The synthesis of aromatics via a 6π-electrocyclic ring closure process

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MC participates in [6+4] cycloaddition

In this context, Ebine’s group reported a one-step synthesis of Azulenes L-105 from 6-aminofulvenes L-103 with MC via [6+4] cycloaddition (Scheme 38). 6- dimethylaminofulvene and MC were dissolved in benzene and stirred for five days in dark at room temperature proceeding successfully to give azulenes by one-step in 17% yield.55.

MC via 1,6 Michael addition reactions

MC has also been employed as a starting material for the synthesis of conjugated α-Z/γ-Z or α-Z/γ-E dienoic acids with high regio- and stereoselectivity. The ester present in 5-position of MC assisted the regioselective 1, 6 addition leading to the 2H-pyran intermediate L-106, after a 6-p electrocyclic process give the dienoic carboxylate L-107. The stereochemical outcomes can be explained by a thermodynamic control sheltering the kinetic products. Our group has reported a one-pot sequential reaction with double alkyl-alkyl 1,6 addition on MC (Scheme 40). The methodology provides a facile access towards β,γ-unsaturated carboxylic acids in a highly regio-, and stereo-selectivity. We explained the key role of the Grignard reagent for the stereoselectivity outcome by proposing a constrained chair-like transition state stablized with bimetallic intermediate. This metal-catalyzed double 1, 6 addition of two Grignard reagents (homo-coupling, 2 RMgX or hetero-coupling, R1MgX+R2MgX) afforded β,γ-unsaturated carboxylic acids A-3 or A-4 in good yields and good to excellent stereoselectivities.57 This part will be detail in the next chapter.
During this Phd thesis we also reported the reaction of MC with various methylene active keto-esters, cyclic or acyclic diketones and keto-sulfones, giving more than thirty 2,3,5,6-tetrasubstituted 2H-pyrans P-1 or P-2 in good to excellent yields. This reaction trigged by 1,6 Michael addition is followed by both 6π- electrocyclic ring opening and 6π electrocyclic ring-closing. In addition, this methodology could take advantage of the readily available starting materials, mild conditions and tolerate a variety of functional groups (Scheme 41).58 This part will be the subject of the chapter 3.

One-pot sequential double 1,6- addition of one same Grignard reagent

First, we investigated the conjugate addition of 4 equiv. Grignard reagents in the presence of TMSCl in THF at 0 oC (Table 1, entries 3, 6, and Table 3 entry 5). Interestingly, under these conditions, methyl Grignard reagent did not give the expected product A-3 when sterically hindered nucleophiles such as i-PrMgBr or t-BuMgCl were used, the reaction stopped after the first addition.9 These first results indicate that in the absence of a catalyst, bulky Grignard reagents do not add to the putative 2,4-dienic magnesium carboxylate. On the other hand, double addition of EtMgBr, n-BuMgBr and PhMgBr at the 6-position of methyl coumalate occurred, giving the expected β,γ unsaturated carboxylic acids A-3b, A-3c, and A-3f in 30, 92, and 90% yields, respectively, with E/Z ratios close to 80/ 20. Assignment of the configuration of the β,γ-double bond in (Z)- A-3b and (E)-
A-3b, A-3c was achieved by NOESY experiments (strong correlation between Ha and Hd in the E isomers). It is noteworthy that in all 1H NMR spectra, proton Hb of (E)-3 was deshielded at around 7 ppm versus 6 ppm for (Z)-3 (Figure 1).

One-pot sequential double 1,6- addition of two different Grignard reagents

Next we examined the outcome of the copper-catalyzed one-pot reaction by using successively two different Grignard reagents (Table 3). We focused our attention on the use of Cu(OTf)2, as we initially observed lower yields with Fe(acac)3 (vide supra, Table 1). Due to obvious chemoselectivity issues, one equivalent of the first Grignard reagent was added before addition of catalyst (in order to ensure efficient formation of the mono-adduct and to avoid formation of the homo-coupling adduct. The new conditions were as follows: 1.1 equiv. of the first Grignard reagent was added without catalyst, then 5 mol% of Cu(OTf)2 , followed by addition of 4 equiv. of the second Grignard reagent. The data in Table 4 illustrate the scope and limitations of the hetero-coupling method.

Proposed mechanism for stereoselective 1,6-double addition

We proposed a mechanism for this transformation, the stereo-results of the process gave us some clues.14 It is worth to notice, we should take into account the difference of stereo outcome observed between the reactions with or without metal catalysis (Table 1). Furthermore, the occurrence of a thermodynamic equilibrium between the stereoisomers during acid treatment of the reactions was ruled out. Indeed, even when the reaction mixture was hydrolyzed overnight (entry 6 in Table 3) with 1M HCl or when the reaction was quenched with higher concentrations of aqueous HCl, no change of the stereoisomeric ratio was observed (E/ Z=97/3). We propose the involvement of a highly chelated transition state A-iii in the second step of the reaction (Scheme 8). As previously demonstrated,9 addition of the first Grignard reagent gives intermediate A-ii resulting in complex C by reaction with the organocopper complex (R2CuOTf). Addition of the second Grignard reagent leads to a chair-like bicyclic transition state A-iii locking the overall stereoselectivity.

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The synthesis of aromatics via a 6π-electrocyclic ring closure process

Anderson and co-workers developed a cascade cyclization of ynamides to azabicycles (Scheme 7).17 The process begin with ynamide carbopalladation / Stille or vinylic Suzuki cross-coupling reactions to form the trienic intermediate FL-17. The 6-π electrocyclization produces the corresponding cyclohexadiene FL-18. The final nitrogen-containing bicyclic derivatives FL-19, which are important scaffolds for many natural products and drugs, could be obtained after a selective oxidation of aminodienes FL-18.

Our hypothesis from MC to CF3 benzene

However, among these processes, the aromatization step often required extra oxidizers. Furthermore, 6π-electrocyclization aromatization reactions for polyfunctionalized benzenes remain challenging.19 To the best of our knowledge, the synthesis of trifluoromethylated benzene via 6π-electrocyclization reaction has not been reported in previous literature. Thus, considering the pharmacokinetic and pharmaceutical values of CF3-functionalized compounds we launched a program in devising an environmentally friendly synthetic method for the preparation of trifluoromethylated benzenes. In order to reach the key intermediate CF3-hexatriene (Scheme 10), MC was selected as an electrophilic pro-diene synthon. This choice was initially based on our recent finding that MC can be readily converted to diene in the presence of certain nucleophiles.20

Table of contents :

List of Abbreviations
Chapter 1 Introduction:Methyl Coumalate
1.1 Introduction
1.2 Preparation of Methyl Coumalate
1.3 MC involved [4+2] Diels-Alder reaction
1.3.1 MC as dienes in Diels-Alder reactions
1.3.2. MC as Dienes to form Aromatics
1.3.3 MC as dienophile in Diels-Alder reactions
1.4. MC participates in [2+2] cycloadditions
1.5. MC reacts with 1,3 dipoles
1.6. Preparation of pyridin-2(1H)-one from MC
1.7. MC participates in [6+4] cycloaddition
1.8. MC via 1,6 Michael addition reactions
1.9. References
Chapter 2: β,γ -Unsaturated carboxylic acids by one-pot sequential double 1,6- addition of Grignard reagents onto methyl coumalate.
2.1. Introduction
2.2. One-pot sequential double 1,6- addition of one same Grignard reagent
2.3. One-pot sequential double 1,6- addition of two different Grignard reagents
2.4 The studies on other substituted α-pyrone substrates
2.5. Proposed mechanism for stereoselective 1,6-double addition
2.6. Conclusions
2.7. Experimental Section
2.8. References
Chapter 3. Preparation of Substituted 2H-Pyrans via a Cascade Reaction from Methyl Coumalate and Activated Methylene Nucleophiles.
3.1. Introduction of the project
3.2. Optimization of the reaction conditions for 2Hpyran synthesis
3.3. Substrate scope for preparation of 2H-pyran
3.4. Proposed unified mechanism
3.5. Conclusion
3.6. Experimental section
3.7. References
Chapter 4. A solvent-free, base-catalyzed domino reaction towards trifluoro methylated benzenes from bio-based methyl coumalate
4.1. Introduction
4.1.1. Cycloaddition towards trifluoromethylated benzenes
4.1.2. The synthesis of aromatics via a 6π-electrocyclic ring closure process
4.1.3. Our hypothesis from MC to CF3 benzene
4.2. Optimization of the Reaction Conditions
4.3. Application to a variety of trifluoromethyl benzenes
4.3.1 Gram scale synthesis of F-2b
4.4. Plausible mechanism for the cascade reaction leading to trifluoromethyl benzenes .
4.6. Experimental section
4.7. Notes and references
Chapter 5. Bio-based methyl coumalate involved Morita-Baylis-Hillman reaction
5.1. General introduction of Morita-Baylis-Hillman reaction
5.2. Methyl coumalate involved MBH reaction
5.2.1.Optimization of reaction condition
5.2.2. Synthesis of bio-based MBH adducts
5.2.3. Plausible mechanism for the novel MBH reaction
5.2.4. Synthesis of diphenylmethanol derivative from MBH adduct
5.3. The regioselective transformation of MBH adducts
5.3.1 General introduction
5.3.2. The study of regioselective substitution
5.3.3. The study of enantioselective synthesis of bicyclic products
5.3.4. The transformation to hydroisobenzofuran and hydroisoindole cores
5.4 Asymmetric Morita-Baylis-Hillman reaction with MC
5.4.1 Bibliographic introduction
5.4.2. MC involved Asymmetric Morita-Baylis-Hillman reaction
5.5. Conclusion
5.6. Experimental section
5.7. References
Chapter 6. A solvent-free, catalyst-free Michael addition dearomatization strategy: A sustainable protocol towards novel fluorescent dyes
6.1. General introduction
6.2. Self promoted Michael addition dearomatization protocol
6.3. Plausible mechanism for the dearomatization
6.4. Photophysical properties of D-2j and its application for protein labelling
6.5. Conclusion
6.6. Experimental part
6.7 References


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