Efficient synthesis of 9H-pyrrolo[1,2-a]indol-9-one derivatives based on active manganese dioxide promoted intramolecular cyclization

Article abstract of DOI:10.1016/j.tet.2009.10.111

A series of 9H-pyrrolo[1,2-a]indol-9-ones have been prepared via in-situ sequential oxidation of [2-(1H-pyrrol-1-yl)phenyl]methanols promoted by active manganese dioxide. The procedure led to title compounds in good yields under mild conditions, without the need to isolate the intermediate aldehydes.

Full text of DOI:10.1016/j.tet.2009.10.111

Tetrahedron 66 (2010) 274–277
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Efficient synthesis of 9H-pyrrolo[1,2-a]indol-9-one derivatives based on active
manganese dioxide promoted intramolecular cyclization
*
Francesca Aiello, Antonio Garofalo , Fedora Grande
`
Dipartimento di Scienze Farmaceutiche, Universita della Calabria, Arcavacata di Rende 87036, Cosenza, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 3 July 2009
Received in revised form 13 October 2009
Accepted 29 October 2009
Available online 1 November 2009
A series of 9H-pyrrolo[1,2-a]indol-9-ones have been prepared via in-situ sequential oxidation of [2-(1H-
pyrrol-1-yl)phenyl]methanols promoted by active manganese dioxide. The procedure led to title com-
pounds in good yields under mild conditions, without the need to isolate the intermediate aldehydes.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
9H-Pyrrolo[1,2-a]indol-9-one
2-(1H-Pyrrol-1-yl)benzaldehyde
Intramolecular cyclization
Oxidation
1. Introduction
More recently, Kobayashi et al.10 prepared fluorazone (1a), along
with some benzo-substituted derivatives, by acidic hydrolysis of 9-
In recent years, many investigations have focused on the
chemistry and biological activities of 9H-pyrrolo[1,2-a]indol-9-one
(fluorazone) (1a) and its derivatives. This considerable interest
arises from the fact that fluorazone represents the direct chemical
precursor of 9H-pyrrolo[1,2-a]indole (fluorazene), the basic
framework of cytostatic mytomycine derivatives.1 Moreover, psy-
chostimulant activity,2 cytotoxic3 and photosensitizing properties4
have been reported for some fluorazone derivatives. Very recently,
we have found that some N0-heteroacyl-9H-pyrrolo[1,2-a]indol-9-
hydrazones, directly obtained from 9H-pyrrolo[1,2-a]indol-9-one,
demonstrate moderate activity against a colon cancer cell line.5
Thus far, several methods are known for the synthesis of 9H-pyr-
rolo[1,2-a]indol-9-ones. The reference ketone was first prepared in
a 25% yield from methyl 2-(1H-pyrrol-1-yl)benzoate via hydrolysis
and subsequent cyclization of the corresponding acid promoted by
polyphosphoric acid.6 The original method was however greatly
improved by use of classical Friedel–Crafts reactants in the cycli-
zation step.7 Unsubstituted fluorazone has also been prepared by
palladium-catalyzed cyclocarbonylation of 1-(2-iodophenyl)-1H-
pyrrole8 or by direct double metallation of 1-phenyl-1H-pyrrole
followed by treatment of the resulting dilithium salt with ethyl
N,N-dimethylcarbamate as a carbonylating reagent.9
phenylimino-9H-pyrrolo[1,2-a]indole, in turn obtained by reaction of
2-(1H-pyrrol-1-yl)benzaldehyde and aniline (Scheme 1). However,
low yield, harsh reaction conditions or the use of harmful reactants
prevented a general application of previous procedures. Thus, our
continued interest in the synthesis of drug-like molecules, derived
from nitrogen containing polycondensed heterocyclic systems,
spurred us to investigate an alternative and efficient method for the
production of fluorazone and its benzo-substituted derivatives.
COCl
CO2H
N
N
SnCl4
PPA
32%
87% ref 7
ref 6
O
CO/Pd(0)
96%
I
HCl
N
64%
ref 8
Ph
N
N
1a
ref 10
EtOCONMe2
84%
N
ref 9
Li
N
Li
* Corresponding author. Tel.: þ39 0984 493118; fax: þ39 0984 493298.
E-mail address: garofalo@unical.it (A. Garofalo).
Scheme 1. Known methods for the synthesis of 1a.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.10.111

F. Aiello et al. / Tetrahedron 66 (2010) 274–277
275
2. Results and discussion
phenyl ring, to give corresponding substituted-ketones 1b–f in 60–
72% yield. As an exception, [5-methoxy-2-(1H-pyrrol-1-yl) phe-
nyl]methanol (2d) generated the corresponding 7-methoxy-
fluorazone (1d) in a 28% yield only, while unreacted aldehyde 3d
was isolated in a 30% yield. This behaviour could be due to a gen-
erally different absorption of methoxy derivatives on the solid
MnO2 surface.12b In all cases, GC monitoring confirmed that the
reaction proceeds through the formation of intermediate aldehyde,
the carbonyl group of which is in turn exposed to intramolecular
nucleophilic attack from the pyrrole, promoted by the temperature
increase and a likely coordinating action of superficial molecules of
MnO2 on the carbonyl. The putative fluorenol-like carbinol formed
is then readily in-situ oxidized by a second equivalent of oxidant12b
driving the reaction to the almost exclusive formation of cyclic
ketone. On the other hand, the same reaction conditions applied to
Recently, we investigated the preparation of some pyrrolo-
benzazepines using 2-(1H-pyrrol-1-yl)benzaldehyde (3a) as
starting material.11a The latter was obtained by oxidation of [2-(1H-
pyrrol-1-yl)phenyl]methanol11b (2a) in benzene at reflux by the
action of active MnO2, an agent widely used for the conversion of
benzylic alcohols to aldehydes by a free radical mechanism.12
During the reaction, the unexpected formation of traces of fluo-
razone (1a) as a side-product was noticed, especially after pro-
longed reaction time (Scheme 2). This result prompted us to
thoroughly re-examine the conditions with the aim of driving the
reaction towards exclusive formation of the ketone 1a. Even though
it has been reported that aldehydes generated by MnO2 oxidation
may be in-situ trapped by nucleophilic species,13 to the best of our
O
H
OH
CH2OH
N
CHO
N
R
R
[Ox]
[Ox]
R
R
N
N
R'
R'
R'
R'
1a-f (28-72%)
2a-f
3a-f
a R=R'=H
b R=F, R'=H
c R=CH3, R'=H
d R=OCH3, R'=H
e R=NO2, R'=H
f R=H, R'=CH3
Scheme 2. Sequential oxidation process.
knowledge, no examples have been yet reported about the use of
MnO2 as a promoter of cyclization reactions through carbon–car-
bon bond formation. Furthermore, it is known that the oxidant
properties of manganese dioxide can be greatly enhanced by in-
creasing temperature.14 Several conditions were then attempted
during the oxidation reaction by varying temperature, solvent, type
of MnO2 used and oxidant/alcohol ratio. As a result, it was con-
cluded that the conversion of alcohol 2a into fluorazone (1a),
through ‘intermediate’ aldehyde 3a, depends mainly on the boiling
temperature of the solvent. Either commercial or freshly-pre-
pared15 active MnO2 was used, but neither the type nor the amount
of oxidant excess used seem to significantly affect the course of the
reaction. Thus, the best results were obtained by using a fivefold
excess of commercially available active MnO2 in toluene at reflux
for 72 h, under Dean–Stark conditions. In these neutral and es-
sentially anhydrous conditions, fluorazone (1a) was obtained in
64% yield, after chromatographic purification. Attempts to shorten
the reaction time, by running the reaction in a sealed tube, were
unsuccessful. A parallel experiment conducted on aldehyde 3a,
under a stream of dry air, in the absence of MnO2, did not lead to the
reference ketone 1a. The MnO2 promoted procedure was then ex-
tended to analogous alcohols 2b–f variously substituted on the
2-biphenylmethanol (4), a commercially available analogue, which
bears an inert phenyl ring instead of the reactive electron-richer
pyrrole, did not promote any conversion to 9H-fluoren-9-one (6),
making the 2-biphenylcarboxaldehyde (5) as the sole product
recovered (Scheme 3).
O
CH2OH
CHO
[Ox]
4
5
6
Scheme 3. Oxidation of 2-biphenylmethanol.
The starting [2-(1H-pyrrol-1-yl)phenyl]methanols 2a–f were
obtained in a three-step procedure from (un)substituted anthra-
nilic acids 7a–f, which were first transformed to esters 8a–f directly
or via isatoic anhydrides. Clauson–Kaas pyrrolation of esters 8a–f
with dimethoxytetrahydrofuran (DMTF) gave pyrrole derivatives
9a–f, which in turn were subjected to lithium aluminium hydride
(LAH) reduction to give alcohols 2a–f in generally good yield
(Scheme 4).16,17
XOH/H+ or
CO2X
CO2H
NH2
CO2X
NH2
1. (Cl3CO)2CO
2. XOH
LAH/Et2O
DMTF/AcOH
R
N
R
R
2a-f
R'
R'
7a-f
R'
8a-f
9a-f
a R=R'=H, X=Me
b R=F, R'=H, X=Me
c R=CH3, R'=H, X=Me
d R=OCH3, R'=H, X=Et
e R=NO2, R'=H, X=Et
f R=H, R'=CH3, X=Me
Scheme 4. Synthesis of [2-(1H-pyrrol-1-yl)phenyl]methanols 2a–f.

276
F. Aiello et al. / Tetrahedron 66 (2010) 274–277
3. Conclusion
(EI, 70 eV): m/z 187 (Mþ, 100), 158 (32), 132 (22). Anal. Calcd for
C11H6FNO (%): 70.59 C; 3.23 H; 7.48 N. Found (%): 70.30 C; 3.09 H;
7.70 N. Mp: 124 ꢁC.
The reaction sequence outlined in Scheme 2 provides an alter-
native and simple route to various (un)substituted-fluorazones via
intramolecular oxidative-cyclization, starting from either [2-(1H-
pyrrol-1-yl)phenyl]methanols or 2-(1H-pyrrol-1-yl)benzaldehydes.
The reaction represents the first example of an intramolecular cy-
clization promoted by active MnO2 through bond formation between
4.2.3. 7-Methyl-9H-pyrrolo[1,2-a]indol-9-one (1c)1b. Following the
identical procedure as described for compound 1a, starting from
[5-methyl-2-(1H-pyrrol-1-yl)phenyl]methanol (2c), compound
1c was obtained after silica gel column chromatography (Me2CO/
a pyrrole
a
-carbon and an aldehyde carbonyl. Studies are in progress
hexanes, 1/9 as eluent). The yield, after recrystallization from
1
with the aim of finding the most suitable conditions to extend the
method to a wider range of substrates.
CHCl3/cyclohexane, was 66%. H NMR (CDCl3, 25 ꢁC),
d
: 7.37 (s,
1H), 7.20 (d, 1H, J¼7.9 Hz), 7.02 (d, 1H, J¼2.5 Hz), 6.98 (d, 1H,
J¼7.8 Hz), 6.74 (d, 1H, J¼3.8 Hz), 6.27 (t, 1H, J¼3.5 Hz), 2.30 (s,
13
4. Experimental
4.1. General
3H). C NMR (CDCl3, 25 ꢁC)
d: 177.3, 138.4, 135.9, 134.2, 133.6,
125.1, 124.2, 119.3, 115.5, 113.7, 109.9, 29.7. IR (KBr discs) 1686,
1619 cmꢂ1. MS (EI, 70 eV): m/z 183 (Mþ, 100), 154 (54), 128 (15),
77 (11). Anal. Calcd for C12H9NO (%): 78.67 C; 4.95 H; 7.65 N.
Found (%): 78.38 C; 5.01 H; 7.88 N. Mp: 110–111 ꢁC (lit.1b Mp:
110–111 ꢁC).
Progress of the reaction was monitored by TLC on silica gel
plates (Riedel-de Hae¨n, Art. 37341) or GC by a Hewlett–Packard
6890 apparatus. Organic solutions were dried over MgSO4 and
evaporated on a rotary evaporator under reduced pressure. Melting
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 spectra were
recorded on a Bru¨ker 300 MHz spectrometer with TMS as an in-
4.2.4. 7-Methoxy-9H-pyrrolo[1,2-a]indol-9-one (1d). Following the
identical procedure as described for compound 1a, starting from
[5-methoxy-2-(1H-pyrrol-1-yl)phenyl]methanol (2d), compound
1d was obtained after silica gel column chromatography (CH2Cl2
as eluent). The yield, after recrystallization from CH2Cl2/cyclo-
ternal standard: chemical shifts are expressed in
d
values (ppm)
hexane, was 28%. 1H NMR (CDCl3, 25 ꢁC),
7.01 (m, 2H), 6.93 (d, 1H, J¼2.5 Hz), 6.75 (d, 1H, J¼3.8 Hz), 6.25
(m, 1H), 3.80 (s, 3H). 13C NMR (CDCl3, 25 ꢁC)
: 179.5, 157.8, 137.4,
d
: 7.13 (d, 1H, J¼2.5 Hz),
and coupling constants (J) in Hz. Mass spectral data were de-
termined after electron impact ionisation at 70 eV with a HP 5973
MS spectrometer. Merck silica gel (Kieselgel 60/230–400 mesh)
was used for flash chromatography columns. Elemental analyses
were performed on a Perkin–Elmer 240C elemental analyzer, and
the results are within ꢀ0.4% of the theoretical values. All reactions
were carried out under a nitrogen atmosphere. Yields refer to
purified products and are not optimized.
d
132.2, 131.5, 119.6, 119.2, 115.3, 114.2, 111.0, 109.7, 55.9. IR (KBr
discs) 1692, 1630, 1607 cmꢂ1. MS (EI, 70 eV): m/z 199 (Mþ, 86),
184 (100), 156 (31), 128 (23), 63 (15). Anal. Calcd for C12H9NO2
(%): 72.35 C; 4.55 H; 7.03 N. Found (%): 72.50 C; 4.84 H; 7.26 N.
Mp: 124–125 ꢁC.
4.2.5. 5-Methoxy-2-(1H-pyrrol-1-yl)benzaldehyde (3d). This com-
4.2. Typical procedure for sequential MnO2 oxidation of
[2-(1H-pyrrol-1-yl)phenyl]methanols
pound was isolated as a brown oil in 30% yield during chromato-
graphic purification of compound 1d. 1H NMR (CDCl3, 25 ꢁC),
d: 9.70
(s, 1H), 7.47 (d, 1H, J¼3.0 Hz), 7.34 (d, 1H, J¼8.7 Hz), 7.19 (dd, 1H,
J¼8.7, 3.0 Hz), 6.87 (t, 2H, J¼2.0 Hz), 6.35 (t, 2H, J¼2.0 Hz), 3.89 (s,
3H). IR (KBr discs) 1695 cmꢂ1. Anal. Calcd for C12H11NO2 (%): 71.63
C; 5.51 H; 6.96 N. Found (%): 71.41 C; 5.76 H; 7.15 N.
4.2.1. 9H-Pyrrolo[1,2-a]indol-9-one (1a)9. A suspension of acti-
vated manganese dioxide (Merck art. 805958) (4.14 g,
47.62 mmol) in toluene (200 mL) was heated at reflux for 1 h
under a Dean–Stark trap. A solution of [2-(1H-pyrrol-1-yl)phe-
nyl]methanol 2a (1.65 g, 9.53 mmol) in toluene (10 mL) was then
added dropwise under stirring. The heating was continued for
72 h. Removal of the solid by filtration on Celite gave a clear so-
lution which was concentrated under vacuum. The residue
obtained was purified by silica gel column chromatography
(AcOEt/hexanes, 1/6 as eluent) to give pure compound 1a as
a yellow solid. The yield, after recrystallization from CHCl3/cy-
4.2.6. 7-Nitro-9H-pyrrolo[1,2-a]indol-9-one (1e)1c. Following the
identical procedure as described for compound 1a, starting from [5-
nitro-2-(1H-pyrrol-1-yl)phenyl]methanol (2e), compound 1e was
obtained after silica gel column chromatography (CH2Cl2 as eluent).
The yield, after recrystallization from CHCl3/cyclohexane, was 68%.
1H NMR (CDCl3, 25 ꢁC),
d
: 8.42 (m, 1H), 7.24 (t, 2H, J¼3.4 Hz), 7.18 (d,
1H, J¼2.1 Hz), 6.91 (d, 1H, J¼3.1 Hz), 6.43 (t, 1H, J¼3.1 Hz). 13C NMR
clohexane, was 1.03 g (64% yield). 1H NMR (CDCl3, 25 ꢁC),
d
: 7.59
(CDCl3, 25 ꢁC)
d: 178.5, 150.5, 139.8, 133.5, 130.3, 126.0, 121.1, 120.4,
(d, 1H, J¼7.7 Hz), 7.40 (dt, 1H, J¼7.7, 1.2 Hz), 7.13–7.06 (m, 3H), 6.76
116.1, 116.3, 110.4. IR (KBr discs) 1696, 1635 cmꢂ1. MS (EI, 70 eV): m/
z 214 (Mþ, 100), 184 (21), 168 (18), 140 (47), 113 (15). Anal. Calcd for
C11H6N2O3 (%): 61.69 C; 2.82 H; 13.08 N. Found (%): 61.44 C; 2.71 H;
13.31 N. Mp: 200–201 ꢁC (lit.1c Mp: 202–204 ꢁC).
(d, 1H, J¼3.7 Hz), 6.29 (dd, 1H, J¼3.7, 2.6 Hz). 13C NMR (CDCl3,
25 ꢁC)
d: 178.6, 142.7, 133.9, 130.9, 129.2, 124.4, 123.4, 118.4, 114.9,
112.9, 109.3. IR (KBr discs) 1680, 1617 cmꢂ1. MS (EI, 70 eV): m/z 169
(Mþ, 100), 140 (25), 114 (17). Anal. Calcd for C11H7NO (%): 78.09 C;
4.17 H; 8.28 N. Found (%): 77.88 C; 4.05 H; 8.39 N. Mp: 121–123 ꢁC
(lit.9 Mp: 121–122 ꢁC).
4.2.7. 5-Methyl-9H-pyrrolo[1,2-a]indol-9-one (1f)1b. Following the
identical procedure as described for compound 1a, starting from
[3-methyl-2-(1H-pyrrol-1-yl)phenyl]methanol (2f), compound 1f
was obtained after silica gel column chromatography (AcOEt/hex-
4.2.2. 7-Fluoro-9H-pyrrolo[1,2-a]indol-9-one (1b). Following the
identical procedure as described for compound 1a, starting from
[5-fluoro-2-(1H-pyrrol-1-yl)phenyl]methanol (2b), compound 1b
was obtained after silica gel column chromatography (AcOEt/
anes, 3/7 as eluent). The yield, after recrystallization from CHCl3/
1
cyclohexane, was 72%. H NMR (CDCl3, 25 ꢁC),
d: 7.49 (d, 1H,
J¼7.3 Hz), 7.23 (d, 1H, J¼7.7 Hz), 7.20 (dd, 1H, J¼2.6, 0.8 Hz), 7.05 (t,
hexanes, 3/7 as eluent). The yield, after recrystallization from
1H, J¼7.4 Hz), 6.82 (dd, 1H, J¼2.9, 0.8 Hz), 6.30 (dd, 1H, J¼2.6,
1
13
Et2O/hexanes, was 60%. H NMR (CDCl3, 25 ꢁC),
d
: 7.22 (dm, 1H,
1.2 Hz), 2.50 (s, 3H). C NMR (CDCl3, 25 ꢁC)
d
: 179.9, 142.1, 136.8,
J¼7.1 Hz), 7.10–6.95 (m, 3H), 6.76 (d, 1H, J¼3.8 Hz), 6.29 (m, 1H).
13C NMR (CDCl3, 25 ꢁC)
: 162.3, 159.0, 120.2, 119.9, 119.8, 116.1,
114.9, 112.4, 112.1, 111.2, 111.1. IR (KBr discs) 1690, 1610 cmꢂ1. MS
133.0, 126.3, 125.3, 122.3, 122.2, 121.1, 115.7, 113.5, 17.7. IR (KBr discs)
1687, 1675, 1620, 1599 cmꢂ1. MS (EI, 70 eV): m/z 183 (Mþ, 83), 154
(100), 127 (13). Anal. Calcd for C12H9NO (%): 78.67 C; 4.95 H; 7.65 N.
d

F. Aiello et al. / Tetrahedron 66 (2010) 274–277
277
Found (%): 78.85 C; 4.71 H; 7.97 N. Mp: 137–139 ꢁC (lit.1b Mp:
139–140 ꢁC).
from ester 9f, compound 2f was obtained as a yellow solid in 93%
yield after column chromatography purification on silica gel
(AcOEt/hexanes, 1/2 as eluent). Mp: 56–58 ꢁC (AcOEt/hexanes). 1H
4.3. Typical procedure for the reduction of 2-(1H-pyrrol-
1-yl)benzoates
NMR (CDCl3, 25 ꢁC),
d
: 7.34–7.13 (m, 3H), 6.58 (t, 2H, J¼2.0 Hz), 6.27
(t, 2H, J¼2.0 Hz), 4.30 (s, 2H), 2.00 (s, 3H), 1.80 (br s, 1H). 13C NMR
(CDCl3, 25 ꢁC)
d: 136.6, 130.4, 128.7, 123.4, 123.2, 122.3, 122.1, 109.3,
4.3.1. [2-(1H-Pyrrol-1-yl)phenyl]methanol (2a)11b. This compound
was prepared by LAH reduction of ester 9a following the method
described in Ref. 11b. The oil obtained was purified by column
chromatography on silica gel (AcOEt/hexanes, 3/7 as eluent).
60.7, 18.4. Anal. Calcd for C12H13NO (%): 76.98 C; 7.00 H; 7.48 N.
Found (%): 76.71 C; 7.21 H; 7.65 N.
Acknowledgements
4.3.2. [5-Fluoro-2-(1H-pyrrol-1-yl)phenyl]methanol (2b). Following
the identical procedure as described for compound 2a, starting from
ester 9b, compound 2b was obtained as a brown oil in 72% yield after
Authors thank Dr. Melissa Millard for careful reading of the
manuscript and Dr. Roberta Cassano for technical assistance.
column chromatography purification on silica gel (AcOEt/hexanes, 3/
1
7 as eluent). H NMR (CDCl3, 25 ꢁC),
d: 7.30 (m, 2H), 7.05 (td, 1H,
J¼8.0, 3.0 Hz), 6.78 (t, 2H, J¼2.1 Hz), 6.34 (t, 2H, J¼2.0 Hz), 4.60 (s,
Supplementary data
13
2H), 2.18 (br s, 1H). C NMR (CDCl3, 25 ꢁC)
d: 160.5, 128.4, 128.2,
Synthesis and analytical data of compounds 9a–f, copies of 1H
NMR spectra of 1a–f, 2f, 3d and 9f, 13C NMR spectra of 1a,b and
d and IR spectra of 1a,b and d. Supplementary data associated with
this article can be found in online version at doi:10.1016/
j.tet.2009.10.111.
122.5, 115.4, 115.1, 114.8, 109.4, 60.7. Anal. Calcd for C11H10FNO (%):
69.10 C; 5.27 H; 7.33 N. Found (%): 68.91 C; 5.45 H; 7.03 N.
4.3.3. [5-Methyl-2-(1H-pyrrol-1-yl)phenyl]methanol (2c). Following
the identical procedure as described for compound 2a, starting
from ester 9c, compound 2c was obtained as an oil in 87% yield after
column chromatography purification on silica gel (AcOEt/hexanes,
1/2 as eluent). 1H NMR (CDCl3, 25 ꢁC),
d
: 7.35 (m, 3H), 6.93 (t, 2H,
J¼2.0 Hz), 6.43 (t, 2H, J¼2.0 Hz), 4.60 (s, 2H), 2.50 (s, 3H), 2.25 (br s,
1H). 13C NMR (CDCl3, 25 ꢁC)
: 135.9,135.7,130.9,130.5, 128.4, 123.6,
References and notes
}
}
1. (a) Fogassy, K.; Kova´cs, K.; Keseru, G. M.; Toke, L.; Faigl, F. J. Chem. Soc., Perkin
Trans. 1 2001, 1039; (b) Artico, M.; Giuliano, R.; Porretta, G. C.; Scalzo, M. Il
Farmaco 1972, 27, 60; (c) Porretta, G. C.; Filacchioni, G.; Stefancich, G.; Giuliano,
R.; Artico, M. Il Farmaco 1978, 33, 263.
d
119.9, 109.8, 60.8, 24.4. Anal. Calcd for C12H13NO (%): 76.98 C; 7.00
H; 7.48 N. Found (%): 77.13 C; 7.18 H; 7.36 N.
2. Rault, S.; Lancelot, J. C.; Bouyazza, L.; Robba, M.; Quermonne, M. A.; Namma-
thao, B.; Louchahi-Raoul, J.; Marcy, R. Eur. J. Med. Chem. 1991, 26, 939.
3. Lisowsky, V.; Le´once, S.; Kraus-Berthier, L.; Sopkova`-de Oliveira Santos, J.;
Pierre´, A.; Atassi, G.; Caignard, D. H.; Renard, P.; Rault, S. J. Med. Chem. 2004, 47,
1448.
4. Bauer, R.; Heisler, G.; Konigstein, C. Spectrochim. Acta, Part A 1994, 50A, 57.
5. Grande, G.; Yamada, R.; Cao, X.; Aiello, F.; Garofalo, A.; Neamati, N. Expert Opin.
Investig. Drugs 2009, 18, 555.
4.3.4. [5-Methoxy-2-(1H-pyrrol-1-yl)phenyl]methanol (2d). Following
the identical procedure as described for compound 2a, starting from
ester 9d, compound 2d was obtained as a yellow solid in 80% yield
after column chromatography purification on silica gel (AcOEt/hex-
anes, 1/2 as eluent). Mp: 83–85 ꢁC (CHCl3/hexanes). 1H NMR (CDCl3,
25 ꢁC),
J¼2.0 Hz), 6.27 (t, 2H, J¼2.0 Hz), 4.50 (s, 2H), 3.82 (s, 3H), 2.00 (br s,
1H). 13C NMR (CDCl3, 25 ꢁC)
: 159.8, 129.7, 129.2, 123.0, 119.9, 113.9,
d: 7.16 (m, 2H), 6.85 (dd, 1H, J¼8.6, 2.8 Hz), 6.75 (t, 2H,
6. Josey, A. D.; Jenner, E. L. J. Org. Chem. 1962, 27, 2466.
7. (a) Mazzola, V. J.; Bernady, K. F.; Franck, R. W. J. Org. Chem. 1967, 32, 486; (b)
Bailey, A. S.; Scott, P. W.; Vandrevala, M. H. J. Chem. Soc., Perkin Trans. 1 1980,
97.
d
111.6,109.5, 60.1, 56.5. Anal. Calcd for C12H13NO2 (%): 70.92 C; 6.45 H;
6.89 N. Found (%): 70.71 C; 6.09 H; 7.11 N.
8. Campo, M. A.; Larock, R. C. J. Org. Chem. 2002, 67, 5616.
9. Kashulin, I. A.; Nifant’ev, I. E. J. Org. Chem. 2004, 69, 5476.
10. Kobayashi, K.; Himei, Y.; Fukamachi, S.; Tanmatsu, M.; Morikawa, O.; Konishi, H.
Tetrahedron 2007, 63, 4356.
4.3.5. [5-Nitro-2-(1H-pyrrol-1-yl)phenyl]methanol (2e). Following
the identical procedure as described for compound 2a, but oper-
ating at a temperature of ꢂ20 ꢁC, starting from ester 9e, compound
2e was obtained as a waxy solid in 64% yield after column chro-
matography purification on silica gel (AcOEt/hexanes, 1/2 as
11. (a) Garofalo, A.; Ragno, G.; Campiani, G.; Brizzi, A.; Nacci, V. Tetrahedron 2000,
56, 9351; (b) Basha, F. Z.; Franck, R. W. J. Org. Chem. 1978, 43, 3415.
12. (a) Tojo, G.; Fernandez, M. In Oxidation of Alcohols to Aldehydes and Ketones;
Springer: New York, NY, 2006; pp 290–309; (b) Pratt, E. F.; Van De Castle, J. F.
J. Org. Chem. 1961, 26, 2973.
13. (a) Wei, X.; Taylor, R. J. K. Tetrahedron Lett. 1998, 39, 3815; (b) Maki, B. E.; Chan,
A.; Phillips, E. M.; Scheidt, K. A. Org. Lett. 2007, 9, 371; (c) Taylor, R. J. K.; Reid,
M.; Foot, M. J.; Raw, S. A. Acc. Chem. Res. 2005, 38, 851.
14. (a) Pratt, E. F.; McGovern, T. P. J. Org. Chem. 1964, 29, 1540; (b) Barton, T. J.;
Banasiak, D. S. J. Organomet. Chem. 1978, 157, 255; (c) Malakov, P. Y.; De la Torre,
M. C.; Rodriguez, B.; Papanov, G. Tetrahedron 1991, 47, 10129.
15. Attenburrow, J.; Cameron, A. F. B.; Chapman, J. H.; Evans, R. M.; Hems, B. A.;
Jansen, A. B. A.; Walker, T. J. Chem. Soc. 1952, 1094.
eluent). 1H NMR (CDCl3, 25 ꢁC),
d
: 8.60 (d, 1H, J¼2.4 Hz), 8.28 (dd,
1H, J¼8.6, 2.5 Hz), 7.50 (dd, 1H, J¼8.6, 2.6 Hz), 6.95 (t, 2H, J¼2.1 Hz),
6.43 (t, 2H, J¼2.1 Hz), 4.75 (s, 2H); 1.90 (br s, 1H). 13C NMR (CDCl3,
25 ꢁC)
d: 147.5, 144.3, 131.0, 123.9, 123.1, 122.9, 121.1, 109.5, 56.9.
Anal. Calcd for C11H10N2O3 (%): 60.55 C; 4.62 H; 12.84 N. Found (%):
60.78 C; 4.29 H; 13.14 N.
16. Bavetsias, V.; Skelton, L. A.; Yafai, F.; Mitchell, F.; Wilson, S. C.; Allan, B.; Jack-
man, A. L. J. Med. Chem. 2002, 45, 3692.
17. Paillet-Loilier, M.; Fabis, F.; Lepailleur, A.; Bureau, R.; Butt-Gueulle, S.; Dau-
phin, F.; Delarue, C.; Vaudry, H.; Rault, S. Bioorg. Med. Chem. Lett. 2005, 15,
3753.
4.3.6. [3-Methyl-2-(1H-pyrrol-1-yl)phenyl]methanol (2f). Following
the identical procedure as described for compound 2a, starting