α-Anilinoketones, Esters and Amides: A Chemical Study

A group of α-anilinoketones, 2-aminoalcohols, α-anilinoesters and α-anilinoamides were successfully synthesized and characterized by NMR spectroscopy and mass spectrometry. The yields were, in general, moderate to good (up to 75.4%), except for the α-anilinoesters (16.9–35.6%). The α-halocarbonyl starting materials showed different chemical reactivities. α-Haloketones and α-chloroacetates afforded monoalkylation, while small α-chloroamides afforded dialkylation. Finally, NMR spectroscopy revealed interesting structural features about the 2-aminoalcohols and diphenylamides.


Figure 1. The general structures of 3-(arylacetylamino)-N-methylbenzamides, 3-(aryloxyacetylamino)-N-methylbenzamides and N-methyl-3-(2-naphthyl-acetylamino)benzamides.
H. pylori is a wide spread pathogen, especially in developing countries, where the incidence of infection can reach up to 50% of the entire population [3]. Infection with H. pylori has been directly associated with the development of duodenal ulcers; 95% of patients reporting to clinics with duodenal ulcers are infected with H. pylori [4,5]. There is also an accumulating body of evidence that associates H. pylori infection the occurrence of stomach cancer, the 2nd most common type of cancer [6,7]. Furthermore, H. pylori has also been associated with some types of lymphomas [8], hepatic encephalopathy [9,10] and ischemic heart diseases [11]. The simplicity and selectivity of Ando et al.'s compounds have prompted us to design and synthesize a structurally analogous series of α-anilinocarbonyls (ketones, esters and amide, Figure 2). Herein, the synthesis of these compounds, in addition to the reduction of the ketone derivatives to the corresponding 2-anilinooalchols will be discussed. Also, some interesting spectroscopic details for  O Ar the synthesized compound and the differences in reactivity of the α-halocarbonyl starting materials will be explained. It is worth mentioning that the antimicrobial activity of these compounds has been determined but will not be published at this time.
While many phenacylbromides and chlorides are commercially available, some were prepared for the purpose of this work (Scheme 2). 2-Bromoindan-1-one (2) was obtained in low yields by treating 1-indanone with bromine in glacial acetic acid [12,13]. Phenacylchorides 3 and 4, on the other hand, were prepared by modifying the procedure of Leiserson and Weissberger for the large scale synthesis of p-(α-chloroacetyl)acetanilide [14]. Friedel-Crafts acylation of acetanilide and benzanilide with α-chloroacetyl chloride was performed in dichloromethane, instead of carbon disulfide, in the presence of aluminum chloride to afford p-(α-chloroacetyl)acetanilide (3) and p-(α-chloroacetyl)benzanilide (4) in good yields. Naphthalene was regioselectively acylated at C-2 to form 2-naphthacylchloride (5), confirmed by singlet at 8.49 corresponding to the proton at C-1 of the naphthalene ring in its 1 H-NMR spectrum.  The work up consisted of adding water to the reaction mixtures, which caused immediate precipitation of the crude product. The filtered solid was then crystallized from the appropriate solvent to afford the desired compound. As for alkylation with α-chloroketones, two modifications were found to be necessary. The first was the addition of sodium iodide to facilitate the otherwise sluggish reaction [15]. The iodine atom displaces the α-chlorine producing in situ a more electrophilic α-iodoketone [16]. The second modification was replacing potassium carbonate by the less basic sodium bicarbonate because coupling of acetanilide 3 to aniline 1 in the presence of potassium carbonate failed to afford the expected product. It was postulated that potassium carbonate was strong enough to deprotonate the anilide and hence, decreased its nucleophilicity. The amide in 3 is expected to have enhanced acidity due to the fact that the formed conjugate base is efficiently stabilized by resonance, as shown in Scheme 4. Furthermore, the reaction of aniline 1 with 2-bromoindan-1-one 2 in the presence of potassium carbonate afforded multiple products, while the reaction in the presence of sodium bicarbonate instead, was much cleaner, affording 15, albeit in low yield. The exclusive formation of monoalkylated products from the reaction of α-haloketones with aniline 1 can be attributed to an indirect alkylation mechanism, which involves the attack by the amino group in 1 on the carbonyl carbon of the α-haloketones, followed by intramolecular replacement of the halogen, as illustrated in Scheme 5. This mechanism most likely involves a bridged transition state that is easily formed by a primary amine; hence, the produced α-anilinoketones, which have a secondary amine, will not participate in such a mechanism [17]. Furthermore, the bulkier α-anilinoketone, compared to the starting aniline 1, will have a slim chance to effect a direct second alkylation.

Scheme 5.
A mechanism involving a bridged-transition state for the alkylation of aniline 1 with α-haloketones. The reduction of the aromatic ketones 6-13 was performed using NaBH 4 . First, the van Vliet et al. procedure to reduce α-aminoketones to 2-aminoalcohols was followed. Using sodium borohydride (1.5 equivalents) suspended in a 1:1 dichloromethane-isopropanol mixture, followed by work up under relatively strong acidic conditions [18] reduced compounds 6, 8 and 12 with satisfactory yields and reduced compound 13 in 9% yield. Alternatively, compounds 7-11 were reduced using NaBH 4 in aqueous basic media. This reaction was generally done by suspending the α-anilinoketone in water, followed by addition of one equivalent of sodium hydroxide and one equivalent of sodium borohydride and the mixture was then stirred overnight. A simple work up by filtering the suspension, then crystallizing the dried cake from ethyl acetate afforded the 2-aminoalcohol. Unfortunately, the yields from this milder and simpler procedure were generally low and α-anilinoketones 7 and 11 failed afford the corresponding 2-anilinoalcohol. Finally, a more standard reduction procedure was employed in which the α-anilinoketones were reduced using one equivalent of sodium borohydride in methanol [19,20]. The yields were higher than the other two procedures and α-anilinoketones 6-11 were reduced to the corresponding 2-aminoaclohols 16-21 in 51.4-75.4% yields. The reduction reactions are summarized in Scheme 6. Scheme 6. Reduction of α-anilinoketones 6-13 to 2-anilinoalcohols 16-23.
Analysis of the 1 H-NMR spectra of the 2-aminoalcohols showed that the protons on the carbon adjacent to nitrogen are not equivalent and show-up as two distinct multiplets. The splitting pattern in their corresponding peaks is due to vicinal coupling and geminal coupling to the aniline proton and to the proton on the benzylic carbon bearing the hydroxyl group. Such nonequivalency of vicinal methylene protons is usually observed in rigid systems such as small or relatively inflexible rings [21][22][23]. This led to the conclusion that the 2-aminoalcohols are relatively rigid, most likely due to an intramolecular hydrogen bond between the aniline nitrogen's lone pairs and the hydroxyl group's hydrogen. This assumption was supported by ab Initio calculation using Hyperchem v7.5 as seen in Figure 3.

Scheme 7. Synthesis of α-anilinoacetates 27-29.
The reaction of both naphthols proceeded smoothly in the presence of triethylamine, albeit in moderate yields, but the reaction with phenol using the same conditions yielded more than one product. When pyridine, a weaker base than triethylamine, was used the desired ester 24 was obtained exclusively. Coupling of chloroacetyl esters 24-26 with N-methyl-3-aminobenzamide (1) was performed following the conditions described earlier as illustrated in Scheme 7. As seen in this scheme, the yields of the α-anilinoacetates 27-29 were rather low. Actually this might indicate that these compounds are formed by the same mechanism of alkylation discussed earlier (Scheme 5). The low yield might be due to the fact that the ester carbonyl's carbon is less nucleophilic than the ketone's. Alternatively, the attack of the amino group in aniline 1 on the ester's carbonyl will lead to the formation of a tetrahedral intermediate as shown in Scheme 8. This tetrahedral intermediate will either proceed to form the desired alkylated aniline (Path A) or the aryloxy group will leave leading to the aminolysis (Path B). Possible products other than the desired α-anilinoacetates were not investigated.

Synthesis of α-Anilinoesters 32 and 33
Aniline or diphenylamine were treated with α-chloroacetyl chloride to produce N-phenyl α-chloroacetamide (30) and N,N-diphenyl α-chloroacetamide (31), respectively. Aniline was coupled to α-chloroacetyl chloride in a biphasic mixture of ethyl acetate and 1 M aqueous sodium bicarbonate to afford amide 30 in very good yield, a procedure that has been used successfully in our labs for chloroacylation of anilines. Alternatively, the stronger triethylamine was used in the prepare N,N-diphenyl-α-chloroacetamide (31). The resultant α-chloroacetamides were then reacted with aniline 1 in the presence of sodium iodide and sodium bicarbonate to afford the α-anilinoester 32 and 33, as seen in Scheme 9. It was interesting to discover that the 1 H-NMR and mass spectrum of 32 show, clearly, that two molecules of phenyl α-chloroacetamide 30 have reacted with one molecule of aniline 1 resulting in a dialkylated product. As mentioned earlier such dialkylation was not observed with either α-chloro-ketones or α-chloroacetates. O  Alkylation of primary amines by α-chloroacetamides under these experimental conditions was reported earlier to proceed by dialkylation [15], which indicates that this reaction follows an S N 2 substitution mechanism. This suggestion is supported further by the fact that the bulkier α-chloroacetamide 31 gave the monoalkylation product exclusively, when reacted with aniline 1 in the same conditions. An intriguing aspect of compound 33 and its starting material, α-chloroacetamide 31 was their NMR spectra, specially the 13 C-NMR spectra. As seen in Figure 4a,b, the peaks corresponding to the carbons in the two phenyl group in the amide side chain of both compounds are not the ordinary sharp narrow peaks usually observed in 13 C-NMR. These two phenyl groups are slowly rotating as a result of restricted rotation around the amide bond and the N-C Ph bonds, which have partial double bond character. This slowed rotation results in efficient relaxation leading to the broadening observed in these NMR spectra [25]. Here, the two phenyl groups are not equivalent, but not totally distinct enough to appear as two resolved sets of peaks, instead, the peaks were rather wide and unresolved.

Materia
Bulk sol obtained ma Belgium) an Scientific-m spectra were Nicolet Ava H-NMR (

Synthesis
2-Bromoindan-1-one (2). To a solution of 1-indanone (2.0 g, 15.1 mmol) dissolved in glacial acetic acid (10.0 mL), bromine (1.00 mL, 19.50 mmol) was added dropwise and the mixture was stirred for 30 min. The reaction mixture was then dissolved in ether (100 mL) and washed with water (100 mL × 2) and saturated sodium bicarbonate solution (100 mL). The ether layer was then dried (MgSO 4 ), filtered and evaporated. The residue was crystallized from ethyl acetate-hexane to yield 1. p-Chloroacetyl acetanilide (3). To a solution of acetanilide (20.0 g, 148.0 mmol) and α-chloroacetyl chloride (27.0 mL, 339.5 mmol) in CH 2 Cl 2 (100 mL), aluminum chloride (59.2 g, 444.0 mmol) was added in portions while stirring, turning the color to dark brown. After completion of addition, the mixture was heated at reflux for 30 min. The reaction mixture was then allowed to cool to room temperature and added slowly with stirring to crushed ice (300 g) containing conc. HCl (10 mL). The precipitate was vacuum filtered, washed thoroughly with water, then left to dry. The solid residue was crystallized from absolute ethanol to yield 25. p-Chloroacetyl benzanilide (4). To a suspension of benzanilide (20.0 g, 101.4 mmol) and α-chloroacetyl chloride (16.0 mL, 201.2 mmol) in CH 2 Cl 2 (100 mL), aluminum chloride (40.6 g, 304.5 mmol) was added in portions while stirring, turning the color to dark brown. After completion of addition, the mixture was heated at reflux for 2 h. The reaction mixture was then allowed to cool to room temperature and added slowly with stirring to crushed ice (300 g) containing conc. HCl (10 mL). The pale yellow precipitate was vacuum filtered, washed thoroughly with water, then left to dry. The solid residue was crystallized from absolute ethanol to yield 19.  (5). To a solution of naphthalene (5.0 g, 39.0 mmol) and α-chloroacetyl chloride (6.2 mL, 78.0 mmol) in CH 2 Cl 2 (30 mL), aluminum chloride (10.4 g, 78.0 mmol) was added in portions while stirring, turning the color to dark brown. After completion of addition, the mixture was heated at reflux for 30 min. The reaction mixture was then allowed to cool to room temperature and added slowly with stirring to crushed ice (300 g) containing conc. HCl (10 mL). The organic layer was taken, dried (MgSO 4 ) and evaporated. The residue was crystallized from ethyl acetate-hexane to  (6). Aniline 1 (10.0 g, 66.6 mmol) and phenacyl bromide (13.3 g, 66.6 mmol) were dissolved in DMF (330 mL). To that solution potassium carbonate (9.2 g, 66.6 mmol) was added and the mixture was stirred overnight. The reaction mixture was then added to water (1.2 L) and the precipitate was vacuum filtered and left to dry. The solid residue was crystallized from ethyl acetate to yield 9.  (7). Aniline 1 (1.0 g, 6.7 mmol) and 4-fluorophenacyl bromide (1.4 g, 6.7 mmol) were dissolved in DMF (15 mL). To that solution, potassium carbonate (0.9 g, 6.5 mmol) was added and the mixture was stirred for 4 h. The reaction mixture was then added to water (200 mL) and the precipitate was vacuum filtered and left to dry. The solid residue was crystallized from absolute ethanol to yield 1.  (8). Aniline 1 (5.0 g, 33.3 mmol) and 4-bromophenacyl bromide (9.3 g, 33.3 mmol) were dissolved in DMF (100 mL). To that solution, potassium carbonate (4.6 g, 33.3 mmol) was added and the mixture was stirred for 2 h. The reaction mixture was then added to water (300 mL) and the precipitate was vacuum filtered and left to dry. The solid residue was crystallized from absolute ethanol to yield 4.  (9). To a solution of aniline 1 (3.6 g, 23.6 mmol) and 4-methylphenacy chloride (4.0 g, 23.6 mmol) in DMF (30 mL), sodium bicarbonate (2.0 g, 23.6 mmol) and sodium iodide (5.1 g, 23.6 mmol) were added and the mixture was stirred overnight. The reaction mixture was then added to water (500 mL) and the precipitate was vacuum filtered and left to dry. The solid residue was crystallized from absolute ethanol to yield 2.  (11). To a solution of aniline 1 (1.  (12). To a solution of aniline 1 (4.5 g, 30.0 mmol) and p-chloroacetyl acetanilide (3) (6.4 g, 30.2 mmol) in DMF (100 mL), sodium bicarbonate (2.5 g, 29.4 mmol) and sodium iodide (6.5 g, 43.4 mmol) were added and the mixture was stirred overnight. The reaction mixture was then added to water (300 mL) and the precipitate was vacuum filtered and left to dry. The solid residue was crystallized from DMF-water to yield 4.7 g of 12 (48.2%) as yellowish brown crystals, mp: 226-230 °C; IR: 3,375, 3,330, 1,682, 1 (13). To a solution of aniline 1 (3.0g, 20.0 mmol) and 4-benzoylaminophenacyl chloride (4) (5.5g, 20.0 mmol) in DMF (75 mL), sodium bicarbonate (1.7 g, 20.0 mmol) and sodium iodide (4.3 g, 28. mmol) were added and the mixture was stirred over 72 h. The reaction mixture was then added to water (800 mL) and the precipitate was vacuum filtered and left to dry. The solid residue was crystallized from DMF-water to yield 5.  (14). Aniline 1 (350.0 mg, 2.3 mmol) and 2-naphthacyl chloride (5) (0.5 g, 2.4 mmol) were dissolved in DMF (10 mL). To that solution, sodium bicarbonate (193.2 g, 2.3 mmol) of and sodium iodide (480.0 mg, 3.3 mmol) were added and the reaction mixture was stirred overnight. The reaction mixture was then added to water (100 mL) and the precipitate was vacuum filtered and left to dry. The solid residue was crystallized from ethyl acetate to yield 0.  196.92, 167.76, 148.64, 135.89, 135.68, 132.81, 132.64, 130.19 (15). To a solution of aniline 1 (1.0 g, 6.7 mmol) and 2-bromo-indan-1-one (2) (1.4 g, 6.7 mmol) in DMF (25 mL), sodium bicarbonate (1.1 g, 13.3 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was then added to water (300 mL) and the precipitate was vacuum filtered and left to dry. The aqueous layer was extracted with CH 2 Cl 2 (100 mL × 2) and the organic layer was dried (MgSO 4 ), filtered then evaporated.

Molecular Modeling
The chemical structure of 2-aminoalcohol 16 was drawn in ChemDraw Ultra v10 as a chm file and was then opened by Hyperchem 7.5. Using the "build" command, a three-dimensional conformation was obtained and the partial atomic charges were calculated using AM1 semi-empirical calculations. The obtained structure was then geometry optimized using Enhanced MM (MM+) force field implemented in HyperChem using the atomic charges and Polak-Ribiere conjugate gradient with an RMS gradient of 0.01 kcal/Ǻ mol options. For the computation of intramolecular hydrogen bonding, Ab initio geometry optimization for the most stable conformer obtained by MM+ using Polak-Ribiere conjugate gradient with an RMS gradient of 0.01 kcal/Ǻ mol was performed.

Conclusions
Ten α-anilinoketones, eight 2-aminoalcohols, three α-anilinoesters and two α-anilinoamides were successfully synthesized and characterized by NMR spectroscopy and mass spectrometry. The yields were moderate to good for the α-anilinoketones (up to 65.4%) and the 2-aminoalcohols (up to 75.4%), low for the α-anilinoesters (16.8-35.1%) and low to moderate for the α-anilinoamides (50.1-54.3%). In addition, α-haloketones and α-chloroacetates afforded monoalkylated products when reacted with 3-amino-N-methylbenzamide (1), while small α-chloroamides afforded the dialkylated product. This implied that the mechanisms for the nucleophilic substitution reactions are not similar and that alkylation by α-chloroamides, only, proceeds by direct S N 2 mechanism. 1 H-NMR spectroscopy showed that the chemical structure of the 2-aminoalcohols is rigidified by the possible formation of a 5-membered ring due to an intramolecular hydrogen bond, while 13 C-NMR spectroscopy indicates that diphenylamides contain two nonequivalent, but not totally distinct phenyl groups that give rise to broad unresolved peaks.