Introduction

Acylhydrazines (RCONHNH2) and diacylhydrazines (RCONHNHCOR′) have attracted considerable attention for decades as important organic synthons [1, 2]. Recently, many compounds containing these moieties have been reported which exhibit extensive application in biological activities such as antibacterial, antifungal [3], anticancer [4], herbicidal [5] and larvicidal [6] activities. N-tert-Butyl-N,N′-diacylhydrazines discovered by Rohm and Haas Co., with their high insecticidal activities and low toxicity to nontarget organisms such as mammalians, have attracted considerable attention in recent years [7]. Tebufenozide, methoxyfenozide, halofenozide and chromafenozide are commercial insecticides and pesticides (Fig. 1).

Fig. 1
figure 1

Commercial insecticides and pesticides contain diacylhydrazine moiety

Full size image

Meanwhile, some compounds bearing a diacylhydrazine unit have been reported as polo-like kinase 1 (PLK1) [8] and malarial plasmepsin [9] inhibitors. It’s worthy of attention that diacylhydrazines have been used as ligands to promote CuI-catalyzed C–N cross-coupling reactions of aryl bromides with N-heterocycles [10].

Generally, acylhydrazines can be obtained by reaction of hydrazine with acyl chlorides or esters [11, 12]. Reaction of acylhydrazines with acyl chlorides or esters has been commonly used for synthesis of diacylhydrazines [13, 14].

Some acyl halides are not commercially available, difficult to prepare or unstable. To promote this transformation from carboxylic acid, some acid activators have been used, including DCC [15], polyphosphoric acid [16] and PhOPCl2 [17]. But some of these reagents are expensive, not readily available, hygroscopic and moisture-sensitive. Low yield, unnecessary waste and painful chromatographic separation are other disadvantages of these reagents.

(Chloromethylene)dimethylammonium chloride (Vilsmeier reagent) 1 has been found to be useful in formylation, dehydration, chlorination, and other reactions [18–21]. It has also emerged as a convenient reagent in the synthesis of β-sultams [22] and β-lactams [23–25]. Vilsmeier reagent is easily prepared as a white solid by reaction of N,N-dimethylformamide (DMF) and chlorinating agents such as (COCl2) or SOCl2 in dry CH2Cl2 [23]. This reagent can be kept for a long time by storage in a well-capped bottle which is also commercially available.

In this paper, we described the use of Vilsmeier reagent as an efficient and versatile reagent for one-pot synthesis of acylhydrazines and symmetrical and asymmetrical diacylhydrazines from carboxylic acids.

Experimental

Materials and methods

All required chemicals were purchased from Merck, Aldrich and Acros chemical companies. The melting points were determined on a silicone oil bath and are uncorrected. IR spectra were measured on a galaxy series FT-IR 5000 spectrometer. NMR spectra were recorded in DMSO-d6 using a Bruker spectrophotometer (1H NMR 300 MHz, 13C NMR 75 MHz) using tetramethylsilane as an internal standard, and coupling constants were given in cycles per second (Hz). Elemental analyses were run on a Vario EL III elemental analyzer. Thin-layer chromatography (TLC) was carried out on silica gel 254 analytical sheets obtained from Fluka.

General procedure for synthesis of acylhydrazines 2–5

A solution of carboxylic acid (1.0 mmol), Vilsmeier reagent (1.0 mmol) and Et3N (3.0 mmol) in dry CH2Cl2 (10 mL) at room temperature was added to a solution of hydrazine hydrate (4.0 mmol) in dry CH2Cl2 (5 mL) and the mixture was stirred 7 h. The mixture was washed successively with saturated NaHCO3 (15 mL) and brine (15 mL). The organic layer was dried (Na2SO4), filtered and the solvent was removed under reduced pressure to give the crude products. The crude residues were purified by crystallization from ethanol 95 %. Spectral data for 2–5 have been previously reported [26–29].

General procedure for synthesis of symmetrical diacylhydrazines 6–16

Hydrazine hydrate (0.2 mmol) was added to a solution of carboxylic acid (1.0 mmol), Vilsmeier reagent (1.0 mmol) and Et3N (4.0 mmol) in dry CH3CN (15 mL) at room temperature and the mixture was stirred 7 h. Saturated NaHCO3 (15 mL) was added and the mixture was extracted with EtOAc (3 × 15 mL). The organic layer was washed with brine (20 mL), dried (Na2SO4), filtered and the solvent was removed under reduced pressure to give the crude products. The crude residues were purified by crystallization from ethanol 95 %. Spectral data for 6–7, 10, 13 and 15 have been previously reported [30–34].

2-(4-Chlorophenoxy)-N′-(2-(4-chlorophenoxy)acetyl)acetohydrazide (8)

White solid. mp: 130–132 °C. IR (KBr) cm−1: 1633 (CO), 3294 (NH); 1H NMR δ 4.70 (2CH2, s, 4H), 6.78–7.28 (ArH, m, 8H), 9.86 (2NH, s, 2H); 13C NMR δ 65.4 (CH2), 115.9, 127.1, 129.3, 157.2 (aromatic carbons), 168.7 (CO). Anal. Calcd for C16H14Cl2N2O4: C, 52.05; H, 3.82; N, 7.59. Found: C, 52.18; H, 3.93; N, 7.67.

2-(1,3-Dioxoisoindolin-2-yl)-N′-(2-(1,3-dioxoisoindolin-2-yl)acetyl)acetohydrazide (9)

Off-white solid. mp >210 °C. IR (KBr) cm−1: 1640 (CO), 1735, 1776 (CO, Phth), 3330 (NH); 1H NMR δ 4.22 (2CH2, s, 4H), 7.47–7.70 (ArH, m, 8H), 9.55 (2NH, s, 2H); 13C NMR δ 46.1 (CH2), 125.0, 132.0, 132.4 (aromatic carbons), 168.7 (CO, phth), 170.4 (CO). Anal. Calcd for C20H14N4O6: C, 59.12; H, 3.47; N, 13.79. Found: C, 59.28; H, 3.60; N, 13.86.

3-Hydroxy-N′-(3-hydroxy-2-naphthoyl)-2-naphthohydrazide (11)

White solid. mp: 153–155 °C IR (KBr) cm−1: 1639 (CO), 3050–3397 (OH), 3415 (NH); 1H NMR δ 7.34–7.91 (ArH, m, 12H), 9.93 (2NH, s, 2H), 11.33 (2OH, s, 2H); 13C NMR δ 113.1, 121.6, 123.4, 126.7, 128.8, 130.2, 130.4, 132.5, 136.6, 155.4 (aromatic carbons), 165.3 (CO). Anal. Calcd for C22H16N2O4: C, 70.96; H, 4.33; N, 7.52. Found: C, 71.06; H, 4.43; N, 7.47.

3-Hydroxy-N′-(3-hydroxybenzoyl)benzohydrazide (12)

White solid. mp: 99–101 °C. IR (KBr) cm−1: 1632 (CO), 3154–3659 (NH, OH); 1H NMR δ 6.93–7.47 (ArH, m, 8H), 10.43 (2NH, s, 2H), 11.59 (2OH, s, 2H); 13C NMR δ 114.3, 120.7, 122.1, 130.5, 133.8, 157.2 (aromatic carbons), 166.7 (CO). Anal. Calcd for C14H12N2O4: C, 61.76; H, 4.44; N, 10.29. Found: C, 61.68; H, 4.50; N, 10.22.

N′-(2,6-Dimethoxybenzoyl)-2,6-dimethoxybenzohydrazide (14)

Off-white solid. mp: 158–160 °C. IR (KBr) cm−1: 1637 (CO), 3441 (NH); 1H NMR δ 3.71 (4 OMe, s, 12H), 6.77–7.45 (ArH, m, 6H), 9.72 (2NH, s, 2H); 13C NMR δ 55.4 (CH3), 123.4, 128.5, 133.9, 148.5 (aromatic carbons), 166.9 (CO). Anal. Calcd for C18H20N2O6: C, 59.99; H, 5.59; N, 7.77. Found: C, 60.11; H, 5.74; N, 7.70.

2-Methoxy-N′-(2-methoxyacetyl)acetohydrazide (16)

White solid. mp: 52–54 °C. IR (KBr) cm−1: 1644 (CO), 3227 (NH); 1H NMR δ 3.29 (2OMe, s, 6H), 4.14 (2CH2, s, 4H), 9.35 (2NH, s, 2H); 13C NMR δ 58.7 (OMe), 70.0 (CH2), 171.8 (CO). Anal. Calcd for C6H12N2O4: C, 40.91; H, 6.87; N, 15.90. Found: C, 41.04; H, 6.99; N, 15.96.

General procedure for synthesis of asymmetrical diacylhydrazines 17–26

Acylhydrazines 2–5 (1.0 mmol) was added to a solution of carboxylic acid (1.5 mmol), Vilsmeier reagent (1.5 mmol) and Et3N (5.0 mmol) in dry CH3CN (15 mL) at room temperature and the mixture was stirred 6 h. Saturated NaHCO3 (20 mL) was added and the mixture was extracted with EtOAc (3 × 15 mL). The organic layer was washed with brine (20 mL), dried (Na2SO4), filtered and the solvent was removed under reduced pressure to give the crude products. The crude residues were purified by crystallization from ethanol 95 %. The data for 19 has been previously reported [35].

2-(4-Chlorophenoxy)-N′-(2-phenoxyacetyl)acetohydrazide (17)

White solid. mp: 130–132 °C. IR (KBr) cm−1: 1635 (CO), 3199 (NH); 1H NMR δ 4.61, 4.64 (2 CH2, 2 s, 4H), 6.84–7.32 (ArH, m, 9H), 9.72, 9.87 (2 NH, 2 s, 2H); 13C NMR δ 60.3, 65.9 (CH2) 115.9, 116.0, 122.3, 126.9, 129.0, 129.5, 157.1, 159.4 (aromatic carbons) 168.9, 176.4 (CO). Anal. Calcd for C16H15ClN2O4: C, 57.41; H, 4.52; N, 8.37. Found: C, 57.55; H, 4.69; N, 8.44.

2-Methoxy-N′-(2-phenoxyacetyl)acetohydrazide (18)

White solid. mp: 81–83 °C. IR (KBr) cm−1: 1639 (CO), 3214 (NH); 1H NMR δ 3.32 (OMe, s, 3H), 4.19, 4.73 (2 CH2, 2 s, 4H), 6.79–7.25 (ArH, m, 5H), 9.59, 9.63 (2 NH, 2 s, 2H); 13C NMR δ 57.7 (OMe), 66.2, 69.7 (CH2), 115.9, 122.5, 129.6, 159.3 (aromatic carbons), 169.1, 172.2 (CO). Anal. Calcd for C11H14N2O4: C, 55.46; H, 5.92; N, 11.76. Found: C, 55.41; H, 6.03; N, 11.70.

2-(4-Chlorophenoxy)-N′-(2-(2,4-dichlorophenoxy)acetyl)acetohydrazide (20)

White solid. mp: 146–148 °C. IR (KBr) cm−1: 1636 (CO), 3217 (NH); 1H NMR δ 4.69, 4.80 (2 CH2, 2 s, 4H), 6.90–7.45 (ArH, m, 7H), 9.50, 10.10 (2 NH, 2 s, 2H); 13C NMR δ 65.6, 65.9 (CH2), 115.5, 117.2, 125.7, 127.1, 128.4, 128.7, 129.2, 130.8, 153.5, 157.4 (aromatic carbons), 169.0, 174.1 (CO). Anal. Calcd for C16H13Cl3N2O4: C, 47.61; H, 3.25; N, 6.94. Found: C, 47.55; H, 3.13; N, 6.86.

2-(2,4-Dichlorophenoxy)-N′-(2-methoxyacetyl)acetohydrazide (21)

White solid. mp: 77–79 °C. IR (KBr) cm−1: 1637 (CO), 3225 (NH); 1H NMR δ 3.44 (OMe, s, 3H), 4.14, 4.75 (2 CH2, 2 s, 4H), 6.71–7.34 (ArH, m, 3H), 9.15, 9.37 (2 NH, 2 s, 2H); 13C NMR δ 58.8 (OMe), 65.9, 69.0 (CH2), 117.3, 125.3, 128.5, 128.8, 130.8, 153.3 (aromatic carbons), 168.0, 171.0 (CO). Anal. Calcd for C11H12Cl2N2O4: C, 43.02; H, 3.94; N, 9.12. Found: C, 43.15; H, 4.11; N, 9.20.

2-(Naphthalen-2-yloxy)-N′-(2-phenoxyacetyl)acetohydrazide (22)

White solid. mp: 142–144 °C. IR (KBr) cm−1: 1650 (CO), 3216 (NH); 1H NMR δ 4.60, 4.72 (2 CH2, 2 s, 4H), 6.96–7.87 (ArH, m, 12H), 9.65, 9.74 (2 NH, 2 s, 2H); 13C NMR δ 64.0, 65.3 (CH2), 109.9, 115.7, 117.6, 121.5, 124.0, 127.2, 127.3, 128.7, 129.4, 129.5, 131.1, 135.2, 156.1, 159.2 (aromatic carbons), 168.7, 175.6 (CO). Anal. Calcd for C20H18N2O4: C, 68.56; H, 5.18; N, 8.00. Found: C, 68.64; H, 5.31; N, 7.92.

2-(4-Chlorophenoxy)-N′-(2-(naphthalen-2-yloxy)acetyl)acetohydrazide (23)

White solid. mp: 146–148 °C. IR (KBr) cm−1: 1638 (CO), 3246 (NH); 1H NMR δ 4.63, 4.80 (2 CH2, 2 s, 4H), 6.85–7.56 (ArH, m, 11H), 9.49, 9.63 (2 NH, 2 s, 2H); 13C NMR δ 60.4, 65.4 (CH2), 110.0, 116.0, 117.6, 124.0, 127.1, 127.2, 127.3, 128.8, 129.3, 129.4, 131.1, 135.2, 156.0, 157.2 (aromatic carbons), 168.7, 174.3 (CO). Anal. Calcd for C20H17ClN2O4: C, 62.42; H, 4.45; N, 7.28. Found: C, 62.51; H, 4.58; N, 7.23.

2-(2,4-Dichlorophenoxy)-N′-(2-(naphthalen-2-yloxy)acetyl)acetohydrazide (24)

White solid. mp: 170–172 °C. IR (KBr) cm−1: 1643 (CO), 3225 (NH); 1H NMR δ 4.72, 4.81 (2 CH2, 2 s, 4H), 6.79–8.00 (ArH, m, 10H), 9.96, 9.97 (2 NH, 2 s, 2H); 13C NMR δ 65.6, 65.9 (CH2), 117.2, 117.7, 123.9, 125.6, 127.1, 127.2, 127.3, 127.4, 128.5, 128.6, 128.7, 129.3, 130.8, 131.0, 135.0, 156.0 (aromatic carbons), 168.6, 175.5 (CO). Anal. Calcd for C20H16Cl2N2O4: C, 57.30; H, 3.85; N, 6.68. Found: C, 57.25; H, 3.94; N, 6.71.

2-Methoxy-N′-(2-(naphthalen-2-yloxy)acetyl)acetohydrazide (25)

White solid. mp: 158–160 °C. IR (KBr) cm−1: 1649 (CO), 3254 (NH); 1H NMR δ 3.36 (OMe, s, 3H), 4.16, 4.80 (2 CH2, 2 s, 4H), 7.05–7.75 (ArH, m, 7H), 9.35, 9.94 (2 NH, 2 s, 2H); 13C NMR δ 58.8 (OMe), 65.3, 69.7 (CH2), 109.7, 117.8, 124.4, 127.0, 127.3, 128.8, 129.4, 131.1, 135.1, 156.3 (aromatic carbons), 168.8, 171.7 (CO). Anal. Calcd for C15H16N2O4: C, 62.49; H, 5.59; N, 9.72. Found: C, 62.62; H, 5.75; N, 9.80.

2-(4-Chlorophenoxy)-N′-(2-methoxyacetyl)acetohydrazide (26)

White solid. mp: 114–116 °C. IR (KBr) cm−1: 1631 (CO), 3228 (NH); 1H NMR δ 3.32 (OMe, s, 3H), 4.17, 4.79 (2 CH2, 2 s, 4H), 6.74–7.27 (ArH, m, 4H), 8.58, 8.62 (2 NH, 2 s, 2H); 13C NMR δ 57.4 (OMe), 66.1, 68.2 (CH2), 115.9, 127.2, 129.4, 157.3 (aromatic carbons), 168.7, 171.7 (CO). Anal. Calcd for C11H13ClN2O4: C, 48.45; H, 4.81; N, 10.27. Found: C, 48.58; H, 4.97; N, 10.21.

Results and discussion

Reaction of carboxylic acids with Vilsmeier reagent in the absence of any nucleophile gives acyl chlorides [36]. Initially, we set up a model reaction with phenoxyacetic acid (1 mmol), triethylamine (3 mmol), Vilsmeier reagent 1 (1 mmol), and hydrazine hydrate (4 mmol) in dry dichloromethane at room temperature. After workup and crystallization from ethyl acetate, 2-phenoxyacetohydrazide 2 was obtained at a 91 % yield. According to this result, acylhydrazines 2–5 were prepared in one stage from carboxylic acids with excellent yields (Scheme 1).

Scheme 1
scheme 1

Synthesis of acylhydrazines 2–5

Full size image

In this method acylhydrazines are formed not from the acyl halides or esters but directly from the carboxylic acids. The by-products are DMF and triethylamine hydrochloride salt which both are easily removed by aqueous workup.

Preparation of diacylhydrazines from acylhydrazines by the general procedure and successful results obtained from one-pot synthesis of acylhydrazines promoted us to undertake one-pot synthesis of symmetrical diacylhydrazines directly from the carboxylic acids. Treatment of phenoxyacetic acid, triethylamine and Vilsmeier reagent 1 with hydrazine hydrate in dry dichloromethane at room temperature gave 2-phenoxy-N′-(2-phenoxyacetyl)-acetohydrazide 6 at a low yield. This reaction was performed in dry acetonitrile and the mixture was washed with saturated sodium hydrogen carbonate. Extraction by ethyl acetate and crystallization from ethanol gave diacylhydrazine 6 with an 89 % yield.

Symmetrical diacylhydrazine 6–16 were synthesized by this method from corresponding carboxylic acids and hydrazine (Table 1). Progress of reactions was checked by TLC monitoring. All products were confirmed by spectral data.

Table 1 One-pot synthesis of symmetrical diacylhydrazines 6–16 from carboxylic acids
figure a
Full size table

Acylhydrazines 2–5 were reacted with a solution of corresponding carboxylic acids, triethylamine and reagent 1 in dry acetonitrile. Asymmetrical diacylhydrazines 17–26 were obtained with good to excellent yields after usual work up and crystallization from ethanol 95 % (Table 2). In this method, Vilsmeier reagent is a versatile and convenient reagent because of reducing by-product formation and a simplifying work-up.

Table 2 Synthesis of asymmetrical diacylhydrazines 17–26
figure m
Full size table

According to the reported mechanism in the literature for [22], the mechanism below is proposed (Scheme 2).

Scheme 2
scheme 2

Proposed mechanism

Full size image

Conclusion

In summary, Vilsmeier reagent serves as a convenient and effective reagent for synthesis of acylhydrazines. In addition, one-pot synthesis provides easy and versatile methods for obtaining pure symmetrical and asymmetrical diacylhydrazines in good to excellent yields under simple and mild conditions. The use of Vilsmeier reagent eliminates the need to handle and prepare acyl halides. This method is very efficient particularly for larger-scale applications because the side-products (DMF and triethylamine hydrochloride salt) are easily removed by aqueous work-up.