Synthesis of new Bis- and Tetra-Acridines

Sourdon, Valérie; Mazoyer, S; Pique, Valérie; Galy, Jean‐Pierre

doi:10.3390/60800673

Cited by 28 publications

(12 citation statements)

References 7 publications

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“…Acridine dipolarophiles 4–6 were obtained from acridine‐4‐carbaldehyde ( 3 ) that was synthesized by a simple Klanderman's method in high yield . To prepare 3 , starting 4‐methylacridine ( 1 ) was first transformed to 4‐bromomethylacridine ( 2 ) with NBS in tetrachloromethane under 2,2′‐azobis(isobutyronitrile) (AIBN) catalysis (Scheme ) . Subsequent reaction of 2 with 2‐nitropropane and sodium in dry methanol afforded the aldehyde 3 in 89% yield.…”

Section: Resultsmentioning

confidence: 99%

Strong deshielding in aromatic isoxazolines

Maľučká

Vilková

Kožı́šek

et al. 2015

Magnetic Reson in Chemistry

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Very strong proton deshielding was found in di/tri-aromatic isoxazoline regioisomers prepared from acridin-4-yl dipolarophiles and stable benzonitrile oxides (BNO). Three alkenes, (acridin-4-yl)-CH=CH-R (R = COOCH3, Ph, and CONH2), reacted with three BNO dipoles (2,4,6-trimethoxy, 2,4,6-trimethyl, 2,6-dichloro) to give pairs of target isoxazolines with acridine bound to C-4 or C-5 carbon of the isoxazoline (denoted as 4-Acr or 5-Acr). Regioselectivity was dependent on both the dipolarophile and dipole character. The ester and amide dipolarophile displayed variable regioselectivity in cycloadditions whereas the styrene one afforded prevailing 4-Acr regioisomers. 2,4,6-Trimethoxy-BNO was most prone to form 5-Acr isoxazolines while mesitonitrile oxide gave major 4-Acr isoxazolines. Basic hydrolysis of the amide cycloadduct led to an unexpected isoxazolone product. The structure of the target compounds was studied by NMR, MS, and X-ray crystallography.

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Section: Resultsmentioning

confidence: 99%

Strong deshielding in aromatic isoxazolines

Maľučká

Vilková

Kožı́šek

et al. 2015

Magnetic Reson in Chemistry

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“…Although aldehydes can be prepared from 9‐methylacridine ( 1 ) and p ‐nitroso‐ N , N ‐diethylaniline or by oxidation of 9‐bromomethylacridine ( 2 ) with pyridinium chlorochromate, we used a simple Klanderman's method affording better yields of the product . The starting 1 was first brominated with NBS and AIBN in tetrachloromethane to give 9‐bromomethylacridine ( 2 ) which reacted with 2‐nitropropane and sodium in dry methanol to give acridine‐9‐carbaldehyde ( 3 ) (Scheme ). This was further transformed to target dipolarophiles, methyl 3‐(acridin‐9‐yl)propenoate ( 4 ) and 9‐(2‐styryl)acridine ( 5 ) (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

Prediction by ¹³C NMR of regioselectivity in 1,3‐dipolar cycloadditions of acridin‐9‐yl dipolarophiles

Vilková

Maľučká

Imrich

2015

Magnetic Reson in Chemistry

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Strong correlation was found between (13)C NMR chemical shifts of dipolarophilic CH=CH carbons and regioselectivity in 1,3-dipolar cycloadditions of new acridin-9-yl dipolarophiles with stable benzonitrile oxides (BNO). Accordingly, two starting dipolarophiles, (acridin-9-yl)-CH=CH-R (R = COOCH3 or Ph), reacted with three BNOs (2,4,6-trimethoxy, 2,4,6-trimethyl, and 2,6-dichloro) to give a mixture of two target isoxazoline regioisomers in which the acridine was bound either to isoxazoline C-4 carbon (4-Acr) or C-5 one (5-Acr). Methyl 3-(acridin-9-yl)propenoate afforded major 4-(acridin-9-yl)-isoxazoline-5-carboxylates (4-Acr) and minor 5-(acridin-9-yl)-4-carboxylates (5-Acr). 9-(2-Styryl)acridine regiospecifically afforded only 4-Acr cycloadducts. The ratios of regioisomers were compared with analogous reactions of acridin-4-yl dipolarophiles. Regioselectivity was dependent on a polarity of the CH=CH bond, donor effects in BNO, and stabilization by stacking of aromatic substituents in the products.

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“…sodium amalgam) 1,7 and oxidative (e.g. nitric acid) 8 conditions. Other methods include the Bernthsen reaction 9 (heating diphenylamines and organic acids with ZnCl 2 between 200 °C and 270 °C), the cyclization of diphenyl-amine-2-carboxaldehyde (TFA, H 2 SO 4 and/or high temperature) 10 or the adaptation of the Pfitzinger quinoline synthesis (heating isatine and 1,3,5-trihydroxy-benzene in NaOH solution).…”

Section: Scheme 1 Acridine and Acridone Structures And Numberingmentioning

confidence: 99%

A New Route to Acridines: Pauson-Khand Reaction on Quinoline-Bearing 1-En-7-ynes Leading to Novel Tetrahydrocyclopenta[c]acridine-2,5-diones

Patin¹,

Belmont²

2005

Synthesis

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Efficient Pauson-Khand reactions on quinolines bearing 1-en-7-ynes features gave tetrahydrocyclopenta[c]acridine derivatives. The quinoline intermediates were obtained in two steps: a Sonogashira reaction with functionalized alkynes (TMS, Bu, Ph, CHB 2 OTHP) followed by a Grignard reaction with allylmagnesium bromide. The sequence provides new acridine structures in four high yielding steps from commercially available quinolines.Acridines are interesting heteroaromatic structures (Scheme 1), they have been known since the 19 th century as pigments and dyes, 1 and are in use in clinics for their antibacterial properties (acriflavine, aminacrine, ethacridine). 1,2 Also, their biological activities against parasite infections (malaria, trypanosomiasis or leishmaniasis) result in clinical applications (quinacrine, acranil). 2 Antitumoral treatments have also been developed (nitracrine, amsacrine) 3 and are of considerable contemporary importance due to the current vigorous search for inhibitors of telomerase and topoisomerases. 2a Scheme 1 Acridine and acridone structures and numberingFollowing our recent work, 4 we are still looking for alternative synthetic pathways to reach functionalized acridines. Reasons for that are the usual harsh conditions needed for synthesizing acridines through the acridone intermediates (Scheme 1), which are obtained by heating diphenylamine-2-carboxylic acids 5 in strong acidic media. 6 Acridines are then reached by harsh reductive (e.g. sodium amalgam) 1,7 and oxidative (e.g. nitric acid) 8 conditions. Other methods include the Bernthsen reaction 9 (heating diphenylamines and organic acids with ZnCl 2 between 200 °C and 270 °C), the cyclization of diphenylamine-2-carboxaldehyde (TFA, H 2 SO 4 and/or high temperature) 10 or the adaptation of the Pfitzinger quinoline synthesis (heating isatine and 1,3,5-trihydroxy-benzene in NaOH solution). 11Our previous work 4 on quinolines bearing a TBS-protected enol-ether at position 3 and an internal alkyne chain at position 2 (i.e., 1-en-5-yne structures), allowed us to obtain 1,3,7-trisubstituted acridines via a 6-endo-dig cyclization process catalyzed by a rhodium (I) complex [Rh(CO) 2 Cl] 2 (Scheme 2). Scheme 2 Previous workWe were interested in finding an alternative approach to acridines that could also provide new tetracyclic structures. For this purpose, Pauson-Khand reaction (PKR) 12 on 1-en-7-yne heteroaromatic structures, such as A (Scheme 3), appeared to suit us since it could open the way to new structures such as tetrahydro-2H-cyclopenta[c]acridine-2,5-diones.To our knowledge, this is the first application of the PKR in order to access acridine derivatives. PKR 13 has become a very useful tool in the synthesis of natural products, 14 and the classical cobalt reagent [Co 2 (CO) 8 ] has been used with different initiators in stoechiometric or catalytic versions, 15 and even in an asymmetric fashion. 14 The intramolecular PKR applied on enynes connected through an aromatic usually gives moderate yields, although some good results are ob...

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Synthesis of new Bis- and Tetra-Acridines

Abstract: A new series of bis- and tetra-acridines has been prepared from 4-(bromo-methyl)acridine; some of them exhibited encouraging in vitro cytotoxic activities against murine cell lines.

Cited by 28 publications

References 7 publications

Strong deshielding in aromatic isoxazolines

Strong deshielding in aromatic isoxazolines

Prediction by ¹³C NMR of regioselectivity in 1,3‐dipolar cycloadditions of acridin‐9‐yl dipolarophiles

A New Route to Acridines: Pauson-Khand Reaction on Quinoline-Bearing 1-En-7-ynes Leading to Novel Tetrahydrocyclopenta[c]acridine-2,5-diones

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Synthesis of new Bis- and Tetra-Acridines

Abstract: A new series of bis- and tetra-acridines has been prepared from 4-(bromo-methyl)acridine; some of them exhibited encouraging in vitro cytotoxic activities against murine cell lines.

Cited by 28 publications

References 7 publications

Strong deshielding in aromatic isoxazolines

Strong deshielding in aromatic isoxazolines

Prediction by 13C NMR of regioselectivity in 1,3‐dipolar cycloadditions of acridin‐9‐yl dipolarophiles

A New Route to Acridines: Pauson-Khand Reaction on Quinoline-Bearing 1-En-7-ynes Leading to Novel Tetrahydrocyclopenta[c]acridine-2,5-diones

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Prediction by ¹³C NMR of regioselectivity in 1,3‐dipolar cycloadditions of acridin‐9‐yl dipolarophiles