[Related articles/posters: 112 077 119 ]

A Direct Route to 4,5-Diazaphthalimides by the Unprecedented Reaction of Maleimides with s-Tetrazines

Liu, Ligong; Warrener, Ronald N.

N-substituted maleimides are shown to react at moderately high temperature with two equivalents of 3,6-disubstituted-s-tetrazine to form 4,5-diazaphthalimides in a one-pot reaction, where the s-tetrazine acts as both cycloaddition reagent and as oxidant. Facile ring-opening of the maleimide ring occurs with nucleophiles; both reactions have been exploited to produce linked di-(2'-pyridyl)-pyridazine (DPP) ligand and bis-ligand systems.

Background

It was recognised by earlier pioneers in the field of s-tetrazine chemistry that cycloadditions involving these reagents were distinctly different from regular dienes.[1-6] Nenitzescu [3] and Sauer [4] were able to put the early reports of Carboni and Lindsey [5] onto a quantitative basis; typically they found that 3,6-dicarbomethoxy-s-tetrazine reacted with the electron-rich dienophile a-morpholinostyrene 4.7 x 10⁵ faster than the electron-poor dienophile acrylonitrile. Indeed, classical electron-poor dienophiles like DMAD, diethyl azodicarboxylate, tetracyanoethylene and even the archetype dienophile maleic anhydride failed to react. Clearly the s-tetrazines were members of the inverse electron-demand Diels-Alder dienes.

When we conducted reactions of 3,6-di(2'-pyridyl)-s-tetrazine (DPT) 2a [7,8] with ring-strained dienophiles such as 1 we noted that these dienophiles reacted rapidly in chloroform solution at room temperature,[9] however, maleimides, DMAD, benzoquinones and maleic anhydride did not react under these conditions. Accordingly, when we were generating highly-reactive isobenzofurans 4, by the s-tetrazine induced fragmentation of 1,4-epoxynaphthalenes 1, it was common to include an electron-poor dienophile such as the N-substituted maleimide 6 in the reaction mixture at the start of the reaction (Scheme 1).[9,10] This was based on the knowledge that 6 was not reactive towards the inverse electron-demand DPT 2a but would react with the normal electron-demand isobenzofuran 4 as it was generated.

We had observed that the reaction of DPT 2a was slowed down by introduction of substituents at the bridgehead position of the 1,4-epoxynaphthalene 1, but a variety of substituents could be tolerated, including electron-donating, electron-withdrawing and sterically demanding groups like the trimethylsilyl group, although the TMS derivative of 1 did require warming to 50 ^oC to ensure reaction. The corresponding 1-substituted IBF 4 could be readily generated under these conditions and trapped as their Diels-Alder adduct. N-methyl maleimide 6a was a common trapping agent as the singlet methyl resonance was clearly detected in the ¹H NMR spectrum and its chemical shift characteristic of the exo v endo stereochemistry of the products. When we sought a route to 1,3-bis(trimethylsilyl) isobenzofuran by reacting 1,4-bis(trimethylsilyl)-1,4-epoxynaphthalene with DPT 2a, we conducted the reaction in the presence of N-methylmaleimide. Because no reaction occurred at room temperature, the mixture was heated under reflux in toluene and it was then that we discovered that N-methyl maleimide 6a reacted with DPT 2a.

Results and Discussion

We now report that this is a general reaction and that maleimides can be made to react with s-tetrazine 2 at higher temperatures to produce cycloadducts: further, s-tetrazine 2 takes on a second role in this reaction, that of oxidant, thereby providing access to N-substituted-4,5-diazaphthalimides 9 in a one-pot reaction (Scheme 2).

Reaction of DPT 2a with one equivalent of N-methyl maleimide 6a in toluene at reflux produces a mixture of products: the 4,5-diazaphthalimide 9a (50%), the dihydro-s-tetrazine 10a (50%) and unchanged maleimide 6a (50%). Increasing the proportion of DPT 2a to two equivalents produces a high yield of the 4,5-diazaphthalimide 9a and one equivalent of reduced DPT 10a. This results is in accord with the reaction pathway shown in Scheme 2, where the initially-formed 4,5-dihydropyridazine 8a (or its rearranged 1,4-dihydro-isomer) is oxidised by DPT 2a to produce the observed 4,5-diazaphthalimide 9a.

The reaction is general and other maleimide (6b,c) or s-tetrazine (2b,c) derivatives undergo analogous reactions.

As the 4,5-diazaphthalimides 9a-c all contain the 3,6-di(2-pyridyl)-pyridazine (DPP) ligand, we also explored the potential of this reaction to produce linked bis-DPPs. Accordingly, the commercially available 1,2-bis(maleimido)-benzene 11 was reacted with DPT 2a under these vigorous conditions to form the linked bis-DPP 12, isolated in crystalline form m.p. 334-335 ^oC. The ortho-relationship of the DPP ligands brings the substituents too close to one another for them to be planar with the benzene ring and a twisted conformation must be adopted as shown in Scheme 3. The observation of total eleven carbons, including one carbonyl (d 163.65 ppm) and ten aromatic (d 124-155 ppm) carbons, could only be explained by this conformation due to its C2v symmetry.

The maleimide ring in these 4,5-diazaphthalimides 9a-c is especially prone to nucleophilic attack owing to the strong electron-withdrawing effect of the pyridazine ring which is further reinforced by the a-pyridyl substituents. Conversion to the ring-opened product 13 occurs, for example simply by washing solid 9b with cold methanol in a filter funnel! Indeed, when chromatographic separation of the phthalimides was conducted and the eluant contained methanol (eg Method A, Experimental section), the ring-opened products 13 (Scheme 4) were obtained rather than the phthalimides 9. Similarly, n-propylamine and glycine ethyl ester gave the ring-opened bis-amide 14a and 14b, respectively. The reactions completed quickly and were followed by the characteristic colour change, i.e., the bright-yellow reactants 9 turned to the colourless products.

We also invested the reaction of DPT 2a with maleic anhydride and found that no cycloaddition products were detected under the above conditions. When prolonging reaction times or increasing reaction temperatures were used we obtained charcolized reaction mixtures from which dihydro-s-tetrazine 10a was obtained as a major product. This suggested that DPT 2a was being reduced, again indicative its role as an oxidising agent. In order to assess its dehydrogenation ability DPT 2a was reacted with acenaphthene in refluxing benzene, but no reaction was observed (¹H NMR monitor) after 46 hours; significantly DDQ effects this dehydrogenation without difficulty. Aromatisation of dihydro-s-tetrazine 10a using DDQ in deuteriochloroform was very fast at room temperature and formation of DPT 2a was complete within one minute (¹H NMR monitor).

Experimental

Melting point were measured with a Gallenkamp melting pointing apparatus in open capillaries and were uncorrected. Infrared spectra were measured on a Perkin Elmer 1600 spectrometer using a pressed potassium bromide disc. Mass spectra (EI, 70 ev) were recorded on Shimadzu GC MS-QP2000A Spectrometer. Combustion microanalysis were performed on Eager 200 instrument. High resolution mass spectra (HRMS-EI) were recorded on a Micromass AutoSpec spectrometer at 70 ev. NMR spectra, ¹H, ¹³C (Proton Coupling and Proton Broad Band Decoupling), HMQC (¹H-detected Heteronuclear Multiple Quantum Coherence) experiments, were recorded on a Bruker AMX 300 MHz Spectrometer in deuteriochloroform solution (unless specified otherwise). The chemical shifts reported in d units from internal reference, i.e. 0.000 ppm for tetramethylsilane (TMS) in CDCl₃, 2.050 ppm for CHD₂COCD₃ in acetone-d6, 3.350 ppm (¹H) or 49.30 ppm (¹³C) for CHD₂OH in methanol-d4, and 2.600 ppm (¹H) or 39.50 ppm (¹³C) for CHD₂SOCD₃ in DMSO-d6. The proton assignment of 2'-pyridyl substituted groups was given in Table 2 and 3 and omitted below. The starting compounds were prepared by a standard method: 2a [7,11], 2c [12], 6c [13]. TLC was Merck TLC aluminium sheets silica gel 60 F254. Column chromatography was operated on Merk silica gel 60.

Diels-Alder reactions of s-tetrazines and maleimides:

General Procedure: One equivalent N-substitutes maleimide 6a,b,c with two equivalents of s-tetrazine 2a,b,c in sutable solvent was refluxed and stirred until the typical violet colour of the s-tetrazine disappeared. Bis-maleimide 11 required 4 equivalents of DPP 2a. Products were obtained by removal of solvent under reduced pressure followed by crystallisation or silica gel column chromatography. Reaction conditions, purification methods and results were summarised in Table 1.

Nucleophilic addition on 4,5-diazaphthalimides 9a-c:

General Procedure: 4,5-diazaphthalimides 9a-c was stirred at room temperature for one to two hours with excess nucleophile, i.e. methanol, n-propylamine or glycine ethyl ester (in dichloromethane solution). Concentration and crystallisation from methanol (for 13a-c) or acetone (for 14a,b) provided crystalline products in high yield (95-100%).

9a yellow needle from acetone, m.p. 222.4-223.8 ^oC.

IR (cm^-1): 1724 (s, CO), 1586 (m), 1436 (m), 1374 (m), 1362 (m), 1270 (m), 1014 (m), 992 (m), 798(m), 752 (m); ¹H NMR: 3.217 (s, 3H, NCH₃); ¹³C NMR: 24.85 (NCH₃), 124.95 (Py-C3'/3''), 125.09 (Py-C5'/C5''), 127.78 (C4/5), 136.85 (Py-C4'/C4''), 149.71 (Py-C6'/C6''), 152.06 (Py-C2'/C2''), 155.27 (C3/6), 165.48 (CO); EIMS m/e (relative intensity) 317 (97), 289 (25), 260 (10), 246 (20), 218 (21), 205 (35), 206 (45), 204 (100), 203 (49), 178 (11), 177 (21), 176 (24), 152 (15), 151 (23), 150 (14), 138 (10), 102 (20), 78 (47). Anal. Calcd for C17H11N5O2.0.25H2O: C, 63.45; H, 3.60; N, 21.76. Found: C, 63.04; H, 3.31; N, 21.76.

9b yellow needle from acetone, m.p. 197.9-198.9 ^oC.

IR (cm^-1): 1734 (s, CO-sym.), 1717 (s, CO-asym.), 1587 (m), 1441 (m), 1395 (m), 1375 (m), 1347 (m), 1047 (m), 993 (m), 800 (m), 754 (m); ¹H NMR: 1.282 (t, 3H, J=7.23 Hz, NCH₂CH₃), 3.782 (q, 2H, J=7.23 Hz, NCH₂CH₃); (acetone-d6): 1.231 (t, 3H, J=7.20 Hz, NCH₂CH₃), 3.717 (q, 2H, J=7.20 Hz, NCH₂CH₃); ¹³C NMR: 14.14 (NCH₂CH₃), 34.79 (NCH₂CH₃), 125.70 (Py-C3'/3''), 125.73 (Py-C5'/5''), 128.40 (C4/5), 137.54 (Py-C4'/4''), 150.31 (Py-C6'/6''), 152.69 (Py-C2'/2''), 155.90 (C3/6), 165.94 (CO); EIMS m/e (relative intensity) 331 (100), 303 (20), 274 (11), 246 (23), 204 (70), 176 (11), 151 (11), 102 (13), 78 (30). Anal. Calcd for C18H13N5O2: C, 65.25; H, 3.95; N, 21.14. Found: C, 65.08; H, 3.87; N, 21.16.

9c yellow needle from acetone, m.p. 304-306 ^oC (fast heating).

IR (cm^-1): 1734 (s, CO), 1566 (w), 1492 (m), 1384 (m), 1374 (m), 1129 (m), 991 (w), 799 (m), 759 (m); ¹H NMR: 7.361-7.532 (m, 5H, 5xPhCH); ¹³C NMR: 125.76 (Py-C3'/3''), 125.81 (Py-C5'/5''), 127.45 (2xPh-ortho), 128.01 (C4/5), 129.48(Ph-para), 129.85 (2xPh-meta), 131.64 (Ph-ipso), 137.63 (Py-C4'/4''), 150.31 (Py-C6'/6''), 152.52 (Py-C2'/2''), 156.18 (C3/6), 165.09 (CO); EIMS m/e (relative intensity) 379 (100), 322 (10), 204 (70), 144 (15), 78 (18). Anal. Calcd for C22H13N5O2: C, 69.64; H, 3.45; N, 18.46. Found: C, 69.87; H, 3.30; N, 18.50.

9d yellow crystal from acetone, m.p. 205.9-206.7 ^oC.

¹H NMR: 3.29 (s, 3 H, NCH₃), 8.05 (d, 4 H, J=3.6 Hz, Py-H3'/5' and Py-H3''/5''), 8.91 (d, 4 H, J=3.6 Hz, Py-H2'/6' and Py-H2''/6''); ¹³C NMR: 25.79, 124.85, 127.05, 140.62, 150.91, 154.57, 166.52; HRMS-EI calcd for C17H11N5O2: 317.0913, found 317.0912.

9e orange crystal from acetone, m.p. 292.4-293.9 ^oC.

¹H NMR: 2.83 (s, 6 H, 2xSCH₃), 3.19 (s, 3 H, NCH₃); ¹³C NMR: 13.14 (SCH₃), 24.82 (NCH₃), 125.23 (C4/5), 155.05 (C3/6), 167.12 (CO); HRMS-EI calcd for C9H9N3O2S2: 255.0136, found 255.0137.

12 yellow powder from acetone, m.p. 333.5-334.5 ^oC (decomp.).

IR (cm^-1): 1748 (s, CO), 1588 (w), 1506 (m), 1391(m), 1380 (m), 998 (w); ¹H NMR: 7.573-7.592 (m, 4H, 4xPhCH); (DMSO-d6): 7.677-7.739 (m, 6H, 2xPhCH and 4xPy-H5), 7.764-7.820 (m, 2H, 2xPhCH); ¹³C NMR (DMSO-d6): 124.90, 124.94 (Py-C5/3), 127.59, 128.65 (Ph-ortho and Ph-meta), 129.65, 129.89 (Ph-ipso and pyridazine-C4/5), 136.71 (Py-C4), 149.44 (Py-C6), 151.51 (Py-C2), 154.64 (pyridazine-C3/6), 163.65 (CO). Anal. Calcd for C38H20N10O4.2H2O: C, 63.69; H, 3.38; N, 19.54. Found: C, 63.69; H, 3.23; N, 19.07.

13a colourless rod from methanol, 100% yield. m.p. 191 ^oC (decomp., fast heating).

IR (cm^-1): 3312 (sharp, m, NH), 1736 (s, CO-O), 1674 (s, CO-N), 1584 (m), 1570 (m), 1560 (m), 1378 (m), 1271 (m), 1203 (m), 1078 (m), 996 (m), 974 (m), 797 (m), 746 (m); ¹H NMR: 2.950 (d, 3H, J=4.86Hz, NCH₃), 3.889 (s, 3H, OCH₃), 6.485 (br q, 1H, J=4.86Hz, NH); ¹³C NMR: 26.82 (NCH₃), 52.94 (OCH₃), 123.19, 124.15, 124.61, 124.87 (Py-C5'/5'', Py-C3'/3''), 130.01, 133.02 (C4/5), 137.11, 137.23 (Py-C4'/4''), 148.73, 148.93 (Py-C6'/6''), 152.59, 153.69 (Py-C2'/2''), 154.47, 155.52 (C3/6), 165.30, 166.51 (2xCO); EIMS m/e (relative intensity) 349 (8), 348 (18), 320 (38), 319 (83), 318 (27), 317 (51), 291(18), 288 (19), 277 (16), 206 (43), 205 (89), 204 (55), 203 (26), 178 (11), 177 (11), 176 (12), 152 (13), 151 (15), 144 (11), 130 (15), 103 (28), 102 (24), 78 (100). Anal. Calcd for C18H15N5O3: C, 61.89; H, 4.33; N, 20.05. Found: C, 61.80; H, 4.25; N, 20.07.

13b colourless rod from methanol, 100% yield. m.p. 177.6-178.6 ^oC (decomp.).

IR (cm^-1): 3244 (sharp, s, NH), 1733 (s, CO-O), 1668 (s, CO-N), 1589 (s), 1576 (m), 1546 (m), 1429 (s), 1384 (s), 1304 (s), 1286 (s), 1275 (s), 1200 (s), 996 (m), 963 (m), 780 (m); ¹H NMR: 1.217 (t, 3H, J=7.26Hz, NCH₂CH₃), 3.703 (dq, 2H, J=7.26Hz, 5.88Hz, NCH₂CH₃), 3.906 (s, 3H, OCH₃), 6.408 (br t,1H, J=5.88Hz, NH); (acetone-d6): 1.209 (t, 3H, J=7.26Hz, NCH₂CH₃), 3.376-3.467 (m, 2H, NCH₂CH₃), 3.918 (s, 3H, OCH₃), 7.505 (br s,1H, NH); ¹³C NMR: 15.02 (NCH₂CH₃), 35.69 (NCH₂CH₃), 53.51 (OCH₃), 123.82, 124.79, 125.25, 125.52 (Py-C5'/5'', Py-C3'/3''), 130.62, 133.71 (C4/5), 137.76, 137.88 (Py-C4'/4''), 149.37 (two peaks, distance < 0.01 ppm, Py-C6'/6''), 153.24, 154.40 (Py-C2'/2''), 155.10, 156.22 (C3/6), 164.98, 167.09 (2xCO); EIMS m/e (relative intensity) 363 (7), 331 (100), 319(97), 303 (22), 291 (16), 288 (39), 246 (22), 204 (70), 177(12), 176 (13), 152 (16), 144 (31), 102 (27), 78 (78). Anal. Calcd for C19H17N5O3: C, 62.80; H, 4.72; N, 19.27. Found: C, 62.76; H, 4.69; N, 19.30.

13c colourless rod from methanol, 100% yield. m.p. 204 ^oC (decomp., fast heating).

IR (cm^-1): 3246 (m, NH), 1735 (s, CO-O), 1661 (s, CO-N), 1608 (s), 1546 (m), 1448 (m), 1408 (m), 1382 (m), 1322 (m), 995 (m), 793 (m), 746 (m); ¹H NMR: 3.871 (s, 3H, OCH₃), 7.173 (tt, 1H, J=7.41, 1.14Hz, PhCH-para), 7.339-7.430 (m, 4H, 2xPhCH-meta and 2xPy-H5), 7.540-7.573 (dm, 2H, J=7.53Hz, 2xPhCH-ortho), 8.513(br s, 1H, NH); (acetone-d6): 3.781 (s, 3H, OCH₃), 7.119 (tt, 1H, J=7.38, 1.17Hz, PhCH-para), 7.305-7.371 (tm, 2H, J=7.95Hz, 2xPhCH-meta), 7.585-7.614 (dm, 2H, J=6.87Hz, 2xPhCH-ortho), 9.451(br s, 1H, NH); (methanol-d4, ppm): 3.389 (s, 3H, OCH₃), 7.142 (tt, 1H, J=7.41, 1.20Hz, PhCH-para), 7.288-7.354 (m, 2H, 2xPhCH-meta), 7.526-7.572 (m, 3H, 2xPhCH-ortho and 1xPy-H5); ¹³C NMR (methanol-d4): 122.31 (Ph-ortho), 125.20, 125.56, 126.00, 126.15, 126.16 (Ph-para, Py-C3'/3'' and Py-C5'/5''), 130.02 (Ph-meta), 132.64 (Ph-ipso), 138.84, 138.92(Py-C4'/4''), 139.25, 139.57 (C4/5), 150.43, 150.45 (Py-C6'/6''), 155.27, 156.03 (Py-C2'/2''), 156.94, 157.28 (C3/6), 171.21, 167.16 (2xCO); EIMS m/e (relative intensity) 411 (<0.1) 379 (77), 319 (100), 291 (21), 204 (59), 177 (7), 152 (5), 144 (19), 102 (6), 78 (35). Anal. Calcd for C23H17N5O3.CH3OH: C, 65.00; H, 4.77; N, 15.79. Found: C, 64.82; H, 4.71; N, 15.84.

14a colourless crystal from acetone, 100% yield, m.p. 209.4-211.0 ^oC.

¹H NMR: 0.94 (t, 3 H, J=7.3 Hz), 1.53-1.62 (m, 2 H), 2.91 (d, 3 H, J=4.9 Hz), 3.30 (q, 2 H, J=6.7 Hz), 6.87 (t, 1 H, J=5.3 Hz), 7.02 (q, 1 H, J=4.5 Hz), 7.27-7.31 (m, 2 H), 7.76-7.81 (m, 2 H), 8.23 (d, 2 H, J=8.0 Hz), 8.47 (d, 1 H, J=4.5 Hz), 8.50 (d, 1 H, J=4.4 Hz). ¹³C NMR: 12.12, 22.96, 27.39, 42.60, 124.47 (2xC), 125.09 (2xC), 133.24, 133.31, 137.58 (2xC), 149.20, 149.40, 154.08, 154.15, 155.58 (2xC), 165.85, 166.58; HRMS-EI calcd for C20H20N6O2: 376.1648, found 376.1651.

14b colourless crystal from acetone, 95% yield, m.p. 197.5-198.9 ^oC.

¹H NMR: 1.25 (t, 3 H, J=7.1 Hz), 2.85 (d, 3 H, J=4.7 Hz), 4.09 (d, 2 H, J=5.3 Hz), 4.15 (q, 2 H, J=7.1 Hz), 7.18 (br m, 2 H), 7.46 (q, 1 H, J=4.7 Hz), 7.64-7.71 (m, 2 H), 7.75 (t, 1 H, J=5.3 Hz), 8.06-8.10 (m, 2 H), 8.32 (d, 1 H, J=4.4 Hz), 8.40 (d, 1 H, J=4.4 Hz); ¹³C NMR: 14.78, 27.44, 42.47, 61.87, 124.15, 124.62, 124.88 (2xC), 132.43, 133.44, 137.43, 137.51, 149.07, 149.31, 153.57, 153.99, 154.87, 155.34, 165.98, 166.21, 169.59; HRMS-EI calcd for C21H20N6O4: 420.1546, found 420.1554.

Spectral Analysis

¹H NMR: The typical splitting signals for the 2'-pyridyl groups were observed at low field which made the total assignment very easy. The 4,5-diazaphthalimides 9a-c showed almost identical ¹H NMR spectra due to the same dipyridyl pyridazine moiety. The methanol addition products 13a-c showed two sets of pyridyl resonances in the aromatic region due to the two different environments of the 2'-pyridyl groups. The order of chemical shifts were in agreement with 2-substituted pyridines a>g>b,[14] i.e., py-H6 > py-H4 > py-H5, with the only exception of py-H3. (Table 2 and Table 3). The remarkable increase of chemical shift at pyridine H3 is ascribed to the deshielding effect of pyridazine or (s-tetrazine ring for 2a and 10a). The total assignment of protons and carbons were achieved by ¹H, ¹³C (broad band decoupling and coupling) and HMQC NMR techniques.

The difficult assignment of carbon signals was three quaternary carbons (C-2'/2'', C-3/6, C-4/5). With compound 9b as the example, the signals were d 155.90 ppm, d 152.69 ppm and d 128.40 ppm. From the structure, d C-3/6 should be similar to and slightly larger than d C-2'/2'' because pyridazine ring was more electron-deficient ring than pyridine. Furthermore, d C-3/6 should be larger than d C-4/5 because of the inductive effect of nitrogen atom and conjugated effect of carbonyl group in maleimide moiety.[15] So the predicted order of chemical shifts was d C-3/6 > d C-2'/2'' > d C-4/5, i.e., C-3/6 155.90 ppm, C-2'/2'' 152.69 ppm and C-4/5 128.40 ppm. The assignment proved to be correct by proton coupling ¹³C NMR spectrum, in which 152.69 ppm appeared as double doublet peak (11.55 Hz and 7.08 Hz) because C-2'/2'' coupled with H-4'/4'', H-6'/6'' by ³J, 155.90 ppm was a broad single peak (W_0.5=4 Hz) because C-3/6 had a long-range coupling (³J) with H-3'/3'' and 128.40 ppm was a sharp peak because C-4/5 had no coupling protons.

The magnitude of interproton coupling constants was consistent with that for heterocyclic compounds, in which nitrogen atom lead to a decrease in Jortho across the adjacent bond, i.e., J_5,6 (ca. 4.8 Hz) was smaller than J_3,4 and J_4,5 (7-8 Hz).[16] (see Table 3)

In the IR spectra, 4,5-diazaphthalimides 9 and 12 showed one strong carbonyl absorption at 1730-1750 cm^-1. The higher frequency of amide carbonyl was due to ring strain from five member ring and electron-withdrawing effects of the fused heterocyclic ring. At this region, ring opening products (13) showed two bands 1730-1750 and 1660-1690 cm^-1, assigned to ester and amide carbonyls respectively. Other typical absorption was C-H bending of methoxy at 1383 cm^-1 (strong) and N-H stretching at 3244 cm^-1 (sharp). All the compounds showed typical absorption near 1000 cm^-1 due to 2-monosubstituted pyridine ring breathing.[17]

The mass spectra showed the cycloaddition products (9) were very stable, molecular peak was base peak (9b,c) or second strongest peak (9a). The methanol addition products 13 showed typical fragmentation ions at m/e 319 (M-NHR) and m/e 291 (M-NHR-CO). This indicates that the C-N bond of the amide is weaker than C-O bond of ester. Characteristically, the fission via thermal elimination of methanol gave the cyclic 9 as a strong fragment. Both structures 9 and 13 favoured the loss of nitrogen and maleimide moiety to form the fragment m/e 204 (path ab) (Scheme 5).

Acknowledgment

The authors thank Mrs Sitalakshmy Sankar for preparing 1,3-bis(trimethylsilyl)-1,4-epoxynaphthalene and treating it with DPT 2a in the presence of N-methyl maleimide which led to the original observation, the Central Queensland University for financial support and the Australian Research Council for the award of a Senior Research Fellowship to R.N.W. (1992-1996)

References

(1) For comprehensive review see: Boger, D. L. and Weinreb, S. N.; In Hetero Diels-Alder Methodology in Organic Synthesis, Academic Press, Inc., San Diego, 1987; p335-348 and references therein.

(2) Gilchrist, T.L.; In Heterocyclic Chemistry, Longmann Scientific and Technical, New York, 2nd ed., 1992; p272-273.

(3) Avram, M, Dinulescu, J. G., Marica, E., Nenitzescu, C. D. Chem. Ber. 1962, 95, 2248.

(4) For a recent review see: Sauer, J. Bull. Soc. Chim. Belg., 1992, 101, 521.

(5) Carboni, R.A.; Lindsey, R.V. Jr. J. Am. Chem. Soc., 1959, 81, 4342.

(6) Boger, D. L.; Sakya, S. M. J. Org. Chem., 1988, 53, 1415.

(7) Geldard, J. F.; Lions, F. J. Org. Chem., 1965, 30, 318.

(8) One of the earliest use of 3,6-di(2-pyridyl)-s-tetrazine 2a acting as an inverse electron-demand diene was reported by Wilson, W. S.; Warrener, R. N. Tetrahedron Lett., 1970, 4787.

(9) Warrener, R. N. J. Am. Chem. Soc., 1971, 93, 2346.

(10) Warrener, R. N.; Evans, D. A. C.; Paddon-Row, M. N., Russell, R. A. Aust. J. Chem., 1982, 34, 757.

(11) Russell, R.A.; Longmore, R.W.; Warrener, R.N. J. Chem. Ed., 1992, 69, 164.

(12) Sandstrom, J. Acta Chem.Scand., 1961, 15, 1575.

(13) Fieser, L.F.; Fieser, M. In Reagents for Organic Synthesis, John Wiley and Sons, Inc., New York, Vol. 1, 1967; p 845-846.

(14) Kemp, W. In Organic Spectroscopy, 3rd ed., MacMillan Education Ltd., Houndmills, 1991; p 175.

(15) Wehrli, F.W.; Marchand, A.P.; Wehrli, S. Interpretation of Carbon-13 NMR Spectra, 2nd ed., 1988, John Wiley and Sons Ltd., Chichester, p 57-63.

(16) Jackman, L.M.; Sternhell, S. Applications of Nuclear Magnetic Resonance Spectroscopy in Organic Chemistry, 2nd ed., 1969, Pergamon Press, Oxford, p 305-310.

(17) Katritzky, A.R. In Physical Methods in Heterocyclic Chemistry, Academic Press, New York, Vol. 2, 1963; p 274-303.