18 Heterocyclic Chemistry Part (ii) Heteroaromatic Compounds By M. H. PALMER Department of Chemistry University of Edinburgh West Mains Road Edinburgh EH9 3JJ The arrangement of the heteroaromatic section this year is to concentrate on major topics rather than widespread coverage of synthetic methods. Thus a higher proportion of material of a physical-organic nature is included. 1 Ground-state Properties of the Ring Systems Molecular Structure.-There is now more interest than formerly in accurate X-ray analysis of simple heterocycles ; this is important to theoretical studies of the bonding in such molecules but much work still remains to be done on systems where microwave studies are presently impracticable. For both 4- cyanopyridine’ and pyridine N-oxide,’ the geometric features are very similar to pyridine itself but for the 4,4’-bis-quaternary salt (l) the ring is marginally larger than in neutral pyridines and perhaps slightly more similar to that of ben~ene.~ The microwave spectrum of thiazole yields a structure very close to that expected by superposition of thiophen and 1,3,4-thiadia~ole.~ The crystal structure of sulphathiazole shows the heterocyclic ring to be non-planar the thiazoline tautomer to be present and the 4,5-bond to be purely 01efinic.~ Substituents e.g.t-butyl can markedly effect ring geometry and 4,5-di-t-butyl- imidazole has a singularly long 4,5-bond for a formal double bond ;the external M. Laing N. Sparrow and P. Somerville Acta Cryst. 1971 B27 1986. D. Ulku B.P. Huddle and L. C. Morrow Acta Cryst. 1971 B27 432. J. H. Russell and S. C. Wallwork Acra Cryst. 1971 B27 2473. L. Nygaard E. Asmussen J. H. Hsg R. C. Maheshwari C. H. Nielson I. B. Petersen J. Rastrup-Andersen and G. 0. Sorensen J. Mol. Structure 1971 8 225. G. J. Kruger and G. Gafner Acta Cryst. 1971 B27 326. 572 Heterocyclic Chemistry-Part (ii) Heteroaromatic Compounds angles between the t-butyl groups are markedly distorted;6a a similar feature is present in the 2,3-bond of 2,3-di-t-b~tylquinazoline.~* In the carbocyclic ring of the latter and of a 1,2-benzothiazole derivative,' the short (orb)and long (bp) bonds are evident as in naphthalene. The N-C bonds of 8-hydroxyquinoline N-oxide' are very long and again the structure is like that of naphthalene.This is also particularly true of various thiathiophthens (1,6,6a-trithiapentalenes) where the parent compound has been redetermined' and a number of substituted systems have been investigated." Results of some of the key types are given here [compounds (2),9 (3),' (4),11and (5),12 bond lengths in A]. 1,83 'm 1.684 1.90 n (4) (5) Among molecules with related structures compounds with nitrogen and oxygen in the rings13 again demonstrate the slight differences in bond lengths. It seems to be generally agreed that these systems do exhibit bonding between classically non-bonded atoms. From the theoretical standpoint the rigid geo- metry makes this inevitable i.e. within the molecular orbital framework all electrons are attracted to all nuclei and the only question is how much electron density lies along a plane through the nuclear centres.X-ray electron spectro- scopy (ESCA) shows differences in environment at sulphur atoms in some thiathiophthens but as in the X-ray-diffraction data care in interpretation is necessary since some of these features can possibly be related to molecular orientation in the crystal." Among other condensed-ring compounds the bond lengths of molecule (6) are very similar to those resulting from fusion of a benzene ring with thiophen ; ' G. J. Visser and A. Vos Acta Cryst. (a) 1971 B27 1802 (6) 1971 B27 1793. ' A. C. Bonamartini M. Nardelli C. Palmieri and C. Pellizzari Acta Cryst. 1971 B27 1775. ' R. Desiderato J. C. Terry G. R. Freeman and H.A. Levy Acta Cryst. 1971 B27 2443. A. Hordvik and K. Julshamn Acta Chem. Scand. 1971 25 1895,2507. lo A. Hordvik Acta Chem. Scand. 1971 25 1583 1822; A Hordvik and K. Julshamn. ihid. p. 1835; R. Kristensen and J. Sletten ibid. p. 2366; T. R. Lynch I. P. Mellor. and S. C. Nyburg Acru Cryst. 1971 B27 1958; I. P. Mellor and S. C. Nyburg ibid. p. 1954; J. Sletten Acta Chem. Scand. 1971 25 3577. D. T. Clark D. Kilcast and D. H. Reid Chem. Comm. 1971 638. M. H. Palmer the bis-sulphone has more aliphatic bond lengths in the centre rings.12 Above 0 “C N-methylazepine yields two dimers ;the higher melting has a trans-piperazine system.l4 The detailed crystal structures of a tram-corrin’ and corrole’ have been published; they are very similar to that of porphin published some time ago except that the PP-bonds are longer and the ctp-bonds shorter than in the latter.Electronic Structure.-Within the hierarchy of molecular orbital calculations empirical (Hiickel and its variants such as the w-technique) semi-empirical (CNDO INDO MINDO etc.) and non-empirical (‘ab iiiitio’),the first category is now redundant. CNDO self-consistent field calculations lead to charge distributions which vary with the method of analysis,” but seem very plausible and often match those of non-empirical calculations. In the latter case ground- state properties such as ionization potential,” dipole moments,’ 8,19and often electronic spectra are being interpreted in detail.’ 8-20 A useful review of the field not cited earlier has been published.2’ CNDO calculations of reacting systems are practicable and in one such case22 various stable n-complexes were calculated for the interaction of hydrogen fluoride and benzene or pyridine.Rapid development of this approach is expected. Determination of the magnetic-susceptibility anisotropy for 2-and 4-pyranone shows that the experimental figure can be entirely accounted for in terms of local group contributions and that the molecules are thus non-ar~matic.~ This contrasts with the results for benzene furan etc. where aromaticity is inferred. The low barriers to inversion calculated for phospholes but larger for their benzo-derivatives have been interpreted in terms of (3p2p)n delocalization and thus ar~maticity.~~ 12 I.Goldberg U. Shmueli Acta Cryst. 1971 B27 2164 2173. 13 P. L. Johnson K. 1. G. Reid and I. C. Paul J. Chem. Soc. (B) 1971 946; K. I. G. Reid and I. C. Paul ibid. p. 952; F. Leung and S. C. Nyburg Canad. J. Chem. 1971 49 167. 14 S. Gottlicher and G. Habermehl Chem. Ber. 1971 104 524. 15 J. D. Dunitz and E. F. Meyer Hela. Chim. .4cra 1971 54 77. 16 H. R. Harrison 0. J. R. Hodder and D. C. Hodgkin J. Chem. Soc. (B) 1971 640. 17 D. D. Shillady F. P. Billingsley and J. E. Bloor. Thwr. Chin?.Artrr 1971 21. 1. I8 M. H. Palmer and A. J. Gaskell Theor. Chim. Acta 1971 23 52; P. Siegbahn Chem. Phys. Letters 1971 8 245. 19 D. T. Clark and D. M. J. Lilley Chem. Phys. Letters 1971 9 234. 20 M. Hackmeyer and J. H. Whitten J. Chem.Phys. 1971 54 3739. 21 ‘Quantum Aspects of Heterocyclic Compounds in Chemistry and Biochemistry,’ ed. E. D. Bergmann and B. Pullman Israel Academy of Sciences and Humanities Academic Press New York 1970 vol. 2. 22 W. Jakubetz and P. Schuster Tetrahedron 1971 27 101. 23 R. C. Benson C. L. Norris W. H. Flygare and P. Beak J. Amer. Chem. Soc. 1971 93. 5591. 24 W. Egan R. Tang G. Zon and K. Mislow J. Amer. Chem. Soc. 1971,93 6205. 575 Heterocyclic Chemistq-Part (ii) Heteroaromatic Compounds N.M.R. and Aromaticity.Xarefu1 analysis of the 'H n.m.r. spectrum of benzo- thiophen shows the similarity to naphthalene and similar diamagnetic ring currents.25 The effects of geometry on coupling constants in five-membered rings have been correlated,26 and two lines are obtained from the correlation of 3J(,,, with 2J(13C,H), which has been interpreted in terms of an aromatic series and olefinic series2' The I3C n.m.r.shifts of various 5,6-fused heterocycles with one or more nitrogen atoms and their anions and cations can be correlated reasonably well with those calculated by the CNDO procedure and average excitation energy approach.28 The 5N magnetic resonance of ~yridine~~ and 14N of both pyridine and other azines3' have been obtained ;the 14Nshifts show a nearly linear correlation with calculated n-electron density but this may be an oversimplification since for N-methylpyridinium salts other effects domi- nate the 14N ~hifts.~' An extensive survey of the 'H chemical shifts of azines their N-oxides and protonated species has been given.32 The site of substituents in monocyclic heteroaromatics is usually fairly unambiguous but extensive compilations of coupling constants which may be useful in this respect have been given for pyridine~~~ and chloromethylthiophens ;34 the former set have been correlated with CNDO calculated values.Interaction of ~yridine~~ and pyra- ~ine~~ with silyl chlorides leads to the dihydro-derivatives (7) and (8) neither of which is stable to air or from the 'H n.m.r. evidence aromatic. In contrast the long-awaited synthesis of isobenzofuran (9) by pyrolysis of two Diels-Alder adducts (10) and (11),37 shows this compound to have 'H chemical shifts (those in CDCI shown) consistent with a diamagnetic ring current and hence aro- maticity [cfi (12)].(7) X = SiCl, Y = CHSiCl (8) X = Y = NSiMe 25 K. D. Bartle D. W. Jones and R. S. Matthews Tetrahedron 1971 27 5177. 26 R. J. Abraham K. Parry and W. A. Thomas J. Chem. Soc. (B) 1971 446. '' D. M. McKinnon and T. Schaefer Canad. J. Chem. 1971,49 89. 28 R. J. Pugmire M. J. Robins D. M. Grant and R. K. Robins J. Amer. Chem. Soc. 1971 93 1887; R. J. Pugmire and D. M. Grant ibid. p. 1880. 29 R. L. Lichter and J. D. Roberts J. Amer. Chem. Soc. 1971 93 5218. 30 M. Witanowski L. Stefanik H. Januszewski and G. A. Webb Tetrahedron 1971 27 3129. " F. W. Wehrli. W. Giger. and W. Simon Helr. Chim. Acra 1971 54,229; W. Giger P. Schauwecker and W. Simon ibid. p. 2488. 32 P. Hamm and W. von Philipsborn Helc.Chim. Acra 1971 54,2363. 33 J. P. Dorie M. L. Martin S. Barnier and M. Blain Org. Magn. Rrsonance 1971 3 661. 34 T. Sone and K. Takahashi Org. Magn. Resonance 1971 3 527. 35 D. Kummer and H. Koster Angew. Chem. Internar. Edn. 1971 10 412. 36 R. A. Sulzbach and A. F. M. Iqbal Angew,. Chem. Internat. Edn. 1971 10 127. 37 D. Wege Tetrahedron Letters 1971 2337; R. N. Warrener J. Amer. Chem. Soc. 1971,93 2346. 576 M. H. Palmer \L"J PY (1 1) py = 2-pyridyl The year 1971 has seen the synthesis of several other interesting ring systems. Selenium dioxide oxidation of semicarbazones gives 1,2,3-~elenadiazoles,~~ the parent compound of which has 4-H and 5-H chemical shifts (neat liquid) at 6.66 and 7.47 6 respectively. The Group Vb homologues of pyridine phospha- (14) arsa- (15) and stiba-benzenes (16) have all been prepared from 1,l-di- n-butyl-1,4-dihydrostannabenzene (13) ;39 full details of the proton resonance have not been given but all absorb in the 'aromatic region'.The a-protons at lowest field are well separated from the others and have progressively higher values of the coupling constant J(2,3).The same starting material (13) yields (13) 0 P I Li' Ph -0 Me '* I. Lalezari A. Shafiee and M. Yalpani J. Org. Chem. 1971 36 2836. 39 A. J. Ashe J. Amer. Chem. SOC., 1971 93 3293 6690. Heterocyclic Chemistry-Part (ii) Heteroaromatic Compounds the 1-phenylborabenzene anion (17).40 This compound shows the heterocyclic protons at 3.05 T (2,6-H) 2.6 T (3,5-H) and 3.66 z(4-H) which considering that there must be some electron donation from the boron atom (i.e.an upfield shift) is strongly indicative of a diamagnetic ring current. The proton resonance of the ring protons in thiabenzene 1-oxide (18) is at very high field:' and the corresponding 13C shifts (109 50 and 89 p.p.m. from CS for a- B- and y-carbon respectively) are also at very high field compared with those of benzene (65 p.p.m.) or thiophen (68 and 66 p.p.m.). The proton coupling J(2,6)=4.4Hz must be one of the highest meta constants in proton resonance. Coupling of two thiapyrylium ions via the radical followed by oxidation yields the 4,4'-bisthiapyrylium salts whose proton resonance lies only slightly downfield of that of the rnon~cation.~~ Azocine (20) prepared by vacuum pyrolysis of diazabasketene (19),43 resinifies above -50 "C but the 2-methoxy- derivatives are rather more The latter have invariant 'H n.m.r.spectra from -75 to +185 "C and show no evidence of the bicyclic system (21) except in their reactivity. U.V. irradiation of the tetracyclo-compound (22) gives the 172-diazocine (23) which shows singlets at 6.08 and 6.936 (4:2 ratio).45 As expected none of these 871-electron rings show diagmagnetic ring currents. Although this is also the case with the 10 or 1471-electron benzo-derivatives (24)46 and (25),47 the 2-methoxydiazocine dianion obtained by reduction with potassium in THF absorbs downfield of the neutral compound rather than upfield as might have been expected from the negative charge.This does appear to be evidence of a diamagnetic ring current.48 40 A. J. Ashe and P. Shu J. Amer. Chem. SOC.,1971,93 1804. 41 A. G. Hortmann and R. L. Harris J. Amer. Chem. SOC.,1971 93 2471. 42 Z. Yoshida S. Yoneda T. Sugimoto and 0. Kikukawa Tetrahedron Letters 1971 3999. 43 D. W. McNeil M. C. Kent E. Hedaya P. F. D'Angelo and P. 0. Schissel J. Amer. Chem. SOC.,1971,93 3817. 44 L. A. Paquette T. Kakihana J. F. Hansen and J. C. Phillips J. Amer. Chem. Soc. 1971 93 152. 45 B. M. Trost and R. M. Cory J. Amer. Chem. SOC.,1971 93 5573. 46 H. J. Shue and F. W. Fowler Tetrahedron Letters 1971 2437. 47 D. L. Coffen Y. C. Poon and M. L. Lee J. Amer. Chem. SOC.,1971,93,4627. 48 L. A. Paquette J. F. Hansen and T. Kakihana J.Amer. Chem. SOC.,1971 93 168. 578 M. H. Palmer (24) X = NMe (25) X = S Tautomeric Equilibria and Conformations.-A distinction can be made by n.m.r. between the spectra of the 7H- and 9H-tautomers of xanthines and the 1-and 3-methyl derivatives appear to be the 7H-ta~tomers.~~ The protonation of purines’’ and of N-methylcarbazoleso has been studied by n.m.r. A similar study of the tautomerism of ‘dihydroxythiophens’ shows the 2,3- 2,4- and 3,4-series to be the 3-hydroxy- and 4-hydroxy-3-thiolen-2-ones, and 3-hydroxy-2- thiolen-4-ones respectively.’ The 4-hydroxyisoxazole tautomer is preferred over the cyclic oxime form.5 The nitrosation of hydroxyaminoacetonitriles yields cyclic compounds which are better represented as 5-amino-1,2,3-oxa-diazole N-oxides (26) rather than the sydnoneimine (27) since in contrast to the latter they do not form salts with Although largely in the 1H-(28)and 3H-forms the purple colour of cyclopenta[b]quinoline arises from the estimated 0.1 2)of the 4H-tautomer (29).55 0-HO \+ Various groups have studied the conformation of furan pyrrole and thiophen aldehydes and ketones by n.m.r.spectra. The nuclear Overhauser effect,56 4y D. Lichtenberg F. Bergmann and Z. Niemann J. Chem. Soc. (C) 1971 1676. ” H. J. Chen L. E. Hakka R. L. Hinman A. J. Kresge and E. B. Whipple J. Amer. Chewz. Soc. 1971 93 5102. ” R. Wagner and W. von Philipsborn Heir. Chim. Acta 1971 54 1543. ’’ J. Z. Mortensen B. Hedegaard and S. 0. Lawesson Tetrahedron 1971 27 3839.53 G. Bianchi M. J. Cook and A. R. Katritzky Tetrahedron 1971 27 6133. M. Gotz and K. Grozinger Tetrahedron 1971 27 4449. 55 J. J. Eisch and F. J. Gadek J. Org. Chrm. 1971 37 2065. 56 S. Combrisson B. Roques P. Rigny and J. J. Basselier Cunad. J. Chern. 1971 49 904; B. Roques C. Jaurequeberry M. C. Fournie-Zaluski and S. Combrisson Tetrahedron Letters 1971 2693. Heterocyclic Chemistry-Part (ii) Heteroaromatic Compounds long-range coupling,57 and low-temperature studies58 are valuable here. An attempt to use nematic-phase measurements normally good for measuring inter-proton distances e.g. for thi~phen,~~ was successful with a thiophen di- aldehyde but not for the furan analogue,60 where a negative distance was cal- culated between two hydrogen atoms ! 2 Quaternary Salts and N-Oxides Alkylation of a range of 2-(4-dimethyIaminophenyl)pyridinesoften leads to kinetically controlled attack on the exocyclic nitrogen but the thermodynamically favoured products are quaternary salts.6 A similar thermal reversal occurs with 5-phenyltetrazoles where the quaternary salts are only stable at low tem- peratures.62 The relative rates of methylation at N-4 of 2-substituted-pyrazines and 3-substituted-pyridines are constant.63 The electron densities at N-1 and N-2 in cinnolines are equal and the proportion of methylated compounds is controlled by steric effects ;64there have been further studies of the methylation of cinnolin-4-0nes.~~ An unusual cycloalkylation is the formation of (30) from 2-(4-iodobutyl)-3-methylbenzothiophen.66The N-oxide of pentachloropyridine Me where the basicity is low can be prepared from the azine by treatment with peracetic acid mixture in the presence of concentrated sulphuric acid ;apparently the peracid is protonated and hence more reactive.67 The differential solvent- induced n.m.r.shifts can be used to determine the site of N-oxidation in substi- tuted pyrazines ;68 3-methoxy- and 3-unsubstituted-l,2,4-triazines give 1-oxides whereas the 3-amino-compounds give 2-0xides.~' '' '' B. Roques and M. C. Fournie-Zaluski Org. Magn. Resonance 1971 3 305. K.-I. Dahlqvist and A.-B. Hornfeldt Tetrahedron Letters 1971 3837. 59 J.-M. Dereppe J.-P. Morisse and M. van Meerssche Org. Magn. Resonance 1971 3 583.(lo T. N. Huckley Tetrahedron Letters 1971 3497. " G. Y. Paris D. L. Garmaise and J. Komlossy J. Heterocyclic Chem. 1971 8 169. '* T. Isida S. Kozima K. Nabika and K. Sisido J. Org. Chem. 1971 36 3807. 63 L. W. Deady and J. A. Zoltewicz J. Amer. Chem. Soc. 1971 93 5475. " M. H. Palmer and P. S. McIntyre Tetrahedron 1971 27 2913 2921. h5 D. E. Ames H. R. Ansari A. D. G. France A. C. Lovesey B. Novitt and R. Simpson J. Chern. Soc. (C) 1971 3088. 6b J. A. Cotruvo and 1. Degani Chem. Comm. 1971 436. (" G. E. Chivers and H. Suschitzky J. Chem. Soc. (C),1971 2867. W. W. Paudler and S. A. Humphrey Org. Magn. Resonance 1971 3 21 7. " W. W. Paudler and T. K. Chen J. Org. Chem. 1971 36 787. M. H. Palmer 3 Aromatic Substitution Hydrogendeuterium exchange using deuterioacetic acid occurs in the 2-methyl and 3-positions of 2,6-di-methylpyrylium salts but not in the 4-position.This is ascribed to formation of the acetate (31) and ring-opened species.70 The partial rate factors for nitration of 4-phenylpyridine show all positions to be strongly deactivated with respect to benzene; this is largely a field effect.71 The rates of nitration in quinoline quinolin-4-one and cinnolin-4-one have been deter- mined.72 The hydrogen-deuterium exchange in quinoline isoquinoline and their N-oxides takes place on the protonated molecules except for the 2-H and 3-H of q~inoline.~~ The rates of exchange in deuterioacetic acid for both the 2-and 3-positions of N-methylpyrrole are higher than for the parent ring but the effect is most marked at the 2-po~ition.~~ The partial rate factors for acetylation of furan (F) and thiophen (T) have been obtained ; furan is more selective at the a-p~sition,~~ and comparison with the corresponding benzo-derivatives (BF/BT) leads to the following order of reactivity a-F >> r-T >> a-BF z B-BT > a-BT z /?-BF > P-F z /3-T.76 The rates of both H-D exchange and nitration in 3,5-dimethyl- isoxazole -isothiazole and 1,3,5-trimethylpyrazole show that the first of these reacts as the free base and the others as the conjugate acid.77 The rates of H-D exchange in the ring positions of various azaindenes correlate well with SCF x-electron calculations but apparently not with the corresponding n-localization energies; further studies of the latter type which include all valence electrons seem de~irable.~ Reduction of pyridines with lithium aluminium hydride followed by direct treatment of the reduced salt with alkyl halide or bromine gives 3-substituted- pyridines in high yield.79 Oxidation of 3-substituted-N-methyl quaternary salts by ferricyanide gives more of the 6-than the 2-pyridinone when the substituent 7" D.Farcasiu A. Vasilescu and A. T. Balaban Tetrahedron 1971 27 681. F. De Sarbo and J. H. Ridd J. Chem. SOC.(B) 1971 712. 72 D. H. G. Crout J. R. Penton and K. Schofield J. Chem. SOC.(B) 1971 1254; R. B. ' Moodie J. R. Penton and K. Schofield ibid. p. 1493. U. Bressel A. R. Katritzky and J. R. Lea J. Chem. SOC.(B) 1971 4 11. G. P.Bean Chem. Comm. 1971 421. 75 G. Ciranni and S. Clementi Tetrahedron Letters 1971 3833; S. Clementi P. Linda and M. Vergoni Tetrahedron 1971 27 4667. j6 S. Clementi P. Linda and G. Marino J. Chem. Soc. (B) 1971 79. 7' A. G. Burton P. P. Forsythe C. D. Johnson and A. R. Katritzky J. Chem. SOC.(B) 1971 2365. j8 W. Engewald M. Muhlstadt and C. Weiss Tetrahedron 1971 27 851 4171. '' C. S. Giam and S. D. Abbott J. Amer. Chem. Soc. 1971 93 1294. Heterocyclic C hemis try-Part (ii) Heteroaromat ic Compounds 581 is electron withdrawing." It seems that the rate-determining step in these reactions is formation of the ferricyanide complex rather than cleavage of the C-H bond.81 Direct alkylation of pyridine with an alkyl-lithium gives high yields of 2- and 2,6-substituted compounds even with t-butyl-lithium.82 The product from pyridine N-oxide and Grignard reagents is apparently acyclic.Addition of lithium alkyls to 2,4,6-triphenylphosphabenzene gives 1,2- dihydro-derivatives (32),which on oxidation lead to the quaternary salts (33)and then the 1-alkyl-1-alkoxyphosphabenzenes(34)on treatment with alcohols. 84 gem-Dihalides and base give benzene derivatives via a 1,2-addition sequence (Scheme l) which can be interrupted to yield (35)by the addition of an acid.85 1-Substituted-phospholes lose the substituent on treatment with alkali metals ; the solutions give e.s.r. signals from the intermediate radical-anion ;re-alkylation is readily achieved. 86 Ph Ph fi" %phn Ph "g(OAc! PhOPhPI1 P P+ P Ph I I R" 'OR' R' R' (32) (33) (34) *l 1 Ph fiPh PH I R CRCl (35) Scheme 1 8o H.Mohrle and H. Weber Chem. Ber. 1971 104 1478. 81 R. A. Abramovitch and A. R. Vinutha J. Chem. Soc. (B) 1971 131. R. F. Francis J. T. Wisener and J. M. Paul Chem. Comm. 1971 1420; F. V. Scalzi and N. F. Golob J. Org. Chem. 1971 36 2541. 83 T. J. van Bergen and R. M. Kellog J. Org. Chem. 1971 36 1705. 84 G. Markl and A. Merz Tetrahedron Letters 1971 1215; G. Markl A. Merz and H. Rausch ibid. p. 2989. 85 G. Markl and A. Merz Tetrahedron Letters 1971 1269. 86 D. Kilcast and C. Thomson Tetrahedron 1971 27 5705; E. H. Braye I. Caplier and R. Saussez ibid. p. 5523. 582 M. H. Palmer Although 3-chloro-1,2-benzisothiazolereacts normally with ethanolic sodium ethoxide with sodium cyanide in acetone (or carbanions) the reaction yields aryl thiocyanates (37) (or sulphides) by attack on sulphur (36)” There is some sitnilarity in the spontaneous cleavage of 3-lithiobenzo[h]thiophen and the metal-hydrogen exchange accompanying its8 [(38H40)] or the spontaneous cleavage of 5-lithio-1 -methyltetrazole to methyl cyanamide.89 Li (39) The rates of displacement of a fluorine atom are greater than those of chlorine for a variety of displacements by methoxide ion or piperidine.” Thus in benzo- 1,2,3-thiadiazoles although the 6-position is normally the most reactive fluorine in other positions is selectively replaced rather than a 6-chloro-sub~tituent.~~ The positional order of reactivity of halogenothiazoles to methoxide ions is 5 >2 >4 but with a rate range of 30.The 4- or 5-reactivity does not involve hetarynes since the 5-phenyl-4-chloro-compound has similar reactivity to the compounds without a substit~ent.~’ The chemistry of hetarynes has been reviewed,93 and there has been further discussion of their significance in reactions of hal~genopyridines.~~ 3-Bromothiophens can be conveniently prepared from the 2-bromo-compound by rearrangement in the presence of potassamide. 95 Benzyne adds across the 1,4-positions of ph~sphabenzene.~~ Further replacements of fluorine in perfluoroheteroaromatics have been reported ;the order of reactivity for a-substitution by hydrogen chloride in ’-D. E. L. Carrington K. Clarke and R.M. Scrowston J. Chem. Soc. (C) 1971 3262 3903. 88 R. P. Dickenson and B. Iddon J. Chem. Soc. (C) 1971 3447. 89 R. Raap Cunad J. Chem. 1971,49 2139. 90 G. B. Bressaw I. Giardi G. Illuminati P. Linda and G. Sleiter J. Chem. SOC.(B) 1971,225. 91 J. H. Davies E. Haddock P. Kirby and S. B. Webb J. Chem. SOC.(C),1971 2843. 92 M. Bosco L. Forlani P. E. Todesco and L. Troisi Chem. Comm. 1971 1093. 93 T. Kauffman and R. Wirthwein Angew. Chem. Internat. Edn. 1971 10 20. 94 H. N. M. van der Lans H. J. den Hertog and A. van Veldhuizen Tetrahedron Letters 1971 1875; J. A. Zoltewicz and A. A. Sale J. Org. Chem. 1971 36 1455. 95 M. G. Reinecke H. W. Adickes and C. Pyun J. Org. Chem. 1971 36 2690. 9h G. Markl F. Lieb and C. Martin Tetrahedron Letters 1971 1249.Heterocyclic Chemistry-Part (ii) Heteroaromatic Compounds 583 sulpholane is quinoline >> isoquinoline > ~yridine.~' The reaction of hexa- fluoropropene with fluorides and tetrafluoro-pyridazine or -pyrimidine leads to 4,5- or 4,6-substitution respectively ;the perfluoropropyl group is better able to absorb the resulting negative charge at the addition stage than the nitrogen atoms.98 Brief treatment of these perfluorinated aromatics at 580 "C or above leads to rearrangement99 of the pyridazines to the pyrimidines (44) plus a smaller amount of the corresponding pyrazines (Scheme 2). These changes are inter- preted in terms of the diazabenzvalene derivatives (45) and (46). An unusual type of cyclization with elimination of a fluoride ion is given in (47) -+ (48j.l" Scheme 2 F F F (47) (48) 4 Oxidation Reactions Examples of anodic oxidation applied to furans and thiophens in the presence of various nucleophiles have been given for example (49)-(50) where X = 0 or S."' Pyrylium and thiapyrylium ions and furans"' react in the triplet ')'R.D. Chambers M. Hole W. K. R. Musgrave and J. G. Thorpe J. Chem. Soc. (0, 1971 61. R. D. Chambers Y. A. Cheburkov J. A. H. MacBride and W. K. R. Musgrave J. ChcJm.SOC.(C) 1971 532; C. J. Drayton W. T. Flowers and R. N. Haszeldine ibid. p. 2750. OY R. D. Chambers J. A. H. MacBride and W. K. R. Musgrave J. Chem. SOC.(C) 1971 3384. loo G. M. Brook W. K. R. Musgrave and T. R. Thomas J. Chem. Soc. (0, 1971 3596. lo' K. Yoshida and T.Fueno J. Org. Chem. 1971 36 1523; K. Yoshida T. Saeki and T. Fueno rbid. p. 3673. T. Tsuchiya H. Arai and H. Igeta Tetrahedron Letters 1971 2579. 584 M. H. Palmer (49) FeOH excited state with ground-state oxygen (Scheme 3) but their ground-state molecules do not react with singlet excited oxygen,lo3 a result showing the electro- philic nature of singlet oxygen. Conversely pyrroleslo4 do react with singlet oxygen giving various products e.g. (51). Ph l* nph % P&%ph -+ PhCHO + PhCOzH Ph \ X Ph x+ + Scheme 3 NH Et Et Et Et Et&z -"Go MeaNI-Iz HO 00 Et Me H In an important series of publications Rees has described the formation and oxidation of N-aminoheterocycles. Reaction of the azine with hydroxylamine- 0-sulphonic acid or chloramine followed by treatment with lead tetra-acetate gives the nitrene which forces the loss of an adjacent carbonyl group and re- cyclization to the 1,2-diaza-systern.Thus quinoxalin-2-ones and indazoles give benzo-1,2,4- (52) and -1,2,3-triazines (53) respectively (Scheme 4). lo5 The 1,2,4- triazine-3-ones in contrast failed to give observable N-amino-derivatives but gave the ring-contracted species (54) and (55). lo6 The cinnolin-3-one and benzo- triazin-4-ones gave normal N-amino-derivatives which on oxidation yielded nitrogen and ring-contracted products ; the latter series showed intermediate '03 Z. Yoshida T. Sugimoto and S. Yoneda Tetruhedron Letters 1971 4259. G. B. Quistad and D. A. Lightner Tetrahedron Letters 1971 4417; Chem.Comm. 1971 1099. B. Adger C. W. Rees A. A. Sale and R. C. Storr Chem. Comm. 1971 695; D. J. C. Adams S. Broadbury D. C. Howell M. Keating C. W. Rees and R. C. Storr ihid. p. 828. '06 C. W. Rees and A. A. Sale Chem. Comm. 1971 (a),531 (6) 532. Heterocyclic Chemis try-Part (ii) Heteroaromatic Compounds NH I :N Scheme 4 formation of benzocyclopropenone. '06','07 In a related reaction oxidation of arylhydrazones gave the nitrile rather than the diazoalkane or sym-tetrazine. Other amine oxidations lead to benzo[c]cinnoline-N-imine'O9 and benzo-1,2,3- triazines' lo from 2,2'-diaminobiphenyl and o-aminophenyl ketone hydrazones. In contrast the oxidation of 1-aminoimidazolo[ 1,2-a]pyridinium ions gave the corresponding azo-compound perhaps showing the electrophilic nature of the nitrene.' ' 5 Reduction The only processes calling for comment are the polarographic reduction' l2 of 2-methoxyazocines directly to the dianion without evidence of the intermediate lo' J.Adamson D. L. Forster T. L. Gilchrist and C. W. Rees J. Chem. Soc. (C) 1971 981. log D. B. Mobbs and H. Suschitzky Tetrahedron Letters 1971 361. log S. E. Gail C. W. Rees and R. C. Storr Chem. Comm. 1971 1545. lo S. Bradbury M. Keating C. W. Rees and R. C. Storr Chem. Comm. 1971 827. 'I1 E. E. Glover and M. Yorke J. Chem. Soc. (C) 1971 3280. L. B. Anderson J. F. Hansen T. Kakihana and L. A. Paquette J. Amer. Chem. SOC. 1971 93 161. M. H. Palmer radical-anion a contrast to cyclo-octatetraene where the two stages are visible.This is interpreted as the first electron addition yielding a planar ring which is much more readily reduced (to a l0.n-electron system) than the neutral com- pound. In Hiickel terms the lowest vacant orbital of oxepin is antibonding and this correlates with the observation that the alkali-metal reduction of the 2,7-dimethyl compound leads to ring opening giving (56) and (57).'13 In a similar way reaction of the 4H-1,3-oxazine (58) with butyl-lithium yields an 8n-electron ring which rearranges to yield (60) and (61) via the identified species (59).'14 Me Me Me Me Me 6 Photochemical Reactions and Valency Isomerism Photolysis of various mesoionic compounds related to the sydnones gives carbon dioxide and a three-atom fragment from the ring which can be trapped by acety- lene dicarboxylic esters.Thus 3-arylsydnones give pyrazoles,' ' via the nitrili- mine and 4-aryl-l,3,2-oxathiazolinium 5-oxides yield isothiazoles via the nitrile sulphide.''6 A thermal reaction on the addition product of aldehydes or thioaldehydes to oxazolium 5-oxides also leads to loss of carbon dioxide (Scheme 5) and the formation of open-chain compounds (62).'17 Scheme 5 'I3 L. A. Paquette and T. McCreadie J. Org. Chem. 1971 36 1402. 'I4 R. R. Schmidt Angew. Chem. Internat. Edn. 1971 10 572. 'Is H. Gotthardt and F. Reiter Tetrahedron Lerters 1971 2749; M. Marky H. J. Hansen and H. Schmidt Helc. Chim. Acta 1971 54 1275; C. S. Angadiyavar and M. V George J. Org. Chem. 1971 36 1589. 'l6 H.Gotthardt Tetrahedron Letters 1971 1277 1281. '" R. Huisgen E. Funke H. Gotthardt and H.-L. Panke Chem. Ber. 1971 104 1532 E. Funke R. Huisgen and F. C. Schaefer Chem. Ber. 1971 104 1550. Heterocyclic Chemistry-Part (ii) Heteroaromatic Compounds Cyclohexa-2,5-dien-1,4-diolscan lead to either phenols or oxepins and suitable substituents such as t-butyl can force formation of the latter."* The synthesis of various oxepins and their Diels-Alder reactions through the benzene oxide form have been described.' l9 2,2,2-Trifluoroethanol is claimed to be unique in promoting nitrene (from nitrosobenzene) addition to benzene ;'2o the direction of nitrene insertion in p-disubstituted-benzenes is subject to marked steric effects. ' ' Carbon-carbon is preferred to nitrogensarbon bond fonna- tion in the photochemical cyclization of 1,2-diazepines (63),122but the latter occurs in the 6-ones (64) to yield (65).123 2-Methoxyazocines react in the form (66).44,124 Ph The photochemical rearrangement of 2-deuterioquinoline N-oxide yields 3-deuterioquinolin-2-one and indolecarbaldehyde derivatives,' whereas the related isatogen rearrangement [(67) +(70)] goes via epoxide-like intermediates (68) and (69) since ethanol fails to intercept the quinoid intermediate (71).126 'I8 A.Rieker Angew. Chem. Internat. Edn. 1971 10 425; S. Berger G. Henes and A. Rieker Tetrahedron Letters 1971 1257. W. Eberbach M. Perroud-Arguelles H. Achenbach E. Drucky and H. Prinzbach Helv. Chim. Acta 1971 54 2579. R. J. Sundberg and R.H. Smith Tetrahedron Letters 1971 267. J. M. Photis J. Heterocyclic Chem. 1971 8 167 729. G. Kan M. T. Thomas and V. Snieckus Chem. Comm. 1971 1022; J. Streith J. P. Luttringer and M. Nastasi J. Org. Chem. 1971 36 2962. 123 J. A. Moore E. J. Volker and C. M. Kopay J. Org. Chem. 1971 36 2676. L. A. Paquette and T. Kakihama J. Amer. Chem. Soc. 1971 93 174; L. A. Paquette Angew. Chem. Internat. Edn. 1971 10 11. 0. Buchardt K. B. Tomer and V. Madsen Tetrahedron Letters 1971 1311. D. R. Eckroth and R. H. Squire J. Org. Chem. 1971,36 224. M. H. Palmer (74) 0'U C N Such intermediates are however involved in the cleavage of anthranils (72) to o-aminoacetophenones (73) 12' and furazans (74) to azepines (75).128 Whereas an e.s.r. signal is obtained from the arylnitrene from the photolysis of 2-azido- acetophenone to (76) and (77) under similar conditions no signal is obtained from 3-methylanthranil where only (76) is obtained.' 29 Bicyclic products (78) arising from quinoid species such as (71) have been isolated from other photolytic reactions.30 Photochemical hydroxyalkylation of azines continues to be studied,' 31 as does the reverse reaction.' 32 27 E. Giovannini J. Rosales and B. de Souza Helv. Chim. Acta 197 1 54 21 11. 12' M. Georgarakis H. J. Rosenkranz and H. Schmid Helv. Chim. Acta 1971 54 819. 129 M. A. Berwick J. Amer. Chem. SOC.,1971 93 5780. 130 R. A. Olofson R. K. Vander Meer and S. Stournas J. Amer. Chem. SOC.,1971 93 1543; M. S. Ao and E. M. Burgess ibid. p. 5298.13' M. Natsume and M. Wada Tetrahedron Letters 1971 4503; T. J. Van Bergen and R. M. Kellogg J. Org. Chem. 1971 36 978; R. A. F. Deeleman H. C. van der Plas A. Koudijs and P. S. Darwinkle-Risseeuw Tetrahedron Letters 1971 4 159. 13' D. Elad I. Rosenthal J. Saloman and J. Sperling Chem. Comm. 1971 49. Heterocyclic Chemistry-Part (ii) Heteroaromatic Compounds (76) (77) (78) X = CO or SO 7 Ring Synthesis Asalways there has been extensive work in this field so any choice must appear arbitrary. Here it is restricted almost entirely to the most common ring systems. The condensation of aldehydes and ammonium salts leads to 1,2-dihydro-pyridines not the 2,3-isomers the ready synthesis of 3-aminoacrolein and its conversion into 3-alkylpyridines and pyrimidines has been noted.' 34 Further simple syntheses of 1,2,4-triazines and diaryl-1,3,5-triazinones have been given.l3 The cyclization of acetals in the Pomeranz-Fritsch isoquinoline synthesis and in indole synthesis can be facilitated by the use of boron trifluoride-trifluoroacetic anhydride as catalyst. '36 The reaction of 2-aminopyridine and P-ketoesters with polyphosphoric acid ethyl ester gives pyrido[ 1,2-a]pyrimidin-4-ones rather than + 1,8-naphthyridines.'37 The group [Me,N-CR=CR-CR=NMe,] X-can be readily cyclized to pyrimidines by reaction with amidines. 38 Quinazolines rather than indazoles are obtained from (79).'39 Two reactions related to the formation of isoxazoles and pyrazoles from dianions are the synthesis of 2- unsubstituted-oxazoles from metallated isonitriles and pyrazoles from trimetallated hydrazones (81).14' High yields of furans are obtained from propargylsulphonium salts and aliphatic ketones.'42 Simple syntheses of 3,2- borazaropyridines (83)'43 via the thiophens (82) and 5,1,3,4-boratriazaroles (84)'44 from amidrazones show these compounds to be fairly stable to air 133 G. Krow. E. Michener. and K. C. Ramev. Tetrahedron Letters. 1971. 3653. 134 E. Britmaier Angew. Chem. Internat. Edn:,'1971 10 268; E. Britrnaier and S. Gassen-mann Chem. Ber. 1971 104 665. T. V. Saraswathi and V. R. Srinwasan Tetrahedron Letters 1971 23 15 ; B. Singh and J. C. Collins Chem. Comm. 1971 498. 136 M. J. Bevis E. J. Forbes N. N. Naik and B. C. Uff Tetrahedron 1971 27 1253. K. Bowden and T.H. Brown J. Chem. SOC.(0,1971 2163. 138 R. M. Wagner and C. Jutz Chem. Ber. 1971 104,2975. 139 N. Finch and H. W. Gschwend J. Org. Chem. 1971 36 1463. I4O U. Schollkopf and R. Schroder Angew. Chem. Internat. Edn. 1971 10 333. 141 C. F. Bean R. S. Foote and C. R. Hauser J. Chem. SOC.(0,1971 1658. 142 J. W. Batty P. D. Howes and C. J. M. Stirling Chem. Comm. 1971 534. 143 S. Gronowitz and A. Maltesson Acta Chem. Scand. 1971 25,2435. 144 M. J. S. Dewar R. Golden and P. A. Spanninger J. Amer. Chem. SOC.,1971,93 3298. 590 M. H. Palmer R7CHLiCRZ=NNLi2 + R2 (81) H N-NR except for those where R = Me. Among large ring compounds the synthesis of 1,2,5,6,9,12-hexa-aza-l and 1,2,4,5,8,9,11,12-octa-aza-[ 121annulene'46 deriva-tives are of interest and a series of porphin-like molecules containing sulphur and oxygen in place of one or more nitrogen atoms has been de~cribed.'~~ Ethoxycarbonylnitrene inserts in the meso-ring 4,5-bond of porphyrins.' 48 145 P.Skrabel and H. Zollinger Helv. Chim. Acta 1971 54 1069. 146 H. Neunhoeffer J. Stastny and L. Motitschke Tetrahedron Letters 1971 1601. 14' M. J. Broadhurst R. Grigg and A. W. Johnson J. Chem. SOC.(c>,1971 3681; P. S. Clezy and V. Diakiw Austral. J. Chem. 1971,24,2665; M. Ahmed and 0. Meth-Cohn J. Chem. SOC.(0,1971 2104. 14' R. Grigg J. Chem. SOC.(0,1971 3664.