Aerobic, transition-metal-free, direct, and regiospecific mono-α-arylation of ketones: Synthesis and mechanism by DFT calculations

Article abstract of DOI:10.1021/ja4074563

We disclose a facile, aerobic, transition-metal-free, direct, and regiospecific mono-α-arylation of ketones to yield aryl benzyl and (cyclo)alkyl benzyl ketones with substitution patterns that are currently inaccessible or challenging to prepare using conventional methods. The transformation is operationally simple, scalable, and environmentally friendly. There is no need for pre-functionalization (i.e., α-halogenation or silyl enol ether formation) or the use of specialized arylating agents (i.e., diaryliodonium salts). DFT calculations suggest that the in situ-generated enolate undergoes direct C-C bond formation with the nitroarene followed by regioselective O₂-mediated C-H oxidation.

Full text of DOI:10.1021/ja4074563

Communication
pubs.acs.org/JACS
Aerobic, Transition-Metal-Free, Direct, and Regiospecific Mono-α-
arylation of Ketones: Synthesis and Mechanism by DFT Calculations
Qing-Long Xu,† Hongyin Gao,† Muhammed Yousufuddin,§ Daniel H. Ess,*,‡ and Laszlo Kurti*,†
́
́
̈
†Division of Chemistry, Department of Biochemistry, UT Southwestern Medical Center, Dallas, Texas 75390, United States
§Center for Nanostructured Materials, The University of Texas at Arlington, Arlington, Texas 76019, United States
‡Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah 84602, United States
S
* Supporting Information
ABSTRACT: We disclose a facile, aerobic, transition-
metal-free, direct, and regiospecific mono-α-arylation of
ketones to yield aryl benzyl and (cyclo)alkyl benzyl
ketones with substitution patterns that are currently
inaccessible or challenging to prepare using conventional
methods. The transformation is operationally simple,
scalable, and environmentally friendly. There is no need
for pre-functionalization (i.e., α-halogenation or silyl enol
ether formation) or the use of specialized arylating agents
(i.e., diaryliodonium salts). DFT calculations suggest that
the in situ-generated enolate undergoes direct C−C bond
formation with the nitroarene followed by regioselective
O2-mediated C−H oxidation.
Figure 1. A sampling of methods for the TM-free synthesis of α-arylated
ketones. Our direct and regiospecific mono-α-arylation process that
delivers structurally diverse ketones is highlighted.
he α-arylated carbonyl structural motif appears in a large
number of biologically active natural products as well as in
T
active pharmaceutical ingredients (APIs). α-Arylated carbonyl
compounds also often serve as key intermediates for the
synthesis of substituted heterocycles such as indoles, furans,
imidazoles, oxazoles, and pyrazoles. Thus, it is not surprising that
the selective installation of an aryl group in the α-position of a
carbonyl group has received considerable attention from the
synthetic community over the past 40 years.1 While the
formation of C(sp3)−C(sp3) bonds at the α-position of
electron-withdrawing groups is now considered routine,2 the
direct installation of C(sp3)−C(sp2) bonds has proven to be far
more challenging. The efficient transition-metal (TM)-catalyzed
α-arylation of ketone enolates with aryl halides and pseudo-
halides, did not emerge until the first reports by Kuwajima,3
Buchwald, and Hartwig,4 in the early 1980s and late 1990s.
Today, enolates derived from other electron-withdrawing
functional groupsaldehydes, esters, amides, nitriles, and
iminesare also efficiently arylated, even in an enantioselective
fashion, using TM catalysis.5 Several TM-free α-arylation
processes of enolates and enolate equivalents have been also
developed (see Figure 1 for a sampling of previous work): (i)
SNAr reaction with highly activated aryl halides;6 (ii) addition to
electron-deficient arenes, followed by oxidation (Figure 1A);7
(iii) addition of enolates derived from α-halogenated carbonyls
to heterocycles and various electron-deficient arenes via vicarious
nucleophilic substitution (VNS, Figure 1B);8 (iv) reaction with
aromatic iodine(III) derivatives (Figure 1C);9 (v) reaction with
aromatic Bi(V) and Pb(IV) derivatives;10 (vi) reaction with
benzynes;11 (vii) reaction with aryl diazonium salts mediated by
base or visible light;12 (viii) organocatalytic enantioselective
approaches that utilize various electrophilic arylating agents;13
and (ix) miscellaneous other methods14 including addition of
triarylaluminum reagents to N-alkoxyenamines14d and reaction
of activated sulfoxides14c with β-keto esters.
Although TM-catalyzed α-arylations are currently the most
widely used, they suffer a number of drawbacks, such as use of
expensive ligands and catalyst, use of a variety of additives, need
to employ harsh conditions (e.g., elevated temperatures for
extended periods of time), and generation of a toxic waste of
heavy metals that is expensive to remove, especially in
production of APIs, in which residual metal contamination
must meet stringent specifications.15 On the other hand, current
TM-free α-arylation processes are also far from being ideal since
the carbonyl compounds often require pre-functionalization
(e.g., formation of enol ethers and enol carboxylates as well as α-
halogenated or α-alkoxy derivatives) and the arylating agents are
prepared via multi-step processes.
There is a need for the development of TM-free direct
arylation16 reactions that are operationally simple, utilize readily
available and inexpensive starting materials, achieve C−C bond
formation with high regioselectivity, build molecular complexity
rapidly (i.e., in one-pot), and complement existing methods by
allowing the preparation of currently inaccessible compounds.
Received: July 19, 2013
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
2) led to no reaction (i.e., recovered 6), while ethereal solvents
(entries 3 and 4) yielded complex mixtures.
Scheme 1. Preliminary Direct α-Arylation Results
Screening various organic (TMG, DBU) and inorganic bases
(t-BuONa, NaOH, NaH, t-BuOLi, KOH) in DMSO indicated
that organic bases are ineffective even at elevated temperatures
(80 °C), while sodium salts gave the best product yields. t-
BuONa gave the highest yield of 7 (68%, 30 min).18 Thus we
selected t-BuONa as our preferred base and DMSO as the
preferred solvent, and set out to find the optimum number of
equivalents of base and nitroarene reaction partner that would
furnish the maximum yield of the α-arylated product (see SI).
These studies showed that the amount of 2a could be reduced
from 3 to 2 equiv without any effect on the isolated yield of 7.
Further decreasing the stoichiometry of 2a (<2 equiv) led to
significant erosion of the yield (<30%). We also found that 1.2
equiv of t-BuONa was sufficient.19
With the optimized reaction conditions in hand, we first
examined the scope of alkyl aryl ketones and nitroarene
substrates (Table 2). 1-Tetralone (6) was an excellent substrate
for eight different substituted nitroarenes (entries 1−8) in
addition to nitrobenzene (2a) itself. Halogens (Cl, F) as well as
cyano and phenyl groups are apparently well-tolerated in the 2-
position of the nitroarene substrates. Surprisingly, products of an
SNAr process were not present in the reaction mixture (discussed
below). Para-substitution is exclusive as no traces of the
corresponding ortho-alkylated nitroarene products were detected
or isolated. 1-Nitronaphthalene (entry 8) was exclusively
substituted at the 4-position, in contrast with the ortho-selective
regiochemistry observed in a VNS reaction8 (Figure 1B).
Electron-rich 1-tetralones (entries 9−11) also reacted readily
with 2a to afford the corresponding α-arylated products (10i−k)
We decided to examine the possibility of α-arylating ketones
directly (not via an SNAr reaction!) in the absence of TMs. Our
initial plan (Scheme 1, I) was to desymmetrize 4-substituted
cyclohexanone 1 in the presence of chiral amine catalysts and
nitroarenes; the in situ-generated C-nucleophile was expected to
add to the nitroarene to form an anionic σH adduct (3) which,
upon oxidation, would furnish the α-arylated ketone 4. But none
of the conditions we tried yielded even trace amounts of the
expected 4 or 5; the starting materials were recovered
unchanged. We suspected that the nucleophilicity of the α-C
in these reactions was insufficient to achieve addition to the
nitroarene coupling partners. A thorough study of the literature
on VNS8 and NSH17 (nucleophilic substitution of hydrogen)
reactions made us realize that the formation of anionic σH-
adducts like 3 is usually a fast and reversible process and the
equilibrium is shifted toward σH-adducts due to either the high
electrophilicity of the arenes or the high nucleophilicity of
nucleophiles. We chose to increase the nucleophilicity of the α-C
in 1 by utilizing KOt-Bu, a strong base. To our delight, a rapid
reaction took place in an open flask, and α-arylated ketone 5 was
isolated in 40% yield. We next reacted 1-tetralone (6) with
nitrobenzene (2a) in DMSO; α-arylated tetralone 7 was isolated
in 62% yield (Scheme 1, II). Surprisingly, the arylation of both
ketones 1 and 6 was very clean (only a single product spot on the
TLC) and no trace of ortho-substituted nitrobenzene
regioisomers (such as 4a) could be isolated.
Table 2. α-Arylation of Alkyl Aryl Ketones
Encouraged by these results, we next conducted a thorough
solvent screen using the reaction 6 + 2a (3 equiv) → 7 as the
model (Table 1). DMSO and DMF were found to be the best
solvents (entries 7 and 8), giving arylated product 7 in 62% and
48% yields, respectively. The reaction in DMA was significantly
slower (entry 6); only 50% of ketone 6 was converted after 18 h
and 30% yield of 7 was isolated. Nonpolar solvents (entries 1 and
Table 1. Solvent Screen for the α-Arylation of 6 with 2a
a,b
Reactions conducted at 0.2 M concn in an open flask for the
c
indicated time. Conversion based on TLC analysis and amount of
recovered starting material. Isolated yield after column chromatog-
d
a,b
c
Reactions conducted at 0.2 M concn in an open flask. Isolated
yield after column chromatography.
raphy.
B
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Communication
Table 3. α-Arylation of Alkyl Alkyl Ketones
Scheme 3. Free Energy (kcal/mol) Surface of Proposed
Mechanism (Bond Lengths in Å)
a,b
c
Reactions conducted at 0.2 M concn in an open flask. lsolated yield
after column chromatography.
We also used DFT calculations to examine the mechanism and
regioselectivity of C−C bond formation and aerobic oxidation.
(U)M06-2X/6-31+G(d,p) calculations were carried out in
Gaussian 09 (see SI) using the SMD solvent model for DMSO.20
Several mechanisms for C−C bond formation between
cyclohexenolate (17) and 9a were considered (see SI).21 One
involves O-enolate addition at the ortho-position of 9a followed
by a [3,3] rearrangement. For O-enolate addition at the ortho-
position of 9a, ΔH⧧ = 7.5 kcal/mol and ΔG⧧ = 19.3 kcal/mol. A
lower energy pathway was found for direct C-enolate addition via
TS1-para at the para-position of 9a with ΔH⧧ = 3.2 kcal/mol
and ΔG⧧ = 15.1 kcal/mol (Scheme 3). We also considered
electron transfer (ET) from 17 to 9a followed by C−C bond
formation. The computed ΔH for ET between enolate 17 and 9a
is 8.9 kcal/mol, suggesting that ET is less viable than C-enolate
addition.22 However, a Marcus−Hush estimate of ΔG⧧ for ET is
13−14 kcal/mol, which may be competitive with C-enolate
addition.
No SNAr product is formed because the Cl atom increases the
ΔH⧧ for C-enolate addition by ∼10 kcal/mol compared to TS1-
para.23 Surprisingly, C-enolate addition ortho to the nitro group
of 9a via TS1-ortho (Scheme 3) has a lower ΔG⧧ than TS1-
para.24 However, experimentally, ketone addition was found to
occur exclusively with para-selectivity. This suggests that ortho C-
enolate addition is reversible. In accordance with this hypothesis,
the ΔG for formation of 18-ortho is close to zero, and the barrier
for subsequent oxidation is higher in energy than reversion back
to reactants.
Scheme 2. Scale-Up Studies and Unique Heterocycles
in good isolated yields; however, indanone was arylated only in
fair yield (entry 12). Electron-rich as well as electron-poor aryl
methyl ketones underwent smooth α-arylation (entries 13−21).
Interestingly, phenyl cyclopropyl ketone (entry 22) did not
undergo α-arylation even with a large excess (5 equiv) of 2a; it is
conceivable that deprotonation at the α-position of this substrate
is challenging. Remarkably, all the alkyl aryl ketones that we
subjected to our α-arylation protocol (Table 2) gave rise
exclusively to mono-arylated products; no traces of α,α-
diarylated ketones were detected or isolated. One limitation of
this method is that α,α-dialkyl ketones (e.g., 2-Me-1-tetralone)
do not undergo α-arylation.
Next we investigated the reactivity of cyclic as well as acyclic
ketones (Table 3). Alkyl alkyl ketones gave rise to α-arylated
derivatives in fair isolated yields; the exclusive para-selectivity as
well as the formation of only mono-α-arylated ketones remained
the same as for the substrates presented in Table 2. The fact that
only the more highly substituted α-position was arylated in
products 12i,j (entries 9 and 10) is noteworthy. Acetone (entry
11) was a poor substrate, presumably because the competing self-
condensation reaction is faster than the α-arylation process.
To demonstrate the synthetic utility of this facile, aerobic, TM-
free, regiospecific, direct mono-α-arylation of ketones on a multi-
gram scale, we chose a combination of two ketones and three
substituted nitroarenes to prepare four α-arylated products: 7,
10a, 10f, and 10m (Scheme 2). We also showed that compounds
10a,f could be readily aromatized to biaryls 13 and 15,
respectively, which in turn could be converted to unusually
substituted heterocycles 14 and 16 in a single step.
Scheme 3 also shows our proposed mechanism for aerobic
3
oxidation. From 18-para, oxidation involves O2-mediated H-
atom abstraction with ΔG⧧ = 14.8 kcal/mol. Importantly, H-
atom abstraction at the ortho position of 18 via TS2-ortho
requires several kcal/mol more energy. This reaction step is likely
irreversible and sets the regiochemistry. After H-atom
abstraction, the resulting hydroperoxyl and carbon radicals can
combine to give 19.25 Oxidation is completed after hydro-
peroxide anion dissociation via TS3.
We also considered whether oxidation proceeds by electro-
philic addition of 3O2 to the meta-positions of 18-para followed
by intra- or intermolecular deprotonation and elimination of
3
reduced O2. Although addition of O2 to 18-para is favorable,
subsequent base elimination of reduced O2 requires a large
barrier. We also considered oxidation via ET between 18-para
3
and O2 followed by H-atom abstraction. The ΔH for ET
C
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products that are challenging or impossible to obtain using
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simple and scalable, the scope of substrates is wide, and there
is no need for pre-functionalization or the use of specialized
arylating agents. DFT calculations suggest that the in situ-
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ASSOCIATED CONTENT
* Supporting Information
Procedures and characterization, and ref20a. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
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AUTHOR INFORMATION
Corresponding Authors
dhe@chem.byu.edu
laszlo.kurti@utsouthwestern.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
L.K. acknowledges the generous financial support of the UT
Southwestern Endowed Scholars in Biomedical Research
Program (W.W. Caruth, Jr., Endowed Scholarship in Biomedical
Research), the Robert A. Welch Foundation (Grant I-1764), the
ACS Petroleum Research Fund (Doctoral New Investigator
Grant 51707-DNI1), and the American Cancer Society &
Simmons Cancer Center Institutional Research Grant (New
Investigator Award in Cancer Research, ACS-IRG 02-196).
D.H.E. thanks BYU and the Fulton Supercomputing Lab.
(16) (a) Gao, H.; Ess, D. H.; Yousufuddin, M.; Kurti, L. J. Am. Chem.
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Soc. 2013, 135, 7086. (b) Li, G.-Q.; Gao, H.; Keene, C.; Devonas, M.;
Ess, D. H.; Kurti, L. J. Am. Chem. Soc. 2013, 135, 7414.
̈
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D
dx.doi.org/10.1021/ja4074563 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX