Cinnolines and Phthalazines

Dihydralazine (67-3) is the less important of the two phthalazine antihypetensive agents its preparation is however recorded first because of its simplicity. Thus, reaction of phthaUiydrazide (67-1) with phosphorus oxychloride leads to the by now very famihar conversion of the amide functions to enol chlorides (67-2). The displacement of halogen by hydrazine leads directly to the antihypertensive agent dihydralazine (67-3) [76]. 

The preparation of a monosubstituted phthalazine hinges on the differing oxidation states of the starting carbonyl groups. Thus reaction of acid-aldehyde (67-4) with hydrazine gives an intermediate (67-5) that contains a hydrazone as well as a 

Replacement of the hydrazine function by a substituted 4-piperidinol leads to a compound that has been investigated as a cardiotonic agent that acts by increasing the contractile force of cardiac smooth muscle. The preparation is quite analogous to those above. The key step involves the displacement of chlorine from the substituted chlorophthalazine (68-1) with the ethyl carbamate from 4-piperidinol (68-2) to afford the alkylation product carbazeran (68-3) [77]. 

Several therapeutic agents are based on phthalazinone nuclei, in which the hydrazide carbonyl group persists in unmodified form. Reaction of keto-acid (69-1) with hydrazine leads to the phthalazinone (69-2). Alkylation of the hydrazide nitrogen with 2-(chloroethyl)-A-methylpyrrolidine (69-3) surprisingly leads to the incorporation of a seven-membered azepine ring rather than the expected ethylpyrroldine. This can be explained by keeping in mind that it is likely that the 

Reaction of phthalic anhydride (70-1) with the ylide from ethyl triphenylphos-phoniumacetate leads to the condensation product (70-2), which in effect consists of a cyclic enol anhydride. Treatment of this product with hydrazine leads to the hydrazone-hydrazide (70-3). Alkylation of the anion from removal of the hydrazide proton with the substituted benzyl bromide (70-4) affords the alkylation product (70-5). Saponification then leads to the aldose reductase inhibitor ponalrestat (70-6) [79]. 

---

Substituents on benzene or benzenoid rings in fused pyridazines, i.e. in cinnolines and phthalazines, usually exhibit reactivity which is similar to that found in the correspondingly substituted fused aromatic compounds, such as naphthalene, and is therefore not discussed here. 

Since the pyridazine ring is generally more stable to oxidation than a benzene ring, oxidation of alkyl and aryl substituted cinnolines and phthalazines can be used for the preparation of pyridazinedicarboxylic acids. For example, oxidation of 4-phenylcinnoline with potassium permanganate yields 5-phenylpyridazine-3,4-dicarboxylic acid, while alkyl substituted phthalazines give pyridazine-4,5-dicarboxylic acids under essentially the same reaction conditions. 

R] Singerman, G. M. Cinnolines. In Heterocyclic Compounds. Condensed Pyridazines Including Cinnolines and Phthalazines-, Weissberger, A., Taylor, E. C. Eds. John Wiley Sons New York-London, 1973 pi. 

Quinoxalinyl, 4-cinnolinyl, and 1-phthalazinyl derivatives, which are all activated by a combination of induction and resonance, have very similar kinetic characteristics (Table XV, p. 352) in ethoxylation and piperidination, but 2-chloroquinoxaline is stated (no data) to be more slowly phenoxylated. In nucleophilic substitution of methoxy groups with ethoxy or isopropoxy groups, the quinoxaline compound is less reactive than the cinnoline and phthalazine derivatives and more reactive than the quinoline and isoquinoline analogs. 2-Chloroquinoxaline is more reactive than its monocyclic analog, 2-chloropyrazine, with thiourea or with piperidine (Scheme VI, p. 350). 

R. N. Castle, Condensed Pyridazines, including Cinnolines and Phthalazines. Wiley (Interscience), New York, 1973. 

The reductions of cinnolines and phthalazines were discussed in Part I, Section IV,B (Ring Contractions) or V,D. 1-Methylisoindole (190) has since been isolated as a hydrochloride from reduction in hydrochloric acid of 1-methylphthalazine with strict control of the potential to avoid further reduction to methylisoindoline (191). Purification requires acidic conditions the free base turned quickly to a tar299,300 [Eq. (113)]. 

Supplement I, The Pyrimidines Supplement II, Pteridines, Quinazolines Supplement I, The Quinoxalines Supplement II, The Pyrazines Supplement /, and Cinnolines and Phthalazines) are also from the pen of Dr. Brown. 

Azine approach. The pyridazines and their cinnoline and phthalazine benzologues can be fused with thiazoles in the same way as pyridine derivatives. The cyclization of the... 

I Pyridazines, pyridazinium salts, dihydropyridazines, tetrahydropyridazines, cinnolines and phthalazines... 

IR and NMR data have been used to study tautomerism in the pyridazine, cinnoline, and phthalazine series. For hydroxypyridazines 45 (R = H, Me), the lac-tim structures 45a rather than the lactam structures 45b were assigned. Although only lactam forms 46a and 47a were observed in the phthalazine 46 and cinnoline 47 series, the presence of betaines 46b and 47b as minor components was suggested on the basis of the chemical reactivity of these compounds (75JCS(P1)1506). 

Mich.), Order No. 66-2137 Dissertation Abstr. 26(10), 5730 (1966) C.A. 65, 3865s (1966) zitiert nach G.M. Singerman in Condensed Pyridazines including Cinnolines and Phthalazines, S. 11, 16, John Wiley Sons, New York London Sydney Toronto 1973. 

In CHEC-I the applications of pyridazines, cinnolines and phthalazines were briefly summarized <84CHEC-l(3B)i>. The antibacterial monamycins were cited as a rare example of naturally occurring pyridazines, while the growth retardant, herbicidal, and fungicidal activities of synthetic pyridazine derivatives are mentioned. Note was made of the hypotensive and antihypertensive activities of hydralazine and dihydralazine, and that in the cinnoline series only 3-and 4-amino derivatives exhibit biological activity. 

Many new pyridazine, cinnoline, and phthalazine syntheses relied on the use of hydrazine-based precursors. 4,5-Dihydro-3(2//)-pyridazinones were obtained by cyclization of hydrazine with Meldrum s acids <97SC3513>, and six-membered cyclic hydrazides 3 were obtained in very high diastereoselectivities by the coupling of azide-substituted bisfenol silanes) <97JOC5680>. PhSeBr-promoted cyclization of alkenyl phenylhydrazones led to tetrahydro-pyridazines <97T7311>, condensation of furofuranones and hydrazines led to pyrrolo[2,3-... 

Cinnolines and Phthalazines Supplement II, The Chemistry of Heterocyclic Compounds, Volume 64, by D.J. Brown Copyright 2005 John Wiley Sons, Inc. 

To keep the tables within manageable proportions, the following categories of cinnolines and phthalazines have been excluded on the grounds that they are not simple ... 

---