Asymmetric Catalysis with Organic Azides and Diazo Compounds Initiated by Photoinduced Electron Transfer

Article abstract of DOI:10.1021/jacs.6b07692

Electron-acceptor-substituted aryl azides and α-diazo carboxylic esters are used as substrates for visible-light-activated asymmetric α-amination and α-alkylation, respectively, of 2-acyl imidazoles catalyzed by a chiral-at-metal rhodium-based Lewis acid in combination with a photoredox sensitizer. This novel proton- and redox-neutral method provides yields of up to 99% and excellent enantioselectivities of up to >99% ee with broad functional group compatibility. Mechanistic investigations suggest that an intermediate rhodium enolate complex acts as a reductive quencher to initiate a radical process with the aryl azides and α-diazo carboxylic esters serving as precursors for nitrogen and carbon-centered radicals, respectively. This is the first report on using aryl azides and α-diazo carboxylic esters as substrates for asymmetric catalysis under photoredox conditions. These reagents have the advantage that molecular nitrogen is the leaving group and sole byproduct in this reaction.

Full text of DOI:10.1021/jacs.6b07692

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Article
Asymmetric Catalysis with Organic Azides and Diazo
Compounds Initiated by Photoinduced Electron Transfer
Xiaoqiang Huang, Richard D. Webster, Klaus Harms, and Eric Meggers
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.6b07692 • Publication Date (Web): 31 Aug 2016
Downloaded from http://pubs.acs.org on August 31, 2016
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Asymmetric Catalysis with Organic Azides and Diazo
Compounds Initiated by Photoinduced Electron Transfer
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Xiaoqiang Huang,1 Richard D. Webster,2 Klaus Harms,1 and Eric Meggers1*
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1Fachbereich Chemie, PhilippsꢀUniversität Marburg, HansꢀMeerweinꢀStrasse 4, 35043 Marburg,
Germany
2Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371, Singapore
*Corresponding author: meggers@chemie.uniꢀmarburg.de
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Abstract: Electronꢀacceptorꢀsubstituted aryl azides and αꢀdiazo carboxylic esters are used as
substrates for visibleꢀlightꢀactivated asymmetric αꢀamination and αꢀalkylation, respectively, of 2ꢀ
acyl imidazoles catalyzed by a chiralꢀatꢀmetal rhodiumꢀbased Lewis acid in combination with a
photoredox sensitizer. This novel protonꢀ and redoxꢀneutral method provides yields of up to 99%
and excellent enantioselectivities of up to >99% ee with broad functional group compatibility.
Mechanistic investigations suggest that an intermediate rhodium enolate complex acts as a reductive
quencher to initiate a radical process with the aryl azides and αꢀdiazo carboxylic esters serving as
precursors for nitrogen and carbonꢀcentered radicals, respectively. This is the first report on using
aryl azides and αꢀdiazo carboxylic esters as substrates for asymmetric catalysis under photoredox
conditions. These reagents have the advantage that molecular nitrogen is the leaving group and sole
byꢀproduct in this reaction.
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INTRODUCTION
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There is a constant demand in organic synthesis for the enantioselective construction of CꢀN/CꢀC
bonds. In particular, a variety of elegant synthetic methodologies have been developed to build
carbonyl compounds bearing an αꢀamino/alkyl group, greatly promoted by their wide distribution in
natural products and biological active molecules.1 Among these strategies, visibleꢀlightꢀinduced
electron transfer provides a mild and powerful tool to generate highly reactive radicals and radical
ions for CꢀN/CꢀC bond formation.2ꢀ4 However, controlling the stereochemistry with such reactive
intermediates,5ꢀ7 along with the need to prevent postreaction racemization of products, makes
visibleꢀlight activated asymmetric αꢀamination/alkylation of ketones a considerable challenge.
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As a result, limited examples of visibleꢀlightꢀinduced catalytic asymmetric αꢀalkylation of
ketones are reported, which employ organic bromides/iodides8 or αꢀsilylalkylamines9 as alkylation
reagents with stoichiometric amount of base or oxidant, respectively (Figure 1a). Recently, two
studies used Nꢀ2,4ꢀdinitrophenylsulfonyloxy functionalized carbamates as nitrogen radical source to
achieve an enantioselective αꢀamidation of aldehydes and ketones with the addition of equivalent
amounts of base and the release of a sulfonate anion as byꢀproduct (Figure 1a).10 Despite great
progress, the development of new reagents for the effective asymmetric construction of CꢀN/CꢀC
bond with higher atom economy and milder conditions is still highly desirable.
Organic azides11 and diazo compounds12 are unique and highly versatile building blocks and
widely used as environmentally benign amination/alkylation reagents featuring the advantage of N2
as leaving group and sole byꢀproduct under redoxꢀneutral conditions. Despite some examples of
these reagents used in the context of photoredox reactions,13,14 the manipulation of these highꢀ
energy synthons under visibleꢀlight conditions in an enantioselective manner remains elusive. Two
main reasons might be responsible for this: First, azides and diazo compounds typically generate
respective nitrene and carbene intermediates under photochemical activation resulting in potential
side reactions and narrow functional group compatibility,15 and second, the highly negative
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reduction potential of organic azides and diazo compounds makes them difficult to be reduced
under mild conditions.16
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Herein, we introduce aryl azides and αꢀdiazo carboxylic esters as radical precursors for
asymmetric catalysis under photoredox conditions for the first time (Figure 1b). A chiralꢀatꢀmetal
rhodium Lewis acid catalyst in combination with a photoredox sensitizer enables chemoselective
and enanotioselective αꢀamination and αꢀalkylation of ketones with good functional group
tolerance. This method is redoxꢀ and protonꢀneutral and molecular nitrogen is the only byꢀproduct
in these reactions.
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Figure 1. Established strategies and this work regarding visibleꢀlightꢀactivated asymmetric αꢀ
alkylation/amination of ketones.
RESULTS AND DISCUSSION
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Initial Experiments. In line with our research using chiralꢀatꢀmetal complexes as
photoredox/Lewis acid catalysts,6c,i we started this investigation with the reaction of 2ꢀacyl
imidazole 1a and pentafluorophenyl azide 2a in the presence of catalytic amounts of
diisopropylethylamine (DIPEA) (Table 1). Although our wellꢀdeveloped dual functional catalyst ꢁꢀ
IrS did not show any reactivity (entries 1ꢀ2), we speculated that the recently introduced
combination of a chiralꢀatꢀmetal rhodiumꢀbased Lewis acid catalyst with a separate photoredox
sensitizer could provide access to desired amination product 4aa.6i Indeed, the chiral Lewis acid
catalyst ꢁꢀRhO (4.0 mol%) together with [Ru(bpy)3](PF6)2 (2.5 mol%) in the presence of visible
light afforded the amination product 4aa in a low yield of just 24% but with encouraging 86% ee
(entry 3). Revealingly, the related catalyst ꢀꢀRhS,17 in which the benzoxazole ligands are replaced
by benzothiazoles, provided 4aa with 70% yield and 97.7% ee (entry 4). Other Lewis acids, such as
Sc(OTf)3, FeCl3, and Cu(OAc)2, could not catalyzed the racemic reaction, highlighting the unique
reactivity of chiralꢀatꢀmetal RhS in this transformation (Table S7). Other photoredox sensitizers,
such as [Ir(ppy)2(dtbbpy)](PF6) and facꢀIr(ppy)3, showed lower efficiency (entries 4ꢀ6). A further
optimization of the reaction conditions (entries 7ꢀ11 and Supporting Information) resulted in the
identification of Na2HPO4 as the preferred base, providing 82% yield and 98.4% ee for the reaction
1a + 2a → 4aa (entry 10). While a base is required (entry 11), it is noteworthy that K3PO4 led to
product decomposition (entry 9 and Table S4), indicating that 4aa is very sensitive to strong basic
conditions. Control experiments confirm that the chiral Lewis acid, the photoredox sensitizer, and
visible light are all indispensable in this process (entries 12ꢀ14).
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Encouraged by these positive amination results, we became interested in investigating the
current catalytic system with related diazo compounds. Indeed, the alkylation product 5aa was
obtained in excellent yield (93%ꢀ94%) with 92% ee when ethyl diazo acetate 3a was used instead of
azide 2a under similar reaction conditions, thus demonstrating the versatility of this newly
developed catalytic system in enolate chemistry (entries 15ꢀ16).
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Table 1. Optimization of the Reaction Conditionsa
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sensitizer
entry reagent chiral cat.
base
hνb
yield (%)c ee (%)d
1e
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
DIPEA
yes
yes
yes
yes
yes
yes
yes
0 (4aa)
0 (4aa)
n.a.
n.a.
86
ꢀ
2a ꢀꢀIrS
2e
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
[Ir(ppy)2(dtbbpy)](PF6)
facꢀIr(ppy)3
2a ꢀꢀIrS
3e
4e
5e
6e
7
ꢀꢀRhO
ꢀꢀRhS
24 (4aa)
70 (4aa)
62 (4aa)
37 (4aa)
77 (4aa)
73 (4aa)
0 (4aa)
2a
2a
97.7
97.8
89
2a ꢀꢀRhS
2a ꢀꢀRhS
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
ꢀ
2a
2a
2a
2a
2a
2a
ꢀꢀRhS
ꢀꢀRhS
ꢀꢀRhS
ꢀ-RhS
ꢀꢀRhS
ꢀ
98.1
98.0
n.a.
98.4
n.a.
n.a.
n.a.
n.a.
92
8
2,6ꢀlutidine yes
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K3PO4
yes
yes
yes
yes
yes
ꢀ
10
11
12
13
14
15
16f
Na2HPO4
ꢀ
82 (4aa)
0 (4aa)
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
0 (4aa)
0 (4aa)
2a ꢀꢀRhS
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
ꢀꢀRhS
ꢀꢀRhS
0 (4aa)
2a
3a
yes
yes
93 (5aa)
94 (5aa)
3a ꢀ-RhS
92
aReaction conditions: 1a (0.10 mmol), 2a or 3a (0.30 mmol), chiral catalyst (4.0 mol%), sensitizer
(2.5 mol%), base (20 mol%), and H2O (20 equiv) in acetone/DMSO (9:1, 0.2 M) were stirred at
b
c
room temperature for 8ꢀ16 h under visible light. Light source: 21 W CFL. Isolated yields.
dDetermined by HPLC on a chiral stationary phase. Acetone/DMSO (4:1, 0.2 M) was employed.
f1.5 mol% of [Ru(bpy)3](PF6)2 was employed. DIPEA = diisopropylethylamine; n.a. = not
applicable; bpy = 2,2’ꢀbipyridine; ppy = 2ꢀphenylpyridine; dtbbpy = 4,4’ꢀdiꢀtertꢀbutylꢀ2,2’ꢀ
bipyridine.
e
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Mechanistic Investigations. Based on previous studies6i,8h,10b and the requirement for a base
we expect that the reaction proceeds through a rhodium enolate intermediate. To support this
assumption, the Rh-enolate was synthesized independently, characterized by Xꢀray diffraction, and
tested for its competence as catalyst in the amination and alkylation reactions (Figure 2a). Indeed,
comparable yields were observed with Rh-enolate as the catalyst in the absence of any base, thus
being consistent with the rhodium enolate serving as a key intermediate in these transformations.
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Next, four sets of experiments support that the reaction proceeds through a radical pathway
rather than a nitrene/carbene process. First, both amination and alkylation were completely inhibited
by air together with the generation of the oxygenation product 6, which implies that αꢀcarbonyl
carbon radicals derived from imidazole substrate might be involved (Figure 2b, eq 1).18 Second,
when silyl enolate 7 was added to the reaction mixture of 1b and 2a, the CꢀC and CꢀN bond
formation products 8 (42% yield) and 9 (22% yield) were isolated, respectively (Figure 2b, eq 2),
indicating the intermediate formation of αꢀcarbonyl carbon radicals and aminyl radicals. Third,
when TEMPO was added to the reaction mixture of 1b and 3a, the TEMPO adducts 10 (84% yield)
and 11 (6% yield) were isolated (Figure 2b, eq 3), being indicative for two types of intermediate αꢀ
carbonyl carbon radicals. Fourth, the isolation of the radical addition product 12 instead of the
cyclopropanation product 13 in the reaction with ethyl diazo acetate 3a renders a mechanism
through carbene intermediates unlikely (Figure 2c). The intermediate formation of the
cyclopropanation compound was ruled out by the independent synthesis of 13 and reꢀsubjection to
the standard photoredox conditions under which no reaction occurred (see Supporting Information
for more details).
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a) Confirmation of Rh-enolate as intermediate
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7
O
O
Ph
N
Ph
N
[Ru(bpy)3](PF6)2
N
2a or 3a
N
R
conditions
oTol
acetone/DMSO/H2O, rt
8
9
oTol
1b
4ba
R = NHC6F5 (
)
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reagent
products
conditions
5ba
R = CH2CO2Et (
)
2a
2a
3a
3a
RhS + Na2HPO4
Rh-enolate
4ba, 79%
Rh-enolate
4ba
, 74%
5ba, 99%
5ba
RhS + Na2HPO4
Rh-enolate
, 99%
b) Probing formation of radical intermediates
air
O
O
rac-RhS (4 mol%)
[Ru(bpy)3](PF6)2
N
1b
1b
2a 3a
4ba 5ba
+
+
or
or
, 0% yield
(1)
N
Ph
oTol
6, quant. yield
Na2HPO4 (20 mol%)
OTMS
O
7
( , 5.0 equiv)
Ph
Ph
N
N
RhS
rac-
(4 mol%)
C6F5
Ph
[Ru(bpy)3](PF6)2 (2.5 mol%)
N
Ph
oTol
O
(2)
(3)
2a
+
4ba +
+
+
H
O
Na2HPO4 (20 mol%)
< 5%
8, 42% yield
9, 22% yield
O
O
TEMPO (3.0 equiv)
rac-RhS (4 mol%)
[Ru(bpy)3](PF6)2 (1.5 mol%)
O
N
N
O
N
EtO
N
Ph
oTol
1b + 3a
5ba +
Na2HPO4 (20 mol%)
13%
10, 84% yield
11, 6% yield
c) Excluding carbene intermediates
CO2Et
O
OTMS
TMSO
Rh-enolate
(4 mol%)
[Ru(bpy)3](PF6)2 (1.5 mol%)
COOEt
3a
+
+
(radical trap product)
12
(carbene trap product)
13
7
, 68% yield
, 0% yield
Figure 2. Mechanistic experiments.
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In order to further confirm a radical pathway in this photoredox reaction, the alkylation
reaction was monitored by electron paramagnetic resonance (EPR) spectroscopy. With the addition
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of DMPO as free radical spinꢀtrapping agent, signals with 6 lines (g=2.006; αN = 15.9 G, αꢁ = 22.5
6
7
ꢀ
8
9
G) were observed and identified as EPR signals of adduct 14, which is in good agreement with the
literature (Figure 3).19 All these results support the formation of an ethyl acetate αꢀcarbon radical
through single electron reduction of the diazo compound 3a, suggesting that the mechanism is
distinct from recent work by Gryko and coworkers in which a direct reaction between an
intermediate radical and a diazo compound was proposed.14
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Furthermore, we were seeking to verify the initial electron transfer (SET) step of the
photoredox process and therefore performed a series of SternꢀVolmer quenching experiments
(Figure 4 and SI). These studies showed that only the intermediate Rh-enolate but no other
component, including the catalyst RhS and the silyl enolate 7, is capable of quenching the excited
state of the photosensitizer [Ru(bpy)3]2+ (PS) and this most likely through a reductive quenching
PS*/PSꢀ
cycle (E1/2
= +0.77 V vs SCE in MeCN).2a This is in agreement with cyclic voltammetry
ox
which reveals that Rh-enolate (Ep = 0.078 V vs Fc/Fc+ in MeCN) has a significantly lower
ox
oxidation peak potential than RhS (Ep = 1.25 V vs Fc/Fc+ in MeCN) (Figure 5). On the other
hand, the reduction peak potential of 2a or 3a is too negative16 so that 2a or 3a cannot quench the
PS+/PS*
excited state of [Ru(bpy)3]2+ (E1/2
= ꢀ0.81 V vs SCE in MeCN)2a by an oxidative quenching
cycle. All these results strongly suggest that SET between the rhodium enolate and excited
[Ru(bpy)3]2+ is a key step of the photoredox cycle. A SET reduction of 2a or 3a by [Ru(bpy)3]+
(E1/2PS/PSꢀ = ꢀ1.33 V vs SCE; < ꢀ1.7 V vs Fc/Fc+)20 appears also feasible.16
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Experimental
Simulated
*
*
10
*
*
*
*
5
0
3260
3280
3300
3320
3340
Magnetic field (G)
Figure 3. EPR spectra (X band, 9.7 GHz, r.t.) of spin adduct 14 generated under conditions: 1a
(0.10 mmol), 2a (0.30 mmol), racꢀRhS (4.0 mol%), [Ru(bpy)3](PF6)2 (1.5 mol%), Na2HPO4 (20
mol%) and H2O (20 equiv) in acetone/DMSO (9:1, 0.2 M) were stirred at room temperature under
visible light; after 60 min stirring, DMPO solution was added and then analyzed by EPR.
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Rh-enolate
RhS
3
Silyl enolate 7
4
6
4
2
0
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0
1
2
3
4
Concentration (mM)
Figure 4. SternꢀVolmer quenching experiments with photoexcited [Ru(bpy)3]2+ (0.5 mM, λex = 530
nm, λem = 610 nm). I0 and I are respective luminescence intensities in the absence and presence of
the indicated concentrations of the corresponding quencher. Silyl enolate 7 = trimethyl((1ꢀ
phenylvinyl)oxy)silane.
15 ꢁA V-1/2 s1/2
Starting and
finishing potential
rac-RhS
Rh-enolate
-2
-1
0
1
2
E / V vs Fc/Fc+
Figure 5. Cyclic voltammograms of RhS and Rh-enolate recorded in CH3CN containing 0.1 M nꢀ
Bu4NPF6 at 22 ± 2 oC. Scan rate = 0.1 V s–1.
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Based on above results, a mechanism consisting of the cooperation between a photoredox
and an asymmetric catalysis cycle is given in Figure 6. Substrate coordination to RhS (intermediate
A) and baseꢀinduced deprotonation generates the electronꢀrich rhodium enolate B, which initially
serves as the single electron donor for photoexcited [Ru(bpy)3]2+ (B → Box + eꢀ), thereby generating
strongly reducing [Ru(bpy)3]+ which in turn transfers a single electron to the organic azide or diazo
substrate. Sequential N2 extrusion and protonation produces nitrogenꢀ or carbonꢀcentered radicals,
respectively.13a The subsequent stereoselective addition of these electronꢀdeficient radicals to the
electronꢀrich double bond of the rhodium enolate B constitutes the chirality generating step and
provides the Rhꢀcoordinated ketyl radical C. The ketyl C is a strong reducing agent and either
directly reduces the azide/diazo reagent to afford chain propagation21 or quenches photoexcited
[Ru(bpy)3]2+ to produce the reduced photoredox sensitizer [Ru(bpy)3]+.22 The oxidation of ketyl C
leads to Rhꢀcoordinated product (intermediate D), which after product release and reꢀcoordination
of new substrate engages in a new catalytic cycle.
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Figure 6. Proposed mechanism.
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Substrate Scope. Having addressed the mechanism, we next explored the substrate scope of
amination with aryl azides under optimal conditions (entry 10, Table 1). As shown in Figure 7,
good yields and excellent enantioselectivities were obtained in the amination of 2ꢀacyl imidazoles
with different substituents at the Nꢀatom of imidazole (4aaꢀ4da) or different electronꢀrich aromatic
groups at the stereogenic carbon (4ea-4ga, 4ja). Other functional groups, such as naphthyl (4ha),
thienyl (4ia), and chloride (4ka), are well tolerated giving moderate yields and satisfying
enantioselectivities. On the other hand, a wide range of electronꢀdeficient aromatic azides
performed well both in yields and enantioselectivities (4bbꢀ4bg). Remarkably, bromo (4bb) and
cyano groups (4bf-4bg), which are vulnerable to reducing conditions, are compatible under the
present mild protocol, providing the potential for further transformations. Intriguingly,
chemoselective amination with an aryl azido group over an aliphatic azido group was observed
(4bh). Notably, 8 examples of these amination products were formed with an enantioselectivity of
99% ee or even higher without any postreaction racemization.
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Finally, the substrate scope with respect to enantioselective alkylation with αꢀdiazo
carboxylic esters under photoredox conditions was evaluated (Figure 8). Accordingly, the alkylation
of a variety of 2ꢀacyl imidazoles worked well, providing asymmetric 1,4ꢀdiketones in good to
excellent yields (81ꢀ99%) with excellent enantioselectivities (95ꢀ98% ee), regardless of the
electronic nature or position of substituents (5baꢀ5qa). As expected from the perspective of the
mechanism, CC double and triple bonds were found to be well tolerated (5bcꢀ5be, 5bh). Notably,
we were pleased to find that the present asymmetric alkylation was compatible with various natural
alcohol derivatives (5beꢀ5bh), highlighting the broad substrate scope and the potential utility of this
protocol in further lateꢀstage functionalization. In addition, the removal of the imidazole moiety of
5ba worked smoothly, giving 1,4ꢀdiester 15 in 81% yield with little loss in enantiomeric excess (95%
ee, eq 4).23
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Figure 7. Substrate scope for enantioselective amination with aryl azides. See SI for detailed
conditions.
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O
O
RhS
Λ-
(4.0 mol%)
O
Ar
OR
N
Ru(bpy)3(PF6)2 (1.5 mol%)
N
N2
+
RO
N
N
O
Ph
Na2HPO4 (20 mol%)
acetone/DMSO/H2O, rt
oTol
1
oTol
3
5
9
O
10
11
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22
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Ar
t (h) yield (%) ee (%)
OEt
N
5ba
5la
5ja
Ph
15
99
97
94
96
98
93
92
81
86
97
95
96
98
95
95
95
97
95
N
Ar
oTol
O
4-MeOC6H4 15
4-MeC6H4 24
5ba-5qa, 15-38 h
81-99% yield, 95-98% ee
5ma 4-FC6H4
16
22
38
26
15
5na
5oa
5ka
5pa
5qa
4-ClC6H4
4-BrC6H4
3-ClC6H4
2-ClC6H4
O
O
O
N
3
N
2-naphthyl 15
O
N
N
N
Ph
oTol
O
5bb
, 16 h
98% yield, 96% ee
O
O
N
O
N
Ph
oTol
O
O
Ph
N
N
5bd
, 18 h
Ph
oTol
O
90% yield, 96% ee
5bc
, 10 h
58% yield, 98% ee
O
Me
Me
O
N
O
Me
O
N
Ph
oTol
O
Ph
oTol
O
H
5bf
, L-(-)-Borneol derivative
24 h, 92% yield, > 98:2 d.r.
5be
, Geraniol derivative
24 h, 82% yield, 96% ee
O
N
O
H
N
O
N
O
H
H
N
Ph
oTol
O
oTol
Ph
O
5bg
5bh
, L-(-)-Menthol derivative
13 h, 93% yield, > 99:1 d.r.
, Cholesterol derivative
60 h, 83% yield, > 97:3 d.r.
Figure 8. Substrate scope for enantioselective alkylation with diazo compounds. See SI for detailed
conditions. The absolute configuration was assigned by the crystal structure of 5oa.
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CONCLUSIONS
We here for the first time demonstrated that acceptorꢀsubstituted aryl azides and αꢀdiazo
carboxylic esters are suitable reagents for generating intermediate radicals for asymmetric
photoredox reactions. These were exploited for the efficient visibleꢀlightꢀactivated enantioselective
αꢀalkylation and amination of 2ꢀacyl imidazoles using a combination of a chiral rhodiumꢀbased
Lewis acid catalyst and a photoredox sensitizer. Detailed mechanistic studies demonstrate that a
radical process instead of a carbene/nitrene pathway is operative. Yields of up to 99% and
enantioselectivities of up to 99.6% ee were achieved. Molecular nitrogen as the sole byꢀproduct,
redox and proton neutral reaction conditions, as well as a broad compatibility with other functional
groups render this transformation attractive. Further investigations on the development of novel
reagents for asymmetric CꢀC/CꢀN bond formations are ongoing in our laboratory.
References
(1) (a) Amino Group Chemistry: From Synthesis to the Life Sciences; Ricci, A., Ed.; WileyꢀVCH:
Weinheim, Germany, 2008. (b) Kohler, M. C.; Wengryniuk, S. E.; Coltart, D. M. in
Stereoselective Synthesis of Drugs and Natural Products; John Wiley & Sons, Inc., 2013, p
183ꢀ213. (c) Davies, H. M. L.; Morton, D. in Science of Synthesis, Stereoselective Synthesis;
DeVries, J. G.; Molander, G. A.; Evans, A. P., Eds.; Thieme, 2011, p 513ꢀ566. (d) Mailyan, A.
K.; Eickhoff, J. A.; Minakova, A. S.; Gu, Z.; Lu, P.; Zakarian, A. Chem. Rev. 2016, 116, 4441ꢀ
4557.
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2
3
4
5
6
7
8
(2) For selected reviews on photoinduced redox chemistry, see: (a) Prier, C. K.; Rankic, D. A.;
MacMillan, D. W. C. Chem. Rev. 2013, 113, 5322ꢀ5363. (b) Hopkinson, M. N.; Sahoo, B.; Li,
J.ꢀL.; Glorius, F. Chem. Eur. J. 2014, 20, 3874ꢀ3886. (c) Chen, J.ꢀR.; Hu, X.ꢀQ.; Lu, L.ꢀQ.;
Xiao, W.ꢀJ. Chem. Soc. Rev. 2016, 45, 2044ꢀ2056. (d) Lang, X.; Zhao, J.; Chen, X. Chem. Soc.
Rev. 2016, 45, 3026ꢀ3038. (e) Huang, H.; Jia, K.; Chen, Y. ACS Catal. 2016, 4983ꢀ4988. (f)
Kärkäs, M. D.; Porco, J. A., Jr.; Stephenson, C. R. J. Chem. Rev. 2016, DOI:
10.1021/acs.chemrev.5b00760. (g) Oelgemöller, M. Chem. Rev. 2016, DOI:
10.1021/acs.chemrev.5b00720. (h) Poplata, S.; Tröster, A.; Zou, Y.ꢀQ.; Bach, T. Chem. Rev.
2016, DOI: 10.1021/acs.chemrev.5b00723. (i) Ravelli, D.; Protti, S.; Fagnoni, M. Chem. Rev.
2016, DOI: 10.1021/acs.chemrev.5b00662. (j) Romero, N. A.; Nicewicz, D. A. Chem. Rev.
2016, DOI: 10.1021/acs.chemrev.6b00057. (k) Skubi, K. L.; Blum, T. R.; Yoon, T. P. Chem.
Rev. 2016, DOI: 10.1021/acs.chemrev.6b00018.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(3) For a comprehensive review on photoinduced electron transfer in organic synthesis, see:
Pandey, G. Top. Curr. Chem. 1993, 168, 175ꢀ221.
(4) For recent examples on racemic CꢀN/CꢀC bond formation activated by visible light, see: (a)
Jouffroy, M.; Primer, D. N.; Molander, G. A. J. Am. Chem. Soc. 2016, 138, 475ꢀ478. (b) Fava,
E.; Millet, A.; Nakajima, M.; Loescher, S.; Rueping, M. Angew. Chem., Int. Ed. 2016, 55,
6776ꢀ6779. (c) Yu, X.ꢀL.; Chen, J.ꢀR.; Chen, D.ꢀZ.; Xiao, W.ꢀJ. Chem. Commun. 2016, 52,
8275ꢀ8278. (d) Hu, X.ꢀQ.; Qi, X.; Chen, J.ꢀR.; Zhao, Q.ꢀQ.; Wei, Q.; Lan, Y.; Xiao, W.ꢀJ. Nat.
Commun. 2016, 7, 11188. (e) Jia, K.; Zhang, F.; Huang, H.; Chen, Y. J. Am. Chem. Soc. 2016,
138, 1514ꢀ1517. (f) Senaweera, S.; Weaver, J. D. J. Am. Chem. Soc. 2016, 138, 2520ꢀ2523. (g)
Meyer, A. U.; Slanina, T.; Yao, C.ꢀJ.; König, B. ACS Catal. 2016, 6, 369ꢀ375. (h) Shaw, M.
H.; Shurtleff, V. W.; Terrett, J. A.; Cuthbertson, J. D.; MacMillan, D. W. C. Science 2016, 352,
1304ꢀ1308. (i) Xie, J.; Yu, J.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Angew. Chem., Int.
Ed. 2016, 55, 9416ꢀ9421. (j) Davies, J.; Svejstrup, T. D.; Fernandez Reina, D.; Sheikh, N. S.;
Leonori, D. J. Am. Chem. Soc. 2016, 138, 8092ꢀ8095. (k) Corcoran, E. B.; Pirnot, M. T.; Lin,
17
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2
3
4
5
6
7
S.; Dreher, S. D.; DiRocco, D. A.; Davies, I. W.; Buchwald, S. L.; MacMillan, D. W. C.
Science 2016, 353, 279ꢀ283. (l) Zhang, J.; Li, Y.; Zhang, F.; Hu, C.; Chen, Y. Angew. Chem.,
Int. Ed. 2016, 55, 1872ꢀ1875.
8
9
(5) For reviews on catalytic asymmetric photoredox reactions, see. (a) Wang, C.; Lu, Z. Org.
Chem. Front. 2015, 2, 179ꢀ190. (b) Meggers, E. Chem. Commun. 2015, 51, 3290ꢀ3301. (c)
Brimioulle, R.; Lenhart, D.; Maturi, M. M.; Bach, T. Angew. Chem., Int. Ed. 2015, 54, 3872ꢀ
3890. (d) PeñaꢀLópez, M.; RosasꢀHernández, A.; Beller, M. Angew. Chem., Int. Ed. 2015, 54,
5006ꢀ5008.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(6) For recent examples on catalytic asymmetric photoredox reactions, see: (a) Uraguchi, D.;
Kinoshita, N.; Kizu, T.; Ooi, T. J. Am. Chem. Soc. 2015, 137, 13768ꢀ13771. (b) Walaszek, D.
J.; RybickaꢀJasińska, K.; Smoleń, S.; Karczewski, M.; Gryko, D. Adv. Synth. Catal. 2015, 357,
2061ꢀ2070. (c) Wang, C.; Qin, J.; Shen, X.; Riedel, R.; Harms, K.; Meggers, E. Angew. Chem.,
Int. Ed. 2016, 55, 685ꢀ688. (d) Murphy, J. J.; Bastida, D.; Paria, S.; Fagnoni, M.; Melchiorre,
P. Nature 2016, 532, 218ꢀ222. (e) Kainz, Q. M.; Matier, C. D.; Bartoszewicz, A.; Zultanski, S.
L.; Peters, J. C.; Fu, G. C. Science 2016, 351, 681ꢀ684. (f) Zuo, Z.; Cong, H.; Li, W.; Choi, J.;
Fu, G. C.; MacMillan, D. W. C. J. Am. Chem. Soc. 2016, 138, 1832ꢀ1835. (g) Wei, G.; Zhang,
C.; Bureš, F.; Ye, X.; Tan, C.ꢀH.; Jiang, Z. ACS Catal. 2016, 3708ꢀ3712. (h) Amador, A. G.;
Sherbrook, E. M.; Yoon, T. P. J. Am. Chem. Soc. 2016, 138, 4722ꢀ4725. (i) Huo, H.; Harms,
K.; Meggers, E. J. Am. Chem. Soc. 2016, 138, 6936ꢀ6939. (j) Tröster, A.; Alonso, R.; Bauer,
A.; Bach, T. J. Am. Chem. Soc. 2016, 138, 7808ꢀ7811. (k) Kizu, T.; Uraguchi, D.; Ooi, T. J.
Org. Chem. 2016, 81, 6953ꢀ6958.
(7) For a recent review on the catalysis of radical reactions, including asymmetric catalysis, see:
Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2016, 55, 58ꢀ102.
(8) (a) Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77ꢀ80. (b) Nagib, D. A.; Scott,
M. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2009, 131, 10875ꢀ10877. (c) Shih, H.ꢀW.;
Vander Wal, M. N.; Grange, R. L.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 13600ꢀ
18
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1
2
3
4
5
6
7
8
13603. (d) Neumann, M.; Füldner, S.; König, B.; Zeitler, K. Angew. Chem., Int. Ed. 2011, 50,
951ꢀ954. (e) Fidaly, K.; Ceballos, C.; Falguières, A.; Veitia, M. S.ꢀI.; Guy, A.; Ferroud, C.
Green Chem. 2012, 14, 1293ꢀ1297. (f) Cherevatskaya, M.; Neumann, M.; Füldner, S.;
Harlander, C.; Kümmel, S.; Dankesreiter, S.; Pfitzner, A.; Zeitler, K.; König, B. Angew.
Chem., Int. Ed. 2012, 51, 4062ꢀ4066. (g) Arceo, E.; Jurberg, I. D.; ÁlvarezꢀFernández, A.;
Melchiorre, P. Nat. Chem. 2013, 5, 750ꢀ756. (h) Huo, H.; Shen, X.; Wang, C.; Zhang, L.;
Röse, P.; Chen, L.ꢀA.; Harms, K.; Marsch, M.; Hilt, G.; Meggers, E. Nature 2014, 515, 100ꢀ
103. (i) Riente, P.; Matas Adams, A.; Albero, J.; Palomares, E.; Pericàs, M. A. Angew. Chem.,
Int. Ed. 2014, 53, 9613ꢀ9616. (j) Zhu, Y.; Zhang, L.; Luo, S. J. Am. Chem. Soc. 2014, 136,
14642ꢀ14645. (k) Silvi, M.; Arceo, E.; Jurberg, I. D.; Cassani, C.; Melchiorre, P. J. Am. Chem.
Soc. 2015, 137, 6120ꢀ6123. (l) Welin, E. R.; Warkentin, A. A.; Conrad, J. C.; MacMillan, D.
W. C. Angew. Chem., Int. Ed. 2015, 54, 9668ꢀ9672. (m) Woźniak, Ł.; Murphy, J. J.;
Melchiorre, P. J. Am. Chem. Soc. 2015, 137, 5678ꢀ5681.
9
10
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12
13
14
15
16
17
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19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(9) Wang, C.; Zheng, Y.; Huo, H.; Röse, P.; Zhang, L.; Harms, K.; Hilt, G.; Meggers, E. Chem.
Eur. J. 2015, 21, 7355ꢀ7359.
(10) (a) Cecere, G.; König, C. M.; Alleva, J. L.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135,
11521ꢀ11524. (b) Shen, X.; Harms, K.; Marsch, M.; Meggers, E. Chem. Eur. J. 2016, 22,
9102ꢀ9105.
(11) (a) Bräse, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem., Int. Ed. 2005, 44, 5188ꢀ
5240. (b) Wang, T.; Jiao, N. Acc. Chem. Res. 2014, 47, 1137ꢀ1145.
(12) (a) Davies, H. M. L.; Denton, J. R. Chem. Soc. Rev. 2009, 38, 3061ꢀ3071. (b) Doyle, M. P.;
Duffy, R.; Ratnikov, M.; Zhou, L. Chem. Rev. 2010, 110, 704ꢀ724. (c) Zhu, S.ꢀF.; Zhou, Q.ꢀL.
Acc. Chem. Res. 2012, 45, 1365ꢀ1377.
(13) For racemic photoredox reaction with azides, see: (a) Chen, Y.; Kamlet, A. S.; Steinman, J. B.;
Liu, D. R. Nat. Chem. 2011, 3, 146ꢀ153. (b) Farney, E. P.; Yoon, T. P. Angew. Chem., Int. Ed.
2014, 53, 793ꢀ797. (c) Xia, X.ꢀD.; Xuan, J.; Wang, Q.; Lu, L.ꢀQ.; Chen, J.ꢀR.; Xiao, W.ꢀJ. Adv.
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5
6
7
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Synth. Catal. 2014, 356, 2807ꢀ2812. (d) Brachet, E.; Ghosh, T.; Ghosh, I.; König, B. Chem.
Sci. 2015, 6, 987ꢀ992. (e) Fumagalli, G.; Rabet, P. T. G.; Boyd, S.; Greaney, M. F. Angew.
Chem., Int. Ed. 2015, 54, 11481ꢀ11484. (f) Scholz, S. O.; Farney, E. P.; Kim, S.; Bates, D. M.;
Yoon, T. P. Angew. Chem., Int. Ed. 2016, 55, 2239ꢀ2242. (g) Wang, Y.; Li, G.ꢀX.; Yang, G.;
He, G.; Chen, G. Chem. Sci. 2016, 7, 2679ꢀ2683. (h) Rabet, P. T. G.; Fumagalli, G.; Boyd, S.;
Greaney, M. F. Org. Lett. 2016, 18, 1646ꢀ1649.
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(14) For one racemic photoredox reaction with αꢀdiazo carboxylic esters, see: RybickaꢀJasińska, K.;
Ciszewski, Ł. W.; Gryko, D. Adv. Synth. Catal. 2016, 358, 1671ꢀ1678.
(15) L'Esperance, R. P.; Ford, T. M.; Jones, M., Jr. J. Am. Chem. Soc. 1988, 110, 209ꢀ213. See also
ref. 13f and ref. 14.
red
(16) For pentafluorophenyl azide 2a, Epred = -1.82 V vs Fc/Fc+. For ethyl diazo acetate 3a, Ep = -
1.97 V vs Fc/Fc+. See SI for more information.
(17) Ma, J.; Shen, X.; Harms, K.; Meggers, E. Dalton Trans. 2016, 45, 8320ꢀ8323.
(18) Su, Y.; Zhang, L.; Jiao, N. Org. Lett. 2011, 13, 2168ꢀ2171.
(19) Julià, L.; Bosch, M. P.; Rodriguez, S.; Guerrero, A. J. Org. Chem. 2000, 65, 5098ꢀ5103.
(20) Bonn, A. G.; Yushchenko, O.; Vauthey, E.; Wenger, O. S. Inorg. Chem. 2016, 55, 2894ꢀ2899.
(21) Cismesia, M. A.; Yoon, T. P. Chem. Sci. 2015, 6, 5426ꢀ5434.
(22) We determined a quantum yield of 0.1 for the reaction 1b + 3a → 5ba which is not conclusive.
Nevertheless, taking into consideration competing light absorption, quenching effects, and
other deactivation pathways, the contribution of a chain process is likely.
(23) Imidazole is among the privileged motif of drugs and natural products, see: Kombarov, R.;
Altieri, A.; Genis, D.; Kirpichenok, M.; Kochubey, V.; Rakitina, N.; Titarenko, Z. Mol. Divers.
2010, 14, 193ꢀ200.
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Journal of the American Chemical Society
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Supporting Information
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Synthetic details, details of mechanistic experiments, HPLC traces, NMR spectra, and
crystallographic data (PDF)
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Xꢀray crystal data of Rh-enolate (CIF)
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Xꢀray crystal data of product 5oa (CIF)
Acknowledgments
We are grateful for funding from the German Research Foundation (ME 1805/13ꢀ1).
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