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Amine and us Named reactions Gabriel synthesis
Delepine synthesis
Ullmann-Goldberg reaction
Buchwald-Hartwig reaction
Leuckart-Wallach reaction
Eschweiler-Clarke reaction
Hofmann rearrangement
Curtius rearrangement
Lossen rearrangement
Schmidt rearrangement
Bamberger rearrangement
Overman rearrangement
Neber rearrangement
Mannich reaction
Strecker reaction
Chichibabin reaction
Bechamp reaction
Aza-Wittig reaction
Staudinger reaction
…..AND SO FORTH!!
ibotenic acid
nicotinic acid
cocaine
nicotine
quinine
nitrogen content
2.6wt% (1.8 kg/70 kg)
Annals of the ICRP Publication 1972, 23, 273 (Table 110).
“N” nucleophile + “C” electrophile – Traditional methodology
Direct C–H bond amination – An extremely attractive alternative
How does achieve this?
e.g. Gabriel amine synthesis
Pioneering work – Breslow (1983), cytochrome mimetic reaction of iminoiodinane
Breslow et al. JACS 1983, 105, 6728.
Mechanism of cytochrome P450 catalyzed oxidn: Chem. Rev. 2004, 104, 3947.
– Reaction requirement
» Hypervalent iodine(III) species (iodinane, TsN=IPh)
» Strong EWG on nitrogen
- Difficult to prepare
- Thermally unstable So what to do?
In situ preparation of iminoiodinane – Che (2000)
Che et al. OL 2000, 2, 2233.
Du Bois et al. ACIE 2001, 40, 598.
– Du Bois (2001)
stereospecific!» Substrate generality was
enlarged to many amide analogues.
Diastereoselective variant – Müller, Dodd, Dauban (2008)
Mueller, Dodd, Dauban et al. JACS 2008, 130, 343.
Davies et al. OL 2006, 8, 5013. Du Bois et al. JACS 2008, 130, 9220.
Enantioselective variant – Davies (2006), intramolecular
– Du Bois (2008), intermolecular
How to generates metal nitrenoid?
Catalytic cycle
» Concerted mechanism
» Similar to carbenoid
C–H insertion
Mechanistic insight: Du Bois et al. JACS 2007, 129, 562.
The robust one – “No reaction was observed under a variety of reaction conditions;
azidoformate was remarkably stable in the presence of various
transition-metal complexes.” (Lebel, 2005)
– “The direct rhodium-catalyzed decomposition of azides is not an
effective method for generating rhodium nitrenes.” (Davies, 2006)
Lebel et al. JACS 2005, 127, 14198.
Davies et al. OL 2006, 8, 5013.
» EWG-bound azide does not have sufficient coordinating ability?
First successful example – Driver (2007), aryl sp2 C–H amination
Driver et al. JACS 2007, 129, 7500.
» Strong EWG ligand on Rh complex is the important feature.
» Deuterium-labeled
experiments suggest
stepwise mechanism.
Complementary solution – Driver (2008), vinyl sp2 C–H amination
Driver et al. ACIE 2008, 47, 5056.
» Both aryl and vinyl C–H amination was suggested to occur
through same stepwise pathway.
Actual mechanism?
Driver et al. JOC 2009, 74, 6442.
Key observation
» Rh catalyst is involved in the C–N 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 – Rh arylnitrenoid might be similar to an arylnitrenium ion.
Potential mechanisms
Adam et al. JACS 1994, 116, 3296.
Driver et al. JOC 2009, 74, 6442.
Kinetic isotope effect (KIE)
» C–H bond cleavage occurs after
product-determining step.
» Concerted insertion is not occurring.
Driver et al. JOC 2009, 74, 6442.
» Ar-fused product was favored when R = EDG,
but nonlinear correlation with σm value.
» C–N bond formation does not occur by SEAr.
Effect of electron density of aryl group - I. – on C–N bond formation: Hammett σm vs. product ratio
Driver et al. JOC 2009, 74, 6442.
» Hammett plot gave V-shaped correlation.
» R substituent assists in the extrusion of N2
from initial Rh-azide complex.
Effect of electron density of aryl group - II. – on Rh nitrenoid formation:
Hammett σ+ vs. product ratio
Driver et al. JOC 2009, 74, 6442.
Plausible mechanism – 4π-Electron-5-atom electrocyclization
1. Electronic donation by the biaryl
π-system to form the Rh nitrenoid.
2. The planar nature of quinoid 35
enables a 4π-electron-5-atom
electrocyclization to form C–N bond.
3. Upon formation of 8aH-carbazole 38,
1,5-H shift then provides carbazole.
Substrate dependent reactivity – EWG-nitrenoid likes carbenoid: concerted mechanism
– Arylnitrenoid likes arylnitrenium: stepwise mechanism
Driver et al. JOC 2009, 74, 6442.
Can azide decomposes to form nitrene? – In current method, substrate should equip EWG on the azide.
– 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
» This work
» Strong EWG or strong oxidant
is not requierd.
Screening of additives – 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 – 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
– If concerted: insertion would produce only two products.
– If stepwise: β-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–N bond.
3. Finally, indoline is produced upon
dissociation of Rh complex.
– Efficient and diastereoselective aliphatic C–H 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–H bond
investigated by using D-leveled azide.
» “Hydroxylation reactions catalyzed by P450s are NOT
always stereospecific.”
Chem. Rev. 2004, 104, 3947.
Driver et al. JOC 2009, 74, 6442.
Requirement for a contiguous array of π-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 π-system.”