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Tetrabutylammonium Tribromide in Organic Synthesis

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I forward his thesis entitled "Peroxovanadium Catalysed Oxidative Transformations of Organic Functional Groups & Tetrabutylammonium Tribromide in Organic Synthesis" which is being submitted for the Ph.D. I acknowledge the Indian Institute of Technology, Guwahati for providing institute fellowship for the entire period of the Ph.D.

Abstract

Peroxovanadium Catalysed Oxidative Transformations of Organic Functional Groups

Alternatively, they are prepared by the oxidation of the cyclic acetals using various oxidizing agents. The methodology works equally well for the synthesis of other esters as described in the previous section.

Tetrabutylammonium Tribromide in Organic Synthesis

We have also investigated the inter- and intramolecular chemoselective deprotection of TBS ethers in the presence of isopropylidene, Bn, Ac, Bz, THP and TBDPS, and the results are very encouraging. The methodology will be useful for chemoselective acetalization of aldehyde in the presence of ketone.

Contents

IIB.1 Tetrabutylammonium tribromide (TBATB)-Methanol as an efficient reagent for deprotection of acid-sensitive groups 128 IIB.1.1 References 138 .

Peroxovanadium Catalysed Oxidative Transformations of

Organic Functional Groups

IA Introduction

Disadvantages of the reaction are the use of toxic reagents, long reaction times, and failure in the case of unconjugated aldehydes. The success of the reaction depends on the selective oxidation of the primary alcohol in the presence of a much higher concentration of methanol.

IB Present Work

Proposed Mechanism of Esterification

The efficacy of the methodology was further demonstrated by the esterification of unsaturated aldehyde such as cinnamaldehyde 14. Several other methods are also available for the direct oxidation of cyclic acetals to glycol monoesters using O3,15 CuCl2,16.

Preparation of Monoesters of Diethylene Glycol

We further attempted to extend the above protocol for the preparation of monoesters of complex diols. To the best of our knowledge, this is the first such ester to be prepared and would be difficult to prepare by any of the existing methods. Higher primary aliphatic diols gave lower yields due to the simultaneous decomposition of active oxidizing species and hydrogen peroxide at longer times.

We believe that the synthesis of monoesters of diethylene glycol from various aldehydes can be achieved by this method. 1H and 13C NMR Spectrum of Diethylene Glycol Monobenzoate In conclusion, the present method represents a simple, yet highly efficient method for the synthesis of esters of the corresponding aldehydes under mild conditions. Although the simplicity and convenience of this oxidation procedure is attractive, the fact that the reaction proceeds in high yields without cis-trans isomerization of the α,β-olefinic bond is even more important.

High catalytic turnover number combined with cheap, easily available reagents and harmless by-products in the reaction make it a suitable alternative for practical application.

IB.1.1 References

Proposed Mechanism

As can be seen from Table 1.5, most substrates gave excellent yields of the corresponding methyl esters. However, moderately deactivated substrate such as m -bromobenzaldehyde 2 and deactivated substrate p -nitrobenzaldehyde 11 gave poor yields of the corresponding esters of 40 and 35%, respectively, by this method and gave the corresponding acid as the major product. It is worth noting that some of the activated substrates were over-oxidized by the later method.

The effectiveness of the methodology was demonstrated by the regioselective esterification of unsaturated aldehyde in 95% yield as shown in the case of cinnamaldehyde 14. All the products are known in the literature and confirmed by comparison with IR and 1H NMR of the authentic sample. The usability of the methodology was tested with few substrates as shown in Table 1.7.

Although the simplicity and convenience of this oxidation procedure is appealing, the fact that the reaction proceeds in high yields, without cis-trans isomerization of α,β-.

IB.2.1 References

However, in H2O2-HCl-mediated reactions, 10 esters corresponding to the solvent alcohol were obtained via a transesterification mechanism. Acyclic acetals 1i and 10i were converted to the corresponding methyl esters, but acetals 11i and 11j containing an electron-withdrawing group were reluctant to yield the ester, probably due to difficulty in regenerating the aldehyde, and also a high activation energy for esterification (Table 1.8). The pH values ​​recorded at the beginning and after completion of the reaction were approx.

In our previous methodology, the reaction times were relatively shorter because the esterification was directly from the aldehyde. In addition, external acid was added to the medium because under acidic conditions, peroxovanadium species, the active oxidizing agent, is stable and active, Chart 1.1 (C) (p.37). An acidic environment also extends the lifetime of the peroxo species of MeReO3 against irreversible decomposition.13 One of the drawbacks of the previous methodology (Table 1.1) was the over-oxidation of some of the aldehydes giving acids instead of esters. Deprotection of acetals to aldehydes and THP and TBS ethers to the corresponding alcohols with V2O5-H2O2.

Surprisingly, in the latter case, along with the benzyl alcohol, some benzaldehyde was also detected, which could originate from the overoxidation of the resulting benzyl alcohol.

IB.3.1 References

IC Experimental

IC.1 General Experimental Section

IC.2 Characterisation of Organic Substrates

IC.3 Experimental Procedures

The solvent was removed in vacuo and the residue redissolved in ethyl acetate (20 mL). General procedure for oxidative esterification of aldehydes to corresponding methyl esters using V2O5 peroxy salt (SPB or SPC). After completion of the reaction, the reaction mixture was concentrated in vacuo and the residue was redissolved in ethyl acetate (20 mL).

General procedure for oxidative esterification of aldehydes to corresponding hydroxyethoxyethyl esters using V2O5-SPB. The resulting homogeneous solution was allowed to stir at ~ 5oC and the progress of the reaction was monitored by GC. Catalysis turnover number of oxidative esterification of aldehydes to corresponding methyl esters using V2O5–SPB or SPC.

Similar to General Procedure IC.3.19 (p.74); Tetrahydropyranyl ether was used in place of the acetal and the reaction mixture was refluxed.

IC.4 Spectral Data

IC.4.1 Methyl esters

IC.4.2 Ethyl esters

Ethyl 4-hydroxy-3-methoxybenzoate (8b)

IC.4.3 Hydroxy-ethyl esters

IC.4.4 Propyl ester

IC.4.5 Butyl ester

IC.4.6 Benzyl ester

IC.4.7 Hydroxy-ethoxy-ethyl Ester

IC.4.8 Aldehydes

IC.4.9 Alcohols

ID Spectra

Tetrabutylammonium Tribromide in Organic Synthesis

IIA Introduction

Nelson and Crouch5 have thoroughly reviewed the selective deprotection of silyl ethers in the presence of other similar or different silyl ethers. Benzyl ether TBS can be selectively deprotected in the presence of aryl ether TBS, Scheme 2.1. The rate difference is sufficient to allow selective cleavage of a TBS primary alkyl ether in the presence of a TIPS primary ether.

Lee and co-workers17 reported a procedure for the cleavage of TBS, TBDPS, and TIPS ethers using carbon tetrabromide (0.1 equiv) in refluxing methanol. In isopropanol, the reaction rate was much slower, allowing selective deprotection of the primary hydroxyl group in the presence of the secondary one, Scheme 2.10. Yadav and co-workers reported the use of Oxone® in 50% methanol for the selective deprotection of TBS ethers of primary alcohols in the presence of TBS phenolic ethers, Scheme 2.14.23 TBS secondary ethers and TBDPS primary ethers are unscratched. Upon refluxing in aqueous acetonitrile in the presence of indium(III) chloride, various TBS ethers are selectively deprotected to the corresponding alcohols in high yields.

Selective deprotection of the THP secondary group in the presence of the TBS primary group was achieved, Scheme 2.26.

IIB Present Work

Proposed Mechanism of Deprotection of TBS Ether

In a control experiment, treatment of 1-decanol silyl ether 34m with 0.01 equiv of 48% HBr in MeOH at room temperature in < 5 min leads to the unprotected alcohol in quantitative yield. When TBS isopropanol ether was treated with TBATB in isopropanol as solvent, no deprotection was observed even after 48 h.

The results of solvent-dependent cleavage of primary TBS ether 34m with TBATB (0.1 mol%) as shown in Table 2.1 suggest that polar organic solvents are relatively more suitable for deprotection and methanol turns out to be the best protic medium for desilylation. Intermolecular chemoselectivity for TBS aliphatic ether 34n in the presence of TBS phenolic ether 41n gave 100% selective deprotection of TBS aliphatic ether to TBS phenolic ether, Scheme 2.45. The primary ether TBS 33m was selectively deprotected compared to the secondary ether TBS 38m and the selectivity was 92% at room temperature (Scheme 2.46).

Similarly, primary ether DMT 33o was selectively cleaved in the presence of primary ether TBS 33m with 95% selectivity in 5 min at room temperature. The o-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluranium tetrafluoroborate (TBTU) reagent 3h selectively deprotected the primary THP ether in the presence of TBS ether. In a competitive intermolecular deprotection between a TBS primary ether 33m and a THP primary ether 33n in methanol at room temperature, it was observed that both were deprotected at nearly equal rates (only 8% selectivity, 0.5 h).

Thus, in a competitive deprotection study between secondary TBS ether 38m and secondary THP ether 38n, the use of methanol at room temperature gave 78% selectivity after 2.2 hours for 38n (Scheme 2.48).

IIB.1.1 References

IIB.2 Tetrabutylammonium Tribromide (TBATB) as an

Efficient Reagent for Acetalisation of Carbonyl Compounds

  • Proposed Mechanism of Acetalisation
  • Electron Density at the Carbonyl Carbon
  • Transacetalisation Reaction
  • Acetal Exchange Reaction with an Alcohol
  • Chemoselective Acetalisation of Aldehyde
  • Chemoselective Acetalisation of Aldehyde

This may be due to the fact that the alcohol accelerates the formation of hemiacetal Y1, as shown in Scheme 2.49, which further facilitates the HBr formed in the medium. It can be mentioned here that the ortho substituted substrate reacts more slowly than the para substituted one, which may be due to steric factors. However, when the same group is present at the ortho position as in the case of o -hydroxy benzaldehyde 4 , the product could not be detected even after 24 h, which may be due to steric and electronic factors.

For o-hydroxybenzaldehyde 4 due to a higher electron density around the carbonyl carbon it is less susceptible to nucleophilic attack by alcohols. The p-hydroxybenzaldehyde substrate 6, where steric crowding is absent due to a relatively higher electron density around the carbonyl carbon, it. However, dialkyl ketalization of hindered ketones such as benzophenone 27 was not successful, possibly due to the higher electron density at the carbonyl carbon (Scheme 2.50), thus making it less susceptible to attack.

Similar acetal exchange has been observed in other acid-catalyzed reactions.14 The formation of a small amount of p-nitrobenzaldehyde may be due to the formation of HBr by the reaction of TBATB with acetonitrile containing traces of water.

IIB.2.1 References

In conclusion, we have shown that acetalization of various carbonyl compounds can be achieved by this methodology. Chemoselective acetalization of aldehydes in the presence of ketones can be accomplished by this method. This method is high-yield, safe, operationally simple under mild reaction conditions, and cost-effective.

IIC Experimental

IIC.1 Preparation of Dry Solvents 1

Sodium wire was placed in the solution along with a catalytic amount of benzophenone and the mixture refluxed until the solution turned blue in color.

IIC.2 Experimental Procedures

After completion of the reaction, the reaction mixture was treated with dilute HCl (2N, 1 × 5 ml) and the product was extracted with ethyl acetate (2 × 15 ml). After completion of the reaction, the reaction mixture was concentrated in vacuo and treated with saturated sodium bicarbonate solution (5 mL). General procedure for the preparation of tert-butyldimethyl silyl ethers.6 To a mixed solution of alcohol (5 mmol) and imidazole (15 mmol) in dry CH2Cl2 (10 mL) was added tert-butyldimethylsilyl chloride (TBSCl), (5.5 mmol) at room temperature temperature.

After completion of the reaction, the reaction mixture was concentrated in vacuo and redissolved in ethyl acetate. General procedure for the preparation of tetrahydropyranyl ethers.8 To a solution of alcohol (5 mmol) in dry dichloromethane (10 mL) was added 3,4-dihydro-2H-pyran (5.5 mmol) and iodine (0.125 mmol). After completion of the reaction, the reaction mixture was treated with 5% NaHCO3 solution (10 mL) and the product was extracted using CH2Cl2 (2 × 20 mL).

After completion of the reaction, the reaction mixture was poured into saturated NaHCO 3 solution (10 mL) (except in the case of hydroxyaldehydes, which were washed with water), and the product was extracted with ethyl acetate (2 x 25 mL).

IIC.3 Spectral Data

IIC.3.1 Benzyl derivatives

IIC.3.2 Benzoyl derivatives

IIC.3.3 Acetyl derivatives

IIC.3.4 Acetonide

IIC.3.6 Tetrahydropyranyl ethers

IIC.3.7 4,4’-Dimethoxytrityl ethers

IIC.3.8 Alcohols

IIC.3.9 Dimethyl acetals

References

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