Key words ketone - oxidative coupling - C–H functionalization - cross-dehydrogenative coupling
- radical
1
Introduction
Sandip Murarka received his Ph.D. from WWU Münster, Germany under the supervision of Prof. Armido
Studer. Subsequently, he worked as a postdoctoral research fellow in the laboratory
of Prof. Herbert Waldmann at Max Planck Institute Dortmund. Since May 2017, he has
held the position of an Assistant Professor at Indian Institute of Technology Jodhpur,
India. His current research activities revolve around the study of novel activation
modes and the development of transition-metal-free and transition-metal-catalyzed
chemoselective and sustainable transformations.Andrey P. Antonchick received his Ph.D. from the Institute of Bioorganic Chemistry of the National Academy
of Sciences of Belarus (Minsk, Belarus) and the Max Planck Institute for Chemical
Ecology (Jena, Germany) under the guidance of Prof. V. A. Khripach and Dr. B. Schneider.
After a postdoctoral appointment with Prof. M. Rueping at Frankfurt University, he
joined the group of Prof. H. Waldmann. He was appointed group leader at the Max Planck
Institute of Molecular Physiology and TU Dortmund. His research interests lie in the
development of new reaction methodologies.
An enolizable ketone typically reacts with a range of electrophiles through the enol
form to furnish conventional nucleophile–electrophile coupling products and this,
thereby, ultimately leads to the α-functionalization of the ketone moiety.[1 ] An alternative way to perform the α-functionalization of ketones would be through
the oxidative coupling of the enolate thus providing a direct and convergent method
to synthetically useful 1,4-dicarbonyl motifs (Scheme [1 ], Path A).[1 ]
[2 ] One advantage of such an oxidative coupling strategy is that it obviates the need
for functional group umpolung and thereby streamlines the synthetic sequence. The
first example of such an oxidative enolate coupling was reported in 1935, when Ivanoff
and Spasoff showed that the enolate of phenylacetic acid undergoes oxidative homocoupling
in the presence of molecular oxygen or molecular iodine.[3 ] This exciting transformation turned out to be less synthetically useful due to low
yields and multiple unwanted side products. This field remained unexplored until the
1970s, when the interest towards the development of preparatively and synthetically
useful oxidative enolate coupling was reinvigorated. In 1971, Rathke and Lindert documented
a Cu(II)-promoted coupling of ester enolates towards the synthesis of succinate esters.[4 ] The first oxidative enolate coupling involving ketones dates back to 1975; when
Saegusa and co-workers documented the use of CuCl2 as an effective oxidant for the dimerization of ketone enolates.[5 ] Subsequent years witnessed the usage of various other oxidants[6 ] and non-enolate carbonyl derivatives in oxidative coupling chemistry.[2a ] In several of these cases more challenging oxidative cross-coupling could be achieved,
but typically they required stoichiometric advantage of one coupling partner. Recent
years have witnessed significant advances in these areas in terms of efficient methodology
development, cross-coupling with equal stoichiometry of reacting partners, and attainment
of high levels of diastereocontrol.[2b ] Strategically, cross-dehydrogenative coupling (CDC) between two simple C–H bonds
leading to the formation of a C–C bond is of great interest due to its atom and step
economy.[7 ] In 1948, in one of the earliest examples of CDC, Kharasch and co-workers showed
that upon treatment with diacetyl peroxide, aliphatic ketones undergo dimerization
through direct C–H functionalization to give the corresponding 1,4-dicarbonyl compounds.[8 ] Interestingly, since this initial report, noteworthy development has been made and
powerful methods have emerged regarding the application of CDC approach towards the
synthesis of 1,4-dicarbonyl compounds through direct C(sp3 )–H functionalizations of ketones (Scheme [1 ], Path B).
Importantly, 1,4-dicarbonyl compounds synthesized through these powerful oxidative
coupling methods serve as highly useful synthetic precursors for various carbocyclic
and heterocyclic compounds (Scheme [1 ], Path C). Moreover, in recent years, several other direct oxidative homocouplings
of ketones and also cross-couplings between ketones and diverse other coupling partners
have been developed that lead to the formation of carbocycles and biologically important
heterocycles. These cross-couplings may (Scheme [1 ], Path C) or may not (Scheme [1 ], Path D) go through the intermediacy of a 1,4-dicarbonyl motif.
Scheme 1 Radical couplings of ketones
The purpose of this brief review is to summarize all these recent contributions and
to provide examples of oxidative coupling involving α-functionalization of ketones
for the synthesis of 1,4-dicarbonyl compounds and diverse heterocycles and carbocycles.
This review specifically covers the advancements made since 2008 in the field of the
metal-catalyzed couplings of ketones which occur through radical pathway and lead
to the α-functionalization of ketones. This review does not cover oxidative coupling
involving carbonyls other than ketones (such as esters and amides) and metal-free
couplings involving ketones.
Synthesis of 1,4-Dicarbonyl Compounds
2
Synthesis of 1,4-Dicarbonyl Compounds
Oxidative coupling of enolates through single-electron oxidation represents a direct
and straightforward approach for the construction of 1,4-diketones. Oxidative dimerization
of ketone-derived lithium enolates was first studied by Saegusa and co-workers in
the 1970s.[5 ]
[9 ] Formally, this transformation utilizes the direct coupling of two identical sp3 -hybridized carbon atoms with no substrate pre-functionalization. A comprehensive
list of an analogous process using two different types of enolates allowing selective
and controlled heterocoupling is quite brief. The first intermolecular oxidative cross-coupling
was reported by Saegusa and co-workers using at least a threefold excess of one of
the ketone coupling partners and gave the desired products in synthetically useful
yields (Scheme [2 ]).[5 ] Although the power of this approach towards the synthesis of unsymmetrical 1,4-diketones
is unquestionable, the necessity of using one coupling partner in manifold excess
has restricted its use in more complex settings.
Scheme 2 Oxidative cross-coupling of lithium enolates
Selective cross-coupling received no further attention and the field remained unexplored
until 2006 when Baran and co-workers reported the intermolecular oxidative heterocoupling
of enolates.[10 ] They showed that a selective heterocoupling between two different enolates can be
achieved by exploiting the natural electronic or steric differences in both coupling
partners. Accordingly, for the first time a cross-coupling between a ketone and an
amide with equal stoichiometry of the reacting partners was demonstrated by Baran
and DeMartino taking advantage of the difference in oxidation potential of ketone
and amide lithium enolates (Scheme [2 ]).[10a ] A subsequent report in 2008 detailing the full scope of the reaction revealed that
good yields were obtained across a range of substrates when appropriate lithium enolates
were cross-coupled in the presence of Fe(III)- or Cu(II)-based oxidants.[10b ] Furthermore, it was also shown that best results were obtained in THF solvent. While
these studies by Baran and co-workers provided important and much needed insight into
oxidative heterocoupling of lithium enolates, subsequent work by Casey and Flowers,
supported by spectroscopic and mechanistic data, showcased that selective formation
of cross-coupled products for the ketones they investigated was due to the heteroaggregation
of the corresponding lithium enolates.[11 ] In an interesting finding, Daugulis and co-workers showed that oxidative dimerization
of ketone enolates can be carried out using a copper catalyst and molecular oxygen
as the terminal oxidant.[12 ] The lithium enolates of diverse ketones underwent facile dimerization in the presence
of Cu(acac)2 catalyst, zinc chloride additive, and molecular oxygen to afford the desired symmetrical
1,4-diketones in moderate to good yields. This is a significant improvement, as the
existing oxidative homocouplings required metal oxidant in stoichiometric amounts.
In 2011, Thomson and co-workers developed a method for the synthesis of axially chiral
biphenols through the oxidative enolate dimerization of enantioenriched monoketal
cyclohex-2-ene-1,4-diones.[13 ] To this end, treatment of enone precursors 1 with LDA, followed by oxidative coupling catalyzed by CuCl2 furnished the dione product 2 while forging the hindered central σ-bond linkage. Finally, a Lewis acid promoted
loss of methanol with a concomitant double aromatization event furnished a range of
desired biphenols 3 with traceless central-to-axial chirality exchange (Table [1 ]).
Table 1 Synthesis of Biphenols from 1,4-Diketones by Traceless Central-to-Axial Chirality
Exchange
Ar
Yield (%) of 2 (er)
Yield (%) of 3 (er)
4-MeOC6 H4
50 (99:1)
86 (99:1)
4-FC6 H4
66 (99:1)
88 (99:1)
2-naphthyl
51 (99:1)
82 (99:1)
In 1998, Schmittel and co-workers revealed that symmetrical and nonsymmetrical bis-enol
ethers in the presence of ceric ammonium nitrate (CAN) undergo intramolecular oxidative
coupling to generate 1,4-diketones.[14 ] In order to further expand the scope of these initial findings, in 2007 Thomson
and co-workers documented a general strategy for the oxidative cross-coupling of tetralone
derivatives to afford unsymmetrical 1,4-diketones.[15 ] Treatment of 2-methyl-1-tetralone (4 ) with LDA followed by addition of chlorosilane 5 resulted in the clean formation of the desired unsymmetrical silyl bis-enol ethers
6 , which were then subjected to oxidative coupling conditions in the presence of CAN
to afford the desired diketones 7 with simultaneous generation of a quaternary stereocenter (Scheme [3 ]). Several methyl ketone derivatives 5 reacted with the tetralone component 4 to furnish the final products in moderate to good yields.
Scheme 3 Oxidative coupling of 2-methyl-1-tetralone-derived unsymmetrical silyl bis-enol ethers
Following this in 2008, Thomson and co-workers investigated the scope of the diastereoselective
synthesis of linked complex bicyclic structures through the oxidative coupling of
unsymmetrical silyl bis-enol ethers.[16 ] Through an extensive screening using several silyl bis-enol ethers with varying
silicon substituents, it was established that sterically congested diisopropylsilyl
bis-enol ether 8 was the optimal substrate giving the highest levels of yield and diastereoselectivity.
The robustness of the protocol was demonstrated through the preparation of several
linked bicyclic diketones 9 with high diastereoselectivity (Scheme [4 ]).
Scheme 4 Diastereoselective oxidative coupling of unsymmetrical silyl bis-enol ethers
Taking this a step further in 2018, Thomson and Robinson developed a modular approach
based on the stereoselective coupling of symmetrical or unsymmetrical silyl bis-enol
ethers, followed by a ring-closing metathesis sequence towards the synthesis of stereochemically
rich polycyclic compounds that are embedded in numerous bioactive natural product
families.[17 ] To this end, optically active silyl bis-enol ether derivatives 10 bearing a vinyl or allyl group at the 5-position were subjected to their previously
documented CAN-promoted oxidative coupling conditions to afford diketo adducts 11 , which upon ring-closing metathesis using Grubbs II catalyst delivered a range of
polycyclic compounds 12 in moderate yield and good diastereoselectivity (Scheme [5 ]). Interestingly, several prepared compounds exhibited potent cytotoxic activity
against a panel of tumor cell lines. Importantly, enones were employed as starting
materials for the regioselective formation of the silyl bis-enol ethers and also to
ensure that subsequent oxidative coupling takes place in the desired fashion. In addition,
using an enantiomerically pure starting material was indispensable to this powerful
reaction sequence, as the union of racemic precursors gave the undesired formation
of diastereomeric mixtures. It is important to mention that the CAN-promoted oxidative
heterocoupling of enol silanes has been successfully applied as a key step in the
total synthesis of the natural product propindilactone G.[18 ]
Scheme 5 Stereoselective oxidative coupling/ring-closing metathesis sequence towards polycyclic
scaffolds
In 2009, Thomson and Clift demonstrated a three-component, two-step merged conjugate
addition/oxidative coupling strategy using CAN and 2,6-di-tert -butylpyridine (dtbpy) towards the synthesis of a diverse collection of 1,4-diketones
15 in moderate yields (Scheme [6 ]).[19 ] The desired unsymmetrical silyl bis-enol ethers 14 required for the oxidative coupling were formed in the first step by 1,4-addition
of methylmagnesium bromide with subsequent trapping of the thus-generated enolate
by chlorosilyl enol ether 5 .
Scheme 6 Merged conjugate addition/oxidative coupling towards 1,4-diketones
In 2014, Hirao and co-workers developed an oxidative homocoupling of boron enolates
16 using oxovanadium(V) compounds to give the corresponding 2,3-disubstituted 1,4-diketones
17 in good yields (Scheme [7 ]).[20 ] The required boron enolates 16 were prepared via the 1,4-hydroboration of enones 13 ; the geometric configuration of the resulting enolate 16 was established using 1 H NMR spectroscopy. Interestingly, the choice of oxovanadium(V) oxidant was critical
to attaining high stereoselectivity. Accordingly, high selectivity (up to 94:6) was
obtained when the oxidative coupling was carried out at –30 °C and in the presence
of VO(Oi -Pr)2 Cl as the oxidant.
Scheme 7 Oxovanadium(V)-induced oxidative homocoupling of boron enolates
Subsequently in 2015, Hirao and co-workers reported a oxovanadium(V)-induced selective
oxidative cross-coupling between boron 18 and ketone-derived silyl enolates 19 as an efficient and straightforward strategy for the synthesis of unsymmetrical 1,4-dicarbonyl
compounds 20 (Scheme [8 ]).[21 ] The reactivity difference between boron and silicon in the enolates 18 and 19 proved to be crucial as it allowed selective one-electron oxidation of the more reactive
boron enolate 18 leaving the silyl enolate 19 intact. Strategically, selective one-electron oxidation of the boron enolate 18 generates an electrophilic α-radical species, which is immediately trapped by the
silyl enolate 19 . A broad substrate scope with regard to both enolates was demonstrated and the resulting
1,4-dicarbonyls 20 were obtained in good yields. In 2017, they also showed that the same oxovanadium(V)-induced
cross-coupling strategy can be extrapolated to the cross-coupling of various combinations
of boron and silyl enolates in a ketone–ester, ester–ester, amide–ester, and amide–ketone
enolate coupling.[22 ] These findings unequivocally established the versatility of this oxovanadium(V)-induced
oxidative cross-coupling strategy.
Scheme 8 Oxovanadium(V)-induced oxidative heterocoupling of enolates
In 2015, Wang and co-workers developed an efficient Cu(II)-promoted direct oxidative
coupling between two C(sp3 )–H bonds in the α-position to a carbonyl group as a more attractive way to build
the 2,3-disubstituted 1,4-diketone motif 22 (Scheme [9 ]).[23 ] The method features a broad substrate scope and high functional group tolerance.
Mechanistically, it was proposed to proceed through the intermediacy of radicals.
Scheme 9 Cu(II)-promoted oxidative coupling of two C(sp3 )–H bonds adjacent to the carbonyl group
Contemporaneously, they developed a more sustainable silver-catalyzed protocol to
achieve a similar cross-dehydrogenative coupling of two C(sp3 )–H bonds for the synthesis of 1,4-diketones with air as the terminal oxidant.[24 ] This catalytic CDC protocol is highly attractive, as besides homocoupling it also
allows the cross-coupling of two different ketones 23 and 24 under similar conditions to afford the corresponding products 25 in good yields (Scheme [10 ]).
Scheme 10 Ag(I)-catalyzed oxidative coupling of two C(sp3 )–H bonds adjacent to a carbonyl group
In their pioneering studies in 2007, MacMillan and co-workers exploited their novel
organocatalytic singly occupied molecular orbital (SOMO) activation strategy to report
the first asymmetric aldehyde α-enolation leading to the formation of γ-ketoaldehydes
starting from simple aldehydes and enolsilanes.[25 ] In 2010, Huang and Xie developed a merging organocatalyst and transition-metal-catalyzed
carbo-carbonylation of styrenes 26 with ketones 27 by cascade SOMO catalysis and oxidation to furnish 1,4-dicarbonyl compounds 28 in moderate to good yields (Scheme [11 ]).[26 ] Under the catalysis of pyrrolidine and Cu(ClO4 )2 ·6H2 O and in the presence of MnO2 and air, several dicarbonyl compounds were obtained. According to the proposed mechanism
(Scheme [11 ]), pyrrolidine initially reacts with cyclohexanone (27a ) (a representative carbonyl) to form enamine A , which then undergoes single-electron oxidation by Cu(II) to generate the corresponding
radical cationic enamine B . Then B reacts with styrene (26a ) to form radical intermediate C , which upon reaction with oxygen and concomitant hydrolysis delivers peroxide intermediate
D . Finally, intermediate D under copper catalysis affords 1,4-diketo species 28 .
Scheme 11 The cascade carbo-carbonylation of styrenes and ketones
Along these lines, Koike, Akita, and Yasu developed a visible-photoredox-catalyzed
oxidative cross-coupling of enamines and silyl enol ethers in the presence of quinone
oxidant to furnish the corresponding γ-diketones in moderate yields.[27 ] In a conceptually novel approach, Xing and co-workers documented a copper/manganese-cocatalyzed
and tert -butyl hydroperoxide (TBHP) promoted direct oxidative coupling of styrene derivatives
26 with ketones 27 through C(sp3 )–H bond functionalization to afford 1,4-dicarbonyls 28 .[28 ] Various ketones underwent a smooth free-radical addition to styrenes to furnish
a range of 1,4-diketone compounds with excellent regioselectivity (Scheme [12 ]). Similarly, Christoffers and Geibel reported a cerium-catalyzed coupling of oxo
esters with enol acetates for the synthesis of 1,4-diketones using atmospheric oxygen
as the oxidizing agent.[29 ]
Scheme 12 Cu/Mn-cocatalyzed oxidative coupling of ketones and styrenes
Synthesis of Heterocyclic Scaffolds
3
Synthesis of Heterocyclic Scaffolds
The direct oxidative C–H functionalization of ketones has been successfully applied
in the synthesis of several heterocycles, such as furans, dihydrofurans, thiophenes,
and pyrroles, that are valuable five-membered heterocycles embedded in multiple natural
products, pharmaceuticals and materials.[30 ] In 2015, Wang and co-workers developed a copper and silver cocatalyzed coupling
of C(sp3 )–H bonds that are adjacent to a carbonyl group to provide a direct and efficient
route to a diverse collection of tetrasubstituted furan derivatives 29 using molecular oxygen as the terminal oxidant (Scheme [13 ]).[23 ] Importantly, the oxidative coupling did not occur when carried out in the presence
of the radical inhibitor TEMPO. Based on this radical trapping experiment, they proposed
that the reaction begins by deprotonation and single-electron-transfer oxidation of
ketone 21 by the Cu(II) catalyst to form alkyl radical A and Cu(I). Then the resulting alkyl radical A undergoes homodimerization to give 1,4-dicarbonyl 22 , which finally, under acidic conditions, produces tetrasubstituted furans 29 . Cu(I) is oxidized by the Ag2 O/O2 system to regenerate Cu(II) and complete the catalytic cycle.
Scheme 13 Cu/Ag-catalyzed oxidative coupling of ketones for the synthesis of tetrasubstituted
furans
In a subsequent report,[24 ] they demonstrated a silver-catalyzed general oxidative coupling approach for the
synthesis of polysubstituted furans, thiophenes, and pyrroles (Scheme [14 ], see also Scheme [10 ]). Initially, silver-catalyzed oxidative coupling of two C(sp3 )–H bonds generates 1,4-diketones, which subsequently undergo cyclization in a one-pot
fashion under different conditions to furnish tetrasubstituted furans (Conditions
A), thiophenes (Conditions B), and pyrroles (Conditions C) in good yields (Scheme
[14 ]).
Scheme 14 Ag-catalyzed one-pot synthesis of furans, thiophenes, and pyrroles
Furans have also been synthesized through intermolecular oxidative coupling between
ketones and electron-deficient alkenes. To this end, in 2013 Zhang and co-workers
reported a novel copper-mediated intermolecular annulation of alkyl ketones 31 with acrylic acids 32 for the synthesis of 2,3,5-trisubstituted furans 33 (Scheme [15 ]).[31 ] It is important to mention that the reaction was more effective in the presence
of both copper salts [CuCl and Cu(OAc)2 ·H2 O] and yields decreased in the absence of either of the copper sources. The reaction
between ketone 31a and cinnamic acid (32a ) was completely suppressed when carried out in the presence of TEMPO as a radical
inhibitor, which supports the intermediacy of radicals in this reaction. According
to the proposed reaction mechanism, in the first step, upon reaction with copper salts,
the cinnamic acid 32 generates Cu(II) cinnamate A and the alkyl ketone 31 produces the corresponding alkyl radical B (Scheme [15 ]). Addition of the generated alkyl radical B to the α-position of the double bond in Cu(II) cinnamate A , followed by single-electron-transfer oxidation delivers the carbocationic intermediate
D . Subsequently, D undergoes intramolecular cyclization to give intermediate E , which upon deprotonation and elimination delivers the corresponding furan product
33 .
Scheme 15 Cu-promoted synthesis of furans using CuCl and Cu(OAc)2 ·H2 O
Following this report, in 2015 Hajra and co-workers reported a similar decarboxylative
annulation between ketones 31 and acrylic acids 32 towards the regioselective synthesis of trisubstituted furans 33 .[32 ] The method was shown to be quite robust and a library of furan derivatives was prepared.
Interestingly, whereas the method of Zhang and co-workers required two different copper
salts in stoichiometric amounts, the protocol of Hajra and co-workers utilized a single
copper salt in catalytic amounts and a stoichiometric amount of water as an important
additive. Furthermore, Hajra and co-workers ruled out the possibility of a radical
pathway, as radical scavengers like quinone and 2,6-di-tert -butyl-4-methylphenol (BHT) did not inhibit the reaction between 31a and 32a and the corresponding furan 33a was obtained in 52% yield (Scheme [16 ]).
Scheme 16 Cu-catalyzed synthesis of furans using Cu(OAc)2 ·H2 O
Also in 2015, Hajra and co-workers demonstrated a copper-mediated annulation of alkyl
ketones 31 and β-nitrostyrenes 34 for the synthesis of 2,3,5-trisubstituted furans 35 using tert -butyl hydroperoxide as an oxidant (Scheme [17 ]).[33 ] In contrast to their previous report, they showed, based on radical trapping experiments,
that this reaction proceeds through a radical pathway.
Scheme 17 Cu-mediated annulation of ketones and β-nitrostyrenes for the synthesis of substituted
furans
Antonchick and Manna showed that besides activated alkenes, electron-deficient alkynes
can also be employed in this type of oxidative cross-coupling reaction. Accordingly,
they developed a copper-catalyzed oxidative coupling, using di-tert -butyl peroxide (DTBP), between acetophenones 36 and electron-deficient alkynes 37 for the synthesis of trisubstituted furans 38 (Scheme [18 ]).[34 ] Subsequent to this report, Luo, He, and co-workers demonstrated a similar Cu(I)-catalyzed
oxidative annulation between substituted acetophenones 39 and alkynoates 40 using benzoyl peroxide (BPO) as an external oxidant (Scheme [18 ]).[35 ] Both protocols are mechanistically similar and work quite efficiently giving multisubstituted
furans in good yields. In contrast to the protocol of Antonchick and Manna, which
exclusively worked for electron-poor acetophenones 36 , the method of Luo, He, and co-workers was shown to be applicable to electron-rich
acetophenones 39 as well.
Scheme 18 Cu-catalyzed annulation of acetophenones and alkynoates for the synthesis of substituted
furans
According to the proposed mechanism,[34 ] first the Cu(I) species is oxidized to Cu(II) in the presence of DTBP (Scheme [19 ]). The enol form of the acetophenone derivative is then oxidized to the corresponding
alkyl radical A by the Cu(II) species. Subsequently, radical A undergoes addition to the electron-deficient alkyne 37a to give intermediate B , which after oxidative addition of Cu(II) generates intermediate C . Intermediate C is in equilibrium with intermediate D through keto–enol tautomerization. A ligand exchange in intermediate D forms metallocycle E , which finally undergoes reductive elimination to afford product 38a . The Cu(II) catalyst is regenerated by oxidation of Cu(I) with DTBP. In an alternative
pathway, radical B can be oxidized to the corresponding cation F by Cu(II), which concomitantly undergoes intramolecular cyclization to the desired
final product 38a . However, this pathway was considered to be less likely, as in control experiments
the authors were not able to trap the cationic intermediate using various nucleophiles.
Scheme 19 Proposed mechanism for the Cu-catalyzed annulation of acetophenones and alkynoates
In 2012, Lei and co-workers demonstrated that simple unactivated terminal alkynes
42 can also be employed in direct oxidative cross-coupling by using 1,3-dicarbonyl compounds
43 possessing an active methylene group instead of simple alkyl ketones as the other
coupling partner. They developed a silver-mediated CDC between 1,3-dicarbonyl compounds
43 and arylacetylenes 42 furnishing a range of polysubstituted furans 44 in good yields (Scheme [20 ]).[36 ] The reaction worked only with terminal alkynes and trace product formation was observed
in cases using internal alkynes. It was speculated that this transformation might
not proceed through an oxidative radical cyclization. In 2014, the mechanism of this
silver-mediated oxidative coupling reaction was studied by Novák, Stirling, and co-workers
and based on their experiments and density functional calculations they unambiguously
established that the reaction is indeed going through a radical intermediate.[37 ] The reaction between phenylacetylene (42a ) and ethyl acetoacetate (43a ) carried out under the optimized conditions was completely inhibited upon addition
of TEMPO or BHT as radical scavengers (Scheme [20 ]).
Scheme 20 Ag-promoted oxidative coupling of arylacetylenes with 1,3-dicarbonyls
Li and co-workers developed a manganese-mediated efficient synthesis of dihydrofurans
46 through direct oxidative coupling of enamides 45 and 1,3-dicarbonyl compounds 43 (Scheme [21 ]).[38 ] Replacing 1,3-dicarbonyl compounds 43 with 2-substituted 1,3-dicarbonyl compounds in the reaction with enamides under otherwise
unchanged conditions, delivered (Z )-dicarbonyl enamides. Importantly, dihydrofurans 46 were conveniently transformed into the corresponding furans 44 and pyrroles 47 in good yields via the classical Paal–Knorr reaction (Scheme [21 ]).
Scheme 21 Mn-mediated oxidative coupling of enamides and 1,3-dicarbonyl compounds
Based on radical trapping experiments, a radical mechanism was proposed for this transformation
(Scheme [22 ]). The reaction begins with the oxidation of 1,3-dicarbonyl compounds 43 by Mn(OAc)3 to generate an electron-deficient radical A , which subsequently adds to the electron-rich enamide 45 to generate radical B . Radical B gets further oxidized by Mn(OAc)3 into carbocation C or iminium ion C′ , which readily undergoes cyclization/deprotonation to afford desired dihydrofuran
46 . Under the influence of acid 46 undergoes ring cleavage to give imine D or enamide D′ , which further hydrolyzes to the corresponding 1,4-dicarbonyl intermediate E . The intermediate E then delivers the corresponding furans 44 and pyrroles 47 under Paal–Knorr conditions.
Scheme 22 Mechanism of Mn-mediated oxidative coupling of enamides and 1,3-dicarbonyl compounds
In 2017, Yu and co-workers developed a Fe(OAc)2 -catalyzed cross-dehydrogenative coupling between 1,3-dicarbonyl compounds 49 and α-oxoketene dithioacetals 48 using tert -butyl peroxybenzoate (TBPB) for the synthesis of a library of tetrasubstituted furans
50 in good yields (Scheme [23 ]).[39 ] Importantly, the highly functionalized furan derivatives are amenable to further
synthetic manipulation through palladium-catalyzed selective C–S bond cleavage and
concomitant arylation to yield 2-arylfurans 51 or through condensation with hydrazine to yield 2,3-furan-fused pyridazinones 52 .
Scheme 23 Fe-catalyzed cross-dehydrogenative coupling of internal alkenes and 1,3-dicarbonyl
compounds
Lei and co-workers reported a copper-catalyzed oxidative coupling between styrenes
and 1,3-dicarbonyl compounds in the presence of di-tert -butyl peroxide as the external oxidant to provide highly substituted dihydrofurans.[40 ] Moreover, they studied the Cu(I)/Cu(II) redox process involved in the oxidative
cyclization of β-ketocarbonyl derivatives by X-ray absorption and EPR spectroscopy
and provided evidence supporting the reduction of Cu(II) to Cu(I) by 1,3-diketones.
In an interesting report, Maiti and co-workers demonstrated a copper-mediated annulation
of aryl ketones 53 and styrenes 54 allowing efficient access to a diverse range of dihydrofurans 55 in good synthetic yields (Scheme [24 ]).[41 ] Meanwhile, along the same lines, Hajra and co-workers showed that aryl ketones 53 and styrenes 56 can also be oxidatively cross-coupled in the presence of catalytic amounts of Cu(II)
salts to furnish multisubstituted furans 57 (Scheme [24 ]).[42 ] Importantly, aliphatic ketones as well as aliphatic alkenes are not viable substrates
under both Maiti and Hajra’s conditions. Both reactions go through the intermediacy
of radicals as demonstrated by the use of radical scavenger experiments. Interestingly,
as per the proposed mechanism of Hajra and co-workers, formation of furans 57 goes through the intermediacy of dihydrofurans 55 . Based on the proposed mechanism, dihydrofurans 55a , following further oxidation under Hajra’s oxidative conditions, generate carbocationic
intermediate 58 , which finally undergoes 1,2-aryl shift and elimination to furnish desired furan
derivative 57 (Scheme [24 ]). Similarly in 2017, Lei and co-workers reported a facile CuCl2 -catalyzed oxidative cyclization of aryl ketones and styrenes towards the synthesis
of multisubstituted furan derivatives.[43 ] Interestingly, through X-ray absorption and electron paramagnetic studies they revealed
that DMSO, besides serving as a solvent, plays the crucial role of an oxidant to promote
the oxidation of Cu(I) to Cu(II).
Scheme 24 Oxidative coupling of ketones and styrenes
Also in 2017, Maiti and co-workers developed a general and elegant oxidative [3+2]
annulation between a variety of cyclic ketones 61 and 63 and diverse alkenes 60 using Cu(OAc)2 in combination with a tri-tert -butylphoshine ligand to furnish a diverse collection of fused furans 62 and naphthofurans 64 under mild conditions (Scheme [25 ]).[44 ] Importantly, naturally occurring chiral substrates, such as (R )-(–)-carvone underwent smooth reaction with styrene to provide fused furan 62a in 58% yield. Using adamantane-1-carbonyl chloride as an additive was essential to
the synthesis of fused furans 62 , but it proved to be ineffective in increasing the yield of naphthofurans 64 . Moreover, the generality of the method was further demonstrate by reacting 1-tetralone
(63a ) with several internal alkynes 65 furnishing 2,3-disubstituted naphthofurans 66 in good yields (Scheme [25 ]). Use of molecular sieves as a drying agent and tert -butyl alcohol as the solvent was critical in obtaining good yields in this transformation.
Scheme 25 Regiospecific synthesis of fused furans and naphthofurans
Based on several control experiments, a radical-based mechanism was proposed as shown
in Scheme [26 ]. The reaction begins by the coordination of a copper complex with 1-tetralone (63a ) to generate intermediate A , which upon elimination of acetic acid leads to B . Subsequently, single-electron transfer from B , followed by radical addition of C onto the β-position of alkene 60 provides intermediate D . Afterwards, an oxidative cyclization results in dihydrofuran derivative F , which finally yields the desired product 64a through a radical-based dehydrogenation/oxidation sequence.
Scheme 26 Proposed mechanism for the synthesis of fused furans and naphthofurans
In 2008, Chiba and Narasaka documented a Cu(II)-catalyzed oxidative annulation between
α-(alkoxycarbonyl)-vinyl azides and ethyl acetoacetate towards the synthesis of 1H -pyrroles.[45a ] However, the inevitable difficulties in introducing an alkoxycarbonyl moiety at
the α-position of the vinyl azide and the inability of 1,3-diketones other than ethyl
acetoacetate to participate in this copper-catalyzed protocol, prompted the further
development of a more general method. Accordingly, they developed a Mn(OAc)3 -catalyzed coupling between diverse vinyl azides 67 and a variety of 1,3-dicarbonyl compounds 68 , including the corresponding diketone analogues, to afford a versatile collection
of 1H -pyrroles 69 (Scheme [27 ]).[45b ]
Scheme 27 Oxidative coupling of vinyl azides with 1,3-dicarbonyl compounds or ketones for the
synthesis of pyrroles
In 2015, Adimurthy and co-workers showed that simple ketones 70 , instead of activated 1,3-dicarbonyl compounds, can also be employed in this kind
of transformation. A copper-catalyzed direct C(sp3 )–H functionalization of ketones 70 with vinyl azides 67 was developed for the straightforward and efficient synthesis of 2,3,5-trisubstituted
1H -pyrroles 71 (Scheme [27 ]).[46 ] Several electronically and structurally diverse vinyl azides reacted with both aliphatic
and aromatic ketones to furnish the desired products in moderate to good yields.
Synthesis of Carbocyclic Scaffolds
4
Synthesis of Carbocyclic Scaffolds
Strained carbocycles, such as cyclopropanes, impart unique reactivity in organic synthesis
and are embedded in many natural products and medicinally important compounds.[47 ] Antonchick and Manna have developed a copper-catalyzed cross-dehydrogenative annulation
of electron-deficient alkenes 72 and acetophenones 36 involving direct double C–H functionalization at the α-position of the ketone using
di-tert -butyl peroxide as the terminal oxidant towards the stereoselective synthesis of fused
cyclopropanes 73 (Scheme [28 ]).[48 ] A broad substrate scope with regard to electronically diverse acetophenones 36 and N -alkyl-substituted maleimides 72 gave versatile fused cyclopropane scaffolds 73 in good yields. Moreover, besides N-substituted maleimides, other electron-deficient
alkenes, such as acrylic acid derivatives, were shown to be tolerated under the reaction
conditions. Importantly, the highly functionalized final products were amenable to
further synthetic transformations. Accordingly, product 73a was transformed into 74 through hydrolysis and subsequent diesterification and into 75 through reduction using lithium aluminum hydride (Scheme [28 ]).
Scheme 28 Cu-catalyzed annulation of electron-deficient alkenes
Scheme 29 Proposed mechanism for the Cu-catalyzed cyclopropane synthesis
Mechanistically, first Cu(I) is oxidized to a Cu(II) species by DTBP (Scheme [29 ]). In the following step, acetophenone 36 through its enol form A gets oxidized by the Cu(II) species to alkyl radical B . The resulting radical B then adds to the maleimide derivative 72 to produce C , which is stabilized through the resonance form C′ . Subsequent addition of C on the Cu(II) species generates intermediate D , which upon enolization at the keto functionality and ligand exchange delivers E . Importantly, formation of E is the stereodetermining step of this annulation process. Finally, reductive elimination
of Cu(I) from E generates the final product 73 and the Cu(II) catalyst is regenerated by oxidation of Cu(I) by DTBP.
Following this, Antonchick and Manna developed an unprecedented copper-catalyzed [1+1+1]
cyclotrimerization cascade of acetophenone derivatives 36 under mild conditions for the stereoselective synthesis of cyclopropanes 74 (Scheme [30 ]).[49 ] Various acetophenone derivatives 36 covering an array of functional groups such as halogens, carbonyl, sulfonamide, nitryl
etc. participated in this oxidative annulation affording the corresponding cyclopropanes
74 in modest to good yields. Importantly, heterocycle derivatives such as 2-acetylthiophene
delivered the desired product in 52% yield.
Scheme 30 Cu-catalyzed [1+1+1] cyclotrimerization
On the basis of several control experiments carried out with possible intermediates,
it was established that this intriguing cyclotrimerization proceeds through the following
steps: (i) initial dimerization of ketones to 1,4-diketones (formation of B in Scheme [31 ]), (ii) oxidation of 1,4-diketones to but-2-ene-1,4-diones (formation of F ), and (iii) annulation of but-2-ene-1,4-diones with the third equivalent of acetophenone
(formation of G ). According to the proposed mechanism, the reaction begins with the oxidation of
Cu(I) to a Cu(II) complex by DTBP (Scheme [31 ]). Next, acetophenone 36 is oxidized by the Cu(II) species to radical A through its enol form. Following this, dimerization of A leads to 1,4-ketone B , which through its enol form C is further oxidized by a Cu(II) species to radical D . Radical D then adds on the Cu(II) species to form organocuprate E that subsequently undergoes β-hydride elimination to yield unsaturated diketone F with complete trans selectivity. Addition of radical A to F , followed by trapping with a Cu(II) species affords organocuprate(III) intermediate
H . Subsequently, H is converted into the metallacycle J through ligand exchange of copper in the enol form I . Finally, the desired cyclopropane products 74 are obtained by the reductive elimination of Cu(I), which in turn is re-oxidized
to Cu(II) by DTBP.
Scheme 31 Proposed mechanism for the [1+1+1] cyclotrimerization
5
Conclusion
In this review we have attempted to cover the tremendous advancement made since 2008
in the field of metal-catalyzed radical coupling reactions leading to the α-functionalization
of ketones. The oxidative enolate coupling focusing on the synthesis of 1,4-dicarbonyl
compounds has witnessed the development of novel and efficient synthetic methods,
cross-couplings with equal stoichiometry of reacting partners, and highly diastereoselective
transformations. Besides elegant homo- and heterocoupling of enolates, powerful methods
involving direct C(sp3 )–H functionalization of ketones towards the synthesis of 1,4-dicarbonyl compounds
have emerged.
Importantly, 1,4-dicarbonyl compounds synthesized through these powerful oxidative
coupling methods served as highly useful synthetic precursors for various heterocyclic
and carbocyclic compounds. An efficient and direct access to these important molecular
scaffolds via oxidative homocoupling of ketones or by cross-coupling between ketones
and diverse other coupling partners has recently evolved.
These methodological advances in the field of radical oxidative coupling have enriched
the repertoire of synthetic tools available to synthetic chemists and should pave
the way for future advancement in this important field of research. Despite these
achievements, more challenges remain to be addressed. Future studies should see further
development of direct oxidative cross-coupling reactions that are more predictable
and highly chemoselective. Further applications of radical C–H functionalization in
the context of synthesis of complex molecular scaffolds would broaden the horizon
in this field. There is a broad scope with regard to the development of asymmetric
transformations involving CDC reactions of ketones. We are convinced that this exciting
field of radical coupling reactions will continue to flourish and more general and
useful methodologies involving such couplings will be developed.
