Palladium-catalyzed selective cycloaddition of diazo compounds to [60]fullerene

The effective catalytic method for cycloaddition of higher diazoalkanes and diazoacetates to [60]fullerene in the presence of the three-component catalytic system Pd(acac) 2 –PPh 3 –Et 3 Al has been developed. The yield and selective formation of the target homo-and methanofullerenes are dependent upon the structure of the original diazo compounds.


Introduction
Homofullerenes and methanofullerenes, synthesized via the 1,3-dipolar cycloaddition between diazo compounds and [60]fullerene or obtained by the Bingel-Hirsch reaction, appear to be one of the most perspective classes of fullerene derivatives as novel materials for various fields of science and technology as evidenced by the numerous reviews 1,2 of both methods for a synthesis of these cycloadducts 1 and their possible applications. 2he Bingel-Hirsch reaction for the synthesis of methanofullerenes is the most cited in the scientific literature.In our view, the reaction of fullerenes with diazo compounds due to its great synthetic potential is regarded as a very promising method to synthesize methanofullerenes and also allows, together with the [6,6]-closed adducts, obtaining the [5,6]-open isomeric ones.
Analysis of domestic and foreign literature has shown that cycloaddition between diazo compounds and [60]fullerene under thermal conditions appears to be nonselective.It is accompanied by the formation of a mixture of [6,6]-closed (methanofullerenes) and stereoisomeric [5,6]-open (homofullerenes) adducts. 3While exploiting Rh2(OAc)4 as a promoter, this reaction selectively affords methanofullerenes. 4But the use of stoichiometric quantities of expensive Rh compounds is considered to be the substantial limitation of this method.
Taking the above into consideration, there is an important and urgent need to study and develop the catalytic cycloaddition methods for the effective synthesis of homo-and methanofullerenes, containing different functional groups, from diazo compounds and carbon clusters.
Over the past 5-10 years, we have been actively engaged in research of the cycloaddition reaction between diazo compounds and [60]fullerene under catalytic conditions and found that among the tested complexes and salts of Cu, Pd and Rh a three-component catalytic system Pd(acac)2-PPh3-Et3Al has the greatest efficiency and selectivity in the reactions of C60 with the simplest diazoalkanes, 5 diazoacetates, 6,7 and diazoketones 8 to promote the selective formation of the corresponding homo-or methanofullerenes.
Herein, we attempted to explore the application boundaries of the cycloaddition reaction of diazo compounds to C60 in the presence of Pd(acac)2-PPh3-Et3Al catalyst on the example of symmetric and asymmetric diazoalkanes and also higher diazoacetates of various structure.

Results and Discussion
Recently, we have implemented selective cycloaddition between [60]fullerene and diazoalkanes generated in situ through oxidation of hydrazones of acetaldehyde, benzaldehyde and acetone mediated by Ag2O or MnO2 in the presence of 20 mol% Pd(acac)2-PPh3-Et3Al (1:2:4) catalyst (20 о С, 30 min) leading to the exclusive formation of homofullerenes in 55-70% yields. 5n continuation of these studies and also to examine the effect of alkyl substituent size in the original diazoalkanes upon the selectivity of the reaction, we have carried out catalytic cycloaddition between C60 and diazoalkanes generated in situ by oxidation of hydrazones of butiric, valeric and caproic aldehydes.The above reaction was found to provide the formation of the corresponding homofullerenes 1-3 (Scheme 1), while the yield of target [5,6]-open adducts decreases slightly with increasing the alkyl chain length of diazoalkane.
Thus, the formation of homofullerene 1 containing the hydrogen atom at the bridging C atom above the plane of a six-membered ring of С60 has been proven on the basis of the characteristic triplet signal of the methine hydrogen atom at δ(Н) 2.78 ppm (J = 7. 6 Hz).
In the 13 С NMR spectrum the bridging C atom resonates at δ (С) 49.06 ppm, while the sp 2hybridized C atoms of the fullerene skeleton are manifested in the field of 134-148 ppm.Similarly, we proved the structure of compounds 2 and 3.In contrast to mono-substituted diazoalkanes, the reaction of [60]fullerene with diazoalkanes, in situ generated from hydrazones of methyl ethyl ketones or methyl hexyl ketones, under optimized conditions (20 mol% Pd(acac)2-2PPh3-4Et3Al, 20 о С, 30 min) gave rise to a mixture of stereoisomeric homofullerenes 4a,b and 5a,b (Scheme 2).
Apparently, the decrease in the selectivity of the reaction is conditioned by the presence of the second alkyl substituent at the bridging C atom of the cycloadduct raising the probability of the stereoisomeric [5,6]-open adduct formation.
It was noted that if negligible difference between substituents in the initial hydrazones, for example, hydrazone of methyl ethyl ketone, the ratio of stereoisomeric homofullerenes tends to unity.
The increase in alkyl chain length of the substituent leads to the predominant formation of the energetically more stable homofullerene with the more bulky substitutent located above the plane of the five-membered ring of the C60 molecule (Scheme 2).The ratio of stereoisomeric homofullerenes 4a and 5a as well as 4b and 5b was 3:2 and 3:1, respectively, and was estimated on the basis of integral curves of the characteristic singlet signals of the methyl group at the bridging C atom the 1 H NMR spectrum of corresponding mixtures.
The location of the methyl group at the bridging C atom above the plane of the fivemembered or six-membered ring of the fullerene molecule in compounds 4a,b and 5a,b was defined by comparison between the characteristic singlet signals of the methyl hydrogen atoms in the 1 H NMR spectrum and the known analogues.3а Thus, the characteristic singlet signal of the methyl hydrogen atoms at the bridging C atom in the 1 H NMR spectrum of homofullerene 4а resonates at the higher field [δ(Н) 1.16 ppm] than that of the stereoisomer 5а [δ(Н) 3.12 ppm] (Figure 2).In turn, the methylene [δ(Н) 3.72 ppm (J = 7.2Hz)] and methyl [δ(Н) 1.54 ppm (J = 7.2Hz)] hydrogen atoms of the ethyl substituent in [5,6]-open adduct 4а manifest themselves at the lower field as compared with the similar signals at δ(Н) 1.50 ppm (J = 7.2 Hz) and δ(Н) 1.00 ppm (J = 7.2Hz) for compound 5а.In order to study the possibility of the selective synthesis of homofullerenes containing heteroatoms, we have carried out cycloaddition between C60 and sulfur-containing asymmetric diazoalkanes generated by oxidation hydrazones of ketosulfides.Thus, the interaction between [60]fullerene and diazoalkanes, generated in situ by oxidation of hydrazones of 3-(pentylthiomethyl)-and 3-(cyclohexylthiomethyl)-2-butanones with MnO2, in the presence of 20 mol% three-component Pd(acac)2-2PPh3-4Et3Al catalyst was found to afford predominantly the corresponding homofullenes 6 and 7 in 50% yield (Scheme 3).Scheme 3. Catalytic synthesis of sulfur-containing homofullerenes.
Their structure has been confirmed by means of negative ion MALDI TOF/TOF MS, oneand two-dimensional ( 1 Н, 13 С, COSY, HSQC and HMBC) NMR experiments and also by analysis of UV and IR spectra.
Thus, the molecular peak m/z 892.984 corresponding to empiric formula С70Н20S was observed in the mass spectrum of compound 6 recorded in the negative-ion mode in the absence of a matrix (unionized molecules of original homofullerene as matrix).
The high-field shielding of the methyl group at C 4' in both 1 H and 13 C spectra evidenced of its location above the plane of the fullerene six-membered ring unlike the low-field shift of the methine proton [δ (НС 2' ) 5.21ppm] above the plane of the fullerene five-membered ring in [5,6]open adduct 6.
Increasing a number of signals of the fullerene carbon atoms up to 40 due to anisotropic influence on the chiral centre at С 2' atom leads to the diastereotopic splitting of signals of the carbon atoms in the α, β and γ environments towards the bridging С 1' atom.
The presence of the minor signals in the 1 H and 13 C NMR spectra (1:10 ratio) indicate the presence of stereoisomer of homofullerene 6 with the methyl group at the bridging C atom located above the plane of the five-membered ring of fullerene C60 molecule.But the low content of this isomer in the reaction mixture has not allowed characterizing it reliably.
Our subsequent efforts have been focused on the possibilities to synthesize carboxy derivatives of methanofullerenes bearing various substituents in the ester group.
At the same time, we were intended to study the influence of the original diazoacetate nature upon the yield of the target cycloadducts.We believed that positive results obtained, in the future, will allow synthesizing functionally substituted methanofullerenes containing complex moieties of the steroid series being identical in all respects (composition, configuration, conformation) with the natural compound.
Realization of the planned study on cycloaddition between C60 and diazoacetic esters bearing iso-propyl, cyclohexyl and tert-butyl substituents in the ester group under previously optimized conditions in the cycloaddition reaction for diazoacetates (80 o C, 1 h, 20 mol% Pd(acac)2-4PPh3-4Et3Al) allowed to synthesize the appropriate methanofullerenes 8-10 in the yields of 70, 60 and 46% respectively (Scheme 4).
As noted, the use of diazoacetates bearing sterically hindered substituents in the ester group leads to some decrease in the yield of final products.Very promising results on the synthesis of functionally substituted methanofullerenes, containing various sterically hindered substituents in the ester group, encouraged us to apply this reaction to the synthesis of methanofullerenes, which bear the carboxyl groups and complex natural moieties as well.
For the study we selected diazoacetate derived from glycine and cholesterol under previously developed conditions, 6 and introduced it in the reaction with C60.As a result, methanofullerene 11 has been first obtained in 50% yield in one preparative stage (Scheme 5).
As shown, the presence of steroid substituent in the ester group of the original diazo compound under catalytic conditions does not substantially reduce the yield of the target adduct.Currently, we are actively pursuing the synthesis of carboxy derivatives of methanofullerenes bearing in the ester group pharmavaluable preparations based on natural and synthetic diazo derivatives of terpenes, steroids, alkaloids and carbohydrates.

Conclusions
Thus, we have shown that the previously suggested three-component catalytic system Pd(acac)2-PPh3-Et3Al can be successfully applied to the reaction of [60]fullerene with the simplest diazo compounds to synthesize higher homo-and methanofullerenes bearing substituents of various structure.
The interaction between C60 and diazoalkanes, generated in situ by oxidation of hydrazones derived from aldehydes, was stated to afford under catalytic conditions individual homofullerenes with the location of hydrogen atom at the bridging C atom above the plane of the fullerene six-membered ring.Replacing of mono-diazomethane in this reaction by disubstituted one resulted in the decrease in selectivity and is accompanied by the formation of a mixture of stereoisomeric [5,6]-open adducts.
For the first time, carboxy derivatives of methanofullerenes have been synthesized in one preparative stage based upon diazoacetates containing in the ester group the steroid molecule such as cholesterol.

Experimental Section
General.Commercially available [60]fullerene (99.5% pure, G. A. Razuvaev Institute of Organometallic Chemistry, Russian Academy of Sciences, Nizhniy Novgorod) was used.The reaction products were analyzied on a HPLC chromatograph Altex (model 330) (USA) equipped with the UV detector at 340 nm.The mixtures were separated on a metal half-preparative column Cosmosil Buckyprep Waters (250×10 mm) at ~20 C.Toluene was used as eluent, the flow rate was 2.0 mL•min -1 .The IR spectra were registered on a VERTEX 70V (Bruker) spectrophotometer in KBr pellets.The UV spectra were recorded on a LAMBDA 750 (Perkin Elmer) in CHCl 3 .The 1 H and 13 C NMR spectra were run on a Bruker Avance-400 spectrometer at 400.13 and 100.62 MHz, respectively.The mixture of CDCl 3 and CS 2 (1:5) was used as a solvent.The negative ion mass spectra were obtained on a MALDI TOF/TOF Autoflex-III Bruker without a matrix operating in a linear mode.For the application on a metal target, the toluene solutions of the samples were used.

Scheme 5 .
Scheme 5. Synthesis of functionally substituted methanofullerenes, containing sterically hindered substituent in the ester group.