The fluoride anion-catalyzed sulfurization of thioketones with elemental sulfur leading to sulfur-rich heterocycles: First sulfurization of thiochalcones ?

molecules

Article

The Fluoride Anion-Catalyzed Sulfurization of Thioketones

with Elemental Sulfur Leading to Sulfur-Rich Heterocycles:

First Sulfurization of Thiochalcones ^†

*

, Jakub Wre˛czycki ^2,*, Katarzyna Urbaniak ¹, Dariusz M. Bielin´ski ²

1,

Grzegorz Mloston´

and Heinz Heimgartner ³

1

2

3

Department of Organic and Applied Chemistry, Faculty of Chemistry, University of Lodz, 12 Tamka Street,

91-403 Lodz, Poland; katarzyna.urbaniak@chemia.uni.lodz.pl

Institute of Polymer and Dye Technology, Faculty of Chemistry, Lodz University of Technology,

12/16 Stefanowskiego Street, 90-924 Lodz, Poland; dariusz.bielinski@p.lodz.pl

Department of Chemistry, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland;

heinz.heimgartner@chem.uzh.ch

*

Correspondence: grzegorz.mloston@chemia.uni.lodz.pl (G.M.); jakub.wreczycki@dokt.p.lodz.pl (J.W.);

Tel.:+48-42-635-57-61 (G.M.)

†

Dedicated to Professor Janusz Jurczak (Warsaw) on the occasion of his 80th birthday.

Abstract: Fluoride anion was demonstrated as a superior activator of elemental sulfur (S₈) to perform

sulfurization of thioketones leading to diverse sulfur-rich heterocycles. Due to solubility problems,

reactions must be carried out either in THF using tetrabutylammonium ﬂuoride (TBAF) or in DMF

using cesium ﬂuoride (CsF), respectively. The reactive sulfurizing reagents are in situ generated,

ꢀꢁꢂꢀꢃꢄꢅꢆꢇ

−

nucleophilic ﬂuoropolysulﬁde anions FS_(8−x), which react with the C=S bond according to the car-

ꢀꢁꢂꢃꢄꢅꢆ

bophilic addition mode. Dithiiranes formed thereby, existing in an equilibrium with the ring-opened

form (diradicals/zwitterions) are key-intermediates, which undergo either a step-wise dimerization

to afford 1,2,4,5-tetrathianes or an intramolecular insertion, leading in the case of thioxo derivatives of

2,2,4,4-tetramethylcyclobutane-1,3-dione to ring enlarged products. In reactions catalyzed by TBAF,

water bounded to ﬂuoride anion via H-bridges and forming thereby its stable hydrates is involved

in secondary reactions leading, e.g., in the case of 2,2,4,4-tetramethyl-3-thioxocyclobutanone to the

formation of some unexpected products such as the ring enlarged dithiolactone and ring-opened

dithiocarboxylate. In contrast to thioketones, the ﬂuoride anion catalyzed sulfurization of their α,β-

unsaturated analogues, i.e., thiochalcones is slow and inefﬁcient. However, an alternative protocol

with triphenylphosphine (PPh₃) applied as a catalyst, offers an attractive approach to the synthesis

Citation: Mloston´, G.; Wre˛czycki, J.;

Urbaniak, K.; Bielin´ski, D.M.;

Heimgartner, H. The Fluoride

Anion-Catalyzed Sulfurization of

Thioketones with Elemental Sulfur

Leading to Sulfur-Rich Heterocycles:

First Sulfurization of Thiochalcones .

Molecules 2021, 26, 822. https://

doi.org/10.3390/molecules26040822

Academic Editor: Oleg A. Rakitin

Received: 18 January 2021

Accepted: 2 February 2021

Published: 5 February 2021

of 3H-1,2-dithioles via 1,5-dipolar electrocyclization of the in situ-generated α,β-unsaturated thio-

cabonyl S-sulﬁdes. All reactions occur under mild conditions and can be considered as attractive

methods for the preparation of sulfur rich heterocycles with diverse ring-size.

Keywords: thioketones; thiochalcones; ﬂuoride anion; elemental sulfur; sulfur heterocycles

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1. Introduction

It is a well-known fact that large amounts of elemental sulfur (S₈) are available as a side

product of diverse technological processes, and its further usage in a sustainable cycle of

conversions leading to useful, organic compounds represents an important and challenging

Copyright:

problem for chemical industry and related branches [1]. Sulfurization reactions performed

Licensee MDPI, Basel, Switzerland.

This article is an open access article

distributed under the terms and

conditions of the Creative Commons

Attribution (CC BY) license (https://

creativecommons.org/licenses/by/

4.0/).

with elemental sulfur and leading to cyclic or acyclic organic compounds constitute an

interesting and practically relevant topic in the current organic chemistry of sulfur. Results,

which were mainly published in the recent two decades, are summarized and compared in

an excellent, comprehensive review [2].

Reactions of thiocarbonyl compounds with elemental sulfur and their conversion into

sulfur-rich heterocycles attract attention since many decades. Aromatic, aliphatic/aromatic

Molecules 2021, 26, 822. https://doi.org/10.3390/molecules26040822

https://ww w .mdpi.com/journal/molecules

Molecules 2021, 26, 822

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or cycloaliphatic thioketones

1, and

2, e.g., thiobenzophenone (1a) and (tert-butyl) phenyl

thioketone (1b), as well as cycloaliphatic analogues such as 2,2,4,4-tetramethylcyclobutane-

1,3-dithione (2a), 2,2,4,4-tetramethyl-3-thioxocyclobutanone (2b) or adamantanethione (2c

are known to undergo sulfurization in the presence of a nucleophilic catalyst or upon

heating without a catalyst in an appropriate organic solvent [ ] (Figure 1). On the other

hand, sulfurization of thiochalcones -unsaturated thioketones) as substrates for the

preparation of sulfur-rich heterocycles has not yet been reported.

)

3–8

3 (α,β

Figure 1. Aromatic and cycloaliphatic thioketones

1 and 2, and thiochalcones 3 applied in the study.

In many cases, the mechanistic interpretation of the observed reactions course was

based on the assumption that the transient thiocarbonyl S-sulﬁdes (thiosulﬁnes) ],

4 [9

generated via the transfer of a sulfur atom to the C=S bond, and considered as ‘sulfur-

rich’ representatives of so called ‘sulfur-centered 1,3-dipoles’, play the crucial role in

the formation of sulfur heterocycles, such as the corresponding 1,2,4-trithiolanes

(Figure 2). On the other hand, the larger rings, e.g., 1,2,4,5-tetrathianes or 1,2,3,5,6-

pentathiepanes , are formed via more complex processes, but the reaction mechanisms are

not fully rationalized to date and require further studies [3,4,11].

5 [10]

6

7

Figure 2. Thiocarbonyl S-sulﬁdes

4, the sulfur-rich heterocycles 1,2,4-trithiolanes 5, 1,2,4,5-

tetrathianes 6, and 1,2,3,5,6-pentathiepanes 7, as well as phenylpolysulﬁde anions 8A.

For example, in some instances, sulfurization of thioketones performed in the pres-

ence of a nucleophilic catalyst, e.g., sodium or potassium thiophenolate, were explained

via involvement of in situ-generated, reactive polysulﬁde anions of type 8A [3,4]. Thus,

Huisgen and Rapp reported that elemental sulfur reacts with thiobenzophenone (1a) in

boiling acetone, in the presence of catalytic amounts of sodium thiophenolate, yielding

3,3,6,6-tetraphenyl-1,2,4,5-tetrathiane (6a) (R = Ph) as the exclusive product [

authors demonstrated that 3-thioxo-2,2,4,4-tetramethyl-cyclobutanone (2b) [ ] and adaman-

tanethione (2c) [ ] also undergo sulfurization under the same conditions. However, the

isolated products are either the bis-spirocyclic 1,2,4,5-tetrathianes 6b 6c (R,R = 6b: spiro-

2,2,4,4-tetramethyl-3-oxocyclobutyl; 6c: spiro-2-adamantyl) or 1,2,3,5,6-pentathiepanes 7a 7b

(R,R = 7a: spiro-2,2,4,4-tetramethyl-3-oxocyclobutyl; 7b: spiro-2-adamantyl), respectively.

3]. The same

4

3

/

Okuma also studied reactions of 2c with elemental sulfur in the presence of cat-

alytic amounts of triphenylphosphine sulﬁde (Ph₃P=S) in boiling CHCl₃and isolated

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1,2,4-trithiolane 5c (R,R = spiro-2-adamantyl) in 59% yield [

5

]. In the same publication, sul-

furization of 1a with elemental sulfur in boiling xylene, in the presence of maleic anhydride

as a trapping reagent for the postulated, intermediate thiobenzophenone S-sulﬁde (4a) (R₁

= R₂= Ph), was also described, and the expected [3+2]-cycloadduct, i.e., 5,5-diphenyl-1,2-

dithiolane-3,4-dicarboxylic acid anhydride, was obtained in 74% yield [5].

Nakayama et al. performed sulfurization of the cycloaliphatic thioketone 1b with

elemental sulfur without a nucleophilic catalyst using DMF or toluene as a solvent. De-

pending on the solvent, either a mixture of the isomeric 1,2,4-trithiolanes cis- and trans-5a

(boiling toluene) or cis-5a as the sole product (DMF, rt), were obtained [6,7]. In these reac-

tions, a plausible mechanistic explanation comprised the in situ-formation of thiocarbonyl

S-sulﬁde 4b and its subsequent stereoselective [3+2]-cycloaddition onto the unconverted

thioketone 1b (Scheme 1).

Toluene

reflux

S

Ph

+

S

+ 1b

Ph

+ S₈

_

+

or

DMF, rt

Ph

S

Ph

4b

1b

trans-

5a

cis-5a

Scheme 1. Reaction of tert-butyl phenyl thioketone (1b) with elemental sulfur S₈in boiling toluene or in DMF at rt (ref. [6,7]).

A similar reaction performed with tert-butyl 4-methylphenyl ketone in boiling pyri-

dine and using tetraphosphorus decasulﬁde (P₄S₁₀) as a thionating and sulfurizing reagent,

was described by Okuma et al. [8].

In spite of the fact that the ﬂuoride anion is well known as a useful reagent acting

not only as a unique catalyst for nucleophilic triﬂuoromethylation reactions [12], as a

desilylating agent [13], but also as a strong base [14], its exploration as an activating

reagent for elemental sulfur in the sulfur transfer reactions is limited to two reports only,

which are known to date [15,16]. In one of them, Petrov and Marshall demonstrated

the utility of the ﬂuoride anion as a potent activator of elemental sulfur used for in situ-

generation of reactive hexaﬂuorothioacetone S-sulﬁde, which subsequently was trapped

by ethylenic dipolarophiles yielding corresponding bis-triﬂuoromethylated 1,2-dithioles

in high yields [15]. In the second publication, sulfurization of cyclopropenethione 2d

and its oxo-analogues with elemental sulfur in DMF solution at room temperature was

described [16] (Scheme 2). In this study, potassium ﬂuoride was used in two-fold excess as

activator and the molar ratio of reagents 2d/[S]/KF was optimized to 1:2:2. Under these

conditions, 3-thioxo-1,2-dithiole 9 was obtained as the product of a cascade reaction and

isolated in good yield (84%). A series of analogous Se-heterocycles was also obtained using

elemental selenium instead of sulfur [16].

Scheme 2. Fluoride anion-catalyzed sulfurization of diphenylcyclopropenethione (2d) (ref. [16]).

Unlike thioketones, similar sulfurization of α,β-unsaturated thioketones 3 (thiochalkones)

with S₈are almost unknown. In an earlier publication, however, sulfurization of rather

complex thiochalcones 11, prepared in situ from corresponding ketones 10, was carried out

in non-polar xylene by treatment with S₈. These reactions led to the polycyclic products

12, which were formed as minor products, exclusively [17] (Scheme 3 ). The formation

of the latter heterocycles was explained via a multi-step mechanism with the respective

α

,β-unsaturated thiocarbonyl S-sulﬁdes 4c as the reactive intermediates in the postulated

intramolecular [5+2]-cycloaddition reactions.

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Scheme 3. Reaction of thiochalcones 11 with sulfur yielding 1,2-dithiepanes 12 via intramolecular

[5+2]-cycloaddition of intermediate thiocarbonyl S-sulﬁdes 4c (ref. [17]).

The main goal of the present study was examination of the utility of the ﬂuoride anion

as a new type of a catalyst for sulfurization of thiobenzophenone (1a) and cycloaliphatic

thioketones 2a

selected thiochalcones 3a

–

2c. In extension of the study with thioketones, ﬁrst sulfurization reactions of

3d were carried out by using elemental sulfur (S₈) in the presence

–

of a nucleophilic catalyst. Elucidation of the mechanisms of the studied reactions, leading

to the formation of sulfur-rich heterocycles with diverse ring size, was of primary interest.

2. Results and Discussion

2.1. Conversions of Thioketones 2a and 2b upon Tretament with Catalytic Amounts of TBAF in the

Absence of Elmental Sulfur

In an earlier publication, unexpected conversions of thiobenzophenone (1a) and cy-

cloaliphatic thioketones 2a–2c upon treatment with catalytic amounts of TBAF in THF

solution were reported [18]. The obtained results demonstrated that the type of products

formed in each reaction strongly depended on the type of thioketone used in the studied

experiment. Interestingly enough, two structurally similar cycloaliphatic thioketones 2a

and 2b—derived from 2,2,4,4-tetramethylcyclobutane-1,3-dione (13)—gave completely dif-

ferent sets of products. Whereas in the case of dithione 2a the only product was the isomeric

thiolactone 14, the monothione 2b afforded a mixture of the unusual dithiocarboxylate 15

and the parent dione 13 (Scheme 4).

Scheme 4. Comparison of unusual conversions of thioketones 2a and 2b upon treatment with catalytic amounts of TBAF in

THF solution at rt in the absence of S₈.

Due to the importance of this observation, both experiments were repeated in the

initial stages of the present study. The already described isomerization of 2a leading to 14

as the sole product was fully conﬁrmed. However, in the experiment with 2b we found

that along with 13 and 15 also the ring-enlarged ﬁve-membered dithiolactone 16b was

present in the crude mixture. Moreover, the molar ratio of dione 13 and dithiolactone 16b

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was ca. 1:1 and this ﬁnding suggests that the monothione 2b can be an actual source of

sulfur incorporated into the four-membered ring of another molecule of the same substrate.

The mechanism of the isomerization of 2a induced by ﬂuoride anion presented in [18

]

is a plausible explanation of this conversion. On the other side, the formation of dithioester

15, which requires reduction of the C=S bond of 2b, as well as the intermolecular transfer

of the sulfur atom from one molecule of 2b to another one in the formation of 16b, has

not convincingly been rationalized yet. Searching for a correct explanation, an additional

experiment with attempted conversion of 2b using catalytic amounts of ﬂame-dried CsF

in dry DMF has also been performed. To our surprise, no effect was observed even after

ca. 2 h at rt. This situation changed immediately after addition of a drop of water to the

solution, which rapidly changed the color to orange indicating thereby conversion of 2b

.

Subsequent control of the composition of products by means of ¹H-NMR spectroscopy

conﬁrmed the formation of the mixture of three known products, namely 13, 15, and 16b.

This result clearly demonstrated that the unexpected conversion of 2b can be performed

only in the presence of water and the involvement of the hydrated ﬂuoride anion in the

reaction solution plays a crucial role in the formation of 15 and 16b. Notably, TBAF is

known to exist as a hydrated complex and the complete removal of water requires a special

procedure [19].

2.2. Activation of Elemental Sulfur with Fluoride Anion

It is very likely that the activation of elemental sulfur with ﬂuoride anion comprises

cleavage of the S₈-ring leading to a mixture of red-colored, highly nucleophilic ﬂuoropoly-

sulﬁde anions 8B with variable length of the sulfur chain S_x(Scheme 5).

Scheme 5. Ring cleavage of the S₈crown and formation of a mixture of ﬂuoropolysulﬁde anions 8B

.

It is worth of mentioning that in the case of TBAF complete removal of water forming

‘ﬂuoride anion hydrates’ is a difﬁcult problem and some amounts of water are still present

in the solution [20]. In contrast, cesium ﬂuoride, which can be used alternatively as a source

of the ﬂuoride anion, can be prepared as a water-free salt. However, due to solubility

problems reactions with CsF have to be performed in dry DMF solution. In the sulfurization

reaction of a thioketone, the C=S bond is believed to react with anions 8B according to the

‘carbophilic’ mode of the initial nucleophilic attack.

2.3. Sulfurization of Thioketones with Elemental Sulfur

All experiments were carried out using optimized protocols elaborated in a series of

preliminary test reactions. Magnetically stirred suspension of elemental sulfur in THF at

rt dissolved immediately after addition of catalytic amounts of TBAF, and the obtained

solution was colored red or olive-green, thereby indicating formation of ﬂuoropolysuﬁde

anions 8B with variable length of the S_xchain. Addition of a thioketone led to the change of

the color within a few minutes, and the completion of the reaction was established by TLC

(see Tables 1 and 2). After pre-puriﬁcation by column chromatography aimed at separation

of the catalyst, the crude mixtures were analyzed in the ¹H-NMR spectra with weighted

standard (1,2-dichloroethane; Method A), and pure products were isolated on preparative

plates (Method B). Alternatively, selected reactions were performed in DMF solution using

pre-dried CsF as a catalyst.

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Table 1. Sulfurization conditions of thioketones 2a and 2b and yields of the products.

Thioketone

Entry

RT [h], rt

Product

Yield (%)

14

16a

63 ^a

A

1

11 ^a

8 ^b

16a

6e

B

1.5

15 ^b

43 ^b

meso-17,D,L-17

14

16a

18

9 ^a

8 ^b

C

2

5 ^a

2a

23 ^b

7c

0

54 ^b

C

24

7c

14

16a

18

7c

19

3 ^a

5 ^a

2 ^a

D

A

2

46 ^b

4 ^b

15

16b

6b

30 ^a

10 ^a

12 ^a

20 ^a

23 ^a

40 ^a

1.5

3

15

16b

6b

B

2b

34 ^b

43 ^b

52 ^b

60 ^b

C

48

24

22

6

7a

0

C

D

E

a

Method A (¹H-NMR); ^bMethod B (isolated products).

Table 2. Sulfurization conditions of thioketones 2c and 1b and yields of the products (isolated amounts).

Yield

(%)

ThioketoneEntry

RT (h)

Product

Yield (%)

59

-

Product

A

72

46

24

5c

-

7b

-

37

47

51

-

B

2c

1a

C

0

C

5c

59

B

72

48

6a

28

52

56

-

C

0

C

2.3.1. Sulfurization of ‘Dithione’ 2a and ‘Monothione’ 2b

A series of experiments aimed at determination of the impact of the molar ratio of 2a

to sulfur on the structure of the formed products, was performed starting with 1:0.5, 1:1,

1:2, 1:4 or 1:8 (Entries A–E) mixtures of the two reagents. In the obtained crude mixtures

both, known and hitherto unknown sulfur-rich heterocycles were initially identiﬁed by

¹H-NMR spectroscopy (see Supplementary Materials part) and subsequently isolated as

pure compounds (Figure 3).

In the ﬁrst experiment, the reaction with a 1:0.5 molar ratio of 2a and atomic [S]

(Entry A) led to a mixture of the isomeric thiolactone 14 (63% yield) and the ring enlarged

ﬁve-membered thiolactone 16a (11%) (Figure 3, Table 1).

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Figure 3. Products of sulfurization of thioketones 2a and 2b with elemental sulfur in the presence of

TBAF in THF solution.

Enhancement of the sulfur amount in the 1:1 experiment (Entry B) resulted in a drastic

change of composition of the products in the reaction mixture. The main component

isolated as the most polar fraction showed in the ¹H-NMR spectrum eight signals with

approximately the same intensities located at 1.32, 1.35, 1.51, 1.51, 1.69, 1.71, 1.74, and

1.75 ppm. More important information was found in the ¹³C-NMR spectrum, which

revealed the presence of two isomeric compounds with very similar patterns of absorptions.

The most characteristic ones were those found at 248.18 and 248.39 ppm, which were

attributed to two C=S groups of the dithiocarboxylate type. In addition, two signals at

78.54 and 78.71 ppm corresponded to non-equivalent C_sp3atoms connected with two sulfur

atoms. In analogy to the ¹H-NMR, eight signals between 26.32 and 30.66 ppm suggested

the presence of structurally similar 16 Me groups. The elemental analysis conﬁrmed the

molecular formula C₁₆H₂₄S₆, which can be attributed to a 1:1-mixture of the isomeric

bis-spiro-1,3-dithietane derivatives meso- and d,l-17. All attempts to separate this mixture

to obtain pure diastereoisomers, either by chromatography or fractional crystallization,

were unsuccessful.

The less polar fraction formed a yellowish oil, which in the ¹H-NMR spectrum showed

the presence of only two broadened singlets located at 1.42 and 1.69 ppm. More infor-

mation delivered the ¹³C-NMR spectrum with two low ﬁeld absorptions at 243.0 and

216.6 ppm. Whereas the ﬁrst signal could be attributed to the C=S group incorporated in

the four-membered ring of cyclobutane, the second one was identiﬁed as the C=O unit of

a cyclobutane moiety. In addition, two closely located signals with low intensity, found

at 79.86 and 79.91 ppm, respectively, revealed the presence of two C_sp3-atoms attached

to two S-atoms like in the molecule of a 1,2,4,5-tetrathiane. As a matter of fact, elemental

analysis conﬁrmed the molecular formula C₁₆H₂₄OS₅, which corresponds to the structure

of the ‘non-symmetric’ dispiro-1,2,4,5-tetrathiane 6e (Figure 3, Table 1 ). Apparently, the ini-

tially formed ‘symmetric’ analogue 6d (not isolated) underwent hydrolysis in the reaction

solution and one C=S group was converted into the C=O moiety.

Finally, the smallest and least polar fraction isolated after chromatography was identi-

ﬁed as the known [4], ﬁve-membered dithiolactone 16a (8%) (Table 1).

Increase of the molar excess of sulfur to 4 mol-equiv. (Entry D) changed dramatically

the composition of the product mixture, and in this case the major fraction consisted of

an orange oil, which in the ¹H-NMR spectrum showed a complicated pattern of signals

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located in the 1.30–2.00 ppm region. In the spectrum registered at 90 ^◦C in CHCl₂–CHCl₂

solution, four broadened signals emerged at 1.92, 1.98. 2.08, and 2.20 ppm, respectively,

indicating thereby the existence of dynamic phenomena, like in the case of pentathiepane

7a described by Huisgen et al. [4]. Elemental analysis conﬁrmed the molecular formula

C₁₆H₂₄S₇expected for the new pentathiepane 7c and allowed to determine the yield of the

isolated product to 46%. In another experiment carried out with 2a and [S] in a ratio 1:2

(Entry C), pentathiepane 7c was isolated in a lower yield (23%) and the already described

sulfur heterocycles 14 (9%), 16a (8%), and 18 (5%) were formed as side products.

Two more sulfur-rich heterocycles were separated as minor products. One of them

was identiﬁed as the known ﬁve-membered dithiolactone 18 [21], and the structure of

the second one was elucidated based on spectroscopic data and elemental analysis as

hitherto unknown spirocyclic 1,2,3,4,5,6-hexathiepane 19 being a thioxo analogue of the

corresponding oxo derivative, which was described in our earlier work [22]. Both com-

pounds revealed very similar chemical shifts for the spiro-C-atoms: 95.6 (for 19) and 92.2

(for the oxo analogue [22]) ppm, respectively.

Notably, the same pentathiepane 7c was isolated chromatographically in 54% yield as

the sole product when the sulfurization of 2a was carried out in DMF solution using dried

0

CsF as a catalyst (Entry C ). In that experiment the molar ratio of 2a and [S] was calculated

to 1:2.

In contrast to the hitherto unexplored dithione 2a, its monothione analogue 2b was

studied extensively by Huisgen and Rapp in sulfurization reactions with elemental sulfur

using potassium thiophenolate as a catalyst [4]. The main goal of that study was the

elucidation of the mechanism of the dimerization of in situ-generated intermediates leading

to 1,2,4,5-tetrathiane 6b. In our hands, reactions of 2b with variable amounts of sulfur and

performed with TBAF as a catalyst led virtually to similar products. Thus, in experiments

starting with 2b and [S] in a molar ratio 1:0.5 (Entry A) or 1:1 (Entry B), the only sulfur-rich

compound identiﬁed in the crude mixture of products was 6b accompanied by the above

reported 3-oxopentanedithioate 15 and dithiolactone 16b. In the 1:1 experiment, the yield

of tetrathiane 6b was higher (40%) (Table 1). Further enhancement of the amounts of sulfur

to 1:2 (Entry C), 1:4 (Entry D), and ﬁnally 1:8 (Entry E) molar ratio suppressed completely

the formation of other products and nothing but 1,2,3,5,6-pentathiepane 7a was isolated in

acceptable yields of 34%, 52%, and 60%, respectively. In a test experiment using pre-dried

CsF (instead of TBAF) in DMF solution and starting with a 1:2 ratio of 2b and atomic [S],

the latter heterocycle was isolated in 43% yield (Entry C⁰). Spectroscopic and physico-

chemical data of 7a ﬁtted well with those reported earlier [4]. In addition, the crystal

structure of this compound showing a complex conformation of this seven-membered,

sulfur-rich hetererocycle has also been reported in another publication [22]. In the present

study, the structure of 7a was redetermined by X-ray analysis and the crystallographic

characterization of this sulfur-rich heterocycle could be reﬁned thereby.

2.3.2. Formation of Sulfur-Rich Heterocycles from Thioketones 2a and 2b; Mechanistic

Interpretations

It has to be underlined that in both series of experiments performed either with 2a or

2b and starting with a 1:0.5 molar ratio of a thioketone

at all of the corresponding 1,2,4-trithiolane of type

of products. These ﬁndings allow to exclude participation of thiocarbonyl S-sulﬁdes

(thiosulﬁnes) 4A derived from the studied thioketones as reactive intermediates in the

2

and elemental sulfur [S], no traces

5

could be detected in the mixtures

–

C

2

herein presented sulfurizations. Instead, these observations suggest to consider dithiiranes

21 and their ring opened forms, i.e., diradicals 22 (or zwitterions 23), as elusive species

involved in the formation of the isolated sulfur-rich heterocycles (Scheme 6 ). The parent

dithiirane and its isomerization to dithioformic acid can serve as a model system helpful

in the formulation of experimentally well founded rational description of the complex

conversions observed in the present study [23].

It seems a plausible explanation that in situ-generated ﬂuoropolysulﬁde anions 8B

undergo the carbophilic addition to the C=S bond forming the intermediate anion 20. The

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latter extrudes a new ﬂuoropolysulﬁde anion with a shortened sulﬁde chain yielding the

elusive dithirane 21, which may exist in an equilibrium with ring opened reactive species

22 and/or 23 (Scheme 6).

Scheme 6. Initial, nucleophilic attack of ﬂuoropolysulﬁde anion 8B onto the C=S bond and subse-

quent ring closure leading to dithiiranes 21 as elusive intermediates.

In the reaction performed with equimolar amounts of thioketone and sulfur, step-

wise dimerization of the latter species leads to the formation of the 1,2,4,5-tetrathiane

6. Alternatively, the intermediate species 22 undergo ring-expansion via intramolecular

insertion of the S-atom into a C–C bond to form dithiolactones 16. However, if there is

a source of sulfur and ﬂuoropolysulﬁde 8B exists in the system, it can transfer one more

sulfur atom to the intermediate 24 yielding ﬁnally 1,2,3,5,6-pentathiepanes 7 (Scheme 7).

Scheme 7. Step-wise formation of 1,2,4,5-tetrathianes 6 and 1,2,3,5,6-pentathiepanes 7.

This interpretation seems to be more likely than an alternative pathway via a secondary

ring opening/ring closure reaction sequence of the initially formed 1,2,4,5-tetrathiane

derivative, after reaction with a polysulﬁde anion, leading either to 1,2,4-trithiolanes or

1,2,3,5,6-pentathiepanes. This pathway has been suggested in an earlier publication, dealing

with similar problems of sulfurization reactions of some aromatic aldehydes [11].

The unexpected formation of diastereoisomeric dispiro-1,3-dithietane 17 deserves

also a comment. It seems likely that in analogy to the earlier observed BTAF/TMSCF₃

induced dimerization of dithione 2a [18] affording 1,3-dithietane 25, also ﬂuoropolysulﬁde

anions 8B can catalyze an analogous reaction. Now, each of the C=S bonds can react with

8B and via addition/ring expansion sequence is converted in mixtures of isomeric, spiro-

heterocycles 17 (Scheme 8). Alternatively, dimerization of the initially formed dithiolactone

16a, induced by ﬂuoride anion can be postulated. Notably, no formation of corresponding

products of type 17, starting with monothione 2b was observed and this is one more feature,

which differs behavior of both cycloaliphatic thioketones in sulfurization reactions.

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Scheme 8. Postulated mechanism of the formation of diastereoisomeric bis-spiro-1,3-dithianes 17 via

initial dimerization of the starting thioketone 2a.

An alternative cyclization pathway of the initial anionic adduct 20, formed via attack

of anions 8B onto the C=S group, leading to the hexathiepane 19, is presented in Scheme 9.

It demonstrates the known tendency for the formation of seven-membered rings consisting

of sulfur and carbon atoms [22].

Scheme 9. Mechanistic explanation of the formation of 1,2,3,4,5,6-hexathiepane 19.

2.3.3. Sulfurization of ‘Adamantanethione (2c) and Thiobenzophenone (1a)

In extension of the study performed with cycloaliphatic thioketones 2a and 2b, derived

from the sterically crowded and ring congested 2,2,4,4-tetramethylcyclobutane-1,3-dione

(

13), sulfurization reactions of easily available thioketones, such as the cycloaliphatic

adamantanethione (2c) and the aromatic thiobenzophenone (1a), were also tested in the

ﬂuoride anion catalyzed sulfurization reactions. In both cases, the reactions were carried

out with TBAF as a catalyst in THF at rt, and required remarkably longer times for com-

pletion (see Table 2, Figure 4). Analysis of the crude mixtures of products by ¹H-NMR

spectroscopy and separation by preparative thin-layer chromatography led to the iden-

tiﬁcation and isolation of three types of sulfur-rich heterocycles. Thus, in the case of 2c

,

irrespective of the molar ratio of thioketone and sulfur, 1:1 (Entry B) or 1:2 (Entry C),

only the symmetric 1,2,3,5,6-pentathiepane 7b was obtained in moderate yields (37–51%).

However, in the experiment with a 1:0.5 molar ratio (2c: [S], Entry A), 1,2,4-trithiolane 5c

was found in the mixture of products as the major component (59%). The same product

was formed in DMF solution at rt exclusively, when the reaction was performed with CsF

(Entry C⁰). Its presence suggests the appearance of adamantane-2-thione S-sulﬁde and

subsequent trapping by another molecule of 2c according to the [3+2]-cycloaddition mode

as suggested in our earlier study [24]. Limited amounts of elemental sulfur available in

the ﬁrst experiment (Entry A) can suggest that the reaction leading to 5c follows a hitherto

unknown mechanism of the reaction of ﬂuoride anion with 2c mentioned in our earlier

publication [18]. Nevertheless, formation of 7b can results from the mechanism initiated

by the attack of ﬂuoropolysulﬁde anion onto the C=S bond according to the pathways

presented in Scheme 7. Notably, no symmetric 1,2,4,5-tetrathiane derived from 2c and

obtained by Huisgen and Rapp [

3] via sulfurization of the latter in reactions catalyzed with

potassium thiophenolate, was observed in our experiments.

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Figure 4. Three types of sulfur-rich heterocycles obtained by sulfurization of adamantanethione (2c

)

and thiobenzophenone (1a) with sulfur, catalyzed with ﬂuoride anion.

The ﬂuoride anion catalyzed sulfurization of thiobenzophenone (1a) was performed

starting with 1:1 or 1:2 molar ratio of 1a to [S] (Entry B or Entry C, respectively). In both

cases colorless products precipitated from THF solution, and the analysis of the obtained

crude mixtures demonstrated that the literature known, symmetric 3,3,6,6-tetraphenyl-

1,2,4,5-tetrathiane (6a) [3] was the sole product in both reactions, isolated in 28% and

52% yield, respectively. Remarkably, no ring expansion to the corresponding 1,2,3,5,6-

pentathiepane in the experiment with molar excess of sulfur (1:2; Entry C) was observed.

This observation suggests that this could be the effect of the limited solubility of 6a, which

precipitated from the THF solution in the course of the reaction. Notably, Huisgen and Rapp

did not observe formation of this 1,2,3,5,6-pentathiepane either [3]. In the present study,

along with 1a, other well-known aromatic thioketones such as xanthione, thioxanthione

and dibenzosuberenethione, which have been frequently applied in our studies, were tested

in the ﬂuoride anion catalyzed sulfurization, but in all cases no reaction was observed at rt,

even after longer reaction time (up to one week). Particularly, thioﬂuorenone (9H-ﬂuorene-

9-thione) converted rapidly into the dimeric ﬂuorenyliden-9-ene (tetrabenzo[5.5]fulvalene)

in analogy to the result described in [18]. Thus, thiobenzophenone (1a) should be con-

sidered as an exceptional case showing superior tendency to undergo the reaction with

ﬂuoropolysulﬁde anion 8B with subsequent ‘head-to-head’ dimerization of a reactive

intermediate leading to tetrasubstituted 1,2,4,5-tetrathiane 6a.

In accordance with the proposal presented in Scheme 9, a plausible mechanistic

interpretation of this multi-step reaction is the initial formation of the unstable 3,3-diphenyl

dithiirane (21c). The latter, after spontaneous cleavage of the S–S bond, converts into a

reactive intermediate of type 24, which undergoes step-wise dimerization leading to the

1,2,4,5-tetrathiane ring (Scheme 7).

2.4. Sulfurization of Thiochalcones 3

In contrast to thioketones

1/2, the α,β-unsaturated analogues, i.e., diaryl thiochal-

cones , are much less investigated as potentially useful reagents in the cycloaddition

3

chemistry. In fact, thiochalcones exhibit a far more complex nature in comparison with

thioketones, which comprises their tendency to form two dimeric molecules existing in

an equilibrium with the monomeric ones. The equilibrium concentration of monomeric

and dimeric forms depends on the solvent polarity that makes thiochalcones difﬁcult to be

tamed in [3+2]-cycloadditions [25], Diels-Alder- [26], and hetero-Diels-Alder-reactions [27].

Correctly, the fraction containing only the monomeric form is often described as ‘thiochal-

cone fraction’ [25,27]. As mentioned in the ‘Introduction’, the single experiment reporting

sulfurization of a rather complex, in situ-generated thiochalcone relates to harsh reaction

conditions with heating of the reaction mixture in boiling xylene [17].

The goal of the present study was to verify whether sulfurization of typical thiochal-

cones

3 can be performed under mild conditions using elemental sulfur activated by TBAF

in THF at room temperature. The test experiment performed with 3a and elemental sulfur

(molar ratio of 3a to [S] was 1:2) according to the protocol described above for thioketones

2a,b (Entry C), was unsuccessful, however. In that case, no conversion of 3a occurred

even after three days of stirring at rt. Instead, slow decomposition of the starting 3a was

observed by TLC.

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Prompted by Okuma’s report [5], we decided to use PPh₃in boiling acetone solution

as a nucleophilic activator of sulfur (Procedure I, Table 3). In the cited study, comparable

results were obtained using either PPh₃or S=PPh₃. In our hands, under these conditions a

part of 3a, consisting of monomeric thiochalcone and its dimer (dithiine derivative, under-

went dissociation) reacted with sulfur yielding an orange-red colored, crystalline product.

In the ¹H-NMR spectrum (see Supplementary Materials part), along with absorptions of

aromatic H atoms, a characteristic set of two doublets with ³J_H,H= 3.0 Hz was found at

5.87 and 6.19 ppm, respectively. In addition, ¹³C-NMR revealed a signal of a C_qatom at

63.7 ppm and two other signals located at 120.7 and 132.9 ppm, respectively, with clearly

different intensities, which could be attributed to a CH=C unit. The elemental analysis

conﬁrmed the molecular formula C₁₅H₁₂S₂expected for a product of monosulfurization of

3a. Based on the collected spectroscopic data, the structure of the obtained product was

established as 3,5-diphenyl-3H-1,2-dithiole (26a, Scheme 10).

Scheme 10. Synthesis of 3H-1,2-dithioles 26a

3a–3d.

–26d via PPh₃-catalyzed sulfurization of thiochalcones

Table 3. Sulfurization conditions of thiochalcones 3a–3d and yields of products.

Thiochalcone

Procedure

RT [h]

Product

Yield (%)

40 ^a(63 ^b)

15 ^a

3a

3b

3c

3d

I

II

III

IV

I

IV

I

3.5

4.0

0.5

72

4.0

3.5

72

26a

26b

26c

26d

41 ^a

15 ^a

20 ^a

17 ^a

3.0

12 ^a

a

Method A (isolated product); ^bMethod B (¹H-NMR).

It has to be underlined that the ¹H-NMR analysis of the crude mixture revealed the presence

of the non-reacted thiopyran as one of the dimers of the starting thiochalcone [25 27 ]. Apparently,

–

this dimer is stable under the reaction conditions and does not undergo dissociation

leading to new portions of the monomeric form. This fact must be taken into account while

calculating the yield of the obtained sulfurization product.

An analogous procedure has been applied to perform sulfurization of three other

thiochalcones 3b–d, which have also been converted into the desired 3H-1,2-dithioles

26b , albeit in all cases the yields of the isolated products were rather low. The results of

–

d

all experiments aimed at the synthesis of heterocycles 26 are summarized in Table 3.

For comparison reasons, two modiﬁcations of the applied procedure were tested in

reactions with 3a. In the ﬁrst case, potassium thiophenolate was used as a catalyst, but

after 4 h reaction time the product 26a was isolated in lower yield (15%) (Procedure II). The

second modiﬁcation comprised replacement of acetone by higher boiling butanone, and in

this case, the reaction was ﬁnished after only 30 min, yielding 26a in the comparable yield

of 41% (Procedure III, Table 3).

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The alternative procedure with pre-dried CsF in DMF solution (Procedure IV) was

also tested in reactions with 3a and 3c. After 3d at rt the reactions were ﬁnished and the

¹H-NMR analysis of the crude mixtures indicated the presence of the expected 3H-1,2-

dithioles 26a and 26c, which were isolated by column chromatography in 15% and 17%

yields, respectively.

Notably, no formation of a corresponding 1,2,4-trithiolane was observed in any experi-

ment performed with thiochalcones 3.

A feasible reaction mechanism is presented in Scheme 10. The PPh₃catalyzed sulfur-

ization of thiochalcones involves α,β-unsaturated thiocarbonyl S-sulﬁdes 4 as plausible

intermediates. They are formed via sulfur transfer from in situ-generated, neutral (and

therefore less nucleophilic) triphenylphosphine polysulﬁdes to the C=S group. In reactions

catalyzed with CsF (Procedure IV), participation of ﬂuoropolysulﬁde anion 8B in the trans-

fer of the sulfur atom is likely. In that case, however, the intermediate dithiirane of type

21, derived from the respective thiochalcone

the C–S bond yielding the respective 1,3-dipole [22

from chalcones belong to the group of -unsaturated 1,3-dipoles and, therefore, they

3, is belived to undergo ring opening along

,

23,28]. Thiocarbonyl S-sulﬁdes derived

α,β

can undergo 1,5-electrocyclization [29] leading to the formation of 3H-1,2-dithioles, which

apparently is a faster intramolecular process than the competitive [3+2]-cycloaddition

with a ‘non-sulfurized’ molecule of the starting thiochalcone. Therefore, in none of the

experiments formation of a respective 1,2,4-trithiolane was observed. Participation of

thiocarbonyl S-sulﬁdes in the [3+2]-cycloaddition with thiocarbonyl dipolarophiles is an

important method for the synthesis of sulfur-rich heterocycles and diverse methods for the

generation of this type of ‘sulfur-centered 1,3-dipoles’ are known [28]. Most importantly,

the described 1,5-dipolar electrocyclization found for the ﬁrst time in sulfurization reactions

of thiochalcones offers a convenient method for the preparation of useful, ﬁve-membered

3H-1,2-dithioles 26.

3. Materials and Methods

3.1. Materials

Elemental sulfur (S₈) in the form of a powder (99.98% purity), molecular sieves

4Å (mesh 8–12), tetrabutylammonium ﬂuoride (TBAF, 1.0 M solution in THF) and ben-

zophenone (99%) were purchased from Merck (Sigma-Aldrich, Darmstadt, Germany).

Triphenylphosphine (Ph₃P) (>95%), cesium ﬂuoride (CsF) and 1,1,2,2-tetrachloroethane,

used as internal standard in NMR analysis, were received from Tokyo Chemical Industry

(TCI, Tokyo, Japan). Organic solvents were purchased from the following companies:

tetrahydrofuran (99.9%) from Chemsolve (Witko, Lodz, Poland), dichloromethane (99.9%)

from Honeywell (Charlotte, NC, USA), anhydrous N,N-dimethylformamide (99.8%) from

Merck (Sigma-Aldrich), methanol (99.8%), acetone (99.5%) and petroleum ether 40/60 from

´

Chempur (Piekary Sla˛skie, Poland). THF was dried over sodium (Na) with an addition

of benzophenone, and acetone was distilled before its usage. Starting thioketones were

obtained following reported procedures: thiobenzophenone (1b) from benzophenone by

treatment with Lawesson’s reagent in toluene solution [18]; 2,2,4,4-tetramethylcyclobutane-

1,3-dithione (‘dithione’) (2a), 2,2,4,4-tetramethyl-3-thioxocyclo-butanone(‘monothione’)

(

2b), and admantanthione (2c) from 2,2,4,4-tetramethylcyclobutane-1,3-dione (13) and

adamantane-2-one, respectively, by treatment with P₄S₁₀in pyridine solution [18]. Thiochal-

cones were prepared from the corresponding chalcones by thionation with Lawesson’s

3

reagent and subsequently puriﬁed by column chromatography on silica gel [25,26].

3.2. Analytical Methods and Equipment

The nuclear magnetic resonance (NMR) spectra were measured using a Bruker Avance

III instrument (Bruker, Billerica, MA, USA) at 600 MHz (¹H-NMR) and at 151 MHz (¹³C-

NMR), respectively. Unless otherwise indicated the measurements were carried out in

deuterochloroform (CDCl₃), using solvent signals as a reference (¹H-NMR,

δ

= 7.26 ppm

(CDCl₃); ¹³C-NMR,

δ = 77.0 ppm (CDCl₃)). Chemical shifts (δ) were presented in ppm

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and coupling constants (J) were calculated in Hz. Integrals are given in accordance with

assignments. Melting points were determined in capillaries with a Melt-Temp II apparatus

(Laboratory Devices, Holliston, MA, USA). Elemental analyses were obtained with a Vario

EL III instrument (Elementar Analysensysteme, Langenselbold, Germany).

3.3. Conversions of Thioketones 2a,2b in the Presence of Fluoride Anion and Absence of S₈

3.3.1. Procedure I: TBAF/THF

To a stirred solution of pre-dried TBAF (0.1 mL of 1.0 M solution in THF) in 1.5 mL of

dried THF, 0.5 mmol of the corresponding thioketone 2a or 2b was added at rt under Ar

atmosphere. The solution was stirred and after ca. 5 min the color changed from rubin-red

(

2a) or orange-red (2b) to yellow-orange. Next, the solvent was evaporated in vacuo and

the residue was pre-puriﬁed by ﬁltration via a short chromatographic column ﬁlled with

SiO₂(ca. 2 cm layer). Crude mixtures were analyzed in the ¹H-NMR spectra with weighted

standard (Cl₂CH–CHCl₂). The products formed were identiﬁed by comparison of their

spectroscopic data with reported ones. Yields reported below refer to the analysis of crude

mixtures performed with weighted standard (method A) or to amounts of isolated products

(method B).

3.3.2. Procedure II: CsF/DMF

In an alternative procedure, conversion of thioketone 2b was carried out in dry DMF

(1.5 mL) using cat. amounts of freshly calcined cesium ﬂuoride at rt under Ar atmosphere.

After 2 h of magnetic stirring, the color still remained orange-red and no formation of other

products was observed by TLC control. After that time, a drop of water was added to the

stirred solution and the mixture rapidly changed the color to orange indicating thereby

conversion of 2b. The reaction solution was diluted with a portion of CH₂Cl₂(5 mL) and

extracted four times with water (4 mL each). Collected organic fractions were dried over

MgSO₄, ﬁltered, and the solvent was evaporated. The mixture of crude products was

analyzed in the ¹H-NMR spectrum with weighted standard (Cl₂CH–CHCl₂); the yields of

identiﬁed products 13, 15, and 16b were determined by method A.

3.3.3. Product Characterization

3,3-Dimethyl-4-(propan-2-ylidene)thietane-2-thione (14). Yield: Procedure I—92% (method

1

A); 69 mg (80%) (method B). Yellow oil (ref. [18]). H-NMR:

δ 1.47 (s, 2CH₃), 1.73 (s, CH₃),

1.86 (s, CH₃) ppm. ¹³C-NMR:

131.0 (=C), 243.5 (C=S) ppm.

δ 20.1 (CH₃), 21.9 (CH₃), 25.2 (2CH₃), 74.2 (C-3), 122.6 (=C),

2⁰,2⁰,4⁰,4⁰-Tetramethyl-3⁰-oxocyclobutyl 2,2,4-trimethyl-3-oxopentanedithioate (15). Yield:

Procedure I—59% (method A), 38 mg (48%) (method B); Procedure II—44% (method A).

◦

1

Yellow solid, m.p. 57–58 C (ref. [18], m.p. 62–63 C). H-NMR:

δ 1.13 (d, J = 6.6 Hz,

2CH₃(CH)), 1.21 (s, 2CH₃), 1.47 (s, 2CH₃), 1.68 (s, 2CH₃), 2.91 (sept., J = 6.6 Hz, 2CH₃(CH)),

0

4.25 (s,

H

C-1 ) ppm. ¹³C-NMR: δ 2₀0.4 (2CH₃), 21.8 (2CH₃), 25.0 (2CH₃), 26.8 (2CH₃), 37.0 (C-

0

4), 57.7 (C-2 , C-4 ), 61.1, 69.4 (C-1 , C-2), 212.0 (C=O, C-3), 218.9 (C=O, C-3 , cyclobutanone),

241.2 (C=S) ppm. C₁₆H₂₆O₂S₂(314.51): calculated, C 61.10, H 8.33, S 20.39; found, C 61.12,

H 8.44, S 20.50.

3,3,5,5-Tetramethyl-2-thioxothiolan-4-one (16b). Yield: Procedure I—13% (method_◦A);

9 mg (10%) (method B); Procedure II: 11% (method A). Yellow thick oil (ref. [4 ], mp 39–41 C).

¹H-NMR:

δ δ 27.8, 28.1 (2CH₃each), 61.3

1.44 (s, 2CH₃), 1.70 (s, 2CH₃) ppm. ¹³C-NMR:

(C-3), 63.4 (C-5), 216.7 (C=O), 234.1 (C=S) ppm.

2,2,4,4-Tetramethylcyclobutane-1,3-dione (13). Yield: Procedure I—12% (method A);

Procedure II—8% (method A). ¹H-NMR: δ 1.34 ppm. (ref. [30]).

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3.4. General Procedures of the Fluoride Anion Catalyzed Sulfurization of Thioketones

Elemental Sulfur (S₈)

1 and 2 with

3.4.1. Procedure I: TBAF/THF

To the suspension of elemental sulfur (calculated on atomic [S]) (0.25 mmol, Entry

A; 0.50 mmol, Entry B; 1.00 mmol, Entry C, 2.00 mmol, Entry D, or 4.00 mmol, Entry E)

in 1.5 mL of dried THF, under argon atmosphere, 0.1 mL (0.1 mmol, 20% mol. calculated

on the amounts of thioketone used) of the tetrabutylammonium ﬂuoride solution (TBAF,

1.0 M in THF), pre-dried over molecular sieves, was added dropwise. The mixture became

red (Entries B–D)) or olive green in color (Entry A) and the sulfur has dissolved forming

a homogenous solution. After ca. 10–15 min of magnetic stirring at rt, 0.5 mmol of the

corresponding thioketone 1a or 2a,2c was added in small portions to the solution and

stirring was continued for an appropriate time at rt (see Tables 1 and 2 ). Next, the solvent

was evaporated in vacuum and the residue was pre-puriﬁed by ﬁltration via a short chro-

matographic column ﬁlled with SiO₂(ca. 2 cm layer). The crude mixtures were analyzed in

the ¹H-NMR spectra with weighted standard (Cl₂CH–CHCl₂) and subsequently separated

on preparative chromatographic plates coated with silica gel. A mixture of petroleum ether

and dichloromethane (in most cases the ratio of both solvents was 9:1 or 8:2) was used as

an eluent. Yields refer either to analysis with weighted standard (method A) or to isolated

amounts (method B).

3.4.2. Procedure II: CsF/DMF

In an alternative procedure reactions of thioketones 1a and 2a–c with 2.0 mmol of

sulfur (Entry C⁰) were carried out in dry DMF (2–3 mL) using catalytic amounts of freshly

calcined cesium ﬂuoride (CsF). After completion of the reactions, the mixture was diluted

with dichloromethane and extracted several times with small portions of water to remove

DMF. Following an alternative method for the removal of DMF, toluene (2–3 mL) was added

in small portions and the solutions obtained thereby were warmed in a water bath (55 ^◦C)

to evaporate the solvents. Crude products were puriﬁed by column chromatography on

silica gel using petroleum ether/dichloromethane mixtures as eluent.

3.4.3. Product Characterization

Dispiro[adamantane-2,3⁰-(1,2,4)-trithiolane-5⁰,2”-adamantane] (5c). Yields: Procedure I—(a)

Entry A: 27 mg (59% based on S/30% based on 1_◦c); (b) Procedure II—Entry C⁰: 54 mg

(59%) (method B). Colorless solid, m.p. 200–201 C (methanol/CH₂Cl₂) (ref. [31], m.p.

◦

191–192 C). ¹H-NMR: 1.75–1.95 (m, 16H), 2.15–2.40 (m, 12H) ppm. ¹³C-NMR:

δ δ 26.6, 26.9

(4CH), 36.7, 37.2, 37.9 (10CH₂, ratio ca. 2:2:1), 39.4 (4CH), 90.3 (C-3⁰, C-5⁰) ppm.

3,3,6,6-Tetraphenyl-1,2,4,5-tetrathiane (6a). Yields: Procedure I—(a) Entry B: 32 mg (28%)

(method B); (b) Entry C: 60 mg (52%) (method B); (c) Procedure II—Entry C⁰: 65 mg (56%)

◦

(method B). Colorless crystals, m.p. 210–212 C (decomposition, blue) (methanol/CH₂Cl₂)

(ref. [

3

], mp. 209–209.5 ^◦C). ¹H-NMR:

δ

7.30–7.36 (m, 12CH_arom.), 7.55–7.59 (m, 8CH_arom.)

ppm. ¹³C-NMR: δ 71.4 (C-3, C-6), 127.9, 128.5, 128.6 (20CH_arom.), 141.7 (4C_arom.) ppm.

1,1,3,3,8,8,10,10-Octamethyl-5,6,11,12-tetrathiadispiro-[3.2.3.3]dodecane-2,9-dione (6b). Yields:

Procedure I—(a) Entry A: 12% (method_◦A); (b) Entry B: 40% (method A), 30 mg (32%)

◦

(method B). Colorless solid, m.p. 170–172 C (methanol/CH₂Cl₂) (ref. [

4

], m.p. 169–170 C).

¹H-NMR:

δ

1.39 (s, br, 4CH₃), 1.54 (s, br, 4CH₃) ppm. ¹³C-NMR:

δ

20.9, 24.9 (4CH₃each),

67.1 (C-1, C-3, C-8, C-10), 71.5 (C-4, C-7), 217.9 (2C=O) ppm.

1,1,3,3,8,8,10,10-Octamethyl-5,6,11,12-tetrathiadispiro-[3.2.3.3]-9-oxododecane-2-thione (6e).

1

Yield: Procedure I—(a) Entry B: 15 mg (15%) (method B). Orange oil. H-NMR:

δ 1.42 (s, br,

4CH₃), 1.69 (s, br, 4CH₃) ppm. ¹³C-NMR:

δ 27.8, 28.1 (4CH₃each), 61.3 (C-1, C-3), 63.4 (C-8,

C-10), 77.86, 77.91 (C-4, C-7), 216.6 (C=O), 243.0 (C=S) ppm.C₁₆H₂₄OS₅(392.69): calculated,

C 48.94, H 6.16, S 40.83; found, C 48.96, H 6.33, S 40.58.

1,1,3,3,8,8,10,10-Octamethyl-5,6,11,12,13-pentathiadispiro-[3.2.3.3]tridecane-2,9-dione (7a).

Yields: Procedure I—(a) Entry C: 35 mg (34%) (method B); (c) Entry D: 53 mg (52%) (method

B); (d) Entry E: 61 mg (60%) (method B); Procedure II—(e) Entry C⁰: 44 mg (43%) (method

Molecules 2021, 26, 822

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B). Colorless crystals, m.p. 146–148 ^◦C (methanol/CH₂Cl₂) (ref. [

4

,

22], m.p. 147–148 ^◦C).

¹H-NMR: 1.20–1.90 (m, 8CH₃) ppm. ¹³C-NMR:

δ

δ 21.0–26.0 (m, 8CH₃), 67.3 (C-1, C-3, C-8,

C-10), 71.5 (C-4, C-7), 216.2 (2C=O) ppm. C₁₆H₂₄O₂S₅(408.69): calculated, C 47.02, H 5.92,

S 39.23; found, C 47.13, H 6.07, S 39.34.

Dispiro[adamantane-2,4⁰-(1,2,3,5,6)-pentathiepane-7⁰,2”-adamantane] (7b). Yields: Proce-

dure I—(a) Entry A: 20 mg (37% based on S/19% based on 2c) (method B); (b) Entry B:

50 mg (47%) (method B); (c) Entry C: 55 mg (51%) (method B). Colorless solid, m.p. > 236 ^◦C

◦

1

(decomposition) (methanol/CH₂Cl₂) (ref. [3]; m.p. > 236 C, decomp.). H-NMR: δ 1.55–3.0

(m, 28H) ppm. ¹³C-NMR:

δ 27.1, 33.7, 34.1, 35.4, 37.6, 38.6 (18C), referred weak signal at

84 ppm (C-4⁰, C-7⁰) is missing (see: ref. [3]).

1,1,3,3,8,8,10,10-Octamethyl-5,6,11,12,13-pentathiadispiro-[3.2.3.3]tridecane-2,9-dithione (7c).

Yields: Procedure I—(a) Entry C: 25 mg (23%) (method B); (b) Entry D: 51 mg (46%) (method

0

1

B); Procedure II—(c) Entry C : 59 mg (54%) (method B); red-orange viscous oil. H-NMR:

1.30–2.00 (m, 8CH₃) ppm; ¹H-NMR (CCl₂=CCl₂, D₂O, 90 ^◦C):

1.92, 1.98, 2.08, 2.20 (4s, br,

2CH₃each) ppm. ¹³C-NMR:

24.0–29.0 (m, 8CH₃), 50.9 (C-1, C-3, C-8, C-10) 53.5 (C-4, C-7),

δ

276.0 (2C=S) ppm. C₁₆H₂₄S₇(440.82): calculated, C 43.59, H 5.49, S 50.92; found, C 43.37, H

5.38, S 50.97.

3,3-Dimethyl-4-(propan-2-ylidene)thietane-2-thione (14). Yields: Procedure I—(a) Entry A:

63% (method A); (b) Entry B: 9% (method A); (c) Entry C: 3% (method A).

2⁰,2⁰,4⁰,4⁰-Tetramethyl-3⁰-oxocyclobutyl 2,2,4-trimethyl-3-oxopentanedithioate (15). Yields:

Procedure I—(a) Entry A: yield: 30% (method A); (b) Entry B: 20% (method A).

3,3,5,5-Tetramethylthiolane-2,4-dithione (16a). Yields: Procedure I—(a) Entry A: 11%

(method A); (b) Entry B: 8 mg (8%) (method B); (c) Entry C: 8% (method A), 8 mg (8%)

(method B); (d) Entry D: 5% (method A); 3 mg (3%) (method B). Red-orange oil (ref. [

b.p. 122 ^◦C). ¹H-NMR: 1.61 (s, 2CH₃), 1.83 (s, 2CH₃) ppm. ¹³C-NMR:

33.5 (2CH₃), 33.7

(2CH₃), 71.0 (C-3), 77.8 (C-5), 245.3 (S=C-2), 267.4 (S=C-4) ppm.

4]:

δ

3,3,5,5-Tetramethyl-2-thioxothiolane-4-one (16b). Yields: (a) Entry A: 10% (method A); (b)

Entry B: 23% (method A), 16 mg (17%) (method B).

1,1,4,4,8,8,11,11-Octamethyl-2,6,9,12-tetrathiadispiro[4.1.4.1]dodecane-3,10-dithione (meso-

17), and 1,1,4,4,8,8,11,11-Octamethyl-2,6,10,12-tetrathiadispiro[4.1.4.1]dodecane-3,9-di-thione (d,l-

17). _◦Yield: Procedure I—(a) Entry B: 44 mg (43%) (method B). Yellow crystals, m.p. 130–

1

138 C (methanol/CH₂Cl₂). H-NMR:

δ

1.32 (s, 2CH₃), 1.35 (s, 2CH₃), 1.51 (s, 2CH₃), 1.51 (s,

2CH₃), 1.69 (s, 2CH₃), 1.71 (s, 2CH₃), 1.74 (s, 2CH₃), 1.75 (s, 2CH₃) ppm. ¹³C-NMR:

δ 26.32

(2CH₃), 26.36 (2CH₃), 26.57 (2CH₃), 26.61 (2CH₃), 29.72 (2CH₃), 29.80 (2CH₃), 30.66 (4CH₃),

58.20 (2C), 58.57 (2C), 64.22 (2C), 64.51 (2C), 78.54 (2C-5), 78.71 (2C-7), 248.18 (2C=S), 248.39

(2C=S) ppm. C₁₆H₂₄S₆(408.75): calculated, C 47.01, H 5.92, S 47.07; found, C 46.91, H 6.15,

S 46.81.

4,4-Dimethyl-5-(propan-2-ylidene)-1,2-dithiolane-3-thione (18). Yields: Procedure I—(a) En-

try C: yield: 5% (method A); (b) Entry D: yield: 2% (method A). Yellow-orange oil (ref. [21],

1

yellow oil). H-NMR:

δ

1.66 (s, 2CH₃), 1.99 (s, CH₃), 2.02 (s, CH₃) ppm. ¹³C-NMR:

δ

21.4

(CH₃), 26.4 (CH₃), 29.6 (2CH₃), 64.2 (C-4), 128.2 (=C), 137.10 (=C), 247.9 (C=S) ppm.

1,1,3,3-Tetramethyl-5,6,7,8,9,10-hexathiaspiro[3.6]decane-2-thione (19). Yield: Procedure

1

I—(a) Entry D: 7 mg (4%) (method B). Pink solid, m.p. 111-114 ^◦C (MeOH/CH₂Cl₂). H-

NMR:

δ δ 22.5, 28.6 (2CH₃each), 70.6 (C-1, C-3), 95.6

1.54 (s, br, 4CH₃) ppm. ¹³C-NMR:

(C-4), 274.2 (C=S) ppm. C₈H₁₂S₇(332.64): calculated, C 28.89, H 3.64, S 67.48; found, C

29.11, H 3.70, S 67.18.

3.5. General Procedures for Sulfurization of Thiochalcones 3 with Elemental Sulfur (S₈)

3.5.1. Procedure I: Ph₃P/Acetone

In a two-necked round-bottomed ﬂask (10 mL) equipped with a magnetic stirrer

0.5 mmol of the corresponding thiochalcone 3a–d, 0.125 mmol of elemental sulfur (S₈)

(1 mmol calculating on atomic [S]) and 0.125 mmol of triphenylphosphine (Ph₃P) were

placed and 2 mL of dry acetone were added. The resulting mixture was heated to the

reﬂux under condenser and under argon and stirred for the appropriate time (discoloring).

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Then, the solvent was evaporated in vacuo and the residue was puriﬁed, ﬁrstly by short

column chromatography and afterwards by thin-layer chromatography, by using SiO₂as

the absorbent and a mixture of petroleum ether and dichloromethane (9:1) as the eluent,

yielding the corresponding 3H-1,2-dithiole derivative 26a–d. Reported yields refer either

to isolated amounts of products 26 (Method A) or to amounts calculated on the basis of

standard analysis performed with weighted amounts of Cl₂CH–CHCl₂added to the crude

mixture (method B).

3.5.2. Procedure II: PhSK/Acetone

In analogy to Procedure I, thiochalcone 3a was reacted with elemental sulfur in the

presence of cat. amounts (0.06 mol-equiv.) of potassium thiophenolate (PhSK) in boiling

acetone (see ref. [3,4]).

3.5.3. Procedure III: Ph₃P/Butanone

In analogy to Procedure I, thiochalcone 3a was reacted with elemental sulfur in the

presence of cat. amounts of PPh₃using butanone as a solvent.

3.5.4. Procedure IV: CsF/DMF

Thiochalcones 3a or 3c, (1 mmol) and 64 mg (2.0 mmol) of sulfur were stirred mag-

netically in dry DMF (2.5 mL) with cat. amounts of freshly calcined cesium ﬂuoride (CsF).

After 72h the reaction solution was diluted with dichloromethane (25 mL) and extracted

several times with small portions of water for removal of DMF. Combined organic layers

were dried over MgSO₄, ﬁltered and puriﬁed by column chromatography on silica gel

using a 95:5 mixture of petroleum ether and dichloromethane as eluent.

3.5.5. Product Characterization

3,5-Diphenyl-3H-1,2-dithiole (26a). Yields: (a) Procedure I—51 mg (40%) (method A),

63% (method B); (b) Procedure II—53 mg (41%) (method A); (c) Procedure III—19 mg (15%)

(method A); Procedure IV: 38 mg (15%) (method A). Orange-red solid, m.p. 78–81 ^◦C. ¹H-

NMR:

7.39–7.44 (m, 5H, CH_arom.); 7.49–7.53 (m, 2H, CH_arom.); 7.57–7.61 (m, 2H, CH_arom.) ppm.

¹³C-NMR:

63.7 (C-3); 120.7 (C-4); 127.4, 127.5, 128.4, 128.8 129.0, 129.3 (10C_arom.); 132.9

δ 5.87 (d, J = 3.0 Hz, 1H, CH); 6.19 (d, J = 3.0 Hz, 1H, CH); 7.34–7.38 (m, 1H, CH_arom.);

δ

(C-5); 140.8, 145.2 (2C_arom.) ppm. C₁₅H₁₂S₂(256.39): calculated, C 70.27, H 4.72, S 25.01;

found: C 70.20, H 4.68, S 25.01.

3-(4-Chlorophenyl)-5-phenyl-3H-1,2-dithiole (26b). Yield: (a) Procedure I—22 mg (15%)

1

(method A). Red oil. H-NMR:

δ

5.80 (d, J = 3.6 Hz, 1H, CH); 6.15 (d, J = 3.6 Hz, 1H, CH);

7.36 (d, J = 9.0 Hz, 2H, CH_arom.), 7.39–7.45 (m, 5H, CH_arom.), 7.56–7.59 (m, 2H, CH_arom.)

ppm. ¹³C-NMR:

δ

62.7 (C-3); 120.1 (C-4); 127.4, 128.8, 129.1, 129.4 (9C_arom.); 132.7 (C-5);

134.2, 139.4, 145.7 (3C_arom.) ppm. C₁₅H₁₁S₂Cl (290.83): calculated, C 61.95, H 3.81, S 22.05;

found: C 61.68, H 3.85, S 22.01.

3-(4-Methylphenyl)-5-phenyl-3H-1,2-dithiole (26c). Yield: (a) Procedure I—27 mg (20%)

(method A); Procedure IV—46 mg (17%) (method A). Red solid, m.p. 79–82 ^◦C. ¹H-NMR:

δ 2.39 (s, 3H, CH₃); 5.86 (d, J = 3.3 Hz, 1H, CH); 6.18 (d, J = 3.3 Hz, 1H, CH); 7.21, 7.59 (2d,

J = 8.4 Hz, 4H, AB system), 7.38–7.42 (m, 5H, CH_arom.) ppm. ¹³C-NMR:

δ 21.2 (CH₃), 63.5

(C-3), 120.9 (C-4), 127.4, 128.7, 129.2, 129.6, (9C_arom.); 133.0 (C-5), 137.8 138.3, 145.0 (3C_arom.)

ppm. C₁₆H₁₄S₂(270.41): calculated, C 71.07, H 5.22, S 23.72; found: C 70.92, H 5.43, S 23.61.

3-(4-Methoxyphenyl)-5-phenyl-3H-1,2-dithiole (26d). Yield: (a) Procedure I—17 mg (12%)

1

(method A). Red oil. H-NMR:

δ

3.84 (s, 3H, OCH₃); 5.87 (d, J = 3.6 Hz, 1H, CH); 6.17 (d,

J = 3.6 Hz, 1H, CH); 6.93 (d, J = 9.0 Hz, 2H, CH_arom.), 7.38–7.44 (m, 5H, CH_arom.), 7.57–7.60

(m, 2H, CH_arom.) ppm. ¹³C-NMR:

55.4 (OCH₃), 63.3 (C-3), 114.3 (C-4), 121.0, 127.4, 127.7,

127.8, 129.21 (9C_arom.); 132.9 (C-5), 133.0, 144.8, 159.7 (3C_arom.) ppm.

δ

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4. Conclusions

The presented study showed that ﬂuoride anion can be applied as an excellent ac-

tivator of elemental sulfur in sulfurization reactions of easily available cycloaliphatic

thioketones derived from 2,2,4,4-tetramethylcyclobutane-1,3-dione. Depending on the

molar ratio of the starting materials, sulfur-rich heterocycles with variable ring size can

be obtained in satisfactory to good yields. In situ-generated ﬂuoropolysulﬁde anions act

as powerful sulfurizing reagents. As a key intermediate in the studied reactions, three-

membered, reactive dithiiranes, formed via the addition of the latter to the C=S group, are

postulated for both cycloaliphatic and aromatic thioketones.

In contrast to thioketones, their α,β-unsaturated analogues, i.e., thiochalcones, do not

undergo the sulfurization reaction with sulfur in the presence of ﬂuoride anion. On the

other hand, their sulfurization with elemental sulfur, leading to 3H-1,2-dithiole derivatives,

can be performed using triphenylphosphine (PPh₃) as a catalyst. The latter heterocycles

are of interest as unique starting materials for the preparation of sulfur-heterocycles based

persistent radicals [32,33]. However, up to now, methods for the synthesis of 3H-1,2-

dithioles and their conversion into the stable organic radicals are rarely reported and they

are described only in rather remote literature [34].

The developed protocols of sulfurization in the presence of ﬂuoride anion can be of

interest not only for the synthesis of sulfur-rich heterocycles, such as 1,2,4-trithiolanes [28],

1,2,4,5-tetrathianes [35

rich polymers starting with alkyl- [37

,

36] or 1,2,3,5,6-pentathiepanes, but also for the preparation of sulfur-

38] or aryl [39] substituted thiiranes. In the present

,

work, ﬂuoride anion was shown to act as an alternative, nucleophilic catalyst and can

replace smelly and unstable sodium (or potassium) thiophenolate in the activation of

elemental sulfur in reactions with thiiranes. The presented research should be considered

as a new contribution to our continuous studies on exploration of elemental sulfur and

small-ring, congested S-heterocycles (thiaziridiens, thiiranes) in sulfurization reactions of

diverse organic compounds, including stable thioketones [10

,22,24,30] but also transient

nucleophilic heterocyclic carbenes (NHC) [40,41].

Supplementary Materials: The Supplementary Materials are available online and they contain the

scanned ¹H- and ¹³C-NMR spectra for the described and isolated compounds. The re-determined

X-ray crystallography data for compound 7a are deposited as CSD Communication under deposition

number 2056867 (doi:10.5517/ccdc.csd.cc271bk6).

Author Contributions: G.M.—project foundation, laboratory work coordination and consultancy;

founds availability; reference checking and collection; manuscript preparation; J.W.—laboratory

work, collection of spectroscopic data, the manuscript and SI part preparation; K.U.—part of the

laboratory work, manuscript preparation; D.M.B.—consultancy and manuscript control; H.H.—

consultancy, manuscript preparation. All authors have read and agreed to the published version of

the manuscript.

Funding: The work was supported by the National Centre for Research and Development (Warsaw,

Poland) within the Grant InterChemMed (grant # WND-POWR.03.02.00-00-I029/16-01) and in part

by the NSC (GM, Grant Beethoven-2; grant #2016/23/G/ST5/04115/l, National Science Center,

Cracow, Poland).

Institutional Review Board Statement: Not applicable.

Informed Consent Statement: Not applicable.

Data Availability Statement: All data supporting the presented study are included into the Supple-

mentary Material part.

Acknowledgments: Re-determination of the X-ray structure of 1,2,3-5,6-pentathiepane 7a by An-

thony Linden (University of Zurich) is acknowledged. The authors also thank Paulina Stefaniak, MSc.

(University of Lodz) for skillful performance of a part of laboratory work related to sulfurization reac-

tions performed in DMF solution. G.M. acknowledges National Science Center (Grant Beethoven-2,

#2016/23/G/ST5/04115/l, Cracow, Poland) for partial support of the presented study relating to

Molecules 2021, 26, 822

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the problem of sulfurization of reactive intermediates using elemental sulfur. J.W. acknowledges

National Centre for Research and Development (Warsaw, Poland) for a stipend.

Conﬂicts of Interest: Authors do not report any conﬂict of interest.

Sample Availability: Samples of the compounds 5a

and 26a-26d are available from the authors.

, 6a,b,e, 7a-7c, 13-15, 16a-16b, meso-17, d,l-17, 19,

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Article Doi

The fluoride anion-catalyzed sulfurization of thioketones with elemental sulfur leading to sulfur-rich heterocycles: First sulfurization of thiochalcones ?

DOI: 10.3390/molecules26040822

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