Copper-catalyzed intramolecular N-arylation of quinazolinones: Facile convergent approach to (-)-circumdatins H and J

Article abstract of DOI:10.1021/ol101597p

A copper-catalyzed intramolecular N-arylation of a quinazolinone nucleus that furnished the central benzodiazepine core unit has been demonstrated to accomplish an efficient convergent total synthesis of (-)-circumdatins H and J.

Full text of DOI:10.1021/ol101597p

ORGANIC
LETTERS
2010
Vol. 12, No. 16
3716-3719
Copper-Catalyzed Intramolecular
N-Arylation of Quinazolinones:
Facile Convergent Approach to
(-)-Circumdatins H and J
Umesh A. Kshirsagar and Narshinha P. Argade*
DiVision of Organic Chemistry, National Chemical Laboratory (CSIR),
Pune 411 008, India
np.argade@ncl.res.in
Received July 12, 2010
ABSTRACT
A copper-catalyzed intramolecular N-arylation of a quinazolinone nucleus that furnished the central benzodiazepine core unit has been
demonstrated to accomplish an efficient convergent total synthesis of (-)-circumdatins H and J.
Quinazolinones are an important class of compounds, and a
large number of structurally interesting and biologically
important natural and synthetic quinazolinones are known
in the literature.1 Presently, some quinazolinones are in
clinical use,1,2 and on the basis of their structural architecture
and promising bioactivities they have been important target
compounds.3 Circumdatins are the marine natural products
from fungi of the genus Aspergillus, and they possess
antitumor, antifungal, insecticide, and antibiotic activities
(Figure 1).4 (-)-Circumdatins H and J have been recently
isolated from Aspergillus ochraceus and Aspergillus ostianus,
respectively, and more specifically, the (-)-circumdatin H
is an inhibitor of the mammalian mitochondrial respiratory
chain, with an IC50 value of 1.5 µM.5 Circumdatins are
basically the quinazolinobenzodiazepines, and the provision
of new efficient synthetic routes to them is the pivotal task
of current interest.6,7 Very recently, syntheses of (-)-
circumdatins H and J have been reported by using an
intramolecular aza-Wittig reaction and reductive cyclization
as the key steps.7 Metal-catalyzed C(aryl)-N bond-forming
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10.1021/ol101597p  2010 American Chemical Society
Published on Web 07/29/2010

potential quinazolinone intermediate 6a (Scheme 1). We
could foresee that our major challenges would be in the
metal-catalyzed intramolecular N-arylation of quinazolinones
to form the intricate seven-membered diazepine cores and
the complete conservation of enantiomeric purity throughout
the synthesis. The EDCI-induced dehydrative coupling
of the Boc-protected L-proline (2) with anthranilamide (1)
at room temperature furnished the diamide 3 in 87% yield.
The subsequent base-catalyzed intramolecular dehydrative
cyclization of compound 3 provided the required quinazoli-
none 4 in 92% yield. The TFA deprotection of the Boc group
in compound 4, followed by the dehydrative couplings of
thus-formed intermediate free amine 5 with 2-bromobenzoic
acid and 2-bromo-5-methoxybenzoic acid, furnished the
desired precursors 6a/b in 85/83% yield but, unfortunately,
with complete racemization in both the cases. Herein, the
acid-catalyzed racemization of our substrate 5 took place
during the TFA-induced Boc-deprotection step, plausibly
because of the presence of an adjacent imine funtionality
from the quinazolinone moiety. We first studied the pal-
ladium-catalyzed intramolecular N-arylation of quinazolinone
6a under a variety of reaction conditions using different
promising ligands (xantphos, BINAP, johnphos), bases
(Cs2CO3/NaOBut), and solvents (toluene/1,4-dioxane) at
elevated temperature, but unfortunately, all our attempts met
Figure 1.
Naturally occurring bioactive circumdatins A-J.4,5
reactions under mild catalytic conditions utilizing amines,
amides, and nitrogen heterocycles are imperative from a
synthetic point of view to design the exotic natural products
and synthetic compounds.8-11 However, metal-catalyzed
intramolecular N-arylation of quinazolinones has not been
studied, to the best of our knowledge.1,2 In continuation of
our studies on quinazolinone chemistry,12 we envisaged the
metal-catalyzed intramolecular N-arylation of quinazolinones
implementing the advanced Goldberg-Buchwald protocol9,10
that would provide an efficient access to a large number of
desired naturally occurring quinazolinones and their ana-
logues and congeners. In this context, we herein report our
results on copper-catalyzed intramolecular N-arylation of the
quinazolinone nucleus and its application in the synthesis
of (-)-circumdatins H and J (Schemes 1 and 2).
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nature most likely utilizes two appropriate anthranilic acid
units and L-proline/L-alanine to create them. We planned our
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Org. Lett., Vol. 12, No. 16, 2010
3717

Scheme 1. Synthesis of Circumdatin Frameworks 7a/b via the Intramolecular N-Arylation of Quinazolinones 6a/b
Scheme 2. Copper-Catalyzed Intramolecular N-Arylation of Quinazolinones: Synthesis of Circumdatins H (7c) and J (7d)
with failure and we always recovered starting material, the
compound 6a (Table 1, entries 1-4). The palladium-
catalyzed N-arylations are known to have some limitations,9h
and hence, we decided to screen cheap and versatile copper
catalysts for the intramolecular cyclization of compound 6a
to form 7a using different ligands.9,10 We noticed that the
copper iodide catalyzed intramolecular N-arylation of com-
pound 6a using 8-hydroxyquinoline/2-oxazolidinone ligands
was feasible, and we could obtain the desired product 7a,
but in low yields (Table 1, entries 5 and 6). All our attempts
to further improve the yield by changing the molar ratios
and reaction conditions were unsuccesful. Finally, we were
delighted to learn that the copper-catalyzed regioselective
intramolecular cross-coupling between the 3-position nitrogen
atom in the polar quinazolinone 6a and an adjacent aryl
bromide using L-proline as the ligand and sodium hydride
as the base in the solvent DMF at 120 °C exclusively
furnished the desired thermodynamically more stable linear
product 7a in 84% yield (Table 1, entry 7). The circumdatin
J has the methoxy group in the nonquinazolinone aromatic
ring, and hence, at this stage we also studied the intramo-
lecular N-arylation of compound 6b. Similarly, the reaction
Table 1. Optimization of Reaction Conditions for the Metal-
Catalyzed Intramolecular N-Arylation of Quinazolinones 6a/b
entry
reaction conditionsa
7a/b (% yield)
Pd(OAc)2, xantphos, Cs2CO3,
dioxane, 100 °C, 24 h
Pd(OAc)2, BINAP, Cs2CO3,
toluene, 100 °C, 24 h
Pd2(dba)3, xantphos, Cs2CO3,
dioxane, 100 °C, 24 h
Pd2(dba)3, johnphos, t-BuONa,
toluene, 100 °C, 24 h
CuI, 8-hydroxyquinoline, K2CO3,
DMSO, 120 °C, 24 h
CuI, 2-oxazolidinone, MeONa,
DMSO, 120 °C, 24 h
CuI, L-proline, NaH, DMF,
120 °C, 10 h
CuI, L-proline, NaH, DMF,
120 °C, 10 h
1
2
3
4
5
6
7
8
7a (NR)b
7a (NR)
7a (NR)
7a (NR)
7a (11)
7a (30)
7a (84)
7b (91)
a 20 mol % of catalyst; 30 mol % of ligand, and 2 equiv of base were
used in all the entries. b NR: no reaction.
3718
Org. Lett., Vol. 12, No. 16, 2010

of compound 6b under the above-mentioned reaction condi-
tions provided the desired product 7b in 91% yield (Table
1, entry 8). Herein, mechanistically the bond formation
between ligand-coordinated copper iodide and quinazolinone
nitrogen atom followed by the copper-catalyzed intramo-
lecular cross-coupling with an aryl bromide which generates
the new carbon-nitrogen bond to deliver the middle diaz-
epine ring is significant from a synthetic point of view. Thus,
the racemic circumdatin frame works 7a/b were obtained in
five steps with 57/61% overall yields, and the obtained
analytical and spectral data for the compound 7a were in
complete agreement with the reported data.6b
7a/c/d in 84-90% yields. Thus, the desired products (-)-
7a/c/d were obtained in five steps with 54/68/59% overall
yields, and the obtained analytical and spectral data for the
natural products (-)-circumdatins H and J (7c,d) were in
complete agreement with the reported data.5,7 Starting from
the (()-methyl ester of proline, we similarly synthesized the
racemic products 7c/d required for the comparison and then
checked the enantiomeric purity of our final products (-)-
7a/c/d by chiral HPLC. The chiral HPLC results revealed
that we obtained the circumdatin framework product (-)-
7a with 73% ee and the (-)-circumdatins H/J (7c/d) with
99/97% ee. These results on the conserved enantiomeric
purity of (-)-7a/c/d clearly indicate that the compounds (-)-
6a and/or (-)-7a experience ∼13% racemization under basic
conditions, while the (-)-circumdatins H/J (7c/d) with the
suitably placed methoxy group in ring A were not prone for
such type of racemization under the set of our reaction
conditions as depicted in Scheme 2. We believe the
π-conjugation of methoxy group with an imine moiety from
the quinazolinone ring is responsible for the preclusion of
racemization at an adjacent allylic asymmetric center in the
compounds (-)-7c/d. The enantiomerically pure circumd-
atins H and J are also the likely biosynthetic precursors of
circumdatins B and A, respectively.5b
To circumvent the associated problem of racemization in
our above-described Scheme 1 and also to accomplish the
synthesis of enantiomerically pure natural products, the (-)-
circumdatins 7c and 7d, we reasoned and decided to suitably
alter our synthetic sequence. In our second approach, we
planned to avoid the use of Boc-protected proline and its
subsequent TFA-catalyzed deprotection for the conservation
of enantiomeric excess. Hence, we first performed the EDCI-
induced dehydrative couplings of the 2-bromobenzoic acid
(8a) and 2-bromo-5-methoxybenzoic acid (8b) with the
methyl ester of L-proline (9) and respectively obtained the
corresponding products (-)-10a13/b in 90/83% yields (Scheme
2). The subsequent base-catalyzed ester hydrolysis of (-)-
10a/b followed by the careful acidification with dilute
hydrochloric acid provided the corresponding N-benzoyl-
prolines (-)-11a/b in high yields. Once again, the EDCI-
induced dehydrative couplings of compound (-)-11a with
both the anthranilamide and 5-methoxyanthranilamide and
(-)-11b with 5-methoxyanthranilamide, respectively, pro-
vided the corresponding triamides (-)-12a/c/d in 83-92%
yields. The triamides (-)-12a/c/d on base-catalyzed selective
intramolecular dehydrative cyclization furnished the essential
quinazolinones (-)-6a/(+)-c/(+)-d in 92-98% yields. Thus,
by altering the reaction sequence we were successful in
avoiding the problem of racemization in the preparation of
our potential precursors 6a/c/d, required for the synthesis
of compounds (-)-7a/c/d. Finally, we decided to expose the
requisite quinazolinones 6a/c/d to our previously established
efficient copper-catalyzed intramolecular N-arylation condi-
tions as described in entries 7 and 8 of Table 1. The copper-
catalyzed intramolecular N-arylation of compounds 6a/c/d
using L-proline as the ligand and sodium hydride as the base
in solvent DMF at 120 °C exclusively furnished the desired
final products, the synthetic and natural quinazolinones (-)-
In summary, we have reported the concise and efficient
total synthesis of (-)-circumdatins H and J by demonstrating
the first copper-catalyzed intramolecular N-arylation of
quinazolinone with the noteworthy generation of a central
benzodiazepine unit. We believe our approach has broad
scope and will be useful in the synthesis of a diverse range
of desired natural and unnatural complex quinazolinones for
SAR studies.
Acknowledgment. U.A.K. thanks CSIR, New Delhi, for
the award of a research fellowship. N.P.A. thanks the
Department of Science and Technology, New Delhi, for
financial support. We thank Dr. S. S. Kunte from NCL, Pune,
for the HPLC data.
Supporting Information Available: Experimental pro-
cedures for the preparation of compounds 3, 4, 10a,b, 11a,b,
12a,c,d, 6a-d, and 7a-d along with their tabulated analyti-
cal and spectral data. 1H NMR, 13C NMR, and DEPT spectra
of compounds 3, 4, 10a,b, 11a,b, 12a,c,d, 6a-d, and 7a-d.
HPLC data for the enantiomeric purity of the compounds
7a,c,d. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) Sato, T.; Kugo, Y.; Nakaumi, E.; Ishibashi, H.; Ikeda, M. J. Chem.
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