Photoredox-Catalyzed α-Aminoalkylcarboxylation of Allenes with CO2

Article abstract of DOI:10.1021/acs.orglett.1c01011

The photoredox-catalyzed α-aminoalkylcarboxylation of aryl allenes with CO2 and N,N-dimethylanilines is reported for the first time (26 examples, up to 96% yield). In the case of electron-deficient allenes, good regioselectivity was observed (up to 94:6), exclusively generating kinetic products over thermodynamic products. This protocol is a novel synthetic method for highly functionalized β,γ-unsaturated γ-aminobutyric esters.

Full text of DOI:10.1021/acs.orglett.1c01011

pubs.acs.org/OrgLett
Letter
Photoredox-Catalyzed α‑Aminoalkylcarboxylation of Allenes with
CO2
Hyungwoo Hahm, Doohyun Baek, Dowon Kim, Seongwook Park, Jeong Yup Ryoo, and Sukwon Hong*
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ABSTRACT: The photoredox-catalyzed α-aminoalkylcarboxylation of aryl
allenes with CO2 and N,N-dimethylanilines is reported for the first time (26
examples, up to 96% yield). In the case of electron-deficient allenes, good
regioselectivity was observed (up to 94:6), exclusively generating kinetic
products over thermodynamic products. This protocol is a novel synthetic
method for highly functionalized β,γ-unsaturated γ-aminobutyric esters.
γ-Aminobutyric acid is the main inhibitory neurotransmitter in
the mammalian central nervous system.1 For this reason, the
synthesis of structurally diverse γ-aminobutyric acid derivatives
has been considered important in the pharmaceutical field.2 In
particular, various γ-aminobutyric acids bearing a tertiary
carbon center at the β-position such as pregabalin,3 baclofen,4
phenibut,5 and rolipram6 have been investigated (Figure 1). In
this regard, more structurally diverse, β-substituted γ-amino-
butyric acid derivatives have been developed to expand the
potential bioactive pharmaceutical library.7
in the presence of 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyano-
benzene (4CzIPN) for γ-aminobutyric acid synthesis was
independently developed by Wu and Xi (Scheme 1a).8c,e Very
recently, the photoredox-catalyzed α-aminoalkylcarboxylation
of activated alkenes with α-amino acids as a bifunctional
reagent for γ-aminobutyric acid synthesis was reported by Yu
and Cheng and Sun (Scheme 1a).8a,h However, β-substituted
γ-aminobutyric acid synthesis with CO2 remains a great
challenge due to the utilization of β-substituted alkenes with
high reduction potential.9 We envisioned that the photo-
catalytic α-aminoalkylcarboxylation of allenes with CO2 and
amines would serve as an ideal approach to deliver a novel γ-
aminobutyric acid through the incorporation of the ethylene
moiety at the β-position. Allenes, as special and versatile
synthons with structural diversity, have received much
attention in organic chemistry.10
Although various allene difunctionalization methods have
been investigated, few studies have been developed on the
transition-metal-catalyzed difunctionalization of allenes with
CO2 for unsaturated carboxylic acid derivatives.11 To the best
of our knowledge, there have been no examples demonstrating
the photocatalytic difunctionalization of allenes with CO2 in a
redox-neutral fashion. Herein we report the visible-light-
mediated α-aminoalkylcarboxylation of aryl allenes with CO2
Figure 1. Important β-substituted γ-aminobutyric acids in the
pharmaceutical field.
Typical approaches have been developed through the
Michael addition of carbonyl compounds to β-substituted
nitroalkenes or the conjugate addition of nitromethane to α,β-
unsaturated aldehydes.7a−d Another approach involves the
photocatalytic radical conjugate addition of α,β-unsaturated
compounds to amines.7e−i Recently, the visible-light-mediated
difunctionalization of alkenes with CO2 and various radical
sources to obtain valuable carboxylic acids has received
increasing attention.8
Received: March 24, 2021
Among the developed methods, the photoredox-catalyzed α-
aminoalkylcarboxylation of electron-deficient alkenes with CO2
https://doi.org/10.1021/acs.orglett.1c01011
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

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Letter
regioselectivity control issues.10,11 A previous report indicated
that the combination of a photocatalyst and base was
important for regioselective radical addition to 2,3-allenoates.12
Encouraged by this result, we initially investigated the reaction
by using 4-trifluoromethylphenylallene 1a as a model substrate
with N,N-4-trimethylaniline 2a as a radical source in the
presence of 1 mol % Ir(dF(CF3)ppy)2(dtbpy)·PF6 when using
1-methyl-2-pyrrolidinone (NMP) and a base under 15 W blue
light-emitting diode (LED) irradiation at room temperature
with CO2 at atmospheric pressure (Table 1). We examined the
reaction with bases such as CsOH·H2O, NaOAc, and K2HPO4
(Table 1, entries 1−3). In base screening, K2HPO4 showed the
best regioselectivity compared with other bases, although the
yield slightly decreased. Next, we tested some other photo-
catalysts. Ir(dF(CF3)ppy)2(bpy)·PF6, Ir(ppy)2(bpy)·PF6, Ir-
(ppy)3, 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene
(4CzIPN), and (2,3,4,6)-3-benzyl-2,4,5,6-tetra(9H-carbazol-
9yl)benzonitrile (4CzBnBN) gave relatively low regioselectiv-
ities and yields (Table 1, entries 4−8). To improve the
selectivity of the kinetic product 3aa, the reaction must
proceed at a low temperature. By reacting at 0 °C, the
selectivity and yield increased (Table 1, entry 9). We observed
that the selectivity significantly increased while reacting at −20
°C, but the yield decreased (Table 1, entry 10). In addition,
some other solvents were investigated. N,N-dimethylforma-
mide (DMF) and N,N-dimethylacetamide (DMA) were both
efficient in terms of the yield and selectivity (Table 1, entries
11 and 12). Finally, no traces of the desired products were
detected in the absence of the photocatalyst or light (Table 1,
entries 13 and 14).
Scheme 1. Sustainable Synthetic Route to γ-Amino Acid
Derivatives with CO2
and amines for β,γ-unsaturated γ-aminobutyric ester synthesis
(Scheme 1b). This reaction is the first example of the
photoredox-catalyzed difunctionalization of aryl allenes with
CO2. Compared with the photocatalytic difunctionalization of
alkenes with CO2,8 the photocatalytic difunctionalization of
allenes with CO2 is more challenging due to their
With these optimized reaction conditions in hand, the
aniline substrate scope of α-aminoalkylcarboxylation with 1a
was examined (Scheme 2). Compared with para-methyl-
a
Table 1. Optimization of α-Aminoalkylcarboxylation of Allenes
bc
,
entry
photocatalyst
base
solvent
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
Ir(dF(CF3)ppy)2(dtbpy)·PF6
Ir(dF(CF3)ppy)2(dtbpy)·PF6
Ir(dF(CF3)ppy)2(dtbpy)·PF6
Ir(dF(CF3)ppy)2(dtbpy)·PF6
Ir(ppy)2(dtbpy)·PF6
CsOH·H2O
NaOAc
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
DMF
DMA
DMA
DMA
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
79 (66:34)
66 (73:27)
63 (77:23)
60 (66:34)
64 (76:24)
38 (55:45)
trace
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
d
4CzIPN
4CzBnBN
d
Ir(ppy)3
trace
9
Ir(dF(CF3/ppy)2(dtbpy)·PF6
Ir(dF(CF3)ppy)2(dtbpy)·PF6
Ir(dF(CF3)ppy)2(dtbpy)·PF6
Ir(dF(CF3)ppy)2(dtbpy)·PF6
Ir(dF(CF3)ppy)2(dtbpy)·PF6
0
81 (79:21)
64 (87:13)
80 (88:12)
81 (89:11)
ND
10
11
12
13
14
−20
−20
−20
−20
−20
e
f
ND
a
Conditions: (1) 0.2 mmol 1a, 0.6 mmol 2a, 0.6 mmol base, 1 or 3 mol % photocatalyst, solvent (2 mL), CO2 (1 bar), 15 W blue LED, 15 h. (2)
b
c
TMSCHN2 2 M in Et2O (0.2 mL), Et2O (8 mL), MeOH (2 mL), 1 h. Yield of 3aa and 4aa, isolated yield. ND, not determined Selectivity of
3aa/4aa determined by H NMR. 3 mol % Reacted in dark. Without photocatalyst.
d
e
f
1
B
https://doi.org/10.1021/acs.orglett.1c01011
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Letter
Scheme 2. Scope of α-Aminoalkylcarboxylation of
Amines
Scheme 3. Scope of α-Aminoalkylcarboxylation of Aryl
a b c
a b c
, ,
, ,
Allenes
a
Conditions: (1) 0.2 mmol 1a, 0.6 mmol 2, 0.6 mmol K2HPO4, 1 mol
% Ir(dF(CF3)ppy)2(dtbpy)·PF6, DMA (2 mL), CO2 (1 bar), 15 W
blue LED, 15 h. (2) TMSCHN2 2 M in Et2O (0.2 mL), Et2O (8 mL),
b
c
1
MeOH (2 mL), 1 h. Selectivity determined by H NMR. Isolated
yield of 3 and 4.
substituted N,N-dimethylaniline (2a), meta-methyl-substituted
N,N-dimethylanilines (2b,c) gave higher yields of the desired
products, but the regioselectivity slightly decreased (3/4aa−
ac). The non- (2d), bromo- (2e), chloro- (2f), fluoro- (2g),
and methoxy- (2h) substituted N,N-dimethylanilines at the
para position of the phenyl ring have an excellent yield and
moderate regioselectivity, except for 4-methoxy-N,N-dimethy-
laniline (3/4ad−ah). Other heteroaryl amines, such as
pyridine and quinoline, successfully gave moderate yields of
the desired products (3/4ai−aj). Notably, the utilization of
secondary amines and tertiary amines such as 4-dimethylami-
nopyridine (DMAP), N,N-dimehtylthiophene-3-amine, potas-
sium (4-methylphenoxy)carbonylaminomethyltrifluoroborate,
and tert-butyl methyl(p-tolyl)carbamate, did not lead to the
desired products.13 (See Scheme S1 in the Supporting
Information.)
Next, the reaction scope was studied with aryl allenes 1 and
2a (Scheme 3). Hammett σm/p values could be in accord with
the selectivity of compounds 3 and 4 under the applied
reaction conditions.14 Electron-deficient phenylallenes with
positive σ values undergo regioselective α-aminoalkylcarbox-
ylation regardless of the substitution pattern. Phenylallenes
bearing highly electron-withdrawing groups such as trifluor-
omethyl (1b), cyano (1c), keto carbonyl (1d), or ester groups
(1e) at the para or meta position in the benzene ring were
effective at giving the desired kinetic products in good yield
with good regioselectivity (3/4ba−3/4ea). The introduction
of weakly electron-withdrawing substituents, such as chloro
a
Reaction conditions: (1) 0.2 mmol 1, 0.6 mmol 2a, 0.6 mmol
K2HPO4, 1 mol % Ir(dF(CF3)ppy)2(dtbpy)·PF6, DMA (2 mL), CO2
(1 bar), 15 W blue LED, 15 h, room temperature. (2) TMSCHN2 2
M in Et2O (0.2 mL), Et2O (8 mL), MeOH (2 mL), 1 h. σ = Hammett
b
c
1
substituent constants. Selectivity determined by H NMR. Isolated
yield of 3 and 4. Room temperature.
d
(1f−h), bromo (1i−j), and fluoro (1k−l) groups at the ortho,
meta, or para position of the phenyl ring, gave moderate to
good yields and regioselectivity, except for 4-fluoro-phenyl-
allene (3/4fa−la). Phenylallene (1m) and phenylallene-
bearing methoxy groups (1n−o) at the meta or para position
of the phenyl ring exhibited poor regioselectivity (3/4ma−oa).
Electron-neutral and electron-donating-group-substituted ben-
zyl radicals with high reduction potentials (−1.43 V vs
standard calomel electrode (SCE) for the H benzyl radical
analog and −1.75 V vs SCE for the p-OMe benzyl radical
analog) were difficult to reduce by Ir(dF(CF3)ppy)2(dtbpy)·
PF6 ((E1/2Ir(II)/Ir(III)) = −1.37 V vs SCE in MeCN).9,15a
Fortunately, it is presumed that allenes are easily reduced via
an allyl-benzyl anion intermediate. When using 1,1-diaryl-
substituted allenes at room temperature, a thermodynamically
favorable product was obtained in moderate yield with
excellent regioselectivity (4pa−qa). The electron density and
C
https://doi.org/10.1021/acs.orglett.1c01011
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structure of aryl allenes have a strong effect on the
regioselectivity. Unfortunately, the utilization of ethyl-2,3-
butadienoate did not lead to the desired products. (See
Scheme S1 in the Supporting Information.)
5. The α-aminomethyl radical (2′′), which is produced by a
photoexcited photocatalyst and base, undergoes addition to the
Scheme 5. Proposed Mechanism
To gain insight into the efficiency of the α-amino-
alkylcarboxylation of allenes with CO2, preliminary mecha-
nistic experiments were conducted (Scheme 4). Continuous-
Scheme 4. Mechanistic Studies
central carbon of the allenes (1a) to give a radical delocalized
intermediate (A). A subsequent single-electron transfer (SET)
between A and the reduced photocatalyst Ir(II) gives the
delocalized allyl-benzyl carbanion. The carbanion intermedi-
ates (B) attack CO2 as nucleophiles, affording the expected
β,γ-unsaturated γ-aminobutyric esters (3a) after treatment with
TMSCHN2. The photocatalyst was regenerated by SET in the
catalytic cycle. A gram-scale reaction was readily conducted.
(See Scheme S4 in the Supporting Information.) To
demonstrate the utility of this reaction, the unsaturated γ-
aminobutyric ester 3aa was reduced by lithium aluminum
hydride (LAH) to form δ-amino alcohol 6. (See Scheme S5 in
the Supporting Information.)
In summary, we demonstrated the photoredox-catalyzed
intermolecular α-aminoalkylcarboxylation of aryl allenes with
CO2 and amines in a redox-neutral fashion for the first time.
Twenty-six examples of various aryl allenes and amines were
demonstrated to afford good isolated yields (up to 96%).
Electron-deficient substituted aryl allenes show great regiose-
lectivity. This sustainable process is the general synthetic
method of unsaturated γ-aminobutyric esters. α-Amino-
alkylcarboxylation has the advantages of step and atom
economy and mild conditions. The application and detailed
reaction mechanism are currently ongoing.
ASSOCIATED CONTENT
* Supporting Information
■
sı
light irradiation was an essential factor preventing hydro-
aminoalkylation.8c Stern−Volmer luminescence studies con-
firm that the light-activated Ir photocatalyst ((E1/2Ir(III)*/
Ir(II)) = +1.21 V vs SCE in MeCN)15 was quenched by 2a
(Eoxp = +0.74 V vs SCE) rather than 1a (Scheme 4; see Figures
S1 and S2 in the Supporting Information). When the radical
scavenger 2,2,6,6-tetramethylpiperdinyloxyl (TEMPO) was
used as an additive in the α-aminoalkylcarboxylation, the
desired products were not observed. The radical adduct was
detected by high-resolution mass spectrometry (HRMS)
(Scheme 4 and Figure S3 in the Supporting Information).
This result indicates that α-aminoalkylcarboxylation might rely
on the radical pathway. The isotope-labeling experiments with
D2O instead of CO2 showed that benzyl allyl anion species
were present in the catalytic cycle (Scheme 4; see Figure S4 in
the Supporting Information).
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01011.
Detailed experimental procedures, mechanistic studies,
and spectral data for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Sukwon Hong − Department of Chemistry, Gwangju Institute
of Science and Technology, Gwangju 61005, Republic of
Korea; School of Materials Science and Engineering, Gwangju
Institute of Science and Technology, Gwangju 61005,
Republic of Korea; orcid.org/0000-0002-2078-9630;
Email: shong@gist.ac.kr
Authors
On the basis of the experimental results and the related refs
10, 12, and 16, the proposed mechanism of the regioselective
α-aminoalkylcarboxylation to aryl allenes is outlined in Scheme
Hyungwoo Hahm − Department of Chemistry, Gwangju
Institute of Science and Technology, Gwangju 61005,
Republic of Korea; orcid.org/0000-0003-3092-2906
D
https://doi.org/10.1021/acs.orglett.1c01011
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Letter
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Seongwook Park − Department of Chemistry, Gwangju
Institute of Science and Technology, Gwangju 61005,
Republic of Korea
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Jeong Yup Ryoo − Department of Chemistry, Gwangju
Institute of Science and Technology, Gwangju 61005,
Republic of Korea
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01011
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Research
Foundation of Korea (NRF) grant funded by the Korean
government (Ministry of Science and ICT) (NRF-
2020R1A2C1009123).
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