Mechanism amide dehydration

The mechanism of dehydration of alcohols by hexamethylphosphortri-amide , phosphorus oxychloride and thionyl chloride in the presence of bases , and sulfur tetrafluoride have been studied. Kirk and Shaw have shown that it is unwise to assume a r/-stereospecificity in dehydration with phosphorus oxychloride or thionyl chloride with basic catalysts. The stereoselectivity is greatly dependent upon the basicity and steric environment of the base. Various steroidal alcohols undergo stereoselective iy -elimination upon treatment with methyl (carboxysulfamoyl) triethylammonium hydroxide inner salt . 

Despite the synthetic utility of this transformation, nearly eighty years elapsed between the discovery of the Bischler-Napieralski reaction and the first detailed studies of its mechanism. " Early mechanistic proposals regarding the Bischler-Napieralski reaction involved protonation of the amide oxygen by traces of acid present in P2O5 or POCI3 followed by electrophilic aromatic substitution to provide intermediate 5, which upon dehydration would afford the observed product 2. However, this proposed mechanism fails to account for the formation of several side products that are observed under these conditions vide infra), and is no longer favored. 

Figure 11 Proposed mechanism of cyclization of dehydrated NisA by NisC. The cyclization reaction shown results in the formation of the B-ring of nisin. The possible stabilization through a /3-turn-like structure via hydrogen bonding between the amide NH of Cys and the carbonyl of Dha/Dhb is shown and may explain the high stereoselectivity observed in nonenzymatic cyclizations involving four amino acids as discussed in the text. Reprinted with permission from B. Li W. A. van der Donk, J. Biol. Chem. 2007, 282, 21169-21175.

It is well documented that the isoimide is the kinetically favoured product and that isomerization yields the thermodynamically stable imide when sodium acetate is used as the catalyst. High catalyst concentrations provide maleimides with low isoimide impurity. The mechanism by which the chemical imidization is thought to occur is shown in Fig. 3. The first step in the dehydration reaction may be formation of the acetic acid-maleamic acid mixed anhydride. This species could lose acetic acid in one of the two ways. Path A involves participation by the neighboring amide carbonyl oxygen to eject acetate ion with simultaneous or subsequent loss of proton on nitrogen to form the isoimide. Path B involves loss of acetate ion assisted by the attack of nitrogen with simultaneous or subsequent loss of the proton on nitrogen to form the imide. If the cyclodehydration is run in acetic anhydride in the absence of the base catalyst, isoimide is the main reaction product. 

In addition to the procedures listed in Table 3.38, further reactions have been used to generate halides upon cleavage. In Section 3.5.2, iodolactonization is presented as a method for the preparation of iodomethyl lactones from resin-bound pentenoic or hexenoic acid derivatives. Closely related to the iodolactonization is the iodine-mediated formation of 2-(iodomethyl)tetrahydrofurans from resin-bound isoxazoli-dines (Entry 9, Table 3.38 for the mechanism, see Figure 15.5). Nitriles can also be prepared by cleavage and simultaneous dehydration of amides RCONH2 from the Rink or Sieber linkers with TFA anhydride (Entry 10, Table 3.38). 

The same isothiocyanate 5 was obtained when 6 was used as the starting material.32 For this 0- N acyl migration, a mechanism has been proposed that involves the oxazoline intermediate 8, which results after dehydration of the initially formed l,2-(orthoacetyl)amide (7). The oxazoline derivative subsequently reacts with the thiocyanate ion at C-l, with Walden inversion. 

From the results presented in Table 2 it can be again deduced that the dehydration process increase in general the selectivity towards the amide, while the presence of certain amounts of water in the solid favours the hydrolysis reaction. With the present data is not possible to establish correlations between conversion and selectivity of the reaction with the nature and topology of the different acidic solids, therefore further investigations are needed to go deeply into the mechanism of the reaction. 

Tetrakis(pyridin-2-yloxy)silane, Si(OPy)4 (6), is a very mild dehydrating agent that can be employed to form amides from acids and amines at 20 °C in THF (Scheme 2), without the need to use any basic promoter such as tertiary amines or 4-(dimethylamino)pyridine. The proposed mechanism (Scheme 3) implicates an intermediate (A) formed from Si(OPy)4 and the acid (7) which reacts with the amine (8) to give the amide (9), with 2-pyridone and silica, (Si02)n, as by products.5... 

In practice the dehydration can be achieved with a broad range of acids or acid anhydrides, such as phosphoric add, phosphorus oxychloride, phosgene (COCI2), and thionyl chloride. An example of the mechanism is shown below for thionyl chloride and involves activation of the amide to imidolyl halide 3.16 then intramolecular attack by the enolic form of the ketone. 

The mechanism for the dehydration of an amide with thionyl chloride is shown below ... 

Figure 7.4 illustrates the dehydration of primary amides A to nitriles B using trifluo-romethanesulfonic acid anhydride. All intermediates correspond to the ones discussed above. When the mixed anhydrides F finally release trifhioromethanesulfonic acid in two steps hy the already familiar El mechanism, the formation of the nitrile B is completed. 

In 1966, Weingarten and White93 reported a simple route to simple 1,1-enediamines. Under mild conditions, aliphatic amides underwent reaction with tetrakis(dimethylami-no)titanium (60) to afford 1,1-enediamines 61. The reaction could be carried out with most of the common acid derivatives such as free acid, ester and anhydride via the amide (equation 22). A probable mechanism involving intramolecular dehydration has been proposed in Scheme 442. 

Dev132 reported that the reaction of 2-(cyclopentan-2-one)butyrate and ammonium acetate gives the 2 M-pyrindin-2-one (197). However, it is difficult to reconcile the reactants and the suggested product (197) since a reasonable mechanism, which involves conversion of the ester to an amide followed by cyclization and dehydration, would predict 198 as a possible product. Alternatively, if the reactant ester was 3-(cyclopentan-2-one)butyrate, the same mechanism would predict 197 as the product.44... 

The addition of thiobenzophenone to nitrosobenzene to give N-(diphenyl-methylene)benzenamine is said to go via a cyclic intermediate that loses sulfur monoxide to give the product. A similar mechanism is invoked in the reaction of aldehydes with 5,5 -diphenylsulfilimine to give enamines or nitriles (e.g., 587). Oxa-2,3-thiazete-2-oxides are suggested as intermediates in the dehydration of aryl amides to nitriles by thionyl chloride.The reaction of Af-sulfilamines with aldehydes, which previously were suggested to give oxa-2,3-thiazetidine-2-oxides, has been shown to yield acyclic compounds. 

It is well known that oxalyl chloride reacts with non-substituted amides to afford acyl isocyanates in high yields (Ref. 214). In contrast, phosgene acts as a dehydrating agent to give nitriles as shown in scheme 160. This interesting reaction, its mechanism and applications will be discussed in volume 2. 

In structural studies on oxytetracycline (Terramycin) and chlorotetracycline (Aureomycin) a Pfizer group found that tosyl chloride in cold pyridine converts the antibiotics into nitrile derivatives through dehydration of the primary carbox-amido group. They then found that simpler amides are dehydrated to nitriles in good yield by adding 1 equivalent of tosyl chloride slowly to a mixture of the amide with 2.25 equivalents of pyridine at a rate such as to maintain a temperature of about 70°. The mechanism proposed involves O-tosylation. 

In the reverse case, for the dimethylation with formaldehyde for example (R2 = R3 = H), the dehydration is impossible. Thus, in this last case, the only possible pathway is the hydrogenolysis of the hemiaminal D. The competitive hydrogenation of carbonyl must be considered carefully because it influences the choice of the reaction conditions. We assume that with amides, anilines and alcohols similar mechanisms should be possible. 

Amino acids are linked together to form peptides by amide formation between the COOH of one amino acid and the amine group of another amino acid. Although the mechanism is not simple, the reaction can be considered as a dehydration between COOH and amine groups ... 

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