View source for Chemistry:Benzylic activation and stereocontrol in tricarbonyl(arene)chromium complexes

'''Benzylic activation and stereocontrol in tricarbonyl(arene)chromium complexes''' refers to the enhanced rates and [[Chemistry:Stereoselectivity|stereoselectivities]] of reactions at the benzylic position of aromatic rings complexed to [[Chemistry:Chromium|chromium(0)]] relative to uncomplexed arenes. Complexation of an aromatic ring to [[Chemistry:Chromium|chromium]] stabilizes both [[Physics:Ion#Anions and cations|anions]] and [[Physics:Ion#Anions and cations|cations]] at the [[Chemistry:Benzyl group|benzylic]] position and provides a [[Chemistry:Steric effects|steric]] blocking element for [[Chemistry:Diastereomer|diastereoselective]] [[Chemistry:Functionality|functionalization]] of the benzylic position. A large number of [[Chemistry:Stereoselectivity|stereoselective]] methods for benzylic and homobenzylic functionalization have been developed based on this property.<ref name=or>Uemura, M. ''Org. React.'' '''2006''', ''67'', 217. {{doi|10.1002/0471264180.or067.02}}</ref><ref name=PK>{{cite journal|journal=Topics Organomet Chem.|year=2004| volume=7|pages=3–20|doi=10.1007/b94489|title=Synthesis of Transition Metal η<sup>6</sup>-Arene Complexes|author=E. Peter Kündig|series=Topics in Organometallic Chemistry |isbn=978-3-540-01604-5 }}</ref>

==Introduction==
The reaction between tricarbonylchromium complexes Cr(CO)<sub>3</sub>L<sub>3</sub> and electron-rich or electron-neutral [[Chemistry:Aromaticity|aromatic rings]] produces tricarbonyl(arene)chromium complexes (arene)Cr(CO)<sub>3</sub>.<ref>Mahaffy, C. A. L.; Pauson, P. ''Inorg. Synth.'' '''1990''', ''28'', 137.</ref> Complexation to chromium(0) activates the side chain of the arene, facilitating dissociation of a benzylic proton, leaving group, or nucleophilic addition to the homobenzylic position of [[Chemistry:Styrene|styrene]]s. Further transformations of the resulting conformationally restricted, benzylic anion or cation involve the approach of reagents ''exo'' to the chromium fragment. Thus, benzylic functionalization reactions of [[Physics:Planar chirality|planar chiral]] chromium [[Chemistry:Aromatic hydrocarbon|arene]] complexes are highly diastereoselective. Additionally, the chromium tri(carbonyl) fragment can be used as a blocking element in addition reactions to ''ortho''-substituted aromatic aldehydes and alkenes. An ''ortho'' substituent is necessary in these reactions to restrict conformations available to the aldehyde or alkene.<ref name=restrict /> Removal of the chromium fragment to afford the metal-free functionalized aromatic compound is possible [[Astronomy:Photodissociation|photolytically]]<ref name=light /> or with an oxidant.<ref name=iodine />
<span style="float:right;padding-right:50px;padding-top:30px;">'''''(1)'''''</span>{{center|[[File:CrAreneGen.png]]}}

==Mechanism and stereochemistry==
The majority of benzylic functionalization reactions of tricarbonyl(arene)chromium complexes proceed by mechanisms analogous to those followed by the free arenes. The aromatic ring and benzylic position are activated towards [[Chemistry:Solvolysis|solvolysis]], [[Chemistry:Deprotonation|deprotonation]], and [[Chemistry:Nucleophile|nucleophilic]] attack (at the [[Chemistry:Arene substitution pattern#Ortho, meta, and para substitution|''ortho'']] and [[Chemistry:Arene substitution pattern#Ortho, meta, and para substitution|''para'']] positions of the arene) upon [[Chemistry:Coordination complex|complexation]] to chromium, which is able to stabilize developing charges in the arene [[Chemistry:Ligand|ligand]]. As a result, these reactions of chromium arene complexes are often faster than analogous reactions of free arenes.<ref>Holmes, J. D.; Jones, D. A. K.; Pettit, R. ''J. Organomet. Chem.'' '''1965''', ''4'', 324.</ref>
<span style="float:right;padding-right:50px;padding-top:30px;">'''''(2)'''''</span>{{center|[[File:CrAreneMech1.png]]}}
Second, in benzylic cations and anions of chromium arene complexes, rotation about the bond connecting the benzylic carbon and aromatic ring is severely restricted. This bond possesses a significant amount of double bond character due to the delocalization of charge into the aromatic ring (and the stabilization of that charge by chromium).<ref name="ReferenceA">Davies, S. G.; Donohoe, T. J. ''Synlett'' '''1993''', 323.</ref>
<span style="float:right;padding-right:50px;padding-top:30px;">'''''(3)'''''</span>{{center|[[File:CrAreneMech2.png]]}}
Finally, the chromium tri(carbonyl) moiety serves as a sterically bulky group in reactions of arene chromium complexes, preventing the approach of a reagent ''endo'' to chromium. In addition, ''ortho''-substituted aromatic [[Chemistry:Aldehyde|aldehyde]]s and styrenes prefer to adopt a [[Chemistry:Conformational isomerism|conformation]] in which the doubly bound oxygen or carbon is pointed away from the  ''ortho'' substituent. As a result, only one face of the double bond is exposed on the ''exo'' face of the aromatic ring. If this were not the case, addition to styrenes and aromatic aldehydes would not be diastereoselective, despite the presence of the chromium tri(carbonyl) group. The ''ortho'' substituent is necessary for high stereoselectivity; ''meta''-substituted arenes exhibit very low diastereoselectivity.<ref name=restrict>Besançon, J.; Tirouflet, J.; Card, A.; Dusausoy, Y. ''J. Organomet. Chem.'' '''1973''', ''59'', 267.</ref>
<span style="float:right;padding-right:50px;padding-top:30px;">'''''(4)'''''</span>{{center|[[File:CrAreneMech3.png]]}}

===Enantioselective variants===
Enantioselective benzylic functionalization methods use the complexed chromium tri(carbonyl) moiety essentially as a chiral auxiliary.<ref>Uemura, M.; Hayashi, Y.; Hayashi, Y. ''Tetrahedron: Asymmetry'', '''1993''', ''4'', 2291.</ref> Approach of the functionalizing reagent ''anti'' to the ----chromium tri(carbonyl) fragment leads to a single diastereomer of the product complex. After removal of the chromium group with light<ref name=light>Mishchenko, O. G.; Klementeva, S. V.; Maslennikov, S. V.; Artemov, A. N.; Spirina, I. V. ''Rus. J. Gen. Chem.'' '''2006''', ''76'', 1907.</ref> or an oxidizing agent such as iodine,<ref name=iodine>Semmelhack, M. F.; Zask, A. ''J. Am. Chem. Soc.'' '''1983''', ''105'', 2034.</ref> a nearly [[Physics:Enantiopure drug|enantiopure]] product remains. See the Scope and Limitations section below for several methods for diastereoselective benzylic functionalization.

==Scope and limitations==
Enantioselective benzylic functionalization reactions depend on the use of enantiomerically pure, planar chiral chromium arene complexes. This section describes methods for the enantioselective synthesis of planar chiral chromium arene complexes, then outlines methods for functionalization of both sp<sup>2</sup>- and sp<sup>3</sup>-hybridized benzylic positions.

===Preparation of enantiopure, planar chiral chromium complexes===
Enantiopure, planar chiral chromium arene complexes can be synthesized using several strategies. Diastereoselective complexation of a chiral, non-racemic arene to chromium is one such strategy. In the example in equation (5), enantioselective Corey-Itsuno reduction<ref>Itsuno, S. ''Org. React.'' '''1998''', ''52'', 395.</ref> sets up a diastereoselective ligand substitution reaction. After complexation, the alcohol is reduced with triethylsilane.<ref>Schmalz, H.-G.; Arnold, M.; Hollander, J.; Bats, J. W. ''Angew. Chem. Int. Ed. Engl.'' '''1994''', ''33'', 109.</ref>
<span style="float:right;padding-right:50px;padding-top:30px;">'''''(5)'''''</span>{{center|[[File:CrAreneScope1.png]]}}
A second strategy involves enantioselective ''ortho''-lithiation and ''in situ'' quenching with an electrophile. Isolation of the lithium arene and subsequent treatment with TMSCl led to lower enantioselectivities.<ref>Price, D. A.; Simpkins, N. S.; MacLeod, A. M.; Watt, A. P. ''J. Org. Chem.'' '''1994''', ''59'', 1961.</ref>
<span style="float:right;padding-right:50px;padding-top:30px;">'''''(6)'''''</span>{{center|[[File:CrAreneScope2.png]]}}
Site-selective conjugate addition to chiral aryl hydrazone complexes can also be used for the enantioselective formation of planar chiral chromium arenes. Hydride abstraction neutralizes the addition product, and treatment with acid cleaves the hydrazone.<ref>Kündig, E. P.; Liu, R.; Ripa, A. ''Helv. Chim. Acta'' '''1992''', ''75'', 2657.</ref>
<span style="float:right;padding-right:50px;padding-top:30px;">'''''(7)'''''</span>{{center|[[File:CrAreneScope3.png]]}}

===Benzylic functionalization reactions===
''ortho''-Substituted aryl aldehyde complexes undergo diastereoselective nucleophilic addition with organometallic reagents<ref>Bitterwolf, T. E.; Dai, X. ''J. Organomet. Chem.'' '''1992''', ''440'', 103.</ref> and other nucleophiles. Equation (8) is an example of a diastereoselective Morita-Baylis-Hillman reaction.<ref>Kündig, E. P.; Xu, L. H.; Romanens, P.; Bernardinelli, G. ''Tetrahedron Lett.'' '''1993''', ''34'', 7049.</ref>
<span style="float:right;padding-right:50px;padding-top:30px;">'''''(8)'''''</span>{{center|[[File:CrAreneScope4.png]]}}
Pinacol coupling and the corresponding diamine coupling<ref>Davies, S. G.; Donohoe, T. J.; Williams, J. M. J. ''Pure Appl. Chem.'' '''1992''', ''64'', 379.</ref> are possible in the presence of a one-electron reducing agent such as samarium(II) iodide.<ref>Taniguchi, N.; Kaneta, N.; Uemura, M. ''J. Org. Chem.'' '''1996''', ''61'', 6088.</ref>
<span style="float:right;padding-right:50px;padding-top:30px;">'''''(9)'''''</span>{{center|[[File:CrAreneScope5.png]]}}
Benzylic cations of chromium arene complexes are conformationally stable, and undergo only ''exo'' attack to afford S<sub>N</sub>1 products stereospecifically, with retention of configuration.<ref name="ReferenceA"/> Propargyl<ref>Müller, T. J. J.; Netz, A. ''Tetrahedron Lett.'' '''1999''', ''40'', 3145.</ref> and oxonium<ref>Davies, S. G.; Newton, R. F.; Williams, J. M. J. ''Tetrahedron Lett.'' '''1989''', ''30'', 2967.</ref> cations undergo retentive substitution reactions, and even β carbocations react with a significant degree of retention.<ref>Merlic, C. A.; Miller, M. M. ''Organometallics'' '''2001''', ''20'', 373.</ref>
<span style="float:right;padding-right:50px;padding-top:30px;">'''''(10)'''''</span>{{center|[[File:CrAreneScope6.png]]}}
Benzylic anions of chromium arene complexes exhibit similar reactivity to cations. They are also conformationally restricted and undergo substitution reactions with retention of stereochemistry at the benzylic carbon. In the example below, complexation of the pyridine nitrogen to lithium is essential for high stereoselectivity.<ref>Davies, S. G.; Shipton, M. R. ''J. Chem. Soc., Chem. Commun.'' '''1990''', 1780.</ref>
<span style="float:right;padding-right:50px;padding-top:30px;">'''''(11)'''''</span>{{center|[[File:CrAreneScope7.png]]}}
Nucleophilic addition to styrenes followed by quenching with an electrophile leads to ''cis'' products with essentially complete stereoselectivity.<ref>Majdalani, A.; Schmalz, H.-G. ''Tetrahedron Lett.'' '''1997''', ''38'', 4545.</ref>
<span style="float:right;padding-right:50px;padding-top:30px;">'''''(12)'''''</span>{{center|[[File:CrAreneScope8.png]]}}
Diastereoselective reduction of styrenes is possible with samarium(II) iodide. A distant alkene is untouched during this reaction, which provides the reduced alkylarene product in high yield.<ref>Schmalz, H.-G.; Siegel, S.; Bernicke, D. ''Tetrahedron Lett.'' '''1998''', ''39'', 6683.</ref>
<span style="float:right;padding-right:50px;padding-top:30px;">'''''(13)'''''</span>{{center|[[File:CrAreneScope9.png]]}}
Complexation of a haloarene to chromium increases its propensity to undergo oxidative addition.<ref>Widdowson, D. A.; Wilhelm, R. ''Chem. Commun.'' '''1999''', 2211.</ref> Suzuki cross coupling of a planar chiral chromium haloarene complex with an aryl boronic acid is thus a viable method for the synthesis of axially chiral biaryls. In the example below, the ''syn'' isomer is formed in preference to the ''anti'' isomer; when R<sup>2</sup> is the formyl group, the selectivity reverses.<ref>Kamikawa, K.; Watanabe, T.; Uemura, M. ''J. Org. Chem.'' '''1996''', ''61'', 1375.</ref>
<span style="float:right;padding-right:50px;padding-top:30px;">'''''(14)'''''</span>{{center|[[File:CrAreneScope10.png]]}}
Tetralones complexed to chromium may be deprotonated without side reactions. Alkylation of the resulting enolate proceeds with complete diastereoselectivity to afford the ''exo'' product.<ref>Davies, S. G.; Coote, S. J.; Goodfellow, C. L. In ''Advances in Metal-Organic Chemistry''; Liebeskind, L.S., Ed.; JAI Press: Greenwich, 1991; Vol. 2. pp. 1–48.</ref>
<span style="float:right;padding-right:50px;padding-top:30px;">'''''(15)'''''</span>{{center|[[File:CrAreneScope11.png]]}}

==References==
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[[Category:Organic reactions]]

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