C–H activation reactions as useful tools for medicinal chemists

Bioorganic & Medicinal Chemistry Letters 26 (2016) 5378–5383

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C–H activation reactions as useful tools for medicinal chemists Eduardo J. E. Caro-Diaz ⇑, Mariangela Urbano, Daniel J. Buzard, Robert M. Jones Medicinal Chemistry, Arena Pharmaceuticals Inc., 6154 Nancy Ridge Drive, San Diego, CA 92102, USA

a r t i c l e

i n f o

Article history: Received 12 January 2016 Revised 13 June 2016 Accepted 14 June 2016 Available online 11 August 2016 Keywords: C–H activation Heterocycles Pharmaceuticals Drug discovery Medicinal chemistry

a b s t r a c t In recent years, there has been an exponential rise in the number of reports describing synthetic methods that utilize catalytic sp3 and sp2 C–H bond activation. Many have emerged as powerful synthetic tools for accessing biologically active motifs. Indeed, application to C–C and C–heteroatom bond formation, provides new directives for the construction of new pharmaceutical entities. Herein, we highlight some recent novel C–H activation processes that exemplify the utility of these transformations in medicinal chemistry. Ó 2016 Elsevier Ltd. All rights reserved.

In recent years, C–H activation reactions have emerged as powerful tools for C–C bond formation1 and provide an efficient synthetic alternative to conventional cross-coupling reactions. C–H transformations are particularly useful for shortening multi-step syntheses since they do not require the installation of activated functional groups such as halogens or triflates. In addition, C–H halogenation and C–H borylation provide a synthetic tool to access challenging substrates that can be subsequently converted to a wide range of motifs through more traditional Pd-catalyzed coupling reactions (Scheme 1). Even though great advances in the field of C–H activation have been achieved, many challenges still remain. In addition to the low reactivity of C–H bonds (due to their high bond strength, ca. 110 kcal/mol), controlling regio-selectivity of C–H transformations has proven difficult since substrates usually display multiple C–H bonds with close dissociation energies. Also, chemoselectivity in the presence of sensitive functional groups still presents a challenge. Herein, we will highlight the application of C–H functionalization for the construction of pharmaceutically relevant scaffolds and describe the latest advances made to overcome these issues, thus rendering C–H activation a powerful tool for medicinal chemists. Medicinal chemists heavily rely on C–C bond-forming reactions in the design of small molecules libraries. Among these reactions, arylations play an important role and, if regioselectivity can be controlled and predicted, arylations via C–H activation methods can represent a powerful synthetic tool. One of the most commonly applied strategies to achieve regioselectivity involves ⇑ Corresponding author. http://dx.doi.org/10.1016/j.bmcl.2016.06.036 0960-894X/Ó 2016 Elsevier Ltd. All rights reserved.

chelation assistance by a proximal Lewis-basic directing group (DG) which leads to ortho-selective C–H functionalization.2 Su and co-workers recently developed a Pd(II)-catalyzed ortho-C–H arylation (Scheme 2) in which variously substituted benzoic acids as well as 3-chlorophenyl acetic acid smoothly underwent C–H arylation with aryl iodides.3 However, the reaction did not work with ortho-substituted aryl iodides or those bearing strong electron-withdrawing groups (e.g., NO2, CF3). Even so, this method provides the first example of C–H functionalization of electrondeficient benzoic acids under mild conditions. Along these lines, Miura and co-workers developed an environmentally benign copper-catalyzed intermolecular biaryl cross-coupling (Scheme 3) of indoles/pyrroles and 1,3-azoles.4 Notably, the cross-coupling proceeded exclusively at the indole/pyrrole C2position, thus providing a selectivity outcome complementary to prior Pd-based methodologies. In parallel, an ortho-selective Cumediated intermolecular direct biaryl coupling was also described for arylazines and azoles (Scheme 3).5 Pd-catalyzed C–H arylations of heterocycles typically produce a mixture of regioisomers or favor the inherently reactive position (Scheme 4). In the absence of DGs, regioselectivity can be achieved through a Pd-catalyzed protocol using a chlorine activating/blocking group (Scheme 5).6 A chlorine atom was installed on a reactive site: (1) to selectively arylate C2 or C5 of substituted thiophenes (Scheme 5, a and b); (2) to obtain exclusively C2- or C3-arylated indoles (Scheme 5, c and d); (3) to divert typical selectivity outcome of C–H arylation of thiazoles or oxazoles from C5 to C4 (Scheme 5, e); (4) to divert the arylation of benzothiophenes or benzoxazoles from C2 to C3 (Scheme 5, f). Additionally, the chlorine atom acted as an activating group to improve the yield of C–

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X

R

R1 Het H

S

H

C2/C5 regioisomer mixture

S H

X = F, Cl, Br, I

n

Ar

H

R1 Het

Ar H

R2N R1

R

n

Het

R1 Het

n

N Me

BR2 R1

Het

Het

H

N Me

Pd (0) H

N

Ar

Y

N R

Scheme 1. C–H activation reactions provide diverse functionalization of aromatic and heteroaromatic motiffs.

R

Y

H

Y = O, S

H

C2/C3 regioisomer mixture

C5 regioisomer exclusively

H H

Ar

Y

Z

C2 regioisomer exclusively

CO2 H CO2 H

I

R1

Pd (II)

R2

R1

Scheme 4. Typical regioselectivity of Pd-catalyzed arylation of heteroaromatics.

R2

H

R

Scheme 2. Pd-catalyzed ortho-C–H arylation of benzoic acids.

R Cl

(a)

H

H H N N

Y

N

Ar

R

N N

N

Y

Cl

N

N

Y H

Ar

S

Cl

Cu air

X

N

N

C5 regioisomer exclusively

Ar

N Me

N

S

Cl

(c)

N

C2 regioisomer exclusively

R

H

H X

S

H

(b)

Cu air

Cl

S

Cl

C3 regioisomer exclusively

Ar

C2 regioisomer exclusively

N Me Pd (0)

Cl

Cl

Ar-Br

Y H

(d)

N Me

N Me

Scheme 3. Cu-catalyzed biaryl cross-coupling via C–H activation.

H

N

(e)

H arylation of imidazoles at C2. This protocol has valuable synthetic utility since it enables selective access to regioisomers that are difficult to synthesize with conventional metal-catalyzed cross-couplings (e.g., formation of C4-biaryl bond in thiazoles/oxazoles in the presence of C5 C–H bonds). It is worth noting that chlorine can be easily introduced on aromatic rings and may be easily removed or exploited for further transformations. Similar halogenblocking strategies have been published for pyrazoles and are not limited to Cl.7 Selectivity towards other substitution patterns on aromatic rings is also possible via C–H activation methods. Interestingly, recent methods have been reported on selective activation of C– H bonds that are in remote meta position from the DG.8–10 A meta-selective C–H arylation (Scheme 6) via Pd/norbornene catalysis has been recently described8 for variously substituted benzylamines with aryl iodides bearing an electron-withdrawing substituent (e.g., CO2Me, COMe, CONMe2, NO2) in ortho-position.3 As highlighted by the authors, the use of a benzyl dimethyl amino DG gives the opportunity to access versatile synthetic precursors (e.g., benzaldehydes, benzyl chlorides) and can also be readily removed under standard hydrogenolysis conditions. Yu and co-workers have developed a method for meta-C–H alkylation of phenylacetic amides that in turn was applied to meta-C–H arylation11 (Scheme 7). The substrate scope is limited since the desired biaryl compounds were obtained only when using aryl iodides bearing an ortho-coordinating group (e.g., CO2Me, COMe) or highly electron withdrawing functionalities. Even so, this approach has interesting applications for the late stage arylation of heterocycles such as dihydrobenzofuran and indolines. Copper has also been proven to be useful in selective meta-arylation of pivalanides.12

Ar

N

Cl

Y

R Cl

Y H

Y = O, S

R Ar

Cl

(f)

Y

C4 regioisomer exclusively

Cl Z

C3 regioisomer exclusively

Scheme 5. Chlorine induce and diverted regioselectivity of C–H direct arylation.

Another commonly employed transformation utilized in the construction of pharmaceuticals is transition metal mediated sp2 alkylation reactions. Traditionally, these reactions are performed through standard Pd-catalysis requiring a variety of reactive groups (e.g., –OTf, –Br, –I) to be pre-installed on the substrate. For this precise reason, the field of C–H activation has begun to address these limitations. Several reports have been published on metal-catalyzed alkylation of C(sp2)–H and C(sp3)–H bonds. Rhodium has been reported to catalyze the oxidative ortho-directed C–H alkylation of arenes (Scheme 8) using potassium alkyltrifluoroborates.13 This protocol is compatible with functionalizable groups (e.g., oximes) as well as other DGs including pyridines and pyrimidines, and is applicable to variously substituted indoles. An alternative protocol for orthoC–H alkylation was developed for phenylacetic and benzoic acids (Scheme 9) using Pd(II)-catalysis and alkylboron reagents.14 This protocol has important applications in medicinal chemistry considering the opportunity to chemically manipulate carboxylic acids and the prevalence of phenylacetic/benzoic acids as scaffolds. Rhcatalyzed C(sp3)–H alkylation, using triarylboroxines as alkylation agents, has been described for various 2-ethyl pyridines and quinolines in the presence of Ag2O.15

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NMe2

NMe2

Pd (OAc)2 (10 mol%), AsPh 3 (25 mol%)

I EWG

EWG

norbornene "acetate cocktail"

H

Scheme 6. meta-Selective C–H arylation of benzylamines.

Me

Me NHArF

NHArF

Pd (II)

O

O

Ar-I

H X

Ar X

ArF = 4-(CF3)C6 F4 NHArF

H

NHArF

Pd (II) Ar-I

O

O Ar

X = O, N-Ts

Scheme 7. meta-Selective C–H arylation of phenylacetic amides.

DG

DG R1

H R

R

1

R BF3K, AgF [RhCp*Cl2 ] 2, AgSbF6 X

N

N R

H

X R 1 = Me, n-Bu, cyclopropyl, n-Pent, cyclopentyl, Bn

N R

N R1

X = CH, N Scheme 8. ortho- and C2-selective C–H alkylation using trialkylfluoroborates.

n

R H

n = 0,1

CO2H

Pd(OAc)2 Ligand Alkylboron

R

nCO 2 H R1

R1 = Me, nBu, nPr, Bn, cycloalkyl

Scheme 9. ortho-Selective C–H alkylation benzoic and phenylacetic acids.

Recent research efforts have been focused on the development of C–H activation/alkylation methods that exploit the coordination of a metal with a functional group to selectively activate remote C– H bonds. Yu and co-workers reported a method for meta-C–H activation of variously substituted phenylacetic amides (Scheme 10) using norbornene as a transient mediator and the appropriate alkyl iodide.4 Methylation, ethoxycarbonyl methylation, and benzylation efficiently occured in meta-position to the DG (arylamide methyl group). Mono- or di-methylated products were observed depending on the sterics. By contrast, the ethylation with ethyl iodide did not produce the desired products, and the use of other alkyl halides was not investigated. It is worth noting that a broad range of a-substituents were tolerated at the benzylic position of the phenylacetic amide, thus enabling the direct meta-functionalization of key biologically active building blocks such as mandelic acid and phenyl glycine (Scheme 10). The incorporation of the trifluoromethyl group in drug candidates is often used to enhance binding affinity, increase cellular membrane permeability and metabolic stability.16 Several reports have been published on C–H functionalizations that trifluoromethylate the inherently reactive positions of the substrate; these methods involve the addition of an electron-deficient CF3

radical to the most electron-rich position of (hetero)arenes (Scheme 11).17,18 This methodology could prove useful to block and identify metabolically susceptible positions. The major drawback of this protocol is the poor regioselectivity observed for substrates that lack electron-rich p-systems and have multiple reactive sites. C–H trifluoromethylations that proceed via transition metal-catalyzed C–H activation have been also described. Pd (OAc)2 has been shown to catalyze ortho-selective C–H activation/trifluoromethylation of 2-phenylpyridines (Scheme 12).19 Imidazole and thiazole, two common motifs in medicinal chemistry, could also be used as DGs. However, the substrate scope of this reaction protocol remains limited. Halogens have served as critical functionalization handles in organic molecules, especially after the development of Pd-catalyzed C–C bond forming reactions. To date, they still play a very important role in a medicinal chemist’s repertoire. For this reason, it is important to continue to develop versatile and robust methods to install these atoms in aromatic molecules. Recently, chemists have taken advantage of C–H bond functionalization to develop novel C–H halogenation reactions. A versatile [Rh(III)Cp⁄]-catalyzed method for the synthesis of ortho-brominated and -iodinated aromatic compounds20 was described and applied to variously substituted benzamides (Scheme 13). Interestingly, this protocol provides also the first example of direct aryl halogenation of acetophenones and benzoic esters via C–H activation. Along these lines, a Pd(II)-catalyzed regio- and chemo-selective chlorination of a variety of challenging electron-poor substrates such as benzoates, benzamides, sulfonamides, ketones and 2-phenylacetates (Scheme 14) was reported.21 Furthermore, it was possible to achieve ortho-bromination as well using NBS under similar conditions. This represents the first reported example of regioselective direct halogenation of such challenging substrates. The significance of this method stems from the suitability and widespread use of aryl chlorides as drug products where the chlorine is often introduced to prevent the oxidative metabolism of aromatic rings. This method is synthetically useful as an alternative approach to classic ortho-lithiation, electrophilic aromatic substitution, and the Sandmeyer reaction which often suffer from poor regioselectivity, low yield, and harsh reaction conditions. Remarkably a single regioisomer can be achieved even in the presence of two different DGs, following a specific priority order (Scheme 15).

X

X Pd(OAc)2 Ligand Norbornene R1 I

NHArF R

O ArF = 4-(CF3)C6 F4

H

OAc NHAr F H3 C

CH3

O Mandelic acid

O R1

R1

X = H, Me, OAc, OBn, NPhth

H 3C

NHArF R

= Me, CH2 CO2Et, Bn

NPhth NHAr F O CH3 Phenyl glycine

Scheme 10. meta-Selective C–H alkylation of phenylacetic amides.

Y

Y

H

a) CF3SO 2Cl photoredoxcatalysis

X R

b) NaSO 2CF3 /t BuOOH

Het H

X

CF3 R Het CF3

Scheme 11. Electrophilic radical trifluoromethylation via photoredox catalysis.

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N

R

N

R

H

CF3 Pd(OAc)2, Cu(OAc)2

X

H

X

TFA

N

N

X = NMe, S

CF3

Scheme 12. ortho-Selective C–H trifluoromethylation of 2-phenylpyridines.

[RhCp*Cl2 ]2 AgSbF6 PivOH or Cu(OAc)2 NBS or NIS

DG H R1 N 1 O R ,

DG: O

NHR , HN

O

X X = Br, I

N

,

DG

Scheme 13. ortho-Selective halogination of benzamides via C–H activation.

DG

DG

R

R H

X

PdII , TfOH, oxidant NCS or NBS

Y

Y CO2 Et

CO2 Et

DG = CO2Et, SO 2NHR1, CONHR1, COR1 , CH2CO2Et

X

H Y = NH, O, S

X = Cl, Br

Scheme 14. ortho-Selective halogination of electron-poor aromatics.

DG1 DG2

H

PdII TfOH NCS

DG1

DG1 DG2

Cl

H

Given their applications in drug discovery and their prevalence in pharmacophoric structures, chiral a-branched amines are important medicinal targets. Notably, Ellmann and co-workers developed a Rh(III)-catalyzed addition of aromatic C–H bonds to N-perfluorobutanesulfinyl imines for the asymmetric synthesis of branched amines (Scheme 17).24 The scope of this reaction remains limited since it was proven to work only in the presence of a pyrrolidinyl amide, azobenzene or quinoline DGs. Nevertheless, this protocol offers a valuable complementary approach to the traditional diasteroselective addition of organometallic reagents to N-tertbutanesulfinyl imines. In contrast to the nitration of aromatic C–H bonds, the selective nitration of aliphatic C–H bonds is challenging with the high temperatures required being the main issue. Interestingly, a transitionmetal-mediated sp3 C–H nitration (Scheme 18) was recently reported for the first time and applied to the selective nitration of 2-methylquinoxaline.25 The same group later developed an efficient and mild nitration of 8-methylquinolines via a Pd(II)-catalyzed sp3 C–H bond activation.26 The reaction was applicable to a variety of 8-methylquinoline, but failed for 8-ethylquinoline, 8isopropylquinoline and 5-methylquinoxaline. Among the recent pioneering examples of meta-selective transformations such as norbornene-assisted C–H alkylation and C–H arylation, it has been reported a meta-selective aromatic C–H borylation reaction (Scheme 19) has been developed that is catalyzed by a novel iridium catalyst in which the H-bonding donor site of the ligand recognizes the H-bonding acceptor site of the substrate.5 The reaction is of high synthetic value, allowing for the preparation of a variety of aryl boronate esters starting from six- or five-membered (hetero)aromatic amides, esters, and phosphonates.

or

DG2 Cl

H

(CF2)CF3

DG

H

H

O

+

R

S

N

DG :

Scheme 15. Chlorination regioselectivity based on directing group.

Ph N

> 98:2 diasteroselectivity

R1 = Ar, CO2Me

N O NHEt

N

R1

R

2) HCl

R1

Order of DG priority: NHAc > CONHR > C=O > SO 2NHR > CO2Et, CONR1R2 , SO 2NR1R2

DG NH2*HCl 1) Rh(III)

Scheme 17. Synthesis of chiral a-amines via C–H activation.

It is worth noting that meta-selective halogenation has been reported22 via ruthenium catalysis. An interesting Pd-catalyzed ortho-C–H iodination (Scheme 16) was developed for various ortho-, meta- and para-substituted phenyl acetic acids.23 This iodination method occurs exclusively at the less-hindered ortho position. This is especially valuable considering the fact that phenylacetic acids cannot be iodinated via the traditional amide formation/ortho-lithiation/iodination sequence. The ortho-iodinated products can undergo subsequent homologation, cross-coupling, amination, cyanation reactions, thus providing a powerful tool for facile drug functionalization. Notably, this protocol drastically shortened the synthesis of commercial drugs diclofenac and lumiracoxib.20

R1 N R4 N

R H

R = H, alkyl, aryl, OPh, halide, acetyl, CF3

no light

2) reduction

R3

R4

1) Pd(OAc) 2 , t-BuONO/O2

R2

R1 N

2) reduction

H

R2 NH2

R3

N

R2

R1 N NH2

Scheme 18. Chlorination regioselectivity based on directing group.

DG

N(hex) 2

R

DG

O H

PdI2 IOAc

1) AgNO2 , K2S2 O8

N

O

Amidation/ortho-lithiation/ halogen quench COOH

R1

R2 H

R

P

R

COOH

H

I

Homologation, Cross-couplings, Amination, Cyanation

Scheme 16. ortho-Selective iodination of phenylacetic acids.

OEt OEt O

H

S

N(hex) 2 O

H

N H

N(hex) 2

[Ir(OMe)(cod)]2 Ligand

R Het H

Het B O O

R = H, OMe, Me, Cl, CF3

Scheme 19. meta-Selective C–H borylation of aromatics and heterocycles.

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In recent years, many elegant strategies employing transitionmetal-catalyzed C–H bond functionalization have emerged for the synthesis of heterocycles that are key motifs in natural products and drug candidates. In particular, Ellman and co-workers have been focusing on transition-metal-catalyzed addition of sp2 C–H bonds to polarized p-bonds (e.g., aldehydes, imines, isocyanates) for the preparation of heterocycles. For instance, 2Hindazoles were prepared by Rh(III)-27 or Co(III)-catalyzed28 addition of azobenzenes to aldehydes (Scheme 20). The azo moiety served as a DG for the ortho-C–H activation as well as a nucleophile to trap the initial aldehyde addition product. In both protocols, the regioselective functionalization of unsymmetrical azobenzenes could be controlled by electronic and steric parameters, although lower regioselectivity was observed for the cost-effective Co(III)catalyst system. Interestingly, both methodologies showed a high level of functional group compatibility and 2H-indazoles lacking N-substitution could be obtained by oxidative cleavage of the N4-hydroxy-3,5-dimethylphentyl substituent.22 The aldehyde addition/cyclative capture approach also enabled a single-step convergent assembly of furans employing a,b-unsaturated oximes as the DGs (Scheme 21).23 Rh(III)- or Co(III)-catalysis provided trisubstituted furans in good and comparable yields, while tetrasubstituted furans were obtained in significantly higher yields under Rh(III)-catalysis. A one-step method for the preparation of 3-fluoropyridines from a-fluoro-a,b-unsaturated oximes and alkynes by Rh(III)-catalyzed C–H functionalization was recently reported.29 Symmetrical dialkyl- or diaryl-alkynes as well as straight-chain alkyl and branched alkyl terminal alkynes coupled efficiently to provide 3-fluoropyridines regioselectively (Scheme 21). Following suit, a Rh(III)-catalyzed ortho-C–H amination–cyclization–aromatization cascade was developed to rapidly access unsymmetrical acridines (Scheme 22).30 The protocol involves the coupling of aromatic azides with imines, generated in-situ or

[Cp*RhCl2]2 AgSbF6 or Cp*Co(III)

O

H N

R1

R2

R2

+

N

R3

H

R3 = Ar, alkyl

H

N N

N N

+

R3

R3 R2

R1 R1

2-substituted 2H-indazoles

Me N R1

N

N

Oxidative cleavage

OH

R1

Me

Ph

NH

N-unsubstituted 2H-indazoles

Ph

Scheme 20. Metal catalyzed addition of azobenzenes to aldehydes.

H R1

O +

+

N OMe

N OMe R1 = Ph, alkyl

HO

H

R2

[Cp*RhCl2]2 AgSbF6 or Cp*Co(III)

R1 O

+

O

R2 Ar

R2 = Ar, (cyclo)alkyl

R3 N

R3

H R1 F

R1 =

Ph, 2-furyl

+

R2 /H

[Cp*RhCl2] 2 CsOPiv

R2/H

N

R1 F

Scheme 21. C–H cycloaddition of aldehydes and a,b-unsaturated oximes and synthesis of 3-fiuoropyridines from unsaturated oximes.

R3

R1

N

R2

Ph

N

+ N3

N

R2

cat. Rh(III)

H R1

R3

R1

N

R2

Ar +

cat. Rh(III)

R1

N3

H

R2

N N

9-substituted Acridines

Scheme 22. Synthesis of acridines via C–H ortho-cycloamination/aromatization cascade.

R2 H R N

N H

R

O Ad

2

+ R1

R = H, Me, halogens CN, CO2Me, CF3 Ad = 1-adamantyl

N

N O

Ad

R R2

NH2

R1

R

R1, R2: Ar, alkyl

R N

[RhCp*Cl2] 2 AgSbF6 oxidant

+

H R, R1, R2 : Ar, alkyl

R1

[RhCp*Cl2 ]2 PhCO2H air

N R1 R2

Scheme 23. Synthesis of aminopyridines via C–H annulation.

pre-formed, to provide acridines with or without substitution at the 9-position. This formal [3+3] annulation approach was also extended to the regioselective synthesis of phenazines from azobenzenes. Synthetic efforts directed at 7-azaindoles, key scaffolds of a variety of drug candidates including kinase inhibitors, led to the development of a Rh(III)-catalyzed C–H activation/annulative coupling of aminopyridines with alkynes (Scheme 23).13 A similar methodology was developed allowing for the preparation of isoquinolines. Although a plethora of methods have been developed to construct the isoquinolines, this powerful approach relies on the transition-metal-catalyzed direct C–H functionalization of arenes containing a DG, followed by coupling with internal alkynes.31 Using rhodium catalysis, this method facilitates the preparation of isoquinolines from aryl hydrazines and internal alkynes under mild conditions (Scheme 23).32 This methodology features the use of a readily available hydrazine DG, does not require an external metal co-oxidant, and proceeds in the presence of simple benzoic acid as an effective additive to promote the catalytic cycle under an atmosphere of air. An interesting approach was developed to enable the DG-activation of C–H in the presence of strongly coordinating nitrogen, sulfur and phosphorous heteroatoms which would poison the Pd (II)catalyst or compete with the DGs for catalyst binding (Scheme 24).33 A simple N-methoxyamide group was employed as an anionic DG-ligand to promote the in situ generation of a reactive Pd(II) catalyst from a Pd(0) species under air. By modifying the conventional selectivity outcome observed with strongly coordinating heterocycles, this method broadens the applications of C– H activation reactions in heterocycle-based drug discovery. The synthetic utility of this protocol was demonstrated by the synthesis of 3-(imino)isoindolinone derivatives which could be readily converted to various useful building blocks (Scheme 25). Fluorinated compounds play a critically important role in drug discovery and development programs. Some breakthroughs have been in made in the field of C–H activation within the synthesis of fluorinated biphenylic compounds. Pd-catalyzed processes have

E. J. E. Caro-Diaz et al. / Bioorg. Med. Chem. Lett. 26 (2016) 5378–5383

H(inacccessible) DG

N

H

O

Anionic DG

H(reactive) Pd

H(unreactive)

N air

H

Pd(0) N OMe

O

Catalyst formation

Pd(II)X

N OMe N

H(unreactive)

Scheme 24. Overriding site-selectivity by on-site generation of Pd-catalyst.

O

t-Bu

O

NHOMe

N

Pd2(dba) 3

H

t-BuNC

Het

O CO2 H NH

N OMe

Het

NH2

CO2 Et

CONHt-Bu

CO2 Et

CO2Et

Scheme 25. Synthesis of 3-(imino)isoindoline derivatives as intermediates to access medicinally useful building blocks.

F

F F

R2

F

Pd II

F

F

+

(a) F

F

X

H

R1

R2

F +

(b)

PdII

R1

F

Br

H

Me

R2

F

F

R2 Me

F

(c)

R2 H

Cr(CO)3

+ I

PdII

F R2

Scheme 26. Synthesis of fluorinated biphenyls via Pd-catalyzed C–H activation.

been described for several different kind of fluorinated substrates (Scheme 26), including perfluorinated benzenes (Scheme 26, a).34 Also, monofluroniated substrates have been shown to undergo smooth alkylation using various substituted fluorobenzenes35 (Scheme 26, b) employing strategies such as chromium-assisted activation36 (Scheme 26, c). In conclusion, we have shown through some selected examples from the recent literature that research in the field of C–H activation has resulted in the discovery of many useful tools for the construction of medicinally relevant structures and motifs. Additionally, these methodologies provide solutions for synthetically challenging late stage functionalization. We believe that new protocols and synthetic conversions exploiting C–H bonds as functional handles will continue to be developed through organic chemistry research. This will be of immense benefit to the medicinal chemistry community by providing more efficient strategies for preparation of synthetically challenging target molecules. Furthermore, these methods may allow for preparation of analogs that are intractable altogether by established methods of organic synthesis.

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