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In the first step of the synthesis of Sertraline, aluminium chloride catalyst was used in a Friedel-Craft's reaction to give the following product. My question is how does the exact mechanism work? 1-napthol does not seem look like an electrophile to me, and I do not understand how AlCl3 is able to turn 1-napthol into an electrophile. The best guess I have is that the phenol tautomerise to give a ketone, and AlCl3 forms a complex with it. Yet again, I do not understand how the γ carbon is made electrophilic using AlCl3. Any help would be appreciated.

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  • $\begingroup$ Even if we assume that the $1$-napthol is getting attacked somehow by $1,2$-dichlorobenzene, instead of substituted $\alpha$-tetralone in the product, shouldn't the product contain $\alpha , \beta$-unsaturated ketone ? The only plausible mechanism generates that by a conjugate addition. $\endgroup$
    – Soumik Das
    Commented Apr 19, 2019 at 11:52
  • $\begingroup$ Note that this is not a Friedel-Crafts acylation. In that reaction, the Lewis-acid is a catalyst. 2 equiv. of aluminium chloride here is definitely not catalytic. In other words, you need a superstoichiometric amount of the Lewis acid to get this reaction to go. Almost certainly coordination of the OH is involved as the first step. But the aluminum chloride is likely not regenerated in this reaction. $\endgroup$
    – Zhe
    Commented Apr 19, 2019 at 14:50
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    $\begingroup$ Also, very importantly, look at the severely reduced unsaturation of the ring. You're going to need a hydride from somewhere. $\endgroup$
    – Zhe
    Commented Apr 19, 2019 at 15:06

1 Answer 1

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The alleged original RSC source for this reaction was not accessible online.1. However, Olah et al. have reported2 that α-naphthol 1 in superacid medium forms a dication species 4. The use of excess AlCl3 provides a mechanism for the formation of superacid 3. Benzylic dication 4 undergoes substitution of o-dichlorobenzene 5 which ultimately forms the sertraline precursor, tetralone 8. For reaction conditions, see ref. 3. No reducing agent is required.

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1) Kavitha, C. V.; Mantelingu, K.; Sarala, G.; Naveen, S.; Anandalwar, S. M.; Prasad, J. S.; Rangappa, K. S. J. Chem. Res. 2006, 11, 730.

2) Koltunov, K. Y.; Chernov, A. N.; Prakash, G. K. S.; Olah, G. A. Chem. Pharm. Bull. 2012, 60, 722.

3) Lee, S. H.; Kim, I. S.; Qing, R. L.; Dong, G. R.; Jeong, L. K.; Jung, Y. H. J. Org. Chem., 2011, 76, 10011.

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