Next Article in Journal
Theoretical-Computational Modeling of Gas-State Thermodynamics in Flexible Molecular Systems: Ionic Liquids in the Gas Phase as a Case Study
Next Article in Special Issue
A Green Approach to 2-Substituted Benzo- and Naphthothiazoles via N-bromosuccinimide/Bromide-Mediated C(aryl)-S Bond Formation
Previous Article in Journal
Use of MALDI-TOF MS to Discriminate between Aflatoxin B1-Producing and Non-Producing Strains of Aspergillus flavus
Previous Article in Special Issue
Synthesis, Self-Assembly in Crystalline Phase and Anti-Tumor Activity of 2-(2-/4-Hydroxybenzylidene)thiazolo[3,2-a]pyrimidines
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 27
Issue 22
10.3390/molecules27227862
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

SNH Amidation of 5-Nitroisoquinoline: Access to Nitro- and Nitroso Derivatives of Amides and Ureas on the Basis of Isoquinoline

by
Elena K. Avakyan
,
Anastasia A. Borovleva
,
Diana Yu. Pobedinskaya
,
Oleg P. Demidov
,
Artem P. Ermolenko
,
Alexander N. Larin
and
Ivan V. Borovlev
*
Department of Chemistry, North Caucasus Federal University, 1a Pushkin St., 355017 Stavropol, Russia
*
Author to whom correspondence should be addressed.
Molecules 2022, 27(22), 7862; https://doi.org/10.3390/molecules27227862
Submission received: 26 October 2022 / Revised: 10 November 2022 / Accepted: 10 November 2022 / Published: 14 November 2022
(This article belongs to the Special Issue Chemistry of Nitrogen Heterocyclic Compounds)
Browse Figures
Versions Notes

Abstract

:
For the first time, amides and ureas based on both 5-nitroisoquinoline and 5-nitrosoisoquinoline were obtained by direct nucleophilic substitution of hydrogen in the 5-nitroisoquinoline molecule. In the case of urea and monosubstituted ureas, only 5-nitrosoisoquinoline-6-amine is formed under anhydrous conditions.

1. Introduction

The molecular framework of isoquinoline is the basis of an extensive family of alkaloids exhibiting diverse biological activity [1,2,3], and their synthetic derivatives are widely used in pharmacology and medicine [4]. Thus, further functionalization of isoquinoline seems to be a very promising direction. Without detracting from the advantages of multistage functionalization methods, where the final stage is cyclization with the formation of an isoquinoline ring [5,6,7,8,9,10,11,12,13], we note that modern requirements for the synthesis of derivatives of aromatic and heteroaromatic compounds imply their direct C–H functionalization, the economy of all transformation parameters, which is in line with the so-called PASE (Pot-, Atom-, and Step-Economic) concept [14], as well as the principles of green chemistry [15].
In the case of π-deficient azines and nitroarenes, oxidative nucleophilic hydrogen substitution (SNH) reactions satisfy these requirements, which do not require the preliminary introduction of a good leaving group into the substrate or reagent molecule, as well as the use of expensive catalysts and ligands [16,17,18,19]. They include an additional step with the formation of σH adduct and its subsequent aromatization due to an external oxidizing agent. Organic and inorganic compounds and atmospheric oxygen are used to oxidize σH adducts [20,21], while electrochemical oxidation is used for stable intermediates [22,23,24]. Even in the absence of an external oxidant, the NO2 [25] group or the C=N bond of the substrate [26] can also act as hydride anion acceptors. The most probable mechanism for the dehydroaromatization of the σH complex is the successive transfer of an electron, a proton, and one more electron (EPE mechanism) to the oxidant molecule [27]. Later, in the arylamination of nitroarenes, in addition to the oxidative one, another way of aromatization of the σH adduct was discovered by its dehydration with the formation of the corresponding nitroso compounds [28,29,30,31,32,33,34]. On the whole, the SNH methodology has already found application in industry [35,36] and, in some cases, is a good alternative to cross-coupling reactions with the participation of transition metals [37].
The aim of the first stage of the work was to study the possibility of direct nucleophilic substitution of hydrogen by the N-amide function in the 5-nitroisoquinoline molecule. It is known that this compound readily enters into reactions of oxidative amination [38], methylamination [39], whereas its quinoline analogue even into arylamination reaction [40]. However, unlike other N-nucleophiles, reactions of direct hydrogen substitution by the N-amide function in the series of azines and nitroarenes are still quite rare. The first report on the SNH amidation of nitrobenzene appeared only in 1993 [41] during the development of an industrial method for the preparation of p-nitroaniline [42].
In continuation of these studies, the oxidative SNH amidation of 1,3,7-triazapyrene [43], acridine [44], 3-nitropyridine [45] and 5(6,7,8)-nitroquinolines [46] was successfully performed in our laboratory. In all cases, the process was carried out in anhydrous DMSO by the action on the substrate with the previously obtained anion of the corresponding carboxamide at room temperature, using atmospheric oxygen [43,46] or K3Fe(CN)6 [44,45] as an oxidizing agent.

2. Results and Discussion

We implemented two approaches to the SNH amidation of 5-nitroisoquinoline (1), which differed mainly in the presence or absence of a small amount of water in the reaction mass, and which led to significantly different results (Scheme 1). The optimization of the first of them (method A) was carried out using the example of the reaction of substrate 1 with p-methylbenzamide in anhydrous DMSO at room temperature, preliminarily generating the amide anion by the action of NaH in the same solvent. The best result was shown by using 2 equiv. amide anion per 1 equiv. substrate (Table 1, entry 1). After adding 5-nitroisoquinoline (1), the process has completed within 1.5 h with the formation of a mixture of 4-methyl-N-(5-nitroisoquinolin-8-yl)benzamide (2a) and 4-methyl-N-(5-nitrosoisoquinoline-6-yl)benzamide (3a) with a total yield of 45%, the separation of which was carried out by chromatography on silica gel. All spectral data are available in the Supplementary Materials file submitted with this article.
Increasing the excess of the amide anion (entries 2,3), changing the ratio of p-methylbenzamide and NaH (entries 4,5), using K3Fe(CN)6 as an external oxidizer (entry 6), and increasing the temperature (entry 7) turned out to be ineffective. The reaction was carried out without isolation from air oxygen; however, its performance in an argon atmosphere only slightly reduced the yield of nitro product 2a (entry 8). These data suggest that, as in the case of 3-nitropyridine [45] and 5-nitroquinoline [46], 5-nitroisoquinoline exhibits a dual reactivity, being not only a substrate, but also the main oxidizer of σH adducts in the formation of nitro-amides 2. Naturally, this reduces the yield of target compounds and leads to the appearance of by-products.
Anions of benzamide- and p-methoxybenzamide react similarly with the formation of the corresponding nitroamides 2b,c and nitrosoamides 3b,c. Note, however, that the reaction of the initial substrate with p-, m-, and o-nitrobenzamides gives only nitroamides 2d–f (Scheme 1).
The mechanism of amidation of 5-nitroisoquinoline (1) includes the addition of a nucleophile in the ortho- and para-positions towards the NO2-group, and the para σH adduct 5 further undergoes oxidative aromatization to form nitroamides 2a–f (Scheme 2, route a), while its ortho analog 6 is aromatized by proton transfer and elimination of a water molecule, giving nitrosoamides 3a–c (Scheme 2, route b).
The starting point for the development of another approach to the SNH amidation of 5-nitroisoquinoline (1) was the fact that the authors of the first work on amidation by direct hydrogen substitution [41] carried out the process in a non-absolute medium, using dihydrate of tetramethylammonium hydroxide as the base, which led to the formation of only products substitution at the p-position of the nitrobenzene molecule. In this approach, we used commercial DMSO containing ~0.5% water as well as KOH instead of NaH as the base (method B). As it turned out, when using a 4-molar excess of the corresponding aromatic amides, only the corresponding N-(5-nitroisoquinolin-8-yl)benzamides 2a–f were formed in 34–53% yields (Scheme 1). Apparently, in the presence of water, the hydrated amide anions, which have a large volume, experience steric difficulties in entering the o-position with respect to the NO2 group, i.e., in position 6 of the 5-nitroisoquinoline molecule. Despite relatively low yields, nitro- 2 and nitroso compounds 3 are of considerable interest for further functionalization of isoquinoline, and it is very problematic to obtain nitrosoamides 3a–c by other methods.
Increasing the water content in the mixture with DMSO to 5% in method B, or using amides of aliphatic acids (acetic, propionic and isobutyric) under the conditions of both methods, led to a complex mixture of substances.
A feature of the 1H NMR spectra of nitrosoamides 3a–c in CDCl3 is a strong downfield shift of NH proton signals (δ~13.5–13.6 ppm), which indicates a strong intramolecular hydrogen bond NH…O=N. The structures of the compounds 2a (CCDC 2159575) and 3a (CCDC 2159573) (Figure 1) were confirmed by X-ray determination [47].
The aim of the second stage of the work was to study the possibility of SNH amidation of 5-nitroisoquinoline with urea and its derivatives. We have previously shown that unsubstituted urea can act as an aminating agent in nucleophilic substitution reactions [47,48,49,50]. For example, the reaction of acridine with the urea anion in anhydrous DMSO led to 9-aminoacridine in 78% yield [50]. However, alkylureas under the same conditions entered into the SNH alkyl(dialkyl)carbamoylamination reaction, allowing to introduce the residues of the corresponding ureas into acridine [50] and 3-nitropyridine [51] molecules. Under anhydrous conditions, urea anions easily form stable ϭ-adducts at position 9 with 10-alkylacridinium cations [52].
We have found that urea and its monosubstituted derivatives such as phenyl-, tert-butyl- and (1,1-dimethylpentyl)urea react with 5-nitroisoquinoline under anhydrous conditions (method A) to form the same compound—5-nitrosoisoquinoline-6-amine (7; Scheme 3). In the 1H NMR spectrum of compound 7, even in such a polar solvent as DMSO-d6, the NH2 group gives two broadened singlets at δ 11.53 and 8.90 ppm, the first of which corresponds to a proton bound by a strong intramolecular hydrogen bond NH…O= N. In the 13C NMR spectrum, the signals at δ 136.6 and 139.2 ppm appear only with increasing accumulation time and are strongly broadened. In our opinion, this is the result of the well-known prototropic tautomerism of the nitrosamine-azaquinone oxime type [53,54,55] (Scheme 3), and the tautomerization rate for this compound is relatively slow in the NMR time scale, and these signals refer to the C5 and C6 atoms of the isoquinoline cycle. All spectral data are available in the Supplementary Materials file submitted with this article.
Unlike amides, SNH reactions of 5-nitroisoquinoline with ureas under anhydrous conditions (method A) proceed exclusively at position 6 in accordance with the mechanism of formation of nitrosoamides 3a–c (Scheme 2, route b). However, the nucleophilic substitution product 8 is unstable, and under the reaction conditions, the urea radical is converted into an amino group according to the route we proposed earlier [43,48] (Scheme 4). The key to it is the elimination of the isocyanic acid molecule or its ester (RNCO) and the formation of the anion 9.
Application of the conditions of method B to the reaction of 5-nitroisoquinoline with anions of urea and its monosubstituted derivatives was unsuccessful, since a complex mixture of substances is formed in the presence of water.
However, 1,1-dialkylurea anions react with 5-nitroisoquinoline (1) under the conditions of both methods, but form different substitution products, albeit in relatively low yields (Scheme 5). So, under anhydrous conditions (method A), the 1,1-dimethylurea anion leads to the SNH product at position 6—1,1-dimethyl-3-(5-nitrosoisoquinolin-6-yl)urea (10a) in 41% yield. Amides of pyrrolidine-1-carboxylic, piperidine-1-carboxylic, and morpholine-4-carboxylic acids also react similarly, forming ureas based on 5-nitrosoisoquinoline 10b–d. Undoubtedly, the mechanism of formation of compounds 10a–d corresponds to the general mechanism for obtaining nitroso compounds (Scheme 2, route b).
In the 1H NMR spectra of these compounds, the NH proton signal is strongly shifted downfield in both CDCl3 and DMSO-d6 (δ~13.5–13.6 ppm), which also indicates a strong intramolecular hydrogen bond. In addition, if under normal conditions of recording the spectrum (25 °C) in CDCl3, the protons of two methyl groups of compound 10a give one broadened singlet, then when cooled to only 13.7 °C, it splits into two signals, which indicates the nonequivalence of methyl groups under these temperature conditions. In our opinion, this is due to the well-known difficulty in rotation relative to the C(O)-N amide bond. At 25 °C the rotation accelerates and the signals from these groups coalesce. However, in the case of N-(5-nitrosoisoquinolin-6-yl)pyrrolidine-1-carboxamide (10b), the protons of both the α- and β-methylene groups of the pyrrolidine ring are not equivalent even at 25 °C and give separate signals (as do the signals of carbon atoms of these groups in 13C NMR). The difficulty of rotation relative to the amide bond of compounds 10c and 10d is noticeable only in the broadening of the signals of the corresponding protons, which appear equivalent. Apparently, this is due to the lower conformational rigidity of the piperidine and morpholine rings of compounds 10c and 10d compared to the pyrrolidine one.
In the presence of water (method B), the reactions of 5-nitroisoquinoline with 1,1-dialkylurea anions proceed by the mechanism of oxidative nucleophilic substitution (Scheme 2, route a) to position 8 with the formation of exclusively SNH dialkylcarbamoylamination products 11a–d (Scheme 5). The structure of the compound 10a (CCDC 2159579, Figure 2) was confirmed by X-ray determination [47].

3. Materials and Methods

1H and 13C NMR spectra were recorded on a Bruker Avance HD 400 spectrometer in the solvent indicated relative to residual DMSO signals [56] or TMS as internal standard when CDCl3 was used as a solvent. ard—85% H3PO4. The NMR-spectra of the newly synthesized compounds could be found in the Supplementary Materials. HRMS were registered on a Bruker UHR-TOF Maxis™ Impact instrument using the ESI technique. All melting points were determined in glass capillaries using REACH Devices RD-MP and Electrothermal IA 9200 instruments and are uncorrected. The reaction progress and the purity of the obtained compounds were controlled by TLC on Silufol UV-254 plates. All experiments were carried out in a reactor protected from atmospheric moisture, but without isolation from atmospheric oxygen. Sodium hydride (60% paraffin oil suspension, Merck, Darmstadt, Germany) and 5-nitroisoquinoline (abcr GmbH & Co. KG, Heilbronn, Germany) were used without further purification.
N-(5-nitroisoquinolin-8-yl)benzamides 2a–f and N-(5-nitrosoisoquinoline-6-yl)benzamides 3a–c; (General Procedures):
Method A: To a solution of 1 mmol of the corresponding benzamide in 4 mL of anhydrous DMSO 40 mg of a suspension of sodium hydride in paraffin oil (1 mmol of NaH) and after 10 min 87 mg (0.5 mmol) 5-nitroisoquinoline were added sequentially at room temperature. The mixture was intensively stirred at room temperature for 1.5 h. Then, the reaction mass was poured into 50 g of ice and, upon reaching room temperature, it was acidified with dilute HCl to pH~7. The precipitate that formed was filtered off, washed with water, and dried. The dry product was separated into the appropriate fractions by dry flash chromatography [57] on silica gel. In the synthesis of compounds 2a–c and 3a–c, the mixture was eluted with toluene—ethyl acetate (15:1) and the second and third fractions were collected (the first one, slightly colored fraction was discarded; it contains the starting benzamides and non-polar impurities). Nitrosoamides 3a–c were obtained from the second green fraction, and nitroamides 2a–c were obtained from the third yellow fraction. In the synthesis of compounds 2d–f, the mixture was eluted with toluene—ethyl acetate (5:1) and the second yellow fraction was collected.
Method B: To a solution of 2 mmol of the corresponding benzamide in 8 mL of DMSO containing 0.5% water, 112 mg of KOH (2 mmol), 87 mg (0.5 mmol) of 5-nitroisoquinoline, and 658 mg (2 mmol) of K3Fe(CN)6 were added sequentially at room temperature. The mixture was vigorously stirred at room temperature for 2.5 h, then the reaction mixture was poured into 50 g of ice and, upon reaching room temperature, acidified with dilute HCl to pH~7. The precipitate was filtered off, washed with water, and dried. The dry product was purified by dry flash chromatography on silica gel eluting with benzene-ethyl acetate (5:1) and collecting a second yellow fraction.
4-Methyl-N-(5-nitroisoquinolin-8-yl)benzamide (2a). Yellow solid; yield: 29.2 mg (19%, Method A); 81.4 mg (53%, Method B); mp 205–206 °C (EtOAc). 1H NMR (400 MHz, DMSO-d6): δ = 11.01 (br s, 1H, NH), 9.68 (d, J = 0.5 Hz, 1H, H-1), 8.79 (d, J = 6.2 Hz, 1H, H-3), 8.74 (d, J = 8.6 Hz, 1H, H-6), 8.45 (d, J = 6.2 Hz, 1H, H-4), 8.15 (d, J = 8.6 Hz, 1H, H-7), 8.04 (d, J = 8.1 Hz, 2H, H-2,6 Ar), 7.42 (d, J = 8.1 Hz, 2H, H-3,5 Ar), 2.43 (s, 3H, CH3). 13C NMR (100 MHz, DMSO-d6): δ = 166.6, 149.4, 146.3, 142.6, 141.9, 140.4, 130.9, 129.9, 129.1, 128.5, 128.3, 122.2, 121.2, 115.1, 21.1. HRMS (ESI): m/z [M + Na]+ calcd for C17H13N3NaO3: 330.0849; found: 330.0831.
4-Methyl-N-(5-nitrosoisoquinolin-6-yl)benzamide (3a). Green solid; yield: 37.8 mg (26%, Method A); mp 168–169 °C (dec., EtOAc). 1H NMR (400 MHz, CDCl3): δ = 13.57 (br s, 1H, NH…O), 9.76 (d, J = 6.6 Hz, 1H, H-4), 9.73 (s, 1H, H-1), 9.56 (d, J = 9.5 Hz, 1H, H-8), 8.84 (d, J = 6.6 Hz, 1H, H-3), 8.64 (d, J = 9.5 Hz, 1H, H-7), 8.11 (d, J = 8.1 Hz, 2H, H-2,6 Ar), 7.50 (d, J = 856.1 Hz, 2H, H-3,5 Ar), 2.53 (s, 3H, CH3). 13C NMR (100 MHz, CDCl3): δ = 168.2, 146.1, 145.7, 145.4, 142.3, 141.1, 136.4, 130.4, 129.5, 128.6, 127.9, 124.3, 123.1, 119.3, 22.0. HRMS (ESI): m/z [M + H]+ calcd for C17H14N3O2: 292.1081; found: 292.1072.
N-(5-Nitroisoquinolin-8-yl)benzamide (2b). Yellow solid; yield: 32.2 mg (22%, Method A); 64.5 mg (44%, Method B); mp 221–222 °C (EtOAc). 1H NMR (400 MHz, DMSO-d6): δ = 11.09 (br s, 1H, NH), 9.70 (s, 1H, H-1), 8.80 (d, J = 6.1 Hz, 1H, H-3), 8.75 (d, J = 8.6 Hz, 1H, H-6), 8.45 (d, J = 6.1 Hz, 1H, H-4), 8.17 (d, J = 8.6 Hz, 1H, H-7), 8.13 (d, J = 8.1 Hz, 2H, H-2,6 Ph), 7.69 (t, J = 7.7 Hz, 1H, H-4 Ph), 7.64–7.59 (m, 2H, H-3,5 Ph). 13C NMR (100 MHz, DMSO-d6): δ = 166.8, 149.4, 146.3, 141.8, 140.5, 133.8, 132.4, 129.8, 128.6, 128.5, 128.3, 122.2, 121.3, 115.1. HRMS (ESI): m/z [M + Na]+ calcd for C16H11N3NaO3: 316.0693; found: 316.0692.
N-(5-Nitrosoisoquinolin-6-yl)benzamide (3b). Green solid; yield: 31.9 mg (23%, Method A); mp 173–174 °C (dec., EtOAc). 1H NMR (400 MHz, CDCl3): δ = 13.53 (br s, 1H, NH…O), 9.41 (br s, 1H, H-1), 9.36–9.33 (m, 2H, H-4,8), 8.88 (d, J = 6.1 Hz, 1H, H-3), 8.43 (d, J = 9.4 Hz, 1H, H-7), 8.20 (d, J = 7.0 Hz, 2H, H-2,6 Ph), 7.74–7.65 (m, 3H, H-3,4,5 Ph). 13C NMR (100 MHz, CDCl3): δ = 168.5, 150.6, 147.6, 145.7, 141.5 (2C), 133.9 (2C), 133.0, 129.6, 128.4, 124.3, 121.0, 116.4. HRMS (ESI): m/z [M + H]+ calcd for C16H12N3O2: 278.0924; found: 278.0919.
4-Methoxy-N-(5-nitroisoquinolin-8-yl)benzamide (2c). Yellow solid; yield: 35.5 mg (22%, Method A); 66.2 mg (41%, Method B); mp 214–215 °C (EtOAc). 1H NMR (400 MHz, DMSO-d6): δ = 10.93 (br s, 1H, NH), 9.67 (s, 1H, H-1), 8.79 (d, J = 6.3 Hz, 1H, H-3), 8.73 (d, J = 8.6 Hz, 1H, H-6), 8.45 (d, J = 6.3 Hz, 1H, H-4), 8.14 (d, J = 8.6 Hz, 1H, H-7), 8.12 (d, J = 8.9 Hz, 2H, H-2,6 Ar), 7.14 (d, J = 8.9 Hz, 2H, H-3,5 Ar), 3.88 (s, 3H, CH3O). 13C NMR (100 MHz, DMSO-d6): δ = 166.0, 162.6, 149.5, 146.3, 142.1, 140.3, 130.3, 129.9, 128.5, 125.8, 122.1, 121.1, 115.1, 113.8, 55.6. HRMS (ESI): m/z [M + Na]+ calcd for C17H13N3NaO4: 346.0798; found: 346.0798.
4-Methoxy-N-(5-nitrosoisoquinolin-6-yl)benzamide (3c). Green solid; yield: 35.3 mg (23%, Method A); mp 186–187 °C (dec., EtOAc). 1H NMR (400 MHz, CDCl3): δ = 13.64 (br s, 1H, NH…O), 9.31 (s, 1H, H-1), 9.29–9.24 (m, 2H, H-4,8), 8.88 (d, J = 6.0 Hz, 1H, H-3), 8.34 (d, J = 9.4 Hz, 1H, H-7), 8.18 (d, J = 8.8 Hz, 2H, H-2,6 Ar), 7.14 (d, J = 8.8 Hz, 2H, H-3,5 Ar), 3.96 (s, 3H, °CH3). 13C NMR (100 MHz, CDCl3): δ = 168.0, 164.1, 151.9, 148.1, 148.0, 141.5, 130.6 (2C), 125.3, 124.4, 120.2, 115.5, 114.7 (2C), 55.8. HRMS (ESI): m/z [M + H]+ calcd for C17H14N3O3: 308.1030; found: 308.1030.
4-Nitro-N-(5-nitroisoquinolin-8-yl)benzamide (2d). Yellow solid; yield: 64.2 мг (38%, Method A); 87.9 mg (52%, Method B); mp 244–245 °C (EtOAc). 1H NMR (400 MHz, DMSO-d6): δ = 11.37 (br s, 1H, NH), 9.75 (s, 1H, H-1), 8.81 (d, J = 6.1 Hz, 1H, H-3), 8.76 (d, J = 8.6 Hz, 1H, H-6), 8.46-8.41 (m, 3H, H-4, H-2,6 Ar), 8.36 (d, J = 8.9 Hz, 2H, H-3,5 Ar), 8.18 (d, J = 8.6 Hz, 1H, H-7). 13C NMR (100 MHz, DMSO-d6): δ = 165.4, 149.6, 149.5, 146.4, 141.3, 140.8, 139.6, 129.9, 129.8, 128.5, 123.6, 122.3, 121.6, 115.2. HRMS (ESI): m/z [M + Na]+ calcd for C16H10N4NaO5: 361.0543; found: 361.0552.
3-Nitro-N-(5-nitroisoquinolin-8-yl)benzamide (2e). Yellow solid; yield: 89.6 mg (53%, Method A); 76.1 mg (45%, Method B); mp 215–216 °C (EtOAc). 1H NMR (400 MHz, DMSO-d6): δ = 11.38 (br s, 1H, NH), 9.74 (s, 1H, H-1), 8.95 (t, J = 1.8 Hz, 1H, H-2 Ar), 8.81 (d, J = 6.2 Hz, 1H, H-3), 8.76 (d, J = 8.6 Hz, 1H, H-6), 8.57–8.50 (m, 2H, H-4,6 Ar), 8.45 (d, J = 6.2 Hz, 1H, H-4), 8.15 (d, J = 8.6 Hz, 1H, H-7), 7.91 (t, J = 8.0 Hz, 1H, H-5 Ar). 13C NMR (100 MHz, DMSO-d6): δ = 164.8, 149.6, 147.8, 146.3, 141.2, 140.9, 135.3, 134.8, 130.3, 129.8, 128.5, 126.8, 123.1, 122.3, 121.8, 115.1. HRMS (ESI): m/z [M + Na]+ calcd for C16H10N4NaO5: 361.0543; found: 361.0546.
2-Nitro-N-(5-nitroisoquinolin-8-yl)benzamide (2f).Yellow solid; yield: 64.2 mg (38%, Method A); 57.5 mg (34%, Method B); mp 242–243 °C (EtOAc). 1H NMR (400 MHz, DMSO-d6): δ = 11.48 (br s, 1H, NH), 9.71 (s, 1H, H-1), 8.81 (d, J = 6.2 Hz, 1H, H-3), 8.79 (d, J = 8.4 Hz, 1H, H-6), 8.45 (d, J = 6.2 Hz, 1H, H-4), 8.27 (br d, J = 8.2 Hz, 2H, H-7, H-3 Ar), 8.03-7.95 (m, 2H, H-5,6 Ar), 7.87-7.81 (m, 1H, H-4 Ar). 13C NMR (100 MHz, DMSO-d6): δ = 165.8, 148.8, 146.5, 146.1, 140.8, 140.5, 134.6, 132.1, 131.4, 130.2, 129.6, 128.6, 124.4, 121.5, 120.1, 115.3. HRMS (ESI): m/z [M + Na]+ calcd for C16H10N4NaO5: 361.0543; found: 361.0524.
5-Nitrosoisoquinolin-6-amine (7)
To a solution of 1 mmol of the corresponding urea (Scheme 3) in 4 mL of anhydrous DMSO 40 mg of a suspension of sodium hydride in paraffin oil (1 mmol of NaH) and after 10 min 87 mg (0.5 mmol) 5-nitroisoquinoline were added sequentially at room temperature. The mixture was vigorously stirred at room temperature for 1 h. Then, the reaction mass was poured into 50 g of ice and, upon reaching room temperature, acidified with dilute HCl to pH~7. The precipitate formed was filtered off, washed with water, and dried. The dry product was purified by crystallization from ethyl acetate.
Green solid; yield: 32.9 mg (38%, from urea); 50.2 mg (58%, from phenylurea); 65.7 mg (76%, from tert-butylurea); 51.9 mg (60%, from 1,1-dimethylpentylurea); mp 256–257 °C (dec., EtOAc). 1H NMR (400 MHz, DMSO-d6): δ = 11.53 (br s, 1H, NH…O), 9.03 (s, 1H, H-1), 8.90 (br s, 1H, NH), 8.82 (d, J = 5.7 Hz, 1H, H-4), 8.62 (d, J = 5.7 Hz, 1H, H-3), 8.02 (d, J = 9.3 Hz, 1H, H-8), 7.13 (d, J = 9.3 Hz, 1H, H-7). 13C NMR (100 MHz, DMSO-d6): δ = 151.2, 147.8, 147.7, 139.2, 137.9, 136.6, 122.1, 121.3, 112.9. HRMS (ESI): m/z [M + H]+ calcd for C9H8N3O: 174.0662; found: 174.0662.
1,1-Dialkyl-3-(5-nitrosoisoquinolin-6-yl)ureas (10a–d); (General Procedure):
To a solution of 1 mmol of the corresponding urea (Scheme 5, Method A) in 4 mL of anhydrous DMSO 40 mg of a suspension of sodium hydride in paraffin oil (1 mmol of NaH) and after 10 min 87 mg (0.5 mmol) 5-nitroisoquinoline were added sequentially at room temperature. The mixture was vigorously stirred at room temperature for 2 h. Then, the reaction mass was poured into 50 g of ice and, upon reaching room temperature, acidified with dilute HCl to pH~7. The precipitate formed was filtered off, washed with water, and dried. The dry product was isolated by dry flash chromatography32 on silica gel, collecting in all cases a second yellow or light green fraction, from which compounds 10a–d were obtained. Eluents: PhMe- EtOAc (10:1) for 10a and 10d; PhMe- EtOAc (3:2) for 10b; PhMe- EtOAc (1:1) for 10c.
1,1-Dimethyl-3-(5-nitrosoisoquinolin-6-yl)urea (10a). Dark green solid; yield: 50.0 mg (41%); mp 161–162 °C (dec., PhMe-EtOAc). 1H NMR (400 MHz, DMSO-d6): δ = 13.43 (br s, 1H, NH…O), 9.30 (s, 1H, H-1), 8.96 (d, J = 5.8 Hz, 1H, H-3), 8.79 (d, J = 5.8 Hz, 1H, H-4), 8.77 (d, J = 9.4 Hz, 1H, H-8), 8.46 (d, J = 9.4 Hz, 1H, H-7), 3.14 (br s, 6H, N(CH3)2). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 13.69 (br s, 1H, NH…O), 9.23 (s, 1H, H-1), 9.17 (d, J = 5.8 Hz, 1H, H-3), 9.00 (d, J = 9.5 Hz, 1H, H-8), 8.81 (d, J = 5.8 Hz, 1H, H-4), 8.19 (d, J = 9.5 Hz, 1H, H-7), 3.26 (br s, 6H, N(CH3)2). 1H NMR (400 MHz, CDCl3, 13.7 °C): δ = 13.58 (br s, 1H, NH…O), 9.56 (d, J = 6.3 Hz, 1H, H-3), 9.46 (s, 1H, H-1), 9.24 (d, J = 9.6 Hz, 1H, H-8), 8.79 (d, J = 6.3 Hz, 1H, H-4), 8.36 (d, J = 9.6 Hz, 1H, H-7), 3.45 (br s, 3H, N(CH3)b), 3.16 (br s, 3H, N(CH3)a). 13C NMR (100 MHz, CDCl3, 25 °C): δ = 154.8, 151.0, 148.1, 146.5, 141.0, 139.4, 129.0, 123.4, 120.3, 115.4, 37.0. HRMS (ESI): m/z [M + H]+ calcd for C12H13N4O2: 245.1033; found: 245.1030.
N-(5-Nitrosoisoquinolin-6-yl)pyrrolidine-1-carboxamide (10b). Green solid; yield: 70.2 mg (52%); mp 179–180 °C (dec., PhMe-EtOAc). 1H NMR (400 MHz, CDCl3, 25 °C): δ = 13.52 (br s, 1H, NH…O), 9.28 (br s, 1H, H-1), 9.26 (d, J = 6.2 Hz, 1H, H-3), 9.15 (br d, J = 9.5 Hz, 1H, H-8), 8.80 (d, J = 6.2 Hz, 1H, H-4), 8.22 (d, J = 9.5 Hz, 1H, H-7), 3.87 (t, J = 5.3 Hz, 2H, NCH2b), 3.59 (t, J = 5.3 Hz, 2H, NCH2a), 2.23–2.20 (m, 2H CH2CH2), 2.04–2.01 (m, 2H, CH2CH2). 13C NMR (100 MHz, CDCl3): δ = 152.7, 149.8, 147.7, 144.6, 140.7 (2C), 123.1, 121.1, 115.9, 46.8, 46.4, 26.3, 24.9. HRMS (ESI): m/z [M + H]+ calcd for C14H15N4O2: 271.1190; found: 271.1186.
N-(5-Nitrosoisoquinolin-6-yl)piperidine-1-carboxamide (10c). Yellow solid; yield: 35.5 mg (25%); mp 198–199 °C (dec., PhMe-EtOAc). 1H NMR (400 MHz, CDCl3): δ = 13.81 (br s, 1H, NH…O), 9.26 (br s, 1H, H-1), 9.21 (d, J = 5.3 Hz, 1H, H-3), 8.93 (d, J = 9.5 Hz, 1H, H-8), 8.80 (br s, 1H, H-4), 8.19 (d, J = 9.5 Hz, 1H, H-7), 3.70 (br s, 4H, N(CH2)2), 1.75 (br s, 6H, (CH2)3). 13C NMR (100 MHz, CDCl3): δ = 153.2, 150.3, 148.0, 145.4, 140.7 (2C), 123.2, 121.1 (2C), 115.7, 29.8, 25.9, 24.3. HRMS (ESI): m/z [M + H]+ calcd for C15H17N4O2: 285.1346; found: 285.1340. HRMS (ESI): m/z [M + Na]+ calcd for C15H16N4NaO2: 307.1163; found: 307.1160.
N-(5-Nitrosoisoquinolin-6-yl)morpholine-4-carboxamide (10d). Brown solid; yield: 28.6 mg (20%); mp 146–147 °C (dec., PhMe-EtOAc). 1H NMR (400 MHz, CDCl3): δ = 13.69 (br s, 1H, NH…O), 9.32 (s, 1H, H-1), 9.26 (d, 1H, J = 6.0 Hz, H-3), 8.97 (d, 1H, J = 9.5 Hz, H-8), 8.82 (d, 1H, J = 6.0 Hz, H-4), 8.26 (d, 1H, J = 9.5 Hz, H-7), 3.83-3.87 (m, 4H, O(CH2)2), 3.74–3.79 (m, 4H, N(CH2)2). 13C NMR (100 MHz, CDCl3): δ = 153.7, 150.3, 148.0, 145.3, 141.2 (2C), 129.7, 123.4, 120.8, 115.9, 66.5, 44.6. HRMS (ESI): m/z [M + H]+ calcd for C14H15N4O3: 287.1139; found: 287.1134.
1,1-Dialkyl-3-(5-nitroisoquinolin-8-yl)ureas (11a–d); (General Procedure):
To a solution of 2 mmol of the corresponding urea (Scheme 5, Method B) in 8 mL of DMSO, containing 0.5% water, 112 mg of KOH (2 mmol), 87 mg (0.5 mmol) of 5-nitroisoquinoline and 658 mg (2 mmol) K3Fe(CN)6 were added sequentially at room temperature. The mixture was intensively stirred at room temperature for 4 h, then the reaction mass was poured into 50 g of ice and, upon reaching room temperature, it was acidified with dilute HCl to pH~7. The aqueous solution was extracted with ethyl acetate (4 × 10 mL), the extract was dried with Na2SO4. After evaporation of the solvent, the dry residue was purified by dry flash chromatography on silica gel,32 collecting in all cases the second yellow fraction, from which compounds 11a–d were obtained. Eluents: PhMe- EtOAc (10:1) for 11a; PhMe- EtOAc (3:2) for 11b; PhMe- EtOAc (1:1) for 11c; ethyl EtOAc for 11d.
1,1-Dimethyl-3-(5-nitroisoquinolin-8-yl)urea (11a). Yellow solid; yield: 46.8 mg (36%); mp 218–219 °C (dec., PhMe-EtOAc). 1H NMR (400 MHz, DMSO-d6): δ = 9.58 (s, 1H, H-1), 9.25 (br s, 1H, NH), 8.73 (d, J = 6.1 Hz, 1H, H-3), 8.66 (d, J = 8.8 Hz, 1H, H-6), 8.46 (d, J = 6.1 Hz, 1H, H-4), 7.90 (d, J = 8.8 Hz, 1H, H-7), 3.07 (s, 6H, N(CH3)2). 13C NMR (100 MHz, DMSO-d6): δ = 155.4, 149.4, 146.2, 144.8, 138.0, 130.4, 128.8, 121.0, 117.9, 115.1, 36.6. HRMS (ESI): m/z [M + H]+ calcd for C12H13N4O3: 261.0982; found: 261.0979. HRMS (ESI): m/z [M + Na]+ calcd for C12H12N4NaO3: 283.0785; found: 283.0792.
N-(5-Nitroisoquinolin-8-yl)pyrrolidine-1-carboxamide (11b). Yellow solid; yield: 32.9 mg (23%); mp 197–198 °C (dec., PhMe-EtOAc). 1H NMR (400 MHz, DMSO-d6): δ = 9.61 (br s, 1H, H-1), 9.10 (br s, 1H, NH), 8.74 (dd, J = 6.2, 0.8 Hz, 1H, H-3), 8.66 (dd, J = 8.8, 0.7 Hz, 1H, H-6), 8.47 (d, J = 6.2 Hz, 1H, H-4), 8.03 (br d, J = 8.8 Hz, 1H, H-7), 3.54 (br s, 4H, N(CH2)2), 1.92 (br s, 4H, (CH2)2). 13C NMR (100 MHz, DMSO-d6): δ = 153.3, 149.4, 146.3, 144.4, 137.9, 130.5, 128.9, 120.8, 117.7, 115.1, 46.1, 25.1. HRMS (ESI): m/z [M + H]+ calcd for C14H14N4O3: 287.1139; found: 287.1126.
N-(5-Nitroisoquinolin-8-yl)piperidine-1-carboxamide (11c). Yellow solid; yield: 52.5 mg (35%); mp 205–206 °C (dec., PhMe-EtOAc). 1H NMR (400 MHz, DMSO-d6): δ = 9.54 (br s, 1H, H-1), 9.44 (br s, 1H, NH), 8.73 (d, J = 6.1 Hz, 1H, H-3), 8.63 (d, J = 8.8 Hz, 1H, H-6), 8.47 (d, J = 6.1 Hz, 1H, H-4), 7.83 (d, J = 8.8 Hz, 1H, H-7), 3.55 (t, J = 5.2 Hz, 4H, N(CH2)2), 1.63-1.56 (m, 6H, (CH2)3). 13C NMR (100 MHz, DMSO-d6): δ = 154.6, 149.4, 146.3, 145.2, 137.9, 130.5, 128.9, 121.0, 117.8, 115.1, 45.2, 25.6, 24.0. HRMS (ESI): m/z [M + Na]+ calcd for C15H16N4NaO3: 323.1115; found: 323.1105.
N-(5-Nitroisoquinolin-8-yl)morpholine-4-carboxamide (11d). Yellow solid; yield: 58.9 mg (39%); mp 230–231 °C (dec., PhMe-EtOAc). 1H NMR (400 MHz, DMSO-d6): δ = 9.59 (s, 1H, H-1), 9.47 (br s, 1H, NH), 8.74 (d, 1H, J = 6.1 Hz, H-3), 8.66 (d, 1H, J = 8.8 Hz, H-6), 8.46 (d, 1H, J = 6.1 Hz, H-4), 7.90 (d, 1H, J = 8.8 Hz, H-7), 3.68 (t, 4H, J = 4.5 Hz, O(CH2)2), 3.56 (t, 4H, J = 4.5 Hz, N(CH2)2). 13C NMR (100 MHz, DMSO-d6): δ = 154.9, 149.4, 146.3, 144.6, 138.2, 130.4, 128.8, 121.1, 118.1, 115.1, 66.0, 44.6. HRMS (ESI): m/z [M + H]+ calcd for C14H15N4O4: 303.1088; found: 303.1089.

4. Conclusions

Thus, different regioselectivity was found in the reactions of SNH substitution of 5-nitroisoquinoline with N-anions of aromatic amides and ureas, depending on the absence or presence of small amounts of water in the reaction mass. So, interaction with amides in anhydrous DMSO usually results in the formation of a mixture of hitherto unknown 8-aroylamino-5-nitroisoquinolines and 6-aroylamino-5-nitrosoisoquinolines in a small or moderate yield. In the presence of water, only nitro derivatives were formed. Anions of 1,1-dialkylureas in anhydrous DMSO give rise to 6-dialkylcarbamoylamino-5-nitrosoisoquinolines, whereas in the presence of water, 8-dialkylcarbamoylamino-5-nitroisoquinolines form. Urea itself and its monosubstituted derivatives under anhydrous conditions form exclusively 5-nitrosoisoquinoline-6-amine.

Supplementary Materials

Crystallographic data for the structures in this paper have been deposited in the Cambridge Crystallographic Data Center as a supplementary publication (2a, CCDC 2159575; 3a, CCDC 2159573; 10a, CCDC 2159579, www.ccdc.cam.ac.uk/getstructures). Copies of the data can be obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge CB12 1EZ, U.K [Fax: +44 1223 336033 or e-mail: deposit@ccdc.cam.ac.uk. The Supplemental Material file of CCDC includes the CIF file of 2a, 3a, 10a. The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27227862/s1, NMR spectroscopy data and X-ray analysis.

Author Contributions

Conceptualization, E.K.A. and I.V.B.; methodology, A.A.B.; validation, O.P.D., investigation, A.A.B., A.P.E., A.N.L. (synthetic chemistry), D.Y.P. (mass analysis) and O.P.D. (X-ray analysis); writing—original draft preparation, A.A.B. and I.V.B.; writing—review and editing, A.A.B. and I.V.B.; visualization, E.K.A.; supervision, O.P.D.; project administration, O.P.D.; funding acquisition O.P.D. All authors have read and agreed to the published version of the manuscript.

Funding

The authors express their gratitude to the North Caucasian Federal University for financial support in the framework of the project to support the projects of scientific groups and individual scientists.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Supporting Information data include NMR spectral charts.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of the all compounds are available from the authors.

References

  1. Bala, M.; Kumar, S.; Pratap, K.; Verma, P.K.; Padwad, Y.; Singh, B. Bioactive isoquinoline alkaloids from Cissampelos pareira. Nat. Prod. Res. 2019, 33, 622–627. [Google Scholar] [CrossRef] [PubMed]
  2. Huang, Q.-Q.; Bi, J.-L.; Sun, Q.-Y.; Yang, F.-M.; Wang, Y.-H.; Tang, G.-H.; Zhao, F.-W.; Wang, H.; Xu, J.-J.; Kennelly, E.J.; et al. Bioactive isoquinoline alkaloids from Corydalis saxicola. Planta Med. 2012, 78, 65–70. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Giri, P.; Kumar, G.S. Isoquinoline alkaloids and their binding with polyadenylic acid: Potential basis of therapeutic action. Mini Rev. Med. Chem. 2010, 10, 568–577. [Google Scholar] [CrossRef] [PubMed]
  4. Luo, C.; Wireko, M.A.; Wang, H.; Wu, C.; Wang, Q.; Zhang, H.; Cao, Y. Isoquinolines: Important Cores in Many Marketed and Clinical Drugs. Anti-Cancer Agents Med. Chem. 2021, 21, 811–824. [Google Scholar] [CrossRef]
  5. Jaryaram, V.; Sridhar, T.; Sharma, G.V.M.; Berrée, F.; Carboni, B. Synthesis of polysubstituted isoquinolines and related fused pyridines from alkenyl boronic esters via a copper-catalyzed azidation/aza-Wittig Condensation Sequence. J. Org. Chem. 2018, 83, 843–853. [Google Scholar] [CrossRef] [PubMed]
  6. Zhou, W.; Zhang, Y.-X.; Nie, X.-D.; Si, C.-M.; Sun, X.; Wei, G.-G. Approach to Chiral 1-Substituted Isoquinolone and 3-Substituted Isoindolin-1-one by Addition–Cyclization Process. J. Org. Chem. 2018, 83, 9879–9889. [Google Scholar] [CrossRef]
  7. Zhu, Z.; Tang, X.; Li, X.; Wu, W.; Deng, G.; Jiang, H. Palladium-Catalyzed C–H Functionalization of Aromatic Oximes: A Strategy for the Synthesis of Isoquinolines. J. Org. Chem. 2016, 81, 1401–1409. [Google Scholar] [CrossRef]
  8. Zhou, S.; Wang, M.; Wang, L.; Chen, K.; Wang, J.; Song, C.; Zhu, J. Bidentate directing-enabled, traceless heterocycle synthesis: Cobalt-catalyzed access to isoquinolines. Org. Lett. 2016, 18, 5632–5635. [Google Scholar] [CrossRef]
  9. Chu, H.; Xue, P.; Yu, J.-T.; Cheng, J. Rhodium-Catalyzed Annulation of Primary Benzylamine with α-Diazo Ketone toward Isoquinoline. J. Org. Chem. 2016, 81, 8009–8013. [Google Scholar] [CrossRef]
  10. Jacob, J.; Varghese, N.; Rasheed, S.P.; Agnihotri, S.; Sharma, V.; Wakode, S. Recent advances in the synthesis of isoquinoline and its analogue: A review. WJPPS 2016, 5, 1821–1837. [Google Scholar] [CrossRef]
  11. Yang, D.; Burugupalli, S.; Daniel, D.; Chen, Y. Microwave-assisted one-pot synthesis of isoquinolines, furopyridines, and thienopyridines by palladium-catalyzed sequential Coupling–Imination–Annulation of 2-bromoarylaldehydes with terminal acetylenes and ammonium acetate. J. Org. Chem. 2012, 77, 4466–4472. [Google Scholar] [CrossRef]
  12. Zheng, L.; Ju, J.; Bin, Y.; Hua, R. Synthesis of isoquinolines and heterocycle-fused pyridines via three-component cascade reaction of aryl ketones, hydroxylamine, and alkynes. J. Org. Chem. 2012, 77, 5794–5800. [Google Scholar] [CrossRef]
  13. Chinnagolla, R.K.; Pimparkar, S.; Jeganmohan, M. Ruthenium-Catalyzed Highly Regioselective Cyclization of Ketoximes with Alkynes by C–H Bond Activation: A Practical Route to Synthesize Substituted Isoquinolines. Org. Lett. 2012, 14, 3032–3035. [Google Scholar] [CrossRef]
  14. Clarke, P.A.; Santos, S.; Martin, W.H.C. Combining pot, atom and step economy (PASE) in organic synthesis. Synthesis of tetrahydropyran-4-ones. Green Chem. 2007, 9, 438–440. [Google Scholar] [CrossRef] [Green Version]
  15. Arends, I.; Sheldon, R.; Hanefeld, U. Green Chemistry and Catalysis; Wiley-VCH: Weinheim, Germany, 2007. [Google Scholar]
  16. Charushin, V.N.; Chupakhin, O.N. Nucleophilic C—H functionalization of arenes: A contribution to green chemistry. Russ. Chem. Bull. 2019, 68, 453–471. [Google Scholar] [CrossRef]
  17. Chupakhin, O.N.; Charushin, V.N. Recent advances in the field of nucleophilic aromatic substitution of hydrogen. Tetrahedron Lett. 2016, 57, 2665–2672. [Google Scholar] [CrossRef]
  18. Charushin, V.N.; Chupakhin, O.N. Metal-free C–H functionalization of aromatic compounds through the action of nucleophilic reagents. Top. Heterocycl. Chem. 2014, 37, 1–50. [Google Scholar] [CrossRef]
  19. Gulevskaya, A.V.; Pozharskii, A.F. The SNH-Amination of Heteroaromatic Compounds. Top. Heterocycl. Chem. 2013, 37, 179–239. [Google Scholar] [CrossRef]
  20. Budyka, M.F.; Terent’ev, P.B.; Kost, A.N. Amination of 5-azacinnoline with aromatic amines. Chem. Heterocycl. Compd. 1978, 14, 663–666. [Google Scholar] [CrossRef]
  21. Borovlev, I.V.; Demidov, O.P.; Saigakova, N.A.; Amangasieva, G.A. SNH-and SNipso-Arylamination of 1, 3, 7-Triazapyrenes. Eur. J. Org. Chem. 2014, 2014, 7675–7683. [Google Scholar] [CrossRef]
  22. Shchepochkin, A.V.; Chupakhin, O.N.; Charushin, V.N.; Steglenko, D.V.; Minkin, V.I.; Rusinov, G.L.; Matern, A.I. C–H functionalization of azines. Anodic dehydroaromatization of 9-(hetero) aryl-9, 10-dihydroacridines. RSC Adv. 2016, 6, 77834–77840. [Google Scholar] [CrossRef]
  23. Makhaeva, G.F.; Lushchekina, S.V.; Boltneva, N.P.; Serebryakova, O.G.; Rudakova, E.V.; Ustyugov, A.A.; Bachurin, S.O.; Shchepochkin, A.V.; Chupakhin, O.N.; Charushin, V.N.; et al. 9-Substituted acridine derivatives as acetylcholinesterase and butyrylcholinesterase inhibitors possessing antioxidant activity for Alzheimer’s disease treatment. Bioorg. Med. Chem. 2017, 25, 5981–5994. [Google Scholar] [CrossRef] [PubMed]
  24. Shchepochkin, A.V.; Chupakhin, O.N.; Charushin, V.N.; Rusinov, G.L.; Subbotina, Y.O.; Slepukhin, P.A.; Budnikova, Y.G. Stable σH-adducts in the reactions of the acridinium cation with heterocyclic N-nucleophiles. Russ. Chem. Bull. 2013, 62, 773–779. [Google Scholar] [CrossRef] [Green Version]
  25. Gulevskaya, A.V.; Tyaglivaya, I.N.; Verbeeck, S.; Maes, B.U.W.; Tkachuk, A.V. Oxidative arylamination of 1, 3-dinitrobenzene and 3-nitropyridine under anaerobic conditions: The dual role of the nitroarenes. Arkivoc 2011, 2011, 238–251. [Google Scholar] [CrossRef] [Green Version]
  26. Garnier, E.; Audoux, J.; Pasquinet, E.; Suzenet, F.; Poullain, D.; Lebret, B.; Guillaumet, G. Easy access to 3-or 5-heteroarylamino-1, 2, 4-triazines by SNAr, SNH, and palladium-catalyzed N-heteroarylations. J. Org. Chem. 2004, 69, 7809–7815. [Google Scholar] [CrossRef]
  27. Matern, A.I.; Charushin, V.N.; Chupakhin, O.N. Progress in the studies of oxidation of dihydropyridines and their analogues. Russ. Chem. Rev. 2007, 76, 23–40. [Google Scholar] [CrossRef]
  28. Makosza, M.; Wojciechowski, K. Nucleophilic Substitution of Hydrogen in Arenes and Heteroarenes. Top. Heterocycl. Chem. 2013, 37, 51–105. [Google Scholar] [CrossRef]
  29. Makosza, M. How does nucleophilic aromatic substitution in nitroarenes really proceed: General mechanism. Synthesis 2017, 49, 3247–3254. [Google Scholar] [CrossRef]
  30. Wróbel, Z.; Kwast, A. 2-Nitroso-N-arylanilines: Products of acid-promoted transformation of σH adducts of arylamines and nitroarenes. Synlett 2007, 10, 1525–1528. [Google Scholar] [CrossRef]
  31. Wróbel, Z.; Kwast, A. Simple synthesis of N-aryl-2-nitrosoanilines in the reaction of nitroarenes with aniline anion derivatives. Synthesis 2010, 2010, 3865–3872. [Google Scholar] [CrossRef]
  32. Kwast, A.; Stachowska, K.; Trawczyński, A.; Wróbel, Z. N-Aryl-2-nitrosoanilines as intermediates in the synthesis of substituted phenazines from nitroarenes. Tetrahedron Lett. 2011, 52, 6484–6488. [Google Scholar] [CrossRef]
  33. Wróbel, Z.; Stachowska, K.; Grudzień, K.; Kwast, A. N-Aryl-2-nitrosoanilines as Intermediates in the Two-Step Synthesis of Substituted 1, 2-Diarylbenzimidazoles from Simple Nitroarenes. Synlett 2011, 10, 1439–1443. [Google Scholar] [CrossRef]
  34. Wróbel, Z.; Wiecław, M.; Bujok, R.; Wojciechowski, K. Synthesis of pyrrolo [3, 2-a] phenazines from 5-nitroindoles and anilines. Monatsh. Chem. 2013, 144, 1847–1853. [Google Scholar] [CrossRef] [Green Version]
  35. Bashkin, J.K.; Rains, R.; Stern, M. Taking green chemistry from the laboratory to chemical plant. Green Chem. 1999, 1, G41–G43. [Google Scholar] [CrossRef]
  36. Triplett, R.D.; Rains, R.K. Process for Preparing 4-aminodiphenylamine Intermediates. US Patent 7504539 B2, 17 March 2009. [Google Scholar]
  37. Patriciu, O.-I.; Finaru, A.-L.; Sandulescu, I.; Guillaumet, G. Synthesis of Nitro N, N′-Dipyridinylamines via Oxidative Nucleophilic Substitution of Hydrogen. Synthesis 2007, 2007, 3868–3876. [Google Scholar] [CrossRef]
  38. Wozniak, M.; Baranski, A.; Nowak, K.; Poradowska, H. Regioselectivity of the amination of some nitroisoquinolines by liquid ammonia/potassium permanganate. Liebigs Ann. Chem. 1990, 1990, 653–657. [Google Scholar] [CrossRef]
  39. Woźniak, M.; Nowak, K. Amination of some nitroisoquinolines with liquid methylamine/potassium permanganate. Liebigs Ann. Chem. 1994, 1994, 355–360. [Google Scholar] [CrossRef]
  40. Demidov, O.P.; Pobedinskaya, D.Y.; Avakyan, E.K.; Amangasieva, G.A.; Borovlev, I.V. SNH Arylamination of Nitroquinolines: Access to Nitro and Nitroso Derivatives of Arylaminoquinolines. Chem. Heterocycl. Compd. 2018, 54, 875–886. [Google Scholar] [CrossRef]
  41. Stern, M.K.; Cheng, B.K. Amination of nitrobenzene via nucleophilic aromatic substitution for hydrogen: Direct formation of aromatic amide bonds. J. Org. Chem. 1993, 58, 6883–6888. [Google Scholar] [CrossRef]
  42. Stern, M.K.; Bashkin, K.J. Method of preparing 4-aminodiphenylamine. US Patent 5 117 063, 26 May 1992. [Google Scholar]
  43. Borovlev, I.V.; Demidov, O.P.; Kurnosova, N.A.; Amangasieva, G.A.; Avakyan, E.K. Direct oxidative SNH amidation of 1,3,7-triazapyrene. Chem. Heterocycl. Compd. 2015, 51, 170–175. [Google Scholar] [CrossRef]
  44. Demidov, O.P.; Borovlev, I.V.; Amangasieva, G.A.; Avakyan, E.K. Oxidative SNH amidation of acridine and tautomerism of N-(acridin-9-yl) benzamides. Chem. Heterocycl. Compd. 2016, 52, 104–109. [Google Scholar] [CrossRef]
  45. Amangasieva, G.A.; Borovlev, I.V.; Demidov, O.P.; Avakyan, E.K.; Borovleva, A.A. Synthesis of Amides by Nucleophilic Substitution of Hydrogen in 3-Nitropyridine. Russ. J. Org. Chem. 2018, 54, 867–872. [Google Scholar] [CrossRef]
  46. Amangasieva, G.A.; Avakyan, E.K.; Demidov, O.P.; Borovleva, A.A.; Pobedinskaya, D.Y.; Borovlev, I.V. SNH Amidation of nitroquinolines: Synthesis of amides on the basis of nitro-and nitrosoquinolines. Chem. Heterocycl. Compd. 2019, 55, 623–631. [Google Scholar] [CrossRef]
  47. Amangasieva, G.A.; Borovlev, I.V.; Demidov, O.P.; Kurnosova, N.A.; Avakyan, E.K. Urea in an aminodemethoxylation reaction of 6-methoxy-1,3,7-triazapyrenes. Chem. Heterocycl. Compd. 2015, 51, 586–588. [Google Scholar] [CrossRef]
  48. Borovlev, I.V.; Demidov, O.P.; Amangasieva, G.A.; Avakyan, E.K.; Kurnosova, N.A. Ureas as new nucleophilic reagents for SNH amination and carbamoyl amination reactions in the 1,3,7-triazapyrene series. ARKIVOC 2016, 2016, 58–70. [Google Scholar] [CrossRef] [Green Version]
  49. Borovlev, I.V.; Demidov, O.P.; Amangasieva, G.A.; Avakyan, E.K.; Kurnosova, N.A. Ureas as a New Nucleophilic Reagents for SNAr Amination and Carbamoyl Amination Reactions in 1,3,7-Triazapyrene Series. J. Heterocycl. Chem. 2017, 54, 406–412. [Google Scholar] [CrossRef]
  50. Borovlev, I.V.; Demidov, O.P.; Amangasieva, G.A.; Avakyan, E.K. Direct and facile synthesis of 9-aminoacridine and acridin-9-yl-ureas. Tetrahedron Lett. 2016, 57, 3608–3611. [Google Scholar] [CrossRef]
  51. Avakyan, E.K.; Borovlev, I.V.; Demidov, O.P.; Amangasieva, G.A.; Pobedinskaya, D.Y. SNH Alkyl carbamoyl amination of 3-nitropyridine: Competitive synthesis of nitro-and nitrosopyridine derivatives. Chem. Heterocycl. Compd. 2017, 53, 1207–1213. [Google Scholar] [CrossRef]
  52. Demidov, O.P.; Amangasieva, G.A.; Avakyan, E.K.; Borovlev, I.V. Nucleophilic Addition of Amides to 10-Alkylacridinium Cations: A Case of Double N-Nucleophilicity of Some Monoamides. Synthesis 2017, 49, 3710–3719. [Google Scholar] [CrossRef] [Green Version]
  53. Iriepa, I.; Bellanato, J. Synthesis, spectroscopic, structural and conformational study of some tri-substituted ureas derived from N-methylpiperazine containing phenyl and N-heterocyclic substituents. J. Mol. Struct. 2013, 1044, 215–220. [Google Scholar] [CrossRef]
  54. Annese, M.; Corradi, A.B.; Forlani, L.; Rizzoli, C.; Sgarabotto, P. Tautomerism in some acetamido derivatives of nitrogen-containing heterocycles: X-ray structural analysis of 2-amino and 2-imino forms of benzothiazole derivatives. J. Chem. Soc. Perkin Trans. 2 1994, 615–621. [Google Scholar] [CrossRef]
  55. Forlani, L.; Mezzina, E.; Boga, C.; Forconi, M. Tautomerism and Dimerization of Acetamidothiazole Derivatives− UV/Vis and NMR Spectroscopic Investigation. Eur. J. Org. Chem. 2001, 2001, 2779–2785. [Google Scholar] [CrossRef]
  56. Gottlieb, H.E.; Kotlyar, V.; Nudelman, A. NMR chemical shifts of common laboratory solvents as trace impurities. J. Org. Chem. 1997, 62, 7512–7515. [Google Scholar] [CrossRef]
  57. Sharp, J.T.; Gosney, I.; Rowley, A.G. Practical Organic Chemistry; Springer: London, UK; New York, NY, USA, 1989; p. 57. [Google Scholar]
Molecules 27 07862 sch001 550
Scheme 1. SNH Amidation of 5-nitroisoquinoline.
Scheme 1. SNH Amidation of 5-nitroisoquinoline.
Molecules 27 07862 sch001
Molecules 27 07862 sch002 550
Scheme 2. Proposed mechanism for the synthesis of nitro- 2a–f and nitroso compounds 3a–c.
Scheme 2. Proposed mechanism for the synthesis of nitro- 2a–f and nitroso compounds 3a–c.
Molecules 27 07862 sch002
Molecules 27 07862 g001 550
Figure 1. (a) ORTEP diagram of nitro compound 2a; (b) ORTEP diagram of nitroso compound 3a (The dashed line shows the intramolecular hydrogen bond). The crystallographic data could be found in the Supplementary Materials.
Figure 1. (a) ORTEP diagram of nitro compound 2a; (b) ORTEP diagram of nitroso compound 3a (The dashed line shows the intramolecular hydrogen bond). The crystallographic data could be found in the Supplementary Materials.
Molecules 27 07862 g001
Molecules 27 07862 sch003 550
Scheme 3. Synthesis and tautomerism of compound 7.
Scheme 3. Synthesis and tautomerism of compound 7.
Molecules 27 07862 sch003
Molecules 27 07862 sch004 550
Scheme 4. Proposed pathway for the formation of the compound 7.
Scheme 4. Proposed pathway for the formation of the compound 7.
Molecules 27 07862 sch004
Molecules 27 07862 sch005 550
Scheme 5. SNH Reactions of 5-nitroisoquinoline (1) with an ureas.
Scheme 5. SNH Reactions of 5-nitroisoquinoline (1) with an ureas.
Molecules 27 07862 sch005
Molecules 27 07862 g002 550
Figure 2. ORTEP diagram of nitroso compound 10a. The crystallographic data could be found in the Supplementary Materials.
Figure 2. ORTEP diagram of nitroso compound 10a. The crystallographic data could be found in the Supplementary Materials.
Molecules 27 07862 g002
Table
Table 1. Optimization of the Reaction Conditions of SNH Amidation of 5-Nitroisoquinoline (1) with the p-Methylbenzamide N-anion in anhydrous DMSO (Method A).
Table 1. Optimization of the Reaction Conditions of SNH Amidation of 5-Nitroisoquinoline (1) with the p-Methylbenzamide N-anion in anhydrous DMSO (Method A).
EntryReaction Time, hExcess of NaH, EquivExcess of Amide, EquivYield, % a
2a3a
1 b1.5221926
2 b1.54430traces
3 b1.566247.5
4 b1.51345traces
5 b1.5422815
6 b,c1.52228traces
7 d0.52240traces
8 b,e1.5221523
a Isolated yields after column chromatography. b The experiment was performed at room temperature. c The experiment was performed in presence of K3Fe(CN)6. d The experiment was performed at 60 °C. e The reaction was performed under argon.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Avakyan, E.K.; Borovleva, A.A.; Pobedinskaya, D.Y.; Demidov, O.P.; Ermolenko, A.P.; Larin, A.N.; Borovlev, I.V. SNH Amidation of 5-Nitroisoquinoline: Access to Nitro- and Nitroso Derivatives of Amides and Ureas on the Basis of Isoquinoline. Molecules 2022, 27, 7862. https://doi.org/10.3390/molecules27227862

AMA Style

Avakyan EK, Borovleva AA, Pobedinskaya DY, Demidov OP, Ermolenko AP, Larin AN, Borovlev IV. SNH Amidation of 5-Nitroisoquinoline: Access to Nitro- and Nitroso Derivatives of Amides and Ureas on the Basis of Isoquinoline. Molecules. 2022; 27(22):7862. https://doi.org/10.3390/molecules27227862

Chicago/Turabian Style

Avakyan, Elena K., Anastasia A. Borovleva, Diana Yu. Pobedinskaya, Oleg P. Demidov, Artem P. Ermolenko, Alexander N. Larin, and Ivan V. Borovlev. 2022. "SNH Amidation of 5-Nitroisoquinoline: Access to Nitro- and Nitroso Derivatives of Amides and Ureas on the Basis of Isoquinoline" Molecules 27, no. 22: 7862. https://doi.org/10.3390/molecules27227862

Article Metrics

Back to TopTop