Synthesis of benzothiazole

Yes, I am still alive, but lot of work, so not time to post something this last weeks...

Of course I have missed a lot of things, but I will start the most recent chemistry.

In looking the e-first of Synthesis, I discover the one-pot synthesis of benzothiazoles starting from o-haloanilide with a tandem thionation with the Lawesson's reagent and an intramolecular cyclization, the authors propose as mechanism an intramolecular nucleophilic substitution, for me that sounds weird because the best results are obtained with both fluoro and iodio thioanilide, I would propose the formation of radical anion on sulfur or something like this which could be consistent with the results, nonetheless, this is a very interesting transformation.

One-Pot Preparation of 2-(Alkyl)arylbenzothiazoles from the Corresponding o-Halobenzanilides, Dan Bernardi, Lalla Aïcha Ba, Gilbert Kirsch, Synthesis, 2007, e-first.

That reaction reminds me a 2006 JOC have read some months ago, talking about, of course, the synthesis of benzothiazoles starting from simple thioanilides and using Dess-Martin periodinane to promote the cyclization in only 15minutes in DCM. And in their case they propose a radical intramolecular cyclization!!!

Hypervalent Iodine Mediated Intramolecular Cyclization of Thioformanilides: Expeditious Approach to 2-Substituted Benzothiazoles, D. Subhas Bose, Mohd. Idrees,J. Org. Chem. 2006, 71, 8261-8263.

Synthesis of Isradipine

Isradipine is a drug used to lower blood pressure but recently it was found by a team from Nortwestern University, that this molecule can also slow the progression of Parkinson's disease, and restore the dopamine neurons (In animals tests). Isradipine is a calcium channel blocker of the 1,4-dihydropyridine class with a benzoxadiazole moiety in position 4.
The synthesis of the 1,4-dihydropyridine ring is quite classic, the first step consists in a Knoevenagel reaction of methyl acetoacetate on the benzoxadiazole 4-carboxaldehyde using piperidine and acetic acid as catalyst and diisopropylether as solvent in a 61% yield (this is the first time I see a Knoevenagel reaction in an ether!!!???? DCM, Toluene OK, but maybe I am wrong). The second step of this synthesis is the condensation of the acrylate obtained with the isopropyl aminocrotonate in ethanol to give the desire 1,4-dihydropyridine Isradipine in 67% yield after recrystallisation.


(WO/2005/005437) An improved Process for the Manufacture of Isradipine (Shasun Chemical & Drugs Limited)

Synthesis of Alprazolam

In reading about Synthesis of Essential Drugs, I have found in my lab (not a very good book, from a chemical point of view, a lot of mistakes), I have come upon a very strange way to synthesize benzodiazepines (actually triazolobenzodiazepines).
This synthesis starts by a nucleophilic substitution of hydrazine on a 2-chloroquinoline (2,6-dichloro-4-phenylquinoline), boiling this hydrazinoquinoline with orthoacetate in xylene affords triazoloquinoline intermediates.



This intermediate undergoes the key step of the synthesis, a oxidative ring opening of the quinoline with sodium periodate and ruthenium oxide, leading to the triazolobenzophenone.



The 1,3,4-triazole is treated with formaldehyde to provide hydroxymethyl intermediate, subsequent bromination using phosphorous tribromide gives bromomethyltriazole which after spontaneous cyclization with ammonia produces the Alprazolam.



Sorry for the lack of informations, I don't have the two patents concerning this molecule.

Solid-Phase Heterocyclic Synthesis

For those who are interested by heterocyclic synthesis on solid-phase and/or by cycloaddition, will be concerned by a recent review published in Journal of Combinatorial Chemistry by Alvarez and coll., you will find [2+2], [3+2] and [4+2] cycloadditions, and a very small chapter on tandem [4+2]/[3+2].


Advances in Solid-Phase Cycloadditions for Heterocyclic Synthesis
Lidia Feliu, Patricia Vera-Luque, Fernando Albericio, and Mercedes Alvarez
http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/cc070019z

Depolymerization of nylon

The world's annual consumption of plastic materials has increased from around 5 million tonnes in the 1950s to nearly 100 million tonnes today.

For ecological but also for economical reasons, it becomes more and more important to recycle plastics. One way to accomplish this recycling is to develop depolymerization methodologies.

In this area, Kamimura and coll. has published in Organic Letters a very intriguing methodology to depolymerize nylon. They heated 6-nylon at 300°C in a ionic liquid (PP13 TFSI) in presence of DMAP as catalyst for 1h under nitrogen atmosphere until the mixture became homogeneous. After distillation with a Kugelrohr apparatus, the caprolactam was obtained in a 86% yield.

An Efficient Method To Depolymerize Polyamide Plastics: A New Use of Ionic Liquids
Akio Kamimura and Shigehiro Yamamoto
Org. Lett.; 2007; ASAP

Synthesis of Indazole nucleus

In reading about kinasepro blog, you can notice the important number of biologically active compounds possessing the indazole core (in blue), Axitinib was synthesized by Pfizer and WO/2007/056170 was developed by Baeyer US as potent IGF-1R kinase inhibitors and ABT-102 was developped in Abbot lab and is currently in clinical development for the treatment of chronic pain.

I was looking for a straigthforward synthesis of indazole nucleus, I found a paper from Abbot lab.
They have depicted the synthesis of indazole starting from benzaldehyde with fluorine as leaving group and hydrazine, we can hope in that case to have formation of the hydrazone and subsequent intramolecular cyclization, but the reaction is very low yielding, because the cyclization is very slow and there is a competitive Wolf-Kishner reduction.



With some experiments they have confirmed that the reaction did not proceed via intramolecular cyclization of the hydrazone, but through a transient aminal (obtained by a previous nucleophilic subsitution of hydrazine on fluorine) which give the indazole core after elimination of hydrazine.



In order to circumvent this problem, they condensed the methyloxime on o-fluorobenzaldehydes to avoid Wolf-Kishner elimination, and with hydrazine cleanly gave indazoles. Good Job....


New Practical Synthesis of Indazoles via Condensation of o-Fluorobenzaldehydes and Their O-Methyloximes with Hydrazine
Kirill Lukin, Margaret C. Hsu, Dilinie Fernando, and M. Robert Leanna
J. Org. Chem. 2006, 71, 8166-8172.

Total synthesis of ageladine A

Sorry for the lack of post last week but I was very busy.
In reading the ASAP of JOC, I found a very interesting paper from Weinreb (ok he has already published on this topic) describing the total synthesis of ageladine A with a 6-pi-1-aza-triene eletrocyclization for the formation of the pyridine ring as key step.




More precisely with the electrocyclization of chloromethoxyimine (synthesized in a single step from a carboxylic acid using carbontetrachloride/PPh3, Methoxyamine hydrochloride with pyridine in acetonitrile with a good yield of 87%) by heating the solution in o-xylene in 150°C to afford the chloropyridine in 84% yield. I find amazing, the first tranformation because starting from a carboxylic acid to chloromethoxyimine, it is possible to achieve different type of reactions, electrocyclization as depicted here, but also cross-coupling reeactions on the chlorine, and certainly synthesize others heterocycles.

Further substitutions, deprotection and a cross-coupling on the chloropyridine have provided the ageladine A as well as analogues for biological evaluation. Interestingly, the synthesis of the imidazole precursor has been synthesized from the tribromoimidazole by sequencial regioselective bromine lithium exchange.

Application of a 6-1-Azatriene Electrocyclization Strategy to the Total Synthesis of the Marine Sponge Metabolite Ageladine A and Biological Evaluation of Synthetic Analogues

Matthew L. Meketa, Steven M. Weinreb, Yoichi Nakao, and Nobuhiro Fusetani

JOC, 2007, ASAP