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As part of a series of studies on synthesis of chiral 1-alkyltetrahydroisoquinolines, asymmetric synthesis of 1-alkoxycarbonylmethyl-1, 2, 3, 4-tetrahydroisoquinolie (IV) was investigated. Two synthetic approaches using intermolecular and intramolecular Reformatsky-type reactions from (3R, 10bS)-3-phenyl-2, 3, 5, 6-tetrahydro-10bH-oxazolo[2, 3-a]isoquinoline (1) were attempted, but high stereoselectivity could not be obtained. For the purpose of determining the absolute structures of the compounds (2, 3) obtained by the Reformatsky-type reactions, transformation of 3a to a chiral 1, 3, 4, 6, 7, 11b-hexahydro-2H-benzo[a]quinolizine (14) was investigated.

Dimethyl 7-acyl-9-cyano-1-azacycl[3.3.3]azine-2, 3-dicarboxylates (4, 6) were synthesized via 1-acyl-3-cyano-4-imino-4H-quinolizines (3, 5) as key intermediates. The nucleophilic substitution of the methylthio group in antiaromatic azacycl[3.3.3]azines (6b, 9, 13) gave the corresponging producs. The reaction of 9 or 13 with methyl acetoacetate gave the fused diazacycl[3.3.3]azines (12, 16), which are examples of a new ring system.

The conversion of 1-(3-chloropropyl)-cis-decahydroquinoline-2, 7-dione (3) into decahydro-3H, 8H-benzo [i, j] quinolizine-3, 8-diones (12a and 12b) was accomplished with retention of the parent stereochemistry. The stereochemistry of the tricyclic system was assigned from chemical and physical evidences. It was postulated that this successful ring closure in the cis ring system resulted from easy fulfilment of the stereoelectronic requirement, for intramolecular alkylation in 3, much reduced as compared to that for N-acrylyl-cis-octahydro-7 (1H)-quinolone (1b).

The catalytic hydrogenation of the cycl[3.3.3]azine derivative (6) or 1-azacycl[3.3.3]azine derivative (15) with PtO2 in tetrahydrofuran at atmospheric pressure gave the dihydrocyclazine derivative (10) or dodecahydro-1-azacycl[3.3.3]azine derivative (16), respectively. On the other hand, the catalytic hydrogenation of 6 or 19 in AcOH gave dodecahydrocyclazine (11) or dodecahydro-2-hydroxymethyl-1-azacyclazine (21), respectively. The catalytic hydrogenation of the hydrochloride 18 in MeOH gave methyl dodecahydro-5-methyl-1-azacycl[3.3.3]azine-2-carboxylate (20). Compounds 11, 20 and 21 should be useful as intermediates for the preparation of natural products, such as coccinelline and cernuine.

Reaction of diketene with ethyl N-benzylacetimidate (Ia) in acetic acid gave 3-acetyl-1, 6-dibenzyl-4, 7-dimethyl-1H, 6H-1, 6-naphthyridine-2, 5-dione (IIa) in 51% yield. Similarly lactim ethers such as 2-methoxy-1-pyrroline (Ib), 2-methoxy-3, 4, 5, 6-tetrahydropyridine (Ic), and 2-methoxy-3, 4, 5, 6-tetrahydro-7H-azepine (Id) gave the corresponding 5-acetyl-6-methyl-4, 7-dioxo-1, 2, 10, 11-tetrahydro-4H, 7H, 9H-dipyrrolo[1, 2-g : 3', 2', 1'-tj]-1, 6-naphthyridine (IIb) (35%), 6-acetyl-7-methyl-5, 8-dioxo-2, 3, 10, 11, 12, 13-hexahydro-1H, 5H, 8H-quinolizino[1, 9-ab]quinolizine (IIc) (66%), and 7-acetyl-8-methyl-6, 9-dioxo-1, 2, 3, 4, 12, 13, 14, 15-octahydro-6H, 9H, 11H-bisazepino[1, 2-g : 3', 2', 1'-tj]-1, 6-naphthyridine (IId) (40%). Treatment of IIa-d with KOH in EtOH resulted in the formation of the deacetylated derivatives IIIa-d.

By the reaction of 6-methyl-4-imino-4H-quinolizine derivatives (5, 8) with the mixed anhydrides (6a-h), 2-phenyl-1-azacycl [3.3.3] azines (7a-p, 9a-g) were obtained.2-Pheny1-1, 3, 6-triazacycl [3.3.3] azine derivatives (15ah, 17a-h, 18a-g) were prepared by the reaction of 2-(2-cyanovinyl) amino-6-aminopyridines (13, 16) with mixed anhydrides (6a-h).The proton nuclear magnetic resonance spectral data of the 2-phenylazacycl [3.3.3] azines (12, 18a) may be interprited in terms of a paramagnetic ring current.

1, 4-Diazabenzo [j] cycl [3. 3. 3] azine derivative (IX) and 1-azabenzo-[h] cycl [3. 2. 2] azine derivative (VII) were synthesized by the reaction of dimethyl acetylenedicarboxylate (DMAD) with 3-cyano-4-imino-4H-isoquinolino [1, 2-a] pyrimidine (IV). Benzo [g] cycl [3. 2. 2] azine derivative (VIII) was synthesized using the reaction of DMAD (VI) with methyl 3-cyano-4-imino-4H-isoquinolino [1, 2-a] pyridine-1-carboxylate (V).

The reaction of tryptamine with δ-valerolactone in tetralin gave δ-hydroxyamide (3) as the main product and the lactam (4) as the minor product. However, the reaction of 5, 6-dihydro-2-pyrone with tryptamine or aniline afforded a mixture of the corresponding αβ- and βγ-unsaturated lactams, whereas, 2-pyrone did not react with either tryptamine or aniline to give the corresponding pyridone. Cyclization of 3 or 4 by Bischler-Napieralski reaction and followed NaBH4 reduction provided a convement synthesis of 1, 2, 3, 4, 6, 7, 12, 12b-octahydroindolo [2, 3-α] quinolizine (23).

Intramolecular photoaddition reactions of 2-(ω-alkenyl)isoquinolin-1(2H)-ones and 1-(ω-alkenyl)pyridin-2(1H)-ones were examined, and the regioselectivity and dependence of these reactions on the length of methylene chain in the alkenyl group were clarified. By utilizing these reactions, a synthetic route to indolizine and quinolizine derivatives was elaborated. By an extension of this approach to the intermolecular reaction, 6-methoxy-3-methyl-1, 2-dihydrocyclobuta[b]pyridin-4(3H)-one was synthesized from 4, 6-dimethoxy-1-methylpyridin-2(1H)-one.

A convenient synthesis of 1, 2, 3, 4, 6, 7, 12, 12b-octahydroindolo [2, 3-a] quinolizine (1) is described. The condensation of tryptamine (2) with diethyl (2-formylethyl) malonate (3a), followed by treatment with alkali, gave the lactam ester (5a). Decarbethoxylation of 5a with LiCl-H2O-Me2SO afforded the lactam (8a), which was reduced with LiAlH4 to give the indoloquinolizine (1). The lactam (8b) which has an ethyl group at C3 was prepared from tryptamine (2) and diethyl ethyl (2-formylethyl) malonate (3b) instead of 3a.

The cyclization of N-acrylyl-trans-and-cis-octahydro-7 (1H)-quinolones (IXa and IXb) was examined under both acidic and basic conditions. Under kinetic conditions, the trans-isomer (IXa) gave two isomeric tricyclic lactams (X and XI) while the cis-isomer (IXb) gave no cyclized compounds. Under thermodynamic conditions, the cis-isomer (IXb) as well as the trans-isomer (IXa) gave the same lactams (X and XI). In the former case with kinetic conditions, the difference in behavior toward cyclization between IXa and IXb was interpreted by taking a stereoelectronic requirement for the Michael addition into consideration, and in the latter case with thermodynamic ones, unexpected formation of the lactams (X and XI) from the cis-isomer (IXb) was rationalized by assuming a reaction pathway via the intermediate enone (XXII) of which we succeeded in isolation from the reaction mixture.

Convenient syntheses of 1, 2, 3, 4, 6, 7, 12, 12b-octahydroindolo[2, 3-α]quinolizine derivatives (4a, b) and a relatd unsaturated lactam (14) are described. The condensation of tryptamine (1) with 8a, b (prepared from 7a, b by decarboethoxylation), followed by treatment with alkali gave the lactams (4a, b), respectively. The stereochemistry of 4b was determined by conversion to the known cis- and trans-compounds (5b). The condensation of 1 with the sulfenylated ester (10), which was prepared in two ways, followed by treatment with alkali gave the lactams (12a, b). Oxidation of 12a, b with m-chloroperbenzoic acid gave the sulfoxides (13) which were heated at 50°C to give the lactams (14, 15) and the pyridone (16).

From the reaction of 4-imino-6-methyl-4H-quinolizine derivatives (I) with acid anhydrides (glutaric anhydride and crotonic anhydride), the corresponding 1-azacycl-[3, 3, 3]azine derivatives (V, VI) were obtained. 1-Aza-5-oxo-2, 3, 4, 5-tetrahydrobenzo[b]cycl[3, 3, 3]azine (X) was yielded, as a stable free base, by the decarboxylation of VI. On the other hand, 2-methyl and 2, 5-dimethyl-1-azacycl[3, 3, 3]azine (XVIa, b), which were very unstable free bases, were prepared by the degradation of II and IV. These nuclear magnetic resonance spectral data of XVIa and XVIb may be interpreted in term of a paramagnetic ring current.

A series of substituted 6,7-dihydro-1-oxo-1H,5H-benzo[i,j]quinolizine-2-carboxylic acids was synthesized and tested for antibacterial activities. Among them, 9-fluoro-6,7-dihydro-5-methyl-8-(4-methyl-1-piperazinyl)-1-oxo-1H,5H- benzo[i,j]quinolizine-2-carboxylic acid (OPC-7241) exhibited potent antibacterial activity against gram-positive and -negative bacteria, including Staphylococcus aureus and Pseudomonas aeruginosa, and 9-fluoro-6,7-dihydro-8-(4-hydroxy-1-piperidyl)-5-methyl-1-oxo-1H, 5H-benzo[i,j]quinolizine-2-carboxylic acid (OPC-7251) showed potent activity characteristically against Propionibacterium acnes.

The four stereoisomers of perhydro-1H, 5H-naphtho [1, 2, 3-i, j] quinolizine were synthesized. The reaction rates of these stereoisomers with alkyl iodide were measured and from this result the configuration of each was clarified.

In expectation of a curariform activity with little side effects, methiodide of 3, 3'-polymethylenediquinolizidines (I : n=4, 6, 8, and 10) were synthesized. Condensation of the potassium salt of 3-ethoxycarbony1-4-oxoquinolizidine and polymethylene bromide, followed by saponification and decarboxylation, and reduction with lithium aluminum hydride of the lactam compound so obtained afforded the objective compounds (I). (I : n=4) was also obtained through 3-(4-phenoxybutyl) quinolizidine (IX) as an intermediate and compounds obtained by the two procedures were found to be identical. The curariform activity of (I) (n=4 and 6) was one-quarter that of tubocurarine chloride while their toxicity was 6 and 10 times, respectively, of tubocurarine. The compound with n=10 had a strong antibacterial and antifungal activity.

Monoester of benzylmalonic acid (I) and 3-carboxy-4-octahydroquinolizinone (V) were coupled with benzenediazonium salt to yield labile phenylhydrazones, Iia and VII, respectively. IIa was kept standing in chloroform or heated to give another phenylhydrazone (IIb). VIa was similarly converted into VIb. The condensed four-cyclic compound (VIIIa) derived from VIa or VIb was heated with hydrochloric acid and the resulting product (IXa) was subjected to Pictet-Spengler reaction by formalin to afford octahydroindolo [3, 2-b] quinolizine (Xa). Xa was also obtained by reduction of VIIIa with LAH. Treatment of IXa with benzaldehyde in aqueous hydrochloric acid produced XII. Some methoxyl derivatives (VIIIb, Xb) were obtained according to the same route as mentioned above.

9-Azahexahydrojulolidine (III) was prepared by saponification and decarboxylation of 2-cyanoperhydropyrido [3, 4, 5-i, j] quinolizine (II) with hydrochloric acid, obtained by reaction of 9-methyl-9-azahexahydrojulolidine (I) and cyanogen bromide. Series of these compounds was assumed to have the cis-quinolizidine ring and, in order to ascertain this assumption, (III) was converted to 9-azajulolidine (IV).

A synthesis of9, 10-dimethoxy-1, 2, 3, 4, 6, 7-hexahydro-2, 6-methano-11bH-benzo [a]-quinolizine having a new ring system was described. Thus, dl-N-benzyl-3-(3, 4-dimethoxyphenyl) alanine ester (VI) was condensed with succinic anhydride followed by esterification to give amido-ester (IX), which on being cyclized with phosphoryl chloride under reflux furnished the corresponding dihydroisoquinoline derivative (X) isolated as iodide. When the latter was reduced with sodium borohydride-methanol, there were obtained α-and β-isomers of tetrahydroisoquinoline derivative (XI)ca. in a ratio 5 : 1. On being cyclized with sodium hydride-toluene they gave one and the same cyclic β-ketoester (XII), which was condensed with ethyl bromoacetate followed by ketone fission to yieldγ-ketoester (XV). An alternative route XV was also discribed. XV was then reduced with sodium borohydride and the resultant alcohol (XVIII) was chlorinated to give the chloride (XIX), which was reduced with lithium aluminum hydride-tetrahydrofuran. The reduction product was directly tosylated and worked up properly furnishing the cyclized product, which was characterized as perchlorate. On being reduced catalytically the latter furnished the ultimate product (I). A smaller quantity of by-product was also obtained in the final cyclization step, to which structure (I-B) was postulated.

The mercuric acetate-(ethylenedinitrilo) tetraacetic acid oxidation of aminoalcohol III furnished lactamalcohol V in 73% yield and its O-acetyl derivative (VI) as a minor product. Treatment of V with phosphoryl chloride gave tetrahydrobenzo [α] quinolizinium salt X in 87% yield, whereas hydrogenolysis of V in the presence of perchloric acid and ring-closure of the resulting lactam VIII afforded hexahydrobenzo [α] quinolizinium salt IX, which produced benzo [α] quinolizidine Ia on hydrogenation. When treated with perchlo-ric acid, lactamalcohol V yielded oxazolinium salt VIIa in a good yield. The facile hydrogenolysis of VIIa to VIII has suggested the possibility that the perchloric acid-accelerated, direct hydrogenolysis of V may proceed through VIIa. The starting aminoalcohol III was synthesized either by the sodium borohydride reduction of aminoketone II obtained from piperidine and 3, 4-dimethoxyphenacyl bromide or by reduction of quaternary salt IV from pyridine and 3, 4-dimethoxyphenacyl bromide.

Some kinds of simple quinolizidine derivatives were recently found to possess sparteine-like uterus contracting action and this time the new substance with stronger contracting action has been found. Among 3-(subst.-benzyl)-quinolizidine derivatives, 3-(4-chlorobenzyl)-quinolizidine (Ib) was found to be the strongest. Ib showed several folds of activity to sparteine sulfate both in vitro and in vivo and the toxicity was found to be about one third of it. The synthesis of Ib was carried out according to the two method (1) and (2), the former synthetic process being found to be beneficial.

2-Cyanomethyl-3-methoxymethylpyridine and ethyl (3-methoxymethyl-2-pyridyl) acetate were prepared from ethyl 2-methylnicotinate. Condensation of these compounds with diethyl ethoxymethylenemalonate afforded 1, 3-bis (ethoxycarbonyl)-9-methoxymethyl-4-oxo-4H-quinolizine and 1-cyano-3-ethoxycarbonyl-9-methoxymethyl-4-oxo-4H-quinolizine. The ethoxycarbonyl group in these compounds was saponified and further decarboxylated on being heated with hydrochloric acid. A more drastic condition easily afforded 3, 6-dioxo-1H, 3H, 6H-pyrano [3, 4, 5-i, j] quinolizine.

Synthesis of 1, 2, 3, 4, 6, 7-hexahydro-11bH-benzo[a]quinolizines (IIIa and IIIb) was described. N-Phenethyl-5-bromovaleramide (IV) and 1-phenethyl-2-piperidone (VIIa) were cyclized with a mixture of phosphoryl chloride-phosphorus pentoxide and phosphoryl chloride-polyphosphoric acid, respectively, and were reduced catalytically. Thus, the hexahydro base (IIIa) was obtained. 9, 10-Methylenedioxy-1, 2, 3, 4, 6, 7-hexahydro-11bH-benzo[a]quinolizine (IIIb) was obtained in a good yield from the cyclized product of the corresponding piperidone (VIIb) by the same method.

6, 7-Cyclobutano-1, 2-cyclopropanoquinolizidine (I) (9-azasteroid ring system) and perhydrodibenzo [c, f] quinolizine (II) (9-aza-D-homosteroid) were synthesized by the routes shown in Chart 1 and 3.

The configurations of the diastereoisomers (Ia and Ib) of 3-(4-chlorobenzyl) quinolizidine were determined from the retention time in gas chromatography, NMR spectra of their methiodides, and from their dipole moments, in comparison with those of 3-lupinine and 3-epilupinine.

The four kinds of stereoisomers of perhydrobenzo [c] quinolizine were isolated as picrates of mp 203-205°, mp 182-184°, mp 171°, and mp 155°, whose stereostructures were elucidated as IIIa, IIIb, IIIg, and IIId (or IIIh), though the last one was not determined conclusively due to the minute quantity available.

Reaction of α, α'-dimethylthiomethylene-2-pyridylacetonitrile (I) and active methylene compounds in dimethyl sulfoxide, in the presence of potassium carbonate, afforded 1-cyano-2-methylthio-4H-quinolizin-4-ones with the corresponding substituent in 3-position. Reaction of some of these 3-substituted compounds with benzylamine produced 2-benzylamino-1-cyano-4H-quinolizin-4-ones. Reduction of one of the 3-substituted compound over Raney nickel catalyst gave 1-cyano-3β-pyridyl-4H-quinolizin-4-one.

There have been synthesized dl-10-desoxy-18, 19-dihydro-15-epi-hunterburnine according to the oxidative cyclization reaction with mercuric acetate, and its structure was determined by nuclear magnetic resonance (NMR) and mass-spectra.

Steric configuration of the two diastereoisomers of ethyl 3-quinolizidinecarboxylate (I) was examined and it was proved from following facts that (Ia) (picrate, m.p. 160∼161°) has the A-type and (Ib) (picrate, m.p. 144∼146°) has the B-type orientation. It was shown that (i) quinolizidine ring is in trans type ; (ii) basic isomerization of (I) and (Ia) afforded a fair amount of (Ib) ; and that (iii) reduction of (Ia) and (Ib) with lithium aluminum hydride resulted in their derivation to 3-lupinine (IIa) and 3-epi-lupinine (IIb), respctively. The steric configuration of (IIa) and (IIb) had previously been approximately determined from measurement of their infrared spectra and dipole moment. It was confirmed through preparation of the tosylates of (IIa) and (IIb), and comparison of their chemical properties that (IIa) had an axial -CH2OH group and (IIb), the equatorial-CH2OH.

Reaction of Δ1, 10-hexahydroquinolizine (I) with methyl iodide in various solvents were carried out. The reaction in the presence of methanol or ethanol proceeded at low temperature to give 10-methoxy-5-methyloctahydroquinclizinium iodide (IIIa) or the corresponding 10-ethoxy methiodide (IIIb), respectively, besides the methiodide (II). Using 70% aqueous methanol as a solvent, the reaction gave 1-methyl-6-decahydroazecinone (IV) accompanied with IIIa and II. The reaction in 70% aqueous tetrahydrofuran or aqueous acetone led to the formation of V besides II. Methiodides, IIIa and IIIb, were respectively converted into IV by heating with hydrobromic acid.

A new approach to the synthesis of optically active indole and isoquinoline alkaloids is described. The key reactions are : (i) the biogenetic-type, asymmetric Pictet-Spengler reaction of optically active α-amino acids (I) with aldehydes (II) (1, 3-asymmetric induction), and (ii) the elimination of the chiral center derived from α-amino acids (1, 3-transfer of asymmetry), shown in Chart 1. To achieve (ii), laboratory simulation of decarboxylative processes of α-amino acids was investigated by oxidative and reductive methods. The former did not give any fruitful results, as shown in Table I. However, the reduction of α-amino nitriles, easily prepared from α-amino acids, by means of sodium borohydride gave the satisfactory result, as shown in Table II. By this new method, two simple indole alkaloids, (S)-(-)-tetrahydroharman (XXIV) and (S)-(-)-1, 2, 3, 4, 6, 7, 12, 12b-octahydroindolo [2, 3-a] quinolizine (XXIX) could be obtained from L-tryptophan in a satisfactory manner.

The proposed structure for rotundine and dihydro-rotundine by Matsuno was proved untenable. The synthesized so-called rac-dihydro-rotundine (II) was dehydrogenated with mercuric acetate in methanolic solution to give the product as well-defined quaternary salt (XII). This was more advantageously prepared by dehydrogenating 2-oxo-3-methyl-9, 10-dimethoxy-1, 2, 3, 4, 6, 7-hexahydro-11bH-benzo [a] quinolizine (IX), the intermediate for (II), with mercuric acetate in 10% acetic acid solution to produce a phenolic quaternary salt (X) and methylating the latter with dimethyl sulfate and an excess of conc. potassium hydroxide solution, giving (XIV). Natural dihydro-rotundine, prepared by reducing the natural alkaloid, gave a dehydro-quaternary salt by a similar method, but the product showed ultraviolet and infrared absorption spectra different from those of (XII). Partial hydrogenation experiments of (XII) and (XIV) under a variety of conditions failed to afford a compound having the diene system, as was proposed for natural rotundine. The products isolated were rac-dihydro-rotundine-type of compound, whose three isomers (II, XV, and XVI) were characterized. In conformity with their structure they smoothly gave the ketone (IX) when treated with dil. hydrochloric acid, whereas the natural dihydro-rotundine was proved to be quite stable to hydrochloric acid even at an elevated temperature. Similar experiments were also conducted with synthetic rac-dihydro-isorotundine (I).

Reaction of 3, 4-dihydroisoquinolineacetonitrile (I) and methyl 1-cyano-2, 2-dimethylthioacrylate (II) gave 3-cyano-2-methylthio-4-oxo-6, 7-dihydrobenzo [α] quinolizines (III). III reacted with various amines to form 1, 3-dicyano-2-amino-4-oxo-6, 7-dihydrobenzo-[α] quinolizines (IVa-g). III also reacted with active methylene compounds to form 1, 3-dicyano-4-oxo-6, 7-dihydrobenzo [α] quinolizines (V-IX).In the reaction of 1, 3-dicyano-2-methylthio-4-oxo-6, 7-dihydrobenzo [α] quinolizines (IIIna) and 2-amino-1, 3-dicyano-4-oxo-6, 7-dihydrobenzo [α] quinolizine (IVd) with concentrated sulfuric acid, the cyano group in 1-position was found to be easily liberated and that in 3-position was converted into a carboxamide group.Reduction of 1, 3-dicyano-4-oxo-6, 7-dihydrobenzo [α] quinolizines (IIIa, b, IVa, Vb) with sodium borohydride in ethanol or N, N-dimethylformamide gave 1, 3-dicyano-4-oxo-1, 6, 7, 11b-tetrahydro-9, 10-dimetoxybenzo [α] quinolizines (XI, XIIa, b, XIII) by the reduction of quinolizine skeleton.

Ethyleneacetal of nicotinaldehyde was quaternized with 3, 4-dimethoxyphenethyl bromide and the product (I) was oxidized with alkaline potassium ferricyanide, yielding 1-(3, 4-dimethoxyphenethyl)-5-(1, 3-dioxolan-2-yl)-2 (1H)-pyridone (II) in a fair yield, from which the aldehyde (III) was recovered in an excellent yield. (III) will serve as a starting material for various syntheses and in this paper a synthesis of rac-c-noremetine-Pyman was described as such an example.

Reaction of ethyl α-(dimethylaminomethylene)-2-pyridineacetate (I) with acetic anhydride gives ethyl 4-oxo-4H-quinolizine-1-carboxylate (Va). Similar reaction with acid anhydrides, such as propionic anhydride and n-butyric anhydride, affords the corresponding 3-substituted-quinolizine derivatives (Vc and Ve). Similarly, α-(dimethylaminomethylene)-2-pyridineacetonitrile (II) and quinolyl homologous (III and IV) react with acid anhydrides to give the corresponding 3-substituted-4-oxo-4H-quinolizine-1-carbonitrile (Vb, Vd and Vf), ethyl 2-substituted-1-oxo-1H-benzo [c] quinolizine-4-carboxylate (VIa, VIc and VIe) and 4-carbonitrile derivatives (VIb, VId, and VIf), respectively. I reacts with diethyl malonate to give diethyl 4-oxo-4H-quinolizine-1, 3-dicarboxylate (Vg). Similar reaction with esters, such as ethyl cyanoacetate, ethyl acetoacetate and ethyl 2-pyridineacetate, affords the corresponding 3-substituted-quinolizine derivatives (Vi, Vk, and Vm). II, III and IV react with esters to form quinolizine and benzoquinolizine derivatives (Vh, Vj, Vn, VIg, VIh, VIi, VIj, VIk, and VIl). Reaction of III with esters affords ethyl 2-(2'-quinolyl)-1-oxo-1H-benzo [c] quinolizine-4-carboxylate (VII), besides the expected product (VIg, VIi, VIk). Reaction of IV with ethyl acetoacetate gives ethyl 3-(2'-quinolyl)-6-methyl-2-pyridone-5-carboxylate (IX) as a main product (33%).

3-Butyl-, 3-pentyl-, 3-isopentyl-, and 3-phenethylquinolizidines were found to have a comparatively strong uterus-contracting action like that of sparteine.

From the reaction of 1-azacycl [3, 3, 3] azine derivatives (I) with some dienophiles, the corresponding cycl [3, 3, 3] azine derivatives (II) and 3, 9a-dihydro-3, 9a-ethano-1-azacycl [3, 3, 3] azine derivatives (IV) were obtained.

The conversion of 1-methylspiro (indoline-3, 1'-indolizine)-2-one to 12-methyl-1, 2, 3, 4, 6, 7, 12, 12b-octahydroindolo [2, 3-a] quinolizine is described as a preliminary for the chemical correlation of N-methylrhynchophyllane with N-methyldihydrocorynantheane.

The enamine, 9, 10-dimethoxy-3, 4, 6, 7-tetrahydro-2H-benzo[a]quinolizine, which was isolated by basifying the aqueous solution of the corresponding immonium chloride, was proved to be reconverted into the immonium cation when dissolved in 85% ethanol to a concentration of ca. 10-4M. The equilibrium between the two is discussed based on its ultraviolet absorption spectra at various pH values.

10-Methoxy-6, 7-dihydro-12H-indolo [2, 3-a] quinolizinium salts were prepared in ca. 90% yield through condensation of 6-methoxytryptophol tosylate with 2-bromopyridine, which is the best record so far described for this type of condensations. The above salt was hydrogenated to the octahydroindolo [2, 3-a] quinolizine derivative.

By the reaction of triazacycl [3, 3, 3] azine derivatives (IV) with dimethyl acetylene-dicarboxylate in dimethylformamide or acetonitrile, the two products, namely dimethyl 4-cyano-1, 6-diazacycl [3, 3, 3] azine-2, 3-dicarboxylate (VIa) and tetramethyl 1, 6-diazacycl-[3, 3, 3] azine-2, 3, 4, 5-tetracarboxylate (VIb), were obtained.

By the reaction of 4-imino-4H-pyrido [1, 2-α] pyrimidine derivative (I), and dimethyl acetylenedicarboxylate or methyl acetylenecarboxylate, with 5% Pd-C, 1, 4-diazacycl-[3.3.3] azine derivatives (III, V) were obtained respectively. Moreover, the degradation of V was attempted to give a new parent compound, namely 1, 4-diazacycl [3.3.3] azine (VIII). VIII may be an antiaromatic compound by the PMR spectrum.