Chemoselective protection of carboxylic acid as methyl ester: A practical alternative to diazomethane protocol

Full text of DOI:10.1021/jo990035l

8014
J . Org. Chem. 1999, 64, 8014-8017
Sch em e 1
Ch em oselective P r otection of Ca r boxylic
Acid a s Meth yl Ester : A P r a ctica l
Alter n a tive to Dia zom eth a n e P r otocol†
Asit K. Chakraborti,*,‡,§
Anindita Basak (ne´e Nandi),§ and Vikas Grover‡
Department of Medicinal Chemistry, National Institute of
Pharmaceutical Education and Research (NIPER),
Sector 67, S. A. S. Nagar 160 062, India, and Department of
Chemistry, The University of Burdwan,
toxicity and explosive nature of diazomethane) make it
unsuitable for large scale reactions.
Burdwan 713 104, India
Therefore we focused on the strategy of carboxylic acid
activation. Recent developments in the area include the
use of P(OMe)5,6 Me3OBF4-iPr2NEt,1a Me3SOH,7 Li2CO3-
MeI,8 CsF-2-fluoropyridinium salt-MeOH,9 O-methylca-
prolactim at 80 °C for 16 h,10 K2CO3-Ph2S+MeBF4--CuBr
(cat.),11 K2CO3-(18-C-6)-Cl3CO2Me,12 Cs2CO3-(18-C-6)-
MeI,1a,13 CsF-MeI,14 aqueous K2CO3-Bu4NBr-MeI,15 and
Me4NOH at 260 °C.16 These methods have the limitations
of the use of costly reagents and/or harsh reaction
conditions.
Although the reaction of carboxylate anion and Me2-
SO4 should be an attractive method for methyl ester
formation, the strategy has rather been neglected. The
limited number of published procedures2a,17 involve use
of aqueous alkali (leading to side reactions such as
hydrolyses of Me2SO4 and the ester formed), stringent
reaction conditions, and costly reagents (e.g., dicyclo-
hexylethylamine or DBN) as proton acceptors.
We report herein an efficient chemoselective protection
of carboxylic acids under mild conditions that replaces
toxic diazomethane or costly reagents by LiOH‚H2O-Me2-
SO4. This protocol exploits the simultaneous electrophilic
activation of the carboxyl function and nucleophilic
activation of Me2SO4 by virtue of coordination with Li+
(Scheme 1).18 In a typical experimental procedure, the
carboxylic acid was treated with a stoichiometric amount
of LiOH‚H2O in dry THF. After the acid-base reaction
(10-30 min), the resultant Li-carboxylate was reacted
Received J anuary 6, 1999
Functional group protection is an indispensable artifice
employed to prevent or to modify the reaction of a specific
functional group during a synthetic sequence. Develop-
ment of newer methods for protection/deprotection of
functional groups constitutes a topic of constant interest.1
In this context carboxylic acid protection is an important
transformation and is frequently achieved via methyl
ester formation2 because of ease of deprotection.1,3
Methods for conversion of carboxylic acids into esters
can be envisioned in terms of two general schemes: (i)
nucleophilic attack (by an alcohol) on the carboxyl carbon
involving the tetrahedral intermediate4 and (ii) alkylation
of the carboxyl oxygen. In the first, the poor leaving group
property of OH- necessitates the use of an acid catalyst
and thus problems are usually encountered with acid-
sensitive compounds. The reversibility of such an esteri-
fication reaction demands the removal of water and use
of a large excess of alcohol to achieve reasonable yields.
Esterification also is difficult for sterically hindered acids
because of increased steric interaction in the tetrahedral
intermediate. Although activation (for nucleophilic at-
tack) through conversion to an acid halide, anhydride,
mixed anhydride, or thiol ester may circumvent the above
problems, these methods require additional steps and
potentially costly reagents.
Esterification by alkylation of the carboxyl oxygen is
not reversible. Since the tetrahedral intermediate is not
involved, esterification of a sterically hindered acid
should not experience much trouble. However, as car-
boxylic acid groups are, in general, poor nucleophiles, the
second approach requires the use of highly active elec-
trophiles (e.g., diazoalkanes) or the activation of the
carboxylic acid via its anion formation. Methyl esters may
be prepared by treatment of carboxylic acids with diazo-
methane,5 but the safety considerations (because of the
(5) Furniss, B. R.; Hannaford, A. J .; Rogers, V.; Smith, P. W. G.;
Tatchell, A. R. Vogel’s Textbook of Practical Organic Chemistry;
Longman: London, 1996.
(6) Denney, D. B.; Meli, R.; Pendse, A. D. J . Org. Chem. 1978, 43,
4672.
(7) Yamauchi, K.; Tanabe, T.; Kinoshita, M. J . Org. Chem. 1979,
44, 638.
(8) (a) Pfister, J . R.; Wyman, W. E.; Mahoney, J . M.; Waterbury, L.
D. J . Med. Chem. 1980, 23, 1264. (b) Ballini, R.; Carotti, A. Synth.
Commun. 1983, 13, 1197.
(9) Shoda, S.; Mukaiyama, T. Chem. Lett. 1980, 391.
(10) Mohacsi, E. Synth. Commun. 1982, 12, 453.
(11) Badet, B.; J ulia, M.; Ramirez-Munoz, M.; Sarrazin, C. A.
Tetrahedron 1983, 39, 3111.
(12) Renga, J . M.; Wang, P.-C. Synth. Commun. 1984, 14, 77.
(13) Krutius, O.; Eremeev, A. V. Chem. Abstr. 1989, 110, 114583n.
(14) Sato, T.; Otera, J .; Nazaki, H. J . Org. Chem. 1992, 57, 2166.
(15) Puntambekar, H. M.; Naik, D. G.; Kapadi, A. H. Indian J .
Chem., Sect. B 1993, 32B, 793.
† NIPER communication no. 17.
‡ NIPER.
§ The University of Burdwan.
(1) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; J ohn Wiley: New York, 1991; 2nd ed. (b) Kocieneski, P. J .
Protecting Groups; Thieme: Stuttgart, 1994.
(2) (a) Sutherland I. O. Comprehensive Organic Chemistry; Barton,
D. H. R., Ollis, W. D., Eds.; Pergamon Press: Oxford, 1979; Vol 2, p
871. (b) Haslam, E. Tetrahedron 1980, 36, 2409. (c) Ladduwahettu, T.
Contemp. Org. Synth. 1997, 4, 326.
(3) (a) Nayak, M. K.; Chakraborti, A. K. Chem. Lett. 1998, 297. (b)
Mascaretti, O. A.; Furlane, R. L. E. Aldrichimica Acta 1997, 30, 55.
(c) Salomon, C. J .; Mata, E. G.; Mascaretti, O. A. Tetrahedron 1993,
49, 3691. (d) McMurry, J . E. Org. React. 1976, 24, 187. (e) Muller, P.;
Siegfried, B. Helv. Chim. Acta. 1974, 57, 987.
(16) Uchama, S.; Nakano, R.; Machida, H. Chem. Abstr. 1995, 123,
9171x.
(17) (a) Bhatia, V. G.; Shaikh, A. S.; Tongare, D. B.; Balasubra-
maniyan, V. Indian J . Chem., Sect. B 1982, 21B, 259. (b) Rao, A. V.
R.; Deshmukh, M. N.; Sivadasan, L. Chem. Ind. (London) 1981, 164.
(c) J amieson, N. C.; Loncrini, D. F. Chem. Ind. (London) 1979, 522.
(18) (a) Ho, G.-J .; Mathre, D. J . J . Org. Chem. 1995, 60, 2271. (b)
Hoobler, M. A.; Bergbreiter, D. E.; Newcomb, M. J . Am. Chem. Soc.
1978, 100, 8182. (c) Meyers, A. I.; Snyder, E. S.; Ackerman, J . J . H. J .
Am. Chem. Soc. 1978, 100, 8186.
(4) March, J . Advanced Organic Chemistry; Wiley Eastern Lim-
ited: New Delhi, 1992.
10.1021/jo990035l CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/23/1999

Notes
J . Org. Chem., Vol. 64, No. 21, 1999 8015
Ta ble 1. Ch em oselectivity of Ca r boxylic Acid P r otection
a s Meth yl Ester s
F igu r e 1.
Ta ble 2. Effect of Ba se on th e P r otection of Ben zoic
Acid a s Meth yl Ester
entry
base
yield (%)a,b
1
2
3
4
5
6
7
8
9
LiOH‚H2O
96
77
30
64
73
25
50
88
48
72
51
50
LiOH
NaOH
KOH
CsOH
Li2CO3
Li2CO3 + 1 equiv H2O
Li2CO3 + 2 equiv H2O
Na2CO3
K2CO3
Cs2CO3
10
11
12
NaOH + 1 equiv LiBr
a
b
Isolated yields. Reactions were carried out in THF under
reflux for 3 h.
protected as the methyl ester without affecting the BOC
functionality or the optical purity of the molecules
(wherever applicable).24 Conventionally N-protected amino
acids are esterified via a mixed anhydride1a or a urethane
N-protected carboxyanhydride25 process. Also, the reac-
tion may be carried out at room temperature. For
example, treatment of the amino acids 1 and 5 afforded
the corresponding methyl esters in 75% and 80% yields,
respectively. Limited examples (entries 1, 4, 8, 12, 13,
16, 17, 21, and 23) demonstrate that both of the methyl
groups of Me2SO4 may be made available for esterifica-
tion, thus representing examples of atom economy.26
The mild basicity of LiOH‚H2O coupled with the
covalent nature of the O-Li bond make chemoselective
ester formation for substrates bearing a phenolic OH
group feasible despite the poor nucleophilic property of
a carboxylate anion. The important role of the Li+
counterion was due to its coordinating capability to bring
the incoming Me group close to the carboxylate anion in
the proposed transition state (TS I) and is confirmed by
the observed poor yields when using other alkali metal
hydroxides and carbonates in place of LiOH‚H2O (Table
2). This is further demonstrated by the increase in
product yield with NaOH in the presence of LiBr (com-
pare entries 3 and 12). The water molecule associated
with the base appears to exhibit an effect,27 since the use
of Li2CO3 under similar conditions does not lead to
a
b
Isolated yields. Figures in parentheses are corresponding
yields using 0.5 equiv of DMS.
with Me2SO4 (0.5-1 equiv) under reflux (0.5-3 h). The
THF was distilled off, and the residue was diluted with
saturated aqueous NaHCO3 and extracted with Et2O. In
most of the cases, the reaction afforded a clean product
requiring no further purification. Wherever necessary,
purification was carried out via crystallization (for solid
esters) in Et2O-hexane or chromatography on neutral
alumina (5% EtOAc-hexane as eluent). Excellent chemo-
selectivity has been observed (Table 1) for substrates
bearing the phenolic hydroxyls19 (entries 5, 11, 12, and
26) or the amine (entry 7) functionalities.20 Similarly, the
amide function (entries 22-26) does not experience any
competitive N-21 or O-22 methylation.23 BOC-protected
amino acids 1-5 (Figure 1) (entries 22-26) are efficiently
(19) Basak, A.; Nayak, M. K.; Chakraborti, A. K. Tetrahedron Lett.
1998, 39, 4883.
(20) The 1H NMR spectrum of the crude product corresponding to
entry 7 showed the formation of N-methylated (10%) and N-,O-
dimethylated (5%) products. The 1H NMR and GC-MS spectra of the
crude products corresponding to entries 5, 11, 12, and 26 did not show
any methylation of the phenolic hydroxyl group.
(24) The methyl esters of optically pure acids 1, 4, and 5 were
obtained in >98% ee as determined by the 1H NMR spectra in the
presence of Eu(hfc)2.
(25) Chevallet, P.; Fehrentz, J .-A.; Kiec-Kononowicz, K.; Devin, C.;
Castel, J .; Loffet, A.; Martinez, J . Lett. Pept. Sci. 1996, 2, 297.
(26) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1995, 34, 259.
(27) Shinkai, S.; Fukunaga, T.; Manabe, O.; Kunitake, T. J . Org.
Chem. 1979, 44, 4990.
(21) (a) Bisarya, S. C.; Rao, R. Synth. Commun. 1992, 22, 3305. (b)
Sukata, K. Bull. Chem. Soc. J pn. 1985, 58, 838. (c) J ohnstone, R. A.
W.; Rose, M. E. Tetrahedron 1979, 35, 2169.
(22) J ulia, M.; Mestdach, H. Tetrahedron 1983, 39, 433.
(23) The methyl ester of the corresponding unprotected amino acids
could not be made with this protocol as the amino acids are insoluble
in THF.

8016 J . Org. Chem., Vol. 64, No. 21, 1999
Notes
Sch em e 2
Ta ble 3. Effect of Solven t on th e P r otection of Ben zoic
Acid a s Meth yl Ester
4.47). A 1:3 selectivity during the competition between
benzoic acid and phenylacetic acid (pKa 4.28) indicated
that when the carboxylic acids have comparable acid
strength the more nucleophilic carboxylate anion is
preferentially alkylated. In analogous competitions be-
tween benzoic acid vs 2-thiophenecarboxylic acid (pKa
3.53) and 1-naphthoic acid (pKa 3.70) vs 2-hydroxy-1-
naphthoic acid (pKa 3.2),28b esterification occurred with
selectivities of 1:2 and 1:4, respectively.
entry
solvent
yield (%)a,b
1
2
3
4
5
6
7
DMF
62
55
71
66
56
50
96
acetone
MeCN
DME
dioxane
THP
THF
In conclusion, the present procedure provides an ef-
ficient method for the methyl ester protection of carboxy-
lic acids. The notable advantages of this method are (a)
the mild reaction conditions, (b) the use of cheaper and
nontoxic reagent, (c) the general applicability, (d) the
selectivity (tolerance of several sensitive functionalities
during esterification), and (e) the high yields.
a
Isolated yields. b All reactions were carried out using LiOH‚H2O
under reflux for 3 h except for entry 1 wherein the reaction was
performed at 80 °C.
significant ester formation. This “specific solvation” effect
was confirmed by the fact that reactions carried out by
addition of 2 equiv of water to the Li-carboxylates,
generated from Li2CO3 and the carboxylic acid, afforded
excellent yields (entry 8, Table 2). Use of other solvents
such as DMF, acetone, MeCN, DME, THP and dioxane
in place of THF was proved to be ineffective for the
esterification (Table 3).
The selectivity of the method was further tested by
using mixtures of carboxylic acids having different pKa
values28a (Scheme 2), and as expected, the stronger
carboxylic acid was preferentially esterified. Thus, when
an equimolar mixture of benzoic acid (pKa 4.19) and
4-nitrobenzoic acid (pKa 3.41) was subjected to esterifi-
cation, the methyl ester formation of only the latter was
observed, whereas a 3:2 selectivity was observed for the
mixture of benzoic acid and 4-methoxybenzoic acid (pKa
Exp er im en ta l Section
Gen er a l. The carboxylic acids are available commercially.
THF was distilled prior to each use adopting the Na-benzophe-
none protocol under argon. Commercially available Me2SO4 was
made acid-free following standard procedure.5
The NMR and IR spectra of the following esters were in
complete agreement with those of the authentic samples: methyl
benzoate, methyl 4-chlorobenzoate, methyl 2-chlorobenzoate,
methyl 4-nitrobenzoate, methyl 4-hydroxybenzoate, methyl
4-methoxybenzoate, methyl 4-aminobenzoate, methyl 2-naph-
thoate, methyl phenylacetate, methyl phenoxyacetate, methyl
trans-cinnamate, N-(tert-butoxycarbonyl)glycine methyl ester,
N-(tert-butoxycarbonyl)-L-phenylalanine methyl ester, N(tert-
butoxycarbonyl)-L-tyrosine methyl ester (Aldrich), methyl thio-
phene-2-carboxylate (Lancaster), and methyl 2,4,6-trimethyl-
benzoate.29 Methyl 1-naphthoate, methyl 1-hydroxy-2-naphthoate,
methyl 2-hydroxy-1-naphthoate, methyl dihydrocinnamate, meth-
yl thiophenoxyacetate, methyl trans-4-methoxycinnamate, meth-
(28) (a) Weast, R. C. Handbook of Chemistry and Physics; CRC:
Cleveland, 1987-88; 68th ed.; (b) Gladilovich, D. B.; Grigor’ev, N. N.;
Stolyarov, K. P. Chem. Abstr. 1977, 88, 66457c.

Notes
J . Org. Chem., Vol. 64, No. 21, 1999 8017
p r olin e m eth yl ester : IR (neat) 1743, 1689 cm-1 1H NMR
(CDCl3) δ 1.34 (s, 9 H), 1.82-1.92 (m, 3 H), 2.10-2.15 (m, 1 H),
3.38-3.49 (m, 2 H), 3.65 (s, 3 H), 4.17-4.21 (m, 1 H). N-(ter t-
Bu toxyca r bon yl)-R-m eth yla la n in e m eth yl ester : IR (neat)
1740, 1715 cm-1; 1H NMR (CDCl3) δ 1.36 (s, 3 H), 1.42 (s, 6 H),
3.66 (s, 3 H).
yl 2-cyclopentene-1-acetate, methyl 1-adamantanecarboxylate,
N-(tert-butoxycarbonyl)-L-proline methyl ester, and N-(tert-bu-
toxycarbonyl)-R-methylalanine methyl ester were obtained from
the corresponding carboxylic acids following standard proce-
dure.5 Physical data of these methyl esters are given below.
;
P h ysica l Da ta . Meth yl 1-n a p h th oa te: IR (neat) 1716 cm-1
;
1H NMR (CDCl3) δ 3.92 (s, 3 H), 7.39-7.54 (m, 3 H), 7.8 (d, J )
7.78 Hz, 1 H), 7.93 (d, J ) 8.22 Hz, 1 H), 8.10 (d, J ) 7.28 Hz,
1 H), 8.82 (d, J ) 8.43 Hz, 1 H); EIMS (m/z) 186 (M+), 155 (100).
Gen er a l P r oced u r e for Ester ifica tion . Rep r esen ta tive
P r oced u r e. 2-Hydroxy-1-naphthoic acid (470.5 mg, 2.5 mmol)
in dry THF (2.5 mL) was treated with LiOH‚H2O (104.9 mg, 2.5
mmol) at room temperature for 30 min followed by Me2SO4 (0.12
mL, 1.25 mmol), and the mixture was heated under reflux for 3
h. Solvent was distilled off, and the mixture was diluted with
saturated aqueous NaHCO3 and extracted with Et2O to afford
the ester (white solid, 404.3 mg, 80%), which was in full
agreement with spectral data (IR, 1H and 13C NMR, and CIMS)
of an authentic sample. The yield could be improved to 96% by
using 2.5 mmol of Me2SO4. This procedure was followed for
esterification of all of the substrates included in Table 1. All
products are known compounds and are easily identified by their
spectral data.
Selective Ester ifica tion in In ter m olecu la r Com p etition .
1-Naphthoic acid (430.45 mg, 2.5 mmol) and 2-hydroxy-1-
naphthoic acid (470.5 mg, 2.5 mmol) in dry THF (5 mL) were
treated with LiOH‚H2O (104.9 mg, 2.5 mmol) at room temper-
ature for 30 min followed by Me2SO4 (0.24 mL, 2.5 mmol), and
the mixture was heated under reflux for 3 h. Solvent was
distilled off, and the mixture was diluted with saturated aqueous
NaHCO3 and extracted with Et2O to afford the ester (425 mg,
85% with respect to 2-hydroxy-1-naphthoic acid). The 1H NMR
spectrum revealed two OMe singlets at δ 3.92 and 4.11 in a ratio
of 19:81, corresponding to methyl 1-naphthoate and methyl
2-hydroxy-1-naphthoate. Other competitive experiments (Scheme
2) were performed in a similar way, and in each case the
selectivity was determined through relative proton integration
of the ester OMe signals in the 1H NMR.
Meth yl 1-h yd r oxy-2-n a p h th oa te: IR (KBr) 1660 cm-1 1H
;
NMR (CDCl3) δ 3.90 (s, 3 H), 7.18 (d, J ) 8.96 Hz, 1 H), 7.40-
7.53 (m, 2 H), 7.66 (d, J ) 8.67 Hz, 2 H), 8.32 (d, J ) 8.26 Hz,
1 H), 11.90 (s, 1 H); 13C NMR (CDCl3) δ 161.63, 137.90, 130.08,
128.14, 126.45, 125.47, 124.92, 124.58, 119.29, 52.98; EIMS (m/
z) 202 (M+), 170 (100). Meth yl 2-h yd r oxy-1-n a p h th oa te: IR
(KBr) 1649 cm-1; H NMR (CDCl3) δ 4.04 (s, 3 H), 7.09 (d, J )
1
9.02 Hz, 1 H), 7.31 (t, J ) 7.9 Hz, 1 H), 7.47 (t, J ) 8.81 Hz, 1
H), 7.68 (d, J ) 7.97 Hz, 1 H), 7.83 (d, J ) 9.02 Hz, 1 H), 8.66
(d, J ) 8.81 Hz, 1 H), 12.19 (s, 1 H); 13C NMR (CDCl3) δ 172.85,
164.38, 136.91, 129.10, 128.47, 125.29, 123.66, 119.29, 52.43;
EIMS (m/z) 202 (M+), 170 (100). Meth yl d ih yd r ocin n a m a te:
IR (neat) 1735 cm-1; H NMR (CDCl3) δ 2.55 (t, J ) 7.56 Hz, 2
1
H), 2.87 (t, J ) 7.56 Hz, 2 H), 3.58 (s, 3 H), 7.10-7.23 (m, 5 H).
Meth yl th iop h en oxya ceta te: IR (neat) 1729 cm-1 1H NMR
;
(CDCl3) δ 3.63 (s, 2 H), 3.68 (s, 3 H), 7.24-7.43 (m, 5 H). Meth yl
tr a n s-4-m et h oxycin n a m a t e: IR (neat) 1716 cm-1 1H NMR
;
(CDCl3) δ 3.72 (s, 3 H), 3.76 (s, 3 H), 6.23 (d, J ) 15.94 Hz, 1 H),
6.83 (d, J ) 6.8 Hz, 2 H), 7.40 (d, J ) 6.8 Hz, 2 H), 7.57 (d, J )
15.94 Hz, 1 H). Meth yl 2-cyclop en ten e-1-a ceta te: IR (neat)
1694 cm-1 1H NMR (CDCl3) δ 1.34-1.44 (m, 2 H), 2.00-2.08
;
(m, 2H), 2.18-2.35 (m, 5 H), 3.60 (s, 3 H), 5.59 (m, 1 H), 5.69
(m, 1 H). Meth yl 1-a d a m a n ta n eca r boxyla te: IR (neat) 1735
cm-1 1H NMR (CDCl3) δ 1.64 (brs, 6 H), 1.81-1.85 (m, 6 H),
;
1.94 (brs, 3 H), 3.57 (s, 3 H). N-(ter t-Bu t oxyca r b on yl)-L-
(29) Grundy, J .; J ames, B. G.; Pattenden G. Tetrahedron Lett. 1972,
757.
J O990035L