The first example of a (1R,2S,5R)-(-)-menthyl chiral auxiliary in intramolecular nitrilimine cycloadditions: Synthesis of enantiopure pyrazolo[1,5-a][4,1]benzoxazepines and pyrazolo[1,5-a][4,1]benzodiazepines

Article abstract of DOI:10.1016/S0957-4166(99)00422-X

By using (1R,2S,5R)-(-)-menthyl as a chiral auxiliary, we have developed a synthesis of hydrazonoyl chlorides 2 and 8, treatment of which with silver carbonate promoted the in situ generation of the corresponding nitrilimines 3 and 9. The latter underwent

Full text of DOI:10.1016/S0957-4166(99)00422-X

Pergamon
Tetrahedron: Asymmetry 10 (1999) 3873–3876
The first example of a (1R,2S,5R)-(−)-menthyl chiral auxiliary in
intramolecular nitrilimine cycloadditions: synthesis of
enantiopure pyrazolo[1,5-a][4,1]benzoxazepines and
pyrazolo[1,5-a][4,1]benzodiazepines
Giorgio Molteni a,∗ and Tullio Pilati b
aDipartimento di Chimica Organica e Industriale, Università di Milano, via Golgi 19, 20133 Milano, Italy
bConsiglio Nazionale delle Ricerche, Centro per lo Studio delle Relazioni tra Struttura e Reattività Chimica, via Golgi 19,
20133 Milano, Italy
Received 6 September 1999; accepted 22 September 1999
Abstract
By using (1R,2S,5R)-(−)-menthyl as a chiral auxiliary, we have developed a synthesis of hydrazonoyl chlorides
2 and 8, treatment of which with silver carbonate promoted the in situ generation of the corresponding nitril-
imines 3 and 9. The latter underwent intramolecular cycloaddition giving, respectively, enantiopure pyrazolo[1,5-
a][4,1]benzoxazepines 4, 5 and pyrazolo[1,5-a][4,1]benzodiazepines 10. © 1999 Elsevier Science Ltd. All rights
reserved.
Stereoselective cycloadditions of nitrilimines have been recently exploited in order to obtain enantio-
merically pure pyrazole derivatives. Chiral dipolarophiles,1–3 as well as homochiral nitrilimines,4 were
employed for this purpose. There is, however, a dearth of the intramolecular version of this methodology
in the literature, the only reports available being two recent papers from our laboratory.5,6 We have now
examined in more detail the behaviour towards stereoselection of various kinds of nitrilimines in which
the chiral unit is placed inside the tether joining the reactive groups. In pursuing our interest in this field,
and recognizing the growing attention towards chiral auxiliaries in cycloadditions,7,8 we present here the
first example in which the chiral auxiliary, namely the (1R,2S,5R)-(−)-menthyl group, is placed outside
the tether joining the reactive groups.
Firstly, we devised (1R,2S,5R)-(−)-menthyl-2-chloroacetoacetate4 as a readily accessible chiral buil-
ding block for the synthesis of both hydrazonoyl chlorides 2 and 8 (see Schemes 1 and 2).9 Since
compound 2 was prepared starting from racemic 1,10 it was obviously obtained as an equal mixture
of diastereoisomers, which was unfortunately inseparable by standard chromatographic methods. On the
other hand, hydrazonoyl chloride 8 was synthesised in enantiopure form. Nitrilimine intermediates 3
∗
Corresponding author. E-mail: garanti@icil64.cilea.it
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00422-X

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G. Molteni, T. Pilati / Tetrahedron: Asymmetry 10 (1999) 3873–3876
and 9 were generated in situ by treating a 0.02 M solution of the corresponding hydrazonoyl chlorides
in dry acetonitrile (or dioxane, respectively) with silver carbonate at room temperature, following a
well-established procedure described by our group.11 The extent of intramolecular cycloadditions was
fully satisfactory, since the diastereoisomeric pyrazolo[1,5-a][4,1]benzoxazepines 4, 5 and pyrazolo[1,5-
a][4,1]benzodiazepines 10 were obtained with 90 and 85% yields, respectively. The separation of cyclo-
adducts 4, 5 and 10 in their enantiopure form was achieved by simple crystallisation from diisopropyl
ether–methanol.12 Furthermore, the slow evaporation of a solution of 5 in methanol gave crystals in
a suitable form for X-ray crystallographic analysis.13 The absolute configuration of the stereocentre
generated in the oxazepinic ring of 5 was (R) (see Fig. 1). Attempts to obtain a single crystal from
either of the diastereoisomers 10 failed, since they were obtained as amorphous solids; the absolute
configuration of the newly-formed stereocentre remains undetermined.
Scheme 1.
In the case of nitrilimine 3, no new stereocentres originate from the intramolecular cycloaddition,
and the (1R,2S,5R)-(−)-menthyl group just allows the separation of enantiopure cycloadducts 4 and 5
from the diastereoisomeric mixture. This target is a relevant one, in that (i) enantiopure pyrazolo[1,5-
a][4,1]benzoxazepines are still largely absent in the literature, and (ii) our synthetic route starts from
racemic 1, which is easily prepared, thus avoiding the tedious synthesis of enantiomerically pure 3-
butyn-2-ol.
The (1R,2S,5R)-(−)-menthyl group could act as a genuine chiral auxiliary in the intramolecular
1
cycloaddition of nitrilimine 9. As far as stereoselection is concerned, H NMR analysis of the reaction
crude revealed that cycloadducts 10 were an equimolecular mixture of diastereoisomers. This lack of
diastereopreference may be due to the distance between the chiral auxiliary and the reactive groups.
Although the good intramolecular cycloaddition yields make the nitrilimine protocol a suitable tool in
the construction of the enantiopure pyrazolo[1,5-a][4,1]benzodiazepine system, the inefficiency of the
(1R,2S,5R)-(−)-menthyl group as the chiral auxiliary in this type of cycloaddition must be acknowledged.

G. Molteni, T. Pilati / Tetrahedron: Asymmetry 10 (1999) 3873–3876
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Scheme 2.
Figure 1. Ortep plot of 5. Ellipsoids are at 50% of probability level
Acknowledgements
Thanks are due to MURST and CNR for financial support. One of us (G.M.) is grateful to Professor
Luisa Garanti for helpful discussions.
References
1. Blake, A. J.; Cook, T. A.; Forsyth, A. C.; Gould, R. O.; Paton, R. M. Tetrahedron 1992, 37, 8053.
2. Fauré, J. L.; Réau, R.; Wong, M. W.; Koch, R.; Wentrup, C.; Bertrand, G. J. Am. Chem. Soc. 1997, 119, 2819.
3. Barluenga, J.; Fernández-Marí, F.; Aguilar, E.; Viado, A. L.; Olano, B. Tetrahedron Lett. 1998, 39, 4887.
4. Grubert, L.; Galley, G.; Pätzel, M. Tetrahedron: Asymmetry 1996, 7, 1137.
5. Broggini, G.; Garanti, L.; Molteni, G.; Zecchi, G. Tetrahedron: Asymmetry 1999, 10, 487.
6. Broggini, G.; Garanti, L.; Molteni, G.; Pilati, T.; Ponti, A.; Zecchi, G. Tetrahedron: Asymmetry 1999, 10, 2203.

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G. Molteni, T. Pilati / Tetrahedron: Asymmetry 10 (1999) 3873–3876
7. Seyden-Penne, J. Chiral Auxiliaries and Ligands in Asymmetric Synthesis; Wiley Interscience: New York, 1995; Chapter
9.
8. Kunz, H.; Rüch-Braun, K. Chiral Auxiliaries in Cycloadditions; Wiley-VCH: Weinheim, 1999.
9. Selected data for compounds 6, 7, 2 and 8. Compound 6: (68% yield) m.p. 126°C (from diisopropyl ether); IR: (Nujol)
1650 cm−1; 1H NMR δ: (CDCl3) 4.63 (2H, s), 4.96 (2H, s), 5.75 (1H, dd, J 19.6, 9.7), 6.50 (1H, dd, J 19.6, 2.2), 6.67 (1H,
dd, J 9.7, 2.2), 7.05–8.10 (9H, m); MS: m/z 296 (M+). Compound 7: (70% yield) m.p. 102°C (from diisopropyl ether);
IR: (Nujol) 3410, 3350, 3230, 1635 (cm−1); 1H NMR δ: (CDCl3) 4.50 (2H, s), 4.58 (2H, s), 4.70 (2H, br s), 5.75 (1H, dd,
J 9.3, 4.3), 6.50–6.70 (2H, m), 6.85–7.40 (9H, m); MS: m/z 266 (M+). Compound 2: (70% yield) gum; IR: (Neat) 3240,
1720, 1690 (cm−1); 1H NMR δ: (CDCl3) 0.80 (3H, d, J 6.9), 0.93 (6H, d, J 7.1), 1.65 (3H, d, J 6.7), 1.20–2.20 (9H, m),
2.51 (1H, d, J 2.2), 4.83 (1H, ddd, J 10.9, 10.7, 4.4), 5.72 (1H, dq, J 6.7, 2.2), 6.90–8.05 (4H, m), 11.60 (1H, br s); MS:
m/z 432 (M+). Compound 8: (65% yield) m.p. 49°C (from diisopropyl ether); [α]D25=−57.6 (MeOH, c=0.072); IR: (Nujol)
3170, 1725, 1645 (cm−1); 1H NMR δ: (CDCl3) 0.84 (3H, d, J 7.0), 0.95 (6H, d, J 6.7), 1.10–2.10 (9H, m), 4.57 (2H, s),
4.63 (1H, d, J 14.8), 4.70 (1H, d, J 14.8), 4.86 (1H, ddd, J 10.9, 10.7, 4.4), 5.78 (1H, dd, J 8.0, 4.3), 6.50–6.60 (2H, m),
6.93–7.69 (9H, m), 10.50 (1H, br s); MS: m/z 509 (M+).
10. Broggini, G.; Garanti, L.; Molteni, G.; Zecchi, G. Heterocycles 1994, 38, 291.
11. Broggini, G.; Bruché, L.; Garanti, L.; Zecchi, G. J. Chem. Soc., Perkin Trans. 1 1994, 433.
12. Selected data for compounds 4, 5 and 10. Compound 4: (45% yield) m.p. 70°C (from diisopropyl ether–methanol);
[α]D25=−29.0 (MeOH, c=0.20); IR: (Nujol) 1740, 1700 (cm−1); 1H NMR δ: (CDCl3) 0.80 (3H, d, J 7.0), 0.90 (3H, d, J
7.2), 0.93 (3H, d, J 7.2), 1.85 (3H, d, J 6.8), 1.10–2.10 (9H, m), 4.94 (1H, ddd, J 10.8, 10.5, 4.4), 5.28 (1H, q, J 6.8), 6.92
(1H, s), 7.42–8.00 (4H, m); MS: m/z 396 (M+). Compound 5: (45% yield) m.p. 162°C (from diisopropyl ether–methanol);
1
[α]D25=−155.0 (MeOH, c=0.08); IR: (Nujol) 1740, 1700 (cm−1); H NMR δ: (CDCl3) 0.82 (3H, d, J 7.0), 0.94 (6H,
d, J 7.3), 1.85 (3H, d, J 6.8), 1.10–2.10 (9H, m), 5.00 (1H, ddd, J 11.0, 10.8, 4.4), 5.25 (1H, q, J 6.8), 6.94 (1H, s),
7.36–8.05 (4H, m); MS: m/z 396 (M+). Compound 10 (first diastereoisomer): (42% yield) m.p. 123°C (from diisopropyl
ether–methanol); [α]D25=+112 (MeOH, c=0.36); IR: (Nujol) 1720, 1670 (cm−1); 1H NMR δ: (CDCl3) 0.84 (3H, d, J 6.9),
0.95 (6H, d, J 6.6), 1.10–2.18 (9H, m), 3.29 (1H, dd, J 17.9, 13.5), 3.83 (1H, d, J 16.8), 4.14 (1H, dd, J 17.9, 9.0), 4.50
(1H, d, J 14.8), 4.90 (1H, ddd, J 10.7, 10.5, 4.3), 4.97 (1H, d, J 14.8), 5.31 (1H, d, J 16.8), 5.74 (1H, dd, J 13.5, 9.0),
6.76–8.25 (9H, m); MS: m/z 473 (M+). Compound 10 (second diastereoisomer): (42% yield) m.p. 90°C (from diisopropyl
ether–methanol); [α]D25=−96.8 (MeOH, c=0.28); IR: (Nujol) 1720, 1665 (cm−1); 1H NMR δ: (CDCl3) 0.80 (3H, d, J 6.8),
0.88 (6H, d, J 6.5), 1.10–2.10 (9H, m), 3.22 (1H, dd, J 18.1, 13.6), 3.79 (1H, d, J 16.8), 4.13 (1H, dd, J 18.1, 8.9), 4.43
(1H, d, J 14.8), 4.84 (1H, ddd, J 10.8, 10.7, 4.4), 4.97 (1H, d, J 14.8), 5.27 (1H, d, J 16.8), 5.72 (1H, dd, J 13.6, 8.9),
6.72–7.68 (9H, m); MS: m/z 473 (M+).
13. Crystal data for compound 5. C23H28N2O4, Fw=396.47, monoclinic, space group P21, a=7.7599(5), b=11.4865(10),
c=11.8772(7) Å, β=96.100(5)°, V=1052.7(2) Å3, Z=2, Dx=1.251 Mg m−3, µ (Mo-Kα)=0.086 mm−1; crystal dimensions
0.56×0.34×0.32 mm3, λ=0.71073 Å (Mo-Kα radiation, graphite monochromator, Siemens P4 diffractometer). Data
collection at 291 K, ω–2θ scan mode, 4<2θ<55°, h 0→10, k −14→14, l −15→15; 5177 collected reflections, 2538
unique [2299 with Io>2·σ(Io)], merging R=0.0174. The structure was solved by SIR92 [Altomare, A.; Cascarano, G.;
Giacovazzo, G.; Guagliardi, A.; Burla, M. C.; Polidori, G.; Camalli, G. J. Appl. Cryst. 1994, 27, 435] and refined
by SHELXL-97 [Sheldrick, G. M. (1997). SHELXL-97. Program for the Refinement of Crystal Structures; University
of Göttingen: Germany] by full-matrix least-squares based on Fo2, with weights w=1/[σ2(Fo)2+(0.0432P)2+0.0112P],
2
where P=(Fo2+2Fc )/3. The final consistency indices were R=0.0314 and Rw=0.0721 (0.0276 and 0.0701, respectively,
for observed reflections), goodness-of-fit=1.027. The final map ranges between −0.11 and 0.13 e/Å3. The absolute
configuration was determined on the base of the known one of menthyl moiety.