I hereby declare that the matter contained in this thesis entitled "Stereo Selective Synthesis of Substituted Dihydro- and Tetrahydropyrans" is the result of investigations carried out by me under the guidance of Dr. Anil K Saikia in the Department of Chemistry, Indian Institute of Technology Guwahati, India. I am sending his thesis entitled "Stereo Selective Synthesis of Substituted Dihydro- and Tetrahydropyrans" which is for the Ph. Science is submitted).
Synthetic Applications of MCRs
The first MCR involving isocyanides was discovered in 1921 by Passerini.8a. The reaction of carboxylic acids (12), carbonyl compounds (13) and isocyanides (14) gave α-acyloxycarboxamides (15) in a one-pot procedure (Scheme 1.1). 6).8b. 5 One of the most widely used multicomponent reactions was discovered in 1959 by Ugi et al.9a Synthesis of α-acylaminoamides (16) was achieved by reacting aldehydes, primary amines, carboxylic acids and isocyanides (Scheme 1.1.7).9b.
Dihydro- and Tetrahydropyans
Importance of Dihydro- and Tetrahydro-pyrans
Polycavernoside A24 31 (Figure 1.2.1) was isolated from the edible red alga PolycaVernosa tsudai as a toxin causing sudden intoxication in humans. by calcitonin receptor agonist.
Prins Cyclization
Prins Reaction Mechanism
There are many variations of the Prins reaction because it is easily prone to cyclization reactions and it is possible to capture the oxo-carbenium ion with a large array of nucleophiles. 10 and undergoes cyclization to form the tetrahydropyranyl carbocation (37b), is captured by various nucleophiles to form a diastereoselective tetrahydropyran derivative.
Tandem Sakurai-Prins Cyclization
- Synthesis of Symmetrical 4-Fluoro-tetrahydropyrans
- Synthesis of Symmetrical 4-Chloro-tetrahydropyrans
The tetrahydropyran (45) was prepared in a one-pot synthesis using optically active alkoxyallylsilane (42), acetaldehyde (43), and 3-(benzyloxy)propanal (44) as the aldehyde components and aluminum chloride as the Lewis acid in 65% yield. . (Scheme 1.3.5). Similarly, compound (56) was prepared from allyl bromide, propanaldehyde and styrene oxide in the presence of palladium catalyst and SnBr2 in 68% yield (Scheme.
Prins Cyclization Involving Homoallylic alcohol Derivatives
- Halo-Prins Cyclization
A stereoselective synthesis of 4-halotetrahydropyran (68) starting from aldehydes and homoallylic alcohols in the presence of AlCl3 or AlBr3 is reported (Scheme 1.3.17).49. The formal synthesis of (+)-SCH 351448 was accomplished by Loh and co-workers with the condensation of two complex fragments, compound (116) and aldehyde (117), using catalytic Prins cyclization (Scheme 1.3.29). 72.
Mukaiyama Aldol−Prins Cyclizations
The key step in the synthesis of (142), reported by Rychnovsky83, was the stereoselective condensation of the aldehyde (140) with homoallyl vinyl ether (141) in the presence of titanium tetetrabromide (Scheme 1.3.47). The key step in the synthesis of (146) was developed from the condensation of the aldehyde (145) with homoallyl vinyl ether (144) in the presence of TiBr4, followed by reduction with Bu3SnH and AIBN (Scheme.
Prins-Pinacol rearrangement
The key step in the synthesis of (146) was developed from the condensation of the aldehyde (145) with homoallyl vinyl ether (144) in the presence of TiBr4, followed by reduction with Bu3SnH and AIBN (Scheme 1.3.48).84. Prins-pinacol reactions are used to construct a wide variety of oxacyclic ring systems and extended to the synthesis of bioactive natural products.
Miscellaneous Prins Cyclization Reactions
Yadav and co-workers95 developed a Prins cyclization of a silicon-stabilized homoallyl cation formed from a cyclopropyl carbinol that was proximately replaced by a silylmethyl function. Cyclization involving allenes: Loh et al.98 showed an efficient Prins cyclization of allenic carboalkyl alcohols with aldehydes.
Thia-Prins cyclization
Aza-Prins cyclization
4-Iodopiperidines were prepared with high selectivity by aza-Prins cyclization using a catalytic amount of gallium(III) iodide and a stoichiometric amount of iodine.109 The treatment of benzaldehyde with N-tosylhomoallylamine in the presence of 10 mol% of GaI3 . They attempted to couple benzaldehyde to N-tosyl-homoallylamine in the presence of 10 mol% phosphomolybdic acid in refluxing dichloromethane.
Conclusion
Stereoselective Synthesis of 4-Amidotetrahydropyrans
Importance and Applications
An Overview of Relevant Synthetic Methods
As illustrated in Scheme 2.2.3, the reaction of 2-naphthalaldehyde with but-3-en-1-ol in acetonitrile in the presence of 10 mol % CeCl3.7H2O and 1.5 equiv. acetyl chloride at ambient temperature gave 4-acetamido tetrahydropyran (9) in 88% yield with all cis selectivity. The multicomponent Sakurai-Prins-Ritter reaction was promoted by Bi(OTf)3 catalyst.11 As illustrated in Scheme 2.2.6, two equivalents of benzaldehyde when treated with allyltrimethylsilane in acetonitrile in the presence of 10 mol % Bi(OTf)3.4 H2O at room. The Prins-Ritter reaction is also possible on alkynols (15) in acetonitrile with H2O in the presence of 2 mol% PtCl4 under reflux.12 Under these conditions, amide derivatives (16) were isolated in very high yields and as single diastereoisomers.
Results and Discussion
Both aliphatic and aromatic aldehydes give good yields with high diastereoselectivity as determined by 1H and 13C NMR spectra of the crude product. The conformations of the compounds are in the chair shape and all three substituents are in the equatorial position. The substituent at the 2-, 4-, and 6-positions of the tetrahydropyran ring are in a cis relationship and are equatorial.
Experimental Section
- Instrumentation and Characterization
- General procedure
The progress of the reaction was monitored by TLC with ethyl acetate and hexane as eluents. After completion of the reaction, the reaction mixture was treated with aqueous sodium bicarbonate and the product was extracted with ethyl acetate, and then washed with brine and water. Progress of the reaction was monitored by TLC with ethyl acetate and hexane as eluents.
60 aqueous sodium bicarbonate and the product was extracted with ethyl acetate and then washed with brine and water. The organic layer was dried (Na2SO4) and evaporated to leave the crude product, which was purified by short column chromatography on silica gel to give 4-acetamido-2,6-diphenyltetrahydropyran 1b (207 mg, 70%) as a crystalline solid with mp. The organic layer was dried (Na2SO4) and evaporated to leave the crude product, which was purified by short column chromatography on silica gel to give N-[2,6-bis-(4-nitro-phenyl)-tetrahydro-pyran- 4 was obtained. -yl-benzamide 2d (300 mg, 67%) as a crystalline solid, m.p.
Spectral data
Selected Spectra of 4-amidotetrahydropyrans
Stereoselective Synthesis of Symmetrical 4-Aryltetrahydropyrans
Importance and Applications
Synthetic Methods
Results and Discussion
To further investigate the usefulness of the method, other arenes as nucleophiles were also studied, as shown in Table 3.3.2. The yield of the cross product was always lower than that of the symmetric products. The mechanism of the reaction can be explained as follows: In the presence of Lewis acid, allyltrimethylsilane (1) reacts with the aldehyde to yield intermediate 2 (Scheme 3.3.2).
Experimental Section
- Instrumentation and Characterization As described in Chapter 2, Section 2.5.1
- General procedure
General procedure for cross-linked 2,6-disubstituted-4-phenyltetrahydropyran (Table 3.3.3): To a mixture of aldehyde (1.0 mmol) and boron trifluoride etherate (1.2 mmol) in benzene (2.0 mL) was added allyltrimethylsilane (0.6 mmol) in benzene (1.0 mL) dropwise at 0 °C. The reaction mixture was stirred for 1 h at the same temperature, then another aldehyde (1.2 mmol), boron trifluoride etherate (1.4 mmol) in benzene (2 mL) was added dropwise at the same temperature. The reaction mixture was stirred for 1 hour at the same temperature, then p-nitrobenzaladehyde (181 mg, 1.2 mmol) and boron trifluoride etherate (1.8 mg, 1.4 mmol) in benzene (2 mL) were added dropwise at the same temperature.
Spectral Data
Selected Spectra of symmetrical 4-aryltetrahydropyrans
Stereoselective Synthesis of Unsymmetrical 4-Aryltetrahydropyrans
Importance and Applications
An Overview of Relevant Synthetic Methods and its Applications
- Tandem Prins-Friedel-Crafts Reactions
- Synthesis of Tetrahydropyrans by using Metal Catalyst a) Reduction of Dihydropyrans
- Michael Reaction for the Synthesis of THPs
An intramolecular Friedel-Crafts reaction of trans-homoallyl alcohol (12) and benzaldehyde proceeded smoothly in ionic liquid under similar conditions and afforded the tricyclic compound (13) in 91% yield (Scheme 4.2.3)7, containing two transfused contains tetrahydropyran. rings with all substituents at the equatorial position. Miyaura coupling of enol triflate (24) with 2,4,6-trialkoxyphenylboronic acid (25), followed by catalytic hydrogenation in a stereocontrolled manner (Scheme 4.2.9).12. Tetrahydropyran derivative (28) was also prepared from the reaction of organomagnesium or lithium reagents generated from compound (27) and tetrahydropyran-4-one (Scheme 4.2.10) with high diastreoselectivity.13.
Results and Discussion
Thus, reaction with toluene gave 22 as inseparable regioisomers in a 4.7:1 ratio and 97% overall yield. Of course, we were tempted to evaluate the efficiency of the above protocol for the construction of the tetrahydropyran ring, so we also tried the reaction with ketones (Scheme 4.3.2). Thus, the reaction with cyclohexanone and 1,4-cyclohexanedione gave the spirocyclic product 28 and 29 in 46% and 30%, respectively, at 40 oC.
Experimental Section
- Instrumentation and Characterization As described in Chapter 2, Section 2.5.1
- General Procedure for the Synthesis of Compounds 1b-21b and 22-25
- General Procedure by using Different Arenes
- General Procedure for the Three Component Reaction with Ketone 28-30 Ketone (1 equiv) and 3-beten-ol (1 equiv) were dissolved in benzene and added boron
The organic layer was dried (Na 2 SO 4 ) and evaporated to leave the crude product, which was purified by flash column chromatography over silica gel to give 2,4,6-triphenyltetrahydropyran 1b (414 mg, 75%) as a gum. The organic layer was dried (Na 2 SO 4 ) and evaporated to leave the crude product, which was purified by flash column chromatography over silica gel to give 25 as two regioisomers with a 2:1 ratio (501 mg, 80%). The organic layer was dried (Na 2 SO 4 ) and evaporated to leave the crude product which was purified by flash column chromatography over silica gel.
113 sodium bicarbonate and the product was extracted with ethyl acetate, and then washed with brine and water. General Procedure for Three-Component Reaction with Ketone 28-30 Ketone (1 equiv) and 3-bethen-ol (1 equiv) were dissolved in benzene and boron ketone (1 equiv) and 3-bethen-ol (1 equiv) were added ) is dissolved in benzene and boron trifluoride etherate (1.2 equiv) is added and then the reaction mixture is stirred for the specified time at 40 oC. The organic layer was dried (Na2SO4) and evaporated to leave the crude product, which was purified by flash column chromatography on silica gel to give 4-phenyl-1-oxa-spiro[5.5]undecane 28 (212 mg , 46%) like a chewing gum. 16) Crystallographic data for the compound VCR-pnb have been deposited at the Cambridge Crystallographic Data Center as Supplementary Publication Number CCDC 687645.
Spectral Data
Selected Spectra of unsymmetrical 4-aryltetrahydropyrans
Synthesis of Substituted 4-Aryl-5,6- dihydro -2H-pyrans
Importance and Applications
An Overview of Relevant Synthetic Methods and its Applications
- Tandem Prins-Friedel-Crafts Reaction
Yadav and Vijaya Kumar developed a Prins cyclization from the reaction of cyclopropyl carbinols.5 As illustrated in Scheme 5.2.2, the reaction of benzaldehyde with (6) in the presence of BF3. The microwave irradiation of alkyne (11) with ethyl vinyl ether (12) and ethyl glyoxalate (13) in toluene and in the presence of Grubb's 2nd generation catalyst gave the 2,3-dihydropyrans (15) as a mixture of cis/trans diastereoisomers (Scheme 5.2.4 ).7 The dihydropyrans (15) were then equilibrated in the presence of ZnCl2. The presence of a Lewis acid led to the formation of the trans-15 compound as the only product in quantitative yield.
Results and Discussion
136 The extent of the reaction was investigated by considering a series of aldehydes as shown in Table 5.3.1. The reaction with toluene thus gave o-/p-15 as an inseparable mixture of regioisomers with a ratio of 2:1 and 72% overall yield. 139 The mechanism of the reaction with epoxide can be explained (Scheme 5.3.3) by taking into account the already reported fact that epoxide (29) rearranges to intermediate (30) after opening with Lewis acid.
Experimental Section
- Instrumentation and Characterization As described in Chapter 2, Section 2.5.1
- General procedure for the synthesis of 4-aryldihydropyran from carbonyl compounds 1b-14b and 15-21
- General procedure for the synthesis of compounds 9b, 25-28
The progress of the reaction was monitored by TLC with ethyl acetate and hexane as eluent. The progress of the reaction was monitored by TLC with EtOAc and hexane as eluent. After completion of the reaction, the reaction mixture was treated with aqueous NaHCO3 and the product was extracted with Et2O, and then the combined organic extracts were washed with brine and H2O.
Spectral data
Selected Spectra of 4-Aryldihydropyrans
List of Publications
