dichloropyrazine

I would like to present you today a reaction I have performed a long time ago (in a galaxy far, far away....), and which can be very useful for different purposes.

As you probably know or should know , the regioselective chlorination of pyridine or quinoline N-oxide in the position 2 can be achieved by treatment with phopshorous oxychloride as chlorinating agent.



But, I have realized this reaction on the pyrazine-1,4-dioxide, if you apply the "classic" mechanism on this structure, you should have either the 2,5-dichloro or 2,3-dichloropyrazine, but of course it is not the case and the only compound isolated is the 2,6-dichloropyrazine.




Unfortunately, I have no explanation for this I only know that when the position 6 is blocked then the chlorination occurs in 5 and when position 6 and 5 are blocked the chlorination is in 3.
A don't have the exact references but they were J Het Chem in the mid 80's from a Yamamoto.

Nicotine

Today, I am a little bit lazy, so I give you one more time some interesting recent literature about hetchem, for the smokers and non-smokers don't forget to read "Recent Advances in the Synthesis of Nicotine and its Derivatives" by Comins, this article is in press in Tetrahedron and should be available soon.

synthesis of quinazolinediones

Quinazoline is a very important ring in natural product synthesis as well as medicinal chemistry. Today, I want to show you a synthesis described by Timothy T. Curran et al. from Pfizer, Ann Arbor, Michigan, where the quinazolinediones have been synthesized by an intramolecular nucleophilic aromatic substitution, using NaH or NaHMDS to generate the dianion for the cyclization, with yields between 67-83% on multigram scale (R=OMe:520g, R=Me:250g).

By the way, the final molecules are potent gyrase/topoisomerase inhibitors.

Metal-Assisted Multicomponent Reactions Involving

Today another short-review concerning the multicomponent synthesis of heterocycles with transition metal catalysts involving carbon monoxyde.
This review is mainly about rhodium catalyze hydroformylation.

Angew. Chem. Int. Ed. 2007, 46, 3612 – 3615.

Synthesis of alkylpyridine

I am just reading the Tetrahedron report number 800 on "Titanium carbenoid reagents for converting carbonyl groups into alkenes" by Hartley and that reminds me a paper of Nicolaou, I read some years ago, concerning the reaction of Titanocene methylidene with isoquinoline N-oxide.




In his paper, KCN noticed that the different "pyridine" N-oxides can be deoxygenated by Tebbe reagent and in the same time the introduction of a methyl group in also possible (in alpha of the N), and regioselectively in the case of isoquinoline. The same reactivity has been observed with Petasis reagent, but with longer time reaction and higher temperature.

Angew. Chem. Int. Ed. 2000, 39, 2529.

Recent progress in catalytic synthesis of imidazoles

For today, I would like to advise you to read a very interesting review from Shin Kamijo and Yoshinori Yamamoto on the recent progress in catalytic synthesis of imidazoles. This review has been published recently in Chemistry an Asian Journal, and shows different catalytic methodologies, mainly involving transition metal chemistry but also organocatalytic to synthesisze this very useful heterocyclic ring. For people who cannot have this paper, stay on-line I will show you some examples very soon.

Recent Progress in the Catalytic Synthesis of Imidazoles
Shin Kamijo and Yoshinori Yamamoto
Chem. Asian J. 2007, 2, 568 – 578.

Synthesis of 2-Ethyl-1,2,3,4-tetrahydroquinoxaline

In 2006, Lectka et al. described the synthesis of quinazolinones by a catalytic, enantioselective hetero-Diels-Alder reaction. The key point of this synthesis is the double activation of the diene (diazadiene) in one hand and the dienophile in the other hand.
Activation of o-Benzoquinone diimide (diene) has been achieved by zinc (II) triflate, whereas activation of ketene enolate (dienophile) by benzoylquinidine starting from corresponding acide chloride. This reaction has been performed in THF at -78°C to give a single enantiomer (%ee >99) in 76% yield. Finally the reduction of both benzoyl group and quinoxalinone with LiAlH4 has provided the 2-Ethyl-1,2,3,4-tetrahydroquinoxaline, which is an inhibitor of cholesteryl ester transfer protein.


Ref: J. AM. CHEM. SOC. 2006, 128, 13370-13371

For the synthesis of o-Benzoquinone diimide see:
J. Am. Chem. Soc. 1954, 76, 2763-2769.