A novel synthesis of chloroacetamide derivatives via C -amidoalkylation of aromatics by 2-chloro-N -(2,2,2-trichloro-1-hydroxyethyl)acetamide

A synthetic approach to the preparation of novel 2-chloro-N -(2,2,2-trichloro-1-arylethyl)acetamides on the basis of C -amidoalkylation of aromatics with 2-chloro-N -(2,2,2-trichloro-1-hydroxyethyl)acetamide has been developed. Scope and limitations of the synthesis of new chloroacetamide derivatives were demonstrated.

In continuation of our interest on chemistry of functionalized chloroacetamide derivatives, 12 we studied C-amidoalkylation of aromatics by 2-chloro-N-(2,2,2-trichloro-1-hydroxyethyl)acetamide 1 (Scheme 1) in order to develop a convenient way to promising biologically active compounds and reagents for heterocyclic chemistry.
Because of the high mobility of chlorine atom and reactive N-H group, compounds containing chloroacetamide moiety are known to be useful synthetic scaffolds for design of aziridines, 13 lactams, 14 piperazines, 15 oxazolidines, 16 imidazolidines and tetrahydropyrimidinesprecursors of heterocyclic carbenes, 17 macrocyclic ligands, 18 dendrimers. 192-Chloracetamide derivatives found application in solid-state chemistry, 20 in synthesis of aminoacids, 21 natural compounds 22 and their homologs, 23 pharmacologically promising substances 24 and biomarkers, 25 reagents for polymer modification, 26 ion-exchange resins for heavy and radioactive metal sorption. 27Chloroacetamide pesticides 28 and dyes 29 are also well known.Thus, investigation of 2-chloroacetamide chemistry is an actual task both from theoretical and applied viewpoints.

Results and Discussion
As preliminary investigation, a range of Lewis and Bronsted acids was screened as catalysts in the model reaction of hemiaminal 1 with toluene (Table 1).The formation of 2-chloro-N-[2,2,2-trichloro-1-(4-methylphenyl)ethyl]acetamide 2a was found to proceed smoothly in the presence of strong Bronsted acids (Entry 5-11).When we used BF3 etherate and ZnCl2 or in the absence of a catalyst (Entry 1-3) no reaction took place.For AlCl3 (Entry 4) C-amidoalkylated toluene derivative 2a was produced after a long period in poor yield.The highest yield was achieved for the mixture of H2SO4 with P4O10 (Entry 9-11).Moreover, excess of toluene had a beneficial effect on the reaction.
It was ascertained for different aromatic structures that C-amidoalkylation also occurred with benzene, phenol, anisole, naphthalene and 2-chlorothiophene (Table 2).Accordingly, mono substituted aromatics containing electron-donating groups, annulated aromatics and nonacidophobic electron-enriched heteroaromatics can be used in the synthesis of 2-chloroacetamide derivatives of the type 2 by C-amidoalkylation with hemiaminal 1. Authors, please redraw the Scheme 1 in ChemDraw or ISISDraw and send it to us as cdx or skc file.Thank you In the earlier works 11 devoted to C-amidoalkylation of aromatics by N-(2,2,2-trichloro-1hydroxyethyl)amides a large excess of sulfuric acid (2-20 equivalents) was used for activation of the process.The reaction time took 50-100 h.In the present paper, we found that under action of H2SO4 -P4O10 mixture the reaction proceeded for 2.5-5 h (Table 2).Unfortunately, under the conditions studied halobenzenes, aromatics, containing electron-withdrawing substituents, and disubstituted aromatics did not react with hemiaminal 1.The results suggest that hemiaminal 1 possesses similar C-amidoalkylating activity in comparison to N-(2,2,2-trichloro-1hydroxyethyl)sulfonamides studied in our earlier works. 30he experimental data obtained allowed one to reach the conclusion that the reaction of aromatics with hemiaminal 1 depends on electronic effect of a substituent in an aromatic ring.So, the C-amidoalkylation proceeded in a selective manner to produce only para-substituted derivatives without admixtures of ortho-or meta-substituted isomers.
It should be noted that heating of reaction mass or increase of reaction time resulted in lower yield (see Table 1, Entry 12) probably due to side processes (sulfonation, acidolysis, resinification).In the case of 2-chlorothiophene when we increased the reaction period over 10 h the formation of minor 2,2′-(2,2,2-trichloroethane-1,1-diyl)bis-(5-chlorothiophene) 3 as admixture took place (Scheme 2).It is likely that amide 2f acted as C-alkylating reagent and chloroacetamide moiety fulfilled the role of a leaving group.We noted earlier 31  The structure of C-amidoalkylated aromatics 2 was proved by NMR spectroscopy and elemental analysis (see Experimental section).The protons of the NH-CH groups are presented as two characteristic doublets in 1 H NMR spectra.The protons of the CH2 groups are diastereotopic and give AB-system.The aromatic protons of the compounds 2a,c,d are presented as AA'BB' spin system that corresponds to para-substituted isomers. 1 H NMR spectrum of naphthalene fragment for the compound 2e points to the formation of 1-naphthyl substituted derivative.

Conclusions
In summary, the method of C-amidoalkylation of aromatics with hemiaminal 1 was developed.Possibilities and limitations of the synthetic way to new 2-chloroacetamide derivatives were demonstrated.The synthesis of a series of novel 2-chloro-N-(2,2,2-trichloro-1-arylethyl)acetamides, which are of interest as objects of spectroscopic investigation, promising reagents and biologically active compounds or their precursors, was carried out.

Table 1 .
The Screening of Lewis and Bronsted Acids for C-amidoalkylation of toluene by

please redraw the Scheme 2 in ChemDraw or ISISDraw and send it to us as cdx or skc file. Thank you
ClScheme 2. Formation of the side product 3.