Transition metal-free direct dehydrogenative arylation of activated C(sp3)-H bonds: Synthetic ambit and DFT reactivity predictions

Article abstract of DOI:10.1039/c8sc02758g

A transition metal-free dehydrogenative method for the direct mono-arylation of a wide range of activated C(sp³)-H bonds has been developed. This operationally simple and environmentally friendly aerobic arylation uses tert-BuOK as the base and nitroarenes as electrophiles to prepare up to gram quantities of structurally diverse sets (>60 examples) of α-arylated esters, amides, nitriles, sulfones and triaryl methanes. DFT calculations provided a predictive model, which states that substrates containing a C(sp³)-H bond with a sufficiently low pK_a value should readily undergo arylation. The DFT prediction was confirmed through experimental testing of nearly a dozen substrates containing activated C(sp³)-H bonds. This arylation method was also used in a one-pot protocol to synthesize over twenty compounds containing all-carbon quaternary centers.

Full text of DOI:10.1039/c8sc02758g

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DOI: 10.1039/C8SC02758G
Journal Name
ARTICLE
Transition Metal-Free Direct Dehydrogenative Arylation of
Activated C(sp3)-H Bonds: Synthetic Ambit and DFT Reactivity
Predictions†
Received 00th January 20xx,
Accepted 00th January 20xx
Kaitlyn Lovato,b Lirong Guo,a Qing-Long Xu,c Fengting Liu,a Muhammed Yousufuddin,d
Daniel H. Ess,*e László Kürti,*b and Hongyin Gao*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
A transition metal-free dehydrogenative method for the direct mono-arylation of a wide range of activated C(sp3)–H bonds
has been developed.This operationally simple and environmentally friendly aerobic arylation uses tert-BuOK as the base and
nitroarenes as electrophiles to prepare up to gram quantities of structurally diverse sets (>60 examples) of α-arylated esters,
amides, nitriles, sulfones and triaryl methanes. DFT calculations provided a predictive model, which states that substrates
containing a C(sp3)–H bond with a sufficiently low pKa value should readily undergo arylation. The DFT prediction was
confirmed through experimental testing of nearly a dozen substrates containing activated C(sp3)–H bonds. This arylation
method was also used in a one-pot protocol to synthesize over twenty compounds containing all-carbon quaternary centers.
Introduction
α-Arylated carbonyl derivatives and triaryl methanes are
versatile structural motifs present in a large number of natural
products and active pharmaceutical ingredients.1 These motifs
have also been identified as important intermediates for the
preparation of substituted heterocycles.2 Given their
importance, it is not surprising that several synthetic methods
have been developed to access these valuable building blocks.
Over the past two decades, the transition metal-catalyzed
α-arylation of activated C(sp3)–H bonds has become a robust
strategy for the construction of sp3−sp2 carbon-carbon bonds
(Scheme 1).3 One prominent example is the palladium-
catalyzed α-arylation of esters and nitriles first reported by
Hartwig and Buchwald (Scheme 1, A
).4,5 Hartwig improved these
α-arylation reactions by utilizing zinc enolates,6 α-silyl nitriles,
and zinc cyanoalkyls7 as enolate precursors, thus making this
transformation feasible under less basic conditions. Similar
transition metal-catalyzed α-arylation conditions have also
a.Ministry of Education Key Laboratory of Colloid and Interface Chemistry, School of
Chemistry and Chemical Engineering, Shandong University Ji’nan 250100 (China).
E-mail: hygao@sdu.edu.cn
b.Department of Chemistry, Rice University, BioScience Research Collaborative,
Houston, Texas, 77005, United States. E-mail: kurti.laszlo@rice.edu
c. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease and State
Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjia
Xiang, Nanjing 210009 (China).
d.Life and Health Sciences Department, The University of North Texas at Dallas,
Dallas, Texas 76016, United States
e. Department of Chemistry and Biochemistry, Brigham Young University, Provo,
Utah 84602, United States E-mail: dhe@chem.byu.edu
†Electronic Supplementary Information (ESI) available: Complete experimental and
computational results, procedures and characterization including 1H and 13C spectra
and X-ray crystallographic data are available. For ESI and crystallographic data in CIF
format see DOI: 10.1039/x0xx00000x
Scheme 1 Transition metal-catalyzed and transition metal-free arylations of
activated C(sp3)-H bonds.
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been reported by Hartwig et al. for amide substrates.8 In
addition to these methods, several other transition metal-
catalyzed α-arylation conditions have emerged over the past
decade.9,10 Although transition metal-catalyzed α-arylations
are widely used, they still suffer from a number of drawbacks,
including; (1) the need for expensive catalysts, ligands and
additives, (2) the use of high reaction temperatures and (3) sub-
optimal functional group tolerance (e.g., halogens). Moreover,
the reactions generate toxic heavy metal waste and also face a
limited availability of pre-functionalized coupling partners.
Because of these drawbacks, the development of practical
transition metal-free approaches is highly desirable.
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DOI: 10.1039/C8SC02758G
To date, several transition metal-free methods have been
developed to obtain α-arylated carbonyls and their derivatives,
including: (a) the arylation of activated C(sp3)-H bonds via
vicarious nucleophilic substitution (VNS, Scheme 1,
B
),11 (b)
oxidative nucleophilic substitution of hydrogen (ONSH, Scheme
1,
C
),12 (c) a recently developed deaminative arylation of α-
13
aminoesters and α-aminoacetonitriles (Scheme 1,
D
)
and (d)
the coupling of arylaectates with nitroarenes to produce diaryl
ketones14. However, these methods still possess various
drawbacks. From a practical standpoint, VNS requires leaving
groups (e.g. halogens) installed in the α-position of the
carbanion
precursors.
Additionally,
ONSH
requires
Scheme 2 Proposed mechanism for the arylation of ketones with nitroarenes under basic
conditions supported by DFT calculations.
stoichiometric amounts of harsh oxidizing agents (e.g. KMnO4,
DMDO and DDQ) as well as cryogenic conditions (e.g. below -40
°C, in liquid ammonia)15. These conditions result in sub-optimal
functional group tolerance and limited structural diversity of
the obtained products.
Table 1 Base, solvent and nitroarene coupling partner optimization studies for the α-
arylation of methyl 2-phenylacetate with nitrobenzene.
The work presented herein builds on the transition metal-
free, direct and general mono-α-arylation of ketones developed
by our group in 2013 (Scheme 1, E)
16, which doesn’t require
substrates with a built-in leaving group, low temperatures or
harsh external oxidants. For this transformation, density
functional theory (DFT) calculations proposed and experiments
supported a novel mechanistic pathway (Scheme 2). In this
pathway the enolate first adds to the nitroarene. Subsequent
O2-induced hydrogen atom abstraction leads to oxidation via
air, which is then followed by radical combination and
rearomatization. Given the fact that O2 is a mild, abundant and
environmentally friendly oxidant, we became intrigued by the
possibility that this mechanism could be extended to a variety
of other activated C(sp3)–H bonds.
In this manuscript, we describe extensive synthetic efforts
and a DFT-based reactivity model for this transition metal-free
direct arylation of activated C(sp3)–H bonds. Through this work,
we aim to provide a general and operationally simple arylation
method and also a description of the reactivity trends in
transformations of this type.
Entrya 2 equiv
Base (equiv)
Solvent
DMSO
Time (h)
yield (%)b
1
2
3
4
5
6
7
8
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
1.2
1.5
3.0
t-BuOK (1.2)
t-BuONa (1.2) DMSO
t-BuOLi (1.2)
NaOH (1.2)
NaH (1.2)
t-BuOK (1.5)
t-BuOK (2.0)
t-BuOK (2.5)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
t-BuOK (2.0)
0.5
0.5
0.5
12
30
25
16
<5
<5
40
53
54
28
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
12
0.5
0.5
0.5
0.5
0.5
0.5
12
9
10
11
12
13
14
15
16
17
DMA
NMP
<5
<5
Dioxane
CF3CH2OH
DMSO
DMSO
DMSO
DMSO
N.R.
N.R.
26c
24c
25c
51
12
0.5
0.5
0.5
0.5
Results and discussion
We began our synthetic arylation studies using methyl 2-
aReaction conditions: 1 (1.0 mmol), 2 (1.0-3.0 equiv), base (1.2-2.5 equiv), solvent (5 mL),
open flask, room temperature. Isolated yield after column chromatography. Yield
calculated from crude NMR spectra using dibromomethane as an internal standard.
b
c
phenylacetate (1) and nitrobenzene (2) as substrates (Table 1).
Screening a series of bases in DMSO indicated that t-BuOK was
most effective at room temperature (Table 1, entries 1-5).
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Scheme 3 α-Arylation of
1
with various nitroarenes.a
aReaction conditions:
1
(1.0 mmol), 2a-m (2.0 equiv), t-BuOK (2.0 equiv), DMSO (5
mL), open flask, room temperature, 30 minutes.
Screening for the optimal amounts of base (Table 1, entries 6-8)
and nitrobenzene coupling partner (Table 1, entries 14-17)
revealed that 2.0 equivalents of t-BuOK and 2.0 equivalents of
nitrobenzene was sufficient to afford a synthetically useful
isolated yield of the α-arylated product. A solvent screen (Table
1, entries 9-13) showed DMSO to be the best solvent for this
transformation.
With the optimized reaction conditions in hand, we next
Scheme 4 α-arylation of various ester substrates with nitroarenes.a
investigated the scope of nitroarene coupling partners (2a
-m)
aReaction conditions: 1a-t (1.0 mmol), 2, 2a, 2j (2.0 equiv), t-BuOK (2.0 equiv),
DMSO (5 mL), open flask, room temperature, 30 minutes.
capable of undergoing this mono -arylation (Scheme 3). It was
found that nitroarenes containing an electron-withdrawing

group in the ortho position successfully reacted with methyl
phenylacetate (1) to give the desired arylated products 3a-3e in complete regioselectivity (Scheme 3, entries 9-12). It is worth
moderate to good yields (Scheme 3, entries 1-6). Nitroarenes noting that the bromo-substituted nitroarene (Scheme 3, entry
with heteroatoms in the ortho position also acted as efficient 11) was an effective arylating agent, which highlights the
arylating agents, leading to the corresponding products 3f and complementarity of this protocol to traditional transition metal-
3g in 62% and 70% yields, respectively (Scheme 3, entries 7 and catalyzed cross-coupling reactions. Additionally, the
8).
halogenated products can be further functionalized using a
Meta-substituted nitroarenes were also suitable coupling myriad of available C-C and C-X bond-forming
partners for this transformation and afforded the para transformations.17
substituted products 3h
-
3k in moderate to good yields and with
The scope of the nitroarene coupling partners could also be
extended to fused systems, which were also exclusively arylated
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para to the nitro group (Scheme 3, entries 13 and 14). Gram- (i.e. not nitroarenes) were tested as substratVeiesw. AIrnticletOhnelisnee
DOI: 10.1039/C8SC02758G
scale experiments have been carried out with 2a and 2h, which reactions, the arylated products were not observed and the
afforded the arylated products 3a and 3h in good isolated yields electrophilic substrates were recovered (see S27).
(Scheme 3, entries 1 and 9).
Next, the arylation of twenty ring-substituted 2-
Greater than a dozen successful electrophilic coupling phenylacetates was evaluated (Scheme 4) with three
partners were identified, however several substrate classes nitroarenes. Both electron-donating and electron-withdrawing
were unable to produce the desired arylated products. For substituents were tolerated on the aryl rings. The α-arylated
example, it was observed that the SNAr pathway, not the products were obtained with high chemo- and regioselectivity
dehydrogenative arylation pathway, is the major pathway when (Scheme 4, entries 15-34). For arylated product 4g the structure
the nitroarene coupling partner possesses a halogen atom in was confirmed using single-crystal X-ray crystallography
the ortho- or para- position (see S25). Interestingly, it was (Scheme 4, entry 24). More complex coupling partners such as
previously found that ketone enolates do not undergo SNAr with 2-(naphthalen-2-yl)acetate (1p), isochroman-3-one (1q), 3-
halogenated nitroarenes.16 When there is a para-non-halogen phenylpropanoates (1r
atom in the nitroarene, dehydrogenative arylation at the ortho- also able to undergo the present transformation and produced
position occurs in some cases but because other SNAr-type the corresponding –arylated products 4p 4t (Scheme 4,
reaction pathways are also possible these reactions have low entries 35-40) in fair to moderate yields. In general, the
, 1s) and methyl propionate (1t) were
α
-
yields (see S26). In addition, other electron deficient arenes
reactions of 2-cyanonitrobenzene (2a) with 2-phenylacetates
1a-t) gave higher yields than the reactions of unsubstituted
nitrobenzene ( ) with the same 2-phenylacetates. This is
presumably due to the stronger electrophilicity of
cyanonitrobenzene (Scheme 4, entries 16 vs 17 18 vs 19
21 26 vs 27, 28 vs 29, and 35 vs 36).
In order to extend this transition metal-free direct
(
2
2-
20 vs
,
,
,
dehydrogenative arylation to other types of substrates, we
examined four new classes of activated C(sp3)–H bonds in
amides, nitriles, sulfones and diaryl methanes. We were pleased
to find that not only 2-arylacetamides but also oxindoles were
suitable substrates for this transformation (Scheme 5, entries
41-46). It was determined that this synthetic protocol could also
be applied to the α–arylation of 2-aryl acetonitriles (Scheme 5,
entries 47-54). The presence of halogenated arene rings in
these substrates (Scheme 5, entries 49-52) further implies that
this arylation method is complementary to the currently used
transition metal-catalyzed methods for the arylation of nitriles.
The dehydrogenative arylation of sulfones, benzyl sulfones and
benzyl pyridine was also possible and gave the desired diaryl
sulfones and triarylmethane products in synthetically useful
isolated yields (Scheme 5, entries 55-59).
Simultaneous to synthetic studies, we undertook DFT
calculations to compare the reactivity of esters, amides and
nitriles to the previously reported ketones.16 We also aimed to
create a simple predictive model for the arylation of unexplored
compound classes. We began by calculating the arylation
reaction pathway outlined by our previous DFT calculations.16
This involved calculating the C-H oxidation reaction between
methoxy-phenylethenolate (enolate 1) and nitrobenzene using
M06-2X/def2-TZVPD//M06-2X/631+G** level of theory with
the continuum SMD solvent model for DMSO (see Scheme 6
energy surface, the Z-enolate conformation is favored
throughout the pathway).18 Enolate 1 and nitrobenzene can
initially form a slightly exothermic, but endergonic, charge-
transfer complex due to the ability of t-BuOK to act as an
19
electron-transfer agent (see S66). However, we believe that
Scheme 5 Arylation of various activated C(sp3)-H bonds with nitroarenes.a
an electron-transfer (ET)/radical recombination pathway for C-
C bond-formation is not as viable because the enthalpy for
enolate ET to nitrobenzene requires 19 kcal/mol.
aReaction conditions: 5a-m (1.0 mmol), 2, 2a, 2g, 2j (2.0 equiv), t-BuOK (2.0 equiv),
DMSO (5 mL), open flask, room temperature, 30 minutes.
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In the proposed C-H oxidation pathway, enolate 1 adds to product. It has also been proposed by Makosza that INT1 could
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12b
nitrobenzene in the para-position to give INT1 (Scheme 6). be deprotonated to generate a dianionDpOrIi:o1r0.1t0o39o/xCi8dSaCt0io2n75.8G
Then, O2-induced C-H oxidation of INT1 occurs through TS2 (the However, our calculations suggest that proton transfer to either

H‡ for TS2 is 11 kcal/mol). This oxidation leads to an aryl anion tert-butoxide (
radical (INT2) as well as an HOO
the oxidized intermediate INT3. The loss of the hydrogen several off-pathway reactions including addition to the ortho-

H >35 kcal/mol) or DMSO is highly endothermic.

radical that combine to form In addition to the C-H oxidation pathway, we also examined
peroxide anion by TS3 gives the final arylation product.
position. After the formation of enolate 1, the enthalpy barrier
(
H‡) for C-C bond-formation at the para-position is 7 kcal/mol
Since our initial discovery and proposal of this O2-mediated
oxidation pathway, it was proposed by Kumar that DMSO serves by TS1 relative to reactants to give INT1. For ketone arylation,
as the major oxidant in a similar cross coupling of aryl we previously showed that there is a similar barrier for C-C
acetamides with nitroarenes.20 This proposal was made based formation at the ortho-position to the nitro group.16 While an
on the GC and NMR detection of dimethyl sulfide (DMS) in a ortho addition intermediate is likely in equilibrium with INT1
,
crude reaction mixture. This proposal is interesting because the we have found that there is generally a higher barrier for its
two-electron reduction potential for DMSO has been estimated subsequent C-H oxidation.16 Therefore, the ortho- enolate
to be ~0.2 V21 while the two-electron reduction potential for O2 addition is reversible and should be considered a minor, non-
is 0.7 V. Therefore, we examined the thermodynamics for the productive, off-reaction-pathway intermediate and not a key
oxidation of INT1 by DMSO. Hydride transfer from INT1 to intermediate.22 Because the enolate-nitrobenzene addition
DMSO to give dimethyl sulfide, hydroxide and the arylated intermediates prior to C-H oxidation are endergonic it is also
product is slightly endothermic by ~2 kcal/mol. Unfortunately, unlikely that the formation of this off-pathway ortho-addition
extensive searching of the potential energy surface did not lead (and ipso-addition) intermediate greatly impacts reaction rates.
to location of a hydride transfer or hydrogen atom transfer Similarly, we also located addition intermediates between tert-
transition state between INT1 and DMSO. Because our butoxide and nitrobenzene, which are also off-pathway and
calculations could not locate a kinetic barrier for INT1 oxidation non-productive.
by DMSO, we also decided to experimentally examine this
oxidation possibility. We conducted a crude NMR study of the
reaction of methyl 2-phenylacetate
(
1
)
with 2-
cyanonitrobenzene (2a) under our standard conditions (see
S43). While we did observe some dimethyl sulfide in the crude
reaction mixture after 30 minutes, it was in a small 1:7 ratio of
DMS: arylated product (3a). This result does not support DMSO
acting as the major (i.e. stoichiometric) oxidant. Additionally,
experiments without exposure to air result in a massively
diminished yield of arylated
Scheme 7 Predicting the success of the arylation reaction based on the pKa value of the
substrate’s activated C(sp3)-H bond.a
aReaction conditions: 7a-i (1.0 mmol), 2 (2.0 equiv), t-BuOK (2.0 equiv), DMSO (5 mL),
open flask, room temperature, 30 minutes. bIsolated yield after column chromatography.
Scheme 6 Ester arylation pathway examined by DFT calculations to compare reactivity
with ketones. Enthalpies include SMD estimate of (Gsolv).
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In order to understand the reactivity trends for these types substrate 7e, which has a C(sp3)–H pKa value of 27.V6ie2w8 pArrtioclde uOcnleinde
of reactions, we compared the barriers of the arylations of other a minimal yield of arylated product 8a. IDtOisI: i1m0.1p0o3r9t/aCn8tSCto02n75o8tGe
activated C(sp3)-H bond substrates. Overall, the barriers for that the reaction conditions were not optimized for compounds
ester arylations are either equal to or lower than the barriers 8a
for the ketone arylations we previously reported.16 We also screens, these yields can presumably be improved.
calculated enolate addition/O2-mediated C-H oxidation for the Experimentally, we examined the lower pKa limit for viable
aminophenylethenolate (Scheme 5, 5a and arylation substrates, which allowed us to determine an optimal
-8c, but it is clear that with a proper solvent and temperature
)
cyano(phenyl)methanide (Scheme 5, 5d) anions. These enolates C(sp3)–H bond pKa range for suitable arylation substrates. The
have enthalpy barriers within ~2-3 kcal/mol of the ester and testing of substrates 7h and 7i, which had C(sp3)–H pKa values
ketone arylations. For example, the
between aminophenylethenolate (Scheme 5, 5a
nitrobenzene ( ) is 5 kcal/mol. We then examined the barriers our experimental results, we determined that an activated

H‡ for C-C bond-formation of 14.2 and 12.2, respectively,24,29 allowed us to determine the
and lower limit of the optimal C(sp3)–H bond pKa range. Based on
)
2
for arylation of (methylsulfonyl)benzene (Scheme 7, 7d) and C(sp3)-H bond with a pKa value less than 28 and greater than 16
(nitromethyl)benzene (Scheme 7, 7i), both of which did not should successfully participate in this arylation process.
undergo arylation with nitrobenzene. In these cases, enolate Presumably, substrates with pKa values lower than 16 form a
addition has 
H‡ = 12 kcal/mol for C-C bond-formation. While highly stabilized enolate – apparently this stabilization impedes
this is ~5 kcal/mol higher than ester enolate addition, the the addition to the nitroarene electrophile and thus limits
barriers are low enough to suggest that if the enolate is formed, arylated product formation.
arylation would likely proceed. This suggested to us that
This optimal pKa range establishes a guide for the potential
unsuccessful substrates might result from thermodynamic substrate scope of this reaction. This guide can be used to
inaccessibility of the enolate rather than failure of the addition identify substrate classes that are likely to produce the
and/or oxidation reaction steps. This is consistent with the corresponding arylated products without committing valuable
report by Xiao that showed a kinetic isotope effect value of ~6 resources and time on substrates that are unlikely to undergo
for the methyl C-H bonds for arylation of 2-methylazaarenes.23 this transformation.
Therefore, we estimated the pKa values of reagents that did not
Naturally, we also explored the preparation of compounds
undergo arylation. For example, we estimated the pKa of containing all-carbon quaternary centers using our direct
α
–
(methylsulfonyl)benzene (Scheme 7, 7d) relative to N,N- arylation protocol (Scheme 8). Initially we tried to form the
dimethyl-2-phenylacetamide (Scheme 5, 5a, pKa value of ~26) highly substituted products via a two-step process. Accordingly,
and determined an experimental pKa value of 30. benzyl bromide was added to methyl 2-phenylacetate (
Computationally we found that, in general, substrates that form the alkylated derivative ( was purified via
).30 Compound
underwent successful arylation had pKa values less than 27. column chromatography and then subjected to our –arylation
1) to
9
9
α
Based on this possible pKa-predictor, we experimentally conditions, which furnished the desired product 10 in a
examined a wide variety of substrates with activated C(sp3)–H moderate yield (Scheme 8, Method A).
bonds (Scheme 7). Indeed, experiments determined that
The low yield and the need for multiple purification steps
substrates which have pKa values greater than 2724,25,26,27 (i.e. compelled us to pursue the preparation of the all carbon
7a-7d) do not produce the corresponding α-arylated products, quaternary center-containing products in a one-pot fashion and
while substrates with pKa values less than 2727 (i.e. 7f and 7g), without the use of a pre-functionalized starting material
were successfully arylated to afford products 8b and 8c. We had (Scheme 8, Method B). We found that subjecting methyl
to establish a new pKa threshold value of 28 due to the fact that 2-phenylacetate (1) to our optimized α–arylation conditions,
followed by the addition of benzyl bromide to the same pot, was
able to produce the highly-substituted product 12u in a
significantly higher yield compared to method A
.
Encouraged by this result we tested a series of electrophiles,
including allylbromide, propargyl bromide, benzyl bromide and
iodomethane. It was found that these electrophiles could be
efficiently attached to the α-position of the arylated substrates
via this one-pot process (Scheme 9, entries 65-88).
To further show the synthetic utility of these arylated
products, we have demonstrated that these compounds could
be transformed into atypical heterocyclic motifs (Scheme 10).
For example, compound 3d could be rapidly converted to an
unusually substituted carbazole (13) using PhMgBr, while the
methyl ester functionality remained intact (Scheme 10,
31
Equation (1)
)
Additionally, compound 12a could be
structurally complex
Scheme 8 Different routes for the synthesis of compounds featuring all carbon
transformed, in two steps into
a
quaternary centers.
tetrahydrofuran (15) which features an all carbon quaternary
center (Scheme 10, (2)).32
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Scheme 10 Synthetic utility of α–arylated products 3d and 12a for the preparation of
heterocycles.
Conclusions
In conclusion, we have developed a direct and general
mono-arylation of activated C(sp3)–H bonds with nitroarenes
under transition metal-free conditions. This environmentally
friendly aerobic arylation method is capable of delivering up to
gram quantities of a wide variety of arylated esters, amides,
nitriles, sulfones as well as triaryl methanes. DFT calculations
provided a reactivity guide for the identification of suitable
arylation substrates. This predictive guide states that C(sp3)-H
bonds within the optimal pKa range of 16 to 28 will readily
undergo arylation. Our studies have confirmed the robustness
of this reactivity guide. These optimized arylation conditions
can also be employed in the one-pot synthesis of a diverse
collection of compounds featuring all-carbon quaternary
centers. Finally, the arylated products can be further
functionalized and used as valuable starting materials in the
synthesis of complex heterocycles.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
H. Gao gratefully acknowledges the generous financial support
of Shandong University, the National Natural Science
Foundation of China (21702122) and the Natural Science
Foundation of Shandong Province (ZR2017MB002). L.K.
gratefully acknowledges the generous financial support of Rice
University, the National Institutes of Health (R01 GM-114609-
01), the National Science Foundation (CAREER: SusChEM CHE-
1546097), the Robert A. Welch Foundation (grant C-1764),
Amgen (2014 Young Investigators’ Award for L.K.), and Biotage
(2015 Young Principal Investigator Award). D.H.E. thanks BYU
and the Fulton Supercomputing Lab. K.L. acknowledges that this
material is based upon work supported by the National Science
Foundation Graduate Research Fellowship under Grant No.
(DGE# 1450681).
Scheme 9 Preparation of all-carbon quaternary center containing compounds using the
one-pot α-arylation/alkylation process.a
aReaction conditions: 1. 1, 5c-f, 5h, 5i, 11a, 11b (2.0 mmol), 2, 2a, 2i, 2j (2.0 equiv),
t-BuOK (2.0 equiv), DMSO (10 mL), open flask, room temperature, 30 minutes; 2.
Electrophiles (2.0 equiv), room temperature, 12 h.
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ARTICLE
Journal Name
Makosza and K. Wojciechowski, Chem. ReVvi.e,w2A0rt0ic4le,O1n0lin4e,
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DOI: 10.1039/C8SC02758G
A direct and general mono-arylation of activated C(sp3)–H bonds with nitroarenes under transition
metal-free conditions has been developed.

Chemical Science
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DOI: 10.1039/C8SC02758G