Simple formylation of aromatic compounds using a sodium formate/triphenylphosphine ditriflate system

Article abstract of DOI:10.1246/cl.170152

A new procedure was developed for formylation of arenes to produce aromatic aldehydes using a sodium formate/triphenylphosphine ditriflate system in ethanol at room temperature in good yields. The simplicity of the procedure, short reaction times, and mild reaction conditions are the other advantages of this metal- and carbon monoxide-free protocol.

Full text of DOI:10.1246/cl.170152

CL-170152
Received: February 16, 2017 | Accepted: March 11, 2017 | Web Released: May 12, 2017
Simple Formylation of Aromatic Compounds Using a Sodium
Formate/Triphenylphosphine Ditriflate System
Mohammad M. Khodaei,* Abdolhamid Alizadeh,* and Hadis Afshar Hezarkhani
Department of Organic Chemistry, Razi University, Kermanshah 67149-67346, Iran
(E-mail: mmkhoda@razi.ac.ir)
A new procedure was developed for formylation of arenes to
Table 1. Optimization of the reaction conditions for formyla-
tion of mesitylenea
produce aromatic aldehydes using a sodium formate/triphenyl-
phosphine ditriflate system in ethanol at room temperature in
good yields. The simplicity of the procedure, short reaction
times, and mild reaction conditions are the other advantages of
this metal- and carbon monoxide-free protocol.
The amount
of promoter
/mmol
Time Yieldb
Entry Solvent
Promoter
/min
/%
1
2
3
4
5
6
7
8
9
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
H2O
Tf2O
1.2
1.2
0.0
1.2
0.6
2.0
1.2
1.2
1.2
1.2
1.2
70
70
70
65
65
65
65
65
65
65
65
0
50
0
82
44
83
5
27
0
5
DMSD
TPPD
TPPD
TPPD
TPPD
TPPD
Keywords: Formylation of arene
|
Metal- and CO-free protocol
|
Aromatic aldehyde
Formylation is an important strategy to form aromatic
aldehydes as intermediates in organic synthesis. These com-
pounds are widely used in pharmaceutical and fine-chemical
industries.1 Classical methods for synthesis of carboxaldehydes
are Vilsmeier and Haack,2 Gatermann and Koch,3 Reimer and
Tiemann,4 and Duff reactions.5 Direct formylating reagent
systems using aryl formate,6a formamidine acetate,6b triethyl
orthoformate,6c triformamide,7a N,N,N¤,N¤-tetraformylhydra-
zine,7b N-methyl formanilide,7c dimethylformamide,7d formyl
fluoride,8a and formic acid8b have been reported. Some of these
methods suffer from some disadvantages such as multisteps
reactions, production of large amounts of noxious waste, need
for excess reagents, use of strongly toxic compounds, low
selectivity, and need for low temperature. Aromatic aldehydes
have also been synthesized using methods such as oxidation of
alcohols,9 and reduction of acids and their derivatives.10 The
H2O-EtOH (1:1) TPPD
CH2Cl2
CHCl3
CH3CN
TPPD
TPPD
TPPD
10
11
20
aConditions: Mesitylene (1 mmol), sodium formate (1 mmol), TPPD
b
(1.2 mmol), EtOH (3 mL), room temperature. Isolated yields.
dichloromethane at 0 °C to room temperature.15 Then, we
focused on finding suitable conditions for optimization of the
efficient and mild reaction of aromatic compound with sodium
formate in the presence of promoter. Thus, mesitylene was
chosen as a model substrate and next, the reaction was carried
out using HCOONa as formylaing agent and Tf2O as promoter
in EtOH at room temperature (Table 1). When 1.2 equivalent
of Tf2O was applied, no corresponding product was obtained
(Entry 1). We decided to test dimethyl sulfide ditriflate (DMSD)
for the formylation reaction. This salt was produced from
dropwise addition of one equivalent of Tf2O to one equivalent
of Me2SO at 0 °C.16 This promoter was tested to formylate
mesitylene and it was found that the reaction proceeded and
the corresponding aldehyde obtained after 70 min in 50% yield
(Entry 2). We further examined TPPD as the promoter for
this reaction under the same reaction conditions. The results
indicated that TPPD is the best promoter with respect to the
yield of the product (82%) (Entry 4).
12
organometallic compounds were reacted with CO,11 and CO2
to form aromatic aldehydes. In one of these approaches syngas
(CO/H2 1:1) was applied as formylating agent of aromatic
compounds.13 This approach is also very useful on an industrial
scale but, utilization of CO is not desirable because of its
toxicity. Hence, CO-free formylation protocols have attracted
much attention. Aryl halides as substrates have also been used
in formylation reactions.14 The aim of this work was synthesis
of aromatic aldehydes from aromatic compounds using a
triphenylphosphine ditriflate/sodium formate system in ethanol
at room temperature (Scheme 1).
Initially, triphenylphosphine ditriflate (TPPD) was produced
as a white precipitate from the reaction of trifluoromethane-
sulfonic anhydride (Tf2O) and triphenylphosphine oxide in
To optimize solvent, H2O was used instead of EtOH and the
result shows water was not effective as a solvent due to its
inability to solvate the arene and as a result a decreased yield of
the product was obtained (5%) (Entry 7). The reaction in H2O-
EtOH (1:1) solution leaded to a lower yield of the product (27%)
(Entry 8). Other solvents such as CH2Cl2, CHCl3, and CH3CN
were also tested and resulted in lower yields of the products
(0%, 5%, and 20%, respectively) (Entries 9-11).
The effect of amount of TPPD on the reaction was also
examined and it was found that 1.2 equiv of TPPD was the best
choice. When up to 2 equiv of TPPD were used, the results did
not show any noticeable differences with respect to the yield and
reaction time. However, the reaction using lower than 1.2 equiv
of the promoter was not complete. Therefore, the optimized
Ph
Ph
Ph
P OTf
TfO
O
C
R
Na+
-O
TPPD
R
H
H
O
+
Ethanol, rt
R= H, Cl, NO2, Br, Me, OH, OMe, F
Scheme 1. Synthesis of aromatic aldehydes.
840 | Chem. Lett. 2017, 46, 840–843 | doi:10.1246/cl.170152
© 2017 The Chemical Society of Japan

HO
Table 2. Synthesis of aromatic aldehydes with sodiom formate
using TPPD
Ph
Ph
Ph
70%
0%
P
OTf
TfO
Ph
HO
Ph
Ph
P OTf
TfO
Na+
CH
TPPD
O
C
O
O
-O
+
Na+
-O
TPPD
R
O
R
H
H
Ethanol, rt
CH
O
O
+
Ethanol, rt
Time
/min
Yielda
/%
Entry ArH
Product
1
2
3
4
5
6
7
8
9
C6H5Cl
2- and 4-Cl-C6H4-CHO
3-NO2-C6H4-CHO
2- and 4-Br-C6H4-CHO
1-C10H7-CHO
80 65 (o/p:9/91)b
120 20
C6H5NO2
C6H5Br
C10H8
C6H5CH3
C6H5OH
C6H5OCH3
C6H6
C5H5N
Scheme 2. Chemoselective formylation of benzyl alcohol.
80 60 (o/p:12/88)b
75 55
Table 3. Comparison of tolualdehyde formation from toluene
under different conditions
2- and 4-CH3-C6H4-CHO 90 60 (o/p:10/90)b
4-HO-C6H4-CHO
4-CH3O-C6H4-CHO
C6H5-CHO
3-C5H4NCHO
2,4-Cl2C6H3CHO
75 70
70 65
90 55
120 20
80 60
65 82
70 75
72 76
70 75
120 30 (o/p:25/75)b
Temp Time Yield
Entry Condition
Ref.
/°C
/h
/%
1
2
3
4
5
6
7
8
C6H12N4, CF3COOH
HCl/NaCN/AlCl3
AlCl3/HCl/CHCl2OCH3
CO/HCl/AlCl3/CuCl
HCOF/BF3/CS2
AlCl3/Zn(CN)2
AlCl3/(CH3)2C(OH)CN
TPPD/HCOONa/EtOH
83-90 12
61
39
80
50
75
65
40
60
17
18
19
20
8a
8a
21
100
0
7
2
10 1,3-C6H4Cl2
11 1,3,5-C6H3(CH3)3 2,4,6-(CH3)3C6H2CHO
12 1,4-C6H4(CH3)2 2,5-(CH3)2C6H3CHO
13 1,2-C6H4(CH3)2 3,4-(CH3)2C6H3CHO
14 1,3-C6H4(CH3)2 2,4-(CH3)2C6H3CHO
50
7
0-10
100
111
rt
3
7
5
1.5
15 C6H5F
2- and 4-F-C6H4-CHO
This work
aIsolated yield. Based on H NMR determination.
b
1
reaction conditions for this reaction are TPPD (1.2 equiv) in
EtOH at room temperature (Table 1). A control experiment
conducted without TPPD indicated that the reaction did not take
place, and the mesitylene remained unreacted at the end of the
reaction.
accounting for the regioselectivity. The formylation reaction of
phenyl acetate as an acid-sensitive compound under the reaction
conditions was not complete and about half of the substrate
remained intact. Phenol (<5%) and 4-hydroxybenzaldehyde
(10%) as side products plus the corresponding aromatic alde-
hyde (15%) were obtained.
To study the generality of this procedure, we examined the
reaction using several arenes under the optimized conditions.
The results are summarized in Table 2. The arenes with electron-
releasing groups reacted with shorter reaction times and good
yields, while the reactions of arenes with electron-withdrawing
groups proceeded with longer reaction times and lower yields.
The formylation of nitrobenzene with an electron-acceptor group
occurred and 3-nitrobenzaldehyde was obtained in 20% yield
(Entry 2). This shows that the formylation agent is highly
reactive and can formylate nitrobenzene with a strong electron-
acceptor group. The formylation of low reactive pyridine
occurred and pyridine-3-carboxaldehyde was obtained in 20%
yield (Entry 9). Of course, the yields of these two products were
low due to the low reactivities of the substrates and incomplete
reaction. The reaction of anisole was carried out with high
regioselectivity in 65% yield (Entry 7). The formylation of
chlorobenzene, bromobenzene, and toluene under the present
reaction conditions afforded a mixture of o- and p-isomers in 65,
60, and 60% yields, respectively (Entries 1, 3, and 5). Benzene
was formylated under the same reaction conditions, and benzal-
dehyde obtained in 55% yield (Entry 8). In addition, the reaction
of naphthalene with sodium formate occurred with high
regioselectivity and 1-naphthaldehyde was obtained as the only
product in 55% yield, (Entry 4). It seems that steric effects have
an important role in the regioselectivity of these reactions under
the present reaction conditions. This selectivity might be due
to the highly hindered formylating reagent which prefers para
position to be mainly or completely formylated. The room
temperature (not high temperature) may also another reason
The reaction of benzaldehyde under the same reaction
conditions was not complete and was accompanied by the
formation of several unidentified products. Efforts to obtain
the corresponding product were not successful in this case.
Formylation of benzyl alcohol was chemoselectively led to
4-hydroxymethylbenzaldehyde in 70% yield and no alcohol
formylation occurred (Scheme 2). It seems that the formylating
agent is soft and hence it prefers to be attacked by aromatic rings
as a soft nucleophile.
To assess the capability of applying this method on a
preparative scale, the formylation reaction of mesitylene with
sodium formate was carried out on a 10 mmol scale (Supporting
Information).
In order to show the efficiency of this method, the results of
toluene formylation by our method are compared with those
reported in the literature. The results show that this method is
comparable to some previously reported methods in terms of
reaction times, temperatures, and yields (Table 3).
Interestingly, TPPD reacts with sodium formate and pro-
duces the formylating agent, while EtOH as a solvent is present
in the reaction. It seems that ethanol as a nucleophile can be a
competitor for sodium formate and attack TPPD to produce an
alkylating agent for the aromatic compounds. But, it was found
that EtOH cannot act as a nucleophile.
In our previous work, it was indicated that benzylation of
arenes can be carried out in the presence of TPPD in CH2Cl2.22
In fact benzyl alcohol reacted with TPPD and produced alkoxy-
triphenylphosphonium triflate intermediate which converted to
Chem. Lett. 2017, 46, 840–843 | doi:10.1246/cl.170152
© 2017 The Chemical Society of Japan | 841

In conclusion, we have developed a simple salt-promoted,
clean, mild, rapid, and efficient method for direct formylation
of arenes to produce aromatic aldehydes.23 This protocol uses
readily available aromatic compounds as the substrates, TPPD
as a promoter, and EtOH as the solvent. This CO and CO2-
free method could tolerate various functional groups and be
performed at room temperature.
O
S
O
S
Ph3P
O
F3C
O
CF3
+
O
O
Ph3P
O
Tf
OTf
Ph3P
O
Tf
OTf
1
It is gratefully acknowledged for the financial support by the
Razi University.
Ph3P
O Tf
Ph3P
O
CHO
OTf
Na
OCHO
+
-NaOTf
-Ph3PO
OTf
Supporting Information is available on http://dx.doi.org/
10.1246/cl.170152.
1
2
R
References and Notes
O
C
1
E. Müller, Methoden der Organischen Chemie (Houben-
Weyl), Thieme, Stuttgart 1954, Bd. VII, Teil 1.
Ph3P
O
H
+
H
OTf
2
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3
2
R
R
OTf
-TfOH
H
CHO
CHO
H
4
3
4
Scheme 3. Plausible mechanism for the synthesis of aromatic
aldehydes.
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5
6
G. J. Hollingworth, in Comprehensive Organic Functional
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(Supporting Information). The presence of intermediate 2 during
the process of formylation reaction might be confirmed by the
observation of FT-IR peak at 1700 cm¹1 related to the stretching
vibrations of the carbonyl group and the peaks at 2734 and
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¹1
2814 cm corresponded to C-H stretching of aldehyde group.
7
In the 1H NMR spectrum of the mixture, a peak at 10 ppm
ascribed to the formyl proton in intermediate 2 was observed.
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to a carbonyl group. Therefore, the formation of intermediate 2
during the process of reaction was confirmed.
As a result of this observation, the following mechanism
indicated in Scheme 3 was proposed for the synthesis of
aromatic aldehydes promoted by triphenylphosphine ditriflate.
The reagent was prepared via a two-step process at low
temperature. In the first step, a nucleophilic substitution reaction
between triphenylphosphine oxide and triflic anhydride leads
to the promoter 1. The produced phosphonium cation accepts a
nucleophilic sodium formate and the triflate leaving group exits
simultaneously. Replacement of triflate with the oxygen of the
sodium formate generates intermediate 2. The resulting reagent
(compound 2) was used for successful formylation of a broad
range of arenes via an ordinary electrophilic aromatic substitu-
tion reaction.
8
9
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© 2017 The Chemical Society of Japan

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23 Typical procedure for the formylation of arenes: To a
solution of TPPD (0.673 g, 1.2 mmol) in EtOH (3 mL),
sodium formate (0.068 g, 1 mmol) was added and the
mixture allowed stirring for 30 min. Then, mesitylene
(0.139 mL, 1 mmol) was added to this solution and the
mixture was stirred for 60 min at room temperature. After
65 min, the solvent was removed under reduced pressure
and then the saturated sodium bicarbonate solution (10 mL)
was added. The mixture was extracted with chloroform
(3 © 5 mL) and the organic layer washed with water and
dried over anhydrous MgSO4. The filtrate was evaporated
and the crude product purified by silica gel column
chromatography using ethyl acetate/n-hexane (3:7) as eluent
to afford 2,4,6-trimethylbenzaldehyde (0.121 g, 82%). The
products are all known compounds.
Chem. Lett. 2017, 46, 840–843 | doi:10.1246/cl.170152
© 2017 The Chemical Society of Japan | 843