Polycondensed heterocycles. Part 11: Preparation and regioselective reductions of 5-phenyl-4H-pyrrolo[1,2-α][1]benzazepin-4-one

Article abstract of DOI:10.1016/S0040-4020(00)00900-5

The Wadsworth-Emmons olefination between 2-(1H-pyrrol-1-yl)benzaldehyde and methyl α-(diethylphosphonyl)phenyl-acetate leads exclusively to the cis-isomer of methyl 2-(1H-pyrrol-1-yl)-α-phenylcinnamate, which, after transformation into the corresponding a

Full text of DOI:10.1016/S0040-4020(00)00900-5

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 9351±9355
Polycondensed Heterocycles. Part 11: Preparation and
Regioselective Reductions of
5-Phenyl-4H-pyrrolo[1,2-a][1]benzazepin-4-one
a
b
c
c
Antonio Garofalo,a, Gaetano Ragno, Giuseppe Campiani, Antonella Brizzi and Vito Nacci
*
aDipartimento di Scienze Farmaceutiche, Universita' della CalabriaÐ87036 Arcavacata di Rende (CS), Italy
bDipartimento di Scienze Farmaceutiche, Universita' di SalernoÐ84084 Fisciano (SA), Italy
cDipartimento Farmaco Chimico Tecnologico, Universita' di Siena, Via Aldo MoroÐ53100 Siena, Italy
Received 17 June 2000; revised 1 September 2000; accepted 21 September 2000
AbstractÐThe Wadsworth±Emmons ole®nation between 2-(1H-pyrrol-1-yl)benzaldehyde and methyl a-(diethylphosphonyl)phenyl-
acetate leads exclusively to the cis-isomer of methyl 2-(1H-pyrrol-1-yl)-a-phenylcinnamate, which, after transformation into the correspond-
ing acid chloride, was easily cyclised to the title enone. This latter was regioselectively reduced to the corresponding saturated ketone or
unsaturated alcohol, under different experimental conditions. An improved preparation of starting 2-(1H-pyrrol-1-yl)benzaldehyde is also
reported. q 2000 Elsevier Science Ltd. All rights reserved.
Introduction
the corresponding saturated alcohol 4 was obtained when
exposing enone 1 to less selective reduction conditions.
The interest in the chemistry of heterocyclic systems with
general formulas I±III arises from the biological activity
showed by several of their derivatives. Our recent work in
this area has concentrated on the production of enolizable
6-arylpyrrolo[2,1-d][1,5]benzoheteroazepin-7(6H)ones I,
as synthetic precursors of ligands II, speci®c for the
peripheral-type benzodiazepine receptor (PBR),1 and the
corresponding 6-alkyl-6-aryl derivatives III, as inhibitors
of HIV-reverse transcriptase (Fig. 1).2
Results and Discussion
An exhaustive literature survey led to only two procedures
for the preparation of pyrrolo[1,2-a][1]benzazepine deriva-
tives,3,4 the more adaptable being the one described by
Plummer et al.,3 who performed a polyphosphoric acid-
catalysed cyclisation of a preformed 3-[2-(1H-pyrrol-1-
yl)phenyl]propionic acid, as the key step. In our case, the
For both classes of compounds, results of biological testing
seemed to prove that the nature of the atom at position 5 was
not crucial for the interaction with receptors. As a proof of
such a hypothesis, we planned to prepare and test analogues
with a methylene group replacing the heteroatom in position
5, as bioisosteres of the above compounds. Accordingly, we
herein report the synthesis of 5-phenyl-4H-pyrrolo[1,2-a]-
[1]benzazepin-4-one 1, which, after selective 1,4-reduction
of the enone moiety, furnishes the corresponding saturated
ketone 2, the common key intermediate for the preparation
of both classes of isosteres (Scheme 1). Selective enone 1,2-
reduction of compound 1 produces allylic alcohol 3, which
allows the preparation of new PBR ligands with a fairly
unchanged overall conformation of the tricyclic system,
but a different electronic arrangement due to the retaining
of the double bond in the original 5,6-position. Furthermore,
Keywords: benzazepines; cyclisation; ole®nation; reduction.
* Corresponding author. Tel.: 139-0577-234173; fax: 139-0577-234333;
e-mail: garofalo@unisi.it
Figure 1.
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00900-5

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A. Garofalo et al. / Tetrahedron 56 (2000) 9351±9355
Scheme 1.
synthesis of a 2-(1H-pyrrol-1-yl)-a-phenylcinnamic acid 5
with which to subject to cyclisation had to be set up and
2-(1H-pyrrol-1-yl)benzaldehyde 6 was accordingly selected
as the starting material.
2-(1H-pyrrol-1-yl)-a-phenylcinnamate 9 exclusively as the
cis-isomer (Scheme 2). No formation of any trans-isomer
was actually detected after this reaction. Alkaline hydrolysis
of ester 9 smoothly gave the desired acid 5 in very good
yield. Our attempts to carry out the cyclisation to the title
compound 1 after the procedure of Plummer et al. (poly-
phosphoric acid, 1208C) resulted in failure. Better results
were achieved when using an uncatalysed Friedel±Crafts
reaction with PCl5, following a method already applied
to similar compounds.5 The choice of methyl ester 8, a
Hence, the Wadsworth±Emmons ole®nation between the
ylide generated by sodium hydride on crude methyl
a-(diethylphosphonyl)phenylacetate 7, (in turn obtained
by action of triethyl phosphite on methyl a-bromophenyl-
acetate 8) and aldehyde 6 afforded the expected methyl
Scheme 2.

A. Garofalo et al. / Tetrahedron 56 (2000) 9351±9355
9353
Scheme 3.
strong lachrymatory compound, which requires accurate
precautions during manipulation, was justi®ed by the fact
that its little encumbering methyl group should correctly
drive the reaction towards a product with the desired
geometry.
Experimental
Where necessary, solvents were dried and puri®ed accord-
ing to the recommended procedures.11 Extracts were dried
over Na2SO4 and solvents were removed under reduced
pressure. Melting points were determined using an Electro-
thermal 8103 capillary apparatus and are uncorrected.
Infrared spectra were recorded on a Perkin±Elmer 398
spectrophotometer using KBr discs and nuclear magnetic
resonance spectra were taken on a Bruker 200 instrument.
The chemical shifts are reported in parts per million relative
to tetramethylsilane as an internal standard. Mass spectral
data were determined by direct insertion at 70 eV with a
VG70 spectrometer. Flash chromatography separations
were performed using Merck 230±400 mesh silica gel as
the solid phase. Elemental analyses were performed on a
Perkin±Elmer 240C elemental analyzer. All reactions were
carried out in an argon atmosphere.
The starting aldehyde 6 had previously been prepared by
Raines et al.,6 after a McFadyen±Stevens reduction of
methyl 2-(1H-pyrrol-1-yl)benzoate 10, but such a method
proved rather unsatisfactory owing to the low overall yield
(,30%). Therefore, we found a new and more ef®cient two-
step procedure, consisting of LAH reduction of the same
starting ester 10 to 2-(1H-pyrrol-1-yl)benzenemethanol
117 which swiftly was subjected to MnO2 oxidation. In
this way, aldehyde 6 was obtained in a 90% yield (Scheme
3).
The enone 1 was then selectively reduced to the racemic
saturated ketone 2 by 5% Pd(C) catalysed hydrogenation
under atmospheric pressure, the reaction interrupted after
absorption of 1 equiv. of hydrogen. In fact, the correspond-
ing saturated racemic cis-alcohol 4 was obtained at higher
pressure of hydrogen and/or prolonged reaction time
(Scheme 1). The relative con®guration of alcohol 4 was
2-(1H-Pyrrol-1-yl)benzaldehyde (6). To a cooled (08C)
and stirred solution of methyl 2-(pyrrol-1-yl)benzoate 10
(0.72 g, 3.6 mmol) in dry diethyl ether (15 mL) was added
dropwise a slurry of LAH (0.28 g, 7.3 mmol) in the same
solvent (10 mL). After 15 min, the unreacted LAH was
cautiously quenched with ethyl acetate and a few drops of
15% sulfuric acid. The mixture was then extracted with
ethyl acetate and the organic layer was evaporated to
dryness to give almost pure 2-(1H-pyrrol-1-yl)benzene-
methanol 11 (0.59 g, 95%) as an oil,7 which was used
without puri®cation in the subsequent step. A solution of
alcohol 11 (0.59 g, 3.4 mmol) in benzene (4 mL) was slowly
added to a suspension of activated manganese dioxide
(1.2 g, 13.8 mmol) in benzene (20 mL) then heated to re¯ux
under a Dean±Stark apparatus for 16 h. After ®ltration, the
solvent was evaporated and the residue was chromato-
graphed (dichloromethane/light petroleum, 1:1) to afford
pure 6 as a colourless oil (0.55 g, 95%), with physical and
chemical data identical to those reported in ref. 5; bp 728C/
0.05 mmg, Lit.6 bp 70±728C/0.05 mmHg; dH (200 MHz,
CDCl3) 9.25 (s, 1H), 7.95 (m, 1H), 7.63 (m, 1H), 7.41 (m,
2H), 6.90 (m, 2H), 6.38 (m, 2H).
1
assigned on the basis of H NMR experiments, in com-
parison to the results previously obtained for related
compounds,8 re¯ecting the preferred approach of a second
equivalent of hydrogen from the less hindered face of tri-
cyclic system of intermediate ketone 2. More straight-
forwardly, cis-alcohol 4 was obtained by action of NaBH4
on enone 1, very likely via an initial carbonyl reduction
(without the possibility of isolating the intermediate
unsaturated alcohol 3) followed by stereospeci®c double
bond saturation.
The regioselective carbonyl reduction of compound 1 was
successfully carried out by use of lithium n-butylboro-
hydride, following a procedure described by Kim et al.,9
to give unsaturated alcohol 3 in a 92% yield. On the other
hand, no such reaction occurred when attempted under
different conditions (i.e.: Meerwein±Ponndorf reduction,
DIBAH).
Methyl cis-2-(1H-pyrrol-1-yl)-a-phenylcinnamate (9). A
mixture of (^)-methyl a-bromophenylacetate 8 (0.92 g,
4 mmol) and triethyl phosphite (8.3 g, 5 mmol) was heated
at 1608C. After 1 h, a further portion of triethyl phosphite
(8.3 g, 5 mmol) was added and heating continued for 1 h.
The excess triethyl phosphite was distilled under vacuum at
608C and the residue, essentially constituting phosphonyl
ester 7 was dissolved in dry THF (10 mL). This solution
was added dropwise into a cooled (08C) suspension of
sodium hydride (60% oil dispersion, 160 mg, 4 mmol) and
dry THF (5 mL). Stirring was then maintained for 10 min at
room temperature, then a solution of aldehyde 6 (0.7 g,
Conclusions
In conclusion, we have herein described a convenient reac-
tion sequence, which allows the preparation of a precursor
of numerous 5-phenylpyrrolo[1,2-a][1]benzazepine deriva-
tives to submit to biological evaluation. Further possibilities
for the reported synthetic method can be envisaged in the
use, as starting materials, of derivatives of 6 and 8 bearing
substituents on aromatic rings,10 thereby obtaining a variety
of substituted analogues.

9354
A. Garofalo et al. / Tetrahedron 56 (2000) 9351±9355
4 mmol) was added dropwise while cooling and left for 1 h
at room temperature. The solvent was evaporated and the
residue partitioned between water and ethyl acetate. The
organic layer was separated, dried and concentrated to
give a residue which was chromatographed (toluene/cyclo-
hexane, 4:1) to give pure compound 9 as a thick oil (1.1 g,
89%); [Found: C, 79.34; H, 5.77; N, 4.55. C20H17NO2
requires C, 79.19; H, 5.65; N, 4.62%]; IR (neat): nmax
1720 cm21; dH (200 MHz, CDCl3) 7.58 (s, 1H), 7.17±7.32
(m, 7H), 6.81±6.98 (m, 4H), 6.38 (t, 2H, Jˆ1.8 Hz), 3.75 (s,
3H); dC (50.3 MHz, CDCl3) 165.4, 138.7, 137.2, 135.3,
130.7, 129.6, 129.4, 129.0, 127.9, 127.5, 127.1, 126.4,
126.0, 122.1, 109.4, 51.0; m/z [EI] 303 (14 M1), 273 (12),
244 (100), 168 (31), 127 (15%).
hexanes, 1:8). Compound 2 was obtained as a white solid
(0.24 g, 88%); mp 157±1588C (hexanes); [Found: C, 83.71;
H, 5.62; N, 5.16. C19H15NO requires C, 83.49; H, 5.53; N,
5.12%]; IR (Nujol): nmax 1705 cm21; dH (200 MHz, CDCl3)
7.23±7.35 (m, 11H), 6.45 (t, 1H, Jˆ3.3 Hz), 3.96 (dd, 1H,
Jˆ9.5, 2.6 Hz), 3.35 (ddd, 2H, Jˆ13.9, 9.5, 2.6 Hz); dC
(50.3 MHz, CDCl3) 190.2, 140.0, 138.7, 132.9, 132.5,
129.8, 129.0, 128.3, 127.8, 127.5, 127.0, 125.7, 122.4,
117.3, 111.4, 50.1, 32.7; m/z [EI] 273 (60 M1), 244 (54),
168 (100), 154 (13), 127 (8%).
(^)4-Hydroxy-5-phenyl-4H-pyrrolo[1,2-a][1]benzazepine
(3). To a solution of enone 1 (0.27 g, 1 mmol) in dry THF
(6 mL), a suspension of lithium n-butylborohydride in
THF±n-hexane [4 mL of a 0.25 M solution (prepared from
borane±dimethyl sul®de complex and n-butyllithium, as
described by Kim et al.), 1 mmol]9 was added dropwise
over 5 min in a dry ice±acetone bath. After 6 h of being
stirred at 2788C, the reaction mixture was hydrolysed
with water (0.5 mL) and then allowed to warm to room
temperature. The reaction mixture was oxidised with 10%
NaOH (3 mL) and 30% H2O2 (2 mL) by stirring overnight at
room temperature. After ethyl acetate (15 mL) was added,
the aqueous layer was separated and extracted with ethyl
acetate. The combined organic layers were washed with
NaHSO3 solution, then dried and concentrated to give a
residue which was puri®ed by chromatography (ethyl
acetate/hexanes, 1:3) to give unsaturated alcohol 3 as a
colourless oil (0.25 g, 92%); [Found: C, 83.33; H, 5.45; N,
5.19. C19H15NO requires C, 83.49; H, 5.53; N, 5.12%]; IR
(neat): nmax 3350 cm21; dH (200 MHz, CDCl3) 7.00±7.51
(m, 11H), 6.45 (s, 1H), 6.35 (t, 1H, Jˆ3.0 Hz), 6.18 (m, 1H),
1.70 (bs, 1H, exchangeable); dC (50.3 MHz, CDCl3) 139.9,
137.6, 135.5, 133.8, 130.0, 129.4, 128.9, 128.3, 127.9,
126.4, 126.1, 122.5, 119.7, 116.9, 108.8, 106.2, 69.7; m/z
[EI] 273 (5 M1), 256 (52), 244 (100), 154 (15), 127 (13%).
cis-2-(1H-Pyrrol-1-yl)-a-phenylcinnamic acid (5).
A
solution of lithium hydroxide monohydrate (84 mg,
2 mmol) in water (2 mL) was added dropwise to a cooled
(08C) solution of ester 9 (0.5 g, 1.65 mmol) in methanol
(3 mL), THF (6 mL) and water (3 mL). The mixture was
stirred for 16 h at room temperature, then concentrated to
a small volume, and acidi®ed (pH 4±5), with cooling, by
dropwise addition of 1 M hydrochloric acid. The solid
formed was extracted into ethyl acetate and the resulting
solution was washed with water to neutrality and dried.
The organic layer was evaporated to dryness to give acid
5 as white prisms (0.44 g, 93%); mp 97±998C (hexanes);
[Found: C, 79.03; H, 5.36; N, 4.68. C19H15NO2 requires C,
78.87; H, 5.23; N, 4.84%]; IR (Nujol): nmax 2980 (b),
1705 cm21; dH (200 MHz, CDCl3) 9.58 (bs, 1H, exchange-
able), 7.54 (d, 1H, Jˆ7.1 Hz), 7.28±7.44 (m, 8H), 6.92 (t,
2H, Jˆ1.9 Hz), 6.83 (s, 1H), 6.28 (t, 2H, Jˆ1.9 Hz); dC
(50.3 MHz, CDCl3) 171.3, 136.5, 137.3, 135.1, 134.0,
129.4, 129.1, 128.8, 127.5, 127.2, 126.8, 126.2, 126.0,
121.4, 109.1; m/z [EI] 289 (8 M1), 244 (100), 154 (44),
127 (18%).
5-Phenyl-4H-pyrrolo[1,2-a][1]benzazepin-4-one (1). To a
well-stirred solution of acid 5 (60 mg, 0.21 mmol) in dry
1,2-dichloroethane (2 mL) freshly sublimed phosphorus
pentachloride (44 mg, 0.21 mmol) was added portionwise.
The resulting mixture was stirred for 2 h at room tempera-
ture. The solvent was removed under vacuum and the
residue was taken up in dichloromethane. The organic
solution was shaken with aqueous sodium bicarbonate,
then dried and concentrated. The resulting residue was
chromatographed (dichloromethane) to give pure 1 as a
colourless solid (50 mg, 89%); mp 186±1888C (hexanes);
[Found: C, 84.30; H, 4.95; N, 5.10. C19H13NO requires C,
84.11; H, 4.83; N, 5.16%]; IR (Nujol): nmax 1680 cm21; dH
(200 MHz, CDCl3) 7.21±7.65 (m, 12H), 6.61 (t, 1H,
Jˆ3.4 Hz); dC (50.3 MHz, CDCl3) 177.4, 140.5, 137.4,
135.3, 132.9, 129.8, 129.5, 129.1, 128.8, 128.2, 127.8,
127.1, 126.4, 126.2, 122.3, 117.0, 111.1; m/z [EI] 271 (15
M1), 243 (100), 168 (18), 154 (7%).
(^)cis-5,6-Dihydro-4-hydroxy-5-phenyl-4H-pyrrolo[1,2-
a][1]benzazepine (4). (a) A mixture of compound 1 (0.27 g,
1 mmol), ethyl acetate (20 mL) and 5% palladium on char-
coal (50 mg) was hydrogenated for 24 h at atmospheric
pressure (or, alternatively, for 1 h at 45 psi). The catalyst
was then removed by ®ltration through Celite and the clear
solution was concentrated to give a residue which was
chromatographed (ethyl acetate/hexanes, 1:3). Compound
4 was obtained as a white solid (0.24 g, 88%); mp 137±
1388C (hexanes); [Found: C, 83.03; H, 6.35; N, 5.21.
C19H17NO requires C, 82.88; H, 6.22; N, 5.09%]; IR
(Nujol): nmax 3360 (b) cm21; dH (200 MHz, CDCl3) 7.24±
7.39 (m, 9H), 7.01 (m, 1H), 6.35 (t, 1H, Jˆ3.0 Hz), 6.17 (m,
1H), 4.84 (d, 1H, Jˆ6.8 Hz), 3.80 (dt, 1H, Jˆ11.4, 6.8 Hz),
2.86 (ddd, 2H, Jˆ13.6, 11.4, 6.8 Hz), 1.60 (bs, 1H,
exchangeable); dC (50.3 MHz, CDCl3) 139.7, 139.4,
133.8, 132.8, 130.0, 129.2, 128.5, 128.0, 127.6, 126.3,
122.4, 119.7, 108.8, 106.3, 68.7, 54.7, 37.5; m/z [EI] 275
(59 M1), 258 (100), 246 (22), 180 (32), 168 (21), 154
(17%).
(^)5,6-Dihydro-5-phenyl-4H-pyrrolo[1,2-a][1]benzazepin-
4-one (2). A mixture of compound 1 (0.27 g, 1 mmol), ethyl
acetate (20 mL) and 5% palladium on charcoal (50 mg) was
stirred under a hydrogen blanket at atmospheric pressure for
2 h at room temperature. The catalyst was then removed by
®ltration through Celite and the clear solution concentrated
to give a residue which was chromatographed (ethyl acetate/
(b) To a stirred suspension of NaBH4 (38 mg, 1 mmol) in
dry methanol (10 mL) was added dropwise a solution of
enone 1 (0.27 g, 1 mmol) in the same solvent (2 mL). The
mixture was stirred overnight at room temperature.
Removal of the solvent gave a white semisolid which was

A. Garofalo et al. / Tetrahedron 56 (2000) 9351±9355
9355
4. Anderson, W. K.; Heider, A. R.; Raju, N.; Yucht, J. A. J. Med.
Chem. 1988, 31, 2097±2102.
stirred in water (20 mL) for 15 min, then extracted with
ethyl acetate. The organic layer was evaporated to dryness
and the resulting residue was chromatographed as above to
give pure alcohol 4 (0.25 g, 91%).
5. Fiorini, I.; Nacci, V.; Ciani, S. M.; Garofalo, A.; Campiani, G.;
Savini, L.; Novellino, E.; Greco, G.; Bernasconi, P.; Mennini, T.
J. Med. Chem. 1994, 37, 1427±1438.
6. Raines, S.; Chai, S. Y.; Palopoli, F. P. J. Org. Chem. 1971, 36,
3992±3993.
Acknowledgements
7. Norman, J. A.; Ansell, J.; Stone, G. A.; Wennogle, L. P.;
Wasley, J. W. F. Mol. Pharmacol. 1987, 31, 535±540.
8. Campiani, G.; Fiorini, I.; De Filippis, M. P.; Ciani, S. M.;
Garofalo, A.; Nacci, V.; Giorgi, G.; Sega, A.; Botta, M.; Chiarini,
A.; Budriesi, R.; Bruni, G.; Romeo, M. R.; Manzoni, C.; Mennini,
T. J. Med. Chem. 1996, 39, 2922±2938.
This work was supported by grants from MURST and CNR,
Roma.
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