Reaction, Reactivity and Behaviour of α-Chloroacetamide in the Synthesis of Acrylamide Derivatives

doi:10.21203/rs.3.rs-3782092/v1

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Reaction, Reactivity and Behaviour of α-Chloroacetamide in the Synthesis of Acrylamide Derivatives

https://doi.org/10.21203/rs.3.rs-3782092/v1

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Reaction α-chloroacetamides (1a-e) with sodium isopropoxide in the corresponding alcohol and carbon disulphide afforded dithiol of ether derivatives (5a-e). The structures of the products were elucidated by ¹H NMR, ¹³C NMR, IR, mass spectra and elemental analyses

α-chloroacetamides

sodiumalkoxide

carbon disulfied

Nowadays, great efforts have been made to synthesis, characterize and investigate the biological activities of acetamides. They possess very promising biological activities as anticonvulsant, [1–3] antimicrobial,[4, 5]. anticancer, [6–9]and anti tumor,[10] herbicides,[11]

Acrylamides are chemical that naturally forms in starchy food and have biologically activity, it's have been interesting essential role in the construction of many bioactive compounds, that they can exhibit antibacterial,[12, 13] antifungal, [14] anti-tumor,[15]antibiotic,[16] anti-microbial,[17, 18] and anti-inflammatory activities.[19]

On the other hand, mercapto-compounds have important role in anti cancer,[20] antimicrobial, [21]

For all the above mentioned reasons, we study the reactions of α-chloroacetamides in the Synthesis of acrylamide derivatives.

Reaction α-chloroacetamides (1a-e) with sodium isopropoxide in the corresponding alcohol and carbon disulphide to give 3,6-bis-(dimercaptomethylene)-piperazine-2,5-diones (2a-e) as we expected. But the reaction proceeds by different way in which the dithiol of ether derivatives (5a-e) (Scheme 1).

The structure of dithiol (5a-e) was confirmed by spectral data as well as element alanalysis. IR spectra of these compounds shows strong absorption at υ_max1661-1692 cm^-1 corresponding to the carbonyl group. Also, it shows the appearance of NH of amide at υ_max 3292 cm^-1.¹H NMR spectra of these compounds shows the following signals, doublet signal for six protons at δ_H = 1.3-1.4 ppm corresponding to two methyl groups, septet signal for one proton at δ_H = 5.7-5.8 ppm corresponding to methine group. multipelt signal at δ_H = 7.0-7.5 ppm for aromatic moiety singlet signal for two protons at δ_H = 3.9-4.1 ppm corresponding to the two SH groups, and singlet signal for one proton at δ_H = 8.1 ppm corresponding to NH.

Scheme 1.

The mechanism for the formation of the isolated products is shown in the following steps:

1-The chlorine atom of α-chloroacetamide is replaced by the isopropoxide to give the corresponding ether (4a-e).

2-The obtained ether (4a-e) deprotonated by the effected isoprpoxide to give the anion (6a-e)

3-The anion (6a-e) attacked the carbon disulphide molecule to give the target product (5a-e) as shown in scheme 2

Scheme 2.

For generalization of this reaction we repeated it with different alkoxide, such as sodium propoxide, sodium ethoxide and sodium methoxide afforded the corresponding to dithiols (5f-q) as shown in scheme 3

Scheme 3.

To illustrate the structures of the new products, different spectral data were performed, such as IR, ¹H and ¹³CNMR, elemental analysis and mass spectrometry. The IR spectra of compounds 5a showed 3269 (NH), 2978 (C-H, aliph), 1672 cm-1 (C=O).

For NMR spectra and as an example, the ¹H NMR spectrum of 5a showed upfield doublet signal at δ_H =1.35 ppm which assigned six protons corresponding to two methyl groups, δ_H = 3.97 ppm singlet signal for two protons corresponding to the two SH groups, δ_H = 5.72 ppm septet signal for one proton corre- sponding to the methine proton, δ_H = 7.1 ppm triplet signal for one proton corresponding to the CH aromatic, δ_H = 7.3 ppm triplet sgnal for two protons corresponding to the CH aromatic δ_H=7.50 ppm doublet signal for two protons correspond-ing to the CH of the aromatic moiety, and δ_H = 8.45 ppm singlet signal for one proton corresponding to the NH of amide group. fig 1

fig 1

with other alkoxid( methoxide, ethoxide, propoxide)the presence of carbon disulphide has a greater effect on the reaction path way. But the question is; why in the presence of carbon disulphide the alkoxide act as a nucleophile while in the absence of carbon disulphide the alkoxide act as a base. The answer of this question is of great important; the presence of carbon disulphide molecule will make a hydrogen bond between the hydrogen atom of amide and the sulfur atom of carbon disulphide which retard to the approach of alkoxide to the hydrogen. Consequently, so that carbon disulphide prevents the release of hydrogen proton. Therefore, the alko-xide act as a nucleophile not as a base.

The postulated mechanism for this reaction is as shown in the following scheme

Scheme 4

Melting points were determined using open gl-ass capillaries on a Gallenkamp melting point apparatus (Weiss-Gallenkamp, Loughborough, UK), and are uncorrected. The IR spectra were recorded from potassium bromide disks with a FT device, Minia University NMR spectra were measured in DMSO-d6 on a Bruker AV-400 spectrometer (400 MHz for 1H, 100 MHz for 13C, and 40.55 MHz for 15N); chemical shifts are expressed in (ppm), versus internal

tetramethylsilane (TMS) = 0 for ¹H and ¹³C, Mass spectra at the Microanalytical Center, Cairo University, Egypt.

3.1 Starting materials

α-chloroacetamides 1a-e were prepared according to the literature (Buckle et al. 1975 and Rao et al. 1988). Dialkyl acetylenedicarbox-ylates 2a,b (Aldrich) were used as received.

3.2 General Procedure

In a dry flask a mixture of alcohol (30 mL) and sodium metal (20 mmol) was left under stirring till all sodium dissolved, then N-aryl-2-chloro-acetamide (1a-e) (10 mmol) was added and then left under stirring for (30 min), then add carbon disulfide (10 mmol). The mixture was left under reflux with stirring for (3h) at (100-150) temp. Cooling and poured to acidified ice water (ice water and HCl), the solid product obtained was collected by filtration and purified by recrystallisation from ethanol.

2-isopropoxy-3,3-dimercapto-N-Phenyl-acryl-amide(5a).

Compound 5a was obtained as yellow crystals, Yield, 78%; m.p. = 85-86. IR (v/cm⁻¹): 3269 (NH), 2978 (C-H, aliph), 1672 cm^-1 (C=O): ¹HNMR [CDCl₃] shows δ_H at 1.35 (d, 6H, 2CH₃₎, 3.97 (s, 2H, 2SH), 5.72 (sp, 1H, CH), 7.1 (t, 1H, H_A-Ar), 7.3 (t, 2H, 2H_B-Ar), 7.5 (d, 2H, 2H_C-Ar) and 8.45 ppm (s, 1H, NH).1 H nmr (DMSO):21.66 (2CH₃), 40.4(CH), 80.27 (C-O), 120.61, 125.15, 129.43, 137.90 (Ar moiety), 166.12 (C=S) and 213.00 ppm (C=O).Anal. Calcd. For (C₁₂H₁₅NO₂S₂): C, 53.50; H, 5.61; N, 5.20 %, Found: C, 53.29; H, 5.43; N, 5.05

2-isopropoxy-3,3-dimercapto-N-p-tolyl-acrylamide (5b)

Compound 5b was obtained as yellow crystals, m.p.108-110 ºC; IR (v/cm⁻¹):3292 (NH), 2981 (C-H, aliph), 1661 cm^-1 (C=O). 1H NMR [CDCl3] shows δH at 1.35 (d, 6H, 2CH3), 2.25 (s, 3H, CH3), 3.9 (s, 2H, 2SH), 5.67 (sp, 1H, CH), 7.05 (d, 2H, Ar-AB), 7.3 (d, 2H, Ar-AB), 8.1 ppm (s, 1H, NH). 13C NMR [DMSO] shows δC at 21.29 (CH3), 21.65 (CH3-Ar), 40.4 (CH), 80.14 ( C-O), 120.59,129.91, 134.78, 135.31 ( Ar moiety), 165.82 (C=S) and 213.00 ppm ( C=O). Mass (EI), shows M+ at m/z 283. .Anal. Calcd. For (C₁₃H₁₇NO₂S₂): C, 55.09; H, 6.05; N, 4.94% Found: C, 54.82; H, 5.91; N, 4.72 %

N-(4-bromo-phenyl)-2-isopropoxy-3,3-dimercapto-acrylmide (5c)

Compound 5c was obtained as yellow crystals, Yield, 86%; m.p. =118-120ºC.. IR (v/cm⁻¹ ): 3436 (NH), 2921 (C-H, aliph), 1692cm^-1 (C=O); H NMR [CDCl₃] shows δ_H at 1.35 (d, 6H, 2CH₃), 4.1 (s, 2H, 2SH), 5.67 (sp, 1H, CH), 7.2-7.8 (m, 4H, Ar-H)), 8.1 ppm (s, 1H, NH). shows M⁺at m/z 348. Anal. Calcd. For (C₁₂H₁₄BrNO₂S₂): C, 41.38; H, 4.05; N, 4.02 % Found: C, 40.91; H, 3.81; N, 3

2-isopropoxy-3,3-dimercapto-N-(4-nitro-phenyl)-acryla mide (5d (

Compound 5d was obtained as yellow crystals, Yield, 78%; m.p. = 96-98ºC. Mass (EI), shows M⁺at m/z 314.Anal. Calcd. For (C₁₂H₁₄N₂O₄S₂): C, 45.85; H, 4.49; N, 8.91 % Found: C, 45.71; H, 4.32; N, 8.54 %

N-(4-chloro-phenyl)-2-isopropoxy-3,3-dimercapto-acrylmide (5e)

Compound 5e was obtained as yellow crystals, Yield, 80%; m.p. = 113-115 ºC. IR (v/cm⁻¹): 3269 (NH), 2978 (C-H, aliph), 1672 cm^-1 (C=O): ¹HNMR [CDCl₃] shows δ_H at 1.3 (d, 6H, 2CH₃), 4.1 (s, 2H, 2SH), 4.4 (sp, 1H, CH), 7.3-7.9 ( m, 4H, Ar-H), 10.4 ppm (s, 1H, NH). Mass (EI), shows M⁺at m/z 303.5. .Anal. Calcd. For (C₁₂H₁₄ClNO₂S₂): C, 47.44; H, 4.64; N, 4.61 % Found: C, 47.01; H, 4.44; N, 4.48 % .

3,3-dimercapto-N-phenyl-2-propoxy-acrylamide (5f)

Compound 5f was obtained as yellow crystals, Yield, 78%; m.p. = 113-115 ºC. IR (v/cm⁻¹): 3293 (NH), 3127 (CH-Ar), 2920 (C-H, aliph),1662 cm^-1 (C=O). Anal. Calcd. For (C₁₂H₁₅NO₂S₂): C, 53.50; H, 5.61; N, 5.20 % Found: C, 52.70; H, 4.80; N, 4.20 %

3,3-dimercapto-2-propoxy-N-p-tolyl-acrylamide (5g)

Compound 5g was obtained as yellow crystals, Yield, 77%, m.p.122-124 ºC; IR (v/cm⁻¹):3291 (NH), 2920 (C-H, aliph), 1661 cm^-1 (C=O). 1H NMR [CDCl3] shows δ H at 1.35 (d, 6H, 2CH3), 2.25 (s, 3H, CH3), 3.9 (s, 2H, 2SH), 5.67 (sp, 1H, CH), 7.05 (d, 2H, Ar-AB), 7.3 (d, 2H, Ar-AB), 8.1 ppm (s, 1H, NH). 13C NMR [DMSO] shows δC at 0.96 (t, 3H, CH₃), 1.73 (m, 2H, CH₂), 2.27 (s, 3H, CH₃-Ar), 4.1 (s, 2H, 2SH), 4.5 (t, 2H, OCH₂), 7.12 (d, 2H, Ar-AB), 7.5 (d, 2H, Ar-AB) and 10.2 ppm (s, 1H, NH). Mass (EI), shows M⁺at m/z 283..Anal. Calcd. For (C₁₃H₁₇NO₂S₂): C, 55.09; H, 6.05; N, 4.94 % Found: C, 54.83; H, 5.90; N,,4. 72.

N-(4-bromo-phenyl)-3,3-dimercapto-2-propoxy-acrylamide (5h)

Compound 5h was obtained as yellow crystals, Yield, 80%; m.p. = 118-120 ºC. IR (v/cm⁻¹): 3292 (NH), 2978 (C-H, aliph), 1662 cm^-1 (C=O). Mass (EI), shows M⁺at m/z 348. .Anal. Calcd. For (C₁₂H₁₄BrNO₂S₂): C, 41.38; H, 4.05; N, 4.02 % Found: C, 41.04; H, 3.70; N, 3.73 %

3,3-dimercapto-N-(4-nitro-phenyl)-2-propoxy-acrylamide(5i)

Compound 5i was obtained as yellow crystals, Yield, 78%; m.p. = 96-98 ºC. ..Anal. Calcd. For (C₁₂H₁₄N₂O₄S₂): C, 45.85; H, 4.49; N, 8.91 % Found: C, 45.71; H, 4.32; N, 8.75 %

2-ethoxy-3,3-dimercapto-N-Phenyl-acrylamide (5j)

Compound 5j was obtained as yellow crystals, Yield, 81%; m.p. =124- 126ºC.. IR (v/cm⁻¹ ): 200 (NH), 2987 (C-H, aliph), 1676 cm^-1(C=O). Anal. Calcd. For (C₁₁H₁₃NO₂S₂): C, 51.74; H, 5.13; N, 5.49% Found: C, 51.54; H, 5.03; N, 5.33%

3-ethoxy-3,3-dimercapto-N-p-tolyl-acrylamide (5k)

Compound 5k was obtained as yellow crystals, m.p.124-126 ºC; IR (v/cm⁻¹):3 3199 (NH), 2987 (C-H, aliph), 1669 cm^-1 (C=O). 1H NMR [CDCl3] shows δ H at 1.57 (t, 3H, CH₃), 2.25 (s, 3H, CH₃-Ar), 4.0 (s, 2H, 2SH), 4.8 (q, 2H, CH₂), 7.1 (d, 2H, Ar- AB), 7.4 ppm (d, 2H, Ar-AB), 8.25 (s, 1H, NH).. ¹³C NMR [DMSO] shows δ_C at 14.16 (CH₃), 21.30 (CH₃), 40.45 (CH₂), 71.76 (C-O), 120.63, 129. 90, 134.83, 135.28 (Ar moiety), 165.75 (C=S) and 213.95 ppm (C=O).Mass (EI), shows M⁺at m/z 269. .Anal. Calcd. For (C₁₂H₁₅NO₂S₂): C, 53.50; H, 5.61; N, 5.20 % Found: C, 53.34; H, 5.44; N, 5.02 %.

N-(4-bromo-phenyl)-2-ethoxy-3,3-dimercapto-acrylamide (5l)

Compound 5e was obtained as yellow crystals, Yield, 80%; m.p. = 110-112 ºC. IR (v/cm⁻¹): 3196 (NH), 2991 (C-H, aliph), 1674 cm^-1 (C=O). Mass (EI), shows M ⁺at m/z 334. . .Anal. Calcd. For (C₁₁H₁₂BrNO₂S₂): C, 39.53; H, 3.62; N, 4.19 % Found: C, 39.38; H, 3.52; N, 4.09 %

2-ethoxy-3,3-dimercapto-N-(4-nitro-phenyl)-acrylamide (5m)

Compound 5m was obtained as yellow crystals, Yield, 78%; m.p. = 102 -104 ºC. IR (v/cm⁻¹): 3203(NH), 2925 (C-H, aliph), 1654 (C=O)..Anal. Calcd. For (C₁₁H₁₂N₂O₄S₂): C, 43.99; H, 4.03; N, 9.33 % Found: C, 43.78; H, 3.95; N, 9.15 %

3,3-dimercapto-2-methoxy-N-phenyl-acrylamide (5n)

Compound 5n was obtained as yellow crystals, Yield, 86%; m.p. =100-102ºC.. IR (v/cm⁻¹ ): 3283 (NH), 1687 cm^-1 (C=O). Mass (EI), shows M⁺at m/z 241. Anal. Calcd. For (C₁₀H₁₁NO₂S₂): C, 49.77; H, 4.59; N, 5.80 % ; Found: C, 49.56; H, 4.40; N, 5.62 %

3,3-dimercapto-2-methoxy-N-p-tolyl-acrylamide (5o)

Compound 5o was obtained as yellow crystals, Yield, 79%; m.p. =108-110ºC.. ¹H NMR [DMSO] shows δ_H at 2.18 (s, 3H, Ar- CH₃), 3.36 (s, 3H, OCH₃), 4.1 (s, 2H, 2SH), 7.13-7.52 (m, 4H, CH-Ar) and 9.61-10.06 ppm (s, 1H, NH., br exchange., OH). Mass (EI), shows M⁺at m/z 255. Elemental analysis, requires (C₁₁H₁₃NO₂S₂): C, 51.74; H, 5.13; N, 5.49 % Found: C, 51.48; H, 5.01; N, 5.25 %

N-(4-bromo-phenyl)-3,3-dimercapto-2-methoxy-acrylamide (2.9p)

Compound 2.9p was obtained as yellow crystals, Yield, 89%; m.p. =112-114ºC.IR, shows υ_max at 3299 (NH), 2971 (C-H, aliph), 1674cm^-1(C=O), Mass (EI), shows M⁺at m/z 320.Elemental analysis, requires (C₁₀H₁₀BrNO₂S₂): C, 37.51; H, 3.15; N, 4.37% Found: C, 37.25; H, 3.01; N, 4.19%

3,3-dimercapto-2-methoxy-N-(4-nitro-phenyl)-acrylamide (2.9q)

Compound 2.9q was obtained as yellow crystals, Yield, 89%; m.p. = 96-98 ºC. IR, shows υ_max at 3363 (NH), 1664 cm^-1 (C=O).Elemental analysis, requires (C₁₀H₁₀N₂O₄S₂): C, 41.95; H, 3.52; N, 9.78 % Found: C, 41.77; H, .3.39; N, 9.56%

Author Contribution

Prof. Fathi A. Abu-Shanaba my supervisor supported me, he suggested the main idea.Dr. Esam. A. Eshaka my supervisor helped me in this research in the lab.Dr Sayed A. S. Mousaa my supervisor helped me with writing and data

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Scheme 1 to 4 are available in Supplementary Files section.

No competing interests reported.

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Reaction, Reactivity and Behaviour of α-Chloroacetamide in the Synthesis of Acrylamide Derivatives

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