Short communication
One-Pot Synthesis of Carboxylic Acid Esters in Neutral and Mild Conditions by Triphenylphosphine
Dihalide [Ph3PX2 (X=Br, I)]
Alireza R. Sardarian,* Maryam Zandi and Soghra Motevally
Chemistry Department, College of Science,Shiraz University, Shiraz 71454, Iran
* Corresponding author: E-mail: sardarian@susc.ac.ir; Tel. ( 711)6137710, Fax: (711)2286008
Received: 30-10-2008
Abstract
We report the preparation of aromatic and aliphatic carboxylic acid esters in the presence of triphenylphosphine dibro-mide or triphenylphosphine diiodide and N,N-dimethylaminopyridine in dichloromethane at room temperature in good to excellent yields.
Keywords: Esterification, triphenylphosphine dibromide, triphenylphosphine diiodide, N,N-dimethylaminopyridine, carboxylic acid
1. Introduction
The equilibrium is the biggest problem that is frequently encountered in the esterification reactions of car-boxylic acids. To overcome this problem one of the reac-tants must be used in excess and /or one of the products must be removed during the reaction. Use of the non-equilibrium esterification reaction approach can be effective to bypass the problem with the aid of a) using an activated derivative of carboxylic acids such as acid anhydrides and halides, b) reaction of carboxylic acid with alkoxides, or c) in situ production of activated forms of carboxylic acid by electrophilic activator reagents.1 Using electrophilic activators is a popular and attractive method for the preparation of esters, for example: carbodiimide activators,2 DEAD/Ph3P (Mitsunobu reaction),3 Ph3P/Ca4,4a Ph3PBr2/3-trimethylsilyl-1-3-oxazolidinone,4b Ph3P/NBS or NBI,4c Ph3P/trichloroisocyanuric acid,4d Ph3P/benzyl azide,4e cyanomethylene tributylphosphorane,5 (RO)2 POH/Ca4,6 phosphonium salt ionic liquid,7 2-halo-1-methyl pyridinium salt,8 CH3SO2a/Et3N,9a TsCl/pyridi-ne,9b Me2NSO2a/DMAP,9c Ph3PO/(F3SO2)2O,10 triflic anhydride,11 N,N-bis(2-oxo-3-oxazolidinyl)phosphordia-mide chloride,12 benzotriazol-1-yloxytris-(dimethylami-no)phosphonium hexafluorophosphate,13 2,2'-bipyridyl-6-yl hexanoate/CsF,14 4,5-dichloro-1,2,3-dithiazolium chlo-
ride,15 1-hydroxybenzotriazole/trichloromethylcarbono chloridate,16 N-hydroxysuccinimide/DCC,17 4-(4,6-di-methoxy-1,3,5-triazin-2-yl)-4-ethylmorpholinium chlori-de/N-methylmorpholine,18 diiodotributylphosphorane and diiodotriphenylphosphorane/HMPTA,19 organocatalytic Mitsunobu reactions,20 fluorous DEAD reagent21 and Ph3PBr2/K2CO3.22 Methods developed so far have their own disadvantages. For example, the use of an extremely anhydrous reaction conditions, long reaction times, high reaction temperatures, expensive reagents, the use of highly toxic solvents and chemicals, tedious work-up, byproduct formation and the use of large excess of reagents. Therefore, the search for development of simple, mild, and highly efficient method is still highly demanded.
We wish to introduce in this account a simple, mild and an efficient method for esterification of carboxylic acids using triphenylphosphine dibromide and triphenylp-hosphine diiodide.
2. Results and Discussion
Esterification of the different aliphatic and aromatic carboxylic acids was studied at room temperature by Ph3PBr2 and Ph3PI2 as a simple and cheap system (Scheme 1).
Scheme 1:
To optimize the reaction conditions, we examined the esterification of 4-nitrobenzoic acid by Ph3PBr2 or Ph3PI2 in the presence of triethylamine, pyridine, N,N-di-methylaminopyridine (DMAP), DBU and K2CO3 as base in dichloromethane as solvent at room temperature. The results showed that N,N-dimethylaminopyridine (DMAP) is the most suitable base (Table 1).
Table 1. Effect of base on the esterification of 4-nitrobenzoic acid with n-butanol at room temperature.
Base
Mole Ratio Base: Acid
Ph3PBr2
Time (min)
Yield
(%)
Ph3PI2
Time Yield (min) (%)
Et3N	3:1	30	80	30	70
Pyridine	3:1	30	70	15	70
DBU	3:1	30	10	30	40
DMAP	2:1	2	99	2	95
K2C03	5:1	30	N.R	30	N.R
The effect of solvent was also investigated among different common solvents (THF, CH3CN, dichlorometha-ne, ethyl acetate, chloroform and n-hexane), and dichloro-methane afforded the best result (Table 2).
With optimized reaction conditions in hand, we initially conduct esterification of 4-nitrobenzoic acid in the presence of PPh3X2 (X=Br, I) and DMAP with simple aliphatic alcohols in dichloromethane at room temperature. Results, presented in Table 3, indicated that the corresponding esters were produced in excellent yields (entries 1-5) in all cases investigated. Moreover, the esterification of t-butanol as a highly sterically hindered alcohol, was also ac-
Table 2. The effect of solvent on the esterification of 4-nitroben-zoic acid with n-butanol in the presence of DMAP at room temperature.
Solvent	Mole ratio	Time (min)		Yield (%)	
	DMAP:Acid	Ph3PBr2	Ph3PI2	Ph3PBr2	Ph3PI
n-Hexane	2:1	720	60	40	N.R
EtOAc	2:1	720	30	N.R	50
THF	2:1	60	60	15	40
CHCl3	2:1	2	2	94	85
CH2Cl2	2:1	2	2	99	95
CH3CNN	2:1	3	2	94	70
hieved in excellent yields, although in a longer reaction time compared to unhindered alcohols. Phenol and its steri-cally hindered derivative, 2,6-dimethylphenol, also reacted with 4-nitrobenzoic acid to the corresponding esters in good yields after 15 min (entries 8, 9). Allyl alcohol was also converted to the corresponding ester in excellent yield within 2 minutes (entry 7). Based on the data collected in Table 3, n-butanol was selected as the most suitable alcohol for studying esterification of the other carboxylic acids.
Esterification of benzoic acid and its derivatives with electron-releasing and electron-withdrawing groups (entries 1-7) were also investigated with n-butanol in the presence of both reagents and DMAP in dichloromethane at room temperature. The results were summarized in Table 4.
Data presented in Table 4 showed that, the rate of the esterification reaction was not sensitive to the type of substitution but to the mole ratio of DMAP:acids. This effect might be related to the pKa of carboxylic acids, because the weaker carboxylic acids required higher amount of DMAP to be converted to the corresponding carboxyla-te anion which was probably necessary for attacking on PPh3X2 (X=Br, I).
In addition, pyridine-2-carboxylic acid as a heteroa-romatic carboxylic acid (entry 8, Table 4) was, at the same reaction conditions, converted to the related ester in good yield. Even anthracene-10-carboxylic acid, despite of having considerable steric hindrance, was converted to the
Table 3. Preparation of different types of esters of 4-nitrobenzoic acid by using Ph3PBr2 and Ph3PI2 as reagent and DMAP in dichloromethane at room temperature.
Entry	Alcohol	Ester	Mole ratio DMAP:Acid		Reaction Time (min)	Ph3PBr2	Yield (%) Ph3PI2
1	CH3OH	Ar C02CH3	2	1	2	96	95
2	CH3CH20H	ArCO2CH2CH3	2	1	2	98	95
3	CH3CH2CH20H	ArCO2CH2CH2CH3	2	1	2	95	93
4	ch3ch2ch2ch2oh	ArCO2CH2CH2CH2CH3	2	1	2	99	97
5	(ch3)2choh	ArCO2CH(CH3)2	2	1	2	80	91
6	(ch3)3coh	ArCO2C(CH3)3	2	1	overnight	99	80
7	ch2=chch2oh	ArCO2CH2CH=CH2	2	1	2	84	95
8	C6H5OH	ArCO2C6H5	2	1	15	78	80
9	c6h3oh	ArCO2C6H3(CH3)2-6,2	2	1	15	83	82
Table 4. Synthesis of n-butyl esters of the various carboxylic acids with Ph3PBr2 and Ph3PI2 in the presence of DMAP in dichloromethane at room temperature.
Entry	Acid
Ester
Mole ratio	Reaction	Yield (%)
DMAP:Acid Time (min) Ph3PBr2 Ph3PI2
2.5:1
2
87	90
2:1
99	97
2.5:1
91	92
2.5:1
90	90
2:1
90	90
2:1
89	92
2:1
93	94
2:1
80 80
2.5:1
90	93
10
2.5:1
90	92
11 CH3(CH2)„CO2H	CH3(CH2)„CO2Bu-n	2.5:1
91	81
12
4:1
95	95
13 (CH3)2CHCH2COCO2H (CH3)2CHCH2COCO2Bu-n 2.5:1
90	90
1
2
2
3
2
4
2
2
6
7
2
8
2
9
2
2
2
2
2
Entry
Acid
Ester
Mole ratio
Reaction
Yield (%)
DMAP:Acid Time (min)
PhPBr
2
Ph3PI2
14 (CH3)3CCO2H
(CH3)3CCO2Bu-n
2.5:1
15
49
48
15
2:1
15
55
60
16
2:1
60
85
90
corresponding n-butyl ester with Ph3PBr2 and Ph3PI2 in 55 and 60% yields respectively (Table 4, entry 15). Phthalic acid reacted with n-butanol in the presence of Ph3PI2 or Ph3PBr2 and DMAP (mole ratio, 1:2:2:4) to provide di-butyl phthalate in excellent yield in dichloromethane at room temperature (Table 4, entry 12).
Aliphatic carboxylic acids such as 3-phenylpropanoic acid, decanoic acid, 4-methyl-2-oxo-pentanoic acid and in-dole-3-butyric acid (Table 4, entries 10, 11, 13, and 16) also afforded the corresponding butyl esters with Ph3PI2 or Ph3PBr2 in the presence of DMAP in excellent yields (molar ratio DMAP:acid = 2.5:1). Even 2,2-dimethylpropanoic acid as a highly sterically hindered aliphatic acid underwent the esterification reaction with both reagents in moderate yields (entry 14). trans-Cinnamic acid was also converted to the corresponding butyl ester in excellent yield, without double bond bromination (entry 9).
3. Conclusions
We have introduced an efficient one-pot method for esterification of carboxylic acids with cheap and readily available Ph3PI2 and Ph3PBr2 under neutral and very mild conditions in the presence of DMAP. The advantages of the present method are very short reaction times and good to excellent yields. Furthermore, by this method one can prepare esters of highly hindered carboxylic acids and alcohols. Although DMAP is used in two-fold excess relative to the each carboxylic group, 80% to 90% of DMAP is recovered by aqueous extraction after completion of the reaction and further extraction of alkaline solution by dichloromethane.
4. Experimental
4. 1. General
1H and 13C NMR spectra were recorded on Bruker Advance DPX FT spectrometer at 250 and 62.9 MHz, res-
pectively, and with TMS as an internal standard. IR spectra were obtained on a Perkin-Elmer FTIR-800 instrument. Mass spectra were obtained on a Shimadzu GCMS0QP 1000EX at 20 and/or 70 eV, and elemental analyses were performed on Thermofinnigan 1112 flash EA. The synthesized esters were characterized with IR, 1H, and 13C NMR spectroscopy and mass spectrometry, and CHN analysis.
4. 2. Typical Procedure for the Esterification of Carboxylic Acids
4. 2. 1. Using Ph3PI2
To a solution of Ph3P (0.39 g, 1.5 mmol) and I2 (0.38 g, 1.5 mmol) in 5 ml of CH2Cl2 was added 4-methoxyben-zoic acid (0.23 g, 1.5 mmol) and DMAP (0.45 g, 3.7 mmol). The solution was stirred for 5 min at room temperature and then n-butanol (0.14 ml, 1.5 mmol) was added. TLC monitoring showed that the reaction was completed after 2 min (plates: aluminum-backed silica gel, Merck 60 GF254). The crude product was purified by short-column chromatography on silica gel with n-hexane/ethyl acetate (4:1) to provide pure n-butyl 4-methoxybenzoate (0.29 g, 90%) as a yellow oil. 1H NMR (CDa3, 250 MHz): 5 0.82(t, 3H, CH3), 1.27 (m, 2H, CH2CH3), 1.55 (m, 2H, OCH2CH2), 3.69 (s, 3H, OCH3), 4.1^2 (t, 2H, OCH2), 6.75 (d, 2H, ArH), 7.85 (d, 2H, ArH); 13C NMR (CDa3, 69.9 MHz): 5 13.70, 18.97, 30.79, 55.24, 64.39, 113.98, 122.88, 131.43, 163.21, 166.29; IR (KBr): v 1714.6 (C=O), 1256.6 (C-O) cm-1; MS (EI, 70eV): m/z (%) 208 (M +, 7), 151(0.7), 135 (100), 107 (13.6), 92 (20.2), 76(5.5). Elemental Anal.(%): Calcd. for C12H1gO3: C 69.21, H 7.74. Found: C 70.7, H 7.81.
4. 2. 1. Using Ph3PBr2
Ph3P (0.26 mg, 1 mmol) and Br2 (0.05 ml, 1 mmol) were added to 5 ml of cold CH2Cl2 on ice bath. 4-Nitro-benzoic acid (0.167 g, 1 mmor) and DMAP (0.24 g, 2
mmol) were added to this solution and the solution was stirred for 3 min on ice bath, and allowed to be warmed up to room temperature. After that phenol (0.094 g, 1 mmol) was added. TLC monitoring showed that the reaction was completed after 15 min (plates: aluminium-backed silica gel, Merck 60 GF254). The crude product was purified on the short-column of silica gel with n-hexane/ethyl acetate (4:1) to provide pure phenyl 4-nitrobenzoate (0.19 g, 78%) as a white solid. M.p. = 105 °C; 1H NMR (CDCl3, 250 MHz): d 7.21 (t, 1H, phenol), 7.22 (d, 2H, phenol), 8.33 (d, 2H, ArH), 8.41 (d, 2H, ArH); 13C NMR (CDCl3 69.9 MHz): d 121.40, 123.71, 126.40, 129.67, 131.28, 134.98, 150.51, 150.91, 167.60; IR (KBr): v 1739.7 (C=O), 1270 (C-O) cm-1; MS (EI, 70eV): m/z (%) 243 (M+, 9.3), 167 (0.2), 150 (100), 122 (0.8), 104, 76. Elemental Anal.(%): Calcd. for C13H9NO4: C 64.20, H 3.73, N 5.76. Found: C 64.08, H 3.68, N 5.62.
5. Acknowledgment
Shiraz university research council are gratefully acknowledged for the support of this study.
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Povzetek
Avtorji v prispevku poročajo o pripravi estrov alifatskih in aromatskih karboksilnih kislin z dobrimi izkoristki v prisotnosti bodisi trifenilfosfin dibromida ali trifenilfosfin dijodida ter N,N-dimetilaminopiridina v diklorometan kot topilu pri sobni temperaturi.