HETEROCYCLES

Paper | Special issue | Vol. 82, No. 1, 2010, pp. 417-429
Received, 11th March, 2010, Accepted, 15th April, 2010, Published online, 16th April, 2010.
DOI: 10.3987/COM-10-S(E)12

■ Isomerization of Diethyl 1-Alkynylphosphonates to 1,3-Dienylphosphonates Followed by Diels-Alder Reaction with Dead, Maleic Anhydride and Maleimide

Abdullatif Azab, Abed Al Aziz Quntar, Tamar Antebi, and Morris Srebnik*

Institute of Drug Research, School of Pharmacy, The Hebrew University of Jerusalem, P. O. Box 12065, Jerusalem 91120, Israel

Abstract

Isomerization of diethyl 1-alkynylphosphonates, 1, with Pd[(PPh)3]4 in refluxing 1,4-dioxane provides 1,3-dienylphosphonates, 2, in satisfactory to excellent isolated yield (45-83%). The reaction is tolerant of chlorides and cyclic substituents. Cycloaddition reaction of 2 with DEAD provided the corresponding diethyl 3-(diethoxyphosphoryl)-6-alkyl-3,6-dihydropyridazine- 1,2-dicarboxylates, 3, in 85% isolated yield. The cycloaddition products can be obtained in a one-pot reaction directly from the isomerized 1-alkynylphosphonates with no loss in yields. Similarly, 1,3-dioxo-1,3,3a,4,7,7a- hexahydroisobenzofuran-4-ylphosphonate, and 1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-ylphosphonate 4 were obtained by reacting 1,3-dienylphosphonates with maleic anhydride and maleimide respectively.

INTRODUCTION
1,3-Dienylphosphonates are interesting compounds that undergo a variety of reactions including 1,3-additions,1 cycloaddition with CH2N2,2 [2 + 2] cycloadditions,3 and enolate alkylations.4 We have previously prepared 1,3-dienylphosphonates by alkyne insertion into zirconacyclopropenes.5 They have also been prepared by reaction of unsaturated cyanophosphonates with N-tosylsulfonylimines,6 by nickel-catalyzed addition of P(O)-H bonds to propargyl alcohols,7 by Knoevenagel reaction,3 and by procedures similar to the preparation of vinylphosphonates.8
1-Alkynylphosphonates are a readily available group of compounds.9 Isomerization of alkynes to 1,3-dienes by metal catalysis is a known process.10,11 Isomerization of 1-alkynylphosphonates to 1,3-dienylphosphonates is essentially unknown. In this paper we discuss our results on the isomerization of 1-alkynylphosphonates to 1,3-dienylphosphonates under a variety of conditions. We also explored a one-pot isomerization/Diels-Alder reaction of 1-alkynylphosphonates with DEAD to give diethyl 3-(diethoxyphosphoryl)-6-alkyl-3,6-dihydropyridazine-1,2-dicarboxylates.12

RESULTS AND DISCUSSION
Isomerization
When 1a was heated in refluxing dioxane in the presence of a Pd[(PPh3)]4, 2a was isolated in very good yield (eq. 1).

Various palladium and other metal catalysts in different solvents were investigated but in all cases either no reaction occurred or a complex reaction mixture was obtained as shown in Table 1. Even under similar conditions, except for using different palladium catalysts, Pd[(PPh)3]4 was most successful (entries 2, 5). In addition, attempts to activate catalysts containing carbonyl ligands such as (Ru3(CO)12, Mo(CO)6) by activation with (CH3)3NO (TMANO) were also unsuccessful.

The optimized conditions were then applied to a series of 1-alkynylphosphonates 1 (Table 2). The reaction proceeds in satisfactory yields (45-85%) and is tolerant of halogenated (1d), cyclic 1h-i, short and long chain alkynylphosphontes. All the reactions were carried out in dioxane at (100 - 135 °C) except 2d which was carried out in toluene. The reaction time was variable from 1.5 h (2d) to 5 h (2a) (see experimental).
The stereochemistry of the products 2a-i was determined by NMR coupling constants. The 3JPC of the C3 carbon (26.4-29.2 Hz) and 3JPH of the hydrogen on C2 (21.2-35.4) are indicatives that C3 is trans to phosphorous and that the hydrogen on C2 is cis. Moreover, the hydrogens on (26.4-29.2 Hz) and 3JPH of the hydrogen on C2 (21.2-35.4) are indicatives that C3 is trans to phosphorous and that the hydrogen on C2 is cis. Moreover, the hydrogens on C3 and C4 are trans, and consequently C3-C4 double bond has E stereochemistry. Thus, the 1,3-dienylphosphonates 2 have E, E stereochemistry.5

Diels-Alder reaction of 2 with DEAD
The 1,3-dienylphosphonates 2 were further utilized by investigating their reactivity with diethyl azodicarboxylate (DEAD). Cycloaddition products 3a and 3b were obtained by reacting 2b and 2a with DEAD respectively. Starting either from pure or in situ prepared 1,3-dienylphosphonates 2a-b, the cyclic products 3 were successfully obtained in 85% yield (Scheme 1).

The structure and the stereochemistry of the cycloaddition products were confirmed by 2D-COSY, 1H, and 13C NMR. The cyclohexene-like nature of the six-membered ring system tetrahydropyridazines is generally regarded to have a half chair configuration based on the relationship between vicinal coupling constants and dihedral angles.13 According to 2D-COSY NMR no coupling between the hydrogen on C4 at ~ 4 ppm and the neighboring vinylic hydrogen at 5.84 ppm was observed (this numbering is just to be consistent with 1,3-dienylphosphonates numbering). Thus, based on the Karplus relation, the ~ 0 Hz coupling constant corresponds to a dihedral angle of ~ 90 º between the hydrogens on C4 and C3. On the other hand, the doublet of doublet in the region 5.07 ppm corresponds to the allylic hydrogen on C1 split by phosphorus and hydrogen of C2 at 5.99 ppm with a coupling constant 3JHH of 4.2 Hz that corresponds to a dihedral angle of ~ 45 º between the hydrogen on C1 and the adjacent vinylic hydrogen on C2.13,14
Thus, the methyl group is in a quasi equatorial configuration, whilst the phosphorus group is in a quasi axial configuration as shown in Figure 1.

Regarding the ethyl carboxylate groups on the nitrogen atoms, we suggest that they are trans axial due to steric factors and energetic stability. This proposed stereochemistry of the cycloaddition compounds is consistent with the literature.15 A Newman's projection conformation for compound 3a is presented in Figure 2.

In a similar manner, various other Diels Alder products were obtained in good yields (Table 3) as a result of reacting 1,3-dienylphosphonates 2 with maleic anhydride and maleimide as shown in scheme 2.

CONCLUSIONS
Various 1,3-butadienylphosphontates have been obtained by isomerization of 1-alkynylphosphonates in good isolated yields. This reaction was studied under many different catalysts and conditions, but it proceeded only when [(C6H5)3P]4Pd is used in dioxane at reflux. Interestingly, the products 1,3-butadienylphosphontates reacted efficiently either pure or in a one-pot reaction with DEAD to produce diethyl 3-(diethoxyphosphoryl)-6-alkyl-3,6-dihydropyridazine-1,2-dicarboxylates. Reactions of some of the 1,3-dienes was also satisfactory, in terms of reaction times and yields, with two other dienophiles: maleic anhydride and maleimide.

EXPERIMENTAL
Typical procedure for the synthesis of diethyl (1E,3E)-hexa-1,3-dienylphosphonate (2a). To (0.116 g, 0.1 mmol) of [(C6H5)3P]4Pd dissolved in dioxane (1 mL) in a screw caped vial were added (1mmol) of 1 under nitrogen atmosphere. After reflux for the required amount of time, the solvent was evaporated and the product was isolated by silica gel column chromatography using (30% EtOAc:70% petroleum ether) and was analyzed by GCMS, elemental analysis, and NMR spectroscopy.

Diethyl (1E,3E)-hexa-1,3-dienylphosphonate (2a). 1H NMR (300 MHz, CDCl3, Me4Si): δ 1.01 (3H, CH3CH2CH, t, JHH = 7.5 Hz), 1.29 (6H, OCH2CH3, t, JHH = 7.2 Hz), 2.15 (2H, CH3CH2CH, m), 4.04 (4H, OCH2CH3, qn), 5.51 (1H, CH-P, dd, 2JPH = 19.5 Hz, JHH = 16.8 Hz), 6.00-6.12 (2H, CH2-CH=CH-CH, m), 7.04 (1H, CH-CH=CH-P, ddd, 3JPH = 21.4 Hz, JHH = 17.4 Hz). 31P NMR (125 MHz, CDCl3, Me4Si): δ 21.06. 13C NMR (75.5 MHz, CDCl3, Me4Si): δ 13.0, 16.6 (d, 3JPC = 6.6 Hz), 26.0, 61.8 (d, 3JPC = 5.1 Hz), 114.5 (d, 1JPC = 191.7 Hz), 128.6 (d, 3JPC = 26.7 Hz), 145.5, 149.6 (d, 2JPC = 6.3 Hz). MS (EI): m/z (%) 109.0 (76.9), 111.0 (70.0), 137.0 (76.9), 161.1 (56.5), 189.1 (59.3), 190.2 (49.1), 191.1 (39.8), 218.2 (100). Anal. Calcd for C10H19O3P: C, 54.54; H, 8.64; P, 14.22. Found: C, 54.51; H, 8.55; P, 14.18.

Diethyl (1E,3E)-penta-1,3-dienylphosphonate (2b). Synthesis identical to procedure 2a except refluxed for 3.5 h.1H NMR (300 MHz, CDCl3, Me4Si): δ 1.26 (6H, OCH2CH3, t, JHH = 7.2 Hz), 1.80 (3H, CH3-CH=CH, d, JHH = 6.0 Hz), 4.03 (4H, OCH2CH3, qn), 5.51 (1H, CH-P, dd, 2JPH = 16.8 Hz, JHH = 16.2 Hz), 6.00-6.12 (2H, CH3-CH=CH, m), 7.04 (1H, CH-CH=CH-P, ddd, 3JPH = 21.2 Hz, JHH = 17.2 Hz); 31P NMR (125 MHz, CDCl3, Me4Si): δ 21.20. 13C NMR (75.5 MHz, CDCl3, Me4Si): δ 16.6 (d, 3JPC = 6.6 Hz), 18.7, 61.8 (d, 3JPC = 5.2 Hz), 114.4 (d, 1JPC = 191.5 Hz), 131.0 (d, 3JPC = 26.4 Hz), 138.8, 149.4 (d, 2JPC = 6.0 Hz). MS (EI): m/z (%) 110.9 (32.4), 130.7 (38.5), 132.7 (58.3), 148.0 (55.6), 158.8 (21.3), 175.8 (39.8), 189.0 (14.8), 204.0 (100). Anal. Calcd for C9H17O3P: C, 52.94; H, 8.33; P, 15.20. Found: C, 52.88; H, 8.28; P, 15.16.

Diethyl (1E,3E)-tetradeca-1,3-dienylphosphonate (2c). Synthesis identical to procedure 2b. 1H NMR (300 MHz, CDCl3, Me4Si): δ 0.85 (3Η, CH3-CH2-CH2, t, JHH = 7.2 Hz), 1.29 (6H, OCH2CH3, t, JHH = 6.9 Hz), 1.20-1.40 (16H, CH3-(CH2)8-CH2, overlap), 2.10 (2H, CH2-CH2-CH, q, JHH = 6.9 Hz), 4.04 (4H, OCH2CH3, qn), 5.52 (1H, CH-P, dd, 2JPH = 19.5 Hz, JHH = 17.1 Hz), 6.00-6.10 (2H, CH2-CH=CH, m), 7.04 (1H, CH-CH=CH-P, ddd, 3JPH = 27.9 Hz, JHH = 9.6 Hz, JHH = 4.2 Hz). 31P NMR (125 MHz, CDCl3, Me4Si): δ 21.03. 13C NMR (75.5 MHz, CDCl3, Me4Si): δ 14.3, 16.3 (d, 3JPC = 6.3 Hz), 22.9, 28.9, 29.4, 29.5, 29.6, 29.8, 29.9, 32.1, 33.0, 61.5 (d, 3JPC = 5.4 Hz), 114.1 (d, 1JPC = 192.0 Hz), 129.3 (d, 3JPC = 26.7 Hz), 144.0, 149.4 (d, 2JPC = 6.3 Hz). MS (EI): m/z (%) 124.9 (27.8), 137.8 (45.6), 151.9 (99.5), 160.9 (62.9), 189.0 (70.4), 204.1 (59.3), 217.0 (100), 231.1 (25.0), 259.2 (24.7), 273.2 (21.3), 287.2 (13.7), 301.3 (11.1), 330.3 (50.9). Anal. Calcd for C18H35O3P: C, 65.45; H, 10.61, 9.39. Found: C, 65.40; H, 10.55; P, 9.33.

Diethyl (1E,3E)-6-chlorohexa-1,3-dienylphosphonate (2d). Synthesis identical to procedure 2a except refluxed in toluene for 1.5 h. 1H NMR (300 MHz, CDCl3, Me4Si): δ 1.29 (6Η, OCH2CH3, t, JHH = 7.2 Hz), 2.62 (2H, ClCH2-CH2-CH, q, JHH = 6.9 Hz), 3.56 (2H, ClCH2, t, JHH = 6.9 Hz), 4.06 (4H, OCH2CH3, qn), 5.63 (1H, CH-P, dd, 2JPH = 19.2 Hz, JHH = 17.1 Hz), 6.05-6.23 (2H, CH2-CH=CH, m), 7.05 (1H, CH-CH=CH-P, ddd, JHH = 10.5 Hz, JHH = 3.9 Hz 3JPH = 27.3 Hz). 31P NMR (125 MHz, CDCl3, Me4Si): δ 20.17. 13C NMR (75.5 MHz, CDCl3, Me4Si): δ 16.3 (d, 3JPC = 6.6 Hz), 35.6, 43.1, 61.7 (d, 3JPC = 5.4 Hz), 116.4 (d, 1JPC = 191.5 Hz), 132.0 (d, 3JPC = 27.0 Hz), 138.0, 148.2 (d, 2JPC = 6.0 Hz). MS (EI): MS (EI): m/z (%) 128.8 (16.7), 132.8 (57.4), 146.8 (25.9), 160.9 (100), 189.0 (85.2), 217.0 (94.4), 252.1 (21.3), 254.2 (16.9). Anal. Calcd for C10H18ClO3P: C, 47.52; H, 7.13; Cl, 14.06; P, 12.28. Found: C, 47.47; H, 7.09; Cl, 14.01 P, 12.25.

Diethyl (1E,3E)-hepta-1,3-dienylphosphonate (2e). Synthesis identical to procedure 2a except refluxed for 3 h. 1H NMR (300 MHz, CDCl3, Me4Si): δ 0.91 (3Η, CH3-CH2-CH2, t, JHH = 7.5 Hz ), 1.32 (6H, OCH2CH3, t, JHH = 6.9 Hz), 1.45 (2H, CH3-CH2-CH2, m), 2.12 (2H, CH2-CH2-CH, q, JHH = 7.2 Hz), 4.07 (4H, OCH2CH3, qn), 5.51 (1H, CH-P, dd, 2JPH = 19.5 Hz, JHH = 17.1 Hz), 6.00-6.18 (2H, CH2-CH=CH, m), 7.04 (1H, CH-CH=CH-P, ddd, 3JPH = 28.0 Hz, JHH = 9.6 Hz, JHH = 4.2 Hz). 31P NMR (125 MHz, CDCl3, Me4Si): δ 21.05. 13C NMR (75.5 MHz, CDCl3, Me4Si): δ 13.7, 16.3 (d, 3JPC = 6.6 Hz), 21.9, 34.8, 61.6 (d, 3JPC = 5.2 Hz), 114.3 (d, 1JPC = 191.8 Hz), 129.5 (d, 3JPC = 26.7 Hz), 143.8, 149.4 (d, 2JPC = 6.0 Hz). MS (EI): m/z (%) 110.9 (40.4.9), 132.8 (57.8), 160.9 (78.0), 175.0 (43.1), 189.0 (54.1), 203.0 (41.8), 204.1 (27.9), 232.1 (100). Anal. Calcd for C11H21O3P: C, 56.90; H, 9.05; P, 13.36. Found: C, 56.85; H, 8.99; P, 13.29.

Diethyl (1E,3E)-hexadeca-1,3-dienylphosphonate (2f). Synthesis identical to procedure 2a except refluxed for 2 h. 1H NMR (300 MHz, CDCl3, Me4Si): δ 0.83 (3Η, CH3-CH2-CH2, t, JHH = 7.2 Hz), 1.28 (OCH2CH3, 6 H, t, JHH = 7.2 Hz), 1.15-1.42 (20H, CH3-(CH2)10-CH2, overlap), 2.09 (2H, CH2-CH2-CH, q, JHH = 6.9 Hz), 4.03 (4H, OCH2CH3, qn, JHH = 3.9 Hz), 5.52 (1H, CH-P, dd, 2JPH = 19.5 Hz, JHH = 16.5 Hz), 6.07-6.14 (2H, CH2-CH=CH, m), 7.04 (1H, CH-CH=CH-P, ddd, 3JPH = 35.4 Hz, JHH = 9.6 Hz, JHH = 4.2 Hz). 31P NMR (125 MHz, CDCl3, Me4Si): δ 21.11. 13C NMR (75.5 MHz, CDCl3, Me4Si): δ 14.3, 16.6 (d, 3JPC = 6.3 Hz), 22.6, 28.1, 28.6, 29.1, 29.2, 29.3, 29.4, 29.5, 29.6, 29.7, 31.8, 61.5 (d, 3JPC = 5.4 Hz), 114.1 (d, 1JPC = 192.0 Hz), 129.2 (d, 3JPC = 26.7 Hz), 144.1, 149.3 (d, 2JPC = 6.3 Hz). MS (EI): m/z (%) 110.9 (21.1), 135.0 (32.1), 138.0 (38.5), 151.9 (100), 160.9 (42.2), 189.0 (40.4), 204.2 (36.7), 217.1 (62.4), 259.3 (18.3), 273.3 (16.5), 287.3 (11.9), 315.3 (9.2), 329.5 (9.2),358.5 (39.4). Anal. Calcd for C20H39O3P: C, 67.04; H, 10.89; P, 8.66. Found: C, 66.99.51; H, 10.87; P, 8.63.

Diethyl (1E,3E)-octadeca-1,3-dienylphosphonate (2g). Synthesis identical to procedure 2a. 1H NMR (300 MHz, CDCl3, Me4Si): δ 0.87 (3Η, CH3-CH2-CH2, t, JHH = 7.2 Hz), 1.29 (6H, OCH2CH3, t, JHH = 7.2 Hz), 1.05-1.46 (24H, CH3-(CH2)12-CH2, m, overlap), 2.11 (2H, CH2-CH2-CH, q, JHH = 6.6 Hz), 4.03 (4H, OCH2CH3, qn), 5.34 (1H, CH-P, dd, 2JPH = 19.5 Hz, JHH = 17.1 Hz), 6.07-6.14 (2H, CH2-CH=CH, m), 7.04 (1H, CH-CH=CH-P, ddd, 3JPH = 27.9 Hz, JHH = 9.6 Hz, JHH = 3.9 Hz). 31P NMR (125 MHz, CDCl3, Me4Si): δ 21.08. 13C NMR (75.5 MHz, CDCl3, Me4Si): δ 14.4, 16.6 (d, 3JPC = 6.3 Hz), 22.9, 28.9, 29.4, 29.6, 29.7, 29.8, 29.9, 32.1, 33.0, 61.8 (d, 3JPC = 5.7 Hz), 114.4 (d, 1JPC = 191.7 Hz), 129.5 (d, 3JPC = 26.7 Hz), 144.4, 149.7 (d, 2JPC = 6.0 Hz). MS (EI): m/z (%) 111.0 (23.6), 125.0 (30.9), 138.0 (36.4), 152.0 (100), 153.1 (31.8), 189.1 (33.6), 204.2 (40.0), 217.2 (60.0), 231.2 (17.3), 259.3 (14.5), 273.3 (14.5), 301.4 (6.4), 341.6 (6.2), 357.7 (6.4) 386.8 (38.2). Anal. Calcd for C22H43O3P: C, 68.39; H, 11.14; P, 8.03. Found: C, 68.31; H, 11.10; P, 7.99.

(E)-Diethyl cyclohex-2-enylidenemethylphosphonate (2h). Synthesis identical to procedure 2a. 1H NMR (300 MHz, CDCl3, Me4Si): δ 1.32 (6H, OCH2CH3, t, JHH = 6.9 Hz), 1.60-1.72 (4H, CH2-CH2-CH2-CH2, overlap), 2.12 (2H, CH2-CH2-C, broad t), 2.19 (2H, CH2-CH2-CH, m), 4.07 (4H, OCH2CH3, qn), 5.34 (1H, CH-P, dd, 2JPH = 19.0 Hz, JHH = 18.0 Hz), 6.02 (1H, CH2-CH-C, dd, JHH = 7.4 Hz, JHH = 7.9 Hz ), 6.96 (1H, C-CH=CH, ddd, 3JPH = 22.5 Hz, JHH = 17.4 Hz). 31P NMR (125 MHz, CDCl3 , Me4Si): δ 20.03. 13C NMR (75.5 MHz, CDCl3, Me4Si): δ 16.4 (d, 3JPC = 6.6 Hz), 22.0, 23.8, 26.3, 30.1, 61.6 (d, 3JPC = 5.1 Hz), 109.3 (d, 1JPC = 191.7 Hz), 131.6 (d, 3JPC = 29.2 Hz), 138.3, 152.4 (d, 2JPC = 6.6 Hz); MS (EI): m/z (%) 106.0 (44.4), 135.1 (25.9), 151.0 (9.3), 169.0 (21.8), 187.0 (50.1), 188.1 (94.4), 215.2 (23.1), 216.2 (47.2), 244.2 (100). Anal. Calcd for C12H21O3P: C, 59.02; H, 8.61; P, 12.70. Found: C, 58.97; H, 8.59; P, 12.66.

(E)-Diethyl 3-cyclohexylideneprop-1-enylphosphonate (2i). Synthesis identical to procedure 2a. 1H NMR (300 MHz, CDCl3, Me4Si): δ 1.27 (6H, OCH2CH3, t, JHH = 6.9 Hz), 1.53-1.58 (6H, CH2-(CH2)3-CH2, overlap), 2.18 (2H, CH2-CH2-C, broad t), 2.37 (2H, C-CH2-CH2, broad t), 4.07 (4H, OCH2CH3, qn), 5.54 (1H, CH-P, dd, 2JPH = 20.4 Hz, JHH = 16.8 Hz), 5.90 (1H,C-CH=CH, d, JHH = 11.4 Hz), 6.96 (1H, CH-CH-CH, ddd, 3JPH = 26.4 Hz, JHH = 11.4 Hz, JHH = 4.5 Hz). 31P NMR (125 MHz, CDCl3, Me4Si): δ 21.66. 13C NMR (75.5 MHz, CDCl3 , Me4Si): δ 16.2 (d, 3JPC = 6.4 Hz), 26.3, 27.5, 29.1, 29.9, 37.5, 61.5 (d, 3JPC = 5.1 Hz), 113.8 (d, 1JPC = 191.2 Hz), 121.8 (d, 3JPC = 27.8 Hz), 145.1, 153.6 (d, 2JPC = 6.2 Hz). MS (EI): m/z (%) 120.0 (100), 121.1 (19.1), 122.0 (5.9), 183.0 (4.5), 201.0 (10.0), 229.1 (9.1), 257.3 (31.8), 258.2 (30.0). Anal. Calcd For C13H23O3P: C, 60.47; H, 8.91; P, 12.02. Found: C, 60.42; H, 8.87; P, 11.99.

Synthesis of diethyl 3-(diethoxyphosphoryl)-6-ethylpyridazine-1,2(3H,6H)-dicarboxylate (3a). Method A: To 0.218 g (1mmol) of 2a dissolved in dioxane (1 mL), was added 0.174 g (1 mmol) of diethyl azodicarboxylate (DEAD). After reflux of the reaction mixture for 12 h, the solvent was evaporated and the product was isolated by silica gel column chromatography using a gradient eluent starting from (50% EtOAc:50% petroleum ether) to pure EtOAc, and was analyzed by GCMS, elemental analysis, and NMR spectroscopy.
Method B: After synthesis of 2a as presented above, 0.174 g (1 mmol) of diethyl azodicarboxylate was in situ added to the reaction mixture. The mixture was refluxed for 12 h, then the solvent was evaporated and the product was isolated by silica gel column chromatography using a gradient eluent starting from (50% EtOAc:50% petroleum ether) to pure EtOAc, and was analyzed by GCMS, elemental analysis, and NMR spectroscopy.

Diethyl 3-(diethoxyphosphoryl)-6-ethylpyridazine-1,2(3H,6H)-dicarboxylate (3a). 1H NMR (300 MHz, CD3OD, Me4Si): δ 0.91 (3Η, CH3-CH2-CH, t, JHH = 7.5 Hz), 1.13-1.41 (12H, OCH2CH3, COOCH2CH3, overlap), 1.93 (2H, CH3-CH2-CH, m), 3.95-4.60 (9H, CH3-CH2-CH, OCH2CH3, COOCH2CH3, overlap), 5.07 (1H, CH-P, dd, 2JPH = 25.2 Hz, JHH = 4.2 Hz), 5.84 (1H, CH2-CH-CH=CH, m), 5.99 (1H, CH=CH-CH-P, m). 31P NMR (125 MHz, CDCl3, Me4Si): δ 19.04. 13C NMR (75.5 MHz, CDCl3, Me4Si): δ 8.49, 14.3, 16.2 (d, 3JPC = 6.4 Hz), 25.7, 51.9 (d, 1JPC = 119.5 Hz), 56.6, 62.4 (d, 3JPC = 6.2 Hz), 63.2, 128.8 (d, 3JPC = 12.1 Hz), 131.9 (d, 2JPC = 12.1 Hz). MS (EI): m/z (%) 66.9 (9.2), 80.8 (83.5), 94.0 (11.3), 108.9 (38.5), 111.0 (17.4), 136.9 (80.7), 153.0 (33.9), 155.0 (9.2), 183.0 (100), 184.2 (11.9), 211.1 (11.9), 255.2 (47.7), 256.3 (5.5), 392.5 (1.8). Anal. Calcd For C16H29N2O7P: C, 48.98; H, 7.40; N, 7.14 P, 7.91. Found: C, 48.88; H, 7.36; N, 7.11 P, 7.87; Isolated yield: 333 mgr, 85%.

Diethyl 3-(diethoxyphosphoryl)-6-methylpyridazine-1,2(3H,6H)-dicarboxylate (3b). Synthesis identical to procedure 3a. 1H NMR (300 MHz, CD3OD, Me4Si): δ 1.13-1.41 (12H, OCH2CH3, COOCH2CH3, overlap), 1.59 (3H, CH3-CH, d, JHH = 6.9 Hz), 3.95-4.40 (9H, CH3-CH, OCH2CH3, COOCH2CH3, overlap), 5.33 (1H, CH-P, dd, 2JPH = 20.4 Hz, JHH = 4.2 Hz), 5.75 (1H, CH2-CH-CH=CH, m), 5.95 (1H, CH=CH-CH-P, m). 31P NMR (125 MHz, CDCl3, Me4Si): δ 19.06. 13C NMR (75.5 MHz, CDCl3, Me4Si): δ 14.4, 16.3 (d, 3JPC = 6.4 Hz), 20.4, 51.0, 52.3 (d, 1JPC = 119.5 Hz), 62.5 (d, 3JPC = 6.2 Hz), 63.2, 128.4 (d, 3JPC = 12.0 Hz), 132.0 (d, 2JPC = 10.0 Hz). MS (EI): m/z (%) 53.0 (10.9), 81.0 (51.5), 95.0 (21.8), 123.0 (59.4), 153.0 (16.3), 169.0 (100), 197.0 (5.9), 207.0 (15.8), 241.0 (26.7), 378.0 (1.1). Anal. Calcd For C15H27N2O7P: C, 47.62; H, 7.14; N, 7.41 P, 8.20. Found: C, 47.57; H, 7.12; N, 7.37 P, 8.17. Isolated yield: 321 mgr, 85%.

Diethyl 7-ethyl-1,3-dioxo-1,3,3a,4,7,7a-hexahydroisobenzofuran-4-ylphosphonate (4a). Identical to 3a except the addition of maleic anhydride and refluxing for 6 hrs. 1H NMR (300 MHz, CDCl3, Me4Si): δ 0.92 (3Η, CH3CH2CH, t, JHH = 7.1 Hz), 1.26 (6H, OCH2CH3, t, JHH = 7.5 Hz), 1.28 (2Η, CH3CH2CH, m), 2.24 (1H, CH2CHCHCO, dd, JHH = 7.5 Hz, JHH = 4.5 Hz), 2.51 (1H, CH3CH2CH, m), 3.39 (1H, COCHCHP, m), 3.47 (1H, CHP, m), 4.10 (4H, OCH2CH3, m), 5.66 (1H, CH2CH-CH=CH, dd, JHH = 6.4 Hz, JHH = 4.5 Hz), 5.81 (m, CH=CH-CHP, 1H). 13C NMR (75.5 MHz, CDCl3, Me4Si): δ 15.2, 16.2 (d, 3JPC = 4.9 Hz), 21.5, 32.1, 33.0 (d, 2JPC = 7.9 Hz), 42.2, 43.1 (d, 1JPC = 160.0 Hz), 60.9 (d, 2JPC = 8.1 Hz), 129.0, 136.2 (d, 2JPC = 8.0 Hz), 176.7, 177.4. 31P NMR (125 MHz, CDCl3, Me4Si): δ 31.55. MS (EI): m/z (%) 79.0 (36.0), 91.0 (100), 105.0 (85.0), 125.0 (94.0), 152.0 (59.0), 173.0 (31.0), 187.0 (22.0), 201.0 (28.0), 229.0 (69.0), 316.0 (11.0). Anal. Calcd for C14H21O6P: C, 53.16; H, 6.69; P, 9.79. Found: C, 53.11; H, 6.68; P, 9.78.

Diethyl 7-methyl-1,3-dioxo-1,3,3a,4,7,7a-hexahydroisobenzofuran-4-ylphosphonate (4b). Identical to 4a. 1H NMR (300 MHz, CDCl3 , Me4Si): δ 1.16 (3Η, CH3CH, d, JHH = 7.3 Hz), 1.28 (6H, OCH2CH3, t, JHH = 7.3 Hz), 2.25 (1H, CH3CHCHCO, dd, JHH = 7.6 Hz, JHH = 4.9 Hz), 2.52 (1H, CH3CH, m), 3.43 (1H, COCHCHP, m), 3.50 (1H, CHP, m), 4.07 (4H, OCH2CH3, m), 5.64 (1H, CH3CH-CH=CH, dd, JHH = 6.8 Hz, JHH = 4.6 Hz), 5.83 (CH=CH-CHP, H2 m). 13C NMR (75.5 MHz, CDCl3 , Me4Si): δ 15.1, 16.2 (d, 3JPC = 5.6 Hz), 31.8, 32.6 (d, 2JPC = 8.6 Hz), 40.1, 40.7 (d, 1JPC = 145.9 Hz), 62.2 (d, 2JPC = 8.6 Hz), 128.2, 133.1 (d, 2JPC = 7.1 Hz), 172.3, 173.4. 31P NMR (125 MHz, CDCl3, Me4Si): δ 29.20. MS (EI): m/z (%) 51.0 (14.9), 77.0 (63.3), 91.0 (100), 109.0 (97.0), 119.0 (33.7), 138.0 (92.1), 155.0 (19.8), 173.0 (11.9), 302.0 (10.9). Anal. Calcd for C13H19O6P: C, 51.66; H, 6.34; P, 10.25. Found: C, 51.61; H, 6.33; P, 10.24.

Diethyl 7-dodecyl-1,3-dioxo-1,3,3a,4,7,7a-hexahydroisobenzofuran-4-ylphosphonate (4c). Identical to 4a. 1H NMR (300 MHz, CDCl3, Me4Si): δ 0.90 (3Η, CH3CH2, t, JHH = 7.4 Hz), 1.24 (6H, OCH2CH3, t, JHH = 7.7 Hz), 1.26-1.36 (20H, CH3(CH2)10CH2, overlap), 1.31 (2H, CH2CH2CH, m) 2.26 (1H, CH2CHCHCO, dd, JHH = 8.1 Hz, JHH = 4.7 Hz), 2.50 (1H, CH2CH, m), 3.36 (1H, COCHCHP, m), 3.44 (1H, CHP, m), 4.08 (4H, OCH2CH3, m), 5.63 (1H, CH2CH-CH=CH, dd, JHH = 6.4 Hz, JHH = 5.0 Hz), 5.82 (1H, CH=CH-CHP, m). 13C NMR (75.5 MHz, CDCl3, Me4Si): δ 15.0, 16.1 (d, 3JPC = 5.1 Hz), 21.3, 21.4, 25.4, 26.4, 27.2, 29.3, 30.4, 30.8, 33.0, 36.4 (d, 2JPC = 8.0 Hz), 36.6, 44.4, 45.1 (d, 1JPC = 159.9 Hz), 61.6 (d, 2JPC = 8.7 Hz), 128.7, 136.8 (d, 2JPC = 8.4 Hz), 171.5, 171.8. 31P NMR (125 MHz, CDCl3, Me4Si): δ 30.83. MS (EI): m/z (%) 163.0 (75.2), 178.1 (59.6), 191.1 (100), 205.1 (35.8), 219.1 (45.0), 233.2 (42.2), 247.2 (31.2), 261.2 (27.5), 275.3 (23.9), 303.4 (20.2), 331.5 (23.9), 360.7 (43.1), 411.4 (2.1), 456.2 (0.1). Anal. Calcd for C24H41O6P: C, 63.14; H, 9.05; P, 6.78. Found: C, 63.05; H, 9.04; P, 6.77.

Diethyl 7-decyl-1,3-dioxo-1,3,3a,4,7,7a-hexahydroisobenzofuran-4-ylphosphonate (4d). Identical to 4a. 1H NMR (300 MHz, CDCl3, Me4Si): δ 0.94 (3Η, CH3CH2, t, JHH = 8.4 Hz), 1.23-1.34 (16H, CH3(CH2)8CH2, overlap), 1.27 (6H, OCH2CH3, t, JHH = 8.2 Hz), 1.30 (2H, CH2CH2CH, m) 2.26 (1H, CH2CHCHCO, dd, JHH = 8.2 Hz, JHH = 5.0 Hz), 2.52 (1H, CH2CH, m), 3.33 (1H, COCHCHP, m), 3.44 (1H, CHP, m), 4.08 (4H, OCH2CH3, m), 5.63 (1H, CH2CH-CH=CH, dd, JHH = 6.3 Hz, JHH = 5.1 Hz), 5.78 (1H, CH=CH-CHP, m). 13C NMR (75.5 MHz, CDCl3, Me4Si): δ 15.7, 16.9 (d, 3JPC = 5.2 Hz), 22.5, 27.8, 29.1, 29.2, 29.3, 29.4, 30.8, 31.6, 38.1 (d, 2JPC = 8.8 Hz), 39.9, 43.6, 46.1 (d, 1JPC = 161.0 Hz), 64.2 (d, 2JPC = 10.0 Hz), 131.2, 139.0 (d, 2JPC = 8.7 Hz), 170.6, 171.9. 31P NMR (125 MHz, CDCl3, Me4Si): δ 30.73. MS (EI): m/z (%) 55.0 (16.3), 91.0 (84.8), 105.0 (43.3), 108.0 (25.2), 111.0 (34.4), 125.0 (90.4), 138.0 (33.9), 152.0 (100), 173.0 (34.3), 199.0 (17.0), 207.0 (19.5), 229.0 (54.6), 301.0 (27.8), 428.2 (4.8). Anal. Calcd for C22H37O6P: C, 61.67; H, 8.30; P, 7.23. Found: C, 61.61; H, 8.70; P, 7.22.

Diethyl 7-methyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-ylphosphonate (4e). Identical to 4a except using maliemide (1H-pyrrole-2,5-dione). 1H NMR (300 MHz, CDCl3, Me4Si): δ 1.14 (3Η, CH3CH, d, JHH = 8.1 Hz), 1.26 (6H, OCH2CH3, t, JHH = 7.9 Hz), 2.27 (1H, CH3CHCHCO, dd, JHH = 7.9 Hz, JHH = 4.7 Hz), 2.54 (1H, CH3CH, m), 3.41 (1H, COCHCHP, m), 3.49 (1H, CHP, m), 4.09 (4H, OCH2CH3, m), 5.65 (1H, CH3CH-CH=CH, dd, JHH = 6.9 Hz, JHH = 4.7 Hz), 5.82 (1H, CH=CH-CHP, m), 8.95 (1H, NH s, broad). 13C NMR (75.5 MHz, CDCl3, Me4Si): δ 15.3, 16.8 (d, 3JPC = 4.9 Hz),, 32.0, 35.1 (d, 2JPC = 9.2 Hz), 44.3, 46.3 (d, 1JPC = 150.1 Hz), 66.1 (d, 2JPC = 9.5 Hz), 130.1, 133.4 (d, 2JPC = 8.9 Hz), 177.7, 178.6. 31P NMR (125 MHz, CDCl3, Me4Si): δ 31.45. MS (EI): m/z (%) 18.0 (65.9), 28.1 (70.2), 29.1 (25.9), 65.0 (36.4), 77.0 (29.7), 83.0 (30.0), 91.0 (96.5), 92.0 (34.0), 93.0 (38.3), 97.0 (45.0), 111.0 (100), 125.4 (65.4), 138.0 (57.0), 152.0 (66.1), 164.0 (13.5), 256.0 (10.3), 301.1 (35.5). Anal. Calcd for C13H20NO5P: C, 51.83; H, 6.69; N, 4.65; P, 10.28. Found: C, 51.76; H, 6.68; N, 4.64; P, 10.27.

Diethyl 7-dodecyl-1,3-dioxo-2,3,3a,4,7,7a-hexahydro-1H-isoindol-4-ylphosphonate (4f). 1H NMR (300 MHz, CDCl3, Me4Si): δ 0.91 (3Η, CH3CH2CH2, t, JHH = 7.5 Hz), 1.22 (2Η, CH2CH2CH, m), 1.25- 1.35 (20H, CH3(CH2)10CH2, overlap), 1.23 (6H, OCH2CH3, t, JHH = 7.9 Hz), 2.25 (1H, CH2CHCHCO, dd, JHH = 7.9 Hz, JHH = 4.6 Hz), 2.51 (1H, CH2CH, m), 3.35 (1H, COCHCHP, m), 3.45 (1H, CHP, m), 4.11 (4H, OCH2CH3, m), 5.67 (1H, CH2CH-CH=CH, dd, JHH = 6.3 Hz, JHH = 4.2 Hz), 5.81 (1H, CH=CH-CHP, m), 9.13 (1H, NH s, broad). 3C NMR (75.5 MHz, CDCl3, Me4Si): δ 14.9, 16.0 (d, 3JPC = 4.6 Hz), 21.4, 23.9, 24.2, 26.5, 27.3, 28.9, 30.1, 32.5, 33.3, 36.8 (d, 2JPC = 7.8 Hz), 36.9, 44.9, 45.8 (d, 1JPC = 166.9 Hz), 63.1 (d, 2JPC = 9.9 Hz), 128.1, 135.9 (d, 2JPC = 8.9 Hz), 177.6, 178.5. 31P NMR (125 MHz, CDCl3, Me4Si): δ 31.47. MS (EI): m/z (%) 163.0 (56.9), 178.1 (55.0), 191.1 (100), 205.1 (34.9), 219.1 (43.1), 233.2 (40.4), 247.2 (33.0), 261.2 (27.5), 275.3 (22.9), 289.3 (20.2), 303.4 (18.3), 317.4 (20.2), 331.5 (18.3), 345.5 (10.1), 360.7 (28.4.1), 410.5 (2.9), 455.2 (0.2). Anal. Calcd for C24H42NO5P: C, 63.27; H, 9.29; N, 3.07; P, 6.80. Found: C, 63.21; H, 9.28; N, 3.07; P, 6.79.

Diphenyl 7-ethyl-1,3-dioxo-1,3,3a,4,7,7a-hexahydroisobenzofuran-4-ylphosphonate (4g). Identical to 4a. 1H NMR (300 MHz, CDCl3, Me4Si): δ 0.91 (3Η, CH3CH2CH, t, JHH = 7.5 Hz), 1.29 (2Η, CH3CH2CH , m), 2.22 (1H, CH2CHCHCO, dd, JHH = 8.1 Hz, JHH = 5.1 Hz), 2.53 (1H, CH2CH, m), 3.35 (1H, COCHCHP, m), 3.45 (1H, CHP, m), 5.61 (1H, CH2CH-CH=CH, dd, JHH = 6.1 Hz, JHH = 4.3 Hz), 5.79 (1H, CH=CH-CHP, m), 7.12-7.31 (10H, C6H5 Aromatic, overlap); 13C NMR (75.5 MHz, CDCl3, Me4Si): δ 15.0, 16.6, 21.0 32.9, 33.8 (d, 2JPC = 8.8 Hz), 41.0, 43.2 (d, 1JPC = 171.0 Hz), 120.4 (d, 3JPC = 10.1 Hz), 120.5, 125.8, 132.1, 134.2 (d, 2JPC = 9.1 Hz), 150.1, 178.2, 178.8; 31P NMR (125 MHz, CDCl3, Me4Si): δ 28.41. MS (EI): m/z (%) 28.0 (31.9), 77.0 (30.8), 92.0 (35.2), 95.0 (53.8), 105.0 (100), 133.0 (6.6), 207.0 (8.8), 263.0 (25.3), 291.0 (6.6), 319.0 (46.2), 412.0 (2.2). Anal. Calcd for C22H21O6P: C, 64.08; H, 5.13; P, 7.51. Found: C, 64.04; H, 5.13; P, 7.50.

ACKNOWLEDGEMENTS
AA and AAAQ thank the School of Pharmacy for fellowships. This work was partially funded by the Israel Science Foundation and by a grant from Applied Grants of the Hebrew University.

References

1. S. F. Martin and P. J. Garrison, Synthesis, 1982, 394. CrossRef
2. T. Minami, S. Tokomasu, R. Mimasu, and I. Hirao, Chem. Lett., 1985, 1099. CrossRef
3. T. Okauchi, T. Kakiuchi, N. Kitamura, T. Utsunomiya, J. Ichikawa, and T. Minami, J. Org. Chem., 1997, 62, 8419. CrossRef
4. S. D. Darling, F. N. Muralidharan, and V. B. Muralidharan, Tetrahedron Lett., 1979, 20, 2761. CrossRef
5. A. A. Quntar and M. Srebnik, Org. Lett., 2001, 3, 1379. CrossRef
6. Y. Shen, G.-F. Jiang, and J. Sun, J. Chem. Soc., Perkin Trans. 1, 1999, 3495. CrossRef
7. L.-B. Han, Y. Ono, and H. Yazawa, Org. Lett., 2005, 7, 2909. CrossRef
8. T. Minami and J. Motoyoshiya, Synthesis, 1992, 333. CrossRef
9. B. Iorga, F. Eymery, D. Carmichael, and P. Savignac, Eur. J. Org. Chem., 2000, 3103. CrossRef
10. R. Shintani, W.-L. Duan, S. Park, and T. Hayashi, Chem. Commun., 2006, 3646, and cited references. CrossRef
11. H. Yasui, H. Yorimitsu, and K. Oshima, Synlett., 2006, 1783. CrossRef
12. Marchand-Brynaert has reported a similar reaction as unpublished data in his review article: R. Robiette, N. Defacqz, D. Peeters, and J. Marchand-Brynaert, Curr. Org. Synth., 2005, 2, 453, but it still has not appeared in print. CrossRef
13. E. Garbisch, J. Am. Chem. Soc., 1964, 86, 5561. CrossRef
14. R. Daniels and K. Roseman, Tetrahedron Lett., 1966, 1335. CrossRef
15. E. W. Bittner and J. T. Gerig, J. Am. Chem. Soc., 1972, 94, 913. CrossRef