Aminal intermediate

Novolaks. Novolak resins are typically cured with 5—15% hexa as the cross-linking agent. The reaction mechanism and reactive intermediates have been studied by classical chemical techniques (3,4) and the results showed that as much as 75% of nitrogen is chemically bound. More recent studies of resin cure (42—45) have made use of tga, dta, gc, k, and nmr (15). They confirm that the cure begins with the formation of benzoxazine (12), progresses through a benzyl amine intermediate, and finally forms (hydroxy)diphenyknethanes (DPM). 

Thermolysis of the 3-acyl-3/f-azepine 32 in Decalin at 250°C also gives the phenacylpyridine but in much reduced yield (6%). In a similar manner, 4-chloro-yV,/V-diethyl-3-phenacylpyridin-2-amine (53 % bp 160 C/0.18 Torr) is produced by the photolysis or thermolysis of 3-benzoyl-5-chloro-Ar,Ar-diethyl-3/f-azepin-2-amine.246 However, if the 3ff-azepine bears a secondary amine residue at the 2-position, e.g. 36, then photolysis or thermolysis yields a pyrrolo[2,3-/>]pyridine by intramolecular cyclization of the 3-phenacylpyridin-2-amine intermediate. 

Unfortunately, the hydroxyl amine intermediate is both explosive and... 

Dendron 32 was incubated in phosphate buffer saline, pH 7.4, in the presence and in the absence of PGA. The progress of the disassembly was monitored by RP-HPLC, and the results are presented in Fig. 5.27. Tryptophan was gradually released from dendron 32 upon incubation with PGA. The release was completed within 48 h in the presence of PGA the control reaction without PGA showed no release at all. Although the disassembly of this dendron occurred more slowly under physiological conditions than dendron 31 in the MeOH/DMSO environment (Fig. 5.24), PGA cleaved its phenylacetamide substrate from dendron 32 and the resulting amine intermediate was disassembled to release the total six molecules of tryptophan. 

Identification of the pivalated amine intermediate (FAPE, 45) as a non-hydroscopic coupling partner. 

The reaction of 77 with alkynes has further been elaborated for the synthesis of substituted phthalonitriles 81. An alternative for the synthesis of these compounds is the cycloaddition reaction of 77 with enamines followed by a retro-Diels-Alder loss of N2 and elimination of the amine (Scheme 16). Generally, more forcing reaction conditions are required and lower yields are obtained in reactions with alkynes than in reactions with enamines, for example, 4-ethyl-5-methylphthalonitrile is obtained in 51% yield from 2-pentyne (xylene, 150°C, 18 days) and in 73% yield from 4-(l-ethylprop-l-en-l-yl)morpholine (CHCI3, 70°C, 7 days) <1998T1809>. The mechanism of the reaction with enamines has been studied in detail. This revealed a [1,5] sigmatropic rearrangement in the cyclohexa-2,4-dien-1-amine intermediates formed after the loss of N2 <1998T10851>. 

A unique acyclic C-nucleoside containing the pyrido[2,3-. ]pyrazine nucleus 675 was prepared by the action of AcOH, whereby rearrangement of 3 -keto-2 -deoxypyrazine C-nucleoside derivatives 673 occurs via the intramolecular aminal intermediate 674, followed by furanose ring opening and subsequent aromatization (Equation 56)... 

Scheme 26. Synthesis of amine intermediate 81 utilizing 4-phthalimido cyclohexanone (78) in the Fischer indole cyclization.

Enzyme-based processes for the resolution of chiral amines have been widely reported [2, 3] and are used in the manufacture of pharmaceuticals, for example, BASF s process for chiral benzylic amine intermediates. Scheme 13.1 [4]. The methods used are enantioselective hydrolysis of an amide and enantioselective synthesis of an amide, both of which are kinetic resolutions. For high optical purity products the processes depend upon a large difference in the catalyzed reaction rates of each enantiomer. 

The application of resin 13 to the sohd-phase synthesis of other useful target compounds was also explored and an example of this is the multistep synthesis of Meclizine (Fig. 10).26 The starting material, 3-methyl-4-hydro-xybenzaldehyde, is attached to the PFS hnker, and a polymer-bound amine intermediate is prepared by a reductive amination of resin 23 with amine 24. The resulting resin 25 is subjected to a palladium-mediated reductive cleavage to give Meclizine 26 in 80% yield, based on the original resin loading. 

In the literature, the simultaneous formation of the major NMMO degradation products N-methylmorpholine, morpholine and formaldehyde [20] is always attributed to the disproportionation of the primary aminyl radical 3, as a - not further defined - redox process between two molecules of 3, in which one is reduced to N-methylmorpholine (2) and the other oxidized to N-(methylene)morpholinium cation (17), which upon addition of water, forms morpholine and formaldehyde. Also this disproportionation can be rationalized as a radical coupling reaction which proceeds through recombination of N-centered 3 and C-centered 4, via the ammonium aminal intermediate 16 as the actual recombination product (Scheme 6). The intermediacy of this species was indeed confirmed by isolation from the reaction mixture and full characterization [17]. Compound 16 is quite labile and immediately de-... 

At relatively high concentrations of amine intermediates, A-pentyl-piperidine forms as a by-product by the disproportionation of piperidine and pentylamine (45, 59). This by-product is denitrogenated at high conversions of the reactant. 

Asymmetric hydrosilylation of imines followed by hydrolysis of the JV-silyl-amine intermediate yields chiral amines. The Kagan group hydrosilylated a series of prochiral imines with both polymethylhydrogensiloxane and diphenyl ... 

An important application of oxidation of a C-H bond adjacent to a nitrogen atom is the selective oxidation of amides. This reaction proceeds in the presence of ferf-BuOOH as the oxidant and Ru(II) salts. Thus in the example of Eq. (36), the a-tert-butylperoxy amide of the isoquinoline was obtained, which is an important synthetic intermediate for natural products [138]. This product can be conveniently reacted with a nucleophile in the presence of a Lewis add. Direct trapping of the iminium ion complex by a nudeophile was achieved in the presence of trimethylsilyl cyanide, giving a-cyanated amines as shown in Eq. (37) [45]. This ruthenium/peracid oxidation reaction provides an alternative to the Strecker reaction for the synthesis of a-amino acid derivatives since they involve the same a-cyano amine intermediates. In this way N-methyl-N-(p-methoxyphenyl) glycine could be prepared from N,N-dimethyl-p-methoxyaniline in 82% yield. 

While cycloaddition approaches have been discussed extensively in this chapter, there are certain substitution patterns that are not amendable to such approaches. In these cases, the more traditional annelative approaches are necessary. For example, the 5,6-dihydropyrrolo[3,4-rf]imidazol-4(3//)-one (286) is obtained from the diamine (285) and triethyl orthoformate. If formamide is used in excess, 6-(formamidomethylene)-5,6-dihydropyrrolo[3,4-d]imidazol-4(3//)-one (287) is obtained (Scheme 53) <70JPS1732>. A variant of the Thorpe cyclization was employed in the preparation of 3-amino-4//-pyrrolo[3,4-c]isoxazoles (289) from a-cyanooximes (288) (Equation (66)) <68JMC453>. 3-Acyltetramic acid (290 X = NR2) and 3-acyltetronic acid (292 X = O) hydrazones undergo ready cyclization in refluxing xylene with catalytic p-toluenesulfonic acid to afford 4-oxo-l,4-dihydro-6/f-pyrrolo[3,4-c]pyrazoles (291) and 4-oxo-l,4-dihydro-6//-furo[3,4-c]pyrazoles (293), respectively (Equation (67)) <82SC43l>. The novel synthesis of 5-amino-6a-hydroxydihydro-6//-pyrrolo[2,3-j]isoxazole (296) from 3,4-disubstituted 4-(amino)isoxazol-(4//)-ones (294) is hypothesized to occur by the cyclization of the ketene aminal intermediates (295) (Scheme 54) <91S127>. 

This reaction takes place in a matter of seconds and produces significantly more fluorescence than the diacetylmonoxime fluorophors. Excess reagent is quickly hydrolyzed to form nonfluorescent water soluble products. Secondary, tertiary, and aromatic amines did not react with fluram to produce any measureable fluorescence. The reaction did not occur when ammonia and ammonium salts were tested for fluorescence. Mass spectrometry of an actual field sample confirmed that the substitution product is the fluorescent species that is shown above. Further mass spectra studies indicated that dimethyl-urea is not produced during this reaction. This was later confirmed by introducing known quantities of the urea and little or no fluorescence was noted. These tests indicate that Fluram does react with the primary amine intermediate on the adsorbent according to the above equation, and that monomethyl amine and other primary aliphatic amines would interfere. 

Table 1 Melting points of Step 2 amine intermediates prepared by hydrogenation of the 2-nilro-V-(4-tnfluoromethylphenyl)benzamide precursor...

Table 2 Selected anthranilic acid derivatives prepared by reductive alkylation of the Step 2 amine intermediate using 4-pyridinecarboxaldehyde and their corresponding melting points. 111-NMR data supplied by author...

Furan itself can be used as the starting material for the synthesis of 1-methylpyrrole <2002MI179>. 7-AI2O3 was found to be an effective catalyst for the dehydration reaction between furan and methylamine to afford 1-methylpyrrole. A yield of 57.6% was achieved under the experimental conditions of a reaction temperature of 400 °C, a methylamine/ furan molar ratio of 1.5, and the molar flow rate of furan approximately 3-3.5 mmol/h. Furan was adsorbed onto Bronsted acid sites on the catalyst, while the methylamine was adsorbed onto Lewis acid sites. With this heterogeneous catalyst, the rate determining step of the mechanism was suggested to be the adsorption of furan on the Bronsted acid sites to form a ring-opened species, which is followed by the insertion of the adsorbed methylamine to form secondary amine intermediates. Further dehydration at the Lewis acid sites would yield 1-methylpyrrole. 

In the hydrogenation of aliphatic dinitriles, cyclization can also be an important reaction pathway.92 Saturation of succinonitrile, 45, (Eqn. 19.45) over Raney nickel gave pyrrolidine, 49, as the primary product even in the presence of ammonia. 24 Intramolecular condensation of the imine-amine intermediate is apparently a very facile reaction, taking place in preference to imine hydrogenation and the intermolecular ammonia-imine condensation. The... 

The reduction of aromatic nitro and azo xenobiotics leads to aromatic primary amine metabolites. Aromatic nitro compounds are reduced initially to the nitroso and hydroxyl-amine intermediates, as shown in the following metabolic sequence ... 

---