Amines, preparation from amides

Amines, preparation from amides, 16, 4 from isothiocyanates, 18, 5 from ketones, 17, 76 from oximes, 11. S8 f -Aminobenzaldehyde, 13, 28... 

Hofmann rearrangement In this reaction, amines (with one less carbon) are prepared from amides by the treatment of halides (Br2 or CI2) in aqueous sodium or potassium hydroxide (NaOH or KOH). 

Amides are the least reactive of the carboxylic acid derivatives, and undergo acid or base hydrolysis to produce the parent carboxylic acids, and reduction to appropriate amines (see Section 4.3.10). They can also be dehydrated to nitriles, most commonly with boiling acetic anhydride, (AcO)20, sulphonyl chloride (SOCI2) or phosphoms oxychloride (POCI3) (see Section 4.3.18). Amines (with one less carbon) are prepared from amides by the treatment of halides (Br2 or CI2) in aqueous NaOH or KOH. This reaction is known as Hofmann rearrangement (see Section 4.3.10). 

Me). The diethyl derivative (411, R, R = Et) was obtained with triethyloxonium fluoroborate and ethylamine. Unsymmetrical dialkylamid-ines were prepared from amides (412) with triethyloxonium fluoroborate to give the salts (413) which with the appropriate primary amine gave the amidines (411). These compounds were successfully developed as antidepressants based on fenmetazole (41) when the dialkyl amidine unit proved to be a bioisostere for the imidazoline group [553]. 

The reaction is applicable to the preparation of amines from amides of aliphatic aromatic, aryl-aliphatic and heterocyclic acids. A further example is given in Section IV,170 in connexion with the preparation of anthranilic acid from phthal-imide. It may be mentioned that for aliphatic monoamides containing more than eight carbon atoms aqueous alkaline hypohalite gives poor yields of the amines. Good results are obtained by treatment of the amide (C > 8) in methanol with sodium methoxide and bromine, followed by hydrolysis of the resulting N-alkyl methyl carbamate ... 

A suspension of sodium amide in 500 ml of anhydrous liquid artmonia was prepared from 18 g of sodium (see Chapter II, Exp. 11). To the suspension was added in 10 min with swirling a mixture of 0.30 mol of 1-chloro-l-ethynylcyclohexane (see VIII-2, Exp. 27) and 50 ml of diethyl ether. The reaction was very vigorous and a thick suspension was formed. The greater part of the ammonia was evaporated by placing the flask in a water bath at 50°C. After addition of 500 ml of ice-water the product was extracted three times with diethyl ether. The ethereal extracts were dried over anhydrous KjCOj and subsequently concentrated in a water-pum vacuum. Distillation of the residue afforded the amine, b.p. 54°C/15 mmHg, n 1.4345, in 87% yield. 

Urea derivadves are of general interest in medicinal chemistry. They may be obtained cither from urea itself (barbiturates, sec p. 306) or from amines and isocyanates. The latter are usually prepared from amines and phosgene under evolution of hydrogen chloride. Alkyl isocyanates are highly reactive in nucleophilic addidon reactions. Even amides, e.g. sulfonamides, are nucleophilic enough to produce urea derivatives. 

Other fairly recent commercial products, poly(vinyl amine) and poly(vinyl amine vinyl alcohol), have addressed the need for primary amines and their selective reactivity. Prior efforts to synthesize poly(vinyl amine) have been limited because of the difficulty hydrolyzing the intermediate polymers. The current product is prepared from /V-ethenylformamide (20) formed from the reaction of acetaldehyde and formamide. The vinyl amide is polymerized with a free-radical initiator, then hydrolyzed (eq. 7). 

Pentafluoroaniline. Pentafluoroaniline [771 -60-8] i2is been prepared from amination of hexafluoroben2ene with sodium amide inbquid ammonia or with ammonium hydroxide in ethanol (or water) at 167—180°C for 12—18 h. It is weakly basic (p = 0.28) and dissolves only in concentrated acids. Liquid crystals have been prepared from Schiff bases derived from pentafluoroaniline (230). 

Acetoiicetyliition Reactions. The best known and commercially most important reaction of diketene is the aceto acetylation of nucleophiles to give derivatives of acetoacetic acid (Fig. 2) (1,5,6). A wide variety of substances with acidic hydrogens can be acetoacetylated. This includes alcohols, amines, phenols, thiols, carboxyHc acids, amides, ureas, thioureas, urethanes, and sulfonamides. Where more than one functional group is present, ring closure often follows aceto acetylation, giving access to a variety of heterocycHc compounds. These reactions often require catalysts in the form of tertiary amines, acids, and mercury salts. Acetoacetate esters and acetoacetamides are the most important industrial intermediates prepared from diketene. 

Lithium acetyhde also can be prepared directly in hquid ammonia from lithium metal or lithium amide and acetylene (134). In this form, the compound has been used in the preparation of -carotene and vitamin A (135), ethchlorvynol (136), and (7j--3-hexen-l-ol (leaf alcohol) (137). More recent synthetic processes involve preparing the lithium acetyhde in situ. Thus lithium diisopropylamide, prepared from //-butyUithium and the amine in THF at 0°C, is added to an acetylene-saturated solution of a ketosteroid to directly produce an ethynylated steroid (138). 

Refluxing linoleic acid and a primary or secondary alkyl amine with -toluenesulfonic acid in toluene for 8—18 h also yields the substituted amides (32—34). The reaction of methyl esters with primary or secondary amines to make substituted amides is catalyzed with sodium methoxide. Reactions are rapid at 30°C under anhydrous conditions (35). Acid chlorides can also be used. Ai,A/-dibutyloleamide [5831-80-17 has been prepared from oleoyl chloride and dibutyl amine (36). 

Amines with Amide Linka.ges, Representatives of this group are prepared from carboxyUc acids and di- and polyamines. The amide linkage connects the amine to relatively inexpensive hydrophobes. Eormulas for typical amide amines are as foUow ... 

Classically, amides and hydrazides have been prepared from an ester or an acid chloride and an amine or hydrazine, respectively they can also be prepared directly from the acid as shown in eqs. 1-3. 

Sulfonamides (R2NSO2R ) are prepared from an amine and sulfonyl chloride in the presence of pyridine or aqueous base. The sulfonamide is one of the most stable nitrogen protective groups. Arylsulfonamides are stable to alkaline hydrolysis, and to catalytic reduction they are cleaved by Na/NH3, Na/butanol, sodium naphthalenide, or sodium anthracenide, and by refluxing in acid (48% HBr/cat. phenol). Sulfonamides of less basic amines such as pyrroles and indoles are much easier to cleave than are those of the more basic alkyl amines. In fact, sulfonamides of the less basic amines (pyrroles, indoles, and imidazoles) can be cleaved by basic hydrolysis, which is almost impossible for the alkyl amines. Because of the inherent differences between the aromatic — NH group and simple aliphatic amines, the protection of these compounds (pyrroles, indoles, and imidazoles) will be described in a separate section. One appealing proj>erty of sulfonamides is that the derivatives are more crystalline than amides or carbamates. 

This amide is readily prepared from the acid chloride (Pyr, rt, 1 h, 77-86% yield) or the acid (DCC, DMAP, CH2CI2, rt, 1 h, 88% yield). Treatment of the amide with camphorsulfonic acid forms an A-acylindole. The acid can be regenerated from the A-acylindole by Li0H/H202/THF/H20 or NaOH/MeOH. Alternatively, it can be transesterified with MeOH/TEA, converted to an amide, by heating with an amine or converted to an aldehyde by DIB AH (62-85% yield). ... 

Among the routes for preparing phosphinous amides, the most frequently used method is the aminolysis of halophosphanes, most usually chlorophosphanes [32-34], because a number of such halophosphanes are easily accessible from commercial sources. These reactions usually provide the target species, i.e., trisubstituted compounds 1 in Scheme 1, in high yield. The HCl liberated from the reaction forms a salt with an organic base (either excess of the starting amine or externally added as, for example TEA or DBU, sometimes in the presence of DM AP) which is insoluble in the reaction solvent, typically diethyl ether... 

The amino interchange reaction is another method commonly used for preparing phosphinous amides [67] (Scheme 9). The low boiling points of di-methylamine and diethylamine allow their displacement from Ar,AT-dimethyl and AT,iV-diethyl phosphinous amides, respectively, by other less volatile amines, leading to new members of the same class. High reaction temperatures are nevertheless required. 

Another method for converting esters to amides involves aluminum amides, which can be prepared from trimethylaluminum and the amine. These reagents convert esters directly to amides at room temperature.142... 

Contrary to an alkoxy benzene scaffold, secondary amides were generated via novel aldehyde linker 43 based upon an indole scaffold (Scheme 15) [52]. The indole resin was prepared from indole-3-carboxy-aldehyde in two steps and reacted with amines under reductive conditions to generate resin-bound secondary amines. Treatment of the resin with... 

Amides prepared from carboxylic acids and primary amines using CDI. Examples ... 

The following amides prepared from 4-(3-nitro-l-pyrazolyl)butanoic acid, CDI, and primary amines represent partial structures of the histamine H2-receptor antagonists roxatidine, cimetidine, ranitidine, and famotidine [37]... 

---