B.R.S.M. Impact Factor 0.00!

23Jun/112

Named Reactions: The Hugershoff Reaction

Now over a hundred years old,[1] the venerable Hugershoff reaction is a great way to convert aryl thioureas to 2-aminobenzothiazoles.[2] Classically, an aryl thiourea in chloroform is treated with an equivalent of bromine at around room temperature then the product is just filtered off. The first step is believed to be bromination on sulfur, followed by electrophilic aromatic substition in the usual manner. Yields are generally good (in my experience), but it's important to get the electronics of the ring right - some activation is usually required, but if it's too electron rich then bromination on the aromatic ring can compete with bromination of the thiourea.

There's actually very little information on the reaction available through casual googling - it has no wikipedia page and I don't believe it's even been reviewed.[3] You're not limited to elemental bromine, with NBS and other halogenating reagents reported to work. A similar transformation (via a different mechanism) can be accomplished by treating aryl thioureas with iodine(III) reagents, or even DDQ.

Here's a Hugershoff reaction I actually did a while back. It worked beautifully with high yields, and after the starting material had been consumed the reaction mixture was simply diluted with an equal volume of ether and the product (as the HBr salt) was collected by filtration. I immediately converted it to the free base and was delighted to find that none of the competing bromination reaction of the aryl ring had occurred, despite its considerable activation. Hell, it worked so nicely I even got a CHN of the crude material. In case you're curious:

Bromine (32.4 mmol) was added dropwise to the arylthiourea (32.4 mmol) and lithium bromide (48.6 mmol) in acetic acid (150 mL), causing the white suspension to become clear and brown. After stirring at room temperature for 18 h a white precipitate had again formed. Ether (100 mL) was added and the suspension was cooled to 0 ºC, filtered, and the solid obtained was washed with cold ether. The solid obtained was dissolved in ethyl acetate (200 mL) and saturated aqueous sodium hydrogen carbonate (200 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (2 x 100 mL). The combined extracts were washed with water (2 x 200 mL) and brine (200 mL), dried (MgSO4), and concentrated to give the benzothiazole as a white solid which was dried in vacuo but did not require additional purification (83 %).

These aren't exactly classic conditions - I believe I adapted this procedure from a medicinal chemistry paper (unfortunately I don't have the reference to hand) - but they worked well on evey substrate I tried. Before you start wondering why one might want to make benzothiazoles, they do occur naturally in some interesting natural products, none of which I was working towards, and the 2-amino group isn't a bad handle for further transformations.[4]

[1] I thought I'd had wide experience of the chemical literature, but I've still yet to read a paper in BDCS

(a) H. Hugerschoff, Ber. Dtsch. Chem. Ges., 1901, 34, 3130;

(b) H. Hugerschoff, Ber. Dtsch. Chem. Ges., 1903, 36, 3121;

[2] And how do you make aryl thioureas? One way might be from the aryl isothiocyanate and an amine. And where do those come from? From anilines and thiophosgene or TCDI! Man, this stuff writes itself.

[3] Okay, there is one in Heterocyclic Compounds, R. C. Elderfield, Ed.; J. Wiley, New York, 1957; Vol.5, Chapter 8, pp 484–721. I have never seen this book.

[4] Look, here's a review on naturally occurring benzothiazoles!

 

Comments (2) Trackbacks (0)
  1. I actually did a variant of this – I had an electron-rich aniline amide of 5-bromofuroic acid. I took it to thioamide with Lawesson (ugly workup). I oxidized the thioamide into benzimidazole thusly: K3Fe(CN)6 (4 mmol; 1.32g) in water 20mL was heated to 90C, a solution of the thioamide (0.8 mmol) in ethanol 10mL was combined with 10 mL of 1M NaOH in water and the alkaline solution of the substrate was gradually added into the hot solution of ferricyanide over 30 min. Then continued for extra 90 min (complete conversion within 1 hour), cooled, extracted repeatedly with DCM, dried, evaporated, column of silica. Y=63% The starting thioamide was only about 85% pure so the yield was tolerable. I also isolated a sideproduct (10%) with an ortho substituent clipped off.

    http://orgprepdaily.files.wordpress.com/2011/06/hugerschoff.gif

  2. Wow, I’ve never met anyone else who’s done one of these, but I guess if it was going to be anyone it would be you! Unfortunately, oxidative methods (K3Fe(CN)6), DDQ and PhI(OCOCF3)2 only caused colourful degradation for my systems. Using CAN you can actually oxidise (in low yield) to the benzoquinone with the thiourea intact, not able to undergo that naughty 5-endo-trig.


Leave a comment


nine + = 12

No trackbacks yet.