Dihydro Compounds

We consider as dihydro derivatives those rings which contain either one or two 5p3-hybridized carbon atoms. According to this definition, all reactions of the aromatic compounds with electrophiles, nucleophiles or free radicals involve dihydro intermediates. Such reactions with electrophiles afford Wheland intermediates which usually easily lose H+ to re-aromatize. However, nucleophilic substitution (in the absence of a leaving group such as halogen) gives an intermediate which must lose H and such intermediates often possess considerable stability. Radical attack at ring carbon affords another radical which usually reacts further rapidly. In this section we consider the reactions of isolable dihydro compounds it is obvious that much of the discussion on the aromatic heterocycles is concerned with dihydro derivatives as intermediates. 

The reactions of dihydro compounds are of two main classes. The first class comprises reactions to regain aromaticity which depend intrinsically on the dihydro six-membered heterocyclic structure and these can in turn be subdivided into four groups, of which the first is by far the most important  

The other class of reactions includes those which are common to alicyclic analogues reactions with electrophiles and nucleophiles and through cyclic transition states. 

We discuss these in turn, but first consider tautomeric structures. 

There are five dihydropyrimidines (455)-(459). Most of those known have either the 1,2- or the tautomeric 1,4- or 1,6-dihydro structures. Gaussian 70 ab initio calculations of the energy of unsubstituted dihydropyrimidines yielded the following order of stability (457) (456) (455) (458) (459). The results agree with the experimentally observed behavior of these compounds 

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This reaction is proof of the structure of the dye, easily obtained from the dihydro compound (3). Yields are low as a result of numerous side reactions. The stereochemical configuration of these quinoid dyes is trans. 

In a series of detailed studies, Armand and coworkers have examined the electrochemical reduction of pyrazines (72CR(C)(275)279). The first step results in the formation of 1,4-dihydropyrazines (85), but the reaction is not electrochemically reproducible. The 1,4-dihydropyrazine is pH sensitive and isomerizes at a pH dependent rate to the 1,2-dihydro compound (83). The 1,2-dihydropyrazine then appears to undergo further reduction to 1,2,3,4-tetrahydropyrazine (88) which is again not electrochemically reproducible. Compound (88) then appears to undergo isomerization to another tetrahydro derivative, presumably (8, prior to complete reduction to piperazine (89). These results have been confirmed (72JA7295). 

The NMR spectra of the parent compounds of the pyrido-[2,3-d]- and -[3,4- f]-pyridazine systems have been studied, together with those of some closely related derivatives parent compound, 282). In the pyrido[4,3-c]pyridazine series, only the spectrum of the dihydro compound (302) has been recorded <79X2027). 

Aluminum or sodium amalgam reduces 3-ones to 1,2-dihydro derivatives (71TH21500), as does borohydride (63JCS5156) and catalytic hydrogenation (Pd/SrCOs) (71TH21500). Catalytic (Pd/C) reduction of a 5-one also gave a 1,2-dihydro compound (74JMC553). 

Cationic rings are readily reduced by complex hydrides under relatively mild conditions. Thus isoxazolium salts with sodium borohydride give the 2,5-dihydro derivatives (217) in ethanol, but yield the 2,3-dihydro compound (218) in MeCN/H20 (74CPB70). Pyrazolyl anions are reduced by borohydride to pyrazolines and pyrazolidines. Thiazolyl ions are reduced to 1,2-dihydrothiazoles by lithium aluminum hydride and to tetrahydrothiazoles by sodium borohydride. The tetrahydro compound is probably formed via (219), which results from proton addition to the dihydro derivative (220) containing an enamine function. 1,3-Dithiolylium salts easily add hydride ion from sodium borohydride (Scheme 20) (80AHC(27)151). 

Dihydro compounds show reactions which parallel those of their aliphatic analogues provided that the aromatization reactions just discussed do not interfere. 

Following the classification of Chapter 4.01, three classes will be considered, (a) Compounds isomeric with aromatic compounds (6), (7) and (8). The quaternary, non-aromatic salts (Scheme 7, Chapter 4.01) will be discussed only in connection with protonation studies which lead to the conclusion of their non-existence. The carbonyl derivatives (9), (10), (13) and (14) will also be included here because it is possible to write an aromatic tautomer for each one, (9 )-(14 ), even if it is energetically unfavoured, (b) Dihydro compounds. In this class not only pyrazolines (15), (16) and (17) but also pyrazolidinones (18) and pyrazolinediones like (1) are included, (c) Tetrahydro compounds. Besides the pyrazolidines (19), the pyrazolidinetriones (2) are included here. 

Borohydride reduction of 3-aryl-l,2-benzisothiazole 1,1-dioxides gives the 2,3-dihydro compounds 73JMC1170). Reduction of either 2-methylsaccharin or 2-hydroxymethylsac-charin with lithium aluminum hydride gives the same product, iV-methyl-o-hydroxymethyl-benzenesulfonamide (73AHC(15)233). 

The A-ring of the 17-ol (25) derived from equilenin 3-methyl ether is reduced rapidly under Birch reduction conditions, since the 1,4-positions are unsubstituted. The B-ring is reduced at a much slower rate, as is characteristic of aromatic compounds in which 1,4-reduction can occur only if a proton enters an alkylated position. Treatment of (25) with sodium and t-butyl alcohol in ammonia reduces only the A-ring to afford the corresponding 1,4-dihydro compound in over 85% yield.On the other hand,... 

Bates and his associates have found that cyclohexadienyl carbanion itself protonates at the central carbon atom from three to eight times as rapidly as at a terminal one, but the conditions involved were different from those encountered in a Birch reduction. Since the Birch reduction of many 3-meth-oxyestra-l,3,5(10)-triene derivatives affords 1,4-dihydro compounds in yields approaching 90%, the cyclohexadienyl carbanions involved in these reductions must protonate about eighteen times faster at the central carbon atom than at a terminal one. 

Lithium-ammonia reduction of l7a-ethyl-19-nortestosterone (68) using Procedure 8a (section V) affords the 4,5a-dihydro compound (69) in 85% yield after a reaction time of 12 minutes after a reaction time of 80 minutes, the yield of (69) is 76%. Lfsing sodium in the same reduction, the yields of compound (69) are 79 and 77 % after reaction times of 8 and 80 minutes respectively. Both the lithium and sodium enolates appear to be reasonably stable in liquid ammonia in the presence of alkali metal. Since the enolate salts are poorly soluble in ammonia, their resistance to protonation by it may be due in part to this factor. 

Residual aromatic ether concentrations are determined from the absorbance at 278 mfi of the crude reduction products in methanol solution. Steroidal ether concentrations of 1 mg/ml are employed. The content of 1,4-dihydro compound is determined, when possible, by hydrolysis to the a, -unsaturated ketone followed by ultraviolet analysis. A solution of the crude reaction product (usually 0.01 mg/ml cone) in methanol containing about 1/15 its volume of water and concentrated hydrochloric acid respectively is kept at room temperature for 2 to 4 hr. The absorbance at ca. 240 mfi is measured and, from this, the content of 1,4-dihydro compound can be calculated. Longer hydrolysis times do not increase the absorbance at 240 mp.. 

The cyclization reaction of some substituted 1,2-dihydroisoquinolines is of interest (255). The reduction of papaverine with tin and hydrochloric acid affords the 1,2-dihydro compound in the form of immonium salt 172, which then undergoes a cyclization reaction in the acidic medium to give compound 173, called pavine (257). 

I, 4- and 3,4-Dihydroquinazolines are tautomeric but any attempts to prepare the former w ithout a 1-substituent have led to the latter. The greater stability to proto tropic change of 1,2-dihydronaphthalene over 1,4-dihydronaphthalene is also found in 3,4-dihydroquinazoline. Earlier claims to the preparation of l,4-dihydroquinazolines ° were erroneous and based on incomplete experimental data. The first 1,4-dihydroquinazoline was prepared as recently as 1961. 1-Methyl and l-benzyl-l,4-dihydroquinazolines were obtained from o-methylamino-and o-benzylamino-benzylamines (42) by formylation and ring closure. Attempts to remove the benzyl group gave 3,4-dihydroquinazoline. These 1,4-dihydro compounds are susceptible to oxidation, and attempts made to prepare 1,2-dimethyl-1,4-dihydroquinazoline from o-... 

Although some tautomerism betw een 1,4- and 3,4-dihydroquinazoline is theoretically possible, the dihydro compound always behaves as the 3,4-derivative except, of course, when a substituent is on N-1. 

The 4,5-dihydro compounds (34) might be expected to show different properties. Here, as with the pyrazolines discussed in Section IV, A, lone pairs of electrons should be available on both nitrogen atoms for reaction to give salts of type 35 and/or 36. No salts of type 35 have been reported. Indeed, the reaction between the alkyl halide... 

However, much greater differences between the spectra of dihydro compounds and the corresponding covalently hydrated species are sometimes found. Thus, the neutral molecule of hydrated quinazoline,... 

Hey and Osbond converted (18) to 5 6-benzoquinoline (19) with copper powder in dilute acid solution, reaction probably going through the dihydro compound (20) which was oxidized by nitrous acid in the... 

Choice of catalyst and solvent allowed considerable flexibility in hydrogenation of 8. With calcium carbonate in ethanol-pyridine, the sole product was the trans isomer 9, but with barium sulfate in pure pyridine the reaction came to a virtual halt after absorption of 2 equiv of hydrogen and traws-2-[6-cyanohex-2(Z)-enyl]-3-(methoxycarbonyl)cyclopentanone (7) was obtained in 90% yield together with 10% of the dihydro compound. When palladium-on-carbon was used in ethyl acetate, a 1 1 mixture of cis and trans 9 was obtained on exhaustive hydrogenation (S6). It is noteworthy that in preparation of 7 debenzylation took precedence over double-bond saturation. 

According to the Hantzsch-Widman system, the seven-membered unsaturated hcterocyclc with one sulfur atom is named thiepin (1). The three different benzothiepins are assigned by the position of sulfur 1-benzothiepin (2), 2-benzothiepin (3) and 3-benzothiepin (4). Of the four possible dibenzothiepins only dibenzo[6,r/]thiepin (5) and dibenzo[A,/]thiepin (6) are of importance for synthesis, while the other two isomers, which contain unfavorable o-quinoid structures, exist mainly as the stable dihydro compounds, i.c. 5,7-dihydrodibenzo[c,t ]thiepin (7) and 6,1 l-dihydrodibenzo[6,c ]thiepin (8). Benzannulation over all double bonds results in tri-benzo[6,(7,/]thiepin (9). 

The bromodihydrodibenz[/>,/]az.epine-5-carbonyl chloride 41, prepared by radical bromination of the 10,11-dihydro compound, on heating under pressure with ammonia undergoes dehydrobromination and amidation to yield Carbamazepine (42).122... 

A detailed study of the dehydrogenation of 10.1 l-dihydro-5//-benz[6,/]azcpinc (47) over metal oxides at 550 C revealed that cobalt(II) oxide, iron(III) oxide and manganese(III) oxide are effective catalysts (yields 30-40%), but formation of 5//-dibenz[7),/]azepinc (48) is accompanied by ring contraction of the dihydro compound to 9-methylacridine and acridine in 3-20 % yield.111 In contrast, tin(IV) oxide, zinc(II) oxide. chromium(III) oxide, cerium(IV) oxide and magnesium oxide arc less-effective catalysts (7-14% yield) but provide pure 5H-dibenz[b,/]azepine. On the basis of these results, optimum conditions (83 88% selectivity 94-98 % yield) for the formation of the dibenzazepine are proposed which employ a K2CO,/ Mn203/Sn02/Mg0 catalyst (1 7 3 10) at 550 C. 

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