Pd-Catalyzed direct C-H functionalization of imidazolones with aryl- and alkenyl halides

Article abstract of DOI:10.1039/c4cc07917e

Direct C-H arylation and alkenylation of 4,4′-dialkylimidazolones with a broad range of halides under palladium and copper catalysis have been developed. This methodology is applied to the preparation of recently discovered fatty acid synthetase (FAS) inhibitors. This journal is

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DOI: 10.1039/C4CC07917E
Journal Name
RSCPublishing
ARTICLE
Pd- Catalyzed Direct C-H Functionalization of
Imidazolones with Aryl- and Alkenyl Halides
Cite this: DOI:
10.1039/x0xx00000x
Mickaël Muselli, Christine Baudequin, Christophe Hoarau,* Laurent Bischoff*
Received 00th January 2012,
Accepted 00th January 2012
Direct C-H arylation and alkenylation of 4,4’-dialkylimidazolones with a broad range of
halides under palladium and copper catalysis have been developed. This methodology is
applied to the preparation of recently discovered fatty acid synthetase (FAS) inhibitors.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Imidazolone is a fundamental naturally-occuring non-aromatic with the inherent difficulty in achieving highly electronically-
heterocycle intensively used in the synthesis of functional different substrate scope so that notably, the 2-alkynylated
materials and pharmaceuticals. Notably, due to both small size imidazolones are mostly obtained via the 2-methyl
and attractive fluorescent properties, imidazolones mostly 4- imidazolones7 or oxazolone intermediates (scheme 1).8
arylidene and/or 2-aryl(alkynyl)ated constitute the main cores Innovative synthetic methods enabling
a
late-stage
of numerous fluorescent probes for biological studies. Among functionalization of simple imidazolones are thus actively
the most-representative members of this family are the green- needed. By contrast with the structurally-related aromatic
fluorescent proteins (GFP), the Kaede protein and BODIPY- imidazole, conventional transition-metal cross-coupling
like Burgess fluorophore (figure 1).1 As recent remarkable reactions are however poorly appropriated due to the hard
applications in drug-design, 2-aryl(alkyl)ated imidazolones access to required 2-metallated or 2-halogenated imidazolones.
have been specifically selected for the treatment of obesity- To our knowledge, only the cross-coupling of 2-methylthio-
related disorders2 and hypertension.3 They have also been imidazolone has been reported.9 In this context, the discovery
found to display important biological activities4 as fatty acid of
synthase (FAS) inhibitors (figure 1).5
direct
C-H
functionalization
of
imidazolones
methodologies10,11 is particularly useful (scheme 1). Herein, the
first direct C-H arylation as well as alkenylation of 4,4’-
dialkylimidazolones at 2-position with aryl- and alkenyl halides
are reported under Pd(0)/Cu(I) bis-catalysis.
Scheme
1 Previous and proposed access to 4-arylidene and 4,4’-dialkyl
imidazolones
Figure 1 Imidazolone framework in functional materials and pharmaceutics
Importantly, the activation of the imidazolone ring by prior
N-
Current synthetic methodologies towards highly functionalized
imidazolones that allow challenging various substitutions at 2-
position are mainly based upon a ring-closing condensation of
oxidation is not required. This work represents a rare use of the
direct C-H functionalization methodology applied to non-
aromatic heterocycles.12
α
-amidoamides (scheme 1).6 This synthetic route is fraught
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DOI: 10.1039/C4CC07917E
Table 2 Pd-catalyzed direct C-H arylation of 4,4’-disubtituted
imidazolones 1a-b with aryl halides .[a]
Table 1 Pd-catalyzed C-H arylation of N-benzyl-4,4’-cyclobutyl
imidazolone 1a with p-bromotoluene 2A [a]
2A ( 1 equiv)
Br
O
O
Ph
Pd(OAc)2 (5 mol%), CuI (1 equiv)
Ph
N
N
N
N
Ligand 10 mol%
H
Base (2 equiv), DMF, 130 °C
1a
3aA
Entry
Ligand
Base
T (°C)
Yield [%][b]
1
2
3
4
5
6
7
8
-
-
-
130
130
130
130
130
110
90
5
63
45
65
92
92
64
92[c]
K2CO3
Cs2CO3
DBU
-
-
PPh3
PPh3
PPh3
PPh3
DBU
DBU[d]
DBU
DBU[d]
110
[a] Pd(OAc)2 (5 mol%), CuI (1 equiv), Ligand (10 mol%), Base (2 equiv), 1a
(1 equiv), 2A (1 mmol), DMF (0.35M), 12 h. [b] Yield based on isolated
product after flash chromatography. [c] Scale up on 2 mmol of halide under
optimized conditions. [d] 1 equiv of DBU used.
We started to explore the direct C-H coupling of 4,4’-
cyclobutylimidazolone 1a with
p-bromotoluene 2A. Indeed,
any reaction occurred under the strictly Bellina’s conditions
under Pd(0)/Cu(I) bis-catalysis without base and ligand
assistance (Table 1, entry 1),13 the use of potassium carbonate
base led to the desired product in 63% isolated yield (Table 1,
entry 2). The reaction became fairly effective by using DBU
base and the full conversion of imidazolone 1a was finally
reached using PPh3 ligand (Table 1, entry 5).14 The reaction
remained highly operative at
a slightly lower 110°C
temperature, interestingly. We next investigated the generality
of the optimized protocol using various arylhalides (Table 2).
We found invariably that the electronic effect and the position
of substituents on the aromatic unit of the halides slightly
influenced the outcome of the reaction since various 2-arylated
imidazolones 3aB-K flanked with trifluoromethyl, cyano,
fluoro and acetamido functions were isolated in good yields.
Remarkably, the procedure remained successfull with
aryliodides to produce imidazolones 3aA
in similar or better yields than those obtained using
corresponding arylbromides. Moreover, reaction of 1a with
, 3aC, 3aG and 3aK
p
-
iodobromobenzene 2K proceeded highly selectively to afford
the imidazolone 3aK in good yield. The latter is useful to
introduce further various substituents on the aromatic unit to
design notably new precursors for biologically-active
substances.
To extend the scope of this methodology, we focused on direct
C-H alkenylation reaction with alkenylhalides. Interestingly,
[a] Pd(OAc)2 (5 mol%), CuI (1 equiv), PPh3 (10 mol%), DBU (1 equiv), 1a-b
the direct C-H alkenylation of 1a with 2-bromostyrene as its (1 equiv), HetAr-I or HetAr-Br (1 equiv), DMF (0.35 M), 110 °C, 12 h. [b]
Yield based on isolated product after flash chromatography.
pure (E)-isomer was successfully achieved applying the above
optimized C-H arylation protocol. However the 2-
styrenylimidazolone 5aA was isolated in poor 12% yield due to
the low conversion of imidazolone 1a
.
However, switching DMF solvent to toluene along with PPh3 to
P(o-tol)3 ligand afforded the expected cycloalkylimidazolone
5aA in 73% yield in line to our previous observations in the
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DOI: 10.1039/C4CC07917E
oxazole series (Table 3).15A similar reactivity was observed In the current context of intensive efforts in the discovery of
using freshly prepared Hermann-Beller palladacycle precluding therapeutics for the treatment of obesity-disorder, we directed
that the direct C-H alkenylation may proceed with this the application towards an innovative synthesis of variously
precatalyst readily formed by reacting Pd(OAc)2 with P(
in toluene at 80°C.14 Interestingly, the C-H alkenylation of 1a acid synthetase inhibitors (scheme 1).4 First, the
N
-
o
-tol)3 alkylated 2-aryl-4,4’-cyloalkylimidazolones claimed as fatty
N-
remained effective under steric effect when 1-iodostyrene isonicotinylimidazolone 1c was successfully submitted to the
coupling partner was used. Several bromoalkenes 4C-E were optimized direct C-H arylation procedure to afford the
also successfully coupled with 1a to afford 2-alkenylated 5C-E imidazolone 3cK in fair yield. Pleasingly, the subsequent
in fair yields (Table 3). The scope was finally completed by the methylation of 3cK with iodomethane occurred only at the
innovative production of the imidazolone 5aF bearing an pyridine nitrogen. The pyridinium salt intermediate was
acrylamide function at 2-position giving novel opportunities in subsequently cleanly reduced through the conventional double
functional-diversity (Table 3). Notably the acrylamide may reduction with sodium borohydride and then dihydrogen under
provide access to complex aminoalkyles through full or partial PtO2 catalysis to provide the FAS inhibitor 6b in 53% yield
reduction of the nitrile in combination with prior Michael-type over two-step synthesis. Furthermore interestingly, we found
addition reaction to the acrylamide system.
that the isonicotinyl protection could be fully removed. Indeed,
the PtO2-catalyzed dihydrogen reduction of the pyridinium salt
intermediate provided quantitatively the unprotected
imidazolone 6a previously used to prepare a wide variety of
Table 3 Pd-catalyzed direct C-H alkenylation of 4,4’-disubtituted
imidazolone 1a with alkenybromides[a]
biologically active N
-alkylated imidazolones.4,16
Conclusions
As summary, we have developed an innovative and efficient
synthetic methodology for direct C-H arylation and
alkenylation of 4,4’-dialkylimidazolones under Pd(0)/Cu(I) bis-
catalysis. Several electronically-different aryl- and alkenyl
halides proved to be efficient coupling partners enabling a wide
range of 4,4’-dialkylated imidazolones to be prepared in
moderate to good yields. This novel methodology is functional
group-tolerant, step-economical and highly flexible. This work
represents one of first investigations in challenging direct C-H
functionalization of non-aromatic heterocycles. Remarkably,
the standard activation via
N-oxidation is not required. This
methodology may find direct applications in pharmacological
and material sciences. As demonstration in this communication,
an innovative and neat preparation of a recently-discovered
N-
alkylated 4,4’-cycloalkylimidazolone-based fatty acid synthase
(FAS) inhibitor is proposed.
[a] Pd(OAc)2 (5 mol%), CuI (1 equiv), P(o-tol)3 (10 mol%), DBU (1 equiv),
1a (1 equiv), Alkenyl-Br (1 equiv), DMF (0.35 M), 110 °C, 12 h. [b] Yield
based on isolated product after flash chromatography. [c] Hermann-Beller
catalyst used.
Acknowledgements
This work has been partially supported by INSA Rouen, Rouen
University, CNRS EFRD, CRUNCH, Labex SynOrg (ANR-11-
LABEX-0029).
Notes and references
a
Mickaël Muselli, Christine Baudequin, Christophe Hoarau, Laurent
Bischoff
Normandie Univ, COBRA, UMR 6014 et FR 3038; Univ Rouen; INSA
Rouen; CNRS, IRCOF, 1 rue Tesnière 76821 Mont Saint Aignan Cedex,
France
†
Electronic Supplementary Information (ESI) available: [NMR spectra
and data for all compounds]. See DOI: 10.1039/b000000x/
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DOI: 10.1039/C4CC07917E
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