Asymmetric induction by the (S)-1-phenylethyl group in intramolecular nitrile imine cycloadditions giving enantiopure 3,3a-dihydro-pyrazolo[1,5- a][1,4]benzodiazepine-4(6H)-ones

Article abstract of DOI:10.1016/S0957-4166(99)00493-0

Stereoselective intramolecular cycloadditions of homochiral nitrile imines 5 are described as a fruitful source of enantiopure 3,3a-dihydro- pyrazolo[1,5-a][1,4]benzodiazepine-4(6H)-ones 6 and 7. (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0957-4166(99)00493-0

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 4447–4454
Asymmetric induction by the (S)-1-phenylethyl group in
intramolecular nitrile imine cycloadditions giving enantiopure
3,3a-dihydro-pyrazolo[1,5-a][1,4]benzodiazepine-4(6H)-ones
Gianluigi Broggini,b Gianluigi Casalone,c Luisa Garanti,a,∗ Giorgio Molteni,a,∗ Tullio Pilati 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
cCSRSRC-Centro per lo Studio delle Relazioni tra Struttura e Reattività Chimica, Università di Milano, via Golgi 19,
20133 Milano, Italy
Received 22 October 1999; accepted 4 November 1999
Abstract
Stereoselective intramolecular cycloadditions of homochiral nitrile imines 5 are described as a fruitful source of
enantiopure 3,3a-dihydro-pyrazolo[1,5-a][1,4]benzodiazepine-4(6H)-ones 6 and 7. © 1999 Elsevier Science Ltd.
All rights reserved.
1. Introduction
The synthesis of enantiomerically pure molecules from simple starting materials represents a major
challenge in contemporary organic chemistry and nearly all organic reactions,1 including 1,3-dipolar
cycloadditions,2 have been exploited for this purpose. However, the available examples of stereoselective
intramolecular cycloadditions of homochiral nitrile imines are still rare, the only contribution being
represented by three recent papers from our laboratory.3–5 In continuing our research in this field, we
report here on the synthesis of enantiopure pyrazolo[1,5-a][1,4]benzodiazepine-4-ones 6 and 7, which are
of potential pharmacological interest.6 The inexpensive, commercially available (S)-1-phenylethylamine
was used as the starting homochiral unit.
∗
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)00493-0
tetasy 3128

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2. Results and discussion
N-[(S)-1-Phenylethyl]-2-nitrobenzylamine 1, which we considered to be the fundamental chiral build-
ing block, was readily obtained by reacting (S)-1-phenylethylamine with 2-nitrobenzyl chloride. The
enantiopure hydrazonoyl chlorides 4 were then synthesised as depicted in Scheme 1. The in situ
generation of the desired nitrile imines 5 was accomplished by treating a 0.02 M solution of 4 with
a twofold molar excess of silver carbonate in dry dioxane at room temperature. Products and their
isolated yields, as well as reaction times and eluants, are collated in Table 1. The material yields of
the intramolecular cycloadditions were extremely satisfactory, since the overall yields were practically
quantitative. Furthermore, a simple column chromatography of the reaction mixtures allowed the clean
separation of the pure diastereoisomeric cycloadducts 6 and 7 in the pure state. In order to test the
influence of the basic medium on reactivity, the generation of nitrile imine 5a was also accomplished
by treating a 0.02 M solution of 4a with an excess of triethylamine in dry dioxane at room temperature.
Table 1
Base-promoted reaction of hydrazonoyl chlorides 4
Structural assignments of the above cycloadducts rely upon analytical and spectroscopic data. In
particular, the 1H NMR spectra of the minor diastereoisomers 7 show the upfielded resonance of the two
aromatic hydrogens in the 7 and 8 positions. The fact that these signals fall in the range 5.61–6.52 δ can
be justified by assuming a shielding effect exerted by the phenyl ring of the chiral pendant moiety. This
shielding effect, which is lacking in the case of major diastereoisomers 6, may be related to the absolute
configuration of the stereocentre in the 5-position of the pyrazolinic ring. In fact, careful inspection of
Dreiding molecular stereomodels revealed that the mentioned hydrogens are shielded when the absolute
configuration of the pyrazolinic C-5 is (R). In the cases where R=H, the trans relationship between the
hydrogens in the 4- and 5-positions of the pyrazolinic ring, which was predictable on the basis of the
concerted nature of the cycloadditions,7 is substantiated by the H–H scalar coupling constants, whose
values encompass the range from 6.3 to 6.8 Hz.8
The X-ray crystallographic analysis of all minor diastereoisomers 7 further supported the above
assignments. As can be viewed from the ORTEPIII9 description in Fig. 1, the spatial orientation of
the phenyl ring of the chiral auxiliary accounts for the observed upfielded resonance. Furthermore,
the (R) absolute configuration to the pyrazolinic C-5 of all minor cycloadducts 7 was unambiguously
demonstrated and consequently the (S) absolute configuration was assigned to the major cycloadducts 6.

G. Broggini et al. / Tetrahedron: Asymmetry 10 (1999) 4447–4454
4449
Scheme 1.
As far as diastereoselection is concerned, intramolecular cycloadditions of nitrile imines 5 display some
preference for diastereoisomers 6. The ratio 6:7, encompassing the range from 78:22 (entry a) to 65:35
(entry b), is remarkable considering that the distance between the chiral auxiliary and the newly formed
stereocentres is rather large.
As can be seen from entries a and d in Table 1, the behaviour of nitrile imine 5a in terms of
stereoselection is almost independent of the complexing nature of the basic agent, the cycloadduct ratio
6a:7a being roughly the same on going from silver carbonate to triethylamine. This means that although
metallated transition states are conceivable in light of the known complexing ability of the silver ion
towards olefins10 and aromatic rings,11 they must be geometrically similar to the metal-free ones. Such
a fact is worthy to note since the intramolecular cycloaddition of a structurally related nitrile imine,
recently reported by us,4 actually reverses the diastereoselectivity as a function of the basic agent.
In conclusion, we have found that the good dipolarophilic character of the α,β-unsaturated amide
fragment makes the intramolecular cycloadditions of nitrile imines 5 very efficient and, hence, valuable

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G. Broggini et al. / Tetrahedron: Asymmetry 10 (1999) 4447–4454
Fig. 1. ORTEPIII9 projection of 7a, 7b and 7c with the crystallographic numbering scheme. As can be see the numbering is the
same for the common moiety. Ellipsoids at 50% probability level. H atoms not to scale.
on a preparative scale. The easy separation of cycloadducts 6 and 7 allows the multi-gram synthesis of
enantiopure 3,3a-dihydro-pyrazolo[1,5-a][1,4]benzodiazepin-4(6H)-ones.
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
apparatus. H NMR spectra were taken with a Bruker AC 300 or a Bruker AMX 300 instrument (in
CDCl3 solutions). Chemical shifts are given as ppm from tetramethylsilane and J values are given in
hertz. Optical rotations, [α]D25, were recorded on a Perkin–Elmer Model 241 polarimeter at the sodium
D line.

G. Broggini et al. / Tetrahedron: Asymmetry 10 (1999) 4447–4454
4451
3.1. Preparation of N-[(S)-1-phenylethyl]-2-nitrobenzylamine 1
A solution of (S)-1-phenylethylamine (5.00 g, 41.3 mmol) in dry toluene (50 mL) was added to
potassium iodide (1.37 g, 8.3 mmol). 2-Nitrobenzyl chloride (3.53 g, 20.6 mmol) in dry toluene (5 mL)
was slowly added and the mixture was refluxed for 3 h under vigorous stirring. Toluene (25 mL) was
added, the white precipitate was filtered off, and the solvent was evaporated under reduced pressure.
Crystallisation of the residue from diisopropyl ether gave analytically pure 1 (3.70 g, 70%), mp 159°C;
[α]D25=−10.2 (MeOH, c=0.40); IR (Nujol): 3350 (cm−1); 1H NMR δ: 1.38 (3H, d, J 6.6), 1.90 (1H, br
s), 3.81 (1H, q, J 6.6), 3.83 (1H, d, J 14.0), 3.88 (1H, d, J 14.0), 7.20–7.95 (9H, m); MS: m/z 256 (M+).
Anal. calcd for C15H16N2O2: C, 70.28; H, 6.30; N, 10.93. Found: C, 70.35; H, 6.33; N, 11.01.
3.2. General procedure for the preparation of N-[(S)-1-phenylethyl]-N-(1-oxo-2-alkenyl)-2-nitrobenzyl-
amines 2
A solution of 1 (5.00 g, 19.5 mmol) in dry toluene (140 mL) was added to K2CO3 (5.38 g, 39.0 mmol).
The appropriate alkenyol chloride (19.5 mmol) in dry toluene (5.0 mL) was added dropwise at 90°C. The
mixture was refluxed for 4 h, then the undissolved material was filtered off. The organic layer was washed
with water (50 mL) and dried over sodium sulfate. The solvent was removed under reduced pressure and
the residue was purified by chromatography on a silica gel column with diethyl ether:dichloromethane
10:1 affording 2a–d as undistillable oils, not analytically pure.
Compound 2a (5.44 g, 90%) as a pale yellow oil; [α]D25=−34.6 (MeOH, c=0.33); IR (neat): 1650
(cm−1); 1H NMR δ: 1.52 (3H, d, J 7.0), 4.65 (1H, d, J 17.1), 4.95 (1H, d, J 17.1), 5.68 (1H, q, J 7.0),
6.00–6.60 (3H, m), 7.15–7.95 (9H, m); MS: m/z 310 (M+).
Compound 2b (5.50 g, 87%) as a pale yellow oil; [α]D25=−48.4 (MeOH, c=0.27); IR (neat): 1660
(cm−1); 1H NMR δ: 1.50 (3H, d, J 7.0), 1.80 (3H, d, J 6.5), 4.70 (1H, d, J 17.4), 4.88 (1H, d, J 17.4),
5.46 (1H, q, J 7.0), 5.90–6.50 (2H, m), 7.20–7.95 (9H, m); MS: m/z 324 (M+).
Compound 2c (6.55 g, 87%) as a yellow oil; [α]D25=−98.0 (MeOH, c=0.12); IR (neat): 1650 (cm−1);
1H NMR δ: 1.51 (3H, d, J 7.1), 4.85 (1H, d, J 18.0), 5.00 (1H, d, J 18.0), 5.57 (1H, q, J 7.1), 6.30 (1H,
d, J 16.2), 6.52 (1H, d, J 16.2), 7.20–7.90 (14H, m); MS: m/z 386 (M+).
3.3. General procedure for the preparation of N-[(S)-1-phenylethyl]-N-(1-oxo-2-alkenyl)-2-aminoben-
zylamines 3
A solution of 2 (15.0 mmol) in ethanol (20 mL) was treated with iron powder (5.96 g, 0.11 mol) and
20% aqueous acetic acid (7.5 mL), and then refluxed for 3 h under vigorous stirring. The mixture was
taken up with ethyl acetate (100 mL) and filtered over Celite. The organic layer was washed firstly with
5% aqueous sodium hydrogencarbonate (40 mL), then with water (2×50 mL), and dried over sodium
sulfate. Evaporation of the solvent gave 3 as undistillable oils, not analytically pure.
Compound 3a (3.86 g, 92%) as colourless oil; [α]D25=−73.0 (MeOH, c=0.10); IR (neat): 3435, 3350,
3240, 1645 (cm−1); 1H NMR δ: 1.51 (3H, d, J 6.5), 4.25 (1H, d, J 15.6), 4.50 (2H, br s), 4.93 (1H, d, J
15.6), 5.52 (1H, q, J 6.5), 6.20–6.50 (3H, m), 6.65–7.30 (9H, m); MS: m/z 280 (M+).
Compound 3b (4.13 g, 94%) as colourless oil; [α]D25=−109.0 (MeOH, c=0.28); IR (neat): 3440, 3350,
3235, 1660 (cm−1); 1H NMR δ: 1.45 (3H, d, J 6.6), 1.78 (3H, d, J 7.5), 3.45 (1H, d, J 15.8), 4.15 (2H,
br s), 4.90 (1H, d, J 15.8), 5.20 (1H, q, J 6.6), 6.00–7.35 (11H, m); MS: m/z 294 (M+).

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G. Broggini et al. / Tetrahedron: Asymmetry 10 (1999) 4447–4454
Compound 3c (5.07 g, 95%) as colourless oil; [α]D25=−41.3 (MeOH, c=0.17); IR (neat): 3435, 3345,
3230, 1645 (cm−1); 1H NMR δ: 1.58 (3H, d, J 7.0), 4.35 (1H, d, J 14.9), 4.68 (2H, br s), 5.02 (1H, d, J
14.9), 5.10 (1H, q, J 7.0), 6.50–7.30 (16H, m); MS: m/z 356 (M+).
3.4. General procedure for the preparation of hydrazonyl chlorides 4
A solution of 3 (7.5 mmol) in 6 M aqueous hydrochloric acid (4.5 mL) and methanol (5.0 mL) was
cooled to 3°C. Sodium nitrite (1.04 g, 15.0 mmol) was added portionwise keeping the temperature
between 0 and 5°C. After 15 min, the pH was adjusted to 5 by adding sodium acetate, and a solution of
methyl 2-chloroacetoacetate (1.13 g, 7.5 mmol) in methanol (2.0 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 hydrogencarbonate (20 mL), then
with water (50 mL), and dried over sodium sulfate. Evaporation of the solvent gave crude hydrazonyl
chlorides 4 as undistillable oils.
Compound 4a (2.69 g, 90%) as pale yellow oil; IR (neat): 3165, 1730, 1640 (cm−1); 1H NMR δ: 1.59
(3H, d, J 7.2), 3.95 (3H, s), 4.40 (1H, d, J 15.1), 4.73 (1H, d, J 15.1), 5.23 (1H, q, J 7.2), 5.60–6.40 (3H,
m), 6.75–7.60 (9H, m), 10.60 (1H, br s).
Compound 4b (2.78 g, 90%) as pale yellow oil; IR (neat): 3160, 1732, 1660 (cm−1); 1H NMR δ: 1.60
(3H, d, J 6.7), 1.80 (3H, d, J 6.3), 3.92 (3H, s), 4.35 (1H, d, J 15.0), 4.68 (1H, d, J 15.0), 5.25 (1H, q, J
6.7), 6.16 (1H, d, J 15.4), 6.87 (1H, d, J 15.4), 6.95–7.55 (9H, m), 11.70 (1H, br s).
Compound 4c (3.35 g, 94%) as yellow oil; IR (neat): 3160, 1730, 1645 (cm−1); 1H NMR δ: 1.64 (3H,
d, J 6.8), 3.91 (3H, s), 4.48 (1H, d, J 15.1), 4.83 (1H, d, J 15.1), 5.29 (1H, q, J 6.8), 6.65 (1H, d, J 15.3),
6.86–7.60 (14H, m), 7.70 (1H, d, J 15.3), 11.80 (1H, br s).
3.5. General procedure for the reaction of hydrazonyl chlorides 4 with silver carbonate
A solution of 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 purified by chromatography
on a silica gel column. Major diastereoisomer 6 was eluted first, followed by the minor diastereoisomer
7. Products, isolation yields and eluants are collected in Table 1. All compounds were obtained in
analytically pure state by recrystallisation.
Compound 6a (0.68 g, 75%), mp 158°C (from diisopropyl ether); [α]D25=+105.8 (MeOH, c=0.11);
IR (Nujol): 1730, 1640 (cm−1); 1H NMR δ: 1.37 (3H, d, J 7.1), 3.27 (1H, dd, J 18.1, 13.5), 3.75 (1H, d,
J 17.1), 3.89 (3H, s), 4.18 (1H, dd, J 18.1, 8.5), 4.76 (1H, d, J 17.1), 5.69 (1H, dd, J 13.5, 8.5), 6.02 (1H,
q, J 7.1), 6.80–7.63 (9H, m); MS: m/z (FAB+) 363 (M+) (36%). Anal calcd for C21H21N3O3: C, 69.39;
H, 5.83; N, 11.57. Found: C, 69.46; H, 5.86; N, 11.64.
Compound 7a (0.19 g, 21%), mp 138°C (from pentane–dichloromethane); [α]D25=−574.0 (MeOH,
1
c=0.08); IR (Nujol): 1725, 1660 (cm−1); H NMR δ: 1.59 (3H, d, J 6.9), 3.28 (1H, dd, J 18.1, 13.6),
3.71 (1H, d, J 16.6), 3.76 (3H, s), 4.18 (1H, dd, J 18.1, 8.5), 5.07 (1H, d, J 16.6), 5.65 (1H, dd, J 13.6,
8.5), 5.97 (1H, q, J 6.9), 5.99 (1H, dd, J 7.5, 0.7), 6.44 (1H, dt, J 7.5, 0.8), 7.01–7.52 (7H, m); MS: m/z
(FAB+) 363 (M+) (23%). Anal. calcd for C21H21N3O3: C, 69.39; H, 5.83; N, 11.57. Found: C, 69.41; H,
5.78; N, 11.51.
Compound 6b (0.58 g, 61%), mp 61°C (from diisopropyl ether); [α]D25=+158.0 (MeOH, c=0.23); IR
(Nujol): 1730, 1650 (cm−1); 1H NMR δ: 1.37 (3H, d, J 8.0), 1.42 (3H, d, J 7.4), 3.78 (1H, d, J 17.2), 3.88

G. Broggini et al. / Tetrahedron: Asymmetry 10 (1999) 4447–4454
4453
(3H, s), 4.47 (1H, dq, J 8.0, 6.8), 4.86 (1H, d, J 17.2), 5.18 (1H, d, J 6.8), 6.02 (1H, q, J 7.4), 6.85–7.65
(9H, m); MS: m/z (FAB+) 377 (M+) (40%). Anal. calcd for C22H23N3O3: C, 69.99; H, 6.15; N, 11.14.
Found: C, 69.93; H, 6.08; N, 11.22.
Compound 7b (0.31 g, 33%), mp 165°C (from diisopropyl ether); [α]D25=−580.0 (MeOH, c=0.20);
IR (Nujol): 1700, 1660 (cm−1); 1H NMR δ: 1.40 (3H, d, J 7.0), 1.59 (3H, d, J 5.5), 3.72 (1H, d, J 16.6),
3.88 (3H, s), 4.47 (1H, dq, J 6.8, 5.5), 5.03 (1H, d, J 16.6), 5.18 (1H, d, J 6.8), 5.93 (1H, q, J 7.0), 5.99
(1H, dd, J 7.6, 0.9), 6.47 (1H, dt, J 7.6, 0.9), 7.05–7.52 (7H, m); MS: m/z (FAB+) 377 (M+) (73%). Anal.
calcd for C22H23N3O3: C, 69.99; H, 6.15; N, 11.14. Found: C, 69.95; H, 6.20; N, 11.20.
Compound 6c (0.76 g, 69%), mp 204°C (from hexane–benzene); [α]D25=+374.0 (MeOH, c=0.12); IR
1
(Nujol): 1710, 1660 (cm−1); H NMR δ: 1.40 (3H, d, J 7.1), 3.75 (1H, d, J 17.4), 3.78 (3H, s), 4.82
(1H, d, J 17.4), 5.56 (1H, d, J 6.3), 5.67 (1H, d, J 6.3), 6.10 (1H, q, J 7.1), 6.90–7.80 (14H, m); MS: m/z
(FAB+) 439 (M+) (49%). Anal. calcd for C27H25N3O3: C, 73.77; H, 5.74; N, 9.57. Found: C, 73.83; H,
5.80 N, 9.66.
Compound 7c (0.30 g, 27%), mp 232°C (from hexane–benzene); [α]D25=−766.0 (MeOH, c=0.04); IR
(Nujol): 1710, 1660 (cm−1); 1H NMR δ: 1.54 (3H, d, J 7.0), 3.73 (1H, d, J 16.8), 3.78 (3H, s), 5.03 (1H,
d, J 16.8), 5.52 (1H, d, J 6.5), 5.61 (1H, d, J 6.5), 6.06 (1H, q, J 7.0), 6.11 (1H, dd, J 7.4, 1.0), 6.52 (1H,
dt, J 7.4, 0.8), 7.15–7.70 (12H, m); MS: m/z (FAB+) 439 (M+) (65%). Anal. calcd for C27H25N3O3: C,
73.77; H, 5.74; N, 9.57. Found: C, 73.72; H, 5.70; N, 9.60.
3.6. X-Ray structure determination of 7a, 7b and 7c
Crystal data were collected with a Bruker P4 diffractometer, using graphite monochromated Mo-Kα
radiation λ=0.71073 Å. The structures were solved by SIR92,12 and refined on F2 by full-matrix least-
squares using SHELX97;13 heavy atoms were anisotropic, H atoms isotropic. Absolute configurations
were based on the reactants knowledge.
Data of 7a. C21H21N3O3, Mr=363.41, triclinic, a=7.1179(4), b=7.8192(5), c=8.7364(5) Å,
α=83.763(6), β=76.012(5), γ=82.907(6)°, V=466.64(5) Å3, space group P1, T=291(1) K, Z=1,
dcalc=1.293 g cm−1, µ(Mo-Kα)=0.088 mm−1; ω/2θ scans, 4<2θ<60°; −9<h<0, −10<k<10,
−12<l<11; 2893 unique reflections collected; used for all calculations. Final R=0.0341 and wR=0.0942,
g.o.f. 1.045, −0.11<∆ρ<0.14 eÅ−3
.
Data of 7b. C22H23N3O3, Mr=377.43, tetragonal, a=9.7685(7), c=21.0340(18) Å, V=2007.1(3) Å3,
space group P41, T=291(1) K, Z=4, dcalc=1.249 g cm−1, µ(Mo-Kα)=0.084 mm−1; ω/2θ scans,
4<2θ<55°; −1<h<12, 0<k<12, −27<l<27; 5844 reflections collected, 4604 unique (Rint=0.0156) used
for all calculations. Final R=0.0635 and wR=0.0822, g.o.f. 1.031; −0.09<∆ρ<0.09 eÅ−3
.
Data of 7c. C27H25N3O3, Mr=439.50, monoclinic, a=9.5131(8), b=9.8418(10), c=12.3063(13) Å,
β=99.242(7)°, V=1137.9(2) Å3, space group P21, T=291(1) K, Z=2, dcalc=1.283 g cm−1, µ(Mo-
Kα)=0.085 mm−1; ω/2θ scans, 4<2θ<55°; −1<h<12, −1<k<12, −15<l<15; 3605 reflections col-
lected, 3077 unique (Rint=0.0258) used for all calculations. Final R=0.0415 and wR=0.0739, g.o.f. 1.012,
−0.11<∆ρ<0.14 eÅ−3
.
Bond distances and bond angles are in the expected range for all three molecules. These compounds
differ mainly because the N2_C3–C5_O18 system is cis in 7a and trans in 7b and 7c. Also, the ring N1,
N2, C3, C4, C5 is quite different, being about planar in 7a, while 7b shows a twisted conformation [4T5,
q2=0.131(2) Å, ϕ =−48.8(8)°]14 and 7c has the opposite one [5T4, q2=0.100(2) Å, ϕ =132.1(10)°]. On
2
2
the contrary, the seven-membered ring has about the same conformation in all molecules.

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G. Broggini et al. / Tetrahedron: Asymmetry 10 (1999) 4447–4454
Acknowledgements
We are grateful to CNR and MURST for financial support.
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