Selective derivatization of oxime-blocked tolylene-2,4-diisocyanate

Article abstract of DOI:10.1016/j.cclet.2013.06.013

A selective reaction of cyclohexanone oxime-blocked tolylene-2,4- diisocyanate (2,4-TDI) with amino siloxane was observed, in which amines were capable of discriminating two reactive groups in the 2,4-TDI molecule. Thus, tolylene-2-tert-butyldimethylsilyloxyethyl carbamide-4-cyclohexanone oxime carbamate was synthesized and its precise structure was determined by single-crystal X-ray diffraction. Moreover, it was found that oxime-blocked isocyanate could react selectively with the NH₂ group with the OH group unprotected in ethanolamine.

Full text of DOI:10.1016/j.cclet.2013.06.013

Chinese Chemical Letters 24 (2013) 1019–1022
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Chinese Chemical Letters
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Original article
Selective derivatization of oxime-blocked tolylene-2,4-diisocyanate
*
Yang Sang, Peng-Fei Yang, Tian-Duo Li
Shandong Provincial Key Laboratory of Fine Chemicals, Shandong Polytechnic University, Jinan 250353, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A selective reaction of cyclohexanone oxime-blocked tolylene-2,4-diisocyanate (2,4-TDI) with amino
siloxane was observed, in which amines were capable of discriminating two reactive groups in the 2,4-
TDI molecule. Thus, tolylene-2-tert-butyldimethylsilyloxyethyl carbamide-4-cyclohexanone oxime
carbamate was synthesized and its precise structure was determined by single-crystal X-ray diffraction.
Moreover, it was found that oxime-blocked isocyanate could react selectively with the –NH2 group with
the –OH group unprotected in ethanolamine.
Received 13 May 2013
Received in revised form 23 May 2013
Accepted 28 May 2013
Available online 15 July 2013
Keywords:
ß 2013 Tian-Duo Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Cyclohexanone oxime
Tolylene-2,4-diisocyanate
Ethanolamine
Selective reactions
1. Introduction
and lowered the yield of product. In this paper, cyclohexanone
oxime is used as a protecting agent to block the isocyanate. The
Highly selective transformations, capable of differentiating
similarly reactive groups in the same molecule, are desirable in
synthetic chemistry [1]. Tolylene-2,4-diisocyanate (2,4-TDI) is
an important asymmetrical diisocyanate. Its isocyanate groups
can react with diols or diamines to produce polyurethanes or
polyureas. They are widely used in many areas such as foamed
plastics, structural elastomers, coating elastomers, adhesives,
leather-like materials and auxiliary agents [2]. Although the
reactivity of the two isocyanate groups in 2,4-TDI is obviously
different [3], it is still very hard to achieve selectivity under
common conditions. For example, the reaction kinetics of 2,4-
TDI and methanol has been reported to be a parallel and
consecutive reaction containing two simultaneous reaction
paths [4].
In order to study the selective reaction of diisocyanate with
regard to carbamate or carbamide formation, different synthetic
methodologies with isocyanate blocking have been reported [5].
Blocking agents, also known as protecting agents, are mainly
phenols [6], oximes [7], uretdiones [8], imidazoles and secondary
amines [9], among which uretdiones are the only molecules that
distinguish different positions of 2,4-TDI. In our previous work
[10], several asymmetrically substituted dicarbamates were
synthesized through the uretdione route (Fig. 1). It was a
convenient and economical route. However, the trimerization of
2,4-TDI occured easily [11], which was an irreversible side reaction
reactivity of otho- and para- isocyanate groups in 2,4-TDI appears
very distinct from each other and they react selectively with amino
groups. Moreover, under controlled conditions, oxime-blocked
isocyanate can only react with the –NH2 group of ethanolamine
containing both the –OH and –NH2 groups.
2. Experimental
Proton magnetic resonance spectra and carbon magnetic
resonance spectra were recorded on a Bruker Avance II spectrom-
eter (400 MHz). All chemical shifts were reported in d units relative
to tetramethylsilane. A single crystal with the dimension of
0.5 mm ꢀ 0.32 mm ꢀ 0.27 mm was used for X-ray diffraction
analysis and the data were collected on a Bruker Smart Apex
diffract meter. The structure was solved and refined by direct
methods using SHELXS program of the SHELXL-97 package.
2.1. Tolylene-2,4-cyclohexanone oxime dicarbamate (1)
Cyclohexanone oxime (6.78 g, 60.0 mmol) was dissolved in
toluene (30.0 mL) under magnetic stirring, then tolylene-2,4-
diisocyanate (5.05 g, 29.0 mmol) was rapidly added and the
reaction mixture was allowed to stir at room temperature for
1 h. After that, toluene was evaporated from the reaction system
and a white solid was obtained. The product was washed with
water three times to remove the excessive cyclohexanone oxime,
and the precipitate was dried in vacuo. Yield: 92%. 1H NMR
(400 MHz, DMSO-d6):
d 9.543 (s, 1H, –NH–), 8.892 (s, 1H, –NH–),
* Corresponding author.
E-mail address: ylpt6296@vip.163.com (T.-D. Li).
7.570 (s, 1H, Ph-H), 7.234 (d, 1H, Ph-H), 7.132 (s, 1H, Ph-H), 2.536
1001-8417/$ – see front matter ß 2013 Tian-Duo Li. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.06.013

1020
Y. Sang et al. / Chinese Chemical Letters 24 (2013) 1019–1022
CH3
CH3
NCO
NHCOOR1
CH3
CH3
NCO
NHCOOR1
a
c
b
N
N
N
N
O
C
C
O
O
C
C
O
NCO
NHCOOR2
NCO
NHCOOR1
CH3
CH3
Fig. 1. The uretdione route to synthesis of asymmetric substituted dicarbamate: (a) (t-Bu)3P, toluene, 0 8C, 3 h; (b) R1OH, chlorobenzene, 60 8C, 3 h; (c) R2OH, (t-Bu)3P, DMF,
90 8C, 3 h.
CH3
CH3
NHCON
NCO
a
O
CH3
O
NHCNHCH2CH2OSi
NHCON
H2N
c
NCO
O
1
2
O
NHCON
b
H2N
OSi
OH
3
Fig. 2. The selective displacement reaction of oxime-blocked 2,4-TDI: (a) cyclohexanone oxime, toluene, 1 h; (b) tert-butyldimethylsilane chloride, imidazole, CH2Cl2, 12 h; (c)
toluene, 12 h.
(m, 4H, –N55C–CH2–), 2.289 (m, 4H, –N55C–CH2–), 2.143 (s, 3H, Ph-
135.0, 133.1, 129.9, 129.5, 117.1, 113.2, 63.0, 44.7, 37.8, 31.8, 27.7,
CH3), 1.595 (m, 12H, –CH2–).
25.8, 24.0, 18.1, 14.8, ꢁ5.7.
2.2. 2-Amino-tert-butyldimethylsilyloxyethane (2)
2.4. Tolylene-2,4-hydroxyethyl carbamide (4)
According to the previous work [12], a solution of tert-
butyldimethylsilyl chloride (9.06 g, 60.0 mmol) in CH2Cl2
(15.0 mL) was added drop-wise under stirring to a solution of
ethanolamine (3.63 g, 59.0 mmol) and imidazole (7.57 g,
111 mmol) in CH2Cl2 (20 mL). The mixture was allowed to stir
at room temperature for 12 h, and then aqueous ammonia
(10.0 mL) and CH2Cl2 (50.0 mL) were added. After that, the
mixture was washed with brine three times. The organic fraction
was dried over MgSO4 and concentrated under reduced pressure.
A mixture of compound 1 (2.72 g, 6.81 mmol) and ethanol-
amine (3.24 g, 53.1 mmol) was added to toluene (15.0 mL), and the
mixture was stirred for 6 h at room temperature, followed by
filtration in vacuo. The precipitate was washed with absolute ether
three times and a white powder was obtained after vacuum drying.
Yield: 65%. 1H NMR (400 MHz, DMSO-d6):
d 8.379 (s, 1H, –NH–),
7.701 (s, 1H, Ph-H), 7.614 (s, 1H, –NH–), 7.114 (d, 1H, Ph-H), 6.920
(d, 1H, Ph-H), 6.615 (m, 1H, –NH–), 6.035 (m, 1H, –NH–), 4.690 (m,
2H, –OH), 3.423 (m, 4H, –CH2–CH2–OH), 3.124 (m, 4H, –CH2–CH2–
OH), 2.070 (s, 3H, Ph-CH3).
Yield: 70%. 1H NMR (400 MHz, CDCl3):
d 3.573 (t, 2H, –CH2–O–),
2.708 (t, 2H, NH2–CH2–), 1.591 (s, 2H, –NH2), 0.845 (s, 9H, –Si–
C(CH3)3), 0.012 (s, 6H, –Si–CH3); 13C NMR (100 MHz, CDCl3):
d
64.85, 44.07, 25.93, 18.3, ꢁ5.31.
2.3. Tolylene-2-tert-butyldimethylsilyloxyethyl carbamide-4-
cyclohexanone oxime carbamate (3)
A mixture of compounds 1 (2.72 g, 6.81 mmol) and 2 (3.01 g,
17.2 mmol) was stirred for 12 h at room temperature in toluene
(15.0 mL), and filtered in vacuo. The solid was washed with
methanol-toluene (1/3, v/v) three times and a white powder was
obtained after vacuum drying. Single crystals grew by allowing
water to diffuse into N,N-dimethylformamide solution slowly at
room temperature. Yield: 90%. 1H NMR (400 MHz, DMSO-d6):
d
9.431 (s, 1H, –NH–) 7.841 (s, 1H, –NH–), 7.710 (s, 1H, Ph-H), 7.092
(d, 1H, Ph-H), 7.023 (d, 1H, Ph-H), 6.514 (m, 1H, –NH–), 3.606 (m,
2H, –O–CH2–CH2–NH–), 3.165 (m, 2H, –O–CH2–CH2–NH–), 2.553
(m, 2H, –N55C–CH2–), 2.287 (m, 2H, –N55C–CH2–), 2.103 (s, 3H, Ph-
CH3), 1.638 (m, 6H, –CH2–), 0.871 (s, 9H –Si–C(CH3)3), 0.049 (s, 6H,
Fig. 3. Molecular structure of tolylene-2-tert-butyldimethylsilyloxyethyl
Si–CH3); 13C NMR (100 MHz, DMSO-d6):
d
160.5, 154.5, 151.9,
carbamide-4-cyclohexanone oxime carbamate.

Y. Sang et al. / Chinese Chemical Letters 24 (2013) 1019–1022
1021
CH3
CH3
NHCNHCH2CH2CH2CH3
O
NHCNHCH2CH2OH
O
O
O
b
a
NHCNHCH2CH2OH
NHCNHCH2CH2CH2CH3
CH3
5
4
NHCON
O
O
CH3
NHCON
CH3
NHCOCH2CH2CH2CH3
NHCOCH2CH2CH2CH3
O
+
d
1
O
c
O
O
NHCOCH2CH2CH2CH3
(no product)
NHCOCH2CH2CH2CH3
6
Fig. 4. The selective reaction of oxime-blocked 2,4-TDI with amine and alcohol: (a) ethanolamine, 6 h; (b) n-butylamine, 12 h; (c) n-butanol, 12 h; (d) n-butanol, dibutyltin
dilaurate, 50 8C, 6 h.
2.5. Tolylene-2,4-n-butyl dicarbamide (5)
As discussed above, siloxane-protected ethanolamine was the
key factor for the high selectivity of the reaction. In order to further
confirm the effect of siloxane group, ethanolamine was used to
directly react with oxime-blocked 2,4-TDI (Fig. 4a). Obviously,
both the groups in oxime-blocked 2,4-TDI reacted, and no
selectivity was observed. However, it was very interesting that
oxime-blocked isocyanate could only react with amino group
when there were both –OH and –NH2 groups in the molecule. In
order to further understand that results, n-butylamine and n-butyl
alcohol were used as model compounds to react with oxime-
blocked 2,4-TDI.
To differentiate the reactivity of amines from that of alcohols,
many successful intermediates had been developed such as
carbonyl azide [13], 1,10-carbonyl diimidazole [14] and cyclic
carbonate [15]. We found that 2,4-TDI could also selectively react
with n-butyl amine in the presence of n-butyl alcohol after being
blocked by cyclohexanone oxime. The reaction rate of oxime-
blocked 2,4-TDI with n-butyl amine was very fast at room
temperature (Fig. 4b), and the reaction of 2,4-TDI with n-butyl
alcohol did not occur under the same conditions (Fig. 4c). The latter
reaction would happen only at higher temperature (50 8C) and
with a catalyst (dibutyltin dilaurate) (Fig. 4d).
n-Butylamine (2.40 g, 32.8 mmol) and compound 1 (2.72 g,
6.81 mmol) were added to toluene (15.0 mL), and the mixture was
stirred for 12 h at room temperature, followed by filtration in
vacuo. The precipitate was washed with absolute ether three times
and a white powder was obtained after vacuum drying. Yield: 65%.
1H NMR (400 MHz, DMSO-d6):
d 8.220 (s, 1H, –NH–), 7.703 (s, 1H,
Ph-H), 7.446 (s, 1H, –NH–), 7.115 (d, 1H, Ph-H), 6.917 (d, 1H, Ph-H),
6.462 (m, 1H, –NH–), 5.918 (m, 1H, –NH–), 3.065 (m, 4H, –CH2–
CH2–CH2–CH3), 2.069 (s, 3H, Ph-CH3), 1.500–1.200 (m, 8H, –CH2–
CH2–CH2–CH3), 0.911 (t, 6H, –CH2–CH2–CH2–CH3).
2.6. Tolylene-2,4-n-butyl dicarbamate (6)
n-Butanol (2.43 g, 32.8 mmol) and compound
1 (2.72 g,
6.81 mmol) were added to toluene (15.0 mL), and the mixture
was stirred for6 h at 50 8C withdibutyltindilaurateasa catalyst. The
mixture was concentrated in vacuo and cyclohexane (15.0 mL) was
used to separate precipitate out. The precipitate was washed with
absolute ether three times and a white powder was obtained after
vacuum drying. Yield: 50%. 1H NMR (400 MHz, DMSO-d6):
d9.473 (s,
1H, –NH–) 8.727 (s, 1H, –NH–), 7.484 (s, 1H, Ph-H), 7.126 (t, 1H, Ph-
H), 7.027 (d, 1H, Ph-H), 4.048 (m, 4H, –CH2–CH2–CH2–CH3), 2.102 (s,
3H, Ph-CH3), 1.583 (m, 4H, –CH2–CH2–CH2–CH3), 1.356 (m, 4H,
–CH2–CH2–CH2–CH3), 0.907 (m, 6H, –CH2–CH2–CH2–CH3).
4. Conclusion
The selective derivatization of 2,4-TDI with amine occurs when
cyclohexanone oxime is used as blocking agent. The two carbamate
groups showed different reactivity toward amine nucleophiles.
Moreover, under controlled conditions, oxime-blocked isocyanate
can only react with an amino group in the presence of a hydroxy
group. This approach can be very useful for the synthesis of novel
monomers and polymers with desired structures.
3. Results and discussion
Fig. 2 showed the selective reaction of oxime-blocked 2,4-TDI
with amino group. Firstly, 2,4-TDI was blocked by reacting with
cyclohexanone oxime. Secondly, t-butyldimethylsilyl chloride was
used as protecting reagent to react with ethanolamine. The
hydroxyl was protected to generate compound 2. Finally, the
selective displacement reaction of oxime-blocked 2,4-TDI (1)
happened when reacted with compound 2.
The intervention of siloxane protecting group was very
important because it changed the solubility of compound 3. The
oxime-blocked 2,4-TDI could be dissolved well in toluene, but
compound 3 precipitated from toluene after one of the oxime
groups in 1 was substituted by the t-butyldimethylsilyloxyethy-
lamino group. The structure of compound 3 was determined by
single-crystal X-ray diffraction as shown in Fig. 3, which provided
the direct evidence that only the carbamate ortho to the methyl
group reacted.
Acknowledgments
This work is financially supported by the National Natural
Science Foundation of China (Nos. 21176147, 21276149 and
21204044) and Program for Scientific Research Innovation Team in
Colleges and Universities of Shandong Province.
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