As Part of Ongoing Research in the Knoerzer Group, We Have Been Interested in Synthesizing

Spring Organic Chemistry – Experiment #3
Acetal protection of various aldehydes using ethylene glycol

Introduction

As part of ongoing research in the Knoerzer group, we have been interested in synthesizing novel heterocyclic molecules that may possess interesting biological or medicinal properties. One such target is the 2-amino-4H-benzothiazine nucleus that is shown incorporated into a peptide-small molecule construct that has been previously investigated by our team (Figure 1).

Figure 1. 2-Amino-4H-benzothiazine as a key heterocyclic building block for peptide-small molecule synthetic targets.

Hari, A.; Miller, B. L. “Rapid and Efficient Synthesis of 2-Amino-4H-benzothiazines” Org. Lett., 2000, 2, 3667-3670.

In order to establish the necessary functionality for the creation of the ring system, it is imperative that we place reactive groups in appropriate positions around the aromatic ring. One such avenue to the key reactive synthon is shown in Figure 2. The first step in this multi-step sequence involves the protection of the benzylic aldehyde group as the ethylene glycol acetal.

Figure 2. Sequence of steps for conversion of nitroaldehydes to substituted nitrocinnamic acids

Therefore, in order to explore the potential aldehyde protecting group capability of ethylene glycol, you will undertake an experiment using the same reaction conditions as utilized in step 1 above (Figure 2) in order to protect an unknown aldehyde. Your task will be to identify the unknown protected aldehyde using IR and 1H-NMR.

List of possible aldehydes:

6-nitroveratraldehyde

3,4,5-trimethoxybenzaldehyde

Piperonal

4-chlorobenzaldehyde

Indole-3-carboxaldehyde

Procedure

A mixture of the aldehyde (given number of mmol on the vial), ethylene glycol (1 equivalent), and a catalytic amount of p-toluenesulfonic acid (0.03 equivalent) in 60 mL of toluene is heated at reflux for 2 hours and the water is removed by Dean-Stark apparatus. Upon completion, the solvent is removed via rotary evaporation. If the product is a solid, it should be recrystallized from an appropriate organic solvent. The mass of the product is determined and a 50 mg sample is used to acquire 1H-NMR. A small portion is also used to acquire an IR spectrum.

Laboratory Follow-Up (LFU)

Due: Thursday, May 1, 2008 at 8:00 am

(1) Compile all data and cross-reference to a ChemDraw structure that is fully labeled (results). You should compose a journal-style discussion that describes the story of structural elucidation – how you determined your product structure (limit 1 page).

(2) Locate an article from the primary literature in which an aldehyde group is protected under similar reaction conditions. Provide a brief explanation as to why the scientists doing the work needed to protect the aldehyde group. Attach a copy of the article in which the relevant chemistry is highlighted.

(3) Hand in your laboratory notebook.