Preparation of 3-Substituted Isoindolin-1-one, Cinnoline, and 1,2,4-[e]-Benzotriazine Derivatives

Herein, we report a new approach to synthesize a series of 1,2,4-[e]-benzotriazine and cinnoline derivatives from 3-substituted isoindolin-1-one. All the reported products are obtained through an economical two-step synthetic procedure resulting in fair-to-high yields. Cinnolines (a) and 1,2,4-[e]-benzotriazines (b) result from an intramolecular cyclization of the corresponding 3-substituted isoindolin-1-ones, which, in turn, are prepared by an addition reaction from 2-cyanobenzaldehyde and 2-(2-nitrophenyl) acetonitrile (a) or 2-nitroaniline derivatives (b). A proposed mechanism for this transformation is presented.


■ INTRODUCTION
Synthetic heterocyclic chemistry has made notable progress in the last few decades. 1−4 Isoindolinones, cinnolines, and 1,2,4benzotriazines represent important classes of nitrogen-containing compounds. 5 In fact, it is reported that seven of the top ten selling drugs in the world are nitrogen-containing heterocycles. 6 Consequently, these heterocyclic compounds have received considerable attention in organic chemistry ranging from their methods of preparation to studies of their physical, chemical, and biological properties. 1,2 The growing interest in these Ncontaining compounds is the result of their wide ranging biological activities such as antimalarial, 7,8 antibacterial, 9,10 antiviral, antifungal, 11 anthelmintic, and anticancer properties for application in pharmaceutical fields ( Figure 1). 12−14 In addition, some analogues of these heterocycles have demonstrated electro-optical activities, and others have been used as dyes ( Figure 2). 15 Taking into consideration all these previous applications, 1,2,4-[e]-benzotriazine and cinnoline heterocycles have been synthesized through various multistep reactions over the past several years. 1 Given their importance, we have developed a simple synthetic method based on reactions and mechanisms reported by Sato et al. (Scheme 1) 16 and Angelin et al. (Scheme 2), 17,18 where 2-cyanobenzaldehyde (1), 2-(2-nitrophenyl) acetonitrile (2; see Scheme 3), or 2-nitroaniline substituents (7a−h; see Scheme 4) are employed as starting materials.
We succeeded in synthesizing a series of substituted isoindolin-1-ones as well as their corresponding novel cinnolines and 1,2,4-[e]-benzotriazines. In this paper, we present the synthesis of the latter compounds through a two-step reaction, which is economical and produces good yield.
1 H NMR, 13 C NMR, and 13 C NMR DEPT 135 spectra were consistent with the structure of 6. Similar to the work reported by Angelin et al., triethylamine was proved most desirable for the reaction. 18 It is important to abstract the proton at the αposition to the nitro group or between the two withdrawing groups as described in the literature. 17,18 In our case, Et 3 N abstracted α-H to the nitrile group and generated a nucleophilic specie in the medium. In fact, replacing Et 3 N with 5% KOH in methanol led to several undesired side products. In addition, the amount of solvent used, methanol in this reaction, was an important factor affecting the product yield; it should be minimized in order to precipitate isoindolin-1-one 6 as it forms. Formation of the isoinolin-1-one carbonyl group was shown by a peak at 1703 cm −1 in the IR spectra, compared to that of the 2cyanobenzaldehyde carbonyl group at 1693 cm −1 . This isoindolin-1-one (6) was isolated as a pure white powder, which was sensitive to light turning the material dark brown. This observation might be explained by the reaction of the nitro group oxygen with the benzylic proton of the cyano group. This reaction also applies to 2-nitrobenzaldehyde yielding 2-nitrosobenzoic acid. 19 The synthesis of 3-aminoisoindolin-1-one derivatives 10a−h (Scheme 4) has been achieved following the same procedure as described for product 6: specifically, a nucleophilic addition reaction between the aldehyde function of the 2-cyanobenzaldehyde (1) and the amine function of the 2-nitroaniline derivatives (7a−h), followed by cyclization and rearrangement.
In keeping with the mechanism reported by the Sato et al. group in 1984, 16 the aniline nitrogen lone pair attacks the carbonyl, and the resulting alkoxide anion then attacks the cyano group to form the cyclic intermediate products 9a−h. A simple subsequent rearrangement occurs to give the lactam isoindolin-1-ones 10a−h.
In contrast to the reaction described in Scheme 3, nitrogen base; triethylamine Et 3 N in our case blocked the reaction and stopped the progress of the isoindolinone formation. Instead, a few drops of the strong base methanolic KOH (5%) initiated the formation of the products 10a−h. Starting from a 1:1.2 mmol equivalent of nitroaniline derivatives, 0.4 mL of 2-cyanobenzaldehyde was sufficient for the isolation of the product. Yet, increasing the volume of the base led to some undesired side reactions that decreased the yield of our isoindolinone intermediates. In addition, the solvent nature was found to have an effect on product formation: when using methanol, ethyl acetate, chloroform, and even dimethylformamide, the yields were very low. Fortunately, adding a small amount of dichloromethane (1 mL) resulted in maximum isolation of the desired 3-substituted isoindolin-1-ones 10a−h as yellow pastes, which were subsequently filtrated and washed with cold methanol. The isolated % yield of product 10c using various solvents are shown in Table 1.
While esters (14 and 16a−h) were the anticipated products from intramolecular cyclization of the isoindolin-1-ones, thin layer chromatography showed the presence of two spots and, indeed, two products were obtained�the esters (14 and 16a− h) as well as the much more polar hydrolyzed acids (15 and 17a−h). In fact, heating the reaction for 30 min caused the ester product to rapidly and completely hydrolyze the carboxylate salt. This is a direct consequence of the increased reaction temperature (∼65°C) and 1 h heating at 60−65°C. The formation of 15 from 14 is evident from the isolated yields of 14 and 15 as presented in Table 2.
Additionally, in the course of this investigation, a serendipitous reaction was found to occur with isoindolinone 10g. It formed benzotriazines 16g and 17g by electrophilic aromatic substitution of the chloro group para to the nitro moiety. Indeed, the 1 H and 13 C NMR data were incompatible with the expected dichloro structures. Theoretically, the dichloro products should show three methoxy protons for the ester at ∼4 ppm in 1 H NMR as well as a OCH 3 carbon at ∼50 ppm in the 13 C NMR. Experimentally, six methoxy protons appeared as two singlets at 4.13 and 4.03 ppm and two OCH 3 carbons at 57.25 and 57.23 ppm, in addition to the other expected peaks. This result can be explained by chloride displacement by methoxide upon heating of 10g, where CH 3 O − displaces the chlorine at position 6, para to the nitro group (Scheme 7).

■ CONCLUSIONS
A total of 27 compounds were successfully synthesized, identified, and characterized by melting points, 1 H NMR, 13 C NMR, 13 C NMR DEPT 135, FT-IR, and HR-MS spectroscopy. The synthesis was accomplished through new, concise, efficient, and low-cost reactions, resulting in fair-to-high yields of the products.   13 C NMR, and Dept 135 spectra were determined in CDCl 3 or DMSO-d 6 using a Bruker AM 500 NMR spectrometer. Chemical shifts were recorded in ppm (δ). Infrared spectra were collected using a Thermo Scientific iD3 ATR for Nicolet iS5 FT-IR spectrometer in cm −1 . High-resolution mass spectra (HR-MS) were recorded using a SCIEX X500R HPLC/QTOF mass spectrometer. Thin layer chromatography (TLC) was performed on TLC silica gel 60 F254. Required starting materials were commercially available.
General Procedure C. The isoindolin-1-one derivative (0.1 g; 0.3 mmol) was dissolved in 10 mL of 5% KOH in MeOH, and the mixture was heated for 30 min. The color of the solution turned brown, the reaction was quenched with water, and extraction with ethyl acetate was performed. The aqueous layer was then acidified with concentrated HCl. The crude precipitate was filtrated using a Buchner funnel. The product was recrystallized in 2 mL of methanol, collected by vacuum filtration, and washed with cold methanol and identified as the cinnoline or benzotriazine acid.