5536
J. E. Drumm et al. / Tetrahedron Letters 48 (2007) 5535–5538
Na+
O
NH2
XH
N
X
a)
H
b)
H2N
N
R'
N
N-
N
R
R
N
H
N
H
R'
+
Reflux
O
3
a) R' = Me
b) R' = Et
c) R' = Ph
X = O, S, NH, NR
d)
SCH3
NH2
O
SCH3
H
N
H
HN
c)
R'
N
H
N
N
R'
.1/2 H2SO4
O
4
a) R' = Et
b) R' = t-Bu
0
0
Scheme 2. Reagents and conditions: (a) R -NCO, NaOH; (b) pH 3.5 buffer, reflux; (c) 2 equiv R -NCO, TEA, CH
3
CN or NaOH; (d) pH 3.5 buffer,
reflux.
We report here the preparations of two distinct reagents
derived from cyanamide and from S-methyl-
thiopseudothiourea and the use of these to form
1,4-dioxane as a co-solvent to assist with the solubiliza-
tion of the starting materials.
§
2
3
fused-ring heterocyclic ureas (Scheme 2). The cyana-
mide reagents 3 were readily prepared from the reactions
of lower alkyl- or phenylisocyanates with excess cyan-
amide under alkaline conditions. The sodium salts of
these compounds show stabilities of over one month in
strongly alkaline aqueous solutions. These salts can
also be prepared and isolated as stable solids under
non-aqueous conditions. Similarly, bis-alkylureido-S-
During the reaction to form the benzimidazoles (hetero-
cycles) from 3, the pH of the medium increases as
ammonia is liberated. Use of an aqueous buffer at pH
3.5 was found beneficial in keeping the reaction medium
acidic. At a pH above 4.5, the reaction rate slowed or
stopped. The buffered reaction solvent was sufficient
when reagents 4 were used. In most instances, the de-
sired heterocyclic urea precipitated as the reaction pro-
gressed. Elevating the pH of the reaction mixture with
bicarbonate prior to filtration often produced additional
amounts of the desired product. A simple water–metha-
nol wash usually gave pure materials. The yields of the
azolylureas were often higher using reagents 4 (Table 1).
à
methiopseudothioureas 4 yielded isolable solids.
As a class, the formation of the bis-acylated thio-
methylpseudothioureas was limited to simple and
branched-chain alkylisocyanate adducts. The reaction
failed to react cleanly with phenylisocyanate. In con-
trast, the cyanamide reagents 3 formed with all
isocyanates.
These reagents were also useful in preparing other fused
ring system ureas, as well. Reaction with o-aminophe-
nols and o-aminothiophenols gave the corresponding
benzoxazoleureas (Table 1, compounds 9 and 10) and
benzothiazoleureas (Table 1, compound 11), respec-
tively; similarly reactions with o-diamino pyridines and
pyrimidines gave the corresponding imidazopyridine-
ureas (Table 1, compound 19) and imidazopyrimidine-
ureas (Table 1, compound 21) (Scheme 3).
Reactions were generally carried out in aqueous buffered
media. It was advantageous to add a small amount of
It was convenient to prepare stock solutions of both reagents.
Reagents 4 were dissolved in dioxane (although they could be used as
a solid); likewise a 0.8 M aqueous solution was made for the
cyanamide reagents 3.
Preparation of sodium N-ethylureidocyanamide: 1.68 g (0.04 mol) of
cyanamide was dissolved in 10 ml 1.5 M sodium hydroxide followed
by dropwise addition of 0.8 ml (0.01 mol) ethylisocyanate. After
stirring for 30 min at room temperature, 5 ml of 3.0 M sodium
hydroxide was added, and again followed by dropwise addition of
In conclusion, we have described two new reagents and
methods for their use to make fused ring azoles. These
§
General Procedure for the preparation of the urea derivatives using S-
methyl N-alkyl carbamoyl-4-alkylthioallophanimidate. A round bot-
tom flask equipped with a reflux condenser was charged with a
diamine (2.0 mmol), S-methyl N-alkyl carbamoyl-4-alkylthioallopha-
nimidate 4 (2.4 mmol, 1.2 equiv), and dioxane (2 ml). The mixture
was then diluted with aqueous buffer, pH 3.5 (sodium acetate
trihydrate/1 N aqueous sulfuric acid, 18 ml), heated to 95–100 ꢁC and
stirred at that temperature for 10 min to 60 h (monitored by HPLC
and LCMS). The resulting mixture was cooled to room temperature,
0
.8 ml (0.01 mol) of ethylisocyanate. The resulting solution was
stirred for 30 min. HPLC (10-90-8 gradient, reverse phase,
8.9%water–1%acetonitrile–0.1%TFA/99.9%acetonitrile–0.1%TFA)
9
gave a characteristic retention time of 3.7 min (214 nm).
Preparation of S-methyl N-t-butyl-carbamoyl-4-t-butylthioallophanim-
idate. Triethylamine (30 ml, 0.215 mol) was added to a suspension of
à
2-methylthiopseudothiourea hemisulfate (10 g, 0.0718 mol) in aceto-
nitrile (72 ml). t-Butylisocyanate (25.6 ml, 0. 215 mol) was added
dropwise over 30 min with stirring. The thick white mixture was
stirred at room temperature for 40 h, then water was added (50 ml).
The biphasic mixture was extracted with ethyl acetate (2 · 150 ml).
The combined organic extracts were washed with water (100 ml),
dried over magnesium sulfate and concentrated in vacuo to give
3
slowly basified to pH 7–8 with saturated aqueous KHCO and diluted
with water. The precipitate was then isolated by filtration and washed
with 30% MeOH in water, and EtOAc in succession, and dried in
vacuo. The resulting desired ureas are essentially pure by HPLC and
1
H NMR (P97% pure), however, if necessary, these can be further
ꢂ
purified by flash chromatography (Isco CombiFlash Companion).
2
4.3 g of white solid. This was recrystallized from hot methanol/water
The analogous procedure was followed when the cyanamide reagents
were used instead of the methylthioallophanates. Ethanol, THF and
DMSO were also used successfully as co-solvents.
to give 17 g of the desired bis-acylated material as a white solid (82%
yield).
Drumm, Joseph E.
