Synthesis of carbamates from amines and dialkyl carbonates: Influence of leaving and entering groups

Article abstract of DOI:10.1055/s-0029-1219927

A number of carbamates were synthesised through a halogen-free process by reacting amines with symmetrical and unsymmetrical carbonates. The results obtained showed a specific trend of preferred leaving groups (in the dialkyl carbonates) depending on whether a catalyst or a base was used. On the other hand, investigations conducted on the preferred entering groups (amines) for the synthesis of carbamates showed the same trend regardless of whether a catalyst or a base was used. Finally, in accordance with the results obtained, it was possible to synthesise sterically hindered carbamates in high yield by transesterification of methyl carbamate with a sterically hindered alcohol. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0029-1219927

LETTER
1567
Synthesis of Carbamates from Amines and Dialkyl Carbonates: Influence of
Leaving and Entering Groups
Synthesis of
C
i
a
rbama
e
tes tro Tundo,*a,b C. Robert McElroy,a Fabio Aricòa,b
a
Consorzio Interuniversitario ‘La Chimica per l’Ambiente’, Interuniversity Consortium ‘Chemistry for the Environment’,
Via delle Industrie 21/8, 30175 Marghera, Venice, Italy
b
Ca’ Foscari Università di Venezia, Dipartimento Scienze Ambientali, Dorsoduro 2137, 30123 Venice, Italy
Fax +39(041)2348620; E-mail: tundop@unive.it
Received 28 January 2010
both aliphatic or both aromatic, which limits the possible
number of accessible products.8
Abstract: A number of carbamates were synthesised through a
halogen-free process by reacting amines with symmetrical and un-
symmetrical carbonates. The results obtained showed a specific
trend of preferred leaving groups (in the dialkyl carbonates) de-
pending on whether a catalyst or a base was used. On the other hand,
investigations conducted on the preferred entering groups (amines)
for the synthesis of carbamates showed the same trend regardless of
whether a catalyst or a base was used. Finally, in accordance with
the results obtained, it was possible to synthesise sterically hindered
carbamates in high yield by transesterification of methyl carbamate
with a sterically hindered alcohol.
In this work we investigated the synthesis of carbamates
by employing a new class of carbonates: unsymmetrical
carbonates. Alkyl methyl carbonates are interesting be-
cause they can lead to the synthesis of different substitut-
ed carbamates depending on the preference of the leaving
group. In fact, recent studies on the reaction of alcohols
with methyl alkyl carbonates have shown that the meth-
oxy anion’s ability to act as a leaving group results in the
preferential formation of the most hindered carbonate
(Scheme 1).9
Key words: green chemistry, amine, dialkyl carbonate, carbamate,
protecting groups
K2CO3
R1OCOOMe
+
R2OH
R1OCOOR2
+
MeOH
60 °C
Carbamates are very useful compounds that are widely
used in the synthesis of pesticides, fungicides, herbicides,
pharmaceuticals, cosmetics and polyurethanes, in addi-
tion to being employed as protecting groups.1 Industrially,
carbamates are synthesised predominantly through the re-
action of the relevant amine with phosgene2 in a process
that is highly toxic and produces large volumes of waste.
In order to improve this phosgene-based synthetic proce-
dure, many environmentally benign pathways have been
investigated, for example, oxidative carbonylation, reduc-
tive carbonylation and methoxy carbonylation.3 In partic-
ular, one of the most promising substitutes for phosgene
as a carboxylating agent is dimethyl carbonate (DMC).
This is a green reagent that is mainly produced in China
Scheme 1 Reaction of unsymmetrical carbonates with an alcohol
An immediate exploitation of the corresponding reaction
with an amine would be the synthesis of tert-butoxycarbo-
nyl (Boc) protected nitrogen through benign pathways. In
fact, due to the prevalence of Boc-protected amines,
which are usually formed by the reaction of an amine with
di-Boc (currently still prepared from phosgene), this novel
pathway would represent a significant advancement in
chemistry beyond the use of halogens.
In this respect, the present work reports a study on the re-
actions of an amine with unsymmetrical carbonates, as
by insertion of CO2 into epoxides and cleavage of the re- well as on an investigation into the reactions of symmetri-
sulting cyclic carbonate with methanol.4 Direct synthesis cal dialkyl carbonates with a range of substituted amines.
of DMC from methanol and CO2 has also been recently The data obtained will help to establish a scale of leaving
reported.5
and entering groups that will extend our knowledge on the
reactivity of amines with unsymmetrical and symmetrical
carbonates for the synthesis of carbamates.
Reactions between amines and DMC, as well as other
symmetrical carbonates, have been investigated, and
these studies have led to good yields of the respective car- Thus, a first set of experiments (Table 1) was carried out
bamate. However, this process is not atom efficient due to in order to investigate the reactivity of a primary amine,
the presence of the related alcohol as by-product.6,7
(2-phenylethyl)amine, with several unsymmetrical car-
bonates (1:2 molar ratio) in the presence of a catalyst at
Another approach to the synthesis of carbamates is using
the reaction of urea with symmetrical carbonates. This
process is very efficient, although it can be used only
when the two components (urea and carbonate) are either
1
60 °C.10 The reaction was monitored by H NMR spec-
troscopy (see Supporting Information). A catalytic
amount of zinc acetate (5% mol) was employed, as at
ROCO2Me
SYNLETT 2010, No. 10, pp 1567–1571
Advanced online publication: 10.05.2010
x
x
.x
x
.2
0
1
0
Ph(CH2)2NH2
Ph(CH2)2NHCO2Me + Ph(CH2)2NHCO2R
DOI: 10.1055/s-0029-1219927; Art ID: D02510ST
© Georg Thieme Verlag Stuttgart · New York
Scheme 2 Reaction of unsymmetrical carbonates with (2-phenyl-
ethyl)amine

1568
P. Tundo et al.
LETTER
As expected, a trend of increasing leaving group ability
from the tert-butoxide through to the methoxy moiety was
found: BnO– > MeO– > OctO– i-PrO– > t-BuO–.
Table 1 Reactions of Unsymmetrical Carbonates with (2-Phenyl-
ethyl)amine in the Presence of Zn(OAc)2
a
ROCO2Me Conv. (%)
R
Product distribution (mol%)
A similar set of experiments was then carried out using
potassium tert-butoxide to observe if the amine reacts dif-
ferently in the presence of a strong base.10 A 25 mol%
loading of base was used to achieve a rate of reaction slow
enough to allow the carbamate formation to be followed
by 1H NMR analysis; Table 2 summarises the results ob-
tained.
Ph(CH2)2NHCO2Me Ph(CH2)2NHCO2R
n-Oct
i-Pr
69.5
69.4
63.1
4.8
26.5
25.5
40.7
1.5
43.0
43.9
22.5
3.3
Bn
t-Bu
The data shows that the use of a strong base leads to the
formation of different products to those observed when a
zinc catalyst is used. The trend of best leaving groups is
opposite to that inherent in the previous set of experi-
ments. Thus, phenylethyl methyl carbamate was observed
as the main product in all the reactions. In addition, the
overall rate of reaction is faster. The sterically hindered
tert-butyl methyl carbonate was the least reactive carbon-
ate, while benzyl methyl carbonate was the most reactive.
Reactions involving tert-butyl methyl carbonate and
prop-2-yl methyl carbonate showed an approximate 2:1
selectivity in favour of the methyl carbamate; exhibiting
an opposite trend to the results seen in Table 1. However,
in the reactions between the amine and either octyl methyl
carbonate or benzyl methyl carbonate, no significant se-
lectivity was observed.
a Reaction conditions: ROCO2Me (2 equiv), Ph(CH2)2NH2 (1 equiv),
Zn(OAc)2 (0.05 equiv), 60 °C, 48 h.
higher loading, no significant increase in the rate of reac-
tion was observed.
The most significant result is that the reaction between (2-
phenylethyl)amine and tert-butyl methyl carbonate occurs
at a slower rate than with any other carbonate. This obser-
vation was expected and is most likely due to the steric ef-
fect of the bulky carbonate. Secondly, the methoxy anion
was found to be a better leaving group in comparison to
others derived from aliphatic alcohols, with a 2:1 ratio of
selectivity in favour of N-phenylethyl alkyl carbamate.
However, when benzyl methyl carbonate was reacted with
the amine, the methyl carbamate was preferentially ob-
tained. It is also unusual that, while the anion derived from
a benzyl alcohol was shown to be a better leaving group
than that derived from methanol, the benzyl methyl car-
bonate was less reactive than the octyl or prop-2-yl methyl
carbonate, which resulted in a lower conversion of the
amine into the carbamate.
To support the findings of these preliminary investiga-
tions, a series of competitive reactions was carried out be-
tween equal quantities of two symmetrical carbonates and
(2-phenylethyl)amine, in the presence of zinc acetate
(Table 3) or potassium tert-butoxide (Table 4).11
(MeO)2CO
Ph(CH2)2NH2
Ph(CH2)2NHCO2Me + Ph(CH2)2NHCO2R
Table 2 Reactions of Unsymmetrical Carbonates with (2-Phenyl-
ethyl)amine in the Presence of t-BuOKa
(RO)2CO
Scheme 3 Competitive reaction of two symmetric carbonates and
(2-phenylethyl)amine
ROCO2Me Time Conv.
Product distribution (mol%)
R
(min) (%) Ph(CH2)2NHCO2Me Ph(CH2)2NHCO2R
The results achieved in the presence of a catalyst (Table 3)
are consistent with those obtained with unsymmetrical
carbonates (Table 1). The relative distributions of phenyl-
ethyl methyl and phenylethyl alkyl carbamates are consis-
tent with those observed in Table 1, but the selectivity
towards phenylethyl methyl carbamate is higher. Howev-
er di-tert-butyl carbonate did not react under these condi-
tions.
n-Oct
i-Pr
Bn
60
60
10
2 h
100
100
100
25.8
55.7
68.2
58.0
18.0
44.3
31.8
42.0
7.8
t-Bu
a Reaction conditions: ROCO2Me (2 equiv), Ph(CH2)2NH2 (1 equiv),
t-BuOK (0.25 equiv), 60 °C.
a
Table 3 Competition of Symmetrical Carbonates with (2-Phenylethyl)amine in the Presence of Zn(OAc)2
Carb. 1
Carb. 2
Amine Conv.
(%)
Product distribution (mol%)
Ph(CH2)2NHCO2Me Ph(CH2)2NHCO2R
(MeO)2CO
(MeO)2CO
(MeO)2CO
(MeO)2CO
(BnO)2CO
(i-PrO)2CO
(n-OctO)2CO
(t-BuO)2CO
71.1
59.9
51.4
51.5
17.8
56.0
45.5
51.5
53.3
3.9
5.9
0
a Reaction conditions: MeOCO2Me (2 equiv), ROCO2R (2 equiv), Ph(CH2)2NH2 (1 equiv), Zn(OAc)2 (0.05 equiv), 60 °C, 48 h.
Synlett 2010, No. 10, 1567–1571 © Thieme Stuttgart · New York

LETTER
Synthesis of Carbamates
1569
Table 4 Competition of Symmetrical Carbonates with (2-Phenylethyl)amine in the Presence of t-BuOKa
Carb. 1
Carb. 2
Conv.
(%)
Product distribution (% mol) after 60 min
Ph(CH2)2NHCO2Me
Ph(CH2)2NHCO2R
(MeO)2CO
(MeO)2CO
(MeO)2CO
(MeO)2CO
(BnO)2CO
(i-PrO)2CO
(n-OctO)2CO
(t-BuO)2CO
100b
100c
100d
100
53.1
77.3
57.2
100
46.9
22.7
42.8
0
a Reaction conditions: MeOCO2Me (2 equiv), ROCO2R (2 equiv), Ph(CH2)2NH2 (1 equiv), t-BuOK (0.25 equiv), 60 °C.
b After 5 min.
c After 30 min.
d After 10 min.
The results obtained by reacting (2-phenylethyl)amine Table 5 Competition of Amines with Dimethyl Carbonate in the
a
Presence of Zn(OAc)2
with symmetrical carbonates in the presence of potassium
tert-butoxide (Table 4) correlate with those detailed in
Amine 1
Amine 2 Product distribution (mol%) after 48 h
Table 2, although following a more distinct trend. The
methyl carbamate was the main product in all cases, al-
though in the reactions involving dioctyl and dibenzyl car-
bonate, the selectivity was not high. However, it is evident
from the results obtained that the reactivity of the carbon-
ate, which appears to be in direct correlation with its steric
bulk, plays a more significant role than the possible trans-
esterification reactions between the carbonates.
[RxNH(3–x)] Ph(CH2)2NHCO2Me RxNH(2–x)CO2Me
b
Ph(CH2)2NH2 n-BuNH2
83.8
86.0
85.3
74.1
67.5
100.0
100.0
0.0
b
Ph(CH2)2NH2 n-OctNH2
Ph(CH2)2NH2 (n-Bu)2NH
Ph(CH2)2NH2
Ph(CH2)2NH2
BnNH2
PhNH2
78.8
0.0
The most likely explanation for the data presented here is
that the formation of the carbamate in the presence of a
catalyst occurs through direct nucleophilic attack upon the
carbonate. In the presence of a base, the amine also forms
the carbamate by nucleophilic attack, but in this case the
carbamate is able to undergo transesterification with the
alcohol, which is the main reaction by-product. The re-
sults shown in Table 2 suggest that primary alcohols par-
take in transesterification of carbamates more readily than
secondary or tertiary alcohols, hence, the selectivity ob-
served in the reactions of octyl or benzyl methyl carbonate
is not significant. On the other hand, there is a pronounced
selectivity in tert-butyl or prop-2-yl methyl carbonate.
The effect is less evident in the data given in Table 4 as the
symmetrical carbonate first needs to undergo nucleophilic
attack in order to produce the alcohol to then partake in
transesterification of the carbamate.
a Reaction conditions: Ph(CH2)2NH2 (1 equiv), RxNH(3–x) (1 equiv),
DMC (4 equiv), Zn(OAc)2 (0.1 equiv), 60 °C (x = 1 or 2).
b Reaction complete after 24 h.
Table 6 Competition of Amines with Dimethyl Carbonate in the
Presence of t-BuOK
Amine 1
Amine 2 Product distribution (mol%) after 5 min
Ph(CH2)2NHCO2Me RxNH(2–x)CO2Me
Ph(CH2)2NH2 n-BuNH2
Ph(CH2)2NH2 n-OctNH2
Ph(CH2)2NH2 (n-Bu)2NH
94.4
93.9
98.2
98.5
96 (100)b
97.6
5.9 (49)c
89.0
Ph(CH2)2NH2
Ph(CH2)2NH2
BnNH2
PhNH2
91.1
0.0
As part of this investigation, a series of competitive reac-
tions between a range of amines and DMC was also car-
ried out to determine the reactivity of the entering groups
(Table 5).12
a Reaction conditions: Ph(CH2)2NH2 (1 equiv), RxNH(3–x) (1 equiv),
DMC (4 equiv), t-BuOK (0.25 equiv), 60 °C (x = 1 or 2).
b Product formed after 10 min.
c Product formed after 2 h.
(MeO)2CO
Ph(CH2)2NH2 + RxNH(3–x)
Ph(CH2)2NHCO2Me + RxNH(2–x)CO2Me.
equilibrium in 24 hours. The secondary amine, dibutyl-
amine, was too sterically hindered to be able to attack the
dimethyl carbonate. Aniline did not react at all, presum-
ably because aromatic amines are weaker nucleophiles
than aliphatic amines.6
Scheme 4 Competitive reaction of dimethyl carbonate with diffe-
rent amines (x = 1 or 2)
The results presented here demonstrate that primary ali-
phatic amines reacted significantly faster than (2-phenyl-
ethyl)amine, since the reactions of the former reached
The results of competitive reactions carried out in the
presence of a base (Table 6) were similar to those ob-
tained in the presence of zinc acetate, with aliphatic
amines reacting faster than (2-phenylethyl)amine.12
Synlett 2010, No. 10, 1567–1571 © Thieme Stuttgart · New York

1570
P. Tundo et al.
LETTER
The competitive reaction between (2-phenylethyl)amine, Table 7 Formation of Hindered Carbamate via Transesterificationa
and dibutylamine shows that 49% of the secondary amine
Carbamate
Alcohol Product distribution (mol%)
Me Free
carbamate carbamate amine
was converted into the corresponding carbamate after two
hours at 60 °C. These data clearly indicate that steric hin-
drance is less of an obstacle to the formation of a carbam-
ate when the reaction is carried out in the presence of a
strong base. Under these mild conditions aniline did not
react.
R
n-OctNHCO2Me
n-OctNHCO2Me
Ph(CH2)2NHCO2Me
Ph(CH2)2NHCO2Me
(n-Bu)2NCO2Me
(n-Bu)2NCO2Me
n-OctOH
t-BuOH
n-OctOH
t-BuOH
n-OctOH
t-BuOH
30.7
36.1
27.7
33.2
94.4
100.0
67.9
57.5
69.7
57.5
3.3
1.4
6.4
2.7
9.3
2.3
0.0
The results reported in Tables 5 and 6 follow the expected
trend of increasing rate of reaction of the amine with in-
creasing pKa values.13 Butylamine has the highest pKa,
while aniline has the lowest; in the case of dibutylamine,
the steric effect is more important in determining the rate
of reactivity. Thus, the reactivity of the entering groups
follows the trend: BuNH2, OctNH2 > Ph(CH2)2NH2,
BnNH2 >> (Bu)2NH >> PhNH2.
0.0
a Reaction conditions: RxN(2-x)CO2Me (1 equiv), ROH (10 equiv),
t-BuOK (1.25 equiv), 60 °C, 2 h.
Finally, while good selectivity towards a more hindered
carbamate is possible when reacting an amine with an un-
symmetrical carbonate in the presence of a catalyst, the
rate of reaction is far too slow to be viable. However, a
methyl carbamate can be formed very quickly and this is
surely a great advantage. In fact, according to the data col-
lected here, if the methyl carbamate is reacted with an ex-
cess of alcohol in the presence of a strong base
(Scheme 5), it is possible to recover sterically hindered
carbamates in high yield (~70%) via transesterification.
t-BuOH
Ph(CH2)2NHCO2Me
Ph(CH2)2NHCO2t-Bu + MeOH
t-BuOK
Scheme 5 Transesterification of methyl carbamate with an alcohol
Figure 1 Formation of N-phenylethyl tert-butyl carbamate via
transesterification15
Table 7 reports the formation of a more hindered carbam-
ate via transesterification of a methyl carbamate after a
relatively short time when reacting carbamates derived
from primary amines.14 Carbamates derived from second-
ary amines are too sterically hindered to allow the reaction
to progress at an appreciable rate with primary alcohols,
and not at all with more bulky reagents. There appears to
hours at 90 °C, the ratio of butyl to methyl carbamate
changes from roughly 60:30 to 80:20, with less free amine
present. On the other hand, comparing the results obtained
after 19 hours at 60 °C and 90 °C, shows the same ratio of
carbamates but with a lower degree of N-methylation. In
be little difference between the reactivity of carbamates fact, it is known that, at higher temperature, the nitrogen
derived from primary aliphatic and aromatic amines, with of the carbamate acts as a soft nucleophile leading to the
both giving good yields when reacted with octan-1-ol and methyl derivative.6,16
tert-butanol. It is also clear that primary alcohols undergo
In conclusion, the reaction of amines with carbonates in
transesterification more readily than bulky alcohols,
the presence of a catalyst follows the same trend of leav-
which supports the findings reported in Tables 2 and 4.
ing groups observed for the alcohols in the presence of a
It is also noteworthy that, as a result of the transesterifica- weak base. Unsymmetrical carbonates always lead to the
tion with tert-butanol, the nitrogen within a tert-butyl car- more hindered product, with the sole exception of benzyl
bamate is Boc-protected. Thus, this process can open up methyl carbonate. Reactions with symmetrical carbonates
confirmed the order of leaving groups, albeit with a more
distinct trend. The scale of entering groups followed the
expected trend, with reactivity being dictated by the pKa
of the amines, with the exception of dibutylamine, where
steric hindrance dominates.
the way to a new methodology for N-protection in organic
chemistry.
In this respect, a number of transesterification reactions
were carried out at differing temperatures in order to
achieve the Boc-protected amine in higher yield;15
Figure 1 shows the results obtained. It is clear that reac-
tion time has a greater overall effect upon the yield of tert-
butyl carbamate than increasing the temperature. Compar-
ing the results obtained after two hours at 60 °C and 19
The reaction of amines with carbonates in the presence of
a strong base gave quite different results to those of alco-
hols. This is due to the transesterification of the carbamate
taking place after nucleophilic attack by the amine. In
these cases, the readiness of an alcohol to undergo trans-
Synlett 2010, No. 10, 1567–1571 © Thieme Stuttgart · New York

LETTER
Synthesis of Carbamates
1571
(10) General procedure for the reaction of unsymmetrical
carbonates with (2-phenylethyl)amine (Table 1 and
esterification had the greatest influence on the results ob-
tained. Finally, the results achieved have enabled a rapid
route to the synthesis of various carbamates (including
tert-butyl carbamate) by tuning of the transesterification
equilibrium.
Table 2): In a 25 mL round-bottom flask, the amine (9.30
mmol) and the carbonate (18.50 mmol) were added,
followed by either zinc acetate (0.46 mmol) or potassium
tert-butoxide (2.30 mmol). The reaction mixture was heated
to 60 °C with continuous agitation. Samples were taken at
regular time intervals and analysed by 1H NMR
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
spectroscopy (see Supporting Information).
(11) General procedure for the reaction of symmetrical
carbonates with (2-phenylethyl)amine (Table 3 and
Table 4). In a 25 mL round-bottom flask, the amine (9.30
mmol), DMC (18.50 mmol) and the carbonate (18.50 mmol)
were added, followed by either zinc acetate (0.46 mmol) or
potassium tert-butoxide (2.30 mmol). The reaction mixture
was heated to 60 °C with continuous agitation. Samples
were taken at regular time intervals and analysed by 1H
NMR spectroscopy (see Supporting Information).
(12) General procedure for the reaction of amines with dimethyl
carbonate (Table 5 and Table 6). In a 25 mL round-bottom
flask, phenyl ethyl amine (4.65 mmol) the selected amine
(4.65 mmol) and DMC (18.50 mmol) were added, followed
by either zinc acetate (0.460 mmol) or potassium tert-
butoxide (1.60 mmol). The solution was heated to 60 °C
with continuous agitation. Samples were taken at regular
time intervals and analysed by 1H NMR spectroscopy (see
Supporting Information).
References and Notes
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(15) General procedure for the transesterification of methyl
carbamates with alcohols (Table 7). In a 25 mL round-
bottom flask, the selected methyl carbamate (9.30 mmol)
and the selected alcohols (93.00 mmol) were added,
followed by potassium tert-butoxide (11.60 mmol). The
solution was heated to the relevant temperature with
continuous agitation. Samples were taken at regular time
intervals and analysed by 1H NMR spectroscopy (see
Supporting Information).
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