Expedient Synthesis of 2-Iminothiazolidines via Telescoping Reactions Including Iron-Catalyzed Nitrene Transfer and Domino Ring-Opening Cyclization (DROC)

Article abstract of DOI:10.1002/ejoc.202001379

2-iminothiazolidines are important scaffold for pharmaceutical drugs. Herein, we describe a fast and easy procedure for their synthesis by a telescoping reaction integrating an iron-catalyzed nitrene transfer under mild conditions. The aziridination react

Full text of DOI:10.1002/ejoc.202001379

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Expedient synthesis of 2-iminothiazolidines via telescoping
reactions including iron-catalyzed nitrene transfer and Domino
Ring-Opening Cyclization (DROC)
Authors: Guillaume Coin, Oriane de Ferrier de Montal, Patrick
Dubourdeaux, and Jean-Marc Latour
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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published online in Early View as soon as possible and may be different
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the VoR from the journal website shown below when it is published
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202001379
Link to VoR: https://doi.org/10.1002/ejoc.202001379
01/2020

10.1002/ejoc.202001379
European Journal of Organic Chemistry
COMMUNICATION
Expedient synthesis of 2-iminothiazolidines via telescoping
reactions including iron-catalyzed nitrene transfer and Domino
Ring-Opening Cyclization (DROC)
Guillaume Coin*[a],[b]‡, Oriane de Ferrier de Montal,[a] Patrick Dubourdeaux[a] and Jean-Marc Latour*[a]
Abstract: 2-iminothiazolidines are important scaffold for
pharmaceutical drugs. Herein, we describe a fast and easy procedure
for their synthesis by a telescoping reaction integrating an iron-
catalyzed nitrene transfer under mild conditions. The aziridination
reaction of olefins is followed by the domino ring-opening cyclization
(DROC) of the aziridine intermediates with organic isothiocyanates
catalyzed by a Lewis acid leading to the desired product. This new
synthetic route allows time, step and purification economies, which is
in agreement with the development of more efficient processes for the
synthesis of small molecules.
disclosed a catalyst-free version using aroyl isothiocyanates
(ArCO-NCS).[14]
To further improve this synthetic route to 2-
iminothiazolidines, we investigated the possibility of developing
telescoping reactions. These are at least a two-step synthesis
where reactants are added successively in the same flask without
isolation and purification of synthetic intermediates.[15] Their
operation simplicity and solvent- and time-saving make them
more economically attractive.[16] As a matter of fact, they were
described as the best way to ‘‘clean up’’ organic synthesis[17] and
have sharply emerged as a synthetic route for the construction of
Over the last decades N-heterocycles appeared as
prevalent structural scaffolds of pharmaceuticals.[1,2] Among them,
2-iminothiazolidines are structural architectures found in several
drugs and biologically active compounds.[3] They possess a wide
range of biological and pharmaceutical activities as anti-
inflammatory, anti-hypertensive, anti-Alzheimer, progesterone
receptor binding agents and antidepressant. This class of
compounds also exhibits radioprotective properties. The
synthesis of such compounds is therefore an important issue for
chemists. Consequently, large efforts have been devoted to the
development of efficient 2-iminothiazolidines syntheses and a few
representative ones are given in Scheme 1. Among them, Sá et
al. have described a base-mediated [3+2] annulation involving
allyl bromide and N-acylthioureas (Scheme 1a).[4] Alper et al. have
reported a rhodium-catalyzed synthesis of thiazolidine using
carbodiimides (Scheme 1b).[5] But one of the most promising
routes is the domino ring-opening cyclization (DROC) of
aziridines with isothiocyanates (Scheme 1c).[6] This reaction
requires the use of catalysts such as phosphines,[7] pyrrolidines,[8]
palladium complex[9] or Lewis acid[10–13] to open aziridine ring. A
few drawbacks are noticeable for some of these methods: (i) the
use of harsh opening conditions (high temperature, work under
pressure); (ii) the use of Lewis acids in stoichiometric quantities.
Recently, a significant improvement was achieved by the groups
of Ghorai[9] and Punniyamurthy[10] and their coworkers who
described the synthesis of 2-iminothiazolidines from aziridines
with respectively, BF3.OEt2 (15 mol %) and an Al(salen) complex
(5 mol %) as catalysts. Very recently, Patel and co-workers
a
large range of compounds,[18–27] including numerous
heterocycles of pharmaceutical and agrochemical interest.[28–30]
Scheme 1. Previous routes for the synthesis of 2-iminothiazolidines and design
of the telescoping reaction including iron-catalysed nitrene transfer.
[a] Dr. G. Coin, O. de Ferrier de Montal, P. Dubourdeaux, Dr. J.-M. Latour
Univ. Grenoble Alpes, CNRS UMR 5249, CEA, LCBM / pmb, F-38000
Grenoble, France
e-mail: jean-marc.latour@cea.fr
Therefore, we intended to use telescoping reactions
integrating the in situ generation of the aziridine followed by its
ring-opening and insertion of an organic isothiocyanate. The
aziridine will be formed by a nitrene transfer reaction using an iron
catalyst. In 2015, the first such telescoping reaction including
nitrene transfer was described by Dauban and co-workers with a
bis-rhodium catalyst.[31] To our knowledge no other such reactions
including nitrene transfer have been published.
gucoin@org.chem.ethz.ch
[b] Univ. Grenoble Alpes, CNRS UMR 5250, DCM, F-38000 Grenoble,
France
Present address: ETH Zürich, Department of Chemistry and Applied
Biosciences, 8093 Zürich, Switzerland
‡
Supporting information for this article is given via a link at the end of the
document
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10.1002/ejoc.202001379
European Journal of Organic Chemistry
COMMUNICATION
Table 1. Efficiency of various Lewis acid for the domino ring-opening cyclization
of (2)[a]
Nitrene transfer is a powerful synthetic route because of its
ability to form a wide range of amines without pre-functionalisation
nor post-deprotection steps.[32] Over the years, iron has emerged
as a ubiquitous metal in the field of catalysis, due to its high
abundance, low price and non-toxicity.[33–35] We reported that the
diiron(III,II) catalyst (1) (Scheme S1) is capable to mediate the
intermolecular nitrene insertion from an imino-iodinane (PhI=NTs)
to a large range of substrate.[36–40] This complex is able to form
aziridine from styrene with a very good yield (87 %) using
PhI=NTs at room temperature in dichloromethane for four
hours.[36,40]
In this paper, we first illustrate the effectiveness of Al(OTf)3
and In(OTf)3 as Lewis acids for the ring opening of aziridine
followed by the insertion of an organic isothiocyanate. Then, we
describe the first telescoping reaction including nitrene transfer
mediated by an iron catalyst with good yields in mild conditions.
Mechanistic insights allow us to propose a plausible mechanism
for the entire process.
Entry
Lewis acid
-
(4a)[b] (%)
Entry
7
Lewis acid
Yb(OTf)3
AlCl3
(4a)[b] (%)
1
2
3
4
5
6
0
34
8
BF3.OEt2
(salen)AlCl
In(OTf)3
Al(OTf)3
Fe(OTf)3
90
0
8
9
Zn(OTf)2
Sc(OTf)3
Sn(OTf)2
69
80
84
87
86
85
10
11
First, we conducted a screening of various Lewis acids for
the aziridine ring-opening with phenyl isothiocyanate. 2-phenyl-N-
tosylaziridine was chosen as representative substrate,
independently prepared and fully characterized, notably by X-ray
crystallography. The reaction was realized in the presence of a
catalytic amount of various Lewis acids in dichloromethane under
mild conditions (Scheme 2).
[a] Reaction conditions : Lewis Acid/ Ph-NCS/ Aziridine molar ratio = 0.15/15/1,
CH2Cl2, 18 h, 25 °C. [b] Yields determined by 1H NMR, using mesitylene as an
internal standard.
Similar results were obtained using Al(OTf)3 (Table S1).
Variation of the reaction time was considered, then and it was
observed that the reaction was almost completed after 8 hours
(Table 2, entry 11). A variation of the reagents concentration had
no incidence on the yield. No improvement was observed by
increasing the Lewis acid molar ratio (15, 20 and 30 mol %).
Table 2. Influence of time and number of cumulene equivalents for the DROC
[a]
of (2a) with (3) catalysed by In(OTf)3
Scheme 2. Lewis acid-catalysed domino ring-opening cyclization of 2-phenyl-
N-tosylaziridine with phenyl isothiocyanate.
At first, we examined the efficiency of different Lewis Acids
(Table 1). In the absence of catalyst, no reaction was observed
(Table 1, entry 1). BF3.OEt2 appears as the best catalyst but
surpasses marginally most triflate salts (Table 1, entries 2 and 4-
11). As expected AlCl3 is far less active than Al(OTf)3. By contrast,
AlCl(salen) is totally unreactive (Table 1, entry 3) in the same
conditions used by Puniyamurthy and co-workers.[10] As a matter
of fact salen and chloride coordination strongly reduce the acidity
of Al which is still able to alkyl and benzyl aziridines but fails to
bind the less basic tosylaziridines in the present work. Excellent
yields were obtained with Al(OTf)3, In(OTf)3 and Fe(OTf)3 (Table
1, entries 4-6) and rank these Lewis acids among the most
performing reported catalysts for the Lewis acid-catalysed DROC
of aziridines with isothiocyanates already reported.[10][12]
Due to the toxicity and the dangerousness of BF3.OEt2 for
the experimentalist and the environment,[41] we decided to work
with In(OTf)3 and Al(OTf)3. Then, an optimization of the
experimental conditions was conducted with indium and
aluminium triflates. At first, we varied the number of equivalents
of cumulene. With one equivalent of phenyl isothiocyanate, the
use of indium triflate allowed the formation of 22 % of 2-
iminothiazolidine (Table 2, entry 1). Increasing the number of
cumulene equivalents led to a steady rise in yield with a plateau
(Table, entries 2 – 8) after 15 equivalents with excellent yields of
87% (Table, entry 7).
eq. of
(3)
time
(h)
(4a)[b]
(%)
eq. of
(3)
time
(h)
(4a)[b]
(%)
Entry
Entry
1
2
3
4
5
6
1
2.5
5
18
18
18
18
18
18
22
45
66
71
80
80
7
8
15
30
10
10
10
18
18
2
87
86
68
69
77
9
7.5
10
10
11
4
8
12.5
[a] Reaction conditions : In(OTf)3/ Ph-NCS/ Aziridine molar ratio = 0.15/x/1,
CH2Cl2, 25 °C. [b] Yields determined by 1H NMR, using mesitylene as an internal
standard.
Next, telescoping reactions have been studied. Firstly, the
aziridination reaction was accomplished with styrene, a nitrene
precursor (PhI=NTs) and the iron catalyst. After the complete
consumption of PhI=NTs, indium triflate and phenyl
isothiocyanate were added into the same vessel and the reaction
mixture was stirred overnight at room temperature to form 2-
iminothiazolidine (Scheme 3). Using 15 equivalents of cumulene
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10.1002/ejoc.202001379
European Journal of Organic Chemistry
COMMUNICATION
led to a lower yield of 2-iminothiazolidine with respect to our initial
conditions (48 % vs 87 %). We thus carried out the telescoping
reaction with increasing numbers of equivalents of phenyl
isothiocyanate. It appeared that 20 equivalents of the cumulene
restored a good yield (ca. 70 %) and is thus a good compromise
(Table 3). The conversion is not complete because of the
formation of several by-products in little amount, which are
probably coming from rearrangements when aziridine is
opened.[42]
reactivity of the opened intermediate, which orients it otherwise at
the expense of 2-iminothiazolidine formation.
In a second set of experiments, we changed the nature of
the isothiocyanate substituent in order to extend the scope of the
reaction and synthesize new 2-iminothiazolidines (Table 4,
entries 14-22). When p-OMe phenyl isothiocyanate is used, good
yields were obtained with styrene and p-halogenated styrenes
(Table 4, entries 14-17). As observed with phenyl isothiocyanate,
the reaction with styrenes bearing electron-withdrawing
substituents led to lower yields (Table 4, entries 18-20).
Through all these experiments, a mechanistic scheme can
be proposed which associates two catalytic cycles (Scheme 4). In
cycle 1 the FeII catalyst first associates with the nitrene precursor
PhI=NTs to give an adduct which rearranges in a two-electron
process akin to an oxidative addition leading to PhI release and
formation of the active species FeIV(=NTs).[38] Reaction with the
olefin produces the desired aziridine and regenerates the catalyst
in its initial FeII form.
Scheme 3. Catalytic telescoping reaction for the synthesis of different 2-
iminothiazolidines.
The in situ formed aziridine enters in cycle 2 and interacts
with the Lewis acid to induce the DROC. Coordination of the
aziridine nitrogen by the Lewis acid facilitates an SN2-type
nucleophilic attack by the isothiocyanate sulphur to create the C-
S bond. This attack is followed by the ring closure via the
intramolecular nucleophilic attack of the nitrogen to the carbon of
the nitrilium ion, leading to the formation of the final 2-
iminothiazolidine. The intervention of a SN2-type nucleophilic
attack is supported by the non-formation of 2-iminothiazolidine
when electron-withdrawing isothiocyanates are used (Table 4,
entries 23-25). Indeed, their reduced nucleophilicity makes the
attack at the benzylic position of the LA-coordinated aziridinium
ion impossible.
Table 3. Influence of the number of equivalents of cumulene on the telescoping
reaction[a]
(4a)[b] (%)
Entry
R1
R2
Eq. of Ph-NCS
1
2
3
H
H
H
Ph
Ph
Ph
15
20
25
48
69
71
[a] Reaction conditions : (1)/ In(OTf)3/ PhI=NTs/ Styrene/ Ph-NCS molar ratio =
0.05/0.15/1/10/20, CH2Cl2, 25 °C. [b] Yields determined by 1H NMR, using
mesitylene as an internal standard.
In order to investigate the substrate scope of the reaction
and get insights into its mechanism, we have varied the para-
substituent of styrene (R) and the substituent of the
isothiocyanate (R').
In an initial set of experiments, a series of substrates
bearing an electron-withdrawing or an electron-donating group on
the para position of styrene have been tested with PhI=NTs as
nitrene precursor (Table 4, entries 1-10). It can be seen that
halogen substitution of styrene has little effect if any (Table 4,
entries 5-7) ; by contrast electron donating substituents led to a
significant lowering of the yield (Table 4, entries 8-10) and the
formation of unidentified products. A drastic lowering of the yield
is noted also for styrenes bearing electron-withdrawing
substituents (Table 4, entries 2-4) and a quite significant amount
of unreacted aziridine could be isolated. These observations
suggest that the lowering of the yields observed either for
electron-donating or electron-withdrawing substituents do not
have the same origin. For the latter they are due to the failure to
open the aziridine, which may be due to a poor interaction with
the Lewis acid catalyst. To verify this hypothesis we used as
nitrene precursor the nosyl analogue PhI=NNs, where the p-nitro
substituent was anticipated to deactivate the aziridine with
respect to its tosyl parent. This was indeed the case (Entries 11-
13) and very low amounts of 2-iminothiazolidine were formed (<
30 %) whereas high amounts of unreacted aziridine were
recovered (up to 83 %). By contrast, no aziridine was recovered
in the case of electron-donating substituents, which suggests that
the lower yield of 2-iminothiazolidine may be due to a higher
Scheme 4. Proposed mechanism for the catalytic telescoping reaction.
In this work, we have designed and developed an original
path for the direct synthesis of 2-iminothiazolidines from p-
substituted styrenes by telescoping reaction methodology
merging nitrene transfer reaction and domino ring-opening
cyclization. To our knowledge, this is the first time that nitrene
transfer is used for the synthesis of a wide range of 2-
iminothiazolidines with moderate to good yields. This procedure
represents a promising and attractive route, which allows time,
step and purification economies for the synthesis of bio-targeted
molecules. We can easily imagine that this new synthetic way can
be applied with other catalysts and nitrene precursors. The use of
this procedure with different cumulenes (isocyanates,
isonitriles…) may offer a large range of diversely substituted N-
heterocycles.
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10.1002/ejoc.202001379
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COMMUNICATION
Table 4. Scope of the catalytic telescoping reaction[a]
[a] Reaction conditions: (1)/ In(OTf)3/ PhI=NR2 / pR1-styrene/ R3-NCS molar ratio
[b]
= 0.05/0.15/1/10/20, CH2Cl2, 25 °C.
Yields determined by 1H NMR, using
mesitylene as an internal standard. [c] n.d. = not detected
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10.1002/ejoc.202001379
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COMMUNICATION
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Keywords: Telescoping catalysis • 2-iminothiazolidines •
Nitrene transfer • DROC • Iron catalyst
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Entry for the Table of Contents
In this work, iron-catalyzed aziridination (nitrene transfer) is combined in a single process to aziridine ring opening (DROC) to produce
2-iminothiazolidines which constitute interesting cores of pharmaceuticals.
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