A new synthesis of (Z)-arylbenzoyl(phenethyl)carbamothioic-N-phenylbenzohydrazonic thioanhydride derivatives by reaction of secondary amides, carbon disulfide and hydrazonoyl chlorides

doi:10.21203/rs.3.rs-4656477/v1

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A new synthesis of (Z)-arylbenzoyl(phenethyl)carbamothioic-N-phenylbenzohydrazonic thioanhydride derivatives by reaction of secondary amides, carbon disulfide and hydrazonoyl chlorides

https://doi.org/10.21203/rs.3.rs-4656477/v1

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A new synthesis of (Z)-arylbenzoyl(phenethyl)carbamothioic-N-phenylbenzohydrazonic thioanhydride derivatives is described using amides, substituted hydrazonoyl chlorides in presence carbon disulfide and MeONa as the base in DMF at room temperature. The approach requires no complex equipment and utilizes inexpensive, and easy to handle hydrazonoyl chloride as third component of starting materials to afford of this novel class of compounds.

dithiocarbamate

hydrazonoyl chloride

carbon disulfide

amide

multicomponent reaction

The synthesis of combinatorial libraries from easily available starting materials under economic conditions become increasingly important [1–3]. Among the most useful methods, the multicomponent reactions have emerged as a particularly powerful transformation to generate greatly expanded chemical collections of diverse molecules in fast, clean, and efficient way [4–7]. Introduce sulfur into organic compounds has received a great deal of attention due to their wide use in many synthetic substances that are of material, pharmaceutical, and biological interest [8–11]. Organic dithiocarbamates and their derivatives are functional organosulfur molecules that have been extensively used in organic synthesis because of their wide utility and interesting chemistry [12–15]. They are used in polymer industry due to their versatile role as photochemical and thermal initiators,[16–18] and recently, in the synthesis of ionic liquids [19, 20]. Some derivatives of dithiocarbamates exhibit medicinal properties including applications in the treatment of cancer and inhibitors of enzymes on biological systems [21–23]. Furthermore, these compounds have shown wide applications as pesticides, fungicides in agriculture, and as linker in solid phase organic synthesis [24]. As a consequence, the development of novel methods for the preparation of functionalized dithiocarbamates with different substitution patterns has become a conscientious choice of synthetic chemists during the past few years. Several methods have been reported previously for their preparation based upon reaction of amines with carbon disulfide and alkyl halides in the presence of strong bases such as TBAI and KOH at harmful organic solvents [25–31]. In this area, some useful reactions in the literature focused on the alkylation of dithiocarbamic acid for the preparation of dithiocarbamate derivatives [32–34]. According to our knowledge, there are not any report on the synthesis of functionalized dithiocarbamates by using amide, carbon disulfide, and hydrazonoyl chlorides in the presence of sodium methoxide as inexpensive and readily base. Thus, as part of our ongoing project in developing multicomponent reaction media for the synthesis of useful compounds, we have succeeded in developing the one-pot synthesis of (Z)-arylbenzoyl (phenethyl)carbamothioic-N-phenylbenzohydrazonic thioanhydride derivatives from amides, carbon disulfide, and hydrazonoyl chlorides under catalyst-free reaction condition. Encouraged by these successful effort and whilst aiming to demonstrate the generality and efficiency of dithiocarbamates, we present a mild, reliable, efficient and scalable three-component synthesis of these novel compounds under mild conditions.

Herein, we wish to incorporate hydrazonoyl chloride into benzyl(arylbenzoyl)carbamodithioic acid or arylbenzoyl(phenethyl)carbamodithioic acid skeleton via MCR strategy to obtain a series of novel sulfur-containing compounds of (Z)-arylbenzoyl(phenethyl)carbamothioic-N-phenylbenzohydrazonic thioanhydrides which could be applications for synthesis and drug discovery. With the optimized reaction conditions, secondary amides 1 and hydrazonoyl chlorides 2 in presence of carbon disulfide were employed to investigate the scope of the three-component strategy. At first, we have focused on the in situ preparation of benzyl(arylbenzoyl)carbamodithioic acid or (arylbenzoyl)(phenethyl)carbamodithioic acid derivatives from amides and carbon disulfide in the presence of MeONa at room temperature. Subsequently we chose to study the behaviour of these sulfur-containing compounds as nucelophiles with hydrazonoyl chlorides in DMF at room temperature for 4h, and upon workup, the (Z)-arylbenzoyl(phenethyl)carbamothioic-N-phenylbenzohydrazonic thioanhydride derivatives 3a-i were isolated in yield 65–72% (scheme 1). The structures of compounds 3a-i were supported by spectroscopic data. In the ¹H NMR spectrum 3a, the benzylic protons resonated as triplet at δ 2.96 (J = 6.9 Hz) while the protons of NH resonsted at δ 6.38 ppm as broad peak. The ¹³C NMR spectrum of this new compound displayed the characteristic signal for C = S carbon at δ 186.0, whereas carbonyl carbons of amide and C = N were observed as two signals at δ 167.5, and 157.3.

A plausible reaction pathway is given in scheme 2. It is conceivable that amide derivatives 1 is deprotonated by sodium methoxide to intermediate 4 followed by the attack of nitrogen atom of this anion to carbon disulfide to generate the intermediate 5. Then, the negatively charged sulphur of this intermediate reacts with hydrazonoyl chloride 2 to afford the product 3.

In conclude, we have developed an easy and efficient method of preparing (Z)-arylbenzoyl(phenethyl)carbamothioic-N-phenylbenzohydrazonic thioanhydride derivatives via one-pot, three-component reaction of amide derivatives, carbon disulfide and substituted hydrazonoyl chlorides. This approach has several advantages, such as easy workup, and high atom economy, readily available starting materials, a catalyst-free procedure, high yield, low costs, mild condition.

Experimental

General Experimental Information

All reagents were purchased from commercial suppliers and used without further purification except amides and hydrazonoyl chlorides [35, 36]. All experiments were carried out under air atmosphere. Column chromatography was carried out with Merck silica gel 60 (63–200 mesh). ¹H and ¹³C NMR spectra (CHCl₃ solutions) were recorded at 300 MHz and 75.4 MHz with chemical shifts (δ) reported in parts per million relative to TMS (δ = 0 ppm) or CDCl₃ (δ = 77.0 ppm) as internal standards. Coupling constants (J) are reported in Hertz (Hz). Mass spectra (ESI, 70ev) were recorded on a AB/SCIEX 3200 QTRAP. IR spectra were recorded on a Perkin-Elmer FT/IR 1760 as KBr pellets. Melting points were recorded on a SMP1 Melting Point apparatus in open capillary.

General procedure for the synthesis of 2

A mixture of amide 1 (1 mmol), and sodium methoxide (1 mmol)) in DMF (4 ml) was stirred at room temperature for 10 min at room temperature. Then, the carbon disulfide (3 mmol) was added and the reaction stirred for 5 min at room temperature. To this, hydrazonoyl chloride 2 (1 mmol) was added and the reaction was allowed to stir for 4 h at this temperature. The mixture was poured onto H₂O (20 ml) and the obtained precipitate was filtered and washed with H₂O and hexane and was later on recrystallized from methanol to afford pure compound 3.

(Z)-(4-methylbenzoyl)(phenethyl)carbamothioic (Z)-N-phenylbenzohydrazonic thioanhydride (3a)

White powder; yield 71%; m.p. 132°C IR (KBr) (ν_max/cm − 1): 3331, 1630, 1573, 1535, 1492, 1273, 1237, 1050, 718, 683, 575. ¹H NMR (300.1 MHz, CDCl₃): δ = 2.41 (s, 3H), 2.96 (t, ³J = 6.9 Hz, 2H), 3.74 (t, ³J = 6.9 Hz, 2H), 6.38 (b, NH), 7.22–7.29 (m, 5H), 7.33–7.36 (m, 2H), 7.50–7.65 (m, 8H), 7.74–7.77 (m, 2H), 7.84–7.87 (m, 2H). ¹³C NMR (75.4 MHz, CDCl₃): δ = 21.4, 35.7, 41.2, 125.8, 126.5, 126.7, 126.9, 128.6, 128.7, 128.8, 129.0, 129.1, 129.2, 129.3, 131.5, 131.7, 138.7, 138.9, 141.9, 157.3, 167.5, 186.0. MS(ESI) m/z: 509 for C₃₀H₂₇N₃OS₂

(Z)-(Z)-4-chloro-N-phenylbenzohydrazonic (4-methylbenzoyl)(phenethyl)carbamothioic thioanhydride (3b)

White powder; yield 69%; m.p. 151°C. IR (KBr) (ν_max/cm − 1): 3312, 1627, 1514, 1506, 1424, 1276, 1208, 983, 730, 612. ¹H NMR (300.1 MHz, DMSO): δ = 2.35 (s, 3H), 2.86 (t, ³J = 6.5 Hz, 2H), 3.48 (d, ³J = 6.5 Hz, 2H), 6.82 (b, NH), 7.26–7.32 (m, 10H), 7.49–7.67 (m, 5H), 7.73–7.86 (m, 3H). ¹³C NMR (75.4 MHz, DMSO): δ = 21.4, 33.6, 41.3, 126.5, 126.6, 127.6, 128.5, 128.6, 128.8, 128.9, 129.1, 129.2, 129.6, 130.0, 132.2, 133.3, 136.1, 140.0, 141.3, 156.2, 166.4, 186.0. MS(ESI) m/z: 544 for C₃₀H₂₆ClN₃OS₂

(Z)-benzoyl(phenethyl)carbamothioic (Z)-4-chloro-N-phenylbenzohydrazonic thioanhydride (3c)

White powder; yield 70%; m.p. 161°C. IR (KBr) (ν_max/cm − 1): 3342, 1638, 1577, 1483, 1269, 1234, 1057, 745, 664, 497. ¹H NMR (300.1 MHz, CDCl₃): δ = 2.97 (t, ³J = 6.9 Hz, 2H), 3.76 (t, ³J = 6.9 Hz, 2H), 6.37 (b, NH), 7.26–7.69 (m, 13H), 7.71–7.75 (m, 4H), 7.84 (d, ³J = 7.9 Hz, 2H). ¹³C NMR (75.4 MHz, CDCl₃): δ = 35.7, 41.2, 125.8, 126.6, 126.9, 127.1, 127.8, 128.6, 128.7, 128.8, 129.0, 129.3, 129.6, 131.5, 134.5, 137.9, 138.6, 138.9, 156.0, 167.6, 185.9. MS(ESI) m/z: 530 for C₂₉H₂₄ClN₃OS₂

(Z)-benzoyl(phenethyl)carbamothioic (Z)-N-phenylbenzohydrazonic thioanhydride (3d)

White powder; yield 65%; m.p. 117°C. IR (KBr) (ν_max/cm − 1): 3334, 1630, 1576, 1528, 1483, 1249, 1214, 984, 737, 653. ¹H NMR (300.1 MHz, CDCl₃): δ = 2.97 (t, ³J = 7.0 Hz, 2H), 3.75 (t, ³J = 7.0 Hz, 2H), 6.41 (b, NH), 7.26–7.60 (m, 14H), 7.73–7.76 (m, 4H), 7.85 (d, ³J = 7.7 Hz, 2H). ¹³C NMR (75.4 MHz, CDCl₃): δ = 35.7, 41.2, 125.9, 126.6, 126.7, 126.9, 128.5, 128.7, 128.8, 128.9, 129.0, 129.2, 129.3, 131.4, 131.8, 134.5, 138.7, 138.9, 157.3, 167.6, 186.0. MS(ESI) m/z: 495 for C₂₉H₂₅N₃OS₂

(Z)-(4-chlorobenzoyl)(phenethyl)carbamothioic (Z)-N-phenylbenzohydrazonic thioanhydride (3e)

White powder; yield 68%; m.p. 106°C. IR (KBr) (ν_max/cm − 1): 3339, 1636, 1525, 1514, 1453, 1268, 1212, 1035, 728, 642, 587. ¹H NMR (300.1 MHz, CDCl₃): δ = 2.94 (t, ³J = 6.9 Hz, 2H), 3.70 (t, ³J = 6.9 Hz, 2H), 6.45 (b, NH), 7.17–7.86 (m, 19H). ¹³C NMR (75.4 MHz, CDCl₃): δ = 35.6, 41.2, 126.5, 126.6, 127.6, 128.5, 128.6, 128.8, 128.9, 129.1, 129.2, 129.6, 130.0, 132.2, 133.3, 136.1, 140.0, 141.3, 158.8, 166.5, 186.0. MS(ESI) m/z: 530 for C₂₉H₂₄ClN₃OS₂

(Z)-(Z)-4-chloro-N-phenylbenzohydrazonic (4-chlorobenzoyl)(phenethyl)carbamothioic thioanhydride (3f)

White powder; yield 70%; m.p. 121°C. IR (KBr) (ν_max/cm − 1): 3312, 1612, 1544, 1509, 1476, 1251, 1208, 985, 714, 686. ¹H NMR (300.1 MHz, CDCl₃): δ = 2.94 (t, ³J = 7.0 Hz, 2H), 3.69 (t, ³J = 7.0 Hz, 2H), 6.48 (b, NH), 6.96–8.12 (m, 18H). ¹³C NMR (75.4 MHz, CDCl₃): δ = 35.6, 41.2, 113.5, 121.4, 125.8, 126.6, 127.5, 127.8, 128.6, 128.7, 128.8, 129.0, 129.2, 129.4, 129.6, 132.9, 137.6, 138.8, 157.1, 166.5, 186.0. MS(ESI) m/z: 564.5430 for C₂₉H₂₃Cl₂N₃OS₂

(Z)-benzyl(4-chlorobenzoyl)carbamothioic (Z)-4-chloro-N-phenylbenzohydrazonic thioanhydride (3g)

White powder; yield 72%; m.p. 155°C. IR (KBr) (ν_max/cm − 1): 3335, 1641, 1586, 1509, 1437, 1287, 1247, 1230, 1025, 974, 748, 714, 687, 527. ¹H NMR (300.1 MHz, CDCl₃): δ 4.63 (d, ³J = 5.7 Hz, 2H), 6.63 (b, NH), 7.34–7.43 (m, 8H), 7.46–7.60 (m, 4H), 7.67–7.76 (m, 4H), 7.81–7.84 (m, 2H). ¹³C NMR (75.4 MHz, CDCl₃): δ 44.2, 125.8, 127.1, 127.7, 127.8, 127.9, 128.4, 128.5, 128.8, 129.0, 129.2, 129.6, 132.7, 137.7, 138.0, 138.5, 157.1, 166.3, 185.9. MS(ESI) m/z: 550 for C₂₈H₂₁Cl₂N₃OS₂

(Z)-benzyl(4-chlorobenzoyl)carbamothioic (Z)-N-phenylbenzohydrazonic thioanhydride (3h)

White powder; yield 70%; m.p. 143°C. IR (KBr) (ν_max/cm − 1): 3310, 1638, 1592, 1551, 1483, 1449, 1318, 1295, 1275, 1090, 988, 735, 711, 575. ¹H NMR (300.1 MHz, CDCl₃): δ 4.63(d, ³J = 5.6 Hz, 2H), 6.651 (b, NH), 7.32–7.43 (m, 8H), 7.49–7.60 (m, 5H), 7.74–7.77 (m, 4H), 7.83 (d, ³J = 7.0 Hz, 2H). ¹³C NMR (75.4 MHz, CDCl₃): δ 44.2, 125.8, 126.7, 127.72, 127.9, 128.5, 128.6, 128.8, 129.0, 129.2, 129.3, 131.8, 132.7, 137.8, 138.0, 138.7, 157.3, 166.3, 186.0. MS(ESI) m/z: 516 for C₂₈H₂₂ClN₃OS₂

(Z)-benzoyl(benzyl)carbamothioic (Z)-N-phenylbenzohydrazonic thioanhydride (3i)

White powder; yield 66%; m.p. 136°C. IR (KBr) (ν_max/cm − 1): 3317, 1641, 1583, 1549, 1465, 1451, 1276, 1234, 1064, 721, 675. ¹H NMR (300.1 MHz, CDCl₃): δ = 4.66 (d, ³J = 5.6 Hz, 2H), 6.57 (b, NH), 7.17–7.87 (m, 20H). ¹³C NMR (75.4 MHz, CDCl₃): δ = 44.1, 113.5, 121.4, 125.8, 126.9, 127.6, 127.8, 127.9, 128.6, 128.7, 128.8, 129.0, 129.2, 129.6, 131.6, 134.3, 138.1, 155.9, 167.9, 185.9. MS(ESI) m/z: 516 for C₂₈H₂₂ClN₃OS₂

Acknowledgements

We thank the Bushehr Branch, Islamic Azad University for support.

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You are reading this latest preprint version

A new synthesis of (Z)-arylbenzoyl(phenethyl)carbamothioic-N-phenylbenzohydrazonic thioanhydride derivatives by reaction of secondary amides, carbon disulfide and hydrazonoyl chlorides

Status:

Version 1

Abstract

Introduction

Results and Discussion

Conclusion

Experimental

General Experimental Information

(Z)-benzoyl(phenethyl)carbamothioic (Z)-4-chloro-N-phenylbenzohydrazonic thioanhydride (3c)

(Z)-benzoyl(phenethyl)carbamothioic (Z)-N-phenylbenzohydrazonic thioanhydride (3d)

(Z)-(4-chlorobenzoyl)(phenethyl)carbamothioic (Z)-N-phenylbenzohydrazonic thioanhydride (3e)

(Z)-(Z)-4-chloro-N-phenylbenzohydrazonic (4-chlorobenzoyl)(phenethyl)carbamothioic thioanhydride (3f)

(Z)-benzyl(4-chlorobenzoyl)carbamothioic (Z)-4-chloro-N-phenylbenzohydrazonic thioanhydride (3g)

(Z)-benzyl(4-chlorobenzoyl)carbamothioic (Z)-N-phenylbenzohydrazonic thioanhydride (3h)

(Z)-benzoyl(benzyl)carbamothioic (Z)-N-phenylbenzohydrazonic thioanhydride (3i)

Declarations

Acknowledgements

References

Schemes

Supplementary Files

Status:

Version 1