A novel domino synthesis of quinazolinediones by palladium-catalyzed double carbonylation

Article abstract of DOI:10.1002/chem.201403417

Combining commercially available bromoanilines and bromobenzonitriles in a novel double carbonylation process allows for a straightforward synthesis of isoindolo[1,2-b]quinazoline-10,12-diones. At least five different C-C and/or C-N bonds are selectively formed in this 3-component reaction, which likely proceeds through sequential carbonylation-cyclization-isomerisation- carbonylation steps. Notably, two molecules of CO are inserted in this highly efficient palladium-catalyzed process.

Full text of DOI:10.1002/chem.201403417

DOI: 10.1002/chem.201403417
Communication
&
Heterocycles
A Novel Domino Synthesis of Quinazolinediones by Palladium-
Catalyzed Double Carbonylation
Haoquan Li, Wanfang Li, Anke Spannenberg, Wolfgang Baumann, Helfried Neumann,
Matthias Beller,* and Xiao-Feng Wu*[a]
significantly increased structural diversity from easily available
Abstract: Combining commercially available bromoani-
lines and bromobenzonitriles in a novel double carbonyla-
building blocks. In this respect, carbonylative coupling reac-
tions allow for the construction of a variety of carbonyl-con-
tion process allows for a straightforward synthesis of
taining compounds, as well as a number of important hetero-
isoindolo[1,2-b]quinazoline-10,12-diones. At least five dif-
cycles.[7] Notably, CO is one of the cheapest C1 feedstocks
ferent CÀC and/or CÀN bonds are selectively formed in
available. While the advantages of incorporating one CO mole-
this 3-component reaction, which likely proceeds through
cule are well-demonstrated, the incorporation of two CO mole-
sequential
carbonylation–cyclization–isomerisation–car-
cules into the parent structure in a one-pot manner is even
more appealing but still challenging.[8]
bonylation steps. Notably, two molecules of CO are insert-
ed in this highly efficient palladium-catalyzed process.
Based on our continuing interest in the carbonylative syn-
thesis of heterocycles,[9] herein we wish to report a novel reac-
tion cascade to give isoindolo[1,2-b]quinazoline-10,12-dione (3)
through a palladium-catalyzed double-carbonylation process.
Starting from commercially available substrates, at least five
bonds were efficiently created during the reaction in a one-pot
process, and two CO molecules were incorporated.
The efficient synthesis of heterocycles represents one of the
most important targets for organic synthesis, because of their
broad applications in pharmaceuticals, agrochemicals, and spe-
cial materials.[1] Notably, seven out of the top ten pharmaceuti-
cal products by worldwide sales in 2009 are heterocyclic com-
pounds.[2] Among the multitude of heterocycles known, quina-
zolinediones have an interesting fused nitrogen-containing or-
ganic framework.[3] Their derivatives display attractive biologi-
cal activities, including anorexic as well as antihypertensive
effects, and several drugs with related structures are applied in
therapy.[4] Due to this importance, a number of procedures for
the synthesis of quinazolinediones have been developed in
the past decades.[5] In general, these protocols are based on
the reaction of anthranilamide with phthalic anhydride or the
reductive coupling of N-substituted 2-nitrobenzamides and 2-
formylbenzoic acids. Although efficient, several substitution
patterns cannot be easily accessed from these substrates.
Thus, multi-step procedures are also used.
Initially, we investigated the palladium-catalyzed carbonyla-
tion of 2-bromobenzonitrile 1a and 2-bromobenzamide 2a. To
our surprise, the fused heterocyclic product 3a was formed
containing an isoindolinone and also a quinazolinone ring.
Later on, NMR spectroscopic assignments of the product struc-
ture were confirmed by the crystal structure of 3ad (Figure 1).
Domino reactions, in which the subsequent reaction step is
a consequence of the functional group formed in the previous
step, have become a key tool for improving the efficiency of
organic synthesis. Advantageously, domino processes often
allow for improved atom economy and circumvent isolating
several intermediates and thus avoid waste generation.[6] Inter-
estingly, the integration of modern palladium-catalyzed cou-
pling reactions into domino processes enables the creation of
Figure 1. X-ray structure of compound 3ad. Displacement ellipsoids are
drawn at the 50% probability level. Only one of the two molecules of the
asymmetric unit is shown.
In order to optimize the reaction conditions, various phos-
phine ligands were tested in the presence of 2 mol% of
Pd(OAc)2 as catalyst precursor. In general, trialkylphosphines
such as BuPAd2, and PCy3 gave better yields compared to PPh3,
DPPF (1,1’-bis(diphenylphosphino)ferrocene), and DPPP (1,3-
bis(diphenylphosphino)propane). Finally, PtBu3·HBF4 was found
to be the most suitable ligand for this reaction. After further
testing of the effect of different solvents (DMF, 1,4-dioxane,
and toluene) and bases (K2CO3, DiPEA, DBU, and Et3N), toluene
[a] H. Li, Dr. W. Li, Dr. A. Spannenberg, Dr. W. Baumann, Dr. H. Neumann,
Prof. Dr. M. Beller, Prof. Dr. X.-F. Wu
Leibniz-Institut fꢀr Katalyse an der Universitꢁt Rostock e.V.
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
E-mail: matthias.beller@catalysis.de
xiao-feng.wu@catalysis.de
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201403417.
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as the reaction media and Et3N as the base was found to be
the most suitable combination. Hence, we succeeded in ob-
taining 3aa in 83% isolated yield under our optimized condi-
tions (1 (1 equiv), 2 (1.05 equiv), 2 mol% Pd(OAc)2, 6 mol%
PtBu3·HBF4, 3 equiv of Et3N, toluene, 1008C, 5 bar of CO).
To reveal the reaction pathway, aniline was reacted under
similar conditions with 2-bromobenzonitrile under a carbon
monoxide atmosphere; compound c was obtained as the
major component and d was observed as well. After optimiza-
tion, c could be obtained with 86% yield (Scheme 1, for detail,
please see the Supporting Information).
tion of 2-bromobenzonitrile with nine different bromoanilines
2b–2j was tested. When 2b was used, the chloro substituent
was found to stay intact under these conditions, and a good
yield (70%) of 3ab was obtained (Table 1, entry 2). Anilines
with electron-withdrawing substituents gave the desired prod-
ucts (2c, 2d, and 2 f) in 57–63% yield. Gratifyingly, when 2e
was subjected to the reaction conditions, the acetyl group was
found to be well-tolerated, leading to 3ae in 87% isolated
yield! Similarly, 82% of the desired product was produced by
using the corresponding cyano-substituted 2-bromoaniline as
a substrate (Table 1, entry 7). Furthermore, the methyl-sub-
stitued 2-bromoanilines (2h and
2i), worked quite well, and the
corresponding quinazolinediones
were obtained in 73 and 61%
yield, respectively. Considering
the broad applications of the tri-
fluoromethyl group in bioactive
compounds, 2j was tested as
Scheme 1. Reaction between 2-bromobenzonitrile and aniline.
well. However, in this latter case
only 37% of the corresponding
Based on the structural determination of the final product,
a likely reaction pathway is given in Scheme 2. Starting from 2-
bromoaniline 2a and 2-bromobenzonitrile 1a, the first amino-
carbonylation occurred forming amide 4 (cycle A). It should be
noted that the oxidative insertion of the active palladium spe-
cies occurrs preferentially at 1a due to the higher reactivity.
Next, base-catalyzed isomerization–cyclization should form the
iminoisoindolinone 5.[10] Interestingly, 5 does not undergo an-
other carbonylation reaction, instead the unexpected isomeri-
zation of 5 to 6 occurs, probably due to steric effects. Subse-
quent intramolecular carbonylative coupling forms 3aa as the
final product (cycle B).
product 3aj was obtained. Despite the lower yield, isolation of
3aj was easy. More specifically, the purification of all the prod-
ucts was facile and no column chromatography was necessary.
The pure compounds were obtained by simply recrystallizing
the crude reaction mixture from ethanol. This simple isolation
certainly adds to the value of the synthetic methodology.
To further demonstrate the applicability of our procedure,
we then performed coupling reactions of 2-bromoaniline with
ten different 2-bromobenzonitriles 1b–1i.
As shown in Table 2, no obvious steric effects on the 2-bro-
mobenzonitrile ring were observed. Thus, good yields (75–
87%) of the respective quinazolinediones were obtained with
either 3-, 4- or 5-methyl-substituted 2-bromobenzonitriles as
substrates (Table 2, entries 1–3). Also, a similar yield was ob-
tained by using 5-methoxy-2-bromobenzonitrile as
the starting material (88%; Table 2, entry 4). 63–76%
of the desired prodcuts were successfully isolated
using 4- and 6-fluoro-substitued 2-bromobenzoni-
triles 1 f and 1g. When changing the bromo substitu-
ent to a iodo leaving group, the reaction proceeded
slightly better (72% isolated yield), and the identical
product was obtained. Finally, satisfactory results
were achieved in the carbonylative coupling of 1b
with 2h, 2g, and 2e without any further optimiza-
tion (82, 79, and 84%, respectively).
Next, we investigated the generality and limitations of this
methodology. Hence, without further optimization, the reac-
Comparing the NMR spectra of the different prod-
ucts, the similar heterocyclic core is unambiguously
proven. For example, in the 13C NMR spectrum of
3ga, the fluorine atom has a smaller coupling con-
stant with the carbonyl carbon (4JCÀF =2.6 Hz) com-
pared to the imidamido carbon (3JCÀF =4.8 Hz), which
also matches the 2D-NMR analysis of compound 3ca,
in which the methyl substituent that is originally at
the ortho-position to the bromo substituent ends up
in the ortho-position of the amido carbon on the iso-
indolinone ring.
Scheme 2. Proposed reaction mechanism.
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Table 1. Pd-catalyzed carbonylative synthesis of quinazolinediones from
different 2-bromoaniline derivatives and 2-bromobenzonitrile.[a]
Table 2. Pd-catalyzed carbonylative synthesis of quinazolinediones from
2-bromoanilines and different 2-bromobenzonitriles.[a]
Entry
2-Bromoanilines
Product
Yield
[%][b]
Entry
2-Bromoanilines
Product
Yield
[%][b]
1
83
70
1
78
75
2
3
2
63
57
3
4
5
6
7
87
88
76
63
72
4
5
87
60
6
7
8
82
73
8[c]
82
79
84
9[d]
9
61
37
10[e]
10
[a] 2-Bromobenzonitrile derivatives (1 mmol), 2-bromoaniline (2a)
(1.1 mmol), CO (5 bar), Pd(OAc)2 (2 mol%), PtBu3·HBF4 (6 mol%), toluene
(4 mL), Et3N (3 mmol), 1008C, 20 h. [b] Isolated yields. [c] 2h instead of
2a. [d] 2g instead of 2a. [e] 2e instead of 2a.
[a] 2-Bromobenzonitrile (1 mmol), 2-bromoaniline (1.1 mmol), CO (5 bar),
Pd(OAc)2 (2 mol%), PtBu3·HBF4 (6 mol%), toluene (4 mL), Et3N (3 mmol),
1008C, 20 h. [b] Isolated yields.
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[2] Top 200 Pharmaceutical Products by Worldwide Sales in 2009, compiled
and produced by the Njardarson Group (Cornell University): D. J. Mack,
M. Brichacek, A. Plichta, J. T. Njardarson.
[3] a) S. W. Pelletier, Alkaloids: Chemical and Biological Prospectives, Wiley,
New York, 1983; b) D. Arora, H. Kumar, D. Malhotra, M. Malhotra, Phar-
macologyonline 2011, 3, 659–668; c) N. Malecki, P. Carato, G. Rigo, J. F.
Goossens, R. Houssin, C. Bailly, J. P. Henichart, Bioorg. Med. Chem. 2004,
12, 641–647.
In summary, the first palladium-catalyzed double-carbonyla-
tion process for the synthesis of quinazolinediones has been
developed. Starting from commercially available 2-bromoben-
zonitriles and 2-bromoanilines a series of isoindolo[1,2-b]quina-
zoline-10,12-diones was synthesized in
a straightforward
manner with good isolated yields (around 20 examples). Nota-
bly, in this novel domino process, both inter- and intramolecu-
lar carbonylation reactions take place, and two CO molecules
are incorporated in the parent product structure. Considering
that at least 5 different CÀC and CÀN bonds are formed, each
of the individual reaction steps proceeds with high selectivity
and excellent yield. Further applications of this methodology
are currently underway in our laboratory.
[4] a) P. Sohꢃr, A. Csꢃmpai, A. E. Szabꢄ, G. Stꢃjer, J. Mol. Struct. 2004, 694,
139–147; b) U. A. Kshirsagar, N. P. Argade, Tetrahedron 2009, 65, 5244–
5250.
[5] For two reviews on the synthesis of quinazolionones, see: a) D. J. Con-
nolly, D. Cusack, T. P. O’Sullivan, P. J. Guiry, Tetrahedron 2005, 61, 10153–
10202; b) L. He, H. Li, J. Chen, X.-F. Wu, RSC Adv. 2014, 4, 12065–12077;
for selected examples on the synthesis of quinazolinediones, see:
c) L. A. Shemchuk, V. P. Chernykh, O. S. Krys’kiv, Russ. J. Org. Chem. 2006,
42, 382–387; d) M. Kurihara, J. Org. Chem. 1969, 34, 2123–2125; e) J.
Khalafy, R. H. Prager, Aust. J. Chem. 1998, 51, 925–929; f) M. Mahdavi, R.
Najafi, M. Saeedi, E. Alipour, A. Shafiee, A. Foroumadi, Helv. Chim. Acta
2013, 96, 419–423.
Experimental Section
[6] a) L. F. Tietze, G. Brasche, K. Gericke, Domino Reactions in Organic Syn-
thesis, Wiley-VCH, Weinheim, 2006; b) L. F. Tietze, Chem. Rev. 1996, 96,
115–136; c) E. Ruijter, R. Scheffelaar, R. V. A. Orru, Angew. Chem. 2011,
123, 6358–6371; Angew. Chem. Int. Ed. 2011, 50, 6234–6246; d) D. M.
D’Souza, T. J. J. Mꢂller, Chem. Soc. Rev. 2007, 36, 1095–1108; e) B. Willy,
T. J. J. Mꢂller, Curr. Org. Chem. 2009, 13, 1777–1790; f) L. F. Tietze, A.
Modi, Med. Res. Rev. 2000, 20, 304–322; g) J. E. Rixson, T. Chaloner, C. H.
Heath, L. F. Tietze, S. G. Stewart, Eur. J. Org. Chem. 2012, 544–558;
h) D. L. Priebbenow, S. G. Stewart, F. M. Pfeffer, Org. Biomol. Chem. 2011,
9, 1508–1515; i) D. L. Priebbenow, S. G. Stewart, F. M. Pfeffer, Tetrahe-
dron Lett. 2012, 53, 1468–1471; j) C. Hulme, V. Gore, Curr. Med. Chem.
2003, 10, 51–80; k) E. Merkul, T. Oeser, T. J. J. Mꢂller, Chem. Eur. J. 2009,
15, 5006–5011; l) A. V. Rotaru, I. D. Druta, T. Oeser, T. J. J. Mꢂller, Helv.
Chim. Acta 2005, 88, 1798–1812.
[7] a) A. Schoenberg, I. Bartolet, R. F. Heck, J. Org. Chem. 1974, 39, 3318–
3326; b) A. Schoenberg, R. F. Heck, J. Org. Chem. 1974, 39, 3327–3331;
c) A. Brennfꢂhrer, H. Neumann, M. Beller, Angew. Chem. 2009, 121,
4176–4196; Angew. Chem. Int. Ed. 2009, 48, 4114–4133; d) X.-F. Wu, H.
Neumann, M. Beller, Chem. Soc. Rev. 2011, 40, 4986–5009; e) X.-F. Wu,
H. Neumann, M. Beller, Chem. Rev. 2013, 113, 1–35; f) X.-F. Wu, X. Fang,
L. Wu, R. Jackstell, H. Neumann, M. Beller, Acc. Chem. Res. 2014, 47,
1041–1053.
General procedure for the synthesis of compound 3
An oven-dried 12 mL vial with stir bar was charged with 2-bromo-
benzonitrile (1.0 mmol, 1 equiv), 2-bromoaniline (1.1 mmol,
1.1 equiv), Pd(OAc)2 (0.02 mmol, 2 mol%), and PtBu3·HBF4
(0.06 mmol, 6 mol%) and was put into a 25 mL Schlenk and then
evacuated and refilled with argon three times. Then, toluene
(3 mL), Et3N (3 mmol, 3 equiv) were injected into the vial under
argon flow sequentially. The vial (or several vials) was placed in an
alloy plate, which was transferred into a 300 mL autoclave of the
4560 series from Parr Instrumentsꢁ under an argon atmosphere.
After flushing the autoclave three times with CO, a pressure of
5 bar CO was adjusted at ambient temperature. The reaction mix-
ture was heated overnight (20 h) at 1008C. After the reaction fin-
ished, the autoclave was cooled down to room temperature and
the pressure was released carefully. The crude reaction mixture
was transferred into a 50 mL beaker with 20 mL of water. After vig-
orous stirring for 1 min, the crude product was obtained, filtered
and washed with 10 mL of 5:1 pentane/EtOAc, and dried under
vacuum. Pure compound was obtained after recrystallization in
EtOH. For some of the compounds, that is, those of low solubility,
pure compound could also be obtained by combining the crude
product and ethanol and heating to the boiling point of ethanol,
followed by cooling down and filtration.
[8] Selected recent examples of double carbonylation processes: a) X.-F.
Wu, J. Schranck, H. Neumann, M. Beller, Chem. Eur. J. 2011, 17, 12246–
12249; b) X.-F. Wu, B. Sundararaju, P. Anbarasan, H. Neumann, P. H. Dix-
neuf, M. Beller, Chem. Eur. J. 2011, 17, 8014–8017; c) H. Li, H. Neumann,
M. Beller, X.-F. Wu, Angew. Chem. 2014, 126, 3247–3250; Angew. Chem.
Int. Ed. 2014, 53, 3183–3186.
[9] For selected recent examples from our group, see: a) X. F. Wu, H. Neu-
mann, M. Beller, Eur. J. Org. Chem. 2011, 4919–4924; b) X.-F. Wu, L. He,
H. Neumann, M. Beller, Chem. Eur. J. 2013, 19, 12635–12638; c) X.-F.
Wu, H. Neumann, S. Neumann, M. Beller, Chem. Eur. J. 2012, 18, 13619–
13623; d) X.-F. Wu, H. Neumann, M. Beller, Chem. Eur. J. 2012, 18,
12595–12598; e) X.-F. Wu, H. Neumann, M. Beller, Chem. Eur. J. 2012,
18, 12599–12602; f) X.-F. Wu, H. Neumann, S. Neumann, M. Beller,
Chem. Eur. J. 2012, 18, 8596–8599; g) J. Schranck, X.-F. Wu, H. Neu-
mann, M. Beller, Chem. Eur. J. 2012, 18, 4827–4831; h) X.-F. Wu, H. Neu-
mann, M. Beller, Org. Biomol. Chem. 2011, 9, 8003–8005; i) H. Li, A.
Spannenberg, H. Neumann, M. Beller, X.-F. Wu, Chem. Commun. 2014,
50, 2114–2116; j) H. Li, L. He, H. Neumann, M. Beller, X.-F. Wu, Green
Chem. 2014, 16, 1336–1343; k) L. He, H. Li, H. Neumann, M. Beller, X.-F.
Wu, Angew. Chem. 2014, 126, 1444–1448; Angew. Chem. Int. Ed. 2014,
53, 1420–1424.
Acknowledgements
The authors thank the state of Mecklenburg-Vorpommern and
the Bundesministerium fꢂr Bildung und Forschung (BMBF) for
financial support. MSc Stefan Oschatz is acknowledged for the
helpful discussions. The Analytic department in LIKAT is ac-
knowledged for the analytic support.
Keywords: carbonylation · coupling · domino reactions ·
multicomponent reactions · palladium
[10] R. ꢅ. Valter, R. B. Kampare, S. P. Valtere, D. ꢅ. Balode, A. ꢅ. Batse, Chem.
Heterocycl. Compd. 1983, 19, 1290–1292.
[1] a) A. R. Katritzky, C. W. Rees, Comprehensive Heterocyclic Chemistry: The
Structure, Reaction, Synthesis and Uses of Heterocyclic Compounds, Perga-
mon Press, New York, 1984; b) L. D. Quin, J. A. Tyrell, Fundamentals of
Heterocyclic Chemistry: Importance in Nature and in the Synthesis of
Pharmaceuticals, Wiley-VCH, Weinheim, 2010.
Received: May 6, 2014
Published online on && &&, 0000
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COMMUNICATION
&
Heterocycles
H. Li, W. Li, A. Spannenberg,
W. Baumann, H. Neumann, M. Beller,*
X.-F. Wu*
InCOrporation: A palladium-catalyzed
domino synthesis of diverse quinazoli-
nediones in an efficient double-carbony-
lation mode has been developed (see
scheme).
&& – &&
A Novel Domino Synthesis of
Quinazolinediones by Palladium-
Catalyzed Double Carbonylation
Chem. Eur. J. 2014, 20, 1 – 5
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