Organosilicon synthesis of isocyanates: I. Synthesis of isocyanates of the furan, thiophene, and mono-and polyfluorophenyl series

Article abstract of DOI:10.1134/S1070363206010208

A convenient synthesis of known and unknown isocyanates of the furan, thiophene, and mono-and polyfluorophenyl series, involving silylation of starting amines with hexamethyldisilazane or chlorotrimethylsilane, followed by phosgenation of the resulting N-silyl-substituted amines. An unusual high-temperature rearrangement of 3-(methoxycarbonyl)-4,5-dimethylthiophene-2-yl isocyanate into its 5-ethyl isomer. ortho-Fluorine substituent in anilines decreases the yield of isocyanates, whereas 2,3,5,6-tetrafluorophenyl isocyanate exists for only a short time as a 5% toluene solution. Pleiades Publishing, Inc. 2006.

Full text of DOI:10.1134/S1070363206010208

ISSN 1070-3632, Russian Journal of General Chemistry, 2006, Vol. 76, No. 1, pp. 110 115.
Original Russian Text A.V. Lebedev, A.B. Lebedeva, V.D. Sheludyakov, S.N. Ovcharuk, E.A. Kovaleva, O.L. Ustinova, 2006, published in Zhurnal
Obshchei Khimii, 2006, Vol. 76, No. 1, pp. 114 118.
Pleiades Publishing, Inc., 2006.
Organosilicon Synthesis of Isocyanates:
I. Synthesis of Isocyanates of the Furan, Thiophene,
and Mono- and Polyfluorophenyl Series
A. V. Lebedev, A. B. Lebedeva, V. D. Sheludyakov,
S. N. Ovcharuk, E. A. Kovaleva, and O. L. Ustinova
State Research Institute of Chemistry and Technology of Organoelement Compounds,
sh. Entuziastov, 38, Moscow, 111123 Russia
Received April 7, 2005
Abstract A convenient synthesis of known and unknown isocyanates of the furan, thiophene, and mono-
and polyfluorophenyl series, involving silylation of starting amines with hexamethyldisilazane or chlorotri-
methylsilane, followed by phosgenation of the resulting N-silyl-substituted amines. An unusual high-tempera-
ture rearrangement of 3-(methoxycarbonyl)-4,5-dimethylthiophene-2-yl isocyanate into its 5-ethyl isomer.
ortho-Fluorine substituent in anilines decreases the yield of isocyanates, whereas 2,3,5,6-tetrafluorophenyl
isocyanate exists for only a short time as a 5% toluene solution.
DOI: 10.1134/S1070363206010208
It is known [1] that organosilicon derivatives of
amines and carbamic acid are effective intermediates
in the synthesis of organic isocyanates. The fact that
the latter are highly reactive starting materials in or-
ganic synthesis, especially in combinatorial synthesis
for bioscreening, necessitates search for convenient
synthetic routes to known and unknown isocyanates.
One of such routes, in view of its facility and con-
sumption of low quantities of toxic reagents, is silyla-
tion of amines followed by treatment of the resulting
N-silyl derivatives with a slight excess of phosgene.
In the present communication that is the first in a
series of publications on the use of organosilicon com-
pounds in the synthesis of a wide range of isocyanates,
we demonstrate the utility of the mentioned procedure
for preparing previously unknown isocyanates of the
furan and thiophene series, as well as mono- and poly-
fluorophenyl isocyanates.
We found that tetrahydrofurfurylamine (Ia), fur-
furylamine (Ib), and substituted thiophen-2-amines
IVa IVe are silylated in high yields when refluxed
with a 5% molar excess of hexamethyldisilazane
(HMDS) in the absence of solvents (procedure a) or
with a 5% excess of equimolar mixture of chlorotri-
methylsilane and triethylamine in toluene (procedure
b) to form N-(trimethylsilyl)amines IIa, IIb, and Va
Ve. Treatment of solutions of the products in toluene
at 5 15 C (IIa, IIb, Vb, and Vc) or diethylene glycol
dimethyl ether (diglyme) (Va, Vd, and Ve) with a
25% toluene solution of phosgene taken in a 10%
excess with respect to silylamine provides isocyanates
IIIa, IIIb, and VIa VIf isolated by vacuum
distillation. Chlorotrimethylsilane is readily re-
generated during distillation and can be reused in the
silylation stage. The process occurs by the following
scheme.
COCl2
a. (Me3Si)2NH
RCH2NH2
Ia, Ib
RCH2NHSiMe3
IIa, IIb
RCH2NCO,
Me3SiCl, HCl
IIIa, IIIb
NH3
R = tetrahydrofuran-2-yl (a), furan-2-yl (b).
COOR3
NH2
R1
COOR3
NHSiMe3
Va Ve
COOR3
NCO
R1
R1
b. Me3SiCl, Et3N
Et3N HCl
COCl2
Me3SiCl, HCl
R2
R2
R2
S
S
S
VIa VIe
VIa VIf
R3 = C2H5, R1 + R2 = (CH2)4 (a); R3 = CH3, R1 = H, R2 = H (b), CH3 (c); R3 = CH3, R1 + R2 = (CH2)4 (d); R1 = R2 =
R3 = CH3 (e); R1 = H, R2 = C2H5, R3 = CH3 (f).
110

ORGANOSILICON SYNTHESIS OF ISOCYANATES: I.
111
The use of diglyme in the case of compounds Va,
Vd, and Vd is explained by their poor solubility in
toluene.
The silylation of amines Ia and Ib proceeds quan-
titatively and does not require a large excess of
HMDS. In the presence of a large excess of HMDS,
substitution of the second proton of the amino group
takes place, yielding bis(trimethylsilyl) derivatives
VIIa and VIIb.
The structure of isocyanates IIIa, IIIb, and VIa VIf
was proved by their elemental analyses and mass and
1H NMR spectra (see table).
SiMe3
COCl2
Ia, Ib(Me Si) NH RCH2N(SiMe3)2
RCH2NC=O
IIIa, IIIb
3
2
NH3
Me3SiCl
Me3SiCl
Cl
VIIa, VIIb
VIIIa, VIIIb
R = tetrahydrofuran-2-yl (a), furan-2-yl (b).
The latter are readily phosgenated in toluene, but
the yield of isocyanates IIIa and IIIb is the same as
that of monosilyl derivatives IIa and IIb (55 and
47%, respectively), which suggests intermediate
formation of carbamoyl chlorides VIIIa and VIIIb in
the case of mono- (IIa, IIb) and bis(trimethylsilyl)
(VIIa, VIIb) derivatives. The moderate yield of iso-
cyanates IIIa, IIIb is probably explained by the low
stability of the heterocycle under the reaction condi-
tions and, as a result, strong tarring of the reaction
mixture.
Higher yields of isocyanates VIa VIf and XI were
obtained with silylated thiophenamines Va Ve and
compound X. In this case, amines IVa IVe and IX
are silylated with HMDS by only 50% because of the
lower basicity of their amino group. The use of pro-
cedure b allows N-silylamines Va Ve and X to be
prepared in yields of more than 90%.
COOR3
NHSiMe3
NH2
NCO
COCl2
Me3SiCl, Et3N
Me3SiCl, HCl
Et3N HCl
COOCH3
COOCH3
S
S
S
IX
X
XI
It should be noted that vacuum distillation of
isocyanates VIa VIe and XI from the reaction mix-
ture containing both these isocyanates and their pre-
cursors, carbamoyl chlorides, requires strong heating
to occur (up to 250 C). Under these conditions, iso-
cyanate VIe partially isomerizes into isocyanate VIf
by the following scheme.
CH3 COOCH3
CH3 COOCH3
COOCH3
NCO
COOCH3
NCO
t
H
H
H
NCO
S
+
+
S
H
H
NCO
C2H5
C
C
S
S
CH2CH2
H
H
VIe
VIf
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 1 2006

112
LEBEDEV et al.
1
Melting or boiling points, H NMR spectra, mass spectra, and elemental analyses of compounds II, III, V VII, X, XI,
XIII, and XIV
Found, %
Calculated,
C H
%
Comp. Yield,
no.
mp,
C
M+
1H NMR spectrum, , ppm
Formula
%
(p, mm Hg) (m/z)
C
H
IIa
IIb
98 175 180 (748) 173
98 163 170 (745) 169 0.06 s (9H, SiMe3), 3.88 s (2H,
CH2), 1.0 br (1H, NH), 6.07 d
55.32 10.99 C8H19NOSi
C8H15NOSi
55.44 11.05
(1Harom), 6.28 t (1Harom),
7.31 d (1Harom
)
IIIa
55
47
61 64 (15)
57 60 (15)
127 1.62 m (1H, CH2), 1.93 m (3H, 56.60
2CH2), 3.23 q (1H, CH2N),
3.36 q (1H, CH2N), 3.79 m (1H,
CH2O), 3.88 (1H, CH2O), 4.01
(1H, CH)
7.10 C6H9NO2
7.10 C6H9NO2
56.68
58.54
7.13
IIIb
Va
123 4.40 s (2H, CH2), 6.30 d
(1Harom), 6.37 t (1Harom),
58.50
4.09
7.79
7.43 d (1Harom
)
91 165 170 (2)
297 0.33 s (9H, SiMe3), 1.32 t (3H, 56.18
CH3), 1.77 m (4H, 2CH2),
2.52 m (2H, CH2), 2.73 m (2H,
CH2), 4.26 q (2H, OCH2),
7.75 s (1H, NH)
7.70 C14H23NO2SSi 56.53
Vb
Vc
88
95 100 (2)
229 0.34 s (9H, SiMe3), 3.80 s (3H, 46.94
OCH3), 6.18 d (1Harom), 7.02 d
(1Harom), 7.45 br (1H, NH)
243 0.32 s (9H, SiMe3), 2.27 s (3H, 49.21
CH3), 3.77 s (3H, OCH3),
6.63 s (1Harom), 7.34 br (1H,
NH)
283 0.31 s (9H, SiMe3), 1.76 m (4H, 55.01
2CH2), 2.52 m (2H, CH2),
2.68 m (2H, CH2), 3.77 s (3H,
OCH3), 5.91 s (1H, NH)
257 0.38 s (9H, SiMe3), 2.20 d (6H, 51.15
2CH3), 3.82 s (3H, OCH3), 7.77
(1H, NH)
251 1.37 t (3H, CH3), 1.78 m (4H, 57.31
2CH2), 2.60 m (2H, CH2),
2.76 m (2H, CH2), 4.35 q (2H,
OCH2)
6.50 C9H15NO2SSi
47.13
6.59
7.04
92 100 105 (2)
88 160 165 (2)
7.17 C10H17NO2SSi 49.35
7.42 C13H21NO2SSi 55.09
7.40 C11H19NO2SSi 51.33
Vd
7.47
Ve
86 165 170 (3)
78 135 140 (1)
7.44
5.21
VIa
5.20 C12H13NO3S
57.35
VIb
VIc
VId
73 103 108 (3)
70 105 110 (3)
79 127 130 (1)
183 3.80 s (3H, OCH3), 6.80 d 46.08
2.68 C7H5NO3S
3.54 C8H7NO3S
4.63 C11H11NO3S
57.35
48.72
55.68
5.21
3.58
4.67
(1Harom), 7.23 d (1Harom
197 2.35 s (3H, CH3), 3.86 s (3H, 48.60
OCH3), 6.88 s (1Harom
)
)
237 1.79 m (4H, 2CH2), 2.59 m (2H, 55.55
CH2), 2.77 m (2H, CH2), 3.80 s
(3H, OCH3)
VIe
66 115 118 (3)
211 2.21 d (6H, 2CH3), 3.86 s (3H, 51.01
OCH3)
4.23 C9H9NO3S
51.17
4.29
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ORGANOSILICON SYNTHESIS OF ISOCYANATES: I.
113
Table (Contd.)
Found, %
Calculated,
%
Comp. Yield,
mp,
C
M+
1H NMR spectrum, , ppm
Formula
no.
%
(p, mm Hg) (m/z)
C
H
C
H
VIf
13 115 118 (3)
211
1.17 t (3H, CH3), 2.77 q (2H, 51.01
CH2), 3.88 s (3H, OCH3),
4.23 C9H9NO3S
51.17
4.29
6.46 s (1Harom
)
VIIa
VIIb
88
90 95 (20)
245
53.63 10.98 C11H27NOSi2
C11H23NOSi2
53.82 11.08
81 180 185 (745) 241 0.09 s (18H, 2SiMe3), 3.83 s
(2H, CH2), 6.08 d (1Harom),
6.28 t (1Harom), 7.32 d (1Harom
)
X
93 100 105 (2.5) 229 0.29 s (9H, SiMe3), 3.81 s (3H, 46.91
OCH3), 6.52 d (1Harom), 6.65 s
6.51 C9H15NO2SSi
2.72 C7H5NO3S
47.13
45.90
6.59
2.75
(1H, NH), 7.29 d (1Harom
183 3.88 s (3H, OCH3), 6.74 d 45.81
(1Harom), 7.39 d (1Harom
)
XI
99 105 110 (3)
)
XIIIa 96
XIIIb 97 180 (750)
58 60 (1.5)
183
183
183
201
201
237
197
217
262
233
233
58.66
58.70
58.61
53.41
53.47
45.40
60.62
49.51
41.07
51.29
51.24
61.28
61.25
61.34
7.62 C9H14FNSi
7.64 C9H14FNSi
7.59 C9H14FNSi
6.40 C9H13F2NSi
6.44 C9H13F2NSi
4.63 C9H11F4NSi
8.07 C10H16FNSi
5.96 C9H13ClFNSi
4.94 C9H13BrFNSi
6.02 C10H14F3NSi
6.01 C10H14F3NSi
2.91 C7H4FNO
58.98
58.98
58.98
53.70
53.70
45.56
60.87
49.65
41.23
51.48
51.48
61.32
61.32
61.32
54.21
7.70
7.70
7.70
6.51
6.51
4.67
8.17
6.02
5.00
6.05
6.05
2.94
2.94
2.94
1.95
XIIIc 95
XIIId 89
XIIIe 94
XIIIf 90
XIIIg 98
XIIIh 95
78 80 (3)
65 (1.5)
88 90 (3)
65 67 (4)
78 82 (2)
85 89 (2)
XIIIi
95 105 106 (3)
XIIIj 93
XIIIk 97
XIVa 50
XIVb 85 159 161 (747) 137
XIVc 81
XIVd 50
65 (4)
90 (6)
48 50 (15)
137 7.06 7.18 m (4Harom
)
)
2.99 C7H4FNO
2.96 C7H4FNO
1.87 C7H3F2NO
58 60 (20)
50 (12)
137 6.97 7.08 m (4Harom
155 6.81 6.87 t. q (1Harom), 6.90 d, 54.06
6.92 q, 6.95 d (1Harom), 7.04 d,
7.06 d, 7.09 d (1Harom
)
XIVe 61
52 54 (14)
155 6.76 6.93 m (2Harom), 7.05 54.12
1.91 C7H3F2NO
54.21
1.95
7.13 m (1Harom
191 6.95 m (1Harom
)
)
XIVf
C7HF4NO
XIVg 59
65 70 (12)
95 96 (22)
151 2.24 s (3H, CH3), 6.74 6.80 m 63.60
(2Harom), 7.10 t (1Harom
171 6.94 6.99 m (1Harom), 7.08 t 48.79
(1Harom), 7.15 q (1arom
3.98 C8H6FNO
63.58
49.01
4.00
1.76
)
XIVh 81
1.69 C7H3ClFNO
)
XIVi
XIVj
XIVk 89
79
49
83 85 (3)
70 72 (20)
57 58 (12)
216
187
187
38.80
51.21
51.30
1.34 C7H3BrFNO
2.13 C8H4F3NO
2.15 C8H4F3NO
38.92
51.35
51.35
1.40
2.15
2.15
The ratio of isolated compounds VIe and VIf is
83:17. Here, probably, the ionotropy shown in the
isomerization scheme takes place. Methyl migration
involves intermediate protonation of the thiophene
sulfur atom, which is favored by the presence of di-
glyme in the reaction mixture. Wittig et al. [2, 3]
observed similar rearrangements in the metalation of
ethers by the following scheme.
PhCH2OMe
PhCH(Li)OMe
PhCH(Me)OLi.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 1 2006

114
LEBEDEV et al.
Mono- and polyfluoroanilines XIIa XIIk are si-
excess of phosgene in toluene 15 20 C gives rise to
isocyanates XIVa XIVk. The yields and spectral and
physicochemical characteristics of the latter are given
in the table.
lylated in high yields when refluxed with a 20% ex-
cess of HMDS (procedure c) to form N-trimethylsilyl
derivatives XIIIa XIIIk whose treatment with a 10%
R5
R4
R5
R5
R4
R4
(Me3Si)2NH
NH3
COCl2
R3
NCO
R3
NH2
R3
NHSiMe3
Me3SiCl, HCl
R1
R2
R1
R1
R2
R2
XIIa XIIk
XIIIa XIIIk
XIVa XIVk
Unspecified R = H; R1 = F (a); R2 = F (b); R3 = F (c); R1 = R3 = F (d); R1 = R4 = F (e); R1 = R2 = R4 = R5 = F (f); R2 =
F, R3 = CH3 (g); R2 = Cl, R3 = F (h); R1 = F, R3 = Br (i); R1 = CF3 (j); R2 = CF3 (k).
As seen from the table, the yields of isocyanates
decreases in the presence of fluorine ortho to the
amino group, which is probably explained by intra-
molecular Si F bonding which hinders reaction of
the amino group with COCl2; as a result, isocyanates
react with unreacted starting amines after removal of
phospene from the reaction mixture, forming the
corresponding ureas.
dropwise with stirring a mixture of 22.78 g of chloro-
trimethylsilane and 21.2 g of dry triethylamine. The
mixture was stirred for 1 h at 80 C and then diluted, if
required, with 100 ml of dry toluene to obtain a fluid
suspension, and cooled to 10 C. The triethylammo-
nium salt that precipitated was filtered off, and the
mother liquor was distilled in a vacuum to obtain
silylamines Va Ve and X in yields of 88 94%.
Given are compound number and melting point, C:
Va, 38; Vb, 50; Vc, 53 55; Vd, 65; Ve, 45 50; and
X, 25.
Generally, with fluroanilines, too, phosgenation of
their N-silyl derivatives provides a convenient syn-
thetic route to isocyanates.
Exhaustive silylation of amines Ia and Ib. To
0.2 mol of amine Ia or Ib we added 39 g of HMDS
and 2 drops of conc. H2SO4. The mixture was slowly
heated to 160 C, kept for 1 h, cooled, and distilled in
a vacuum to isolate compounds VIIa and VIIb in
yields of 87 and 90%, respectively.
It should be noted that 2,3,5,6-tetrafluorophenyl
isocyanate (XIVf) could only be isolated as a short-
lived (no more than 2 days) 5% toluene solution
stable below 5 C, which is explained by an exceptio-
nally strong tendency of compound XIVf for poly-
merization.
Silylation of amines XIIa XIIk with HMDS.
c. To 0.2 mol of amine XIIa XIIk we added 19.4 g
of HMDS and 2 drops of conc. H2SO4. The mixture
was slowly heated to 170 175 C, kept for 1 h, cooled,
and distilled in a vacuum to isolate silylamines
XIIIa XIIIk. Given are compound number and n2D0:
XIIIa, 1.5008; XIIIb, 1.5005; XIIIc, 1.4980; XIIId,
1.4795; XIIIe, 1.4802; XIIIg, 1.5031; XIIIh, 1.5102;
XIIIi, 1.5470; XIIIj, 1.4605; XIIIk, 1.4560.
EXPERIMENTAL
1
The H NMR spectra were measured on a Bruker
AM-360 spectrometer at 360.14 MHz in CDCl3 solu-
tions.
The mass spectra were obtained on a QP-5000
instrument at an ionizing energy of 70 eV.
Silylation of amines I and IV with HMDS. a. To
0.2 mol of amine Ia, Ib, or IVa IVe we added 16.9 g
of HMDS and 2 drops of conc. H2SO4. The mixture
was slowly heated to 160 C, kept for 30 min, cooled,
and distilled to isolate silylamine IIa, IIb, or Va Ve.
The yield of compounds Va Ve was 48 55%.
Synthesis of isocyanates IIIa, IIIb, VIa VIf, XI,
and XIVa XIVk. To a solution of 21.8 g of phos-
gene in 75 ml of toluene at 5 15 C (for compounds
II, V, VII, and X) or 15 20 C (for amines XIII) we
added slowly, by maintaining the temperature range,
dropwise a solution of 0.2 mol of silylamine in 30
50 ml of toluene (for compounds IIa, IIb, Vb, Vc,
VIIa, VIIb, and XIIIa XIIIk) or 75 ml of dry di-
methyl ether of diethylene glycol (for amines Va, Vd,
Silylation of amines IV and IX with chlorotri-
methylsilane. b. To a solution of 0.2 mol of amine
IVa IVe or IX in 200 ml of dry toluene we added
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ORGANOSILICON SYNTHESIS OF ISOCYANATES: I.
115
and Ve). The reaction mixture was then stirred for 1 h,
maintaining the above temperature ranges, after which
excess phosgene, chlorotrimethylsilane, and toluene
up to a vapor temperature of 105 C. The residue was
distilled in a vacuum, and isocyanates IIIa, IIIb,
VIa VIf, XI, and XIVa XIVk were collected in the
last fraction. Isocyanates VIe and VIf distilled to-
gether. Compound XIVf was collected into a receiver
containing 100 ml of toluene cooled to 0 C. After the
distillation had been complete, the toluene solution of
isocyanate XIVf was filtered to remove the polymeric
precipitate and handled at 0 C. Given are compound
number and n2D0: IIIa, 1.4610; and IIIb, 1.4790.
Given are compound number and meting point, C:
VIa, 20; VIb, 68 70; VIc, 42 45; VId, 25; VIe:VIf
(83:17), 73; and XI, 54 56.
REFERENCES
1. Mironov, V.F. and Kozyukov, V.P., Zh. Obshch. Khim.,
1984, vol. 54, no. 6, p. 1217.
2. Wittig, G. and Lohmann, L., Justus Liebigs Ann. Chem.,
1942, vol. 550, p. 260.
3. Muller, E., in Novye vozzreniya v organicheskoi khimii
(New Concepts in Organic Chemistry), Moscow:
Inostrannaya Literatura, 1960, p. 534.
RUSSIAN JOURNAL OF GENERAL CHEMISTRY Vol. 76 No. 1 2006