Amidines from amines

Amidines from amines and nitriles. CuCl activates ordinary nitriles towards attack by amines except those with low nucleophilicity (e.g., ArNH2). 

Synthesis of Amidines from Amines and Nitriles. An efficient one-step preparation of Af,Af -disubstituted amidines is possible by direct nucleophilic addition of an amine to a nitrile using catalytic amounts of samarium iodide (eq Alternatively, an... 

A somewhat different approach is used to prepare the compounds containing the amine at the 4 position. Condensation of the amidine from acetonitrile (138) with the enol ether from formylacetonitrile (137) leads to the requisite pyrimidine (139). 

It effects a synthesis of amidines from simple carboxylic acids and amines ... 

The formation of amidines from lactim ethers and amines proceeds readily with high yields,8, >18,21,70-70 e.g., in the synthesis of imidazo-[l,2-6]azepine derivatives reported by Stolle et al.77 (Scheme 9), and in the preparation of the pyrimido[l,2-a]-azepine derivative (Scheme 10).70... 

The usual procedure36 is to add a slight excess of a secondary amine to an ethereal solution of ethylmagnesium bromide (50% excess relative to the nitrile) and, when evolution of ethane ceases, to heat the mixture under reflux for about 20 min before adding an ethereal solution of the nitrile the whole is then boiled under reflux for 2-3 h, then decomposed with ice. In many cases this method is superior to the Pinner synthesis of amidines from imidoyl esters. 

Acylation of nitrogen compounds by orthoesters. The formation of amidines from orthoesters (preferably orthoformates) and ammonia or an aromatic amine has been known for about 100 years (for a review see Post803). As an example for the acylation of ammonia a modern procedure is reproduced, in which acetamidine is obtained as acetate 804... 

Acylation of nitrogen compounds by imidic esters. It was mentioned above that synthesis of amidines from orthoesters proceeds through imidic esters, so that both classes of compound are normally treated together in reviews.819-821 Accordingly, also, it is, of course, possible to use imidic ester hydrochlorides as usually prepared from nitriles and to treat these with ammonia or amines.820 Care must be taken, however, with primary amines lest the imido group be also exchanged for the residue from the amine, particularly at higher temperatures ... 

Carbodiimides are potential nitrogen sources for amidines [44]. Zirconaaziridines, generated in situ from amines, butyllithium (BuLi) and bis(ri -cylopentadienyl)methyl (trifluoromethanesulfonyl)zirconium [Cp2ZrMe(OTf)], are efficiently trapped by carbodiimides. Zirconacycles 11, produced by insertion of carbodiimides into the Zr-C bond of zirconaaziridines, are supposed to be key intermediates, which are hydrolyzed to give ot-aminoamidines (Scheme 3.25). 

In amidines transamination is possible,especially useful for such purposes are imidoylimid-azolides, e.g, (341 equation 172). In some cases it is useful to prepare amidines by ring opening of suitable heterocycles, which can be achieved by treatment with amines or other nucleophilic (baisic) compounds. Examples are the synthesis of amidines from 1,3,5-oxadiazinium salts (342), 3-amino-1,2-benzisothiazoles (343), 2-ethoxycarbonyl-3,l-benzoxazin-4(4//)-one (344), 1,2,5-oxa-diazolo[3,4]pyrimidine 1-oxides (pyrimidofuroxans 345) and l,2,4,6-thiatriazenium-5-olate 1,1-dioxides (346) as shown in Scheme 58. 

As a class of compounds, nitriles have broad commercial utility that includes their use as solvents, feedstocks, pharmaceuticals, catalysts, and pesticides. The versatile reactivity of organonitnles arises both from the reactivity of the C=N bond, and from the abiHty of the cyano substituent to activate adjacent bonds, especially C—H bonds. Nitriles can be used to prepare amines, amides, amidines, carboxyHc acids and esters, aldehydes, ketones, large-ring cycHc ketones, imines, heterocycles, orthoesters, and other compounds. Some of the more common transformations involve hydrolysis or alcoholysis to produce amides, acids and esters, and hydrogenation to produce amines, which are intermediates for the production of polyurethanes and polyamides. An extensive review on hydrogenation of nitriles has been recendy pubHshed (10). 

As in 10-55 hydrazides and hydroxamic acids can be prepared from carboxylic esters, with hydrazine and hydroxylamine, respectively. Both hydrazine and hydroxylamine react more rapidly than ammonia or primary amines (the alpha effect, p. 445). Imidates, RC(=NH)OR, give amidines, RC(=NH)NH2. Lactones, when treated with ammonia or primary amines, give lactams. Lactams are also produced from y- and 5-amino esters in an internal example of this reaction. 

Because of their ease of crystallization, alkylzinc alkoxides are often isolated as decomposition products in reactions involving organozinc compounds. The methylzinc lithium tert- butoxide heterocubes [ (THF)LiOBut 2-(MeZnOBu1 ]182 (Figure 58, 123) and [(LiOBu MeZnOBu1 ]183 124 were isolated as hydrolysis products from reactions involving amines, amidines, /< //-butyllithium, and dimethylzinc. 

Glycoamidines have been readily prepared by a mercury-promoted reaction of the corresponding thioamides with amines.69 TV-Boc protected amidines have been prepared from /V-(Boc) thioamides by treatment with base and mercury(II) chloride (Scheme 34).70... 

A,A-Dialkylformamide acetals (7) react with primary amines to give the corresponding amidines (8). Kinetics of the reaction of a range of such acetals with ring-substituted anilines—previously measured in neutral solvents such as methanol or benzene —have been extended to pyridine solution. In pyridine, the reactions are irreversible, with first-order kinetics in each reactant, and mechanistically different from those in non-basic solvents. Two mechanisms are proposed to explain Hammett plots for a range of anilines, in which the p value switches from negative to positive at a cr value of ca 0.5. The pyridine solvent substantially enhances the rate in the case of very weakly basic anilines. 

The most frequently used synthesis of guanidines involves the displacement by an amine of a suitable group, X, from the amidine-type compound shown. 

From A(-substituted carboxamides, the 3-unsubstituted derivatives were formed, with loss of the corresponding amine. This reaction is to be expected from the mechanism of the ring closure amidine formation and subsequent nucleophilic attack of the amidine nitrogen on the carbonyl group. 

The condensation reaction of cyclic amidines with trichloromethylsulfenyl chloride yields sul-fenamides, which afford 5-arylimino-l,2,4-thiadiazolines on treatment with aromatic amines <84CHEC-I(6)463>. An example of this type of reaction starting from 2-amino-4-arylthiazoles (271) affords 3/f-thiazolo[2,3-c]-l,2,4-thiadiazoles (272), via the sulfenamide (270) (Scheme 60) <88IJC(B)501>. 

A useful method for the synthesis of 5-chloro-l,2,4-thiadiazoles (206) is the reaction of amidines with trichloromethylsulfenyl chloride (see Equation (30)). 3-Halo derivatives (349) (X = Cl, Br, I) (Equation (57)) have been obtained in moderate yields from the corresponding amines (348) via the Sandmeyer-Gatterman reaction <84CHEC-I(6)463>. 3-Chloro-l,2,4-thiadiazolin-5-ones (350) and (351) can be prepared by reacting chlorocarbonylsulfenyl chloride with carbodiimides or cyanamides respectively (Scheme 79) <84CHEC-I(6)463>. 

When solid-phase peptide synthesis was initially being developed, the question of whether or not a separate neutralization step is necessary was considered. Since it was known from the work of others that the chloride ion promotes racemization during the coupling step in classical peptide synthesis, and since we were deprotecting the Boc group with HC1, it seemed advisable to neutralize the hydrochloride by treatment with TEA and to remove chloride by filtration and washing. This short, additional step was simple and convenient and became the standard protocol. Subsequently, we became aware of three other reasons why neutralization was desirable (1) to avoid weak acid catalysis of piperazine-2,5-dione formation, 49 (2) to avoid acid-catalyzed formation of pyroglutamic acid (5-oxopyr-rolidine-2-carboxylic acid), 50 and (3) to avoid amidine formation between DCC and pro-tonated peptide-resin. The latter does not occur with the free amine. 

Platinum-catalyzed hydrolytic amidation of unactivated nitriles was reported by Cobley and coauthors. The platinum(ii) complex, [(Me2PO- H- PMe2)PtH (PMe2OH)], efficiently catalyzes the direct conversion of unactivated nitriles into N-substituted amides with both primary and secondary amines. Possible mechanisms for this reaction are discussed and evidence for initial amidine formation is reported. Isolated yields vary from 51 to 89% [25]. 

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