Investigations providing a plausible mechanism in the hexamethyldisilazane- catalyzed trimerization of alkyl isocyanates

Article abstract of DOI:10.1016/j.tet.2010.12.013

Using HMDS as catalyst for the trimerization of isocyanates presents many advantages as the expected isocyanurate is not contaminated by the catalyst or other side-products resulting from its degradation. In addition, HMDS presents a low toxicity, and is compatible with industrial applications. This article describes the hexamethyldisilazane (HMDS)-catalyzed trimerization of octylisocyanate. Experimental investigations and mechanistic considerations indicate that the true catalyst of the trimerization is trimethylsilyloctylamine, which results from the preliminary condensation of HMDS with octylisocyanate.

Full text of DOI:10.1016/j.tet.2010.12.013

Tetrahedron 67 (2011) 1506e1510
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Investigations providing a plausible mechanism in the
hexamethyldisilazane-catalyzed trimerization of alkyl isocyanates
,
b
b
Mihaela Roman a, Bruno Andrioletti a, Marc Lemaire a , Jean-Marie Bernard , Johannes Schwartz ,
*
Philippe Barbeau b
ˇ
a
ꢀ
ꢀ
ꢀ
Universite Claude Bernard-Lyon1, Institut de Chimie et Biochimie Moleculaires et Supramoleculaires (ICBMS-UMR CNRS 5246), Campus de la Doua, Batiment Curien (CPE),
43, Boulevard du 11 Novembre 1918, 69622 Villeurbanne Cedex, France
b
ꢁ
Perstorp France (PERL), 85 Avenue des freres Perret, 69190 Saint Fons, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 July 2010
Received in revised form 3 December 2010
Accepted 6 December 2010
Available online 10 December 2010
Using HMDS as catalyst for the trimerization of isocyanates presents many advantages as the expected
isocyanurate is not contaminated by the catalyst or other side-products resulting from its degradation. In
addition, HMDS presents a low toxicity, and is compatible with industrial applications. This article
describes the hexamethyldisilazane (HMDS)-catalyzed trimerization of octylisocyanate. Experimental
investigations and mechanistic considerations indicate that the true catalyst of the trimerization is
trimethylsilyloctylamine, which results from the preliminary condensation of HMDS with octylisocyanate.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Alkyl isocyanate
Trimerization
Mechanism
Isocyanurate
HMDS
Organocatalysis
Low VOC
1. Introduction
to their stability and increased thermal resistance.4 In addition, they
were used as activators for the polymerization of 3
-caprolactam,5 as
Isocyanates and polyisocyanates constitute a very important
class of starting materials in many industrial applications, such as
foams, elastomers, paints, surface coatings, and fibers.1 Yet, the high
toxicity of isocyanate constitutes a serious drawback for potential
applications. Indeed, Bhopal disaster is by far, the most catastrophic
accident in the history of chemical industry, and resulted from a leak
of methyl isocyanate in the atmosphere.2 Conversely, the atom
efficiency is ideal when ureas or urethanes are synthesized from
isocyanates and amines or alcohols as precursors, respectively. As no
economically viable alternative to isocyanates has been discovered
to date, different approaches for limiting the inherent toxicity of
isocyanates were proposed. The major drawback of isocyanates
dealing with its volatility, substitution of volatile monomers by
higher molecular weight oligomers or derivatives was developed.
Thus, urethane, biuret, carbodiimide, uretdione, and isocyanurate
were proposed as low vapor pressure (non VOC) building blocks.3
Among these oligomers, isocyanurates play an important role due
precursors in the preparation of flame-retardant materials for
electrical devices,6 in the preparation of copolymer resins7 and more
recently in organosilicon nanochemistry.8
Many catalysts, such as Lewis bases9 (phosphines, carboxylates,
ammonium salts, cyanates, carbamates, carbenes) or organometallic
complexes10 were employed for the trimerization of isocyanates.
Nevertheless, very little information concerning the mechanism and
the advantages/limitations of these approaches were reported. A
ꢀ
noticeable exception concerns one recent report by Horvath et al.
that described the mechanism of the phosphine-catalyzed trimeri-
zation of aryl isocyanates. In their study, they demonstrated that the
initial step concerns the activation of the isocyanate by a nucleo-
philic attack of the phosphine on the electro-deficient isocyanate
carbon atom affording a zwitterionic intermediate that was also
proposed earlier by Verkade et al.11
As alkyl isocyanates generally exhibit a different behavior
compared with the aryl analogues, and as they also constitute
a very important class of industrial building blocks, we dedicated
our attention towards the elucidation of the intrinsic mechanism of
the hexamethyldisilazane (HMDS)-catalyzed cyclotrimerization of
octylisocyanate (C8H17NCO). This catalyst presents potentially two
* Corresponding author. E-mail address: marc.lemaire@univ-lyon1.fr(M. Lemaire).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.12.013

M. Roman et al. / Tetrahedron 67 (2011) 1506e1510
1507
specific advantages: on the one hand it exhibits a relatively low
toxicity and on the other hand it can be readily eliminated at the
end of reaction due to its low boiling point compared to that of
isocyanate oligomers. If this catalyst was claimed in several
important patents,12 to date very little is known concerning the
mechanism of the catalysis. This lack of information is detrimental
from both the academic and the industrial point of view. We believe
that the mechanistic investigations disclosed in this paper will help
improving the control and the optimization of such a complex
process. The choice of octylisocyanate relies on its close similarity
to the industrially relevant hexamethylenediisocyanate (HDI).
Moreover, our choice is justified by its ease of handling and the fact
that it affords easy-to-characterize low molecular weight products
and by-products upon oligomerization.
Urea 1a was prepared in quantitative yield by mixing directly
octylisocyanate with an excess of octyl amine at room temperature.
When the temperature was raised to 130 ꢀC in the presence of octy-
lisocyanate, 1a was quantitatively converted into biuret 2a. The syn-
theses of the low molecular weight oligomers (3e5) were also carried
out. On a laboratory scale, we discovered that the easiest synthesis of
isocyanurate 3 involved a catalytic amount (0.5 mol %) of trime-
thylsilanolate as catalyst. Use of such nucleophile as catalyst had al-
ready been claimed (but not described!) in several patents for the
oligomerizationofisocyanates.13 Uponadditionoftrimethylsilanolate,
trimerization of C8H17NCO occurred readily in 1 h at room tempera-
ture and the expected isocyanurate was isolated in 83% yield. When
the amount of Me3SiONa was increased to 50% and the temperature
raised to 60 ꢀC, 3 was isolated in 94% yield. On the other hand, the
preparation of the iminotrimer analogue 4 appeared more challeng-
ing. Even if it was reported that triphenylphosphine oxide catalyzes
efficiently the trimerization of EtNCO and the formation of the cor-
responding iminotrimer,14 in our hands, this procedure did not afford
the expected iminotrimer 4 in decent yield. The major by-product of
the reaction appeared to be the iminodimer 5 (10%). Actually, we
found that the best catalyst for the formation of 4 was Sn(acac)2. Using
these conditions, after 3 h at 40 ꢀC, the expected iminotrimer was
isolated in 40% yield after purification by a silica-gel chromatography.
2. Results and discussion
The solvent-free reaction between C8H17NCO and different
amounts of HMDS leads to a complex mixture of oligomers, such as
dioctyl urea 1a, octyltrimethylsilyl urea 1b, biuret 2a, trimethylsilyl
biuret 2b, isocyanurate 3, iminotriazinedione 4, etc.. impossible to
analyze without the complete characterization of the pure products
(Scheme 1).
Scheme 1. Reaction between octylisocyanate and HMDS.
Accordingly, the first part of our work was devoted to the syn-
thesis of the different products and by-products of the trimerization
reaction. Inspired by methods described in the literature for alkyl or
aryl isocyanates, we developed the synthesis of the intermediates
using octylisocyanate as starting material (Scheme 2). Details con-
cerning these syntheses are presented in the Experimental section.
Based on classical spectroscopic analyses, we unambiguously
determined the structure of all isolated products. Thus, using the
spectroscopic signatures of the pure products (Fig. 1), we could
analyze the 1H NMR spectrum of a complex reaction mixture.
Taking into account the formation of a complex mixture in the
case of the HMDS-catalyzed oligomerization of octylisocyanate, we
Scheme 2. Synthesis of oligomerization products of octylisocyanate.

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M. Roman et al. / Tetrahedron 67 (2011) 1506e1510
Fig. 1. 1H NMR spectra of C8H17NCO and the isolated pure products.
first carried out a reaction using a stoichiometric amount of HMDS in
order to identify the first intermediates formed during this process.
The reaction mixture was heated at 120 ꢀC for 2 h before the tem-
perature was increased to 150 ꢀC for an additional 2 h. The progress
of the reaction was monitored by analyses and NMR spectroscopy.
After 4 h, the conversion was complete and we identified the
octyltrimethylsilyl urea 1b as the major product (>50% yield), and
isocyanurate 3 and biuret 2a as by-products (Scheme 3).
presence of trimethylsilyl isocyanate. This experiment clearly
demonstrates that TMSNCO is a by-product in the reaction.
To determine the exact role of TMSNCO we carried out three
additional 10% HMDS-catalyzed-oligomerizations of octylisocya-
nate in the presence of an excess TMSNCO (10, 25 or 100%,
respectively). Two experimental procedures were tested: the first
one in a double-necked round-bottom equipped with a condenser
under argon atmosphere and the second one in a sealed tube. The
results of this study are disclosed in Table 1.
Table 1
Influence of TMSNCO
Entry
TMSNCO
(%) added
Total conversion
(%) after 4 ha
3 (%) after 4 ha
1b
2b
3c
4c
5c
6c
0
10
0
10
25
100
70
66
75
60
60
50
35
34
40
32
30
18
a
2 h at 120ꢀ and 2 h at 150 ꢀC.
Open vessel.
Reaction in sealed tube.
b
c
Scheme 3. Proposed reaction pathway for the reaction between stoichiometric
amount of octylisocyanate and HMDS.
When the reaction was carried out in an open vessel (argon at-
mosphere), the addition of an excess TMSNCO did not influence the
outcome of the reaction (Table 1, entries 1 and 2). This observation
could be ascribed to the low boiling point (bp¼90e92 ꢀC) of TMSNCO,
that is, rapidlyevaporated from the reaction mixture. Conversely, when
the reaction was performed in a sealed tube, the addition of TMSNCO
clearly reduced the conversion of the starting material (Table 1, entries
4e6). Correlatively, the formation of the isocyanurate decreased.
Therefore the key stepdi.e., the formation of TMS-octyl amine 7 from
6 e hence elimination of TMSNCO should be considered as reversible.
The following step leading to the formation of the isocyanurate
3 was determined after the reaction between an excess of octyli-
socyanate with 1b at 120e150 ꢀC. These experimental conditions
afforded the expected isocyanurate and the trimethylsilyl biuret 2b
intermediate. On the basis of these observations, we can propose
the following mechanism for the formation of the symmetrical
isocyanurate (Scheme 4).
We explained the formation of 1b by assuming that the reaction
starts with the nucleophilic attack of HMDS on the electrophilic car-
bon atom of C8H17NCO leading to the formation of N,N-bis(trime-
thylsilyl)octylurea.Then, thelatterundergoesaTMSmigrationleading
to the less hindered N,N0-bis(trimethylsilyl)octylurea, 6. The driving
force of this reaction can be attributed to the steric decongestion
resulting from the migration of a TMS group. Such a mechanism was
recently proposed by Cheng and Lu as the key step of the oligomeri-
zation of
a
amino acid N-carboxyanhydrides catalyzed by HMDS.15
Following, the transformation of 6 in trimethylsilyldioctylurea
1bdthe main product of the stoichiometric reactiondrequired the
elimination of trimethylsilyl isocyanate. This hypothesis was con-
firmed by carrying the same reaction with argon flushing. Indeed,
under these conditions, we analyzed the volatiles and detected the

M. Roman et al. / Tetrahedron 67 (2011) 1506e1510
1509
Scheme 4. Formation of isocyanurate starting from the intermediate 1b.
In parallel, in order to confirm the crucial role of 7, we attempted
to prepare the silylated amine 7 by reaction of octyl amine with
TMSCl in the presence of a base (Scheme 5).
This result undoubtedly strongly indicates that 6 constitutes the ‘true
catalyst’ for the trimerization of C8H17NCO.
On the basis of the aforementioned results, we can propose the
following mechanism for the HMDS-catalyzed cyclotrimerization
of C8H17NCO (Scheme 6).
The key point of the mechanism concerns the crucial role of the
catalyst that does not only acts as a nucleophile but also was proved
to be extremely active because the TMS group can migrate during
the catalytic process. In that respect, this mechanism is very dif-
Scheme 5. Synthesis of trimethylsilyloctylamine.
ꢀ
ferent from that described earlier by Horvarth and Richter in the
case of the PPh3-catalyzed trimerization of aromatic isocyanates.
We believe that these new results will help designing new catalysts
for a better control of industrially relevant reactions. Thus, HMDS
appears as a powerful, relatively benign organocatalyst particularly
suitable for the cyclotrimerization of aliphatic isocyanates.
Even though similar approaches were described in the litera-
ture,16,17 neither the use of n-BuLi nor Et3N as a base afforded the pure
N-trimethylsilyloctylamine 6. In our hands, an inseparable mixture of
starting compound, mono- and disilylated amines was obtained. Upon
careful distillation, it appeared that the expected mono-silylated
amine undergoes a rapid trimethylsilyl migration that regenerates the
starting material as well as the bis-silylated species. As we could not
isolatethepuremono-silylatedamine6, wereacteda70:30mixtureof
mono-silylated amine and disilylated amine analyses with a large
excess of isocyanate. As expected, the isocyanurate 3 was obtained as
the main product. Moreover, no traces of bis-silylated amine were
observed at the end, indicating the fast dismutation of this product.
3. Experimental part
3.1. General
1H and 13C NMR spectra were recorded on a Bruker spectrom-
eter at 300 and 75 MHz, respectively. The chemical shifts were
Scheme 6. Plausible mechanism for the HMDS-catalyzed trimerization of octylisocyanate.

1510
M. Roman et al. / Tetrahedron 67 (2011) 1506e1510
recorded in
d
relative to the residual solvent peaks at 7.26 (1H) and
the formation of a precipitate that was filtered off. The filtrate was
directly evaporated under vacuum affording a viscous orange oil
that was purified over a silica-gel column chromatography. Using
a mixture of cyclohexane/EtOAc 30:1 as eluent, the expected
compound 4 (0.9 g, 40% yield) was eluted as the less polar product
(Rf¼0.55), before the isocyanurate 3 (Rf¼0.42). 1H NMR (300 MHz,
77.7 ppm (13C), respectively.18 MS analyses were carried out on
a Thermofinnigan MAT 95 XL spectrometer located at the Centre
ꢀ
ꢀ
Commun de Spectrometrie de masse de l’Universite Claude Bernard
Lyon1. TLC analyses were performed on silica-gel 60 F254-coated
aluminum sheets. Analytical data for compounds 1a and 2a are in
agreement with the literature.19,20
CDCl3):
3.43 (t, 2H, J¼6.5 Hz,
(75 MHz, CDCl3): 14.41, 23.0, 27.0, 27.1, 27.3, 27.6, 29.5, 29.6e29.8,
d
0.89 (m, 12H, CH3), 1.28 (m, 40H, CH2), 1.60 (m, 6H,
bCH2),
aCH2), 3.77e3.92 (m, 4þ2H,
a
CH2). 13C NMR
3.2. Synthesis of urea 1a
d
31.9, 32.1, 32.2, 41.0, 44.0, 48.0, 53.8, 145.8, 160.1. ESI-HRMS (posi-
tive mode) calculated for C35H69N4O2 (MþHþ) 577.5421; found
577.5442.
Octylamine (1 equiv) was dissolved in CH2Cl2 (0.5 M) and cooled
at 0 ꢀC. Octylisocyanate (1 equiv) was added and the reaction
mixture was allowed to warm to room temperature and stirred
until the amine was totally consumed (TLC). The reaction mixture
was filtered off, and the precipitate was collected and washed with
cold CH2Cl2. After drying the expected urea was isolated in
3.6. Synthesis of iminodimer, 5
At room temperature, a sealed tube was charged with C8H17NCO
(15 mmol, 2.64 mL) and O]PPh3 (1.5 mmol, 0.579 g). The reaction
mixture was brought to 200 ꢀC. When the reaction had reached
200 ꢀC, small bubbles of CO2 were evidenced in the reaction mix-
ture and the reaction turned dark. After 12 h, the CO2 bubbling had
stopped and the reaction had become black. After cooling, the
reaction mixture was directly poured on a silica-gel column chro-
matography and eluted with an increasing amount of AcOEt in
cyclohexane. The iminodimer (157 mg, 10% yield) was isolated as
the fourth spot, after elution of the iminotrimer 4, di-iminotrimer,
and the isocyanurate 3. Two chromatography columns were
required for isolating the almost pure iminodimer 5 (4 and 5 dis-
play very similar polarities whatever the solvent). 1H NMR
a quantitative yield. 1H NMR (300 MHz, CDCl3):
6H, CH3), 1.21 (m, 24H, CH2), 1.42 (m, 4H, CH2), 3.07 (t, 4H,
5.69 (m, 2H, NH). 13C NMR (75 MHz, DMSO-d6):
14.4, 24.1, 28.2,
d
0.85 (t, J¼6.7 Hz,
b
a
CH2),
d
30.8, 30.9, 31.8, 33.4 (CO signal missing). ESI MS (positive mode) m/
z¼284.35 (Mþ).
3.3. Synthesis of biuret 2a
Dioctylurea 1a (10 mmol, 1 equiv) and C8H17NCO (12 mmol,
1.2 equiv) were mixed and reacted together in a sealed tube. After
15 min at 90 ꢀC, the reaction mixture became clear. The reaction
temperature was raised up to 130 ꢀC and stirring was maintained
for 20 h, until the urea was totally consumed (TLC monitoring). The
yellowish reaction mixture was cooled to room temperature, and
pentane was added. A white precipitate was filtered off, and the
filtrate was evaporated to dryness affording the expected biuret 2a
as pale yellow oil in a quantitative yield. 1H NMR (300 MHz, CDCl3):
(300 MHz, CDCl3):
d
0.80 (m, 12H, CH3), 1.21 (m, 30H, CH2), 1.55 (m,
CH2), 3.20 (t, 2H, J¼7.2 Hz, CH2),
6H,
b
CH2), 3.10 (t, 2H, J¼7.1 Hz,
a
a
3.32 (t, 2H, J¼7.2 Hz,
aCH2). ESI-HRMS (positive mode) calculated
for C26H52N3O (MþHþ) 422.4110; found 422.4103.
d
0.79 (m, 9H, CH3),1.19e1.22 (m, 30H, CH2),1.47 (m, 6H,
(m, 4H, CH2), 3.64 (m, 2H,
CH2), 6.99 (m, 2H, NH). 13C NMR
14.4, 23.0, 27.4, 27.4, 29.3, 29.6, 29.66, 29.7, 30.0,
bCH2), 3.27
References and notes
a
a
(75 MHz, CDCl3):
32.1, 41.1, 156.6.
d
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Chemistry; Interscience: New York, NY, 1962; S. 69; (b) Ulrich, H. The Chemistry
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At 0 ꢀC, under Argon, Me3SiONa (0.4 mmol, 0.4 mL of a 1 M
solution in CH2Cl2) was slowly added over C8H17NCO (20 mmol,
3.10 g). Upon stirring at room temperature, the solution becomes
very viscous. After 48 h stirring, the reaction mixture was quenched
with water and CH2Cl2 (20 mL) was added. The organic layers were
washed with water (ꢁ3) and NaCl (ꢁ1). After drying with anhy-
drous MgSO4, the crude product (oil) was purified by flash chro-
matography (cyclohexane/ethyl acetate¼8/2) to give 2.9 g of pure
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product (Yield: 83%). 1H NMR (300 MHz, CDCl3):
d
0.71 (m, 9H,
CH2), 3.70 (t, 6H,
d 12.8, 21.3, 25.4, 26.5,
CH3), 1.10e1.15 (m, 30H, CH2), 1.47 (m, 6H,
b
J¼7.6 Hz,
a
CH2). 13C NMR (75 MHz, CDCl3):
27.9, 30.4, 41.7, 52.1, 147.7. ESI-HRMS (positive mode) calculated for
C27H52N3O3 (MþHþ) 466.4009; found 466.4026.
3.5. Synthesis of iminotrimer, 4
14. Niclas, H. J.; Martin, D. Tetrahedron 1977, 34, 703e706.
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Holmes, A. B. Chem. Commun. 2008, 2152e2154.
At room temperature, a sealed tube was charged with C8H17NCO
(15 mmol, 2.64 mL) and Sn(acac)2 (1.5 mmol, 0.47g). After 45 min
stirring at room temperature, the reaction mixture was heated
to 80 ꢀC. Immediately, a green precipitate appeared before the
reaction mixture became reddish. Heating was maintained for 3 h.
After, a 10:1 acetone/water mixture (15 mL) was added, inducing
17. Nielson, A. J. Inorg. Synth. 1990, 27, 327e329.
18. Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62, 7512e7515.
19. Mizuno, T.; Masatoshi, M.; Takeo, N.; Toshiyuki, I.; Takatohi, I. Synthesis 2006, 17,
2825e2830.
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