Alkylation of ammonia and its derivatives

Syntheses from Acyclic Compounds Another approach to the synthesis of quinuclidine and its derivatives was found by Prelog,114,115 based on the action of ammonia on tribromoalkanes (55) under pressure at 110°-120° or on twofold intramolecular alkylation by treatment of dibromoalkylamines (56) with alkali. 

Perhaps the simplest reaction to envisage is the alkylation of a co-ordinated amine. These reactions are well-known and usually occur under strongly basic conditions. It is most likely that these reactions involve deprotonated amido intermediates, and are considered in that context. As we have seen in Chapter 2, the acidity of an amine proton should increase upon co-ordination to a metal centre, and with the charge on that metal. As a consequence, we might expect to see new types of reaction products derived from the amido ligand, particularly with high oxidation state metal complexes. The former effect is indeed the case, and dramatic reduction of the pKa of ammonia and amines is observed upon co-ordination to a metal ion (Table 5-1). 

The first synthesis of the parent compound of the benzo[4,5]thieno[2,3-c]pyrrole ring system 99 [27] and its derivatives was accomplished using the same synthetic sequence (Scheme 16). Starting with 2-mcthyl benzolb thiophcnc-3-carbaldehyde 100, an intermediate 101 was obtained. Treatment of bromo compound 101 with sodium azide in ethanol led to the stable triazoline 102.1,3-Dipolar cycloreversion of 102 was induced by a catalytic amount of p-TsOH to give the parent 27/-benzo [4,5]thieno[2,3-c]pyrrole 99. Alternatively, direct treatment of bromo compound 101 with excess ammonia furnished 99 in one step. Compound 99 was treated with Boc20 and DMAP to give the /V-Boc derivative 103. Reaction of 101 with alkyl- and arylamines, respectively, afforded the N-substituted benzo[4,5]thieno[2,3-c]pyrroles 105 via a retro-malonate addition from intermediate 104. 

In contrast to the acid/base behaviour of polymeric bulk water, monomeric water is a relatively weak acid and base in the gas phase compared to its substituted derivatives (R—OH, R—O—R, etc.), whose conjugated base or acid ions are stabilized by polarization of the alkyl groups. The gas-phase basicity of water is 138 kJ/mol (33 kcal/mol) below that of ammonia. Its gas-phase acidity is comparable to that of propene and it is less acidic than phenol by about 167 kJ/mol (40 kcal/mol). With respect to the well-known acid/base properties of water, ammonia, and phenol in aqueous solution, one has to conclude that enormous solvation energies must contribute to the difference from the behaviour of isolated water molecules. See Section 4.2.2 for further discussions and references. 

Polyalkylene polyamines are typical by-products in the amination of dihydroxy compounds. Some of these oligomers, e. g. diethylenetriamine and triethylene-tetramine, are valuable compounds they are produced industrially from ethanol-amine (sometimes directly from ethylene oxide) and ammonia or a mixture of ammonia and ethylenediamine. Over a Ni-Re boride catalyst the selectivity for diethylenetriamine was ca 25 %, almost independent of the conversion [27]. Higher temperatures favored the formation of worthless cyclic products, mainly piperazine and its N-alkylated derivatives (Scheme 9). Recycling the cyclic byproducts can minimize their formation and the higher oligomers can be decomposed to useful dimers and trimers [26]. 

Preparation of secondary amines by reductive alkylation of ammonia is not such a general reaction as that of primary amines. In the aliphatic series treating ammonia with 2 moles of a carbonyl compound usually affords a mixture of mono-, di-, and tri-alkylamines. However, 80-90% yields of the corresponding dibenzylamine are obtained from benzaldehyde or its o-chloro or o-methyl derivative.996... 

Proton affinities of ammonia and some of its alkyl and fluoro derivatives (in kcal/mol)... 

Photoamination via Category III has been investigated in polycyclic arenes such as phenanthrene (la) and its derivatives (Ib-li), anthracene (Ij), and naphthalene derivatives (Ik-lv) [36-37], A typical example was photoamination of la with NHj, which was performed by the irradiation of an ammonia-saturated MeCN-H O solution containing la and m-DCB for 17 h to give the Type I aminated product, 9-amino-9,10-dihydrophenanthrene (10a), in 84% yield (Scheme 6.11). It was apphed to photoamination with primary amines such as alkylamines, ethanolamine, allylamine, and glycine ethyl ester and so on, which gave efficiently A-alkyl derivatives of 10a. But photoamination with secondary alkylamines such as dimethylamine and diethylamine were inefficient [38]. 

Amines are derivatives of ammonia in which one or more of the hydrogens is replaced with an alkyl, aryl, cycloalkyl, or heterocycHc group. When more than one hydrogen has been replaced, the substituents can either be the same or different. Amines are classified as primary, secondary, or tertiary depending on the number of hydrogens which have been replaced. It is important to note that the designations primary, secondary, and tertiary refer only to the number of substituents and not to the nature of the substituents as in some classes of compounds. 

Key intermediates in the industrial preparation of both nicotinamide and nicotinic acid are alkyl pyridines (Fig. 1). 2-Meth5l-5-ethylpyridine (6) is prepared in ahquid-phase process from acetaldehyde. Also, a synthesis starting from ethylene has been reported. Alternatively, 3-methylpyridine (7) can be used as starting material for the synthesis of nicotinamide and nicotinic acid and it is derived industrially from acetaldehyde, formaldehyde (qv), and ammonia. Pyridine is the principal product from this route and 3-methylpyridine is obtained as a by-product. Despite this and largely due to the large amount of pyridine produced by this technology, the majority of the 3-methylpyridine feedstock is prepared in this fashion. 

Two substituents on two N atoms increase the number of diaziridine structures as compared with oxaziridines, while some limitations as to the nature of substituents on N and C decrease it. Favored starting materials are formaldehyde, aliphatic aldehydes and ketones, together with ammonia and simple aliphatic amines. Aromatic amines do not react. Suitable aminating agents are chloramine, N-chloroalkylamines, hydroxylamine-O-sulfonic acid and their simple alkyl derivatives, but also oxaziridines unsubstituted at nitrogen. Combination of a carbonyl compound, an amine and an aminating agent leads to the standard procedures of diaziridine synthesis. 

The first clue to the existence of the SrnI mechanism came from product studies both in aliphatic and aromatic cases. It was noticed that in the reaction of benzyl and substituted benzyl chlorides with the 2-nitropropane anion, oxygen alkylation, yielding the oxime and then the aldehyde, occurs exclusively in the case of benzyl chloride and 3-nitrobenzyl chloride, whereas, with 4-nitrobenzyl chloride, the yield of aldehyde is only 6% and the carbon-alkylated (104) product is obtained in 92% yield (Kornblum, 1975). This was interpreted as the result of a competition between 8, 2 (O-alkylation) and S l (C-alkylation) reactions. In the aromatic case, it was observed that the reaction of 5- and 6-halopseudocumenes with KNHj in liquid ammonia (Kim and Bunnett, 1970) forms the 5- and 6-pseudocumi-dines in a ratio which is the same whether the starting compound is the 5- or 6-isomer in the case of the chloro- and bromo-derivatives, as expected from an aryne mechanism (Scheme 9), whereas much more non-rearranged... 

The amide derived from the carboxylic acid in Ugi adducts is in most cases tertiary, and therefore it cannot serve as nucleophilic partner in post-condensation transformations, unless a post-Ugi rearrangement converts it into a free amine [52, 54]. An exception is represented by Ugi adducts derived from ammonia, which give rise to two secondary amides, each of them potentially involved, as nucleophile, in nucleophilic substitution processes. Four competitive pathways are in principle possible (N- or 0-alkylations of the two amides), and the reaction is mainly driven by the stability of the formed rings. In the example shown in Fig. 12, 0-alkylation of the carboxylic-derived amide is favoured as it generates a 5-membered ring (oxazoline 62), while the alternative cyclization modes would have formed 3- or 4-membered rings [49]. When R C02H is phthalic acid, however, acylaziridines are formed instead via Walkylation [49]. In both cases, the intramolecular 8 2 reactions takes place directly under the Ugi conditions. 

Chromium has a maximum co-ordination number of six the chromium atom, therefore, may combine with, at most, six monovalent atoms or groups, over and above its ordinary valency value, with formation of a complex radicle. Hence chromic chloride is capable of associating with, or adding on, six molecules of ammonia with formation of the derivative, [Cr(NH3)8]Cl3. Ammonia may be replaced by a substituted ammonia group or some other basic group, such as alkyl amine, pyridine, or ethylenediamine. 

---