Reaction of Some Substituted (Un)Substituted Isatins with 1,ω-Alkanes and Their Products with Sodium Azide ^†

Abstract

Azide derivatives of isatins were the initial materials needed for click chemistry, so as to form 1,2,3-triazoles in order to synthesize the hybrid compounds of 1,2,3-triazole–isatin with monosaccharide moieties. The required substituted isatins were prepared according to the Sandmeyer method from corresponding substituted anilines. N-(ω-bromoalkyl) isatins were prepared through the nucleophilic reaction, S_N2, of (un)substituted isatins with appropriate dibromoalkanes. Some ω-azidoalkylisatins were synthesized by the reaction of corresponding ω-bromoalkylisatins with sodium azide. The reactions were performed in dry DMF as solvents in the presence of K₂CO₃ as the base and KI as the promoting agent. The product yields reached 30–85%.

1. Introduction

The chemistry of isatin is of interest to chemists [1] because the derivatives of isatin, such as hydrazones [2] and thiosemicarbazones [3], and hybrid compounds containing simultaneous isatin rings and other heterocycles, have diverse biological activities [4,5,6], including antiviral, antibacterial, anticancer, anticonvulsant, and antidepressant activity [7,8,9]. Isatin and its derivatives showed specific reactivity towards electrophiles [6,10], including alkyl halides (N-alkylation), formaldehyde and amines (Mannich reaction), halogens (halogenation on the aromatic nucleus), acyl chlorides or anhydrides (N-acylation), and sulfonyl chlorides (N-sulfonylation). Among the reactions of isatin, the substitution of the reactions of hydrogen atoms with N–H bonds on position N-1 was shown to be particularly important [6,10]. An alkylation reaction was used in order to functionalize isatin and its derivatives and was carried out by reactions with alkyl halide in the presence of bases (such as sodium or calcium hydrides, potassium or cesium carbonates) [11]. A variety of methods have been developed for the N-alkylation of isatins to target products with high yields, such as iodin and tert-butyl hydroperoxide in DMSO as solvent (to produce isatin N-methyl and N-benzyl isatins) [12], 2-iodoxybenzoic acid-SO₃K in DMSO–water at 60 °C (to produce isatin N-methyl and N-benzyl isatins) [13], and oxygen and tert-butyl nitrite in THF (to produce isatin, N-methyl, N-phenyl, N-benzyl, and N-Boc isatins) [14]. However, these methods cannot be used for the synthesis of isatins with the N-propargyl group because 1-alkyne can be changed under these reaction conditions. By using this method, direct N-alkylation was performed easily and produced high yields of N-alkyl isatins [11,15,16]. Some of the more general methods include the use of sodium hydride for substrate activation in nucleophilic substitution reactions in DMF at 25–80 °C [17], as well as the use of the following bases: calcium hydride in DMF at 40–60 °C for 2–4 h with yields of 21–96% [18,19], or at 100 °C for 4 h, with a yield of 89% [20]; anhydrous K₂CO₃ or Cs₂CO₃ in DMF (r.t. at 80 °C for 5–24 h) in the presence of KI, with yields of 25–93% [21]; K₂CO₃/DMF (with yields of 76–94%) or NaOEt/EtOH (with yields of 24–81%) in a domestic microwave oven [15]; and K₂CO₃ or Cs₂CO₃, DMF or N-methyl-2-pyrrolidinone (NMP) [11], and K₂CO₃/KI in acetonitrile under microwave conditions (160 °C, 10 min) [22], and in DMF at 150 °C for 5–15 min under microwave irradiation, with product yields of 53–96% [23].

Among N-alkyl isatins, N-(ω-azidoalkyl) isatins play an important role in the conversion of isatin rings into isatin/1,2,3–triazole hybrid compounds [24,25,26,27]. Isatin derivatives with azido groups or 1-alkyne components (N-propargylated isatins) are one of two reagents necessary for click chemistry [28,29,30,31]. The synthesis of N-functionalized isatins with a ω-azidoalkyl group made these derivatives the azido components in click chemistry. Therefore, in this article, we report on the synthesis of some (un)substituted 2-amino-7-hydroxy-4H-chromene-3- carbonitriles via a one-pot, three-component reaction in aqueous media (Scheme 1 and Scheme 2).

2. Results and Discussion

With the exception of isatin that could not be made available for use (for the preparation of ω-bromoalkyl compounds 4f–g and ω-azidoalkyl compounds 5f–g, respectively), the remaining isatins (3a–g) were synthesized from anilines corresponding to 1a–g, containing appropriate substituents, by the Sandmeyer reaction of the N-isonitrosoacetanilide derivatives 2a–g (Scheme 1). The 2a–e compounds were easily obtained through the reaction of these anilines with chloral hydrate and hydroxylamine in a solution of saturated sodium sulfate [32,33]. The N-(ω-bromoalkyl) isatin derivatives were synthesized through the nucleophile reaction of the corresponding 1,ω-dibromoalkane derivatives to the appropriate isatins (Scheme 2). This alkylization reaction was carried out in the dry DMF solvent in the presence of anhydrous potassium carbonate as a base. Potassium iodide was added in order to promote this nucleophilic substituted reaction. The reaction was carried out by stirring the reaction mixture at temperatures of 25–27 °C.

Next, the ω-bromoalkylisatins 4a–g were converted into ω-azidoalkyl derivatives through a reaction with sodium azide. The potassium iodide was also used as a promoter for this reaction. The reaction was carried out by heating on a water-bath at 70 °C. The reaction times were 1.5–3 h. The end of the reaction was determined by TLC with the solvent system of n-hexane/ethyl acetate at a ratio of 7:3 (in volume). The results are represented in

Table 1. Synthesis of ω-azidoalkyl derivatives 5a–g.

Compound	R	n	Reaction Time (h)	Yield (%)
5a	5-Me	4	1.5	79
5b	7-Me	4	1.5	46
5c	5-Et	4	2	70
5d	5-iPr	4	2	85
5e	5-F	3	1.5	62
5f	H	3	1,5	35
5g	H	4	3	76

.

The formation of azide derivatives from the corresponding bromo derivatives of the aforementioned isatins was identified by the IR spectra. Figure 1 displays the IR spectra comparison of representative compounds, including N-(4-bromoprop) isatin and the corresponding azide derivative, N-(4-azidopropyl) isatin. This showed that the stretching vibrations of the two functional groups, C=O of lactam and C=O ketone, were virtually unchanged, whereas a strong absorption band appeared at ν = 2092 cm⁻¹ in the IR spectrum of the azide derivative. This confirmed that the conversion of the bromide derivatives into the azide derivatives was successful. The ketone carbonyl group of 5a–g compounds was characteristically absorbed in the region at ν = 1738–1726 cm⁻¹. The characteristic band of the >C=O lactam group was located in the ν = 1622–1620 cm⁻¹ region; in some cases, this absorption band was superimposed by the stronger absorption band of the ketone carbonyl group.

The ¹H NMR spectra of the 5a–g compounds showed the resonance signals of all the protons in the molecule, including signals in the δ = 7.66–7.04 ppm region for the aromatic protons (Figure 2). The methylene protons in the alkane chains attached to the nitrogen atoms of the isatin appeared in the region at δ= with δ = 4.05–3.67 ppm for the methylene groups associated with the nitrogen–isatin. The methylene group associated with the azido group had signals located at the upfield, at δ = 3.39–3.36 ppm. The methylene groups in the middle of the alkane chains had chemical shifts in the higher fields (δ = 1.69–1.18 ppm). The alkyl groups attached to the benzene aromatic rings had distinct resonance signals; for example, the 5-methyl group had δ = 2.27 ppm, and the 7-methyl group had δ = 2.48 ppm.

3. Conclusions

N-(ω-bromoalkyl) isatins were synthesized from appropriate isatins and converted into corresponding N-(ω-azidoalkyl) isatin derivatives with yields of 35–85%. The structures of the azide derivatives were confirmed by IR spectrum and 1H NMR.

4. Experimental Procedure

The melting points were determined by the open capillary method on STUART SMP3 (BIBBY STERILIN, UK). The IR spectra were recorded by FT-IR Affinity-1S Spectrometer (Shimadzu, Japan) in KBr pellet. The ¹H NMR spectra were recorded at 500 MHz (on an Avance AV500 Spectrometer, Bruker, Bremene, Germany) and at 600 MHz (on an AvanceNEO Spectrometer, Bruker, Germany), and ¹³C NMR spectra at 125 and 160 MHz, respectively, using DMSO-d₆ as solvent and TMS as an internal standard. ESI-mass spectra were recorded on LC-MS LTQ Orbitrap XL (Thermo Fisher Scientific Inc., USA) in methanol/dichloromethane or methanol using ESI method. The analytical thin-layer chromatography (TLC) was performed on silica gel 60WF₂₅₄ No. 5715 aluminum sheets (Merck, Germany) with toluene:ethyl acetate (1:1 by volume) as solvent system, and spots were visualized directly due to the colors of the corresponding isatin derivatives. All chemical reagents were high in purity (reagent grade for organic synthesis) and purchased from the Merck Chemical Company.

General Procedure for Synthesis of N-(ω-azidoalkyl) Isatins (5a–g)

A reaction mixture consisting of N-(ω-bromoalkyl) isatins (4a–g, 1 mmol), sodium azide (1.5 mmol, 945 mg), and some KI crystals in anhydrous DMF (5 mL) was stirred in a water-bath at a temperature of 70–75 °C for 1.5–3 h. The reaction was monitored by thin-layer chromatography. After the reaction finished, water (10 ml) was added to the mixture to quench the reaction and to dissolve the inorganic salts. The mixture was extracted with ethyl acetate (3×5 mL). The combined extract was dried with anhydrous sodium sulfate. The drying agent was filtered out. After distilling the solvent, the product was isolated from the residue by column chromatography on silica gel with the appropriate solvent system.

N-(4-azidobutyl)-5-methylisatin (5a): From 4a (1 mmol, 296 mg). Yield: 204 mg. M.p. 48–50 °C. IR (KBr), ν (cm⁻¹): 2928, 2867, 2098, 1737, 1622, 1599, 1491, 1346, and 822; ¹H NMR (DMSO-d₆), δ (ppm): 7.45 (d, J = 2.0, 8.0 Hz, 1H, H-6), 7.34 (d, J = 2.0 Hz, 1H, H-4), 7.08 (d, J = 8.0 Hz, 1H, H-7), 3.66 (t, J = 6.75 Hz, 2H, >NCH₂CH₂CH₂CH₂N₃), 3.36 (t, J = 6.5 Hz, 2H, >NCH₂CH₂CH₂CH₂N₃), 2.27 (s, 3H, 5-CH₃), 1.68–1.63 (m, 2H, >NCH₂CH₂CH₂CH₂N₃), and 1.61–1.56 (m, 2H, >NCH₂CH₂CH₂CH₂N₃).

N-(4-azidobutyl)-7-methylisatin (5b): From 4b (1 mmol, 296 mg). Yield: 119 mg. IR (KBr), ν (cm⁻¹): 3024, 2939, 2870, 2092, 1726, 1597, 1485, 1346, 1305, and 781; ¹H NMR (DMSO-d₆), δ (ppm): 7.46 (d, J = 7.0 Hz, 1H, H-4), 7.40 (dd, J = 1.5, 7.0 Hz, 1H, H-6), 7.04 (t, J = 7.0 Hz, 1H, H-5), 3.85 (t, J = 7.0 Hz, 2H, >NCH₂CH₂CH₂CH₂N₃), 3.39 (t, J = 7.75 Hz, 2H, >NCH₂CH₂CH₂CH₂N₃), 2.48 (s, 3H, 7-CH₃), 1.69–1.66 (m, 2H, >NCH₂CH₂CH₂CH₂N₃), and 1.65–1.59 (m, 2H, >NCH₂CH₂ CH₂CH₂N₃).

N-(4-azidobutyl)-5-ethylisatin (5c): From 4c (1 mmol, 310 mg). Yield: 190 mg. IR (KBr), ν (cm⁻¹): 2964, 2931, 2870, 2090, 1728, 1618, 1487, 1346, 1168, and 827; ¹H NMR (DMSO-d₆), δ (ppm): 7.51 (dd, J = 1.5, 8.0 Hz, 1H, H-6), 7.38 (d, J = 1.5 Hz, 1H, H-4), 7.11 (d, J = 8.0 Hz, 1H, H-7), 3.67 (t, J = 7.5 Hz, 2H, >NCH₂CH₂CH₂CH₂N₃), 3.36 (t, J = 6.75 Hz, 2H, >NCH₂CH₂CH₂CH₂N₃), 2.58 (q, J = 7.5 Hz, 2H, 5-CH₂CH₃), 1.69–1.63 (m, 2H, >NCH₂CH₂CH₂CH₂N₃), 1.62–1.56 (m, 2H, >NCH₂CH₂CH₂CH₂N₃), and 1.16 (t, J = 7.5 Hz, 3H, 5-CH₂CH₃).

N-(4-azidobutyl)-5-isopropylisatin (5d): From 5d (1 mmol, 324 mg). Yield: 243 mg. IR (KBr), ν (cm⁻¹): 2958, 2868, 2092, 1732, 1620, 1597, 1487, 1352, and 1174; ¹H NMR (DMSO-d₆), δ (ppm): 7.55 (dd, J = 2.0, 8.0 Hz, 1H, H-6), 7.42 (d, J = 2.0 Hz, 1H, H-4), 7.12 (d, J = 8.0 Hz, 1H, H-7), 3.67 (t, J = 6.75 Hz, 2H, >NCH₂CH₂CH₂CH₂N₃), 3.36 (t, J = 6.75 Hz, 2H, >NCH₂CH₂CH₂CH₂N₃), 2.90 [quintet, J = 7.0 Hz, 1H, 5-CH(CH₃)₂], 1.69–1.63 (m, 2H, >NCH₂CH₂CH₂CH₂N₃), 1.61–1.56 (m, 2H, >NCH₂CH₂CH₂CH₂N₃), and 1.19 [d, J = 7.0 Hz, 6H, 5-CHCH₃)₂].

N-(3-azidopropyl)-5-fluoroisatin (5e): From 5e (1 mmol, 286 mg). Yield: 154 mg. IR (KBr), ν (cm⁻¹): 3069, 2933, 2873, 2094, 1730, 1620, 1608, 1481, 1261, 1168, and 823; ¹H NMR (DMSO-d₆), δ (ppm): 7.5 (td, J_FH = 2.75 Hz, J_HH = 9.0 Hz, 1H, H-6), 7.45 (dd, J_HH = 2.5 Hz, J_FH = 7.0 Hz, 1H, H-4), 7.22 (dd, J_FH = 3.75 Hz, J_HH = 9.0 Hz, 1H, H-7), 3.73 (t, J = 6.75 Hz, 2H, >NCH₂CH₂CH₂N₃), 3.44 (t, J = 6.75 Hz, 2H, >NCH₂CH₂CH₂N₃), and 1.84 (quintet, J = 6.75 Hz, 2H, >NCH₂CH₂CH₂N₃).

N-(3-azidopropyl) Isatin (5f): From 5f (1 mmol, 268 mg). Yield: 81 mg (35%). IR (KBr), ν (cm⁻¹): 3062, 2931, 2870, 2092, 1730, 1606, 1467, 1354, 1091, and 754; ¹H NMR (DMSO-d₆), δ (ppm): 7.66 (td, J = 1.5, 8.0 Hz, 1H, H-6), 7.55 (dd, J = 0.5, 7.5 Hz, 1H, H-4), 7.18 (d, J = 8.0 Hz, 1H, H-7), 7.13 (td, J = 0.5, 7.5 Hz, 1H, H-5), 4.05 (t, J = 6.25 Hz, 2H, >NCH₂CH₂CH₂N₃), 3.75 (t, J = 6.25 Hz, 2H, >NCH₂CH₂CH₂N₃), and 1.93 (quintet, J = 6.25 Hz, 2H, >NCH₂CH₂CH₂N₃).

N-(4-azidobutyl) Isatin (5g): From 5g (1 mmol, 282 mg). Yield: 185 mg. IR (KBr), ν (cm⁻¹): 3062, 2935, 2874, 2069, 1738, 1611, 1468, 1360, 1092, and 753; ¹H NMR (DMSO-d₆), δ (ppm): 7.65 (td, J = 1.0, 8.0 Hz, 1H, H-6), 7.53 (d, J = 7.5 Hz, 1H, H-4), 7.19 (d, J = 8.0 Hz, 1H, H-7), 7.12 (t, J = 7.5 Hz, 1H, H-5), 3.69 (t, J = 7.0 Hz, 2H, >NCH₂CH₂CH₂CH₂N₃), 3.56 (t, J = 6.75 Hz, 2H, >NCH₂CH₂CH₂CH₂N₃), 1.88 (quintet, J = 7.0 Hz, 2H, >NCH₂CH₂CH₂CH₂N₃), and 1.74 (sextet, J = 7.0 Hz, 2H, >NCH₂CH₂CH₂CH₂N₃).