Access to a novel class of tetracyclic 1,4-benzodiazepin-5-ones starting from α-amino acids by Pd-catalyzed amination/1,3-dipolar cycloaddition as the key steps

Article abstract of DOI:10.1002/ejoc.200901290

A convenient procedure for the preparation of the novel class of tetracyclic imidazo[2,1-c]pyrazolo[1,5-α][1,4]benzodiazepine-5,8-diones is reported. The protocol uses cheap and easily accessible α-amino acids as chiral-pool starting materials and leads to products in an enantiopure form. An intramolecular palladium-catalyzed amination process to form the imidazole nucleus and an intramolecular 1,3-dipolar cycloaddition reaction to simultaneously achieve the pyrazole and 1,4-diazepine rings are the key steps.

Full text of DOI:10.1002/ejoc.200901290

FULL PAPER
DOI: 10.1002/ejoc.200901290
Access to a Novel Class of Tetracyclic 1,4-Benzodiazepin-5-ones Starting from
α-Amino Acids by Pd-Catalyzed Amination/1,3-Dipolar Cycloaddition as the
Key Steps
Luca Basolo,[a] Egle M. Beccalli,*[a] Elena Borsini,[a] Gianluigi Broggini,[b]
Maisaa Khansaa,[b] and Micol Rigamonti[b]
Keywords: Fused-ring systems / Nitrogen heterocycles / Palladium / Cycloaddition / Diastereoselectivity
A convenient procedure for the preparation of the novel class
of tetracyclic imidazo[2,1-c]pyrazolo[1,5-a][1,4]benzodiazep-
ine-5,8-diones is reported. The protocol uses cheap and
lecular palladium-catalyzed amination process to form the
imidazole nucleus and an intramolecular 1,3-dipolar cycload-
dition reaction to simultaneously achieve the pyrazole and
easily accessible α-amino acids as chiral-pool starting materi- 1,4-diazepine rings are the key steps.
als and leads to products in an enantiopure form. An intramo-
Introduction
1,4-Benzodiazepines play an important role in medicinal
chemistry due to a wide range of pharmaceutical applica-
tions.[1] 1,4-Benzodiazepin-5-ones, one of the most signifi-
cant classes of these structures, are recognized as being en-
dowed with anxiolytic, anticonvulsant, antiepileptic, muscle
relaxant, antidepressant, sedative, and hypnotic activities
related to the treatment of CNS disorders.[2] Moreover, this
range of therapeutic activities has been significantly en-
hanced by annulation of the benzodiazepine skeleton to an-
other carbo- or heterocyclic ring. Tricyclic 1,4-benzodi-
azepin-5-one systems, beyond solving anxiety and stress
problems, as in the case of flumazenil (1),[3] are also antihis-
taminic compounds, for example, tarpane (2),[4] antibiotics,
like the pyrrolo-fused abbeymicin[5] (3), and antitumor
agents, such as structures 4 (Figure 1).[6] More recently, in-
spired by the attention given to bretazenil (5) due to its
potential application in neurodegenerative diseases,[7] some
tetracyclic 1,4-benzodiazepinones have appeared in the lit-
Figure 1. Tri- and tetracyclic pharmacologically active 1,4-benzodi-
azepin-5-ones.
erature. These structures have the benzodiazepine nucleus
fused to different hetero- and carbocycles such as pyrimid-
ines, imidazoles, 1,2,4-triazoles, pyrazoles, benzopyrans, or
naphthalenes.[8–10]
Among the several procedures reported in articles and
patents to synthesize 1,4-benzodiazepin-5-ones, approaches
involving the formation of the 1–2 nitrogen–carbon bond
as the final step are commonly used. Intramolecular cycliza-
tion of amines with carbonyls[11] or acetals/thioacetals,[12]
reductive cyclization of nitro derivatives with carbonyls,[13]
intramolecular 1,3-dipolar cycloadditions of azides[14] and
nitrilimines[15] to alkenes and/or alkynes, aza-Wittig ring-
closure of iminophosphoranyls with carbonyls,[16] intramo-
lecular Michael addition of amines to enones,[17] intramo-
[a] DISMAB, Sezione di Chimica Organica “A. Marchesini”, Uni-
versità di Milano,
Via Venezian 21, 20133 Milano, Italy
Fax: +39-02-50314476
E-mail: egle.beccalli@unimi.it
[b] Dipartimento di Scienze Chimiche e Ambientali, Università
dell’Insubria,
Via Valleggio 11, 22100 Como, Italy
Fax: +39-031-2386449
E-mail: gianluigi.broggini@uninsubria.it
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Novel Tetracyclic 1,4-Benzodiazepin-5-ones
lecular nucleophilic substitutions by aniline derivatives,[18]
ring-opening reactions of amines on furan moieties,[19] in-
tramolecular Pd-catalyzed cyclizations,[6,20] and the cycliza-
tion of amines with nitriles[21] on differently substituted
benzamides have proven to be fruitful methodologies for
promoting the formation of the nitrogen–carbon bond,
eventually with the simultaneous construction of a new
ring.
This paper concerns a protocol for the synthesis of a new
class of tetracyclic 1,4-benzodiazepin-5-ones that we have
developed through our recent interest in allenylamide
heterocyclization[22] and long-time experience of 1,3-dipolar
cycloaddition reactions.[23] The starting point for planning
the new synthetic strategy arose from the recent synthesis
of the enantiopure 2-vinylimidazolidinones 7, obtained
by heteroannulation of the amino-allenylamides
6
(Scheme 1).[22b] The imidazolidinones 7 are envisaged as
building blocks for the construction of 1,3-dipolar sub-
strates suitable for intramolecular cycloaddition due to the
presence of the ethylenic C–C double bond as a potential
dipolarophile.
Scheme 2. Synthesis of 2-aminobenzamides 11.
ment of 12 with triethylamine in boiling toluene gave di-
rectly the tetracyclic imidazo[2,1-c]pyrazolo[1,5-a][1,4]-
benzodiazepine-5,8-dione systems 14 (Scheme 3).
Scheme 1. Synthesis of imidazolidinones 7.
Results and Discussion
First, having recognized the major diastereoisomer imid-
azolidinone (2R,5S)-7 as a convenient starting material, our
approach required the synthesis of 2-aminobenzamides 11
as suitable compounds for accessing the azide and nitrilim-
ine 1,3-dipoles due to the presence of the aniline moiety.
With this aim, the Boc-protecting group was removed by
treatment with TFA to give imidazolidinones 8 (Scheme 2).
These latter compounds were functionalized by reaction
with 2-nitrobenzoyl chloride (9) to give the 2-nitrobenz-
amides 10, which in turn were reduced to the 2-aminobenz-
amides 11.
The diazotization of the aniline moiety permitted access
to the corresponding azido compounds, but their intramo-
lecular 1,3-dipolar cycloaddition furnished unstable 4,5-di-
hydro-1,2,3-triazole products, which decomposed into com-
Scheme 3. Generation of nitrilimines and their intramolecular cy-
cloaddition reaction.
Further to the total regiochemical outcome that was ex-
plex mixtures with no synthetic interest. Such a failure pected as a consequence of the propargylic nature of the
prompted us to turn our attention to the nitrilimine 1,3- 1,3-dipole, the cycloaddition reaction was totally diastereo-
dipole, a well-established functional group in the synthesis selective giving rise to only one diastereoisomeric product.
of variously substituted azoles.[24] To this end, compounds This feature, highly important from a synthetic point of
11 were submitted to diazotization and subsequent Japp– view, probably arises from the bulky phenyl substituent and
Klingemann reaction,[25] that is, coupling with ethyl 2-chlo- the rather rigid imidazolidinone moiety working against the
roacetoacetate, furnished the hydrazonyl chlorides 12, pre- intramolecular approach of the dipole to the si face of the
cursors of the transient nitrilimine species 13. In fact, treat- dipolarophile, so dictating the exclusive formation of the cis
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E. M. Beccalli et al.
FULL PAPER
(Ph,H) diastereoisomer 14. The absolute configuration was
assigned on the basis of 1H NMR NOESY experiments car-
ried out on compound 14a. As shown in Figure 2, further
to obvious interactions between the hydrogen atoms at the
2- and 5-positions of the imidazole nucleus, the cross-peak
between the hydrogen at the 2-position of the imidazolid-
inone and the ortho hydrogen atoms on the phenyl group
resulted in the determination of the S configuration of the
newly created stereocenter and thus the (3aS,3bR,6S) dia-
stereoisomer. The enantiomeric purity was proven to be
better than 99.5% by HPLC analysis of compound 14a with
an AD chiral column and in comparison with a sample of
Figure 2. Selected NOESY correlations for compound 14a.
We next examined the reactions of imidazolidinones 7
the corresponding racemic mixture synthesized starting and 5-chloro- and 5-fluoro-2-nitrobenzoyl chlorides (9a and
from (Ϯ)-alanine.
9b, respectively) to broaden the scope of the reaction and
Table 1. Scope of the procedure.
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Eur. J. Org. Chem. 2010, 1694–1703

Novel Tetracyclic 1,4-Benzodiazepin-5-ones
(2S,5S)-5-Isopropyl-3-methyl-2-(1-phenylvinyl)imidazolidin-4-one
(8b): Yield 95%; cream crystals; m.p. 93 °C (iPr2O). [α]2D5 = +22.5
the interest of the products from a biological point of view,
having a halo-substituted 1,4-benzodiazepine nucleus. The
halide-containing products, 2-nitrobenzamides 10, 2-amino-
benzamides 11, hydrazonyl chlorides 12, and tetracyclic
products 14, are presented in Table 1. The preparation of
hydrazonyl chlorides as well as the nitrilimine cycloaddition
reactions occurred analogously to those described for the
unsubstituted 2-nitrobenzoyl chloride.
(c = 0.45, CHCl ). IR (Nujol): ν = 1664, 3428 cm–1. 1H NMR
˜
3
(400 MHz, CDCl3, 25 °C): δ = 0.87 (d, J = 7.0 Hz, 3 H), 1.00 (d,
J = 7.1 Hz, 3 H), 2.39 (dqq, J = 3.9, 7.0, 7.1 Hz, 1 H), 3.05 (s, 3
H), 4.19 (d, J = 3.9 Hz, 1 H), 5.74 (s, 1 H), 5.87 (s, 1 H), 5.98 (s,
1 H), 7.28–7.32 (m, 2 H), 7.41–7.50 (m, 3 H), 11.07 (br. s, 1 H) ppm.
13C NMR (100 MHz, CDCl3, 25 °C): δ = 16.4 (q), 18.2 (q), 28.1
(d), 28.9 (q), 60.1 (d), 74.6 (d), 124.7 (t), 127.5 (d), 129.9 (d), 130.7
(d), 133.6 (s), 139.3 (s), 168.6 (s) ppm. MS: m/z = 244 [M]+.
C15H20N2O (244.33): calcd. C 73.74, H 8.25, N 11.47; found C
73.82, H 8.09, N 11.25.
Conclusions
(2S,5S)-5-Benzyl-3-methyl-2-(1-phenylvinyl)imidazolidin-4-one (8c):
Yield 93%; white crystals; m.p. 91 °C (iPr2O). [α]2D5 = –30.3 (c =
We have reported a new procedure for the synthesis of a
new class of tetracyclic 1,4-benzodiazepin-5-ones bearing 0.27, CHCl ). IR (Nujol): ν = 1682, 3444 cm–1 1H NMR
.
˜
3
(400 MHz, CDCl3, 25 °C): δ = 2.86 (s, 3 H), 3.13–3.20 (m, 2 H),
4.14–4.18 (m, 1 H), 5.14 (s, 1 H), 5.38 (s, 1 H), 5.54 (s, 1 H), 5.75
(br. s, 1 H), 7.08–7.36 (m, 10 H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 28.8 (d), 34.3 (t), 59.3 (q), 74.9 (d), 124.1 (t),
127.3 (d), 129.2 (d), 129.8 (d), 129.9 (d), 130.2 (d), 130.4 (d), 132.1
(s), 134.0 (s), 139.6 (s), 168.4 (s) ppm. MS: m/z = 292 [M]+.
C19H20N2O (292.37): calcd. C 78.05, H 6.89, N 9.58; found C
77.93, H 7.02, N 9.74.
the imidazo[2,1-c]pyrazolo[1,5-a][1,4]benzodiazepine-5,8-
dione structure. The synthetic protocol consists of the fol-
lowing key steps: i) a palladium-catalyzed heteroannulation
of allenyl amides starting from α-amino acids to give the
imidazole ring and ii) an intramolecular nitrilimine cycload-
dition reaction leading to the simultaneous formation of
the 1,4-diazepine and pyrazole rings. Moreover, the novel
scaffold of these heteropolycyclic systems was accessible in
an enantiopure form, as inferred by the starting α-amino
acids and conserved during the synthetic sequence.
General Procedure for the Synthesis of Compounds 10: TEA
(0.51 mL, 3.64 mmol) was added to a solution of 8 (0.7 mmol) in
dry CH2Cl2 (3 mL). The mixture was cooled to 0 °C and a solution
of 9 in dry CH2Cl2 (2 mL) was added dropwise whilst stirring. Af-
ter 24 h at room temperature the mixture was washed with 5% HCl
(30 mL) and with aq. NaHCO3 (30 mL) and then the organic layer
was dried with Na2SO4. The solvent was evaporated and the crude
mixture was purified by silica gel column chromatography with
light petroleum ether/AcOEt (1:1) as eluent to give 10.
Experimental Section
General: Melting points were determined by the capillary method
with a Büchi B-540 apparatus. Optical rotations were measured
with a Jasco P-1010 polarimeter. NMR spectra were recorded with
an AVANCE 400 Bruker spectrometer at 400 MHz for 1H NMR
and 100 MHz for 13C NMR spectroscopy. Chemical shifts are given
as δ values in ppm relative to residual solvent peaks (CHCl3 or
DMSO) as the internal reference. 13C NMR spectra were 1H-de-
coupled and the multiplicities were determined by the APT pulse
sequence. IR spectra were measured with a Jasco FT/IR 5300 spec-
trometer. Elemental analyses were executed with a Perkin–Elmer
CHN Analyzer Series II 2400. Thin-layer chromatographic separa-
tions were performed on Merck silica gel 60 F254 precoated sheets.
Preparative separations were performed by flash chromatography
by using Merck silica gel 0.035–0.070 mm. The enantiomeric purity
was determined by HPLC (pump: Merck–Hitachi L 7100; detector:
DAD HP 1050; column: Chiralpak® AD; flow: 0.8 mL/min; eluent:
hexane/2-propanol, 4:1).
(2R,5S)-3,5-Dimethyl-1-(2-nitrobenzoyl)-2-(1-phenylvinyl)imidazol-
idin-4-one (10a): Yield 51% (as a mixture of two conformers in a
ratio of 2:1); pale-yellow crystals; m.p. 160 °C (iPr2O). [α]2D5 = –10.2
(c = 0.10, CHCl ). IR (Nujol): ν = 1652, 1704 cm–1. Major con-
˜
3
former: 1H NMR (400 MHz, CDCl3, 25 °C): δ = 0.41 (d, J =
6.9 Hz, 3 H), 3.04 (s, 3 H), 3.78 (q, J = 6.9 Hz, 1 H), 5.56 (s, 1 H),
5.77 (s, 1 H), 6.06 (s, 1 H), 6.98–8.26 (m, 9 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 18.2 (q), 27.5 (q), 55.6 (d), 79.2 (d),
122.3 (t), 124.9 (d), 128.0 (d), 128.8 (d), 129.0 (d), 129.4 (d), 131.0
(d), 132.0 (s), 134.8 (d), 138.1 (s), 144.4 (s), 144.8 (s), 167.5 (s),
170.2 (s) ppm. Minor conformer: 1H NMR (400 MHz, CDCl3,
25 °C): δ = 1.22 (d, J = 6.9 Hz, 3 H), 2.84 (s, 3 H), 4.65 (q, J =
6.9 Hz, 1 H), 4.69 (s, 1 H), 5.13 (s, 1 H), 5.31 (s, 1 H), 6.98–8.26
(m, 9 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 16.9 (q),
27.4 (q), 55.8 (d), 80.1 (d), 122.4 (t), 125.2 (d), 128.0 (d), 128.9 (d),
129.2 (d), 129.7 (d), 130.5 (d), 132.2 (s), 134.8 (d), 136.8 (s), 144.4
(s), 144.9 (s), 167.5 (s), 170.9 (s) ppm. MS: m/z = 365 [M]+.
C20H19N3O4 (365.38): calcd. C 65.74, H 5.24, N 11.50; found C
65.98, H 5.09, N 11.44.
General Procedure for the Synthesis of Compounds 8: A solution
of (2R,5S)-7[22b] (2.55 mmol) in TFA (6 mL) was stirred at room
temperature for 3 h. The solvent was then evaporated under re-
duced pressure and the residue purified by column chromatography
using light petroleum ether/AcOEt (4:1) as eluent.
(2R,5S)-1-(5-Chloro-2-nitrobenzoyl)-3,5-dimethyl-2-(1-phenylvinyl)-
imidazolidin-4-one (10aa): Yield 55% (as a mixture of two conform-
ers in a ratio of 1.25:1); pale-yellow crystals; m.p. 62 °C (iPr2O).
(2S,5S)-3,5-Dimethyl-2-(1-phenylvinyl)imidazolidin-4-one
(8a):
Yield 93%; pale-yellow oil. [α]2D5 = +27.5 (c = 0.37, CHCl3). IR
(Nujol): ν = 1670, 3430 cm–1. 1H NMR (400 MHz, CDCl3): δ = [α]2D5 = –13.5 (c = 26.7, CHCl ). IR (Nujol): ν = 1640, 1690 cm–1.
˜
˜
3
1.38 (d, J = 7.1 Hz, 3 H), 3.04 (s, 3 H), 4.08 (q, J = 7.1 Hz, 1 H),
Major conformer: 1H NMR (400 MHz, CDCl3, 25 °C): δ = 0.40
5.71 (s, 1 H), 5.72 (s, 1 H), 5.89 (s, 1 H), 6.57 (br. s, 1 H), 7.28– (d, J = 6.8 Hz, 3 H), 2.97 (s, 3 H), 3.74 (q, J = 6.8 Hz, 1 H), 5.50
7.30 (m, 2 H), 7.42–7.48 (m, 3 H) ppm. 13C NMR (100 MHz, (s, 1 H), 5.70 (s, 1 H), 5.98 (s, 1 H), 6.97–8.12 (m, 8 H) ppm. 13C
CDCl3, 25 °C): δ = 14.7 (q), 28.1 (q), 54.1 (d), 74.2 (d), 122.9 (t),
126.9 (d), 129.2 (d), 129.8 (d), 134.5 (s), 139.5 (s), 169.3 (s) ppm.
MS: m/z = 216 [M]+. C13H16N2O (216.28): calcd. C 72.19, H 7.46,
N 12.95; found C 72.26, H 7.38, N 12.86.
NMR (100 MHz, CDCl3, 25 °C): δ = 17.8 (q), 27.1 (q), 55.0 (d),
78.6 (d), 121.8 (t), 126.0 (d), 126.4 (d), 127.3 (d), 128.4 (d), 128.7
(d), 130.6 (d), 133.0 (s), 137.5 (s), 141.1 (s), 142.8 (s), 143.8 (s),
165.3 (s), 169.4 (s) ppm. Minor conformer: 1H NMR (400 MHz,
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CDCl3, 25 °C): δ = 1.21 (d, J = 6.5 Hz, 3 H), 2.81 (s, 3 H), 4.57
(q, J = 6.5 Hz, 1 H), 4.75 (s, 1 H), 5.20 (s, 1 H), 5.32 (s, 1 H), 6.98–
8.12 (m, 8 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 16.4
32.2 (q), 63.3 (d), 78.6 (d), 120.0 (s), 121.3 (t), 125.9 (d), 127.2 (d),
128.3 (d), 128.6 (d), 128.8 (d), 130.4 (d), 133.4 (s), 137.1 (s), 141.1
(s), 142.8 (s), 144.7 (s), 169.8 (s) ppm. Minor conformer: H NMR
1
(q), 26.9 (q), 55.3 (d), 79.4 (d), 122.1 (t), 126.0 (d), 126.4 (d), 127.3 (400 MHz, CDCl3, 25 °C): δ = 0.55 (d, J = 5.6 Hz, 3 H), 0.67 (d,
(d), 128.5 (d), 128.9 (d), 130.6 (d), 133.1 (s), 136.2 (s), 141.1 (s),
J = 5.9 Hz, 3 H), 1.20–1.26 (m, 1 H), 2.93 (s, 3 H), 3.57–3.63 (m,
1 H), 5.52 (s, 1 H), 5.62 (s, 1 H), 6.15 (s, 1 H), 6.95–8.07 (m, 8
142.7 (s), 144.2 (s), 165.3 (s), 170.1 (s) ppm. MS: m/z = 399 [M]+.
C20H18ClN3O4 (399.83): calcd. C 60.08, H 4.54, N 10.51; found C H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 16.8 (q), 20.4
60.20, H 4.31, N 10.73.
(q), 28.0 (d), 31.9 (q), 64.9 (d), 77.4 (d), 120.0 (s), 121.3 (t), 126.3
(d), 127.8 (d), 128.1 (d), 128.6 (d), 129.5 (d), 130.6 (d), 133.4 (s),
137.1 (s), 141.1 (s), 142.8 (s), 144.7 (s), 169.8 (s) ppm. MS: m/z =
427 [M]+. C22H22ClN3O4 (427.88): calcd. C 61.75, H 5.18, N 9.82;
found C 61.89, H 5.03, N 10.02.
(2R,5S)-1-(5-Fluoro-2-nitrobenzoyl)-3,5-dimethyl-2-(1-phenylvinyl)-
imidazolidin-4-one (10ab): Yield 60% (as a mixture of two conform-
ers in a ratio of 2:1); yellow oil. [α]2D5 = –4.9 (c = 5.2, CHCl3). IR
(Nujol): ν = 1638, 1702 cm–1. Major conformer: 1H NMR
˜
(400 MHz, CDCl3, 25 °C): δ = 0.45 (d, J = 6.9 Hz, 3 H), 3.04 (s, 3
H), 3.77 (q, J = 6.9 Hz, 1 H), 5.57 (s, 1 H), 5.76 (s, 1 H), 6.03 (s,
(2R,5S)-1-(5-Fluoro-2-nitrobenzoyl)-5-isopropyl-3-methyl-2-(1-phen-
ylvinyl)imidazolidin-4-one (10bb): Yield 49% (as a mixture of two
1 H), 6.86–8.30 (m, 8 H) ppm. 13C NMR (100 MHz, CDCl3, conformers in a ratio of 4:1); yellow oil. [α]2D5 = +0.24 (c = 28.7,
2
25 °C): δ = 17.8 (q), 27.0 (q), 54.9 (d), 78.6 (d), 116.7 (dd, JC-F
=
CHCl ). IR (Nujol): ν = 1640, 1698 cm–1. Major conformer: 1H
˜
3
2
23.2 Hz), 117.6 (dd, JC-F = 23.0 Hz), 121.8 (t), 127.4 (d), 128.0
NMR (400 MHz, CDCl3, 25 °C): δ = 0.88 (d, J = 5.9 Hz, 3 H),
1.07 (d, J = 6.6 Hz, 3 H), 1.55 (dqq, J = 5.9, 6.6, 9.0 Hz, 1 H),
(dd, 3JC-F = 9.9 Hz), 128.4 (d), 128.7 (d), 134.4 (d, JC-F = 8.0 Hz),
3
1
137.5 (s), 140.7 (s), 143.8 (s), 165.2 (d, JC-F = 259.6 Hz), 169.4 2.82 (s, 3 H), 4.33 (d, J = 9.0 Hz, 1 H), 4.94 (s, 1 H), 5.24 (s, 1 H),
(s), 170.1 (s) ppm. Minor conformer: 1H NMR (400 MHz, CDCl3,
5.35 (s, 1 H), 6.91–8.15 (m, 8 H) ppm. 13C NMR (100 MHz,
25 °C): δ = 1.27 (d, J = 6.9 Hz, 3 H), 2.86 (s, 3 H), 4.64 (q, J = CDCl3, 25 °C): δ = 19.3 (q), 19.8 (q), 27.2 (d), 32.2 (q), 63.4 (d),
2
2
6.9 Hz, 1 H), 4.80 (s, 1 H), 5.25 (s, 1 H), 5.33 (s, 1 H), 6.86–8.30
78.4 (d), 116.6 (dd, JC-F = 27.4 Hz), 117.4 (dd, JC-F = 23.1 Hz),
(m, 8 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 16.4 (q), 120.9 (t), 127.2 (d), 127.6 (dd, 3JC-F = 9.4 Hz), 128.3 (d), 128.6 (d),
2
3
26.9 (q), 55.3 (d), 79.2 (d), 115.9 (dd, JC-F = 23.4 Hz), 117.5 (dd, 134.4 (d, JC-F = 8.3 Hz), 137.3 (s), 140.7 (s), 144.8 (s), 165.1 (d,
2JC-F = 22.9 Hz), 122.0 (t), 127.3 (d), 127.7 (dd, JC-F = 9.7 Hz),
1JC-F = 259.7 Hz), 166.4 (s), 169.8 (s) ppm. Minor conformer: H
3
1
3
128.4 (d), 128.8 (d), 134.5 (d, JC-F = 8.0 Hz), 136.3 (s), 140.6 (s),
NMR (400 MHz, CDCl3, 25 °C): δ = 0.49 (d, J = 6.2 Hz, 3 H),
0.64 (d, J = 6.6 Hz, 3 H), 1.32–1.42 (m, 1 H), 2.89 (s, 3 H), 3.54–
3.61 (m, 1 H), 5.48 (s, 1 H), 5.60 (s, 1 H), 6.12 (s, 1 H), 6.70–8.29
144.4 (s), 165.4 (d, 1JC-F = 260.2 Hz), 169.3 (s), 169.9 (s) ppm. MS:
m/z = 383 [M]+. C20H18FN3O4 (383.37): calcd. C 62.66, H 4.73, N
10.96; found C 62.88, H 4.56, N 11.07.
(m, 8 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 16.6 (q),
2
20.4 (q), 28.0 (d), 31.8 (q), 64.8 (d), 77.3 (d), 116.4 (dd, JC-F
=
(2R,5S)-5-Isopropyl-3-methyl-1-(2-nitrobenzoyl)-2-(1-phenylvinyl)-
imidazolidin-4-one (10b): Yield 75% (as a mixture of two conform-
ers in a ratio of 3:1); yellow oil. [α]2D5 = –18.3 (c = 0.21, CHCl3).
2
27.2 Hz), 117.6 (dd, JC-F = 23.5 Hz), 120.0 (t), 127.2 (d), 127.8
(dd, 3JC-F = 9.0 Hz), 128.0 (d), 128.6 (d), 134.2 (d, JC-F = 8.2 Hz),
3
138.0 (s), 139.9 (s), 144.2 (s), 165.4 (d, 1JC-F = 259.4 Hz), 166.8 (s),
170.1 (s) ppm. MS: m/z = 411 [M]+. C22H22FN3O4 (411.43): calcd.
C 64.22, H 5.39, N 10.21; found C 64.44, H 5.12, N 10.32.
IR (Nujol): ν = 1665, 1688 cm–1. Major conformer: 1H NMR
˜
(400 MHz, CDCl3, 25 °C): δ = 0.92 (d, J = 5.9 Hz, 3 H), 1.11 (d,
J = 6.6 Hz, 3 H), 1.44 (dqq, J = 5.9, 6.6, 9.2 Hz, 1 H), 2.84 (s, 3
H), 4.40 (d, J = 9.2 Hz, 1 H), 4.86 (s, 1 H), 5.34 (s, 1 H), 5.54 (s,
(2R,5S)-5-Benzyl-3-methyl-1-(2-nitrobenzoyl)-2-(1-phenylvinyl)imid-
1 H), 6.92–6.94 (m, 2 H), 7.23–7.31 (m, 3 H), 7.31–7.38 (m, 2 H), azolidin-4-one (10c): Yield 50% (as a mixture of two conformers in
7.54–7.63 (m, 1 H), 8.16–8.20 (m, 1 H) ppm. Minor conformer: 1H a ratio of 1:1); yellow oil. [α]2D5 = +4.3 (c = 0.1, CHCl3). IR (Nujol):
NMR (400 MHz, CDCl3, 25 °C): δ = 0.51 (d, J = 5.9 Hz, 3 H),
ν = 1658, 1706 cm–1. 1H NMR (400 MHz, CDCl , 25 °C): δ = 2.46–
˜
3
0.63 (d, J = 6.3 Hz, 3 H), 1.23–1.34 (m, 1 H), 2.94 (s, 3 H), 3.60– 2.52 (m, 2 H), 2.81 (s, 3 H), 3.10 (s, 3 H), 3.15–3.22 (m, 2 H), 3.93–
3.65 (m, 1 H), 5.54 (s, 1 H), 5.67 (s, 1 H), 6.18 (s, 1 H), 6.91–8.24 4.12 (m, 1 H), 4.17 (s, 1 H), 4.85–4.88 (m, 1 H), 5.17 (s, 1 H), 5.43
1
(m, 9 H) ppm. H NMR (400 MHz, [D6]DMSO, 100 °C): δ = 0.83
(s, 1 H), 5.59 (s, 1 H), 5.71 (s, 1 H), 6.19 (s, 1 H), 6.48–7.92 (m, 28
(d, J = 6.9 Hz, 3 H), 0.89 (d, J = 6.7 Hz, 3 H), 1.55 (dqq, J = 6.7, H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 26.9 (q), 27.6
6.9, 7.3 Hz, 1 H), 2.77 (s, 3 H), 4.06 (d, J = 7.3 Hz, 1 H), 5.15 (s, (q), 36.8 (t), 39.0 (t), 60.5 (d), 61.4 (d), 76.7 (d), 78.7 (d), 121.4 (t),
1 H), 5.27 (s, 1 H), 5.71 (s, 1 H), 7.11–7.12 (m, 2 H), 7.13–7.31 (m, 121.8 (t), 125.1 (d), 125.7 (d), 126.2 (d), 127.0 (d), 127.5 (d), 128.0
3 H), 7.46 (dd, J = 1.3, 7.5 Hz, 1 H), 7.68 (ddd, J = 1.3, 7.7, 8.2 Hz,
1 H), 7.76 (ddd, J = 1.1, 7.5, 7.7 Hz, 1 H), 8.16 (dd, J = 1.1, 8.2 Hz,
1 H) ppm. 13C NMR (100 MHz, [D6]DMSO, 100 °C): δ = 20.1 (q),
20.9 (q), 27.8 (d), 32.4 (q), 63.5 (d), 78.9 (d), 120.6 (s), 122.6 (t),
125.7 (d), 128.7 (d), 128.9 (d), 129.1 (d), 129.8 (d), 131.6 (d), 132.3
(s), 135.8 (d), 138.1 (s), 144.9 (s), 145.0 (s), 169.7 (s) ppm. MS: m/z
(d), 128.2 (d), 128.3 (d), 128.4 (d), 128.5 (d, overlapped), 128.6 (d),
129.3 (d), 129.4 (d), 129.8 (d), 130.0 (d), 130.3 (d), 130.4 (d), 130.8
(d), 132.4 (d), 133.0 (d), 136.1 (s), 136.9 (s), 137.2 (s), 137.4 (s),
141.1 (s), 141.4 (s), 142.5 (s), 142.7 (s), 143.9 (s), 144.0 (s), 168.6
(s), 168.8 (s), 169.2 (s), 169.6 (s) ppm. MS: m/z = 441 [M]+.
C26H23N3O4 (441.48): calcd. C 70.73, H 5.25, N 9.52; found C
= 393 [M]+. C22H23N3O4 (393.44): calcd. C 67.16, H 5.89, N 10.68; 70.50, H 5.51, N 9.43.
found C 67.34, H 5.67, N 10.75.
(2R,5S)-5-Benzyl-1-(5-chloro-2-nitrobenzoyl)-3-methyl-2-(1-phenyl-
(2R,5S)-1-(5-Chloro-2-nitrobenzoyl)-5-isopropyl-3-methyl-2-(1-phen- vinyl)imidazolidin-4-one (10ca): Yield 62 % (as a mixture of two
ylvinyl)imidazolidin-4-one (10ba): Yield 34% (as a mixture of two
conformers in a ratio of 5:1); white crystals; m.p. 145 °C (iPr2O).
conformers in a ratio of 1:1); pale-yellow crystals; m.p. 75 °C
(iPr2O). [α]2D5 = +4.4 (c = 11.9, CHCl ). IR (Nujol): ν = 1636,
˜
3
1
[α]2D5 = +55.7 (c = 13.0, CHCl ). IR (Nujol): ν = 1644, 1710 cm–1.
1688 cm–1. H NMR (400 MHz, CDCl3, 25 °C): δ = 2.79 (s, 3 H),
˜
3
Major conformer: 1H NMR (400 MHz, CDCl3, 25 °C): δ = 0.88
2.84–2.95 (m, 2 H), 3.07 (s, 3 H), 3.12–3.20 (m, 2 H), 3.93–4.15 (m,
(d, J = 5.5 Hz, 3 H), 1.09 (d, J = 6.6 Hz, 3 H), 1.58 (dqq, J = 5.5, 1 H), 4.21 (s, 1 H), 4.80–4.86 (m, 1 H), 5.16 (s, 1 H), 5.44 (s, 1 H),
6.6, 8.9 Hz, 1 H), 2.85 (s, 3 H), 4.36 (d, J = 8.9 Hz, 1 H), 4.91 (s, 5.57 (s, 1 H), 5.68 (s, 1 H), 6.18 (s, 1 H), 6.47–6.51 (m, 2 H), 6.75–
1 H), 5.26 (s, 1 H), 5.34 (s, 1 H), 6.95–8.07 (m, 8 H) ppm. 13C 7.48 (m, 22 H), 7.84–7.96 (m, 2 H) ppm. 13C NMR (100 MHz,
NMR (100 MHz, CDCl3, 25 °C): δ = 19.4 (q), 19.7 (q), 27.2 (d),
CDCl3, 25 °C): δ = 26.9 (q), 27.6 (q), 36.8 (t), 39.0 (t), 60.5 (d),
1698
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1694–1703

Novel Tetracyclic 1,4-Benzodiazepin-5-ones
61.4 (d), 76.9 (d), 78.6 (d), 121.5 (t), 121.7 (t), 125.7 (d), 126.1 (d),
126.3 (d), 126.9 (d), 127.2 (d), 128.2 (d), 128.3 (d), 128.4 (d), 128.5
(d), 128.6 (d, overlapped), 128.7 (d), 129.4 (d), 129.7 (d), 129.8 (d),
(2R,5S)-1-(2-Amino-5-fluorobenzoyl)-3,5-dimethyl-2-(1-phenyl-
vinyl)imidazolidin-4-one (11ab): Yield 87%; colorless oil. [α]2D5
+9.9 (c = 2.43, CHCl ). IR (Nujol): ν = 1654, 1702, 3450 cm–1. 1H
=
˜
3
130.0 (d), 130.3 (d), 130.4 (d), 132.4 (s), 133.0 (s), 136.1 (s), 136.9 NMR (400 MHz, CDCl3, 25 °C): δ = 0.67 (d, J = 7.0 Hz, 3 H),
(s), 137.2 (s), 137.7 (s), 141.0 (s), 141.2 (s), 142.4 (s), 142.5 (s), 144.0
2.96 (s, 3 H), 3.87 (br. s, 2 H), 4.12 (q, J = 7.0 Hz, 1 H), 5.37 (s, 2
(s), 168.6 (s), 168.7 (s), 169.1 (s), 169.4 (s) ppm. MS: m/z = 475 H), 5.82 (s, 1 H), 6.61–7.35 (m, 8 H) ppm. 13C NMR (100 MHz,
[M]+. C26H22ClN3O4 (475.92): calcd. C 65.62, H 4.66, N 8.83; CDCl3, 25 °C): δ = 17.2 (q), 27.4 (q), 55.7 (d), 79.4 (d), 113.8 (dd,
2
3
found C 65.43, H 4.81, N 8.96.
2JC-F = 23.7 Hz), 118.1 (dd, JC-F = 22.1 Hz), 118.3 (dd, JC-F
=
3
7.2 Hz), 121.9 (t), 122.0 (d, JC-F = 6.6 Hz), 128.6 (d), 128.8 (d),
129.0 (d), 137.5 (s), 140.7 (s), 144.8 (s), 155.5 (d, 1JC-F = 238.3 Hz),
168.4 (s), 170.8 (s) ppm. MS: m/z = 353 [M]+. C20H20FN3O2
(353.39): calcd. C 67.97, H 5.70, N 11.89; found C 67.86, H 5.82,
N 11.74.
(2R,5S)-5-Benzyl-1-(5-fluoro-2-nitrobenzoyl)-3-methyl-2-(1-phenyl-
vinyl)-imidazolidin-4-one (10cb): Yield 65% (as a mixture of two
conformers in a ratio of 1:1); white crystals; m.p. 88 °C (iPr2O).
[α]2D5 = –4.0 (c = 19.1, CHCl ). IR (Nujol): ν = 1660, 1700 cm–1.
˜
3
1H NMR (400 MHz, CDCl3, 25 °C): δ = 2.48–2.56 (m, 2 H), 2.79
(s, 3 H), 3.08 (s, 3 H), 3.01–3.20 (m, 2 H), 3.92–4.13 (m, 1 H), 4.21 (2R,5S)-1-(2-Aminobenzoyl)-5-isopropyl-3-methyl-2-(1-phenylvinyl)-
(s, 1 H), 4.82–4.89 (m, 1 H), 5.15 (s, 1 H), 5.44 (s, 1 H), 5.58 (s, 1
imidazolidin-4-one (11b): Yield 95%; colorless oil. [α]2D5 = +56.1 (c
1
H), 5.69 (s, 1 H), 6.21 (s, 1 H), 6.25–6.42 (m, 1 H), 6.48–6.51 (m, = 0.38, CHCl ). IR (Nujol): ν = 1640, 1690, 3492 cm–1. H NMR
˜
3
3 H), 6.75–7.08 (m, 7 H), 7.25–7.48 (m, 12 H), 7.98–8.05 (m, 3
H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 26.9 (q), 27.6
(q), 36.8 (t), 39.1 (t), 60.6 (d), 61.5 (d), 76.7 (d), 78.6 (d), 116.0 (dd,
(400 MHz, CDCl3, 25 °C): δ = 0.75 (d, J = 6.8 Hz, 3 H), 0.97 (d,
J = 6.5 Hz, 3 H), 1.26–1.29 (qqd, J = 6.5, 6.8, 9.1 Hz, 1 H), 2.81
(s, 3 H), 4.15 (br. s, 2 H), 4.35 (d, J = 9.1 Hz, 1 H), 5.24 (s, 1 H),
5.36 (s, 1 H), 5.64 (s, 1 H), 6.70–6.75 (m, 2 H), 7.13–7.34 (m, 7
H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 19.3 (q), 20.6
(q), 28.0 (d), 32.6 (q), 63.6 (d), 79.5 (d), 117.1 (d), 117.7 (d), 120.7
(s), 121.2 (t), 128.2 (d), 128.4 (d), 128.7 (d), 128.8 (d), 131.7 (d),
138.3 (s), 145.4 (s), 145.8 (s), 170.6 (s), 172.5 (s) ppm. MS: m/z =
363 [M]+. C22H25N3O2 (363.45): calcd. C 72.70, H 6.93, N 11.56;
found C 72.58, H 7.02, N 11.78.
2
2
2JC-F = 21.8 Hz), 116.2 (dd, JC-F = 22.0 Hz), 117.1 (dd, JC-F
=
21.6 Hz), 117.4 (dd, 2JC-F = 21.9 Hz), 121.3 (t), 121.7 (t), 126.2 (d),
3
3
126.8 (dd, JC-F = 11.6 Hz), 127.4 (dd, JC-F = 11.0 Hz), 128.4 (d),
128.6 (d, overlapped), 130.0 (d), 133.5 (d, 3JC-F = 5.6 Hz), 134.3 (d,
3JC-F = 6.2 Hz), 136.3 (s), 136.6 (s), 136.7 (s), 137.0 (s), 137.4 (s),
137.7 (s), 144.0 (s), 144.2 (s), 165.1 (d, 1JC-F = 231.6 Hz), 166.4 (s),
167.6 (d, 1JC-F = 259.3 Hz), 168.7 (s), 168.8 (s), 169.1 (s) ppm. MS:
m/z = 459 [M]+. C26H22FN3O4 (459.47): calcd. C 67.97, H 4.83, N
9.15; found C 67.84, H 4.99, N 9.26.
(2R,5S)-1-(2-Amino-5-chlorobenzoyl)-5-isopropyl-3-methyl-2-(1-phen-
ylvinyl)imidazolidin-4-one (11ba): Yield 84%; colorless oil. [α]2D5
=
General Procedure for the Synthesis of Compounds 11: A solution
of 10 (1.04 mmol) in EtOH (10 mL) and 20% aq. AcOH (2.5 mL)
was treated with Fe powder (0.464 g, 8.32 mmol) and heated at
reflux for 5 h under vigorous stirring. The mixture was diluted with
AcOEt (50 mL) and filtered through a pad of Celite. The filtrate
+63.7 (c = 12.0, CHCl ). IR (Nujol): ν = 1654, 1706, 3466 cm–1.
˜
3
1H NMR (400 MHz, CDCl3, 25 °C): δ = 0.67 (d, J = 6.6 Hz, 3 H),
0.96 (d, J = 6.3 Hz, 3 H), 1.23–1.25 (m, 1 H), 2.78 (s, 3 H), 4.30
(br. s, 2 H), 4.32–4.36 (m, 1 H), 5.15 (s, 1 H), 5.36 (s, 1 H), 5.51 (s,
1 H), 6.63–6.65 (m, 1 H), 7.11–7.31 (m, 7 H) ppm. 13C NMR
was washed with aq. NaHCO3 (50 mL) and water (2ϫ25 mL) and (100 MHz, CDCl3, 25 °C): δ = 19.0 (q), 20.0 (q), 27.5 (d), 32.1 (q),
then the organic layer was dried with Na2SO4. The solvent was
evaporated under reduced pressure and the products purified by
column chromatography with light petroleum ether/AcOEt (1:1) as
eluent.
62.9 (d), 79.5 (d), 117.8 (d), 120.9 (s), 121.5 (t), 121.9 (s), 127.9 (d),
128.0 (d), 128.4 (d), 128.5 (d), 131.0 (d), 137.4 (s), 143.7 (s), 145.0
(s), 170.0 (s), 171.0 (s) ppm. MS: m/z = 397 [M]+. C22H24ClN3O2
(397.90): calcd. C 66.41, H 6.08, N 10.56; found C 66.53, H 6.01,
N 10.44.
(2R,5S)-1-(2-Aminobenzoyl)-3,5-dimethyl-2-(1-phenylvinyl)imidazol-
idin-4-one (11a): Yield 96%; yellow oil. [α]2D5 = +25.3 (c = 0.22,
(2R,5S)-1-(2-Amino-5-fluorobenzoyl)-5-isopropyl-3-methyl-2-(1-phen-
ylvinyl)imidazolidin-4-one (11bb): Yield 93%; white crystals; m.p.
CHCl ). IR (Nujol): ν = 1648, 1698, 3488 cm–1 1H NMR
.
˜
3
(400 MHz, CDCl3, 25 °C): δ = 0.66 (d, J = 6.9 Hz, 3 H), 2.96 (s, 3
44 °C (iPr2O). [α]2D5 = +26.7 (c = 21.8, CHCl ). IR (Nujol): ν =
˜
3
H), 4.13 (br. s, 2 H), 4.30 (q, J = 6.9 Hz, 1 H), 5.36 (s, 2 H), 5.87 1640, 1696, 3438 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ =
(s, 1 H), 6.70–6.75 (m, 2 H), 7.00–7.35 (m, 7 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 17.3 (q), 27.5 (q), 55.9 (d), 79.5 (d),
0.73 (d, J = 6.8 Hz, 3 H), 0.97 (d, J = 6.5 Hz, 3 H), 1.32 (qqd, J =
6.5, 6.8, 9.0 Hz, 1 H), 2.83 (s, 3 H), 3.47 (br. s, 2 H), 4.29 (d, J =
117.1 (d), 118.2 (d), 119.2 (s), 121.3 (s), 121.8 (t), 127.2 (d), 127.6 9.0 Hz, 1 H), 5.20 (s, 1 H), 5.36 (s, 1 H), 5.60 (s, 1 H), 6.65–7.35
(d), 128.8 (d), 128.9 (d), 131.4 (d), 137.8 (s), 144.7 (s), 144.9 (s),
171.1 (s) ppm. MS: m/z = 335 [M]+. C20H21N3O2 (335.40): calcd.
C 71.62, H 6.31, N 12.53; found C 71.45, H 6.52, N 12.33.
(m, 8 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 18.8 (q),
2
20.1 (q), 27.5 (d), 32.1 (q), 63.1 (d), 78.9 (d), 114.3 (dd, JC-F
=
3
2
23.8 Hz), 117.7 (dd, JC-F = 8.1 Hz), 117.8 (dd, JC-F = 20.2 Hz),
3
120.9 (t), 121.2 (d, JC-F = 6.1 Hz), 127.9 (d), 128.3 (d), 128.4 (d),
(2R,5S)-1-(2-Amino-5-chlorobenzoyl)-3,5-dimethyl-2-(1-phenyl-
vinyl)imidazolidin-4-one (11aa): Yield 96%; yellow crystals; m.p.
137.6 (s), 140.8 (s), 145.2 (s), 154.8 (d, 1JC-F = 236.3 Hz), 169.9 (s),
170.6 (s) ppm. MS: m/z = 381 [M]+. C22H24FN3O2 (381.44): calcd.
C 69.27, H 6.34, N 11.02; found C 69.41, H 6.12, N 11.29.
106 °C (iPr2O). [α]2D5 = +21.4 (c = 24.1, CHCl ). IR (Nujol): ν =
˜
3
1636, 1694, 3448 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ =
0.55 (d, J = 6.6 Hz, 3 H), 2.80 (s, 3 H), 4.15 (q, J = 6.6 Hz, 1 H),
(2R,5S)-1-(2-Aminobenzoyl)-5-benzyl-3-methyl-2-(1-phenylvinyl)-
4.26 (br. s, 2 H), 5.16 (s, 1 H), 5.20 (s, 1 H), 5.68 (s, 1 H), 6.51– imidazolidin-4-one (11c): Yield 97%; yellow crystals; m.p. 130 °C
6.54 (m, 1 H), 6.90–6.97 (m, 4 H), 7.13–7.21 (m, 3 H) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 16.6 (q), 26.9 (q), 55.2 (d),
79.0 (d), 117.4 (d), 121.4 (t), 121.5 (s), 121.6 (s), 126.5 (d), 128.0
(d), 128.3 (d), 128.4 (d), 130.6 (d), 137.1 (s), 143.1 (s), 144.2 (s),
(iPr2O). [α]2D5 = +130.0 (c = 0.28, CHCl ). IR (Nujol): ν = 1642,
˜
3
1696, 3472 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.87–
1.94 (m, 1 H), 2.37–2.43 (m, 1 H), 2.93 (s, 3 H), 4.01 (br. s, 2 H),
4.50–4.54 (m, 1 H), 5.19 (s, 1 H), 5.46 (s, 1 H), 5.80 (s, 1 H), 6.71–
170.0 (s), 170.3 (s) ppm. MS: m/z = 369 [M]+. C20H20ClN3O2 7.40 (m, 14 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 27.5
(369.84): calcd. C 64.95, H 5.45, N 11.36; found C 64.87, H 5.61,
N 11.27.
(q), 38.7 (t), 60.5 (d), 79.0 (d), 117.2 (d), 118.3 (d), 121.1 (s), 121.7
(t), 126.8 (d), 127.4 (d), 128.5 (d), 128.8 (d, overlapped), 128.9 (d),
Eur. J. Org. Chem. 2010, 1694–1703
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1699

E. M. Beccalli et al.
FULL PAPER
129.8 (d), 131.5 (d), 137.4 (s), 138.0 (s), 144.8 (s), 145.0 (s), 169.9
H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 14.2 (q), 16.7
(s), 170.2 (s) ppm. MS: m/z = 411 [M]+. C26H25N3O2 (411.50): (q), 27.0 (q), 55.6 (d), 63.0 (t), 79.6 (d), 117.8 (d), 118.6 (s), 121.7
calcd. C 75.89, H 6.12, N 10.21; found C 76.02, H 5.97, N 10.40.
(s), 121.8 (s), 121.9 (t), 127.0 (d), 128.3 (d), 128.5 (d), 128.6 (d),
131.4 (d), 136.8 (s), 138.4 (s), 144.1 (s), 159.1 (s), 167.0 (s), 170.1
(s) ppm. MS: m/z = 502 [M]+. C24H24Cl2N4O4 (503.38): calcd. C
57.26, H 4.81, N 11.13; found C 57.40, H 4.62, N 11.21.
(2R,5S)-1-(2-Amino-5-chlorobenzoyl)-5-benzyl-3-methyl-2-(1-phen-
ylvinyl)imidazolidin-4-one (11ca): Yield 79%; yellow oil. [α]2D5
=
+13.7 (c = 8.47, CHCl ). IR (Nujol): ν = 1650, 1696, 3480 cm–1.
˜
3
1H NMR (400 MHz, CDCl3, 25 °C): δ = 2.03–2.36 (m, 2 H), 2.93
(s, 3 H), 4.15 (br. s, 2 H), 4.56–4.60 (m, 1 H), 5.12 (s, 1 H), 5.36 (s,
1 H), 5.70 (s, 1 H), 6.58–7.41 (m, 13 H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 27.1 (q), 38.2 (t), 60.0 (d), 78.9 (d), 113.4 (d),
118.0 (d), 121.4 (s), 121.7 (t), 122.4 (s), 126.6 (d), 127.1 (d), 128.2
(d), 128.4 (d), 128.6 (d), 129.3 (d), 129.4 (d), 130.9 (d), 131.3 (d),
136.9 (s), 137.3 (s), 143.2 (s), 144.4 (s), 168.7 (s), 169.3 (s) ppm.
MS: m/z = 445 [M]+. C26H24ClN3O2 (445.94): calcd. C 70.03, H
5.42, N 9.42; found C 70.18, H 5.31, N 9.38.
Ethyl (2R,5S)-2-Chloro-2-(2-{2-[3,5-dimethyl-4-oxo-2-(1-phenyl-
vinyl)imidazolidin-1-ylcarbonyl]-4-fluorophenyl}hydrazono)acetate
(12ab): Yield 49%; yellow crystals; m.p. 125 °C (iPr2O). [α]2D5
=
–0.35 (c = 10.3, CHCl ). IR (Nujol): ν = 1642, 1708, 1732,
˜
3
3412 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 0.64 (d, J =
6.3 Hz, 3 H), 1.39 (t, J = 7.1 Hz, 3 H), 2.96 (s, 3 H), 4.30 (q, J =
6.3 Hz, 1 H), 4.37 (q, J = 7.1 Hz, 2 H), 5.38 (s, 2 H), 5.86 (s, 1 H),
6.95–7.51 (m, 8 H), 9.22 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 14.2 (q), 16.7 (q), 27.0 (q), 55.7 (d), 62.9 (t),
2
3
79.4 (d), 113.8 (dd, JC-F = 24.3 Hz), 118.0 (s), 118.2 (dd, JC-F
=
(2R,5S)-1-(2-Amino-5-fluorobenzoyl)-5-benzyl-3-methyl-2-(1-phen-
ylvinyl)imidazolidin-4-one (11cb): Yield 60%; white crystals; m.p.
2
7.5 Hz), 118.5 (dd, JC-F = 22.4 Hz), 121.8 (t), 128.3 (d), 128.5 (d),
1
142 °C (iPr2O). [α]2D5 = +4.7 (c = 5.07, CHCl ). IR (Nujol): ν =
128.6 (d), 136.1 (s), 136.8 (s), 140.6 (s), 144.1 (s), 157.5 (d, JC-F
=
˜
3
242.8 Hz), 159.2 (s), 166.8 (s), 170.1 (s) ppm. MS: m/z = 486 [M]+.
C24H24ClFN4O4 (486.92): calcd. C 59.20, H 4.97, N 11.51; found
C 59.08, H 5.12, N 11.31.
1662, 1708, 3490 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ =
2.03–2.36 (m, 2 H), 2.93 (s, 3 H), 4.15 (br. s, 2 H), 4.56–4.60 (m, 1
H), 5.12 (s, 1 H), 5.36 (s, 1 H), 5.70 (s, 1 H), 6.58–7.41 (m, 13
H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 27.1 (q), 38.2
Ethyl (2R,5S)-2-Chloro-2-(2-{2-[5-isopropyl-3-methyl-4-oxo-2-(1-
2
2
(t), 60.0 (d), 78.6 (d), 113.7 (dd, JC-F = 23.7 Hz), 117.9 (dd, JC-F
phenylvinyl)imidazolidin-1-ylcarbonyl]phenyl}hydrazono)acetate
3
3
(12b): Yield 51%; cream crystals; m.p. 69 °C (iPr2O). [α]2D5 = +45.6
= 22.6 Hz), 118.1 (dd, JC-F = 7.4 Hz), 121.5 (t), 121.2 (d, JC-F
=
1
(c = 0.4, CHCl ). IR (Nujol): ν = 1656, 1688, 1724, 3436 cm–1. H
6.1 Hz), 126.6 (d), 128.2 (d), 128.4 (d), 128.6 (d, overlapped), 129.4
˜
3
1
(d), 137.6 (s), 137.4 (s), 140.4 (s), 144.4 (s), 155.2 (d, JC-F
=
NMR (400 MHz, CDCl3, 25 °C): δ = 0.72 (d, J = 6.8 Hz, 3 H),
0.98 (d, J = 6.5 Hz, 3 H), 1.17–1.21 (m, 1 H), 1.43 (t, J = 7.1 Hz,
3 H), 2.83 (s, 3 H), 4.39–4.45 (m, 3 H), 5.32 (s, 1 H), 5.42 (s, 1 H),
5.68 (s, 1 H), 7.01 (dd, J = 7.4, 7.5 Hz, 1 H), 7.10–7.13 (m, 2 H),
7.27–7.36 (m, 3 H), 7.40 (d, J = 7.5 Hz, 1 H), 7.45 (dd, J = 7.4,
8.2 Hz, 1 H), 7.64 (d, J = 8.2 Hz, 1 H), 9.51 (s, 1 H) ppm. 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 14.6 (q), 19.3 (q), 20.5 (q),
28.0 (d), 32.6 (q), 63.3 (t), 63.8 (d), 79.7 (d), 116.7 (d), 118.9 (s),
120.6 (s), 121.4 (t), 122.0 (d), 128.2 (d), 128.3 (d), 128.9 (d), 129.0
(d), 132.4 (d), 138.1 (s), 140.8 (s), 145.8 (s), 159.9 (s), 170.3 (s),
171.2 (s) ppm. MS: m/z = 496 [M]+. C26H29ClN4O4 (496.99): calcd.
C 62.83, H 5.88, N 11.27; found C 62.71, H 5.96, N 11.10.
236.8 Hz), 168.6 (s), 169.4 (s) ppm. MS: m/z = 429 [M]+.
C26H24FN3O2 (429.49): calcd. C 72.71, H 5.63, N 9.78; found C
72.60, H 5.81, N 9.61.
General Procedure for the Synthesis of Compounds 12: NaNO2
(0.156 g, 2.26 mmol) was added portionwise to a solution of 11
(1.13 mmol) in MeOH (2 mL) and 6  HCl (0.65 mL) cooled to
0 °C. After 30 min AcONa was added until pH 5 and then a solu-
tion of ethyl 2-chloroacetoacetate (1.13 mmol, 0.122 mL) in MeOH
(1 mL) was added dropwise under vigorous stirring at room tem-
perature. After 24 h the solvent was evaporated under reduced pres-
sure and the residue extracted with Et2O (2ϫ15 mL). The organic
layer was washed with aq. NaHCO3 (15 mL) and water (30 mL)
and then dried with Na2SO4. The solvent was evaporated under
reduced pressure and the products purified by silica gel column
chromatography with light petroleum ether/AcOEt (1:1) as eluent.
Ethyl (2R,5S)-2-Chloro-2-(2-{4-chloro-2-[5-isopropyl-3-methyl-4-
oxo-2-(1-phenylvinyl)imidazolidin-1-ylcarbonyl]phenyl}hydrazono)-
acetate (12ba): Yield 82%; pale-yellow oil. [α]2D5 = –0.81 (c = 6.20,
CHCl ). IR (Nujol): ν = 1634, 1686, 1716, 3424 cm–1. 1H NMR
˜
3
(400 MHz, CDCl3, 25 °C): δ = 0.62 (d, J = 6.6 Hz, 3 H), 0.91 (d,
J = 6.4 Hz, 3 H), 1.00–1.09 (m, 1 H), 1.33 (t, J = 7.1 Hz, 3 H),
2.77 (s, 3 H), 4.27–4.35 (m, 3 H), 5.18 (s, 1 H), 5.36 (s, 1 H), 5.53
(s, 1 H), 7.05–7.48 (m, 8 H), 9.49 (s, 1 H) ppm. 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 14.1 (q), 18.9 (q), 19.9 (q), 27.4 (d),
32.0 (q), 62.9 (t), 63.0 (d), 79.6 (d), 117.7 (d), 118.8 (s), 121.2 (s),
121.7 (t), 126.7 (s), 127.8 (d), 127.9 (d), 128.3 (d), 128.5 (d), 131.6
(d), 137.2 (s), 138.9 (s), 145.0 (s), 159.2 (s), 169.8 (s), 169.9 (s) ppm.
MS: m/z = 530 [M]+. C26H28Cl2N4O4 (531.43): calcd. C 58.76, H
5.31, N 10.54; found C 58.54, H 5.44, N 10.43.
Ethyl (2R,5S)-2-Chloro-2-(2-{2-[3,5-dimethyl-4-oxo-2-(1-phenyl-
vinyl)imidazolidin-1-ylcarbonyl]phenyl}hydrazono)acetate (12a):
Yield 57%; pale-yellow crystals; m.p. 65 °C (iPr2O). [α]2D5 = +2.1 (c
1
= 0.15, CHCl ). IR (Nujol): ν = 1650, 1703, 1716, 3338 cm–1. H
˜
3
NMR (400 MHz, CDCl3, 25 °C): δ = 0.62 (d, J = 6.6 Hz, 3 H),
1.42 (t, J = 7.1 Hz, 3 H), 2.98 (s, 3 H), 4.35 (q, J = 6.6 Hz, 1 H),
4.41 (q, J = 7.1 Hz, 2 H), 5.38 (s, 1 H), 5.40 (s, 1 H), 5.91 (s, 1 H),
7.00–7.61 (m, 9 H), 9.40 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 14.6 (q), 17.1 (q), 27.5 (q), 56.2 (d), 63.3 (t),
79.9 (d), 116.7 (d), 118.5 (s), 121.0 (s), 122.1 (t), 122.4 (d), 127.3
(d), 128.8 (d), 128.9 (d), 132.1 (d), 132.2 (d), 137.4 (s), 140.3 (s),
144.7 (s), 159.2 (s), 168.5 (s), 170.7 (s) ppm. MS: m/z = 468 [M]+.
C24H25ClN4O4 (468.93): calcd. C 61.47, H 5.37, N 11.95; found C
61.34, H 5.48, N 11.77.
Ethyl (2R,5S)-2-Chloro-2-(2-{4-fluoro-2-[5-isopropyl-3-methyl-4-
oxo-2-(1-phenylvinyl)imidazolidin-1-ylcarbonyl]phenyl}hydrazono)-
acetate (12bb): Yield 57%; colorless oil. [α]2D5 = +16.4 (c = 5.00,
CHCl ). IR (Nujol): ν = 1638, 1710, 1722, 3384 cm–1. 1H NMR
˜
3
Ethyl (2R,5S)-2-Chloro-2-(2-{4-chloro-2-[3,5-dimethyl-4-oxo-2-(1-
(400 MHz, CDCl3, 25 °C): δ = 0.70 (d, J = 6.8 Hz, 3 H), 0.97 (d,
phenylvinyl)imidazolidin-1-ylcarbonyl]phenyl}hydrazono)acetate J = 6.5 Hz, 3 H), 1.18–1.23 (m, 1 H), 1.40 (t, J = 7.1 Hz, 3 H),
(12aa): Yield 62%; pale-yellow crystals; m.p. 174 °C (iPr2O). [α]2D5
= +2.4 (c = 17.8, CHCl ). IR (Nujol): ν = 1646, 1694, 1728,
2.83 (s, 3 H), 4.33–4.41 (m, 3 H), 5.29 (s, 1 H), 5.42 (s, 1 H), 5.64
(s, 1 H), 7.08–7.17 (m, 4 H), 7.27–7.33 (m, 3 H), 7.53–7.57 (m, 1
˜
3
3392 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 0.66 (d, J = H), 9.30 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
6.5 Hz, 3 H), 1.37 (t, J = 6.9 Hz, 3 H), 2.94 (s, 3 H), 4.31–4.37 (m, 14.2 (q), 18.9 (q), 20.3 (q), 27.5 (d), 32.1 (q), 62.9 (t), 63.3 (d), 79.2
2
3
3 H), 5.37 (s, 2 H), 5.83 (s, 1 H), 7.04–7.47 (m, 8 H), 9.33 (s, 1 (d), 114.7 (dd, JC-F = 24.4 Hz), 118.1 (dd, JC-F = 7.4 Hz), 118.5
1700
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1694–1703

Novel Tetracyclic 1,4-Benzodiazepin-5-ones
(s), 118.8 (dd, 2JC-F = 22.3 Hz), 121.3 (t), 127.8 (d), 128.6 (d), 128.9
H), 4.33 (q, J = 7.1 Hz, 2 H), 5.57 (s, 1 H), 7.13 (dd, J = 7.4,
8.0 Hz, 1 H), 7.18–7.21 (m, 2 H), 7.36–7.38 (m, 3 H), 7.52 (ddd, J
= 1.6, 7.4, 8.7 Hz, 1 H), 7.84 (d, J = 8.7 Hz, 1 H), 8.11 (dd, J =
1
(d), 136.6 (s), 137.3 (s), 140.0 (s), 145.2 (s), 157.2 (d, JC-F
=
242.7 Hz), 159.3 (s), 169.5 (s), 169.7 (s) ppm. MS: m/z = 514 [M]+.
C26H28ClFN4O4 (514.98): calcd. C 60.64, H 5.48, N 10.88; found 1.6, 8.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ =
C 60.88, H 5.23, N 10.65.
14.2 (q), 14.6 (q), 30.5 (q), 44.7 (t), 55.9 (d), 62.4 (t), 77.4 (d), 81.7
(s), 116.8 (s), 118.1 (d), 122.4 (d), 126.5 (d), 129.5 (d), 129.9 (d),
133.3 (d), 134.0 (d), 137.9 (s), 141.5 (s), 143.4 (s), 162.1 (s), 164.5
(s), 172.4 (s) ppm. MS: m/z = 432 [M]+. C24H24N4O4 (432.47):
calcd. C 66.65, H 5.59, N 12.96; found C 66.41, H 5.70, N 12.82.
Ethyl (2R,5S)-2-(2-{2-[5-Benzyl-3-methyl-4-oxo-2-(1-phenylvinyl)-
imidazolidin-1-ylcarbonyl]phenyl}hydrazono)-2-chloroacetate (12c):
Yield 44%; yellow oil. [α]2D5 = –33.8 (c = 0.21, CHCl3). IR (Nujol):
ν = 1646, 1692, 1720, 3404 cm–1 1H NMR (400 MHz, CDCl3,
.
˜
25 °C): δ = 1.42 (t, J = 7.1 Hz, 3 H), 2.01–2.05 (m, 1 H), 2.08–2.13
(m, 1 H), 2.98 (s, 3 H), 4.41 (q, J = 7.1 Hz, 2 H), 4.60 (t, J =
4.7 Hz, 1 H), 5.23 (s, 1 H), 5.37 (s, 1 H), 5.83 (s, 1 H), 6.75–7.56
(m, 14 H), 9.31 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C):
δ = 14.6 (q), 27.5 (q), 38.7 (t), 60.9 (d), 63.3 (t), 79.4 (d), 116.8 (d),
118.5 (s), 120.9 (s), 122.0 (t), 122.4 (d), 126.5 (d), 126.9 (d), 127.5
(d), 128.6 (d), 128.8 (d), 129.3 (d), 129.7 (d), 132.1 (d), 136.8 (s),
137.8 (s), 140.3 (s), 144.8 (s), 159.8 (s), 168.9 (s), 169.6 (s) ppm.
MS: m/z = 544 [M]+. C30H29ClN4O4 (545.03): calcd. C 66.11, H
5.36, N 10.28; found C 65.98, H 5.54, N 10.12.
Ethyl (3aS,3bR,6S)-10-Chloro-4,6-dimethyl-5,8-dioxo-3a-phenyl-
3,3a,3b,4,5,6-hexahydro-8H-benzo[e]imidazo[1,2-a]pyrazolo[5,1-c]-
[1,4]diazepine-2-carboxylate (14aa): Yield 62 %; yellow crystals;
m.p. 143 °C (iPr2O). [α]2D5 = +89.7 (c = 2.31, CHCl3). IR (Nujol):
1
ν = 1647, 1704, 1728 cm–1. H NMR (400 MHz, CDCl , 25 °C): δ
˜
3
= 0.32 (d, J = 6.7 Hz, 3 H), 1.33 (t, J = 7.0 Hz, 3 H), 3.21 (s, 3 H),
3.57 (d, J = 16.1 Hz, 1 H), 3.82 (d, J = 16.1 Hz, 1 H), 4.17 (q, J =
6.7 Hz, 1 H), 4.28 (q, J = 7.0 Hz, 2 H), 5.53 (s, 1 H), 7.11–7.40 (m,
6 H), 7.76–7.79 (m, 1 H), 8.04 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 13.7 (q), 14.2 (q), 30.1 (q), 44.4 (t), 55.5 (d),
62.1 (t), 76.7 (d), 81.1 (s), 117.2 (s), 119.3 (d), 126.6 (d), 127.2 (s),
129.1 (d), 129.6 (d), 132.1 (d), 133.4 (d), 137.2 (s), 139.7 (s), 143.5
(s), 161.4 (s), 162.7 (s), 171.8 (s) ppm. MS: m/z = 466 [M]+.
C24H23ClN4O4 (466.92): calcd. C 61.74, H 4.97, N 12.00; found C
61.48, H 5.23, N 12.27.
Ethyl (2R,5S)-2-(2-{2-[5-Benzyl-3-methyl-4-oxo-2-(1-phenylvinyl)-
imidazolidin-1-ylcarbonyl]-4-chlorophenyl}hydrazono)-2-chloroacet-
ate (12ca): Yield 43%; yellow oil. [α]2D5 = +0.022 (c = 4.49, CHCl3).
IR (Nujol): ν = 1650, 1702, 1726, 3456 cm–1. 1H NMR (400 MHz,
˜
CDCl3, 25 °C): δ = 1.41 (t, J = 7.1 Hz, 3 H), 2.22–2.26 (m, 2 H),
2.98 (s, 3 H), 4.40 (q, J = 7.1 Hz, 2 H), 4.65 (t, J = 6.4 Hz, 1 H),
5.19 (s, 1 H), 5.40 (s, 1 H), 5.79 (s, 1 H), 6.77–6.80 (m, 2 H), 7.10–
7.43 (m, 11 H), 9.24 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 14.2 (q), 27.1 (q), 38.3 (t), 60.3 (d), 63.0 (t), 79.3 (d),
117.8 (d), 118.7 (s), 121.3 (s), 122.0 (t), 126.6 (d), 127.0 (s), 127.1
(d), 128.3 (d), 128.7 (d), 128.8 (d, overlapped), 129.1 (d), 130.2 (d),
131.5 (d), 136.3 (s), 137.3 (s), 138.6 (s), 144.2 (s), 159.2 (s), 167.4
(s), 169.0 (s) ppm. MS: m/z = 578 [M]+. C30H28Cl2N4O4 (579.47):
calcd. C 62.18, H 4.87, N 9.67; found C 61.95, H 5.04, N 9.87.
Ethyl (3aS,3bR,6S)-10-Fluoro-4,6-dimethyl-5,8-dioxo-3a-phenyl-
3,3a,3b,4,5,6-hexahydro-8H-benzo[e]imidazo[1,2-a]pyrazolo[5,1-c]-
[1,4]diazepine-2-carboxylate (14ab): Yield 71%; white crystals; m.p.
145 °C (iPr2O). [α]2D5 = +912.1 (c = 3.23, CHCl ). IR (Nujol): ν =
˜
3
1655, 1690, 1724 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ =
0.29 (d, J = 6.7 Hz, 3 H), 1.35 (t, J = 7.1 Hz, 3 H), 3.24 (s, 3 H),
3.58 (d, J = 16.1 Hz, 1 H), 3.82 (d, J = 16.1 Hz, 1 H), 4.21 (q, J =
6.7 Hz, 1 H), 4.31 (q, J = 7.1 Hz, 2 H), 5.54 (s, 1 H), 7.15–7.40 (m,
6 H), 7.78–7.83 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 13.7 (q), 14.2 (q), 30.1 (q), 44.4 (t), 55.6 (d), 62.0 (t),
Ethyl (2R,5S)-2-(2-{2-[5-Benzyl-3-methyl-4-oxo-2-(1-phenylvinyl)-
2
76.7 (d), 81.1 (s), 118.1 (s), 118.3 (dd, JC-F = 24.6 Hz), 119.7 (dd,
imidazolidin-1-ylcarbonyl]-4-fluorophenyl}hydrazono)-2-chloroacet-
2
3JC-F = 6.7 Hz), 121.1 (dd, JC-F = 22.7 Hz), 126.7 (d), 129.2 (d),
ate (12cb): Yield 47%; yellow crystals; m.p. 105 °C (iPr2O). [α]2D5
=
129.6 (d), 137.4 (s), 137.5 (s), 142.9 (s), 157.8 (d, 1JC-F = 240.7 Hz),
161.5 (s), 162.8 (s), 171.8 (s) ppm. MS: m/z = 450 [M]+.
C24H23FN4O4 (450.46): calcd. C 63.99, H 5.15, N 12.44; found C
64.08, H 5.02, N 12.31.
–0.13 (c = 4.43, CHCl ). IR (Nujol): ν = 1647, 1704, 1728,
˜
3
3462 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.40 (t, J =
7.1 Hz, 3 H), 2.17–2.25 (m, 2 H), 2.96 (s, 3 H), 4.39 (q, J = 7.1 Hz,
2 H), 4.60 (t, J = 6.4 Hz, 1 H), 5.17 (s, 1 H), 5.37 (s, 1 H), 5.83 (s,
1 H), 6.78–7.44 (m, 13 H), 9.12 (s, 1 H) ppm. 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 14.2 (q), 27.1 (q), 38.3 (t), 60.4 (d), 63.0 (t),
Ethyl (3aS,3bR,6S)-6-Isopropyl-4-methyl-5,8-dioxo-3a-phenyl-
3,3a,3b,4,5,6-hexahydro-8H-benzo[e]imidazo[1,2-a]pyrazolo[5,1-c]-
[1,4]diazepine-2-carboxylate (14b): Yield 62%; yellow crystals; m.p.
2
3
79.0 (d), 114.1 (dd, JC-F = 24.3 Hz), 118.0 (s), 118.3 (dd, JC-F
=
2
138 °C (iPr2O). [α]2D5 = +975.0 (c = 0.38, CHCl ). IR (Nujol): ν =
7.5 Hz), 118.5 (dd, JC-F = 22.4 Hz), 121.5 (s), 121.8 (t), 126.6 (d),
˜
3
1644, 1702, 1720 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ =
0.16 (qqd, J = 6.6, 6.7, 9.8 Hz, 1 H), 0.45 (d, J = 6.7 Hz, 3 H),
0.81 (d, J = 6.6 Hz, 3 H), 1.36 (t, J = 7.1 Hz, 3 H), 3.20 (s, 3 H),
3.55 (d, J = 15.9 Hz, 1 H), 3.76 (d, J = 15.9 Hz, 1 H), 4.04 (d, J =
9.8 Hz, 1 H), 4.32 (q, J = 7.1 Hz, 2 H), 5.42 (s, 1 H), 7.12 (dd, J =
7.3, 8.1 Hz, 1 H), 7.26–7.37 (m, 5 H), 7.50 (ddd, J = 1.6, 7.3,
8.6 Hz, 1 H), 7.80 (d, J = 8.6 Hz, 1 H), 8.19 (dd, J = 1.6, 8.1 Hz,
1 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 14.6 (q), 19.3
(q), 22.2 (q), 30.1 (d), 33.3 (q), 45.0 (t), 62.5 (t), 63.5 (d), 79.9 (d),
81.1 (s), 116.7 (s), 118.5 (d), 122.4 (d), 127.7 (d), 129.3 (d), 129.7
(d), 133.7 (d), 134.4 (d), 137.8 (s), 142.3 (s), 145.6 (s), 161.9 (s),
166.5 (s), 172.1 (s) ppm. MS: m/z = 460 [M]+. C26H28N4O4
(460.52): calcd. C 67.81, H 6.13, N 12.17; found C 67.54, H 6.24,
N 12.02.
128.2 (d), 128.3 (d, overlapped), 128.6 (d), 129.2 (d), 136.1 (s), 136.3
1
(s), 137.3 (s), 144.2 (s), 157.4 (d, JC-F = 243.0 Hz), 159.3 (s), 167.3
(s), 169.1 (s) ppm. MS: m/z = 562 [M]+. C30H28ClFN4O4 (563.02):
calcd. C 64.00, H 5.01, N 9.95; found C 63.81, H 5.13, N 10.07.
General Procedure for the Synthesis of Compounds 14: A solution
of 12 (0.2 mmol) in toluene (9 mL) was treated with TEA (0.11 mL,
0.8 mmol) and heated at reflux for 24 h. The organic layer was
washed with aq. NaHCO3 (10 mL) and water (20 mL) and then it
was dried with Na2SO4. The solvent was evaporated under reduced
pressure and the products purified by silica gel column chromatog-
raphy with light petroleum ether/AcOEt (1:1) as eluent.
Ethyl (3aS,3bR,6S)-4,6-Dimethyl-5,8-dioxo-3a-phenyl-3,3a,3b,4,5,6-
hexahydro-8H-benzo[e]imidazo[1,2-a]pyrazolo[5,1-c][1,4]diazepine-
2-carboxylate (14a): Yield 55%; yellow crystals; m.p. 90 °C (iPr2O).
[α]2D5 = +667.0 (c = 0.20, CHCl ). IR (Nujol): ν = 1652, 1705,
Ethyl (3aS,3bR,6S)-10-Chloro-6-isopropyl-4-methyl-5,8-dioxo-3a-
˜
3
1716 cm–1. 1H NMR (400 MHz, CDCl3, 25 °C): δ = 0.32 (d, J = phenyl-3,3a,3b,4,5,6-hexahydro-8H-benzo[e]imidazo[1,2-a]pyrazolo-
6.8 Hz, 3 H), 1.37 (t, J = 7.1 Hz, 3 H), 3.25 (s, 3 H), 3.60 (d, J = [5,1-c][1,4]diazepine-2-carboxylate (14ba): Yield 53%; yellow crys-
16.1 Hz, 1 H), 3.82 (d, J = 16.1 Hz, 1 H), 4.25 (q, J = 6.8 Hz, 1
tals; m.p. 135 °C (iPr2O). [α]2D5 = +818.0 (c = 3.94, CHCl3). IR
Eur. J. Org. Chem. 2010, 1694–1703
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1701

E. M. Beccalli et al.
FULL PAPER
(Nujol): ν = 1652, 1688, 1716 cm–1. H NMR (400 MHz, CDCl ,
jol): ν = 1646, 1692, 1734 cm–1
.
1H NMR (400 MHz, CDCl3,
1
˜
˜
3
25 °C): δ = 0.18 (qqd, J = 6.6, 6.5, 9.7 Hz, 1 H), 0.42 (d, J = 6.6 Hz,
25 °C): δ = 0.82–0.88 (m, 1 H), 1.37 (t, J = 7.1 Hz, 3 H), 2.30–2.35
3 H), 0.80 (d, J = 6.5 Hz, 3 H), 1.36 (t, J = 7.2 Hz, 3 H), 3.20 (s, (m, 1 H), 3.23 (s, 3 H), 3.62 (d, J = 16.0 Hz, 1 H), 3.82 (d, J =
3 H), 3.56 (d, J = 16.1 Hz, 1 H), 3.76 (d, J = 16.1 Hz, 1 H), 4.03
(d, J = 9.7 Hz, 1 H), 4.32 (q, J = 7.2 Hz, 2 H), 5.42 (s, 1 H), 7.22–
16.0 Hz, 1 H), 4.31–4.37 (m, 3 H), 5.53 (s, 1 H), 7.13–7.79 (m, 13
H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 14.2 (q), 29.9
7.44 (m, 6 H), 7.79 (d, J = 9.1 Hz, 1 H), 8.18 (s, 1 H) ppm. 13C (q), 34.6 (t), 44.2 (t), 60.3 (d), 62.0 (t), 76.4 (d), 81.2 (s), 114.0 (s),
2
3
NMR (100 MHz, CDCl3, 25 °C): δ = 14.2 (q), 18.9 (q), 21.7 (q),
29.8 (d), 32.9 (q), 44.7 (t), 62.2 (t), 63.2 (d), 76.5 (d), 80.6 (s), 117.1
119.7 (dd, JC-F = 23.2 Hz), 120.2 (dd, JC-F = 7.4 Hz), 125.6 (dd,
2JC-F = 21.8 Hz), 126.4 (d), 127.1 (s), 128.1 (d), 129.2 (d), 129.8
(s), 119.7 (d), 127.1 (d), 127.4 (s), 129.0 (d), 129.4 (d), 132.6 (d), (d), 130.2 (d), 130.3 (d), 135.4 (s), 137.6 (s), 137.9 (s), 142.1 (s),
1
133.8 (d), 137.1 (s), 140.4 (s), 145.3 (s), 161.4 (s), 164.8 (s), 171.5
(s) ppm. MS: m/z = 494 [M]+. C26H27ClN4O4 (494.97): calcd. C
63.09, H 5.50, N 11.32; found C 63.27, H 5.29, N 11.44.
157.8 (d, JC-F = 245.6 Hz), 164.0 (s), 170.8 (s) ppm. MS: m/z =
526 [M]+. C30H27FN4O4 (526.56): calcd. C 68.43, H 5.17, N 10.64;
found C 68.20, H 5.34, N 10.88.
Ethyl (3aS,3bR,6S)-10-Fluoro-6-isopropyl-4-methyl-5,8-dioxo-3a-
phenyl-3,3a,3b,4,5,6-hexahydro-8H-benzo[e]imidazo[1,2-a]pyrazolo-
[5,1-c][1,4]diazepine-2-carboxylate (14bb): Yield 46%; yellow crys-
Acknowledgments
tals; m.p. 144 °C (iPr2O). [α]2D5 = +207.4 (c = 2.23, CHCl3). IR
Ministero dell’Università e della Ricerca (MIUR) is acknowledged
for financial support and for a Ph. D. fellowship to M. R. (Progetto
Giovani 2006). We are also grateful to the Centro Interuniversitario
sulle Reazioni Pericicliche.
1
(Nujol): ν = 1644, 1701, 1733 cm–1. H NMR (400 MHz, CDCl ,
˜
3
25 °C): δ = 0.07 (d, J = 6.6 Hz, 3 H), 0.45 (qqd, J = 6.6, 6.5, 9.1 Hz,
1 H), 0.82 (d, J = 6.5 Hz, 3 H), 1.22 (t, J = 7.2 Hz, 3 H), 3.19 (s,
3 H), 3.53 (d, J = 16.0 Hz, 1 H), 3.75 (d, J = 16.0 Hz, 1 H), 4.02
(d, J = 9.1 Hz, 1 H), 4.31 (q, J = 7.2 Hz, 2 H), 5.32 (s, 1 H), 7.10–
7.83 (m, 8 H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 14.2
(q), 18.9 (q), 21.9 (q), 29.7 (d), 32.8 (q), 44.5 (t), 62.1 (t), 63.1 (d),
[1] a) D. J. Greenblatt, R. I. Shader, in: Benzodiazepines in Clinical
Practice, Raven Press, New York, 1974; b) Benzodiazepines di-
vided: A Multidisciplinary Review (Ed.: M. Trimble), Wiley,
New York, 1983; c) B. E. Evans, K. E. Rittle, M. G. Bock,
R. M. DiPardo, R. M. Freidinger, W. L. Whitter, G. F. Lundell,
D. F. Veber, P. S. Anderson, R. S. L. Chang, V. J. Lotti, D. J.
Cerino, T. B. Chen, P. J. Kling, K. A. Kunkel, J. P. Springer, J.
Hirschfeld, J. Med. Chem. 1988, 31, 2235–2246; d) M. G. Bock,
R. M. DiPardo, B. E. Evans, K. E. Rittle, W. L. Whitter, D. F.
Veber, P. S. Anderson, R. M. Freidinger, J. Med. Chem. 1989¸
32, 13–16; e) A. Walser, R. I. Fryer, in: Bicyclic Diazepines,
Wiley, New York, 1991, chapter VII; f) D. E. Thurston, D. S.
Bose, Chem. Rev. 1994, 94, 433–465; g) A. A. Patchett, R. P.
Nargund, Annu. Rep. Med. Chem. 2000, 35, 289–298.
2
76.5 (d), 81.2 (s), 114.5 (d), 118.7 (d), 119.3 (dd, JC-F = 23.7 Hz),
3
2
120.0 (dd, JC-F = 7.5 Hz), 125.2 (dd, JC-F = 22.4 Hz), 127.2 (d),
127.3 (d), 137.5 (s), 137.8 (s), 143.2 (s), 156.9 (d, 1JC-F = 244.1 Hz),
160.8 (s), 163.0 (s), 170.6 (s) ppm. MS: m/z = 478 [M]+.
C26H27FN4O4 (478.52): calcd. C 65.26, H 5.69, N 11.71; found C
65.51, H 5.44, N 11.43.
Ethyl (3aS,3bR,6S)-6-Benzyl-4-methyl-5,8-dioxo-3a-phenyl-
3,3a,3b,4,5,6-hexahydro-8H-benzo[e]imidazo[1,2-a]pyrazolo[5,1-c]-
[1,4]diazepine-2-carboxylate (14c): Yield 65%; yellow oil. [α]2D5
=
+94.6 (c = 0.20, CHCl ). IR (Nujol): ν = 1643, 1691, 1735 cm–1.
˜
3
1H NMR (400 MHz, CDCl3, 25 °C): δ = 0.82–0.91 (m, 1 H), 1.39
(t, J = 7.1 Hz, 3 H), 2.34–2.38 (m, 1 H), 3.24 (s, 3 H), 3.64 (d, J =
16.1 Hz, 1 H), 3.84 (d, J = 16.1 Hz, 1 H), 4.29–4.38 (m, 3 H), 5.56
(s, 1 H), 7.15–8.16 (m, 14 H) ppm. 13C NMR (100 MHz, CDCl3,
25 °C): δ = 14.6 (q), 28.7 (q), 35.0 (t), 44.7 (t), 60.6 (d), 60.8 (t),
76.8 (d), 81.7 (s), 116.8 (s), 118.2 (d), 122.5 (d), 126.8 (d), 127.5
(d), 128.5 (d), 129.6 (d), 129.8 (d), 130.2 (d), 133.3 (d), 134.1 (d),
137.9 (s), 138.3 (s), 141.6 (s), 143.7 (s), 162.0 (s), 164.5 (s), 171.2
(s) ppm. MS: m/z = 508 [M]+. C30H28N4O4 (508.57): calcd. C 70.85,
H 5.55, N 11.02; found C 70.69, H 5.67, N 11.13.
[2] a) A. A. Santilli, T. S. Osdene, U.S. Patent 3336330, 1967
[Chem. Abstr. 1967, 68, 21972]; b) A. A. Santilli, T. S. Osdene,
U.S. Patent 3457258, 1969 [Chem. Abstr. 1969, 71, 101898]; c)
K. Meguro, Y. Kuwada, Tetrahedron Lett. 1970, 11, 4039–4042;
d) J. B. Hester, A. D. Rudzik, B. V. Kamdar, J. Med. Chem.
1971, 14, 1078–1081; e) J. B. Hester, U.S. Patent 3896109, 1975
[Chem. Abstr. 1975, 84, 17440]; f) T. Kaneko, H. Wong, T. W.
Doyle, W. C. Rose, W. T. Bradner, J. Med. Chem. 1985, 28, 388–
392; g) G. Mohiuddin, P. S. Reddy, K. Ahmed, C. V. Ratnam,
Heterocycles 1986, 24, 3489–3530; h) R. M. Keenan, J. F. Calla-
han, J. M. Samanen, W. E. Bondinell, R. R. Calvo, L. Chen,
C. DeBrosse, D. S. Eggleston, R. C. Haltiwanger, S. M. Hwang,
D. R. Jakas, T. W. Ku, W. H. Miller, K. A. Newlander, A. Nich-
ols, M. F. Parker, L. S. Southhall, I. Uzinskas, J. A. Vasko-
Moser, J. W. Venslavsky, A. S. Wong, W. F. Huffman, J. Med.
Chem. 1999, 42, 545–559; i) A. N. Osman, A. A. El-Gendy,
R. H. Omar, L. Wagdy, A. H. Omar, Ind. J. Chem. Sect. B
2002, 41, 871–874.
[3] a) W. Frostl, L. Maitre, Pharmacopsych. 1989, 22, 54–101; b)
G. Broggini, G. Molteni, A. Terraneo, G. Zecchi, Tetrahedron
1999; 55, 14803–14806; c) G. Broggini, M. Orlandi, A. Turconi,
C. Zoni, Org. Prep. Proced. Int. 2003¸ 35, 609–612.
[4] a) A. R. Hanze, R. E. Strube, M. E. Greig, J. Med. Chem.
1963, 6, 767–771; b) F. Hunziker, H. Lauener, J. Smutz, Arz-
neim. Forsch. 1963, 13, 324–328; c) E. Waldvogel, G. Schwarb,
J.-M. Bastian, J.-P. Bourquin, Helv. Chim. Acta 1976, 59, 866–
877.
Ethyl (3aS,3bR,6S)-6-Benzyl-10-chloro-4-methyl-5,8-dioxo-3a-
phenyl-3,3a,3b,4,5,6-hexahydro-8H-benzo[e]imidazo[1,2-a]pyrazolo-
[5,1-c][1,4]diazepine-2-carboxylate (14ca): Yield 44%; yellow crys-
tals; m.p. 141 °C (iPr2O). [α]2D5 = +914.0 (c = 1.89, CHCl3). IR
1
(Nujol): ν = 1641, 1708, 1722 cm–1. H NMR (400 MHz, CDCl ,
˜
3
25 °C): δ = 0.86–0.92 (m, 1 H), 1.37 (t, J = 7.2 Hz, 3 H), 2.18–2.26
(m, 1 H), 3.23 (s, 3 H), 3.64 (d, J = 16.1 Hz, 1 H), 3.83 (d, J =
16.1 Hz, 1 H), 4.33–4.41 (m, 3 H), 5.52 (s, 1 H), 7.13–8.13 (m, 13
H) ppm. 13C NMR (100 MHz, CDCl3, 25 °C): δ = 14.2 (q), 30.3
(q), 34.6 (t), 44.5 (t), 60.3 (d), 62.2 (t), 76.3 (d), 81.1 (s), 117.2 (s),
119.4 (d), 126.5 (d), 126.9 (d), 127.7 (s), 128.2 (d), 129.2 (d), 129.3
(d), 129.9 (d), 132.2 (d), 133.6 (d), 137.2 (s), 137.8 (s), 139.7 (s),
143.6 (s), 161.4 (s), 162.7 (s), 170.7 (s) ppm. MS: m/z = 542 [M]+.
C30H27ClN4O4 (543.01): calcd. C 66.36, H 5.01, N 10.32; found C
66.12, H 5.14, N 10.55.
[5] a) S. Eguchi, K. Yamashita, Y. Matsushita, A. Kakehi, J. Org.
Chem. 1995, 60, 4006–4012; b) P. Molina, I. Diaz, A. Tarraga,
Tetrahedron 1995, 51, 5617–5630; c) A. Kamal, P. W. Howard,
B. S. N. Reddy, B. S. P. Reddy, D. E. Thurston, Tetrahedron
1997, 53, 3223–3230; d) G. A. Kraus, A. Melekhov, Tetrahe-
dron 1998, 54, 11749–11754; e) T. Wang, A. S. Lui, I. S.
Ethyl (3aS,3bR,6S)-6-Benzyl-10-fluoro-4-methyl-5,8-dioxo-3a-
phenyl-3,3a,3b,4,5,6-hexahydro-8H-benzo[e]imidazo[1,2-a]pyrazolo-
[5,1-c][1,4]diazepine-2-carboxylate (14cb): Yield 77%; yellow crys-
tals; m.p. 146 °C (iPr2O). [α]2D5 = +0.64 (c = 2.2, CHCl3). IR (Nu-
1702
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 1694–1703

Novel Tetracyclic 1,4-Benzodiazepin-5-ones
Cloudsale, Org. Lett. 1999, 1, 1835–1837; f) P. G. Baraldi, G.
Balboni, B. Cacciari, A. Guiotto, S. Manfredini, R. Romag-
noli, G. Spalluto, D. E. Thurston, P. W. Howard, N. Bianchi,
C. Rutigliano, C. Mischiati, R. Gambari, J. Med. Chem. 1999,
42, 5131–5141; g) A. Kamal, E. Laxman, N. Laxman, N. V.
Rao, Bioorg. Med. Chem. Lett. 2000, 10, 2311–2313; h) Q.
Zhou, W. Duan, D. Simmons, Y. Shayo, M. A. Raymond, R. T.
Dorr, L. H. Hurley, J. Am. Chem. Soc. 2001, 123, 4865–4866;
i) I. A. O’Neil, S. Thompson, S. B. Kalindjian, T. C. Jenkins,
Tetrahedron Lett. 2003, 44, 7809–7812.
Paladino, T. Pilati, G. Pontremoli, Tetrahedron: Asymmetry
2004, 15, 687–692; d) A. W. Thomas, Bioorg. Med. Chem. Lett.
2002, 12, 1881–1884; e) V. Santagada, E. Perissutti, F. Fiorino,
B. Vivenzio, G. Caliendo, Tetrahedron Lett. 2001, 42, 2397–
2400.
[15] a) G. Molteni, G. Broggini, T. Pilati, Tetrahedron: Asymmetry
2002, 13, 2491–2495; b) G. Broggini, L. Garanti, G. Molteni,
T. Pilati, A. Ponti, G. Zecchi, Tetrahedron: Asymmetry 1999,
10, 2203–2212; c) G. Broggini, I. De Marchi, M. Martinelli, G.
Paladino, T. Pilati, A. Terraneo, Synthesis 2005, 2246–2252.
[16] a) B. Anwar, P. Grimsey, K. Hemming, M. Krajniewski, C.
Loukou, Tetrahedron Lett. 2000, 41, 10107–10110; b) T. Sugi-
mori, T. Okawa, S. Eguchi, A. Kakehi, E. Yashima, Y. Okam-
oto, Tetrahedron 1998, 54, 7997–8008; c) S. Eguchi, K. Yama-
shita, Y. Matsushita, Synlett 1992, 295–297.
[6] L. P. Tardibono, M. J. Miller, Org. Lett. 2009, 11, 1575–1578.
[7] A. G. Katsifis, M. E. McPhee, F. Mattner, D. D. Ridley, Aust.
J. Chem. 1999, 52, 1061–1070.
[8] For examples concerning pyrimidine-fused benzodiazepines,
see: L. Zheng, J. Xiang, Q. Dang, S. Guo, X. Bai, J. Comb.
Chem. 2006, 8, 381–387.
[9] For examples of azolic-fused benzodiazepines, see: M. Gerecke,
E. Kyburz, R. Borer, W. Gassner, Heterocycles 1994, 39, 693–
721.
[10] For examples of carbocyclic-fused benzodiazepines, see: G.
Tóth, A. Lévai, A. Szöllösy, Liebigs Ann. Chem. 1992, 803–
807.
[17] a) See ref.[2g]; b) J. D. White, W. E. Haefliger, M. J. Dimsdale,
Tetrahedron 1970, 26, 233–242.
[18] a) L. Banfi, A. Basso, G. Guanti, N. Kielland, C. Repetto, R.
Riva, J. Org. Chem. 2007, 72, 2151–2160; b) G. A. Kraus, P.
Liu, Tetrahedron Lett. 1995, 36, 7595–7598.
[19] T. A. Stroganova, A. V. Butin, V. K. Vasilin, T. A. Nevolina,
G. D. Krapivin, Synlett 2007, 7, 1106–1109.
[11] a) A. C. Tiberghien, D. A. Evans, K. Kiakos, C. R. H. Martin,
J. A. Hartley, D. E. Thurston, P. W. Howard, Bioorg. Med.
Chem. Lett. 2008, 18, 2073–2077; b) A. Kamal, V. Devaiah, K.
Laxma Reddy, N. Shankaraiah, Adv. Synth. Catal. 2006, 348,
249–254; c) I. Philipova, A. Linden, H. Heimgartner, Helv.
[20] a) M. D. Surman, M. J. Mulvihill, M. J. Miller, Org. Lett. 2002,
4, 139–141; b) E. M. Beccalli, G. Broggini, G. Paladino, A.
Penoni, C. Zoni, J. Org. Chem. 2004, 69, 5627–5630; c) E. M.
Beccalli, G. Broggini, G. Paladino, C. Zoni, Tetrahedron 2005,
61, 61–68.
Chim. Acta 2005, 88, 1711–1733; d) Z. Chen, S. J. Gregson, [21] M. Julia, N. Hurion, D. T. Huynh, Chim. Therapeutica 1970,
P. W. Howard, D. E. Thurston, Bioorg. Med. Chem. Lett. 2004,
14, 1547–1549; e) L. A. Masterson, S. J. Croker, T. C. Jenkins,
P. W. Howard, D. E. Thurston, Bioorg. Med. Chem. Lett. 2004,
14, 901–904; f) G.-D. Kang, P. W. Howard, D. E. Thurston,
Chem. Commun. 2003, 1688–1689; g) S. J. Gregson, P. W. How-
ard, D. E. Thurston, Bioorg. Med. Chem. Lett. 2003, 13, 2277–
2280; h) L. Abrous, J. Hynes, S. R. Friedrich, A. B. Smith, R.
Hirschmann, Org. Lett. 2001, 3, 1089–1092; i) D. Subas Bose,
P. Srinivas, M. K. Gurjar, Tetrahedron Lett. 1997, 38, 5839–
5842; j) D. R. Langley, D. E. Thurston, J. Org. Chem. 1987, 52,
91–97; k) A. A. Santilli, T. S. Osdene, J. Org. Chem. 1965, 30,
2100–2102.
5, 343–346.
[22] a) G. Broggini, S. Galli, M. Rigamonti, S. Sottocornola, G.
Zecchi, Tetrahedron Lett. 2009, 50, 1447–1449; b) E. M.
Beccalli, G. Broggini, F. Clerici, S. Galli, C. Kammerer, M.
Rigamonti, S. Sottocornola, Org. Lett. 2009, 11, 1563–1566;
c) A. M. Manzo, A. D. Perboni, G. Broggini, M. Rigamonti,
Tetrahedron Lett. 2009, 50, 4696–4699.
[23] a) G. Broggini, G. Zecchi, Gazz. Chim. Ital. 1996, 126, 479–
488; b) G. Broggini, G. Molteni, A. Terraneo, G. Zecchi, Het-
erocycles 2003, 59, 823–858; c) G. Broggini, G. Molteni, G. Zec-
chi, J. Org. Chem. 1994, 59, 8271–8274; d) E. M. Beccalli, G.
Broggini, C. La Rosa, D. Passarella, T. Pilati, A. Terraneo, G.
Zecchi, J. Org. Chem. 2000, 65, 8924–8932; e) E. M. Beccalli,
G. Broggini, M. Martinelli, N. Masciocchi, S. Sottocornola,
Org. Lett. 2006, 8, 4521–4524; f) E. Borsini, G. Broggini, A.
Contini, G. Zecchi, Eur. J. Org. Chem. 2008, 2808–2816.
[24] a) A. S. Shawali, Chem. Rev. 1993, 93, 2731–2777; b) G. Brog-
gini, G. Molteni, G. Zecchi, Heterocycles 1998, 47, 541–557; c)
R. Benelbaghdadi, A. Hasnaoui, J.-P. Lavergne, M. Giorgi, M.
Pierrot, Synth. Commun. 1998, 28, 4221–4232; d) G. Broggini,
G. Casalone, L. Garanti, G. Molteni, T. Pilati, G. Zecchi, Tet-
rahedron: Asymmetry 1999, 10, 4447–4454; e) A. Aatif, A. Ba-
ouid, A. Benharref, A. Hasnaoui, Synth. Commun. 2000, 30,
2647–2659; f) G. Broggini, L. Garanti, G. Molteni, G. Zecchi,
Tetrahedron: Asymmetry 1999, 10, 487–492; g) G. Broggini, G.
Molteni, T. Pilati, Tetrahedron: Asymmetry 2000, 11, 1975–
1983; h) G. Molteni, Heterocycles 2005, 65, 2513–2537; i) A. S.
Shawali, M. M. Edrees, ARKIVOC 2006, 292–365.
[12] a) A. Kamal, V. Tekumalla, P. Raju, V. G. M. Naidu, P. V. Di-
wan, R. Sistla, Bioorg. Med. Chem. Lett. 2008, 18, 3769–3773;
b) A. Kamal, P. P. Kumar, K. Sreekanth, B. N. Seshadri, P. Ra-
mulu, Bioorg. Med. Chem. Lett. 2008, 18, 2594–2598; c) S.-C.
Lee, S. B. Park, Chem. Commun. 2007, 3714–3716; d) K. K.
Kothakonda, D. S. Bose, Bioorg. Med. Chem. Lett. 2004, 14,
4371–4373; e) ref.[5h]; f) N. Matsunaga, H. Harada, T. Aoyama,
T. Shioiri, Heterocycles 1992, 33, 235–255; g) D. E. Thurston,
G. B. Jones, M. E. Davis, J. Chem. Soc., Chem. Commun. 1990,
874–876.
[13] a) K. Hemming, C. Loukou, Tetrahedron 2004, 60, 3349–3357;
b) T. Kaneko, H. Wong, T. W. Doyle, W. C. Rose, W. T.
Bradner, J. Med. Chem. 1985, 28, 388–392; c) M. Miyamoto,
S. Kondo, H. Naganawa, K. Maeda, M. Ohno, H. Umezawa,
J. Antibiot. 1977, 30, 340–343; d) K.-H. Weber, Arch. Pharm.
1969, 302, 584–590.
[14] a) G. Broggini, G. Molteni, G. Zecchi, Synthesis 1995, 647–648;
b) I. Akritopoulou-Zanze, V. Gracias, S. W. Djuric, Tetrahedron
Lett. 2004, 45, 8439–8441; c) E. M. Beccalli, G. Broggini, G.
[25] R. R. Phillips, Org. React. 1959, 10, 143–178.
Received: November 10, 2009
Published Online: February 4, 2010
Eur. J. Org. Chem. 2010, 1694–1703
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
1703