Active manganese dioxide promoted cyclization of ortho-(1H-pyrrol-1-yl)aryl and heteroaryl carboxylic acids to 5H-pyrrolo[1,2-a][3,1]benzoxazin-5-one derivatives

Article abstract of DOI:10.1016/j.tet.2013.09.072

The hitherto unknown lactone 5H-pyrrolo[1,2-a][3,1]benzoxazin-5-one and six of its substituted derivatives have been prepared by active manganese dioxide promoted oxidative cyclization of the corresponding 2-(1H-pyrrol-1-yl)benzoic acids, under mild conditions, in moderate yields. The method was successfully extended to the cyclization of some ortho-(1H-pyrrol-1-yl)heteroaryl carboxylic acids and 2-(1H-indol-1-yl)benzoic acids.

Full text of DOI:10.1016/j.tet.2013.09.072

Tetrahedron 69 (2013) 9951e9956
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Active manganese dioxide promoted cyclization of ortho-(1H-pyrrol-
1-yl)aryl and heteroaryl carboxylic acids to 5H-pyrrolo[1,2-a][3,1]
benzoxazin-5-one derivatives
,
Fedora Grande a, Antonella Brizzi b, Antonio Garofalo a, Francesca Aiello a
*
a
ꢀ
Dipartimento di Farmacia e Scienze della Salute e della Nutrizione, Universita della Calabria, Edificio Polifunzionale, 87036 Rende (CS), Italy
b
ꢀ
Dipartimento di Biotecnologie, Chimica e Farmacia, Universita degli Studi di Siena, Via Aldo Moro, 2, 53100 Siena, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2013
Received in revised form 12 September 2013
Accepted 24 September 2013
Available online 30 September 2013
The hitherto unknown lactone 5H-pyrrolo[1,2-a][3,1]benzoxazin-5-one and six of its substituted
derivatives have been prepared by active manganese dioxide promoted oxidative cyclization of the
corresponding 2-(1H-pyrrol-1-yl)benzoic acids, under mild conditions, in moderate yields. The method
was successfully extended to the cyclization of some ortho-(1H-pyrrol-1-yl)heteroaryl carboxylic acids
and 2-(1H-indol-1-yl)benzoic acids.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Pyrrole
Benzoxazines
Indole
Oxidative cyclization
Lactones
1. Introduction
antidotes,3 DNA gyrase inhibitors4 and other polycyclic com-
pounds.5 The structure of Terresoxazine, an alkaloid isolated from
Based on a 1-phenyl-1H-pyrrole (1) skeleton, the lactone 2
(4H-pyrrolo[2,1-c][1,4]benzoxazin-4-one) has been known quite
some time1 while its isomer, 5H-pyrrolo[1,2-a][3,1]benzoxazin-5-
one (3a), has not yet been described (Fig. 1). This latter belongs to
the pyrrolo[1,2-a][3,1]benzoxazine class, which, although related to
several biologically active compounds, so far has received little
attention from chemists, probably due to the lack of general pro-
cedures for their synthesis. Derivatives of this heterocyclic system
might be of great interest, since this is a framework2 embedded in
larger fused structures of active compounds such as herbicide
a plant used in oriental medicine, is based on the same skeleton.6
On the other hand, the 5H-pyrrolo[1,2-a][3,1]benzoxazin-5-one
skeleton is present in compounds obtained by methods leading to
polysubstituted derivatives, but not applicable to the synthesis of
the basic tricyclic lactone 3a.7 During the search for active cardio-
vascular agents, we envisaged lactones 2 and 3a as suitable in-
termediates for the preparation of bioisosteres of previously
identified pyrrolobenzothiazines acting as calcium channels
blockers.8 Some procedures for the preparation of compound 2,
starting from 2-(1H-pyrrol-1-yl)phenol and essentially based on an
intramolecular FriedeleCrafts acylation of pyrrole as the key step1
or, more recently, by a copper-catalyzed intramolecular arylation
of the NH group on 2-iodophenyl-1H-pyrrole-2-carboxylate,9 were
already reported in the literature. No methods to isomer lactone 3a
are so far known. The hypothesis of applying these same ap-
proaches to lactone 2 for the synthesis of ‘reversed’ isomer 3a was
discarded, however, due to the impossibility of getting the suitable
corresponding substrate 1-phenyl-1H-pyrrol-2-ol, that, although
cited as a lithiated anion, was never isolated.10
O
O
O
O
N
N
N
2
1
3a
Fig. 1. 1-Phenyl-1H-pyrrole based lactones.
The need for a general synthetic method to 3a spurred us to
investigate an alternative approach, and the cyclization of easily
accessible 2-(1H-pyrrol-1-yl)benzoic acid 4a,11 the closest pre-
cursor of 3a, was taken into consideration. In this case the
* Corresponding author. Fax: þ39 (0)9840493118; e-mail address: frances-
ca.aiello@unical.it (F. Aiello).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.09.072

9952
F. Grande et al. / Tetrahedron 69 (2013) 9951e9956
cyclization would have been achieved by an oxidative process.
Although the oxidation of pyrroles usually leads to uncontrolled
polymerization and decomposition, Franck and Auerbach12 first
explored an oxidative cyclization of acid 4a or its sodium salt by
a photooxygenation reaction, which led to pyrrolinone 5 with loss
of pyrrole aromaticity (Fig. 2, left). Oxidative radical cyclizations
to pyrroles, although not from a carboxylate, have been also de-
scribed.13 The attention was therefore turned to find mild de-
hydrogenation conditions of acid 4a for an intramolecular reaction
from commercially available anthranilic acid derivatives 5aej
through pyrrole formation using dimethoxytetrahydrofuran
(DMTF) in 1,4-dioxane with 4-chloropyridine hydrochloride as
catalyst (Scheme 2).17
COOH
NH2
COOH
N
i
Ar
Ar
between the carboxylic group and the pyrrole
right).
a-carbon (Fig. 2,
5
4
a Ar = C6H4
g Ar = 5MeO-C6H3
h Ar = 2,3-naphtho
i Ar = 3,2-pyrido
O
b Ar = 5F-C6H3
c Ar = 5NO2-C6H3
d Ar = 5Me-C6H3
e Ar = 3Me-C6H3
f Ar = 5Br-C6H3
O
N
CO2H
N
3a
j Ar = 3,2-thiazolo
k Ar = 4-phenyl-2,3-thiazolo
O
Reagents and conditions: (i) 2,5-dimethoxytetrahydrofuran,
4a
5
4-chloropyridine hydrochloride, 1,4-dioxane, reflux.
Fig. 2. Cyclization reactions of 2-(1H-pyrrol-1-yl)benzoic acid.
Scheme 2. Synthesis of ortho-(1H-pyrrol-1-yl)aryl and heteroaryl carboxylic acids.
Recently, we used activated manganese dioxide, a selective ox-
idant widely used in organic synthesis and usually acting in het-
erogeneous media with a free radical mechanism, as the reagent
able to promote intramolecular cyclization on pyrrole derivatives
without affecting the pyrrole electronic integrity.14 This reagent has
been used in the past to catalyze various cyclization reactions. As an
example, a MnO2-promoted cyclization to 2,3,4,4a-tetrahydro-5H-
pyrrolo[1,2-a][3,1]benzoxazine through a carboneoxygen bond
formation was reported formerly,15 although no attempts to cyclize
compounds bearing both the pyrrole ring and a carboxylic acid
group were performed. The moderate oxidative potency, that can
be modulated by temperature,16 and a weak character as a Lewis
acid would make MnO2 the ideal reagent for the intramolecular
cyclization of carboxylic acid 4a to give the corresponding lactone
3a. After these preliminary remarks, the starting acid was subjected
to the action of activated MnO2 under different reaction conditions
achieving a smooth conversion, although with a moderate yield.
Attempts were also made to improve the yield and shorten the
reaction time. The method proved to be successful towards several
benzo-substituted derivatives of 2-(1H-pyrrol-1-yl)benzoic acid
and some of its heteroaryl analogues. Finally, the cyclization re-
action was proved to be effective even for the conversion of 2-(1H-
indol-1-yl)benzoic acids, analogues with an indole system replac-
ing the pyrrole (Scheme 1).
4-Phenyl-3-(1H-pyrrol-1-yl)thiophene-2-carboxylic acid 4k
was synthesized following the above procedure starting from
3-amino-4-phenylthiophene-2-carboxylic acid 5k, in turn prepared
by a known method.18 Copper-catalyzed arylation reaction of in-
doles 5l,m with methyl 2-iodobenzoate led to methyl 2-(1H-indol-
1-yl)benzoate esters, which were in turn subjected to hydrolysis to
give acids 4l,m under classical conditions (Scheme 3).9
R
R
i
N
COOH
N
H
5l R = H
5m R = Br
4l,m
Reagents and conditions: (i) 1) methyl 2-iodobenzoate,
CuI, K2CO3, DMF, reflux, under N2 atmosphere;
2) LiOH, THF, CH3OH, H2O, rt then 2M HCl
Scheme 3. Synthesis of 2-(1H-indol-1-yl)benzoic acids.
The intramolecular oxidative cyclization of 2-(1H-pyrrol-1-yl)
benzoic acid 4a by activated MnO2 was investigated as a model
reaction under different conditions, the significant results of which
are shown in Table 1. The monitoring of the course of all reactions
was performed by TLC or GC at 1 h time intervals. The first set of
experiments was done by mixing the acid with a 5-fold excess of
oxidant in three different solvents, dichloromethane, DMF and
toluene, under a nitrogen atmosphere, at room temperature (en-
tries 1e3, Table 1). The formation of the expected lactone 3a was
observed in all cases, although in very low yields (8, 17, and 12%,
respectively), after a reaction time of 72 h. The structure of tricyclic
lactone 3a was confirmed by usual spectroscopic and analytical
techniques. The same experiments performed at reflux tempera-
ture led to comparable yields for reactions in the first two solvents
(10 and 14%, respectively, entries 4 and 5, Table 1), but significantly
O
CO2H
N
O
N
R
MnO2
R
solvent, Δ
R = H, 5-F, 5-NO2, 3-Me, 5-Me, 5-Br, 4,5-(-CH=CH-)2
Scheme 1. MnO2-promoted cyclization reaction.
2. Results and discussion
2.1. Synthesis of ortho-(1H-pyrrol-1-yl)aryl and heteroaryl
carboxylic acids and 2-(1H-indol-1-yl)benzoic acids (4aek)
ꢁ
higher in the case of reaction with dry toluene and 4 A molecular
sieves to ensure anhydrous conditions (45%, entry 6, Table 1), after
72 h and a simple work up. In this case, the yield was not influenced
by the exclusion of oxygen from the reaction vessel. A result
The ortho-(1H-pyrrol-1-yl)aryl and heteroaryl carboxylic acids
4aej, required to carry out the cyclization reactions, were obtained

F. Grande et al. / Tetrahedron 69 (2013) 9951e9956
9953
Table 1
time (72 h). In particular, the cyclization reaction was carried out
adopting the sealed-tube technique. However, the best yield
recorded was a 20% after 2 h heating to 110 ꢀC (entry 14, Table 1).
We then evaluated the intramolecular cyclization of acid 4a by
using MW irradiation. In a first experiment we started with the
usual conditions by simply replacing the conventional heating with
MW irradiation at fixed power in a sealed pressurized system. After
15 min at 150 ꢀC and a power of 70 W, no formation of lactone 3a
was observed, although the starting material was completely
decomposed (entry 15, Table 1). We then decided to use DMF,
a solvent more sensitive to MW irradiation, and a weaker irradia-
tion power of 50 W at 100 ꢀC, but results were comparable with
those above described (entry 16, Table 1). In conclusion, the best
conditions for cyclization remained those outlined in entry 6 of
Table 1, which led to lactone 3a with the acceptable yield of 45%. In
all the above experiments, despite the moderate cyclization rate
and the almost complete consumption of starting material, it was
not possible to isolate any significant amount of products from side
reactions.
Search of conditions for oxidative cyclization to 5H-pyrrolo[1,2-a][3,1]benzoxazin-5-
one (3a)
O
O
N
oxidant
solvent
OH
O
N
4a
3a
Entry Oxidanta
Conditionsb
Solvent
Yieldc
(%)
Time (h) Temperature/system
1
2
3
4
5
6
7
8
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
MnO2
CrO3
DCM
DMF
72
72
rt
rt
rt
Reflux
Reflux
8
17
12
10
14
45
38
ND
ND
5
Toluene 72
DCM
DMF
48
48
ꢁ
Toluene 72
Reflux/4 A MS
Reflux/4 A MS
ꢁ
Xylene
Acetone
72
1
rt
ꢁ
9
Air/cat MnO2
MnO2/cat TBC
MnO2/cat AIBN Toluene 72
MnO2/cat AIBN Toluene 72
d/cat AIBN
MnO2
Toluene 72
Toluene 72
Reflux/4 A MS
reflux/4A MS
reflux/4A MS
ꢁ
10
11
12
13
14
15
16
ꢁ
7
2.2. Synthesis of pyrrole and indole benzoxazinone de-
rivatives (3aem)
rt
rt
37
12
20
ND
ND
Toluene 72
Toluene
Toluene
DMF
2
0.25
0.5
110ꢀC/Sealed tube
150 ꢀC/MW 70 W
100 ꢀC/MW 50 W
MnO2
MnO2
The MnO2-promoted oxidative cyclization procedure outlined
with acid 4a, to give compound 3a, the prototype of a new class of
compounds, was extended to analogous acids 4beg, variously
substituted on the phenyl ring, to give corresponding substituted
lactones 3beg in 20e56% yield (entries 2e7, Table 2). As an
a
Molar ratio oxidant/substrate 5:1.
The reactions were performed under N2 atmosphere, except for entry 9.
Isolated yield, after chromatographic purification.
b
c
comparable to this latter was obtained by replacing xylene for
toluene, at reflux (38%, entry 7, Table 1), suggesting that solvents
with higher boiling temperature than toluene were not worth in-
vestigating. In a parallel experiment, using CrO3 as an alternative
oxidant and acetone as solvent, the starting acid was completely
consumed after 1 h at room temperature, but no formation of
lactone was observed (entry 8, Table 1). These latter conditions
proved to be too harsh towards our substrate. After a control ex-
periment on acid 4a conducted in toluene at reflux, under a con-
tinuous stream of dry air and only a catalytic amount of MnO2, the
starting material was recovered almost unchanged even after
a prolonged reaction time (entry 9, Table 1), thus confirming the
primary role of MnO2 as oxidant for cyclization. After this first se-
ries of experiments, the best result was therefore represented by
the 45% yield obtained by use of a 5-fold excess of oxidant in tol-
uene after the procedure described in the Experimental section and
now assumed as the reference condition for the synthesis of lactone
3a. After this promising result, a second set of experiments was
designed with the aim to improve yield. Since it is known that the
majority of the reactions promoted by activated MnO2 proceed
with radical formation, we could confirm the same mechanism by
attempting our reaction in the presence of a radical scavenger. In
fact, when the reaction was conducted under the reference condi-
tion, but with the addition of a catalytic amount of TBC (4-tert-
butylcatechol), the yield was dramatically lowered to only 5% (entry
10, Table 1). On the other hand, the addition of a radical initiator
such as AIBN gave variable results. In fact, when catalytic AIBN was
added under the reference condition, the cyclization proceeded
with a yield of 7% (entry 11, Table 1), while a similar reaction
conducted at room temperature produced lactone 3a in 37% yield
(entry 12, Table 1). This suggests that high temperatures could be
detrimental when used in combination with the radical initiator. It
is worth noting that a 12% yield of lactone was also achieved by
using a catalytic amount of AIBN only, without the presence of
MnO2, at room temperature (entry 13, Table 1). After these disap-
pointing results, no more efforts were made in this direction.
Finally, several attempts were made in order to shorten the reaction
Table 2
Synthesis of pyrrole and indole lactones 3aem
O
COOH
O
Ar
Ar
5 eq. MnO2
N
N
toluene, reflux
Entry
Substrate
Product
Time Yielda
(h)
(%)
O
N
COOH
O
1
4a
4b
3a
3b
72
45
N
O
F
COOH
F
O
2
3
4
5
24
72
72
72
56
20
25
20
N
N
O
O2N
COOH
O2N
Me
O
4c
4d
4e
3c
3d
3e
N
N
O
Me
COOH
N
O
N
O
O
N
COOH
N
Me
Me
(continued on next page)

9954
F. Grande et al. / Tetrahedron 69 (2013) 9951e9956
Table 2 (continued )
into the tetracyclic corresponding lactones. Under the same
condition above described, lactones 3l,m were smoothly obtained
from acids 4l,m, with yields of 49 and 54%, respectively.
The results obtained were compatible with a mechanism con-
sisting of a radical formation at carboxyl oxygen followed by attack
onto the position two of pyrrole or indole. Further studies are in
progress to confirm such hypothesis and establish a coherent re-
lationship between the chemical structure of substrates and the
cyclization rate.
Entry
Substrate
Product
Time Yielda
(h)
(%)
O
N
Br
COOH
Br
O
6
4f
4g
4h
4i
3f
3g
3h
3i
24
30
N
O
MeO
COOH
MeO
3. Conclusions
O
7
96
48
24
72
d
N
N
In summary, we herein present an original and simple route for
the preparation of 5H-pyrrolo[1,2-a][3,1]benzoxazin-5-one and
several of its pyrrole and indole congeners, which constitute a class
of fused heterocycles so far unknown and potentially useful in the
synthesis of biologically active derivatives. The utilization of acti-
vated MnO2, a cheap and well known reagent, together with mild
conditions and a simple work up make this method particularly
attractive. To the best of our knowledge, this oxidative cyclization
procedure represents the first example of lactone formation from
a carboxylate moiety onto the 2-carbon of pyrrole or indole. The
reaction could also have great potential for the production of
C-acyloxy derivatives of N-substituted pyrroles and indoles since
the reluctance for such compounds to in general undergo C-sub-
stitutions by oxygenated species is known.
O
COOH
N
O
8
71
38
21
N
O
O
COOH
9
N
N
N
N
O
COOH
N
O
10
4j
3j
S
S
N
4. Experimental section
4.1. General method
O
N
COOH
N
S
S
O
All reagents were commercial and were used as received. Sol-
vents were dried and distilled according to conventional pro-
cedures. Progress of the reaction was monitored by TLC on silica
11
12
4k
3k
72
72
20
49
€
gel plates (Riedel-de Haen, Art. 37341) or GC by a Hewlett-Packard
O
6890 apparatus. Organic solutions were dried over MgSO4 and
evaporated on a rotary evaporator under reduced pressure. Melt-
ing points were measured using an Electrothermal 8103 apparatus
and are uncorrected. IR spectra were recorded as KBr discs on
a Jasco FT/IR-4200 spectrophotometer. 1H NMR and 13C NMR
COOH
N
O
4l
3l
N
€
spectra were recorded on a Bruker 300 MHz spectrometer with
TMS as an internal standard: chemical shifts are expressed in
O
N
COOH
N
d
values (ppm) and coupling constants (J) in hertz (Hz). Mass
O
spectral data were determined after electron impact ionization at
70 eV with an HP 5973 MS spectrometer. Merck silica gel (Kie-
selgel 60/230e400 mesh) was used for flash chromatography
columns (n-hexane/ethyl acetate 6:1, as eluent for final com-
pounds 3aem). All reactions were carried out under a nitrogen
atmosphere. MW-induced reactions were performed in a CEM-
Discover reactor equipped with a non-contact infrared sensor to
measure the temperature. Yields refer to purified products and are
not optimized.
13
4m
3m
72
54
Br
Br
a
Isolated yield.
exception, 5-methoxy-2-(1H-pyrrol-1-yl)benzoic acid 4g did not
produce any cyclization product, so confirming the trend of
methoxy derivatives to be unreactive towards MnO2, due to a dif-
ferent absorption on the solid MnO2 surface.14a,19
4.2. Procedure for the preparation of lactones 3aem
4.2.1. 5H-Pyrrolo[1,2-a][3,1]benzoxazin-5-one (3a). To a solution of
2-(1H-pyrrol-1-yl)benzoic acid 4a11 (0.925 mmol, 0.173 g) in
The best result was however recorded for the cyclization of
3-(1H-pyrrol-1-yl)naphthalene-2-carboxylic acid 4h into lactone
3h, which was obtained in 71% yield (entry 8, Table 2). The gener-
ality of this method was also confirmed after the good results
achieved by the synthesis of three hetero-isosteres of lead lactone
3a, namely, the pyridine analogue 4i and two thiazole analogues
4j,k, which were obtained in 38, 21, and 20% yields, respectively
(entry 9e11, Table 2). Finally, we decided to apply the same pro-
cedure for the cyclization of 2-(1H-indol-1-yl)benzoic acids, ana-
logues of above acids bearing an indole system instead of pyrrole,
ꢁ
toluene (5 mL) and 4 A MS (0.5 g) was added activated manga-
nese dioxide (4.625 mmol, 0.435 g). The reaction mixture was
stirred for 72 h under reflux and then filtered on CeliteÒ. The
filter cake was washed several times with chloroform, then the
filtrate was washed with a saturated solution of NaHCO3 (5 mL).
The layers were separated and the organic phase, dried over
anhydrous Na2SO4, was concentrated to dryness under vacuum.
The residue was purified by chromatographic column on silica
gel (n-hexane/ethyl acetate 6:1, as eluent) to give 3a as a yellow

F. Grande et al. / Tetrahedron 69 (2013) 9951e9956
9955
solid. Mp 96e97 ꢀC (cyclohexane). 1H NMR (300 MHz, CDCl3,
25 ꢀC)
8.13 (1H, d, J¼7.7 Hz), 7.70 (1H, t, J¼7.7 Hz), 7.4 (1H, d,
for C11H6BrNO2 263.9001, found 263.9050. IR (KBr) nmax: 1750,
1620 cmꢁ1
d
.
J¼8.1 Hz), 7.27 (1H, t, J¼7.2 Hz), 6.94e6.92 (1H, m), 6.35 (1H, t,
J¼1.5 Hz), 5.72e5.69 (1H, m). 13C NMR (300 MHz, CDCl3)
d
157.9,
4.2.7. 5H-Naphtho[2,3-d]pyrrolo[2,1-b][1,3]oxazin-5-one (3h). This
compound was obtained following the procedure applied for 3a
starting from 3-(1H-pyrrol-1-yl)naphthalene-2-carboxylic acid 4h
(see Supplementary data). The product was isolated as a yellow
solid. Mp 164e165 ꢀC (cyclohexane). 1H NMR (300 MHz, acetone-
140.1, 137.9, 136.6, 131.4, 124.7, 113.4, 111.1, 110.7, 106.6, 89.5.
GCeMS (EI, 70 eV) (m/z): 185 (Mþ, 100), 157 (37), 129 (35). HRMS
calcd for C11H7NO2 186.0555, found 186.0551. IR (KBr) nmax: 1749,
1615 cmꢁ1
.
d6, 25 ꢀC)
d
8.89 (1H, s), 8.20 (1H, s), 8.10 (1H, d, J¼7.8 Hz), 7.94 (1H,
4.2.2. 7-Fluoro-5H-pyrrolo[1,2-a][3,1]benzoxazin-5-one (3b). This
compound was obtained following the procedure applied for 3a
starting from 5-fluoro-2-(1H-pyrrol-1-yl)benzoic acid 4b.20 The
product was isolated as a yellow solid. Mp 153e154 ꢀC (petroleum
d, J¼7.9 Hz), 7.71e7.64 (1H, dt, J¼1.2, 8.1 Hz), 7.59e7.51 (1H, dt,
J¼1.1, 8.1 Hz), 7.42e7.39 (1H, m), 6.37 (1H, t, J¼3.5 Hz), 5.77e5.72
(1H, m). 13C NMR (300 MHz, acetone-d6)
d 157.4, 139.6, 137.2, 133.7,
133.2, 130.3, 129.9, 129.7, 127.2, 126.1, 111.3, 110.1, 109.9, 107.9, 88.8.
GCeMS (EI, 70 eV) (m/z): 235 (Mþ, 100), 207 (37), 179 (32). HRMS
calcd for C15H9NO2 236.0674, found 236.0602. IR (KBr) nmax: 1712,
ether). 1H NMR (300 MHz, CDCl3, 25 ꢀC)
d 7.86e7.82 (1H, m),
7.48e7.40 (2H, m), 6.90 (1H, q, J¼3.6 Hz, 1H), 6.34 (1H, t, J¼3.6 Hz),
5.74 (1H, dd, J¼2.1, 3.7 Hz). 13C NMR (300 MHz, CDCl3)
d
159.0 (d,
1680 cmꢁ1
.
JCF¼246.8 Hz), 157.3, 139.4, 134.6, 124.5 (d, JCF¼24.1 Hz), 117.1 (d,
JCF¼24.1 Hz), 115.5 (d, JCF¼8.3 Hz), 112.5, 110.7, 106.7, 89.6. GCeMS
(EI, 70 eV) (m/z): 203 (Mþ, 100), 175 (42), 148 (34). HRMS calcd for
4.2.8. 5H-Pyrido[2,3-d]pyrrolo[2,1-b][1,3]oxazin-5-one
(3i). This
compound was obtained following the procedure applied for 3a
starting from 2-(1H-pyrrol-1-yl)pyridine-3-carboxylic acid 4i.23
The product was isolated as a brown solid. Mp 153e154 ꢀC
C
11H6FNO2 204.0402, found 204.0398. IR (KBr) nmax
: 1749,
1624 cmꢁ1
.
(diethyl ether). 1H NMR (300 MHz, CDCl3, 25 ꢀC)
d 8.73 (1H, dd,
4.2.3. 7-Nitro-5H-pyrrolo[1,2-a][3,1]benzoxazin-5-one
(3c). This
J¼1.8, 4.8 Hz), 8.51 (1H, dd, J¼1.8, 7.8 Hz), 7.45e7.40 (1H, m),
compound was obtained following the procedure applied for 3a
starting from 5-nitro-2-(1H-pyrrol-1-yl)benzoic acid 4c.21 The
product was isolated as an orange solid. Mp 187e188 ꢀC (chloro-
7.37e7.31 (1H, m), 6.42 (1H, tt, J¼2.5, 3.5 Hz), 5.87e5.84 (1H, m). 13
C
NMR (300 MHz, CDCl3) d 165.5,161.0,155.6,140.1,120.8,118.5, 117.5,
117.0, 110.8, 107.9. GCeMS (EI, 70 eV) (m/z): 186 (Mþ, 100), 158 (75),
form). 1H NMR (300 MHz, CDCl3, 25 ꢀC)
d
9.00 (1H, s), 8.55 (1H, d,
J¼7.2 Hz), 7.58 (1H, d, J¼8.1 Hz), 7.0 (1H, s), 6.44 (1H, d, J¼2.4 Hz),
5.82 (1H, s). 13C NMR (300 MHz, CDCl3)
158.0, 151.1, 141.7, 139.7,
130 (28). HRMS calcd for C10H6N2O2 187.0445, found 187.0450. IR
(KBr) nmax: 1729, 1605 cmꢁ1
.
d
131.3, 127.8, 114.7, 112.8, 111.5, 107.8, 91.1. GCeMS (EI, 70 eV) (m/z):
4.2.9. 4H-Pyrrolo[2,1-b]thieno[2,3-d][1,3]oxazin-4-one
(3j). This
230 (Mþ, 100), 156 (44), 75 (23). HRMS calcd for C11H6N2O4
compound was obtained following the procedure applied for 3a
starting from 2-(1H-pyrrol-1-yl)thiophene-3-carboxylic acid 4j.24
The product was isolated as a brown solid. Mp 125e126 ꢀC
231.0345, found 231.0325. IR (KBr) nmax: 1752, 1622 cmꢁ1
.
4.2.4. 7-Methyl-5H-pyrrolo[1,2-a][3,1]benzoxazin-5-one (3d). This
compound was obtained following the procedure applied for 3a
starting from 5-methyl-2-(1H-pyrrol-1-yl)benzoic acid 4d.22 The
product was isolated as a yellow solid. Mp 121e126 ꢀC (n-hexane).
(n-hexane/ethyl acetate). 1H NMR (300 MHz, CDCl3, 25 ꢀC)
d 7.90
(1H, d, J¼5.3 Hz), 7.23 (1H, d, J¼8.1 Hz), 6.84 (1H, t, J¼3.3 Hz), 6.40
(1H, t, J¼3.4 Hz), 5.82 (1H, d, J¼3.7 Hz). 13C NMR (300 MHz, CDCl3)
d
158.0, 141.0, 135.3, 133.1, 125.0, 112.5, 110.6, 107.5, 89.1. GCeMS
1H NMR (300 MHz, CDCl3, 25 ꢀC)
d
7.55 (1H, dd, J¼1.2, 8.4 Hz), 7.37
(EI, 70 eV) (m/z): 191 (Mþ, 100), 135 (75), 108 (28). HRMS calcd for
(1H, d, J¼8.4 Hz), 6.95 (1H, dd, J¼1.7, 3.5 Hz), 6.36 (1H, t, J¼3.5 Hz),
C9H5NO2S 192.0071, found 192.0075. IR (KBr) nmax: 1719,1633 cmꢁ1
.
5.77 (2H, dd, J¼1.7, 3.4 Hz), 2.45 (3H, s). 13C NMR (300 MHz, CDCl3)
d
156.0, 140.0, 134.5, 131.0, 128.0, 127.1, 125.0, 124.5, 117.0, 109.5,
4.2.10. 1-Phenyl-4H-pyrrolo[2,1-b]thieno[3,2-d][1,3]oxazin-4-one
(3k). This compound was obtained following the procedure ap-
plied for 3a starting from 4-phenyl-3-(1H-pyrrol-1-yl)thiophene-
2-carboxylic acid 4k.18 The product was isolated as a grey solid. Mp
140e141 ꢀC (n-hexane/ethyl acetate). 1H NMR (300 MHz, CDCl3,
91.0, 14.1. GCeMS (EI, 70 eV) (m/z): 199 (Mþ, 100), 184 (40). HRMS
calcd for C12H9NO2 200.0689, found 200.0685. IR (KBr) nmax: 1749,
1622 cmꢁ1
.
4.2.5. 9-Methyl-5H-pyrrolo[1,2-a][3,1]benzoxazin-5-one (3e). This
compound was obtained following the procedure applied for 3a
starting from 3-methyl-2-(1H-pyrrol-1-yl)benzoic acid 4e.22 The
product was isolated as a pale yellow solid. Mp 118e119 ꢀC
25 ꢀC)
d 7.70 (1H, s), 7.55e7.51 (3H, m), 7.47e7.44 (2H, m),
6.27e6.23 (1H, m), 6.15 (1H, t, J¼3.6 Hz), 5.83e5.80 (1H, m). 13C
NMR (300 MHz, CDCl3) d 154.5,141.0,137.4, 136.3,135.0,133.0,131.1,
129.6 (ꢂ2C),129.2,128.5 (ꢂ2C),109.1,108.5, 81.0. GCeMS (EI, 70 eV)
(n-hexane). 1H NMR (300 MHz, CDCl3, 25 ꢀC)
d 7.44 (1H, d,
(m/z): 267 (Mþ, 100), 238 (27), 210 (47). HRMS calcd for C15H9NO2S
J¼7.3 Hz), 7.2e7.1 (2H, m), 7.02 (1H, t, J¼7.3 Hz), 6.80 (1H, d,
268.0445, found 268.0440. IR (KBr) nmax: 1769, 1623 cmꢁ1
.
J¼3.8 Hz), 6.32e6.28 (1H, m), 2.50 (3H, s). 13C NMR (300 MHz,
CDCl3)
d
160.1, 147.3, 137.2, 127.6, 125.5, 125.6, 122.3, 117.4, 113.6,
4.2.11. 5H-Indole[1,2-a][3,1]benzoxazin-5-one (3l). This compound
was obtained following the procedure applied for 3a starting from
2-(1H-indol-1-yl)benzoic acid 4l.25 The product was isolated as
a brown solid. Mp 123e124 ꢀC (cyclohexane). 1H NMR (300 MHz,
110.1, 90.1, 18.1. GCeMS (EI, 70 eV) (m/z): 199 (Mþ, 100), 184 (35).
HRMS calcd for C12H9NO2 200.0685, found 200.0683. IR (KBr) nmax
1739, 1686 cmꢁ1
:
.
CDCl3, 25 ꢀC)
d
¼8.31 (dd, J¼1.6 Hz, 6.3 Hz, 1H), 8.18 (1H, d,
4.2.6. 7-Bromo-5H-pyrrolo[1,2-a][3,1]benzoxazin-5-one (3f). This
compound was obtained following the procedure applied for 3a
starting from 5-bromo-2-(1H-pyrrol-1-yl)benzoic acid 4f.22 The
product was isolated as a yellow solid. Mp 173e174 ꢀC (cyclohex-
J¼8.5 Hz), 8.10 (1H, dd, J¼1.9, 4.6 Hz), 7.90e7.84 (1H, m), 7.68e7.63
(1H, m), 7.35e7.30 (3H, m), 6.20 (1H, s). 13C NMR (300 MHz, CDCl3)
d
158.0, 154.0, 144.8, 140.0, 136.9, 131.9, 129.0, 128.3, 123.9, 122.3,
121.0, 114.4, 112.7, 111.2, 84.6. GCeMS (EI, 70 eV) (m/z): 235 (Mþ,
ane). 1H NMR (300 MHz, CDCl3, 25 ꢀC)
d
8.35 (1H, d, J¼2.2 Hz), 7.86
100), 207 (15), 179 (32), 152 (15). HRMS calcd for C15H9NO2
(1H, dd, J¼2.3, 8.7 Hz), 7.40 (1H, d, J¼8.7 Hz), 6.99e6.92 (1H, m),
236.0601, found 236.0603. IR (KBr) nmax: 1701, 1618 cmꢁ1
.
6.41 (1H, t, J¼3.7 Hz), 5.85e5.82 (1H, m). 13C NMR (300 MHz, CDCl3)
d
156.6,146.7, 139.4,136.8, 133.8, 117.3, 115.2,112.6, 111.1, 106.8, 89.9.
4.2.12. 12-Bromo-5H-indole[1,2-a][3,1]benzoxazin-5-one (3m). This
compound was obtained following the procedure applied for 3a
GCeMS (EI, 70 eV) (m/z): 263 (Mþ, 100), 235 (40). HRMS calcd

9956
F. Grande et al. / Tetrahedron 69 (2013) 9951e9956
7. For some examples see: (a) Elkholy, Y. M. J. Heterocycl. Chem. 2008, 45,
1237e1241; (b) Mahmoud, F. F.; Mohamed, N. R.; Sherif, S. M.; Erian, A. W.
Phosphorus Sulfur to Phosphorus, Sulfur Silicon Relat. Elem. 2000, 167, 133e149;
(c) Erian, A. W.; Issac, Y. A. E.; Sherif, S. M.; Mahmoud, F. F. J. Chem. Soc., Perkin
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Ferrara, J. J. Enzyme Inhib. Med. Chem. 2006, 21, 133e138.
starting from 2-(5-bromo-1H-indol-1-yl)benzoic acid 4m (see
Supplementary data). The product was isolated as a beige solid. Mp
162e163 ꢀC (chloroform/n-hexane). 1H NMR (300 MHz, CDCl3,
25 ꢀC)
d
8.36e8.30 (1H, m), 8.10 (1H, dd, J¼3.2, 5.1 Hz), 7.93e7.86
(1H, m), 7.78 (1H, d, J¼2.0 Hz), 7.69 (1H, d, J¼2.0 Hz), 7.52e7.40 (2H,
m), 6.18 (1H, s). 13C NMR (300 MHz, CDCl3)
158.7, 154.2, 145.8,
d
8. Campiani, G.; Garofalo, A.; Fiorini, I.; Botta, M.; Nacci, V.; Tafi, A.; Chiarini, A. R.;
Budriesi, G.; Bruni, M.; Romeo, R. J. Med. Chem. 1995, 38, 4393e4410.
9. Vaillard, V. A.; Rossi, R. A.; Martin, S. E. Org. Biomol. Chem. 2011, 9, 4927e4935.
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12. Franck, R. W.; Auerbach, J. J. Org. Chem. 1971, 36, 31e36.
13. Menes-Arzate, M.; Martinez, R.; Cruz-Almanza, R.; Muchowski, J. M.; Osornio,
Y. M.; Miranda, L. D. J. Org. Chem. 2004, 69, 4001e4004.
144.4, 139.0, 133.9, 131.9, 125.0, 124.3, 121.9, 121.3, 121.0, 117.0, 112.7,
111.2. GCeMS (EI, 70 eV) (m/z): 313 (Mþ, 66), 234 (100), 178 (21).
HRMS calcd for C15H8BrNO2 313.9771, found 313.9700. IR (KBr)
nmax: 1771, 1619 cmꢁ1
.
Supplementary data
14. (a) Aiello, F.; Garofalo, A.; Grande, F. Tetrahedron 2010, 66, 274e277; (b) Tojo, G.;
Fernandez, M. Oxidation of Alcohols to Aldehydes and Ketones; Springer: New
York, NY, 2006; pp 290e309.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.09.072.
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