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I've stumbled upon an interesting article about reduction of amino acids and from there to reduction of L-valine to L-valinol using $\ce{LiAlH4}$ in THF.

Article says that because of the cost of $\ce{LiAlH4}$, better method using $\ce{NaBH4}$ with $\ce{I2}$ in THF has been developed.

But I haven't found anything about $\ce{HI}$. Is it possible to reduce amino acids all the way down to their corresponding amines with concentrated $\ce{HI}$ solution?

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  • $\begingroup$ For alternative process: orgsyn.org/demo.aspx?prep=CV7P0530. $\endgroup$ – Mathew Mahindaratne Nov 29 '19 at 23:52
  • $\begingroup$ No, all you would get is the HI salt of the amino acid. The I2/NaBH4 system works because it produces BH3 in situ. HI would not do that. $\endgroup$ – Waylander Nov 30 '19 at 8:32
  • $\begingroup$ And what would you propose to reduce the hydroxyl group? The best option would be without need to protect the amino group. So, HI/P reduction might work here? $\endgroup$ – steve d. Nov 30 '19 at 8:35
  • $\begingroup$ I would use the BH3/Me2S procedure from the orgsyn reference above. I would not use HI/P for anything $\endgroup$ – Waylander Nov 30 '19 at 10:21
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    $\begingroup$ If you want to reduce the alcohol to the methyl group I would tosylate, displace with Me or PhS- then reduce with Raney Ni. You'll need the NH protected $\endgroup$ – Waylander Dec 1 '19 at 21:12
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Chiral amino alcohols such as L-valinol are generally prepared by the reduction of corresponding α-amino acids and suitable reducing reagent. Most commonly used reducing agent is $\ce{LiAlH4}$ since most common reducing reagent, $\ce{NaBH4}$ does not reduce carboxylic acid to corresponding alcohols. However, use of $\ce{LiAlH4}$ has notable disadvantages such as being expensive and highly flammable. To avoid these disadvantages on high scale syntheses, some novel methods have been developed. One such method is reduction of carboxylic acid using $\ce{NaBH4/I2}$ reducing sysrem (Ref.1). The most remarkable feature of this reagent is its selectivity over other known strong reducing agents. For example, if $\ce{NaBH4/I2}$ is used to reduce bicarboxylic acid, it would reduce both carboxylic groups to $100\%$. However, if one carboxylic acid i group was protected (say, ester-carboxylic acid combo), $\ce{NaBH4/I2}$ would reduce only carboxylic acid group leaving ester group alone (Ref.1).

Two years after this important discovery, McKennon, et al. (1993) found out that this same method can be used to reduce N-protected or naked amino acids to their corresponding N-protected amino alcohol or amino alcohol, respectively (Ref.2). A typical procedure is as follows:

Preparation of (S)-tert-Leucinol: A dry 5-L three-necked round-bottom flask equipped with a mechanical stirrer and a 250-mL addition funnel was charged with sodium borohydride ($\pu{55.6 g}, \pu{1.47 mol}, \pu{2.41 equiv}$) and $\pu{1.6 L}$ of anhydrous THF. The solution was stirred while (S)-tert-leucine ($\pu{80.0 g}, \pu{610 mmol}$) was added in one portion. The flask was cooled to $\pu{0 ^\circ C}$ and fitted with a reflux condenser. The addition funnel was charged with a solution of $\ce{I2}$ ($\pu{155.0 g}, \pu{610 mmol}, \pu{1 equiv}$) in $\pu{200 mL}$ of THF, which was added dropwise to the flask over a $\pu{1.5 h}$ period with considerable gas evolution. The solution was allowed to warm to room temperature. When the brown color had dissipated to give a cloudy white solution, the reaction was brought to reflux for $\pu{19 h}$. The cloudy white suspension was cooled to room temperature with the aid of a water bath. The addition funnel was charged with $\pu{150 mL}$ of $\ce{MeOH}$, which was added drop-wise with rapid stirring. Vigorous gas evolution was observed. Small aliquots of $\ce{MeOH}$ were then added until all of the solid white material had dissolved. The solution was concentrated by rotary evaporation to give a white pasty oil that was dissolved in $\pu{1.20 L}$ of $20\% (w/w)$ aqueous $\ce{KOH}$ and mechanically stirred for $\pu{6 h}$ at room temperature. The light green solution was extracted with $\ce{CH2Cl2}$ ($\pu{3 \times 1.50 L}, \pu{1 \times 600 mL}$). To minimize the emulsion, $\pu{200 mL}$ of brine was added to the aqueous layer after the first extraction. The combined organic extracts were dried over $\ce{Na2SO4}$, filtered through glass wool, and concentrated in vacuo to give $\pu{74.1 g}$ of a white crystalline solid in a thick, slightly yellow oil. Distillation of (S)-tert-leucinol, bp $70$-$\pu{73 ^\circ C}$/$\pu{2 mmHg}$ (Lit. $117$-$\pu{120 ^\circ C}$/$\pu{57 mmHg}$) from a $\pu{30.0 g}$ reduction reaction performed in the above manner yielded $\pu{21.3 g}$ of product ($79\%$ yield) as a clear oil, which solidified upon cooling to room temperature.

References:

  1. J. V. Bhaskar Kanth, Mariappan Periasamy, “Selective reduction of carboxylic acids into alcohols using sodium borohydride and iodine,” J. Org. Chem. 1991, 56(20), 5964-5965 (https://doi.org/10.1021/jo00020a052).
  2. Marc J. McKennon, A. I. Meyers, Karlheinz Drauz, Michael Schwarm, “A convenient reduction of amino acids and their derivatives,” J. Org. Chem. 1993, 58(13), 3568-3571 (https://doi.org/10.1021/jo00065a020).
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    $\begingroup$ Matthew, thank you for your answer. However, the main question was about HI reduction to amines. Nontheless, thank you for your contribution with many valuable information. $\endgroup$ – steve d. Nov 30 '19 at 8:29
  • $\begingroup$ I did not address about reduction by $\ce{HI}$ since it wasn't clear whether you are mainly asking about $\ce{NaBH4/I2}$ system. However, to my knowledge, any $\ce{HI}$ system reducing carboxylic acid is not known. Only one existing is discussed here: chemistry.stackexchange.com/questions/15586/…. $\endgroup$ – Mathew Mahindaratne Nov 30 '19 at 14:50
  • $\begingroup$ I thought so as well, but then I managed to find some reference on sciencemadness forums. It's a paper discussing reduction of ketone to hydrocarbon with special section to HI here : sciencemadness.org/talk/files.php?pid=161627&aid=8575 $\endgroup$ – steve d. Nov 30 '19 at 15:24
  • $\begingroup$ Thanks for sharing. It's also $\ce{HI/P}$ system as one in my previous comment. But it is interesting chemistry, which reduces aromatic aldehydes and carboxylic acids all the way to toluene (note that not to benzyl alcohol). I wonder it would do the same to aliphatic counterpart. $\endgroup$ – Mathew Mahindaratne Nov 30 '19 at 15:46

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