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Protecting and Deprotecting groups in Organic Chemistry

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Ashwani Dalal
Ashwani Dalal

It gives the concise and complete protecting and deprotecting groups. A protecting group or protective group is introduced into a molecule by chemical modification of a functional group to obtain chemoselectivity in a subsequent chemical reaction. It plays an important role in multistep organic synthesis

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Protection And Deprotection In Organic Chemistry Presented by Ashwani Kumar
Protecting groups for the amino group Why must an amino group be protected? N nucleophile acylation O N O- N + The most general way of masking nucleophilicity is by acylation. it reacts with electrophiles because it is a nucleophilic site it can be deprotonated by strong bases because it can contain acid protons
Protection of amino groups as carbamates 1) Carbobenzoxy group (CBz). The most widely used group is the carbobenzyloxy group (Cbz). O OCl + RNH2 O ORHN O ORHN H2/cat O NR2HO + +PhCH3 CO2 + HNR2 PhCH3 PROTECTION: DEPROTECTION: Because of the lability of the benzyl bond toward hydrogenolysis, the amine can be regenerated from a Cbz derivative by hydrogenolysis, which is accompanied by spontaneous decarboxylation of the resulting carbamic acid.
Protection of amino groups as carbamates 2) tert-butyloxycarbonyl (t-Boc) RNH2 R2NH O OO O O O OO N Ph CN R2N O O t-butoxypyrocarbonate 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile BOC-ON PROTECTION: DEPROTECTION: CF3COOH, p-toluensulfonic acid
Protection of amino groups as amides a) phtalimides N O O R H2N NH2 RNH2 + HN HN O O NaBH4/EtOHaq N O R HO H H O RHN O BH4 - HO RHN O O O H2NR + PROTECTION: formation of the amide starting from the corresponding acyl chloride or anhydride DEPROTECTION: the use of these amides is characterized by the possibility of a cleavage in mild conditions
b) trifluoroacetamides O AcO OAcAcO AcO O NH COOEt O F3C O HO OHHO HO O NH2 COOH Ba(OH)2 18h, 25属C mild basic hydrolysis b) trichloroacetamides, benzamides O CCl3N H R NaBH4 ROH O CCl3N H R BH3 RNH2 + Cl3CHO O PhH2N R2AlH O PhR2N AlR R2NH + PhCHO partial reduction
b) sulphonamides NR2 S O O Ar + OMe OMe h僚 R2N - + ArSO2 + OMe OMe + photochemical cleavage 3) Allyloxy group The allyloxy group is removed by Pd-catalyzed reduction or nucleophilic substitution. These reactions involve liberation of the carbamic acid by oxidative addition to the palladium. The allyl-palladium species is reductively cleaved by stannanes, phenylsilane, formic acid and NaBH4.
O OR2N O OR2N Pd Bu3SnH O SnBu3R2N RNH2 + CO2 H Pd Pd 0 H2O Carbamic acid is removed by oxidative addition to palladium. The allylpalladium is then reductively cleaved by stannane
Protecting groups for the carbonyl group Why must a carbonyl group be protected? it reacts with nucleophiles because it is an electrophilic site it reacts with reducing agents because it can be reduced
Protection of carbonyl groups as acetals and thioacetals PROTECTION: acid catalysed formation of acetals O R'R + HC OMe OMe OMe MeO R' R OMe + O OMeH O R'R + OMe OMe MeO R' R OMe + O orthoester 2,2-dimethoxypropane acid catalysed exchange with a ketal + R'O R R OR' 2 O RR ROSiMe3 Me3SiO3SCF3 + Me3SiOSiMe3 trimethylsilyl trifluoromethylsulfonate DEPROTECTION: a)The carbonyl group can be deprotected by acid- catalyzed hydrolysis by the general mechanism for acetal hydrolysis LiBF4/CH3CN
b) non hydrolityc conditions (硫-haloalcohols) DEPROTECTION (硫-elimination): H+ + O RR OH HO Br O BrO R R 3-bromo-1,2-dihydroxypropane 2,2,2-trichloroethanol H+ + O RR CCl3HO OO RR CCl3Cl3C 2 PROTECTION: + O RR O BrO R R + O RR HO OO RR CCl3Cl3C Cl ClH H Zn Zn THF
c) non-acid conditions DEPROTECTION: + O RR 1,3-oxathiolanemercaptoethanol SH HO BF3 /-H2O O S R R PROTECTION: O RR chloramine T O S R R Ni-Raney ROH O S+ R R CH3 S OO - N ClNa+ X H2O X =Cl or NSO2Ar
Protecting groups for the carboxyl group O OHR The carbonyl group can be protected in several ways The hydroxy group is generally protected as t-buthyl ester, that allows cleavage in acid conditions, or as 2,2,2-trichloroethyl ester, that can be cleaved in reductive conditions with Zn
a) oxazolidines DEPROTECTION: + O OHR HN O NR O N H R (+) N O R H+ 2,2-dimethylaziridine PROTECTION: HO NH2 N O R + O OHR 2-amino-2-methylpropanol The carboxylic acid group can be regenerated by acidic hydrolysis or converted to an ester by acid-catalyzed reaction with the appropriate alcohol.
a) ortho esters. Ortho esters derived from simple alcohols are very easily hydrolyzed, and a more useful ortho ester protecting group is the 4-methyl-2,6,7- trioxabicyclo[2.2.2]octane structure. These bicyclic orthoesters can be prepared by exchange with other ortho esters, by reaction with iminoethers, or by rearrangement of the ester derived from 3-hydroxymethyl-3- methyloxetan. R OMe OMe OMe CH3C(CH2OH)3 CH3C(CH2OH)3 BF3 NH OR'R O O O R O O OR 4-methyl-2,6,7-trioxabicyclo[2.2.2]octane exchange rearrangement
Protection of ester groups In general, the methods for protection and deprotection of carboxylic acids and esters are not as convenient as those for alcohols, aldehydes, and ketones. O O O + Al S S Al SS a) cyclic b) acyclic O OR' R R + Al S S Al S S R2C It is, therefore, common to carry potential carboxylic acids through synthetic schemes in the form of protected primary alcohols or aldehydes. The carboxylic acid can then be formed at a late stage in the synthesis by an appropriate oxidation. This strategy allows one to utilize the wider variety of alcohol and aldehyde protective groups indirectly for carboxylic acid protection.

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Protecting and Deprotecting groups in Organic Chemistry

  • 1. Protection And Deprotection In Organic Chemistry Presented by Ashwani Kumar
  • 2. Protecting groups for the amino group Why must an amino group be protected? N nucleophile acylation O N O- N + The most general way of masking nucleophilicity is by acylation. it reacts with electrophiles because it is a nucleophilic site it can be deprotonated by strong bases because it can contain acid protons
  • 3. Protection of amino groups as carbamates 1) Carbobenzoxy group (CBz). The most widely used group is the carbobenzyloxy group (Cbz). O OCl + RNH2 O ORHN O ORHN H2/cat O NR2HO + +PhCH3 CO2 + HNR2 PhCH3 PROTECTION: DEPROTECTION: Because of the lability of the benzyl bond toward hydrogenolysis, the amine can be regenerated from a Cbz derivative by hydrogenolysis, which is accompanied by spontaneous decarboxylation of the resulting carbamic acid.
  • 4. Protection of amino groups as carbamates 2) tert-butyloxycarbonyl (t-Boc) RNH2 R2NH O OO O O O OO N Ph CN R2N O O t-butoxypyrocarbonate 2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile BOC-ON PROTECTION: DEPROTECTION: CF3COOH, p-toluensulfonic acid
  • 5. Protection of amino groups as amides a) phtalimides N O O R H2N NH2 RNH2 + HN HN O O NaBH4/EtOHaq N O R HO H H O RHN O BH4 - HO RHN O O O H2NR + PROTECTION: formation of the amide starting from the corresponding acyl chloride or anhydride DEPROTECTION: the use of these amides is characterized by the possibility of a cleavage in mild conditions
  • 6. b) trifluoroacetamides O AcO OAcAcO AcO O NH COOEt O F3C O HO OHHO HO O NH2 COOH Ba(OH)2 18h, 25属C mild basic hydrolysis b) trichloroacetamides, benzamides O CCl3N H R NaBH4 ROH O CCl3N H R BH3 RNH2 + Cl3CHO O PhH2N R2AlH O PhR2N AlR R2NH + PhCHO partial reduction
  • 7. b) sulphonamides NR2 S O O Ar + OMe OMe h僚 R2N - + ArSO2 + OMe OMe + photochemical cleavage 3) Allyloxy group The allyloxy group is removed by Pd-catalyzed reduction or nucleophilic substitution. These reactions involve liberation of the carbamic acid by oxidative addition to the palladium. The allyl-palladium species is reductively cleaved by stannanes, phenylsilane, formic acid and NaBH4.
  • 8. O OR2N O OR2N Pd Bu3SnH O SnBu3R2N RNH2 + CO2 H Pd Pd 0 H2O Carbamic acid is removed by oxidative addition to palladium. The allylpalladium is then reductively cleaved by stannane
  • 9. Protecting groups for the carbonyl group Why must a carbonyl group be protected? it reacts with nucleophiles because it is an electrophilic site it reacts with reducing agents because it can be reduced
  • 10. Protection of carbonyl groups as acetals and thioacetals PROTECTION: acid catalysed formation of acetals O R'R + HC OMe OMe OMe MeO R' R OMe + O OMeH O R'R + OMe OMe MeO R' R OMe + O orthoester 2,2-dimethoxypropane acid catalysed exchange with a ketal + R'O R R OR' 2 O RR ROSiMe3 Me3SiO3SCF3 + Me3SiOSiMe3 trimethylsilyl trifluoromethylsulfonate DEPROTECTION: a)The carbonyl group can be deprotected by acid- catalyzed hydrolysis by the general mechanism for acetal hydrolysis LiBF4/CH3CN
  • 11. b) non hydrolityc conditions (硫-haloalcohols) DEPROTECTION (硫-elimination): H+ + O RR OH HO Br O BrO R R 3-bromo-1,2-dihydroxypropane 2,2,2-trichloroethanol H+ + O RR CCl3HO OO RR CCl3Cl3C 2 PROTECTION: + O RR O BrO R R + O RR HO OO RR CCl3Cl3C Cl ClH H Zn Zn THF
  • 12. c) non-acid conditions DEPROTECTION: + O RR 1,3-oxathiolanemercaptoethanol SH HO BF3 /-H2O O S R R PROTECTION: O RR chloramine T O S R R Ni-Raney ROH O S+ R R CH3 S OO - N ClNa+ X H2O X =Cl or NSO2Ar
  • 13. Protecting groups for the carboxyl group O OHR The carbonyl group can be protected in several ways The hydroxy group is generally protected as t-buthyl ester, that allows cleavage in acid conditions, or as 2,2,2-trichloroethyl ester, that can be cleaved in reductive conditions with Zn
  • 14. a) oxazolidines DEPROTECTION: + O OHR HN O NR O N H R (+) N O R H+ 2,2-dimethylaziridine PROTECTION: HO NH2 N O R + O OHR 2-amino-2-methylpropanol The carboxylic acid group can be regenerated by acidic hydrolysis or converted to an ester by acid-catalyzed reaction with the appropriate alcohol.
  • 15. a) ortho esters. Ortho esters derived from simple alcohols are very easily hydrolyzed, and a more useful ortho ester protecting group is the 4-methyl-2,6,7- trioxabicyclo[2.2.2]octane structure. These bicyclic orthoesters can be prepared by exchange with other ortho esters, by reaction with iminoethers, or by rearrangement of the ester derived from 3-hydroxymethyl-3- methyloxetan. R OMe OMe OMe CH3C(CH2OH)3 CH3C(CH2OH)3 BF3 NH OR'R O O O R O O OR 4-methyl-2,6,7-trioxabicyclo[2.2.2]octane exchange rearrangement
  • 16. Protection of ester groups In general, the methods for protection and deprotection of carboxylic acids and esters are not as convenient as those for alcohols, aldehydes, and ketones. O O O + Al S S Al SS a) cyclic b) acyclic O OR' R R + Al S S Al S S R2C It is, therefore, common to carry potential carboxylic acids through synthetic schemes in the form of protected primary alcohols or aldehydes. The carboxylic acid can then be formed at a late stage in the synthesis by an appropriate oxidation. This strategy allows one to utilize the wider variety of alcohol and aldehyde protective groups indirectly for carboxylic acid protection.