A Desulfurative Strategy for the Generation of Alkyl Radicals Enabled by Visible-Light Photoredox Catalysis

Article abstract of DOI:10.1002/anie.201802710

Herein, we present a new desulfurative method for generating primary, secondary, and tertiary alkyl radicals through visible-light photoredox catalysis. A process that involves the generation of N-centered radicals from sulfinamide intermediates, followed by subsequent fragmentation, is critical to forming the corresponding alkyl radical species. This strategy has been successfully applied to conjugate addition reactions that features mild reaction conditions, broad substrate scope (>60 examples), and good functional-group tolerance.

Full text of DOI:10.1002/anie.201802710

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Accepted Article
Title: A Desulfurative Strategy for the Generation of Alkyl Radicals
Enabled by Visible-Light Photoredox Catalysis
Authors: Yong Qin, Fei Xue, Falu Wang, Jiazhen Liu, Jiamei Di, Qi
Liao, Huifang Lu, Min Zhu, Liping He, Huan He, Dan Zhang,
Hao Song, and Xiao-Yu Liu
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201802710
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10.1002/anie.201802710
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A Desulfurative Strategy for the Generation of Alkyl Radicals
Enabled by Visible-Light Photoredox Catalysis
Fei Xue,† Falu Wang,† Jiazhen Liu, Jiamei Di, Qi Liao, Huifang Lu, Min Zhu, Liping He, Huan He, Dan
Zhang, Hao Song, Xiao-Yu Liu, and Yong Qin*
Abstract: Herein, we present a new desulfurative protocol for
generating primary, secondary and tertiary alkyl radicals via visible-
light photoredox catalysis. A process that involves the generation of
N-centered radicals from sulfinamide intermediates, followed by
subsequent fragmentation, is critical to forming the corresponding
alkyl radical species. This strategy has been successfully applied to
conjugate addition reactions that features mild reaction conditions,
broad substrate scope (>60 examples), and good functional-group
tolerance.
to generate alkyl radicals and undergo photoredox cross-
coupling reactions.[16] However, these known methods suffer
from poor reaction generality,[14] the necessity of UV light,[15] or
generally low reaction yields.[16] Thus, the development of more
efficient ways to generate alkyl radicals from thiol or sulfide
derivatives and the expansion of the synthetic utility of such
methods remains desirable.
Radicals play a significant role in a variety of chemical
transformations that have influenced and shaped the
development of organic synthesis.[1] Today, one of the
challenges of radical chemistry is identifying efficient ways to
generate radicals under mild conditions. Methods for accessing
alkyl radicals were greatly improved by the development of
visible-light photoredox catalysis in the past few years.[2]
Functional groups such as carboxylic acids,[3] oxalates,[4]
Katritzky salts,[5] halides,[6] organoboron[7] and organosilicon
compounds,[8] as well as their derivatives have proven to be
good precursors for the generation of alkyl radicals under light-
mediated conditions (Figure 1). The resulting alkyl radical
species can be involved in an array of functionalization
processes, leading to the formation of increased molecular
complexity and diversity in a selective and environmentally
benign manner.
Thiols and sulfides are important reagents and intermediates
commonly used in organic, bioorganic, and material chemistry.[9]
As mentioned above, while various functional groups have been
demonstrated to serve as notable radical precursors, examples
of generating alkyl radical intermediates via desulfurative
approaches under visible-light photocatalytic conditions are rare.
Most previous reports using sulfones,[10] sulfinates,[11] sulfonium
salts,[12] or sulfonyl chlorides[13] to form carbon-centered radicals
are limited to fluoroalkyl radical species, especially
trifluoromethyl (CF3) radicals (Figure 1). In 1978, Kellogg et al.
first reported a reductive desulfuration of sulfonium salts to
afford the corresponding alkanes via alkyl radical intermediates
under photocatalytic conditions.[14] Very recently, the Li group
developed a protocol for using sulfone compounds as alkyl
radical source with UV light irradiation.[15] Knauber and co-
workers have also demonstrated that sulfinate salts can be used
Figure 1. Visible-light photocatalytic generation of alkyl radicals from various
precursors.
Recently, in our studies of N-centered radicals,[17] we found
that N-acyl alkyl-sulfinamides (A, Figure 1) can be used to
generate alkyl radicals via visible-light-mediated desulfuration.
These reagents can be easily prepared from thiol or sulfide
compounds.[18] As illustrated in Figure 1, upon subjection of
sulfinamides (A) to a base and photoredox catalyst with visible
light irradiation, the N-centered radical intermediates (B) would
be first generated and subsequently undergo fragmentation,
thus yielding the corresponding alkyl radicals. Herein, we report
the synthetic utility and mechanistic insights of this unique
process.
We first prepared a series of N-acyl tert-butyl-sulfinamides
(Figure 1, compound A, R = t-Bu) to explore their ability to
generate alkyl radicals under visible-light photocatalysis. In our
initial experiments, N-benzoyl tert-butyl-sulfinamide
1 was
observed to be the superior precursor among the tested
sulfinamides.[18] A brief evaluation of photocatalysts showed that
[Ir(ppy)2(dtbbpy)]PF6 was superior over others [e.g., Ru(bpy)3Cl2
•6H2O, Ir(ppy)3, etc]. Cyclic voltammetry (CV) of N-benzoyl tert-
butyl-sulfinamide 1 demonstrated its redox potential at +0.43 V
and +0.66 V, suggesting that the visible-light-excited
photocatalyst *Ir(ppy)2(dtbbpy)+ (E1/2 = +0.66 V vs SCE in
MeCN) is active enough for the first single-electron transfer
(SET) oxidation.[19] The conjugate addition reaction between 1
and diethyl 2-ethylidenemalonate (2) occurred in the presence of
[Ir(ppy)2(dtbbpy)]PF6 (1 mol%) and K2HPO4 (4 equiv) in
tetrahydrofuran under the irradiation of 8 W blue LED strips at
40 ºC, affording adduct 3 in 55% yield in 8 h (entry 1, Table 1). A
survey of different light sources (entries 2–4) indicated that the
reaction was more effective and showed an improved yield of
[*]
Dr. F. Xue,[†] F. Wang,[†] J. Liu, J. Di, Q. Liao, H. Lu, M. Zhu, L. He,
H. He, Dr. D. Zhang, Dr. H. Song, Dr. X.-Y. Liu, Prof. Y. Qin.
Key Laboratory of Drug Targeting and Drug Delivery Systems of the
Ministry of Education, and Sichuan Research Center of Precision
Engineering Technology for Small Molecule Drugs, West China
School of Pharmacy, Sichuan University, Chengdu 610041 (P. R.
China)
E-mail: yongqin@scu.edu.cn
These authors contributed equally
[†]
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/anie.201802710
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COMMUNICATION
yield, respectively. Moreover, other Michael receptors containing
sulfone, amide, ketone, and nitrile functional groups could also
be employed in this addition reaction (18–21, 36–74% yield),
although some of them were less efficient.[20] Of note, the
reaction of methyl phenylacrylate with 1 could be conducted on
a gram scale with no decrease in the yield (9).
74% within 3 h when using 34 W blue LEDs (entry 4). Solvent
screening indicated that acetone was the best solvent and gave
the highest yield of 90% (entries 5–9). Reducing the equivalents
of base (K2HPO4) from 4.0 equiv to 2.0 equiv required a longer
reaction time (48 h) and resulted in a decreased yield (65% yield,
entry 10). Additionally, the equivalents of 1 also influenced the
reaction results (entries 9, 11–13); slightly reducing the loading
of 1 to 1.8 equiv delivered comparable efficacy (88%, entry 11)
to that obtained when using 2.0 equiv (90%, entry 9), whereas
using 1.2 equiv led to significantly diminished yield (69%, entry
13).
Table 2. Desulfurative Conjugate Addition: Michael Acceptor Scope[a]
Table 1. Optimization of the Reaction Conditions[a]
entry
light source
equiv of 1
solvent
yield
1
2
8 W blue LEDs
15 W white LEDs
26 W CFL
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.8
1.6
1.2
THF
THF
55%
56%
40%
74%
83%
49%
66%
31%
90%
65%
88%
84%
69%
3
THF
4
34 W blue LEDs
34 W blue LEDs
34 W blue LEDs
34 W blue LEDs
34 W blue LEDs
34 W blue LEDs
34 W blue LEDs
34 W blue LEDs
34 W blue LEDs
34 W blue LEDs
THF
5
CH2Cl2
PhMe
6
7
MeCN
DMSO
acetone
acetone
acetone
acetone
acetone
8
9
10[b]
11[c]
12[d]
13[e]
[a] Reactions were conducted on 0.4 mmol scale with 4.0 equiv of K2HPO4
unless otherwise stated. Yields were determined according to the isolated
material. [b] 2.0 equiv of K2HPO4 was used. [c] Carried out with 3.6 equiv of
K2HPO4. [d] Carried out with 3.2 equiv of K2HPO4. [e] Carried out with 2.4 equiv
of K2HPO4.
[a] Reactions were run on 0.4 mmol scale with 1.8 equiv of sulfinamide 1
and 3.6 equiv of K2HPO4 unless otherwise stated. Yields were determined
according to the isolated material. [b] 4.0 equiv of 1 was used. [c] 5.0 equiv
of 1 was used. [d] The dr value was more that 20:1. Isolated as cis isomer.
[e] The dr value was determined by 1H NMR of the crude mixture of 15.
With the optimized reaction conditions in hand (1 mol%
[Ir(ppy)2(dtbbpy)]PF6, 4.0 equiv of K2HPO4, 1.8 equiv of 1, and
34 W blue LEDs at 40 ºC, acetone), we then focused our
attention on evaluating the scope of Michael acceptors for this
new desulfurative conjugate addition (Table 2). Gratifyingly, we
found that a wide array of electron-deficient alkenes can be used
as acceptors in the Michael addition reaction. -Aryl and -alkyl
substituted methylenemalonates, including coumarin derivatives,
afforded the corresponding alkylation products in good to
excellent yields (4–8, 60–92% yield). Various acrylates with -
aryl and -alkyl groups also proved to be effective reaction
partners (9–15). Notably, varying the electronic nature of the
aromatic ring in -aryl acrylates had no significant effects on the
results of the reaction (9–12, 61–90% yield). Functional groups
such as a free alcohol and an epoxide moiety, were well-
tolerated in the photocatalytic Michael addition reactions (14 and
15). In addition, ,-unsaturated carboxylic acids furnished
corresponding conjugate adducts 16 and 17 in 86% and 76%
Next, we investigated the generation of secondary and
primary alkyl radicals and the scope of the Michael addition
reactions. As illustrated in Table 3A, subjecting secondary
radical precursors to this desulfurative process typically afforded
the desired adducts with good yields. As a representative
example, N-benzoyl cyclopentyl-sulfinamide reacted with a
variety of Michael acceptors, including ,-unsaturated ester,
carboxylic acid, sulfone, amide, and nitrile substrates, to
efficiently generate the corresponding products (22–29, 65–93%
yield). The ring expanded cyclohexyl-sulfinamide (corresponding
products 30–37) showed similar reactivity to that of its
cyclopentyl counterpart. Moreover, the addition reactions of
acyclic sulfinamides (e.g., N-benzoyl isopropyl-sulfinamide)
occurred smoothly to yield corresponding products with good
levels of efficacy (38–42, 49–96% yield). Although the free
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Table 3. Desulfurative Conjugate Addition with Secondary and Primary Alkyl N-Benzoyl Sulfinamides[a]
A) secondary alkyl radical products
O
CN
O
O
CO2Et
CO2Et
CO2Et
CO2Et
OMe
NMe2
OH
Br
SO2Ph
Ph
R
Ph
26 93% yield
O
Me
22 80% (R = Me)
23 86% (R = Ph)
27 85% yield
25 90% yield
28 65% yield
29 66% yield
24 77% yield
O
O
CO2Et
CO2Et
CO2Et
CO2Et
OMe
OH
Ph
36 68% yield
OH
CO2Et
CO2Et
R
SO2Ph
Ph
R
R
38 91% (R = Me)
39 96% (R = Ph)
30 89% (R = Me)
31 90% (R = Ph)
32 68% (R = H)
33 82% (R = 2-Br)
34 62% (R = 4-OMe)
40 85% yield
35 75% yield
37 40% yield
Boc
Boc
N
O
O
N
O
O
BocN
CO2Et
CO2Et
OH
Ph
45 87% yield
O
O
BocN
CO2Et
SO2Ph
R
Ph
46
OMe
51% yield
BocN
41 58% yield[b]
43 93% (R = Me)
44 60% (R = Ph)
42 49% yield
47 49% yield
48 47% yield
dr > 20:1
B) primary alkyl radical products
O
O
O
CO2Et
CO2Et
53 45% yield
CO2Et
OMe
R
NMe2
Ph
OH
SO2Ph
CO2Et
R
Ph
49 63% (R = Me)
50 67% (R = Ph)
51 44% (R = H)
52 69% (R = Br)
56 27% yield
NHBoc
54 46% yield
55 33% yield
O
NHBoc
O
O
O
CO2Et
CO2Et
O
BocHN
OMe
R
BocHN
OH
Ph
BocHN
BocHN
62 37% yield
Ph
OMe
Me
60 39% yield
63 35% yield
61 37% yield
58 53% (R = H)
59 86% (R = Br)
57 62% yield
O
O
O
O
CO2Et
CO2Et
CO2Et
BnO
OMe
Br
TBSO
OMe
Br
BnO
OH
Ph
69 29% yield
TBSO
OH
BnO
TBSO
CO2Et
Me
Me
Ph
64 55% yield
65 75% yield
66 35% yield
67 28% yield
68 51% yield
[a] Reactions were run on 0.4 mmol scale with 1.8 equiv of sulfinamide 1 and 3.6 equiv of K2HPO4 unless otherwise stated. Yields were determined according to
the isolated material. [b] Isolated as cis isomer.
amine functionality was not tolerated, N-Boc protected
sulfinamides could be used successfully (43–48, 47–93% yield).
Reported methods for generating primary alkyl radicals and
for utilizing these reactive species under photocatalytic
conditions are limited.[21] With this new protocol in hand, we
explored the desulfurative conjugate addition of different primary
alkyl radical precursors (Table 3B). Generally, the reactions of
primary alkyl radicals were less efficient than those of the tertiary
and secondary radicals. However, most of these N-benzoyl
sulfinamides were well-tolerated in this reaction, affording the
desired products under the optimal reaction conditions. For
instance, N-benzoyl n-butyl-sulfinamide smoothly underwent the
conjugate addition with various Michael acceptors to deliver the
corresponding adducts (49–56).[22] Moreover, functional groups
including NHBoc, OTBS, and OBn were all tolerated in this
conjugate addition with primary alkyl radicals (57–69). Notably,
among the few reported reactions of primary alkyl radicals
through the desulfurative strategy,[15,16] our method has revealed
superior functional-group compatibility and comparable
efficiency.
To further understand the reaction mechanism, control
experiments were carried out. Evidently, each component (e.g.,
visible light, base, and photocatalyst) was essential for the
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10.1002/anie.201802710
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COMMUNICATION
desired conjugate addition (Figure 2A). Moreover, adding
TEMPO to the reaction mixture greatly suppressed the formation
of conjugate addition product 3, and instead, the reaction
produced TEMPO-alkyl radical adduct 70 as the major product.
This result suggested the reaction occurs via an alkyl radical
intermediate, which encouraged us to propose the plausible
mechanism shown in Figure 2B. Initial deprotonation of an
acidified N–H bond occurs in the presence of base to provide
amidyl anion I. The photoexcited IrIII complex then oxidizes I via
SET, yielding nitrogen-centered radical II. This alkylsulfinamide-
approaches. Studies concerning the utilization of the alkyl
radical species in other synthetic transformations are ongoing in
our laboratory and will be reported in due course.
Acknowledgements
We are grateful for the financial surpport from National Natural
Science Foundation of China (21732005 and 21702140),
National Science and Technology Major Projects for “Major New
Drugs Innovation and Development” (2018ZX09711003-015),
and the Fundamental Research Funds for the Central
Universities (the Postdoctoral Foundation of Sichuan University,
2018SCU12027).
associated
radical
species
automatically
undergoes
fragmentation during the reaction, resulting in the generation of
N-sulfinylbenzamide (III)[23] and corresponding alkyl radical IV.
The former is hydrolyzed to benzamide, which could be isolated
after reaction workup,[24] while the latter participates in the
subsequent Michael addition. Thus, alkyl radical IV adds to an
electron-deficient alkene to furnish carbon radical V. After
intermediate V accepts one electron from the reductive IrII
complex, the resulting carbon anion VI is then protonatd to
afford the final product. Meanwhile, the ground state IrIII
photocatalyst is regenerated, thus completing the catalytic cycle.
Keywords: alkyl radical • catalysis • conjugate addition •
desulfuration • photoredox
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Figure 2. A) Control experiments and B) proposed catalytic cycle
In conclusion, we have developed
a
photocatalytic
desulfurative method to generate primary, secondary and
tertiary alkyl radicals using N-acyl alkyl-sulfinamides as radical
precursors. These alkylation reagents are bench-stable, easy-to-
handle solids that can be readily accessed from thiol or sulfide
compounds. Central to the success of this novel protocol is the
generation of alkyl radicals from N-centered radical
intermediates via subsequent fragmentation processes. This
strategy, with the successful application in conjugation addition,
has provided new synthetic utility of N-acyl alkyl-sulfinamides as
alkyl radical precursors and complements the existing
[4]
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Overman, J. Org. Chem. 2015, 80, 6012; c) X. Zhang, D. W. C.
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Jamison, P. Zhao, J. Lee, Y. H. Rhee, L. E. Overman, J. Am. Chem.
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COMMUNICATION
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[18] For more details, see the Supporting Information.
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due to its high volatility.
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[22] No reaction was observed when using N-benzoyl methyl-sulfinamide as
the precursor in the conjugate addition. Presumably, the methyl radical
was difficult to be generated through this approach. See also ref. [15].
[23] W. Huang, J.-L. Ye, W. Zheng, H.-Q. Dong, B.-G. Wei, J. Org.
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This article is protected by copyright. All rights reserved.

10.1002/anie.201802710
Angewandte Chemie International Edition
COMMUNICATION
COMMUNICATION
Fei Xue,† Falu Wang,† Jiazhen
Liu, Jiamei Di, Qi Liao, Huifang
Lu, Min Zhu, Liping He, Huan
He, Dan Zhang, Hao Song,
Xiao-Yu Liu, and Yong Qin*
A new desulfurative protocol for
generating primary, secondary
and tertiary alkyl radicals via
visible-light photoredox catalysis
is reported. The key process for
forming the alkyl radical species
involves the generation of N-
Page No. – Page No.
centered
sulfinamide
followed
radicals
from
A Desulfurative Strategy for the
Generation of Alkyl Radicals
Enabled by Visible-Light
Photoredox Catalysis
intermediates,
subsequent
by
fragmentation.
This article is protected by copyright. All rights reserved.