mardi 31 juillet 2007
mercredi 18 juillet 2007
Nice way to synthesize phenantrolines...
vendredi 13 juillet 2007
And a very small post for my friend Pierre who indicates me a very potent molecule for the treatment of colorectal cancer....the vatalanib a tyrosine kinase inhibitor and should be on the market in 2008...(Sorry today no chemistry).
jeudi 12 juillet 2007
The yields obtained with this type of reaction are between 52 and 90%, which is good, but there is still drawbacks first of all the R1 must be introduced before the MCR, second, depending on the substituents needed the carbodiimides have also to be synthesized before, and third we have a racemic mixture....
mercredi 11 juillet 2007
From a chemical point a view, these guys have synthesized an imidazole library with different substituents in 1,2, 4 and 5 on solid support (Wang resin), with amino-conjuguated diethylene glycol, more than 300 imidazoles have been obtained with a purity >70%. Three different polymer supported platforms have been realized, you will see below only one example using a benzylamine derivative. The imidazole ring has been synthesized with the classical multicomponent reaction with an aldehyde (R1CHO) , an 1,2-dicarbonyl compound (R2COCOR3) , and with ammonium acetate.
R1, R2, and R3 are mainly aromatic compounds
To see the other platforms, chemistry and biological tests see Supporting info.
Synthetic Small Molecules that Induce Neurogenesis in Skeletal Muscle
Darren R. Williams, Myung-Ryul Lee, Young-Ah Song, Sung-Kyun Ko, Gun-Hee Kim, and Injae Shin
JACS, 2007, DOI: http://pubs3.acs.org/acs/journals/doilookup?in_doi=10.1021/ja072817z
mardi 10 juillet 2007
Iromycins are microbial metabolites which exibit an interesting biological activity as NO synthase inhibitors, their structures are fully substituted pyridones.
Recently, von Zezschwitz et al. from Gottingen in Germany, described the synthesis of Iromycin A and different analogues via cross-coupling reaction.
This synthesis of the nucelus starts with the construction of the pyrone ring by successive condensation reactions followed by cyclization. The starting material, the ethyl 2-methyl-3-oxo-butanoate 1 is lithiated by LDA at 0°C, and alkylated with propyl iodide to provide 2 in 56% yield, a second metalation also with LDA give the acetylated intermediates 3 using N-acetylimidazole as acetylating agent. The subsequent lactonization is performed on the crude employing DBU to furnish the desired 2-pyrone 4.
The pyrone in hand, the preparation of pyrone 4 has been realized with aqueous ammoniac in dioxane at 120°C in a sealed tube, through a 1,6-michael addition-ring opening-ring closure procedure in 75%.
Interestingly, the same pyridone can be obtained by a stepwise way, with the same type of reaction in presence of hydrazine, the intermediate hydrazone 5 is hydrolyzed with potassium hydrogenolsulfate to supply the N-aminopyridone 6. The diazotation of 6 in acetic acid lead to the 2-pyrone in 88% (on 2 steps).
Of course, some guys will tell me, this type of reactions are well-known, since "century".
But I like this type chemistry, this is not the usual clockwise metalation of pyridine or synthesis of pyridine by DA reaction.....
Iromycins: A New Family of Pyridone Metabolites from Streptomyces sp. II. Convergent Total Synthesis, Streptomyces sp. II. Convergent Total Synthesis
Heydar Shojaei, Zhen Li-Bo¨hmer, and Paultheo von Zezschwitz, JOC, 2007, 72, 5091.
mercredi 4 juillet 2007
And sometimes we can find very interesting stuff, as this synthesis of the 2-methyltryptamine by the Grandberg methodology, which is indeed a modified Fisher indole synthesis.
This chemistry starts with the formation of the hydrazone between the phenylhydrazine and the 5-chloropentan-2-one, after cyclization and isomerization from iminium to enamine form, the rearrangment takes place to afford the tricyclic intermediates, which after loss of a proton provides the 2-methyltryptamine with 42% in almost 20 Kg scale!!!!! in A 800L reactor!!!!!!!!!!
Optimization and Scale-Up of the Grandberg Synthesis of 2-Methyltryptamine
Joel Slade, David Parker, Michael Girgis, Raeann Wu, Scott Joseph, and Oljan Repi
lundi 2 juillet 2007
I like this synthesis first, of course because this is indole ring, but also because the author uses one of my favorite reaction, the aza-claisen rearrangement, and my favorite tool for organic synthesis, a micro-wave oven.
Practical Synthesis of 7-Prenylindole
Xin Xiong and Michael C. Pirrung
For the application of the 7-Prenylindole from the same author see:
Glyceraldehyde 3-Phosphate Dehydrogenase Is a Cellular Target of the Insulin Mimic Demethylasterriquinone B1
Hyunsoo Kim, Liu Deng, Xin Xiong, William D. Hunter, Melissa C. Long, and Michael C. Pirrung
vendredi 29 juin 2007
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.
mardi 12 juin 2007
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)
lundi 11 juin 2007
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.
Advances in Solid-Phase Cycloadditions for Heterocyclic Synthesis
Lidia Feliu, Patricia Vera-Luque, Fernando Albericio, and Mercedes Alvarez
mercredi 6 juin 2007
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
lundi 4 juin 2007
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.
dimanche 3 juin 2007
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
vendredi 18 mai 2007
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.
mercredi 16 mai 2007
mardi 15 mai 2007
dimanche 13 mai 2007
This review is mainly about rhodium catalyze hydroformylation.
Angew. Chem. Int. Ed. 2007, 46, 3612 – 3615.
samedi 12 mai 2007
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.
mercredi 9 mai 2007
Recent Progress in the Catalytic Synthesis of Imidazoles
Shin Kamijo and Yoshinori Yamamoto
Chem. Asian J. 2007, 2, 568 – 578.
mercredi 2 mai 2007
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.
mardi 17 avril 2007
This synthesis described by Fortunak in 1996, has an intramolecular Diels-Alder [4+2] cycloaddition as key step between an unactivated alkyne and a imidate generated in situ by action of Me3OBF4 on a N-arylamide.
This synthesis has been recently improved by Yao et al. using a mixture of Ph3PO and Tf2O (2:1) instead of Me3OBF4, by this methodology a wide range of tetracyclic "camptothecin-like" molecules has been synthesized.
Organic Letters, ASAP, April 14, 2007
samedi 14 avril 2007
Ref: Organic Syntheses, Vol. 80, p.133 (2003).
dimanche 25 mars 2007
Organic Syntheses, Coll. Vol. 10, p.382 (2004); Vol. 76, p.142 (1999).
vendredi 16 février 2007
jeudi 15 février 2007
In 2004, Baldwin and coll. tried to synthesize the 5,5',6,6'-tetrahydroxy-3,3'-biindolyl, a potent antioxidant, he proposed as key step a bis-cyclization of the two 2-aminoaryl substituents on the furan (as 1,4-dialdheyde precursor).
Cyclization was attempted with para-toluenesulfonic acid in benzene, and lead to the formation of a 3-arylquinoline in poor 25% yield along with the starting material.
Finally, the 3,3'-biindole has been synthesized by a palladium catalyzed homocoupling reaction from the corresponding 3-iodoindole.
For the mechanism of the quinoline formation and other informations see:
Tetrahedron 60 (2004) 3695–3712
mardi 13 février 2007
(1) Fieser, L. F.; Fieser, M. "Reagents for Organic Synthesis"; Wiley: New York, 1967; Vol. 1, p.
For more information about the procedure and the synthesis of pyridazine see:
Organic Syntheses, Coll. Vol. 9, p.335 (1998); Vol. 70, p.79 (1992).
jeudi 8 février 2007
For more information:
Organic Syntheses, Coll. Vol. 5, p.635 (1973); Vol. 40, p.54 (1960).
James Cason and James D. Willett.
This synthesis starts with the formation of quinoxaline, by the reaction of glyoxal and o-phenylendiamine in water with a 85-90% yield(1). Then the benzene fused ring is cleaved with a hot aqueous potassium permanganate solution (2), the mixture is cooled at room temperature and acidified with a 36% hydrochloric acid (3). The crude material is filtered off and recristallized in acetone to give the 2,3-pyrazinedicarboxylic acid with a 75-77% yield.
Interestingly, this synthesis can be applied to quinolines, isoquinolines and naphtalenes to provide the corresponding dicarboxylic derivatives.
For more information:
Organic Syntheses, Coll. Vol. 4, p.824 (1963); Vol. 30, p.86 (1950).
Reuben G. Jones and Keith C. McLaughlin.