Benzylamine isomerization

The increasingly common theme of developing new pyrrole syntheses that involve cyclopropane fragmentations appeared in a type Ilae pyrrole synthesis <06OL835>. Treatment of doubly activated cyclopropane 43 with benzylamine in the presence of magnesium sulfate led to complex pyrrole 44 via a nucleophilic cleavage of the cyclopropane ring, intramolecular condensation, and isomerization of the exocyclic JC-bond. 

When benzyl chloride is treated with ammonia under suitable conditions benzylamine, C6H5.CH2NH2, is obtained. It is a rather strong, liquid base which exhibits all the characteristics of the aliphatic amines and differs completely from the ring-substituted aminotoluenes (tolui-dines) which are isomeric with it. 

The triplet reaction of 2-nitrodibenzo[fc,primary amines (n-propylamine and benzylamine) was studied110 in polar and apolar solvents. In polar solvents, the irradiation results in the formation of two isomeric compounds, (alky-lamino)hydroxynitrodiphenyl ether andiV-(alkylamino)-2-nitrophenoxazine (equation 54). In apolar solvents, only the nitrophenoxazine is obtained. In polar solvents, the exciplex formed between the 2-n i trodi benzol h,e [ 1,4]dioxin triplet state and amines dissociates to the solvated radical ions, from which the diphenyl ether arises. 1-Nitrodibenzo[fr,e][l,4]dioxin is stable even on prolonged irradiation. 

A a-5-bonded r-alkene (r] ) intermediate (325) has been invoked to account for the hydrogenation of the thiaplatinacycle (324) to the complex (326) in which two hydrogens have been added and a hydrogen shift has occurred." When coordinated to neutral and cationic palladium(II) and platinum(II) centres, the diphosphine 2,3-bis(diphenylphosphino)propene, on treatment with benzylamine, was found to undergo isomerization to coordinated c/i-l,2-bis(diphenylphosphino)propene rather than the expected nucleophilic addition to the double bond. 

Structures have been determined for [Fe(gmi)3](BF4)2 (gmi = MeN=CHCF[=NMe), the iron(II) tris-diazabutadiene-cage complex of (79) generated from cyclohexanedione rather than from biacetyl, and [Fe(apmi)3][Fe(CN)5(N0)] 4F[20, where apmi is the Schiff base from 2-acetylpyridine and methylamine. Rate constants for mer fac isomerization of [Fe(apmi)3] " were estimated indirectly from base hydrolysis kinetics, studied for this and other Schiff base complexes in methanol-water mixtures. The attenuation by the —CH2— spacer of substituent effects on rate constants for base hydrolysis of complexes [Fe(sb)3] has been assessed for pairs of Schiff base complexes derived from substituted benzylamines and their aniline analogues. It is generally believed that iron(II) Schiff base complexes are formed by a template mechanism on the Fe " ", but isolation of a precursor in which two molecules of Schiff base and one molecule of 2-acetylpyridine are coordinated to Fe + suggests that Schiff base formation in the presence of this ion probably occurs by attack of the amine at coordinated, and thereby activated, ketone rather than by a true template reaction. ... 

The adduct of benzylamine to the chloro ester 1-fBu (89b-fBu) in a three-step sequence yielded the -lactam 107 and the isomeric iminolactone 108 in approximately equal amounts (Scheme 36) [26]. The mechanism for the formation of 108 remains unknown presumably it was formed from 107 via a 1,3-shift, in fact 107 and 108 are stable in pure form, but would be equilibrating under the reaction conditions. 

Diphenyl-2//-thiopyran 233 is one of the products (12 to 72%) formed by ethanolic methylamine, ethylamine, benzylamine or triethylamine with 2,4-diphenylthiopyrylium perchlorate.273 Trichlorosilane was found to demethylate thiabenzene sulfoxide 234 reductively to mixtures of isomeric thiopyrans 222 and 223.267,274... 

Rhodium-catalyzed hydroformylation of 2-amino-/V-(but-3 -enyl)- and -A-(3 -rnethylbut-3 -enyi)benzylamines (381) in the presence of rho-dium(II) acetate dimer and triphenylphosphine in deoxygenated ethyl acetate gave mixtures of 5,5a,6,7,8,9-hexahydro-llH-pyrido[2,l-b]quinazo-line (382), isomeric 6-methyl-5,5a,6,7,8,10-hexahydropyrrolo[2,l-b]quina-zolines (383), and 6-methyl-6,7,8,10-tetrahydropyrrolo[2,l-ft]quinazoline (384), as well as a stereoisomeric mixture of 7-methyl-5,5a,6,7,8,9-hexahy-dro-ll//-pyrido[2,l-b]quinazolines (385) and 15% of 7-methyl-6,7,8,9-tetrahydro-llH-pyrido[2,l-fr)quinazolme (386), (95AJC2023). When the bulky tricyclohexylphosphine was used instead of triphenylphosphine, a 3 7 mixture of compounds 382 and 383 and a 3 1 mixture of isomeric 385 were formed. 

Rhodium-catalyzed hydroformylation of -(substituted amino)benzyl-amines (387, X = H2) and -(substituted amino)benzamides (387, R = H, X = O) in the presence of rhodium(II) acetate dimer and triphenylphos-phine in deoxygenated ethyl acetate gave a 7 3 mixture of 1,2,3,4,4 ,5-hexahydro-6//-pyrido[l,2-a]quinazolines (388, X = H2,0) and isomeric 3-methyl-l,2,3,3fl,4,5-hexahydropyrrolo[l,2-a]quinazolines (389, X = H2, O) (94AJC1061). The methyl derivative of benzylamine 387 (R = Me, X = H2) afforded a mixture of diastereoisomers 390 and 391 (X = H2). Their ratio depended on the reaction time. Longer reaction times gave more 391 (X = H2), containing the methyl group in an equatorial position. Compound 390 isomerized into 391 (X = H2), under the aforementioned conditions. The benzamide derivative (387, R = Me, X = O) yielded only one isomer (391, X = O), independent of the reaction period. 

Substitution of hydrogen with phenyl, as in trifluoro-substituted acetophenone derivative 14h, enhances the rate of Lhe isomerization reaction. In fact, small amounts of 15h have been formed in the preparation of 14h, presumably catalyzed by benzylamine.14 Use of the stronger base l,8-diazabicyclo[5.4.0]undec-7-ene (DBU) accelerates the isomerization and is a very effective catalyst for the tautomerization reaction in the ketimine series.13... 

The 1,3-proton shift reaction has also been applied to the synthesis of a-(perfluoroalkyl)-a-amino acids, specifically 3.3,3-trifluoroalanine.2 -26 Attempts to prepare the A-benzylimine of ethyl 3,3.3-trifluoro-2-oxopropanoate by direct condensation with benzylamine were very difficult due to the exceptionally high stability of the intermediate a-amino alcohol, which fails to dehydrate. By contrast, 1-phenylethanamine reacted with ethyl 3,3,3-trifluoro-2-oxo-propanoate to form ketimine 33 in 83 % yield.26 The 1,3-proton shift reaction of 33 is much faster than those of ketimines derived from perfluoroalkyl ketones or perfluoroaldehydes (see Table 5). Complete conversion in triethylamine required 6 hours at room temperature and afforded the isomeric Shiff base 34 in 92 % yield. Mild hydrolysis of Shifif base 34 gives a-amino ester 35, which in turn hydrolyzes to 3,3,3-trjfluoroalanine hydrochloride (36). 

H and, 3C NMR spectra of monoimines have been reported and are shown in Table 3. These data fit the Hammett relationship and good correlations are found between various o constants and, 3C chemical shifts at positions remote from the substituent.1413C chemical shifts of imines derived from BA and variously substituted benzylamines are affected by substituents through up to 11 bonds.15 The influence of ZjE isomerism (Figure 3) and the effect of substituents on NMR spectra of some unsaturated imines have been studied.16 The photochemically induced isomerization of several substituted Schiff bases derived from BA and arylamines and their chemical shifts, as well... 

Triflic acid has been used in the ring closure of allyl-substituted heterocycles to synthesize compounds 96 and 97,326 whereas isomeric compounds 98 was isolated in the reaction of propargyl-substituted benzylamines.308... 

In the presence of a catalytic amount of a metal carbonyl, benzylamine reacts with carbon tetrachloride to form a mixture of 2,4,5-triphenylimidazole and 2,4,5-triphenyl-2-imidazo-line. The reaction is probably of the free radical type involving, ultimately, cyclization of a species such as (57). When hydrobenzamide (58) is treated with an acid chloride in the presence of triethylamine the product is an iV-acyl-3-imidazoline (59). When, however, (58) is heated and subsequently reacts with an acid chloride in the presence of triethylamine, the isomeric 2-imidazoline is formed (Scheme 31) (72JOC2158). 

The use of 4-s-alkylamino-5-nitrosopyrimidines can still produce purines as in the case of the 4-isopropylamino-5-nitrosopyrimidine (290) which afforded the 8,8-dimethylpurine (291). This readily isomerized to 8-methylcaffeine when melted (Scheme 103) (64ZC454). The method may be modified in several ways thus the 4-amino-5-nitrosopyrimidine with methylamine or benzylamine gave theophylline or 8-phenyltheophylline, respectively (66LA(691)142). Similarly the Vilsmeier-Haack reagent (DMF plus phosphoryl chloride) has also been used to produce 8-dimethylaminotheophylline (Scheme 104) (73BCJ1836). 

Methyl 3- /7/-D-daunosaminide 154 has been derived from d-149 via a Wittig-type olefination using (2-thiazolylmethylene)triphenylphosphorane (Scheme 13.53). A 1 1 mixture of (E)- and (Z)-alkenes is obtained, which is isomerized in the presence of iodine into a 9 1 mixture of ( )-152 and (Z)-152. Methylation of the thiazole moiety increases the electrophilicity of the alkene, which then accepts nucleophiles such as benzylamine. The adduct is treated with NaBH4 to give a thiazolidine. Acetylation and mercury-mediated hydrolysis of the thiazolidine ring generates 153, which, on acidic treatment in methanol, yields the A-benzyl 3- /7/-D-daunosaminide 154 [99]. 

Imines derived from benzylamine and a,3-unsaturated ketones which represent 1-azadiene systems can be isomerized to the corresponding 2-azadienes with potassium t-butoxide. Addition of r-butyl-lithium occurs smoothly to afford simple imine anions that undergo alkylation in the usual fashion. 3S The two examples provided in Scheme 17 illustrate the power of this method to provide either a,a- or a,a -substitution. On the other hand, reaction of similar 1-azadiene systems with Grignard reagents results in addition to form the imine anion directly (equation 44). This example represents one of the early contributions to asymmetric induction in this area and will be elaborated in Section 4.1.3.5. 

Bergbreiter and Newcomb have shown that the benzylamine imine of 3-pentanone is deprotonated by lithium diisopropylamide selectively at the benzylic position of a 2-azaallyllithium system that slowly isomerizes by a protonation-deprotonation sequence to afford the 1-azaallyl system (equation 46). ... 

Another route to amine ID used the isomerically-mixed 1,2-cyclopropanedicarboxylic acid 2. directly without recourse to the anhydride D. Thus, ca. one mole of crude acid 2. was treated with benzylamine at 180°C to afford a crystalline sample of impure imide D (72%). Nevertheless, when this impure material was reduced with lithium aluminum hydride, the amine D (68%) was isolated by distillation in a high state of purity. As before, catalytic hydrogenolysis of the N-benzyl group led to a quantitative yield of the bicyclic amine hydrochloride ID. In this... 

N,N-disubstituted benzylamine (65) was allowed to react in a high-dilution Dieckmann cyclization to give the ketoester (66) (88%), which displayed a typical transannular interaction [Eq. (23)]. Conversion into the perchlorate salt produced a bicyclic structure (67). Hydrogenation of 67 gave the de-benzylated salt (68) in 69% yield. The stereospecificity of this reaction probably arises from cis-addition of the hydrogen atoms from the less hindered side of the likely intermediate iminium salt (69). The free base derived from 68 was reduced to give ( )-isoretronecanol (22) (53%) with an isomeric purity of 98%, as determined by GLC analysis. 

Treatment of virosecurinine 108 with monoperphthalic acid gave two nonbasic isomeric products, 123 and 124, in a 1 5.5 ratio. The oxidative reaction may be envisaged to proceed via the A-oxide intermediate 122 which suffers rearrangement analogous to known transformations of A-allyl- and A-benzylamine oxides to 0-allyl and... 

Michaelis-Becker reactions have been carried out in two-phase systems even under such mild conditions, isomerization of prop-2-ynylphosphonic diesters occurs to give a 90% combined yield consisting of a mixture of diethyl propadienylphosphonate and diethyl-propy-l-nylphosphonate (85 15). Some of the allylic halides furnish small amounts of phosphonic esters, but others, and also benzyl halides, only undergo reaction in the presence of a long-chain tertiary amine hydrochloride catalyst. Dialkyl hydrogenphospho-nates and tertiary benzylamines react together to give dialkyl benzylphosphonates ". ... 

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