Transition-Metal-Free α-Arylation of Enolizable Aryl Ketones and Mechanistic Evidence for a Radical Process

Article abstract of DOI:10.1002/anie.201502332

The α-arylation of enolizable aryl ketones can be carried out with aryl halides under transition-metal-free conditions using KOtBu in DMF. The α-aryl ketones thus obtained can be used for step- and cost-economic syntheses of fused heterocycles and Tamoxifen. Mechanistic studies demonstrate the synergetic role of base and solvent for the initiation of the radical process.

Full text of DOI:10.1002/anie.201502332

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201502332
German Edition: DOI: 10.1002/ange.201502332
À
C C Coupling
Transition-Metal-Free a-Arylation of Enolizable Aryl Ketones and
Mechanistic Evidence for a Radical Process**
Martin Pichette Drapeau, Indira Fabre, Laurence Grimaud,* Ilaria Ciofini,* Thierry Ollevier,*
and Marc Taillefer*
Abstract: The a-arylation of enolizable aryl ketones can be
carried out with aryl halides under transition-metal-free
conditions using KOtBu in DMF. The a-aryl ketones thus
obtained can be used for step- and cost-economic syntheses of
fused heterocycles and Tamoxifen. Mechanistic studies dem-
onstrate the synergetic role of base and solvent for the initiation
of the radical process.
arylation of aryl ketones. The reaction of acetophenone with
iodobenzene in DMSO was disclosed, but photostimulation
was reported to be mandatory.[8f,g] Other methods make use of
pre-formed enolates and activated aryl chlorides in associa-
tion with metallic potassium or sodium amalgam [Na(Hg)] in
liquid ammonia.[8b, 9b,d] The specific phenylation of large
excesses of preformed aryl enolates or ketones has also
been reported using phenylazo tert-butyl sulfide[11a] or an
excess of a triphenylaluminum isoxazolidine, as the phenyl
source, respectively.[11b] Therefore, from a synthetic chemistry
point of view, it would be highly desirable to develop general
and practical transition-metal-free methods for the arylation
of enolizable aryl ketones.
Herein, we describe the potassium tert-butoxide promoted
a-arylation of various enolizable aryl ketones with aryl
halides. We also disclose some evidence to explain the role
of KOtBu and DMF in this process and propose a mechanistic
pathway based on combined theoretical and experimental
studies.
T
he a-arylation of enolizable carbonyl compounds is a trans-
formation of high importance in synthetic organic chemistry.[1]
Semmelhack and co-workers reported the nickel-mediated
intramolecular arylation of a lithium enolate as the key step in
a total synthesis.[2] The groups of Buchwald, Hartwig, and
Miura independently reported methods based on palladium
catalysis for the intermolecular a-arylation of ketones.[3]
Improved procedures involving palladium or nickel catalysis
have since been disclosed.[4] As a complementary approach,
our group recently reported the copper-catalyzed a-arylation
of benzyl aryl ketones.[5] Whereas transition-metal-catalyzed
processes are now commonly employed, methods for the
arylation of ketone enolates by radical nucleophilic aromatic
substitution (SRN1), first reported as early as 1970, are seldom
used.[6] These reactions can proceed in the presence of iron or
samarium catalysts[7] or without transition metals by photo-
chemical,[8] thermal,[9] or microwave-induced thermal[10] acti-
vation. However, these methods have not found widespread
use in organic synthesis, probably because of substrate-scope
We initially discovered that KOtBu and DMF alone could
promote the a-phenylation of propiophenone with iodoben-
zene with low conversion. Indeed, without a metal catalyst,
compound 1 was obtained in low yield (1.2:1 ketone/PhI)
using five equivalents of KOtBu in DMF at 408C (Table 1,
entry 1). Increasing the temperature to 608C was moderately
beneficial (entry 2), whereas using a 2:1 ketone/PhI ratio at
Table 1: a-Phenylation of propiophenone with iodobenzene.[a]
limitations. Indeed, very few procedures describe the SRN
1
[*] M. Pichette Drapeau, Dr. M. Taillefer
Institut Charles Gerhardt Montpellier, ENSCM
8 rue de l’Ecole Normale, 34296 Montpellier (France)
E-mail: marc.taillefer@enscm.fr
Entry Base
Solvent Propiophenone/PhI T [8C] Yield [%][b]
M. Pichette Drapeau, Prof. Dr. T. Ollevier
DØpartement de chimie, Pavillon Alexandre-Vachon
UniversitØ Laval
1
2
3
4
5
6
7
8
9
KOtBu
DMF
DMF
DMF
DMF
DMF
DMF
1.2:1
1.2:1
2:1
2:1
2:1
2:1
2:1
2:1
2:1
40
60
60
60
23
60
60
60
60
60
60
37
56
99 (97)
85[c]
85[d]
<5
<5
0
0
0
KOtBu
KOtBu
KOtBu
KOtBu
LiOtBu
1045 avenue de la MØdecine, QuØbec (Qc) G1V 0A6 (Canada)
I. Fabre, Dr. L. Grimaud
UPMC-ENS-CNRS-UMR 8640, Ecole Normale SupØrieure
DØpartement de chimie
NaOtBu DMF
24 rue Lhomond, 75231 Paris (France)
KOtBu
KOtBu
KOtBu
KOtBu
THF
toluene
MeCN
DMSO
I. Fabre, Dr. I. Ciofini
Institut de Recherche de Chimie Paris
CNRS-Chimie ParisTech
10
11
2:1
2:1
<1
11 rue Pierre et Marie Curie, 75005 Paris (France)
[a] Reactions were performed on a 1 mmol scale in 3 mL of the indicated
solvent. [b] Yield determined by 1H NMR spectroscopy using 1,3,5-
trimethoxybenzene as an internal standard. Yields of isolated products
are given in parentheses. [c] The yield was 85% when either 5 equivalents
of DMF (380 mL) or undistilled DMF (3 mL) under an air atmosphere
were used. [d] 48 h; 99% yield after 72 h.
[**] This work was financially supported by NSERC, FQRNT, CGCC, and
CNRS. M.P.D. thanks FQRNT and CGCC for doctoral scholarships.
ANR (CD2I) is greatly acknowledged for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201502332.
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608C led to a quantitative yield (entry 3). The reaction also
proceeded smoothly when either five equivalents of DMF or
undistilled DMF under an air atmosphere were used, as an
85% yield was obtained in both cases (entry 4). Interestingly,
the reaction was also efficient at room temperature, giving
85% yield after 48 hours (99% yield after 72 h; entry 5).
Among the other bases tested, LiOtBu and NaOtBu gave very
poor conversion (entries 6 and 7). A solvent screen revealed
that THF, toluene, acetonitrile, and DMSO were unsuitable
for this reaction (entries 8–11). Therefore, it is clear that
KOtBu/DMF is the combination of choice.[12] Being aware of
the fact that undesired metal contaminants in commercial
KOtBu could catalyze the reaction,[13] we resublimed the base.
Using this purer base led to the same quantitative yield
(entry 3).[14]
reaction outcome. Using a larger amount of propiophenone
(4 equiv) led to quantitative yields of 2–4 (the excess ketone
was completely recovered following chromatography). Mod-
erate to good yields were obtained for the three iodoanisole
isomers (5–7). For these substrates, using an excess of ketone
(4 equiv) slightly increased the yields. Compound 8 was
synthesized in very good yield from 1-fluoro-4-iodobenzene.
Compounds 12–14 were obtained in good to excellent yields
from electron-rich or electron-poor propiophenones. The
reaction also proceeded efficiently in the presence of
electron-donating (Et, cyclopropyl, OMe: 15–17) or elec-
tron-withdrawing (Ph: 18) substituents at the enolizable
position, although the reaction was completely shut down
when a stronger deactivating group (CN) was employed.
Acetophenone is also a suitable substrate for the coupling
with iodobenzene, and the corresponding a-arylation product
19 was indeed isolated in excellent yield (92%); traces of the
disubstitution product 18 were also obtained.[15] Importantly,
bromoarenes could also be used, giving products 1, 2, 5, and
9–11 in moderate to very good yields, but the reactions had to
be heated to 1208C. Interestingly, chloroarenes could be used
in two cases. Product 1 was obtained in a low yield of 29%
from chlorobenzene, whereas the use of 1-chloronaphthalene
resulted in the isolation of 9 in a promising yield of 55%.
An interesting application of this method is the synthesis
of fused heterocycles (Scheme 1a).[16] After protection of 2-
iodophenol and 2-iodobenzylalcohol as the tetrahydropyranyl
(THP) acetals, benzofuran 20 and 1H-isochromene 21 were
obtained.[17] Tamoxifen (22; Z/E 2.8:1) could also be synthe-
sized in a three-step sequence (Scheme 1b).[18] Overall, active
(Z)-Tamoxifen (22), the most prescribed drug for the treat-
ment of breast cancer worldwide,[19] was obtained in 62%
yield (the E isomer can be selectively crystallized),[20] and
a scale-up to 20 mmol of PhBr is possible.
We subsequently turned our attention to the scope of the
reaction (Table 2). Under the standard conditions, the three
iodotoluene isomers (ortho, meta, para) gave good yields of 2–
4. The substitution pattern thus has little impact on the
Table 2: Scope of the a-arylation of enolizable aryl ketones with aryl
halides.[a]
Scheme 1. Syntheses of fused heterocycles and Tamoxifen (see the
Supporting Information for details).
As we suspected the reaction to proceed through radical
intermediates, we added some common radical scavengers.
[a] Reactions performed on a 1 mmol scale, yields of isolated products
are given. [b] The reaction conditions of Table 1, entry 3, X=I, T=608C
(for X=Br or Cl, T=1208C). [c] The reaction conditions of Table 1,
entry 3, T=808C. [d] T=608C, enolizable ketone/aryl halide=4:1 (for
X=Br, T=1208C). [e] T=408C, enolizable ketone/aryl halide=4:1.
[f] T=238C, 48 h, X=I, acetophenone/PhI=2:1.
Galvinoxyl
and
(2,2,6,6-tetramethylpiperidin-1-yl)oxyl
(TEMPO) completely inhibited the coupling of propiophe-
none with iodobenzene. Complementary experiments showed
that the reaction was not inhibited in the dark (78% yield of
1 after 48 h at room temperature), and good conversions were
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achieved under UV irradiation (46% yield after 2 h at room
temperature, l = 365 nm). Previous work on homolytic aro-
matic substitution (HAS) already evoked the possibility that
potassium tert-butoxide could be involved in a ligand-
assisted[21] direct electron transfer to an aryl halide, such as
iodobenzene.[22] However, owing to the extremely unfavor-
able energy variation computed for this reaction (DE =
50.51 kcalmolÀ1 for KOtBu + PhI!PhC + tBuOC + K+ + IÀ in
DMF, see below for computational details),[23] its role as
a radical initiator seemed very unlikely. This is in agreement
with the conclusion drawn by Murphy and co-workers,[24]
although their proposal of benzyne intermediates is incon-
sistent with the absence of regioisomers in our reaction (only
ipso substitution occurred). Moreover, all of these mecha-
nisms are not able to explain the key role played by the
solvent and the potassium cation.
pathway. The arene radical 25 undergoes coupling with an
enolate to generate radical anion 26. A final SET from 26 to
another aryl halide molecule releases a-aryl ketone 1.
This hypothesis was confirmed at the theoretical level
using density functional theory (DFT) calculations at the
M06-2X/6-311 + G(d,p) level of theory; bulk solvent effects
were included by means of a polarizable continuum model
(PCM; Scheme 3, see the Supporting Information for
details).[27] The reaction paths computed in the absence and
in the presence of the cation (K+ or Li+) were thus compared.
DMF and tBuOÀ are able to form a stable intermediate owing
to hydrogen bonding (DE = À4.40 kcalmolÀ1). However, the
presence of a cation leads to much more stable complexes:
DE = À21.74 kcalmolÀ1 for K+ and DE = À31.30 kcalmolÀ1
for Li+. Successive deprotonation is then achievable with
a reasonably low activation barrier: Ea = 12.12 kcalmolÀ1 (no
cation), Ea = 13.80 kcalmolÀ1 (K+), and Ea = 18.07 kcalmolÀ1
(Li+). In all cases, the computed transition state is very close
in energy to the product of the reaction, a carbamoyl anion
stabilized by tert-butanol through hydrogen bonding. Overall,
the computed reaction barriers are consistent with the
experimental conditions and clearly show the synergetic
role played by the base and the solvent in the initiation
process.
The electron-rich carbamoyl anion can thus react with PhI
through a SET mechanism to form the corresponding
benzene radical 25. Calculations showed that the radical
anion of iodobenzene dissociated spontaneously to the
corresponding iodide anion and benzene radical 25. The
variation of the total energy associated with this SET process
is computed to be higher in the presence of K+ (DE =
15.86 kcalmolÀ1) and Li+ (DE = 22.53 kcalmolÀ1) than in the
absence of a cation (DE = 8.66 kcalmolÀ1), and this dissoci-
ation actually represents the rate-determining step of the
reaction. From a thermodynamic point of view, the overall
reaction is driven by the last steps, which are extremely
favorable. Indeed, a DE value of À56.57 kcalmolÀ1 was
computed for the reaction of the enolate with the benzene
radical 25 to form radical anion 26, which can then react (by
SET) with PhI (DE = À9.07 kcalmolÀ1) to yield the final
product, along with the regeneration of the benzene radical
25.
The hypothesis[25] of Yan and co-workers, namely that an
electron-rich carbamoyl anion is generated by the deproto-
nation of DMF with KOtBu, seems more reasonable to
explain the experimental observations. The formation of this
intermediate was first reported by Reeves and co-workers.[26]
In our case, 1H and 13C NMR experiments confirmed the
rapid exchange of the formamide proton in a solution of
KOtBu in wet [D7]DMF (see the Supporting Information). It
is noteworthy that no proton exchange was observed after
12 hours under the same conditions when NaOtBu was used
instead of KOtBu, which might be due to the lower solubility
of the former base. Furthermore, we were not able to detect
the dimerization product of DMF even after prolonged
reaction times.
On the basis of these experiments, we postulate a radical
chain mechanism in which the solvent acts as the initiator of
the overall process (Scheme 2). The tert-butoxide anion
abstracts a proton from DMF, generating carbamoyl anion
23, which can be stabilized by the interaction with the
associated cation M+ and tert-butanol. Anion 23 then trans-
fers an electron to the aryl halide, generating XÀ and arene
radical 25 along with the carbamoyl radical 24, which is
stabilized by interactions with both MX and tBuOH (see the
Supporting Information). Propagation then follows an SRN
1
Whereas the roles of DMF and tBuOÀ are relatively clear
from the computed reaction paths, it is more delicate to define
the role of the cation and to justify the peculiar efficiency
observed with K+. It is clear that the cation can help in the
stabilization of reaction intermediates. Indeed, the lower
barrier found in the presence of potassium with respect to
lithium can give some, albeit non exhaustive, information on
the role of the cation. Too much stabilization, such as in the
case of Li+, can be deleterious, as it translates into too high
reaction barriers (for deprotonation) or energies (SET). It is
indeed important to stress that all issues related to solubility,
which can play a role in this process, cannot be addressed by
this computational method. It is important to note that owing
to the difficulty associated with estimating the energy of
formation of LiI and KI in solution using the current
theoretical approach, the computed energy values associated
with the SET elementary step should be considered as an
Scheme 2. An SRN1 mechanism as the proposed mechanistic pathway.
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Scheme 3. Energy profiles computed for the SRN1 pathway in DMF at the M06-2X/6-311+G(d,p) level of theory; DE values are given in kcalmolÀ1
.
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In conclusion, we have disclosed conditions for the
transition-metal-free a-arylation of various enolizable aryl
ketones with aryl halides.[29] Experimental and computational
studies provide unambiguous evidence that DMF is an active
species in the initiation step. Under the experimental
conditions, deprotonation of this solvent is indeed possible,
and the carbamoyl anion thus generated is able to promote
the SRN1 process, which leads to the formation of a-aryl
ketones. Further developments will be reported in due course.
À
Keywords: arylation · C C coupling · ketones ·
reaction mechanisms
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[29] The results presented in this Communication are protected as
a
patent: “Transition-metal-free a-arylation of enolisable
ketones”, M. Pichette Drapeau, T. Ollevier, M. Taillefer, FR
[15] Starting from PhI, the expected product was obtained in very
low yield under our standard conditions when dialkyl ketones
were employed, whereas with a-tetralone, no reaction was
observed.
1457458 CNRS/ENSCM/Univ. Laval, 2014.
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Information.
Received: March 23, 2015
Revised: May 11, 2015
Published online: July 1, 2015
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