A Convenient Protocol for the Esterification of Carboxylic Acids with Alcohols in the Presence of di-t-Butyl Dicarbonate

Article abstract of DOI:10.1055/s-2003-44986

Stoichiometric mixtures of carboxylic acids and primary or secondary alkyl alcohols are cleanly converted into their corresponding esters by treatment with di-t-butyl dicarbonate [(BOC)₂O] in the presence of catalytic amounts of N,N′-dimethylaminopyridine (DMAP). This convenient procedure provides a general access to a broad variety of esters including those bearing highly sensitive functional groups such as phenol esters or BOC-groups. Purification of the products is particularly easy since the byproducts t-BuOH and CO₂ are volatile - a great advantage over the standard DCC/DMAP method.

Full text of DOI:10.1055/s-2003-44986

LETTER
263
A Convenient Protocol for the Esterification of Carboxylic Acids with Alcohols
in the Presence of di-t-Butyl Dicarbonate
E
sterification of
u
Carboxylic
k
A
cids
w
ith
A
a
lcohols in
sthe Presence of
d
i-
t
-Butyl.DicarbonateGooßen,* Arno Döhring
Max-Planck-Institut für Kohlenforschung, Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Fax +49(208)3062985; E-mail: goossen@mpi-muelheim.mpg.de
Received 12 November 2003
has been utilized for the synthesis of a limited range of
Abstract: Stoichiometric mixtures of carboxylic acids and primary
or secondary alkyl alcohols are cleanly converted into their corre-
sponding esters by treatment with di-t-butyl dicarbonate [(BOC)2O]
in the presence of catalytic amounts of N,N¢-dimethylaminopyridine
(DMAP). This convenient procedure provides a general access to a
broad variety of esters including those bearing highly sensitive
functional groups such as phenol esters or BOC-groups. Purifica-
tion of the products is particularly easy since the byproducts t-
BuOH and CO2 are volatile – a great advantage over the standard
DCC/DMAP method.
esters, in particular of amino acids.9
The reaction was found to proceed reasonably fast with
dimethyl dicarbonate (R¢ = Me), but is much slower with
the sterically demanding di-t-butyl dicarbonate (R¢ = t-
Bu).9,10 This is not surprising since the reaction mecha-
nism probably involves an intermolecular attack of the
liberated alcohol onto the mixed anhydride 3, and the re-
activity of the alcohol drastically decreases with its steric
bulk.
Key words: di-t-butyl dicarbonate, esters, esterification, carboxyl-
ic acids, catalysis
The esterification of carboxylic acids is undoubtedly one
of the most frequently employed transformations in or-
ganic chemistry. Many applications are covered by the
classical acid-catalyzed reaction of carboxylic acids with
excess alcohols.1 Although the atom efficiency of this
reaction is almost ideal, it is not suitable for substrates
bearing acid-sensitive functional groups, i.e. acetals,
esters, BOC-groups, etc.2 The alternative alkylation of
carboxylates with dialkylsulfates,3 alkyl halides4 or other
reagents5 has a higher functional group tolerance, but
alkylating agents are available in much less variety than
alcohols. For these reasons, the reaction of carboxylic
acids with alcohols in the presence of coupling reagents,
e.g. under Steglich or Mitsunobu conditions, is the
method of choice for many applications involving sensi-
tive molecules.6–8 However, separation of the products
from the waste derived from the coupling reagents is often
experienced as an important drawback of this approach.
For this reason, the use of coupling reagents that solely
produce volatile side products could lead to a significant
improvement of this methodology. We now wish to report
a broadly applicable, convenient esterification of carbox-
ylic acids with alcohols in the presence of di-t-butyl dicar-
bonate [(BOC)2O] as activating agent.
Scheme 1 Decarboxylative esterification of carboxylic acids with
dialkyl dicarbonates
We therefore reasoned that the inferior reactivity of t-bu-
tanol in comparison to primary and secondary alcohols
might allow for the general use of (BOC)2O as an activat-
ing agent for the coupling of a carboxylic acid with other
alcohols. Indeed, when we reacted 3-phenylpropionic
acid (1a) with (BOC)2O in the presence of a stoichiomet-
ric amount of benzyl alcohol (5a), in spite of the presence
of t-butanol, only traces of the t-butyl ester 4a were
formed (Scheme 2). Instead, the benzyl ester 6a was pro-
duced in high selectivity, albeit in low yield.
Encouraged by this observation, we tested several cata-
lysts under various conditions to identify optimal reaction
parameters for our model reaction. Selected results are
summarized in Table 1.
Dialkyl dicarbonates 2 react with carboxylic acids 1 to
give mixed carbonic carboxylic anhydrides 3 together
with one equivalent of the alkyl alcohol 5. Upon the addi-
tion of N,N¢-dimethylaminopyridine (DMAP) to such
mixtures, CO2 is released and the corresponding alkyl es-
ters 4 are formed (Scheme 1). This type of transformation
SYNLETT 2004, No. 2, pp 0263–0266
0
2.
0
2.
2
0
0
4
Advanced online publication: 08.12.2003
DOI: 10.1055/s-2003-44986; Art ID: G30703ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Esterification of 3-phenylpropionic acid with benzyl
alcohol and (BOC)2O

264
L. J. Gooßen, A. Döhring
LETTER
Table 1 Optimization of the Conditions for the Esterification According to Scheme 2a
Entry
1
Catalyst
Hf(OTf)4
Mg(ClO4)2
Sc(OTf)3
Yb(OTf)3
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
DMAP
Amount (mol%)
Solvent
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
THF
Temp (°C)
Conversion (%)
Selectivity (%)
1
1
25
25
25
25
25
25
50
50
50
50
50
50
50
50
50
25
17
10
13
99
48
95
95
97
97
97
96
98
87
97
82
65
54
47
99
99
99
99
98
99
99
99
99
98
99
2
3
1
4
1
5
10
5
6
7
5
8
5
9
5
Toluene
DMF
10
11
12b
13c
14d
15e
5
5
CH3CN
CH3NO2
CH3NO2
CH3NO2
CH3NO2
5
5
5
5
a Conditions: 1.0 mmol 3-phenylpropionic acid (1a), 1.3 mmol (BOC)2O (2a), 1.3 mmol benzyl alcohol (5a), 4 mL nitromethane, 16 h.
Conversions and selectivities are based on 1a and were determined by GC using n-tetradecane as an internal standard.
b 1.0 mmol benzyl alcohol.
c 2.0 mmol benzyl alcohol.
d 1.0 mmol (BOC)2O.
e 2.0 mmol (BOC)2O.
Using various Lewis acids, which we had previously
shown to be excellent catalysts for decarboxylative ester-
ifications,10 mixtures of the benzyl ester and some t-butyl
ester were obtained (entries 1–4). In sharp contrast to this,
high selectivities for the benzyl ester were observed in the
presence of DMAP (entries 5–15). Upon increasing the
Scheme 3 Esterification of carboxylic acids with alcohols in the
presence of (BOC)2O
temperature to 50 °C, with a catalyst load as low as 5
mol%, near quantitative conversions and excellent selec-
As can be seen from Table 2, the reaction proceeded in
tivities for the desired benzyl esters were achieved within
excellent yields with many primary and secondary alco-
several hours (entries 5–7). Due to its excellent solubiliza-
hols. Various functionalities were tolerated including
tion of a broad variety of carboxylic acids, nitromethane
cyano, keto, ester, and even less reactive hydroxy groups.
Even highly sensitive alcohols such as a-hydroxy-
ketones, -esters or -ketals were smoothly coupled.
proved to be a particularly efficient reaction medium, but
other solvents can also be used (entries 7–11).
Only a slight excess of (BOC)2O is required to achieve
The scope of the transformation was also investigated by
full conversion (entries 12–15). It is advisable to stop the
reacting a broad variety of carboxylic acids with benzyl
reaction after complete conversion, since later, small
alcohol (Scheme 3, R¢ = Bn). The general applicability of
quantities of benzyl-t-butyl carbonate slowly begin to
the process is visible also in Table 3. The reaction can be
form from the excess reagents. Although this side reaction
performed with aromatic, aliphatic, vinylic, and heterocy-
does not reduce the yield, it may complicate the work-up.
clic carboxylic acids and tolerates a broad variety of func-
In order to probe the generality of this protocol, we ap-
tional groups in the acid component, such as esters,
plied it to the esterification of 3-phenylpropionic acid with
ketones, amides, ethers, nitriles.
a series of different alcohols (Scheme 3, R = C2H4-C6H5).
Only for very few derivatives, namely o-fluorobenzoic
acid and m-NO2-benzoic acid, decomposition of the start-
ing materials and unsatisfactory yields were observed.
Synlett 2004, No. 2, 263–266 © Thieme Stuttgart · New York

LETTER
Esterification of Carboxylic Acids with Alcohols in the Presence of di-t-Butyl Dicarbonate
265
Table 2 Synthesis of 3-Phenylpropionates of Various Alcohols
Table 3 Synthesis of Benzyl Esters of Various Carboxylic Acids
According to Scheme 3a
According to Scheme 3a
R’OH
Product
Yield (%)
90
R-COOH
Product
Yield (%)
99
6a
6b
6c
95
6n
6o
94
92
6d
6e
97
93
6f
89
6p
6q
6r
86
89
81
6g
6h
91
99
6i
6j
88
95
6k
91
6s
6t
95
94
6l
92
91
6m
a Conditions: 1.0 mmol 3-phenylpropionic acid, 1.3 mmol alcohol,
1.3 mmol (BOC)2O, 0.05 mmol DMAP, 4 mL nitromethane, 50 °C,
16 h, isolated yields.
6u
6v
6w
6x
94
94
92
< 5
The work-up of the reaction products is very convenient
since the residual (BOC)2O is easily hydrolyzed by dilute
HCl, leaving volatile t-BuOH and CO2 as the only by-
products. Thus, the products are usually obtained in pure
form after a simple aqueous work-up – a great advantage
over the standard DCC/DMAP protocol.
In summary, a convenient and generally applicable proto-
col for the esterification of carboxylic acids with primary
or secondary alcohols in the presence of di-t-butyl dicar-
bonate and catalytic amounts of DMAP was developed.
The tolerance of this process of a wide range of function-
alities and the fact that only volatile or water-soluble
byproducts are released render the transformation very at-
tractive for the preparative chemist and especially useful
for applications in combinatorial chemistry and drug dis-
covery.
6y
< 5
a Conditions: 2.0 mmol carboxylic acid, 2.0 mmol benzyl alcohol, 2.6
mmol (BOC)2O, 0.10 mmol DMAP, 4 mL nitromethane, 50 °C, 16 h,
isolated yields.
Synlett 2004, No. 2, 263–266 © Thieme Stuttgart · New York

266
L. J. Gooßen, A. Döhring
LETTER
Synthesis of Adipic Acid Benzyl Ethyl Ester (6s): A dried flask
was charged with adipic acid monoethyl ester (1s, 352 mg, 2.0
mmol), di-t-butyl dicarbonate (2a, 585 mg, 2.6 mmol), benzyl alco-
hol (5a, 210 ml, 2.0 mol), and DMAP (12.0 mg, 0.10 mmol). Dry ni-
tromethane (4 mL) was added by syringe and the reaction was
stirred overnight at 50 °C. After the reaction was complete (TLC),
EtOAc was added and the organic layer was washed consecutively
with 2 M HCl, NaHCO3 solution, H2O and brine. After drying with
MgSO4 and removal of the volatiles in vacuo, the product was ob-
tained in high purity. For spectroscopic characterization, the prod-
uct was filtered through a small plug of silica using hexane/CH2Cl2
(3:7) as eluent. After concentrating to dryness, 6s (509 mg, 96%)
References
(1) (a) Otera, J. Esterification. Methods, Reactions and
Applications; Wiley-VCH: Weinheim, 2003. (b) Greene, T.
W.; Wuts, P. G. M. Protective Groups in Organic Synthesis,
3rd Ed.; Wiley: New York, 1999, 369. (c) Patai, S. The
Chemistry Acid Derivatives, Vol. 1; Wiley: New York,
1979, 267. (d) Falbe, J. Methods in Organic Chemisry
(Houben-Weyl), 4th Ed.; Thieme: Stuttgart – New York,
1985, Vol. E5. (e) Haslam, E. Tetrahedron 1980, 36, 2409.
(2) For particularly effective systems, see for example:
(a) Ishihara, K.; Ohara, S.; Yamamoto, H. Science 2000,
290, 1140. (b) Wakasugi, K.; Misaki, T.; Yamada, K.;
Tanabe, Y. Tetrahedron Lett. 2000, 41, 5249. (c) Xiang, J.;
Toyoshima, S.; Orita, A.; Otera, J. Angew. Chem. Int. Ed.
2001, 40, 3670; Angew. Chem. 2001, 113, 3782. (d) Xiang,
J.; Orita, A.; Otera, J. Adv. Synth. Catal. 2002, 344, 84.
(3) (a) Chakraborti, A. K.; Basak, A.; Grover, V. J. Org. Chem.
1999, 64, 8014. (b) Merz, A. Angew. Chem., Int. Ed. Engl.
1973, 12, 846; Angew. Chem. 1973, 85, 868.
1
was obtained as a colorless oil. H NMR (300.1 MHz, CDCl3):
d = 7.41–7.26 (m, 5 H), 5.11 (s, 2 H), 4.11 (q, 3J = 7 Hz, 2 H), 2.42–
2.27 (m, 4 H), 1.74–1.60 (m, 4 H), 1.24 (t, 3J = 7 Hz, 3 H) ppm. 13
C
NMR (75.5 MHz, CDCl3): d = 173.3, 173.1, 136.0, 128.5, 128.1,
128.1, 66.1, 60.2, 33.9, 24.3, 14.2 ppm. MS (EI): m/z (%) = 264 (4),
[M]+, 236 (17), 157 (38), 130 (20), 111 (37), 91 (100), 55 (15).
HRMS (EI): m/z calcd for C15H20O4 [M]+: 264.136160; found:
264.136221.
(4) For examples, see (a) Johnstone, R. A. W.; Rose, M. E.
Tetrahedron 1979, 35, 2169. (b) Chevallet, P.; Garrouste,
P.; Malawska, B.; Martinez, J. Tetrahedron Lett. 1993, 34,
7409. (c) Wang, T.; Lui, A. S.; Cloudsdale, I. S. Org. Lett.
1999, 1, 1835.
The reactions in Table 2 and Table 3 were performed following the
above procedure. All products were isolated and characterized by
means of 1H NMR and 13C NMR as well as by GC-MS and HRMS.
(5) Shieh, W.-C.; Dell, S.; Repič, O. J. Org. Chem. 2002, 67,
Acknowledgment
2188.
(6) Staab, H. A. Angew. Chem. 1962, 74, 407.
(7) (a) Neises, B.; Steglich, W. Angew. Chem., Int. Ed. Engl.
1978, 17, 522; Angew. Chem. 1978, 90, 556. (b) Hassner,
A.; Alexanian, V. Tetrahedron Lett. 1978, 4475.
(8) Mitsunobu, O. Synthesis 1981, 1.
We thank Prof. Dr. M. T. Reetz for generous support and constant
encouragement, and the DFG, the FCI, and the BMBF for financial
support.
(9) (a) Takeda, K.; Akiyama, A.; Nakamura, H.; Takizawa, S.;
Mizuno, Y.; Takayanagi, H.; Harigaya, Y. Synthesis 1994,
1063. (b) Pozdnev, V. F. Int. J. Pept. Protein Res. 1992, 40,
407.
(10) Gooßen, L. J.; Döhring, A. Adv. Synth. Catal. 2003, 345,
943.
Synlett 2004, No. 2, 263–266 © Thieme Stuttgart · New York