Tandem palladium-catalyzed urea arylation-intramolecular ester amidation: Regioselective synthesis of 3-alkylated 2,4-quinazolinediones

Article abstract of DOI:10.1021/ol062009x

(Chemical Equation Presented) o-Halo benzoates can be combined with monoalkyl ureas in a tandem palladium-catalyzed arylation-ester amidation sequence to deliver quinazolinedione products. The reactions are regioselective for formation of the 3-N-alkyl isomers. Significant variation of both coupling partners is possible, allowing the synthesis of a diverse array of substituted quinazolinediones, exemplified by the preparation of a simple unsymmetric-dialkylated natural product.

Full text of DOI:10.1021/ol062009x

ORGANIC
LETTERS
2006
Vol. 8, No. 22
5089-5091
Tandem Palladium-Catalyzed Urea
Arylation Intramolecular Ester
−
Amidation: Regioselective Synthesis of
3-Alkylated 2,4-Quinazolinediones
Michael C. Willis,* Robert H. Snell, Anthony J. Fletcher, and Robert L. Woodward
Department of Chemistry, UniVersity of Bath, Bath, BA2 7AY, United Kingdom
m.c.willis@bath.ac.uk
Received August 14, 2006
ABSTRACT
o-Halo benzoates can be combined with monoalkyl ureas in a tandem palladium-catalyzed arylation−ester amidation sequence to deliver
quinazolinedione products. The reactions are regioselective for formation of the 3-N-alkyl isomers. Significant variation of both coupling
partners is possible, allowing the synthesis of a diverse array of substituted quinazolinediones, exemplified by the preparation of a simple
unsymmetric-dialkylated natural product.
The quinazolinedione motif is an important heterocycle, as
not only are these units embedded in a variety of natural
products and designed molecules, but they also serve as
precursors to a range of related structures.1 Quinazolinediones
are responsible for a variety of biological responses, including
applications to hypertension,2 diabetes,3 and immunosup-
pression.4 A large number of these biologically interesting
examples feature unsymmetrical alkylation patterns across
the two N-atoms; the natural product 1,5 and medicinal agents
Figure 1. Representative alkylated quinazolinediones.
26 and 33 are illustrative examples (Figure 1). A significant
complication in the synthesis of these molecules is that
formation of mixtures of regioisomers,7 and this has led to
alkylation of the parent heterocycle often results in the
the development of synthetic routes involving the stepwise
introduction and functionalization of the individual N-atoms.8
In this Letter we report a new quinazolinedione synthesis
(1) Undheim, K.; Benneche, T. In ComprehensiVe Heterocyclic Chemistry
II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.; Elsevier: Oxford,
UK, 1996; Vol. 6, p 93.
(2) Ismail, M. A. H.; Barker, S.; El Ella, D. A. A.; Abouzid, K. A. M.;
Toubar, R. A.; Todd, M. H. J. Med. Chem. 2006, 49, 1526.
that involves the regioselective introduction of both N-atoms
in a single operation.
(3) Hashimoto, M.; Oku, T.; Ito, Y.; Namiki, T.; Sawada, K.; Kasahara,
C.; Baba, Y. European Patent Application EP 218999 A2, 1987. Goto, S.;
Tsuboi, H.; Kagara, K. Chem. Exp. 1993, 8, 761.
(7) For example; Goto, S.; Tsuboi, H.; Kanoda, M.; Mukai, K.; Kagara,
K. Org. Proc. Res. DeV. 2003, 7, 700. Also see, ref 2.
(4) Buckley, G. M.; Davies, N.; Dyke, H. J.; Gilbert, P. J.; Hannah, D.
R.; Haughan, A. F.; Hunt, C. A.; Pitt, W. R.; Profit, R. H.; Ray, N. C.;
Richard, M. D.; Sharpe, A.; Taylor, A. J.; Whitworth, J. M.; Williams, S.
C. Bioorg. Med. Chem. Lett. 2005, 15, 751.
(5) Dreyer, D. L.; Brenner, R. C. Phytochemistry 1980, 19, 935.
(6) Kakuta, H.; Tanatani, A.; Nagasawa, K.; Hashimoto, Y. Chem.
Pharm. Bull. 2003, 51, 1273.
(8) For some recent examples, see; (a) Nikpour, F.; Paibast, T. Chem.
Lett. 2005, 34, 1438. (b) Tran, T. P.; Ellsworth, E. L.; Watson, B. M.;
Sanchez, J. P.; Showalter, H. D. H.; Rubin, J. R.; Stier, M. A.; Yip, J.;
Nguyen, D. Q.; Bird, P.; Singh, R. J. Heterocycl. Chem. 2005, 42, 669. (c)
Rivero, I. A.; Espinoza, K.; Somanathan, R. Molecules 2004, 9, 609. (d)
Makino, S.; Suzuki, N.; Nakanishi, E.; Tsuji, T. Synlett 2001, 333. See
also, ref 4.
10.1021/ol062009x CCC: $33.50
© 2006 American Chemical Society
Published on Web 09/26/2006

Continuing our interest in the application of palladium-
catalyzed C-N and C-O bond forming reactions in tandem
processes for heterocycle synthesis,9 we speculated that the
combination of an N-alkyl urea with an o-halo benzoate
would provide a direct route to monoalkylated quinazo-
linediones (Scheme 1).10,11 The heterocycle would be con-
Table 1. Reaction Optimizationa
entry
ligand
base
time (h)
product
yieldb (%)
1
2
3
4
5
6
7c
9
9
NaOtBu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
24
24
48
24
24
24
24
7
8
8
21
43
89
0
Scheme 1. Tandem Urea Arylation-Ester Amidation Route to
9
Quinazolinediones
10
11
12
9
0
0
79
8
a Reaction conditions; substrate (1.0 equiv), urea (1.2 equiv), Pd2(dba)3
(0.5 mol %), ligand (1 mol %), base (2.0 equiv). b Isolated yields. c 5.0
mol % Pd2(dba)3, 10.0 mol % ligand.
structed by using a tandem reaction sequence involving Pd-
catalyzed urea arylation and base-promoted ester amidation.
The utility of the process would be dependent on achieving
selectivity for either the 3-N-alkyl (4) or 1-N-alkyl (5)
regioisomer. We anticipated that regiocontrol would be
possible by dictating the order of the two bond-forming steps,
and by the regioselectivity of the arylation reaction.
Although palladium-catalyzed N-arylation is now a routine
operation in synthetic chemistry,12 there are only a handful
of reports of the use of urea nucleophiles.13,14 To establish
that the proposed route was feasible we chose to ignore the
issue of regioselectivity and to focus on the coupling of
o-bromo benzoate 6 and urea (Table 1). On the basis of
literature precedent we selected Xantphos15 as the initial
ligand for study;13 reaction between benzoate 6 and urea
employing NaOtBu as base delivered only amide 7 in 21%
yield (entry 1). However, the use of the weaker base Cs2-
CO3 provided the parent quinazolinedione 8 in 43% yield
(entry 2). Simply extending the reaction time to 48 h
increased the yield of 8 to 89% (entry 3). In an effort to
reduce the reaction time we briefly explored the use of the
structurally similar ligand DPEphos, and the two biphenyl
ligands 1116 and 12;17 however, even when Cs2CO3 was used
as base, no reaction was observed (entries 4-6). Finally,
the simplest method to reduce the reaction times was to
increase the catalyst loading from 1 mol % palladium to 10
mol % (entry 7).
With conditions for the synthesis of the parent heterocycle
available, we next explored the scope of the urea coupling
partner and the regioselectivity of the process (Table 2). The
Table 2. Scope of the Urea Componenta
(9) (a) Willis, M. C.; Taylor, D.; Gillmore, A. D. Org. Lett. 2004, 6,
4755. (b) Willis, M. C.; Brace, G. N.; Holmes, I. P. Angew. Chem., Int.
Ed. 2005, 44, 403. (c) Willis, M. C.; Brace, G. N.; Findlay, T. J. K.; Holmes,
I. P. AdV. Synth. Catal. 2006, 348, 851.
(10) For the use of o-halobenzaldehydes as substrates for a Pd-catalyzed
amination based route to naphthyridinones, see: Manley, P. J.; Bilodeau,
M. T. Org. Lett. 2004, 6, 2433.
entry
R1, R2
time (h)
yield (%)b
1
2
3
4
5
6
7
8
Me, Me
H, Me
H, Bu
H, Oct
H, Cy
H, allyl
H, Bn
H, Ph
24
48
48
48
48
48
48
48
90
99
95
84
97
62
95
63
(11) For a Pd-catalyzed cyclocarbonylation route to quinazolinones,
see: Larksarp, C.; Alper, H. J. Org. Chem. 2000, 54, 2773.
(12) General Pd-catalyzed C-N arylation reviews: (a) Hartwig, J. F. In
Handbook of Organopalladium Chemistry for Organic Synthesis; Negishi,
E., Ed.; Wiley-Interscience: New York, 2002; Vol. 1, p 1051. (b) Muci,
A. R.: Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131. (c) Prim, D.;
Campagne, J.-M.; Joseph, D.; Andrioletti, B. Tetrahedron 2002, 58, 2041.
(13) (a) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043.
(b) Artamkina, G. A.; Sergeev, A. G.; Beletskaya, I. P. Tetrahedron Lett.
2001, 42, 4381. (c) Sergeev, A. G.; Artamkina, G. A.; Beletskaya, I. P.
Tetrahedron Lett. 2003, 44, 4719. (d) Abad, A.; Agullo´, C.; Cun˜at, A. C.;
Vilanova, C. Synthesis 2005, 915. (e) Artamkina, G. A.; Sergeev, A. G.;
Stern, M. M.; Beletskaya, I. P. Synlett 2006, 235.
(14) For the use of Pd-catalyzed intramolecular urea arylation in the
synthesis of dihydroquinazolinones, see; (a) Ferraccioli, R.; Carenzi, D.
Synthesis 2003, 1383. (b) Schlapbach, A.; Heng, R.; Di Padova, F. Bioorg.
Med. Chem. Lett. 2004, 14, 357. Also see: (c) Bened´ı, C.; Bravo, F.; Uriz,
P.; Ferna´ndez, E.; Claver, C.; Castillo´n, S. Tetrahedron Lett. 2003, 44, 6073.
(15) Kranenburg, M.; van der Burgt, Y. E. M.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J. Organometallics 1995, 14,
3081.
a Reaction conditions; substrate (1.0 equiv), urea (1.2 equiv), Pd2(dba)3
(2.5 mol %), ligand (5.0 mol %), base (2.0 equiv). b Isolated yields of pure
regioisomer.
use of N,N′-dimethylurea led to a faster reaction with the
desired product obtained in 90% yield after 24 h (entry 1).
(16) Walker, S. D.; Barder, T. E.; Martinelli, J. R.; Buchwald, S. L.
Angew. Chem., Int. Ed. 2004, 43, 1871.
(17) Huang, X.; Anderson, K. W.; Zim, D.; Jiang, L.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
5090
Org. Lett., Vol. 8, No. 22, 2006

We next explored the variation possible in the benzoate
component (Table 3). Although reaction of the o-chloroben-
zoate substrate with our standard conditions delivered only
trace amounts of the desired product, this could be increased
to 33% by employing Buchwald’s 2-(dimethylamino)-2′-
dicyclohexylphosphine-substituted biphenyl ligand (entry
1).19 Returning to the Br-substituted substrates we were
pleased to find that both an electron-donating methoxy
substituent and an electron-withdrawing nitro group could
be readily incorporated (entries 2 and 3). The remainder of
the examples serve to demonstrate that functionality suitable
for modification of the heterocyclic products can be incor-
porated into the cyclization substrates; Cl substituents could
be introduced at both the quinazolinedione 5- and 6-positions
and methyl esters at both positions 6 and 7 (entries 4-7).
Finally, to demonstrate the utility of the quinazolinedione
synthesis we prepared the simple natural product 1, isolated
from Mexican seed husks (Scheme 2).5,8b Tandem urea
Table 3. Scope of the Halo Benzoate Componenta
Scheme 2. Synthesis of Natural Product 1 and Regioisomer 14
arylation-ester amidation with bromobenzoate 6 and urea
13 delivered the 3-N-alkylquinazolinedione in 94% yield.
Methylation with methyl iodide and sodium hydride provided
the natural product. The regioisomeric compound (14) could
also be readily prepared by simply employing N-methylurea
for initial heterocycle formation and then alkylating with the
indicated electrophile.
In conclusion, we have demonstrated an efficient one-step
route to 3-alkyl quinazolinediones using o-bromobenzoates
as substrates. Heterocycle formation involves tandem, regio-
selective, palladium-catalyzed arylation of a monoalkyl urea
followed by an intramolecular amidation reaction. A variety
of both functionalized ureas and benzoate coupling partners
can be employed, allowing access to a diverse range of
functionalized quinazolinedione products.
a Reaction conditions; substrate (1.0 equiv), urea (1.2 equiv), Pd2(dba)3
(2.5 mol %), ligand (5.0 mol %), base (2.0 equiv). b Isolated yields. c 2-
(Dimethylamino)-2′-dicyclohexylphosphino-1,1′diphenyl employed as ligand
(10.0 mol %).
When monoalkylated ureas were employed the reactions
required 48 h to reach completion; methyl-, butyl-, octyl-,
cyclohexyl-, allyl-, benzyl-, and phenyl-substituted ureas all
performed well, delivering the quinazolinedione products in
good yields (entries 2-8). In all of these examples the 3-alkyl
regioisomer was obtained as the exclusive product. This was
established by comparison with literature data, nOe studies,
and by conversion to known compounds. We are confident
that this selectivity arises from an initial arylation reaction
followed by a ring-closing amidation. In addition, the
arylation reaction occurs on the least hindered, unsubstituted
N-atom of the urea.18 In a control reaction we established
that combination of bromobenzoate 6 with N,N-dimethylurea,
under our standard reaction conditions, leads to formation
of the N-arylated urea with the ester group remaining intact.
Acknowledgment. This work was supported by the
EPSRC and the University of Bath. The EPSRC Mass
Spectrometry Service at the University of Wales Swansea
is also thanked for their assistance.
Supporting Information Available: Experimental pro-
cedures and full characterization for all novel compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(18) For an example of similar selectivity in the arylation of monoalkyl
ureas with 2-chloropyridines, see ref 13d.
(19) Old, D. W.; Wolfe, J. P.; Buchwald, S. L. J. Am. Chem. Soc. 1998,
120, 9722.
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