Diastereoselective and enantioselective reduction of tetralin-1,4-dione

Background The chemistry of tetralin-1,4-dione, the stable tautomer of 1,4-dihydroxynaphthalene, has not been explored previously. It is readily accessible and offers interesting opportunities for synthesis. Results The title reactions were explored. L-Selectride reduced the diketone to give preferentially the cis-diol (d.r. 84 : 16). Red-Al gave preferentially the trans-diol (d.r. 13 : 87). NaBH4, LiAlH4, and BH3 gave lower diastereoselectivities (yields: 76–98%). Fractional crystallization allowed isolation of the cis-diol and the trans-diol (55% and 66% yield, respectively). Borane was used to cleanly give the mono-reduction product. Highly enantioselective CBS reductions afforded the trans-diol (72% yield, 99% ee) and the mono-reduction product (81%, 95% ee). Conclusion Diastereoselective and enantioselective reductions of the unexplored tetralin-1,4-dione provides a very convenient entry into a number of synthetically highly attractive 1,4-tetralindiols and 4-hydroxy-1-tetralone.


Introduction
In this article, we briefly review synthetic approaches to 2,3dihydro-1,4-naphthoquinone, more simply named tetralin-1,4dione (2). This symmetric diketone is the stable tautomer of 1,4dihydroxynaphthalene (1). Although known for many years, it has never been used in synthesis. The reactions of 2 that are reported in this article are those given in the title.
Tetralin-1,4-dione (2) is accessible by tautomerization, reduction, oxidation, and photolytic cycloreversion (Scheme 1 and Scheme 2). Tautomerization takes place upon melting 1 under an inert atmosphere or in a vacuum (>200 °C) [1][2][3]. The equilibrium mixture at this temperature consists of 1 and 2 in a ratio of 2 : 1 [3]. After cooling to ambient temperature, equilibration ceases and extracts with non-polar solvents are enriched with the more soluble 2. Tautomerization of 1 was also reported in trifluoroacetic acid, with 2 being the largely dominant species in solution [4].
While dione 2 is readily synthesized, it remains a chemically unexplored curiosity. This simple molecule, and its π-metal complexes, drew our attention and interest for their potential in synthesis. Using the tautomerization of 1 in trifluoroacetic acid to generate 2 [4], we found that upon solvent evaporation the tautomer obtained was dihydroxynaphthalene 1, rather than diketone 2. During evaporation, the lower solubility of 1 led to its precipitation and this shifted the equilibrium back. This problem was solved by adding toluene to the mixture before evaporation under vacuum. This, and recrystallization (iPr 2 O) afforded 2 in 72% yield [8]. The straightforward route allowed the synthesis of gram quantities of 2 and the opportunity to study its uncharted chemistry. This paper details the results of our studies of reductions of the carbonyl functions in diketone 2.

Results and Discussion
Diastereoselective bis-reduction of 2 Reduction of tetralin-1,4-dione (2) with a number of reducing agents afforded mixtures of diastereoisomeric cis-diol 6 and trans-diol 7 in the ratios shown in Table 1. It is important to mention here that these reactions do not occur when tautomer 1 is used. The reductions with NaBH 4 ( Table 1, entry 1) and BH 3 ·THF (entry 4) gave the diols in high yields but with low diastereoselectivity, slightly favoring the cis-diastereoisomer 6. In contrast, reduction with LiAlH 4 (entry 2) and, more pronounced, with [Al(H 2 )(OCH 2 CH 2 OMe) 2 ][Na] (Red-Al) favored the transdiastereoisomer 7. Fractional crystallization of the 13 : 87 mixture (entry 3) afforded pure 7 in 55% yield. The reason for the diastereoselectivity in this reaction may have its origin in the delivery of the second hydride from the same aluminium moiety (Scheme 3). Conversely, lithium tri-sec-butylborohydride (L-selectride) afforded a product enriched with cistetralin-1,4-diol (6) (entry 5). The high diastereoselectivity presumably is a consequence of the bulky reducing agent. Following the first reduction and formation of the 4-(boranyloxy)-1-tetralone, addition of a second equivalent of L-selectride would be expected to occur from the less hindered face. Hydrolysis then yields preferentially the cis-diastereoisomer 6. The ca. 5 : 1 mixture of 6 and 7 could not be efficiently separated by flash chromatography but recrystallization from iPr 2 O gave cis-1,4-dihydroxytetralin (6) in 66% yield.
Diols 6 and 7 have been reported previously. They were obtained by treatment of tetralin with NBS to give a 1 : 1 mixture of the corresponding cis and trans-dibromides, which were converted into diacetates with AgOAc (81% yield). Saponification and fractional recrystallization from MeOH / Et 2 O then afforded pure 6 and 7 though isolated yields were not reported [9]. The meso-diol 6 has been used as substrate in enantioselective oxidation [10] and in asymmetric acylation [9,11].
We conclude that while conditions for an efficient highly diastereoselective one-step reduction of both carbonyl functions in 2 have not been realized, enrichment of one or the other diastereoisomer by choice of reducing agent is feasible and acceptable yields of pure diastereoisomers can be obtained.

Enantioselective bis-reduction of 2
Asymmetric reduction of dione 2 was probed next. This was carried out successfully as shown in Scheme 4 and gave, after two recrystallizations from diisopropylether, (−)-(1R,4R)tetralin-1,4-diol (R,R-7) in 72% yield and 99% ee [8]. Only small amounts (ca. 7%) of the cis stereoisomer 6 were detected by 1 H NMR in the crude product. The synthesis of diol 7 in highly enantiomerically enriched form is thus easier than that of the racemate.
The absolute configuration of (−)-(1R,4R)-7 agrees with the reliable stereochemical model for the CBS reduction. To our knowledge there is no viable published alternative synthetic access to this C 2 symmetric chiral diol. Compound (−)-(1R,4R)-7 was previously obtained by HPLC separation of a 1 : 1 mixture of the cisand trans-diols obtained in 55% yield from a four step sequence from (R)-1-tetralol [12].

Mono-reduction of 2
Mono-reduction was achieved with a reduced amount of borane compared to the reduction detailed above. For the bis reduction, a molar ratio of 2 / BH 3 of 0.83 was used. Adjusting the ratio to 2.2 (see experimental part) afforded rac-9 in good yield (Scheme 5).
The high yield in mono-reduction is in accord with the expected higher reactivity of the dione 2 compared to the mono-ketone 9. Enantioselective mono-reduction of 2 With an efficient protocol for the synthesis of rac-9 and of R,R-7 in hand, research then focused on the more challenging task of enantioselective mono-reduction. First, CBS reduction was performed by slow (1 h) addition of dione 2 to a solution of BH 3 ·THF (0.45 equiv) and catalyst 8. However, background reduction by BH 3 ·THF was competitive under these conditions and while (−)-(4R)-4-hydroxy-1-tetralone (R-9) could be isolated in 93% yield, its enantiomeric excess was a modest 53% ee.
Cyanohydrin silylether 10 partially hydrolyzes on silica and, as it turned out, isolation of this intermediate is not required and this provided a reliable and efficient sequence to highly enantiomerically enriched 9 (Scheme 5). In the course of this optimization, we also isolated cyanohydrin 11.