6-Aryl fulvenes

Within this review we describe a second reaction pathway, which includes a carbolithiation reaction and leads to achiral-substituted titanocene dichlorides also. Therefore, aryl lithium species are added to the identical substituted 6-aryl fulvenes. This leads to the formation of highly substituted, but achiral diarylmethyl-functionalised lithium cyclopentadienides as seen in Scheme 5, which can still be used in the transmetallation reaction with titanium tetrachloride. 

In agreement with predictions based on frontier orbital arguments56, dienamines undergo [6 + 4] cycloaddition to alkyl or aryl fulvenes to give dihydroazulenes 66 and hence azulenes 67 and 68 in moderate yield57,58 (Scheme 35). 

More recently, a very efficient asymmetric carbolithiation of N,N-dimethyl-aminofulvene 30, leading to a chiral cyclopentadienide anion, was reported by Hayashi et al. [6] for the synthesis of chiral metallocenes (Scheme 6). By adding an aryl lithium such as 31 complexed with a chiral ligand on fulvene 30, a cyclopentadienide ion 32 bearing a stereogenic center at the a position was generated. This anion was reacted with [RhCl(nbd)]2 to yield... 

Aryl-substituted fulvenes can be dimerised with titanium dichloride in THF the resulting mixtures of chiral ama-titanocenes (see Fig. 2) can be synthesised in yields of around 50% and show low anti-proliferative potential with IC50 values of between 930 in (1) and 160 pM in (2) [12], This is moderate improvement with respect to titanocene dichloride, which exhibits an IC50 value of only 2,000 pM against LLC-PK and is therefore not cytotoxic at all against this kidney cell line. 

Super Hydride is one of the most powerful nucleophilic reducing agents available, capable of reducing many functional groups. It is also highly selective. The exocyclic double bond in aryl-substituted fulvenes has an increased polarity, due to the inductive effects of their respective aryl groups. This increased polarity allows for selective nucleophilic attack at this double bond and not at the diene component of the fulvenes. Other examples of the nucleophilic addition of hydrides to substituted fulvenes (albeit with alkyl or unsubstituted phenyl group functionality)... 

Scheme 2 Synthesis of benzyl-substituted titanocenes through the hydridolithiation reaction of aryl-substituted fulvenes using superhydride...

Carbolithiation proved to be a very effective approach to highly cytotoxic titanocenes. The reaction of aryl or heteroaryl lithium species with 6-/V,/V-d i me thy I am i n o fulvene and subsequent transmetallation reaction led to dimethylamino-functiona-lised titanocenes with IC50 values of 6.8, 5.5 and 5.4 pM. Furthermore, this reaction proved to be tolerant to many substituents and to be a versatile tool for the synthesis of a wide variety of substituted titanocene dichlorides as seen in Scheme 3. 

A first series was reported on the reaction of simple aryl lithium species with 6-(V,(V-dimethylamino fulvene and subsequent transmetallation. Thereby, it was possible to synthesise para-methoxy phenyl (15), /V./V-di methyI -pheny I (16) and benzo[l,3]dioxole phenyl-substituted (17) dimethylamino-functionalised titanocene dichlorides, which show IC50 values in the range of 54 pM [22]. This represents a significant improvement in cytotoxicity compared with the benzyl-substituted titanocenes by a factor of 3 for titanocene 16 (IC50 for the benzyl-substituted analogue 120 pM) and even 10 for titanocene 17 (IC50 for the benzyl-substituted analogue 280 pM). The sole decrease in cytotoxic activity was... 

Scheme 3 Synthesis of dimethylamino-functionalised titanocenes from the carbolithiation reaction of 6-/V,/V-dimcthylamino fulvene and aryl lithium species...

In order to avoid the presence of stereoisomers, a further pathway including a carbolithiation reaction delivering achiral titanocene dichlorides was explored. Different aryl or heteroaryl lithium species were reacted with 6-bis-/V,/V-di methyl -amino fulvene and therefore, the intermediate lithium cyclopentadienide and the resulting 6-bis-/V./V-dimethylamino-functionalised titanocene dichlorides become achiral. 

Scheme 5 Synthesis of achiral aryl and heteroaryl-substituted titanocenes from the carbolithia-tion reaction of 6-substituted fulvenes...

We have described the cycloadditions of a variety of dienes, ranging from cyclo-pentadiene to cyclopentadienones with alkyl and aryl fulvenes80-82. In these cases, only the [4 + 2] cycloadducts across the 2 and 3 positions are observed. Similarly, 1,3-dipoles such as nitrones and nitrile oxides add in this fashion, as well. We discovered the first authentic [6 + 4] cycloaddition of a fulvene in 197083. The cycloadditions of tropone to fulvenes, which we originally suggested involved [6-fulvene + 4-tropone] cycloadditions, now appear to be [6-tropone + 4-fulvene] cycloadditions8... 

Diels, O., Alder, K., Pries, P. Syntheses in the hydroaromatic series. IV. Addition of maleic anhydride to arylated dienes, trienes and fulvenes. Ber. 1929, 62B, 2081-2087. 

When a 2-thiomethyl-l,3-selenothiolium iodide such as (84) reacts with an aryl ketone (85) in pyridine-acetic acid, fulvenes such as (86) are obtained reaction with a Wittig-Homer reagent takes place at both carbonyl groups (Equation (8)) <90PAC473,91JCS(Pl)157>. 

The parent compound (R=R =H] is highly reactive and polymerises and undergoes autoxidation readily. In air it is destroyed in minutes. Fulvenes wherein R = alkyl and R =H also turn to tars in air within minutes of their formation but increasing substitution at the 6-position and especially substitution by aryl groups increase the longevity. 

Another interesting arylation is described under the section titled Other Reactions . Cinnamils (167) undergo an unusual NHC-catalysed transformation to 2,3,8-triaryl vinyl fulvenes (168a), using two equivalents of sodium hydride, plus an ortfto-terphenyl derivative (168b). Crossover experiments employing two (different) cinnamil starters (167) have been used to probe the mechanism. 

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