Amination by substitution

Jorgensen et al. described a highly enantioselective amination of a-substituted a-cyanoacetates with di-tert-butyl-azodicarboxylate (DEAD) catalysed by the quinidine-derived constrained alkaloid, p-isocupreidine (p-ICPD). ° Products were isolated in excellent yield and enantioselectivity (up to 98%). The generality of the method was demonstrated by the reaction on both open-chain and cyclic p-ketoesters. Products were again obtained in up to 99% yield, but in somewhat lower ee (up to 90%). Deng 

Jorgensen et al. reported on enantioselective electrophilic additions to allylic C-H bonds activated by a chiral base, in a reaction of allylidene cyanoacetates or malononitriles with DBAD, catalysed by (DHQ)2PYR, giving y-aminated products in high yield (up to 90%) and excellent enantioselectivity (up to 99% ee). Ye et al. described y-amination of a,p-unsaturated acyl chlorides with azodicarbojylates, catalysed by O-trimethylsilylquinidine (O-TMS-QD) or O-trimethylsilylquinine (O-TMS-Q) to give dihydropyri-dazinones in up 92% yield, and up to 99% ee. Jorgensen s group also reported on asymmetric Friedel-Crafts amination of 2-naphthols with DBAD, to afford nonbiaryl atropisomers in up to 98% ee.  

Chen et al. described allylic amination of Morita-Baylis-Hillman carbonates with cyclic imides catalysed by (DHQD)2PYR affording a-methylene-p-amino 

An enantioselective Amadori-Heynes rearrangement of racemic a-hydrojgt ketones with arylamines to a-amino ketones with up to 81% ee catalysed by p-isocupreidine was also reported.  

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Now, contrary to popular opinions, this method need not be conducted in a sealed pipe bomb. Secondary amination by substitution is as much a reaction of opportunity as it is of brute force and heat. In fact, heating can tend to cause the reformation of safrole and isosafrole. So the simplest way to do this would be to use 500mL of ammonium hydroxide or alcoholic ammonia or, for those wishing to make MDMA or meth, 40% aqueous methylamine or alcoholic methylamine (to tell you the truth, methylamine is preferable in this method because it is more reactive that ammonia so yield will increase). This 500mL is placed in a flask and into it is poured a solution of 35g bromosafrole (30g phenylisopropyl-bromide) mixed with 50mL methanol. The flask is stoppered and stirred at room temperature for anywhere from 3 to 7 days. The chemist could also reflux the same mixture for 6-12 hours or she could throw the whole mix into a sealed pipe bomb (see How to Make section) and cook it for 5 hours in a 120-130°C oil bath. 

Ammonia is well known to be a strong nucleophile. The nucleophilic substitution reactions in the ionized clusters of X-benzene (X = F, Cl) have been widely studied (Brutschy 1989, 1990 Brutschy et al. 1988, 1991 Mayeama and Mikami 1988, 1990, 1991 Riehn et al. 1992). All these experiments clearly show a specific behaviour not encountered in the hydroxylic solvents depending on the substituted aromatic and the cluster size, two types of substitution reaction can be detected. The first type leads to ionic amines by substitution of X by the -NH2... 

Synthesis of chiral allylic amines by substitution reaction has many choices of protocol, in terms of metal complexes and ligands. Pd catalysts having pairing with a C2-s)mimetric mthenocene (32) are quite novel among other mote conventional P,N-Ugands that include... 

Nitramines are obtained from primary or secondary amines by substitution of the nitrogen-bound hydrogen by a --NO2 group. 

In general, the preparation of amines by nucleophilic displacement is restricted to inexpensive alkyl halides and to easily separated amines. Separation by distillation using efficient fractionating columns makes possible the industrial preparation of some simple amines by substitution reactions. 

SYNTHESIS OF AMINES BY SUBSTITUTION REACTIONS Alkylation of Amines by Alkyl Halides... 

The amino group on sulfur in 133 may be replaced by substituted amines with evolution of ammonia to give compounds such as 134 (Scheme 68) (316). 

Nucleophilic acyl substitution (Sections 20 4 20 6 and 20 12) Acylation of am monia and amines by an acyl chloride acid anhydride or ester is an excep tionally effective method for the for mation of carbon-nitrogen bonds... 

The preparation of amines by the methods described m this section involves the prior synthesis and isolation of some reducible material that has a carbon-nitrogen bond an azide a nitrile a nitro substituted arene or an amide The following section describes a method that combines the two steps of carbon-nitrogen bond formation and reduction into a single operation Like the reduction of amides it offers the possibility of prepar mg primary secondary or tertiary amines by proper choice of starting materials... 

Aminophenols are either made by reduction of nitrophenols or by substitution. Reduction is accompHshed with iron or hydrogen in the presence of a catalyst. Catalytic reduction is the method of choice for the production of 2- and 4-aminophenol (see Amines BY reduction). Electrolytic reduction is also under industrial consideration and substitution reactions provide the major source of 3-aminophenol. 

Amines are insufficiently nucleophilic to react with most azoles which do not contain a ring oxygen, and the stronger nucleophile NH2 is required. When treated with amide ions, thiazoles can be aminated in the 2-position by NaNHa at 150 °C. Only TV-substituted condensed imidazoles such as 1-alkylbenzimidazole react in such Chichibabin reactions. Imidazoles are aminated by alkaline NH2OH. 

B) Preparation of 4-Amino-2-Chloro-5-(Methylsulfamyl)Benzenesulfonamide The 5-sub-stituted-2,4-dlsulfamyl anilines may be prepared by procedures described in the literature, for example, the general procedures in Monatsch. Chem. vol. 48, p 87 (1927), which involves the treatment of a m-substituted aniline with from 10 to 20 parts by weight of chlorosulfonic acid followed by the gradual addition of from about 90 to 170 parts by weight of sodium chloride. The resultant mixture is heated at approximately 150°C for about 2 hours after which the reaction mixture is poured into water and the resultant 5-substituted aniline-2,4-disulfonyl chloride is filtered and is then treated with concentrated ammonium hydroxide or suitable amine by standard procedures to obtain the corresponding disulfonamide. 

Notable examples of general synthetic procedures in Volume 47 include the synthesis of aromatic aldehydes (from dichloro-methyl methyl ether), aliphatic aldehydes (from alkyl halides and trimethylamine oxide and by oxidation of alcohols using dimethyl sulfoxide, dicyclohexylcarbodiimide, and pyridinum trifluoro-acetate the latter method is particularly useful since the conditions are so mild), carbethoxycycloalkanones (from sodium hydride, diethyl carbonate, and the cycloalkanone), m-dialkylbenzenes (from the />-isomer by isomerization with hydrogen fluoride and boron trifluoride), and the deamination of amines (by conversion to the nitrosoamide and thermolysis to the ester). Other general methods are represented by the synthesis of 1 J-difluoroolefins (from sodium chlorodifluoroacetate, triphenyl phosphine, and an aldehyde or ketone), the nitration of aromatic rings (with ni-tronium tetrafluoroborate), the reductive methylation of aromatic nitro compounds (with formaldehyde and hydrogen), the synthesis of dialkyl ketones (from carboxylic acids and iron powder), and the preparation of 1-substituted cyclopropanols (from the condensation of a 1,3-dichloro-2-propanol derivative and ethyl-... 

Primary and secondary aliphatic amines, morpholine and 2-methylaziridine and aniline and even the sterically hindered 2.2,6,6-tetramethylpiperidine readily react with 6-bromo-trithiadiazepine 7, in certain cases in the presence of /V./V-diisopropylethylamine, at room temperature by substitution of the bromine atom ammonia, for example, yields trithiadiazepin-6-amine 22 (R1 = R2 = H). There is compelling evidence that these reactions proceed by an elimination-addition mechanism via the heteroaryne, trithiadiazepyne 21.391... 

Hydrazine hydrate, in preparation of sulfonylhydrazides, 40, 93, OS in reduction of 2-nitrofiuorene to 2-aminofluorene, 40, 5 in Wolff-Kishner reduction, 43, 34 Hydrazines, asymmetrically substituted by N-aminatiou of amines by hydroxylamine-O-sulfonic acid, 43,2... 

Unactivated aryl halides can be converted to amines by the use of NaNH2, NaNHR, or NaNR2. With these reagents, the benzyne mechanism generally operates, so cine substitution is often found. Ring closure has been effected by this type of reaction,for example. 

Other reactions that resulted in the formation of P=N double bonds are those of NH phosphinous amides with tetrahalomethanes [106-108]. The reaction products, P-halophosphazenes 19, may be further elaborated by substituting the halogen atom with amines or Grignard reagents (Scheme 19). 

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