Photoredox-Catalyzed Decarboxylative C-H Acylation of Heteroarenes

Article abstract of DOI:10.1055/s-0037-1609911

A mild, environmentally friendly, and regioselective acylation of heterocycles with inexpensive carboxylic acids is reported via photoredox catalysis. The strategy is highlighted with good functional group tolerance and substrate scope which could rapidly

Full text of DOI:10.1055/s-0037-1609911

SYNLETT
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2
1
4
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-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–F
letter
A
de
W. Jia et al.
Letter
Synlett
Photoredox-Catalyzed Decarboxylative C–H Acylation of
Heteroarenes
Wei Jia
het
OEt
Yong Jian
H
R
HOOC
formylation with
Binbin Huang
Chao Yang*
Wujiong Xia*
OEt
O
het
H
COCOOH
0
0
0
0
0-
0
0
1
9-
3
9
6
9-
5
2
0
or
R
het
R = alkyl, aryl, heteroaryl
State Key Lab of Urban Water Resource and Environment,
Harbin Institute of Technology (Shenzhen), Shenzhen
518005, P. R. of China
O
43 examples, yield up to 84%
xyyang@hit.edu.cn
xiawj@hit.edu.cn
Received: 15.06.2018
Accepted after revision: 24.06.2018
Published online: 23.07.2018
acylation is a prevalent synthetic strategy for late-stage
modification of heterocycles, the Minisci reaction is a com-
monly used heterocyclic acylation method that introduces
nucleophilic acyl groups to electron-deficient heterocyclic
aromatics.9 However, the conditions of these reactions are
either harsh or costly. Therefore, developing a mild, eco-
nomical, and environmentally friendly formylation method
is still urgent.
DOI: 10.1055/s-0037-1609911; Art ID: st-2018-w0303-l
Abstract A mild, environmentally friendly, and regioselective acyla-
tion of heterocycles with inexpensive carboxylic acids is reported via
photoredox catalysis. The strategy is highlighted with good functional
group tolerance and substrate scope which could rapidly realize the ac-
ylation of various heterocyclic compounds.
Key words 2,2-diethoxyacetic acid, α-keto acids, heterocycles, C–H
Palladium-Catalyzed Protocol
functionalization, acylation
CHO
X
Pd
a)
R
R
Aldehydes and ketones are both prevalent compounds
that can participate in various chemical transformations or
serve as key synthons for complex scaffolds. Besides, they
are also widely found in pharmaceuticals, fine chemicals,
and natural products.1 Direct activation and functionaliza-
tion of C–H bonds in organic molecules to construct new C–
C bonds provides a new synthetic strategy for organic syn-
thesis.2 However, it is still a challenging goal because of the
relative inertness of the unactivated C–H bonds. Various
available methods require strong oxidants or harsh condi-
tions, limiting their application in the late-stage functional-
ization of complex molecules.3
Photoredox-Catalyzed Protocol
X
OEt
OEt
HOOC
CHO
b)
blue LED
R
R
RCO2H
c)
het
het
R
H
Ir-PC, blue LED
This work
het
het
OEt
OEt
H
Although aromatic aldehydes are widely applicable in
synthetic chemistry,4 methods to access them are to some
extent limited. Classical methods such as Vilsmeier–Haack,
Reimer–Tiemann, and Duff reactions5 suffer from relatively
poor regioselectivity due to the nature of aromatic electro-
philic substitution reactions. Another alternative tradition-
al approach to introduce an aldehyde group employs pre-
functionalized organometallic reagents and N,N-dimethyl-
formamide (DMF) at low temperature,6 with low tolerance
of functional groups as its drawback. In addition, more
works are reported on the reductive formylation of aryl ha-
lides catalyzed by the transition metal palladium (Scheme
1, a),7 the first of which was reported by Heck in 1974.8 C–H
HOOC
formylation with
O
O
d)
het
H
COCOOH
or
R
R
R = alkyl, aryl, heteroaryl
43 examples, yield up to 84%
Scheme 1 C–H functionalization
Recently, visible-light photocatalysis has become a
powerful synthetic tool for the construction of C–H and C–X
bonds via single-electron transfer.10 In particular, the use of
carboxylic acids as radical precursors to construct C–C
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

B
W. Jia et al.
Letter
Synlett
bonds has been the focus of recent interest.11 Formylation
of aromatic compounds has been realized through visible-
light induced single-electron transfer, energy conversion, or
hydrogen-atom-transfer processes. Wang reported a photo-
chemical, regioselective hydroformylation reaction, in
which a cheap organic dye 4CzIPN was employed as the
photosensitizer (Scheme 1, b).12 Hydroformylation results
are also impressive from Doyle,13 Wang,14 and Li.15 Glorius
reported the use of inexpensive carboxylic acids as alkyl
radical precursors of visible-light-induced Minisci reactions
(Scheme 1, c).11e In addition, Minisci transformations using
N-acyloxyphthalimides, alcohols, and peroxides as alkylat-
ing agents have recently been reported.16 However, formy-
lation of heterocyclic compounds under visible-light irradi-
ation is rarely reported. Herein, we report a visible-light-in-
duced formylation of heterocycles with 2,2-diethoxyacetic
acid at room temperature without any photosensitizer
(Scheme 1, d). Furthermore, a visible-light-induced acyla-
tion of heterocycles using α-keto acids has also been devel-
oped.
Initially, isoquinoline (1a) and 2,2-diethoxyacetic acid
(2a) were selected as the model substrates for condition op-
timization. First, we screened the effect of different sol-
vents (see Supporting Information) with ammonium per-
sulfate (2 equiv) as the oxidant and cesium carbonate (2
equiv) as the base under the irradiation of 15 W blue LEDs.
We were pleased to find that the reaction in dimethyl sulf-
oxide (DMSO) give the highest yield of 3a. Subsequently, the
influence of the catalyst was investigated (Table 1, entries
1–3). The reaction proceeded well to afford the desired
product in high yield in the absence of any photocatalyst.
Different oxidants were also tested which only resulted in
lower yields of 3a (Table 1, entries 4, 5). Then various bases
were screened, and the results indicated that cesium car-
bonate could significantly improve the reaction efficiency
(Table 1, entries 6–8). The highest yield of 3a was finally ob-
tained by increasing the amount of 2a and oxidant (Table 1,
entries 9, 10). Furthermore, control experiments showed
that the reaction did not work well in the absence of light,
oxidants, or bases (Table 1, entries 11–13).
Table 1 Optimization of Reaction Conditionsa,b
photocatalyst
O
H
N
oxidant, base, solvent
N2, blue LEDs
COOH
N
+
O
O
then HCl
1a
2a
3a
Entry
2a (eq)
Oxidant (eq)
Base (eq)
Yield (%)b
1
5
5
5
5
5
5
5
5
5
7
7
7
7
7
(NH4)2S2O8 (2)
(NH4)2S2O8 (2)
(NH4)2S2O8 (2)
K2S2O8 (2)
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2HPO4
K2CO3
45
43
19
24
39
29
40
38
49
73
19
0
2c
3d
4
5
Na2S2O8 (2)
6
(NH4)2S2O8 (2)
(NH4)2S2O8 (2)
(NH4)2S2O8 (2)
(NH4)2S2O8 (3)
(NH4)2S2O8 (3)
(NH4)2S2O8 (3)
none
7
8
Na2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
none
9
10
11e
12
13
14f
(NH4)2S2O8 (3)
(NH4)2S2O8 (3)
10
26
Cs2CO3
a General conditions: 1a (0.1 mmol), 2a (0.5 mmol), (NH4)2S2O8(0.2
mmol), Cs2CO3(0.2 mmol), and DMSO (1 mL) under argon atmosphere,
stirred under 15 W blue LEDs.
b Isolated yield.
C4CzIPN was added.
d [Ir{dF(CF3ppy)}2(dtbbpy)]PF6 was added.
e In the dark.
f Under air atmosphere.
53%), phenanthridine (3m, 80%), N-methylbenzimidazole
(3n, 40%) and benzothiazole (3o, 37%) which proved that
this transformation has a good generality.
Additionally, application to natural product caffeine also
turned out to be successful, product 3p was acquired in 20%
yield.
The applicability of the method was further explored
with different combinations of 1 and α-keto acids 4. After
the optimization of the reaction conditions and the propo-
sition of a plausible mechanism (see Supporting Informa-
tion), we subsequently explored the substrate scope
(Scheme 3). Quinolines with both electron-donating and
electron-withdrawing substituents exhibited excellent effi-
ciency (products 5aa–fb, 30–76% yield). Isoquinolines could
also undergo this transformation smoothly (products 5g–o,
45–81% yield), and quinoxaline and quinazoline were well
tolerated (products 5p–r). More types of heterocyclic sub-
strates such as 4-tert-butylpyridine, phenanthridine, and
benzoxazole were then examined, affording the corre-
sponding benzoyl products (5s–u). Of the application to
natural product caffeine was also successful (5bb, 41%).
With optimized reaction conditions in hand, we then
focused on the substrate scope of the formylation reaction
(Scheme 2). Generally speaking, this method provides a
new route for the preparation of a series of formylated het-
erocycles in yields up to 80%. Reaction between isoquino-
line 1a and 2a yielded the regioselective formylation prod-
uct (3a, 73%). The corresponding products (3b–f,h) were
obtained in good yields (53–72%) using isoquinolines bear-
ing substituents such as Cl, CH3, Br at their C4, C5, C6, C8
positions. The reaction was also proved applicable to C3-
substituted isoquinolines and 4-Cl-, 4-CH3-, 2-CH3-substi-
tuted quinolines (products 3g,i–k). The scope of hetero-
cycle substrate was further extended to quinoxaline (3l,
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

C
W. Jia et al.
Letter
Synlett
N2
H
(NH4)2S2O8, Cs2CO3
15 W, blue LEDs
H
COOH
O
het
+
het
O
O
then HCl
1
2a
3a–p
Br
R
R
N
H
N
N
H
N
O
O
H
O
O
H
3d, R = CH3, 72%
3e, R = Br, 64%
3b, R = Cl, 68%
3c, R = Br, 61%
3f, 53%, 66%
3a, 73%
R
O
H
N
N
H
N
Cl
N
O
H
O
O
H
3i, R = Cl, 34%, 51%
3j, R = CH3, 68%, 80%
3g, 65%
3h, 41%, 53%
3k, 75%
N
N
H
O
S
N
H
O
N
N
H
N
O
O
H
3l, 53%
3m, 80%
3n, 40%
3o, 37%
O
N
H
O
N
N
N
O
3p, 20%
from caffeine
Scheme 2 Scope of heteroarenes formylation reaction.a,b aSee Supporting Information for detailed procedures. b Isolated yields. Numbers in red are
isolated yields based on recovered starting material.
Next, we studied the reactivity of different α-keto acids.
The straight-chained or branched aliphatic α-keto acids
smoothly gave the acylated products (5v,w) via decarboxyl-
ation. Similarly, heterocyclic keto acids also showed good
reactivity (5x,y). Surprisingly, the corresponding function-
alization of isoquinoline with trimethyl pyruvate gave the
alkylated product 5z with the loss of one molecule of car-
bon dioxide and carbon monoxide.
In order to explore the mechanism of the reaction, some
control experiments were performed (Scheme 4). Under
the optimal conditions, radical scavenger TEMPO ((2,2,6,6-
tetramethylpiperidin-1-yl)oxyl) was added before the reac-
tion. Notably, product 6a was not obtained (Scheme 4, b),
suggesting that the reaction may proceed via a radical pro-
cess. The reaction performed in the absence of ammonium
persulfate also yielded no 6a (Scheme 4, c), further illustrat-
ing the important role of ammonium persulfate.
Based on these experimental results and previous re-
ports,11e,17 a reasonable reaction mechanism is presented in
Scheme 5. Under visible-light irradiation, SO4•– is formed af-
ter the homolysis of S2O82–. 2,2-Diethoxyacetate 2 was oxi-
dized by S2O82– to form radical 7. Next, radical 7 adds to iso-
quinoline 1 to form intermediate 8, which is further oxi-
dized by ammonium persulfate to form the final product 6.
Acid-catalyzed hydrolysis of 6 produces the target product 3.
In conclusion, we have developed a visible-light-in-
duced C–H functionalization of heterocycles, which fea-
tures mild and environmentally friendly conditions, broad
substrate scope of N-containing heterocycles.18 This meth-
od is a good complement to traditional acylation methods
and allows direct functionalization of natural products.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

D
W. Jia et al.
Letter
Synlett
O
[Ir{dF(CF3ppy)}2(dtbbpy)]PF6
het
het
H
+
R
R
OH
(NH4)2S2O8, DMSO, N2
15 W blue LEDs
O
O
1
4
5aa–z
R
R
N
R
R
R
O
N
N
N
N
N
O
O
O
O
O
O
N
5e, 56%
5aa, R = H, 30%
5ab, R = Bz, 50%
5b, R = CH3, 76%
5c, R = Cl, 63%
5d, R = Br, 60%
5fa, R = H, 26%
5fb, R = Bz, 48%
5g, 81%
5h, R = CH3, 59%
5i, R = Br, 75%
5j, R = Cl, 81%
5k, R = Br, 80%
Br
R
N
N
N
R
O
N
N
N
N
N
Cl
O
O
O
N
O
O
O
5l, 71%
5m, 61%
5n, R = COOCH3, 45%
5o, R = CH3, 68%
5p, 46%
5q, R = H, 40%
5r, R = Cl, 64%
5s, 32%
5t, 84%
O
N
O
N
N
N
N
N
N
O
N
N
O
S
N
O
O
O
O
O
NH
5bb, 41%
5u, 39%
5v, 76%
5w, 69%
5x, 49%
5y, 63%
5z, 54%
from caffeine
Scheme 3 Scope of heteroarenes and α-ketoacids.a,b a Reaction conditions: heteroarenes (0.1 mmol), α-keto acids (1mmol), [Ir{dF(CF3ppy)}2(dtbb-
py)]PF6 (0.2 mol %), (NH4)2S2O8 (0.2 mmol) and DMSO (1 mL) under argon atmosphere. b Isolated yield.
Cs2CO3 (2 eq)
N
(NH4)2S2O8 (3 eq)
COOH
O
N
a)
b)
+
O
O
O
DMSO, rt, blue LEDs
O
O
1
1
1
2
6a, 79%
TEMPO
COOH
O
N
N
N
O
+
+
optimized conditions
O
2
6a, 0%
without (NH4)2S2O8
optimized conditions
COOH
O
N
O
c)
O
2
6a, 0%
Scheme 4 Control experiments
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F

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Letter
Synlett
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hv
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O
N
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S2O8
O
H
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6
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Scheme 5 Proposed mechanism
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We are grateful for the financial supports from China NSFC (Nos.
21372055, 21472030 and 21672047), SKLUWRE (No. 2018DX02)
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609911.
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extracted with CH2Cl2, the combined organic layers were
washed with brine, then dried over anhydrous Na2SO4. The
desired products were obtained in the corresponding yields
after purification by flash chromatography on silica gel eluting
with PE and EtOAc.
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Isoquinoline-1-carbaldehyde (3a)
Yellow oil. 1H NMR (400 MHz, CDCl3): δ = 10.38 (s, 1 H), 9.38–
9.22 (m, 1 H), 8.74 (d, J = 5.5 Hz, 1 H), 7.97–7.82 (m, 2 H), 7.83–
7.68 (m, 2 H). 13C NMR (151 MHz, CDCl3): δ = 195.79, 195.74,
149.88, 142.54, 136.97, 130.88, 130.15, 127.05, 126.41, 125.80,
125.63. GC-MS (EI): 157.1, 129.1, 102.1, 75.0, 63.1, 51.1, 29.1.
Procedure B for Compounds 5a–z,bb
Heterocycle (0.10 mmol), ammonium persulfate (0.20 mmol),
[Ir{dF(CF3ppy)}2(dtbbpy)]PF6 (0.2 mol%), α-keto acids (1.0
mmol) were placed in a dry glass tube. Anhydrous DMSO (1 mL)
was injected into the tube by a syringe under a N2 atmosphere.
The solution was then stirred at room temperature under the
irradiation of 15 W blue LEDs strip for 12 h. After completion of
the reaction, saturated Na2CO3 solution was added to adjust pH
to basic. The combined organic layer was washed with brine
and then dried over anhydrous Na2SO4. The desired products
were obtained in the corresponding yields after purification by
flash chromatography on silica gel eluting with PE and EtOAc.
(4-Methylquinolin-2-yl)(phenyl)methanone (5b)
(18) Procedure A for Compounds 3a–p
Heterocycle (0.10 mmol), ammonium persulfate (0.30 mmol)
and Cs2CO3 (0.20 mmol) were placed in a dry glass tube. Anhy-
drous DMSO (1 mL) and 2,2-diethoxyacetic acid (0.7 mmol)
were injected into the tube by syringe under N2 atmosphere.
The solution was then stirred at room temperature under the
irradiation of 15 W blue LEDs strip for 24 h. After completion of
the reaction, the mixture was quenched by addition of 1.2 mL of
3.0 M HCl and stirred for another 20 h. Then saturated Na2CO3
Brownish solid. 1H NMR (400 MHz, CDCl3): δ = 8.22 (dd, J = 14.0,
7.9 Hz, 3 H), 8.07 (d, J = 8.3 Hz, 1 H), 7.94 (s, 1 H), 7.77 (t, J = 7.6
Hz, 1 H), 7.72–7.65 (m, 1 H), 7.62 (t, J = 7.4 Hz, 1H), 7.51 (t,
J = 7.7 Hz, 2H), 2.80 (s, 3 H).13C NMR (151 MHz, CDCl3): δ =
194.33, 154.52, 146.72, 145.78, 136.32, 133.18, 131.59, 131.27,
129.86, 129.08, 128.30, 128.27, 123.90, 121.43,19.08. GC-MS
(EI): 247.1, 232.1, 218.1, 204.1, 140.0, 105.0, 77.1, 51.1, 28.1.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–F