Synthesis of benzo-fused five- and six-membered heterocycles by palladium-catalyzed cyclocarbonylation

Article abstract of DOI:10.1016/j.tetlet.2011.06.049

A novel and simple synthetic methodology, based on palladium-catalyzed cyclocarbonylation reaction, is presented for preparing five- and six-membered benzo-fused heterocycles. A mechanism for the process is also proposed and discussed.

Full text of DOI:10.1016/j.tetlet.2011.06.049

Tetrahedron Letters 52 (2011) 4330–4332
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of benzo-fused five- and six-membered heterocycles by
palladium-catalyzed cyclocarbonylation
⇑
Luigino Troisi , Catia Granito, Serena Perrone, Francesca Rosato
Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali, University of Salento, Via Prov.le Lecce-Monteroni, 73100 Lecce, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel and simple synthetic methodology, based on palladium-catalyzed cyclocarbonylation reaction, is
presented for preparing five- and six-membered benzo-fused heterocycles. A mechanism for the process
is also proposed and discussed.
Received 13 April 2011
Revised 7 June 2011
Accepted 10 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Cyclocarbonylation
Palladium-catalyzed
Heterocycles
Benzo-fused ring
Benzimidazol-, benzoxazol-, benzothiazol-, benzoxathiol-, ben-
zodioxol-2-ones and their derivatives are important pharmaco-
phores which occur in both pharmaceutical and agrochemical
Cu-catalyzed reaction of 2-haloaryl isocyanates with O or S
nucleophiles leads to 2-benzothiazolones in a cascade process,11
while 2-benzoxazolones and 2-benzimidazolones have been also
synthesized, in moderate to good yields, under a high pressure of
CO by one-pot reductive carbonylation of 2-nitrophenols or
2-nitroanilines, respectively, in the presence of selenium as the
1
products. Due to their ability to act as a metabolically stable mi-
mic of phenol, catechol, coumarin, phenylurethane, phenylthioure-
tane groups, and related compounds have a broad spectrum of
2
12
13
14
biological activities. For example, the analgesic Paraflex I, the
catalyst.
were reported to be prepared by PdI
carbonylation starting from o-aminophenols or o-phenylenediam-
2-Benzoxazolidinones
and 2-benzimidazolones
3
4
OP2 agonist II, the insecticide and acaricide Phosalone III, all pos-
sess a benzoxazolone scaffold (Fig. 1). 6-Arylbenzothiazolones IV
2
/KI catalyzed oxidative cyclo-
1
5
were examined and found to be effective for progesterone receptor
ines, respectively. 2-Benzimidazolones have been also obtained
using urea derivatives for carbonylation of o-phenylenediamines.
2-Benzoxathiolones were synthesized by cyclization of the corre-
sponding S-(2-methoxyphenyl) N,N-dimethylthiocarbamates in
5
(
PR) antagonist activities, while Benazolin V and Chlobenthiazone
VI are widely used in agriculture as herbicides and fungicides,
6
respectively. A series of 2-benzoxazolones VII and 2-benzothiazo-
7
16
lone VIII derivatives were evaluated for anticonvulsant activity. A
HI. It was also reported that a short heating in formamide
series of monoalkylated benzimidazolones IX were shown to stim-
converts anthranylohydroxamic acids into 2-benzimidazolones
1
7
ulate chloride secretion and thus useful for the treatment of cystic
almost quantitatively. A novel one-pot method was found for
the synthesis of 2-benzimidazolones, 2-benzoxazolone and 2-ben-
zothiazolone via in situ generation and cyclization of ortho-substi-
8
fibrosis and chronic obstructive pulmonary disease, (Fig. 1).
All these compounds were usually produced by the reaction of
1
8
phosgene with o-aminophenols, or o-phenylenediamines, or o-
tuted benzoic acid azides. More recently, the partial reduction of
a nitrobenzene in the presence of a chloroformate followed by a
microwave-assisted rearrangement/ring closure sequence was also
9
aminothiophenols or analogous ortho-disubstituted compounds.
However, because phosgene is highly toxic and corrosive, develop-
ing a non-phosgene method is highly desirable. Then, several
alternative synthetic methodologies have been reported: the reac-
tions of o-aminophenols, or o-phenylenediamines, or catechols
with dimethyl carbonate have been used for the preparation of
1
9
reported as a procedure to prepare 2-benzoxazolones.
The growing importance of these pharmacophores drove us to
develop a new and simple synthetic methodology based on our
knowledge on palladium-catalyzed cyclocarbonylation reactions.
This report discusses the preparation of benzo-fused five- and
six-membered heterocycles through a palladium-catalyzed cyclo-
carbonylation of phenols, thiophenols and anilines ortho-substi-
tuted by OH, SH and NH groups. This novel and easy protocol of
synthesis consists in a cyclocarbonylation in THF of one of
1
0
2
-benzoxazolones, or 2-benzimidazolones or 2-benzodioxolone.
⇑
Corresponding author. Fax: +39 0832 298626.
E-mail address: luigino.troisi@unisalento.it (L. Troisi).
0
040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.06.049

L. Troisi et al. / Tetrahedron Letters 52 (2011) 4330–4332
4331
XH
X Pd H
YH
CO
X
N
O
O
O
HO
O
O
N
H
YH
N
H
Ph
N
Cl
O
CH3
I
II
C Pd H
S
Cl
S
Pd(0)
YH
O
O
O
O
N
S
N
H
N
Ar
Et N
3
Cl CH COOH
2
X
Y
P
S
OEt
O
III
OEt
IV
V
O
X
C
Pd H
X
Y
O
R
X
Pd
S
N
N
O
N
Y
Et NH
3
O
O
N
R
CH3
(CH ) -R'
2 n
H
X
Y
Cl
O
Et NH
3
VI
VII, VIII
IX
Pd
Et N
3
+
H2
H
VII: X = O
VIII: X = S
R = H; alkyl; acyl
R' = H; alkyl; acyl; N-alkyl
n = 0-3
Figure 1. Biologically active benzo-fused heterocycles.
Scheme 1. Suggested mechanism for the palladium-catalyzed cyclocarbonylation
reaction.
Table 1
Palladium-catalyzed cyclocarbonylation of ortho-substituted phenols, thiophenols
Table 2
and anilines
Synthesis of benzo-fused six-membered heterocycles by palladium-catalyzed
cyclocarbonylation
6
7
4
1
X 2
1
6
5
XH
2
YH
CO(400psi), Et N
3
R
R
X
O
YH CO(400psi), Et3N
Pd(OAc) , Ph P, T H F
R4
R
Y
Pd(OAc) , Ph P, T H F
2
3
5
Y
3
3
XH
2
3
O
1
-12
1a-11a
1
3-16
13a-16a
Entry
X
Y
R
Reaction time (h)
Product
Yielda (%)
Yielda (%)
Entry
R
Y
X
Reaction time (h)
Product
b
1
2
3
4
5
6
7
8
9
O
O
O
O
O
O
O
O
NH
S
S
S
NH
NCH
NH
NH
NCH
S
H
4-CH
H
15
15
60
15
15
15
72
72
60
60
60
72
1a
89
93
95
90
92
94
45
60
62
73
63
—
13ab
1
2
3
4
SO
SO
2
NH
NCH
O
NH
NH
O
72
72
6
35
27
60
45
b
3
2a
b
c
2
3
14a
3a
c
CH
CH
2
2
15a
d
H
4a
16ab
O
NH
10
d
4-OCH
6-CH
H
H
H
6-CH
H
H
3
5a
d
a
b
c
3
6a
Yield measured by GC analysis on the basis of the converted starting material.
Product commercially available.
e
NH
NH
S
7a
e
3
3
8a
Data from Ref. 21.
c
9a
f
1
1
1
0
1
2
S
S
S
3
10a
11ac
—
a
b
c
d
e
f
Yield measured by GC analysis on the basis of the converted starting material.
Product commercially available.
Data from Ref. 7.
Data from Ref. 16.
Data from Ref. 19.
In order to better understand the mechanism of the cyclocarb-
onylation process we performed a few more experiments. Firstly,
we verified that the triethylamine presence is essential for the cat-
alytic cycle. In the absence of Et N the reaction times became much
3
longer and the transformation yield very poor: after 90 h only 10%
of the product was recovered. In a second instance, the generation
Data from Ref. 11.
2
of H during the cycle has been proved by performing the reaction
substrates 1–12 performed in autoclave under CO pressure and in
described in Table 1, entry 1 adding styrene (1 mmol): a partial
reduction to ethylbenzene was observed at the end of the reaction.
On the basis of these results we suggest the mechanism reported
on Scheme 1 for the cyclocarbonylation reaction.
3 2 3
the presence of Et N, Pd(AcO) , and Ph P. The reaction was carried
out at 100–110 °C under magnetic stirring.20 The optimum
reaction time for a good transformation yield was obtained moni-
toring the starting material by gas chromatography. Compounds
The starting material is first complexed by the catalyst Pd(0),
1
a–11a were isolated and characterized; the spectroscopic data
3
then CO insertion occurs between X and Pd. The base Et N removes
were consistent with assigned structures reported in the
literature.
the proton from YH forming the anion that closes the ring at the
2
0
PdÀH moiety affording an anionic hydropalladacycle. This latter
Table 1 shows 12 examples of this easy cyclocarbonylation that
proceeded in moderate to good yields. All reactions were
completed over-night, and the lowest yields even at longer reac-
tion times were observed using o-phenylenediamines as
substrates.
undergoes a reductive elimination to give the benzo-fused
heterocycle.
The successful cyclocarbonylation procedure described above
was also applied to the preparation of benzo-fused six-membered
heterocycles.

4
332
L. Troisi et al. / Tetrahedron Letters 52 (2011) 4330–4332
2006, 14, 8280–8285; (d) Kato-Noguchi, H.; Macias, F. A.; Molinillo, J. M. G. J.
Sulfonamides 13 and 14, o-hydroxybenzyl alcohol 15 and o-
Plant Physiol. 2010, 167, 1221–1225.
aminobenzyl alcohol 16 were reacted under the same aforemen-
tioned conditions affording compounds 13a–16a, respectively.
Yields and reaction times are summarized in Table 2. The lower
yields and the longer reaction times observed for compounds 13a
and 14a are probably due to the lowered nucleophilicity of the
anionic sulfamidic NH group, responsible of the ring closure.
In summary, we have developed an efficient and simple
synthetic procedure for preparing benzo-fused five- and six-mem-
bered heterocycles in good yields. Such an easy procedure can be
applied to the synthesis of substrates having great pharmaceutical
and agrochemical interest. Furthermore, this new protocol can be
extended to the synthesis of several other heterocycles structurally
comparable.
7
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We thank for financial support the University of Salento and the
C.I.N.M.P.I.S. (Consorzio Interuniversitario Nazionale Metodologie e
Processi Innovativi di Sintesi).
2
0. General procedure for the synthesis of benzo-fused five and six-membered
heterocycles. A solution of substrate (1.0 mmol), Et N (2.0 mmol), Pd(AcO)
P (0.08 mmol) in THF (15 mL) was pressurized by CO
400 psi) in autoclave and warmed up at 100–110 °C under magnetic stirring
3
2
(
0.02 mmol), and Ph
3
(
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.
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3
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.
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4
5 7
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3
133.4, 171.0. IR (KBr): 3150 (NH), 1661 (CO). HRMS (ESI): calcd for C
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8
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6