Stereoselective intramolecular cycloadditions of homochiral nitrile imines: Synthesis of enantiomerically pure 3,3a-dihydro-pyrazolo[1,5-a][1,4]benzodiazepine-6(4H)-ones

Article abstract of DOI:10.1016/S0957-4166(99)00227-X

Starting from the commercially available (S)-1-phenylethylamine, we have synthesised the homochiral hydrazonoyl chlorides 4. The intramolecular cycloaddition of the corresponding nitrile imines 5 gave the diastereoisomeric 3,3a-dihydro-pyrazolo[1,5-a][1,4]benzodiazepine-6(4H)-ones 6 and 7 in enantiopure form.

Full text of DOI:10.1016/S0957-4166(99)00227-X

Pergamon
Tetrahedron: Asymmetry 10 (1999) 2203–2212
Stereoselective intramolecular cycloadditions of homochiral
nitrile imines: synthesis of enantiomerically pure 3,3a-dihydro-
pyrazolo[1,5-a][1,4]benzodiazepine-6(4H)-ones
Gianluigi Broggini,b Luisa Garanti,a,∗ Giorgio Molteni,a,∗ Tullio Pilati,c Alessandro Ponti c
and Gaetano Zecchi b
aDipartimento di Chimica Organica e Industriale, Università di Milano, via Golgi 19, 20133 Milano, Italy
bDipartimento di Scienze Chimiche, Fisiche e Matematiche, Università dell’Insubria, via Lucini 3, 22100 Como, Italy
cConsiglio Nazionale delle Ricerche, Centro per lo Studio delle Relazioni tra Struttura e Reattività Chimica, via Golgi 19,
20133 Milano, Italy
Received 14 May 1999; accepted 4 June 1999
Abstract
Starting from the commercially available (S)-1-phenylethylamine, we have synthesised the homochiral hydra-
zonoyl chlorides 4. The intramolecular cycloaddition of the corresponding nitrile imines 5 gave the diastereoiso-
meric 3,3a-dihydro-pyrazolo[1,5-a][1,4]benzodiazepine-6(4H)-ones 6 and 7 in enantiopure form. © 1999 Elsevier
Science Ltd. All rights reserved.
1. Introduction
Annulated [1,4]benzodiazepines and their oxo-derivatives constitute valuable synthetic targets due to
their well-known pharmacological activity as hypnotics and sedatives.1,2 Among them, pyrazolo[1,5-
a][1,4]benzodiazepines have been synthesised in a number of ways,3–6 including the intramolecular
nitrile imine cycloaddition route.7 Even though it would be desirable to obtain such compounds in the
enantiomerically pure form, it must be noted that, to date, stereoselective intramolecular cycloadditions
of homochiral nitrile imines have been almost entirely neglected, the only report in the field being a
paper from our laboratory.8 This is in contrast to the wide and detailed knowledge about stereoselective
cycloadditions of related 1,3-dipolar species, e.g. nitrile oxides9 and nitrones.10 The present work is
focused on the stereochemical outcome of the intramolecular cycloadditions of nitrile imines 5, which
contain the (S)-1-phenylethyl unity.
∗
Corresponding authors. E-mail: garanti@icil64.cilea.it
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00227-X

2204
G. Broggini et al. / Tetrahedron: Asymmetry 10 (1999) 2203–2212
2. Results and discussion
First of all, our approach required the synthesis of enantiopure hydrazonoyl chlorides 4, which was
achieved recognising N-[(S)-1-phenylethyl]-2-nitrobenzamide 1 as a readily accessible chiral building
block (Scheme 1). Nitrile imines 5 were generated in situ by treating the corresponding hydrazonoyl
chlorides 4 with a 2:1 molar ratio of silver carbonate in dry dioxane at room temperature, following a
well-established procedure elaborated by us.11 Products and their isolation yields, as well as reaction
times and eluants, are collected in Table 1. Besides the recovery of some amounts of the starting
hydrazonoyl chlorides, the reaction outcomes were quite satisfactory in terms of the good cycloaddition
yields. Furthermore, each diastereoisomeric cycloadduct 6 and 7 was obtained in its enantiomerically
pure form by simple column chromatography. For the sake of comparison, nitrile imine 5a was also
generated following the standard triethylamine method (Table 1).
Analytical and spectral data of the cycloaddition products were consistent with the above formulae,
1
but deserve some comments. As far as the H NMR is concerned, we focused on the proton situated
at the junction of the heterocyclic rings. Minor cycloadducts 7a,c,d exhibit resonances in the 4.21–4.41
ppm region, which is in agreement with the literature data for the 5-position of the pyrazolinic ring.12
Conversely, the signal appears upfielded between 3.15–3.62 ppm within the series of major diastereoiso-
mers 6a,c,d. A similar statement applies to the pair 6b and 7b having R=Me; minor diastereoisomer 7b
shows the methyl resonance at 1.12 ppm, while the signal is upfielded at 0.73 ppm in the case of major
diastereoisomer 6b. The somewhat anomalous upfielded values could be justified by taking into account
the shielding effect induced by the phenyl ring of the chiral pendant. Careful inspection of Dreiding
stereomodels indicates that such shielding effects are possible provided that the absolute configuration
of the pyrazolinic C-5 is (R).
The slow evaporation of a solution of 7a in chloroform gave crystals in a suitable form for X-ray
diffractometric analysis, which revealed the absolute configuration of the pyrazolinic C-5 to be (S) (see
Fig. 1) in harmony with our expectations on the basis of proton resonance spectra. Even in the solid
state, 7a exists in two distinct crystallographic forms (namely molecules A and A0), which differs for
some dihedral angles (see Section 3.7); however, the (S) configuration at the pyrazolinic C-5 remains
unambiguously defined in both molecules A and A0. Corroborated by the crystallographic evidence, we
were confident in assigning the (S) configuration to the pyrazolinic C-5 of all cycloadducts 7 and the (R)
one to the diastereoisomeric products 6. It remains to be added that the cis relationship between R and R1
(entries c, d) is dictated by the stereoconservative nature of cycloaddition reactions, and in addition the
H–H scalar coupling constants fall in the range 9.2–10.8 Hz and are consistent with the expected trans
disposition.13
As can be inferred from Table 1, intramolecular cycloadditions of labile nitrile imine intermediates
5 proceed with stereoselectivities ranging from fair to good; this is worth noting because the distance
between the pre-existing and the newly formed stereocentres is rather large. In the presence of silver
carbonate, the cycloadducts ratio 6:7 encompasses the range from 60:40 (entry b) to 75:25 (entry c).
Surprisingly, when 4a was reacted in the presence of triethylamine, a reversal of the stereochemical
preference occurred, cycloadduct 7a being predominant over 6a (6a:7a=35:65, entry e).
To gain insight about the origin of the observed diastereopreference, we undertook a computational
study on nitrile imine 5a, cycloadducts 6a and 7a, and the corresponding transition states TS6 and TS7
(Fig. 2). All geometries were fully optimised at the RHF/6-31G and RHF/6-31G* level; in addition, single
point calculations were performed at the RHF/6-31G**//RHF/6-31G and RHF/6-31G**//RHF/6-31G*
level.14 The resulting energies are given in Table 2. Notwithstanding cycloadduct 6a being predicted
to be more stable than 7a, the transition state TS6 lies higher than the diastereoisomeric one, TS7;

G. Broggini et al. / Tetrahedron: Asymmetry 10 (1999) 2203–2212
2205
Scheme 1.
so that the formation of 7a is kinetically favoured. Assuming the cancellation of both entropic effect
and electronic correlation energy, because of the high electronic and geometric similarity between the
competitive transition states, the predicted product ratio 6a:7a at room temperature should be 34:66. This
just matches the experimental evidence when using triethylamine, but not when using silver carbonate.
In the light of the known coordinative effect of the silver ion toward olefins15 and aromatic rings,16 one
may suggest a stabilised, complexed transition state, the geometry of which resembles TS6.
In conclusion, the present work demonstrates that nitrile imine intermediates 5 are capable of
intramolecular cycloadditions onto the ethylenic moiety giving rise to enantiomerically pure 3,3a-
dihydro-pyrazolo[1,5-a][1,4]benzodiazepine-6(4H)-ones 6 and 7 with good overall yields. Some degree

2206
G. Broggini et al. / Tetrahedron: Asymmetry 10 (1999) 2203–2212
Table 1
Base-promoted reaction of hydrazonoyl chlorides 4
Figure 1. ORTEP plot of 7a (molecule A) with the crystallographic numbering scheme (the same for molecule A0). Anisotropic
displacement parameters are at the 50% probability level. H atoms not to scale
of diastereoselection is operative due to the homochiral α-methylbenzyl pendant. Interestingly, the
stereoselectivity of the cycloaddition can be reversed by switching the basic agent.
3. Experimental
Melting points were determined with a Büchi apparatus and are uncorrected. IR spectra were recorded
with a Perkin–Elmer 1725 X spectrophotometer. Mass spectra were determined with a VG-70EQ
1
instrument. H NMR spectra were taken with a Bruker AC 300 instrument (in CDCl3 solutions).
Chemical shifts are given as ppm from tetramethylsilane and coupling constants are given in hertz.

G. Broggini et al. / Tetrahedron: Asymmetry 10 (1999) 2203–2212
2207
Figure 2. Ab initio RHF/6-31G* computed structures of transition states TS6 and TS7. Only atoms involved in the ring closure
are labelled. Computed distances N1–C5 and C3–C4 are also shown

2208
G. Broggini et al. / Tetrahedron: Asymmetry 10 (1999) 2203–2212
Table 2
Ab initio computed energies E of cycloadducts 6a and 7a and transition states TS6 and TS7a
Optical rotations, [α]D25, were recorded on a Perkin–Elmer Model 241 polarimeter at the sodium D
line.
3.1. Preparation of N-[(S)-1-phenylethyl]-2-nitrobenzamide 1
A solution of (S)-1-phenylethylamine (6.00 g, 49.6 mmol) in dry toluene (130 mL) was treated with
K2CO3 (34.2 g, 0.25 mol). 2-Nitrobenzoyl chloride (9.18 g, 49.6 mmol) in dry toluene (10 mL) was
slowly added and the mixture was refluxed for 4 h under vigorous stirring. The undissolved material was
filtered off, and the solvent was evaporated under reduced pressure. Crystallisation of the residue from
acetone/benzene gave analytically pure 1 (12.1 g, 90% yield), mp 159°C; [α]D25=−49 (MeOH, c 0.21);
IR (Nujol): 3290, 1640 (cm−1); 1H NMR: δ 1.63 (3H, d, J=7.6), 5.40 (1H, dq, J=7.8, 7.6), 6.17 (1H, br
d, J=7.8), 7.25–8.05 (9H, m); MS: m/z 270 (M+). Anal. calcd for C15H14N2O3: C, 66.64; H, 5.22; N,
11.57. Found: C, 66.71; H, 5.20; N, 11.50.
3.2. General procedure for the preparation of N-alkenyl-N-[(S)-1-phenylethyl]-2-nitrobenzamides 2
A solution of 1 (5.00 g, 18.5 mmol) in dry toluene (80 mL) was treated with K2CO3 (3.06 g, 22.2
mmol), NaOH (2.81 g, 70.3 mmol) and Bu4N+ HSO4 (0.82 g, 2.4 mmol). The appropriate alkenyl
−
bromide (entries a, d) or chloride (entries b, c) (30.3 mmol) in dry toluene (7.5 mL) was added dropwise
at 60°C. The mixture was warmed to 75°C for 4 h, then the undissolved material was filtered off. The
solvent was removed under reduced pressure and the residue was chromatographed on a silica gel column
with light petroleum:ethyl acetate, 1:1, affording 2a–d as undistillable oils not analytically pure.
2a (4.87 g, 85% yield); [α]D25=−167.6 (MeOH, c 0.30); IR (neat): 1640 (cm−1); 1H NMR: δ 1.58 (3H,
d, J=7.0), 3.42 (1H, dddd, J=16.7, 6.7, 2.8, 1.4), 3.53 (1H, dddd, J=16.7, 6.7, 2.8, 1.4), 4.38–4.78 (2H,
m), 5.32 (1H, dddd, J=17.0, 16.7, 9.4, 6.7), 6.17 (1H, q, J=7.0), 7.30–8.20 (9H, m); MS: m/z 310 (M+).
2b (2.10 g, 35% yield); [α]D25=−44.2 (MeOH, c 0.20); IR (neat): 1640 (cm−1); 1H NMR: δ 1.30 (3H,
s), 1.58 (3H, d, J=7.0), 3.41 (2H, AB, J=17.1), 4.52 (1H, d, J=2.6), 4.62 (1H, d, J=2.6), 5.98 (1H, q,
J=7.0), 7.30–8.20 (9H, m); MS: m/z 324 (M+).

G. Broggini et al. / Tetrahedron: Asymmetry 10 (1999) 2203–2212
2209
2c (5.75 g, 96% yield); [α]D25=−108 (MeOH, c 0.84); IR (neat): 1640 (cm−1); 1H NMR: δ 1.34 (3H,
d, J=7.0), 1.65 (3H, d, J=7.2), 3.33 (1H, dd, J=16.3, 6.6), 3.42 (1H, dd, J=16.3, 6.3), 4.75–4.95 (2H, m),
6.15 (1H, q, J=7.2), 7.20–8.20 (9H, m); MS: m/z 324 (M+).
2d (5.71 g, 80% yield); [α]D25=−76.0 (MeOH, c 0.10); IR (neat): 1640 (cm−1); 1H NMR: δ 1.73 (3H,
d, J=7.0), 3.52 (1H, dd, J=17.0, 6.8), 3.67 (1H, dd, J=17.0, 6.5), 5.50–5.65 (2H, m), 6.26 (1H, q, J=7.0),
7.25–8.20 (14H, m); MS: m/z 386 (M+).
3.3. General procedure for the preparation of N-alkenyl-N-[(S)-1-phenylethyl]-2-aminobenzamides 3
A solution of 2 (10.0 mmol) in ethanol (12 mL) was treated with iron dust (4.47 g, 80 mmol) and
20% aqueous acetic acid (5.0 mL), and then refluxed for 3.5 h under vigorous stirring. The mixture was
taken up with ethyl acetate (75 mL) and filtered over Celite. The organic layer was washed firstly with
5% aqueous sodium hydrogen carbonate (80 mL), then with water (2×50 mL), and dried over sodium
sulfate.
Evaporation of the solvent gave 3 as undistillable oils not analytically pure.
3a (2.41 g, 86% yield); [α]D25=−20.9 (MeOH, c 0.16); IR (neat): 3340, 1620 (cm−1); 1H NMR: δ 1.62
(3H, d, J=7.3), 3.46 (1H, dd, J=15.8, 5.8), 4.01 (1H, dd, J=15.8, 5.1), 4.75 (2H, br s), 4.90–5.10 (2H, m),
5.40–5.60 (1H, m), 5.72 (1H, q, J=7.3), 6.65–7.30 (9H, m); MS: m/z 280 (M+).
1
3b (2.64 g, 90% yield); [α]D25=−137.5 (MeOH, c 0.08); IR (neat): 3330, 1615 (cm−1); H NMR: δ
1.58 (3H, s), 1.60 (3H, d, J=7.2), 3.28 (2H, AB, J=16.0), 4.30–4.50 (2H, m), 4.75 (2H, br s), 5.50 (1H,
q, J=7.2), 6.70–7.40 (9H, m); MS: m/z 294 (M+).
3c (2.38 g, 81% yield); [α]D25=−122 (MeOH, c 0.52); IR (neat): 3340, 1620 (cm−1); 1H NMR: δ 1.52
(3H, d, J=4.2), 1.61 (3H, d, J=7.0), 3.42 (2H, dd, J=15.7, 5.4), 3.89 (1H, dd, J=15.7, 3.8), 4.25 (2H, br
s), 5.25–5.60 (3H, m), 6.70–7.30 (9H, m); MS: m/z 294 (M+).
1
3d (3.20 g, 90% yield); [α]D25=−82.0 (MeOH, c 0.14); IR (neat): 3340, 1620 (cm−1); H NMR: δ
1.76 (3H, d, J=7.2), 3.78 (1H, dd, J=15.6, 6.6), 4.12 (1H, dd, J=15.6, 6.0), 4.70 (2H, br s), 5.58 (1H, q,
J=7.2), 6.00–6.18 (2H, m), 6.80–7.30 (14H, m); MS: m/z 356 (M+).
3.4. General procedure for the preparation of hydrazonyl chlorides 4
A solution of 3 (5.5 mmol) in 6 M aqueous hydrochloric acid (3.2 mL) and methanol (3.0 mL) was
cooled to 0°C. Sodium nitrite (0.76 g, 11.0 mmol) was added portionwise keeping the temperature
between 0 and 5°C. After 30 min, the pH was adjusted to 5 by adding sodium acetate, and a solution of
methyl 2-chloroacetoacetate (0.83 g, 5.5 mmol) in methanol (1.5 mL) was added under vigorous stirring
and ice-cooling. The mixture was allowed to stand overnight under stirring at room temperature. The
solvent was partly removed under reduced pressure and the resulting mixture was extracted with diethyl
ether (75 mL). The organic layer was washed firstly with 5% sodium hydrogen carbonate (25 mL), then
with water (75 mL), and dried over sodium sulfate. The residue was chromatographed on a silica gel
column with diethyl ether to give the hydrazonyl chlorides 4 as undistillable oils not analytically pure.
4a (1.69 g, 77% yield); [α]D25=−46.0 (MeOH, c 0.25); IR: 3280, 1730, 1620 (cm−1); 1H NMR: δ 1.65
(3H, d, J=7.1), 3.52 (1H, dd, J=16.5, 5.9), 3.91 (3H, s), 4.10 (1H, dd, J=16.5, 4.7), 4.80–5.10 (2H, m),
5.56 (1H, q, J=7.1), 5.58–5.90 (1H, m), 6.90–7.70 (9H, m), 9.65 (1H, br s); MS: m/z 399 (M+).
1
4b (1.86 g, 82% yield); [α]D25=−27.7 (MeOH, c 0.044); IR: 3270, 1730, 1625 (cm−1); H NMR: δ
1.55 (3H, s), 1.66 (3H, d, J=7.1), 3.38 (2H, AB, J=16.0), 3.93 (3H, s), 4.76 (1H, d, J=2.1), 4.84 (1H, d,
J=2.1), 5.54 (1H, q, J=7.1), 6.95–7.70 (9H, m), 9.80 (1H, br s); MS: m/z 413 (M+).

2210
G. Broggini et al. / Tetrahedron: Asymmetry 10 (1999) 2203–2212
4c (1.20 g, 53% yield); [α]D25=−37.0 (MeOH, c 0.12); IR: 3270, 1730, 1645 (cm−1); 1H NMR: δ 1.52
(3H, br d), 1.66 (3H, d, J=7.2), 3.48 (1H, d, J=4.0), 3.54 (1H, d, J=3.1), 3.93 (3H, s), 5.20–5.80 (3H, m),
6.90–7.20 (9H, m), 9.60 (1H, br s); MS: m/z 413 (M+).
4d (1.96 g, 75% yield); [α]D25=−58.0 (MeOH, c 0.06); IR: 3270, 1735, 1620 (cm−1); 1H NMR: δ 1.80
(3H, d, J=7.1), 3.78 (1H, dd, J=15.8, 6.0), 3.96 (3H, s), 4.24 (1H, dd, J=1.8, 4.8), 5.60–6.10 (2H, m),
6.20 (1H, q, J=7.1), 7.05–7.75 (14H, m), 9.60 (1H, br s); MS: m/z 475 (M+).
3.5. General procedure for the reaction of hydrazonyl chlorides 4 with silver carbonate
A solution of the hydrazonyl chlorides 4 (2.5 mmol) in dry dioxane (125 mL) was treated with silver
carbonate (1.38 g, 5.0 mmol), and stirred in the dark at room temperature for the time indicated in
Table 1. The undissolved material was filtered off, the solvent was evaporated, and then the residue was
chromatographed on a silica gel column. Unreacted hydrazonoyl chlorides 4 were eluted first. Further
elution gave 6, followed by 7. Isolation yields and eluents are collected in Table 1. All compounds were
obtained in an analytically pure state by recrystallisation.
6a (0.54 g, 60% yield) mp 145°C (from diisopropyl ether); [α]D25=−26.5 (MeOH, c 0.20); IR: 1725,
1625 (cm−1); 1H NMR: δ 1.50 (3H, d, J=7.0), 2.62 (1H, dd, J=18.1, 11.7), 2.80 (1H, dd, J=18.1, 12.5),
3.26 (1H, dd, J=14.5, 0.9), 3.38 (1H, dd, J=14.5, 7.2), 3.51–3.62 (1H, m), 3.92 (3H, s), 6.20 (1H, q,
J=7.0), 7.02–8.08 (9H, m); MS: m/z 363 (M+). Anal. calcd for C21H21N3O3: C, 69.39; H, 5.83; N, 11.57.
Found: C, 69.44; H, 5.88; N, 10.36.
7a (0.24 g, 26% yield) mp 89°C (from diisopropyl ether); [α]D25=+678 (MeOH, c 0.20); IR: 1725,
1
1625 (cm−1); H NMR: δ 1.60 (3H, d, J=7.0), 2.77 (1H, dd, J=18.0, 11.4), 3.14 (1H, dd, J=15.0, 0.7),
3.23 (1H, dd, J=15.0, 8.4), 3.38 (1H, dd, J=18.0, 12.5), 3.85 (3H, s), 4.24–4.37 (1H, m), 6.22 (1H, q,
J=7.0), 7.03–8.18 (9H, m); MS: m/z 363 (M+). Anal. calcd for C21H21N3O3: C, 69.39; H, 5.83; N, 11.57.
Found: C, 69.41; H, 5.77; N, 10.22.
6b (0.37 g, 39% yield) mp 140°C (from diisopropyl ether); [α]D25=−213 (MeOH, c 0.12); IR: 1700,
1610 (cm−1); 1H NMR: δ 0.73 (3H, s), 1.58 (3H, d, J=7.2), 2.83 (1H, d, J=17.3), 3.13 (1H, d, J=17.3),
3.17 (1H, d, J=15.2), 3.34 (1H, d, J=15.2), 3.82 (3H, s), 6.38 (1H, q, J=7.2), 7.10–8.20 (9H, m); MS: m/z
377 (M+). Anal. calcd for C22H23N3O3: C, 69.99; H, 6.15; N, 11.14. Found: C, 70.08; H, 6.21; N, 11.20.
7b (0.25 g, 26% yield) mp 73°C (from diisopropyl ether); [α]D25=+67.0 (MeOH, c 0.08); IR: 1703,
1620 (cm−1); 1H NMR: δ 1.12 (3H, s), 1.58 (3H, d, J=7.0), 2.16 (1H, d, J=17.3), 2.59 (1H, d, J=17.3),
3.18 (1H, d, J=15.3), 3.28 (1H, d, J=15.3), 3.83 (3H, s), 6.17 (1H, q, J=7.0), 7.20–8.10 (9H, m); MS: m/z
377 (M+). Anal. calcd for C22H23N3O3: C, 69.99; H, 6.15; N, 11.14. Found: C, 70.03; H, 6.11; N, 11.11.
6c (0.28 g, 30% yield) mp 122°C (from methanol); [α]D25=−328 (MeOH, c 0.12); IR: 1720, 1620
(cm−1); 1H NMR: δ 0.70 (3H, d, J=6.9), 1.53 (3H, d, J=7.1), 2.95 (1H, qd, J=10.6, 6.9), 3.15–3.26 (2H,
m), 3.34 (1H, dd, J=14.8, 7.6), 3.82 (3H, s), 6.45 (1H, q, J=7.1), 7.04–8.18 (9H, m); MS: m/z 377 (M+).
Anal. calcd for C22H23N3O3: C, 69.99; H, 6.15; N, 11.14. Found: C, 70.05; H, 6.19; N, 11.22.
7c (24 mg, 10% yield) mp 75°C (from methanol); [α]D25=+430 (MeOH, c 0.16); IR: 1710, 1625
(cm−1); 1H NMR: δ 1.03 (3H, d, J=7.2), 1.62 (3H, d, J=7.0), 3.27 (1H, dd, J=15.7, 8.3), 3.37 (1H, dd,
J=15.7, 1.3), 3.46 (1H, qd, J=10.6, 7.2), 3.87 (3H, s), 4.41 (1H, ddd, J=10.6, 8.7, 1.0), 6.30 (1H, q,
J=7.0), 7.05–8.08 (9H, m); MS: m/z 377 (M+). Anal. calcd for C22H23N3O3: C, 69.99; H, 6.15; N, 11.14.
Found: C, 70.08; H, 6.11; N, 11.21.
6d (0.42 g, 38% yield) mp 185°C (from methanol); [α]D25=−487 (MeOH, c 0.24); IR: 1720, 1620
(cm−1); 1H NMR: δ 1.50 (3H, d, J=7.1), 3.31 (1H, dd, J=14.6, 0.8), 3.44 (1H, dd, J=14.6, 7.5), 3.62 (1H,
ddd, J=9.2, 7.5, 0.8), 3.68 (3H, s), 4.02 (1H, d, J=9.2), 6.35 (1H, q, J=7.1), 6.95–8.22 (14H, m); MS: m/z
439 (M+). Anal. calcd for C27H25N3O3: C, 73.33; H, 5.74; N, 9.57. Found: C, 73.39; H, 5.78; N, 9.66.

G. Broggini et al. / Tetrahedron: Asymmetry 10 (1999) 2203–2212
2211
7d (0.24 g, 22% yield) mp 80°C (from methanol); [α]D25=+612 (MeOH, c 0.44); IR: 1710, 1624
(cm−1); 1H NMR: δ 1.22 (3H, d, J=7.0), 3.22 (1H, dd, J=15.7, 1.6), 3.33 (1H, dd, J=15.7, 6.5), 3.73 (3H,
s), 4.13 (1H, d, J=10.8), 4.21 (1H, ddd, J=10.8, 6.5, 1.6), 6.12 (1H, q, J=7.0), 7.10–8.15 (14H, m); MS:
m/z 439 (M+). Anal. calcd for C27H25N3O3: C, 73.33; H, 5.74; N, 9.57. Found: C, 73.30; H, 5.70; N,
9.53.
3.6. Reaction of hydrazonyl chloride 4a with triethylamine
A solution of 4a (1.00 g, 2.5 mmol) in dry dioxane (125 mL) was treated with triethylamine (1.26 g,
12.5 mmol), and stirred at room temperature for the time indicated in Table 1. The solvent was evaporated,
and then the residue was chromatographed on a silica gel column. Products, isolation yields and eluants
are collected in Table 1.
3.7. X-Ray structure determination of 7a
C21H21N3O3, monoclinic, space group I2, Mr=363.41, a=28.331(3), b=7.4968(4), c=17.4630(14)
Å, β=90.947(8)°, V=3708.5(5) Å3, room temperature [291(1) K], Z=8, dcalc=1.302 g cm−1,
µ(MoKα)=0.089 mm−1; Siemens P4 diffractometer, MoKα radiation, λ=0.71073 Å. Data collection:
ω/2θ scans, 4.5<2θ<55.0°; −36<h<1, −1<k<9, −22<l<22; 5533 reflections collected, 5230
independent, 3697 with I>2σ(I), averaging R=0.0100. The structure was solved by SIR92,17 and refined
on F2 by full-matrix least-squares using SHELX97.18 Heavy atoms anisotropic, H atoms isotropic,
final discrepancy indexes based on F2: R=0.0372 (0.0637 for all 5230 reflections) and wR=0.0710
(0.0793), g.o.f. 1.003; difference map ranges from −0.11 to 0.11 e Å−3. Absolute configuration was
based on knowledge of the reactant’s [(S)-1-phenylethylamine]. The main differences between the
two independent molecules A and A0 are due relative to the torsion angles: the more relevant are
N2–C3–C15–O18 [−2.3(4) and 172.6(3)° for molecule A and A0, respectively] and C8–N7–C20–C27
[127.9(2) and 99.5(3)° for A and A0, respectively]; other differences, greater than 10° are found for some
torsion angles around the bonds N2–N1, N1–C5, N1–C14, N7–C8 and N7–C20. These differences can
be explained only by the different environment of the two independent molecules.
3.8. Ab initio calculations
All calculations have been performed by means of Sun Ultra Enterprise workstations running the
program suite Gaussian 94.19 Ab initio restricted Hartree–Fock (RHF) calculations were carried out
using the 6-31G, 6-31G* and 6-31G** basis sets. Because of the large size of the studied molecules
(48 atoms, 192 electrons), stationary points (energy minima and transition states) were fully optimised
by analytical gradient techniques only with the RHF/6-31G and RHF/6-31G* basis sets. Transition state
structures (with one negative eigenvalue of the second-derivatives matrix) were obtained by the quadratic
synchronous transit search method QST2.20 Single-point calculations at the optimised geometries were
performed with the RHF/6-31G** basis set.

2212
G. Broggini et al. / Tetrahedron: Asymmetry 10 (1999) 2203–2212
Acknowledgements
We are grateful to CNR and MURST for financial support. One of us (A.P.) is grateful to Dr. M.
Barzaghi (CNR-CSRSRC, Milano) and to Prof. E. Ortoleva (Università di Milano) for their expert help
with Gaussian 94.
References
1. Vida, J. A. Medicinal Chemistry, Part III; Wolf, M. V.; Burger, A., Eds.; John Wiley: New York, 1981.
2. Watser, A.; Fryer, R. I. Bicyclic Diazepines; John Wiley: New York, 1991.
3. Gilman, N. W.; Holland, B. C.; Fryer, R. I. J. Heterocycl. Chem. 1977, 14, 1163.
4. Dattolo, G.; Cirrincione, G.; Almerico, A. M.; D’Asdia, I.; Aiello, E. J. Heterocycl. Chem. 1982, 19, 1237.
5. Cecchi, L.; Filacchioni, G. J. Heterocycl. Chem. 1983, 20, 871.
6. Melani, F.; Cecchi, L.; Filacchioni, G. J. Heterocycl. Chem. 1984, 21, 813.
7. Bruché, L.; Zecchi, G. Tetrahedron 1989, 45, 7427.
8. Broggini, G.; Garanti, L.; Molteni, G.; Zecchi, G. Tetrahedron: Asymmetry 1999, 10, 487.
9. (a) Annunziata, R.; Cinquini, M.; Cozzi, F.; Raimondi, L. Gazz. Chim. Ital. 1989, 119, 253; (b) Cinquini, M.; Cozzi, F.
In Methoden der Organische Chemie (Houben-Weyl), E 21c, Stereoselective Synthesis; G. Thieme: Stuttgart, 1995; pp.
2953–2987; (c) Raimondi, L. Gazz. Chim. Ital. 1997, 127, 167.
10. (a) Tufariello, J. J. Acc. Chem. Res. 1979, 12, 396; (b) Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410; (c)
Balasubramanian, N. Org. Prep. Proc. Int. 1985, 17, 25; (d) Confalone, P. N.; Huie, E. M. Org. React. 1988, 36, 1;
(e) Tsuge, O.; Kanemasa, S. Adv. Heterocycl. Chem. 1989, 45, 231; (f) Frederickson, M. Tetrahedron 1997, 53, 403; (g)
Curran, D. P. Advances in Cycloaddition; Curran, D. P., Ed.; JAI Press: London, 1988; vol. 1, pp. 129–189.
11. Broggini, G.; Bruché, L.; Garanti, L.; Zecchi, G. J. Chem. Soc., Perkin Trans. 1 1994, 433.
12. Batterham, T. J. NMR Spectra of Simple Heterocycles; Wiley, New York, 1971.
13. Elguero, J. Comprehensive Heterocyclic Chemistry; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon Press: Oxford, 1985;
vol. 5, chapter 4.04, pp. 182–190.
14. Szabo, A.; Ostlund, N. S. Modern Quantum Chemistry; McGraw-Hill: New York, 1982; chapter 3, pp. 108–230.
15. Hartley, F. R. Chem. Rev. 1973, 73, 163.
16. (a) Van Koten, G.; Noltes, J. G. Comprehensive Organometallic Chemistry; Abel, E. W.; Stone, F. G. A.; Wilkinson, G.,
Eds.; Pergamon: Oxford, 1982; vol. 2, chapter 14, pp. 709–764; (b) Van Koten, G.; James, S. L.; Jastrzebski, J. T. B. H.
Comprehensive Organometallic Chemistry II; Abel, E. W.; Stone, F. G. A.; Wilkinson, G., Eds.; Pergamon: Oxford, 1995;
vol. 3, chapter 2, pp. 57–133.
17. Altomare, A.; Cascarano, G.; Giacovazzo, G.; Guagliardi, A.; Burla, M. C.; Polidori, G.; Camalli, M. J. Appl. Crystallogr.
1994, 27, 435.
18. Sheldrick, G. M. SHELX97. Program for the Refinement of Crystal Structures; University of Göttingen: Germany, 1997.
19. Gaussian 94, Revision E.1, Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Gill, P. M. W.; Johnson, B. G.; Robb, M. A.;
Cheeseman, J. R.; Keith, T.; Petersson, G. A.; Montgomery, J. A.; Raghavachari, K.; Al-Laham, M. A.; Zakrzewski, V. G.;
Ortiz, J. V.; Foresman, J. B.; Cioslowski, J.; Stefanov, B. B.; Nanayakkara, A.; Challacombe, M.; Peng, C. Y.; Ayala, P. Y.;
Chen, W.; Wong, M. W.; Andres, J. L.; Replogle, E. S.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Binkley, J. S.; Defrees, D.
J.; Baker, J.; Stewart, J. P.; Head-Gordon, M.; Gonzales, C.; Pople, J. A.; Gaussian Inc.: Pittsburgh, PA, 1995.
20. Peng, C.; Schlegel, H. B. Israel J. Chem. 1994, 33, 449.