Tetrahedron Letters
2
d 0.5 equiv of p-TsOH was employed.
e Isolated as a 5:1 mixture with deprotected ketone (1H NMR).
f Diacetylated product was also isolated in 30% yield after column chromatography.
When, the crude reaction mixture was poured in 10%
aqueous sodium hydrogen carbonate, extracted with ethyl
acetate and dried over sodium sulfate, pure acetyl ester 2a
was obtained in 98% yield after column chromatography on
silica gel. Replacing p-TsOH with milder acids, such as
acetic and cictric acid, there was no conversion of the
starting material. We also found that this protocol can be
successfully applied to a variety of differently substituted
alcohols11 and the results obtained are collected in Table 2.
Thus, the preparation of ester 2a and the data reported in
Table 2 clearly demonstrate that the acetylation of primary
alcohols 1a-h proceed smoothly in dichloromethane or
acetonitrile to afford the corresponding acetyl esters 2a-h in
good to excellent yields at room reaction temperature. For
alcohols 1c and 1f a gentle reflux was necessary to promote
the reaction. It is noteworthy that the mild experimental
conditions employed are compatible with different
functional groups such as double bound, alogen, ether, tert-
butoxycarbonyl and acetonide groups. Interestingly, the
reaction works well also with substrates possessing acid
labile groups (compound 1c and 1d). In the case of
compound 1c a non-catalytic amount of p-TsOH (0.5
equiv) was added to advance the reaction. The acetylation
of alcohol 1f gave an inseparable 5:1 mixture of the
protected ketone 2f together with deprotected acetoxy
ketone. In this case partial hydrolysis of the ketal group
occurred. The phenolic compound 1g containing also an
alcoholic hydroxyl group (Table 2, entry 6) reacted with
IPA to give the protected alcoholic hydroxyl group
derivative 2g in good yield together with some diprotected
product, thus showing that hydroxyl group of phenol is less
reactive than that of the alcohol. This fact was confirmed
by the long reaction time (36 h) required to acetylate the
phenolic compound 1h (Table 2, entry 7). The scope of the
present investigation was extended to the protection of
some representative secondary and tertiary alcohols as 1i-k
and 2l-m respectively. Functionalized secondary and
tertiary alcohols also gave the corresponding acetyl ester
derivatives in excellent yields. The various functionalities
present in the secondary and tertiary alcohols (e.g. tert-
butyl(diphenyl)silyl, carbethoxy and carbon-carbon triple
bond) were compatible with the mild reaction conditions
employed. Thus, the hydroxyl groups of silyl ether 1j and
β-hydroxy ester 1k were successfully protected as acetyl
derivatives (Table 2, entries 9 and 10) and no dehydration
products were observed. It should be noted that tertiary
alcohol 1l and O-benzyl ethinylestradiol (1m), which might
be subjected to dehydration or rearrangement reactions,
gave the corresponding acetyl derivatives 2l and 2m in high
yields. In the case of tertiary alcohol 1l, a gentle reflux was
necessary to promote the reaction.
acetylating reagent. However, the use of IPA significantly
increases the range of acetylation substrates, making it
highly effective even on alcohols containing acid labile
functional groups and under metal-free and mild reaction
conditions.
Acknowledgements
Financial support from University of Perugia, Fondo per il
Sostegno della Ricerca di Base 2015, project “Metodologie
Sintetiche Innovative a Basso Impatto Ambientale” and
Fondazione Cassa Risparmio Perugia, FCR 2015.0381.01
is gratefully acknowledged.
References and notes
1. Wuts, P. G. M.; Green, T. W. Protective Groups in Organic
Chemistry; 4th Ed.; John Wiley & Sons; New York, 2007.
2. (a) Tomohumi, S.; Kousaburo, O.; Takeshi, O. Synthesis,
1999, 1141-1144. (b) Steglich, W.; Hofle, G. Angew. Chem.
Int. Ed. 1969, 8, 981. (c) Vedejs, E.; Diver, S. T. J. Am.
Chem. Soc. 1993, 115, 3358-3359.
3. (a) Zareyee, D.; Ghadikolaee, A. R.; Khalilzadeh, M. A. Can.
J. Chem., 2012, 90, 464-468. (b) Ishihara, K.; Kubota, M.;
Kurihara, H.; Yamamoto. H. J. Am. Chem. Soc., 1995, 117,
4413–4414. (c) Saravanan, P.; Singh, V. K. Tetrahedron Lett.
1999, 40, 2611-2614. (d) Baker, R. H.; Bordwell, F. G. Org.
Synth. 1955, 3, 141-145. (e) Iqbal, J.; Srivastava, R. R. J.
Org. Chem. 1992, 57, 2001-2007.
4. (a) Hagemeyer, H. J.; Hull, D. C. Ind. Eng. Chem., 1949, 41,
2920-2924. (b) Sarel, S.; Newman, M. S. J. Am. Chem. Soc.
1956, 78, 5416-5420. (c) Smith, W. B.; Chen, T-K. J. Org.
Chem. 1965, 30, 3095-3099. (d) Alarcon, P.; Pardo, M.; Soto,
J. L. J. Heterocyclic Chem. 1985, 273. (e) Tibor, G.; Kalman,
H. Synth. Commun. 1990, 20, 2365-2371.
5. (a) Ishii, Y.; Takeno, M.; Kawasaki, Y.; Muromachi, A.;
Nishiyama, Y.; Sakaguchi, S. J. Org. Chem. 1996, 61, 3088-
3092. (b) Orita, A.; Sakamoto, K.; hamada, Y.; Mitsutome,
A.; Otera, J. Tetrahedron 1999, 55, 2899-2910. (c) Lin, M.-
H. ; RajanBabu, T. V. Org. Lett. 2000, 2, 997-1000. (d)
Shirae, Y.; Mino, T.; Hasegawa, T.; Sakamoto, M.; Fujita, T.
Tetrahedron Lett. 2005, 46, 5877-5879. (e) Sugahara, K. ;
Satake, N. ; Kamata, K. ; Nakajima, T. ; Mizuno, N. Angew.
Chem. Int. Ed. 2014, 53, 13248-13252.
6. Ilankumaran, P.; Verkade, J. G. J. Org. Chem. 1999, 64,
9063-9066.
7. (a) Grasa, G. A.; Guveli, T.; Singh, R.; Nolan, S. P. J. Org.
Chem. 2003, 68, 2812-2819. (b) Zeng, T.; Song, G.; Li, C-J.
Chem. Commun., 2009, 6249-6251. (c) Chiarotto, I.; Feroci,
M.; Sotgiu, G.; Inesi, A.; Eur. J. Org. Chem. 2013 , 326-331.
8. Chiarotto, I. Synth. Commun. 2016, 46, 1840-1847.
9. (a) Bosco, J. W. J.; Agrahari, A.; Saikia, A. K. Tetrahedron
Lett. 2006, 47, 4065-4068. (b) Ahmed, N.; van Lier, J. E.
Tetrahedron Lett. 2006, 47, 5345-5349.
10. (a) Curini, M.; Epifano, F.; Marcotullio, M. C. ; Rosati, O.
Synt. Commun., 2000, 30, 1319-1329. (b) Temperini A.;
Terlizzi, R. ; Testaferri L.; Tiecco M. Synlett, 2009, 2429-
2432. (c) Temperini A.; Terlizzi, R. ; Testaferri L.; Tiecco M.
Synth. Commun. 2010, 40, 295-302). (d) Temperini A.;
Annesi, D.; Testaferri L.; Tiecco M. Tetrahedron Lett. 2010,
In conclusion, we have shown that an almost forgotten
system for acetylation such as IPA and p-TsOH is able to
acetylate various alcohols under mild conditions. The
results confirm that IPA can be considered as a valid
alternative to acetic anhydride or acetyl chloride as