New synthetic methods using the TiCl 4 -NR 3 reagent system

The TiCl 4 -NR 3 reagent system is useful for carbon-carbon bond forming reactions such as the aldol and related condensation reactions, the diastereoselective coupling of phenyl acetic acid derivatives, the conversion of aryl alkyl ketimines and ketoximes to pyrroles, ketazines to dihydrodiazines, enamines to aromatic amines, N,N -dialkylanilines to the corresponding benzidine derivatives, trialkylamines to unsaturated aldehydes, diarylcyclobutanones, diarylcyclobutylamine derivatives via iminium ion intermediates and for the reductive coupling of aromatic aldehydes, aldimines and intramolecular reductive coupling of chiral diimine derivatives. In all cases, the organic products are obtained in moderate to good yields, in single-pot operations under ambient reaction conditions. Hence, these synthetic methods have considerable synthetic potential.


Introduction
Titanium reagents are widely used in organic synthesis. 1Whereas the organotitanium reagents are useful in C-C bond forming reactions, the simple TiX 4 1a-c and TiX 3 1d,e (X = Cl, OR) are frequently used in both stoichiometric and catalytic quantities in C-C bond forming reactions and functional group transformations.Among various titanium reagents, TiCl 4 has vast applications in organic synthesis.It has been used as such or in combination with an additive.
In the last 20 years, several useful synthetic transformations involving the use of TiCl 4 along with a tertiary amine NR 3 were uncovered.These results are presented in this account.

Discussion
The TiCl 4 -NR 3 reagent system has been widely used for the preparation of titanium enolates for applications in aldol and related reactions in organic synthesis.It was first used in Knoevenagel condensation reactions (Scheme 1).

Scheme 1
In 1986, it was discovered that the titanium enolate prepared using propiophenone reacts with arylaldehydes to give the corresponding aldols with very high syn selectivity (Scheme 2). 3  Similar reactivity pattern has been also observed in reactions using aliphatic ketones (Scheme 3). 4 O Stereoselective aldol reaction has been also observed in the reaction a titanium enolate prepared using a ketone and TiCl 4 /Bu 3 N reagent system with another ketone (Scheme 4). 5 TiCl 4 /Bu

Scheme 4
Aldehyde complexes of TiCl 4 reacts with another aldehyde in the presence of TMEDA to give the corresponding aldol with very high syn selectivity (Scheme 5). 6

Scheme 5
Titanium enolate of an α-dialkoxyketone gives the corresponding aldol adduct in the presence of TMSCl catalyst (Scheme 6). 7

Scheme 7
In these transformations, syn selectivity was realized.In contrast, high anti selectivity was realized in the reaction of a chiral amino indanol derived titanium enolate (Scheme 8). 9 Enantiomerically pure anti-aldols can be readily obtained upon hydrolysis of the anti adduct (Scheme 8). 9  The titanium enolates can be readily captured using a Michael acceptor.For example, the titanium enolate generated using N-propionyloxazolidone reacts with Michael acceptors to give the corresponding adducts with high diatereoselectivity (Scheme 9). 10

Scheme 11
In all these transformations the titanium species remains as Ti(IV) species.In recent years, several new organic transformations have been uncovered using the TiCl 4 /R 3 N reagent system in which the TiCl 4 species becomes Ti(III).For example, in 1996, it was reported that the TiCl 4 -NR 3 reagent system is useful in the preparation of the (dl)-C 2 symmetric 2,3-diphenylsuccinic acid esters (Scheme 12). 12The reaction is highly chemo and diastereoselective.

Scheme 12
The reaction proceeds through the formation of the corresponding titanium enolates, followed by oxidative coupling with concomitant formation of the titanium (III) species (Scheme 13).

Scheme 13
Asymmetric versions of such oxidative coupling reactions have been reported (Scheme 14). 13 X O DABCO Ph

Scheme 14
Methods have been developed for the resolution of the corresponding racemic dicarboxylic acid for applications in the synthesis of chiral 3,4-diphenylpyrrolidine system (Scheme 15).During these research efforts, it was observed that the oxidative coupling of the chiral binaphthyl esters leads to diastereoselective formation of the corresponding cyclic compound (Scheme 16). 15

Scheme 16
The reactivity pattern of the TiCl 4 /Et 3 N reagent system with organic substrates containing acidic hydrogens were further examined.It was observed that the reaction of acetophenone with TiCl 4 /Et 3 N reagent gave the corresponding 1,4-diketone in low yields (10-20%) along with the corresponding aldol condensation product. 16However, the reaction of aromatic ketimines produced the corresponding 2,5-disubstituted pyrroles in good yields, through oxidative coupling and aromatisation reactions (Scheme 17). 17

Scheme 17
The results can be rationalised by the mechanism shown in Scheme 18. 17

Scheme 18
Also, it was found that certain ketoximes react with the TiCl 4 /NEt 3 system to give the corresponding tetrasubstituted pyrroles (Scheme 19). 18

Scheme 20
The reactions of hydrazones derived from ketones are expected to form the corresponding 1,2-diazines.However, in this case, the reaction gave the corresponding dihydro derivative (Scheme 21).Aromatisation takes place when certain enamines are used in the reaction with the TiCl 4 /NEt 3 system (Scheme 22). 20The results can be rationalized considering initial deprotonation similar to that outlined in Scheme 18. NR 2

Scheme 22
It has been observed that the TiCl 4 -NR 3 system reacts with 1-alkynes to give the corresponding diynes, through the intermediacy of the alkynyltitanium species. 21Also, the alkynyltitanium species can be readily functionalised using certain electrophiles (Scheme 23). 21uch direct metalation is an interesting observation, as previously alkynyl titanium reagents were prepared via metalation of 1-alkynes with alkyllithium reagents followed by exchange reaction with titanium complexes. 22 HNEt 3 HC(OCH 3 ) 3

Scheme 23
Interesting oxidative coupling reactions have been observed using N,N-dialkylaniline derivatives. 23The corresponding benzidine derivatives are the products.Again, this transformation can be rationalised considering the intermediacy of the corresponding aryltitanium species. 23The aryltitanium species prepared in this way can be readily functionalized using certain electrophiles (Scheme 24). 23

Scheme 24
In 1955, it was reported that the TiCl 4 oxidises tertiary amines.Presumably, the corresponding iminium ions would be the organic product and the reaction can be rationalised by the intermediates shown in Scheme 25. 24 Clearly, the tertiary amine can be oxidised by TiCl 4 in the absence of organic substrates containing acidic hydrogen.Accordingly, we have examined the reaction of organic substrates that could trap such iminium ion intermediates formed in situ from the amines.It was found that the reaction in the presence of benzophenone gives the corresponding unsaturated aldehydes via condensation with the iminium ions (Scheme 26). 25  The results can be rationalized considering the mechanism outlined in Scheme 27.

Scheme 27
Interestingly, the reaction of an N,N-diisopropylalkylamine leads to the formation of the corresponding cyclobutanone in low yields in addition to the aldehydic products Scheme 28.

Scheme 28
Fortunately, iminium ions prepared from N,N-diisopropylbenzylamine using I 2 react with TiCl 4 /NR 3 reagent system to give the corresponding cyclobutanones in good yields (Scheme 29). 26t has been reported certain diarylcyclobutylamine derivatives are biologically active. 27ccordingly, we have examined the synthesis of the cyclobutylamine derivatives by carrying out the reduction of the iminium ion intermediates containing cyclobutyl moiety.It was observed that the corresponding cyclobutylamines are isolated in 60-70% yields under these conditions (Scheme 31).

Scheme 31
Reductive amination of carbonyl compounds with secondary amines is achieved via the reaction using TiCl 4 /NEt 3 followed by Na(CN)BH 3 reduction (Scheme 32).

Scheme 32
The TiCl 4 /amine system has been also used in the oxidation of certain alcohols.For example, the TiCl 4 /pyridine reagent combination is useful for the oxidative cleavage of methyl diphenyltartrate to methyl phenylglyoxalate (Scheme 33).

Scheme 35
As discussed previously (Scheme 25), the TiCl 3 species are produced in the reaction of TiCl 4 with NR 3 .We have observed that the TiCl 3 produced in situ in this way can be readily exploited to achieve reductive coupling of aromatic aldehydes and aldimines (Scheme 36).

Scheme 36
Also, the reaction of TiCl 3 prepared in this way is useful for the diastereoselective intramolecular reductive coupling reaction of aromatic aldimines containing chiral 1,2cyclohexyldiamine moiety, albeit in low yields (Scheme 37). 34However, the yields are better when the reaction is carried out with the TiCl 3 species prepared using the TiCl 4 /Zn reagent system.

Scheme 37
In conclusion, the TiCl 4 /R 3 N has been shown to be useful for the diastereoselective aldol and related reactions, oxidative coupling of phenylacetic acid derivatives, for the conversion of aryl alkyl ketimines and ketoximes to pyrroles, ketazines to dihydrodiazines, enamines to aromatic amines, N,N-dialkylanilines to the corresponding benzidine derivatives, trialkyl amines to unsaturated aldehydes, diarylcyclobutanones and diarylcyclobutylamine derivatives via metalation of iminium ion intermediates and for the reductive coupling of aromatic aldehydes, aldimines and intramolecular reductive coupling of certain chiral imine derivatives.Several of these transformations were previously carried out via multi-step syntheses.Since the transformations using the TiCl 4 /R 3 N reagent system described here are carried out in essentially single pot operations starting from readily accessible organic substrates under Scheme 2