Journal Archive

Platinum Metals Rev., 2013, 57, (4), 234
doi: 10.1595/147106713X672311

The Directed ortho Metallation–Cross-Coupling Fusion: Development and Application in Synthesis

Platinum group metals catalytic synthetic strategy for pharmaceutical, agrochemical and other industrial products

  • By Johnathan Board
  • Snieckus Innovations,
  • Innovation Park, 945 Princess Street, Kingston, Ontario, K7L 3N6, Canada
  • Jennifer L. Cosman
  • Department of Chemistry, Queen's University,
  • 90 Bader Lane, Kingston, Ontario, K7L 3N6, Canada
  • Toni Rantanen, Suneel P. Singh and Victor Snieckus*
  • Snieckus Innovations,
  • Innovation Park, 945 Princess Street, Kingston, Ontario, K7L 3N6, Canada
    • *Email: victor.snieckus@chem.queensu.ca

Article Synopsis

This review constitutes a detailed but non-exhaustive examination of the directed ortho metallation (DoM)–cross-coupling fusion in its many flavours. Special attention is paid to the application of the concept of the linked reactions and the synthetic utility that it endows, particularly in the case of one-pot reactions that can greatly increase the ease and efficiency of the process. Personal experience of particular issues that can arise from these reactions and examples of their solutions are given, as well as illustrations of the rapid access to complex molecules that the technique encourages.

Introduction

Since its disclosure, the combination of DoM and transition metal-catalysed cross-coupling has evolved into a common strategy in synthesis (1, 2) and, in particular, has found widespread use in the preparation of biologically interesting aromatic and heteroaromatic compounds. A variety of functional groups such as I, Br, Cl, SiR3, SnR3, B(OR)2 have been introduced using DoM, followed by different cross-coupling reactions to form carbon–carbon, carbon–oxygen, carbon–nitrogen and carbon–sulfur bonds in order to prepare synthetically and biologically interesting molecules. Herein we present selected examples of the use of the DoM–cross-coupling strategy from the period of 2000 to 2012 in order to demonstrate its advantages and outline the potential issues that may be faced in its application. The main focus will be on cross-couplings involving the platinum group metals (pgms); however several examples using other metals such as copper are included for comparison. In order to make this review more accessible, it is divided into sections according to the type of bond being formed and the type of metallation reaction. For further clarification, a scheme describing the reaction discussed appears at the beginning of each section.

1. DoM–C–C Cross-Coupling Reactions

 

1.1 Sequential (Multi-Pot) DoM–Cross-Coupling Methods

The formation of C–C bonds through the sequence of DoM–halogenation to insert an ortho halide or pseudohalide, followed by cross-coupling has been carried out using Ullmann, Heck, Sonogashira, Negishi, Stille and Suzuki-Miyaura reactions, among others. As an example, Sanz et al. (3) have synthesised valuable 4-fluoro-2-substituted-1H-indoles 4 through a sequence involving DoM mediated iodination of 3-fluorotrifluoroacetanilide 1, followed by reaction with terminal aromatic or aliphatic alkynes by a Sonogashira coupling–cyclisation process (Scheme I). When the DoM reaction was carried out at temperatures higher than –60°C, competitive lithium fluoride elimination took place forming a benzyne intermediate 5 which underwent subsequent intramolecular cyclisation to provide iodinated benzoxazole 7. This phenomenon occurring during the directed metallation of 3-fluoroaniline bearing N-pivaloyl, N-Boc directing metallation groups (DMGs) or an N-benzoyl group had been previously observed (4).

Scheme I.

Sequential DoM and Sonogashira cross-coupling for the synthesis of indoles

 

The Suzuki-Miyaura cross-coupling is one of the most popular and widely used reactions in the C–C DoM–cross couple fusion strategy (for examples, see (5, 6)). When partnered with DoM, the major advantage of the Suzuki-Miyaura reaction is that boronation reagents such as B(OR)3 are often compatible with lithium bases (usually lithium dialkylamides, but some boronates are even compatible with s-BuLi) (7). This allows the boronating agent to be present in the same reaction vessel as the base in order to quench the metallated species as it is formed. These conditions are known in our laboratories as either Barbier or Martin (8, 9) type conditions according to the order of addition. (Descriptions of these in situ quench conditions are as follows: under Barbier type conditions the base is added to a mixture of substrate and electrophile; under inverse Barbier conditions a solution of substrate and electrophile are added to a solution of the base; under Martin conditions the substrate is added to a solution of base and electrophile; under inverse Martin conditions a solution of base and electrophile are added to a solution of the substrate. Compatible electrophiles include, but are not limited to, trimethylsilyl chloride (TMSCl), Me2SiCl2, B(OMe)3 and B(OiPr)3.) Halide sources are not usually compatible with strong bases; for instance, premixing I2 and lithium 2,2,6,6-tetramethylpiperidide (LiTMP) before addition of the metallation substrate has resulted in low yields of iodinated material in our laboratories. Vedsø et al. have shown that ester, cyano and halogen substituents are tolerated when LiTMP/B(OiPr)3 is used for in situ boronation of unstable ortho metallated species (10).

In our group we have found that the DoM–cross-coupling strategy finds particular utility in the functionalisation of indoles. Stimulated by work performed by Iwao et al. (11), we have developed routes to 3,4-substituted indoles by utilising DoM–Negishi cross-coupling sequences to afford gramines 8 which undergo useful retro-Mannich fragmentation to give indoles 9 (12). Similarly, C-7-substituted indoles 12 have also been synthesised by either sequential or one-pot C-2 metallation, C-2 silylation, C-7 metallation and C-7 electrophile treatment of indoles 10 to provide the boronates or halides 11, followed by Suzuki-Miyaura cross-coupling to give 12 (13). In addition, 2-aryl/heteroarylindoles 15 have also been synthesised from N-carbamoyl-2-bromoindoles using either Suzuki-Miyaura (13a) or one-pot ipso borodesilylation–Suzuki-Miyaura (13b) reactions to provide indoles 14, followed by a lithium diisopropylamide (LDA)-induced anionic N–C carbamoyl migration (Scheme II) (14).

Scheme II.

Indole functionalisation utilising the DoM and cross-coupling protocol

 

Due to the higher C–H acidity of heteroaromatic systems, the DoM component of the DoM–cross-coupling fusion of these systems is dominated by the use of bases other than butyllithium, such as the lower pKa lithio dialkylamides or Grignard bases; the cross-coupling component has been dominated by Suzuki-Miyaura and Negishi reactions. The consideration of which base to choose is heavily influenced by the DMG and by the other functionalities within the system. For instance, if the DMG is a halogen then benzyne formation may need to be avoided through the use of lower temperatures or milder bases less prone to induce MX elimination. On the other hand, if the DMG is weak and the system is electron rich then stronger bases will be required which may result in nucleophilic attack of the base upon the heteroaromatic ring, especially in the case of π-deficient systems. Usually the accepted wisdom is to use as mild a base as possible, at a temperature as close to room temperature as is possible in order to achieve the greatest degree of functional group compatibility and experimental simplicity. Certain DMGs are less tolerant of higher temperatures than others, such as N,N-diethyl-O-carbamate which may undergo the anionic ortho Fries rearrangement (1, 15, 16). We have found also that the variation of solvents can have a profound effect on the selectivity of the metallation; in particular the switch between tetrahydrofuran (THF) and diethyl ether can make the difference between the success or failure of a reaction.

Although in many cases this type of DoM–cross-coupling strategy can be performed with relative ease simply by using conditions precedented for a similar system, both the DoM and cross-coupling may have non-trivial problems which should be solved through methodical application of standard optimisation techniques, such as variation of solvent, base and catalyst system. An instructive example concerns work which eventually led to the discovery of soraprazan (16, Figure 1), a clinically studied H+/K+-ATPase inhibitor (17).

Fig. 1.

Soraprazan, a H+/K+-ATPase inhibitor (17)

 

Thus, as shown by deuterium quench experiments, the ortho deprotonation of an N-pivaloyl imidazo[1,2-a]pyridine 17 gave the highest ratio of C-5:C-7 (18:19) deprotonation when t-butyllithium was used in diethyl ether (Scheme III). When this reaction was performed in THF, products 18 and 19 were obtained in almost equal conversion. These results were rationalised by the observed poor solubility of the kinetically preferred C-7-anion in diethyl ether which presumably prevented it from undergoing equilibration with the more thermodynamically preferred C-5-anion. On the other hand, in THF the greater solubility of the C-7 anion allowed it to equilibrate with the C-5 anion thereby eradicating the selectivity. When the reaction was performed using the weaker n-butyllithium, no selectivity between C-5 and C-7 metallation was achieved, and a large amount of starting material was recovered even when the reaction was conducted over longer periods of time or at higher temperatures. This is presumably due to the moderate ortho-directing ability of the N-pivaloyl group. Use of the optimised deprotonation conditions followed by stannylation afforded the desired C-7 product 21 in acceptable yield in a 1:9 ratio together with the undesired C-5 regioisomer 20.

Scheme III.

DoM studies of the N-pivaloyl-imidazo[1,2-a]pyridine 17 (17)

 

The derived compound 21 was used in acylative Stille cross-couplings with cinnamoyl chlorides to give compounds 23, which by straightforward acid-mediated Michael cyclisation-depivaloylation afforded compounds 24, which are intermediates for sorapazan (16) and its analogues (Scheme IV). The execution of the Stille cross-coupling was far from trivial and therefore deserves comment. Experiments with a variety of palladium sources were unsuccessful and only the combination of PdCl2(MeCN)2 and a three-fold excess of the cinnamoyl chloride led to cross-coupled products 23, in poor yields, which precipitated from the reaction mixture as the hydrochloride salts. The known advantages of using halide salts in Stille cross-couplings of aryl triflates (18–20) led to speculation about the role of halide salts in the reaction. Thus, on addition of one equivalent of lithium chloride to the reaction mixture, conversion to products 23 was achieved in moderate yield.

Scheme IV.

Acylative Stille cross-coupling of 21 to provide products 23 and thence sorapazan precursors 24

 

Despite the demonstration in our laboratories of the advantages of performing a DoM–Suzuki Miyaura cross-coupling in a one-pot fashion (such as fewer chemicals used, eradication of at least one workup step, higher efficiency and convenience), most reported reactions are performed with isolation of the DoM products. Schemes V and VI (21, 22) depict cases in which the boronic acids 26 and 30, generated from DoM reactions, are isolated prior to cross-coupling. Of particular note is the low yield of boronic acid 30, which is likely attributable in part to the instability of this heterocyclic boronic acid.

Scheme V.

Sequential DoM–Suzuki Miyaura synthesis of arylpyridazines 28 (21)

 

 

Scheme VI.

Sequential DoM–Suzuki Miyaura synthesis of aryl-2-chloropyridines 31 (22)

 

 

1.2 One-Pot DoM–Cross-Coupling Methods

A more efficient process than shown so far is a DoM–cross-coupling protocol carried out without isolation of the intermediate species (boronic acid, zincate for instance) which is most often accomplished using Suzuki-Miyaura or Negishi cross-coupling reactions. For instance, as part of a campaign towards the synthesis of the antimicrobial agent GSK966587 (32, Figure 2), a ‘one-pot’ DoM–cross-coupling method was developed (23).

Fig. 2.

Antimicrobial agent GSK966587

 

Thus, the DoM–iodination reaction of 33 was investigated (Scheme VII) in preparation for Heck coupling chemistry (Scheme VIII). The use of the more traditional alkyllithium and lithium amide bases was complicated by the formation of dianions and by competitive fluoride displacement. The use of LDA at low temperatures under short reaction times was promising but gave mixtures of both mono-iodides 34 and 35 and bis-iodide 36. Although the Uchiyama zincate mixed metal base TMPZn(tBu)2Li gave predominantly the undesired mono-iodide 35, the analogous (iPr)2NZn(tBu)2Li gave an encouraging result. A further shift to (iPr)2NZnEt2Li (prepared by mixing Et2Zn and LDA) gave excellent selectivity for the desired iodide 34 which was eventually isolated in 85% yield (74% from starting material 39, Scheme VIII).

Scheme VII.

DoM route to 7-fluoro-8-iodo-2-methoxynaphthyridine 34 (23)

 
Scheme VIII.

Sequential and ‘one-pot’ DoM–Heck coupling synthesis of naphthyridine 37 (Note: The authors provide the yields for the optimisation, but also for a process whereby all of the batch is taken through the whole process with only minimal purification. Hence overall yields comparing the two processes are given even though no yield is given for the conversion of 39 to 33)

 

After extensive screening, Heck coupling of iodide 34 with allyl alcohol was achieved to give the α-coupled product 37 in 77% yield (57% yield from 39, Scheme VIII). As a more efficient alternative to this sequential procedure, the Negishi cross-coupling of the zincate intermediate 38 (the presumed metallated species from the DoM reaction of 33) was realised and gave a comparable yield of 37 (68% yield from 39) but required no iodine and fewer purification steps.

By its nature, the DoM–Negishi cross-coupling protocol lends itself to a one-pot procedure whereby the deprotonation, transmetallation (if necessary) to a zincate and transition metal-catalysed cross-coupling occur sequentially in the same reaction vessel. Among the cases illustrated in Schemes IX–XI (24–26), of note is the use of the oxazole DMG which by hydrolysis provides the desired carboxylic acid in the target molecule 43 (Scheme IX). This is a further demonstration of the use of tetrazole as a DMG in the synthesis of the ‘sartan’ pharmaceutical 46 (Scheme X) and the use of catalytic zinc chloride and of the pyridine N-oxide as a DMG in the preparation of azabiaryl 49 (Scheme XI).

Scheme IX.

One-pot DoM–Negishi cross-coupling strategy for the synthesis of telmisartan 43 angiotensin II receptor antagonist (24)

 
Scheme X.

One-pot DoM–Negishi cross-coupling strategy to synthesise valsartan 46 angiotensin II receptor agonist (25)

 
Scheme XI.

One-pot DoM–Negishi cross-coupling strategy using catalytic zinc chloride for the synthesis of azabiaryl N-oxide 49 (26)

 

Recently, a one-pot DoM–Negishi cross-coupling strategy that can utilise esters as DMGs has been developed by Knochel and coworkers involving the amide bases tmpMgCl·LiCl (tmp = 2,2,6,6-tetramethylpiperidyl), tmp2Mg·2LiCl and tmp2Zn·2MgCl2·2LiCl (27). These bases are used in stoichiometric amounts (no extreme excess is required), facilitated by LiCl which complexes and solubilises the bases and leads to monomeric metallic amides. Due to its stability (at least 6 months at 25°C under inert atmosphere) (28, 29) tmpMgCl·LiCl is commercially available and is capable of metallating moderately C–H acidic aromatic compounds. For more demanding aromatic cases tmp2Mg·2LiCl (30) may be used and for systems that contain sensitive functional groups tmp2Zn·2MgCl2·2LiCl (31) has proven to be effective. Unfortunately the latter two bases are not as stable as tmpMgCl·LiCl; for instance tmp2Mg·2LiCl is stable only for 24 h at 25°C (27). These reagents are usually prepared fresh for each reaction, or set of reactions, from tmpMgCl·LiCl by the addition of LiTMP or ZnCl2, respectively. The use of these bases for combined metallation–cross-coupling reactions greatly increases the potential substrate scope of this strategy, as illustrated by the synthesis of aromatic esters 51, 53 and 55 (Schemes XII–XIV). Noteworthy is the last case since nitrile groups are not normally compatible with the use of Grignard reagents. In addition, only 0.5 equivalents of tmp2Zn·2MgCl·2LiCl are required (i.e. both potential TMP anions are available) and transmetallation is unnecessary as this reagent directly provides a zincate suitable for Negishi cross-coupling under relatively standard conditions. Although these reactions were developed and optimised on 1–2 mmol scale, all of these examples were performed on 80–100 mmol scale in order to demonstrate good scale up potential.

Scheme XII.

One-pot DoM–Negishi cross-coupling protocol using commercially available tmpMgCl·LiCl

 
Scheme XIII.

One-pot DoM–Negishi cross-coupling protocol using tmp2Mg·2LiCl

Scheme XIV.

One-pot DoM–Negishi cross-coupling protocol using 0.5 equivalents tmp2Zn·2MgCl·2LiCl

 

The combined DoM–Suzuki-Miyaura cross-coupling also lends itself to a one-pot procedure. An illustration of this is our recent extension of previous work on one-pot DoM–Suzuki-Miyaura reactions (32), in which the synthesis of heterobiaryl sulfonamides was developed with the aim of increasing the available methodology for the construction of bioactive molecules bearing the popular sulfonamide pharmacophore (Scheme XV) (7).

Scheme XV.

One-pot DoM–Suzuki-Miyaura cross-coupling route to heterobiaryl sulfonamides 57 (7)

This one-pot metallation-boronation–cross-coupling procedure was generalised for tertiary and secondary sulfonamides 56 in couplings with electron-rich and -poor aryl and heteroaryl bromides and chlorides to furnish biaryl sulfonamides 57. A change to a bulkier catalyst was needed when meta or ortho substituted sulfonamides were used as shown by example 57c.

1.3. Iridium-Catalysed Boronation–Suzuki-Miyaura Cross-Coupling: A Complementary Method

The knowledge that iridium-catalysed boronation of aromatics is qualitatively determined by steric effects (33–37) led us to explore this reaction in DMG-bearing substrates in order to establish complementarity with the DoM–Suzuki-Miyaura cross-coupling process (Scheme XVI) (38). Thus, complementary methods of considerable scope for the synthesis of biaryls and heterobiaryls were demonstrated by C–H activation at C-2 (DoM) and at C-3 (Ir-catalysed boronation) of 58 which offer new routes for the regioselective construction of substituted biaryls 60 and 59 respectively.

Scheme XVI.

Complementary ortho and meta boronation/Suzuki–Miyaura cross-coupling reactions of DMG bearing aromatics (38)

1.4 The Use Of DoM–Cross-Coupling Strategies in Total Synthesis

We have also employed the DoM–cross-coupling strategy as part of syntheses of targeted drugs and natural product intermediates. In 2004, we reported a synthesis of the tetracyclic A/B/C/D ring core 66 of the antitumour agent camptothecin (Scheme XVII) (39). This route is highlighted by an anionic ortho-Fries rearrangement of O-carbamate 61 to give the quinolone 62, a Negishi cross-coupling of triflate 63 to give biaryl 65, and a modified Rosenmund–von Braun reaction to provide the tetracyclic core 66 of the antitumour alkaloid camptothecin in seven steps with an overall 11% yield.

Scheme XVII.

Key reactions in the synthesis of the tetracyclic core 66 of camptothecin: anionic ortho-Fries rearrangement 61–62 and Negishi cross-coupling 64–65 (39)

 

Most recently, we have completed a total synthesis of schumanniophytine 72 (Scheme XVIII) (40), a natural product which had been prepared only once previously (41). Starting with DoM chemistry to obtain the cross-coupling partners 68 from 67, our route takes advantage of a combined DoM–cross-coupling strategy using Stille or Suzuki-Miyaura reactions to synthesise biaryl 69, and also incorporates a key ortho-silicon-induced O-carbamate remote anionic Fries rearrangement of carbamates 70 to provide amides 71.

Scheme XVIII.

Key reactions in the total synthesis of schumanniophytine 72 (40)

2. DoM–C–Heteroatom (N, S, O) Cross-Coupling Reactions

 

With the advent of transition metal-catalysed C–N, C–O and C–S cross-coupling technologies, these reactions have also been fused with DoM and the combined DoM–heteroatom cross-coupling methodology has become viable for the construction of biologically interesting molecules and natural products. Thus the naphthyldihydroisoquinoline alkaloid ancistrocladinium B 76 (Scheme XIX), which shows high in vitro antileishmanial activities, has been synthesised from 73 via methoxymethyl (MOM) directed metallation-bromination to provide bromide 74, followed by Buchwald-Hartwig amination to furnish the key intermediate 75. The synthesis of ancistrocladinium C (77) was also achieved using a similar strategy (42).

Scheme XIX.

Synthesis of ancistrocladinium B 76 as atropo-diasteromers (P/M) 46/54 and ancistrocladinium C 77 as atropo-diasteromers (P/M) 3/2 using a DoM–C–N cross-coupling strategy (42)

 

Similarly, the construction of a C–O bond has been accomplished using DoM–cross-coupling strategies. Although copper catalysis is the preferred choice for C–O bond formation (43–45), it is also possible to use pgm catalysis as an alternative (46–48).

Among the DoM–C–heteroatom cross-coupling strategies, the DoM–C–S regimen is far less evident in the literature. In an instructive study which shows the utility of inverting the coupling partners, substituted 2-iodo-anisoles 79 (Scheme XX) were synthesised using DoM chemistry and subjected to Buchwald-Hartwig coupling with 3-fluorobenzenethiol 81, to afford biaryl sulfide derivatives 83 which were further modified to give the desired compounds 84. Alternatively, 3-chloro-2-methoxyphenyl thiol 80 was coupled with 3-fluoroiodobenzene 82 to furnish similar analogues 83. These were demonstrated to possess in vitro potency for blocking glycine transporter-1 (GlyT-1), which has been recognised as a potential strategy for the treatment of schizophrenia (49).

Scheme XX.

DoM–C–S cross-coupling route to diaryl sulfides 84

3. DoM–Halogen Dance–Cross-Coupling Reactions

 

The DoM reaction on halogenated aromatic and heteroaromatic compounds may be accompanied by halogen dance reactions in which halogens, most notably iodine, undergo migration to the incipient anion and provide, generally but not invariably, the most thermodynamically stable anion (50). This not only provides an option to halogenate positions which are otherwise difficult to access, but also enables the introduction of an external electrophile at the site bearing the newly formed anion. In this context, we have developed routes to polyfunctionalised pyridines (51) and others have utilised halogen dance in the formation of heterobiaryls (Scheme XXI) to provide substituted 2-arylquinolines as novel CRF1 receptor antagonists (52). Thus, metallation-iodination of quinoline 85 afforded iodoquinoline 86 which, when subjected to a second metallation-protonation, gave the halogen dance product 87. Suzuki-Miyaura cross-coupling and subsequent steps led to the substituted arylquinolines 88. We have found that it is important to be vigilant for potential undesired halogen dance reactions which may arise in many metallation reactions of halogenated heterocycles.

Scheme XXI.

Metallation–halogen dance–Suzuki-Miyaura route to 2-arylquinoline 88 CRF1 receptor antagonist

4. DoM–Cross-Coupling–DreM Reactions

 

The synthesis of interesting polycyclic aromatic and heteroaromatic molecules has a long history in the Snieckus laboratories (a recent example uses the Suzuki-Miyaura cross-coupling (53)). To construct these systems, the directed remote metallation (DreM) reaction (54, 55) on specifically designed 2-DMG biaryls is the key reaction to forge the central aromatic bridging ring. Generally this method complements already established methods for their synthesis and allows easy access to previously unreported compounds. The standard conditions for a DreM reaction are formation of the anion by treatment with LDA at –20°C or 0°C, followed by warming to room temperature to ensure completion of the anionic cyclisation. Depending on the type of substituents in the biaryl starting material, often a minimum of 2 equivalents of LDA is required, proposed to be due to ‘losing’ one or more equivalents to coordination with these substituents.

4.1 Synthesis of Biaryls Using DoM–Cross-Coupling Reactions

For the construction of requisite biaryls, the DoM–Suzuki-Miyaura protocol is frequently practiced, although other cross-coupling strategies such as DoM–Negishi are also used. Thus, in general (Scheme XXII), cross-coupling partners 2-halodiethylbenzamides 91 and boronic acids 92 are synthesised using standard DoM conditions from diethylbenzamides 89 and by metal halogen exchange on bromobenzenes 90 respectively, although currently many of the boronic acids may be purchased. Alternatively, the cross-coupling partners may be inverted so that DoM derived boronic acids 91 (X = B(OH)2) may be directly coupled with aromatic triflates or with bromobenzenes 90 without the need for metal halogen exchange. We have found that the Suzuki-Miyaura reaction usually requires only minimal development using standard palladium sources and ligands, although the reactions are still substrate dependent. On the other hand, certain boronic acids, especially heteroaromatic cases, can be difficult to handle and unstable due to their propensity for protodeboronation. As a notable example, we have learned from experience that 3-methoxy-N,N-diethylbenzamide-2-boronic acid is difficult to isolate, and is reliably synthesised only if the aqueous quench of the reaction mixture is performed at –40°C slowly by the addition of a CH2Cl2/H2O mixture. Others have reported similar problems regarding this boronic acid (56).

Scheme XXII.

DoM–Suzuki-Miyaura cross-coupling synthesis of biaryls 93

 

The absence of reports concerning aryl sulfonamide ortho-boronic acids prompted a study in which the problems associated with the synthesis of this class of unstable boronic acids was solved, at least in this particular case (7). Although it was determined that metallation of aryl sulfonamides proceeds uneventfully, as evidenced by deuterium quench experiments, quenching the metallated species with B(OR)3 reagents followed by aqueous workup provided boronic acids in low yields, accompanied by recovery of starting material, which suggested instability of the ortho-boronic acids. This problem was circumvented by utilising an in situ quench with MeOBpin or iPrOBpin as electrophiles, leading directly to the boropinacolate derivatives which are known to be more stable than the corresponding boronic acids. Similarly in the even more unstable pyridine boronic acid series, in situ formation of boropinacolates was advantageous in isolation of compounds useful for Suzuki-Miyaura cross-coupling reactions (32).

Another solution for the synthesis of problematic arylboronic acids stemming from our laboratories is the ipso-borodesilylation reaction of trimethylsilyl arenes (57). The silylated starting materials are readily obtained in high yields using DoM chemistry, and are quite stable with the exception of certain heteroaromatic silanes. Treatment with BCl3 or BBr3 affords the Ar-BX2 species which, without isolation, may be converted into the corresponding boropinacolates by stirring with pinacol, or otherwise may be used directly in a one-pot cross-coupling process.

4.2 Combined DoM–Suzuki-Miyaura–DreM Synthesis of Fluorenones

Treatment of biaryl-2-amides 93a, derived from DoM–cross-coupling reactions, under standard DreM conditions results in alternate ring deprotonation followed by cyclisation to provide fluorenones 94 in good yields (Scheme XXIII). As ourselves and others (58, 59) have demonstrated, various substituted fluorenones, azafluorenones and two natural products dengibsinin 95 and dengibsin 96 may be synthesised using this strategy (60, 61).

Scheme XXIII.

Synthesis of fluorenones using the combined DoM–cross-coupling–DreM strategy for dengibsinin 95 and dengibsin 96

 

Generally the highest yields are obtained for biaryl cases bearing an additional 3′-DMG which promotes synergistic metallation, thereby leading to regioselective cyclisation. In the synthesis of azafluorenones 99 using this strategy (Scheme XXIV), the use of a one-pot DoM–Suzuki-Miyaura protocol was essential due to the instability of the pyridyl boronates towards protodeboronation (32).

Scheme XXIV.

One-pot DoM–Suzuki-Miyaura–DreM synthesis of azafluorenones 99 (32)

This method proved useful for the construction of diverse azafluorenones with electron-donating and electron-withdrawing substituents. This sequential DoM–cross-coupling–DreM strategy allows the construction of azafluorenones which are inaccessible or afford isomeric mixtures by the traditional Friedel-Crafts reactions.

4.3 Combined DoM–Suzuki-Miyaura–DreM Synthesis of Phenanthrols and Phenanthrenes

Treatment of biaryls exhibiting 2′-methyl substituents 93b under standard DreM conditions affords 9-phenanthrol derivatives 100 (Scheme XXV). The deprotonation is often – but not always – indicated by a deep red colour attributed to the generated tolyl anion. Conversion of the resulting phenanthrols 100 to phenanthrenes 101 is readily achieved using triflation followed by palladium-catalysed hydrogenolysis. Often no purification is required for the intermediate steps, and the final phenanthrenes may be obtained in good yield and high purity after a simple recrystallisation.

Scheme XXV.

Synthesis of phenanthrenes 101 by the combined DoM–Suzuki-Miyaura–DreM strategy

This route is scalable and reliably provides substituted phenanthrenes in high purity which have been used successfully in our collaborative projects to conduct toxicity studies concerning the effects of substituted polyaromatic hydrocarbons on fish (62).

4.4 Combined DoM–Suzuki-Miyaura–DreM Synthesis of Acridones and Benzazepinones

A DreM process analogous to that shown in Scheme XXV may also be achieved on diarylamines 103, which are prepared using palladium-catalysed Buchwald-Hartwig cross-coupling of anilines 102 with DoM derived halo or pseudohalo diethylbenzamides 91, followed by N-alkylation. Thus treatment of diarylamine 103a (R2 = H), under standard DreM conditions provides acridones 104a (n = 0) in good to excellent yields. In an analogous fashion to the formation of phenanthrenes (Scheme XXV), subjection of the diarylamine 103b (R2 = Me) to standard DreM conditions affords dibenzazepinones 104b (n = 1), also in good to excellent yields (Scheme XXVI) (63).

Scheme XXVI.

Synthesis of acridones and dibenzazepinones using DoM–C–N cross-coupling–DreM strategy

These protocols constitute anionic equivalents of Friedel-Crafts type cyclisations affording acridones, and complement existing syntheses of dibenzoazepinones, compound classes which both exhibit significant bioactivities. For instance, acridone derivatives possess antimalarial properties (64), and dibenzoazepinone derivative trileptal is an antiepileptic drug (65).

In a collaborative study, we investigated the multi-nitrogen-containing imidazo[1,5-a]pyrazine 105 for use as a scaffold for the preparation of potentially bioactive molecules. Without prediction based on available precedent, the metallation of 105a and 105b followed by iodination afforded C-5 iodinated compounds 106a and 106b in high yields. Subsequent Suzuki-Miyaura cross-coupling with 2-(diethylcarbamoyl)phenylboronic acid (synthesised from N,N-diethylbenzamide using a DoM protocol) provided biaryls 107a and 107b. Treatment of 107b with LiTMP at cryogenic temperatures furnished the previously unknown triazadibenzo[cd,f]azulen-7(6H)-one 108b (Scheme XXVII) (66). To the best of our knowledge, DreM processes of complex heterocycles such as 107 had not been previously reported.

Scheme XXVII.

DoM–Suzuki–DreM–cyclisation route to triazadibenzo[cd,f]azulen-7(6H)-one 108b (64)

5. Scale-Up and Industrial use of DoM–Cross-Coupling–DreM Reactions

If proper safety protocols are followed and temperature and stirring of the reaction mixture are controlled and maintained, metallation chemistry may be effectively used for large scale synthesis. In fact, there is often no viable alternative to the use of a DoM–cross-coupling sequence at multi-kilogram scale in the pharmaceutical and fine chemical industry (67–69). For instance, Merck has recently demonstrated a practical, efficient and multi-hundred gram synthesis of 3-bromo-6-chloro-phenanthrene-9,10-dione 113 using a DoM–cross-coupling–DreM sequence (Scheme XXVIII) (70). Compound 113 is a useful building block for the preparation of pharmaceutically important phenanthrenequinones and phenanthreneimidazoles.

Scheme XXVIII.

Large scale synthesis of phenanthrene-9,10-diones 113 using a combined DoM–cross-coupling–DreM strategy. 109 was used at a scale of 245.7 g, 111 was produced at a scale of 311.5 g and 112 at 200 g (68)

 

Similarly, as further evidence of utility, Merck has achieved a kilogram-scale chromatography-free synthesis of mPGE synthase I inhibitor MK-7285 119 (Scheme XXIX) (71). Thus DoM–boronation of 114 provided the lithioborate 115 which, without isolation, was subjected to Suzuki-Miyaura cross-coupling with bromobenzene 116 to afford biaryl 117. In the key step, treatment of biaryl 117 with lithium diethylamide resulted in a DreM cyclisation to provide the phenanthrol 118 in acceptable yield. A significant observation was that in the DreM reaction, at concentrations greater than 0.24 M, competitive intermolecular condensation provided 5–10% of an undesired product.

Scheme XXIX.

Large scale synthesis of mPGE synthase I inhibitor 119 using the combined DoM–cross-coupling–DreM strategy. 114 was used at a scale of 3.75 kg, 117 was produced at a scale of 7.69 kg (69)

6. Diversification of the DoM–Cross-Coupling Strategy

 

The unique power and considerable synthetic advantage of DoM chemistry is the regioselective ortho introduction of only one functional group per DMG. Furthermore, synthetic strategies may be devised to use the same DMG to achieve 2,6-disubstitution and thus to construct 1,2,3-trisubstituted aromatic systems (72). Using the N-cumylsulfonamide DMG, this strategy has been adapted for the synthesis of 7-substituted saccharins (Scheme XXX) (73). Thus, as conceptually illustrated below, the straightforward DoM–halogenation–Suzuki-Miyaura coupling of N-cumylbenzenesulfonamides 120 provided, via iodide 121, the biaryls 122. Then the same N-cumyl sulfonamide DMG served for a second DoM–carbamoylation to furnish the biaryl amide sulfonamide 123. Decumylation of 123 using TFA, followed by acid-mediated cyclisation gave rapid access to saccharins 124 in good overall yield.

Scheme XXX.

Double use of the N-cumylsulfonamide DMG in the synthesis of substituted saccharins 124

Aside from interesting pharmaceutical properties and use in the fields of flavour, polymer and coordination chemistry, the saccharin core has played a role in the discovery of a human leukocyte elastase inhibitor, KAN400473 (125, Figure 3), used for the treatment of emphysema (74). It also features in the Merck carbapenem antibacterial agents (126, Figure 3) (75).

 
Fig. 3.

Biologically active saccharins KAN400473 125 and Merck antibacterial agents 126

 

Double DoM–double cross-coupling reactions involving multiple DMGs are also useful synthetic tactics. Thus the first total syntheses of natural, unsymmetrical 2′,3′-diacyloxy-p-terphenyls, thelephantin O 131a (Scheme XXXI) and terrestrins C and D (131b and 131c, respectively), were achieved using double DoM and bromination of 127 to give the hexasubstituted benzene 128 which, after Suzuki-Miyaura cross-coupling with 129, afforded the key intermediate teraryl 130. Synthesis of the symmetrical diesters vialinin A/terrestrin A 131d and terrestrin B 131e was also achieved using the same sequence (76).

Scheme XXXI.

Synthesis of teraryl natural products using double DoM–Suzuki-Miyaura cross-coupling sequence

7. The DMG as a Pseudohalide in Cross-Coupling Reactions

 

As documented in this review, cross-coupling of DoM derived species such as B, Zn, Sn and Mg has become a highly useful synthetic strategy. The development of DMGs that themselves act as cross-coupling partners was first achieved in our group with O-carbamates (77) and subsequently with sulfonamides (78) under Ni(acac)2 conditions. Furthermore, these DMGs may be excised from the aromatic framework using the β-hydride donor properties of iPrMgCl and iPr2Mg respectively, thus establishing the latency concept of DMGs (77, 78). Recently additional DMGs such as ethers, esters, O-carbamates under Suzuki-Miyaura conditions (79, 80) and O-sulfamates (79) have been established as cross-coupling partners (81). The non-reactive nature of some of these groups in palladium-catalysed coupling reactions allows the establishment of orthogonal processes (82, 83). For example, subsequent to work in our laboratories (80), Garg et al. (84) recently explored regioselective construction of biaryls based on differential reactivity of bromide, O-carbamate and O-sulfamate groups toward Pd and Ni catalysts (Scheme XXXII). Thus, DoM–bromination of 132 furnishes aromatic bromide 133, which undergoes sequential and selective palladium-catalysed Stille, nickel-catalysed Suzuki-Miyaura and nickel-catalysed C–N cross-coupling to rapidly provide biaryl 136 in good yield. Recent efforts on transition metal-catalysed cross-coupling reactions of new O-based electrophiles via C–O bond activation have focused on nickel and iron based catalysis (85–87).

Authors’ note added in proof: after the submission of this review, Feringa and co-workers established the palladium-catalysed cross-coupling of alkyl, alkenyl and aromatic lithiates (some derived using DoM) with aromatic bromides (88).

Scheme XXXII.

Use of O-carbamate and O-sulfamate DMGs as cross-coupling partners

 

Conclusions

This brief review has demonstrated that the combined DoM–cross-coupling strategy, first developed in our laboratories in the mid-1980s, has considerable value in organic synthesis. In this aim, we have attempted firstly to provide supportive evidence using selected recent examples derived from industrial and academic laboratories, including many from our own work. Emphasis has been placed on heterocycles, which constitute 80% of current marketed drugs, with synthetic case studies on a variety of bioactive molecules in early, clinical or process stages of development, including soraprazan (Figure 1), GSK966587 (Figure 2), ancistrocladinium B and C (Scheme XIX) and CRF1 receptor antagonist (Scheme XXI). As will be recognised, the heterocycles range from recognisable to more unusual and complex frameworks (for example Scheme XXVII). The pgms, particularly palladium, catalyse many of the processes, contributing to the enormous versatility of this strategy.

The second aim of the review has been to offer, in various described processes, practical from-the-bench tips based on our experience, at least in small-scale reactions. These include the advantage of deuterium-quench experiments to establish the extent of the DoM step before taking the road to scale-up (for example Scheme III), and the caveat regarding purity of starting materials and their instability.

Prognosis for the DoM–Cross Coupling Strategy

Emerging from the content of this review are the following features:

  1. DoM–C–C Cross-Coupling Reactions

    • This section suggests that among the cross-coupling reactions used in combination with DoM: Ullmann, Heck, Sonogashira, Negishi, Stille and Suzuki-Miyaura, the latter dominates the synthetic landscape with increasing presence of the Negishi protocol.

    • The advent of new nontraditional lithium bases such as the commercial Knochel type tmpMgCl·LiCl combined with zinc transmetallation and Negishi coupling (Scheme XII) are beginning to provide more convenient conditions for the DoM–cross-coupling strategy.

    • Iridium-catalysed boronation offers a complementary method for meta boronation compared to the DoM–Suzuki-Miyaura coupling process (Scheme XVI).

    • Only an inkling has been given of the potential for DoM–cross-coupling in natural product synthesis (Schemes XVII and XVIII) and this can only be expected to grow in importance.

  2. DoM–C–Heteroatom (N, S, O) Cross-Coupling Reactions

    • Based on our literature review, this motif has considerable use in combined DoM–Hartwig-Buchwald C–N and C–O cross-coupling processes and is as yet underdeveloped for C–S fusion reactions.

  3. DoM–Halogen Dance–Cross-Coupling Reactions

    • Although the agreeably named halogen dance is of some vintage, its application in the construction of substituted aromatics and heteroaromatics has considerable, as yet unfulfilled, promise.

    • Among the practical tips is the caveat that, to eventual regret, it may be easy to overlook the occurrence of the halogen dance in the dash to publication.

  4. DoM–Cross-Coupling–DreM Reactions

    • The DoM–cross-coupling sequence finds additional advantage in synthesis when combined with the DreM process.

    • Thus, the regioselective synthesis of substituted fluorenones (Schemes XXIII and XXIV), phenanthrenes (Scheme XXV) and acridones and dibenzazepinones (Scheme XXVI) become feasible in practical, efficient and environmentally friendly ways compared with, for example, traditional electrophilic substitution methods. Specifically, the DreM approach to fluorenones and azafluorenones (Scheme XXIV) demonstrates the complementarity between Friedel-Crafts and DreM tactics.

  5. Scale-Up and Industrial use of DoM–Cross-Coupling–DreM Reactions

    • As in the case of DoM chemistry which was dormant for about a decade after developments in our laboratories in the late 1970s, the DreM concept has been nurtured in industry and is now appearing in the open literature. It is encouraging to see the application of the combined DoM–cross-coupling technology (Scheme XXVIII), including DreM (Scheme XXIX) methods, on a multi-kilogram scale.

  6. Diversification of the DoM–Cross-Coupling Strategy

    • While DoM reactions constitute one functional group per DMG for synthetic considerations, significant advantage is gained in diversification, with or without protection requirements, to the creation of 2,6-disubstituted DMG-bearing aromatics. Perhaps insufficiently appreciated and adapted as yet, such a sequence is shown in Scheme XXX.

    • Another conceptual element, a double DoM process (Scheme XXXI), may also be the tip of the iceberg in synthesis.

  7. The DMG as a Pseudohalide in Cross-Coupling Reactions

    • Adaption of methodology which uses the DMG aromatic as a pseudohalide coupling partner, already demonstrated in our Corriu-Kumada reaction of aryl O-carbamates in the early 1990s, has taken on new possibilities in O-carbamate, O-sulfamate and sulfonamide Corriu-Kumada and Suzuki-Miyaura reactions (Scheme XXXII) in our laboratories as well as others. The potential of this chemistry, including the excision of the DMG by transition metal-catalysed β-hydride elimination processes, is only now surfacing in the literature.

We hope the aims of this review have been met and will be valuable to synthetic chemists. The prognostic views expressed throughout this final section are, as many times experienced by all, dangerous to place, as we do, into the literature.

Acknowledgements

This review is dedicated to Alfred Bader, benefactor of Snieckus Innovations, for giving us the opportunity to impel our basic knowledge of chemistry to reach practical ends.

Victor Snieckus thanks the Natural Sciences and Engineering Research Council of Canada (NSERC) for support by the Discovery Grant program. Suneel Singh is grateful to NSERC for an industrial post doctoral fellowship award.

Glossary
Term Definition
DoM directed ortho metallation
DreM directed remote metallation
DMG directed metallation group
Het heterocycle

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The Authors

Johnathan Board received his MChem from the University of Sussex, UK, and subsequently undertook his PhD with Professor Philip J. Parsons, also at the University of Sussex, working towards the synthesis of the backbone of lactonamycin. He joined the Snieckus group at Queen's University Kingston, Ontario, Canada in 2007 as a postdoctoral fellow and worked on projects with industrial partners. In 2010 he helped set up Snieckus Innovations in which organisation he is currently a laboratory and research manager.

Jennifer Cosman received her BScH in Chemistry at Queen's University Kingston in 2010. She joined Snieckus Innovations in early 2011, working on the custom synthesis of small molecules. In 2013 she began her MSc degree under the co-supervision of Professors P. Andrew Evans and Victor Snieckus, and is currently at Queen's University completing this programme.

Toni Rantanen received his PhD from RWTH Aachen University, Germany, where he studied under the supervision of Professor Carsten Bolm on the topics of organocatalysis, microwave chemistry and ball milling. In 2007 he joined the Snieckus group first as an industrial postdoctoral fellow followed by academic research on the synthesis and functionalisation of heterocycles. In 2010, he helped to inaugurate Snieckus Innovations at which he is currently utilising his formidable experience as a laboratory and research manager.

Suneel Pratap Singh was born in India, where he obtained his PhD degree (Organic Chemistry) in 2008 from the Indian Institute of Technology, New Delhi, under the supervision of Professor H. M. Chawla. After postdoctoral training on synthetic aspects of organosulfur chemistry with Professor Adrian Schwan at University of Guelph, Guelph, Ontario, Canada, he joined Snieckus Innovations in 2011. His research interests include directed ortho metallation and development of new synthetic methodologies for heterocycles.

Victor Snieckus was born in Kaunas, Lithuania and spent his childhood in Germany during World War II. His training was at the University of Alberta, Canada, (BSc Honors), strongly influenced by the iconoclastic teacher, Rube Sandin; the University of California, Berkeley, USA, (MSc), where he gained an appreciation of physical organic principles under D. S. Noyce; the University of Oregon, USA, (PhD), discovering his passion for organic synthesis under the excellent mentor, Virgil Boekelheide; and at the National Research Council, Ottawa, Canada, where he completed a postdoctoral tenure with the ardent Ted Edwards. His appointments have been at the University of Waterloo, USA, (Assistant Professor, 1966); Monsanto (NRC Industrial Research Chair, 1992–1998); and Queen's University, Canada, (Inaugural Bader Chair in Organic Chemistry, 1998–2009). Some of his awards include A. C. Cope Scholar (2001, one of 4 Canadians); Order of the Grand Duke Gediminas (2002, from the President of Lithuania); Arfedson-Schlenk (2003, Geselschaft Deutscher Chemiker); Bernard Belleau (2005, Canadian Society for Chemistry); Givaudan-Karrer Medal (2008, University of Zurich, Switzerland); Honoris causa (2009, Technical University Tallinn, Estonia); and Global Lithuanian Leader in the Sciences (2012). In research, the Snieckus group has contributed to the development and application of the directed ortho metallation reaction (DoM) and used it as a conceptual platform for the discovery of new efficient methods for the regioselective synthesis of polysubstituted aromatics and heteroaromatics. The directed remote metallation (DreM) reaction and DoM–linked transition metal catalysed cross-coupling reactions (especially Suzuki-Miyaura) were first uncovered in his laboratories. These have found broad application in the agrochemical and pharmaceutical industries, e.g. the fungicide silthiofam (Monsanto), the anti-AIDS medication efavirenz and the anti-inflammatory losartan (Bristol-Myers Squibb). He continues fundamental research as Bader Chair Emeritus as well as Director of Snieckus Innovations, an academic unit that undertakes synthesis of small molecules for the pharmaceutical and agrochemical industries.

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