‫ﺑﺴﻢ ﺍﷲ ﺍﻟﺮﲪﻦ ﺍﻟﺮﺣﻴﻢ‬                    A PRIMER TOPrepared by:                 Mr. Mohammed H. Raidah                   ...
*Contents:Introduction to Organic synthesis …………………………………………………3One group disconnectiondisconnection of simple alcohol ………...
Introduction to Organic synthesisSynthesis is the process of making a desired compound using chemical reaction. moreoften ...
CO2H                 CO2Me                     KMnO4                 MeOH                                           H2SO 4...
Therefore the target molecule could be synthesized as follows :                                                    OH     ...
A second possible synthesis :                                                                         OH                  ...
Analysis number five :                                                    O          O                                    ...
DEFI ITIO STARGET MOLECULE (T.M)        What you need to makeRETROSYNTHETIC ANALYSIS      The process of deconstructing th...
Some synthons and synthetic equivalents:     synthon                                 equivalent(s)                        ...
Latent PolarityThink about some of the reaction weve looked at for carbonyl compounds:                                    ...
The partial positive and negative charges indicate the latent polarity of the bonds in  a molecule. They help us choose th...
1.One group disconnection    ** disconnection of simple alcohol:                                            disconnection ...
Example.1.3                     Ph                             OH                    Me       Et                       OH ...
Alkylhalids                                                                                              Ketones       Com...
Example.1.6                     OH                                     O                                                  ...
Example.1.7                  Me    O                  Me    O            OH2                                              ...
**disconnection of simple olefins:Example.1.8                                                                         O   ...
Example.1.10                                                OH                                  O                         ...
Example.1.12                        O                                                              O                      ...
Example.1.15         N                                               + HO                          CO2       +            ...
One group disconnections sum m ary       1. alcohols                         R1                                           ...
Example.2.2                                                                      O                  O                     ...
** α-β unsaturated carbonyl compoundsExample.2.3                                                                          ...
** 1,3-dicarbonyl compounds                                                                                    δ−         ...
Example.2.10               Ph                            Ph                                                     + Ph      ...
** 1,5-dicaronyl compounds:                                                      δ−                            δ−         ...
Example.2.15        O                                    O                                  O   α        CO2Et            ...
Mannich reaction:                                                                          O        O                O    ...
Example.2.19           O                                       O                                                          ...
Example.2.21        OH                                   O                                                 O          O   ...
Example.2.22      Ph    OH                                        O                             OH                        ...
Example.2.24                                                                               Ph        Ph                   ...
** 1,2-diol           Reminder:                                        HO OH                          KMnO4               ...
Example.2.27                                                        O                        CO2H                         ...
A closely allied reductive linking of carbonyl groups is an intramolecular    version with esters, called the acyloin reac...
Example.2.30                                                                         CO2Et                                ...
Example.2.31                                                                                       CO2Et                  ...
** Bichler- apieralski reaction    Synthesis of dihydro isoquinoline from β-phenylethylamide using phosphorus oxychloride....
Example.2.33                                                           O                   H                              ...
** Benzilic acid rearrangement              Rearrangment of Benzil to Benzilic acid via aryl migration.               O   ...
** Birch reduction       The reduction of aromatic substrates with alkali metal, alcohol in liquid ammonia       , known a...
References:1) Stuart G. Warren; designing organic synthesis , John Wiley,19782) CM3001 Dr.Alan Ford (lab 415) ,text :Willi...
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A primer to designing organic synthesis

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Synthesis is the process of making a desired compound using chemical reaction. more
often than not, more than one step is involved.
: The importance of synthesis
1. Total synthesis of interesting and/or useful natural products
2. Industrially important compounds
3. Compounds of theoretical interest
4. Structure proof
5. Development of new synthetic methodology
6. Importance to other areas of science and technology
: Basic steps of solving synthetic problems
a. Choice of TARGET MOLECULE (T.M)
b. Consideration of applicable synthetic methodology
c. Design of synthetic pathway
d. Execution of synthesis
-- these steps are highly interactive

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A primer to designing organic synthesis

  1. 1. ‫ﺑﺴﻢ ﺍﷲ ﺍﻟﺮﲪﻦ ﺍﻟﺮﺣﻴﻢ‬ A PRIMER TOPrepared by: Mr. Mohammed H. Raidah 2008-200900972599497541 Brkaa2002@hotmail.com
  2. 2. *Contents:Introduction to Organic synthesis …………………………………………………3One group disconnectiondisconnection of simple alcohol ………………………………………………….12disconnection of simple olefins……………………………………………………17disconnection of aryl ketones…………..………………………………………….18Two group disconnection ……………………………………………………….21β-Hydroxy carbonyl compounds …………………………………………………21α-β unsaturated carbonyl compounds……………………………………………..231,3-dicarbonyl compounds ……………….............................................................241,5-dicaronyl compounds…………………………………………………………26Mannich reaction………………………………………………………………….28α-Hydroxy carbonyl compounds………………………………………………….291,2-diol…………………………………………………………………………….33The Pinacol-Pinacolone rearrangement……………………………………………34Allan-Robinson reaction…………………………………………………………...36Bischler-Napieralski reaction………………………………………………………37Bartoli Indol synthesis…………………………………………………………… .38Benzilic acid rearrangement……………………………………………………….39Benzoin condensation……………………………………………………………..39Birch reduction……………..………………………………………………………40 -2-
  3. 3. Introduction to Organic synthesisSynthesis is the process of making a desired compound using chemical reaction. moreoften than not, more than one step is involved.The importance of synthesis :1. Total synthesis of interesting and/or useful natural products2. Industrially important compounds3. Compounds of theoretical interest4. Structure proof5. Development of new synthetic methodology6. Importance to other areas of science and technologyBasic steps of solving synthetic problems :a. Choice of TARGET MOLECULE (T.M)b. Consideration of applicable synthetic methodologyc. Design of synthetic pathwayd. Execution of synthesis-- these steps are highly interactiveApproaching the design of a synthesis (part one)For simple molecules it can be obvious just by looking at the target structure ,for example: BrbromocyclohexaneBromoalkanes are available from alkenes or from alcohols Br HBr OH Br PBr3 CO2Me Esters are available from carboxylic acids by reaction with alcohols ;benzoic acid is available from toluene methyl benzoate -3-
  4. 4. CO2H CO2Me KMnO4 MeOH H2SO 4 Approaching the designing of a synthesis (part two) For more complex molecules , it help to have a formalized , logic-centred approach; RETROSYNTHETIC ANALYSIS Retrosynthetic analysis is the process of working backwards from the target molecule to progressively simpler molecules by means of DISCONNECTIONS and /or FUNCTIONAL GROUP INTERCONVERSIONS that correspond to know reactions . When you`ve got to a simple enough starting material (like something you can buy and usually is cheap) then the synthetic plan is simply to reverse of the analysis . The design of a synthesis needs to take into account some important factors 1. it hase to actually work 2. In general , it should be as short as possible 3. Each step should be efficient 4. Side products (if formed) and impurities (there always are ) should be easily separable from the desired product 5. Environmental issues may be relevant 6. Theres more than one way to skin a cat Example retrosynthetic analysis Target molecule : OH Disconnect B A OH OHSYNTHONS SYNTHONS OREAGENTS ? ? PhMgBr H REAGENTS -4-
  5. 5. Therefore the target molecule could be synthesized as follows : OH Br i) Mg/Et2O ii) CHO What is a synthon? When we disconnect a bond in target molecule , we are imagining a pair of charged fragments that we could stick together , like Lego bricks , to make the molecule we want . these imaginary charged species are called SYNTHONS . When you can think of a chemical with polarity that matches the synthon , you can consider that a Synthetic equivalent of the synthon. Thus, OH O δ- ≡ δ+ R H R H An aldehyde is a synthetic equivalent for the above synthon. There can be more than one synthetic equivalent for a given synthone, but if you cant think of one …try a different disconnection. Always consider alternative strategies. OH B A OH OHSYNTHONS SYNTHONSSynthetic BrMgequivalents PhCHO Br Synthetic ? equivalents -5-
  6. 6. A second possible synthesis : OH Br i)Mg/Et2O Ph ii)PhCHO similary OH OH Ph Ph ≡ ≡ O BrMg Phthus a third possible synthesis is BrMg OH O Ph Ph Besides disconnections , we can also considerfunctional group interconversion . Our target molecule is a secondary alcohol ,which could be prepareby reduction of a ketone . this is represented as follows: OH O FGIPh Ph DISCONNECT O O Ph Ph Br Synthesis number four O OH O LiAlH4 i)base Ph Ph Ph ii) Br T.M Target Molecule -6-
  7. 7. Analysis number five : O O Ph Ph O Ph LiCu 2Synthesis number five : O OH O t-Bu2CuLi NaBH4 Ph PhPh T.M Disconnecting heteroatoms can also be a good idea: OH OH H2O Ph Ph Ph 6th approach : OH i) Hg(OAc)2 Ph Ph ii) NaBH4 There are other possibilities , but lets not bother with any more. How do you choose which method? Personal choice .If you have a favourite reagent, or if you are familiar with a particular reaction (or if you have a strong aversion to a reaction/reagent) then this will affect your choice .Also you need to bear in mind the efficiency of the reaction involved, and any potential side reactions (for example ,self- condensation of PhCOMe in method 4 ). -7-
  8. 8. DEFI ITIO STARGET MOLECULE (T.M) What you need to makeRETROSYNTHETIC ANALYSIS The process of deconstructing the T.M by breaking it into simpler molecules until you get to a recognizable SMSTARTING MATERIAL (SM) An available chemical that you can arrive at by retrosynthetic analysis and thus probably convert into the target moleculeDISCONNECTION Taking apart a bond in the T.M to see if it gives a pair of reagentsFUNCTIONAL GROUP Changing a group in the T.M into aINTERCONVERSION (FGI) different one to see if it gives accessible intermediateFUNCTIONAL GROUP ADDITION Add a functional group to facilitate bond(FGA) formation ,FGA especially applies in the case of molecule containing no reactive functional groupSYNTHON Conceptual fragment that arise from disconnectionSYNTHETIC EQUIVALENT Chemical that reacts as if it was a synthon -8-
  9. 9. Some synthons and synthetic equivalents: synthon equivalent(s) RCl ,RBr , RI , ROMs , ROTs R only when R= alkyl OH O R R R R OH O OH Br R R O O R R O O O O O R OEt R Cl R O R R R RMgBr , RLi , R2CuLi , other organometallic reagents(alkyl ; NOT"RH+base") O O O CO2Et R R R make sure you dont lose CH2 group if you represent eg. RCH2 as R ( viz. make sure the product hase the right number of carbon atoms) -9-
  10. 10. Latent PolarityThink about some of the reaction weve looked at for carbonyl compounds: δ− O OH O A Nu δ+ Nu O O B H base E δ− O δ− δ+ O E O O C Nu Nu E δ− O δ− δ+ δ+ O Nu E δ− ie O δ+ δ− δ+ δ− δ+ δ− δ+these polarities apply quite generally: δ− δ− OH Br δ− δ+ δ− δ+ δ− δ+ δ− δ− δ+ δ− δ+ δ− δ+ δ− δ− δ− NHR NR δ− δ+ δ− δ+ δ− δ+ δ− δ− δ+ δ− δ+ δ− δ+ δ− - 10 -
  11. 11. The partial positive and negative charges indicate the latent polarity of the bonds in a molecule. They help us choose the synthons for key disconnections in a retrosynthetic analysis . viz. δ− OH OH δ+ δ−Equivalents for synthons with reversed polarity synthon equivalent(s) OH O OH ,or Br R R R R O O O O Br R R ,or Br R O OEt Me + sec-BuLi OEt OEt E OEt s-BuLi Li E (VERY strong base) ethoxy vinillithium H3O+ EVL similary from acetylene: OH O E + i) base H3O tautom. E E ii) E HgO - 11 -
  12. 12. 1.One group disconnection ** disconnection of simple alcohol: disconnection connection A + B C A + BExample.1.1 disconnection Me OH + CN Me CN OH Synthesis Me OH H NaCN O + + Me CN OH T.M mechanism O + H CNExample.1.2 Ph OH Ph C CH Me C OH + CH Me Synthesis Ph Ph H base OH O + + HC CH Me Me C CH mechanism Ph HC CH base HC C OH T.M Me - 12 -
  13. 13. Example.1.3 Ph OH Me Et OH + H3C CH2 Synthesis Mg/Et2O EtMgBr EtBr Ph Ph OH O + H + EtMgBr Me Me Et mechanism Ph T.M O + H OH Me Et MgBrExample.1.4 Me Me O C OEt OH + 2MeMgBr Synthesis Me Me O C OEt OH + 2MeMgBr mechanism O O O C OEt C Me T.M C OEt + + Me MgBr Me MgBr - 13 -
  14. 14. Alkylhalids Ketones Compounds derived from alcohols Esters alcohol Aldehydes OlefinsExample.1.5 OH OAc FGI Ph Ph Ph Ph O OH + HC OEt 2 Ph Ph Ph Synthesis: OH O MgBr 2 Ph + HC OEt Ph Phmechanism: OH O O Ph H Ph Ph HC OEt MgBr Ph MgBr Ph OAc OH Ph Ph Ph Ph + CH3COOH T.M Rem inder: O O O SOCl2 R`OH R C OH R C Cl R C OR` - 14 -
  15. 15. Example.1.6 OH O BrMg H + Ph Ph O FGI H OH O Br H H + H C H formaldehyde cyclopentanecarbaldehyde cyclopentylmethanol (aldehyde) (alcohol)Synthesis Br Mg/Et2O MgBr O O H OH MgBr oxidation H H C H H OH O BrMg Ph H + Ph - 15 -
  16. 16. Example.1.7 Me O Me O OH2 O H OH HO Me HO + Me Me O Me O HO Me Me O H O HO 2 H H + H C C H HO Synthesis: O O Me O HO Me Me Me O H + 2 H C C H HO Hmechanism: O O HO H H HO BaSO4 HO H C C H H C C HO reduction HO O Me OH O Me O HO Me Me Me O HO Me HO - 16 -
  17. 17. **disconnection of simple olefins:Example.1.8 O Ph FGI OH Ph + PhM gBr a cyclohexanone b FGI Ph no helpful disconnection OH Example.1.9 O Ph FGI Ph Ph + BrMg a OH FGI b Ph H Ph + BrMg OH O another analysis for synthesis: in example 1.9 the pathway (a) use Wittig reaction instead of Grinard. Ph Ph Ph base Br Ph3P H Ph3P Ph3P O PPh3 O PPh3 Ph + O PPh3 Ph Ph R e m in d e r OH H H a c id - 17 -
  18. 18. Example.1.10 OH O FGI Ph Ph + Ph H Ph3P a b FGI Ph H Ph PPh3 + O OH **disconnection of aryl ketones: Example.1.11 O O + Cl MeO MeO Synthesis: O O + AlCl3 Cl MeO MeO mechanism: O O O H Cl MeO MeO MeO - 18 -
  19. 19. Example.1.12 O O O + O Cl O O OH2 O HO H O + H C H H HO O Synthesis HO O O + H C H + H HO O O O O AlCl3 O + O Cl O Example.1.13 Me Me NO2 NO2 + Cl a O a b MeO O MeO Pathway (b) not occur because NO2 group is electrons withdrawExample.1.14 O O O FGI a b CH + Me I b a O O CH + BrMg + HC CH Br COOEt - 19 -
  20. 20. Example.1.15 N + HO CO2 + NH BrMg O OExample.1.16 OH O R2 R2 R2 + R2 R1 R1 R1 R1 H BrMgExample.1.17 MgBr O OH +Synthesis Br i) Mg/Et2O i) H3PO4 OH O ii) H2/Pd ii) T.M Reminder: acid + H2O C C heat H OH heat + H2 C C H H LiAlH4 O C OH H - 20 -
  21. 21. One group disconnections sum m ary 1. alcohols R1 R2 R2 OH R 1 MgBr + O R3 R3 2. O lefins PPh 3 + O 3. acids O R C OH RMgBr + CO 2 4. carbonyl com pounds O O Ar C OR ArH + Cl R O O O Et R CH 2 C R RBr + R O 2.Two group disconnection **β-Hydroxy carbonyl compoundsExample.2.1 O O OH O + H β H H αSynthesis: O H O O O O OH O H Base H H H H H - 21 -
  22. 22. Example.2.2 O O OH O Ph + Ph α β O Ph Ph OH Synthesis: O OH O O Ph Ph Ph OH Ph OReminder: O the C group is attached to a carbon atom that has at least one H substituent (e.g.-CHCHO,-CHCOR, -CHCO2Et ),then electron-withdrawal by the O group results in such H atom being acidic: C HO H OH C C O C C O C C O α H2 O H H H - 22 -
  23. 23. ** α-β unsaturated carbonyl compoundsExample.2.3 O O O OH O β α H + H3C H H HSynthesis: O OH O O O Base H O H α H3C H H2 C H H2C H O OH O β acid α H H heat T.M Example.2.4 O OH O O O β + H3C CO2H Ph α CO2H Ph CO2H Ph H Synthesis: O O O O OH O base Ph H acid Ph CO2H heat Ph CO2H H3C CO2H H2C CO2H T.M Example.2.5 O HO O O O + β α R R R Synthesis: O OH base O O acid O O R heat R R R Exam ple.2.6 OH O β α O O O - 23 -
  24. 24. ** 1,3-dicarbonyl compounds δ− δ− O O δ− δ+ δ− δ+ δ−Example.2.7 O O O O O OPh Ph Ph + Ph Ph OEt PhSynthesis: O O O O O Base Ph OEt Ph Ph Ph Ph NaOEt T.M Example.2.8 Ph Ph a b b OEt OEt Ph + Ph O O O O a Ph EtO OEt Ph Ph O O Ph OEt O + O Ph OEt Ph OEt O O Example.2.9 O O OEt Ph Ph OEt + OEt OEt O O Ph O OEt EtO OEt O - 24 -
  25. 25. Example.2.10 Ph Ph + Ph C OEt Br O Ph C OEt O Synthesis: Ph Base T.M + Ph C OEt Br O mechanism: Ph T.M Ph C OEt Br O Example.2.11 O δ− O O O Me +Me H δ+ H O O Me EtO H Synthesis: O O Me base + EtO H NaOEt T.M - 25 -
  26. 26. ** 1,5-dicaronyl compounds: δ− δ− O O δ− δ+ δ− δ+ δ− δ+ δ− Michael addition O O O Ph EtO Ph H 2 Ph Ph Ph 1 H Ph α H + 5 O 3 O β 4 O H Example.2.12 O O O O O O a β b b R α R` R + R` R + R` H a O O R + R` Example.2.13 O O O O O O CO2Et CO Et CO2Et 1 2 3 5 + + 2 4 HExample.2.14 CN CN CN a b b EtO EtOEtO + H + O Ph O O Ph O O Ph O a CN CN EtO EtO + Ph O + Ph O O O - 26 -
  27. 27. Example.2.15 O O O α CO2Et CO2Et O O O 5 4 CO2Et β HO CO2Et 3 + Ph Ph Ph 1 Ph Ph 2 Ph Example.2.16 O O O 3 4 1 2 5 O + β O O α O O Example.2.17 OMe OMe O + O O O 3 1 5 2 4 Example.2.18 O O O H H + O O - 27 -
  28. 28. Mannich reaction: O O O H R R CH3 + H C H + R2NH R N formaldehyde R mechanism: H R H R R2NH H N CH2 H O N CH2 OH2 R R O I Me R CH2 R O N CH2 CH2 C R R R Me H O R N CH2 CH C R R O R MeI Me was attacked by N thus N bearing +ve charge make easy remove N R Application for mannich reaction O O O H N R + CH2O + R2NH R mechanism: H R H R R2NH H N CH2 H O N CH2 OH2 R R O I Me O R N CH2 R O R Me H O N CH2 R - 28 -
  29. 29. Example.2.19 O O O O Ph 1 2 O Ph Ph + 4 3 5 O O + CH2O remember Mannich reactionExample.2.20 O O O O NR3 NR2 + CH2 NR2 + CH2 NR2 OH O O O H + HO CH2 NR2 + HO CH2 NHR2 + CH2O + R2NH ** α-Hydroxy carbonyl compounds Ph OH Ph O + COOH α C OH Ph Ph O or CN Synthesis: O Ph OH CN Ph NaOH OH C OH Ph Me H2O H Ph CN Ph O T.M - 29 -
  30. 30. Example.2.21 OH O O O COOH 2 1 H + + H C OH or CN C 3 C EtO OEtO2C O EtO O C O + EtO H EtO Br EtO C O + CH2COOEt Synthesis: O O O C OEt C OEt O C OEt OEt H2C OEt H2C OEt + H2C C C EtO OEt O O OEt O O H O OEt H C OEt H C OEt Br CO2Et CO2Et CO2Et H2C OH CN O C OH HO/H2O EtO2C - 30 -
  31. 31. Example.2.22 Ph OH O OH OH + 2PhMgBr Ph EtO OH OH H OH + CN O Synthesis: O CH2 O CN OH OH OH CN HO/H2O HO C K2CO3 OH CHO H C H HO O O OH OH Ph 2PhMgBr EtO EtOH/H OH Ph OH OH T.M Example.2.23 + CN HOOC NH H NH H + NH3 H OReminder: NH2 NH2 NH3 RCHO R C CN R C COOH CN H H mechanism: O OH H CN H HO/H2O NH3 R C H R C CN R C COOH R C H R C H NH NH2 NH2 NH3 NH2 - 31 -
  32. 32. Example.2.24 Ph Ph PhPh Ph Ph O O HO + O Ph OPh Ph Ph HO Ph Ph FGI Ph O 2PhCH2MgBr + EtO H OH PhSynthesis: O OH Ph OH Ph O CN Ph MgBr CrO3 Ph C H Ph C H HO/H2O Ph O O O OH Ph Ph O Ph + 2PhCH2MgBr CrO3 H C OEt OH O Ph Ph Ph H Ph Ph Ph Ph Ph O HO acid O + O heat O Ph Ph Ph Ph Ph HO Ph T.M Reminder: O OH LiAlH4 C H - 32 -
  33. 33. ** 1,2-diol Reminder: HO OH KMnO4 or OsO4 hydration OH OH OH Al2O3 OH One useful radical reaction is the pinacol reduction: HO OH Mg - Hg O benzene HO OH O PPh3 FGI + remember Witting reaction Example.2.25 OH OH Ph3P O + Ph Ph PhExample.2.26 H O H O CO2Me CO2Me CO2Me HO CO2Me + α + O HO β H H α−β unsaturated carbonyl - 33 -
  34. 34. Example.2.27 O CO2H C H + Ph3P CH2 CO2H O α FG + C H I β OH OH ** The Pinacol-Pinacolone rearrangement HO OH O R4 R1 R4 H R3 R2 R3 R1 R2 mechanism: HO OH2 HO O R4 H R1 R4 HO OH R1 R4 R1 R4 R3 R2 R3 R2 R3 R1 R2 R2 R3Example.2.28 O O reverse -pinacol OH OH pinacol 2 reduction rearrangementSynthesis: OH OH OH2 OH Mg - Hg OH O H+ benzene T.M - 34 -
  35. 35. A closely allied reductive linking of carbonyl groups is an intramolecular version with esters, called the acyloin reaction, which again gives a 1,2-dioxygenated skeleton: C O CO2Et Na (CH2)n (CH2)n Xylene CO2Et CHOHMechanism of Acyloin Condensation Na+ Na+ Na+ Na+ O O O O O O O2 0 + -2NaOMe R OMe + 2Na R OMe R OMe MeO OMe R R R R Na+O O Na+ O O 0 Na+ O O Na+ H O HO OH O OH 2Na 2 tautomerism R R R R R R -2NaOH R R R R Example.2.29 CO2Et CO2Et O acyloin Diels–Alder 2 + OH CO2Et CO2Et - 35 -
  36. 36. Example.2.30 CO2Et C CO2Et CO2Et + C CO2Et CO2Et CO2Et OMe OMe OMe Ph CH2Br + HO C O H OH OMe OMeSynthesis: Ph3P O CH3 CH2Br CH2Br HC C Br2/light Me2SO4 i) Ph3P H ii) Base CHO Ph iii) Ph OH OH OMe OMe CO2Et OMe CO2Et C C CO2Et CO2Et OMe OMe T.M - 36 -
  37. 37. Example.2.31 CO2Et CO2Et CO2Et C O O O + CO2Et C CO2Et CO2Et Synthesis: CO2Et CO2Et C O O C CO2Et CO2Et T.M ** Allan-Robinson reaction: Synthesis of flavones O O O R OH R O R RCO2Na R R O Omechanism: OH O O H OH OH HO RCO2Na R R R O O R R O H O R O R R O O O R R O - 37 -
  38. 38. ** Bichler- apieralski reaction Synthesis of dihydro isoquinoline from β-phenylethylamide using phosphorus oxychloride. POCl3 HN N O R Rmechanism: O HN Cl2P Cl HN N H N H O OPOCl2 H R R R OPOCl2 R OPOCl2 N R Example.2.32 H2C H3C O OH FGI + Ph3P CH2 Synthesis: i) Ph3P Br CH3 Ph3P CH2 ii)base O PPh3 O PPh3 CH2 CH2 - 38 -
  39. 39. Example.2.33 O H N N N OH + H Synthesis: O H N N OH acid N H heat + ** Bartoli Indol synthesis Synthesis of 7-substituted indol from Ortho-substituted nitro benzene and vinyl Grignard reagent. i) MgBr NO2 ii) H3O N R Hmechanism: MgBr O O MgBr N N N O N O O MgBr O MgBr H H H HO H O MgBr O N N N H H MgBr - 39 -
  40. 40. ** Benzilic acid rearrangement Rearrangment of Benzil to Benzilic acid via aryl migration. O O KOH Ar Ar C OH C Ar Ar O OH Benzil Benzilic mechanism: Ar O O O O OH Ar Ar Ar ArAr Ar C O C OH C O acidic C OH C Ar Ar workup Ar O O OH OH O OH a proton transfer leads to formation of carboxylate anion ** Benzoin condensation Its a cyanide-catalyzed condensation of aryl aldehyde to Benzoin. OH Ar H CN Ar Ar O O aryl aldehyde Benzoin mechanism: O Ar H CN CN CN CN -H O Ar +H Ar Ar H Ar H Ar O CN O OH OH Ar H OH OH OH CN Proton Ar Ar Ar Ar transfer Reminder: O O CN such H bond to Carbon connect with two electron withdrawal groups Ar H thus this H is Acidic. OH - 40 -
  41. 41. ** Birch reduction The reduction of aromatic substrates with alkali metal, alcohol in liquid ammonia , known as “Birch reduction” 1) Benzene ring with an electron donating substituent. X X Na,liq,NH3 ROH X=OR,R,NH2 X X X X H Single Electron Transfere H H H OR SET H H Radical anion X X H +e- H H H OR2) Benzene ring with an electron withdrawing substituent: W W Na,liq,NH3 W=CO2H,CO2R,COR,CONR2,CN,Ar W W W W +e- +e- H NH2 H H H Radical anion W W H NH2 H H - 41 -
  42. 42. References:1) Stuart G. Warren; designing organic synthesis , John Wiley,19782) CM3001 Dr.Alan Ford (lab 415) ,text :Willis&Wills organic Synthesis (OUP) - 42 -

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