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Synthesis of novel 1,10‐phenanthrolines and cyclic analogs, potential anticancer and antimalarial
agents
Laura Fouilland
Final degree project thesis Institut de Chimie et Biochimie Moleculaires et Supramoléculaires ICBMS‐UMR 5246, « synthesis of therapeutic interest molecules »
Université Lyon 1 KTH Chemical Science and Engineering School, 2010
Supervisors: Dr Maurice Médebielle (Université Lyon 1) Dr Krister Zetterberg (KTH)
Sammanfattning
Syntes av nya 1,10‐fenantroliner och cykliska analoger, potentiella anticancer och antimalaria
substanser Tidigare studier har indikerat att molekyler med 1,10‐phenanthrolineskelett har en skyddande effekt mot malaria och cancer. Syftet med detta projekt är att syntetisera nya 1,10‐phenanthrolinar och cykliska analoger. Framställningsmetoden som användes i denna studie har inte undersökts tidigare.
Föreningen skapades genom en originalmetod utnyttjande en redoxreaktion med hjälp av en TDAE‐reagens. TDAE är en elektronrik organisk molekyl och fungerar som en effektiv reduktionsagent. Med hjälp av en enelektronöverföring (SET) kan en anjon framställas under milda förhållanden utifrån halogena derivat. Anjonen tillförs 1,10‐phenanthroline‐5,6‐dione. De olika substraten är heteroaromatiska nitro‐benzyliska och quinoniska derivat, samt bromodifluorometylheteroarylerade. Cykliska produkter erhölls genom en tvåstegsreaktion (reduktion, dehydratisering) genomförd i ett enda reaktionskärl.
Med detta projekt har dessa reaktioner för första gången testats på den här typen av
molekyler. Det krävs mer optimering eftersom utbytena var låga till medelhöga. Utav sex möjliga substrat fungerade additionsreaktionen med TDAE med fyra stycken. I detta försök testades dock endast en cyklisk reaktion på additionsprodukten. Med ytterligare förbättringar av reaktionsvillkor och upparbetningar förväntas man kunna producera önskad produkt i gott utbyte.
Abstract The potential antimalarial and anticancer effect of molecules containing 1,10‐phenanthroline skeleton has been suspected on several previous studies. It is why the goal of this project is to synthesize novel 1,10‐phenanthrolines and cyclic analogs. The originality of this project is the synthesis way of these novel compounds. Indeed, these structures will be obtained through an original redox approach developed in the SMITH laboratory using the tetrakis(dimethylamino)ethylene (TDAE) reagent. The TDAE is an electron rich organic molecule which is an effective reducing agent capable of generating an anion from halogenated derivatives under mild conditions via a single electron transfer (SET). From the different substrate we will work with, the TDAE will generate an anion which will be additioned on the 1,10‐phenanthroline‐5,6‐dione. These different substrates will be aromatic and heterocyclic nitro‐benzylic, and quinonic derivates as well as bromodifluoromethyl heteroarylated substrates. A one pot two step (reduction, dehydration) reaction will be done on these addition products, in order to obtain a cyclised product. It is the first time we try these reactions on these kind on molecules, it is why this project needs a lot of optimization and that the yield obtained are medium or equal to zero. However, we observed that the addition reaction with TDAE worked with 4 substrates out of 6. We tried the cyclisation reaction on only one addition product and we think that after some improvement of the reaction conditions and the work‐up, we will be able to obtain the product with a good yield.
Acknowledgments First of all, I would like to thank Dr Maurice Médebielle to have let me join his work team
SMITH for six months, where I could work on a subject of great interest in organic synthesis
with therapeutic interests.
My grateful thanks also go to Dr. Krister Zetterberg to have accepted to follow me during
these six months and being my supervisor.
Thank you to Pr. Benoit Joseph and Dr. Guy Fournet. Their cordial welcome, their help
and their valuable advice have been really pleasant all along my internship.
I wish to thank Dr. D. Bouchu, C. Duchamps and N. Henriques, who helped me with the
interpretation of my analysis results.
I also extend my gratitude to Dr. K. Kollappillil and the entire SMITH team. So thank you to
Nicolas Chopin, Céline Perez and Sophie Decamps to have share their experiences with me
and also for their welcoming attitudes.
Table of contents GLOSSARY ..................................................................................................................................... 6
INTRODUCTION ............................................................................... Error! Bookmark not defined.
BIBLIOGRAPHY ............................................................................................................................. 10
I. Synthesises of substrate ..................................................................................................... 10
1. Preparation of 1,10‐phenanthroline‐5,6‐dione 10
2. Preparation of naphthalene derivatives compounds 10
3. Preparation of nitrobenzyl chloride derivatives 11
II. TDAE methodology ............................................................................................................. 11
1. Addition with TDAE in the literature 11
2. Reactivity of TDAE 11
III. Cyclization ........................................................................................................................... 12
RESULTS AND DISCUSSIONS ............................................................................................................ 13
I. Synthesis of 1,10‐phenanthroline‐5,6‐dione ...................................................................... 13
II. Preparation of 2‐bromo/chloro‐1‐(4‐bromo‐1‐(dimethylamino)naphthalen‐2‐yl)‐2,2‐difluoroethanone compounds ................................................................................................. 13
III. Non‐fluorinated series ........................................................................................................ 14
1. Addition with TDAE 14
2. Cyclization 15
IV. Fluorinated series ............................................................................................................... 16
CONCLUSION AND PERSPECTIVES ..................................................................................................... 17
EXPERIMENTAL PART ..................................................................................................................... 18
I. General comments ............................................................................................................. 18
II. Synthesis ............................................................................................................................. 18
1. Oxidation 18
2. Dimethyl amination 19
3. Friedel & Craft Acylation 19
4. Addition of nitrobenzyl chloride derivatives with TDAE 20
5. Other addition with TDAE 22
6. Cyclization 25
REFERENCES ................................................................................................................................ 26
Glossary BrCF2COCl Bromodifluoroacetyl chloride
CDFAA Chlorodifluoroacetic anhydride
CI Chemical ionization
d Doublet
DCM Dichloromethane
dd Doublet of doublet
DMF Dimethylformamide
DMSO Dimethyl sulfoxide
EI Electron ionization
eq Equivalent
ESI Electrospray ionization
EtOAc Ethyl acetate
m Multiplet
MeI Iodomethane
mp Melting point
NMR Nuclear magnetic resonance
RT Room temperature
s Singulet
TDAE Tetrakis Dimethylamino Ethylene
TLC Thin layer chromatography
Figure 1: Life circle of malaria parasites
Introduction Malaria is one the most important infectious disease with every year hundreds of million clinical cases and the death of 1 to 3 million humans, mostly children under the age of five and pregnant woman. Malaria parasites are members of the genus Plasmodium. There is four Plasmodium species in human’s malaria P. falciparum, P. malariae, P. ovale and P. vivax. P. falciparum and P. vivax are the most common cause of infection and are responsible for about 95% of all malaria cases. P. falciparum is also responsible for about 90% of the deaths from malaria.[1] Malaria parasites are naturally transmitted by the bite of female Anopheles mosquitos. After having bitten an infected person, a small amount of contaminated blood is taken by the mosquito, and when it takes its next blood meal, about 15 to 20 parasites called sporozoites are injected with the mosquito’s saliva into the blood person being bitten. The sporozoites are cells that leave the mosquito and enter the human liver where they develop into a tissue schizont (a cell that divides by asexual reproduction). After 1‐2 weeks the schizont burst releasing 10 000 to 30 000 merozoites into the blood stream, which then invade red blood cells. The merozoites develop into blood schizont. After 48h to72h, the blood schizonts rupture and release 16 to 32 new merozoites into blood stream which again invade red blood cells. After several asexual life‐cycles, some merozoites develop into sexual forms, the gametocytes, which are transferred to a mosquito during another blood meal. These gametocytes undergo sexual reproduction within the mosquito midgut producing thousands of infective sporozoites, which migrate to the salivary gland ready for a new infection cycle.[1] With the rupture of the red blood cell, the parasite’s waste and cell debris are released into the blood stream causing some of the clinical symptoms of malaria that include fever, chill, headache, abdominal and back pain, nausea, diarrhea and in severe cases hallucinations, coma and death.
There are seven classes of antimalarial drugs which are 4‐Aminoquinolines, Arylaminoalcohols, 8‐Aminoquinolines, Artemisinines, Antifolates, Inhibitors of the respiratory chain and Antibiotics. The most used classes are 4‐Aminoquinolines, Arylaminoalcohols and 8‐Aminoquinolines.
When malaria parasite digests hemoglobin, it releases high quantities of free heme. A heme is a non‐protein compound containing iron atom, which is toxic for the parasite cells expect when it is convert into an insoluble crystalline form called hemozoin. By forming a complex with a ferriprotoporphyrine IX[1], the 4‐Aminoquinoline drug class prevents the formation of this hemozoin. Thereby, the parasite cannot survive because of the high concentration of free heme. Chloroquine (Fig.2) from the 4‐Aminoquinolines class, has been the most successful single drug used as treatment and prevent against malaria. It was an effective and affordable drug until the 1960s when a resistant malaria strains (due to a mutation in the gene of transport protein) to chloroquine starts to develop.
For the Arylaminoalcohols class, the mechanism of action is not known exactly. This class of drugs is still used a lot even if a resistance (due to an amplification of the pfmdr1 gene) has been observed[1]. Quinine (Fig.3) from this class of drug is still the most important drug used for the treatment of uncomplicated and severe malaria. A combination of Quinine and other drugs from Antibiotic class is often recommended. Quinine has multiple side effects which can be either reversible or severe. Some other molecules like Mefloquine and Halofantrine, from the same class of drugs, displays interesting activity against most chloroquine resistant Plasmodium strains.
In the class of 8‐Aminoquinoline, Primaquine (Fig.4) is the only drug used currently. The potential of this last class of drug is quite interesting, because it displays a marked activity against gametocytes from all species of Plasmodium that affects humans, including chloroquine‐resistant P.falciparum[2]. It is a transmission‐blocking drug. However, there are still two main problems limiting the use of this drug. The most serious is a life‐threatening hemolysis in humans with glucose‐6‐phosphate‐dehydrogenase deficiency. The second problem is the extensive conversion to its inactive metabolite carboxyprimamique.
NCl
HNN
Figure 2: Structure of Chloroquine
N
O
HON
H
H
Figure 3: Structure of Quinine
N
HN
O
NH2
Figure 4: Structure of Primaquine
Previous studies on this 8‐Aminoquinoline class of drug have shown that its pharmacological profile should be improved by structural arrangement of the amino alkyl chain[2]. Different peptide and amino acid derivatives of primaquine have been synthesized in order to reduce the metabolic oxidative deamination pathway. But it has been shown that they are rapidly hydrolyzed to primaquine[2]. Other studies based on a conformational approach have shown that, the 1‐10‐phenanthroline skeleton could be a new pharmacophore for the development of new antimalarial.
Based on these studies, we have decided to synthesize 1,10‐phenanthroline derivatives molecules, using original redox methodologies, in order to improve the knowledge about this potentially new pharmacophore in malarial drug development.
The pharmacophores synthesis strategy envisaged is represented on these schemas (Fig.5) and (Fig. 6)
NO2
Cl
R1
R2
N
N
O
O
+
NO2R1
R2
N
N
O
OH
Addition
with TDAE
Reduction -NO2 NH2
CyclisationDeshydratation
N N
N
R1
R2
R1=R2= HR1=R2=OMeR1=R2= -OCH2O-R1=Cl; R2=H
Figure 5: schema of the synthesis for the non‐fluorinated compounds
Br
NR R
O
X
FF N
N
O
O
Br
NR R
O
FF
N
N
O
OH
Br
N
NN
O
F
F
OH
Br
N
NN
O
F
+Addition
with TDAE
Deprotection NR2 NH2Cyclysation
Reduction
-HF
X= Cl, Br
R= protecting group, Me
Figure 6: Schema of the synthesis for the fluorinated compounds
Moreover, these molecules present also an interest as anticancer agents. Indeed, the
1,10‐phenanthroline has been recognized as a very good ligand for transition metals (copper, platinum) or ruthenium and the derived complexes. These complexes are able to induce a high degree of DNA stabilization and to inhibit telomerase[3]. They can be seen as new potential antitumor agents. The capacity of making a telomeric quadruplex with DNA os the novelty pf these potential antitumor agents.
Bibliography The strategy envisaged in order to obtain 1,10‐phenanthroline and cyclic analogues is based on the soft reduction of different substrates by using the Tetrakis(dimethylamino ) ethylene (TDAE)methodology. In the literature, such reactions have been performed on different electrophiles, but never on 1,10‐phenanthroline derivatives. The previous publications have been helpful to develop this project. The synthesis of starting materials and electrophiles, which have been realized in this project, are already known in the literature.
I. Synthesises of substrate
1. Preparation of 1,10‐phenanthroline‐5,6‐dione The electrophile 1,10‐phenanthroline‐5,6‐dione can be obtained by an oxidative reaction of 1‐10‐phenanthroline (Fig.6) (although it is also a commercial product but expensive). In the literature, the reactants used for this oxidation are sulphuric acid, nitric acid and KBr or NaBr. However, the number of equivalents differs from one publication to another. x = 1 eq and y(KBr)= 1.5 eq[4] x = 1 eq and y(NaBr)= 1 eq[5] x = 1 eq and y(KBr)= 1.5 eq[6] Figure 6
2. Preparation of naphthalene derivatives compounds The starting materials are readily obtain from previous work in the laboratory[7]. They can be obtain in two steps (Fig.7), first the N,N‐dimethylation of 4‐bromonaphthalen‐1‐amine (a commercial compound) and then a Friedel‐Crafts acylation in order to introduce COCF2X group in a orhto position compared with the N,N‐dimethyl group.[7] and [8]
NH2
Br Br
N
KOH/ MeI/ DMSO
Br
N
Acylation
CDFAA or BrCF2COCl
O
X
FF
Figure 7
N
N
NaBr / KBr (y eq)N
N
O
O
H2SO4, HNO3
x eq
3. Preparation of nitrobenzyl chloride derivatives The nitrobenzyl chloride derivatives are either commercial products or prepared in the partner’s laboratory (Faculty of Pharmacy, in Marseille, France)
II. TDAE methodology
1. Addition with TDAE in the literature The TDAE methodology have never been used on a 1,10‐phenanthroline skeleton. Nevertheless, studies on similar molecules have been done. For instance, reactions of p‐nitrobenzyl chloride with various α‐halocarbonyl derivatives[9] (Fig. 8) have been realized. The studies on TDAE‐initiated reaction of p‐nitrobenzyl chloride with naphthalene‐1,2‐dione or benzyl[10] (Fig. 9) are even closer to the reaction we want to explore. These studies have shown the efficiency of the TDAE methodology compared to classical methods using organometallic compounds or traditional metal catalysts. Indeed, it shows that TDAE strategy is an easy, original and selective method to create carbon‐carbon bounds.
O2N
Cl
+
X R
RO
O2N
R R
OTDAE
DMF1h at -20°C; 2h et 70°C
Figure 8
R
R
NO2
Cl
O O
O O
R
R
NO2
HO
O
R
R
NO2
HOO
+
TDAE
DMF, N2,1h at -20°C; 2h at 80°C
TDAE
DMF, N2,1h at -20°C; 2h at 80°C
Figure 9
2. Reactivity of TDAE The key reaction is the addition of the anion, generated by the TDAE, on the 1,10‐phenanthroline‐5,6‐dione. The Tetrakis dimethylamino ethylene is an electron rich organic molecule which is an effective reducing agent capable of generating an anion from halogenated derivatives under mild conditions via a single electron transfer (SET). The reaction schema is shown below (Fig.10).
RCl
HH+ -20°CN
N
N
N
RHH+ TDAE + Cl
RHH+ TDAE R
HH+ TDAE
2
RHH
+ TDAE RHH
+ TDAE
RHH
+ N
N
O
O
N
N
O
OHR
H H
ClRHH
TDAE
Figure 10
III. Cyclization
The step called cyclization, is actually a reduction step of nitro group to amino group. Then, the process is not really known but it probably involves the nucleophilic attack of the amino group onto the carbonyl one and the acid‐promoted double dehydration of the corresponding intermediate[10]. Depending on the compounds, the reduction step can also be a deprotecting step for compounds with a protecting group instead of nitro group. An example of this one‐pot two step reaction from the publication 10 is shown below (Fig. 11).
R1
R2
NO2
O
HO
R1
R2
NH2
O
HO
Fe
AcOH
HN
OH
OH
R1
R2
NR1
R2
Figure 11
The reducing agent used in this example is Fe with AcOH, but Sn in HCl solution or SnCl2 are also well‐known as reducing agents of nitro groups[11].
Results and discussions
I. Synthesis of 1,10‐phenanthroline‐5,6‐dione
N
N
NaBr / KBr (y eq)N
N
O
O
H2SO4, HNO3
The synthesis of 1,10‐phenanthroline‐5,6‐dione has been tried following the different conditions indicated in the previous publications. The summary of results can be found in Table 1.
Entry 1,10‐phenanthroline eq. KBr eq. Reflux time Yield %
1 1 1 40 min 3 2 1 10 3h 25 3 1 1.5 3h 53
Table 1 The product was obtained in a pure form using the optimized conditions (entry 3) after a simple recristallization to remove unreacetd 1,10‐phenanthroline and impurities, while a by‐product was systematically formed with the other conditions.
II. Preparation of 2‐bromo/chloro‐1‐(4‐bromo‐1‐(dimethylamino)naphthalen‐2‐yl)‐2,2‐difluoroethanone compounds
NH2
Br Br
N
KOH/ MeI/ DMSO
Br
N
Acylation
O
X
FF
The synthesis of 4‐bromo‐N,N‐dimethylnaphthalen‐1‐amine, was straightforward obtain pure after a simple purification by silica gel chromatography with a yield of 75%. The Friedel‐Crafts acylations were achieved easily as these reactions have been improved in a previous study. The fluorinated compounds were obtain in a good yield and were purified by silica‐gel chromatography. However, the chloro‐difluoro compound tends to form easily an hydrate, which is always present even after purification.
1 1a
2 2a 3: X=Cl 4: X=Br
NO2
Cl
Cl
4-chloro-1-(chloromethyl)-2-nitrobenzene
III. Non‐fluorinated series
1. Addition with TDAE The addition with TDAE has been realized with 5 different substrates, with DMF as solvent :
The different conditions used in order to optimized these reactions are represent on the table 2a and 2b below.
Product Dione eq. Time at ‐20°C Heating time Yielda %
NO2 N
N
O
OH
1,5 1h 3h 32
1,5 1h 1 night 47
3 1h 3h 36
3 1h 1 night 77
NO2 N
N
O
OH
Cl
1 1h 3h 24
1 1h 1 night 2
3 1h 3h 56
3 1h 1 night 25/21
NO2 N
N
O
OH
O
O
1,3 1h 3h 7
1,3 1h 1 night 20
3 1h 3h 17,4
3 1h 1 night 53 Tableau 2a
The table 2a shows that the addition on these three first substrates gave indeed the addition products. The yields are better when 3 equivalents of 1,10‐phenanthroline‐5,6‐dione are used with overnight heating at 80°C, expect for the product 7a which gives a good yield with only 3h heating. This may be due either to some mistakes done during the manipulation or to the fact that the TDAE seemed to be less reactive at the end of the internship. The addition products are always contaminated with unreacted 1,10‐phenanthroline‐5,6‐dione, which was difficult at the present time to eliminate. Therefore all the yields reported in table 2a are estimated by 1HNMR. So far all attempts to purify the final product by chromatography on silica gel or alumina have been unsuccessful. Recent TLC analysis on Reversed phase silica gel indicate that separation could be better. Mass analysis has confirmed the presence of the addition product 6a, 7a and 8a.
NO2
Cl
1-(chloromethyl)-2-nitrobenzene
NO2
Cl
O
O5-(chloromethyl)-6-nitrobenzo[d]
[1,3]dioxole
NO2
Cl
O
O1-(chloromethyl)-4,5-dimethoxy-2-
nitrobenzene
O OMe
O OMe
NO2
Br
2-(bromomethyl)-1,4-dimethoxy-3-nitroanthracene-9,10-dione
6 7 8 9 10
a 1HNMR yield in CDCl3 as solvent
6a
7a
8a
For the last two substrates (table 2b), none of the addition product was detected by 1HNMR neither by mass analysis.
Product Dione eq. Time at ‐20°C Heating time Yield
NO2 N
N
O
OH
O
O
1 1h 3h 0
1 1h 1 night 0
3 1h 3h 0
3 1h 1 night 0
O OMe
O OMe
NO2N
N
O
HO
1 1h 1 night 0
Tableau 2b
2. Cyclization The optimization reaction conditions to prepare the cyclised product have been performed with the addition product 6a, which has been obtained with the best yield.
NO2 N
N
O
OH
N N
N
Reduction
CyclisationDeshydratation
Different reducing agents have been tried; As it has been describe in the bibliography part, Fe/AcOH has been used with some success in previous studies[10] and others Sn or Sncl2 are known to reduce nitro or derivatives[11]
Produit Réactif Heating time Entry
N N
N
Fe (14eq) Solvent : AcOH
4h at 120°C 1 3h at 120°C 2 3h at 120°C 3
Sn (2eq)/ HCl (5eq) Solvent : EtOH Reflux 24h 4
SnCl2(2H20) (5eq) Solvent : MeOH
Reflux 1h 5 Reflux 3h 6
Tableau 3
This last reaction has been quite hard to execute. The product obtained was so insoluble that the extractions which have been done were non efficient. The only possibility was to remove the solvent of the reaction by evaporation and make a mass analysis in order to determine if the desired product was present. Some MNR analyses have also be done, but they were really hard to interpret because of the low solubility (even in DMSO solvent), and also because of the several protons present in the evaporated product.
6a 6b
6b
9a
10a
IV. Fluorinated series
The addition with TDAE on chloro‐difluorinated and bromo‐ difluorinated compounds has been realized.
N
Br
X
FF
O
+
N
N
O
O
TDAE, DMF, N2
N
Br
ON
N
O
OHFF
*
Contrary to the other substrates (6 to 10), these both substrates 3 and 4 are supposed more reactive. The optimal reaction conditions are then supposed to be a bit different. The condition use for both reaction are shown on the table 4.
Substrate Dione eq Time at ‐20°C Time at RT
N
Br
Cl
FF
O
1 1h 3h
N
Br
Br
FF
O
3 1h 3h
Tableau 4
The same addition product 5 was supposed to be obtain either starting from compounds 3 or 4. In both cases, an AB system characteristic of an asymmetric centre created by the chiral carbon (*) should be observed on the 19F NMR spectra. 19F NMR analysis have been done on both addition product obtained. These analyses showed an AB system but unfortunately not with the same chemical shift. An additional mass analysis has been done on the compounds 5 (coming from the addition of the compound 4). This analysis confirmed the successful addition of the compound 4 because the right product has been obtain. The fact that only 1 equivalent of 1,10‐phenanthroline‐5,6‐dione has been used, for realized the reaction starting with the product 3, can explain why this reaction has not led to the addition product desired. Moreover, the reactivity of the compound 4 is supposed better due to its brome atom than the compound 3. The yield of the successful reaction has not been calculated because the product was not obtained pure and is also difficult to purified with usual techniques. However it could be calculated by using PhOCF3 ad internal standard in 19F NMR of the product 5.
3: X=Cl 4: X=Br
1a 5
4
3
Conclusion and perspectives In this report, different synthesis optimisation have been studied. First of all, the synthesis of the 1,10‐phenanthroline‐5,6‐dione has not given the results expected by the previous studies. Indeed the yield obtained was always lower than the one presented previously. After different tries we finally find out the right condition in order to obtain a product pure with a decent yield. The outcome on the addition products is divided in two parts, the successful reaction and the unsuccessful one. In the fluorinated series, 3 products out of 5 have been synthesized, and the conditions have been optimized in order to obtain the best yield. However, the purification step still need to be improve because the products are still impure. The recent TLC analysis showed that the separation was better on reversed phase silica‐gel. It is why, the purification by reversed phase chromatography seems to be promising. In the fluorinated series, the addition of the bromo‐difluoro compound seems to be more efficient than the one with the chloro‐difluoro compound. This synthesis still need to be improve, especially the research of the best conditions as the number of 1,10‐phenanthroline‐5,6‐dione equivalent and the heating time. The unsuccessful reaction concern two substrates (9 and 10). The reasons why the reactions have not been a success is still unexplained. It can be due to the steric hindrance in the case of the compound 10. The cyclised product has indeed be characterized by mass analysis showing that the original one‐pot reaction was working. But this analysis showed that the product has been obtained in a really low quantities. It might be due to the actual work‐up, inspired from previous studies, which is not suitable for this kind of molecules. In fact, the cyclised product is insoluble in the solvent used and it was really hard to extract the product from the rest (impurities, unreacted products). But it might also be due to the reaction conditions which are not yet optimized, even if the reaction with the tin in HCl solution seemed to be the best conditions found so far. When a suitable reaction conditions and work‐up will be found, this one‐pot reaction could be used to cyclise the other addition products (7a to 10a).
Experimental part
I.General comments
The NMR spectra were recorded with a Bruker Avance 300 spectrometer, at 300,13MHz for proton, 282,41MHz for fluorine and 75,46MHz for carbon. Solvents used for these analysis were of highest purity and anhydrous. The anhydrous solvents used for the reaction are anhydrous and keep on molecular sieve (Sigma‐Aldrich). The mass spectra have been recorded on a Thermo Finnigan LCQ Advantage spectrometer, in Electrospary (ESI), Electron Impact (EI) mode and Chemical ionisation (CI) Melting points (uncorrected) were determined in capillary tubes on a Büchi apparatus. Silica gel 60M (0.04‐0.063: macherey‐nagel) has been used for the column chromatography, and TLC were performed using Merck Kiesegel 60 F254 plates. The names of the molecules were generated using ChemDraw (version ultra 8).
II. Synthesis
1. Oxidation
Synthesis of 1‐10,phenanthroline‐5,6‐dione
An ice cold mixture of concentrated H2SO4 (40 mL) and HNO3 (20 mL) is added dropwise to 1,10‐phenanthroline (4.0 g; 22.2 mmol; 1 eq) and KBr (4 g; 33.3 mmol; 1.5 eq) in a three‐necked flask connected to a bromine vapour trap. The mixture is then heated at reflux for 3h. The hot yellow solution is poured on ice (500 mL) and carefully neutralized with NaOH (pH ~ 6‐7). Extraction with DCM (3 x 100 mL) followed by drying over Na2SO4, removal of solvent and purification by recrystallization from EtOH gave pure 1‐10,phenanthroline‐5,6‐dione (2.5 g; 11.9 mmol, 53 %).
Appearance: Yellow powder. 1H NMR (CDCl3): δ = 7.59 (dd, J = 7.80 Hz , J(2,3)=4.80 Hz, H2+H5); 8.50 (dd, J(1,2) = 7.80Hz, J(1,3) = 1.80 Hz, H1+H6); 9.12 (dd, J(2,3) = 4.50, J(1,3)=1.80 Hz, H3+H4). Yield: 53%. mp: <210°C (260°C from literature)
N
32
1
65
4
NO
O
C12H6N2O2Mol. Wt.: 210,19
2. Dimethyl amination
Synthesis of 4‐bromo‐N,N‐dimethylnaphtalen‐1‐amine
Into a dry 50mL round‐bottom flask, the 4‐bromonaphtalen‐1‐ylamine (1 g; 4.5 mmol; 1 eq) is dissolved in DMSO (16 mL). To this violet solution, KOH powder (631 mg; 11.25 mmol; 2 eq) is added followed by slow addition of a MeI solution (1.7 mL; 27 mmol; 6 eq). After 18h of stirring at room temperature, the solution is poured into a NaCl saturated aqueous solution and extracted with DCM ( 3 x 40 mL). The organic phase is washed with a NaCl saturated aqueous solution, and with water (3 x 40 mL). The combined organic phases are dried over Na2SO4 and the solvent is removed by evaporation. Purification by silica gel chromatography (Petroleum ether 95/ Ethyl acetate 5) gave pure compound (1.69 g, 6.75 mmol, 75 %).
Appearance: Red liquid. 1H NMR (CDCl3): δ= 2.88 (s, 3H7 + 3H8); 6.94 (d, J = 8.1Hz, H6); 7.55 (m, H2
+ H1); 7.69 (d, J = 8.1 Hz, H5); 8.24 (dd, J = 7.4, 2.1Hz, H3); 8.30 (dd, J = 7.9, 1.7 Hz; H4) Yield: 75%
3. Friedel & Craft Acylation
N
Br
X
FF
O
Pyridine/ DCM
N
Br
BrCF2COClor CDFAA
X= Br, Cl In a round‐bottom flask under nitrogen, the 4‐bromo‐N,N‐dimethylnaphthalen‐1‐amine (1.3 g, 5.2 mmol, 1 eq) is dissolved in DCM (10 mL). Pyridine (822 mg, 10.4 mmol, 2 eq) is added, and the solution is cooled with an ice cooling bath. Either the bromodifluoroacetyl chloride (2.0 g, 10.4 mmol, 2 eq) or chlorodifluoroacetic anhydride (2.5 g, 10.4 mmol, 2 eq) is then added dropwise. At the end of the addition, the cooling bath is removed and the reaction is stirred at room temperature during 3days with BrCF2COCl or 18h with CDFAA. Then, the solution is poured into aqueous solution of HCl (50 mL, 0.1 M) and diluted with DCM. The organic phase is washed with an aqueous solution of HCl (3 x 50 mL, 0.1 M), with a NaCl saturated aqueous solution (2 x 50 mL) and with water (1 x 50 mL). The combined organic phase is dried over Na2SO4 and the solvents are removed by evaporation.
2
34
1
5
6
N
Br
7 8
C12H12BrNMol. Wt.: 250,13
Synthesis of 2‐bromo‐1‐(4‐bromo‐1‐(dimethylamino)naphthalen‐2‐yl)‐2,2‐difluoroethanone
Purification: silica gel chromatography (Petroleum ether 98/ Ethyl acetate 2) Appearance: Orange oil which slowly crystallised. 1H NMR (CDCl3): δ= 2.98 (s, 3H7+3H8); 7.7 (ddd, J = 8.0, 7.2, 0.9 Hz, H3); 7.72 (ddd, J = 8.2, 7.1, 1.2 Hz, H2); 7.85 (s, H5); 8.20 (d, J = 8.4 Hz, H1); 8.31 (d, J = 8.5Hz; H4)+impurities. 19F NMR (CDCl3): δ= ‐58.34 Yield: 43%. mp: 84‐88°C
Synthesis of 1‐(4‐bromo‐1‐(dimethylamino)naphthalen‐2‐yl)‐2‐chloro‐2,2‐difluoroethanone
Purification: silica gel chromatography (Petroleum ether 95/ Ethyl acetate 5) Appearance: Red oil. 1H NMR (CDCl3): δ= 2.97 (s, 3H7 + 3H8); 7.61 (ddd, J = 8.1, 7.1, 1.1 Hz, H3); 7.69 (ddd, J = 8.2, 7.1, 1.2 Hz, H2); 7.80 (s, H5); 8,20 (d, J= 8.4 Hz, H1); 8.27 (d, J = 8.5Hz; H4) +impurities. 19F NMR (CDCl3): δ= ‐61.80 +impurities. Yield: 96%.
4. Addition of nitrobenzyl chloride derivatives with TDAE
The nitrobenzyl chloride derivative (1 eq) and the 1,10‐phenanthroline‐5,6‐dione (3 eq) are added into a round‐bottom flask, under nitrogen at ‐20°C, in anhydrous DMF (8 mL). The solution was stirred and maintained at this temperature for 30min and then was added dropwise (via a syringe) the TDAE (1 eq). The coloration of the solution change immediately (from yellow to violet) and a precipitate is formed. The solution is stirred at ‐20°C for 1h and then warm up to 80°C and maintained at this temperature overnight. The brownish solution is then filtered, diluted with 50 mL of DCM and the organic solution washed with water (3 x 50 mL). The aqueous solution is extracted again with DCM and the combined organic phases dried over Na2SO4 and evaporate to dryness. The crude product thus obtained is recrystallizated from a DCM /cyclohexane mixture to remove most of the unreacted 1,10‐phenanthroline‐5,6‐dione.
2
3
4
1
5
N
Br
7 8
Br
FF
O
C14H11Br2F2NOMol. Wt.: 407,05
Synthesis of 6‐(2‐nitrobenzyl)‐6‐hydroxy‐1,10‐phenanthroline‐5‐one
Appearance: orange‐brown solid. 1H NMR (CDCl3): δ= 1.75 (large s, H6); 3.59 system AB (d, J= 13.50Hz, H5ou H5'), (d, J=13.50Hz, H5ou H5'); 6.86 (m, H8); 7.33 (dd, J=7.80, 4.50 Hz, H11); 7.40 (m, H2+H4); 7.52 (dd, J=7.50, 4.80 Hz, H3); 7.75 (dd, J=7.80, 1.50 Hz, H7); 7.86 (m, H1); 8.28 (dd, J=7.80, 1.80 Hz, H12); 8.83 (dd, J=4.50, 1.50 Hz, H9); 9.08 (dd, J=4.80, 1.80 Hz, H10) +impurities. Yield: 77%
Mass: (ESI) mz= 370 (M‐Na+)
Synthesis of 6‐(4‐chloro‐2‐nitrobenzyl)‐6‐hydroxy‐1,10‐phenanthroline‐5‐one
Appearance: brownish oil. 1H NMR (CDCl3): δ= 1.63 (large s, H6); 3.50 system AB (d, J= 13.81Hz, H5ou H5'), (d, J=13.51Hz, H5ou H5'); 6.86 (d, J=8.40Hz, H8); 7.38 (m, H11+H4); 7.52 (dd, J=7.80, 4.50Hz, H3); 7.76 (dd, J=8.10, 1.50Hz, H7); 7.88 (d, J=2.10Hz, H1); 8.28 (dd, J=7.80, 1.80Hz, H12); 8.85 (dd, J= 4.50, 1.50Hz, H9); 9.12 (dd, J= 3.00, 1.50Hz, H10) +impurities. Yield: 25%
Mass: (CI) mz= 381,9 (M‐H+)
Synthesis of 6‐hydroxy‐6‐((6‐nitrobenzo[d][1,3]dioxol‐5‐yl)methyl)‐1,10‐phenanthroline‐5‐one
Appearance: light brown solid. NMR 1H (CDCl3): δ= 1.65 (large s, H6); 3.55 system AB (d, J= 13.81Hz, H5ou H5'), (d, J=13.81Hz, H5ou H5'); 6.09 (s, H2+H3); 6.39 (s, H4); 7.39 (s, H1); 7.40 (dd, J=7.80, 4.80Hz, H3); 7.51 (dd, J=7.80, 4.50Hz, H8); 7.90 (dd, J= 7.80, 1.50Hz, H7); 8.26 (dd, J=7.80, 1.80Hz, H12); 8.85 (dd, J= 4.50, 1.50Hz, H9); 9.09 (dd, J= 4.50, 1.80Hz, H10) +impurities. Yield: 53% Mass: (CI) mz= 391,9 (M‐H+)
4
1
5+5'
NO2
N
1011
12
78
9
N
O
HO6
O
O
2+3
C20H13N3O6Mol. Wt.: 391,33
34
1
5+5'
NO2
N
1011
12
78
9
N
O
HO6
Cl
C19H12ClN3O4Mol. Wt.: 381,77
2
34
1
5+5'
NO2
N
1011
12
78
9
N
O
HO6
C19H13N3O4Mol. Wt.: 347,32
5. Other addition with TDAE
a. Addition on 1,10‐phenanthroline‐5,6‐dione
Synthesis of 6‐(2‐(4‐bromo‐1‐(dimethylamino)naphthalen‐2‐yl)‐1,1‐difluoro‐2‐oxoethyl)‐6‐hydroxy‐1,10‐phenanthrolin‐5(6H)‐one
N
Br
X
F F
O
+
N
N
O
O
TDAE, DMF, N2N
Br
ON
N
O
OHFF
X= Br, Cl
The 2‐bromo/chloro‐1‐(4‐bromo‐1‐(dimethylamino)naphthalen‐2‐yl)‐2,2‐difluoroethanone (1 eq) and the 1,10‐phenanthroline‐5,6‐dione (1 eq) are added into a round‐bottom flask, under nitrogen at ‐20°C, in anhydrous DMF. The solution was stirred and maintained at this temperature for 30min and then was added dropwise (via a syringe) the TDAE (1 eq). The coloration of the solution change immediately and a precipitate is formed. The solution is stirred at ‐20°C for 1h and then warm up to room temperature during 3h. The brownish solution is then filtered, diluted with 50mL of DCM and the organic solution washed with water (3 x 50 mL). The aqueous solution is washed with DCM and the combined organic phases dried over Na2SO4 and evaporate to dryness. The crude product thus obtained is recrystallized from a DCM /cyclohexane mixture to remove most of the unreacted 1,10‐phenanthroline‐5,6‐dione.
Appearance: brownish oil. 19F NMR (CDCl3): δ= ‐81.05 (dd, J=148.47, 4.50Hz, F16); ‐90.52 (d, J= 148.61Hz, F15) +impurities. Mass: (ESI) mz= 538,0 (M‐H+)
2
34
1N
Br
13 14
ON
1011
12
78
9
N
O
OH5 F
16F
15
C26H18BrF2N3O3Mol. Wt.: 538,34
6
b. Addition on 4‐fluorobenzaldehyde
Synthesis of 1‐(4‐bromo‐1‐(dimethylamino)naphthalen‐2‐yl)‐2,2‐difluoro‐3‐(4‐fluorophenyl)‐3‐hydroxypropan‐1‐one
N O
Br
F
Cl
F
H O
F
+
N O
Br
FF
OH
F
TDAE
Into a three‐necked flask, under nitrogen, is added under nitrogen anhydrous DMF (4 mL) and then 1‐(4‐bromo‐1‐(dimethylamino)naphthalen‐2‐yl)‐2‐chloro‐2,2‐difluoroethanone (340 mg, 0.94 mmol, 1 eq) follow by 4‐fluorobenzaldehyde (582 mg, 4.69 mmol, 5 eq). The solution is cooled down to ‐20°C, stirred and maintained at this temperature for 30min and then is added dropwise (via a syringe) TDAE (187.8 mg, 0.94 mmol, 1 eq). A red colour is developed with the formation of a white fine precipitate. The solution is vigorously stirred at ‐20°C for 1h and then warm up to room temperature overnight. The orange‐red turbid solution was filtered and diluted with EtOAc (30 mL) then wash with an aqueous NaCl solution (3 x 30 mL). The aqueous solution is extracted with EtOAc (3 x 30 mL), the combined organic solutions dried over Na2SO4. The solvent is removed by evaporation.
Appearance: brownish oil. 1H NMR (CDCl3): δ= 1.56(s, H11); 2.90 (s, H12+H13); 5.44 (dd, J= 17.71, 6.60Hz, H10); 7.11 (m,H7+H8);7.48(s, H5); 7.50 (m,H9+H6); 7.62(m,H2+H3);8.21 (m,H1+H4) +impurities. 19F NMR (CDCl3): δ = ‐108.22 (dd, J=269.87, 6.77Hz, F15 or F14); ‐113.02 (m, F16); ‐119.32 (dd, J = 269.87, 17.20Hz, F14 or F15) +impurities.
Synthesis of 1‐(4‐fluorophenyl)‐2‐(4‐nitrophenyl)ethanol
H O
F
NO2
Cl
+
O2N
F
OH
Into a two‐necked flask is added, under nitrogen at ‐20°C, anhydrous DMF solution (7 mL) of p‐nitrobenzyl chloride (100 mg, 0.58 mmol, 1 eq) and p‐fluorobenzaldehyde (0.19 mL, 1.75 mmol, 3 eq). The solution is stirred and maintained at ‐20°C for 30min and then is added dropwise (via a syringe the TDAE (0.14 mL, 0.58 mmol, 1 eq). A red colour is developed with the formation of a fine precipitate. The solution is vigorously stirred at ‐20°C for 1h and then warm up to the room temperature for 2h. The orange‐red turbid solution was filtered and hydrolysed with 80mL of water. The aqueous solution is extracted with toluene (3 x 40 mL).
2
34
1
5
N12 13
O
Br
F
10
F
OH11
67
89
F
C21H17BrF3NO2Mol. Wt.: 452,26
14 1516
The combined organic layers wash with water (3 x 40 mL) and dried over Na2SO4. The solvents are removed by evaporation. The orange viscous liquid is triturated several times with hot cyclohexane (to remove most of the unreacted aldehyde) and decanted to left an orange solid.
Appearance: orange‐brown solid 1H NMR (CDCl3): δ= 9.09 (dd, J= 4.50, 1.80Hz, H10). 19F NMR
c. Addition on 2‐bromobenzaldehyde
NO2
Cl
H O
Br
O2N
Br
OH+ TDAE
Into a two‐necked flask is added, under nitrogen at ‐20°C, anhydrous DMF solution (6 mL) of p‐nitrobenzyl chloride (100 mg, 0.58 mmol, 1 eq) and o‐chlorobenzaldehyde (0.20 mL, 1.75 mmol, 3 eq). The solution is stirred and maintained at ‐20°C for 30min and then is added dropwise (via a syringe the TDAE (0.14 mL, 0.58 mmol, 1eq). A red colour is developed with the formation of a fine precipitate. The solution is vigorously stirred at ‐20°C for 1h and then warm up to the room temperature for 1h30. The orange‐red turbid solution is filtered and hydrolysed with 80mL of water. The aqueous solution is extracted with toluene (3 x 40mL). The combined organic layers washed with water (3 x 40mL) and dried over Na2SO4.
Appearance: yellow solid 1H NMR (CDCl3): δ= 2.87 (dd, J= 13.51, 8.70Hz, H5); 3.14 (dd, J= 13.81, 3.30Hz, H5); 5.24 (dd, J= 8.70, 3.30Hz, H6) +impurities. 19F NMR
2
34
1
O2N
5+5' 68
9
1011 F
OH7
C14H12FNO3Mol. Wt.: 261,25
2
34
1
O2N
5+5'6
89
1011
Br
OH7
C14H12BrNO3Mol. Wt.: 322,15
6. Cyclization Into a round‐bottom flask, add the 6‐(2‐nitrobenzyl)‐6‐hydroxy‐1,10‐phenanthroline‐5‐one (173.3 mg; 0.5 mmol, 1 eq) into methanol (4 mL). Warm up at reflux for 3h. After cooling down, the solvents were removed by evaporation.
Appearance: red‐brown solid. 1H NMR (DMSO):δ= 9.09 (dd, J=4.50, 1.80Hz, H10). 2
34
1
5
N N
1011
12
78
9
N
C19H11N3Mol. Wt.: 281,31
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11. Unprecedented SnCl2.2H2O‐mediated intramolecular cyclization of nitroarenes via C‐N bond formation: a new entry to the synthesis of cryptotackieine and related skeletons; Tetrahedron Letters, 2008, 49, 7062‐7065 ; Sunil Sharma, Bijoy Kundu.