Benzylation of alcohols by using bis[acetylacetonato]copper as catalyst

Article abstract of DOI:10.1016/j.tetlet.2003.09.106

Selective O-benzylation of primary hydroxy compounds has been achieved in the presence of bis[acetylacetonato]copper with benzyl chloride. We showed that bis[acetylacetonato]copper was very efficient in promoting the benzylation of primary aliphatic alcohols versus secondary aliphatic alcohols and phenolic hydroxy groups selectively.

Full text of DOI:10.1016/j.tetlet.2003.09.106

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8483–8485
Benzylation of alcohols by using bis[acetylacetonato]copper as
catalyst
Okan Sirkecioglu,* Bekir Karliga and Naciye Talinli
Istanbul Technical University, Faculty of Science and Letters, Chemistry Department, Maslak 34469 Istanbul, Turkey
Received 16 June 2003; revised 3 September 2003; accepted 12 September 2003
Abstract—Selective O-benzylation of primary hydroxy compounds has been achieved in the presence of bis[acetylacetonato]copper
with benzyl chloride. We showed that bis[acetylacetonato]copper was very efficient in promoting the benzylation of primary
aliphatic alcohols versus secondary aliphatic alcohols and phenolic hydroxy groups selectively.
© 2003 Elsevier Ltd. All rights reserved.
There have been many reports on the formation of the
ether linkage, but only a few are known from hydroxy
compounds and halides.1 Numerous methods are avail-
able for protecting an alcohol moiety. Conversion into
corresponding ethers has been recognized as a common
and useful method for the protection of hydroxyl
groups. Most commonly used by protecting groups are
the tetrahydropyranyl (THP), t-butyldimethylsilyl
(TBDMS) and benzyl (Bn) groups. Benzyl ethers are
widely utilized as alcohol protecting groups. They are
easily installed but with poor selectivity between pri-
mary and secondary alcohol groups,2 e.g. in carbohy-
drates, are stable to a wide range of reagents and
readily removed in the presence of many common
functionalities via catalytic hydrogenolysis, dissolving
metals or Lewis/Bro¨nsted acids.3 On the other hand,
selectivity of reaction pathways is extremely important
in organic reactions such as etherification.4,5
We report here an effective, inexpensive and selective
benzylation reaction of hydroxyl groups using
Scheme 1.
Table 1. Benzylation of various alcohols using Cu(acac)2
Entry
Alcohol (R%-OH)
Reaction time (h)
Yielda (%)
Yieldb (%)
1
2
3
4
5
6
7
8
n-Octyl alcohol
Cyclohexanol
Cholesterol
3
3
4
5
3
4
5
5
3
2
4
5
92
90
85
60
94
85
12
10
10
8
Benzyl alcohol
4-Hydroxybenzyl alcohol
4-Methoxybenzyl alcohol
3-Butyn-2-ol
Iso-propyl alcohol
Ethylene glycol
Propylene glycol
Glycerol
15
10
c
c
–
–
–
–
c
c
9
90
70
70
65
10
8
8
10
11
12
2-Ethyl-1,3-hexane diol
10
a Reaction performed without solvent.
b Reaction performed in THF.
c No benzylic ether derivative formed.
Keywords: selective etherification; benzylic ether; bis[acetylacetonato]copper.
* Corresponding author. E-mail: sirkeci@itu.edu.tr
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.106

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O. Sirkecioglu et al. / Tetrahedron Letters 44 (2003) 8483–8485
bis[acetylacetonato]copper which was found to be an
efficient and cheaper catalyst than the nickel complex.6
Benzyl alcohol, 4-(hydroxymethyl)phenol, ethylene gly-
col, propylene glycol, glycerol, 2-ethylhexane-1,3-diol,
cholesterol, 4-(hydroxymethyl)anisole, n-octyl alcohol,
iso-propyl alcohol, 3-butyn-2-ol and cyclohexanol
reacted with benzyl chloride. When a mixture of the
alcohol and the halide are heated under reflux in the
presence of catalytic amount of the copper complex,
evolution of hydrogen halide occurred immediately and
a high yield of the corresponding ether was obtained.
This reaction can be conducted in an open vessel; the
materials and catalyst can be used as obtained from
commercial sources without any purification. The high
yields of the products and simple reaction procedure
make this method attractive for the syntheses of benz-
ylic ethers. The reaction is described in Scheme 1 and
representative results are summarized in Tables 1 and 2.
The data reported in Tables 1 and 2 lead to the
following remarks:
(i) Most of the alcohols studied here were converted
into their corresponding benzylic ethers in good
yields using a catalyst cheaper than those reported in
the literature.1,2,6
(ii) Etherification was completed within 2–5 h.7,8
(iii) In the presence of our catalyst system, phenolic
hydroxy groups did not give the corresponding ben-
zylic ethers.
(iv) When cyclic secondary alcohols such as cyclo-
hexanol and cholesterol were reacted with benzyl
chloride the expected benzylic ethers were formed.
7,8
Table 2. Selective benzylation using Cu(acac)2

O. Sirkecioglu et al. / Tetrahedron Letters 44 (2003) 8483–8485
8485
However, iso-propyl alcohol and 3-butyn-2-ol did not
yield corresponding ethers as in the case of cyclic
alcohols. This result can be attributed to the low boil-
ing point of the alcohols used, since, the reaction yields
decreased when benzylations reactions were performed
using THF as solvent,9 as seen in Table 1.
4. Boyer, B.; Keramane, J. L.; Roque, J. P.; Pavia, A. A.
Tetrahedron Lett. 2000, 41, 2891–2894.
5. (a) Keramane, E. M.; Boyer, B.; Roque, J. P. Tetrahedron
2001, 57, 1917–1921; (b) Falck, J. R.; Barma, D. K.;
Venkataraman, S. K.; Baati, R.; Mioskowski, C. Tetra-
hedron Lett. 2002, 43, 963–966.
(v) Benzylic ethers on primary alcohol groups were
selectively formed from di or tri hydroxy alcohols. It is
noteworthy that, when the benzylation reactions were
carried out with an excess of benzyl chloride, the same
ether products which were synthesized before were iso-
lated.
(vi) Benzylation of cholesterol was carried out in
PhCH2Cl as reactant and solvent on a large scale. The
driving force for this reaction was the higher boiling
point of benzyl chloride which was higher than the
melting point of cholesterol. A similar result has been
reported by Yamashita6 using a nickel catalyst.
6. Yamashita, M.; Takegami, Y. Synth. Commun. 1977, 803.
7. Preparation of benzyl ethers with bis[acetylaceto-
nato]copper. General procedure:
Method 1: Benzyl chloride (1 mmol), alcohol (1 mmol) and
bis[acetylacetonato]copper (0.025 mmol) were heated under
reflux for 2–5 h. The reaction mixture was cooled then
passed through a short column of neutral aluminum oxide
to remove the catalyst. The crude product was distilled
under vacuum to give the benzyl ether in high yield.
8. Selective benzylation: Method 2: Excess benzyl chloride,
alcohol (1 mmol) and bis[acetylacetonato]copper (0.075
mmol) were heated under reflux for 2–5 h. The reaction
mixture was cooled then passed through a short column of
neutral aluminum oxide to remove the catalyst. The crude
product was distilled under vacuum to give the benzyl ether
in high yield.
References
1. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 2nd ed.; John Wiley & Sons: New York,
1991; (b) Schelhaas, M.; Waldmann, H. Angew. Chem., Int.
Ed. Engl. 1996, 35, 2056–2083.
2. (a) Madsen, J.; Viuf, C.; Bols, M. Chem. Eur. J. 2000, 6,
1140–1146; (b) Hori, H.; Nishida, Y.; Ohrui, H.; Meguro,
H. J. Org. Chem. 1989, 54, 1346–1353.
3. Kocienski, P. J. In Protective Groups; Enders, D.; Noyori,
R.; Trost, B. M., Eds.; Georg Thieme Verlag: New York,
1994.
9. Preparation of benzyl ethers with bis[acetylaceto-
nato]copper in THF. General procedure:
Method 3: A solution of benzyl chloride (1 mmol), alcohol
(1 mmol) and bis[acetylacetonato]copper (0.025 mmol) in
dry THF (30 ml) was heated under reflux for 2–10 h. The
reaction mixture was cooled then passed through a short
column of neutral aluminum oxide to remove the catalyst.
The crude product was distilled under vacuum and to give
the benzyl ether in high yield.