Using benzotriazole esters as a strategy in the esterification of tertiary alcohols

Article abstract of DOI:10.1055/s-0030-1258970

Benzotriazole esters formed in situ were found to be efficient intermediates in the esterification of tertiary alcohols using 4-(dimethylamino)pyridine (DMAP) as the base. These mild and basic reaction conditions allow the conversion of various substrates into esters in good yield

Full text of DOI:10.1055/s-0030-1258970

PAPER
4261
Using Benzotriazole Esters as a Strategy in the Esterification of Tertiary
Alcohols
B
enzotriaz
o
ole Esters in
s
the Ester
é
ification of Tertia
A
ry Alcohols ntonio Morales-Serna,a Aline Vera,a Ehecatl Paleo,a Eréndira García-Ríos,a Rubén Gaviño,a
Gustavo García de la Mora,b Jorge Cárdenas*a
a
Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, Coyoacán 04510,
D. F. México City, México
Fax +52(55)56162217; E-mail: rjcp@unam.mx
Departamento de Química Orgánica, Facultad de Química, Universidad Nacional Autónoma de México, Circuito Interior,
b
Ciudad Universitaria, Coyoacán 04510, D. F. México City, México
Received 13 August 2010; revised 24 September 2010
tert-butyl bromide in a nucleophilic substitution reac-
tion;28 esterification by an oxidation–reduction process in
the presence of an alkoxydiphenylphosphine;29 and, final-
ly, using an acyl chloride or bromide30 over alumina to ob-
tain the ester (Scheme 1).
Abstract: Benzotriazole esters formed in situ were found to be ef-
ficient intermediates in the esterification of tertiary alcohols using
4-(dimethylamino)pyridine (DMAP) as the base. These mild and
basic reaction conditions allow the conversion of various substrates
into esters in good yield.
Key words: esterification, hindered alcohols, 1-hydroxybenzotria-
zole, carbodiimides, hydrotalcites
In this context, we considered the possibility of develop-
ing a new protocol for the esterification of sterically hin-
dered alcohols using benzotriazole esters as a strategy. It
is well known that carbodiimides and 1-hydroxybenzotri-
azole (HOBt) can be used in the formation of the peptide
bond.31 The easy access to that bond has been attributed to
the high reactivity of benzotriazole esters I and II
(Scheme 2), which are formed from the dehydration of
carboxylic acid by means of a carbodiimide. In a recent
publication, Chan and Cox described the influence of
HOBt in the formation of the amide bond.32 They demon-
strated, by calorimetric procedure, that the reaction rate is
independent of the HOBt concentration; however, HOBt
is necessary to obtain high yields. In an attempt to
synthesize a Weinreb active amide of N-trityl-protected
phenylalanine using benzotriazol-1-yloxytris(dimethyl-
The esterification of organic acids with tertiary alcohols is
a persistent problem in organic synthesis and has therefore
been the object of interest over the past year. It is well
known that the tert-butyl group has been extensively used
for carboxylic acid protection due to its relative resistance
to nucleophilic attack and its ready removal under mild
acidic conditions.1 The simple reaction of a carboxylic
acid and isobutylene in the presence of an acid catalyst is
the most straightforward way to obtain these esters.2
Alternatively, a series of procedures has been introduced
to synthesize not only solely esters of tert-butyl alcohol,
but other sterically hindered alcohols as well. These pro-
tocols include transesterification with lithium3 and potas-
sium alkoxides;4 transesterification in the presence of
perchloric acid;5 transesterification mediated by metal,6
N-heterocyclic carbene7 and iodine catalysts;8 transesteri-
fication using Meldrum’s acid;9 dehydration by means of
carbodiimides;10 direct esterification of carboxylic acids
using diphenylammonium triflate in fluorous media;11 the
use of Al-MCM-41,12 silica chloride13 or Keggin, Dawson
and Preyssler heteropolyacids14 to catalyze the direct es-
terification of carboxylic acids; esterification in enzymat-
ic mediums;15 esterification with anhydrides in the
presence of Lewis acids,16 montmorillonite K10 and
KSF,17 Si-MCM-41,18 alumina,19 magnesium bromide,20
neutral ionic liquid [BMIm]BF4,21 pentaalkylguanidines22
and cyclocopolymer containing pyrrolidinopyridine;23 es-
terification of anhydrides in the absence of solvent and
catalyst;24 obtaining esters from carbonates;25 activating
alcohols by employing N,N-dimethylformamide di-tert-
butyl acetal26 or tert-butyl trichloroacetimidate;27 using
amino)phosphonium
hexafluorophosphate
(BOP),
Liskamp and co-workers33 isolated the corresponding
intermediates I and II. The latter intermediate reacted
with potassium tert-butoxide to provide the tert-butyl es-
ter of N-tritylphenylalanine. Finally, we recently reported
that the use of benzotriazole esters I and II in the synthesis
of macrolactones afforded excellent yields in the cycliza-
tion of w-hydroxy acids.34 With this interesting back-
ground, we wondered whether this approach could also be
used in the esterification reactions of other tertiary alco-
hols. Fully aware of the benefits and difficulties of this re-
action, we decided to pursue an answer. The following is
a description of the efficient esterification process of ter-
tiary alcohols by the use of 1-ethyl-3-(3-dimethylamino-
propyl)carbodiimide (EDC) and HOBt to achieve the
formation of intermediates I and II. A representative ex-
ample of the original process is depicted in Scheme 2.
We initially investigated the intermolecular reaction of
tert-butyl alcohol and phenylacetic acid (1) in the pres-
ence of EDC, HOBt and 4-(dimethylamino)pyridine
(DMAP). Taking into consideration that the intermediates
I and II are the precursors of the final product, it was nec-
essary to identify the best solvent for their formation. In
SYNTHESIS 2010, No. 24, pp 4261–4267
x
x.
x
x
.
2
0
1
0
Advanced online publication: 12.11.2010
DOI: 10.1055/s-0030-1258970; Art ID: M05410SS
© Georg Thieme Verlag Stuttgart · New York

4262
J. A. Morales-Serna et al.
PAPER
carbonates
di-tert-butyl acetal
O
O
O
O
NMe2
R1
O
O
R1
OH
O
anhydride reaction
trichloroacetimidate
NH
O
O
HO
R1
O
R1
O
R1
OH
N
Cl3C
O
direct
R2
N
C
R2
esterification
transesterification
HClO4
O
O
Ph2NH2OTf
R2
metal catalysts
O
R1
O
R1
OH
R1
O
silica chloride or Al-MCM-41 or
heteropolyoxometalates
carbene catalysts
I2 catalysts
HO
HO
biocatalytic
esterification
+
electrophilic addition
O
H
O
R1
OH
alkyl halide
O
O
R1
OH
O
Br
R1
X = Cl or Br
X
HO
acyl halide
O
Ph
P
R1
OH
Ph
O
oxidation–reduction condensation
Scheme 1 Esterification strategies
order to do this, we compared three different solvents: tet- Our initial survey revealed that temperature has an influ-
rahydrofuran, chloroform and dichloromethane. In gener- ence on the development of the reaction (Table 1, entries
al, each of these solvents can be used as a medium for 1 and 3), that variations in the concentration of tert-butyl
ester formation with HOBt; however, only chloroform alcohol and DMAP have an effect on the reaction yield
gave a 98% yield of intermediates I and II. These results (Table 1, entries 2, 4–6) and that the use of four or eight
were confirmed by the use of NMR spectroscopy, in equivalents of tert-butyl alcohol and DMAP gives the best
which the raw material from the ester formation was ana- results (Table 1, entries 7 and 8). These results contrast
lyzed. Once we identified the best solvent for the forma- with that obtained in the esterification of the same carbox-
tion of the benzotriazole esters, we studied the reaction of ylic acid with tert-butyl alcohol in the absence of HOBt,
these intermediates with tert-butyl alcohol, which in- where the formation of product 2 was not observed.
volved stirring the following for 30 minutes at room tem-
It is important to note that, when the reaction was carried
perature: one equivalent of carboxylic acid, one
out with 3, 4 or 8 equivalents of DMAP, the formation of
equivalent of EDC and one equivalent of HOBt in chloro-
side product 3 was observed, as a consequence of the eno-
late acylation of ester 2 with intermediates I and II
form. Subsequently, tert-butyl alcohol and DMAP were
added and the reaction mixture was stirred for 18 hours.
(Scheme 3, eq 1). A similar behavior has been observed
O
R
N
O
O
N
N
EDC
t-BuOH
base
N
O
N
+
+
R
OH
R
O
HOBt
O
N
O
–
R
I
II
Scheme 2 General transesterification process
Synthesis 2010, No. 24, 4261–4267 © Thieme Stuttgart · New York

PAPER
Benzotriazole Esters in the Esterification of Tertiary Alcohols
4263
Table 2 Esterification of Phenylacetic Acid (1) with tert-Butyl Al-
Table 1 Esterification of Phenylacetic Acid (1) with tert-Butyl Al-
cohol in the Presence of Other Bases or Hydrotalcitesa
cohol in the Presence of DMAPa
1. EDC, HOBt
Entry Base
Equivalents
Yieldb (%) of 2
O
O
CHCl3
1
2
3
4
5
6
Et3N
1
48
82
43
79
80
20
2. t-BuOH, DMAP
CHCl3
O
OH
1
2
Et3N
4
Entry
DMAP
(equiv)
t-BuOH Temp
(equiv)
Time
(h)
Yieldb
DIPEA
1
(%)
15
50
21
51
61
65
89
84
DIPEA
4
1
2
3
4
5
6
7
8
1
1
2
2
2
3
4
8
2
r.t.
48
18
48
18
18
18
18
18
hydrotalcite, x = 0.33
200 mg/mmol
2
reflux
r.t.
hydrotalcite (Aldrich) 200 mg/mmol
2.5
2.5
4
a Reaction conditions: phenylacetic acid (1 mmol), EDC (1 mmol),
HOBt (1 mmol), CHCl3, r.t., 30 min, and then t-BuOH (4 mmol), base
or hydrotalcite, reflux, 18 h.
reflux
reflux
reflux
reflux
reflux
b Yield of isolated product after chromatographic purification.
6
acetic acid (1) was reacted with tert-butyl alcohol under
reflux in the presence of EDC and HOBt, ester 2 was ob-
tained in 48% yield after 18 hours (Table 2, entry 1). The
yield increased to 82% when four equivalents of triethyl-
amine were used (Table 2, entry 2). Similar results were
obtained when the reaction was carried out in the presence
of DIPEA (Table 2, entries 3 and 4). Additionally, we
used a calcined hydrotalcite Mg2+/Al3+ ratio x = 0.33 as
the base instead of DMAP (Table 2, entries 5 and 6). Hy-
drotalcites are materials that have basic properties and can
be used instead of classic bases, which are needed for the
reaction to take place.36 Hydrotalcites have the following
advantages: ease of separation of the products, reduction
of waste streams, possible regeneration of the catalyst and
low cost. The aforementioned hydrotalcite was used, tak-
ing into consideration that the basicity of the calcined
product can be modified by changing the Al/Mg ratio.37
As shown in Table 2 (entry 5), the reaction performed
with the calcined hydrotalcite afforded the corresponding
ester in 80% yield; however, the use of commercial hydro-
4
8
a Reaction conditions: phenylacetic acid (1 mmol), EDC (1 mmol),
HOBt (1 mmol), CHCl3, r.t., 30 min, and then t-BuOH, DMAP.
b Yield of isolated product after chromatographic purification.
with 1-acylbenzotriazoles, such as compound 4,35 which
are efficient C-acylation reagents for the regioselective
conversion of ketones 5 into b-diketones 6 when lithium
diisopropylamide is used as a base (Scheme 3, eq 2). With
this observation, our group glimpsed the possibility of ob-
taining b-oxo esters from carboxylic acids in the presence
of HOBt.
At this point in our research, we considered the possibility
of using other bases. Therefore, a screen of alternative
bases for the esterification reaction was conducted, focus-
ing on the replacement of DMAP with triethylamine or
N,N-diisopropylethylamine (DIPEA). Thus, when phenyl-
O
N
N
I
O
N
O
O
–
O
O
base
(1)
O
O
O
O
3
2
2
II
N
N
+
N
O
–
O
O
O
R3
R2
R3
R2
O
R1
5
(2)
R1
N
LDA
N
N
4
6
Scheme 3 Side product in the esterification reaction
Synthesis 2010, No. 24, 4261–4267 © Thieme Stuttgart · New York

4264
J. A. Morales-Serna et al.
PAPER
talcite resulted in ester 2 in poor yield (20%, entry 6). This carried out in the presence of calcined hydrotalcite, ester
result, obtained with calcined hydrotalcite, increases the 16 was obtained as a single enantiomer.
already diverse range of possibilities for the use of solid
catalysts in the esterification of tertiary alcohols, specifi-
cally tert-butyl alcohol.
To test the scope of this protocol in biologically relevant
molecules, the esterification of Naproxen (17) was tested
under the standard conditions. To our delight, ester 19 was
Following the discovery of these results, we tried to ex- obtained in 95% yield when DMAP was used as the base
tend the methodology to other carboxylic acids (Table 3). and 79% yield with calcined hydrotalcite as the base
(4-Methoxyphenyl)acetic acid (7) can also be esterified (Table 4, entry 1). We also demonstrated that the esterifi-
with tert-butyl alcohol in the presence of DMAP or cal- cation reaction could be successfully achieved in a good
cined hydrotalcite, under the same reaction conditions yield with other tertiary alcohols. Thus, Naproxen (17)
used for phenylacetic acid (1), giving the ester 8 in 45% was treated with 2-methylbutan-2-ol (20) in the presence
yield with DMAP and 40% yield with calcined hydrotal- of DMAP or calcined hydrotalcite to provide ester 21 in
cite (Table 3, entry 1). When the reaction was carried out 75% and 58% yield, respectively (Table 4, entry 2). In the
with cinnamic acid (9), the yields were 60% and 55%, re- same context, the reaction was performed using another
spectively (Table 3, entry 2). The tert-butyl esters can be sterically hindered alcohol, norethisterone (17a-ethynyl-
generated in a low yield when (2,4-dichlorophenoxy)ace- 19-nortestosterone, 23) (Table 4, entry 3). Norethisterone
tic acid (11) and 4-bromobutanoic acid (13) are used as (23) belongs to the first generation of synthetic progestins;
starting materials (Table 3, entries 3 and 4), with DMAP this compound is still widely employed as a contragesta-
or calcined hydrotalcite as the base. The reaction of the tional agent as well as in hormone replacement therapy.38
glutamic acid derivative 15 was also probed under the Additionally, it has been demonstrated that norethisterone
standard conditions in the presence of the following three induces in vitro transactivation of an estrogen-regulated
bases: DMAP, DIPEA and calcined hydrotalcite. Ester 16 reporter vector transiently cotransfected with the estrogen
was obtained in 95%, 90% and 80% yield, respectively receptor a or estrogen receptor b in African green monkey
(Table 3, entry 5). In this case, there was complete racem- kidney CV-1 cells.39 In the case of the reaction of alcohol
ization of ester 16 when DMAP was used as the base. The 23 with acetic acid (22), the yield of ester 24 was 93%
use of DIPEA allowed us to obtain the ester in an enanti- when DMAP was used as the base and 90% with calcined
omeric excess of 70%; however, when the reaction was hydrotalcite as the base (Table 4, entry 3). Ester formation
Table 3 Esterification of Various Carboxylic Acids with tert-Butyl Alcohol in the Presence of DMAP or Calcined Hydrotalcitea
1. EDC, HOBt
CHCl3, r.t.
30 min
O
O
R
O
2. t-BuOH, DMAP or hydrotalcite
R
OH
CHCl3, reflux
18 h
Entry
1
Acid
Ester product
Base
Yieldb (%)
MeO
MeO
O
O
DMAP
hydrotalcite
45
40
O
7
9
8
O
OH
O
O
DMAP
hydrotalcite
60
55
2
3
10
OH
O
Cl
O
Cl
DMAP
hydrotalcite
25
25
O
O
11
12
O
OH
Cl
Br
Cl
Br
O
O
DMAP
hydrotalcite
20
18
4
5
13
15
14
16
O
OH
O
O
DMAP
DIPEA
hydrotalcite
95
90
80
BnO
BnO
O
OH
NHBoc
O
NHBoc
O
a Reaction conditions: carboxylic acid (1 mmol), EDC (1 mmol), HOBt (1 mmol), CHCl3, r.t., 30 min, and then t-BuOH (4 mmol), DMAP (4
mmol) or hydrotalcite (200 mg), reflux, 18 h.
b Yield of isolated product after chromatographic purification.
Synthesis 2010, No. 24, 4261–4267 © Thieme Stuttgart · New York

PAPER
Benzotriazole Esters in the Esterification of Tertiary Alcohols
4265
Table 4 Esterification of Sterically Hindered Alcohols Using Benzotriazole Estersa
Entry Acid
Alcohol
Ester product
Base
Yieldb
(%)
DMAP
hydrotalcite 79
95
OH
OH
O
O
1
2
17
17
18
19
OH
O
O
O
O
MeO
MeO
DMAP
hydrotalcite 58
75
20
21
OH
MeO
O
MeO
O
OH
O
DMAP
hydrotalcite 90
93
3
4
22
22
23
24
OH
O
O
O
OH
O
O
DMAP
hydrotalcite 90
95
25
26
OH
O
O
O
OH
O
O
DMAP
hydrotalcite
–
–
5
27
23
28
OH
O
O
a Reaction conditions: carboxylic acid (1 mmol), EDC (1 mmol), HOBt (1 mmol), CHCl3, r.t., 30 min, and then alcohol (1 mmol), DMAP (4
mmol) or hydrotalcite (200 mg), reflux, 18 h.
b Yield of isolated product after chromatographic purification.
chromatographically and spectroscopically (1H and 13C NMR) ho-
was not observed when both the acid and the alcohol are
mogeneous materials, unless otherwise stated. All glassware uti-
lized was flame-dried before use. Reactions were monitored by
TLC carried out on 0.25-mm E. Merck silica gel plates. Developed
TLC plates were visualized under a shortwave UV lamp and by
sterically hindered (Table 4, entry 5). Finally, the reaction
was carried out with testosterone (25) in the presence of 1
equivalent of acetic acid (22), which resulted in the ester
product 26 in 95% yield with DMAP as the base and 90%
yield with calcined hydrotalcite as the base (Table 4, entry
4).
heating plates that were dipped in Ce2(SO4)3 solution. Flash column
chromatography was performed using silica gel (230–400) and em-
ployed a solvent with polarity correlated with TLC mobility. Opti-
cal rotations were measured at 589 nm on a Jasco DIP-370 digital
polarimeter using a 100-mm cell. NMR experiments were conduct-
ed on a Varian 300-MHz instrument using CDCl3 (99.9% D) as the
solvent, with chemical shifts (d) referenced to internal standards
CDCl3 (7.26 ppm, 1H; 77.00 ppm, 13C) or TMS as internal reference
(0.00 ppm). Chemical shifts are relative to the solvent peak and are
in parts per million (ppm). Mass spectra were recorded on a Jeol
JS102 high-resolution mass spectrometer.
In summary, a method for the esterification of tertiary al-
cohols has been described. The reaction conditions have
been optimized, leading to an efficient procedure. The re-
action is broad in scope and uses commercially available
reagents. Additionally, a calcined hydrotalcite was used
as the base, replacing DMAP, with excellent results for
the formation of such esters. To further demonstrate the
synthetic value, we have shown that the method can be
used in the esterification of biologically relevant mole-
cules.
Esterification Reaction; General Procedure
In a round-bottom flask, 1 equivalent of the carboxylic acid was
added, followed by 1 equivalent of HOBt and EDC in anhyd CHCl3
(30 mL), under argon atmosphere, and the mixture was stirred for
30 min; then, DMAP (4 equiv) was added and the tertiary alcohol
(1 equiv) was injected via syringe. The reaction mixture was re-
fluxed for 18 h. At the end of the reaction time, the solvent was
All reactions were conducted under a dried argon stream. All chem-
icals were purchased from Aldrich Chemical Co. and used without
further purification, unless stated otherwise. Yields refer to the
Synthesis 2010, No. 24, 4261–4267 © Thieme Stuttgart · New York

4266
J. A. Morales-Serna et al.
PAPER
evaporated and the mixture was dissolved in Et2O (30 mL). The or-
ganic layer was washed with 10% NaHCO3 soln (2 × 10 mL), 10%
citric acid soln (2 × 10 mL), 10% K2CO3 soln (2 × 10 mL) and brine
(2 × 10 mL), then dried (anhyd Na2SO4), and the solvent was re-
moved by evaporation. The residue was purified by flash chroma-
tography on silica gel to afford the pure ester.
tert-Butyl 2-(6-Methoxy-2-naphthyl)propanoate (19)
[a]D25 +26.8 (c 1.0, CH2Cl2) {Lit.41 [a]D25 +26.9 (c 1.0, CH2Cl2)}.
1H NMR (300 MHz, CDCl3): d = 7.66 (m, 3 H), 7.40 (dd, J = 8.6,
1.8 Hz, 1 H), 7.11 (m, 2 H), 3.90 (s, 3 H), 3.73 (q, J = 7.2 Hz, 1 H),
1.51 (d, J = 7.2 Hz, 3 H), 1.38 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 173.9, 157.5, 136.3, 133.5, 129.2,
128.9, 126.9, 126.3, 125.7, 118.7, 105.6, 80.4, 55.3, 46.4, 27.9,
18.5.
tert-Butyl Phenylacetate (2)
1H NMR (300 MHz, CDCl3): d = 7.33–7.24 (m, 5 H), 3.52 (s, 2 H),
1.43 (s, 9 H).
HRMS (FAB): m/z calcd for C18H22O3: 286.1569; found: 286.1562.
13C NMR (75 MHz, CDCl3): d = 170.9, 134.7, 129.2, 128.4, 126.8,
tert-Pentyl 2-(6-Methoxy-2-naphthyl)propanoate (21)
1H NMR (200 MHz, CDCl3): d = 7.66 (m, 3 H), 7.40 (dd, J = 8.4,
1.8 Hz, 1 H), 7.10 (m, 2 H), 3.90 (s, 3 H), 3.75 (q, J = 7 Hz, 1 H),
1.71 (q, J = 7.2 Hz, 2 H), 1.55 (d, J = 7.1 Hz, 3 H), 1.35 (s, 3 H),
1.34 (s, 3 H), 0.75 (t, J = 7.2 Hz, 3 H).
13C NMR (75 MHz, CDCl3): d = 173.8, 157.5, 136.3, 133.5, 129.2,
126.7, 126.4, 125.8, 118.7, 105.6, 82.9, 55.3, 46.5, 33.5, 25.5, 25.3,
18.4, 8.0.
80.7, 42.6, 28.0.
HRMS (FAB): m/z calcd for C12H16O2: 192.1150; found: 192.1152.
tert-Butyl 3-Oxo-2,4-diphenylbutanoate (3)
1H NMR (300 MHz, CDCl3): d = 7.36–7.05 (m, 10 H), 4.72 (s, 1 H),
3.78 (d, J = 15.9 Hz, 1 H), 3.71 (d, J = 15.9 Hz, 1 H), 1.44 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 206.1, 170.0, 139.5, 134.1, 129.8,
129.2, 128.9, 127.6, 127.2, 82.1, 60.4, 48.7, 28.8.
HRMS (FAB): m/z calcd for C19H24O3: 300.1725; found: 300.1720.
HRMS (FAB): m/z calcd for C20H22O3: 310.1569; found: 310.1566.
17a-Ethynyl-19-nortestosterone Acetate (24)
tert-Butyl (4-Methoxyphenyl)acetate (8)
[a]D25 –33.1 (c 1.0, CHCl3) {Lit.42 [a]D25 –33.0 (c 1.0, CHCl3)}.
1H NMR (300 MHz, CDCl3): d = 7.18 (m, 2 H), 6.84 (m, 2 H), 3.78
(s, 3 H), 3.46 (s, 2 H), 1.43 (s, 9 H).
1H NMR (300 MHz, CDCl3): d = 5.83 (s, 1 H), 2.75 (m, 1 H), 2.61
(s, 1 H), 2.48 (m, 1 H), 2.41 (m, 1 H), 2.29 (m, 1 H), 2.28 (m, 2 H),
2.11 (m, 1 H), 2.05 (s, 3 H), 2.04 (m, 1 H), 1.93 (m, 1 H), 1.86 (m,
1 H), 1.85 (m, 1 H), 1.77 (m, 2 H), 1.74 (m, 1 H), 1.57 (m, 2 H), 1.37
(m, 2 H), 1.28 (m, 1 H), 1.12 (m, 1 H), 0.935 (s, 3 H).
13C NMR (75 MHz, CDCl3): d = 171.2, 158.5, 130.1, 126.8, 113.8,
80.6, 55.2, 41.7, 28.0.
HRMS (FAB): m/z calcd for C13H18O3: 222.1256; found: 222.1250.
13C NMR (75 MHz, CDCl3): d = 198.9, 168.7, 166.3, 124.0, 83.4,
82.1, 70.5, 49.5, 47.4, 46.9, 43.3, 39.3, 36.6, 35.0, 33.8, 33.0, 31.3,
29.4, 26.6, 23.3, 20.4, 13.2.
tert-Butyl (E)-Cinnamate (10)
1H NMR (300 MHz, CDCl3): d = 7.37 (m, 5 H), 6.44 (d, J = 15.9
Hz, 1 H), 6.37 (d, J = 16.1 Hz, 1 H), 1.54 (s, 9 H).
HRMS (FAB): m/z calcd for C22H28O3: 340.2038; found: 340.2035.
13C NMR (75 MHz, CDCl3): d = 166.3, 143.5, 129.9, 128.8, 127.9,
118.3, 80.5, 28.2.
Testosterone Acetate (3-Oxo-4-androsten-17b-yl Acetate (26)
[a]D25 +82.3 (c 1.0, CHCl3) {Lit.43 [a]D25 +82.2 (c 1.0, CH2Cl2)}.
HRMS (FAB): m/z calcd for C13H16O2: 204.1150; found: 204.1145.
1H NMR (300 MHz, CDCl3): d = 5.72 (s, 1 H), 4.60 (dd, J = 9.2, 7.9
Hz, 1 H), 2.40 (ddd, J = 16.8, 16.7, 5.2 Hz, 1 H), 2.39 (m, 1 H), 2.35
(ddd, J = 16.8, 5.1, 3.3 Hz, 1 H), 2.28 (ddd, J = 14.6, 4.3, 2.3 Hz, 1
H), 2.18 (dddd, J = 13.8, 9.5, 9.2, 6 Hz, 1 H), 2.04 (s, 3 H), 2.04
(ddd, J = 13.4, 5.2, 3.3 Hz, 1 H), 1.83 (m, 1 H), 1.79 (dt, J = 12.8,
6.8 Hz, 1 H), 1.70 (ddd, J = 16.8, 13.4, 5.1 Hz, 1 H), 1.66 (m, 1 H),
1.55 (m, 2 H), 1.52 (m, 1 H), 1.41 (m, 1 H), 1.36 (m, 1 H), 1.19 (s,
3 H), 1.18 (m, 1 H), 1.07 (m, 1 H), 1.04 (m, 1 H), 0.95 (m, 1 H), 0.84
(s, 3 H).
tert-Butyl (2,4-Dichlorophenoxy)acetate (12)
1H NMR (300 MHz, CDCl3): d = 7.39 (d, J = 2.6 Hz, 1 H), 7.15 (dd,
J = 9, 2.6 Hz, 1 H), 6.75 (d, J = 9 Hz, 1 H), 4.58 (s, 2 H), 1.47 (s, 9
H).
13C NMR (75 MHz, CDCl3): d = 167.1, 152.5, 130.2, 127.4, 126.7,
124.1, 114.4, 82.8, 66.7, 28.0.
HRMS (FAB): m/z calcd for C12H14Cl2O3: 276.0320; found:
276.0321.
13C NMR (75 MHz, CDCl3): d = 199.2, 171.0, 170.7, 124.0, 82.4,
53.8, 50.3, 42.5, 38.6, 36.7, 35.8, 35.5, 33.9, 32.7, 31.5, 27.5, 23.5,
21.1, 20.6, 17.4, 12.0.
tert-Butyl 4-Bromobutanoate (14)
1H NMR (300 MHz, CDCl3): d = 3.45 (t, J = 6.8 Hz, 2 H), 2.40 (t,
J = 7.2 Hz, 2 H), 2.13 (quint, J = 6.8 Hz, 2 H), 1.45 (s, 9 H).
HRMS (FAB): m/z calcd for C21H30O3: 330.2195; found: 330.2193.
13C NMR (75 MHz, CDCl3): d = 178.4, 85.2, 59.3, 34.5, 33.1, 27.5.
Mg–Al Hydrotalcite34
HRMS (FAB): m/z calcd for C8H15BrO2: 222.0255; found:
Hydrotalcite was characterized by powder X-ray diffraction with
Cu Ka radiation, using a Siemens diffractometer in the range from
4 to 70° (2q). FT-IR spectra were recorded on a Nicolet Magna 750
spectrometer; data collection was performed using DRIFT and KBr
disc techniques. DTA and TGA analyses were carried out on a Du-
Pont thermobalance, using He flow at a heating rate of 10 °C/min.
Specific surface areas were calculated by N2 adsorption at 75.25 K
(BET method) using a Micromeritics ASAP 2000 instrument; the
samples were first outgassed at 523 K. Mg–Al hydrotalcite with
x = Mg/Al ratio 0.33 was prepared by coprecipitation following the
procedure described by Reichle.44 Mg10Al2(OH)24CO3·6H2O:
Al(NO3)3·9H2O (0.01 mol) and Mg(NO3)2·6H2O (0.05 mol) were
dissolved in deionized H2O (70 mL). A second deionized H2O solu-
tion (100 mL) of Na2CO3 (0.1 mol) and NaOH (0.35 mol) was pre-
pared. The first solution was slowly added to the second solution.
222.0259.
tert-Butyl 2-[(Benzyloxy)carbonyl]-1-(tert-butoxycarbonyl)eth-
ylcarbamate (16)
[a]D25 +2.34 (c 1.95, EtOAc) {Lit.40 [a]D25 +2.34 (c 1.95, EtOAc)}.
1H NMR (200 MHz, CDCl3): d = 7.35 (m, 5 H), 5.45 (d, J = 8.4 Hz,
1 H), 5.15 (d, J = 12.2 Hz, 1 H), 5.1 (d, J = 12.2 Hz, 1 H), 4.45 (dt,
J = 8.4, 4.8 Hz, 1 H), 3.0 (dd, J = 16.8, 4.3 Hz, 1 H), 2.82 (dd,
J = 16.8, 4.8 Hz, 1 H), 1.44 (s, 9 H), 1.41 (s, 9 H).
13C NMR (75 MHz, CDCl3): d = 170.8, 169.9, 155.4, 135.5, 128.5,
128.3, 128.3, 82.3, 79.8, 66.6, 50.5, 37.1, 28.3, 27.8.
HRMS (FAB): m/z calcd for C20H29NO6: 379.1995; found:
379.1992.
Synthesis 2010, No. 24, 4261–4267 © Thieme Stuttgart · New York

PAPER
Benzotriazole Esters in the Esterification of Tertiary Alcohols
4267
The resulting mixture was heated at 338 K with vigorous stirring for
18 h. After the heating period, the slurry was cooled to r.t., washed
with deionized H2O until pH 9 and dried at 383 K for 18 h. Hydro-
talcites were activated by calcination at a rate of 2 °C/min up to 773
K and maintained for 2 h in a flow of air. Samples were then cooled
in dry nitrogen and stored.
(19) Salavati-Niasari, M.; Khosousi, T.; Hydarzadeh, S. J. Mol.
Catal. A: Chem. 2005, 235, 150.
(20) Vedejs, E.; Daugulis, O. J. Org. Chem. 1996, 61, 5702.
(21) Duan, Z.; Gu, Y.; Deng, Y. J. Mol. Catal. A: Chem. 2006,
246, 70.
(22) Barcelo, G.; Grenouillat, D.; Senet, J.-P.; Sennyey, G.
Tetrahedron 1990, 46, 1839.
(23) Liang, C. O.; Helms, B.; Hawker, C. J.; Fréchet, J. M. J.
Chem. Commun. 2003, 2524.
Acknowledgment
(24) Kammoun, N.; Bigot, Y. L.; Delmas, M.; Boutevin, B.
Synth. Commun. 1997, 27, 2777.
Support for this research has been provided by the Programa de
Apoyo a Proyectos de Investigación e Inovación Tecnológica
(PAPIIT-UNAM, Project No. IN207602-3). We wish to thank Ale-
jandrina Acosta and Gabriela Salcedo for their technical assistance.
(25) (a) Pozdnev, V. F. Zh. Obshch. Khim. 1988, 58, 670.
(b) Jouin, P.; Castro, B.; Zeggaf, C.; Pantaloni, A.; Senet,
J.-P.; Lecolier, S.; Sennyey, G. Tetrahedron Lett. 1987, 28,
1661. (c) Loffet, A.; Galeotti, N.; Jouin, P.; Castro, B.
Tetrahedron Lett. 1989, 30, 6859. (d) Ravi, D.; Rao, N. R.;
Reddy, G. S. R.; Sucheta, K.; Rao, V. J. Synlett 1994, 856.
(e) Gooßen, L.; Döring, A. Adv. Synth. Catal. 2003, 345,
943.
(26) (a) Widmer, U. Synthesis 1983, 135. (b) Ludwig, J.; Lehr,
M. Synth. Commun. 2004, 34, 3691.
(27) (a) Armstrong, A.; Brackenridge, I.; Jackson, R. F. W.; Kirk,
J. M. Tetrahedron Lett. 1988, 29, 2483. (b) Fritsche, A.;
Deguara, H.; Lehr, M. Synth. Commun. 2006, 36, 3117.
(28) Chevallet, P.; Garrouste, P.; Malawska, B.; Martinez, J.
Tetrahedron Lett. 1993, 34, 7409.
References
(1) (a) Wuts, P. G. M.; Greene, T. W. Greene’s Protective
Groups in Organic Synthesis, 4th ed.; John Wiley & Sons:
New Jersey, 2007. (b) Kocieński, P. J. Protecting Groups,
3rd ed.; Georg Thieme Verlag: Stuttgart, 2005.
(2) (a) McCloskey, A. L.; Fonken, G. S.; Kluiber, R. W.;
Johnson, W. S. Org. Synth., Coll. Vol. IV 1963, 261.
(b) Wright, S. W.; Hageman, D. L.; Wright, A. S.; McClure,
L. D. Tetrahedron Lett. 1997, 38, 7345. (c) Krasnov, V. P.;
Levit, G. L.; Bukrina, I. M.; Demin, A. M.; Chupakhin, O.
N.; Yoo, J. U. Tetrahedron: Asymmetry 2002, 13, 1911.
(d) Taber, D. F.; Gerstenhaber, D. A.; Zhao, X. Tetrahedron
Lett. 2006, 47, 3065.
(3) (a) Meth-Cohn, O. J. Chem. Soc., Chem. Commun. 1986,
695. (b) Bhawal, B. M.; Khanapure, S. P.; Biehl, E. R.
Synthesis 1991, 112.
(4) Vasin, V. A.; Razinb, V. V. Synlett 2001, 658.
(5) Bavetsias, V.; Bisset, G. M. F.; Jarman, M. Synth. Commun.
1995, 25, 947.
(29) Mukaiyama, T.; Shintou, T.; Fukumoto, K. J. Am. Chem.
Soc. 2003, 125, 10538.
(30) (a) Nagasawa, K.; Yoshitake, S.; Amiya, T.; Ito, K. Synth.
Commun. 1990, 20, 2033. (b) Nagasawa, K.; Ohhashi, K.;
Yamashita, A.; Ito, K. Chem. Lett. 1994, 209.
(31) Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60, 2447.
(32) Chan, L. C.; Cox, B. G. J. Org. Chem. 2007, 72, 8863.
(33) Sliedregt, K. M.; Arie, S.; Kroon, J.; Liskamp, R. M. J.
Tetrahedron Lett. 1996, 37, 4237.
(6) Grasa, G. A.; Singh, R.; Nolan, S. P. Synthesis 2004, 971.
(7) Singh, R.; Kissling, R. M.; Letellier, M.-A.; Nolan, S. P.
J. Org. Chem. 2004, 69, 209.
(8) Ramalinga, K.; Vijayalakshmi, P.; Kaimal, T. N. B.
Tetrahedron Lett. 2002, 43, 879.
(34) (a) Cárdenas, J.; Morales-Serna, J. A.; Sánchez, E.; Lomas,
L.; Guerra, N.; Negrón, G. ARKIVOC 2005, (vi), 428.
(b) Morales-Serna, J. A.; Sánchez, E.; Velázquez, R.;
Bernal, J.; García-Ríos, E.; Gaviño, R.; Negrón-Silva, G.;
Cárdenas, J. Org. Biomol. Chem. 2010, 8, 4940.
(35) Katritzky, A. R.; Pastor, A. J. Org. Chem. 2000, 65, 3679.
(36) (a) Corma, A.; Iborra, S. Adv. Catal. 2006, 49, 239.
(b) Debecker, D. P.; Gaigneaux, E. M.; Busca, G. Chem.
Eur. J. 2009, 15, 3920.
(37) (a) Di Cosimo, J. I.; Díez, V. K.; Xu, M.; Iglesia, E.;
Apesteguía, C. R. J. Catal. 1998, 178, 499. (b) Corma, A.;
Hamid, S. B. A.; Iborra, S.; Velty, A. J. Catal. 2005, 234,
340.
(38) (a) Wan, A. S. C.; Ngiam, T. L.; Leung, S. L.; Go, M. L.;
Heng, P. W. S.; Natarajan, P. N.; Shafiee, A.; Vossoghi, M.;
Savabi, F.; Francisco, C. G.; Freire, R.; Hernandez, R.;
Salazar, J. A.; Suarez, E.; Garcia de la Mora, G. A.;
Grillasca, R. Y.; Jimeno, O. Steroids 1983, 41, 309.
(b) Francisco, C. G.; Freire, R.; Hernandez, R.; Salazar, J.
A.; Suarez, E.; Garcia de la Mora, G. A.; Noguez, A. J. A.;
Acosta, H. A.; Jimeno, O. Steroids 1983, 41, 267.
(39) Pasapera, A. M.; Gutiérrez-Sagal, R.; Herrera, J.; Galicia-
Canales, N.; García de la Mora, G.; Ulloa-Aguirre, A. Eur.
J. Pharmacol. 2002, 452, 347.
(9) Tararov, V. I.; Korostylev, A.; König, G.; Börner, A. Synth.
Commun. 2006, 36, 187.
(10) (a) Wiener, H.; Gilon, C. J. Mol. Catal. 1986, 37, 45.
(b) Barker, D.; McLeod, M. D.; Brimble, M. A.; Savage, G.
P. Tetrahedron Lett. 2001, 42, 1785. (c) Nahmany, M.;
Melman, A. Org. Lett. 2001, 3, 3733. (d) Shimizu, T.;
Hiramoto, K.; Nakata, T. Synthesis 2001, 1027. (e) Streinz,
L.; Koutek, B.; Šaman, D. Synlett 2001, 809. (f) Falck, J.
R.; Sangrasa, B.; Capdevila, J. H. Bioorg. Med. Chem. 2007,
15, 1062.
(11) Gacem, B.; Jenner, G. Tetrahedron Lett. 2003, 44, 1391.
(12) Jermy, B. R.; Pandurangan, A. Appl. Catal., A 2005, 288, 25.
(13) Srinivas, K. V. N. S.; Mahender, I.; Das, B. Synthesis 2003,
2479.
(14) Alizadeh, M. H.; Kermani, T.; Tayebee, R. Monatsh. Chem.
2007, 138, 165.
(15) (a) Hills, M. J.; Kiewitt, I.; Mukherjee, K. D. Biochim.
Biophys. Acta 1990, 1042, 237. (b) Gulati, R.; Arya, P.;
Malhotra, B.; Prasad, A. K.; Saxena, R. K.; Kumar, J.;
Watterson, A. C.; Parmar, V. S. ARKIVOC 2003, (iii), 159.
(16) (a) Moghadam, M.; Tangestaninejad, S.; Mirkhani, V.;
Mohammadpour-Baltork, I.; Shaibani, R. J. Mol. Catal. A:
Chem. 2004, 219, 73. (b) Dumeunier, R.; Markó, I. E.
Tetrahedron Lett. 2004, 45, 825. (c) Karimi, B.; Maleki, J.
J. Org. Chem. 2003, 68, 4951.
(17) Choudhary, V. R.; Mantri, K.; Jana, S. K. Catal. Commun.
2001, 2, 57.
(18) Choudhary, V. R.; Mantri, K.; Jana, S. K. Microporous
Mesoporous Mater. 2001, 47, 179.
(40) Li, X.; Atkinson, R. N.; King, S. B. Tetrahedron 2001, 57,
6557.
(41) Nagasawa, K.; Yoshitake, S.; Amiya, T.; Ito, K. Synth.
Commun. 1990, 20, 2033.
(42) Iriarte, J.; Djerassi, C.; Ringold, H. J. J. Am. Chem. Soc.
1959, 81, 436.
(43) Iwasaki, T.; Maegawa, Y.; Hayashi, Y.; Ohshima, T.;
Mashima, K. Synlett 2009, 1659.
(44) Reichle, W. T. J. Catal. 1985, 94, 547.
Synthesis 2010, No. 24, 4261–4267 © Thieme Stuttgart · New York