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Synlett 2005(1): 125-126  
DOI: 10.1055/s-2004-836046
LETTER
© Georg Thieme Verlag Stuttgart · New York

Reverse Regioselection in the Synthesis of Spiropyrazolobarbiturates Using C-Br and C-H Nitrilimines

Francesco Foti*, Giovanni Grassi, Francesco Risitano
Dipartimento di Chimica Organica e Biologica, Università, Vill. S. Agata, 98166 Messina, Italy
Fax: +39(090)393897; e-Mail: ffoti@isengard.unime.it;
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Publikationsverlauf

Received 30 September 2004
Publikationsdatum:
29. November 2004 (online)

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Abstract

The 1,3-dipolar cycloaddition of arylmethylenebarbiturates 4 with C-Br 2 and C-H 3 nitrilimines gives spiropyrazolo­barbiturates 5 and 6 with reverse regioselectivities.

Key words

dipolar cycloaddition - nitrile imines - spirans - bromo­derivatives

    References

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5

The formation of the new dipole 3 is further confirmed by the formation of tetrazine 7. Indeed, after being prepared and left for one hour under stirring in the same reaction conditions, compound 3 is transformed into the known self-condensation derivative 7 (obtained by the alkaline hydrolysis of ester derivative 8, Scheme [2] ). [12]

6

Typical Procedure for C-Br Nitrilimine Cycloaddition.
To a stirred solution of phenylhydrazone 1 (10 mmol) in DMF (20 mL) at r.t. was added dropwise a solution of NBS (20 mmol) in DMF (20 mL) under nitrogen. After additional stirring (15 min), dipolarophile 4 (50 mmol) was added at r.t. and then dropwise TEA (10 mmol). The reaction mixture was left to stand for 2 h, poured into cold H2O (100 mL) and extracted three times with Et2O; the organic layer was washed with H2O and brine, dried over anhyd Na2SO4 and concentrated. The cycloadducts 5 were isolated by flash chromatography on silica gel (eluent: Et2O).

7

Typical Procedure for C-H Nitrilimine Cycloaddition.
This procedure is similar to the above but with an operating temperature in the first phase of -60 °C and the addition of 10 mmol of NBS in DMF (10 mL). Cycloadducts 6 were isolated by flash chromatography on silica gel (eluent: Et2O).

8

By varying the above conditions, traces of the other regioisomers can be detected.

9

Selected data. Compound 5a: mp 254-255 °C. IR (nujol): 1714 cm-1. 1H NMR (DMSO-d 6): δ = 5.53 (s, 1 H), 6.75-7.41 (m, 10 H). 13C NMR (DMSO-d 6): δ = 68.6, 76.7, 112.8, 120.3, 128.6, 129.3, 130.1, 130.8, 142.1, 148.7, 164.3, 167.2. MS (EI): m/z = 412/414 [M+]. Compound 5b: mp 236-237 °C. IR (nujol): 1724 cm-1. 1H NMR (DMSO-d 6): δ = 3.74 (s, 3 H), 5.45 (s, 1 H), 6.71-7.33 (m, 9 H). 13C NMR (DMSO-d 6): δ = 55.2, 68.3, 76.7, 112.8, 114.1, 120.3, 129.2, 129.3, 131.5, 142.2, 146.0, 148.9, 159.9, 164.5, 167.4. MS (EI): m/z = 442/444 (M+). Compound 5c: mp 251-252 °C. IR (nujol): 1718 cm-1. 1H NMR (DMSO-d 6): δ = 5.84 (s, 1 H), 6.71-8.42 (m, 9 H). 13C NMR (DMSO-d 6): δ = 67.0, 76.4, 113.0, 120.6, 123.7, 127.3, 129.3, 131.7, 138.4, 141.8, 148.0, 148.6, 164.1, 166.5. MS (EI): m/z = 457/459 (M+). Compound 5d: mp 250-251 °C. IR (nujol): 1720 cm-1. 1H NMR (DMSO-d 6): δ = 5.61 (s, 1 H), 6.68-7.88 (m, 9 H). 13C NMR (DMSO-d 6): δ = 67.6, 76.5, 112.9, 120.5, 128.2, 128.8, 129.4, 130.0, 132.0, 142.0, 148.8, 162.4, 164.3, 167.0. MS (EI): m/z = 446/448/450 (M+).

10

Selected data. Compound 6a: mp 138-139 °C. IR (nujol): 1713 cm-1. 1H NMR (DMSO-d 6): δ = 5.39 (s, 1 H), 6.86 (s, 1 H), 6.70-7.40 (m, 10 H). 13C NMR (DMSO-d 6): δ = 70.3, 73.8, 114.6, 120.3, 128.6, 128.8, 134.3, 137.4, 144.3, 146.0, 150.1, 166.4, 169.7. MS (EI): m/z = 334 (M+). Compound 6b: mp 130-131 °C. IR (nujol): 1713 cm-1. 1H NMR (DMSO-d 6): δ = 3.71 (s, 3 H), 5.31 (s, 1 H), 6.87 (s, 1 H), 6.78-7.20 (m, 9 H). 13C NMR (DMSO-d 6): δ = 55.0, 70.3, 73.5, 112.8, 113.9, 114.6, 125.9, 128.7, 144.3, 145.9, 150.1, 159.4, 167.1, 169.7. MS (EI): m/z = 364 (M+). Compound 6c: mp 135-136 °C. IR (nujol): 1713 cm-1. 1H NMR (DMSO-d 6): δ = 5.75 (s, 1 H), 6.90 (s, 1 H), 6.75-8.32 (m, 9 H). 13C NMR (DMSO-d 6): δ = 70.1, 71.5, 114.3, 120.4, 123.5, 129.0, 129.1, 137.2, 142.2, 143.6, 147.6, 149.9, 166.1, 168.8. MS (EI): m/z = 379 (M+). Compound 6d: mp 155-156 °C. IR (nujol): 1718 cm-1. 1H NMR (DMSO-d 6): δ = 5.48 (s, 1 H), 6.84 (s, 1 H), 6.72-7.42 (m, 9 H). 13C NMR (DMSO-d 6): δ = 70.1, 72.3, 112.8, 114.4, 120.2, 128.5, 128.8, 129.3, 133.3, 137.2, 143.9, 145.9, 150.0, 166.3, 169.3. MS (EI): m/z = 368/370 (M+).

11

X-ray data to be submitted to Acta Crystallogr.