Recent Advances in Radical-Initiated C(sp3)-H Bond Oxidative

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Recent Advances in Radical-Initiated C(sp3)H Bond Oxidative Functionalization of Alkyl Nitriles Xue-Qiang Chu, Danhua Ge, Zhi-Liang Shen, and Teck-Peng Loh ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b03334 • Publication Date (Web): 22 Nov 2017 Downloaded from http://pubs.acs.org on November 22, 2017

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ACS Catalysis

Recent Advances in Radical-Initiated C(sp3)-H Bond Oxidative Functionalization of Alkyl Nitriles Xue-Qiang Chu,a Danhua Ge,a Zhi-Liang Shen,*a Teck-Peng Loh*ab a

Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic

Innovation Center for Advanced Materials, Nanjing Tech University, Nanjing 211816, China b

Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang

Technological University, Singapore 637371, Singapore.

Graphic Abstract:

Abstract: Chemoselective functionalization of intrinsically less reactive C(sp3)–H bonds of alkyl nitriles are of particular interest to the chemical community in view that these strategies provide opportunities for the introduction of important cyanoalkyl groups onto target frameworks in a step-economic fashion. In recent years, the introduction of nitrile-containing alkyl radicals in tandem radical additions and oxidative couplings inarguably brings chemists a new radical reaction platform for the diverse synthesis of natural products and pharmaceuticals. Compared with the wide applications of various C-centred radicals adjacent to a heteroatom, however, the nitrile-containing alkyl radicals remain largely unexplored. New methods for C(sp3)−H bond oxidative functionalization of alkyl nitriles and new mechanistic manifolds would result in the development of a broad range of novel reactions. Therefore, this review will give an overview of various types of radical cyanoalkylation by using the key alkyl nitrile reactants, which is beyond traditional coupling chemistry.

Keywords: nitrile-containing alkyl radicals, C(sp3)-H bond functionalization, oxidative coupling, tandem radical reaction, copper catalysis

1. Introduction Direct transformations of C-H bonds into C–X (X = C, heteroatom) bonds have emerged as a powerful and robust strategy for the efficient construction of synthetically valuable molecules and advanced fragments of pharmaceuticals

or

atom/step-economy.

[1]

natural products,

which

generally

avoid

pre-functionalization

while

improving

However, the appealing chemoselective functionalization of intrinsically less reactive

3

C(sp )–H bonds remains rather rudimentary due to their poor acidity, high bond energy and unreactive molecular orbital profile.[2] Normally, organometallic activation of C(sp3)–H bonds by coordinating transition-metal catalyst with functional groups embedded in substrates represents one of the most straightforward routes.[3] As a distinct and complementary alternative, fascinating achievements have been made in homolytic cleavage of C(sp3)–H

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bonds via radical oxidative coupling and single electron transfer (SET) process in recent decades.[4-11] Many prominent review articles have summarized oxidative dehydrogenative reactions of various coupling precursors, such as ethers,[5] alcohols,[5b-d] amines,[6] methylarenes,[7] carbonyl derivatives,[8] and other activated compounds.[9-11]

Scheme 1. C(sp3)–H Functionalization of Simple Alkyl Nitriles via Radical Pathways Nitrile groups are versatile moieties for the commercial manufacture of organic targets, pharmaceuticals, and specialty chemicals.[12] Early research efforts on the C–H activation of alkyl nitriles by using stoichiometric amounts of transition metal (M = Rh, Ru, Fe, Ni, etc.) have been well documented.[13] Nevertheless, the direct α-functionalization of stable alkyl nitrile is considerably limited, mainly due to the following reasons: 1) its enolate chemistry requiring strongly basic conditions; 2) the formation of insoluble oligomers with main group reagents; 3) slow reductive elimination of related metal-nitrile anions complexes.[14] Despite the aforementioned issues, the α-C(sp3)-H bond adjacent to nitrile group, which shows weak acidity [pKa(MeCN) ≈ 31.3 in DMSO] and slightly low bond dissociation energy (BDE = 96 Kcal/mol) (Scheme 1a), would cleave prior to other inert C(sp3)-H bonds.[15] Recently, new bond construction involving free radical initiated α-C–H functionalization of alkyl nitriles has grown in an exponential manner (Scheme 1b). To the best of our knowledge, there is still no review devotes to this emerging topic. This review mainly highlights the recent advances on selective C(sp3)-H bond functionalization of simple nitriles under oxidative conditions through α-cyano sp3-hybridized carbon-centered radical intermediates. These focal procedures and strategies along with their scopes, limitations, and suggested mechanisms are mainly summarized and organized based on different types of reaction acceptors used.

2. Oxidative Radical Reactions of Alkyl Nitriles with Simple Alkenes, Arenes and Alkanes 2.1 Oxidative Coupling Reactions of Simple Alkenes In fact, as the simplest alkyl nitrile, acetonitrile is routinely regarded as inactivated chemical entity and frequently used as reaction solvent. Conversely, the electrophilic carbon-centered nitrile radical would be ready to participate in various reactions once the cleavage of the α-C-H bond of acetonitrile occurs.

Scheme 2. Silver(I)-Photocatalyzed Addition of Acetonitrile to Norbornene As early as 1981, the radical addition of acetonitrile to alkenes was reported by Lewis.[16] UV irradiation of norbornene

and

silver

trifluoromethanesulfonate

with

acetonitrile

results

in

the

formation

of

norbornene-acetonitrile adduct exo-2-(cyanomethyl)bicyclo[2.2.1]heptane (Scheme 2a). Investigation of the plausible mechanism indicates that the reaction is initiated by photoinduced electron transfer from coordinated


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ACS Catalysis

norbornene 1 to silver ion. The final product was generated through free-radical chain addition of the cyanomethyl radical to norbomene (Scheme 2b). In 1990, an improved light-mediated procedure for cyanomethylation of cycloalkenes with acetonitrile in the presence of hydrogen peroxide (80%) was revealed by Sonawane.[17] They found that ·CH2CN radical may be obtained via hydrogen abstraction from acetonitrile by a β-hydroxy adduct radical without using metal ions (Scheme 3).

Scheme 3. Light-Mediated Cyanomethyl Radical Formation The harsh reaction conditions, limited substrate scope, low reaction efficiency, and the use of excess alkyl nitrile as both reaction solvent and coupling partner involved in the generation of cyanomethyl radical proved to be the limiting factors for establishing valuable synthetic methods. Recently, Liu and co-workers[18] reported a copper-catalyzed hydrocyanoalkylation of unactivated alkenes with alkyl nitriles (Scheme 4a). This catalytic protocol for efficient additions of alkyl nitriles to a wide range of alkyl olefins with complete anti-Markovnikov regioselectivity allows convenient access to functionalized nitriles bearing halogen, heterocycle, amide, hydroxyl group, epoxide, etc. in a simple way (Scheme 4b). Radical chain propagation reaction with acetonitrile proceeds smoothly because the nascent acetonitrile radical was stabilized by SOMO-π delocalized effect (Scheme 4c). Notably, styrene and its derivatives are not effective in this system. It is entirely reasonable to believe that reaction regioselectivity is determined by the steric hindrance and the stability of reactive intermediates, and the radical-mediated oxidative functionalization reactions of alkenes often proceeds via anti-Markovnikov addition.

Scheme 4. Copper-Catalyzed Hydrocyanoalkylation of Unactivated Alkenes with Alkyl Nitriles


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Scheme 5. Metal-Free Oxyalkylation of Vinylarenes with Alkyl Nitriles Generally, the C-H bond adjacent to a heteroatom can be easily oxidized and transformed to the corresponding carbon-centered radical under peroxide conditions.[5-6] Wang, Chen and Xing developed a pioneering oxyalkylation for the synthesis of γ-ketonitriles from terminal vinylarenes with acetonitrile (Scheme 5a).[19] With tert-butyl hydroperoxide (TBHP; 5.5 M in decane) as the oxidant and DBU as the additive, a variety of vinylarenes and alkyl nitriles oxidatively coupled to afford the desired products in moderate yields. Unfortunately, both electron-poor vinylarenes and nonconjugate alkenes were not suitable for this transformation. The authors believed that the phenyl group could disperse the electron of the transient free radical 3. The stability of radical 3 was the key for the coupling with t-BuOO· to form the peroxide intermediate 4. Finally, DBU-promoted Kornblum-DeLaMare rearrangement[20] gave the ketonitrile products (Scheme 5b). Mechanistic studies showed that the C(sp3)-H bond cleavage of acetonitrile may be the rate-determining step, but such a conclusion cannot be fully confirmed without further experimental evidence (Scheme 5c).[21]

Scheme 6. Copper-Catalyzed Three-Component Carboetherification of Alkenes with Acetonitrile and Alcohols Difunctionalization of unsaturated alkenes is attractive as it allows introduction of two versatile handles in a one-step manipulation. In 2015, Zhu et al.[22] extended radical cyanomethylation strategy to the synthesis of γ-alkoxy alkyl nitriles through an intermolecular three-component carboetherification of α-substituted styrenes with simple nitriles and alcohols (Scheme 6a). The formation of two new C(sp3)–C(sp3) and C(sp3)–O bonds with concomitant generation of a quaternary carbon center was observed. Heating a solution of different substituted olefin in alcohol with propionitrile, butyronitrile, or 2-methoxypropionitrile in the presence of Cu(OTf)2, 1,10-phenanthroline (1,10-Phen), and di-tert-butyl peroxide (DTBP) produced the corresponding three-component adducts in good yields (Scheme 6b). Especially noteworthy is that a trisubstituted alkene could be successfully oxyalkylated.


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ACS Catalysis

Scheme 7. Plausible Mechanism When (1-cyclopropylvinyl)benzene (5) was added to the reaction system under standard conditions, dihydronaphthalene 6 was afforded in 57% yield (Scheme 7a). The radical clock experiment provided clear evidence that the reaction proceeds through a benzylic radical intermediate. Furthermore, the authors proposed that the C-H bond of alkyl nitrile was not directly activated by the peroxide (DTBP), because coordinating cyano group with CuII-complex 7 would lower the pKa of acetonitrile enough to be deprotonated to afford cuprate 8 (Scheme 7b). Homolytic cleavage of organocopper 8 could furnish cyanomethyl radical 2, which upon reacting with alkene would generate tertiary radical 10 (Scheme 7c). Finally, oxidation of intermediate 10 followed by trapping of the resulting tertiary carbocation 11 by MeOH would provide the γ-alkoxy alkyl nitrile product. Noteworthily, benzylic radical intermediate generated in situ from organocopper complex 9 cannot be ruled out in this transformation.

Scheme 8. Copper-Catalyzed Formal [2+2+1] Heteroannulation of Alkenes with Alkyl Nitriles and Water Afterwards, Zhu and co-workers[23] developed a domino process of copper-catalyzed three-component [2+2+1] heteroannulation of alkenes, alkyl nitriles, and water (Scheme 8a). Intermolecular hydroxy-cyanoalkylation of alkenes and subsequent lactonization led to a wide range of γ-butyrolactones by using alkyl nitriles as key reactants. A carbon-centered radical addition-oxidation-cyclization mechanism consisting of three successive steps is shown in Scheme 8b. In step 1, generation of a tertiary carbocation 11 via radical addition of cyanoalkyl radical to alkenes followed by further oxidation with the aid of transition metals and peroxides occurs. In step 2, trapping of intermediate 11 by H2O provides γ-hydroxy alkyl nitrile 12. Step 3 involves the intramolecular attack of hydroxyl group to cyano group followed by acidic hydrolysis of the thus-formed imidate to furnish lactones. It should be noted that Lewis acids catalyst (calcium trifluoromethansulfonate) played a key role to accelerate the lactonization step. An

18

O-labeled experiment with H218O suggested that the carbonyl oxygen atom of the final product


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originated from water molecule. Meanwhile, similar observations are powerful complements with their previous conclusions that 1) DTBP serves mainly as an oxidant to regenerate the copper(II) species; 2) the copper catalyst is important for the formation of the benzylic carbenium ion 11. Moreover, this synthetic procedure was illustrated by a concise synthesis of other γ-lactone derivatives (±)-sacidumlignan D (Scheme 8c).

Scheme 9. Copper-Catalyzed Carboazidation of Alkenes with Acetonitrile and Sodium Azide Multi-component carboazidation reaction with the formation of C(sp3)-C(sp3) bond from simple starting materials remains a long-standing challenge.[24] Later, the same research group[25] found an elegant carboazidation reaction employing acetonitrile and sodium azide as precursors of alkyl and azide groups (Scheme 9a). This reaction showed excellent substrate compatibility and functional group tolerance and provided an easy access to γ-azido alkyl nitriles (Scheme 9b). Unfortunately, other nitriles (except acetonitrile) failed to react under optimized conditions. A similar aforementioned reaction mechanism for copper-promoted alkylative difunctionalization of alkenes was also proposed (Scheme 9c). Detailed mechanistic studies revealed that the reaction of copper-azide intermediate 14 with radical 10 was more likely the key process for the formation of the final product 15. Furthermore, the cationic pathway b could be excluded based on the fact that no competitive γ-methoxy alkyl nitrile product was formed in the catalytic system.

Scheme 10. Silver-Catalyzed Carboamination of Alkenes with Alkyl Nitriles and Amines Almost simultaneously, a Ag2CO3-mediated oxidative intermolecular 1,2-alkylamination of alkenes with alkyl nitriles and amines proceeding via radical alkylation and polar amination catalyzed by iron salts (10 mol% FeCl3 or


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ACS Catalysis

Fe(OTf)3) was described by Li and co-workers (Scheme 10a).[26] A particularly attractive feature of this alkylamination is the ability to enable the conversion of a wide scope of di-/tri-substituted internal alkenes, alkyl nitriles and amines to diverse γ-amino alkyl nitriles in good yields (Scheme 10b). Synthetic potential of this strategy and its application to the synthesis of other valuable 1,4-diamine, γ-amino acid and γ-amino amide synthons have also been examined by the authors (Scheme 10c).[27]

Scheme 11. Control Experiments and Possible Mechanism Some detailed experiments were carried out to probe the real mechanism of this cascade reaction. First, a radical clock study with vinylcyclopropane 5 revealed a free-radical triggered process (Scheme 11a). Second, radical trapping experiments using radical inhibitors, such as 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO), 2,6-di-tert-butyl-4-methylphenol (BHT) and hydroquinone proved the existence of cyanomethyl radical intermediate 2 (Scheme 11b). Third, the kinetic isotope effect experiment gave a large kinetic isotope effect value (kH/kD = 2.7), implying that cleavage of the C(sp3)–H bond may be rate-limiting step (Scheme 11c). Based on these mechanistic insights, a plausible mechanism was proposed by the authors (Scheme 11d). Acetonitrile coordinated with silver(I) ion with the assistance of the nitrogen atom, which was subsequently converted to oganosilver complex 17. The decomposition of AgCH2CN intermediate under heating occurred to form the cyanomethyl radical via single electron transfer (SET).[28] Radical addition across the C–C double bond followed by a sequence of oxidation and nucleophilic addition of amines furnished the desired products. Notably, the alkyl radical 10 could be stabilized by iron species, thus resulting in improved product yields.

Scheme 12. Copper-Catalyzed Allylic Cyanoalkylation of Olefins with Alkyl Nitriles (E/Z ratios of products are shown in parentheses) The combination of copper catalysis and nitrile-containing alkyl radicals inarguably brings chemists a new radical coupling platform. Very recently, Dong and co-workers disclosed the first cross-dehydrogenative coupling of unactivated olefins with alkyl nitriles through dual sp3 C-H bond cleavage facilitated by copper(II) and peroxides (Scheme 12a).[29] During the course of optimization, the authors observed that more basic copper(II) pivalate showed higher efficiency and only trace amounts of undesired hydrocyanoalkylated by-products[18] was


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detected. Addition of electron-rich veratronitrile as an additive improved the catalyst solubility, the desired cyanoalkene was obtained in 90% yield, greater than 20:1 rr, and 4:1 E/Z. Both terminal and internal olefins could be readily transformed into γ,δ-unsaturated nitriles in a regio- and stereoselective manner (Scheme 12b). In particular, the regioselectivity was unaffected by increased steric hindrance at the 4-position of the olefins. Remarkably, in the case of the transformation with styrene which does not have allylic C-H bond, direct alkenylated nitrile was only produced in 10% yield. a) Control experiments: n-Pr n-Pr

18, 62%, E/Z = 11:1 n-Pr 20 mol% Cu(OPiv)2 1 equiv Veratronitrile

(E)-17

n-Pr

n-Pr

4 equiv DTBP 110 oC, 24 h

n-Pr (Z)-17

18

CN

+ n-Pr

18, 60%, E/Z = 12:1

n-Pr

n-Pr 19, 0%

NC

n-Pr 20, 0%

CN

Not involved intermediates: n-Pr

n-Pr

n-Pr

n-Pr

n-Pr

Cu Int. 22

Int. 21 b) Suggested mechanism:

n-Pr

n-Pr

Int. 23 CN Me or t-BuO

n-Pr Int. 24 CN

CH4 or t-BuOH

H N (OPiv)2CuII

pathway a

(PivO)CuII 8

DTBP

R1

t-Bu O

CuIOPiv

R1

CN

R2 R3

O H R1

CuI

N SET

N pathway b CuIII

R3 R2 H 26

R2

NC

CH2CN 2

H

OTEMP 16

R3

Cu(OPiv)2 H R1

R3

CN

R2 H 25

Scheme 13. Control Experiments and Possible Mechanism By means of control experiments with internal olefins (E)-5-decene and (Z)-5-decene, Dong et al. proposed that allylic radical 21, π-allylcopper 22 or carbocations 23-24 were most likely not key intermediates in their cross-coupling reactions (Scheme 13a). A catalytic scenario is discussed in the generalized Scheme 13b. Accordingly, cyanoalkylcopper(II) species 8 is initially formed by pivalate-assisted deprotonation of alkyl nitrile with copper(II), which upon homolytic cleavage, would afford cyanoalkyl radical 2 and copper(I) species. Addition of the generated cyanomethyl radical to the olefin furnishes known radical intermediate 25, which in turn undergoes E2-type elimination to yield final product and Cu(I) species. The catalytic cycle is closed with the final reoxidation of Cu(I) by DTBP to give Cu(II) (pathway b). The DTBP could also abstract a hydrogen atom from alkyl nitrile to produce the cyanoalkyl radical 2 (pathway a), in accordance with reported studies.[18] The authors proposed that π-bonding of the cyano group to copper(III) intermediate 26 shields the H atom at the β position to direct the pivalate to abstract the H atom at the δ position.

2.2 Oxidative Coupling Reactions of Simple Arenes

Scheme 14. Copper-Catalyzed Dehydrogenative Coupling of Heterocycles with Alkyl Nitriles


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ACS Catalysis

Scheme 15. Proposed Reaction Mechanism A radical substitution to an aromatic compound represented by Minisci reaction[30] resembling traditional Friedel-Crafts alkylation but with opposite reactivity and selectivity. Radical aromatic substitution methodology has been recently employed to install cyanoalkyl groups on heteroarenes such as furans, thiophenes, indoles, and pyrroles via a site-specific cross-dehydrogenative coupling reaction (Scheme 14a).[31] Liu’s method enriches our toolbox for efficient and facile access to various C-2 alkylated heterocycles (Scheme 14b). Moreover, this reaction could be successfully scaled up to gram level, thereby facilitating a chance for further application. Firstly, NMR integration measurement found that an intermolecular competing KIE is significant (KH/KD = 4.7) for directing the rate-determining step. Additionally, a radical trapping experiment confirmed the existence of α-cyano methylenyl radical intermediate. Initiation begins by reducing DCP with Cu(I) to give Cu(II) and a methyl radical. Subsequently, HAT from acetonitrile to the methyl radical putatively afford the cyanomethyl radical 2, which then selectively adds to the C-2 position of heterocycle leading to radical 29. Although the direct hydrogen atom abstraction from intermediate 29 by the methyl radical to afford the product 28 is favored in this reaction, the formation of a possible radical anion 30 could not be fully excluded, namely, intermediate 30 formed via deprotonation of radical 29 by the t-BuO anion and then further oxidized by DCP to provide the final product and regenerate the methyl radical (Scheme 15). a) Xu and Rao's work: N

R1

CN

Ar

CN

+

N

X

H

31

(2.0 mL)

10 mol% FeCp2 2 equiv DCP 100 oC, 20 h, Ar

b) Miscellaneous examples: CN R

1

32 CN

N

R2 N 24-79% R1, R2 = Me, X, OMe CN

N N

F

N N 43% c) Plausible mechanism: O O DCP

O

N

Ph

52%

CH3CN O

[Fe(III)]-OC(Me)2Ph 33 CN N

N 35

N

N O 41%

Ph [Fe(II)]

74% CN

CN

Ph

CN

N

N

43%

N

N

Ar N

X

CN

N

Ph

N

R1

CH2CN 2

31

Ph N

34

Scheme 16. Iron-Catalyzed Dehydrogenative Coupling of Pyrimidazoles with Acetonitrile The addition of radicals to π-systems contributes to the emerging use of alkyl nitriles for catalytic cross-coupling with arenes. Very recently, Xu and Rao’s group[32] realized an iron-catalyzed dehydrogenative sp3-sp2 coupling of 2-arylimidazo[1,2-a]pyridines with acetonitrile (Scheme 16a). The merit of this novel approach toward heteroarylacetonitriles was proved by the broad functional groups tolerance and the potential derivatization in the manufacture of pharmaceuticals (such as Zolpidem precursor) (Scheme 16b). Evidence for radical nature of the transformation was ascertained by the employment of radical scavengers, where the addition of TEMPO completely inhibited the reaction. The tentative mechanism by the authors (Scheme 16) occurs via a single-electron-transfer process between DCP and FeCp2 to yield Fe(III) complex 33 and the cumyloxyl radical. Hydrogen abstraction from acetonitrile and intermolecular homolytic aromatic substitution take


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place to release the final product 35. Meanwhile, the Fe(II) complex was regenerated by reducing Fe(III) complex 33 with intermediate 34 to continue the catalytic cycle.

2.3 Oxidative Coupling Reaction of Simple Alkanes

Scheme 17. Iron-Catalyzed Dehydrogenative Coupling of 1,3-Dicarbonyl Compounds with Acetonitrile

Scheme 18. Proposed Reaction Mechanism Although significant progress has been achieved in the cross-dehydrogenative coupling (CDC) reaction to forge C-C bonds, the direct C-H bond oxidative functionalization involving the formation of C(sp3)–C(sp3) bonds is still urgently required and also more challenging. In 2016, the group of Wu solved this problem,[33] where cyanoalkylation of simple 1,3-dicarbonyls was first developed by using less reactive CH3CN as alkylation reagent (Scheme 17a). The generality and substrate scope of β-dicarbonyls was investigated to give the corresponding α-cyanomethyl-β-dicarbonyls in satisfactory yields under Fe-catalyzed radical CDC reaction (Scheme 17b). The results of several controlled experiments as well as their electrospray ionization mass spectrometry (ESIMS) gain insights into the reaction mechanism: 1) the premier tert-butoxyl radical could be obtained via thermal decomposition of DTBP; 2) the organocomplex Cl-FeII-CH2CN might indeed be the active catalytic species (Scheme 17c); 3) the coupling of radical 2 and 38 was not the main pathway for the conversion, although alternative pathways cannot be ruled out. There should be a couple of reaction possibilities for the novel cyanomethylation of β-dicarbonyls illustrated in Scheme 18.

3. Oxidative Radical Reactions of Alkyl Nitriles with Functionalized Alkenes and Alkynes 3.1 Cascade Reactions of Functionalized Alkenes


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ACS Catalysis

Scheme 19. Metal-Free 1,2-Aryl Migration Reaction of Allylic Alcohols with Alkyl Nitriles In the past several years, the most widely investigated migration reaction is certainly the β-aryl carbon-centred radical-mediated 1,2-aryl migration, the neophyl type rearrangement, which stands at the intersection of both radical and rearrangement reaction.[34] In 2015, Ji and co-workers[35] achieved a radical alkylation–neophyl rearrangement of α,α-diarylallylic alcohol with simple acetonitrile under metal-free conditions (Scheme 19a). The generality of such C(sp3)–H bond oxidative functionalization with aryl migration is successfully demonstrated to assemble various 5-oxo-pentanenitriles. Scheme 19b shows a possible mechanism. Initially, tert-butyl perbenzoate (TBPB) decomposed to give tert-butoxyl radical and benzoate radical. Abstraction of a hydrogen atom from acetonitrile by these radicals provided α-carbon-centered cyanomethyl radical, which then added to the C=C bond of diarylallylic alcohol 42 to induce the 1, 2-aryl migration via a 3-membered spiro[2, 5]octadienyl intermediate 43. It should be noted that the migratory aptitude of aryl groups in this addition–migration cascade is different from that in the cationic semipinacol rearrangement. Both the electronic character and steric demand of the substituents affected migration procedure, and the migratory reactivity decreased as follows: 4-chlorophenyl > phenyl > 4-benzyloxyphenyl > 2-chlorophenyl. Preferential migration of the more electron-poor aryl groups was in line with the mechanism of the neophyl rearrangement. Additionally, activated nitriles, such as malononitrile, methyl 2-cyanoacetate and 3-oxo-3-phenylpropanenitrile were also tolerated, providing the corresponding products in 53-72% yields (Scheme 19c). The special diaryl structure is necessary in their case, because the reaction between mono-aryl allylic alcohol and acetonitrile failed. In comparison, similar reaction process reported by Li’s group[36] was specially applicable to 2-(pyridin-4-yl)but-3-en-2-ol. The present methodology can be conveniently used in the synthesis of dihydropyridone 61 and 2,3-diphenylpiperidine derivative 62 (Scheme 19d).[35]

Scheme 20. Copper-Catalyzed 1,2-Aryl Migration Reaction of Allylic Alcohols with Acetonitrile All-carbon containing quaternary stereo-centers are valuable skeletons in organic synthesis.[34b] Soon afterwards, the group of Zhu[37] disclosed similar results involving a copper-catalyzed oxidative coupling of allylic alcohols


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with alkyl nitriles which proceeded via a C(sp3)-H functionalization/migration protocol (Scheme 20a). The researchers paid their extensive attention on the construction of new α-quaternary centers in the ketone products. The work feature a quite broad substrate scope, as various aryl- and alkyl-substituted tertiary allylic alcohols were efficiently converted into the desired products with high yields (Scheme 20b). Alkyl groups other than methyl (such as Et, n-Bu, Ph) at the internal position of the double bond were also well-tolerated. Interestingly, propionitrile and 3-methoxypropionitrile were compatible with the mild reaction conditions without the isolation of epoxides (by-products). As a result, this radical rearrangement has been identified as an efficient and versatile approach for access to these important structural units. It is no doubt that the development of an enantioselective version of radical migration in the presence of an appropriate chiral ligand will be of great importance in future.[38]

Scheme 21. Control Experiments and Possible Mechanism Mechanistically, the copper-catalyzed generation of nitrile-containing alkyl radicals, intermolecular radical addition and 1,2-aryl migration are all incorporated in the carbonyl functionalities (Scheme 21a). The reaction was proposed to undergo through the radical intermediate 46, in which a trace amount of 4-oxo-4-phenylbutanenitrile (50) was produced under air conditions. Then, a control experiment showed that primary by-product epoxide 49 was not the precursor of ketone product 48. The observations that ketones 51-52 rather than the desired products were obtained in 69-91% yields by copper triflate-promoted Wagner–Meerwein-type rearrangement indicated that these two compounds (48 and 49) were formed through two competitive pathways. Preferential formation of phenonium ion 53 could explain this different regioselectivity (Scheme 21b). Importantly, the reaction was completely inhibited in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (2.0 equiv) and the TEMPO adducts 16 and 54 were simultaneously isolated, both supporting the putative radical mechanism.

Scheme 22. General Tandem Radical Addition/Cyclization Process Considerable research interest has been attracted into the areas of tandem radical addition-cyclization reactions for the concise construction of molecular complexity and biological frameworks in organic synthesis.[39] Normally, free-radical initiated cyclization of activated alkenes 55 with different precursors proceeded via a sequence of radical addition and intramolecular homolytic aromatic substitution (HAS) process (Scheme 22).[40] The


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oxidatively generated radical easily adds to the alkene functionality to give alkyl radical 56 which ipso-substitutes to the contiguous arene to provide cyclohexadienyl radical 57. The bicyclic radical intermediate can be oxidized to the corresponding cation 58, whereby re-aromatization eventually occurs with the loss of proton (H+).

Scheme 23. Transition-Metal-Catalyzed 1,2-Alkylarylation Reaction of N-Arylacrylamides with Alkyl Nitriles In particular, easily accessible N-arylacrylamides have recently emerged as a new class of radical acceptors for the synthesis of indolinone motifs by intermolecular addition of carbon- or heteroatom-centered radicals and subsequent HAS. In this context, You’s group,[41] Zhu’s group,[42] and Li’s group[43] independently reported the synthesis of 3,3-dialkylated oxindoles by oxidative C–H bond cleavage/carbocyclization of N-arylacrylamides 60 with alkyl nitriles (Scheme 23). In the approach introduced by You, CuCl was used as a catalyst and di-tert-butyl peroxide was employed as the oxidant (Scheme 23, 2a). During their reaction optimization, Lewis acid FeCl3 showed poor catalytic activity but the use of IrCl3 gave a similar high yield as CuCl. Zhu’s group employed a low loading of Fe(acac)2 (5 mol%) as the promoter in combination with DTBP as radical initiator (Scheme 23, 2b). Li and co-workers applied an oxidative combination of t-BuOOt-Bu and diisopropyl azodicarboxylate (DIAD) in the presence of CuI catalyst under a relatively low temperature (95 °C) (Scheme 23, 2c). In all these transformations, initiation occurred either by homolysis of oxidants or transition metal salt-induced SET to generate reactive t-butoxyl, methyl, or i-PrO2C radicals which abstracted α-hydrogen of alkyl nitriles to afford the key cyanoalkyl radical intermediates (Scheme 23, 2). The generated ·CH2CN reacted with N-arylacrylamides via 56 to form cyclohexadienyl radical 57 which were further oxidized via a SET process (by catalyst or oxidant) to yield cyclohexadienyl cation 58. Next, deprotonation of 58 delivered the final cyanomethyl oxindoles 61. These protocols exhibited broad substrate scope with respect to the N-arylacrylamides (Scheme 23, 3). Notably, the nitromethylation could also occur under identical conditions in You’s method. [41]


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Scheme 24. Visible-Light Promoted 1,2-Alkylarylation of N-Arylacrylamides with Alkyl Nitriles Visible-light photoredox catalysis has significant advantages for facilitating activation of organic molecules and engineering new chemical processes owing to its environmentally benign nature and mild reaction conditions. The use of a photochemical strategy for the 1,2-alkylarylation of N-phenylacrylamides with acetonitrile in the presence of [Ru(bpy)3Cl2], 4-MeOC6H4N2BF4, Na2CO3 and 36 W compact fluorescent light has been described by Li and co-workers in 2015 (Scheme 24a).[44] In contrast to the previous reported results,[41-43] the reaction was carried out at a relatively low temperature (50 oC), entailing its potential application for late-stage modification of sensitive molecules. Reasoning that the cyanomethyl radical has a higher reactive aptitude than aryl radical under basic conditions, the by-product derived from diarylation of acrylamide 60 with 4-MeOC6H4N2BF4 was observed in less than 5% yield. Moreover, the measured quantum yield for the process (Φx = 0.099) revealed that the 1,2-alkylarylation protocol proceeds through a photoinduced mechanism. The decomposition of diazonium salt 63 into the 4-methoxyphenyl radical 64 was assisted by heating or under the action of the photoredox catalyst and base (Scheme 24b). Consequently, cyanoalkyl radical intermediate was generated through the selective hydrogen atom abstraction by the aryl intermediate 64 from either alkyl nitrile or cation radical 65.

Scheme 25. 1,2-Alkylarylation of N-Arylacrylamides with Alkyl Nitriles by in situ Generated Aryl Radicals In addition, a Mn(OAc)3-arylboronic acid-mediated protocol to access cyano-containing oxindoles from the same starting materials was disclosed by Zhao and Tang’s group (Scheme 25a).[45] Compared to Zhang’s method, they replaced diazonium salts 63[44] with phenylboronic acids (2.0 equiv) as radical initiator mediated by Mn(OAc)3 (2.0 equiv) in acetonitrile, and various substituted arylacrylamides 60 were examined to probe the scope of the reaction. Diazonium salts 70, which were generated in situ from arylamines 69 and tert-butyl nitrite (t-BuONO), could be used as an alternative radical promoter for the C–H functionalization of alkyl nitriles without the use of transition-metal salts or photocatalyst. Later, Pan and co-workers[46] demonstrated a metal-free method for the construction of 3,3-substituted oxindoles by radical 1,2-alkylarylation of N-arylacrylamides with simple operation (Scheme 25b). Mechanistic studies implied that aryl radicals (64 and 68) are intermediates in these cascade reactions[45-46] and the procedure is similar to the generalized scheme discussed above.


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Scheme 26. Copper-Mediated 1,2-Alkylarylation of Unactivated Alkenes with Alkyl Nitriles It should be noted that the above documented intermolecular dicarbonation of N-arylacrylamides with nitriles were seriously restricted to the oxindole framework by using activated substrates. Polycyclic aromatic hydrocarbons (PAHs) are privileged in naturally occurring and biologically active compounds, they also exhibit unique physical properties. Recently, Ji and Xu[47] found a novel Cu-mediated/catalyzed selective dual C–H bond cleavage of an arene and alkyl nitrile or acetone to construct highly functionalized fluorene and pyrroloindole derivatives with the participation of unactivated 2-aryl styrenes, which are useful skeletons in pharmaceutical and photoelectronic areas (Scheme 26a). Notably, two new C(sp3)–C(sp3) and C(Ar)–C(sp3) bonds, a five-membered ring and a quaternary carbon center are simultaneously formed in this autotandem radical cyclization. Considering that π-conjugated fluorene derivatives are important structural constituents of optoelectronic materials,[48] the authors then explored the generality of this novel cascade reaction to alkenes with fused rings and heterocycles, such as phenanthrene, dibenzo-[b,d]furan, dibenzo[b,d]thiophene, triphenylamine, 9-phenyl-9H-carbazole, and indoles (Scheme 26b). It is noteworthy that the obtained cyanomethylated fluorenes 72 could be further applied in synthetic transformations, leading to an unexpected fluorene 73 and substituted amide 74 in 35% and 62% yields, respectively (Scheme 26c).

Scheme 27. Proposed Reaction Mechanism Initial assumption that radical intermediates were involved in this oxidative C–C/C–C cross-coupling sequence was proved by the radical trapping experiment. A plausible mechanism is depicted in Scheme 27b, and the reaction was proposed to occur by Cu salt-induced SET to release the thermodynamically stable ·CH2CN. Acetonitrile radical reacts with the alkene functionality to give benzyl radical 76 followed by a HAS in analogy to the


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mechanism illustrated in Scheme 22. The researchers believed that a free radical pathway (Scheme 27b, path b) was more likely than a process involving the formation of an organocopper species 79 (path a).

Scheme 28. General Radical Cascade Oxyalkylation to Access Heterocyclic Compounds The preparation of functionalized heterocyclic compounds remains a fundamental challenge. Among the available methods, the domino oxyalkylation of alkenes represents as an indispensable tool for this purpose (Scheme 28). These reactions generally proceed through an intermolecular oxidative addition/intramolecular cyclization of alkenes tethered with a nucleophilic portion.

Scheme 29. Copper-Mediated 1,2-Oxyalkylation of Unactivated Alkenes with Alkyl Nitriles In 2014, Zhu and co-workers[49] first accomplished the cyanoalkylative cycloetherification of alkene using tethered N,N-dimethyl amide or carboxylic acid as an internal nucleophile in the presence of stoichiometric or catalytic amounts of copper salts (Scheme 29a). 3,3-Disubstituted phthalides and isochromanones with the formation of new C(sp3)-C(sp3) and C(sp3)-O bonds were furnished in moderate to good yields (Scheme 29b). Interestingly, the amide group (X = NHt-Bu, NHMe, or NMe2) significantly influenced the selectivity of products. When N,N-dimethylamide (X = NMe2) 84 was used as starting material, phthalide 85 was formed as a sole product. Additionally, adding water to the reaction mixture is conducive to good yield. Importantly, the broad substrate scope of alkyl nitriles (propionitrile, n-butyronitrile, n-valeronitrile, 3-methoxypropionitrile and isobutyronitrile) was impressive.

Scheme 30. Proposed Reaction Mechanism In their preliminary experiment, by-product alkene 87 was isolated, suggesting that the domino oxyalkylation was initiated by the formation of the intermolecular C-C bond rather than the intramolecular C-O bond. Based on


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the TEMPO trapping and radical clock experiments in Scheme 30a, a reasonable mechanism is proposed (Scheme 30b). Dual action of copper salt and potassium phosphate is absolutely necessary for the formation of nitrile-containing alkyl radicals. Indeed, oxidant DTBP was not essential for acetonitrile activation. Electrophilic radical addition to N,N-dimethylamide 84 would produce the adduct 88. Cyanomethylated intermediate 88 could be further oxidized by metal salt to a carbenium ion 89, which upon intramolecular cyclization and hydrolysis could afford the anticipated lactones.

Scheme 31. Copper-Catalyzed 1,2-Oxyalkylation of (2-Vinylaryl)methanols with Alkyl Nitriles Shortly thereafter, the same group[50] demonstrated another electrophilic radical-induced cycloetherification of (2-vinylphenyl)methanol 91 using the pendant hydroxyl group in a solution of MeCN/MeOH (v/v = 7/3) (Scheme 31a). As a result, a variety of substituted 1,3-dihydroisobenzofurans 92 were synthesized in the presence of a catalytic amount of copper(II) tetrafluoroborate hydrate, bathophenanthroline, K3PO4, BnOH and DTBP (Scheme 31b). The intriguing effect of MeOH as a co-solvent and BnOH as an additive on the reaction outcome was systematically examined by the researchers. However, alkenes with secondary benzylic alcohol moiety afforded a complex mixture due to their instability. Compared with their previous results,[22] methoxy cyanomethylation of the electron-rich alkenes was not found under this reaction manifold. Mechanistic hypothesis showed that the generation of cyanoalkyl radical 93 was the key step, and the formed radical could be stabilized by the adjacent benzene ring in favor of its final ring-closure step. In addition, the corresponding 1,3-dihydrobenzofuran can be further derivatized to medicinally relevant heterocycle (Scheme 31c).

Scheme 32. Copper-Catalyzed 1,2-Oxyalkylation of Olefinic Amides with Acetonitrile Following these pioneering studies, Ji and Xu[51] focused on the synthesis of important benzoxazine derivatives via analogous cascade reactions by utilizing with olefinic amides 96 as radical acceptors (Scheme 32a).


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Intermediates such as radical 98, organocopper 99 and carbenium ion 100 might be implicated in olefin oxycyanoalkylation and bifunctionalization. Although low to moderate yields of benzoxazine derivatives 97 were obtained which might somewhat lower its synthetic value, the protocol provided a straight route to site-specific cyanomethylated benzoxazines 97. Further radical-trapping experiment supported the proposed radical addition-cyclization pathway (Scheme 32b).

Scheme 33. Copper-Catalyzed Alkylative Epoxidation of Allylic Alcohols with Alkyl Nitriles Another interesting example of olefin oxyalkylation[52] was reported by Zhu et al. in early 2015 in the expansion of copper-catalyzed coupling/rearrangement reaction to convert allylic alcohols to δ-oxo alkyl nitriles.[37] Cyanoalkylative epoxidation of the same allylic alcohols 42 by simply changing the catalytic conditions was successfully achieved to offer homologated epoxides 49 in moderate to excellent yields, complementing the portfolio of traditional palladium-catalyzed arylation sequence[53] (Scheme 33a-b). Remarkably, a series of substituents at the α position of allylic alcohols were well tolerated, leading to polysubstituted epoxides including spirooxiranes that are otherwise difficult to access in good yields.

Scheme 34. Proposed Reaction Mechanism As shown in Scheme 34, the postulated catalytic cycle begins with the generation of reactive cyanomethyl radical either by DTBP or Cu(OAc)2-base induced hydrogen atom abstraction. The proposed pathways of intramolecular cyclization via tertiary carbocation intermediate 101 or radical intermediate 46 were ruled out by the authors, because carbocation intermediate 101 was susceptible to Wagner-Meerwein rearrangement, while alkyl radical 46 could undergo the neophyl migration. The epoxide was formed most probably by reductive elimination of the Cu(III) intermediate 103 generated in situ by recombination of Cu(II) with radical 46. Zhu et al. summarized that the formation of epoxides 49 was favored when an aryl group was present at the α-position of allylic alcohol substrates, while rearrangement became competitive if R1 was an alkyl group.

3.2 Cascade Reactions of Functionalized Alkynes


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a) Sun's work: Ar2

Ar

Ar2

2 equiv TBPB CN 2 equiv Na2CO3

1

o

130 C, 16 h, N2

R4

O O 104

Ar

R4 CN

1

O O 105

(2.0 mL)

b) Selected examples:

Ph Ph

R2

CN

Cl CN

R1 O

O

R1, R2 = Alkyl, OMe, Ph, OPh, X, CF3, 83-50%

CN O Ph

O

O

O

O 0%

O

Cl

72% (2:1) CN

O O trace

CN

Scheme 35. TBPB-Mediated Cyclization of Alkynoates with Acetonitrile

Scheme 36. Proposed Reaction Mechanism By far the availability of alkenes and alkynes coupled with their diverse radical reactions has been regarded as the most popular approach to deliver functionalized molecules. In an effort to further expand the scope of tandem radical reactions with alkyl nitriles, Sun and co-workers[54] disclosed cyanomethylation and cyclization of aryl alkynoates using cheap and available tert-butyl peroxybenzoate (TBPB) as an oxidant under transition metal-free conditions (Scheme 35a). The nature of the terminal oxidants played a crucial role for the design of carbocyclization, and it was found that several other peroxides such as DTBP, TBHP, BPO, and DCP showed very low efficiency. As mentioned before, the cyanomethyl group could be facilely incorporated into the family of coumarin derivatives in good yields (Scheme 35b). However, when sterically hindered o-tolyl phenylpropiolate was used, almost no anticipated product was obtained, and in the case of alkyl alkynoate, the reaction did not take place as well. Based on some experimental findings, a possible reaction mechanism is proposed in Scheme 36. Initially, thermal homolysis of the O–O bond in TBPB occurs to form the corresponding O-centered radicals, which then abstract a hydrogen atom from CH3CN to afford the alkyl radical 2 (Scheme 36). Addition of the radical 2 to a carbon-carbon triple bond can provide the highly reactive vinyl radical 106, which undergoes an intramolecular spirocyclization to afford the spiro-radical intermediate 107. The subsequent ester migration followed by further HAS take place via a carboxyl radical intermediate 108 to eventually give the product 105.

Scheme 37. Copper-Catalyzed Divergent Bicyclizations of 1,7-Enynes with Alkyl Nitriles


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Scheme 38. Proposed Reaction Mechanism Owing to both unsaturated moieties, 1,n-enynes serve as important building block for substrate-specific domino bicyclization reactions in organic synthesis. In 2016, a copper-catalyzed [2+2+1] annulation of 1,7-enynes with alkyl nitriles through cyanoalkyl radical-triggered tandem additions across the C=C bond and the C≡C bond in a step-economical manner to achieve cyclopenta[c]quinolines and benzo[j]phenanthridines has also been found by Li’s group (Scheme 37a).[55] This radical strategy features the selective construction of two different polycyclic structures with chemical and bioactive importance which mainly relies on the substitution effect at the 2-position of the acrylamides 110. The substrate of 1,7-enynes was crucial for the success of the method, substrate 110 possessing a free N-H bond was inert under the same reaction conditions (Scheme 37b). On the other hand, alkyl nitrile bearing strong electron-withdrawing group and sterically hindered O-nucleophile were not well tolerated. Notably,

the

anticipant

product

was

not formed

by

using

a

pre-synthesized

intermediate

of

2H-cyclopenta[c]quinolone 111' in the presence of methanol by a simple addition reaction under optimal conditions (Scheme 37c). The deuterium-labeled experiment resulted in the generation of 113-D2, suggesting a 1,5-hydride shift process. In the depicted plausible mechanism, the radical 2 could be generated from acetonitrile under heating with the aid of Cu(OTf)2 catalyst and DTBP oxidant (Scheme 38). Two reaction pathways can be envisioned on the basis of the substitution effect (R4) through alkyl radical addition/1,5-hydrogen atom shift (pathway a) as well as alkyl radical addition/HAS (pathway b) respectively from 1,7-enynes in the presence of Cu(n+1)+(t-BuO) species, thereby providing the opportunity to construct cyclopenta[c]quinolines and benzo[j]phenanthridines with simplicity.

Scheme 39. Scandium-Catalyzed Bicyclization of 1,6/7-Enynes with Alkyl Nitriles Along a similar line, the same group[56] reported a follow-up report on the oxidative divergent bicyclizations of 1,6/7-enynes through C(sp3)–H functionalization of alkyl nitriles using Sc(OTf)3 as catalyst and Ag2O as oxidant for the synthesis of ring-fused quinolinones in moderate to good yields (Scheme 39).

4. Conclusion and Perspectives In summary, the recent breakthroughs of radical-initiated α-C(sp3)–H oxidative functionalization of alkyl nitriles during the past four years have been classified and discussed based on different types of radical acceptors used, namely, alkenes, alkynes, arenes, and alkanes. Inarguably, these extensive cyanoalkylations have found wide applications in an increasing number of oxidative couplings and tandem radical reactions, which offer efficient methodologies for incorporation of synthetically useful building blocks. Among all transition metals employed,


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copper and iron catalysts show the most versatile catalytic activities. Additionally, transition metal-free oxidative couplings were also employed to achieve C−H functionalization of alkyl nitriles on this issue. Importantly, this review summarizes the activation models of alkyl nitriles, the generality of substrate scope, the details of suggested mechanism and challenges that will continue to drive discoveries of this important topic in synthetic chemistry. Continuing progress in their utility in organic transformations will make it possible for the diverse synthesis of natural products and drugs. Furthermore, reducing the amount of catalyst loading and alkyl nitrile reactant, replacement of metal catalysts to common metal-free catalysts, and development of tandem reactions to rapidly build-up molecular complexity by facile C(sp3)−C(sp3) bond formation will be the next research topics in this oxidative functionalization of alkyl nitriles. In addition, more general and practical procedures compatible with most of simple styrenes and aliphatic olefins would be highly desirable. We hope its advent would serve as a handy reference for chemists interested in cyanoalkylation reactions by using simple alkyl nitriles and who wish to expand this important field in an environmentally-benign manner.

Author Information Corresponding Author *E-mail: [email protected]; E-mail: [email protected]. Author Contributions All authors have given approval to the final version of the manuscript.

Acknowledgements We gratefully acknowledge the financial support from Nanjing Tech University, SICAM Fellowship from Jiangsu National Synergetic Innovation Center for Advanced Materials, and Nanyang Technological University.

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Recent Advances in Radical-Initiated C(sp3)-H Bond Oxidative Functionalization of Alkyl Nitriles Xue-Qiang Chu, Danhua Ge, Zhi-Liang Shen, Teck-Peng Loh


Recent Advances in Radical-Initiated C(sp3)-H Bond Oxidative

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