Aniline, derivatives

The most important uses for aniline today are the production of 4,4 -diphenyl-methane diisocyanate (MDI) and chemicals used in rubber processing, especially as vulcanization accelerators or antioxidants. Additional applications, which were dominant in former times, e.g. dyestuffs, plant protection agents and raw materials for fibers, complete the range of aniline applications. 

The most important commercial intermediates from aniline are the mixture of 4,4 - and 2,4 -diaminodiphenylmethane, obtained by reaction with formaldehyde, and the higher polyamines as well as 2-mercaptobenzothiazole and cyclohexyl-amine, used as rubber additives. N,N-Dialkylanilines are commonly used for the production of dyestuffs, while phenylhydrazine is used as an intermediate in the manufacture of plant protection agents, pharmaceuticals and dyestuffs. Other important aniline products are sulfanilic acid and acetanilide. 

Many local anesthetics have a selective depressant action on heart muscle when given system cally. This is useful in t.reatment of cardiac arrhythmias, and a 1 idocaine-1 ike drug with this kind of action is tocainide (2).  

Part of the reason for ortho substitution in such compounds is to decrease metabolic transformation by enzymic 

When the side chain involves an unsymmetrical urea moiety, muscle relaxant activity is often seen. One such agent, 1 id-amidi ne ( ) exerts its activity as an anti peristaltic agent. Its synthesis involves the straightforward reaction of 2,6-di- 

J -methylpyrrolidone by conversion to the imine ( 7) by sequential reaction with triethyloxonium tetraf1uoroborate and then anhydrous ammonia. When this is reacted with 2,6-dimethyl-phenyl i socyanate, the centrally acting muscle relaxant xilobam (8) is formed.  

A number of muscle relaxants are useful anthelmintic agents. They cause the parasites to relax their attachment to t he gut wall so that they can be eliminated. One such agent s carbantel 9), Its synthesis follows the classic pattern of r eaction of 4-chlorophenyl isocyanate with ji -amylamidine.  

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The diazonium salts 145 are another source of arylpalladium com-plexes[114]. They are the most reactive source of arylpalladium species and the reaction can be carried out at room temperature. In addition, they can be used for alkene insertion in the absence of a phosphine ligand using Pd2(dba)3 as a catalyst. This reaction consists of the indirect substitution reaction of an aromatic nitro group with an alkene. The use of diazonium salts is more convenient and synthetically useful than the use of aryl halides, because many aryl halides are prepared from diazonium salts. Diazotization of the aniline derivative 146 in aqueous solution and subsequent insertion of acrylate catalyzed by Pd(OAc)2 by the addition of MeOH are carried out as a one-pot reaction, affording the cinnamate 147 in good yield[115]. The A-nitroso-jV-arylacetamide 148 is prepared from acetanilides and used as another precursor of arylpalladium intermediate. It is more reactive than aryl iodides and bromides and reacts with alkenes at 40 °C without addition of a phosphine ligandfl 16]. 

A Pd-cataly2ed reaction of amines with halides is expected, but actually little is known about the reaction. The CDE ring system of lavendamycin (805) has been constructed by the intramolecular reaction of aryl bromide with aniline derivative in 804, but 1.2 equiv, of Pd(Ph3P)4 is required[679]. 

Category Ic cyclizations involve formation of the C3-C3a bond and require aniline derivatives with a nitrogen substituent appropriate for such reaction. Some, but not all, such cyclizations also require an o-substituent, frequently halogen. The rctrosynthetic transformations corresponding to the most important of this group of syntheses are shown in Scheme 4.1... 

In aniline derivatives (458) the mechanism of this reaction is still not fully settled (459-461). However, the latest results seem to favor a pathway that, applied to 2-nitraminothiazole, would give Scheme 138, where the key step is the formation of a radical ion (223). Reexamination of the original reports on this reaction (16, 374, 378. 462) with EPR and Chemically Induced Dynamic Nuclear Polarisation techniques could be fruitful. 

Rubber chemicals, primarily antioxidants (qv), stabiLhers, and antio2onants (qv), account for 12% of the demand for aniline woddwide. Important agricultural uses for aniline derivatives include fungicides, insecticides, animal repellents, and defoHants. It is estimated that less than 5% of the aniline produced in 1988 was consumed for agricultural chemicals. 

Production figures for the aminophenols are scarce, the compounds usually being classified along with many other aniline derivatives (86). Most production of the technical grade materials (95% purity) occurs on-site as they are chiefly used as intermediate reactants in continuous chemical syntheses. World production of the fine chemicals (99% purity) is probably no more than a few hundred metric tons yearly, at prices of about 45 per kg in 1990. 

Guanidines. Guanidines (10) were one of the first aniline derivatives used as accelerators. They are formed by reaction of two moles of an aromatic amine with one mole of cyanogen chloride. Diphenylguanidine (DPG) has enjoyed a resurgence ia demand as an activator for sulfenamides and a co-accelerator ia tire tread compounds which employ siUca fillers for low rolling resistance. Guanidines alone show too Htde activity to be extensively used as primary accelerators. There were no U.S. producers as of mid-1996. 

The o-nitrobenzyl and p-nitrobenzyl ethers can b prepared and cleaved by many of the methods described for benzyl ethers. The p-nitrobenzyl ether is also prepared from an alcohol and p-nitrobenzyl alcohol (trifluoroacetic anhydride, 2,6-lutidine, CH2CI2, 67% yield). In addition, the o-nitrobenzyl ether can be cleaved by irradiation (320 nm, 10 min, quant, yield of carbohydrate " 280 nm, 95% yield of nucleotide ). The p-nitrobenzyl ether has been cleaved by electrolytic reduction (—1.1 V, DMF, R4N X, 60% yield) and by reduction with Na2S204 (pH 8-9, 80-95% yield). These ethers can also be cleaved oxidatively (DDQ or electrolysis) after reduction to the aniline derivative. ... 

Certain reactions between carbonyl compounds and nucleophiles are catalyzed by amines. Some of these reactions are of importance for forming carbon-carbon bonds, and these are discussed in Chapter 2 of Part B. The mechanistic principle can be illustrated by considering the catalysis of the reaction between aldehydes and hydroxylamine by aniline derivatives. 

Therefore it is possible to determine absorption spectra directly on the TLC plate by comparison with a substance-free portion of the layer. The wavelengths usually correspond to the spectra of the same substances in solution. However, adsorbents (silanols, amino and polyamide groups) and solvent traces (pH differences) can cause either bathochromic (ketones, aldehydes [60, 61], dyestuffs [62]) or hypsochromic (phenols, aniline derivatives [63]) shifts (Fig. 23). 

Phenylurea herbiades are first hydrolyzed to the corresponding aniline derivatives and then reacted at the start with 4 pi 0 25% dansyl chlonde solution... 

The Hegedus indole synthesis involves one of the earlier (formal) examples of olefin hydroamination. An ortho-vinyl or ortho-nllyl aniline derivative 1 is treated with palladium(II) to deliver an intermediate resulting from alkene aminopalladation. Subsequent reduction and/or isomerization steps then provide the indoline or indole unit 2, respectively. 

P-amino acid products. Treatment of oxazoline 53 with 7V-lithiopiperidine followed by alkylation with iodomethane affords aniline derivative 54 in 94% yield and 99% de. Hydrolysis of the oxazoline group provided amino acid 55 in 92% yield and >99% ee. 

A number of dihydroquinolines have been prepared by treating aniline derivatives with acetone or mesityl oxide in the presence of iodine. In these cases aromatization to the fully unsaturated quinoline would require the loss of methane, a process known as the Riehm quinoline synthesis. Such Skraup/Doebner-von Miller-type reactions are often low yielding due to large amounts of competing polymerization. For example, aniline 37 reacts with mesityl oxide to give dihydroquinolines 39, albeit in low yield. ... 

Indoles 118 (99IZV400, 99RCB398) and indolizines 120 (99IZV2375, 99RCB2349) have been obtained by the condensation of suitably functionalized pyridinium salts 119 and aniline derivatives (Scheme 71). 

Tamaoku and colleagues presented an efficient enzymatic photometric determination of hydrogen peroxide ffiat is essentially a color reaction resulting from the oxidative condensation of A/-ethyl-A/-(2-hydroxy-3-sulfopropyl)aniline derivatives wiffi 4-aminoantipyrine in the presence of hydrogen peroxide and peroxidase (82CPB2492). A similar calorimetric detection of hydrogen peroxide has been patented (83GEP3301470). 

Reaction of aniline derivatives with 4-chlorobutyroyl chloride followed by cyclization with sodium ethoxide and subsequent thionation promoted by sonication gave the corresponding A -arylpyrrolidine-2-thiones 126. Zinc-mediated condensation of diethyl bromomalonate with 126 using iodine as activator gave the vinylogous urethanes 127 whose cyclization with PPA gave the tricyclic compound 128 which upon hydrolysis afforded the acid 129 (96TL9403). 

The aniline derivative 332, prepared from 2-fluoro-6-nitrotoluene, was transformed through successive reactions as shown in Scheme 60 to give the functionalized indole 333. It was then reduced with LiAlH4 to the dimethylaminopropyl derivative which was quaternized with Mel to the trimethyl ammonium salt 334. Subsequent cyclization and functionalization afforded the pyrroloquinoline 335. The latter could be transformed to the tetracyclic acid 336 (90JHC2151). (Scheme 60)... 

A simple aniline derivative acts as a prostatic antiandro-t (>n. Its synthesis involves simple acylation of disubstituted iiriiline 13 with isobutyryl chloride to give flutamide (14). 

A compound closely related to classical adrenergic agonists in which the para hydroxy function is however replaced by an amino group has been investigated for its activity as a growth promoter in domestic animals. Acylation of the aniline derivative 26 with chloracetyl chloride will afford acetophenone 27 the amino-ketone 28 is obtained on reaction with isopropylamine. Removal of the protecting group (29) followed by reduction of the ketone affords cimaterol (30) 5J. 

Another useful aniline derivative is acetanilide, which is simply the amide formed from aniline and acetic arid ... 

Azcpincs under acid conditions reportedly117-225 yield aniline derivatives although ring contraction to pyridines is more usual. Thus, highly substituted 3//-azepines, e.g. 28, with a vacant 7-position, formed by cycloaddition of 2//-azirines with cyclopentadienones, on heating in acetic acid isomerize rapidly to the correspondingly substituted anilines 29.117... 

The basic principle of all diazotizations of aromatic amines with a hydroxy- or a sulfonamido group in the 4-position relative to the amino group involves a deprotonation of the OH or NH group, respectively, after diazotization of the amino group. There is also a case of a deprotonation of a CH group in the 4-position of an aniline derivative, namely in the diazotization of 4-aminophenylmalononitrile (2.41) which, by the sequence of steps shown in Scheme 2-23, yields 3-diazo-6-dicyanomethylene-1,4-cyclohexadienone (2.42), as found by Hartzler (1964). This product can also be represented by a zwitterionic carbanion-diazonium mesomeric structure. 

AG° was calculated for eleven amines, ranging from 2,4-dinitroaniline (AG° = + 50 kJ mol-1) to aniline ( — 41), 4-morpholinoaniline ( — 99), and 4-dimethyl-aminoaniline ( — 108). The results demonstrate clearly that a primary electron transfer is very likely, at least for those aniline derivatives with a strong electron donor in the 4-position. 

The rate-limiting step in diazotizations with nitrosyl halides can in some cases be the formation of the nitrosyl halide (Scheme 3-26) this occurs with very reactive aniline derivatives (Hughes and Ridd, 1958). Alternatively it can be the deprotona-... 

The base of the aniline derivative has zero charge, and therefore H0 has to be used in 2-aminothiazole the heterocyclic nitrogen is protonated first and at much lower acidities than is the amino group (see Sec. 3.2). The protonation of the amino group of a cationic species therefore has to be treated using the H+ function (Rochester, 1970). 

Benzo-l,2,3-triazin-4-ones with the general structure 6.54 (X = O, S, or H2) are obtained by diazotization of the appropriate aniline derivatives 6.53 (Scheme 6-38). In polar aprotic solvents (e. g., nitrobenzene) the reverse reaction takes place to give the diazonium ion (for an example see Kullick, 1966). Diazotization of 1,8-diamino-naphthalene yields l-i/-naphthol[l,8-cfe]triazine (6.55 Tavs et al., 1967). In concentrated HC1 the triazine ring is opened again. 

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