Synthesis of salicylaldehydes from phenols via copper-mediated duff reaction

Article abstract of DOI:10.1007/s11164-014-1881-5

A copper-mediated Duff reaction for ortho-selective formylation of phenols has been developed. In the presence of copper species, significant improvements of yield and ortho-selectivity of the Duff formylation were achieved, which provides an easy access to salicylaldehydes from phenols.

Full text of DOI:10.1007/s11164-014-1881-5

Res Chem Intermed
DOI 10.1007/s11164-014-1881-5
Synthesis of salicylaldehydes from phenols
via copper-mediated duff reaction
•
•
•
Xue-wen Fu Wen-chen Pu Guo-lin Zhang
Chun Wang
Received: 6 August 2014 / Accepted: 20 November 2014
Ó Springer Science+Business Media Dordrecht 2014
Abstract A copper-mediated Duff reaction for ortho-selective formylation of
phenols has been developed. In the presence of copper species, significant
improvements of yield and ortho-selectivity of the Duff formylation were achieved,
which provides an easy access to salicylaldehydes from phenols.
Keywords Ortho-selective Á Duff reaction Á Formylation Á Salicylaldehyde Á Cu2O
Introduction
Salicylaldehydes, synthesized from ortho-formylation of phenols, were widely used
as intermediates for the synthesis of various fragrances [1, 2], pharmaceuticals [3,
4], tobacco chemicals [5], agrochemicals, and other products. Numerous formyla-
tion methods were developed to prepare diverse aromatic aldehydes from
corresponding phenols [6], such as the Duff reaction [7–9], Vilsmeier–Haack
reaction [10–12], Reimer–Tiemann reaction [13–15], Gattermann–Koch reaction
[16, 17], Gattermann reaction [18, 19], Rieche reaction [20–22], and paraformal-
dehyde/MgCl2 reaction [23, 24]. These methods possess their individual advanta-
ges, however, low ortho-selectivity of the most of these methods and poor yields
Electronic supplementary material Theonlineversionofthisarticle(doi:10.1007/s11164-014-1881-5)
contains supplementary material, which is available to authorized users.
X. Fu Á W. Pu Á G. Zhang Á C. Wang (&)
Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, People’s Republic
of China
e-mail: wangchun@cib.ac.cn
X. Fu Á W. Pu
University of Chinese Academy of Sciences, Beijing 100049, People’s Republic of China
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X. Fu et al.
sharply limited their application in industry [25]. Ortho-formylation of phenols by
formaldehyde, POCl3/DMF or Cl2CHOMe in the presence of metal salts, such as Ag
[25], Ti [26], and Sn [27] salts were reported. Despite the difficulty in preparation of
intermediates and harsh conditions required, most of the methods were limited for
the formylation of phenols bearing electron-withdrawing groups.
Although the Duff reaction can be used to obtain salicylaldehydes, the yields are
very low when formylation at both para- and ortho-positions of the OH group are
possible. To the best of our knowledge, there is no report on manipulation of
regioselectivity of the Duff reaction. Herein, we report a metal-mediated Duff
formylation with enhanced yield and ortho/para selectivity.
Experimental
Reagents and apparatus
All the reagents and solvents were commercially available with analytical grade and
were used as received. All reactions under standard conditions were monitored by
thin-layer chromatography (TLC) on silica GF254 plates. Column chromatography
was performed on silica gel (200–300 mesh). NMR spectra were performed on
Bruker Avance 600 and 400 spectrometers; d in ppm, J in Hz; residual solvent peak
as reference. The MS spectra were obtained on a Bruker micro TOF-QII.
General procedure for the synthesis of target compounds
To a solution of substrates (1a–1q, 0.15 mmol) in trifluoroacetic acid (5 ml),
hexamethylenetetramine (0.3 mmol) and cuprous oxide (0.15 mmol) were added.
The reaction mixture was refluxed for about 5 h, cooled to room temperature,
followed by addition of hydrochloric acid (3 N, 5 ml). After stirring for another 1 h,
the solution was concentrated under reduced pressure. The products were purified
by silica gel column chromatography (200–300 mesh).
3-Formyl-2-hydroxybenzoic acid (2a)
The light yellow solid 2a was purified by silica gel column chromatography with
1
petroleum ether/acetone = 5:1. Yield: 55.7 %. H NMR (600 MHz, DMSO-d6): d
10.36 (s, 1H); 8.08 (d, J = 7.6 Hz, 1H); 7.88 (d, J = 7.6 Hz, 1H); 7.02 (t,
J = 7.7 Hz, 1H). 13C NMR (150 MHz, DMSO-d6): d 189.2; 171.9; 164.4; 137.3;
134.0; 124.2; 119.3; 115.8. HR-ESIMS: m/z 165.0183 [M-H]- (calcd. for C8H5O4:
165.0193).
5-Formyl-2-hydroxybenzoic acid (3a)
The light yellow solid 3a was purified by silica gel column chromatography with
1
petroleum ether/acetone = 5:1. Yield: 24.3 %. H NMR (600 MHz, DMSO-d6): d
9.87 (s, 1H); 8.34 (d, J = 1.9 Hz, 1H); 7.99 (dd, J = 8.6, 1.9 Hz, 1H); 7.11 (d,
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Synthesis of salicylaldehydes from phenols
J = 8.6 Hz, 1H). 13C NMR (150 MHz, DMSO-d6): d 191.4; 171.5; 166.2; 135.5;
134.3; 128.7; 118.7; 114.3. HR-ESIMS: m/z 165.0188 [M-H]- (calcd. for C8H5O4:
165.0193).
3-Formyl-2-hydroxy-4-methylbenzoic acid (2b)
The light yellow solid 2b was purified by silica gel column chromatography with
petroleum ether/acetone = 5:1. Yield: 27.3 %. 1H NMR (400 MHz, CDCl3): d
10.50 (s, 1H); 8.22 (d, J = 8.0 Hz, 1H); 6.93 (d, J = 8.0 Hz, 1H); 2.74 (s, 3H). 13
C
NMR (100 MHz, DMSO-d6): d 191.4; 172.1; 165.4; 148.3; 135.7; 122.7; 122.2;
112.5; 21.7. HR-ESIMS: m/z 179.0346 [M-H]- (calcd. for C9H7O4: 179.0350).
5-Formyl-2-hydroxy-4-methylbenzoic acid (3b)
The light yellow solid 3b was purified by silica gel column chromatography with
petroleum ether/acetone = 5:1. Yield: 13.7 %. 1H NMR (400 MHz, CDCl3): d
10.97 (s, 1H); 10.08 (s, 1H); 8.37 (s, 1H); 6.89 (s, 1H); 2.69 (s, 3H). 13C NMR
(100 MHz, DMSO-d6): d 191.7; 171.5; 165.1; 148.7; 136.3; 126.9; 120.3; 112.1;
20.0. HR-ESIMS: m/z 179.0339 [M-H]- (calcd. for C9H7O4: 179.0350).
3-Formyl-2, 4-dihydroxybenzoic acid (2c)
The white solid 2c was purified by silica gel column chromatography with
1
petroleum ether/acetone = 5:1. Yield: 25 %. H NMR (400 MHz, DMSO-d6): d
12.16 (s, 1H); 10.29 (s, 1H); 7.93 (d, J = 8.9 Hz, 1H); 6.47 (d, J = 8.9 Hz, 1H).
13C NMR (100 MHz, DMSO-d6): d 193.4; 171.9; 167.2; 166.5; 139.4; 110.1; 108.5;
105.3. HR-ESIMS: m/z 181.0139 [M-H]- (calcd. for C8H5O5: 181.0142).
5-Formyl-2, 4-dihydroxybenzoic acid (3c)
The white solid 3c was purified by silica gel column chromatography with
petroleum ether/acetone = 5:1. Yield: 5 %. 1H NMR (400 MHz, DMSO-d6): d
11.54 (s, 1H); 10.06 (s, 1H); 8.19 (s, 1H); 6.43 (s, 1H). 13C NMR (100 MHz,
DMSO-d6): d 190.2; 167.9; 166.5; 134.6; 119.9; 116.6; 103.6. HR-ESIMS:
m/z 181.0125 [M-H]- (calcd. for C8H5O5: 181.0142).
4-Chloro-3-formyl-2-hydroxybenzoic acid (2d)
The white solid 2d was purified by silica gel column chromatography with
1
petroleum ether/acetone = 5:1. Yield: 28 %. H NMR (400 MHz, DMSO-d6): d
10.40 (s, 1H); 7.98 (d, J = 8.4 Hz, 1H); 7.04 (d, J = 8.4 Hz, 1H). 13C NMR
(100 MHz, DMSO-d6): d 188.2; 170.5; 165.8; 142.3; 133.4; 124.55; 119.3; 114.3.
HR-ESIMS: m/z 198.9801 [M-H]- (calcd. for C8H435ClO4: 198.9804), 200.9799 [M-
H]- (calcd. for C8H347ClO4: 200.9764). Elemental analysis calcd. for C8H5ClO4: C,
47.90; H, 2.51; Cl, 17.68. Found: C, 47.91; H, 2.53; Cl, 17.51.
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X. Fu et al.
4-Chloro-5-formyl-2-hydroxybenzoic acid (3d)
The white solid 3d was purified by silica gel column chromatography with
1
petroleum ether/acetone = 5:1. Yield: 14 %. H NMR (400 MHz, DMSO-d6): d
10.14 (s, 1H); 8.26 (s, 1H); 7.19 (s, 1H). 13C NMR (100 MHz, DMSO-d6): d 188.2;
170.5; 165.8; 142.3; 133.4; 124.5; 119.3; 114.3. HR-ESIMS: m/z 198.9809 [M-H]-
(calcd. for C8H345ClO4: 198.9804), 200.9797 [M-H]- (calcd. for C8H437ClO4:
200.9764). Elemental Analysis calcd. for C8H5ClO4: C, 47.90; H, 2.51; Cl, 17.68.
Found: C, 47.92; H, 2.54; Cl, 17.43.
5-Chloro-3-formyl-2-hydroxybenzoic acid (2e)
The yellow solid 2e was purified by silica gel column chromatography with
1
petroleum ether/acetone = 5:1. Yield: 25 %. H NMR (400 MHz, DMSO-d6) d
10.29 (s, 1H); 7.97 (d, J = 2.7 Hz, 1H); 7.74 (d, J = 2.7 Hz, 1H). 13C NMR
(100 MHz, DMSO-d6): d 188.5; 170.3; 164.4; 135.8; 131.9; 125.5; 121.9. HR-
ESIMS: m/z 198.9799 [M-H]- (calcd. for C8H435ClO4: 198.9804), 200.9744[M-H]-
(calcd. for C8H347ClO4: 200.9764).
Methyl 3-formyl-2-hydroxybenzoate (2f)
The white crystal 2f was purified by silica gel column chromatography with
1
petroleum ether/acetone = 100:1. Yield: 2.75 %. H NMR (600 MHz, CDCl3): d
11.52 (s, 1H); 10.51 (s, 1H); 8.10 (dd, J = 7.8, 1.8 Hz, 1H); 8.02 (dd, J = 7.6,
1.6 Hz, 1H); 7.00 (t, J = 7.7 Hz, 1H); 4.00 (s, 3H). 13C NMR (150 MHz, CDCl3): d
189.1; 169.8; 163.7; 136.4; 134.7; 124.4; 119.1; 114.1. HR-ESIMS: m/z 179.0346
[M-H]- (calcd. for C9H7O4: 179.0350).
Methyl 5-formyl-2-hydroxybenzoate (3f)
The white crystal 3f was purified by silica gel column chromatography with
1
petroleum ether/acetone = 100:1. Yield: 2.75 %. H NMR (600 MHz, DMSO-d6):
d 11.40 (s, 1H); 9.87 (s, 1H); 8.31 (d, J = 1.9 Hz, 1H); 7.99 (dd, J = 8.6 Hz, 1H);
7.14 (d, J = 8.6 Hz, 1H); 3.90 (s, 3H). 13C NMR (150 MHz, DMSO-d6): d 191.4;
168.2; 164.5; 135.4; 134.1; 128.8; 118.9; 115.1; 53.1. HR-ESIMS: m/z 179.0356
[M-H]- (calcd. for C9H7O4: 179.0350).
2-Hydroxyisophthalaldehyde (2g)
The yellow crystal 2g was purified by silica gel column chromatography with
1
petroleum ether/acetone = 50:1. Yield: 10.5 %. H NMR (400 MHz, CDCl3): d
11.67 (s, 1H); 10.25 (s, 2H); 7.97 (d, J = 7.6 Hz, 2H); 7.14 (t, J = 7.6 Hz, 1H). 13
C
NMR (100 MHz, CDCl3): d 192.0; 163.7; 137.7; 123.1; 119.9. HR-ESIMS:
m/z 149.0243 [M-H]- (calcd. for C8H5O3: 149.0244).
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Synthesis of salicylaldehydes from phenols
4-Hydroxyisophthalaldehyde (3g)
The yellow crystal 3g was purified by silica gel column chromatography with
petroleum ether/acetone = 50:1. Yield: 9.5 %. 1H NMR (400 MHz, CDCl3): d
11.56 (s, 1H); 10.01 (s, 1H); 9.94 (s, 1H); 8.14 (s, 1H); 8.08 (d, J = 8.7 Hz, 1H);
7.26 (s, 1H); 7.14 (d, J = 8.7 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 196.2;
189.4; 166.3; 137.2; 136.5; 129.3; 120.3; 118.9. HR-ESIMS: m/z 149.0249 [M-H]-
(calcd. for C8H5O3: 149.0244).
3,4-Dihydroxyisobenzofuran-1(3H)-one (2i)
The yellow crystal 2i was purified by silica gel column chromatography with
1
petroleum ether/acetone = 10:1. Yield: 36 %. H NMR (400 MHz, DMSO-d6) d
7.43 (t, J = 7.7 Hz, 1H); 7.23 (d, J = 7.4 Hz, 1H); 7.14 (d, J = 8.0 Hz, 1H); 6.61
(s, 1H). 13C NMR (100 MHz, DMSO-d6): d 169.2; 153.9; 133.0; 132.5; 128.9;
121.5; 115.2; 97.6. HR-ESIMS: m/z 165.0189 [M-H]- (calcd. for C8H6O4:
165.0193).
3-Formyl-4-hydroxybenzoic acid (2j)
The white powder 2j was purified by silica gel column chromatography with
1
petroleum ether/acetone = 10:1. Yield: 36 %. H NMR (400 MHz, DMSO-d6) d
11.54 (s, 1H); 10.29 (s, 1H); 8.24 (s, 1H); 8.04 (d, J = 9.4 Hz, 1H); 7.08 (d,
J = 8.7 Hz, 1H). 13C NMR (100 MH z, DMSO-d6): d 191.1; 166.8; 164.5; 137.3;
131.2; 122.5; 122.4; 117.9. HR-ESIMS: m/z 165.0184 [M-H]- (calcd. for C8H6O4:
165.0182).
3-Methoxy-2-hydroxybenzaldehyde (2k)
The yellow crystal 2k was purified by silica gel column chromatography with
1
petroleum ether/acetone = 50:1. Yield: 11.5 %. H NMR (400 MHz, CDCl3) d
11.10 (s, 1H); 9.91 (s, 1H); 7.18 (dd, J = 7.8, 1.4 Hz, 1H); 7.11 (d, J = 7.7 Hz,
1H); 6.97 (dd, J = 9.8, 6.0 Hz, 1H); 3.92(s, 3H). 13C NMR (100 MHz, CDCl3): d
196.6; 151.6; 148.3; 124.5; 120.7; 119.5; 117.9; 56.3. HR-ESIMS: m/z 151.0385
[M-H]- (calcd. for C8H7O3: 151.0401).
4-Hydroxy-3-methoxybenzaldehyde (3k)
The white powder 3k was purified by silica gel column chromatography with
1
petroleum ether/acetone = 50:1. Yield: 38 %. H NMR (400 MHz, DMSO-d6) d
9.77 (s, 1H); 7.43 (dd, J = 8.1, 1.8 Hz, 1H); 7.39 (d, J = 1.8 Hz, 1H); 6.96 (d,
J = 8.0 Hz, 1H); 3.84 (s, 3H). 13C NMR (100 MHz, CDCl3): d 190.9; 151.7; 147.1;
129.9; 127.5; 114.4; 108.7; 56.1. HR-ESIMS: m/z 151.0388 [M-H]- (calcd. for
C8H7O3: 151.0411).
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4-Hydroxy-5-methoxyisophthalaldehyde (4k)
The yellow crystal 4k was purified by silica gel column chromatography with
petroleum ether/acetone = 50:1. Yield: 9.5 %. 1H NMR (600 MHz, CDCl3) d
11.66 (s, 1H); 10.02 (s, 1H); 9.89 (s 1H); 7.74 (s, 1H); 7.62 (s, 1H); 4.00 (s, 3H). 13
C
NMR (100 MHz, CDCl3): d 195.8; 189.4; 157.0; 149.4; 129.3; 129.1; 120.0; 114.3;
56.5. HR-ESIMS: m/z 179.0345 [M-H]- (calcd. for C9H7O4: 179.0350).
3-Chloro-2-hydroxybenzaldehyde (2l)
The yellow liquid 2l was purified by silica gel column chromatography with
1
petroleum ether/acetone = 20:1. Yield: 21 %. H NMR (400 MHz, DMSO-d6) d
10.14 (s, 1H); 7.79–7.63 (m, 2H); 7.11–6.94 (m, 1H). 13C NMR (100 MHz, DMSO-
d6): d 194.7; 156.3; 136.6; 130.9; 123.7; 121.9; 121.0. HR-ESIMS: m/z 154.9900
[M-H]- (calcd. for C7H345ClO2: 154.9905), 156.9882 [M-H]- (calcd. for C7H347-
ClO2: 156.9865).
3-Chloro-4-hydroxybenzaldehyde (3l)
The yellow powder 3l was purified by silica gel column chromatography with
1
petroleum ether/acetone = 50:1. Yield: 34 %. H NMR (400 MHz, DMSO-d6) d
9.69 (s, 1H); 7.82 (s, 1H); 7.65 (d, J = 7.1 Hz, 1H); 6.99 (d, J = 8.4 Hz, 1H). 13C
NMR (100 MHz, DMSO-d6): d 190.1; 162.1; 132.0; 130.7; 127.5; 121.8; 117.8.
HR-ESIMS: m/z 154.9906 [M-H]- (calcd. for C7H435ClO2: 154.9905), 156.9878 [M-
H]- (calcd. for C7H437ClO2: 156.9865).
5-Chloro-4-hydroxyisophthalaldehyde (4l)
The white crystal 4l was purified by silica gel column chromatography with
petroleum ether/acetone = 50:1. Yield: 5.8 %. 1H NMR (600 MHz, CDCl3) d
12.05 (s, 1H); 10.01 (s, 1H); 9.92 (s, 1H); 8.16 (s, 1H); 8.07 (s, 1H). 13C NMR
(150 MHz, CDCl3): d 195.6; 188.1; 161.8; 136.6; 134.0; 124.0; 120.9. HR-ESIMS:
m/z 182.9850 [M-H]- (calcd. for C8H435ClO3: 182.9854), 184.9810 [M-H]- (calcd.
for C8H347ClO3: 184.9815).
2-Hydroxybenzaldehyde (2n)
The transparent liquid 2n was purified by silica gel column chromatography with
petroleum ether. Yield: 3 %. 1H NMR (400 MHz, CDCl3): d 11.04 (s, 1H); 9.92 (s,
1H); 7.58 (d, J = 8.0 Hz, 1H); 7.55 (t, J = 8.0 Hz, 1H); 7.04 (t, J = 8.0 Hz, 1H);
7.01 (t, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): d 196.6; 161.6; 137.01;
133.74; 120.68; 119.86; 117.62. HR-ESIMS: m/z 121.0923 [M-H]- (calcd. for
C7H5O2: 121.0925).
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Synthesis of salicylaldehydes from phenols
4-Hydroxybenzaldehyde (3n)
The white crystal 3n was purified by silica gel column chromatography with
1
petroleum ether/acetone = 10:1. Yield: 7 %. H NMR (400 MHz, CDCl3): d 9.88
(s, 1H); 7.84 (d, J = 8.0 Hz, 2H); 7.02 (d, J = 8.0 Hz, 2H); 6.76 (s, 1H). 13C NMR
(100 MHz, CDCl3): d 191.5; 161.9; 132.6; 116.1. b: m/z 121.0920 [M-H]- (calcd.
for C7H5O2: 121.0925).
Results and discussion
In our work to synthesize benzofurans and benzopyrans, we attempted to obtain
3-formylsalicylic acid and its analogues by Duff reaction. We firstly carried out our
experiment with salicylic acid as substrate under traditional Duff conditions. The
result exhibited that the para-formylated product was apparently dominant with
0.5:1 ortho/para ratio (Table 1, entry 13), which was in accordance with the result
reported [7]. The challenge to obtain ortho-selective formylation was to activate the
ortho C-atom of the OH group in phenols. Since metal salts are frequently used for
promoting ortho-formylation in several other methods [11–14], a few metal salts (or
oxides) were selected for our investigation in the Duff reaction (Scheme 1), and
Cu2O with oxygen came out to be the best choice for promotion of ortho-selective
formylation, the ortho/para selectivity of 2.3:1 and total yield of 80 % were
achieved (Table 1, entry 5). All the Cu (II) salts (Table 1, entries 3, 4 and 7),
including CuSO4, Cu(OAc)2, CuO and CuCl2, exhibited better performance than
their corresponding Cu(I) salts under anaerobic conditions, in terms of both total
yields and ortho/para formylation selectivities (Table 1, entries 3, 10, 4 VS 5, and 7
VS 8). However, they behaved similarly with Cu(I) salts under aerobic condition.
These suggest that Cu(II) was the active species for promoting the Duff reaction.
Other metal salts could improve the total yields to a certain extent (entry 1, 2, 11,
12). Zinc oxide, manganous sulfate, and aluminum chloride were less effective for
ortho-formylation while palladium acetate was in favor of para-formylation (entry
12, 0.26:1 ortho/para ratio). Furthermore, the addition of coordinating ligands, i.e.,
Ph3P or 1,10-phenanthroline, had no impact on the total yields, Ph3P showed no
influence on the regioselectivity, and 1,10-Phenabthroline reduced the formation of
ortho products (Table 1, entries 3–5 and 7–8).
A few acids, including formic acid, acetic acid, propionic acid, butyric acid, and
trifluoroacetic acid, were tested for the model reaction. Trifluoroacetic acid was the
best one, which gave 80 % total yield.
The effect of equivalents of Cu2O towards the reaction was tested. When 0.5 eq
of Cu2O was added, the total yield was increased from 33 to 72 % (Table 2, entries
1 and 2). Increasing of Cu2O from 0.5 eq to 1 eq had a slight effect on total yield
but doubled the ortho/para ratio (Table 2, entries 2 and 3). Further increasing of
Cu2O from 1 eq to 3 eq did not change either total yield or ortho/para selectivity
(Table 2, entries 1–6). The results indicate that 1 eq of cupric ion was needed to
activate the formylation and 2 eq. of cupric ions were needed to optimize the ortho-
selectivity in the Duff reaction.
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X. Fu et al.
Table 1 Formylation of salicylic acid in the presence of metals and ligands
Entry
[M]
Yield [%]b
Ligand
1d
Ortho/para ratioa
Nf
Ligand
Nf
2e
1d
2e
1
ZnO
–
–
52
48
80
76
80
40
70
65
33
75
76
56
33
–
–
0.55:1
0.65:1
2.04:1
1:1
2
MnSO4
CuSO4
CuO
–
–
–
–
3
77
78
80
–
72
78
77
–
2:1
0.45:1
4
1:1
0.55:1
5
Cu2O
2.3:1
0.7:1
2.30:1
0.75:1
1.95:1
1.66:1
0.86:1
2.10:1
1.26:1
0.26:1
0.5:1
6
Cu2Og
CuCl2
CuCl
CuClg
Cu(OAc)2
AlCl3
–
–
7
68
66
–
68
68
–
2:1
0.53:1
8
1.61:1
0.65:1
9
–
–
–
–
–
–
–
–
–
–
10
11
12
13
–
–
–
–
Pb(OAc)2
c
–
–
–
–
–
The reactions were conducted with 1a (1 equiv.), HMTA (2 equiv.), Cu2O (1 equiv.), other metal
additives (2 equiv.), ligands (1 equiv.) and TFA at 90 °C for 5 h under oxygen
a
The ortho/para ratio was determined by 1H NMR spectrum
b
Total yield of isolated product
c
No metal additive was added
d
Ligand 1 = PPh3
e
Ligand 2 = 1,10-phenanthroline
f
N absence of ligand, HMTA hexamethylenetetramine, TFA trifluoroacetic acid
g
No oxygen
Scheme 1 Copper-mediated Duff reaction
With optimized condition in hand, we further studied the substrate scope of the
reaction (Scheme 2). Selected examples in Table 3 demonstrated that ortho-
selective formylation of salicylic acid (1a), salicylic acid with 4-substituents of
methyl 1b), hydroxyl (1c), chloride (1d), and salicylic derivatives 1e, 1f, and 1g,
could be improved at certain degrees by Cu(II) (Table 3, entries 1–7).
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Synthesis of salicylaldehydes from phenols
Table 2 Effect of equivalent of Cu2O
Entry
Equivalent [Cu2O]
Yield [%]b
Ortho/para ratioainseins
1
2
3
4
5
6
0
33
72
80
80
79
80
0.5:1
0.5
1
1.13:1
2.30:1
2.28:1
2.33:1
2.31:1
1.5
2
3
The reactions were conducted with 1a (1 equiv.), HMTA (2 equiv.), Cu2O (equiv. varied), TFA at 90 °C
for 5 h
a
The ortho/para ratio was determined by 1H NMR spectrum
b
Total yield of isolated product
Scheme 2 Substrate scope
Despite the selectivity, the total yields of 1a, 1f, and 1g had also been improved
about two times. There were little changes of total yields of substrate 1b, 1c, and 1d
on addition of Cu2O, possibly due to the steric influence of substituents at C-(4). To
verify the hypothesis, we used 1e as substrate. As expected, similar to 1a, 1f, and 1g,
the total yield of 1e had increased nearly twice on addition of Cu2O. There is no
selectivity existing in the case of 1e. 1h resulted in complicated products (Table 3,
entry 8), due to the existence of reactive hydrogen of acetyl group. These results
revealed that the selectivity of ortho formylation was achieved for substrates
bearing carbonyl groups (or carboxyl group) at the ortho position of hydroxyl group.
The influence of relative location of hydroxyl and carbonyl groups on phenyl ring
on Cu2O promoted Duff reaction was further investigated with 1i and 1j. As listed in
Table 3, 1i and 1j (entries 9 and 10), which also bore a carboxyl group on the
123

X. Fu et al.
Table 3 Formylation of substituted phenols under modified Duff reaction condition
Entry
Substrate
Products ortho, para,
diformylated
Yield [%]b
Ortho/para ratioa
N
Y
N
Y
1
1a
1b
1c
1d
1e
1f
2a, 3a
2b, 3b
2c, 3c
2d, 3d
2e
33
80
0.5:1
2.30:1
2:1
2
34
41
0.63:1
4.25:1
0.74:1
3
28
30
5:1
4
40
42
2:1
5
14.5
5.5
6.5
n.d
31
25
6
2f, 3f
10.6
11.8
n.d
36
0.35:1
0.3:1
1:1
7
1g
1h
1i
2g, 3g
2h, 3h
2i
2.8:1
8
9
10
11
12
13
14
15
16
17
1j
2j
70
72
1k
1l
2k, 3k, 4kc
2l, 3l, 4lc
2m, 3m
2n, 3n
2o, 3o
2p, 3p
2q, 3q
59
60
0.30:1:0.25
0.64:1:0.17
0.34:1:0.28
0.60:1:0.20
62
60
1 m
1n
1o
1p
1q
n.d
8
n.d
10
0.4:1
0.5:1
n.d
n.d
n.d
n.d
n.d
n.d
The reactions were conducted with 1 (1 equiv.), HMTA (2 equiv.), Cu2O (1 equiv.) and TFA at 90 °C for
5 h under oxygen
a
b
c
1
The ortho/para ratio was determined by H-NMR spectrum, entries 11 and 12 are ortho/para/di ratio
Total yield of isolated product, N = absence of Cu2O, Y = presence of Cu2O
4k and 4l instead of diformylated products
phenolic ring, but with the carboxyl group meta- or para- to the hydroxyl group of
phenol, the addition of Cu2O had no effect on neither selectivity nor total yields.
Furthermore, for substrates bearing non-carbonyl group (Table 3, entries 11–14),
addition of Cu2O had no impact on both selectivity and formylation yield of Duff
reaction. Finally, for substrates bearing carbonyl group but no hydroxyl group,
formylation by Duff reaction was not successful (Table 3, entries 15–17).
Cu2+
4+
Cu2+
O
Cu2+
H
CF3COO
NH
O
O
N
N
NH
O
X
N
X
N
N
N
2B-
4B-
B-=CF3COO-, Cl-, 1/2SO42-....
Fig. 1 Possible role of Cu(II) in Duff reaction
123

Synthesis of salicylaldehydes from phenols
Based on our experimental results, phenol is the basic unit for the Duff reaction.
Salicylic acid gave the best results in both total yield and ortho/para selectivity.
Ortho-selective formulations of phenols with carbonyl substituents adjacent to OH
group, were achieved by addition of metal salts in Duff reaction (Table 3, entries
2–7).
The possible role of Cu (II) additives in Duff reaction is proposed as Fig. 1.
The key step in the Duff reaction is the addition of iminium ion of HMTA to the
aromatic ring, resulting in an intermediate at the oxidative state of a benzylamine
[28]. In order to initialize the formylation, an electron-donating effect to the
aromatic ring would be favorable for the nucleophilic attack of the aromatic ring to
the electrophile. The stoichiometric amount of Cu(II) gave the maxima formylation,
indicating the activating effect of metal to the phenyl ring. Increasing of Cu(II) from
1 eq to 2 eq. further improved the ortho/para ratio of formylation but the total yield
did not vary significantly. The proposed mechanism was illustrated in Fig. 1; the
coordination of the first equivalent of Cu(II) with adjacent carbonyl group and
hydroxyl group induced the deprotonation of phenol by trifluoroacetate (Fig. 1,
left). This was followed by coordination of the second Cu(II) with the phenoxyl
group and the amine of HMTA (Fig. 1, right), which brought the HMTA closing to
the ortho position of phenol, promoting the ortho-formylation. The highest
improvement of total yield and selectivity was obtained for salicylic acid, probably
due to the stronger coordination between Cu (II) and carboxyl group than carbonyl
group.
More evidence for the mechanistic explanation is the ligand’s effect on the yields
and ortho/para selectivity. The addition of either Ph3P or 1,10-phenanthroline could
not improve the total yields of Cu(II)-mediated Duff reactions, and the weaker
chelator, Ph3P had little effect on the ortho/para selectivity. However, the bi-dental
chelator 1,10-phenanthroline can compete with HMTA for coordination to copper,
resulting in lowered ortho formylation.
Conclusions
A modified Duff reaction was developed. With the aid of Cu2O, salicylaldehydes
were synthesized from phenols with carbonyl substituent adjacent to OH group,
significant improvements of selectivity and total yield were achieved through the
Duff formylation.
Supplemental material
Supplemental data for this article can be accessed on the publisher’s website.
Acknowledgments This work was financially supported by the National Natural Science Foundation of
China (No. 21172214).
123

X. Fu et al.
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