reactionspyridone 7, Et3N‚HOTf, and BnEt3N+ TfO-sare
water soluble and are not observed after aqueous workup. As
benzyl esters are among the most useful masking agents for
carboxylic acids, especially amino acids, this convenient
protocol will be useful for a wide range of chemical endeavors.
SCHEME 1. Proposed Mechanism for the Chemoselective
Benzylation of Carboxylic Acids
Experimental Section
Synthesis of Benzyl Esters. A mixture of pyridinium triflate 1
(26 equiv), NEt3 (2 equiv), and carboxylic acid 3 (1 equiv) in
solvent7 (R,R,R-trifluorotoluene (PhCF3), trichloroethylene (TCE),
or dimethylformamide (DMF); 2 mL/mmol) was heated at 83 °C
for 1 day. The resulting mixture was cooled to room temperature
and then partitioned between water and ethyl acetate. The organic
phase was washed with water and brine, dried (MgSO4), filtered,
concentrated under a vacuum, and purified on silica gel to yield
benzyl ester 4.
Benzoic Acid Benzyl Ester (4a) using 1.3 equiv of 1. A mixture
of pyridinium triflate 1 (149 mg, 0.43 mmol, 1.3 equiv), TCE (660
µL), NEt3 (60 µL, 0.43 mmol, 1.3 equiv), and benzoic acid (3a)
(40 mg, 0.33 mmol) was heated at 83 °C for 1 day. The reaction
mixture was cooled to room temperature, diluted with H2O (5 mL),
and extracted with EtOAc (2 × 10 mL). The combined organic
phase was washed with H2O (10 mL) and brine (10 mL), dried
over MgSO4, filtered, and concentrated under a vacuum. The residue
was purified by flash chromatography on silica gel (elution with
2:3 EtOAc/hexane) to give 4a (65 mg, 93%) as a colorless oil. 1H
NMR (300 MHz, CDCl3) δ 8.11-8.08 (m, 2H), 7.60-7.55 (m,
1H), 7.47-7.33 (m, 7H), 5.38 (s, 2H).17
2-tert-Butoxycarbonylamino-3-hydroxy-propionic Acid Ben-
zyl Ester (4n). A mixture of pyridinium triflate (1) (150 mg, 0.43
mmol), PhCF3 (460 µL), NEt3 (65 µL, 0.46 mmol), and N-Boc-
serine (3n) (48 mg, 0.23 mmol) was heated at 83 °C for 1 day.
Isolation and purification as above provided 4n (61 mg, 91%) as a
colorless oil: 1H NMR (300 MHz, CDCl3) δ 7.35 (s, 5H), 5.47 (d,
1H, J ) 6.8 Hz), 5.21 (s, 2H), 4.42 (bs, 1H), 3.98-3.88 (m, 2H),
2.34 (t, 1H, J ) 5.9 Hz), 2.04 (s, 9H); 13C NMR (75 MHz, CDCl3)
δ 171.0, 156.0, 135.5, 128.8, 128.6, 128.4, 80.5, 67.6, 56.1, 28.3;
IR (neat) 3371, 2977, 1716, 1506, 1455, 1068, 697 cm-1; HRMS
(ESI+) calcd for C15H21NO5Na 318.1317, found 318.1301.
isoureas13 for the synthesis of benzyl esters, among which BTCA
is commercially available and the most widely used. The major
advantage of benzyloxypyridinium salt 1 over other imidate-
type reagents is that 1 is pre-activated, whereas isoureas and
imidates require activation from acidic protons.14 2-Benzyloxy-
1-methylpyridinium triflate thus offers an immediate benefit for
the benzylation of any acid-sensitive substrate. Oxypyridinium
salt 1 is commercially available,15 trivial to prepare,1a and stable
indefinitely to storage.1b
This new protocol is attractive for derivatization of carboxylic
acids, perhaps even as a convenient alternative to diazomethane.
Although 1 was originally intended to address challenges
associated with the synthesis of benzyl ethers, it is at least
equally suitable for generating benzyl esters. As described
above, benzylation of carboxylic acids proceeds in high yield
and in the presence of alcohols, phenols, protected amines,
acetals, and other functionality.
Taking into account previous mechanistic observations on
the benzylation of alcohols,1 including minor side products
attributed to Friedel-Crafts-type benzylation of toluene using
1,1b,16 we propose that esterification reactions proceed as outlined
in Scheme 1. Thermal activation of benzyloxypyridinium salt
1 provides a highly electrophilic species (6) that is quickly
trapped by the carboxylate end of the acid-base complex 3‚
NEt3. Once the supply of complex 3‚NEt3 is exhausted, the
remaining 6 is quenched with excess triethylamine before it (6)
can react with water, alcohols, or other functionality that may
be present.
Acknowledgment. We thank the FSU Department of
Chemistry and Biochemistry and the James and Ester King
Biomedical Research Program (Florida Department of Health)
for generous financial support, the Thailand Research Fund,
RGJ-PhD program, for a fellowship for J.T. (PHD/0239/2547),
Dr. Tom Gedris for assistance with the NMR facilities, Dr.
Umesh Goli for the mass spectrometric analyses, and the Krafft
Lab for use of their FT-IR instrument. We thank Leo Paquette
(Ohio State) for helpful discussions related to other aspects of
this project.
In conclusion, 2-benzyloxy-1-methylpyridinium triflate (1)
reacts chemoselectively with carboxylic acids to provide the
corresponding benzyl esters. The presumed byproducts of the
(13) (a) Nicolaou, K. C.; Yue, E. W.; Naniwa, Y.; De Riccardis, F.;
Nadin, A.; Leresche, J. E.; La Greca, S.; Yang, Z. Angew. Chem., Int. Ed.
Engl. 1994, 33, 2184-2187. (b) Review: Mathias, L. J. Synthesis 1979,
561-576.
(14) Or Lewis acid reagents, which likely give rise to protic acid in situ.
(15) 2-Benzyloxy-1-methylpyridinium triflate [26189-59-3] is licensed,
manufactured, and distributed by Sigma-Aldrich Chemical Co., catalog
#679674. See (a) Dudley, G. B. Compounds and methods of arylmethylation
(benzylation) as protection for alcohol groups. U. S. Patent Appl. 11/399,-
300, 2006. (b) ChemFiles 2007, 7 (3), 3.
Supporting Information Available: Experimental procedures,
characterization data for all new compounds, and copies of 1H NMR
spectra. This material is available free of charge via the Internet at
JO7018625
(16) For Friedel-Crafts benzylation reactions using 1, see: Albiniak,
P. A.; Dudley, G. B. Tetrahedron Lett. 2007, DOI: 10.1016/j.tet-
let.2007.09.116.
(17) For full characterization data, see: Chen, C. T.; Munot, Y. S. J.
Org. Chem. 2005, 70, 8625-8627.
8964 J. Org. Chem., Vol. 72, No. 23, 2007