Selenium-assisted one-pot synthesis of carbodiimides from isocyanides and primary amines

Article abstract of DOI:10.1055/s-1999-2559

Reaction of isocyanides with primary amines in the presence of selenium and DBU, followed by introduction of molecular oxygen in refluxing THF affords carbodiimides in high yields.

Full text of DOI:10.1055/s-1999-2559

LETTER
75
Selenium-Assisted One-Pot Synthesis of Carbodiimides from Isocyanides and
Primary Amines
Shin-ichi Fujiwara,*a Takahiro Matsuya,b Hajime Maeda,b1 Tsutomu Shin-ike, a Nobuaki Kambe, b and Noboru
Sonoda*c
aDepartment of Chemistry, Osaka Dental University, Hirakata, Osaka 573-1121, Japan
Fax +81-720-643062; E-mail: fujiwara@cc.osaka-dent.ac.jp
bDepartment of Applied Chemistry, Faculty of Engineering, Osaka University, Suita, Osaka 565-0871, Japan
cDepartment of Applied Chemistry, Faculty of Engineering, Kansai University, Suita, Osaka 564-8680, Japan
Received 7 October
Since selenoureas 1 can be formed by the reaction of iso-
Abstract: Reaction of isocyanides with primary amines in the pres-
cyanides with selenium and amines,3 we then attempted
ence of selenium and DBU, followed by introduction of molecular
one-pot synthesis of carbodiimides 2 from isocyanides
oxygen in refluxing THF affords carbodiimides in high yields.
and primary amines in the presence of selenium (eq 2).7
Key words: carbodiimide, selenourea, selenium, isocyanide
O2
reflux, 5 h
Se, DBU
reflux, 1 h
Carbodiimides2 are important condensing reagents for the
construction of functional groups such as peptides, nucle-
otides, amides, acid anhydrides, and esters. They are also
useful intermediates for the preparation of a variety of het-
erocycles. Elimination of hydrogen sulfide from thioureas
is a classical and still the most commonly employed meth-
od for the synthesis of carbodiimides. Since selenocarbo-
nyl compounds are generally more reactive than the
corresponding thiocarbonyl compounds, similar elimina-
tion of hydrogen selenide from selenoureas 1 is expected
to proceed under somewhat milder conditions. After sev-
eral preliminary experiments, we have found that carbodi-
imides 2 were obtained in high yields from 1 by the use of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as a base in
the presence of molecular oxygen (eq 1).
+
RNC
R'NH2
RN=C=NR' (2)
2
Equation 2
A mixture of t-BuNC (2 mmol), n-BuNH2 (2 mmol), sele-
nium (2 mmol) and DBU (8 mmol) was stirred for 1 h in
refluxing THF (5 mL). Then molecular oxygen was intro-
duced by a peristaltic pump at 20 mL/min for 5 h under re-
flux. After deposited selenium was filtered off, the filtrate
was diluted with Et2O (50 mL), washed with brine (50 mL
x 3), dried over MgSO4, and concentrated in vacuo to give
essentially pure 2a in 82% yield (Table 1, Run 1). The re-
action also proceeded efficiently with 2 equiv of DBU
(Run 2). However, the use of only 1 equiv of DBU result-
ed in a low yield of 2a (Run 3). A stoichiometric amount
of selenium is needed in the present transformation, and
attempts for catalytic use of selenium failed. The reaction
proceeded in acetonitrile as well as in THF (Run 4), but 2a
was obtained in a moderate yield in benzene (Run 5). In a
similar manner, carbodiimides 2b-d4,5 were also obtained
in good to high yields (Runs 6-9).
Se
DBU, O2
THF, reflux, 6 h
RNHCNHR'
1
RN=C=NR'
(1)
2
Equation 1
A plausible reaction pathway is shown in Scheme 1. Iso-
cyanides react with selenium to yield isoselenocyan-
ates,3,8 which react with amines to give selenoureas 1.
Proton abstraction from selenoureas 1 with DBU affords
azaselenoenolates 3. Oxidation of 3 with molecular oxy-
gen followed by homocoupling gives diselenides 4.9 At-
tempts for isolation or detection of 4 in the present
reaction failed, probably due to the rapid proton abstrac-
tion from 4 with another molecule of DBU giving rise to
carbodiimides 2 and 5. The subsequent elimination of se-
lenium from 5 regenerates 3. This pathway accounts for
the fact that two equivalents of DBU are required for the
generation of 2 in the present reaction.
For example, selenourea 1a3 (R = t-Bu, R’ = n-Bu, 2
mmol) was treated with 4 equiv of DBU in THF (5 mL)
under reflux in the presence of molecular oxygen, feeded
by a peristaltic pump at 20 mL/min, for 6 h. After removal
of the deposited selenium by filtration, the filtrate was di-
luted with Et2O (50 mL), washed with brine (50 mL x 2),
dried with MgSO4, and concentrated to afford carbodiim-
ide 2a4,5 in 78% yield. DBU and molecular oxygen are
both essential for the present reaction. Thus, without mo-
lecular oxygen the reaction proceeded sluggishly to afford
2a only in 10% yield, and when Et3N or N-methylpyrroli-
dine (NMP) was used instead of DBU, 1a was recovered
unchanged. It is also noticeable that under the same con-
ditions the corresponding thiourea6 did not afford 2a and
was recovered unchanged.
In summary, selenoureas were found to readily undergo
formal elimination of hydrogen selenide in the presence of
Synlett 1999, No. 1, 75–76 ISSN 0936-5214 © Thieme Stuttgart · New Yorkrk

76
S.-i. Fujiwara et al.
LETTER
Se
RNHCNHR'
1
(2) Reviews for synthesis, properties, and reactions of carbodi-
imides: (a) Muthyala, R. In Comprehensive Organic Functio-
nal Group Transformations, Katritzky, A. R., Meth-Cohn, O.,
Rees, C. W., Eds; Pergamon Press: Oxford, 1995; Vol. 5, pp
1061-1089. (b) Williams, A.; Ibrahim, I. T. Chem. Rev. 1981,
81, 589-636. (c) Wagner, K.; Findeisen, K.; Schaefer, W.;
Dietrich, W. Angew. Chem., Int. Ed. Engl. 1981, 20, 819-830.
(d) Mikolajczyk, M.; Kielbasinski, P. Tetrahedron 1981, 37,
233-284. (e) Kurzer, F.; Douraghi-Zadeh, K. Chem. Rev.
1967, 67, 107-152.
R'NH2
Se
RNC
RNCSe
DBU
RNHC=NR'
Se
RNHC=NR'
3
Se
Se
O2
DBU
RN=C=NR'
(3) Sonoda, N.; Yamamoto, G.; Tsutsumi, S. Bull. Chem. Soc.
Jpn. 1972, 45, 2937-2938.
2
RNHC=NR'
(4) All carbodiimides prepared are known compounds. 1H and 13
C
NMR spectral data of 2b-c were in good accordance with those
in a handbook: The Aldrich Library of 13C and 1H FT NMR
Spectra, Vol. 1, 1993, 1413B and 1413A, respectively.
(5) 1H and 13C NMR spectral data of 2a and 2d:
4
SeSe
Butyl-tert-butylcarbodiimide (2a): 1H NMR (400 MHz,
CDCl3) d 0.93 (t, J = 7.3 Hz, 3 H), 1.28 (s, 9 H), 1.41 (sext,
J = 7.3 Hz, 2 H), 1.57 (quint, J = 7.3 Hz, 2 H), 3.21 (t, J = 7.3
Hz, 2 H); 13C NMR (100 MHz, CDCl3) d 13.6, 20.0, 31.3,
33.5, 46.5, 54.8, 139.6.
RNHC=NR'
- Se
5
Scheme 1. A Plausible Reaction Pathway
tert-Butylphenylcarbodiimide(2d):1HNMR(400MHz,CDCl3)
d 1.40 (s, 9 H), 7.05-7.12 (m, 3 H), 7.28 (t, J = 7.6 Hz, 2 H);
13C NMR (100 MHz, CDCl3) d 31.5, 57.3, 122.9, 124.3, 129.0,
135.9, 140.6.
DBU and molecular oxygen to give carbodiimides. By the
use of this reaction, a new one-pot procedure for the syn-
thesis of carbodiimides from isocyanides and primary
amines has been developed.
(6) N-Butyl-N’-tert-butylthiourea was prepared by the reaction of
tert-butylisothiocyanatewithbutylamine:Nair,G. V. IndianJ.
Chem. 1966, 4, 516-520; Chem. Abstr. 1967, 67, 11290.
(7) One-pot synthesis of carbodiimides from isocyanides and
amines by the use of transition metal complexes, see: (a) Ito,
Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1975, 40, 2981-2982.
(b) Kiyoi, T.; Seko, N.; Yoshino, K.; Ito, Y. J. Org. Chem.
1993, 58, 5118-5120. (c) Pri-Bar, I.; Schwartz, J. Chem. Com-
mun. 1997, 347-348.
Acknowledgement
This work was supported in part by a Grant-in-Aid from the Mini-
stry of Education, Science, Sports and Culture, Japan. S. F. thanks
Osaka Dental University Research Funds for financial support
(A98-23). Thanks are due to the Instrumental Analysis Center, Fa-
culty of Engineering, Osaka University.
(8) Bulka, E.; Ahlers, K. D.; Tucek, E. Chem. Ber. 1967, 100,
1367-1372.
(9) Selenolates and selenols are readily oxidized with molecular
oxygen to afford the corresponding diselenides: (a) Sharpless,
K. B.; Lauer, R. F. J. Am. Chem. Soc. 1973, 95, 2697-2699. (b)
Sharpless, K. B.; Young, M. W. J. Org. Chem. 1975, 40, 947-
949. Although the detailed mechanism is not clear, molecular
oxygen may act as a four-electron oxidizing agent in the pre-
sent reaction to give water as the final product.
References and Notes
(1) PresentAddress:DepartmentofAppliedChemistry,Collegeof
Engineering, Osaka Prefecture University, Sakai, Osaka 599-
8531, Japan
Synlett 1999, No. 1, 75–76 ISSN 0936-5214 © Thieme Stuttgart · New York