Acceleration of the Dakin reaction by trifluoroacetic acid

Article abstract of DOI:10.3184/174751914X14014814873316

An acceleration of the Dakin reaction caused by addition of trifluoroacetic acid is described. The modified protocol converts aromatic aldehydes to the corresponding phenols within 4 hours at room temperature by means of hydrogen peroxide in acidic medium. This acceleration is attributed to the stability of hydrogen peroxide in an acidic medium. This modified protocol provides alternative and easy access to important phenolic precursors that have been used in the synthesis of various natural products.

Full text of DOI:10.3184/174751914X14014814873316

JOURNAL OF CHEMICAL RESEARCH 2014
VOL. 38 JUNE, 381–382
RESEARCH PAPER 381
Acceleration of the Dakin reaction by trifluoroacetic acid
Arun D. Natua*, Ameya S. Burdeb, Rohan A. Limayea and Madhusudan V. Paradkara
aPost graduate & research centre, MES Abasaheb Garware College, Karve Road, Pune-411004, India
bFergusson College, Pune-411004, India
An acceleration of the Dakin reaction caused by addition of trifluoroacetic acid is described. The modified protocol converts
aromatic aldehydes to the corresponding phenols within 4 hours at room temperature by means of hydrogen peroxide in acidic
medium. This acceleration is attributed to the stability of hydrogen peroxide in an acidic medium. This modified protocol
provides alternative and easy access to important phenolic precursors that have been used in the synthesis of various natural
products.
Keywords: Dakin reaction, trifluoroacetic acid
Phenols are key precursors in the synthesis of numerous
oxygen heterocyclic natural products of pharmacological
importance.1 There are many synthetic methods available
for their preparation; however, the Dakin reaction2 is one of
the privileged protocols used for preparation of differently
substituted phenols from their corresponding aldehydes.
Several modifications and improvements to the Dakin reaction
have been made.3–17 However, all the evolved methods are
sluggish and require anything between 12 hours and a few days
for their completion. These reactions are also accompanied
by some oxidised side products. In order to assist our work on
the synthesis of oxygen heterocycles, which requires phenolic
intermediates, we tried to develop an improved protocol for
the Dakin reaction in terms of time and yield. We thought that
the sluggishness of the reaction could be due to the possible
decomposition of hydrogen peroxide. It has been reported that
hydrogen peroxide is stored under slightly acidic conditions to
avoid its decomposition. We therefore applied this logic and
considered whether the Dakin reaction can be accelerated using
an acidic medium.
We screened methanesulfonic acid (MSA), chloromethyl‑
sulfonic acid (Cl‑SA) and trifluoroacetic acid (TFA). A solution
of benzaldehyde in dichloromethane, 30% H2
O , a pinch of
SeO2 and an acid additive was stirred at room 2temperature.
The reaction was monitored by TLC (Merck 60 F254 silica gel
plates) and we found that there was considerable decrease in
reaction time with almost all the acid additives (Table 1).
However, addition of TFA notably reduced the reaction time
to 4 hours. It was also observed that formation of side products
was minimal in the presence of TFA. Furthermore, we varied
the percentage of TFA added to the reaction mass and optimised
it for the best results in terms of reaction time and fewer side
products (1.2 equiv. with respect to aldehydes; Scheme 1).
These reaction conditions were generalised to 11 differently
substituted aromatic aldehydes (Table 2). The formation of
phenol was confirmed by comparison of TLC and physical
constants18 with the standard phenols. Compounds 11 and
1. H2O2-SeO2
TFA
Table 1 Results of screening of acid additive (10% v/v) in the Dakin
reaction
DCM, 4h,RT
Ar CHO
Yield/%
Phenol Benzoic acid
Ar OH
Entry
Acid
Time/h
2. NaOH/MeOH
3. H+
12 examples
1
2
3
MSA
Cl-SA
TFA
8
6
4
60
26
80
32
62
12
Scheme 1 TFA accelerated Dakin protocol.
Table 2 Differently substituted phenols obtained by TFA accelerated Dakin reaction
Lit.18,19 m.p./
Entry
Ar–CHO
C6H5CHO
4-OMe–C6H4CHO
3-OMe–C6H4CHO
3,4-Di-OMe–C6H3CHO
3,5-Di-OMe–C6H3CHO
4-Br–C6H4CHO
4-Cl–C6H4CHO
3,4-Di-Cl–C6H3CHO
3-NO2–C6H4CHO
2-OMe–C10H6–CHO
4-OMe–C10H6–CHO
3-Br-4-OMe–C10H5–CHO
Ar–OH
Yield/%a
M.p./oC
56
B.p./oC
182
b.p./oC
1
2
3
4
5
6
7
8
9
C6H5OH
80
78
76
78
80
82
80
84
88
80
82
81
182
56
Oil
79–82
44–46
61–64
220
67–68
96–98
326
4-OMe–C6H4OH
3-OMe–C6H4OH
3,4-Di-OMe–C6H3OH
3,5-Di-OMe–C6H3OH
4-Br–C6H4OH
Oil
80
44
62
4-Cl–C6H4OH
220
oil
3,4-Di-Cl–C6H3OH
3-NO2–C6H4CHO
2-OMe–C10H6–OH
4-OMe–C10H6–OH
3-Br-4-OMe–C10H5–OH
66
96
10
11
12
124
118
126
118
aThe yields mentioned are isolated yields.
* Correspondent. E‑mail: arun.natu@gmail.com
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382 JOURNAL OF CHEMICAL RESEARCH 2014
refluxed for 1 hour. Excess methyl alcohol was removed under reduced
pressure and the residue was acidified using conc. HCl to a light brown
solid, which was filtered, dried and recrystallised from alcohol–water
to obtain the desired phenols in excellent yields (Table 2).
1-Methoxy-4-hydroxynaphthalene (11): M.p. 124°C, (lit.3 m.p.
124–126°C); IR (KBr) 3300, 1564, 1080, 766; νmax; 1H NMR (CDCl3,
300 MHz) δ ppm., 8.12–8.2 (m, 2H), 7.56 (m, 2H), 6.72 (d, J=8 Hz)
1H), 6.62 (d, J=8 Hz) 1H), 5.24 (bs, 1H), 3.92 (s, 3H) (spectral data is in
accordance with ref. 19).
2-Bromo-1-methoxy-4-hydroxy naphthalene (12): M.p. 118°C, (Lit.19
m.p. 118 °C); IR (KBr) 3300, 1560, 1090, 763; νmax; 1H NMR (CDCl3,
300 MHz) δ ppm, 8.12 (m, 2H), 7.48 (m, 2H), 6.96 (s, 1H), 5.34 (bs, 1H),
3.96 (s, 3H) (spectral data is in accordance with ref. 19).
12 were characterised using IR (PerkinElmer Spectrum BX
FT‑IR), NMR (Varian mercury spectrometer on 300 MHz using
CDCl3 as the solvent) spectra and confirmed by comparison
with literature data.19 The utility of this methodology was
proved by our being able to synthesise some of the important
phenolic precursors. For example, veratraldehyde was
converted to the corresponding phenol 4, which was utilised
as a precursor for synthesis of natural products.14 Similarly
compounds 11 and 12 are key intermediates in the synthesis
of pyranonaphthoquinones whereas some of these phenols are
key precursors in the synthesis of coumarins, flavones and
chromans.
We further carried out the TFA accelerated Dakin reaction in
the absence of SeO2.
We thank Dr S.G. Gupta, Principal, Abasaheb Garware
College for providing the necessary facilities, DST‑FIST for
an infrastructure grant, the University of Pune and Agharkar
Research Institute, Pune for providing spectral analysis. RAL
thanks U.G.C for a senior research fellowship. ASB thanks
PICC and Muktangan Exploratory Science Centre for his
project grant
A solution of benzaldehyde in dichloromethane, 30% H2O2,
and TFA was stirred at room temperature and the reaction
was monitored by TLC. It was observed that even after 24 h
stirring, there was no reaction. This observation indicates that
the use of SeO2 is mandatory as it plays important role as either
carbonyl activator or a participator in the reaction by forming
peroxyseleninic acid which has been reported as the actual
oxidising species in Dakin reaction.10,11
In conclusion we have standardised the protocol to achieve
the Dakin reaction in just 4 hours by acceleration through
addition of TFA and generalised the reaction to a group of
substituted aldehydes to provide easy access to phenols.
Received 19 March 2014; accepted 28 April 2014
Paper 1402539 doi: 10.3184/174751914X14014814873316
Published online: 10 June 2014
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was stirred at room temperature for 4 hours. The reaction mixture was
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