nitriles

Problem # 757

Propose a synthesis to accomplish each transformation. The only carbon sources allowed are alkenes and NaCN.

a) The starting alkene has 4 carbons, and the product has 5 carbons and a nitrogen. So you have to add 1C and 1N. This screams "add cyanide!"

Based on the location of the alcohol on the product, it looks like the way to go is to add NaCN to an epoxide. This puts the -CN and the -OH in the right positions.

b) The best way to prepare 2º and 3º amines is via reductive amination. Working backwards, the product can be prepared from a 4-carbon aldehyde (butyraldehyde) and a 3-carbon amine (propyl amine).

Performing hydroboration on the butene results in the anti-Markovnikov alcohol, which can be oxidized to the aldehyde using PCC.

To prepare propyl amine from an alkene, add HBr/peroxides to make the bromide (anti-Markovnikov), and then add NaN₃ follow by H₂/Pd.

Problem Details

MendelSet practice problem # 757 submitted by Matt on July 27, 2011.

Subject: Organic Chemistry

Subject Topic(s): Amines (Basicity, Hoffman Elimination, Gabriel Amine Synthesis)

Question Type: Synthesis (show how to prepare X from Y..)

Keyword(s): nitriles, reductive amination

Problem # 735

Show how each ketone below can be prepared from sodium cyanide and either ethylene or propene.

You may also use methyl Grignard and ethylene oxide.

Solution

Nitriles react with Grignard reagents to form ketones, so the carbonyl carbon on each product must have came from a nitrile.

You also have the restriction that the longest carbon chain building must be three carbons.

a) Working backwards, the left side must have come from a nitrile, so the left side came from a Grignard.

How can we make each starting from propene?

To make the Grignard, prepare propyl bromide from propene via anti-Markovnikov HBr addition (HBr/peroxides), and then add Mg⁰/ether.

To make the nitrile, add sodium cyanide (NaCN) to propyl bromide.

Then add the nitrile and Grignard together, which forms the imine intermediate, which will hydrolyze to the ketone after you add water (H₃O⁺).

b) This problem is harder because you're limited to starting materials with three carbons or less, so we have to make three "cuts" instead of two, like in a).

Working backwards again, prepare propyl Grignard from propene as described in a), and then add ethylene oxide to form 1-pentanol. Form the 6-carbon nitrile by first converting the alcohol to a bromide using PBr₃, and then adding NaCN. Finally, add methyl Grignard followed by H₃O⁺ to form the desired ketone.