A comprehensive overview of directing groups applied in metal-catalysed C–H functionalisation chemistry

The present review is devoted to summarizing the recent advances (2015–2017) in the field of metal-catalysed group-directed C–H functionalisation.


Introduction
This supporting material covers literature in the field of directing group assisted C-H functionalization published until 2015. Since the main manuscript covers only literature from 2015 onwards. The SI is mainly organized as tables which are first of all organized according to the type of directing group. Selected examples of each directing group are discussed in the accompanying text sections. In cases where it helps the general understanding of a transformation, additional schemes or figures are added, for example to explain an important mechanism. In the first column of the tables (besides the Entry column) the structure of the directing group is displayed. In the second column the type of transformations which have been reported with this directing group will be listed in alphabetical order (e.g. alkylation, arylation, nitration, trifluoromethylation, etc.). Here it has to be mentioned that sometimes different publications use different terms for the very same transformation. For the sake of simplicity, in this review each transformation has the same name in all entries. For example, the coupling of olefins with arenes to give alkylated arenes is either classified as alkylation or hydroarylation. It was decided to look at the reaction product and see what happened to the part of the molecule which carried the DG. Hence, in case the arene carried the DG, the reaction is always classified as alkylation reaction. In the third column the reaction/coupling partner is listed. For some transformations, numerous examples have been reported with a specific directing group. For example, the direct arylation of ketones in ortho position knows many examples in the literature. It was aimed at being comprehensive in the regard that all DGs and potential transformations with the DG are listed, however, reporting every single variant of a given transformation would have been beyond the scope. In such cases typically the first report and important further developments are listed in the tables. For example, if originally for arylation reactive aryl iodides were required, relevant further examples would make more readily available aryl chlorides accessible for the same transformation, just to give an example. It is clear that such a selection will always be biased and you might find that one or the other example should have been selected differently.
In the fourth column the structure of a typical product of the C-H activation reaction will be shown with the newly formed bond clearly indicated (bold or in color). In the fifth column general comments to the specific transformation are given. Most importantly which metal catalyst was required, was there a crucial additive (e.g. a specific base), or which solvent had to be applied. Additionally, information whether the directing group is cleavable or not is included here as well. Finally, in the sixth column the reference to the original research paper is given.
The format with a strong focus on tables and the aim to give a comprehensive overview on all DGs which have been applied in the past brings it about that not every contribution which is listed in a table can be discussed in the text. Discussions have been limited to examples of special interest, e.g. by establishing a new DG or a new catalytic system applicable to a manifold of other transformations. Such a selection made by the authors is naturally biased and not all readers will agree with the selections which have been made. However, once again it should be noted that the most important part are the tables and the information compiled therein.
The speed in which new contributions are brought forward in the field is amazing. This shows the high relevance of this area of research and the potential scientists see in it.
For writers of a review it brings certain problems as well, most importantly when to make the cut for selecting contributions to be included. It was decided to include all original papers (full articles and communications) until the end of 2015.  Mixtures of mono and bis-alkylation products are formed.

Bidentate heterocyclic directing groups in C-H activation
Due to their versatility and reliability, bidentate directing groups have been heavily used in many types of C-H functionalizations in combination with a broad spectrum of transition-metal based catalysts. Catalytic systems based on N,N'-as well as N,S-bidentate directing groups have been developed for the functionalization of C(sp 3 ) as well as C(sp 2 ) carbon centers. As shown by van Koten and coworkers in 1993 43 , bidentate groups promote the activation of C-H bonds via the formation of a stable metallacycle.

Scheme 2: Effect of a bidentate directing group.
The most widely used representative is without doubt the aminoquinoline auxiliary. It has been used for the first time in 2005 in a seminal study by Daugulis et al. 44 (Table 2, Entry 62) together with picolinamideand since then was extended to more complex substrates and other coupling partners such as alkyl halides. It was even successfully applied in the total synthesis of celogentin C 45 or pipercyclobutanamide A 46 via direct C(sp 3 )-H bond activation.

Scheme 3: Application of bidentate directing groups in total synthesis.
Wang et al. 47 presented a protocol for the acetoxylation of C(sp 3 )-carbon centers also at relatively complex starting materials with the potential for late stage functionalization( Table 2, Entry 27).
Significant progress has been made in the replacement of precious metals by less expensive ruthenium-nickel-or iron-based systems. In 2012, the Ru(II)-catalyzed arylation of ortho C(sp 2 )-H bonds in aromatic amides was presented( Table 2, Entry 64). 48 The presence of the bidentate aminoquinolineamide directing group was reported as crucial for the reaction to proceed also in the Ru-catalyzed alkylation of -unsaturated ketones ( Table 2, Entry 46). 49 The first Ni(II)-catalyzed ortho-alkylation of benzamides was published shortly after by the same authors (Table 2, Entry 38). 50 The double chelating aminoquinolineamide and picolinamide have been utilized by Nakamura and coworkers 51 for the C(sp 2 ) and C(sp 3 ) alkylation ( Table 2, Entry 34). A remarkable robust setup has been presented by the Cook group (Table 2, Entry 35). 52 The orthobenzylation of various aromatic or olefinic substrates was achieved on gram-scale in air.
The effects of bidentate directing groups have recently been reviewed in more detail elsewhere. 53-55

Pyrimidine as directing group in C-H activation chemistry
Pyrimidine is after pyridine the second most frequently applied heterocyclic directing group. Typically, the 2-position of pyrimidine is connected to the substrate to be functionalized. If this attachment is via a C-C bond, pyrimidine is a permanent directing group and will remain in the final substrate. This of course is a drawback and limits the applicability to products which have pyrimidine as part of their structure. In case of a connection to a heteroatom, e.g. nitrogen, the pyrimidine DG can be cleaved using relatively simple conditions (e.g. NaOMe, DMSO, 100 °C). The more facile cleavage as compared to pyridine, where typically a twostep process of either reduction and hydrolysis or N-alkylation and hydrolysis is required, is due to the high electrophilicity of the C2 position due to electron withdrawal of 3 adjacent heteroatoms.
The group of Ackermann applied alkenyl acetates (  130 Notable, the catalytic system consisted of the non-precious metal cobalt, which is of course highly desirable in metal catalysis. The simple salt CoI 2 in combination with a NHC ligand and either CyMgCl or DMPU as base promoted the desired transformation. More common are acrylates as reaction partners in alkenylations reactions. 131 However, in such cases (e.g.  133 N-2-Pyrimidinylindolines were used as substrates leading to alkylation in position 7. Examples with secondary and mainly tertiary carboxylic acids were reported. Decarboxylative arylation is typically more common and was applied to the C2 arylation of indole (Table 3, Entry 29). 134 Alkylation via ring opening of 2-vinyloxirane was reported under Rh catalysis by the group of Li (Table 3, Entry 14). 26 Yields were usually very high, often surpassing 90%.
One drawback is the poor E/Z selectivity of the double bond in the products, which is often around 2:1, at best 6.1:1.
Meta selective alkylation has been reported by Ackermann and coworkers (Table 3, Entry 17). 135 Naturally, the pyrimidine DG mainly applied cannot reach out far enough to direct Ru insertion into the meta C-H bond. Indeed, "normal" ortho C-H insertion takes place. This leads to a metal complex in which the bond para to the Ru-C bond is weakened and prone to attack by a radical species formed from the tertiary alkyl bromides. This position para to the initially formed Ru-C bond is concomitantly meta to the position of the directing group, hence the observed meta alkylation. Detailed mechanistic studies have been carried out which support this mechanistic proposal.
A very comprehensive study on the alkynylation of various substrates has been reported by Xingwei Li and coworkers ( Amides are important functional groups in organic chemistry and naturally the introduction of this functionality via C-H activation chemistry was investigated. Amidation reactions have been reported under rhodium catalysis using either isocyanates, N-hydroxycarbamates, or N-(2,4,6-trichlorobenzolyloxy)amides as amidating reagents (Table   3, Entries 21-25, 45). The latter one shows significant drawbacks regarding atom efficiency, which foils somehow the idea of C-H activation ( Table 3, Entry 21). 136 Still, it gives very reliable results, only large amides such as pivaloylamide cannot be introduced via this method. Isocyanates are of course very reactive species and proved to be reliable amide precursors (Table 3, Entry 24). 137 It is worth mentioning that in a DG screening the usually very efficient 2-pyridyl group was significantly outperformed by the 2-pyrimidyl group. Most examples were carried out using aliphatic isocyanates, however also aromatic ones did work but with mediocre yields <50%.
Cyclopropenone ring opening towards chalcones was reported by the group of Li (Table 3, Entry 33). 138 With a single set of reaction conditions ([RhCp*Cl 2 ] 2 and AgSbF 6 ) the transformation worked in combination with a series of directing groups including 2-pyrimidyl (others were 2-pyridyl, N-pyrazyl, and N-methoxy imine). These reaction conditions are quite common in C-H activation chemistry. The non coordinationg anion SbF 6 facilitates the formation of a cationic Rh-species which undergoes C-H insertion. Noteworthy, the authors were able to isolate several Rh(III) complexes and could show that they are part of the catalytic cycle. Hence, a mechanism was proposed strongly supported by experimental evidence.
Meta selective bromination by using NBS as brominating reagent was reported in a study focused on 2-aryl pyridines as substrates, but in three cases also pyrimidine was used as DG (Table 3, Entry 30). 139 The catalyst naturally inserts into the C-H bond ortho to the directing group. This activates the position para to this Ru-C bond for attack by a bromine radical generated from NBS. Hence, the meta bromination in respect to the DG.
Trifluoromethylallylation under Rh-catalysis was reported by Kim and coworkerspyrimidine (Table 3, Entry 42). 39 The reaction was quite selective for the E-configuration of the resulting allyl group with E/Z selectivities ranging from 13:1 up to 35:1.
Cyanation in position 2 of indoles using tBuNC as the cyano source was reported by Xu and coworkers (Table 3, Entry 43, 47, 48). 12 The DG overrides the intrinsic reactivity of indoles, where the more electron rich 3-position would be preferentially cyanated in absence of a DG.
Cu-catalyzed oxidative coupling between indoles and benzoxazoles has been reported by Hirano and Miura (Table 3, Entry 34). 140 In this paper, they present a stoichiometric and a catalytic variant of this transformation, the latter one using air as terminal oxidant. Also removal of the DG was reported under standard conditions for cleaving Nlinked 2-pyrimidyl groups. A second oxidative coupling method was reported as well, this time between indoles and N-oxides of 6-membered N-heterocycles (Table 3, Entry 35). 13 A noteworthy example is also the indole synthesis reported by the group of Ackermann (Table 3, Entry 37). 141 In this case N-2-pyrimidyl anilines are coupled to alkynes under Ni-catalysis, whereas the two carbons of the triple bond end up as C2 and C3 of the final indole products.

Pyrazole derivatives in C-H activation chemistry
Studies which focus on the application of pyrazole as directing group are reaction quite rare. It is much more common that a method is developed for another directing group and then a few examples are given in substrate scope tables showing that also other directing groups can be reacted under certain reaction conditions. It is amongst these "other directing groups" where pyrazole typically finds its place. Hence, the examples given in certain studies are typically only few, which can be seen in the table. Most of the reports have already been discussed in other sections, and hence, here only studies will be discussed in more detail, which have not been discussed elsewhere and in which pyrazole really plays a prominent role.
First of all, in comparison to electron poor heterocycles, pyrazole can be directly functionalized itself under e.g. palladium catalysis 145,146 and this is a potential side reaction which has to be considered when pyrazole shall be used as DG. Either substituted pyrazoles have to be used which cannot undergo C-H activation anymore, or catalytic systems unable to activate a pyrazole C-H bond have to be found. Hence, typical conditions use Rh, Ru, or Ir but not Pd. Palladium becomes an option when pyrazole cannot be activated, or when this is a desired step, as it is the case in the intramolecular reaction given in Table 4, Entry 20. 147 Here, the reaction consists of actually three C-H activation steps, in which the first one is a pyrazole directed arylation of a C(sp 3  Alkenylations using a Rh or Ru catalyst, an alkyne as coupling partner (leading to alkenes via a hydroarylation pathway), an additive with a non-coordinating anion (e.g. AgSbF 6 ) and a carboxylic acid are quite common and have been reported on a number of occasions. Also N-phenylpyrazole was used in such a transformation giving high yields in all prepared examples (Table 4, Entry 1). 148 The alkynes applied were however limited to substituted 1,2-diphenylacetylenes in most cases. When 1-phenyl-1propyne was used as coupling partner, the new C-C bond was predominantly formed to the C2 position of the alkyne and only minor amounts of isomers were detected.
Phosphoramidation using diphenyl phosphorazidate as coupling partner was reported under iridium catalysis (Table 4, Entry 16). 149 In five examples pyrazole was the DG (typically 2-pyridyl was used) and in all examples yields between 60-69% were obtained. Also in this case it can be expected that a cationic metal complex plays a key role since [IrCp*Cl 2 ] 2 in combination with AgSbF 6 was used. Phosphoramidates are reoccurring motifs in pharmaceuticals making this method interesting for medicinal chemistry applications.
Carbenoid C-H functionalization is an area which has gained some prominence in the last year. Huw Davies pioneered the reaction of a series of saturated carbocyclic and heterocyclic substrate using a chiral Rh catalyst, leading to high ees in most cases. [150][151][152] These transformations did not require a DG. Directed carbenoid insertion was then first reported by Yu. 153 Using pyrazole as directing group, Osipov and coworkers developed a pyrazole directed protocol (Table 4, Entry 22) which was then expanded to other DGs (ketone methoximes, pyrimidines) in the same contribution. 143 Typical for this type of reactions is the necessity of two electron withdrawing substituents on the diazo compound, CF 3 and COOMe in the present case. In the same year also a Co-catalyzed carbenoid insertion was published using diazo malonates as coupling partners (Table 4, Entry 11). 144 One of the earliest examples using pyrazole as DG was reported by Chatani and coworkers (Table 4, Entry 12). 154 They used N-phenylpyrazole as substrate and developed a carbonylation protocol under neutral conditions using Ru 3 (CO) 12 as catalyst, of CO and ethylene at pressures of 20 atmospheres. Electron donating substituents on the phenyl ring gave significantly better yields than electron withdrawing ones. Also electron rich thiophene could be carbonylated in a reasonable yield of 54%.
Oro and Castarlenas reported the coupling of N-vinylpyrazoles with alkynes to give Markovnikov selective butadienylpyrazole derivatives (Table 4, Entry 23). 155 A rhodium catalyst carrying an NHC ligand proved to be most effective and the reaction worked at relatively mild temperatures of 70 °C. The proposed mechanism, which was supported by isolation of some intermediate Rh-complexes of the catalytic cycle, starts with precoordination of Rh to pyrazole and subsequent activation of the vinyl substituent.
Subsequent alkyne coordination, hyrdometallation and reductive elimination delivered the target products.
Miao and Zhang delivered a report in which a pyrazolone directing group played a dual role (Table 4, Entry 24). 156 First, it precoordinated a Rh catalyst allowing C-H insertion in ortho position of the attached phenyl ring. According to the suggested mechanism, the pyrazole N-N bond of the directing group is cleaved, one nitrogen ending up in the indole ring of the final product (red nitrogen Table entry), the other forming the amino group on the side chain. Huang and coworkers reported a similar transformation but using a differently substituted DG as starting material which also leads to differently substituted indole products (

Triazole derivatives in C-H activation chemistry
Even though triazole was used as DG in a silylation reaction already in 2003 (Table 5, Entry 4), 161 it took a while until it was revisited and only in the last three years examples were reported in higher frequency, showing the potential also of this nitrogen heterocycle. Also triazole is potentially a substrate for C-H activation. For example, direct arylation of 4-phenyl-1,2,3-triazole has been reported under Pd catalysis in position 5 of the triazole ring 162-164 which is of course somewhat detrimental for its use as DG, since DG should usually not undergo any side reactions.
Palladium catalyzed acylation using aldehydes as acyl sources have been reported by Kuang and coworkers ( Table 5, Entry 1). 165 Triazoles directs the insertion of Pd into the ortho C-H bond of the N2-phenyl substituent. The aldehyde is transformed to an acyl radical by reaction with t-butylhydroperoxide, which then gets attached to Pd and after reductive elimination delivers the final products. Both aliphatic and aromatic aldehydes were applied and the transformation showed good functional group tolerance. Using carboxylic acids instead of aldehydes the same group reported also an acyloxylation protocol.
Triazole directed acyloxylation under Pd-catalysis using simple carboxylic acids as coupling partners was reported by the group of Kuang (Table 5, Entry 2). 166 Both, aliphatic and aromatic carboxylic acids were applied and also cinnamic acid derivatives gave high good results.
One of the earliest examples using triazole as DG was reported by Kakiuchi and coworkers (Table 5, Entry 4). 161 The investigated the silylation of arenes carrying different DGs, in one case also 1-methyl-1,2,3-triazole. This Ru 3 (CO) 12 catalyzed transformation used an excess of 5 equivalents HSiEt 3 giving a mixture of mono (14%) and bissilylation products (46%).
The group of Ackermann reported two Ru catalyzed protocols for the direct arylation of arenese directed by 1,2,3-triazole (Table 5, Entry 6). 167 In the first protocol published, the aryl sources which can be applied include aryl bromides, tosylates, and also the cheap and readily available aryl chlorides. However, with triazole directing groups only examples using aryl bromides were disclosed and chlorides and tosylates were only used in combination with oxazoline, pyridine, and pyrazole directing groups. This limitation was soon erased when a slightly modified protocol allowed also the application of aryl chlorides in combination with triazole DGs ( Specifically noteworthy is also the iron catalyzed arylation protocol, again developed in the Ackermann lab (Table 5, Entry 8). 169 The attractiveness of iron as catalyst in synthesis does not require any explanation. The catalytic system consisted of simple FeCl 3 and dppe as ligand. As aryl source a aryl Grignard reagents were required, which of course leads to certain limitations regarding functional group tolerance. Regarding the substrate scope, C(sp 2 )-H bonds of arenes and alkenes as well as C(sp 3 )-H bonds could be activated. In later work also methylation with MeMgBr was reported using almost the same catalytic system. 170 In this contribution a large diversity of substrates was reacted (arenes, heteroarenes, olefins and even aliphatic ones) and generally high yields were obtained. The need to use Grignard reagents is of course a drawback regarding functional group tolerance. Switching to Ru catalysis, this could be overcome and simple aryl bromides can be applied (Table 5, Entry 10). 171 Using aryl iodides as aryl source also allowed the development of an C(sp 3 )-H arylation protocol under Pd-catalysis using a removable triazol based DG ( The group of Shi described two relatively elaborate triazole containing directing groups, which promote actually two different transformations on the same substrate, once a substitution, more specific an acetoxylation reaction (Table, Entry ), and ones an intramolecular cyclization ( Table 5, Entry 14). 175 For the acetoxylation, N2-pyridine-1,2,3triazole-4-carboxylic acid is the precursor of the DG, abbreviated TA-Py. The acid functionality is used to attach the substrate to be functionalized by forming an amide bond.
Using a system of Pd(OAc) 2 , PhI(OAc) 2 , and AgOAc both, C(sp 2 )-H and C(sp 3 )-H bonds can be functionalized, the latter requiring somewhat harsher reaction conditions (80 °C sp 2 vs 140 °C sp 3 ). Noteworthy, halide substituents in the starting material were well tolerated, which is remarkable in presence of Pd(OAc) 2 .
In the same contribution N1-aryl-1,2,3-triazole-4-carboxylic acid was introduced as precursor for another DG, abbreviated TAA (Table 5, Entry 15). 175 In this case indoline and azetidine formation was obtained via intramolecular cyclization reactions. Reaction conditions required again of Pd(OAc) 2 and PhI(OAc) 2 but no AgOAc and halide substituents were once more unaffected and well tolerated. As could be expected, the more strained ring system azetidine required higher temperature for the cyclization to take place (120 °C vs. 80 °C). It is important to note that cleavage of the TAA group has been demonstrated in one example giving indoline in 95% and also the DG precursor was isolated in 82% yield.
So far 1,2,3-triazoles were the DG of choice. Punniyamurthy and coworkers applied also a 1,2,4-triazole derivative as DG in their cupper catalyzed nitration of arenes using simple Fe(NO 3 ) 3 ·9H 2 O as NO 2 source (  The group of Seki has reported tetrazole directed ortho arylation due to their interest of efficient synthesis of angiotensin II receptor blockers (Table 6, Entry 11). 184-187 They explored various N1 substituted tetrazoles under Ru catalysis using bromobenzenes as the aryl source. However, the substrate scope regarding the aryl source was not fully explored and seems to be quite limited.
A much more comprehensive study regarding the aryl bromide substrate scope was reported by Ackermann and coworkers (Table 6, Entry 9) 188 . A bulky carboxylic acid as additive improved the yield significantly. Importantly, also two heterocyclic aryl bromides were successfully coupled. 2-Bromothiophene gave a good yield of product of 63%, whereas 3-bromopyridine gave only 30% yield. due to the N1-benzyl group in the DG, only mono-arylation products were observed.
An interesting quinolone synthesis has been reported by Hua and coworkers (  2 gives only low yields of the quinolones whereas the mono hydrate gives almost quantitative conversion. In most cases symmetrical diarylalkynes were used. In cases were mixed alkyl-aryl alkynes were used, the alkyl residue ended up in R 3 position with high regioselectivity.

Scheme 4: Tetrazole directed annulation/N 2 extrusion towards 2-aminoquinolines.
A convenient nitration protocol was reported by Punniyamurthy and coworkers ( be cleaved afterwards, giving 2-nitro substituted anilines. In one case the transformation was also carried out in gram scale with no decreased yield.

Oxazole based directing groups
Oxazole itself is rarely applied as DG since its C2 and C5 position can be readily C-H activated themselves. 192 The much more frequently applied variant is oxazoline, typically attached via C2 to the substrate to be activated. Even though not shown in many contributions, oxazoline is a cleavable DG since it can be hydrolyzed to a carboxylic acid, [193][194][195]  This study focused on oxazoline, however also several other DGs were reported, amongst them oxazole itself ( Table 7, Entry 1), which proved to be significantly less efficient.
Kakiuchi reported Ru 3 (CO) 12 catalyzed silylation with a series of DGs (Table 7, Entry 18). 161 As starting point in their development served 4,4-dimethyloxazoline and high yields of the mono-silylation products were obtained. Twofold silylation, which was often an issue with other DGs was never an issue in the oxazoline directed case.
An interesting alkylation using tetraalkyl tin reagents was reported by the group of Yu (Table 7, Entry 12). 197 It turned out that batch wise addition of the organotin reagent over prolonged reaction times (up to 60h) was necessary in order to get good yields. The reactions could be accelerated significantly when carried out in the microwave.
Nishimura reported a branch-selective alkylation of arenes with vinyl ethers (or hydroarylation of vinyl ethers) using an iridium catalyst ( Alkylation and arylation with alkyl or aryl iodides has been reported by the group of Liu (Table 7, Entries 33 & 34). 199 In this case, an isoxazole containing directing group was used. Remarkable is the functional group tolerance, which was especially demonstrated for the arylation case. Here, it was shown that halides were well tolerated and also a boronic ester, nitro and an azide group gave high yields.
Shi and coworkers reported the remote activation and arylation with aryl iodides of -methylene C(sp 3 )-H bonds ( Table 7, Entry 15) and -C(sp 2 )-H bonds ( using an amide linked oxazoline directing group. 200 A remarkably large functional group tolerance was reported. Additionally, it is a rare example in which cleavage of the oxazoline DG was really tested and successfully carried out. Bidentate amino oxazoline directing groups, chiral and achiral ones, have been used for the direct arylation of secondary C-H bonds by the group of Shi (Table 7, Entry 24). 201 Reaction optimization started with Pd(OAc) 2 as catalyst and carboxylic acids as additives, a typical combination to start a screening in the field. Interestingly, dibenzyl phosphate ((BnO) 2 PO 2 H) proved to be more affective, in the end in combination with Pd(OPiv) 2 as palladium source. Iodo arenes had to be used as aryl source and it was shown that many functional groups were well tolerated. Only sterically demanding 2-iodotoluene gave no conversion. Also C(sp 2 )-H activation was tried using this protocol but no conversion was observed. Additionally, a chiral variant of the DG was applied and three examples with d.r. of 88:12 -90:10 were reported ( Table 7, Entry 25).
Alternative aryl sources have been applied as well, e.g. aryl tosylates ( and as high as 99:1. Naturally, the reaction was also carried out in a racemic fashion as well, with typically high yields of up to 97%. In subsequent years the method was further explored in a series of papers 205,206 and also detailed mechanistic investigations were reported. 207 . The group of Sanford also reported a single example for an isoxazoline directed iodination, this time using NIS as iodination reagent ( A copper catalyzed method for the coupling of amides with malonates was reported by Dai and Yu (Table 7, Entry 26). 208 The initial C-H activation and C-C coupling reaction with malonates was followed by an intramolecular oxidative C-N bond formation, ultimately leading to isoindolin-1-ones. The functional group tolerance was good, yields however were often only around 50%.
Besides oxazoline, also benzoxazole can be used as DG since in that case positions 4 and 5 are blocked due to annulation and C2 is typically used to attach the substrate. A comprehensive study of the ortho acylation of 2-arylbenzoxazoles has been reported by the group of Yang and Wu (Table 7, Entry 29-31). 209 Aldehydes were applied as readily available acyl source, which are transformed to acyl radicals by action of the organic oxidant TBHP. Only aromatic aldehydes were applied and in most cases and a large excess of 6 equivalents was required.

Heterocyclic and related directing groups in C-H activation chemistry
Imidazole derivatives are rarely applied as DGs, since the imidazole ring system is relatively prone to C-H insertions itself. One example has been reported by Kakiuchi and coworkers in their well-known ruthenium catalyzed silylation protocol ( Here, amongst series of other heterocyclic DGs, also one example using a imidazole derivative was reported. Another single example in a larger study came from the lab of Inoue. N-Methylimidazole proved to be efficient in promoting only mono-arylation, whereas other heterocyclic DGs often also gave bis-arylation (Table 8, Entry 3). 157 Most likely, the N-methyl group prevents free rotation around the phenyl-DG bond and the second ortho position cannot be activated anymore.
Thiazole compared to other heterocycles, is underrepresented as DG. Reasons are again that thiazole can be C-H activated itself, primarily in positions 2 and 5. Hence, conditions in which thiazole is applied as DG need to leave the thiazole C-H bonds untouched. The Ru-catalyzed arylation protocol reported by Inoue and coworkers is such an example (Table 8, Entry 3). 157 In order to get selective mono-arylation of arenes, one ortho position had to be blocked in advanced, otherwise mixtures of mono-and bisarylation were obtained. Taking such precautions, the reaction was generally high yielding (up to 98%).
Already in 2000 Murai and coworkers 196 reported one example of thiazoline as DG in a carbonylation reaction with CO and ethylene (Table 8, Entry 7).
The triazene motif was used as 'internally cleavable' directing group in the synthesis of free indoles by Sun et al. 216 The so formed indole derivatives could be further  Table 8, Entry 13) 218 The attempted chlorination using dichloroethane as halogen-source proceeded smoothly and according to the mechanism proposed, the directing effect is attributed to the pyridine -nitrogen.
Phenidones (      The same group reported an extremely mild (the reaction is conducted at 45 °C) iridium-catalyzed arylation of benzamides with aryldiazonium tetrafluoroborates as coupling partners (Table 9, Entry 13). 226 With this reaction conditions, also (Z)-selective arylation of enamides was accomplished in good yields (40-83%). In 2012 Sharma et al.
presented the tandem ortho-acylation of N-i-propylbenzamides followed by intramolecular cyclization (Table 9, Entry 6). 227 This Rh-catalyzed sequential process allowed for the elegant preparation of substituted 3-hydroxyisoindoles and was later developed further towards an enantioselective transformation utilizing and iridium-based catalyst and a chiral bidentate phosphoramidite ligand 228, 229 employing N,N-dimethylamide as directing group (Table 9, Entry 17).

Scheme 5: Proposed mechanism of the Rh-catalyzed amination of t Bu-benzamides.
The disubstituted N,N-diethylamide was successfully applied in the meta-selective borylation of aromatic substrates (Table 9, Entry 19). 230 Although this reactivity was not exclusively shown for the N,N-diethylamide (OMOM, SONEt 2 and OCONEt 2 could also be applied to the reaction conditions), this unique meta-selectivity should be mentioned here. The investigated sequential meta-borylation, Suzuki-coupling is perfectly complementary to directed ortho-metalation and Suzuki coupling or an ortho functionalization via directed C-H activation. The transformation shows a good functional group tolerance and the meta-selectivity seems to be driven by steric influences rather than electronic effects. A Rh-catalyzed protocol for the Z-selective -halogenation of alkenes was presented by the Glorius group (Table 9, Entry 27). 231 Haloacrylamides could be prepared using NXS as the halogen source which in most cases gave the best yields as NIS. The relatively mild conditions (60 °C) gave rise to a broad functional group tolerance allowing the reaction to proceed also in the presence of p-or m-bromine bringing about attractive synthetic intermediates.
The Glorius group utilized N,N-di-i-propylamide as directing group in the synthesis of the synthetically challenging [3]dendralene-motif. 232 Allenyl carbinol carbonates were used as reaction partner allowing for the installation of this motif on aromatic as well as olefinic starting materials under mild conditions with excellent functional group tolerance (Table 9, Entry 23).
Amongst aromatic amides, many serve for the alpha selective functionalization of sp 3 -carbon centers. The enantioselective arylation of very congested cyclobutane is a particularly interesting example (Table 9, Entry 39). 233 The highly electron deficient N-(4-cyano-2,3,5,6-tetrafluorophenyl)amide in combination with a modified amino acid as chiral ligand enables the Pd-catalyzed alpha functionalization in good yields and high ees.
The very often challenging meta-modification of aromatic substrates was accomplished utilizing a modified norbornene which temporarily blocks the ortho position of the aromatic substrate thereby allowing for selective meta substitution with aryl-or alkyl iodides (Scheme 6). The relatively mild reaction conditions allow for a broad functional group tolerance and generally high yields. A second example for the rare meta functionalization was presented by the Yu group. 234 A U-shaped weakly coordinating fully functionalized amide-directing group enables the highly selective meta arylation (Table 9, Entry 40) 234 and olefination 235 of substituted and unsubstituted aromatic substrates.
The immensely bulky amide totally shields the ortho position and can be cleaved at room temperature.

Scheme 7: Formation of isoquinolines or hydrobenzofurans depending on the used directing group.
The N-methoxybenzamide motif was also used in the intramolecular transformation towards dihydrobenzofurans (Table 10, Entry 8). 274 Starting from substrates of type 1, two possible positions for C-H insertion can lead to either functionalization at the less hindered ' position or, less likely, at the sterically more demanding -position. Taking advantage of the reversibility of the insertion-process, the overall equilibrium is driven towards the seven membered rhodacycle 3. From here, reductive C(sp 3 )-N bond formation or proto-demetalation yielding the desired 4 can occur. In the case of the C(O)-NHOMe directing group 275 , the -elimination towards 5 in usually observed with Rh-catalysis which could be successfully suppressed via addition of PivOH (1 equiv) as additive and good to excellent enantiomeric ratios were reached.

Scheme 8: Mechanistic rationale for the formation of the cyclized product 6.
The activation of C(sp 3 ) carbon centers is usually a challenging task due to the inherently low activity of these centers. Yu and coworkers 276 investigated the stereoselective arylation of modified alanine (Table 10, Entry 10). Via a 2-step Pd-catalyzed protocol with extremely broad substrate scope, the -position of the protected amino acid could be substituted with 2 different aryl groups. The process could be realized in synthetically useful yields over 2 steps with good diastereomeric ratios.
Geminal disubstituted allenylsilanes have been submitted to Ru-catalyzed aromatic C-H allenylation by Nakanowatari et al. (Table 10, Entry 9) 277 . Allenes are enourmosly versatile functional groups for further modification, their use in C-H activation is however fairly rare. Employing a Ru-catalyst and substituted N-methoxybenzamides, terminal allenes with various substituents could be connected to the ortho position of the aromatic substrates.
The utilization of diynes as coupling partners in alkenylation followed by intramolecular cyclization gives rise to the synthesis of unsymmetrical heterocyclic products. The Glorius group realized the coupling of diynes including unsymmetrical substrates and could thereby show the preparation of a number of bisheterocyclic compounds (Table   10, Entry 12). 278

N-Acyl-containing directing groups
N-Acyl -substituents are commonly used as directing groups which is also due to the activating effect of this motif. A protocol for the mild ortho acylation of N-acetanilides was presented by Szabo et al. (Table 11, Entry 1) 287 Aromatic as well as aliphatic aldehydes could be directly coupled to numerous N-acetanilides with good functional group tolerance due to the very mild conditions. The reaction could be conducted under air in aqueous media. Under more forcing conditions (100°C in DMSO), the same class of products could be prepared starting from toluene derivatives by Yin and Sun (Table 11, Entry 2). 288 TBHP (4 equiv) serves as external oxidant producing the reactive acyl radical which adds to the palladacycle formed between Pd(II) and the acetanilide.
The tendency of N-O bonds to be cleaved during oxidizing coupling reactions was the rationale in the ortho alkenylation of N-phenoxyacetamides( Table 11, Entry 3). 289 Via the choice of solvent the reaction outcome could be controlled either towards the formation of benzofuran-derivatives or ortho-hydroxyphenyl-substituted derivatives (Scheme 9). The transformation showed good selectivity and a broad substrate scope.
Scheme: 9: Formation of benzofurane-or ortho-hydroxyphenylderivatives depending on the applied solvent.

Directing groups containing the carbonyl motif
Carbonyl compounds such as esters, ketones and carboxylic acids are essential building blocks for the synthesis of fine chemicals, pharmaceuticals and natural compounds.
Form a synthetic point of view, weakly coordinating DGs such as carbonyl or electron rich functional groups (e.g. ethers, hydroxy) show several benefits due to low toxicity, ability for further transformations as well as that they can serve as traceless DGs (e.g. decarboxylation). 306

Aldehydes as directing groups in C-H activation
Even though aldehydes are common functional groups in many organic compounds, they have been used as directing groups in only few examples (e.g. alkenylation, 307,308 annulation, 309,310 Table 12). The two main reasons are, the low directing ability (  310 During optimization studies, tetrahydrofuran and a catalyst loading of 3.5 mol% resulted in improved yields, but interestingly the choice of the oxidant (Ag 2 CO 3 ) and AgSbF 6 as an additive are crucial for the reaction. The mechanism involves several steps, first a Rh catalyzed C4-H activation followed by a [4+2] cyclization/aromatization and finally a nucleophilic addition of water leads the final motif (Scheme 10, left).

Scheme 10: Regioselective Rh-catalyzed cyclization depending on the presence of CsOPiv.
In 2015 the group of You showed the effect of CsOPiv to differentiate between C4-H (Scheme 10, left) and C2-H activation (Scheme 10, right) for similar starting materials.
The rhodium catalysed C2-H activation/cyclization requires elevated temperature (140 °C), Cu(OAc) 2 as an oxidant in dioxane. This is another example for a traceless aldehyde DG and this procedure leads to bioactive indolo-[1,2-a]-quinolone derivatives (Table 12, Entry 5). 312 In the published mechanism, they have stated that coordination of the carbonyl oxygen atom to Rh(III) and pivalate is required for C2−H bond activation to form a five-membered rhodacycle. After the insertion of the alkyne, protonolysis and recyclorhodation to a seven membered rhodacycle was proposed and this intermediate affords after reductive elimination the final product by regeneration of the Rh (III) catalyst.
In 2014, the group of Ackermann reported the first aldehyde directed oxygenation catalysed via a ruthenium(II) complex for ortho/ meta and para substituted benzaldehyde derivatives with increased reactivity towards electron rich arenes. The optimized protocol consists of a rate-determining C-H metalation and the hypervalent iodine (III) reagent (PhI(OTFA) 2 ) is required as an oxidant but without further additives.

Scheme 11: Lack of directing power of aldehydes in C-H activation.
Intermoleculare competition experiments between aldehyde to ketone (1: 6.6) or amide (1:17.5) directed oxygenation (Scheme 11), clearly show the bottleneck of the weakly coordinating aldehydes due to significantly lower directing activity and product formation (

Carboxylic acid-based directing groups
In contrast to well-studied DG´s such as pyridine, oxazoline, carboxylate-directed C-H activation shows some advantages: cleavage ability, easy to synthesise from other functional groups and availability in organic compounds and a variety of protocols (e.g. alkenylation, [314][315][316] arylation, 311, 317, 318 hydroxylation 319,320 etc.) are summarized in the following Table 13.
First published C-H activation on benzoic or naphthoic acids was performed by Miura et al. already in 1998 (Table 13, Entry 17). 321 In comparison to the wellstudied ruthenium catalysed ketone (Table 15) or carboxylic acid ester (Table 14) directed alkylation reactions, carboxylate directed alkylation reactions (Table   13) promoted by Pd(OAc) 2 and Cu(OAc) 2 in DMF provided a new access to alkylation reactions. This procedure gave access to phthalides or isocoumarins via an ortho-vinylation/nucleophilic cyclization or Wacker type oxidative cyclization.
The group of Yu presented several alkenylation reaction (  316 To control the regioselectivity of this Pd(II) promoted alkylation towards the meta position, the carboxylated directing scaffold is exchanged by an CN motif combined with an amino acid ligand system to perform meta selective olefination reactions in good yields.
Annulation reaction can be performed via Pd, Rh and Ru but nearly all of these procedures requires CuOAc 2 ·H 2 O as oxidizing agent for cyclization. In general, benzoic acid derivatives serves as substrates, which undergoes annulation reactions with alkenes as well as alkynes. For the second mentioned type of reaction, the regioselectivity of the alkyne insertion is controlled by ( Alternatively, lactonization depicts a common cyclization methodology to synthesize different lactones starting for aromatic benzoic acid derivatives. This type of transformation is mainly catalyzed by Pd but also Cu and Rh complexes at high temperatures (80-150 °C) are represented. A novel Pt catalyzed lactonization procedure in water was developed by the group of Chang ( The group of Yu published a highly selective mono-carboxylation of benzoic acid and phenylic acetic acid derivatives and under optimized conditions. The optimized protocol was also applied to vinylic C-H bond ( O the direct Pd(OAc) 2 mediated oxygenation was confirmed and the desire target molecules were obtained in good yields using the uncommon solvent (DMA) at 115°C. In contrast to electron rich arenes (yields up to 82 %), electron-withdrawing substituents gave decreased overall yields of around 50%.

Carboxylic Esters
In 1995, first alkylation reactions on aromatic and hetero-aromatic esters were reported by Trost (  3 complex in toluene at reflux conditions for 24. Kakiuchi's procedure was limited to fluoro and tri-fluoro substituted aromatic systems, with exception of two additional presented transformations, using a thiophene carboxylic ester or a lactone. The alkylation established byTrost was demonstrated on different cyclic alkenes containing an ester or ketone directing group combined with alkoxy or alkylsilanes under well established conditions (e.g Murai type reaction) ( Table 15, Entry 7). 351 This method was also extended to the addition of styrene (Scheme 12, left) as well as for a regioselective alkenylation with 2 equiv of the depicted silylalkyne (Scheme 12, right) in excellent yields of 82%.

Scheme 12: Early developments in ester-directed alkylation and alkenylation reactions.
The weakly coordinating ester group was used by Padala et al., for highly chemo and diastereoselective ruthenium catalysed alkenylation. During optimization studies, the effects of additives described and most promising results were obtained with Cu(OAc) 2   Besides this amidation reaction only a few examples for carbon-heteroatom bond formation reactions (e.g. halogenation 354 or hydroxylation 355 ) are published. A highly efficient ortho hydroxylation using a mixture of trifluoro-acetic acid and trifluoro-acetic anhydride (TFA/TFAA) and palladium(II) was described for a broad range of starting materials such as aryl ketones, benzoates, benzamides, acetanilides and sulfamides. During optimization studies, the effect of the ratio between TFAA and TFA was evaluated due to reaction speed as well as their role in the catalytic cycle. Most suitable ratio TFA/ TFAA (9:1) showed fast consumption of the starting material and serves also as the required oxygen source ( In 2012, a novel carboxylic ester directed β-arylation was published by the group of Boudoin. Especially the effect of the aryl-bromide structure on the β/α selectivity for the arylation of tert-butyl isobutyrate should be underlined. Using ortho fluoro-aryl bromid, perfect β/α selectivity of 98/2 was obtained (Scheme 13).

Scheme 13: Ligand-controlled regioselective aryltion of C(sp 3 ) centers.
To control the selectivity due to β/α arylations, several different ligands were tested and depending on the structure, the conversions were improved as well as the selectivity.
In contrast, meta-fluoro or para-fluoro substituted aryl bromides showed mixture of both possible products (

Ketones
The carbonyl group in ketones was historically amongst the first directing groups to be used in C-H activation chemistry. Over the last years, several ketone directed C-H functionalizations were reported for a broad substrate scope of sp 2 C-H bonds 361 except of some specific examples (Table 15, Entry 9). 362, 363 Ruthenium proved to be especially well suited for ketone directed C-H activation reactions. As can be seen in Table 15, most example take advantage of ruthenium catalysts followed by rhodium as the second most frequently applied metal. Palladium 364 , has been used successfully only in a handful of examples.
Already in 1993, pioneering work for ketone directed alkylations was published by Murai et al. (Table 15, Entry 7) 351 In this landmark contribution, the first highly efficient and selective carbon-hydrogen cleavage with a simultaneous C-C bond formation mediated by a ruthenium complex on different aromatic ketones (e.g. naphtyl, furan, thiophen) with a mono and disubstitued olefines was shown. (Scheme 14).

Scheme 14: Proposed mechansim of carbonyl-directed C-H functionalization.
The mechanism proposed in this paper served as guideline for many more contributions to come, and can be considered as one of the most important starting points for the field of C-H activation chemistry, as we experience it today. 365, 366 It was proposed, that the carbonyl function first precoordinates the metal catalyst, in this case a ruthenium species, which brings it into a position in close proximity of the a-C-H bond next to the ketone function. This allows C-H insertion of Ru into the C-H bond. Basically, the majority of directed C-H activation reactions rely on this type of strategy. In this early example of Murai, olefin insertion and reductive elimination delivered the -alkylated ketones, the final products of the reported transformation. The reaction was performed with aRuH 2 (CO)(PPh 3 ) 3 pre-catalyst, which was reduced to the active Ru(0) in toluene at 135 °C. Further improvements towards reduced reaction temperature (r.t. to 40 °C) and mechanistic studies were published in 2010. 365 Independently, the groups of Chaudret (Table 15, Entry 10) 367 and Leitner (Table 15, Entry 9) 363 presented optimized alkylation protocols at room temperature catalysed via athermolabileRuH 2 (H 2 )(PCy 3 ) 2 catalystfor aromatic ketones with ethylene. An Ru(II) promoted ortho alkylation with an unusual coupling partner, namely maleimides at high temperature (120 °C) with 4 equiv. of water to generate 3-arylated succinimide derivatives in excellent yields (96%) was published ( In 1995, the first catalytic addition of an inactive aromatic C-H bond to a triple bond catalysed by Ru(H) 2 (CO)(PPh 3 ) 3 in toluene at 135 °C was reported with moderate to good regioselectivity (E/Z= 5/1-16/1) ( Table 15, Entry 4). 369 Besides different coupling reagents, such as symmetric or asymmetric acetylenes and different vinylsilanes also furan or thiophen was shown as model substrates. An alkenylation protocol to install fluorine scaffolds via perfluoro-alkenylation, mediated by 1 mol% [(RhCp*Cl 2 ) 2 ] was presented for cyclic and acyclic aromatic ketones (Table 15, Entry 5). 370 In the proposed mechanism, the final β-hydrogen elimination exclusively gives the E isomer of perfluoroethyl acrylate derivatives. In contrast to the well studied Murai type alkylation, which provides linear products, in 2014 a Ir promoted alkene-hydroarylation to generate disfavored branched compounds was publishied (Table 15, Entry 22). 371 The selectivity towards the C-C bond forming with the internal carbon of styrene is controlled by the ligand (e.g. d F ppb c ) and the styrene loading (coupling reagent) was reduced during optimization studies form 450 mol% to 200 mol% to gave exclusively the branched products.
The effect ofnon-coordinating anions (e.g. AgSbF 6 , KPF 6 ) for ruthenium catalysed annulation reactions is depicted in Scheme 15 (Table 15, Entry 28-30). 372-374 The addition of AgSbF 6 is required, to increase the activity of the rhodium catalyst by removing the chloride ligands [(RhCp*Cl 2 ) 2 ] (Table 15, Entry 28). 68 Furthermore to favour the ring closure reaction, the addition of a Cu(OAc) 2 as an oxidant as well as the solvent are crucial, to avoid the well-known alkenylation reaction of aromatic ketones with alkynes.

Scheme 15 Ketone directed alkenylation and annulaion controlled by the catalyst.
In 2011, Patureau et al. presented a novel annulation process to synthesize indenols and fulvenes depending on the substrate structure involved an α, γ dehydration step (loss of a H 2 O) or non-dehydrative reaction progress (Table 15, Entry 28). 372 In order to avoid several bottlenecks (e.g. regioselectivity) of β-functionalization, a selective Pd-catalyzed arylation using aryl iodides with excellent functional group tolerance at the β-position of cyclic or acyclic ketones was reported (Table 15, Entry 24). 375 The selective arylation in β-position was obtained by a Pd promoted ketone dehydrogenation followed by the formation of an Pd(II)-enlolate, a β-H elimination and finally a reductive elimination for catalyst reactivation are part of the catalytic cycle to end up at the regioselective product molecule. Furthermore, a rhodium catalysed β alkylation of 4-phenyl-3-buten-2-one utilizing diethylamine as an chelation assistant tool to give β, γ unsaturated ketones in 2:1 ratio of E/Z isomers (Table 15, Entry 12). 376 Key step of this amine assisted functionalisation is the formation of an dienamine intermediate by the condensation of α,β-unsaturated ketone and diethylamine. The active rhodium complex is then coordinating and reductive elimination followed by acidic hydrolysis, which yields in the final product.
A ketone directed C-H activation for a enantioselective hydroarylative and hydrovinylative cyclizations were presented by the group Shibata (Table 15, Entry 34). 377 They also stated a possible mechanism for the presented cyclization, which follows a (1) directed C-H activation of an enone, (2) a hydrorhodation of the diyne or enyene and (3) intramolecular carborhodation followed by the generation of the thermodynamically favoured product.
Ketone directing groups have not only been applied in C-C bond forming reactions but also in C-heteroatom bond formations. For example, ruthenium or palladiumcatalysed hydroxylation, 364, 370, 378 amination 379 , as well as halogenation. 380 To install a nitrogen containing functional group on an aromatic system, ortho amidation procedures by sulfonyl azides were studied in presence of a RuCl 2 (p-cymene)] 2 (Table 15, Entry 19-21). 381-383 This methodology was adapted to broad substrate scope, do not require external oxidants and only nitrogen is generated as byproduct. Another opportunity for direct C-hetereoatom formation, is described for benzophenones via Pd(OAc) 2 catalyzed mono-or di-hydroxylation reactions. In 2012, the first ketone directed mono-selective arene oxidation using PhI(OTFA) 2 as oxidant in DCE was presented (Table 15, Entry 35). 378 The protocol was extended to substituted benzophenones and the final product is formed after aqueous work up of 2-trifluoro-acetoxylbenzophenone with perfect regioselectivity. Only tolyl-phenylketone was described to generate the dihydroxylated product.
Another direct hydroxylation protocol to synthezise ortho-acylphenols by Pd(TFA) 2 combined with the oxidant (BTI: bis(trifluoroacetoxy)iodo]benzene) at low temperature was reported by the group of Dong (Table 15, Entry 36). 364 For benzophenone derivatives, both electron neutral and electron rich aromatic systems are di-hydroxylated and for unsymmetrical benzophenones a mono-selectivity trend towards more electron rich aromatic rings is reported.
A ketone or ester directed hydroarlytion catalysed via inexpensive CoBr 2 and a bidendate phosphine complex (e.g. dppp or dppe) represents a novel protocol to prepare biologically relevant scaffolds containing an exocyclic double bond. During the catalytic cycle, Co(II) is reduced by Zn dust to Co(I), which promotes the oxidative cyclization of 1,6 enynes. Finally the rate determine step, a reductive elimination gave access to functionalized pyrrolidines and dihydrofurans by an atom efficient synthetic process at 40 °C (Table 15, Entry 33). 384 Additionally the reaction progress is limited to chlorinated solvents (DCM or DCE), only low yields were obtained in dioxane, THF or toluene. Furthermore, CoI 2 orCoCl 2 combined with different ligands decreasing the activity towards hydroarylatative cyclization.
The groups of Shi and Cheng disclosed independently and simultaneously an identical protocol for the synthesis of fluorenones from benzophenones via oxidative dual C-H activation (Table 15, Entry 38 & 39). 385, 386 Both groups also presented an plausible mechanism with the rate determing step, the formation of an six membered palladium complex after double C-H activation. Finally, a reductive elimination leads to the target molecules and the catalyst is recycled with Ag 2 O.

Hydroxyl-and Phenol-based derivatives
In general hydroxyl directed C-H functionalization is restricted to the ortho position due to the electron-donating ability of the oxygen group. To control the regioselectivity for meta-alkenylation, a modified phenol molecule containing a hydrolytic removable CN moiety was published by the group of Yu (Table 16, Entry 17). 401 An asymmetric rhodium catalysed cyclization using several directing groups such as ether, sulfide and sulfoxide groups to synthesize seven or eight membered heterocycles via olefin hydroacylation was reported by the group of Dong (Table 16, Entry 15). 402 During mechanistic studies they showed the catalytic process contains several steps (C-H bond activation, olefination insertion, and reductive elimination) to perform intramolecular cyclization reactions with controlled regioselectivity, which is highly depending on the catalyst-ligand and the substrate structure.
The group of Yu presented a catalytic system, which consists of Pd(OAc) 2 pre-catalyst, Li 2 CO 3 as base and Ph(IOAc) 2 as oxidantwith a hydroxyl directing moiety to synthesize dihydrobenzofurans ( An enantioselective fluorination reaction for a broad range of acyclic alcohols via an in-situ generation of a boronic acid monoester, which will act as a removable directing group was presented by the group of Toste (Table 16, Entry 14). 405 After condensation between the boronic acid and the primary alcohol a γ selective fluorination by Selectfluor at r.t. catalysed by S-(AdDIP), a phosphate bearing 4-(1-adamantyl)-2,6-diisopropyl BINOL ligand system gives the final products in high yields (94%) and excellent enantioselectivity (up to 94% ee).
Hydroxy-directed arylation reactions can be divided into three different types (1) an ortho arylation catalysed by [RhCl(PPh) 3 ] 3 with a phosphinite co-catalyst ( A switchable C-H functionalization of substrate molecules, containing different reactive C-H bonds will give access to a variety of products from the same starting material. In this approach 2-aryl cyclic 1,3-dicarbonyl compounds that contains two position for activation were used and the product selectivity was controlled by the catalyst-ligand structure. A palladium−N-heterocyclic carbine complex promotes the oxidative annulation with alkynes to spiroindenes in good yields (87%) within 5h. In comparison, [RuCl 2 (p-cymene) 2 ] gave in 22h selectively the benzopyran product using Cu(OAc) 2   monoacylated products proceeded to a Rh-catalyzed addition of the second ortho C-H bond to aldehydes, when highly deficient benzaldehydes are employed as coupling partners. In this case, no mono-acylation products were observed and two C-C bonds were generated simultaneously (          Further, acylsilanes were employed by Becker et al. in a rhodium-catalyzed olefination process for ortho olefinations of aroylsilanes(

Azo-containing directing groups
In 2013 the Wang group developed a Pd-catalyzed protocol for the synthesis of acylated azobenzenes from aromatic azo compounds and aldehydes via an azo-directed C-H bond activation process and with TBHP as an oxidant (Table 25, Entry 2). 486 Moreover, an unprecedented C−H functionalization ofaryldiazo compounds without a preinstallation of a directinggroup has been performed by Qiu et al. This procedure differs from other reports in its use of diazo compounds as coupling partners in directed C−H activations by application of a rhodium self-relay catalysis. This tandem process includes the in situ formation of a directing groupand a sequential C−H bond activation ( Moreover, an azo-group directed, highly regioselective synthesis of 2-alkoxy aromatic azo compounds via palladium(II)-catalyzed alkoxylation of azobenzene derivatives using alcohols as the alkoxylation reagents has been demonstrated by the Sum group. This method is applicable to both primary and secondary alcohols( Another cascaded procedure that also gives access to ortho-acyl azoarenes is the palladium catalyzed oxidation/sp 2 C-H acylation of azoarenes with ary methanes, which were used as in situ generated acyl sources (Table 25, Entry 1). 497