Chemoselective Catalytic Dehydrogenative Cross-Coupling of 2-Acylimidazoles: Mechanistic Investigations and Synthetic Scope

Article abstract of DOI:10.1021/acscatal.8b02361

Chemoselective iron-catalyzed dehydrogenative cross-coupling using 2-acylimidazoles is described. The addition of a phosphine oxide ligand substantially facilitated the generation of tert-butoxy radicals from di-tert-butyl peroxide, allowing for efficient benzylic C-H bond cleavage under mild conditions. Extensive mechanistic studies revealed that the enolization of 2-acylimidazole proceeded through dual iron catalyst activation, followed by subsequent chemoselective cross-coupling with a benzyl radical over an undesired benzyl radical-derived homocoupling dimer that inevitably formed in earlier reported conditions. A variety of alkylarenes, aliphatic alkane, and functionalized 2-acylimidazoles were applicable, demonstrating the synthetic utility of the present catalysis. Contiguous all-carbon quaternary carbons were constructed through dehydrogenative cross-coupling. The catalytic chemoselective activation of 2-acylimidazole over bidentate coordinative and much more acidic malonate diester was particular noteworthy. Catalytic oxidative cross-enolate coupling of two distinct carboxylic acid equivalents was also achieved using acetonitrile as a coupling partner.

Full text of DOI:10.1021/acscatal.8b02361

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Article
Chemoselective Catalytic Dehydrogenative Cross Coupling of 2-
Acylimidazoles: Mechanistic Investigations and Synthetic Scope
Tsukushi Tanaka, Kayoko Hashiguchi, Takafumi Tanaka, Ryo Yazaki, and Takashi Ohshima
ACS Catal., Just Accepted Manuscript • Publication Date (Web): 30 Jul 2018
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Chemoselective Catalytic Dehydrogenative Cross Coupling of 2-
Acylimidazoles: Mechanistic Investigations and Synthetic Scope
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Tsukushi Tanaka, Kayoko Hashiguchi, Takafumi Tanaka, Ryo Yazaki* and Takashi Ohshima*
Graduate School of Pharmaceutical Sciences, Kyushu University, Maidashi, Higashiꢀku, Fukuoka 812ꢀ8582 Japan
ABSTRACT: Chemoselective ironꢀcatalyzed dehydrogenative crossꢀcoupling using 2ꢀacylimidazoles is described. The addition of
a phosphine oxide ligand substantially facilitated the generation of tertꢀbutoxy radicals from diꢀtertꢀbutyl peroxide, allowing for
efficient benzylic C–H bond cleavage under mild conditions. Extensive mechanistic studies revealed that the enolization of 2ꢀ
acylimidazole proceeded through dual iron catalyst activation, followed by subsequent chemoselective crossꢀcoupling with a benzyl
radical over an undesired benzyl radicalꢀderived homoꢀcoupling dimer that inevitably formed in earlier reported conditions. A variꢀ
ety of alkylarenes, aliphatic alkane and functionalized 2ꢀacylimidazoles were applicable, demonstrating the synthetic utility of the
present catalysis. Contiguous allꢀcarbon quaternary carbons were constructed through dehydrogenative crossꢀcoupling. The catalytꢀ
ic chemoselective activation of 2ꢀacylimidazole over bidentate coordinative and much more acidic malonate diester was particular
noteworthy. Catalytic oxidative crossꢀenolate coupling of two distinct carboxylic acid equivalents was also achieved using acetoniꢀ
trile as a coupling partner.
Keywords: redox catalysis, Lewis acid, CꢀH activation, dehydrogenative, dual iron activation, hydrocarbon, αꢀalkylation, quaterꢀ
nary carbon center
9,10
cies. These reactions required a high temperature, however,
presumably to efficiently generate transient radicals derived
from alkylarenes (thermal radical generation) (Scheme 1C).
Introduction
Inert C–H bond transformation to a C–C bond is considered an
ideal process for constructing carbon frameworks in terms of
atomꢀ and stepꢀeconomy. Abundant hydrocarbon feedstock,
such as toluene derivatives and alkanes, is a highly attractive
starting material for sp C–H bond functionalization. Transꢀ
formation of an sp C–H bond to a C–C bond, however, reꢀ
mains a significant challenge in modern organic chemistry
compared to the transformation of an sp C–H bond due to the
1
Alkylation of carbonyls is one of the most fundamental and
3
3
11
wellꢀestablished Csp –Csp bondꢀforming transformations. In
general, alkylation of carbonyls is performed using alkyl halꢀ
ide with stoichiometric amounts of strong bases such as lithiꢀ
um diisopropylamide for activating carbonyls. This convenꢀ
tional method, however, has several drawbacks. 1) Basic conꢀ
ditions limit the functional group tolerance and chemoselecꢀ
tive deprotonative activation of less acidic carbonyls over
13
3
3
2
2
lack of a coordinating πꢀbond. Due to the intrinsic low acidity
3
of the sp C–H bonds of hydrocarbon feedstock, deprotonative
12
more acidic carbonyls. 2) Alkyl halides must be prepared.
3
activation by Brønsted bases alone is quite difficult. On the
other hand, a radical process is considered an efficient activaꢀ
For example, benzyl bromide is commonly prepared from
toluene with bromine or Nꢀbromo succinimide. 3) Stericallyꢀ
hindered substrates are difficult to use. Especially, constructꢀ
ing a contiguous allꢀcarbon quaternary carbon center is quite
3
4
tion mode for sp C–H bond functionalization, but the radical
process generates extremely reactive transient radical species
and these radical species easily couple with each other, thereꢀ
by providing undesired homoꢀcoupling dimers as major prodꢀ
14
challenging. In contrast, dehydrogenative C–C bond forꢀ
mation of carbonyls with hydrocarbon feedstock is an ideal
process. Li’s pioneering work was performed using tautomerꢀ
izable 1,3ꢀdiketones with diarylmethane derivatives. Several
examples were recently reported using hydrocarbon feedstock
as an alkylating reagent for coupling with carbonyls. These
5
ucts. Therefore, olefins, aromatics, and organometallic reaꢀ
gents as an activated form are generally utilized as coupling
partners to readily capture the transient radicals generated over
undesired homoꢀcoupling dimer formation derived from tranꢀ
15
16
6
ꢀ8
sient radicals (Scheme 1A). On the other hand, coupling an
reported reactions, however, require the use of tautomerizable
carbonyls, 1.3ꢀdiketones or 1,3ꢀketoesters, to rapidly capture
3
sp carbon with transient radicals is a formidable challenge
because efficient inꢀsitu activation such as deprotonation may
be required to avoid generating a significant amount of homoꢀ
17
the transient radicals (Scheme 1A). Moreover, high temperaꢀ
ture is needed to generate radical species and most cases sufꢀ
coupling dimers derived from the transient radicals (Scheme
fered from the homoꢀcoupling formation of hydrocarbon, reꢀ
8
1
B). Recently, Chatani’s and You’s groups reported elegant
16d,17
sulting in only a moderate chemical yield.
Herein we deꢀ
directing groupꢀassisted strategies for dehydrogenative crossꢀ
coupling reactions to generate inꢀsitu catalytic active speꢀ
3
3
veloped a catalytic dehydrogenative Csp –Csp bondꢀforming
reaction using hydrocarbon feedstock with nonꢀtautomerizable
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8,19
2
ꢀacylimidazole under mild conditions (Scheme 1D).
Noꢀ
fective for the present catalysis (entry 5). Next, we investigatꢀ
ed monophosphine ligands (entries 6–8). Among them, L7
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tably, we observed only a trace amount of the undesired hoꢀ
moꢀcoupling dimer derived from hydrocarbon feedstock. Exꢀ
tensive mechanistic studies revealed that ligand addition subꢀ
stantially facilitated the generation of tertꢀbutoxy radicals
from diꢀtertꢀbulyl peroxide (DTBP), allowing for catalystꢀ
controlled transient radical generation from feedstock hydroꢀ
carbon. In addition, dual activation of 2ꢀacylimidazoles by an
iron catalyst occurred for efficient enolization.
afforded product 3aa in high yield. To confirm the effectiveꢀ
ness of the monodentate ligands, we evaluated several bidenꢀ
tate ligands (entries 9–11). N,Nꢀligand, 2,2'ꢀbipyridyl (L8),
1,10ꢀphenanthroline (L9), and BINAP (L10) afforded product
3aa in only low chemical yield. These results led us to further
a
Table 1. Conditions Screening
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Scheme 1. Radical Process for C-H to C-C Transformation
Results and Discussion
a
Conditions: 1a (0.23 mmol), 2a (1.14 ml, 47 equiv). Yields
1
were determined by HꢀNMR analysisb using 1,2,4,5ꢀ
1. Development of Iron-Catalyzed Dehydrogenative Cou-
pling of 2-Acylimidazole with Toluene
Tetramethylbenzene as an internal standard. Isolated yield was
c
shown. A mixture of toluene (0.49 ml, 20 equiv) and benzene
(0.65 ml, 0.20 M) was used.
We began our investigation using 2ꢀacylimidazole 1a as an
enolate precursor in toluene (2a) with FeCl and DTBP at
3
1
20 °C (Table 1). A low chemical yield was observed without
the ligand (entry 1). Pyridine derivatives considerably faciliꢀ
tated the reaction and benzylated product 3aa was produced in
moderate yield (entries 2–4). Pyridine oxide (L4) was not efꢀ
investigate the optimal amount of ligand L7 (entries 12–15).
Although a range of 5ꢀ20 mol% of the ligand did not affect the
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chemical yield, 30 mol% ligand decreased the yield. To
demonstrate the mildness of the present catalysis, the reaction
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a
Table 2. Control Experiments
was performed under lower temperature. Previous catalytic
dehydrogenative crossꢀcoupling reactions of toluene derivaꢀ
tives were generally performed at temperatures higher than
20
1
20 °C. In contrast, our catalysis can be performed at 80 °C,
and product 3aa was observed in 79% yield with a prolonged
reaction time (entry 16). In addition, the amount of DTBP was
reduced to 1.7 equivalents with no detrimental effects (entry
1
7). During the reaction optimization process, we found that
L7 was completely oxidized to phosphine oxide L11 within
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several minutes based on crude PꢀNMR, indicating that the
actual ligand was L11.Thus, we evaluated L11 as a ligand. We
envisioned that Fe(III) species would be reduced to afford
Fe(II) species followed by Fentonꢀtype reaction, generating
t
tertꢀbutyoxy radical and BuOꢀFe(III) species. Thus we also
investigate FeCl as a catalyst. Although combined use with
2
FeCl afforded a yield comparable to that obtained using L7
3
(
entry 18), the FeCl ꢀL11 system exhibited superior catalytic
2
performance, and the desired product was isolated in 83%
yield (entry 19). It is noteworthy that only a trace amount of
dibenzyl, an undesired homoꢀcoupling product of toluene (2a),
was observed under the optimized conditions (entry 19), while
some dibenzyl was observed at 120 °C. The combination of
FeCl with L7 was less effective (entry 20). Ligand could be
2
reduced to 2.5 mol% without significant loss of the chemical
yield (entry 21). Benzene could be used as a coꢀsolvent and
product 3aa was observed in 76% yield using 20 equivalents
of toluene (entry 22).
a
Conditions: 1a (0.23 mmol), 2a (1.14 ml, 47 equiv). Yields
were determined by HꢀNMR analysis using 1,2,4,5ꢀ
Tetramethylbenzene as an internal standard.
1
As control experiments, each component was omitted from
the standard conditions (Table 2). No product was observed in
the absence of L11 or FeCl (entries 2 and 3). DTBP was also
2
2
. Mechanistic Studies
essential for promoting the reaction, presumably to generate
2
1
2-1. Elucidation of the Role of Ligand
the benzyl radical (entry 4). Single use of each component
was also ineffective for promoting the reaction (entries 5–7).
Although the reaction was not promoted at 80 °C in the abꢀ
sence of L11 (entry 3), moderate yield was observed at 120
To check the effect of Lewis base, Lewis basic product 3aa
was added to the reaction conditions using pꢀxylene (2b) as a
substrate without L11 at 120 °C (Scheme 2a). In the absence
of 3aa, product 3ab was produced in 4% yield after stirring for
1 h. In the presence of 1.0 equivalent of 3aa, the yield inꢀ
creased, indicating that Lewis basic 3aa also facilitated the
reaction rate and no catalyst deactivation by product 3aa ocꢀ
curred. Next, we evaluated 3aa and L11 as a ligand to faciliꢀ
tate the reaction rate at lower reaction temperature (Scheme
°
C, a temperature at which the tertꢀbutoxy radical would not
be generated by heating without the assistance of FeCl /L11.
2
These results indicated that FeCl /L11 facilitated the homolytꢀ
2
ic cleavage of DTBP, generating tertꢀbutoxy radicals at low
temperature. The superiority of L11 was further confirmed by
the reaction at 80 °C (entries 9 and 10).
2
b). Although 10 mol% 3aa facilitated the reaction (0% yield
vs 36% yield), L11 was a more effective ligand, affording
product 3ab in 92% yield.
Scheme 2. Effect of Lewis Bases
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―
(a) FeCl in DCE
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Next, we investigated the Lewis base effect of the C–H bond
― (b) FeCl in CH CN
― (c) BuO-FeCl in CH CN
3 3
t
cleavage of toluene (Scheme 3). Without FeCl and L11, no
2
3
2
homoꢀcoupling dimer 4 was observed at 80 °C. On the other
hand, 4 was detected at 120 °C, suggesting that tertꢀbutoxy
radicals could be thermally generated at 120 °C (Scheme 3a).
In the presence of FeCl at 80 °C, no homoꢀcoupling dimer 4
2
was observed. In sharp contrast, homoꢀcoupling dimer 4 was
observed in the presence of both FeCl and L11, indicating
2
that FeCl /L11 facilitated the generation of tertꢀbutoxy radiꢀ
2
2
2
cals through a Fentonꢀtype reaction (Scheme 3). We also
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confirmed that in the absence of FeCl , no homoꢀcoupling
2
dimer 4 was observed using L11 and DTBP, indicating that
0.200
0.000
the combined use of FeCl and L11 efficiently controls the
2
generation of tertꢀbutoxy radicals.
2
40.00
300.00
350.00
nm
400.00
450.00
Scheme 3. Effect of Lewis Bases in C-H Bond Cleavage
Figure 1. UVꢀVis Spectroscopic Analysis of FeCl in different
solvent (a) FeCl in DCE (black line). (b) FeCl in CH CN (orꢀ
ange line). (c) BuOꢀFeCl in CH CN (FeCl and DTBP were
stirred in PhCl for 4 h at 120 °C. After removal of PhCl, resulting
3
3
3
3
t
2
3
2
mixture was heated in CH CN for 1 h at 80 °C) (purple line)
3
t
Due to the low solubility of BuOꢀFeCl prepared from FeCl
with DTBP in chlorobenzene, further studies were conducted
using FeCl (Figure 2). As a control, phosphine oxide L11 and
acylimidazole 1a in DCE were used respectively, and no abꢀ
sorption around 300ꢀ400 nm was observed (Figure 2a, 2b).
The mixed solution of FeCl with L11 did not provide the
characteristic absorptions derived from FeCl4 ions, suggesting
that L11 would not generate L FeCl2 species (Figure 2c). In
contrast, the mixed solution of FeCl with 2ꢀacylimidazole 1a
provided absorptions derived from FeCl4 ions (Figure 2d),
suggesting that the combined use of both FeCl and 1a would
generate L FeCl species. We also confirmed the generation
of FeCl species by ESIꢀmass analysis (Figure S11). Furtherꢀ
more, the premixed solution of FeCl with acylimidazole 1a
and L11 provided absorptions derived from FeCl4 ions (Figꢀ
2
2
3
3
–
+
n
3
–
3
+
n
2
–
4
3
2
-2. UV-Vis Spectrum Measurements
–
To gain insight into in situꢀgenerated iron species, we perꢀ
formed UVꢀVis spectrum measurements. Iron(III) chloride
ure 2e), although the absorptions were weaker than that withꢀ
out L11 (Figure 2d). These results indicated that L11 slightly
disturbs the coordination of 1a to iron catalysts. This assumpꢀ
tion is also consistent with the findings that the use of an inꢀ
creased amount of ligand L11 decreased the chemical yield
+
–
affords L FeCl2 and FeCl species in a Lewis basic solvent
n
4
2
3
such as acetonitrile (eq. 1).
(
Table 1, entry 15).
We first confirmed the characteristic absorptions derived
–
from FeCl , as shown in Figure 1. When FeCl was dissolved
4
3
in nonꢀcoordinative dichloroethane (DCE), no characteristic
–
absorptions derived from FeCl4 ions were observed (Figure
1
a). On the other hand, the characteristic absorptions derived
–
from FeCl4 ions were observed in acetonitrile at around 312
and 360 nm, indicating the generation of an enhanced Lewis
+
acidic L FeCl2 species (Figure 1b). The premixed solution of
n
FeCl with DTBP in chlorobenzene provided similar absorpꢀ
2
t
tions to the FeCl in acetonitrile, suggesting that BuOꢀFeCl
would also generate BuOꢀL FeCl and BuOꢀFeCl species
3
2
t
+
t
–
n
3
(
Figure 1c).
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0
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.000
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-3. Kinetic Isotope Effect Studies and Kinetic Studies
―
―
(a) L11 in DCE
(b) 1a in DCE
1
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To obtain mechanistic insight into the turnoverꢀlimiting step, a
series of kinetic isotope effect (KIE) studies were performed
― (c) FeCl + L11 in DCE
― (d) FeCl + 1a in DCE
―
3
24
3
(Scheme 4). A competitive KIE study using a mixture of
(e) FeCl + L11 + 1a in DCE
3
8
2a/2a(d ) revealed a large KIE value (k /k = 5.94) (Scheme
H
D
4A). On the other hand, no significant KIE was observed
k /k = 1.97), when the two parallel reactions were performed
(
H
D
8
under optimized conditions using 2a or 2a(d ) (Scheme 4B).
These results suggest that the C–H bond cleavage step of toluꢀ
ene has only minor contribution to the turnoverꢀlimiting and
the overall rate of the reaction. In sharp contrast, relatively
large KIE (k /k = 4.75) was observed from two parallel reacꢀ
tions using 1a/1a(d ) (Scheme 4C), indicating that enolization
of 2ꢀacylimidazole has major contribution to the turnoverꢀ
limiting and occur in the turnoverꢀlimiting transition state.
1
1
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H
D
2
7
b,24f
0.000
40.00
The initialꢀrate kinetic study of the reaction of 1a and 2a was
performed next to gain further information about the reaction
mechanism. The reaction profiles of the present catalytic deꢀ
hydrogenative coupling are summarized in Table 3.
2
300.00
350.00
nm
400.00
450.00
Figure 2. UVꢀVis spectrum of iron catalysts (a) phosphine oxide
L11 in DCE (light blue line). (b) 2ꢀacylimidazole 1a in DCE
pink line). (c) FeCl with L11 in DCE (blue line) (d) FeCl with
ꢀacylimidazole 1a (red line) (e) FeCl with 2ꢀacylimidazole 1a
3
and L11 in DCE (green line)
(
2
3
3
Table 3. Kinetic Profile of the Catalytic Dehydrogenative
Benzylation of 2-Acylimidazoles 1a
Scheme 4. Kinetic Isotope Effect
The reaction rate displayed secondꢀorder dependency on the
catalyst (FeCl /L11), almost zeroth order dependency on 2ꢀ
2
acylimidazole 1a and DTBP. The nearly secondꢀorder kinetic
dependence with respect to the catalyst suggests that two iron
species would be involved in turnoverꢀlimiting step, enolizaꢀ
tion of 2ꢀacylimidazole. These result and UVꢀVis spectroꢀ
scopic analysis (Figure 2) and ESIꢀmass analysis (Figure S11)
suggest that Lewis acid/Brønsted base dual activation of 2ꢀ
acylimidazole 1a by the two iron species would be operative,
as depicted in Scheme 5.
25
Scheme 5. Dual Activation Mode of 2-Acylimidazole by
Two Iron Complex
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5
5
5
5
6
2
-4. Enolate-Radical Pathway vs Radical-Radical Pathway
2-5. Proposed Catalytic Cycle
Mechanistic insights based on the obtained results are summaꢀ
rized as follows.
To elucidate whether C–C bond formation proceeded with
radicalꢀenolate coupling or radicalꢀradical coupling, we conꢀ
ducted a series of control experiments (Scheme 6). When the
2
6
1
.
Ligand L11 facilitates the generation of tertꢀbutoxy
radicals from iron(II) and DTBP, achieving efficient C–
H bond cleavage of toluene under mild conditions.
premixed catalyst prepared from FeCl with DTBP was subꢀ
2
jected to the reaction with benzaldehyde (5), aldol product 6
was observed in 22% yield with a small amount of dehydrated
product, suggesting inꢀsitu enolate formation of 1a (Scheme
+
2.
Lewis basic 2ꢀacylimidazoles generate the FeCl and
FeCl4 species.
2
–
7
a). Cyclopropylꢀsubstituted 2ꢀacylimidazole 1b as a substrate
3
4
.
.
The turnoverꢀlimiting step is enolization of 2ꢀ
acylimidazole and dual activation by iron species is
achieved in enolization.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
for the radical clock experiment afforded the benzylated prodꢀ
uct 3ba in 79% yield without any ringꢀopened products
27
(Scheme 7b). In addition, no dimerization of 1a was obꢀ
served using premixed catalyst prepared from FeCl2 with
DTBP, suggesting that an enolateꢀradical coupling pathway
would be operative rather than a radicalꢀradical coupling
pathway (Scheme 7c).
Enolateꢀradical coupling is operative in the C–C bond
forming step.
Based on a series of mechanistic studies, a plausible catalytꢀ
ic cycle is depicted in Figure 3. First, iron(III) species I would
be generated from FeCl and DTBP through a Fentonꢀtype
2
reaction with the assistance of L11. 2ꢀAcylimidazole 1a coorꢀ
+
–
Scheme 6. Enolate-Radical Pathway vs Radical-Radical
Pathway
dinates to the iron catalyst, affording Fe(III) and Fe(III) speꢀ
cies II. The enolization step involves two iron species as a
Lewis acid/Brønsted base cooperative catalyst, affording enoꢀ
26
late form III and radical form IV. Benzyl C–H bond
(PhCH –H: BDE = 89.8 ± 0.6 kca/mol) cleavage is achieved
2
t
by tert-butoxy radicals ( BuO–H: BDE = 105.7 ± 0.7 kcal/mol)
whose generation is controlled by Fe(II)/L11, not by thermal
27
heating. The benzyl radical V couples with enolate III rather
than radical intermediate IV to afford intermediate VI. Oxidaꢀ
tion of iron(II) was again facilitated by L11, providing product
3
aa with regeneration of the active iron species I.
Scheme 7. Detection of 2-Acylimidazole-Derived Enolate
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1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 3. Proposed Catalytic Cycles
. Reaction Scope
3
a
We investigated the scope of the ironꢀcatalyzed dehydrogenaꢀ
tive coupling (Table 4). Product 3aa was isolated in 64% yield
using reduced amount of toluene (15 equivalents) under 3
mol% catalyst. The gramꢀscale reaction also proceeded withꢀ
out any detrimental effects and product 3aa was isolated in
Table 4. Substrate Scope of Alkylarenes
3
.94 g. Various xylenes were applicable to the present catalyꢀ
sis (3ab–3ad). The reactions of 4ꢀ and 3ꢀbromotoluenes afꢀ
forded the products in high yield (3ae and 3af), although 2ꢀ
bromotoluene afforded the product 3ag in moderate yield,
presumably due to the steric hindrance. Other arylhalides,
chloroꢀ and iodoꢀtoluenes, afforded the product in high yield
(3ah and 3ai). Electronꢀrich methylarene was applicable, altꢀ
hough the chemical yield was moderate (3aj). Baseꢀsensitive
substrates having pꢀacetoxy and methoxycarbonyl groups afꢀ
forded the product at high temperature without L11 (3ak and
3
al). 2,5ꢀDimethyl thiophene was incorporated into 2ꢀ
acylimidazole in high yield (3am). A secondary benzylic subꢀ
strate including 3ꢀchloroꢀ1ꢀphenylpropane, which has addiꢀ
tional electrophilic sites, selectively reacted at a benzylic posiꢀ
tion (3an and 3ao).
a
Conditions: 1 (0.23 mmol), 2 (1.14 ml), 24 h. Isolated yields were
b
c
shown. Reaction time was 8 h. 3 mol% catalyst and 15 equiv of
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d
e
a
toluene was used for 48 h. 3.94 g of 3aa was isolated. Reaction
Table 5. Substrate Scope of 2-Acylimidazoles
f
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
was performed at 90 °C. Reaction was performed at 120 °C using
.3 equiv of DTBP without L11 Yield was determined by Hꢀ
g
1
3
NMR analysis using 1,2,4,5ꢀTetramethylbenzene as an internal
standard.
Next, we examined various 2ꢀacylimidazoles (Table 5). A
cyclopropylꢀsubstituted substrate afforded product 3ba in high
yield without forming ringꢀopened products. A benzylꢀ
substituted substrate was selectively benzylated in high yield
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(3ca). Terminal alkene survived under the optimized condiꢀ
tions (3da). A sterically congested substrate was applicable to
the present catalysis (3ea). Although protecting groupꢀfree
hydroxy groups terminated the catalysis, TBSꢀprotected hyꢀ
droxy groups had no detrimental effects (3fa). αꢀPhenyl and 3ꢀ
thienyl 2ꢀacylimidazole afforded the products 3ga and 3ha in
moderate yield. NꢀBoc glycineꢀattached substrate was smoothꢀ
ly converted to benzylated product 3ia. It is noteworthy the
further functional group tolerance was demonstrated using
complex molecules, such as important pharmaceuticals, indoꢀ
methacin,
febuxostat
and
telmisartan,
attachedꢀ2ꢀ
acylimidazoles (3jaꢀ3la).
a
Conditions: 1 (0.20 mmol), 2 (1.0 ml, 47 equiv), 24 h. Isolated
b
c
yields were shown. Reaction was performed at 100 °C. Reaction
concentration was 0.10 M.
Conventional alkylation of carbonyls using alkyl halides for
the construction of an allꢀcarbon quaternary center, is difficult
1
4
due to the steric repulsion of bulky coupling partners. The
present dehydrogenative catalysis enabled the construction of
allꢀcarbon quaternary centers (Scheme 8). Coupling cumene
and 2ꢀbromocumene with 2ꢀacylimidazole 1g afforded 8 and 9,
respectively, in moderate yield. α,αꢀDisubstituted 2ꢀ
acylimidazole 1m was also applicable (10). Furthermore, the
construction of contiguous allꢀcarbon quaternary centers was
achieved (11), and this is the first example of the construction
of contiguous allꢀcarbon quaternary centers in catalytic dehyꢀ
drogenative coupling of carbonyls.
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a
Scheme 8. Construction of All-Carbon Quaternary Center
nate diester using the UVꢀVis spectrum (Figure 4). As deꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
scribed in section 2ꢀ2, a mixed solution of FeCl and 2ꢀ
acylimidazole 1a provided FeCl4 ion characteristic absorpꢀ
3
–
tions around 312 and 360 nm, suggesting the generation of the
+
LnFeCl species (Figure 4b). In contrast, the mixed solution of
2
FeCl with diethyl malonate did not provide the characteristic
3
–
absorptions derived from FeCl4 ions (Figure 4c) and similar
absorption as the FeCl solution (Figure 4a) was observed. In
3
addition, the premixed solution of FeCl with 2ꢀacylimidazole
3
1
a and diethyl malonate provided characteristic absorptions
–
derived from FeCl4 ions (Figure 4d), suggesting that 2ꢀ
acylimidazole could preferentially coordinate with L FeCl
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
a
+
Conditions: 1 (0.20 mmol), 2 (1.0 ml), 24 h. Isolated yields were
n 2
b
c
shown. 1.7 equiv of DTBP was used. Reaction was performed at
120 °C without L11
species even in the presence of bidentate coordinative diethyl
malonate.
1
0
0
.000
.800
.600
Scheme 9. Chemoselective Dehydrogenative Cross Cou-
pling in the Presence of Other Enolizable Carbonyls
―
(a) FeCl in DCE
3
― (b) FeCl + 1a in DCE
―
― (d) FeCl + diethyl malonate + 1a in DCE
3
(c) FeCl + diethyl malonate in DCE
3
3
0.400
0
0
.200
.000
2
40.00
300.00
350.00
nm
400.00
450.00
Figure 4. UVꢀVis spectrum of iron catalysts (a) FeCl in DCE
3
(
black line). (b) FeCl with 2ꢀacylimidazole 1a in DCE (red line)
3
(c) FeCl with diethyl malonate in DCE (blue line) (d) FeCl with
3
3
2
ꢀacylimidazole 1a and diethyl malonate in DCE (orange line)
Based on these results, we examined 1n bearing malonate
diester as a challenging substrate for chemoselective reaction.
First, to confirm the innate reactivity of the two functional
groups, 1n was subject to the conventional benzylation condiꢀ
t
tions using KO Bu and benzyl bromide (Scheme 9a). Under
conventional conditions, malonate diester was benzylated exꢀ
clusively and benzylated product 12 was observed with conꢀ
comitant formation of diꢀbenzylated product 13, clearly indiꢀ
cating that the αꢀproton of the malonate functionality is innateꢀ
ly much more acidic than the corresponding αꢀproton of 2ꢀ
acylimidazole. In stark contrast, the 2ꢀacylimidazole functionꢀ
ality was chemoselectively benzylated under the optimized
ironꢀcatalyzed conditions (Scheme 9b). Chemoselective benꢀ
zylation of 1,4ꢀdiketone 1o was achieved under the optimized
conditions and product 3oa was isolated in 51% yield (Scheme
9c). An aryl methyl ketone functionality was also applicable
(Scheme 9d).
Key to the present catalysis is the combined use of an iron
catalyst with Lewis basic 2ꢀacylimidazoles, enabling efficient
enolization of 2ꢀacylimidazole through dual iron species (see,
section 2ꢀ2). We envisioned that 2ꢀacylimidazole would be
chemoselectively activated even in the presence of more acidic
carbonyls. Malonate diester exhibits quite high acidity (diethyl
malonate; pK = 16.4 in DMSO, propiophenone; pK = 24.4 in
DMSO). Furthermore, the bidentate coordinative nature of
the malonate diester makes chemoselective enolization of a
less acidic functionality extremely difficult. Thus, we first
checked the coordination ability of 2ꢀacylimidazole and maloꢀ
a
a
29
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Page 10 of 13
We next applied the present catalytic dehydrogenative couꢀ lectively activated, even in the presence of bidentate coordinaꢀ
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
pling reaction to other substrates (Scheme 10). Cyclohexane
tive and much more acidic malonate diester.
(14) and anisole (16) could be used as alkylating agents, altꢀ
3
0
hough the yields were not high. Catalytic crossꢀoxidative
enolate coupling of two distinct carboxylic acid equivalents
2
6,31
Scheme 11. Transformation of the 2-Acylimidazole
was one of the most challenging reactions.
Acetonitrile is a
fascinating carboxylic acid equivalent because it is readily
available and transforms into versatile functional groups, altꢀ
hough the bond dissociation energy of the αꢀC–H bond is relaꢀ
32
tively high (BDE = 96 kcal/mol). In previous reports, αꢀ2
radicals derived from alkyl nitriles efficiently coupled with sp
carbons, including those of tautomerized 1,3ꢀketoesters, under
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
3
catalytic conditions. When acetonitrile was used instead of
toluene under slightly modified conditions, the crossꢀcoupling
reaction with 1a proceeded smoothly and the crossꢀcoupling
product derived from distinct two carboxylic acid equivalents
1
9 was isolated in 53% yield.
ASSOCIATED CONTENT
Supporting Information
Scheme 10. Dehydrogenative Cross Coupling using 2-
Acylimidazole 1a
The supporting information is available free of charge on the ACS
Publications website at DOI:
Detailed experimental procedures and spectroscopic data for all
new compounds (PDF).
AUTHOR INFORMATION
Corresponding Author
*
*
yazaki@phar.kyushuꢀu.ac.jp
ohshima@phar.kyushuꢀu.ac.jp
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was financially supported by JSPS KAKENHI
Grant Number JP15H05846 in Middle Molecular Strategy,
JP16H01032 in Precisely Designed Catalysts with Customꢀ
ized Scaffolding, GrantꢀinꢀAid for Scientific Research (C)
4. Transformation of the Product
Finally, the utility of the present iron catalysis was demonꢀ
strated by further elaboration of the 2ꢀacylimidazole functionꢀ
(
#16K08166) and Platform Project for Supporting Drug
3
4
ality (Scheme 11). The 2ꢀacylimidazole functionality was
efficiently transformed into the corresponding carboxylic acid
Discovery and Life Science Research (Basis for Supporting
Innovative Drug Discovery and Life Science Research
upon treatment with MeOTf followed by the addition of H O
and DBU, affording 20 in high yield. The use of BnOH instead
2
(
BINDS)) from AMED under Grant Number
JP17am0101091. R.Y. thanks the Sumitomo Foundation for
financial support.
of H O provided benzyl ester 21 in high yield.
2
Conclusion
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