Efficient and controllably selective preparation of esters using uronium-based coupling agents

Article abstract of DOI:10.1021/ol201005s

Carboxylic acid esters can be prepared in excellent yields at room temperature from an acid and either a phenol or an aliphatic alcohol using the peptide coupling reagents, TBTU, TATU, or COMU, in the presence of organic bases. Reactions using TBTU and TATU are faster but do not occur with tertiary alcohols. Selectivity between reaction with primary or secondary alcohols in diols and polyols can be achieved with choice of base and coupling agent.

Full text of DOI:10.1021/ol201005s

ORGANIC
LETTERS
2011
Vol. 13, No. 12
2988–2991
Efficient and Controllably Selective
Preparation of Esters Using
Uronium-Based Coupling Agents
Jean-d’Amour K. Twibanire and T. Bruce Grindley*
Department of Chemistry, Dalhousie University, Halifax, NS, Canada B3H 4J3
bruce.grindley@dal.ca
Received March 24, 2011
ABSTRACT
Carboxylic acid esters can be prepared in excellent yields at room temperature from an acid and either a phenol or an aliphatic alcohol using the
peptide coupling reagents, TBTU, TATU, or COMU, in the presence of organic bases. Reactions using TBTU and TATU are faster but do not occur
with tertiary alcohols. Selectivity between reaction with primary or secondary alcohols in diols and polyols can be achieved with choice of base
and coupling agent.
A very large number of methods are available for
formation of esters from carboxylic acids and alcohols.1
When both the carboxylic acid and the alcohol are large
and acid or base sensitive, fewer options are available, but
these are still numerous. The methods used most com-
monly include dehydration with dicyclohexylcarbodiimide
(DCC) and DMAP2 or 4-(1-pyrrolidinyl)pyridine3 and
reaction with 2-halopyridinium salts4 orsterically hindered
aromatic acid anhydrides5 or chlorides.6 Some newer
reagents include dimethylsulfamoyl chloride,7 triphenyl-
phosphine dihalides,8 1-tosylimidazole,9 and O-alkyli-
soureas.10 We wanted conditions for ester formation that
could be used for the efficient convergent synthesis of
polyester dendrimers under very mild conditions.11 The
ester groups present in both the divergently assembled
polyalcoholic core and the carboxylic acid-terminated
dendron ruled out transesterification conditions and either
strong Brønsted or Lewis acids or bases. Agents for
formation of amides from amino acids under conditions
that are mild enough that racemization is minimized12
meet these requirements. Many of these reagents are
commercially available compounds that are stable in air
at room temperature. They are very effective at promoting
amide formation at room temperature, but only scattered
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r
10.1021/ol201005s
Published on Web 05/19/2011
2011 American Chemical Society

reports13 have appeared about their application to ester
formation and those concerned formation of phenolic
esters13a and primary aliphatic esters13 using 2-(1H-benzo-
triazole-1-yl)-1,1,3,3-tetramethyluronium salts (TBTU
and HBTU). An alternative approach employed only with
primary alcohols is to use the uronium salt precursor,
1-hydroxybenzotriazole, with DCC and DMAP.14
Figure 3. Structures of the alcohols used.
obtained under these conditions, with the yields given being
of isolated products. The reactions worked equally well
in acetonitrile but were much slower in tetrahydrofuran.
In DMF, ester formation with phenols occurred rapidly
and in good yields with all three coupling agents. With a
variety of primary alcohols, ester formation was again very
efficient, if somewhat slower. With secondary alcohols,
reactions took about 4 h to complete with the benzotria-
zole-derived coupling agents, TATU and TBTU, but were
5À10 times slower with COMU. Reactions with tert-butyl
alcohol were achieved with COMU in good yield, but only
when the stronger16 base, 7-methyl-1,5,7-triazabicyclo-
[4.4.0]dec-5-ene (MTBD), was used. The use of MTDB
did not appear to significantly accelerate the COMU-
promoted reaction of benzoic acid and isopropanol.
TATU and TBTU did not promote esterification with
tertiary alcohols.
Figure 1. Structures of the uronium-based coupling agents used.
Here, we report that uronium-based peptide cou-
pling agents, namely, 2-(1H-benzotriazole-1-yl)-1,1,3,3-
tetramethyluronium tetrafluoroborate (TBTU) (1),12a 2-
(1H-7-azabenzotriazole-1-yl)-1,1,3,3-tetramethyluronium
tetrafluoroborate (TATU) (2),12b and 1-[(1-(cyano-2-
ethoxy-2-oxoethylideneaminooxy)dimethylaminomorpho-
linomethylene)]methanaminium hexafluorophosphate
(COMU) (3),12d depicted in Figure 1 and commercially
available, are efficient reagents for the promotion of ester
formation at room temperature.
Several other differences were noticed between the reac-
tions performed with COMU as opposed to those with
TATU and TBTU. The two latter reagents required a ∼30
min activation timeofthe acidbythe coupling agent before
the alcohol was added. COMU did not require an activa-
tion time. With COMU, it did not matter whether diiso-
propylethylamine (DIEA) or the stronger16 base, DBU,
was used for phenols or primary or secondary alcohols.
However, with TBTU and TATU, secondary alcohols did
not react when DIEA was used as the base.
Figure 2. Structures of the carboxylic acids used.
Yields were observed to be lower for secondary alcohols
when equimolar amounts of acid, alcohol and coupling
agent were used. Using 1.2 equiv of acid and 1.5 equiv of
coupling agent increased the yield of esterification of
benzoic acid with cyclopentanol using COMU from 68%
in 16 h to 81% in 10 h. Similarly, esterification of benzoic
acid with isopropyl alcohol and TBTU under these condi-
tions gave a yield of 91%, as opposed to 63% under
equimolar conditions.
The acids and alcohols used in this study are shown in
Figures 2 and 3. Most are known compounds; compound
9 was made from tri-O-benzylpentaerythritol11,15 (see the
Supporting Information).
Reactions were initially performed in anhydrous DMF
using equivalent amounts of acid and alcohol at room
temperature with 2 equiv of base. Table 1 shows the results
(14) (a) Matsukawa, Y.; Isobe, M.; Kotsuki, H.; Ichikawa, Y. J. Org.
Chem. 2005, 70, 5339–5341. (b) Yakura, T.; Yoshimoto, Y.; Ishida, C.;
Mabuchi, S. Tetrahedron 2007, 63, 4429–4438. (c) Nordly, P.; Korsholm,
K. S.; Pedersen, E. A.; Khilji, T. S.; Franzyk, H.; Jorgensen, L.; Nielsen,
H. M.; Agger, E. M.; Foged, C. Eur. J. Pharmaceut. Biopharmaceut.
2011, 77, 89–98.
An evaluation of whether the base sensitivity of reaction
outcome to alcohol structure could be used to obtain
regioselectivity was tested with a diol (21) and a polyol
(15) Al-Mughaid, H.; Grindley, T. B. Carbohydr. Res. 2004, 339,
€
€
€
€
€
2607–2610. (16)(a) Kaljurand, I.; Kutt, A.; Soovali, L.; Rodima, T.;
€
(16) (a) Kaljurand, I.; Kutt, A.; Soovali, L.; Rodima, T.; Maemets,
Maemets, V.; Leito, I.; Koppel, I. A. J. Org. Chem. 2005, 70, 1019–1028.
V.; Leito, I.; Koppel, I. A. J. Org. Chem. 2005, 70, 1019–1028.
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33, 588–597.
2009, 33, 588–597.
Org. Lett., Vol. 13, No. 12, 2011
2989

Scheme 1. Selective Esterificationsa
Table 1. Reactions of Carboxylic Acids and Alcohols at Room
Temperature
acid alcohol coupling agenta
baseb
time (h) yieldc (%)
5
16
16
16
12
17
17
17
20
13
13
13
14
14
14
15
15
15
15
15
17
16
19
20
18
17
17
17
11
TBTU
TATU
DIEA
DIEA
DIEA
DBU
DBU
DIEA
DBU
DBU
DBU
DBU
MTBD
DBU
DBU
DBU
DBU
DBU
DBU
MTBD
MTBD
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
0.25
0.25
3
86
96
79
89
81
95
74
69
63
71
79
59
89
68
0
COMU
COMU
TBTU
TATU
2.5
0.5
0.5
4.5
5
a Note that 23 was accompanied by 5% of the ester of the secondary
alcohol.
COMU
COMU
TBTU
COMU
COMU
TBTU
TATU
steps: addition of the carboxylate salt to the uronium
reagent, decomposition of the resulting tetrahedral inter-
mediate, addition of the released anion to the carbonyl
center followed by loss of a urea derivative, and alcohol
addition to the activated carbonyl group. The base sensi-
tivity of the reaction with secondary alcohols performed
with the benzotriazole-derived coupling agents indicates
that the last step is rate determining in this case. Conver-
sely, for the slower base-insensitive COMU reactions, an
earlier step must be rate determining for primary and
secondary alcohols, either the decomposition of the initial
tetrahedral intermediate or the readdition of the stable
anion. However, with the tertiary alcohol, tert-butyl alco-
hol, ester formation only occurs with the strong organic
base MTBD using COMU. Clearly, the rate-determining
step for COMU has switched to being the last step for this
hindered alcohol. The relative acidities in DMSO and
4
16
11
4
3.5
COMU
TBTU
TATU
16
36
36
36
36
16
2
0
COMU
TATU
0
0
COMU
COMU
COMU
COMU
COMU
TBTU
COMU
TBTU
COMU
COMU
79
86
81
83
67
72
73
60
62
81
4
6
6
6
7
7
8
8
9
3
4
4
1
12
3
14
2
a Reactions with TATU were conducted with 1.2 equiv of the
acid and 1.3 equiv of TATU. b Abbreviations: DIEA, diisopropylethy-
lamine; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; MTBD, 7-methyl-
1,5,7-triazabicyclo[4.4.0]dec-5-ene. c Isolated yields.
Scheme 2. Proposed Reaction Mechanisms: (a) Level on Each
Line, TBTU Mechanism; (b) Level, COMU Mechanism
(22) using TBTU and DIEA with an aryl (5) and an
aliphatic acid (10). The reactions were highly selective for
the primary hydroxyls; in only one reaction was a small
amount of the secondary product obtained, that is for 1,3-
butanediol (21) (see Scheme 1), where benzoylation gave
5% of the secondary product in addition to the major
primary product (90%). Most other selective esterification
methods17 are less selective in benzoylation of 21 than this
method.
Mechanisms have been proposed for the reactions in-
volving COMU and amines18 and for TBTU and alcohols
(see Scheme 2).13a These mechanisms have the following
(17) (a) Iwasaki, F.; Maki, T.; Onomura, O.; Nakashima, W.;
Matsumura, Y. J. Org. Chem. 2000, 65, 996–1002. (b) Wakita, N.; Hara,
S. Tetrahedron 2010, 66, 7939–9645. (c) Caddick, S.; McCarroll, A. J.;
Sandham, D. A. Tetrahedron 2001, 57, 6305–6310. (d) Morcuende, A.;
ꢀ
Valverde, S.; Herradon, B. Synlett 1994, 89–91.
(18) El-Faham, A.; Subiros-Funosas, R.; Albericio, F. Eur. J. Org.
Chem. 2010, 3641–3649.
2990
Org. Lett., Vol. 13, No. 12, 2011

for the convergent synthesis of polyester dendrimers.
Diol 20 is a dendrimer core molecule that we recently pre-
pared.11 We have shown that tribranched dendrons
can be added to core 20 to form ester linkages if the
carboxylic acid of the dendron is preactivated as the
anhydride.11 In Scheme 3, we show that peptide coupling
agents can also be used for this purpose, forming the two
ester linkages of 32 in good yield under mild conditions.
This approach eliminates one chemical step during the
creation of each generation of a polyester dendrimer.
The formation of other esters from acid 31 and simple
alcohols as well as the synthesis of the tribranched second
generation dendron 31 is described in the Supporting
Information.
Scheme 3. TBTU-Promoted Convergent Synthesis of a Second-
Generation Dendrimera
In summary, we have demonstrated that the peptide
coupling reagents COMU, TBTU, and TATU can be used
to prepare esters in excellent yields from all types of
alcohols at room temperature under mild conditions using
organic bases and short reaction times. Esterification of
secondary alcohols promoted by TBTU and TATU re-
quire a base, such as DBU, that is stronger than tertiary
amines. Only COMU is effective for the preparation of
esters from tertiary alcohols, and then only when the still
stronger base, MTBD, is used. The base sensitivity of the
TBTU and TATU promoted reactions can be utilized for
the selective esterification of primary hydroxyls in diols
and polyols. Applications of this latter observation will be
reported shortly.
a The synthesis of the second-generation dendron 31 is outlined in the
Supporting Information.
acetonitrile of alcohols and the conjugate acids of the
organic bases employed16,19 indicate that the alcohol will
only be slightly ionized. The difference in pKa between
isopropyl alcohol and tert-butyl alcohol19a is similar to
that between DBU and MTBD.16 It appears that the
tetrahedral intermediate for alcohol addition is lower in
energy relative to starting materials for COMU than for
the benzotriazole-derived coupling agents, for either elec-
tronic or steric reasons.
Acknowledgment. We thank NSERC for support and
Dr. Spencer Williams of the University of Melbourne for
discussion of COMU. We thank NMR-3 for NMR time.
Having established that these conditions were effective
for ester formation, we tested whether they could be used
Supporting Information Available. Experimental
procedures for all syntheses, characterization data of
1
new compounds, and H and 13C NMR spectra for all
(19) (a) Olmstead, W. N.; Margolin, Z.; Bordwell, F. G. J. Org.
Chem. 1980, 45, 3295–3299. (b) Bordwell, F. G. Acc. Chem. Res. 1988,
21, 456–463.
compounds prepared. This information is available free
of charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 12, 2011
2991