Carbon dioxide as a reversible amine-protecting agent in selective Michael additions and acylations

Article abstract of DOI:10.1039/c3gc40568k

Carbon dioxide can be used as a temporary protecting group for amines. A carbamic acid is formed reversibly when CO₂ is bubbled through a solution of a sufficiently basic primary amine at room temperature and atmospheric pressure. This reaction is employed for the protection of the amine functionality in several reactions at room temperature where inter- or intramolecular selectivity is desired. The concept is demonstrated for the selective Michael additions to methyl acrylate of a normally less reactive sulfonamide in the presence of a strong amine nucleophile, or of a cyclic secondary amine in the presence of an aliphatic primary amine, or of a β-ketoester in the presence of amines. The selective acylation of an alcohol in the presence of an amine can be achieved under a CO₂ atmosphere as well.

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Graphical abstract
Carbon dioxide as a reversible amine-protecting agent in selective Michael additions and acylations
authors: Annelies Peeters, Rob Ameloot and Dirk E. De Vos
CO2 can be used as an efficient protecting agent for amines in Michael additions and acylations at
room temperature and atmospheric pressure by the reversible formation of a carbamic acid.

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Carbon dioxide as a reversible amine-protecting agent in selective
Michael additions and acylations†
Annelies Peeters, Rob Ameloot and Dirk E. De Vos*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
Carbon dioxide can be used as a temporary protecting group for amines. A carbamic acid is formed
reversibly when CO2 is bubbled through a solution of a sufficiently basic primary amine at room
temperature and atmospheric pressure. This reaction is employed for the protection of the amine
functionality in several reactions at room temperature where inter- or intramolecular selectivity is desired.
10 The concept is demonstrated for the selective Michael additions to methyl acrylate of a normally less
reactive sulfonamide in the presence of a strong amine nucleophile, or of a cyclic secondary amine in the
presence of an aliphatic primary amine, or of a β-ketoester in the presence of amines. The selective
acylation of an alcohol in the presence of an amine can be achieved under CO2 atmosphere as well.
acylation of alcohols in the presence of these amines is therefore
Introduction
very challenging. Simple and sustainable amine protection
35 methods would allow to considerably expand the flexibility of
Michael additions and acylations.
15 In the preparation of organic compounds, there is a constant drive
to develop synthesis routes with increased atom efficiency,
following the guidelines of green chemistry.1 Increasing
selectivity by means of a traditional protection/deprotection
strategy is strongly undesired due to the introduction of extra
20 reaction steps, extra costs for additional reagents, and of course
formation of more waste. Instead, there is a need for safe,
environmentally friendly and simple procedures.
The Michael addition is a classical route for the addition of a
nucleophile to an activated olefin.2 Due to its simplicity and atom
25 efficiency, it continues to be widely used. Simple base catalysts
often allow for quickly reaching full conversion at room
temperature, with a vast range of nucleophiles. Like the Michael
addition, acylation is another fundamental reaction in organic
chemistry. Due to the high nucleophilicity of basic primary
30 amines, both Michael additions and acylations of these amines
proceed smoothly with various catalysts. The selective Michael
addition using other types of nucleophiles or the selective O-
Here we demonstrate that this can be accomplished under mild
conditions by working under a CO2 atmosphere. Amines can
react reversibly with CO2 forming carbamic acids or the
40 corresponding carbamate salts (Scheme 1).3 This principle is
applied in CO2 recovery from industrial exhaust streams,4 but it
can be applied in organic synthesis as well. Till now, CO2 has
only scarcely been employed for enhancing the selectivity in
organic transformations5 and typically high pressures or even
45 supercritical conditions are necessary to accomplish the desired
effect. In the Rh-catalyzed hydroaminomethylation of N-
ethylmethallylamine, a beneficial effect was reported when
supercritical CO2 (scCO2) was used as solvent.6 Cyclization of
the intermediately formed amine was suppressed by formation of
50 the carbamic acid in scCO2.
Scheme 1 Principle of reaction inhibition through the formation of carbamic acid and/or carbamate salt from an amine and CO2.
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In the ring closing metathesis (RCM) of an amine-containing
when the atmosphere is changed to CO2, these amines no longer
diene, working in scCO2 can be an effective strategy against 45 undergo aza-Michael additions. In the reaction mixture, only
poisoning of the catalyst by the amine.7 In hydrogenation
reactions of nitriles, imines or even anilines,8 protection of the
amine products at high CO2 pressures (> 20 bar) or in scCO2 can
suppress dimerization of the amines or poisoning of the catalyst.
traces or a very small amount of the mono-addition product could
be detected. Under Ar atmosphere, secondary amines were easily
reacted to form monoalkylated compounds. Dipropylamine, a
non-cyclic secondary amine was converted to the Michael
5
In this work we report on selective Michael additions and 50 product for 80 % after 2 h, while only a trace amount was formed
acylations in the presence of amines simply by changing the
reaction atmosphere to CO2. No high pressures are necessary.
10 Reactions of the amine functions can be suppressed in favour of
other desired routes, without the need for extra reaction steps, and
no additional waste is produced.
under CO2 atmosphere after the same reaction time. Cyclic
secondary amines like piperidine and morpholine are distinctly
more reactive, and yields of 99 % or more are achieved in 2 h
under Ar. Their reactivity is so high that the CO2 atmosphere only
55 partially inhibits their reaction (Table 1). In general the CO2
protection seems less effective for the secondary than for primary
amines, leaving room for a competitive Michael addition.
Results and discussion
15 Concept of protection by CO2
The concept of protection by CO2 is first demonstrated for the
aza-Michael addition of benzylamine to methyl acrylate (Scheme
2). Bicyclic bases such as 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) are known to promote this reaction even at room
20 temperature.9 However, when the reaction mixture was shortly
flushed with CO2 prior to the addition of methyl acrylate, almost
no product was formed (Fig. 1). The CO2 in the mixture reacts
with the amine and forms a carbamic acid, which does not react
with methyl acrylate. Clearly, CO2 successfully acts as a
25 protecting group for the amine function.
60
Fig. 1 Aza-Michael addition of benzylamine to methyl acrylate under
CO2 atmosphere (conditions: 0.5 mmol benzylamine, 0.5 mmol DBU in 2
ml acetonitrile, flushed with CO2; reaction started by addition of 1.2
mmol methyl acrylate; RT = room temperature)
Scheme 2 Aza-Michael addition of benzylamine to methyl acrylate:
formation of mono- and di-addition products
Interestingly, after reaction the CO2 can simply be removed by
30 flushing with an inert gas such as N2 or Ar, or by heating. At
slightly raised temperatures the equilibrium of carbamic acid
formation shifts back to the free amine and CO2. This becomes
apparent when different reactions are performed at increasing
temperatures while maintaining the CO2 atmosphere: at a higher
35 reaction temperature, there is more of the free amine in the
reaction mixture and the aza-Michael addition is less inhibited
(Fig. 1, 30 °C – 70 °C). At 70 °C the conversion curve
approaches the curve for a reaction at room temperature under
inert atmosphere (Fig. 1, diamonds vs. dotted line). This principle
40 can be extended to other amines (Table 1). Strongly basic
primary amines such as benzylamine, cyclohexylamine, 1-
hexylamine and 1-octylamine undergo the aza-Michael addition
with great ease at room temperature under Ar or air. However,
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Table 1 Aza-Michael addition of different amines under Ar and CO2
atmosphere
CO2, the reaction of benzylamine with methyl acrylate was also
tested in dimethylsulfoxide (DMSO), without the addition of a
base. This solvent is known to promote the Michael addition
without any additives.12 Under Ar atmosphere, at room
35 temperature, a conversion of 67% of benzylamine was found after
one hour with an excess of methyl acrylate. When the same
reaction was performed under CO2 atmosphere, the reaction was
strongly inhibited and a conversion of only 4% benzylamine was
obtained.
Ar
ratio a:b
CO2
ratio a:b
amine
pKa (R- X%
X%
+
NH3 ) a
40
In a next step, the concept of protection by CO2 was expanded
to intermolecular competitions. In aza-Michael additions,
stronger bases are generally more competent nucleophiles, and
they are preferentially converted. In order to reverse this
selectivity, CO2 can be used as a protecting group for the strong
9.06
10.57
10.69
96
93
2.5:1
1:0
< 1
< 1
3
-
-
-
> 99
1.3:1
45 primary amines, while the weaker bases can still undergo aza-
Michael additions (see Table 2 entries 1 and 2). The competitive
aza-Michael addition of p-toluenesulfonamide and benzylamine
to methyl acrylate was performed under both Ar and CO2
atmosphere. Under Ar, almost complete conversion of
50 benzylamine was observed, forming the mono- and di-addition
10.75
10.94
> 99
80
1:1
-
2
3
-
-
11.12
8.97
> 99
> 99
-
-
44
34
-
-
product,
while
the
mono-addition
product
of
p-
toluenesulfonamide was formed with 52 % yield. When the
reaction was performed under CO2 atmosphere, almost no aza-
Michael addition products of benzylamine were observed (<
55 2 %), while the mono-addition product of p-toluenesulfonamide
was obtained with a yield of 46 %.
5.01
<0
n.r.
68b
-
n.r.
62b
-
18:1
17:1
Similarly, the reactivity differences between primary and
secondary amines can be exploited to achieve an intermolecular
selectivity. As noted before, the reaction of morpholine and
60 piperidine is only partially inhibited by CO2. A selective aza-
Michael addition of a cyclic amine in the presence of a primary
amine such as benzylamine can therefore be achieved under CO2
atmosphere (Table 2, entries 3 and 4, 5 and 6). Under Ar, both
amines undergo Michael addition with great ease. Under CO2 the
65 major product retrieved is the aza-Michael addition product of the
cyclic amine.
The concept was also successfully expanded to intramolecular
competitions, like in 4-(aminomethyl)piperidine (Table 2, entries
7 and 8). Under Ar, both the secondary and primary amine groups
70 in this molecule react with methyl acrylate, resulting in a mixture
of di- and trialkylated compounds. By contrast, under CO2, only
the product of monoalkylation at the secondary amine is obtained,
with 84 % yield. Detailed structural analysis by NMR proves that
exclusively the secondary amine function is alkylated, while the
75 primary amine is effectively protected (see ESI). Similar results
were obtained for 1-(2-aminoethyl)piperazine (Table 2, entries 9
and 10). For 2-(aminomethyl)piperidine, the addition of the cyclic
amine to methyl acrylate is somewhat slowed down by the nearby
aminomethyl group, but the reaction under CO2 still heavily
80 favours the secondary over the primary amine, resulting in 44%
yield of the product resulting from monoalkylation at the
secondary nitrogen atom.
Reaction conditions: 0.5 mmol amine, 0.25 mmol internal standard in 2
ml of acetonitrile and 0.5 mmol of DBU base, under Ar or CO2
5 atmosphere. Reaction was started by addition of 1.1 mmol of methyl
acrylate; Room temperature, 2 h (n.r. = no reaction); X% = conversion of
the amine. a Values of pKa of conjugate acid; b 24 h instead of 2 h.
Anilines like p-isopropylaniline do not undergo aza-Michael
10 additions under these conditions, and more strenuous conditions
are needed to convert them. However, p-toluenesulfonamide did
undergo aza-Michael addition at room temperature. Due to its
negligible basicity it does not react with CO2, and the yield under
Ar and CO2 is very comparable.
15
When a carbamic acid is formed in the presence of DBU, the
latter will be protonated. Yamada and co-workers described this
reaction previously as the reversible formation of a room-
temperature ionic liquid (Scheme 3).10 In the context of reversible
protection of an amine reactant, the formation of a salt pair
20 consisting of DBU-H+ and the carbamate results in an extra
stabilization of the protected amine. Even then, the carbamate
formation remains completely reversible and CO2 is removed
upon heating or by flushing with N2. Since it is also well known
that DBU itself reacts with CO2 in the presence of water with
-
25 formation of the amidinium bicarbonate ([DBU-H+][HCO3 ])11,
all experiments were performed in dry acetonitrile.
Detection of carbamic acid formation
1H and 13C NMR can be utilized to detect the formation of the
carbamic acid/carbamate salt.3,6-7,13 For benzylamine the proton
NMR spectra of the amine in deuterated DMSO before and after
CO2 flushing are shown in Fig. 2. Before exposure to CO2, the
Scheme 3 Formation of a reversible room temperature ionic liquid
(RTIL) according to Yamada et al.10
85
30 In order to investigate the impact of DBU on the inhibition under
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benzylic protons are detected as a singlet in the spectrum, and
after CO2 flushing the signal shifts downfield and appears as a
doublet with J = 6.6 Hz.3 The amine protons themselves show a
broad signal at 1.7 ppm before CO2 flushing, and the amide
proton formed after CO2 flushing shifts downfield and overlaps
with the aromatic protons. The shift of the amide proton in the
carbamate is better observed in Fig. 3. Here, the proton spectra
before and after CO2 exposure are shown for 1-hexylamine. The
N-H proton shifts from about 1.3 ppm to 6.7 ppm after CO2
5
10 exposure, while the signal of the neighbouring CH2 group is also
shifted downfield from 2.5 ppm to 2.9 ppm.
13C NMR further confirms the presence of the carbamic acid
by observation of a C=O signal at 156 ppm (Figure 4).13a For the
1
Fig. 4 13C NMR spectra of 1-hexylamine in d-DMSO (top) and after
strongly basic amines cyclohexylamine and 1-octylamine the H
15 and 13C NMR spectra show comparable signal shifts after CO2
flushing (ESI Fig. SI.1-4). Although morpholine is still reactive in
the Michael addition to methyl acrylate under CO2 atmosphere,
the 1H NMR spectrum indicates that it is largely converted to the
carbamic acid (ESI, Fig. SI.5). In contrast, both p-
20 isopropylaniline and p-toluenesulfonamide are not affected by
CO2 flushing and their NMR spectra before and after flushing are
the same (ESI, Fig. SI.6 and SI.7).
flushing with CO2 at room temperature and atmospheric pressure
(bottom)
35
Selective Michael vs. aza-Michael additions
Besides creating selectivity between different N-nucleophiles, the
concept of CO2-protection can also be applied to the selective
addition of β-ketoesters to methyl acrylate in the presence of
40 amine functions. In order to selectively perform such a reaction,
one would have to work with protecting groups to limit the
participation of the amine group in the (aza-)Michael addition
reaction. Again, a simple change of the reaction atmosphere to
CO2 seems an ideal solution. Amines form the corresponding
45 carbamic acid, which hinders reaction of this functional group,
while typical Michael donors such as -diketones or -ketoesters
remain unaltered under CO2 pressure. This is demonstrated in
Table 3: both under Ar and CO2 atmosphere the Michael addition
proceeds smoothly with these carbon nucleophiles. 1H NMR
50 spectra of ethyl acetoacetate (EAA) confirm that this reactant is
not altered by flushing with CO2 (Fig. SI.8).
Since the Michael donors are not affected by CO2, CO2 can
again be used as reaction atmosphere to selectively inhibit the
reaction of amines. We investigated the selective Michael
55 addition using a solution containing the amine and EAA in a 1:1
ratio. Methyl acrylate was added as Michael acceptor. The results
of these competitive reactions are shown in Table 4.
Fig. 2 1H NMR spectra of benzylamine in d-DMSO (top) and after
flushing with CO2 at room temperature and atmospheric pressure
(bottom)
25
Fig. 3 1H NMR spectra of 1-hexylamine in d-DMSO (top) and after
flushing with CO2 at room temperature and atmospheric pressure
(bottom)
30
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Table 2 Competitive aza-Michael addition of two amine (or sulphonamide) groups (inter- or intramolecular competition) to methyl acrylate under Ar or
CO2 atmosphere; R = -CH2CH2COOMe.
Y% of mono-alkylated
products
Y% of di- alkylated
products
Y% of tri-
alkylated products
entry
1a
Michael donor(s)
atm
Ar
59 %
37 %
1 %
51 %
2 %
1
2b
CO2
46 %
3
4
Ar
15 %
72 %
3 %
>99 %
1
CO2
76 %
5
6
Ar
11 %
71 %
>99 %
1
CO2
96 %
7
8
Ar
CO2
Ar
3 %
90 %
7 %
84 %
9
3 %
92 %
5 %
10
CO2
75 %
4 %
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18 %
36 %
11
12
Ar
1 %
45 %
44 %
<2 %
CO2
Reaction conditions: 0.5 mmol of amine, 0.25 mmol internal standard in 2 ml of acetonitrile and 0.5 mmol of DBU base, under Ar or CO2 atmosphere.
Reaction was started by addition of 1.2 mmol of methyl acrylate. Room temperature, 2 h. Y% = GC yield of product based on respective amine. a 24 h
instead of 2 h and 0.75 mmol DBU; b 24 h instead of 2 h and 1 mmol DBU.
5 Table 3 Michael reactions of a β-ketoester, β-diketone or β-diester with
methyl acrylate under Ar and CO2 atmosphere
Table 4 Competitive Michael and aza-Michael additions under Ar and CO2
35 atmosphere
Ar
CO2
ratio a:b
Michael-donor
X%
ratio a:b
0.01:1
X%
> 99
> 99
0.14:1
0.11:1
3.4:1
> 99
0.01:1
0.25:1
> 99
Ar
X%
EAA
(b1:b2)
CO2
X%
EAA
(b1:b2)
> 99a
88%a
X%
amine
(a1:a2)
ratio
a:b
X%
amine
ratio
a:b
amine
Reaction conditions: 0.5 mmol Michael donor, 2 ml acetonitrile and 0.5
mmol DBU; reaction atmosphere of Ar or CO2; room temperature, 2h. The
reaction was started by addition of 1.1 mmol of methyl acrylate. X% =
10 conversion of Michael donor. a 3h reaction
95
(2.8:1)
> 99
(0:1)
> 99
(0.01:1)
0.96:1
< 1
0.01:1
96
> 99
> 99
0.96:1
1:1
< 1
< 1
1
0.01:1
0.01:1
0.02:1
0.23:1
(1:0)
(0:1)
(0.1:1)
Under Ar both the amine and EAA react smoothly with methyl
acrylate towards the respective addition products. However, when
the reaction atmosphere is changed to CO2, the aza-Michael
15 addition is inhibited very efficiently, and only the Michael addition
products of EAA are formed. This is the case for benzylamine,
cyclohexylamine, 1-hexylamine and 1-octylamine. The only
exception here is morpholine; with this cyclic amine, a fraction of
the aza-Michael addition product is still formed.
> 99
(1.08:1)
> 99
(0:1)
> 99
(0.06:1)
> 99
(0.88:1)
> 99
(0:1)
> 99
(0.09:1)
1:1
> 99
(1:0)
> 99
(0:1)
> 99
(0.16:1)
1:1
23
Reaction conditions: 0.5 mmol amine, 0.5 mmol EAA, 2 ml acetonitrile and
0.75 mmol DBU; reaction atmosphere of Ar or CO2; room temperature, 2h.
The reaction was started by addition of 2.2 mmol of methyl acrylate. X% =
conversion.
20
Selective O-acylations
40
Not only can a CO2 atmosphere be used to inhibit 1,4-additions of
amines; it can also be used to direct selectivity in acylations. Here,
attention is focused on acylation of amine vs. alcohol groups.
A first attempt used Candida antarctica lipase B (CalB)
immobilized on an acrylic resin (Novozym 435). These enzymes
are able to catalyse the acylation by virtue of a serine-histidine-
aspartate triad.14 Amines are preferentially acylated over alcohol
functions, as expected based on their higher nucleophilicity.15
Ar atmosphere. When the same reaction is performed under CO2,
the amine should be protected by the formation of the
corresponding carbamic acid. However, still a yield of 30 % of the
acylated amine was retrieved, indicating that the inhibition is not
45 complete. When benzyl alcohol was reacted under identical
conditions the yield remained largely unaffected (71 % under Ar vs.
68 % under CO2). For the competitive reaction of benzyl alcohol
and benzylamine with an excess of isopropyl acetate it is apparent
that benzylamine is much more reactive than benzyl alcohol, with a
50 yield of 95 % of N-benzyl acetamide and 45 % of benzyl acetate
under Ar atmosphere. This 2:1 ratio is inversed under CO2 (30 %
25
30 When benzylamine is acylated with an excess of isopropyl acetate
in acetonitrile at room temperature with Novozym 435, a yield of
91 % of the amide product is obtained after 24 h under
6
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N-benzyl acetamide vs. 57 % benzyl acetate), but the reaction of temperature allows a complete reversal of selectivity in several
benzylamine could not be completely inhibited when using CalB. A cases. By adopting the existing procedure for Michael additions in
plausible explanation is that the catalytic pocket of CalB has a high40 the presence of DBU, and by short saturation with CO2, the reaction
affinity for the amine, withdrawing free amine from the amine- of primary amines can be inhibited, in favour of normally less
5
carbamic acid equilibrium.
reactive sulfonamides or cyclic secondary amines, or β-ketoesters.
The changed selectivity has been succesfully demonstrated both for
As an alternative, Yang and co-workers reported the 1,2,4-triazole intermolecular and intramolecular competition. In acylation
anion as an efficient catalyst for acyl transfer to amines and alcohol45 reactions catalyzed by the 1,2,4-triazole anion, complete
reactants, even at room temperature.16 Since 1,2,4-triazole is a weak inhibition of the acylation of benzylamine in favour of benzyl
a
10 base (the pKa of the protonated triazole is 2.88), it is not affected by alcohol can be achieved. CO2 can easily be removed by flushing
CO2 in the reaction medium. Isopropenyl acetate was used as the with N2 or Ar under mild heating (50-60°C). No additional by-
acyl donor, which drastically lowers reaction times because the products are created and there are no tedious procedures needed to
vinylic alcohol product rapidly tautomerizes to acetone (Scheme50 introduce the protecting group. In conclusion,
a safe and
4).17
environmentally friendly system for protection of amines has been
described.
Experimental section
55 Typical procedure for Michael additions with DBU
15
Scheme 4 Acylation of benzylamine and benzyl alcohol with isopropenyl
In a typical procedure for (aza-)Michael addition, benzylamine (0.5
mmol) and DBU (0.5 mmol) are dissolved in 2 ml of dried
acetonitrile in a capped vial. Benzaldehyde dimethyl acetal was
used as internal standard (0.25 mmol). This solution was briefly
60 flushed with Ar or CO2 for approximately 1 minute at room
temperature. A balloon was used to keep the vial under an
atmosphere of the respective gases during the reaction. The reaction
was then started by addition of 100 µl of the Michael acceptor
methyl acrylate. During reaction, the vial was kept at room
65 temperature (25°C) unless stated otherwise. After reaction the
mixture was flushed with N2 (2 minutes) under mild heating (60
°C) to remove the CO2. Samples were taken at different time
intervals and immediately analyzed with gas chromatography (GC).
acetate, catalysed by 1,2,4-triazole.
With this triazole catalyst, the reaction of both benzylamine and
benzyl alcohol proceeds smoothly under Ar. A base like DBU or
20 DBN (1,5-diazabicyclo[4.3.0]non-5-ene) is used to abstract a
proton from 1,2,4-triazole in order to form the triazole anion.
When the reaction was performed under CO2 atmosphere, the
acylation of benzylamine was very effectively inhibited. Fig. 5
shows the yield of the acylation products of benzyl alcohol and
25 benzylamine in
a competitive reaction with an excess of
isopropenyl acetate, catalysed by 1,2,4-triazole under CO2
atmosphere. The yield of benzyl acetate rises steadily to 100 %
while only a trace of N-benzyl acetamide is formed.
Typical procedure for enzymatic acylations
70 Acylations with an enzymatic catalyst were performed at room
temperature with 60 mg of Novozym® 435 for reaction of 0.5 mmol
of benzylamine or benzyl alcohol reactant in a capped vial.
Reactions were conducted in 3 ml of acetonitrile solvent and
anisole was used as an internal standard (0.5 mmol). Again the
75 reaction mixture was flushed with Ar or CO2 for approximately 1
minute at room temperature and kept under that atmosphere during
the reaction. The reaction was then started by addition of an excess
(100 µl) of the acylating agent isopropyl acetate. After reactions
performed under CO2 atmosphere, the reaction mixture was diluted
80 with 2 ml of acetonitrile. Novozym® 435 catalyst was removed by
filtration prior to GC analysis.
Typical procedure for triazole anion catalyzed acylations
Acylations with the triazole anion were typically performed in a
glass capped vial. First, a stock solution of 1,2,4-triazole was
30
Fig. 5 Yields in the acylation of benzyl alcohol (0.25 mmol) and
benzylamine (0.25 mmol) with excess isopropenyl acetate (0.9 mmol)
catalyzed by 2.5 mol% 1,2,4-triazole under CO2 atmosphere; competitive 85 prepared by dissolving 34.5 mg (0.5 mmol) in 10 ml of dry
reaction (2 ml acetonitrile, 0.5 mmol DBN).
acetonitrile (0.05 M). 250 µl of this stock solution was added to a
solution of benzylamine (0.5 mmol) and DBN (0.5 mmol) in 1.75
Conclusions
ml of dry acetonitrile. Anisole was used as an internal standard (0.5
mmol). This solution was then brought and kept under Ar or CO2.
90 The reaction was started by addition of 100 µl isopropenyl acetate
with a syringe. For the competitive reaction, both 0.25 mmol of
benzylamine and 0.25 mmol of benzyl alcohol were reacted under
35 The results show that CO2 can be used as an unusual but effective
protecting group for amines in organic reactions. No high pressures
are necessary, and a simple and straightforward procedure at room
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the abovementioned conditions. After flushing with N , samples
were taken and immediately analyzed.
55 9 (a) C.-E. Yeom, M. J. Kim and B. M. Kim, Tetrahedron, 2007, 63, 904;
(b) Y. V. S. Rao, D. E. De Vos and P. A. Jacobs, Angew. Chem. Int.
Ed., 1997, 36, 2661; (c) W. Ye, J. Xu, C.-T. Tan and C.-H. Tan,
Tetrahedron Lett., 2005, 46, 6875.
2
Instrumentation
All GC analyses were performed on a Shimadzu 2014 GC,
10 T. Yamada, P. J. Lukac, M. George and R. G. Weiss, Chem. Mater.,
5
equipped with a CP-sil 5 CB capillary column and a FID detector.
60
2007, 19, 967.
The chosen temperature program allowed baseline separation of all
compounds. GC areas were corrected and validated with the use of
an internal standard.
11 D. J. Heldebrant, P. G. Jessop, C. A. Thomas, C. A. Eckert and C. L.
Liotta, J. Org. Chem., 2005, 70, 5335.
12 Y. Genisson and L. Gorrichon, Tetrahedron Lett., 2000, 41, 4881.
13 (a) Z. J. Dijkstra, A. R. Doornbos, H. Weyten, J. M. Ernsting, C. J.
Elsevier and J. T. F. Keurentjes, J. Supercrit. Fluids, 2007, 41, 109; (b)
Q. Yang, M. Bown, A. Ali, D. Winkler, G. Puxty and M. Attalla,
Energy Procedia, 2009, 1, 955.
Compounds were identified with gas chromatography coupled to
10 mass spectrometry (GC-MS). These measurements were performed
65
on an Agilent 6890 GC with HP-5MS column, coupled to an
Agilent 5973 Network MSD mass spectrometer. MS data are added
1
in the Electronic Supplementary Information. H NMR spectra of
products were recorded on a Bruker AMX-300 at 300 MHz and 13
C
14 M. C. de Zoete, F. van Rantwijk and R. A. Sheldon, Catal. Today,
1994, 22, 563.
15 NMR spectra at 75.5 MHz. Samples were prepared by dissolution
of 20 µl of the sample in 600 µl of d-DMSO. To study the reaction
of the product with CO2, samples were flushed at room temperature
with CO2 for approximately 1 minute. After flushing, the solution
was transferred to an NMR tube and sealed immediately and
20 spectra were recorded as soon as possible.
70 15 F. van Rantwijk, M. Hacking and R. A. Sheldon, Monatsh. Chem.,
2000, 131, 549.
16 X. Yang and V. B. Birman, Org. Lett., 2009, 11, 1499.
17 R. Pelagalli, I. Chiarotto, M. Feroci and S. Vecchio, Green Chem.,
2012, 14, 2251.
75
Acknowledgements
A.P. acknowledges the Fund for Scientific Research Flanders
(FWO-Vlaanderen) and L’Oréal/UNESCO Belgium for financial
25 support (Aspirant of FWO). D.E.D.V. thanks the Belgian Science
Policy (BELSPO) for financing the Interuniversity Attraction Poles
(IAP-PAI P7/05) and the Flemish government for long-term
structural funding (Methusalem).
Notes and references
30 Centre for Surface Chemistry and Catalysis, Department of Microbial and
Molecular Systems, KU Leuven, Kasteelpark Arenberg 23, 3001 Leuven,
Belgium. E-mail: Dirk.DeVos@biw.kuleuven.be
1
† Electronic Supplementary Information (ESI) available: H and 13C NMR
spectra of substrates before and after CO2 flushing; Identification of
35 compounds. See DOI: 10.1039/b000000x/
1
2
I. S. Young and P. S. Baran, Nature Chem., 2009, 1, 193.
B. D. Mather, K. Viswanathan, K. M. Miller and T. E. Long, Prog.
Polym. Sci., 2006, 31, 487.
40 3 E. M. Hampe and D. M. Rudkevich, Tetrahedron, 2003, 59, 9619.
4
D. M. D'Alessandro, B. Smit and J. R. Long, Angew. Chem. Int. Ed.,
2010, 49, 6058.
5
P. G. M. Wuts and T. W. Greene Greene's protective groups in organic
synthesis; 4 ed.; John Wiley & Sons, Inc.: Hoboken, New Jersey, 2007.
45 6 K. Wittmann, W. Wisniewski, R. Mynott, W. Leitner, C. L.
Kranemann, T. Rische, P. Eilbracht, S. Kluwer, J. M. Ernsting and C.
L. Elsevier, Chem. Eur. J., 2001, 7, 4584.
7
A. Furstner, L. Ackermann, K. Beck, H. Hori, D. Koch, K. Langemann,
M. Liebl, C. Six and W. Leitner, J. Am. Chem. Soc., 2001, 123, 9000.
50 8 (a) X. F. Xie, C. L. Liotta and C. A. Eckert, Ind. Eng. Chem. Res.,
2004, 43, 7907; (b) M. Chatterjee, H. Kawanami, M. Sato, T. Ishizaka,
T. Yokoyama and T. Suzuki, Green Chem., 2010, 12, 87; (c) M.
Chatterjee, M. Sato, H. Kawanami, T. Ishizaka, T. Yokoyama and T.
Suzuki, Appl. Catal., A, 2011, 396, 186.
8
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