Synthesis of 6-substituted 2-pyrrolyl and indolyl benzoxazoles by intramolecular O-arylation in photostimulated reactions

Article abstract of DOI:10.1021/jo202386b

The synthesis of a series of 6-substituted 2-pyrrolyl and 2-indolyl benzoxazoles by photostimulated C-O cyclization of anions from 2-pyrrole carboxamides, 2-indole carboxamides, or 3-indole carboxamides has been found to proceed in good to excellent yields (41-100%) in DMSO and liquid ammonia. The pyrrole and indole carboxamides are obtained in good to very good isolated yields by an amidation reaction of different 2-haloanilines with 2-carboxylic acid of pyrrole and 2- or 3-carboxylic acid of indole. To explain the regiochemical outcome of these reactions (C-O arylation vs C-N or C-C arylation), a theoretical analysis was performed using DFT methods and the B3LYP functional.

Full text of DOI:10.1021/jo202386b

Article
pubs.acs.org/joc
Synthesis of 6-Substituted 2-Pyrrolyl and Indolyl Benzoxazoles by
Intramolecular O-Arylation in Photostimulated Reactions
Victoria A. Vaillard, Javier F. Guastavino, María E. Buden, Javier I. Bardagí, Silvia M. Barolo,
́
and Roberto A. Rossi*
INFIQC, Departamento de Química Organ
́ ́
ica, Facultad de Ciencias Químicas, Universidad Nacional de Cordoba, X5000HUA
Cordoba. Argentina
́
S
* Supporting Information
ABSTRACT: The synthesis of a series of 6-substituted 2-
pyrrolyl and 2-indolyl benzoxazoles by photostimulated C−O
cyclization of anions from 2-pyrrole carboxamides, 2-indole
carboxamides, or 3-indole carboxamides has been found to
proceed in good to excellent yields (41−100%) in DMSO and
liquid ammonia. The pyrrole and indole carboxamides are
obtained in good to very good isolated yields by an amidation
reaction of different 2-haloanilines with 2-carboxylic acid of
pyrrole and 2- or 3-carboxylic acid of indole. To explain the regiochemical outcome of these reactions (C−O arylation vs C−N
or C−C arylation), a theoretical analysis was performed using DFT methods and the B3LYP functional.
Benzoxazole L-697,661 was reported to inhibit the spread of
HIV infection by 95% in MT4 cell culture.7 ERB-041 is used
in the treatments of rheumatoid arthritis.8 CP 2289 is a ligand
of the 5-HT3 receptor showing agonistic activities on the
gastroenteric motility,9 and UK-1 is a structurally unique bis-
benzoxazole (natural product) isolated from a strain of
Streptomyces, which has been reported to exhibit anticancer
activity.10
INTRODUCTION
The benzoxazole core is an important type of heterocycle found
in many natural products and pharmacological agents (Figure 1).
■
Compounds with a benzoxazole structure possess fluores-
cence properties and find application in electronic devices,11
sensors for metals,12 and photoluminescent dyes.13
The classical methods of synthesis used to obtain 2-aryl-
benzoxazole employ the use of 2-aminophenols as starting
precursors (Scheme 1). Several synthetic strategies consist of
coupling the 2-aminophenols with aromatic carboxylic acid or
acid derivatives by dehydration, which can be generally
catalyzed by strong acid, such as polyphosphoric acid,14 or by
p-toluensulfonic acid under microwave irradiation.15 Another
approach involves the condensation of aldehydes followed
by oxidative cyclization conditions16 or by a bioenzymatic
transformation17 (step a, Scheme 1). Oxidative cyclization requires
the use of a stoichiometric amount of oxidant, and the further
purification involves toxic workup procedures to remove the
transition metals. In addition, these approaches are limited by
the availability of the properly substituted 2-aminophenols.
Another methodology to furnish this type of heterocycle is
via an aryne reaction using N-(2-halophenyl)benzamide and
potassium amide in liquid ammonia (step b, Scheme 1).18
From N-(2-halophenyl)benzamide by intramolecular O-aryla-
tion copper19 or iron-catalyzed20 reactions, 2-arylbenzoxazoles
Figure 1. Examples of biologically active benzoxazoles.
The discovery of these types of compounds served as a basis for
the development of new derivatives containing the benzoxazole
structure. For example, benzoxazole derivatives have been used
in disease treatments1 and have biological activities as antibiotic,2
antimycobacterial,3 antiparasitic,4 and antitumoral agents.5 For
example, benoxaprofen is a potent anti-inflammatory agent.6
Received: November 18, 2011
Published: December 22, 2011
© 2011 American Chemical Society
1507
dx.doi.org/10.1021/jo202386b | J. Org. Chem. 2012, 77, 1507−1519

The Journal of Organic Chemistry
Article
indole 2- and 3-carboxamides (2 and 3), where the leaving
group and nucleophilic center are in the same molecule in an
appropriate position (Scheme 2). In 1 or 2 there are three main
Scheme 1. 2-Arylbenzoxazoles Synthesis
Scheme 2. Intramolecular Arylation of Anions from
2-Pyrrole Carboxamides (1), 2-Indole Carboxamides (2) or
3-Indole Carboxamides (3)
a
b
Classical methods or bioenzymatic transformation. X = halogen,
C−O bond formation by aryne mechanism, cross-coupling or photo-
c
substitution; X = H, C−H activation/cross-coupling. −N/C−O
cross-coupling.
are obtained in very good yields (step b). Similar intramolecular
C−O bond formation by photostimulation of N-(2-
halophenyl)benzamide in basic medium afforded the benzox-
azole in low yield.21
Recently, bond formation through C−H activation/cross-
coupling approach using transition metal complexes has gained
importance, as it obviates the need for prior activation steps. An
efficient method of synthesis of functionalized benzoxazoles
through C−H activation was described, which used a
copper(II)-catalyst (step b, Scheme 1, X = H).22 Recently,
the synthesis by copper-catalyzed conversion of bisaryloxime
ethers was reported.23 This reaction involves a cascade of C−H
functionalization and C−O bond formation. The disadvantage
of this method is the synthetic availability of the precursors,
which requires many steps and purification.
Another possibility exists starting from 1,2-dihaloarenes and
primary amides by intermolecular aryl−amide bond formation,
followed by intramolecular aryl−oxygen coupling reactions
catalyzed by copper (step c, Scheme 1).19b,24
The unimolecular radical nucleophilic substitution (SRN1)
reaction is a synthetically useful process to mediate aromatic
nucleophilic substitutions for the preparation of carbo- and
heterocycles.25 This reaction has been used to obtain
oxindoles,26 benzothiazoles,27 aporphines,28 phenantridines,29
carbazoles,30 and carbolines.31 While anions derivatives from
anilines, phenols, amides, and ketones were used as
nucleophiles in intramolecular SRN1 reactions, pyrrolyl and
indolyl anions have not been exhaustively studied.32
By employing the intermolecular SRN1 reaction, arylpyrroles
and arylindoles were synthesized electrochemically by the
reaction of pyrrolyl and indolyl anions with aryl halides in liquid
ammonia.33 For pyrrolyl anion, C2 is more reactive (50−70%)
than C3 (3−15%) toward the coupling reaction. In this case,
mono- and diarylation products were formed. On the other
hand, for the indolyl anion, only the C-arylation product
substitution at C3 product was observed.33b
Herein, we propose the use of these types of anions to study
reactivity and regiochemistry in an intramolecular nucleophilic
substitution in photostimulated reactions. To carry this out, we
synthesized precursors such as pyrrole 2-carboxamides (1) or
different nucleophilic centers: (i) C3, (ii) the nitrogen in the
pyrrole or indole ring, and (iii) the O- of the amide function.
We expected to obtain the C-substitution product, but the
O-substitution was the only product obtained, resulting in the
synthesis of a new family of 2-(1H-pyrrol-2-yl)benzo[d]oxazoles
(4) or 2-(1H-indol-2-yl)benzo[d]oxazoles (5). In a similar
manner, 3 has two main nucleophilic centers: (i) C2 in the indole
ring and (ii) the O- of the amide moiety; only O-substitution
product (6) was afforded
In view of the importance and applicability of 2-pyrrolyl and
indolyl benzoxazoles, we report here a practical and efficient
route to obtain these heterocycles from pyrrole and indole
carboxamides. As a first step, the synthetic strategy involves an
amidation reaction of different 2-haloanilines with 2-carboxylic
acid of pyrrole and 2- or 3-carboxylic acids of indole followed
by a photostimulated reaction in liquid ammonia (NH3(l)) or
DMSO as solvents.
Furthermore, we demonstrated mechanistic probes and
computational studies that suggest that these reactions occur
by a photoinduced electron transfer (ET).
RESULTS AND DISCUSSION
■
Pyrrole and indole carboxamides derivatives 1, 2, and 3 were
obtained by reaction of 2-carboxylic acid of pyrrole and 2- or 3-
carboxylic acid of indole with 2-haloanilines, following previously
reported methods19d,34 (Scheme 3). Within this approach, the acyl
1508
dx.doi.org/10.1021/jo202386b | J. Org. Chem. 2012, 77, 1507−1519

The Journal of Organic Chemistry
Article
Scheme 3. Synthesis of Amide Derivatives from 2-Carboxylic Acid of Pyrrole and 2- or 3-Carboxylic Acid of Indole
chloride was obtained and used without purification in a one-
pot procedure.
The reaction was shown not occur in the dark (entry 5,
Table 1), which would rule out an aryne or other polar
mechanism. If a good electron acceptor is added, such
p-dinitrobenzene (p-DNB), the product of the reaction is not
observed, which could be attributed to inhibiting electron trans-
fer events25 (entry 6, Table 1). Besides, the use of 20 mol %
of p-DNB results in complete inhibition of the substitution
reaction, which suggests the involvement of a chain mechanism.
Under the same conditions, substrate 1a was more reactive
than 1b and 1c (entries 4, 9, and 12, Table 1). For substrates
1b and 1c, longer reaction times and an excess of base were
required to achieve complete conversion (entries 7−13,
Table 1). However, the reactions of 1b and 1c demonstrate
that the reaction was useful for both chlorine- and bromine-
containing substrates. These results are in agreement with those
of the order of reactivity of the different halogens in photo-
stimulated SRN1 reactions (I > Br > Cl).25 In some cases,
reduced product 7a was detected (entries 8 and 10, Table 1),
which also indicates that aryl radicals are intermediates and that
The synthesis of 2-pyrrolyl benzoxazoles was initially studied
with N-(2-iodophenyl)-1H-pyrrole-2-carboxamide (1a) as a
model substrate. When 1a reacted under photostimulation
conditions with 2 equiv of t-BuOK as a base, 2-(1H-pyrrol-2-yl)-
benzo[d]oxazole 4a was obtained in 75% yield (liquid ammonia)
and in 73% yield (DMSO), following 2 h of irradiation (eq 1;
entries 1 and 3, Table 1). None of the reduction product 7a was
found.32,35 Complete conversion of 1a was accomplished by
extending the reaction time and afforded the ring closure
products 4a in quantitative yield (liquid ammonia) and in 83%
yield (DMSO) (entries 2 and 4, Table 1), respectively.36
a
Table 1. Photostimulated Reactions of Substrates 1a−c and 1i
b
c
d
−
entry
substrate (%)
solvent (conditions)
NH3(l)
base (equiv)
time (h)
4a (%)
X (%)
1
1a (25)
1a
2
2
2
2
2
2
4
4
2
4
4
2
4
2
4
4
2
3
2
3
3
3
3
4
3
3
5
3
5
3
3
3
75
80
100
75
2
NH3(l)
100
3
1a (27)
1a
DMSO
73
4
DMSO
83
100
<5
<5
72
e
5
1a (95)
DMSO (dark)
−
−
35
6
1a (>99)
1b (20)
1b
DMSO (20 mol % p-DNB)
7
NH3(l)
f
8
NH3(l)
60
91
g
9
1b
DMSO
62
64
h
10
11
12
13
14
15
16
1b
1c
DMSO
72
89
NH3(l)
44
79
g
1c
DMSO
48
47
1c
DMSO
57
11
70
g
1c
DMSO (34 mol % p-DNB)
23
g
i
1i
DMSO
NH3(l)
6 + 4i (44)
39
90
1i
96 (Br−) 78 (Cl−)
a
The reactions were run in 200 mL of liquid ammonia or 4 mL of DMSO, with 1 equiv of substrate (0.25 mmol) and t-BuOK as base. Irradiation
b
was conducted in a photochemical reactor equipped with two HPI-T 400 W lamps (cooled with water). Substrate recovered was determined by GC
(internal standard method). Yields were determined by GC (internal standard method). Halide ions were determined potentiometrically. Isolated
yield. 8% of reduced product 7a, isolated yield. Substrate was detected but not quantified. 9% of reduced product 7a, isolated yield. Only one
c
d
e
f
g
h
i
equivalent point was detected.
1509
dx.doi.org/10.1021/jo202386b | J. Org. Chem. 2012, 77, 1507−1519

The Journal of Organic Chemistry
Article
no polar reactions are involved. The photostimulated reaction
of 1c was inhibited in presence of p-DNB (entry 14, Table 1),
and only 11% yield of 4a was obtained; a similar behavior for
the substrate 1a was observed.
The pyrrole carboxamides 1 bear two hydrogens that can be
ionized under basic reaction conditions, the N−H of the
pyrrolyl moiety (N1) and the N−H of the carboxamide moiety
(N2) (Scheme 4). The pKas for these compounds are unknown
for liquid ammonia or DMSO.37 To gain further knowledge
into the type of anion actually formed, computational calcula-
tions were performed for 1b to estimate the pKa of each anion.
Using a DFT method with polarized continuum model (PCM)
to evaluate the effect of the solvent,38 it was determined that
the pyrrole anion 1-N1 is energetically more stable than the
amide anion 1-N2 by 2.1 kcal/mol.39
Scheme 4. Ionization of Pyrrole Carboxamide 1b in the
Basic Reaction Conditions
Other results that support the involvement of radical anions
as an intermediate is the reaction of the precursor 1i bearing
two leaving groups. In the photostimulated reaction of anion
1i− in DMSO, the product 4i with retention of chlorine was
obtained as the major product, and a low amount of 4a was
obtained without retention of chlorine (entry 15, Table 1).
When liquid ammonia was used as solvent, only product 4a was
achieved (entry 16, Table 1). Competition between inter-
molecular electron transfer (ETinter) and an intramolecular
electron transfer (ETintra) from a radical anion intermediate 11i
may account for this behavior (Scheme 5).25 In this system, we
To evaluate the importance of the pyrrolyl moiety in the
reaction, the photostimulated reaction of N-(2-bromophenyl)-
benzamide (8) with an excess of t-BuOK in DMSO was
performed (same experimental conditions as previously used in
Table 1), which gave no reaction at all, recovering the substrate
(eq 2). When 1.13 equiv of Ph2P− ions were used as electron
donors, reduced product N-phenylbenzamide 9 was obtained in
52% yield. These results indicate that the pyrrolyl moiety is
important not only to the initiation of the reaction but also for
the cyclization step.
Scheme 5. Competition ETinter and ETintra for Intermediate
11i
On the basis of the present and previous results, an SRN
1
mechanism was proposed to be operative in the reaction
described here (eqs 3−6). Substrate 1 forms the anion 1− in the
basic reaction conditions (eq 3); under irradiation, it receives
an electron from an adequate electron source.40 After
fragmentation of the C−X bond, the distonic radical anion
10 is formed (eq 4); the aryl radical 10 then couples at the
oxygen to give the conjugated radical anion 11. The radical
anion 11 affords the final product 4 by ET and is followed by
deprotonation/protonation events (eq 5). With some sub-
strates, the radical anion 10 can also be reduced by hydrogen
abstraction and protonation to yield 7 (eq 6).
propose that once the conjugated radical anion 11i is formed, it
can transfer its extra electron to the substrate (ETinter), and in
this case, the more stable tautomer 4i with retention of halogen
is formed. Alternatively, the ETintra to the C−Cl bond results in
fragmentation to form a radical 12 and ultimately leads to 4a.
On the basis of the concentration difference of anion 1i−, which
1510
dx.doi.org/10.1021/jo202386b | J. Org. Chem. 2012, 77, 1507−1519

The Journal of Organic Chemistry
Article
is greater in DMSO, the ETinter is faster than the ETintra process,
and a product with retention of the second halogen is obtained
in this solvent.
Scheme 7. Main Conformers for Radical Anion 11, C−C and
a
C−N Coupling
It has been established that anions from anilines and
phenols react by an intramolecular SRN1 mechanism in
photostimulated reactions.25,28−31 Some examples show
where aryl radicals can react with an oxygen nucleophile in
intramolecular reactions.41 The results of the computational
studies indicated that conformations of the distonic radical
anion are important in determining the regiochemistry of the
coupling.29 We decided to perform a detailed computational
study aimed at determining which electronic and/or geo-
metric factor was responsible for establishing the preferred
regiochemistry.
The system was investigated using computational modeling
with the DFT methodology and the B3LYP functional.38 The
anion 1-N1 exhibits various conformers; the more stable con-
former has a planar conformation (Figure S1 in the Supporting
Information). This conformer provides, after dissociative
electron transfer (DET), a distonic radical anion 10a. This inter-
mediate does not possess an appropriate geometry to afford C-, N-,
or O-coupling, so internal rotations were needed to give any of
the three possible coupling reactions (Scheme 6 and 7).42
a
Energies are in kcal mol−1.
Scheme 6. Main Conformers for Radical Anion 10, C−O
a
Coupling
The results illustrated in eq 8 agree with the experimental
results because 8 only provided the reduced product 9 when
initiation was achieved by the presence of Ph2P− ions (eq 2).
However, the proposed mechanism fails to explain the
experimental results in the case of compound 1b. There
does not exist an apparent reason to explain why the
calculation methodology is not adequate; DFT functionals
have been used to study different steps of SRN1 reaction.29,43
An alternative mechanism could be operant, which must have
common characteristics with the SRN1 mechanism, like ET
events and chain process, but having a different order of
steps.
The scope of photostimulated reactions for the synthesis
of various 6-substituted 2-(pyrrol-2-yl)benzoxazoles (4d−h)
were explored. The results of the photostimulated reaction
of 2-pyrrole carboxamides 1d−h in liquid ammonia and
DMSO, in the presence of excess t-BuOK, are presented in
Table 2 (eq 1).
a
Energies are in kcal mol−1.
Under these reaction conditions, very good to excellent
yields (78−91%) of 6-substituted 2-(pyrrol-2-yl)benzoxazole
4d−h are obtained; many substituents, such as electron-releasing
groups (Me, OMe) and electron-withdrawing groups (CN, OCF3,
CO2Et), were compatible with this reaction.
Therefore, substrates 2a−f and 3a,b were studied under
photostimulated conditions, affording good to excellent yields
of 2-(indol-2-yl) (5a−f) and 2-(indol-3-yl)benzoxazoles (6a,b)
(Scheme 8). With a similar behavior as 2-pyrrole carboxamides,
many substituents are compatible with this reaction. Results are
shown in Table 3.
Conformer 10a gives, after internal rotation (Earot = 4.2 kcal/mol),
10b, which affords conjugated radical anion 11b with a high
calculated activation energy of 23.6 kcal/mol. On the other hand,
internal rotation from 10a (Earot = 14.6 kcal/mol) is required
(Scheme 6) to give C−N (EaC−N = 2.7 kcal/mol) or C−C coupl-
ing (EaC−C = 1.9 kcal/mol) with a lower barrier (Scheme 7).
A similar analysis was performed for the radical anion derived
from 1-N2 and the anion of 8, which also gives high calculated
activation energies for the C−O coupling (eqs 7 and 8).
We decided to study the regiochemistry of the reaction in a new
system, changing the nature of the bridge. 2-Iodophenyl-1H-
indole-2-carboxylate (17), which has an ester function as a bridge
connecting the nucleophilic center and the leaving group, was
synthesized. Ester derivative 17 was obtained by reaction of
2-carboxylic acid indole and 2-iodophenol, following reported
methods19d (eq 9). When 17 reacted with 2.5 equiv of t-BuOK
1511
dx.doi.org/10.1021/jo202386b | J. Org. Chem. 2012, 77, 1507−1519

The Journal of Organic Chemistry
Article
that the nature of the bridge has a high impact on the coupling
step.
Table 2. Synthesis of 6-Substituted 2-(1H-Pyrrol-2-yl)benzo-
[d]oxazoles by Photostimulated Reactions
a
−
base
time
(h)
X
b
c
entry substrate solvent (equiv)
yield (%)
(%)
1
2
3
4
5
6
7
8
9
1d
1d
1e
1e
1f
NH3(l)
DMSO
NH3(l)
DMSO
NH3(l)
DMSO
NH3(l)
DMSO
NH3(l)
DMSO
2.5
4
3
4d (59) + 7d (36)
4d (85)
100
100
100
100
82
3
10
4.5
4.5
3
4e (40) + 7e (53)
4e (82) + 7e (14)
8
d
2.5
2.5
4
4f (78)
d
1f
3
4f (66)
72
e
CONCLUSIONS
1g
1g
1h
1h
3
4g (91)
99
■
e
2.5
4
3
4g (54)
63
We develop a simple and efficient synthetic strategy to obtain
2-pyrrolyl and indolyl benzoxazole derivatives by a photo-
stimulated process. This approach does not involve the use of
transition metals or drastic reaction conditions, and a variety of
substituents are tolerated under the reaction conditions
employed. In addition, we have shown that (i) the reaction
only occurs under photostimulation and (ii) the photo-
stimulated reaction was inhibited by p-DNB, which suggest
that there are probably electron transfer events.
f
3
4h (26)
4h (88)
85
f
10
4
3
91
a
The reactions were run in 200 mL of liquid ammonia or 4 mL of
DMSO, with 1 equiv of substrate (0.25 mmol) and t-BuOK as base.
Irradiation was conducted in a photochemical reactor equipped with
b
two HPI-T 400 W lamps (cooled with water). Yields were
c
determined by 1H NMR (internal standard method). Halide ions
d
e
were determined potentiometrically. Isolated yield. Yields were
determined by GC (internal standard method). The product was
f
From the computational results, the anion derivative from
the heterocycle is involved in the reaction. According to the
experimental results, an SRN1 mechanism is consistent with the
formation of the benzoxazol heterocycle; however, this fact was
not supported by quantum calculations.
The nature of the bridge in the precursor is important for the
regiochemistry of the reaction; in the case of the amide
derivatives, only O-substitution was achieved, whereas when an
ester derivative was employed as substrate, C-substitution was
observed.
obtained as its acid form. After the photostimulated reaction, the acid
was esterified and quantified as the ester.
Scheme 8. Photostimulated Reaction of Indole 2- and
3-Carboxamides
EXPERIMENTAL SECTION
■
Computational Procedures. All calculations were performed
with the Gaussian09 program.44 First, the most stable conformers of
1b and the anions 1-N1 and 1-N2 were evaluated through an AM1
conformational search by scanning the two or three main torsion
angles. The conformers thus obtained were then refined with complete
geometry optimization within the B3LYP45 DFT functional with the
6-31+G* basis set.
The radical anions that formed once the halides are released were
fully optimized with the same functional and the 6-31+G* basis set.
The geometries thus found were used as starting points for the
evaluation of the potential surface of the different reaction steps with
the same functional and the latter basis set and the reaction coordinate
approach.
The effect of the solvent was evaluated for all of the DFT calcula-
tions through Tomasi’s polarized continuum model (PCM),46 as
implemented in Gaussian09, using methanol and complete geometry
optimization. The characterization of stationary points was done by
Hessian matrix calculations. The energy informed for TSs, anions, and
radical anions includes zero-point corrections.
1
General Methods. H NMR (400.16 MHz), 13C NMR (100.62
under photostimulation in liquid ammonia as the solvent, only the
C-arylation product, chromeno[3,4-b]indol-6(7H)-one (18), was
obtained in 54% yield (eq 10; entry 1, Table 4). When the
reaction was carried out in DMSO, 18 was found in 19% yield
(entry 2, Table 4). To reduce the decomposition of the starting
material, 2-naphtoxide ion was used instead of t-BuOK as an
entrainment reagent. In this case, a similar behavior was observed
in liquid ammonia, and the yield of the cyclization product was
found to increase in DMSO (entries 3 and 4, Table 4).
MHz), and 19F NMR (376.50 MHz) were conducted on a high
resolution spectrometer 400 MHz in CDCl3, acetone-d6, and DMSO-
d6 as a solvent. Coupling constants are given in Hz, and chemical shifts
are reported in ppm. Data are reported as follows: chemical shift,
integration, multiplicity (s = singlet, s br = broad singlet, d = doublet,
t = triplet, dd = double doublet, dt = double triplet, ddd = double
double doublet, m = multiplet), and coupling constants (J). Gas
chromatographic (GC) analyses were performed on an instrument
with a flame ionization detector equipped with a VF-5ms column
(30 m × 0.25 mm × 0.25 μm). GC−MS analyses were carried out on a
GC−MS equipped with a quadrupole detector and a VF-5ms column
(30 m × 0.25 mm × 0.25 μm). High resolution mass spectra were
performed in a MS/MS instrument in pure products. These data were
In this case, the photostimulated reaction of 17 afforded the
C−C arylation product 18, and the regiochemistry was
according to expectations for an SRN1 reaction. This indicated
1512
dx.doi.org/10.1021/jo202386b | J. Org. Chem. 2012, 77, 1507−1519

The Journal of Organic Chemistry
Article
Table 3. Synthesis of 6-Substituted 2-(1H-Indol-2-yl)benzo[d]oxazoles (5a-f) and 2-(1H-Indol-3-yl)benzo[d]oxazoles (6a−b)
a
by Photostimulated Reactions
b
c
entry
substrate
solvent (conditions)
base (equiv)
time (h)
yield (%)
X− (%)
d
1
2
3
4
5
6
2a
2a
2b
2b
2c
2c
2c
2d
2d
2e
2e
2f
NH3(l)
2.5
2.5
2.5
2.5
8
3
5a (85)
100
100
80
d
DMSO
NH3(l)
3
5a (94)
3
5b (60)
5b (86)
5c (74)
DMSO
NH3(l)
3
100
93
4.5
4.5
4.5
3
DMSO
DMSO (dark)
NH3(l)
8
5c (34) 15c (30)
100
<7
e
7
8
5c (−)
f
8
4
5d (75)
88
f
9
DMSO
NH3(l)
4
3
5d (19)
70
g
10
11
12
13
14
15
16
4
6
5e (42)
100
g
DMSO
NH3(l)
4
6
5e (19)
82
d
4
3
5a (32)
75 (Br−) 61 (Cl−)
2f
DMSO
NH3(l)
4
3
5f (6) 5a (16)
6a (41) 16a (25)
6a (66)
79 (Br−) 44 (Cl−)
h
3a
3a
3b
4
3
DMSO
DMSO
4
3
84
93
f
4
3
6b (80)
a
The reactions were run in 200 mL of liquid ammonia or 4 mL of DMSO, with 1 equiv of substrate (0.25 mmol) and t-BuOK as base. Irradiation
b
1
was conducted in a photochemical reactor equipped with two HPI-T 400 W lamps (water refrigerated). Yields were determined by H NMR
(internal standard method). Halide anions were determined potentiometrically. Yields were determined by GC (internal standard method). The
substrate was recovered almost quantitatively. Isolated yields. The product was obtained as its acid form. After the photostimulated reaction, the
acid was esterified and quantified as the ester. The product 16a was not isolated but detected by GC−MS and quantified assuming the same
response as 6a.
c
d
e
f
g
h
a
oxalyl chloride (1 mL) for 1 h. The oxalyl chloride was then eva-
porated, and the resulting solid was dissolved in anhydrous dichloro-
methane (3 mL). The reaction was cooled in an ice bath, and 2-
haloaniline (5 mmol) was added. After addition, the mixture was
warmed to rt and stirred overnight. Water (100 mL) was then added,
and the reaction mixture was extracted with dichloromethane (3 × 30 mL).
The organic layer was washed with a solution of HCl 10% (3 × 30 mL),
dried over anhydrous sodium sulfate, filtered, and concentrated in vacuum.
The product was purified by chromatography on silica gel.
Table 4. Photostimulated Reactions of 17
b
c
entry
solvent
base (equiv) 2-naphtol (equiv) 18 (%)
I− (%)
1
2
3
4
NH3(l)
DMSO
NH3(l)
DMSO
2.5
2.5
3
54
19
48
47
85
46
60
57
d
2
4
5
a
The reactions were run in 200 mL of liquid ammonia or 4 mL of
DMSO, with 1 equiv. of 17 (0.25 mmol) and t-BuOK as base.
Irradiation (2.5 h) was conducted in a photochemical reactor equipped
with two HPI-T 400 W lamps (cooled with water). Yields were
The compounds 1a, 1b, 1d, 1f, 1i, 2a, 2b, and 2f were previously
reported and spectroscopy data are in agreement with the literature.19d
b
1
Copies of H and 13C spectra are in the Supporting Information.
c
determined by GC (internal standard method). Halide ions were
N-(2-Chlorophenyl)-1H-pyrrole-2-carboxamide (1c). The
amide was purified by column chromatography on silica gel eluting
with a petroleum ether/CH2Cl2 gradient (100:0 → 30:70) as white
d
determined potentiometrically. Isolated yield.
1
obtained by ESI or APPI mode ionization and TOF detection. Melting
points were performed with an electrical instrument and are
uncorrected. Irradiation was conducted in a reactor equipped with
two HPI-T 400 W lamps (cooled with water). The maxima of emis-
sion of the lamps used are 380−390, 420, 460, 560, and 600 nm.47
Potentiometric titration of halide ions was performed in a pH-meter
solid, mp 145.0−146.0 °C. H NMR (400 MHz, CDCl3) δH: 6.32
(1H, m); 6.78−6.79 (1H, m); 7.02−7.03 (1H, m); 7.05−7.07 (1H,
m); 7.28−7.32 (1H, m); 7.40 (1H, dd, J = 8.1, 1.5); 8.19 (1H, s br);
8.48 (1H, dd, J = 8.3, 1.5); 9.70 (1H, s br). 13C NMR (101 MHz,
CDCl3) δC: 110.0 (CH); 110.4 (CH); 121.2 (CH); 122.6 (C); 122.8
(CH); 124.3 (CH); 125.9 (C); 127.8 (CH); 129.1 (CH); 134.7 (C);
using an Ag/Ag+ electrode. Quantification by GC and H NMR was
1
1
158.8 (C). H−1H COSY NMR (CDCl3) δH/δH: 6.32/6.79; 6.32/
7.02; 7.06/7.30; 7.06/7.40; 7.30/8.48. 1H−13C HSQC NMR (CDCl3)
δH/δC: 6.32/110.4; 6.79/110.0; 7.02/122.8; 7.06/124.3; 7.30/127.8;
7.40/129.1; 8.48/121.2. 1H−13C HMBC NMR (CDCl3) δH/δC: 6.32/
122.9; 6.32/125.9; 6.79/122.9; 6.79/125.9; 7.02/110.4; 7.02/125.8;
7.05/121.1; 7.05/122.5; 7.30/121.2; 7.30/122.6; 7.40/122.7; 7.40/
129.1; 8.48/121.2; 8.48/122.8; 8.48/124.4; 8.48/134.8. GC−MS
(m/z): 220 (24, M+); 185 (54); 129 (30); 127 (100); 94 (59); 66
(30). HRMS (ESI) [M + H+] calcd for C11H10ClN2O+ 221.0476,
found 221.0477.
performed by the internal standard method.
Materials. 1H-Pyrrole-2-carboxylic acid, 1H-indole-2-carboxylic
acid, 1H-indole-3-carboxylic acid, oxalyl chloride, 2-iodoaniline,
2-chloroaniline, 2-bromoaniline, 2-bromo-4-(trifluoromethoxy)aniline,
2-bromo-4-methylaniline, 2-iodophenol, 1,1′-carbonyldiimidazole,
benzoyl chloride, potassium tert-butoxide, and 1,4-dinitrobenzene
were commercially available and used as received from the supplier.
2-Bromo-4-chloroaniline, 4-amino-3-bromobenzonitrile, 2-bromo-4-
methoxyaniline, and ethyl 4-amino-3-bromobenzoate were obtained by
reported methods.48 THF was dried over Na metal and stored under
nitrogen, over molecular sieves (4 Å). CH2Cl2 was distilled and stored
over molecular sieves (4 Å). DMSO was stored over molecular sieves
(4 Å). Silica gel (0.063−0.200 mm) was used in column chromatography.
Representative Procedure for the Synthesis of Amide
Derivatives 1a−i, 2a−f, and 3a−b. The procedure is representative
of all these reactions, following previous reports.19d,34 They were
carried out in a 25 mL three-neck round-bottomed flask equipped with
nitrogen inlet and magnetic stirrer. 1H-Pyrrole, 1H-indole 2-carboxylic
acid, or 1H-indole 3-carboxylic acid (2 mmol) was heated at 50 °C in
N-(2-Bromo-4-methoxyphenyl)-1H-pyrrole-2-carboxamide
(1e). The amide was purified by column chromatography on silica gel
eluting with a petroleum ether/diethyl ether gradient (80:20 → 0:100)
and recrystallized in petroleum ether as white needle crystals, mp
200.0−201.0 °C. 1H NMR (400 MHz, CDCl3) δH: 3.80 (3H, s); 6.31
(1H, s); 6.76 (1H, s); 6.91 (1H, dd, J = 9.0, 2.3); 7.00 (1H, s br); 7.13
(1H, d, J = 2.3); 7.96 (1H, s br); 8.27 (1H, d, J = 9.0); 9.62 (1H, s br).
13C NMR (101 MHz, CDCl3) δC: 55.7 (OCH3); 109.7 (CH); 110.3
(CH); 114.0 (CH); 114.3 (C); 117.6 (CH); 122.5 (CH); 122.8
1
(CH); 125.9 (C); 129.1 (C); 156.3 (C); 158.7 (C). H−1H COSY
1513
dx.doi.org/10.1021/jo202386b | J. Org. Chem. 2012, 77, 1507−1519

The Journal of Organic Chemistry
Article
NMR (CDCl3) δH/δH: 6.31/6.76; 6.91/7.13; 6.91/8.27; 7.00/6.31;
N-(2-Bromo-4-(trifluoromethoxy)phenyl)-1H-indole-2-car-
boxamide (2d). The amide was purified by column chromatography
on silica gel eluting with petroleum ether/CH2Cl2 gradient (90:10 →
20:80) as needle-like white crystals, mp 219.0−220.0 °C. H NMR
1
7.13/6.91; 8.27/6.91. H−13C HSQC NMR (CDCl3) δH/δC: 3.80/
55.7; 6.31/110.3; 6.76/109.7; 6.91/114.0; 7.00/122.5; 7.13/117.6;
8.27/122.8. 1H−13C HMBC NMR (CDCl3) δH/δC: 3.80/156.3; 6.76/
122.5; 6.91/117.6; 6.91/129.1; 7.00/109.7; 7.00/110.3; 7.00/125.9;
7.13/114.0; 7.13/129.1; 7.13/156.3; 8.27/114.3; 8.27/129.1; 8.27/
156.3. GC−MS (m/z): 296 (14, M+ + 1); 294 (15); 215 (12); 204
(9); 203 (100); 202 (14); 201 (99); 200 (8); 188 (36); 186 (47); 106
(14); 95 (8); 94 (83); 93 (6); 80 (9); 79 (17); 78 (13); 66 (71); 65
(13); 63 (10); 52 (14); 51 (11). HRMS (ESI) [M + H+] calcd for
1
(400 MHz, CDCl3) δH: 7.10 (1H, d, J = 1.6); 7.17−7.21 (1H, m),
7.27−7.29 (1H, m); 7.32−7.36 (1H, m); 7.46 (1H, d, J = 8.4); 7.51
(1H, d, J = 2.0); 7.72 (1H, d, J = 8.0); 8.47 (1H, s br); 8.59 (1H, d, J =
8.8); 9.44 (1H, s br). 13C NMR (101 MHz, CDCl3) δC: 103.5 (CH);
112.1 (CH); 113.2 (C); 120.4 (CF3, q, J = 256); 121.2 (CH); 121.4
(CH); 121.9 (CH); 122.3 (CH); 125.2 (CH); 125.5 (CH); 127.6 (C)
; 130.0 (C); 134.5 (C); 136.9 (C); 144.9 (C); 159.4 (C). 19F NMR
+
C12H12BrN2O2 295.0077, found 295.0081.
1
(377 M, CDCl3) δF: −58.20. H−1H COSY NMR (CDCl3) δH/δH:
N-(2-Bromo-4-(trifluoromethoxy)phenyl)-1H-pyrrole-2-car-
7.10/9.44; 7.19/7.34; 7.19/7.72; 7.28/7.51; 7.28/8.59; 7.34/7.46.
1H−13C HSQC NMR (CDCl3) δH/δC: 7.10/103.5; 7.19/121.2; 7.28/
121.4; 7.34/125.5; 7.46/112.1; 7.51/125.2; 7.72/122.3; 8.59/121.9.
GC/MS (m/z): 399 (2, M+); 319 (21); 145 (10); 144 (100); 143
(24); 116 (28); 115 (17); 89 (66); 69 (17); 63 (12). HRMS (ESI)
boxamide (1g). The product was isolated as white solid, mp 154.8−
1
156.6 °C. H (400 MHz, CDCl3) δH: 6.34 (1H, m), 6.80 (1H, m),
7.04 (1H, m), 7.20−7.49 (1H, m), 7.50−7.74 (1H, ddd, J = 70.7,
5.7, 3.3); 8.15 (1H, s br); 8.52 (1H, d, J = 9.11), 9.34 (1H, s br).19F
(377 MHz, CDCl3) δF: −58.24. 13C NMR (101 MHz, CDCl3) δC:
110.4 (CH); 110.6 (CH); 112.9 (C); 121.3 (CH); 121.7 (CH); 123.2
(CH); 125.1 (CH); 125.5 (C); 134.8 (C); 144.5 (C); 158.7 (C).
1H−1H COSY NMR (CDCl3) δH/δH: 6.34/6.81; 6.34/7.04; 6.80/
7.04; 7.35/8.52. GC−MS (m/z): 348 (3, M+ − 1); 269 (14); 257
(25); 255 (22); 94 (100); 69 (19); 66 (46). HRMS (ESI) [M + H+]
+
[M + H+] calcd for C16H10BrF3N2O2 398.9951, found 398.9968.
Ethyl 3-Bromo-4-(1H-indole-2-carboxamido)benzoate (2e).
The amide was purified by column chromatography on silica gel
eluting with petroleum ether/diethyl ether gradient (100:0 → 50:50)
1
as a yellow solid, mp 235.0−236.0 °C. H NMR (400 MHz, DMSO-
+
d6) δH: 1.35 (3H, t, J = 7.2); 4.35 (2H, q, J = 7.2); 7.07−7.11 (1H, m),
7.23−7.27 (1H, m); 7.43−7.49 (1H, m); 7.48 (1H, d, J = 8.1); 7.70
(1H, d, J = 8.1); 7.90 (1H, d, J = 8.4); 8.02 (1H, dd, J = 8.4, 1.9); 8.22
(1H, d, J = 1.9); 10.04 (1H, s br); 11.86 (1H, s br). 13C NMR (101
MHz, DMSO-d6) δC: 14.6 (CH3); 61.7 (CH2); 105.1 (CH); 112.9
(CH); 119.1(C); 120.6 (CH); 122.4 (CH); 124.6 (CH); 127.4 (CH);
127.6 (C); 128.8 (CH); 129.4 (C); 131.0 (C) ; 133.8 (CH); 137.5
(C); 140.9 (C); 160.1 (C); 164.7 (C). 1H−1H COSY NMR (DMSO-
d6) δH/δH: 1.35/4.35; 7.09/7.25; 7.09/7.70; 7.25/7.48; 7.43/11.86;
7.90/8.02. 1H−13C HSQC NMR (DMSO-d6) δH/δC: 1.35/14.6; 4.35/
61.7; 7.09/120.6; 7.25/124.6; 7.43/105.1; 7.48/112.9; 7.70/122.4;
calcd C12H9BrF3N2O2 348.9794, found 348.9820.
Ethyl 3-Bromo-4-(1H-pyrrole-2-carboxamido)benzoate (1h).
The amide was purified by radial thin-layer chromatography on silica
gel eluting with a petroleum ether/diethyl ether gradient (50:50) and
recrystallized in acetone as white needle crystals, mp 202.8−203.6 °C.
1H NMR (400 MHz, DMSO-d6) δH: 1.32 (3H, t, J = 7.1); 4.32 (2H, q,
J = 7.1); 6.19−6.21 (1H, m); 7.02−7.03 (1H, m); 7.06−7.07 (1H, m);
7.91 (1H, d, J = 8.5); 7.97 (1H, dd, J = 8.5, 1.8); 8.17 (1H, d, J = 1.8),
9.43 (1H, s br), 11.82 (1H, s br). 13C NMR (101 MHz, DMSO-d6) δC:
14.6 (CH3); 61.6 (CH2); 109.7 (CH); 112.7 (CH); 118.0 (C); 123.9
(CH); 125.6 (C); 126.5 (CH); 128.0 (C); 129.4 (CH); 133.7 (CH);
1
7.90/127.4; 8.02/128.8; 8.22/133.8. H−13C HMBC NMR (DMSO-
1
141.2 (C); 159.2 (C); 164.7 (C). H−1H COSY NMR (DMSO-d6)
d6) δH/δC: 1.35/61.7; 4.35/14.6; 4.35/164.7; 7.09/112.9; 7.09/127.4;
7.25/122.4; 7.25/137.5; 7.43/127.6; 7.43/127.4; 7.43/137.5; 7.48/
120.6; 7.48/127.6; 7.70/124.6; 7.90/119.1; 7.90/128.8; 8.02/133.8;
8.02/140.9; 8.02/164.7; 8.22/119.1; 8.22/129.6; 8.22/140.9; 10.04/
160.1; 11.86/127.6. HRMS (ESI) [M + Na+] calcd for C18H15Br-
N2O3Na+ 409.0158, found 409.0158.
1
δH/δH: 1.32/4.32; 6.20/7.07; 7.03/11.82; 8.17/7.97. H−13C HSQC
NMR (DMSO-d6) δH/δC: 1.32/14.6; 4.32/61.6; 6.20/109.7; 7.02/
123.9; 7.07/112.7; 7.91/126.5; 7.97/129.4; 8.17/133.7. 1H−13C
HMBC NMR (DMSO-d6) δH/δC: 1.32/61.6; 4.32/14.6; 4.32/164.7;
7.02/109.7; 7.02/125.6; 7.91/118.0; 7.91/128.0; 7.97/133.7; 7.97/
141.2; 7.97/164.7; 8.17/118.0; 8.17/129.4; 8.17/141.2; 8.17/164.7;
9.43/118.0; 9.43/126.5; 8.17/159.2. GC−MS (m/z): 338 (15, M+ + 1);
336 (16, M+ − 1); 258 (17); 257 (72); 245 (48); 244 (7); 243 (52);
217 (19); 215 (20); 200 (28); 199 (7); 198 (32); 94 (100); 90 (11);
66 (40). HRMS (ESI) [M + Na+] calcd for C14H13BrN2O3Na+ 359.0002,
found 359.0023.
N-(2-Bromophenyl)-1H-indole-3-carboxamide (3a). The
amide was purified by column chromatography on silica gel eluting
with petroleum ether/diethyl ether gradient (100:0 → 70:30) as a
palid orange solid, mp 204.0−205.0 °C (lit. 197 °C).49 1H NMR (400
MHz, CDCl3) δH: 7.14−7.23 (3H, m); 7.40−7.44 (1H, m); 7.44−7.51
(1H, m); 7.71 (1H, dd, J = 8.0, 1.3); 7.74 (1H, dd, J = 8.0, 1.5); 8.16−
8.18 (1H, m); 8.31 (1H, d, J = 2.8); 9.34 (1H, s br); 11.79 (1H, s br).
13C NMR (101 MHz, CDCl3) δC: 110.5 (C); 112.6 (CH); 119.6 (C);
121.3 (CH); 121.3 (CH); 122.7 (CH); 126.6 (C); 127.2 (CH); 128.3
(CH); 128.4 (CH); 129.6 (CH); 133.0 (CH); 136.8 (C); 137.3 (C);
N-(2-Bromo-4-methoxyphenyl)-1H-indole-2-carboxamide
(2c). The amide was purified by radial thin-layer chromatography
eluting with a petroleum ether/diethyl ether gradient (90:10 → 80:20)
and recrystallized in CH2Cl2 as white needle crystals, mp 182.7−
1
1
163.5 (C). H−1H COSY NMR (CDCl3) δH/δH: 7.18/7.42; 7.18/
183.4 °C. H NMR (400 MHz, CDCl3) δH: 3.81 (3H, s); 6.94 (1H,
7.50; 7.18/7.71; 7.18/8.17; 7.42/7.74; 8.31/11.79. 1H−13C HSQC
NMR (CDCl3) δH/δC: 7.18/121.3; 7.18/122.7; 7.18/127.2; 7.42/
128.4; 7.50/112.6; 7.71/133.0; 7.74/128.3, 8.17/121.3, 8.31/129.6.
1H−13C HMBC NMR (CDCl3) δH/δC: 7.18/112.6; 7.18/119.6; 7.18/
dd, J = 9.1, 2.8); 7.06 (1H, d, J = 1.2); 7.17−7.19 (2H, m); 7.29−7.33
(1H, m); 7.46 (1H, d, J = 8.3); 7.70 (1H, d, J = 8.0); 8.30 (1H, s); 8.37
(1H, d, J = 9.1); 9.73 (1H, s). 13C NMR (101 MHz, CDCl3) δC: 55.7
(OCH3); 102.8 (CH); 112.1 (CH); 114.0 (CH); 114.5 (C); 117.6
(CH); 120.9 (CH); 122.1 (CH); 123.0 (CH); 125.0 (CH); 127.6
121.3; 7.18/126.6; 7.18/127.2; 7.18/128.3; 7.18/136.8; 7.42/119.6;
7.42/133.0; 7.42/137.3; 7.50/121.3; 7.50/126.6; 7.50/133.0; 7.71/
119.6; 7.71/128.4; 7.71/137.3; 7.73/119.6; 7.73/127.2; 8.17/110.5;
8.17/122.7; 8.17/136.8; 8.31/110.5; 8.31/126.6; 8.31/136.8; 8.30/
129.6; 9.34/119.6; 9.34/128.4; 9.34/163.5; 11.79/110.5; 11.79/126.6.
GC/MS (m/z): 316 (10), 314 (2), 313 (10), 235 (32), 173 (24), 171
(19), 145 (15), 144 (100), 118 (14), 116 (26), 89 (25).
1
(C); 128.8 (C); 130.6 (C); 136.8 (C); 156.6 (C); 159.4 (C). H−1H
COSY NMR (CDCl3) δH/δH: 6.94/7.16; 6.94/8.34; 7.06/9.73; 7.17/
7.30; 7.17/7.70; 7.31/7.46. 1H−13C HSQC NMR (CDCl3) δH/δC:
3.81/55.7; 6.93/114.0; 7.06/102.8; 7.17/117.6; 7.16/120.9; 7.31/
125,0; 7.45/112.1; 7.69/122.1; 8.36/123.0 1H−13C HMBC NMR
(CDCl3) δH/δC: 3.81/156.6; 6.94/117.6; 6.94/128.8; 6.94/156.6;
7.06/127.6; 7.06/130.56; 7.06/136.8; 7.17/112.1; 7.17/114.0; 7.17/
127.6; 7.31/122.1; 7.31/136.8; 7.45/120.9; 7.46/127.6; 7.70/102.8;
7.70/112.1; 7.70/125.0; 7.70/136.8; 8.30/114.5; 8.30/123.0; 8.30/
159.4; 8.37/114.5; 8.37/128.7; 8.37/156.6; 9.74/127.6. GC−MS (m/z):
347 (5); 346 (37); 344 (35); 266 (17); 265 (98); 203 (100); 201 (93);
188 (18); 186 (23); 144 (66); 116 (29); 115 (12); 89 (61); 63 (10).
HRMS (ESI) [M + H+] calcd for C16H14BrN2O2+ 345.0233, found
345.0247.
N-(2-Bromo-4-methylphenyl)-1H-indole-3-carboxamide
(3b). The amide was obtained by the reported methodology and was
purified by radial thin-layer chromatography eluting with petroleum
ether/diethyl ether (50:50) and was isolated as white solid, mp 208.5−
1
210.1 °C. H NMR (400 MHz, acetone-d6) δH: 2.32 (3H, s); 7.20−
7.26 (3H, m); 7.48 (1H, m); 7.52−7.55 (1H, m); 8.21 (2H, dd, J =
5.6, 2.6); 8.30 (1H, dd, J = 5.2, 4.0); 8.47 (1H, s br); 10.95 (1H, s br).
13C NMR (101 MHz, acetone-d6) δC: 20.5 (CH3); 112.4 (C); 113.0
1514
dx.doi.org/10.1021/jo202386b | J. Org. Chem. 2012, 77, 1507−1519

The Journal of Organic Chemistry
Article
(CH); 115.6 (C); 121.6 (CH); 122.1 (CH); 123.5 (CH); 124.5
(CH); 126.8 (C); 129.4 (CH); 129.6 (CH); 133.4 (CH); 135.3 (C);
Preparation of Chromeno[3,4-b]indol-6(7H)-one Derivatives
in DMSO. This product was obtained following the same procedure
for benzoxazole derivatives.
1
136.0 (C); 137.8 (C); 163.6 (C). H−1H COSY NMR (acetone-d6)
2-(1H-Pyrrol-2-yl)benzo[d]oxazole (4a). The benzoxazole was
purified by radial thin-layer chromatography eluting with petroleum
ether/diethyl ether (90:10 → 50:50) and was isolated as a white solid,
mp 159.0−161.0 °C (lit. 149 °C).50 1H NMR (400 MHz, CDCl3) δH:
6.38−6.39 (1H, m); 7.04−7.05 (1H, m); 7.10 (1H, m); 7.28−7.35
(2H, m); 7.53−7.55 (1H, m); 7.65−7.68 (1H, m); 10.51 (1H, s br).
13C NMR (101 MHz, CDCl3) δC: 110.4 (CH); 110.8 (CH); 113.2
δH/δH: 7.23/7.55; 7.23/8.21; 7.23/8.30; 7.54/8.30; 8.21/10.95.
1H−13C HSQC NMR (acetone-d6) δH/δC: 2.32/20.5; 7.23/122.1;
7.23/123.5; 7.23/129.6; 7.48/133.4; 7.54/113.0; 8.21/129.4; 8.22/
1
124.5; 8.31/121.6. H−13C HMBC NMR (acetone-d6) δH/δC: 2.32/
129.6; 2.32/133.4; 2.32/136.0; 7.23/113.0; 7.23/121.6; 7.23/133.4;
7.23/135.3; 7.48/115.6; 7.48/129.6; 7.48/135.3; 7.54/122.1; 8.21/
112.4; 8.21/115.6; 8.21/126.8; 8.21/135.9; 8.21/137.8; 8.30/123.5.
GC−MS (m/z): 331 (2); 330 (13); 328 (11, M+); 249 (26); 187
(61); 186 (8); 185 (65); 144 (100); 116 (36); 106 (15); 89 (27).
HRMS (ESI) [M + H+] calcd for C16H13BrN2O+ 329.0284, found
329.0303.
Procedure for the Synthesis of N-(2-Bromophenyl)-
benzamide (8). To a Schlenk tube was added 10 mL of CH2Cl2, 2
mmol of 2-bromoaniline (344 mg, 0.226 mL), and 2.5 mmol of
triethylamine (253 mg, 0.348 mL). The reaction was cooled in an ice
bath, and 2.5 mmol of benzoyl chloride (0.290 mL) was added. After
addition, the mixture was warmed to rt and stirred overnight. Water
(100 mL) was added, and the reaction mixture was extracted with
dichloromethane (3 × 30 mL). The organic layer was washed with a
solution of HCl 10% (3 × 30 mL), dried with anhydrous sodium
sulfate, filtered, and concentrated in vacuum. The product 8 was ob-
tained in 90% (497 mg) isolated yield as yellowish solid, mp 105.0−
106.0 °C (lit. 107.0−108.0 °C).49 1H NMR (400 MHz, CDCl3) δH:
7.00−7.04 (1H, m); 7.36−7.40 (1H, m); 7.51−7.61 (4H, m); 7.95
(2H, d, J = 7.2); 8.47 (1H, s br); 8.56 (1H, dd, J = 8.3, 1.1). 13C NMR
(101 MHz, CDCl3) δC: 113.8 (C); 121.8 (CH), 125.3 (CH); 127.1
(CH); 128.6 (CH); 129.0 (CH); 132.2 (CH); 132.3 (CH); 134.6
(C); 135.8 (C); 165.3 (C).
(CH); 118.8 (CH); 119.8 (C); 123.0 (CH); 124.4 (CH); 124.6
(CH); 141.8 (C); 150.2 (C); 158.2 (C). 1H−1H COSY NMR
1
(CDCl3) δH/δH: 6.38/7.05; 6.38/7.10; 7.32/7.54; 7.32/7.66. H−13C
HSQC NMR (CDCl3) δH/δC: 6.38/110.8; 7.05/123.0; 7.10/113.2;
7.32/124.4; 7.32/124.6; 7.54/110.4; 7.66/118.8. 1H−13C HMBC
NMR (CDCl3) δH/δC: 6.38/113.2; 6.38/119.8; 6.38/123.0; 7.05/
110.8; 7.05/113.2; 7.10/119.8; 7.10/123.0; 7.32/118.8; 7.32/141.8;
7.32/150.4; 7.54/124.4; 7.54/124.6; 7.54/141.8; 7.54/150.2; 7.66/
124.4; 7.66/124.5; 7.66/141.9; 7.66/150.2. 1H−1H NOESY NMR
(CDCl3) δH/δH: 6.38/7.09; 7.05/6.38; 7.05/10.51. GC−MS (m/z):
185 (13); 184 (100, M+); 92 (11); 64 (13); 63 (13).
6-Methyl-2-(1H-pyrrol-2-yl)benzo[d]oxazole (4d). The ben-
zoxazole was purified by radial thin-layer chromatography on silica gel
eluting with a petroleum ether/diethyl ether gradient (80:20 → 50:50)
1
as white crystals, mp 168.0−170.0 °C. H NMR (400 MHz, CDCl3)
δH: 2.48 (3H, s); 6.34−6.37 (1H, m); 7.00−7.02 (1H, m); 7.06−7.08
(1H, m); 7.12 (1H, d, J = 7.9); 7.33 (1H, s); 7.52 (1H, d, J = 8.2);
10.97 (1H, s br). 13C NMR (101 MHz, CDCl3) δC: 21.7 (CH3); 110.6
(2 CH); 112.9 (CH); 118.1 (CH); 119.9 (C); 122.9 (CH); 125.7
1
(CH); 134.7 (C); 139.5 (C); 150.4 (C); 158.0 (C). H−13C HSQC
NMR (CDCl3) δH/δC: 2.48/21.7; 6.35/110.6; 7.01/122.9; 7.07/112.9;
1
7.12/125.7; 7.33/110.7; 7.52/118.1. H−13C HMBC NMR (CDCl3)
δH/δC: 2.48/110.6; 2.48/125.7; 2.48/134.7; 6.35/119.9; 6.35/122.9;
7.01/110.6; 7.01/112.9; 7.01/119.9; 7.07/119.9; 7.07/122.9; 7.12/
21.7; 7.12/110.7; 7.12/139.5; 7.33/21.7; 7.33/118.1; 7.33/125.7;
7.33/139.5; 7.33/150.4; 7.52/110.7; 7.52/134.7; 7.52/150.4. GC−
MS (m/z): 199 (13); 198 (100, M+); 197 (50); 169 (14); 99 (8); 94
(8); 78 (15); 77 (9); 52 (7); 51 (8). HRMS (ESI) [M + H+] calcd for
C12H11N2O+ 199.0866, found 199.0886.
Procedure for the Synthesis of 2-Iodophenyl-1H-indole-2-
carboxylate (17). The amide was obtained by the reported method-
ology. The spectroscopy data of product 17 is in agreement with the
literature.19d Copies of 1H and13 C spectra are in the Supporting
Information.
Representative Procedure for Photostimulated Rea-
ctions. Preparation of Benzoxazole Derivatives in Liquid
Ammonia. The following procedure is representative for all these
reactions. Liquid ammonia (200 mL), previously dried over Na metal,
was distilled into a 250 mL three-necked, round-bottomed flask equipped
with a coldfinger condenser, a nitrogen inlet, and a magnetic stirrer. The
base (t-BuOK) and then the substrate were added to the liquid ammonia,
and the solution was irradiated for the time specified for each substrate.
The reaction was quenched with an excess of ammonium nitrate, and
the liquid ammonia was allowed to evaporate. Water was added to the
residue, and the mixture was extracted with CH2Cl2 (3 × 30 mL). The
organic layer was washed with water, dried over anhydrous sodium
sulfate, filtered, and the solvent was removed to leave the crude products.
The products were separated and isolated by chromatography on silica
gel. The yield of halide ions in the aqueous solution were determined
potentiometrically.
Preparation of Benzoxazole Derivatives in DMSO. The
following procedure is representative for all these reactions. The
reaction was carried out in a flame-dried Schlenk tube equipped with a
nitrogen inlet and magnetic stirrer. Dried DMSO (4 mL) was
deoxygenated, the t-BuOK and the substrate were added, and the
reaction mixture was irradiated for the time specified for each sub-
strate. The reaction was quenched with water and ammonium nitrate
in excess. The residue was extracted with CH2Cl2 (3 × 30 mL). The
organic layer was washed with water, dried over anhydrous sodium
sulfate, filtered, and the solvent was removed to leave the crude
products. The products were separated and isolated by chromatog-
raphy on silica gel. The halide ions in the aqueous solution were deter-
mined potentiometrically.
6-Methoxy-2-(1H-pyrrol-2-yl)benzo[d]oxazole (4e). The ben-
zoxazole was purified by radial thin-layer chromatography on silica gel
eluting with a petroleum ether/diethyl ether gradient (75:25 → 0:100)
1
as white crystals, mp 137.1−137.6 °C. H NMR (400 MHz, CDCl3)
δH: 3.87 (3H, s); 6.35−6.37 (1H, m); 6.92 (1H, dd, J = 8.7, 2.3);
7.00−7.04 (2H, m); 7.08 (1H, d, J = 2.3); 7.53 (1H, d, J = 8.7); 10.55
(1H, s br). 13C NMR (101 MHz, CDCl3) δC: 55.9 (OCH3); 95.7
(CH); 110.6 (CH); 112.3 (CH); 112.4 (CH); 118.7 (CH); 120.0
(C); 122.6 (CH); 135.4 (C); 150.9 (C); 157.5 (C); 157.7 (C).
1H−1H COSY NMR (CDCl3) δH/δH: 6.36/7.02; 6.92/7.08; 6.92/
1
7.53. H−13C HSQC NMR (CDCl3) δH/δC: 3.87/55.9; 6.36/110.6;
1
6.92/112.3; 7.01/122.6; 7.03/112.4; 7.08/95.7; 7.53/118.7. H−13C
HMBC NMR (CDCl3) δH/δC: 3.87/157.7; 6.36/120.0; 6.36/122.6;
6.92/95.7; 6.92/135.4; 6.92/157.7; 7.01/110.6; 7.01/112.3; 7.01/
120.0; 7.03/122.5; 7.08/112.4; 7.08/135.4; 7.08/150.9; 7.08/157.7;
7.53/95.7; 7.53/135.4; 7.53/150.9; 7.53/157.7. GC−MS (m/z): 215
(11); 214 (85, M+); 200 (13); 199 (100); 171 (9); 107 (11); 94 (22);
+
79 (34); 51 (22). HRMS (ESI) calcd for C12H11N2O2 (M + H+)
215.0815, found 215.0819.
2-(1H-Pyrrol-2-yl)benzo[d]oxazole-6-carbonitrile (4f). The
benzoxazole was purified by column chromatography on silica gel
eluting with petroleum ether/diethyl ether gradient (25:75 → 35:65)
and recrystallized from CH2Cl2 as colorless crystals, mp 198.0−199.0
1
°C. H NMR (400 MHz, DMSO-d6) δH: 6.34−6.35 (1H, m); 7.08
(1H, s br); 7.21 (1H, s br); 7.79 (1H, d, J = 8.4); 7.82 (1H, d, J = 8.4);
8.28 (1H, s br); 12.45 (1H, s br). 13C NMR (101 MHz, DMSO-d6)
δC: 105.8 (C); 110.8 (CH); 114.6 (CH); 114.7 (CH); 117.8 (C);
119.0 (CH); 119.5 (C); 125.6 (CH); 129.3 (CH); 146.0 (C); 148.9
1
(C); 160.4 (C). H−1H COSY NMR (DMSO-d6) δH/δH: 6.34/7.08;
Preparation of Chromeno[3,4-b]indol-6(7H)-one Derivatives
in Liquid Ammonia. This product was obtained following the same
procedure for benzoxazole derivatives.
6.34/7.21; 7.79/7.82; 8.28/8.28.1H−13C HSQC NMR (DMSO-d6)
δH/δC: 6.34/110.8; 7.08/114.7; 7.21/125.6; 7.79/129.3; 7.82/119.0;
1515
dx.doi.org/10.1021/jo202386b | J. Org. Chem. 2012, 77, 1507−1519

The Journal of Organic Chemistry
Article
8.28/114.6. GC−MS (m/z): 210 (14); 209 (100, M+); 182 (8); 154
(6); 86 (6); 84 (8); 62 (6); 51 (6); 49 (11). HRMS (ESI) [M + H+]
calcd for C12H8N3O+ 210,0662, found 210.0677.
HSQC NMR (CDCl3) δH/δC: 7.18/120.9; 7.31/124.9; 7.37/124.9;
7.37/125.2; 7.41/106.5; 7.41/111.7; 7.61/110.6; 7.73/119.6; 7.73/
122.0. 1H−13C HMBC NMR (CDCl3) δH/δC: 7.18/111.7; 7.18/128.1;
7.31/110.6; 7.31/122.0; 7.31/137.5; 7.37/119.6; 7.37/141.6; 7.41/
120.9; 7.41/124.8; 7.41/128.1; 7.41/137.5; 7.61/124.9; 7.61/141.6;
7.73/106.5; 7.73/124.9; 7.73/137.5; 7.73/141.6; 7.73/150.6. GC−MS
(m/z): 235 (17); 234 (100, M+); 205 (13); 117 (13). HRMS (ESI)
[M + H+] calcd. C15H11N2O+ 235.0866, found 235.0883.
2-(1H-Pyrrol-2-yl)-6-(trifluoromethoxy)benzo[d]oxazole
(4g). The benzoxazole was purified by radial thin-layer chromato-
graphy eluting with petroleum ether/diethyl ether (90:10 → 50:50)
and was isolated as a white solid, mp 103.0−105.0 °C. 1H NMR
(400 MHz, CDCl3) δH: 6.44−6.47 (1H, m); 7.12−7.15 (1H, m);
7.15−7.16 (1H, m); 7.26−7.29 (1H, m); 7.49 (1H, m); 7.68 (1H, d,
J = 8.5); 9.71 (1H, s br). 19F (377 MHz, CDCl3) δF: −58.24. 13C
NMR (101 MHz, CDCl3) δC: 104.5 (CH); 111.2 (CH); 113.6 (CH);
118.2 (CH); 119.0 (CH); 121.8 (C); 123.2 (CH); 140.6 (C); 145.8
(C); 149.9 (C); 159.2 (C). 1H−1H COSY NMR (CDCl3) δH/δH:
6.45/7.12; 6.45/7.15; 7.27/7.49; 7.27/7.68. 1H−13C HSQC NMR
(CDCl3) δH/δC: 6.45/111.2; 7.12/123.2; 7.15/113.6; 7.27/118.2;
2-(1H-Indol-2-yl)-6-methylbenzo[d]oxazole (5b). The benzox-
azole was purified by radial thin-layer chromatography on silica gel
eluting with a petroleum ether/diethyl ether (80:20) and was isolated
as white solid, mp 200−201 °C. 1H NMR (400 MHz, acetone-d6) δH:
2.50 (3H, s); 7.14 (1H, ddd, J = 8.0, 7.0, 1.0); 7.23 (1H, ddd, J = 8.1,
1.5, 0.6); 7.29 (1H, ddd, J = 8.2, 7.0, 1.1); 7.34 (1H, dd, J = 2.2, 0.9);
7.50−7.51 (1H, m); 7.59−7.62 (2H; m); 7.71−7.73 (1H, m); 11.20
(1H, s). 13C NMR (101 MHz, acetone-d6) δC: 21.7 (CH3); 106.1
(CH); 111.5 (CH); 113.0 (CH); 119.9 (CH); 121.4 (CH); 122.4
(CH); 125.2 (CH); 126.0 (C); 126.8 (CH); 129.0 (C); 136.5 (C);
1
7.49/104.5; 7.68/119.0. H−13C HMBC NMR (CDCl3) δH/δC: 6.45/
119.3; 6.45/123.2; 7.12/111.2; 7.12/113.6; 7.12/119.3; 7.15/123.2;
7.27/104.6; 7.27/140.6; 7.27/145.8; 7.45/149.9; 7.68/104.5; 7.68/
145.8; 7.68/149.9; 7.68/119.0. GC−MS (m/z): 269 (12); 268 (100,
M+); 200 (12); 199 (95); 94 (24); 79 (46); 69 (28); 51 (32). HRMS
1
139.0 (C); 140.8 (C); 151.7 (C); 158.2 (C). H−1H COSY NMR
(acetone-d6) δH/δH: 2.50/7.5; 7.14/7.29; 7.14/7.72; 7.22/7.60; 7.29/
7.60. 1H−13C HSQC NMR (acetone-d6) δH/δC: 2.53/21.7; 7.12/
121.4; 7.22/126.8; 7.28/125.2; 7.32/106.1; 7.51/111.5; 7.60/119.9;
7.60/113.0; 7.71/122.4. 1H−13C HMBC NMR (acetone-d6) δH/δC:
2.50/111.5; 2.50/126.8; 2.50/136.5; 7.14/113.0; 7.14/129.0; 7.23/
111.5; 7.23/140.8; 7.29/122.4; 7.29/139.0; 7.34/126.0; 7.34/129.0;
7.51/126.8; 7.51/140.8; 7.51/151.7; 7.60/121.4; 7.60/129.0; 7.60/
136.5; 7.60/151.7; 7.72/125.2; 7.72/139.0. GC−MS (m/z): 250 (2);
249 (16); 248 (100, M+); 247 (26); 142 (17); 123 (17); 115 (13); 89
(16); 78 (17); 77 (20); 52 (13); 51 (16). HRMS (ESI) [M + Na+]
calcd C16H12N2NaO+ 271.0842, found 271.0864.
+
(ESI) [M + H+] calcd C12H8F3N2O2 269.0532, found 269.0558.
Ethyl 2-(1H-Pyrrol-2-yl)benzo[d]oxazole-6-carboxylate (4h).
The benzoxazole was purified by radial thin-layer chromatography on
silica gel eluting with a petroleum ether/diethyl ether (90:10) and
recrystallized in acetone as white needle crystals, mp 162.2−163.7 °C.
1H NMR (DMSO-d6) δH: 1.35 (3H, t, J = 7.2); 4.34 (2H, q, J = 7.2);
6.32−6.34 (1H, m); 7.05−7.07 (1H, m); 7.18−7.20 (1H, m); 7.75
(1H, d, J = 8.2); 7.98 (1H, dd, J = 8.2, 1.1); 8.16 (1H, d, J = 1.1);
12.40 (1H, s br). 13C NMR (DMSO-d6) δC: 14.7 (CH3); 61.4 (CH2);
111.1 (CH); 111.6 (CH); 114.7 (CH); 118.7 (C); 118.9 (CH); 125.7
(CH); 126.2 (C); 126.6 (CH); 146.5 (C); 149.8 (C); 160.6 (C);
165.8 (C). 1H−1H COSY NMR (DMSO-d6) δH/δH: 1.35/4.34; 6.33/
7.06; 6.33/7.19; 6.33/12.40; 7.06/12.40; 7.19/12.40; 7.75/7.98; 7.75/
8.16. 1H−13C HSQC NMR (DMSO-d6) δH/δC: 1.35/14.7; 4.34/61.4;
6.33/111.1; 7.06/114.7; 7.19/125.7; 7.75/118.9; 7.98/126.6; 8.16/
2-(1H-Indol-2-yl)-6-methoxybenzo[d]oxazole (5c). The ben-
zoxazole was purified by radial thin-layer chromatography on silica gel
eluting with a petroleum ether/diethyl ether gradient (80:20 → 0:100)
1
and was isolated as yellow pale solid, mp 162.5−164.0 °C. H NMR
(400 MHz, acetone-d6) δH: 3.90 (3H, s); 7.00 (1H, dd, J = 8.7, 2.4);
7.11−7.15 (1H, m); 7.26−7.30 (3H, m); 7.58−7.61 (2H, m); 7.71
(1H, d, J = 8.0); 11.15 (1H, s br).13C NMR (101 MHz, acetone-d6)
δC: 56.4 (CH3); 96.3 (CH); 105.7 (CH) ; 113.0 (CH); 113.9 (CH);
120.5 (CH); 121.4 (CH); 122.4 (CH); 125.1 (CH); 126.1 (C); 129.2
(C); 136.6 (C); 139.0 (C); 152.4 (C); 157.8 (C); 159.6 (C).1H−1H
COSY NMR (acetone-d6) δH/δH: 7.00/7.28; 7.00/7.59; 7.13/7.28;
7.13/7.71; 7.28/7.59. 1H−13C HSQC NMR (acetone-d6) δH/δC: 3.90/
56.4; 7.00/113.9; 7.13/121.4; 7.28/96.3; 7.28/105.7; 7.28/125.1;
7.59/113.0; 7.59/120.5; 7.71/122.4. 1H−13C HMBC NMR (ace-
tone-d6) δH/δC: 3.90/159.6; 7.00/96.3; 7.00/136.6; 7.00/159.6; 7.13/
113.0; 7.13/129.2; 7.28/113.9; 7.28/122.4; 7.28/126.1; 7.28/129.2;
7.28/136.6; 7.28/139.0; 7.28/152.4; 7.28/159.6; 7.59/121.4; 7.59/
129.2; 7.59/152.4; 7.59/159.6; 7.71/125.1; 7.71/125.1; 7.71/139.0.
GC−MS (m/z): 265 (17); 264 (100, M+); 250 (14); 249 (93); 144
1
111.6. H−13C HMBC NMR (DMSO-d6) δH/δC: 1.35/61.4; 4.34/
14.7; 4.34/165.8; 6.33/118.7; 6.33/125.7; 7.06/118.7; 7.06/125.7;
7.19/111.1; 7.19/114.7; 7.19/118.7; 7.75/126.2; 7.75/149.8; 7.98/
111.6; 7.98/146.5; 7.98/165.8; 7.98/118.9; 8.16/126.6; 8.16/146.5;
8.16/149.8; 8.16/165.8. GC−MS (m/z): 257 (15); 256 (99, M+); 228
(51); 212 (16); 211 (100); 155 (44); 106 (12); 78 (15); 63 (13).
+
HRMS (ESI) calcd for C14H12N2NaO3 (M + Na+) 279.0740, found
279.0766.
6-Chloro-2-(1H-pyrrol-2-yl)benzo[d]oxazole (4i). The benzox-
azole was purified by radial thin-layer chromatography eluting with
petroleum ether/diethyl ether (90:10 → 50:50) as a white solid, mp
1
220.0−223.0 °C. H NMR (400 MHz, CDCl3) δH: 6.39 (1H, m);
7.04−7.05 (1H, m); 7.08−7.09 (1H, m); 7.30 (1H, dd, J = 8.4, 1.9);
7.53−7.55 (2H, m); 10.10 (1H, s br). 13C NMR (101 MHz, CDCl3)
δC: 111.0 (CH); 111.1 (CH); 113.6 (CH); 119.2 (CH); 119.4 (C);
123.3 (CH); 125.2 (CH); 129.8 (C); 140.6 (C); 150.3 (C); 158.7
(C). 1H−1H COSY NMR (CDCl3) δH/δH: 6.39/7.05; 6.39/7.09; 7.30/
+
(9); 132 (12); 79 (18). HRMS (ESI) [M + H+] calcd C16H13N2O2
265.0972, found 265.1000.
1
7.54. H−13C HSQC NMR (CDCl3) δH/δC: 6.39/111.0; 7.05/123.3;
2-(1H-Indol-2-yl)-6-(trifluoromethoxy)benzo[d]oxazole (5d).
The benzoxazole was purified by column chromatography on silica gel
eluting with petroleum ether/CH2Cl2 gradient (50:50 → 0:100) as
white crystals, mp 174−175 °C. 1H NMR (400 MHz, CDCl3) δH: 7.19
(1H, ddd, J = 8.1, 7.0, 1.2); 7.24−7.26 (1H, m); 7.32 (1H, ddd, J = 8.1,
6.9, 1.2); 7.39−7.43 (2H, m); 7.50 (1H, d, J = 1.2); 7.69 (1H, d, J =
8.4); 7.73 (1H, dd; J = 8.0, 0.8); 9.52 (1H, s br). 19F NMR (377 MHz,
CDCl3) δF: −58.19. 13C NMR (101 MHz, CDCl3) δC: 104.7 (CH);
107.1 (CH); 111.7 (CH); 118.6 (CH); 119.9 (CH); 120.6 (OCF3, d,
J = 256); 121.1 (CH); 122.2 (CH); 124.1 (C); 125.3 (CH); 128.1
7.09/113.6; 7.30/125.2; 7.54/111.0; 7.54/119.2. 1H−13C HMBC
NMR (CDCl3) δH/δC: 6.39/119.4; 6.39/123.3; 6.39/113.6; 7.05/
111.0; 7.05/113.6; 7.05/119.4; 7.09/123.3; 7.09/119.4; 7.30/111.1; 7.30/
119.2; 7.30/129.8; 7.30/140.6; 7.54/125.2; 7.54/129.8; 7.54/140.6; 7.54/
150.5. GC−MS (m/z): 220 (29); 219 (14); 218 (100, M+); 191 (12);
155 (22); 63 (31). HRMS (ESI) [M + H+] calcd C11H8ClN2O+
219.0320, found 219.0330.
2-(1H-Indol-2-yl)benzo[d]oxazole (5a).51 The benzoxazole was
purified by radial thin-layer chromatography eluting with petroleum
ether/diethyl ether (90:10 → 50:50) and was isolated as white solid,
mp 245.0−246.0 °C. 1H NMR (400 MHz, CDCl3) δH: 7.18 (1H, m);
7.31 (1H, m); 7.37 (2H, m); 7.41 (2H, m); 7.61 (1H, m); 7.73 (2H,
m); 9.76 (1H, s br). 13C NMR (101 MHz, CDCl3) δC: 106.5 (CH);
110.6 (CH); 111.7 (CH); 119.6 (CH); 120.9 (CH); 122.0 (CH);
124.8 (C); 124.9 (CH); 124.9 (CH); 125.2 (CH); 128.1 (C); 137.5
(C); 141.6 (C); 150.6 (C); 157.9 (C). 1H−1H COSY NMR (CDCl3)
δH/δH: 7.18/7.31; 7.18/7.73; 7.31/7.41; 7.37/7.61; 7.37/7.73. 1H−13C
1
(C); 137.6 (C); 140.4 (C); 146.4 (C); 150.4 (C); 159.2 (C). H−1H
COSY NMR (CDCl3) δH/δH: 7.19/7.32; 7.19/7.73; 7.25/7.50; 7.25/
7.69; 7.32/7.41; 7.41/9.52. 1H−13C HSQC NMR (CDCl3) δH/δC:
7.19/121.1; 7.25/118.6; 7.32/125.3; 7.41/107.1; 7.41/111.7; 7.50/
1
104.7; 7.69/119.9; 7.73/122.2. H−13C HMBC NMR (CDCl3) δH/
δC: 7.19/111.7; 7.19/128.1; 7.25/140.4; 7.25/146.4; 7.32/122.2; 7.32/
137.6; 7.41/124.1; 7.41/137.6; 7.41/121.1; 7.41/128.1; 7.50/118.6;
7.50/140.4; 7.50/146.4; 7.50/150.4; 7.69/146.4; 7.69/150.4; 7.73/107.1;
1516
dx.doi.org/10.1021/jo202386b | J. Org. Chem. 2012, 77, 1507−1519

The Journal of Organic Chemistry
Article
+
7.73/125.3; 7.73/137.6. HRMS (ESI) [M + H+] calcd C16H10F3N2O2
319.0689, found 319.0692.
(CH); 134.9 (C); 137.9 (C); 141.5 (C); 150.9 (C); 161.6 (C).
1H−1H COSY NMR (acetone-d6) δH/δH: 7.17/7.57; 7.28/7.57; 7.28/
8.46. 1H−13C HSQC NMR (acetone-d6) δH/δC: 2.48/21.6; 7.17/
126.0; 7.28/122.1; 7.28/123.8; 7.44/111.0; 7.57/113.0; 7.57/119.1;
Ethyl 2-(1H-Indol-2-yl)benzo[d]oxazole-6-carboxylate (5e).
The benzoxazole was purified by column chromatography on silica gel
eluting with a petroleum ether/diethyl ether gradient (100:0 → 50:50)
1
8.22/129.1; 8.46/122.0. H−13C HMBC NMR (acetone-d6) δH/δC:
1
as orange solid serous. H NMR (400 MHz, CDCl3) δH: 1.44 (3H, t,
2.48/111.0; 2.48/126.0; 2.48/134.9; 7.17/21.6; 7.17/111.0; 7.17/
141.5; 7.28/113.0; 7.28/122.0; 7.28/126.1; 7.28/137.9; 7.44/21.6;
7.44/126.0; 7.44/141.5; 7.44/150.9; 7.57/122.1; 7.57/126.1; 7.57/
134.9; 7.57/150.9; 8.22/105.2; 8.22/126.1; 8.22/137.9; 8.46/123.8;
8.46/129.1; 8.46/137.9. GC−MS (m/z): 250 (2); 249 (17); 248 (100,
M+); 247 (29); 219 (10); 142 (10); 124 (13). HRMS (ESI) [M + H+]
calcd C16H13N2O+ 249.1022, found 249.1013.
J = 7.2); 4.44 (2H, q, J = 7.1); 7.18−7.22 (1H, m); 7.33 (1H, m);
7.44−7.48 (2H, m); 7.73−7.76 (2H, m); 8.12 (1H, dd, J= 8.4, 1.5);
8.28 (1H, m); 9.32 (1H, s br). 13C NMR (101 MHz, CDCl3) δC: 14.4
(CH3); 61.3 (CH2); 107.6 (CH); 111.7 (CH); 112.1 (CH); 119.1
(CH); 121.2 (CH); 122.2 (CH); 124.1 (C); 125.5 (CH); 126.7
(CH); 127.5 (C), 128.1 (C); 137.6 (C); 145.6 (C); 150.3 (C); 160.0
(C); 166.1 (C). 1H−1H COSY NMR (CDCl3) δH/δH: 1.44/4.44;
7.20/7.35; 7.20/7.73; 7.35/7.46; 7.46/9.32; 7.73/8.12; 7.76/8.12.
1H−13C HSQC NMR (CDCl3) δH/δC: 1.44/14.4; 4.44/61.3; 7.20/
121.2; 7.35/125.5; 7.46/107.6; 7.46/111.7; 7.73/119.1; 7.76/122.2;
8.12/126.7; 8.28/112.1. 1H−13C HMBC NMR (CDCl3) δH/δC: 1.44/
61.3; 4.44/14.4; 4.44/166.1; 7.20/111.7; 7.20/128.1; 7.35/122.2;
7.35/137.7; 7.46/121.2); 7.46/124.2; 7.46/128.1; 7.46/137.7. GC−
MS (m/z): 306 (100, M+); 279 (11); 278 (48); 261 (19); 233 (11);
N-Phenyl-1H-pyrrole-2-carboxamide (7a). The amide was
purified by radial thin-layer chromatography eluting with petroleum
ether/diethyl ether (90:10 → 50:50) and was isolated as a white solid,
1
mp 181.0−182.0 °C. H NMR (400 MHz, CDCl3) δH: 6.29−6.31
(1H, m), 6.71 (1H, m); 6.99−7.00 (1H, m); 7.11−7.15 (1H, m);
7.34−7.38 (2H, m); 7.55 (1H, s br); 7.59−7.61 (2H, m); 9.54 (1H, s
br). 13C NMR (101 MHz, CDCl3) δC: 109.4 (CH); 110.2 (CH);
120.0 (CH); 122.3 (CH); 124.2 (CH); 126.0 (C); 129.1 (CH); 137.8
(C); 159.0 (C). 13C DEPT-135 NMR: 109.4; 110.2; 120.0; 122.3;
124.2; 129.1. GC−MS (m/z): 186 (25, M+); 94 (47); 93 (100); 66
(31). HRMS (ESI) calcd. for C11H11N2O+ [M + H+] 187.0866, found
187.0866.
+
205 (28); 102 (17). HRMS (ESI) [M + H+] calcd C18H15N2O3
307.1077, found 307.1099.
6-Chloro-2-(1H-indol-2-yl)benzo[d]oxazole (5f). The benzox-
azole was purified by radial thin-layer chromatography eluting with
petroleum ether/diethyl ether (90:10 → 50:50) and was isolated as
N-(p-Tolyl)-1H-pyrrole-2-carboxamide (7d). The amide was
purified by radial thin-layer chromatography on silica gel eluting with a
petroleum ether/diethyl ether gradient (80:20 → 50:50) as white
1
white solid, mp 185.0−186.0 °C. H NMR (400 MHz, CDCl3) δH:
7.19−7.21 (1H, m); 7.32−7.36 (2H, m); 7.39−7.43 (2H, m); 7.60−
7.61 (2H, m); 7.73 (1H, dd, J = 8.0, 0.7); 9.53 (1H, s br). 13C NMR
(101 MHz, CDCl3) δC: 107.0 (CH); 111.3 (CH); 111.7 (CH); 120.0
(CH); 121.1 (CH); 122.1 (CH); 124.2 (C); 125.2 (CH); 125.6
(CH); 128.1 (C); 130.8 (C); 137.6 (C); 140.5 (C); 150.8 (C); 158.4
(C). 1H−1H COSY NMR (CDCl3) δH/δH: 7.19/7.33; 7.19/7.73; 7.33/
1
crystals. H NMR (400 MHz, CDCl3) δH: 2.33 (3H, s); 6.27−6.30
(1H, m); 6.68 (1H, s); 6.97−6.98 (1H, m); 7.15 (1H, s); 7.17 (1H, s);
7.47 (2H, d, J = 8.5); 7.51 (1H, s br); 9.62 (1H, s br). 13C NMR (101
MHz, CDCl3) δC: 20.9 (CH3); 109.2 (CH); 110.1 (CH); 120.1 (CH);
122.2 (CH); 126.1 (C); 129.6 (CH); 133.9 (C); 135.2 (C); 159.0
1
(C). H−13C HSQC NMR (CDCl3) δH/δC: 2.33/20.9; 6.29/110.1;
7.40; 7.33/7.61. H−13C HSQC NMR (CDCl3) δH/δC: 7.19/121.1;
1
6.68/109.2; 6.98/122.2; 7.15/120.1;7.17/129.6;7.47/120.1; 7.47/
129.6. 1H−13C HMBC NMR (CDCl3) δH/δC: 2.33/129.6; 2.33/
133.9; 6.68/122.2; 6.98/110.1; 6.98/126.1; 7.16/20.9; 7.16/120.1;
7.16/129.6; 7.16/135.2; 7.47/120.1; 7.47/133.9. GC−MS (m/z): 201
(3); 200 (25, M+); 107 (100); 106 (33); 94 (19); 66 (13). HRMS
(ESI) calcd. for C12H13N2O+ [M + H+] 201.1022, found 201.1032.
N-(4-Methoxyphenyl)-1H-pyrrole-2-carboxamide (7e). The
amide was purified by radial thin-layer chromatography on silica gel
eluting with a petroleum ether/diethyl ether gradient (75:25 → 0:100)
7.33/125.2; 7.33/125.6; 7.40/107.0; 7.40/111.7; 7.61/111.3; 7.61/
120.0; 7.73/122.1. 1H−13C HMBC NMR (CDCl3) δH/δC: 7.19/
111.7; 7.19/128.1; 7.33/111.3; 7.33/122.1; 7.33/137.6; 7.33/140.5;
7.40/121.1; 7.40/124.2; 7.40/128.1; 7.40/137.6; 7.61/111.3; 7.61/
130.8; 7.61/140.5; 7.61/150.8; 7.73/107.0; 7.73/125.2; 7.73/128.1;
7.73/137.6. GC−MS (m/z): 270 (33); 269 (18); 268 (100, M+); 205
(15); 134 (15); 115 (12); 89 (11); 63 (21). HRMS (ESI) [M + H+]
calcd. for C15H10ClN2O+ 269.0476, found 269.0451.
2-(1H-Indol-3-yl)benzo[d]oxazole (6a). The benzoxazole was
purified by radial thin-layer chromatography on silica gel eluting with a
petroleum ether/diethyl ether gradient (50:50 → 0:100) and was
isolated as white solid, mp 190.0−191.0 °C (lit. 190−191 °C).52 1H
NMR (400 MHz, CDCl3) δH: 7.35−7.38 (4H, m); 7.46−7.48 (1H,
m); 7.56−7.58 (1H, m); 7.74−7.77 (1H, m); 8.09 (1H, d, J = 2.9);
8.50−8.52 (1H, m); 8.88 (1H, s br). 13C NMR (101 MHz, CDCl3) δC:
105.5 (C); 110.1 (CH); 111.6 (CH); 119.1 (CH); 121.6 (CH); 122.0
(CH); 123.6 (CH); 124.0 (CH); 124.2 (CH); 125.0 (C); 127.5
1
as white crystals, mp 177.5−178.3 °C. H NMR (400 MHz, acetone-
d6) δH: 3.77 (3H, s); 6.18−6.20 (1H, m); 6.86−6.90 (2H, m); 6.93−
6.95 (1H, m); 7.01−7.03 (1H, m); 7.65−7.67 (2H, m); 9.04 (1H, s
br); 10.78 (1H, s br). 13C NMR (101 MHz, acetone-d6) δC: 54.7
(OCH3); 109.1 (CH); 109.8 (CH); 113.7 (CH); 121.3 (CH); 121.9
(CH); 126.7 (C); 132.6 (C); 155.8 (C); 158.9 (C). GC−MS (m/z):
217 (2), 216 (M+, 16), 124 (8), 123 (100), 108 (59), 94 (27), 80 (11),
+
66 (19), 65 (8). HRMS (ESI) [M + H+] calcd for C12H13N2O2
1
(CH); 136.3 (C); 142.3 (C); 150.0 (C); 161.3 (C). H−1H COSY
217.0972, found 217.0957.
N-(4-Methoxyphenyl)-1H-indole-2-carboxamide (8c).53 The
amide was purified by radial thin-layer chromatography on silica gel
eluting with a petroleum ether/diethyl ether gradient (80:20 → 0:100)
NMR (CDCl3) δH/δH: 7.35/7.47; 7.35/7.57; 7.35/7.76; 7.73/8.51;
1
8.09/8.88. H−13C HSQC NMR (CDCl3) δH/δC: 7.35/122.0; 7.35/
123.6; 7.35/124.0; 7.35/124.2; 7.47/111.6; 7.57/110.1; 7.76/119.1;
8.09/127.5; 8.51/121.6. 1H−13C HMBC NMR (CDCl3) δH/δC: 7.35/
110.1; 7.35/111.6; 7.35/119.1; 7.35/121.6; 7.35/125.0; 7.35/136.3;
7.35/142.3; 7.35/150.0; 7.47/122.0; 7.47/125.0; 7.57/124.0; 7.57/
142.3; 7.57/150.0; 7.76/124.2; 7.76/150.0; 8.09/105.5; 8.09/125.0;
8.09/127.5; 8.09/136.3; 8.09/161.3; 8.51/105.5; 8.51/123.6; 8.51/
136.3. GC−MS (m/z): 235 (16), 234 (100, M+). HRMS (ESI) [M + H+]
calcd C15H11N2O+ 235.0866, found 235.0879.
1
and was isolated as yellow crystals. H NMR (400 MHz, acetone-d6)
δH: 3.80 (3H, s); 6.91−6.95 (2H, m); 7.07−7.11 (1H, m); 7.25 (1H,
ddd, J = 8.2, 7.1, 1.1); 7.30 (1H, m); 7.58 (1H, dd, J = 8.3, 0.7); 7.64−
7.66 (1H, m); 7.74−7.77 (2H, m); 9.49 (1H, s br); 10.88 (1H, s br).
13C NMR (100 MHz, acetone-d6) δC: 55.7 (OCH3); 103.7 (CH);
113.2 (CH); 114.7 (CH); 121.1 (CH); 122.5 (CH); 122.7 (CH);
124.8 (CH); 128.8 (C); 132.8 (C); 133.2 (C); 138.0 (C); 157.1 (C);
160.3 (C). 1H−1H COSY NMR (acetone-d6) δH/δH: 6.93/7.75; 7.09/
7.25; 7.09/7.65; 7.25/7.58. 1H−13C HSQC NMR (acetone-d6) δH/δC:
3.80/55.7; 6.93/114.7; 7.09/121.1; 7.25/124.8; 7.30/103.7; 7.58/
113.2; 7.65/122.7; 7.75/122.5. 1H−13C HMBC NMR (acetone-d6)
δH/δC: 3.80/157.1; 6.93/114.7; 6.93/132.8; 6.93/157.1; 7.09/113.2;
7.09/128.8; 7.25/122.7; 7.30/132.8; 7.30/138.0; 7.58/121.0; 7.58/
128.8; 7.65/124.8; 7.65/138.0; 7.75/122.5; 7.75/133.2; 7.75/157.1.
GC−MS (m/z): 267 (8); 266 (M+, 43); 144 (19); 124 (8); 123
(100); 116 (11); 115 (4); 108 (25); 89 (24); 80 (2).
2-(1H-Indol-3-yl)-6-methylbenzo[d]oxazole (6b). The benzox-
azole was purified by radial thin-layer chromatography eluting with a
petroleum ether/diethyl ether gradient (80:20 → 0:100) and was
1
isolated as white solid, mp 235.5−237.3 °C. H NMR (400 MHz,
acetone-d6) δH: 2.48 (3H, s); 7.17 (1H, d, J = 8.0); 7.27−7.31 (2H,
m); 7.44 (1H, m); 7.55−7.59 (2H, m); 8.22−8.23 (1H, m); 8.45−8.47
(1H, m); 11.08 (1H, s br). 13C NMR (101 MHz, acetone-d6) δC: 21.6
(CH3); 105.2 (C); 111.0 (CH); 113.0 (CH); 119.1 (CH); 122.0
(CH); 122.1 (CH); 123.8 (CH); 126.0 (CH); 126.1 (CH), 129.1
1517
dx.doi.org/10.1021/jo202386b | J. Org. Chem. 2012, 77, 1507−1519

The Journal of Organic Chemistry
Article
N-Phenylbenzamide (9). The product was obtained following
reported methods.54 1H NMR (400 MHz, CDCl3) δH: 7.15 (1H, t, J =
7.4); 7.36 (2H, t, J = 7.9); 7.44−7.48 (2H, m); 7.52−7.56 (1H, m);
7.64 (2H, d, J = 7.8); 7.85−7.87 (2H, m); 7.93 (1H, s br). 13C NMR
(101 MHz, CDCl3) δC: 120.2 (CH); 124.5 (CH); 127.0 (CH); 128.7
(CH); 129.1 (CH); 131.8 (CH); 135.0 (C); 137.9 (C); 165.8 (C).
N-Phenyl-1H-indole-3-carboxamide (16a). The amide was not
isolated but detected by GC−MS. GC−MS (m/z): 237 (17); 236
(M+, 100); 235 (85); 220 (12); 219 (45); 218 (11); 217 (22); 208 (14);
207 (28); 206 (14); 180 (11); 118 (15); 109 (12); 90 (12), 89 (15).
Chromeno[3,4-b]indol-6(7H)-one (18). The chromeno was
purified by column chromatography on silica gel eluting with
petroleum ether/diethyl ether gradient (80:20 → 60:40) and recrys-
tallized from CH2Cl2 as white crystals, mp 290.0−291.0 °C. 1H NMR
(400 MHz, DMSO-d6) δH: 7.33 (1H, t, J = 7.20); 7.42−7.53 (4H, m);
7.62 (1H, d, J = 8.40); 8.40−8.45 (2H, m); 12.69 (1H, s br). 13C
NMR (101 MHz, DMSO-d6) δC: 113.4 (CH); 116.9 (C); 118.4 (C);
119.9 (CH); 121.3 (C); 121.4 (C); 121.6 (CH); 122.6 (CH); 123.6
(CH); 124.9 (CH); 127.2 (CH); 127.4 (CH); 139.8 (C); 150.4 (C);
155.3 (C). 1H−1H COSY NMR (DMSO-d6) δH/δH: 7.33/7.48; 7.33/
8.43; 7.48/7.62; 7.48/8.43. 1H−13C HSQC NMR (DMSO-d6) δH/δC:
7.33/121.6; 7.48/116.9; 7.48/124.9; 7.48/127.2; 7.48/127.4; 7.62/
113.4; 8.43/122.6; 8.43/123.6. 1H−13C HMBC NMR (DMSO-d6)
δH/δC: 7.33/113.4; 7.33/121.4; 7.48/122.6; 7.48/124.9; 7.62/121.4;
8.43/119.9; 8.43/121.3; 8.43/127.2; 8.43/127.4; 8.43/150.4. GC−MS
(m/z): 236 (16); 235 (M+, 100); 206 (6); 179 (7); 178 (10); 177 (5);
153 (7); 152 (23); 151 (11); 150 (5); 76 (15); 75 (6). HRMS (ESI)
(4) Tipparaju, S. K.; Joyasawal, S.; Pieroni, M.; Kaiser, M.; Brun, R.;
Kozokowski, A. P. J. Med. Chem. 2008, 51, 7344−7347.
(5) (a) Aiello, S.; Wells, G.; Stone, E. L.; Kadri, M.; Bazzi, R.; Bell,
D. R.; Stevens, M. F. G.; Matthews, C. S.; Bradshow, T. D.; Westwell,
A. D. J. Med. Chem. 2008, 51, 5135−5139. (b) Mckee, M. L.; Kerwin,
S. M. Bioorg. Med. Chem. 2008, 16, 1775−1783.
(6) Dunwell, D. W.; Evans, D. J. Med. Chem. 1977, 20, 797−801.
(7) Rostom, S. A. F.; Fahmy, H. T. Y.; Saudi, M. N. S. Sci. Pharm.
2003, 71, 57−74.
(8) Roman-Blas, J. A.; Castaneda, S.; Cutolo, M.; Herrero-Beaumont,
G. Arthritis Care Res. 2010, 62, 1588−1593.
(9) Yamada, M.; Sato, Y.; Kobayashi, K.; Konno, F.; Soneda, T.;
Watanabe, T. Chem. Pharm. Bull. 1998, 46, 445−451.
(10) Kumar, D.; Jacob, M. R.; Reynolds, M. B.; Kerwin, S. M. Bioorg.
Med. Chem. 2002, 10, 3997−4004.
(11) Ko, C.-W.; Tao, Y.-T.; Danel, A.; Krzeminska, L.; Tomasik, P.
Chem. Mater. 2001, 13, 2441−2446.
(12) Tian, Y.; Chen, C.-Y.; Yang, C.-C.; Young, A. C.; Yang, S.-H.;
Chen, W.-C.; Jen, A. K.-Y. Chem. Mater. 2008, 20, 1977−1987.
(13) Kocher, C.; Smith, P.; Weder, C. J. Mater. Chem. 2002, 12,
2620−2626.
(14) (a) Hein, D. W.; Alheim, R. J.; Leavitt, J. J. J. Am. Chem. Soc.
1957, 79, 427−429. (b) So, Y.-H.; Heeschen, J. P. J. Org. Chem. 1997,
62, 3552−3561. (c) Ertan, T.; Yildiz, I.; Tekiner-Gulbas, B.; Bolelli, K.;
Temiz-Arpaci, O.; Ozkom, S.; Kaynok, F.; Yalcin, I.; Aki, E. Eur. J. Med.
Chem. 2009, 44, 501−510.
(15) Harikrishnan, L. S.; Kamau, M. G.; Herpin, T. F.; Morton,
G. C.; Liu, Y.; Cooper, C. B.; Salvati, M. E.; Qiao, J. X.; Wang, T. C.;
Adam, L. P.; Taylor, D. S.; Chen, A. Y. A.; Yin, X.; Seethala, R.;
Peterson, T. L.; Nirschl, D. S.; Miller, A. V.; Weigelt, C. A.; Appiah,
K. K.; O’Connell, J. C.; Lawrence, R. M. Bioorg. Med. Chem. Lett. 2008,
18, 2640−2644.
(16) (a) Chang, J.; Zhao, K.; Pan, S. Tetrahedron Lett. 2002, 43, 951−
954. (b) Praveen, C.; Kumar, K. H.; Muralidharan, D.; Perumal, P. T.
Tetrahedron 2008, 64, 2369−2374. (c) Vinsova, J.; Cermakova, K.;
Tomeckova, A.; Ceckova, M.; Jampilek, J.; Cermak, P.; Kunes, J.;
Dolezale, M.; Staud, F. Bioorg. Med. Chem. 2006, 14, 5850−5865.
(d) Liao, C.-H.; Wang, C.-S.; Sheu, H.-S.; Lai, C. K. Tetrahedron 2008,
64, 7977−7985. (e) Riadi, Y.; Mamouni, R.; Azzalou, R.; El Haddad,
M.; Routier, S.; Guillaumet, G.; Lazar, G. Tetrahedron Lett. 2011, 52,
3492−3495.
(17) Kumar, A.; Sharma, S.; Maurya, R. A. Tetrahedron Lett. 2010, 51,
6224−6226.
(18) (a) El-Sheik, M. I.; Marks, A.; Biehl, E. R. J. Org. Chem. 1981,
46, 3256−3259. (b) Hrutfiord, B. F.; Bunnett, J. F. J. Am. Chem. Soc.
1958, 80, 2021−2022. (c) Hrutfiord, B. F.; Bunnett, J. F. J. Am. Chem.
Soc. 1961, 83, 1691−1697.
+
[M + H+] calcd for C15H10NO2 236.0706, found 236.0716.
ASSOCIATED CONTENT
* Supporting Information
■
S
Copies of 1H, 13C, COSY, HSQC, and HMBC NMR spectra of
all compounds and spectroscopic characterization and full
assignation of products 4d, 4e, 4h, 4i, 5b, 5c, 5d, 5e, 5f, and 6b
are available in Experimental Supporting Information (SI-1).
Schematic profiles (Figures S1 and S2), xyz coordinates, and
total energies in atomic units of the species calculated are
available in Calculation Supporting Information (SI-2). This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Fax: (+54) 351-4333030/4334174. Phone: (+54) 351-4334170/73.
E-mail: rossi@fcq.unc.edu.ar.
■
(19) (a) Evindar, G.; Batey, R. A. J. Org. Chem. 2006, 71, 1802−1808.
(b) Altenhoff, G.; Glorius, F. Adv. Synth. Catal. 2004, 346, 1661−1166.
(c) Barbero, N.; Carril, M.; San Martin, R.; Domínguez, E. Tetrahedron
2007, 63, 10425−10432. (d) Vaillard, V. A.; Rossi, R. A.; Martín, S. E.
Org. Biomol. Chem. 2011, 9, 4927−4935.
(20) Bonnamour, J.; Bolm, C. Org. Lett. 2008, 10, 2665−2667.
(21) (a) Park, Y.-T.; Jung, C.-H.; Kim, K.-W.; Kim, H. S. J. Org. Chem.
1999, 64, 8546−8556. (b) Mayouf, A. M.; Park, Y.-T. J. Photochem.
Photobiol., A 2002, 150, 115−123. (c) Mayouf, A. M. J. Photochem.
Photobiol., A 2005, 172, 258−268.
(22) (a) Ueda, S.; Nagasawa, H. J. Org. Chem. 2009, 74, 4272−4277.
(b) Ueda, S.; Nagasawa, H. Angew. Chem., Int. Ed. 2008, 47, 6411−
6413.
ACKNOWLEDGMENTS
This work was supported in part by Agencia Cor
■
́
doba Ciencia,
́
the Consejo Nacional de Investigaciones Cientificas y Tec
́
nicas
nologia, Universidad
doba, and Fondo para la Investigacio
Cientifica y Tecnologica Argentina. V.A.V., J.F.G., M.E.B., and
́
́
(CONICET), Secretaria de Ciencia y Tec
Nacional de Cor
́
́
́
n
́
́
J.I.B. gratefully acknowledge receipt of fellowships from
CONICET.
REFERENCES
■
(1) Chancellor, D. R.; Davies, K. E.; De Moor, O.; Dorgan, C. R.;
Johnson, P. D.; Lawrence, D.; Lecci, C.; Maillol, C.; Middleton, P. J.;
Nugent, G.; Poignant, S. D.; Potter, A. C.; Price, P. D.; Pye, R, J.;
Storer, R.; Tinsley, J. M.; van Well, R.; Vickers, R.; Vile, J.; Wilkes,
F. J.; Wren, S. P.; Wynne, G. M. J. Med. Chem. 2011, 54, 3241−3250.
(2) Michel, K. H.; Boeck, L. D.; Hoehn, M. M.; Jones, N. D.; Chaney,
M. O. J. Antibiot. 1984, 37, 441−445.
(23) (a) Guru, M. M.; Ali, M. A.; Punniyamurthy, T. Org. Lett. 2011,
13, 1194−1196. (b) Guru, M. M.; Ali, M. A.; Punniyamurthy, T. J. Org.
Chem. 2011, 76, 5295−5308.
(24) Viirre, R. D.; Evindar, G.; Batey, R. A. J. Org. Chem. 2008, 73,
3452−3459.
(25) For reviews, see: (a) Rossi, R. A.; Pierini, A. B.; Santiago, A. N.;
In Organic Reactions; Paquette, L. A., Bittman, R., Eds.; Wiley & Sons:
Hoboken, NJ, 1999; pp 1−271. (b) Rossi, R. A.; Pierini, A. B.;
(3) (a) Klimeso
U. Eur. J. Med. Chem. 2009, 44, 2286−2293. (b) Rodríguez, A. D.;
Ramírez, C.; Rodríguez, I. I.; Gonzalez, E. Org. Lett. 1999, 1, 527−530.
̌
va, V.; Kocí, J.; Waisser, K.; Kaustova, J.; Mollmann,
́
̌
́
̈
́
Penen
́
ory, A. B. Chem. Rev. 2003, 103, 71−167. (c) Rossi, R. A. In
̃
̃
1518
dx.doi.org/10.1021/jo202386b | J. Org. Chem. 2012, 77, 1507−1519

The Journal of Organic Chemistry
Article
Synthetic Organic Photochemistry; Griesberck, A. G., Mattay, J., Eds.;
Marcel Dekker: New York, 2005; Vol. 12, Chapter 15, pp 495−527.
(26) Goehring, R. R.; Sachdeva, Y. P.; Pisipati, J. S.; Wolfe, M. C.
J. Am. Chem. Soc. 1985, 107, 435−443.
Cioslowski, J.; Fox, D. J. Gaussian 09, Revision A.1; Gaussian, Inc.:
Wallingford, CT, 2009.
(45) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B: Condens. Matter
Mater. Phys. 1988, 37, 785−789. (b) Becke, A. D. Phys. Rev. A: At.,
Mol., Opt. Phys. 1988, 38, 3098−3100. (c) Miehlich, B.; Savin, A.;
Stoll, H.; Preuss, H. Chem. Phys. Lett. 1989, 157, 200−206.
(46) (a) Miertus, S.; Scrocco, E.; Tomasi, J. Chem. Phys. 1981, 55,
117−129. (b) Miertus, S.; Tomasi, J. Chem. Phys. 1982, 65, 239−245.
(c) Cossi, M.; Barone, V.; Cammi, R.; Tomasi, J. Chem. Phys. Lett.
1996, 255, 327−335.
(47) Guide to Uplamping for High Intensity Discharge Lamps;
Philips Electronics UK Ltd: Surrey, U. K., 2010;http://www.
ribaproductselector.com/Docs/9/05799/external/COL605799.pdf
(48) Beugelmans, R.; Chbani, M. Bull. Soc. Chim. Fr. 1995, 132, 290−
305.
(27) Bowman, W. R.; Heaney, H.; Smith, P. H. G. Tetrahedron Lett.
1982, 23, 5093−5096.
(28) Barolo, S. M.; Teng, X.; Cuny, G. D.; Rossi, R. A. J. Org. Chem.
2006, 71, 8493−8499.
(29) Buden
R. A. J. Org. Chem. 2010, 75, 2206−2218.
(30) Buden, M. E.; Vaillard, V. A.; Martín, S. E.; Rossi, R. A. J. Org.
́
, M. E.; Dorn, V. B.; Gamba, M.; Pierini, A. B.; Rossi,
́
Chem. 2009, 74, 4490−4498.
(31) Laha, J. K.; Barolo, S. M.; Rossi, R. A.; Cuny, G. D. J. Org. Chem.
2011, 76, 6421−6425.
(32) Vaillard, V. A.; Buden
Tetrahedron Lett. 2009, 3529−3532.
(33) (a) Chahma, M.; Combellas, C.; Thieb
1995, 60, 8015−8022. (b) Chahma, M.; Combellas, C.; Thieb
Synthesis 1994, 366−368. (c) Chahma, M.; Combellas, C.; Marzouk,
H.; Thiebault, A. Tetrahedron Lett. 1991, 32, 6121−6124.
(34) (a) Mahboobi, S.; Teller, S.; Pongratz, H.; Hufsky, H.; Sellmer,
A.; Botzki, A.; Uecker, A.; Beckers, T.; Baasner, S.; Schachtele, C.;
́
, M. E.; Martín, S. E.; Rossi, R. A.
(49) Carlock, J. T.; Bradshaw, J. S.; Stanovnik, B.; Tiler, M. J. Org.
Chem. 1977, 42, 1883−1885.
(50) George, B.; Papadopoulos, E. P. J. Org. Chem. 1977, 42, 441−
443.
́
ault, A. J. Org. Chem.
ault, A.
́
(51) Chen, W.; Wang, M.; Li, P.; Wang, L. Tetrahedron 2011, 67,
5913−5919. The 13C NMR spectrum is in agreement with the literature.
(52) Harris, R. L. N. Aust. J. Chem. 1974, 27, 2635−2643.
(53) Lee, A. R.; Huang, W. H.; Cherng, J. Y. Chin. Pharm. J. 1994, 46,
307−311.
(54) Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R.
Vogel's Textbook of Practical Organic Chemistry, 5th ed.; Addison-
Wesley Longman Ltd: Essex, U. K., 1989; p 1274.
́
̈
̈
Uberall, F.; Kassack, M. U.; Dove, S.; Bohmer, F.-D. J. Med. Chem.
̈
2002, 45, 1002−1018. (b) Beccalli, E. M.; Bernasconi, A.; Borsini, E.;
Broggini, G.; Rigamonti, M.; Zecchi, G. J. Org. Chem. 2010, 75, 6923−
6932.
(35) These reactions were performed and reported previously (see
ref 32). The product was assigned as C-coupling substitution; later,
experiments by RMN spectroscopy (COSY, HSQC, HMBC, and
NOESY) were performed, which allowed us to determine that the
product obtained is the O-coupling substitution.
(36) The potentiometric determination of halide ions was used as a
tool for balance mass determination. In an ideal case, if the conversion
is complete, the dehalogenation is nearly 100%.
(37) The pKa of pyrrole is 23.0 and the pKa of N-phenyl benzamide is
18.8 in DMSO; see: Bordwell, F. G. Acc. Chem. Res. 1988, 21,
456−463. However pyrrole is a poor approximation to N-phenyl-1H-
pyrrole-2-carboxamide.
(38) B3LYP/6-31+g* was used with PCM (MeOH).
(39) When DMSO was used as a solvent, the same difference energy
(2.1 kcal mol−1) was obtained. See the Calculation Supporting
Information (SI-2).
(40) We propose that the electron could come from different
sources: (a) from the excited anion of the substrate to the substrate
anion (homocoupled redox reaction) or (b) from the base, which acts
as entrainment reagent.
(41) (a) Baumgartner, M. T.; Pierini, A. B.; Rossi, R. A. J. Org. Chem.
1993, 58, 2593−2598. (b) Tempesti, T. C.; Pierini, A. B.; Baumgartner,
M. T. J. Org. Chem. 2005, 70, 6508−6511.
(42) The structures of all conformer are indicated in Figures S1 and
S2 in the Supporting Information Calculations file.
(43) (a) Uranga, J. G.; Vera, D. M. A.; Santiago, A. N.; Pierini, A. B.
J. Org. Chem. 2006, 71, 6596−6599. (b) Pierini, A. B.; Santiago, A. N.;
Allende, S. G.; Vera, D. M. A. ARKIVOC 2003, Part x, 477−490.
(c) Pierini, A. B.; Vera, D. M. A. J. Org. Chem. 2003, 68, 9191−9199.
(44) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;
Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.;
Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, Jr., J. A.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.;
Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo,
C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin,
A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma,
K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
̈
Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.;
1519
dx.doi.org/10.1021/jo202386b | J. Org. Chem. 2012, 77, 1507−1519