Titanium Reagents in Heterocyclic Synthesis

This review confronts the diversity and selectivity of titanium reagents that mediate heterocyclic synthesis. Applications of different t itanium based reagents in various organic react ions leading to the format ion of heterocyclic compounds are discussed. Among others, epoxide-opening arene annulations, intramolecular coupling of carbonyl groups intermolecular hydroamination, intramolecular aza-Heck, reg ioselective synthesis of indoles, anti-Markovnikov hydration of internal and terminal alkynes, and the synthesis of polyarylpyrroles under microwave conditions, are reviewed.


Introduction
Transition metals med iated reactions are one of the most attractive methods in synthetic organic chemistry. [1] These meta ls catalyzed react ions offer pro mising range of selectivities such as chemoselectivity, regioselectivity, diastereoselectivity, enantioselectivity and atom economy, among others. A wide range of heterocyclics are now accessible following novel and efficient pathways based on intra-mo lecular cross-coupling of functional groups. Titaniu m is widely used among the various transition metals emp loyed for the synthesis of heterocyclic co mpounds. Pinacol and McMurry coupling react ions are the most powerful methods for constructing carbon-carbon bonds and have served as the key step in the synthesis of various heterocyclics, natural products and pharmacologically active compounds.
[2] Synthesis of substituted pyrroles from alkynes, imines, and carbon monoxide via an organotitanium intermediate or fro m alkynes, nitriles, imines, and titanium-imine comp lexes have been reported. [3,4] The indole ring system is a crucial structure in drug discovery and has become an essential co mponent in many pharmacologically active co mpounds. Regioselectively substituted pyrroles represent indispensable structural motifs of biologically active natural products and molecular sensors. [5] This review exp lores the recent literature, and describes o rg an ic sy nthes is app licatio ns and d ev elop men ts in mechanistic understanding of hetrocyclic synthesis catalyzed by d ifferent t itan iu m reagents such as TiCl 4 , Cp 2 TiCl 2 , Cp 2 TiMe 2 , TiCl 4 -BINOL, TiO 2 , and Ti(IV)-isopropo xide.

Titanium (IV) Chloride
Titaniu m ch lorides are the most important and much widely used catalyst for different synthetic applications.
McMurry coupling reaction has extended the scope of low-valent titaniu m chemistry beyond the classical reductive dimerization of aldehydes and ketones to alkenes. [6] Titaniu m ch loride pro motes the intramolecular coupling of carbonyl groups of distinctly different redox potentials co mpetently. This has open a new and flexib le entry into hetro-aromatic co mpounds such as furans, benzo(b)furans, pyrroles and indoles by reductive cyclization of o xo-ester or o xo-amides as depicts in the Scheme 1. [7-9] Scheme 1. Reductive cyclization for the synthesis of hetrocyclics, X = O, NR A user friendly procedure for intermo lecular hydroamination reactions which employs inexpensive and readily available TiCl 4 has been reported. [10] Ackermann and coworker used TiCl 4 /t-BuNH 2 as catalyst for hydroamination based Fisher Indole synthesis. The reaction commence with the addit ion of 1,1-disubstituted hydrazines onto aryl and alkyl-substituted alkynes catalyzed by the addition of t-BuNH 2 to a solution of TiCl 4 in toluene competently. [11] (Scheme 2) In this process, hydrazine is directly converted to the indole derivative.

Scheme 5. Synthesis of three component polysubstituted pyrroles
Under the same condition, this method can be applied to the aromatic aldehydes with either electron-withdrawing groups (such as halide groups) as well as electron-donating groups (such as alkyl and alko xy l groups) and aliphatic aldehydes. The advantage of this method includes easily accessible starting materials, short reaction time, high yields, regioselectivity, and convenient manipulation, among others. In another report, Ackermann et al. have described the synthesis of pyrro le through titaniu m cataly zed inter-mo lec ular hydroamination reaction through diasteromeric mixtu re of chloroenyes. [29] Synthesis of pyrrole ut ilizes α-haloalky TiCl 4 , Sm ,THF rt, 15 min nols through a reaction sequence comprising dehydration, intermolecularhydroamination, [1,5]H-sig matropic shift and intramolecular nucleophilic substitution. (Scheme 6) Scheme 6. T itanium catalyzed synthesis of pyrrole using α-haloalkynols Duan et al. achieved a total synthesis of cicerfuran, a naturally occurring benzofuran co mpound using a simp le procedure and readily availab le reagents. [30] Th is synthetic approach promotes the scope of cross McMurry reaction and provide a novel approach for the facile synthesis of 2-ary lbenzofurans. In another paper, Abbiati  Application of TiCl 4 as catalyst extends to the synthesis of aromat ic thiazoles. 2-Arylbenzothiazole has been prepared fro m bis-(2-benzalaminophenyl)disulfide using titaniu m tetrachloride and samariu m powder in anhydrous tetrahydrofuran (Scheme 8). [32] Disulfides give the expected products either bearing electron-withdrawing groups (such as halide) or electron-donating groups (such as alky l and alko xy l groups) under the same reaction conditions with moderate to good yields. The electronic nature of the substituent has no significant effects on this reaction.

Cp 2 TiCl 2
Titanocene chloride is a well-known reagent for generating carbon-centred rad icals fro m epo xides.Diastereo selective inter-and intramo lecular p inacol couplings of aldehydes have been reported using a titanium(III) complex. [33,34] Zhou and Hirao reported catalytic reductive cyclization of o lefinic iodoethers by use of Cp 2 TiCl 2 in the presence of Mn and Me 3 SiCl. [35] (Scheme 9) This protocol provides a versatile method for the selective format ion of mu ltisubstituted tetrahydrofurans. In the absence of Cp 2 TiCl 2 , this react ion led to a much lower yield.

Scheme 9. Preparation of multi-substituted tetrahydrofuran
Diastereoselective inter-and intra-mo lecular pinacol coupling of aldehydes have been reported using a titanium(III) co mp lex. [36] Jana and Roy have developed a method to synthesize benzopyrans by radical cyclizat ion of aromat ic carbonyl compounds using titanium(III) chloride as the radical init iator. [37] The radical in itiator (Cp 2 TiCl) is prepared in situ from co mmercially available titanocene dichloride (Cp 2 TiCl 2 ) and zinc dust in THF under argon. (Sche me 10) Intermo lecular coupling product is the major product when Cp 2 TiCl was added in the normal way. However, slow addition of carbonyl co mpound to the reagent (Cp 2 TiCl) yields the cyclized product in good yield without any of the coupling product.   In another paper, Maciejewski and Wipf reported the conversion of N-epo xyalky lanilines into indolines catalyzed by Titanocene (III) Ch loride. [39] The react ion proceeds through Curtius rearrangement of the known carbo xylic acid followed by subsequent trapping of the intermediate isocyanate with benzyl alcohol afford ing the Cbz-protected aminopyridine in 33% yield over 3 steps. (Scheme 12) Subsequent methally lation and epo xidation using m-CPBA led to epoxide, wh ich on treatment with catalytic titanocene(III) chloride in the presence of stoichio metric manganese powder, p rovided an intermed iate 4,6-dich loro-5-azaindoline. Further conversion of this intermed iate with Pd/C under an atmosphere of H 2 gave azaindoline in 52% yield over 2 steps.

Cp 2 TiMe 2
Petasis reagent (dimethyltitanocene, Cp 2 TiMe 2 ) has proven to be very effective for the methylenation of esters. [40,41] Cp 2 TiCl 2 also serves as a precursor for the synthesis of Cp 2 TiMe 2 . A new synthetic entry to the 1,4-dihydroquinoline nucleus involves dimethyltitanocene catalysed methylenation of N-(alko xycarbonyl)amides derived fro m 2-allylan ilines, followed by ring-closing metathesis of the resulting enamides. [42,43] Bytschkov and Doye have reported intra-molecu lar hydroamination/ cyclization of aminoalkynes catalyzed by Cp 2 TiMe 2 . [44] This catalyst has been found a competent catalyst for the intramolecular hydroamination/cyclization of aminoalkynes The hydroamination reactions proceed smoothly in the presence of 5.0 mo l% Cp 2 TiMe 2 at 100-110℃ to give fiveand six-membered cyclic imines within 4-6 hours. After subsequent reduction with zinc-modified NaBH 3 CN at room temperature cyclic amines can be isolated in good yields. In combination with an imine reduction, the intramolecular hydroamination reactions can be used for a convenient one-pot synthesis of cyclic amines fro m aminoalkynes. (Sche me 13) Scheme 13. One-pot synthesis of cyclic amines from aminoalkynes by Cp2TiMe2 catalyzed intramolecular hydroamination and subsequent reduction Indoles have also been synthesized v ia alky lidenation of acylphenylhydrazides using phosphoranes and the Petasis reagent, followed by in situ thermal rearrangement of the product enehydrazines. The Petasis reagent provides an essentially neutral equivalent of the [acid -catalysed] Fischer indole synthesis with acyl phenylhydrazides as starting substrates. [45] (Scheme 14) Alkylidene triphenylphosphoranes convert aryl phenylhydrazide to indoles, but acyl phenylhydrazides derived fro m aliphatic carbo xy lic acids undergo a Brunner reaction to form indolin -2-ones.

Conclusions
Transition metal med iated reactions are one of the most attractive methods in synthetic organic chemistry. Analysis of a variety of t itaniu m reagents in hetrocyclic synthesis has revealed that their efficiency strongly depends on the nature of the active t itaniu m species and the experimental conditions. The reasons that exp lain the interest shown by many researchers includes, among others, regio-and stereochemical control of the reaction, together with the mildness of the experimental conditions which include the use of catalytic quantities of titanium.
The rapid access to indoles as well as the selection of environmentally benign and chemoselective methods are the major goals in heterocyclic synthesis using titanium reagents based catalysts. The exp loration for new annulations and heterocyclizat ion procedures is a very co mpetitive and determined research field. Many organic reactions catalyzed by titanium reagents are presented involving the use of transition-metal co mplexes (especially palladiu m co mp lexes, but many other transition-and main-group metals and their complexes are continuously being studied and introduced in the chemistry of heterocycles, thermal react ions, photochemical procedures, solid-support synthesis for a combinatorial approach, green procedures with the auxiliary techniques of microwaves and ultrasound for environ mental friendly reaction conditions.