The Journal of Organic Chemistry
NOTE
studied by 31P NMR,22 showing chemical shifts at 40 ppm, similar to
that observed for our proposed intermediate.
Doctores” contracts. We thank Prof. J. M. Cuerva for his
contribution to this work
The selectivity observed in our reaction could be explained by
the formation of this much hindered intermediate III. Thus,
when III suffers attack by primary alcohols, the corresponding
ester is obtained easily. However, when more hindered alcohols
are used, a bigger steric repulsion appears between the ligands of
the phosphine and the substituents of the alcohols, avoiding the
nucleophilic addition. However, we could not detect the inter-
mediate III using 31P NMR experiments, the signal correspond-
ing to Ph3PO appearing exclusively. This fact can be due to the
high reactivity of the intermediate III, which in the absence of
alcohol can suffer the attack of a second molecule of the acid to
generate an anhydride and Ph3PO.25
In conclusion, a mild, safe, and economic method for the
esterification/amidation of carboxylic acids based on the Garegg-
Samuelsson’s type conditions is described. This method allows the
selective esterification of primary alcohols in the presence of more
hindered hydroxyl groups with complete selectivity, which may be
of interest in the synthesis of polyfunctionalized substrates. The
“in situ” activation of the carboxylic acid makes our method an
excellent alternative to the known esterification procedures, useful
for the synthesis of complex natural products.
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’ EXPERIMENTAL SECTION
General Procedure for the Esterification/Amidation of
Carboxylic Acids with Phosphine/I2/Base. To a solution of I2
(1.5 mmol) in dry CH2Cl2 (20 mL) was added the phosphine (1.5
mmol), giving the solution a brown-yellow color. Then, imidazole (3.3
mmol) was added, changing the color to light yellow. Subsequently, the
carboxylic acid (1 mmol) was added and the solution was stirred for 5
min at room temperature, and then the alcohol or amine (1.5 mmol) was
added. The mixture was stirred until completely consumption of the
starting material (checked by TLC, around 12-24 h). Then, CH2Cl2
was added, and the solution was washed with 2 N HCl and water before
being dried with anhyd Na2SO4 and the solvent removed. The residue
was submitted to flash chromatography (EtOAc/hexane) to give the
corresponding esters/amides. Products 2-12, 14, and 26-40 were
purified by flash chromatography on silica gel (hexane:EtOAc) and
characterized by spectroscopic techniques.26 The yields obtained are
reported in Tables 1-3.
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’ ASSOCIATED CONTENT
S
Supporting Information. General experimental details,
b
synthesis of acids 18, 20-21, 1H NMR and 13C NMR spectra of
all new compounds, and 31P NMR for proposed intermediates.
This material is available free of charge via the Internet at http://
pubs.acs.org.
(13) Tolman, C. A. Chem. Rev. 1977, 77, 313–348.
(14) The esterification of 1 in MeOH, in the presence of highly
acidic conditions (pTsOH, 10% mol) under reflux, yields 90% of ester 2.
(15) In the case of secondary alcohols, amounts of iodination pro-
ducts from the classical Garegg-Samuelsson reaction were observed.
(16) Some amounts of compound 6 were obtained.
(17) When Ph3P was used, a 91% yield of compound 14, together
with 5% yield of esterification product with secondary alcohol, were
obtained.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: rrobles@ugr.es.
(18) Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446,
404–408.
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ꢀ
(19) Alvarez-Manzaneda, E.; Chahboun, R.; Bentaleb, F.; Alvarez,
E.; Escobar, M. A.; Sad-Diki, S.; Cano, M. J.; Messouri, I. Tetrahedron
2007, 63, 11204–11212.
’ ACKNOWLEDGMENT
We thank the Regional Government of Andalucía (project
P09-FQM-4571) for financial support. S.P.M. thanks the Regio-
nal Government of Andalucía for her fellowship. L.A.d.C. and J.J.
thank the University of Granada for their “Reincorporaciꢀon de
(20) See the Supporting Information for more details.
(21) Possible acylimidazole intermediates, similar to those proposed
in ref 10, were ruled out due to secondary alcohols being efficiently
2280
dx.doi.org/10.1021/jo102395c |J. Org. Chem. 2011, 76, 2277–2281