Group 6 Dihapto-Coordinate Dearomatization Agents for Organic

Review Cite This: Chem. Rev. 2017, 117, 13721-13755

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Group 6 Dihapto-Coordinate Dearomatization Agents for Organic Synthesis Benjamin K. Liebov and W. Dean Harman* Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904, United States ABSTRACT: This review covers publications ranging from 2005 to 2017 concerning the organic reactions of aromatic ligands η2-coordinated to tungsten or molybdenum and the use of these reactions in the synthesis of novel organic substances. An emphasis is placed on C−C bond-forming reactions using conventional building blocks of organic synthesis such as acetals, enolates, Michael acceptors, acylating reagents, and activated aromatics. Substrates activated by the metal include arenes, pyridines, pyrroles, pyrimidines, furans, and thiophenes. General reactivity patterns are elucidated, as well as stereochemical preferences. These trends are compared to those of osmium and rhenium forebears as well as to the reactivity patterns of other methods of stoichiometric transition-metal-based dearomatization (i.e., η6-arene complexes).

CONTENTS 1. Introduction 2. General Features of Dihapto-Coordinate Dearomatization 2.1. Dearomatization Agent (Metal Complex) 2.1.1. Pentaammineosmium(II) 2.1.2. Second-Generation Dearomatization Agents 2.2. Common Aromatic Substrates for Dearomatization 2.3. Isomerizations, Tautomerizations, and Latent Functionality 2.4. Overview of Organic Reactions Derived from η2-Aromatics 2.4.1. Range of Electrophiles and Nucleophiles 2.4.2. Relative Stereochemistry of Organic Products 2.5. Early Examples of Dihapto-Dearomatization 2.5.1. Pentaammineosmium(II) 2.5.2. ReTp(CO)(L) Complexes 3. Organic Reactions Enabled by Tungsten η2Coordination 3.1. Fundamental Features of the WTp(NO)(PMe3) System 3.1.1. 31P NMR, IR, and Electrochemical Data 3.1.2. Stereochemical Control 3.2. Dearomatization of Arenes 3.2.1. Benzene and Naphthalene Complexes 3.2.2. Anisole Complexes 3.2.3. Phenol Complexes 3.2.4. Aniline Complexes 3.2.5. Fluorinated Benzene Complexes 3.3. Dearomatization of Aromatic Heterocycles 3.3.1. Pyrrole Complexes 3.3.2. Furan and Thiophene Complexes 3.3.3. Pyridine Complexes © 2017 American Chemical Society

3.3.4. Pyrimidine Diels−Alder Cycloaddition Reactions 4. Organic Reactions Effected by Molybdenum η2Coordination 4.1. Molybdenum Arene Complexes 4.1.1. 4-Dimethylaminopyridine: An AcidModulated Auxiliary Ligand 4.1.2. Tandem Addition Reactions with Naphthalene and Anthracene 4.1.3. Progress toward Molybdenum Benzene Complexes 4.1.4. Recycling Dearomatization Agents 4.2. 1,3-Diene Complexes and Cyclization Reactions 5. Controlling Absolute Stereochemistry 5.1. Chemical Differentiation of Diastereomers: The α-Pinene Strategy 5.2. Separation of Diastereomeric Salts 6. Remaining Challenges and Future Directions 6.1. Resolution of MoTp(NO)(L) Systems 6.2. Manipulation through Redox Catalysts 6.3. Utilization of Bound Carbons 6.4. Adjacent Ring Activation 6.5. Application to Medicinal Chemistry: Escaping “Flatland” 7. Concluding Thoughts Author Information Corresponding Author ORCID Author Contributions Notes Biographies Acknowledgments References

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Received: August 10, 2017 Published: October 24, 2017 13721

DOI: 10.1021/acs.chemrev.7b00480 Chem. Rev. 2017, 117, 13721−13755

Chemical Reviews

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Ag(I),17 Pt(0),18,19and Ni(0),20−23 d2 Ta(III)24−26 and Nb(III),27 d8 Rh(I)28−31 and Ru(0),32 and d6 Ru(II)33,34 and Re(I)35−42 complexes having been reported.43 But if an η2arene complex is to be an effective substrate for organic reactions, it must be substitution-inert, and the ancillary ligand complex (i.e., all but the bound aromatic) must resist decomposition by acids, bases, oxidants, and reductants. These stringent requirements can best be met with a saturated (18e), octahedral complex that features a strong metal−arene π-backbonding interaction. 2.1.1. Pentaammineosmium(II). Nearly 30 years ago, the complex [Os(NH3)5(η2-benzene)](OTf)2 (1) was first reported,44 along with its facile hydrogenation to [Os(NH3)5(η2cyclohexene)](OTf)2 (2) (see Scheme 1).45 The advent of the pentaammineosmium(II) system was significant in that it constituted the first example of an aromatic complex bound through only two carbons that was kinetically stable with respect to ligand exchange, in solution, and at ambient temperature (t1/2 > 5 h). This allowed for the isolation of these materials and their subsequent exposure to reagents and reaction conditions that would not be tolerated by more labile systems. Specifically, most of the reagents used in organic transformations (e.g., dienes, enones, phosphines, alkyl and acyl halides, and Brønsted acids) would readily react with the 16e {Os(NH3)5}2+ intermediate (Figure 2). Furthermore, com-

1. INTRODUCTION Owing to the development of high-throughput bioassays and small-molecule libraries to identify potential pharmaceutical leads (e.g., Lilly’s Open Innovation drug discovery program), new synthetic methods are sought that allow the efficient, stereoselective syntheses of novel molecules.1 This is especially true of new approaches that can expand chemical space.2 In principle, aromatic molecules are ideally suited as precursors to functionalized alicyclic systems. They are commercially available with a diverse range of substituents and substitution patterns and feature a ring of unsaturated carbons and heteroatoms, which provide multiple points for chemical elaboration. These unique structural features render aromatics ideal platforms for both functional and stereochemical diversity. For these reasons, reactions that utilize aromatics as synthons for more saturated molecules, such as the Birch reduction,3,4 photocycloaddition,5 and enzymatic oxidations,6 have become important tools for the synthetic chemist.7 The chemical reactivity of aromatic molecules can be enhanced by their coordination to a transition metal (Figure 1).8 For example, the arene ligands in complexes such as (η6-

Figure 1. Comparison of hexahapto- and dihapto-coordinate activation.

arene)Cr(CO)3, [(η6-arene)Mn(CO)3]+, [(η6-arene)FeCp]+, [(η6-arene)RuCp]+, and (η6-arene)Mo(CO)3 are activated toward nucleophilic substitution or addition reactions, ultimately leading to the formation of substituted benzenes or cyclohexadienes.9 A complementary approach is the activation of aromatic molecules through dihapto-coordination.10,11 Here, the metal−arene bond is stabilized primarily by the interaction of a filled metal dπ orbital with a π* orbital of the aromatic ligand. This shift of electron density from the metal to the arene (backbonding) activates η2-bound aromatic systems toward electrophilic rather than nucleophilic addition reactions. Thus, the metal not only acts as a protecting group for the coordinated double bond, but also activates the uncoordinated portion of the aromatic through π-donation, similar to the amino group of an enamine (vide infra). The aim of this review is to summarize the progress over the past decade in the development of new synthetic transformations for aromatic molecules that are enabled through dihapto-coordination. It begins, however, with a brief review of the fundamental features and early examples of dihaptodearomatization that have provided the foundation for the current chemistry.

Figure 2. Contrast in reactivity patterns for an η2-arene complex and a typical σ-donor (e.g., water) for pentaammineosmium(II).

plexes such as [Os(NH3)5Cl]+ or [Os(NH3)5(H2O)]2+ are powerful reducing agents, with reduction potentials approaching −1 V with respect to the normal hydrogen electrode (NHE). However, replacement of water with benzene or another aromatic molecule dramatically stabilizes the complex toward oxidation [cf. benzene, +0.30 V (NHE)], owing to strong metal-to-ligand donation of electron density (π-backbonding) and weak donation to the metal from the arene (σbond). As a consequence, arene complexes of pentaammineosmium(II) react with a wide range of organic reagents at the arene ligand rather than at the metal. Dearomatization reactions have been realized for pentaammineosmium(II) with arene and aromatic heterocycle substrates,44−78 and these reactions have been extensively reviewed.79−81 2.1.2. Second-Generation Dearomatization Agents. Developing a dearomatization agent based on metals other than osmium was unexpectedly difficult. First appearing in the literature over a decade later, the second generation of dihaptocoordinate dearomatization agents were Re(I) complexes of the form {ReTpL(CO)} [where L = N-methylimidazole (MeIm),

2. GENERAL FEATURES OF DIHAPTO-COORDINATE DEAROMATIZATION 2.1. Dearomatization Agent (Metal Complex)

A number of transition metals have shown the ability to bind aromatic molecules in a dihapto fashion, with d10 Cu(I),12−16 13722


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copy and the associated 183W−31P coupling constants.87 Conversely, the molybdenum dearomatization agents require a more electron-donating ancillary ligand, such as Nmethylimidazole (MeIm) or 4-dimethylaminopyridine (DMAP), to compensate for the weaker backbonding characteristics of the second-row metal.88 As described earlier, a critical feature of a viable dihaptocoordinate dearomatization agent is the ability to form a substitution-inert (t1/2 > 10 min) complex with aromatic molecules. Substitution rate data have been collected in Table 1

pyridine, PMe3, or tBuNC]. Of critical importance, by electrochemically matching the d5/d6 reduction potential with that of pentaammineosmium(II), the ability to dihaptocoordinate arenes could be mirrored by the rhenium complexes. In particular, the N-methylimidazole variant, {ReTp(MeIm)(CO)}, was found to bind a full range of aromatic molecules, including benzenes, furans, and pyrroles.82 The benzene complex ReTp(MeIm)(CO)(η2-benzene) served as a valuable precursor to the other η2-aromatic complexes via facile replacement of the benzene. In addition to being more activating than its osmium forebear, this chiral rhenium(I) complex can be enantioenriched, leading to the creation of various enantioenriched organic products.83−85 Despite these features, the {ReTp(L)(CO)} family is not without its shortcomings. High cost and limitations with scalability hastened the development of more practical dearomatization agents. Lessons learned in the development of {ReTp(CO)(L)} systems were eventually applied to group 6 transition metals. A comparison of reduction potentials for various Re, W, and Mo complexes with similar ligand sets suggested that moving from rhenium(I) to molybdenum(0) or tungsten(0) effects a decrease in the d5/ d6 reduction potential of roughly 1 V. Additionally, such comparisons showed that replacement of CO with NO+ results in an increase of nearly equivalent magnitude. Thus, just as a rhenium analogue to the pentaammineosmium(II) system was developed through replacement of an amine with a carbonyl ligand, it was hypothesized that a molybdenum or tungsten analogue could be produced through replacement of the carbonyl ligand with the stronger π-acid NO+ (Figure 3).

Table 1. Substitution Rate Dataa

a

Half-life data were converted to free energies of activation and to enthalpies of activation by approximating ΔS⧧ as 12 eu. See ref 88. ΔG⧧ corresponds to benzene intrafacial isomerization at coalescence (roughly −10 °C). These values for WTp(NO)(PMe3)(η2-benzene) and MoTp(NO)(DMAP)(η2-benzene) were determined from 1H NMR data (coalescence temperature; this work). The values for ReTp(CO)(PMe3)(η2-naphthalene) and MoTp(NO)(PMe3)(η2-benzene) are estimated from DFT calculations. MoTp(NO)(PMe3)(η2naphthalene) can be generated in solution at 25 °C but cannot be isolated.

for a variety of η2-benzene and η2-naphthalene complexes in acetone. Acetone also forms stable η2-bound complexes with all of the dearomatization agents listed, and recent work links halflives for the arene-to-acetone substitution reactions to estimates of metal−aromatic bond strengths.88 As seen in Table 1, the most stable systems are {Os(NH3)5}2+, {ReTp(CO)(MeIm)}, and {WTp(NO)(PMe3)}. To date, these have been most heavily utilized in dihapto-coordinate dearomatization reactions.10 Of note, all three of these systems are highly sensitive to adjustments of the ligand set. For example, for the rhenium system, replacement of MeIm with PMe3 reduces the π-basicity of the metal to the point that a benzene complex cannot be isolated. And yet, for the tungsten system, replacement of PMe3 with MeIm is equally debilitating because the electron-rich W(0) oxidation state is not sufficiently stabilized by π-acids.89 The most stable molybdenum-based dearomatization agents are the DMAP and MeIm analogues, which are roughly equivalent to the {ReTp(CO)(t-BuNC)} system. Isolation of naphthalene complexes with these systems is straightforward, but isolation of a benzene complex is a formidable challenge, owing to a short substitution half-life (20:1 for all examples provided in this review. 2.4. Overview of Organic Reactions Derived from η2-Aromatics

2.3. Isomerizations, Tautomerizations, and Latent Functionality

Before specific examples of organic transformations of dihaptocoordinate aromatics are described, it will be helpful to briefly discuss the broader features (Figure 6). Early studies tended to focus on heteroatom-driven reactions with the uncoordinated π-system. A single π-donor substituent on a benzene ring directs the metal to an ortho or meta carbon, and such coordination enhances the interaction of the donor group with the uncoordinated diene portion, such that the para and ortho positions are further activated toward electrophilic addition reactions. In a similar manner, furans and pyrroles direct the metal to C2 and C3, which enhances the vinyl ether or enamine character of the π-system. Consequently, electrophilic addition is directed to the uncoordinated β-carbon. For pyridinium salts, the metal favors the 3,4-position, enhancing the ability for nucleophiles to add to C2. In these cases, the metal enhances the natural polarization of the molecule, primarily through

Despite clear thermodynamic preferences for η2-binding at certain positions in an aromatic ring (Figure 4), an important feature of dihapto-coordinated aromatic complexes is the ability of the metal to transiently bind at different locations in the πsystem. For all of the dearomatization agents listed in Table 1, the metal is able to rapidly move from one location to another at ambient temperatures, without detachment of the aromatic. For benzene and pyrrole ligands, these intrafacial (ring-walk) migrations occur with half-lives typically less than 1 s at 25 °C. For η2-naphthalene, η2-thiophene, and η2-furan complexes, these isomerizations take somewhat longer (t1/2 ≈ 1 min). Bonding to the metal at different positions in the aromatic ring allows for the possibility of several different organic functional groups to arise from each class of aromatic molecule. In 13724


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addition or deprotonation regenerates a neutral ligand. Finally, this transformed organic can be oxidatively liberated from the metal or subjected to an additional tandem addition reaction of an electrophile and nucleophile, described generically as E+ and Nu−. Examples are provided in Table 2 of reagents that have Table 2. Examples of Reagents That Have Been Successfully Utilized with Dihapto-Coordinated Aromatics Electrophilic Reagents (E+) alkyl halides Brønsted acids acetals/H+ Michael acceptors aldehydes and ketones/H+ nitrilium salts/H2O anhydrides tertiary alcohols/H+ peroxyacids N-halosuccinimides Selectfluor Nucleophilic Reagents (Nu−) R3SiH, NaBH4, LAH, NaBH3CN organozincs, organocuprates masked enolates nitroalkanes allyl silanes pyrrole, indole, furan, thiophene pyrazoles, imidazoles arenes amines alkoxides, hydroxide phosphines, thiols Cyclization Reagents Et2Zn, CH2I2 ketenes acetylenes alkenes

Figure 6. Overview of reactivity trends for dihapto-coordination.

disruption of the substrate’s aromaticity (class I, Figure 6). The second class of dearomatization reaction involves a highly reactive intermediate derived from the metal binding away from its thermodynamically preferred position. This intermediate is typically not directly detected but inferred on the basis of the product formed. Thus, 3,4-η2-pyrrole complexes are transformed into azomethine ylides, 3,4-η2-furans develop oxomethine ylide character, and 2,3-η2-naphthalene displays properties of an o-quinodimethane (class II, Figure 6). The third form of activation is characterized by the metal acting as the π-donor. In these cases, either the aromatic system does not have a π-donor or a tautomerization or protonation creates an η2-coordinated 1,3-diene system. In this scenario, the metal strongly interacts with the lowest unoccupied molecular orbital (LUMO) of the diene, rendering the terminal carbon highly nucleophilic (class III, Figure 6). 2.4.1. Range of Electrophiles and Nucleophiles. The polarization illustrated in Figure 6 enables a remarkably broad range of reactions with common electrophiles and nucleophiles. In contrast to those observed for hexahapto-coordinated arenes, organic reactions with dihapto-coordinated metals are initiated with addition of an electrophile. Depending on the nature of the aromatic ring, the electrophile can be as mild as an ammonium salt or weakly activated dienophile, but the initiating reagent will always be electrophilic. If the reaction results in a cationic ligand (based on a formalism in which the metal oxidation state does not change), then nucleophilic

a

-R -H -C(OR)R2 -CH2CH2a -C(OH)R2 -C(O)NHR -C(O)OH -CR3 −OH -Br, -Cl -F -H -R, -Ph -CH2C(O)R -CH2NO2 -CH2CHCH2 -Het (C) -Het (N) -Ar -NR2 -OR, -OH -PR3+, -SR cyclopropanation cyclobutanation cyclobutenation cyclopentanation cyclohexanation

Where Z is an electron-withdrawing group.

been successfully utilized with dihapto-coordinated aromatics, including those used for cyclization reactions. An important feature of dihapto-dearomatization is that addition of an electrophile to the bound aromatic often creates intermediates with considerable carbocation character. Thus, conjugation and hyperconjugation play significant roles in determining the chemoselectivity for addition of both the electrophile and the nucleophile. Because of this feature, aromatics bearing alkyl groups (R), withdrawing groups (Z), and π-donor substituents (X) that affect stability of carbocations are best thought of as distinct classes of substrates with complementary reaction patterns. 2.4.2. Relative Stereochemistry of Organic Products. In general, electrophiles and nucleophiles add to the face of the aromatic molecule that is opposite to that coordinated by the metal. This high stereoselectivity is strictly a result of steric interactions with the metal and ancillary ligands. As a result, the cyclic products typically have all newly added substituents in a mutually cis configuration. The one exception to this general rule is found in cases where a prochiral carbon is reversibly protonated. In these cases, protonation can sometimes occur syn to the metal in order to minimize steric interactions 13725


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2.5.2. ReTp(CO)(L) Complexes. The development of the ReTp(CO)(L) systems allows for some ability to tune the metal’s π-basicity by adjustment of the ancillary ligand (L). While several systems can bind furans and naphthalenes, only the MeIm system is capable of binding benzenes, and this system has been used for the majority of the organic manipulations described. Compared to the osmium system, ReTp(CO)(MeIm) is more π-basic, owing to the lower oxidation state of the metal. As a consequence, aromatic substrates are more activated toward electrophilic addition and cycloaddition reactions (Scheme 2). In particular, a Diels−

between ring substituents. As described in later sections, absolute stereochemistry of the organic products also depends on which face of the prochiral aromatic is coordinated by the metal. 2.5. Early Examples of Dihapto-Dearomatization

2.5.1. Pentaammineosmium(II). Most of the early studies of dihapto-coordinate dearomatization utilized pentaammineosmium(II) and focused primarily on C−C bond-forming reactions with benzenoid systems. These included Michael additions, acetal additions, and cycloaddition reactions. Several examples are provided in Scheme 1 that

Scheme 2. Examples of Aromatic Activation via η2Coordination to the Electron-Rich Re(I) Fragmenta

Scheme 1. Aromatic Molecules as Scaffolds for Organic Synthesis Enabled by Dihapto-Coordination with the Pentaammineosmium(II) System

a

{ReTp(NO)(MeIm)} = [Re].

Alder reaction occurs with the anisole complex at room temperature and pressure. Subjecting the resulting cycloadduct to oxidation liberates the bicyclic organic 8.88 A similar product is derived from naphthalene and methyl acrylate, but in this case, cycloadduct 9 is formed sequentially, initiated by a tertbutyldimethylsilyl (TBS)-promoted Michael addition.96 The resulting silyl enolate closes upon oxidation of the metal. Alternatively, with the 2-methoxynaphthalene analogue, the silylated enolate reacts with a second equivalent of the Michael acceptor to give the Michael−Michael ring closure product 10.96 Furans bound to this rhenium system can undergo [2 + 2] cyclization sequence via a Michael reaction to form a [3.2.0]oxabicycloheptadiene. Upon heating, this strained bicyclic opens to give the oxepin 11.97 Finally, in a particularly interesting transformation, dihapto-coordinated furan complexes of rhenium can function as 1,3-propene dipoles, reacting with Michael acceptors to form cyclopentenes such as 12

highlight the use of these reactions to prepare novel organic products. As already discussed, many of these examples (2, 3, 4, and 7) are initiated by a heteroatom-directed addition of an electrophile to the aromatic ring (class I, Figure 6). Examples are also included where the metal acts as the π-donor (1; class III) or activates the π-system through alternate coordination (5 and 6, class II). Further discussion of the chemistry of the pentaammineosmium(II) metal fragment can be found in several reviews.43,79,81,91−,95 13726


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through a novel cyclopentannulation reaction.98 None of the reactions in Scheme 2 is known to occur with pentaammineosmium(II).

this review in two parts: First, relative stereocontrol is discussed, which depends on the stereoselectivity of the organic transformations (section 2.4.2), along with the coordination diastereomer ratio (cdr). This ratio indicates the selectivity for binding a particular face of a C−C double bond. Second, the absolute stereocontrol of the organic products will be considered, which depends on the ability to resolve the metal stereocenter and retain this stereochemistry throughout functionalization of the organic ligand (section 5). 3.1.2.1. Controlling the Coordination Diastereomer Ratio. In the case of pentaammineosmium(II), coordination of a prochiral aromatic molecule results in a racemic mixture. However, when the metal itself is a stereocenter, faces of the aromatic can be differentiated. This is quantified by the coordination diastereomer ratio (cdr), which has been defined as the ratio of diastereomers resulting from coordination of the aromatic from the re or si faces of the alkene (eq 1):

3. ORGANIC REACTIONS ENABLED BY TUNGSTEN η2-COORDINATION 3.1. Fundamental Features of the WTp(NO)(PMe3) System

The remainder of this review covers the period 2005−2017 and focuses on the organic transformations of dihapto-coordinated aromatic complexes of tungsten and molybdenum. Coverage is divided into three parts, with tungsten described in section 3 and molybdenum in section 4, followed by section 5 on controlling absolute stereochemistry. The majority of research over this period utilizes the {WTp(NO)(PMe3)} system, for which large-scale syntheses have been reported,87 and precursors are commercially available. 3.1.1. 31P NMR, IR, and Electrochemical Data. For the {WTp(NO)(PMe3)} system, 31P NMR has proven to be an exceptionally valuable technique. In particular, 183W−31P coupling constants are highly sensitive to the chemical nature of the organic ligand and how it is coordinated to the metal. Though a detailed analysis is beyond the scope of this review, Table 3 is provided as a quick reference for characterization of Table 3. Characterization of {WTp(NO)(PMe3)} Complexes compd WTp(NO)(PMe3)(η2-benzene) WTp(NO)(PMe3)(η2-anisole) WTp(NO)(PMe3)(η2trifluorotoluene) WTp(NO)(PMe3)(η2naphthalene) WTp(NO)(PMe3)(η2cyclopentene) WTp(NO)(PMe3)(η2-C5H7) (allyl) WTp(NO)(PMe3)(η2-furan) WTp(NO)(PMe3)(H)(pyrrolyl) (N) WTp(NO)(PMe3)(η2-lutidine) WTp(NO)(PMe3)(η2-lutidinium) WTp(NO)(PMe3)(H)(lutidinyl) WTp(NO)(PMe3)(κ1pyrimidine)

J(183W−31P) (Hz)

Ep,aa (V)

ν(NO) (cm−1)

314 312 307

−0.13 −0.18 0.06

1564 1568 1575

297

0.16

1570

288

0.35

1541

273

n/o

1634

300 128

0.03 n/o

1651 1590

310 296 109 415

−0.07 0.68 n/o −0.65

1565 1592 1607 1515

Rate studies of rotation, intrafacial isomerization (ringwalking), interfacial isomerization (face-flipping), and ligand exchange have been previously reviewed,10,100 all as a function of redox potential, ancillary ligand, metal, oxidation state, and degree of aromaticity.10,100 From these foundational studies, it was determined that once the addition of an electrophile has occurred, epimerization of the metal stereocenter is no longer an issue, since the rate of interfacial isomerization (face-flip) for a nonaromatic π-ligand (alkene, diene, allyl, etc.) is much slower (typically ≫1 week at 25 °C in solution) than that for an aromatic ligand (typically 20:1. 3.1.2.2. Hyperdistorted (η2) Allyl Intermediates. In order to understand the regio- and stereoselectivity encountered in many of the following examples of tungsten-promoted dearomatization, it is important to consider the stereoelectronic features of allyl complexes such as [WTp(NO)(PMe3)(η2C6H9)]OTf (21),103 which are often products resulting from η2-arene and η2-diene transformations (see Figure 6). Although the uncoordinated allyl ligand would be symmetrical, density

a

Versus normal hydrogen electrode (NHE), at a scan rate of 100 mV/ s.

{WTp(NO)(PMe3)} complexes. Aromatic complexes typically have 183W−31P coupling constants between 300 and 320 Hz, whereas isolated alkenes are roughly 20 Hz lower, and this is largely independent of the withdrawing power of the ligand. In comparison, κ1 ligands and hydrides differ by 100 Hz or more from these values. In contrast, IR data [ν(NO)] and electrochemical data (Ep,a) tend to track more closely with the overall electron density of the metal. 3.1.2. Stereochemical Control. In virtually all the examples of dearomatization shown in this review, new stereocenters are created from prochiral aromatic precursors. If the relative stereochemistry between the metal stereocenter and the organic ligand can be controlled, then a resolved metal stereocenter can lead to enantioenriched organic products.96,98,99 Thus, controlling stereochemistry is considered in 13727


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3.2. Dearomatization of Arenes

functional theory (DFT) calculations and experimental data indicate that, when bound to tungsten, the allyl ligand is highly distorted. The central carbon and one of the terminal carbons are almost equidistant from the metal (∼2.3 Å), while the third is much less tightly bound (Figure 7; 2.5−2.9 Å). As a result,

3.2.1. Benzene and Naphthalene Complexes. While there are extensive examples of benzene and alkylated benzenes

undergoing osmium-12,43,66−68 and rhenium-promoted electrophilic addition reactions,44,75,120−124 the complex WTp(NO)(PMe3)(η2-benzene) and its alkylated benzene analogues are more sensitive to acid-induced oxidation of the metal, and consequently, relatively few examples of tandem addition have been reported. In a rare example, when a solution of the tungsten benzene complex was treated with methyl vinyl ketone (MVK) and tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf), followed by the oxidant Cu(OTf)2 and dimethyl malonate, the free 1,4-addition product was recovered in 25% yield (eq 2).118 In general, however, the WTp(NO)(PMe3)(η2-benzene) system appears to be more challenging to develop organic reactions for than its {ReTp(CO)(MeIm)} analogue.

3.2.1.1. Cycloaddition Reactions. When benzene is coordinated by {WTp(NO)(PMe3)}, the uncoordinated portion of the ring resembles cyclohexadiene, and as such, the benzene complex undergoes a room-temperature Diels− Alder cycloaddition reaction with N-methylmaleimide (14),86 similar to that observed for ReTp(CO)(MeIm)(η2-benzene).119 Not surprisingly, anisole and dimethoxybenzene show similar reactivity when bound by the tungsten complex, but with an expanded range of suitable dienophiles (see section 3.2.2.1).120 Less obvious are the examples of naphthalene and anthracene, which must first undergo isomerization to the unstable 2,3-η2 isomers before they are suitable as diene surrogates (Scheme 3).121 An interesting countertrend is observed when rates of cycloaddition are compared with those of the organic hydrocarbons (Figure 8). Whereas free anthracene and naphthalene are far more reactive than benzene with N-methylmaleimide (NMM), when complexed to tungsten, there is an inverse correlation between isomerization energy (DFT) to the 2,3-η2 isomer and the overall rate of the cycloaddition reaction (see Figure 8, 14−16).121 Note that while the equilibrium concentration of the 2,3-η2 isomer is likely to be very low, the quinodimethane-like character makes it highly reactive toward cycloaddition. Significantly, when the anthracene complex undergoes cycloaddition, it is the A ring that is dearomatized rather than the B (center) ring, which would normally be observed.121 3.2.1.2. Hydroarylation Reactions of Naphthalene. The tungsten naphthalene complex undergoes protonation at C1, and the resulting naphthalenium intermediate (17), which resembles a π-allyl complex, is highly electrophilic and readily

Figure 7. Molecular structure of the complex [WTp(NO)PMe3(η2C6H9)]OTf (21), showing the distorted nature of the η2-allyl ligand.

both nucleophilic addition to the allyl and elimination to the diene are highly regioselective. The distortion that causes this stereochemical preference places a greater positive charge on the allyl terminus away from the PMe3 group. This preference has been attributed to two factors. First, differing interactions with the nitrosyl group create a large difference in energy in the dπ orbitals of the {WTp(NO)(PMe3)} system, causing the η3to-η2 distortion. Second, a significant component of the highest occupied molecular orbital (HOMO) of this system involves the pyrazole ring trans to the PMe3, and this interaction results in orienting the allyl fragment in such a way that the carbocation character (i.e., the weakly bound allyl carbon) is away from the PMe3 group (Figure 7). While DFT calculations indicate that the other stereoisomer of the dihapto-coordinated allyl is readily accessible in a kinetic sense (the enthalpic barrier is only ∼6 kcal/mol), there is roughly 4 kcal/mol energy difference between the two isomers. The result is a distinct preference for addition and elimination away from the PMe3. Of course, this is not to imply that this preference supersedes all other factors, such as steric interactions. 13728


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Scheme 3. Tungsten-Promoted Cycloaddition of Naphthalenes with N-Methylmaleimide via a Quinodimethane Intermediate

Scheme 4. Hydroarylation Reactions with a Tungsten Naphthalene Complex

and the remaining diene fragment is better able to interact with the π-donating methoxy group. One consequence of this is that the η2-anisole complex is a more reactive diene for Diels−Alder reactions than the benzene analogue (Scheme 5).120 An additional methoxy group predictably activates the arene still further, with 1,3-dimethoxybenzene (DMB) now resembling the electronic structure of Danishefsky’s diene. Thus, WTp(NO)(PMe3)(η2-DMB) reacts with dienophiles as mild as Scheme 5. Diels−Alder Cycloaddition Reactions with Anisole and 1,3-Dimethoxybenzene Complexes

Figure 8. Rates of cycloaddition with N-methylmaleimide for several aromatic hydrocarbons.

reacts with weak nucleophiles (Scheme 4).122 Aromatic heterocycles such as pyrrole, indole, and 2-methylfuran undergo Friedel−Crafts alkylation, releasing a proton, and completing a catalytic cycle. Thus, 0.1 mol equiv of a moderate Brønsted acid (e.g., [H 2NPh 2]OTf) can effect the hydroarylation of naphthalene in good yield. Subsequent oxidative decomplexation with ceric ammonium nitrate (CAN) yields the final products in isolated yields ranging from 28% to 61% (Scheme 4).122 3.2.2. Anisole Complexes. 3.2.2.1. Diels−Alder Cycloaddition Reactions. When anisole is dihapto-coordinated to the tungsten fragment,123 the aromatic π-system is disrupted, 13729


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acrylonitrile to form the bicycloadduct (23), which can be hydrolyzed to the corresponding bicyclooctenone 25 in moderate yield. Unfortunately, while the exo−endo selectivity is typically high, the low coordination diastereomer ratio (cdr ∼3:1) translates into poor diastereoselectivity of the product complex (e.g., 22−24). 3.2.2.2. 1-Oxadecalin and [3.3.1]Bicyclononane Syntheses. Despite the low cdr of the anisole complex, protonation with diphenylammonium triflate (DPhAT, pKa ∼ 0.78) results in a single diastereomer of the 2H-anisolium 28 with a cdr of >20:1.123 When this species is combined with acrolein or methyl vinyl ketone and weak base (e.g., N,N-dimethylformamide, DMF), a deprotonation/Michael addition reaction ensues, but not at C2. Instead the 4H-anisolium complex (29) is obtained, still retaining the high cdr of its 2H forebear. This compound is a useful precursor to novel oxadecalin cores. Addition of various nucleophiles occurs at the pendant carbonyl, followed by a ring closure at the meta carbon (30). Subsequent protonation, reduction to 31, and elimination results in an allylic species (32), which itself can react with nucleophiles to form oxadecalin products (33) (see Scheme 6).123

Scheme 7. Synthesis of Bicyclo[3.3.1]nonane Complex 37

intermediate.123 As with the oxadecalin products, the cdr of 37 is >20:1. 3.2.3. Phenol Complexes. 3.2.3.1. Tautomerizations. When WTp(NO)(PMe3)(η2-benzene) undergoes ligand exchange with phenol, dihapto-coordination occurs across C2 and C3 as with anisole, but in contrast to that observed with osmium, the bound phenol immediately tautomerizes to its 2H form (38, Scheme 8).124 As the 2H isomer, the ligand functions

Scheme 6. Synthesis of 1-Oxadecalins from 2H-Anisolium Complex 28

Scheme 8. Synthesis of a Tungsten η2-2H-Phenol Complex

as an electron-deficient alkene (i.e., a dienone) and is a superior π-acid compared to its phenol precursor. The electronic properties of η2-coordinated 2H-phenol are demonstrated by the red-shifted carbonyl stretching frequency of 1619 cm−1, compared to the stretching frequency of an uncoordinated carbonyl such as 2,4-cyclohexadiene-1-one at 1690 cm−1.125 The effects of this enhanced π-acidity can also be observed by cyclic voltammetry. The anodic wave of the WTp(NO)(PMe3)(η2-2H-phenol) (38) shifts by nearly 1.0 V compared to that of its η2-benzene precursor.124 3.2.3.2. C4-Addition Reactions. Early studies with phenol were hampered by the low 2:1 coordination diastereomer ratio (cdr) of the 2H-phenol complex 38. When this complex was treated with base followed by methyl or ethyl iodide, alkylation occurred selectively at the ortho carbon and anti to metal coordination. However, for each of the two diastereomers of the dienone, two different constitutional isomers were isolated (Scheme 9). In addition to the expected 5,6-η2-2H-phenol

In contrast, when sodium thiophenoxide was combined with the acrolein-derived anisolium complex 34, nucleophilic addition occurs to C3 (35). This is followed by electrophilic addition of the aldehyde carbonyl to C2 of the arene and subsequent demethylation of 36 (Scheme 7). A crystal structure determination of the resulting complex (37) revealed that the initial Michael addition, thiolate addition, and aldol reaction all occur anti to metal coordination. In addition, the stereochemistry at C8 is consistent with a dipole-directed synclinal approach of the aldehyde to the purported vinyl ether 13730


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Scheme 9. Alkylations and Aldol Condensation of an η2Phenol Complex

Scheme 10. Tandem Electrophilic/Nucleophilic Addition to W (η2-2H-Phenol)a

a

Conditions: (a) NBS in MeOH; (b) Selectfluor in MeOH; (c) mCPBA in MeOH; (d) mCPBA followed by HSPh; (e) mCPBA followed by morpholine; (f) diacetoxyiodobenzene, [Ph3PMe]Br−, HOAc. Yields: 61−83%.

49) could be isolated as single diastereomers [diastereomeric ratio (dr) >20:1]. Several of the complexes in Scheme 10 (45, 47, and 49) were ultimately oxidized to liberate the novel organic ligands (60−90%).104 3.2.3.4. Cyclobutanation Reactions. As seen in section 3.2.3.3, the 2H-phenol complex (38) undergoes electrophilic addition at the meta position of a phenol ring. This reactivity pattern was found to hold true for carbon electrophiles as well. In the case of ketenes derived from acyl chloride precursors (Scheme 11), a [2 + 2] cycloaddition takes place with 2Hphenol 38 to generate novel bicyclo[4.2.0]octenone complexes (50−52).105 The reaction is most likely a stepwise process, initiated by electrophilic addition to the ketene sp carbon, followed by enolate addition to the phenol-ring para carbon. The two carbonyl groups in the resulting [4.2.0] dione complexes (50−52) are chemically differentiated by the πbasic metal: when NaBH4 is added to a solution of 51, reduction of the cyclobutanone proceeds with high stereoselectivity, resulting in a single isomer of the cyclobutanol complex 53 (dr >20:1).105 Subsequent oxidative decomplexation results in a bicyclooctenone with four new stereocenters set by the metal. α-Chlorocyclobutanones are known to undergo ring contraction under basic conditions,128 and the metal does not interfere with this reaction. When 50 is stirred in a mixture of lithium methoxide and methanol, the butanone ring contracts to form the cyclopropyl methyl ester complex 54 in 58% yield. Finally, a [2 + 2] reaction sequence can be effected for 2Hphenol 38 with the electron-deficient alkyne DMAD, in this case rendering a bicyclooctadienone system (55).105 3.2.4. Aniline Complexes. The complementary reactivity patterns demonstrated for anisole and phenol complexes of {WTp(NO)(PMe3)} come together in the rich chemistry of anilines (Scheme 12). The fragment {Os(NH3)5}2+ coordinates aniline at either the nitrogen or the ring.49,61 Unfortunately, the

(40), the 3,4-η2-2H-phenol was isolated (41). In contrast, when Michael acceptors were used as the electrophile, only para alkylation was observed (42, 43). The addition occurs exclusively anti to the metal, but the complex is again isolated in low cdr. Finally, treatment of the dienone complex 38 with benzaldehyde resulted in ortho addition followed by elimination to provide the o-quinone methide 39. In contrast to organic quinone methides, which are observable only at very low temperatures,126 the tungsten-bound quinone methide complex 39 does not react with either electron-rich (e.g., 2,3η2-dihydrofuran) or electron-deficient dienophiles (e.g., Nphenylmaleimide); without the driving force associated with the formation of an aromatic benzene ring, the o-quinone methide ligand is rendered chemically inert. 3.2.3.3. 2H-Phenol C4,C5-Tandem Addition Reactions. Eventually, it was discovered that a single diastereomer of the dienone complex could be prepared in methanol, owing to differences in solubility (see Scheme 8). With this matter resolved, focus turned to the reactivity of the remaining π-bond. The uncoordinated double bond of 2H-phenol is highly activated by the electron-rich tungsten and readily undergoes reactions with electrophiles at C3 (formerly the meta carbon of phenol). Several highlights can be seen in Scheme 10 (44− 49).104,105,122,124,127 Given that electrophiles normally react at C2, C4, or the oxygen of phenol, the reactivity of 30 constitutes an umpolung in reactivity.106 Even strongly oxidizing reagents could be utilized, owing to the high d5/d6 reduction potential of the 2H-phenol complex. Thus, C3 could be hydroxylated, fluorinated, or brominated. All of these electrophilic additions were followed by additions of nucleophiles, with both additions occurring exclusively anti to the metal. In this manner, a full range of highly functionalized cyclohexenone complexes (44− 13731


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Scheme 11. Cyclobutanation of a Tungsten 2H-Phenol Complex

Scheme 12. Aniline and Anilinium Complexes of {WTp(NO)(PMe3)}a

a

Conditions: (a) Benzyl bromide or allyl bromide; (b) 1-bromobutan2-one; (c) methyl vinyl ketone, H+.

system103 and is prone to electrophilic addition at the uncoordinated terminus of the diene. Thus, treating the 2Hanilinium salt 58 with strong acid can result in a second protonation at C5 (58H).108 Although one could consider 58H a W(II) complex bound to an aminodiene, there is no indication that the organic ligand is bound η4, as would be expected for a 14e− {WIITp (NO)(PMe3)}2+ fragment. Rather, 58H behaves chemically and spectroscopically as a W(0) system with an allylic cation that can be chemically elaborated. Parenthetically, 183W−31P coupling constants for authentic 7coordinate W(II) species are relatively low, ranging from 100 to 200 Hz.87 In contrast, this dication has a JWP of 248 Hz, similar to other π-allyl species [cf. WTp(NO)(PMe3)(π-C3H5), 252 Hz]. The resulting dicationic allyl system readily reacts at the C4-position with nucleophiles as weak as electron-rich arenes and aromatic heterocycles (Scheme 13).108 Even oxidizing electrophiles can be added to the ring without compromising the metal complex, including 1-chloromethyl-4-fluoro-1,4diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (Selectfluor), N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), and m-chloroperoxybenzoic acid (mCPBA). Again, good coordination diastereomer control is maintained along with high regioselectivity for the addition reactions, and products such as 60−63 are isolated with dr >20:1. Furthermore, under Simmons−Smith conditions, cyclopropanation of 58 is observed.129 The cyclopropane ring of 64 can be ring-opened under strong acid conditions (pKa ≈ −10), functioning as a synthon for the addition of CH3+ to C3 of the aniline ring. If base is used to effect elimination (67), a

N−H insertion product 56 dominates when the tungsten benzene complex is combined with aniline itself.108 Although the purported η2-aniline complexes are unstable, the N,Ndimethylaniline variant (57) can be trapped as its conjugate acid (58) by use of diisopropylammonium triflate (DiPAT, pKa = 11.5). This method of acid-trapping converts the aniline into a potent π-acid, much in the same way that the phenol tautomerization does (section 3.2.3.1). The resulting 2Hanilinium species is now so stabilized that even acetonitrile solutions of triflic acid (pKa = −10) do not oxidize the metal. Instead, the 2H-anilinium undergoes a second protonation at the ring, this time at the meta carbon (vide infra). 3.2.4.1. C4-Addition Reactions. The 2H-anilinium complex 58 can be easily handled in air and is an excellent synthon for aniline species. As illustrated in Scheme 12, a solution of 58 treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) regenerates the neutral aniline species (57), which, if formed in the presence of a carbon electrophile, reacts to generate 4Hanilinium salts. Examples include MVK (59d), benzyl bromide (59a), allyl bromide (59b), and 1-bromobutan-2-one (59c). As with anisolium complexes, the asymmetric HOMO of the {WTp(NO)(PMe3)} system orients the positive charge at C1 of anilinium 58 away from the PMe3 ligand. As long as care is taken to avoid allowing the neutral aniline complex to stand in solution, a high cdr is maintained for the electrophilic addition products (59a−59d) (Scheme 12). 3.2.4.2. Tandem Addition Reactions of 2H-Anilinium Complexes. Even though it is a cation, the 2H-anilinium 58 acts like other η2-1,3-diene complexes of this tungsten 13732


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Scheme 13. Tandem Addition Reactions to C3 and C4 of 2H-Anilinium System 58a

Scheme 14. Cyclopropanation to C3 and C4 of 2HAnilinium System 58a

a

Conditions: (a) mCPBA; (b) NCS, MeOH; (c) Selectfluor, MeOH; (d) indole (cat. H+). a Conditions: (a) CH2I2, Et2Zn. (b) HOTf; 2-methylfuran. (c) HOTf; pyrazole. (d) HOTf; base. (e) CH2I2, Et2Zn; pyrazole. (f) CAN, H2O.

second cyclopropanation can be carried out (Scheme 14), which upon ring-opening and treatment with a suitable nucleophile generates compounds such as 68 that feature an installed gem-dimethyl group.129 The regio- and stereoselectivity of the addition reactions in Scheme 14 is high, with both electrophile and nucleophile adding opposite to the face of coordination. Oxidation and hydrolysis affords the organic enones 69 and 70. 3.2.4.3. Perhydroindole Syntheses. The chemistry outlined for anilines serves as the foundation for synthesis of several bicyclic alkaloids. For example, when N-methylindoline is combined with WTp(NO)(PMe3)(η2-benzene) and the weak acid DiPAT, a mixture of two indolinium complexes is formed, the desired 3aH-tautomer (ortho to nitrogen) and the 5Htautomer (para to nitrogen), in a 1.5:1 ratio, respectively.107 Fortunately, under the same reaction conditions, for the Nethyl analogue the desired tautomer 71 precipitates from an ether solution in a >10:1 ratio of coordination diastereomers. The reactivity of this 3aH-indolinium species is similar to that of the dimethylaniline analogue. Protonation occurs selectively at C4, providing a π-allyl species that reacts with a broad range of nucleophiles, including imidazole (74), pyrazole, amines (73, 76), indoles (72), furans (77), and silylated enolates (75) (Scheme 15).130 All additions of nucleophiles occur at C5 and anti to the metal, consistent with the regio- and stereoselectivity observed for N,N-dimethylaniline (vide supra). Similar reaction sequences were carried out with other electrophiles including Selectfluor (79), mCPBA (78), and CH2 (Simmons−Smith; 80), as shown in Scheme 16.130 These tetrahydroindolium complexes were next converted to hexahydroindoles via reduction of the iminium group with lithium aluminum hydride. Of note, weaker reducing agents that normally react

with iminium salts (e.g., NaBH4) fail in this application, owing to the strong backbonding from the tungsten into the iminium π* orbital. The final organic hydroindoles (81−88) were oxidatively released from the metal by use of NOPF6 (Scheme 17).130 3.2.5. Fluorinated Benzene Complexes. 3.2.5.1. Oxidative Addition of C−F Bonds. In 2007, a report was published that described the reaction of fluorobenzene with the WTp(NO)(PMe3)(η2-benzene) system.131 Instead of the expected η2-fluorobenzene complex, a seven-coordinate phenyl−fluoride complex was isolated (89) (Figure 9). While the C−F insertion chemistry is beyond the scope of this review,131 a DFT analysis and experimental data indicate that C−H insertion is also competitive with the dihaptocoordinated form. The reaction coordinate diagram determined for 89 is shown in Figure 10. It remains to be determined whether organic chemistry of the ring can be accessed, either by pre-empting the C−F insertion (see section 3.2.4) or driving the equilibrium back toward the dihapto form through chemical manipulations (see section 3.2.3.3). Interestingly, when the benzene complex is combined with 1,2,3,4-tetrafluorobenzene, the aryl hydride species 90 is the dominant product (Figure 11). It is unclear whether this is a consequence of an increased barrier to C−F insertion or a change in the thermodynamic profile. Alternatively, when α,α,α-trifluorotoluene or hexafluorobenzene is combined with WTp(NO)(PMe3)(η2-benzene), the η2-arene complexes 91 and 93 dominate. The trifluorotoluene complex 91 is particularly noteworthy in that it represents a stable η2-benzene 13733


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Scheme 15. Regio- and Stereoselective Protonation/ Nucleophilic Addition to Indolinium Complex 71a

Scheme 17. Novel Hexahydroindoles, with up to Four Stereocenters, Prepared from Indoline

a

Conditions: HOTf/CH3CN, followed by (a) indole, (b) propylamine, (c) imidazole, (d) MMTP, (e) morpholine, or (f) 2methylfuran.

Scheme 16. Regio- and Stereoselective Hydroxylation, Fluorination, and Cyclopropanation of Indolinium Complex 71

Figure 9. ORTEP diagram for complex 89, WTp(NO)(PMe3)(F)(Ph).

have involved the unadorned hydrocarbon. In the former scenario, the π-basic metal and π-donor substituent work in unison to activate the arene toward the first (and most difficult) electrophilic addition reaction. Conventional wisdom argues that an electron-withdrawing substituent will counteract the effect of the metal η2-bound to the arene. While this may be true, the metal still serves to disrupt aromaticity, and the withdrawing group could have a stabilizing effect on the arene complex, since lower-energy π* orbitals in the arene would enhance the backbonding interaction. The hope was that as the shift from Os to Re to W optimized the π-backbonding, a withdrawing group would not completely prohibit the arene from reacting with electrophiles and acids and might have a chemodirecting effect complementary to electron-donor groups. The trifluorotoluene complex WTp(NO)(PMe3)(η2-PhCF3) (91), like other neutral arene complexes, exists in solution as a mixture of two coordination diastereomers, with the metal binding across meta and para carbons. However, upon treatment with a strong Brønsted acid (HOTf/CH3CN; pKa

complex with a single withdrawing group. In the next section, the synthetic implications for this type of system are discussed. 3.2.5.2. α,α,α-Trifluorotoluene: Prototype for ElectronDeficient Arenes. Prior to this point in the review, and indeed for the entire history of rhenium and osmium dearomatization, all of the chemical transformations of η2-arene complexes have been enabled or influenced by electron-donating substituents or 13734


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Scheme 18. Elaboration of Trifluorotoluene through Sequential Tandem Additions

Figure 10. Reaction coordinate diagram for C−F and C−H insertion reactions of the complex WTp(NO)(PMe3)(FPh).

complex is subjected to these conditions, oxidation readily occurs (see section 3.2.1). For Re and Os, protonation followed by enolate addition results in 1,4-diene complexes.75 However, the diene ligand in 95 is conjugated, which allows a second protonation/nucleophile addition to be carried out. 132 Productive nucleophiles include enolates (99), cyanide (97), hydride, and amines (Scheme 18). Both the stereochemistry and regiochemistry are highly predictable, with the two nucleophiles adding in a cis orientation to the para and meta carbons of the original trifluorotoluene ring. As shown in Scheme 19, by switching the sequence of nucleophiles, the substitution pattern of the resulting cyclohexene can be adjusted systematically. Note that the second protonation occurs such that the CF3 group is oriented away from the metal. As a result, all the carbon substituents of the cyclohexene in 98, 100, 103, and 104 are mutually syn to each other.132 3.3. Dearomatization of Aromatic Heterocycles

Many aromatic heterocycles may also be utilized as substrates for the tungsten dearomatization agent {WTp(NO)(PMe3)}. However, care must be taken with aromatic heterocycles that can form a strong σ-bond through a heteroatom (e.g., pyridine). As with arenes, when dihapto-coordinated to tungsten, a heterocycle is activated toward electrophilic additions and cycloadditions. Electrophilic addition can be followed by various nucleophilic addition reactions. Aromatic heterocycles that have been successfully coordinated and

Figure 11. Dihapto-coordinated fluorinated benzenes and their C−H and C−F insertion isomers (the dominant isomers are boxed).

= −10), protonation occurs to give a single η2-arenium intermediate (94; Scheme 18). Upon addition of the silylated ester enolate 1-methoxy-2-methyl-1-trimethylsiloxypropene (MMTP), the diene complex 95 is produced and can be isolated in good yield (79%).132 In contrast, when the toluene 13735


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Scheme 19. Controlling Substitution Pattern of Alkylated Trifluoromethylcyclohexenes

Scheme 20. Wide Range of Products Resulting from Reaction of {WTp(NO)(PMe3)} with Various Alkylated Pyrrolesa

chemically elaborated include pyrroles,133,134 furan,135 and pyridines.109−111,113,114,136−138,100 3.3.1. Pyrrole Complexes. Pyrroles are available in a wide array of derivatives and in general are more reactive than arenes toward electrophilic addition. Alkylations typically are difficult to control, often resulting in polyalkylated pyrroles and oligomers.139 Therefore, activation through dihapto-coordination can be a useful tool for their chemical elaboration. Osmium(II)79−81 and rhenium(I)10,133,134 dearomatization agents are both able to η2-coordinate pyrrole across C2 and C3 and activate the ring toward electrophilic addition reactions at the uncoordinated β-carbon. Often this action is followed by the addition of a nucleophile to the α-carbon;134 however, studies involving tungsten pyrrole complexes largely have focused on ring-forming reactions. 3.3.1.1. Tautomerization and N−H Insertion Reactions. Just as was observed for rhenium,133 when {WTp(NO)(PMe3)} is combined with the parent pyrrole, oxidative addition across the N−H bond is observed (105). NMethylpyrrole (106), 2-methylpyrrole (108), 2,4-dimethylpyrrole (113), and 2,5-dimethylpyrrole (111) form dihaptocoordinate complexes with {WTp(NO)(PMe3)}. However, for cases where the nitrogen is unprotected, tautomerization readily occurs, analogous to what is observed for phenol complexes of tungsten (see section 3.2.3.1). In the cases of 2methylpyrrole and 2,5-dimethylpyrrole, a 3H-pyrrole is initially formed (108, 111).134 Over time, the 2-methylpyrrole analogue converts to a pyrrolyl hydride, and this species is also observed for 2,4-dimethylpyrrole (109, 113) and pyrrole itself (105). Calculations for WTp(NO)(PMe3)(η2-pyrrole) suggest that both C−H and N−H insertion isomers (i.e., pyrrolyl hydrides) are roughly 16 kcal/mol lower in energy than any dihaptocoordinated isomer. However, treatment of the pyrrolyl hydrides with acid can, in some cases, reverse this preference. Initially, the pyrrolyl ring undergoes protonation, as seen, for example, with the 2,4-dimethylpyrrole derivative 114 (Scheme 20). Over time, however, the protonated pyrrolyl hydrides convert back into dihapto-coordinated 2H-pyrrolium complexes such as 110 and 115. Of note, C−H insertion products

a ORTEP diagram shows (5H-2,4-dimethylpyrrolyl) hydride 114 (triflate omitted).

have not been observed to date, although they have been reported for the more Lewis-acidic system [CpRe(NO)(PPh3)]+ by Gladysz and co-workers.140 3.3.1.2. Dipolar Cycloaddition Reactions. Despite the indiscriminant nature of {WTp(NO)(PMe3)} with pyrroles, dihapto-coordinated isomers are accessible and exceedingly reactive toward electrophilic carbon reagents used in organic synthesis. For example, consider the η2-(3H-2,5-dimethylpyrrole) complex (111), which exists in equilibrium with its 1H tautomer (116). This isomer in turn has access to the azomethine ylide intermediate that, in the presence of dimethyl fumarate, undergoes a cycloaddition, leading to 7-azanorbornene products (117) (Scheme 21).134 Unfortunately, in contrast to the wide range of cycloadducts obtained from osmium−pyrrole complexes, this reaction for tungsten is presently of limited scope, owing to the propensity of the tungsten 1H-pyrrole complexes such as 106 to undergo Michael reactions at the β-carbon with would-be asymmetric dipolarophiles (e.g., methyl acrylate and MVK).134 3.3.1.3. Tetrahydroindole Syntheses. The 3H-tautomer of the 2,5-dimethylpyrrole complex is in equilibrium with the 1H 13736


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Scheme 21. Dipolar Cycloaddition Reaction of a Tungsten Pyrrole Complex

Scheme 22. Formation of Indole Core via a Michael−Aldollike Cyclization Sequence

form (116), and this isomer can react with enones at the βcarbon in a Michael fashion to form 3H-pyrrole complexes such as 118 in high cdr (>20:1). The addition happens regioselectively at the C3-position, with the electrophile adding exclusively anti to the metal. These Michael addition products can then undergo an intramolecular cyclization, via enamine (119) intermediates derived from the 2-methyl group. With MVK, for example, the ring closure, which forms a 4,5,6,7tetrahydroindole core (120, Scheme 22), also occurs stereoselectively, presumably due to a synclinal orientation of the carbonyl group in the transition state.112 Oxidation of the bicyclic product (120) with CAN results in the aromatized product (121) in moderate yield (63%). A similar reaction with cyclopentenone produces 122 in more modest yield (26%). 3.3.2. Furan and Thiophene Complexes. 3.3.2.1. Furan 2,3- and 2,5-Tandem Addition Reactions. Neutral tungsten η2-furan complexes, like their nitrogen counterparts, exist as mixtures of coordination diastereomers (cdr ∼2:1).135 They also can undergo protonation and addition of electrophiles at the uncoordinated β-carbon. However, in contrast to the η2pyrrole complexes, the 3H-furanium intermediate is susceptible to ring opening to form a vinyl cation complex (a carbene),141 similar to that observed for osmium and rhenium.142,143 Thus, the dominant modes of reactivity for these complexes are 2,3addition and 2,5-addition, as shown in Figure 12. Reactions reported for tungsten furan complexes generally parallel those observed for rhenium.97,116,144 They include 2,3addition of phosphonium salts and 2,5-addition of thiophenol.141 In addition to these intermolecular examples, two examples of intramolecular 2,3-addition reactions are illustrated in Scheme 23. 3.3.2.2. Furan Dipolar Cycloaddition Reactions. Furan complexes of the {WTp(NO)(PMe3)} system show reactivity of dipolarophiles similar to that with pyrrole complexes, but the furan system is significantly less activated than the nitrogen analogue. Nonetheless, the 2,5-dimethylfuran complex is

Figure 12. Different modes of chemical reactivity for a dihaptocoordinated furan.

activated. In particular, the 2,5-dimethylfuran complex is considerably more reactive than the parent furan, owing to destabilization by the methyl groups of the 2,3-η2 and 4,5-η2 isomers. It readily reacts through the 3,4-η2 intermediate with N-methylmaleimide, N-phenylmaleimide, and acrylonitrile at ambient temperature and pressure, leading to novel bicyclic products (e.g., 129 in eq 3).135 In comparison, the reaction of

acrylonitrile and free 2,5-dimethylfuran requires Lewis acids. Unfortunately, both the exo:endo selectivity and the cdr of the final products are poor,135 and the range of dipolarophiles that successfully add to tungsten η2-furan complexes is disappointingly limited. 13737


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Scheme 23. 2,3- and 2,5-Tandem Addition Reactions with Tungsten−Furan Complexes

Scheme 24. Reactions of Dihapto-Coordinated Thiophene Complexes of Tungsten

oxidation (132, 133) of the sulfur atom and protonation (130) or Michael addition (136) at the uncoordinated α-carbon. Notably, the thiophene complex can also be hydrogenated under 1 atm of H2, albeit with a low isolated yield (131).145 Furthermore, a sulfur ylide (135) appears to be accessible via the methylated thiophene complex 134, but this reaction manifold has not been widely explored. The only example of possible reactivity initiated by the β-carbon is the cycloaddition of dimethyl acetylenedicarboxylate (DMAD) to form a cyclobutene ring system (137).145 In this case, the initial Michael addition could be envisioned as initiating from either the α- or β-carbon. 3.3.3. Pyridine Complexes. 3.3.3.1. η2 versus κ-N Coordination. Pyridine dearomatization has been relatively late to develop, with virtually no examples reported for Os or Re. In contrast to pyrrole, pyridine has a basic nitrogen through which it can readily bind to {WTp(NO)(PMe3)}. However, ring substituents adjacent to the nitrogen inhibit such coordination, and η2-bound complexes can be achieved. Cyclic voltammetry is a particularly valuable tool for determining which binding mode dominates. When a pyridine is bound through the nitrogen, the strong σ-bond stabilizes the higher oxidation state [W(I)], and this shifts the reduction potential negative, close to −1 V (NHE). In contrast, when the pyridine is coordinated through a π-bond, the dominant interaction is πbackbonding, which stabilizes the W(0) oxidation state. Correspondingly, the reduction potential (as indicated by Ep,a) is close to 0 (NHE). Thus, as seen in Table 4, pyridine and 2-ethyl-, 3-methoxy-, and 4-methoxypyridine all form complexes through nitrogen, while 2-methoxy-, 2-dimethylamino-, and 2,6-dimethylpyridine all form dihapto-coordinated complexes with {WTp(NO)(PMe3)}.

3.3.2.3. Thiophene Alkylations and Oxidations. Relatively little has been reported for the organic chemistry of thiophenes coordinated to the {WTp(NO)(PMe3)} system. However, a preliminary study indicates significant differences compared to its oxygen analogue (Figure 13).145 The reduced ability of

Figure 13. Comparison of dihapto-coordinated furan and thiophene reactivity.

sulfur to form strong π bonds with carbon has two important consequences. Just as with the organic heterocycle, the sulfur in the tungsten thiophene complex is more nucleophilic and the carbons are less nucleophilic than for furan. Thus, whereas most reactions for η2-furan complexes are initiated by addition of an electrophile to the β-carbon,141 for thiophene complexes, practically all of the reported reactions take place at the sulfur or at the α-carbon, with the metal acting as the π-donor.145 These reactions (Scheme 24) include methylation (134) or 13738


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equilibrium of the lutidine complex (145) and its lutidinyl hydride (157) (t1/2 < 5 min). This C−H insertion appears to be similar to those observed for the benzene and fluorobenzene complexes (see section 3.2.5.1)131 in that its formation is both rapid and reversible and, from a synthetic perspective, relatively benign. As seen earlier, C−F and N−H insertions with tungsten have proven to be far less reversible and can sometimes preempt dearomatization reactions. 3.3.3.3. Diels−Alder Cycloaddition Reactions. The η2coordinated lutidine complex 145 functions as a 2-azadiene and, as such, readily reacts with acrylonitrile in a Diels−Alder cycloaddition, yielding a 2-azabicyclo[2.2.2]octadiene ligand (154) that can be oxidatively liberated from the metal and isolated (156; Scheme 25) in good yield.100 Similar reactions with other substituted pyridines, such as 2-DMAP (148) and 2,6-dimethoxypyridine (DMP) (146), provide a broad range of cycloaddition products (e.g., 153 and 154).114,136 Unfortunately, the dimethoxypyridine cycloadducts are isolated as ∼1:1 mixtures of coordination diastereomers. In the case of the DMAP-substituted complex, the dominant isomer (3,4-η2) is not the most reactive (eq 4). Prior to

Table 4. Formation of Dihapto-Coordinated Complexes with {WTp(NO)(PMe3)}

3.3.3.2. C−H Insertions. When WTp(NO)(PMe3)(η2benzene) is combined with 2,6-lutidine, two products are formed in a 3:1 ratio: the 3,4-η2-coordinated product (145) and the C4−H oxidative addition product (152; Scheme 25).100 Interestingly, when this mixture is treated with acid, the lutidinium complex 157 is formed as the only product (two coordination diastereomers). Deprotonation reestablishes an

cycloaddition, complex 148 isomerizes to a minor isomer (4,5η2), which in turn reacts with ethyl vinyl ketone (EVK) (148a). Similar cycloadditions were observed for N-methylmaleimide (92%), acrylonitrile (76%), and methyl acrylate (20%). By isomerizing prior to cycloaddition, the cycloadduct products have the highly stabilizing amidine functionality intact (vide infra). While exo:endo ratios vary, in all cases the cdr is >20:1. Organic pyridines are generally unreactive in Diels−Alder reactions owing to their aromatic nature. The only reports involving cycloaddition to a pyridine are those of Gompper and Heinemann146 and Neunhoeffer and Lehmann,147 who independently described the cycloaddition of dimethyl 2,6bis(dimethylamino)pyridine-3,4-dicarboxylate and DMAD. 3.3.3.4. New Aromatics from Azabarrelene Intermediates. With alkyne and nitrile dienophiles, new aromatic systems can be created via azabarrelene and diazabarrelene intermediates (Scheme 26). When the 2,6-dimethoxypyridine complex 146 reacts with DMAD, a cycloadduct forms that, upon oxidation with CuBr2, rearranges to form the tetrasubstituted benzene 161, which in turn spontaneously cyclizes into a phthalimide (162). When ethyl cyanoformate is used as the dienophile, nitrile metathesis occurs via the cycloadduct 163 to cleanly generate the η2-pyridine complex 164 (43% isolated). This type of reaction appears to be unprecedented for pyridine. 3.3.3.5. Acetylpyridinium and Dihydropyridine Complexes. For the parent pyridine, coordination at nitrogen pre-empts dearomatization of the heterocycle. However, pyridinium compounds provide a solution: while pyridinium triflate and methylpyridinium triflate oxidize the {WTp(NO)(PMe3)} system,137 the pyridine−borane adduct readily forms a πcomplex with {WTp(NO)(PMe3)} (164), which can be isolated as a 3:1 mixture of coordination diastereomers.137 Addition of acid in acetone effects the removal of the protecting

Scheme 25. Diels−Alder Cycloaddition Reactions with Various Dihapto-Coordinated Pyridine Derivatives

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charge of the ligand, backbonding from the tungsten in 166 polarizes the C5−C6 bond such that strong electrophiles can add to C6, and this action is immediately followed by nucleophilic addition to C5 (Scheme 28, upper path). At this

Scheme 26. Generation of New Aromatic Systems from Dihapto-Coordinated Pyridines via (A) Azabarrelene and (B) Diazabarrelene Intermediates

Scheme 28. Two Approaches to Elaboration of Acetylpyridinium Complex into Tetrahydropyridines

point, a second nucleophile can be added to C2, providing a tetrahydropyridine (THP) complex. An example is shown with the action of Selectfluor in methanol, followed by either hydride or cyanide addition (Scheme 29).

group, and subsequent protonation of the nitrogen prevents the complex from reverting to the nitrogen-bound isomer. Yet, when this pyridinium complex (165) is combined with acetic anhydride along with 2,6-di(t-butyl)pyridine base (DTBP), the acylpyridinium complex (166) can be synthesized in over 90% yield and with a cdr >10:1 (Scheme 27). Complexes derived from 166 typically can be precipitated and isolated with cdr > 20:1. 3.3.3.6. Tetrahydropyridine Syntheses. The acetylpyridinium synthon 166 is exceptionally versatile. Even with the withdrawing acyl group on nitrogen and the overall positive

Scheme 29. Examples of Electrophile-Initiated Dearomatization of Acetylpyridinium Complex

Scheme 27. Coordination of Pyridine−Borane Adduct and Subsequent Conversion to an Acetylpyridinium Synthon for Pyridine Addition Reactions

Alternatively, a nucleophile can be added to C2 of the acetylpyridinium complex 166 to generate a dihydropyridine complex (DHP). While the uncoordinated portion of the DHP ligand appears to be an enamide, the C5−C6 bond is polarized by π-donation, not from the nitrogen but from the tungsten, such that C6 is now nucleophilic (Scheme 28, lower path). Thus, C6 can be readily protonated to form a π-allyl complex, which upon reaction at C2 with an additional nucleophile delivers a tetrahydropyridine complex. The range of nucleophiles for this pathway is exceptionally broad,111 and several examples of the syntheses of dihydropyridine complexes (172− 179; Scheme 30) and tetrahydropyridine complexes (180 and 182; Scheme 31) are shown below. As with η2-arene complexes, these reactions are highly regio- and stereoselective. Finally, the metal can be oxidatively removed to provide novel tetrahydropyridines (181 and 183) synthesized from pyridine.109−111,113,114,137,138 In comparison, organic acylpyridinium16,17 or η6-pyridine complexes18 typically require strong nucleophiles to overcome the aromatic stabilization of the 13740


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Scheme 30. Examples of Nucleophile-Initiated Dearomatization of Acetylpyridinium Complex To Form Dihydropyridine Complexesa

Scheme 32. Cyclocondensation Reactions of Dihydropyridine Complexes with C−C, C−N, and N−O Electrophilesa

a

Isolated cdr >10:1; dr >20:1.Conditions: (a) TMSCN, DABCO; (b) Et2Zn; (c) indole, 2,6-lutidine; (d) MeMgBr; (e) Zn, methyl bromoacetate; (f) allyl bromide, Zn; (g) MeLi,TMSCCH, ZnBr2; (h) MeNO2, NEt3.

Scheme 31. Further Elaboration of Dihydropyridine Complexes into Tetrahydropyridine Analogues a

For 184−191, cdr >20:1.

effective in forming cycloadducts. When tosyl isocyanate was added to DHP complexes 173, 176, and 177, the [4 + 2] cycloadducts were formed (187−189), rather than the anticipated [2 + 2] isomers. Note that the electrophilic portion of alkene, nitroso, or isocyanate adds to C6 of the DHP ring, consistent with the nucleophilic nature of the dihaptocoordinated diene fragment (see Figure 6). In all of these cyclocondensation reactions, products are obtained with cdr > 20:1. 3.3.3.8. The Special Case of 2-Dimethylaminopyridine. The chemistry of 2-DMAP is considered separately from other pyridines in this review because of the powerful influence of the latent amidine functional group (Scheme 33). Recall that when the 2-DMAP complex was combined with various dienophiles, cycloadducts were formed that conserved the amidine functionality, even if it meant shifting the metal to a less stable pyridine isomer prior to cyclization (eq 4; amidine shown in red).100 In many ways, the better parallel for the tungsten 2DMAP complex is with N,N-dimethylaniline. As discussed earlier (Scheme 13),108 when this arene is coordinated to tungsten, it can undergo sequential addition of two electrophiles to the aromatic ring followed by reaction with a nucleophile. Similar chemistry is observed for the pyridine analogue, where typically the first electrophile is a proton. In the case of 2-DMAP, protonation creates the exceptionally stable amidinium fragment 192, which renders the remaining portion of the complex chemically similar to an η2-diene. Not only are hydroarylation reactions possible (e.g., 194 and 195),

pyridine ring. Also, without the use of directing groups, such nucleophilic additions can show poor regioselectivity.16,17 3.3.3.7. Dihydropyridine Cyclization Reactions. Dihydropyridine complexes such as 172−179 (Scheme 30), having η2diene character, also should be able to undergo cyclization reactions analogous to those [2 + 2] cyclizations observed for 2H-phenol tungsten complexes (Scheme 11) or the [4 + 2] cyclizations seen with rhenium−naphthalene complexes (Scheme 2, 9). The addition of alkene dienophiles such as methyl vinyl ketone (MVK) or cinnamaldehyde was accomplished by use of Yb(OTf)3 or BF3·Et2O catalysts to effect formation of azabicyclooctene complexes 190 and 191 (Scheme 32; Figure 14). When nitrosobenzene (NOB) was combined with DHP complexes 173, 176, and 177, novel oxadiazabicyclo[2.2.2]octenes were formed (184−186). Nitroso Diels−Alder reactions with dienes are a valuable source of heteroatom incorporation into structural frameworks.148−151 Isocyanates, the nitrogen congeners of ketenes, also are 13741


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Scheme 33. Comparison of N,N-Dimethylaniline and 2Dimethylaminopyridine Systems and the Special Amidine Character of 2-Dimethylaminopyridine

4. ORGANIC REACTIONS EFFECTED BY MOLYBDENUM η2-COORDINATION 4.1. Molybdenum Arene Complexes

The molybdenum complex {MoTp(NO)(PMe3)} is incapable of forming stable complexes with aromatics, owing to the reduced ability of the second-row metal to engage in backbonding. However, the N-methylimidazole analogue {MoTp(MeIm)(NO)}, forms stable complexes with naphthalene, anthracene, thiophene, and furans.152,153 The Mo(I) precursor, MoTp(MeIm)(NO)(I), can be made on 40 g scale from Mo(CO)6, and without chromatography, and this universal precursor can then be reduced with Na0 in the presence of an arene to form MoTp(MeIm)(NO)(η2-arene). 4.1.1. 4-Dimethylaminopyridine: An Acid-Modulated Auxiliary Ligand. One drawback to the {MoTp(NO)(MeIm)} system is its sensitivity toward metal oxidation. Consequently, the scope of electrophiles that could be added is limited. To counteract this, the MeIm ancillary ligand can be replaced with 4-dimethylaminopyridine (4-DMAP). The DMAP ancillary ligand is roughly parallel to MeIm as a σdonor, but the dimethylamino substituent can be protonated, an action that helps to inhibit metal oxidation (Figure 15).154 Thus, the DMAP system provides improved yields compared to MeIm and is better able to tolerate alkylating reagents employed in organic synthesis, such as acetals and Michael acceptors (vide infra). 4.1.2. Tandem Addition Reactions with Naphthalene and Anthracene. 4.1.2.1. 1,2-Addition Reactions. The {MoTp(NO)(DMAP)} and {MoTp(NO)(MeIm)} systems form complexes with naphthalene and anthracene (200) that show similar stabilities with regard to substitution. But as mentioned above, the DMAP system shows an increased tolerance toward oxidation at the metal. In Table 5, results are

Figure 14. Molecular structures of isocyanate cycloadduct 189 and nitroso cycloadduct 186.

but electrophiles as harsh as Selectfluor can be used without oxidation of the metal (e.g., 197; Scheme 34). 3.3.4. Pyrimidine Diels−Alder Cycloaddition Reactions. Like their pyridine cousins, pyrimidines and pyrazines bind tungsten through nitrogen, where the complex benefits from both σ- and π-stabilization in the metal−diazine bond. For the parent complex WTp(NO)(PMe3)(κ1-pyridine), the κ-N and C,C-η2 isomers are separated by ∼15 kcal/mol, and this makes any chemistry occurring through the dihapto-coordinate species sufficiently slow at ambient temperature that oxidation of the metal will typically pre-empt cycloaddition.141 However, when a solution of WTp(NO)(PMe3)(κ1-pyrimidine) is allowed to stand in the presence of either methyl acrylate or acrylonitrile, over a period of several days, an aza-Diels−Alder reaction takes place (Scheme 35). In both cases (198 and 199), the ring carbon between the pyrimidine nitrogens (C2) forms a bond with the β-carbon of the dienophile. This regioselectivity is in contrast to that seen with the tungsten−pyridine complexes, in which the β-carbon of acrylonitrile bonds to C3. While the reaction with acrylonitrile results in four diastereomers (exo/endo and coordination diastereomers), the acrylate cycloaddition is highly diastereoselective. Attempts to remove the metal from these cycloadducts were unsuccessful. 13742


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Scheme 34. Dearomatization Reactions with 2Dimethylaminopyridine Complex

Scheme 35. Diels−Alder Reactions with DihaptoCoordinated Pyrimidine

shown that compare the yields of various dihydronaphthalenes and dihydroanthracenes prepared from protonation at C1 followed by addition of a carbon nucleophile at C2. Treatment with iodine or oxygen liberates the final organic dihydronaphthalene or dihydroanthracene (202). The regioselectivity observed for 1,2-addition (>20:1) is superior to that of the {ReTp(CO)(L)} systems.85 However, diastereoselectivity is only moderate: While the cdr values of η2dihydronaphthalene complexes (201) (ranging from 5:1 to 7:1) represent an improvement from those observed for the arene precursor complexes (∼3:1), they are not as high as those observed in the {ReTp(CO)(L)} systems (>20:1).85 The high cdrs seen for the heavy metal system can be attributed to the high stereoselectivity of the arene complex in the solid state (Figures 16, 17).155 The MoTp(NO)(MeIm)(η2-naphthalene) complex exists as a single diastereomer in crystalline form as well (B).155 However, for the molybdenum systems, equilibration of the allyl structures C and D appears to be too rapid to give a high cdr for the product. Furthermore, while D is the lowest-energy isomer (DFT calculations, electrophile = H, ligand = DMAP), it apparently is not favored enough to provide a high cdr. 4.1.2.2. 1,4-Addition Reactions. A limited number of Michael acceptors and acetals have been successfully added to C1 of naphthalene or anthracene. Reaction of the arene complex 200 with these carbon electrophiles creates an

Figure 15. Strategy of using acid-modulated σ-donor DMAP.

arenium system that is similar to that observed for protonation. However, just as observed for the rhenium systems, the bulkier substituent tends to guide the subsequent nucleophilic addition to C4 rather than C2 (Figure 16, isomers E and F; Table 6, 203).118 The coordination diastereomer ratio for these reactions typically was not determined. The one exception was for addition of dimethoxypropane to anthracene, where the cdr was found to be 10:1, favoring the nucleophile proximal to DMAP (isomer H in Figure 16). Treatment with iodine or oxygen liberates the final dihydronaphthalene or dihydroanthracene products (204). 4.1.3. Progress toward Molybdenum Benzene Complexes. Compared to the heavy-metal analogues, the weaker metal−arene bond strengths for Mo present a challenge in synthesizing benzene complexes.88 DFT calculations and 13743


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Table 5. Comparison of {MoTp(NO)DMAP} and {MoTp(NO)MeIm} Systems

Figure 17. Molecular structure determinations of MoTp(NO)(DMAP)(L) and MoTp(NO)(MeIm)(L), where L = methyl 2-(1,2dihydronaphthalen-2-yl)-2-methylpropanoate.

roughly 8 kcal/mol less stable, owing to less efficient backbonding by the second-row metal. This situation is improved by replacing the PMe3 ligand with electron-rich nitrogen heterocycles such as DMAP, which raise the M−L bond strength from ∼18 to ∼21 kcal/mol. But until recently, it was thought that MoTp(NO)(DMAP)(η2-benzene) was too unstable to isolate. However, the addition of a single CF3 group to the benzene ring raises the metal−arene bond strength by an additional 3 kcal/mol, allowing for convenient isolation of the complex MoTp(NO)(DMAP)(η2-TFT) (where TFT = α,α,αtrifluorotoluene).88 This TFT complex can be prepared in pure form, without chromatography, on a 37 g scale (65−70%) from MoTp(NO)(DMAP)(I). Further, when 5 mg of the TFT complex is dissolved in 1 mL of neat benzene, the ratio of benzene to TFT is sufficiently large that the benzene complex MoTp(NO)(DMAP)(η2-benzene) is observed in solution as the major species (>90%). The benzene complex can also be formed by sodium reduction of MoTp(NO)(DMAP)(I) in neat benzene solvent (∼70% yield by NMR and cyclic voltammetry; 11% isolated). The half-life for substitution is roughly 30 s at 20 °C, but this key result provides proof of concept for accessing the entire family of aromatic complexes accessible by the heavy metals. 4.1.3.1. Trifluorotoluene. When a solution of the molybdenum trifluorotoluene complex is treated with triflic acid (−60 °C) followed by MMTP, a substituted η2-1,3-cyclohexadiene complex is cleanly formed, analogous to the tungsten analogue 95 (Scheme 18). Both protonation and nucleophilic addition reactions are highly regioselective, and the addition of this masked enolate is also stereoselective, with addition occurring

Figure 16. Formation and isomerization of naphthalenium intermediates leading to different regio- and stereoisomers. Isomer G is favored when the electrophile is a hydrogen; isomer H is favored otherwise.

substitution kinetics data indicate that the complex WTp(NO)(PMe3)(η2-benzene) has a M−L bond strength (∼ΔH⧧) of about 26 kcal/mol (see Table 1), allowing its synthesis, isolation, and spectroscopic characterization at ambient temperature. In comparison, the molybdenum analogue is 13744


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Table 6. Reactions of MoTp(NO)(DMAP) with Acetals and Michael Acceptors

Scheme 36. Synthesis of Trifluoromethylated Dienes from Trifluorotoluene Promoted by Molybdenum

DMAP or MeIm and substrate = naphthalene, anthracene, or TFT (Scheme 37).156 Scheme 37. Recycling a Molybdenum Dearomatization Agent

anti to the metal (Scheme 36).88 As with the tungsten analogue, the cdr for the diene complexes is >20:1. When iodine is used as the decomplexation agent, the Mo(I) iodide precursor can be recovered in 89% yield, and the organic diene 207 is isolated in 46% yield. A similar reaction sequence was successfully carried out with N-methylpyrrole as the nucleophile (208; 52% yield). These yields are similar to those obtained with tungsten (vide supra) and can be carried out on a large scale, with efficient recycling of the MoTP(NO)(DMAP)(I) fragment. 4.1.4. Recycling Dearomatization Agents. As seen in section 4.1.3, iodine effectively oxidatively releases the molybdenum diene organics 207 and 208 and returns the Mo(I) precursor in good yield. Aside from the reduced cost of the complex, what sets the molybdenum dearomatization agent apart from the tungsten fragment is its ability to undergo oxidation to Mo(I) without overoxidizing to Mo(II). MoTp(NO)(L)(η2-alkene) complexes have d5/d6 reduction potentials about 200 mV lower than those of tungsten (L = MeIm, DMAP).156 This lowered reduction potential allows for easier removal of the organic ligand with milder oxidants (e.g., I2), and the resulting Mo(I) species, MoTp(NO)(L)(I), is more stable to further oxidation: the d4/d5 reduction potential is roughly 300 mV more positive for MoTp(NO)(DMAP)(I) than for WTp(NO)(PMe3)(I). As a result, decomplexation can be achieved (up to 1 g of organic product) with I2, and MoTp(NO)(L)(I) can be recycled (80−90%), where L =

4.2. 1,3-Diene Complexes and Cyclization Reactions

This section focuses on the ability of {MoTp(NO)(MeIm)} to promote cyclization reactions with η2-1,3-cyclohexadiene. Although they are not aromatic substrates, η2-1,3-cyclohexadiene complexes are products of many of the dearomatization reactions in this review, as well as being integral components of dihapto-coordinated arenes such as η2naphthalene, the 2H-tautomer of η2-phenols, and η2-(2H13745


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anilinium) complexes. As discussed in several earlier sections of this review, η2-1,3-diene complexes can undergo reactions with a Michael acceptor at the terminal unbound carbon of the diene, with the metal activating this reaction through πbackbonding. The resulting π-allyl complex is highly electrophilic and can react with a nucleophile at either end of the allyl ligand (see Scheme 32). In the case of MoTp(NO)(MeIm)(η21,3-cyclohexadiene), upon Michael addition, the resulting enolate (209) cyclizes to form the bicyclo[2.2.2]octene core (210, Scheme 38).157 The complex is isolated with a 6:1

Scheme 39. Strategy for Achieving High Enantioenrichment

Scheme 38. [4 + 2] Cyclocondensation Reactions with Michael Acceptors and a Mo η2-Cyclohexadiene Complexa

5.1. Chemical Differentiation of Diastereomers: The α-Pinene Strategy

a

The strategy previously employed with {ReTp(CO)(MeIm)} and {WTp(NO)(PMe3)} systems to resolve the metal stereocenter used α-pinene.85,99 Once the metal stereocenter was resolved, enantioenriched organic products were obtained from both systems [five examples; enantioenrichment (ee) ranges from 80 to 96].96,98,99 The only example with tungsten involved combining the benzene complex with (R)-α-pinene (Scheme 40). Of the two possible diastereomers, one combination is much more stable than the other toward displacement of the pinene. Hence, (R)-α-pinene forms a highly stable complex with the R form of {WTp(NO)(PMe3)} but is readily displaced from the S form, and the lutidine solvent can replace the terpene to form (S)-157 (after protonation). Following deprotonation and separation from the other diastereomer, the lutidine complex (S)-145 is reacted with acrylonitrile to form the cycloadduct (S)-154. Oxidative removal from the metal and HPLC analysis reveals that the cycloadduct (S)-156 has an enantiomer ratio of 90:10 enantioenriched. Unfortunately, half the tungsten is sacrificed, and recovered yields of the lutidine complex are low.

cdr ≈ 1.5:1 for all products.

endo:exo ratio, but unfortunately, it is isolated with low coordination selectivity (cdr ≈ 1.5:1), exactly mirroring that of the diene complex it originated from. Oxidation with Ag+ or air removes the bicyclic product (211). Even bulky enones undergo this reaction with what is normally a very hindered and sluggish diene, albeit in lower yield than less hindered Michael acceptors (212−216). In the case of ethyl vinyl ketone, the cyclohexadiene complex successfully reacts in methanol without the aid of any Lewis acid (60%).157

5.2. Separation of Diastereomeric Salts

A more global strategy for tungsten was ultimately achieved via protonation of an arene complex by use of a chiral acid.158 The resulting diastereomeric salts were then separated and deprotonated to recover both hands of the arene complex in enantioenriched form. Specifically, 1,3-dimethoxybenzene complex was found to react with L-dibenzoyl tartaric acid (LDBTH2) to produce a 1:1 ratio of the diastereomeric salts [(R,R)-219 and (S,R)-219, Scheme 41]. Once these salts were isolated in pure form, they could be stirred in a butanone/water solution to cause one to precipitate from the other.158 Subsequent treatment with base regenerated the neutral η2dimethyoxybenzene complex, which could be used directly or converted into the enantioenriched η2-coordinated benzene complex 220.

5. CONTROLLING ABSOLUTE STEREOCHEMISTRY Influencing the absolute stereochemistry of the final organic products depends on both the interaction of a prochiral aromatic ligand with the metal stereocenter (re and si faces; see eq 1) and control of the metal stereocenter itself (R and S) (Scheme 39). Earlier sections of this review addressed the issue of controlling the coordination diastereomer ratio, and numerous examples have been provided where the cdr of the final product complex is >20:1. This section describes efforts to control the absolute stereochemistry of the dearomatization agent. 13746


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fluorinated cyclohexenes.132 Four examples are provided of such products, with ee values ranging from 92 to 99 (Scheme 42). Of course, the true value in this approach is that virtually

Scheme 40. α-Pinene Strategy Applied to Pyridine Cycloaddition

Scheme 42. Preparation of Enantioenriched Trifluoromethylated Cyclohexadienes and Cyclohexenes

Scheme 41. Enantioenrichment of WTp(NO)(PMe3)(benzene) 220

any aromatic system can be used with the resolved tungsten system as a scaffold to prepare enantioenriched organic products.

6. REMAINING CHALLENGES AND FUTURE DIRECTIONS 6.1. Resolution of MoTp(NO)(L) Systems

The molybdenum chemistry outlined in section 4 offers some practical advantages over tungsten in terms of scale and recyclability. However, obtaining enantioenriched organics is still a challenge. Earlier work demonstrated that racemic ReTp(CO)(MeIm)(η2-benzene) and WTp(NO)(PMe3)(η2benzene) react with α-pinene to form two diastereomers, differing by the configuration of the metal stereocenter. These isomers have differing substitution rates.85 Whereas the matched isomer is inert, even at elevated temperature, the mismatched diastereomer undergoes displacement of the pinene for other unsaturated hydrocarbons, with retention of the metal stereocenter [e.g., (S,S)-95]. In analogous fashion, the complex (S,S)-MoTp(NO)(DMAP)(η2-α-pinene) [(S,S)-224] can be synthesized in moderate yield (∼50%) by reducing MoTp(NO)(DMAP)(I) in the presence of (S)-α-pinene. In this case, the weaker π-base {MoTp(NO)(DMAP)} cannot sufficiently compensate for the steric interaction of the alkene methyl group with the pyrazole trans to the NO (Figure 18,

By a modification of the procedure outlined above, the trifluorotoluene complex can be prepared from the dimethoxybenzene complex, and used to prepare highly functionalized 13747


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Scheme 43. Proposed Mechanism for Redox-Catalyzed Substitution of Alkene for Aldehyde or Ketone Ligand

Figure 18. Matched and mismatched isomers of the complex MoTp(NO)(DMAP)(α-pinene).

shown in red for (R,S)-225), and only the matched form is isolated from the reaction mixture (Figure 18).159 In contrast to that observed for rhenium, the matched α-pinene isomer (S,S)224 is able to undergo substitution with a wide range of unsaturated ligands under ambient conditions, including trifluorotoluene. Unfortunately, under ambient conditions, the metal complex racemizes during the substitution process. These observations are consistent with a mechanism in which dissociation of the α-pinene ligand results in a square pyramidal intermediate that can rapidly invert. DFT calculations indicate that the enthalpic activation barrier (ΔH*) to this inversion is only 8 kcal/mol, with the transition state approximating a trigonal bipyramidal structure. However, complexation of the incoming ligand (L) should have an enthalpic barrier approaching 0, so the main factor contributing to the activation free-energy barrier comes from the negative entropy expected for an associative process. Thus, ligand addition to the square planar intermediate could pre-empt racemization, provided that the concentration of L is sufficiently high and temperature is reduced. Consistent with this premise, the extent of epimerization appears to be highly sensitive to temperature.159 At 15 °C, racemization can be minimized. Unfortunately, at this temperature direct substitution of the α-pinene complex is impractically slow. However, by starting with the α-pinene complex (S,S)-224, oxidizing this species to (R)-MoTp(NO)(DMAP)(I) with iodine, and then reducing this Mo(I) compound in trifluorotoluene at 15 °C, the enantioenriched trifluorotoluene complex can be prepared with an ee as high as 95. This is a work in progress, but preliminary observations indicate that enantioenriched dearomatization with molybdenum is an obtainable goal.159

molybdenum complexes may be realized by preparing them through Mo(I) intermediates (vide supra). In principle, a redox catalysis approach could be used to catalyze substitution reactions with other aromatic ligands and for other metals, provided that the active form of the catalyst [M(I)] is not intercepted by a σ-donor ligand that could shift the potential out of range. In addition, isomerizations and chemical transformations could be catalyzed in this manner, provided, of course, that they are thermodynamically favorable (Scheme 44) and that a redox catalyst is chosen with the appropriate formal reduction potential (E° for [O]/[R]). Scheme 44. Proposed Redox-Catalyzed Synthetic Manipulations with Mo or W

6.2. Manipulation through Redox Catalysts

The molybdenum α-pinene complex (S,S)-224 undergoes substitution with most ligands over several days. With aldehydes and ketones, the process can be greatly accelerated with 0.1 equiv of a one-electron oxidant such as [Fe(Cp)2]PF6. This redox-enabled substitution mechanism appears to be facilitated by an η2/κ1 equilibrium of isomers for these η2carbonyl complexes (225 and 226) and their widely differing reduction potentials, which depend on their coordination geometries. The proposed reaction mechanism is shown in Scheme 43 for generic alkene and aldehyde ligands. Remarkably, when the aldehyde is chiral and enantioenriched (e.g., (1R)-myrtenal), conversion from the pinene complex (S,S)-224 to the (1R)-myrtenal complex takes place with complete retention of stereochemistry. These observations suggest that more efficient routes to enantioenriched 13748


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6.3. Utilization of Bound Carbons

oxidizing the metal, an electrophilic allyl may be generated that can effectively undergo an SN2′ reaction, resulting in allylic inversion (shown in red).160,161 Alternatively, when heteroatoms are attached to the bound alkene, or perhaps even a carbon bearing a π-withdrawing group (Π), ring opening could be induced, passing through an η2-vinyl cation (a metallocyclic carbene) intermediate.162 In the presence of a suitable alkene, acetylene, imine, nitrile, etc., a net ring expansion can occur prior to oxidation of the metal (shown in purple). Such a ring expansion has been observed for osmium vinyl ether complexes.162

The vast majority of reaction sequences described in this review conclude with an oxidative decomplexation step, which deprotects the final alkene. However, the potential exists to utilize these bound prochiral carbons, with the metal influencing the stereochemistry of their chemical elaborations. Exploration in this regard would include classical organometallic transformations such as oxidative addition/insertion/ reductive elimination sequences (eq 5) and oxidation/ nucleophilic addition sequences (eq 6).

6.4. Adjacent Ring Activation

The highly π-basic nature of the MTp(NO)(L) systems can also serve a useful purpose by activating an aromatic ring to which the complex is not directly attached. Several proposed examples are shown in Scheme 45, some the products of Scheme 45. Examples of Adjacent-Ring Activation: Using the Dearomatization Agent as an Electron-Donor Group for Electrophilic Aromatic Substitution However, there are also numerous opportunities to take advantage of the allylic and vinylic properties of the complexes prepared from aromatics. In Figure 19, generic representations of known dihapto-dearomatization reaction sequences are summarized. Note how many of them result in nucleophiles in an allylic position (shown in red). Through the process of

dearomatization and some not, where the metal enhances the ability of a conjugated aromatic ring to undergo electrophilic aromatic substitution. This effect with pentaammineosmium(II) has been documented for a β-vinylpyrrole complex54,60 and with ReTp(CO)(MeIm) for a dihydronaphthalene,83 but in general this avenue has not been well explored. This would be particularly attractive for complexes resulting from a dearomatization reaction of a bicyclic aromatic (e.g., naphthalene or quinolone), since the metal is already present. 6.5. Application to Medicinal Chemistry: Escaping “Flatland”163

With the advent of high-throughput bioassays and smallmolecule libraries (e.g., PubChem or DrugBank) and academic and commercial programs to identify potential leads for new pharmaceuticals (e.g., Lilly’s Open Innovation drug discovery program), new synthetic methods are desired by the medicinal chemistry community, which would allow the rapid stereoselective synthesis of novel molecular frameworks.2 Most molecular libraries currently utilized in drug development contain largely flat molecules, lacking asymmetric carbons. This

Figure 19. Dominant reaction patterns (known) and hypothesized allyl inversion (red) and vinyl insertion (purple) elaborations. 13749


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is due in large part to the abundance of reliable methods for coupling and substituting aromatic molecules.163 Yet, as molecular topology is increasingly considered to be an important factor influencing pharmacokinetics of biologically active substances,164 medicinal chemists seek more complex structures with multiple carbon stereocenters. A recent analysis by Brown and Boström1 found that, of the current methods used in discovery chemistry, none were discovered in the past 20 years, and only two (Suzuki−Miyaura and Buchwald− Hartwig) were discovered in the 1980s and 1990s. The authors lament the fact that this has led to an overpopulation of certain types of molecular shapes and properties to the exclusion of others, which limits the effectiveness of current molecular libraries. In other words, the diversity of a chemical library is limited by the diversity of available chemical reactions. The group 6 dearomatization agents described herein do not represent a single new chemical transformation. Rather, they enable countless new functional groups derived from aromatic precursors that naturally lead to new substances of potential medicinal significance.1 Conventional wisdom holds that the most valuable synthetic methodologies are those that are sufficiently mild and selective that they can be utilized in late-stage synthetic sequences. But the vast majority of recent advances in methodology optimize existing methods, making them faster, more selective, milder, greener, etc., but in the end, it is the same chemical bond that has been achieved. While dihapto-coordinate dearomatization may not always fit the requirements of a late-stage transformation, the true value of this methodology comes from the plethora of new functional groups resulting from a broad range of dihapto-coordinated aromatic precursors and the exceptional structural diversity derived from them. Once the metal is bound to an aromatic system, the access to new chemical transformations, coupled with the exceptional regioselectivity and stereoselectivity often observed, allows the rapid practical scale (up to 1 g) preparation of substances that would be virtually impossible to prepare by conventional means. Figure 20 illustrates the diversity of polycyclic frameworks that have been generated by these dearomatization methods originating from a simple aromatic substrate.

Figure 20. Diversity in polycyclic cores derived from simple aromatics.

behavior of practically any organic molecule with a lone pair of electrons, so too can these metals alter the chemical nature of any molecule with a π-bond.

AUTHOR INFORMATION Corresponding Author

*E-mail [email protected]. ORCID

W. Dean Harman: 0000-0003-0939-6980 Author Contributions

This review is dedicated with gratitude to William H. Myers, who for more than 25 years helped train and inspire the many researchers that have contributed to the work described in this review. Notes

The authors declare no competing financial interest.

7. CONCLUDING THOUGHTS With the development of group 6 dearomatization agents over the past decade, the methodology of using η2-binding to activate aromatic molecules toward addition reactions has become considerably more practical. Large-scale and low-cost precursors, the broad range of reactions and substrates that can participate in these reactions, and the high regio- and stereoselectivity of these reactions could one day make this unconventional approach to aromatic chemistry an appealing new tool for drug discovery. This is particularly true with regard to accessing new chemical space. With tungsten, entirely new avenues of pyridine, phenol, and aniline chemistry have been discovered: reaction sequences that were not possible with the rhenium and osmium predecessors of the {WTp(NO)(PMe3)} system. And while the molybdenum complex {MoTp(NO)(DMAP)} ($1.40/mmol; all materials), when compared to {WTp(NO)(PMe3)} ($15/mmol), presently has a narrower range of substrates that can be coordinated, the lower cost, large scale, and recyclability are attractive features of the second-row metal. Perhaps most exciting is the extraordinary range of possible applications that these metal complexes may find over time. For just as a Lewis acid can modify the chemical

Biographies Benjamin Kaufman Liebov obtained his undergraduate degrees in chemistry and English from Muhlenberg College in Allentown, PA. There he conducted undergraduate research in synthetic inorganic chemistry under Dr. Joseph M. Keane in the pursuit of chiral metal fragments that could activate aromatic molecules. He continued his research in the metal activation of aromatics at the University of Virginia in Charlottesville, VA, under the mentorship of Dr. W. Dean Harman. After earning his Ph.D. in 2016, Dr. Liebov accepted a postdoctoral research position in the Department of Radiology at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, PA. Presently, under the direction of Dr. Anatoliy V. Popov, Dr. Liebov synthesizes novel near-infrared fluorescent imaging probes to be used for the detection of breast cancer. W. Dean Harman was born in 1960 in Stanford, CA. He received his B.Sc. from Stanford University in 1983. He remained at “The Farm” to attend graduate school under the guidance of Professor Henry Taube. In 1987, he received his Ph.D. from Stanford and stayed on as a research associate with Taube until 1989, when he joined the faculty at the University of Virginia. In 1997, he was promoted to full professor 13750


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(17) Rundle, R. E.; Goring, J. H. Structure of the Silver PerchlorateBenzene Complex. J. Am. Chem. Soc. 1950, 72, 5337. (18) Browning, J.; Green, M.; Spencer, J. L.; Stone, F. G. Reactions of Low-Valent Metal Complexes with Fluorocarbons. Part XXIX. Zerovalent Nickel alnd Platinum Complexes with Hexafluorobut-2yne and Hexakis(trifluoromethyl)benzene. J. Chem. Soc., Dalton Trans. 1974, 97−101. (19) Cobbledick, R. E.; Einstein, F. W. B. Acta Crystallogr., Sect. B: Struct. Crystallogr. Cryst. Chem. 1978, B34, 1849−1853. (20) Brauer, D. J.; Krüger, C. Bonding of Aromatic Hydrocarbons to Ni(0). Structure of Bis Tricyclohexylphosphine(1,2-η2-anthracene)nickel(0)-Toluene. Inorg. Chem. 1977, 16, 884−891. (21) Stanger, A.; Boese, R. The Crystal structure of (R3P)2NiAnthracene. J. Organomet. Chem. 1992, 430, 235−243. (22) Scott, F.; Krüger, C.; Betz, P. Preparation of New Nickel(0) Naphthalene Complexes, Crystal Structure of [Ni(C10 H 8 )(iC3H7)2PCH2CH2P(i-C3H7)2]. J. Organomet. Chem. 1990, 387, 113− 121. (23) Boese, R.; Stanger, A.; Stellberg, P.; Shazar, A. A NickelAnthracene Complex Having η3 and η4 Coordinaton in One Crystal. Angew. Chem., Int. Ed. Engl. 1993, 32, 1475−1477. (24) Neithamer, D. R.; Párkányi, L.; Mitchell, J. F.; Wolczanski, P. T. η2-(N,C)-Pyridine and m-η2(1,2):(4,5)-Benzene Complexes of (silox)3Ta. J. Am. Chem. Soc. 1988, 110, 4421−4423. (25) Smith, D. P.; Strickler, J. R.; Gray, S. D.; Bruck, M. A.; Holmes, R. S.; Wigley, D. S. Early-Transition-Metal-Mediated [2 + 2+2] Cycloadditions: Formation and Fragmentation of a Reactive Metallacyclopentadiene and Its Direct Conversion to η6-Arene and η2Pyridine Complexes of Tantalum. Organometallics 1992, 11, 1275− 1288. (26) Gray, S. D.; Smith, D. P.; Bruck, M. A.; Wigley, D. E. Regioselective C-N Bond Cleavage in an η2(N,C)-Coordinated Pyridine and an η1(N) –> η2(N,C) Bonding Rearrangement in Coordinated Quinoline: Models for Hydrodenitrofication Catalysis. J. Am. Chem. Soc. 1992, 114, 5462−5463. (27) Kleckley, T. S.; Bennett, J. L.; Wolczanski, P. T.; Lobkovsky, E. B. Pyridine CN Bond Cleavage Mediated by (silox)3Nb. J. Am. Chem. Soc. 1997, 119, 247−248. (28) Jones, W. D.; Feher, F. J. Comparative Reactivities of Hydrocarbon C-H Bonds with a Transition-Metal Complex. Acc. Chem. Res. 1989, 22, 91−100. (29) Jones, W. D.; Feher, F. J. Mechanism of Arene CarbonHydrogen Bond Activation by [C5(CH3)5]Rh[P(CH3)3](H)(C6H5). Evidence for Arene Precoordinaton. J. Am. Chem. Soc. 1982, 104 (15), 4240−4242. (30) Jones, W. D.; Feher, F. J. The Mechanism and Thermodynamics of Alkane and Arene Carbon-Hydrogen Bond Activation in (C5Me5)Rh(PMe3)(R)H. J. Am. Chem. Soc. 1984, 106, 1650−1663. (31) Chin, R. M.; Dong, L.; Duckett, S. B.; Jones, W. D. Multiple η2Arene Coordination. Structure and Isomerism of Naphthalene Complexes of [(C5Me5)Rh(PMe3)]. Organometallics 1992, 11, 871− 876. (32) Tagge, C. D.; Bergman, R. G. Synthesis, X-ray Structure Determinaton, and Reactions of (Pentamethylcyclopentadienyl)(nitrosyl)ruthenium η2-Arene Complexes. J. Am. Chem. Soc. 1996, 118, 6908−6915. (33) Harman, W. D.; Gebhard, M.; Taube, H. Crystal Structure and Pyrolysis of [(Os(NH3)5)2-(η2: η2-m-C6H6))]4+: Evidence for the Formation of a Stable η2:η6-m-Arene Complex. Inorg. Chem. 1990, 29, 567−569. (34) Chen, Y.; Shepherd, R. E. A Proton-Induced N-1 to η2 Migration of a Fluxional Pyrazine. Inorg. Chem. 1998, 37, 1249−1256. (35) van der Heijden, H.; Orpen, A. G.; Pasman, P. Photochemistry of [(η5-C5Me5)Re(CO)3] in Benzene Solution; Crystal Structure of [{(η5-C5Me5)Re(CO)2}2(m-η2,η2’-C6H6)]. J. Chem. Soc., Chem. Commun. 1985, 1576−1578. (36) Sweet, J. R.; Graham, W. A. G. Cationic η2 Arene Complexes of Rhenium in Carbon-Hydrogen Bond Activation. J. Am. Chem. Soc. 1983, 105, 305−306.

and named as the Cavalier Distinguished Teaching Chair. Professor Harman has been named as a Camille and Henry Dreyfus Teacher− Scholar (1992−1995), an NSF Young Investigator (1993−1998), and an Alfred P. Sloan Research Fellow (1994−1996), and he has been the recipient of several university teaching awards. He is coauthor of more than 160 refereed journal publications that collectively explore the diverse interactions of electron-rich transition metal complexes with unsaturated organic molecules. He currently lives in Earlysville, VA, at the edge of the Blue Ridge Mountains with his wife Lisa.

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Double Protonation of Amino-Substituted Pyridine and Pyrimidine Tungsten Complexes: Friedel−Crafts-Like Coupling to Aromatic Heterocycles. Organometallics 2014, 33, 5464−5469. (111) Harrison, D. P.; Zottig, V. E.; Kosturko, G. W.; Welch, K. D.; Sabat, M.; Myers, W. H.; Harman, W. D. Stereo- and Regioselective Nucleophilic Addition to Dihapto-Coordinated Pyridine Complexes. Organometallics 2009, 28, 5682−5690. (112) Welch, K. D.; Harrison, D. P.; Sabat, M.; Hejazi, E. Z.; Parr, B. T.; Fanelli, M. G.; Gianfrancesco, N. A.; Nagra, D. S.; Myers, W. H.; Harman, W. D. Michael-Aldol Ring Closures with DihaptoCoordinated Pyrrole Complexes and the Synthesis of Tetrahydroindole Cores. Organometallics 2009, 28, 5960−5967. (113) Harrison, D. P.; Sabat, M.; Myers, W. H.; Harman, W. D. Polarization of the Pyridine Ring: Highly Functionalized Piperidines from Tungsten−Pyridine Complex. J. Am. Chem. Soc. 2010, 132, 17282−17295. (114) Kosturko, G. W.; Graham, P. M.; Myers, W. H.; Smith, T. M.; Sabat, M.; Harman, W. D. Tungsten-Promoted Diels−Alder Cycloaddition of Pyridines: Dearomatization of 2,6-Dimethoxypyridine Generates a Potent 2-Azadiene Synthon. Organometallics 2008, 27, 4513−4522. (115) You, F.; Friedman, L. A.; Bassett, K. C.; Lin, Y.; Sabat, M.; Harman, W. D. Rhenium(I) eta-2-Coordinated Furan Complexes: Converting Furan into a 1,3-Carbon Dipole. Organometallics 2005, 24, 2903−2912. (116) Schiffler, M. A.; Friedman, L. A.; Brooks, B. C.; Sabat, M.; Harman, W. D. Stereoselective Aldehyde Addition to RheniumCoordinated Furans. Organometallics 2003, 22, 4966. (117) Valahovic, M. T.; Gunnoe, T. B.; Sabat, M.; Harman, W. D. Ligand-Modulated Stereo- and Regioselective Tandem Addition Reactions of Rhenium-Bound Naphthalene. J. Am. Chem. Soc. 2002, 124, 3309−3315. (118) Ding, F.; Harman, W. D. Stereoselective Tandem 1,4-Addition Reactions for Benzenes: A Comparison of Os(II), Re(I), and W(0) Systems. J. Am. Chem. Soc. 2004, 126, 13752. (119) Chordia, M. D.; Smith, P. L.; Meiere, S. H.; Sabat, M.; Harman, W. D. A Facile Diels-Alder Reaction with Benzene: Synthesis of the Bicyclo[2.2.2]octene Skeleton Promoted by Rhenium. J. Am. Chem. Soc. 2001, 123, 10756−10757. (120) Salomon, R. J.; Lis, E. C., Jr.; Kasbekar, M. U.; Bassett, K. C.; Myers, W. H.; Trindle, C. O.; Sabat, M.; Harman, W. D. Stereoelectronic Effects in Dihapto-Coordinated Complexes of TpW(NO)(PMe3) and Their Manifestation in Diels-Alder Cycloaddition of Arenes. Organometallics 2009, 28, 4724−4734. (121) Strausberg, L.; Li, M.; Harrison, D. P.; Myers, W. H.; Sabat, M.; Harman, W. D. Exploiting the o-Quinodimethane Nature of Naphthalene: Cycloaddition Reactions with η2-Coordinated Tungsten−Naphthalene Complexes. Organometallics 2013, 32, 915−925. (122) Pienkos, J. A.; Zottig, V. E.; Iovan, D. A.; Li, M.; Harrison, D. P.; Sabat, M.; Salomon, R. J.; Strausberg, L.; Teran, V. A.; Myers, W. H.; Harman, W. D. Friedel−Crafts Ring-Coupling Reactions Promoted by Tungsten Dearomatization Agent. Organometallics 2013, 32, 691−703. (123) Lis, E. C.; Salomon, R. J.; Sabat, M.; Myers, W. H.; Harman, W. D. Synthesis of 1-Oxadecalins from Anisole Promoted by Tungsten. J. Am. Chem. Soc. 2008, 130, 12472−12476. (124) Todd, M. A.; Grachan, M. L.; Sabat, M.; Myers, W. H.; Harman, W. D. Common Electrophilic Addition Reactions at the Phenol Ring: The Chemistry of TpW(NO)(PMe3)(η2-phenol). Organometallics 2006, 25, 3948−3954. (125) Todd, M. A. Ph.D. Dissertation, University of Virginia, Charlottesville, VA, 2008. (126) Diao, L.; Yang, C.; Wan, P. Quinone Methide Intermediates from Photolysis of Hydroxybenzyl Alcohols in Aqueous Solution. J. Am. Chem. Soc. 1995, 117, 5369−5370. (127) Zottig, V. E.; Todd, M. A.; Nichols-Nielander, A. C.; Harrison, D. P.; Sabat, M.; Myers, W. H.; Harman, W. D. Epoxidation, Cyclopropanation, and Electrophilic Addition Reactions at the meta 13754


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