Catalysts Containing the Adamantane Scaffold

Author Manuscript

Title: Catalysts Containing the Adamantane Scaffold

Authors: Kylie Agnew-Francis; Craig Mckenzie Williams

This is the author manuscript accepted for publication and has undergone full peer review but has not been through the copyediting, typesetting, pagination and proofrea- ding process, which may lead to differences between this version and the Version of Record.

To be cited as: 10.1002/adsc.201500949

Link to VoR: https://doi.org/10.1002/adsc.201500949 REVIEW

DOI: 10.1002/adsc.201((will be filled in by the editorial staff)) Catalysts Containing the Adamantane Scaffold

Kylie A. Agnew-Francis,a and Craig M. Williamsa* a School of Chemistry and Molecular Biosciences, The University of Queensland, Brisbane, Queensland, Australia, 4072 E-mail: [email protected], Homepage:http://www.scmb.uq.edu.au/homepages/williams/index.html

In memory of Paul von Ragué Schleyer

Received: ((will be filled in by the editorial staff))

Abstract. The bulky, but symmetrically beautiful, 2. Organometallic Catalysts adamantane ring system is now pervasive throughout 2.1. Aryl Palladium couplings physical, medicinal and synthetic chemistry, since it was first 2.2. C-H activation discovered in 1924 and coined “dekaterpene”. This 2.3. Metathesis fascinating name lived up to its natural product roots when 2.4. Hetero-Diels-Alder Reactions adamantane was isolated from crude oil in 1933, but it was 2.5. Cyclopropanation not until 1957 in a landmark contribution by von Ragué 2.6. Alkyne Addition Reactions Schleyer that adamantane was made readily accessible 2.7 Hydrogenation through synthesis. Beyond the legacy to physical and 2.8 Dendritic Catalysis medicinal chemistry the adamantane moiety has been 3. Organocatalysts quintessential in the development of some of the most 3.1 Alcohol oxidation important catalysts to-date. Considering adamantane’s 3.2 Michael additions impact to catalyst development past, present and future, this subject is for the first time reviewed herein. 3.3 Acyl transfer and lipase mimics 3.4 Reactions of 1,3-dicarbonyls Table of Contents 3.5 Strecker Reactions 1. Introduction 3.6 NHC catalysis 1.1. Stereoelectronic Influences in Ligand Design – 4. Summary and Outlook Why Adamantane? 1.2. Functionalization of Adamantane Keywords: adamantane; adamantyl; metal catalysis; organo catalysis; ligand design

1 Introduction Adamantane (1, Scheme 1), the simplest of the diamondoid structures,[1] is a highly symmetrical and stable tricycloalkane first discovered as natural constituent of fossil fuel, being first isolated from petroleum sources in 1933.[2] Though the structure was first proposed by Decker in 1924 (as dekaterpene),[3] it was not until 1941 that the compound was finally constructed by Prelog and his group.[4] A later more robust synthesis was provided by Schleyer,[5] based on the Lewis acid catalyzed rearrangement of endo-trimethylenenorbornane 2 (Scheme 1). This development sparked substantial physical organic chemistry interest, especially in the 1960’s, and opened the door to functional group Scheme 1. Schleyer’s synthesis of adamantane. incorporation (e.g. bromo 3 and alcohol 4 derivatives; both obtainable in 95% from 1).[6]

Since this time, the adamantane scaffold has seen extensive application. Notably within the context of Kylie A. Agnew-Francis was born this review, the desirable properties that adamantane in Wellington, New-Zealand. She relocated to Brisbane, Australia in provides to catalyst development include, inert 1999. In 2011, she received her hydrocarbon reactivity, rigidity and symmetry, and BSc(Hons) in chemistry from the steric bulk. Not surprisingly, these features have been University of Queensland, receiving the chemistry honors adopted into the design portfolio of those developing research prize for that year. Kylie new catalytically driven reactions. Over the past commenced her PhD under the decade or so, the number of literature examples of supervision of Craig M. Williams successful catalysts featuring the adamantyl moiety and Luke Guddat in 2015, focusing on the synthesis and biological has certainly increased. The review presented herein application of anti-fungal compounds. focuses on the application of the adamantane scaffold to metal and organocatalyst-based ligand design and highlights key organic reactions mediated by these catalytic systems. Craig M. Williams was born in Adelaide, Australia. He received his BSc(Hons) degree in chemistry in 1994 and in 1997 was awarded his PhD in organic chemistry from Flinders University under the supervision of Prof. Rolf H. Prager. He worked as an Alexander von Humboldt Postdoctoral Fellow with 1.1 Stereoelectronic Influences in Ligand Design – Prof. Armin de Meijere at the Why Adamantane? Georg-August-Universität, Göttingen, Germany until 1999 and then took up a postdoctoral fellowship at the Australian Tuning the reactivity of catalysts is an essential National University with Prof. Lewis N. Mander. He has held an academic position, currently Assoc. Professor, at process in optimizing or adapting systems to suit The University of Queensland since 2000 and during this particular reactions. Within this, it follows that ligand time has won a number of awards including a Thieme selection and / or design must play an important role. Chemistry Journals Award in 2007. The primary research Indeed, over the past few decades, a number of focus of the Williams group is the construction and isolation of biologically active complex natural products, ligand selection guides for various reaction types and [7] and designing methodology to assist in this endeavour. The metal centers have been reported. Two primary group also enjoys dabbling in medicinal, physical organic factors used to control the reactivity and stability of and computational chemistry. catalyst systems are steric saturation and electron o [12] richness. In transition metal catalysis, optimizing angle ≥ 160 and the pKa exceeded 6.7. It could be these features are observed to play major roles in said that this key observation paved the way for the controlling key steps of the catalytic cycle, namely generation of many successful catalysts in the through their influence on incoming ligand approach, subsequent decades. ligand dissociation rates and geometric isomerism.[8] Mechanistic implications of added bulk or basicity has been extensively reviewed.[8b, 9]

Numerous methods exist for quantifying the stereoelectronic properties of a ligand, however the most commonly used in the case of monodentate Figure 1. a) Tolman cone angle of a phosphine ligand. ligands is through calculating Tolman cone angles (θ) The M-P bond length is set to 2.8 Å by default; b) - defined as the apex angle of a cone emanating from Bite angle of a bidentate phosphine ligand. the metal center towards the van der Waals radii of the outermost ligand atoms (Figure 1.) - and Tolman electronic parameters, based on the Strohmeier Though particularly useful for phosphine ligands, the approach.[10] These and other methods of describing rough approximations used in the Tolman approach ligand properties have been well reviewed.[11] In 1989, mean that it is not as applicable to more complex Osborn and co-workers reported their conclusion that ligands, such as N-heterocyclic carbenes (NHCs) or optimal catalytic activity of Pd-phosphine complexes bidentate ligands. Improvement on the mathematics towards the carbonylation of dichloromethane and for calculating the exact cone angle by Allen and chlorobenzene was only observed where the cone coworkers have alleviated some of these issues,[13]

This article is protected by copyright. All rights reserved although alternate means, such as calculation of One consequence of the above can be observed in buried volume and solid cone angles (Θ), have also melting points of hydrocarbons. Caged hydrocarbons been proposed.[14] commonly high melting points compared to other hydrocarbons. The uniqueness of adamantane in this The low cost, ready availability, stereoelectronic regard may be illustrated through comparing its properties and relative ease of functionalization of melting point to other caged hydrocarbons and those adamantane makes it an ideal candidate for of similar molecular weights (Table 2). These data incorporation into catalyst design. Certainly, there indicates that polyhedranes, and adamantane exist many commercially available inexpensive particular, must possess significant intermolecular ligands and catalyst systems with this moiety pre- attractive forces not normally associated with installed.[15] Based on the conclusions highlighted by hydrocarbons. Recently, it has been suggested that the Osborn and in comparing the cone angles of relative strength of the C-H H-C interaction could phosphine ligands containing ligands with various be accounted for by the tertiary nature of the carbons present, the higher number of short H H contacts, amounts of steric bulk (Table 1), it is easy to see why [19] its incorporation into ligand design has seen so much and low level of pyramidality. Overall, this makes success. adamantane (or indeed, other caged systems) an excellent, polarizable electron donor.

The introduction of various groups onto ligands is an effective and simple method for tuning the electronic properties and thus, the reactivity of a catalyst system. Table 2. Comparison of the melting point of adamantane Ligands containing groups that are highly electron (1) to other hydrocarbons of similar molecular mass. donating will in turn have higher donor power themselves, thereby making the ligands more basic. In Melting Point organometallic catalysis, this allows the metal center [20] o to have a high level of electron density, making it Adamantane (1) 266-268 C more susceptible towards oxidative addition. [21] o Typically, these reactive ligands are unstable towards Bicyclo[2.2.2]octane (5) 169-170 C air and moisture and must either be stored under inert atmosphere or in the case of phosphine ligands, as the Norbornane (6)[22] 86-87oC HBF4 salt (the phosphine is then regenerated in situ in [16] the presence of base). It is interesting to note, [23] o however, that many adamantane-containing ligands Cubane (7) 130-131 C do not suffer this problem, despite being highly active. [24] o Camphene (8) 51-52 C Table 1. Comparison of the Tolman cone angles of various, commonly used phosphine ligands. Limonene (9)[25] -89.03oC Ligand a) Tolman Cone Angle Solid Cone Angle (θ)[10] (Θ)[17] o o PMe3 118 124 o o PPh3 145 129 [26] o o Twistane (10) 163- P(i-Pr)3 160 163 o o o 164.5 C P(t-Bu)3 182 182 PBz 165 o 163 o 3 Decane (11)[27] -29.61oC a) Data for PAd3 not available

[28] Table 3. pKa’s of common dialkyl phosphines Typically, groups that occupy a large amount of space a) (i.e. are sterically bulky) are considered to exhibit Ligand pKa high degrees of repulsion owing to clashing electron PMe3 8.65 densities. However, attractive forces between neutral PPh3 2.73 atoms (i.e. London dispersion forces) can play a large PEt3 8.69 P(t-Bu) 11.4 role in the intermolecular interactions between bulky 3 PCy 9.7 molecules, which impacts significantly on many 3 physical and chemical properties of a given Table 4. pKa’s of common imidazolium cations used to molecule.[8a, 18] synthesize NHC’s[29]

a) R pKa

Me 21.1 t-Bu 22.6 i-Pr 24.0 Ph 16.1

This phenomenon is further exemplified by the trends in the pKa values of phosphines (Table 3). Although data for the analogous adamantyl compounds was not forthcoming, it is obvious from these examples that an increase in molecular size and branched character significantly increases the basic nature of the Scheme 2. Synthesis of Ad2PH (13) and Ad2PCl (14) compound. This does not hold as true for NHC from adamantane catalysts, however (Table 4), since the basicity of these compounds derives primarily from the [28-29] Constructing trialkylphosphines from these base imidazolium ring. compounds is easily achieved by substitution of alkyl halides with commercially available Ad2PH. These 1.2 Functionalization of Adamantane reactions can provide high yields of product, particularly where primary halides are used (ca. 90% yield). Purification of these is often a simple matter of One of the most widely used catalysts on the market [8b] filtering off insoluble phosphonium salts. The free currently is that of Pd/PtBu . Although this system 3 phosphines can then be released by treatment with has proven successful in many reactions, the t-Bu triethylamine. Other approaches, such as the one groups present on the ligand are extremely difficult to employed by Beller to synthesize commercially modify and so the catalyst system suffers from a lack available Ad PBu (15), utilize the corresponding of tuneability. By comparison, adamantane is more 2 chlorophosphine (i.e. 14) in combination with easily functionalized at each of its tertiary positions. lithiated alkyl compounds (Scheme 3).[32] With the adamantane cage in hand, these positions may be (for example) brominated and then substituted as desired (Scheme 1).[30]

The assembly of di(1-adamantyl) phosphines is achievable through the facile and inexpensive initial generation of Ad2PH or Ad2Cl (both of which are now commercially available compounds), which may then be easily elaborated into more complex trialkylphosphines. Synthesis of Ad2PH and Ad2Cl Scheme 3. Beller synthesis of the phosphine ligand, was first reported by Gӧrlich and Schmutzler in the Ad2PBu (marketed as cataCXium®) mid-1990’s by reacting adamantane with PCl3 and AlCl3, under Friedel Crafts conditions, to give Synthesis of NHC type catalysts generally proceeds [31] Ad2P(O)Cl in 93% yield. This is subsequently via a precursor salt. Many of these are commercially reduced at room temperature in the presence of available, including the di(1-adamantyl) salt (17). HSiCl3 to give Ad2PH (13) in 93% yield, which can Construction of this molecule is also possible using then finally be chlorinated quantitatively with CCl4 the same general method used for other such (Scheme 2). imidazolium salts.[33] Generating the carbene is usually performed in situ by treatment with strong base (Scheme 4). The adamantyl varieties are no different in this respect. Indeed, the first example of a crystalline NHC catalyst, reported by Arduengo,[34] was a di(1-adamantyl) NHC (18), the synthesis of which was achieved in high yield through the treatment of the salt (17) with sodium hydride.

This article is protected by copyright. All rights reserved Construction of this salt itself is possible by relatively The use of adamantane in organometallic catalysis is facile means via 16 and allows for the entry of many relatively commonplace and has shown a great deal of different substitution patterns on the final catalyst. success across a number of reaction types. In addition to the general benefits of these systems outlined in Section 1.1, adamantane is believed to play crucial roles at various key stages of the catalytic cycle on account of its large steric bulk and electron donating abilities. Broadly, these may be broken down as follows:

Oxidative Addition

The relative cost and availability compared to other aryl halides make alkyl and aryl chlorides attractive targets for cross coupling reactions. The electron-rich properties of large alkyl moieties also make them Scheme 4. Synthesis of the imidazolium cation (17) ideal candidates for reaction with these less active and Arduengo carbene (18) molecules. This is generally ascribed to the comparative strength of the C-Cl bond, leading to a lower rate of oxidative addition to the Pd(0) species in As well as paving the way for modifiable peripheries [36] within a catalyst, adamantane may be elaborated into the initial stage of the reaction cycle. It is suggested that the reactivity of bulky phosphine densely functionalized cores. This development ligands, such as those containing adamantane, allows for the generation of molecules with multiple catalytic sites, particularly in the case of higher towards aryl chlorides is due to the formation of coordinatively unsaturated phosphane complexes. generation dendrimers, of which there are a few examples in the literature (see Section 2.8). A simple This in turn results in the acceleration of the reaction rate of all aspects of the catalytic cycle.[7b] yet effective example of this may be seen in the Furthermore, the ease of oxidative addition observed synthesis of a recyclable hypervalent iodine catalyst designed by the Kita group (Scheme 5).[35] with sterically congested ligands, particularly phosphines and (NHCs), allows for the use of milder Construction of the active complex (20) was achieved through initial synthesis of 1,3,5,7-tetrakis(4- conditions. iodophenyl)-adamantane (19), followed by oxidation of the iodide to give the hypervalent complex in an Reductive Elimination overall yield of 75%. The process of reductive elimination, as the name implies, is the reverse process to that of the initial oxidative addition step. It follows that while oxidative addition is promoted by the presence of highly electron donating ligands, reductive elimination would be hindered under the same conditions. Although it is certainly true that having electron poor ligands can increase reaction rate, the reality is not so straightforward. It is known, for example, that when a reaction proceeds via palladium catalysts with odd coordination numbers, the resulting T-shaped intermediates will undergo reductive elimination.[37] As well, the presence of bulky ancillary groups on the ligands is known to create high-energy intermediates Scheme 5. Synthesis of a recyclable, heavily following oxidative addition, which acts as a driving functionalized hypervalent iodine catalyst (20) based force to release the final product via reductive around an adamantane core. elimination.

2. Organometallic Catalysts β-Hydride Elimination

This article is protected by copyright. All rights reserved One major consideration for metal catalyzed reactions is the possibility of premature reaction termination or the formation of by-products through β-hydride elimination. Where this is not desirable (e.g. in olefin cross-metathesis polymerization reactions), a few main counteraction strategies exist. The first and more common method is to simply use a ligand lacking β- hydrogens. Similarly, ligands for which the corresponding alkene is highly strained and unstable Figure 2. Phosphonium ligands cataCXium® AHI (e.g. consider the anti-Bredt compound, (26), cataCXium® ABn (27), and PH(Ad)2 (13). adamantene[38]) may prohibit unwanted elimination products. It has also been suggested that having sterically cumbersome ligands helps to destabilize the transition state needed for the catalyst to undergo β- hydride elimination. This trend has been demonstrated throughout the literature, both experimentally and computationally.[39] Scheme 7. Beller modified Heck conditions involving ligand 15 2.1. Aryl Palladium couplings

The Beller group went on to illustrate the use of In 2000, Beller and colleagues described a new di(1- Ad2PBu (15) in the Heck reaction of similarly non- adamantyl) phosphine ligand (15) for the palladium activated and deactivated, aryl chlorides (21) (Scheme catalysed Suzuki coupling of non-activated and 7).[32] Using terminal alkenes (24) in the presence of deactivated aryl chlorides (21) with arylboronic acids [40] Pd(dba)2 and 15, styrenes (24) could be constructed in (22) (Scheme 6). This ligand, BuPdAd2 (15), nearly quantitative yields. To further demonstrate its provided the corresponding biaryl compound (23) in potential usefulness, the commercially important UV- yields above 80%. Even with more challenging absorber, 2-ethylhexyl 4-methoxycinammate was also electron-rich MeO substituents, good yields between synthesized under optimized conditions in 82%. 58 - 64% could be achieved with very low catalyst loading [0.005% Pd(OAc)2] and good turnover number (TON). .This class of ligands has been used successfully in a variety of reactions originating from heteroaryl substrates (28) (Figure 3), including the assembly of enamides from the corresponding aminothioester,[42] arylation of electron-rich heterocycles,[43] Sonogashira coupling,[44] α-arylation of ketones,[45] and synthesis of indoles.[46] The cataCXium® ligands have also been found to act efficiently within the space of Pd- catalysed carbonylation reactions, e.g. the alkoxy carbonylation of aryl and heteroaryl halides,[47] formylation of aryl and heteroaryl halides and triflates,[48] reductive carbonylation of vinyl halides and triflates,[48b] synthesis of vinylbenzoates,[49] Scheme 6. Suzuki coupling of substituted aryl carbonylative Suzuki coupling,[50] synthesis of chlorides, 8, and arylboronic acid, 9, utilising di(1- benzimidazoles and quinazolinones[51] and the adamantyl)phosphorous ligand, 15. carbonylative construction of 2- alkylbenzoxazinones.[52] The success of the Ad2PBu (15) ligand has since led to its commercial synthesis under the name, cataCXium®, and subsequent expansion to the commercially available di(1-adamantyl) phosphine ligands, cataCXium® AHI (26) and cataCXium® ABn (27) (Figure 2).[41]

This article is protected by copyright. All rights reserved proved to be a good substrate, generating the aldehyde in 93% yield, although electron withdrawing systems (i.e. 34) did not prove as effective using this catalyst. Extended aryl systems performed moderately (e.g. 35). In addition, the synthesis of the ligand could only be achieved in 30% yield, whereas cataCXium® A was additionally found to act in as good (or better) fashion in the construction of the same aryl aldehydes.

Scheme 8. Carbonylation driven by di(1- Figure 3. Various heterocyclic carbonylation and adamantyl)phosphinite ligand, 31. coupling reactions mediated by Pd (0) and the cataCXium® ligands. Tokoro and Fukuzawa[55] recently reported that (TAdPh-PEPPSI (36), a new 1,2,3-triazol-5-ylidene Other examples of di(1-adamantyl) phosphines have based ligand, promoted the Hiyama coupling reaction also shown to be successful in Pd-catalysed cross- between aryl bromides (37) and coupling reactions. The structurally simpler secondary phenyltrimethoxysilane, giving the biaryl (e.g. 38) in excellent yields (Scheme 9). phosphine, PH(Ad)2 (13) (Figure 2), was used for the first time in the Heck coupling of electron rich and electron poor aryl chlorides with a variety of olefins. The success of this system was varied; electron poor aryl chlorides gave consistently excellent yields (up to 90%) and complete conversion, whereas electron-rich halides gave slightly lower yields (71% using 4- chloroanisole as a substrate) and heteroaryl chlorides showed mixed success.[53] The success of adamantyl ligands in these systems is in agreement with the notion that the addition of electron-rich steric bulk within the catalyst allows for reaction with typically unreactive chlorides. By comparison, reaction of butyl acrylate with the model deactivated chloride, 4- chloroanisole, furnished similar amounts of the Scheme 9. TAdPh-PEPPSI catalyst (36) promoted coupled product when the secondary phosphine, Hiyama couplings. HP(Bu)2, was used (86% yield compared to 77% for the adamantyl ligand) and significantly less when In addition to C-C bond formation, the cataCXium® either HP(Cy)2 or P(Cy)3 were used (39% and 40% A group of ligands (e.g. 26 and 27) have also been yield, respectively). applied successfully to Buchwald-Hartwig amination reactions. It is well established that the more difficult More recently, the Beller group synthesized a group of these transformations often benefit from the of phosphinite ligands for the carbonylation (i.e. 30) addition of electron-rich, bulky ligands. As well as of aryl bromides (29) (Scheme 8).[54] The di(1- assisting in the initial oxidative addition steps, the use adamantyl) version of this ligand (31) was able to of these ligands also assists in promoting the binding effect the synthesis of electron-rich 4- of the amine substrate and / or reductive elimination methoxybenzaldehyde (32) in 86% yield and 98% of the aryl-amine product. conversion. The 4-chloroaryl bromide (33) also

This article is protected by copyright. All rights reserved The monoarylation of simple amines (45) with aryl above 90%, with high selectivity towards the chlorides (21), has been disclosed, achieving yields of monoarylated product.[58] substituted anilines (e.g. 39 - 44) far in excess of previously reported systems (Scheme 10).[56]

Figure 4. DalPhos-type ligands.

Scheme 10. CataCXium® A mediated Buchwald- The suite of DalPhos ligands was extended with the Hartwig amination. creation of Pyr-DalPhos (58) and OTips-DalPhos (59), the latter of which was employed in the synthesis of [57] Later, the same group extended the reaction to a indoles in good yields.[59] The former Pyr-DalPhos series of new cataCXium® AHI type ligands (26, 47 - ligand was reported to promote the efficient 52) (Scheme 12). Of these, the original n-Bu (26) and carbonylative amination of aryl (60) and heteroaryl allyl (50) derivatives proved to be the most successful, (62) bromides with various primary and secondary achieving conversions of 100% with excellent alkylamines (Scheme 7). Moderate yields of the isolated yields (e.g. 53 – 55) (Scheme 11). corresponding amide in the case of primary amines (56 - 66%) (e.g. 61) and lower yields for secondary amines (29 - 45%) (e.g. 63) (Scheme 12).[60]

Scheme 11. Aryl amination promoted by cataCXium® AHI type ligands. Scheme 12. Carbonylative amination of aryl and heteroaryl bromides with ammonia and other amines. Another class of phosphine ligand prevalent in the recent literature is that of the DalPhos-type ligands The AdBrettPhos ligand (65) and precatalyst (64) was (Figure 4). Their use began with the development of shown to be an effective component of the Pd- Mor-DalPhos (56) and Me-DalPhos (57), which were catalysed chemoselective monoheteroarylation (e.g. utilized in Buchwald-Hartwig type reactions between 67) of ammonia, achieving the corresponding aryl and heteroaryl chlorides and alkyl amines, products (68 – 75) in yields above 75% in most cases ammonia or hydrazine. In most of the reported cases, and 100% conversion (Scheme 13).[61] products were synthesized in excellent yields, often

Scheme 14. Aryl and diaryl ethers obtained from palladium (0) coupling in conjunction with ligands 76 and 77. Scheme 13. Heteroaryl amination promoted by Buchwald-type ligands. 2.2. C-H activation

Lastly, a significant improvement in the area of diaryl The group of Jin-Quan Yu reported[65] the ether synthesis was developed by Aranyos et al. in 3 [62] [63] alkynylation (i.e. 91) of C(sp )–H bonds in aliphatic 1997. A later improvement was made in 1999 amides (89) using a brominated TIPS protected with the introduction of palladium(0) catalysts in the acetylene (90). Key to this work was the combination presence of the sterically bulky aryldialkylphosphine of the Arduengo bis-adamantyl NHC[34] (92) and the ligand 76. It was discovered that aryl halides (78) palladium π-allyl precatalyst. Reasonable variety was could be reacted with phenols (79) to give diaryl demonstrated (e.g. 93 - 96) (Scheme 15). ethers (80 – 82) (Scheme 14). The di(1-adamantyl) imidazole ligand 77, developed by Gowrisankar et. al.,[64] was also found to be highly suitable to this end, furnishing a wide array of aryl-alkyl ethers (e.g. 84 - 88) from aryl halides (83), in unprecedented high yields.

The versatility of the Arduengo catalyst (92) within the C-H activation space was further demonstrated by Flores-Gaspar et al.[66] disclosing NHC catalysed syntheses of benzo fused cyclobutanes (e.g. 98) from aldehydes (e.g. 97). A screening study revealed significant differences in selectivity between various NHC catalysts, giving undesired decarbonylated products such as 99. This process highlighting that the Arduengo catalyst was superior even against the mono-adamantyl system 100, also surveyed in terms of selectivity, but not yield. Optimization via the use of a π-allyl palladium (0) precatalyst together with 92 Scheme 17. Takemoto spirooxindole synthesis using or 100 gave good to excellent yields of the target ligand 15. cyclobutanes (e.g. 101 - 103) (Scheme 16). In 2011, Novák et al.[70] reported the successful Pd- catalysed synthesis of a series of benzolactones (i.e. 114), from aryl carboxylic acids (i.e. 113) (Scheme 18). Two Ad catalysts (111 and 112) were found to be beneficial, achieving moderate to good yields. Athough, it should be noted that neither ligand was ultimately found to be the best of those surveyed, due to the formation of the decarboxylated products (e.g. 115).

Scheme 16. Palladium (0) cyclobutane synthesis promoted by ligands 92 and 100.

Takemoto elegantly showed that using the Scheme 18. Benzolactone 114 derived from the cataCXium® A free base (15) in combination with ortho-substituted benzoic acid, 113. palladium(0) converts ortho-methylated carbamoyl chlorides (104) into oxindoles (e.g. 105 - 110) in good [67] Betley et al. prepared a range of iron complexes, to excellent yields. The study was expanded to initially demonstrating that the bis-adamantyl ortho-carbocycles, such as cyclopropanes, to give [68] complex (116) could facilitate benzylic C-H insertion, spirooxindoles (Scheme 17). The cataCXium® A via azide (117) in the case of toluene (118), which class of ligand has also been found to promote the [71] [69] afforded N-benzyladamantylamine (119). On this regioselective C-H functionalization of L-histidine. precedent, Betley’s team applied complex 116 to intramolecular examples (120, 123, 125 and 127), which afforded various functionalized pyrrolidines and piperidines (i.e. 121, 124, 125 and 127) (Scheme 19).[72]

This article is protected by copyright. All rights reserved In the same year that the PTAD (129) catalysis was disclosed (Scheme 13) by the Davies group, they also reported the tetrachloro derivative (TCPTAD, 130),[75] which was found to mediate both intra- (e.g. 137) and intermolecular (e.g. 139) C-H amination, affording cyclic carbamates (138) and aminoindanes (140) (Scheme 21).

Scheme 19. Nitrenoid C-H insertion facilitated by bis-adamantyl iron complex 116.

Dirhodium catalysis have seen widespread application in synthesis, and the application of the adamantyl containing variety has been extensively explored by [73] the Davies group. In terms of C-H functionalisation, Scheme 21. Cyclic carbamates and aminoindanes Rh2(S-PTAD)4 (129) and the chlorinated derivative, arising from rhodium catalsyed C-H amination. Rh2(S-TCPTAD)4 (130), drive carbon-carbon bond formation via insertion of the dirhodium carbenoid into various intra- (e.g. 134 - 136) and intermolecular 2.3. Metathesis (e.g. 131 via 132) activated C-H bonds. Both the yield and asymmetric induction are usually excellent using Alkene and alkyne metathesis are potent and the donor-acceptor diazo combination (133), ingrained tools for the assembly of a variety of particularly in the case of 130 (Scheme 20).[74] complex chemical architectures.[76] Metathesis reactions tend to be E-selective, owing to the thermodynamic stability of the E transition state.[77] Reversing selectivity to promote formation of the Z- olefin is not a trivial matter, however there have been examples recently surface wherein bulky, typically NHC-type ligands have been found to destabilize the E-transition state, leading to Z-selectivity.[78]

Some of the earliest examples of Z-selective metathesis involved the use of W, V and Mo catalysts.[78a, 79] Primarily, Z-selective Mo and V catalysts have found use within the space of polymerisation, due to their high tendency to generate synthetically difficult syndiotactic cis polymers. In 2009, Flook et al.[80] reported the ring opening polymerization (ROMP) of 141 using the Mo catalysts (142 and 143) giving almost exclusively the cis syndiotactic polymer (144, Scheme 22).

Scheme 20 Bold solid bonds represent C-C bond formation resulting from C-H insertion as facilitated by rhodium catalysts, 129 and 130.

This article is protected by copyright. All rights reserved Following this, in 2011, the Grubbs group reported the development of novel chelated Ru catalysts for the synthesis of Z-olefins.[78b, 82] The catalysts (131 - 135) were found to be successful in both the cross- metathesis (CM) (e.g. 156 and 157) homocoupling (HC) (e.g. 158) and ring-opening metathesis (ROM) of numerous olefins (e.g. 155 and 154) (Scheme 23). Using this system, moderate conversion of the cross- product could be obtained with excellent selectivity towards the Z-product (159 - 160). Subsequent density functional theory studies revealed that the steric bulk of the adamantyl group causes the Z- transition state to be lower in energy than that of the E-transition state, giving rise to a high degree of Z selectivity.[83]

These catalysts and their derivatives have since been Scheme 22. Mo catalysed synthesis of a syndiotactic shown to be efficacious in numerous Z-selective (and polymer. often chemoselective)[84] metathesis reactions, including the ROM of norbornane derivatives,[85] Vanadium catalysts, such as those presented in Figure macrocyclization of a number of industrially [86] 5 (145 - 148), have also been applied in a similar important molecules, CM of allylic-substituted [87] [78b] [88] fashion, affording highly selective ROMP of olefins, ROMP, ethenolysis, and ring-closing [89] norbene.[81] metathesis (RCM). The utility of these catalysts is further demonstrated through the total synthesis of various olfactory compounds and the cytotoxic alkaloid, motuporamine C (163) (Scheme 24), the latter of which was obtained via macrocyclization of 162 in 30% yield and 84% selectivity using 153 (compared to 44% in previous work).[88a]

Figure 5. Vanadium Z-selective metathesis catalysts.

Scheme 24. Z-Selective RCM to produce motuporamine C.

2.4. Hetero-Diels-Alder Reactions

The Diels-Alder (DA) and related Hetero-Diels-Alder (HDA) reactions have established themselves as two of the most synthetically useful tools to organic chemistry,[90] due primarily to their facile and predictable nature and their ability to act in an enantioselective manner.

Within this area, adamantane-containing ligands have contributed a great deal. In 1999, the Jacobson group reported the construction of enantiomerically enriched Scheme 23. Z-Selective ruthenium based metathesis. pyranones (168) from readily available, accessible

This article is protected by copyright. All rights reserved aldehydes (167) and activated dienes (166) (Scheme and excellent ee’s, both above 95%. Subsequent 25) using a variety of chiral chromium (III) conversion of 176 to 178 and 177 to 179 set the stage complexes.[91] It was found that the adamantyl for accessing 180 and completing the synthesis. catalysts 164 and 165 could achieve ee’s of greater than 90% for some products (169 - 171). In contrast, the same reaction that afforded an ee of 98% using 164 as the catalyst attained an ee of only 57% when the structurally related di-t-butyl SbF6 derivative was used.[91a]

The scope of the adamantyl catalyst system was later extended by Jacobsen[92] to generate dihydropyrans in excellent yields and ee’s using Cr(II) complex 165. Application to the doubly diastereoselective reaction of Danishefsky’s diene (See 164 Scheme 26), and a variety of chiral aldehydes, gave good yields, diastereomeric ratios, and ee’s in excess of 99% in most cases.[93]

Scheme 25. Jacobsen asymmetric HAD synthesis of chiral pyranones Scheme 26. Jacobsen’s total synthesis of FR901464 (181).

Aza-Diels-Alder reactions using adamantyl-catalysts The Jacobsen catalyst system has since been have appeared in the literature, but with limited employed in the total synthesis of over 13 natural [95] [94] success. Unlike the Jacobsen system, the analogous products and the partial synthesis of many others. reaction between Danishefsky’s diene (184) and the In 2000, Jacobsen’s group completed the first total aldimine (183) in the presence of an adamantane- synthesis using this chemistry in the completion of containing scandium (III) catalyst [(S,R)-182] gave a FR901464 (181), a potent anti-tumour compound [95a] [931] poor ee of 25% for 185 (Scheme 27). A similar (Scheme 26). Key to this synthesis was the HDA reaction between 1,2-dihydropyridine and N- generation of two intermediates, 176 (via 172 and acryloyloxazolidinone gave only a moderate ee of 173) and 177 (via 174 and 175), which were 65%.[95b] generated using the Cr(III) catalyst 165 in good yields

Scheme 27. A rare asymmetric aza-Diels-Alder reaction in the presence of the adamantane-containing scandium (III) catalyst 182.

2.5. Cyclopropanation

Three main catalysts have been identified that drive Scheme 29. Asymmetric cyclopropanation using cyclopropanation. All of these are ligand-bound TCPTAD 130. dirhodium systems of which the adamantyl carboxylic [96] complex (183) has been found by Lindsay et al. to 2.6. Alkyne Addition Reactions promote not only cyclopropanation (e.g. 185, 187 and

188), but also cyclopropenation (186, 189 and 190), [99] albeit in the racemic series using diazo 184 (Scheme Zhang and co-workers utilized Mor-DalPhos (56) 28).[97] to construct the gold (I) chloride complex 198. This tridentate ligand modulated the normal high reactivity of gold (I) such that it promoted amide (200) addition The Davies PTAD (129) system will also facilitate to triple bonds (199) followed by a cyclisation step to asymmetric cyclopropanation, but the clear front- build, via a formal [3 + 2] annulation, 2,4- runner in this space is the TCPTAD (130) catalysis, disubstituted oxazoles (e.g. 201 - 207) (Scheme 30). which is particularly good at cyclopropanation (e.g. The synthesis of oxazolines has been investigated 193) of electron-deficient alkenes (192) using donor- with alternate gold (I) complexes, but the adamantyl acceptor diazo compounds (191) with excellent substituent was not superior.[100] stereoinduction (e.g. 194 - 197) (Scheme 29).[98]

Scheme 28. Cyclopropanation and cyclopropenation.

Scheme 30. Gold complex 198 catalysed 2,5-oxazole synthesis.

Soon after Zhang reported the use of the Mor- DalPhos gold complex above (198, Scheme 30), his group reported a more bulky ligand variation (207).[7a]

This article is protected by copyright. All rights reserved Utility was found in the conversion of alkynes (199) into enol ethers (209) from acids (208), ketones (211) and imines (210) (Scheme 31). Bertrand also reported conversion of alkynes into imines using a spiroadamantyl N-heterocyclic carbene gold (I) complex, but it was not competitive against other reported NHCs.[101]

Scheme 32. Hashmi’s gold (I) complex performance Scheme 31. Conversion of acetylenes into enol ethers, comparison. imines and ketones using Zhang’s catalyst 207. 2.7 Hydrogenation Hashmi et al., who are leaders in the gold catalysis [102] field, developed two adamantyl based phosphate It has been established throughout this review that gold (I) chloride catalyst systems (213 and 214) and chiral phosphines play a critical role as ligands in applied them to three alkyne cyclisation reactions to asymmetric, metal-catalyzed reactions. Their specifically study turnover numbers. In the case of the application to asymmetric hydrogenation was first phenol (216 from 215) and spiroacetal synthesis (221 illustrated by the key discovery of P-chiral and 222 from 220), both complexes catalysed the phosphines such as (R,R)-1,2-bis[(o- reaction. However, in the case of the methoxyphenyl)phenylphosphino]ethane (DIPAMP) cycloisomerisation (218 and 219 from 217), only the in the 1960’s – 1980’s.[104] binaphthol adamantyl ether hybrid (214) facilitated conversion to product (Scheme 32).[103] In 1998, Imamoto et al.[105] developed a new class of P-chiral phosphines, 1,2-bis(alkylmethylphosphino) ethanes. A vital feature of these ligands was the incorporation of both a bulky alkyl and non-bulky alkyl group directly to phosphorus. When chelated to a rhodium center, these formed asymmetric five- membered rings of C2-symmetry. The asymmetric environments of these chelates and directing power of the sterically bulky alkyl substituents was proposed by the authors to lead to asymmetry in the hydrogenation of α-(acylamino)acrylic derivatives (224) (Scheme 33). To this end, the adamantane derivative (223) proved to be very effective, furnishing the hydrogenated product (e.g. 225 - 229) in excellent ee’s of up to >99.9%.

This article is protected by copyright. All rights reserved enantioselectivity on a variety of homoallylic alcohols (231), of which there were previously very few examples (e.g. 232). Products (233 – 236) were obtained in over 99% conversion and high ee (Scheme 34).

Josiphos ligands represent a class of chiral phosphines containing ferrocenyl moieties and have been shown, since their development by the Togni group in the 1990’s, to be efficacious in numerous asymmetric reactions in the past few decades.[107]

In 2011, Togni and co-workers[108] developed an additional series of novel chiral ferrocenyl diphosphines containing trifluoromethyl units for use in asymmetric hydrogenation. These ligands were Scheme 33. Asymmetric hydrogenation utilizing 223 easily synthesized in 21 - 41% across 3 steps. The affording protected chiral amino acids. adamantyl ligand (237), though not superior at the time, was nevertheless found to be active towards Rh- catalysed hydrogenation of two model compounds,

(240 and 241), achieving high yields (81 - 88%) and excellent ee’s of hydrogenated products (242 and 243) (Scheme 35)

The same group later extended this suite of catalysts, incorporating new alkyl substitution patterns on the phosphorus atoms (Scheme 35).[109] The adamantyl ligands (238 and 239), demonstrated some of the best results amongst this group, achieving yields >99% and ee’s of up to 99%.

Scheme 34. Chiral triskelion phosphine (230) supported Rh-catalysed asymmetric hydrogenation of homoallylic alcohols.

Chiral triskelion phosphines, containing three-fold rotational symmetry, offer an alternative approach in the area of asymmetric hydrogenation. Mynott and colleagues[106] disclosed the use of bulky, and thereby Scheme 35. Performance enhanced adamantane configurationally stable, chiral P(OR) ligands. The 3 modified Josiphos ligands 238 / 239. (R,R,R,) adamantyl derivative of this ligand (230) was found to be a crucial component in locking the phosphite ligand into a single helical form. This locked structure imparts a high degree of

This article is protected by copyright. All rights reserved 2.8 Dendritic Catalysis polyphenylated, tetrahedral adamantane core (Figure 7). The in situ formation of Efficient recovery of metal catalysts is of great polyperoxophosphotungstates using these dendrimers importance when considering the cost of precious was then used to catalyze the construction of epoxides metals such as gold, palladium, platinum and rhodium. from alkenes in the presence of H2O2 with excellent Having catalysts immobilized on solid supports is one selectivity and moderate yield. The protonated approach that allows for very easy recovery and derivative of dendritic support 241, tetrakis-1,3,5,7- examples of this using adamantyl catalysts have been (4-phosphonatophenyl)adamantane (TPPha), has also reported,[110] though this often comes at the expense been used to generate the layered vanadium of product yield. Recently, the use of dendrimers as a organophosphonate, TPPha-V. This was shown to catalyst support has been proposed as a more suitable successfully promote the aerobic oxidation of alternative. It has repeatedly been shown that benzylic alcohols (243) to aldehydes (e.g. 244 - 247) recovery of metal catalysts from their dendritic in typically excellent conversion and selectivity support is at least as fruitful as with other solid (Scheme 36). supports (particularly with the advent of nanofiltration) without resulting in a loss of product.

Though dendrimers that contain the adamantane motif have been extensively reported upon, they have received little attention as potential catalyst supports. The rigid, well-defined structure of adamantane lends itself well to acting as a dense, tetrahedral functionalized core. Some examples do exist in the literature. For example, the second generation dendrimer, 240, containing eight ferrocenyl Josiphos ligands (Figure 6) was found to be as effective as the mononuclear catalyst system at implementing the Rh- catalysed hydrogenation of dimethyl itaconate.[111]

Figure 7. Neumann’s polyphenylated dendrimers, 241 and 242.

Figure 6. Josiphos dendrimer 240. Another approach in the dendritic support arena is in noncovalently functionalized dendrimers, which offer The Neumann group[112] have also contributed to this the added ability of reversible functionalization of the area, disclosing first and second generation periphery. This may be done in a controlled manner, phosphonate dendrimers, 241 and 242, based around a through ionic interactions and hydrogen bonding,

This article is protected by copyright. All rights reserved thereby allowing easy regeneration of the support. core, is recyclable and operates with very high The first example of this came in 2000,[113] in which a efficiency.[118] fifth generation poly(propylene imine) dendrimer with substrate-directing urea adamantyl moieties at the periphery was revealed. Later, this dendrimer was used to anchor a total of 32 triphenylphosphine ligands, giving the functionalized dendrimer (248) (Figure 8).[114] This was then utilized in the Pd- catalysed allylic amination of crotyl acetate and piperidine, achieving rates similar to that of the unbound catalyst.

Scheme 36. Aerobic oxidation of benzylic alcohols to aldehydes. Scheme 37. 1,3,5,7-tetrakis[4-(diacetoxyiodo)phenyl] adamantane 20 alcohol to carbonyl oxidation.

3.2 Michael additions

Michael additions and related reactions have been widely studied within the organocatalytic field, and the utility of the adamantyl system is well represented. Mukherjee reported the asymmetric vinylogous Figure 8. Fifth generation poly(propylene imine) Michael addition of butenolides (263) to N- dendrimer with urea adamantyl moieties. phenylmaleimide (264) using the thiourea 265, which afforded addition products type 266 (Scheme 38).[119] 3. Organocatalysts The use of a catalyst diastereomer was also found to be viable but would not facilitate addition to [120] 3.1 Alcohol oxidation nitroalkenes.

The Kita group has dedicated much time and effort developing hyperiodide promoted reactions over many years.[115] In 2004, his group reported the synthesis of 1,3,5,7-tetrakis[4-(diacetoxyiodo)phenyl] adamantane (20) and further detailed its ability to perform alcohol (e.g. 249 - 255) to carbonyl oxidation

(e.g. 256 - 262) (Scheme 37).[35, 116] The initial experimental conditions were later superseded in a subsequent disclosure by combining 20 with the Scheme 38. Thiourea promoted vinylogous Michael TEMPO catalyst.[117] However, a main feature of this addition of N-phenylmaleimide (253). catalyst system is that reagent 20, similar to the dendritic catalysts mentioned in Section 2.8 that Feng investigated the Friedel–Crafts alkylation of employ adamantane as a tetrahedrally functionalized electron-rich phenols (268) with arylenones (267).

This article is protected by copyright. All rights reserved High yields of adducts (e.g. 269) and excellent afforded the optimum steric environment. This asymmetric inductions were achieved using the organocatalytic approach gives rise to excellent yields proline N-oxide catalyst (S,S)-182 (Scheme 39).[121] of the alcohol (275) in high enantiomeric excess, although interestingly bulky ester residues are required (Scheme 41). Very similar catalysts to that of 274 promote the asymmetric alkynylation of 1,3- dicarbonyls (C-C bond formation).[125] More recently, Lu has applied such catalysts to the fluorination and chlorination of similar substrates.[126]

Scheme 39. Friedel–Crafts alkylation of electron-rich phenols using proline N-oxide catalyst (S,S)-182.

3.3 Acyl transfer and lipase mimics Scheme 41. Asymmetric oxidiation of 1,3- dicarbonyls. The Schreiner group has spent many years developing their adamantyl backbone peptides for the kinetic 3.5 Strecker Reactions resolution and desymmetrization of diols (e.g. 271 and 272) (Scheme 40).[122] Numerous elegant The Strecker reaction has seen great utility, as it variations on the basic catalytic system (270) have provides an extremely direct route to α-amino acids been synthesized and investigated. Chemo- and and α-amino acid derivatives through simple starting enantioselectivities are generally very high and often materials. Numerous catalytic systems have been compete with enzymatic variants.[123] developed to promote asymmetric Strecker reactions and these have been reviewed extensively elsewhere.[127]

The Feng group reported the first metal-free catalyst systems for the highly enantioselective Strecker synthesis of ketimines (276), an important motif for the construction of quaternary α-amino nitriles (277).[128] The bulky Lewis N,N’-dioxide base catalyst (282) afforded the synthesis of a broad range of α,α- dialkylated amino nitriles in yields up to 99% and [128b] ee’s of up to 92%. Moreover, the construction of ketimines was also achieved using a chiral N-oxide (278) in combination with a sub-stoichiometric Scheme 40. Schreiner peptides (e.g. 270) as effective additive, 2,5-di-(1-adamantyl)hydroquinone (279, diol desymmetrization catalysts. DAHQ). This route produced excellent yields of between 90 - 99% and ee’s up to 91% (primarily 3.4 Reactions of 1,3-dicarbonyls favoring the S isomer) (Scheme 42).[128a]

Yao et al.[124] discovered that the cinchona alkaloid- Alkali-metal salt catalysts (i.e. 280) for the Strecker derived scaffold 274, in combination with synthesis have also been disclosed (Scheme 42). phenylisopropyl hydroperoxide, asymmetrically Catalytic amounts of para-tert-butyl-ortho- oxidises suitably protected 1,3-dicarbonyls (e.g. 273) adamantylphenol (281, PBAB) in combination with at the 2 position. After extensive screening, it was chiral sodium salts (280) were able to promote the determined that the use of adamantanecarboxylates

Scheme 43. Arduengo catalyst (92) promoted organocatalytic reactions.

Scheme 42. Strecker synthesis catalysts. 4. Summary and Outlook

3.6 NHC catalysis The ever-increasing number of ligand/catalyst combinations available to the organic chemist has The adamantyl system, mainly via Arduengo’s undoubtedly given access to a number of catalyst (92),[34] has been moderately utilized in NHC- transformations hitherto considered unattainable. mediated organocatalytic reactions.[130] This catalyst Adamantane (1), a cheap, readily available and easy also has applications in combination with transition to functionalize compound, has been an extremely metal catalysis as described in section 2.2 above powerful player within this context, providing a (Schemes 15 and 16). unique inertness in conjunction with a useful level of symmetrical steric bulk. Furthermore, even though Nolan’s group was the first to report that 92 catalyses adamantane does not offer any inherent transesterification reactions (i.e. 283 – 284) (Scheme stereochemical features, its bulk can instill a high 43).[131] The utility of 92 was further demonstrated by degree of asymmetric ligand control and may even assist in chiral separation, as recently reported for P- Song et al., who showed that aldehydes and ketones [135] (285) could be trifluoromethylated using stereogenic ligands. Therefore, it is clear that trimethylsilyl trifluoromethane (286, Scheme 43).[132] adamantane (1) will continue to maintain its A later report by the same group[133] revealed that 92 prominent status well into the future. facilitates smooth conversion of ketones (287) into TMS or TBS silyl enol ethers (288) via 289, which However, is adamantane the perfect inert steric bulk circumvents traditional procedures such as using provider for all ligand design? lithium N,N-diisopropylamide (Scheme 43). A polymer support version of Arduengo’s catalyst (92) In formulating this review it was evident that in a few has been reported. The recyclable catalyst was found cases, adamantane did not provide the key ingredient to promote, with outstanding catalytic activity, the to superior catalyst design. Four situations can arise; copper-assisted click reaction, affording 1,2,3- 1) the sheer size of adamantane can negatively affect triazoles.[134] catalyst performance, 2) the desired steric bulk provided by 1 cannot fully satisfy steric volume requirements (i.e. not big enough), 3) 1 may not impart enough basicity to the ligand through electron donation, or 4) the desired asymmetry is not able to be achieved. Examples to further highlight the first two situations are provided below.

Steric overcrowding 400

300 Throughout this review, we have illustrated many examples where the addition of extra bulk is 200 beneficial in promoting stereoselectivity, reducing the production of byproducts, increasing yields and / or 100 encouraging reaction with typically unreactive 0 substrates. However, too much congestion around the metal center of a catalyst may have the obvious absolute reactivity [1/h] consequence of blocking the approach of incoming substrates, effectively slowing or even stopping reaction progress. This may be observed in the work [108-109] Figure 9. Absolute rate of reactivity of Ad2PtBu phosphine of Togni, described here in section 2.7 (Scheme ligand in the Pd catalyzed Sonogashira coupling of tri- 35), wherein a series of novel Josiphos catalysts were substituted aryl bromides with phenylacetylene developed for use in asymmetric hydrogenation. Although the adamantyl ligand (239) provided a high level of asymmetric induction, as measured by the Higher steric demand Rh-catalyzed transformation of enamines (241) to protected amino acids (243), it was ultimately In other catalytic systems, however, increasing steric outperformed by the cyclohexyl derivative, 289 bulk beyond what the adamantane moiety can provide (Scheme 44). The observed difference in ee of has been an area of recent interest, albeit an area that approximately 10% is substantial in relative terms, requires further development. Schreiner’s group have and suggests that the adamantyl moiety perturbs been leading the charge with the development and use optimum substrate complexation in this instance. In of diamondoids,[1a, 30, 137] however, the higher another example, the Pt-catalyzed Sonogashira diamondoids remain relatively unexplored in the reaction of phenylacetylene and a sterically congested context of global catalyst design opportunities, even 2,4,6-iPr3 aryl bromide (293) with the Ad2PtBu ligand despite the ready availability of simpler members of (15) was found to be ca. 20 times slower than the the family (diamantane and triamantane, for example). same reaction using the analogous 2,4,6-Me3 aryl An interesting example by Schreiner and Glorius bromide (290, Figure 9).[136] demonstrated that diamantane, the second member of the diamondoid family, could be deployed for use in the Sonogashira coupling (Scheme 45).[1a, 137-138] Similarly to adamantane, diamantane has a relatively high melting point of 244-245.5oC[139] (compared to 266-268oC), suggesting that it should be highly polarizable and thus possess an elevated capacity for acting as an electron donor. In this case the diamantane version (294) of Arduengo’s catalyst (92) gave higher yields of the C-C coupled product (298), as compared to using 92. A similarly high yielding result was obtained when investigating the Suzuki– Miyaura coupling reaction of phenylboronic acid (22) with 4-bromotoluene (299) utilizing the cataCXium® AHI variant 295, giving 300 (Scheme 45).[137]

Scheme 44. Comparing adamantyl to cyclohexyl in Tongi asymmetric hydrogenations.

The physicochemical attributes of adamantane continue to provide optimum stabilization to ever increasingly reactive systems, which bodes well for the future development of new chemical transformations and understanding their reactive intermediates. Recent examples by Doye, Beckhaus and Meyer reinforce this trajectory.

Doye and Beckhaus et al.,[142] using titanocene 306, were able to capture, isolate and characterize mechanistic intermediates associated with the titanium-catalyzed hydroaminoalkylation of alkenes, and thus greatly assist in the mechanistic understanding of these reactions. Furthermore, an Scheme 45. Cross-coupling reactions promoted by efficient synthetic route to hydroaminoalkylation the diamantane containing ligand systems 294 and products 307 and 308 in high yield and selectivity 295. could be obtained starting from N-methylanilines (e.g. 304) and alkenes (e.g. 305) at slightly elevated What about hetero-adamantane variants? temperature (40°C) (Scheme 46).

Heteroatomic derivatives of adamantane (1) are known to promote a variety of chemical transformations, although this aspect will not be comprehensively reviewed herein. Nevertheless, some derivatives are worthy of note. For example, 1,3,5- triaza-7-phosphaadamantane (301),[140] which was observed amongst other reactions to catalyze the Baylis-Hillman reaction. In addition, as with the adamantane system, much of the utility is derived from the unique stability of 301 towards air and water. Scheme 46. C-H activation and trapping of key The tertiary nature of the phosphorous atom in these intermediates in the hydroamination of alkenes using compounds imparts greater nucleophilicity and lower titanocene 306. basicity, as well as a lower toxicity than their nitrogenous counterparts (i.e. 300).[140a] In another interesting example, the tetramethyl-2,4,8-trioxa-6- Finally, as chemists pursue more precise control over phosphaadamantane derivative 301 was reported by their syntheses, catalyst design will continue to seek Capretta to facilitate Suzuki-type cross couplings of novel and creative approaches. It is difficult not to alkyl halides containing β-hydrogens with either predict that adamantane will be omnipresent in this alkylboranes or boronic acids (Figure 10).[141] role by facilitating 1) ligand scope broadening, 2) Moreover, phosphaadamantanes are in general water reactive metal capture and taming and 3) controlling the electronic and steric environments of reaction soluble and thus potentially exploitable in a more [143] environmentally friendly manner. transition states and intermediates.

Acknowledgements

We thank the University of Queensland for financial support. CMW gratefully acknowledges an Australian Research Council Future Fellowship award (FT110100851). We gratefully acknowledge Tim Jepson and Samuel J. Richardson for the artwork contribution to the cover illustration. Figure 10. Hetero-adamantane derivatives.

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Catalysts Containing the Adamantane Scaffold

Adv. Synth. Catal. Year, Volume, Page – Page

Kylie A. Agnew-Francis and Craig M. Williams*