A convenient palladium-catalyzed carbonylative synthesis of 4(3H)-quinazolinones from 2-bromoformanilides and organo nitros with Mo(CO) 6 as a multiple promoter

Article abstract of DOI:10.1039/c4gc00801d

A novel and convenient procedure for the synthesis of quinazolinones has been developed. Using 2-bromoformanilides and organo nitros as substrates and Mo(CO)₆ as a multiple promoter, the desired products were isolated in moderate to excellent yields in the presence of a palladium catalyst. Here, Mo(CO)₆ was not only a CO source, but also a nitro compound reducing reagent and a cyclization promoter. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4gc00801d

Green Chemistry
View Article Online
View Journal | View Issue
COMMUNICATION
A convenient palladium-catalyzed carbonylative
synthesis of 4(3H)-quinazolinones from
2-bromoformanilides and organo nitros with
Mo(CO)6 as a multiple promoter†
Cite this: Green Chem., 2014, 16,
3763
Received 2nd May 2014,
Accepted 25th June 2014
Lin He,‡a Muhammad Sharif,‡a,b Helfried Neumann,a Matthias Bellera and
DOI: 10.1039/c4gc00801d
www.rsc.org/greenchem
Xiao-Feng Wu*a,c
A novel and convenient procedure for the synthesis of quinazoli- matory, anti-microbial cholinesterase inhibitors, antifolate,
nones has been developed. Using 2-bromoformanilides and antitumor, protein kinase inhibitors and many others.2 In
organo nitros as substrates and Mo(CO)6 as a multiple promoter, view of their importance, a number of methods for 4(3H)-qui-
the desired products were isolated in moderate to excellent yields nazolinone preparation have been developed. These routes,
in the presence of a palladium catalyst. Here, Mo(CO)6 was not however, mainly rely on using anthranilic acid or its derivatives
only a CO source, but also a nitro compound reducing reagent and as the starting materials, and generally suffer from low yields
a cyclization promoter.
and multistep reactions.3 The search for new methodologies to
synthesize this class of compounds is a research field of
undoubted current attention.
Nitrogen-containing heterocycles are widely distributed in
nature and are essential to life, playing a vital role in the
metabolism of all living cells. Among these, 4(3H)-quinazoli-
nones represent one of the most prevalent compounds found
in natural products and biologically active pharmaceuticals
(Fig. 1).1 They are now known to have a wide range of useful
biological properties, e.g. anticancer, antiviral, anti-inflam-
Palladium-catalyzed carbonylative transformation has
already become a unique, powerful, and versatile tool for the
synthesis of carbonyl containing compounds.4 In contrast to
the traditional use of carboxylic acids to form nucleophile-acyl
bonds, aryl halide carbonylation generates these same pro-
ducts with palladium catalysts and CO. Regrettably, the high
toxicity and the cumbersome handling of CO gas severely limit
the usefulness of this transformation in drug discovery and
other small-scale applications. Therefore, solid reagents that
can release CO in a controlled manner have gained consider-
able interest over the past few decades. Among them, Mo(CO)6
has emerged as an ideal candidate and has been previously
demonstrated in a wide range of carbonylative reactions.5
However, to date, the application of Mo(CO)6 as the CO sup-
plier for the synthesis of carbonyl containing heterocycles is
rarely exploited.
Regarding the nitrogen sources, nitro compounds are
attractive due to their low cost and wide availability.6 In indus-
try, they are used as the major raw materials for the synthesis
of a wide range of N-containing compounds.7 But compared to
the impressive progress being made in the palladium-catalyzed
aminocarbonylation (a key step in the N-containing heterocycle
synthesis) with amines as starting materials, there are scarcely
available reports dealing with the direct use of organo nitros
for such transformations. This is not surprising as the selec-
tive reduction of the nitro group in the presence of other sensi-
tive competing functionalities is still a challenging problem.8
Moreover, the compatibility between the conditions of nitro
reduction and aminocarbonylation is generally hard to be
Fig. 1 Selected examples of bio-active quinazolinones.
aLeibniz-Institut für Katalyse an der Universität Rostock, e.V. Albert-Einstein-Str. 29a,
18059 Rostock, Germany
bDepartment of Chemistry, Comsats Institute of Information Technology,
22060 Abbottabad, Pakistan
cDepartment of Chemistry, Zhejiang Sci-Tech University, Xiasha Campus, Hangzhou,
Zhejiang Province 310018, People’s Republic of China.
E-mail: xiao-feng.wu@catalysis.de
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4gc00801d
‡These authors contributed equally to this work.
This journal is © The Royal Society of Chemistry 2014
Green Chem., 2014, 16, 3763–3767 | 3763

View Article Online
Communication
Green Chemistry
achieved. To address these critical issues, we wish to report entries 16–18). This scenario, in conjunction with the signifi-
here our discovery on palladium-catalyzed carbonylative syn- cantly retarded yield identified for using other metal carbonyl
thesis of quinazolinones. In this new procedure, nitro com- compounds as the CO sources (Table 1, entries 19, 20),
pounds (aromatic and aliphatic) and 2-bromoformanilides strongly suggests that the Mo(CO)6 is not just a solid CO in the
were applied as the substrates and Mo(CO)6 as a multirole title reaction. To clarify this point, we investigated the catalytic
reactant, the desired quinazolinones were formed in moderate performance in the absence of Pd(OAc)2/BuPAd2. Although
to excellent yields.
Mo(CO)6 did not promote the carbonylation step, the complete
Initially, the direct transformation of nitrobenzene, 2-bromo- reduction of nitrobenzene to aniline went smoothly. Taken
formanilide and Mo(CO)6 in 1,4-dioxane using NEt3 as a base together, these results indicate that the cooperation between
was investigated as a model reaction to identify the potential the palladium-catalyzed aminocarbonylation and the Mo(CO)6-
catalysts. Summarizing these experiments, we observed that mediated reduction is essential to facilitate the desired reac-
the Pd(OAc)2/BuPAd2 catalyst system gave an impressive con- tion in a domino fashion. The attempt to decrease the temp-
version of starting materials to afford the desired product 4 erature was performed in the last stage, decreased conversion
(3H)-quinazolinone in 87% isolated yield at 140 °C within 16 h and yield were observed if the reaction was performed at
(Table 1, entry 1). In the absence of a ligand only traces of the 120 °C (Table 1, entry 21).
product are observed (Table 1, entry 2). Other monodentate
Once suitable reaction conditions for the model system are
and bidentate phosphine ligands including PPh3, PCy3, Xant- identified, the scope and limitations of this novel procedure
phos, DPPB, BINAP and DPPF gave poor yields (Table 1, are explored (Tables 2 and 3). Several alkyl substituted nitro-
entries 3–8). Variations of bases and solvents were also exam- benzenes, such as methyl-, isopropyl-, and tert-butyl-, were
ined, but no better yields were obtained, except in the case of tested at the first stage, 61–97% of the desired quinazolinones
using DiPEA as a base (Table 1, entries 9–15).
were isolated (Table 2, entries 2–6). 1-Nitronaphthalene can be
Notably, using CO gas (either 10 bar, 5 bar, or 2 bar) applied as a substrate as well and gave the corresponding
instead of Mo(CO)6, only 10–13% of the corresponding quina- 3-(naphthalen-1-yl)quinazolin-4(3H)-one in 81% isolated yield
zolinone was produced with low conversion of starting (Table 2, entry 8). Several electron-withdrawing group substi-
materials (nitrobenzene and 2-bromoformanilide) (Table 1, tuted aromatic nitro compounds were tested subsequently.
Moderate to excellent yields can be achieved without further
optimization (Table 2, entries 9–13). However, this procedure
seems quite sensitive to the steric properties of the substrates.
In detail, 41% of the product was isolated from ortho-chloro
substituted nitrobenzene while 95% yield was achieved with
the meta-chloro substituted substrate (Table 2, entries 9 and 10).
Additionally, groups like hydroxyl and alkene, which are
potentially active in palladium-catalyzed coupling reactions,
can be tolerated under our conditions and gave the corres-
ponding quinazolinones in 53–59% yields (Table 2, entries 14
and 15). More interestingly, in addition to aromatic nitro com-
pounds, aliphatic nitro compounds can be applied as sub-
strates as well (Table 2, entries 16 and 17). 53–74% of the
desired quinazolinones were isolated from the reaction
between 2′-bromoformanilide and the corresponding alkyl
nitros.
We then choose nitrobenzene as the model substrate to test
with various 2′-bromoformanilides (Table 3). In general,
63–83% of different substituted quinazolinones were isolated.
Both electron-donating and withdrawing functional groups are
tolerable (Table 3, entries 1–3). Of particular note is the utility
of our method for the preparation of fluorinated 4(3H)-
quinazolinones from 2-bromoformanilides. It is well known
that fluorine-containing functional groups can drastically
change both the biological and physical properties of organic
molecules. We are pleased to find that all six 2-bromoformani-
lides bearing fluoro, trifluoromethyl and trifluoromethoxyl are
Table 1 Cross-coupling of 2’-bromoformanilide with nitrobenzene
under various conditionsa
Entry CO source
Ligands
Bases
Solvents
Yieldb [%]
1
2
3
4
5
6
7
8
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
Mo(CO)6
BuPAd2
—
PPh3
PCy3
Xantphos NEt3
DPPB
NEt3
NEt3
NEt3
NEt3
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
94(87)
Trace
15
8
33
20
31
41
9
NEt3
NEt3
NEt3
K3PO4
BINAP
DPPF
9
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
10
11
12
13
14
15
16
17
18
19
20
21
Na2CO3 Dioxane
25
91
11
DiPEA
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
NEt3
Dioxane
DMF
Mesitylene 41
DMSO
THF
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
7
34
11
10
13
19
6
CO (10 bar) BuPAd2
CO (5 bar)
CO (2 bar)
Co2(CO)8
Fe3(CO)12
Mo(CO)6
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
59c
a 2′-Bromoformanilide (1 mmol), nitrobenzene (1.1 mmol), CO source suitable substrates for this procedure (Table 3, entries 4–9).
In order to understand the reaction in more detail, several
control experiments on nitrobenzene reduction were carried
hexadecane as an internal standard (number in parenthesis refer to an
(1 mmol), Pd(OAc)2 (2 mol%), ligand (6 mol%), solvent (2 mL), base
(2 mmol), N2 (10 bar). b Yields were determined by GC analysis using
isolated yield). c 120 °C.
out (Scheme 1). Under our standard reaction conditions, 43%
3764 | Green Chem., 2014, 16, 3763–3767
This journal is © The Royal Society of Chemistry 2014

View Article Online
Green Chemistry
Communication
Table 2 Palladium-catalyzed, Mo(CO)6-mediated carbonylative coup-
ling of 2’-bromoformanilide with nitro compoundsa
Table 2 (Contd.)
Entry
16c
Nitro compounds
Product
Yieldb [%]
53
Entry
1
Nitro compounds
Product
Yieldb [%]
87
17c
74
2
3
79
90
a 2′-Bromoformanilide (1 mmol), nitro compounds (1.1 mmol),
Mo(CO)6 (1 mmol), Pd(OAc)2 (2 mol%), BuPAd2 (6 mol%), 1,4-dioxane
(2 mL), NEt3 (2 mmol), N2 (10 bar). b Isolated yield. c 2′-Bromo-
formanilide (0.5 mmol), nitro compounds (0.55 mmol), Mo(CO)6
(1 mmol), Pd(OAc)2 (4 mol%), ligand (12 mol%), 1,4-dioxane (2 mL),
NEt3 (1 mmol), N2 (10 bar).
4
5
6
7
97
61
63
80
of aniline was produced from nitrobenzene with Mo(CO)6 as
the reductant (Scheme 1, a); and the yield of aniline can be
improved to 96% by adding 3 mmol of water (Scheme 1, b).
These results indicated the importance of water for nitro
reduction, as the solvent was used as received and the already
present water can initiate the reaction. The water will be
regenerated after intramolecular condensation; this explains
why we do not need to add additional water in our reaction
system. The presence of a palladium catalyst was found not
necessary for nitro reduction while the presence of a base was
proved to be crucial (Scheme 1, a vs. c vs. d).
Then aniline was tested in place of nitrobenzene under our
typical conditions (Scheme 2). To our delight, 67% of the
desired quinazolinone was formed without any optimization.
This result further proves that nitro compounds were reduced
to the corresponding amines initially and were then ready for
further transformations.
Based on the previous mechanistic studies on palladium-
catalyzed carbonylations,9 a most possible reaction pathway is
proposed and shown in Scheme 3. The reaction started with
the oxidative addition of 2′-bromoformanilide to Pd(0) to give
the organopalladium intermediate. Then followed by the
coordination and insertion of CO which was released from
Mo(CO)6; the acylpalladium complex was formed as the key
intermediate. At the same time, the nitro compound was
reduced by Mo(CO)6 under this condition and the formed
amine nucleophilically attacked the acylpalladium complex.
Finally, the eliminated 2-formamido-N-phenylbenzamide gave
the final quinazolinone product after intramolecular conden-
sation, which is promoted either by palladium or molybdenum
salts as Lewis acids.
8
81
95
41
57
9
10
11
12
49
13
14
71
59
15
53
Conclusions
In conclusion, an interesting and convenient procedure for the
synthesis of quinazolinones from 2′-bromoformanilides and
This journal is © The Royal Society of Chemistry 2014
Green Chem., 2014, 16, 3763–3767 | 3765

View Article Online
Communication
Green Chemistry
Table 3 Palladium-catalyzed, Mo(CO)6-mediated carbonylative coup-
ling of 2’-bromoformanilides with nitrobenzenea
Scheme 2 Palladium-catalyzed,
Mo(CO)6-mediated
carbonylative
coupling of 2’-bromoformanilides with aniline.
Entry
1
2′-Bromoformanilides
Product
Yieldb [%]
69
2
3
4
76
70
68
5
6
7
74
74
63
Scheme 3 Proposed reaction mechanism.
for this novel transformation. Both electron-donating and
withdrawing substituents are tolerable under our conditions.
Notably, Mo(CO)6 plays a role as more than a CO source in this
system.
8
9
77
83
General procedure for the synthesis of quinazolinone
A 12 mL vial was charged with Pd(OAc)2 (2 mol%), BuPAd2
(6 mol%), 2′-bromoformanilide (1 mmol), Mo(CO)6 (1 mmol)
and a stirring bar. Then, nitro compounds (1.1 mmol), NEt3
(2 mmol) and 1,4-dioxane (2 mL) were injected using a syringe
under argon. The vial (or several vials) was placed in an alloy
plate, which was transferred to a 300 mL autoclave of the 4560
series from Parr Instruments® under an argon atmosphere.
After flushing the autoclave three times with N2, a pressure of
10 bar N2 was adjusted at ambient temperature. Then, the
reaction was performed for 16 h at 140 °C. After completion of
the reaction, the autoclave was cooled down to room tempera-
ture and the pressure was released carefully. The solution was
extracted 3–5 times with 2–3 mL of ethyl acetate. After evapor-
ation of the organic solvent the residue was adsorbed on silica
gel and the crude product was purified by column
chromatography.
a 2′-Bromoformanilides (1 mmol), nitrobenzene (1.1 mmol), Mo(CO)6
(1 mmol), Pd(OAc)2 (2 mol%), BuPAd2 (6 mol%), 1,4-dioxane (2 mL),
NEt3 (2 mmol), N2 (10 bar). b Isolated yield.
Acknowledgements
Scheme 1 Reduction of nitrobenzene with Mo(CO)6.
The authors thank the state of Mecklenburg-Vorpommern, the
Bundesministerium für Bildung und Forschung (BMBF) and
the Deutsche Forschungsgemeinschaft for financial support.
We also thank Dr C. Fischer, S. Schareina and Dr W. Baumann
for their excellent technical and analytical support.
nitro compounds has been developed. 26 examples of the
desired products were isolated in 41–97% yields. Not only
aromatic nitros but also aliphatic nitros are suitable substrates
3766 | Green Chem., 2014, 16, 3763–3767
This journal is © The Royal Society of Chemistry 2014

View Article Online
Green Chemistry
Communication
(b) N.-F. K. Kaiser, A. Hallberg and M. Larhed, J. Comb.
Chem., 2002, 4, 109–111; (c) J. Wannberg and M. Larhed,
J. Org. Chem., 2003, 68, 5750–5753; (d) X. Wu, J. Wannberg
and M. Larhed, Tetrahedron, 2006, 62, 4665–4670; (e) X. Wu
and M. Larhed, Org. Lett., 2005, 7, 3327–3329; (f) X. Wu,
J. K. Ekegren and M. Larhed, Organometallics, 2006, 25,
1434–1439.
Notes and references
1 (a) J. D. Hepworth, C. D. Gabbut and B. M. Heron, Compre-
hensive Heterocyclic Chemistry, Pergamon Press, Oxford, 2nd
edn, 1996; (b) D. Arora, H. Kumar, D. Malhotra and
M. Malhotra, Pharmacologyonline, 2011, 3, 659–668;
(c) N. Malecki, P. Carato, G. Rigo, J. F. Goossens, R. Houssin,
C. Bailly and J. P. Henichart, Bioorg. Med. Chem., 2004, 12, 6 (a) P. N. Rylander, Hydrogenation Methods, Academic Press,
641–647.
London, 1985, pp. 104–117; (b) S. Nishimura, Handbook of
Heterogeneous Catalytic Hydrogenation for Organic Synthesis,
Wiley, Chichester, 2001, pp. 315–387.
2 (a) A. R. Katritzky and C. W. Rees, Comprehensive Heterocyclic
Chemistry. The Structure, Reaction, Synthesis and Uses of
Heterocyclic Compounds, Pergamon Press, New York, 1984; 7 (a) J. P. Adams and J. R. Paterson, J. Chem. Soc., Perkin Trans.
(b) S. W. Pelletier, Alkaloids: Chemical and Biological Prospec-
tive, John Wiley & Sons Ltd, New York, 1983.
3 (a) D. J. Connolly, D. Cusack, T. P. O’Sullivan and P. J. Guiry,
Tetrahedron, 2005, 61, 10153–10202; (b) L. He, H. Li, J. Chen
and X.-F. Wu, RSC Adv., 2014, 4, 12065–12077.
1, 2000, 3695–3705; (b) J. G. Lee, K. I. Choi, H. Y. Koh,
Y. Kim, Y. Kang and Y. S. Cho, Synthesis, 2001, 81–84;
(c) Y. Liu, Y. Lu, M. Prashad, O. Repic and T. J. Blacklock,
Adv. Synth. Catal., 2005, 347, 217–219; (d) S. Chandrasekhar,
S. J. Prakash and C. L. Rao, J. Org. Chem., 2006, 71, 2196–
2199; (e) S. Iyer and G. M. Kulkarni, Synth. Commun., 2004,
34, 721–725.
4 (a) Handbook of Organopalladium Chemistry for Organic Syn-
thesis, ed. E.-I. Negishi, Wiley-VCH, Weinheim, 2002;
(b) G. Balme, E. Bossharth and N. Monteiro, Eur. J. Org. 8 (a) I. Pogorelic and S. Merkas, J. Mol. Catal. A: Chem., 2007,
Chem., 2003, 4101–4111; (c) X.-F. Wu, H. Neumann and
M. Beller, Chem. Soc. Rev., 2011, 40, 4986–5009; (d) X.-F. Wu,
H. Neumann and M. Beller, Chem. Rev., 2013, 113, 1–35;
(e) X.-F. Wu, H. Neumann and M. Beller, ChemSusChem,
2013, 6, 229–241; (f) Q. Liu, H. Zhang and A. Lei, Angew.
Chem., 2011, 123, 10978–10989, (Angew. Chem. Int. Ed., 2011,
274, 202–207; (b) A. Saha and B. Ranu, J. Org. Chem., 2008,
73, 6867–6870; (c) A. Corma and P. Serna, Science, 2006, 313,
332–334; (d) H. U. Blaser, H. Steiner and M. Studer, Chem-
CatChem, 2009, 1, 210–221; (e) L. He, L. C. Wang, H. Sun,
J. Ni, Y. Cao, H. Y. He and K. N. Fan, Angew. Chem., Int. Ed,
2009, 48, 9538–9541.
50, 10788–10799); (g) C. F. J. Barnard, Organometallics, 2008, 9 For mechanic studies on palladium-catalyzed carbonyla-
27, 5402–5422.
tions, see: (a) A. G. Sergeev, A. Spannenberg and M. Beller,
J. Am. Chem. Soc., 2008, 130, 15549–15563; (b) A. M. Trzeciak
and J. J. Ziolkowski, Coord. Chem. Rev., 2005, 249, 2308–
2322.
5 For an excellent review on using Mo(CO)6 as a CO source,
see: (a) L. R. Odell, F. Russo and M. Larhed, Synlett, 2012,
685–698; and selected examples from the same group, see:
This journal is © The Royal Society of Chemistry 2014
Green Chem., 2014, 16, 3763–3767 | 3767