An expeditious method for the selective cyclotrimerization of isocyanates initiated by TDAE

Article abstract of DOI:10.1016/j.tetlet.2014.03.045

We developed a rapid and green synthesis of various isocyanurates by cyclotrimerization of isocyanates using TDAE (tetrakis(dimethylamino)ethylene). TDAE displays excellent performance in catalytic quantities, affording the corresponding trimer of isocyanates very rapidly, under air and at room temperature in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2014.03.045

Tetrahedron Letters 55 (2014) 2700–2702
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An expeditious method for the selective cyclotrimerization
of isocyanates initiated by TDAE
⇑
Alain G. Giuglio-Tonolo, Cédric Spitz, Thierry Terme, Patrice Vanelle
Aix-Marseille Université, Institut de Chimie Radicalaire (ICR), UMR CNRS 7273, Equipe de Pharmacochimie Radicalaire (LPCR), Faculté de Pharmacie, 27 Bd Jean Moulin,
13385 Marseille-CS30064-cedex 05, France
a r t i c l e i n f o
a b s t r a c t
Article history:
We developed a rapid and green synthesis of various isocyanurates by cyclotrimerization of isocyanates
using TDAE (tetrakis(dimethylamino)ethylene). TDAE displays excellent performance in catalytic quanti-
ties, affording the corresponding trimer of isocyanates very rapidly, under air and at room temperature in
good to excellent yields.
Received 5 February 2014
Revised 4 March 2014
Accepted 7 March 2014
Available online 14 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Isocyanates
Cyclotrimerization
TDAE
Solvent-free
Isocyanurates
1,3,5-Triazinane-2,4,6-triones or isocyanurates, with their high
thermal stability, are used to enhance the physical properties of
polyurethanes and coating materials.1 Incorporation of isocyanu-
rates into the framework of polyurethanes increases thermal and
chemical resistance, flame retardation, as well as film-forming
characteristics.2 Isocyanurates are also employed in other areas
such as chiral discrimination,3 selective ion bonding,4 and drug
delivery.5 Triaryl isocyanurates are often used as activators for
(H3C)2N
(H3C)2N
N(CH3)2
N(CH3)2
Figure 1. Structure of TDAE.
Therefore, developing catalysts which promote cyclotrimeriza-
tion selectively is of great importance due to wide application of
isocyanurate structure in both industry and academic studies.1–6
Tetrakis(dimethylamino)ethylene21 (Fig. 1) is an electron-rich
organic reductant, which reacts with halogenated derivatives to
generate an anion under mild conditions via two sequential single
electron transfers.
During our investigation of 9-bromofluorene addition to phenyl
isocyanate in the presence of TDAE, we discovered that TDAE al-
lowed the cyclotrimerization of isocyanates to their respective
isocyanurates. Herein, we report further details about this efficient
and straightforward isocyanurate synthesis using commercially
available TDAE.
Phenyl isocyanate 1a was used as a model substrate for the
optimization of the cyclotrimerization conditions and the results
are summarized in Table 1. We first carried out a reaction using
an equimolar amount of TDAE and phenyl isocyanate in anhydrous
THF at room temperature. The conversion, monitored by TLC, was
complete after 15 min. A complex mixture was obtained and
triphenylisocyanurate 2a was isolated in only 25% yield (entry 1).
Using 40 mol % of TDAE resulted in a small decrease of the
the polymerization and postpolymerization of
e-caprolactam in
the production of nylons with high melt viscosities.6
The general route for the preparation of isocyanurates is the
cyclotrimerization of the corresponding isocyanates. A number of
reports have been published concerning this method using a
variety of different Lewis-basic catalysts, including phosphines,7
amines,8 NO,9 alkoxyallenes,10 fluoride anions,11 p-toluenesulfi-
nates,12 carbamate anions,13 cyanates,14 and N-heterocyclic
carbenes.15 Organometallic catalysts such as lithium amides,16
alkylzinc amines and alkoxides,17 tin complexes,18 palladium(0),19
copper(II) and nickel(II) halides9 also allowed the cyclotrimeriza-
tion of isocyanates. But, many of the known cyclotrimerization
procedures suffer from low catalyst activity, diazetidine byproduct
formation, lengthy reaction times, product separation difficulties,
and the use of toxic solvents.15,20
⇑
Corresponding author. Tel.: +33 491835580.
E-mail address: patrice.vanelle@univ-amu.fr (P. Vanelle).
http://dx.doi.org/10.1016/j.tetlet.2014.03.045
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

A. G. Giuglio-Tonolo et al. / Tetrahedron Letters 55 (2014) 2700–2702
2701
Table 1
Table 2
Optimization of the cyclotrimerization of phenyl isocyanate initiated by TDAE
Scope of the cyclotrimerization of various isocyanates
Ph
N
R
N
TDAE
O
O
R
O
R
O
TDAE, r.t.
(2 mol%)
Ph NCO
R
NCO
1a-k
N
N
N
N
r.t., 10 s
Ph
Ph
1a
O
2a
O
2a-k
Entry
TDAE (mol %)
Solvent
Time
% Yielda 2a
Entry
RNCO
Solvent
None
% Yielda,b 2a–k
1
2
3
4
5
6
7
8
9
10
11
12
13
100
40
15
15
15
15
15
15
15
5
THF
THF
THF
Cyclohexane
n-Heptane
Diethyl ether
Ethyl acetate
Ethyl acetate
None
None
None
Ethyl acetate
None
15 min
15 min
15 min
15 min
15 min
15 min
15 min
15 min
10 s
10 s
10 s
15 min
12 h
25b
35b
69b
63b
70b
46b
71b
69c
67c
80c
81c
70c,d
16c
NCO
1
2
3
81 2a
95 2b
92 2c
Me
NCO
NCO
NCO
None
MeO
None
4
5
None
None
94 2d
91 2e
MeO
Cl
2
2
NCO
None
a
Isolated yields.
NCO
NCO
b
Reactions were performed under nitrogen at room temperature using 2 mL of
6
7
None
None
91 2f
93 2g
anhydrous non-degassed solvent.
c
Reactions were performed under air at room temperature.
Reaction was performed with 0.5 mL of ethyl acetate.
d
O2N
Cl
NCO
NCO
NCO
8
9
EtOAc
EtOAc
EtOAc
81c 2h
76c 2i
90c 2j
by-product proportions and allowed 2a in 35% yield (entry 2). With
15 mol % of TDAE, a dramatic improvement was observed and 2a
was isolated in 69% yield (entry 3). A variety of solvents were
screened (entries 4–7) and ethyl acetate gave the best result
(71% yield, entry 7). Performing the reaction under air gave a sim-
ilar yield than under nitrogen (entry 7 vs 8).
NC
Cl
10
NCO
11
EtOAc
82c 2k
Then, we explored the possibility to run the reaction without
solvent under air with 15 mol % of TDAE. After 10 s, the mixture be-
came completely solid, so the reaction was stopped. Interestingly,
trimer 2a was isolated in a yield similar to those obtained with
ethyl acetate as the solvent (entry 8 vs 9). This encouraging finding
prompted us to investigate the influence of TDAE amount under
solvent-free conditions and air. Decreasing the amount of TDAE
from 15 mol % to 5 mol % resulted in a slight improvement (80%
yield, entry 10). No significant effect was observed between
5 mol % and 2 mol % of TDAE (entry 10 vs 11). Using a small
amount of ethyl acetate as solvent resulted in a slightly lower yield
of trimer 2a (entry 12). A control experiment without catalyst (en-
try 13) showed the importance of TDAE to achieve good yields.
So, the method developed here is very simple, fast, and environ-
mentally-friendly as it allowed the formation of the trimer under
air at room temperature in only 10 s without solvent. Furthermore,
separation of the desired product was achieved by simply triturat-
ing and filtering the crushed reaction mixture with cold diethyl
ether and water, successively.
Cl
a
b
c
Isolated yields.
Reactions were performed under air at room temperature.
0.5 mL of EtOAc was used and the reaction was stirred for 15 min.
TDAE was added to a solution of nitrophenyl isocyanate in
0.5 mL of ethyl acetate under air, the corresponding trimer 2h
was isolated in 81% yield (entry 8). With these new conditions
for solid isocyanates in hand, the scope of the cyclotrimerization
using a variety of solid isocyanates was explored and gave good
to excellent yields of the corresponding isocyanurates 2i-k (entry
9–11).
Based on the ability of TDAE to give electrons and on a recent
Letter showing that the trimerization of isocyanates can be initi-
ated by an electron,23 we propose a similar mechanism involving
an anion radical intermediate formed by donation of an electron
of TDAE to the isocyanate.
With the optimized conditions in hand, we proceeded to inves-
tigate the substrate scope of the reaction. The results are shown in
Table 2.22 Under the optimized solvent-free reaction conditions, a
variety of liquid isocyanates were converted to the corresponding
isocyanurates in very good yields (entry 1–7). Both electron-donat-
ing and electron-withdrawing substituents on the aryl group are
well tolerated. Interestingly, a benzyl substituent gave also a very
good 93% yield of the corresponding isocyanurate 2g (entry 7).
The reactivity of solid isocyanates was then studied with the
optimized conditions. But, our preliminary attempt with nitro-
phenyl isocyanate, previously powdered in a mortar with a pestle,
and 2 mol % of TDAE at room temperature, did not allow the forma-
tion of the corresponding isocyanurate 2h. So, we further investi-
gated the use of a minimum amount of solvent. When 2 mol % of
In conclusion, commercially available TDAE has been used for
the first time to catalyze the cyclotrimerization of a wide range
of aryl isocyanates and benzyl isocyanate to isocyanurates in high
yield. The important features of our method are: solvent-free
conditions with liquid isocyanates, mild reaction conditions
under air, very short reaction time, and simple purification
procedure.
Acknowledgments
This work was supported by the Centre National de la Recher-
che Scientifique and the Aix-Marseille Université. The authors
thank V. Remusat for 1H and 13C spectra recording and T. Schembri
for mass spectra recording.

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A. G. Giuglio-Tonolo et al. / Tetrahedron Letters 55 (2014) 2700–2702
Synlett 2005, 251; (d) Amiri-Attou, O.; Terme, T.; Vanelle, P. Molecules 2005, 10,
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