Studies of the Reaction of Various 1,2-Disubstituted Benzenes with Crotonic Acid in Polyphosphoric Acid

Hamish G. Grant* Department of Organic Chemistry, University of Adelaide G.P.O. Box 498, South Australia 5001

Z. Naturforsch. 34b, 728-733 (1979); received November 27, 1978

5,6-Disubstituted Indan-l-ones, Crotonic Acid, Polyphosphoric Acid, 1-Methyl Benzofurocyclopentan-3-one, 13C NMR

The reaction of several 1,2-disubstituted benzenes with crotonic acid in polyphosphoric acid has provided a number of previously undescribed 5,6-disubstituted indan-l-ones. Guaiacol, o-cresol, 1,3-benzodioxole, 1,4-benzodioxan and dihydrobenzofuran yielded indanones (4-8) in which acylation of the benzene ring occurred exclusively para to the free hydroxyl groups of the first two substrates and para to the ether oxygen in the last. Catechol, salicylaldehyde, o-hydroxy acetophenone and o-chloro phenol yielded no indanones and formed crotonate esters. A further four indanones (9-12) were derived from demethylation and acetylation procedures. Annelation of the methyl cyclopentanone ring occurred acrose the furan ring in benzofuran to provide the new heterocycle 1-methyl benzofurocyclopentan-3-one in moderate yield. The assigned carbon-13 NMR spectral shifts for all indanones are set out in Table II.

Interest in this laboratory in the investigation of ultimately provide, via the oxime, the required the physiological activity in the central nervous benzovalerolactam structure 1. system of benzovalerolactam analogs of structure 1 Herein is described an evaluation of the "one- has engendered the quest for easily acessable pre- pot" method for the synthesis of 5,6-disubstituted cursors. Of primary consideration was the 5,6-di- 3-methyl indan-l-ones from 1,2-disubstituted ben- substituted indan-l-one system (2) of which only zenes with crotonic acid in polyphosphoric acid a very small number of examples have been pre- where at least one substituent was a hydroxyl or viously described in the chemical literature. These ether group including the heterocycles benzofuran, were obtained from a "one-pot" condensation reac- dihydrobenzofuran, 1,3-benzodioxole and 1,4-benzo- tion of 1,2-dimethoxy benzene and o-cresol methyl dioxan. ether with acrylic and substituted acrylic acids in The reaction of the various substrates with a polyphosphoric acid (PPA), a procedure found to 0.1 molar excess of crotonic acid in commercial give high specificity of annelation of the cyclo- polyphosphoric acid was carried out at 125-130 °C pentanone ring at carbons 4 and 5 with respect to for 30 min. These conditions were ultimately used the benzene substituents [1, 2]. for all condensations and were arrived at from the evaluation of yields from a number of experiments. Other conditions were subsequently applied to those substrates which refused to form indanones R2 NH 0 R, at 130 °C/30 min but without success. Above 150 °C 1 excessive amounts of a black intractable tar formed Huisgen et al. [3, 4] have shown that oximation after only 15 min whereas temperatures below of small and medium ring benzocycloalkanones 100 °C favoured ester formation with the phenolic gives only the anti isomer (e.g. 3) and, providing a substrates. bulky substituent is not present at C-7, the Beck- In Table I the results of the reaction carried out mann rearrangement has been found to procede on eleven 1,2-disubstituted benzenes are set out. with phenyl migration to afford the required lactam These directly provided the five new indanones in moderate yield [5, 6]. Thus, in this manner, the 4-8 and subsequently a further four, 9-12 from the indanones of structure 2 could be anticipated to demethylation of 5 and acetylation of the hydroxyl substituents. None of these compounds appears to

* Reprints requests to Dr. H. G. Grant. have been described previously in the chemical 0340-5087/79/0500-0728/$ 01.00/0 literature. H. G. Grant • Reaction of Various 1,2-Disubstituted Benzenes 729

In all cases where the substrate carried a free hydroxyl group, varying amounts of the crotonate esters (16) were detected. With catechol however, the o-hydroxy phenyl crotonate (16), R=OH, was obtained in high yield (~75%) with less than 5% of the indanone observed. Considerable variation of the reaction conditions did not afford the required Table I. PPA cyclisations attempted. indanone in greater yield. With o-cresol and guaiacol, acylation occurred virtually exclusively Substrate Major Yield m.p. (>95%) para to the hydroxyl group to provide product indanone [°C] [%] the 5-hydroxy indanones (4) and (5). This orien- tation of the 5- and 6-substituents was assigned o-Cresol 4, R = CH3 64 152-153 from observation of the UV spectra of 4 and 5 in Guaiacol 5, R = CH3O 34 89.5-90 ethanol and ethanolic potassium hydroxide. It has 1,3-Benzodioxole 6 10 105-106 been well established that the long wavelength 1,4-Benzodioxan 7 72 78-79 electron transfer band in ortho- and para-substituted Dihydrobenzofuran 8 60 90-91 aryl aldehydes and ketones undergoes a pronounced Benzofuran 19 — — (ca. 40-50 nm) shift to longer wavelength with a Catechol ester — — o-Hydroxy aceto- concomittant increase in extinction coefficient on a phenone ester — — addition of a strong base to the alcohol solution [7, o-Methoxy aceto- 8]. For example, this band in vanillin (17) at phenone esterb — — 310 nm (£1% = 710) in ethanol is displaced to Salicylaldehyde estera — — 353 nm (ex% = 1980) in 0.014% potassium hy- a o-Chloro phenol ester — — droxide in aqueous ethanol (7% water). In contrast, a Substrate recovered ca. 70% unchanged, the corresponding band at 313 nm (e = 710) for b Substrate recovered ca. 90% unchanged. isovanillin (18) while shifting to 365 nm in alkaline ethanol, shows a decrease in extinction coefficient In all reactions which produced indanones in (e = 680). Both indanones (4) and (5) gave UV acceptable yield, a number of minor neutral pro- spectra in ethanol very similar to vanillin and like- ducts were also observed by GLC and TLC. The wise exhibited the shift to long wavelength (310 -> presence of some precursor phenyl vinyl ketones 340 nm) and substantial increase in extinction co- (13) was inferred from MS, NMR and IR data. In efficient (E = 2100). the case of the reaction with dihydrobenzofuran, the ketone 14 was isolated from the product in 15% yield after the half hour reaction period. Extension of this period to one hour reduced the yield of this precursor to less than 2% but con- comittantly reduced the overall yield of the ind- anone also as a consequence of tar formation. In some instances, the presence of small quantities of the intermolecular products of type 15 obtained

R=CH3 While the 5,6-dihydroxy indanone (9) could not R=CH3O be satisfactorily prepared from the reaction with R=AcO catechol, it was readily obtained in quantitative by Marquardt [1] was inferred from the observation yield from the demethylation in refluxing hydriodic of low intensity peaks corresponding to the molec- acid of the 5-hydroxy-6-methoxy compound (5). ular ion in the mass spectrum of the crude products. The phenolic indanones (4), (5) and (9) were acetyl- 730 H. G. Grant • Reaction of Various 1,2-Disubstituted Benzenes 730 ated with acetic anhydride/pyridine to yield crys- could reasonably be assigned to C-7 H as a conse- talline acetates (10) and (12) and an oily acetate quence of the predicted deshielding influence of the (11) which, although obtained analytically pure by approximately co-planar carbonyl group in the column chromatography, steadfastly refused to peri-position at C-l. This low field signal also ex- crystallise from a variety of solvents. hibits a line width at half height ca. 30% greater The reaction carried out with benzofuran did not than that of the upfield signal (ca. 2.5 Hz) which is provide any detectable indanones, instead annel- indicative of a higher degree of long range coupling ation occurred on the furan ring to form 1-methyl with the former than the latter spin. Low power benzofurocyclopentan-3-one (19) in 34% yield. This Rf. irradiation of the center line of the triplet at constitutes a new tri-cyclic system and is the 3.16 ppm arising from the /3-methylene protons of subject of a preliminary communication [9] de- the dihydrofuran ring (C-6' in 8) resulted in a nar- scribing details of preparation, characterising de- rowing of the singlet at 7.44 ppm to 2.2 Hz while rivatives and structure assignment. the line width of the upfield aromatic proton signal remained unchanged. This behaviour is consistent with allylic coupling of C-7 H with C-6' -CH2- in structure 8; additional support for this orientation cw of the dihydrofuran ring is discussed below. 19 0 Carbon-13 chemical shifts for the various indan- Various indanones have been the subject of ones have been tentatively assigned and are listed detailed examination by proton NMR spectroscopy in Table II. Assignments were made utilising model [10-12] while only limited data for the carbon- compounds [13, 14], the additive correlation of 13 NMR shifts of this system is available. Proton empirical substituent effects in the benzene ring NMR shifts for the indanones listed in Table I and system [15] and off-resonance and single frequency those derived therefrom are set out in the experi- heteronuclear decoupling experiments. Further cor- mental section. Structure 8 was confidently as- roboration for the assignment of the orientation of signed to the indanone obtained from dihydro- the 5- and 6-substituents in the indanone (4) ob- benzofuran on the basis of the following observa- tained from o-cresol was obtained from the carbon- tions. Of the two singlets at 7.44 and 6.72 ppm in 13 spectrum of this compound. This showed inter the proton NMR spectrum (unambiguously as- alia two quaternary aromatic resonances consider- signed to C-4 H/C-7 H), the signal at lower field ably removed downfield at 162.2 and 162.7 ppm

Table II. Carbon-13 NMR shifts of 5,6-disubstituted 3-methyl indan-l-ones (ppm from TMS).

Indanone C-l -2 -3 -3' -3a -4 -5 -6 -7 -7a Other shifts

/162.7 linR /162.7 /126.3 J 126.3 4 207.1 45.6 32.6 21.3 126.3 Ph-CHg 16.2 f 162.2 11U'8 \162.2 \128.4 \128.4 5 205.5 45.4 32.4 21.3 147.4 110.2 156.1 153.2 104.0 128.6 OCHg 56.1 6 204.1 45.8 32.7 21.5 157.7 102.3 154.3 148.4 104.6 131.1 0CH20 101.9

7 205.0 45.2 32.2 21.6 154.4 111.4 150.3 144.0 113.1 130.1 OCH2 64.5, 64.8 /128.5 8 204.5 46.0 32.8 21.5 163.5 105.4 167.0 {Jg®"5 120.3 OCH2 72.8 \130.5 Ph-CHa 28.7 9 204.6 45.2 31.9 21.5 154.4 108.0 153.0 145.6 110.5 128.4 125.7 134.3 COCH3 20.8 CH3CO 168.6 10 204.9 45.6 32.5 21.3 155.0 118.7 159.3 130.4 Ph-CHg 16.4 105.4 134.9 COCH3 20.5 CH3CO 168.4 11 204.9 45.5 32.3 21.3 146.0 119.7 153.2 151.5 OCH3 56.1 120.2 134.7 COCH3 20.7, 20.8 CH3CO 168.1, 167. 12 204.1 45.5 32.7 21.1 147.6 118.1 158.1 142.2

(Shifts bracketed thus { are interchangeable assignments.) H. G. Grant • Reaction of Various 1,2-Disubstituted Benzenes 731 which can be attributed only to C-3a and the Polyphosphoric acid reaction hydroxyl substited benzene carbon. For C-3a to The disubstituted benzene (0.5 mole), crotonic experience a deshielding of this order it would re- acid (0.55 mole) and polyphosphoric acid (400 mis) were mixed thoroughly and heated with periodic quire the methyl to be para and the hydroxyl meta stirring in an oil bath maintained at 125-130 °C. as has been assigned from the UV spectral data After 30 min the mixture was poured immediately discussed above. In this configuration C-3a would into crushed ice (ca. 1.5 Kg) and stood with occa- experience a small shielding effect from the para sional stirring until the resultant dark red/brown methyl group at C-6 and a small deshielding effect slurry reached ambient temperature. This was extracted twice with diethyl ether (1 L) and the from the meta hydroxyl at C-5. Conversely, for the combined extracts washed twice with 15% potas- alternative orientation of the C-5 and C-6 substi- sium bicarbonate solution (500 mis) and once with tuents, C-3a Avould experience a large shielding water. After drying, evaporation of the ether yielded effect from the para hydroxyl and essentially zero the crude product. effect from the meta methyl group [15]. Thus, the latter orientation was considered inconsistent with 3,6-Dimethyl-5-hydroxy indan-l-one (4) the carbon-13 NMR shifts observed. Unfortunately, This compound was obtained from the PPA cy- clisation reaction in 64% yield and recrystallised this analysis cannot also be applied to the spectrum from diethyl ether to give colourless prisms, m.p. from indanone (5) obtained from guaiacol due to 152-153 °C. the comparable remote shielding effects of the C11H12O2 hydroxyl and methoxyl substituents although the Found C 75.2 H 7.1, UV data provides a cogent argument in support of Calcd C 75.0 H 7.0. the assignment proposed originally. JW: 3400 (broad), 2882, 1679, 1605, 1582, 1480, Structure 8 rather than the alternative (20) for 1330, 1292, 1264, 1120 cm-MH NMR: <5 9.0, broad the product from dihydrobenzofuran is favoured s, Wh/2 8 Hz, OH; 7.51, s, Ph-H; 6.92, s, Ph-H; also from the consideration of the carbon-13 NMR 3.32, m, CH; 2.97, dd, J = 19.4, 7.2 Hz. CH2; 2.22, dd, J = 19.4, 3.1 Hz. CH2; 2.2, s, Ph-CH3; 1.38, d, shifts observed. The two quaternary carbon signals J = 7 Hz, CH3. M.S.: M+ 176.0838 (C11H12O2). at 163.5 and 167 ppm can only be assigned to the The acetate (10) was obtained by heating the branched alkyl and alkoxyl substituted benzene indanone (4) from above (5 g) with pyridine (2.3 g) carbons (C-3a and C-5 in 8). In the alternative and acetic anhydride (50 ml) for one half hour on the steam bath, followed by quenching in water and extraction into ether which was washed with sodium bicarbonate solution and dried over sodium sulfate. Evaporation gave 10 in 95% yield; recrys- 20 0 tallisation from benzene/petroleum ether gave col- ourless prisms, m.p. 86-87 °C. structure 20 where these carbons are para to each Cl3Hl403 other, the alkoxy substituent at C-6 would effect Found C 71.6 H 6.3, a considerable upfield shift on the C-3a resonance Calcd C 71.5 H 6.5. which cannot be reconciled with the observed low t-max: 2900, 1765, 1715, 1620, 1590, 1480, 1460, 1368, field position of this signal. 1280, 1200, 1105, 1042, 1008, 920 cm-1. NMR:

<5 7.44, s, Ph-H; 7.09, s, Ph-H; 2.33, s, OCOCH3;

2.18, s, Ph-CH3; CH3, CH2, CH protons as for 4. Experimental M.S.: M+ 218.0940 (C13H14O3). Infrared spectra were recorded as Nujol mulls or liquid films on a Jasco IRA-1 grating spectrometer. 5-Hydroxy-6-methoxy-3-methyl indan-l-one (5) Melting points were determined on a Reichert hot- This compound was obtained in 34% yield and stage and are uncorrected. Proton NMR spectra was purified by dry column chromatography over were recorded with 10% solutions in CDCI3 at alumina (Woelm) using methylene chloride as elu- 80 MHz; carbon-13 spectra with 20% solutions at ent. Recrystallisation from 1 : 1 methylene chlo- 20.1 MHz on a Bruker WP-80 spectrometer using ride/hexane gave colourless needles, m.p. 89.5 to a ca. 45° pulse and 4K data points. Accurate mass 90.0 °C. measurements were recorded on an AEIMS-30 spectrometer at a resolution of 10000. Combustion CnH1203 analyses were performed by the Australian Micro- Found C 68.8 H 6.3, analytical Service. Calcd C 68,7 H 6.3. 732 H. G. Grant • Reaction of Various 1,2-Disubstituted Benzenes 732

Vmax : 3400 (broad), 2880, 1695, 1610, 1585, 1495, 5,6-Methylenedioxy-3-methyl indan-l-one (6) 1320, 1300, 1210, 1130. 1045 cm-i. *H NMR: Ö 7.15, This compound was obtained in 10% yield and s, Ph-H; 7.0, broad s, Wh/2 20 Hz. OH; 6.94, s, recrystallised from petroleum ether to give prisms Ph-H; 3.83, s, OCH3; CH3, CH2, CH protons as for m.p. 105-106 °C. 4. M.S.: M+ 192.0788 (CnH1203). The acetate (11) was obtained from the indanone C11H10O3 (5) above by the same procedure utilised for the Found C 69.2 H 5.4, acetylation of 4. Calcd C 69.5 H 5.3. Distillation of the crude product afforded 11 in Vmax: 2900, 1692,1605, 1590, 1340,1305, 1292, 1255, 84% yield as an oil b.p. 105-108 °C (0.5 mm). 1220,1072,1020,1010, 928, 860. 842 cm-i. *H NMR:

C13H14O4 6 6.99, s, Ph-H; 6.83, s, Ph-H; 6.0, s, 0CH20: Found C 67.0 H 6.2, CH3, CH2, CH protons as for 4. M.S.: M+ 190.0631 Calcd C 66.7 H 6.0. (CuHioOs). vmax: 2900.1765,1719.1604, 1492, 1420, 1368, 1300. 1280, 1205, 1190, 1165, 1105, 1040, 1020 cm-*. 5,6-Ethylenedioxy-3-methyl indan-l-one (7) iHNMR: <5 7.32, s, Ph-H; 7.25, s, Ph-H; 3.80, s, This compound was obtained in 72% yield and OCH3; 2.35, s, OCOCH3; CH3, CH2, CH protons as recrystallised from hexane/ethyl acetate to give for 4. M.S.: M+ 234.0892 (C13H14O4). prisms m.p. 78-79 °C. Demethylation of 5 (2.25 g) was achieved by refluxing in HI (25 ml) for 70 min followed by Ci2H1203 neutralisation of liberated iodine with sodium meta- Found C 70.3 H 6.0, bisulfite solution. Extraction with ether afforded, Calcd C 70.6 H 5.9. on evaporation, the 5,6-dihydroxy-3-methyl indan- vmax: 2900, 1694,1618,1588,1480,1330, 1308.1298, 1-one (9) in 90% yield. Recrystallisation from di- 1058, 922, 898 cm-1. *H NMR: 6 7.1, s, Ph-H; 6.84, isopropyl ether gave colourless prisms, m.p. 196- s, Ph-H; 4.28, s, 0CH2CH20; CH3, CH2, CH protons 196.5 °C. as for 4. M.S.: M+ 204.0788 (Ci2H1203). C10H10O3 Found C 67.6 H 5.6, 5,6-Ethyleneoxy-3-methyl indan-l-one (8) Calcd C 67.4 H 5.7. This compound was obtained in 60% yield and fmaX: 3400 (broad), 2880, 1688, 1615, 1585, 1504, recrystallised from ethanol to give prisms m.p. 1464, 1320, 1300, 1260, 1220, 1200, 1154, 1120 cm-i. 90-91 °C. iHNMR: <5 9.0, broad s, Wh/2 8 Hz, OH; 7.0, s,

Ph-H; 6.82, s, Ph-H; CH3, CH2, CH protons as Ci2HI202 for 4. M.S.: M+ 178.0628 (C10H10O3). Found C 76.5 H 6.4, The 5,6-diacetoxyl-3-methyl indan-l-one (12) was Calcd C 76.6 H 6.4. obtained in 85% yield from 9 above by the same method utilised for the acetylation of 4. This was vmax: 2900, 1695, 1602, 1580, 1278, 1242, 1224, 1095. -1 recrystallised from methanol to yield colourless 1065, 922, 842 cm . iHNMR: <5 7.44, s, Ph-H: prisms, m.p. 158-159.5 °C. 6.72, s, Ph-H; 4.64, t, 8 Hz, OCH2; 3.16, t, 8 Hz. Ph-CH2; CH3, CH2, CH protons as for 4. M.S.: C14H14O5 M+ 188.0838 (C12H12O2). Found C 63.8 H 5.5, Calcd C 64.1 H 5.4. vmax: 1762, 1705, 1605, 1310, 1292, 1258, 1195, 1142, The author wishes to thank Dr. R. H. Prager for -1 1100, 1020, 1012, 912, 875 cm . *H NMR: <5 7.45, the preparation of the 5,6-methylenedioxy indanone s, Ph-H; 7.21, s, Ph-H; 2.18, s, 6 H, OCOCH3; and express gratitude for the support and advice CH3, CH2, CH protons as for 4. M.S.: M+ 262.0840 (C14H14O5). of Dr. T. M. Spotswood.

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[9] H. G. Grant, J. Heterocycl. Chem. 15, 1235 [13] L. F. Johnson and W. C. Jankowski, Carbon - (1978). 13 NMR Spectra. A Collection of Assigned, Coded [10] G. Agahigian, H. Plant, G. P. Vickers, and J. van and Indexed Spectra, p. 338, 454 et al., Wiley- der Veen, J. Analyt. Chem. 39(13), 1583 (1967). Interscience, New York 1972. [11] W. E. Rosen, L. Dorfman, and M. P. Linfield, J. [14] H. G. Grant, unpublished results. Org. Chem. 29, 1723 (1964). [15] F. W. Wehrli and T. Wirthlin, Interpretation of [12] C. A. Kerr and I. D. Rae, Aust. J. Chem. 31, 341 Carbon-13 NMR Spectra, p. 47, Heyden & Sons (1978). Ltd., London 1978.