Thiourea participation in [3+2] cycloaddition with donor–acceptor cyclopropanes: a domino process to 2-amino-dihydrothiophenes

Abstract

The Yb(OTf)₃-catalyzed [3+2] cycloaddition of donor–acceptor cyclopropanes with thiourea offers an efficient route to diverse 2-amino-4,5-dihydrothiophenes (up to 92% yield), in which optically active 2-amino-dihydrothiophenes can be produced from enantiomerically pure cyclopropanes. Thiourea, which is an odorless and cheap reagent, provides a C=S double bond, serves as an amino source, and functions as a decarbalkoxylation reagent in this reaction. Preliminary mechanistic studies demonstrate that the reaction undergoes a sequential [3+2] cycloaddition/deamination/decarboxylation process.

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2-Aminothiophene is a special structural moiety present in many biologically active molecules.¹ Examples of such molecules are shown in Fig. 1. Olanzapine is an atypical antipsychotic drug used for treating schizophrenia and bipolar disorder.² Tinoridine is an anti-inflammatory drug that has potent antiperoxidative properties.³ T-62 is an allosteric enhancer of the adenosine A1 receptor, and TPCA-1 is a small-molecule IκB kinase β inhibitor.⁴ AX20017 has antituberculosis properties and has been identified as a specific inhibitor of protein kinase G.⁵ 2-Amino-4,5-dihydrothiophene I exhibits antibacterial and antifungal properties.⁶ For most of these 2-aminothiophenes, which exhibit biological activities, it is found that an electron-withdrawing group (e.g., ester, C=O, or CN) is connected to the C3 position of the thiophenes. The most convenient method for preparing 2-aminothiophenes is the Gewald reaction, which involves the condensation of a ketone (or aldehyde) with activated nitrile and elemental sulfur.^1,7 Although great achievements to construct 2-aminothiophenes have been made through the Gewald reaction, developing an alternative method to synthesize 2-aminothiophenes and their derivatives, which have an electron withdrawing group at the C3 position, is still highly desirable.⁸

Fig. 1 Examples of bioactive agents with 2-aminothiophene fragments.

Donor–acceptor (D–A) cyclopropanes are exceptionally useful three-carbon building blocks due to their synthetic utility and ease of preparation.⁹ In the presence of a Lewis acid, the normal [3+n] cycloaddition reactions of D–A cyclopropanes with various dipolarophiles, such as C=C, C=O, C=N, N=O, N=N, C≡C, C≡N, nitrones, heterocumulenes, and other dipolarophiles, have proven to be valuable tools for producing highly functionalized cyclic ring systems.^10–19 However, the C=S double bond has less been employed as a 2π component to react with D–A cyclopropanes.^20,21 Very recently, the normal [3+2] cycloaddition of thioketones and D–A cyclopropanes has been published concurrently with the preparation of the present manuscript (Scheme 1a).^20a Highly substituted tetrahydrothiophenes with two adjacent quaternary carbon atoms were generated in high yields using AlCl₃ as a catalyst. Soon afterwards, a highly efficient Fe(OTf)₃-promoted normal [3+2] cycloaddition of thionoesters with D–A cyclopropanes was developed for the synthesis of trans-configured tetrahydrothiophenes (Scheme 1b).²¹ As an odorless, cheap, and easy-to-handle sulfur source,²² thiourea has never previously been employed to react with D–A cyclopropanes. Herein, we report the Yb(OTf)₃-catalyzed [3+2] cycloaddition of thiourea with D–A cyclopropanes to generate 2-amino-4,5-dihydrothiophene derivatives with only one ester group at the C3 position of thiophene (Scheme 1c).

Scheme 1 Different C=S 2π components react with D–A cyclopropanes.

Initially, D–A cyclopropane 1a and thiourea 2a were selected as the model reactants (Table 1). When Cu(OTf)₂ or Ni(OTf)₂ was employed as a Lewis acid catalyst, the reaction did not occur (entries 1 and 2). When MgI₂ was used, 2-amino-4,5-dihydrothiophene 3aa, which has only one ester group at the C3 position of dihydrothiophene, was obtained in 9% yield (entry 3). When the Lewis acid was changed to Yb(OTf)₃, the yield of 3aa increased to 15% (entry 4). In the presence of Sc(OTf)₃, only the cyclic imine 4aa, which has two ester groups at the C3 position of dihydrothiophene, was generated (entry 5). The solvents were then explored, and DCE is the optimal solvent (entries 4, 6 and 7). Increasing the temperature from rt to 90 °C resulted in an enhanced yield (entries 7 and 8). Several bases were then added, and the inorganic base Rb₂CO₃ delivered monoester 3aa in a better yield (entries 9–12). The cycloadduct 3aa can be afforded in 84% yield when 20 mol% of Yb(OTf)₃ was employed (entry 13). When 1 equiv. of thiourea 2a was employed, the yield decreased (entry 14).

Table 1 Optimization of the reaction conditions^a

Entry	LA	Solvent	T (°C)	Base	Yield^b (%)
					3aa	4aa
a Unless otherwise noted, the reaction conditions were: 1a (0.2 mmol), 2a (0.4 mmol), LA (10 mol%), solvent (3.0 mL), and base (20 mol%) at rt for 8 h. b Isolated yield. c Yb(OTf)3 (20 mol%). d 2a (0.2 mmol) was used. NR = no reaction.
1	Cu(OTf)2	CH2Cl2	rt	—	NR
2	Ni(OTf)2	CH2Cl2	rt	—	NR
3	MgI2	CH2Cl2	rt	—	9	—
4	Yb(OTf)3	CH2Cl2	rt	—	15	—
5	Sc(OTf)3	CH2Cl2	rt	—	—	7
6	Yb(OTf)3	CHCl3	rt	—	Trace	—
7	Yb(OTf)3	DCE	rt	—	29	—
8	Yb(OTf)3	DCE	90	—	41	—
9	Yb(OTf)3	DCE	90	Cs2CO3	53	—
10	Yb(OTf)3	DCE	90	Na2CO3	61	—
11	Yb(OTf)3	DCE	90	Rb2CO3	65	—
12	Yb(OTf)3	DCE	90	Et3N	NR
13^c	Yb(OTf)3	DCE	90	Rb2CO3	84
14^d	Yb(OTf)3	DCE	90	Rb2CO3	43

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Under the optimized reaction conditions (Table 1, entry 13), the scope of D–A cyclopropanes was explored (Scheme 2). For cyclopropanes bearing electron-rich substituents at the aryl moieties, the adducts 3ba–3fa were produced in 65–83% yields. In the case of naphthalene-2-yl cyclopropane 1g and tetrahydronaphthalene-derived cyclopropane 1h, the adducts 3ga and 3ha could also be obtained. For the cyclopropanes with electron-withdrawing groups at the aryl moieties, the adducts 3ia–3oa were given in 62–86% yields. The structure of adduct 3na was determined by X-ray diffraction analysis. With respect to cyclopropanes with an alkyl group as the donor-substituent, the adducts 3pa and 3qa were afforded in 80–82% yields. In addition, D–A cyclopropanes with different ester groups were good reactants. It should be noted that the geminal diesters 4 were not observed in all of the cases.

Scheme 2 Substrate scope of D–A cyclopropanes. ^a Unless otherwise noted, the reaction conditions are: 1a–1s (0.2 mmol), 2a (0.4 mmol), Yb(OTf)₃ (20 mol%), Rb₂CO₃ (20 mol%), and DCE (3.0 mL) at 90 °C for 8 h. Isolated yields were reported. ^bReaction time: 24 h.

When ethyl 1-cyano-2-phenylcyclopropane-1-carboxylate 1t was reacted with thiourea 2a, the ester group was removed and the cyano group remained, giving the 2-amino-3-cyano-4,5-dihydrothiophene 3ta in 56% yield (Scheme 3a). Then, several 2-amino-4,5-dihydrothiophenes (3aa, 3la, 3ra, and 3sa) were selected as the representative substrates to react with DDQ, and the oxidation products, 2-aminothiophene derivatives (5aa, 5la, 5ra, and 5sa), were obtained in 43–78% yields (Scheme 3b). As for 2-aminothiophene 5aa, the corresponding ring-fused thienopyrimidinedione could be afforded in 2 steps.²⁴ With 2-aminothiophene 5la as the reactant, the desired small-molecule IκB kinase β inhibitor TPCA-1 could be generated in 3 steps (Scheme 3b).²³

Scheme 3 (a) Synthesis of 2-amino-3-cyano-4,5-dihydrothiophene; (b) transformation of 2-amino-4,5-dihydrothiophenes.

Stereospecificity of the cycloaddition was explored using the enantiopure cyclopropane (R)-1a (>99% ee), and (S)-3aa was obtained in 92% yield and >99% ee (Scheme 4). The absolute configurations of (R)-1a and (S)-3aa were determined by X-ray analysis, and these configurations confirmed that an inversion at the stereogenic center was observed.

Scheme 4 Stereospecificity experiments.

To understand the cycloaddition process, several control experiments were performed (Fig. 2). When Sc(OTf)₃ was used as the catalyst, the reaction between cyclopropane 1a and thiourea 2a generated cycloadduct 4aa and released NH₃ gas (Fig. 2a(i)). The released NH₃ gas was detected by wet red litmus paper with blue color. When 1-methylthiourea 2b was used to react with cyclopropane 1a, NH₃ or CH₃NH₂ could also be released (see ESI† for details). After that, geminal diester 4aa was then reacted with thiourea 2a in the presence of Yb(OTf)₃, and the final product 3aa was formed in 87% yield within 0.5 h, indicating that the geminal diester 4aa might be an intermediate in the model reaction (Fig. 2b(ii)). Meanwhile, in the formation of monoester 3aa from geminal diester 4aa, an esterified thiourea 7aa was obtained (52% yield) and confirmed by X-ray diffraction analysis, which showed that thiourea 2a might function as a decarboxylation reagent (Fig. 2b(ii)). In the absence of thiourea 2a, geminal diester 4aa could also be converted into monoester 3aa with the release of CO₂ gas, which was captured by 2-phenyloxirane (Fig. 2b(iii)). By comparing different reaction times (0.5 h vs. 1 h), the decarboxylation step proceeded faster in the presence of thiourea 2a (Fig. 2b(ii) and (iii)). Finally, the cycloaddition of D–A cyclopropane 1a with thiourea 2a produced the monoester 3aa (78% yield), esterified thiourea 7aa (45% yield), NH₃ gas, CO₂ gas, and a ring-opened triester 8aa (see ESI† for details) under the standard conditions (Fig. 2c(iv)). Formation of the esterified thiourea 7aa in a large proportion indicates that thiourea 2a participated in the decarboxylation reaction and was the main pathway during the decarboxylation step.

Fig. 2 Preliminary mechanistic studies.

A plausible sequential mechanism of [3+2] cycloaddition/deamination/decarboxylation was proposed for this reaction on the basis of the stereospecificity experiments (Scheme 4) and preliminary mechanistic studies (Fig. 2), and this mechanism is depicted in Scheme 5. First, D–A cyclopropane (R)-1a is activated by Yb(OTf)₃via coordination with the geminal diester moiety (A). The sulfur atom in thiourea 2a attacks the activated cyclopropane (R)-1a in an S_N2 manner to produce the zwitterionic intermediate (B),^11a–c which generates the cycloadduct 4,5-dihydrothiophene (C) through a ring-closure step. Because two amino groups are both connected at the C2 position in the dihydrothiophene (C), the dihydrothiophene (C) is unstable and produces the cyclic imine (S)-4aa along with a release of NH₃ gas. The cyclic imine (S)-4aa is activated by Yb(OTf)₃via coordination with the geminal diester moiety to enhance the positive charge at the carbonyl group (D). The nitrogen atom in another thiourea 2a attacks the carbonyl group and generates the tetrahedral intermediate (E).²⁵ The crowded tetrahedral intermediate eliminates the protonated methyl carbamothioylcarbamate and generates the dihydrothiophene anion with a single ester group (F). Finally, the dihydrothiophene anion deprotonates the protonated methyl carbamothioylcarbamate, generating 2-amino-4,5-dihydrothiophene (S)-3aa and the esterified thiourea 7aa and releasing Yb(OTf)₃.

Scheme 5 Proposed reaction pathways for the domino process.

In summary, thiourea, which is an odorless, cheap, and easy-to-handle sulfur source, was developed to react with D–A cyclopropanes to construct 2-amino-dihydrothiophenes. In this reaction, thiourea exhibited three functions: (1) providing a C=S double bond, (2) serving as an amino source for the 2-amino thiophenes, and (3) acting as a decarboxylation reagent. Through a Yb(OTf)₃-catalyzed [3+2] cycloaddition/deamination/decarboxylation domino process, a range of D–A cyclopropanes could produce 2-amino-4,5-dihydrothiophenes in moderate to good yields (up to 92% yield).

We are grateful for the financial support from the NSFC (No. 21472037 and 21672055), China Postdoctoral Science Foundation funded project (2016M592293 and 2018T110726), and the 111 Project (No. D17007).

Conflicts of interest

There are no conflicts to declare.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1849437 (3na), 1852130 ((R)-1a), 1852128 ((S)-3aa), 1852129 (7aa) and 1852131 (8aa). For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c8cc09595g

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