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Isolation and rearrangement of 5aH-pyrido- [1,2-d] [1,3,4]thiadiazepine derivatives

Akikazu Kakehi,* Suketaka Ito and Fumihito Ishida

Faculty of Engineering, Shinshu University, Wakasato 500, Nagano 380, Japan

Novel hetero-cage compounds, dimethyl 8-thia-10,11-diazatricyclo[,11]undeca-2,5,9-triene-6,7-dicarboxylates, were synthesized from the reactions of 1-pyridinio(arylthiocarbonyl)aminides with dimethyl acetylenedicarboxylate, and the title compounds, 5aH-pyrido[1,2-d][1,3,4]thiadiazepine derivatives, proposed previously as possible reaction intermediates in these reactions were first isolated from the reactions of 1-(2-methylquinolinio)(arylthiocarbonyl)aminides with the same reagent.

Recently, we reported a first syntheses of dimethyl 10aH-pyrido[1,2-d][1,4]thiazepine-1,2-dicarboxylate derivatives from the reactions of various 1-pyridinio[(substituted thiocarbonyl)methylides] with dimethyl acetylenedicarboxylate (DMAD) and their smooth transformations to the intramolecular Diels-Alder adducts, dimethyl 4-thia-1-azatetracyclo[,11.06,8]undeca-2,9-diene-5,6-dicarboxylates. More recently, we also proved that the reactions of the 1-pyridiniomethylides with DMAD proceed stepwise via the formation of primary 1 : 1 zwitterionic intermediates such as A (see Scheme 1) followed by their 1,7-cyclization, since the trapping of the intermediates using various alcohols, which were added into the reaction mixtures, and the intramolecular Diels-Alder reactions of the resulting adducts gave quite different types of products, 2-alkoxy-6-thia-3-azatricyclo[,8]undeca-4,9-diene derivatives.

As an extension of this reaction, we were interested in the reactions of 1-pyridinio(substituted thiocarbonyl)aminides with DMAD. Our previous efforts to isolate any significant products from the reactions of 1-pyridinio[(methylthio)thiocarbonyl]aminides with DMAD under various reaction conditions were fruitless. The initially expected 5aH-pyrido[1,2-d][1,3,4]thiadiazepines and/or 4-thia-1,2-diazatetracyclo[,11.06,8]undeca-2,9-dienes could not be obtained, and trace amounts of dimethyl fumarate and hexamethyl benzenehexacarboxylate only were detected. (Scheme 2)

We explained these unsuccessful results as follows

  1. Steric restrictions on the intramolecular 1,7-cyclization
  2. The extreme instability of the isocyanate dithioacetal structure in the primary zwitterionic intermediates and/or pyrido[1,2-d][1,3,4]thiadiazepines toward various nucleophiles including H2O (moisture) and alcohol

In order to confirm the second assumption we modified the structure of 1-pyridinioaminides, and their reactivities toward DMAD were examined.

Interestingly, the reactions of 1-pyridinio(thiobenzoyl)aminides with DMAD in dry and alcohol-free chloroform at 50-60 oC gave neither the initially predicted 5aH-pyrido[1,2-d][1,3,4]thiadiazepines nor their intramolecular Diels-Alder adducts, but they afforded quite different types of products, dimethyl 9-phenyl-8-thia-10,11-diazatricyclo[,11]undeca-2,5,9-triene-6,7-dicarboxlates, in moderate yields. (See Scheme 3)

Here, we will describe the application of this reaction to various 1-pyridinio-(arylthiocarbonyl)aminides and on first isolation of two title compounds, 5aH-pyrido[1,2-d] [1,3,4]thia-diazepine derivatives. Their possible reaction mechanisms involving pyridothiadiazepine and 4-thia-1,2-diazatricyclo[,11]undeca-2,9-dien-8-yl-6-ide intermediates will be also discussed.

Results and discussion

1-Pyridinio- and 1-Quinolinio(arylthiocarbonyl)aminides

The 1-pyridinio(arylthiocarbonyl)aminides 3a-o were prepared from the reactions of 1-aminopyridinium iodides 1a-c or 1-amino-2-methylquinolinium p-toluenesulfonate 1d with methyl dithiobenzoate 2a, methyl p-methoxydithiobenzoate 2b, methyl o-methoxydithiobenzoate 2c, methyl p-dimethylaminodithiobenzoate 2d, methyl p-chlorodithiobenzoate 2e, and methyl 2-thiophenedithiocarboxylate 2f in the presence of a base in ethanol in 34-93% yields, respectively. However, similar treatment of 1-aminoquinolinium and 2-aminoisoquinolinium mesitylenesulfonates did not give the corresponding 1-quinilinio- and 2-isoquinolinio(arylthiocarbonyl)aminides, though the reasons why they were not formed is unclear.

Reactions of 1-pyridinioaminides 3a-o and DMAD

When 1-pyridinio(arylthio-carbonylaminides) 3a-m, thus obtained, were treated with DMAD 4 in dry and alcohol-free chloroform at 50-60 oC for 8 h, colourless crystalline products 5a-m were formed in 0-35% yields, respectively. (Scheme 5) Although the elemental analyses of these products 5a-m were in good accord with the compositions of 1 : 1 adducts between ylides 3a-m and DMAD 4, but their IR and NMR spectra (See Table 1 for those of some compounds) were very different to those of the initially expected pyridothiaziazepines 6 and 4-thia-1,2-diazatetracyclo[,11.06,8]undeca-2,9-dienes 7. In particular, the chemical shifts and signal patterns of the skeletal protons in their NMR spectra clearly indicated a rearrangement of the pyridine skeleton. Eventually, the structures of compounds 5a-m were determined using single crystal X-ray analyses for 5c,l. The ORTEP drawing for compound 5l is shown in Figure 1.

As observed in the reactions of 1-pyridinio[(substituted thiocarbonyl)methylides] with DMAD, these reactions seems to proceed via the formation of 5aH-pyrido[1,2-d][1,3,4]thiadiazepine derivatives such as 6 and their rearrangements. Here, we presumed the presence of the 4,9-cyclized intermediate, 4-thia-1,2-diazatricyclo[,11]undeca-2,9-dien-8-yl-6-ide (see below) from these 5aH-pyrido[1,2-d][1,3,4]-thiadiazepine derivatives 6 in the latter rearrangement, and planned the syntheses and the isolation of benzo-fused 5aH-pyrido[1,2-d][1,3,4]thiadiazepine derivatives in which this transition state is energitically less favourable. As might be expected, the reactions of 1-(2-methylquinolino)(phenyl- 3n and 1-(2-methylquinolino)(2-thienylthiocarbonyl)aminide 3o with 4 gave smoothly the corresponding dimethyl 5a-methyl-2-phenyl- 6n and 2-(2-thienyl)-5aH-1,3,4-thiadiazepino[4,5-a]quinoline-4,5-dicarboxlate 6o in 41 and 43% yields, respectively , as yellow crystals. (Scheme 6) Compounds 6n,o were very unstable and decomposed gradually at room temperature.

Figure 1

Similarly, the structures of the above thiadiazepinoquinolines 6n,o were assigned by theri elemental analyses, and IR and NMR spectroscopy (see below), and finally comfirmed by the X-ray analysis of 6n. The ORTEP drawing for 6n is shown in Figure 2.

Figure 2


Possible mechanisms for these reactions are shown in Scheme 7. These reactions seem to proceed via the formation of 5aH-pyrido[1,2-d][1,3,4]thiadiazepines such as 6 from the reactions of 1-pyridinio(arylthiocarbonyl)aminides 3 and DMAD 4 and their intramolecular Diels-Alder adducts, 4-thia-1,2-diazatetracyclo[,11.06,8]undeca-2,9-diene derivatives 7, since the final products 5a-m have a 1,3,4-thiadiazine skeleton in the molecule. However, such type of the rearrangement (retro-di-pi-methane rearrangement) from 7 to 5 is a thermally forbidden process and such transformation for the 2-deaza derivatives could not be detected. Hence, we propose a new intermediate, 4-thia-1,2-diazatricyclo[,11]undeca-2,9-dien-8-yl-6-ide 8, which described above, in the route from 7 to 5. Because of higher strain accompanied by the formation of a cyclopropane ring, one C-N bond in this intermediate 8 may shift easier to the adjacent carbocation (Path a) rather than the cyclopropane ring formation through the cyclization between the cationic and anionic centers (Path b).

The reason why only this type of compound 5a-m was obtained in the reactions of aminides 3a-m with 4 while other types of product such as 6 and 7 were not is still unclear. However, the facts that these reactions did not give any significant products at room temperature but, only on heating, the corresponding compounds 5 could be obtained may indicate the following.

  1. The final products 5a-m were formed from pyridothiadiazepines 6 via thermodynamically controlled reaction through intermediate 8 (Path a).
  2. The intramolecular Diels-Alder adducts 7 may be the kinetically controlled products and they may be very unstable because of the increase of the ring strain accompanied by the incorporation of a more shortened C-N double bond into this molecule.


We have uncovered a novel type of skeletal rearrangement in the reactions of 1-pyridinio(arylthiocarbonyl)aminides with DMAD.