Communication
cently, Yampolsky group proposed an inversed synthetic strat-
egy providing notably the 2-H-4-benzylidene imidazolones,
albeit in a poor 22% yield over a four-step synthesis
We started our study of the direct C2ÀH arylation by react-
ing N-benzylated and picolinyl 4-benzylidene imidazolones
5a–bA with 4-iodobenzonitrile 6A using Pd(OAc) as catalyst
2
[
5]
(
Scheme 1b). In this context, the development of innovative
and PPh3 as ligand, under copper(I) and several carbonate,
[
12]
synthetic methods, which streamline the access to imidazo-
lone-based fluorophores from readily available and safe start-
ing materials (avoiding in particular the current use of hazard-
ous azide precursors), would be of meaningful importance in
material sciences.
phosphate, and amine bases assistance. In a broad set of ex-
periments, no product resulting from a competitive Heck-type
reaction of the double bond was identified, and first satisfacto-
ry result was obtained from 5bA, when employing a combina-
tion of DBU/DMF, to afford the 2-arylated N-picolinyl benzyli-
dene imidazolone 7bA in a fair 78% yield (Table 1, entries 1
and 2). In this case, the picolinyl protective group may prevent
Recently, the transition-metal-catalyzed CÀH activation has
emerged as a powerful synthetic tool to build and functional-
[
6]
ize molecules. Notably, most of the related achievements
have been directed to main standard classes of heterocy-
[
7]
[a]
cles, but their applications in organic materials remain
Table 1. Optimized reaction conditions for direct C2ÀH arylation.
[
8]
sparse. In the current context of promotion of this
recent field towards biomedical applications, we recently
demonstrated that 4,4’-dialkylimidazolones are valuable in
[9]
the direct CÀH functionalization methodology. We report
here our effort towards the synthesis and late-stage direct
C2ÀH functionalization of 2-H-4-benzylidene imidazolones
by addressing two major challenges (Scheme 1c): i) Friend-
ly, flexible and large-scale access to key synthetic precur-
sors through the development of an azide-free synthesis
of 2-H-4-benzylidene imidazolones, including challenging
ortho-hydroxylated models recently explored to display
[
b]
Entry
Y
[Cu] (equiv)
Ligand
Solvent
Yield [%]
1
2
3
4
5
CH
N
N
N
N
CuI (1)
CuI(1)
CuBr·DMS (1)
CuBr·DMS (0.5)
–
PPh
PPh
3
3
DMF
DMF
DMF
DMF
DMF
15
78
86 (78)
27
[c]
PPh
PPh3
PPh
3
3
n.r.
[10]
optimized quantum yields;
ii) The multi and selective
[
2
a] Reaction conditions: 5a–bA (0.5 mmol), 6A (1 equiv), Pd(OAc) (5 mol%),
C2ÀH functionalization of arylidene imidazolones using
specifically nitrogen-chelating protective groups of the
imidazolone ring, such as picolinyl and 2-N,N-dimethylami-
noethyle (DMAE). The latter may be also used for a late-
stage chemical modulation of the nitrogen appendage to in-
crease solubility along with achieving bioconjugation to specif-
ic vector, such as radioisotope tagging.
[Cu] (n equiv), DBU (1 equiv). [b] Yield of isolated product. [c] Reaction scaled-
up to 10 mmol of 5bA.
the inherent difficulty of the side formation of ring-opening
products resulting from the C2-metalated imidazolone,
through a better stabilization of imidazolon-2-yl copper that is
often suggested in several Cu(I)- and base-assisted Pd(0)-cata-
lyzed direct CÀH arylations of structurally related imidazo-
With this plan in mind, we started to set up an innovative
neat synthetic method to produce N-substituted 2-H-4-benzyli-
dene imidazolones. The amido isocyanides 1a–c were first
quantitatively prepared by amidification of the commercially
available methylisocyanoacetate with benzylamine,
[
7d–f]
les.
An optimized 86% yield of the production of 7bA was
then reached under CuBr·DMS co-catalysis (entry 3). We no-
[11]
N-picolinylamine or N,N-dimethylethylenediamine.
A first attempt of condensation of N-picolinylamide
b with 4-methoxybenzaldehyde 2A provided a mix-
1
ture of 2-hydroxybenzyl and 2-benzylidene glycine
intermediates 3bA and 4bA (Scheme 2). Fortunately,
N,O-bis(trimethylsilyl)acetamide (BSA) was found
highly efficient to cleanly achieve the expected ring-
closing condensation of both the latter intermediates
that afforded 2-H-4-benzylidene imidazolone 5bA in
fair 60% yield over the one-pot synthesis. Remarka-
bly, the large-scale production of mono- and disubsti-
tuted N-picolinyl-4-benzylidene imidazolones 5bA–E
and 5bF as well as the more sterically hindered 4-4’-
fluorenylimidazolones 5bG was also successfully ach-
ieved in a range of 51–91% isolated yields. Moreover,
the procedure remained highly efficient to produce
N,N-dimethylaminoethyl (DMAE) imidazolones 5cH–I
in large amounts and good yields.
Scheme 2. Synthesis of 4-benzylidene imidazolones. [a] Reaction conditions: 1a–
c (10 mmol), 2A–F (1 equiv), NaH (1.2 equiv) and then BSA (25 mmol). [b] Yield of isolat-
ed product.
Chem. Eur. J. 2016, 22, 5520 – 5524
5521
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim