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

9.2 {Os(NH3)5}2þ --- The Pentaammineosmium(II) Fragment 303

Tab. 3. Tandem additions to xylene complexes of [Os].

Entry	R1	R2	E	Yield (%)
1	CH3	H	H	67
2	CH3	H		28
3	H	CH3		32

the regioand stereospecific addition of an electrophile and a nucleophile to generate a cis- 1,4-dihydronaphthalene complex. When the nucleophile is tethered to the electrophile, an intramolecular cyclization occurs with the nucleophile now attacking at C2 to generate a hydrophenanthrone core after oxidative decomplexation.

9.2.5.1 Tandem Addition Reactions

The naphthalene complex of [Os] (3) reacts with triflic acid to form a h3-1H-naphthalenium species, which has been characterized at 40 C [16]. Unfortunately, most nucleophiles react as bases with this species and return the naphthalene complex. However, MMTP and the mild hydride donor triethylsilane (Table 4, entries 1 and 2) both add to C4 of the complex and yield 1,4-dihydronaphthalenes in moderate overall yield following decomplexation [17].

Methyl vinyl ketone (entry 3) and the tert-butyl cation (entry 4) are also reactive toward complex 3. The naphthalenium complexes resulting from the addition of these electrophiles will add the conjugate base of dimethyl malonate (generated in situ from a combination of dimethyl malonate (DMM) and diisopropylethylamine (DIEA)) to complete the tandem additions. Oxidation of the resulting complexes yields cis-1,4-dihydronaphthalenes. The entire sequence of complexation, tandem addition, and demetalation employed for all entries in Table 4 can be performed using bench-top conditions (i.e., a non-inert atmosphere).

As mentioned in the introduction, one of the major advantages of using transition metals for dearomatization is that they allow the isolation of reaction intermediates and, consequently, broaden the range of accessible manipulations. For example, when the naphthalene complex of [Os] (3) is treated with dimethoxymethane in the presence of HOTf, the resulting h3-1H-naphthalenium species 23 can be isolated in 88 % yield and stored for days at room temperature (Table 5). The electrophile adds anti to the face involved in metal coordination and pushes the proton at C1 toward the metal, which prevents spontaneous rearomatization. As shown in Table 5, 23 reacts with MMTP, the conjugate base of dimethyl malonate, 2-trimethylsiloxypropene, tetrabutylammonium cyanoborohydride (TBAC), dime-

3049 Osmiumand Rhenium-Mediated Dearomatization Reactions with Arenes

Tab. 4. Overall yields for tandem additions to naphthalene.

Entry	Electrophile	E	Nucleophile					Nu		Overall Yield
1	HOTf	H								77 %

2	HOTf	H	HSiEt3	H	56 %
3					41 %b

4

t-BuOHa

25 %b

a ¼ t-BuOH added in the presence of HOTf; b ¼ Nucleophile premixed with DIEA.

thylzinc, and phenyllithium. Demetalation with AgOTf liberates the cis-1,4-dihydronaph- thalenes in moderate overall yields [17]. An interesting stereochemical consequence is observed when PhLi is used as the nucleophile. When the phenyl group adds to C4, a doubly benzylic carbon is generated and the 1H NMR spectrum of the demetalated material reveals the presence of two diastereomers, presumably due to racemization of the doubly benzylic position.

Tandem additions to [Os]-naphthalene could yield either a 1,2- or a 1,4-addition product, but remarkably, the 1,4-pathway is the only one observed. This outcome is theorized to be the result of C4 having a greater partial positive charge because of its overlap/delocalization with the adjacent unbound ring [17].

9.2.5.2 Cyclizations

An alternative mode of reactivity is observed for [Os]-naphthalene when the nucleophile for the tandem addition is built into the electrophile. The normal mode of reactivity results in the formation of cis-1,4-dihydronaphthalenes (vide supra), but when a solution of the methyl vinyl ketone Michael addition product 24 in methanol (Table 6, entry 1) and a catalytic amount of triflic acid are allowed to react, the complexed hydrophenanthrenone 25 is isolated in 89 % yield [18]. This reactivity results from the pendant ketone undergoing a tautomerization to form an enol, which can then attack the allyl cation at C2. The stereochemistry of the nucleophilic addition is still anti to the face involved in the metal coordination, but the

9.2 {Os(NH3)5}2þ --- The Pentaammineosmium(II) Fragment 305

Tab. 5. Nucleophilic addition reactions of the h3-1H-naphthalenium complex 23.

Nucleophile

R

Overall Yielda

65 %

54 %b

69 %

Bu4NBH3CN	H	45 %
Zn(CH3)2	CH3	40 %c
PhLi	Ph	40 %d

a ¼ Calculated with respect to naphthalene; b ¼ Nucleophile premixed with DIEA; c ¼ Reaction run with Cu(OTf ); d ¼ Reaction run with Cu(CN).

regiochemistry now favors addition at C2. This change in regiochemistry is likewise observed when the Michael acceptor is either ethyl vinyl ketone (EVK, entry 2) or isopropyl vinyl ketone (IVK, entry 3). Decomplexation using AgOTf releases the hydrophenanthrenones 26 in moderate to low yields [18].

Tab. 6. Hydrophenanthrenone synthesis from complex 3.

Entry	R1	R2	Yield	Yield	Yield
1	H	H	90 %	89 %	40 %
2	CH3	H	99 %	91 %	40 %
3	CH3	CH3	97 %	65 %	35 %

3069 Osmiumand Rhenium-Mediated Dearomatization Reactions with Arenes

9.2.6

Anisole

Anisole and its derivatives have thus far demonstrated the widest variety of [Os]-mediated dearomatization reactions. These transformations have included substitutions, asymmetric tandem addition sequences, and a variety of cyclizations.

9.2.6.1 Electrophilic Substitutions

As with [Os] complexes of benzene and naphthalene, a significant p-backbonding interaction renders anisole complexes far more nucleophilic than the free arenes [19]. As a result, they are reactive towards weaker electrophiles than those typically used in electrophilic aromatic substitutions. In the presence of HOTf at 40 C, the anisole complex (5) attacks a wide variety of electrophiles, including Michael acceptors (Table 7, entries 1–8) and acetals (entries 9 and 10). The additions occur exclusively at C4 of the anisole complex, and this fact can be rationalized in terms of both the methoxy group e ectively blocking C2 and a thermodynamic preference for more conjugation in the uncoordinated portion of the resulting anisolium species 27. This complex is observable at 40 C, but has only been isolated when an arene starting material containing an additional p-donor group has been utilized (e.g., 1,3-dimethoxybenzene). The addition of an amine base results in deprotonation of the anisolium species at C4 to yield a substituted anisole complex. The substitution product 28 can be liberated in high yield by oxidation or on heating [20].

9.2.6.2 Tandem Additions

Racemic tandem additions Mild carbon nucleophiles add to the [Os]-anisolium complex 27 exclusively at C3 to a ord substituted 1,3-cyclohexadiene complexes 29–32 in moderate to high yields (Table 8) [21]. Nucleophiles that have been utilized in this manner include MMTP (29 and 30), N-methylpyrrole (31), and 2-trimethylsilyloxyfuran (32). As with other tandem additions to [Os] complexes, both the nucleophile and the electrophile add to the arene face opposite to that involved in metal coordination, such that the products are those of syn addition.

The cyclohexadiene complex 29 has been further elaborated to a ord either the cyclohexenone 34 or the cyclohexene 36 in moderate yields (Scheme 1) [21]. The addition of HOTf to 29 generates the oxonium species 33, which can be hydrolyzed and treated with cerium(IV) ammonium nitrate (CAN) to release the cyclohexanone 34 in 43 % yield from 29. Alternatively, hydride reduction of 33 followed by treatment with acid eliminates methanol to generate the h3-allyl complex 35. This species can be trapped by the conjugate base of dimethyl malonate to a ord a cyclohexene complex. Oxidative decomplexation of this species using silver trifluoromethanesulfonate liberates the cyclohexene 36 in 57 % overall yield (based on 29).

Asymmetric tandem additions In order to further take advantage of the high degree of stereoselectivity observed in tandem additions to [Os]-arene complexes, a chiral anisole derivative has been prepared, which has demonstrated high coordination diastereoselectivity

9.2 {Os(NH3)5}2þ --- The Pentaammineosmium(II) Fragment 307

Tab. 7. Electrophillic substitutions of complex 5.

Entry	E					R1	R2	Yield (%)
1						H	H	84
2		"				H	CH3	93
3		"				CH3	CH3	79
4		"				H	Ph	70
5						–	–	59
6						H	H	94
7		"				CH3	CH3	85
8						–	–	81
9						–	–	90
10						–	–	95

(>9:1) upon complexation [22]. Complex 37 can be prepared in 83 % yield and >90 % de by a two-step sequence involving the coupling of phenol and (S)-( )-methyl lactate followed by complexation (Scheme 2). In addition to the h2-bond common to other [Os]-arene complexes, NMR studies of 37 provided evidence of a hydrogen-bonding interaction between the acidic ammine ligands [13] and the ester carbonyl group (Figure 4) [23]. The result of these interactions is a thermodynamic di erentiation of the arene faces. It is thought that if the metal binds to the re face of the arene, the methyl group adjacent to the methine group is

3089 Osmiumand Rhenium-Mediated Dearomatization Reactions with Arenes

Tab. 8. Tandem additions to [Os]-bound anisole.

Complex	E	Nu	Yield (%)
29	H		92
30			50
31	H		92
32	H		42

Scheme 1. Elaborations of [Os]-anisole tandem addition product 29.

9.2 {Os(NH3)5}2þ --- The Pentaammineosmium(II) Fragment 309

Scheme 2. Synthesis of the asymmetric anisole complex 37.

forced into a sterically disfavored position near an ortho ring proton. If the metal binds to the si face of the arene, the proton of the methine group is forced into the same position. As a smaller steric repulsion results in this second situation, it is thermodynamically preferred, and so the metal binds preferentially to the si face.

The chiral anisole derivative 37 has been used in the synthesis of several asymmetric functionalized cyclohexenes (Table 9) [22]. In a reaction sequence similar to that employed with racemic anisole complexes, 37 adds an electrophile and a nucleophile across C4 and C3, respectively, to form the cyclohexadiene complex 38. The vinyl ether group of 38 can then be reduced by the tandem addition of a proton and hydride to C2 and C1, respectively, a ording the alkene complex 39. Direct oxidation of 39 liberates cyclohexenes 40 and 41, in which the initial asymmetric auxiliary is still intact. Alternatively, the auxiliary may be cleaved under acidic conditions to a ord h3-allyl complexes, which can be regioselectively attacked by another nucleophile at C1. Oxidative decomplexation liberates the cyclohexenes 42–44. HPLC analysis revealed high ee values for the organic products isolated both with and without the initial asymmetric group.

Fig. 4. Interactions responsible for the diastereoselectivity observed in complex 37.

3109 Osmiumand Rhenium-Mediated Dearomatization Reactions with Arenes

Tab. 9. Tandem additions to Complex 37.

Compound	E	Nu1	Nu2	% Yield from 37	ee(%)
40	H		–	46	97

41

–

41

97

42

33

81

43

28

90

44

H

19

93

9.2.6.3 Cyclization Reactions

One of the most versatile applications of [Os]-anisole chemistry is the e cient generation of complex polycyclic systems. Through the application of a variety of methodologies, anisole complexes have been used to generate a number of cyclic arrangements, including a bicyclo[2.2.2]octadiene, decalins, tetralins, and tricyclic arrays.

9.2 {Os(NH3)5}2þ --- The Pentaammineosmium(II) Fragment 311

Cycloaddition reactions The anisole complex 5 undergoes a cyclization reaction with N- methylmaleimide under Lewis acidic conditions to a ord the bicyclo[2.2.2]octadiene complex 46, a formal [4þ2] process (Scheme 3) [24]. Mechanistic studies have suggested that this reaction occurs not as a concerted process but rather through an initial Michael addition at C4 to generate 45, which then cyclizes by an intramolecular nucleophilic attack at C1. Despite this stepwise pathway, a high degree of diastereoselectivity is observed in the reaction. The succinimide ring is oriented endo with respect to the unbound portion of the former arene. This observation is consistent with the Michael addition proceeding through an ordered Diels–Alder-like transition state. The metal-bound bicyclo[2.2.2]octene can be decomplexed in 25 % yield (based on 5) by means of low-temperature oxidation, but the resulting organic compound is unstable with respect to cycloreversion (t1=2 ¼ 0.5 h at 20 C).

Scheme 3. The formal [4þ2] cylization of [Os]-anisole and N-methylmaleimide.

Michael–Michael ring-closures In a variation of the tandem addition reaction discussed previously, the anisolium species 48 generated from the Michael addition of MVK or EVK to the p-methyl anisole complex 47 cyclizes in acidic methanol (Scheme 4) [21]. The enol form of the pendant ketone acts as an intramolecular nucleophile, attacking the electrophilic C3 position of the ring and generating the cis-decalin complex 49. Following protonation and hydrolysis of the resulting vinyl ether, the free organic product can be liberated by oxidation of the metal fragment. In this way, the diketones 50 and 51 can be produced in yields of 31 % and 17 %, respectively (based on 47).

Michael–aldol ring-closures In another variant, the addition of an amine base to the 3,4- dimethyl anisolium species 52 results in deprotonation at the benzylic C3 methyl group,

312 9 Osmiumand Rhenium-Mediated Dearomatization Reactions with Arenes

Scheme 4. The synthesis of the decalin system by means of a Michael–Michael ring-closure sequence.

generating the extended vinyl ether 53 (Scheme 5) [25]. Under Lewis acidic conditions, this group acts as an intramolecular nucleophile, attacking the pendant ketone to form an additional six-membered ring. The resulting oxonium species 54 can be further modified to ultimately yield the enone 56 or the diene 58 (Scheme 5). Treatment of 54 with TBAC leads to regioselective reduction of the oxonium species in a 1,4-fashion to form the vinyl ether complex 55. Protonation and hydrolysis of the vinyl ether generates an enone complex, from which 56 can be liberated by oxidative decomplexation in 51 % yield (based on 54). Alternatively, with Li-9BBNH the oxonium species 54 is regioselectively reduced in a 1,2-fashion to form the diene complex 57. Treatment of 57 with HOTf eliminates methanol to generate an h3-allyl complex, which can be trapped by the conjugate base of dimethyl malonate. Oxidative decomplexation using silver trifluoromethanesulfonate liberates 58 in 79 % yield (based on 54).

When the anisolium complex generated by the addition of MVK to the 2-methoxytetra- hydronaphthalene complex 59 is utilized in the above cyclization sequence, the tricyclic oxonium complex 61 is generated (Scheme 6). Deprotonation of 59 with pyridine forms the extended vinyl ether complex 60, which cyclizes and eliminates water to form 61 when exposed to TBSOTf. Hydrolysis of 61, followed by oxidation of the metal fragment, yields the dienone 62 in 15 % yield (based on 59).

If an [Os]-anisolium complex bears a proton at C4 (63, Scheme 7), exposure to DIEA at low temperature results in a kinetic deprotonation of the benzylic carbon attached to C3 generating the extended vinyl ether 64. This complex cyclizes under Lewis acidic conditions to generate an anisolium ion, which can then be deprotonated at C4 to generate a tetralin complex [25]. Heating this species liberates the tetralin 65 in 39 % yield (based on 63).

4-Methoxystyrenes The Diels–Alder cyclization of the 4-methoxystyrene complex 67 and a dienophile provides a direct route to substituted decalin systems. Unfortunately, direct complexation of 4-methoxystyrene to [Os] results in the formation of a significant amount of the vinyl-bound coordination isomer. However, the ring-bound form, 67, can be synthesized