
yield vs 0.5 h, 92% yield for DCM, see Scheme 4).
In contrast to the reaction in DCM, the metathesis
product 17 was highly insoluble in acetone and precip-
1
0
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Advanced Synthesis & Catalysis
10.1002/adsc.202100669
Scheme 6. Metathesis of pharmaceutical relevant com-
pounds 16 and 20 catalyzed by Sil-II' in acetone (isolated
yields of analytically pure substances).
pseudo first-order conditions ([3a] >> [Ru]) as a func-
tion of the concentration of 3a (from 0.03 – 2 M). The
Plenio’s group elegantly demonstrated that the de-
pendence of kobs on olefin concentration allows the dif-
ferentiation between the activation mechanisms of the
respective catalysts. In the case of a dissociative mech-
anism, the corresponding fit of kobs-[olefin] plot is a hy-
perbolic function defined by eq. 2. From a theoretical
point of view, such definition of kobs is the result of the
combination of a two-step reaction involving a limit-
Mechanism of the Sil-II' initiation.
In order to gain information on the mechanism of
activation of the SIPr-catalysts used in this study (de-
picted in Figure 8) and, in particular, to check the pos-
sible influence of the ethoxy chelating moiety of Sil-
II' on this mechanism, kinetic evaluations were con-
[51]
ing pre-equilibrium i.e., k
d
<<k-d and k
d
<<k
1
.
(Fig-
[49]
ducted using a model diene 3a in DCM utilizing
ure 8 and see demonstration in ESI)
time-dependent UV-VIS spectroscopy according to
[33]
ꢃ
1
the procedure described by Plenio and co-workers,
ꢁ *
[ퟑ풂]
ꢂ
ꢃ
ꢄꢂ
1
푘표푏푠 = (
(eq. 2)
2
kobs=k *[3a] (eq. 3)
i.e. monitoring the evolution of the absorbance (at the
peak of maximal absorption for each catalysts) as a
function of time which lead to the determination of
ꢃ
ꢅ+
*[ퟑ풂])
ꢃ
ꢄꢂ
k
obs(Ru-SIPr) according to the kinetic model in equa-
[50]
tion 1.
푑[푹풖푰푰′]
푑푡
푣 = −
= 푘표푏푠*[푹풖푰푰ꢀ] (eq 1)
The activation parameters of the rate determining
step (RDS) of the initiation mechanism, namely, acti-
⧧
⧧
vation energy (Ea), entropy (ΔH ), enthalpy (ΔS ), and
⧧
Gibbs free energy (ΔG ), were obtained for each pre-
catalyst and reported in Table 2. Gratifyingly, the acti-
vation energies (E ) as well as the Gibbs free energies
a
of the rate determining step of the pre-catalysts activa-
tion reflect the trend of reaction rate observed in Fig-
ure 6, namely Gre-II' > Sil-II' > Mau-II' > Hov-II'
Figure 8. Two possible mechanisms of Hoveyda-Grubbs
catalyst initiation: interchange and dissociative.
-1
with respective values of E
a
of 9.1 kcal·mol ,
-
1
-1
-1
1
3.2 kcal·mol , 17.7 kcal·mol , and 21.8 kcal·mol
⧧
-1 -1
and ΔG values of 20.2 kcal·mol , 20.6 kcal·mol ,
-1
-1
Table 2. Activation parameters (obtained for [3a] = 0.66 M,
2
1.0 kcal·mol , 22.5 kcal·mol . Enthalpy and entropy
-
4
[
Ru] = 10 M) and kinetic parameters for the initiation of
values were found to be more disparate with values
⧧
complexes Gre-II', Sil-II', Mau-II' and Hov-II' with 3a.
-
1
ranging from 8.4 to 21.2 kcal·mol for ΔH and from -
⧧
-1
-1
1
8.1 to -167.1 J·mol ·K for ΔS . The small value of
Activation Parameters
-
1
-1
entropy of Hov-II' (-18.1 J·mol ·K ) indicates that
the number of degrees of freedom of the RDS does not
change significantly from the initial state of the reac-
tion which could be explained by the absence of the
⧧
⧧
⧧
E
a
ΔH
kcal/mol)
8.4 ± 0.4
3.2 ± 1.3 13.0 ± 0.6
ΔS
ΔG
(
kcal/mol)
(
(J/mol/K)
-167.1± 5.3
-108.3 ± 8.9
(kcal/mol)
20.2 ± 1.1
20.6 ± 0.9
Gre-II'
Sil-II'
Mau-II'
Hov-II'
9.1 ± 0.3
1
1
2
coordination of the olefin to the ruthenium center at
⧧
7.7 ± 1.4 11.9 ± 1.4 -130.4 ± 19.9 21.0 ± 0.9
1.8 ± 1.8 21.2 ± 3.2
the RDS. Combined with the important ΔH (Hov-II')
-18.1 ± 44.1
22.5 ± 6.4
parameter, these results would suggest that the activa-
tion mechanism of Hov-II' is purely dissociative. (Fig-
Kinetic Parameters
⧧
ure 8) The high negative entropy values ΔS in the
k
d
k
2
-1
-1
other cases, i.e. -167.1, -108.3, and -130.4 J·mol ·K
-
1
-3
-3
(
s ·10 )
(L/mol/s·10 )
for Gre-II', Sil-II' and Mau-II' respectively, do not
exclude the dissociative pathway as the activation
mechanism of these pre-catalysts but only indicates a
significant contribution of the step of the coordination
of the olefin to the ruthenium center on the RDS (i.e.
Gre-II'
Sil-II'
Mau-II'
Hov-II'
34.9 ± 9.9
-
3.4 ± 0.9
0.6± 0.3
-
4.3
-
-
contribution of k , figure 8). Therefore, it is impossible
1
On the other hand, a linear fitting of the plot of
obs- [olefin] would indicate that the activation mecha-
to conclude on the mechanism type of the three latter
systems relying only on these activation parameters.
Consequently, further mechanistic investigations
were required to elucidate the initiation mechanisms of
these three catalysts. To do so, UV-visible spectros-
copy was employed to evaluate the evolution of kobs
k
nism of the catalysts involves an associative inter-
change (I ) pathway. In the latter case, the slope of the
fit determines k of the interchange pathway as defined
a
2
in eq. 3 (see Figure 8). Finally, it is plausible in some
cases that both pathways i.e. dissociation and inter-
change, intervene in the initiation mechanism. In such
(
defined in eq. 1) of the SIPr systems under second and
1
1
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Advanced Synthesis & Catalysis
10.1002/adsc.202100669
case, the fit of the plot of kobs- [olefin] would be defined
by the combination of the two equations such as
of the steric bulk at the alkoxy moiety (-OiPr to -OEt)
impacts dramatically the mechanism of activation
when compared to its SIPr-counterpart.
k
obs = eq. 2 + eq. 3. The experiments previously de-
scribed were thus carried out for each catalyst (at a
-4
concentration of 10 M) with 3a (from 0.03 to 2 M) in
CD Cl at 20 °C. The respective data obtained are re-
2
2
ported in Figure 9. Gratifyingly, the kobs vs [3a] of Conclusion
Hov-II' were fitted satisfactorily with the hyperbolic
function of eq. 2 which is confirming the dissociative
pathway of this catalyst. The same behavior of kobs was
observed for Gre-II' and Mau-II' and the resulting fits
correspond to a hyperbola. Importantly, the attempt to
fit these plots with eq. 2 + eq. 3 did not converge to a
satisfactory set of parameters indicating a purely dis-
sociative pathway for these three pre-catalysts. The
We have shown that large-scale produced API (ac-
tive pharmaceutical ingredient) precursor, sildenafil
aldehyde, can be used as a convenient starting material
in the preparation of EWG-activated Hoveyda-Grubbs
type ruthenium olefin metathesis catalysts. Stability
and catalytic activity tests disclosed that the smaller
NHC-ligand bearing complex (Sil-II, with SIMes lig-
and) is visibly less stable and productive than its ana-
logue, Sil-II', featuring bulkier NHC SIPr ligand.
Good application profile of the latter catalyst was con-
firmed in a set of diverse metathesis reactions includ-
ing ring-closing (RCM) and cross-metathesis (CM) of
both model substrates and complex polyfunctional
pharmaceutical building-blocks, including a challeng-
ing macrocyclization of Pacritinib precursor. Compat-
ibility of the new catalyst with various green solvents
selected according to the CHEM21 guide was checked
and the metathesis reactions of Sildenafil and Tadala-
fil-based substrates were successfully conducted in ac-
etone, showing that the new catalyst may be used in
green pharmaceutical production. The mechanism of
Sil-II' initiation has been investigated through kinetic
experiments and the obtained results unveiled that the
decrease of the steric hindrance of the chelating alkoxy
moiety (from iPrO to EtO) favors the interchange ini-
tiation pathway over the dissociation pathway typical
value of the dissociation rate constant k
d
for these com-
-3
-
plexes could thereby be determined as 0.6·10 , 3.4·10
and 34·10 s for Hov-II', Mau-II' and Gre-II' re-
3
-3 -1
,
spectively.
nd
for other 2 generation Hoveyda-Grubbs catalysts.
We believe that the reported results may be not only to
interest of chemists applying olefin metathesis in or-
ganic synthesis, but also useful for organometallic
chemistry experts designing new ruthenium-based cat-
alysts.
Figure 9. Plot of kobs vs [3a] for complexes Gre-II' (red),
Sil-II' (orange), Mau-II' (green) and Hov-II' (blue). Lines
correspond to the hyperbolic fit of the data according to
eq. 2 (dissociative pathway) for Gre-II', Mau-II' and Hov-
II' and to a linear fit for Sil-II' (interchange mechanism).
Experimental Section
The attempt to fit the dependencies of kobs(Sil-II')
on [3a] with eq. 2 led to aberrant values of the param-
Unless otherwise noted, all materials were purchased from
commercial suppliers and used as received. All reactions re-
quiring exclusion of oxygen and moisture were carried out
in dry glassware with dry solvents (purified using MBraun
SPS) under a dry and oxygen-free atmosphere using
Schlenk technique. The bottles with ruthenium catalysts
were stored under argon atmosphere, but no special precau-
tions were taken to avoid air or moisture exposure in the mo-
12 -1
eters (k > 10 s ) and showed an important deviation
d
of the fit residuals. These data appeared to be best fit-
ted with a linear function such as eq. 3. These results
point out that the mechanism of initiation of the pre-
catalyst is a pure interchange (associative type) one.
-3
1
Thus, we can extract the value of k
2
which 4.8·10
ment of extracting catalysts from the bottles. NMR ( H and
-1
-1
13
C) spectra were recorded on Agilent Mercury 400 MHz
L·mol ·s .
3 2 2
spectrometer at ambient temperature with CDCl or CD Cl
Since the electronic properties of the EWG of Sil-II'
are comprised between those of Hov-II' and NG-II'
used as a solvent. GC measurements were carried out using
PerkinElmer Clarus 580 employing InertCap 5MS-Sil col-
umn and helium as a carrier gas. IR spectra were recorded
using JASCO FT/IR-6200 spectrometer. The substances
(
H and NO respectively), we can assume that the
2
change of the initiation mechanism is mainly relying
on the decrease of the steric congestion of the alkoxy
moiety. Such behavior is reminiscent with the obser-
vation of the group of Plenio evaluating the effect of
MeO-substituted benzylidene derivatives of Gre-II
and Hov-II on the mechanism of activation. What is
striking in the case of Sil-II' is that the small decrease
were examined as a film or in the solution. Wavenumbers
-1
(
ῦ) are reported in cm . The obtained data was processed
with the software Omni32. UV-Vis spectra were recorded
using Thermo Fischer Scientific Evolution 300 UV-Vis
spectrophotometer in 10.00 mm QS cuvettes. Wavelenghts
(
λ) are reported in nanometres (nm), whereas absorbance
A) is given in absorbance units (a.u.). Scan speed was set to
(
600 nm/min, range 300 – 500 nm, bandwidth 1 nm and data
interval 1 nm. HRMS measurements were carried out using
1
2
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Advanced Synthesis & Catalysis
10.1002/adsc.202100669
AutoSpec Premier spectrometer. Elemental Analysis were
carried out at the Polish Academy of Science, Institute
of Organic Chemistry. ICP-MS: Ruthenium content was de-
termined using NexION 300D apparatus (Perkin Elmer,
USA). Column Chromatography was performed using
Merck Millipore silica gel (60, particle size 0.043 – 0.063
nm). TLC was performed using Merck Silica Gel 60 F254
precoated aluminium sheets. Substances were visualised us-
ing UV-light (254 or 365 nm) or by stains after
In a Schlenk flask, to a suspention of NHC precursor
SIPr•HCl (156 mg, 0.365 mmol, 1.20 equiv.) in dry toluene
(10 mL), LiHMDS (0.35 M in toluene, 891 mg, 1 mL,
0.350 mmol, 1.15 equiv.) solution was added dropwise at
20 °C and the resulting mixture was stirred for 20 minutes
until the suspension became almost completely clear (ho-
mogenous). The resulting mixture was transferred
to a Schlenk flask containing the solution of Ind-I (281 mg,
0.304 mmol, 1 equiv.)/Gru-I (250 mg, 0.304 mmol,
1 equiv.) in dry toluene (10 mL) and was stirred at 70 °C for
4 2 3
KMnO /K CO /NaOH reagent treatment (aqueous solution)
2
hours. The progress of the reaction was monitored by TLC
stationary phase: SiO , eluent: EtOAc/n-hexane 5:95 v/v).
Then, styrene 2 (99 mg, 0.304 mmol, 1 equiv.) and CuClanh
67 mg, 0.670 mmol, 2.2 equiv) were added and the result-
ing mixture was stirred at 80 °C for 1 hour. The progress of
the reaction was monitored by TLC (stationary phase: SiO
(
2
1
-((4-ethoxy-3-(prop-1-en-1-yl)phenyl)sulfonyl)-4-me-
thylpiperazine (Styrene 2):
(
To a suspension of ethyltriphenylphosphonium bromide
(
5.25 g, 14 mmol, 1.4 equiv.) in THF (30 mL), a solution of
2
,
potassium tert-pentoxide (25% in toluene, 7.57 g, 15 mmol,
eluent: EtOAc/n-hexane – 50:50 v:v). When the reaction
reached completion, the volatiles were removed under the
reduced pressure (up to the volume ~3 mL) and the crude
was purified using column chromatography (stationary
phase: SiO2, eluent: EtOAc/n-hexane from 50:50 to 100:0
v/v). The product was obtained as green solid (starting from
Ind-I: 123 mg, 43%; starting from Gru-I: 176 mg, 61%),
1
.5 equiv.) was added dropwise. The resulting orange mix-
ture was stirred at room temperature for 30 min. Then, the
mixture was cooled down to 0 °C and a solution of aldehyde
1
(3.12 g, 10 mmol, 1 equiv.) in THF (10 mL) was added
dropwise. The reaction mixture was stirred at 0 °C for
5 min, then was allowed to warm up to room temperature
and was stirred for 20 h. The reaction was quenched with a
1
1
which turned out to be an ethyl acetate solvate. H NMR
4
saturated aqueous solution of NH Cl (3 mL) and then ex-
(
400 MHz, CD
2
Cl ) δ: 16.24 (d, J = 0.7 Hz, 1H), 7.87 (dd,
2
tracted with EtOAc (3 x 5 mL). The combined organic lay-
ers were washed with brine (5 mL), and dried over anhy-
J = 8.6, 2.2 Hz, 1H), 7.58 – 7.54 (m, 2H), 7.38 (d, J = 7.8
Hz, 4H), 7.17 (d, J = 2.2 Hz, 1H), 7.01 (d, J = 8.3 Hz, 1H),
4
drous MgSO . Solids were filtered out and all the volatiles
4
4
.31 (q, J = 7.0 Hz, 2H), 4.19 (s, 4H), 3.54 (hept, J = 6.7 Hz,
H), 2.93 (s, 4H), 2.42 (s, 4H), 2.22 (s, 3H), 1.35 (t, J = 7.0
were removed under reduced pressure to afford crude prod-
uct 2 which was then purified using column chromatog-
Hz, 3H), 1.26 (d, J = 6.8 Hz, 12H), 1.20 (d, J = 6.6 Hz, 12H).
2 3
raphy (stationary phase: Al O , eluent: EtOAc/n-hexane
1
3
C NMR (101 MHz, CD
145.0, 138.5, 132.4, 131.6, 130.1, 126.3, 122.3, 114.3, 69.9,
2.1, 56.5, 47.7, 30.6, 28.1, 27.8, 25.1, 16.2, 15.9, 2.7. FT-
Cl film): 3063, 2966, 2929, 2867, 2800, 1736,
683, 1577, 1458, 1411, 1391, 1352, 1328, 1265, 1236,
165, 1148, 1091, 1063, 1024, 946, 901, 806, 760, 735, 703,
2
2
Cl ) δ: 284.5, 212.7, 158.3, 151.0,
from 20:80 to 40:60 v/v). The product was obtained as a
1
white solid (1.55 g, 71%, E/Z = 88/12). H NMR (400 MHz,
6
CDCl ) δ: 7.72 (d, J = 2.3 Hz, 1H), 7.54 (dd, J = 8.6, 2.3
3
IR (CH
2
2
Hz, 1H), 6.89 (d, J = 8.7 Hz, 1H), 6.67 (dq, J = 15.8, 1.5 Hz,
1
1
1
2
1
H), 6.30 (dq, J = 15.9, 6.6 Hz, 1H), 4.10 (q, J = 7.0 Hz,
H), 3.02 (bs, 4H), 2.47 (t, J = 4.8 Hz, 4H), 2.26 (s, 4H),
-
1
1
3
646, 625, 566, 504, 457 cm . HRMS (ESI): calculated
.91 (dd, J = 6.7, 1.7 Hz, 3H), 1.48 (t, J = 7.0 Hz, 3H).
C
+
mass for C41
8
(
H
2
59Cl N
4
O
3
RuS [M+H] : 859.2728; found:
RuS
NMR (101 MHz, CDCl
3
) δ: 158.8, 128.8, 128.3, 127.8,
26.4, 126.0, 124.4, 111.2, 64.2, 54.0, 46.0, 45.7, 18.9, 14.7.
Cl film): 3040, 2979, 2938, 2850, 2797, 2744,
651, 1590, 1490, 1471, 1453, 1394, 1348, 1329, 1287,
254, 1187, 1167, 1133, 1090, 1066, 1039, 1006, 942, 816,
59.2722. EA: analysis calculated for C45H66Cl N O
2 4 5
1
Sil-II’ + EtOAc): C 57.07, H 7.02, Cl 7.49, N 5.92, O 8.45,
FT-IR (CH
2
2
Ru 10.67, S 3.39; found: C 57.21, H 7.05, Cl 7.48, N 6.10,
1
1
7
S 3.35. UV-Vis: λmax = 367 nm.
-
1
89, 736, 673, 657, 629, 585, 545, 506, 434, 406 cm .
+
HRMS (ESI): calculated mass for C16
H
25
N
2
O
3
S [M+H] :
25.1586; found: 325.1578. EA: analysis calculated for
S: C 59.23, H 7.46, N 8.63; found: C 59.13, H
.44, N 8.60
3
16 24 2 3
C H N O
General procedure for RCM catalyzed by Sil-II’:
Under argon atmosphere, the substrate 3a-3h (118-274 mg,
8
0
.5/1.0 mmol, 1 equiv.) was placed in the Schlenk flask.
Complex Sil-II:
Then, 4.5-9.0 mL of dry DCM from ampula was added.
Stock solution of the catalyst Sil-II’ (4.8 mg, 0.005 mmol,
1 M) in DCM (5 mL) was prepared. 0.5/1.0 mL of the re-
sulting stock solution was added to the reaction mixture
(0.48/0.96 mg, 0.0005/0.0010 mmol, 0.1 mol%). The con-
centration of the solution obtained is 0.1 M. It was stirred at
room temperature for 1-2 hours until the completion of the
RCM reaction was reached (progress of the reaction was
monitored using TLC). Then, SnatchCat solution (4.4 equiv.
vs the catalyst, 0.44 mol%) was added in order to quench
Dry Schlenk vessel was charged with ruthenium complex
Ind-II (100 mg, 0.105 mmol, 1 equiv.) under argon atmos-
phere. Then, 15 mL of anhydrous toluene was added, result-
ing in a deep red solution. Styrene 2 (34 mg, 0.105 mmol,
1
equiv.) and CuClanh (15 mg, 0.158 mmol, 1.5 equiv.) were
added to this solution. Reaction mixture was stirred and
heated up to 60 °C. After 30 minutes, TLC (stationary
2
phase: SiO , eluent: EtOAc/n-hexane 10:90 v/v, RF,Ind-II =
0
.39, RF,Sil-II’ = 0) was performed in order to control the pro-
gress of the reaction. No spot from Ind-II could be observed. the reaction progress. The products 4a-4h were purified us-
All the volatiles were removed under reduced pressure and
the crude product was purified using column chromatog-
raphy (stationary phase: SiO , eluent: EtOAc/n-hexane from
2
2
ing column chromatography (stationary phase: SiO , eluent:
EtOAc/n-hexane).
0
:100 to 50:50 v/v). Product Sil-II was obtained as a green
General procedure for CM catalyzed by Sil-II’:
1
solid (67 mg, 82%). H NMR (400 MHz, CD
s, 1H), 7.94 (dd, J = 8.7, J = 2.1 Hz, 1H), 7.30 (d, J = 2.1
Hz, 1H), 7.10 (s, 4H), 7.00 (d, J = 8.6 Hz, 1H), 4.25 (q, J =
.0 Hz, 2H), 4.20 (s, 4H), 3.02 (bs, 4H), 2.41-2.47 (m, 22
2
Cl
2
) δ: 16.31
Alkene (1 equiv.) and the cross partner (2-3 equiv.) were
dissolved in dry DCM under argon atmosphere. To the re-
sulting mixture, the solution of the catalyst Sil-II’ (0.2-
(
7
0
.5 mol%) was added and the mixture was stirred at rt. After
1
3
H), 2.25 (s, 4H), 1.17 (t, J = 7.0 Hz, 3H). C NMR (101
reaction completion, it was quenched using ethyl vinyl ether
or SnatchCat (4.4 equiv. vs the catalyst). All the volatiles
were removed under reduced pressure and the crude product
was purified using column chromatography (stationary
MHz, CD
1
4
2
Cl
31.4, 129.7, 128.8, 121.1, 112.8, 68.2, 54.5, 51.9, 46.2,
5.9, 32.3, 29.41, 23.1, 21.2, 19.5, 14.3, 13.7. FT-IR
2
) δ: 290.0, 208.9, 156.6, 144.5, 139.5, 139.4,
(
CH
2
Cl film): 2918, 2853, 2798, 2743, 1730, 1605, 1577,
2
2
phase: SiO , eluent: EtOAc/n-hexane).
1
1
6
483, 1453, 1423, 1399, 1350, 1317, 1264, 1164, 1149,
135, 1111, 1092, 1022, 946, 900, 853, 811, 788, 735, 673,
-
1
46, 625, 611, 568, 504, 424 cm . HRMS (ESI): calculated
+
mass for C35
7
H
46
N
4
O
3
SClRu [M-Cl] : 739.2023; found:
CCDC 2086445, 2086446 and 2086447 contain the supple-
mentary crystallographic data for this paper. These data can
39.2002.
Complex Sil-II’:
1
3
This article is protected by copyright. All rights reserved.

Advanced Synthesis & Catalysis
10.1002/adsc.202100669
be obtained freely via http://www.ccdc.cam.ac.uk/data_re-
quest/cif, by e-mailing data_request@ccdc.cam.ac.uk or by
contacting directly the Cambridge Crystallographic Data
Centre (12 Union Road, Cambridge CB2 1EZ, UK. Fax:
13. H. Clavier, F. Caijo, E. Borré, D. Rix, F. Boeda, S. P. Nolan,
M. Mauduit, Eur. J. Org. Chem. 2009, 2009, 4254-4265.
1
1
1
4. A. Kajetanowicz, K. Grela, Angew. Chem., Int. Ed., DOI:
0.1002/anie.202008150
5. For
a discussion on various synthetic strategies in
+
44 1223 336033).
preparation of substituted chelating benzylidene ligands precursors
see: R. Bujok, M. Bieniek, M. Masnyk, A. Michrowska, A.
Sarosiek, H. Stȩpowska, D. Arlt, K. Grela, J. Org. Chem. 2004, 69,
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1
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894-6896.
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7. Eur-Lex (European Union Law) - A new Circular Economy
Acknowledgements
Action Plan for a Cleaner and More Competitive Europe, 2020
https://eur-lex.europa.eu/resource.html?uri=cellar:9903b325-
6388-11ea-b735-01aa75ed71a1.0017.02/DOC_1&format=PDF
Authors are grateful to the „Catalysis for the Twenty-First Century
Chemical Industry” project carried out within the TEAM-TECH
programme of the Foundation for Polish Science co-financed by
the European Union from the European Regional Development un-
der the Operational Programme Smart Growth. The study was car-
ried out at the Biological and Chemical Research Centre, Univer-
sity of Warsaw, established within the project co-financed by Eu-
ropean Union from the European Regional Development Fund un-
der the Operational Programme Innovative Economy, 2007–2013.
Authors are grateful to Dr. Michał Chmielewski for granting ac-
cess to his equipment and to Dr. Jakub Karasiński for the help.
(accessed on July 19, 2021)
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Moreover, SO
2
NMe
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since the functional group are very similar.
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NH , SO
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Advanced Synthesis & Catalysis
10.1002/adsc.202100669
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