Recent advances in ipso -nitration reactions

In the present review the various types of ipso -nitration reactions, in particular those advances in ipso - nitration reactions that have been reported since the beginning of this century (i


Introduction
The nitration 1,2 of organic compounds (aliphatic, aromatic, heterocyclic, and others) is one of the key reactions of both organic synthesis and organic chemistry in general. 3,4][10] A key difference between ordinary nitration and ipso-nitration is described in Figure 1.The key difference between nitration and ipso-nitration.
The ipso-nitration of organic compounds was initially developed with the use of nitric acid (HNO3) or nitrating mixtures (HNO 3 /AcOH or HNO 3 /H 2 SO 4 ), approaches which are now referred to as traditional or classical methods.However, there are several problems with these traditional methods when it comes to forming regioselective nitro products.However, in spite of these problems, researchers have nonetheless tried, in the hope of obtaining selective nitro products, to refine these nitrating mixtures by increasing or decreasing the levels of nitric acid in the mixtures, by using catalysts or non-catalytic methods and various metal salts in making the mixtures, and by bypassing poor regioselectivity, low yields, and the formation of undesired by-products.
In recent years, several literature investigations have focused on such reported developments of ipsonitration reactions.In this review, we provide a general overview of recent advances and developments in ipso-nitration reactions that have been reported since the beginning of this century (i.e., in the period 2000-2015).Scheme 1. ipso-Nitration of tert-butylcalix [4]arene.

ipso-Nitration of heterocycles
][25][26] This research also revealed that, in the absence of a substituent in position 3, the electrophilic ipsosubstitution of the methyl group by a nitro group with the formation of a 5-nitro derivative would take place.Thus, we found that, when the interaction of the compounds with electron-donating groups at N-3 position of the thienopyrimidine molecule was conducted with a nitrating mixture (HNO3/H2SO4 at 0-5 o C), instead of the ipso-nitration of methyl groups at C-5 the reaction proceeded in an unexpected direction, i.e., there was oxidation of the methyl groups.

Cerium (IV) ammonium nitrate (CAN) as nitrating agent
Messere et al. described the ipso-nitration reaction of substituted cinnamic acids with cerium (IV) ammonium nitrate (CAN) with the support of silica in a solid-phase approach. 27In their work, substituted-hydroxycinnamic acids were selected as substrates, and among them, only 4-hydroxycinnamic acid, when reacted under the above conditions for 15 min.in methanol, produced an ipso-nitration product in a yield as high as 34%.It was observed, that during the reaction process formed nitration products (57%) and 4-hydroxycinnamaldehyde (4%) as a side product in low yields (Scheme 8).When cinnamic acid was reacted with CAN/SiO2, it failed to produce any ipso-nitration product; rather, the retention of the carboxylic functional group was observed.Scheme 8. ipso-Nitration of 4-hydroxycinnamic acid with CAN/SiO2.
On the other hand, the ipso-nitration of a vinyl carboxyl group with HNO3 is unusual.Probably, the ipsonitrated product and 4-hydroxycinnamic acid go through hydrolysis and oxidation to yield benzoic acid, which is then susceptible to ipso-nitration with decarboxylation. 28,29aLonde and colleagues discovered that the use of CAN in acetic acid/water (9:1) results in the conversion of (3aR,4S,9aR) and (3aR,4S,9aS) tetrahydrofurans into ipso-products via simultaneous ipso-nitration and oxidation through the opening of the B-ring of the tetrahydrofurans (Scheme 9).Scheme 9. ipso-Nitration of (3aR,4S,9aR) and (3aR,4S,9aS) tetrahydrofurans with CAN When the (3aR,4S,9aS) derivative was treated with CAN in neat acetic acid, the yield of the final product rose to 41%, whereas the treatment of (3aR,4S,9aR) derivative under the same conditions resulted in a similar yield of mononitroburseran (39%) favoring one of two diastereomeric acetates.
Scheme 10.Proposed mechanism for the decarboxylative ipso-nitration.In 2015, Azad et al. developed an efficient, cost-effective, and green methodology for the ipso-nitration of 3-carboxy-4-quinolones via the quantitative use of copper acetate and silver nitrate in water. 32The effect of the metal nitrating agent, catalyst, and solvent was investigated under the conditions of an open atmosphere and a temperature of 100 o C over 24 h, with 7-chloro-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid used as the substrate.Copper (II) acetate was selected for the condition screening with AgNO3 as a nitrating agent, and water as the solvent.The results indicated that 60 mol% Cu(OAc)2 converted the substrate Page 51 © ARKAT USA, Inc into a nitro product at 92% yield (Table 4).When NaNO3 and La(NO3)3 were each used as the nitrating agent, the nitro products were formed at yields of 72 and 66%, respectively.The reaction did not proceed at all if no catalysts were used.Copper (I) was also effective, albeit affording lower yields.Further, the same researchers used dihalo (F/Cl, F/F, and Cl/Cl) quinolones related with various alkyl groups at the N1 position for ipso-nitration.Ipso products were obtained in yields 80-96%, when the relevant reactions were allowed proceeded for 12-20 hrs (Table 5).

ipso-Nitration of halogens
In order to circumvent the need for a phase transfer catalyst, Lakshmi Kantam and colleagues studied the copper catalyzed ipso-nitration of iodoarenes, bromoarenes, and heterocyclic haloarenes under ligand-free conditions. 33In their experiments, 4-bromothioanisole was initially selected as the substrate for performing the optimization reaction, while 25 mol% copper salts and 3 equiv of KNO2 were selected as the catalysts and nucleophile, respectively.Among the various optimization studies for the ipso-nitration of 4-bromothioanisole, the most promising result (an 84% yield) was obtained using 25 mol% of Cu(OSO2CF3)2 and 3 equiv of KNO2 in 0.6 mL of DMSO at 130 o C. A wide variety of electron-rich and electron-deficient iodoarenes and bromoarenes were then studied for ipso-nitration after the optimization.It was observed that a lot of electron-rich haloarenes reacted smoothly, irrespective of the nature and orientation of the functional groups present, to produce the nitro products in good yields (Table 6).It is important to note that several functional groups, including NO2, CHO, CN, COPh, NMe2, OCH2Ph, OMe, SMe, Ph, and Me, were tolerated in this condition, except for 4-bromoaniline and 4iodophenol.In addition, this method could be carried out for the ipso-nitration of heterocycles such as 2-

ipso-Nitration of arylboronic acids
Surya Prakash and co-workers have reported a simple, convenient, and mild method for the ipso-nitration of arylboronic acids using inorganic nitrate salt and chlorotrimethylsilane (TMSCl) (Table 7). 34In this type of ipsonitration, 2-10% nitrochlorination was observed in certain cases.It was found that when AgNO3 was used instead of NH4NO3 as the nitrate salt, the extent of chlorination was significantly decreased.In addition, it was investigated the effect of various nitrate salts and solvents on ipso-nitration reactions and it was observed that AgNO3 and DCM provided the best results, respectively.TMSCl reacts with nitrate salts to generate TMS-O-NO2 species.The dinitro product, however, was not observed in any such reactions; it is likely that there exists a prominent electronic interaction between the boronic acid group and the intermediate active nitrating agent TMS-O-NO2 species via the boron and the siloxy group due to the high oxophilicity of boron (Scheme 11).This would help the nitration to occur at the ipso position.TMS-O-NO2 can then undergo further reaction with excess TMSCl to produce hexamethyldisiloxane and nitryl chloride, which can also act as the nitrating species.For the generation of nitryl chloride, an excess of TMSCl is required, but it was observed that phenylboronic acid can undergo nitration completely with 1 equiv of TMSCl.Generally, this reaction takes 72 h for completion.It should be noted, that this method was found more selective than the method in which Crivello's reagent 35 were used to provide the ipso-nitration products in moderate to high yields.Another significant feature of this method is the complete absence of dinitro product.Based on this result, the same group studied the interaction of arylboronic acids with a NaNO2-TMSCl system, and ultimately observed ipso-nitrosation reactions in most cases. 36Initially, 4-methoxyphenylboronic acid was selected for optimization, and was then added to a stirred mixture of NaNO2 (2.2 equiv) and TMSCl (2.2 equiv) in anhydrous dichloromethane under argon at room temperature for 72 h.However, as the initial results proved to be unsuccessful, the conditions of an open-air atmosphere and the addition of 0.5 equiv of water were applied for a reaction time of 3 h., all of which appeared to be suitable conditions for the reaction.The mechanism of the ipso-nitrosation reaction of arylboronic acids with sodium nitrite and TMSCl (Scheme 12) is similar to the mechanism illustrated above in Scheme 12, the key difference being the formation of TMS-O-NO species instead of TMS-O-NO2 species.If arylboronic acids with various substituents in the aromatic portion react under the above conditions, ipso-nitrosation and ipso-nitration products in different ratios can be observed as the final resulting compounds (Table 8).It was observed, for example, that 4-alkoxy-and 4-phenoxyphenylboronic acids underwent the reaction smoothly to produce the corresponding nitrosoarenes in both high yields and good chemoselectivities.On the whole, the amount of nitro products was found to decrease with the increasing electron donating ability of the substituents.However, electron-rich 2-alkoxy substituted phenylboronic acids produce relatively low yields with these substrates, apparently because the inductive effect of oxygen may also play a pivotal role in the reaction yield (Table 8).
A simple and convenient method for the conversion of arylboronic acid to nitroarenes using Bi(NO3)3•5H2O/K2S2O8 as the nitrating agent was reported by Manna et al. in 2012. 37In their research, this ipso-nitration protocol was investigated in the context of reactions of phenylboronic acid with different nitrate sources in various solvents.The best result was achieved with 1 mmol of Bi(NO3)3•5H2O with 0.5 mmol of the arylboronic acids at 80 o C. Other nitrate sources such as NaNO3, Pb(NO3)2, NaNO2, and AgNO2 failed to yield the nitro products.However, if Cd(NO3)2 was used as the nitrating agent at 100°C, nitro products was formed in a yield of 51%, while a better result was obtained with AgNO3 under the same reaction conditions.Herein, ipso-nitration proceed successfully in solvents such as toluene, o-xylylene, benzene, and trifluorotoluene, but it was observed that temperatures higher than 80 o C led to lower conversion due to increased protodeboronation reactions, therefore, only toluene and benzene were used in further investigations.Furthermore, the Bi(NO3)3 •5H2O/K2S2O8 catalyzed transformation of arylboronic acids to nitroaromatics has also been studied (Table 9).ipso-Nitration of the heterocyclic, alkyl, and aryl substituted arylboronic acids formed products in good to excellent yields (63-96%), including with base-sensitive functional groups such as keto with an acidic alkyl and ester group (Table 9).
Ar NO 2 Ar  Scheme 13.Proposed mechanism for ipso-nitration of arylboronic acid.
The mechanism of ipso-nitration by Bi(NO3)3•5H2O is illustrated in Scheme 14.At first, the researchers investigated whether the catalyst-free ipso-nitration occurs via a free-radical mechanism; the reaction of phenylboronic acid was performed in the presence of the free-radical scavengers TEMPO and thiourea.The reaction took place smoothly in the presence of TEMPO and thiourea, thus ruling out the possibility of a freeradical mechanism.The fact that aliphatic boronic acid did not participate in this reaction indicates that the aromatic ring plays an important electronic role in the ipso-nitration and that bismuth nitrate is presumably responsible for the in situ production of Bi-O-NO2 species.Insofar as boron is highly oxophilic, it is likely that through electronic interactions between the boronic acid group and the species of Bi-O-NO2, be formed an ionic species, which helps to occur the ipso-nitration reactions.Chatterjee et al. reported a highly efficient [bis-(trifluoroacetoxy)]iodobenzene (PIFA)-mediated oxidative regioselective nitration of aryl-, alkyl-and heteroarylboronic acids, with their first example being the use of a PIFA-NBS-NaNO2 combination to generate nitroarenes under transition metal-free conditions. 39In their study, it was observed that the presence as well as the amount of an additive (NBS) is important for better conversion of the organoboronic acids to the nitroarenes.Increasing the amount of NBS to 2.1 eq. and that of PIFA to 3.0 eq.resulted in quantitative ipso-nitration of the m-tolylboronic acid.In addition, the PIFA-mediated ipso-nitration of aryl-, alkyl-and heteroarylboronic acids with either an electron donating or withdrawing group, which was investigated in their work, was found to generate nitro compounds in excellent yields (74-94%) (Table 11).
The preliminary mechanism of these previously investigated reactions probably takes place via the generation of an O-centered radical in the presence of NBS and PIFA; this further reacts with the nitro radical, which itself is formed through the one-electron oxidation of NaNO2 in the presence of PIFA, to form the metastable species A.
After all, as shown in Scheme 15, the nitroarenes are formed via nitro transfer to the aryl moiety through 1,3-aryl migration from the tetra-coordinated species B, which is itself produced from A through coordination by the succinimide.Recently, Yang and colleagues reported a simple, efficient, and practical ipso-nitration of arylboronic acids with 0.5 equiv. of iron nitrate without the addition of any additive. 40At first, 4-methylboronic acid was selected as a substrate and the reaction conditions were studied systematically with a variety of nitrate salts and solvents; in addition, various reaction temperatures and atmospheres were also screened (Table 12).If the reaction was performed under air or oxygen atmosphere, the final product yields were reduced.When 4-methylboronic acid was reacted with Fe(NO 3 ) 3 •9H 2 O under a nitrogen atmosphere in toluene (at 80 o C), however, nitro products were obtained at a yield of 93%.Therefore, it was selected as the optimal conditions for further ipso-nitration reaction.For instance, screening of the ipso-nitration of arylboronic acids with electron-donating and electron-withdrawing groups indicated that final products were obtained in higher yields with the arylboronic acids with electron-donating groups than with those containing electronwithdrawing groups (Table 13).

Conclusions
In summary, the recent advances in ipso-nitration reactions, including those carried out via both classical and modern methods have been highlighted in this review.The most commonly used traditional ipso-nitration reaction involves the synthesis of nitrocalixarenes, whereas arylboronic acids are preferred in the more modern approaches using various metal salts and mild nitrating agents.In the 1990s, it was observed that, in a lot of experimental investigations, only alkyl groups were transformed into nitro groups by ipso-nitration.However, this type of reaction has been noticeably developed in more recent years, and now various functional groups, such as hydroxyl, carbonyl, carboxyl, cycloalkane, and halo-derivatives, can be converted into selective nitro products, whereby can be used as building blocks in organic synthesis.Thus, our research group believes that, in organic synthesis methodology, the conversion of any functional group into a nitro group will always be an important point to consider, which is why perspectives on ipso-nitration will continue to develop in the future.

Scheme 15 .
Scheme 15.Mechanism of the ipso-nitration of organoboronic acids in the presence of NBS.

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22showed this by applying a comparative analysis to a variety of reaction conditions (Table2).As indicated, ipso-nitration with acetic anhydride/nitric acid ensures a good yield of p-nitrocalix[n]arenes; however, a similar reaction with p-tert-butylcalix[n]arenes leads to a mixture from which nitrocalix[n]arenes can only be separated in lower yields due to acetylation.Similarly, the use of CAN/acetic acid also produces lower yields due to the oxidation of substrates.

Table 3 .
ipso-Nitration of alkyl and aryl carboxylic acids

Table 4 .
Effect of copper salts and nitrating agents on ipso-nitration

Table 12 .
Continued a Under air.b Under oxygen atmosphere.