Astruc D. - Modern arene chemistry (2002)(en)

316 9 Osmiumand Rhenium-Mediated Dearomatization Reactions with Arenes

Scheme 9. Elaborations of the complexed Diels–Alder cycloaddition product 71.

Michael acceptors exclusively at C4 to ultimately generate substitution products in high yields [27]. Reaction with acetic anhydride (entry 3) yields the C4-acylated complex. Decomplexed anilines are obtained by heating the substituted complexes at 70 C in a coordinating solvent such as CH3CN. For example, the MVK product (entry 1) can be isolated in 74 % yield [27].

9.2.7.2 4H-Anilinium Michael Additions

As stated above, the isolation of ring-bound [Os]-aniline is di cult because the nitrogenbound form competes with the ring-bound form. However, if the nitrogen is first protected with a TMS group, complexation at the ring proceeds cleanly to yield 78 (Table 12). Deprotection and C4-protonation using HOTf forms the 4H-anilinium complex 79. This com-

3189 Osmiumand Rhenium-Mediated Dearomatization Reactions with Arenes

pound will add Michael acceptors (entries 1–3) anti to the face involved in metal coordination and regioselectively at C4 to a ord 4H-anilinium adducts (80) in high yields (Table 12) [27].

9.2.7.3 Electrophilic Addition Reactions

In the presence of Lewis acids, N-substituted aniline complexes of [Os] also add electrophiles at C4, again at the arene face opposite to that involved in metal coordination. This reaction has been shown to be general for a broader range of Michael acceptors than may be utilized with anisole complexes of [Os]. The N-ethyl aniline complex, for example, adds Michael acceptors and acetals in yields ranging from 53–95 % (Table 13, entries 1–6) [27]. The N,N-dimethyl aniline complex (entries 7–9) also adds Michael acceptors to C4 in moderate to high yields (Table 13) and adds to the d-carbon of an a,b,g,d-unsaturated ester (entry 3).

9.2.7.4 Michael–Michael–Michael Ring-Closure

The N,N-dimethyl aniline complex 81 undergoes a Michael–Michael–Michael ring-closure in the presence of excess a-methylene-g-butyrolactone (Scheme 10). In this sequence, the intermediate enolate 82 intercepts another molecule of the Michael acceptor, which then closes at C3 to generate the di-spiro tetracyclic complex 83. The tetracyclic adduct is generated as a single diastereomer, and its structure has been confirmed by X-ray di raction analysis. This molecule undergoes reduction of the enamine through protonation at C2 followed by a stereochemically anomalous hydride reduction at C1. Oxidation of the metal fragment liberates 84 in 77 % yield (based on 83) [28].

9.2.8

Phenol

Phenol complexes of [Os] display pronounced reactivity toward Michael acceptors under very mild conditions. The reactivity is due, in part, to the acidity of the hydroxyl proton, which can be easily removed to generate an extended enolate. Reactions of [Os]-phenol complexes are therefore typically catalyzed using amine bases rather than Lewis acids. The regiochemistry of addition to C4-substituted phenol complexes is dependent upon the reaction conditions. Reactions that proceed under kinetic control typically lead to addition of the electrophile at C4. In reactions that are under thermodynamic control, the electrophile is added at C2. These C2-selective reactions have, in some cases, allowed the isolation of o- quinone methide complexes. As with other [Os] systems, electrophilic additions to phenol complexes occur anti to the face involved in metal coordination.

9.2.8.1 Electrophilic Substitution Reactions

When the parent phenol complex of [Os] 85 is combined with MVK and pyridine in acetonitrile, a Michael addition occurs to give the 4H-phenol complex 86 in 91 % yield (Scheme 11). This complex is remarkably stable and resists rearomatization even when allowed to stand in an acidic solution of acetonitrile for 24 h. However, addition of an amine base induces rearomatization to yield complex 87. This complex may be heated to a ord the demetalated substitution product 88 (raspberry ketone) in 71 % yield (based on 85) [29].

9.2 {Os(NH3)5}2þ --- The Pentaammineosmium(II) Fragment 319

Tab. 13. Scope of electrophilic additions for N-substituted aniline complexes.

a Isomer ratio for asymmetric carbon located on R. This ratio is based on the relative heights of 13C NMR resonances and is thus approximate. b Unoptimized yields. c Reaction performed at 40 C.

d ¼ 1. HOTf (1 eq.), 2. H2O. e ¼ 1. HOTf (1 eq.), 2. MeOH.

320 9 Osmiumand Rhenium-Mediated Dearomatization Reactions with Arenes

Scheme 10. A Michael–Michael–Michael ring-closure reaction sequence with complex 81.

Scheme 11. The osmium(II)-promoted C4 alkylation of phenol with MVK.

9.2.8.2 Michael Addition Reactions

Base-catalyzed The parent phenol complex 85 undergoes a variety of base-catalyzed Michael addition reactions at room temperature to generate 4H-phenol complexes in yields in the range 79–99 % (Table 14) [29]. Michael additions with MVK, methyl acrylate, acrylonitrile, N-methylmaleimide, cyclopentenone, and crotonaldehyde (entries 1–6, respectively) proceed with high regioand stereocontrol. Demetalation and isolation of the dienone is typically accompanied by tautomerization to the aromatic substitution product.

Estradiol A notable application of phenol activation by [Os] is the C10 alkylation of estradiol 89 (Figure 5). The metal fragment preferentially binds to the a face of the steroid (to form 90) and thus promotes the addition of MVK to the b face. This forms a quaternary

9.2 {Os(NH3)5}2þ --- The Pentaammineosmium(II) Fragment 321

Tab. 14. Conjugate addition reactions with the h2-phenol complex 85 and various Michael acceptors.

6 83b

a ¼ Reaction run with Zn(OTf )2 as co-catalyst. b ¼ Reaction run with BF3 instead of NR3.

center at C10 (91), and demetalation releases the steroid 92 in 69 % yield (based on 89). This process results in a steroid that has the C10 stereochemistry of androgens and, consequently, suggests a method for converting estrogen cores to androgen cores in a three-step sequence [30].

Regiocontrol Although Michael additions to [Os]-phenol occur selectively at C4, addition at C2 is thermodynamically favored for phenol complexes that are substituted at C4. For C4substituted phenol complexes, the regiochemistry can be controlled by varying the time, temperature, and catalyst (Figure 6) [29]. Additions of MVK to the estradiol complex 90 and the p-cresol 94 at 40 C in the presence of an amine base catalyst result in regioselective C4 alkylation in high yields (91 and 95). However, when this reaction is performed at room temperature in the presence of a Zn2þ co-catalyst, the Michael acceptor adds at C2 to a ord