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. 2021 Nov 19;6(48):32571-32588.
doi: 10.1021/acsomega.1c04141. eCollection 2021 Dec 7.

2-Amino-4,5-dihydrothiophene-3-carbonitriles: A New Synthesis, Quantum Chemical Studies, and Mannich-Type Reactions Leading to New Hexahydrothieno[2,3-d]pyrimidines

Victor V Dotsenko  1   2   3 , Alexander V Bespalov  1 , Arthur S Vashurin  3 , Nicolai A Aksenov  2 , Inna V Aksenova  2 , Elena A Chigorina  4   5 , Sergey G Krivokolysko  1
Affiliations

2-Amino-4,5-dihydrothiophene-3-carbonitriles: A New Synthesis, Quantum Chemical Studies, and Mannich-Type Reactions Leading to New Hexahydrothieno[2,3-d]pyrimidines

Victor V Dotsenko et al. ACS Omega. .

Abstract

trans-2-Amino-4-aryl-5-benzoyl-4,5-dihydrothiophene-3-carbonitriles were prepared either by the reaction of 3-aryl-2-cyanothioacrylamides with α-thiocyanatoacetophenone or by the Michael-type addition of cyanothioacetamide to α-bromochalcones followed by intramolecular cyclization. The mechanism of the first reaction was studied using high-level quantum chemical calculations. Density functional theory (DFT) studies were carried out to determine the mechanism of the first reaction. A new approach toward the construction of the thieno[2,3-d]pyrimidine core system was demonstrated by the reaction of the prepared dihydrothiophenes with HCHO and RNH2 under noncatalyzed Mannich conditions.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Selected biologically active 2-aminothiophenes.
Figure 2
Figure 2
Biologically active compounds featuring an ADHT scaffold.
Scheme 1
Scheme 1. The Reported Methods for the Preparation of ADHTs
Scheme 2
Scheme 2. Different Approaches toward the Synthesis of ADHTs 6
Scheme 3
Scheme 3. Synthesis of ADHTs 6a–d
Scheme 4
Scheme 4. Preparation of ADHTs 6 from α-Bromochalcones 9
Scheme 5
Scheme 5. Possible Mechanisms of the Formation and Stereochemistry of ADHTs 6
Figure 3
Figure 3
The most stable conformations R1 (for the S,S-isomer) and R2 (for the R,S-isomer). Geometry optimized at the r2SCAN-3c level.
Figure 4
Figure 4
The optimized molecular structures of SN transition states (TS) for S,S-(TS1c, TS1) and R,S-isomers (TS2c, TS2) (geometry optimized at the r2SCAN-3c level).
Figure 5
Figure 5
The optimized molecular structures of transition states formed during the thiophene ring formation through the addition–elimination mechanism starting from S,S- (TS1.1, TS1.2, TS1.3, TS1.4) and R,S-isomers (TS2.1, TS2.2, TS2.3, TS2.4) (geometry optimized at the r2SCAN-3c level).
Figure 6
Figure 6
The optimized molecular structures of intermediates formed during the thiophene ring formation through the addition–elimination mechanism starting from S,S- (I1.1, I1.2, I1.3) and R,S-isomers (I2.1, I2.2, I2.3) (geometry optimized at the r2SCAN-3c level).
Figure 7
Figure 7
Energy diagrams of the proposed cyclization mechanisms: intramolecular nucleophilic substitution of thiocyanate anion (S,S/R,R-diastereomeric channel, pathway A) or nucleophilic addition at the SCN nitrile fragment with subsequent elimination of thiocyanate anion (R,S/S,R-diastereomeric channel, pathway B). The calculated Gibbs energies are given relative to the energy of the most stable conformation of the S,S-isomer (R1).
Scheme 6
Scheme 6. The Aminomethylation of ADHTS 6
Figure 8
Figure 8
The scope and yields of products 11.
Figure 9
Figure 9
The structure of compound 11l according to X-ray data. Thermal ellipsoids of nonhydrogen atoms are shown at the 30% probability level.
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