The Chemoselective and Regioselective Hydroxylation or Chlorination onto The Aryl Ring of N-(4-Substituted-Aryl) Nitrones. Preparation of 2-Amino- phenols by Regiospecific Ortho-Hydroxylation

N-(substituted-aryl) Nitrones, in the reactions with a chlorinating reagent such as trichloroacetyl chloride, oxalyl chloride, or thionyl chloride, produce a hydroxylation or a chlorination onto the aryl ring of the arylnitrones. The chemoselectivity and the region selectivity (hydroxylation or chlorination) depend largely on the nature of chlorinating reagent and on that of the 4-substituent in the aryl ring of the arylnitrones. This work provides a novel synthetic route to important intermediates: 2-aminophenols, 2-chloroanilines and 3-chloroanilines which are important industrial intermediates for pharmaceutical products (API), for azo-dye ingredients and for agricultural products.


Introduction
Nitrones are emerging chemicals belonging to an important class of synthetic intermediates. They are used in the reactions of 1, 3 dipolar cycloadditions. They are important synthons for the synthesis of 5-membered heterocyclic rings [1,2]. Nitrones possess high reactivity towards nucleophiles to form useful compounds of general importance [3][4][5][6][7]. In addition to the aforementioned ability of forming heterocyclic rings and the reactivity towards nucleophiles, arylnitrones have another utility in that they can be served as a synthon for the introduction of ortho-hydroxylation, ortho-chlorination or meta-chlorination to the aryl ring by the action of an acid chloride or thionyl chloride. Arylnitrone compounds lend themselves to being very useful for that purpose. The final results of the ortho-hydroxylation, the ortho-chlorination or the meta-chlorination to the aromatic ring may be considered as a nucleophilic aromatic substitution. In order to gain some insight of these substitution reactions, we embarked in an investigation of the reactions between N-(4-substituted-phenyl) Nitrones and different chlorinating reagents. For this work, we chose three chlorinating reagents: trichloroacetyl chloride, oxalyl chloride, and thionyl chloride, and selected N-(4-substituted-aryl) Nitrones with a variety of 4-substituents: activating group and deactivating group.
The rationale behind this investigation is the expectation that under the action of different chlorinating reagents to the different N-(4-substituted-aryl) nitrone compounds, the results of the reaction products would offer us the information about what products would form: hydroxylated or chlorinated anilines, and that about at what position of the aryl ring where the substitution would take place. The success of the accomplishment of this project would provide to us the information relating to the influence of (1) the nature of the 4-substituent in the aryl ring of the arylnitrones: (activating or deactivating group), and (2) that of the chlorinating + Zn + NH 4  The arylnitrones were prepared from 4-substituted-nitrobenzene, zinc powder, ammonium chloride and benzaldehyde in a mixture of solvents comprising methanol and water. The yields of the prepared Nitrones are, in general, good to excellent. We submitted each of the synthesized Nitrones to a chlorinating reagent (trichloroacetyl chloride, oxalyl chloride or thionyl chloride) in dichloromethane or in THF at room temperature for two hours. The resulting intermediate was hydrolyzed by concentrated hydrochloric acid. The aminoproducts resulted from these reactions of the N-(4-substituted-aryl) Nitrones with each of the three chlorinating agents were given in the (   A number of important generalizations emerge from the data in Tables 1,2. First, when the substituted group R in N-(4substituted-aryl) Nitrones was a deactivating group such as F, Cl, Br or a moderate activating group such as CH 3 , the reactions of arylnitrones with chlorinating reagents (trichloroacetyl chloride or oxalyl chloride) gave rise chemo specifically and region specifically to ortho-hydroxylated aniline products: 5-R-2-amimophenols (compounds A) [Entries 1a,1b;2a,2b;3a,3b;and 4a,4b]. It is well known that the direct nucleophilic aromatic substitution with (OH)to make phenol compounds was achieved under harsh conditions: high pressure and high temperature (ca 350 o C) [14]. The formation of the phenol compounds, via the nitrone route, is accomplished under much milder conditions [room temperature, no pressure, and short reaction time]. The ortho-hydroxylation via nitrone methodology could offer a novel route to important intermediates: ortho-amino-phenols [15] ( Figure 3). It is also noteworthy that while with moderate activating group (CH 3 ), the isolated yield of ortho-hydroxylation products (compound [A]) is good (60.7%) [4b], the isolated yields of ortho-hydroxylation products (compound [A]) with the deactivating groups (such as F, Cl or Br] are low (less than 36.1%) [for example: 3b]. It is worth mentioning that the traditional method of making 2-aminophenols by the nitration of the starting phenol compounds, followed by the hydrogenation of the nitro group. However, the nitration always leads to a mixture of the ortho and para nitrophenos, and the separation of these two isomers are tedious [16].  Second, when the substituted group R in N-(4-substitutedaryl) nitrone was a strong activating group such as OCH 3 or OC 2 H 5 , the reactions with chlorinating reagents: oxalyl chloride and trichloroacetyl chloride failed to produce chemo specifically ortho-hydroxylated products. Instead, a mixture of three products was produced: one major product: 3-chloro-4-alkoxyaniline (compound [C]), accompanied with two minor products: 2-chloro- 4-alkoxyaniline (compound [B]) and 5-alkoxy-2-aminophenol (compound [A]). It is noteworthy that (1) based on the analysis by HPLC and 1 HNMR, the order of the magnitude of the percentage of three compounds in the mixture is [C] ≥ [B] > [A] for the reaction of N-(4-alkoxy-aryl)nitrone with chlorinating reagents: trichloroacetyl chloride and oxalyl chloride (entries 5a, 5b, 6a and 6b); and (2) the reaction with oxalyl chloride offered higher percentage of [C] than that with trichloroacetyl chloride (entries 5b versus 5a, and 6b versus 6a); and (3) in the case with a stronger activating group (example: R group is C 2 H 5 O), the reaction with oxalyl chloride offered chemo specifically and region specifically 3-chloro-4-ethoxy-aniline (Entry 6b, Compound [C]), and no minor products: [A] and [B] were detected. From the commercial standpoint, 3-chloro-4-ethoxyaniline and 3-chloro-4-methoxyaniline are expensive chemicals. They are valuable intermediates, especially for the dye industry [17][18][19]. It is remarkable that in any event there is no hydroxylation substitution taken place at the 3-position on the phenyl ring. Third, when the substituted group R in the N-(substituted-aryl) Nitrones is a deactivating group such as F, Cl, Br or moderate activating group such as CH 3 , the reactions with thionyl chloride gave rise exclusively to ortho-chlorinated products: 2-chloro-4-halo-anilines [B] (entries 1c, 2c, and 3c) or 2-chloro-4-methyl-anilines [B] (entry 4c). Finally, when the substituted group R in the N-(4-alkoxy-aryl) nitrone is a strong activating group such as OCH 3 or OC 2 H 5 , the reactions with thionyl chloride gave rise to a mixture of two products: a major product: 2-chloro- 4-alkoxyanilines, (compound [B]) [entries 5c and 6c] which were accompanied by a minor product 3-chloro-4alkoxy-aniline (compounds [C]) [entries 5c and 6c]. There is no compound [A] produced in the reaction with thionyl chloride. It is worth mentioning that the ratio of the percentage of two isomers: [B] and [C] depended largely on the electronic donating strength of the activating group on the aryl ring. The stronger the activating group was, the higher the ratio [B] over [C] (entries 6c versus 5c) resulted. The compounds produced by these reactions are Important Industrial Intermediates for Pharmaceutical products (API), for azo-dye ingredients and for agricultural products.
In terms of plausible mechanism, we postulate that the first step would be the nucleophilic attack of the negatively charged oxygen atom of the nitrone compound to the acid chloride (trichloroacetyl chloride, oxalyl chloride or thionyl chloride) giving rise to the intermediate I ( Figure 4,5). The formation of intermediate I was followed by a possible cyclic six-membered transition state, and a nucleophilic aromatic substitution by oxygen atom leading to the intermediate II (oxygenation in the aromatic ring, as shown in Figure 4) or by chlorine atom leading to the intermediate II-a (chlorination in the aromatic ring, as shown in Figure 5). The following step was the hydrogen transfer step with the re-aromatization leading to the ortho-substituted intermediate III or III Intermediate III

2-aminophenol [ Compound A]
Hydrolysis Y= Cl-CO or Cl 3 C- When the substituted group R in N-(4-substituted-aryl) nitrone is a deactivating group such as F, Cl, Br or a moderate activating group such as CH 3 , the reaction of Nitrones with an acid chloride (trichloroacetyl chloride or oxalyl chloride) gave rise chemo specifically and region specifically to the ortho-hydroxylated amino-products: 5-R-2-aminophenols (Compound [A]). Likewise, the action of thionyl chloride offered chemo specifically and region specifically 5-R-2-chloroanilines (Compound [B]). Nonetheless, when the substituted group R in N-(4-substituted-aryl) nitrone is a strong activating group such as OCH 3 or OC 2 H 5 , the reaction of nitrones with acid chlorides (trichloroacetyl chloride or oxalyl chloride) gave a mixture of three compounds in which the major product is [C] and the minor products are [A] and [B]. Likewise, with thionyl chloride, the reaction offered a mixture of two chlorinated anilines. The formation of this unexpected 3-chloro-4-alkoxyanilines from theses reaction, has not been previously reported in the literature. While the six-membered ring mechanism explains well the formation of the ortho-substituted products, it could not, however, account for the formation of 3-chlorinated product: 3-chloro-4-alkoxyaniline (compound C). Other pathways leading to these two compounds could be account for their formation.

Conclusion
The reaction of N-(4-substituted-aryl) Nitrones with chlorinating reagents such as trichloroacetyl chloride, oxalyl chloride, or thionyl chloride produced a hydroxylation or a chlorination to the aryl ring of the nitrone compounds. The chemoselective and the regioselective hydroxylation or chlorination to the ring depend largely on the nature of chlorinating reagents and on that of the 4-substituent in the aryl ring. When the substituted group R in the aryl ring is a deactivating group such as F, Cl, Br or a moderate activating group such as CH 3 , the reactions of Nitrones with trichloroacetyl chloride or oxalyl chloride gave rise chemo selectively and region specifically to ortho-hydroxylated aminoproducts: 5-R-2 amino-phenols (compound [A]). The reported methodology, via nitrone intermediate, provides a novel synthetic route to the preparation of the valuable ortho-aminophenol compounds. Ortho-aminophenol compounds are important industrial intermediates for pharmaceutical products (API), for azo-dye industrial ingredients and for agricultural products. Likewise, the same reactions with thionyl chloride offered chemo specifically and region specifically 5-R-2-chloroanilines (compound [B]). Nonetheless, when the substituted group R in N-(4-substituted-aryl) nitrone is a strong activating group such as OCH 3 or OC 2 H 5 groups, the aforementioned chemo specificity and region specificity did not occur in the reactions of arylnitrones with chlorinating reagents (trichloroacetyl chloride, oxalyl chloride or thionyl chloride).

Supporting Information
Detailed description of the full experiments including 1 H & 13 C NMR and HRMS were given in the supporting information section Part One: Experimental details for the preparation of Compounds General a.

1
H and 13 C NMR spectra were recorded in DMSO-d 6 on a Bruker AV III 400 spectrometer (400MHz). The chemical shifts were reported in ppm relative to Me4Si as internal standard. Mass spectra were obtained with a Waters Xevo G2 QT of mass spectrometer. Thin Layer Chromatography (TLC) on pre-coated plates with silica gel F254, purchased from Qingdao Haiyang Chemical Co. Ltd., was employed to monitor the progress of the reaction. Dichloromethane was purchased from Beijing Chemical Works and dried over molecular sieves 4Å before use. Ethanol was purchased from Beijing Chemical Works and dried over molecular sieves 4Å before use. All reagents of analytical grade were purchased from Sigma-Aldrich, Beijing Inno-Chem Co. Ltd., Alfa Aesar, Beijing Chemical Works, and other commercial sources. They were used without further purification. All reactions were carried out in ovendried glassware. Dried nitrogen was used to purge the reactor and all the glass apparatus before the reaction and to protect the reaction during the entire operation

2-Amino-5-Fluorophenol Hydrochloride (Compound  1a [A])
To an oven dried 50-mL, three-necked, round-bottomed flask equipped with a thermometer, a reflux condenser fitted with a T-joint inlet, glass toppers and a Teflon coated magnetic stirring bar was charged with N-(4-fluoro phenyl)-1-phenylethan-1-imine oxide ((0.43g, 2 mmol, 1 equiv.) and 4 mL of THF. The mixture was stirred for 20 min at room temperature, then cooled to 0 o C. Trichloroacetyl chloride (0.40g, 2.2 mmol, 1.l equiv.) was added dropwise during which the reaction was maintained less than 3oC. After the addition, the reaction was stirred at about 3 o C for 30 min. The reaction was allowed to warm up to room temperature, and stirred at room temperature for 2h. TLC analysis (eluent: butyl acetate/ toluene / DCM: 1/2/6 v/v) indicated that the disappearance of nitrone. Concentrated hydrochloric acid (0.5mL, 6mmol, 3 equiv.) was added to the reaction mixture, and the resulting mixture was heated for 4h at ca 72 o C. Upon cooling, the reaction was poured with stirring into a mixture of ether (35ml) and petroleum ether (5mL) leading to a dark grey solid which was collected and washed with petroleum ether (2x25mL) and dried in vacuo first with a water aspirator and with an oil pump for 12 h to yield a dark grey solid 0.06g (18.33%). The obtained product was identified using HPLC analysis by comparison with a purchased authentic sample [VWR]. 1 H NMR (400MHz, CD 3 OD): δ=7.34(1H, dd, J 1 =8.65Hz, J 2 =5.73Hz), 6.78 (1H, dd, J 1 =9.82Hz, J 2 =2.33Hz), 6.73 (1H, m). 13

2-Amino-5-Fluorophenol Hydrochloride (Compound  1b [A])
Following the general procedure described as above, the title compound was prepared using 4-fluoroarylnitrone (0.43g, 2 mmol), oxalyl chloride (0.30g, 2.2 mmol) and THF (4ml). Acid hydrolysis was conducted by using concentrated hydrochloric acid (0.5mL, 6mmol, 3 equiv.) for 4h at ca 72 o C. Upon cooling, the reaction was poured with stirring into a mixture of ether (30ml) and dichloromethane (60mL) leading to a dark grey solid. The title compound was obtained as a dark grey solid (0.063g, 19.2%). The obtained product was identified using HPLC analysis by comparison with a purchased authentic purchased sample and with the compound 1a [A].

2-Amino-5-Chlorophenol Hydrochloride (Compound  2b [A])
The title compound was prepared using 4-chlorophenylnitrone (0.46g, 2 mmol), oxalyl chloride (0.28g, 2.2 mmol) and THF (4ml). Acid hydrolysis was conducted by using concentrated hydrochloric acid (0.5mL, 6mmol, 3 equiv.) for 4h at ca 72 o C. Upon cooling, the reaction was poured with stirring into dichloromethane (40 ml) leading to a dark grey solid. The title compound was obtained as a light purple solid (0.098g, 27.2%). The obtained product was identified using HPLC analysis by comparison with a purchased authentic sample and with a sample of the compound 2a [A].

2-Amino-5-Methylphenol Hydrochloride (Compound 4a  [A])
The title compound was prepared using 4-methylphenylnitrone (0.13g, 0.63 mmol. 1.0 equiv.), trichloroacetyl chloride (0.13g, 0.69 mmol, 1.1 equiv.) and THF (4ml). Acid hydrolysis was conducted by using concentrated hydrochloric acid (0.8mL, 9.6mmol, 15 equiv.) for 4h at ca 72 o C. Upon cooling, the reaction was poured with stirring into ethyl acetate (40 ml) and petroleum ether (40 ml) leading to a solid. The title compound was obtained as a light brown solid (0.051g, 50.8%). The obtained product was identified using HPLC analysis by comparison with a purchased authentic sample and with a sample of the compound 4b [A].

Reaction of 4-Methoxyphenylnitrone with Oxalyl Chloride  (Compounds 5b [A], [B] and [C])
The reaction was conducted using 4-methoxyhenyl nitrone (6.82g, 30 mmol. 1.0 equiv.), oxalyl chloride (4.19g, 33 mmol, 1.1 equiv.) and THF (60ml). Acid hydrolysis was conducted by using concentrated hydrochloric acid (7.8mL, 93.6mmol, 3.1 equiv.) for 4h at ca 72 o C. Upon cooling, the reaction mixture was basified to pH=8. The organic compounds were extracted with ethyl acetate. The organic layer was separated, washed with water, and dried over anhydrous potassium carbonate. After the filtration, the organic layer was evaporated in vacuo to dryness. The resulting residue was subjected to HPLC and 1H NMR analyses by comparison with purchased authentic samples and with the pure compound 5b[C] to determine the composition of these three aryl amines.

Reaction of 4-Methoxyphenylnitrone with Thionyl  Chloride (Compounds 5c [B] and [C]):
The reaction was conducted using 4-methoxyhenylnitrone (0.227g, 1.0 mmol. 1.0 equiv.), thionyl chloride (0.14g, 1.17 mmol, 1.17 equiv.) and THF (30ml). Acid hydrolysis was conducted by using concentrated hydrochloric acid (0.25mL, 3mmol, 3 equiv.) for 4h at ca 72 o C. Upon cooling, the reaction mixture was basified to pH=8. The organic compounds were extracted with ethyl acetate. The organic layer was separated, washed with water, and dried over anhydrous potassium carbonate. After the filtration, the organic layer was evaporated in vacuo to dryness. The resulting residue was subjected to HPLC and 1H NMR analyses by comparison with purchased authentic samples to determine the composition of the two aryl amines: 2-chloro-4-methoxyaniline and 3-chloro-4-methoxyaniline.

Reaction of 4-Ethoxyphenylnitrone with Trichloro Acetyl  Chloride (Compounds 6a [A], [B] and[C])
The reaction was conducted using 4-ethoxyhenylnitrone (0.24g, 1 mmol. 1.0 equiv.), trichloroacetyl chloride (0.19g, 1.04 mmol, 1.04 equiv.) and THF (4ml). Acid hydrolysis was conducted by using concentrated hydrochloric acid (0.25mL, 3mmol, 3 equiv.) for 4h at ca 72 o C. Upon cooling, the reaction mixture was basified to pH=8. The organic compounds were extracted with ethyl acetate. The organic layer was separated, washed water, and dried over anhydrous potassium carbonate. After the filtration, the organic layer was evaporated in vacuo to dryness. The resulting residue was subjected to HPLC and 1 H NMR analyses by comparison with purchased authentic samples and with a sample of the compound 6b [C] to determine the composition of the three aryl amines.

Reaction of 4-Ethoxyphenylnitrone with Oxalyl Chloride  (Compounds 6b [A], [B] and [C])
The reaction was conducted using 4-ethoxyhenylnitrone (0.24g, 1 mmol. 1.0 equiv.), oxalyl chloride (0.14g, 1.1 mmol, 1.1 equiv.) and THF (4ml). Acid hydrolysis was conducted by using concentrated hydrochloric acid (0.25mL, 3 mmol, 3 equiv.) for 4h at ca 72 o C. Upon cooling, the reaction mixture was basified to pH=8. The organic compounds were extracted with ethyl acetate. The organic layer was separated, washed water, and dried over anhydrous potassium carbonate. After the filtration, the organic layer was evaporated in vacuo to dryness. The resulting residue was subjected to HPLC and 1 H NMR analyses by comparison with authentic samples and with a sample of the compound 6b [C] to determine the composition of aryl amines.