ISRN Organic ChemistryVolume 2012 (2012), Article ID 945893, 6 pagesdoi:10.5402/2012/945893

Research Article

Interaction of the O-Benzoyl--aminopropioamidoximes with Lawesson's Reagent and Spectral Characterization of the Products

Lyudmila Kayukova,¹ Kaldubai Praliyev,¹ Ulan Kemelbekov,² Asel Abdildanova,² and Vanda Gutyar¹

¹Laboratory of Synthetic and Natural Drug Chemistry, JSC “A. B. Bekturov Institute of Chemical Sciences”, 106 Shokan Ualickhanov Street, Almaty 050010, Kazakhstan²Laboratory of Physical Methods, Sh. Ualikhanov Kokshetau State University, 76 Abay Street, Kokshetau 020000, Kazakhstan

Received 11 October 2011; Accepted 30 October 2011

Academic Editors: P. M. T. Ferreira and I. Tellitu

Copyright © 2012 Lyudmila Kayukova 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.

Abstract.

Interaction of O-benzoyl--aminopropioamidoximes [-amino group: pyperidin-1-yl; morpholin-1-yl; thiomorpholin-1-yl; 4-phenylpiperazin-1-yl; benzimidazol-1-yl] with Lawesson's reagent was done in tetrahydrofuran at heating to during 10 h. New O-thiobenzoyl--aminopropioamidoximes were obtained with the outputs 57–96%; they were characterized with the help of physicochemical, IR, and NMR spectra.

1. Introduction

Representatives of thion-containing compounds, in particular, ethionamide and prothionamide are used in medicine as anti-TB drugs [1]. A high anti-HIV activity of thion derivative of dibenzoyl substituted piperazine was revealed; thion derivative gives 100% inhibition of the HIV virus in comparison with 11% inhibition of the original carbonyl compounds [2]. In our group samples with high antitubercular activity were revealed within the row of β-aminopropioamides [3–5]. For us it was interesting to investigate the effect of replacing the oxygen atom in carbonyl group on a sulfur atom on the biological properties of studied compounds, primarily on the antitubercular properties.

There are several methods for conversion of carbonyl compounds to thion contained; the main one is the interaction of carbonyl compounds with phosphorus pentasulfide P₄S₁₀ (reagent Berzelius) [6], as well as Lawesson’s reagent [7]. Reaction with phosphorus pentasulfide requires high temperatures and large excess of this substance. Lawesson’s reagent [2,4-bis (4-methoxyphenyl)-1,3-dithia-2,4-diphosphethane-2,4-disulfide] is a convenient thionation reagent for ketones, ethers, and amides which allows to conduct synthesis of corresponding thion analogs with good outputs. The reaction can be carried out in solvents (THF, benzene, toluene, dioxane, pyridine) at heating [7–12] or at exposition to microwave radiation on a neutral Al₂O₃ support at solvent free conditions [12–14]. The ratio of substrate—Lawesson’s reagent can be varied from 1 : 0.5 up to 1 : 1. Herein we would like to report an efficient way of thion derivatives synthesis from O-benzoyl-β-aminopropioamidoximes in good yields.

2. Results and Discussion

In this work the synthesis of several O-thiobenzoyl-β-aminopropioamidoximes [β-amino groups are piperidin-1-yl (6), morpholin-1-yl (7), thiomorpholin-1-yl (8), 4-phenylpiperazin-1-yl (9), benzimidazol-1-yl (10)] was performed at the interaction of O-benzoyl-β-aminopropioamidoximes with Lawesson’s reagent in tetrahydrofuran with heating at 70°C during 10 h; the ratio of reactants was as 1 : 0.5. When heated, the disclosure of a central four-membered diphosphethane cycle of Lawesson’s reagent occurs with the formation of two particles of thiophosphene ylide interacting with 1–5 as shown in Schemes 1 and 2.

Scheme 1

Scheme 2

The reaction products were characterized by physicochemical data, IR, and NMR spectra (Tables 1–3 and Scheme 3).

Table 1: Physicochemical characteristics of O-thiobenzoyl-β-aminopropioamidoximes (6–10).

No.
β-Amino group
Output, %

Mp/°C (solvent)
Found (%)
Molecular formula

Calculated (%)

C
H
N

6
Piperidin-1-yl
57
0.82
170 (CHCl₃)
61.52
7.70
16.62
C₁₅H₂₁N₃OS

61.83
7.26
16.20

7
Morpholin-1-yl
63
0.7
168 (EtOH)
57.59
6.60
14.03
C₁₄H₁₉N₃O₂S

57.32
6.53
14.32

8
Thiomorpholin-1-yl
75
0.45
217 (EtOH)
54.75
6.67
13.87
C₁₄H₁₉N₃OS₂

54.34
6.19
13.58

9
4-Phenylpiperazin-1-yl
96
0.75
130 (CHCl₃)
65.65
6.23
15.61
C₂₀H₂₄N₄OS

65.20
6.60
15.20

10
Benzimidazol-1-yl
62
0.79
126 (CHCl₃)
62.75
4.67
17.70
C₁₇H₁₆N₄OS

62.94
4.97
17.27

Table 2: IR-spectra of O-benzoyl- and O-thiobenzoyl-β-aminopropioamidoximes (1–10).

No.
β-Amino group
Stretching and bending bond vibrations, cm⁻¹, KBr pellets

ν C=O
ν C=N
δ N-H and ν C=C
ν C=S
ν C-O
ν C-N
ν N-O
ν N(-H)2

1
Piperidin-1-yl
1719
1637
1611
—
1277
1117
1070
3201; 3329; 3455

2
Morpholin-1-yl
1719
1637
1610; 1613
—
1280
1117
1070
3198; 3331; 3455

3
Thiomorpholin-1-yl
1717
1637
1613
—
1278
1104
1070
3196; 3311; 3457

4
4-Phenylpiperazin-1-yl
1718
1637
1601; 1618
—
1280
1100
1072
3200; 3324; 3454

5
Benzimidazol-1-yl
1717
1635
1612; 1618
—
1277
1069
954
3196; 3310; 3452

6
Piperidin-1-yl
—
1674
1568; 1600
1297
1268
1123
1072
3340

7
Morpholin-1-yl
—
1674
1600
1296
1269
1123
1072
3334

8
Thiomorpholin-1-yl
—
1675
1568; 1600
1296
1267
1123
1073
3340

9
4-Phenylpiperazin-1-yl
—
1688
1600; 1642
1290
1249
1133
1100
3300

10
Benzimidazol-1-yl
—
1643
1600
1316
1257
1092
1025
3399

Table 3: ¹H NMR spectra of O-benzoyl- (1–5) and O-thiobenzoyl-β-aminopropioamidoximes (6–10).

δ, ppm (J/Hz)

No.
β-Amino group
N(CH₂)2 (4H)
(CH₂)₃ (1, 6); O(CH₂)2 (2, 7); S(CH₂)2 (3, 8); PhN(CH₂)₂ (4, 8)
Csp²H
α-CH2 (2H) (t)
β-CH2 (2H) (t)
NH₂ (2H) (s)

1
Piperidin-1-yl
2.37 m
1.37 m and 1.50 m (6H)
7.40–8.10 m (5 H)
2.26 (7.0)
2.54 (7.0)
6.58

2
Morpholin-1-yl
2.40 t (4.5)
3.56 t (4.5) (4H)
7.49–8.11 m (5 H)
2.29 (7.2)
2.58 (7.2)
6.58

3
Thiomorpholin-1-yl
2.66 m
2.69 m (4H)
7.23–8.11 m (5 H)
2.27 (7.0)
2.70 (7.0)
6.54

4
4-Phenylpiperazin-1-yl
2.60 t (5.0)
3.12 t (5.0) (4H)
6.77–8.13 m (10 H)
2.35 (6.5)
2.66 (6.5)
6.61

5
Benzimidazol-1-yl
—
—
7.62–8.12 m (9H); 8.62 s [1H; C(2)sp²H]
2.74 (7.0)
4.63 (7.0)
6.82

6
Piperidin-1-yl
3.73 m
1.42 m and 2.46 m (6H)
7.66–9.18 m (5H)
2.70 (7.0)
3.73 (7.0)
6.87

7
Morpholin-1-yl
3.51 m
3.73 m (4H)
7.45–9.16 m (5H)
2.69 (7.0)
3.05 (7.0)
6.87

8
Thiomorpholin-1-yl
3.80 t (7.0)
3.95 t (7.0)
7.50–9.25 m (5H)
2.79 (7.0)
3.15 (7.0)
6.97

9
4-Phenylpiperazin-1-yl
3.69 t (7.0)
3.93 t (7.0)
6.80–8.02 m (12 H)*
3.15 (7.0)
3.93 (7.0)
*

10
Benzimidazol-1-yl
—
—
7.83–8.33 m (11H)*; 8.90 s [1H; C(2)sp²H]
2.93 (7.0)
4.85 (7.0)
*

* Signal of NH₂-group protons is in the field of aromatic protons signal at δ 6.60–8.02 ppm (9) and at δ 7.83–8.33 ppm (10).

Scheme 3

In Table 2 the infrared spectra of O-ethers-β-aminopropioamidoximes (1–5) are given for comparison with the products spectra (6–10).

IR spectra of O-thiobenzoyl-β-aminopropioamidoximes (6–10) show disappearing of the bands of stretching vibrations of carbonyl groups ν C=O of parent compounds (1–5) in the region 1717–1719 cm⁻¹, when the bands of stretching vibrations of thion bonds are at ν C=S 1290–1316 cm⁻¹. Group of bands of stretching vibrations of N–H bonds (ν N-H) of the initial compounds (1–5) consisting of three bands above 3196 cm⁻¹ became one broadband at ν N-H 3300–3399 cm⁻¹ in the spectra of the products (6–10). In addition the IR spectra of compounds (6–10) have a number of characteristic bands of stretching and bending vibrations: 1643–1688 cm⁻¹ (ν C=N); 1568–1642 cm⁻¹ (δ H-N and ν C=C), 1249–1269 cm⁻¹ (ν C-O); 1092–1133 cm⁻¹ (ν C-N), 1025–1100 cm⁻¹ (ν N-O) (Table 2).

Table 3 and Scheme 3 show the ¹H NMR spectra of O-thiobenzoyl-β-aminopropioamidoximes (6–10); data of proton magnetic resonance for the initial O-ether-β-aminopropioamidoximes (1–5) are shown there for comparison. ¹H NMR spectra signals of 6–10 indicate the preservation of the original structure of β-aminopropioamidoximes O-ethers. It should be pointed out that all signals of the thion derivatives 6–10 in different degrees are shifted to the lower fields in comparison with starting O-benzoyl-β-aminopropioamidoximes (1–5).

Thus compounds 6–10 in the resonance region of aromatic protons Csp2 H give signals at δ 6.80–9.25 ppm, whereas these signals of O-benzoyl groups in 1–5 are at δ 6.77–8.62 ppm.

Proton signals of NH₂ groups of 6–10 are situated in the area δ 6.87–6.97 ppm; analogous signals of 1–5 in the region δ 6.54–6.87 ppm with the highest shift to the low field Δδ 0.43 ppm for a pair of compounds 3 and 8.

Protons of α-methylene group of compounds 6–10 have a resonance at δ 2.69–3.15 ppm and compounds 1–5 in the area δ 2.26–2.74 ppm with a maximum shift to the low field Δδ 0.80 ppm for a pair of compounds 4 and 9. β-Methylene protons of 6–10 give signals at δ 3.05–4.85 ppm and of 1–5 in the region δ 2.54–4.63 ppm with a maximum shift to the low field Δδ 1.27 ppm for a pair of compounds 4 and 9.

Protons of methylene groups of β-heterocycles: (CH₂)₃ (6), as well as the protons attached to the heteroatom in the 4-position of compounds (7–9), have a resonance at δ 1.42 and 2.46 ppm and δ 3.73–3.93 ppm, respectively, while the similar protons of the oxygen analogues 1 and 2–4 at δ 1.37 and 1.50 ppm and δ 2.69–3.56 ppm with a maximum shift to low field Δδ 1.26 ppm for a pair of compounds 3 and 8.

Signals of methylene groups of heterocycles connected to the nitrogen atom (N1) – N(CH₂)₂ have the largest shifts to the low field: region δ 3.51–3.80 ppm (6–9) compared with the region δ 2.37–2.66 ppm (1–4) with the maximum shift to low field Δδ 1.36 ppm which is characteristic for the pair of compounds 1 and 6.

Obviously such descreening effect of thiocarbonyl sulfur atom in the last three groups of protons reflects the spatial structure of thion derivatives 6–10 where the sulfur atom may be closed to these descreened groups of protons in the syn-isomer with the s-trans conformation as shown in Scheme 4.

Scheme 4

A similar spatial structure with a syn-arrangement of N–O bond and the amino group NH₂ about C=N bond with s-trans conformation of the substituents with respect to N–O linkage was found in the hydrochlorides of aroylation products of O-β-aminopropioamidoximes with the help of X-ray analysis [15].

3. Conclusion

Thus, we have elaborated acceptable method of synthesis of O-thiobenzoyl-β-aminopropioamidoximes by using of interaction of O-benzoyl-β-aminopropioamidoximes with Lawesson’s reagent at a ratio 1 : 0.5 at heating in THF at 70°C for 10 h. NMR spectral characteristics of new O-thiobenzoyl-β-aminopropioamidoximes confirm the structure established on the basis of elemental analysis and infrared spectra and provide proof of the spatial arrangement of functional groups in the s-trans-syn-configuration.

4. Experimental Section

IR spectra were recorded on a device NICOLET 5700 FT-IR in the range 400–3600 cm⁻¹ in KBr pellets. ¹H NMR spectra were taken on a JNN-ECA400 (400 MHz) spectrometer with HMDS as internal standard (δ 0.05 ppm); DMSO-d₆ was used as a solvent. Monitoring of the reaction progress was carried out by thin layer chromatography (TLC) on Sorbfil plates (EtOH–benzene, 3 : 1, as the eluent). Solvents used for synthesis and recrystallization of the original β-aminopropionitriles, β-aminopropioamidoximes, O-aroyl- and O-thioaroyl-β-aminopropioamidoximes (EtOH, CHCl₃, i-PrOH, THF), as well as solvents used for TLC (EtOH, benzene), were prepared according to standard procedures.

Syntheses of starting β-aminopropionitriles, β-aminopropioamidoximes and O-benzoyl-β-aminopropioamidoximes (1–5) are given in [16–20].

O-Thiobenzoyl-β-(piperidin-1-yl)propioamidoxime (6, Table 1)Portionwise under cooling with ice water and stirring, Lawesson’s reagent (1.38 g, 0.0035 mol) was added to the solution of O-benzoyl-β-(piperidin-yl)propioamidoxime (1) [16] (1.88 g, 0.007 mol) in 15 mL of dry THF. The reaction mixture was heated at 60–70°C through an hour of stirring at room temperature. After 1 h white precipitate of thiobenzoylation product (6) started to precipitate; it was heated for 9 h with TLC monitoring every hour and then product (6) was filtered off and dried. Recrystallization of the precipitate from CHCl₃ gave 1.17 g (57%) of O-thiobenzoyl-β-(piperidin-1-yl)propioamidoxime (6) with 0.82 and mp 170°C.

O-Thiobenzoyl-β-(morpholin-1-yl)propioamidoxime (7, Table 1)Portionwise under cooling with ice water and stirring, Lawesson’s reagent (0.65 g, 0.0016 mol) was added to the solution of O-benzoyl-β-(morpholin-1-yl)propioamidoxime (2) [17] (0.89 g, 0.0032 mol) in 15 mL of dry THF. After 1 h of stirring at room temperature the reaction mixture was heated for 10 h at 60–70°C with TLC monitoring every hour. Through 1 h of heating a white precipitate of product 7 began to form; then at the end of reaction it was filtered off and dried. Recrystallization from EtOH gave 0.59 g (63%) of O-thiobenzoyl-β-(morpholin-1-yl)propioamidoxime (7) with 0.70 and mp 168°C.

O-Thiobenzoyl-β -(thiomorfolin-1-yl)propioamidoxime (8, Table 1)Under cooling with ice water and stirring, portions (5 times) of Lawesson’s reagent (0.47 g, 0.00115 mol) were added to O-benzoyl-β-(thiomorpholin-1-yl)propioamidoxime (3) [18] (0.66 g, 0.0023 mol) in 15 mL of dry THF. Turbidity of reaction mixture was forming after stirring at room temperature for about 1 h; then the reaction mixture was heated at 70°C during 10 hours with TLC monitoring. After 2 h of heating a white precipitate of 8 began to fall. At the end of the reaction 8 was filtered and recrystallized from EtOH. O-Thiobenzoyl-β-(thiomorpholin-1-yl)propioamidoxime (8) was gathered in amount 0.54 g, 75% with 0.45; mp 217°C.

O-Thiobenzoyl-β-(4-phenilpiperazin-1-yl)propioamidoxime (9, Table 1)Under cooling with ice water, stirring portions of Lawesson’s reagent (0.14 g, 0.00035 mol) were added to a solution of O-benzoyl-(β-4-phenilpiperazin-1-yl)propioamidoxime (4) [19] (0.2 g, 0.00056 mol) in 15 mL of dry THF. The reaction mixture was stirred at room temperature for an hour and heated at 70°C with TLC monitoring. Product 9 was isolated after 10 h of heating and recrystallization from CHCl₃ (0.2 g, 96%; 0,75; mp 130°C).

O-Thiobenzoyl-(β-benzimidazol-1-yl)propioamidoxime (10, Table 1)Portions of Lawesson’s reagent (0.2 g, 0.005 mole) were added to a solution O-benzoyl-(β-benzimidazol-1-yl) propioamidoxime (5) [20] (0.3 g, 0.001 mol) in 15 mL of dry THF under cooling with ice water and stirring. The reaction mixture was heated at 70°C with TLC monitoring during 10 h; white precipitate of 10 began to fall after 2 h of heating; it was isolated at the end of the reaction and recrystallized from CHCl₃ (0.2 g, 62%; 0,79; mp 126°C).

References

M. D. Mashkovskii, “Medicinal remedies,” Moscow: New Wave, vol. 2, pp. 309–310, 2002.

N. Serradji, O. Bensaid, M. Martin et al., “Structure-activity relationships in platelet-activating factor. Part 13: synthesis and biological evaluation of piperazine derivatives with dual anti-PAF and anti-HIV-1 or pure antiretroviral activity,” Bioorganic and Medicinal Chemistry, vol. 14, no. 23, pp. 8109–8125, 2006.

L. A. Kayukova, K. D. Praliyev, R. A. Agzamova, and V. L. Bismilda, “In vitro antitubercular testing of the new derivatives of amidoximes on the Bactec system,” in Proceedings of the 33rd Iuatld World Conference on Lung Health & 3rd stop tb dots expansion working group meeting, p. 165, Montreal, Canada, October 2002.

L. A. Kayukova, R. A. Agzamova, V. L. Bismilda, U. A. Kozhamkulov, and G. M. Pichkhadze, “Biological activity of the new derivatives of β-aminopropioamidoximes,” in Proceedings of the Congress and 86th Conference of The Canadian Society for Chemistry, p. 280, Ottawa, Canada, August 2003.

L. A. Kayukova, M. A. Orazbaeva, V. L. Bismilda, and L. T. Chingisova, “Synthesis and antituberculosis activity of O-aroyl-β-(4- phenylpiperazin-1-yl)propioamidoximes,” Pharmaceutical Chemistry Journal, vol. 44, no. 7, pp. 356–359, 2010.

T. Ozturk, E. Ertas, and O. Mert, “A berzelius reagent, phosphorus decasulfide (P₄S₁₀), in organic syntheses,” Chemical Reviews, vol. 110, no. 6, pp. 3419–3478, 2010.

M. Jesberger, T. P. Davis, and L. Barner, “Applications of Lawesson's reagent in organic and organometallic syntheses,” Synthesis, no. 13, pp. 1929–1958, 2003.

Th. J. Curphey, “Thionation with the Reagent Combination of Phosphorus Pentasulfide and Hexamethyldisiloxane,” Journal of Organic Chemistry, vol. 67, no. 18, pp. 6461–6473, 2002.

D. Brayton, F. E. Jacobsen, S. M. Cohen, and P. J. Farmer, “A novel heterocyclic atom exchange reaction with Lawesson's reagent: a one-pot synthesis of dithiomaltol,” Chemical Communications, no. 2, pp. 206–208, 2006.

Z. Kaleta, B. T. Makowski, T. Soós, and R. Dembinski, “Thionation using fluorous Lawesson's reagent,” Organic Letters, vol. 8, no. 8, pp. 1625–1628, 2006.

T. Nishio, “Reaction of (1,ω)-N-acylamino alcohols with Lawesson's reagent: synthesis of sulfur-containing heterocycles,” Journal of Organic Chemistry, vol. 62, no. 4, pp. 1106–1111, 1997.

Sh. Araki, T. Goto, and Ya. Butsugan, “One-step conversion of mesoionic olate to thiolate by Lawesson’s reagent,” Bulletin of the Chemical Society of Japan, vol. 61, pp. 2977–2978, 1988.

R. Rico-Gomes, F. Naiera, J. M. Lopez-Romero, and P. Canada-Rudner, “Solvent free synthesis of thioalkylxanthines from alkylxanthines using microwave irradiation,” Heterocycles, vol. 53, no. 10, pp. 2275–2278, 2000.

R. S. Varma and D. Kumar, “Microwave-accelerated solvent-free synthesis of thioketones, thiolactones, thioamides, thionoesters, and thioflavonoids,” Organic Letters, vol. 1, no. 5, pp. 697–700, 1999.

K. M. Beketov, J. T. Welch, P. Toskano, L. A. Kayukova, A. L. Akhelova, and K. D. Praliev, “Crystal and molecular structure of β-piperidinopropioamidoxime monochloroacetate and hydrochlorides of its O-benzoylation products,” Journal of Structural Chemistry, vol. 45, no. 3, pp. 509–517, 2004.

L. A. Kayukova, I. S. Zhumadildaeva, and K. D. Praliyev, “Cyclization of O-benzoyl-β-piperidinopropionamidoximes to form 5-phenyl-3-(β-piperidino)ethyl-1,2,4-oxadiazoles,” Russian Chemical Bulletin, vol. 51, no. 11, pp. 2100–2105, 2002.

L. A. Kayukova, “Conditions for the heterocyclization of O-aroyl--morpholinopropioamide oximes to 5-aryl-3-(-morpholino)ethyl-1,2,4-oxadiazoles,” Chemistry of Heterocyclic Compounds, vol. 39, no. 2, pp. 223–227, 2003.

L. A. Kayukova and M. A. Orazbaeva, “Synthesis of -(thiomorpholin-1-yl)propionitrile and -(thiomorpholin-1-yl)propioamidoxime; obtaining of O-aroyl-β-( thiomorpholin-1-yl) propioamidoximes, as potential antitubercular means,” Bulletin of the National Academy of Sciences of the Republic of Kazakhstan. Chemical Series, no. 5, pp. 37–42, 2007.

L. A. Kayukova, M. A. Orazbaeva, V. L. Bismilda, and L. T. Chingisova, “Synthesis and antituberculosis activity of O-aroyl--(4-phenylpiperazin-1-yl)propioamidoximes,” Pharmaceutical Chemistry Journal, vol. 44, no. 7, pp. 356–359, 2010.

L. A. Kayukova, K. M. Beketov, A. L. Akhelova, and K. D. Praliev, “Synthesis of 2-[2-(5-phenyl-1,2,4-oxadiazol-3-yl)-ethyl]benzimidazole and its X-Ray analysis,” Chemistry of Heterocyclic Compounds, vol. 42, no. 7, pp. 914–917, 2006.