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Synlett 2025; 36(11): 1548-1552
DOI: 10.1055/s-0043-1773524
letter

Ring-Opening Reactions of Donor–Acceptor Cyclopropanes with Some Enolizable Azaheterocyclic Thiones: S- versus N-Attack

Grzegorz Mlostoń∗
a   Department of Organic & Applied Chemistry, University of Łodź, Tamka 12, 91-403 Łodź, Poland
,
Mateusz Kowalczyk
a   Department of Organic & Applied Chemistry, University of Łodź, Tamka 12, 91-403 Łodź, Poland
b   The Bio-Med-Chem Doctoral School of the University of Łodź and Łodź Institutes of the Polish Academy of Sciences, Faculty of Biology and Environmental Protection, University of Łodź, 90237 Łodź, Poland
,
Małgorzata Celeda
a   Department of Organic & Applied Chemistry, University of Łodź, Tamka 12, 91-403 Łodź, Poland
,
Gwyndaf A. Oliver
c   Institute of Organic Chemistry, Albert-Ludwigs-Universität Freiburg, Albertstraße 21, 79104 Freiburg im Breisgau, Germany
,
Daniel B. Werz
c   Institute of Organic Chemistry, Albert-Ludwigs-Universität Freiburg, Albertstraße 21, 79104 Freiburg im Breisgau, Germany
› Author Affiliations

This work was in part supported by the University of Lodz within the IDUB-Grant (to G.M.). M.K. thanks the Bio-Med-Chem Doctoral School of the Uniwersytet Łódzki and Łodź Institutes of the Polish Academy of Sciences for a stipend.
› Further Information
 
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This work is dedicated to Professor Mieczysław Mąkosza (Warsaw) on the occasion of his 90th birthday

Abstract

We report ring-opening reactions of donor–acceptor (D–A) cyclopropanes with a variety of five- and six-membered enolizable azaheterocyclic thiones, using Sc(OTf)3 as catalyst in dichloromethane. The majority of these systems reacted through nucleophilic S-attack at the donor position of the cyclopropane. 5-Mercapto-1,3,4-triazoles were shown to give the products of formal N-attack, and systems bearing two external C-S bonds could react with two equivalents of D–A cyclopropane to generate difunctionalized azaheterocycles.


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Key words

azaheterocycles - thiones - donor–acceptor systems - cyclopropanes - ring opening

Donor–acceptor (D–A) cyclopropanes have been a system of significant interest in the past decade.[1] Their inherent zwitterionic nature, coupled with their stability despite their relatively high ring-strain (115.4 kJmol–1)[2] makes them desirable C3 synthons. Activation of these systems is most commonly achieved through chelation with Lewis acids, although organocatalysis,[3] Brønsted base catalysis,[4] electrochemistry,[5] and radical reactions[6] have all been explored. Reactivity of D–A cyclopropanes in a variety of cycloadditions,[7] rearrangements,[8] and ring-opening reactions[9] has been explored with many carbon- and heterocycle-based systems. In particular, sulfur[10] and nitrogen[11] nucleophiles have been of interest, and our groups have developed methods in recent years for [3+2], [3+4], and [3+8] cycloadditions of nonenolizable thioketones with D–A cyclopropanes.[12] Most recently, we reported ring-opening nucleophilic addition of enolizable 5-mercapto-1H-tetrazoles 1 with D–A cyclopropanes 2 (Scheme [1], A).[13] In that work, we also observed an interesting, previously unreported, thermal rearrangement, allowing for the S-attack products to rearrange to the formal N-attack products. Based on this observation, we looked to further exploit this reactivity with a broader palette of enolizable azaheterocyclic thiones, including both five-membered (compounds of type 4–7) and six-membered (compounds of type 14) species (Scheme [1], B).

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Scheme 1 A) Previous work: reactions of D–A cyclopropanes with enolizable 5-mercapto-1H-tetrazoles; B) this work: reactions of D–A cyclopropanes with some enolizable azaheterocyclic thiones

Various azaheterocyclic thiones have been extensively studied,[14] and they are known to find uses in coordination chemistry,[15] agrochemistry,[16] and medicinal chemistry.[17] In solution, the enolizability of these structures means that a mixture of the mercapto 1 and thione 1′ forms is present (Scheme [2], A).[14] The ability of these azaheterocyclic thiones 1′ to tautomerize to the mercapto forms 1 is considered key to their reactivity with D–A cyclopropanes 2; this was shown when we combined dihydro-2H-imidazole-2-thione 3, D–A cyclopropane 2a, and a Lewis acid (ScOTf3) and observed no reaction (Scheme [2], B). This is in stark contrast to our earlier studies of thioketone systems, where the C=S bond reacted across the cyclopropane yielding thiolanes.[12]

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Scheme 2 (A) Tautomerism in enolizable azaheterocyclic thiones; (B) lack of reactivity in nonenolizable systems

We initiated our studies by interrogating the reactivity of enolizable imidazole-2-thiones 4 with D–A cyclopropanes 2a–c, using Sc(OTf)3 as the Lewis acid catalyst (Scheme [3]).[18]

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Scheme 3 Substrate scope for S-attack of five-membered azaheterocyclic thiones 4–6.[18] For conditions see the Supporting Information.

To our delight, products of S-attack were observed, albeit in mediocre yield, when using a cyclopropane 2a bearing a phenyl donor and N-methyl (4a), N-phenyl (4b), and N-benzyl (4c) substituted dimethyl imidazole-2-thiones. Changing the dimethyl imidazole backbone to diphenyl substitution allowed us to obtain the target N-benzyl variant 7d also in a good yield (79%), whereas an N-cyclohexyl group (in 4f) allowed only 32% yield. Installation of an electron-donating methoxy group in the para-position of the N-phenyl group, coupled with only a single phenyl-substituted imidazole backbone (in 4g), afforded an excellent yield (85%) of product 7g. An electron-poorer p-(trifluoromethyl)phenyl donor substituent on the cyclopropane 2b was also well tolerated, furnishing the ring-opened compound 7h in 60% yield. Moving to other five-membered azaheterocycles, we found that excellent yields could be obtained for the reactions of 1,3,4-triazole and benzo[d]oxazole-derived thiones 5 and 6, respectively, with D–A cyclopropane 2a, and an almost quantitative yield (98%) was obtained for the reaction of benzo[d]oxazole-2(3H)-thione (6) with the β-naphthyl-bearing D–A cyclopropane 2c. In all these cases, we exclusively observed the products of S-attack at the donor position, and the thermal rearrangement previously observed with mercapto-1H-tetrazoles was not seen to occur for these substrates. This was further confirmed by heating a sample of pure 7a in CH2Cl2 for 24 h.

Turning our attention to 5-methyl-2-mercapto-1,3,4-thiadiazole (10a), we observed differing behavior depending on the donor group present. NMR studies run in deuterated solvents showed that all three cyclopropanes 2a,d,e initially reacted to form the S-insertion products 11. Phenyl-substituted derivative 11a was isolated chromatographically with no isomerization in 91% yield; however, the S-attack products 11b and 11c, bearing the more electron-donating 4-MeC6H4 and thien-2-yl donors, respectively, could not be isolated but underwent isomerization upon heating or chromatography using silica gel. The respective N-insertion products 12b and 12c could be isolated chromatographically in mediocre yields (Scheme [4]).

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Scheme 4Substrate scope with 5-methyl-2-mercapto-1,3,4-thiadiazole (10a). For conditions see the Supporting Information.

Interestingly, 2,5-bismercapto-1,3,4-thiadiazole (10b) was able to react with two equivalents of D–A cyclopropane 2a, one being opened by nucleophilic S-attack and the second by nucleophilic N-attack (see the Supporting Information, Figure S15, multiplets A and C). In this case the yield of isolated products was also significantly higher, with 69% of the disubstituted azaheterocycle 14 found in the isolated material as a ca. 1:1 mixture of diastereoisomers which were identified as the ‘mixed’ N,S-insertion products. Notably, in a control experiment complete conversion of the starting cyclopropane 2a was observed after only 15 min. At this early stage in the reaction, a third compound was observed in the crude NMR, which is tentatively believed to be the double S,S-insertion product 13 (see the Supporting Information, Figure S15). Apparently, the initially formed S,S-insertion product 13 underwent complete isomerization during the chromatographic workup. In addition, thermal isomerization of the latter was confirmed by heating the solution at 70 °C (Scheme [5]).

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Scheme 5 Reaction of 2,5-bismercapto-1,3,4-thiadiazole (10b) with cyclopropane 2a. For conditions, see the Supporting Information.

Notably, a second isomerization process leading to the dithione isomer did not take place. The observed results suggest that in the case of 2a the ring opening initially occurs via competitive S- and N-insertion, thereby demonstrating the ambident reactivity of the bis(mercapto)-substituted 1,3,4-thiadiazole ring 10b (Scheme [5]).

Extension of our method to six-membered enolizable heterocyclic thiones 15 was also possible (Scheme [6]). 2-Mercaptopyridine (15a) was transformed to the respective sulfane 16a in good yield. Pyrimidine-2-thiol (15b) afforded the ring-opened product 16b in an excellent 92% yield; however, entry 16c shows that the 4-hydroxy derivative (thiouracyl) 15c produced in a slow reaction satisfactory yield (55%) after heating of the reaction mixture (8 days, CHCl3 as a solvent) to 80 °C. Interestingly, changing the hydroxy group for a thiol (pyrimidine-2,4-dithiol, dithiouracyl) 15d allowed for significantly improved reactivity; two equivalents of D–A cyclopropane 2a reacted with this substrate, both undergoing ring opening through S-attack exclusively, giving disulfane-substituted pyrimidine 17 in good yield (67%) and a dr of ca 1:1. This result differs from 2,5-bismercapto-1,3,4-thiadiazole 10b, where the initial products found in the control experiment suggested the first step of the ring opening occurring through competitive S- and N-attack (see Scheme [6]).

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Scheme 6Substrate scope with six-membered enolizable azaheterocyclic thiones. For conditions, see the Supporting Information.

In summary, we have presented reactions of several enolizable azaheterocyclic thiones with D–A cyclopropanes, leading to ring-opened products. The use of five- and six-membered heterocycles was well tolerated, and systems with two external C–S (or C=S) bonds were shown to react with two equivalents of D–A cyclopropane, generating the N,S-product as a ca. 1:1 mixture of diastereomers. Initial formation of the exclusive S-products was also observed in the case of 2-mercapto-5-methyl-1,3,4-thiadiazole and their tendency to isomerize to the N-product was dependent on the cyclopropane’s donor substituent. Notably, variation of the substituents on the heterocycle and the donor group of the cyclopropanes was tolerated, albeit with some variation in yields. The nature of the azaheterocycle was shown to influence whether S-attack or N-attack is preferred.


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

G.A.O. thanks Heinrich F. von Köller and Silas E. Wittmer (both University of Freiburg) for assisting in the synthesis of starting materials.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055s-0043-1773524.
  • Supporting Information

Corresponding Author

Grzegorz Mlostoń
Department of Organic & Applied Chemistry
University of Łodź, Tamka 12, 91-403 Łodź
Poland   

Publication History

Received: 24 November 2024

Accepted after revision: 04 February 2025

Article published online:
20 March 2025

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   Permissions and Reprints All articles of this category
Zoom Image
Scheme 1 A) Previous work: reactions of D–A cyclopropanes with enolizable 5-mercapto-1H-tetrazoles; B) this work: reactions of D–A cyclopropanes with some enolizable azaheterocyclic thiones
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Scheme 2 (A) Tautomerism in enolizable azaheterocyclic thiones; (B) lack of reactivity in nonenolizable systems
Zoom Image
Scheme 3 Substrate scope for S-attack of five-membered azaheterocyclic thiones 4–6.[18] For conditions see the Supporting Information.
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Scheme 4Substrate scope with 5-methyl-2-mercapto-1,3,4-thiadiazole (10a). For conditions see the Supporting Information.
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Scheme 5 Reaction of 2,5-bismercapto-1,3,4-thiadiazole (10b) with cyclopropane 2a. For conditions, see the Supporting Information.
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Scheme 6Substrate scope with six-membered enolizable azaheterocyclic thiones. For conditions, see the Supporting Information.