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Litseminar 121121

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Kaoru Arisue
Kaoru Arisue

The document summarizes recent advances in the direct C-H amination of aromatic and aliphatic compounds using rhodium catalysis. Key developments include the use of electron-neutral aryl azides as nitrogen sources without requiring strong electron-withdrawing groups, and evidence from kinetic isotope effect studies that the reaction proceeds through a stepwise mechanism involving rate-determining C-H bond cleavage. The reaction is diastereoselective for aliphatic substrates and allows efficient synthesis of substituted indolines.

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Litseminar 121121
Table of Contents ¡ö ¡ö ¡ö
Amine and us Named reactions Gabriel synthesis Delepine synthesis nitrogen content Ullmann-Goldberg reaction 2.6wt% (1.8 kg/70 kg) Buchwald-Hartwig reaction Leuckart-Wallach reaction Eschweiler-Clarke reaction Hofmann rearrangement Curtius rearrangement Lossen rearrangement Schmidt rearrangement nicotinic acid Bamberger rearrangement nicotine Overman rearrangement Neber rearrangement Mannich reaction Strecker reaction Chichibabin reaction Bechamp reaction Aza-Wittig reaction ibotenic acid quinine Staudinger reaction cocaine ¡­..AND SO FORTH!! Annals of the ICRP Publication 1972, 23, 273 (Table 110).
¡°N¡± nucleophile + ¡°C¡± electrophile ¨C Traditional methodology e.g. Gabriel amine synthesis Direct C¨CH bond amination ¨C An extremely attractive alternative How does achieve this?
Pioneering work ¨C Breslow (1983), cytochrome mimetic reaction of iminoiodinane ¨C Reaction requirement ? Hypervalent iodine(III) species (iodinane, TsN=IPh) ? Strong EWG on nitrogen - Difficult to prepare So what to do? - Thermally unstable Breslow et al. JACS 1983, 105, 6728. Mechanism of cytochrome P450 catalyzed oxidn: Chem. Rev. 2004, 104, 3947.
In situ preparation of iminoiodinane ¨C Che (2000) ¨C Du Bois (2001) ? Substrate generality was stereospecific! enlarged to many amide analogues. Che et al. OL 2000, 2, 2233. Du Bois et al. ACIE 2001, 40, 598.
Diastereoselective variant ¨C M¨¹ller, Dodd, Dauban (2008) Enantioselective variant ¨C Davies (2006), intramolecular ¨C Du Bois (2008), intermolecular Mueller, Dodd, Dauban et al. JACS 2008, 130, 343. Davies et al. OL 2006, 8, 5013. Du Bois et al. JACS 2008, 130, 9220.
Catalytic cycle ? Concerted mechanism ? Similar to carbenoid C¨CH insertion How to generates metal nitrenoid? Mechanistic insight: Du Bois et al. JACS 2007, 129, 562.
Table of Contents ¡ö ¡ö ¡ö
The robust one ¨C ¡°No reaction was observed under a variety of reaction conditions; azidoformate was remarkably stable in the presence of various transition-metal complexes.¡± (Lebel, 2005) ¨C ¡°The direct rhodium-catalyzed decomposition of azides is not an effective method for generating rhodium nitrenes.¡± (Davies, 2006) ? EWG-bound azide does not have sufficient coordinating ability? Lebel et al. JACS 2005, 127, 14198. Davies et al. OL 2006, 8, 5013.
First successful example ¨C Driver (2007), aryl sp2 C¨CH amination ? Strong EWG ligand on Rh complex is the important feature. ? Deuterium-labeled experiments suggest stepwise mechanism. Driver et al. JACS 2007, 129, 7500.
Complementary solution ¨C Driver (2008), vinyl sp2 C¨CH amination ? Both aryl and vinyl C¨CH amination was suggested to occur through same stepwise pathway. Actual mechanism? Driver et al. ACIE 2008, 47, 5056.
Key observation ? Rh catalyst is involved in the C¨CN bond-forming step. ? Differences between Rh arylnitrenoid and arylnitrene suggest that arylnitrenes might not be the best models for Rh arylnitrenoids. Driver et al. JOC 2009, 74, 6442.
Working hypothesis ¨C Rh arylnitrenoid might be similar to an arylnitrenium ion. Potential mechanisms Driver et al. JOC 2009, 74, 6442.
Kinetic isotope effect (KIE) ? C¨CH bond cleavage occurs after product-determining step. ? Concerted insertion is not occurring. Adam et al. JACS 1994, 116, 3296. Driver et al. JOC 2009, 74, 6442.
Effect of electron density of aryl group - I. ¨C on C¨CN bond formation: Hammett ¦Òm vs. product ratio ? Ar-fused product was favored when R = EDG, but nonlinear correlation with ¦Òm value. ? C¨CN bond formation does not occur by SEAr. Driver et al. JOC 2009, 74, 6442.
Effect of electron density of aryl group - II. ¨C on Rh nitrenoid formation: Hammett ¦Ò+ vs. product ratio ? Hammett plot gave V-shaped correlation. ? R substituent assists in the extrusion of N2 from initial Rh-azide complex. Driver et al. JOC 2009, 74, 6442.
Plausible mechanism ¨C 4¦Ð-Electron-5-atom electrocyclization 1. Electronic donation by the biaryl ¦Ð-system to form the Rh nitrenoid. 2. The planar nature of quinoid 35 enables a 4¦Ð-electron-5-atom electrocyclization to form C¨CN bond. 3. Upon formation of 8aH-carbazole 38, 1,5-H shift then provides carbazole. Driver et al. JOC 2009, 74, 6442.
Substrate dependent reactivity ¨C EWG-nitrenoid likes carbenoid: concerted mechanism ¨C Arylnitrenoid likes arylnitrenium: stepwise mechanism Driver et al. JOC 2009, 74, 6442.
Table of Contents ¡ö ¡ö ¡ö
Can azide decomposes to form nitrene? ¨C In current method, substrate should equip EWG on the azide. ¨C Decomposition catalyst is required redox activity (?) Example of redox-driven azido decomposition, see: Zhang et al. Organometallics 2010, 29, 389.
Electron-neutral azide as N-atom source ? Current method ? Strong EWG or strong oxidant ? This work is not requierd.
Screening of catalysts ¨C Table 1. ? Only Rh2(II) complexes gave indoline.
Screening of additives ¨C Table 1. ? Control experiment revealed that oxidative decomposition of the indoline occurred during purification. ? In situ protection by Boc or Ac improved yield. ? Aniline was formed when the stronger acid byproducts were produced.
para-Aryl and ortho-alkyl substituent ¨C Table 2, 3. ? Both electron-rich or poor aryl azides were suitable substrate. ? Most reactions proceeded in a highly diastereoselective manner.
Reactivity trend ? Electron-rich aryl azides were more reactive.. ? The increased reactivity could be due to either above reasons.
Again, isotope labeling study ¨C If concerted: insertion would produce only two products. ¨C If stepwise: ¦Â-stereocenter could scramble to racemize, four product would be formed. ? In support of stepwise mechanism, two diastereomers and two isotopomers were observed. ? H-abstraction: KIE = 12 to 14 ? H-shift: KIE = approx. 2
Possible mechanism 1. Coordination of Rh to azide, then extrusion of N2 form nitrenoid 8. 2. H-shift or H-abstraction to form 9 or 10 followed by reconbination produces the C¨CN bond. 3. Finally, indoline is produced upon dissociation of Rh complex.
¨C Efficient and diastereoselective aliphatic C¨CH amination that uses an aryl azide as the N-atom source. ? Strong EWG on the N-atom is not required. ? Reaction occurred stepwise with the syn-C¨CH bond investigated by using D-leveled azide.
Litseminar 121121
? ¡°Hydroxylation reactions catalyzed by P450s are NOT always stereospecific.¡± Chem. Rev. 2004, 104, 3947.
Unusual reactivity of methoxy azidoacrylates EAS = SEAr Driver et al. JOC 2009, 74, 6442.
Requirement for a contiguous array of ¦Ð-orbitals >95% recovery ? ¡°The lack of reactivity of 40 agrees with our proposed electrocyclization mechanism and is inconsistent with an electrophilic aromatic substitution mechanism, which would not require a contiguous ¦Ð-system.¡± Driver et al. JOC 2009, 74, 6442.
Temperature dependence of kH/kD ? Isokinetic temperature was approx. 43 deg C.
Exceptional behavior of strained azide ? The spatial constraints of this reaction override these isotope effects.

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Litseminar 121121

  • 3. Amine and us Named reactions Gabriel synthesis Delepine synthesis nitrogen content Ullmann-Goldberg reaction 2.6wt% (1.8 kg/70 kg) Buchwald-Hartwig reaction Leuckart-Wallach reaction Eschweiler-Clarke reaction Hofmann rearrangement Curtius rearrangement Lossen rearrangement Schmidt rearrangement nicotinic acid Bamberger rearrangement nicotine Overman rearrangement Neber rearrangement Mannich reaction Strecker reaction Chichibabin reaction Bechamp reaction Aza-Wittig reaction ibotenic acid quinine Staudinger reaction cocaine ¡­..AND SO FORTH!! Annals of the ICRP Publication 1972, 23, 273 (Table 110).
  • 4. ¡°N¡± nucleophile + ¡°C¡± electrophile ¨C Traditional methodology e.g. Gabriel amine synthesis Direct C¨CH bond amination ¨C An extremely attractive alternative How does achieve this?
  • 5. Pioneering work ¨C Breslow (1983), cytochrome mimetic reaction of iminoiodinane ¨C Reaction requirement ? Hypervalent iodine(III) species (iodinane, TsN=IPh) ? Strong EWG on nitrogen - Difficult to prepare So what to do? - Thermally unstable Breslow et al. JACS 1983, 105, 6728. Mechanism of cytochrome P450 catalyzed oxidn: Chem. Rev. 2004, 104, 3947.
  • 6. In situ preparation of iminoiodinane ¨C Che (2000) ¨C Du Bois (2001) ? Substrate generality was stereospecific! enlarged to many amide analogues. Che et al. OL 2000, 2, 2233. Du Bois et al. ACIE 2001, 40, 598.
  • 7. Diastereoselective variant ¨C M¨¹ller, Dodd, Dauban (2008) Enantioselective variant ¨C Davies (2006), intramolecular ¨C Du Bois (2008), intermolecular Mueller, Dodd, Dauban et al. JACS 2008, 130, 343. Davies et al. OL 2006, 8, 5013. Du Bois et al. JACS 2008, 130, 9220.
  • 8. Catalytic cycle ? Concerted mechanism ? Similar to carbenoid C¨CH insertion How to generates metal nitrenoid? Mechanistic insight: Du Bois et al. JACS 2007, 129, 562.
  • 10. The robust one ¨C ¡°No reaction was observed under a variety of reaction conditions; azidoformate was remarkably stable in the presence of various transition-metal complexes.¡± (Lebel, 2005) ¨C ¡°The direct rhodium-catalyzed decomposition of azides is not an effective method for generating rhodium nitrenes.¡± (Davies, 2006) ? EWG-bound azide does not have sufficient coordinating ability? Lebel et al. JACS 2005, 127, 14198. Davies et al. OL 2006, 8, 5013.
  • 11. First successful example ¨C Driver (2007), aryl sp2 C¨CH amination ? Strong EWG ligand on Rh complex is the important feature. ? Deuterium-labeled experiments suggest stepwise mechanism. Driver et al. JACS 2007, 129, 7500.
  • 12. Complementary solution ¨C Driver (2008), vinyl sp2 C¨CH amination ? Both aryl and vinyl C¨CH amination was suggested to occur through same stepwise pathway. Actual mechanism? Driver et al. ACIE 2008, 47, 5056.
  • 13. Key observation ? Rh catalyst is involved in the C¨CN bond-forming step. ? Differences between Rh arylnitrenoid and arylnitrene suggest that arylnitrenes might not be the best models for Rh arylnitrenoids. Driver et al. JOC 2009, 74, 6442.
  • 14. Working hypothesis ¨C Rh arylnitrenoid might be similar to an arylnitrenium ion. Potential mechanisms Driver et al. JOC 2009, 74, 6442.
  • 15. Kinetic isotope effect (KIE) ? C¨CH bond cleavage occurs after product-determining step. ? Concerted insertion is not occurring. Adam et al. JACS 1994, 116, 3296. Driver et al. JOC 2009, 74, 6442.
  • 16. Effect of electron density of aryl group - I. ¨C on C¨CN bond formation: Hammett ¦Òm vs. product ratio ? Ar-fused product was favored when R = EDG, but nonlinear correlation with ¦Òm value. ? C¨CN bond formation does not occur by SEAr. Driver et al. JOC 2009, 74, 6442.
  • 17. Effect of electron density of aryl group - II. ¨C on Rh nitrenoid formation: Hammett ¦Ò+ vs. product ratio ? Hammett plot gave V-shaped correlation. ? R substituent assists in the extrusion of N2 from initial Rh-azide complex. Driver et al. JOC 2009, 74, 6442.
  • 18. Plausible mechanism ¨C 4¦Ð-Electron-5-atom electrocyclization 1. Electronic donation by the biaryl ¦Ð-system to form the Rh nitrenoid. 2. The planar nature of quinoid 35 enables a 4¦Ð-electron-5-atom electrocyclization to form C¨CN bond. 3. Upon formation of 8aH-carbazole 38, 1,5-H shift then provides carbazole. Driver et al. JOC 2009, 74, 6442.
  • 19. Substrate dependent reactivity ¨C EWG-nitrenoid likes carbenoid: concerted mechanism ¨C Arylnitrenoid likes arylnitrenium: stepwise mechanism Driver et al. JOC 2009, 74, 6442.
  • 21. Can azide decomposes to form nitrene? ¨C In current method, substrate should equip EWG on the azide. ¨C Decomposition catalyst is required redox activity (?) Example of redox-driven azido decomposition, see: Zhang et al. Organometallics 2010, 29, 389.
  • 22. Electron-neutral azide as N-atom source ? Current method ? Strong EWG or strong oxidant ? This work is not requierd.
  • 23. Screening of catalysts ¨C Table 1. ? Only Rh2(II) complexes gave indoline.
  • 24. Screening of additives ¨C Table 1. ? Control experiment revealed that oxidative decomposition of the indoline occurred during purification. ? In situ protection by Boc or Ac improved yield. ? Aniline was formed when the stronger acid byproducts were produced.
  • 25. para-Aryl and ortho-alkyl substituent ¨C Table 2, 3. ? Both electron-rich or poor aryl azides were suitable substrate. ? Most reactions proceeded in a highly diastereoselective manner.
  • 26. Reactivity trend ? Electron-rich aryl azides were more reactive.. ? The increased reactivity could be due to either above reasons.
  • 27. Again, isotope labeling study ¨C If concerted: insertion would produce only two products. ¨C If stepwise: ¦Â-stereocenter could scramble to racemize, four product would be formed. ? In support of stepwise mechanism, two diastereomers and two isotopomers were observed. ? H-abstraction: KIE = 12 to 14 ? H-shift: KIE = approx. 2
  • 28. Possible mechanism 1. Coordination of Rh to azide, then extrusion of N2 form nitrenoid 8. 2. H-shift or H-abstraction to form 9 or 10 followed by reconbination produces the C¨CN bond. 3. Finally, indoline is produced upon dissociation of Rh complex.
  • 29. ¨C Efficient and diastereoselective aliphatic C¨CH amination that uses an aryl azide as the N-atom source. ? Strong EWG on the N-atom is not required. ? Reaction occurred stepwise with the syn-C¨CH bond investigated by using D-leveled azide.
  • 31. ? ¡°Hydroxylation reactions catalyzed by P450s are NOT always stereospecific.¡± Chem. Rev. 2004, 104, 3947.
  • 32. Unusual reactivity of methoxy azidoacrylates EAS = SEAr Driver et al. JOC 2009, 74, 6442.
  • 33. Requirement for a contiguous array of ¦Ð-orbitals >95% recovery ? ¡°The lack of reactivity of 40 agrees with our proposed electrocyclization mechanism and is inconsistent with an electrophilic aromatic substitution mechanism, which would not require a contiguous ¦Ð-system.¡± Driver et al. JOC 2009, 74, 6442.
  • 34. Temperature dependence of kH/kD ? Isokinetic temperature was approx. 43 deg C.
  • 35. Exceptional behavior of strained azide ? The spatial constraints of this reaction override these isotope effects.