Published as part of the 50 Years SYNTHESIS – Golden Anniversary Issue
Key words difunctionalization - C–H activation - regioselectivity
1
Introduction
Selective construction of properly functionalized target molecules from simple and
readily available starting materials in a small number of steps is an important goal
in synthetic organic chemistry. In addition, the development of sustainable reaction
processes with environmentally friendly and operationally safe technology is another
key issue. If two or more C–X bonds can be formed in a one-pot operation with a single
catalyst, a variety of molecules can be created more efficiently. A frequently utilized
strategy is the multi-component cascade reaction via inter- and intramolecular addition
to unsaturated π-bonds. Various compounds have been synthesized elegantly with the
site- and regioselective installation of appropriate functional groups.[1 ] In past decades, transition-metal-catalyzed C–X bond formation via C–H bond cleavage
has received considerable attention as a straightforward method to modify the structure
and function of organic molecules.[2 ] Because structurally complicated functional molecules are obtained through the activation
of generally unreactive ubiquitous C–H bonds, they are highly useful in view of atom-
and step-economy.
Masahito Murai (left) was born in Okazaki, Aichi, Japan, in 1981. He graduated with a B.Eng. from
Kyoto University, and received his Ph.D. from the same university under the supervision
of Prof. Kouichi Ohe in 2010. During his Ph.D. studies, he joined Prof. David J. Procter’s
group at the University of Manchester for three months. Following postdoctoral work
as a JSPS research fellow at the Tokyo Institute of Technology with Prof. Munetaka
Akita and at the University of California, Santa Barbara with Prof. Craig J. Hawker,
he joined Prof. Takai’s research group at Okayama University as an assistant professor
in 2012. He received the Adeka Award in Synthetic Organic Chemistry, Japan (2013),
and The Chemical Society of Japan Award for Young Chemists (2018). His research has
focused on the design and development of novel catalytic transformations of unsaturated
hydrocarbons and their applications in the synthesis of carbon-based advanced functional
materials.
Kazuhiko Takai (right) was born in Tokyo, Japan, in 1954. He received his B.Eng. and Ph.D. from
Kyoto University under the direction of Prof. Hitosi Nozaki. In 1981, he was appointed
as an assistant professor in Prof. Nozaki’s group at Kyoto University, during which
time he joined Prof. Clayton H. Heathcock’s group at the University of California,
Berkeley as a postdoctoral fellow (1983–1984). In 1994, he moved to Okayama University
as an associate professor, and became a full professor in 1998. He received the Chemical
Society of Japan Award for Young Chemists (1989), the Award of the Society of Synthetic
Organic Chemistry, Japan (2008), and the Chemical Society of Japan Award (2014). He
has developed several synthetic methods using early transition metals such as chromium,
titanium, and tantalum. Current research in his group is aimed toward the use of the
complexes of group 7 metals as catalysts in organic synthesis and C–H activation initiated
by insertion of transition metals into heteroatom–hydrogen bonds.
Even though much success has been achieved in this field, one C–H bond is usually
activated and converted into another functional group in most of the reported transformations.
Simultaneous multiple introduction of different functionalities with the activation
of several C–H bonds existing in one or two molecules remains challenging. The major
difficulty arises from site-selective control of multiple C–H functionalization, and
examples are limited mainly to the introduction of the same functional group.[3 ] This is because catalysts and directing groups that control the regioselectivity
of the reaction are usually highly specific for one reaction, and therefore additional
steps with different catalyst systems are required for the next C–H activation to
install a different functional group.[4 ] In addition, the correct choice of two functionalizing methods, in which the intermediate
in the initial functionalization does not hamper the overall reaction sequence, is
very important. Therefore, the strategy for unsymmetrical multiple functionalization
of C–H bonds in a one-pot operation was limited until the last decade. This short
review focuses on recent advancements in the one-pot reaction involving two sequential
C–H functionalizations with the formation of two different C–X bonds. The graphics
in this short review show the initially installed functional group in red, and the
secondary introduced group in blue, except for Scheme [1 ]. Note that the following three types of transformations, which have already been
highlighted in previous excellent reviews,[5 ] have been omitted: (1) Annulation with multiple bonds existing in one molecule containing
alkynes and alkenes (Scheme [1 ], eqs a and b), (2) Catellani-type coupling reactions using norbornene derivatives
as promoters (eq c), and (3) cross-dehydrogenative coupling of two different (hetero)aromatic
compounds (eq d).
Scheme 1 Catalytic, one-pot, sequential C–H functionalizations not covered in this short review
ortho -Selective Functionalization of Two Different C–H Bonds Relative to the Directing
Group
2
ortho -Selective Functionalization of Two Different C–H Bonds Relative to the Directing
Group
2.1
Unsymmetrical Difunctionalization with the Introduction of Similar Functional Groups
A one-pot method for formation of two different C–X bonds via two C–H bond cleavages
involving rhodium-catalyzed direct alkenylation of a C–H bond of 1-phenylpyrazole
was reported in 2009 by Miura, Satoh and co-workers.[6 ] They demonstrated the one-pot synthesis of unsymmetrically substituted 1,3-dialkenylbenzene
derivatives using a pyrazolyl moiety as the directing group. As a typical example,
1-phenylpyrazole was treated with n -butyl acrylate in the presence of [Cp*RhCl2 ]2 as the catalyst and Cu(OAc)2 ·H2 O as the oxidant, followed by addition of an excess amount of styrene which, after
2–7 hours, furnished the corresponding meta -dialkenylated pyrazolylarene 1a in 74% yield (Scheme [2 ]). Changing the order of addition of the two alkenes did not affect the reactivity.
Olefination with tert -butyl acrylate required post-treatment with a catalytic amount of PdCl2 (PhCN)2 to induce isomerization of the olefinic double bond and furnish the thermodynamically
more stable E -isomer of 1b . As expected, dialkenylation with two equivalents of the same alkenes also occurred
as a side reaction in most cases. However, the current rapid approach to functionalized
meta -phenylene vinylene structures enabled the discovery of luminescence of the derivatives
having a tert -butyl group, such as 1b , in the solid state.
Scheme 2 Rhodium-catalyzed one-pot meta -dialkenylation of 1-phenylpyrazoles
Similar sequential ortho -C–H olefination of a 4-methoxyphenol was demonstrated by Lan, You and co-workers
using a 2-pyridylmethyl group as a removable directing group (Scheme [3 ]).[7 ]
[8 ] After initial reaction with N ,N -dimethylacrylamide for 10 hours, n -butyl acrylate was added and the reaction stirred for a further 10 hours to yield
meta -dialkenylated 2 with an unsymmetrical structure. Both alkenylations presumably proceeded via formation
of an unstable seven-membered ring palladacycle intermediate, and the use of Boc-Val-OH
[N -(tert -butoxycarbonyl)-l -valine][9 ] as a ligand was essential to accelerate the reaction. The 2-pyridylmethyl group
in the product could be removed by BBr3 with the alkenyl double bonds remaining intact. Although the yield was moderate,
the reaction provided an efficient approach to meta -dialkenylphenol derivatives, which are important structural motifs in synthetic organic
chemistry and materials science.
Scheme 3 Palladium-catalyzed one-pot meta -dialkenylation of a 4-methoxyphenol derivative
In 2012, Gevorgyan et al. reported a palladium-catalyzed one-pot sequential acetoxylation
and pivaloxylation of C–H bonds (Scheme [4 ]).[4c ] Using a 2-pyrimidyldiisopropylsilyl group as a directing group,[10 ] orthogonally protected resorcinol derivatives 3 were obtained in good yield. The acetyl group in the products could be selectively
cleaved under basic conditions while keeping the pivaloyl group intact. The 2-pyrimidyldiisopropylsilyl
group could also be removed easily or substituted with various other functional groups.[5i ]
Scheme 4 Palladium-catalyzed, one-pot, sequential acetoxylation and pivaloxylation of C–H
bonds
In 2017, Zhang, Fan and co-workers reported the synthesis of naphthoquinolizinone
derivatives 6 via rhodium-catalyzed carbenoid insertion into two different C(sp2 )–H bonds of 2-aryl-3-cyanopyridine 4 followed by annulation (Scheme [5 ]).[11 ] The protocol provided a facile approach to azapyrene skeletons, which possess potentially
unique biological and optical properties. Several control experiments revealed that
the reaction proceeded via an initial carbene insertion followed by C-cyclization,
and a second carbene insertion followed by N-cyclization (Scheme [5 ]). Although the same functional group was introduced at two ortho -positions initially, the subsequent double cyclization led to the formation of the
unsymmetrical structure.
Scheme 5 Rhodium-catalyzed carbenoid insertion into two different C(sp2 )–H bonds of 2-aryl-3-cyanopyridine 4 and the proposed reaction mechanism
2.2
Unsymmetrical Difunctionalization with the Introduction of Different Functional Groups
As described so far, catalytic unsymmetrical difunctionalization of two C–H bonds
existing in one molecule through three-component coupling reactions (i.e., difunctionalization via two sequential intermolecular bond formations) is
limited, and most methods have been used to incorporate similar functional groups (see Schemes 13, 15, 22 and 30 for exceptions). Heteroatom-containing
directing groups were indispensable for controlling the site selectivity of C–H bond
activation. However, control of the chemoselectivity to achieve multiple functionalization
was difficult, because directing groups are usually highly selective for a certain
specific bond formation.
To overcome this limitation, Sahoo et al., in 2016, used benzoic acid derivatives
having O-tethered double bonds as substrates and demonstrated unsymmetrical difunctionalization
with the introduction of two different functional groups.[12 ] They envisioned a one-pot sequential reaction involving a rapid intramolecular ortho -C–H hydroarylation followed by intermolecular functionalization of a second ortho -C–H bond. The use of a methylphenylsulfoximidoyl (MPS) moiety as a directing group[13 ] and the combination of [RuCl2 (p -cymene)]2 with AgSbF6 as the catalyst were essential to realize the expected transformation. Differently
functionalized dihydrobenzofuran derivatives 7a and 7b were obtained by hydroarylation/amidation cascades with sulfonylazides, and the reaction
with phenyl vinyl sulfone through intra- and intermolecular sequential hydroarylations
introduced an alkyl group at the 5-position leading to 7c (Scheme [6 ]). In contrast, the reaction with ethyl acrylate selectively yielded the alkenylated
product 7d . The substrate scope could be expanded to N-tethered olefins to furnish highly substituted
indoline derivatives 7e and 7f in moderate yields. Because the initial intramolecular cyclization occurred at low
temperature with a high functional group tolerance, the overall reaction could be
performed in a single operation simply by raising the temperature for the second coupling
reaction. The sequential intramolecular hydroarylation with two different double bonds
of alkenes was also demonstrated as an unsymmetrical difunctionalization under mild
conditions (Scheme [6 ], eq 1).
Scheme 6 Ruthenium-catalyzed one-pot hydroarylation–amidation/alkylation/alkenylation of aroylmethylphenyl
sulfoximines
Properly functionalized phenol derivatives are not only common structures observed
in many pharmaceuticals and functional materials but are also useful building blocks
in organic synthesis. However, conventional approaches toward their synthesis often
require multi-step transformations using reactive organolithium reagents and harsh
conditions, which limits the number of allowable functional group. In 2018, Zhou et
al. reported the rhodium-catalyzed sequential ortho -C–H alkylation/amidation of N -phenoxyacetamides 9 leading to unsymmetrically substituted phenol derivatives 10 (Scheme [7 ]).[14 ]
Scheme 7 Rhodium-catalyzed one-pot alkylation/amidation of N -phenoxyacetamides
The acetylamino group worked as an oxidizing directing group,[15 ] which not only facilitated site-selective alkylation with diazomalonate but also
generated an acetylamino group in the migration reaction step without using any oxidants
under mild conditions. Diverse functional groups, such as methoxycarbonyl, chloro,
and cyano groups, were compatible, and even bromo groups tolerated the reaction conditions.
When using phenol derivatives having substituents at meta -positions, alkylation occurred selectively at the sterically less hindered position,
and 1,2,3,4-tetrasubstituted benzenes were formed exclusively as a single product
after the overall reaction.
Several mechanistic studies revealed that the C(sp2 )–H bond cleavage was involved in the rate-determining step, and a shift of an acetylamino
group occurred intramolecularly. Because the use of N -(2-hydroxyphenyl)acetamide as a precursor did not provide the desired product, intermolecular
C–H alkylation with diazo compounds occurred before the intramolecular 1,2-shift of
the acetylamino group (Scheme [8 ]).
Scheme 8 Mechanistic insights
Based on these results, the mechanism shown in Scheme [9 ] was proposed. First, ligand exchange of [Cp*RhCl2 ]2 with CsOAc provided Cp*Rh(OAc)2 (A ), which was then converted into rhodacycle intermediate B by reaction with N -phenoxyacetamide 9 . Coordination of the diazo compound to the rhodium center, followed by 1,2-migratory
insertion of the aryl group provided the six-membered ring intermediate C . Next, Rh(V) nitrenoid intermediate D was formed via oxidative addition of Rh(III) into the N–O bond. Subsequent protonation
leading to acyclic E , and then intramolecular electrophilic nitrenoid addition furnished dearomatized
intermediate F . Finally, product 10 was formed by sequential protonation of F and rearomatization along with the regeneration of A . In contrast to the aforementioned work of Sahoo (see Scheme [6 ]),[12 ] intermolecular C–H functionalization occurred prior to intramolecular C–H functionalization
due to the slow generation of nitrenoid intermediate D .
Scheme 9 Proposed reaction mechanism
This protocol can be also applied to the transformation of biologically active molecules
such as estrone derivatives (Scheme [10 ]). The first alkylation again occurred site selectively at the sterically less hindered
position. This result confirmed that the current unsymmetrical ortho C–H functionalization provided a reliable shortcut to highly substituted phenol derivatives,
which are inaccessible by conventional synthetic methods.
Scheme 10 Transformation of a biologically active estrone derivative
Recently, a similar strategy was described by Song et al. involving a palladium-catalyzed
one-pot alkenylation (Heck reaction)/sulfenylation of aryl thiocarbamates (Scheme
[11 ]).[16 ] For this difunctionalization, intermolecular alkenylation proceeded rapidly during
the slow C–S bond formation by reductive elimination of a CAr –Pd–S species. Diverse tri- or tetrasubstituted benzenes 11 were obtained using a catalytic amount of Pd(OAc)2 and benzoquinone as the oxidant in an acidic medium. Styrene as well as acrylate
esters could be used as coupling partners. When aryl thiocarbamates possessing two
unsymmetrical meta C–H bonds were used, the initial intermolecular alkenylation occurred selectively
at the sterically less hindered position.
Scheme 11 Palladium-catalyzed one-pot alkenylation/sulfenylation of aryl thiocarbamates
The resulting products could be transformed into tetrasubstituted phenol derivatives
via ring opening of the oxathiol-2-one ring triggered by amination or saponification
(Scheme [12 ]). Although the use of an excess amount of the olefin was required to control the
reactivity, excellent functional group compatibility and site selectivity proved the
usefulness of this one-pot difunctionalization protocol.
Scheme 12 Transformation of product 11
2.3
ortho-Selective Unsymmetrical Difunctionalization Promoted by Two Different Directing
Groups Appearing During the Progress of the Reaction
One-pot difunctionalization in a three-component coupling reaction was achieved by
Qian, Dong and co-workers in 2014.[17 ] The rhodacycle intermediate generated from the reaction of N -sulfonyl ketimines 12 and internal alkynes was trapped by different aldehydes leading to polycyclic products
13 (Scheme [13 ]). Functional groups, including iodide, nitro, and alkoxycarbonyl, were all well-tolerated,
and the substrate scope was broad. The addition of di-tert -butyl dicarbonate [(Boc)2 O] was indispensable, with the two-component coupling product 14a being obtained as the major product without (Boc)2 O (Scheme [13 ]). Thus, the reaction mechanism shown in Scheme [14 ] is most plausible, which involves: (1) imino-group-directed ortho -C–H alkenylation leading to seven-membered ring rhodacycle intermediate G , (2) intramolecular cyclization via insertion of the alkenylrhodium species into
the C=N bond, (3) amino-group-assisted C–H activation leading to azarhodacycle H followed by insertion of a formyl group, and (4) final dehydrogenative cyclization
assisted by (Boc)2 O, which promoted the leaving ability of the OH group, leading to 13 . Although directing groups are usually highly specific for a certain C–H bond, they
changed with the progress of the reaction in this difunctionalization.
Scheme 13 Rhodium-catalyzed three-component coupling reaction of N -sulfonyl ketimines, internal alkynes and aldehydes
Scheme 14 Plausible reaction mechanism
Adapting a similar strategy, Sahoo et al. reported unsymmetrical annulation via the
activation of two C(sp2 )–H bonds.[18 ] By controlling the pH of the reaction medium, two C–C and two C–N bonds were formed
efficiently in a single operation. The reaction proceeded with broad substrate scope
and good functional group tolerance, providing structurally complicated spiroisoquinolones
15 from readily accessible starting materials (Scheme [15 ]). Based on the mechanistic studies, the following three key steps were postulated
in the current transformation (Scheme [16 ]): (1) Initial annulation of the proximal C–H bond of the MPS group with alkynes
under acidic conditions, (2) formation of an isoquinolone or pyridone intermediate
along with regeneration of the ruthenium active species; the MPS group acted as an
internal oxidant to promote this regeneration step,[15 ] and (3) the second C–H bond annulation with quinone, which was assisted by the coordination
of a ruthenium complex to the N–H bond of isoquinolone or pyridone, under basic conditions.
Cu(OAc)2 oxidized the Ru(0) species back to the reactive Ru(II) species in the second annulation
step.
Scheme 15 Ruthenium-catalyzed unsymmetrical annulation with alkynes and quinones leading to
spiroisoquinolones
Scheme 16 Stepwise annulation via two different C–H bond activations
A unique skeletal reconstruction of benzyl aryl sulfoxides into dibenzothiophene-1-carbaldehydes
16 through unsymmetrical difunctionalization of two C–H bonds was reported by Anthonchick
in 2011.[19 ] Although the yields were moderate, variously substituted dibenzothiophene derivatives
having unsymmetrical structures were obtained from simple precursors through the formal
abstraction of four hydrogen atoms (Scheme [17 ]). The transformation appears complicated, but the following pathway supported by
several mechanistic studies was proposed (Scheme [18 ]): (1) Formation of cyclic sulfoxide J promoted by sulfoxide-group-assisted regioselective direct arylation of the C–H bond,
(2) Pummerer rearrangement leading to mercaptoaldehyde K , and (3) sulfur-group-directed C–S bond formation. Addition of p -fluoroiodobenzene and AgOAc was crucial for decreasing the catalyst loading of PdCl2 . In the absence of p -fluoroiodobenzene, stoichiometric amounts of a palladium complex were required. This
iodoarene was thought to play a key role in generating mononuclear Pd(IV) species,
which then underwent reductive elimination along with C–H activation to produce palladacycle
I . Interestingly, neither Pummerer rearrangement of the starting benzyl aryl sulfoxides
nor arylation of several palladacycle intermediates with iodoarene was observed. Similar
to the transformations shown in Schemes 13 and 15, two different directing groups
appeared during the progress of the reaction, and promoted the current strictly defined
reaction sequence.
Scheme 17 Palladium-catalyzed regioselective intramolecular arylation and sulfenylation of
C–H bonds leading to dibenzothiophene-1-carbaldehydes
Scheme 18 Plausible reaction mechanism
ortho /meta -Selective C–H Bond Difunctionalization Relative to the Directing Group
3
ortho /meta -Selective C–H Bond Difunctionalization Relative to the Directing Group
In 2017, Li et al. reported a conceptually different one-pot difunctionalization based
on ortho /meta C–H bond cleavage.[20 ]
[21 ] The use of [RuCl2 (p -cymene)]2 without ligands and bases allowed ortho -chlorination and meta -sulfonation of 2-phenoxypyridines 17 with arylsulfonyl chlorides. The typical promoter for meta -sulfonation of 2-phenylpyridines,[22 ] K2 CO3 , did not improve the efficiency of the current ortho /meta -difunctionalization. The choice of solvent appears to be important, and the desired
difunctionalized products 18 were obtained only in xylene or toluene. Although substituents at the meta -position of the 2-pyridyloxy group and strongly electron-withdrawing substituents
shut down the reaction, site-selective incorporation of chloro and sulfonyl groups
was observed in a variety of 2-aryloxypyridines and pyrimidines (Scheme [19 ]). A 2-pyridyl group in the product could be removed to release the free phenolic
hydroxy group by treatment with MeOTf followed by MeONa.
Scheme 19 Ruthenium-catalyzed one-pot ortho -chlorination and meta -sulfonation of 2-phenoxypyri(mi)dines
Insight into the reaction mechanism was obtained from the following reactions. First,
the desired difunctionalized product 18a was obtained from 2-phenoxypyridine 19 having a p -tosyl group at the meta -position, indicating that chlorination occurred after sulfonation (Scheme [20, a ]). Second, the cyclic six-membered ruthenacycle intermediate 20 reacted with p -tosyl chloride to give the expected product 18a , quantitatively (Scheme [20, b ]). Third, the radical scavenger TEMPO completely quenched the reaction (Scheme [20, c ]).
Scheme 20 Mechanistic studies
Supported by the experimental results, a plausible reaction pathway involving complex
20a is shown in Scheme [21 ]. First, the para position of the Ru–C bond of ruthenacycle intermediate 20a , generated via ortho C–H activation of 2-phenoxypyridine 17a , was attacked by p -tosyl chloride to form intermediate L .[22b ] A strong para -directing effect of the Ru–C σ-bond determined the site-selectivity in this step.[22 ] Oxidative addition of p -tosyl chloride gave Ru(IV) intermediate M , which then underwent reductive elimination to provide 18a and ruthenium complex N . Although the details of the regeneration of 20a by the reaction of N with another molecule of 17a was not described, the authors detected (chloromethyl)methylbenzene and p -tolyl-4-methylbenzenesulfonothioate as side products under standard reaction conditions
by GC-MS analysis. Thus, they concluded that p -tosyl chloride acted not only as a sulfonation and chlorination source, but also
as an oxidant to regenerate 20a . Although the reaction efficiency was not high enough for practical use, this work
demonstrated the novel strategy of unsymmetrical difunctionalization with the introduction
of two different functional groups.
Scheme 21 Proposed reaction mechanism [Ru = Ru(p -cymene)]
At about the same time, Ackermann et al. developed a three-component coupling reaction
of 2-aryloxazolines, sec -alkyl halides (2-bromoalkanoates), and aryl halides.[23 ] ortho -Arylation and meta -alkylation occurred efficiently with complete site selectivity in this reaction.
First, they reported that the combination of a ruthenium(II) biscarboxylate complex
[Ru(OCOR)2 (p -cymene)]2 with PPh3 displayed excellent catalytic performance toward alkylation of meta C–H bonds with sec -alkyl halides.[24 ] The yield was reduced to less than 5% using the typical [RuCl2 (p -cymene)]2 as the catalyst. In contrast to Li’s work using 2-phenoxypyridines as substrates
(see Scheme [19 ]), formation of ortho -halogenated products was not observed. Next, the simple addition of aryl bromides
after completion of the initial meta -alkylation was found to provide variously substituted 2-aryloxazolines 21 in good yields. [Ru(OCOMes)2 (p -cymene)]2 was used for aryloxazolines (Scheme [22 ]), while a similar ruthenium complex containing a bulkier adamantyl group substituted
ligand was chosen for other arylheterocycles, such as 1-aryl-1H -pyrazoles and 6-phenyl-7H -purines (Scheme [23 ]).
Scheme 22 Sequential meta -alkylation/ortho -arylation of aryloxazolines
Scheme 23 Sequential meta -alkylation/ortho -arylation of aryl-pyrazoles and -purines
Several control experiments confirmed that the reaction occurred via reversible C–H
bond cleavage exclusively at the ortho -position (Scheme [24, a ]), and the stereochemistry of the sec -alkyl bromide was not preserved during meta -alkylation (Scheme [24, b ]). These observations could be rationalized by considering the mechanism of the typical
ruthenium-catalyzed meta -alkylation, which involved attack of the radical species generated from sec -alkyl halides at the para -position of the Ru–C σ-bond of the ruthenacycle intermediate.[22 ]
Scheme 24 Control experiments
The good reactivity and high functional group tolerance observed in the initial alkylation
allowed sequential ortho /meta -difunctionalization in a single operation simply by raising the temperature for the
second arylation (Scheme [25 ]). Most of the directing groups used in this study could be easily converted into
various carbonyl groups, and the current difunctionalization technique provided a
robust and straightforward approach to highly functionalized benzene derivatives.
Scheme 25 Sequential ortho /meta -difunctionalization in a single operation
Sequential Difunctionalization of Fused Aromatic Compounds and Heterocycles
4
Sequential Difunctionalization of Fused Aromatic Compounds and Heterocycles
Unsymmetrical difunctionalization of fused aromatic compounds, which have multiple
potentially reactive C–H bonds with close bonding energies, is difficult. A unique
example is the catalytic chloroamination of indoles with N -chloro-N ,4-dimethylbenzenesulfonamide (TsMeNCl) reported by Liu et al. in 2011.[25a ]
[26 ] Using a combination of palladium and copper as the catalyst, the difunctionalization
proceeded efficiently under mild conditions to yield 2-amino-3-chloroindoles 23 without producing other regioisomers (Scheme [26 ]). The nature of the substituents on the benzene ring of the indoles affected the
reactivity, with electron-withdrawing groups decreasing the reactivity. Pyrrole also
afforded a chloro-aminated product under the same reaction conditions. Interestingly,
replacing the CuCl complex with Cu(acac)2 /2,2′-bipyridine and decreasing the amount of TsMeNCl (1.8 equiv) gave the 2-aminoindole
instead of the chloro-aminated product. However, no reaction insights gained using
the conditions shown in Scheme [26 ], including the order of functionalization as well as the role of palladium and copper
catalysts, were described. The metal-free chloroamination of indoles with sulfonamides
and NaClO has also been reported.[26b ]
Scheme 26 Palladium/copper-catalyzed site-selective chloroamination of indoles and a pyrrole
One-pot C–H bond difunctionalization of indoles was also achieved using a stoichiometric
amount of copper salts. Nicholas reported the bromoamination of indoles with oxime
esters and CuBr·SMe2 (Scheme [27, a ]).[25c ] Attempted catalytic variants of this reaction using NaBr, LiBr, and
n
Bu4 NBr as the external bromide source failed, instead giving 3-bromo-N -methylindole exclusively.[27 ] Because this brominated indole was obtained as a side product, and not converted
into the expected bromo-aminated product 24 under the conditions shown in Scheme [27, a ], the yield of the difunctionalized products in the current method were moderate
to low. The authors proposed a mechanism involving electrophilic addition of a (AcO)CuIII Br(N=CPh2 ) species at the 3-position of the indole ring followed by installation of a nucleophilic
imino unit at the 2-position prior to reductive elimination of the copper species
to form the C–Br bond. Recently, copper-mediated one-pot iodination and nitration
was demonstrated by Jiang et al. (Scheme [27, b ]).[25d ]
t
BuONO and CuI were used as nitrating and iodinating reagents, respectively. Several
control experiments revealed that iodination proceeded even at room temperature prior
to the nitration, and nitration occurred with NO2 radicals generated from thermal decomposition and oxidation of
t
BuONO. Although the protocol required directing groups to promote nitration at the
2-position, they could be easily cleaved by methylation and alcoholysis.
Scheme 27 (a) One-pot C–H bond difunctionalization of indoles. (b) Copper-mediated one-pot
iodination and nitration of indoles
A rare example of difunctionalization involving C(sp3 )–H bond activation was demonstrated by Baudoin[28 ] Treatment of a 2-chloro-3-alkylthiophene or -furan with aryl bromides resulted in
sequential C(sp2 )–Η and C(sp3 )–H bond arylations with a single palladium catalyst having tricyclopentylphosphine
[P(Cyp)3 ] as a ligand (Scheme [28, a ]). Since 1-chloro-2-alkyl-5-phenylthiophene was obtained as a by-product if the reaction
was quenched before complete substrate conversion, intermolecular C(sp2 )–H arylation occurred before intramolecular C(sp3 )–H arylation. Good to high diastereocontrol was achieved during C(sp3 )–H arylation with the desymmetrization of two isopropyl groups. Intramolecular sequential
arylation of C(sp2 )–Η and C(sp3 )–H bonds was also conducted and revealed that the initial C(sp2 )–H arylation occurred site selectively at a sterically less hindered position (Scheme
[28, b ]).
Scheme 28 (a) Difunctionalization involving C(sp3 )–H bond activation. (b) Intramolecular sequential arylation of C(sp2 )–Η and C(sp3 )–H bonds
In 2018, Murai and Takai developed conceptually different approaches that took advantage
of the high site-selective control observed in the iridium-catalyzed intermolecular
dehydrogenative silylation of aromatic C–H bonds.[29a ]
[b ] They found that sequential treatment of triethylsilane and bis(pinacolato)diboron
with quinoline in the presence of an iridium complex resulted in the site-selective
introduction of both silyl and boryl groups to the quinoline ring to provide 28a (Scheme [29, a ]).[30 ] Control experiments revealed that this difunctionalization occurred via initial
dehydrogenative silylation at the 8-position (Scheme [29, b ]) followed by direct C–H borylation at the 3- and 6-positions of the quinoline ring.[31 ] Excess amounts of triethylsilane, the precatalyst [Ir(OMe)(cod)]2 , and 5,6-dimethyl-1,10-phenanthroline (29 ) were required for the difunctionalization of quinolines having no substituent at
the 2-position due to the competitive formation of very stable iridium-quinoline complexes
in the first silylation step. Introduction of alkyl groups at the 2-position greatly
improved the reaction efficiency, and variously functionalized quinoline and acridine
derivatives 28 were obtained in a one-pot operation (Scheme [30 ]).
Scheme 29 (a) Site-selective introduction of silyl and boryl groups to a quinoline ring. (b)
Control experiments reveal that difunctionalization occurs via initial dehydrogenative
silylation at the 8-position
Scheme 30 Iridium-catalyzed site-selective sequential silylation and borylation of quinoline
and acridine derivatives
In this sequential difunctionalization, silylation proceeded under chelation control
by the nitrogen of the quinoline ring, whereas borylation with additional ligand 29 was accomplished under steric control. Addition of 29 in the first silylation step to prevent chelation gave an inseparable mixture of
silylated quinoline regioisomers. Although both silylation and borylation were promoted
by a single iridium catalyst, the reaction order was very important in controlling
the selectivity. For example, borylation of 2-methylquinoline and 2,8-dimethylquinoline
provided a mixture of mono- and diborylated quinoline derivatives (Scheme [31 ]). Although its exact role was unclear, the silyl group at the 8-position was important
for controlling the site selectivity in the second borylation step.
Scheme 31 Borylation of 2-methylquinoline and 2,8-dimethylquinoline
Electron-rich five-membered ring heteroarenes could also be applied in this sequential
silylation and borylation (Scheme [32 ]). Addition of dtbpy (4,4′-di-tert -butyl-2,2′-bipyridyl) was required for both the first silylation and second borylation
steps of these substrates. A silyl group was introduced at the α-position of these
heterocycles in all cases. Adducts derived from competitive reductive dechlorination
were not observed, and the reaction of the indole did not require protection of the
N–H group.
Scheme 32 Iridium-catalyzed site-selective sequential silylation and borylation of electron-rich
heteroarenes
All the substrates introduced so far contained heteroatoms, which was key to controlling
the site-selectivity of the difunctionalization and increased the efficiency of the
overall multistep reaction sequence. Reports on the unsymmetrical difunctionalization
of pure aromatic hydrocarbons, which requires C–H activation without chelation assistance,
are rare. In 2015, Murai and Takai demonstrated sequential silylation and borylation
of pyrene using a similar strategy to that described above.[29a ] Treatment of triethylsilane in the presence of [Ir(OMe)(cod)]2 and 3,4,7,8-tetramethyl-1,10-phenanthroline followed by addition of bis(pinacolato)diboron
resulted in the selective introduction of both silyl and boryl groups at the 2- and
7-positions of pyrene, respectively, leading to compound 30 (Scheme [33 ]). In this difunctionalization, both silylation and borylation proceeded under steric
control. The resulting adduct 30 could be converted into the donor–acceptor substituted pyrene 31 by an additional two-step transformation.
Scheme 33 Iridium-catalyzed sequential silylation/borylation of pyrene and transformation of
the product
Another example reported by the same research group was the sequential diarylation
of azulene. Treatment with 2-bromothiophene followed by bromobenzene led to unsymmetrically
substituted diarylazulene 32 , albeit in low yield (Scheme [34 ]).[32 ] The fused structure of the cycloheptatrienyl cation and cyclopentadienyl anion can
be drawn as a uniquely polarized resonance of azulene, which might be important to
fix the reactive palladium species near the C–H bonds of the azulene.[33 ] The yield was too low for practical use due to the difficulty of controlling the
reactivity of the initial arylation with 2-bromothiophene. However, this one-pot protocol
could potentially provide arylated azulene conjugates in a single operation, which
is difficult to achieve by the conventional coupling reaction with generally unstable
haloazulene derivatives.
Scheme 34 The sequential diarylation of azulene
5
Summary and Outlook
This short review is intended to attract the reader’s attention and encourage future
progress in the one-pot unsymmetrical difunctionalization of two C–H bonds. Noteworthy
progress has been achieved in the last decade, and unique functionalized molecules
have been constructed via one-pot operations. Although most of the products can be
synthesized by stepwise transformations, the current one-pot protocols allow efficient
shortcuts to many molecular architectures without purification of intermediates and
removal of organic and inorganic wastes. While rhodium- and palladium-based catalysis
was used initially, less expensive metals, such as ruthenium, are becoming more common
these days. Ruthenium catalysis has also enabled site-selective ortho - and meta -difunctionalization relative to the directing groups. Recent sequential silylation
and borylation of fused aromatic compounds has also introduced a new concept of the
initial functionalization creating new reactive sites for the next regioselective
functionalization.
Despite these significant advances, opportunities remain for further exploration in
this field. (1) Some reported protocols required the subsequent addition of reagents
and additives or different reaction conditions for each step. Although automated flow
reaction systems can help to execute these intricate operations, development of a
real ‘one-pot’ protocol allowing addition of all chemicals at the beginning without
further additives or changes in the reaction conditions is desirable. Heterogeneous
solid catalysts having several well-defined, uniform reactive sites may be suitable
for this purpose. (2) Most of the reactions required heteroatom-containing directing
groups to control the site selectivity of the C–H cleavage. Leveraging the C–H functionalization
protocol without the aid of chelation control will expand the scope and applicability
of the current difunctionalization.[2j ] (3) Difunctionalization involving C(sp3 )–H bond activation remains rare. Merging with radical transformations[2p ]
[34 ] should provide several clues, although regioselective control of the C–H cleavage
may be a key issue. (4) Application to the synthesis and screening of novel biologically
active molecules and functional materials is currently limited. Although the correct
design of precursors and optimization of the reaction order and conditions is required,
the current protocol can provide rapid access to a library of target molecules with
structural and functional diversity. The use of earth-abundant metal-based catalysts,
such as manganese, iron, cobalt, nickel and copper complexes, will also improve the
practicality of the difunctionalization protocol.[2p,35 ] This novel concept will find widespread application, especially in the field of
pharmaceutical chemistry.[36 ] Further synthetic potential is anticipated not only in academia but also in industry.
Finally, although this short review is as comprehensive as possible, it may not cover
all relevant examples, as some of them may have been incorporated into the literature
without the key words of ‘difunctionalization’, etc. Representative examples are highlighted,
and any oversights are unintentional.
