J. Org. Chem. 1993,58, 4398-4404
4398
Synthesis of Substituted Fluorenones and Substituted 3~,3f-Dichlorospiro[fluorene-9,2f-thiiranes] and Their Reactivities Warren Chew, Rosemary C. Hynes, and David N. Harpp’ Department of Chemistry, McCill University, Montreal, Quebec, Canada H3A 2K6 Received November 11,1992 (Revised Manuscript Received April 19,1993)
Several novel 9-fluorenones were synthesized and were used as precursors in an attempt to prepare unique substituted 3’,3’-dichlorospiro[fluorene-9,2’-thiiranranea].Severalof the thiiranes were unstable and desulfurizedduring their preparation (7a-d, 11,121. 3’,3’-Dichloro(2,5-dimethoxyspiro[fluorene9,2’-thiiranel (70 was prepared along with 2,2-dichloro-3,3-bis(4-methoxyphenyl)thiirane (16), and 3’,3’-dichloro-l0,11-dihydrospiro[5H-dibenzo[a,dlcycloheptane-5,2’-thiiranel(17) all of which were stable at room temperature. A study of the reactivity of fluorenyl-substituted thiiranes and other related thiiranes showed that the extent of aromaticity of the substituents at the 3-position of the thiiranes influences their stabilities.
Introduction As part of our investigation on the mechanism of sulfur extrusion from thiiranes of type 1,’ it is necessary to have a general approach to the synthesis of the fluorenones which would serve as precursors to the synthesis of the fluorenyl-substituted thiiranes.
1
T w o known methods for the preparation of fluorenones involve intramolecular cyclization steps. The first is a C-C bond formation from a carbonyl to aryl group and the second from aryl to aryl. Another convenient route to substituted fluorenones was recently described by Snieckus and co-workers and involved a remote aromatic metalation strategyS2We have successfully utilized the intramolecular cyclization approaches to the synthesis of substituted fluorenones, and we present our results here as well as attempts to prepare thiiranes with various substitution patterns. A study of the reactivity of these thiiranes was also undertaken.
4
3
Results and Discussion The general method employed is outlined in Scheme I. The synthesis of biphenyloxazolines 2 and biphenylcar.~ boxylic acids 3 is based on that described by M e y e r ~The 2-oxazolinegroup was suitable protection for the carboxyl function because of its resistance to Grignard reagents used in a subsequent step in the ~ynthesis.~ The methodology was recently extended in the synthesis of 2-substituted naphthalenes: The deprotection of the oxazoline moiety was accomplished by alkaline hydrolysis, although a milder method for converting oxazolines to carboxylic (1) Chew, W.; Harpp, D.N. Tetrahedron Lett, 1992,33,45. (2) Fu, J.-M.; Zhao,B.-P.; Sharp,M. J.; Snieckus, V. J. Org. Chem. 1991,56,1683. (3) Meyers, A. I.; Gabel, R.; Mihelich, E. D. J. Org. Chem. 1978,43, 1372. (4) (a) Meyers, A. 1.; Temple, D.L.; Haidukewych, D.; Mihelich, E. D. J. Org. Chem. 1974,39, 2787. (b) Meyers, A. I.; Meier, A.; Rawson, D. J. Tetrahedron Lett. 1992,33, 853. (5) Gant, T. C.; Meyers, A. I. J. Am. Chem. SOC.1992,114, 1010.
oO22-3263/93l1958-4398$04.00f0
Conditions: (a) SOC12,25 “C, 24 h; (b)NHZCH~C(CH~)ZCHZOH, 0 OC; (c) (i) SOCl2; (ii) 20% N a O H (d) (i) CHsI, 3 h; (ii) aq NaOH/ CHsOH, reflux 24 h; (e) polyphosphoric acid, 3 h; (0NHnNHrHaO, reflux 24 h; (g) HgO, NazSO1,10% KOH, 26 OC, 24 h; (h) CSClz, 0 “C.
acids was recently described by Phillion and co-workers in which trifluoromethanesulfonic anhydride was employed followed by alkali saponification.6 With the substituted biphenyls in hand, intramolecular Friedel-Crafts-type acylation was affected by polyphosphoric acid.’ In the preparation of 4d, polyphosphoric acid cyclization gave two isomeric compounds, 3,6(6) Phillion, D. P.; Pratt, J. K. Synth. Comm. 1992,22, 13. (7) (a) Koo, J. J. Am. Chem. SOC. 1963, 75,1891. (b) Dupriwt, M. T.; Schmidt,C. L.; Kuzmich, D.; Williams,S. B. J. Org. Chem. 1986,51,2021.
1993 American Chemical Society
Synthesis of Substituted Fluorenones
J. Org. Chern., Vol. 58, No. 16, 1993 4399
Scheme I1
w 9 R,=H; R2=CH3
10
dimethoxy-9-fluorenoneand 1,6-dimethoxy-9-fluorenone, which were easily separated. Conversionof the fluorenones 4 to their hydrazones 5 and then to their diazo derivatives 6 was relatively straightforward following the method described by BaltzlyB or Schuster.9 However, under the reaction conditions, fluorenone 4c could not be converted to its hydrazone. The diazo derivatives 6 were not isolated but were treated immediately with thiophosgene in situ in an attempt to prepare the fluorenyl-substituted derivatives 7. The coupling of diazo compounds with thiocarbonyls is one of the easiest methods to prepare thiiranes.1° This method has been employed with a wide range of both diazo reagents and thioketones and has resulted in a variety of different thiiranes.ll This route (without isolation of the diazo compound) minimizes generation of azine side products. Azines are known to form readily from diazo cornpoundsl2 and hydrazones.13 Most of the thiiranes 7 were found to be unstable under the reaction conditions, and they underwent ready desulfurization to their corresponding olefins 8. Thiirane 7f was stable long enough to obtain analytical data. The synthesis of the 3-methylfluorenyl derivative involved C-C bond formation from aryl to aryl. Ring closure was easily effected by Pschorr-type cyclization conditions which have been used to synthesize avariety of substituted fluorenone and azafluorenones.14 3-Methylfluorenone (9) was obtained which was converted to ita hydrazone 10, oxidized, and then treated with thiophosgene to give thiirane 11; this thiirane promptly lost sulfur to give the corresponding olefin product 13 (Scheme 11). An attempt to prepare the 2-fluorospiro[fluorene8,2’-thiiranell2was also unsuccessful, and only 1:3 ratio of thiirane to the desulfurized product (14)was obtained. Three other related thiiranes, 2,2-dichloro-3,3-diphenylthiirane (15), 2,2-dichloro-3,3-bis(4-methoxypheny1)N
(8) Baltzly, R.; Mehta, N. B.; Ruseell, P. B.; Brooks, R. E.; Grivsky, E. M.; Steinberg, A. M. J. Org. Chem. 1961,26, 3669. (9)Chuang, C.; Lapin, S. C.; Schrock, A. K.; Schueter, G.B. J. Am. Chem. SOC.1985,107,4238. (10) (a) Staudinger, H.; Pfenninger, F. Chem. Ber. 1916,49,1941. (b) Staudinger, H.; Siegwart, J. Helu. Chem. Acta 1920,3, 833, 840. (11) (a) Tashiro, M.; Makata, S.;Iechi, S. Heterocycles 1979,12,184. (b) Raaech, M. S.J. Org. Chem. 1979,44,632. (c) L’abbe, G.;Dekerk, J.P.;Martens,C.;Toppet,S.J. Org. Chem. 1980,45,4366. (d) Schaumann, E.; Behr, H.; Adwidjaja, G.;Tangerman, A.; Lammerink, B. H. M.; Zwanenberg, B. Tetrahedron 1981,37, 219. (e) Barbaro, G.;Battaglia, A.; Giorgianni, P.;Maccagnani, G.;
[email protected], D.; Bonini, B. F.; Mazzanti, G.;Zani, P. J. Chem. SOC.,Perkzn Tram. 1 1986, 381. (0 Furuhata, T.; Ando, W. Tetrahedron Letts. 1987,28,1179. (g) Rall, K.; Sundermeyer, W. d. Flllorine Chem. 1990,47, 121. (12) (a) Szmant, H. H.;McGinnis,C. J. Am. Chem. SOC.1950,72,2890. (b) Cohen, S.G.;Cohen, F.; Wang, C. H. J. Org. Chem. 1963,28, 1479. 1989, 111, 1796. (d) (c) Abelt, C. J.; Pleier, J. M. J. Am. Chem. SOC. Sugiyama, M. H.; Celebi, S.;Platz, M. S.J. Am. Chem. SOC.1992,114, M.
(13) Kolb, V. M.; Kuffel, A. C.; Spiwek, H. 0.; Janota, T. E. J. Org. Chem. 1989,64, 2771. (14) Kyba, E. P.; Liu, S.-T.; Chockalingam, K.; Reddy, B. R. J. Org. Chem. 1988,53, 3513.
11 R,=H; R2=CH,
13 R p H ; R,=CH,
12 R,=F; R,=H
14 R,+F; R,=H
thiirane (16), and 3’,3’-dichloro-l0,1l-dihydrospiro[5Hdibenzo[a,d]cycloheptene-5,2’-thiiranel (17) were successfully prepared using the Staudinger methodology.1° The 3-membered ring heterocycle in 15 and 17 is likely to be more stable than the fluorenyl-substituted compounds because the degree of aromaticity of the phenyl or benzo groups is less than that of the fluorenyl group (videinfra).
15
16
17
A substantial mechanistic study which extends our original observations on the mechanism has been carried out.16 The major thrust of these proposals is consistent with the structure-activity results obtained here. The essential mechanistic pathway is included for clarity (Scheme 111). It should be mentioned that we carried out trapping experimentsl6Je in an effort to intercept the cationic intermediate portrayedin Scheme 111. These were unsuccessful, indicating that the concatenation of sulfur atoms is a fast process. There is literature precedent for this pro~ess.’~ The study of the general reactivity of substituted derivatives of 1 entailed measuring the possible loss of sulfur when heated in toluene at 80 O C for 45 min. The unsubstituted thiirane 1, as expected, w a transformed entirely to the corresponding olefin under the reaction conditions. Our proposed mechanism has as the ratedetermining step (unimolecular path) the ionization of the C-S bond as shown in intermediate 18 (vide infra, SchemeIV).lJS Therefore,the reaction would be predicted to lose sulfur much faster in the presence of activating groups on the fluorenylring system since these substituenta would stabilize the developing cation. In the presence of deactivating groups, the dipolar intermediate would be unfavourable and the compound would not be expected to lose sulfur as easily. The inability to isolate a pure sample of the fluorosubstituted thiirane derivative 12 is consistent with our (15) Chew, W.; Harpp, D. N. J. Org. Chem. Following paper in thia issue. (16) Our trapping experimentswere similarto those previously carried out: McClelland, R. A.; Mathivanen, N.;Steedsen, 5. J. Am. Chem. SOC. 1990,112,4867. Cozens, F.; Li, J.; McClelland, R A. Angeu. Chem., Znt. Ed. Engl. 1992,31, 743. (17) Davie,R. E. J. Am. Chem.SOC.1968,80,3665. Steude1,R.;& d e , J.-J. Z . Anorg. Allg. Chem. 1979,457,165. Harpp, D.N.Perspectives in the Organic Chemietry of Sulfur; Zwanenburg, B.; N u d e r , A. 3. H., Eds.; Elaevier: Amsterdam, 1987; pp 1-22. Steudel, R.; Prenzel, S., Z. Naturforsch. 1989,44b,1499. Will~ams,C. R.; MacDonald, J. G.;Harpp, D. N.; Steudel, R.; Forster, S. Sulfur Lett. 1992, 13, 247. Chew, W.; Harpp, D. N.; Steudel, R.; Forster, S.Sulfur Lett. 1993, 16, 247.
4400 J. Org. Chem., Vol. 58, No.16, 1993 Scheme I11
blrnokcular slow
1
ctp. + sI
Scheme I V
argument. The fluorine atom could stabilize the dipolar intermediate via resonancel8 facilitating desulfurization. Countering this, by its inductive effect, the intermediate would be destabilized and thus inhibit desulfurization. Our experiments show that a mixture of 12 and 14 was obtained, strongly suggesting that the inductive and the resonance effects on the fluorenyl ring system are approximately balanced and episulfide 12 is partially converted to olefin 14. A similar explanation can be envisioned for the instability of thiiranes 7. The presence of methoxy substituents would stabilize the proposed cationic intermediate and enhance ita decomposition. The presence of additional activating methyl groups in 7b and 7c further increases desulfurization. The synthesis of 2,5-dimethoxy-substituted fluorenylthiirane7fwas successful,although in poor yield. Initial studies show that when 7f was heated in (18) Pew, R. G. J. Am. Chem. SOC.1967,89,5605.
Chew et al. toluene at 80 OC for 2 h, no desulfurization occurred. The reaction was followed by ‘H NMR and found to be unchanged after heating for 2 h whereas compound 1 completely desulfurized under the same conditions. Although the two methoxy substituents present in 7f would enhance desulfurization by a resonance effect, a closer examination of the resonance contributors suggests why we do not observe ready desulfurization (Scheme IV). In order for 7f to desulfurize, resonance structures I or I1 should be strong contributors to the hybrid. However, these contributors destroy the overall aromaticity of the ring system, and therefore, both I and I1 deliver a small resonance contribution. Conversely, resonance contributor I11 in compounds 7a-d does not disrupt the aromaticity of the entire ring system; as a consequence, desulfurization is more likely to occur. Furthermore, it was discovered that introduction of a stabilizing methyl substituent at the 3-position of the fluorenyl group in 1 (thiirane 11) causes desulfurization. It should be emphasized that in the cases of attempted preparation of 7a-d, and 11, the only products isolated were the correspondingalkenes 8a-d and 13. The episulfides must have been formed but underwent ready desulfurization. An interesting result was observed when we studied the reactivity of the diphenyl-substituted thiiranes 15 and 16. These two compounds are easily prepared in high yield, and the precursors as well as the thiirane are stable for months in the refrigerator without noticeable decomposition. Unlike 1,15 does not desulfurize when heated at 80 OC for 45 min. This observation can be explained by the differencesin the two aromaticsystemswhich influence their ability to promote the cation generated in the unimolecular rate-determining step. The planar fluorenyl group in 1 can delocalize the cation more efficiently than the noncoplanar phenyl groups of 15. It is known from solvolysisreactions of alkyl chlorides containing either the fluorenyl or biphenyl aromatic systems that the fluorenyl substituent is a better transmitter of ?r electrons in stabilizing carbonium ions.19 The phenyl groups, meanwhile, are less effective in stabilizing the incipient carbonium ion since the ?r system is twisted out of the plane. Further supporting this position is the recent observation of Johnston and Lee-Ruff who have demonstrated the comparablestabilities of the two cation systems (fluorenyl and biphenyb.20 They have reported that when reactivities with the same solvent are compared the diphenylmethyl cation is less reactive than the fluorenyl counterpart. Conversely, the bis(4-methoxyphenyl)-substituted derivative 16 was found to decompose readily in solution. This would be expected since the p-methoxygroups would assist in stabilizing the incipient carbonium ion and facilitate desulfurization. 3’,3’-Dichloro-lO,ll-dihydrospiro[5H-dibenzo[a,dlcycloheptene-5,2’-thiiranel(17)did not desulfurize under the reaction conditions (2 h, 80 “C) but was found to desulfurize to a 50% extent when heated at 100 OC for 8 days. After 17 days, approximately75 % had decomposed. This is consistent with the overall mechanistic picture because the two methylene groups bridging the phenyl (19) (a) Bolton, R.;Jones, M.E.; Tucker, S.W.J. Chem. SOC.1964, 1464. (b) Bolton, R.J. Chem. SOC.1986,1642. (c) Bolton, R.; Burley, R. E. M.J. Chem.Soc.,Perkin Trans.2,1977,426. (d)Tsuno,Y.;Tairaka, Y.; Sawada, M.; Fujii, T.Bull. Chem. SOC.Jpn. 1978,51, 601. (20) Johnston, L. J.; Kwong, P.; Shelemax, A.; Lee-Ruff,E. J. Am. Chem. SOC.1993,115,1664.
J. Org. Chem., Vol. 58, No. 16, 1993 4401
Synthesis of Substituted Fluorenones
Table 11. Atomic Coordinates (I,y, z)and Temperature Factors (Bw)for Compound 17 (Estimated us Refer to the Last Digit) atom X Y 2 BOU S c11 c12
c1
Figure 1. ORTEP representation of thiiranes 15 and 17. Table I. Atomic Coordinates (I,y, z)and Temperature Factors (Bw)for Compound 15 (Estimated urn Refer to the Last Digit) atom X N 2 B, ~~
c11 c12 S
c1
c2 c3 c4 c5 C6 c7 C8 c9 c10 c11 c12 C13 C14 CllA C12A SA C1A C2A C3A C4A C5A C6A C7A CBA C9A ClOA CllA C12A C13A C14A
0.0877(3) -0).0202(3) 0.0426(3) 0.0524(12) 0.0895(12) 0.1638(6) 0.1966(9) 0.2647(9) 0.3000(6) 0.2672(9) 0.1990(9) 0.0665(8) 0.0771(7) 0.0576(7) 0.0275(8) 0.0169(7) 0.0364(7) 0.6579(4) 0.5726(4) 0.5933(4) 0.6250(15) 0.6619(11) 0.7308(6) 0.7429(8) 0.8065(9) 0.8581(6) 0.8460(8)
0.7824(9) 0.6575(7) 0.6796(7) 0.6777(7) 0.6536(7) 0.6315(7) 0.6334(7)
0.3652(11) 0.0534(3) 0.4118(11) 0.1232(3) 0.0785(3) 0.8129(11) 0.1048(11) 0.543(4) 0.1503(9) 0.685(4) 0.1537(7) 0.676(3) 0.1334(6) 0.8525(22) 0.1377(6) 0.8483(23) 0.1621(7) 0.668(3) 0.1823(7) 0.4909(22) 0.4951(23) 0.1781(7) 0.2127(6) 0.728(3) 0.2611(9) 0.6720(22) 0.609(3) 0.3210(7) 0.3326(6) 0.802(3) 0.2843(9) 0.9581(23) 0.2243(7) 0.9210(25) -0).3601(14) -0.0320(3) 0.0591(4) -0.4533(15) 0.0270(4) O.OllO(14) -0).252(4) 0.0354(12) 0.0817(12) -0).117(5) 0.0698(7) -0.058(3) 0.139(3) 0.0425(7) 0.0342(6) 0.1933(21) 0.051(3) 0.0532(7) 0.0805(7) -0.146(3) -0).2009(21) 0.0888(6) 0.1520(5) -0.143(3) -0.3271(24) 0.1867(8) -0).3386(24) 0.2531(8) 0.2847(5) -0.166(3) 0.018(3) 0.2500(9) 0.1836(8) 0.0291(23)
5.4(4) 5.5(4) 4.4(4) 4.4(15) 4.2(15) 3.6(3) 6.9(3) 6.4(3) 5.0(3) 6.8(3) 6.1(3) 4.3(3) 6.2(3) 5.7(3) 6.7(3) 9.6(3) 5.3(3) 8.2(5) 9.5(6) 7.5(5) 6.3(19) 5.2(16) 5.0(3) 6.7(3) 6.0(3) 5.6(3) 7.8(3) 5.3(3) 3.4(3) 6.6(3) 6.2(3) 6.2(3) 7.8(3) 8.3(3)
groups cause the ?r system to become more planar than the diphenyl system but less than that of the fluorenyl system. Crystal structure determinations of 15 and 17 were carried out. Figure 1shows the ORTEP representations of both 15 and 17. Atomic coordinates and temperature factors are reported in Tables I and 11. As predicted, the phenyl groups in 15 are not coplanar and are arranged in such a fashion as to minimize their interaction. In 17, a similar nonplanarity of the aromatic rings is also found. The aryl groups in 17 are -60° out of the plane, and the phenyl groups in 15 are >60° out of the plane; of course, the fluorenyl group in 1 is planar. Since the fluorenyl system decomposes readily while the diphenyl system does not desulfurize, we would expect some decomposition to occur with 17 but a t a very slow rate. Consequently,we can summarize the aromatic systems in increasing order of reactivity: diphenyl < dibenzosub-
c2 c3 c4 c5 C6 c7 C8 c9 c10
c11 c12
C13 C14 C15 C16
0.62296(19) 0.54225(18) 0.75718(18) 0.6712(6) 0.7574(6) 0.9152(7) 0.9485(7) 1.0918(9) 1.1976(9) 1.1643(8) 1.0231(7) 1.0055(8) 0.8679(9) 0.7803(6) 0.7550(7) 0.6760(7) 0.6217(7) 0.6462(6) 0.7255(6)
0.6257(3) 1.0721(3) 1.0136(3) 0.8961(10) 0.7600(9) 0.7150(10) 0.5357(12) 0.4897(14) 0.6260(18) 0.8035(15) 0.8520(12) 1.0434(14) 1.1112(11)
0.9424(10) 0.9529(11) 0.8005(13) 0.6345(11) 0.6201(9) 0.7735(9)
0.06797(7) 0.09744(7) 0.01891(6) 0.07392(22) 0.11535(23) 0.10565(23) 0.0762(3) 0.0675(3) 0.0864(4) 0.1158(3) 0.1267(3) 0.1629(4) 0.1805(3) 0.2072(3) 0.2638(3) 0.2879(3) 0.2568(3) 0.20059(24) 0.1759(23)
5.15(9) 5.68(9) 5549) 4.4(3) 3.7(3) 4.0(3) 5.5(4) 7.2(5) 7.7(6) 6.8(5) 5.2(4) 7.7(5) 7.2(4) 4.6(3) 5.2(4) 5.2(4) 4.9(3) 4.1(3) 3.6(3)
eronyl < fluorenyl and diphenyl
