Cl3CCONH2/PPh3: A versatile reagent for synthesis of esters

Article abstract of DOI:10.1080/00397910801979361

Cl3CCONH2/PPh3 was a versatile reagent to convert carboxylic acids into their corresponding acid chlorides. This intermediate was clearly confirmed by spectroscopic methods (IR, 1H, 13C NMR). This one-pot reaction of in situ acid chloride generated with various alcohols successfully furnished the corresponding esters in moderate to excellent yields. Copyright ? Taylor & Francis Group, LLC.

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Cl3CCONH2/PPh3: A Versatile
Reagent for Synthesis of Esters
Oraphin Chantarasriwong a , Doo Ok Jang b &
Warinthorn Chavasiri a
a Natural Products Research Unit, Department
of Chemistry, Faculty of Science, Chulalongkorn
University, Bangkok, Thailand
b Department of Chemistry, Yonsei University,
Wonju, Republic of Korea
Version of record first published: 25 Aug 2010.
To cite this article: Oraphin Chantarasriwong , Doo Ok Jang & Warinthorn Chavasiri
(2008): Cl3CCONH2/PPh3: A Versatile Reagent for Synthesis of Esters, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 38:16, 2845-2856
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Synthetic Communications1, 38: 2845–2856, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910801979361
Cl3CCONH2/PPh3: A Versatile Reagent for
Synthesis of Esters
Oraphin Chantarasriwong,1 Doo Ok Jang,2 and
Warinthorn Chavasiri1
1Natural Products Research Unit, Department of Chemistry, Faculty of Science,
Chulalongkorn University, Bangkok, Thailand
2Department of Chemistry, Yonsei University, Wonju, Republic of Korea
Abstract: Cl3CCONH2=PPh3 was a versatile reagent to convert carboxylic acids
into their corresponding acid chlorides. This intermediate was clearly confirmed
1
by spectroscopic methods (IR, H, 13C NMR). This one-pot reaction of in situ
acid chloride generated with various alcohols successfully furnished the
corresponding esters in moderate to excellent yields.
Keywords: Acid chloride, ester, one-pot conversion, PPh3, trichloroacetamide
INTRODUCTION
The ester functional group is important in organic and biological
chemistry.[1] The preparation of esters from their corresponding
carboxylic acids is one of the most fundamental reactions. The general
method involves either the use of mineral acid (H2SO4, HCl, HF,
H3PO4, and ClSO2OH) or Lewis acid catalysts (BCl3, AlCl3, SiCl4, and
FeCl3). However, the corrosive nature, extremely slow reaction, and long
reaction time are drawbacks. The activation of carboxylic acids has been
recognized as another effective alternative.[2] These activation processes
can be achieved either by conversion into more reactive functional groups
such as acyl halides, anhydrides, acyl azides, and active esters, or in situ
activation by coupling reagents such as carbodiimides.[3] Acid chloride,
Received December 10, 2007
Address correspondence to Warinthorn Chavasiri, Natural Products Research
Unit, Department of Chemistry, Faculty of Science, Chulalongkorn University,
Bangkok 10330, Thailand. E-mail: warintho@yahoo.com
2845

2846
O. Chantarasriwong, D. O. Jang, and W. Chavasiri
a valuable intermediate, is generally prepared by the reaction of
carboxylic acid with common reagents such as SOCl2, PCl3, POCl3,
PCl5, and oxalyl chloride.[4] However, such protocols cannot be applied
to acid-sensitive compounds because of the vigorous conditions and the
formation of strong acids.[5] The application of PPh3 in combination with
halogenated reagents such as CCl4,[6] cyanuric chloride,[7] tetramethyl-a-
chloroenamine,[8] Cl3CCOCCl3,[9] N-bromo and N-iodosaccharins,[10]
trichloroisocyanuric acid,[11] and Br3CCO2Et[12] has been extensively
explored for the conversion of alcohols to the corresponding halides or
carboxylic acids to their acid halides. Recently, the combination of
Cl3CCN=PPh3 has been found to efficiently convert carboxylic acids into
acid chlorides to manipulate amides, esters, and acid anhydrides.[13]
These combined reagents have also been reported to convert sulfonic
acids into sulfonyl chlorides toward the preparation of sulfonamides.[14]
Despite the fact that many reagents and methods have been documented
for coupling carboxylic acids and alcohols, certain methods still have
their own disadvantages.[15]
More recently, the novel combination of Cl3CCONH2=PPh3 has been
reported to serve as another efficient coupling reagent for the transform-
ation of alcohols into the corresponding chlorides.[16] and conversion of
carboxylic acids into acid chlorides, which were subsequently trans-
formed to the corresponding amides.[17] As an extension to this work
and our interest in developing a new protocol for the formation of esters
using the combined reagents of Cl3CCONH2=PPh3, we report herein a
new mild and efficient synthesis for such compounds.
RESULTS AND DISCUSSION
Interestingly, carboxylic acids can be converted to the corresponding acid
chlorides under very mild conditions by simply mixing PPh3 and
Cl3CCONH2 in refluxing CH2Cl2. Subsequent addition of alcohols
in the presence of 4-picoline afforded the corresponding esters in a
one-pot procedure (Scheme 1).
PhCOOH–PPh3–Cl3CCONH2 in a 1:2:2 ratio was utilized in the first
step, and the reaction completely proceeded to offer benzoyl chlorides.
After 1 h, 4-picoline and 1-octanol were added, and the reaction mixture
Scheme 1. General protocol for the conversion of carboxylic acid to ester.

Cl3CCONH2/PPh3
2847
was stirred in refluxing CH2Cl2 for another 1 h to afford octyl benzoate in
98% yield (entry 1, Table 1).
To investigate the generality and scope of the developed method, the
reaction was carried out with various structurally diverse alcohols
(Table 1).
When secondary alcohols such as 2-octanol and cyclooctanol were
employed, the corresponding benzoates were afforded in 77 and 66%,
respectively (entries 2 and 3). The refluxing time in step 2 for the reaction
of 2-octanol was prolonged from 1 to 3 h with the expectation to increase
the yield of benzoate ester; the desired benzoate was nevertheless slightly
increased. In the case of allylic alcohol as cinnamyl alcohol, the reaction
efficiently furnished the target alcohol in good yield (entry 4). In
addition, when phenols such as 4-chlorophenol and carvacrol were
employed, the desired benzoates were obtained in good yields
(75–78%, entries 5 and 6). Moreover, this method was applicable to
prepare benzoate esters of (ꢀ)-nopol, cholesterol, and geraniol, natural
=
occurring alcohols containing C C. The reaction proceeded smoothly;
=
C C was intact (entries 7–9). Additionally, when (ꢀ)-borneol was
employed to react with benzoic acid, the corresponding ester was
obtained in good yield (81%, entry 10). In the case of t-butyl alcohol,
the desired benzoate was obtained in 53% (entry 11). This may be
because of either the steric hindrance of alcohol[13b] or the very high
reactivity of t-butyl alcohol, causing a rapid dehydration of the alcohol
to alkene.[18] Even though the product was achieved in moderate yield,
this present method revealed a more superior result than those reported.
For example, with the use either of alumina sulfuric acid[19a] or activated
basic alumina,[19b] the amount of catalyst relative to the reactants was
very large and the reaction period was also very long.
The preparation of esters was then performed using a variety of
carboxylic acids to determine the limitations of the method. The results
are presented in Table 2.
Treating PPh3=Cl3CCONH2 with acetic acid and phenethyl alcohol
furnished phenethyl acetate in moderate yield (59%, entry 1). To increase
the yield of the desired acetate, 2 equivalents of acetic acid were exploited
to react with (þ)-borneol under the reaction conditions. Unfortunately,
the acetate was isolated only in moderate yield similar to the case of
phenethyl acetate (entry 2). Treatment of palmitic acid with Cl3CCONH2
and PPh3, followed by phenethyl alcohol, furnished the formation of the
corresponding ester in high yield (74%, entry 3). In the case of sorbic
acid, the desired ester was attained in moderate yield (51%, entry 4).
Satisfyingly, the reaction of tertiary carboxylic acid such as pivalic
acid proceeded smoothly to gain the corresponding ester in high
yield (87%, entry 5). However, when the reaction was performed at room

2848

2849

2850

Cl3CCONH2/PPh3
2851
temperature in step 2, no desired ester was attained. Finally, in the case of
naphthalic acid, the corresponding ester was afforded in moderate yield
(68%, entry 6).
This methodology was further applied to the synthesis of five bio-
logically active esters as presented in Table 3.
The synthesis of benzyl benzoate, an insecticide,[20] was obtained in
85% yield (entry 1). Phenethyl cinnamate and cinnamyl cinnamate,
important ingredients of perfume and cosmetics, could be achieved in
98% and 84% yields, respectively (entries 2 and 3). Utilizing this method-
ology, cholesteryl butyrate and cholesteryl nonanoate, which are widely
used for pharmaceutical formulations,[21] could be obtained in high yields
(78–89%, entries 4 and 5).
The mechanism of the reaction of carboxylic acids, PPh3=CCl4, and
PPh3=Cl3CCONH2 was previously reported to occur via the formation of
a reactive intermediate, acid chloride.[6a,16a] To confirm this intermediate
of the reaction of carboxylic acid, PPh3, and Cl3CCONH2, various spec-
1
troscopic methods (IR, H and 13C NMR) were employed.
Cl3CCN was employed instead of Cl3CCONH2 to avoid the shade
from the C O peak in IR and 13C NMR experiments. The IR spectrum
=
=
of benzoic acid displayed the strong C O stretching vibration at
1691 cmꢀ1 [22]
.
The strong stretching absorption peak of the C O was
=
shifted to 1772 cmꢀ1 in the case of the reaction mixture derived from
the reaction. This strong peak corresponded well to that of commercially
available benzoyl chloride.[22] The exploration on the 13C NMR spectrum
of the reaction mixture revealed a signal of carbonyl carbon at dC 168.4,
which coincided well with that of benzoyl chloride, whereas the carbon
signal of benzoic acid was detected at dC 172.3.
For the 1H NMR experiment, 4-chlorophenylacetic acid was selected
as a model compound. In the absence of PPh3, all starting material was
recovered because only the singlet methylene signal at dH 3.50 was dis-
played. On the other hand, when PPh3 was employed to couple with
Cl3CCONH2, the reaction proceeded to give the new peak at dH 4.18,
corresponding to that of phenyl acetyl chloride. (Phenylacetyl chloride
was attained from the reaction of 4-chlorophenylacetic acid and SOCl2.)
In addition, the reaction was examined using several ratios of
Cl3CCONH2 and PPh3 to compare yields of acid and its acid chloride.
When the ratio of Cl3CCONH2 and PPh3 was increased from 1=1 to
2=2, the yield of the corresponding acid chloride increased from 11 to
72%. In contrast, the yield of the desired product decreased to 57% when
the ratio of Cl3CCONH2 and PPh3 increased to 3=3.
In conclusion, a new protocol utilizing Cl3CCONH2=PPh3 for the
preparation of ester was introduced. Primary, secondary, and tertiary
alcohols smoothly proceeded to the corresponding esters. Moreover, this

2852

Cl3CCONH2/PPh3
2853
procedure has proven to be suitable for the synthesis of tertiary
1
carboxylic acid and biologically active esters. IR, H NMR, and 13C
NMR studies strongly endorse the presence of acid chloride as the
reactive intermediate.
EXPERIMENTAL
A typical experimental procedure is as follows: Ph3P (6 mmol, 1.57 g, 2
equiv) in CH2Cl2 (3 mL) was added to a mixture of carboxylic acid
(3 mmol, 1 equiv) and Cl3CCONH2 (6 mmol, 2 equiv) in refluxing
CH2Cl2 (3 mL). The mixture was stirred for 1 h. A mixture of alcohol
(3 mmol, 1 equiv) and 4-picoline (9 mmol, 3 equiv) was added to this mix-
ture. The reaction mixture was stirred in refluxing CH2Cl2 for another 1 h
and followed by thin-layer chromatography (TLC). When the reaction
was completed, the organic layer was washed with 10% HCl and satu-
rated NaHCO3, dried over anhydrous Na2SO4, and evaporated in vacuo.
The mixture was separated with a silica-gel column, eluting with
hexane=EtOAc (9:1). Purification by recrystallization with a mixture of
CH2Cl2 and hexane or another appropriate solvent was conducted to
achieve the desired ester products. The identities of all isolated products
were compared with commercially available acetates and those reported
in previous literature.[23]
Procedure for IR and 13C NMR Experiments
The reaction mixture of benzoic acid (1 mmol, 122.2 mg, 1 equiv),
Cl3CCN (2 mmol, 0.20 mL, 2 equiv), and PPh3 (2 mmol, 526.0 mg, 2
equiv) was stirred in refluxing CH2Cl2 for 1 h. The reaction was then
=
ceased by evaporating all reaction mixture in vacuo. PPh3 and O PPh3
were separated from the reaction mixture by filtration through Celite1,
eluting with n-hexane. The mother liquor was evaporated in vacuo, and
the crude mixture was then characterized by the presence of benzoyl
chloride using spectroscopic methods. IR (neat), cmꢀ1: 1772. 13C NMR
d (ppm): 168.4.
1
Procedure for H NMR Experiment
The reaction mixture of 4-chlorophenylacetic acid (0.25 mmol, 34.0 mg,
1 equiv), Cl3CCONH2 (0.50 mmol, 81.2 mg, 2 equiv), and PPh3 (0.50
mmol, 131.2 mg, 2 equiv) was stirred in CH2Cl2 at room temperature
1
for 20 min. The reaction mixture was then subjected to the H NMR

2854
O. Chantarasriwong, D. O. Jang, and W. Chavasiri
experiments. The shift of the singlet methylene signal of 4-chlorophenyl-
acetic acid and its chloride were manifestly observed, and yield (%) was
1
determined by H NMR technique utilizing toluene as the internal stan-
1
dard. For 4-chlorophenylacetyl chloride, H NMR d (ppm) 4.18 (2H, s,
CH2CO2H).
ACKNOWLEDGMENTS
Financial support from the Thailand Research Fund through the Royal
Golden Jubilee Ph.D. Program (Grant No. PHD=0223=2548) to O. C.
and W. C. is acknowledged. O. C. and W. C. are also indebted to the
Graduate School, Chulalongkorn University, for a grant. One of us
(D. O. J.) is also grateful for the support from Institute for NanoBio
Molecular Assemblies.
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