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I. The Benzannulation Reaction of Unsaturated Complexes with Alkynes.

 

Carbene Complexes

Introduction

 I. Benzannulation Reaction

II. Cyclohexadienone Annulation

III. Tautomer Arrested Annulation

IV. Aldol Reaction

V. Diels-Alder Reaction

VI. Cyclobutanone Formation

VII. Biaryl Synthesis

VIII. Macrocycles 

 

Asymmetric Catalysis

I. Ligand Design and Synthesis

II. Asymmetric Diels-Alder Reaction

III. Imino Aldol Reaction

IV. Asymmetric Aziridination 

The reaction of Fischer carbene complexes that has grown to greatest prominence in applications in organic synthesis is the benzannulation reaction. This is a truly amazing reaction that was discovered by Karl Heinz Dötz and involves the reaction of  unsaturated complexes with alkynes to give 4-alkoxyphenols of the type 4 as the primary product of the reaction.The initial product of the reaction is 3, the corresponding arene chromium tricarbonyl complex of the phenol 4, but these typically are unstable to air such that workup in air and purification of the product on silica gel leads to the complete loss of the metal.The phenol 4 is the result of the assembly of the alkyne, the carbene ligand and a carbon monoxide ligand in the coordination sphere of the metal. That this highly orchestrated process occurs under neutral conditions and near ambient temperatures (45 oC) to typically produce high yields of the phenol products has never ceased to be a source of amazement and inspiration.

 With unsymmetrical acetylenes mixtures of products are usually obtained where the ratio normally correlates with the steric differential between the two substituents [1]. The largest group (RL) is incorporated adjacent to the carbon monoxide derived carbon. Terminal alkynes are usually highly regioselective with selectivities typically of 100 : 1 or more. This reaction can produce a wide variety of phenol products. The reaction of vinyl complexes generate phenols, that of aryl complexes gives naphthols and heteroaryl complexes can give a variety of benzannulated heterocycles. This reaction is of enormous synthetic importance not only for its utility in the synthesis of highly substituted phenols but also as a result of the further conversion of these phenols to quinones. Quinones are ubiquitous subunits that occur in a vast variety of biological active natural products and pharmaceutical agents. Despite the extensive study that has been devoted to this reaction over the last twenty-eight years, much remains to be learned about this reaction. We have recently completed a comprehensive review of this reaction and the Table containing all of the known examples of this reaction is over 500 pages long [2].

 

Synthesis of Natural Products and Pharmaceuticals

 

 

 

 

 

 

Typically, Fischer carbene complexes are solids which means their preparation and reactions can be performed on open ended scale since purification can be accomplished by crystallization rather than by chromatography. One example that we have scaled up is the preparation and reaction of the naphthalene complex 7.This complex was prepared from 1-bromonaphthalene on a 285 gram scale in 77 % yield (3 crops). The reaction of naphthyl complex 7 with phenylacetylene was carried out in THF to give the phenanthrol 8 which was not isolated, but directly acetylated to give the acetate 9 on a 250 gram scale in 72 % overall yield for the two steps. In the photograph, Eliza Yeung is performing the benzannulation of complex 7 with phenylacetylene. The red pile is 250 grams of the naphthalene complex 7 and in the flask is another 250 grams of the complex reacting with phenylacetylene. This particular reaction is used in the synthesis of the VAPOL ligand and its chemistry will be discussed in the section on asymmetric catalysis.

[1] For recent citations to the literature, see:  Wang, H.; Wulff, W. D.; Rheingold, A. L.; J. Am. Chem. Soc., 2000, 122, 9862.

[2] Waters, M. L.; Wulff, W. D., Organic Reactions, in press.

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  I-a:The mechanism of the benzannulation reaction.

The mechanism of the reaction of unsaturated carbene complexes with alkynes is not known in complete detail and remains a challenge after nearly three decades of experimental and theoretical studies. For recent citations to the mechanism of this reaction see [[3].[ A summary of the current understanding of the reaction is presented in Scheme II. The first and rate limiting step of the reaction was long ago proposed, on the basis of kinetic studies, to be a carbon monoxide dissociation from the starting carbene complex to give the 16-e- unsaturated species 13.  Mechanistic studies are thus hindered by the fact that all subsequent steps are fast which means that isolation and/or in-situ detection of any of the intermediates would be difficult. The subsequent steps are thought to be reaction of intermediate 13 with the alkyne to give the h1,h3-vinyl carbene intermediate 14 and then a carbon monoxide insertion to give the h4-vinyl ketene complex 15. The ring-closing step is thought to involve an electrocyclic ring closure of the vinyl ketene complex 15, which presumably is a six-electron electrocyclization. The final step is a tautomerization of the intermediate 16 via a migration of hydrogen from carbon to oxygen, which is driven by the formation of an aromatic system.

(If you want to see animated mechanism  click  mechanism.swf (Flash Player 6) or gif animated )

One of the current questions concerning the mechanism that we have addressed is the issue of whether or not the insertion of alkyne to give intermediate 14 is reversible. Specifically, the question we decided to test was whether the formation of the regioisomeric vinyl carbene complexed intermediates 21-A and 21-B shown in Scheme III are formed reversibly. Some theoretical studies have suggested that this is possible, but others have suggested that it is not. One of the key reasons to understanding this issue is that this reaction can produce a number of other products in addition to phenols. An example is the formation of the five-membered ring product 24, which results from cyclization without insertion of a carbon monoxide ligand. The ultimate control over the product distribution from the reaction of carbene complexes with alkynes will depend on a detailed understanding of each step of the reaction including the alkyne insertion step. Specifically, it will be important to know if the vinyl carbene complexed intermediate is in equilibrium relative to subsequent steps in the mechanism.

In our study regiochemistry was used as a label [[3]. The regio-selectivity of alkyne incorporation into the three different products from the reaction of 1-phenylpropyne with carbene complex 25 was examined in detail (Table I).The phenol product (isolated as quinone 27 upon workup with ceric ammonium nitrate (CAN)) is formed with a substantial regioselectivity but the five-membered ring side-products (obtained as two compounds; indene 28 and indenone 29) are formed as a nearly equal mixture of regioisomers. The proportion of indene and phenol products is dependent on the concentration with greater amounts of phenol products being formed at higher concentrations. The total regioselectivity (S A:B) of all of the products is also a function of the concentration.  This result could either be due to an equilibration of the h1,h3-vinyl carbene intermediates 21-A and 21-B in this reaction or to a change in the mechanism of the formation of the h1,h3-vinyl carbene intermediate from one involving a dissociative incorporation of the alkyne to one involving an associative incorporation of the alkyne. Kinetic studies rule out the latter and thus these observations constitute the first direct experimental evidence for the equilibration of the vinyl carbene intermediates during the benzannulation reaction.These experiments could not tell us whether the alkyne completely dissociated to give the intermediate 19 or whether 21-A and 21-B equilibrate by a mechanism that does not involve loss of alkyne (such as 20).This will have to await some future experiments.

[[3] Waters, M. L.; Bos, M. E.; Wulff, W. D., J. Am. Chem. Soc., 1999, 121, 6403.

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I-b:Asymmetric Induction in the Benzannulation Reaction

 

One of the very difficult challenges in the development of the benzannulation reaction is the search for useful asymmetric versions of this reaction. In its most fundamental form, the asymmetric benzannulation reaction involves the formation of a planar center of chirality due to the presence of the chromium tricarbonyl group coordinated to the newly formed arene ring. As discuss above, the phenol chromium tricarbonyl complex that is the initial product of this reaction (3 in Scheme I) is not stable to air. Thus in order for the asymmetric benzannulation to be explored, the first requirement was to develop a method for the protection of the phenol function in the benzannulation product. We published a method to do this in 1993 that involved simply performing the benzannulation reaction of the carbene complex and the alkyne in the presence of a silyl chloride and a base [4].Thus if either the carbene complex or the alkyne were to be chiral, then the reaction could produce the arene complexes 31 or 32 which have the chromium tricarbonyl group coordinated to the arene from the bottom or the top, respectively. There are three opportunities to look for asymmetric induction in this reaction where there would be transfer of chirality from a chiral center at a carbon atom to the planar chirality in the product. These are from those reactions that have a chiral center in the carbene ligand, those that have a chiral center in the heteroatom stabilizing substituent of the carbene complex and those reactions that involve a chiral center in the alkyne. A number of examples in the first category are known and while some reactions involve good asymmetric induction, most reactions, like that of complex 33 with 3-hexyne do not [5]. The degree of asymmetric induction does depend on the location of the substituent on the cyclohexenyl substituent. A number of chiral complexes have been studied which have been prepared from chiral alcohols such as complex 36, which was generated from (-)-menthol [6].

In most instances the asymmetric induction observed from complexes in the class has been low to modest. The reaction of complex 36 with 1-pentyne illustrates a general observation that has been made for these reactions. It is more difficult to retain the chromium tricarbonyl group on the product from the reactions of aryl complexes than it is from the reactions of alkenyl complexes.T he major side-product from the reaction of 36 with 1-pentyne is the product without the metal coordinated to the naphthalene ring and this helps to account for the low combined yield of 37 and 38. The most successful asymmetric benzannulation that has been found up to this point is from the reactions with chiral alkynes [7]. As illustrated by the reaction of complex 39 with the chiral propargyl ether 40, this reaction gives excellent induction in the formation of the planar chiral complex 41. These inductions require the presence of an electron-rich oxygen atom in the propargylic position and do not work well with all substitution patterns of the alkenyl complex. Nonetheless, this is a very synthetically attractive process for the stereoselective synthesis of arene chromium tricarbonyl complexes.  to top

[4] Chamberlin, S.; Wulff, W. D.; Bax, B., Tetrahedron, 1993, 49, 5531.

[5] Hsung, R. P.; Wulff, W. D.; Challener, C. A., Synthesis, 1996, 773.

[6] Hsung, R. P.; Wulff, W. D.; Chamberlin, S.; Liu, Y.; Liu, R.-Y.; Wang, H.; Quinn, J. F.; Wang, S. L. B.; Rheingold, A. L., Synthesis, 2001, 200.

[7] Hsung, R. P.; Wulff, W. D.; Rheingold, A. L., J. Am. Chem. Soc., 1994, 116, 6449.