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

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.

dipolar cycloaddition - nitrile imines - spirans - bromo­derivatives

References

1a Fisher E. Von Mering JR. Ther. Ggw.  1903,  44:  97 

1b Doran WJ. J. Med. Chem.  1959,  4:  1 

1c Burger A. Medicinal Chemistry   3rd ed.:  Wiley-Interscience; New York: 1970. 

1d Bojarski JT. Mokrosz JL. Barton HJ. Paluchowska MH. Adv. Heterocycl. Chem.  1985,  38:  229 

2 For a recent review, see: Moussier N. Bruche L. Viani F. Zanda M. Curr. Org. Chem.  2003,  7:  1071 

3a Foti F. Grassi G. Risitano F. Tetrahedron Lett.  1999,  40:  2605 

3b Foti F. Grassi G. Risitano F. Nicolò F. Rotondo A. Helv. Chim. Acta  2001,  84:  3313 

4 This initial biological screening was carried out exclusively on the mixtures of bromospiranic derivatives obtained in the initial experiments, see: Galati EM. Monforte MT. Miceli N. Ranieri E. Il Farmaco  2001,  56:  459 

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.

12 Huisgen R. Aufderhaar E. Wallbillich G. Chem. Ber.  1965,  1476