Novel reactions of metallocene and phosphorus isocyanates and isothiocyanates
by Kevin Wing Koon Leung
vi, 115 leaves : ill. ; 30 cm
Introduction Methods for the synthesis of β-lactams are classified according to the various bond forming strategies, namely cyclization methods such as Nl-C2, C2-C3, C3- C4, C4-N1 bond formations and annulation methods such as ketene-imine, ester-imine and isocyanate-alkene methods. The most popular methods nowadays are Nl-C2 cyclization and ketene-imine annulation. Each kind of method is briefly discussed. Examples are given in each case....[ Read more ]
Introduction Methods for the synthesis of β-lactams are classified according to the various bond forming strategies, namely cyclization methods such as Nl-C2, C2-C3, C3- C4, C4-N1 bond formations and annulation methods such as ketene-imine, ester-imine and isocyanate-alkene methods. The most popular methods nowadays are Nl-C2 cyclization and ketene-imine annulation. Each kind of method is briefly discussed. Examples are given in each case.
Discussion Proposal of our Project
We aim to design new, convenient and convergent methods for the synthesis of β-lactams. Two approaches were explored, namely the isocyanate-alkene approach and iodoisocyanate approach. Both approaches are based on functionalization of alkenes.
a. Isocyanate-Alkene Approach
Our interest in this approach is twofold. First, by using a chirally modified isocyanate we may obtain an enantioselective isocyanate-alkene cycloaddition. Second, the mechanism of such [2 + 2] cycloadditions is of theoretical interest. We have employed different early transition metal or electron deficient main group isocyanates and isothiocyanates such as Cp2Ti(NCO)2, Cp2Ti(NCS)2, Cp2Zr(NCO)2, Cp2Zr(NCS)2 and l,l'-bi-2-naphthoxyphosphoryl isothiocyanate in the trials. Different alkenes, including ordinary, electron rich and electron deficient, were included in the reactivity screen.
Metallocene Isocyanates and Isothiocyanates Based on X-ray data, the lone pair of the pseudohalide is delocalized over the π-bond network and such delocalization is mainly over the NC bond. However, by considering electronic properties, we expect there wiIl be significant delocalization in the MN bond. Such ligand to metal π-donation will make the isocyanate ligand electron deficient and thus more susceptible to nucleophilic attack by alkenes. The IR and 13C NMR (δ) data offer some support of this supposition.
In all cases we cannot get the desired cyclized β-lactam or thio-β-lactam. Cp2Ti(NCO)2 was unreactive towards reactions with alkenes. Instead we observed a first-order dissociation of Cp ligand from Cp2Ti(NCO)2 in various solvents: DMSO, DMF, 95% DMSO, THE, acetone. We have established that the dissociation results in Cp ligand dissociation to form cyclopentadiene. Because of the first order kinetics, the protonation of the Cp ligand from water should not be a rate determining step. To accomodate all the data we have proposed a mechanism for the dissociation which involves the attack of DMSO on the metal species, followed by π-σ rearrangement and then hydrolysis to give the observed cyclopentadiene.
The zirconocene diisocyanate used was not pure but mixed with oxo bridged dimer (Cp2ZrNCO)2O in the ratio monomer:dimer = 3:l. In the reactions with styrene, silyl enol ethers and imine, Cp2Zr(NCO)2 completely converted to (Cp2ZrNCO)2O. In the reaction with TCNE, a [4 + 2] cycloaddition norbomene product 2,2,3,3-tetracyano-bicyclo [2.2.1]hept-2-ene and a purple organometallic solid were obtained. In our proposed mechanism, the alkene first formed cycloadduct with the Cp ligand and then hydrolysis gave the isolated product. This reaction is interesting because examples of such metal template cycloaddition in early transition metal chemistry are rare.
In many cases of the reactions between Cp2Ti(NCS)2 and alkenes, a new chroma tographically mobile organometallic species, the oxo bridged dimer (Cp2TiNCS)2O was found. The previous workers thought that the mechanism was an electron transfer process. In addition to that, we have established a base catalysed hydrolytic pathway. In the reaction with cyclohexanone pyrrolidine enamine, 6,6-pentamethylenefulvene (47) was isolated. We have established that this is not due to cyclohexanone or iminium salt. There are also some NMR evidences for the same reaction of 'Cp2Zr(NCO)2' and enamine. Functionalization of a Cp ligand by enamines appears to be unprecedented.
Phosphoryl Isocyanate and Isothiocyanate We could not isolate l,l'-bi-2-naphthoxyphosphoryl isocyanate yet. Only chemistry of analogous phosphoryl isothiocyanate was studied. Phosphoryl isothiocyanate reacted with nucleophiles such as methanol and amines to give the expected thiocarbamate or thioureas. The reactions with cyclohexanone pyrrolidine enamine and cyclohexane carbaldehyde pyrrolidine enamine yielded a mixture. One of the products was identified to be l,l'-bi-2- naphthoxyphosphoryl pyrrolidine thiourea. This product is most likely derived from free pyrrolidine, liberated by hydrolysis of the enamine in situ.
b. Iodoisocyanate approach This approach is an attempted C2-C3 cyclization method. Reagents such as tBuLi, CrCl2, nBu3SnH and NaCoI(TPP) were tried. In the tBuLi and CrCl2 reactions, no involatile product was collected. The failure of these attempts is attributed to β-elimination.
nBu3SnH reacted with trans-1-iodo-2-isocyanato-2- phenylethane to form an urea N,N'-di-(1-phenyl)-ethylurea (63). The mechanism is thought to proceed via a hydrolytic pathway catalysed by tin compound.
Na[CoI(TPP)] reduced the alkyl iodo isocyanate and resulted in the formation of a diamagnetic Co(III) compound as indicated by the high resolution of peak splittings in NMR spectra. The IR showed significant shifts in NCO and CO stretching frequencies. FAB/MS did not show the molecular pass peak for the expected Co(III)(TPP) alkyl species. No β-lactam was obtained from this reaction.