Photoinduced umpolung addition of carbonyl compounds with α,β-unsaturated esters enables the polysubstituted γ-lactone formation

Article abstract of DOI:10.1039/d0cc05306f

We herein report the photoinduced intermolecular umpolung addition of aromatic ketones/aldehydes with α,β-unsaturated esters via ketyl radical intermediates. Following an intramolecular transesterification, a variety of γ-lactone derivatives are readily accessed. Mechanistic investigations demonstrate the significant role of Hantzsch ester, which serves both as the electron and proton donor. This journal is

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Conformational control of nonplanar free base porphyrins:
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DOI: 10.1039/D0CC05306F
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Photoinduced umpolung addition of carbonyl compounds with
α,β-unsaturated esters enables the polysubstituted γ-lactone
formation
Received 00th January 20xx,
Accepted 00th January 20xx
Jia-Yi Gu,a Wei Zhang,a Seth R. Jackson,b Yan-Hong He*a and Zhi Guan*a
DOI: 10.1039/x0xx00000x
We herein report the photoinduced intermolecular umpolung excited-state chemistry methodology, which not only enables
addition of aromatic ketones/aldehydes with α,β-unsaturated the discovery of numerous nontraditional bond-forming
esters via ketyl radical intermediates. Following an intramolecular strategies, but also obviates the need for tough reaction
transesterification, a variety of γ-lactone derivatives are readily conditions
and
rigorous
laboratory
instruments.8
accessed. Mechanistic investigations demonstrate the significant Photoinduced ketyl radicals enjoy a surge of popularity, which
role of Hantzsch ester, which serves both as the electron and could stem from carbonyl compounds9 (while most of the
proton donor.
existing successful photoinduced ketyl radical reactions mainly
involve aldehydes10 due to the relative high redox potentials),
alcohols,11 acetals12 and ketals,13 either catalyzed by Lewis
acids or Brønsted acids,14 getting rid of environmentally
unfriendly, harsh and cumbersome reaction conditions.
Ketyl radicals are versatile synthons for constructing plenty of
functionalized alcohols, especially by ketyl-olefin coupling
reactions.1 However, conversion of carbonyl compounds to
ketyl radicals is largely confined by their extremely negative
The radical addition reaction between ketyl radicals and
redox potentials (e.g. E1/2 = - 2.11 V vs SCE for acetophenone).2 acrylates is one of the most effective methods for the
synthesis of γ-lactones.15 Such reactions usually require high
temperature to generate ketyl radicals, yet elevated
temperatures can also accelerate the polymerization of
acrylates, thus resulting in complex side reactions. In this
context, the emergence of strategies to produce ketyl radicals
by visible-light catalysis makes the synthetic conditions for γ-
lactones mild, excluding the use of free-radical initiators and
high temperatures. In 2013, Knowles and coworkers
Alkali,3 alkaline earth,4 and transition metals5 are the most
powerful reducing agents for converting carbonyl compounds
to ketyl radicals. Among them, SmI2 (E1/2 = - 0.89 V vs SCE) is a
frequently used one, which is typically combined with
hexamethylphosphoramide (HMPA) for the sake of superior
activities as the reduction potential of SmI2 is dramatically
enhanced by this Lewis-basic additive (E1/2 as low as - 1.79 vs
SCE).6 Additionally, the combination of tributyltin hydride (as a
hydrogen radical source) and 2,2'-azobisisobutyronitrile (AIBN,
as a radical initiator) at high temperatures is also commonly
used to generate ketyl radicals from carbonyl compounds.7
Although these methods can effectively convert carbonyls to
ketyl radicals, they still have some disadvantages, such as the
use of stoichiometric or even excessive amounts of expensive
reagents, or the use of chemicals that are extremely harmful
to the environment and highly hazardous to health. To
circumvent the high activation barrier issues and avoid the use
of toxic or costly reducing agents, new procedures for
generating ketyl radicals are highly desired. Recently, visible-
light triggered photoredox catalysis represents a unique
uncovered
a
new photochemical protocol for the
intramolecular ketyl-olefin coupling to produce -lactone
structure through concerted proton-coupled electron transfer
(PCET) pathway (Scheme 1A).16 In 2015, Macmillan and
colleagues accomplished the lactonization of diverse alcohols
with methyl acrylates via a hydrogen atom transfer (HAT)
mechanism (Scheme 1B).17 Inspired by these outstanding
A. Knowles's Photocatalytic Intramolecular Ketyl-Olefin Reductive Coupling
O
PCET
Ru
MeO2
C
5-trig-exo
O
CO2Me
HO
O
Intramolecular
Addition
h
B. Macmillan's H-bond Photopromoted C-alkylation of Alcohols
HO
O
O
P
HAT
Ir
H
CO2Me
O
OH
O
H
OH
Giese-type
Addition
OH
H
h
O
C. This Work: Photoinduced Intermolecular Reductive Coupling of Carbonyl Compounds with Alkenes
OH
a. Key Laboratory of Applied Chemistry of Chongqing Municipality, School of
Chemistry and Chemical Engineering, Southwest University, Chongqing 400715,
China. E-mail: heyh@swu.edu.cn, guanzhi@swu.edu.cn
O
PCET
Ir
H+
HO
O
O
CO2Et
b. Department of Chemistry, College of Saint Benedict and Saint John’s University,
Collegeville MN, 56321 USA
h
CO2Et
Scheme 1 Photocatalyzed strategies for γ-lactone synthesis via ketyl radical
intermediate.
†Electronic
Supplementary
Information
(ESI)
available.
See
DOI: 10.1039/x0xx00000x
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Journal Name
O
R3
works, we developed
a
method for synthesizing
[Ir]PF
HE1
(2.0 equiv.)
1.
6 (1 mol%),
B(C6F5 3 (10 mol%), DMSO (2 mL)
9 W blue LEDs, Ar atm, 36 h, rt
View Article Online
O
R3
)
O
polysubstituted γ-lactones through intermolecular umpolung
addition of ketones with acrylates via photoinduced ketyl
radicals (Scheme 1C).
DOI: 10.1039/D0CC05306F
+
R1 R2
ketones
CO2Et
alkenes
R1
R2
2. pTSA (1.0 equiv.), air, 24 h, rt
products
Variation of Ketones
4
5
6
7
8
9
10
11
12
, R = H, 97% yield, 1.2:1 dr
, R = 4-F, 89% yield, 1.1:1 dr
, R = 4-Cl, 72% yield, 1.6:1 dr
, R = 4-Br, 65% yield, 1.6:1 dr
, R = 3-Br, 72% yield, 1.1:1 dr
, R = 2-Br, 87% yield, 1.1:1 dr
, R = 4-I, 61% yield, 1.1:1 dr
, R = 4-Me, 67% yield, 1.3:1 dr
, R = 4-OMe, 80% yield, 1:1 dr
We first investigated the coupling reaction between model
substrate acetophenone (1) and α,β-unsaturated ester ethyl 2-
O
O
O
O
Ph
Ph
Ph
O
O
O
R
phenylacrylate (2) in the presence of
1
mol%
O
[Ir(dF(CF3)ppy)2dtbbpy]PF6 ([Ir]PF6) as the photoredox catalyst
and Hantzsch ester (HE1) as the sacrificial reductant. The
reaction proceeded smoothly to produce γ-hydroxy ester (3) in
42% yield with only a trace amount of γ-lactone (4) observed
(Table 1, entry 1). After screening various factors affecting the
reaction efficiency, the standard conditions were determined
(Table 1, footnote a). Notably, screening of the additives
showed that catalytic amount of Lewis acid like 10 mol%
B(C6F5)3 could enhance the yield (Table 1, entry 2). This
phenomenon might be attributed to the activation of ketone
substrates by Lewis acid, as several previous researches
reported.18 Subsequent screening of different external
reductants proved HE1 to be the best hydrogen source with an
optimal loading of 2.0 equivalents (Table 1, entries 2-6). After
full consumption of the initial reactants, direct addition of a
Brønsted acid [1.0 equiv. p-toluenesulphonic acid (pTSA)] into
16
17
, 78% yield
1.5:1 dr
, 84% yield
1.2:1 dr
13, R = 4-Ph, 80% yield, 1.4:1 dr
14
15
, R = 4-OPh, 46% yield, 1.1:1 dr
, R = 3,4-Me, 91% yield, 1.1:1 dr
O
O
O
Ph
Ph
O


Ph
Ph
13a

, ( )-anti-diastereomer (major)
13b

, ( )-syn-diastereomer (minor)
O
O
O
Ph
O
O
O
Ph
Ph
Ph
Ph
O
Ph
O
O
O
O
O
Ph
Ph
S
Ph
O
18
19
20
21
22
23
, 49% yield
1.3:1 dr
, 77% yield
1.3:1 dr
, 49% yield
1.6:1 dr
, 96% yield
1:1 dr
, 95% yield
1.3:1 dr
, 91% yield
1.2:1 dr
O
O
O
O
O
O
Ph
Ph
Ph
Ph
Ph
O
O
O
O
Ph
Ph
Ph
the reaction system realized
a
nearly quantitative
24
25
26
27
28
, 92% yield
1.4:1 dr
, 59% yield
1.1:1 dr
, 50% yield
2.1:1 dr
, 63% yield
1.1:1 dr
, 58% yield
1.4:1 dr
transesterification after stirring for another 24 hours, affording
the anticipated γ-lactone (4) in 97% yield (Table 1, entry 7; for
more details, see ESI†, Table S1-S9).
H
O
Ph
H
H
O
O
H
H
O
Ph
O
O
Table 1 Selected optimization experimentsa
O
O
from Nopol
from Cholesterol
b
O
b
29
, 58% yield
1.1:1 dr
30
, 37% yield
1.2:1 dr
O
Ph
Ph
HO
Ph
O
Standard
O
O
+
+
Variation of Alkenes
Conditions
O
O
O
31
32
, R =4-Br, 81% yield, 1.2:1 dr
, R = 4-Me, 86% yield, 1.2:1 dr
O
1
2
3
4
O
O
O
O
O
O
Ph
O
O
Ph
O
33, R = 4-CN, 93% yield, 1.5:1 dr
O
Cy
O
R
S
34
35
, R = 3,4-Cl, 89% yield, 1.4:1 dr
O
Ph
Ph
EtO
OEt
tBuO
OtBu
EtO
OEt
t
, R = 4- Bu, 89% yield, 1.2:1 dr
Ph
N
H
36, R = 3,4-(CH2
37, 42% yield
1.1:1 dr
38, 35% yield b
)
2, 52% yield, 1.1:1 dr
N
H
N
H
N
H
1.6:1 dr
HE1
HE2
HE3
TZ
Other Electron-deficient Alkenes
OH
Entry Variations from standard conditions 3b (%) 4b (%)
OH
OH
O
N
OH
O
S
O
Ph
Ph
Ph
Ph
1
2
3
4
5
6
7c
1.0 equiv. of HE1, no B(C6F5)3
1.0 equiv. of HE1
1.0 equiv. of HE2
1.0 equiv. of HE3
1.0 equiv. of TZ
None
42
67
43
41
61
95
0
trace
trace
trace
trace
trace
trace
97
N
O
O
c
c
c
39
40
41
42
, 0% yield
, 34% yield
, 49% yield
, 72% yield
1.3:1 dr
Scheme 2 Substrate scopea Reaction conditions: ketone (0.25 mmol), alkene
(0.50 mmol). Acid catalyzed transesterification in CH2Cl2 instead of DMSO for
24 hours (for details, see ESI†). Without acid treatment. All yields are isolated
a
b
C
None
yields.
a Standard reaction conditions: a mixture of 1 (0.25 mmol), 2 (0.50 mmol), HE1 (2.0
equiv.), B(C6F5)3 (10 mol%) and [Ir]PF6 (1 mol%) in DMSO (2 mL) was irradiated with
b
tolerated under the reaction conditions. Sulfur and oxygen
containing heteroaryl and other aryl ketones were proved to
be competent substrates for the reaction (17-20) as well. In
addition to abovementioned ketones, various alkyl phenyl
ketones also performed well in this reaction, giving the
corresponding products (21-28) in moderate to excellent
yields. Alkyl substituted ketones with bulky structures were
also successful candidates, while a small decline in yields was
detected (27 and 28). Besides, derivatives from complex
molecules, such as Nopol and Cholesterol, were feasible
substrates as well (29 and 30). Subsequently, the scope of the
alkene partner was tested (31-42). Olefins with aromatic rings
9 W blue LEDs under argon atmosphere at room temperature for 36 hours.
C
Isolated yield. After full consumption of initial reactants, pTSA was added and
stirred for 24 hours without light irradiation.
Control experiments confirmed the crucial role of
photocatalyst, Hantzsch ester, and visible-light because no
reaction was observed when lacking any of these components.
Besides, when the reaction was performed in air instead of an
argon atmosphere, the expected reaction did not occur,
indicating that O2 had an inhibitory effect on the reaction.
With the optimized conditions in hand, we next explored the
substrate scope (Scheme 2). Ketones with both mono- and
poly-substituted phenyl rings were first surveyed (5-16). Either
electron-donating or electron-withdrawing groups were well-
2 | J. Name., 2012, 00, 1-3
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functionalized with a diverse set of distinct substituents all standard conditions with radical scavengVeierw Art2icl,e2O,6n,li6ne-
worked well while the alkyl-substituted acrylate 38 was not, tetramethylpiperidine-1-oxyl (TEMPO). DIOnI: 1t0h.1e039p/rDe0sCeCn0c5e306oFf
emphasizing the importance of the α-aryl substitution to TEMPO, the reaction was completely inhibited, suggesting a
stabilize the vicinal free radicals. Olefins with other electron radical pathway. Intriguingly, a cyclic compound (50) was
withdrawing groups, such as sulfone (39), nitrile (40) and isolated in 30% yield in the radical clock experiment (Scheme
multi-substituted unsaturated ketone (41) were also feasible 4). We ascribed this observation to a [3+2] cycloaddition
substrates, providing the corresponding reductive coupling between cyclopropyl phenyl ketone 49 and the alkene partner
products with acetophenone. However, vinyl amide (42) 2 via a radical tandem reaction, which implied the existence of
seemed to be unreactive.
ketyl radical intermediate.21 Typically, there are two possible
To further broaden the generality of this reductive coupling radical termination pathways of the acrylate radical
methodology, we selected several aromatic aldehydes as the intermediate B (Scheme 5): (1) the hydrogen atom transfer
potential coupling partners to react with ethyl 2- (HAT) with Hantzsch ester radical cation;22 and (2) a radical
phenylacrylate 2 (Scheme 3). After screening the reaction reduction/protonation sequential process.23 Given that, we
conditions (see ESI†, Table S10-S11), we decided to perform first utilized deuterium-labelled Hantzsch ester as the
this transformation under
a mild metal-free conditions reductant to testify the feasibility of the HAT pathway. It was
(Scheme 3, footnote a). As illustrated in Scheme 3, different found that deuterium was not incorporated in the coupling
aryl aldehydes all worked well, which exhibited a better product at all, indicating that a HAT process might be less
reactivity compared with some previously reported reductive prone to happen. Based on this result, a single electron
coupling reactions of aldehydes.19
transfer (SET) between the acrylate radical intermediate B and
Hantzsch ester radical followed by protonation is, hence,
highly possible.13 Moreover, Stern-Volmer fluorescence
quenching experiments showed a strong interaction between
the photocatalyst and Hantzsch ester, which suggested a SET
O
Ph
1. 4CzlPN (2 mol%)
HE1
9 W blue LEDs, Ar atm, 18 h, rt
O
Ph
CO2Et
(1.5 equiv.), DMSO (2 mL)
O
+
R1
H
R1
H
2. pTSA (1.0 equiv.), CH2Cl2 (2 mL)
products
Aldehydes
2
air, 24 h, rt
Variation of Aldehydes
O
O
O
O
process (see ESI†, 6.1-6.7 for more details).
Ph
Ph
Ph
O
O
R
O
O
[Ir]PF
HE1
(2.0 equiv.)
6 (1 mol%),
)
NC
CN
Ph
Ph
B(C6F5 3 (10 mol%), DMSO
H
H
H
O
O
+
Cl
R
R
9 W blue LEDs, Ar atm, 36 h, rt
O
O
43
44
45
, 97% yield
1.6:1 dr
, 94% yield
1.4:1 dr
, 90% yield
1:1 dr
R
49
2
50, 30% yield
Scheme 4 Radical clock experiment.
O
O
O
O
O
O
N
Ph
Ph
Ph
R =
On the basis of Knowles’s work,24 effective “BDFE” (bond-
dissociation free energy) of the IrII/HE1·+ pair was calculated to
be 17 kcal/mol, which is less than the 26 kcal/mol (O-H BDFE
for acetophenone ketyl) threshold. Moreover, acid/base
addition experiments9b, 9c demonstrated that basic compounds
suppressed the reaction greatly, verifying the necessity of the
Brønsted acidic species HE1·+ (see ESI†, 6.8 & 6.9). Collectively,
all these results suggested a PCET process.
H
H
H
O
S
4CzlPN
46
47
48
, 91% yield
1:1 dr
, 61% yield
1.4:1 dr
, 72% yield
1.4:1 dr
Scheme 3 Substrate scope of aromatic aldehydesa Reaction conditions: a mixture of
aldehyde (0.25 mmol), 2 (0.50 mmol), HE1 (1.5 equiv.) and 4CzIPN (2 mol%) in DMSO (2
mL) was irradiated with 9 W blue LEDs under argon atmosphere at room temperature
for 18 hours. Acid catalyzed transesterification was all carried out in CH2Cl2. All yields
are isolated yields. 4CzlPN = 2,4,5,6-tetrakis(carbazol-9-yl)-1,3-dicyanobenzene.
a
Considering the above mechanistic studies and literature
reports, a plausible mechanism was proposed (Scheme 5).
Firstly, visible-light excitation of [Ir]PF6 forms the active *IrIII
species [E1/2 (*IrIII/IrII) = + 1.21 V vs SCE in MeCN],25 which is
efficiently quenched by Hantzsch ester [E1/2 (HE1/HE1·+) = +
0.85 V vs SCE in MeCN] and generates Hantzsch ester radical
cation HE1·+. Next, the resulting IrII species [E1/2 (IrIII/IrII) = - 1.37
V vs SCE in MeCN]26 surmounts the thermodynamic barriers
and reduces the carbonyl compound (e.g. E1/2 = - 2.11 V vs SCE
for acetophenone 1) to ketyl radical intermediate A via PCET
with the activation of the radical cation HE1·+ and regenerates
IrIII.9e,27 Here, the addition of Lewis acid B(C6F5)3 (LA) as
described above can slightly improve the yield, which may be
partly due to its activation effect on the ketone substrate.
Afterwards, radical addition between ketyl radical A and α,β-
Unfortunately, dialkyl ketones and aliphatic aldehydes failed
to undergo the reaction, presumably by virtue of their lower
redox potentials (e.g. E1/2 = - 2.33 V vs SCE for cyclohexanone2,
20), and aza-heterocyclic ketones showed no reactivity too.
Only in cases where unsuitable alkenes employed, self-
coupling products of acetophenone were observed
(unsuccessful substrates, see ESI†, 8). In order to get a better
conversion efficiency, the transesterification process of some
specific substrates proceeded in CH2Cl2 instead of DMSO.
Diastereomers of all products are separable by flash
chromatography on silica gel except 27 and 28. The relative
configuration of the two diastereomers of compound 4 was
determined by 2D 1H-13C HMQC and NOESY spectrum (see
ESI†, Figure S17-S20). The structure of the two diastereomers
(13a and 13b) of product 13 was confirmed by single crystal X-
ray diffraction analysis. The relative configuration of other
products was assigned by analogy.
unsaturated ester
2 leads to radical intermediate B.
Intermediate B is reduced by Hantzsch ester radical HE1· via
SET, and then protonated to produce product 3, while
Hantzsch ester radical HE1· is converted to oxidized Hantzsch
ester OxHE1. Finally, product 3 undergoes an acid-catalyzed
intramolecular transesterification to furnish the γ-lactone
product 4.
In order to obtain in-depth details of the reaction
mechanism, further experiments were carried out (Scheme 4).
Radical-trapping experiment was conducted under the
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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COMMUNICATION
Journal Name
HE1
8. C. K. Prier, D. A. Rankic and D. W. C. MacMillan, Chem. Rev.,
View Article Online
HE1
2013, 113, 5322-5363.
DOI: 10.1039/D0CC05306F
SET
*IrIII
9. (a) C.-X. Ye, Y. Y. Melcamu, H.-H. Li, J.-T. Cheng, T.-T. Zhang, Y.-P.
Ruan, X. Zheng, X. Lu and P.-Q. Huang, Nat. Commun., 2018, 9,
410; (b) M. Nakajima, E. Fava, S. Loescher, Z. Jiang and M.
Rueping, Angew. Chem. Int. Ed., 2015, 54, 8828-8832; (c) L. Qi
and Y. Chen, Angew. Chem. Int. Ed., 2016, 55, 13312-13315; (d)
K. Cao, S. M. Tan, R. Lee, S. Yang, H. Jia, X. Zhao, B. Qiao and Z.
Jiang, J. Am. Chem. Soc., 2019, 141, 5437-5443; (e) F. Li, D. Tian,
Y. Fan, R. Lee, G. Lu, Y. Yin, B. Qiao, X. Zhao, Z. Xiao and Z. Jiang,
Nat. Commun., 2019, 10, 1774; (f) A. L. Berger, K. Donabauer
and B. König, Chemical Science, 2018, 9, 7230-7235.
10. K. D. Nguyen, B. Y. Park, T. Luong, H. Sato, V. J. Garza and M. J.
Krische, Science, 2016, 354, aah5133.
11. (a) J. Twilton, M. Christensen, D. A. DiRocco, R. T. Ruck, I. W.
Davies and D. W. C. MacMillan, Angew. Chem. Int. Ed., 2018, 57,
5369-5373; (b) K. Sakai, K. Oisaki and M. Kanai, Adv. Synth.
Catal., 2020, 362, 337-343.
Ph
EtO2
C
CO2Et
Me
Reductive
Quenching
Cycle
IrII
or LA
Me
N
H
h
O
Activated
by Acid
O
Ph
PCET
O
IrIII
4
H
H
Transesterification
O
Ph
OH
A
O
H
O
C-C Bond
Formation
3
Ph
O
OxHE1
SET
Ph
OH
O
O
2
O
B
HE1
HE1
- H+
12. (a) K. M. Arendt and A. G. Doyle, Angew. Chem. Int. Ed., 2015,
54, 9876-9880; (b) K. Qvortrup, D. A. Rankic and D. W. C.
MacMillan, J. Am. Chem. Soc., 2014, 136, 626-629.
13. T. Rossolini, B. Ferko and D. J. Dixon, Org. Lett., 2019, 21, 6668-
6673.
Structures
OxHE1
LA
HE1
HE1
HE1
F
F
Ph
Ph
Ph
Ph
F
F
F
F
EtO2
C
CO2Et
Me
EtO2
C
CO2Et
Me
EtO2
C
CO2Et EtO2
C
CO2Et
Me
F
F
F
B
F
F
F
Me
N
Me
N
Me
N
Me
Me
N
H
F
H
H
H
F
F
Scheme 5 Plausible reaction mechanism.
14. (a) Q. Xia, J. Dong, H. Song and Q. Wang, Chem. - Eur. J., 2019,
25, 2949-2961; (b) K. N. Lee and M.-Y. Ngai, Chem. Commun.,
2017, 53, 13093-13112.
In summary, we have developed the first intermolecular
reductive coupling reaction (umpolung addition) between 15. (a) K. Otsubo, J. Inanaga and M. Yamaguchi, Tetrahedron Lett.,
1986, 27, 5763-5764; (b) Y. Qin, L. Zhu and S. Luo, Chem. Rev.,
2017, 117, 9433-9520; (c) S. Liu, F. Fan, N. Wang, D. Yuan, Y.
Wang, Z. Luo and Z.-Q. Liu, Adv. Synth. Catal., 2019, 361, 3086-
3093; (d) G. S. C. Srikanth and S. L. Castle, Tetrahedron, 2005,
61, 10377-10441.
diverse aromatic carbonyls and ,β-unsaturated esters for the
synthesis of -lactones via a ketyl radical pathway. Hantzsch
ester plays an imperative role in the activation of carbonyl
compounds and functioned as the electron and proton donor
to facilitate the key SET and PCET processes. The addition of p-
toluenesulfonic acid successfully promoted the intramolecular
transesterification of the coupling products, to afford a wide
range of polysubstituted γ-lactones in good yields.
We gratefully acknowledge the National Natural Science
Foundation of China (Nos. 21672174, 21977084 and 22078268)
and the Natural Science Foundation of Chongqing (No.
cstc2019jcyj-msxmX0297).
16. K. T. Tarantino, P. Liu and R. R. Knowles, J. Am. Chem. Soc.,
2013, 135, 10022-10025.
17. J. L. Jeffrey, J. A. Terrett and D. W. C. MacMillan, Science, 2015,
349, 1532.
18. (a) C. Wang, J. Qin, X. Shen, R. Riedel, K. Harms and E. Meggers,
Angew. Chem., 2016, 128, 695-698; (b) W. Ding, L.-Q. Lu, J. Liu,
D. Liu, H.-T. Song and W.-J. Xiao, J. Org. Chem., 2016, 81, 7237-
7243; (c) N. J. Foy, K. C. Forbes, A. M. Crooke, M. D. Gruber and
J. S. Cannon, Org. Lett., 2018, 20, 5727-5731.
19. K. N. Lee, Z. Lei and M.-Y. Ngai, J. Am. Chem. Soc., 2017, 139,
5003-5006.
Conflicts of interest
There are no conflicts to declare.
20. For aliphatic ketones and aldehydes, see: H. Seo and T. F.
Jamison, Org. Lett., 2019, 21, 10159-10163.
21. W. Hao, J. H. Harenberg, X. Wu, S. N. MacMillan and S. Lin, J.
Am. Chem. Soc., 2018, 140, 3514-3517.
22. A. Trowbridge, D. Reich and M. J. Gaunt, Nature, 2018, 561,
522-527.
23. (a) C. P. Seath, D. B. Vogt, Z. Xu, A. J. Boyington and N. T. Jui, J.
Am. Chem. Soc., 2018, 140, 15525-15534; (b) Y. Yin, Y. Dai, H.
Jia, J. Li, L. Bu, B. Qiao, X. Zhao and Z. Jiang, J. Am. Chem. Soc.,
2018, 140, 6083-6087.
24. E. C. Gentry and R. R. Knowles, Acc. Chem. Res., 2016, 49, 1546-
1556.
25. M. S. Lowry, J. I. Goldsmith, J. D. Slinker, R. Rohl, R. A. Pascal, G.
G. Malliaras and S. Bernhard, Chem. Mater., 2005, 17, 5712-
5719.
26. T. Koike and M. Akita, Inorganic Chemistry Frontiers, 2014, 1,
562-576.
27. M. Chen, X. Zhao, C. Yang and W. Xia, Org. Lett., 2017, 19, 3807-
3810.
Notes and references
1. D. J. Edmonds, D. Johnston and D. J. Procter, Chem. Rev., 2004,
104, 3371-3404.
2. H. G. Roth, N. A. Romero and D. A. Nicewicz, Synlett, 2016, 27,
714-723.
3. S. K. Pradhan, Tetrahedron, 1986, 42, 6351-6388.
4. Z. Hou, X. Jia, A. Fujita, H. Tezuka, H. Yamazaki and Y. Wakatsuki,
Chem. - Eur. J., 2000, 6, 2994-3005.
5. B. E. Kahn and R. D. Rieke, Chem. Rev., 1988, 88, 733-745.
6. (a) R. A. Flowers Ii, Synlett, 2008, 2008, 1427-1439; (b) R. J.
Enemærke, T. Hertz, T. Skrydstrup and K. Daasbjerg, Chem. -
Eur. J., 2000, 6, 3747-3754.
7. (a) C. D. Donner, Org. Lett., 2013, 15, 1258-1261; (b) E. J.
Enholm, K. M. Moran, P. E. Whitley and M. A. Battiste, J. Am.
Chem. Soc., 1998, 120, 3807-3808.
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Table of contents entry
O
R'
R'
HO R
R'
O
H+
Hantzsch ester
O
O
O
+
Ar
Ar
R
Photoredox catalysis
Ar
O
O
R
Ketyl radical pathway
One-pot two-step
45 examples
Up to 97% yield
Photoinduced reductive coupling of carbonyl compounds and α,β-unsaturated esters via ketyl
radical intermediates for the synthesis of γ-lactones is described.