Catalyst-free generation of acyl radicals induced by visible light in water to construct C-N bonds

Article abstract of DOI:10.1039/d0ob02364g

We describe herein a catalyst-free and redox-neutral photochemical strategy for the direct generation of acyl radicals from α-diketones, and its selective conversion of nitrosoarenes to hydroxyamides or amides with AcOH or NaCl as an additive. The reaction was carried out under mild conditions in water with purple LEDs as the light source. A broad scope of substrates was demonstrated. Mechanistic experiments indicate that α-diketones cleave to give acyl radicals, with hydroxyamides being further reduced to amides.

Full text of DOI:10.1039/d0ob02364g

Volume 19
Number 9
7 March 2021
Pages 1869-2066
Organic &
Biomolecular
Chemistry
rsc.li/obc
ISSN 1477-0520
PAPER
Chao-Jun Li, Qiuli Yao et al.
Catalyst-free generation of acyl radicals induced by visible
light in water to construct C–N bonds

Organic &
Biomolecular Chemistry
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PAPER
Catalyst-free generation of acyl radicals induced
by visible light in water to construct C–N bonds†
Cite this: Org. Biomol. Chem., 2021,
19, 1970
Maogang Ran,a Jiaxin He,a Boyu Yan,a Wenbo Liu,b Yi Li,a Yunfen Fu,a
a
Chao-Jun Li *b and Qiuli Yao
*
We describe herein a catalyst-free and redox-neutral photochemical strategy for the direct generation of
acyl radicals from α-diketones, and its selective conversion of nitrosoarenes to hydroxyamides or amides
with AcOH or NaCl as an additive. The reaction was carried out under mild conditions in water with
purple LEDs as the light source. A broad scope of substrates was demonstrated. Mechanistic experiments
indicate that α-diketones cleave to give acyl radicals, with hydroxyamides being further reduced to
amides.
Received 27th November 2020,
Accepted 4th January 2021
DOI: 10.1039/d0ob02364g
rsc.li/obc
other amine derivatives.12 Diverse strategies have been pro-
posed for their syntheses catalyzed by enzymes, organic cata-
Introduction
Green chemistry is one of the most important research fields lysts, metals and others.13 However, the direct reaction of acyl
to address sustainability challenges in chemical transform- radicals with nitroso compounds is still unknown. The photo-
ations.1 Many efforts have been made to increase resource and induced catalyst-free transformation of nitroso compounds
energy efficiency for chemical synthesis. Examples include into hydroxylamides or amides has not yet been achieved. The
reactions enabled by light2 and catalyst- or metal-free reac- radical chemistry of nitroso compounds remains largely
tions,3 as well as reactions using water rather than harmful unexplored.14
organics as a solvent.4
In this context, we report a general approach to convert
Acyl radicals are key intermediates in organic synthesis.5 α-diketones to acyl radicals promoted by visible light without
They can generally generated from α-ketoacids,6 aldehydes,7 any catalysts or redox agents under aqueous conditions
acid chlorides,8 and other acid derivatives (Scheme 1a).9 (Scheme 1b).
Although these elegant strategies provide effective solutions for
the direct synthesis of carbonyl compounds, most of these reac-
tions require stoichiometric strong oxidants or photo-redox
reagents. Approaches to convert readily available precursors
such as diketones to acyl radicals in a mild and green manner
are highly desirable, since diketones are stable, easy to handle
and low cost. Although high-power Hg lamps can be used in the
homolytic cleavage of α-diketones,10 the cleavage of the Csp2
–
Csp2 bond of α-diketones irradiated by visible light has not been
reported. Also, further transformation of the resulting acyl rad-
icals from α-diketones has rarely been explored.
Besides, amides and hydroxylamides are also important
bioactive compounds in medical or agricultural studies.11 They
are frequently used as building blocks in the formation of
aKey Laboratory of Biocatalysis & Chiral Drug Synthesis of Guizhou Province, Generic
Drug Research Center of Guizhou Province, Department of Pharmacy, Zunyi Medical
University, 6 Xuefu Road West, Zunyi, 563000, China. E-mail: yaoqiuli@zmu.edu.cn
bDepartment of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal,
Quebec H3A 0B8, Canada. E-mail: cj.li@mcgill.ca
†Electronic supplementary information (ESI) available: Experimental details and
spectroscopic characterization information. See DOI: 10.1039/d0ob02364g
Scheme 1 Converting carbonyl compounds to acyl radicals.
1970 | Org. Biomol. Chem., 2021, 19, 1970–1975
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dition optimization with water as the solvent under purple
LED irradiation (12 W) at room temperature under air atmo-
Results and discussion
This approach proceeds via a homolytic cleavage mechanism sphere for 12 h. To our delight, the addition of acetyl radicals
(Scheme 2): biacetyl displays obvious absorption in the purple to the nitroso group proceeded smoothly and gave the coup-
light region (λmax = 417 nm, Fig. S1†) and can be activated by ling product hydroxyamide 3a in an isolated yield of 36%
purple light. It cleaves to give acetyl radicals, which can be (Table 1, entry 1), with by-products N-phenylacetamide (4a)
trapped by 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) to and nitrobenzene (5a) detected by GC-MS. Compound 4a is a
give a 12% TEMPO-Ac (Fig. S2†) or NvO group to construct C– reduction product from 3a, but 5a is a by-product from the oxi-
N bonds (Scheme 1b).
dation of 2a by O2 in air. The acidity of the reaction system
This strategy was tested (Table 1) using biacetyl (1a) and may affect this transformation. Thus, a series of additives and
nitrosobenzene (2a, 0.4 mmol) as model substrates for con- their amounts were examined (Table 1, entries 2–15): no
product or only a trace amount of product was detected under
basic conditions (Table 1, entries 2–4); with 6 equiv. of acetic
acid, an 84% yield of 3a was obtained (Table 1, entry 13). To
further improve the atom efficiency of this procedure, the con-
centration of 1a was further studied (Table 1, entries 16–19):
1a can be reduced to 6.8 equiv., which gave similar yields
(85%, Table 1, entry 19). An inert atmosphere was not necess-
ary for this coupling reaction (Table 1, entries 20 and 21).
Purple light gave the highest yield compared with other light
Scheme 2 Trap of acetyl radicals by TEMPO.
(Table 1, entries 22–26).
Subsequently, the optimized reaction conditions for the
preparation of hydroxylamides (Table 1, entry 19) were selected
Table 1 Optimization of conditions for the synthesis of 3aa
for substrate study (Table 2). The reactive hydroxyl group made
product 3 unstable on silica gel, which was further converted
to O-acetyl derivative 6 in a one-pot reaction for purification
purpose.
An array of functional groups including Cl (6b, 6g, and 6h),
Br (6c, 6e, and 6f), 4-MeO (6d), 4-tert-butyl (6i), 4-acetyl (6j),
4-CF3 (6k), methyl (6l and 6m), 4-ethyl (6n), carboxylic ester
(6o–6q) and phenyl (6r and 6s) groups, as well as the ben-
zothiazolyl group (6t), were all well tolerated and provided
yields from 72% to 94% for two steps after purification
(Table 2). Other α-diketones were also tested: hexane-3,4-dione
(1b) and 1,4-dibromobutane-2,3-dione (1c) can be transformed
into the corresponding products in moderate yields (6u and
6v). Because of the resonance effect of the benzyl and carbonyl
group, which makes it stable and difficult to cleave homolyti-
cally, 1d remained unchanged after 12 h. The alkyl-substituted
nitroso compounds were not stable, and thus they were not
tested in this reaction.
The direct transformation of nitrosoarene (2) to amide (4)
without the use of a reductant has not been reported before.
Also, the synthesis of amides is fundamentally important in
the pharmaceutical industry.15 This led us to explore related
chemical reactivities and mechanisms.
Aqueous acetone was used as the solvent for condition
optimization with 0.4 mmol 2a and 1.1 mmol 1a as substrates
(Table 3). Under the acidic conditions presented in Table 2,
only a trace amount of 4a was formed; so other additives were
examined (Table 3, entries 1–5), with NaCl giving the highest
yield (32%, Table 3, entry 2). Only a trace amount of 4a was
obtained with the addition of 1 equiv. of base (including
N-methylpiperidine, DIPEA, NaOH or KOH in Table 3, entries
6–9). We were delighted to find that 76% of 4a could be selec-
tively formed as a major product with the use of 2 equiv. of
Entry
Additive/equiv.
1a/equiv.
Yield [%]
1
2
3
4
5
6
7
8
—
11
11
11
11
11
11
11
11
11
11
11
11
11
11
11
1.1
2.2
4.5
6.8
6.8
6.8
6.8
6.8
6.8
6.8
6.8
36
K2CO3/1
NaOH/1
N-Methylpiperidine/1
H2SO4/1
H3PO4/1
Benzoic acid/1
AcOH/1
HCOOH/1
1.2 M HCl/1
AcOH/4
AcOH/5
AcOH/6
AcOH/7
AcOH/8
AcOH/6
AcOH/6
AcOH/6
AcOH/6
AcOH/6
AcOH/6
AcOH/6
AcOH/6
N.R.
N.R.
Trace
N.R.
N.R.
15
44
35
N.R.
35
67
84
78
79
70
71
78
85
83
9
10
11b
12b
13b
14b
15b
16
17
18
19
20c
21d
22e
23f
24g
25h
26i
80
79
Trace
Trace
35
AcOH/6
AcOH/6
AcOH/6
32
a Reactions were performed with 1a and 2a (0.4 mmol) in water
(0.6 mL) at room temperature under purple LED irradiation (12 W) for
12 h unless otherwise indicated. Yields were determined after purifi-
cation by column chromatography. b The reaction was carried out with
2a (0.1 mmol) in water (0.15 mL). c The reaction was carried out under
an argon atmosphere. d The reaction was carried out under a nitrogen
atmosphere. e Blue LEDs were used. f Yellow LEDs were used. g Red
LEDs were used. h Green LEDs were used. i UV light (254 nm) was used.
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Table 2 Catalyst-free coupling of nitrosoarenes with α-diketones in
Table 3 Optimization of conditions for the synthesis of amide 4aa
watera
Entry
Additive/equiv.
Yield [%]
1
2
NH4Cl/1
NaCl/1
31
32
3
4
5
MgSO4/1
Na2SO4/1
NaBr/1
22
24
28
6
7
8
9
10
11
12
13
14b
15c
16b
N-Methylpiperidine/1
DIPEA/1
NaOH/1
KOH/1
NaCl/2
NaCl/3
NaCl/4
NaCl/5
NaCl/2
NaCl/2
Trace
Trace
N.R.
N.R.
40
30
31
24
76
76
21
—
a Reactions were performed with 1a (1.1 mmol, 0.1 mL) and 2a
(0.4 mmol) in water (0.6 mL) and acetone (3 mL) at room temperature
in air under purple LED irradiation (12 W) for 12 h unless otherwise
indicated. Yields were determined after purification by column chrom-
atography. b The reaction was carried out under an argon atmosphere.
c The reaction was carried out under a nitrogen atmosphere.
Table 4 Catalyst-free and redox-neutral conversion of nitrosoarenes to
amides under aqueous conditionsa
a Conditions (1): 1 (2.7 mmol, 6.8 equiv.), 2 (0.4 mmol) and AcOH
(2.4 mmol) in water (0.6 mL) at room temperature under purple LED
irradiation (12 W) for 12 h. Conditions (2): NEt3 (0.1 mmol) and AcCl
(0.6 mmol), 0 °C to room temperature for 1 h. Isolated yields for 2
steps.
NaCl as the additive under an argon or nitrogen atmosphere
(Table 3, entries 14 and 15). An inert atmosphere is needed to
minimize the oxidation of 2a to nitrobenzene (5a) and sup-
press the quenching of radical intermediates. NaCl may be
involved in the electron-transfer process and is crucial for this
reductive reaction, without which only 21% of 4a was obtained
(Table 3, entry 16).
With the optimized conditions (Table 3, entry 14), the sub-
strate scope was studied (Table 4). Besides the unsubstituted
substrate (4a), functional groups including Cl (4b, 4g, and 4h),
Br (4c, 4e, and 4f), 4-MeO (4d), 4-tert-butyl (4i), 4-acetyl (4j),
4-CF3 (4k), methyl (4l and 4m), 4-ethyl (4n), carboxylic ester
(4o–4q), and phenyl (4r and 4s) groups, as well as the ben-
zothiazolyl group (4t), were all well tolerated, giving amides 4
in moderate to good yields. Likewise, the reaction of other
α-diketones such as 1c also furnished the product 4u in a mod- a Conditions: 1a (1.1 mmol, 2.8 equiv.), 2 (0.4 mmol) and NaCl
(0.8 mmol) in water (0.6 mL) and acetone (3 mL) at room temperature
erate yield.
under purple LED irradiation (12 W) for 12 h under argon. Isolated
yields. b Reactions were performed with 1c (2.2 mmol) and 2a
Furthermore, the practicability of this transformation was
demonstrated by scaling up to 12 mmol under standard con- (0.8 mmol).
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ditions to furnish 1.806 g of 6a in 78% yield after chromato- performed for prolonged time, 81% yield was obtained
graphic purification (Scheme 3). (Scheme 4e). Without the use of light (Scheme 4f) or replacing
To study the reaction mechanism, a control experiment was light with heat at 60 °C (Scheme 4g), no 4a was formed. To
carried out in the dark without the irradiation of light further confirm the transformation of 3a and 4a, kinetic
(Scheme 4a), in which the coupling product 3a was not studies were performed (Fig. 1, Table 5): within 8 h, 95%
detected. When TEMPO was added, only a trace amount of 3a nitrosobenzene (2a) was transferred into 3a and 4a (Table 5,
was detected by TLC (Scheme 4b). These results confirmed the entry 4). Yields of 3a increased to 42% in 6 h (Table 5, entry 3),
radical nature of the reaction.
and then decreased to 17% after 12 h (Table 5, entry 5). Yields
Other experiments helped to study the formation of 4a: of 4a increased over time and reached the highest after 12 h
Compound 3a can be partially transferred to 4a under purple (Table 5). These results indicate that 4a can be formed by the
LED irradiation for 12 h (Scheme 4c), but only traces of 4a reduction of 3a under irradiation of light. When 3a was irra-
were converted to 3a under the corresponding optimized con- diated with purple LEDs in benzene in the presence of 2,6-di-
ditions (Scheme 4d). When the transformation of 3a to 4a was tert-butylphenol, product 7 can be detected by GC-MS and
HRMS (Scheme 5, Fig. S3 and S4†). Thus, this procedure pro-
Scheme 3 Reaction at the gram-scale.
Fig. 1 Plots of product formation as a function of time.
Table 5 Study of product formation as a function of timea
Yield [%]
Entry
Time/h
3a
4a
3a + 4a
1
2
3
4
5
6
0
4
6
8
12
24
0
0
0
24
42
34
17
15
17
37
61
76
78
41
79
95
93
93
a Standard conditions in Table 4.
Scheme 4 Control experiments.
Scheme 5 Capture of radical intermediates by phenol.
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ZYDC2020123 and 20195201900) and Zunyi Medical University
(no. 18zy-003) for financial support.
Notes and references
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vides redox-neutral conditions for the direct reduction of
hydroxylamides to amides.
A mechanism is proposed based on these observations
(Scheme 6): acyl radical A formed via the homolytic cleavage of
α-diketone (1) can add to the NvO group. This forms the
radical intermediate B that is subsequently transformed to
product 3 by hydrogen-abstraction or other pathways.16 In the
presence of NaCl, compound 317 is cleaved to give the radical
intermediate C, which finally leads to amide 4.
Conclusions
In summary, we report the generation of acyl radicals from
α-diketones via a redox-neutral and catalyst-free strategy under
aqueous conditions induced by purple LEDs. Both hydroxyla-
mides and amides can be selectively and directly formed from
nitrosoarene compounds with acetic acid or NaCl as the only
additive. Different functional groups are well tolerated and
give moderate to excellent yields. Mechanistic experiments
confirmed the formation of acetyl radicals after irradiation of
biacetyl in water. The results demonstrate that the reduction of
hydroxylamides into amides can be promoted by visible light
in the presence of NaCl. While traditional approaches mostly
require the use of a reductant and a transition-metal catalyst
(Pd, Zn, et al.),18 these redox-neutral conditions only use NaCl
as the additive in water. We plan to extend this redox-neutral
strategy to other systems and provide greener approaches for
organic synthesis.
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