And Chromium(III)-Mediated Organic Synthesis Ludger A

REVIEW 1

Recent Advances in Chromium(II)- and Chromium(III)-Mediated Organic Synthesis Ludger A. Wessjohann, GŸnther Scheid Ludger A. Wessjohann,* GŸnther Scheid Vakgroep Organische en Anorganische Chemie, Faculty of Chemistry, Vrije Universiteit Amsterdam, De Boelelaan 1083, NL-1081 HV Amsterdam Fax: +31(20)4447488; E-mail: [email protected] Received 7 September 1998 Dedicated to Professor Dr. Wolfgang Steglich on the occasion of his 65th birthday

4.1 Dehalogenations and Reductions Abstract: Synthetic transformations utilizing chromium(II) or 4.2 CÐC Coupling Reactions: Radicals from Carbonyl Groups chromium(III) reagents, mainly CÐC-coupling reactions, are dis- 4.3 CÐC Coupling Reactions: Radicals from Alkyl Halides cussed. Chromium reagents find increasing application in complex 5 Reactions Catalytic in Chromium(II) total syntheses where other organometallics are difficult to apply. 5.1 General Aspects They are easy to prepare and exhibit extraordinary chemoselectivity 5.2 Chromium(II) Recycled with Reductive Metals and high diastereoselectivity. In this article emphasis is laid on re- 5.3 Electrochemical Reactions cent results in synthetic procedures, on little known general aspects 5.4 Chromium(II/III) Compounds in Alkene Polymerization and of (organo)chromium chemistry, and on areas not reviewed before. Alkane formation The most important recent advances include reactions catalytic in 6 Asymmetric Synthesis with Chromium(II)-Mediated Reac- chromium ions, anti-selective Reformatsky-type aldol reactions tions with excellent asymmetric induction, domino radical/carbanion re- 6.1 Auxiliary Based Methods actions, asymmetric chromium(III) catalyzed epoxide openings and 6.2 Ligand Based Methods homogeneous alkene polymerization catalysts. Some progress is 7 Reactions at Heteroatoms also made in ligand controlled enantioselective reactions with Cr(II) 8 Chromium(III)-Mediated Reactions reagents, but satisfying solutions remain a major challenge in the 9 Conclusion and Outlook field. Key words: chromium(II), chromium(III) alkyls and enolates, radical cyclizations, Reformatsky-type aldol reactions, NozakiÐHiya- ma and TakaiÐKishi reactions. 1 Introduction

1 Introduction The first organic chemical reactions involving chrom- 2 Importance of the Specific Properties of the Central Ions ium(II) made use of the reductive potential of the ion, Chromium(II) and Chromium(III) in the Design of Cr(II/ mainly to achieve dehalogenations.1Ð3 Later, alkene for- III)-Based Reactions mation from organic 1,2-dihalides and the first CÐC-cou- 3 Addition of Organochromium(III) Intermediates to Carbon- 4Ð17 yl Compounds plings were also discovered. Chromium(II) reagents 3.1 The Chromium-Reformatsky Reaction: Chromium(III) Eno- gained their place in modern organic synthesis in the late lates and Related Species 1970s when Nozaki and Hiyama discovered the ion to 3.1.1 General Aspects of the Chromium-Reformatsky Reaction promote chemoselective CÐC-couplings in aprotic solvent 3.1.2 Reactivity and Stereoselectivity with Simple α-Halocarbon- (WurtzÐ and HiyamaÐNozaki reactions).18Ð21 This was the yl Derivatives onset of an ever increasing development of synthetic 3.1.3 Reactions of 4-Bromocrotonates 3.1.4 Chemoselectivity in the Chromium-Reformatsky Reaction methods based on chromium(II) reagents, mainly chrom- 3.2 The NozakiÐHiyama Reaction: Allyl- and Propargylchromi- ium dichloride, and is reflected in the amount of reviews um(III) Intermediates; Benzylchromium(III) Intermediates devoted to the subject in organic chemistry. The early 3.2.1 Reactions Involving Allylchromium(III) Intermediates ones covered mainly reductions,1,22 later organochromium 3.2.2 Reactions Involving Propargyl- and Allenylchromium(III) reactions became the center of interest.15,20,23 In the early 3.2.3 Reactions of Benzylchromium(III) Derivatives 1990s, with applications in total synthesis exploding, the 3.3 Reactions of Alkylchromium(III) Intermediates; Chromium- number of specialized reviews rose rapidly,24Ð32 but chrom- Mediated Alkenation Reactions 3.3.1 General Aspects ium(II) reagents were also covered in other, more general 22,33Ð48 3.3.2 Reactions of Alkyl Halides with an Activating Substituent in reviews and books. Other recent reviews concen- α-Position trate on inorganic and physical chemistry and technical 3.3.3 Alkenation Reactions (TakaiÐHodgson) aspects like the surface chemistry of chromium ions de- 3.3.4 Reactions of Nonactivated Haloalkyl Derivatives posited on oxides;49 structure, reactivity and polymeriza- 3.3.5 Reactions of Halocyclopropanes tion activity of organochromium(III) compounds;50 and 3.4 The TakaiÐKishi (NozakiÐHiyamaÐKishi) Reaction: Vinyl-, complexes and kinetics of organochromium(III).51 Aryl- and Ethynylchromium(III) Intermediates 3.4.1 Vinyl- and Arylchromium(III) Intermediates The purpose of this review is to catch up on recent develop- 3.4.2 Reactions Involving Alkynylchromium(III) ments since the comprehensive review of Saccomano on nu- 4 Reactions of Carbon Centered Radical Intermediates Gener- cleophilic organochromium reagents,29 and the more speci- ated with Chromium(II) and Related Reactions alized one of Cintas which appeared in this journal in 1992.28

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2 L. A. Wessjohann, G. Scheid REVIEW

However, since some aspects of the field have remained un- prox. Ð0.41 V (Figure 1) allows the mild reduction of covered in most reviews, we felt that for some minor areas a alkyl halides but in most cases is not sufficient to attack larger timeframe had to be covered. Often quite underesti- carbonyl groups directly, thus avoiding a problem com- mated is, for instance, the importance of chromium(II/III) in mon to strong and oxophilic ions like samarium(II). Com- technical processes, e.g. as the center of the second most im- pared to most metals used in similar reactions (Grignard, portant family of alkene-polymerization catalysts. Barbier reaction, etc.) chromous salts have little reducing power. They are best comparable to the also highly Most reactions with chromium(II) compounds proceed via 53 chromium(III) intermediates. Thus the properties discussed chemoselective indium metal, but without the disadvan- are usually those of organochromium(III), not of Cr(II). We tage of being a heterogeneous reagent. hope to bring some general aspects of chromium(III) chemistry into focus, which appear to be less well known to the purely synthetic chemist, in order to aid method design and applications in the future. Recently chromium(III) compounds have become of greater importance in their own right, and thus syntheses utilizing defined chromium(III) reagents are reviewed for the first time. Although the reduction properties of Cr(II) are in most cases still the bases for Figure 1 Reduction potentials of some metals and low valent ions the many reactions and applications developed, other prop- commonly used in organic synthesis (vs. standard hydrogen elec- erties of these ions and especially of Cr(III) have become trode)54 the center of interest and account for the immense success of Cr(III)-centered reactions in the total syntheses of com- The reduction potential of chromium(II) can be modified to plex molecules and in other reactions. Some basic proper- a large extent by ligands, or counter ions and solvents if ties of the ions involved and organochomium(III) are these act as ligands. Donor solvents like DMF increase the highlighted in the following section. reduction potential considerably, as do strong donor ligands like cyclopentadienyl (cp) or polydentate nitrogen ligands. Apart from this thermodynamic effect some ligands seem 2 Importance of the Specific Properties of the to improve the kinetics of electron transfer by breaking up Central Ions Chromium(II) and Chromium(III) the common dimeric or clustered structures of chromi- in the Design of Cr(II/III)-Based Reactions um(II) compounds. Monomeric donor complexes like chromocene are extremely reactive even at low temperature Chromium(II) is the strongest reductive metal ion soluble (vide infra). In general, chromium(II) is one of the kineti- but not rapidly reacting in water.52 The potential of ap- cally most labile transition metal ions (Figure 4).55

Biographical Sketches

Ludger Wessjohann was Skatteb¿l in Oslo (Norway) completed Habilitation at born in 1961 in Melle, and after his Ph.D. as lectur- the Ludwig-Maximilians- Germany. He studied in er at the Universidade Fed- UniversitŠt MŸnchen in Hamburg (Germany) and eral de Santa Maria in Brazil 1992. Since June 1998 he is Southampton (UK) and re- (1990), where he also was full professor of bio-organic ceived his degrees from the visiting professor in 1993 chemistry at the Vrije Uni- University of Hamburg (Di- and 1995. After a postdoc- versiteit Amsterdam, The ploma 1987, Ph.D. 1990, toral stay with Professor Netherlands. His research both with Professor de Paul Wender at Stanford interests include the devel- Meijere). During his Ph.D. University (USA) working opment of new synthetic he worked 1987/88 as a vis- on the total synthesis of methods, biocatalysis, and iting scientist with Professor Taxol he started his recently natural products chemistry. GŸnther Scheid was born (LMU). The work was car- thesis. His current interest is in Landshut, Bavaria ried out under the supervi- focused on the total synthe- (Germany), in 1971. He ob- sion of Ludger Wessjohann, sis of biologically active tained his diploma in 1997 whom he followed to the compounds. from the Ludwig-Maximi- Vrije Universiteit Amster- lians-UniversitŠt MŸnchen dam to work on his Ph.D.

Synthesis 1999, No. 1, 1Ð36 ISSN 0039-7881 © Thieme Stuttgart á New York

REVIEW Recent Advances in Chromium(II)- and Chromium(III)-Mediated Organic Synthesis 3

Important for overall reactivity is the concentration of iour of the organic part.51 These are competing reactions, Cr(II), i.e. the solubility of the reagent. For the standard extremely dependent on Cr(II)-concentration, tempera- reagent CrCl2 it follows the order H2O > DMF >> THF > ture, pressure, ligands and the nature of the alkyl MeCN. A positive effect on solubility and reactivity is ob- group.63Ð65,73,74 Homolysis is not observed with primary served by the addition of lithium iodide.56,57 The effect is alkylchromium(III). Benzylchromium(III) and secondary neither only that of nucleophilic iodide catalysis nor a alkylchromium(III) have homolysis rates of ~10Ð3 Ð 10Ð4 Ð1 ∆ Ð1 51 simple Lewis acid influence of the cation on the sub- s [ H (Cr(III)ÐCH2Ar-bond) = 100Ð140 kJmol ]. The strates. A large part of the increased reactivity can be as- CÐCr(III) heterolysis reaction usually is much faster than signed to the enhanced solubility and possibly electronic heteroatom-Cr(III) cleavages and strongly dependent on modification and ÒmonomerizationÓ of CrCl2. According- the ligands (τ1/2 of hydrolysis is around ~30 minutes, but ly the effect is strong in the poor solvents THF and MeCN, can range from microseconds to months).51,65,73,75 Thus but very small in DMF. A color change is observed and water ligands or polydentate N-ligands stabilize the com- the formation of chromate(II) species, e.g. Li2[CrX4], has plexes, rendering them often unreactive to carbonyl been proposed to explain the effect.56,57 groups (or protons or air, Scheme 1), whereas acetate and 64,65,73 A very important factor is the purity of the chromous salts, phosphate catalyze the heterolysis. In RÐCr(III)L5- 28,56Ð58 compounds the exchange rate of a trans-ligand is approx- especially if the dichloride is used. For reliable ex- 5 51 periments chromium dichloride of > 99.9% purity should imately 10 times faster than that of a cis-ligand. be used. Commercial material should be free flowing, grey or ideally even white colored, but not greenish. The best way to synthesize pure material is the reduction of an- 59 hydrous, pure CrCl3 in a hydrogen/HCl-stream. Reduc- tion with LiAlH4, which may be done in situ in some solvents, gives material of a different (sometimes higher) reactivity.18,20,60,61 Figure 2 Radii of metal ions commonly used as reaction centers (coordination number 6)76 The two major pathways to obtain organochromium(III) reagents are metal exchange (Scheme 1-B) or redox reac- Chromium(III) possesses an ion radius76 comparable to tion of Cr(II) with organic halides (Scheme 1-A). The lat- that of titanium(IV).37 Most other metal ions acting as re- ter reaction is much more useful and reliable in organic action centers in carbanion type reactions not only have a synthesis. Although chromium(III) alkyls possess carb- much larger radius (Figure 2),76 but they often also have a anion reactivity, they are pure metalorganic com- less densely packed ligand sphere. Chromium(III) almost pounds,9,62Ð67 as is clearly shown in the extraordinary exclusively favours an ideally octahedral arrangement. stability of some complexes to hydrolysis enabling CÐC- Both factors result in a tight transition state, especially if coupling reactions even in the presence of water (see Sec- a ZimmermanÐTraxler model is followed.57,77Ð79 This tion 4). The ion appears to be preferentially σ-bound to model (Figure 3) easily explains the chemo- and diastereo- carbon even in allyl-type systems, if a primary allyl posi- selectivity of allyl chromium(III) or chromium(III) eno- tion is available. However, rapid scrambling of the double lates. Thus, strong 1,3-interactions of the endo-axial bond configuration, likely via π-intermediates, is occur- (ÒsuperaxialÓ) ligand with the pseudoaxially oriented ring, unless one end of the allylic system is tertiary and thus R2 group in the electrophile would greatly encourage reac- energetically inaccessable (With CtertÐCr-σ-bond the tions of electrophiles with a small R2 group, i. e. aldehydes homolysis equilibrium favours the dissociated products16). (R2 = H) will be preferred to ketones, methyl ketones to The fact has been used for stereodivergent NozakiÐHiyama larger ketones. The YR-group (e.g. alkoxy in esters) is reactions (Section 3.2.1).68,69 With phosphane ligands or no also impaired by this effect and adds additional 1,3-diax- primary allyl carbons available, π-complexes prevail.70Ð72 ial strain compared to α-unsubstituted allylchromium. Al- lylic strain influences the double bond configuration and the diastereoselectivity in a cooperative effect with the 1,3-strain. The model explains the excellent anti-selectivity of allylchromium (YR = H, E-conf.), the YR-dependent

Scheme 1 Typical formation procedures and ligand influence on the reactivity of organochromium(III) complexes

The dissociation kinetics of carbonÐchromium(III) bonds is different from the detachment of heterobonded ligands (vide infra). Two differing types of detachment have to be considered: Homolysis to Cr(II) and organic radical, and Figure 3 A Zimmerman-Traxler transition state model successful- alternatively heterolysis resulting in carbanion like behav- ly applied in HiyamaÐNozaki and chromium-Reformatsky reactions (Y = CH2, O)

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4 L. A. Wessjohann, G. Scheid REVIEW anti-selectivity of ester enolates (YR = OR, E-conf.), and the ions. The isomers were then tested in reactions of muscle syn-selectivity of ketone enolates (YR = Alkyl, Z-conf.) and pyruvate kinase, and only the ∆-â,γ -bidentate Cr-ATP some 2-substituted allyl compounds (YR ≠ H). Individual re- was active in phosphoryl transfer.85 actions will be discussed in Section 3. The kinetic properties are also responsible for the low tox- The ligand exchange kinetics of chromium(III)-product icity of chromium(III) salts compared to the highly carci- complexes, mainly alcoholates, influences all possible sub- nogenic Cr(VI)-compounds.86Ð92 In toxicity discussions sequent steps, from retro-reactions, rearrangements, and the two ions are often mixed up, although speciation now catalytic recycling of the metal ion to the ÒsimpleÓ hydrol- becomes more important in environmental analyses.93Ð95 ysis to alcohols or other electrophilic quench reactions. Apart from the deserved bad reputation of its higher oxi- Chromium(III) is extremely resistant to ligand exchange, dized form unfortunately also the green colour of the aqua stabilizing even thermodynamically labile complexes for complex adds a lot to the Òpsychological toxicityÓ of extended periods of time. The exchange rates are ca. 15 or- chromium(III). The toxicity of Cr(III) is similar to that of ders of magnitude lower than those of most other ions (Fig- other first row transition metal ions.96 Many Cr(III) com- 45,80Ð83 ure 4). As a result most reactions, with the exception pounds, like CrCl3 are not only insoluble in water, even of simple protonation (hydrolysis), appear to be slowed most soluble complexes are not easily bioaccessible un- down or even inhibited by chromium(III), even under con- less a proper complex is used, nor is Cr(III) as easily trans- ditions where other metal ions rapidly release the alcohol- ported through cell walls as Cr(VI).87,89,99,100 Not much is ate. This distinctive behaviour can explain some of the known about the toxicity of Cr(II). special properties of chromium(II/III) based reactions. Be- ing aware of this can also help the development of new methods, for example to avoid subsequent reactivity and 3 Addition of Organochromium(III) thus e.g. making the use of protective groups unnecessary. Intermediates to Carbonyl Compounds The ligand exchange inertness helps to isolate distinctive kinetic products, as will be exemplified in Section 3.1 for A major advantage of chromium reagents is their excel- the chromium-Reformatsky reaction. Sometimes the rapid lent chemoselectivity in both steps, the formation of the electron exchange of Cr(III) with Cr(II) offers the possibil- organochromium(III) intermediate, and its subsequent re- ity of a catalyzed ligand exchange,75 a fact also utilized in action with an electrophile. The formation of the metalor- 84 the zinc catalyzed solvation of CrCl3. ganic reagents from CrCl2 and organic halide in aprotic solvent (THF, DMF) follows roughly the order: (A) α-halo ketones; 4-haloalk-2-enoates > α-halo esters; benzyl halides ≥ α-haloacetates > allyl halides, α-hetero- alkyl halides >> alkyl halides >> vinyl and aryl halides. (B) halides: I > Br >> Cl [nonhalogen leaving groups (OTf, OPO(OEt)2, OR etc.) react only after catalytic activation (IÐ, Co(I), Ni(0), TMSI), except 1-hydroperoxo- methylethyl]. (C) solvent/ligands (see also Section 2): cyclopentadie- ≥ Figure 4 Half-lifetimes of a ligand in metal complexes nyl (Cp) > polydentate N-ligands > H2O DMF, DMA, m+ 82,83 DMSO > THF > MeCN, Et O>> alkanes; haloalkanes; es- [M(H2O)n] in water at 25¼C 2 ters. An interesting application of the exchange-inertness of Simple alkyl, vinyl and aryl halides only react under co- chromium(III) complexes is the fixation of conformers of catalysis of Co(I) or Ni(0) (see Sections 3.3 and 3.4). biologically important enzyme substrates in the ligand Almost all types of nucleophilic organochromium(III) re- sphere. Thus several conformations of the triphosphate agents show a similar order of reactivity with regard to the moiety in ATP were fixed as Cr(III)-complexes of known electrophiles attacked (in THF): structure and stereochemistry (one of which is shown in Figure 5). CrX2+ substitutes the exchange labile Mg2+- (D) aliphatic aldehydes ≥ aromatic aldehydes > methyl ketones ≥ higher ketones >> [acid chlorides and anhy- drides; nitriles; imines and iminium salts; γ-mono- and unsubstituted Michael acceptors] >> ester; allyl-, benzyl and alkyl halides. Higher yields are generally achieved with an excess of halide/CrCl2 compared to an excess of aldehyde or equal amounts of reactants. The following subsections are devoted to the aspects of reactivity, chemoselectivity and Figure 5 The ∆-â,γ-bidentate Cr(III)-ATP complex with a fixed stereoselectivity of individual classes of intermediates, conformation of the triphosphate moiety active in phosphoryl transfer of a pyruvate kinase

Synthesis 1999, No. 1, 1Ð36 ISSN 0039-7881 © Thieme Stuttgart á New York REVIEW Recent Advances in Chromium(II)- and Chromium(III)-Mediated Organic Synthesis 5 with special aspects like catalytic (Section 5) and enantioselective (Section 6) reactions excluded.

3.1 The Chromium-Reformatsky Reaction: Chromium(III) Enolates and Related Species Scheme 3 Racemization at C-α suggests a planar intermediate 3.1.1 General Aspects of the Chromium-Reformatsky the Reformatsky intermediates. Lithium enolate / CrCl Reaction 3 mixtures show stereoselectivities between those of pure α-Halo ketones, esters, nitriles and other Reformatsky lithium enolates and the chromium(III) enolates of the Re- substrates readily react with chromium(II) salts, usually formatsky route. Increased side reactions and much lower chromium dichloride, in the presence of carbonyl electro- yields of aldol products make the method synthetically philes to give the corresponding aldol compounds (cf. useless. A possible reason may be the ligand exchange Scheme 2).56,57,78,79,81,103Ð110 Most reactions proceed stability of chromium(III), impairing the necessary chlo- smoothly within a few minutes or hours between room ride-enolate-exchange as well as the complexation of the temperature and 60¡C, usually in THF, DMF or acetoni- aldehyde electrophile. However, improved transmetal- trile. 2-Halo ketones108 and vinylogous compounds are the ation procedures may be useful tools in the future. most reactive substrates. Esters, especially acetates are much less reactive, and may require either lithium iodide addition and/or slightly elevated temperatures.56 Most chromium-Reformatsky reactions have been performed with equal amounts of reagents or excess of the usually cheaper electrophiles. However, as with other chromium(II) reactions, the inverse ratio of reagents with excess Scheme 4 Crossover experiments exclude possible reformation of halide/Cr(II) gives improved yields. enolate: Only the product with the initially added aldehyde is found [Experiment A: R1 = Ph, R2 = i-Pr; Experiment B: R1 = i-Pr, R2 = Ph]

The most important difference between the chromium- Reformatsky reaction and other aldol-type reactions is the fact that kinetic aldolates are formed exclusively, inde- Scheme 2 The chromium-Reformatsky reaction pendent of the reaction time and (changes in) reaction temperature.57,81,104,105,112 Any aldolate formed during the 3+ The formation of the reactive intermediate, which may be metal ion centered reaction is also a ligand of the Cr -ion, which itself is formed in situ from the exchange labile considered a chromium(III) enolate (2, vide infra), pro- 2+ 3+ ceeds quickly by reduction of the corresponding halide 1 Cr . Retro-aldolization at Cr -centers would be identical with two equivalents of chromium(II).111 Since acid/base to the first step of a ligand exchange, a process usually reactions are not involved, the process takes place under much too slow to happen within the reaction time. As a extremely mild, neutral conditions. The enolate is gener- consequence, the chromium aldolate is kinetically stable, ated at a location predetermined by the halide, and thus in- the retro reaction is inhibited, i. e. in this Òintrinsic kinetic dependent of kinetic or thermodynamic CÐH-acidities at quench mechanism (inkquem)Ó, reaction and quenching other sites in the molecule. Combined with the excellent (as Cr(III)-aldolate) are coupled mechanistically. The ki- chemoselectivity of chromium(II) these are ideal condi- netic stability of the chromium(III) aldolates of esters was proven by a series of experiments, e. g. through crossover- tions for the formation of sensitive enolates at unusual po- 57,112,114 sitions in complex, functionalized molecules.57,78 reactions with two aldehydes (Scheme 4). As will be reviewed below, the intrinsic kinetic quench mechan- Intra- or intermolecular scavenging of the suspected inter- ism improves aldol reactions of sensitive substrates, al- mediate radical, which might be present after the first lows selectively formed unusual products to be locked electron transfer, was not possible if sufficient chrom- even at elevated temperatures, e. g. in anti-selective ium(II) and aldehyde were present. However, reactions of Evans aldol reactions with excellent inverse induction at α-carbonyl radicals from the corresponding halides can be room temperature,106 or in the synthesis of a retro-reactive affected as will be shown in Section 4.3. We could prove Epothilone fragment.104 Also the excess or lack of re- the intermediacy of a planar intermediate utilizing nonra- agents, a common problem in microscale and solid phase cemic 2-bromopropionate 5 which gave racemic aldol reactions, has no effect on the integrity of the kinetic prod- 57,112 products 6 exclusively (Scheme 3). ucts. An alternative process, the transmetalation of a lithium Recently presented mechanistic experiments show that enolate with chromium trichloride, is not very effi- chromium-Reformatsky intermediates react exactly as 57,113 cient. The nature of the intermediate obtained this predicted for well-behaved metal enolates (CrÐO).115Ð120 way might be considered even more doubtful than that of

Synthesis 1999, No. 1, 1Ð36 ISSN 0039-7881 © Thieme Stuttgart á New York 6 L. A. Wessjohann, G. Scheid REVIEW

Exceptions are simple α,α-unsubstituted acetates and primary vinylogous substrates. Both, but most certainly the latter, can be regarded as CrÐC-species. This explains their contrasting behavior and allows predictions regarding the stereochemical outcome of reactions of 4-halo- crotonates (vide infra).105 Scheme 5 Reaction of ketones with Reformatsky substrates and chromium dichloride 3.1.2 Reactivity and Stereoselectivity with Simple α-Halocarbonyl Derivatives The nature and bulkiness of the aldehyde seems to have Ketone enolates are known to prefer Z-configura- little influence on the reactions and most yields are in the tion.115Ð120 Accepting a ZimmermanÐTraxler transition 80Ð98% range.56 Even aldehydes prone to self-condensa- state (Z.-T.-TS, cf. Figure 3), reactions of prochiral chro- tion, like phenylacetaldehyde (entry q), react cleanly. Re- mium enolates with aldehydes accordingly gave syn- actions with ketones are smooth but give lower yields, products preferentially (Table 1). Large α'-residues give mostly in the 60% range (Scheme 5, cf. also Scheme 9).79 excellent diastereomeric excesses, which rapidly cease Since retroaldolization is not observed, the construction of with decreasing bulkiness (Table 1, entries a, b, d).108 Im- adjacent quarternary centers is easily achieved. provements have recently been achieved through salt addition and by switching from THF to acetonitrile solvent In contrast to α-halo ketones 9, the simple diastereoselec- (entry d vs. e, f).56,79 Lithium iodide also reduces the reactivity of the aldol products 12 of esters (Table 2, entries aÐ tion time and allows chlorides as substrates to be used. s), imides (Scheme 6), nitriles (entries AÐF) and amides The assumption of an enolate intermediate reacting (entries αÐδ) is opposite to that usually observed with through a Z.-T.-TS is supported by the reaction of cyclic lithium- or zinc-enolates (Tables 2 and 3 for nitriles and substrate 9c. Forced to give the E-enolate, it yields exclu- esters respectively).56,57,121 The diastereomeric excesses of sively the anti-product. Ketones are also suitable electro- nitriles (Table 2, AÐF) and especially amides (αÐδ) are philes (entries gÐj). Self-condensation of the halo ketones unfortunately as low as the ones observed with the lithium was not observed when the reactions were run in Barbier- enolates, however, with the opposite configuration (most- type fashion.79 ly syn). The deÕs obtained with chiral α-halo esters (11aÐ s) and Evans-type α-halo imides 18, however, are not only Table 1 Reactions of α-Halo Ketones with Aldehydes and Ketones anti-configured but are mostly better than those achieved with other low valent metal ions or metals (Table 3).56 Taking into account the reaction temperature (r.t. vs. usually Ð78¡C), deÕs with chromium are much better. Increas- ing α-substitution leads to a reversal of stereochemistry for substituents bigger than isopropyl (Table 2, entries i, j), i. e. chromium is again showing a behavior inverse to #R1 R2 R3 R4 Solvent/ t anti:syn Yield Ref. Additive (h) (%) similar lithium/zinc compounds. In fact one could state that the chromium(III) ion shows Òtext book behaviourÓ a t-Bu Me Ph H THF 24 0:100 50 108 with the expected E-propionyl enolate (Òtrans-enolateÓ) b t-Bu Me i-Pr H THF 24 0:100 81 108 leading to the anti-product via a Z.-T.-TS (cf. Figure 3, c -(CH2)4- Ph H THF 24 100:0 75 108 d Ph Me Ph H THF 24 50:50 68 108 Y = O, R4 > R3). Although most other propionyl enolates e Ph Me Ph H THF/LiI 1.0 28:72 68ab f Ph Me Ph H MeCN/LiI 0.25 20:80 72 b are supposed or proven to be Òtrans-enolatesÓ as well, g Ph H Me Me THF/LiI 1.0 Ð 78 79 e. g. lithium ester enolates [formally Z-configured (CIP: h Ph H Ph Me THF/LiI 1.0 Ð 44 79 i Ph Me Me Me THF/LiI 1.0 Ð 88 79 OLi < OC)], on reaction with an aldehyde, they prefer to j Ph Me Et Me THF/LiI 1.0 Ð 84 79 form the syn-products mostly.115Ð117 a Reaction run at 55¡C b This publication57

α-Halo nitriles, esters, imides and amides react smoothly in chromium-Reformatsky reactions, with moderately decreasing reactivity, roughly in this order (Table 2).56,57,112,121 Nitriles (AÐF) are especially well behaved and for the examples studied did not give rise to the com- Scheme 6 Highly anti-selective chromium-Reformatsky reaction of mon problems of retroaldolization and Blaise-reactions EvansÕ oxazolidones (self-condensation). The lowest reactivity is observed with acetates and their derivatives, which in many aspects Evans-type imides like 18, in particular, give anti-prefer- show a different behaviour than higher homologues (see ences of > 95% (Scheme 6),106 apart from inducing a pref- also Section 6). Lithium iodide catalysis is mandatory to erential absolute configuration (as will be discussed achieve acceptable reaction times with these substrates.

Synthesis 1999, No. 1, 1Ð36 ISSN 0039-7881 © Thieme Stuttgart á New York REVIEW Recent Advances in Chromium(II)- and Chromium(III)-Mediated Organic Synthesis 7

Table 2 Selected Reactions of 2-Bromo- and 2-Chloroalkanoates and their Amide and Nitrile Derivatives with Simple Aldehydes

#TtR1 R2 EWG R3 anti:syn Yield (¡C) (h) (%) a 20 1.0 H Me CO2Me i-Pr 78:22 81 b 55 1.0 H Me CO2Me i-Pr 60:40 86 a c 55 3.0 H Me CO2Me i-Pr 71:29 72 d 20 2.0 H Me CO2Me Ph 78:22 81 b e 55 0.5 H Me CO2Me Ph 60:40 87 f 20 2.0 H Me CO2t-Bu Ph 70:30 95 b g 55 3.0 H Et CO2Me Ph 74:26 82 h 20 2.0 H i-Pr CO2Me Ph 50:50 83 * i 55 2.0 H i-Pr CO2Me Ph 30:70 85 c j 55 2.0 H Ph CO2Me Ph 79:21 84 c k 20 2.0 H -CH2CH2CO2- Ph >95:<5 81 * l 20 1.0 Me Ph CO2Me i-Pr 67:33 86 d m 55 1.0 H H CO2Me Ph Ð 89 n 20 1.0 Me Me CO2Me Et Ð 89 o 55 4.0 Me Me CO2Me i-Pr Ð 93 p 55 4.0 Me Me CO2Me Ph Ð 90 q 20 1.0 Me Me CO2Me PhCH2-Ð 98 r 55 6.0 Me Me CO2CH2CH=CH2 i-Pr Ð 93 s 20 3.0 Me Me CO2Me PhCH(CH3) 76:24* 84 a 55 1.0 H H CONMe2 Ph Ð 81 b 55 1.0 H Me CONMe2 Ph 36:64 83 c g 25 1.0 H Ph CONMe2 Ph 55:45 67 d 55 1.0 Me Me CONMe2 Ph Ð 93 A 55 24 H H CN i-Pr Ð 81 B 55 24 H Me CN Ph 50:50 66 LDAe) Ð78 0.1 H Ph CN Ph 85:15e 70122,e 53123,e e e 123,e LDA/ZnCl2 Ð78 0.5 H Ph CN Ph 52:48 69 e e 123,e LDA/AlCl3 Ð78 0.5 H Ph CN Ph 55:45 48 C 20 2.0 H Ph CN Ph 19:81 81 D 55 2.0 H Ph CN Ph 30:70 89 E 20 2.0 H Ph CN c-Hex 23:77 87 F 55 24 Me Me CN Ph Ð 89 a X = Cl b × 2 With CrCl2 THF c Technical CrCl2 (purity 80Ð90%) d Incomplete conversion e X = H (deprotonation reactions/Li-, Zn-, and Al-enolate reactions for comparison) * assignment uncertain separately in Section 6). With α-chiral aldehydes (Table classical conditions γ-product 23 is formed quantitatively, 2, entry s) a minor preference for the less usual anti-Cram whereas with activated zinc various amounts of α-prod- product is observed, but as with allylchromium com- ucts 22 can be obtained, though usually without diastereo- pounds (Section 3.2.1) stereocenters in the halide reactant selection [see Table 4 (Zn)]. exhibit a much stronger influence. In contrast to these results, methyl 4-bromocrotonates 20 react well with Cr(II) and a variety of aldehydes and ket- 3.1.3 Reactions of 4-Bromocrotonates ones, yielding the α-syn products (syn-22) preferentially, often exclusively (Table 4).78,105,107 Regio- and diastereo- Aldol reactions of crotonates and related compounds can selectivity are influenced by lithium iodide addition and be difficult as these compounds tend to add amide bases 129 the solvent. Increasing selectivity is observed in the order rather than being deprotonated. In addition a regiose- DMF < THF << MeCN. The rate of the reaction follows lectivity problem arises, as the thermodynamically more the opposite order. stable γ-product (cf. 23) can be formed. One method to overcome the amide addition problem is the Reformatsky Recently it was found that extended reaction times, espe- reaction of 4-bromocrotonate 20.130Ð135 However, under cially with less pure chromium dichloride, reduce the

Synthesis 1999, No. 1, 1Ð36 ISSN 0039-7881 © Thieme Stuttgart á New York 8 L. A. Wessjohann, G. Scheid REVIEW

Table 3 Comparison of the Diastereoselectivity in Reactions of Me- anti-allyl-product, if the vinyl group is taken into the prin- tal-1-Methoxypropenolates (Enolates of Methyl Propionates) with cipal chain). It also behaves more like an allyl species, re- Benzaldehyde. acting e. g. with imines, which are unreactive to chromium enolates.145

3.1.4 Chemoselectivity in the Chromium-Reformatsky Reaction

Metal Ion (Reagent) T (¡C) Solvent anti:syn YieldRef. Under the usual conditions alkyl, alkenyl and aryl halides are not competitive substrates for the chromium-Refor- 56 Cr(III)(CrCl2) 20 THF 78:22 81 matsky reaction. ++ 124 Zn (act.: Hg ) 80 Benzene 37:63 87 Unreactive electrophiles in intermolecular reactions in- Li (LDA) Ð70 THF 38:62 81125 126a clude alkyl, alkenyl and aryl halides, esters, amides, imi- Sn (act.: SnCl2/LAH) 20 THF 45:55 81 127 SnPh3/TiCl4 20 CH2Cl2 38:62 74 des, imines, immonium salts and α-halocarbonyl 128 Zr(Cp)2Cl (Transmetal.) Ð78 THF 13:87 80 compounds. Usually unreactive (< 5%) are nitriles, Michael acceptors, allyl and benzyl halides, sulfoxides a Ethyl ester and others. Problems most easily arise with reducible groups like nitro, N-oxides and others listed in Section 7. yield of isolated product. Although conversion is quanti- However, the standard conditions used for Cr(II)-reduc- tative, such conditions seem to promote the formation of tions (water, ethylene diamine) are much more vigorous a different species of chromium/product complex which then those applied in the Reformatsky reaction, which does not release all of the product easily. Benzaldehyde- then often becomes possible even with these groups derived aldols proved to be more sensitive towards this present (e. g. in DMSO solvent). 57 process than aliphatic electrophiles. The excellent chemoselection of aldehydes over ketones The syn-diastereoselectivity of aldols from crotonate op- known from allylchromium reagents is equalled and sur- poses the anti-selectivity of simple esters, e. g. butyrates. passed in the chromium-Reformatsky reaction, thereby ri- It could be shown that a switch in the nature of the chrom- valling the selectivity of titanium enolates (Scheme 7).78 ium(III) intermediate is the cause.105,114 Most likely an al- Aldehydes are preferred more then 50 to 100 times over lyl chromium species is involved, not a tautomeric methyl ketones, and even more so over higher ketones chromium dienolate, thus leading in the usual NozakiÐ (> 200 : 1) which thus can be used as solvent. Again the Hiyama manner to the syn-aldol (which is identical to the selectivity is influenced by salt and solvent, increasing se-

Table 4 Reaction of Methyl 4-Bromocrotonate 20 with Simple Aldehydes at 20¡C with Chromium Dichloride and Lithium Iodide Catalysis

Entry R1 R2 Solvent t a :g syn:anti Yield # (min) (%) a H Ph THF 15 60:40 64:38 94 b H Ph MeCN 15 >97:3 92:8 78 Zn H Ph THF 120 0:100 Ð 20132,136 (rfx) Zn, activated H Ph THF 120 60:40 to 86:14 45:55 to 53:47 60 to 85135,136 (graphite etc.) (0¡C) c H Et MeCN 120 89:11 82:18 64a d H i-Pr i-PrCN 180 91:9 90:10 56a e H t-Bu i-PrCN 180 69:31 91:9 58a 133 Zn H CH=CH2 THF 120 0:100 Ð ~5 f H CH=CH2 MeCN 30 >90:10 90:10 39 g Me Me THF 60 100:0 Ð 71 h Me Et butanone 60 95:5 60:40* 95 i Me Ph MeCN 60 95:5 65:35* 46 j -(CH2)5- THF 60 82:18 Ð 83 a With technical chromium dichloride (~80Ð90%), yield reduced by extended reaction time (see text). * Assignment uncertain, based on methyl-13C/1H-2 coupling constant and analogy.

Synthesis 1999, No. 1, 1Ð36 ISSN 0039-7881 © Thieme Stuttgart á New York REVIEW Recent Advances in Chromium(II)- and Chromium(III)-Mediated Organic Synthesis 9

then 6-endo-trig cyclizations. It was also shown that methyl ketones are successfully differentiated from higher ketones with > 98 : 2 selectivity utilizing 4-bromocrotonate 20 (Scheme 9). In summary, the chromium-Reformatsky reaction offers well separated reactivity towards carbonyls in the order: RCHO ≥ ArCHO / C=CCHO > RCOMe > RCOR >>> RCOYR (C≡N / C=N)

3.2 The NozakiÐHiyama Reaction: Allyl- and Propargylchromium(III) Intermediates; Benzylchromium(III) Intermediates 3.2.1 Reactions Involving Allylchromium(III) Intermediates Y. Okude, S. Hirano, T. Hiyama and H. Nozaki described Scheme 7 Chemoselection of aldehydes vs. ketones for the first time a carbonÐcarbon bond formation via addition of an intermediate chromium(III) allyl species to a carbonyl compound.19,20 In a Barbier type reaction of lectivity in the following order: lithium iodide < no salt, CrCl2 in THF or DMF the electrophile is added first and and DMF < THF << MeCN. Reactivity follows the in- subsequently the allyl halide to form the corresponding verse order. Only α,α-disubstituted α-halo esters 25 (R4 = homoallyl alcohols (Scheme 10). Me) show less selectivity against methyl ketones (7 Ð 15- fold) and a deviating solvent effect.

Scheme 10 Regiochemistry in the HiyamaÐNozaki reaction

With γ,γ-disubstituted allylic halides (36, R1,2 ≠ H), the more substituted carbon is attached to the carbonyl group to build a quarternary center, alk-2-enals (37, R3 = alkenyl) react under 1,2-addition. The addition of the intermediate allylchromium(III) species occurs with excellent Scheme 8 Only secondary alcohols are formed from oxo aldehyde aldehyde selectivity, even in the presence of various elec- 28 (80% 27) without subsequent internal nucleophilic reactions (ar- trophiles like nitriles, esters or ketones.19,20,25,28 The reac- rows) tion soon attracted the interest of synthetic chemists because of its excellent chemo- and stereoselectivity.137Ð144 Accordingly oxo aldehyde 28 gave only the sensitive secondary alcohols 27 and 29, which were obtained without In a recent paper the addition to imines was shown to be intramolecular cyclization to the bicyclic acetals, in con- possible.145 The otherwise sluggish reaction of ketones is trast to other methods. The stability and nonbasic behav- overcome when activated Cr(II) is used. For the latter pur- iour of the chromium(III) aldolates seems to be pose Wipf et al. reacted CrCl2 with 2.0 eq. PhMgX and responsible for the inhibition of subsequent 5-exo-trig and 1.0 eq. TMEDA at low temperatures (Scheme 10).146 Sub- sequent addition of allyl or propynyl halides followed by a ketone at Ð60°C results in the formation of carbonyl addition products 38 in >75% yield. Crotyl bromide and other γ-monosubstituted allylic halides add to aldehydes with high anti-selectivity, independent of the double bond configuration (Scheme 11). The observed anti:syn-ratios in THF vary from 94 : 6 to 100 : 0, as long as the aldehyde is not too bulky, for example, pivaldehyde. In this case, the simple diastereoselectivity is inverse with a 35 : 65 ratio. The anti-selectivity also decreases, when DMF is used as a solvent.21 The selectivity can be explained by a chairlike transition state in which the γ-substituent of the allylic system and the alde- Scheme 9 Differentiation of ketones: 32:33:34:35 = 94:6:0:0 (± 2%)

Synthesis 1999, No. 1, 1Ð36 ISSN 0039-7881 © Thieme Stuttgart á New York 10 L. A. Wessjohann, G. Scheid REVIEW hyde substituent prefer equatorial positions (cf. Figure 3, (2E)-Diethyl-2-(trimethylsilyl)hept-2-enyl phosphate R4 and R1 respectively).21,77 Mulzer proposed a more de- (45) also reveals that due to the bulky â-substituent (cf. tailed mechanism, only mentioned in a review article by Figure 3, YR), the butyl residue occupies an axial position Hoppe,25,147,148 that can additionally explain the formation in the transition state (cf. Figure 3, R3) and therefore the of side products, coupling and reduction products of the otherwise unusual syn-adduct is obtained. Further exam- allylic halide. This mechanism does, however, not apply ples of syn-selectivity (Scheme 13) are reactions of 2- to chromium enolates which may be regarded as TMS-substituted crotyl bromides 47,152 2-phenylsulfonyl oxaallylchromium(III) species (Section 3.1).56,57 substituted allylic bromides 49154,155 and γ-substituted α- bromomethyl acrylates, which are used in the synthesis of α-methylene-γ-butyrolactones.156

Scheme 11 Simple diastereoselectivity in reactions of monosubstituted allyl bromides

Various 1- and 3-halo-substituted allyl bromides were reacted successfully.149Ð151 anti-Products dominate as usual and subsequent reactivity of the homoallyl alcoholates with the remaining internal halide, e. g. to epoxides from halohydrins, is not observed, in contrast to other metals.149,151 TMS-substituted allylic bromides were used in moderate yields and with low selectivities (regio- and Scheme 13 Recent examples of syn-selective HiyamaÐNozaki reac- 152 simple diastereoselectivity). Acetals derived from alk- tions of 2-substituted allyl bromides enals and alkenones can be activated by TMSI at Ð30°C to give HiyamaÐNozaki reactions of the intermediate alkoxy-substituted allyl iodides.153 Diastereofacial selectivity in the reaction of α-chiral aldehydes and non-chiral allylic halides is determined by steric Recently Knochel et al. could show that allylic phosphates approach control (Scheme 14). The bulkiness of the γ-sub- are also suitable substrates when a catalytic amount of LiI is stituent is the predominant factor.25,157,158 With very bulky present to give allylic iodide intermediates by nucleophilic 68,69 α-substituents the Felkin-Anh diastereomer can be ob- substitution. In their studies they recognized that in con- tained predominantly with up to 98% de (58 → 59), but of- trast to linear allylic halides, â,γ- or γ,γ-disubstituted E- and ten only a 2- to 4-fold excess of one diastereomer is Z-allylic halides and phosphates 41 react in a stereodivergent achieved.77,157Ð159 Chelate control of α-alkoxy substituents manner to the corresponding homoallyl alcohols 42, proba- was not observed158 despite the cheleselectivity reported for bly because the allylic rearrangement of chromium and dou- chemoselection of chromium(III) organyls.48,160 ble bond isomerization is inhibited (Scheme 12).69

Scheme 14 Influence of an α-stereocenter in the aldehyde reactant on the C4,C5-diastereoselection of the 3,4-anti-products Scheme 12 HiyamaÐNozaki reactions of 2,3- and 3,3-disubstituted allyl halides and phosphates. E- and Z-isomers yield opposite dia- In the reaction of asymmetric allylic halides bearing an stereomers asymmetric center at the δ-position with achiral aldehydes good stereocontrol is possible (Scheme 15).161 Usu-

Synthesis 1999, No. 1, 1Ð36 ISSN 0039-7881 © Thieme Stuttgart á New York REVIEW Recent Advances in Chromium(II)- and Chromium(III)-Mediated Organic Synthesis 11 ally the anti, anti-diastereomer (N.B! Consider the â,γ-or γ,γ-disubstituted ones react in a stereospecific formula projections) is formed in high excess.25,161 The manner depending on the original stereochemistry of the configuration of the newly formed chiral centers is only substrate. Double stereodifferentiation is controlled by determined by the δ-stereocenter, whereas the simple adjacent stereocenters. Allylic halides exhibit the domi- diastereoselection of the Hiyama reaction is not affected nant influence, whereas only little influence is observed by the presence of chiral centers in the allylic bromide.161 from the aldehyde electrophiles, mostly in favour of Fel- In double stereodifferentiation experiments with chiral al- kin-Anh stereochemistry. dehydes and chiral allylic halides, the matched case com- Apart from the direct reduction of allyl halides, allylchro- binations led exclusively to the formation of a single mium(III) species could be generated by transmetallation adduct. The mismatched combinations revealed that the reactions. Studies of Kauffmann et al. revealed that trans- stereochemical course of the reaction is completely direct- 161,162 metallation of allyl Grignard reagents with CrCl3 prefer- ed by the influence of the allylic halide. entially gives bisallylchromium(III) chloride. However, this species did not show the usual chemoselectivity of the HiyamaÐNozaki reaction in a competition experiment aldehyde vs. ketone (benzaldehyde vs. cyclohexanone).165

3.2.2 Reactions Involving Propargyl- and Allenylchromium(III) The chromium(II)-mediated addition of propargylic bromides to carbonyl compounds gives either homopropargylic alcohols 78 or allenic alcohols 79 (Scheme 17).146,166Ð169 In contrast to allylic halides, ketones also react well as electrophiles to form the corresponding ad- ducts. The ratio of alkyne vs. allene product depends mainly on the structure of the propargylic bromide and on solvent effects. With primary propargylic bromides (R1 = H, R2 ≠ H), the allenols 79 are obtained predominantly, while secondary propargylic bromides (R1 ≠ H, R2 ≠ H) exhibit a preference to form alkynols 78 (in ethers). With addition of HMPA168 and even better in dimethylacetamide (DMA)169 allenes 79 can be obtained Scheme 15 Influence of a δ-stereocenter (α-allylic stereocenter) in the allyl bromide reactant on the C4,C5-diastereoselection of the almost exclusively and in high yields from all internal 2 3,4-anti-products (N.B. Consider the formula projections, the prin- alkynes (R ≠ H). However, with ketone electrophiles and cipal chain with the vinyl group is twisted) terminal alkynes (77, R2 = H) homopropargylic alcohols 78 are preferred.146,169 Recently, Mulzer et al. investigated the influence of stereocenters of substituents in 2-position of the allylic bromide on the newly formed stereocenter by addition to achiral aldehydes (Scheme 16).163,164 Good 1,4-induction was observed, favouring the syn-adduct in an average ratio of 85:15 in acceptable yields with aryl and alkyl aldehydes. The preference of the 1,4-syn-products was explained by an antiperiplanar approach of the aldehyde to the benzyl- oxy moiety, consistent with the Felkin-Anh model. Gly- oxylic ester or crotonaldehyde could not be reacted in satisfactory yields under the applied conditions.163,164 Scheme 17 Preferential regiochemistry in reactions of propargylic bromides

3.2.3 Reactions of Benzylchromium(III) Derivatives Benzylchromium(III) is the oldest170 and one of the best studied reactive chromium(III) organyls. It can be formed Scheme 16 1,4-Induction of a â-substituted allyl bromide by the reaction of benzyl radical with Cr(II),5 for synthetic purposes most easily from the halides with In summary linear γ-monosubstituted allylic halides give ≥ 2 equivalents of Cr(II).6,171 In contrast to primary alkyls almost exclusively anti-products, independent of their the reaction of benzyl is reversible (homolysis rates are configuration, â-substituted ones give syn-products and ~10Ð3Ð10Ð4 sÐ1) and dependent on the Cr(II) concentration

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(Scheme 18, 80 → 82).51 Wurtz reactions may proceed as is commonly observed with other methods of prepara- through homolysis, although heterolysis, i. e. nucleophilic tion. Cyclization and aromatization can be brought about benzylation cannot be excluded for synthetic reactions in by the addition of one equivalent of Lewis acid to yield up polar solvents (vide infra). An alternative mechanism in- to 96% benzofuran 91 in a one pot reaction. volves a diorganochromium(IV) intermediate (Section 4.3).171 Most kinetic studies have been performed with 3.3 Reactions of Alkylchromium(III) benzylchromium(III)- and pyridiniummethylchromi- Intermediates; Chromium Mediated um(III)-pentaqua complexes (80 and 81 respectively, L = Alkenation Reactions OH2). These and polydentate amine complexes appear to be stable in water and air, sometimes for up to several 3.3.1 General Aspects hours.51,73,74,172Ð174 Heterolysis is indirectly dependent on Alkylchromium reagents can be obtained by 3 methods: the presence of Cr(II)73,75 but is strongly influenced by the (A) generation of aliphatic free radicals which are then trans-ligand, phosphate and acetate facilitating hydrolysis captured by chromium(II); (B) chromium(III)Ðmetal ex- best.73 change from a corresponding alkylmetal compound; and (C) Reformatsky-type redox reaction with alkyl halides. In group (A) a modified Fenton reaction with Cr(II) or similar fragmentation reactions of alkyl peroxides are commonly employed to generate alkyl radicals.62Ð65,(5,6) This approach is preferentially used for kinetic studies, usually in aqueous medium and papers before 1991 have been reviewed, including other methods of preparation along this general line.51 For synthetic purposes it is less useful because of the problematic starting materials or the limitation to aqueous solvent. It must be remembered that chromium(III) alkyl pentaqua complexes are not reactive towards carbonyl groups.51,73,74,172Ð174,178 Alkylmetal compounds can be reacted with chromium(III) salts to give alkylchromium(III) compounds which exhibit enough reactivity towards electrophiles Scheme 18 useful for CÐC-coupling reactions (B).37,48,160,178Ð181 Alkyllithium37,178, alkylmagnesium15,16 and alkylalumini- All paths discussed have been described for the reaction um compounds80 have been used for this purpose.23,29 The of benzyl bromide 85 with chromium dichloride (Scheme advantage of the alkylchromium reagents is their excel- 19).175,176 The intermediate benzylchromium(III) 86 is sta- lent chemo- and cheleselectivity,37,48 and their insensitiv- ble and only slowly reacts with the internal ester, in con- ity to traces of water.48,160,178,179 Lately only allyl- trast to external ones which are not reactive at all. With chromium reagents have been prepared by this method water, hydrolysis to 89 is observed, as water-ligands slow (see Section 3.2.1).165 down reactions with carbonyls even more and thus allow hydrolysis to compete. With an excess of bromide 85, es- Apart from the extra step, the method is limited to inter- pecially in donor solvents like HMPA, coupling to dimer molecular reactions, and mainly methylchromium(III) re- 90 is preferred. On the other hand in THF, avoiding an ex- agents have been used. Often the intermediates involved cess of 85, ketones 88 (M = H) are formed in up to 85% do not appear to be well characterized, especially if the yield and can be isolated without subsequent cyclization transmetallation and subsequent addition to an electrophile is done in situ (see also Section 3.1.1). Reactions do not always proceed as cleanly as with the parent alkyl metal or as with organochromiums from Takai's procedure (vide infra, Section 3.3.4). The latter thus is the method of choice to generate chromium(III) alkyls, but is limited to primary alkyls and certain solvents. Although secondary or even tertiary chromium(III) alkyls have been reported from metalÐchromium(III) exchange,16,80 they have not yet been employed in organic synthesis, probably due to their problematic homolytic properties.51,182 The umpolung of alkyl halides to alkylchromium(III) derivatives (C) in a redox-reaction employing two equivalents of chromium(II) would be most suitable for synthetic Scheme 19 R = Me, Et, t-Bu, Ph etc. [FG177 = Alkyl; Ar; 4-Cl; 4- applications. Starting materials are easily available, in- OR; 3,4-OCOR; α-Thienyl] tramolecular reactions are possible and the approach is

Synthesis 1999, No. 1, 1Ð36 ISSN 0039-7881 © Thieme Stuttgart á New York REVIEW Recent Advances in Chromium(II)- and Chromium(III)-Mediated Organic Synthesis 13 principally better suited for complex substrates with other â-substituent have been generated from 2-bromoethyl- functional groups. Such reactions proceed well in water, sulfonate.190 especially in acid or if donor ligands like ethylenediamine are added, but the resulting chromium(III) alkyls lack reactivity (see above) and slowly decompose to the dehalogenated alkanes. However, most simple alkyl halides do not react directly with chromium dichloride in an organic medium.183 Among others, Takai and co-workers in particular found suitable substrates and methods to overcome this drawback which will be discussed in the following subsections. With these tools, proper use of chromium methods enables the chemist to selectively address different types of organic halides in unprecedented chemoselectivity, e. g. the stepwise independent reaction of halides in allylic, primary alkyl and vinylic positions in the same Scheme 21 molecule is possible with chromium(II) with the proper additives and conditions applied.182 α-Phenylselenoalkyl halides react in a similar way to their sulfur analogs to give 2-phenylselenenyl alcohols.57,191,192 Also haloalkyl halides193 including perfluoroalkyl 3.3.2 Reactions of Alkyl Halides with an Activating halides194Ð196 were reacted with chromium(II), but give rad- Substituent in α-Position ical rather than carbonyl addition reactions (cf. Section Alkyl halides can be activated towards reactions with 5.2). However, most 1,1-di- and 1,1,1-trihaloalkanes give chromium(II) by radical and/or carbanion stabilizing alkenation products (vide infra). Activation of alkyl mono- α-substituents, mainly chalcogeno- and halo-substitu- halides by other α-hetero substituents, e. g. silyl groups, has ents.184 not been reported, although some similar reactions of carbonyl compounds with (alkylhetero)methyl chromium(III) (α-sulfanylalkyl)chromium(III) compounds are easily ob- obtained from transmetalations have been successful.37,180 tained from the respective α-haloalkyl thioethers like 92, which are probably the most well behaved substrates of this section (Scheme 20). The method offers an excellent 3.3.3 Alkenation Reactions (TakaiÐHodgson) neutral alternative to the strongly basic deprotonation pro- The use of gem-dihalides instead of alkyl halides with ex- cedures. As usual aldehydes are strongly preferred to ke- cess of Cr(II) in the presence of an aldehyde leads to the tones and, with a proper choice of ligands, very good formation of carbonÐcarbon double bonds (Table 5). The excesses of anti-products like anti-93 can be obtained.185 reaction is a non-basic and mild alternative to the Wittig and related alkenations and is applicable to a large spectrum of substrates. Diiodomethane (Y = H, X = I) reacts

Table 5 Carbonyl Alkenation Reactions of Substituted 1,1-Dihalo- methanes 97 with >4 equiv. Chromium(II) [FG177= -CN, -CO-, -S-, ≡ -SiR3, -C CH, -O-, -CO2R, -SnR3, OTBS, OAc, OTHP, OCH2Ph, 2- Scheme 20 halovinyl, methallyl] Much less is known from reactions of α-halo ethers. Wurtz-coupling, dehalogenation and other radical reactions seem to be preferred to carbonyl addition.186 α-Ac- etoxy bromides can be reacted with CrCl3/Zn in donor Y X Yield (%) E (rel%) Ref. solvents like DMF or TMEDA to give trans-alkenes directly (vide infra).187 The likely pinacol intermediates H I 70Ð92 Ð 198 were not isolated. The reaction does not proceed with Alkyla I 73Ð97 88Ð98 197,198 (commercial) CrCl and direct attack of the acetoxy brom- Cl Cl ~75 >90 199 2 Br Br 55Ð73 Ð 199 ides by zinc cannot be excluded from the experiments I I 66Ð80 80Ð92 199 published. Peracetylglycosyl chloride 94 was also sub- SiR'3 Br 70Ð80 Ð 197 → b jected to chromium(III) (Scheme 21). As expected, in SnR'3 Br( I) ~60% 200Ð203 aqueous solvent and with good nitrogen donors, a glyco- SR' Cl 68Ð83 70Ð80 197 syl-chromium(III) complex 95 with a stability of several Cl(→I) 78Ð91 (87Ð)97 204 hours was generated, with half-lifetimes depending on the ligand.188 However, it finally collapses under elimination of the â-acetate to yield glycal 96. This happens somewhat R = Alkyl, Aryl (→I) = LiI-addition (possible nucleophilic exchange) 186,188,189 a Ketones react too: 85Ð96% yield (Z > E) faster in an organic solvent. Similar long-lived b chromium(III) pentaqua complexes with a functional Rest (~35%) is mainly methylenation product. For R = t-Bu: 6% 98.

Synthesis 1999, No. 1, 1Ð36 ISSN 0039-7881 © Thieme Stuttgart á New York 14 L. A. Wessjohann, G. Scheid REVIEW

smoothly with aldehydes to the corresponding methylene tion of a ketone followed by an intramolecular vinyl- compounds. Terminal alkyl diiodides (Y = alkyl, X = I) chromium 10-ring-cyclization to a bis(α,â-unsaturated) react with aldehydes to form disubstituted alkenes with alcohol (Scheme 22, bottom; cf. also Section 3.4). high E-selectivity, while geminal dibromides (Y = alkyl, The alkenation reaction tolerates other heteroatoms in X = Br) give alkenes only in poor yield. The E / Z-ratio in- geminal position (Table 5). The application of Bu3SnÐ creases with the bulkiness of the aldehyde substituent, up 200,201,213 203 197 CHBr2, Me3SnÐCHBr2, PhSÐCHCl2, and to 99 with pivalaldehyde and 1,1-diiodobutane. In order to 204 (RO)2BCHCl2 allows the direct synthesis of syntheti- obtain trisubstituted alkenes, ketones have also been ap- cally valuable vinyl stannanes, thioenol ethers and vinyl- plied successfully in the reaction with 1,1-diiodoethane in boronates with high E-selectivity. Me3SiCHBr2 reacts the presence of Cr(II), while other terminal diiodo com- with aldehydes to form E-configured TMS-substituted pounds did not react (but cf. Scheme 42). An internal di- 197 alkenes. (Me3Si)2CBr2 forms the corresponding bis(tri- alkyl diiodo compound (2,2-diiodopentane) failed in the 213,214 197,198 methylsilyl)-substituted alkenes, which is astonish- reaction with benzaldehyde. ing because 2,2-diiodopentane, as mentioned above, The use of haloforms (X = Y = Cl, Br, I) allows the C-1 failed in the reaction with benzaldehyde. In a closely re- elongation of aldehydes and ketones to the corresponding lated process a Me3SiCH2ÐCrCl2 species, prepared by haloalkenes in reasonable yields and good E-selectivity. transmetallation of Me3SiCH2MgCl with CrCl3, was add- α,â-unsaturated aldehydes can also serve as substrates to ed to two different aldehydes to form â-hydroxytrimeth- produce halodienes. In a competition experiment with al- ylsilanes after careful workup.180 α-Acetoxy bromides dehyde and oxo groups in one molecule, the aldehyde is may also serve as substrates to form alkenes with alde- converted to the haloalkene almost exclusively and only a hydes on treatment with in situ prepared Cr(II) from CrCl3 small amount of the double alkenated product is obtained. and Zn-dust in fair yields.187 If ketones are used as the only carbonyls, alkenation can be achieved in good yields, thus 4-tert-butylcyclohex- anone was converted into the resulting iodoalkene with 199 iodoform and CrCl2 / NiCl2 in a 75% yield. Iodometh- ylenation is the most common application in total syntheses and recently many examples for the C1-elongation of aldehydes and ketones to terminal haloalkenes have been reported.205Ð211 Jung's total synthesis of Aplysiapyra- noid A (101) deserves special attention (Scheme 22, top).211 The aldehyde 99 which possesses a free α-hy- droxyl group and a â-bromide is successfully transformed to intermediate 100. Another example is the use of two chromium(II) mediated synthetic steps in the synthesis of Solenolide F by Procter et al.,212 showing the iodoalkena-

Scheme 23

Two mechanisms, (A) and (B), shown in Scheme 23 have been discussed, of which path (B) seems to be the more likely one.198,199,215 With four equivalents of Cr(II) geminal dichromoalkyl compound 107 is formed. This reacts with aldehydes, possibly diastereoselectively,201,202 to a chromium 2-chromium alcoholate which eliminates preferentially syn under formation of the E-alkenes 111.7 (α- Haloalkyl)chromium(III) carbenoids 106 are known,193 but the aldehyde addition products 110 (or 109) on further reaction with two equivalents Cr(II) do give different results. If elimination occurs, almost no or even Z-diastereoselection is found.7,198,199,216 No hydrolysis products of either 106 or 110 were detected, as well as no cyclopropanes from insertion reactions of the chromium carbenoid 106 (or 108) into C=C-double bonds of unsaturated aldehydes.198,199 Another methylenechromium equivalent, chromium(III) carbene 108, was discussed too.217 An interesting offspring of the alkenation reactions is the Scheme 22 Recent applications of chromium(II)-mediated halo- conversion of aldehydes 112 to homologous methyl ke- 218 methylenations of difficult substrates tones 113 in good yield (Scheme 24). The reagent is

Synthesis 1999, No. 1, 1Ð36 ISSN 0039-7881 © Thieme Stuttgart á New York REVIEW Recent Advances in Chromium(II)- and Chromium(III)-Mediated Organic Synthesis 15

Scheme 24 HodgsonÕs chemoselective homologation of aldehydes 218 177 to methyl ketones [FG = Ph, CO2R, -CO-, CN]

prepared in situ by reaction of CrBr3 with LiAlH4 and addition of the aldehyde and trimethylsilylbromoform.

3.3.4 Reactions of Non-Activated Haloalkyl Derivatives Although Kauffmann's transmetallation provided the first reactions of simple alkylchromium reagents with aldehydes,37,178,181 the use of alkyl halides as starting materials only became available with Takai's application of nucleophilic cobalt catalysts.182 The method is based on the early findings of an alkyl transfer from cobalt to chromium by Espenson et al.220,221 As stabilized nucleophilic cobalt(I) complexes, the most prominent one being reduced vitamin B12, react with alkyl halides to the alkylcobalt(III) complexes, the combination Scheme 25 Catalytic cycle for the reaction of alkyl halides with can be used to create a catalytic cycle with Co(I/III) to CrCl2/cat. Co(I)-complex generate alkylchromiums (Scheme 25). The reaction is high yielding (73Ð97%, cf. Table 6) and tolerates many obtained in a template Schiff base synthesis from biacetyl, functional groups, including lower halogens, esters,182 ke- 57,222 1,3-diaminopropane, hydrogen iodide, cobalt acetate and tones and nitriles. Also leaving groups other than ha- air.223 Unfortunately the Takai method for alkylchromi- lides may be used. The expensive coenzyme B12 can be ums even with this catalyst is limited to primary halides substituted by cheaper complexes, e. g. the less reactive 114,219 182 and amide solvents. The reaction does not work with Co-phthalocyanine. Easier to obtain and catalytically ketone-electrophiles or in solvents like THF, acetonitrile more active is a sterically less hindered complex with a 57,112,114,219 or water. macrocyclic diazadiene, Co(TIM)I2. It is easily

Table 6 Cobalt(I) Catalyzed Reaction of Primary Alkyl Halides with Chromium Dichloride and Aldehydes (Pc = Phthalocyanin, B12 = Vitamin B12, TIM: s. text)

X n FG R Catalyst T t Yield Ref. (¡C) (h) (%)

I 11 H Ph B12 30 5 89 182 Br 11 H Ph B12 30 5 95 182 Br 11 H Ph CoPc 30 10 75 182 Cl 11 H Ph B12 30 16 45 182 Cl 11 H Ph CoPc 30 16 <1 182 OTs 11 H Ph B12 30 24 74 182 OTs 11 H Ph CoPc 30 24 <1 182 I 11 Cl Ph CoPc 30 3.5 85 182 Br 1 CO2Et Et B12/LiI 38 24 96 57, 114, 219 Br 1 CO2Et Ph B12/LiI 38 24 88 57, 114, 219 Br 1 CO2Et Ph Co(TIM)I2/LiI 30 1 79 57, 112, 114 Br 1 CO2Et Ph CoPc/LiI 55 12 55 57, 114, 219 Br 2 CO2Et Ph B12/LiI 38 24 94 57, 114, 219 Br 2 COPh i-Pr B12/LiI 55 24 97 57, 114, 219 Br 2 CN i-Pr B12/LiI 55 24 41 57, 112, 114, 219 Br 3 CO2Et Ph B12/LiI 38 24 97 57, 112, 114, 219 Br 4 CO2Et Ph B12/LiI 38 24 57 57, 112, 114, 219 I4CO2Et Ph CoPc 30 5 91 182

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3.3.5 Reactions of Halocyclopropanes not quite clear to what extent aluminium ions play a second role and act as Lewis acids, promoting ring opening. Monobromocyclopropanes 118 usually do not react with An activating influence of aluminium ion has also been chromium(II) salts.17 However, the geminal dibromides observed in other chromium(II) reactions.56,57,103,114 4Ð5 do, if a chromium(II)-activating donor solvent and weak equivalents of Cr(II) instead of the formal 2 equivalents ligand like DMF is used. Decomposition of the intermedi- are required for the DMS reaction. The intermediate cy- ate chromium(III) carbenoids to allenes in a DoeringÐ clohexa-1,2-diene, which more likely can be regarded as MooreÐSkatteb¿l (DMS) reaction occurs and the reaction cyclohexene-1,6-diyl, could be captured with styrene to has been used for the synthesis of medium sized cyclic al- give 120 in the usual manner.229 With excess chrom- lenes 117 (Scheme 26).17,18,217,224,225 The DMS-reaction ium(II) the intermediate cyclohexene-1,6-diyl appears to was not only one of the first synthetic applications of give chromium(III) organyls, because small amounts of chromium(II) in nonaqueous solvent,17 it also is the first nucleophilic addition products can be found in the pres- application of asymmetric synthesis utilizing Cr(II) (Sec- ence of electrophiles, including even DMF (to yield cy- tion 6),217 as well as the first one to be run catalytically in clohexenylformaldehyde).227,228 chromium (see Section 5.3).226 The reactivity is dependent on the preparation method of the chromium(II). In addition, the counterions and sol- 3.4 The TakaiÐKishi (NozakiÐHiyamaÐKishi) vent/complex ligands play a crucial role in the course of Reaction: Vinyl-, Aryl and the reaction, the two major pathways being DMS-reaction Ethynylchromium(III) Intermediates to allenes and reduction to dehalogenated cyclopropanes. 3.4.1 Vinyl- and Arylchromium(III) Intermediates 226 Steckhan and Wolf could show that the type of complex The addition of aryl and vinyl bromides, iodides and tri- and thus the type of electron transfer (ET), either through flates to aldehydes via an intermediate chromium(III) spe- an inner or an outer sphere complex, is important for the cies is achieved by CrCl2 with a catalytic amount course of the reaction. The inner sphere complex should ≤ 230Ð233 ( 2 mol%) of NiCl2. A mechanism explaining the allow the rapid capture of the intermediate 1-bromo- role of nickel in the reaction was suggested by Takai231 as cyclopropyl radical by chromium(II) to form the chrom- well as Kishi.232 It is assumed that Cr(II) reduces the ium(III) carbenoid to enter the DMS rearrangement. With Ni(II) to Ni(0). An oxidative addition of the vinyl halide an outer sphere complex this is more difficult and dehalo- to the Ni(0) results in a vinyl nickel(II) species, which is genation is preferred. This is also true in the presence of transmetallated with Cr(III) to the proposed nucleophilic water (Scheme 26). vinyl chromium(III) which adds to an aldehyde (Scheme 27). The use of DMF as solvent is recommended for a successful formation of the desired allylic alcohols, because the reaction fails in THF.230 In DMSO the yields sometimes turn out to be low, but for the coupling of iodo- alkenes cleaner results are often obtained.27,232

Scheme 27 Proposed catalytic cycle for the TakaiÐKishi reaction

Scheme 26 Reduction and DoeringÐMooreÐSkatteb¿l (DMS) reac- Excellent chemoselectivity towards aldehydes, very mild, tion of gem-dihalocyclopropanes to allenes non-basic reaction conditions and a large substrate spectrum are general features of this reliable CÐC-bond forma- Recently it could be shown that even strained cyclic al- tion process. A beautiful demonstration of the reaction is given in KishiÕs synthesis of Palytoxin featuring two such lenes (6-, 8-membered) can be formed with chromium(II) 234 reagent.228 The reaction depends strongly on the chrom- steps. Unfortunately, sometimes reactivity problems ium(II) source, and it was found that chromium(II) freshly occur. Thus in a model study of the 8-membered ring closure of the sterically encumbered taxane precursor 125 the prepared from 2 CrCl3/LAH, from reduction in THF followed by a solvent switch to DMF, gives the best results.20 desired product 126 was obtained only after 20 days in 50% yield (Scheme 28).235 Similar intermolecular reac- Very pure chromium dichloride (> 99.98%) in DMF in 236 our hands did not react with 116 (n = 3).227,228 Thus it is tions of taxane-A-ring precursors were not successful with chromium(II).237,238

Synthesis 1999, No. 1, 1Ð36 ISSN 0039-7881 © Thieme Stuttgart á New York REVIEW Recent Advances in Chromium(II)- and Chromium(III)-Mediated Organic Synthesis 17

Scheme 28 8-Membered ring closure for the formation of a taxane skeleton

A recent and curious example is the macrocyclic ring closure in the synthesis of a protected aglycone (128) of Spi- ramycin by Oddon and Uguen, in which they use the tremendous amount of 100 equivalents CrCl2 doped with 1% NiCl2 to achieve cyclization of intermediate 127 (Scheme 29).239 The authors wrote, that a four fold excess of CrCl2 containing 1% NiCl2 could not bring about the desired reaction. After all, the reaction may not be catalytic in nickel in this case and the use of such a large amount of Cr(II)/Ni(II)-reagent might be necessary to provide enough nickel. The current ÒrecordÓ was reported for the Scheme 30 Aryliodonium salts: TakaiÐKishi substrates in nickel- 10-membered ring closure of a solenolide F precursor free and domino processes (Scheme 22) where 200 eq. CrCl2 / 2 eq. NiCl2 have been applied.212 Possibly a higher Ni(II) / Cr(II)-ratio could also have been effective in these cyclization reactions. 3.4.2 Reactions Involving Alkynylchromium(III)

The CrCl2/NiCl2-system also allows the addition of alkynyl iodides and bromides to aldehydes. The main advantage in the use of alkynylchromium(III) over conventional alkali metal or magnesium alkynes is their high chemoselectivity towards aldehydes in the presence of other electrophilic groups.242 Alkynylchromium compounds add to a,b-unsaturated aldehydes to give exclusively the 1,2-addition products. The reaction is especially suited for the addition to very sensitive aldehydes. In specific cases, Scheme 29 Macrocyclic ring closure to a Spiramycin aglycon pre- the addition occurs in high diastereoselectivity, as is cursor with the TakaiÐKishi procedure shown in the reaction between trimethylsilyliodoacety- lene (139) and aldehyde 138 in KishiÕs synthesis of Nor- A new aspect in the chemistry of arylchromium com- halichondrin B.27,243 pounds is their generation from diaryliodonium salts 129, which was also the first example of reactivity umpolung for this class of compounds (Scheme 30).240 In contrast to aryl halides, the diaryliodonium salts are able to react with chromium(II) directly to arylchromium(III) without nickel catalysis. However, nickel chloride addition improves the yields. In the same paper a radical cyclization / carbanion domino process of compound 131 is reported. The proposed mechanism via a 5-exo-dig radical cyclization is based on a known rate constant for the cyclization of the aryl radi- Scheme 31 Chemoselective reaction of alkynyl iodide 139 with a cal 135241 in comparison with the rate constant for the re- precursor for Norhalichondrin B duction of 5-hexenyl radical,9 indicating that the reduction with Cr(II) could not compete with the cyclization of the The method also can be used for intramolecular cycliza- radical 135. The resulting alkyl radical 136 is reduced by tion reactions to form strained rings. It has been especially Cr(II) to the ÒcarbanionicÓ alkylchromium species 137 useful in the synthesis of several sensitive enediyne deriv- which adds to present benzaldehyde. atives.244Ð249 Thus, the treatment of aldehyde 141 with Reactions catalytic in chromium (15 mol%) have been 3 equivalents of CrCl2 and 1 equivalent of NiCl2 leads to 58 the formation of the enediyne derivative 142 (Scheme performed by FŸrstner et al. and will be discussed in 248 Section 5.2. 32).

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A variety of chromous salts have been used in the reduction of unsaturated systems.250,254 Phenyl-substituted alkynes can be reduced with Cr(ClO4)2 in aqueous DMF in the presence of ethylenediamine stereoselective to cis- alkenes, terminal alkynes also react to form terminal alkenes.255 Propargylic alcohols reacted under similar conditions (Et3N instead of ethylenediamine) to cis-con- figurated allyl alcohols.255 Aqueous DMF-solutions of Scheme 32 BrŸcknerÕs ring closure of the enediyne core of neocarcinostatine248 CrSO4 or aqueous THF-solutions of CrCl2 allow the trans-selective reductions of α-acetylenic ketones to In the latter case it has to be remarked, however, that the trans-enones in the presence of different functional groups, even epoxides stayed intact.256 Recently chromi- use of 1 equivalent of NiCl2 in the presence of um(II) acetate monohydrate dimer [Cr(OAc)2áH2O]2 in 3 equivalents CrCl2 allows the reaction in principle to be stoichiometric in Ni(0) and therefore may not necessarily aqueous THF was used to reduce an alkynone to the 257 involve alkynylchromium(III). trans-enone in the synthesis of (+)-Zaragozic acid C. The reduction of the C=C double bond in enones,258,259 alkenes with carboxylate substituents260 and in 1,2- 261 4 Reactions of Carbon Centered Radical bis(2-pyridyl)ethylene is also possible, but yields are Intermediates Generated with Chromium(II) usually mediocre. and Related Reactions The reaction of benzil with [Cr(OAc)2áH2O]2 in aqueous DMF (1:1) at pH=5.5 enables the reduction to benzoin 4.1 Dehalogenations and Reductions [2.0 eq. Cr(II)] and trans-stilbene epoxide [4.0 eq. Cr(II)], The reduction of organic substrates is the oldest applica- reduction of isolated benzoin to the epoxide is also possi- tion of chromium(II) salts and has already been reviewed ble. Reduction of the epoxide to the alcohol [2.0 eq. 2 several times.1,22,250 Although â-hydroxy alkyl halides are Cr(II)] was achieved by the more active [Cr(edta)] -com- 2+ plex.262 reduced to form alkenes with Cr(II)(en)2 , it is possible to dehalogenate these substrates with Cr(II) in the presence of a hydrogen donor like an alkylthiol without or at least 4.2 CÐC Coupling Reactions: with minimal formation of C=C double bonds and other Radicals from Carbonyl Groups byproducts.251 A recent, impressive example is the reduction of a tertiary halide in the presence of three â-alkoxy Pinacol type couplings of aromatic aldehydes to diols are groups in the synthesis of the hexacyclic steroid unit 144 among the oldest reactions reported for chromous 4,263Ð265 of the Cephalostatin family (Scheme 33).252 Dehalogena- salts. Catalytic versions of these reactions have tion of halogen-desoxynucleotides with a catalytic been reported, recycling chromium(II) either electro- 265,266 58,267 amount of chromium(II) by cathodic regeneration was re- chemically or more recently also chemically. alized by Steckhan et al.253 The reactions will be covered in Sections 5.2 and 5.1 respectively. Pinacolization of α,â-unsaturated aldehydes in mediocre yield has also been reported.265,268 In general no special advantage of chromium-promoted diol couplings is observed vs. procedures with other metals or low valent ions.269Ð273 Couplings between C=C and C=O bonds have recently been added to the spectrum of radical couplings of two sp2-carbons. Micskei et al.274 achieved a five-membered diastereoselective ring closure of nepenthone to a mor- phine derivative in 62% yield with Cr(EDTA)2Ð in water. Other complexing ligands give different results such as carbonyl reduction. Monosubstituted α,â-unsaturated aldehydes react in similar couplings to give cyclopropanols exclusively trans- substituted (Table 7).268 The reaction is, however, sensitive to the substitution pattern with 2-substituted acroleins being favoured substrates, and some 3-substituted ones reacting too. 2,3-Disubstituted acroleins appear unreactive, but few examples are given. Nickel chloride addition is beneficial but probably not crucial.

Scheme 33 Dehalogenation of a tertiary halide with three â-alkoxy substituents

Synthesis 1999, No. 1, 1Ð36 ISSN 0039-7881 © Thieme Stuttgart á New York REVIEW Recent Advances in Chromium(II)- and Chromium(III)-Mediated Organic Synthesis 19

Table 7 2-Substituted trans-Cyclopropanols from Acroleins

R1 R2 Yield (%)

Bu H 31 cyclohexyl H 63 1,1-dimethylpropyl H 69 H hexyl 51 HMeÐa Pent Bu 0 a Crotonaldehyde is reactive, but 2-methylcyclopropanol could not be isolated from the DMF-solution, probably due to its volatility and solubility in water.

4.3 CÐC Coupling Reactions: Radicals from Alkyl Halides Chromous salts can promote Wurtz-type couplings of allyl and alkyl halides and peroxides,5,18,275 including cy- cloalkane formation from α,ω-dihalides.8 However, these processes do not appear to be simple radical dimeriza- tions: From tri- and diphenylmethyl halides the corresponding polyarylethanes are formed and not the usual Scheme 34 Reductive radical addition of organic halides to Michael acceptors Gomberg type products.276 Sustmann171 proposed an oxidative addition of a radical to organochromium(III) and decomposition of the resulting diorganochromium(IV) to The intermediacy of an anionic species formed from rad- the dimer and chromium(II). Following this process it be- ical and Cr(II) can not be excluded in all cases of Michael came possible to achieve cross couplings, not just dimer- additions. Especially primary alkyls might prefer this izations, of stabilized radicals (benzyl, allyl or tertiary). route, whereas higher-substituted or benzyl compounds 51 Recently Sustmann extended the scope of the reductive should favor radical routes (cf. Section 3.2.3). Anionic coupling by adding radicals generated with bis(ethylene- reactions of very similar α-boryl and α-thioalkyl halides, 185,204 diamine)chromium(II) to a variety of Michael acceptors e. g. with aldehyde electrophiles, are known. Also 148 (Scheme 34).277,278 In DMF, benzyl and tert-alkyl brom- the product radical may be captured by Cr(II) to give a ides 147 gave the best results (68Ð84% yield), followed by chromium(III) enolate. Subsequent reactions of these in 56,79,104,106 secondary (50Ð68%) and primary halides (40Ð45%), pref- analogy to the chromium-Reformatsky reaction erentially iodides. Aryl and hetaryl iodides 150 and to offer interesting aspects for the development of tandem some extent aryl bromides also add to Michael acceptors reactions, especially since these enolates are slow to add 148 under these conditions (35Ð78%).278 As usual many to Michael acceptors but rapidly do so with alde- 57,78,280 functional groups are acceptable with nitro-substituents hydes. Accordingly the addition of the product eno- being one of the few exceptions (Section 7). Many accep- lates (or α-EWG-radicals) to a second Michael-acceptor tor groups (EWG) are acceptable. Their influence on the molecule was not observed with borylalkyl or perfluoro- 195,279 yields follows the usual order but appears to be of minor alkyl radicals, but has been reported in others cases 281 importance. (vide infra, cf. products 166, 167). The reductive 1,4-addition of α-boryl alkyl halides 152 Not only might the product radical be utilized for tandem was studied by Takai (Scheme 34).279 Through the use of reactions, also the initial radical can be intercepted. Takai lithium iodide even chlorides reacted well and in all cases recently reported a three component reaction (Scheme yields are very good, ranging from 79% to 92%, except 35): t-butyl or isopropyl radicals generated with chromi- for borylmethyl iodide (152, R' = H) which was unreac- um(II) add to a diene 155 and the thus formed intermedi- tive. Perfluoroalkyl radicals have been added in a princi- ate allyl radical 157 subsequently reacts with another pally identical matter, but with catalytic amounts of equivalent Cr(II) and an aldehyde in HiyamaÐNozaki 282 chromium ions and Fe-powder as reducing agents.195 The fashion. Diene polymerization is not observed. Addi- reaction is more thoroughly discussed in Section 5.2. tion to the diene occurs preferentially at the least substituted double bond (see box). The usual anti-products 156 are

Synthesis 1999, No. 1, 1Ð36 ISSN 0039-7881 © Thieme Stuttgart á New York 20 L. A. Wessjohann, G. Scheid REVIEW

present in the molecule, intramolecular radical addition to the carbonyl or a pinacol type coupling (Section 3.2.) could occur. External aldehydes, however, were reactive in a similar radical cyclization domino process of unhin- dered alkyl radicals 136 (Scheme 30, Section 3.4.1).240 Cyclizations of various 6-haloalkene and alkyne derivatives to form 5-membered ring compounds have been extensively studied by SchŠfer and co-workers (Table 8).281,286Ð288 Mainly 3-allyloxy and 3-propargyl- oxy-2-iodopropionates (161 and 163) have been cyclized to the corresponding iodomethyl-THF-3-carboxylates (162 and 164 respectively) by radical processes induced 287 by 30 mol% Cr(OAc)2. Some examples are shown in Scheme 37. The cyclized radical intermediates can be Scheme 35 TakaiÕs three component radical addition/ÒcarbanionÓ reaction Table 8 Examples of Schäfer’s Cyclizations of ∆6,7-Unsaturated 2- Halo Esters Induced with (Catalytic Amounts of) Divalent Chromium preferentially formed in the HiyamaÐNozaki reaction. (Some dehalogenated byproducts have been omitted for clarity.) Dienes can be converted to allylchromium compounds di- 283 rectly under B12-catalysis in the presence of water. Hy- drocobaltation generates allylcobalt(III) which dissoci- ates to allyl radical and cobalt(II) complex which reenters the catalytic cycle. The allyl radical then enters the Hiya- maÐNozaki route in the usual manner (cf. Section 3.3). R1 R2 R3 X Cr(II) X' Yield (mol%) (%)

H H H I 30 I 79 H H OEt I 30 I 93 H Me OEt I 30 I 93 H H OEt Br 275 H 79 H Me OEt Br 275 H 83 H i-Pr OEt Br 275 H 57 H Ph OEt Br 275 H 99 Me (E/Z) H OEt Br 275 H 83 Ph (E/Z) H OEt Br 275 H 76 -(CH2)3- OEt Br 275 H 78

Scheme 36

A similar process utilizing aryl iodide in a double intramolecular domino cyclization was published by Hodg- son (Scheme 36).284 Thus arylalkynals 158 give tricycles 160 in low yield. In the absence of an internal aldehyde function, exo-methylene compounds (cf. box in Scheme 36) are obtained, similar to the cyclization of w-alkynyl halides by ethylenediamine complexes of Cr(II) in aqueous DMF.285 It was not possible to trap the assumed vinyl- chromium intermediate with external aldehyde and D2O did not give deuterated products. Most likely a vinyl radical intermediate 159 ¥ is formed and can not be reduced by Cr(II) to the vinyl metal compound due to steric hinder- ance (allylic strain) and rather abstracts a hydrogen from the solvent.284 If on the other hand an aldehyde group is Scheme 37 Chromium(II) induced alkyl halide addition of io- doalkyne 164 and a reductive radical domino reaction

Synthesis 1999, No. 1, 1Ð36 ISSN 0039-7881 © Thieme Stuttgart á New York REVIEW Recent Advances in Chromium(II)- and Chromium(III)-Mediated Organic Synthesis 21 scavenged with excess chromium(II) salt to produce the a self-regenerating center in a catalytic cycle; these are re- corresponding organochromium(III) compounds. With actions dealt with in Section 5.4. (Cr(II)), and Section 8. bromides and stoichiometric amounts of chromous salt re- (Cr(III)). Type II are reactions usually stoichiometric in ductive cyclization to the corresponding halogen free chromium(II) proceeding via organochromium(III) inter- THF-derivatives can be achieved in the presence of water mediates. After reacting, the Cr(III) is recycled by in situ (Table 8). The relative diastereoselectivity along the new- reduction to active Cr(II), rendering the stoichiometric ly formed bond is mostly low (d.r. ≈ 1 : 1 to 1 : 3.9).286 process catalytic, thereby utilizing directly the specific The organochromium(III) intermediates have also been stereoelectronic properties of the ion, but only indirectly utilized to react further, e. g in a â-elimination if a suitable its reducing power. Type III reactions are radical chain leaving group is present. Alternatively acrylic ester can processes merely induced by chromium(II). They most interfere either on the radical or the carbanionic stage to likely do not include organochromium intermediates and produce further CÐC-bonds. In a domino (tandem) reac- are treated in the respective Sections (4.3 and 7), despite tion of bromoalkene 165 mainly 1 : 1-adduct 166 but also the fact that they also may be formulated via Cr(II/III)- some 1 : 2-adduct 167 from addition to a further acrylate catalytic cycles of type I. Some reactions offering the pos- is formed (cf. the reaction of borylalkyl radicals). Benzal- sibility to either follow a type III radical chain mechanism dehyde was less successful as electrophile.281 or alternatively the pseudostoichiometric type II route are, In similar reactions the reductive cyclization of 2-bromo however, included in this section. allylic (170) and propargylic acetals and ethers was The often mentioned toxicity of Cr3+ as a reason for devel- achieved by various methods including catalytic varia- oping such processes may be of secondary importance for tions with chemical (LiAlH4) or electrochemical recycling standard laboratory applications. [For remarks on the tox- of the chromous ion in 54Ð93% yield (Scheme 38).288 The icity of Cr(III) see Section 2.96,100] For catalytic versions chromous ion is activated by a (bidentate) nitrogen ligand. of type II it becomes merely an ostensible reason if the re- Despite the presence of water acyclic products were never ductant used, e. g. another transition metal, is equally or observed and thus anionic early intermediates may be ex- even more problematic than the easily recovered chrom- cluded. The diastereoselectivity of the reaction depends ium(III),289 or if further hazardous chemicals have to be on the substitution pattern and solvent, less on the method used. The catalytic use of chromium, however, is essential used, with trans : cis-ratios ranging from ca. 30 : 1 (R2- for at least two types of applications: efficient processes substituent on allyl) to 1 : 55 (R3ÐR4 cyclic acetals = with catalytic chirality transfer in order to minimize the endo-selectivity). The endo selectivities of cyclic 2-bro- amount of expensive chiral auxiliaries or ligands (these mo allyloxy ethers are twice as high or better than those reactions still await their discovery), and large scale tech- achieved with tributylstannane cyclizations of similar car- nical processes in order to reduce salt waste. The ideal so- bon analogs. lution would be electrochemical recycling of chromium(II), but a major problem is the often more facile direct reduction of the organic halide at the electrode. This and some recent advances are discussed in Section 5.3. Another general problem of type II catalytic systems are the Cr(III)-ions formed in the process. Liberation of this ion from the product (= ligand) to give a solvated ion or even a free ligand site to dock onto a reductant for recycling is an unlikely event in the timescale necessary for efficient catalysis. Being protected by their ligand sphere, inner sphere contacts of Cr(III) with the reducing agent will be difficult to achieve unless especially labile ligands (alkyls) or electronic (photochemical) activation are applied. Outer sphere (long distance) electron transfer is possible of course, but will result in a different Cr(II)-spe- Scheme 38 Cyclization of 2-Bromo Allylacetals cies compared to the originally employed one, it thus may also display a different reactivity.226 With the product be- A domino reaction of iodoacetate to a simple double bond ing also a ligand, the formed chromium(II)-product com- of 2,2-diallylmalonate followed by 5-exo-trig cyclization plex has to be well-behaved to give the same result in the and iodine transfer has been achieved with 1.3 equivalents next reaction cycle as does fresh Cr(II), a Monte-Carlo ap- chromium diacetate in 88% yield.287 proach, or the product ligand has to be removed effective- ly. Some approaches of both types have recently been successful and are discussed in Section 5.2. 5 Reactions Catalytic in Chromium(II) Indirect reduction via a Cr(II) ↔ Cr(III) electron shuffling 5.1 General Aspects process has to be considered as well, a process that in addition impairs configurational stability in simple chiral There are three types of catalytic chromium reactions. chromium(III)alkyls.51,75,172 This common process is most Type I is truly catalytic in chromium. The ion is acting as

Synthesis 1999, No. 1, 1Ð36 ISSN 0039-7881 © Thieme Stuttgart á New York 22 L. A. Wessjohann, G. Scheid REVIEW evident in the Cr(II)-catalyzed solvation of otherwise in- Similar reactions of perfluoroalkyl iodides 175 to 2-al- soluble (inert) Cr(III)-salts.45,61,97,290 A similar Cr(II→III) lylmalonate derivatives 176 gave perfluoroalkylmethyl SET may also be responsible for the successuful reduction cyclopropanes 177 with an average yield of 85% (Scheme of chromium(III) in the Cr(III)-alcoholates formed in 39).196 As in the previous paper by the same authors, no chromium-alkyl additions. Finally the somewhat less like- information about the applicability to non-fluorinated ly but unproven possibility of having chromium(II) alkyls alkyl iodides was given and no mechanism is proposed. A reacting with the electrophiles, not the chromium(III) purely radical (tandem) type III mechanism can be formu- alkyls, has not been discussed in literature yet. Chrom- lated, but would require a less common intermediate after ium(II) alkyls might by formed by exchange of an electron radical cyclization. A possible alternative pathway with solvent-chromium(II), or chromium(II) still bound to (Scheme 39, bottom half) may involve initial CrCl2-cata- the freshly formed Cr(III) in one of the common dinuclear lyzed addition of the perfluoroalkyl iodide across the dou- complexes. In the TakaiÐKishi-reaction the intermediate ble bond. Similar Cr(II)-catalyzed radical addition to aryl- or vinyl-nickel(II) may also exchange with Cr(II), ini- double bonds are well known to proceed without inter- tially present in a large excess over Cr(III) (mostly > change of the abstracted halide (iodide) with the halide 100 : 1) to form the corresponding chromium(II)-organyls. ligands on Cr(II) (vide infra, Section 4.3 and 7).287,297,298 Alkyl, benzyl, allyl and aryl chromium(II) compounds are The resulting 2-(2'-iodoalkyl)malonate (178/179) can un- well known and often exhibit high reactivity not yet pur- dergo a standard nucleophilic ring closure of the enol(ate) posely utilized in organic synthesis.70Ð72,291Ð296 179, e. g. Lewis acid catalyzed by chromium or iron ions, under release of hydrogen iodide. This may finally react with the iron powder in the ethanol/water-mixture. Unfor- 5.2 Chromium(II) Recycled with Reductive Metals tunately no observations about pH-changes in the early Among the first reactions catalytic in chromium(II) were stages of the reaction or hydrogen evolution have been re- CrCl3¥6H2O / Fe-powder / ethanol systems utilized by Hu ported. Without mechanistic evidence all types (I, II or et al. with 20 mol% Cr(III) in 1993.195 They describe what III) of substoichiometric Cr(II) reactions remain possible: most likely is a radical addition of bromodifluoromethyl, an initiated radical chain mechanism (III); a type I reac- generated from the dibromide 172, to a variety of Michael tion as shown in Scheme 39 (i. e. a self-preserving acceptors 173 to yield 3-bromo-3,3-difluoro esters, ni- CrCl2-catalyzed radical addition), or a type II reaction triles and ketones 174 (Table 9). Even acrylic acid and with the iron recycling Cr(III) to Cr(II). Similar reactions acrylamide were substrates, whereas with a more hindered tried with CrCl3 ¥n THF / Fe-powder in purely non-protic crotonate the yield drops to 43%. At the same time, poly- solvent as well as Reformatsky reactions which are likely merization of the acryl derivatives was not observed de- to proceed only via chromium organyls did not work.57 spite the fact that α-radicals or potentially also anion intermediates must be present at some time. CF2-formation or difluoromethylenation were not observed. Iron powder alone could not initiate the reaction, but CrCl2 could, albeit in much lower yield. It remains unclear, however, if the Cr(II) formed just initiates a chain reaction to form intermediate α-radical or α-iodo esters (type III), which then are reduced by further CrCl2 (from Fe-reduction) via the enolate, or if the complete reduction at the substrate is achieved to give a trihalomethyl anion193 adding in Michael fashion in a type II reaction.

Table 9 Chromium-Catalyzed Reductive Addition of Perfluorobro- moalkane to Acryl Derivatives Scheme 39 Chromium(II) catalyzed synthesis of perfluoroalkylmethyl substituted electrophilic cyclopropane derivatives

The breakthrough in catalytic chromium(II/III) reactions EWG R Yield (%) was achieved by FŸrstner and Shi (Scheme 40, Tables 10, 11).58,299 In two excellent papers they introduced the first CO2HH 64general catalytic versions of the HiyamaÐNozaki and the CONH2 H72TakaiÐKishi (HiyamaÐNozakiÐKishi) reactions. They in- COMe H 60 CN H 62 troduced a system to recycle chromium(III) to chromium(II) with manganese metal, which is cheap and gives CO2Me H 75 CO2Et 2-Me 80 less toxic salts. The choice of manganese is crucial to re- CO2Et 3-Me 43 tain the useful properties of the organochromium reaction. -CO- 1,3-(CH2)3 18 The metal does not react directly with the organic halides

Synthesis 1999, No. 1, 1Ð36 ISSN 0039-7881 © Thieme Stuttgart á New York REVIEW Recent Advances in Chromium(II)- and Chromium(III)-Mediated Organic Synthesis 23

Table 10 Some Representative Examples of Fürstners Catalytic Ta- kai-Kishi Reactions58, 299

Alkenyl-/Aryl-halide Aldehyde Yield (RX) (R'-CHO) (%)

PhI Ph-CHO 62a a PhI CH3(CH2)6CHO 67 b PhI ClÐCH2(CH2)4CHO 66 4-EtO2CÐC6H4 PhCHO 57 octen-2-yltriflate PhCHO 67 octen-2-yltriflate CH3(CH2)6CHO 61 hexen-2-yltriflate 4-MeOC6H4CHO 76 2-iodohexene 4-MeOC6H4CHO 75 Scheme 40 A tentative mechanism for NozakiÐHiyama and TakaiÐ ≡ c CH3(CH2)3C CI PhCHO 62 Kishi reactions catalytic in chromium according to FŸrstner58,299 ≡ c CH3(CH2)3C CI CH3(CH2)4CHO 79 ≡ d CH3(CH2)3C CI CH3(CH2)4CHO 80

a and does not form salts with high Lewis acidity. The latter 88% and 72% resp. with ClMe2Si(CH2)3CN as silyl chloride. aspect excludes zinc because enolizable aldehydes will b Isolated as O-acetate after acetylation. c In THF form enol ethers with the added TMSCl. d With 5 mol% Cp2Cr as Cr-catalyst A working hypothesis for a catalytic cycle has been proposed and is shown in Scheme 40. According to this tentative mechanism the ligand exchange stability of the cycles alone, shortcutting the chromium. However, FŸrst- chromium alcoholates was overcome by adding trimeth- ner could prove that this is not the case and thus chromium ylsilyl chloride (TMS-Cl) and scavenging the products as organyls are the nucleophilic agent in the CÐC-coupling. TMS-ethers in order to liberate chromium(III) chlo- A big advantage of the FŸrstner method vs. electrochemi- ride.58,299 However, it is doubtful if the exchange stable cal methods is its applicability to allyl halides, which are chromium(III) alcoholates are really cleaved with TMSCl otherwise prone to direct reduction bypassing chromium. as such reactions do not take place if tried in stoichiomet- Reactivity and selectivity is in all aspects similar to the ric Hiyama reactions.153 An alternative pathway not dis- stoichiometric version if chromium chlorides are used as cussed by FŸrstner could be the reduction of the catalyst. Again yields appear to be better with excess allyl chromium(III) alcoholate directly by manganese (or via halide and are slightly inferior to the stoichiometric proce- Cr(II) ↔ Cr(III) shuffling, see above) to the exchange la- dure. Some examples are given in Table 11. bile chromium(II) alcoholate prior to reaction with TMS- Chromium dichloride could be substituted by the trichlo- Cl.300 The feasability of such a course of events is ride as demanded by theory. With other chromium tem- supported by electrochemically driven catalytic versions plates, especially cyclopentadiene ligands (Cp Cr or of the same reaction without added TMSCl (vide infra301). 2 CpCrCl ), amounts as low as 1 mol% Cr could be However, the formation of the TMS-ether bond appears to 2 achieved for HiyamaÐNozaki reactions, but de's drop to be a crucial driving force in the chemical catalytic reac- 30Ð56%. Smaller amounts of chromium salt could not be tion and it provides the chloride ions consumed in the cat- employed successfully. Incomplete ligand exchange was alytic cycle. Similar approaches were successful in other suggested as a possible cause.58 The process so far was not systems devised by FŸrstner et al.302 A role of TMSCl in applicable to the chromium-Reformatsky reaction, proba- a Lewis acid-base activation of the carbonyl group has bly due to the better complexation properties of the chelat- been discussed as well. Other trialkylsilyl chlorides show ing aldolate.57,112,114 similar effectivity and sometimes slightly better yields.267,302 Aromatic aldehydes 182, especially with electron-with- drawing substituents, or the more powerful CpCr-cata- A wide spectrum of TakaiÐKishi reactions of aryl, vinyl lysts give pinacol coupling preferentially (Scheme 41).58 and alkynyl iodides and triflates has been studied.58,299 The reaction is common in donor solvents like water, Some selected examples are shown in Table 10. They are DMF or DMSO4,57,112,263,265 and is even observed as a side fully comparable to the stoichiometric reactions, but seem reaction in THF.56 Boland267 studied the catalytic version to be slightly lower in total yield (62Ð80%). Usually more closely. With the aromatic aldehydes, zinc can sub- 15 mol% CrCl and a twofold excess of halide or triflate 2 stitute manganese but is less active. As little as 1 mol% have been used. In analogy to the noncatalytic versions CrCl may be used, but 5 mol% give better yields which the reactions also require catalytic amounts of nickel (see 3 range from 51Ð79%. Even acetophenone 184 reacts well Section 3.4). In FŸrstnerÕs setup the whole process in prin- but, as expected, much more slowly (Scheme 41). Water ciple could also proceed through Ni(0) ↔ Ni(II) redox

Table 11 Some Representative Examples of Fürstner’s Catalytic Hi- Takai applied FŸrstnerÕs method to his three component yama-Nozaki Reactions58 coupling discussed in Section 4.3, but the results were somewhat inferior to the stoichiometric process.282 Al- ready in 1995 Utimoto, Matsubara et al. used the extremely strong reducing agent Sm/SmI2 in the presence of catalytic amounts of CrCl3 for the alkylidenation of ketones with gem-dibromo alkanes (Scheme 41).215 Unlike many other methods, especially Wittig type reactions, this Allyl bromide Aldehyde Catalyst anti:syn Yield (200 mol%) (R3-CHO) (mol%) (%) alkenation procedure is suitable for ketones sensitive to enolization. Even sterically hindered ketones and 1,1-di- R1 R2 R3 bromoalkanes react. However, the reaction did not proceed with CrCl2 alone, but did so with SmI2 or better Sm/ HHCH CrCl (7) Ð 78 7 13 2 SmI2. Addition of the chromium salt did improve the re- HHC7H13 Cp2Cr (1) Ð 76 action considerably, but direct involvement via a catalytic HHCH Cp Cr (0.5) Ð 62 7 13 2 Cr(II)↔Cr(III) cycle is doubtful. Finally, recycling of Me (E) H Ph CrCl2 (7) 94:6 79 Me (Z) H Ph CrCl2 (7) 90:10 64 chromium(II) with lithium alanate was reported for reduc- 288 Me (E) H Ph CrCl3 (7) 91:9 85 tive cyclizations (see Section 4.3, Scheme 38). a Me (E) H Ph Cp2Cr (1) Ð 37 Me (E)H C5H11 CrCl2 (7) 94:6 84 Me (E)H C7H13 Cp2Cr (1) 77:23 76 Me (E)H C7H13 CpCrCl2 (1) 78:22 92 b homoprenyl 3-Me Ph CrCl2 (7) 94:6 79 c H 2-CO2Et Ph-(CH2)2 CrCl2 (7) Ð d H H (2-octanone) CrCl2 (7) Ð 68 a Pinacolization product (vide infra): 56% Scheme 42 Alkenation of ketones with samarium/samarium di- b i.e. geranyl bromide was used. Cf. the findings of Knochel et al. iodide modified with catalytic amounts chromium(II/III) (Section 3.2)68,69 c The g-butyrolactone was isolated after acidic workup. No yield is reported. 5.3 Electrochemical Reactions d 2-Octanone was used as electrophile instead of an aldehyde. A general problem with the theoretically ideal electrochemical recycling of chromium(II) is the competing di- has to be excluded to avoid simple reduction to alcohols, rect reduction of the substrate, i. e. usually an organic and the usual aprotic donor solvents are best. Acetonitrile bromide or iodide. Since allyl- and benzyl halides are the was unsuitable.303 A significant problem in pinacol cou- most easily reduced common substrates, no practical elec- plings is the relative (simple) diastereoselectivity.273 Un- trochemical version of the HiyamaÐNozaki reaction has fortunately with TMSCl the diastereoselectivity is been published. Thus simple electrochemical setups are negligible. With bulkier silyl groups (TBDPSCl) benzal- limited either to the less easily reduced substrates like aryl dehyde reacts to the dl-compound in 90% de but requires or cyclopropyl halides or will require membrane technol- reaction times of several days with GC-yields below 38%. ogy or other protection methods complicating the whole The reaction is limited to aromatic and heteroaromatic al- procedure. Techniques depending on the separation of the dehydes. The catalytic pinacol coupling can also be done starting organic halide, the formed Cr(III) and the product electrochemically (vide infra). The latter process is appli- from each other in one setup are thwarted by the slow cable to alk-2-enals as well.265,266 ligand exchange of the product complexes. Most easily these chromium(III)-complexes are recycled directly, without prior release of the product. This can be considered a likely course of events in one compartment setups and is supported by voltammetric studies,266,300 and, most striking, by the formation of different products after the first cycle.226 Nevertheless, a number of chromium(II) reactions with electrochemical recycling of the ion have been reported. These include radical cyclizations (Section 4.3),288 pinacol couplings (Section 5.2.),265,266 DoeringÐMooreÐSkat- teb¿l reaction or reduction of gem-dihalocyclopropanes (Section 3.3.5);226 dehalogenations of â-halo ethers without elimination,253 and elimination from chloromethyl- carbinols (189) to 1,1-dichloroalkenes (191) or Z-chloro- Scheme 41 Chromium(II) catalyzed pinacol couplings according to 267 177 alkenes (190) depending on their substitution pattern Boland. [FG = 4-Cl, 4-Br, 4-CO2Me. Furylformaldehyde was (Scheme 43).216 â-Lactone 192 exceptionally gives dimerized too.]

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the most important catalysts for the production of high density polyethylene (HDPE). Linear low density PE is also produced by the method. Some chromium loaded ze- olites are also active catalysts.49 The catalysts allow polymerization at low pressures and relatively low temperatures (~100¼C) without any cocatalyst. Technical polymerization until recently, however, was almost exclusively limited to ethylene, allowing at most copolymerisa- tion with some higher α-alkenes using Phillips catalyst. This was a major drawback to the competing ZieglerÐNat- ta type catalysis. Another contrast is the limited knowledge of the reaction mechanism and active sites. Almost nothing is known Scheme 43 Electrochemical chromium(II) promoted halohydrin about the nature of the latter, owing to the difficult (elec- elimination to Z-chloroalkenes (190) and dichloroalkenes (191) tronic) properties of solid phase bound Cr(II/III). There is an ongoing dispute even if Cr(II) or Cr(III) is the active species, with evidence for both.49 The Union Carbide cat- dichloro compound 193, although it is not a tertiary alco- alyst (A) offers more chances for investigations than the hol derivative. Phillips types (B). Solid phase NMR studies by BlŸmel, Most recently Grigg et al.301 described an electrochemi- Kšhler et al.304,305 have shown that a number of chromi- cally driven TakaiÐKishi reaction in DMF (Scheme 44). um-species, including a mono- and a dinuclear one, are The reaction is cocatalyzed by palladium(0) rather than present, without new insight regarding the oxidation state nickel and seems to be limited to aromatic aldehydes. of chromium, however. There has been evidence of com- Careful control of the current density is crucial to avoid plex formation for ÒPhillipsÓ-chromium(II) with CO and side reactions like biaryl formation or inactivation of the ethylene, which then reacts with a second molecule ethyl- mediator. Lithium perchlorate is used as electrolyte and ene.306 Soft evidence indicates the formation of a chroma- electrophile for the liberation of the alcoholate at the same cyclohexanone 197 which is suggested as a starting point time, substituting TMSCl in the latter function. for the insertion of further ethylene. It was also found that Phillips catalyst pre-reduced with CO does not require the usual induction time.49,307 The Theopold group, trying to design homogeneous polymerization catalysts, was unable to do so with Cr(II),291,296,308 but could finally synthesize Cr(III) complexes with an unsaturated coordination sphere, e. g. 196, Scheme 44 Electrochemical Version of a TakaiÐKishi reaction cat- which polymerized alkenes at temperatures as low as alytic in chromium and palladium Ð78¼C [Scheme 45, (C)].50,309,310 Even higher α-alkenes could be polymerized successfully.310 Although this can not be regarded as definitive evidence for a Cr(III)-oxida- Electrochemical recycling of chromium(II) certainly con- tion state at active sites in technical catalysts, it is truly a stitutes the ultimate solution in catalytic organochromi- breakthrough in the area. Unfortunately no high tempera- um(III) reactions. It will depend on the development of ture polymerizations were reported with the Theopold- reliable, easy to use and high yield techniques in this area catalysts C (196). These could have indicated if the inabil- to promote chromium(II/III) reactions from laboratory or ity of the solid phase catalysts to react with higher alkenes specialized industrial use to applications in small and me- is merely a temperature effect, caused by the thermal sen- dium large industrial processes. The HiyamaÐNozaki re- sitivity of intermediate secondary Cr(III)alkyls to ho- action still remains a formidable task for electrochemists. molytic cleavage, or if other problems like â-fission are responsible for the limitations.50,51,62Ð65 â-Hydride elimi- 5.4 Chromium(II/III) Compounds in Alkene nation, however, is not a typical reaction of chromium(III) Polymerization and Alkane Formation alkyls.50,51,296 By far the most important application of chromium(II/III) Catalysts similar to the Phillips-type (e. g. the so-called is the polymerization of ethylene (Scheme 45). Mainly ÒKrauss-MasseÓ, CrO3 on silica reduced with hydrogen or two catalysts, named after the companies of their inven- carbon monoxide at high temperature) catalyze quite a tors, have been used: The ÒPhillips catalystÓ (B), in reality number of other reactions, the course of these depend strongly on temperature and preparation conditions. They a family of catalysts of inorganic chromium compounds 311 deposited on silicas and then activated by high tempera- are frequently used for the reaction with oxygen (deoxy- genations, gas purifications) and alkane formation (cf. ture reduction; and the ÒUnion Carbide catalystÓ (A), 312 chromocene deposited on dry silica. These are probably Scheme 45). Other solid-phase based chromium cata-

missing the necessary handles in most cases. Thus an auxiliary approach was used only in chromium-Reformatsky reactions. So far it proved to be quite successful and much less wasteful than the ligand based alternatives which, however, in combination with the catalytic use of chromium(II) remain the ultimate goal. Another possibility, the generation of non-racemic secondary or tertiary organochromium(III) reagents with a stereocenter at the CÐCr carbon is not feasible because of the rapid racemisation of such centers.51

6.1 Auxiliary Based Methods Auxiliary based methods have successfully been used in the chromium-Reformatsky reaction.57,104,106,112 With one equivalent of chiral template, easily attached and cleaved off, and with eeÕs usually > 96% this method currently is the best approach to non-racemic compounds in a chromium(II)-promoted reaction. By far the best results were obtained with EvansÕ oxazolidinones (Table 12, Scheme 46). Other common auxiliaries like OppolzerÕs sultam or 8-phenylmenthyl ester were much less effective. The oxazolidinones 198 can be attached to (mostly commercial) 2-bromoalkanoyl bromides quantitatively and may be followed by the Reformatsky reaction in the same pot without loss in total yield. 2-Bromo- propionyloxazolidinones 200 and other α-chiral 2-ha- Scheme 45 Chromium catalysts in alkane formation and polyethy- loalkanoyloxazolidinones form diastereomeric mixtures. lene production: The second most important ethylene polymeriza- However, the α-stereocenter has no influence as it is equil- tion process ibrated during reaction with chromium(II) (Section 3.1, Scheme 3) and match/mismatch effects were not observed. lysts were used for alcohol and hydrocarbon oxidation, (light) alkane dehydrogenation and other reactions of Table 12 Synthesis and anti-selective asymmetric chromium-Refor- matsky reactions of N-(2-bromopropionyl) oxazolidones 200. technical importance. However, it is not always clear if Cr(II), Cr(III) or even higher oxidized species are involved, or an interplay of these. Some aspects of solid phase bound chromium have been reviewed recently.49

6 Asymmetric Synthesis with Chromium(II)-Mediated Reactions

In strong contrast to the many publications discussing relative diastereoselectivity of chromium(II) based reactions, very few publications are devoted to enantioselective or auxiliary based methods to achieve absolute control of stereocenters. Unfortunately ligand based methods have not been very successful so far. Most simple approaches with readily available chiral ligands #R1 R 200a 201 dr failed. Complexation of the extremely ligand-exchange- (α-R:S) labile chromium(II) and its tendency to form dimers or Yield (%) Yield (%) syn:anti clusters with linear polydentate ligands makes the ion an unusually difficult candidate for such a route. The few a i-Pr i-Pr 85% 96% 11:89 >98:2 b b somewhat successful experiments require a manifold ex- b CH2Ph i-Pr 94% 88% <5:95 >98:2 c i-Pr Ph 85% 86% 23:77 >98:2 cess of specially designed ligands (often > 400 mol%) and d CH Ph Ph 94% 81% 16:84 97:3 give only mediocre yields. Unfortunately reactions like 2 the HiyamaÐNozaki or TakaiÐKishi reaction are not im- a ~ 100% conversion. Yields refer to isolated products. mediately susceptable to auxiliary attachment as they are b anti-201-b was found exclusively.

Synthesis 1999, No. 1, 1Ð36 ISSN 0039-7881 © Thieme Stuttgart á New York REVIEW Recent Advances in Chromium(II)- and Chromium(III)-Mediated Organic Synthesis 27

In analogy to the simple esters (Section 3.1) the N-(2- Nevertheless, these were better than those obtained with bromopropionyl)oxazolidones 200 gave the unusual anti- butyllithium/(Ð)-sparteine. 106 products, but with improved deÕs. The induction is GorŽ and co-workers report the syntheses of nonracemic mostly excellent (>> 96%de) and leads to products of the allenes from propargyl bromides with CrCl2 modified opposite enantiomeric series compared to the standard with HMPA and menthol or borneol.167,168 The latter alco- lithium and boron type Evans aldolizations. The product hol gave the best results with up to 23% ee. Ligands like configuration was secured by X-ray analysis. Not only is camphor acid, tartaric acid, ephedrine, amino acids and this the first Reformatsky reaction providing useful enan- octan-2-ol, among others, were much less successful. tiomeric excesses, it also gives the only Evans aldol product of four possible ones which is not attainable by other The same group applied a similar set of ligands (as lithum methods is formed preferentially. Interestingly the salts) to the HiyamaÐNozaki reaction of allyl and methal- 323 4-benzyl auxiliary (200 b/d) proved to be slightly superior lyl bromide (Table 13). Monodentate ligands like men- to the valin derived one. As usual, benzaldehyde appeared thyl alcoholate proved to give product alcoholates to be one of the worst electrophiles with respect to both, inseparably bound to chromium(III). The lithium salt of yields and enantiomeric excess. N,N-dimethylephedrine (212) gave the best overall results in this study with up to 17 % ee and up to 60% yield. Re- EvansÕ type enolates so far have been unsuitable reagents 313Ð315 cently this approach was taken up and the alcohol and for the asymmetric transfer of acetate units. Quite amino alcohol ligands were optimized as well as the reac- some effort was directed to this long standing problem, tion conditions (Table 13).324 With most ligands yields and the solutions of Braun,119,316,317 a basic procedure, and 318 were below 70% and eeÕs below 50%. By far the best Oppolzer, using a multistep acidic route, are the best ligand tested was proline derivative 216. In an optimized methods available to date. In the chromium-Reformatsky setup four equivalents of this ligand were reacted with bu- reaction of bromoacetyloxazolidone 202 similar enantio- tyllithium and two equivalents chromium dichloride. meric excesses as with these methods can be achieved, but With this mixture allyl bromide was reacted with a variety under neutral conditions and at room temperature 104,106,112 of aromatic aldehydes in 43Ð84% yield and with 49Ð98% (Scheme 46). The reaction is extremely easy to ee. Yields were better at lower temperature (Ð30¼C), carry out, but great care has to be taken to avoid residual whereas eeÕs improved if the alcoholate was prepared at water as 2-haloacetyl substrates show lower reactivity and room temperature. The reaction appears to be limited to higher sensitivity than more highly substituted 2-halo- unsubstituted allyl bromide. The procedure was applied to acyls. the chromium-Reformatsky reaction, but ee's were below 20% and the basic reagents caused severe side reactions (aldolizations).57 A totally different set of ligands was applied by Kishi et al.325 Bipyridyl derivate 217 proved to be the most successful one, giving an almost 7-fold excess of one enantiomer, whereas chiral phosphanes only produced racemate. Unfortunately no yields were reported.

Scheme 46 The chromium-Reformatsky reaction provides a simple method for asymmetric acetate transfer under neutral conditions Table 13 Selected Examples of Hiyama-Nozaki Reactions with (20¡C, THF, cat. LiI, 5 h).106 [Comparison to analogous low tem- Chromium Dichloride Modified by Nonracemic Ligands perature aldol reactions of other metal imidenolates]314

Asymmetric chromium-Reformatsky reactions were applied towards the total synthesis of Epothilones (cf. n L* R Yield (%) ee (%) Ref. Epothilone B, 208),103,104 highly potent anticancer com- 319,320 1 i-Bu 58 16 (S) 323 pounds. The combination of asymmetric acetate Ph 60 11.5 (R) 323 transfer, inhibited retro-aldolization (the Epothilone 212 C3(OH)-C4-bond is base labile) and aldehyde selectivity 2 Li-mentholate 213 Ph 27 20 324 enabled the shortest synthesis of the aldol fragment (C1Ð 1Li2-binolate 214 Ph 49 11 324 C5) of Epothilones to date (Scheme 47).104,320 1Li2-taddolate 215 Ph 56 46 324 Ph 62 82 (R) 324 2 4-ClC6H4 47 98 (R) 324 6.2 Ligand Based Methods PhCH2CH2 60 61 (S) 324 The first experiments to use chiral chromium(II) com- 216 plexes were based on chromous (+)-tartrate. In DoeringÐ MooreÐSkatteb¿l reactions non-racemic allenes were 217 generated from gem-dibromocyclopropanes. Only very 2 Ph n.r. 74 325 low optical rotations and no ee-values were reported. 217

Scheme 47 Two rapid chromium-Reformatsky routes to the aldol-moiety of Epothilones with configurational control at C-3.104 [cpgc = chiral phase gc / (a) cf. NicolaouÕs320 and (b) SchinzerÕs similar building blocks321 (c) 211 can rearrange to the equally useful oxinandion.322]

The effect of bipyridyl ligands was also surveyed in Ta- tions could be run below 0¼C or with ketone electrophiles. kaiÐKishi reactions of vinyl iodides (Table 14).325 The ad- The best ligand tested was 217. With this ligand average dition of another metal ion required in the process, in this eeÕs are still below 60% at 30¡C. A maximum of ca. 80% case nickel, demands the design of a chromium(II) specif- ee was achieved with an α-chiral aldehyde at Ð20¡C after ic ligand. (This would also be a crucial requirement in a 66 h in THF. Match/mismatch-effects were not studied, perspective manganese driven catalytic version). Phos- however. No yields were reported except for the best com- phanes and 2,2'-dipyridyls which can adopt a planar con- bination which gave 93% (8 : 1). formation inactivated the reagents, probably through A new application of chirally modified chromium(II) was nickel complexation. It was discovered that at least one 6- recently discovered by Micskei et al., who could reduce substituent at one pyridyl unit is required. Ligands with aryl ketones like acetophenone (184) to the corresponding proper substitution patterns applied with NiCl2/CrCl2 (1 : alcohol with up to 55% ee.326 2) even enhanced the reactivity of the system and reac-

7 Reactions at Heteroatoms Table 14 Takai-Kishi Reaction with Chromium Dichloride Modified with the Homochiral Bipyridyl Ligand 217 Most common are reductions of heteroÐhetero bonds. The majority of these have been reviewed before,22,250,327 and some examples are shown in Table 15. Chromium(II) compounds appear to be fairly weak and mild reducing agents, limited to the cleavage of very weak bonds. Also reducing power and course of reaction are dependent on the counter ion, solvent and presence of protons. Except for the most easily reduced groups (NO2, N3, SÐS), most R T t Enantiomer functional groups are not effected by chromium(II) in the (¡C) (h) ratio aprotic environments usually employed for organic reactions. Bu 30 1 1.8:1 Bu Ð20 48 2.5:1 From N-haloamides (220, 222Ð224)337,338 and carb- 298 CO2Me 30 1 2.2:1 amates amidyl radicals can be formed, which rather CO2Me Ð20 48 3.1:1 than abstracting allylic hydrogen undergo addition to dou-

Synthesis 1999, No. 1, 1Ð36 ISSN 0039-7881 © Thieme Stuttgart á New York REVIEW Recent Advances in Chromium(II)- and Chromium(III)-Mediated Organic Synthesis 29

Table 15 Selected Heteroatom Reductions with Chromium(II). In principal the reaction is catalytic in chromium(II), and + [Tolerated Functional Groups (FG): 2-,3-,4-OH, OR, NH3 , NMe2, the halide abstracted is the same one captured by the (cy- Cl, Br, CN, Aryl] clo)alkyl radical formed after the the initial addition to the Reaction Typical Ref. double bond. Thus reaction of an N-chloroamide with Yield (%) chromium dibromide yielded the N-acyl 2-chloroamine, not the bromo compound.297,298 Sometimes, however, hy- 58Ð97 328 drogen abstraction is observed instead of chlorine transfer and usually almost equimolar amounts of chromium(II) are used for the reaction.338 ~60 328 8 Chromium(III)-Mediated Reactions ~80 329Ð331 Organic reactions of chromium(III) which do not start 60Ð80 13 from chromium(II) are rare. Despite the considerable Lewis acidity to be expected from the small Cr3+-ion the unavailability of free ligand sites and/or slow dissociation of bound reactants prevents useful Lewis acid behaviour 40Ð96 332 and catalysis in most cases. However, ligand exchange kinetics is strongly dependent on the co-ligands and the 100 333 ligand geometry [cf. the reactivity and trans ligand effect of chromium(III)organyls].50,51 By altering these parame- ters, active species can be obtained and recently a number ~20 328 of very interesting reactions using chromium(III) species have been discovered. The new Cr(III)-polymerization 334 catalysts of Theopold et al.309,310 have already been men- Ð 335 tioned in Section 5.4 and are of immense potential for industrial application in homogeneous polymerization. Apart from these results, homochiral asymmetric 60a 336 (salen)chromium(III) complexes account for the most exciting new application in organic synthesis. Jacobsen et al. a Based on Cr(II). used complexes like 225-N3 to catalyze the stereospecific ring opening of epoxides with TMS-azide (Scheme 49). ble bonds (Scheme 48).337 Intramolecular reactions to 5- The reaction can be used for the deracemization of meso- and 6-membered rings are favoured (cf. 221). Those with epoxides339Ð341 as well as for kinetic resolution, e. g. of the carbonyl group being part of the new ring appear to rac-228, giving excellent yield and ee-values for both, the form slightly better then those with external acyl groups azido alcohol 229 as well as the remaining epoxide enan- (cf. 223). Intermolecular amidyl additions (cf. 224) are tiomer R-228.342 Only about 2 mol% catalyst are required. much less useful synthetically and yield a certain amount Kinetic experiments reveal a dual role of the catalyst act- of reduced amide. However, they are mostly higher in ing as chiral Lewis acid as well as chiral nucleophile, re- yield than photolytically induced reactions with the quiring two molecules of catalyst per turnover.343 amidyl radical adding to the less substituted end of the The same type of complex is effective in the catalysis of double bond.337 asymmetric hetero-DielsÐAlder reactions, e. g. the reaction of 229 to 230, believed to be concerted. Most ee-values are in the 80% range, and a very broad spectrum of aldehydes is accepted.344 Chiral (salen)chromium(III) complexes have also been used as catalysts in asymmetric epoxidation reactions with iodosylbenzene as oxygen source involving an intermediate Cr(V)-oxo compound which can be isolated (Scheme 49, 226 → 227).345Ð347 Although so far ee-values and especially chemical yields are mostly lower than with the manganese counterparts, comparably little is yet known about the ligand influence in the chromium case. An interesting solvent/coligand effect was already discovered: By changing from toluene to acetonitrile/ Scheme 48 Chromium(II) induced addition of N-chloroamides to double bonds, and the typical yields for three types of starting ma- 4-phenylpyridine N-oxide, the enantioselectivity of bi- terials naphthyl derived (salen)chromium(III) is inverted. This is

Scheme 50 Oxidative macrocyclization of biladiene salts with chromium(III) acetate hydroxide

hyde (236, Scheme 51).350 Although in principle catalytic, the reaction still requires equimolar amounts of Cr3+-ion because the complexation of the lactate is quantitative. A comparison of the proposed mechanism with that of glyoxylase I enzyme has been made. Scheme 49 Asymmetric (salen)chromium(III) complexes as efficient catalysts in asymmetric epoxide formation, enantioselective epoxide ring openings and hetero-DielsÐAlder reactions explained by a mechanism switch, with the chromium complexes, unlike the manganese ones, acting electro- philically, finally forming a metallaoxetane intermediate.346 The same argument was used for the unusual effect of having better ee's with E-alkenes than with Z-alkenes.345 Finally, alkynes can be oxidized to 1,2-diones in low to mediocre yields.348 A rather unusual application is the use of Òchromium(III) acetateÓ (a hydroxide acetate) as oxidant in the macrocyclization of a,c-biladiene salts like 231 (Scheme 50). This method proved superior to using copper(II). Especially noteworthy is the fact that access to the metal free macro- cycles was obtained. Cr(III)-porphin-type complexes are not easily formed, whereas the copper complexes often can only be demetallated under decomposition. In ethanol Scheme 51 Lactate formation from isomeric oxopropanediols catalyzed by a chiral chromium(III) complex at room temperature the kinetic product 232 was formed, at 140¼C in DMF the thermodynamic one (233) is preferred. Interconversion of the former to the latter under reaction conditions was also shown.349 In the future there is certainly much to expect of chromium(III) catalysts such as (salen)chromium(III) com- Chromium(III) complexes have also been used in the pounds (cf. 225) or the Theopold polymerization catalysts asymmetric formation of nonracemic lactate from meth- (cf. 196) as ligand optimization only began very recently ylglyoxal (234), dihydroxyacetone (235) or glyceralde-

Synthesis 1999, No. 1, 1Ð36 ISSN 0039-7881 © Thieme Stuttgart á New York REVIEW Recent Advances in Chromium(II)- and Chromium(III)-Mediated Organic Synthesis 31 and seems to offer many possibilities. The importance of References a well-designed ligand field, especially with the otherwise (1) Hanson, J. R. Synthesis 1974, 1. exchange stable chromium(III) ion, is stressed by the fact (2) Julian, P. L.; Cole, W.; Magnani, A.; Meyer, E. W. J. Am. that simple chromium(III) acetylacetonates are not active Chem. Soc. 1945, 67, 1728. as epoxidation catalysts, in contrast to almost all other (3) Berthelot, M. Ann. Chim. (Paris) 1866, 9, 401. similar transition metal complexes of this type.351 (4) Conant, J. B.; Cutter, H. B. J. Am. Chem. Soc. 1926, 48, 1016. (5) Kochi, J. K.; Rust, F. F. J. Am. Chem. Soc. 1961, 83, 2017. (6) Kochi, J. K.; Davis, D. D. J. Am. Chem. Soc. 1964, 86, 5264. (7) Kochi, J. K.; Singleton, D. M. J. Am. Chem. Soc. 1968, 90, 9 Conclusion and Outlook 1582. (8) Kochi, J. 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