Synthesis of New Imidazolidine and Tetrahydropyrimidine Derivatives

Beyzaei, Hamid; Aryan, Reza; Keshtegar, Zahra

doi:https://doi.org/10.1155/2014/834641

Advances in Chemistry

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Research Article | Open Access

Volume 2014 | Article ID 834641 | https://doi.org/10.1155/2014/834641

Synthesis of New Imidazolidine and Tetrahydropyrimidine Derivatives

Hamid Beyzaei,¹Reza Aryan,¹and Zahra Keshtegar¹

Academic Editor: Hideaki Shirota

Received04 May 2014

Accepted23 Jun 2014

Published14 Jul 2014

Abstract

Synthesis of new imidazolidine and tetrahydropyrimidine derivatives 3a, b and 4a–c as cyclic 1,3-diamines under two reaction conditions (A and B) is described. Under reaction conditions-A, a suspension of (E)-2-cyano-2-(oxazolidin-2-ylidene)ethanethioamide 1 (1 eq.) and diaminoalkanes 2a–e (2 eq.) in absolute ethanol is heated under reflux for 16–22 h to afford 3a, b and 4a–c. Alternatively, under reaction conditions-B, a solution of thioamide 1 (1 eq.) in diaminoalkanes 2a–e (3 eq.) is stirred under solvent-free conditions at room temperature for 3 days to give desired products. Reaction conditions-A for having higher yields, shorter reaction times, and required less diamines is more effective than reaction conditions-B. Oxazolidine ring opening is observed by reacting compound 1 with all of the diamines 2a–e, but the thioamide group only reacts with nonbulky diamines 2a, b. The chemical structures of novel compounds were confirmed by ¹H NMR, ¹³C NMR, elemental analysis, and FT-IR spectrometry.

1. Introduction

Imidazolidines (tetrahydroimidazoles) are important building blocks in biologically active compounds [1] and carriers of pharmacologically active carbonyl compounds [2]. They have been reported to have important biological activities including, for example, 2-[(arylmethoxy) imino]imidazolidines as potential α-adrenergic receptor agonist [3], bisimidazolidines and 1,3-disubstituted imidazolidines as antimicrobial [4], 5-(4-chloro or fluoro-benzylidene-3-(4-nitrebenzyl)-4-thioxo-imidazolidin-2-one as antiparasitic [5], sulfonyliminoimidazolidines as oral hypoglycaemic [6], imidazolidin-2,4-diones, 2-thioxoimidazolidin-4-ones, 5-cycloalkylidene-hydantoins, and 5-cycloalkylidene-thiohydantoins as antiarrhythmic and anticonvulsant [7, 8], 1,3-dibenzyl-2-arylimidazolidine as anti-inflammatory [9], N,N′-di-aryl-methyl-2-(4-diethylamino phenyl) tetrahydroimidazoles and N,N′-di-4-diethylamino benzyl-2-(aryl) tetrahydroimidazoles as analgesic [10]. They have also been utilized as a versatile template for the synthesis of compounds with potential cyclooxygenase-2 inhibition activity [11] and termed as a promising group of NSAIDs with potential anti-inflammatory activities [9].

The pyrimidine fragment is present in various biologically active compounds, many of which have been found to be used in medical practice [12, 13]. Recently, much attention has been paid to derivatives of pyrimidine, including their hydrogenation products. This class of compounds displays wide ranges of biological and pharmacological properties such as anti-inflammatory [14], analgesic [15], antitumor [16], antidepressant [17], antibacterial, antifungal, and antitubercular effects [18–20].

The application of these compounds in pharmaceutical field prompted us to synthesize some new imidazolidines and tetrahydropyrimidines under two reaction conditions. These synthesized compounds are characterized by NMR, IR spectral data, and elemental analysis.

2. Results and Discussion

Cyclic 1,3-diamines 3a, b and 4a–c were prepared under two reaction conditions. Under reaction conditions-A, a mixture of (E)-2-cyano-2-(oxazolidin-2-ylidene)ethanethioamide 1 (1 eq.) and appropriate diaminoalkanes 2a–e (2 eq.) in absolute ethanol are refluxed for 16–22 h to afford the solid products 3a, b and 4a–c (Scheme 1). Under reaction conditions-B, similar treatment of the thioamide 1 (1 eq.) with appropriate diaminoalkanes 2a–e (3 eq.) under solvent-free conditions at room temperature for 3 days afforded the desired products. The yields of the products obtained are depicted in Table 1.

A comparison between the results obtained from both reaction conditions leads us to the conclusion that reaction conditions-A is from 65% to 77% as efficient as reaction conditions-B, also the former has shorter reaction times and required less diamines but requires a supply of heat. It is worth noting that oxazolidine ring opening is observed by reacting compound 1 with all of the diamines 2a–e, but the thioamide group only reacts with nonbulky diamines 2a, b. This is probably due to the rigid structure of compound 1 that prevents the effective interaction with bulky diamines 2c–e.

A plausible mechanism is depicted for the formation of these compounds (Scheme 2). As depicted in Scheme 2, intermediates 3′a, b and 4a–c probably were produced from two successive Michael substitution reaction thioamide 1 and diaminoalkanes 2a–e. It predicts that during adding amine to oxazolidine ring, the C–O bond breaks faster than the C–N bond because alkoxy is a better leaving group than amine. Note that in this multistep synthesis, the likely key intermediates 3′a, b were not isolated except for intermediates 4a–c which were isolated and their structures identified by spectral analysis. When intermediates 3′a, b were treated with diaminoalkanes 2a, b, amidines 4′a, b that are produced as intermediates followed by a ring closure to 3a, b.

The structural assignments of compounds 3a, b and 4a–c were based on their analytical and spectral data. The ¹H NMR spectra of compounds 3a–e showed broad signals due to –NH– groups within δ = 7.70–9.51 ppm region. The ¹³C NMR spectra of the products exhibited signals within δ = 27–65, 117–119, 157–166 ppm regions attributed to the N≡C–C=C–, –C≡N, N≡C–C=C– carbons, respectively. The FT-IR spectra of 3a, b and 4a–c in KBr disk showed the absorption bands within ν = 3273–3311 cm⁻¹ corresponding to –NH– groups, within ν = 2170–2187 cm⁻¹ belonging to nitrile groups and within ν = 1589–1688 cm⁻¹ attributed to the –C=C– exocyclic bonds. All this evidence plus microanalytical data strongly supports the formation of all products.

3. Materials and Methods

3.1. Materials

Melting points were recorded on a Kruss type KSP1N melting point meter and are uncorrected. The IR spectra of products 3a, b and 4a–c were determined using KBr disks with Bruker Tensor-27 FT-IR spectrometer and only major absorptions are listed. The ¹H and ¹³C NMR spectra of DMSO-d₆ solutions were recorded on a Bruker FT-NMR Ultra Shield-400 spectrometer (400 and 100 MHz, resp.) with residual protons of the solvent as internal standard (2.50 ppm for ¹H and 39.48 ppm for ¹³C). Elemental analyses were performed on a Thermo Finnigan Flash EA microanalyzer. Monitoring of the progress of reactions and the purity of the products were effected by TLC on alufoil plates precoated with silica gel (60, Merck); eluent was CHCl₃-CH₃OH, 9 : 1, visualization with I₂ vapor. Compound 1 was obtained according to the published method [21].

3.2. Methods

3.2.1. General Procedure for the Synthesis of Cyclic 1,3-diamines (3a, b and 4a–c)

Reaction conditions-A. A suspension of (E)-2-cyano-2-(oxazolidin-2-ylidene)ethanethioamide 1 (0.845 g, 5 mmol) and diaminoalkanes 2a–e (10 mmol) in absolute ethanol (10 mL) is heated under reflux for 16–22 h. The reaction mixture is treated with 2-propanol (10 mL), refrigerated overnight, filtered, and washed with 2-propano1; the residual products are recrystallized from methanol to give 3a, b and 4a–c.

Reaction conditions-B. A solution of (E)-2-cyano-2-(oxazolidin-2-ylidene)ethanethioamide 1 (0.845 g, 5 mmol) in diaminoalkanes 2a–e (15 mmol) is stirred at room temperature for 3 days. Excess diamines are then evaporated in vacuo and the residual products are recrystallized from methanol.

4. Data for Compounds

2-(4,5-Dihydro-1H-imidazol-2-yl)-2-(imidazolidin-2-ylidene)acetonitrile 3a . White needles, mp 218-219°C; FT-IR,ν, cm⁻¹: 3280 (broad, medium, –NH–), 2170 (strong, sharp, –C≡N), and 1688 (strong, sharp, –C=C–); ¹H NMR, δ, ppm: 3.55 (s, 8H, –CH₂–); 8.21 (b, 3H, –NH–, D₂O exchangeable); ¹³C NMR, δ, ppm: 27.8 (N≡C–C=C–), 43.7 (–CH₂–), 117.8 (–C≡N), and 166.5 (N≡C–C=C–). Anal. Calcd. for C₈H₁₁N₅ (177) C 54.22; H 6.26; N 39.52%, Found: C 54.11; H 6.34; N 39.55.

2-(Tetrahydropyrimidin-2(1H)-ylidene)-2-(1,4,5,6-tetrahydropyrimidin-2-yl)acetonitrile 3b. White needles, mp 209–210°C; FT-IR, ν, cm⁻¹: 3286 (broad, medium, –NH–), 2171 (strong, sharp, –C≡N), and 1688 (strong, sharp, –C=C–); ¹H NMR, δ, ppm (J, Hz): 1.77 (q, 4H, J = 5.5, –NHCH₂CH₂–), 3.18 (t, 8H, J = 5.5, –NHCH₂–), and 7.70 (b, 3H, –NH–, D₂O exchangeable); ¹³C NMR, δ, ppm: 19.6 (–NHCH₂CH₂–), 29.2 (N≡C–C=C–), 38.6 (–NHCH₂), and 118.7 (–C≡N); 159.3 (N≡C–C=C–). Anal. Calcd. for C₁₀H₁₅N₅ (205) C 58.51; H 7.37; N 34.12%, Found: C 58.53; H 7.27; N 34.20.

2-Cyano-2-(5,5-dimethyltetrahydropyrimidin-2(1H)-ylidene)ethanethioamide 4a. White needles, mp 216–218°C; FT-IR, ν, cm⁻¹: 3416 (broad, medium, –NH₂), 3311 (broad, medium, –NH–), 2175 (strong, sharp, –C≡N), and 1615 (strong, sharp, –C=C–); ¹H NMR, δ, ppm (J, Hz): 0.95 (s, 6H, –CH₃), 3.00 (d, 4H, J = 2.2, –CH₂–), 7.27 (b, 2H, –NH₂, D₂O exchangeable), and 9.51 (b, 2H, –NH–, D₂O exchangeable); ¹³C NMR, δ, ppm: 23.5 (–CH₃), 25.0 (–C(CH₃)₂–), 49.2 (–CH₂–), 65.0 (N≡C–C=C–), 119.4 (–C≡N), 157.1 (N≡C–C=C–), and 186.7 (–C=S). Anal. Calcd. for C₉H₁₄N₄S (210) C 51.40; H 6.71; N 26.64; S 15.24%, Found: C 51.35; H 6.78; N 26.72; S 15.15.

(Z,E)-2-Cyano-2-(4-methylimidazolidin-2-ylidene)ethanethioamide 4b . Yellow needles, mp 189-190°C; FT-IR, ν, cm⁻¹: 3422 (broad, medium, –NH₂), 3282 (broad, medium, –NH–), 2182 (strong, sharp, –C≡N), and 1626 (strong, sharp, –C=C–); ¹H NMR, δ, ppm (J, Hz): 1.21 (d, 3H, J = 6.2, –CH₃), 3.18, 3.74 (dd, 1H, J = 2.3, J = 7.5, t, 1H, J = 9.7, –CH₂–); 4.05 (m, 1H, –CHCH₃), 7.29 (b, 2H, –NH₂, D₂O exchangeable), and 9.13 (b, 2H, –NH–, D₂O exchangeable). ¹³C NMR, δ, ppm: 20.4 (–CH₃), 50.2 (–CH₂–), 51.2 (–CHCH₃), 63.0 (N≡C–C=C–), 118.9 (–C≡N), 164.3 (N≡C–C=C–), and 188.7 (–C=S). Anal. Calcd. for C₇H₁₀N₄S (182) C 46.13; H 5.53; N 30.74; S 17.59%, Found: C 46.08; H 5.61; N 30.81; S 17.50.

2-Cyano-2-(octahydro-2H-benzo[d]imidazol-2-ylidene)ethanethioamide 4c . Brown needles, mp 238–240°C; FT-IR, ν, cm⁻¹: 3418 (broad, medium, –NH₂), 3273 (broad, medium, –NH–), 2187 (strong, sharp, –C≡N), and 1589 (strong, sharp, –C=C); ¹H NMR, δ, ppm (J, Hz): 1.28–1.56 (m, 4H, –CHCH₂CH₂–), 1.64–1.74, 2.12 (m, 2H, d, 2H, J = 11.0, –CHCH₂CH₂–), 3.07, 3.82 (m, 1H, m, 1H, –NHCH–), 7.63 (b, 2H, –NH₂, D₂O exchangeable, 54.0 (NHCH), 62.5 (N≡C–C=C–), 118.5 (–C≡N), 165.2 (N≡C–C=C–), and 189.0 (–C=S). Anal. Calcd. for C₁₀H₁₄N₄S (222) C 54.03; H 6.35; N 25.20; S 14.42%, Found: C 54.10; H 6.44; N 25.12; S 14.34.

5. Conclusion

In summary, several new imidazolidines and tetrahydropyrimidines have been synthesized from the reaction of a single thioamide with several various diaminoalkanes. On the basis of our previously reported work [21], the thioamide itself was synthesized in a regioselective manner from functionalized oxazolidine with phosphorus pentasulfide.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Acknowledgment

The authors would like to thank Mrs. Marzieh Akbari for recording spectral NMR analyses.

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Copyright © 2014 Hamid Beyzaei et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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