A mild and simple method for the preparation of isocyanates from aliphatic amines using trichloromethyl chloroformate. synthesis of an isocyanate containing an activated disulfide

Full text of DOI:10.1021/jo9521920

J . Org. Chem. 1996, 61, 3883-3884
3883
A Mild a n d Sim p le Meth od for th e
P r ep a r a tion of Isocya n a tes fr om Alip h a tic
Am in es Usin g Tr ich lor om eth yl
Sch em e 1. Syn th esis of Isocya n a tes fr om
Alip h a tic Am in es
Ch lor ofor m a te. Syn th esis of a n Isocya n a te
Con ta in in g a n Activa ted Disu lfid e
Snorri Th. Sigurdsson, Bodo Seeger, Ursula Kutzke, and
Fritz Eckstein*,†
isocyanates in small quantities and for generating com-
binatorial isocyanate libraries. By using this method,
1,6-diisocyanatohexane, benzyl isocyanate, and (R)-(+)-
methylbenzyl isocyanate were prepared from their cor-
responding amines in 73%, 78%, and 81% yields, respec-
tively.
Max-Planck-Institut f u¨ r experimentelle Medizin,
Hermann-Rein-Str. 3, D-37075 G o¨ ttingen, Germany
Received December 11, 1995
2
For the synthesis of 1, compound 2 was prepared and
partitioned between aqueous NaOH and CH Cl to yield
2 2
Recently we developed a cross-linking methodology for
probing the tertiary structure of RNA and used it to
the free amine, which partially degraded upon subse-
quent concentration of the organic phase. Therefore, a
solution of the free amine, after extraction, was used
directly in the reaction with diphosgene to yield 1.
However, due to the sensitivity of the pyridyl disulfide
functionality in 1 toward diphosgene, the general proce-
dure used for the preparation of the aforementioned
isocyanates was slightly modified: the amine was reacted
with only 0.4 equiv of diphosgene, as opposed to 0.6, and
the excess amine present after the reaction was extracted
from the solution with 1 N HCl, to prevent the formation
of a substituted urea. This modified procedure afforded
assess the catalytic competence of two different three-
dimensional models of the hammerhead ribozyme.1 Dur-
ing our continued effort toward unravelling tertiary
interactions within complex nucleic acid structures, we
were interested in the preparation of isocyanate 1 for the
site-specific incorporation of an activated thiol into oli-
gonucleotides. We decided to prepare 1 from the corre-
sponding amine, which was readily available in one step
from commercially available materials.2 Preliminary
attempts to synthesize 1 using a variety of methods3-5
were not successful, primarily resulting in complex
mixtures of products. It was concluded that the pyridyl
disulfide functionality was incompatible with the reaction
conditions and a milder method for the preparation of 1
was sought.
1
in 39% yield (based on 2) which was stable for several
days in CDCl
3
at 25 °C.
In conclusion, we present a simple procedure for the
conversion of aliphatic amines to the corresponding
isocyanates. The mildness of the reaction was demon-
strated by the successful synthesis of 1 whose application
to structural studies of nucleic acids will be reported in
due course.
Trichloromethyl chloroformate (diphosgene) has been
used for the preparation of aromatic isocyanates from the
corresponding amine hydrochlorides.6 However, this
method could not be extended to aliphatic amines, as
illustrated by their lack of success in converting 1,6-
Exp er im en ta l Section
Gen er a l. 1H NMR and 13C NMR spectra were recorded in
CDCl at 360.13 and 90.55 MHz, respectively. Chemical shifts
3
are reported in ppm, relative to tetramethylsilane at δ 0.0 ppm.
Coupling constants (J ) are reported in hertz. Reactions were
carried out in dry dichloromethane (Merck) with exclusion of
moisture. Other chemicals were purchased from Aldrich. The
isocyanates, with the exception of 1, were characterized by
comparison to commercially available material (Aldrich) using
H and C NMR spectroscopy.
Gen er a l P r oced u r e. Warning: Trichloromethyl chlorofor-
mate (diphosgene) and aliphatic isocyanates are toxic and thus
should be handled wearing protective clothing in well-
ventilated area. The procedure is illustrated by the preparation
of (R)-(+)-methylbenzyl isocyanate. A solution of (R)-(+)-meth-
ylbenzylamine (0.470 g; 3.88 mmol) and 1,8-bis(dimethylamino)-
diaminohexane hydrochloride to its corresponding diiso-
cyanate.6 We have now established that the reaction of
aliphatic amines with diphosgene at 0 °C, in the presence
of the non-nucleophilic base 1,8-bis(dimethylamino)-
naphthalene, affords isocyanates in good to excellent
yields (Scheme 1). Furthermore, the products can be
obtained in greater than 95% purity by mere extractive
workup of the reaction mixtures, making further purifi-
cation unnecessary. This is in contrast to most other
reported procedures for the preparation of isocyanates
which rely on distillation for the purification of products.7
Thus, this procedure enables the preparation of heat-
sensitive and/or nonvolatile isocyanates. Additionally,
this technique would be useful in the synthesis of
1
13
a
naphthalene (1.66 g; 7.75 mmol) in CH
dropwise to a stirred solution of trichloromethyl chloroformate
(0.460 g; 2.33 mmol) in CH Cl (10 mL) at 0 °C over a period of
min. The ice bath was then removed and the solution stirred
for a further 10 min before evaporation of the volatiles in vacuo.
The residue was partitioned between CH Cl (20 mL) and 1 N
2 2
Cl (10 mL) was added
-9
2
2
5
2
2
HCl (10 mL), and the organic phase was separated and washed
†
Tel. (+49)-551-3899-274; fax (+49)-551-3899-388; e-mail eckstein@
successively with 1 N HCl (3 × 10 mL) and 1 N NaOH (10 mL).
exmed1.dnet.gwdg.de.
(
(
2 4
After the organic phase was dried (Na SO ), the solvent was
1) Sigurdsson, S. T.; Tuschl, T.; Eckstein, F. RNA 1995, 1, 575.
2) Ebright, Y. W.; Chen, Y.; Pendergrast, P. S.; Ebright, R. H.
removed in vacuo to yield (R)-(+)-methylbenzyl isocyanate as a
pale yellow oil (0.460 g; 81%), whose optical purity was not
determined. For the synthesis of 1,6-diisocyanatohexane, the
amount of both diphosgene and 1,8-bis(dimethylamino)naph-
thalene was doubled.
Biochemistry 1992, 31, 10664.
(
(
(
(
3) Greber, G.; Kricheldorf, H. R. Angew. Chem. 1968, 80, 1028.
4) Staab, H. A.; Benz, W. Angew. Chem. 1961, 73, 66.
5) Mironov, V. F. J . Organomet. Chem. 1984, 271, 207.
6) Kurita, K.; Matsumura, T.; Iwakura, Y. J . Org. Chem. 1976, 41,
2
-Isocya n a t oet h yl 2-P yr id yl Disu lfid e (1). S-(2-Pyrid-
2
070.
2
yldithio)cysteamine hydrochloride (2) (0.173 g; 0.775 mmol) was
partitioned between CH Cl (2 mL) and 1 N NaOH (2 mL), and
the organic phase was separated and dried (Na SO ). 1,8-Bis-
(
(
(
7) Wilson, C. V. Org. Chem. Bull. 1963, 35, 1.
8) Ozaki, S. Chem. Rev. 1972, 72, 457.
9) Saunders, J . H.; Slocombe, R. J . Chem. Rev. 1948, 43, 203.
2
2
2
4
S0022-3263(95)02192-X CCC: $12.00 © 1996 American Chemical Society

3
884 J . Org. Chem., Vol. 61, No. 11, 1996
Notes
(broad, NCO), 137.1, 149.8, 159.1. IR: ν 2264 cm- (NCO).
1
(dimethylamino)naphthalene (0.333 g; 1.55 mmol) was dissolved
in the solution containing the amine and the resulting solution
added dropwise to a stirred solution of trichloromethyl chloro-
HRMS: 212.0072 (calcd 212.0078 for C H N OS ).
8
8
2
2
formate (0.061 g; 0.31 mmol) in CH
period of 1 min. After the solution was stirred for 2 min, 1 N
HCl (5 mL) and CH Cl (10 mL) was added, the mixture was
2 2
Cl (2 mL) at 0 °C over a
Ackn owledgm en t. We thank J. Thomson, A. Heaton,
S. Alefelder, and B. Patel for critical reading of the
manuscript and K. Eckart for HRMS analyses. Sup-
ported by the Deutsche Forschungsgemeinschaft and
the Fonds der Chemischen Industrie. S.Th.S. gratefully
acknowledges a postdoctoral fellowship from the Euro-
pean Molecular Biology Organisation.
2
2
shaken, and the organic phase was separated and washed
successively with 1 N HCl (4 × 5 mL) and 1 N NaOH (1 × 5
2 4
mL). After the organic phase was dried (Na SO ), the solvent
was removed in vacuo to yield 1 as a pale yellow oil (0.064 g;
1
3
9% based on 2) which was ca. 95% pure as determined by H
1
NMR analysis. H NMR: δ 2.99 (2H, t, J ) 6.2, SCH
(
8
2
), 3.61
2H, t, J ) 6.2, CH N), 7.13 (1H, m, ArH), 7.66 (2H, m, ArH),
.50 (1H, m, ArH). C NMR: δ 40.1, 41.6, 120.4, 121.2, 123.7
2
1
3
J O9521920