This is an introductory lecture describing the concept of C-H activation. The lecture covers the following topics: what is C-H activation?; the relation of C-H activations with cross-couplings; electrophilic aromatic substitutions are not C-H activations; historical overview of C-H activations; popularity of C-H activations; the reasons behind the popularity of C-H activations; the main issues in C-H activation; reactivity of saturated and unsaturated compounds in C-H activations; selectivity of C-H activation in saturated and unsaturated compounds; computational prediction of the reactivity and selectivity in C-H activations; the role of directing groups in C-H activation; overcoming the problems related to reactivity and selectivity; scope of C-C bond forming reactions by C-H activation; scope of C-heteroatom bond forming reactions by C-H activation; scope of reagents used for C-H arylation; scope of reagents used for C-H alkylation; scope of reagents used for C-H trifluoromethylation; scope of reagents used for C-H carboxylation; scope of reagents used for C-H amination; overview of the main mechanisms of C-H bond cleavage; C-H activation via oxidative addition; C-H alkylation of derivatives of urea; C-H silylation of aromatic compounds; C-H activation via sigma-bond metathesis; C-H alkylation of aniline derivatives; C-H activation via photoredox catalysis; intramolecular C-H thiolation of arenes; amination of benzylic C-H bond; C-H activations catalyzed by enzymes; C-H activations in nature; C-H activation via insertion of carbenes and nitrenes; C-H amination of arenes by azides; intramolecular allylic C-H alkylation with diazo compounds; C-H activation via heck-type insertion; C-H arylation of furans; C-H activation via concerted metalation-deprotonation; the difference between traditional and removable/modifiable directing groups; overview of the main removable/modifiable directing groups used for C-H activation of aromatic systems; overview of the main removable/modifiable directing groups used for C-H activation of saturated hydrocarbons; C-H halogenation of arenes enabled by removable directing groups based on pyridine; the main issues associated with the use of removable directing groups based on pyridine; nitro group as a directing group for C-H arylation of aromatic heterocycles; C-H functionalization of purine-like compounds; regioselective arylation of imidazoles and pyrazoles; removal and/or further transformations of the directing group; directed C-H acetoxylation of alcohol derivatives; what is an oxidizing directing group?; the main oxidizing directing groups used in C-H activation; N-oxides as oxidizing directing groups; C-H olefination of aniline N-oxides; mechanism of the external oxidant-free C-H olefination; what is a transient directing group?; the main transient directing groups used in C-H activation; transient directing groups for aromatic aldehydes; transient directing groups for phenols; transient directing groups for aliphatic carbonyl compounds; transient directing groups for aliphatic amines; C-H amination of aromatic aldehydes; C-H arylation of aromatic aldehydes; C-H halogenation of aromatic aldehydes; late-stage C-H functionalization of Celecoxib enabled by transient directing groups; transient directing groups for C-H arylation of aliphatic amines; the main strategies for the meta-selective C-H transformations; the main strategies for the para-selective C-H transformations; meta-selective C-H transformations enabled by specialized templates and directing groups; meta-selective C-H transformations enabled by weak interactions with specialized ligands; meta-selective C-H transformations enabled by norbornene; Catellani reaction; meta-selective C-H transformations enabled by cyclometallation; applications of the meta-selective C-H transformations in drug discovery; para-selective C-H transformations enabled by specialized templates and directing groups; preparation of oligomers and polymers by C-H activation; C-H arylation of thiophenes; common substrates for the preparation of oligomers and polymers via C-H activation; total synthesis of natural products involving C-H activation; Synthesis of Dragmacidin D; preparation of pharmaceuticals by C-H activation; synthesis of Diclofenac and Celecoxib; regioselective C-H iodination phenylacetic acids; innate C-H arylation of pyrazole; late-stage functionalization of pharmaceuticals via C-H activation; C-H functionalization of Hongoquercin A. Among others, this lecture describes the key figures in the field of C-H activation. The cover picture is adapted from the stock image library of Office 365.
Greetings to all and welcome back to the course on homogeneous catalysis the present module is devoted to CH activation in this lecture I will provide a general overview of CH activation in the following lectures I will describe the factors controlling reactivity and selectivity in ch Transformations as well as the main
Mechanisms in ch activation this will be followed by lectures devoted to the modern directions and CH activation finally I will present selected works on the Practical applications of CH Transformations let’s start with definitions first of all it should be mentioned that in the modern chemical literature quite often you may face
Other synonyms of CH activation the most commonly applied synonyms are CH transformation and CH functionalization however depending on the specific transformation you may see a number of other synonyms such as CH aeration ch amination CH halogenation Etc the most frequently used definition for CH activation was given by Birdman which is
As follows most generally CH activation means treating a CH bond in some way that allows a reagent to react rapidly with the carbon atom this activation can be achieved by most transition metals which can serve as catalysts as you may recall from the preceding module on Cross couplings in organic chemistry a
Crosscoupling reaction is a reaction where two fragments are joined together with the Aid of a metal Catalyst here it is not important what type of bonds are being activated in the process of joining two fragments together in other words CH activations can be considered a specific case of cross couplings where
At least one CH bond is activated in the process of constructing a new Bond as you will learn later in this module CH activations have many similarities with the cross coupling studied earlier besides cross couplings there is another group of well-known Transformations that can be confused with CH activations I’m
Talking about electrophilic aromatic substitutions here too CH bonds are transformed into carbon carbon or carbon hetero atom bonds and very often this process is facilitated by an acid used as a catalyst electrophilic aromatic substitutions are not considered CH activations because the Catalyst does not activate the CH bonds instead it is
Responsible for the generation of cationic intermediates moreover electrophilic aromatic substitutions have have many drawbacks and limitations they are confined to aromatic compounds and are effective only on electron-rich systems another significant issue is the poe selectivity and the necessity to employ highly reactive and corrosive reagents for instance let’s consider
Nitration it works effectively only for electron-rich systems like phenols and stopping the reaction after introducing one Nitro group is challenging attempting to do so will likely result in a mixture of regioisomers and in addition it may lead to a significant explosion modern developments and transition metal catalyzed CH Transformations address most of the
Problems inherent to electrophilic aromatic substitution as I will demonstrate later using transition metal catalysis allows for the selective functionalization of all classes of organic compounds including electron deficient orangins and aliphatic compounds to the best of my knowledge the first transition metal catalyzed CH transformation was developed by fujiwara
And his co-workers in 19 67 initially they found that stochiometric quantities of padium acetate could be used for the olefination of benzene with styrene furthermore they discovered that in the presence of an oxidant padium acetate could be used as a catalyst in the beginning of the 1970s schulen and
Shilov developed the Platinum catalyzed CH halogenation and hydroxy of alkanes in the case of halogenation they demonstrated that the reaction does not involve radicals which is in agreement with the halogenation of of the terminal methyl group this is not typical for radical halogenation which predominantly occurs at secondary carbons further
Progress was achieved again in fujiwara’s group in the 1980s they showed that unfunctionalized Benzene can be carboxilate using padium catalysis and carbon monoxide the rodium catalyzed CH insertion of carbons was developed during the same period this topic will be covered in detail in the lecture devoted to metal carbine complexes the
Final historically important CH transformation I want to highlight is the idium catalyzed olefination of alkanes developed by Falcon and Crabtree during the 80s this reaction later found some industrial applications now let’s see how popular this topic is and why it became so popular on this chart one can
Observe the number of Publications per year in the field of CH activation the number of Articles has been growing exponentially especially within the last decade crossing the threshold of 1,000 articles per year for two 2016 and 2017 some CH Transformations are quite popular While others are not for
Instance in 2017 the number of papers on CH aeration was almost 250 on CH amination we had about 200 papers while works on CH carboxy were around 10 on the last chart one can see the comparison of CH transformations in SP2 and sp3 hybridized systems the SP2 CH
Activations are much more popular which can be explained by The increased reactivity of aromatic systems in the ease of dealing with purification and separation of products derived from aromatics to understand why this field is so popular let’s go through two examples first let’s consider the synthesis of bi aals traditional
Approaches to bi aals are based on well-known cross-coupling reactions between aeral organometallics and aeral halides or pseudohalides such as Suzuki coupling in this case one needs to First prepare prepare the starting aerol halide and organometallic reagent from commercially available chemicals the preparation of aeral organometallics is particularly difficult and timec
Consuming besides it might involve the use of highly reactive and dangerous chemicals such as butti lithium on the other hand modern developments and CH activation allow the direct assembly of unfunctionalized ARS as a second example let’s consider the preparation of secondary amines the traditional approach involves the use of alkal
Alides which must be isolated from other isomer formed during radical halogenation this is not an easy task however the real challenge lies ahead stopping the reaction at the secondary Aman stage is extremely difficult the typical outcome of sn2 alkal at nitrogen is the formation of a mixture of amines
And a quinary ammonium salt modern developments in ch activation offer solutions to overcome these challenges based on the numbers from previous charts in these examples you might have the impression that direct CH activations are the easiest Transformations one could possibly try to employ to address the issues you are
Facing in your projects involving cross couplings unfortunately CH Transformations are not as straightforward as they might seem in this promising field of research is still in its infancy to sum it up in this lecture you have been introduced to the main definitions of CH activation we compared CH Transformations with other
Relevant reactions and I provided a brief historical overview of the development of this field of research in the following lecture I will describe the main drawbacks that limit the widespread application of CH activations along with some potential solutions for these limitations thank you for your attention hello everyone and welcome
Back to the series of lectures on CH activation in the previous learning material you were introduced to the most important definitions regarding CH activation in this lecture I will describe the main strategies enabling selective CH Transformations and discuss issues related to the reactivity of different CH bonds there are two major
Challenges limiting this chemistry as in many other cases issues related to reactivity and selectivity for instance in Benzene all CH bonds are equal however by changing one of the carbons to nitrogen we get purine which has three different types of CH bonds adding a dening ring to Pine gives us quinoline
In which all CH bonds are different similarly in PIP paradine we have three different types of CH bonds and so on the question is how can we differentiate these CH bonds from each other when conducting a CH transformation another question is what factors determine and control the reactivity of these systems
You will soon learn that under proper conditions these systems can be quite active for CH Transformations and acceptable selectivities are achieved achievable when speaking about reactivity it should be noted that among aromatic compounds the most reactive systems are electron Rich arant such as phenols and their derivatives five membered heterocycles infused five
Membered heterocycles the reactivity Trends in ch activation are very similar to those observed in electrophilic aromatic substitutions you will understand the reasons controlling the reactivity in SP2 hybridized CH bonds when we come to the mechanisms of CH activation among aliphatic systems the most reactive compounds are the so-called CH acids saturated
Heterocycles ethers and related aliphatic compounds possessing a hetero atom in contrast electron deficient RN and unfunctionalized alkanes or paraffins are quite inert the reactivity of these systems can be significantly enhanced by the introduction of special functional groups which I will show you soon due to their pronounced inertness
These systems are frequently used as solvents in homogeneous catalysis in the context of CH Transformations it is important to highlight that in certain categories of aromatic and aliphatic compounds specific CH bonds show marketly greater reactivity than their counterparts for instance in five membered heterocycles like theopen and
Purs the CH Bond at position two is usually more reactive in transition metal catalyzed CH Transformations enhanced reactivity at position two is in good agreement with the analogous reactivity pattern for electrophilic aromatic substitution similarly in indol the most reactive CH bond is the one located at position three in oxisol
Imidazol and related fused heterocycles the most reactive CH bond is the one located between two hetero atoms as the CH Bond at this position is more acidic among saturated heterocycles the most reactive CH bonds are located at the alpha position to the hetero atom here’s well the presence of a hetero atom makes
The alpha CH bonds more acidic I it should be noted that depending on the reaction conditions and especially on the used transition metal the reactivity May alter most of the studies in this field were performed using Palladium based catalysts in addition to empirical studies there are numerous theoretical studies devoted to Palladium catalyzed
CH Transformations for many aromatic systems the Gibs free energies of Palladium catalyzed CH activation were calculated and are presented here with the most reactive CH bonds indicated in red once more I want to emphasize that systems possessing a CH bond with increased reactivity are extremely limited the first transition metal
Catalyzed CH Transformations were developed in the 1960s however until the 21st century this field of research was not really popular the main reasons were poor reactivity of CH bonds limited scope and a lack of selectivity a real breakthrough in this field was the introduction of so-called directing groups directing groups are functional
Groups possessing a hetero atom with lone pairs of electrons that can coordinate to the Catalyst acting as ligans directing groups guide the Catalyst to the position that needs to be functionalized in doing so they are able to address the issues of selectivity and reactivity here you can see the range of directing groups
Developed within the last two decade among others the most popular directing groups are those based on purines amides and shift bases as mentioned earlier unfunctionalized alkanes are generally reactive however the introduction of a directing group into paraffins can dramatically alter known reactivity patterns consider this example published in 2011 the Palladium catalyzed aeration
Of cyclohexane which possesses a purine-based directing group leads to aerated cyclohexane in good yield and excellent Regio selectivity under these conditions unfunctionalized cyclohexane is not reactive in this work the authors demonstrated the role of the directing Group by isolating a p a cycle where the catalyst is coordinated by the directing
Group let me show you another example based on the rodium catalyzed alkal of indul rodium catalyzed alcal of unfunctionalized indol occurs at position three however the introduction of a directing group Alters the selectivity to position two these examples show that if you have a proper directing group in the molecule the
Directing effects are more dominant than the inherent reactivity of the given system the introduction of the main directing groups was crucial for the velopment of this field and has allowed scientists to achieve many challenging CH activations here I present the main carboncarbon Bond forming CH Transformations using modern
Developments in this field we can introduce aeral aleny aleny trifluoromethyl alkal cyano carbonyl and carboxy groups via CH activation the main carbon hetero atom Bond forming reactions are shown here using CH activation it is possible to introduce halogens organ metallic functionalities Amino groups calcin hydroxy aido and phosphor groups each of these
Transformations deserves a separate lecture in what follows I will present several examples describing some of these CH functionalizations here I want to briefly describe the range of reagents suitable for a given CH transformation this should give you an idea of the amount of work that has been done in ch
Activation within the last few years here the scope of reagents suitable for CH aeration is presented the most popular reagents are Aero halides additionally CH aeration can be accomplished by using derivatives of phenol iodonium salts aeral organometallics such as bonic acids and Organo silicon reagents as well as derivatives of carboxylic acid and
Sulfonic acid among others now let’s consider the range of coupling Partners suitable for CH alcal in this case the most frequently used reagents are olins and alkal halides additionally you often come across examples of CH alkal based on the application of derivatives of alcohols sulfonic acid and sulfoxides carboxilic acids organometallic reagents
Ammonium salts unfunctionalized activated systems like CH acids and carbine precursors among others the mechanisms of CH alkal can be quite diverse predominantly depending on the coupling partner used the most frequently used reagents for triome methylation include the rupper precau agent as well as the reagents developed
By tan and omoto for CH carox one can apply radical initiators like aob bobon trial keto acids derivatives of formic acid isocyanates nitromethane and carbon monoxide as well as CO2 the final transformation I want to present here is CH amination which can be achieved by the application of amides amines and
Analin as well as derivatives of hydroxyamine and aides among others once again the mechanism of CH amination mainly depends on the reagent used to sum it up this lecture covered the main factors controlling the reactivity and selectivity in ch activations you witness that the most prominent approach used to control selectivity in ch
Transformations is based on the use of directing groups you were introduced to the main types of CH activations and common reagents used for selected CH Transformations the next lecture will cover the most important mechanisms of CH Bond cleavage enabled by transition metals thank you for your attention hello everyone and welcome
Back to the series of lectures on CH activation in the previous Learning Materials we covered the main definitions of CH activation and discussed the factors controlling the reactivity of CH Bonds in the selectivity of CH transformations in this lecture I will summarize the main mechanisms of CH Bond cleavage enabled
By transition metals most transition metals are capable of activating and cleaving CH bonds through one of the mechanisms I am going to describe here I will show you only the stage of CH Bond cleavage later complete mechanisms on representative examples will be discussed so you can see the full
Catalytic Cycles the following three mechanisms are typical for the activation of CH Bonds in all three hybridization states of carbon the first mechanism is based on the oxidative addition of the metal to the CH bond this type of CH activation is common for late transition metals in their low
Oxidation state the second mechanism of CH activation is based on Sigma Bond metathesis common for early transition metals the next mechanism shares some similarities with entic ch activations occurring in nature and is based on Photo redo catalysis in this case the Catalyst being activated by light abstracts electrons from the substrate
Or donates electrons to the sub substrate generating radicals cats or other reactive intermediates that further undergo coupling reactions the main catalysts in this case are based on aridium and ruthenium moreover transition metals are known to greatly facilitate the selective CH insertions of carbons and nitrates this chemistry works well with late transition metals
Including iron rodium and ruthenium the following two mechanisms are typical for the activation of SP2 hybridized CH bonds for instance CH activation can occur via HEC type insertion followed by a beta hydride elimination this mechanism is typical for rodium padium and copper the final mechanism of CH activation shares some similarities with
Electrophilic aromatic substitution and is known by the name concerted metalation deprotonation it can also operate for some sp3 hybridized CH bonds this mechanism is typical for late transition metals in their High oxidation States and it works well for electron-rich aromatic systems now let’s delve into specific examples starting
With CH activation through the oxidative addition of the metal to the CH bond this mechanism is typical for late transition metals in their low oxidation States for instance if you encounter a CH transformation catalyzed by aridium 1 or rodium 1 complexes it’s likely that the reaction proceeds via the oxidative
Addition of the Catalyst to the CH Bond generating aridium 3 or rodium 3 intermediates the intermediates through subsequent Elementary reactions will lead to the formation of the product resulting from CH activation as an example let’s consider the idium catalyzed CH alcal of Ura derivatives in this reaction the amide acts as a
Directing group guiding idium one to the nearest CH Bond the oxidative addition of aridium 1 to the CH Bond generates an idium 3 cyclometalated intermediate which undergo a sin insertion into the Olin generating this intermediate the final stage of the process is reductive elimination which upon hydrolysis produces the product and regenerates the
Active Catalyst aridium one the next example is the rodium catalyzed culation of aromatic compounds published in 2008 the mechanism is quite similar to the previous one a ligant substitution reaction occurs at rodium accompanied by the cleavage of the Silicon silicon Bond the formed rodium 1 intermediate after coordination to the directing group
Under go oxidative addition to the CH Bond generating this rodium 3 intermediate the final stage of the catalytic cycle is reductive elimination producing the product and regenerating the active Catalyst rodium one the next mechanism is CH activation via Sigma Bond metathesis whenever you encounter a CH transformation catalyzed by early
Transition metals you should think about Sigma Bond metathesis as an example I want to show you the itum catalyzed alkal of analine derivatives published in 20 2016 before we delve into the mechanism I want to offer a word of caution this will perhaps be the most challenging part of today’s lecture here
We go in the first step of the process the trle carbocadon displaces one of the sigma bonded lians of itum generating the active Catalyst this active Catalyst initially coordinates to the nitrogen of the substrate followed by CH Bond cleavage via Sigma Bond metathesis subsequently an Olan coordinates to the
Generated complex initiating a HEC type insertion through a process quite similar to Sigma Bond metathesis next the generated intermediate undergoes Lian substitution with another molecule of analine resulting in this intermediate the final stage of the process involves the CH Bond cleavage of the newly coordinated substrate via another Sigma Bond metathesis leading to
The formation of the product and the active Catalyst now possessing another substrate the following mechanism is CH activation via photo redox catalysis these processes are mostly radical so whenever you encounter aridium Bodine or ruthenium Bodine complexes you should think about photo redo catalysis let’s consider the first example the ruthenium
And Cobalt co-catalyzed inmolecular thiolation of RN published in 2015 the initial step of the process is the deprotonation of the thioamide followed by a single electron transfer from the substrate to the photoactivated ruthenium Catalyst generating the following radical the sulfur centered radical attacks the aromatic ring producing a more stable radical which
Under go a one electron oxidation by the Cobalt Catalyst forming a cationic intermediate the final stage of the process is the elimination of a proton producing the benzole the eliminated proton oxidizes the reduced Cobalt one to the active Cobalt 3 generating hydrogen gas overall we have three single electron transfer processes and
Two interconnected catalytic Cycles the next example is an aridium catalyzed inmolecular amination of the benzilic CH bond with inhal Ogen tsat published in 2015 in this case the photoactivated aridium 3 Catalyst donates an electron to the substrate generating this in centered radical the radical abstracts a hydrogen atom from the benzilic position
Creating a more stable benzilic carbon centered radical in the next stage of the process the formed radical undergos a one electron oxidation by an aridium for intermediate it regenerating the active photocatalyst and producing a benzilic carbo cat I this carbo cat I undergoes inmolecular coupling with the amide forming the product and releasing
A proton in this example the activated photocatalyst donates an electron to the substrate while in the previous example the activated photocatalyst took an electron from the substrate to initiate the reaction both processes are possible and the outcome depends on the substrate and reaction conditions CH transform occurring in nature are mostly radical
Processes and share some similarities with ch activations by photo redo catalysis notably in nature CH activations are catalyzed by Metallo enzymes particularly by cytochromes located in our livers for instance one can observe the couplings of phenols anolin and their derivatives catalyzed by cytochromes initially the enzyme abstracts an electron and a proton from
The substrate which can then undergo a number of selective radical C CS forming carbon carbon or carbon hetero atom bonds the selectivity of these processes is determined by the enzyme in contrast to photo redo catalysis enzymes typically do not require a source of light for these Transformations now let’s consider the C
Insertion of carbons and nitrates whenever you encounter azides or diazo compounds combined with late transition metals you should think about the CH insertion of carbons and nitrates the first example is an iron catalyzed intr molecular CH amination of Orin by corresponding azides published in 2016 the reaction was conducted under
Microwave irradiation typical for diazidation reactions in the first stage of the process the substrate loses nitrogen and forms an iron nitr complex it is proposed that the formed complex undergo several electron shifts as shown here forming the carbosil and the active form of the Catalyst the next example is
An iron catalyzed intr molecular alyc alkaline with diazo compounds initially the substrate loses nitrogen accompanied by the formation of the corresponding iron carbine complex in contrast to the previous example in this case electron shifts produce intermediate radicals that eventually undergo inmolecular radical coupling yielding the product and regenerating the active Catalyst C
Activation via HEC type insertion is less studied and is debatable however whenever you encounter a late transition metal catalyzed CH activation of a five membered heterocycle with low resonance energy such as furans you should consider the possibility of this mechanism this mechanism was proposed for the Palladium catalyzed CH aeration
Of furans possessing an electron withdrawing group according to the proposed mechanism the reaction starts with the oxidative addition of padium 0 to the aeral halide generating the corresponding Palladium 2 complex further this complex undergoes a HEC type insertion into furan followed by Beta hydride elimination to generate the
Product and a Palladium 2 hydride intermediate the active catalyst is regenerated by the reductive elimination of hydrobromic acid which is trapped by the base now let’s consider the last mechanism CH activation via concerted metalation deprotonation this mechanism is typical for late transition metals in their High oxidation States therefore
Whenever you encounter renum 2 rodium 3 aridium 3 or padium 2 complexes combined with bases like acetate or carbonate you should think about this mechanism the first example is the idium catalyzed CH amination of orangins published in 2015 before I show you the mechanism pay attention to the reagents used by the
Authors they employed aridium 3 as a catalyst a silver salt and copper pivalate the silver salt serves multiple roles in this process firstly it removes chlorides from aridium forming the active Catalyst and it can also act as an oxidant the active form of the Catalyst coordinates to the directing
Group and undergos a concerted metalation deprotonation sequence forming the cyclometalated intermediate shown here the formed intermediate undergoes a liant substitution involving the amine followed by the double oxidation of the system by silver generating a nit ran complex of aridium 5 as shown here this is followed by reductive elimination and protonolysis
Leading to the product and the Regeneration of the active Catalyst the final example for today is the ruthenium Catal analyzed CH olefination of Orin published in 2012 in this case as well the initial step of the process involves silver mediated formation of the active form of the Catalyst through the
Substitution of chlorides by acetates the active form of ruthenium 2 first coordinates to the substrate followed by a concerted metalation deprotonation sequence forming this cyclometalated intermediate the next step of the process includes a HEC type insertion followed by Beta hydde elimination generating the product the active catalyst is reproduced through a
Sequence of reductive elimination followed by the oxidative regeneration of the renum 2 Catalyst enabled by copper 2 acetate to sum it up in this lecture we have learned the main mechanisms of CH Bond cleavage initiated by transition metals accordingly CH activation can occur via oxidative addition to the metal Sigma Bond
Metathesis photo redo catalysis HEC typ additions and a concerted metalation deprotonation sequence in the next lecture we will concentrate on the modern developments in ch activation thank you for your attention greetings to all and welcome back to the series of lectures on CH Activation so far we have examined the
Main Pathways of transition metal initiated CH Bond cleavages we observed that maintaining the selectivity of CH Transformations is crucial requiring directing groups capable of coordinating to the Catalyst and guiding it to the nearest CH Bond the present lecture will cover selected applications of modern directing groups and Regio selective CH
Activations here once more one can observe most of the directing groups developed during the last two decades a common feature for most of them is that they are connected to the main molecule via a carboncarbon bond as you know from the general organic chemistry course carbon carbon Bond bonds are not easily
Accessible for chemical Transformations meaning that the removal or further functionalization of these directing groups is almost impossible the inertness of these directing groups may become a serious issue during multi-step processes where all the functional groups need to be removable or modifiable this drawback has motivated many scientists to work on the
Development of Novel directing groups that can be easily introduced to the molecule undergoing CH transformation and subsequently removed or modified if necessary as a result a number of removable or modifiable directing groups were introduced the most important examples for aromatic systems are presented here and described in the
Review articles below as you can see most of the removable or modifiable directing groups are based on purine connected to the main molecule by a carbon hetero atom Bond other interesting examples include selenols protected bonic acids and Nitro compounds the only removable directing group based on a carboncarbon bond is
The carox group however this strategy has limited scope because decarbox silation requires harsh conditions for obvious reasons there is not a single removable or modifiable directing group suitable for CH activation of unfunctionalized aliphatic compounds however for functionalized aliphatic compounds such as aliphatic amines or alcohols there are some removable
Directing groups that are typically attached to the functional group within the molecule now let’s explore a few examples in more detail let’s consider the pyodine directing group attached to the main molecule via a carbon silicon Bond developed by the group of gorgian from the University of Texas at Dallas
In one of their initial reports they described a Palladium catalyzed CH halogenation of aromatic compounds directed by the removable puril group shown here as one can see the substrate scope is quite broad allowing for the presence of various reactive functional groups such as halogens and Esters in
Most cases the yields of the reaction were quite quite high they could demonstrate that afterward the directing group can be easily removed or transferred into other useful functional groups such as halide Esther of bonic acid and hydroxy group in the following reports they describ the introduction of the directing group into the molecules
Undergoing CH activation however it was found that this task is not easy and necessitates the use of expensive reagents to establish proper conditions more than 40 experiments were conducted another limitation arises from the fact that the removable directing group is not stable in the presence of bases rendering it unsuitable for CH
Functionalizations requiring the use of fluorides and other strong bases the Nitro group is another highly promising directing group its advantage over others is attributed to the fact that it can be converted into essentially anything the main disadvantage is that the Nitro group being a strong electron withdrawing group makes the systems to
Which it is bound less reactive as an example let me share with with you the work performed by the group of Langer at the University of rostock Germany they have developed a Palladium catalyzed methodology suitable for the selective CH aeration of several heterocyclic systems these conditions were quite
Successful for imidazol pizol and puring like compounds for 25 unsubstituted idazzle it was found that the reaction proceeds Regio selectively towards aeration at the fifth position when using 1.1 equivalents of aeral halide in this case position two can be aerated by the addition of another aeral halide
When the aerating reagent is used in excess the main product of the reaction is a diated idazzle this is another example where the directing effect is more dominant than the inherent reactivity of the system in the case of pazoles further optimization showed that position three can be aerated in the
Presence of an excess of copper iodide based on this finding it was possible to prepare three five diated pizol each possess ing two different Arrow groups the potential of the Nitro group as a useful directing group was demonstrated through several model Transformations for instance the reduction of the Nitro
Group under different conditions led to the formation of analin dimethylated analin and derivatives of phenanthridine Additionally the Nitro group was transformed into a bromide enabling the introduction of aeral aleny and aleny groups using Suzuki sonogashira and hecc cross coupling reactions respectively the next example is the CH acet oxolation of aliphatic alcohols
Developed by the group of Dong from the University of Texas they apply derivatives of hydroxyamine as a removable directing group for the functionalization of aliphatic systems with the directing group presented here they have examined several oxidative CH Transformations enabled by Palladium catalysts for CH acetoxy the best Catalyst was found to be Palladium
Acetate combined with stochiometric quantities of a hypervalent i reagent phenyliodine diacetate which acts as a source of acetate and an oxidizing agent as one can see the reaction operates on both acyclic and cyclic alcohol derivatives furthermore they have demonstrated that the directing group can be selectively removed under two different conditions including basic
Hydrolysis and zinc mediated reduction under these conditions the newly introduced functional group remains intact in this case the introduction of the directing group was easier and took two steps first they substituted the hydroxy group of the alcohol with in hydroxyamide followed by De protection of the amino group and the formation of
A shift base with an alahh to sum it up in this lecture We examined the main removable directing groups used in selective CH Transformations we explored the principles underlying the development of removable and modifiable directing groups and specifically focused on CH Transformations Guided by the pine directing group attached to the
Main molecule via a carbon silicon Bond Nitro group directed CH relations and hydroxyamine based directing groups used in aliphatic systems in the following lecture we will delve into two additional families of directing groups demonstrating added value thank you for your attention greetings to all and welcome
Back to the module on CH activation in the previous lectures we learned about traditional directing groups that determine the selectivity of CH Transformations we also examined removable and modifiable directing groups which open new avenues for sophisticated organic synthesis based on CH activations in this lecture you will learn about other important families of
Directing groups offering New Perspectives for atom economy and synthesis a promising Direction in ch functionalization is based on the use of so-called oxidizing directing groups many CH transformation s in addition to the Catalyst require stochiometric quantities of an oxidant the most effective oxidants for CH activation
Have proven to be salts of silver one and copper 2 however these salts are quite toxic and expensive therefore finding less toxic and inexpensive oxidants is an ongoing task an interesting solution to this issue was recently developed and is based on the application of directing groups possessing functionality that can act as
An oxidant for the Catalyst the main representatives of oxidizing directing groups are presented here with most of them based on derivatives of hydroxyamine where the nitrogen oxygen bond is responsible for the oxidation of the Catalyst during the catalytic cycle additionally it has been recently discovered that in oxides and
Derivatives of hydrazine may also act as an oxidizing directing group so far All the known CH Transformations enabled by oxidizing directing groups have been based on aromatic systems unfortunately I was not able to find any oxidizing directec group suitable for the oxidative CH transformation of aliphatic compounds hopefully one of you will
Develop one in the future here is an example of a CH functionalization enabled by an oxidizing directing group the group of you from Sichuan University developed a rodium catalyzed external oxidant-free CH olefination of analine derivatives as presented here they used analine and oxides as the oxidizing directing group the substrate scope
Involved various anoline derivatives and different molx receptors rodium 3 is involved so the CH activation occurs via a concerted metalation deprotonation sequence as shown here the reaction starts with the activation of the rodium complex through Lian substitution reactions this is followed by the coordination of the substrate and CH
Activation via a concerted metalation deprotonation sequence next we have Olan insertion followed by Beta hydride elimination leading to the formation of this rodium 3 intermediate in the last step there is a reductive elimination of pivalic acid resulting in a rodium one intermediate the rodium one intermediate undergo oxidative addition to the an
Oxide followed by protonolysis and ligant substitution regenerating the active rodium 3 Catalyst this process is accompanied by the release of the ortho elated analine the directing effect of an oxides was demonstrated by isolating the cyclometalated intermediate presented here which in the presence of acrylate leads to the formation of a
Leaned analine in a 42% yield the preparation of starting in oxides is quite simple and can be achieved by oxidizing analine derivatives with metaco peroxybenzoic acid here’s another extension of the directing group strategy a modern variation of removable directing groups is known as transient directing groups this strategy is based
On reversible reactions for instance if your substrate contains a functional group that may not serve as an effective directing group but can be reversibly trans formed into other functional groups you can apply this strategy using a directing group that can be attached and attached to your functional group
During the reaction let me provide some examples to make everything clear for instance alahh are not good directing groups for late transition metals however in the presence of catalytic amounts of primary amines they can be reversibly transformed into corresponding shift bases which serve as far better directing groups after the CH
Transformation the shift base can be hydrolized back to the corresponding alahh allowing the amine to be used in catalytic amounts based on this strategy recent developments include CH aeration halogenation hydroxy amination and boration reactions applying the same concept it is possible to selectively functionalize phenols using transient directing groups based on phosphonite in
This case a reversible transesterification at phosphorus generates phosphinites derived from the initial phenol with phosphorus serving as a directing group for the Catalyst insitu formation of shift bases was also applied for CH transformations of aliphatic carbonal compounds this approach can be employed for both aliphatic alahh and ketones a similar
Strategy can be applied to CH transformations of aliphatic amines however in this case one needs to use a directing group possessing an alahh functionality let’s go through two examples in more detail the group led by you from the scrips Research Institute was among the first to develop this chemistry in their recently published
Work they identified three different transient directing groups for metal catalyzed CH halogenation aeration and amination reactions all were based on in cidu shift based formation between the starting alahh material and transient directing groups which included various analin and amino acids a portion of the substrate scope is presented here as one
Can observe the developed conditions tolerate numerous reactive functional groups and the yields are above average the developed approach was so successful that it could be extended to the late stage CH functionalization of an analog of the commercial drug celic coxib celic coxib is a non-steroidal anti-inflammatory drug and is one of the
Top selling drugs in the world the group led by you was among the first to extend this strategy to aliphatic systems for aliphatic primary amans they identified a suitable transient directing group based on alahh enabling the Palladium catalyzed CH aeration described here the optimal reaction conditions are
Presented here this CH a relation worked with Palladium based catalysts combined with silver salts used in STO ometric quantities they screened several transient directing groups among which the underlined purine derivatives showed the best results furthermore they applied the developed strategy for the direct CH aeration of various aliphatic
Amines the scope of the reaction includes both cyclic and acyclic amines it should be noted that after the CH aeration step they we protected the amino group to facilitate the separation process to sum it up we have seen that directing groups can play a dual role in ch Transformations it is possible to
Include additional functionalities in the directing group that can act as an oxiden for the Catalyst thus eliminating the need to use an external oxidant based on salts of precious metals the directing group does not have to be permanently bound to the substrate being functionalized transient directing groups can enter the substrate and after
Selective functionalization leave the product this strategy is based on reversible reactions meaning that transient directing groups can also be used in catalytic quantities now you are familiar with the main directions and Regio selective CH Transformations enabled by directing groups the directing groups discussed so far guide the Catalyst to the ortho bonds which
Are normally the nearest CH bonds to the group in the coming lecture I will describe strategies for the Regio selective functionalization of more remote CH bonds your attention and participation are greatly appreciated hello everyone and welcome back to the series of lectures on CH activation in our previous session we
Delved into the factors influencing selectivity in ch Transformations We examined the main Pathways of CH Bond cleavage enabled by transition metals and I introduced the concept of directing group assisted CH activation so far I have described only direct CH transformations of CH Bonds located Ortho to the directing group but what
About meta and Par positions with modern developments and directing group assisted CH activation it is now possible to selectively functionalize even remote CH bonds for instance there are four strategies available for meta selective CH transformation the first one is based on the application of directing groups connected to the
Substrate through a special template this template is designed so that the directing group appears in close proximity to the metac bond directing the Catalyst to that position the second approach operates only on substrates possessing a hydrogen bond acceptor in this case the catalyst is used in combination with a specialized Li which
Along with coordination to the Catalyst can act as a hydrogen bond donor as described here overall this rather complex system positions the Catalyst near the metac bond that is being activated this strategy has some similar ities with the application of transient directing groups the following strategy is based on the catalani reaction which
You may recall from the lectures on Cross couplings the key point of the catalani reaction is that the addition of Norborne to aromatic systems is reversible if a typical directing group is present in the molecule the first step of the process involves directing group assisted Ortho alcal with Norborne
Instead of beta hydride elimination the formed intermediate undergo another CH activation sequence followed by the elimination of Norborne the described sequence leads to the formation of a meta substituted product the Final Approach is based on the application of renum paracine complexes in some cases cyclometalation products of renum are
Quite stable and can have an activating effect on the substrate in the product of cyclometalation the CH bonds of the substrate indicated in red are sterically hindered due to the directing group in the lians on ruthenium therefore the second molecule of the Catalyst can only functionalize the
Metac bond indicated in blue except meta functionalization the strategy based on the use of specialized templates and directing groups was recently extended to par a CH functionalization of aromatic systems now let’s briefly go through some specific examples the template strategy for metac Activation was developed by the group of you at the
Scripts Research Institute their initial paper was published in 2012 they have developed two directing groups both suitable for padium catalyzed meta CH olefination a short optimization was required for this directing group eventually indicating that the best meta selectivity can be achieved Winer one inner two or isbut and tbal groups
Respectively the substrate scope is presented here following their report it should be mentioned that the reaction works well for a wide range of substrates producing corresponding meta olefination products and good yields they successfully applied their strategy for the late stage ch functionalization of the commercial drug blean although in
This case they obtained a onetoone mixture of mono and disubstituted products the approach based on the hydrogen bonding of specialized lians and the substrate was developed in the group of Kai at the University of Tokyo they conducted studies on aridium catalyzed CH Bor relation on amides and related hydrogen bond acceptors to
Enhance the selectivity of the reaction toward the metapos they screened a number of ligans as described here the table presents not only the yield of the product but also the ratio of meta and Par substituted products the best meta selectivity was observed when using the
LI width r equal to a cyclohex group the overall yield of the product was further increased by replacing the solvent hexane with parylene and here one can observe the scope of the reaction their strategy proved successful not only for substituted benzines but also for heteroarenes hydrogen bond acceptors
Such as amides Esters and phosphinates were applied the role of hydrogen bonding in the selectivity of the reaction was also examined any manipulations involving the positioning of the Ura subunit significantly decreased the selectivity likewise the replacement of hydrogen atoms with alkal groups in the Ura subunit also led to a
Decrease in selectivity the approach based on the application of nor borian was primarily studied in the group of you in their recently published work they examined padium catalyzed metac amination using derivatives of of hydroxyamine it is worth mentioning that instead of Norborne they used a derivative of Norborne indicated in red
The researchers found that the reaction proceeds well only in the presence of purine-based ligans among others the underlying Lian showed the best efficiency the exact function of the Lian is not clear and overall compared to traditional cross couplings the role of lians and CH activations is not well understood after optimizing the reaction
Conditions they study the scope and limitation of the process in general the reaction proceeds well for a wide range of substituted Orin producing corresponding amination products with good yields and selectivity in the same paper they also described meta alation of orins using a similar strategy for this new transformation they changed the
Purine based Lian and applied aliny bromides as coupling partners for metac Activation enabled by cyclometalation let me share the work conducted by the group of acran from the univers of godian in their 2017 publication they explored renum catalyzed Dome methylation of various arants the study revealed that Dome methylation can be
Achieved using a variety of directing groups the most promising results were observed with purines pyrimidines indoo and pazoles interestingly applying the same strategy made it possible to introduce monofloral alal groups furthermore they successfully extended their strategy to puring derivatives dorom vation proved effective for purans with a protected sugar this concludes
The strategies for meta functionalization now let’s explore an example of selective par transformation the strategy based on Specialized templates and directing groups was extended to para CH functionalization in the group of Mighty from the Indian Institute of Technology they investigated the Palladium catalyzed CH olefination of derivatives of phenol as
Described here initially they screened several templates including control experiments without directing groups it was found that unprotected phenols are not reactive while protected phenols can be olefinated though with poor selectivity they observed good par selectivity using the specialized template with a cyano group which acts as a directing group for the Catalyst on
This slide one can observe the scope of the reaction the brackets present the ratio of products with par selectivity over others the reaction performs well with a variety of substituted Orin and Michael acceptors they demonstrated that the template with the directing group can be removed through acid catalyzed hydrolysis and
Later reused for another substrate as described here so far I have shown you only examples in aromatic systems as the functionalization of remote CH Bonds in aliphatic systems is far less studied in this context the work by the group of Sanford from the University of Michigan is unique and highly promising they
Successfully developed proper conditions in directing groups for the Palladium catalyzed C a relation of aliphatic CH Bonds located at Gamma or other remote positions another noteworthy finding was that for some cases the functionalization of remote positions was only possible in unstable conformations of cyclic systems such as the boat conformation of piperidine
Presented here the reaction conditions were optimized for this bicyclic amine and part of the optimization table is presented here the best directing group turned out to be the amide possessing a perlin analine to to minimize the formation of intermolecular amination byproducts the silver salts were replaced by cesium pivalate as silver
Among other roles can act as an oxidant promoting inmolecular amination following the optimization they screen the scope of aerolites the yields were moderate but the Regio selectivity and chemos selectivity of the reaction were exceptional additionally they explored the scope of cyclic amines which was quite impressive although the yields of
The products were not very high high and in some cases they observe double aeration hopefully in the near future we will see some extensions to this chemistry to Summit up in this lecture you have been introduced to the main Concepts applied for the selective CH functionalization of remote positions
For aromatic systems it is possible to design specialized templates for directing groups and ligans guiding the Catalyst to the metapos alternatively meta selective CH Transformations are achievable via the modified catalani reaction or through cyclometalated intermediates blocking the ortho positions the template strategy for remote CH functionalization can be
Extended to par positions and CH activation at remote CH bonds of aliphatic systems is also achievable these were the main modern directions in ch activation I encourage you to proceed to the concluding lecture of the module where I will describe selected applications of CH functionalizations thank you for your attention
Greetings to all and a warm welcome to the concluding part of the module on CH activation in this course you learn the basic concepts about CH activation we systematically covered the main mechanisms of the CH Bond cleavage initiated by Metals the selectivity determining factors in ch Transformations and some Modern
Directions in the field of CH activation this lecture is devoted to the description of Select applications of modern developments in ch functionalization traditional approaches to conjugated iggers and polymers are based on Cross coupling reactions the first option involves the coupling of RNs possessing two organometallic functionalities with dihalogenated orns
The second option is based on the self-coupling of orangins possessing both organometallic and Halli functionalities conjugated iggers and polymers prepared by these methodologies can be applied as organic semiconductors florescent probes Etc selected examples can be seen here similar oligomers and polymers can be prepared using CH activation of aromatic systems the
Replacement of traditional cross couplings by modern direct CH a relations can revolutionize this field of research as CH activations demonstrate High atom economy and sustainability the research on theopen conducted by the group of ducet from the University of Ren has significantly influenced modern developments in this field the set group has published over
150 papers describing highly efficient padium catalyzed CH aerations involving theopen perhaps the most extensively studied systems among AR consequently iggers and polymers demonstrating promising properties are currently prepared by Palladium catalyzed CH aeration of theophine derivatives as described in this General scheme the list of the most frequently used
Theophine derivatives is shown in red while the most important aeral halides are indicated in blue modern developments and CH activation have found applications in the total synthesis of natural products and other complex systems in here you can see drag mid and d a natural product isolated
From sponges the group led by atami from ngoya University suggested and successfully performed the total synthesis of this natural product mainly relying on Direct CH Transformations specifically they utilized multiple CH aerations as will be described in what follows they began with the padium catalyzed CH aeration of the silop
Protected theophine using an iodinated indul derivative in the next stage they performed the reductive desulfurization of the newly introduced theophine followed by the replacement of protecting groups at nitrogen and oxygen with a methoxymethyl protecting group abbreviated as Mom this step was succeeded by a padium catalyzed oxidative aeration at the third position
Of the indol with the in oxide of pine subsequently an acid and hydride mediated inmolecular m migration of the oxygen atom from the in oxide to the second position of the purine ring was carried out this was followed by an acid catalyzed electrophilic substitution at the indol Ring of six brool at this
Stage fral Craft’s chemistry was involved distinct from CH activation during this process methoxymethyl protecting groups were removed as they are label under acidic conditions in the final stage of the synthesis they halogenated the alpha position of the carbonal subunit followed by cyc condens ation with guanidine to afford the
Imidazol ring overall the synthesis included two CH aerations and a fredal crafts aeration now let me describe two examples of the synthesis of commercial Pharmaceuticals the production of the anti-inflammatory drug diac can involve a CH activation step in 2010 the group led by you developed a Palladium catalyzed approach for carboxy directed
CH iodination of orence their methodology was quite successful for a range of substitute Ed or as presented here the reaction worked well even for electron deficient substrates which are normally inactive for electrophilic aromatic substitutions as a potential application of this reaction they suggested and successfully performed the synthesis of Diclofenac they prepared
The iodinated fin atic acid using padium catalyzed CH iodination followed by copper mediated Omen amination to yield dhac in 61% yield in another paper scientists from fiser veloped a novel approach to celic coxib involving a CH aeration step initially they prepared the sulfinamide which was subsequently couped with a trifluoromethylated pizol
Via copper catalyzed alen amination the resulting pizol derivative was selectively aerated at position five using padium acetate combined with beller’s ligant the subsequent de protection of the sulfinamide gave celic oxy in a 69% yield one of the key approaches in modern drug Discovery involves the late stage function alization of potential drug candidates
Or commercial drugs this method allows for the rapid preparation of libraries of biologically active substances for bioti dists the modern developments and CH activation can greatly facilitate drug Discovery through late stage CH functionalization as demonstrated in previous lectures here’s another interesting example of late stage CH functionalization elaborated by the
Group of Baron in collaboration with Scientists from leoa the focus of their work was on analoges of the antibacterial natural product hongo kersen a they prepared two analoges with directing groups such as perlin amide or carboxy group utilizing directing group assisted CH functionalization they successfully introduced a variety of
Functional groups into these molecules this included CH aminations aerations amidations olefinations hydroxylations and alkal further biological examinations revealed that the prepared analoges of hongo kersen a demonstrated enhanced antibacterial activity to sum it up modern developments and CH functionalization allow for the effective synthesis of materials natural products Pharmaceuticals and biologically active ingredients further
Advancements in the field may eventually replace traditional cross coupling approaches which rely on prefunctionalized starting materials with direct CH transformations in conclusion I want to highlight the scientists who have made a significant impact on the development of CH activation all the academics described here have well-established websites detailing their research and
Publications if you wish to delve deeper into a specific C transformation I encourage you to explore the works of the researchers mentioned below the actual boom we have witnessed in this field was driven by the development of padem based directing groups in the Sanford group the group led by you has
Also contributed significantly by developing many other efficient directing groups and Transformations the research conducted by Sanford and youu was primarily focused on aromatic systemss key advancements in directing group assisted CH transformations of aliphatic compounds were made in the groups of dogus and chatani here are some other scientists who have made a
Significant impact on the development of selected aspects of CH activation for instance if you are interested in ch aeration I would suggest considering the works of Fong nil if Hydro aeration via CH activation catches your interest you should explore the research from the groups of Birdman and Elman for those
Intrigued by photo redo catalysis the works from McMillan’s group are worth exploring if the application of first row transition medals in ch activation is your focus acran group has valuable contributions CH insertion of carbons was predominantly studi by the Davis Group while for the insertion of nitr
You should check the works from dub group for CH metalation refer to the works from myora and Hartwick Hartwig among others is renowned for systematic studies on the mechanisms of selected CH Transformations oxidative and radical CH Transformations were primarily studied in LS group if you’re interested in the
Total synthesis and applications of CH activation you should explore the works from the groups of Baron and atami finally for those interested in understanding exact mechanisms and theoretical studies on CH activations checking the works from the groups of schunck Gorski and musve is recommended most of these scientists used to be part
Of a scientific Community known known as the center for Selective CH functionalization led by houd Davies they have an official website and a YouTube channel where you can find numerous videos covering modern Trends in the field while I believe the center for Selective CH functionalization is no longer active the valuable material and
Wonderful lectures produced in the cinder are still available I appreciate your time and thoughtful consideration best wishes for your midterm evaluations and continued success throughout the rest of the course