Palladium-catalyzed carbonylative synthesis of quinazolinones from 2-aminobenzamide and aryl bromides

Article abstract of DOI:10.1002/chem.201302182

C from CO! A straightforward procedure for the carbonylative synthesis of quinazolinones from readily available 2-aminobenzamide and aryl bromides has been developed. In the presence of a palladium catalyst, various quinazolinones were produced in moderate to excellent yields. Remarkably, no chromatography was needed for purification (see scheme). Copyright

Full text of DOI:10.1002/chem.201302182

COMMUNICATION
DOI: 10.1002/chem.201302182
Palladium-Catalyzed Carbonylative Synthesis of Quinazolinones from
2-Aminobenzamide and Aryl Bromides
Xiao-Feng Wu,*[a, b] Lin He,[b] Helfried Neumann,[b] and Matthias Beller*[b]
2-Aryl quinazolin-4(3H)-one (quinazolinone) is a natural-
ly occurring class of heterocycles which can exhibit a wide
range of biological activities (Scheme 1). Their reported
properties included anticancer, antiviral, anti-inflammatory,
anti-microbial activity among others[1] Additionally, quinazo-
Remarkably, an interesting palladium-catalyzed intramolec-
ular oxidative carbonylation of N-arylamidines was reported
by Zhu and co-workers as well.[4p] In the presence of one
equivalent of CuO, with AcOH as solvent, under one bar of
CO, various quinazolinones were produced from N-arylami-
dines in good yields. The advantages of carbonylation reac-
tions are detailed below.
Since the original work of Heck and co-workers in 1974,
palladium-catalyzed carbonylation reactions have experi-
enced impressive progress and growth in recent years.[5]
Today, palladium-catalyzed carbonylative transformation of
organohalides has become a powerful tool in modern organ-
ic synthesis.[6] The most obvious advantages of carbonylation
reactions are that carbon monoxide (CO) can be used as a
cheap C1 source and that carbonyl containing compounds
can be easily prepared by introducing one or even more
CO. The carbon chain of the parent molecules can thus be
easily prolonged and primed for further modifications. In
addition, carbonylated compounds themselves have impor-
tant applications in organic synthesis and advanced materi-
als.
As the recognized advantages of carbonylation reactions
and the importance of heterocycles, carbonylations may
have value in heterocyclic compound preparation. By apply-
ing the concept of a cascade reaction, the target heterocyclic
compound can be readily prepared by the reaction of an in
situ produced carbonylation product with another compo-
nent.[7] On this basis, furanones, benzoxazinones, flavones
and a number of other heterocycles were prepared by car-
bonylation reactions.[8] Herein, we wish to report a conven-
ient procedure for the synthesis of quinazolinones from 2-
aminobenzamide and aryl bromides, in good yields by incor-
poration of one molecule of CO under the action of a palla-
dium catalyst.
Scheme 1. Selected examples of bio-active molecules.
linones are used as ligands for benzodiazepine and AMPA
receptors in the CNS system or as DNA binders.[2] Because
of their importance, many useful synthetic procedures have
been developed for their preparation.[3,4] Among them, the
reactions of 2-aminobenzamide with benzyl alcohols, acyl
chlorides or their analogues are the typical methodologies.
Initially, the reaction was carried out with bromobenzene
(1 mmol),
2-aminobenzamide
(1 mmol),
[PdACHTUNGTRENNUNG(OAc)2]
(2 mol%), BuPAd2 (6 mol%), in DMF (2 mL), under 10 bar
of CO, at 1208C. 2-Phenyl quinazolin-4(3H)-one (10%) was
produced with 2 mmol of DiPEA (diisopropylethylamine)
as base, whereas the yield can be improved to 95% by using
2 mmol of DBU (1,8-diazabicycloundec-7-ene). In the pres-
ence of DBU, DPPP [1,3-bis(diphenylphosphino)propane]
or DPPB [1,4-bis(diphenylphosphino)butane] can be applied
as alternative ligands for this transformation and gave com-
parable yields of quinazolinone. At a lower reaction temper-
ature (1008C), quinazolinone was formed in poor yield and
[a] Dr. X.-F. Wu
Department of Chemistry, Zhejiang Sci-Tech University
Xiasha Campus, Hangzhou, Zhejiang Province 310018, (P.R. China)
E-mail: xiao-feng.wu@catalysis.de
[b] Dr. X.-F. Wu, Dr. L. He, Dr. H. Neumann, Prof. M. Beller
Leibniz-Institut fꢀr Katalyse an der Universitꢁt Rostock e.V.
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
E-mail: xiao-feng.wu@catalysis.de
matthias.beller@catalysis.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302182.
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Table 1. Palladium-catalyzed carbonylative synthesis of quinazolinACHTUNGTRENNUNG
ones.[a]
a large amount of non-cyclized amide [N-(2-carbamoylphe-
nyl)benzamide] was detected as the by product.
With the optimized reaction conditions in hand ([Pd-
ACHTUNGTRENNUNG(OAc)2] 2 mol%, BuPAd2 6 mol%, DBU 2 mmol, DMF
2 mL, CO 10 bar; 1208C, 16 h), the generality of this con-
venient methodology was tested (Table 1). As shown in
Table 1, 22 examples of quinazolinones were produced in
good to excellent yields under identical conditions. tert-
Butyl-, methylthiel-, and N,N-dimethylamine- substituted
quinazolinones were produced in 74–86% yields (Table 1,
Entry
1
Aryl bromides
Product
Yield[b] [%]
94
entries 2–4). A 75% yield of 2-(benzo[d]
quinazolin-4(3H)-one was obtained from the reaction of 2-
aminobenzamide and 4-bromobenzo[d][1,3]dioxole (Table 1,
ACHTUNGTREN[NUNG 1,3]dioxol-4-yl)-
ACHTUNGTRENNUNG
AHCTUNGTRENNUNG
2
3
4
86
83
74
entry 5). The same reactivity was found in the case of 4-
bromo-1,2-dimethoxybenzene (Table 1, entry 6). 1-Bromo-
naphthalene can be applied as substrate as well and gave
the corresponding 2-(naphthalen-1-yl)quinazolin-4(3H)-one
in 96% isolated yield, whereas 2-bromonaphthalene gave
77% of the corresponding quinazolinone (Table 1, entries 7
and 8). Bromoarenes with electron-withdrawing substituents
are challenging substrates for carbonylative coupling reac-
tions. Four representative examples of activated bromoar-
enes were applied under our standard conditions, to our de-
light, 43–75% of the desired products were isolated without
further optimization (Table 1, entries 9–12). Remarkably, 7
different 2-heterocycle substituted quinazolinones were pro-
duced by this methodology in 59–91% yields (Table 1, en-
tries 13–19). Additionally, 3-aminobenzofuran-2-carboxa-
mide can be used as substrate as well instead of 2-amino-
benzamide and gives the corresponding quinazolinone in
62% yield after reaction with bromobenzene (Table 1,
entry 20). Two examples of biologically active analogues
(Scheme 1) were prepared by this methodology through the
reaction of 4-amino-1-methyl-3-n-propyl-5-pyrazolecarboxa-
mide with bromoarenes (67–71%; Table 1, entries 21 and
22). A lower yield (30%) of 2-phenyl quinazolin-4(3H)-one
was produced in the case of iodobenzene, and no desired
products were formed in the reactions of benzyl chloride or
cinnamyl chloride with 2-aminobenzamide under the stand-
ard conditions. Remarkably, all of the products described
here were purified by simply filtration or recrystallization
and no chromatography was needed. This demonstrates the
suitability of this method for large scale application.
5
6
75
75
7
8
96
77
9
62
A possible reaction mechanism is shown in Scheme 2. The
reaction started with the reduction of PdII to Pd0 which was
followed by the oxidative addition of bromobenze to Pd0 to
give the organopalladium species. After the coordination
and insertion of CO, the key intermediate acylpalladium
complex was formed. N-(2-carbamoylphenyl)benzamide was
eliminated after nucleophilic attack of 2-aminobenzamide
on the acylpalladium complex, giving the final product after
intramolecular condensation. Pd0 can be regenerated with
the assistance of base and is thus returned to the catalytic
cycle. The intramolecular condensation of N-(2-carbamoyl-
phenyl)benzamide to give quinazolinones is responsible for
the relatively high reaction temperature required.
10
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Palladium-Catalyzed Carbonylative Synthesis of Quinazolinones
Table 1. (Continued)
COMMUNICATION
Entry
Aryl bromides
Product
Yield[b] [%]
12
75
13
14
15
16
81
67
88
91
Scheme 2. Proposed reaction mechanism.
in moderate to excellent yields under identical reaction con-
ditions. Remarkably, all of the products were purified by
simple filtration or recrystallization, and no chromatography
was needed.
Experimental Section
17
18
72
70
Typical reaction procedure for the synthesis of 2-phenyl quinazolin-
A 12 mL vial was charged with [PdACHUTTGNENRNUG
BuPAd2 (6 mol%), 2-aminobenzamide (1 mmol), and
4(3H)-one:
a
Then, DMF (2 mL), bromobenzene (1 mmol) and DBU (2 mmol) were
injected by syringe under an argon atmosphere. The vial (or several
vials) was placed in an alloy plate, which was transferred into a 300 mL
Parr Instruments 4560 series autoclave under an argon atmosphere. After
flushing the autoclave three times with CO, a pressure of 10 bar CO was
fixed at ambient temperature. The autoclave was heated for 16 h at
1208C. After the reaction had finished, the autoclave was cooled to room
temperature and the pressure was released carefully. The pure product
can be isolated by either washed with water, ethyl acetate and finally
hexane or recrystallized from MeOH.
19
20
59
62
Acknowledgements
21
22
71
67
The authors thank the state of Mecklenburg-Vorpommern and the Bun-
desministerium fꢀr Bildung und Forschung (BMBF) for financial support.
We also thank Mr. K. Mevius, Drs. W. Baumann, C. Fischer, and Mr. S.
Buchholz (LIKAT) for analytical support.
Keywords: aryl bromides
·
carbonylation
·
cascade
reactions · palladium · quinazolinones
[a] Aryl bromide (1.0 mmol), 2-aminobenzamide (1.0 mmol), [PdACTHNUTRGEN(UNG OAc)2]
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dure for the carbonylative synthesis of quinazolinones from
readily available 2-aminobenzamides and bromobenzenes
has been developed. Various quinazolinones were produced
Chem. Eur. J. 2013, 00, 0 – 0
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Received: June 7, 2013
Published online: && &&, 0000
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Palladium-Catalyzed Carbonylative Synthesis of Quinazolinones
COMMUNICATION
Carbonylation Cascade
X.-F. Wu,* L. He, H. Neumann,
M. Beller* ..................... &&&& — &&&&
C from CO! A straightforward proce-
dure for the carbonylative synthesis of
quinazolinones from readily available
2-aminobenzamide and aryl bromides
has been developed. In the presence of
a palladium catalyst, various quinazoli-
Palladium-Catalyzed Carbonylative
Synthesis of Quinazolinones from
2-Aminobenzamide and Aryl
Bromides
nones were produced in moderate to
excellent yields. Remarkably, no chro-
matography was needed for purifica-
tion (see scheme).
Chem. Eur. J. 2013, 00, 0 – 0
ꢂ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!