Large-Scale Synthesis of a Niche Olefin Metathesis Catalyst Bearing an Unsymmetrical N-Heterocyclic Carbene (NHC) Ligand and its Application in a Green Pharmaceutical Context

Article abstract of DOI:10.1002/chem.202003830

A large-scale synthesis of known Ru olefin metathesis catalyst VII featuring an unsymmetrical N-heterocyclic carbene (NHC) ligand with one 2,5-diisopropylphenyl (DIPP) and one thiophenylmethylene N-substituent is reported. The optimised procedure does not require column chromatography in any step and allows for preparation of up to 0.5 kg batches of the catalyst from simple precursors. The application profile of the obtained catalyst was studied in environmentally friendly dimethyl carbonate (DMC). Although VII exhibited low efficiency in cross-metathesis (CM) with electron-deficient partners, good to excellent results were noted for substrates featuring easy to isomerise C?C double bonds. This includes polyfunctional substrates of medicinal chemistry interest, such as analogues of psychoactive 5F-PB-22 and NM-2201 and two PDE5 inhibitors—Sildenafil and Vardenafil. Finally, a larger scale ring-closing metathesis (RCM) of a Vardenafil derivative was conducted in DMC, allowing for straightforward isolation of the expected product (23 g) in high yield and with low Ru contamination level (7.7 ppm).

Full text of DOI:10.1002/chem.202003830

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&
Catalysts
Large-Scale Synthesis of a Niche Olefin Metathesis Catalyst
Bearing an Unsymmetrical N-Heterocyclic Carbene (NHC) Ligand
and its Application in a Green Pharmaceutical Context
Tomasz Nienałtowski+,[a, b] Paweł Szczepanik+,[a] Paweł Małecki+,[a] Dorota Czajkowska-
Szczykowska+,[a] Stefan Czarnocki,[c] Jolanta Pawłowska,[b] Anna Kajetanowicz,*[a] and
Karol Grela*[a]
Abstract: A large-scale synthesis of known Ru olefin meta-
thesis catalyst VII featuring an unsymmetrical N-heterocyclic
carbene (NHC) ligand with one 2,5-diisopropylphenyl (DIPP)
and one thiophenylmethylene N-substituent is reported. The
optimised procedure does not require column chromatogra-
phy in any step and allows for preparation of up to 0.5 kg
batches of the catalyst from simple precursors. The applica-
tion profile of the obtained catalyst was studied in environ-
mentally friendly dimethyl carbonate (DMC). Although VII
exhibited low efficiency in cross-metathesis (CM) with elec-
tron-deficient partners, good to excellent results were noted
for substrates featuring easy to isomerise CÀC double
bonds. This includes polyfunctional substrates of medicinal
chemistry interest, such as analogues of psychoactive 5F-PB-
22 and NM-2201 and two PDE5 inhibitors—Sildenafil and
Vardenafil. Finally, a larger scale ring-closing metathesis
(RCM) of a Vardenafil derivative was conducted in DMC, al-
lowing for straightforward isolation of the expected product
(23 g) in high yield and with low Ru contamination level
(7.7 ppm).
closely associated with the so-called Circular Economy,[3] aimed
at “minimizing waste and making the most of resources”, and
encouraging use of renewable raw materials instead of fossil
ones as substrates and solvents. Given the mild reaction condi-
tions and high atom-economy, the catalytic olefin metathesis
reaction[4] is currently undergoing a thriving development as a
powerful transformation leading to complex organic mole-
cules, including natural products, Active Pharmaceutical Ingre-
dients (APIs),[5] and much more.[6]
Introduction
One of the main challenges faced by the chemical industry is
to provide effective technologies to enable performing reac-
tions in a truly environmentally friendly manner.[1] This involves
the development of cleaner and more efficient catalytic pro-
cesses based on new types of catalysts, which exhibit high ac-
tivity and selectivity, even in the presence of varying levels of
impurities present in biomass-based substrates and solvents.[2]
Such approaches not only give access to many products that
have not been available owing to synthetic limitations, but
also allow to reduce generation of waste, reduce reaction
times and decrease general production costs. The trend is
In the same context, it is important to note that the particu-
lar class of metathesis catalysts belonging to the family of ruth-
enium(II) carbene complexes is not very sensitive towards air
and moisture, and in general is compatible with so-called
“green solvents”, such as 2-MeTHF, ethyl and methyl carbonate,
ethyl acetate,[7] and even more polar media, such as water,[8] al-
cohols[9] or ethyl lactate.[10] This attribute is primarily because
of the existing consensus regarding the pressing need to
switch away from fuel-based aromatic or chlorinated solvents
to their more ecologically friendly and green alternatives.[11]
This is especially important in pharmaceutical production,
which is highly material inefficient (E-factor of 25 to 100) and
uses relatively large volumes of solvents.[12] According to our
best knowledge, only one example of a pharmaceutically rele-
vant larger scale (1.5 kg) metathesis reaction in such solvent is
the known synthesis of IDX320, a hepatitis C virus protease in-
hibitor by Idenix Pharmaceuticals Inc. performed in ethyl ace-
tate (Figure 1).[13] Other APIs described in recent review litera-
ture[5c,14] were prepared in non-green solvents, usually in chlori-
nated ICH Class 1 solvents or in toluene (ICH Class 2 solvent).
[a] T. Nienałtowski,+ P. Szczepanik,+ P. Małecki,+
Dr. D. Czajkowska-Szczykowska,+ Dr. A. Kajetanowicz, Prof. K. Grela
Biological and Chemical Research Centre, Faculty of Chemistry
University of Warsaw, Zwirki i Wigury 101, 02-089 Warsaw (Poland)
E-mail: a.kajetanowicz@uw.edu.pl
˙
prof.grela@gmail.com
[b] T. Nienałtowski,+ Dr. J. Pawłowska
Polpharma SA Pharmaceutical Works
Pelplinska 19, 83-200 Starogard Gdanski (Poland)
[c] Dr. S. Czarnocki
Apeiron Synthesis SA, Dunska 9, 54–427 Wrocław (Poland)
[+] These authors contributed equally to this work.
´
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.202003830.
Part of a Special Issue celebrating the 1000th Issue of Chemistry—A Euro-
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Figure 2. Representative general-purpose Ru catalysts bearing SIMes and
SIPr ligands (I–V) and selected specialised complexes with uNHC ligands
(VI–VIII).
Herewith, we present for the first time the large-scale syn-
thesis of a “niche” olefin metathesis uNHC catalyst VII; its
scope and limitations study in diverse metathesis reactions
were carried out in a green solvent—dimethyl carbonate
(DMC). This study was additionally extended to the small- and
large-scale synthesis of some pharmaceutically relevant com-
pounds, such as new analogues of Sildenafil and Vardenafil,
popular drugs used in a treatment of erectile dysfunction.
Figure 1. Selected examples of APIs and drug candidates prepared by RCM,
including reported scale and solvent (DCM=dichloromethane; DCE=1,2-di-
chloroethane; PhMe=toluene).
Results and Discussion
The soaring popularity of ruthenium olefin metathesis catalysts
is strongly associated with the introduction of N-heterocyclic
carbene (NHC) ligands.[15] Although the vast majority of Ru cat-
alyst applications is dominated by complexes I–III—true top-
sellers bearing symmetrical NHC ligands (Figure 2a)—their ana-
logues with unsymmetrical NHC (uNHC) ligands, although usu-
ally displaying lower general activity than their symmetrical
counterparts, have carved a niche for themselves in demand-
ing transformations such as high-concentration macrocyclisa-
tion,[16] ethenolysis[17] or self-metathesis of a-olefins[18] and
others, owing much higher selectivity.[19] Additionally, engi-
neered uNHC Ru catalysts, such as VIII are very useful in the
stereocontrolled formation of Z-configured CÀC double
bonds.[6g]
Large-scale preparation of uNHC catalyst VII
For the scale-up study, we selected known uNHC catalyst
(VII),[20] which was found to offer good results in a number of
“difficult” self-metathesis reactions of a-olefins and in macro-
cyclisation reactions.[16,20a] The low-scale (up to 320 mg) synthe-
sis of this catalyst was reported,[20a] however, the larger scale
synthesis was never attempted. The growing demand for this
catalyst forced us to start a scale-up study to prepare this com-
plex in at least 0.5 kg scale (Scheme 1).
The first decision to make in the planned large-scale synthe-
sis was the choice of suitable ruthenium source. Therefore, the
first step in our synthesis was transformation of the simplest
commercially available ruthenium source—ruthenium(III) chlo-
ride hydrate—into an appropriate RuII complex, on which the
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Scheme 1. Large-scale synthesis of catalyst VII from inexpensive commercially available reagents (t-Am=tert-pentyl (tert-amyl); COD=1,5-cyclooctadiene;
DCM=dichloromethane; DBU=1,8-diazabicyklo(5.4.0)undec-7-en; Cy=cyclohexyl).
ligand exchange can be performed. Considering the present
high cost of platinum metals on the market, and the limited
number of ruthenium producers,[21] we were looking for a
high-yielding but also cost-effective route. For example, in a
number of protocols, ruthenium(III) chloride is converted by a
reaction with triphenylphosphine into a common precursor
“RuCl2(PPh3)3” and then into more elaborate carbene com-
plexes.[22] However, after calculating the estimated material–op-
eration costs for this route, as well as for a number of alterna-
tive strategies, and considering various risks (such as the for-
mation of impurities and safety aspects), it was decided in-
stead to use a route proceeding via known ruthenium(II) com-
plex X (Scheme 1).[23] Synthesis of the above precursor was
possible in a few straightforward steps. First, RuCl3·H2O was re-
acted with cycloocta-1,5-diene and ethanol,[24] a reaction which
even at >1 kg scale went uneventfully in our hands. Next, the
product—poorly soluble polymer IX—was transformed into
complex X as a result of a one-pot, two-step procedure. In the
first step of this transformation, an oxygen and moisture-sensi-
tive ruthenium hydride complex was obtained, which then
without isolation was reacted with propargyl alcohol providing
2.25 kg of complex X with an overall 70% yield. Independently,
the benzylidene and uNHC ligands precursors were prepared
in an appropriate quantity, based on scaled-up and optimised
original procedures.[20a] The thiophene-based uNHC ligand pre-
cursor (salt S3) was synthesised in three steps, which consisted
of imine formation by reaction of thiophene-2-carbaldehyde
with N,N’-(2,6-diisopropylphenyl)ethane-1,2-diamine (S1), re-
duction the resulting imine with NaBH4 and condensation of
the newly formed diamine with triethyl orthoformate in 70%
total yield (Scheme 1). 2-Isopropoxystyrene (S6) was obtained
in >75% yield in two straightforward steps—Williamson alkyl-
ation of salicylaldehyde with 2-iodopropane (1.25 kg scale) and
subsequent Wittig reaction at 0.65 kg scale. Next, the reaction
of styrene S6 with X in the presence of CuCl as the phosphine
scavenger gave >1 kg of the Hoveyda–Grubbs first-generation
complex (XI, 72%) without much difficulty. With all precursors
in hand, we attempted the large-scale synthesis of VII for the
first time. The exploratory runs were made at 55 and 200 g
scale giving reproducibly 64–66% yield. Analytical data of the
produced complex were in full agreement with those obtained
in a previously published low-scale procedure.[20a] Encouraged
by these results, we moved to the final scale-up experiment,
using a 60 L reactor and starting from 0.58 kg of salt S3, which
under deprotonation with potassium tert-amylate (0.92 L of
1.7m solution in toluene) afforded in situ a corresponding car-
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bene, which was then installed on RuII complex XI (0.79 kg),
yielding finally 0.56 kg (66% yield) of the expected complex
VII, isolated as a green microcrystalline solid.
Having secured a suitable amount of catalyst VII, we at-
tempted to study its scope and limitations in diverse metathe-
sis reactions carried out in a green solvent—dimethyl carbon-
ate (DMC).[7a,b,25]
Application of catalyst VII in RCM of simple and moderately
complex substrates in DMC
Our previous studies on this type of thiophene-based uNHC
catalysts in solvents such as toluene[20a] or 2-methyltetrahydro-
furan[20a] suggest that although relatively poorly potent at am-
bient temperature, these complexes activate at 50–708C; how-
ever, in general, they exhibit lower productivity levels com-
pared with general-purpose catalysts featuring symmetrical
NHC ligands.[20a] To complete this picture, a model RCM of 1
(DEDAM) has been performed in DMC, comparing uNHC VII
with II and III. Time-conversion curves presented in Figure 3
show, as it may be expected from previously published
studies,[20a] that VII was slightly less active than SIMes and SIPr
complexes. However, at 0.1 mol%, VII still gave 91% conver-
sion and at 0.2 mol% full conversion was observed (see
Table 1).
Figure 3. Time/conversion curves for the RCM reaction of diethyl 2,2-diallyl-
malonate (1) with 0.1 mol% of Ru complexes at 708C in DMC (monitored by
GC). Lines are visual aids only.
Application of catalyst VII in CM and self-CM in DMC
Next, we attempted to study more challenging self-cross meta-
thesis (self-CM) and cross-metathesis (CM) reactions.
First, we planned to examine the self-CM (sometimes re-
ferred as “homodimerisation”) reaction (Scheme 2) of selected
functionalised alkenes belonging either to natural product
families (such as 19) or containing structural fragments of
pharmaceutical interest (21, 23). Self-CM is sometimes used in
a medicinal chemistry context to obtain “homodimers” of
products such as steroids, carbohydrates, or antibiotics.[28] In
our previous work, we have noted that standard symmetrical
NHC-bearing Ru catalysts produce unsatisfactory selectivity
We noted that even relatively low amounts of catalyst VII in
DMC were enough to form five- and six-membered carbocycles
with high selectivity (entries 1–4). The same was the case for
RCM and enyne cycloisomerisation with 0.5 mol% of VII lead-
ing to various five- to seven-membered O- and N-heterocycles
(entries 5–9). It should be noted that uNHC catalyst VII gave
generally high selectivity levels,[18,20a,26] which was especially
visible in the case of 12, which is sensitive to a CÀC double
bond shift.[27]
Scheme 2. Self-CM reactions catalysed by VII. Sel.=100ꢁ(moles of the desired product)/(moles of all products created in the reaction).
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Table 1. RCM and enyne reactions in the presence of VII and II performed in DMC.
Entry Substrate Product
Loading [mol%]/
Time [h]
Catalyst:
Conversion [%]
VII: 99
III: 99
1
0.2/1
0.2/1
2
VII: 91
3
4
0.5/1
VII: >99
VII: 94 (sel. 92%)
III: 99 (sel. 94%)
0.5/24
5
0.5/1
VII: >99
VII: 98 (sel. 97%)
III: 98 (sel. 44%)
6
7
0.5/24
0.5/24
VII: 94
VII: 90
8
9
0.5/24
0.5/24
VII: 86
Conditions: c=0.02m, 708C, 1 or 24 h. Sel.=100ꢁ(moles of the desired product)/(moles of all products created in the reaction).
levels in such reactions, owing to their tendency to isomerise
(shift) CÀC double bonds in the course of the metathesis pro-
cess.[29] Therefore, we were pleased to find that in the case of
reactions presented in Scheme 2, no severe isomerisation was
found for uNHC VII catalyst, and the reactions were in general
very clean. This was especially visible in the case of substrate
23—a close analogue of 5F-PB-22[30] and NM-2201,[31] designer
drugs acting as cannabinoid agonists. Self-CM reaction of this
compound performed in the presence of catalyst VII produced
the conjugate 24 in high selectivity and yield (Scheme 2c).
Next, we decided to study CM reactions of selected terminal
olefins with a set of CM partners, such as 1,4-diacetoxybut-2-
ene (27), crotonaldehyde (28) and ethyl acrylate (29)
(Scheme 3).[32] Importantly, we noted rather disappointing re-
sults when crotonaldehyde or acrylic ester were used. In such
cases, large proportions of self-CM “dimers” were formed, dem-
onstrating the low reactivity of uNHC catalyst VII towards elec-
tron-poor CM partners. This is in strong contrast with the usu-
ally excellent results noted in analogous reactions for Hovey-
da–Grubbs NHC catalysts.[33] Interestingly, with non-electron-
poor partner-1,4-diacetoxybut-2-ene (27), the uNHC catalyst
gave good to very good isolated yields of the expected CM
products (Scheme 3), which is in agreement with the previous-
ly published results.[20a] These show some serious limitations in
thus-far very good application profile of VII, restricting its use
in CM to only non-electron-deficient partners.
Scope and limitations study of catalyst VII in a medicinal
chemistry context
Having secured the route to larger quantities of VII and know-
ing its general reactivity picture, we looked for more challeng-
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Scheme 3. CM reactions catalysed by VII.
ing targets of practical interest. The opportunity for such “re-
connaissance by fire” came from an industrial doctoral project
related to new phosphodiesterase type 5 inhibitors (PDE5 in-
hibitors).[34] In the framework of this programme, we opted to
apply self-CM and RCM to obtain some new analogues of Sil-
denafil[35] (marketed inter alia under the brand name Viagra)
and Vardenafil[36] (sold inter alia under the trade name Levi-
tra)—popular drugs used to treat erectile dysfunction and pul-
monary arterial hypertension. Although both Vardenafil and Sil-
denafil share the same mode of action as PDE5 inhibitors, the
major structural difference between them is a nitrogen atom
position and the change of the Sildenafil piperazine ring
methyl group to an ethyl group (Figure 4). From the point of
view of catalytic olefin metathesis, both of these structures ex-
hibit some potential risks, as they contain a number of Lewis
basic centres that can chelate (arrest) the propagating 14eÀ Ru
species, thus inhibiting the catalytic activity of an olefin meta-
thesis catalyst.
First, we attempted to obtain precursors of Vardenafil and
Sildenafil “dimers” through self-CM reaction (Scheme 4). Analy-
sing potential hazards associated with this transformation, we
focused on known problems regarding the metathesis of N-
allyl sulfonamides, which are considered as rather reluctant
substrates for CM.[37] When the N(H)-allyl derivative of Vardena-
fil was used (Scheme 4a) only less than 10% of the expected
self-CM product was formed, accompanied by the same
amount of N-desallyl derivative.[38] Other catalysts, such as III,
unfortunately gave no better results. Also Lewis acid additives,
Figure 4. Chemical structures of Sildenafil and Vardenafil.
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Scheme 4. Preparation of Vardenafil and Sildenafil “dimers” by CM catalysed by VII and the solid-state structure of the (E)-42 isomer. Isolated yields.
such as B(OMe)3 made no improvement in this challenging
self-CM. Fortunately, when the N(Bn)-allyl derivative 39 was
used, the clean metathesis reaction occurred in the presence
of 4–5 mol% of VII in dimethyl carbonate, giving 40 in 56%
isolated yield (Scheme 4a). A slightly higher yield was noted in
the case of 41, which gave 75% isolated yield on a scale of
100 mg, and 88% in 1.4 g scale (Scheme 4b).
alyst VII was applied in this reaction, 63% of only-RCM product
44 was isolated, however, accompanied by a second, more
polar fraction, which was a mixture of 45 (formed from a se-
quence of two RCM and one self-CM reactions) and its not-
fully cyclised derivatives (unfortunately we were not able to
separate and fully characterise this side product mixture). Inter-
estingly, SIPr-bearing catalyst III, although giving a lower yield
of 44, produced 45 as the only side product, which was isolat-
ed in pure form in 38% yield. Looking for a way to manufac-
ture the desired RCM product 44 with higher efficiency, we
speculated that the unsatisfactory results obtained above were
related to the insufficient RCM activity of catalyst VII. Although
Another challenge was related to triallyl derivative 43
(Scheme 5). We hoped that the rate of the RCM reaction (intra-
molecular) should be sufficiently higher than the rate of the al-
ternative self-CM intermolecular reaction, thus allowing for se-
lective formation of the desired product 44. Indeed, when cat-
Scheme 5. RCM versus CM in metathesis of the triallyl derivative of Vardenafil. Isolated yields. [a] Total yield of an inseparable mixture of 45 and its not-fully
cyclised derivatives. n.d.=not determined.
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the Hoveyda–Grubbs’ catalyst III was able not only to fully cy-
clise the five-membered ring in 43, it also catalysed the un-
wanted self-CM reaction. In contrast, catalyst VII acted appa-
rently slower, being unable to react with all N,N-diallylsulfon-
amide fragments even. Therefore, we looked at the electron-
withdrawing group-activated[39] version of the same catalyst
(XII) published by us previously.[20a] In this case, we were satis-
fied to see that CM product 44 was formed in 94% isolated
yield, and only as low as 2% of the more polar self-CM product
was observed (Scheme 5).[40]
this low contamination level is related to the slow crystallisa-
tion of 47 from the cooling of the reaction mixture, during
which the Ru complexes remained in DMC solution. In a con-
trol experiment, when half of the solvent volume was evapo-
rated before the reactor content was cooled down, crystallisa-
tion from a more concentrated solution gave the product con-
taining a ten-times higher amount of Ru (86.0 ppm, Table 2,
entry 2). Finally, when the reaction mixture was evaporated to
dryness, the obtained residue exhibited 1694 ppm of Ru. It
shall be noted that it was then relatively difficult to purify such
contaminated product. For example, the purification procedure
consisted of dissolving the crude product (1697 ppm of Ru) in
10% aqueous solution of NaOH at 808C, treatment with acti-
vated charcoal and precipitation by drop-wise addition of con-
centrated HCl, which led to a product containing 11 ppm of
Ru, so actually more than in the case where product 47 pre-
cipitated freely after the reaction. An alternative purification
protocol, consisting of use of a scavenger developed in our
laboratories[41] led to 9.6 ppm of Ru (Table 2, entry 5).
Finally, we decided to prepare Vardenafil analogues bearing
other heterocyclic moieties at the sulfonamide fragment. One
such, 47 (Scheme 6), seemed to be easily accessible by RCM of
similar N,N-diallylsulfonamide substrates as tested above. In
this case, having no concerns about the chemo- and regiose-
lectivity of the attempted metathesis process, we focused on
more practical aspects of this transformation, such as scale-up,
product separation and Ru catalyst removal. After checking
that the target RCM reaction proceeds well on a small scale, a
set of larger scale experiments was initiated. After a number of
minor optimisation steps, we worked out a procedure in which
the catalyst (weighed and handled on air) was added as a
powder to a stirred solution of 46 (28 g, 60 mmol) in dimethyl
carbonate (650 mL) placed in a 1 L reactor. The reaction mix-
ture was stirred under a protective atmosphere of argon at
658C until TLC monitoring showed complete conversion (2 h).
The reaction mixture was then cooled to 58C and stirred for
60 min. The precipitated product was filtered off and dried in
vacuum dryer (see the Supporting Information). The product
of HPLC purity of 99.7% was obtained as a cream-coloured
solid (23.9 g, 91%). Interestingly, the crude product contained
only 7.7 ppm of Ru (as checked by ICP-MS). We believe that
Conclusion
A large-scale synthesis of known 2-isopropoxybenzylidene
ruthenium catalyst VII[20a] bearing an unsymmetrical NHC
ligand with one 2,6-diisopropylphenyl (DIPP) and one thiophe-
nylmethylene N-substituent has been reported. This procedure,
staring from simple precursors and not using column chroma-
tography in any step, allowed preparation of up to 0.5 kg
batches of the catalyst. The application profile of the obtained
catalyst was studied in environmentally friendly dimethyl car-
bonate (DMC) to explore the limitations of this system. Al-
though a number of metathesis reactions can be successfully
Scheme 6. Preparation of Vardenafil analogue RCM catalysed with VII. [a] Catalyst added in 4 portions over 8 h.
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Table 2. Purification attempts after RCM of 46 in DMC.[a]
Entry
Purification method
Trace Ru [ppm]
1
2
3
4
5
Precipitated from the reaction mixture
7.72
86.02
1694.60
11.03
Precipitated from the concentrated (1= ) reaction mixture
2
Reaction mixture evaporated to dryness
As in entry 3, then the residue was dissolved in NaOH, treated with charcoal, precipitated with HCl
As in entry 3, then the residue dissolved in DCM, treated with SnatchCat metal scavenger
9.64
[a] For detailed procedures, see the Supporting Information. DCM=dichloromethane.
[2] F. Cavani, G. Centi, S. Perathoner, F. Trifirꢂ, Sustainable Industrial Chemis-
try: Principles, Tools and Industrial Examples, Wiley-VCH, Weinheim,
2009.
performed with VII, its low efficiency in CM with electron-defi-
cient partners such as a,b-unsaturated aldehydes or esters is of
note. Accordingly, in this specific field of applications, com-
plexes I–V bearing symmetrical SIMes and SIPr ligands are su-
perior to VII. Next, we focused on polyfunctional substrates of
medicinal chemistry interest, such as 5F-PB-22 and NM-2201
and a number of new analogues of PDE5 inhibitors—Sildenafil
and Vardenafil. We were pleased to find that with these sub-
strates, catalyst VII (and its nitro-activated analogue XII) shows
high levels of selectivity and productivity. Finally, a larger scale
(28 g) RCM of Vardenafil derivative was attempted in DMC, al-
lowing the straightforward isolation of the expected product
in high yield and with a low Ru contamination level (7.7 ppm).
Therefore, we believe that catalyst VII can find a niche in appli-
cations where high selectivity is required, such as metathesis
of substrates featuring easy to isomerise CÀC double bonds.
[3] https://www.eea.europa.eu/policy-documents/com-2015-0614-final.
[4] a) Handbook of Metathesis (Eds.: R. H. Grubbs, A. G. Wenzel, D. J.
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WO2012129479A2; d) T. Shinde, V. Varga, M. Polꢃsek, M. Horꢃcek, N.
ˇ
The 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 Region-
al Development under the Operational Programme Smart
Growth. TN thanks the Industrial Doctorates Programme. The
study was carried out at the Biological and Chemical Research
Centre, University of Warsaw, established within the project co-
financed by the European Union from the European Regional
Development Fund under the Operational Programme Innova-
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Keywords: large-scale synthesis · medicinal chemistry · N-
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ruthenium catalysts
· olefin metathesis ·
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Manuscript received: August 18, 2020
Revised manuscript received: September 14, 2020
Version of record online: && &&, 0000
[29] It shall be noted, however, that the higher selectivity observed for a
given catalyst may not be only attributed to its structure and particular
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ÝÝ These are not the final page numbers!

Full Paper
doi.org/10.1002/chem.202003830
Chemistry—A European Journal
FULL PAPER
A large-scale synthesis of known Ru
olefin metathesis catalyst VII featuring
an unsymmetrical N-heterocyclic car-
bene (NHC) ligand with one 2,6-diiso-
propylphenyl (DIPP) and one thiophe-
nylmethylene N-substituent is reported.
The optimised procedure does not re-
quire column chromatography in any
step and allows for preparation of up to
0.5 kg batches of the catalyst from
simple precursors.
&
Catalysts
T. Nienałtowski, P. Szczepanik, P. Małecki,
D. Czajkowska-Szczykowska, S. Czarnocki,
J. Pawłowska, A. Kajetanowicz,* K. Grela*
&& – &&
Large-Scale Synthesis of a Niche
Olefin Metathesis Catalyst Bearing an
Unsymmetrical N-Heterocyclic
Carbene (NHC) Ligand and its
Application in a Green Pharmaceutical
Context
Chem. Eur. J. 2020, 26, 1 – 11
www.chemeurj.org
11
ꢀ 2020 Wiley-VCH GmbH
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These are not the final page numbers! ÞÞ