Synthesis of highly functional carbamates through ring-opening of cyclic carbonates with unprotected α-amino acids in water

Article abstract of DOI:10.1039/c7gc02862h

The present work shows that it is possible to ring-open cyclic carbonates with unprotected amino acids in water. Fine tuning of the reaction parameters made it possible to suppress the degree of hydrolysis in relation to aminolysis. This enabled the synthesis of functionally dense carbamates containing alkenes, carboxylic acids, alcohols and thiols after short reaction times at room temperature. When Glycine was used as the nucleophile in the ring-opening with four different five membered cyclic carbonates, containing a plethora of functional groups, the corresponding carbamates could be obtained in excellent yields (>90%) without the need for any further purification. Furthermore, the orthogonality of the transformation was explored through ring-opening of divinylenecarbonate with unprotected amino acids equipped with nucleophilic side chains, such as serine and cysteine. In these cases the reaction selectively produced the desired carbamate, in 70 and 50% yield respectively. The synthetic design provides an inexpensive and scalable protocol towards highly functionalized building blocks that are envisioned to find applications in both the small and macromolecular arena.

Full text of DOI:10.1039/c7gc02862h

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Synthesis of Highly Functional Carbamates through Ring-Opening
of Cyclic Carbonates with Unprotected α-Amino Acids in Water
Peter Olséna*, Michael Oschmanna, Eric V. Johnstona* and Björn Åkermarka*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
The present work shows that it is possible to ring-open cyclic carbonates with unprotected amino acids in water. Fine
tuning of the reaction parameters made it possible to suppress the degree of hydrolysis in relation to aminolysis. This
enabled the synthesis of functionally dense carbamates containing alkenes, carboxylic acids, alcohols and thiols after short
reaction times at room temperature. When Glycine was used as the nucleophile in the ring-opening with four different five
membered cyclic carbonates, containing a plethora of functional groups, the corresponding carbamates could be obtained
in excellent yields (>90 %) without the need of any further purification. Furthermore, the orthogonality of the
transformation was explored through ring-opening of divinylenecarbonate with unprotected amino acids equipped with
nucleophilic side chains, such as serine and cysteine. In these cases the reaction selectively produced the desired
carbamate, in 70 and 50 % yield respectively. The synthetic design provides an inexpensive and scalable protocol towards
highly functionalized building blocks that are envisioned to find applications in both the small and macromolecular arena.
www.rsc.org/
as this may otherwise lead to deactivation of the catalyst.10
Introduction
The question we raised was if it would be possible to achieve
this transformation within an aqueous environment, and by
Sustainable chemical synthesis of highly diverse functional
building blocks is becoming increasingly important.1 The
that, both widen the substrate scope and removing the
necessity of dry reaction conditions. This would open the
possibility to use unprotected amino acids as substrates for
the ring opening reaction. Such transformation would be
highly desirable for the synthesis of new protection groups,
conjugation chemistry in an aqueous environment as well as
new functional precursors for material science.
carbamate motif is
a central building block in many
applications, spanning from protection chemistry to material
science.2 This chemical motif can be acquired in a sustainable
and isocyanate free manner through ring opening of a cyclic
carbonate with an amine nucleophile.3 Since a wide range of
amines and cyclic carbonates are available, highly diversified
transformations are possible.4 However, there are a number of
limitations of the use of these ring opening reactions.
Within an aqueous environment, no organic super base
catalytic systems are feasible. Additionally more hydrolysis of
the cyclic carbonate is expected to occur.11 In order to achieve
high yield of the desired carbamate product it is important to
suppress the degree hydrolysis relative to aminolysis. It is
believed that the stronger nucleophilic character of the amine
of an amino acid relative to water in conjunction with the high
polarity of the solvent should enable fast and selective
transformation under very specific conditions.12 In order to
elucidate this, we have studied the reaction between amino
acids and cyclic carbonates in aqueous solution, including
kinetics, selectivity, mechanism, generality, and scope of the
reaction.
One important factor is the size of the ring.6 Five membered
cyclic carbonate rings are generally not sufficiently strained to
undergo poly-addition at normal temperatures and pressures.7
This is beneficial because it promotes irreversible formation of
the carbamate motif, but it also results in slow kinetics.8 When
performing the reaction in organic solvents, or under neat
conditions, addition of different super bases such as, DBU,
phosphazene and triazabicyclodecene (TBD) improves the
kinetics.9 However, this also place severe restrictions on the
reaction, and all substrates need to be free from functional
groups such as carboxylic acids, phenols, thiols and even water
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Table 1. Ring opening behavior of DVC with GLY either catalyzed
with TEA or in 2 M NaHCO3/Na2CO3 buffer
Results and discussion
Ring Opening of divinylethylene carbonate in water
O
O
Our initial efforts centered on employing glycine as the amine
nucleophile for the ring opening of divinylethylene carbonate
(DVC) in water under basic conditions. DVC is an interesting
substrate; it can be derived from renewable resources, and is
multi-functional and selective towards amine nucleophiles.13
Additionally, it has been shown that DVC is susceptible to Pd-
catalysed sterospecific decarboxylative conjugations with a
wide scope of nucleophiles, thus it is envisioned that the
formed ring-opened product will be deprotected by the
orthogonal palladium catalysed reaction with nucleophiles.14
When performing the ring-opening reaction within an aqueous
system, there is a direct competition between aminolysis and
hydrolysis of the cyclic carbonate, DVC, which results in
formation of both the desired carbamate product and the
O
[b]
[c]
NH2
OH
H
N
HO
O
O
HO
O
or
HO
OH
TEA
H2O, RT
O
[e]
[d]
[a]
Entry
GLY [mM]
0.5
[a]:[b]:[c]
Conv.[a] [%]
2i (7)ii
[d] [%]
[e] [%]
1 (4)
[1]
[2]
[3]
[4]
[5]
[1.0]:[1.5]:[0.1]
[1.0]:[1.5]:[0.5]
[1.0]:[1.5]:[1.0]
[1.0]:[1.5]:[2.0]
[1.0]:[1.5]:[4.0]
1 (3)
0.5
17 (27)
12 (16)
31 (35)
33 (38)
32 (33)
5 (11)
0.5
42 (59)
13 (24)
40 (56)
53 (67)
0.5
73 (94)
0.5
82 (100)
O
O
O
[b]
NH2
OH
H
HO
O
O
HO
O
N
or
HO
OH
2 M NaHCO3/Na2CO3
H2O, RT, 24 h at pH 9.5
O
[e]
[d]
[a]
undesired diol (Table 1). Thus precise control of the
concentration difference between free hydroxyl ion and the
deprotonated amine of glycine is important for achieving high
selectivity of the transformation.15
Entry
GLY [mM]
0.5
[a]:[b]
Conv.[a] [%]
[d] [%]
11
[e] [%]
[6]
[7]
[8]
[9]
[1.0]:[1.5]
[2.0]:[1.5]
[4.0]:[1.5]
[6.0]:[1.5]
33
36
41
32
23
11
6
1.0
15
Basicity and reaction behaviour – buffered or triethylamine
2.0
35
4.0
29
3
The initial screening focused on variations of the amount of
TEA and on the relative ratio of glycine to DVC, (Table 1) as
well under buffered reaction conditions. A close relation was
found between the basicity, i.e. amount of TEA, and rate of the
reaction (Table 1 entries 1-5). When using 0.1 equiv. of TEA to
glycine only negligible conversion of DVC was observed after 2
h, whereas 4.0 equiv. of TEA to glycine resulted in 85%
conversion of DVC with 32% carbamate formation after the
i after 2 h reaction time, all conversions was determined from 1H NMR
ii in parenthesis after 24 h reaction time.
Basicity and reaction behaviour – kinetic insights
The initial results indicated that the ring-opening reaction of
DVC proceeded with an initial preference for carbamate
formation relative to hydrolysis (Table 1, entries 2-4). To
elucidate the underlying reason for this preference, the
reaction kinetics was studied in more detail. Within this system
the concentration of the reactants is not directly correlated to
the initially added amounts. Specifically, the partial miscibility
between DVC and water makes the reaction concentration of
DVC diffusion controlled; additionally glycine has been
proposed to be in equilibrium with its dimeric form in water,
thus making the concentration of free glycine monomer both
dependent on temperature and pH.17 The kinetics of system
was analysed via 1H NMR conversion data at different time
points, evaluating carbamate formation, degree of hydrolysis,
and conversion of DVC (see Figure 1, for more detailed kinetic
data please refer to supporting information Figures S1-S5).
same reaction time (Table 1 entries
1 and 5). There is a clear
dependence of the rate of the reaction and the amount of TEA.
However, increased reaction rate also gave an increased
degree of hydrolysis.
Reaction under buffered conditions, pH 9.5 in
a 2 M
NaHCO3/Na2CO3, after addition of a stoichiometric amount of
TEA relative to glycine (Table 1, entry 6-9) produced very
different results. Buffered conditions severely diminished both
the reaction rate and the amount of product formed (Table 1
,
entry 6-9) even at several equivalents of glycine to DVC. The
reason behind the poor reaction outcome under buffered
conditions may be that the increased ionic strength of the
medium reduces the electrostatic association between glycine
and the DVC.16
The kinetics revealed clear trends regarding the desired ring-
opened product formation (Figures 1b–d). Initially there was a
bias toward carbamate formation as a higher concentration of
glycine is present. However, as the reaction proceeds,
hydrolysis of DVC becomes the dominant reaction. The
conversion plateau of the carbamate formation is reached
after 20 h (Figures 1c and 1d). The conversion plateau is
reached prior to high conversion of both glycine and DVC.
After 24 h only 40% of DVC had been converted to the
corresponding carbamate whereas 60% of the DVC remained
unreacted even in the presence of glycine (Figure 1c).
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Figure 1a-d, The kinetic behaviour of the ring-opening reaction of
DVC with GLY at different concentration of TEA. All the reactions
were performed in D2O with 0.5M glycine. At the specified times,
aliquots of 50 µL were withdrawn and the reaction was quenched
by addition of 5 equiv. AcOH in respect to TEA.
Figure 2a-d. The kinetic behaviour of the ring-opening reaction of
DVC with glycine at the same amount of TEA with different relative
amount of reactants. All the reactions were performed in 1 ml D2O
with
a different amount of GLY and DVC with the same
concentration of 0.7 M TEA.
By increasing the ratio of glycine relative to DVC selective
carbamate formation could be obtained (Table 2 and Figure 2).
Specifically, a glycine to DVC ratio of 4 resulted in product
selectivity ratio (S) after 2.5 h of 19 whereas DVC ratio of 6
The kinetic data revealed that higher ratio of glycine to DVC
resulted in close to full conversion of DVC to carbamate after
only 2.5 h at ambient temperature with a low degree of
hydrolysis ((Figure 2c and 2d), for more data see the
Supporting Information, Figures S2-S5). However, a higher
ratio of DVC to glycine did not produce satisfactory result with
only moderate degree of carbamate formation and hydrolysis,
even after 24 h (Figure 2a and 2b). Nonetheless, high reactivity
was initially observed for both carbamate formation and
hydrolysis. The observed reduction in rate is believed to arise
from surfactant like properties exerted by the formed
carbamate (Figure 2a and 2b). The optimum conditions found
for the ring-opening of DVC with glycine in water were the
under same conditions gave an S value of 22. (Table 2 entry
6
and 7). The high selectivity was in contrast to all other
reactions performed with an excess of DVC relative to glycine,
where the highest conversion to carbamate of 63 % was
reached for 6 equiv. DVC relative to 1 glycine, (Table 2 entry
1), although accompanied by a low selectivity ratio S of 0.6,
after 24 h at ambient temperature.
Table 2. Relationship between reaction equivalents and ring-
opening reaction behaviour
following; [DVC]:[Glycine]:[TEA]
= [1]:[4]:[2] with 1 M
concentration of glycine in water at ambient temperature for 2
h.
O
O
O
[b]
[c]
NH2
OH
H
N
HO
O
O
HO
O
HO
OH
or
O
TEA
H2O, RT
Scope of the reaction
[e]
[d]
[a]
Siii
With the optimized conditions in hand, we were interested to
study the generality of the transformation with three
additional cyclic carbonates and different unprotected amino
acids. It was envisioned that the optimized conditions obtained
from ring-opening of DVC would be highly beneficial, mainly
due to the sterically encumbered nature of the substrate
towards the approaching nucleophile. To our delight all
transformations with glycine as the nucleophile proceeded
with excellent yields. The reactions were performed at
ambient temperature for 2 h with [Carbonate]:[Glycine]:[TEA]
= [0.7 mmol]:[2.8 mmol]:[1.4 mmol] in 1 mL of water (Table 3).
Entry GLY [mM]
[a]:[b]:[c]
Conv.[1] [%] [d] [%] [e] [%]
25i (26)ii
32 (39)
[1]
0.3
[6.0]:[1.0]:[2.0]
54 (63)
9 (17)
1.0 (0.6)
[2]
[3]
[4]
[5]
[6]
[7]
0.3
0.3
0.3
0.7
1.0
1.3
[4.0]:[1.0]:[2.0]
[2.0]:[1.0]:[2.0]
[1.0]:[1.0:[2.0]
[1.0]:[2.0]:[2.0]
[1.0]:[4.0]:[2.0]
[1.0]:[6.0]:[2.0]
52 (60) 17 (26)
50 (58) 40 (58)
49 (45) 51 (55)
82 (80) 18 (20)
0.8 (0.6)
0.6 (0.5)
1.0 (0.8)
4.5 (4.0)
19 (13)
63 (92)
100 (100)
99 (100)
99 (100)
91 (100)
94 (93)
87 (95)
5 (7)
4 (5)
22 (19)
i after 2.5 h reaction time, all conversions was determined from 1H NMR
ii in parenthesis after 24h reaction time.
iii
S is defined as the ratio of [d]/([e]*[a])
The kinetic insight revealed the necessity to have
a
superstoichiometric amount of glycine for achieving high
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Reaction conditions; 1 equiv. [a] and 4 equiv. glycine with 2 equiv. TEA at
ambient temperature for 2h
[i] Isolated yield from the concentrated solute after precipitation, taking
into account the TEA adduct as determined from 1H NMR.
[ii] Isolated yield after purification of 2 through a siica plug with eluent
system {EtOAc]/[AcOH] = 20:1
selectivity. It has been shown that glycine can easily
precipitate out quantitatively from an aqueous solution by
adding either methanol or ethanol.18 In our case, all excess of
glycine was precipitated-out by slow addition of the water
solution into a THF:MeOH (3:1) mixture, thus recovering
unreacted glycine from the reaction mixture (Figures S6 and
S8). The concentrated supernatant contained the desired
carbamate with complete absence of glycine. After the
precipitation, the target molecule was isolated as a non-
stoichiometric TEA-salt adduct in nearly quantitative yield,
[iii] Product contained 10% of a condenstation side product after the silca
plug.
Table 4. Ring-Opening behavior of DVC with different functional
amino acids
Table 3 entry
2. The TEA adduct can be removed by passing
the compound through
a
silica plug; however, this is
associated with a slight reduction in yield (Table 4).
For unsymmetrical carbonates, such as the mono-substituted
carbonates, propylene carbonate (PC, Table 3 entry
2) and 4-
vinyl-1,3-dioxolan-2-one (MVC, Table 3 entry 3), two isomers
are produced (Table 3 entries 2b and 3b). For PC (Table 3 entry
1b), there is a slight preference towards the formation of a
secondary alcohol with 60:40 ratio (Table 3, entry 2b). This is
in contrast to the product ratio observed with MVC where a
slight bias was observed towards formation of the primary
alcohol (Table 3, entry 3b). Both reaction outcomes are
consistent with what has been reported in literature for the
ring-opening of PC and MVC with aniline, catalysed with 30
mol% TBD.9c We believe that the reaction outcome is a
consequence of the slight difference in pKa of the alcoholic
species released after the subsequent nucleophilic attack of
glycine.19
Table 3. Ring-Opening behavior with different cyclic five-membred
carbonates.
Reaction conditions; 1 equiv. [a] and 4 equiv. [b] with 2 equiv. TEA at
ambient temperature for 2h
[i] Conversion of DVC ([a]) as determined from 1H NMR.
[ii] Yield determined from 1H NMR if not otherwise stated.
[iii] Isolated yield
The high selectivity observed for the ring opening of the
different cyclic carbonates with glycine (Table 3) prompted us
to evaluate several other amino acids as nucleophiles. Due to
the orthogonal reactivity of five membered cyclic carbonates,
it was envisioned that highly functional amino acids could be
employed in this transformation.20 The functional cyclic
carbonate, DVC, was chosen as a model and the selected
amino acids were as follows, serine, cysteine, asparagine and
arginine.
The ring opening of DVC by different amino acid nucleophiles
resulted in formation of the desired carbamates in low to good
yields (Table 4). Serine (Table 4 entry
yielded the corresponding carbamate in 70 % yield, whereas
cysteine (Table 4 entry ) gave 50 % yield. The difference
1) as the substrate
2
amongst the two is interpreted as a consequence of the
difference in solubility.
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In the case of asparagine (Table 4 entry
3) only 20 % Figure 3. Changes in the chemical shift of the carbonate carbon as a
conversions towards the desired carbamate (Table 4 entry 3c
was obtained. These transformations (Table 4 entries 1-3
)
)
function of the reaction equivalents ( X = Gly or Gly-OMe ).
O
O
NH3
O
showed that it was possible to selectively synthesize highly
functional carbamates in water. The reduction in yield
compared to glycine is interpreted as a combination of the
increased steric bulk of the nucleophile and the solubility of
the substrates. However, in the case of arginine (Table 4 entry
O
-
NH3
H
O
O
O
O
O
N
O
O
NH2
O
O
O
HO
O
O
H2O
O
H2N
O
Int. 2
Int. 1
O
4) this explanation does not hold. Arginine is fully soluble
H
O
N
HO
O
under the selected reaction conditions, although only 22 %
conversion to the desired carbamate (Table 4 entry 4c) was
obtained. Under the specific reaction conditions, the side chain
of arginine has a cationic charge. The charge is believed to
result in surfactant like properties within the system that in
turn decrease the accessibility of DVC.
O
TEA-H
TEA
Scheme 1. Proposed mechanistic features of the reaction via
zwitterion activation of the carbonate motif.
The chemical shift of the carbonyl carbon of ethylene
carbonate is highly dependent on whether glycine has a free
carboxylic acid or a methyl ester (Figure 3). In the case of the
methyl ester of glycine, a linear relationship in downward shift
of the carbonyl carbon and reaction equivalents are observed
Mechanistic features
The high selectivity and reactivity of the ring-opening reaction
prompted us to further investigate the mechanistic features of
the developed transformation. In an aqueous system, under
the pH range employed, glycine will mainly exist in the zwitter-
ionic form. Insights from the kinetic evaluation pointed
towards the necessity of having free GLY in the system to
maintain high reactivity of both hydrolysis and aminolysis
(
Figure 3). As the reaction equivalents increase so does the
electron density surrounding the carbonate carbon, which in
turn would reduce the electrophilicity. This is in contrast to the
unprotected glycine where a non-linear trend is observed and
the total downward shift change is lower as a function of
reaction equivalents. The difference in chemical shift relates to
a decrease in electron density on the central carbon atom that
in term relates to the electophilicity.22 These results, in
connection with the observed kinetic behavior, led to the
proposed mechanistic features depicted in Scheme 1, were the
zwitterionic form of glycine activates the carbonate motif
towards nucleophilic attack from an adjacent glycine. The
highly polar transition state, Int. 2, is stabilized by the high
polarity of water leading to the irreversible formation of the
carbamate bond.
(Figure 2 and 3). Previous result suggested a cooperative
activation exerted by both the protonated amino group of
glycine and the free carboxylic acid. To evaluate this effect, we
chose to monitor the carbonyl carbon using 13C NMR. The
carbonyl carbon is highly sensitive to changes in the chemical
environment.21 To simplify the analysis, ethylene carbonate
was selected as the model substrate because of its high
solubility in water, and its planar symmetry which gives rise to
only one peak in the carbonyl area. The evaluation was
performed in a D2O/CD3CN 10:1 with CH3CN as an internal
reference. Because the chemical shift of the carbonyl is
dependent on the ionic strength of the aqueous solution the
evaluation was based between the difference of the free
carboxylic acid of glycine and the methyl ester of glycine
(Figure 3). This will reveal how the carboxylic acid affects the
electron density surrounding the carbonate motif.
Conclusions
During optimizations of the reported transformation, it was
found that triethylamine was far superior to the
NaHCO3/Na2CO3 buffered system for mitigating carbamate
formation between divinylcarbonate and glycine, with
conversion to product above 90 % with triethylamine and 40 %
with buffer under equal conditions. With triethylamine as
base a clear relationship between the rate of the reaction and
initial basicity of the system was found; however, high pH also
leads to a higher degree of hydrolysis. The degree of hydrolysis
could be suppressed by modulating the amount of glycine
within the system thus acquiring selective transformation
towards the desired product.
The developed methodology was applied to synthesize highly
functional building blocks containing alkenes, carboxylic acids,
thiols and alcohols with a central carbamate motif. In the cases
where glycine was used as a nucleophile, all products were
obtained in excellent yields (> 90%) after 2 h at ambient
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D, Liu. B, Gan. Q, Li. H, Darensbourg. D. J, ACS Catal., 2012, 2,
temperature without the need of further purification besides
precipitation. More sterically congested amino acid
nucleophiles, under the same reaction conditions, resulted in
lower yields, 70 % for serine, 50 % cysteine and 20 % for
asparagine and arginine. The only side reaction was hydrolysis
of divinylcarbonate. The differences in yield are interpreted as
a combined effect of the increased hindrance and difference in
solubility of the amino-nucleophiles compared to glycine.
2029; (c) Coady. D. J, Horn. H. W, Jones. G. O, Sardon. H,
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5
6
The necessity for excess of amino acid over cyclic carbonate
for selective transformation was explored the by looking at the
activation of the central carbonyl carbon of ethylene
carbonate, as a function of reaction equivalents of either
unprotected glycine, or the methyl ester of glycine. This
revealed that the free carboxylic acid of glycine is crucial for
achieving sufficient electrophilicity of the carbonate carbonyls.
Based on these results, together with the kinetic data, we
propose that the reaction proceeds through zwitterionic
cooperative activation of the cyclic carbonate motif prior to
the nucleophilic attack of the amine.
7
(a) Ivin. K. J, J. Polym. Sci., Part A Polym. Chem., 2000, 38,
2137; (b) Duda. A, Penczek. S, ACS Symp. Ser., 2000, 160; (c)
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2016, 17, 699;
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The results presented herein provide an inexpensive, green
protocol for synthesizing highly functional building blocks,
which could be of value for both the small and
macromolecular arena.
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Conflicts of interest
There are no conflicts to declare
ChemSusChem, 2016, 9, 2269
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Ring Opening of cyclic carbonates with unprotected amino acids in water – a route to highly functional
carbamates