One-pot synthesis of selenoureas and selenocarbamates via selenation of isocyanates with bis(dimethylaluminum) selenide

Article abstract of DOI:10.1016/j.tetlet.2010.11.069

Isocyanates were efficiently selenated by the reaction with bis(dimethylaluminum) selenide to give the corresponding isoselenocyanates. One-pot synthesis of unsymmetrical selenoureas and selenocarbamates was achieved in high yields by the subsequent addit

Full text of DOI:10.1016/j.tetlet.2010.11.069

Tetrahedron Letters 52 (2011) 415–417
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Tetrahedron Letters
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One-pot synthesis of selenoureas and selenocarbamates via selenation
of isocyanates with bis(dimethylaluminum) selenide
⇑
⇑
Hajime Maeda , Masaru Takashima, Koichi Sakata, Tatsuya Watanabe, Mitsunori Honda, Masahito Segi
Division of Material Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Isocyanates were efficiently selenated by the reaction with bis(dimethylaluminum) selenide to give the
corresponding isoselenocyanates. One-pot synthesis of unsymmetrical selenoureas and selenocarba-
mates was achieved in high yields by the subsequent addition of amines and alcoholates to the reaction
mixture.
Received 28 September 2010
Revised 10 November 2010
Accepted 15 November 2010
Available online 18 November 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Recent advances of heteroatom chemistry enabled to design
and synthesize various heteroatom-containing organic molecules.
Among them, compounds having carbon-heteroatom double bonds
play significant roles for organic syntheses as synthetic intermedi-
ates due to their high reactivities. We have developed a useful sel-
enating reagent, bis(dimethylaluminum) selenide,1 which can
transform various carbonyl compounds and related compounds
such as ketones,2 aldehydes,2b,c,3 amides,4 and acetals,5 directly
to selenocarbonyl compounds in high yields. During the course of
our study about the synthetic utility of the reagent, we found
that direct conversion of isocyanates to isoselenocyanates could
be achieved. Moreover, selenoureas and selenocarbamates were
obtained in one-pot reactions by the subsequent trapping with
amines and alcoholates without isolation of isoselenocyanates.
Herein, the results of this study are described.
a clear homogeneous colorless solution. Addition of n-butyl isocy-
anate (1.2 equiv) and stirring at 100 °C for 3 h followed by aqueous
workup gave a yellow residue. Purification by a silica gel column
chromatography gave n-butyl isoselenocyanate in 86% isolated
yield (Table 1, entry 1).6 Reaction of cyclohexyl, p-chlorophenyl,
and 1-naphthyl isocyanates also proceeded in a similar manner
to give the corresponding isoselenocyanates in 90–95% isolated
yields (entries 2–4).
These successful results impelled us to examine the one-pot
synthesis of unsymmetrical selenoureas without isolation of isose-
lenocyanates, by the addition of amines before aqueous workup
(Scheme 2, Table 2). p-Chlorophenyl isoselenocyanate, generated
in situ from p-chlorophenyl isocyanate and (Me2Al)2Se under the
conditions described above, was allowed to react with n-propyl-
amine (2 equiv) at 70 °C for 0.5 h before aqueous workup to
give N-p-chlorophenyl-N0-propylselenourea in 93% isolated yield
(Table 2, entry 1). This synthetic method could be applied to the
reaction with other primary and secondary amines (entries 2–6),
and the reaction of 1-naphthyl (entries 7–11) and n-butyl isocya-
nates (entries 12–15). The use of isopropylamine (entries 2, 8, and
13) slightly improved the yields than that of n-propylamine (entries
1, 7, and 12). Decreasing yields when tert-butylamine was used are
attributable to the bulkiness of the nucleophile (entries 3 and 14).
Secondary amines such as diethylamine, di-n-propylamine, and
diisopropylamine could be used for the synthesis of selenoureas
For the preparation of bis(dimethylaluminum) selenide,
a
hexane solution of trimethylaluminum (2.2 equiv) was added to
a toluene solution of bis(tributylstannyl) selenide and stirred at
80 °C for 2 h (Scheme 1). White-suspended solution was obtained,
that indicates the formation of bis(dimethylaluminum) selenide.
After cooling to room temperature, 1,4-dioxane was added to give
2 Me3Al
(Bu3Sn)2Se
(Me2Al)2Se
toluene
80 °C, 2 h
Table 1
R
N C O
Synthesis of isoselenocyanates by the reaction of bis(dimethylaluminum) selenide
with isocyanates
R
N C Se
toluene, dioxane
100 °C, time
Entry
R
Time (h)
Yielda (%)
Scheme 1. Synthesis of isoselenocyanates.
1
2
3
4
n-Bu
3
2
5
5
86
93
95
90
Cyclohexyl
p-ClC6H4
1-Naphthyl
⇑
Corresponding authors. Tel.: +81 76 264 6290; fax: +81 76 234 4800 (H.M); tel./
fax: +81 76 234 4787 (M.S.).
E-mail addresses: maeda-h@t.kanazawa-u.ac.jp (H. Maeda), segi@t.kanazawa-
u.ac.jp (M. Segi).
a
Isolated yield.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.11.069

416
H. Maeda et al. / Tetrahedron Letters 52 (2011) 415–417
1) 2 Me3Al, toluene, 80 °C, 2 h
2)
1) MeONa, MeOH
25 °C, 0.5 h
Se
, toluene, dioxane,
N C O
R
p-ClC6H4
N C Se
100 °C, 3-5 h
Se
2) H2O
p-ClC6H4NH
OMe
(Bu3Sn)2Se
3) R'R''NH, 70 °C, 0.5 h
4) H2O
Yield = 100%
RNH
NR'R''
Scheme 4. Reaction of p-chlorophenyl isoselenocyanate with sodium methoxide.
Scheme 2. One-pot synthesis of unsymmetrical selenoureas.
(65 °C) enabled to shorten the reaction time to 0.5 h and increased
the yield to 63% (entry 2). Further increment of the stoichiometry
of methanol to 10 equiv was not effective (entry 3). Reaction with
sodium ethoxide at 25 °C also proceeded to give O-ethyl derivative
in 77% isolated yield (entry 4). Reaction with sodium ethoxide un-
der ethanol-refluxing conditions shortened the reaction time to 1 h
(entry 5). Reaction using allyl alcohol smoothly proceeded even at
25 °C for 1 h (entry 6). One-pot reaction from p-chlorophenyl iso-
cyanate also proceeded but the yields were poor and the formation
of unidentified by-products was observed (entries 7–9). Lowering
of the reaction temperature from 25 °C to 0 °C improved the yield
to 22% (entry 10). Reaction of isolated p-chlorophenyl isoselenocy-
anate with MeONa at 25 °C for 0.5 h gave the corresponding sele-
nocarbamate in quantitative yield (Scheme 4), so it is unclear
why the one-pot procedure is not suitable for the preparation of
N-aryl selenocarbamate.7
There are many synthetic methods for the preparation of isose-
lenocyanates.8 They are roughly classified into seven categories,
those are (i) reaction of isocyanides with elemental selenium,9
(ii) nucleophilic substitution of alkyl halides or related compounds
by selenocyanate anion,10 (iii) photochemical and thermal conver-
sion of alkyl selenocyanates,11 (iv) reaction of amines with CSe2 to
give diselenocarbamates followed by the reaction with electro-
philes,12 (v) reaction of imidoyl dichlorides with alkali metal selen-
ocyanates followed by elimination of cyanogen chloride,13 (vi)
insertion reaction of diazoalkanes to arylselenenyl selenocya-
nates.14 Those methods often have inevitable problems such as
bad smell of isocyanides, difficulty of separation of products from
selenocyanates, and the use of hazardous metals and reagents.
The seventh category is the direct selenation of isocyanate to isose-
lenocyanate, which is closely related with this study. However, to
the best of our knowledge, there is only one literature in this cat-
egory by using diphosphorus pentaselenide under severe condi-
tions (160 °C, 3–4 h) in extremely low yields (<10%).15 Our
method described herein is easily handled from commercially
available substrates under mild conditions. So the synthetic meth-
od developed here will be a useful one in the preparation of isose-
lenocyanates, selenoureas, and selenocarbamates.
Table 2
One-pot synthesis of unsymmetrical selenoureas
Entry
R
R0
R00
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
1-Naphthyl
1-Naphthyl
1-Naphthyl
1-Naphthyl
1-Naphthyl
n-Bu
H
H
H
Et
n-Pr
i-Bu
H
H
Et
n-Pr
i-Bu
H
H
H
n-Pr
i-Pr
t-Bu
Et
n-Pr
i-Bu
n-Pr
i-Pr
Et
n-Pr
i-Bu
n-Pr
i-Pr
t-Bu
Et
93
98
65
76
72
84
70
96
74
97
79
79
84
71
69
n-Bu
n-Bu
n-Bu
Et
a
Isolated yield.
1) 2 Me3Al, toluene, 80 °C, 2 h
2)
, toluene, dioxane,
N C O
R
Se
100 °C, 3-5 h
(Bu3Sn)2Se
3) R'ONa, temp, time
4) H2O
RNH
OR'
Scheme 3. One-pot synthesis of selenocarbamates.
in high to excellent yields (entries 4–6, 9–11, and 15). It is demon-
strated that nucleophilic addition of amines to isoselenocyanates
proceeded even in the presence of Lewis acidic aluminum species.
One-pot synthesis of selenocarbamates could be achieved by
the addition of sodium alkoxides instead of amines (Scheme 3,
Table 3). To a toluene-dioxane solution containing n-butyl isose-
lenocyanate, generated by the reaction of n-butyl isocyanate with
(Me2Al)2Se under the conditions described above, was added
sodium methoxide (3 equiv) prepared from methanol and sodium
in another flask. Stirring at 25 °C for 24 h followed by aqueous
workup and purification by silica gel column chromatography gave
N-n-butyl O-methyl selenocarbamate in 50% yield (entry 1).
Increased stoichiometry of MeONa (5 equiv) and temperature
In conclusion, we developed direct selenation reaction of
isocyanates to isoselenocyanates by using (Me2Al)2Se. One-pot
synthesis of selenoureas and selenocarbamates can also be
achieved by the subsequent addition of amines and alcoholates
in high yields.
Table 3
One-pot synthesis of selenocarbamates
Entry
R
Alcohol (mL)
Na (equiv)
Temp (°C)
Time (h)
Yielda (%)
1
2
3
4
5
6
7
8
9
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
n-Bu
p-ClC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
MeOH (1.5)
MeOH (3.0)
MeOH (6.0)
EtOH (3.0)
3
5
10
5
5
5
5
5
10
5
25
65
65
25
78
25
25
25
25
0
24
0.5
0.5
20
1
1
0.5
2
50
63
64
77
79
83
<1
<1
13
22
EtOH (3.0)
Allyl-OH (3.0)
MeOH (3.0)
MeOH (3.0)
MeOH (10)
MeOH (3.0)
0.5
0.5
10
a
Isolated yield.

H. Maeda et al. / Tetrahedron Letters 52 (2011) 415–417
417
the mixture was stirred at 100 °C for 2-5 h. After cooling to 0 °C by an ice bath,
water (10 mL) was added. The product was extracted with ether (three times).
The organic layers were combined, washed with brine (three times), dried over
MgSO4, and evaporated in vacuo. Purification by silica gel column
chromatography gave pure isoselenocyanates.
A reviewer suggested that adduct of (Me2Al)2Se onto isocyanate before
hydrolysis and/or ate complexes formed from Bu3SnMe and (Me2Al)2O with
RONa may be involved.
Acknowledgment
This work was partially supported by the Grant-in-Aids for Sci-
entific Research (C) from the Ministry of Education, Culture, Sports,
Science and Technology (MEXT) of Japan.
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Supplementary data
Supplementary data (general experimental procedures, 1H and
13C NMR data) associated with this article can be found, in the on-
line version, at doi:10.1016/j.tetlet.2010.11.069.
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temperature, 1,4-dioxane (10 mL) and isocyanate (1.2 mmol) were added and
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