Guide Advances in Heterocyclic Chemistry, Vol. 38

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Koenig and H. I Org. Weis and D. Zamir, unpublished results Bodor and R. Pearlman, J. Bohm and J. Kuthan, Collect. Fowler, J. Weis and U. Degan, unpublished results Despite a paucity of theoretical calculations, those available agree with experimental data. In addition, when the energy difference between the imine and enamine is large, corresponding cyclic imines E, F, and G usually isomerize spontaneously via proton transfer to the theoretically more stable A or B. When it is small, the two isomers exist in tautomericequilibrium.

Tautomerism can also be achieved by proper selection of solvent and substituents. On the other hand, antiaromtic DHA C and D are usually less stable than the corresponding cyclic imines. With regard to cyclic imines E, F, and G, only those containing disubstitution have so far been isolated because geminal disubstitution prevents the above-mentioned isomerization from taking place. For types C and D, stabilization can also be achieved by gem disubstitution, but for these compounds substituents on the nitrogen 1 stabilize as well. Hedges, Ph. Thesis, University of New Orleans Baker, W.

Hedges, J. Timberlake, and L. Tzefomas, J. Molecular Geometry and Conformation The molecular geometry of a number of solid DHA have been determined by X-ray diffraction crystallography. Naturally, the majority of structures are available for the most stable dihydropyridines 7a,b. Of course, important information was also obtained regarding bond lengths and angles, i. Thus an X-ray diffraction study of 4,6,6-trimethyl2-phenyldihydropyrimidine 19 23 clearly showed the 1,6-dihydro structure 19b ,where, similar to the 1,2-dihydropyridinesYslight deviations from strict planarity were observed N-1 and C-6 atom out of ring , while the lone pair of N-1 undoubtedly takes part in conjugation with the double bonds.

Atoms N-1 and C-4are out 23 24 A. Weis and F. Frolow, Heterocycles 19, Particularly interesting data were obtained from the X-ray 21a in which only diffraction analysis of 4,6-diphenyl-lY2-dihydropyrimidine C-2 and C-5 were found to be out of plane and N-1 was nearly coplanar. The molecule is in a boat conformation with C-6 and C-3 pointing upward, with dihedral angles of N-1 was found to be sp2 hybridized, and the NN-2, N-2C-3, CN-4, and NN-5 bond distances were intermediate between those of single- and double-bond lengths. It is striking that the character of the NN-2 1.

The quaternary nitrogen N- 1 is tetrahedral, causing the ring to assume the boat shape. There is evidence for substantial delocalization of the N-4 electron pair hybridization between sp2 and sp3 , whereas N-1 is 0. It should be noted that the crystal structures of 22 and 23 have remarkable similarities. Both molecules are in the boat conformation with their prows twice as high as their sterns. Also, carbons occupy these apices in L. Weis, F. Frolow, and R. Vishkaucan, unpublished results Stam, A. Counotte-Pottman, and H. Counotte-Pottman, H. Hoskin, G. Wooden, and R.

Olofson, J. B 22, while nitrogens occupy these sites in It should be noted that all attempts to decrease ring inversion in 1,2dihydropyrimidine 21 under the conditions reportedz4 failed. The reason for this failure probably lies in the close proximity of C-2 to the plane, which acts to increase the rate of inversion.

However, the degree of antiaromaticity must depend critically upon the conformation of the dihydropyrazine ring, which controls the ability of the nitrogen lone pairs to interact with the K system. The degree of antiaromaticity may be controlled by the substituents on the dihydropyrazine ring, and the reason for unexpected stability of some potentially antiaromatic 1,Cdihydropyrazines can result only from a special conformation opposing cyclic delocalization of the eight electrons. This was confirmed by X-ray structural analysis of 1,4-bis p chlorophenyl -2,6-diphenyl-1,4-dihydropyrazine The position of the aryl group on N-1 apparently leads to separation of the electronic interactions, yielding a six-n-electronic delocalized homoaromatic system CCN C-6 plane and an almost orthogonal lone pair on N According to Schmidt: this structural observation supports the notion that six-membered, formally antiaromatic ring systems can counteract electronic destabilization by assuming a conformation of substituents, which substantially reduces or eliminates delocalization of the eight K electrons.

The dihydrotriazine ring was found to take the boat conformation, which, because of the delocalization of the K electrons and lone-pair electrons of N-2, was significantly squashed. Streitwieser, Jr. Wiley, New York, Sterowski, Cryst. Lown, M. Akhtar, and R. McDaniel, J. Kohn and R. Ayato, I. Tanaka, T. Yamane, T. Ashida, T. Sasaki, K. Minamoto, and K. Harada, Bull. Besides these two main types, some more specific approaches have also been designed. For example, 4 2 combinations have found wide application in the preparation of 4,5- 8f and 1,4- 8b dihydropyridazines by condensation of 1,Cdiones with hydrazine Scheme 1.

WEIS On the other hand, 2,3-dihydropyrazines 10c are formed most readily by a condensation of 1,Zdiones with bisamines Scheme 2. The latter represents the widely used classical Hantzsch's synthesis, which combines two molecules of an active a-methylenic carbonyl compound, an aldehyde, and an ammonia source Scheme 3. For over a century, the mechanisms by which these reactions were suggested had no experimental justification. It is easy to note the similarities in formation of the intermediate cyclic N,O hemiacetals carbinolamines 26a-d.

The dehydration step also requires further investigation because the initial dehydration product may be stable, it may exist in tautomeric equilibrium, or it may be converted spontaneously to the more stable isomer ring, depending on the relative stabilities of the various isomers. If a detailed mechanism for these reactions is known, control of experimental conditions can be used to direct reaction products and improve yields. As the name suggests, dihydroazines may be, and some actually are, formed by the addition of two hydrogens to the azine nucleus.

According to Evans,35 reductions of organic species can be classified according to the active entities involved: 1. Hydrogen atoms are implicated or thought to be implicated in a catalytic reduction, b electrochemical reduction at a low-overvoltage electrode, c photochemical reduction, d reduction involving complex metal 34 35 K. Marsi and K. Thorre, J. WElS [Sec.

Advances in Heterocyclic Chemistry: Volume 97 by Alan R. Katritzky -

Hydrogen is transferred as hydride ion in g reduction involving complex metal hydrides containing boron or aluminum, h homogeneous hydrogenation involving certain monohydride complexes of Group VIII metals, and i hydrogen transfer from one substrate to another. Finally, hydrogen is transferred as protons in j reduction brought about by dissolving metals, k electrochemical reduction at a high-overvoltage electrode, and 1 reduction, the first stage of which is attack by an anion.

However, it is symptomatic of the present state of DHA chemistry that only a few of the possible reductions have been used systematically to produce azine compounds. Reduction chemistry is best known for the pyridine series. The addition of organometallic reagents to six-membered nitrogen heterocyclic aromatic compounds azines is fairly general, leading to the corresponding dihydro derivatives.

It should be noted, however, that organomagnesium compounds are less reactive toward these substrates, as shown by the requirement of more vigorous reaction conditions. Therefore, their use is often subject to complications, and they generally give results inferior to those of organolithium compounds. In general, both 1,2- or 1,6- and 1,Caddition occur, but under kinetic control organolithium compounds show a greater tendency to 1,Zaddition than do organomagnesium compounds. However, the reversibility of 1,Zaddition can lead to the eventual formation of 1,Cadducts under thermodynamic cont r 0 1.

The study of these isomerizations is still in its infancy. What is known will be presented below. Wilkinson, ed. Lown and M. Akhtar, Chem. Akhtar, Tetrahedron Lett. Thermal isomerizations, including hydrogen transfer in DHA, may be divided into those involving, formally, either [1,3]- amidinic and imineenamine tautomerism or [1,q-hydrogen shifts. In the chemical literature it is common practice to classify hydrogen migrations as either rearrangements or tautomerisms, depending on their kinetic and thermodynamic parameters, the former being reserved for irreversible or slow processes, while the latter are used to describe fast reversible exchanges.

Minkin and co-workers have provided criteria for distinguishing between tautomerism and rearrangement, which are summarized in Eqs. Equation 2 serves to define tautomeric rearrangements as those transformations in which the lifetimes of the isomers are too short to enable the preparative separation of the two forms. Obviously, the above criteria should be regarded as no more than guidelines.

Nevertheless, they do form a useful basis for distinguishing tautomeric reactions from rearrangements. Amidinic Tautomerism The prototropic tautomerism of compounds containing an amidine moiety has been studied extensively. The difficulties encountered in this work stem primarily from the common experience that proton transfer between electronegative atoms, such as nitrogen, is very fast. Minkin, L. Olekhnovich, and Y. Zhdanov, Acc. Schwenker and K. Bod, Pharmazie 24, Katritzky and J.

Lagowski, Adu. Elguero, C. Marzin, A. Katritzky, and P. Linda, Adv. Kresp, Acc. Zefirov and S. Tratch, Chem. Acyclic: I I R R 2. Semicyclic: H 3. Most efforts were devoted to investigation of the amidinic tautomeric equilibrium in imidazoles or cyclic systems containing the imidazole fragment moiety histidine, purine, etc. Experimental evidence concerning annular tautomerism in six-membered cyclic amidines is very limited.

Moreover, in the dihydroazine series no data were available until recently. Moreover, it is to be expected that amidinic tautomerism could serve as a convenient model for investigating, in general, the factors governing tautomerism in cyclic molecules and could also be used for comparative studies on the factors controlling corresponding tautomeric effects in noncyclic analogues. Imine-Enamine Tautomerism Imine-enamine tautomeric equilibrium was observed in different substituted dihydroazines by NMR spectroscopy.

Ph n",s'"- fyPh Ph H 27s 27b This result shows that the two isomers are in thermodynamic equilibrium. Moreover, when deuterated acetone is added to the chloroform solution, equilibrium is displaced toward the 1,Zdihydro derivative 27b. For example, on the basis of NMR measurements in CDCI,, it has been shown that 3,6diphenyl-4,5-dihydropyridazine 28a exists in tautomeric equilibrium with the corresponding 1,4-dihydro compound 28b in the ratio Armand, K.

Chekir, and J. Pinson, Can. WEIS Imine-enamine equilibrium depends on the difference between the two isomers, solvent polarity, and substituent effects on the dihydroazine ring; and according to the definition of tautomerism, where the energy difference is not overwhelmingly large [Eq.

Whereas in the case of large energy differences, fast rearrangement to the thermodynamically more stable isomer occurs, for instance, the rapid transformation of 4,5-dihydropyrimidines to tautomeric 1,4- and 1,6-dihydropyrimidines see Section V,C, 1 or the formation of 1,4-dihydropyridazines by cycloaddition to 1,2,4,5-tetrazines see Section IV,B,2. Some other examples of rearrangements have been published. Detailed research of these processes will certainly provide a deeper understanding of the problems of tautomerism and rearrangements as a whole as well as of the energetics, reactivity, and mechanisms of the formation of a variety of dihydroazines.

To date no systematic study of the physical properties have been undertaken, nor have any measurements of theoretical interest been carried out, such as photoelectron emission, mass spectrometry, and electrochemical determinations. Schweizer and C. Kopay, J. De Mayo and M. Usselman, Can. Hoffmann and E. Muehle, 2. Dihydropyridazines A. Since those dihydropyridazines with unsubstituted ring nitrogens exist almost exclusively as isomeric pairs 8f and 8b-often in tautomeric fast equilibrium with one anotherit has sometimes been difficult to differentiate clearly the chemistry of the 4,5-dihydropyridazines 8f from that of the 1,4-dihydropyridazines 8b.

Before the advent of modern spectroscopic techniques, workers found it difficult to assign a given tautomeric form to a particular dihydropyridazine. Thus many compounds originally reported as 4,5-dihydropyridazines may in fact exist predominantly as the corresponding 1,Cdihydro isomer. The reader should, therefore, note that in the following discussion, we have assumed that tautomeric forms of the various dihydropyridazines, as assigned by the original authors, are correct, unless subsequent data have contradicted their validity.

Cyclization Methods One of the most common and versatile methods for synthesizing dihydropyridazines is the condensation of saturated 1,Cdicarbonyl compounds with hydrazines Scheme 1, Section ,C. Following this work, several dihydropyridazines were synthesized by other early T. Erdelfield, ed. Tisler and B. Stanovnik, Ado. Curtius, J. WEIS at the beginning of this century. The results obtained by different authors gave rise to much controversy, since not all condensations of hydrazine with saturated diketones yield single products mono- and bishydrazones, aminopyrroles, polymers, etc.

Therefore, the reaction has been thoroughly investigated, especially with regard to reaction conditions, since different by-products can be produced under different reaction environments. Paal and E. Dencks, Chem. Smith, Justus Liebigs Ann. Paal and G. Kuhn, Chem. Bulow and H. Filchner, Chem.

Korshun, Chem. Jones, J. Mosby, J. Korshun and C. Roll, Gazz. Blaise, C. Seances Acad. Zimmerman and H. Lochte, J. Gapuano, Gazz. Borshe and A. Klein, Justus Liebigs Ann. Alder and C. Schmidt, Ber. B 76, Heller, R. Pasternak, and H. Acta 29, Overberger, N. Byrd, and R. Mesrobian, J. Arcus and P.

Hallgarten, J. Cohen, S. Hsiao, E. Wang, J. Fatutta, Ann. Rome 51, Rome 52, Williams and W. Dolbier, Jr. For example, acetonylacetone Different reaction conditions may also influence the reaction course. More recently, Russian workers have shown that l-alkyl-3,6-dimethyl-1,4dihydropyridazines 30 are produced in the condensation of acetonylacetone with alkyl hydrazines.

Some relatively simple 1,4-dihydropyridazines 31 were prepared by condensation of monosubstituted hydrazines with succinic or levulinic aldehyde. Schlenk, H. Hillemann, and J. Rodloff, Justus Liebigs Ann. Desaty, 0. Hadzija, and D. Keglevic, Croat. Acta 37, Helferich and 0. Lecher, Ber. B 54, Schlenk, Justus Liebigs Ann. Verzele and F. Govaert, Bull. Westphal, 2. Zelenin and J. Dumpis, Khim.

Dumpis, Zh. Bandlish, J. Brown, J. Trefonas, J. Dodge, W. Timber1ake;and L. These authors did not report any trimerization of the dihydropyridazine. Apparently, the steric requirements of the phenyl groups preclude this eventuality. However, it has been shown that 35 exists in the 86 K. Zelenin, V.

Nikitin, N. Anodina, and Z. Matvejeva, Zh. Henoch, K. Harnpton, and C. Hauser, J. Severin et aLS9 found that l-phenylphenylhydrazonobuten undergoes cyclization to 1,2-dihydropyridazine 38 in the presence of p-toluenesulfonic acid. Cycloaddition Reactions The cycloaddition reaction of 1,2,4,5-tetrazineswith olefins developed by Carboni and Lindseygo represents a second major route to dihydropyridazines Scheme 5.

Schweizer, C. Kim, C. Labaw, and W. Murray, Chem. Severin, R. Adam, and H. Lerche, Chem. Carboni and R. Lindsey, J. B SCHEME 5 According to the mechanism proposed, the 1,Ccycloaddition Diels-Alder reaction of the diene part of the tetrazine to the dienophile olefin gives an unstable bicyclic intermediate, which spontaneously eliminates a molecule of nitrogen, forming a 4,5-dihydropyridazine, which in the absence of appropriate stabilization by gem disubstitution in positions 4 and 5, easily isomerizes to the thermodynamically more stable 1,4-dihydropyridazine The structure of the latter intermediates were unambiguously proved using NMR.

Thus tetrazines bearing electron-withdrawing substituents such as methoxycarbonyl, polyfluoroalkyl, and 2-pyridyl react with an olefinic component more rapidly than do those substituted with methyl or phenyl groups. Conversely, electron-rich olefins such as vinyl ethers show much greater reactivity than do electron-deficient olefins such as acrylonitrile and acrolein. Sauer and Heinrichsg3 found, for example, that N-morpholinostyrene a very electron-rich olefin , ethylene, and acrolein showed relative reaction rates of ,,, respectively, with 3,6-dicarbomethox ytetrazine. Carboni and Lindseygohave also pointed out the significant role played by steric restrictions, which may be important for the reactivity of dienophiles in the synthesis of dihydropyridazines.

For instance, 2,3-dimethylbutene an electron-rich but sterically hindered olefin reacts only with the polyfluoroalkyl substituted tetrazines 39a and 39b, giving correspondingly 4,5-dihydropyridazine 40ag5and 40b. Sauer, A. Mielert, D. Lang, and D. Peter, Chem. Avram, G. Bedford, and A. Katritzky, Red. Pays-Bas 82, Sauer and G. Heinrichs, Tetrahedron Lett. Avram, J. Dinulescu, E. Marica, and C. Nenitzescu, Chem. Barlow, R. Haszeldine, and J. Pickett, J. Perkin I , At the same time, however, tetrazine 39a reacts rapidly with styrene to give 1,Cdihydropyridazine However, a large number of olefins have been treated with these few tetrazines, yielding a large variety of dihydropyridazines.

Cycloadditions are also known with diazoalkanes and related compounds. Diazomethane reacts with a cyclopropene, and the pyrazoline cycloadduct 42 is rearranged by acid to the dihydropyridazine Franck-Neumann and C. Buchecker, Tetrahedron Lett. Komendantov and R. Bekmukhametov, Zh. WElS cycloadduct 44 is converted by alkali or acid to 3,5-diphenylpyridazine via the corresponding dihydropyridazine intermediates H 46 2W One of the products isolated by treatment of cyclopropene with methyl diazoacetate is dihydropyridazine 48,'" apparently formed via an unstable adduct 47 [Eq.

Me Me Me Me Me Me I H 47 48 Diazomethane reacts in ether with the cyclopropenes 49 to yield the corresponding cycloadducts, which may be transformed by base catalysis or by chromatography on silica gel to 1,4-dihydropyridazine Komendantov, R. Bekmukharnetov, and V. Novinskii, Zh. Zaitseva, I. Avezov, 0. Subbotin, and 1. Bolesov, Zh. Padwa and H. Ku, Tetrahedron Lett.

Aue, R. Lorens, and G. Helwig, J.

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Regitz, W. Welter, and A. Hartmann, Chem. Carpenter and co-workers lo4 have shown that 2,3-diazabicyclo C2.

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Stickler and W. Hoffmann, Angew. Wildi, D. Carpenter, J. Under the conditions of their experiment, they found that a dimeric species which could be characterized only partially because of its instability was formed along with trimer From Pyridazine and its Derivatives a. A third major route to. These reactions proceed via nucleophilic attack at the electron-deficient positions of the pyridazine ring, followed in many cases by 1,2-, 1,4-, or 1,6-addition, and further hydrolysis to give the desired dihydropyridazine.

Letsinger and Lasco reportedlo5 that dihydropyridazines formed by the action of Grignard reagents or organolithium compounds on pyridazines are too unstable to permit characterization and thus underwent spontaneous aromatization. This reaction was reinvestigated by van der Stoel and van der Plas,'06 who managed to isolate the dihydropyridazines resulting from phenyllithium addition.

However, these also proved too unstable for complete analysis. Letsinger and R. Lasco, J. Bas 97, In addition, an interesting example of nucleophilic 1,2-and 1,4-addition of thienyllithium to pyridazine, with the formation of corresponding 1,6- 56 and 1,4-dihydropyridazine 57 , has been published [Eq. Bourguignon, C. Becue, and G. Queguiner, J. Miniprint, ; J. Chem, Res. WEIS The addition of organometallics to substituted pyridazines was studied '' Symmetrically 3,6-disubstituted pyridazines yield homoextensively.

Electronic considerations favor addition of organometallics such that the resultant negative charge is localized on the side of the more electron-withdrawing substituent. The formation of dihydropyridazines by the reaction of tert-butyl Grignard with trisubstituted pyridazines has attracted particular attention. Crossland, Acta Chem. Christensen and 1. Avellen and I. Crossland and H. Kofod, Acta Chem. Avellen, 1.

Crossland, and K. Lund, Acta Chem. Crossland and L. Rasmussen, Acta Chem. Crossland and E. Kelstrup, Acta Chem. Fateen and N. Shams, J. I2O E. Baddar, M. Nosseir, N. Doss, and N. Messiha, J. Perkin I, Upon treatment with acid, 65 converts rapidly to cis-4,5-di-tert-butyl-3,6-dimethoxy-4,5-dihydropyridazine 66 , owing to the proton entering at the least hindered face of The cis compound is then slowly transformed to the more stable trans isomer 67 , presumably through equilibrium with The reaction of 60x0- 1,4,5,6-tetrahydropyridazineswith Grignard reagents or LiAlH, leads to dihydropyridazines.

WEIS [Eq. Mustafa, W. Asker, A. Harhash, K. Hoda, H. Jahine, and N. Kassab, Tetrahedron Baddar, A. El-Habashi, and A. Fateen, J. Baddar, N. Latif, and A. Nada, J. El-Kaschef, F. Abdel-Megeid, and M. Michael, Egypt. Iz6 J. Aubagnac, J. Elguero, R.

Advances in Heterocyclic Chemistry, Volume 112

Jacquier, and R. Robert, Bull. The majority of known 1,4- and 1,6-dihydropyridazines are highly substituted or have strong electronwithdrawing groups on the pyridazine ring. Simple 1,6-dihydropyridazines 71 have now been prepared from 1-methylpyridazinium salts and sodium borohydride. If, however, the reduction is performed in the presence of methyl chloroformate, stable l-methoxycarbonyl-l,6-dihydrocompounds 72 were obtained, accompanied by a small amount of the 1,Cdihydro isomers 73 [Eq. For instance, the action of lithium aluminum hydride on the diethyl ester of 3,6-dimethylpyridazine-4,5-dicarboxylicacid produces 74 in addition to other compounds [Eq.

Attention has been given to the electrochemical reduction of pyridazines. The following mechanism in Eq. A second reduction wave is also observed, but it is reported to be due to the reduction of a ring-opened species. Kaneko, T. Tsuchiya, and H. Igeta, Chem. Adembri, F. De Sio, R. Nesi, and M. Scotton, J. Klatt and R. Rouseff, J. Interfacial Electrochem. WEIS H H Lund studied the electrochemical reduction of substituted pyridazines and reported that reduction of 3,6-diphenylpyridazine gave the 1,4,5,6-tetrahydro derivative Lund, Faraday Discuss.

Heterocycl Chem. Lund and J. Simonet, C. C , Rosseels, Ing. Brussels 46,7 Brussels 42, Alder, H. Niklas, R. Aumuller, and B. Olsen, Justus Liebigs Ann. Altman, M. Semmelhack, R. Hornby, and J. Vederas, Chem. Vederas, Org. Rink, S. Mehta, and K. Grabowski, Arch. Weinheim, Ger. D Crossland and Avellen' l o observed that addition of trifluoroacetic acid to a chloroform solution of 28a and 28b shifts the equilibrium entirely toward the 4,5-dihydro tautomer 28a. Neutralizing the solution, however, restores the original equilibrium. Equilibrium positions were also determined for two other 3,6-diaryl compounds, and in both cases the equilibrium favored the 1,4dihydro tautomer.

The ratio of 4,4-dimethyl-3,6-diphenyl-1,4-dihydropyridazine 81 to the 4,5-dihydro tautomer is 3. The difference in free energy, A G O , between the two tautomers can be calculated from the ratio of the two forms in solution using Eq. For the 3,6-di-tertbutyl tautomers, a value of only 0. Infrared Spectra The correlation of dihydropyridazine structure with absorption maxima in the IR region has not been systematically studied. Information presented here has been gleaned from data contained in original works.

Two intense absorption bands have been reported for 1,4-dihydropyridazines at and cm-'. However, some discrepancy exists in the assignment of these bands. Some workers Other authors95reverse the assignment. According to Zelenin et a1. Ultraviolet Spectra Only isolated UV spectra appear in the original literature. Nuclear Magnetic Resonance Spectra Nuclear magnetic resonance is an invaluable tool for investigating dihydroazines and, in particular, the dihydropyridazines. Unfortunately, until recently, most investigators have reported only proton resonance data. No doubt, in the future, more attention will be paid to I3C and 15N,which can contribute much information.

The most useful applications of NMR have been in structural determinations and in identifying the presence of tautomeric equilibria. Table I summarizes some typical dihydropyridazine spectra. The chemical shifts of the ring protons at unsaturated centers range from 6 4. WEIS be expected, proximity of an electron-withdrawing substituent on a ring nitrogen results in shifts to lower fields. Ring protons at saturated centers produce signals at 6 2. The NH protons have been found for 42dihydropyridazine at 6 1. The ring methylene protons are usually equivalent, indicating, apparently, a rapidly occurring interconversion.

Long-range coupling constants across the ring are frequently observed see Table I. The only known property of most of the N-unsubstituted dihydropyridazines is that they can be easily oxidized very often spontaneously in air to the corresponding aromatic pyridazines. Padwa and Gehrlein reported'39 that excited-state behavior of 1,6dihydropyridazines differs from that of other diazacyclohexadienes. Furthermore, the authors noted that the dihydropyridazine system underwent a deep-seated skeletal rearrangement when treated with aqueous acid. Thus reaction of 36a with aqueous hydrochloric acid results in the formation of 1,3,4-triphenylpyrazole 85 [Eq.

Padwa and L. Gehrlein, J. Dihydropyrimidines A. However, most of the known dihydropyrimidines have either the 9a or the tautomeric 1,4- 9b and 1,6- 9c dihydro structures Section ,B. The chemistry of dihydropyrimidines is virtually a closed book owing to an absence of efficient synthetic methods. Moreover, there is also a dearth of quantitative data on the stabilization-destabilization effects of substituents on these ring systems. In addition, structures and relative stabilization of the various isomers and the tautomeric 1,6- and 1,4-dihydropyrimidines, in particular, were unknown until recently.

In most published reports, suggested structures for products have been proposed with insufficient information to justify the given assignments. Cyclization Methods a. However, until recently, only a few reactions of this type were known, the result of a fortuitous combination of reaction conditions and starting materials. De Mayo, J. Stothers, and M. Weissberger, ed. Wiley Interscience , New York, Silversmith has shown that the spectral data IR and NMR contradict the proposed structure, but are consistent with either of the tautomeric 1,4- and 1,6dihydropyrimidines.

It has been demonstrated that the product obtained by Traube and Schwarz exists in the solid state as a 2-phenyl-4,6,6-trimethyl1,6-dihydropyrimidine 19b , whereas in solution a tautomeric equilibrium mixture of the 1,4 and 1,6 forms is observed. In the course of confirming this reaction scheme, the intermediacy of tetrahydropyrimidines and dihydropyrimidines was demonstrated.

Further improvements that facilitated each step of this reaction using molecular sieves, DMSO, and air led to a new one-pot synthesis of "'W. Traube and R. Schwarz, Ber. Silversmith, J. Ruhemann, J. Dodson and J. Seyler, J. Moreover, this understanding has led to selective preparation of cyclic adducts of benzamidine with chalcone and cinnamic aldehyde. Therefore, in the author's laboratory, a new strategy to prepare these compounds was proposed, which executes the two key steps in the reaction mechanism in separate stages: a preparation of hydroxytetrahydropyrimidine 86 [Eq.

Usually a nearly quantitative yield of 6hydroxyl- 1,4,5,6-tetrahydropyrimidineswas achieved under mild conditions, and optimal methods of dehydration were developed. This gives a new and versatile synthetic route, enabling the preparation of a large variety of dihydropyrimidines see Table First step: R3 P3 86 V.

Mamaev and A. Weis, Khim. Weis and V. Mamaev, Izv. Nauk, 91 [CA 84, t J A. Weis, V. Shirina,and V. Nauk, [ C A 84,r l. Nauk, [CA84,u l. Mamaev, Khim. Heyes and J. Roberts, J. Yield in parentheses according to NMR. Unstable compounds. Isomeric mixture. Therefore, if one could interfere with this polymerization, the Michaeltype addition, leading to the desired product, could then proceed unhindered.

Hydroquinone was found to provide the best such protection against polymerization of acrolein. Dehydration of these products was carried out by boiling in dimethoxyethane or other solvents such as acetonitrile and DMF , giving 2-phenyl- and 2methyldihydropyrimidine in reasonable yields Table Unsubstituted dihydropyrimidine was also prepared by this method; however, high instability did not allow isolation in a pure state, and therefore only spectral verification could be provided. Good yields were also obtained by dehydration, using acid catalysis or acetic acid as a solvent. All dihydropyrimidines synthesized by this method exist in solution in tautomeric equilibrium of 1,4- and 1,6-dihydro compounds Section V,C,l.

Besides the high yields of dihydropyrimidines, another valuable advantage of this method is that one can usually follow the transformation to dihydropyrimidine visually by choosing a suitable solvent, namely, one with a low solubility for hydroxytetrahydropyrimidine Moreover, the reaction is very clean, and evaporation of the solvent alone usually gives an analytically pure dihydropyrimidinic product.

Le Berre and C. Renault, Bull. Frolow, D. Zamir, and M.

2 Heterocyclic nomenclature I

Bernstein, Heterocycles 22, WEIS The initial product of dehydration of hydroxytetrahydropyrimidine 86 is the unstable 4,5-dihydropyrimidine 87, which presumably undergoes either thermal suprafacial [ 1,5]-hydrogen migration to the corresponding 1,6- Apparently, the rate of hydrogen migration is fast, since 4,5-dihydropyrimidines were neither isolated nor detected spectroscopically.

However, some indirect proofs for intermediacy of 4,5-dihydropyrimidines were obtained. The key step in this reaction is likely the formation of highly reactive 4,5-dihydropyrimidine 91, which is rapidly attacked by the phenolic hydroxy group before it undergoes proton migration to the stable dihydropyrimidine [Eq. The mechanism of this hydrogen migration needs further study. Frolow, M. Bernstein, and J. Fahima, Isr. By using the reaction pathway developed in our laboratory, reaction of the ester function can be avoided, and high yields of dihydropyrimidines are obtained from hydroxytetrahydropyrimidines.

Weis, Israel Patent Application pending. Honors include 14 honorary doctorates from 11 countries and membership of foreign membership of the National Academies of Britain, Catalonia, India, Poland, Russia and Slovenia. We are always looking for ways to improve customer experience on Elsevier. We would like to ask you for a moment of your time to fill in a short questionnaire, at the end of your visit. If you decide to participate, a new browser tab will open so you can complete the survey after you have completed your visit to this website.

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