Selective esterifications of alcohols and phenols through carbodiimide couplings

Article abstract of DOI:10.1039/b312559a

Esterification of carboxylic acids capable of forming ketene intermediates upon treatment with carbodiimides permits the selective acylation of alcohols in the presence of phenols lacking strong electron-withdrawing groups. The selectivity of acylations involving highly acidic phenols could be reversed through the addition of catalytic amount of acid. Esterification of other carboxylic acids was found to proceed through the formation of symmetric anhydrides and provide the opposite chemoselectivity. In both cases the relative acylation rates of substituted phenols are consistent with a reaction mechanism involving an attack of phenolate anions on electrophilic intermediates such as ketenes and symmetric anhydrides, with the carbodiimides serving both as an activating reagent and as a basic catalyst.

Full text of DOI:10.1039/b312559a

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Selective esterifications of alcohols and phenols through
carbodiimide couplings†
Rimma Shelkov, Moshe Nahmany and Artem Melman*
Department of Organic Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904,
Israel
Received 10th October 2003, Accepted 1st December 2003
First published as an Advance Article on the web 5th January 2004
Esterification of carboxylic acids capable of forming ketene intermediates upon treatment with carbodiimides
permits the selective acylation of alcohols in the presence of phenols lacking strong electron-withdrawing groups.
The selectivity of acylations involving highly acidic phenols could be reversed through the addition of catalytic
amount of acid. Esterification of other carboxylic acids was found to proceed through the formation of symmetric
anhydrides and provide the opposite chemoselectivity. In both cases the relative acylation rates of substituted phenols
are consistent with a reaction mechanism involving an attack of phenolate anions on electrophilic intermediates such
as ketenes and symmetric anhydrides, with the carbodiimides serving both as an activating reagent and as a basic
catalyst.
Table 1 Acylation rates of alcohols and phenols with the carboxylic
Introduction
acids 1a,b-DCC relative to methanol in MeCN at 25 ЊC
The condensation of carboxylic acids with a variety of nucleo-
pKa of
philes in the presence of dialkylcarbodiimides continues to be
one of the most commonly used synthetic methods1 despite the
development of new reagents.2 While the main application of
carbodiimide couplings remains the formation of amide
bonds,3 this method is also highly useful for the preparation of
anhydrides,4 esters,5 and thioesters.6
To adjust carbodiimide couplings to these multiple appli-
cations a number of coupling catalysts and additives have been
proposed. N-Hydroxybenzotriazole (HOBt) and, to a lesser
extent, N-hydroxysuccinimide (HOSu) as well as substituted
phenols are widely used for the preparation of the corre-
sponding active esters capable of the efficient acylation of
amino groups in amino acids and peptides with low racemiz-
ation. Acylation catalysts, mainly pyridine derivatives, are used
to increase the reactivity of electrophilic species which is usually
necessary for the preparation of esters through carbodiimide
couplings.7
Product
R1
krel for 1a
krel for 1b
R1OH
5
6
BrCH2CH2–
EtOCH2CH2–
Ph–
4-MeOC6H4–
4-CNC6H4–
4-NO2C6H4–
2,4,6-C6Cl3H2–
C6F5–
0.12
0.21
<0.02
<0.02
0.07
0.35
14
0.69
0.72
<0.02
<0.02
0.03
0.12
2.1
14.4
14.8
9.9
10.2
7.9
7.2
6.0
7
8
9
10
11
12
13
3.5
1.5
0.69
0.10
5.5
4.7
C6Cl5–
into symmetric anhydrides are known to proceed at a compar-
able rate.9 With such a variety of applications and modifications
of carbodiimide couplings the problem of chemoselectivity of
the method, particularly in the preparation of esters, has not
been adequately addressed.
We have recently described our results on the acylation of
alcohols through ketene intermediates,10 thus indicating that
carboxylic acids, possessing a strong electron-withdrawing
group in the α-position easily produce ketenes upon treatment
with carbodiimides. The resulting ketenes were found to be
highly efficient acylating reagents for sterically hindered sub-
strates. In exploring potential applications of this method for
polyfunctional substrates we examined the chemoselectivity of
carbodiimide-induced esterifications and its dependence and
the reaction mechanism.
The nature of electrophilic species in the reaction has been a
subject of a prolonged discussion.8 While it is commonly
accepted that O-acylureas of type 2 (Scheme 1) are the primary
intermediates of the reaction, their formation and conversion
Results and discussion
A
Chemoselectivity of the esterification proceeding through
ketene intermediates
Our initial studies were focused on the investigation of the
influence of electron-withdrawing substituents in alcohols and
phenol on their acylation rates using the competitive acylation
of a mixture of substrates (Scheme 1) by carboxylic acids 1a,b
in the presence of DCC. All reaction products were independ-
ently prepared and characterized prior to the competition
studies. Reactions were performed with 1 eq. of DCC and 2 eq.
of each alcohol and the results are summarized in Table 1.11,12
As seen from Table 1, the introduction of electron withdraw-
ing substituents into the beta position of aliphatic alcohols
Scheme 1
† Electronic supplementary information (ESI) available: the character-
ization of new compounds and literature references for known com-
pounds. See http://www.rsc.org/suppdata/ob/b3/b312559a/
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 9 7 – 4 0 1
397

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Table 2 The influence of MeSO3H on the chemoselectivity of the
esterification of carboxylic acids 1a,b
Table 3 Acylation rates of alcohols and phenols with the carboxylic
acids 1c,d-DCC system relative to phenol in MeCN at 25 ЊC
Relative rate for 2,4,6-
trichlorophenol : methanol
XR1
krel for 1c
krel for 1d
pKa of R1H
17
18
19
20
21
22
23
24
25
26
27
28
29
30
OMe
OCH2Ac
OCH2CF3
OC6H4-2, 6-Me2
OC6H4-2-Me
OC6H4-4-OMe
OC6H4-4-CN
O-2,4,6-C6H2Cl3
OC6H4-4-NO2
OC6Cl5
<0.02
<0.02
<0.02
<0.02
0.5
1
30
20
40
100
400
3 × 103
10
<0.02
<0.02
<0.02
<0.02
0.5
1
20
70
90
280
850
1 × 104
4
15
Equiv. of MeSO3H
krel for 1a
krel for 1b
14.2
12.4
10.6
10.4
10.2
7.9
6.0
7.2
4.7
5.5
0
14
2.3
0.38
0.08
2.1
0.05
0.10
0.15
0.77
0.13
0.02
substantially decreases the acylation rates for diethylphos-
phonoacetic acid (1a) but only slightly decreases the acylation
rate for ethyl malonic acid (1b). This different influence can be
attributed to the existence of a unique concerted (pseudo-
pericyclic) mechanism of addition of alcohols or water to
acylketenes of type 3b (Scheme 2, eq 2).13
OC6F5
N-Oxysuccinimide
SCH2CH2OH
SCH2CO2Me
6.0
9.5
7.8
50
110
decreasing the ratio of 2,4,6-trichlorophenyl : methyl esters and
eventually reversing of the chemoselectivity.
The deprotonation of phenols in these experiments could be
reasonably explained by the basic properties of dialkylcarbo-
diimides used as coupling reagents. Unfortunately, because of
the high reactivity of dialkylcarbodiimides, any experimental
determination of their basicity is obviously complicated and
indeed, to the best of our knowledge no such data is in the
literature.15 Some experiments, however, suggest the existence
of basic catalysis from diisopropylcarbodiimide.16
B
Chemoselectivity in esterification reactions proceeding
through an addition–elimination pathway
Scheme 2
The investigation of the chemoselectivity of esterification of
acids 1a,b prompted us to compare the obtained results with
the chemoselectivity and mechanism of other, “conventional”
carboxylic acids that are unable to produce ketene intermedi-
ates upon the treatment with carbodiimides. Despite a huge
amount of preparative work involving the carbodiimide–
carboxylic acid esterifications, neither the chemoselectivity nor
the mechanism of the reaction are known in detail.17 It is
known that the reaction per se does not provide adequate yields
of esters and several modifications involving the addition of
acylation catalysts such as pyridine or DMAP, have been used,7
albeit without chemoselectivity studies.
As with carboxylic acid 1a,b we studied the chemoselectivity
of esterification of carboxylic acids 1c,d using the competitive
acylation of a mixture of two substrates (Scheme 3). Reaction
products 21–30c,d were prepared and characterized before
the competition studies. Relative rates of esterification of
carboxylic acids 1c,d were measured using excess of alcohols/
phenols in acetonitrile solutions with 1 eq. of DCC. Reaction
mixtures were analyzed by 1H NMR and the results are
summarized in Table 3 (the rate with PhOH is taken as 1).
Regular phenols were found to be much less reactive than
aliphatic alcohols for both acids 1a,b and therefore the acyl-
ation of even sterically hindered aliphatic hydroxy groups
could be easily conducted in the presence of aromatic ones.14
However, the presence of electron withdrawing groups in the
phenols resulted in a dramatic increase in their acylation
rates for both acids 1a,b (Table 1) reaching a maximum for
2,4,6-trichlorophenol and decreasing for pentafluoro- and
pentachlorophenols.
The opposite influence of electron withdrawing groups in
alcohols and phenols on the acylation rates can be most reason-
ably explained by the existence of different mechanisms of
acylation for alcohols and phenols. According to this hypo-
thesis, while the reaction of ketene intermediates of type 3a,b
with alcohols proceeds through the concerted or zwitterionic
transition state with a neutral molecule of an alcohol (Scheme
2, eq. 2), the acylation of phenols proceeds through a nucleo-
philic attack of phenolate anions on ketenes according to eq. 3,
Scheme 2. Consequently, the increase in reaction rates for the
formation of 7–11a,b could be explained by a higher equi-
librium concentration of the corresponding phenolate anions.
The decrease in acylation rates for more acidic pentafluoro-
and pentachlorophenols vs. 2,4,6-trichlorophenol could be
explained by decreasing the nucleophilicity of the corre-
sponding phenolates.
Since the equilibrium concentration of phenolate anions is
pH dependent, their intermediacy in the reaction with ketenes
of type 3a,b could be verified by a variation in pH. It is expected
that the addition of a strong acid should result in the suppres-
sion of the dissociation of phenols, thus causing a substantial
decrease in their acylation rates. At the same time, this pH
adjustment should not appreciably affect the acylation of an
aliphatic alcohol, so the resultant decrease of pH must result in
a substantial change in chemoselectivity of the reaction. Indeed
a competitive acylation of acids 1a,b with mixture of methanol
and 2,4,6-trichlorophenol (Table 2) clearly illustrates the influ-
ence of methanesulfonic acid on relative rates of acylation
Scheme 3
As seen from Table 3, aliphatic alcohols did not produce any
detectable (by 1H NMR) amounts of acylation products.
Instead, the 1H NMR spectrum of the reaction mixture showed
only peaks of the corresponding symmetric anhydrides and
N-acylureas that do not undergo any reaction with alcohols
under these reaction conditions.18 Even if alcohols (methanol)
are used as reaction solvents only minor amounts of the
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 9 7 – 4 0 1
398

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corresponding esters could be observed. Numerous data involv-
ing successful esterifications in the presence of acylation
catalysts such as pyridine and dimethylaminopyridine5,7a
should be attributed to the activation of the intermediate
symmetric anhydride or, less likely, a direct trapping of O-acyl
isourea intermediate. More acidic alcohols like trifluoroethanol
and acetol19 under the reaction conditions also did not produce
any appreciable amounts of the corresponding esters.
In contrast to aliphatic alcohols, the reactions with phenols
proceeded smoothly giving the corresponding aryl esters as
major reaction products. Carbodiimide couplings of carboxylic
acid 1c,d with substituted phenols provided isolated yields of
the esters 7c,d, 22c,d in the range of 70–75% and that of the
esters 23–27c,d in the range of 88–98%. Aromatic acids reacted
similarly and benzoic acid produced 4-methoxyphenyl ester in a
75% yield. We were surprised to find only a few isolated reports
describing acylation of regular phenols with carbodiimides.20 In
contrast, reactions of carboxylic acid–carbodiimide systems
with pentachloro-, pentafluoro-, and 4-nitrophenol as well as
N-hydroxysuccinimide and N-hydroxybenzotriazole, have been
extensively used for decades for the preparation of active
esters.21 In line with their acidity thiols were also acylated
smoothly to give thioesters 29, 30c,d.
C
The intermediacy of symmetric anhydrides in esterifications
According to literature data, depending on reaction conditions,
both protonated O-acyl isourea and symmetric anhydrides
can be active intermediates.24,25 In order to determine the
reactive species in the esterification of phenols the acylation of
4-methoxyphenol with a deficiency of DCC (Scheme 6 and
Table 4) was carried out. As seen from Table 4, when less than
0.5 eq. of DCC were added, only minor amounts of the ester
22c could be observed while the anhydride 33c was the main
reaction product. The anhydride 33c was also separately pre-
pared by the treatment of the acid 1c with 0.5 eq. of DCC. The
addition of 4-methoxyphenol and 0.5 eq. of DCC to the pre-
formed anhydride 33c produced ester 22c with the yield that
was identical to the original procedure.
Acylation of phenol and 4-methoxyphenol with carboxylic
acids 1c,d is accompanied by the formation of ca. 20% of
N-acyldicyclohexyl ureas 31c,d (Scheme 4).22 No traces of
N-acyldicyclohexyl ureas 31c,d have been detected in reactions
with more reactive phenols.
Scheme 4
The difference in acylation rates between aromatic and
aliphatic hydroxy groups is substantial and therefore can be
useful for chemoselective acylation of polyfunctional substrates
containing both types of hydroxyls. It should be mentioned
that the commonly used DMAP catalysis for carbodiimide
couplings substantially decreases this chemoselectivity.14a More-
over, this difference in reactivity could be used for conducting
esterification in aqueous solutions (Scheme 5). In order to
compensate for the hydrolysis of intermediate O-acylisoureas
more than 1 eq. of carbodiimide should be used. The necessary
excess of carbodiimide depends on the reactivity of the phenol
and its concentration. For propionic acid and 1 M concen-
trations of reagents acceptable yields of pentafluorophenyl 32b
(79%) or 4-cyanophenyl 32a (62%) esters could be obtained
with 2 eq. of water-soluble carbodiimide EDC.23 Similarly, the
treatment of an aqueous solution of propionic acid with EDC
(2 eq.) in the absence of phenols produced propionic anhydride
(70%).
Scheme 6
Similar results for the esterification of carboxylic acid 1c with
0.5 eq. of carbodiimide were also obtained for other phenols
(Table 4). In all these cases variable amounts of anhydride 33c
were detected in the reaction mixture (except the acylation
of N-hydroxysuccinimide) that decreased for more reactive
phenols.
These results are consistent with the formation of the sym-
metric anhydrides of type 33c on the first step of the reaction
with DCC followed by a slower reaction of the resultant
anhydride 33c with phenol, and not with a direct trapping of
O-acylisourea intermediates of type 2 (Scheme 6). While it is
known that anhydrides do not acylate alcohols or phenols in
the absence of acylation catalysts the presence of DCC could
provide the necessary basic catalysis for the deprotonation
of phenols.16 Indeed, we found that acetic anhydride readily
acetylates 4-methoxyphenol, pentafluorophenol, and penta-
chlorophenol in the presence of 0.5 eq. of DCC producing the
corresponding acetate esters with good yields. No reaction with
4-methoxyphenol without DCC or with DCC in the absence
of phenols took place. It could be concluded that in these reac-
tions the molecule of carbodiimide provides the basic catalysis
for the acylation of phenols with symmetric anhydrides and
converts the released carboxylic acid back into a symmetric
anhydride.
Scheme 5
As in the case of carboxylic acids 1a,b, the comparison of the
reactivities of phenols possessing similar steric properties like
tri-/pentachlorophenol or phenol/4-cyanophenol/4-nitrophenol
shows a clear correspondence between acylation rates and their
pKa values pointing to the participation of phenolate anions in
the nucleophilic attack on a reactive intermediates.
Analogous symmetric anhydrides could also be considered as
intermediates in reactions of carboxylic acids 1a,b serving as
precursors for ketenes of type 3a,b. However, in contrast to
diphenylacetic acid (1c), analogous reactions with tert-butanol
in the deficiency of DCC (Table 4) failed to produce even traces
of the corresponding anhydrides 33a,b (according to 1H NMR
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 9 7 – 4 0 1
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Table 4 Effect of DCC deficiency on the esterification of carboxylic acids 1a–c
Acid
Equiv. of DCC
Estera/mol%
Acid/mol%
Anhydride/mol%
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
1a
1b
1a
1b
0.2
0.4
0.5
0.6
0.8
1.0
0.5
0.5
0.5
0.5
0.2
0.2
0.4
0.4
3 (22c)
9 (22c)
61 (1c)
43 (1c)
12 (1c)
7 (1c)
18 (33c)
48 (33c)
75 (33c)
52 (33c)
17 (33c)
0 (33c)
28 (33c)
52 (33c)
14 (33c)
0 (33c)
0 (33a)
0 (33b)
0 (33a)
0 (33b)
12 (22c)
42 (22c)
78 (22c)
100 (22c)
38 (23c)
21 (24c)
41 (27c)
43 (28c)
20 (34a)
18 (34b)
41 (34a)
40 (34b)
5 (1c)
0 (1c)
34 (1c)
27 (1c)
45 (1c)
57 (1c)
80 (1a)
82 (1b)
59 (1a)
60 (1b)
a Ester 22c is contaminated with 20% N-acylisourea 31c.
analysis of the reaction mixture) giving instead equivalent
amounts of the tert-butyl esters 34a,b as sole reaction products.
It should be therefore be concluded that for carboxylic acids
1a,b the elimination of dicyclohexyl urea and the formation of
ketenes of type 3a,b proceed at a much higher rate than the
formation of symmetric anhydrides of type 33a,b.
General procedure C for the determination of relative rates of
acylation in the presence of methanesulfonic acid
To a mixture of methanol (1 mmol), trichlorophenol (1 mmol),
methanesulfonic acid (0, 0.025, 0.05, 0.075 mmol) and carb-
oxylic acid 1a,b (0.5 mmol) in acetonitrile (5 ml) wass added
DCC (0.5 ml of 1 M solution in acetonitrile). The reaction
mixture was stirred for 30 min at room temperature, iso-
propanol (2 mmol) was added to be used for detecting possible
transesterification, and the reaction mixture was filtered, and
Conclusions
Carboxylic acids that are capable of forming ketenes upon the
treatment with DCC preferably acylate aliphatic hydroxy
groups in the presence of aromatic ones while carboxylic acids
possessing only alkyl or aryl groups in the α-position provide
the opposite chemoselectivity. The relative acylation rates of the
substituted phenols in all cases are consistent with a reaction
mechanism involving an attack of phenolate anions on electro-
philic intermediates such as ketenes and symmetric anhydrides,
with the carbodiimides serving both as an activating reagent
and as a basic catalyst.
1
evaporated. After integration of characteristic peaks in the H
1
NMR of the residue relative rates were calculated. H NMR
of the reaction mixture did not show any visible signals of pro-
tons associated with isopropyl ester group indicating that no
appreciable acid-catalyzed transesterification took place in the
work-up.
General procedure D of esterification of carboxylic acids 1c,d
To a solution of carboxylic acid 1c,d (1 mmol) in acetonitrile
(5 ml) were consequently added a solution of a phenol or a
thiol (1.2 mmol) in acetonitrile (1 ml) and a solution of DCC
(1 mmol) in acetonitrile (1 ml). The reaction mixture was stirred
for 1 h at room temperature, the residue was evaporated, dis-
solved in 7 : 3 ethyl acetate : 40–60 petroleum ether mixture
(20 ml), and filtered through a cintered glass. The filtrate was
washed with 1 M NaOH (3 × 5 ml), brine, dried, and evapor-
ated. Resulting aryl esters 23–30c,d were pure and could be used
in this form. Aryl esters 7c,d, 21–22c,d contain approx. 20% of
N-acyl ureas and were purified by column chromatography.
Experimental
General
Unless otherwise stated, all reagents used are from com-
mercially available sources. The characterization of new
compounds and literature references for known compounds are
provided as ESI.†
General procedure A for the preparations of esters 5–13a,b
General procedure E for the determination of relative rates of
esterification of acids 1c,d
To a solution of carboxylic acid 1a,b (1 mmol) and a corre-
sponding alcohol/phenol (1 mmol) in acetonitrile (5 ml) was
added a solution of DCC (1 mmol) in acetonitrile (1 ml). After
15 min the reaction mixture was filtered, the filtrate was evapor-
ated and purified by flash chromatography. During chromato-
graphy compounds 9–13a,b undergo rapid hydrolysis on silica
gel so isolated yields were very low (10–25%). Compounds
9a,10a cannot be isolated by chromatography or vacuum
To a mixture of two substrates (1 mmol of each) and carboxylic
acid 1c,d (0.5 mmol) in acetonitrile (5 ml) was added DCC
(0.5 ml of 1 M solution in acetonitrile). The reaction mixture
was stirred for 1 h at room temperature, filtered, and evapor-
1
ated. After integration of characteristic peaks in the H NMR
of the residue, relative rates were calculated. Relative rates for
compounds 21–23c,d, 29c,d were calculated with competition
against phenol. Relative rates for compounds 24–27, 30c,d were
calculated with competition against 4-cyanophenol and
recalculated to phenol. Relative rates for N-hydroxysuccinimide
(compounds 28c,d) were calculated against pentafluorophenol
using 1.2 eq. vs. 4 eq. ratio.
1
distillation and H NMR spectra of reaction mixtures before
chromatography are provided as ESI.†
General procedure B for the determination of relative rates of
esterification of acids 1a,b
To a mixture of two substrates (1 mmol of each) and carboxylic
acid 1a,b (0.5 mmol) in acetonitrile (5 ml) was added DCC
(0.5 ml of 1 M solution in acetonitrile). The reaction mixture
was stirred for 1 h at room temperature, filtered, and evapor-
ated. After integration of peaks of α-hydrogens in the 1H NMR
of the residue relative rates were calculated using the ratio of
logarithms.
General procedure F for the esterification of propionic acid in
water solutions using EDC
To a solution of propionic acid (1 mmol) and a phenol
(1.1 mmol) in water (1 ml) was added neat EDC. The reaction
mixture was stirred 10 min at room temperature, and was
O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 9 7 – 4 0 1
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5 B. Neises and W. Steglich, Org. Synth., 1985, 63, 183.
extracted by 3 : 7 ethyl acetate : 40–60 petroleum ether mixture
6 (a) J. R. Grunwell and D. L. Foerst, Synth. Commun., 1976, 6, 453–
455; (b) K. Horiki, Synth. Commun., 1977, 7, 251–259.
7 (a) A. Hassner and V. Alexanian, Tetrahedron Lett., 1978, 4475–
4478; (b) K. Holmberg and B. Hansen, Acta Chem. Scand., 1979, 33,
410–412.
(20 ml), washed with 1 M NaOH, brine, dried, and evaporated.
General procedure G for the preparation of symmetric anhydrides
33c–d
8 (a) D. J. Hudson, Org. Chem., 1988, 53, 617–624; (b) N. L. Benoiton
and F. M. F. Chen, Can. J. Chem., 1981, 59, 384–389; (c) G. Barany
and R. Merrifield, in The Peptides, Analysis, Synthesis, and Biology,
eds. E. Gross and J. Meienhofer, Academic Press, New York, 1980,
vol. 2A, pp. 123–127.
9 The rate of formation of symmetric anhydrides from O-acyl
isoureas substantially slows down in polar solvents like DMF, see
ref. 8a.
To a solution of carboxylic acid 1c,d (1 mmol) in dichloro-
methane (5 ml) was added a solution of DCC (0.5 mmol) in
dichloromethane (1 ml). The reaction mixture was stirred for
1 h at room temperature, the residue was evaporated, dissolved
in 3 : 7 ethyl acetate : 40–60 petroleum ether mixture (20 ml),
and filtered through a cintered glass. The filtrate was washed
with 1 M NaOH (3 × 5 ml), brine, dried, and evaporated, the
residue was purified by flash chromatography.
10 (a) M. Nahmany and A. Melman, Org. Lett., 2001, 3, 3733–3735;
(b) R. Shelkov, M. Nahmany and A. Melman, J. Org. Chem., 2002,
67, 8975–8982.
11 The relative rates of esterification were calculated through the ratio
General procedure H for reactions with deficiency of DCC
1
of logarithms of concentrations obtained by H NMR analysis of
To a solution of carboxylic acid 1a–c (1 mmol) in acetonitrile
(5 ml) were consequently added a solution of 1.2 mmol of
4-methoxyphenol (for 1c) or t-BuOH (for 1a,b) in acetonitrile
(1 ml) and a solution of 1 M solution of DCC in acetonitrile
(0.2–1.0 ml). The reaction mixture is stirred for 1 h at room
temperature, the residue is evaporated, filtered, evaporated, and
the residue was analyzed by 1H NMR.
the reaction mixture.
12 For references on pKa values see: (a) CRC Handbook of Biochemistry
and Molecular Biology, 3rd edn, CRC Press, Ohio, 1975–1976, 314–
315; (b) Tables of Rate and Equilibrium Constants of Heterolytic
Organic Reactions, ed. V. A. Palm., VINITI, Moscow, 1975, 32–96;
(c) D. E. Ames and T. F. Grey, J. Chem. Soc., 1955, 631.
13 (a) H. Meyer, H. Wengenroth and W. Lauer, Chem. Ber., 1988, 121,
1643–1646; (b) A. D. Allen, M. A. McAllister and T. T. Tidwell,
Tetrahedron Lett., 1993, 34, 1095–1098; (c) D. M. Birney and P. E.
Wagenseller, J. Am. Chem. Soc., 1994, 116, 6262–6270; (d ) W. W.
Shumway, N. K. Dalley and D. M. Birney, J. Org. Chem., 2001, 66,
5832–5839; (e) For competitive trapping of trifluoroethanol by
acylketene see: D. M. Birney, X. Xu, S. Ham and X. Huang, J. Org.
Chem, 1997, 62, 7114–7120.
14 A very recent work provides an indirect way to obtain similar
selectivity through the Mitsunobu reaction: (a) G. Appendino,
A. Minassi, N. Daddario, F. Bianchi and G. Tron, Org. Lett., 2002,
4, 3839–3841; (b) For similar selectivity in Lewis catalyzed
acylations see: K. L. Chandra, P. Saravan and V. K. Singh,
Tetrahedron, 2002, 58, 1369–1374.
General procedure I for the acylation of phenols with acetic
anhydride
To a solution of a phenol (1 mmol) and acetic anhydride
(0.5 mmol) in acetonitrile (2 ml) is added a solution of DCC in
acetonitrile (0.5 mmol). The reaction mixture is stirred for 1 h
at room temperature, filtered, and evaporated to give the
acetylated phenols.
15 For an indirect estimation of pKa of unsubstituted carbodiimide see:
(a) S. V. Hill, A. Williams and J. L. Longridge, J. Chem. Soc., Perkin
Trans. 2, 1984, 1009–1013; (b) A. Williams and I. T. Ibrahim, J. Am.
Chem. Soc., 1981, 103, 7090–7095.
16 For evidence of basic catalysis by carbodiimides see J. Izdebski,
A. Orlowska, R. Anulewicz, E. Witkowska and D. Fiertek,
Int. J. Pept. Protein Res., 1994, 43, 184–189.
17 For early reports on the mechanism of carbodiimide couplings see:
(a) H. G. Khorana, Chem. Rev., 1953, 53, 145–166; (b) H. G.
Khorana, Chem. Ind., 1955, 1087–1088; (c) I. T. Ibrahim and
A. Williams, J. Chem. Soc., Chem. Commun., 1980, 25–26.
18 For the formation on anhydrides see: F. M. F. Chen, K. Kuroda and
N. L. Benoiton, Synthesis, 1978, 928–929.
19 (a) B. Kundu, Tetrahedron Lett., 1992, 33, 3193–3196; (b) B. J.
Johnson and P. M. Jacobs, J. Chem. Soc., Chem. Commun., 1968,
73–74.
20 (a) I. J. Galpin, P. M. Hardy, G. W. Kenner, R. McDermott,
R. Ramage, J. H. Seely and R. G. Tyson, Tetrahedron, 1979, 35,
2577–2582; (b) J. Huang and J. Hall, J. Chem. Res. Synop., 1991,
292–293; B. Castro, G. Evin, C. Selve and R. Seyer, Synthesis, 1977,
413–413.
21 M. Bodanszky, in The Peptides, ed. E. Gross, Academic Press,
New York, vol. 1, 1979, 105–196.
Acknowledgements
This research was supported by the Israel Science Foundation
(Grant No. 176/02-1).
References and notes
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23 A. Williams and I. T. Ibrahim, J. Am. Chem. Soc., 1981, 103,
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O r g . B i o m o l . C h e m . , 2 0 0 4 , 2, 3 9 7 – 4 0 1
401