Protic Ionic Liquid as Reagent, Catalyst, and Solvent: 1-Methylimidazolium Thiocyanate

Article abstract of DOI:10.1002/anie.202016593

We propose a new concept of the triple role of protic ionic liquids with nucleophilic anions: a) a regenerable solvent, b) a Br?nsted acid inducing diverse transformations via general acid catalysis, and c) a source of a nucleophile. The efficiency of this strategy was demonstrated using thiocyanate-based protic ionic liquids for the ring-opening of donor-acceptor cyclopropanes. A wide variety of activated cyclopropanes were found to react with 1-methylimidazolium thiocyanate under mild metal-free conditions via unusual nitrogen attack of the ambident thiocyanate ion on the electrophilic center of the three-membered ring affording pyrrolidine-2-thiones bearing donor and acceptor substituents at the C(5) and C(3) atoms, respectively, in a single time-efficient step. The ability of 1-methylimidazolium thiocyanate to serve as a triplex reagent was exemplarily illustrated by (4+2)-annulation with 1-acyl-2-(2-hydroxyphenyl)cyclopropane, epoxide ring-opening and other organic transformations.

Full text of DOI:10.1002/anie.202016593

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How to cite: Angew. Chem. Int. Ed. 2021, 60, 7927–7934
International Edition: doi.org/10.1002/anie.202016593
German Edition: doi.org/10.1002/ange.202016593
Ionic Liquids
Protic Ionic Liquid as Reagent, Catalyst, and Solvent:
1-Methylimidazolium Thiocyanate
Ivan A. Andreev+,* Nina K. Ratmanova+, AndrØ U. Augustin, Olga A. Ivanova, Irina I. Levina,
Victor N. Khrustalev, Daniel B. Werz,* and Igor V. Trushkov*
Abstract: We propose a new concept of the triple role of protic
ionic liquids with nucleophilic anions: a) a regenerable solvent,
b) a Brønsted acid inducing diverse transformations via
general acid catalysis, and c) a source of a nucleophile. The
efficiency of this strategy was demonstrated using thiocyanate-
based protic ionic liquids for the ring-opening of donor-
acceptor cyclopropanes. A wide variety of activated cyclo-
propanes were found to react with 1-methylimidazolium
thiocyanate under mild metal-free conditions via unusual
nitrogen attack of the ambident thiocyanate ion on the
electrophilic center of the three-membered ring affording
pyrrolidine-2-thiones bearing donor and acceptor substituents
at the C(5) and C(3) atoms, respectively, in a single time-
efficient step. The ability of 1-methylimidazolium thiocyanate
to serve as a triplex reagent was exemplarily illustrated by
(4+2)-annulation with 1-acyl-2-(2-hydroxyphenyl)cyclopro-
pane, epoxide ring-opening and other organic transformations.
One of the most attractive solutions to all these problems
is the use of protic ionic liquids (PILs), i.e., low-melting salts
of Brønsted acid and base.[5] On the one hand, PILs can
pursue a threefold role serving cooperatively as: a) an
excellent reaction medium, dissolving both hydrophobic and
hydrophilic molecules, b) process initiator via acid-base
catalysis, and c) reagent, if the PIL contains highly nucleo-
philic species, red-ox agent, etc. On the other hand, PILs can
be easily recycled and employed repeatedly, satisfying
environmental demands.[5] So much more astonishing, to the
best of our knowledge, is the absence of reports on the use of
this triple role of PILs in organic synthesis (Scheme 1a).
To test this new strategy, we selected transformations of
donor-acceptor (D-A) cyclopropanes[6] due to our long-
standing interest in this rapidly growing area of synthetic
chemistry, which gave birth to a plethora of reactions, from
quite simple to very unusual ones,[7] and continues to inspire
and guide the elaboration of interesting original processes.
Thus, we and others have developed ring-openings of D-A
cyclopropanes with diverse nitrogen-containing nucleophiles
followed by a new ring formation as a powerful tool for the
synthesis of N-heterocycles,[8] including pharmacologically
important ones (Scheme 1b). Nevertheless, the reaction of D-
A cyclopropanes with various sources of thiocyanate ion has
not been reported yet.
Introduction
Modern demands of synthetic chemistry require the
selection of reaction conditions providing both high yields
of the target products due to high chemo-, regio-, and
stereoselectivity of the processes employed and conformity
with the fundamental principles of green chemistry.[1] Among
them, the essential ones are concepts such as atom and step
economy,[2] design and application of less hazardous reagents
and catalysts, as well as minimization of waste production.[3,4]
We believe that this reaction can be performed using
a thiocyanate-based PIL as Brønsted acids are known to
induce reactions of D-A cyclopropanes.[8b,e, 9] PILs provide
a high concentration of both nucleophile and proton,
[*] Dr. I. A. Andreev,[+] Dr. N. K. Ratmanova,[+] Prof. Dr. I. V. Trushkov
Dmitry Rogachev National Medical Research Center of Pediatric
Hematology, Oncology and Immunology
I. I. Levina
Institute of Biochemical Physics, Russian Academy of Sciences
Kosygina 4, 119334 Moscow (Russian Federation)
Samory Mashela 1, 117997 Moscow (Russian Federation)
E-mail: ivan.andreev@fccho-moscow.ru
Dr. I. A. Andreev,[+] Dr. O. A. Ivanova, Prof. Dr. V. N. Khrustalev,
Prof. Dr. I. V. Trushkov
Prof. Dr. V. N. Khrustalev
Faculty of Science, RUDN University
Miklukho-Maklaya 6, 117198 Moscow (Russian Federation)
[+] These authors contributed equally to this work.
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of
Sciences, Leninsky pr. 47, 119991 Moscow (Russian Federation)
E-mail: trush@ioc.ac.ru
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under https://doi.org/10.
1002/anie.202016593.
Homepage: https://trushkovgroup.com/igor-trushkov
ꢀ 2021 The Authors. Angewandte Chemie International Edition
published by Wiley-VCH GmbH. This is an open access article under
the terms of the Creative Commons Attribution License, which
permits use, distribution and reproduction in any medium, provided
the original work is properly cited.
Dr. A. U. Augustin, Prof. Dr. D. B. Werz
Technische Universität Braunschweig, Institute of Organic Chemistry
Hagenring 30, 38106 Braunschweig (Germany)
E-mail: d.werz@tu-braunschweig.de
Homepage: http://www.werzlab.de
Dr. O. A. Ivanova
Department of Chemistry, Lomonosov Moscow State University
Leninskie Gory 1–3, 119991 Moscow (Russian Federation)
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and trialkylammonium thiocyanates, which were typically
studied as PILs in electrochemistry, chromatography, etc.,[5,16]
have pKa (BH+) values between 9.5 and 11;[17] these PILs are
expected to have low activity in initiating reactions of D-A
cyclopropanes. To check these assumptions, we decided to
investigate PILs with three different basic components: 1-
methylimidazole (Mim, pKa (BH+) 7.1[18]) as a base of choice;
triethylamine as non-nucleophilic species with basicity, typical
for alkylamines (pKa (BH+) 10.7);[19] and N,N,N’,N’-tetrame-
thylguanidine (Tmg) as an amine with increased basicity (pKa
(BH+) 13.6).[19]
To obtain salts formed by (iso)thiocyanic acid with
amines, two main approaches are usually applied: anion
metathesis by a reaction of the corresponding ammonium
halides with metal thiocyanate[16b,20] and cation metathesis by
the displacement of ammonia in NH4SCN with more basic
amines.[21] For the preparation of 1-methylimidazolium thio-
cyanate (HMimNCS, 3a), we applied the first method, using
the modified procedure for the reaction of commercial
HMimCl with sodium thiocyanate.[22] On the contrary to the
original report, wherein the product was poorly purified and
almost uncharacterized, we obtained HMimNCS on a molar
scale as an analytically pure bench-stable compound and
proved its structure by single-crystal X-ray analysis (Sche-
me 2a).[23,24]
Scheme 1. General strategy of using PIL as solvent, reagent, and
catalyst and its application for the ring-opening of D-A cyclopropanes
with thiocyanate ion.
facilitating a transformation. Moreover, the protonation of an
intermediate enolate ion in the acidic media allows the
avoidance of: a) the process reversibility, proved in the
related ring-opening with azide ion,[10] and b) CH-acid
elimination, detected in the reaction of D-A cyclopropanes
with sodium cyanide.[11]
Herein, we describe the synthesis of relevant PILs and
their utilization for the chemoselective ring-opening of D-A
cyclopropanes 1 via nitrogen attack on the three-membered
ring affording pyrrolidine-2-thiones 2 bearing two acceptor
groups at the C(3) and donor substituent at the C(5) atom in
a single time-efficient step (Scheme 1c). Such behavior of
ambident thiocyanate ion differs crucially from the typical
reactivity of this nucleophile with saturated carbon atoms
when S-attack proceeds predominantly or exclusively.[12] It
should be noted that our previous two-step transformation of
cyclopropanes 1 to pyrrolidine-2-thiones 2 required pro-
longed heating and tremendous combined reaction times,
provided much lower yields and involved toxic reagents.[13]
Two other thiocyanate-based PILs Et3N·HNCS (3b)[21b]
and HTmgNCS (3c) were synthesized by the reaction of
ammonium thiocyanate with the corresponding amines;
triethylammonium thiocyanate was characterized by single-
crystal X-ray analysis (Scheme 2b). We found that the
completeness of the cation metathesis can be controlled by
an “ammonium test”: if the dissolution of the obtained PIL
(ca. 150 mg) in CDCl3 (ca. 550 mL) during the preparation of
an NMR sample was not accompanied by the appearance of
a visible suspension of NH4SCN, the PIL contained no
residual ammonium ion.
Results and Discussion
We started this work by searching for optimal reaction
conditions. To be a stable reaction medium, PIL should have
a full proton transfer from an acid to a base;[5] full ionicity is
also desired for the highest nucleophilicity of the thiocyanate
ion in the PIL. This is best achieved when the difference of the
pKa values (DpKa) of the two PIL-forming components is
larger than 8.[14] For thiocyanate-derived PILs, isothiocyanic
acid (HNCS) should be considered as an acidic component;
its pKa was determined to be À1.28,[15] therefore, BH+ should
have a pKa > 6.7. Nevertheless, the PIL should be acidic
enough to induce a ring-opening of D-A cyclopropanes, i.e.,
pKa (BH+) value should be as low as possible. Alkyl-, dialkyl-,
Scheme 2. Syntheses of PILs 3 and single-crystal X-ray structures of
HMimNCS (3a) and Et3N·HNCS (3b); thermal ellipsoids are shown at
50% ellipsoid probability.
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Using the obtained PILs, we optimized reaction condi-
yield and conversion even after 4 h at 1008C (Table 1,
tions for the transformation of D-A cyclopropane 1a as
a model substrate. Under heating in HMimNCS, 1a was found
to produce 5-aryl-2-thioxopyrrolidine-3,3-diester 2a in good
yield. The best result (81%) was achieved when cyclopropane
1a was heated in HMimNCS (3a) at 708C for 1 h (Table 1,
entry 1). Product 2a was obtained with the same yield when
the reaction was performed at 508C for 2 h (Table 1, entry 2).
Oppositely, the increase of the reaction temperature afforded
2a contaminated with inseparable side products (Table 1,
entries 3–5).
The above optimizations were performed at 1 M concen-
tration of 1a in HMimNCS (ca. 8 equiv), which ensured the
homogeneity of reaction mixtures. The attempt to decrease
PIL quantity resulted in a diminished yield of 2a (Table 1,
entry 6). This outcome can be explained by the fact that the
excess of 3a not only facilitates the reaction but also allows
suppression of side-processes as D-A cyclopropanes possess
numerous modes of reactivity, including rearrangements and
dimerizations. Thus, the optimal excess of HMimNCS corre-
sponded to 1 M solution of D-A cyclopropane 1a in PIL.
As for other less acidic PILs, at 708C, the conversion of 1a
was moderate in triethylammonium thiocyanate (3b) and
very low, if at all, in HTmgNCS (3c) (Table 1, entries 7, 8); the
increase of reaction temperature led to decomposition only
(Table 1, entry 9).
entry 10). A tremendous increase in the reaction time allowed
us to achieve almost complete conversion of the starting
material (Table 1, entry 11). However, the yield of 2a was
even lower than that after 4 h. The attempt to improve the
above results by switching from Et3N·HCl to HMimCl was
unsuccessful (Table 1, entry 12). Thus, the conventional
reaction conditions were rendered unsuitable for the title
transformation. Finally, the reaction of 1a with a combination
of NaSCN and PILs containing no nucleophilic anion
(Table 1, entries 13, 14) produced a complex mixture of
non-identified products.
With the optimized conditions in hand (method A), we
investigated the scope of this formal (3+2)-cycloaddition of
=
D-A cyclopropanes to the C N bond of unstable isothio-
cyanic acid. We found that a broad range of cyclopropane-1,1-
dicarboxylates bearing electron-releasing groups at the C(2)
atom of the three-membered ring efficiently participate in the
disclosed reaction (Scheme 3).
Good yields of 2 were obtained in reactions of D-A
cyclopropanes containing mono-, di- and trialkoxyphenyl
groups (1a–h,k). The lower yields of pyrrolidine-2-thiones 2i,j
can be explained by the partial hydrolysis of the acetal moiety
during the reaction followed by side processes involving the
formed phenolic group.[25]
D-A cyclopropanes 1l and 1m afforded the target
products 2l and 2m, respectively, in low yields (16% and
13%). These substrates are too reactive and undergo
a significant decomposition under the reaction conditions.
However, in a less acidic PIL Et3N·HNCS, yields of pyrroli-
dines 2l and 2m[23] were much better (59% and 56%),
especially when substrates were slowly added to preheated
PIL (method B), that allowed minimization of side product
formation. Oppositely, cyclopropane 1n, bearing the 4-
dimethylamino-2-nitrophenyl group, produced pyrrolidine
2n in good yield.
We also tested reaction conditions, similar to those
employed for the ring-opening of D-A cyclopropanes with
sodium azide.[10] However, heating of 1a with sodium
thiocyanate and Et3N·HCl as a proton source in N,N-
dimethylformamide (DMF) produced crude 2a in moderate
Table 1: Optimization of reaction conditions for the transformation of 1a
to 2a.[a]
When the electron-releasing effect of methoxy group is
attenuated by the involvement of an additional aromatic ring
between donor group and three-membered ring (1o), the
yield of 2o dropped to 40%. Oppositely, the efficiency of the
transformation of 6-methoxy-2-naphthyl-substituted cyclo-
propane 1p did not principally differ from that of substrates
1c–1h and 1k. A reasonably good yield of the target product
was also obtained in the reaction of phthalimido derivative
1q, but the corresponding aminal 2r bearing a succinimidyl
group was formed in moderate yield (45%). These results are
well consistent with a much higher reactivity of 1q vs. 1r in
the Lewis acid-catalyzed (3 + 2)-cycloaddition with alde-
hydes.[26]
Heteroaryl-substituted cyclopropanes 1s–1u containing
2-furyl, 2- and 3-thienyl groups as donor as well as (1-
benzylindol-4-yl)-derived cyclopropane 1w were found to
participate in the discussed transformation providing the
target heterocycles in reasonable to excellent yields. On the
contrary, (1-methylpyrrol-2-yl)-substituted D-A cyclopro-
pane 1v was found to be too reactive, producing a significant
quantity of admixtures. Similarly to the behavior of 1l and
1m, the replacement of HMimNCS by the less acidic
triethylammonium thiocyanate allowed for increasing yield
Entry “HNCS” source
T [8C] t [h] Yield
of 2a[b]
1
2
3
4
5
6
7
8
9
10
HMimNCS
HMimNCS
HMimNCS
HMimNCS
HMimNCS
HMimNCS (2 M solution of 1a)
Et3N·HNCS
HTmgNCS
70
50
80
100
150
70
70
70
1
2
2
81[c]
81[c]
79[d]
1.5 65[c,d]
[e]
1
1
–
66[e]
13.5 58[f]
[g]
1
4
4
–
[e]
HTmgNCS
NaSCN (2 equiv), Et3N·HCl (2 equiv),
100
100
–
62[h]
58[c]
56[h]
DMF
11
NaSCN (2 equiv), Et3N·HCl (2 equiv),
DMF
100
17
12
13
14
NaSCN (2 equiv), HMimCl (2 equiv), DMF 70
NaSCN (2 equiv), Et3N·3AcOH
NaSCN (2 equiv), Et3N·TFA
6
4
[e]
100
100
–
[e]
5.5
–
[a] 1 M solution of 1a in PIL; 0.5 M solution in DMF. [b] NMR yield in
[%]. [c] Isolated yield. [d] Contaminated by 3–7% of inseparable side
products. [e] Complex mixture. [f] 59% conversion. [g] No conversion.
[h] ca. 70% conversion.
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Scheme 3. Scope of the formal (3+2)-cycloaddition of isothiocyanic acid with D-A cyclopropanes 1 affording pyrrolidine-2-thiones 2. Reaction
conditions: Method A: 1 M Solution of 1 in HMimNCS, 708C, 1 h if not otherwise specified. Method B: 1 was added in small portions for 40–
45 min to Et3N·HNCS preheated to 708C, then stirred at the same temperature for 15–20 min (total reaction time À1 h). All yields are given for
analytically pure compounds. aCrude second diastereomer was also obtained in 27% yield. bThermal ellipsoids are shown at 50% probability.
of the target product, however, to 29% only. 2-Vinylcyclo-
propane-1,1-diester 1y reacted with HMimNCS via both SN2-
like and SN2’-like processes, affording the product of N-attack
on the terminal CH2 group 4 in 76% yield together with
a small quantity (5%) of 5-vinylpyrrolidine-2-thione 2y.
Oppositely, a series of styryl-substituted cyclopropanes 1z–
1ac gave rise to the target pyrrolidinethiones 2z–2ac in good
yields of 79–87%.
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Unfortunately, dimethyl cyclopropane-1,1-dicarboxylates
and proton shift accomplished the pyrrolidine-2-thione for-
bearing aryl groups, which stabilize the cationic center only in
a moderate manner, such as para-methyl- or para-fluoro-
phenyl, produced a complex mixture of products under
heating in both HMimNCS and Et3N·HNCS.[24] A similar
difference in the reactivity of diversely substituted D-A
cyclopropanes was earlier pointed out in some other trans-
formations.[11,26,27] This problem was usually solved by a proper
selection of Lewis or Brønsted acid for the process initiation.
This work is currently in progress.
The effect of electron-withdrawing groups on the reaction
efficiency is more ambiguous. The substitution of methox-
ycarbonyl functionalities by ethoxycarbonyl ones influenced
insignificantly the reaction efficiency providing 2ad in 73%
yield. Cyanoester 1ae produced two diastereomeric products
in a similar total yield. The structure of the major diastereo-
mer was unambiguously proved by single-crystal X-ray
analysis.[23] On the other hand, Meldrumꢀs acid-derived D-A
cyclopropanes 1af,ag were transformed into pyrrolidines
2af,ag despite the presence of the phenyl and even para-
cyano-phenyl group as the aryl substituent decelerating
cyclopropane reactivity significantly.
Therefore, reactive D-A cyclopropanes 1 can be efficient-
ly transformed into 2 by heating in 1-methylimidazolium
thiocyanate, which serves as a synthetic equivalent of
isothiocyanic acid, at 708C. If substrates were extremely
active (1l, 1m, 1v, etc.), the target products were obtained
with low yields as various side reactions proceeded. We
showed that tuning of PIL allows for solving this problem. In
the less acidic triethylammonium thiocyanate, products 1l
and 1m were obtained in reasonable yields. A variety of
acceptor substituents in cyclopropanes 1 are tolerated by the
reaction conditions. Moreover, we showed that D-A cyclo-
propanes 1 bearing donor groups with lower cation-stabilizing
ability could be introduced into this formal (3+2)-cyclo-
addition if more efficient electron acceptors were present in
the molecule. Namely, Meldrumꢀs acid-derived cyclopropanes
1af,ag underwent a transformation into pyrrolidines 2af,ag,
which can be easily converted into the corresponding methyl
diesters.[28]
mation (Scheme 4, path a).
Based on multiple reports that S-attack of thiocyanate is
kinetically preferred in both SN2 and SN1 reactions,[12,31] the
alternative mechanism including an initial formation of
thiocyanate B followed by its isomerization to A could also
be supposed (Scheme 4, path b). The cyclization of inter-
mediate A to the target pyrrolidine-2-thione 2[13] is a key step
for both possible mechanisms. Our failure to identify thio-
cyanates B in reaction mixtures supports path a, but cannot be
considered as an argument against the alternative route.
Additionally, we showed that the obtained pyrrolidine-2-
thiones 2 could be easily modified to prepare other important
products. In particular, we found that the oxidation of 2a with
meta-chloroperbenzoic acid (mCPBA) led to the correspond-
ing pyrrolidone 5, which can be considered as the product of
the formal (3+2)-cycloaddition of D-A cyclopropane 1a with
HNCO (Scheme 5). Moreover, we demonstrated that the
alkylation of 2a with dimethyl sulfate afforded thioimidate 6
(Scheme 5). This compound corresponds to the product of the
formal (3+2)-cycloaddition of D-A cyclopropanes 1 with
alkyl thiocyanates, a process that has not been studied yet.
To achieve further proof of concept for the triple role of
PILs, we employed 1-methylimidazolium thiocyanate to
perform the annulation of isothiocyanic acid with 2-hydrox-
yphenyl-derived cyclopropane 1ah,[32] serving as the equiv-
alent of the corresponding ortho-quinone methide.[33] Indeed,
under heating in HMimNCS at 708C, cyclopropane 1ah was
smoothly transformed into [1,3]benzoxazine-2-thione 7 in
The developed procedure can be scaled up without the
loss of efficiency and sustainability.[24,29] Thus, when 10 mmol
(3 g) of 1a were introduced into the reaction, product 2a was
isolated in 89% yield. Moreover, PILs 3a and 3b can be
efficiently recovered. In particular, the outcome of 2a did not
change after 4 cycles of regeneration, the yield of regenerated
3a being close to quantitative.[24,29]
Scheme 4. Proposed mechanistic pathways for the formation of pyrro-
lidines 2.
Pyrrolidine-2-thiones 2 are products of the formal (3+2)-
cycloaddition of HNCS with D-A cyclopropanes 1. However,
(3+2)-cycloadditions of D-A cyclopropanes with diverse alkyl
and aryl isothiocyanates afforded 2-iminotetrahydrothio-
phenes, but not pyrrolidine-2-thiones.[27g,30] Both these liter-
ature data and our results demonstrate that products 2 are
formed by a stepwise mechanism, including protonation of an
acceptor group in the D-A cyclopropane followed by an SN2-
like attack on the protonated substrate 1·H+ with thiocyanate
ion leading to intermediate A. The intramolecular attack of
the emerging enol functionality on the isothiocyanate moiety
Scheme 5. Follow-up chemistry. DIPEA: N,N-diisopropylethylamine.
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reasonable yield. We believe that this reaction proceeds by
a similar stepwise mechanism, including the nucleophilic
opening of a three-membered ring with thiocyanate ion
followed by an attack of the ortho-hydroxy group on the
formed isothiocyanate moiety (Scheme 6). This process,
together with the reported transformations of 2-hydroxy-
phenyl-containing D-A cyclopropanes,[33,34] could be respon-
sible for the diminished yields of pyrrolidine-2-thiones 2i and
2j in the reactions of the corresponding cyclopropane-1,1-
diesters 1i,j (Scheme 3).
transformations to proceed in triple-role protic ionic liquids.
Nevertheless, it is noteworthy that the described synthesis of
13 was carried out under much milder conditions compared to
the single reported one-step preparation of this compound.
Namely, the reaction of l-proline with thiourea required
heating of an inhomogeneous mixture at 170–2108C under
careful control of the reaction, as local over-heating led to
significant decrease of the yield.[37] This indicates the high
potential for further applications of PIL in various trans-
formations.
Taking into account the somewhat sophisticated character
of the D-A cyclopropanes 1 as substrates, we opted to transfer
the triple role PILs concept onto organic transformations Conclusion
proceeding with conventional starting materials (Scheme 7).
First, the treatment of cyclohexene oxide (8) with a stoichio-
metric amount of HMimNCS at r.t. resulted in the S-selective
nucleophilic ring-opening producing 2-hydroxycyclohexyl
thiocyanate 9[35] (Scheme 7a). Heating of HMimNCS with
1-(3-aminopropyl)imidazole (10) at 808C led to the displace-
ment of 1-methylimidazole in HMimNCS with the more basic
amine providing new protic ionic liquid 11 via a cation
metathesis reaction (Scheme 7b). This compound may find
broad use as a room temperature PIL; further, it might
possess interesting biological properties accounting for the
nature of the cationic part.[36] Under harsher conditions, L-
proline 12 underwent formal (3+2)-cycloaddition with iso-
thiocyanic acid affording bicyclic 2-thiohydantoin 13 (Sche-
me 7c). Yields of products 9 and 13 were unoptimized as our
goal was only to demonstrate a principal possibility for these
In summary, we have demonstrated that protic ionic
liquids containing nucleophilic anions are able to serve in
concert as a resplendent trio, namely, as recoverable reaction
medium, as Brønsted acid, initiating the process as a catalyst,
and as a source of the nucleophile. The efficiency of this
strategy was exemplarily shown for the ring-opening of donor-
acceptor cyclopropanes with the thiocyanate ion. 1-Methyl-
imidazolium thiocyanate was selected as an appropriate PIL
possessing an almost perfect balance of acid-base properties
of components forming this reagent that can be regarded as
a bench-stable surrogate of isothiocyanic acid. Unusual
chemoselectivity of the ambident thiocyanate ion was found
for this process: attack of the nitrogen rather than the sulfur
on the activated three-membered ring produced isothiocya-
nate, which underwent immediate cyclization affording 3,5-
disubstituted pyrrolidine-2-thiones, products of the formal
(3+2)-cycloaddition of D-A cyclopropanes with isothiocyanic
acid. A broad scope of D-A cyclopropanes was successfully
employed. Scaling up and PIL recovery were demonstrated.
Other applications of thiocyanate-containing PILs as triplex
reagents in diverse reactions were also investigated. Further
development of the triple-role PILs is in progress now; the
results will be reported in due course.
Scheme 6. Triple role of 1-methylimidazolium thiocyanate in the trans-
formation of cyclopropane 1ah to [1,3]benzoxazine-2-thione 7.
Acknowledgements
We thank the Russian Foundation for Basic Research
(projects 20-33-70014 and 18-03-00954) for financial support
of this work. D.B.W. is grateful to the European Union for an
ERC Consolidator Grant (GAINBYSTRAIN). Open access
funding enabled and organized by Projekt DEAL.
Conflict of interest
The authors declare no conflict of interest.
Keywords: (iso)thiocyanates ·donor-acceptor cyclopropanes ·
ionic liquids ·nitrogen heterocycles ·small ring systems
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Manuscript received: December 14, 2020
Accepted manuscript online: January 12, 2021
Version of record online: February 26, 2021
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