I am recently working on some synthesis of Nucleolipids and I want to transform $\ce{-OH}$ to terminal $\ce{S}$ group.
Can anyone help?
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asked Jun 1 '19 at 18:56
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1$\begingroup$ The first thing that comes to my mind is replacing a $\ce{-OH}$ group with a $\ce{-Cl}$ group using $\ce{PCl3}$ (though remember that this would change the configuration) and then replacing the newly made Halogen using $\ce{HS-}$ may be from Sodium hydrosulfide , I really don't know about the yield of reaction and ease of doing reaction but indeed this is a way . $\endgroup$ – Advil Sell Jun 1 '19 at 20:26
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1$\begingroup$ Mesylate, react with thiourea, hydrolyse $\endgroup$ – Waylander Jun 1 '19 at 20:48
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2$\begingroup$ I've also successfully converted benzylic OH groups to SH groups using thiourea without the mesylation step, if the system has electron-donating groups in ortho and para positions. I used thiourea (2 eq.) in acetone/water, followed by hydrolysis with 3 eqv. NaOH on a 2,4-dimethoxybenzyl aclohol to get the thiol in 70% yield. Alternatively, you can try Mitsunobu reaction using thiobenzoic acid, Ph3P and DIAD/DEAD/DCAD, followed by hydrolysis. Take care not to oxidise your compound during synthesis! If you end up forming disulfide, keep TCEP handy ;) $\endgroup$ – Zachr Jun 2 '19 at 1:48
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An alcohol can be converted to a corresponding thiol using Lawesson's reagent (LR; 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide). However, the reaction is messy and could give you a mixture of products in addition to intended thiol, including eliminated product, alkene (Ref.1). For example, treatment of acyclic 1,4-diols with LR gives the 1,3-dienes (Ref.1).
However, the substitution versus elimination outcome with LR is depends on the structural features of the substrate (Ref.2), and hence, worth considering. The computational mechanism is depicted below:
Alternatively, you can use highly efficient Mitsunabu type reaction with diisopropyl azodicarboxylate (Ref.3). The abstract summerize the reaction as:
Various alcohols were converted to their corresponding thiolacetates by treatment with triphenylphosphine and diisopropyl azodicarboxylate in the presence of thiolacetic acid. The overall conversion was both highly efficient (89–99% yields) and stereoselective (99.5% inversion).
References:
- T. Nishio, “Direct conversion of alcohols into thiols,” J. Chem. Soc., Perkin Trans. 1 1993, (10), 1113–1117 (DOI: 10.1039/P19930001113).
- M. A. Chiacchio, L. Legnani, P. Caramella, T. Tejero, P. Merino, “Pivotal Neighboring‐Group Participation in Substitution versus Elimination Reactions – Computational Evidence for Ion Pairs in the Thionation of Alcohols with Lawesson's Reagent,” Eur. J. Org. Chem. 2017, (14), 1952–1960 (https://doi.org/10.1002/ejoc.201700127).
- R. P. Volante, “A new, highly efficient method for the conversion of alcohols to thiolesters and thiols,” Tetrahedron Letters 1981, 22(33), 3119–3122 (https://doi.org/10.1016/S0040-4039(01)81842-6).
answered Jun 1 '19 at 20:53
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$\begingroup$ Lawesson's stinks like hell and is a serious pain to work up and don't underestimate how much of nuisance getting rid of triphenylphosphine oxide is. $\endgroup$ – Waylander Jun 1 '19 at 22:07
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$\begingroup$ @Waylander: Tell me about it! :-) $\endgroup$ – Mathew Mahindaratne Jun 1 '19 at 23:42
