Catalytic Enantioselective Oxidative Homocoupling of 2-Acyl Imidazoles

Article abstract of DOI:10.1002/adsc.202100837

A diastereoselective and enantioselective construction of 2,3-disubstituted 1,4-dicarbonyl compounds is reported. Nishiyama's RuPhebox complex (2.0 mol% catalyst loading) serves as a chiral Lewis acid catalyst in conjunction with BrCCl₃ and a base for the oxidative homocoupling of 2-acyl imidazoles via the stereocontrolled reaction of intermediate Ru enolates with in situ brominated 2-acyl imidazoles. Cleavage of the achiral imidazole auxiliary provides optically active 2,3-disubstituted succinic acids which are useful intermediates in the synthesis of chiral compounds like the natural product class of lignans. (Figure presented.).

Full text of DOI:10.1002/adsc.202100837

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doi.org/10.1002/adsc.202100837
Catalytic Enantioselective Oxidative Homocoupling of 2-Acyl
Imidazoles
Nemrud Demirel,a Jie Qin,a Sergei I. Ivlev,a Klaus Harms,a and Eric Meggersa,*
a
Fachbereich Chemie, Philipps-Universität Marburg, Hans-Meerwein-Strasse 4, 35043 Marburg, Germany
phone: +49-6421-2821534
fax: +49-6421-2822189
E-mail: meggers@chemie.uni-marburg.de
Manuscript received: July 5, 2021; Revised manuscript received: August 25, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100837
© 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH. This is an open access article under the
terms of the Creative Commons Attribution Non-Commercial License, which permits use, distribution and reproduction in any
medium, provided the original work is properly cited and is not used for commercial purposes.
ers made use of chiral auxiliaries to achieve a syntheti-
cally useful selective intermolecular cross-coupling
Abstract: A diastereoselective and enantioselective
construction of 2,3-disubstituted 1,4-dicarbonyl
derived from lithium enolates of oxazolidinones or
compounds is reported. Nishiyama’s RuPhebox
oxindoles with ketones or esters utilizing Fe(III) and
complex (2.0 mol% catalyst loading) serves as a
Cu(II) as oxidants.[5] Beside the mentioned methods
chiral Lewis acid catalyst in conjunction with
which are based on lithium enolates, oxidative
BrCCl3 and a base for the oxidative homocoupling
couplings could also be accomplished via silyl bis-enol
of 2-acyl imidazoles via the stereocontrolled reac-
ethers.[6] This strategy allowed for the convergent and
tion of intermediate Ru enolates with in situ bromi-
nated 2-acyl imidazoles. Cleavage of the achiral
imidazole auxiliary provides optically active 2,3-
disubstituted succinic acids which are useful inter-
stereoselective assembly of polycyclic molecules
through cross-coupling of chiral substrates.[7]
In 2001, Schäfer et al. reported the enantioselective
oxidative homocoupling by using a stoichiometric
mediates in the synthesis of chiral compounds like
chiral ligand as additive, instead of a chiral auxiliary,
the natural product class of lignans.
which afforded the homocoupling of N-acyl-oxazolidi-
nones with up to 76% ee (Figure 1b).[8] Unfortunately,
the meso-product rather than the dl-product was
Keywords: Asymmetric catalysis; Chiral Lewis
obtained as the major diastereomer. All the examples
acid; Dimerization; Homocoupling; Oxidative cou-
described above required the application of chiral
pling; Ruthenium
substrates or stoichiometric amounts of chiral ligands
to attain enantioselective transformations.
The first report of catalytic enantioselective oxida-
The oxidative coupling of two carbonyl compounds tive enolate coupling was disclosed by MacMillan and
offers a direct and efficient way to build molecules co-workers in 2007 through enamine catalysis.[9] The
with 1,4-dicarbonyl units, which are important precur- enamine generated by reaction of the aldehyde sub-
sors for the construction of various structural motifs strate and the chiral imidazolidinone catalyst under-
including pyrroles, furans and even a series of natural went oxidative bond formation with enol silane in the
products.[1] The first report[2] of an oxidative enolate presence of ceric ammonium nitrate (CAN), providing
coupling dates back to 1935 but it was not until the the coupling products in high yields (55–92%) with
1970s that synthetically useful methods emerged.[3] In excellent enantioselectivities (86–96% ee). Very re-
the early to mid-1990s Porter, Kise and Helmchen cently, Jørgensen et al. succeeded in developing a
developed stereocontrolled enantioselective oxidative direct asymmetric oxidative homocoupling of α-
dimerizations through the use of stoichiometric branched aldehydes with varying yields (28–79%) and
amounts of chiral auxiliaries (e.g. Evans oxazolidi- enantioselectivities (6–96% ee) in the presence of
nones, Figure 1a).[4] Furthermore, Baran and co-work- 40 mol% chiral amine catalyst and Ag2CO3 as the
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of the reaction conditions using (S,S)-RuPhebox
(2 mol%) to catalyze the homocoupling of 2-acyl
imidazole 1a to the dicarbonyl compound (S,S)-2a.
We found that the addition of small amounts of H2O
was beneficial to the outcome of the reaction and
therefore H2O (5.56 equiv.) was included in every
reaction. Performing the reaction in a mixture of
MeOH/THF (3:1) in the presence of BrCCl3 (1 equiv.)
°
and NaHCO3 (1.1 equiv.) at 40 C for 48 hours
provided the homocoupling product (S,S)-2a with high
enantioselectivity (96% ee) and without any traces of
the meso-diastereomer, but only in a modest yield of
45% along with the methyl ether side product 3
(entry 1). Replacing NaHCO3 with the organic base
N,N-diisopropylethylamine (DIPEA) provided slightly
higher yields of 54% but the enantioselectivity dropped
to 94% ee (entry 2). Despite the lower enantioselectiv-
ity, DIPEA was selected as the most suitable base due
to its excellent solubility in different solvents. After
screening a variety of solvents, we identified MeCN as
the most suitable solvent. Compared to the solvent
mixture MeOH/THF, the reaction in MeCN proceeded
significantly faster with full conversion observed in
under 24 h and with high enantioselectivity (96% ee)
(entry 3). Although the yield of the homocoupling
product was initially just 27%, we identified the
brominated compound 4 in 50% yield. Assuming that
4 is not a side product but an intermediate in the
coupling process, we next adjusted the amount of the
brominating agent BrCCl3. Indeed, when reducing the
amount of BrCCl3 from 1.0 to 0.65 equivalents, the
yield of (S,S)-2a increased to 84% with 94% ee
Figure 1. Previous work and this study on asymmetric homo-
couplings of carbonyl compounds. Previous stereoselective
oxidative homocoupling mediated via a) chiral auxiliary, b)
chiral ligand and c) chiral organocatalyst. d) This work: chiral
catalyst mediated enantioselective oxidative homocoupling.
oxidant (Figure 1c).[10] Overall, many of the developed (entry 4). These conditions were then tested at 30, 50
°
°
methodologies for the stereoselective synthesis of 2,3- and 80 C (entries 5–7) and 50 C was selected as the
substituted 1,4-dicarbonyl units achieved sometimes optimal reaction temperature for further optimizations,
only modest yields and diastereo- and/or enantioselec- as the enantioselectivity was the highest (95% ee) with
tivity. Most enantioselective oxidative couplings a sufficiently fast reaction time of 21 hours (entry 6).
mainly relied on the use of stoichiometric chiral Next, the reaction concentration was screened (en-
reagents or substrates containing a chiral auxiliary and tries 8–10). To our delight, the concentration had a
catalytic asymmetric versions are very limited.
high impact on the enantiomeric excess of the product.
In this work we present a highly diastereo- and Lower concentrations like 0.10 m and 0.05 m led to an
enantioselective oxidative homocoupling of carbonyl increased ee of 96.6% and 98.1% (entries 8 and 9),
compounds containing imidazoles as an achiral auxil- while higher concentrations of 0.40 m resulted in a
iary group. The remarkable stereoselectivity of this decreased ee of 91.0% (entry 10). To get a better
reaction is enabled using Nishiyama’s RuPhebox understanding if either the concentration of the
catalyst as a chiral Lewis acid, which catalyzes the substrates or the catalyst had an impact on the
oxidative homocoupling of 2-acyl imidazoles in the enantioselectivity, the reaction was conducted with
presence of a base and BrCCl3 as the oxidant via an 1 mol% of catalyst (entry 11). However, this just
enolate pathway, enabled through the electron rich slowed the reaction down further without having a
properties of the cyclometalated ruthenium complex significant impact on the ee of the homocoupling
(Figure 1d).
product. Hence, we concluded that the concentration of
Nishiyama’s RuPhebox catalyst has previously the substrate had an impact on the enantioselectivity.
been utilized in asymmetric (transfer-)hydrogenation At last, the amount of BrCCl3 was fine tuned to 0.50
and alkynylation reactions.[11] Serendipitously, we equivalents and the reaction time set to 24 h to ensure
discovered that RuPhebox can catalyze the oxidative a complete conversion of the starting materials. The
homocoupling of 2-acyl imidazoles using BrCCl3 as homocoupling product 2a was obtained in 88% yield
the oxidant and a base. Table 1 shows an optimization with an ee of 97.4% (entry 12).
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Table 1. Initial experiments and optimization.[a]
°
Entry
Base
Solvent (conc.)
BrCCl3/eq
T/ C
t/h
Yield/%[b]
ee/%
1[c]
2[c]
3
4
5
6
7
8
9
10
11[d]
12
13[e,f]
14[f]
15[f]
16[g],[f]
NaHCO3
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
–
MeOH/THF 3:1 (0.20 m)
MeOH/THF 3:1 (0.20 m)
MeCN (0.20 m)
MeCN (0.20 m)
MeCN (0.20 m)
MeCN (0.20 m)
MeCN (0.20 m)
MeCN (0.10m)
MeCN (0.05m)
MeCN (0.40m)
MeCN (0.10 m)
MeCN (0.10 m)
MeCN (0.10 m)
MeCN (0.10 m)
MeCN (0.10 m)
MeCN (0.10 m)
1.00
1.00
1.00
0.65
0.65
0.65
0.65
0.65
0.65
0.65
0.65
0.50
0.50
0.50
–
40
40
40
40
30
50
80
50
50
50
50
50
50
50
50
50
48
48
24
22
43
21
2
14
16
14
16
24
24
24
24
24
45
53
27
86
84
92
83
90
63
84
73
88
3
96
94
96
94
92
95
94
96.6
98.1
91.0
97.0
97.4
–
–
–
–
–
–
15
DIPEA
DIPEA
0.50
[a] Reaction conditions: (S,S)-RuPhebox (2 mol%), BrCCl3 (0.50–1.0 equiv.), H2O (5.56 equiv.) and base (1.10 equiv.) were
dissolved in the indicated solvent (0.05–0.20 m) and stirred under N2-atmosphere in the dark for the corresponding time at the
corresponding temperature.
[b] Isolated yield.
[c] The side product 3 also formed.
[d] 1 mol% of catalyst was used.
[e] No catalyst was used.
[f] NMR-yields with C2H2Cl4 as standard.
[g] Under air: side product 5 was isolated in 43% yield.
Subsequently, some control reactions were carried position of the phenyl moiety were successfully trans-
out. Without catalyst, only traces of product formed formed to the homocoupling products 2b–c with
next to the formation of the brominated compound 4 excellent yields (94–99%) and enantioselectivity (95–
(entry 13). In the absence of base or BrCCl3 no 98% ee), but a substitution on the sterically demanding
conversion to product or the brominated compound 4 ortho-position totally suppressed the formation of the
were observed (entries 14 and 15). In the presence of homocoupling product 2d. The electronic property of
air the reaction was not completely suppressed. The the phenyl group has great influence on both the yield
desired product formed in 15% while 1,2-diketone 5 and enantioselectivity of this transformation. Sub-
was isolated as the major product in 43% yield. Further strates with electron-withdrawing groups achieved
details about the optimization and control experiments good to excellent yields (homocoupling products 2f–i,
are provided in the Supporting Information.
2k, 74–99%) and moderate to very good enantioselec-
With the optimized conditions in hand (entry 12), a tivities (68–92%). Compound 2l with an electron-
substrate scope was carried out to determine the scope donating methoxy-group in para-position was synthe-
and limitations of this method. Notably, diastereoselec- sized in good yield (79%) and good enantioselectivity
tivities were extremely high (>20:1 dr) for almost all (86% ee) but lower diastereoselectivity (15:1 dr). A
presented substrates. As illustrated in Scheme 1, compound (2m) bearing an azide in para-position of
substrates with a methyl group at the para- or meta- the phenyl moiety was also provided with moderate
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Scheme 2. Key mechanistic experiments.
Scheme 1. Scope of the new catalytic asymmetric homo-
coupling. See Table 1, entry 12 for the reaction conditions.
involvement of a base-induced enolate intermediate in
the reaction mechanism. The structure of the ruthenium
yield (63%) and enantioselectivity (74% ee). Finally, enolate intermediate was obtained by single crystal X-
phenyl can also be replaced with other aromatic groups ray diffraction, confirming the presence of a Ru-
like biphenyl (2j) and 2-naphthyl (2n). The biphenyl coordinated Z-enolate (see frame in Scheme 2).[12]
2j was obtained in good yields (71%) and very good
Further insight was offered by monitoring the
1
enantioselectivity (91% ee). The naphtyl substrate 2n reaction by H-NMR (Figure 2). At the beginning of
was also synthesized in good yields (82%) and very the reaction, an exponential growth in the formation of
good enantioselectivity (90% ee). The thiophenyl the product was observed. After a turning point at 7 h
compound 2o gave only low yields (33%) and a low (70% conversion), a limited and slow growth was
diastereoselectivity (2:1 dr). This can be explained by observed. Besides, the brominated compound 4 was
the competitive coordination of the heterocycle to the initially formed rapidly and then disappeared with a
Lewis acid. Finally, 2-acyl imidazole with aliphatic rate similar to the formation of the homocoupling
substituents display a strongly decreased reactivity and product 4, which confirms its involvement as an
stereoselectivity (homocoupling products 2p and 2q), intermediate in the reaction.
thus revealing the limitation of the reaction scope.
Interestingly, when the brominated intermediate 4
Several experiments were performed to investigate was reacted with 2-acyl imidazole 1c under hetero-
the mechanism. Firstly, the bromo-intermediate 4, coupling conditions in the absence of BrCCl3, three
which is proposed to be a key intermediate in the coupling products were obtained in 60% combined
homocoupling reaction, was isolated in 99% yield in yield, including two homocoupling products and one
the stoichiometric reaction of the 2-acyl imidazole 1a heterocoupling product (Scheme 2c). This can be
under standard conditions without the use of the explained by an uncatalyzed rapid bromine transfer
catalyst (Scheme 2a). Next, the coupling reaction between 1c and 4, which renders a clean heterocou-
between 1a and brominated compound 4 was con- pling impossible (see Supporting Information).
ducted in the absence of BrCCl3 and at first also
At last, TEMPO-trapping experiments were con-
without base. No product formation could be observed ducted. Under standard conditions in the presence of
after 20 h. It was only after the addition of base that 10 equivalents of TEMPO, the homocoupling product
the product was formed and could be isolated in 69% could be isolated in 72% yield with high diastereo- and
yield wit 96% ee (Scheme 2b). This suggests the enantioselectivity (Scheme 2d). TEMPO adduct 7
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Scheme 3. Cleavage of the directing group.
diastereoselective and enantioselective, only one enan-
tiomer of the racemic mixture 4 should react. And
indeed, control reactions reveal that the α-position of 4
can easily epimerize via both bromide exchange with 1
and base-promoted enolate formation (see Supporting
Information for more details). Thus, the rapid racemi-
zation of 4 allows a dynamic kinetic resolution
mechanism. However, alternatively, it cannot be ruled
out that the substitution itself is not a concerted SN2
reaction but rather involves a single electron transfer
(SET), fragmentation and radical/enolate coupling.
The directing group can be cleaved under previous
reported conditions.[12] For example, the product (S,S)-
2a was transformed into the ethyl ester (S,S)-8a in
1
Figure 2. Kinetic H-NMR experiment: Starting point at 5 min.
formed in 28% yield which is most likely due to a 54% yield without any loss of ee (Scheme 3). The
redox side reaction (see Supporting Information for absolute configuration was determined by the crystal
more details). Overall, this experiment excludes a structure of the enantiopure (>99.9% ee) compound
radical chain process and rather supports an enolate 2n. Thus, the (S,S)-RuPhebox catalyst generates the
SN2 substitution pathway.
(S,S)-homocoupling products. Finally, it is worth
Taken into account the discussed mechanistic noting that the enantiomeric excess of the homocou-
experiments, the following mechanism is proposed pling products 2 could be raised via recrystallization
(Figure 3). 2-Acyl imidazole 1 binds to RuPhebox in a from EtOAc/n-hexane. By doing this, the enantiomeric
bidentate fashion and deprotonates to generate the excess of the product 2n could be raised from 90% ee
ruthenium enolate complex I. Complex I then reacts as to >99.9% ee in 80% yield.
a nucleophile with the brominated compound 4, which
In conclusion, we have developed a catalytic
is formed from 1 in a non-catalyzed fashion, to method for the construction of chiral 1,4-carbonyl
generate intermediate II. Dissociation of the homocou- compounds by a stereocontrolled oxidative homocou-
pling product then allows for a new catalytic cycle. We pling without utilizing stoichiometric amounts of chiral
propose that the stereocontrolled reaction of Ru- reagents or chiral substrates. The oxidative dimeriza-
enolate I with the brominated compound 4 is a SN2 tion could be accomplished in a diastereo- and
reaction. Since this reaction of I with 4 is highly enantioselective fashion. Furthermore, the coupling
products are intermediates of chiral 2,3-disubstituted
succinic acids, which are important precursors for the
construction of several natural products like (À )-
hinokinin.[4b]
Experimental Section
General Procedure for the Synthesis of the Homo-
Coupling Products 2
Under nitrogen, a flame dried Schlenk tube was charged with
the corresponding 2-acyl imidazole 1 (0.10 mmol, 1.00 equiv.)
and ruthenium catalyst (2 mol%). The solids were dissolved in
absolute and degassed MeCN (0.10 m) and H2O (0.56 mmol,
5.56 equiv.), DIPEA (0.11 mmol, 1.10 equiv.) and BrCCl3
Figure 3. Proposed mechanism for the enantioselective oxida-
tive homocoupling.
(0.05 mmol, 0.50 equiv.) were added, successively. The reaction
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mixture was degassed via freeze-pump-thaw for three cycles.
After the reaction mixture was thoroughly degassed, the vial
was sealed, coated with aluminum foil, and placed in a pre-
Kumada, Y. Terao, N. Ueda, Tetrahedron 1998, 54, 2697;
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°
heated oil bath. The reaction was stirred at 50 C for 24 h.
[5] a) P. S. Baran, M. P. DeMartino, Angew. Chem. Int. Ed.
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A. Haeuseler, J. Organomet. Chem. 2002, 661, 169;
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Dugan, C. L. Stern, R. J. Thomson, Org. Lett. 2008, 10,
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Afterwards, the mixture was concentrated under reduced
pressure and the residue was purified by silica gel column
chromatography (n-pentane/EtOAc 4:1!2:1) to afford the
desired homocoupling product 2. Enantiomeric excess was
determined by HPLC analysis on a chiral stationary phase.
X-Ray Crystallography
CCDC numbers 2093617 and 2101732 contain the supplemen-
tary crystallographic data for the structures of the product 2n
and the ruthenium enolate complex, respectively. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[8] P. Q. Nguyen, H. J. Schäfer, Org. Lett. 2001, 3, 2993.
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Chem. Soc. 2007, 129, 7004. For initial work on
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Narasaka, T. Okauchi, K. Tanaka, M. Murakami, Chem.
Lett. 1992, 21, 2099; c) Y. Yasu, T. Koike, M. Akita,
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Acknowledgements
We thank the Deutsche Forschungsgemeinschaft (ME 1805/15-
1) and the Philipps-University Marburg for financial support.
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Catalytic Enantioselective Oxidative Homocoupling of 2-
Acyl Imidazoles
Adv. Synth. Catal. 2021, 363, 1–7
N. Demirel, J. Qin, S. I. Ivlev, K. Harms, E. Meggers*