Synthesis of p -phenylthio- peri -hydroxy polyaromatic compounds by strong-base-induced [4+2] cycloaddition of 4-(phenylthio)homophthalic anhydrides with phenylsulfinyl-dienophiles

A direct and regioselective synthesis of p -phenylthio-substituted peri -hydroxy polyaromatic compounds ( 9 – 12 ) was developed via the strong-base-induced [4+2] cycloaddition of the 4-(phenylthio)homophthalic anhydrides ( 1a – d ) to the phenylsulfinyl-substituted dienophiles ( 5 – 8 ). The sulfinyl group in 5 – 8 is the key to producing the desired reaction under mild conditions (at – 20 °C to room temperature) in good yields. A reaction mechanism explaining the remarkable effect of the sulfinyl group is discussed.


Introduction
General and efficient syntheses of peri-hydroxy polyaromatic p-quinones (I) and their dihydroquinone derivatives (II) are important in recent synthetic organic-and medicinal chemistry because these compounds are key components of many biologically important natural products such as anthracyclines 1 and fredericamycin A. 2 For the synthesis of these quinone compounds, the transformation of phenols into p-benzoquinones or p-dihydrobenzoquinone derivatives has been one of the most important steps. 3Recently, we reported a new method for the synthesis of I and II from p-(phenylthio)phenols (III) via the aromatic Pummerer-type reaction of the derived sulfoxides (IV). 4The synthesis of III has been achieved by two methods; viz, the p-specific thiocyanation of phenols (V) using the combination of PhICl 2 and Pb(SCN) 2 followed by reaction with PhMgBr (method A) 4d,5 and the oxidative intramolecular [4+2] cycloaddition of o-[(ω-phenylthio-ethynyl)acyl]-phenols (VI) (method B). 6 Recently, we briefly reported a third method, based on the strong-base-induced [4+2] cycloaddition of 4-(phenylthio)homophthalic anhydrides (1a,b) to sulfinyl-substituted dienophiles, in which we found that the sulfinyl groups were essential for producing the desired reaction under mild conditions in good yields (method C) (Scheme 1). 7We now give a full account of our studies on method C, with additional examples using the new homophthalic anhydrides (1c and 1d).A reaction mechanism to explain the remarkable effect of the sulfinyl group is also discussed.The starting 4-(phenylthio)homophthalic anhydrides (1a-d) were readily prepared from the corresponding homophthalic acid dimethyl esters (2a-d), in good overall yields.That is, the reaction of 2 with lithium bis-(trimethylsilyl)amide followed by treatment with PhSSO 2 Ph afforded the phenylthio-substituted diesters (3).Alkaline hydrolysis of 3 and dehydration of the resultant dicarboxylic acids with trimethylsilyl(ethoxy)acetylene 8 afforded 1.As in our previous study using the related homophthalic anhydrides, 9 the cycloaddition of 1b, d with acetylenedicarboxylic acid diethyl ester took place in the presence of NaH to give directly the pphenylthio-substituted adducts (4b and 4d) in 58% and 64% yields, respectively (Scheme 2).

Scheme 2
In order to establish the regioselective synthesis of the p-phenylthio-substituted peri-hydroxy polyaromatic compounds, we examined the strong-base-induced [4+2] cycloaddition of 1a with naphthoquinones (5a-d) bearing various types of activating groups (X).The reactions of 1a with the known halogen-substituted naphthoquinones (5a,b) 1e,f,10 took a long time to produce the tetracyclic product (9a), in 65-67 yields (Table 1, runs 1 and 2).The similar reaction with the phenylthio derivative (5c) 11 did not proceed at all, even in refluxing THF (run 3).On the other hand, the reaction with the phenylsulfinyl derivative (5d) 12 was very fast at room temperature, to give 9a in 72% yield (run 4).
In a like manner, the reactions of a highly-oxygen-substituted homophthalic anhydride (1d) and the spiro-dienophiles (6a-e) were investigated.The reaction of 1d with the bromide (6a) required refluxing in THF to give a mixture of the desired product 10d and the product lacking the phenylthio group, (10d'), in low yield (run 5).Similar low reactivity and/or the formation of 10d' were also observed in the reactions with the arylthio-(6b, c) and the phenylsulfonylderivative (6e) (runs 6, 7 and 9).In contrast, the reaction with the sulfinyl derivative (6d) was again very fast at room temperature, to afford 10d (77% yield) without forming 10d' (run 8).Thus, the sulfinyl group was unique, because other electron-withdrawing substituents, viz., the pnitrophenylthio-(6c), and the phenylsulfonyl-(6e) groups, were not efficient.
The NaH-induced [4+2] cycloaddition reaction of 1 was found to be generally applicable for a range of sulfinyl-substituted dienophiles (5d, 6d, 7, and 8) as summarized in Table 1.All the reactions were completed at or below room temperature and gave the expected adducts (9-12) in 66-82% yields.The reactions with a set of two regioisomers (5d and 7) afforded the corresponding products (9 and 11) as a single product, and thus, the regiochemistry of each reaction was proved to be controlled exclusively by the position of the sulfinyl group.Some results of the reactions with the corresponding bromo-substituted dienophiles are also given in brackets (runs 10, 14, 17, and 21) to emphasize the general superiority of the phenylsulfinyl group over the halogen substituents.
In order to obtain some insights into the reactivity of dienophiles, the frontier molecular orbital (FMO) energy levels of 5-8 and some related compounds were calculated using the PM3 Hamiltonian in the Spartan (ver.3.1.2)program (Table 2).The results show that the LUMO levels of the sulfinyl-substituted dienophiles (5d, 6d, 7, and 8) are similar to, or lower than, those of the halogen derivatives (5a, 5b, 6a, etc.) but higher than that of the sulfonyl derivative (6e).Therefore, the LUMO levels are not the only factor that causes the remarkable effect of the sulfinyl group in our case.
The following reaction mechanism seems plausible.First, the δ-oxy-quinodimethanes A, generated by the treatment with NaH, would produce the oxyanion-assisted Diels-Alder type cycloaddition 9,13 to dienophiles to provide the adduct B in which the X and H groups are situated syn-to each other.In the case of the sulfinyl-substituted dienophiles [X = S(O)Ph], the easy synelimination of PhSOH followed by the oxyanion-assisted retro-Diels-Alder reaction 14 of the resultant C would give the cycloadducts (9-12) with CO 2 release 15 (Scheme 3).These irreversible reactions from B to the final products could proceed at or below room temperature, as reported in the literature. 12,14Thereby, the fast and exclusive formation of 10d from 6d was attained. 16On the other hand,, the reactions of the halogen-and sulfonyl-substituted dienophiles must have suffered a slow elimination of the X and H groups in B, which not only retarded the overall reaction but also brought about the side reaction leading to 10d'.This explanation may be consistent with the fact that the reaction of 1d with diethyl acetylenedicarboxylate gave exclusively 4d, in which the intermediate (C') was formed directly from A. a The molar ratio of the reagents is generally as follows: 1 (1.3 equiv), and 5-8 (1.0 equiv).b Isolated yield of the product based on 5-8.c The reaction conditions and the yield of the product of the similar reaction with the corresponding bromo-subtituted dienophile are given in the bracket.We have applied this anionic cycloaddition to the synthesis of the ABCD-ring analog of fredericamycin A. 2 The tetracyclic compound (10b), obtained in 82% yield from 1b and 6d (Table 1, run 14), was subjected successively to debenzylation by BCl 3 , protection of the diol by silylene formation, and the oxidation of the phenylthio group to give 13 in 97% overall yield.The aromatic Pummerer-type reaction 4c of 13 followed by sequential deprotection using aqueous NaHCO 3 and Bu 4 NF provided the ABCD-ring analog, 15.Since 15 was susceptible to autoxidation during chromatography, to give a mixture of 15 and the p-quinone 16, the product was isolated as either 16 or 17 (Scheme 4).

Conclusions
We have succeeded in producing the efficient and versatile synthesis of p-phenylthio-substituted peri-hydroxy polyaromatic compounds, whose structure is expected to be capable of various modifications.In this cycloaddition, use of the sulfinyl-substituted dienophile is crucial, and this method offers very mild reaction conditions and the direct formation of the desired compounds in good yields.

Experimental Section
General Procedures.All melting points are uncorrected.The 1 H NMR spectra were measured using 200-500 MHz spectrometers with SiMe 4 as internal standard.Infrared (IR) absorption spectra were recorded in CH 2 Cl 2 solutions or by diffuse reflectance measurement of the samples dispersed in KBr powder.Column chromatographic purification was performed on silica gel BW-300 (200-400 mesh, Fuji Silysia Chemical Co., Ltd., Japan).RT denotes room temperature.

Table 2 .
HOMO and LUMO level values of 5-8 and some related compounds using the PM3 calculation

Table 1 , run 14)
Under a nitrogen atmosphere, a solution of 1b (94 mg, 0.25 mmol) in anhydrous THF (4 mL) was added to a suspension of sodium hydride (60% in mineral oil, 11 mg, 0.27 mmol) in THF (4 mL) at 0 °C.The reaction mixture was stirred at 0 °C for 1.5 h, and a solution of 6d (53 mg, 0.19 mmol) in anhydrous THF (8 mL) was added.The mixture was stirred at RT for 30 min, then quenched with saturated aqueous NH 4 Cl and extracted with EtOAc.The organic layer was washed with brine, dried over Na 2 SO 4 and concentrated in vacuo.