Base-Catalyzed Transcarbamoylation

Article abstract of DOI:10.1055/s-0036-1588866

Inorganic bases such as NaH, KO t -Bu, NaOH, or KOH are efficient catalysts to promote the transcarbamoylation reaction between urethanes and a variety of primary and secondary alcohols under mild conditions. They constitute an alternative to organometallic catalysis and can be applied to aliphatic or aromatic urethanes.

Full text of DOI:10.1055/s-0036-1588866

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–D
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B. Rhoné, V. Semetey
Letter
Synlett
Base-Catalyzed Transcarbamoylation
Benoît Rhonéa,b,c
Vincent Semetey*a,b
R2OH (3 equiv),
KOH (1.2 equiv)
H
H
OR1
N
OR2
N
R
R
60 °C
O
O
a Chimie ParisTech, PSL Research University, CNRS, Institut de
Recherche de Chimie Paris, 11 Rue Pierre et Marie Curie,
75005 Paris, France
14 examples, up to 97% conversion
vincent.semetey@chimie-paristech.fr
b Laboratoire Physico Chimie Curie, Institut Curie, PSL Research
University, 75005 Paris, France
c Sorbonne Universités, UPMC Univ Paris 06, 75005 Paris,
France
Received: 09.03.2017
Accepted after revision: 12.05.2017
Published online: 07.06.2017
isopropoxide,13 tin,14 bismuth triflate,15 zinc acetate,16 or
lanthanum(III)17,18 salts. However, these reaction conditions
require rather high temperatures, around 100 °C, and the
metal catalysts can be hard to remove from the product.
DOI: 10.1055/s-0036-1588866; Art ID: st-2017-d0172-l
Abstract Inorganic bases such as NaH, KOt-Bu, NaOH, or KOH are effi-
cient catalysts to promote the transcarbamoylation reaction between
urethanes and a variety of primary and secondary alcohols under mild
conditions. They constitute an alternative to organometallic catalysis
and can be applied to aliphatic or aromatic urethanes.
O
O
+ R2OH
R1
R1
+ MeOH
N
OMe
N
OR2
H
H
1
2
Scheme 1 Transcarbamoylation reaction of a urethane (R1 = aliphatic
Key words urethane, carbamate, transcarbamoylation, transurethani-
sation, base
or aromatic group and R2 = aliphatic group)
Urethanes as well as ureas are classically prepared start-
ing from isocyanate reactants or intermediates.1–3 Isocya-
nates such as 4,4′-diphenylmethane diisocyanate (MDI) and
toluenemethyl diisocyanate (TDI) are widely used in poly-
mer chemistry to prepare polyurethanes. To avoid the use
of toxic isocyanates,4 various synthetic sustainable routes
have been investigated,5 including the ring-opening polym-
erization of cyclic carbonates with diamines6 or ring-open-
ing polymerization of aliphatic cyclic urethanes.7 However,
most of these isocyanate-free routes do not allow segment-
ed polyurethanes, commonly used commercially, to be ob-
tained. To synthesize these commercial polyurethanes, new
routes have been developed by using a transcarbamoylation
between a diol and a diurethane in the presence of a titani-
um or a tin catalyst.8,9 A bicyclic organic base, 1,5,7-triazab-
icyclo[4.4.0]dec-5-ene (TBD) can also be used catalyze this
reaction.10 This transcarbamoylation, also called transure-
thanization, involves the reaction of an alcohol with a car-
bamate group 1 to obtain a new carbamate 2 (Scheme 1).
This reaction has also been studied on small molecules for
its application in organic synthesis.11 Several metal cata-
lysts are known to be able to activate the carbonyl group
and catalyze transcarbamoylation,12 such as titanium(IV)
Bases such as sodium hydroxide or metal alkoxides are
often used for transesterification reactions19 and they are
known to be more efficient than acid catalysts.20 The tran-
scarbamoylation reaction is similar but it requires a higher
energy input, as the urethane carbon is far less electrophilic
than an ester carbon. Even though these two reactions are
very similar mechanistically, little work has been carried
out on transcarbamoylation.
Most examples of transcarbamoylation have been re-
ported for ring-closing reactions and involve the use of
strong bases such as LiHMDS,21 sodium hydride,22,23 or sodi-
um methoxide.24 Thus, the reaction mixture has to be heat-
ed for reaction to occur, sometimes at temperatures up to
200 °C in the latter case. In some circumstances, with high-
ly reactive carbamates, such as sulfonyl carbamates, trans-
carbamoylation occurs simply by heating with an alcohol.11
To the best of our knowledge, the only example of this reac-
tion catalyzed by soft bases was published by Tundo et al.
who showed that potassium tert-butoxide at 60 °C could
catalyze this reaction to give new carbamates or Boc-pro-
tected amines.25 They performed the reaction in pure alco-
hol (10 equiv) without additional solvent and observed the
formation of undesired amine as a side product.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

B
B. Rhoné, V. Semetey
Letter
Synlett
In this Letter, we describe the reaction conditions of
transcarbamoylation using inorganic bases to avoid forma-
tion of side products. Different inorganic bases were com-
pared for this reaction and we studied the impact of param-
eters such as temperature, substrate and concentration of
base, and alcohol on transcarbamoylation. We show herein
that bases milder than the ones classically used allow tran-
scarbamoylation with good conversions under mild condi-
tions. Using inorganic bases as catalysts, the reaction can be
performed under gentle heating (60 °C).
clo[2.2.2]octane (DABCO, Table 1, entries 7 and 8) did not
afford the desired product. Attempts to use acidic catalysis
with trifluoroacetic acid or sulfuric acid failed to promote
transcarbomoylation (data not shown). As expected, no re-
action occurred in the absence of a base (Table 1, entry 9),
proving the catalytic effect of other bases.
The effect of quantity of base (KOH) to catalyze the reac-
tion was then studied, and the results are reported in Table
2. Decreasing the number of equivalents of base led to a
slower reaction, but it was noticed that even a catalytic
amount of base gave a 50% conversion after four hours (Ta-
ble 2, entries 6–8). As expected, increasing the temperature
allowed a significant reduction of reaction time due to bet-
ter reaction kinetics and probably better elimination of the
methanol formed during the reaction (Table 2, entries 5, 9,
and 10). At 40 °C a conversion of 23% was obtained after
four hours, offering very mild reaction conditions (Table 2,
entry 2) with KOH as a base.
Table 1 Impact of the Base on Reaction Conversiona
base (2 equiv),
BuOH (3 equiv)
H
H
N
OMe
N
OBu
toluene
O
O
Entry
Base (2 equiv) Conversion (%,b t = 4 h) Conversion (%,c t = 20 h)
1
2
3
4
5
6
7
8
9
LiOH
0
38
70
47
41
23
0
3
87
95
88
45
90
0
NaOH
KOH
Table 2 Impact of the Amount of Base and Temperature on Reaction
Conversiona
KOt-Bu
NaH
Entry
Temp (°C)
KOH (equiv)
Conversion (%,b t = 4 h)
1
2
20
40
50
60
60
60
60
60
80
100
1.2
1.2
1.2
2
0
23
54
80
60
57
54
50
90
95
TBD
N(CH2CH3)3
DABCO
–
3
0
0
4
0
0
5
1.2
0.3
0.2
0.1
1.2
1.2
a Reaction conditions: PhNHCO2Me (1 equiv, 0.3 M in toluene), BuOH (3
equiv), 60 °C.
6
b Determined by HPLC analysis.
c Determined by HPLC and NMR analysis.
7
8
9
First, the impact of the base was studied. Conversions of
methyl N-phenylcarbamate to butyl N-phenylcarbamate via
transcarbamoylation, determined by HPLC (Figure S1) or
NMR analysis (Figure S2) are summarized in Table 1. Vari-
ous hydroxides (2 equiv) were used with only three equiva-
lents of alcohol and compared to stronger bases such as so-
dium hydride and potassium tert-butoxide. Lithium hy-
droxide was ineffective (Table 1, entry 1), possibly due to its
poor dissociation in toluene. Sodium hydroxide catalyzed
the reaction, but with potassium hydroxide as a base the
reaction was faster (Table 1, entry 2). Sodium hydride did
not result in full conversion into the desired product (Table
1, entry 5), probably because it can also deprotonate the
more acidic urethane. Potassium hydroxide was therefore
chosen for the rest of the studies (Table 1, entry 3). No trace
of amine was found when this set of conditions was used
(Table 1, entries 1–5); whereas when alcohol (isopropanol)
was used as the solvent, degradation occurred, leading to
the formation of the amine.25 Finally, the organocatalyst
1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) was also tested
and showed very good conversion after 20 hours. Other or-
ganic bases such as triethylamine and 1,4-diazabicy-
10
a Reaction conditions: PhNHCO2Me (1 equiv), BuOH (3 equiv), 0.3 M in tol-
uene.
b Determined by HPLC and NMR analysis.
The reactivity of a variety of alcohols with methyl N-
phenylcarbamate was investigated using 1.2 equivalents of
KOH at 60 °C (Table 3).26
All primary alcohols tested in this study (propanol, iso-
propanol, butanol, octanol, and methoxyethanol) showed
excellent reactivity. The number of equivalents of primary
alcohol could be lowered to two equivalents without im-
pacting the conversion significantly (Table 3, entry 5).
With the reaction conditions described (3 equiv), sec-
ondary and tertiary alcohols such as isopropanol and tert-
butanol did not react with the carbamate (Table 3, entries 2
and 9), although no degradation byproducts were observed.
The amount of alcohol had to be increased to six equiva-
lents to observe reaction with isopropanol (Table 3, entry
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

C
B. Rhoné, V. Semetey
Letter
Synlett
Table 3 Reaction of Various Alcohols with Methyl N-Phenylcarbamatea
conditions (Table 5). We found that aliphatic urethanes
could also be transcarbamoylated to new urethanes, but the
aromatic urethane was slightly more reactive than an ali-
phatic urethane with similar N-substituent (Table 5, entries
1, 6). This difference can be explained because the aromatic
urethane carbon is more electrophilic than in the aliphatic
analogue. However, a small aliphatic substituent (ethyl) in-
stead of the bulky cyclohexyl group allowed high conver-
sion (Table 5, entries 3 and 4). Again, a secondary alcohol
(isopropanol) did not react under this set of conditions (Ta-
ble 5, entries 2 and 5).
Entry
Alcohol
Conversion
Conversion
(%,b t = 4 h)
(%,c t= 20 h)
1
2
PrOH (3 equiv)
54
0
83
0
i-PrOH (3 equiv)
i-PrOH (6 equiv)
BuOH (3 equiv)
3
65
60
52
7
90
95
90
18
85
97
0
4
5
BuOH (2 equiv)
6
BuOH l (1 equiv)
octanol (3 equiv)
methoxyethanol (3 equiv)
t-BuOH (3 equiv)
t-BuOH (6 equiv)
t-BuOH (as solvent)
7
76
62
0
Table 5 Transcarbamoylation Reaction of Aliphatic and Aromatic Ure-
8
thanes with Different Alcoholsa
9
10
11
0
0
Entry Urethane (reactant) Alcohol (3 equiv)
Conversion (%, t = 4 h)
0
0
1
2
3
4
5
6
7
PhNHCO2Me
EtNHCO2Me
BuOH
60b
0c
a Reaction conditions: PhNHCO2Me (1 equiv, 0.3 M in toluene), alcohol,
KOH (1.2 equiv), 60 °C.
i-PrOH
b Determined by HPLC analysis.
EtNHCO2Me
BuOH
86c
72c
0c
c Determined by HPLC and NMR analysis.
EtNHCO2Me
CH3OCH2CH2OH
i-PrOH
C6H11NHCO2Me
C6H11NHCO2Me
C6H11NHCO2Me
BuOH
40c
28c
3), but no product was obtained when tert-butanol was
used, either in six equivalents or as solvent, probably due to
steric hindrance (Table 3, entries 10 and 11).25
Several solvents were evaluated under the optimized re-
action conditions, and the conversions of the transcarbam-
oylation reaction of methyl N-phenylcarbamate with buta-
nol are reported in Table 4.
CH3OCH2CH2OH
a Reaction conditions: urethane (1 equiv, 0.3 M in toluene), alcohol (3
equiv), KOH (1.2 equiv), 60 °C.
b Determined by HPLC and NMR analysis.
c Determined by NMR analysis.
Higher molecular mass carbamates were obtained by
this reaction, but this reaction is reversible and can allow
the conversion of high molecular-mass carbamates into
smaller molecular-mass ones. However, a large excess of
the alcohol has to be used to reach good conversion
(Scheme 2), because the butanol formed during the reac-
tion remains in solution.
Table 4 Impact of the Solvent on Reaction Conversiona
Entry Solvent
Conversion (%,b t = 4 h) Conversion (%,c t= 20 h)
1
2
3
toluene
60
44
71
95
76
80
MeCN
cyclohexane
MeOH (10 equiv),
KOH (1.2 equiv)
a Reaction conditions: PhNHCO2Me (1 equiv, 0.3 M in toluene), BuOH (3
equiv), KOH (1.2 equiv), 60 °C.
H
H
N
OBu
N
OMe
b Determined by HPLC analysis.
60 °C, 20 h, 90%
O
O
c Determined by HPLC and NMR analysis.
Scheme 2 Reaction with short chain alcohol
In the three solvents tested (toluene, acetonitrile, cyclo-
hexane), good conversions were obtained, with a signifi-
cant difference between acetonitrile and toluene (Table 4,
entries 1 and 2). However, it was noticed that, when a small
amount of water (2 vol%) was added to the reaction mix-
ture, the reaction was much slower and only went to 50%
conversion. Solvation of the inorganic base by the water
may decrease its reactivity. It is therefore important to use
anhydrous solvents to improve conversions.
As aromatic and aliphatic urethanes can have different
reactivities due to the possible delocalization of the nitro-
gen lone pair into the aromatic ring, the reactivity of ali-
phatic urethanes was compared using the same reaction
In conclusion, we have shown that the transcarbamoy-
lation reaction catalyzed by inorganic bases such as NaOH
and KOH allows high-yielding conversion of carbamates to
other carbamates using mild conditions. It can be carried in
various solvents with only two equivalents of alcohol,
which could make it a suitable reaction for the synthesis of
complex molecules. It is an alternative to metal-catalyzed
transcarbamoylation. Transcarbamoylation catalyzed by in-
organic bases is of particular interest in the field of polymer
chemistry to provide efficient sustainable routes for the
synthesis of polyurethanes without the use of metal cata-
lysts or toxic isocyanates.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D

D
B. Rhoné, V. Semetey
Letter
Synlett
(19) Schuchardt, U.; Sercheli, R.; Vargas, R. M. J. Braz. Chem. Soc.
1998, 9, 199.
Acknowledgment
This work was supported by Vygon, the CNRS (Centre National de la
Recherche Scientifique), Institut de Recherche de Chimie Paris,
Chimie ParisTech, and Institut Curie.
(20) Freedman, B.; Butterfield, R. O.; Pryde, E. H. J. Am. Oil Chem. Soc.
1986, 63, 1375.
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Supporting Information
(23) Barber, C. G.; Blakemore, D. C.; Chiva, J.-Y.; Eastwood, R. L.;
Middleton, D. S.; Paradowski, K. A. Bioorg. Med. Chem. Lett.
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(24) Bernáth, G.; Stájer, G.; Szabó, A. E.; Fölöp, F.; Sohár, P. Tetrahe-
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Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588866.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
ortioInfgrmoaitn
(25) Tundo, P.; McElroy, C.; Aricò, F. Synlett 2010, 1567.
(26) General Procedure for Transcarbamoylation
In a 25 mL round-bottom flask, the urethane (0.66 mmol) was
dissolved in dry toluene (2 mL). The alcohol (3 equiv, 1.98
mmol) and the base (1.2 equiv, 0.79 mmol) were added, and the
reaction mixture was heated at 60 °C with continuous agitation.
Samples were taken at regular time intervals and analyzed by
HPLC and 1H NMR spectroscopy to estimate conversion. To
isolate the pure product, water (10 mL) and EtOAc (10 mL) were
added to the reaction mixture. The organic layer was separated,
dried over MgSO4, filtered, and the solvent was evaporated. The
residue was purified by silica column chromatography eluting
with a 10–50% EtOAc–cyclohexane gradient. The fractions were
concentrated under reduced pressure to give the desired prod-
uct.
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Butyl N-Phenylcarbamate
White solid (115 mg, 90% yield). HPLC: tR = 16.1 min (linear gra-
dient, 0–60% B, 20 min). 1H NMR (300 MHz, DMSO-d6): δ = 9.57
(s, 1 H), 7.43 (d, J = 7.5 Hz, 2 H), 7.24 (t, J = 7.5 Hz, 2 H), 6.95 (t,
J = 6 Hz, 1 H), 4.05 (t, J = 6.8 Hz, 2 H), 1.46–1.72 (m, 2 H), 1.23–
1.46 (m, 2 H), 0.89 (t, J = 7.3 Hz, 3 H) ppm.
Octyl N-Phenylcarbamate
White solid (135 mg, 82% yield). HPLC: tR = 18.9 min (linear gra-
dient, 0–60% B, 20 min). 1H NMR (300 MHz, CDCl3): δ = 7.38 (d,
J = 7.5 Hz, 2 H), 7.31 (t, J = 7.5 Hz, 2 H), 7.06 (t, J = 7.5 Hz, 1 H),
7.06 (br s, 1 H), 4.16 (t, J = 6.8 Hz, 2 H), 1.59–1.76 (m, 2 H), 1.12–
1.45 (m, 10 H), 0.79–0.89 (m, 3 H) ppm.
(16) Dumrul, H.; Yuksel, F. Polyhedron 2013, 63, 83.
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2011, 13, 430.
2-Methoxyethyl N-Phenylcarbamate
White solid (120 mg, 93% yield). HPLC: tR = 14.5 min (linear gra-
dient, 0–60% B, 20 min).1H NMR (300 MHz, CDCl3): δ = 7.22–
7.49 (m, 4 H), 6.99–7.12 (m, 1 H), 6.64–6.83 (m, 1 H), 4.33 (t, J =
4.5 Hz, 2 H), 3.65 (t, J = 4.5 Hz, 2 H), 3.42 (s, 3 H).
(18) Hatano, M.; Ishihara, K. Chem. Commun. 2013, 49, 1983.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–D