Visible-Light-Activated Catalytic Enantioselective β-Alkylation of α,β-Unsaturated 2-Acyl Imidazoles Using Hantzsch Esters as Radical Reservoirs

Article abstract of DOI:10.1021/acs.joc.8b01588

An efficient and practical method for the enantioselective β-functionalization of α,β-unsaturated 2-acyl imidazoles is described. The method uses a previously devised chiral-at-metal rhodium catalyst (Δ-RhS, 4 mol %) along with Hantzsch ester derivatives as alkyl radical sources. The rhodium complex exerts a dual role as the visible-light-absorbing unit upon substrate binding and as the asymmetric catalyst. The method provides up to quantitative yields with excellent enantioselectivities up to 98% ee and can be classified as a redox-neutral, electron-transfer-catalyzed reaction.

Full text of DOI:10.1021/acs.joc.8b01588

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Visible-Light-Activated Catalytic Enantioselective β‑Alkylation of
α,β-Unsaturated 2‑Acyl Imidazoles Using Hantzsch Esters as Radical
Reservoirs
Francisco F. de Assis,†,‡ Xiaoqiang Huang,‡ Midori Akiyama,§ Ronaldo A. Pilli,† and Eric Meggers*,‡
†Instituto de Química, Universidade Estadual de Campinas, Campinas, Sao Paulo 13084-971, Brazil
‡
̈
Fachbereich Chemie, Philipps-Universitat Marburg, Hans-Meerwein-Strasse 4, 35043 Marburg, Germany
§Department of Chemistry & Biotechnology, Graduate School of Engineering, The University of Tokyo, Tokyo, Japan
S
* Supporting Information
ABSTRACT: An efficient and practical method for the enantioselective β-functionalization of α,β-unsaturated 2-acyl
imidazoles is described. The method uses a previously devised chiral-at-metal rhodium catalyst (Λ-RhS, 4 mol %) along with
Hantzsch ester derivatives as alkyl radical sources. The rhodium complex exerts a dual role as the visible-light-absorbing unit
upon substrate binding and as the asymmetric catalyst. The method provides up to quantitative yields with excellent
enantioselectivities up to 98% ee and can be classified as a redox-neutral, electron-transfer-catalyzed reaction.
complex serves as a very efficient chiral Lewis acid to catalyze
the enantioselective radical addition to α,β-unsaturated 2-acyl
imidazoles or α,β-unsaturated N-acyl pyrazoles (Figure 1b).6,7
Intriguingly, at Lewis-acid catalyst loadings of just 4 mol %, up
to 99% ee can be observed. However, two catalysts are
required: a photoredox catalyst for the oxidative generation of
the intermediate alkyl radicals and the chiral Lewis acid
catalyst. In contrast, Kang recently devised a catalytic
enantioselective Giese reaction under photoredox conditions
for which just a single chiral rhodium catalyst is required.8
Although the results are very impressive with respect to low
catalyst loadings and the obtained enantioselectivities, the
system is limited to N-aryl tetrahydroisoquinolines as radical
precursors (Figure 1c). Thus, despite the described progress,
more general and more practical catalytic enantioselective
Giese reactions are highly desirable.
INTRODUCTION
■
The addition of alkyl radicals to acceptor-substituted alkenes
under formation of a new C−C bond (Giese reaction)
constitutes one of the most established radical reactions.1 Sibi
and Porter were the first to introduce chiral Lewis acids to
perform such reactions in a catalytic enantioselective fashion.2
However, the prevailing uncatalyzed background chemistry
required typically very high catalyst loadings. Recently,
photoredox catalysis3,4 has been applied to catalytic
enantioselective Giese reactions. In 2015, Yoon reported the
conjugate addition of α-aminoalkyl radicals to α,β-unsaturated
pyrazolidinones under photoredox conditions, reaching
enantioselectivitites of up to 96% ee (Figure 1a).5 The dual-
catalysis strategy uses [Ru(bpy)3]Cl2 as the photoredox
catalyst to convert α-silylalkyl anilines into free radicals,
while a Sc(III)/Pybox complex serves as the chiral Lewis acid
to catalyze the radical conjugate addition and to provide the
asymmetric induction. However, high loadings of the Sc(III)-
based Lewis acid are required, and the method is limited to α-
silylalkyl anilines as radical precursors. Our group reported a
more practical catalytic enantioselective Giese reaction.
Organotrifluoroborates are converted to alkyl radicals under
photoredox conditions, and a bis-cyclometalated rhodium
Recently, 4-alkyl-substituted Hantzsch ester (HE) deriva-
tives have emerged as easily available, mild, and general
reservoirs of alkyl radicals in photoredox reactions.9 Upon
single-electron oxidation, the C−C bond to the alkyl group in
Received: June 25, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.8b01588
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Figure 1. Chiral Lewis-acid-catalyzed asymmetric radical conjugate additions reported by Yoon, Meggers, Kang, and the work presented in this
study.
the 4 position is cleaved homolytically to generate free alkyl
radicals. The growing interest in these compounds can be
traced back to their well-accessible oxidation potentials, their
straightforward preparation from inexpensive starting materi-
als, and a broad scope as precursors for a range of alkyl radicals.
Cheng and Ma reported the use of 4-alkyl HEs as alkyl radical
precursors under photoredox conditions in the synthesis of
congested ketones containing all-carbon quaternary centers.10
Nishibayashi11 and independently Molander12 reported the
combination of photoredox catalysis and nickel catalysis in the
coupling of aryl halides or carboxylic acids with alkyl radicals
generated from 4-alkyl HE derivatives. HE derivatives were
also used as alkyl radical precursors in the radical alkylation of
imines, as described by Yu.13 Another interesting trans-
formation involving alkyl radicals generated from HEs such
as radical additions to styrenes and acceptor-substituted olefins
was recently reported by Cheng.14 With respect to applying 4-
alkyl HEs as radical precursors in asymmetric catalysis, we are
only aware of a single study by Melchiorre on the asymmetric
photoredox-mediated alkylation of aromatic enals.15
In this work, we report a robust and practical catalytic
asymmetric Giese reaction that combines rhodium-based chiral
Lewis acid catalysis with Hantzsch ester derivatives as
convenient radical precursors (Figure 1d). Interestingly, no
additional photoredox catalyst is required for this reaction,
which allows functionalization of α,β-unsaturated 2-acyl
imidazoles in the β position with a variety of alkyl groups.
B
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a
Table 1. Optimization of a Single Catalyst System
b
c
d
entry
subst.
catalyst
light
CFL
CFL
blue LEDs
blue LEDs
blue LEDs
blue LEDs
CFL
CFL
CFL
CFL
CFL
CFL
CFL
CFL
CFL
CFL
CFL
CFL
CFL
solvent
HE equiv
conc. (M)
yield (%)
ee (%)
1
2
3
4
5
6
7
8
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1b
1a
1a
1a
1b
1a
1b
1b
Λ-RhS (8 mol %)
Λ-RhS (8 mol %)
Λ-RhS (8 mol %)
Λ-RhS (8 mol %)
Δ-RhO (8 mol %)
Δ-RhO (8 mol %)
Λ-RhS (4 mol %)
Λ-RhS (4 mol %)
Λ-RhS (4 mol %)
Λ-RhS (4 mol %)
Λ-RhS (4 mol %)
Λ-RhS (4 mol %)
Λ-RhS (4 mol %)
Λ-RhS (4 mol %)
Λ-RhS (4 mol %)
Λ-RhS (4 mol %)
Λ-RhS (4 mol %)
Λ-RhS (4 mol %)
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
acetone
THF
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.0
2.0
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.1
0.1
32
79
35
75
35
38
34
76
32
76
38
77
96
97
92
95
82
85
89
94
87
94
92
95
n.d.
n.d.
93
93
93
95
0
9
10
11
12
13
14
15
16
17
18
e
<15
<15
e
DMF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
62
91
81
96
30
f
19
none
a
b
c
d
Conditions: 0.1 mmol of 1a or 1b, 14 h. Concentration with respect to the substrate 1a or 1b. Isolated yields. Enantioselectivities of 3a and 3b
e
f
determined by HPLC on chiral stationary phase. n.d. = not determined. NMR yield. 60 h.
and 14). CH2Cl2 turned out to be very suitable, providing
RESULTS AND DISCUSSION
■
product 3a in 62% yield and 93% ee and 3b in 91% yield and
93% ee (entries 15 and 16). These results were improved
further by performing the reaction less concentrated. By
reducing the substrate concentration from 0.2 to 0.1 M, the
reaction proceeded in 81% yield and 93% ee for 3a and 96%
yield and 95% ee for 3b (entries 17 and 18). Interestingly, in
the absence of rhodium catalyst some racemic product is
formed (entry 19). Thus, to summarize this part, we found
that α,β-unsaturated 2-acyl imidazoles can be β-alkylated
enantioselectively under photoredox conditions with 4-benzyl
HE 2a using the single catalyst Λ-RhS without any need for an
additional photocatalyst. A careful optimization of the reaction
conditions provided satisfactory results for two representative
substrates with respect to yields and enantioselectivities.
Substrate Scope. Next, the substrate scope was evaluated.
The C−C bond formation products 3a−h were provided in
yields of 53−96% and with 91−96% ee (Figure 2). The
presence of electron-donating (3c) and electron-withdrawing
(3d) substituents at the aromatic ring is well tolerated as well
as a more sterically demanding bromine atom at ortho position
(3e). Our method was also shown to be quite mild and robust,
which was demonstrated by the disubstituted aromatic ring in
3f, in which the ortho position carries a labile phenolate ester.
Substrates with aliphatic substituents at the β position are also
applicable (3g and 3h).
Initial Experiments and Conditions Optimization. We
started our study by evaluating the reaction between the α,β-
unsaturated 2-acyl imidazole substrate (1a) and 4-benzyl-
substituted Hantzsch ester 2a under photoredox conditions.
Using the “chiral-at-metal”16,17 catalyst Λ-RhS18 (8 mol %),
substrate 1a, and HE 2a (1.5 equiv) in acetone as solvent (0.2
M) under irradiation with a CFL light source, the conjugate
addition product 3a was obtained in 32% yield and with 96%
ee in the absence of any additional photocatalyst (Table 1,
entry 1). Using the substrate 1b with a phenyl substituent in
the β position provided 3b in an improved yield of 79% with
satisfactory 97% ee (entry 2). Changing the light source from
CFL to blue LEDs led to a small decrease in ee for both
products (entries 3 and 4), and replacement of Λ-RhS by the
related catalyst Δ-RhO18a resulted in a decrease in
enantioselectivity (entries 5 and 6). When the catalyst loading
of Λ-RhS was reduced to 4 mol %, the reaction 1a → 3a
proceeded with 34% yield and 89% ee while 1b → 3b
proceeded with 76% yield and 94% ee (entries 7 and 8).
However, considering to the cost of the rhodium catalyst, we
chose to continue the optimization with this lower catalyst
loading of 4 mol %.
Further optimizations were pursued, and we started with the
equivalents of the HE 2a. An increase in the amount of HE 2a
(2.0 equiv) did not improve the outcome (entries 9 and 10).
On the other hand, decreasing the amount of 2a to 1.2 equiv
turned out to be beneficial and afforded product 3a in 38%
yield and 92% ee and 3b in 77% yield and 95% ee (entries 11
and 12). In our next step, we evaluated the influence of solvent
in the reaction outcome. THF and DMF gave unsatisfactory
results, providing 3a and 3b yields of less than 15% (entries 13
The evaluation of different HE derivatives also performed
well, and reasonable yields (36%−quant.) and enantioselectiv-
ities (88−98% ee) were obtained for target products (3i−o).
Rendering the aromatic ring more electron-rich provided the
best results, affording 3i in a quantitative yield and with 98%
ee. Interestingly, the presence of an electron-withdrawing
fluorine atom at the para position did not inhibit product
C
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Figure 2. Scope with respect to α,β-unsaturated 2-acyl imidazoles and
4-alkyl HE derivatives. Reaction conditions: see Table 1, entries 17
and 18. aPerformed with 1.5 equiv of 2d. Configurations were
assigned by comparison of 3a−e, 3g−i, 3m, and 3o with reported
data.6
formation. Compound 3j was obtained with 92% yield and
88% ee, which demonstrates that electron-deficient moieties
can also take part in C−C bond formation in this method.
Introduction of ortho-bromo benzyl and 2-(thienyl)methyl
moieties to the β position also proceeded well (3k and 3l).
Compound 3m is the only example in which a low yield was
obtained, albeit stereoselectivity still remained satisfactory.
Good tolerability was observed when an N-(Boc)methyl
moiety was introduced (3n) as well as a secondary alkyl
group (3o).
Proposed Mechanism. The proposed mechanism is based
on mechanistic investigations of our related previous
work6,7,19−22 and the absorption properties of all individual
reaction components as shown in Figure 3a. Almost no visible
light is absorbed by the substrate 1b, whereas the HE 2a
displays a very weak absorption shoulder in the blue region,
and the catalyst RhS has a small absorption band in the violet/
blue region. However, the rhodium complex (RhS-1b) that is
formed upon coordination of the substrate 1b to the rhodium
catalyst by far shows the strongest absorption in the visible
Figure 3. (a) Absorption spectra (1b, RhS, and RhS-1b at 0.05 mM
and 2a at 0.5 mM, all in CH2Cl2 at room temperature), (b) overview
of relevant redox potentials, and (c) TEMPO trapping.
region, with an exctinction coefficient at 400 nm of ε400
=
34 950 M−1 cm−1.23,24 This is 5 times higher compared to the
catalyst RhS (ε400 = 7020 M−1 cm−1) and 89 times higher
compared to the HE 2a (ε400 = 294 M−1 cm−1). Since the
reaction mixture is devoid of any free catalyst RhS due to the
D
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Figure 4. Mechanistic proposal involving radical−radical recombination (path A) and Giese-type radical addition (path B).
excess of substrate at the beginning of the reaction and the HE
absorbs blue light by 2 orders of magnitude weaker compared
to the complex out of catalyst RhS and the 2-acyl imidazole
substrate (RhS-1b), we conclude that the RhS-substrate
complex must be the photoactive species in this system.25
On the basis of the visible-light absorption properties of the
individual components (Figure 3a) and relevant redox
potentials (Figure 3b), we propose the following mechanism
(Figure 4). The substrate coordinates to the rhodium catalyst
to form the RhS-substrate complex I and absorbs visible light
to form the photoexcited I*. I* is an oxidant in the
photoexcited state (Ered* = +0.88 V vs Fc/Fc+)24,26 and
engages in an exergonic single-electron transfer to oxidize the
HE (Epox = +1.03 V vs Ag/AgCl for 2a)27 to its radical cation
(HE·+), which then fragments to release an alkyl radical. The
formation of this alkyl radical is supported by a TEMPO
trapping experiment (Figure 3c). Now there are two options.
The alkyl radical can engage in a radical−radical coupling with
the reduced rhodium−substrate complex (enolate radical
anion II) to form the C−C bond formation product III.
Protonation forms the Rh-bound product (IV) which is
released to close the catalytic cycle. This pathway through the
radical−radical coupling with a rhodium−enolate radical anion
would be mechanistically analogous to a previously reported
rhodium-catalyzed β-amination.19 In addition, rhodium enolate
radical anions were recently proposed as reaction intermediates
in several developed methods.20−22
one photon per catalytic cycle, which is consistent with a
determined quantum yield of Φ = 0.14. Thus, both pathways
differ in the timing of the second electron transfer and the role
of the rhodium−substrate complex I. In both pathways this
rhodium−substrate complex is the photoactive species, which
upon visible-light activation oxidizes the HE and gets reduced
to the enolate radical anion II. However, in pathway A this
photoreduced species II is part of the catalytic cycle and reacts
with the alkyl radical, whereas in pathway B the rhodium−
substrate complex serves as a photoredox catalyst.
The here introduced method of rhodium-catalyzed asym-
metric radical conjugate additions using 4-substituted
Hantzsch esters warrants a comparison with our previous
method of employing organotrifluoroborates as radical
precursors for radical conjugate additions to α,β-unsaturated
2-acyl imidazoles and α,β-unsaturated N-acyl pyrazoles in the
presence of an additional photocatalyst.6 It is not obvious why
organotrifluoroborates in contrast to 4-substituted Hantzsch
esters require an additional photocatalyst because the photo-
induced electron transfer both from 4-substituted Hantzsch
esters9−15 and from organotrifluoroborates29 to the photo-
excited Rh-bound substrate complex (intermediate I*) is
apparently thermodynamically feasible, although 4-substituted
Hantzsch esters are slightly easier to oxidize. We speculate that
the differences are associated with the kinetics of the strongly
exergonic back electron transfer30 since the oxidized Hantzsch
ester can undergo a rapid deprotonation, thereby suppressing
any energy-wasting charge recombination. A similar deproto-
nation can occur from N-aryl tetrahydroisoquinoline radical
cations which might be responsible for obviating the need for
an additional photocatalyst in Kang’s recent work8 on the
addition of N-aryl tetrahydroisoquinolines to α,β-unsaturated
2-acyl imidazoles under visible-light-activated rhodium catal-
ysis. Coulomb and solvation effects on the driving force of the
photoinduced electron transfer and the kinetics of the back
Alternatively or in parallel, the formed alkyl radical upon
fragmentation of the oxidized HE (HE·+) performs a radical
conjugate addition to the Rh-coordinated substrate to afford
the radical intermediate V (path B).6,7 V will be reduced by II
to form III and is then protonated to form the catalyst-bound
product IV.28 Redox potentials disfavor a direct oxidation of
HE by intermediate V (see Figure 3b) so that a chain
mechanism is unlikely. Both pathways therefore need at least
E
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recorded on a Spectra Max M5 microplate reader in a 10.0 mm quartz
cuvette.
electron transfer might also be considered when evaluating the
effectiveness of the photoreaction between the cationic
photoexcited rhodium−substrate complex and the anionic
trifluoroborates or the neutral 4-substituted Hantzsch esters
and the N-aryl tetrahydroisoquinolines.30 In the course of the
photoinduced electron transfer (forward electron transfer) an
enolate radical anion of the rhodium−substrate complex
(intermediate II) is generated, and it is therefore conceivable
that in the here presented work on using 4-substituted
Hantzsch, in contrast to our previous work on using
organotrifluoroborates as radical precursors, the rhodium
enolate radical anion directly engages in a stereocontrolled
radical−radical recombination with a free alkyl radical.
However, since the steady state rhodium enolate radical
anion concentration should be very low, this radical−radical
recombination (pathway A) must directly compete with a
Giese-type radical conjugate addition to the more abundant
rhodium−substrate complex (pathway B) so that both
pathways might be operational in parallel under our
experimental conditions. In contrast, the here discussed
radical−radical recombination pathway is unlikely playing a
significant role in our previous work on organotrifluoroborates
as radical precursors because the electron transfer from the
reduced photocatalyst [Acr-Mes]ClO4 to the rhodium-bound
N-acyl imidazole substrates is not thermodynamically favor-
able.6,31
Synthesis of Substrates and Hantzsch Ester Derivatives.
α,β-Unsaturated 2-acyl imidazoles6 were synthesized according to
published procedures. Substrates 1a,33 1b and 1c,34 1d and 1e,6 1g
and 1h,6 2a and 2b,10 2e,10 and 2g and 2h14 have been reported.
5-Bromo-2-formylphenyl Acetate (S1).35 Compound S1 was
prepared by a modified method.36 To a solution of 4-bromosalicy-
laldehyde (201.0 mg, 1.0 mmol) and DMAP (12.2 mg, 0.10 mmol) in
pyridine (1.0 mL) at 0 °C, Ac2O (142 μL, 1.5 mmol) was added. The
mixture was stirred for 3 h at room temperature and then diluted with
AcOEt (15 mL). The mixture was washed with HCl(aq) 1 M (3 × 15
mL) and H2O (15 mL). The organic phase was separated and dried
with Na2SO4. The solvent was removed under vacuum at 35 °C,
furnishing the target compound as a white solid (231.1 mg, 0.95
mmol, yield 95%). 1H NMR (300 MHz, CDCl3) δ 10.06 (s, 1H), 7.74
(d, J = 8.3 Hz, 1H), 7.55 (dd, J = 8.3, 1.7 Hz, 1H), 7.40 (d, J = 1.8 Hz,
1H), 2.39 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 187.6, 168.7, 151.7,
132.0, 129.9, 129.5, 127.0, 20.7. IR (film): ν (cm−1) 1762, 1686,
1592, 1398, 1370, 1257, 1195, 1180, 1067, 1017, 924, 883, 846, 824,
806. HRMS (ESI, m/z) calcd for C9H8BrO3 [M + H]+: 242.9657.
Found: 242.9686.
(E)-5-Bromo-2-(3-oxo-3-(1-phenyl-1H-imidazol-2-yl)prop-1-en-
1-yl)phenyl Acetate (1f). According to our published procedure,6 the
corresponding Wittig reagent S233 (178.6 mg, 0.40 mmol) reacted
with 5-bromo-2-formylphenyl acetate (S1) (194.4 mg, 0.80 mmol) in
toluene (2.0 mL) at 85 °C for 15 h. Compound 1f was obtained as a
pale yellow solid (124.4 mg, 0.30 mmol, yield 76%) after column
chromatography purification (hex:AcOEt = 70:30), followed by
recrystallization from AcOEt/n-hexane. Only the E isomer was
1
CONCLUSION
obtained. H NMR (300 MHz, CDCl3) δ 8.11 (d, J = 16.1 Hz, 1H),
■
7.75 (d, J = 5.6 Hz, 1H), 7.71 (d, J = 1.9 Hz, 1H), 7.54−7.46 (m,
3H), 7.41 (dd, J = 8.4, 1.6 Hz, 1H), 7.36−7.30 (m, 4H), 7.24 (d, J =
0.9 Hz, 1H), 2.35 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 178.6,
168.7, 150.0, 143.9, 138.5, 135.5, 130.0, 129.6, 129.0, 128.9, 128.9,
127.5, 126.7, 126.5, 126.0, 124.8, 124.4, 20.9. IR (film): ν (cm−1)
3051, 1769, 1660, 1596, 1481, 1399, 1364, 1307, 1188, 1148, 1038,
1012, 973, 925, 874, 817, 764, 692, 546. HRMS (ESI, m/z) calcd for
C20H15BrN2O3Na [M + Na]+: 433.0158. Found: 433.0187.
General Procedure for the Syntheses of Hantzsch Esters
Derivatives 2c, 2d, and 2f. In a 25 mL round-bottom flask was
added the corresponding aldehyde (1 equiv) and absolute ethanol
(0.5 M). tert-Butyl acetoacetate (2 equiv) was added, followed by an
aqueous solution of ammonia 20% (2 equiv). The flask was equipped
with a condenser, and the system was flushed with N2. The flask was
immersed in a preheated oil bath and refluxed overnight. The mixture
was cooled down to room temperature, and the solvent was removed
under vacuum. The crude material was extracted with CH2Cl2 (3 ×
20 mL) and H2O (20 mL). The organics were put together and dried
over Na2SO4, and the solvent was removed under vacuum at 35 °C.
The crude product was purified by column chromatography with
silica gel using hex:AcOEt at the indicated proportion, followed by
recrystallization, when necessary.
Di-tert-butyl 4-(4-fluorobenzyl)-2,6-dimethyl-1,4-dihydropyri-
dine-3,5-dicarboxylate (2c). According to the general procedure, to
a solution of 2-(4-fluorophenyl)acetaldehyde (276.3 mg, 2.00 mmol)
in absolute EtOH (4.0 mL) was added tert-butyl acetoacetate (0.65
mL, 4.00 mmol) and ammonia (0.80 mL of a 20% aqueous solution,
4.00 mmol). Compound 2c was obtained as a white solid (320.4 mg,
0.77 mmol, yield 38%) after column chromatography purification
(hex:AcOEt = 90:10), followed by recrystallization from CH2Cl2/n-
hexane. 1H NMR (300 MHz, CDCl3) δ 6.95 (tt, J = 5.0, 2.4 Hz, 2H),
6.86 (tt, J = 8.8, 2.3 Hz, 2H), 5.15 (bs, 1H), 4.11 (t, J = 5.5 Hz, 1H),
2.52 (d, J = 5.5 Hz, 2H), 2.14 (s, 6H), 1.44 (s,18H). 13C NMR (75
MHz, CDCl3) δ 167.0, 163.2, 156.0, 144.4, 135.2, 135.1, 131.4, 131.3,
114.2, 113.9, 103.0, 79.4, 40.8, 35.9, 28.3, 19.2. IR (film): ν (cm−1)
3315, 3235, 3093, 3003, 2974, 2931, 2850, 1694, 1680, 1645, 1508,
1482, 1364, 1234, 1219, 1156, 1124, 1114, 1088, 1012, 852, 820, 790,
779, 756, 746, 533, 475, 453. HRMS (ESI, m/z) calcd for
C24H32FNO4Na [M + Na]+: 440.2208. Found: 440.2218.
We have devised a very efficient and practical method for
the β-functionalization of 2-acyl imidazoles using our
previously developed RhS catalyst as the chiral Lewis acid
and the photoactivating agent along with 4-alkyl HE
derivatives as precursors in the generation of alkyl radicals.
The presented method appears to be superior to published
methods with respect to simplicity of execution, catalyst
loading, scope, and high enantioselectivities. The application of
this method to the synthesis of bioactive dihydrocoumarins
and chromanes is ongoing in our laboratories.32
EXPERIMENTAL SECTION
■
General Information. All catalytic reactions were performed in a
Schlenk tube (10 mL). A 21 W CFL (OSRAM DULUX SUPER-
STAR Micro Twist) served as the light source. The catalysts Λ-
RhS18b and Δ-RhO18a were synthesized according to our published
procedures. THF was distilled under nitrogen from sodium/
benzophenone. HPLC grade acetone, CH2Cl2, and DMF was used
without further purification. Reagents that were purchased from
commercial suppliers were used without further purification. Flash
column chromatography was performed with silica gel 60 M from
Macherey-Nagel (irregular shaped, 230−400 mesh, pH 6.8, pore
volume 0.81 mL μg−1, mean pore size 66 Å, specific surface 492 m2
μg−1, particle size distribution 0.5% < 25 μm and 1.7% > 71 μm, water
1
content 1.6%). H NMR and proton decoupled 13C NMR spectra
were recorded on Bruker Avance 300 (300 MHz) or Bruker AM (500
MHz) spectrometers at ambient temperature. NMR yields were
determined using 1,1,2,2-tetrachloroethane as internal standard. NMR
standards were used as follows: 1H NMR spectroscopy δ = 7.26 ppm
(CDCl3), 13C NMR spectroscopy δ = 77.0 ppm (CDCl3). IR spectra
were recorded on a Bruker Alpha FT-IR spectrophotometer. High-
resolution mass spectra were recorded on a Bruker En Apex Ultra 7.0
TFT-MS instrument (FT-ICR analyzer) using the ESI technique.
Chiral HPLC chromatography was performed with an Agilent 1200 or
Agilent 1260 HPLC system. Optical rotations were measured on a
22
Kru
̈
ss P8000-T polarimeter with [α]D values reported in degrees
with concentrations reported in g/100 mL. UV−vis absorbance was
F
DOI: 10.1021/acs.joc.8b01588
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Di-tert-butyl 4-(2-bromobenzyl)-2,6-dimethyl-1,4-dihydropyri-
dine-3,5-dicarboxylate (2d). According to the general procedure,
to a solution of 2-(2-bromophenyl)acetaldehyde (452.5 mg, 2.27
mmol) in absolute EtOH (4.5 mL) was added tert-butyl acetoacetate
(0.73 mL, 4.54 mmol) and ammonia (0.90 mL of a 20% aqueous
solution, 4.60 mmol). Compound 2d was obtained as a white solid
(487.1 mg, 1.02 mmol, yield 45%) after column chromatography
by HPLC analysis using a Chiralcel OJ-H column, ee = 95% (HPLC:
OJ-H, 254 nm, n-hexane/isopropanol = 50:50, flow rate 1.0 mL/min,
25 °C, tr (minor) = 13.6 min, tr (major) = 22.3 min). 1H NMR (300
MHz, CDCl3) δ 7.40−7.33 (m, 3H), 7.25−7.13 (m, 9H), 7.10−7.06
(m, 3H), 7.01−6.97 (m, 2H), 3.71−3.59 (m, 2H), 3.44−3.34 (m,
1H), 2.94 (d, J = 7.2 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 190.0,
144.0, 143.3, 139.8, 138.2, 129.4, 129.3, 128.8, 128.5, 128.2, 128.1,
127.8, 126.8, 126.2, 126.0, 125.6, 44.4, 43.6, 43.0. All analytical data
are in accordance with the literature.6
1
purification (hex:AcOEt = 90:10). H NMR (300 MHz, CDCl3) δ
7.46 (d, J = 8.0 Hz, 1H), 7.19−7.11 (m, 1H), 7.10 (dd, J = 12.1, 4.6
Hz, 2H), 5.39 (bs, 1H), 4.31 (t, J = 6.3 Hz, 1H), 2.74 (d, J = 6.4 Hz,
2H), 2.24 (s, 6H), 1.42 (s, 18H). 13C NMR (75 MHz, CDCl3) δ
166.9, 144.6, 138.9, 132.6, 132.3, 127.3, 126.4, 125.6, 103.2, 79.3,
40.4, 34.6, 28.3, 28.2, 19.4. IR (film): ν (cm−1) 3340, 3317, 3070,
3005, 2976, 2930, 2869, 2817, 1714, 1688, 1647, 1472, 1443, 1364,
1291, 1258, 1233, 1153, 1109, 1044, 1023, 857, 770, 748, 706. HRMS
(ESI, m/z) calcd for C24H32BrNO4Na [M + Na]+: 500.1407. Found:
500.1422.
(R)-3-(4-Methoxyphenyl)-4-phenyl-1-(1-phenyl-1H-imidazol-2-
yl)butan-1-one (3c). According to the general procedure, α,β-
unsaturated acyl imidazole 1c (30.4 mg, 0.10 mmol) reacted with
Hantzsch ester 2a (47.9 mg, 0.12 mmol) for 14 h, affording 3c as a
pale yellow oil (30.0 mg, 0.076 mmol, yield 76%) after column
chromatography purification (hex:AcOEt = 65:35). Enantiomeric
excess established by HPLC analysis using a Chiralpak AD-H column,
ee = 91% (HPLC: AD-H, 254 nm, n-hexane/isopropanol = 90:10,
flow rate 1.0 mL/min, 25 °C, tr (minor) = 17.2 min, tr (major) = 18.9
Di-tert-butyl 4-((benzyloxy)methyl)-2,6-dimethyl-1,4-dihydro-
pyridine-3,5-dicarboxylate (2f). According to the general procedure,
to a solution of benzyloxyacetaldehyde (0.29 mL, 2.00 mmol) in
absolute EtOH (4.0 mL) was added tert-butyl acetoacetate (0.65 mL,
4.00 mmol) and ammonia (0.80 mL of a 20% aqueous solution, 4.00
mmol). Compound 2f was obtained as a white solid (304.7 mg, 0.71
mmol, yield 35%) after column chromatography purification
(hex:AcOEt = 75:25), followed by recrystallization from Et2O/
1
min). H NMR (300 MHz, CDCl3) δ 7.37 (d, J = 7.5 Hz, 3H), 7.25
(d, J = 13.1 Hz, 1H), 7.18 (t, J = 7.0 Hz, 2H), 7.13 (d, J = 7.0 Hz,
1H), 7.07 (dd, J = 14.9, 6.9 Hz, 5H), 7.01 (d, J = 6.8 Hz, 2H), 6.76
(d, J = 8.1 Hz, 2H), 3.75 (s, 3H), 3.67−3.54 (m, 2H), 3.35 (d, J =
11.2 Hz, 1H), 2.90 (d, J = 6.2 Hz, 2H). 13C NMR (75 MHz, CDCl3)
δ 190.1, 158.0, 143.3, 139.9, 138.2, 136.0, 129.3, 128.82, 128.75,
128.5, 128.0, 126.8, 125.9, 125.6, 113.6, 55.2, 44.6, 43.7, 42.2. All
analytical data are in accordance with the literature.6
1
pentane. H NMR (300 MHz, CDCl3) δ 7.19−7.29 (m, 5H), 5.39
(bs, 1H), 4.50 (s, 2H), 4.17 (t, J = 5.6 Hz, 1H), 2.31 (d, J = 5.6 Hz,
2H), 2.24 (s, 6H), 1.46 (s, 18H). 13C NMR (75 MHz, CDCl3) δ
167.2, 144.3, 139.3, 128.1, 127.3, 127.0, 102.0, 79.4, 73.3, 72.5, 34.8,
28.3, 19.5. IR (film): ν (cm−1) 3328, 3241, 3100, 3027, 3003, 2969,
2930, 2854, 1688, 1657, 1641, 1490, 1363, 1305, 1225, 1155, 1123,
1105, 1084, 1067, 1048, 1026, 995, 778, 752, 697, 610. HRMS (ESI,
m/z) calcd for C25H35NO5Na [M + Na]+: 452.2407. Found:
452.2421.
General Procedure for Rhodium-Catalyzed Photoredox Reac-
tions. A dried 10 mL Schlenk tube was charged with the
corresponding α,β-unsaturated acyl imidazole (0.1 mmol), catalyst
Λ-RhS (4 mol %), and the corresponding Hantzsch ester (0.12 or
0.15 mmol). To the mixture was added 1.0 mL of HPLC CH2Cl2,
followed by degasification via freeze−pump−thaw for three cycles.
After the mixture was thoroughly degassed, the tube was sealed and
positioned approximately 5−6 cm from a 21 W CFL lamp. The
reaction was stirred at room temperature for the indicated time
(monitored by TLC) under nitrogen atmosphere. The solvent was
removed under vacuum at 30 °C, and the crude product was purified
by column chromatography on silica gel using hex:AcOEt at the
indicated proportion. Racemic samples were obtained by carrying out
the reactions with rac-RhS. The enantiomeric excess was determined
by HPLC analysis on a chiral stationary phase.
(R)-3-Methyl-4-phenyl-1-(1-phenyl-1H-imidazol-2-yl)butan-1-
one (3a). According to the general procedure, α,β-unsaturated acyl
imidazole 1a (21.2 mg, 0.10 mmol) reacted with Hantzsch ester 2a
(47.9 mg, 0.12 mmol) for 14 h, affording 3a as a pale yellow solid
(24.8 mg, 0.081 mmol, yield 81%) after column chromatography
purification (hex:AcOEt = 75:25). Enantiomeric excess established by
HPLC analysis using a Chiralpak AD-H column, ee = 93% (HPLC:
AD-H, 254 nm, n-hexane/isopropanol = 95:5, flow rate 1.0 mL/min,
25 °C, tr (minor) = 10.2 min, tr (major) = 11.4 min). 1H NMR (300
MHz, CDCl3) δ 7.38−7.35 (m, 3H), 7.19−7.15 (m, 5H), 7.10−7.07
(m, 4H), 3.09−2.95 (m, 2H), 2.63−2.57 (m, 1H), 2.47−2.32 (m,
2H), 0.85 (d, J = 6.3 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 191.0,
143.4, 140.6, 138.5, 129.4, 129.3, 128.9, 128.7, 128.1, 127.0, 125.9,
125.8, 45.6, 43.3, 31.3, 19.8. All analytical data are in accordance with
the literature.6
(R)-3-(4-Fluorophenyl)-4-phenyl-1-(1-phenyl-1H-imidazol-2-yl)-
butan-1-one (3d). According to the general procedure, α,β-
unsaturated acyl imidazole 1d (29.2 mg, 0.10 mmol) reacted with
Hantzsch ester 2a (47.9 mg, 0.12 mmol) for 14 h, affording 3d as a
pale yellow solid (35.1 mg, 0.091 mmol, yield 91%) after column
chromatography purification (hex:AcOEt = 75:25). Enantiomeric
excess established by HPLC analysis using a Chiralcel OJ-H column,
ee = 95% (HPLC: OJ-H, 254 nm, n-hexane/isopropanol = 70:30, flow
rate 1.0 mL/min, 25 °C, tr (minor) = 15.2 min, tr (major) = 26.7
1
min). H NMR (300 MHz, CDCl3) δ 7.45−7.34 (m, 3H), 7.24 (d, J
= 0.8 Hz, 1H), 7.22−7.08 (m, 6H), 7.03 (dd, J = 5.3, 2.6 Hz, 4H),
6.95−6.84 (m, 2H), 3.63 (dq, J = 13.1, 8.3 Hz, 2H), 3.45−3.30 (m,
1H), 3.00−2.81 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 189.8,
163.0, 159.8, 143.2, 139.5, 139.5, 138.2, 129.4, 129.3, 129.2, 129.2,
128.9, 128.6, 128.1, 126.9, 126.0, 125.6, 115.1, 114.8, 77.4, 77.0, 76.6,
44.5, 43.6, 42.3. All analytical data are in accordance with the
literature.6
(R)-3-(2-Bromophenyl)-4-phenyl-1-(1-phenyl-1H-imidazol-2-yl)-
butan-1-one (3e). According to the general procedure, α,β-
unsaturated acyl imidazole 1e (35.3 mg, 0.10 mmol) reacted with
Hantzsch ester 2a (47.9 mg, 0.12 mmol) for 13 h, affording 3e as a
pale yellow solid (34.4 mg, 0.077 mmol, yield 77%) after column
chromatography purification (hex:AcOEt = 75:25). Enantiomeric
excess established by HPLC analysis using a Chiralcel OJ-H column,
ee = 96% (HPLC: OJ-H, 254 nm, n-hexane/isopropanol = 70:30, flow
rate 1.0 mL/min, 25 °C, tr (minor) = 10.4 min, tr (major) = 15.6
min). 1H NMR (300 MHz, CDCl3) δ 7.41 (dd, J = 8.0, 1.2 Hz, 1H),
7.31−7.23 (m, 4H), 7.18−7.06 (m, 7H), 7.02 (d, J = 0.9 Hz, 1H),
6.97−6.90 (m, 3H), 4.18−4.09 (m, 1H), 3.55 (dd, J = 16.8, 8.1 Hz,
1H), 3.36 (dd, J = 16.8, 6.7 Hz, 1H), 2.96 (dd, J = 13.6, 6.3 Hz, 1H),
2.72 (dd, J = 13.6, 8.4 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 189.3,
143.1, 142.8, 139.2, 138.2, 133.0, 129.4, 128.8, 128.6, 128.2, 128.1,
127.7, 127.4, 126.9, 126.1, 125.6, 125.0, 43.0, 42.1, 41.2. All analytical
data are in accordance with the literature.6
(R)-5-Bromo-2-(4-oxo-1-phenyl-4-(1-phenyl-1H-imidazol-2-yl)-
butan-2-yl)phenyl acetate (3f). According to the general procedure,
α,β-unsaturated acyl imidazole 1f (41.1 mg, 0.10 mmol) reacted with
Hantzsch ester 2a (47.9 mg, 0.12 mmol) for 18 h, affording 3f as a
pale yellow oil (43.7 mg, 0.087 mmol, yield 87%) after column
chromatography purification (hex:AcOEt = 70:30). Enantiomeric
excess established by HPLC analysis using a Chiralcel OJ-H column,
ee = 94% (HPLC: OJ-H, 254 nm, n-hexane/isopropanol = 85:15, flow
rate 1.0 mL/min, 25 °C, tr (minor) = 19.8 min, tr (major) = 33.4
min). [α]D22 = −4.2° (c 1.0, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ
(R)-3,4-Diphenyl-1-(1-phenyl-1H-imidazol-2-yl)butan-1-one
(3b). According to the general procedure, α,β-unsaturated acyl
imidazole 1b (27.4 mg, 0.10 mmol) reacted with Hantzsch ester 2a
(47.9 mg, 0.12 mmol) for 14 h, affording 3b as a pale yellow oil (35.3
mg, 0.096 mmol, yield 96%) after column chromatography
purification (hex:AcOEt = 75:25). Enantiomeric excess established
G
DOI: 10.1021/acs.joc.8b01588
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
7.43−7.35 (m, 3H), 7.30−7.27 (m, 1H), 7.24−7.13 (m, 6H), 7.11 (d,
J = 0.9 Hz, 1H), 7.08−7.01 (m, 4H), 3.90 (p, J = 7.4 Hz, 1H), 3.46
(d, J = 7.4 Hz, 2H), 2.88 (d, J = 7.4 Hz, 2H), 2.24 (s, 3H). 13C NMR
(75 MHz, CDCl3) δ 189.2, 168.7, 148.9, 143.0, 139.1, 138.2, 134.8,
129.6, 129.4, 129.2, 129.1, 128.8, 128.6, 128.2, 127.0, 126.2, 125.8,
125.7, 119.6, 43.7, 42.0, 35.8, 20.9. IR (film): ν (cm−1) 3133, 3108,
3062, 3027, 2921, 2854, 1766, 1682, 1492, 1482, 1445, 1402, 1366,
1189, 1011, 915, 761, 737, 693, 511. HRMS (ESI, m/z) calcd for
C27H23BrN2O3Na [M + Na]+: 525.0784. Found: 525.0797.
MHz, CDCl3) δ 189.8, 163.0, 159.7, 143.6, 143.2, 138.2, 135.4,
135.40, 130.7, 130.6, 129.4, 128.8, 128.6, 128.3, 127.8, 126.9, 126.3,
125.6, 114.9, 114.6, 44.4, 43.1, 42.6. IR (film): ν (cm−1) 3138, 3108,
3063, 3029, 2923, 2855, 1682, 1598, 1507, 1493, 1445, 1403, 1304,
1218, 1156, 964, 913, 825, 757, 692, 538, 521, 488. HRMS (ESI, m/
z) calcd for C25H22FN2O [M + H]+: 385.1711. Found: 385.1721.
(R)-4-(2-Bromophenyl)-3-phenyl-1-(1-phenyl-1H-imidazol-2-yl)-
butan-1-one (3k). According to the general procedure, α,β-
unsaturated acyl imidazole 1b (27.4 mg, 0.10 mmol) reacted with
Hantzsch ester 2d (71.8 mg, 0.15 mmol) for 16 h, affording 3k as a
colorless oil (33.2 mg, 0.074 mmol, yield 74%) after column
chromatography purification (hex:AcOEt = 75:25). Enantiomeric
excess established by HPLC analysis using a Chiralcel OJ-H column,
ee = 90% (HPLC: OJ-H, 254 nm, n-hexane/isopropanol = 50:50, flow
rate 1.0 mL/min, 25 °C, tr (minor) = 11.3 min, tr (major) = 29.8
min). [α]D22 = −6.8° (c 1.0, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ
7.49 (d, J = 8.0 Hz, 1H), 7.38−7.30 (m, 3H), 7.25−7.20 (m, 5H),
7.19−7.10 (m, 1H), 7.07 (d, J = 7.0 Hz, 2H), 6.99 (dd, J = 12.1, 5.0
Hz, 4H), 3.89−3.69 (m, 2H), 3.39−3.22 (m, 1H), 3.14−2.98 (m,
2H). 13C NMR (75 MHz, CDCl3) δ 189.8, 143.6, 143.3, 139.1, 138.2,
132.8, 131.5, 129.4, 128.8, 128.5, 128.2, 127.8, 127.8, 126.9, 126.8,
126.4, 125.6, 124.9, 44.0, 43.5, 41.3. IR (film): ν (cm−1) 3133, 3108,
3061, 3028, 2923, 2855, 1682, 1492, 1444, 1403, 1304, 1024, 964,
913, 753, 692, 659, 548, 519. HRMS (ESI, m/z) calcd for
C25H22BrN2O [M + H]+: 445.0910. Found: 445.0921.
(R)-3-Benzyl-1-(1-phenyl-1H-imidazol-2-yl)hexan-1-one (3g).
According to the general procedure, α,β-unsaturated acyl imidazole
1g (24.0 mg, 0.10 mmol) reacted with Hantzsch ester 2a (47.9 mg,
0.12 mmol) for 13 h, affording 3g as a colorless oil (19.2 mg, 0.058
mmol, yield 58%) after column chromatography purification
(hex:AcOEt = 80:20). Enantiomeric excess established by HPLC
analysis using a Chiralpak AD-H column, ee = 92% (HPLC: AD-H,
254 nm, n-hexane/isopropanol = 99:1, flow rate 1.0 mL/min, 25 °C,
1
tr (minor) = 13.5 min, tr (major) = 14.8 min). H NMR (300 MHz,
CDCl3) δ 7.47−7.42 (m, 3H), 7.25−7.19 (m, 5H), 7.17−7.12 (m,
4H), 3.18 (dd, J = 16.9, 6.7 Hz, 1H), 3.04 (dd, J = 16.9, 6.4 Hz, 1H),
2.67 (dd, J = 13.5, 6.9 Hz, 1H), 2.56 (dd, J = 13.5, 7.4 Hz, 1H), 2.47−
2.36 (m, 1H), 1.40−1.35 (m, 4H), 0.84 (t, J = 6.7 Hz, 3H). 13C NMR
(75 MHz, CDCl3) δ 191.2, 143.4, 140.8, 138.5, 129.4, 128.9, 128.7,
128.1, 126.9, 125.9, 125.8, 43.1, 40.7, 36.3, 35.7, 19.9, 14.2. All
analytical data are in accordance with the literature.6
(S)-3-Phenyl-1-(1-phenyl-1H-imidazol-2-yl)-4-(thiophen-2-yl)-
butan-1-one (3l). According to the general procedure, α,β-
unsaturated acyl imidazole 1b (27.4 mg, 0.10 mmol) reacted with
Hantzsch ester 2e (48.7 mg, 0.12 mmol) for 17 h, affording 3l as a
colorless oil (28.5 mg, 0.076 mmol, yield 76%) after column
chromatography purification (hex:AcOEt = 75:25). Enantiomeric
excess established by HPLC analysis using a Chiralcel OJ-H column,
ee = 92% (HPLC: OJ-H, 254 nm, n-hexane/isopropanol = 50:50, flow
rate 1.0 mL/min, 25 °C, tr (minor) = 20.4 min, tr (major) = 24.9
min). [α]D22 = −2.4° (c 1.0, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ
7.44−7.32 (m, 3H), 7.28−7.13 (m, 6H), 7.10 (d, J = 1.0 Hz, 1H),
7.06−6.97 (m, 3H), 6.82 (dd, J = 5.1, 3.4 Hz, 1H), 6.69−6.62 (m,
1H), 3.73−3.57 (m, 2H), 3.52−3.36 (m, 1H), 3.27−3.06 (m, 2H).
13C NMR (75 MHz, CDCl3) δ 189.7, 143.5, 143.2, 142.2, 138.2,
(R)-3-Benzyl-4-methyl-1-(1-phenyl-1H-imidazol-2-yl)pentan-1-
one (3h). According to the general procedure, α,β-unsaturated acyl
imidazole 1h (24.0 mg, 0.10 mmol) reacted with Hantzsch ester 2a
(47.9 mg, 0.12 mmol) for 13 h, affording 3h as a colorless oil (17.7
mg, 0.053 mmol, yield 53%) after column chromatography
purification (hex:AcOEt = 80:20). Enantiomeric excess established
by HPLC analysis using a Chiralpak AD-H column, ee = 93%
(HPLC: AD-H, 254 nm, n-hexane/isopropanol = 98:2, flow rate 1.0
1
mL/min, 25 °C, tr (minor) = 8.4 min, tr (major) = 9.9 min). H
NMR (300 MHz, CDCl3) δ 7.45−7.40 (m, 3H), 7.25−7.11 (m, 9H),
3.17 (dd, J = 17.1, 5.9 Hz, 1H), 3.04 (dd, J = 17.1, 6.8 Hz, 1H), 2.69
(dd, J = 13.3, 6.4 Hz, 1H), 2.52−2.45 (m, 1H), 2.44−2.33 (m, 1H),
1.78−1.68 (m, 1H), 0.95 (d, J = 6.9 Hz, 3H), 0.91 (d, J = 6.9 Hz,
3H). 13C NMR (75 MHz, CDCl3) δ 191.2, 143.4, 141.1, 138.5, 129.3,
128.8, 128.6, 128.1, 126.9, 125.9, 125.7, 41.4, 39.6, 37.7, 29.6, 19.6,
18.5. All analytical data are in accordance with the literature.6
(R)-4-(4-Methoxyphenyl)-3-phenyl-1-(1-phenyl-1H-imidazol-2-
yl)butan-1-one (3i). According to the general procedure, α,β-
unsaturated acyl imidazole 1b (27.4 mg, 0.10 mmol) reacted with
Hantzsch ester 2b (51.5 mg, 0.12 mmol) for 16 h, affording 3i as a
pale yellow oil (39.6 mg, 0.10 mmol, yield quant.) after column
chromatography purification (hex:AcOEt = 75:25). Enantiomeric
excess established by HPLC analysis using a Chiralcel OJ-H column,
ee = 98% (HPLC: OJ-H, 254 nm, n-hexane/isopropanol = 50:50, flow
rate 1.0 mL/min, 25 °C, tr (minor) = 17.3 min, tr (major) = 45.5
min). 1H NMR (300 MHz, CDCl3) δ 7.40−7.33 (m, 3H), 7.25−7.12
(m, 6H), 7.09 (bs, 1H), 7.00−6.96 (m, 4H), 6.72 (d, J = 8.6 Hz, 2H),
3.74 (s, 3H), 3.67−3.54 (m, 2H), 3.45−3.34 (m, 1H), 2.88 (d, J = 7.0
Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 190.0, 157.9, 144.1, 143.3,
138.2, 131.9, 130.2, 129.3, 128.8, 128.5, 128.2, 127.9, 126.8, 126.2,
125.6, 113.5, 55.1, 44.3, 43.2, 42.7. All analytical data are in
accordance with the literature.6
129.4, 128.9, 128.6, 128.3, 127.9, 126.8, 126.5, 126.5, 125.7, 123.5,
44.6, 43.3, 37.2. IR (film): ν (cm−1) 3132, 3107, 3062, 3028, 2916,
2849, 1682, 1597, 1492, 1444, 1403, 1305, 1034, 962, 914, 850, 757,
690, 518. HRMS (ESI, m/z) calcd for C23H21N2OS [M + H]+:
373.1369. Found: 373.1379.
(R)-4-(Benzyloxy)-3-phenyl-1-(1-phenyl-1H-imidazol-2-yl)butan-
1-one (3m). According to the general procedure, α,β-unsaturated acyl
imidazole 1b (27.4 mg, 0.10 mmol) reacted with Hantzsch ester 2f
(51.5 mg, 0.12 mmol) for 16 h, affording 3m as a colorless oil (14.3
mg, 0.036 mmol, yield 36%) after column chromatography
purification (hex:AcOEt = 80:20). Enantiomeric excess established
by HPLC analysis using a Chiralpak OD-H column, ee = 93%
(HPLC: OD-H, 254 nm, n-hexane/isopropanol = 95:5, flow rate 1.0
1
mL/min, 25 °C, tr (minor) = 20.4 min, tr (major) = 23.1 min). H
NMR (300 MHz, CDCl3) δ 7.43−7.32 (m, 3H), 7.32−7.17 (m,
11H), 7.12 (d, J = 0.9 Hz, 1H), 7.04−6.97 (m, 2H), 4.45 (s, 2H),
3.85−3.57 (m, 4H), 3.52−3.38 (m, 1H). 13C NMR (75 MHz,
CDCl3) δ 189.8, 143.3, 141.9, 138.3, 129.4, 128.8, 128.5, 128.4, 128.2,
128.0, 127.6, 127.4, 126.8, 126.6, 125.7, 74.9, 73.0, 42.3, 41.7. All
analytical data are in accordance with the literature.6
(R)-4-(4-Fluorophenyl)-3-phenyl-1-(1-phenyl-1H-imidazol-2-yl)-
butan-1-one (3j). According to the general procedure, α,β-
unsaturated acyl imidazole 1b (27.4 mg, 0.10 mmol) reacted with
Hantzsch ester 2c (50.1 mg, 0.12 mmol) for 18 h, affording 3j as a
pale yellow oil (35.5 mg, 0.092 mmol, yield 92%) after column
chromatography purification (hex:AcOEt = 75:25). Enantiomeric
excess established by HPLC analysis using a Chiralcel OJ-H column,
ee = 88% (HPLC: OJ-H, 254 nm, n-hexane/isopropanol = 50:50, flow
rate 1.0 mL/min, 25 °C, tr (minor) = 12.3 min, tr (major) = 22.9
min). [α]D22 = −5.8° (c 1.0, CH2Cl2). 1H NMR (300 MHz, CDCl3) δ
7.41−7.34 (m, 3H), 7.24−7.20 (m, 3H), 7.17−7.13 (m, 3H), 7.10 (d,
J = 0.9 Hz, 1H), 7.04−6.96 (m, 4H), 6.88−6.82 (m, 2H), 3.65−3.54
(m, 2H), 3.49−3.38 (m, 1H), 2.97−2.84 (m, 2H). 13C NMR (75
(R)-tert-Butyl (4-oxo-2-phenyl-4-(1-phenyl-1H-imidazol-2-yl)-
butyl)carbamate (3n). According to the general procedure, α,β-
unsaturated acyl imidazole 1b (27.4 mg, 0.10 mmol) reacted with
Hantzsch ester 2g (52.6 mg, 0.12 mmol) for 18 h, affording 3n as a
pale yellow oil (38.5 mg, 0.095 mmol, yield 95%) after column
chromatography purification (hex:AcOEt = 60:40). Enantiomeric
excess established by HPLC analysis using a Chiralpak OD-H column,
ee = 93% (HPLC: OD-H, 254 nm, n-hexane/isopropanol = 95:5, flow
rate 1.0 mL/min, 25 °C, tr (minor) = 23.4 min, tr (major) = 27.1
min). [α]D22 = −11.6° (c 1.0, CH2Cl2). 1H NMR (300 MHz, CDCl3)
δ 7.44−7.37 (m, 3H), 7.30−7.26 (m, 2H), 7.25−7.18 (m, 4H), 7.14−
H
DOI: 10.1021/acs.joc.8b01588
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The Journal of Organic Chemistry
Article
7.10 (m, 3H), 4.50 (bs, 1H), 3.56−3.26 (m, 5H), 1.36 (s, 18H). 13C
NMR (75 MHz, CDCl3) δ 189.4, 155.7, 143.0, 141.8, 138.2, 129.5,
128.9, 128.6, 128.6, 127.9, 127.0, 126.8, 125.7, 79.1, 45.8, 42.6, 41.1,
28.3. IR (film): ν (cm−1) 3435, 3354, 3137, 3109, 3062, 3029, 3004,
2975, 2929, 1685, 1493, 1447, 1404, 1365, 1267, 1248, 1164, 965,
914, 755, 692, 666, 515. HRMS (ESI, m/z) calcd for C24H27N3O3Na
[M + Na]+: 428.1945. Found: 428.1955.
Pblank is the radiant power transmitted by the cuvette with a blank
solution, and Psample is the radiant power transmitted by the cuvette
with reaction mixture.
TEMPO Trapping Experiment. According to the general
procedure described for the rhodium-catalyzed photoredox reactions,
α,β-unsaturated acyl imidazole 1b (27.4 mg, 0.10 mmol) reacted with
Hantzsch ester 2a (47.9 mg, 0.12 mmol) and TEMPO (39.1 mg, 0.25
mmol) for 38 h, affording 4 in approximately 70% NMR yield using
1,1,2,2-tetrachloroethane as internal standard.
(S)-4-Methyl-3-phenyl-1-(1-phenyl-1H-imidazol-2-yl)pentan-1-
one (3o). According to the general procedure, α,β-unsaturated acyl
imidazole 1b (27.4 mg, 0.10 mmol) reacted with Hantzsch ester 2h
(42.2 mg, 0.12 mmol) for 15 h, affording 3o as a pale yellow oil (27.0
mg, 0.085 mmol, yield 85%) after column chromatography
purification (hex:AcOEt = 75:25). Enantiomeric excess established
by HPLC analysis using a Chiralpak AD-H column, ee = 97%
(HPLC: AD-H, 254 nm, n-hexane/isopropanol = 95:5, flow rate 1.0
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.8b01588.
1
Voltamogram of HE 2a, 1H and 13C NMR spectra of all
mL/min, 25 °C, tr (minor) = 9.7 min, tr (major) = 12.2 min). H
NMR (300 MHz, CDCl3) δ 7.39−7.29 (m, 3H), 7.25−7.21 (m, 3H),
7.17−7.13 (m, 3H), 7.08 (d, J = 0.8 Hz, 1H), 6.88 (dd, J = 7.9, 1.6
Hz, 2H), 3.61 (dd, J = 16.1, 9.7 Hz, 1H), 3.46 (dd, J = 16.1, 5.6 Hz,
1H), 3.13 (ddd, J = 9.6, 7.5, 5.7 Hz, 1H), 1.97−1.81 (m, 1H), 0.97 (d,
J = 6.7 Hz, 3H), 0.77 (d, J = 6.7 Hz, 3H). 13C NMR (75 MHz,
CDCl3) δ 190.8, 143.4, 143.3, 138.2, 129.3, 128.8, 128.7, 128.4, 127.9,
126.6, 126.0, 125.5, 48.1, 42.8, 33.7, 20.7, 20.4. All analytical data are
in accordance with the literature.6
Absorption Measurements. Molar extinction coefficients ε were
determined on a Spectra Max M5 microplate reader using a 1.0 cm
quartz cuvette at room temperature at 400 nm according to the Beer−
Lambert Law. These values were used to calculate molar xtinction
coefficients for 1b, RhS, RhS-1b, and 2a: ε400 of 1b (1.5 mM in
CH2Cl2) = (0.310/0.0015) = 207 M−1 cm−1; ε400 of RhS (0.05 mM in
CH2Cl2) = (0.351/0.00005) = 7020 M−1 cm−1; ε400 of RhS-1b (0.02
mM in CH2Cl2) = (0.699/0.00002) = 34 950 M−1 cm−1; ε400 of 2a
(0.5 mM in CH2Cl2) = (0.147/0.0005) = 294 M−1 cm−1.
Determination of Quantum Yields. The quantum yield of the
reaction 1b + 2a → 3b was determined by a method and setups
developed by the Riedle group.37 As light source a 420 nm LED was
employed. A powermeter was used as the detector. The measurement
was accomplished in a dark room with a 1.1 W red LEDs.
Step 1: The radiant power of light transmitted by the cuvette with a
blank solution was measured as Pblank = 21.2 mW.
compounds, and HPLC traces (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: meggers@chemie.uni-marburg.de.
ORCID
Xiaoqiang Huang: 0000-0002-0927-4812
Ronaldo A. Pilli: 0000-0002-5919-7763
Eric Meggers: 0000-0002-8851-7623
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge funding from Sao
Foundation, FAPESP, the Obesity and Comorbidities
Research Center, OCRC (2017/06836-4 and 2013/07607-
8), and the Deutsche Forschungsgemeinschaft (ME 1805/13-
1). M.A. thanks JSPS for a Research Fellowship for Young
Scientists.
■
̃
Paulo Research
REFERENCES
Step 2: The reaction mixture of 1b (54.8 mg, 0.20 mmol), 2a (95.9
mg, 0.24 mmol), and rac-RhS (6.9 mg, 4.0 mol %) in CH2Cl2 (2.0
mL, 0.1 M) was filled into a fluorescence cuvette with a stirring bar
and septum. CH2Cl2 (0.2 mL) was added to the cuvette, and the
mixture was degassed by bubbling with nitrogen until the extra solvent
evaporates completely (10 min). The cuvette was put into the setups
and illuminated with the 420 nm LED. The transmitted radiant power
Psample = 0.589 mW was noted. The transmitted radiant power was
monitored during the irradiation and remained constant.
■
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Step 3: After illumination for 2 h (t = 2 × 3600 s), the amount of
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A
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Quantum Yield =
=
absorbed × t
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λ
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× 108 m s−1 × 6.022 × 1023 mol−1 × 7.252 × 10−5 mol]
/[(21.2 − 0.589) × 10−3 J s−1 × 2 × 3600 s × 420 × 10−9 m]
= 0.14
A
=
= [6.626 × 10−34 J s × 2.998
where Nproduct is the number of molecules of product 3b formed,
photon is the number of photons absorbed, NA is Avogadro’s constant,
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N
I
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