One-step synthesis of quinazolino[3,2-a ]quinazolinones via palladium-catalyzed domino addition/carboxamidation reactions

Article abstract of DOI:10.1021/ol101428v

A highly efficient palladium-catalyzed domino process has been developed for the synthesis of quinazolino[3,2-a]quinazolinones by forming five new bonds in a single step. Despite the high density and variety of functional groups on the substrates, the tetracyclic quinazolinones were obtained in good to excellent yields.

Full text of DOI:10.1021/ol101428v

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3642-3644
One-Step Synthesis of
Quinazolino[3,2-a]quinazolinones via
Palladium-Catalyzed Domino Addition/
Carboxamidation Reactions
Fanlong Zeng and Howard Alper*
Centre for Catalysis Research and InnoVation, Department of Chemistry, UniVersity of
Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada, K1N 6N5
howard.alper@uottawa.ca
Received June 21, 2010
ABSTRACT
A highly efficient palladium-catalyzed domino process has been developed for the synthesis of quinazolino[3,2-a]quinazolinones by forming
five new bonds in a single step. Despite the high density and variety of functional groups on the substrates, the tetracyclic quinazolinones
were obtained in good to excellent yields.
Domino reactions have recently attracted considerable
attention due to their high efficiency for the construction
of complex molecular architectures from readily available
building blocks.1,2 These reactions typically entail the
consecutive formation of multiple new bonds in a single step
under identical reaction conditions, which potentially mini-
mize requisite reagents, separation processes, waste, energy,
time, and cost. Hence, the need to develop new efficient
domino processes is of major interest to the synthetic
community.
skeletons in a variety of natural products such as rutaecarpine
isolated from EVodia rutaecarpa,3 luotonin A isolated from
Peganum nigellastrum,4 tryptanthrin isolated from Couropita
guianensis5 and deoxyvasicinone isolated from Adhatoda
Vasica.6 In addition, these quinazolinone alkaloids exhibit a
(2) For selected recent papers on domino reactions, see: (a) He, H.; Liu,
W.-B.; Dai, L.-X.; You, S.-L. Angew. Chem., Int. Ed. 2010, 49, 1496. (b)
Hojo, D.; Noguchi, K.; Tanaka, K. Angew. Chem., Int. Ed. 2009, 48, 8129.
(c) Liu, L.; Zhang, J.-L. Angew. Chem., Int. Ed. 2009, 48, 6093. (d)
Yamamoto, Y.; Hayashi, H.; Saigoku, T.; Nishiyama, H. J. Am. Chem. Soc.
2005, 127, 10804. (e) Elford, T. G.; Hall, D. G. J. Am. Chem. Soc. 2010,
132, 1488. (f) Wender, P. A.; Stemmler, R. T.; Sirois, L. E. J. Am. Chem.
Soc. 2010, 132, 2532. (g) Nguyen, N. N. M.; Lecle`re, M.; Stogaitis, N.;
Fallis, A. G. Org. Lett. 2010, 12, 1684. (h) Jiang, B.; Tu, S.-J.; Kaur, P.;
Wever, W.; Li, G. J. Am. Chem. Soc. 2009, 131, 11660. (i) Tietze, L. F.;
Spiegl, D. A.; Stecker, F.; Major, J.; Raith, C.; Grosse, C. Chem.sEur. J.
2008, 14, 8956. (j) Tietze, L. F.; Du¨fert, A. Pure Appl. Chem. 2010, 82,
1375. (k) Tietze, L. F.; Du¨fert, A.; Lotz, F.; So¨lter, L.; Oum, K.; Lenzer,
T.; Beck, T.; Herbst-Irmer, R. J. Am. Chem. Soc. 2009, 131, 17879.
(3) (a) Asahina, Y.; Kashiwaki, K. J. Pharm. Soc. Jpn. 1915, 405, 1293;
Chem. Abstr. 1916, 10, 607. (b) Asahina, Y.; Mayeda, S. J. Pharm. Soc.
Japan 1916, 416, 871; Chem. Abstr. 1917, 11, 3.
Ring-fused quinazolinones represent an important class of
heterocyclic motifs that were found as the core structural
(1) For selected reviews on domino reactions, see: (a) Tietze, L. F. Chem.
ReV. 1996, 96, 115. (b) Parsons, P. J.; Penkett, C. S.; Shell, A. J. Chem.
ReV. 1996, 96, 195. (c) Ikeda, S.-I. Acc. Chem. Res. 2000, 33, 511. (d)
Tietze, L. F.; Brasche, G.; Gericke, K. Domino Reactions in Organic
Synthesis; Wiley-VCH, Verlag GmbH & Co: Weinheim, 2006. (e) Hussain,
M. M.; Walsh, P. J. Acc. Chem. Res. 2008, 41, 883. (f) Sun, X. L.; Tang,
Y. Acc. Chem. Res. 2008, 41, 937
.
10.1021/ol101428v  2010 American Chemical Society
Published on Web 07/28/2010

wide range of biological and medicinal activities, i.e.,
antimicrobial, anti-inflammatory, antidepressant, antirheu-
matic, and anti-infective properties.7 There are a number of
methods that have been developed for the synthesis of ring-
fused quinazolinones;7,8 however, these approaches often
suffer from the poor availability of the requisite o-aminoben-
zoic acid derivatives, multistep reactions, and low yields.
Recently several new synthetic strategies have been described
including radical cascade reactions,9 R-functionalization
reactions of cyclic amines,10 solid-supported synthesis,11 and
microwave irradiation.12
The starting materials, carbodiimides (4a-d), were ef-
ficiently prepared in 83-93% yields by metathesis reactions
of the corresponding isocyanates (2) with N-(o-iodoaryl)
triphenyliminophosphoranes (3) (Scheme 1).
Scheme 1. Synthesis of Carbodiimides 4a-d
Transition-metal-catalyzed carbonylation reactions, par-
ticularly palladium-catalyzed carbonylations, are unique,
powerful, and versatile tools for the synthesis of carbonyl-
containing heterocyclic compounds.13 We have described
new protocols for the synthesis of ring-fused isoquinolino-
nes,14 lactones,15 1,3-benzothiazin-2-ones,16 quinazolin-
4(3H)-ones,17 different ring-sized lactams,18 1,4-benzo or
pyrido-oxazepinones,19 and 2-acetyl-3,4-dihydronaphthale-
nones.20 Herein, we report a highly novel and efficient
domino strategy to synthesize 6-substituted quinazolino[3,2-
a]quinazolinones.
We began our investigation with N,N′-di-o-iodophenyl
carbodiimide (4a) and hexylamine as the model substrates
to examine the reaction conditions, which we previously
developed for the synthesis of 2-heteroquinazolin-4(3H)-ones
from the carbodiimides (Table 1) [4 mol % Pd(OAc)2, 8 mol
(4) Ma, Z.-Z.; Hano, Y.; Nomura, T.; Chen, Y.-J. Heterocycles 1997,
46, 541.
(5) (a) Sen, A. K.; Mahato, S. B.; Dutta, N. L. Tetrahedron Lett. 1974,
7, 609. (b) Bergman, J.; Egestad, B.; Lindstro¨m, J. O. Tetrahedron Lett.
1977, 18, 2625.
Table 1. Optimization of the Reaction Conditions Using
N,N′-Di-o-iodophenyl Carbodiimide with Hexylaminea
(6) (a) Amin, A. H.; Mehta, D. R. Nature 1959, 183, 1317. (b) Mehta,
D. R.; Naravane, J. S.; Desai, R. M. J. Org. Chem. 1963, 28, 445.
(7) For selected recent reviews on the chemistry of quinazolinone
alkaloids, see: (a) Witt, A.; Bergman, J. Curr. Org. Chem. 2003, 7, 659.
(b) Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J. Tetrahedron
2005, 61, 10153. (c) Mhaske, S. B.; Argade, N. P. Tetrahedron 2006, 62,
9787.
(8) For selected papers on the synthesis of quinanolino[3,2-a]quinazoli-
nones, see: (a) Butler, K.; Partridge, M. W. J. Chem. Soc. 1959, 1512. (b)
Peet, N. P.; Sunder, S.; Brawn, W. H. J. Org. Chem. 1976, 41, 2728. (c)
Palazzo, S.; Giannola, L. I.; Neri, M. J. Heterocycl. Chem. 1975, 12, 1077.
(d) Molina, P.; Alajar´ın, M.; Vidal, A. Tetrahedron 1989, 45, 4263. (e)
entry
[Pd]
solvent
t (°C)
yield (%)b
1
2
3
4
5
6
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3·CHCl3
Pd(OAc)2
Pd(OAc)2
THF
THF
THF
CH2Cl2
PhMe
THF
80
120
120
120
120
120
75
81
81
78
79
80c
Ram, V. J.; Kushwaha, D. S. Liebigs Ann. Chem. 1990, 701
.
(9) (a) Servais, A.; Azzouz, M.; Lopes, D.; Courillon, C.; Malacria, M.
Angew. Chem., Int. Ed. 2007, 46, 576. (b) Larraufie, M.-H.; Ollivier, C.;
Fensterbank, L.; Malacria, M.; Lacoˆte, E. Angew. Chem., Int. Ed. 2010,
49, 2178. (c) Larraufie, M.-H.; Courillon, C.; Ollivier, C.; Lacoˆte, E.;
Malacria, M.; Fensterbank, L. J. Am. Chem. Soc. 2010, 132, 4381.
(10) Zhang, C.; De, C. K.; Mal, R.; Seidel, D. J. Am. Chem. Soc. 2008,
130, 416.
Pd(OAc)2
a All reactions were carried out using 0.50 mmol of 4a, 0.55 mmol of
5a, [Pd]/PPh3/4a ) 4:8:100, 3.0 equiv of base, 6 mL of solvent, 500 psi of
CO, 15 h. b Isolated yield. c 1.0 mmol of 5a.
(11) Kamal, A.; Shankaraiah, N.; Devaiah, V.; Reddy, K. L. Tetrahedron
Lett. 2006, 47, 9025.
(12) Tseng, M.-C.; Yang, H. Y.; Chu, Y.-H. Org. Biomol. Chem. 2010,
8, 419.
(13) (a) Handbook of Organopalladium Chemistry for Organic Synthesis;
Negishi, E., de Meijere, A., Eds.; John Wiley & Sons: New York, 2002;
Vol. 2, p 2309. (b) Skoda-Foldes, R.; Kollar, L. Curr. Org. Chem. 2002, 6,
1097. (c) Beller, M.; Cornils, B.; Frohning, C. D.; Kohlpaintner, C. W. J.
Mol. Catal. A 1995, 104, 17. (d) Tsuji, J. Palladium Reagents and Catalysis:
InnoVation in Organic Synthesis; John Wiley & Sons: Chichester, U.K.,
1995. (e) Colquhoun, H. M., Thompson, D. J., Twigg, M. V. Carbonylation,
Direct Synthesis of Carbonyl Compounds; Plenum Press: New York, 1991.
(14) (a) Chouhan, G.; Alper, H. Org. Lett. 2008, 10, 4987. (b) Chouhan,
G.; Alper, H. J. Org. Chem. 2009, 74, 6181.
% PPh3, K2CO3, 500 psi of CO, in THF].17a We were
gratified to find that the desired 6-hexyl-12H-quinazolino-
[3,2-a]quinazoline-5(6H),12-dione (6a) was obtained in 75%
isolated yield. Performing the same reaction at 120 °C
resulted in the isolation of 6a in 81% yield (entry 2). Other
reaction parameters, i.e., solvents and palladium catalyst,
were investigated (entries 3-5), but no significant reactivity
differences were observed. Hence, the simple system,
Pd(OAc)2 (4%)-PPh3 (8%)-K2CO3, was chosen as the
optimized catalytic system. It is noteworthy that using 2.0
equiv of hexylamine as the nucleophile afforded no byprod-
ucts (entry 6), demonstrating that the intramolecular car-
boxamidation is very regioselective to form the tetracyclic
quinazolinone (6a).
(15) (a) Cao, H.; Xiao, W.-J.; Alper, H. AdV. Synth. Catal. 2006, 348,
1807. (b) Li, Y.; Alper, H. Org. Lett. 2006, 8, 5199.
(16) Rescourio, G.; Alper, H. J. Org. Chem. 2008, 73, 1612.
(17) (a) Zeng, F. L.; Alper, H. Org. Lett. 2010, 12, 1188. (b) Zheng, Z.;
Alper, H. Org. Lett. 2008, 10, 829.
(18) (a) Lu, S. M.; Alper, H. J. Am. Chem. Soc. 2008, 130, 6451. (b)
Lu, S. M.; Alper, H. Chem.sEur. J. 2007, 13, 5908. (c) Lu, S. M.; Alper,
H. J. Am. Chem. Soc. 2005, 127, 14776.
(19) Chouhan, G.; Alper, H. Org. Lett. 2010, 12, 192.
(20) Zheng, Z.; Alper, H. Org. Lett. 2009, 11, 3278.
Org. Lett., Vol. 12, No. 16, 2010
3643

to the nitrogen atom does not influence the reaction (Scheme
2, products 6a, 6b, and 6c). However, when tert-butylamine
was employed as the nucleophile, the desired product (6d)
was formed in low yields (10% yield at 80 °C and 38% yield
at 120 °C), and this may be due to the strong steric hindrance
effect of the tert-butyl group. Using benzylamine derivatives,
including 4-hydrogen, 4-methyl, 4-methoxyl, and 4-fluo-
robenzylamine, as the nucleophiles gave the corresponding
products in 85-89% yields (Scheme 2, products 6e-h). Thus
the reaction occurs independent of the electronic nature of
the substituents on the benzyl group. In contrast, when aniline
was used instead of an aliphatic amine, the reaction
proceeded sluggishly, giving the analogous product (6i) in
41% yield. Surprisingly, the reaction of carbodiimide (4a)
with N,N′-dimethylethylenediamine did not afford the desired
medium-ring product (6k). The influence of the substituents
on the aryl groups of carbodiimides (4a-d) was also
examined (Scheme 2, products 6l-p). These results suggest
that the cascade process tolerates both electron-donating (p-
MeO) and electron-withdrawing (p-Cl) groups on the aryl
groups of carbodiimides. The same transformation of the
unsymmetrical carbodiimide (4d) gave a mixture of the two
products 6p/6p′ in a 3/2 ratio, the latter ratio determined by
1H NMR spectroscopic analysis of the mixture of 6p and
6p′.
ab
,
Scheme 2. Domino Synthesis of Tetracyclic Quinazolinones (6)
In summary, we have demonstrated a highly novel and
efficient method for the synthesis of 6-substituted quinazoli-
no[3,2-a]quinazolinones via a palladium-catalyzed domino
addition/carboxamidation reaction by forming five new bonds
in one step. This protocol displays good functional group
compatibility and provides a more facile and straightforward
access to potentially important aza-fused tetracyclic quinazo-
line derivatives.
a All reactions were carried out with 0.50 mmol of 4, 0.55 mmol of 5,
Pd(OAc)2/PPh3/4 ) 4:8:100, 3.0 equiv of K2CO3, 6 mL of THF, 120 °C,
15 h. b Isolated yield.
Acknowledgment. We are grateful to the Natural Sciences
and Engineering Research Council of Canada (NSERC) for
support of this research
The scope of this new protocol was further explored by
reacting various carbodiimides (4a-d) with a wide variety
of amines, and the results are summarized in Scheme 2.
The reaction of N,N′-di-o-iodophenyl carbodiimide (4a)
with hexylamine, isopropylamine, and cyclohexylamine
afforded target products in excellent isolated yields (81-85%),
revealing that the methyl or methylene group that is closest
Supporting Information Available: Experimental pro-
cedures, characterization data for all new compounds, and
copies of 1H NMR and 13C NMR spectra for substrates and
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL101428V
3644
Org. Lett., Vol. 12, No. 16, 2010