Study on Alkenyl Fluorinated Building Blocks
Introduction
Due to the small radius of fluorine atom and its strongest electronegativity (4.0), the introduction of fluorine atom will change the polarity direction of C-F bond and the electron cloud distribution of the whole molecule, which will affect the dipole moment, acidity and basicity of the molecule, and then affect the physical and chemical properties of the whole molecule.
The introduction of fluorine atoms or fluorine-containing groups usually also increases the lipid solubility and hydrophobicity of molecules, improves the solubility of drug molecules, and promotes the conduction and absorption of drugs. Therefore, many fluorine-containing drugs or pesticides have relatively low dosage, low toxicity and high efficacy, which makes the proportion of fluorine-containing drugs or pesticides increasingly high.
Among the various fluorinated building blocks, alkenyl fluorinated building blocks are very important bioactive molecular structures with various pharmacological activities (e.g. anticancer, antibacterial, anti-HIV, antidiabetic) and can also be used as synthetic building blocks for the preparation of different fluorinated functional groups.
Figure 1. Bioactive alkene-based fluorinated building blocks
1. Histone deacetylase inhibitors -- anti-cancer
2.Dipeptidyl peptidase 4 inhibitors -- type 2 diabetes
3. HIV fusion inhibitor -- anti-HIV agent
4. Protein synthesis inhibitors -- antimicrobial agents
5. Retinoid X receptor regulator -- type 2 diabetes
6. Ribonucleotide reductase inhibitor -- anti-cancer
7. DNA gyrase inhibitor -- anti-bacterial agent
1.Olefination reactions
Triethyl 2-fluoro-2-phosphonoacetate and fluoromethyl phenyl sulfone are the more classical monofluorinated blocks.
Triethyl 2-fluoro-2-phosphonoacetate is usually synthesized from triethyl phosphonoacetate by fluorination with electrophilic fluorination reagents, which can be used with aldehydes and ketones in the presence of bases to yield α-fluoro-α,β-unsaturated carboxylic acid esters via the phosphinolide intermediate . Among them, the aldehyde carbonyl reaction activity is higher than the ketone carbonyl reaction activity, and also has a better cis-trans selectivity. (Scheme 1)
Scheme 1. 2-Fluoro-2-phosphonoacetic acid triethyl ester as fluorinated building blocks
In 1994, Patrick's group reported glyceraldehyde and 2-fluoro-2-phosphonoacetic acid triethyl ester in the presence of butyllithium as a single product of formula E[1]. (Scheme 2)
Scheme 2. Triethyl 2-fluoro-2-phosphonoacetate as fluorinated building blocks
Gernert's group also used triethyl 2-fluoro-2-phosphonoacetate in 2003 to synthesize fluorinated products by reacting with ketocarbonyl compounds, but the products were non-cis-trans-selective[2]. (Scheme 3)
Scheme 3. Synthesis of fluorinated olefins using fluorinated building blocks of triethyl 2-fluoro-2-phosphonoacetate
The fluoromethyl phenyl sulfone mentioned above has also been frequently used as a fluorinated block in recent years. In 1985, McCarthy's group studied the preparation method, reaction properties and reaction mechanism as early as 1985. Fluoromethyl phenyl sulfone first reacts with butyl lithium to form the lithium salt intermediate of fluoromethyl phenyl sulfone, which then reacts directly with aromatic aldehydes to give the corresponding α-fluoro-β-hydroxysulfone compound. This compound is then subjected to the removal of the sulfone group in order to form monofluorinated terminal olefins[3-5]. (Scheme 4)
Scheme 4. Fluoromethyl phenyl sulfone as fluorinated building blocks
2.Elimination reactions
Elimination reactions are commonly used to prepare α-substituted α-fluoro-olefins. To convert terminal olefins to their fluorinated equivalents, halogenation reactions and elimination reactions are widely used[6].(Scheme 5)
This elimination process is usually considered as a competing process for the SN2 reaction, especially when a strong base is present. It can occur with primary, secondary and tertiary substrates. Unless a specific non-nucleophilic amine base is used, primary substrates in the presence of a strong base will usually only produce substitution.
Elimination is easy with secondary and tertiary substrates having strong bases and amine bases. Elimination is secondary and depends on the substrate and base concentration. The base needs to attack the β-hydrogen in a one-step process.
Most E2 reactions provide the most substituted olefin as the primary isomer, but conditions may be used that alter regioselectivity. The formation of more substituted olefins is called Saytzeff elimination. The regioselectivity of the reaction is strongly influenced by the nature of the base. Large tert-butanol bases are too large to attack the internal CH2 group and thus the CH3 group. Methanol is smaller than tert-butanol and attacks the CH2 group more, but the main product is still the 1-olefin.
Almost all elimination reactions produce a mixture of olefins, rather than a clean product. The reactions are determined by the stability (and transition state) of the products, so there is little difference in the stability of the olefins. Olefins with high substitution are more stable than those with low substitution, but the energy difference is small.
In addition, when E and Z olefin isomers may be present, the major isomer is the E isomer, but the Z isomer is usually present to some extent.
3. Cross-coupling reactions
In the field of metal-catalyzed cross-coupling, the Heck reaction is a very convenient method for the aromatization of olefins. In most cases, the hydrogen atom of the vinyl group is substituted by the organic residue of the organohalide. When asymmetrically substituted olefins are used, the high regioselectivity determined by spatial site resistance leads to olefin arylation at fewer substitution sites. One of the key steps of the reaction is β-hydride elimination.
In 1991, Heitz and Knebelkamp attempted to synthesize β,β-difluorostyrene from aryl iodides and vinylidene difluoride. In the presence of palladium acetate catalysis, β,β-difluorostyrene should be the only reaction product if β-hydride elimination is a necessary reaction step. And β,β-difluorostyrene was formed only as a by-product in these reactions. For the first time, a one-step reaction was found to react aryl iodides with 1,1-difluoroethylene to obtain α-fluoroethylene derivatives under Pd(OAc)2-catalyzed conditions[7]. (Scheme 6)
4. Electrophilic fluorination
Pacheco and Gouverneur investigated the reactivity of allylmethylsilane under Selectfluors reaction conditions for the preparation of fluorodiene fears by electrophilic fluoride desilylation reaction without the use of fluorinated building blocks[8]. (Scheme 7)
Among them, Selectfluor fluorination reagent (N-fluoro-N'-(chloromethyl)triethylenediamine bis(tetrafluoroborate) or F-TEDA) is a user-friendly, mild, stable in air and moisture conditions, non-volatile electrophilic fluorination reactant. Selectfluor fluorination reagent is capable of introducing fluorine into organic substrates in a single step with a very wide range of reactions[9]. The vast majority of these reactions exhibit excellent regioselectivity.
Allyl fluorides can be prepared by the cross-recombination reaction/electrophilic fluoride desilylation route (Scheme 8). This route avoids the formation of by-products resulting from allyl translocation when nucleophilic substitution or ring opening reactions are performed using DAST[10].
Applications
Fluorinated blocks have been widely used in various chemical fields such as pharmaceuticals, pesticides, dyes, surfactants, fluorocarbon materials, and aerospace.
Among them, alkenyl fluorinated blocks have potential applications in materials science and synthetic organic chemistry, and can be used as fluorinated synthons for further functionalization. In addition, fluorinated alkenyl groups can be used as peptide bond isozymes in medicinal chemistry, which opens up new opportunities for the search of new bioactive compounds.
Reference
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3. McCarthy, J. R.; Peet, N. P.; LeTourneau, M. E.; Inbasekaran, M., J. Am. Chem. Soc.1985,107, 735.
4. McCarthy, J. R.; Peet, N. P.; LeTourneau, M. E.; Inbasekaran, M., J. Am. Chem. Soc.1985,107, 735.
5. McCarthy, J. R.; Huber, E. W.; Le, T.-B.; Mark Laskovics, F.; Matthews, D. P., Tetrahedron 1996,52, 45.
6. Takeuchi Yoshio,Yamada Asuka,Suzuki Takanori,Koizumi Toru. Synthetic studies towards proline amide isosteres, potentially useful molecules for biological investigations[J]. Tetrahedron,1996,52(1).
7. Walter Heitz,Arno Knebelkamp. Synthesis of fluorostyrenes via palladium‐catalyzed reactions of aromatic halides with fluoroolefins[J]. Macromolecular Rapid Communications,1991,12(2).
8. Furuya Takeru,Ritter Tobias. Fluorination of boronic acids mediated by silver(I) triflate.[J]. Organic letters,2009,11(13).
9. Singh, R. P. , Shreeve, J. M.. 2004. For a review of recent highlights: Acc. Chem. Res..37, 31.
10. Thibaudeau S, Gouverneur V. 2003. Sequential Cross-Metathesis/Electrophilic Fluorodesilylation:? A Novel Entry to Functionalized Allylic Fluorides. Org. Lett.. 5(25):4891-4893.