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Molecules 2000, 5(6), 874-879;

Spiro Cyclohexadienones from the Reaction of Phenolic Enaminone Derivatives with Hypervalent Iodine Reagents
Laboratory of Organic Chemistry, Chemistry Department, University of Thessaloniki, Thessaloniki 54006, Greece
Author to whom correspondence should be addressed.
Received: 6 May 2000 / Accepted: 25 May 2000 / Published: 9 June 2000


Phenolic enamino compounds, prepared from 2-(4-hydroxyphenyl)-ethylamine and the corresponding β-keto carbonyl compounds, afford spiro cyclohexadienone derivatives on reaction with hypervalent iodine reagents.
Spiro cyclohexadienones; hypervalent iodine; enamino esters


The action of hypervalent iodine compounds on phenols gives rise to a variety of products depending on the nature of the phenol and the reaction conditions. The most interesting reaction pathway is oxidation of the phenolic moiety with simultaneous nucleophilic attack on the para position of the phenolic ring. When this attack occurs place intramolecularly, a variety of spirodienone derivatives are formed with considerable synthetic possibilities [1,2,3]. Especially noteworthy is the oxidative coupling of phenolic derivatives of β-phenylethylamine, studied extensively by Kita and coworkers [4]. This coupling, outlined below, offers an easy access to pharmacologically interesting natural products, when the substituent on nitrogen is an aromatic or a quinone ring.
Figure 1.
Figure 1.
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Results and Discussion

Continuing the exploration of the chemistry of hypervalent iodine reagents [5], we investigated the possibility of analogous cyclization reactions using enamino carbonyl systems of type I. Recently we reported the isolation of stable iodonium salts of type II, resulting from enamino carbonyl compounds such as amino quinones [6], aminocrotonates [7] and cyclic enaminones [8] (in the last case the Ph of the iodonium salt group had been replaced by the CF3CH2 group). We have also reported the oxidative cyclization of analogous enamino carbonyl compounds with an indole ring, resulting into the formation of tetrahydro-β-carbolines [9].
Figure 2.
Figure 2.
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Interesting results were obtained from the reaction of amino crotonic esters 1 with [(hydroxy)(tosyloxy)iodo]benzene, 2. These esters, easily prepared from the reaction of 2-(4-hydroxyphenyl)-ethylamine with the corresponding β-keto acetate according to the literature method [10], react with 2 under mild conditions (CH2Cl2, 0°C) to give the products indicated in the scheme below. All new compounds have spectral and analytical data consistent with their structure.
Scheme 1.
Scheme 1.
Molecules 05 00874 sch001
The first step of the reaction involves probably the formation of an iodonium intermediate, 6. This affords the tosyloxy derivative 3 through an internal nucleophilic displacement of the phenyliodonio group by the tosylate. This displacement takes place with retention of the configuration and was observed in analogous isolable iodonium salts [7]. Enamino tosylates 3 were partially hydrolyzed to keto tosylates 4 during work-up.
Figure 3.
Figure 3.
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A second reaction pathway leads to the formation of spiro cyclohexadienone derivatives 5, by attack of the electron rich aromatic ring on the electrophilic carbon bearing the phenyliodonio group, with the simultaneous elimination of p-toluenesulfonic acid.
The same reaction was tried using the trimethyl silyl ethers of the phenolic derivatives 1. Under conditions described by Kita [4], (CF3CH2OH as solvent, PhI(OCOCF3)2 as oxidant) the reaction afforded a complicated mixture of products and no spiro cyclohexadienone derivatives were detected among them.
This cyclization reaction was extended to other enamino carbonyl systems. Thus, enamino compound 7, prepared from the condensation reaction of dimedone with 2-(4-hydroxyphenyl)-ethylamine, afforded spiro cyclohexadienedione 9 as the sole isolable product. This time the cyclization was effected by [bis(trifluroacetoxy)iodo]benzene 8 in CH2Cl2 at room temperature in 12 hours.
Scheme 2.
Scheme 2.
Molecules 05 00874 sch002
In contrast, enaminone 10, prepared analogously from acetylacetone, afforded a complex mixture of products with [bis(trifluroacetoxy)iodo]benzene. However, it reacted smoothly with [(hydroxy)(tosyloxy)iodo]benzene to afford the tosyloxy enaminone 11 in 45% yield, but no cyclization product was isolated.
Scheme 3.
Scheme 3.
Molecules 05 00874 sch003


The reported oxidative cyclization offers an interesting entry to spiro cyclohexadienones; research will be continued to explore the scope of the reaction with other enamino carbonyl systems.


Typical procedure for the preparation of 5 and 9 

[(Hydroxy)(tosyloxy)iodo]benzene (1 mmol) was added to a stirred solution of enamino carbonyl derivative 1 (1 mmol) in CH2Cl2 (10 mL) at 0°C under argon. The reaction mixture was allowed to reach room temperature and, after all enamino ester was consumed (5 h), it was concentrated and chromatographed on column (SiO2, hexanes-ethyl acetate) to afford, after iodobenzene, 3 and 4 as oils; Finally spiro cyclohexadienones 5a and 5b were eluted as light-yellow crystals.

2-Methyl-3-carboxyethyl-1,4,5,6-tetrahydropyridino-4-spiro-4'-cyclohexa-2',5'-dien-1'-one 5a

Mp 180-182°C (dec.). IR (Nujol): 3320, 1645, 1710, 1605, 1115 cm-1; 1H NMR (CDCl3): δ 1.07 (t, J = 7 Hz, 3H), 1.83 (t, J = 5 Hz, 2H) 2.32 (s, 3H), 3.33 (m, 2H), 3.95 (q, J = 7 Hz, 2H), 4.65 (s, br, 1H), 6.21 (d, J = 10 Hz, 2H), 6.94 (d, J = 10 Hz, 2H); MS m/z 247 (M+, 50), 202 (45), 174 (93), 146 (100), 91 (60). Anal. Calcd for C14H17NO3: C, 68.00; H, 6.93; N, 5.66. Found: C, 67.42; H, 7.03; N, 5.31.

2-Phenyl-3-carboxyethyl-1,4,5,6-tetrahydropyridino-4-spiro-4'-cyclohexa-2',5'-dien-1'-one 5b

Mp 199-201°C. IR (Nujol): 3310, 1650 cm-1; 1H NMR (CDCl3): δ 0.73 (t, J = 7 Hz, 3H), 1.94 (t, J = 5 Hz, 2H), 3.47 (m, 2H), 3.69 (q, J = 7 Hz, 2H), 4.70 (s, br, 1H), 6.27 (d, J = 10 Hz, 2H), 7.05 (d, J = 10 Hz, 2H), 7.27-7.38 (m, 5H); 13C NMR (CDCl3/DMSO-d6): δ 13.39, 34.73, 38.54, 41.22, 58.99, 94.63, 127.32, 127.52, 128.12, 128.80, 139.26, 155.63, 156.12, 166.92, 186.15 ; MS m/z 309 (M+, 7), 236 (31), 208 (100), 105 (50), 77 (47). Anal. Calcd for C19H19NO3: C, 73.77; H, 6.19; N, 4.53. Found: C, 73.57; H, 5.94; N, 4.22.

7,7-Dimethyl-1,2,3,4,5,6,7,8-octahydro-quinoline-5-one-4-spiro-4'-cyclohexa-2',5'-dien-1'-one 9

Mp 130-135°C. IR (Nujol): 3320, 1660 cm-1; 1H NMR (CDCl3/DMSO-d6): δ 1.03 (s, 6H), 1.74 (t, J = 5 Hz, 2H), 2.04 (s, 2H), 2.29 (s, 2H), 3.33 (m, 2H), 6.12 (d, J = 10 Hz, 2H), 6.88 (d, J = 10 Hz, 2H), 7.52 (s, br, 1H) ; 13C NMR (CDCl3/DMSO-d6): δ 27.60, 31.18, 33.76, 37.05, 38.07, 42.24, 50.40, 100.82, 126.02, 155.70, 159.15, 185.37, 190.26 ; MS m/z 257 (M+, 24). Anal. Calcd for C16H19NO2: C, 74.68; H, 7.44; N, 5.44. Found: C, 74.59; H, 7.17; N, 5.63.

References and Notes

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  • Samples Availability: Not available.
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