Decarboxylative formylation of aryl halides with glyoxylic acid by palladium catalysis under oxygen

Article abstract of DOI:10.1055/s-0040-1707140

A new free radical/palladium cooperative catalyzed formylation of aryl halides with glyoxylic acid as the formyl source under oxygen conditions has been developed. Various aromatic and heteroaromatic aldehydes were produced in medium to good yields.

Full text of DOI:10.1055/s-0040-1707140

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Georg Thieme Verlag Stuttgart · New York
2020, 31, A–D
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Synlett
H. Cao et al.
Letter
Decarboxylative Formylation of Aryl Halides with Glyoxylic Acid
by Palladium Catalysis under Oxygen
Hualiang Cao
Weiwen Pu
Jie Zhang
O
I or Br
[Pd], Et3N
CHO
H
H
R
+
O
R
AIBN, O2
O
Peijun Yan
Jun Zhang
Sheng Xu*
H2O
2
4 examples
R = Me, t-Bu, MeO, Ac, CHO, F, Cl, Br, Ph
27–72% yields
Key Laboratory for Advanced Materials and Institute of Fine
Chemicals, School of Chemistry & Molecular Engineering, East
China University of Science and Technology, 130 Mei Long
Road, Shanghai 200237, P. R. of China
xusheng@ecust.edu.cn
Received: 19.04.2020
Accepted after revision: 18.05.2020
Published online: 18.06.2020
with phenylboronic acid13 and aryl halide14 has been pub-
lished. Our group recently reported the acylation of pheny-
lacetylene15 and aryl halide with glyoxylic acid to prepare
cinnamaldehyde and other aromatic aldehydes.
16
DOI: 10.1055/s-0040-1707140; Art ID: st-2020-r0225-l
Abstract A new free radical/palladium cooperative catalyzed formyla-
tion of aryl halides with glyoxylic acid as the formyl source under oxy-
gen conditions has been developed. Various aromatic and heteroaro-
matic aldehydes were produced in medium to good yields.
Previous work
N
H
ArB(OH)2
+
CHOCOOH·H2O
Ar CHO
Key words aryl halide, reductive carbonylation, aldehydes, palladium
MeCN
catalysis, synthetic methods
Wang's group
4CzIPN
Aromatic aldehydes are important chemical intermedi-
ates that are widely used in medicine, food additives, pesti-
cides, chemical raw materials etc. Hence, their preparation
Pd(Xantphos)Cl2
Ar
X
+
CHOCOOH·H2O
Ar CHO
CsOAc, DMF
blue LEDs
1
X = I, Br
Fu's group
has been a core interest of synthetic chemists for a long
2
time. Traditional synthetic methods are mainly electro-
Pd(PPh3)2Cl2
CHO
Ar
philic acylation of aromatic compounds, including the Duff
Ar
+ CHOCOOH·H2O
dppp, PPh3
DMF
3
4
5
reaction, Reimer–Tiemann reaction, Vilsmeier reaction,
6
our group
and Gattermann–Koch reaction, which generally use high
amounts of reagents, require multiple steps or generate
waste.
Pd(AcO) , PPh
2
3
CHO
Ar
X
+
+
CHOCOOH·H O
+
Ar CHO
2
Ar
Et3N, DMF
With the development of transition-metal catalysis,
great progress has been made in palladium-catalyzed
X = I, Br
our group
7
formylation. Since the pioneering work of Heck and co-
This work
Ar
X = I, Br
8
workers in 1974, the carbonylation reaction with CO gas
Pd(PPh3)2Cl2
X
CHOCOOH·H O
Ar CHO
catalyzed by palladium has become a powerful method for
2
Et3N, AIBN, O2
9
constructing aldehydes. However, carbonylation in the lab-
oratory is severely limited by the high toxicity and flamma-
bility of CO. Fortunately, in recent years, new formyl re-
Scheme 1 Overview of formylation of glyoxylic acid
10
11
agents such as N-formylsaccharin, paraformaldehyde,
1
2
13
formic acid, glyoxylic acid and 2,2-diethoxyglyoxylic
For wider applicability and higher yield, the initiation
mode and reaction mechanism of the non-photoactivated
palladium-catalyzed formylation reaction was studied fur-
ther (Scheme 1). 4-Methoxy-iodobenzene was exploited as
the model substrate for the studies. Here, 6 or 12 mol%
7a
acid have been developed as CO surrogates.
Glyoxylic acid, containing both an aldehyde and a car-
boxyl group, can decarboxylate to produce the formyl
group. Indeed, the formylation reaction of glyoxylic acid
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–D
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
Synlett
H. Cao et al.
Letter
phosphine ligands, 3 mol% of Pd catalyst and 600 mmol% of
glyoxylic acid were added in DMF, and the reaction bottle
was sealed and heated to 110 °C for 4 hours.
the reaction time (3–10). Substrates with electron-donating
groups such as CH CO, COOMe and CHO gave lower reaction
3
yields (13, 14, 15), and the reaction reached the highest
yield in about 6 hours. The position of the substituent on
the aryl ring was also vital; the yields of 2-iodotoluene (6)
were significantly lower than that of 4-iodotoluene (3),
which may be related to the steric hindrance of the substit-
uent. Compared with aryl iodide, aryl bromide was less ac-
tive, resulting in only moderate yields of substrates (2, 5, 9).
Besides aryl halides, heteroaryl halides were also suitable
substrates.
Table 1 Studies of the Reaction Conditionsa
Pd (3 mol%)
O
ligand (6 mol%)
AIBN (5 mol%)
I
+
CHOCOOH·H2O
Et3N (6 equiv)
O2, solvent
O
O
110 °C, 4 h
1
mmol
6 mmol
As shown in Scheme 2, both 5-iodoindole (20) and 2-io-
dothiophene (22) worked well to afford the corresponding
products in moderate yields, and 5-bromoindole (21),
Entry
Ligand
Catalyst
Solvent
Yield (%)b
84 (72)c
1
2
3
4
5
6
7
8
9
–
–
–
–
PdCl
Pd(OAc)
Pd(PPh
2
(PPh
3
)
2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
2-bromonaphthalene (23) and 3-bromocarbazole (24) can
2
23
56
61
76
73
69
65
67
65
37
62
19
trace
51
also give the corresponding aldehyde.
3 4
)
Pd(PPh3)2Cl2 (3 mol%)
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
PdCl
2
2
2
2
2
2
2
2
2
2
2
2
AIBN (5 mol%)
PPh
3
3
(PPh
(PPh
(PPh
(PPh
(PPh
3
3
3
3
3
)
)
)
)
)
2
2
2
2
2
+
CHOCOOH·H2O
Ar CHO
Ar
X
Et3N (6 equiv), DMF (2 mL)
O2, 110 °C, 4–8 h
PCy
1
mmol
6 mmol
XPhos
dppe
dppp
CHO
CHO
CHO
CHO
1
0
1
2
3
4
5
PPh
–
3
1, X = I, 4 h, 70%
3
, 4 h, 71%
4, X = I, 4 h, 63%
5, X = Br, 5 h, 52%
6, 4 h, 44%
CHO
2, X = Br, 5 h, 61%
1
1
1
1
(PPh
(PPh
(PPh
(PPh
(PPh
3
3
3
3
3
)
)
)
)
)
2
2
2
2
2
3
CH CN
CHO
CHO
O
CHO
–
DMSO
O
Ph
–
toluene
7, 4 h, 71%
8, X = I, 4 h, 72%
10, 4 h, 61%
11, 6 h, 39%
CHO
–
H
2
O
9, X = Br, 5 h, 51%
1
–
EtOH
CHO
CHO
CHO
O
a
Reaction conditions: 4-methoxy-iodobenzene (1 mmol), CHOC-
O(6 mmol), Et N(6 mmol), ligand(6 or 12 mol%, P/Pd = 4:1), Pd (3
(1 atm), sealed, 110 °C, 4 h.
H NMR yield.
Isolated yield.
O
OOH·H
2
3
N
H
mol%), solvent (2 mL), O
2
O
O
O
b 1
c
12, 6 h, 43%
13, 6 h, 41%
14, 6 h, 53%
15, 6 h, 45%
CHO
CHO Cl
CHO
CHO
As shown in Table 1, the yield was greatly influenced by
the nature of the solvent and Pd catalyst. It was also found
that PdCl (PPh ) has the best effect as a palladium source
F
Cl
Br
16, 4 h, 67%
17, 4 h, 69%
18, 4 h, 54%
CHO
19, 4 h, 53%
CHO
2
3 2
and the yield clearly decreased when PdCl (PPh ) was re-
OHC
2
3 2
placed with Pd(OAc) , Pd(PPh ) or PdCl (entries 1–4, 10).
S
CHO
2
3
4
2
N
H
On the other hand, the effect of ligands on the reaction
yield was not so obvious. Both monodentate ligands such as
PPh , PCy and XPhos and bidentate phosphine ligands such
N
H
2
2
0, X = I, 6 h, 53%
1, X = Br, 8 h, 46%
22, 4 h, 59% 23, X = Br, 6 h, 27% 24, X = Br, 8 h, 34%
3
3
as dppe and dppp gave lower yields (entries 5–9). Screening
of the effect of the solvent revealed that larger polar amides
were more favorable for the reaction, and DMF was superi-
or to other solvents (entries 11–15).
Scheme 2 Reaction conditions: Aryl iodide (1 mmol), CHOCOOH·H O
2
(6 mmol), Et
N (6 mmol), PdCl (PPh ) (0.03 mmol), DMF (2 mL), O (1
3
2
3
2
2
atm), sealed, 110 °C, 4–8 h. Isolated yields are given.
With the optimized reaction conditions (Table 1, entry
), the reaction scope with respect to aryl halides was in-
In order to gain insight into the reaction mechanism,
the effect of a free radical initiator and oxygen on the reac-
tion was investigated; the results are summarized in Table
2. Surprisingly, unlike the general Pd-catalyzed coupling re-
action, both oxygen and AIBN (free radical initiator) have a
crucial influence on the formylation reaction (entries 1–5).
1
vestigated. As shown in Scheme 2, this formylation reaction
can be extended to a variety of aryl halide, and the corre-
sponding aromatic aldehydes were isolated in 27–72%.17 It
was found that the presence of electron-donating groups
was beneficial for high product yields as well as for reducing
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

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Synlett
H. Cao et al.
Letter
Table 2 Effects of Free Radical Initiators and Oxygen on the Reactiona
O
CHO
I
Pd(PPh3)2Cl2 (3 mol%)
+
CHOCOOH·H2O
+
Et3N (6 equiv), DMF (2 mL)
O
O
110 °C, 4 h
O
1
mmol
6 mmol
Entry
AIBN (mol%)
O
2
(%)b
0
Yield (%)c
1
2
3
4
5
6
0
0
32
trace
27
100
21
5
100
trace
29
72
100
5
0
33
0
50
19
11
5
9
55
7d
5
100
trace
71
a
Reaction conditions: 4-methoxyiodobenzene (1 mmol), CHOCOOH·H
2
O (6 mmol), Et
3
2 3 2
N (6 mmol), PdCl (PPh ) (0.03 mmol), DMF (2 mL), sealed, 110 °C, 4 h.
b
c
The amount of O
Isolated yield.
In the dark.
2 2
in the container was controlled by adding different volumes of O and Ar at normal temperatures and pressures.
d
Oxygen can effectively inhibit the self-coupling reaction
Table 2, entries 3, 5–6). AIBN is necessary for good yield,
but an excess amount of AIBN reduced the yield of aromatic
aldehyde (entries 3 and 4). Furthermore, when the light
was blocked, there was no significant change in yield (entry
reaction possibly proceeds though a Pd(0)/Pd(II)/Pd(III) cy-
cle combined with a free radical cycle. Initially, oxidative
addition of aryl halide to Pd(0) species A generates an aryl-
palladium complex B. The aryl Pd(II) intermediate B may
intercept a formyl radical generated via oxidative decarbox-
ylation of glyoxylic acid by peroxyl radical, and a formyl
aryl Pd(III) species C is proposed to form. The palladium(III)
intermediate C oxidizes isobutyronitrile to form an isobuty-
ronitrile radical and generates a formyl aryl Pd(II) interme-
diate D, which is then reduced to deliver the aldehyde prod-
(
7
), which indicates that the reaction is not related to photo-
14
catalysis.
Although a precise reaction mechanism is not clear at
this moment, one plausible catalytic cycle based on the
above experimental results is depicted in Scheme 3. This
0
Ar-X
Ar-CHO
Pd L2
A
O
Ar
Ar
Pd L
L
X Pd L
H
L
D
+
–
B
Et3NH X
NC
N
N
CN
CN
3
Et N
O
Ar
L
X
Pd
L
H
O2
C
CN
O
O
CN
O
CO2 + O2
+
H
O
O
H
H
O
Scheme 3 Proposed catalytic cycle for this reaction
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–D

D
Synlett
H. Cao et al.
Letter
uct, and the palladium catalytic cycle is completed.
Throughout the free radical cycle, oxygen may be combined
with isobutyronitrile radicals to form peroxyl radicals,
thereby reducing the extent of polymerization between
free radicals.
In summary, enabled by free radical/palladium syner-
gistic catalysis, glyoxylic acid monohydrate has been suc-
cessfully used as a formyl source, which decarboxylatively
couples with aryl halides to synthesize a variety of aromatic
aldehydes. It is worth noting that this reaction must be car-
ried out in oxygen, which provides a new idea for studying
the mechanism of palladium-catalyzed formylation.
Firouzabadi, H.; Etemadi, E.; Rostami, A.; Moghadam, K. R. Appl.
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(g) Yu, B.; Zhao, Y.; Zhang, H.; Xu, J.; Hao, L.; Gao, X.; Liu, Z.
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2
Funding Information
(
(
(
(
We are grateful to the National Key Research and Development Pro-
gram of China (2017YFB0306701), and the National Natural Science
Foundation of China (NO. U1362111).
8
N
ati
o
n
a
l Natural S
c
i
e
n
c
e
F
o
u
n
d
ati
o
n
of
C
h
i
n
a
(U
1
3
6
2
1
1
1)Nati
o
n
a
lK
e
y
R
esearc
h
a
n
d
D
e
v
e
l
o
p
m
e
ntProgra
m
of
C
h
i
n
a
(2
0
1
7
Y
F
B
0
3
0
6
7
0
1)
Acknowledgment
1
29, 8313.
We thank Professor Yifeng Chen (East China University of Science and
Technology) for discussion and guidance.
(
(
14) Zhao, B.; Shang, R.; Fu, Y. Org. Chem. Front. 2018, 5, 1782.
15) Liu, Y.; Pu, W. W.; Cai, L. Z.; Xu, S.; Tao, X. C. Chem. Commun.
2018, 54, 2166.
Supporting Information
(16) Shen, Y. CNIPA CN 109824567 A, 2019.
(17) Typical Procedure: Iodobenzene (1; 0.204 g, 1.0 mmol), PdCl2
Supporting information for this article is available online at
(PPh ) (0.021 g, 0.03 mmol), glyoxylic acid monohydrate (0.552 g,
3
2
https://doi.org/10.1055/s-0040-1707140.
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p
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u
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n
6.0 mmol) and AIBN (0.082 g, 0.05 mmol) were transferred into
a 50 mL Schlenk tube that was filled with oxygen. After DMF
(
2.0 mL) and Et N (0.606 g, 6.0 mmol) were added successively,
3
References and Notes
the tube was sealed and the mixture was stirred at 110 °C for 4
h. Upon completion of the reaction, the mixture was poured
into saturated aqueous NaCl solution (25 mL) and extracted
with CH Cl (4 × 15 mL). The combined organic layers were
washed with brine (4 × 20 mL), dried over MgSO , filtered, and
concentrated. The residue was purified by column chroma-
tography on silica gel (PE/EtOAc, 25:1) to afford the correspond-
ing product (0.074 g, 70%) as a colorless oil. H NMR (400 MHz,
CDCl ):  = 10.01 (s, 1 H), 7.89–7.86 (m, 2 H), 7.65–7.65 (m, 1 H),
7
1
(
(
(
(
(
1) Ferguson, L. N. Chem. Rev. 1946, 38, 227.
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1993, 49, 4015.
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(
7) (a) Huang, H.; Li, X.; Yu, C.; Zhang, Y.; Mariano, P. S.; Wang, W.
Angew. Chem. Int. Ed. 2017, 56, 1500. (b) Sun, G.; Lv, X.; Zhang,
Y.; Lei, M.; Hu, L. Org. Lett. 2017, 19, 4235. (c) Han, W.; Liu, B.;
Chen, J.; Zhou, Q. Synlett 2017, 28, 835. (d) Iranpoor, N.;
13
.53 (t, J = 7.6, 2 H). C NMR (101 MHz, CDCl ):  = 192.48,
3
36.37, 134.50, 129.77, 129.02.
©
2020. Thieme. All rights reserved. Synlett 2020, 31, A–D