Ligand-Free Pd-Catalyzed and Copper-Assisted C-H Arylation of Quinazolin-4-ones with Aryl Iodides under Microwave Heating

Article abstract of DOI:10.1021/acs.orglett.5b00467

A microwave-assisted method for the palladium-catalyzed direct arylation of quinazolin-4-one has been developed under copper-assistance. This method is applicable to a wide range of aryl iodides and substituted (2H)-quinazolin-4-ones. This protocol provides a simple and efficient way to synthesize biologically relevant 2-arylquinazolin-4-one backbones.

Full text of DOI:10.1021/acs.orglett.5b00467

Letter
pubs.acs.org/OrgLett
Ligand-Free Pd-Catalyzed and Copper-Assisted C−H Arylation of
Quinazolin-4-ones with Aryl Iodides under Microwave Heating
Sylvain Laclef, Marine Harari, Julien Godeau, Isabelle Schmitz-Afonso, Laurent Bischoff,
Christophe Hoarau, Vincent Levacher, Corinne Fruit,* and Thierry Besson*
Normandie Univ, COBRA, UMR 6014 et FR 3038; Univ Rouen; INSA Rouen; CNRS, IRCOF, 1 rue Tesnier
Aignan Cedex, France
̀
e, 76821 Mont Saint
S
* Supporting Information
ABSTRACT: A microwave-assisted method for the palladium-
catalyzed direct arylation of quinazolin-4-one has been
developed under copper-assistance. This method is applicable
to a wide range of aryl iodides and substituted (2H)-quinazolin-
4-ones. This protocol provides a simple and efficient way to
synthesize biologically relevant 2-arylquinazolin-4-one back-
bones.
uinazolin-4-one derivatives are usually key core motifs in
conditions no arylated compound was isolated. However, we
were pleased to observe that the addition of a catalytic amount of
Pd(OAc)2 in the reaction mixture, provided the C-2 phenylated
quinazolin-4-one 2a with a complete conversion. Nevertheless,
this palladium/copper cooperative catalysis was not reproducible
and provided the desired phenylated product 2a in erratic
conversions. This phenomenon was previously reported in the
literature for the C−H arylation of purines and oxazoles.13 The
problem was overcome by applying a premixing step.13a In our
case, the copper source was first mixed with the base and the
quinazolin-4-one substrate for 10 min before adding the rest of
the reactants. Microwave irradiation14 was also used to shorten
reaction times, and complete conversion was observed within 30
min at 120 °C (Table 1, entry 1). Initial experiments were aimed
at screening the copper source and catalyst loading. The desired
product 2a was isolated in 91% yield using a substoichiometric
amount of CuI (50 mol %, entry 2). Even if both Cu(I) and
Cu(II) catalysts could be employed in the transformation, Cu(I)
provided better results (entries 2−5). Addition of TEMPO to the
reaction mixture did not affect the conversion rate, providing
strong support to rule out a radical mechanism. Decreasing the
amount of CuI source resulted in lower yields (entries 6−7), and
no reaction occurred without copper (entry 8).
Evaluation of solvent and base was then performed to optimize
the reaction conditions. As reported in Table 2, the screened
conditions revealed that the choice of the solvent drastically
affected the yields of desired product 2a (entries 1−5).
Either no reaction or low conversion was observed with
common solvent such as DMPU, DMSO, or dioxane used for
copper-catalyzed arylation reaction. Moderate to good con-
versions were only obtained with DMA and DMF as solvent.
This could be explained by the ability of these solvents to reduce
Pd(II) to Pd(0).15a Indeed, this high reactivity could be a result of
Q many natural products, pharmaceuticals, and biologically
active compounds.1 Thus, development of efficient functional-
ization methodologies of these heterocycles is required and their
C-2 arylation remains a challenging goal for organic chemists.2
Traditional strategies to synthesize such molecules involve the
construction of the heterocycle part, starting from anthranilic
acid derivatives, by a ring-closure condensation2,3 or C−H
amidation,4 or by palladium-catalyzed carbonylation of 2-
halogenoaniline derivatives or N-arylamidines.5 Copper-cata-
lyzed coupling reactions of 2-halogenobenzoic acid derivatives
with amidines are also described.6 Radical approaches have been
recently developed as a strategy to assemble 2-arylquinazolinone
structures.7 Among these methodologies, transition-metal-
catalyzed intermolecular C−C coupling of quinazolin-4-ones
through C−H functionalization represents an extremely
attractive approach. During the past decade, palladium-catalyzed
C−H functionalization of heteroarenes has been intensively
developed as an efficient and versatile approach in complex
molecule syntheses.8 Direct arylation or heteroarylation of
heteroarenes is increasingly attractive as a C−C bond formation
methodology, offering a powerful alternative to standard cross-
coupling reactions. Examples of direct Pd-catalyzed C−H
arylation involving nonaromatic nitrogen heterocycles are
sparsely reported in the literature9 and appear to be limited to
the synthesis of some natural products and analogues in the case
of quinazolin-4-ones.10 Following our effort for the construction
of a broad range of substituted quinazoline derivatives as
potential inhibitors of kinases,11 we report herein the first
extensive study of palladium-catalyzed direct C-2-H arylation of
N3-benzylated quinazolin-4-ones with aryl iodides.
The direct arylation of N3-benzylated quinazolin-4-one 1a was
initially explored using CuI (1 equiv), LiOtBu (2 equiv), and
iodobenzene (PhI, 2 equiv) in DMF at 120 °C for 12 h, according
to the conditions reported by Daugulis12 allowing the C−H
arylation of various heteroarenes. Unfortunately, under these
Received: February 13, 2015
Published: March 17, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b00467
Org. Lett. 2015, 17, 1700−1703

Organic Letters
Letter
a
Table 1. Effect of Copper Source
Table 3. Direct Arylation of N3-Benzylated Quinazolin-4-one
1a with Aryl Iodides
a
b
entry
Ar-
2
yield (%)
b
entry
copper source
Cu catalyst loading
yield (%)
1
4-MeO-Ph-
4-PhO-Ph-
4-Me-Ph-
4-nBu-Ph-
4-Br-Ph
2b
2c
2d
2e
2f
96
95
94
76
1
2
3
4
5
6
7
8
CuI
1 equiv
50%
50%
50%
50%
30%
10%
96
91
54
0
2
CuI
3
CuBr
CuOAc
CuCl2
CuI
4
c
5
0 (43)
56
78
66
0
6
4-Cl-Ph-
2g
2h
2i
94
93
90
89
65
92
91
14
90
68
93
80
76
7
4-F-Ph-
CuI
8
4-CN-Ph
4-CF3-Ph
4-NO2-Ph
3-Me-Ph
none
9
2j
a
Conditions: Reactions were performed in a sealed tube at 0.4 M with
10
11
12
13
14
15
16
17
18
2k
2l
premixing 1a (1 equiv), LiOtBu (2 equiv), and the copper source in a
microwave reactor for 10 min at 120 °C, before adding PhI (2 equiv)
b
3-MeO-Ph
2-MeO-Ph
2-Me-Ph
2m
2n
2o
2p
2q
2r
and Pd(OAc)2 (5 mol %). Reported yields are isolated yields.
a
Table 2. Effect of Solvent and Base
1-naphthyl
2-naphthyl
9-phenanthryl
3-pyridyl
2s
a
Conditions: Reactions were performed in a sealed tube at 0.4 M with
premixing 1a (1 equiv), LiOtBu (2 equiv), and CuI (50 mol %) in a
microwave reactor, before adding ArI (2 equiv) and Pd(OAc)2 (5 mol
%). Reported yields are isolated yields. C−H arylation proceed at
both halogen atoms.
b
entry
solvent
base
yield (%)
b
c
c
1
2
3
4
5
6
7
DMF
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
KOtBu
K3PO4
91 (90)
DMA
43
0
DMPU
DMSO
dioxane
DMF
0
partner (entry 11) and the 2-methoxyiodobenzene has given a
low yield of expected product (entry 13), while further
experiments involving 2-fluorophenyl iodide, 2-iodopyridine,
and 2-iodo-pyrazine, were unsuccessful.
0
14
0
DMF
a
Conditions: Reactions were performed in a sealed tube at 0.4 M with
To further examine the versatility of this methodology, the
arylation was attempted with pyrido-pyrimidin-4-ones 1b−e and
substituted N3-benzylated quinazolin-4-ones 1f−g (Scheme 1).
We were pleased to observe that N3-benzylated quinazolin-4-
ones bearing chloro or methyl groups on the aromatic nucleus
led to the corresponding C-2 phenylated compounds 2x and 2y
in good yields. Likewise, the C-2 arylation could be applied to the
four isomers of pyrido-pyrimidin-4-ones 1b−e affording
compounds 2t−w in good yields ranging from 62 to 87%.
A plausible reaction mechanism for the C-2 arylation of
quinazolin-4-ones is depicted in Scheme 2 on the basis of
previously reported investigations.12a,15
It could be expected that the metalation step may be facilitated
by coordination of copper species to nitrogen of quinazolin-4-
one (Scheme 2). In addition, without ligand, the in situ generated
dimethylamine (resulting from the microwave degradation of
DMF at 120 °C) may stabilize the Cu(I)-amide type complex.
Interestingly, during the activation step with 1 equiv of CuI,
LiOtBu, and quinazolinone 1a, we were able to observe the [(Cu-
1a) + H]+ cation (m/z 299) using ESI-MS/MS analysis, which
upon MS/MS gave the same fragmentation as that of the product
1a alone (m/z 91).17 It was proposed that exchange of the most
acidic proton at C-2 with Cu results in an organocopper
intermediate. The latter is enabled to undergo cross-coupling
with iodoarylpalladium species to form C-2 arylated product 2.
premixing 1a (1 equiv), base (2 equiv), and CuI (50 mol %) in a
microwave reactor for 10 min at 120 °C, before adding PhI (2 equiv)
b
c
and Pd(OAc)2 (5 mol %). Reported yields are isolated yields. Scale
up, 8.5 mmol of 1a under optimized conditions.
the rapid microwave degradation of DMF, affording in situ
generated dimethylamine.16 Whereas stronger base such as
KOtBu provided poor yield (entry 6), no conversion was
observed with weaker base such as K3PO4 (entry 7). Upon
examining various bases and solvents, LiOtBu and DMF were
found to give optimal results (entry 1). Interestingly, the
optimized protocol was also easily scaled up from 0.8 to 8.5
mmol without a decrease in yield (entry 1).
With the optimized conditions in hand, the scope of the
reaction was undertaken by using N3-benzylated quinazolin-4-
one 1a with a broad range of aryl iodides, bearing electron-
donating or -withdrawing groups (Table 3). We were pleased to
observe the formation of the desired C2-arylated products, 2b−s
in good yields. The present strategy was tolerant to various
functional groups including fluoro (2h), cyano (2i), trifluor-
omethyl (2j), and nitro (2k) (entries 7−10). We assume that
electronic effects may influence the performance of the direct
coupling of 1a with ortho-substituted aryl iodides: the 2-
methyliodobenzene has been revealed as an excellent coupling
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Organic Letters
Letter
Scheme 1. Arylation of N3-Benzylated Pyrido-Pyrimidin-4-
ones 1b−e and Quinazolin-4-ones 1f−g with Phenyl Iodide
Scheme 3. Deprotection of Arylated Quinazolinones 2a−b,g
a
In conclusion, we have developed the first ligand-free Cu/Pd-
catalyzed microwave-enhanced C−H (hetero)arylation of
quinazolin-4-ones with aryl iodides in high yields. This
innovative methodology tolerates a broad range of aryl iodides
substituted by electronically different groups. The scope of
substrate model was also successfully extended to pyridinopyr-
imidin-4-ones. This method provides an efficient, versatile, and
rapid access to important 2-arylquinazolin-4-ones, which are
potentially active compounds or key intermediates for the
synthesis of molecules of therapeutic interest. Efforts are now
underway to extend this methodology to other classes of fused
pyrimidin-4-one derivatives. Similarly, mechanistic investigations
are currently in progress in our laboratory and will be reported in
due course.
a
Conditions: Reactions were performed in a sealed tube at 0.4 M with
premixing 1b−g (1 equiv), LiOtBu (2 equiv), and CuI (50 mol %) in a
microwave reactor for 10 min at 120 °C, before adding PhI (2 equiv)
and Pd(OAc)2 (5 mol %).
ASSOCIATED CONTENT
* Supporting Information
■
S
Scheme 2. Plausible Mechanism for the C-2 Arylation of
Quinazolin-4-one 1
Experimental procedures and characterization for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: corinne.fruit@univ-rouen.fr.
*E-mail: thierry.besson@univ-rouen.fr.
Author Contributions
T.B. and C.F. conceived the project and designed the
experiments with S.L., M.H., and J.G., who executed the
chemical synthesis. MS analyses were realized by I.S.-A. The
manuscript was written through contributions of all authors who
have given approval to the final version.
Notes
The authors declare no competing financial interest.
To obtain easy access to N3-H 2-aryl-quinazolin-4-ones, we
have focused our attention on the cleavage of benzyl protecting
group. Indeed, N3-H 2-aryl-quinazolin-4-ones are key inter-
mediates for the synthesis of more challenging and complex 4-
amino-2-aryl-quinazoline derivatives as potential inhibitors of
kinases.11a The deprotection was achieved using conditions
developed in our laboratory with AlCl3 under microwave
heating18 (Scheme 3), and compounds 3a−c were isolated in
high yields. Under these reaction conditions, the aromatic
methoxy group of quinazolin-4-one 2b was also cleaved,
providing the corresponding phenol 3b. Since the two-step
synthesis of N3-H 2-aryl-quinazolin-4-ones 3a−c was achieved in
85% overall yield from 1a, our method could be employed as a
convenient tool for molecular diversity.
ACKNOWLEDGMENTS
Financial support from the MESR (Minister
■
̀
e de l’Enseignement
Super
́
ieur et de la Recherche) is gratefully acknowledged for the
doctoral fellowships to M.H. We thank the LABEX SynOrg
(ANR-11-LABX-0029) for financial support (to S.L. and J.G.).
We also acknowledge Anton Paar GmbH (Graz, Austria) for
provision of single-mode microwave reactor (Monowave 300)
and for technical support.
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