Nitriles: New Reactions and Reactivities
1. Metalated Nitriles: Arylthio-Metal Exchange (Org. Lett. 2013, 13, in press.)
Building on our advances in exchange-based routes to metalated nitriles (Eur. J. Org. Chem. 2011, 6843) addition of BuLi, Bu3MgLi, Et2ZnBuLi, or Me2CuLi to α-arylthioalkanenitriles is found to trigger an arylthio-metal exchange. NMR spectroscopic analyses implicate organometallic attack on sulfur forming a three coordinate sulfidate as the key intermediate. Electrophilic trapping affords tertiary and quaternary nitriles in high yield. The method addresses the challenge of improving the functional group tolerance and preventing polyalkylations.
2. Metalated Nitriles: SNi and SNi' Installation of Quaternary Centers (Chem. Eur. J. 2013, 19, 8746–8750.)
A series of vicinal quaternary-tertiary and quaternary-quaternary centres were installed through an SNi' displacement of an N-lithiated nitrile with a trisubstituted allylic chloride. The SNi' displacement proceeds with excellent stereocontrol at the ring junction and the adjacent quaternary centre. Collectively, the cyclizations form decalins ideally suited to terpenoid synthesis, reveal a fundamental preference of metalated nitriles for SNi displacements, and provide a strategy for controlled SNi' displacements to form contiguous quaternary centers.
3. Nitrile Alkylations through Sulfinyl–Metal Exchange (Chem. Eur. J. 2013, 19,2023–2029)
Sequential alkylation and sulfinyl-metal exchange allows phenylsulfinylacetonitrile to function as an acetonitrile trianion equivalent. The metalated nitriles alkylate a range of electrophiles to install a diverse array of quaternary stereocenters typical of those found in nitrile-containing pharmaceuticals. The sulfinyl-metal exchange has a high functional group tolerance ideally suited for complex settings.
4. Metalated Nitriles: N- and C-Coordination Preferences of Li, Mg, and Cu Cations (Chem. Commun. 2013, 14, 4700–4702)
Metalated nitriles are chemical chameleons whose precise structural identity depends upon the solvent, the carbon scaffold, the temperature, and the metal. NMR analyses of metalated arylacetonitriles and metalated cyclohexanecarbonitriles demonstrate that Lewis acidic lithium preferentially coordinates to the nitrile nitrogen in both structural types. Magnesiated nitriles exhibit greater coordination changes, preferring N-magnesiation with arylacetonitriles and C-magnesiation with cyclohexanecarbonitrile. The less electropositive metal, copper prefers C-metalation with both arylaceto- and alkylnitriles.
5. Oxonitrile Synthesis (Org. Synth. 2013, 90,229–239)
Cyclic oxoalkenenitriles juxtapose three orthogonal functionalities capable of selective functionalization; an olefin, a ketone, and a nitrile functionality. Rapid access to 2-bromocycloalkex-2-enones from the corresponding ketones is fast and virtually quantitative. The subsequent conjugate addition of cyanide provides an intermediate ketone from which dehydrohalogenation is readily achieved simply through modest heating. The syntheses of 3-oxocyclohex-1-ene-1-carbonitrile and 3-oxocyclohept-1-ene-1-carbonitrile are inexpensive and readily afford analytically pure material.