Water at elevated temperatures (WET): Reactant, catalyst, and solvent in the selective hydrolysis of protecting groups

Article abstract of DOI:10.1039/c3gc42569j

Water at elevated temperatures (WET) can act simultaneously as reactant, solvent, and catalyst in reaction processes. WET has been successfully employed in the removal of protecting groups alleviating the need for added strong acids/bases, subsequent neutralization and waste salt elimination. The protocols for the water-mediated removal of several common protecting groups such as tert-butyl carbamates (N-Boc) from 125 to 150 °C, acetamide (N-Ac) at 275 °C and acetate esters (O-Ac) at 250 °C are reported for different model aryl compounds. In addition, high yields and selective deprotection of one protecting group in the presence of another by simply tuning the temperature is demonstrated. In order to gain further insights into reaction processes, the aqueous solubilities of several of the reactants, the kinetics and mechanisms associated with some of these reactions are also discussed. the Partner Organisations 2014.

Full text of DOI:10.1039/c3gc42569j

Volume 16 Number 4 April 2014 Pages 1651–2300
Green
Chemistry
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PAPER
Charles L. Liotta et al.
Water at elevated temperatures (WET): reactant, catalyst, and solvent in the
selective hydrolysis of protecting groups

Green Chemistry
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Water at elevated temperatures (WET): reactant,
catalyst, and solvent in the selective hydrolysis of
protecting groups†
Cite this: Green Chem., 2014, 16,
2147
Wilmarie Medina-Ramos,a Mike A. Mojica,b Elizabeth D. Cope,b Ryan J. Hart,a
Pamela Pollet,b,c Charles A. Eckerta,b,c and Charles L. Liotta*a,b,c
Water at elevated temperatures (WET) can act simultaneously as reactant, solvent, and catalyst in reaction
processes. WET has been successfully employed in the removal of protecting groups alleviating the need
for added strong acids/bases, subsequent neutralization and waste salt elimination. The protocols for the
water-mediated removal of several common protecting groups such as tert-butyl carbamates (N-Boc)
from 125 to 150 °C, acetamide (N-Ac) at 275 °C and acetate esters (O-Ac) at 250 °C are reported for
different model aryl compounds. In addition, high yields and selective deprotection of one protecting
group in the presence of another by simply tuning the temperature is demonstrated. In order to gain
further insights into reaction processes, the aqueous solubilities of several of the reactants, the kinetics
and mechanisms associated with some of these reactions are also discussed.
Received 17th December 2013,
Accepted 4th February 2014
DOI: 10.1039/c3gc42569j
www.rsc.org/greenchem
for conducting organic transformations, product separation
and isolation are also more facile. In principle, simply cooling
Introduction
Water is considered by many to be a green solvent for conduct- of the reaction mixture will result in phase separation of the
ing reaction processes. Unfortunately, water at ambient temp- organic products from water. WET, therefore, can provide an
eratures is a poor solvent for most organic reactants. In attractive and environmentally benign solvent for reactions
contrast, however, water at elevated temperatures (WET) has and processes. Indeed, WET has been used in hydrolysis reac-
substantially different physiochemical properties and can be tions,5 Claisen–Schmidt condensation reactions,6 and Friedel–
employed for conducting a wide range of synthetic transform- Crafts alkylation and acylation reactions7 without the addition
ations and subsequent separations.1 In particular, as water is of “external” acids or bases. In addition, unique transform-
heated from ambient temperature to 275 °C the dielectric con- ations can also be easily achieved. In particular, acetyl and
stant (ε), the auto-ionization constant (Kw), and the density (ρ) nitro substituents attached to electron-rich aromatic rings can
of water change continuously. Specifically, the dielectric con- be efficiently removed and replaced by hydrogen.8 In general,
stant2 decreases from 78 to approximately 20, the auto-ioniza- each of these reactions takes place at different rates and there-
tion constant3 increases from 10−14 to 10−11, and the density4 fore at substantially different temperatures. As a result, the
decreases from 1 g cm−3 to 0.75 g cm−3. Thus, WET takes on properties of water can be tuned by adjusting the temperature
the character of an organic solvent; the solubility of organic to meet specific solvent property and reactivity needs. This
molecules increases. In addition, since the auto-ionization unique capability is an opportunity to design greener protocols
constant increases at elevated temperatures, both acid and for acid-catalyzed transformations such as the removal of pro-
base catalyzed processes are also enhanced. While these phy- tecting groups.9
siochemical properties of WET can provide an effective vehicle
The use of protecting groups in multistep organic synthesis
is ubiquitous.10 Commonly however their removal requires
strong acidic conditions followed by post-reaction neutraliz-
ation steps leading to large waste stream. From a green chem-
istry9 point of view it would be preferable to develop selective
reactions which do not require protecting groups, but the
reality is that this is not always possible. As a consequence the
development of green protocols for the protection and sub-
sequent removal of these groups have become important con-
siderations. Herein, we address the use of WET to effectively
aDepartment of Chemical and Biomolecular Engineering, Georgia Institute of
Technology, Atlanta, Georgia 30332-0100, USA
bDepartment of Chemistry and Biochemistry, Georgia Institute of Technology,
Atlanta, Georgia 30332-0400, USA
cSpecialty Separations Center, Georgia Institute of Technology, Atlanta,
Georgia 30332-0100, USA. E-mail: charles.liotta@chemistry.gatech.edu
†Electronic supplementary information (ESI) available. See DOI:
10.1039/c3gc42569j
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and selectively remove some typical protecting groups from approximate concentration of 0.033 M in a volume of water of
amine and alcohol functionalities. We demonstrate that by 1.5 mL. The titanium reactors were then placed in a thermo-
just tuning the temperature of the water, selective removal of stated aluminum heating block. The temperature of the
one protecting group in the presence of a second can be rea- heating block varied by 1 °C and was maintained using four
lized. The temperatures employed range from 125 °C to cartridges heaters (Omega Technologies Co.) and a tempera-
275 °C. In addition, the kinetics and the associated mecha- ture controller (Omega Model CN76000). An over-temperature
nisms for the WET hydrolyses are presented. Typical protecting probe (I2R Model OTP-1500) was also employed as safety pre-
groups investigated for amines are tert-butyl carbamate (N-Boc) caution to prevent the block from overheating in the case of a
and acetamide (N-Ac) derivative and for alcohols the acetate temperature controller failure. The heating block was pre-
(O-Ac) derivatives. We report the protocols for the deprotection heated to desire temperatures ranging from 125 to 275 °C and
of the individual protecting groups as well as the competitive the pressures in the individual reactors was generated solely by
and selective deprotection of molecules containing two the vapor pressure of the liquid medium (approximately 0.5 to
different protecting groups.
4 MPa). The reactors reached the reaction temperatures in less
than 5 minutes and were withdrawn at various reaction times
and quenched in a room temperature water bath. Upon com-
pletion, the reactor contents were diluted in acetonitrile in a
single phase and separated and quantified using HPLC (HP
1100 with a UV detector using a Phenomenex Luna 5 µm
C18(2) reverse phase column) and LCMS (Waters Alliance 2965
Separations Module with a Waters 2998 PDA and a Waters
3100 SQD MS (ESI positive) using a Phenomenex Luna C18(2)
column (3 µm, 4.6 × 75 mm).
tert-Butyl(4-acetamidophenyl)carbamate. To 2 g (0.00960
mol) of tert-butyl(4-aminophenyl)carbamate was added
200 mL anhydrous DCM under nitrogen with stirring in an ice-
water bath. 1.0 mL (0.0124 mol) of anhydrous pyridine was
added dropwise to the cold solution. The reaction mixture was
stirred for 10 minutes and 1 mL (0.0106 mol) of acetic an-
hydride was added dropwise. After 10 minutes of stirring, the
ice-water bath was removed and the reaction proceeded at
room temperature for 4 hours. The reaction mixture was neu-
tralized with saturated sodium carbonate under vigorous stir-
ring. Additional water and DCM were added and the organic
layer separated, dried, and evaporated under reduced pressure.
The product was recrystallized in toluene. The white solid was
filtered, washed with toluene, and dried in a vacuum oven
overnight yielding 0.903 g of product (82%), mp. 180–186 °C.
1H NMR (DMSO) δ 1.46 (s, 9H), δ 2.00 (s, 3H), δ 7.34 (d, 2H),
δ 7.43 (d, 2H), δ 9.20 (s, 1H), δ 9.78 (s, 1H). 13C NMR (DMSO-
d6) δ 23.84, δ 28.14, δ 78.81, δ 118.50, δ 119.52, δ 133.89,
δ 134.79, δ 152.85, δ 167.86. Elemental analysis: Theoretical: C:
62.38%, H: 7.25%, N: 11.79%. Found: C: 62.35%, H: 7.36%, N:
11.07%. Mass (ESI+): 151.1 m/z.
Experimental
Materials
Unless otherwise noted, all compounds were purchased from
commercial sources. The following reactants and reagents
were used without further purification: acetonitrile (Aldrich,
HLPC Grade 99+%), water (Aldrich, HPLC grade), tert-butyl
phenylcarbonate (Aldrich, 97%), aniline (Aldrich, ACS reagent
grade ≥99.5%), p-methoxyaniline (Aldrich, ACS reagent grade),
p-chloroaniline (Aldrich, ACS reagent grade), acetanilide
(Aldrich, 97%), p-acetanisidide (TCI, 98%), 4′-acetoxyacetani-
lide (TCI, >98%), di-tert-butyl dicarbonate (Aldrich, 97%),
ethanol (Aldrich), diethyl ether (Aldrich), magnesium sulfate
(Aldrich, 98%). The deionized water was obtained in-house
using a Barnstead B-Pure dual filter water filtration system,
with a resistivity >18 MΩ.
Experimental apparatus and procedure
The reactions were performed in closed 3 mL titanium batch
reactors (Fig. 1). These reactors were designed and produced
in-house and were sealed with titanium NPT plugs. Titanium
was used as the material of construction due to the very low
level of transition metals and corrosion resistance of the metal
(316 Stainless Steel reactors were found to catalyze unwanted
side reactions). The reactors were loaded to have an
tert-Butyl(4-pivalamidophenyl)carbamate. To 0.8 g (0.00384
mol) of tert-butyl(4-aminophenyl)carbamate was added 65 mL
anhydrous DCM under nitrogen with stirring in an ice-bath.
0.350 mL (0.0043 mol) of anhydrous pyridine was added drop-
wise to the cold solution. The reaction mixture was stirred for
10 minutes and 0.512 mL (0.00416 mol) of pivaloyl chloride
was added dropwise. After 10 minutes of stirring, the ice-water
bath was removed and the reaction proceeded at room temp-
erature for 4 hours. The reaction mixture was neutralized with
saturated sodium carbonate under vigorous stirring.
Additional water and DCM were added and the organic layer
separated, dried, and evaporated under reduced pressure. The
product was recrystallized from toluene. The white solid was
Fig. 1 Titanium batch reactor and thermostated aluminum heating
block.
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filtered, washed with toluene, and dried in a vacuum oven of water at 150 °C is approximately 40, a value similar to aceto-
overnight yielding 0.903 g of product (80%), mp. 214–220 °C. nitrile which is a relatively good solvent for organic substrates.
1H NMR (DMSO-d6) δ 1.21 (s, 9H), δ 1.47 (s, 9H), δ 7.36 (d,
In order to gain a deeper mechanistic understanding of
2H), δ 7.49 (d, 2H), δ 9.07 (s, 1H), δ 9.22 (s, 1H). 13C NMR this important deprotection protocol, the tert-butyl carbamate
(DMSO) δ 27.29, δ 28.17, δ 38.96, δ 78.79, δ 118.10, δ 120.90, (N-Boc) derivatives of aniline, p-methoxyaniline, and p-chloro-
δ 133.78, δ 134.96, δ 152.82, δ 176.09. Elemental analysis: aniline were subject to WET at 150 °C. These three substrates
Theoretical: C: 65.73%, H: 8.27%, N: 9.58%. Found: C: were chosen to explore the effect of electron-donating (p-OMe)
66.00%, H: 8.12%, N: 9.48%. Mass (ESI+): 193.3 m/z.
and electron-withdrawing (p-Cl) substituents on the rates of
4-((tert-Butoxycarbonyl)amino)phenyl acetate. A 25 mL hydrolysis. Each of the hydrolysis rates was followed as a func-
round bottom flask was charged with 0.75 g (0.00496 mol) of tion of time using HPLC and the results are summarized in
4-aminophenyl acetate and 1.37 g (0.00595 mol) of melted Table 1 and graphically in Fig. 2. All the reactions proceeded
(about 40 °C) of di-tert-butyl dicarbonate. 0.12 g (5% mol) of successfully with short reaction times. The rates of hydrolysis
ground Bi(NO3)3·5H2O was added to the neat mixture. The
mixture was stirred at 40 °C for 10 minutes. Water was added
to the mixture and the organics were extracted with ethyl
acetate. The organic layer was dried with MgSO4, filtered and
the solvent removed by rotary evaporation. The crude was puri-
fied with on a silica column with hexane–ethyl acetate (80 : 20,
50 : 50). 0.76 g (61%) of product (white solid) isolated. 1H NMR
(CDCl3) δ 1.49 (s, 9H), δ 2.25 (s, 3H), δ 6.76 (broad, 1H),
δ 6.99–6.95 (dt, 2H), δ 7.34–7.32 (d, 2H). 13C NMR (CDCl3) δ
20.98, δ 28.24, δ 80.48, δ 119.34, δ 121.81, δ 136.03, δ 145.84,
δ 152.72, δ 169.66. Elemental analysis: Theoretical: C: 62.14%,
H: 6.82%, N: 5.57%. Found: C: 61.61%, H: 7.14%, N: 4.95%.
Mass (ES+): 252 m/z.
Table 1 WET hydrolysis of tert-butyl carbamatesa
Entry
R1
Time (min)
Yieldb (%)
1
2
3
H
20
40
90
100
95
0
5
0
12
OCH3
Cl13
100
a Reactions were conducted with 0.05 mmol of substrate in 1.5 mL de-
ionized water at 150 °C in a closed vessel (see Experimental section).
b Yield was calculated using the HPLC data and calibration curves.
Results and discussion
WET hydrolysis of tert-butyl carbamates
Amine protecting groups are frequently employed in multistep
synthetic sequences. Among the various amine protecting
groups, the tert-butyl carbamate (N-Boc) group is perhaps the
most widely used due to its stability towards a variety of
reagents and reaction conditions. In addition, it can be easily
cleaved with a strong acid. Typical deprotections protocols
involve the use of hydrochloric acid, trifluoroacetic acid or
methanesulfonic acid.11 Recently it has been reported that the
hydrolysis of the N-Boc group can be achieved in hot water.
Specifically, G. Wang et al. reported the hydrolysis of N-Boc
derivatives of a wide variety of aryl amines at 150 °C and con-
cluded that electron-donating groups facilitated the reaction
while electron-withdrawing groups retarded the reaction.5d
Almost simultaneously, J. Wang et al. reported the hydrolysis
of N-Boc derivatives of nitrogen-containing heterocycles (imi-
dazole, pyrazole, benzimidazole, and benzotriazole), aryl
amines, and a variety of aliphatic and alicyclic amines in
boiling water (100 °C) open to the atmosphere.5a In comparing
a series of N-Boc derivatives of 3- and 4-substituted anilines,
they reported that “no obvious electronic substitution effect on
the phenyl ring was observed”. They further suggested that the
dominant influence on the rate of hydrolysis is the relative
solubilities of the N-Boc derivatives at the reaction tempera-
tures. Could a difference of 50 degrees increase the substrate
solubilities and account for these qualitative observations? In
Fig. 2 WET hydrolysis of tert-butyl carbamate group from different
protected anilines as a function of time at 150 °C: (A) yield of aniline
(entry 1), (B) yield of p-methoxyaniline (entry 2), (C) yield of p-chloro-
principle, this could be the case since the dielectric constant aniline (entry 3).
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of the N-Boc protecting groups follow the order: aniline >
p-methoxyaniline > p-chloroaniline. In addition, the hydrolysis
rates for aniline and p-methoxyaniline were characterized by
S-shaped curves, whereas the p-chloroaniline was not. Also, the
hydrolysis of the N-Boc derivative of p-chloroaniline requires
longer reaction times compared to the parent and methoxy
substituted aniline.
In all cases, it was observed in the HPLC chromatograms
that, in addition to the two peaks associated with the reactant
and product, an additional peak appeared shortly after the
reaction began, remained through the reaction, and sub-
sequently disappeared at the end of the reaction (see Fig. 3).
Employing LC-MS analysis these species were identified as dia-
rylureas as shown in Fig. 4. It is postulated that these species
arise from the reaction of the initially formed aniline with the
N-Boc protected aniline. Under the conditions of the reaction,
these diarylureas are ultimately hydrolyzed to yield the corres-
ponding aniline (Fig. 5). Although the removal of the N-Boc
group from different protected anilines in water has been
reported,5a,d there has been no mention of urea formation and
disappearance.
Fig. 5 Equations describing the WET hydrolysis of the N-Boc group
from protected anilines.
the different observations arise from different solubilities at
100 °C and 150 °C?
Kinetics of N-Boc-derivative hydrolyses. As indicated above
the rate profiles for the formation of aniline and p-methoxy-
aniline are described by S-shaped curves. These observations
could arise from the operation of autocatalytic processes or
possibly from two consecutive first order processes. While
each of these reaction does show the presence of a diarylurea,
which could be interpreted as an intermediate, these particu-
lar species are formed in very small quantities and remain con-
stant throughout most of the reaction – an observation which
is not consistent with two consecutive first order reactions.
Indeed, the corresponding diarylurea is also observed in the
hydrolysis of the N-Boc derivative of p-chloroaniline even
though the corresponding kinetic profile does not exhibit the
S-shaped character.
As seen in Fig. 2, the hydrolysis rate profiles are quite
different for the N-Boc derivatives of aniline and p-methoxy-
aniline as compared to p-chloroaniline. The former are character-
ized by S-shaped curves while the latter is not. In addition, the
electron-donating methoxy and electron-withdrawing chloro
substituted substrates reacted more slowly than the parent
derivative. These results are conflicting with the conclusions
reported by G. Wang et al. and appear to be in agreement with
those of J. Wang et al. Thus, in order to gain a better under-
standing of the reaction process the following questions are
pertinent: Why are the kinetic profiles of the N-Boc derivative
different? Is mass transfer affecting the rate profiles? Could
The kinetic data for each of the N-Boc derivatives were ana-
lyzed using the integrated rate expressions for both pseudo-
first order and auto-catalytic processes14 (see ESI†). The results
are displayed in Table 2. It appears that auto-catalysis kinetics
fits best for the Boc derivatives of aniline while first order kine-
tics best describes the p-chloroaniline. Based on the corre-
lation coefficients, it is not clear which of these kinetic
descriptions fits the Boc derivative of p-methoxyaniline.
Since the reactions reported herein were conducted in
closed systems, the carbon dioxide produced during the
course of reaction is confined to the reaction vessel. As a con-
sequence, it is conjectured that the released carbon dioxide
would react with water to form carbonic acid, with tert-butanol
to form tert-butylcarbonic acid, and/or with the amine product
to form arylammonium carbamates (see Fig. 6). In principle,
each of these species could function as an acid catalyst in the
hydrolysis pathway and could account for auto-catalysis kine-
tics. At this juncture the explanation for the different kinetic
descriptions between the Boc derivatives of aniline and
p-methoxyaniline compared to p-chloroaniline is not yet fully
understood. However, the significant lower reactivity of the
Fig. 3 HPLC chromatograms for the removal of the N-Boc group from
tert-butyl phenylcarbamate showing the appearance of aniline (1), the
appearance and disappearance of 1,3-diphenylurea (2) and the disap-
pearance of tert-butyl phenylcarbamate (3) as a function of reaction
time.
Fig. 4 Diarylureas formed during WET hydrolysis.
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difference between the model amides and the actual Boc
derivative is an oxygen atom. In order to validate the use of
these models, the room temperature (25 °C) solubilities of the
actual Boc derivatives employed in this study were experi-
mentally determined and also estimated using COSMOtherm16
and ACD software packages.17 The agreement is excellent. It is
concluded that (1) the experimental room temperature (25 °C)
solubilities of the model amides are comparable to the experi-
mental and calculated solubilities of the corresponding Boc
derivatives and (2) the calculated solubilities of the model
amides at 150 °C indicate that under the hydrolysis conditions
presented here the N-phenylpivalamide and N-(4-methoxy-
phenyl)pivalamide would be completely soluble while the N-(4-
chlorophenyl)pivalamide would only be partially soluble
(approximately 22%). It is assumed that the Boc derivatives
exhibit similar relative and “absolute” solubilities as the
model amides.
Table 2 The first-order an autocatalytic rate constants with correlation
coefficientsa
First order reaction
Auto-catalytic reaction
R1
k (min−1
)
R2
k (L mol−1 min−1
)
R2
H
OCH3
Cl
0.19
0.08
0.02
0.7967
0.9317
0.9779
86.76
35.63
13.32
0.9255
0.9503
0.7960
a Initial concentration was calculated at 5 minutes, since this is the
time needed to reach reaction temperature (150 °C).
While the results reported here clearly show that the Boc
derivative of 4-chloroaniline reacts more slowly than the
4-methoxy counterpart, in agreement with J. Wang, the expla-
nation could be a consequence of partial solubility and the
accompanying contribution of mass transfer to the overall kine-
tics. Overall, the facile deprotection protocol proceeds smoothly
and quantitatively. The work reported here coupled with recent
literature reports5a,d demonstrate that WET can be an effective
vehicle for the removal of the Boc protecting group.
Competitive and selective WET hydrolyses. The competitive
and selective removal of the tert-butyl carbamate (N-Boc) pro-
tecting group in the presence of other amine or alcohol pro-
tecting groups using WET at 150 °C has also been investigated.
The Boc derivatives of N-(4-aminophenyl)acetamide and N-(4-
aminophenyl)pivalamide were used in exploring the competi-
tive cleavage of the N-Boc protecting group in the presence of
an amide protecting group (Table 4). The yields as a function
of time for each of these reactions are graphically displayed in
Fig. 7. The rates of hydrolysis of the N-Boc-(4-aminophenyl)
acetamide is greater than that of N-Boc-(4-aminophenyl)pival-
amide; the former was completed in 20 minutes while the
latter required approximately 75 minutes. The rate profile for
the pivalamide derivative exhibits the S-shaped curve reminis-
cent of the Boc derivatives of aniline and p-methoxyaniline. In
this particular case, however, it is conjectured that the rate
profile differences as well as the overall rates are attributed to
differences in solubility. The pivalamide (N-Piv) derivative is
more hydrophobic and therefore less soluble than the corres-
ponding acetamide (N-Ac) derivative. Indeed, solubility esti-
mates using COSMOtherm software package indicate that the
acetamide substrate is fifteen times more soluble in water at
room temperature than the pivalamide16 substrate (see ESI†).
It is projected that this difference should also be reflected at
the higher temperatures. Solubilities and rate profiles aside, in
both cases, the N-Boc groups were cleaved selectively to the
corresponding amines in excellent yields with the amide
groups remaining intact.
Fig. 6 Formation of carbonic acid, tert-butylcarbonic acid, and aryl-
ammonium arylcarbamates from CO2 generated during the WET hydro-
lysis of the N-Boc protecting group.
chloro derivatives suggest that mass transfer may be affecting
the rate profile of the reactions. As a consequence, we chose to
estimate the solubility of the N-Boc substrates in water at
150 °C.
Solubility estimates of N-Boc protected aniline derivatives.
Experimentally, it would be difficult to accurately determine
the solubilities of the N-Boc derivatives at elevated tempera-
tures since hydrolysis would compete with the measurements.
In addition, accurate sampling of the water solutions at temp-
eratures above 100 °C would be experimentally problematic. As
a consequence the solubilities were estimated by experiments
coupled with theoretical calculations. The solubilities of ana-
logous model aryl amides which were “hydrolytically stable”
were determined experimentally by gravimetric analysis at a
series of temperatures below 100 °C. Using a non-ideal solubi-
lity equation,15 the activity coefficients were determined using
the experimental data and the solubility at 150 °C for the
different model amide substrates were then calculated (see
ESI†). The experimental and estimated solubilities of the Boc
substrates as well as for the model amide substrates are sum-
marized in Table 3. It should be pointed out that the only
The selective removal of the N-Boc group in the presence of
an alcohol protecting group, O-acetyl (O-Ac), was also
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Table 3 Summary of experimental and calculated solubilities
Boc substrates
Analogous model substrates (amide)
Experimental solubility Estimated by
Estimated by ACD
software at 25 °C
Experimental solubility Estimated with experimental
at 25 °C
COSMO-RS at 25 °C
at 22 °C
data at 150 °C
R1
Solubility (g L−1
)
H
OCH3
Cl
0.22
—
0.12
0.12
0.12
0.03
0.33
0.31
0.06
0.363
0.437
0.061
5.84
8.44
1.70
investigated. 4-((tert-Butoxycarbonyl)amino)phenyl acetate was
subject to WET at 150 °C. A 96% conversion after 40 minutes
with an accompanying 70% yield of 4-aminophenyl acetate
(desired product) was achieved. Under these conditions,
however, the side products N-(4-hydroxyphenyl)acetamide,
4-acetamidophenyl acetate and 4-aminophenol were also
formed (see Fig. 8). At still higher temperatures (200 °C) the
amounts of these side products dramatically increased. It is
believed that these side products arose from acyl transfer pro-
cesses between the free amino nitrogen on one molecule with
the acyl ester on another molecule. Clearly, the reaction con-
ditions were too severe. In addition, the desired product itself
was not stable over time. Indeed, it was observed that over a
period of a week the isolated product, 4-aminophenyl acetate,
slowly underwent acyl transfer to form these same side pro-
ducts. Milder conditions and subsequent derivatization of the
product would be necessary in order to employ this deprotec-
tion protocol. As a consequence a lower WET reactions temp-
erature of 125 °C was investigated (Table 5). It was found that
100% conversion could be achieved over a 150 minute time
period with a yield of 90%. Less than 10% of the side products
were detected. The yields of 4-aminophenylacetate as function
of time at 125 °C are displayed in Fig. 9. By tuning the temp-
erature, we were able to selectively remove the N-Boc group
while leaving the O-Ac group intact. The lower reaction temp-
erature was necessary to maintain high selectivity toward the
removal of the N-Boc group.
Table 4 Selective WET hydrolysis of the Boc group in the presence of
an amide protecting groupa
Entry
R1
Time (min)
Yieldb (%)
4
5
N-Acc
20
75
100
97
0
1
N-Pivd
a Reactions were conducted with 0.05 mmol of substrate in 1.5 mL de-
ionized water at 150 °C in a closed vessel (see Experimental section).
b Yield was calculated using the HPLC data and calibration curves.
c Ac = acetyl (CvO)CH3. d Piv = pivaloyl (CvO)C(CH3)3.
Fig. 7 WET hydrolysis of N-Boc group of different protected anilines
containing a second amine-protecting group as a function of time at
150 °C: (D) yield of N-(4-aminophenyl) acetamide (entry 4), (E) yield of
N-(4-aminophenyl) pivalamide (entry 5).
Fig. 8 Formation of desired product along with side products such as
N-(4-hydroxyphenyl)acetamide, 4-acetamidophenyl acetate, and
4-aminophenyl at higher temperatures due to acyl migration.
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Table 5 WET hydrolysis of the Boc group in the presence of an acetate
groupa
Table 6 WET hydrolysis of amide groupsa
Entry
R2
Time (min)
Yieldb (%)
Entry
6
R1
Time (min)
150
Yieldb (%)
90
7
H
H
OMe
OMe
250
250
400
400
35
97
46
92
8c
9
O-Acc
a Reactions were conducted with 0.05 mmol of substrate in 1.5 mL de- 10c
ionized water at 150 °C in a closed vessel (see Experimental section).
b Yield was calculated using the HPLC data and calibration curves.
c Ac = acetyl (CvO)CH3.
a All reactions were conducted with 0.05 mmol of substrate in 1.5 mL
de-ionized water at 275 °C in a closed vessel (see Experimental
section). b Yield was calculated using the HPLC data and calibration
curves. c Reaction conducted with degassed water and under nitrogen
atmosphere.
Fig. 9 Removal of N-Boc group of a protected aniline containing a
second alcohol-protecting group as a function of time at 125 °C: (F)
yield of 4-aminophenyl acetate (entry 6).
WET hydrolysis of amides. Another common protecting
group for amines is the acetyl derivative (N-Ac). Removal of
this protecting group usually requires strongly acidic or basic
conditions. For example, N-Ac group could be hydrolyzed
using a hydrochloric acid–water solution at reflux temperatures
for one hour.18 This procedure, of course, must be
accompanied by the subsequent neutralization of the acid in
order to isolate the amine products. To investigate the use of
WET, where the neutralization step is not needed, model sub-
strates were employed. Acetanilide and 4-methoxyacetanilide
were subject to WET at 275 °C. The results are summarized in
Table 6 and the yields of products as a function of time are
illustrated in Fig. 10. In previous reactions with Boc protected
substrates no precautions were made to exclude air from the
closed vessels. Under these conditions, the yields of aniline
and 4-methoxyaniline were 35% (entry 7) and 46% (entry 9),
respectively. The major side products were phenazine deriva-
tives – the products from an oxidative coupling of the aryl
amine products (Fig. 11). These side products were identified
by means of LC-MS analyses. When the same reactions were
conducted in the absence of oxygen, the desired hydrolysis
products were obtained in near quantitative yields (entries 8
and 10). Under these conditions only trace quantities of the
phenazines were detected. It was concluded that high tempera-
Fig. 10 Removal an amide protecting group from different protected
anilines as a function of time: (G) yield of aniline (entries 7 and 8) under
□
■
air atmosphere ( ) and under N2 atmosphere ( ), (H) yield of 4-amino-
□
phenol (entries 9 and 10) under air atmosphere ( ) and under N2 atmos-
■
phere ( ).
Fig. 11 Formation of phenazine derivatives in the presence of air at
ture deprotection procedures forming easily oxidized products
high temperature.
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must be conducted in the absence of air. It is interesting to 30 minutes. In the case of the phenyl acetate (entry 11), the
note that the methoxy substituent is stable under the con- deprotection was achieved in 20 minutes and 92% yield was
ditions of amide hydrolysis.
obtained. In the case of the acetamide (N-Ac) substituted ester
WET hydrolysis of esters. Acetate esters are often used as (entry 12), complete and selective deprotection of the O-Ac was
protecting groups for alcohol functionalities. Generally, acetate obtained in 30 minutes at 250 °C, leaving the acetamide group
esters can be hydrolyzed under acidic or basic conditions.11 intact.
Neutralization of the acid or base, however, must also precede
the isolation of the alcohol product – an additional process
step which produces waste salts. We previously reported that Conclusions
meta- and para-substituted methyl and ethyl benzoate esters
The Boc derivatives of anilines and substituted anilines were
are hydrolyzed using WET at temperatures greater than
fully deprotected under relatively mild conditions (125 °C to
250 °C.5c In contrast, no phenyl esters have yet to be subjected
150 °C) and short reaction times (less than 2 hours). Acet-
amides (N-Ac) and acetates (O-Ac) were also successfully hydro-
lyzed at higher temperatures, 275 °C and 250 °C, respectively.
to WET conditions. Since the phenol products are electron-
rich aromatics which can be easily oxidized and since the
temperatures for ester hydrolysis are near of those for hydro-
Excellent yields were achieved in all cases. It was demonstrated
lysis of amides, the WET procedure was conducted under a
that the reaction selectivity can be tuned by simply adjusting
nitrogen atmosphere. Phenyl acetate and 4-acetamidophenyl
the temperature of the WET system. Several scenarios were
acetate were investigated as substrates for this process. The
explored for proof of concept: (1) selective removal of a carba-
latter substrate was chosen in order to determine if the ester
functionality could be hydrolyzed in the presence of the
amide. The deprotection of the phenyl acetate derivatives to
their corresponding phenols was conducted in WET at 250 °C.
The results are summarized in Table 7. Fig. 12 shows the
yields as a function of time for N-(4-hydroxyphenyl)acetamide
(entry 12). The reactions proceeded rapidly in less than
mate group (i.e. N-Boc) in the presence of amides and acetate
(i.e. N-Ac, N-Piv, O-Ac); (2) selective deprotection of an acetate
(i.e. O-Ac) group in the presence of an amide (i.e. N-Ac) and (3)
removal of an acetamide (N-Ac) derivative. In all cases, selec-
tive and near quantitative deprotection of the targeted func-
tional group was achieved. It should be emphasized, however,
that the protocols discussed here may not be applicable to sub-
strates which cannot tolerate high temperatures. Nevertheless
this study demonstrates that WET can be an attractive alterna-
Table 7 WET hydrolysis of estersa
tive solvent vehicle for the development of sustainable,
environmentally greener processes.
Acknowledgements
We would like to thank James O. Andrews and Todd Zhen for
their laboratory assistance; and Maria Gonzalez-Miquel for
calculating the predicted properties using COSMOtherm.
Entry
R3
Time (min)
Yieldb (%)
11
12
H
N-Ac
20
30
92
99
a Reactions were conducted with 0.05 mmol of substrate in 1.5 mL de-
ionized water at 250 °C in a closed vessel (see Experimental section).
b Yield was calculated using the HPLC data and calibration curves.
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