Efficient and selective esterification of aromatic aldehydes with alcohols (1:1) using air as the simplest available oxidant and KCN

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1 Indian Journal of hemistry Vol. 55B, August 2016, pp Efficient and selective esterification of aromatic aldehydes with alcohols (1:1) using air as the simplest available oxidant and KN Ghasem Aghapour* & Maryam Karimzadeh School of hemistry, Damghan University, Damghan, , Iran Received 31 July 2015; accepted (revised) 2 May 2016 A new and efficient method is described for the oxidative esterification of aromatic aldehydes with different types of alcohols such as primary, secondary, benzylic, allylic and cyclic alcohols and phenols using air as the simplest available oxidant and potassium cyanide in DMF under neutral conditions in high yields. The present method esterifies aldehydes with alcohols in 1:1 molar ratio with excellent chemoselectivity and avoids the use of an external oxidant beside 2 from air. Keywords: Esterification, aldehyde, alcohol, potassium cyanide, chemoselectivity arboxylic esters are important and useful compounds in pharmaceutical chemistry and materials science. This functional group is also applied as a protective group in organic synthesis and can be found in fragrances and synthetic polymers 1. The classical route of ester preparation is the reaction of carboxylic acids or their derivatives with the desired alcohols. However, an important alternative route for this purpose is the direct oxidative esterification of aldehydes with alcohols in the presence of an oxidant and catalyst. A variety of oxidants and catalysts have been used in this area such as Mn 2 /NaN/H 3 2 H (Ref 2), H 2 2 /titanosilicate (Ref 3), sodium perborate or sodium percarbonate/v 2 5 /Hl 4 (Ref 4), pyridinium hydrobromide perbromide 5, Mn 2 (Ref 6) or NS (Ref 7)/N-heterocyclic carbenes, air as the oxidant in the presence of supported gold nanoparticles as catalyst 8, H 2 2 / silica supported manganese complex as catalyst 9, 4-acetylamino- 2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate 10, acetone cyanohydrin 11, H 2 2 / V(acac) 2 (Ref 12), oxone/ In(Tf) 3 (Ref 13), and H 2 2 / (PhSe) 2 (Ref 14). However, many of these methods suffer from some disadvantages such as the use of acidic or basic conditions, applicability for only some alcohols with relatively low boiling point such as specially methanol, the use of alcohols in excess amounts, the use of unavailable or expensive oxidant or catalyst, tedious work-up, formation of undesired products, and long reaction times. Selective oxidative esterification of 25,27-bis- (3-formylphenoxyethoxy)-p-tert-butylcalix[4]arene to only its ethyl and isopropyl esters has been reported using KN and 2 from air in ethanol and isopropanol respectively as solvent in moderate to low yields and after long reaction times 15. Also, oxidative esterification of aromatic aldehydes has been carried out using KN and potassium iodide under air in only three alcoholic solvents methanol, ethanol and isopropanol. However, low yields especially in the preparation of isopropyl ester, long reaction times, limitation in selection of alcohols and the use of these in excess amounts are considered as disadvantages of this reported method 16. Therefore, on the basis of the above descriptions, the development of new methods that are more convenient for this important synthetic transformation is desirable. Herein, we report a simple, efficient and selective method for the oxidative esterification of various aromatic aldehydes with different types of alcohols (1:1) using air as the simplest available oxidant and potassium cyanide in DMF under heating (Scheme I). G H + RH DMF, heat G R Scheme I xidative esterification of aldehydes with alcohols (1:1) using air and KN in DMF

2 1014 INDIAN J. HEM., SE B, AUGUST 2016 Results and Discussion First, we took 4-chlorobenzaldehyde (1 mmol) and 3-phenyl-1-propanol (1 mmol) as examples and optimized the reaction conditions for their conversion to 3-phenylpropyl 4-chlorobenzoate using 2 from air and KN in DMF. The results are shown in Table I. As shown in this table, this reaction was completely unsuccessful in the absence of KN in DMF (0.5 ml) at 100 so that the starting materials remained completely unreacted after 5 h (Table I, entry 1). Addition of KN (0.5 eq.) to the reaction mixture resulted in the rapid progress of this reaction. In this case, 3-phenylpropyl 4-chlorobenzoate was formed in 50% yield after 4 h (Table I, entry 2). Both yield and the rate of this reaction were increased with increasing of the molar ratio of KN (Table I, entries 3-6). n the other hand, the increasing of volume of DMF caused a decrease of the rate of this reaction due to decreasing of the concentration of the reactants (Table I, entries 7, 8). However, the desired ester was obtained in only very low yield (10%) in the case when DMF was omitted (Table I, entry 9). In addition, the rate and yield of this reaction was decreased when the reaction temperature was decreased (Table I, entries 10-12). Also, 3- Table I xidative esterification of 4-chlorobenzaldehyde (1 mmol) with 3-phenyl-1-propanol (1 mmol) using air and KN in DMF under various conditions Entry Molar ratio of Ald:Alc:KN DMF (ml) Temp. ( ) Time (h) Yield (%) 1 1:1: :1: :1: :1: :1: :1: :1: :1: :1: :1: :1: :1: r. t :1: a 14 1:1: b 15 1:1: c a In this case, DMS was used instead of DMF. b In this case, 1-hexyl-3-methylimidazolium iodide was used instead of DMF. c In this case, the reaction was carried out under N 2 atmosphere. phenylpropyl 4-chlorobenzoate was produced in 80% and 30% yields in DMS and 1-hexyl-3- methylimidazolium iodide respectively instead of DMF (Table I, entries 13-14). Finally with respect to the results from Table I, the conditions mentioned in the entry 6 of this table (Ald:Alc:KN (1:1:1.5); DMF (0.5 ml); Temp. (100 ); under air) was selected as the optimized condition for performing of this valuable synthetic transformation. Thereafter, this optimized reaction conditions (Table I, entry 6) was applied for oxidative esterification of different aromatic aldehydes with various types of alcohols. The results are shown in Table II. As shown in this table, oxidative esterification of various aromatic aldehydes with different types of alcohols such as primary, secondary, benzylic, allylic and cyclic is carried out in excellent yields in relatively short reaction times via the present method. However, the use of cyclic alcohol caused an increase of the reaction time (Table II, entry 5). Also, an electron donating group in para position in the aromatic aldehyde caused a decrease of both the rate and yield of the reaction (Table II, entries 6 and 12). In addition, the reaction between 2-nitrobenzaldehyde and ethanol and also benzaldehyde and tert-butanol was unsuccessful so that the starting materials remained completely intact after 4 h. This result is probably related to steric hindrance of 2-nitrobenzaldehyde and tert-butanol respectively. Also, application of this method for oxidative esterification of aromatic aldehydes with phenols was not very satisfactory. In this case, the corresponding ester was formed in low yield probably due to low nucleophilic ability of phenols compared to aliphatic alcohols (Table II, entry 19). n the other hand, for obtaining deeper insight into the applicability, selectivity and limitations of this new method, the possibility of the oxidative esterification of aromatic aldehydes with alcohols was studied in the presence of some other functional groups in different mixtures. For this purpose, KN (1.5 mmol) was treated with a mixture of aldehyde, alcohol and another compound containing a specified functional group (each of them 1 mmol) in DMF (0.5 ml) at 100. However, for preparation of the ethyl ester, KN (1 mmol) was treated with a mixture of aldehyde (1 mmol) and other compound (1 mmol) in ethanol (0.5 ml) at 70. The conversion yields obtained for these selective reactions of different mixtures are shown in Table III.

3 AGHAPUR & KARIMZADEH: EFFIIENT AND SELETIVE ESTERIFIATIN 1015 Table II xidative esterification of aldehydes with alcohols (1:1) using air as oxidant and KN (1.5 eq.) in DMF a at 100 Entry Aldehyde Alcohol Ester Time (h) Yield (%) b 1 p-l- 6 H 4 H Ph(H 2 ) 3 H p-l- 6 H 4 2 (H 2 ) 3 Ph p-l- 6 H 4 H PhH=HH 2 H p-l- 6 H 4 2 H 2 H=HPh p-l- 6 H 4 H H 3 H 2 H p-l- 6 H 4 2 H 2 H c 4 p-l- 6 H 4 H p-br-phh 2 H p-l- 6 H 4 2 H 2 Ph-Br-p H 5 H H Ph p-h 3-6 H 4 H H 3 H p-h 3-6 H 4 2 H d 7 p-br- 6 H 4 H Ph(H 2 ) 2 H p-br- 6 H 4 2 (H 2 ) 2 Ph m-f- 6 H 4 H H 3 (H 2 ) 6 H m-f- 6 H 4 2 (H 2 ) 6 H m-f- 6 H 4 H H 3 (H 2 ) 3 HH m F 6 H 4 2 H(H 2 ) 3 H H 3 H 2 H 2 H 2 H 2 H 3 10 p- 2 N- 6 H 4 H Ph(H 2 ) 2 H p- 2 N- 6 H 4 2 (H 2 ) 2 Ph p- 2 N- 6 H 4 H H 3 (H 2 ) 3 HH p 2 N 6 H 4 2 H(H 2 ) 3 H H 3 H 2 H 2 H 2 H 2 H 3 12 p-h 3-6 H 4 H Ph(H 2 ) 2 H p-h 3-6 H 4 2 (H 2 ) 2 Ph m-h 3-6 H 4 H H 3 H m-h 3-6 H 4 2 H d 14 6 H 5 H H 3 (H 2 ) 5 H 6 H 5 2 (H 2 ) 5 H p- 2 N- 6 H 4 H H 3 H 2 H p- 2 N- 6 H 4 2 H 2 H c 16 p- 2 N- 6 H 4 H H 3 H p- 2 N- 6 H 4 2 H d 17 p-l- 6 H 4 H H 3 H p-l- 6 H 4 2 H d 18 p-l- 6 H 4 H Ph(H 2 ) 2 H p-l- 6 H 4 2 (H 2 ) 2 Ph p-l- 6 H 4 H p-br- 6 H 4 H p-l- 6 H H 4 -Br-p 5 30 a DMF (0.5 ml) was used for 1 mmol of aldehyde. b Isolated yield. c In this case, the reaction was carried out in ethanol (0.5 ml) instead of DMF using 1 equivalent of KN at 70. d In this case, the reaction was carried out in methanol (0.5 ml) instead of DMF using 1 equivalent of KN at 60.

4 1016 INDIAN J. HEM., SE B, AUGUST 2016 Table III Various selectivities in the oxidative esterification of aldehydes with alcohols using air as oxidant and KN a Entry Selectivity 1 p-l- 6 H 4 H Ph Ph(H 2 ) 2 H p-l- 6 H 4 2 (H 2 ) 2 Ph Ph 2 p-l- 6 H 4 H Ph 2 H Ph(H 2 ) 2 H p-l- 6 H 4 2 (H 2 ) 2 Ph Ph 2 H 3 p-l- 6 H 4 H p-l- 6 H 4 2 (H 2 ) 2 Ph Ph(H 2 ) 2 H PhH 3 PhH 3 4 p-l- 6 H 4 H PhH 2 (H 3 ) 2 H Ph(H 2 ) 2 H p-l- 6 H 4 2 (H 2 ) 2 Ph PhH 2 (H 3 ) 2 H 5 b p-l- 6 H 4 H PhH H 3 H 2 H, 2 h p-l- 6 H 4 2 H 2 H 3 PhH a KN (1.5 mmol) was treated with a mixture of aldehyde, alcohol and another compound (each of them 1 mmol) in DMF (0.5 ml) at 100. b In this case, KN (1 mmol) was treated with a mixture of 4-chlorobenzaldehyde (1 mmol) and phenol (1 mmol) in ethanol (0.5 ml) at 70. As shown in this table, it is obvious that aromatic aldehydes can be oxidatively esterified with alcohols in the presence of epoxides, carboxylic acids and ketones with excellent selectivity using the present method (Table III, entries 1-3). Also, primary alcohols are more active than tertiary ones and phenols in this new method (Table III, entries 4 and 5). When the present method was applied for esterification of benzoic acid, only carboxylic acid was recovered after 4 h. Thus it is concluded that the ester cannot be formed by oxidation of aldehyde to a carboxylic acid followed by the simple esterification of the resultant carboxylic acid in the presence of alcohol. With this description although

5 AGHAPUR & KARIMZADEH: EFFIIENT AND SELETIVE ESTERIFIATIN H 3 N KN R 2 H R 2 H H 2 N H R 2 Scheme II The proposed mechanism of the oxidative esterification of aldehydes with alcohols (1:1) using air and KN the exact mechanism of this reaction is not clear, it is assumed that a transient benzylic alcohol intermediate 2 is formed by the addition of cyanide anion to benzaldehyde (Scheme II). The phenyl and cyanide groups in α position of this intermediate accelerate the oxidation to acyl cyanide 3 using air as the simplest available oxidant in the reaction medium. Finally, 3 is converted to the desired ester via treatment with an alcohol. In order to determine the effect of 2 from air, 4-chlorobenzaldehyde (1 mmol) was treated with 3-phenyl-1-propanol (1 mmol) in the presence of KN (1.5 mmol) in DMF (0.5 ml) at 100 under N 2 atmosphere. In this case, 3-phenylpropyl 4-chlorobenzoate was produced in only 10% yield after 2 h (Table I, entry 15). This result obviously indicates the important role of 2 from air as the simplest available oxidant in this reaction. Experimental Section Solvents, reagents and chemicals were obtained from Merck (Germany) and Fluka (Switzerland) hemical ompanies. The products are known compounds 4,17 and were characterized by comparison of their physical or spectral data with those prepared according to known literature procedures 18. FT-IR spectra were recorded on a Perkin-Elmer RXI spectrophotometer. Nuclear magnetic resonance spectra were recorded on a Bruker-400 spectrometer. Thin layer chromatography was carried out on silica-gel 254 analytical sheets obtained from Fluka. air Typical procedure for the oxidative esterification of 4-chlorobenzaldehyde with 3-phenyl-1-propanol using KN in DMF 3-Phenyl-1-propanol (1 mmol, g) and KN (1.5 mmol, g) were added to an open glass flask fitted with a condenser containing 4-chlorobenzaldehyde (1 mmol, 0.14 g) and DMF (0.5 ml) in an oil bath at 100. The reaction mixture was stirred until TL showed the completion of the reaction (2 h). The reaction mixture was cooled to RT and then filtered after addition of n-hexane (2 3 ml). rganic layer was washed with water (2 3 ml). 3-Phenylpropyl 4-chlorobenzoate was obtained in 96% yield (0.264 g) after drying of organic phase using anhydrous sodium sulfate and evaporation of the solvent (Table II, entry 1). FT-IR (KBr): 3063 (w), 3027 (w), 2952 (m), 2860 (w), 1720 (s), 1595 (s), 1488 (m), 1454 (m), 1272 (s), 1118 (s), 1104 (s), 1015 (s), 850 (m), 760 (s), 699 (s), 529 (w) cm 1 ; 1 H NMR (Dl 3, 400 MHz): δ (m, 2H), (t, 2H, J = 7.2 Hz), (t, 2H, J = 6.4 Hz), (m, 3H), (m, 2H), (d, 2H, J = 8.4 Hz), (d, 2H, J = 8.4 Hz); 13 NMR (Dl 3, MHz): δ 30.24, 32.35, 64.61, , , , , , , , , onclusion In conclusion, the present investigation has demonstrated that the use of KN in DMF in the presence of air as the simplest available oxidant under heating offers a simple and efficient method avoiding the use of an external oxidant beside 2 from air for the oxidative esterification of different aromatic aldehydes with alcohols. In many of the previously described methods converting aldehydes to esters, the use of only alcohols having relatively low boiling point such as methanol, ethanol and isopropanol in excess amounts (as solvent) has been reported, but the present method performs the oxidative esterification of aldehydes with various types of alcohols such as primary, secondary, benzylic, allylic and cyclic alcohols and phenols in 1:1 molar ratio. The present method can be efficiently used for preparation of esters even in the presence of some functional groups with excellent chemoselectivity. Easy work-up, high yields, short reaction times and simple operation in neutral media are considered as other advantages of this new method.

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