Esterification of carboxylic acids catalyzed by in situ generated tetraalkylammonium fluorides

Article abstract of DOI:10.1016/S0040-4039(01)02035-4

Esterification of carboxylic acids with alkyl halides can be efficiently catalyzed by tetrabutylammonium fluoride (TBAF) generated in situ from tetrabutylammonium hydrogensulfate (TBAHSO₄) and KF·2H₂O in THF. The general applicability and the characteristic feature of this approach has been amply demonstrated.

Full text of DOI:10.1016/S0040-4039(01)02035-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 9245–9248
Esterification of carboxylic acids catalyzed by in situ generated
tetraalkylammonium fluorides
Takashi Ooi, Hayato Sugimoto, Kanae Doda and Keiji Maruoka*
Department of Chemistry, Graduate School of Science, Kyoto University, Sakyo, Kyoto 606-8502, Japan
Received 28 September 2001; revised 11 October 2001; accepted 26 October 2001
Abstract—Esterification of carboxylic acids with alkyl halides can be efficiently catalyzed by tetrabutylammonium fluoride
(TBAF) generated in situ from tetrabutylammonium hydrogensulfate (TBAHSO4) and KF·2H2O in THF. The general applicabil-
ity and the characteristic feature of this approach has been amply demonstrated. © 2001 Elsevier Science Ltd. All rights reserved.
Undoubtedly, esterification of carboxylic acids by reac-
tion with alkyl halides represents a fundamental and
often encountered transformation in organic synthesis,1
and a number of useful procedures using metal halides2
and carbonates3 have been introduced. Our recent con-
tribution to this subject is the facile conversion of
trialkylsilyl esters to the corresponding alkyl esters with
commercially available tetrabutylammonium fluoride
trihydrate (TBAF·3H2O) by taking advantage of the
high affinity of the fluoride ion toward the silicon
atom.4 However, preparation of silyl esters and the use
of a stoichiometric amount of highly hygroscopic
TBAF·3H2O with careful handling turned out to be an
inevitable drawback. Quite recently, we disclosed that
desired quaternary ammonium fluoride can be
efficiently generated in situ from the corresponding
hydrogensulfate and potassium fluoride dihydrate
(KF·2H2O) in THF,5 which led us to investigate the
possibility of direct esterification of carboxylic acids
with catalytic, in situ prepared TBAF, taking the basic
character of the fluoride ion into account.6 Herein we
wish to report an efficient esterification of carboxylic
acids with alkyl halides catalyzed by TBAF generated
under solid–liquid phase-transfer conditions (Scheme 1).
THF at room temperature for 1 h and subsequent
addition of 3-phenylpropionic acid [1a, R1=Ph(CH2)2]
and benzyl bromide (R2=PhCH2) with continuous stir-
ring for 3 h gave rise to the corresponding benzyl ester
2a [R1=Ph(CH2)2, R2=PhCH2] quantitatively.7 Fur-
ther, we found that the premixing of TBAHSO4 and
KF·2H2O was not necessarily required in this reaction,
and that a catalytic amount of TBAHSO4 could be
reduced to 5 mol% with no sign of the reactivity
decrease (entry 1 in Table 1), which simplifies the
operation of the present direct esterification procedure
without TBAF itself.8,9 It should be added that the
esterification did not proceed at all in the absence of
either TBAHSO4 or KF·2H2O under otherwise identi-
cal conditions, as included in Table 1 (entries 2 and 3).
Table 1, which summarizes the results with a wide
variety of carboxylic acids and alkyl halides, shows that
the desired esters were generally obtained in excellent
isolated yields. Not only reactive alkyl halides such as
allyl and propargyl bromides but simple aliphatic
halides can be employed as an electrophile as also
demonstrated in the reaction of 1a (entries 4–9). The
catalytic esterification of sec- and tert-alkylcarboxylic
acids proceeded smoothly (entries 12–14). Notably,
even triphenylacetic acid and 1-adamantanecarboxylic
Initial treatment of tetrabutylammonium hydrogensul-
fate (TBAHSO4) (10 mol%) with KF·2H2O (5 equiv.) in
TBAHSO4 (5 mol%), KF•2H2O (5.0 eq)
R2X (1.1~5.0 eq)
THF, r.t., 3~24 h
O
O
OR2
R1
R1
OH
1
2
Scheme 1.
Keywords: esterification; phase transfer; potassium fluoride dihydrate; tetraalkylammonium hydrogensulfate.
* Corresponding author. Tel./fax: +00 81 75 753 4041; e-mail: maruoka@kuchem.kyoto-u.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02035-4

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T. Ooi et al. / Tetrahedron Letters 42 (2001) 9245–9248
Table 1. In situ generated TBAF-catalyzed esterification of carboxylic acidsa
Entry
R1CO2H, 1
R2X
React. time (h)
Yield of 2b (%)
1
2
3
4
5
6
7
8
Ph(CH2)2CO2H (1a)
PhCH2Br
3
12
12
3
3
3
3
6
6
99
N.r.c,d
N.r.c,e
88
99
CH2ꢀCHCH2Br
trans-PhCHꢀCHCH2Br
CHꢁCCH2Br
EtBr
BuBr
i-PrBr
99
97f
99f
9
77f,g (99)f,g,h
10
11
12
13
14
15
16
CH3(CH2)7CO2H
PhCH2Br
BuBr
PhCH2Br
EtBr
PhCH2Br
PhCH2Br
EtBr
3
6
3
3
3
3
3
99
99f
99
c-C6H11CO2H
93f
98
t-BuCO2H
Ph3CCO2H
99
99f
CO2H
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
PhCH2Br
CH2ꢀCHCH2Br
BuBr
3
3
3
24
3
3
3
3
6
6
99
99
99f
71f (99)f,g
99
i-PrBr
PhCO2H
PhCH2Br
CH2ꢀCHCH2Br
BuBr
PhCH2Br
BuBr
PhCH2Br
PhCH2Br
EtBr
PhCH2Br
BuBr
99
88f
96
trans-EtCHꢀCHCO2H
86f
85
trans-PhCHꢀCHCO2H
PhCꢁCCO2H
3
3
3
6
99
91f
96
CH3O2C(CH2)5CO2H
97f
51
PhCH2Br
24
OH
OH
CH3
CO2H
CH3
80
CO2Bn
32
33
PhCH2Br
24
OH
OH
CO2H
CO2Bn
Br(CH2)4CO2H
5
96
O
O
a Unless otherwise specified, the reaction was carried out in dry THF (0.5 M) with TBAHSO4 (5 mol%), KF·2H2O (5 equiv.) and 1.1 equiv. of
alkyl halides at room temperature.
b Isolated yield.
c N.r.=no reaction.
d In the absence of TBAHSO4.
e Without KF·2H2O.
f Use of 5 equiv. of alkyl halide.
g At 55°C.
h Stirring for 12 h.

T. Ooi et al. / Tetrahedron Letters 42 (2001) 9245–9248
3 (2 mol%)
9247
O
O
KF•2H2O (5 eq)
+
OH
Ph
O
Ph
Br
THF
r.t., 42 h
1a
2b
98%, 58% ee (S)
(3 eq)
1N NaOH
MeOH, r.t.
Ar
HSO4
N
CF3
HO
4
Ar =
Ar
3 [3,5-(CF3)2-Ph-NAS-HSO4]
CF3
Scheme 2.
acid can be efficiently transformed into the corresponding
primary esters, despite their steric bulkiness (entries
15–20). Aromatic as well as a,b-unsaturated carboxylic
acids including phenylpropiolic acid were found to be
goodcandidatesforthepresentmethod, givingthedesired
product in high yields (entries 21–28). The synthetic utility
of this procedure was further exemplified by the facile
conversion of adipic acid monomethyl ester to the
corresponding unsymmetrical ester (entries 29 and 30).
Moreover, selective transformation of carboxylic acids
possessing hydroxy functionality appeared feasible to
produce the corresponding hydroxy esters, though a
certain decrease of the chemical yield was observed
(entries 31 and 32). As expected from our previous study,
5-bromovaleric acid, upon exposure to the standard
reaction conditions, afforded d-valerolactone in 96% yield
(entry 33).
Chapter 5; (b) Larock, R. C. Comprehensive Organic
Transformations, 2nd edn; VCH: New York, 1999.
2. (a) Tam, J. P.; Kent, S. B. H.; Wong, T. W.; Merrifield,
R. B. Synthesis 1979, 955; (b) Clark, J. H.; Miller, J. M.
J. Am. Chem. Soc. 1977, 99, 498; (c) Clark, J. H.; Miller,
J. M. Tetrahedron Lett. 1977, 599; (d) Clark, J. H. J.
Chem. Soc., Chem. Commun. 1978, 789; (e) Sato, T.;
Otera, J.; Nozaki, H. J. Org. Chem. 1992, 57, 2166; (f)
Lee, J. C.; Choi, Y. Synth. Commun. 1998, 28, 2021.
3. (a) Gisin, B. F. Helv. Chim. Acta. 1973, 56, 1476; (b)
Wang, S.-S.; Gisin, B. F.; Winter, D. P.; Makofske, R.;
Kulesha, I. D.; Tzougraki, C.; Meienhofer, J. J. Org.
Chem. 1977, 42, 1286; (c) Kruizinga, W. H.; Kellog, R.
M. J. Am. Chem. Soc. 1981, 103, 5183; (d) Lerchen,
H.-G.; Kunz, H. Tetrahedron Lett. 1985, 26, 5257.
4. Ooi, T.; Sugimoto, H.; Maruoka, K. Heterocycles 2001,
54, 593.
5. Ooi, T.; Doda, K.; Maruoka, K. Org. Lett. 2001, 3, 1273.
6. For the basicity of TBAF, see: Kuwajima, I.; Murofushi,
T.; Nakamura, E. Synthesis 1976, 602.
7. After the reaction of the in situ formed ammonium
carboxylates with alkyl bromides, the resulting tetra-
butylammonium bromide (TBAB) would be converted
into TBAF by the anion exchange with the excess potas-
sium fluoride, establishing the catalytic cycle.
8. Use of catalytic TBAF·3H2O (5 mol%) and KF·2H2O (5
equiv.) in the reaction of 1a with benzyl bromide brought
a slight decrease of the chemical yield of 2a (94%). The
carboxylic ester 2a was obtained in only 2% yield, when
the reaction was simply performed with 5 mol% of
TBAF·3H2O as a catalyst.
The distinct advantage of our approach over the ordinary
metal fluoride-mediated esterification is highlighted by
the facile preparation of optically active esters via alkyla-
tive kinetic resolution of sec-alkyl halides using in situ
generated chiral ammonium fluorides as catalyst. For
instance, simple stirring of the mixture of 1a, 1-(1-bro-
moethyl)naphthalene [R2=1-Np(CH3)CH], C2-symmet-
ric chiral quaternary ammonium hydrogensulfate 3 (2
mol%)5 and KF·2H2O (5 equiv.) in THF at room
temperature for 42 h afforded the desired ester 2b
[R1=Ph(CH2)2, R2=1-Np(CH3)CH] in 98% yield with
58% ee,10 from which enantioenriched sec-alcohol 4 was
readily obtained by basic hydrolysis as shown in Scheme
2.
9. A typical experimental procedure is as follows. Tetra-
butylammonium hydrogensulfate (8.7 mg, 0.025 mmol)
and potassium fluoride dihydrate (purchased from Kanto
Chemical Co., Ltd., 240 mg, 2.5 mmol) were placed in a
two-neck flask with a stirring bar under argon and dried
in vacuo (0.6 mmHg) for 10 min.11 After being flushed
back with argon, freshly distilled THF (1 mL) was intro-
duced. Then, 3-phenylpropionic acid (1a, 76.6 mg, 0.5
mmol) and benzyl bromide (66.8 mL, 0.55 mmol) were
added sequentially at room temperature. After being
stirred for 3 h at room temperature, the resulting reaction
mixture was poured into water (5 mL) and extracted with
ether (10 mL×2). The combined organic extracts were
Acknowledgements
This work was partially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan.
References
1. (a) Greene P. W.; Wuts, P. G. M. In Protective Groups in
Organic Synthesis; John Wiley & Sons: New York, 1999;

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T. Ooi et al. / Tetrahedron Letters 42 (2001) 9245–9248
the optical rotation of 4 with the value of commercially
washed with brine and dried over Na2SO4. Evaporation
of solvents and purification of the residual oil by column
chromatography on silica gel (hexane/ether=10:1 as elu-
ant) gave pure benzyl ester 2a (120 mg, 99% yield) as a
colorless oil (entry 1 in Table 1).
available (R)-(+)-a-methyl-1-naphthalenemethanol.
11. Attempted esterification of 1a with benzyl bromide using
anhydrous KF gave 2a in only 9% yield, suggesting the
importance of omega phase [KF(nH2O)] for facile anion
exchange. See: Ref. 5.
10. Absolute configuration was determined by comparison of