My sincere regards to all the lecturers of the Department of Chemistry for their motivation and encouragement. Reddy, Kiran, Paramartha, Kotipalli, Shibananda, Deepti, Sabera and Priya for their help, timely support and creating a pleasant atmosphere in the laboratory.
General Approaches for the Synthesis of Tetrahydro-pyrans, -thiopyrans and -quinolines
- The Prins Cyclization
- Mechanism of the Prins Reaction
- Stereoselectivity in Prins Cyclization
- Scope of the Prins Reaction
- Cyclization Involving Electron-rich Double Bonds
- Thia-Prins Cyclizations
- Aza-Prins Cyclizations
Recently, the cyclization of thia-Prins received considerable attention and showed significant progress in the synthesis of tetrahydrothiopyrans. 2-Alkyl substituted piperdines 89 were synthesized by reaction of epoxides 88 with homoallylamines in the presence of BiCl3.
Ene Reaction
- Intermolecular Carbonyl-ene Reaction
- Intramolecular Carbonyl-ene Reaction
- Intramolecular Oxonium-ene Reactions
- Intramolecular Imino-ene Reaction
- Intramolecular Thionium-ene Reaction
Tietze and co-workers have applied the intramolecular imino-ene reaction to the synthesis of unnatural derivatives of non-proteinogenic α-amino acids. There are no reports in the literature on the synthesis of tetrahydrothiopyrans via the thionium-ene reaction.
Conclusion
Stereoselective Synthesis of 4-Fluorotetrahydropyran
Importance and Applications of Organofluorine Compounds
On the other hand, the carbon-fluorine bond is very strong (485 KJ mol-1, compared to C-H, 416 KJ mol-1), so they are more resistant to metabolic degradation. One is by electrophilic fluorination with reagents capable of transferring the F+ ion to an electron-rich site.
Electrophilic Fluorination
Great progress in the field of electrophilic fluorinating reagents is achieved by the development of the N-F reagents. The choice of the counterion is important and must be non-nucleophilic for their stability.
Nucleophilic Fluorination
The Prins Cyclization Reaction in Fluorine Chemistry
Dicobalt-hexacarbonyl complexes 36 derived from propargyl acetals undergo Lewis acid-mediated Nicholas–Prins cyclization in the presence of homoallylic alcohols. Dobbs and co-workers described Prins cyclization involving 2-fluorobut-3-en-1-ol 40 in the presence of InCl3 with various aldehydes 41.
Present Work
Both aliphatic and aromatic aldehydes give good yields with a high degree of diastereoselectivity as determined from the 1H and 13C NMR spectrum of the raw table 2.5.1. To expand the scope of the reaction, we performed the reaction with acyclic and cyclic ketones (Scheme 2.5.2).
Experimental Section
- Instrumentation and Characterization
- Synthesis of substituted homoallyl alcohols 53n and 53p: The alcohols 53n and 53p were synthesized according to the literature procedures. Both the compounds are known
- General Procedure for the Synthesis of Compounds 54a-54q & 57a-57d
The solvent was removed under reduced pressure and the product was purified by column chromatography (silica gel) using ethyl acetate and hexane (EtOAc:hexane, 1:4) as eluent to give 278 mg (82%) of 1c as a colorless liquid. color.
Spectral Data
Selected Spectra of 4-fluorotetrahydropyrans
Crystal Parameters
Synthesis of Dihydro- and Tetrahydropyrans via Oxonium-ene Cyclization Reaction
Importance and Applications
Literature Methods for the Synthesis of Dihydro- and Tetrahydropyrans
Hinkle has reported a Bi(OTf)3-catalyzed cascade reaction involving rearrangement of epoxides 21 to aldehyde electrophiles, which then undergo cyclization with (Z)-δ-hydroxyalkenylsilane 20 via intramolecular silyl-modified Sakurai reaction (ISMS) to form 2 .6 to be delivered. - disubstituted 3,6-dihydro-2H-pyrans 22 in moderate yields (Scheme 3.2.4).11. More recently, Saikia and co-workers developed an efficient method for the synthesis of 4-aryldihydropyrans 34 from carbonyl compounds 32, homopropargyl alcohols, and arenes mediated by boron trifluoride etherate via the Prins–Friedal–Crafts reaction (Scheme 3.2.8). Some procedures in the literature for the preparation of tetrahydropyrans with an exomethylene double bond.
The second step, trimethylsilyl triflate, promoted annulation of the allylsilane with another aldehyde 40 to give cis-2,6-tetrahydropyran 41 containing an exo-methylene at the 4-position. Rychnovsky has developed the tandem Mukaiyama aldol-Prins (MAP) cyclization reaction using allylsilane derivatives and aldehydes for the synthesis of 4-methylenetetrahydropyrans (scheme The cascade reaction involves the Mukaiyama aldol condensation of an aldehyde 43. Minehan and co-workers developed an environmentally friendly method for the environmentally friendly synthesis of cis -2,6-disubstituted-4-methylenetetrahydropyran systems through a two-step one-pot process (scheme in which allylation of aldehyde 47 occurs with silyl-substituted allyl iodide 46 in the presence of indium metal to form substituted homoallyl alcohol 48, followed by annulation of homoallyl alcohol with another aldehyde 49 to give cis-2,6-disubstituted-4-methylenetetrahydropyran 50.
Hoveyda and colleagues reported a highly stereoselective method for the synthesis of cis-2,6-disubstituted-4-methylenetetrahydropyrans using a Brønsted acid-catalyzed reaction of.
Present Work
The scope of the reaction was investigated using different types of aldehydes and alcohols (Table 3.3.2) and it was observed that the reaction of aromatic aldehydes 59a–g with methyl substituted alcohol 60a–g gave endocyclic compounds 61a–g as the major product with a smaller exocyclic product 63a–g , whereas the aliphatic aldehydes (entries 59h, i ) gave two isomeric endocyclic products with ratios of 75:25 and 80:20, respectively. The structure of the compounds was determined by NMR and X-ray analysis (Figure 3.3.1) and comparison with authentic samples.15. However, in the case of two endocyclic isomeric mixtures, the major isomer could not be separated from its minor isomer.
The formation of two isomeric endocyclic compounds in the case of aliphatic aldehydes is further confirmed by hydrogenation with hydrogen on palladium carbon. The formation of mainly endocyclic compounds instead of the exocyclic compounds is due to the higher stability of the endocyclic compounds compared to the exocyclic compounds, as shown by Gil-Av and Shabtai24, as well as by Turner and Garner.25 - disubstituted exocyclic products in the case of alcohols 60p-v can be attributed to the presence of two substituents at positions 2 and 6, which makes them more stable. The structure and stereochemistry of the major isomer were determined by single crystal X-ray analysis (Figure 3.3.4).26.
The formation of axial isomer as the main product can be explained from the reaction mechanism (scheme 3.3.6).
Experimental Section
- Instrumentation and Characterization
- Synthesis of Substituted Homoallylic Alcohols 60l, 60p , and 60t: The alcohols 60l, 60p, and 60t were synthesized according to the literature procedure 27 and the
- General procedure for the Synthesis of 3,6-Dihydropyrans and 4- Methylene tetrahydropyrans: To a stirring solution of aldehyde (1.0 equiv) and boron
- Separation of Alkene Regio-isomeric Mixture by Using Preparative TLC Impregnated with AgNO 3 : A slurry was prepared from 60 g of TLC silica gel
- Procedure for the Hydrogenation of Dihydropyrans 61i and 62i
- General Procedure for the Synthesis of 4-Amidotetrahydropyrans 74 and 75: To a mixture of aldehyde (1.0 equiv), nitrile (2.0 equiv) and boron trifluoride etherate
This was purified by either column chromatography or preparative TLC impregnated with silver nitrate to afford the title compounds. After the reaction was complete, the reaction mixture was quenched with saturated sodium bicarbonate solution. This was purified by preparative TLC impregnated with silver nitrate to give 4-methyl-2-phenyl-3,6-dihydro-2H pyran (136 mg, 78%) as an oily liquid.
The reaction mixture was filtered using celite pad and the filtrate was concentrated to leave the crude product. This was further purified by column chromatography to afford the tetrahydropyrans 64a and 64b (161mg, 85%) as an oily liquid. General procedure for the synthesis of 4-Amidotetrahydropyrans 74 and 75: To a mixture of aldehyde (1.0 equiv.), nitrile (2.0 equiv.) and boron trifluoride etherate and 75: To a mixture of aldehyde (1.0 equiv.), nitrile (2.0 equiv.)0. and boron trifluoride etherate (1.0 eq.) in benzene (2 mL) at room temperature homoallyl alcohol (1.1 eq.) in benzene (2 mL) was added dropwise over 5 min.
The organic layer was dried over Na 2 SO 4 and evaporated to leave the crude product.
Spectral Data
Selected Spectra of Dihydro- and Tettrahydropyrans
Crystal Parameters
Stereoselective Synthesis of Substituted Tetrahydrothiopyrans
- Importance and Applications of Tetrahydrothiopyrans
- An Overview of Relevant Synthetic Methods
- Present Work
- Experimental section
- Instrumentation and Characterization
- General procedure for the synthesis of Tetrahydrothiopyrans 18a-18r
On this account, the well-known compound 6-methylhept-5-en-2-thiol was prepared from readily available 6-methylhept-5-en-2-ol in good yield by literature procedures (Scheme 4.3.2),12 which is was used as a model substrate to optimize the reaction conditions. Thus, reaction of 6-methylhept-5-ene-2-thiol 17a with benzaldehyde 16a in the presence of boron trifluoride etherate in toluene afforded 3-isopropenyl-6-methyl-2-phenyl-tetrahydrothiopyran 18a in 86% yield. with good diastereoselectivity. The reaction was found to be good for both electron-withdrawing and electron-donating groups on the aromatic ring of aromatic aldehydes.
The reaction is diastereoselective as determined from the 1H and 13C NMR spectrum of the crude product and in all cases the substituents at 2 and 3 are trans, while substituents at 2 and 6 are in cis position. It is clear from the above two results that the reaction proceeds in a stepwise manner via carbocation intermediate, but not in a concerted manner. The structure of 18m was confirmed by X-ray crystallographic analysis.13 The reaction is very fast and within 30 min all the starting material is consumed to give the products.
The reaction mixture was extracted with ethyl acetate and then washed with brine and water.
Synthesis of 3-isopropenyl-6-methyl-2-phenyl-tetrahydrothiopyran
- References and Notes
- Spectral Data
- Selected Spectra of Tetrahydrothiopyrans
- Crystal Parameters
Hetero Diels-Alder methodology in organic synthesis. Crystallographic data for compounds 18b and 18m have been deposited with the Cambridge Crystallographic Data Center as Supplementary Publication no.
Stereoselective Synthesis of 2,3-Disubstituted Tetrahydroquinolines
Structure and Nomenclature
Importance and Application of Tetrahydroquinolines
Relevant Methods for the Synthesis of Tetrahydoquinolines
Hong and co-workers have developed a SnCl4-promoted N-acylinium ion-mediated cyclization for the synthesis of pyrroloquinoline derivatives. This protocol allowed the synthesis of a large number of simple and fused tetrahydroquinolines based on the nature of the substituents on the nitrogen atom (Scheme 5.3.4).10. Batey and co-workers demonstrated a facile method for the synthesis of tetrahydroquinolines using the BF3.Et2O catalyzed aza-Diels-Alder reaction.
A three-component reaction between arylamines 26, arylaldehydes 27 and norbornene 28 in the presence of 20 mol% BF3.Et2O in dichloromethane afforded the corresponding tetrahydroquinoline derivatives 29 in moderate yields with good diastereoselectivity (Scheme 5.3.5).11. The reaction between arylamines and enol ethers in the presence of a catalytic amount of CAN (5 mol%) afforded tetrahydroquinoline derivatives in moderate to good yields. The reaction between 6-bromopiperonal 35, arylamine 36 and cyclopentadiene 37 in the presence of 10 mol % Sc(OTf)3 in acetonitrile gave tetrahydroquinoline 38 (G-15) in almost quantitative yield with a diastereomeric ratio of 94:6 (Scheme 5.3.7). 13.
The reaction was completely diastereoselective and provided exclusively the cis-fused isomers 42 in excellent yields (Scheme 5.3.8).14.
Present Work
Therefore, it is noteworthy to mention that temperature has a significant influence on the diastereoselectivity of the reaction. Once the optimized reaction conditions were established, the scope of the reaction was then investigated using a wide variety of methods. In the case of aromatic aldehydes, substitution on the aromatic ring has a significant effect on the yield of the reaction.
This is believed to be the instability of the N-arylaldimine 59 formed during the reaction. The stereochemistry of the 2,3-disubstituted tetrahydroquinolines was determined by COZY experiments and 1H NMR coupling constant values. The coupling constants of H-2 and H-3 protons of the main isomer are in the range of 2.8–4.0 Hz, indicating the cis relationship of the substitutions.
Furthermore, the cis geometry of the substitution was unambiguously confirmed by X-ray diffraction analysis of single crystals of compound (56e), as shown in (Figure 5.4.1).16.
Experimental Section
- Instrumentation and Characterization
- General Procedure for the Alkylation of Bromonitrobenzene: An oven- dried round-bottomed flask equipped with a magnetic stir bar, rubber septum under a nitrogen
- General Procedure for the Synthesis of Tetrahydroquinolines 56a-56j
After the addition was complete, stirring was continued for 20 min at 0 °C, the resulting solution was diluted to 50 mL with dry THF under nitrogen and the solution cooled to -78 °C (ethanol/liquid N2). The combined ethereal fractions were dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (SiO2, hexanes:ethyl acetate), which afforded 1-(3-methylbut-2-en-1-yl)-2-nitrobenzene 58 as a brown oil (62%).
After completion of the reaction (monitored by TLC), the reaction mixture is filtered through celite. The organic layer was evaporated and the residue was dissolved in ether and washed with brine to remove ammonium formate. An oven-dried round-bottom flask was charged with aldehyde (1.0 equiv) and dichloromethane (2 mL), and the resulting solution was cooled to −20 °C.
After being stirred at room temperature for 1 h, the mixture was poured into saturated NaHCO 3 (5 mL).
Spectral Data
Selected Spectra of Tetrahydroquinolines
Crystal Parameters
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