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Shapiro reaction

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Rinshana Fathima

This document discusses the Shapiro reaction, which was discovered by Robert H. Shapiro in 1967. The reaction involves converting aryl sulfonyl hydrazones of aldehydes and ketones into olefins using alkyl lithium reagents, grignard reagents, or alkali metal amides at -78¡ãC. The reaction mechanism proceeds through deprotonation, elimination, and loss of nitrogen to form alkenyl intermediates. The Shapiro reaction has been used in the total synthesis of natural products like phytocassane D and in the formation of ring B in the Nicolaou Taxol total synthesis.

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SHAPIRO REACTION [TOSYL HYDRAZONE DECOMPOSITION] SUBMITTED BY : RINSHANA FATHIMA ABDUL AZEEZ FIRST YEAR M.PHARM PHARMACEUTICAL CHEMISTRY AL SHIFA COLLEGE OF PHARMACY 1
? Discovered by Robert H. Shapiro in 1967 ? Shapiro reaction (1967) involves the conversion of aryl sulfonyl hydrazones of aldehydes and ketones into olefins by reacting with alkyl lithium reagent, grignard reagent, or alkali metal amide.[1] ? This reaction is carried out at a temperature of -78¡æ 2
The reaction similar to Bamford Stevens reaction where bases such as Na, NaOMe, LiH, NaH, NaNH2, etc. are used. Another major difference between the two reactions is that Shapiro reaction yields less substitued olefins as kinetcic products (the product that predominates when the reaction is done at low temperature.) While Bamford Stevens reaction yields more substituted olefins as the thermodynamic product (the product that predominates when the reaction is done at high temperature.)[2] 3
GENERAL SCHEME 4
? Tosyl hydrazone is a functional group with the general structure RR'C=N-NH-Ts , where Ts is a tosyl group. ? Tosyl or Toluene sulfonyl group with the molecular formula CH3C6H4SO2 ? This is used as ¡°Protecting Group¡± for alcohols and amines. ? Proctecting groups are introduced in to a molecule by chemical modification of a functional group to obtain chemoselectivity in a multistep reaction. 5
MECHANISM 1. Deprotonation of -NH proton from aryl sulfonyl hydrazone. 2. Second deprotonation adjacent to the hydrazone group to give a dianion. 3. Elimination of toluene sulfinate to form an intermediate (carbanion mechanism). 4. Loss of N2 to form alkenylithium species which is then protonated (treated with an electrophile) to give olefins.[1] 6
MECHANISM 7
8
9 Assymetrical highly substituted enolates are thermodynamically more stable.
10
11 BREDT'S RULE States that ¡°a double bond cannot be placed at the bridgehead of a bridgehead ring system, unless the rings are large enough.¡±
? Synthesis of an allylic alchol, which is an intermediate in the synthesis of Mequitazine, Which is an H1 anti histaminic used to treat allergies and rhinitis. [5] 12 SYNTHETIC APPLICATIONS
? (-)-phytocassane D was synthesized from (R)-Wieland Miescher Ketone by this reaction, for determining the absolute configuration of the phytocassane group of the phytoalexins.[3] 13 WMK is a racemic bicyclic diketone used in the total synthesis of more than 50 natural compounds
? Shapiro reaction is involved in the formation of ring B in the Nicolaou Taxol total synthesis.[4] A B D C 14
? A class of Chiral indenes (Verbindenes) was prepared from Verbenone by utilising Shapiro reaction as one of the key transformation step.[3] 15
REFERENCE 1. Jie Jack Li; Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications Fifth Edition; Springer Science & Business Media, 30-Jan-2014; Page no. 544 2. Jie Jack Li; Name Reactions Third Edition; Springer Science & Business Media, 2006; Page no.529 3. Laszlo Kurti, Barbara Czako; Strategic Applications of Named Reactions in Organic Synthesis; Elsevier, 29-Apr-2005; Page no. 37 16
4. Pei-Qiang Huang, Zhu-Jun Yao, Richard P. Hsung; Efficiency in Natural Product Total Synthesis; John Wiley & Sons, 24-Jul-2018; Page no.9- 93. 5. https://patents.google.com/patent/US20100105897 17 REFERENCE
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Shapiro reaction

  • 1. SHAPIRO REACTION [TOSYL HYDRAZONE DECOMPOSITION] SUBMITTED BY : RINSHANA FATHIMA ABDUL AZEEZ FIRST YEAR M.PHARM PHARMACEUTICAL CHEMISTRY AL SHIFA COLLEGE OF PHARMACY 1
  • 2. ? Discovered by Robert H. Shapiro in 1967 ? Shapiro reaction (1967) involves the conversion of aryl sulfonyl hydrazones of aldehydes and ketones into olefins by reacting with alkyl lithium reagent, grignard reagent, or alkali metal amide.[1] ? This reaction is carried out at a temperature of -78¡æ 2
  • 3. The reaction similar to Bamford Stevens reaction where bases such as Na, NaOMe, LiH, NaH, NaNH2, etc. are used. Another major difference between the two reactions is that Shapiro reaction yields less substitued olefins as kinetcic products (the product that predominates when the reaction is done at low temperature.) While Bamford Stevens reaction yields more substituted olefins as the thermodynamic product (the product that predominates when the reaction is done at high temperature.)[2] 3
  • 5. ? Tosyl hydrazone is a functional group with the general structure RR'C=N-NH-Ts , where Ts is a tosyl group. ? Tosyl or Toluene sulfonyl group with the molecular formula CH3C6H4SO2 ? This is used as ¡°Protecting Group¡± for alcohols and amines. ? Proctecting groups are introduced in to a molecule by chemical modification of a functional group to obtain chemoselectivity in a multistep reaction. 5
  • 6. MECHANISM 1. Deprotonation of -NH proton from aryl sulfonyl hydrazone. 2. Second deprotonation adjacent to the hydrazone group to give a dianion. 3. Elimination of toluene sulfinate to form an intermediate (carbanion mechanism). 4. Loss of N2 to form alkenylithium species which is then protonated (treated with an electrophile) to give olefins.[1] 6
  • 8. 8
  • 9. 9 Assymetrical highly substituted enolates are thermodynamically more stable.
  • 10. 10
  • 11. 11 BREDT'S RULE States that ¡°a double bond cannot be placed at the bridgehead of a bridgehead ring system, unless the rings are large enough.¡±
  • 12. ? Synthesis of an allylic alchol, which is an intermediate in the synthesis of Mequitazine, Which is an H1 anti histaminic used to treat allergies and rhinitis. [5] 12 SYNTHETIC APPLICATIONS
  • 13. ? (-)-phytocassane D was synthesized from (R)-Wieland Miescher Ketone by this reaction, for determining the absolute configuration of the phytocassane group of the phytoalexins.[3] 13 WMK is a racemic bicyclic diketone used in the total synthesis of more than 50 natural compounds
  • 14. ? Shapiro reaction is involved in the formation of ring B in the Nicolaou Taxol total synthesis.[4] A B D C 14
  • 15. ? A class of Chiral indenes (Verbindenes) was prepared from Verbenone by utilising Shapiro reaction as one of the key transformation step.[3] 15
  • 16. REFERENCE 1. Jie Jack Li; Name Reactions: A Collection of Detailed Mechanisms and Synthetic Applications Fifth Edition; Springer Science & Business Media, 30-Jan-2014; Page no. 544 2. Jie Jack Li; Name Reactions Third Edition; Springer Science & Business Media, 2006; Page no.529 3. Laszlo Kurti, Barbara Czako; Strategic Applications of Named Reactions in Organic Synthesis; Elsevier, 29-Apr-2005; Page no. 37 16
  • 17. 4. Pei-Qiang Huang, Zhu-Jun Yao, Richard P. Hsung; Efficiency in Natural Product Total Synthesis; John Wiley & Sons, 24-Jul-2018; Page no.9- 93. 5. https://patents.google.com/patent/US20100105897 17 REFERENCE