A simple monocyclic 8n electron thiepin, 2,7-di-tert-butyl-4-
-ethoxycarbonyl-5-methylthiepin (13) stabilized by two bulky tert-
-butyl groups at 2- and 7-positions, was synthesized from 2,6-di-
-tert-butyl-4-methylthiopyrylium tetrafluoroborate (11). In spite of
of its monocyclic thiepin structure, the compound 13 showed remarkable
thermal stability and had a half-life of 7.1 h at 130 °C.
Judging from the 1H-NMR spectrum, the thiepin 13 is considered
to be an atropic molecule.
Synthetic details of 11 and 13, and the chemical and physical
properties of 13 are also described

I. Murata

K. Nishino

K. Yamamoto

S. Yano

Y. Kohashi

English

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CROATICA CHEMICA ACTA CCACAA 53 (4) 615-623 (1980) CCA-1247 YU ISSN 0011-1643 UDC 547.89 Conference Paper A Remarkably Stable and Simple Monocyclic Thiepin. Synthesis and Properties of 2, 7-Di-tert-butyl-4-ethoxycarbonyl-5-methylthiepin1* I. Murata*, K. Nishino, S. Yano, Y. Kohashi, and K. Yamamoto Department of Chemistry, Faculty of Science, Osaka University, Toyonaka, Osaka 560, Japan Received September 3, 1979 A simple monocyclic 8n electron thiepin, 2,7-di-tert-butyl-4--ethoxycarbonyl-5-methylthiepin (13) stabilized by two bulky tert--butyl groups at 2- and 7-positions, was synthesized from 2,6-di--tert-butyl-4-methylthiopyrylium tetrafluoroborate (11). In spite of of its monocyclic thiepin structure, the compound 13 showed re-markable thermal stability and had a half-life of 7.1 h at 130 °C. Judging from the 1H-NMR spectrum, the thiepin 13 is considered to be an atropic molecule. Synthetic details of 11 and 13, and the chemical and physical properties of 13 are also described. Recently, the question of the antiaromaticity of sulfur heterocyclic Brr electron system, thiepin, has been a subject of interest for both synthetic and theoretical chemists. The apparent instability of the thiepin ring system is in good agreement with theoretical calculations. Thus, Dewar and Trinajstic2 reported that the thiepin is found to be weakly antiaromatic (RE = - 1.45 kcal/mol) based on the Pariser-Parr-Pople type calculations. On the other hand, Hess, Jr. and Schaad3 have found it to be substantially antiaromatic (RE = - 0.232~) by using the Hiickel MO method. The latter result is also supported by a graph theoretical treatment of Aihara.4 Despite the extensive studies concerning azepines5 and oxepins,6 little is known about thiepins7 because of their pronounced thermal instability due to ready sulfur extrusion.8 Although some thiepin derivatives annelated with aromatic ring have been isolated, parent thiepin has never been synthesized.' In order to gain insight into the detailed properties of thiepin, the synthesis of a simple monocyclic thiepin is required. It was generally accepted that the valence isomerization of the thiepin ring into its corresponding thianorcaradiene tautomer is considered to play an essential role in a facile sulfur extrusion.9 Examination of the molecular models of a thiepin possessing two bulky groups at 2- and 7-positions indicate * Presented in part at the International IUPAC Symposium on Aromaticity, held in Dubrovnik, Croatia, Yugoslavia, September 3- 5, 1979. 616 I. MURATA ET AL. that these groups force the nonbonding interaction in the corresponding thianor-caradiene structure to be large, and hence the thiepin structure will be favored. 0 Dewar, Trinajstic : CP-P-Pl a~ electron heterocycles: X = o : oxepin X =NH: azep ine X = s : thiepin Hess,Jr,, Schaad: <Huckel > weakly antiaromatlc substantially antlaromatic RE=-1.45 kcal /mo! RE= -0.2326 thiepin thianorcaradiene ~~ less hindered Aihara: <Graph) substantially ant laromat tc RE= -0.209N -0.2326 s more hindered This concept has already been revealed by the successful synthesis and isolation of a stable but heavily substituted thiepin derivative (1) by Schles-singer et. al.,10 whereas the thiepin having no bulky groups at these positions such as 2 never has been isolated though it can be generated and was detected by NMR spectroscopy at - 30 °C by Reinhoudt and Kowenhoven. 11 Furthermore, we have previously shown that the thiepin 3 having two iso-propyl groups at 2- and 7-positions readily undergoes sulfur extrusion to give ultimately the corresponding benzene derivative even at - 70 °C.12 It means that the bulkiness of an isopropyl group is not sufficient to permit isolation of the monocyclic thiepin. 13 We would like to report the first example of a simple monocyclic thiepin stabilized by two bulky tert-butyl groups. MONOCYCLIC THIEPIN 61 7 Schless!nger et al., JACS,, .92_, 5253 (1 970) c Isolated> Relnhoudt et al., Murata et al., Chem . Coom., 1233 (1972) Chem. Lett., l et., 20_, 2093 Cl974l 723 0 978> (detected at -30'C> <not detected even at -78' Cl The construction of the key intermediate in our synthesis, 2,6-di-tert--butyl-4-methylthiopyrylium salt (11), is illustrated in Scheme I. The Friedel-(]I) HOl (9) -Crafts reaction of 2-tert-butyl-thiophene (4) 14 with pivaloyl chloride upon stirring in benzene solution at room temperature in the presence of stannic chloride to yield a single crystalline 2-ter t-butyl-5-pivaloylthiophene (5) (color-less needles, m. p. 65.5 °C, IR (KBr) 1620 cm-1, 1H-NMR (o , CDC13) 1.35 (s, 9H, t-C4H 9) , 1.41 (s, 9H, t-C4Hu), 6.90 (d, lH, H-3, J = 4.0 Hz), 7.60 (d, lH H-4, J = 4.0 Hz)), in 94~/o yield. Birch reduction of 5 (addition of a solution of 5 and tert-butyl alcohol (5 equiv) in ether to 3 equiv of lithium in liquid ammonia at - 78 °C over 5 min, stirring at - 78 °C for 5 min, quenching with ammonium chloride) gave (88°/o) 2-tert-butyl-5-pivaloyl-2,5-dihydrothiophene (6) (colorless liquid, m/e 226.1404 (calcd for C1 3H220S 226. 1391, 1H-NMR (o, CDC13 ) 0.98 (s, 9H, t-C4H9), 1.20 (s, 9H, -CO-t-C4H9) , 4.19 (dt, lH H-2, J 25 = 3.5, J 23 = J 24 = = 1.5 Hz), 4.91 (dt, lH, H-5, J 52 = 3.5, J 54 = J 53 = 1.5 Hz), 5.55 (dt, lH, H- 3, J 34 = 4.0, J 32 = J 35 = 1.5 Hz), 5.89 (dt, lH, H-4, J 43 = 4.0, J , 5 = J 53 = 1.5 Hz)) contaminated with small amounts c< 5'l/o) of the corresponding 2,3- and 4,5--dihydrothiophenes. The compound 6 could be used in the subsequent reaction without further purification. The next step of the synthesis, ring expansion of 6 to the thiopyrans 7 and 8, was originally attempted using the carboniurn 618 I. MURATA ET AL. ion rearrangement of the alcohol derived from 6. However, since this method failed completely, alternative routes were examined. The conversion of 6 into 7 and 8 was achieved by the use of a novel strategy for the generation of an organozinc carbenoid at the carbonyl carbon atom.15 Thus, treatment of 6 with a large excess of zinc dust and trimethylchlorosilane in THF at 0 °C for 3 h gave, after quenching with lN sodium hydroxide, a 1 : 8 mixture of 7 (colorless liquid, m/e 210.1443 (calcd for CrnH2 2S 210.1441), 1H-NMR (o, CDC13) 1.20 (s, 18H, two t-C4H9), 2.60 (t, 2H, H-4,4', J = 8.0 Hz), 5.63 (t, 2H, H-3.5, J = 8.0 Hz)) and 8 (colorless liquid, m/e 210. 1440, 1H-NMR (o, CDC13 ) 1.12 (s, 9H, t-C4H9), 1.18 (s, 9H, t-C4H9), 3.20 (m, lH, H-2), 5.60 (m, 3H, H-3,4,5)) in 860/o yield which could be separated by column chromatography on silica gel with hexane. Hydride abstraction of the mixture of 7 and 8 with trityl tetrafluoroborate in acetonitrile afforded the thiopyrylium salt (9) (colorless needles, m. p. 177.5 °c, 1H-NMR (o, CF3C02H) 1.69 (s, 18H, t-C4H9), 8.66 and 8.84 (A2B, H-3,5 and 4, J 3 4 = J 45 = 4.1 Hz)) in 684>/o yield. Methylation of 9 with methyllithium in ether at - 78 °c gave the thiopyran 10 (colorless liquid, 1H-NMR (o, CC14) 1.06 (s, 18H, t-C4H 9), 1.20 (d, 3H, -CH3, J = 12.0 Hz), 2.59 (tq, lH, H-4, J = 12.0 and 3.9 Hz), 5.38 (bd, 2H, H-3,5, J = 3.9 Hz)) which was finally converted into the desired 2, 6-di-tert-buty 1-4-methyl thiopyry lium tetrafluoro borate ( 11) (color less needles, m. p. 134-135 °c, 1H-NMR (o, CF3C02H) 1.73 (s, 18H, t-C4H9}, 2.99 (s, 3H, -CH3}, 8.58 (s, 2H, H-3,5)) by the usual method. These overall reactions pave the way to the 2,6-di-tert-butylthiopyrylium salt not readily accessible via previously available methodologies.16 With the thiopyrylium salt 11 in hand we focused our efforts on the trans-formation of 11 into the thiepin ring system via the sequence of reactions shown in Scheme II. The thiopyrylium salt 11 was treated with ethyl lithio-~ LI CN2cooc2H5 ~2 :O:°''"' li"''"' -12o·c PdCl!l s o·c (!}) (12) (13) Ye! low needles ye! low Prisms mp:32 - 33°C mP•23.s - 24.s0c . vcN : 2oso cm-I 2 diazoacetate using conditions reported by us previously12•17 to give diazo com-pound 12, yellow needles, m. p. 32-33 °c in 900/o yield. The 1H-NMR (o 1.21 (s, 18H, t-C4H9), 1.25 (t, 3H, -CH2-CH3 , J = 7.2 Hz), 4.18 (q, 2H, -CH2-CH3 , J = 7.2 Hz), 1.28 (s, 3H, -CH3), and 5.53 (s, 2H, -CH=)) and IR (vcN, 2080 cm-1) data were consistent with the structure 12. Final ring enlargement of 12 was achieved as follows. The treatment of 12 with n:-allylpalladium chloride dimer (5 mol O/o) in chloroform at - 60 °C and stirring at 0 °C for 1 h gave> thiepin 13 as yellow prisms of m. p. 23.5-24.5 °C quantitatively. MONOCYCLIC THIEPIN 619 The structure of 13 was supported by the elemental analysis and 1H- and • 3C-NMR spectral data shown in Figure 1. Thiepin 13 exhibits ultraviolet ppm downfleld from TMS 2.12 Cd, J=0,9 Hz) }·23 Cql \.ti HOOCH CH «- l. 32( tl 3 2 3 ..-\.; -6, 14Cs> H ~ h H"-6,50(q,J=0.9 HZ) CCH3l3C S C(CH3l3 r ~ 1.22Csl !.23Csl 13c-NMR ring C : 132,l, 146.2, 151.4, 155.8 absorption maxima in cyclohexane at 234 nm (log c 4.11) and 356 (2.95) with very low-intensity with tailing to 510 nm (Figure 2). This behavior . is quite parallel to the UV spectrum of 1 which showed tailing to 500 nm. 10 The IR spectrum of 13 (in KBr) shows typical absorption for an a.,~-unsaturated ester carbonyl group at 1715 cm-1• log c 234 flll (]Oge 4,]]) 4.0 Hxooc2H5 uv sDectnlll of ~s~ In cvclohexone 356 (2.95) 3.0 2.0 200 300 400 500 nm In spite of its monocyclic thiepin structure, 13 shows remarkable thermal stability and can be handled under atmospheric conditions without detectable decomposition. However, on prolonged heating in toluene at 140 °C in a sealed tube 13 was converted in nearly quantitative yields into sulfur and ethyl 4,5-di-tert-butyl-2-methylbenzoate (14), colorless needles, m. p. 21-22 °C. The compound 14 discloses 1H-NMR signals at c5 1.53 (s, 18H), 2.43 (s, 3H), 7.25 (s, 620 I. MURATA ET AL. lH), 8.04 {s, lH) along with the ethyl ester protons at 1.37 and 4.27 (J = 7.0 Hz). The relatively downfield chemical shift of the tert-butyl groups permits the assignment of the ortho arrangement to the two tert-butyl groups of the benzene ring. A similar paramagnetic shift of the proton signal of the tert--butyl groups has also been reported in o-di-tert-butylbenzene systems.18 2.43Csl 4.27(q), l.37Ctl ~H3C COOC2H5 ,,,';;:;'HRH "'Ls.om> + s ~ y <14) (13) t112 <at 131°Cl = 7.1 h l.53Csl s (3) The half-life of the thiepin 13 at 131 °c in deuterated toluene, monitored by 1H-NMR spectroscopy, is 7.1 h. It should be noted that the corresponding isopropyl derivative 3 is extremely unstable and could not be detected even at - 70 °C.12 As would be expected, the substitution of tert-butyl groups on the 2- and 7-positions of a thiepin ring produces a monocyclic thiepin which has substantial high thermal stability. Presumably, the resistance to aromatizat-ion of 13 via sulfur extrusion may be attributed to the fact that formation of the thianocaradiene intermediate does not arise owing to the increased steric hindrance. Schlessinger (1970) ~NO fro ~6.7-7.0 lsoelectronlc with downfleld ® o Me shift Q-~ ~ ~@ O Me 2...1:.LlZ 0 e Cll might possess a paramagnetic ring current MONOCYCLIC THIEPIN 621 Finally, I should like to add some comments on the antiaromaticity of thiepin. The thiepin is isoelectronic with the 8:n: electron cycloheptatrienide ion of 13 via sulfur extrusion may be attributed to the fact that formation of concluded that the thiepin ring proton of 1 resonates at a higher field (o 6.50) than that of its precursor furanothiepin (a 6.80). In addition, the ortho protons of the imide phenyl group in 1 resonate at a lower field (o 6.70-7.00) than comparable protons of the corresponding benzenoid derivative (o 6.20-6.45); these were taken as indicative of the presence of a paramagnetic ring current. substltuent shielding coefficient Z 6 = 5 '28 + 0' 96 = 6' 24 Z <-C=C-l=+l.26 gem Zeis <olkYll = -0.26 Ztrans <-SRl= -0.04 r.z = + o.96 However, the methyl protons of 13 resonate at a 2.11 which is very similar to the value reported for the methyl group cis to methoxycarbonyl in methyl 3,3-dimethylacrylate (o 2.12).19 Furthermore, the chemical shift of the ring Mock et al,, Kasal et al., Kasal et al., JACS,, 9Q., 4501 (1965) Acta Cryst., . Angew. Chem., B31, 2729 ( 1975) fili, 295 (1976) the thlePln Cl3> must exist in a boat conformation 622 I. MURATA ET AL. proton (H-6) of 13 (o 6.14) is in fair agreement with the value (o 6.24) calculated by using the sulfstituent shielding coefficient Z 20 for olefinic protons. In addition, available X-ray crystallographic results of thiepin 1,1-dioxide,21 benzo[b]thiepin 1,1-dioxide,22 and parent benzo[b]thiepin23 suggested that 13 must exist in a boat conformation. From these results we consider the thiepin 13 to be an atropic (an olefinic) molecule. Acknowledgments. - The authors thank Dr. Kazuhiro Nakasuji for his effort in the early stage of this work. Financial support by a Grant-in-Aid for Scientific Research (No. 343007) from the Ministry of Eductation, Science, and Culture, Japan is gratefully acknowledged. REFERENCES 1. Preliminary communication of this work, see: K. Nishi no, S. Yan o, Y. Koh ash i, K. Yamamoto, and I. Murat a, J. Amer. Chem. Soc. in pres (1979). 2. M. J. S. Dewar and N. Trina j st i c, J. Amer. Chem. Soc. 92 (1970) 1453. 3. B. A. Hess, Jr. and L. J. Schaad, J. Amer. Chem. Soc. · 95 (1973) 3907. 4. J. Aihara, J. Amer. Chem. Soc. 98 (1976) 2750, 6840. 5. For review, see: L. A. Paquette, Nonbenzenoid Aromatics, J. P. Snyder Ed., Academic Press, New York, 1969, Vol. 2, p. 249. 6. For reviews, see: E. Voge 1, and H. G ii nth er, Angew . . Chem. Int. Ed. Engl. 6 (1967) 385; D. M. Jeri n a, H. Yagi, and J. W. D a 1 y, Heterocydes 1 (1973) 267. 7. For reviews, see: U. Eisner and T. Krishnamurthy, Int. J. Sulfur Chem. Part B, 6 (1971) 267. K. Na k as u j i and I. Murat a, Kagaku, 32 (1976) 435; K. Na k as u j i, T. Ta ts u o k a, and I. Murat a, Kagaku 33 (1977) 32. 8. T. J. Barton, M. B. Martz, and R. E. Z i k a, J. Org. Chem. 37 (1972) 552. 9. B. P. St ark and A. J. Duke, Extrusion Reactions, Pergamon Press, Elmsford, N. Y., 1967, p. 91. 10. J.M. Hoffmann, Jr. and R.H. Schlessinger, J. Amer. Chem. Soc. 92 (1970) 5263. 11. D. N. Reinhoudt and C. G. Kowwenhoven, J. Chem. Soc. Chem. Commun. (1972) 1233. 12. S. Y a n o, K. Ni s h i n o, K. N a k a s u j i, and I. M u r a t a, Chem. Lett. (1978) 723. 13. A popular measure of the steric requirements is so-called »A« value, the free energy difference involved in the axial-equatorial equilibrium of substituted cyclohexane. Recommended A value for i-C3H7 and tert-C4H9 are 2.1 and ) 4.4, respectively. E. L. E 1ie1, J. Chem. Educt. 37 (1960) 126; Angew. Chem., Int. Ed. Engl. 4 (1965) 761. 14. M. Sy, Ng. Ph. Bu u - Ho i, and Ng. D. Xu on g, J. Chem. Soc. (1954) 1975. 15. Cf. I. E 1 phi me ff - Fe 1 kin and P. S a rd a, J. Chem. Soc. Chem Commun. (1969) 1065; W. B. Mother we 11, ibid., (1973) 935; P. Hodge and M. N. K h am, J. Chem. Soc., Perkin I, (1975). 809. 16. Cf. Organic Compounds of Sulfur Selenium, and Tellurium, D. H. Reid, Ed., The Chemical Society, London, 1973, Vol 2 (Specialist Periodical Reports). 17. K. Nishi no, K. Na k as u j i, and I. Murat a, Tetrahedron Lett. (1978) 3567; K. Nakasuji, K. Kawamura, T. Ishihara, and I. Murata, Angew. Chem. Int. Ed. Engl. 15 (1976) 611. 18. A. W. Burgs ta h 1 er, P.-L. Chien, and M. 0. Ab de r - Rahman, J . Amer. Chem. Soc., 86 (1964) 5281; C. Hoo g z and and W. Hube 1, Tetrahedron Lett. (1961) 637; W. A. Gibbson s and V. M. S. Gil, Mol. Phys. 9 (1965) 163. 19. L. M. Jackman and R. H. W i 1 e y, J. Chem. Soc. (1960) 2881. 20. C. Pascua 1, J . Meier, and W. Simon, Helv. Chim. Acta 49 (1966) 164. 21. H. L. Ammon, P. H. Watts, Jr., J. M. Stewart, and W. L. Mo ck, J. Amer. Chem. Soc. 90 (1968) 4501. MONOCYCLIC THIEPIN 623 22. N. Ya s u o k a, Y. Kai, and N. Kasai, Acta Crystallogr., Sect. B, 31 (1975) 2729. 23. N. Ya s u o k a, Y. K a i, N. Kasai, T. Tats u o k a, and I. Murat a, Angew. Chem., Int. Ed. Engl. 15 (1976) 297. SAZETAK NeobiCno stabilan i jednostavan monociklicki tiepin. Priprava i svo'jstva 2, 7 -di-t-d util-4-etoksikarbonil-5-mctiltiepina I . Murata, K. Nishina, S. Yano, Y. Kohashi i K. Yamamoto Jednostavni monociklicki tiepin s 8 Jt elektrona, 2,7-di-t-butil-4-etoksikarbonil--5-metiltiepin (I), pripravljen iz 2,6-di-t-butil-4-metiltiopirilijum tetrafluoroborata (II). Uprkos tiepinskoj strukturi spoj I pokazao je neobienu termicku stabilnost. Prikazani su detalji priprave spojeva I i II, kao kemijska i fizikalna svojstva spoja I. ODJEL ZA KEMIJU SVEUCILISTE U OSAKI Prispjelo 3. rujna 1979. OSAKA, JAPAN 

A Remarkably Stable and Simple Monocyclic Thiepin. Synthesis and Properties of 2, 7-Di-tert-butyl-4-ethoxycarbonyl-5-methylthiepin

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