Ph3P-I2 mediated aryl esterification with a mechanistic insight

Article abstract of DOI:10.1016/j.tetlet.2016.03.105

In order to better understand the reaction mechanism and to obtain optimal conditions, the Ph₃P-I₂/Et₃N mediated aryl esterification reaction was thoroughly investigated. Using a specific reagent addition sequence, the reaction proceeds remarkably well especially with acidic substrates. ³¹P NMR studies revealed that the formation of an aryloxyphosphonium salt is crucial in governing the reaction path toward the formation of phenolic esters.

Full text of DOI:10.1016/j.tetlet.2016.03.105

Accepted Manuscript
Ph3P-I2 mediated aryl esterification with a mechanistic insight
Wong Phakhodee, Chuthamat Duangkamol, Mookda Pattarawarapan
PII:
S0040-4039(16)30334-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.03.105
TETL 47493
Reference:
Tetrahedron Letters
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18 February 2016
22 March 2016
31 March 2016
Please cite this article as: Phakhodee, W., Duangkamol, C., Pattarawarapan, M., Ph3P-I2 mediated aryl esterification
with a mechanistic insight, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.03.105
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Ph3P-I2 mediated aryl esterification with a mechanistic insight
Wong Phakhodee,* Chuthamat Duangkamol, and Mookda Pattarawarapan
Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand
To whom correspondence should be addressed.
Department of Chemistry,
Faculty of Science,
Chiang Mai University,
Chiang Mai
50200
Thailand
Tel. +66 5394 3341
Fax. +66 5389 2277
e-mail : wongp2577@gmail.com

Ph3P-I2 mediated aryl esterification with a mechanistic insight
Wong Phakhodee,* Chuthamat Duangkamol, and Mookda Pattarawarapan
Department of Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand
Abstract: In order to better understand the reaction mechanism and to obtain optimal conditions, the
Ph3P-I2/Et3N mediated aryl esterification reaction was thoroughly investigated. Using a specific
reagent addition sequence, the reaction proceeds remarkably well especially with acidic substrates. 31P-
NMR studies revealed that the formation of an aryloxyphosphonium salt is crucial in governing the
reaction path toward the formation of phenolic esters.
Keywords: carboxylic acids; esterification; iodine; phenols; phosphorus
Introduction
Among the various phosphorous-mediated organic transformations,1 it is undeniable that the
classical Mitsunobu2 and Appel3 reactions are the most well-known methods for in-situ activation of
the hydroxyl group of alcohols or carboxylic acids toward nucleophilic substitution. In the synthesis of
carboxylic acid derivatives in particular, a number of methods have been developed using
triphenylphosphine (Ph3P) in combination with various additives. Apart from the azo derivatives used
in variants of the Mitsunobu reaction,4 electrophilic halogen sources such as BrCCl3,5 CCl3CN,6 NCS,7
9
NBS,8 and I2 have also been applied as co-reagents in Appel-type reactions. Although these methods
allow convenient access to various important products, the mechanism underlying most of these
reactions remains uninvestigated leading to contradictory results in terms of reaction rates, yields, and
selectivity.
In the synthesis of phenolic esters, for instance, despite the fact that in most reactions an
acyloxyphosphonium salt was proposed as the key intermediate, we were surprised to observe some
controversy, especially utilising acidic substrates. As summarized in Table 1, condensation between
aryl acids and 4-nitrophenol under Mitsunobu conditions required high temperatures and long reaction
times to give aryl esters in various yields (entries 1-3). While the Appel system (entries 4 and 5) gave
poor yields with the nitro containing substrates, a similar system using N-chlorobenzotriazole (entry 6)
or iodine (entry 7) led to a significant improvement in both the reaction rate and the product yields.
Unfortunately, the conditions were, in most cases, applied to aliphatic alcohols without mechanistic
study.

Based on our previous experiences in the Ph3P-I2/Et3N mediated reactions of carboxylic
acids,14 we have observed the profound effect that the order of reagent addition has on the
reaction path which could influence the outcome of the above esterification reactions. To better
understand the Ph3P-I2 mediated acylation reaction mechanism and to obtain optimal conditions
toward the formation of phenolic esters, herein, the esterification between carboxylic acids and
31
phenols with a range of acidities was thoroughly investigated. P{H} NMR studies were also
carried out to gain an insight into the reaction mechanism.
Table 1. Representative examples of phosphorous-mediated aryl esterification of nitro-containing substrates
Entry
14b
24c
34a
412
512
613
79c
Reaction conditions
Ph3P, diisopropylazodicarboxylate (DIAD), THF, reflux
Ph3P, 4,4'-azopyridine, CH3CN, 80 °C
Ph3P, 5,5'-dimethyl-3,3'-azoisoxazole, CH3CN, 80 °C
Ph3P, CCl4, Et3N, CH3CN, RT
Time
16 h
Yield (%)
X
MeO
H
Y
NO2
NO2
NO2
NO2
H
42
83
85
13
34
90
80
5 h
10.5 h
4 h
NO2
H
Ph3P, CCl4, Et3N, CH3CN, RT
4 h
NO2
NO2
NO2
Ph3P, N-chlorobenzotriazole, Et3N, CH2Cl2 RT
Ph3P, I2, DMAP, CH2Cl2, RT
90 min
15 min
H
H
In our preliminary study, the effect of the reagent addition sequence was investigated
using benzoic acid and 3-nitrophenol as model substrates. It was found that following the
reported procedure,9a where a mixture of Ph3P (1.5 equiv.) and I2 (1.5 equiv.) in
dichloromethane was treated with Et3N (3 equiv.), prior to the addition of benzoic acid (1
equiv.), then 3-nitrophenol (1.1 equiv.), benzoic anhydride was formed exclusively. Switching
the order of reagent addition between benzoic acid and Et3N similarly gave the anhydride
without ester formation. Addition of the alcohol to the Ph3P-I2 mixture before treatment with
Et3N then benzoic acid led to the rapid formation of triphenylphosphine oxide without the
desired product. Interestingly, when Et3N was added as the last component, the respective ester
was obtained quantitatively within 20 min indicating various reaction paths are involved
depending on the order of reagent addition.
To evaluate the effect of the substrate’s acidity on the reaction, a series of carboxylic
acids (
Table 2, the reaction using benzoic acid and its derivatives proceeded smoothly to provide the
esters in good to excellent yields regardless of their pKa values. Steric hindrance at the ortho
position of the acids was well tolerated, while the acetyloxy group (entry 5) was unaffected
1) were reacted with 3-nitrophenol to provide 3-nitrophenolic esters 2. As shown in
2

under the applied reaction conditions. Notably, the corresponding acid anhydride side-products
were not detected in these reactions.
Table 2. Reaction of various carboxylic acids with 3-nitrophenola
Entry
1, R =
pKa of 1 15b
4.47
4.37
4.19
4.09
3.49
3.46
3.44
2, Yield (%)
2a, 92
2b, 97
2c, 99
2d, 85
2e, 85
1
2
3
4
5
6
7
8
9
4-CH3OC6H4
4-CH3C6H4
C6H5
2-CH3OC6H4
2-AcOC6H4
3-NO2C6H4
4-NO2C6H4
2,4-Cl2C6H3
2-NO2C6H4
2f, 96
2g, 93
2h, 87
2i, 90
2.68
2.17
aReaction conditions: carboxylic acid (0.41 mmol), 3-nitrophenol
(0.45 mmol), Ph3P (0.62 mmol), I2 (0.62 mmol), Et3N (1.23 mmol),
CH2Cl2 (2 mL), 0 °C-RT, 20 min.
Interestingly, unlike the related Appel conditions,12 acidic phenols were preferable
substrates when reacting with carboxylic acids with a low pKa. As summarized in Table 3, aryl
esterification of benzoic acid was less effective with less acidic phenols as well as sterically
hindered substrate (entries 1-3). In these reactions, the benzoic anhydride side-product was
observed to various extents. The reaction proceeded more efficiently with more acidic phenols
including those containing sterically bulky groups (entries 4–11).
Table 3. Reaction of benzoic acids with substituted phenolsa
Entry
1
2
3
pKa of 315b
11.83
9.99
9.90
8.39
4, Yield (%)
4a, 0 (98)
4b, 72 (21)
4c, 81 (14)
4d, 95
3, Ar =
2-tBu-4-CH3OC6H3
C6H5
2-CH3O-C6H4
2-BrC6H4
4
5
6
7
2-CHO-4-CH3O-C6H3
4-(CHO)-2-CH3OC6H3
4-CHOC6H4
N/A
7.78
7.58
4e, 86 (10)
4f, 99
4g, 98
8
2-NO2C6H4
7.23
4h, 99
9
4-NO2C6H4
7.18
4i, 91
10
11
2,4-(NO2)2C6H3
2,6-(NO2)2C6H3
4.10
3.74
4j, 99
4k, 89
aReaction conditions: benzoic acid (0.41 mmol), substituted phenol
(0.45 mmol), Ph3P (0.62 mmol), I2 (0.62 mmol), Et3N (1.23 mmol),
CH2Cl2 (2 mL), 0 °C-RT, 20 min. Yield of benzoic anhydride given in
parenthesis. N/A = not available.
To further demonstrate the applicability of the protocol, a series of aryl esters was
synthesized using acidic substrates. According to Figure 1, the reaction of nitro-substituted

phenols was found to proceed well with a variety of carboxylic acids including aliphatic,
allylic, and aromatic acids containing reactive functional group (see for examples).
Additionally, in contrast to the reaction of benzoic acid, all of the more acidic nitro-containing
acids reacted smoothly with sterically hindered phenols to provide esters 12 in good to
5-8
9
-
excellent yields within 30 min. The observed results indicated that the acidity of both the
carboxylic acid and phenolic units play crucial roles in determining the reaction pathways
toward ester formation rather than the competing anhydride formation. It is noteworthy that
both sterically hindered and electron-deficient phenols are difficult substrates in a number of
known esterification procedures.12,16 Our protocol thus provides a convenient means towards
the synthesis of challenging ester products using simple, low-cost, and easy to handle reagents.
Figure 1. Examples of aryl esters prepared using the Ph3P-I2/Et3N system.
31
In order to probe the reaction for phosphorous intermediates, a P{H} NMR study was
carried out by performing the reaction between 3-nitrophenol and benzoic acid in an NMR
tube. A 31P{H} NMR spectrum was acquired after each reagent addition (Fig. S1, ESI).
Mixing Ph3P with I2 resulted in the rapid disappearance of the free phosphine signal at
p -5.30 ppm and the appearance of three new peaks at p 42.64, -8.47, and -17.23 ppm
indicating the presence of triphenylphosphonium iodide [lit.9a 49.7 ppm (CDCl3)] which was in
equilibrium with triphenylphosphine diiodide (Ph3PI2) [lit.17 -15.77 ppm (CDCl3)]. The
addition of 3-nitrophenol led to downfield shifts of all signals. The signal shift at -11.57 ppm
could be attributed to the formation of another pentavalent phosphorane species derived from
iodide displacement with the phenol. Addition of benzoic acid caused no change to the P-
containing species in the reaction mixture. Upon addition of Et3N, two new sharp peaks
appeared at 67.40 and 29.40 ppm which corresponded to an aryloxyphosphonium salt [lit.16
66.25 ppm (CDCl3)] and Ph3P=O [lit.17 30.60 ppm (CDCl3)], respectively. The intensity of the
peak at 67.40 ppm gradually decreased until it disappeared after ca. 20 min.
Based on the observed results, a mechanism for the Ph3P-I2/Et3N mediated aryl
esterification was proposed (Scheme 1). Nucleophilic attack of Ph3P to iodine provides

pentavalent triphenylphosphine diiodide
of the reactive phenol, phosphorane III could be formed before subsequent reaction with a
carboxylic acid in the presence of base to generate the aryloxyphosphonium salt IV
Since the SN2 displacement of a carboxylate ion at the sp2-center of IV is highly
unlikely, the plausible pathway leading to the ester product would be through intermediate or
an acyloxyphosphonium salt VI which could be present in equilibrium with IV 18
Intramolecular substitution at the acyl group within phosphorene could give rise to ester
I and a triphenylphosphonium salt II. Upon addition
.
V
.
V
bond formation (path a). Alternatively, the direct nucleophilic attack of a phenolate anion onto
the carbonyl carbon of VI could also lead to an ester product (path b).
Through the intermediacy of an acyloxyphosphonium salt VI, anhydride formation
would take place in competition with the esterification reaction (path c). In cases where
anhydride formation was not observed (e.g. acidic carboxylic acids and phenols), the reaction
is more likely to proceed through path a rather than path b as commonly proposed in other
phosphine-mediated esterifications.
Scheme 1. Proposed mechanism for the Ph3P-I2/Et3N mediated aryl esterification.
In conclusion, an investigation into aryl esterification promoted by the Ph3P-I2/Et3N system
revealed that the reactions using acidic carboxylic acids and phenols are highly effective
leading to rapid formation of phenolic esters in high yields without anhydride side-products.
Contrary to the earlier proposed mechanism,4,9c,12 the presence of an aryloxyphosphonium
intermediate IV strongly suggests involvement of the pentavalent acyoxyaryloxyphosphorane
species in governing the acyl substitution of these substrates toward the desired esters.
Supplementary data

Supplementary data (general experimental method, spectroscopic data, and 1H and 13C NMR spectra
for new compounds associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.xxxx
Acknowledgment
Financial support from the Thailand Research Fund through the Royal Golden Jubilee Ph.D. Program
(Grant No. PHD/0086/2557) to C.D. is gratefully acknowledged.
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Graphical Abstract
Ph3P-I2 mediated aryl esterification with a mechanistic
insight
Wong Phakhodee,* Chuthamat Duangkamol, and Mookda
Pattarawarapan
Highlights
 Aryl esterification mediated by Ph3P-I2/Et3N was investigated.
 The reaction proceeds remarkably well with acidic carboxylic acids and phenols.
 Formation of the aryloxyphosphonium salt is crucial in minimizing the anhydride side
reaction.