Organic Letters
Letter
precursor), generating byproducts and limiting the scope of the
reaction. In particular, the ring opening of the ImSyd salts,
which occurs under basic conditions, dramatically affects the
yield and efficiency of the process. In 2003, Hoffmanna and
coworkers synthesized an iminosydnone bearing a p-nitro-
phenyl carbamate on the exocyclic nitrogen. Such a
substitution activated the carbonyl toward the addition of
several nucleophiles.14 This strategy was then used more
recently by O’Hagan on 3-phenyl-ImSyd with few nucleo-
philes, essentially anilines, phenols, primary amines, and
alcohols,15 generating a limited number of N6-substituted
ImSyds in moderate yield.
Table 1. Optimization for Amine Addition on 2a and 4a
Carbonylimidazoles and carbonylimidazolium derivatives are
well-known activated intermediates for the synthesis of
unsymmetrical ureas and other acylated products.16,17 Given
its versatility, this strategy was attractive for improving the
synthesis of N6-substitued ImSyds. In this work, we
demonstrated that this synthetic approach is highly suitable
for the straightforward and efficient preparation of a large panel
of ImSyds derivatized in position N6 (Scheme 1b). In
addition, the selective addition of substrates bearing multiple
nucleophiles was achieved without a need for protecting
groups.
a
No NEt3 was added. SM, starting material.
At first, the carbonylimidazole-ImSyds were synthesized
starting from the ImSyd salts 1a and 1b (Scheme 2). The
variety of amines. The reaction with alkyl amines was efficient,
leading to the desired products in good to excellent yield
(6a,b,d,e,h,n,o). Steric hindrance was not a limitation (6e),
and even though the reaction with tris(2-aminoethyl)amine
required heating to reach completion, the desired tris-ImSyd
6g was provided in 66% yield. Secondary amines, such as
proline and dibenzylamine, showed excellent reactivity heading
to 6d and 6n in 88 and 66% yield, respectively. Synthetic
access to such derivatives would be extremely challenging by a
traditional approach based on the utilization of isocyanates.
Less reactive anilines could also react with carbonylimidazo-
lium (6f, 6i). Using the same reaction conditions as those for
alkyl amines with the model aniline gave the desired product 6f
in 87% yield. However, the poor nucleophilicity of aniline
required a considerable increase in the time required to reach
reaction completion. Heating the reaction in chloroform
allowed the desired product to be obtained without any yield
erosion in only 30 min. We chose to use those conditions for
anilines and other weak nucleophiles. To expand the scope, we
investigated the reaction with ImSyds functionalized on the
aryl (6j−m), giving the expected products in good yield. Other
chemical functionalities were also tolerated, such as esters (6d,
6h, 6m, 6o) or sensitive boronic ester (6i). ImSyds 5a and 5b,
the thiocarbonyl analogues of 4a and 4b, also reacted with
amines, giving the corresponding thioureas 7a−d in good yield,
although heating was needed in some cases.
Considering the good reactivity of ImSyd-carbonylimidazo-
lium with a wide variety of amines, we decided to expand the
reaction to alcohols, phenols, and thiols. After a short
optimization using n-butane-thiol, we determined that the
best conditions for such nucleophiles were the same as those
for the anilines, that is, refluxing in chloroform. The reaction
with hydroxyl groups was performed with both alkyl alcohols
(8a) and phenols (8b−e), leading to the corresponding
carbamates in good yield. The addition of thiols was revealed
to be more intricate. The reaction gave lower yields, especially
with the volatile butanethiol (9a). However, we could obtain
S-benzyl and S-tolyl thiocarbamates in good yield, including
Scheme 2. Access to Carbonylimidazolium and
Thiocarbonylimidazolium Iminosydnone Salts
a
a
(a) CO, Pd(PPh3)2Cl2, EtOH, NEt3, 80 °C.
reaction proceeded smoothly, without the addition of any base,
therefore limiting the formation of the opened nitroso
derivative commonly observed under basic conditions,
affording the desired products 2a−c in good yield.
Thiocarbonylimidazole reacted with the ImSyd salts to afford
the related thio-compounds 3a,b in 81 and 65% yield. The
treatment of those substrates with iodomethane generated the
corresponding carbonylimidazolium and thiocarbonylimidazo-
lium derivatives 4a−c and 5a,b in 91−98% yield.
With those derivatives in hand, we investigated their
reactivity with two model nucleophiles (Table 1). ImSyd
carbonylimidazole 2a was found to be unreactive (entries 1
and 2), even under prolonged heating, and the starting ImSyd
was fully recovered. When compound 2a was solubilized in n-
butylamine or morpholine (100 equiv, entries 3 and 4), the
desired product could be obtained only in poor yield due to
substrate decomposition. On the contrary, carbonylimidazo-
lium-ImSyd 4a appeared to be a better substrate: Excellent
yields were obtained at room temperature with only one
equivalent of n-butylamine or morpholine (entries 5 and 6).
Following the optimized reaction conditions for urea
formation, we next investigated the substrate scope (Scheme
3). We first derivatized the unsubstituted ImSyd 4a with a large
B
Org. Lett. XXXX, XXX, XXX−XXX
Audisio, Davide
