Guaiacol transprotection: Replacement of the phenoxy isopropyl protecting function by acetyl

Article abstract of DOI:10.1016/j.tetlet.2003.11.065

A one-step method for the conversion of isopropyl protected guaiacols to the corresponding acetates is reported. Treating 6-substituted isopropyl protected guaiacols with trimethylsilyl trifluoromethanesulfonate in a mixture of acetic anhydride and acetonitrile affords 6-substituted guaiacol acetates in yields ranging from 35% to 99%.

Full text of DOI:10.1016/j.tetlet.2003.11.065

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 667–669
Guaiacol transprotection: replacement of the phenoxy isopropyl
protecting function by acetyl
Craig M. Williamsa,* and Lewis N. Manderb
aDepartment of Chemistry, School of Molecular and Microbial Sciences, University of Queensland, St. Lucia,
Brisbane 4072, QLD, Australia
bResearch School of Chemistry, Australian National University, Canberra 0200, ACT, Australia
Received 15 October 2003; revised 7 November 2003; accepted 14 November 2003
Abstract—A one-step method for the conversion of isopropyl protected guaiacols to the corresponding acetates is reported. Treating
6-substituted isopropyl protected guaiacols with trimethylsilyl trifluoromethanesulfonate in a mixture of acetic anhydride and
acetonitrile affords 6-substituted guaiacol acetates in yields ranging from 35% to 99%.
ꢀ 2003 Elsevier Ltd. All rights reserved.
Methods to effect transprotection are valued tools in
organic synthesis for the simple fact that they eliminate
two synthetic sequences, deprotection and subsequent
reprotection. Transprotection on alkyl nitrogen (e.g.,
interconversion of carbamates,1 2,4-dinitrobenzene-
sulfonamides to acetates, thioacetates, ureas and thio-
ureas,2 and N-benzoyl to N-dialkylaminomethylene3),
alkyl oxygen (e.g., tetrahydropyran to acetate4 or silyl
ethers,5 silyl ethers to acetates,6;4c;d p-methoxybenzyl
ethers to methoxymethyl ethers,7 benzyl ethers to ace-
tates,8 trityl ethers to esters,9 methoxymethyl ethers to
acetates4f ) and alkyl sulfur (e.g., thiolacetate to disul-
fide,10 enol ethers to thiolacetals11) have been reported.
However, transprotection of non-benzylic aryl ethers,
has, as far as we can determine, yet to be reported.
MeN
MeN
Br
Br
O
O
O
OMe
OMe
OH
O
EtO2C
EtO2C
O
1
2
Scheme 1.
of this methodology, establishing that it provides a
useful extension to the utility of the isopropyl protecting
group for phenols.13 The outcome is disclosed in this
letter.
During the course of investigating numerous mono-,
di- and tri-substituted phenols with single isopropyl
protection, it was determined that for transprotection to
proceed, the substitution pattern seen with the original
discovery must be maintained, that is, the isopropyloxy
group must be flanked by substituents on both ortho-
positions (Table 1). If this substitution pattern is
ignored, for example, as with isopropyl phenyl ether,
then Friedel–Crafts acetylation is the dominant reaction
pathway and in many cases no transprotection products
are observed; 4-isopropoxyacetophenone is formed in
48% yield. Moreover, transprotection proceeds most
efficiently when one substituent is both bulky and elec-
tron withdrawing; cf. entries 3, 5, 8, 11 and 12 (Table 1).
Poor yields, not surprisingly, were obtained when sen-
sitive functional groups such as benzyl alcohols (entry
7), benzaldehydes (entry 6), and terminal acetylenes
Recently, we described an expeditious synthesis of an
advanced intermediate for C-20 diterpene alkaloid syn-
thesis.12 This work unexpectedly revealed that the iso-
propyl protecting group in guaiacol derivatives could be
replaced in one step under especially mild conditions
using
trimethylsilyl
trifluoromethanesulfonate
(TMSOTf) and acetic anhydride in acetonitrile; 1, for
example, could be transformed into 2 in 89% yield
(Scheme 1). We have now explored the scope and utility
Keywords: Transprotection; Isopropyl phenyl ether; Trimethylsilyl
trifluoromethanesulfonate.
* Corresponding author. Tel.: +61-7-3365-3530; fax: +61-7-3365-4299;
e-mail: c.williams3@mailbox.uq.edu.au
0040-4039/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.11.065

668
C. M. Williams, L. N. Mander / Tetrahedron Letters 45 (2004) 667–669
Table 1. One-step conversion of 6-substituted isopropyl protected guaiacols to acetates15
Entry
1
Isopropyl ether
Acetate
Yield (%)
77
MeN
Br
MeN
Br
O
O
O
O
O
OMe
OMe
OH
HO
OH
OMe
OMe
MeN
Br
MeN
68 (R ¼ H)
86 (R ¼ Ac)
Br
O
O
O
2
O
O
OH
RO
OH
O
O
O
O
3
98
O
O
Br
Br
O
O
O
O
4
62
O
O
O
O
O
5
96
O
O
O
O
H
O
O
O
H
O
O
O
O
6
35
O
O
O
O
7
0
O
H
O
O
HO
Br
O
O
O
O
O
8
75
Br
H
Br
Br
O
O
O
O
9
35
O
O
O
O
O
O
O
10
11
12
99
ONO
ONO
O
O
O
O
+
60 + 12
50 (100)
O
O
O
O
NHAc
N
N
O
O
O
O
O
NO2
NO2
(entry 9) were present. We note that terminal acetylenes
are also sensitive to other isopropyl ether deprotection
protocols.13 In the case of the benzonitrile (entry 11) the
cyano group was partially converted into an imide
(12%), whereas, for no apparent reason, the nitrobenz-
ene (entry 12) could only be driven to 50% completion;
however, based on recovered starting material, the yield
was 100%. Use of the solvent acetonitrile seems to be
essential for transprotection. Dichloromethane, for
example, substantially decreased the rate of reaction,
while the addition of nitrogen bases to neutralise
trifluoromethanesulfonic acid reduced yields signifi-
cantly. Lower yields were obtained with the alternative
silylating reagents TESOTf and TBDMSOTf. Mecha-

C. M. Williams, L. N. Mander / Tetrahedron Letters 45 (2004) 667–669
669
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H
O
Ac2O
OTMS
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O
O
R
R
R
3
TMSOTf
4
5
Scheme 2.
nistically, the isopropyl group (e.g., 3), under the
strongly acidic conditions, possibly undergoes elimina-
tion to the silylated phenol 4, which is then acetylated
with acetic anhydride, activated by excess Lewis acid,
affording the acetate 5 (Scheme 2).14
5. Oriyama, T.; Yatabe, K.; Sugawara, S.; Machiguchi, Y.;
Koga, G. Synlett 1996, 523–525.
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Oriyama, T. Synthesis 2003, 484–486.
In conclusion, we have discovered that 6-substituted
isopropyl protected guaiacols undergo transprotection
in one step when treated with TMSOTf in acetonitrile.
When the substituent at position 6 is bulky and electron
withdrawing the reaction proceeds in very high yield.
Unfortunately, mono- and di-substituted isopropyl
phenyl ethers do not undergo transprotection but rather
Friedel–Crafts acetylation occurs.
10. Iimura, S.; Manabe, K.; Kobayashi, S. Org. Lett. 2003, 5,
101–103.
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3502.
13. Banwell, M. G.; Flynn, B. L.; Stewart, S. G. J. Org. Chem.
1998, 63, 9139–9144.
14. A similar process has been observed in the presence of
TiO2/SO4ꢀ: Jin, T.-S.; Li, Y.-W.; Sun, G.; Li, T.-S.
J. Chem. Res. (S) 2003, 98–100.
Acknowledgements
The authors thank the following people for their assis-
tance: Dr. Tri Le for performing NMR analysis and Mr.
Graham McFarlane for mass spectroscopy.
15. Typical procedure: 1-bromo-2-isopropoxy-3-methoxybenz-
ene (100 mg, 0.041 mmol) was dissolved in acetic anhy-
dride (0.4 mL) and anhydrous acetonitrile (0.4 mL) under
nitrogen. TMSOTf (90 lL, 0.049 mmol) was then added
dropwise over 30 s. The reaction mixture was stirred at
room temperature. After 20 min the reaction was
quenched with a saturated solution of sodium hydrogen
carbonate (5 mL), extracted with diethyl ether (3 · 5 mL),
dried (Na2CO3) and evaporated. The residue was sub-
jected to column chromatography (dichloromethane/light
petroleum) affording 2-acetoxy-3-bromo-1-methoxybenz-
ene (98 mg, 98%) as a colourless oil, which slowly solidified
on standing, mp 37 ꢁC (lit.16 39 ꢁC). Spectral data are in
exact agreement to that reported.16
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