Palladium-catalyzed intermolecular cyclocarbonylation of 2-iodoanilines with N-toluenesulfonyl aldimines

Article abstract of DOI:10.1016/j.tetlet.2012.03.031

A single step synthesis of 2,3-dihydro-4(1H)-quinazolinones is described using palladium-catalyzed cyclocarbonylation of 2-iodoanilines with N-toluenesulfonyl aldimines.

Full text of DOI:10.1016/j.tetlet.2012.03.031

Tetrahedron Letters 53 (2012) 2540–2542
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed intermolecular cyclocarbonylation of 2-iodoanilines
with N-toluenesulfonyl aldimines
⇑
Kazumi Okuro, Howard Alper
Centre for Catalysis Research and Innovation, Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, Canada K1N 6N5
a r t i c l e i n f o
a b s t r a c t
Article history:
A single step synthesis of 2,3-dihydro-4(1H)-quinazolinones is described using palladium-catalyzed
cyclocarbonylation of 2-iodoanilines with N-toluenesulfonyl aldimines.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 2 February 2012
Revised 5 March 2012
Accepted 8 March 2012
Available online 15 March 2012
Keywords:
Cyclocarbonylation
Quinazolinone
Palladium
N-Toluenesulfonyl aldimines
2,3-Dihydro-4(1H)-quinazolinones have attracted attention by
synthetic and medicinal chemists due to some derivatives having
a wide range of biological activities.1 For example, 2-ethyl-6-sulfa-
We have developed synthetic applications for the synthesis of
valuable heterocycles using transition metal catalyzed carbonylation
moyl-7-chloro-2,3-dihydro-4(1H)-quinozolinones,
known
as
Aquamox, have been launched as antihypertensive diuretics.2 In
addition, according to recent studies in academia as well as in
industry, they inhibit the activity of thermolysin,3 zinc-metallopro-
teinase, and tubulin polymerization,4 which can possess anti-bac-
Table 1
Screening for the intermolecular cyclocarbonylation of 1 with 2aa
CO (300 psi)
O
Pd (dba)
2
Ts
3
X
Ts
Ph
N
N
Ligand
+
terial and anti-tumor activities.
synthetic methods have been utilized to prepare 2,3-dihydro-
4(1H)-quinazolinone derivatives; particular well-established
A considerable number of
NH
N
H
o
2
Ph
2a
NEt 80
C
3
3aa
X=I; 1a
a
X=Br; 1a'
method for their synthesis involves the condensation of 2H-3,1-
benzoxazine-2,4(1H)-diones with amines and aldehydes, or 2-ami-
nobenzoic amides with aldehydes.5 The latter can also be applied
to the asymmetric synthesis of optically active 2,3-dihydro-
4(1H)-quinazolinones using chiral Lewis acids as a catalyst.2,6
Although these methods are simple, there are some drawbacks
associated with these strategies. The methodology itself as well
as the preparation of the starting materials, 2-aminobenzoic
amides and 2H-3,1-benzoxazine-2,4(1H)-diones, have limited
functionality tolerance since the reactions usually require moder-
ate to strong acidic conditions and elevated temperatures. Addi-
tionally, this condensation usually suffers from the inherent
formation of 4-quinazolinones (not the 2,3-dihydro form) as a side
product. In the view of these circumstances, more efficient, and
functionality tolerant methodologies would be desirable here.
Entry
1
Ligand
PPh3
Solvent
Yieldb (%) 3aa
1
2
3
1a
1a
1a
THF
THF
THF
52
59
67
PCy3HBF4
PBut3HBF4
ArPtBu2
THF
THF
THF
THF
THF
THF
Toluene
CH3CN
Toluene
Toluene
65
7
c
4
1a
1a
1a
1a
1a
1a
1a
1a
1a0
1a0
5d
6
ArPtBu2
c
e
ArPCy2
53
46
59
72
75
56
10
12
7
8
9
10
11
12
13
dppp
dppb
dppf
dppf
dppf
dppf
PBut3HBF4
a
Reaction conditions: 1a (1.0 mmol), 2a (1.2 mmol), Pd2(dba)3 (0.025 mmol),
monodentate ligand (0.1 mmol) or bidentate ligand (0.05 mmol), NEt3 (2.0 mmol),
solvent (2 mL), 80 °C, 20 h.
b
Isolated yield after column chromatography.
2-(Di-tert-butylphosphino)biphenyl.
Cs2CO3 (1.2 mmol) was used in place of NEt3.
2-Dicyclohexylphosphinobiphenyl.
c
d
⇑
Corresponding author. Tel.: +1 613 562 5189; fax: +1 613 562 5871.
E-mail address: howard.alper@uottawa.ca (H. Alper).
e
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.03.031

K. Okuro, H. Alper / Tetrahedron Letters 53 (2012) 2540–2542
2541
1a R1=R2=R3=H
2a R4=phenyl
CO (300 psi)
1b R1=Cl, R2=R3=H
1c R1=H, R2=Cl, R3=H
1d R1=Cl, R2=H, R3=Cl
1e R1=CH3, R2=R3=H
2b R4=2,5-difluorophenyl
2c R4=4-methoxyphenyl
2d R4=4-methoxycarbonylphenyl
2e R4=cyclohexyl
O
Pd2(dba)3 (0.025 mmol))
R1
R2
I
Ts
R1
R2
Ts
R4
N
dppf (0.05 mmol)
N
+
R4
NH2
N
H
NEt3(2.0 mmol),
Toluene, 80 oC, 20 h
R3
R3
1f R1=H, R2=CH3, R3=CH3 2f R4=n-Pr
1g R1=CH3, R2=H, R3=CH3
1h R1=H, R2=OCH3, R3=H
1
2
3
1i R1=R2=H, R3=OCH3
O
O
O
O
O
O
Ts
Ts
Ts
Ts
Cl
Ts
N
F
Ts
N
F
N
N
N
N
F
F
N
H
N
H
Cl
N
H
N
H
N
H
N
H
Ph
COOCH3
3ae: 36 %
3ba: 83 %
3cb: 93 %
3ad: 94 %
3ab: 89 %
3af: 25 %
O
O
O
O
O
O
Ts
N
Ts
N
Ph
Ts
Cl
Ts
N
Ph
Ts
Ts
Ph
N
N
N
F
N
H
N
H
N
H
N
H
N
H
N
CH3O
H
CH3O
Cl
COOCH3
F
OCH3
3da: 93 %
3ia: 89 %
3eb: 99 %
3fa: 70 %
3gc: 85 %
3hd: 55 %
Figure 1. Intermolecular cyclocarbonylation of 1 with 2.
methodology. Recent examples include the syntheses of quinazolin-
4-(3H)-ones,7 isoquinolinones,8 isoquinolin-1(2H)-ones,9 3,4-dihy-
dronaphthalenones,10 2-carbonylbenzo[b]thiophenes,11 1,4-benzot-
hiazepin-5-ones,12 quinazolino[3,2-a]quinazolinones,13 1,4-benzo-,
and pyrido-oxazepinones,14 etc. Some of these reactions are inter-
molecular, in nature, where multiple bond forming steps are in-
volved in a single operation. In the course of our studies, we
reasoned that metal catalyzed cyclocarbonylation of 2-iodoanilines
with imines would provide a new straightforward synthesis of 2,3-
dihydro-4(1H)-quinazolinones. We now describe our results for
this reaction using palladium complexes as catalysts.
cant reduced yields of these reactions are due to the thermal
instability of the alkylideneamines. In fact, it is reported that
N-toluenesulfonyl alkylaldimines are thermally unstable, in partic-
ular when alkyl groups are small such as methyl and ethyl
groups.16 The attempt to improve the yield of 3ae failed when
the reaction temperature was reduced to 60 °C, with the yield
being 25%.
The reaction tolerates substituents on the phenyl ring of 2-iod-
oanilines. Thus, 2-iodoanilines containing electron-donating and -
withdrawing substituents react smoothly with arylaldimines to
provide the corresponding 2-aryl-2,3-dihydro-4(1H)-quinazoli-
nones in good yields, with a few exceptions. In terms of steric ef-
fect, the substituents at the ortho-position of the amino group
did not have an unfavorable effect on the yield of the products,
all reactions affording the corresponding products in 85–93% yields
(3da, 3gc and 3ia).
The reaction conditions were optimized using 2-iodoaniline
(1a) and N-toluenesulfonylbenzylideneamine (2a) as model reac-
tants (Table 1). Upon treatment of 1a (1.0 mmol) and 2a
(1.2 mmol) in the presence of Pd2(dba)3 (0.025 mmol) and PPh3
(0.1 mmol) using NEt3 (2.0 mmol) as a base in THF at 80 °C for
20 h under 300 psi of carbon monoxide, the desired 2-phenyl-
2,3-dihydro-4(1H)-quinazolinone (3aa) was obtained in 52% yield
after column chromatography (entry 1). When several monoden-
tate phosphines were examined as added ligands, the catalyst
systems using tBu3P (as HBF4 complex)15 and 2-(di-tert-buty-
lphosphino)biphenyl increased the yield of 3aa to 67% and 65%,
respectively (entries 3 and 4). Standard bidentate phosphine li-
gands were also evaluated for the reaction. The use of dppf was
found to be most effective, affording 3aa in 72% yield (entry 9),
whereas dppp and dppb showed a similar level of activity to
PPh3 (entries 7 and 8). In terms of solvent effect, THF and toluene
were superior to acetonitrile, with the former affording 3aa in
comparable yield. The inorganic base, Cs2CO3 was totally ineffec-
tive (entry 5). The use of 2-bromoaniline (1a0) instead of 1a with
A possible reaction mechanism is depicted in Scheme 1. 2-Iodo-
aniline 1 can react with N-toluenesulfonyl aldimine to give the
adduct A. The phosphine ligated Pd(0) species, then undergoes oxi-
dative addition to the C–I bond of A, followed by the insertion of
carbon monoxide to produce an aroylpalladium intermediate B.17
Ts
Ts
R2
I
I
N
HN
+
R2
NH2
N
R1
H
R1
1
2
A
PdLn
O
Ts
R2
N
dppf or But HBF4 as ligands resulted in the low yields of 3aa (en-
N
H
3
R1
NEt HI
tries 12 and 13).
3
I
3
Having found the optimal conditions, a variety of combinations
of 1 and 2 were examined, and the results are summarized in Fig-
ure 1. Reaction of 1a with N-toluenesulfonylarylideneamines hav-
ing electron-withdrawing substituents (2b, d) afforded the
corresponding 2-aryl-2,3-dihydro-4(1H)-quinazolinones 3ab, 3ad
in good to excellent isolated yields. The product yield appears
higher when N-toluenesulfonylarylideneamines having electron-
withdrawing substituents were used. The reactions of alkylidene-
amines 2e, 2f were unsatisfactory, with the yields of 3ae and 3af
being 36% and 25%, respectively. It is conceivable that the signifi-
PdLn
NHTs
R2
N
H
R1
O
I
PdLn
NHTs
N
H
B
R1
CO
R2
Scheme 1. A possible reaction mechanism.

2542
K. Okuro, H. Alper / Tetrahedron Letters 53 (2012) 2540–2542
Bhargava, K. P.; Kishore, K. J. Indian Chem. Soc. 1979, 56, 219; (g) Parmar, S. S.;
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toluensulfonylamino group to complete the catalytic cycle, afford-
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the Pd(0) species.
In conclusion, we have demonstrated an effective synthetic pro-
cess for the preparation of 2,3-dihydro-4(1H)-quinazolinone by
palladium catalyzed intermolecular cyclocarbonylation of 2-iodo-
anilines and N-toluenesulfonyl aldimines. Because the preparation
of 2-iodoanilines having a wide variety of functional groups has
been well established, this protocol is particularly useful for pre-
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Acknowledgment
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We are grateful to the Natural Sciences and Engineering Council
of Canada (NSERC) for support of this research.
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References and notes
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