The first case of asymmetric induction in intramolecular nitrile imine cycloadditions: Synthesis of enantiopure 3-substituted 6-oxo-2,3,3a,5- tetrahydro-4-carbomethoxy-furo[3,4-c]pyrazoles

Article abstract of DOI:10.1016/S0957-4166(99)00012-9

Intramolecular cycloaddition of homochiral nitrile imines 5, generated in situ from base treatment of the corresponding hydrazonoyl chlorides 4, involves diastereoselective formation of the title compounds in the enantiomerically pure form.

Full text of DOI:10.1016/S0957-4166(99)00012-9

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 487–492
The first case of asymmetric induction in intramolecular nitrile
imine cycloadditions: synthesis of enantiopure 3-substituted
6-oxo-2,3,3a,5-tetrahydro-4-carbomethoxy-furo[3,4-c]pyrazoles
Gianluigi Broggini,a Luisa Garanti,b Giorgio Molteni b,∗ and Gaetano Zecchi a
aDipartimento di Scienze Chimiche, Fisiche e Matematiche, Università dell’Insubria, via Lucini 3, 22100 Como, Italy
bDipartimento di Chimica Organica e Industriale, Università di Milano, via Golgi 19, 20133 Milano, Italy
Received 7 December 1998; accepted 11 January 1999
Abstract
Intramolecular cycloaddition of homochiral nitrile imines 5, generated in situ from base treatment of the
corresponding hydrazonoyl chlorides 4, involves diastereoselective formation of the title compounds in the
enantiomerically pure form. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
Stereoselective 1,3-dipolar cycloadditions have received much attention in the last two decades.1 In
this respect, the cycloadditive route has been successfully exploited in both inter-2 and intramolecular3
versions, and the number of available examples increases constantly. Many papers deal with stereo-
selective cycloadditions as key steps in the construction of complex targets such as natural products
or their analogues,4 while simpler systems have been studied to acquire an accurate rationale of the
observed stereoselectivities.5 Nitrile oxide and nitrone cycloadditions play a major role in this field,1
due to the easy generation of the dipole and to the astonishing array of latent functionalities displayed
by the corresponding cycloadducts.6 Much less work has been done on other kinds of 1,3-dipoles. For
example, a few reports on nitrile imines have recently appeared describing intermolecular nitrile imine
cycloadditions onto a chiral dipolarophile,7 but there is a complete lack of data regarding intramolecular
versions.
We present here the first example of an intramolecular cycloaddition of homochiral nitrile imines 5 in
which the stereogenic unit is placed inside the tether joining the reactive groups, in the allylic position
with respect to the dipolarophile.
∗
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)00012-9

488
G. Broggini et al. / Tetrahedron: Asymmetry 10 (1999) 487–492
2. Results and discussion
Our synthetic sequence starts from the 4-substituted 2-(R)-hydroxy-3-(E)-butenoic acid methylesters 1
as chiral building blocks.8 Hydrazonoyl chlorides 4, which we devised as the suitable precursors of nitrile
imines 5, were synthesised from 1 following a well-established procedure elaborated by us9 (Scheme 1).
The in situ generation of the transient species 5 was accomplished by treating the appropriate hydrazonoyl
chlorides 4 with a twofold molar excess of silver carbonate in dry acetonitrile at room temperature.10
Scheme 1.
The diastereoisomeric cycloadducts 6 and 7 were obtained chemically and enantiomerically pure by
simple column chromatography. Their isolated yields were fair, since some amount of tarry material
was formed. Structural assignments rely upon analytical and spectral data, and are unambiguous in
1
the light of the H NMR chemical shifts and scalar coupling values, compared with literature data.11
The absolute configurations of the newly formed stereocentres were determined, taking into account
the (R) configuration of the starting centre, by NOE measurements reported in Fig. 1. In order to gain
deeper insight into the spatial relationships between HA and HC, full geometry optimisation of the major

G. Broggini et al. / Tetrahedron: Asymmetry 10 (1999) 487–492
489
Figure 1. NOE enhancements for cycloadducts 6 and 7
cycloadducts 6 was carried out12 at the AM1 level of theory.13 The calculated distances HA–HC were
2.43 Å for 6a and 2.41 Å for 6b; so justifying the observed mutual NOE enhancements.
Some particular features characterise the cycloaddition reactions described above: (i) they take place
with good overall yields; (ii) the relative configuration of the two new stereocentres is exclusively anti
as a consequence of the stereoconservative nature of the concerted mechanism; and (iii) a fair degree of
stereoselectivity is operating due to the effect of the pre-existing stereocentre. The latter stereoselective
result may be rationalised by means of the proposed transition states A and B (Fig. 2). The former of
these is plausibly the more accessible because of the lack of steric encumbrance due to the carbomethoxy
group. Hence, the preferred formation of 6 finds rationalisation.
Figure 2. Proposed transition states for the formation of 6 and 7
In conclusion, the present work has made accessible the enantiopure targets 6 and 7 by way of an
unprecedented stereoselective intramolecular cycloaddition of homochiral nitrile imines.

490
G. Broggini et al. / Tetrahedron: Asymmetry 10 (1999) 487–492
3. Experimental
Melting points were determined with a Büchi apparatus and are uncorrected. IR spectra were recorded
with a Perkin–Elmer 1725X spectrophotometer. Mass spectra were determined with a VG-70EQ appara-
tus. 1H 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. Optical rotations,
25
D
[α] , were recorded on a Perkin–Elmer Model 241 polarimeter at the sodium D line.
3.1. General procedure for the preparation of alkenyl acetoacetates 2
A solution of 1 (25 mmol) in xylene (8 mL) was treated with 2,2,6-trimethyl-4H-1,3-dioxin-4-one
(3.55 g, 25 mmol). The mixture was refluxed for 1.5 h. Evaporation of the solvent under reduced pressure
and subsequent in vacuo distillation of the residue gave the acetoacetates 2 as analytically pure samples.
25
2a (5.08 g, 95% yield) bp 56°C (1 mmHg); [α] =−56 (CHCl3, c=0.36); IR (neat): 1750, 1720, 1700
D
1
(cm−1); H NMR δ: 1.76 (3H, d, J=6.0), 2.32 (3H, s), 3.54 (2H, s), 3.78 (3H, s), 5.46 (1H, d, J=7.0),
5.50–5.60 (1H, m), 5.90–6.05 (1H, m); MS: m/z 214 (M+). Anal. calcd for C10H14O5: C, 56.05; H, 6.59.
Found: C, 56.11, H, 6.64.
25
D
2b (4.35 g, 63% yield) bp 106°C (0.5 mmHg); [α] =−74 (CHCl3, c=0.23); IR (neat): 1745, 1720,
1
1700 (cm−1); H NMR δ: 2.27 (3H, s), 3.55 (2H, s), 3.75 (3H, s), 5.66 (1H, d, J=6.3), 6.20 (1H, dd,
J=15.4, 6.3), 6.80 (1H, d, J=15.4), 7.20–7.40 (5H, m); MS: m/z 276 (M+). Anal. calcd for C15H16O5: C,
65.19; H, 5.84. Found: C, 65.23, H, 5.90.
3.2. General procedure for the preparation of alkenyl chloroacetoacetates 3
A solution of sulfuryl chloride (2.51 g, 18.6 mmol) in dry chloroform (30 mL) was slowly added (1 h)
to a solution of 2 (15 mmol) in dry chloroform (15 mL), on keeping the temperature in the range 0–5°C.
After 2 h at room temperature, chloroform (30 mL) was added and the organic solution was washed with
5% aqueous sodium hydrogencarbonate (25 mL). The organic layer was then washed with water (50 mL)
and dried over sodium sulfate. The solvent was removed to give chloroacetacetates 3 as undistillable oils
which were not analytically pure.
25
1
3a (3.53 g, 95% yield); [α] =−27 (CHCl3, c=0.28); IR (neat): 1760, 1730, 1700 (cm−1); H NMR:
D
δ 1.76 (3H, d, J=6.0), 2.42 (3H, s), 3.76 (3H, s), 4.86 (1H, s), 5.49 (1H, d, J=6.9), 5.50–5.60 (1H, m),
5.85–6.00 (1H, m); MS: m/z 248 (M+).
25
3b (1.86 g, 40% yield); [α] =−39 (CHCl3, c=0.48); IR (neat): 1760, 1730, 1690 (cm−1); 1H NMR:
D
δ 2.42 (3H, s), 3.78 (3H, s), 4.89 (1H, s), 5.69 (1H, d, J=6.3), 6.20 (1H, dd, J=15.4, 6.3), 6.82 (1H, d,
J=15.4), 7.30–7.40 (5H, m); MS: m/z 310 (M+).
3.3. General procedure for the preparation of hydrazonyl chlorides 4
A cold aqueous solution of 4-chlorobenzenediazonium chloride (6.0 mmol) was added dropwise to
a solution of 3 (6.0 mmol) in 80% aqueous methanol (25 mL) under vigorous stirring and ice-cooling.
During the addition, the pH was adjusted to 5 by adding sodium acetate. 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 (25 mL), then with water (75 mL), and dried over sodium sulfate.

G. Broggini et al. / Tetrahedron: Asymmetry 10 (1999) 487–492
491
Evaporation of the solvent gave a solid and subsequent recrystallisation with diisopropylether gave the
hydrazonyl chlorides 4 in the pure state.
25
4a (1.41 g, 76% yield) mp 65°C; [α] =−80 (CHCl3, c=0.29); IR: 3180, 1730, 1710 (cm−1); 1H NMR
D
δ: 1.78 (3H, d, J=6.6), 3.78 (3H, s), 5.58 (1H, d, J=7.0), 5.60–5.80 (1H, m), 6.00–6.17 (1H, m), 6.80–7.20
(5H, m), 8.58 (1H, br s); MS: m/z 310 (M+). Anal. calcd for C14H15ClN2O4: C, 54.18; H, 4.88; N, 9.03.
Found: C, 54.24; H, 4.86; N, 8.95.
25
1
4b (1.02 g, 42% yield) mp 152°C; [α] =−59 (CHCl3, c=0.36); IR: 3180, 1750, 1715 (cm−1); H
D
NMR: δ 3.80 (3H, s), 5.75 (1H, dd, J=6.3, 1.0), 6.32 (1H, dd, J=15.4, 6.3), 6.90 (1H, dd, J=15.4, 1.0),
7.20–7.50 (9H, m), 8.40 (1H, br s); MS: m/z 406 (M+). Anal. calcd for C19H16Cl2N2O4: C, 56.15; H,
3.97; N, 6.90. Found: C, 56.09; H, 4.02; N, 6.99.
3.4. General procedure for the reaction of hydrazonyl chlorides 4 with silver carbonate
A solution of the hydrazonyl chlorides 4 (2.5 mmol) in dry acetonitrile (125 mL) was treated with silver
carbonate (1.38 g, 5.0 mmol), and stirred in the dark at room temperature for 20 h (entry a, Scheme 1)
or 2 h (entry b, Scheme 1). The undissolved material was filtered off, the solvent evaporated, and then
the residue was chromatographed on a silica gel column with ethyl acetate:hexane, 2:1. Products and
isolation yields are collected in the Scheme 1. All compounds were obtained in analytically pure state by
recrystallisation.
25
D
6a (0.30 g, 44% yield) mp 116°C (from hexane–benzene); [α] =−98 (CHCl3, c=0.31); IR: 1760,
1
1720 (cm−1); H NMR δ: 1.58 (3H, d, J=6.0), 3.70 (3H, s), 3.85 (1H, dd, J=11.1, 9.0), 4.45 (1H, dq,
J=11.1, 6.0), 4.90 (1H, d, J=9.0), 7.00–7.10 (5H, m); MS: m/z 274 (M+). Anal. calcd for C14H14N2O4:
C, 61.29; H, 5.15; N, 10.22. Found: C, 61.36; H, 5.20; N, 10.29.
25
D
7a (0.15 g, 22% yield) mp 89°C (from diisopropyl ether); [α] =+34 (CHCl3, c=0.33); IR: 1770, 1740
(cm−1); 1H NMR δ: 1.68 (3H, d, J=6.0), 3.76 (3H, s), 4.04 (1H, dd, J=12.1, 9.4), 4.30 (1H, dq, J=12.1,
6.0), 5.25 (1H, d, J=9.4), 7.00–7.15 (5H, m); MS: m/z 274 (M+). Anal. calcd for C14H14N2O4: C, 61.29;
H, 5.15; N, 10.33. Found: C, 61.28; H, 5.22; N, 10.29.
25
D
6b (0.46 g, 50% yield) mp 187°C (from hexane–benzene); [α] =−128 (CHCl3, c=0.38); IR: 1770,
1
1730 (cm−1); H NMR δ: 3.70 (3H, s), 3.92 (1H, dd, J=11.5, 9.0), 4.96 (1H, d, J=11.5), 5.53 (1H, d,
J=9.0), 6.90–7.40 (9H, m); MS: m/z 370 (M+). Anal. calcd for C19H15ClN2O4: C, 61.61; H, 4.08; N,
7.57. Found: C, 61.57; H, 4.02; N, 7.62.
25
D
7b (0.15 g, 16% yield) mp 125°C (from diisopropyl ether); [α] =+19 (CHCl3, c=0.25); IR: 1760,
1
1730 (cm−1); H NMR δ: 3.88 (3H, s), 4.28 (1H, dd, J=12.4, 9.4), 5.15 (1H, d, J=12.4), 5.26 (1H, d,
J=9.4), 6.90–7.40 (9H, m); MS: m/z 370 (M+). Anal. calcd for C19H15ClN2O4: C, 61.61; H, 4.08; N,
7.57. Found: C, 61.66; H, 4.13; N, 7.66.
Acknowledgements
We are indebted to Professor van der Gen’s group of Gorlaeus Laboratoria in Leiden, the Netherlands,
for the training offered to two of our students, who performed the synthesis of 1a and 1b, in connection
with the Erasmus Project.
Thanks are due to CNR and MURST for financial support.

492
G. Broggini et al. / Tetrahedron: Asymmetry 10 (1999) 487–492
References
1. (a) 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed. Wiley-Interscience: New York, 1984; Vols 1 and 2; (b)
Annunziata, R.; Cinquini, M.; Cozzi, F.; Raimondi, L. Gazz. Chim Ital. 1989, 119, 253; (c) Cinquini, M.; Cozzi, F.
Methoden der Organische Chemie (Houben-Weyl), E 21c, Stereoselective Synthesis; G. Thieme: Stuttgart, 1995; pp.
2953–2987; (d) Gothelf, K. V.; Jorgensen, K. A. Acta Chem. Scand. 1996, 50, 652.
2. Padwa, A. Comprehensive Organic Synthesis; Trost, B.; Fleming, I., Eds. Pergamon Press: New York, 1992; vol. 4, ch.
4–9, pp. 1069–1109.
3. Wade, P. A. Comprehensive Organic Synthesis; Trost, B.; Fleming, I., Eds. Pergamon Press: New York, 1992; vol. 4, ch.
4–10, pp. 1111–1168.
4. (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. Proced. 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) Carruthers, W. Cycloaddition Reactions in Organic
Synthesis; Pergamon Press: Oxford, 1990; (g) Frederickson, M. Tetrahedron 1997, 53, 403.
5. Raimondi, L. Gazz. Chim. Ital. 1997, 127, 167 and references cited therein.
6. (a) Curran, D. P. Advances in Cycloaddition; Curran, D. P., Ed. JAI Press: London, 1988; vol. 1, pp. 129–189; (b) Koroleva,
E. V.; Lakhvich, F. A. Russ. Chem. Rev. 1997, 66, 27.
7. (a) Blake, A. J.; Cook, T. A.; Forsyth, A. C.; Gould, R. O.; Paton, R. M. Tetrahedron 1992, 37, 8053; (b) Green, B.; Sheu,
K. Steroids 1994, 479; (c) Grubert, L. Galley, G.; Pätzel, M. Tetrahedron: Asymmetry 1996, 7, 1137; (d) Barluenga, J.;
Fernández-Marí, F.; Aguilar, E.; Viado, A. A.; Olano, B. Tetrahedron Lett. 1998, 39, 4887.
8. (a) 1a: Warmerdam, E. G. J. C.; van der Nieuwendijk, A. M. C. H.; Kruse, G. C.; Brussee, J.; van der Gen, A. Tetrahedron:
Asymmetry 1996, 7, 2539; (b) 1b: Warmerdam, E. G. J. C.; van der Nieuwendijk, A. M. C. H.; Kruse, G. C.; Brussee, J.;
van der Gen, A. Rec. Trav. Chim. Pays-Bas 1996, 115, 20.
9. Broggini, G.; Garanti, L.; Molteni, G.; Zecchi, G. Tetrahedron 1998, 54, 2843.
10. Broggini, G.; Bruché, L.; Garanti, L.; Zecchi, G. J. Chem. Soc., Perkin Trans. 1 1994, 433.
11. Batterham, T. J. NMR Spectra of Simple Heterocycles. Wiley: New York, 1971.
12. As implemented in the HYPERCHEM package of programs.
13. Dewar, M. J. S.; Zoebisch, E. G.; Healy, E. F.; Stewart, J. J. P. J. Am. Chem. Soc. 1985, 107, 3902.