A new, practical and efficient method for protecting alcohols as tert-butyl ethers

Article abstract of DOI:10.1055/s-0029-1219360

A new method for protecting alcohols as tert-butyl ethers is reported. The reaction is performed in tert-butyl acetate in the presence of a catalytic amount of HClO₄. The process is extremely efficient and primary and secondary alcohols as well as diols are protected under very mild conditions. Remarkably, tert-butyl acetate can be easily recovered after the workup of the reaction and recycled.

Full text of DOI:10.1055/s-0029-1219360

812
LETTER
A New, Practical and Efficient Method for Protecting Alcohols as tert-Butyl
Ethers
t
ert-Butyl Ethers
f
l
r
om
A
l
e
a
Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giura 9, 10125 Torino, Italy
Dipartimento di Chimica, Università di Firenze, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy
E-mail: ernesto.occhiato@unifi.it
Dipartimento di Chimica Generale e Chimica Organica, Università di Torino, Via P. Giuria 7, 10125 Torino, Italy
E-mail: cristina.prandi@unito.it
b
c
Received 1 December 2009
ether that is stable under strong basic conditions, it can be
easily removed, and its bulkiness could play a crucial role
in stereoselective syntheses.4
Abstract: A new method for protecting alcohols as tert-butyl ethers
is reported. The reaction is performed in tert-butyl acetate in the
presence of a catalytic amount of HClO4. The process is extremely
efficient and primary and secondary alcohols as well as diols are
protected under very mild conditions. Remarkably, tert-butyl ace-
tate can be easily recovered after the workup of the reaction and re-
cycled.
In the course of a project aimed at the stereoselective syn-
thesis of cis and trans 4-hydroxypipecolic acid,4c we came
across unexpected difficulties in the protection of 4-cy-
ano-3-hydroxybutyric acid ethyl ester (Table 1, entry 6)
as its O-tert-butyl ether in the early stages of the synthesis.
Both traditional methodologies gave low conversions,
whereas the procedure proposed by Bartoli et al.3c re-
quired the use of a large excess of Boc2O due to its decom-
position through a competing reaction – conditions that
we preferred to avoid in view of future large-scale appli-
cations. Furthermore, the latter procedure is not appropri-
ate for substrates containing a free amino group which, in
principle, can be converted into a N-Boc derivative.
Therefore, for the generation of the tert-butyl cation, we
decided to apply experimental conditions known to lead to
the esterification of carboxylic acids.5 We thus added a
catalytic amount (0.1 equiv) of HClO4 to a solution of our
secondary alcohol in tert-butyl acetate at 25 °C, and were
delighted to observe the complete conversion of the sub-
strate into the corresponding tert-butyl ether after three
days. To our knowledge, no examples of the protection of
alcohols as their tert-butyl ethers under such conditions
have been reported. This result gave us the opportunity to
complete our planned synthesis and, in addition, prompt-
ed us to explore and expand the scope of the reaction as a
general alternative and inexpensive route to the genera-
tion of tert-butyl ethers. To this end, primary, secondary,
and propargylic alcohols, as well as diols were consid-
ered. The best results obtained by applying the proposed
methodology are reported in Table 1. Aliphatic primary
alcohols (entries 1–3) gave complete conversion into the
corresponding O-tert-butyl ethers after reasonably short
times at room temperature in the presence of 0.2 equiva-
lents of catalyst at a 0.04–0.05 M concentration of sub-
strate. Both N-Cbz and N-Fmoc protecting groups were
compatible with the reaction conditions, although, unex-
Key words: protecting groups, tert-butyl ethers, alcohols, tert-
butyl acetate
The tert-butyl ether is reported to be ‘one of the most un-
derused alcohol protecting groups’.1 Traditionally, alco-
hols can be protected as their tert-butyl ethers through
either of two commonly used procedures; in both cases, a
tert-butyl carbocation intermediate is generated either
from isobutylene or tert-butyltrichloroacetimidate, in the
presence of a strong mineral or Lewis acid catalyst. Al-
though the use of isobutylene generally leads to the for-
mation of clean products in high yields, the requirement
for gas to be bubbled through substrate solutions for long
periods of time is often an unattractive option. The use of
tert-butyltrichloroacetimidate as an alternative is, instead,
costly and, although the reagent can be easily prepared in
a work day,2 its use for large amounts of substrate is not
appealing because of the atom waste in the form of
trichloroacetamide. Moreover, chromatographic purifica-
tion from residual trichloroacetamide is often difficult. In
both cases, the presence of a strong mineral or Lewis acid
catalyst is mandatory for successful conversions and this
can hamper the application of these methodologies to the
protection of tertiary alcohols and phenols; furthermore,
in some cases, even the protection of secondary alcohols
is unsatisfactory. Recently, Bartoli et al.3 reported an in-
teresting alternative to the procedures mentioned above:
in their approach, Boc2O was used as a tert-butyl source
and anhydrous Mg(ClO4)2 as a catalyst – these mild con-
ditions were found to be compatible with many functional
groups.
The tert-butyl ether moiety has somewhat unusual fea- pectedly, with the N-Fmoc-protected 3-amino-1-propanol
tures as a protecting group: it is one of the few types of (entry 2), 23 hours were necessary to reach complete con-
version.6 The conversion rate with acyclic aliphatic sec-
ondary alcohols was more difficult to predict based on the
substrate structure. Whereas (S)-diethyl 2-hydroxysuccin-
ate (entry 4) was quantitatively converted into the corre-
SYNLETT 2010, No. 5, pp 0812–0816
Advanced online publication: 08.02.2010
DOI: 10.1055/s-0029-1219360; Art ID: G36909ST
© Georg Thieme Verlag Stuttgart · New York
1
6.
3
.2
0
1
0

LETTER
tert-Butyl Ethers from Alcohols
813
sponding tert-butyl ether7 in one hour at a 0.05 M tio using 0.2 equiv of catalyst after four days. We obtained
substrate concentration, a larger excess of tert-butyl ace- practically the same results with (R,R)-tartaric acid dime-
tate (substrate concentration equal to 0.025 M) and three thyl ester (entries 13 and 14) at a 0.05 M concentration
days of stirring were necessary to generate 75% conver- and 0.2 equiv of HClO4, we measured a 2:1 ratio of mono-
sion in the case of 2-octanol (entry 5). Cyclic secondary (13a) and diprotected (13b) compounds after 23 hours. As
alcohols such as cyclohexanol (entry 7), (R)-menthol (en- in the case of cyclohexanediol, longer reaction times did
try 8), cyclododecanol (entry 9), cholesterol and desmos- not increase the conversion into 13b, meaning that equi-
terol (cholesta-5,24-dien-3b-ol, entries 10 and 11, librium was reached. By changing the reaction conditions,
respectively), could all be successfully converted into the we managed to obtain a 1:1 ratio between the two prod-
corresponding tert-butyl ether with yields ranging from ucts (entry 14) by extremely diluting the solution to
66 to 100%. In general, shorter reaction times and lower 0.0025 M. After 44 hours, we stopped the reaction as it no
amounts of catalyst are required for unhindered cyclic longer proceeded, and the two products were separated by
secondary alcohols (entries 7, 9, 10, and 11) compared to chromatography (EtOAc–n-Hexane, 1:4) to give 13b
open chain ones, whereas for menthol an increase in both (Rf = 0.35; 43%) and 13a (Rf = 0.11; 41%). When the
dilution (0.025 M) and reaction time was required.
monoprotected derivative 13a was again subjected to the
same conditions, a 1:1 ratio was again established, the
reaction was worked-up and the two products separated.
In this way we managed to obtain the desired diprotected
compound 13b in an acceptable 63% yield. This is a good
result because, as far as we know, the protection of tartaric
acid as the synthetically useful di-tert-butyl ether8 is noto-
riously difficult and generally leads to low yields. Al-
though the use of large volumes of tert-butyl acetate in
this case (and, in general, where a 0.025 M substrate con-
centration was necessary) appears economically unfavor-
able, we found that the tert-butyl acetate can be easily
recovered almost quantitatively by distillation after work-
up of the reaction mixture.
O
R
path A
O
+
O
Me
OH
O
Me
H+
+
R
OH
O
R
R
Me
O
path B
elimination products
Scheme 1 Different pathways occurring in the reaction medium
Unfortunately, elimination is the main pathway followed
by tertiary and tertiary allylic alcohols (entries 15 and 17
respectively), whereas the tetrahydropyridin-4-ol shown
in entry 18 gave exclusively the corresponding acetate de-
rivative.
This data may be explained by the high conformational
mobility of the open chain alcohols that could hamper the
attack of the tert-butyl cation. As for 1,2-diols (entries 12–
14), cyclohexandiol (entry 12) gave a mixture of mono
(12a) and disubstituted (12b) tert-butyl ethers in a 2:1 ra-
Table 1 Protection of Alcohols as their Corresponding tert-Butyl Ethers
Entry
ROH
[ROH] (M)
Cat.a
0.2
Product
Time (h) Conv.b (yield)c (%)
Cbz
N
1
0.05
1
4.5
100
H
OH
Ph
Fmoc
N
2
3
0.04
0.05
0.2
0.2
2
3
23
100
100
OH
H
OH
4.5
Cl
OH
4
5
6
0.05
0.025
0.8
0.2
0.2
0.1
4
5
6
1
100
75
COOEt
OH
EtOOC
3 d
3 d
OH
OH
100
NC
COOEt
7
0.1
0.1
7
3 d
100
Synlett 2010, No. 5, 812–816 © Thieme Stuttgart · New York

814
A. Barge et al.
LETTER
Table 1 Protection of Alcohols as their Corresponding tert-Butyl Ethers (continued)
Entry
8
ROH
[ROH] (M)
0.025
Cat.a
0.2
Product
Time (h) Conv.b (yield)c (%)
8
5 d
20
70 (60)
94 (70)
OH
OH
9
0.01
0.05
0.2
0.1
9
10
10
5
100 (91)
87 (66)
HO
11
0.05
0.3
11
23
HO
12
13
14
15
0.1
0.2
0.2
0.2
0.2
12
13
13
14
4 d
23
100d
100d
100e
–
HO
OH
OH
OH
OH
COOMe
MeOOC
0.05
OH
MeOOC
OH
0.0025
0.025
44
COOMe
3 d
OH
16
17
0.05
0.05
0.1
0.2
15
16
24
7
15
–
OH
OH
N
18
0.04
0.2
17
4
100f
CO2Me
CO2Me
OH
19
20
0.05
0.2
0.2
18
19
1
1
100 (78)
100 (75)
0.025
OH
a Equivalents of HClO4.
b Conversions determined by GC and or H1NMR analysis.
c Isolated products.
d 2:1 ratio between mono and deprotected.
e 1:1 ratio between mono and deprotected.
f The O-acetylated product was recovered.
Synlett 2010, No. 5, 812–816 © Thieme Stuttgart · New York

LETTER
tert-Butyl Ethers from Alcohols
815
(7) Cicchi, S.; Goti, A.; Brandi, A. J. Org. Chem. 1995, 60,
As depicted in Scheme 1, besides the formation of the
tert-butyl cation according to path A, the protonation of
the hydroxy group (path B) induces the competitive for-
mation of a stable carbocation through loss of water. As a
result, the attack of acetic acid on this stable carbocation
leads to the corresponding acetylated derivative. Predict-
ably, the more stable the alkyl carbocation, the more path
B is the favored process. In these cases, a large excess of
the tert-butylating agent could disadvantage the compet-
ing elimination pathway, however, with 2-methyl-1-phe-
nylpropan-2-ol (entry 16) we were able to obtain the tert-
butyl ether in only 15% yield. Nevertheless, propargylic
alcohols such as 2-hexyn-1-ol and 3-hexyn-2-ol (entries
19 and 20) were easily converted into the correspondent
protected ethers in one hour.10
4743.
(8) (a) Polonski, T. J. Chem. Soc., Perkin Trans. 1 1988, 629.
(b) Uray, G.; Lindner, W. Tetrahedron 1988, 44, 4357.
(9) Several phenols have also been considered. Unfortunately
most of them mainly gave FC alkylation products. Only
mono- and di-nitro phenols were converted into the
correspondent tert-butyl ethers although in low yields.
(10) General Procedure for the Synthesis of tert-Butyl Ethers: To
a solution of the alcohol in t-BuOAc, was added HClO4 and
the mixture was stirred at 25 °C until the reaction was
complete (reaction monitored by TLC or GC). Na2CO3 (2
equiv) was added and the mixture was stirred for 40 min.
After filtration, the solvent was removed under vacuum (for
the re-use of t-BuOAc, this was washed with a saturated
solution of NaHCO3, then with H2O and finally dried over
Na2SO4). The tert-butyl ether was separated from the
residual alcohol by flash chromatography on silica gel
(petroleum ether–Et2O or n-hexane–EtOAc). Compounds
4,7 5,3d 6,4c 7,14 8,3d 10,3d 12a,12,13 12b,11,13 13a,8 and 13b8 are
known, and their spectroscopic data correspond to those
reported. 1: 1H NMR (CDCl3, 200 MHz): d = 7.40–7.31 (m,
5 H), 7.30–7.15 (m, 5 H), 5.26–5.12 (br s, 1 H), 5.09 (s, 2 H),
4.03–3.86 (s, 1 H), 3.34–3.20 (m, 2 H), 2.94–2.83 (m, 2 H),
1.16 (s, 9 H); 13C NMR (CDCl3, 50.33 MHz): d = 155.8 (s),
138.3 (s), 136.5 (s), 129.4 (d, 2 C), 128.4 (d, 2 C), 128.2 (d,
2 C and 1 C), 128.0 (d, 2 C), 126.2 (d), 72.8 (s), 66.5 (t), 61.1
(t), 52.5 (d), 37.8 (t), 27.5 (q, 3 C). MS (ESI): m/z (%) = 364
(100)[M+ + Na], 341 (14) [M]+, 286 (19). 2: 1H NMR
(CDCl3, 200 MHz): d = 7.76 (d, J = 7.3 Hz, 2 H), 7.60 (d,
J = 7.3 Hz, 2 H), 7.43–7.29 (m, 4 H), 5.68–5.52 (br s, 1 H),
4.41–4.36 (m, 2 H), 4.28–4.18 (m, 1 H), 3.46 (t, J = 5.5 Hz,
2 H), 3.40–3.20 (m, 2 H), 1.82–1.66 (m, 2 H), 1.21 (s, 9 H);
13C NMR (CDCl3, 50.33 MHz): d = 156 (s), 143.8 (s, 2 C),
141.1 (s, 2 C), 127.4 (d, 2 C), 126.8 (d, 2 C), 124.9 (d, 2 C),
119.7 (d, 2 C), 73.0 (s), 66.4 (t), 60.6 (t), 47.3 (d), 40.1 (t),
29.8 (t), 27.5 (q, 3 C). MS (ESI): m/z (%) = 376 (100)[M+ +
Na], 353 (19) [M]+, 298 (6). MS (EI, 70 eV): m/z (%) = 353
(0.1) [M]+, 178 (100). 3: 1H NMR (CDCl3, 200 MHz): d =
7.27–7.14 (m, 4 H), 3.52 (t, J = 7.3 Hz, 2 H), 2.79 (t, J = 7.3
Hz, 2 H), 1.16 (s, 9 H); 13C NMR (CDCl3, 50.33 MHz): d =
137.9 (s), 131.7 (s), 130.2 (d, 2 C), 128.1 (d, 2 C), 72.9 (s),
62.7 (t), 36.8 (t), 27.6 (s, 3 C). MS (EI, 70 eV): m/z (%) = 212
(2)[M]+, 182 (3), 57 (100). 9: 1H NMR (CDCl3, 200 MHz):
d = 3.58–3.65 (m, 1 H), 1.61–1.50 (m, 2 H), 1.34 (br, 20 H),
1.19 (s, 9 H); 13C NMR (CDCl3, 50.33 MHz): d = 73.1 (s),
68.6 (d), 31.9 (t, 2 C), 28.7 (q, 3 C), 24.6 (t, 2 C), 24.0 (t),
23.2 (t, 4 C), 21.1 (t, 2 C). MS (EI, 70 eV): m/z (%) = 240
(3)[M]+, 183 (18), 166 (3), 57 (100). 11: 1H NMR (CDCl3,
400 MHz): d = 5.31–5.29 (m, 1 H), 5.10–5.06 (m, 1 H),
3.34–3.26 (m, 1 H), 2.32–2.23 (m, 2 H), 2.12 (ddd, J = 13.4,
4.9, 2.1 Hz, 1 H), 2.06–1.93 (m, 2 H), 1.87–1.79 (m, 4 H),
1.70–1.35 (m, 11 H), 1.68 (s, 3 H), 1.60 (s, 3 H), 1.34–1.00
(m, 7 H), 1.18 (s, 9 H), 0.99 (s, 3 H), 0.93 (d, J = 6.6 Hz, 3
H), 0.670 (s, 3 H); 13C NMR (CDCl3, 100.4 MHz): d = 142,
131, 125, 120, 73.3, 71.4, 56.8, 56.1, 50.3, 42.3, 42.1, 39.8,
37.8, 36.6, 36.1, 35.6, 32.0, 31.9, 31.3, 28.5 (3 C), 28.2, 25.7,
24.7, 24.3, 21.0, 19.3, 18.6, 17.6, 11.8. MS (EI, 70 eV): m/z
(%) = 440 (2) [M]+, 57 (100). 17: 1H NMR (CDCl3, 400
MHz): d = 5.90 (d, J = 4.4 Hz, 1 H), 5.28 (pseudo q, J = 4.3
Hz, 1 H), 4.09 (dt, J = 13.3, 4.4 Hz, 1 H), 3.79 (s, 3 H), 3.73
(s, 3 H), 3.28 (ddd, J = 13.3, 9.2, 5.5 Hz, 1 H), 2.04 (s, 3 H),
1.98–1.95 (m, 2 H); 13C NMR (CDCl3, 100.4 MHz): d =
170.0 (s), 164.7 (s), 153.9 (s), 135.3 (s), 116.3 (d), 63.5 (d),
53.4 (q), 52.4 (q), 40.5 (t), 29.2 (t), 21.0 (q); MS: m/z (%) =
257 (14)[M]+, 225 (40), 198 (49), 183 (60), 152 (77), 94
(100). 18: 1H NMR (CDCl3, 200 MHz): d = 4.00 (s, 2 H),
In conclusion, the HClO4/tert-butyl acetate procedure rep-
resents a practical tool to synthesize protected tert-butyl
ethers. It can be considered as a good compromise be-
tween efficiency and low cost of the reagents. Good re-
sults have been obtained with primary, secondary and
cyclic alcohols, with the mild reaction conditions being
compatible with the presence of many other functional
and protecting groups. The products can be easily recov-
ered from the crude reaction mixture and easily purified;
moreover, for large-scale preparations, the excess of tert-
butyl acetate can be easily recovered by simple distillation
of the crude material and used in further experiments.
Acknowledgment
We thank the Italian Miur and the Regione Piemonte (Cipe 2007,
BioBits project) for funding.
References and Notes
(1) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis.; Wiley: New York, 1999, 65–67.
(2) Armstrong, A.; Brackenridge, I.; Jackson, R. F. W.; Kirk,
J. M. Tetrahedron Lett. 1988, 29, 2483.
(3) (a) Bartoli, G.; Bosco, M.; Carlone, A.; Dalpozzo, R.;
Locatelli, M.; Melchiorre, P.; Palazzi, P.; Sambri, L. Synlett
2006, 2104. (b) Bartoli, G.; Bosco, M.; Carlone, A.;
Dalpozzo, R.; Locatelli, M.; Melchiorre, P.; Sambri, L.
J. Org. Chem. 2006, 71, 9580. (c) Bartoli, G.; Bosco, M.;
Carlone, A.; Locatelli, M.; Marcantoni, E.; Melchiorre, P.;
Sambri, L. Adv. Synth. Catal. 2006, 348, 905. (d) Bartoli,
G.; Bosco, M.; Locatelli, M.; Marcantoni, E.; Melchiorre, P.;
Sambri, L. Org. Lett. 2005, 7, 427.
(4) (a) Goti, A.; Cicchi, S.; Cordero, F. M.; Fedi, V.; Brandi, A.
Molecules 1999, 4, 1. (b) Cicchi, S.; Corsi, M.; Goti, A.
J. Org. Chem. 1999, 64, 7243. (c) Occhiato, E. G.; Scarpi,
D.; Guarna, A.; Tabasso, S.; Deagostino, A.; Prandi, C.
Synthesis 2009, 3611.
(5) (a) Anelli, P. L.; Fedeli, F.; Gazzotti, O.; Lattuada, L.; Lux,
G.; Rebasti, F. Bioconjugate Chem. 1999, 10, 137.
(b) Chen, H.; Feng, Y.; Xu, Z.; Ye, T. Tetrahedron 2005, 61,
11132; This procedure is commonly used to convert
N-unprotected amino acids into tert-butyl esters.
(6) The conversion of unprotected 5-aminopentan-1-ol into the
corresponding 5-tert-butoxypentan-1-amine has been
successfully performed in the presence of 0.5 equiv of
HClO4.
Synlett 2010, No. 5, 812–816 © Thieme Stuttgart · New York

816
A. Barge et al.
LETTER
2.11 (t, J = 4.3 Hz, 2 H), 1.45 (m, 2 H), 1.17 (s, 9 H), 0.86 (t,
J = 7.3 Hz, 3 H); 13C NMR (CDCl3, 50.33 MHz): d = 85.1
(s), 81.2 (s), 73.8 (s), 50.6 (t), 27.3 (q), 21.8 (t), 20.7 (t), 13.3
(q). MS (EI, 70 eV): m/z (%) = 139 (88), 81 (100), 79 (96),
59 (74), 57 (63). 19: 1H NMR (CDCl3, 200 MHz): d = 4.19
(q, J = 6.6 Hz, 1 H), 2.10 (q, J = 7.5 Hz, 2 H), 1.31 (d, J = 6.6
Hz, 3 H), 1.17 (s, 9 H), 1.10 (t, J = 7.5 Hz, 3 H); 13C NMR
(CDCl3, 50.33 MHz): d = 84.8 (s), 82.3 (s), 73.9 (s), 57.0 (d),
27.9 (q), 23.8 (q), 13.6 (q), 12.3 (t). MS (EI, 70 eV): 139
(70), 81 (100), 79 (80), 59 (88), 57 (94).
(11) Schauble, J. H.; Trauffer, E. A.; Deshpande, P. P.; Evans,
R. D. Synthesis 2005, 1333.
(12) Kim, B. K.; Piao, F.; Lee, E. J.; Kim, J. S.; Jun, M. J.; Lee,
B. M. Bull. Korean Chem. Soc. 2004, 25, 881.
(13) Iranpoor, N.; Baltork, I.; Mohammadpour, I. Tetrahedron
Lett. 1990, 31, 735.
(14) Brown, H. C.; Kurek, J. T.; Rei, M.-H.; Thomson, K. L.
J. Org. Chem. 1985, 50, 1171.
Synlett 2010, No. 5, 812–816 © Thieme Stuttgart · New York

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