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Arene Chromium Complexes: Heterocyclic Chiral Auxiliaries and Synthetic Targets

E. Peter Kündig, Gérald Bernardinelli, Dov Beruben, Benoît Crousse, Angelika Fretzen, Hassen Ratni, Barbara Schnell, and Long-He Xu.

Département de Chimie Organique, Université de Genève, 30 quai Ernest Ansermet, CH-1211 Geneva, Switzerland.

Coordination of an arene to the electrophilic Cr(CO)3 group profoundly modifies the arene reactivity. Temporary complexation thus offers new possibilities of arene functionalization and transformation. Since the faces of the arene in the complex are no longer equivalent, reactions occur either on the face opposite to the metal (exo) or on the same face as the metal (endo). Excellent control of stereochemistry is often observed in these reactions which further enhances the potential of this methodology.1 In this article we show that heterocycles, either as auxiliaries or as synthetic targets, play a key role in the chemistry of chromium complexed arenes. The subjects covered are:

1. Phenyl oxazoline complexes are representative examples of the use of heterocyclic auxiliaries in this area of chemistry.

Topics presented are:

2. Cycloaddition and cyclization reactions involving planar chiral benzaldehyde imine complexes.

Topics presented are:

1. Phenyl oxazoline complexes.

1.1. Synthesis of phenyloxazoline Cr(CO)3 complexes, nucleophilic addition, and structural characteristics of a nucleophile addition product

The tricarbonylchromium complexes 2 of the phenyl oxazolines 1 are orange, air-stable crystalline solids and are readily accessible in high yields (Scheme 1).2 A wide range of nucleophiles (alkyl-, vinyl-, aryl lithium reagents, nitrile stabilized carbanions, a-phenylsulfinyl stabilized carbanions, thioanisole stabilized carbanions, and ester enolates) react with complex 2a by addition to the aromatic ring. ortho-Regioselectivity predominates and is the exclusive mode of addition for small nucleophiles. para-Regioselectivity can become important with bulky nucleophiles. The ortho-regioselectivity is thought to be the result of a combination of the electron-withdrawing effect of the arene substituent and the ability of the nitrogen lone pair to coordinate the incoming organolithium reagent.

Scheme 1
Scheme 1

The addition of carbanions to the arene exo-face leads to anionic (h5-cyclohexadienyl) Cr(CO)3 complexes which can be isolated as air sensitive yellow crystals. In applications in synthesis, isolation is not carried out and the cyclohexadienyl complexes are generated and reacted in situ with electrophiles. Complex 3 poses an interesting structural question and its isolation was therefore undertaken. The interest centers on the fact that complexes 2a-c contain both a p-bound (Cr(CO)3) and a s-bound (oxazoline) electrophilic group. Depending on which functional group dominates reactivity, the structure of 3 could be a 'normal' cyclohexadienyl Cr(CO)3 complex with the lithium cation coordinated to a CO ligand oxygen or an aza-enolate with a N-bound lithium in a N,O-ketene-acetal structure. The former (A) has literature precedence in the x-ray structure of the addition product of lithium dithiane to benzene Cr(CO)3,3 whereas the latter structure type (B) has been proposed in addition reactions of RLi reagents to naphthyl oxazolines.4 In B, the Cr(CO)3 group may be bound to both the endocyclic diene system and the exocyclic double bond; and we note that triene Cr(CO)3 complexes with these bonding characteristics are known.5

Scheme

Figure 1 shows the crystal structure of product 3a, obtained by naphthyllithium addition to complex 2a and crystallization in dioxane. The surprising answer to the above question is that in 3a both structural types are represented though A clearly dominates. The lithium ligands are: a carbonyl ligand oxygen, two molecules of solvent and a water molecule. The water apparently is instrumental as it provides the link between the predominant cyclohexadienyl structure and the aza-enolate structure.6 The distance of 2.776(8) Å between the water oxygen and the oxazoline nitrogen of a second cyclohexadienyl chromium complex clearly points to O-H.....N=C hydrogen bridge. Further evidence for the contribution of the aza-enolate structure is the shortening of the C-C bond between the cyclohexadienyl and the oxazoline (1.42(1) Å in 3a, 1.470(6) Å in 2a) and the lengthening of the C=N bond in 3a compared to 2a (1.29(1) Å vs. 1.260(5) Å).

Figure 1: Crystal structure of complex 3a featuring elements of both structures A and B (see text) via an intermolecular CO....Li....OH2....N(oxazoline) bridge.

Nucleophilic addition to the ortho and to the meta position of mono-substituted arene Cr(CO)3 complexes yields planar chiral addition products 3. The two ortho and the two meta-positions become diastereotopic when the arene carries a chiral substituent. ortho-Directing chiral substituents have been applied with much success (90-100% de) in this reaction.7 We also note the extension of this methodology to diastereoselective meta-addition reactions.8 Not surprisingly, in meta additions the levels of induction are considerably lower than in ortho-additions (48% de 8a ; up to 76% de 8b,c ).

Chiral hydrazones and chiral oxazolines have been shown to be excellent diastereoselective o-directing groups. With L-valinol and L.-tert-butylglycinol derived oxazolines, the product stereochemistry (see 1.2.2-1.2.4) reflects a transition state in which the substituent at the stereogenic center of the auxiliary is syn to the metal fragment. In the anti-rotamer, the lithium coordination controlled addition of the C-nucleophile would lead to a more congested transition state as shown below. The X-ray structure of complex 2b (R = i-Pr) shows both an endo- and an exo-rotamer in the unit cell. It also shows that the i-propyl group in the endo-rotamer is far from the Cr(CO)3 group. It is therefore unlikely that one of the rotamers is largely favored in solution. The structure further reveals that the pseudo-equatorial i-propyl group may not be bulky enough to completely prevent nucleophilic addition to the arene in the exo-rotamer (hence diastereomeric excesses around 90%). Indeed, its replacement by a t-Bu group (complex 2c (R1 = t-Bu, R2 = H)) leads to considerable improvement of diastereoselectivity (see 1.2.3.).

Scheme

Figure 2: Crystal structure of complex 2b

In a complementary approach, regio- and enantioselective addition of alkyl-, vinyl- and aryllithium reagents to prochiral (h6-arene)Cr(CO)3 complexes was achieved in the presence of an external chiral ligand. The best results were obtained with the readily accessible C2-chiral dimethoxydiphenylethane. Some examples of these reactions with complex 2a will be shown in sections 1.2.1 and 1.2.4. It should be pointed out that this methodology has the potential to be catalytic in the added chiral ligand.9

1.2. Reactions of complexes 3 with electrophiles

The anionic cyclohexadienyl complex 3a reacts with electrophiles to give complexed or decomplexed substituted arenes or cyclohexadienes. An overview is shown in Scheme 2.
Scheme 2
Scheme 2

Examples of these selective transformations are given in Schemes 3-10.

1.2.1. Nucleophile addition/oxidation reactions with complex 2a

Formally, this sequence is a nucleophilic substitution of a hydride by a carbanion. Its merits are a) a regioselectivity that is often complementary to electrophilic substitution and b) a reaction that takes place under very mild conditions yielding substituted aromatics in high yield.1k Although the mechanism has not been established, a reasonable sequence involves metal oxidation in complex 3 followed by intramolecular C(6)-H(endo) hydride transfer to the metal and oxidative cleavage of the metal arene bond. Applied to complex 2a a range of o-disubstituted arenes 4 have been obtained.10
Scheme 3
aAfter equilibration of the intermediate. bo/p = ca. 4:1.
Scheme 3

1.2.2. Nucleophile addition/hydride-abstraction reactions with complex 2a

A recent reinvestigation of the feasibility of endo-hydride abstraction in anionic cyclohexadienyl chromium complexes resulted in a reaction protocol for the transformation 2 ® 5 shown in Scheme 4. The highly regioselective nucleophilic aromatic substitution of a hydride for a carbanion6 in benzaldehyde imine, hydrazone and, as shown here, in phenyl oxazoline complexes, yields planar chiral arene complexes. It shows that the metal arene bond can indeed be conserved in the aromatic substitution and used in subsequent metal activated transformations.
Scheme 4
Scheme 4

An enantioselective synthesis of planar chiral complexes is based on the chiral external ligand mediated nucleophile addition mentioned in section 1.1 (Scheme 5).11

Scheme 5
Scheme 5

1.2.3. Nucleophile addition/allylation or propargylation with complexes 2a - 2c.

In situ reaction of the anionic cyclohexadienyl complexes 3 with allyl or propargyl bromides yields dienes 6.12 The trans stereochemistry between nucleophile and allyl- or propargyl groups was established by 1H-NMR and confirmed by an X-ray structure determination. It suggests a sequence of allylation/propargylation at the metal followed by reductive elimination and decomplexation.
Scheme 6
Scheme 6

Yields with propargyl bromides are usually higher (>70%) than with allyl and benzyl bromides (<70%) since with the latter, the crude products also contain 10-20% of ketone products resulting from migratory CO insertion prior to reductive elimination.

Figure 3: Crystal structure of cyclohexadiene 6a resulting from the addition of PhLi and allyl bromide to the phenyl oxazoline Cr(CO)3 complex 2a.

Cyclohexadienes 6 offer a number of possibilities for polar, radical13 and transition metal mediated14-15 intramolecular cyclization reactions.

Scheme

As an example we show in Scheme 7 the transformation of the alkynyl moiety in 6b to a vinylic radical which then undergoes a 5-exo-trig cyclization. Depending on R in 6b the reaction goes through one or the other of the two regioisomeric vinylic radical intermediates and this then determines the cyclization to either C(1) or C(4).16

Scheme 7
Scheme 7

Examples of diastereoselective syntheses of enantioenriched cyclohexadienes are shown in Scheme 8 7 and Scheme 9.

Scheme 8
Scheme 8
 
Scheme 9
Scheme 9

1.2.4. Nucleophile addition/acylation/alkylation

In contrast to propargyl- and allyl halides, alkyl bromides and iodides react with 3 to yield ketone products. Metal alkylation is thus followed by migratory carbonylation prior to reductive elimination. An added alkylation step completes the one-pot reaction which consists of forming in a highly regio-and diastereoselective way three new C-C bonds and two new stereogenic centers (Scheme 10, Figure 4).12 Again, diastereoselective non-racemic versions have been demonstrated.
Scheme 10
Scheme 10


Figure 4: Crystal structure of cyclohexadiene 7a (see Scheme 10).

Conversion of the oxazoline function in complex 5 by alkylation/reduction or carrying out the same chemistry described above with benzaldehyde imine or hydrazone complexes yields, after hydrolysis, highly enantioenriched benzaldehyde complexes. The nucleophile addition, hydride abstraction sequence in Scheme 5 provides a new enantioselective entry to these compounds.17 We take the opportunity of this symposium to report on two applications of these complexes in aza-heterocycle synthesis.

2. Cycloaddition and cyclization reactions involving planar chiral benzaldehyde imine complexes.

2.1. Diastereoselective intra- and intermolecular aza-Diels-Alder reactions

2.1.1. Intramolecular cycloaddition. Chiral aryl-2-aza-diene complex.

The enantiopure complex 8 was readily obtained from the corresponding aldehyde complex using a literature method.18 Lewis acid mediated cycloaddition and decomplexation afforded a 4: 1 mixture of the enantiopure diastereoisomers 9 and 10 (Scheme 11). This result shows that the facial selectivity of the diene is perfectly controlled by the chiral complex whereas the exo/endo selectivity of the dienophile is not as good as hoped for.19
Scheme 11
Scheme 11

2.1.2. Intermolecular cycloaddition: chiral benzaldehyde imine complex as dienophile

The planar chiral benzaldehyde imine complexes undergo Lewis acid mediated aza-Diels-Alder reactions with Danishefsky's diene to give the dihydropyridinones with fair to excellent diastereoselectivity.18,20 (Scheme 12). Radical cyclization of the enantiopure complexes 11e and 11f yield quinolizidines 12 (Scheme 13) and indolizidines (not shown).18

Scheme 12
Scheme 12
 
 
 
 
Scheme 13
Scheme 13

2.2. Pd-catalyzed intramolecular Heck reactions of planar chiral arene complexes

We have recently reported the first intramolecular Heck-reactions with planar chiral arene Cr(CO)3 complexes21 and have now extended these studies to the dihydropyridinone complexes 11c,d. By carefully controlling the reaction conditions these cyclizations can be carried out without decomplexation from the Cr(CO)3 unit and without alkene isomerization. (Scheme 14).
Scheme 14
Scheme 14

Acknowledgements

We thank the Swiss National Science Foundation for financial support of this work.
We gratefully acknowledge the help of Carmine Chiancone in the construction of these Web pages.

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(c) ECHET98. June 1998