Syntheses of quinazolinones from 2-iodobenzamides and enaminones via copper-catalyzed domino reactions

Article abstract of DOI:10.1039/c4ob00400k

N-Substituted 2-iodobenzamides and enaminones undergo cascade transformations to achieve quinazolinones via a copper-catalyzed Ullmann-type coupling, a Michael addition and a retro-Mannich reaction. A unique stereochemical feature of this domino process was that Z-enaminones reacted without external ligands, whereas E-enaminones required the assistance of ligands. This journal is

Full text of DOI:10.1039/c4ob00400k

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Syntheses of quinazolinones from
2-iodobenzamides and enaminones via
copper-catalyzed domino reactions†
Cite this: DOI: 10.1039/c4ob00400k
Received 21st February 2014,
Accepted 15th April 2014
Teerawat Songsichan, Jaturong Promsuk, Vatcharin Rukachaisirikul and
Juthanat Kaeobamrung*
DOI: 10.1039/c4ob00400k
www.rsc.org/obc
N-Substituted 2-iodobenzamides and enaminones undergo
cascade transformations to achieve quinazolinones via a copper-
catalyzed Ullmann-type coupling, a Michael addition and a retro-
Mannich reaction. A unique stereochemical feature of this domino
process was that Z-enaminones reacted without external ligands,
whereas E-enaminones required the assistance of ligands.
Transition metal-catalyzed domino reactions have been one of
the most selective tools for synthesizing complex organic mole-
cules.1 Especially, the copper-catalyzed Ullmann N-arylation2
has been a powerful strategy for constructing N-containing het-
erocycles.3 Quinazolinones are one of the most important
N-containing heterocyclic compounds due to their common
occurrence in alkaloid natural products.4 Furthermore, they
also show a variety of biological activities.5 Therefore, a
number of methodologies have been developed towards quina-
zolinone synthesis.6
Recently, Fu described a remarkable domino synthesis of
quinazolinone derivatives via an Ullmann-type coupling fol-
lowed by aerobic oxidation, starting from 2-halobenzamides
and amines.7 This system provided a powerful synthetic tool to
synthesize aromatic-substituted quinazolinones (Fig. 1a).
Later, Ma also reported the elegant domino reactions of 2-bromo-
benzamides and amides catalyzed by Cu(I), to facilitate aryl
amidation followed by dehydration.8 In Ma’s system, a variety
of substituted quinazolinones were possible. However, cycliza-
tion with the use of HMDS/ZnCl2 was required (Fig. 1b). We
have undertaken studies aimed specifically at copper-catalyzed
domino reactions to produce N-containing heterocyclic com-
pounds under mild and simple reaction conditions. During our
studies, we found that N-substituted 2-iodobenzamides and
enaminones could undergo domino processes in the presence
of CuI to furnish quinazolinone derivatives (Fig. 1c). In our cata-
Fig. 1 Copper-catalyzed domino reactions for quinazolinone synthesis.
lytic system, the enaminone serves as a stable surrogate of an
unstable imine equivalent, to construct the quinazolinone core
structure in one cascade process. We believe that the enami-
none could be a synthetically useful coupling partner in
Ullmann-type reactions for the synthesis of N-containing hetero-
cyclic molecules. Furthermore, a variety of enaminones have
been readily prepared from the condensation reactions of nitro-
gen sources and 1,3-diketone compounds.9
To investigate our reaction, we initially began with reaction
optimization. N-Benzyl-2-iodobenzamide (1a), (Z)-4-amino-
pent-3-en-2-one (2a), and the use of CuI as the catalyst were
selected as the model system (Table 1). The reaction’s outcome
depended on the nature of the base, and the use of K2CO3 gave
no reaction (entry 1). However, quinazolinone 3 was obtained
in 14% yield by changing the base from K2CO3 to Cs2CO3
under otherwise identical conditions (entry 2). 2-Iodobenz-
amide 1a was completely consumed when the reaction was
carried out at 90 °C, and gave the highest yield (entry 3). The
effects of the solvent were also investigated, and CH3CN was
chosen as the optimal solvent (entries 3–5). An investigation
for finding the optimal source of copper was undertaken
(entries 3, 6, 7 and 8), revealing that CuI was the most suitable
for this domino transformation. Interestingly, in the presence
Department of Chemistry, Prince of Songkla University, 15 Kanjanavanit Road,
Kohong, Hat-Yai, Songkhla 90112, Thailand. E-mail: juthanat.k@psu.ac.th;
Fax: +66 74558841; Tel: +66 74288401-2
†Electronic supplementary information (ESI) available: Including experimental
data and characterization data. See DOI: 10.1039/c4ob00400k
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Table 1 Copper-catalyzed domino reactions of N-benzyl 2-iodobenza-
mide (1a) and enaminone (2a): optimization of reaction conditionsa
Table 2 CuI-catalyzed domino syntheses of quinazolinones from 2-
iodobenzamides and Z-enaminonesa
Quinazolinones (% yield)b
Entry Cu salt
Base
Solvent Temp (°C) Yieldb (%)
Entry
1
2-Iodobenzamides
1
2
3
4
5
6
7
8
9
CuI
CuI
CuI
CuI
K2CO3
Cs2CO3 CH3CN 60
Cs2CO3 CH3CN 90
Cs2CO3 DMSO
Cs2CO3 DMF
Cs2CO3 CH3CN 90
Cs2CO3 CH3CN 90
Cs2CO3 CH3CN 90
CH3CN 60
0
14
78
49
56
62
50
46
51
90
90
CuI
CuCl
CuBr
Cu(OAc)2
2
3
4
CuI + (L-proline)c Cs2CO3 CH3CN 90
a Reaction conditions: all reactions were performed with 0.3 mmol of
1a, 30 mol% of Cu salt, 2.0 equiv. of 2a, 2.5 equiv. of base, and 3.0 mL
of solvent, for 24 h. b Isolated yield. c Reaction was performed with
30 mol% of L-proline.
of L-proline as a ligand, the reaction gave a lower yield (entry
9). Based on this result, we believe that 2a played not only the
role of a substrate but also as a ligand for this transformation,
corresponding to a recent finding from Liu.10 Note that, 2.0
equiv. of 2a were crucial to promoting the highest product
yields. The use of 1.0 equiv. of 2a with 30 mol% L-proline and
without L-proline under the optimal conditions gave 31% and
36% yields respectively.
5
6
7
After the optimized conditions had been established, the
scope of the substrates in the copper-catalyzed domino reac-
tions was investigated. A variety of N-substituted benzamides
and enaminones were applicable for the copper-catalyzed
domino reactions (Table 2). As the size of the substituents on
the enaminones increased, the yields of corresponding quina-
zolinones were dramatically diminished (entry 1, compounds
3–5), demonstrating that steric hindrance, especially the sub-
stituents on the enaminones, played a crucial role in determin-
ing the product yields.
8
9
On the other hand, the enaminones with aryl substituents
were efficiently converted to the corresponding quinazolinones
a Reaction conditions: all reactions were carried out with 0.5 mmol of
(entry 1, compounds 6 and 7). N-Phenyl substituted benz- 2-iodobenzamides, and 2.5 equiv. of Cs2CO3, in 0.1 M CH3CN.
b Isolated yield. c 3-Amino-4-methyl-1-phenylpent-2-en-1-one was used.
amides (1c and 1d) gave low yields due to their low nucleophili-
cities for Michael additions. In addition, the comparable
d 3-Amino-5-methyl-1-phenylhex-2-en-1-one was used.
yields of 12 and 14 suggested that the steric hindrance of the
(1h), were isolated in low to moderate yields, showing that 1h
was fairly tolerant of this catalytic system (entry 8). It is note-
worthy that the Cl-substituted quinazolinone (22), a precursor
of the Ispinesib synthesis reported by Holland,11 was gener-
ated smoothly and in a moderate yield (entry 9).
Next, we turned our interest to the effects of the geometries
of the enaminones. E-Enaminones would serve as better nitro-
gen nucleophiles than Z-enaminones, since they lack intra-
molecular H-bonding. Surprisingly, when 3-aminocyclohex-
2-enone (23 as the E-enaminone representative) was subjected to
the reaction conditions, the corresponding quinazolinone was
N-phenyl substituted benzamides had a minor impact on the
reactions (entries 3 and 4). Moreover, the moderate yield from
the reaction of 1e, a naked amide, and a phenyl-substituted
enaminone suggested that the nucleophilicity of the amide
nitrogen dictated the product yield (entry 5). N-Benzyl-2-iodo-
benzamide (1f), with electron-donating substituents on the
aromatic ring, was compatible in the domino reaction (entry
6). However, the reaction of N-benzyl-3-methyl-2-iodobenz-
amide (1g) gave a low yield (entry 7). The results indicated that
accessibility to the C–I bond was vital. The Br-substituted
quinazolinones, derived from N-benzyl-5-bromo-2-iodobenzamide
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Table 3 CuI-catalyzed domino syntheses of quinazolinones from
2-iodobenzamides and 3-aminocyclohex-2-enonea
Scheme 1 (A) The CuI-catalyzed domino reaction of 1a and 23. (B) The
comparison reaction between 2a and 23. (C) The CuI-catalyzed domino
reaction with 2a as a ligand.
obtained in low yield (Scheme 1, (A)). The results gave us a
clue about the geometrically-dependant reactivities of the two
types of enaminones.
Interestingly, exposure of 1a with a mixture of enaminones,
2a and 23 (2.0 equiv. each), under standard conditions, gave
quinazolinones 3 and 24 in 15% and 63% yields respectively
(Scheme 1, (B)). Based on the results, the E-enaminone exhibi-
ted a better reactivity than the Z-enaminone in the cascade
process, demonstrating that the domino reaction of the 2-iodo-
benzamides and the E-enaminones required the assistance of
a Reaction conditions: all reactions were carried out with 0.5 mmol of
2-iodobenzamides, and 2.5 equiv. of Cs2CO3, in 0.1 M CH3CN.
the Z-enaminone, in which we believe that 2a played the role b Isolated yield.
of a ligand. To emphasize the ligand requirement, 30 mol% of
2a was used as a ligand, resulting in the facile domino trans-
nilamides and 1,3-diketones.12 Along with the mechanistic
formation of 1a and 23 to afford 24 with 85% conversion
(Scheme 1, (C)).
study of copper-catalyzed arylation of nucleophiles,13 the com-
plexation of ligands and Cu(I) was crucial, allowing the coup-
ling reaction to occur smoothly at a low temperature.14 Our
initial mechanism involves the association of Cu(I) and the
Z-enaminone to generate the active Cu(I) complex I,10 which
undergoes an Ullmann-type coupling to form the N-arylation
intermediate, III, under relatively mild coupling conditions
due to the ortho-substitution effect performed by the N-substi-
tuent.15 Subsequently, the intramolecular Michael addition of
III takes place to form the dihydroquinazolinone intermediate
IV, followed by the retro-Mannich reaction to produce the qui-
nazolinone and to expel acetone (Scheme 2A).
We were delighted to find that L-proline was a compatible
ligand, albeit we have not thoroughly explored a variety of
ligands. After further optimization of the reaction of 1a and
23, the use of 10 mol% CuI, 20 mol% L-proline, and 2.5 equiv.
Cs2CO3, in 0.1 M CH3CN, with a reaction temperature of 90 °C
were identified as the optimal conditions.
As we expected, better nucleophiles allowed us to lower the
catalyst loading to 10 mol%, along with the amount of enami-
nones. Although we have not exhaustively explored the scope
for this reaction, we found that 23 could be coupled with a
variety of N-substituted 2-iodobenzamides with moderate to
good yields (Table 3, compounds 24–29). The results showed
that the electronic effects of the aromatic rings of the 2-iodo-
benzamides had only a minor impact on the reactions. On the
other hand, the reaction of 1d and 23 gave a low yield (Table 3,
compound 30), indicating that steric hindrance and the effect
of the aryl substituent greatly affected the reaction. We were
pleased to discover that the domino transformation of 23 was
possible, as being a surrogate of a hydrocarbon chain, with a
ketone functionality, it could be further functionalized.
The possible mechanism of the quinazolinone syntheses
from 2-iodobenzamides and enaminones was postulated via a
domino process, an Ullmann-type coupling, an intramolecular
Michael addition, and a retro-Mannich reaction. The last two
steps were proposed according to the condensation of anthra-
Although the geometries of the enaminones affect the reac-
tions, we believe that both geometries undergo domino pro-
cesses with the same reaction mechanisms. Z-Enaminones are
promoted with the possible mechanism shown in Scheme 2A.
On the other hand, in the case of E-enaminones (Scheme 2B),
L-proline plays the role of a ligand in the copper-catalyzed
Ullmann-type coupling, as remarkably described by Ma.16 The
E-enaminone, 23, acts as the nitrogen nucleophile to form
complex VI, and then undergoes reductive elimination to gene-
rate the N-arylation intermediate followed by the sequential
mechanisms described in Scheme 2A, revealing the pendant
ketone functionality.
In order to explore the sequence of the reactions, attempts
to detect the intermediates described in the proposed mechan-
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under mild and simple reaction conditions. The geometry of
the double bonds in the enaminones played an important role
in the reactions. Z-Enaminones could undergo sequential reac-
tions without the addition of any external ligands. On the
other hand, E-enaminones showed better reactivity, but
required the assistance of ligands. Furthermore, the two major
contributions to the reaction were the steric hindrance of the
enaminones and the nucleophilicities of the amide nitrogens.
Although the product yields suffered from steric hindrance,
our method provides a variety of quinazolinones from one-pot
syntheses using simple enaminones. Further applications of
the reaction and a study of the reaction mechanism are
ongoing.
Acknowledgements
Scheme 2 Possible mechanism for the domino syntheses of quinazoli-
nones via CuI-catalyzed Ullmann-type coupling.
This work was supported by the Thailand Research Fund with
a research grant (RTA5480002) for Professor Dr Vatcharin
Rukachaisirikul. Further support was generously provided by
the Development and Promotion of Science and Technology
Talents Project (DPST) for Mr Songsichan, and the Science
Achievement Scholarship of Thailand (SAST) for Mr Promsuk.
Valuable preliminary work was performed by Mr Burawat
Pruethakul. We thank Professor Dr Bode (ETH-Zürich) and
Dr Mahatthananchai (ETH-Zürich) for their helpful discussions.
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