Water-promoted ortho-selective monohydroxymethylation of phenols in the NaBO2 system

Article abstract of DOI:10.1039/c4ob00228h

Water-promoted ortho-selective monohydroxymethylation of phenols in the NaBO₂ system generates salicyl alcohols in 65-97% yields. A remarkable rate-enhancement by water was observed, and NaBO₂ appeared to serve the dual role of a suitable base and an efficient chelating reagent. This protocol possesses many advantages such as short reaction times, expanded substrate scope, and high mono- and regio-selectivities. The experimental results were explained by the calculations based on local ionisation energy minima, leading to a possible reaction mechanism.

Full text of DOI:10.1039/c4ob00228h

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Water-promoted ortho-selective
monohydroxymethylation of phenols in the
NaBO2 system†
Cite this: Org. Biomol. Chem., 2014,
12, 3100
Hui-Jing Li,*a,b Ying-Ying Wu,a Qin-Xi Wu,a Rui Wang,a Chun-Yang Dai,a
Zhi-Lun Shen,a Cheng-Long Xiea and Yan-Chao Wu*a
Water-promoted ortho-selective monohydroxymethylation of phenols in the NaBO2 system generates
salicyl alcohols in 65–97% yields. A remarkable rate-enhancement by water was observed, and NaBO2
appeared to serve the dual role of a suitable base and an efficient chelating reagent. This protocol pos-
sesses many advantages such as short reaction times, expanded substrate scope, and high mono- and
regio-selectivities. The experimental results were explained by the calculations based on local ionisation
energy minima, leading to a possible reaction mechanism.
Received 29th January 2014,
Accepted 7th March 2014
DOI: 10.1039/c4ob00228h
www.rsc.org/obc
the efficient and fast hydroxymethylation of phenols under
mild conditions with high selectivity and expanding substrate
Introduction
Hydroxymethylation is one of the most important carbon– scope.
carbon bond-forming reactions, which has been widely
On the other hand, a huge amount of effort has been dedi-
applied in the syntheses of many natural products and biologi- cated to the development of chemical reactions in agreement
cally active compounds.1 The obtention of high selectivity in a with the principles of green chemistry. Water is a unique green
hydroxymethylation reaction is a long-standing challenge for solvent for chemical transformations in view of its low cost,
organic chemists. For example, hydroxymethylation of
a
safety, and environmentally benign properties.8 Organic reac-
phenol usually occurs at the positions that are ortho and para tions performed in water have made great progress since the
to the site of the phenolic hydroxyl group;2 in instances where concept of on-water reaction was presented by Sharpless in
the para position is blocked, hydroxymethylation occurs at the 2005, and this new concept has been used to explain the
ortho positions with respect to the phenolic hydroxyl group.3 unusual reaction rate enhancement compared to the same
Bishydroxymethylation of para-substituted phenols went reaction in an organic solvent or under solvent free con-
smoothly under many basic conditions, whereas, as men- ditions.9 Various water-promoted reactions help to narrow the
tioned by Bew, the corresponding mono-specific hydroxy- gap between the use of water as a reaction medium and practi-
methylation using seemingly straightforward procedures cal green chemistry.10 However, pursuing practical organic
proved problematic,3c,4 which was verified in our synthesis of reactions in water is still at its early stages and further research
4-tert-butyl salicyl alcohol that was a key intermediate for the is needed to fully understand the role that water plays. In con-
preparation of a mono-arm-Trost-type ligand.5 Hydroxymethy- nection with our consistent interest in aqueous reactions and
lation of phenols has gained some success in the synthesis of selective reactions,4,11 herein we would like to report a water-
salicyl alcohols,2–4,6 which have found widespread utility as promoted mono- and ortho-selective hydroxymethylation of
substrates for the synthesis of a large number of pharmaceuti- phenols in the NaBO2 system.
cals, natural products, functional materials, and so forth.7
However, it is still a challenge to develop a direct approach for
Results and discussion
aSchool of Marine Science and Technology, Harbin Institute of Technology at Weihai,
The hydroxymethylation of 4-tert-butylphenol (1a) with formal-
dehyde was used as a probe for evaluating the reaction con-
ditions, and the representative results are summarized in
Table 1. Bishydroxymethylation of phenol 1a went
smoothly under basic conditions. By treating 1a with excess
formaldehyde in sodium hydroxide aqueous solution, the
Shandong 264209, China. E-mail: lihuijing@iccas.ac.cn, ycwu@iccas.ac.cn
bBeijing National Laboratory for Molecular Sciences (BNLMS), and Key Laboratory of
Molecular Recognition and Function, Institute of Chemistry Chinese Academy of
Sciences, Beijing 100190, China
†Electronic supplementary information (ESI) available: Copies of 1H NMR and
13C NMR spectra of compounds 2a–t, 3a, 3i and 4d. See DOI: 10.1039/
c4ob00228h
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identical conditions (entry 7). With the basic chelating
reagent, sodium metaborate (NaBO2), in comparison with
Na2B4O7, a shorter reaction time, a higher yield and a lower
reaction temperature were observed (entries 6–8). With the use
of organic solvents such as toluene, dichloromethane, aceto-
nitrile and tetrahydrofuran, no reaction took place and the
starting material was recovered (entries 9–12). The use of
ethanol only afforded a trace amount of 2a (entry 13). It is par-
ticularly noteworthy that the yield of 2a rose dramatically with
the increase of the proportion of water in the co-solvent EtOH–
H2O (entries 14–16). The NaBO2 system was chosen in our
investigations because of its relatively high yield, low reaction
temperature, and short reaction time. It was found that 8
equivalents of the boron chelating reagent were needed to
ensure the excellent ortho-selectivity.
The procedure turned out to be applicable to a wide range
of phenols, and the results are summarized in Table 2. With
weak electron-donating groups, tert-butyl, ethyl and methyl, at
the para position of phenols, hydroxymethylation of phenols
1a–c with aqueous formaldehyde under the standard con-
ditions afforded salicyl alcohols 2a–c in high yields within
20–28 hours, demonstrating a high mono-selectivity (entries
1–3). Non-substituted phenol 1d reacted with aqueous formal-
dehyde uneventfully to afford salicyl alcohol 2d in 93% yield
under the standard conditions, demonstrating a high regio-
selectivity (entry 4). With the para position of phenols bearing
electron-withdrawing groups such as fluoro, chloro and
bromo, phenols 1e–g reacted equally well with aqueous form-
aldehyde under the standard conditions to afford salicyl alco-
Table 1 Survey of conditions for hydroxymethylation of 4-tert-butyl-
phenol (1a) with aqueous formaldehydea
Entry Conditions
Solvents
Time Yield of 2a
1
2 equiv. NaOH, R.T.
2 equiv. NaOH, R.T.
8 equiv. H3BO3, 110 °C H2O
2 equiv. Na2B4O7, R.T. H2O
H2O
H2O
0.5 d 0 (98%)b
0.5 d 15% (72%)b
1.5 d 41% (5%)b
1.5 d Trace
2c
3
4
5
2 equiv. Na2B4O7, 40 °C H2O
2 equiv. Na2B4O7, 60 °C H2O
2 equiv. Na2B4O7, 50 °C H2O
1.5 d 20%
6
1.5 d 84% (4%)b
1.5 d 85%
7d
8
8 equiv. NaBO2, 40 °C
8 equiv. NaBO2, 40 °C
8 equiv. NaBO2, 40 °C
8 equiv. NaBO2, 40 °C
8 equiv. NaBO2, 40 °C
8 equiv. NaBO2, 40 °C
8 equiv. NaBO2, 40 °C
8 equiv. NaBO2, 40 °C
8 equiv. NaBO2, 40 °C
H2O
1 d
1 d
1 d
1 d
1 d
1 d
86%
0
0
0
0
8%
23%
46%
65%
9
PhCH3
CH2Cl2
CH3CN
THF
10
11
12
13
14
15
16
EtOH
EtOH–H2O (3 : 1) 1 d
EtOH–H2O (1 : 1) 1 d
EtOH–H2O (1 : 3) 1 d
a General conditions: 1a (1.0 equiv.), promoter (2.0–8.0 equiv.) and
aqueous formaldehyde (37%, 5.0 equiv.) in the solvent (c = 0.2 M).
R.T.: room temperature. b Yield of 3a. c Aqueous formaldehyde (37%,
0.05 equiv.) was added to the mixture of 1a (1.0 equiv.) and sodium
hydroxide (2.0 equiv.) in water (c = 0.2 M), and the yield was calculated
based on formaldehyde. d NaOH (1.0 equiv.) was added.
bishydroxymethylated product 3a was obtained in 98% yield hols 2e–g in excellent yields (entries 5–7). Hydroxymethylation
within 0.5 day (entry 1),5 which in turn facilitated our synthesis of 4-phenylphenol (1h) and 4-(benzyloxy)phenol (1i) with
of a semi-crown Trost-type ligand.5 In contrast, treatment of aqueous formaldehyde afforded salicyl alcohols 2h–i in good
formaldehyde with excess phenol 1a under the same con- yields within 48 hours under the standard conditions, albeit at
ditions did not ensure the isolation of the monohydroxymethy- a relatively higher reaction temperature (entries 8, 9). By treat-
lated product 2a with
a
satisfactory yield (entry 2).5 ing 4-methoxyphenol (1j) with aqueous formaldehyde under
Monohydroxymethylation of 1a with formaldehyde can possi- the standard conditions, salicyl alcohol 2j was obtained in
bly take place in the presence of excess phenylboronic acid2a,b 90% yield within 12 hours (entry 10). 3,4-Disubstituted phenol
or orthoboric acid2c,g at high temperatures in benzene, toluene 1k has also been investigated, which reacted smoothly with
or xylene, and the potential bishydroxymethylation could be aqueous formaldehyde under the standard conditions to
suppressed by chelating 2a with the acidic boron reagent.2a–c,g afford salicyl alcohol 2k in 95% yield (entry 11). L-N-Benzyloxy-
The reaction can be also performed in water at 110 °C, which carbonyl-3-hydroxymethyl-tyrosine (1l) reacted smoothly with
affords 2a in 41% yield within one and a half days, along with aqueous formaldehyde under the standard conditions to
the bishydroxymethylated product 3a (5% yield, entry 3). afford salicyl alcohol 2l in 80% yield within 1 day (entry 12).
However, the reaction could not be completed in many days, This reaction has been achieved previously in the presence of
and low selectivity was observed when the reaction was per- borax in 5–17 days,3a,c,d which in turn facilitated the synthesis
formed at a higher temperature. When sodium tetraborate of methylene-bridged (S)-tyrosine-phenol dimers,3c as well as
(Na2B4O7), a basic boron reagent, was used as the chelating the total synthesis of antitumor antibiotic jorumycin and
reagent, monohydroxymethylation of 1a with aqueous formal- renieramycin G.12 Double monohydroxymethylation went
dehyde could take place at room temperature (entry 4). An smoothly between 2,2-bis(4-hydroxyphenyl)propane (1m) and
increased yield was observed when the reaction was performed excess aqueous formaldehyde under the standard conditions
at 40 °C, reflecting the temperature factor effect on this reac- to give salicyl alcohol 2m in 65% yield (entry 13). With a meth-
tion (entries 4, 5). As expected, the reaction in the Na2B4O7 oxyl group (a strong electron-donating group), a methyl group
reaction system at 60 °C afforded 2a in 84% yield within one (a weak electron-donating group) and a fluoro group (a weak
and a half days, along with the bishydroxymethylated product electron-withdrawing group) at the ortho position of phenols,
3a (4% yield, entry 6). When one equivalent of NaOH was hydroxymethylation of phenols 1n–p with aqueous formal-
added, the reaction went smoothly at 50 °C under otherwise dehyde under the standard conditions afforded salicyl alcohols
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Table 2 Water-promoted hydroxymethylation of phenols
aqueous formaldehyde in the NaBO2 systema
1
with
Table 2 (Contd.)
Entry
11
Phenols
Time
10 h
Products
Entry
1
Phenols
Time
28 h
Products
12
13
24 h
2
3
20 h
20 h
36 h
4
5
12 h
30 h
14
15
16
17
12 h
12 h
12 h
12 h
6
30 h
16 h
48 h
48 h
7
8b
18
19
20
12 h
12 h
12 h
9b
10
12 h
a General conditions: 1a (1.0 equiv.), NaBO2 (8.0 equiv.) and aqueous
formaldehyde (37%, 5.0 equiv.) in water (c = 0.2 M) at 40 °C. b The
reaction was performed at 50 °C.
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ionization energies (IEs) of phenoxide anions are 3.18 eV
(ortho), 4.24 eV (meta) and 3.32 eV (para).13 Since changes in
the IEs result in exponential changes in the relative rates of
reaction at different sites, the estimated regioisomer ratios, in
an electrophilic substitution, are 97% (ortho), 0 (meta) and 3%
(para).13 It can also be proposed that similar resonant effects
come into play at the ortho and para positions, but the ortho
positions are more inductively activated than the para posi-
tion.13 However, a higher reaction temperature makes more
collisions effective, including the collisions at the position
para to the phenolic hydroxyl group, and thereby results in a
lower ortho-selectivity. One resolution is to perform the hydro-
xymethylation at temperatures as low as possible, which would
make the collisions at the para position ineffective and thus
increase the ortho-selectivity. The effective reaction tempera-
ture for ortho-hydroxymethylation in the NaBO2–H2O system
(40 °C) was lower than that in the Na2B4O7–H2O system (60 °C)
or H3BO3–H2O system (110 °C), and thus could display a
higher ortho-selectivity.
On the other hand, as shown in Fig. 2, an obvious bigger
ionization energy minimum is required in the electrophilic
substitution of anisole compared with a phenoxide anion (i.e.
3.18 eV versus 8.9 eV, Fig. 2), indicating that a phenoxide anion
is far more active than anisole in an electrophilic substitution.
Although a methoxyl group activates an aromatic ring toward
electrophilic attack, an oxyanion substituent is an even more
powerful activator because electron delocalization in a phenox-
ide anion leads to strongly increased electron density at the
aromatic ring. The possible compounds 7 (Fig. 3), resulted
from the reaction of NaBO2 with monohydroxymethylated pro-
ducts 2, help to prevent the formation of new strongly active
phenoxide anions, and thus obviate a further hydroxymethyla-
tion under mild conditions. However, further hydroxymethyla-
tions would occur if the temperature is high enough, and
thereby result in a lower mono-selectivity. The effective reac-
tion temperature for the monohydroxymethylation in the
NaBO2–H2O system was lower than that in the Na2B4O7–H2O
Fig. 1 Structures of the bishydroxymethylated product 3i and the para-
hydroxymethylated product 4d.
2n–p in high yields within 12 hours (entries 14–16). meta-Sub-
stituted phenols 1q–r have also been investigated, which
reacted smoothly with aqueous formaldehyde under the stan-
dard conditions to afford salicyl alcohols 2q–r in 90–91%
yields (entries 17, 18). 2,3-Disubstituted phenol 1s and 2,5-di-
substituted phenol 1t reacted equally well with aqueous form-
aldehyde under the standard conditions to afford salicyl
alcohols 2s–t in excellent yields (entries 19, 20). It is worth
mentioning that the mono- and ortho-selectivities of these
hydroxymethylations decreased with the increase of the reac-
tion temperature. For example, the partial para-hydroxymethy-
lation of 1d, in either the NaBO2–H2O system or the Na2B4O7–
H2O system, was observed when the reaction was performed at
60 °C, which afforded a para-hydroxymethylated product 4d in
about 10% yield (Fig. 1), along with salicyl alcohol 2d (about
80% yield). The partial bishydroxymethylation of phenols 1a
and 1i, in either the NaBO2–H2O system or Na2B4O7–H2O
system, was also observed when the reaction was performed at
60 °C, which afforded bishydroxymethylated products 3a and 3i
(Fig. 1) in about 5% yields, along with salicyl alcohols 2a and 2i
(80–85% yields). These reactions did not work in the H3BO3–
H2O system at 60 °C. The NaBO2–H2O system was found to be
the best conditions as its lowest effective reaction temperature
was the lowest one in these boron reaction systems.
The high mono- and regio-selectivities of these reactions
could be understood by the special properties of NaBO2, which
appeared to serve the dual role of a suitable base and an
efficient chelating reagent. On the one hand, as phenols were
converted to the corresponding phenoxide anions in the basic
NaBO2–H2O system, the high ortho-selectivity could be
explained from the calculated average local ionization energy
surfaces of the phenoxide anion.13 As shown in Fig. 2, the
Fig. 2 Prediction of the regio-selectivity with the local ionization
energies (IEs) [sites of electrophilic substitution: primary (dark), second-
ary (gray), tertiary (light gray)].12
Fig. 3 A plausible mechanism for the hydroxymethylation of phenols
with aqueous formaldehyde in the NaBO2–H2O system.
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system or H3BO3–H2O system, and thus could display a higher HRMS (ESI) m/z: calcd for C9H11O2 [M − H]−: 151.0759. Found:
mono-selectivity.
151.0758.
Based on the above results, a plausible mechanism for the
Salicyl alcohol 2c. Light yellow solid; m.p. = 104–105 °C
hydroxymethylation of phenols with formaldehyde is outlined (lit.,6a,15 104–105 °C); H NMR (400 MHz, DMSO-d6) δ 7.08 (s,
in Fig. 3. Reaction of phenols 1 with NaBO2 affords strongly br, 1H), 6.83 (d, br, 1H, J = 8.0 Hz), 6.65 (d, 1H, J = 8.0 Hz), 4.46
active phenoxide anions 5, which in turn would react with (s, 2H), 2.19 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 151.8,
aqueous formaldehyde to form salicyl alcohols 2. The pro- 128.1, 127.8, 127.5, 126.8, 114.4, 58.3, 20.2; FTIR (film): 3436,
duced salicyl alcohols 2 in situ react with NaBO2 to form 3159, 1445, 1335, 1297, 1210, 1091, 827, 690 cm−1. HRMS (ESI)
relatively stable compounds 7, and thus obviate a bishydroxy- m/z: calcd for C8H9O2 [M − H]−: 137.0597. Found: 137.0595.
1
methylation. Finally, acidic work-up of the reaction mixture
Salicyl alcohol 2d. Light yellow solid; m.p. = 82–84 °C (lit.,16
facilitates the conversion of compounds 7 into salicyl alcohols 81–84 °C); 1H NMR (300 MHz, CDCl3) δ 7.40 (s, br, 1H), 7.20 (t,
2.
1H, J = 8.1 Hz), 7.04 (d, 1H, J = 8.1 Hz), 6.87 (d, 1H, J = 8.1 Hz),
6.85 (t, 1H, J = 8.1 Hz), 4.82 (s, 2H), 2.71 (s, br, 1H); 13C NMR
(75 MHz, CDCl3) δ 155.8, 129.4, 127.9, 124.8, 120.1, 116.4,
64.3; FTIR (film): 3155, 1596, 1483, 1461, 1417, 1291, 1256,
1217, 1115, 1044, 995, 938, 774, 753, 735, 714 cm−1. HRMS
Conclusions
In summary, ortho-selective monohydroxymethylation of (ESI) m/z: calcd for C7H7O2 [M − H]−: 123.0441. Found:
phenols proceeds efficiently in the NaBO2–H2O system. The 123.0439.
reaction rate was greatly enhanced with water. The process pro-
Salicyl alcohol 2e. Light yellow solid; m.p. = 67–69 °C (lit.,17
1
vided a highly efficient and environmentally benign approach 68–70 °C); H NMR (300 MHz, CDCl3) δ 8.45 (s, 1H), 6.78–6.68
for the synthesis of salicyl alcohols, important substrates for (m, 3H), 4.61 (s, 2H), 4.46 (s, br, 1H); 13C NMR (75 MHz,
the synthesis of various pharmaceutical agents and functional CDCl3) δ 156.0 (d, 1C, JC–F = 235.1 Hz), 151.5, 127.5 (d, 1C, JC–F
natural products. Applications of this hydroxymethylation pro- = 6.6 Hz), 116.3 (d, 1C, JC–F = 7.9 Hz), 114.2 (d, 1C, JC–F = 22.5
tocol to the total synthesis of proanthocyanidin-type natural Hz), 113.9 (d, 1C, JC–F = 23.1 Hz), 62.0 (d, 1C, JC–F = 3.5 Hz);
products are in progress in our research group.
FTIR (film): 3174, 1512, 1455, 1415, 1373, 1307, 1277, 1197,
1155, 1008, 883, 822, 760, 697 cm−1. HRMS (ESI) m/z: calcd for
C7H6O2F [M − H]−: 141.0346. Found: 141.0344.
Salicyl alcohol 2f. Light yellow solid; m.p. = 89–90 °C
(lit.,6a,15 90–93 °C); 1H NMR (400 MHz, DMSO-d6) δ 7.27 (d,
1H, J = 2.4 Hz), 7.06 (dd, 1H, J = 8.8 Hz), 6.76 (d, 1H, J = 8.8
Hz), 4.45 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 154.6, 129.1,
Experimental
General procedure for water-promoted hydroxymethylation of
phenols 1 with formaldehyde in the NaBO2 system (Table 2)
To a mixture of phenols 1 (1.0 mmol) and NaBO2·4H2O 127.4, 126.0, 124.7. 117.9, 64.0; FTIR (film): 3435, 3156, 1497,
(98.5%, 1.12 g, 8.0 mmol) in water (5 mL) at 40 °C was added 1205, 1177, 1117, 873, 807, 761 cm−1. HRMS (ESI) m/z: calcd
aqueous formaldehyde (37%, 372 μL, 5.0 mmol) in one for C7H6O2Cl [M − H]−: 157.0051. Found: 157.0048.
portion. The mixture was stirred at 40 °C (Table 2, entries 9,
Salicyl alcohol 2g. Light yellow solid; m.p. = 109–111 °C
10, 50 °C) for 10–48 hours, and neutralized with 3 N hydro- (lit.,6a,18 109–114 °C); 1H NMR (300 MHz, CDCl3) δ 8.78 (s, 1H),
chloric acid at room temperature until pH = 6. The resulting 7.14 (d, 1H, J = 2.1 Hz), 7.05 (dd, 1H, J = 8.4, 2.1 Hz), 6.60 (d,
mixture was extracted with ethyl acetate (5 × 20 mL). The com- 1H, J = 8.1 Hz), 4.54 (s, 2H), 4.50 (s, 1H); 13C NMR (75 MHz,
bined organic extracts were washed with brine, dried over CDCl3) δ 154.5, 130.5, 130.0, 128.7, 117.2, 110.8, 61.2; FTIR
anhydrous sodium sulfate, filtered, and concentrated. The (film): 3436, 3159, 1434, 1406, 1302, 1243, 1217, 1177, 1126,
residue was purified by column chromatography over silica gel 1012, 999, 898, 877, 819, 776, 743, 706 cm−1. HRMS (ESI) m/z:
to afford salicyl alcohols 2a–p.
calcd for C7H6O2Br [M − H]−: 200.9546. Found: 200.9545.
Salicyl alcohol 2h. Light yellow solid; m.p. = 215–216 °C; H
1
Salicyl alcohol 2a. Light yellow solid; m.p. = 85–86 °C (lit.,14
1
84–86 °C); H NMR (400 MHz, CDCl3) δ 7.23 (dd, 1H, J = 8.4, NMR (400 MHz, DMSO-d6) δ 7.60–7.34 (m, 6H), 7.27 (t, 1H, J =
2.4 Hz), 7.05 (d, 1H, J = 2.4 Hz), 6.82 (d, 1H, J = 8.4 Hz), 4.84 (s, 7.6 Hz), 6.85 (d, 1H, J = 8.4 Hz), 4.55 (s, 2H); 13C NMR
2H), 1.29 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 153.5, 142.9, (100 MHz, DMSO-d6) δ 154.0, 140.5, 130.5, 128.8, 128.6, 125.8,
126.3, 124.8, 124.0, 116.0, 64.9, 34.0, 31.5; FTIR (film): 3437, 125.5, 125.4, 115.0, 58.2; FTIR (film): 3435, 3156, 1451, 1267,
3159, 1447, 1255, 1210, 928, 870, 801 cm−1. HRMS (ESI) m/z: 834, 762 cm−1. HRMS (ESI) m/z: calcd for C13H11O2 [M − H]−:
calcd for C11H15O2 [M − H]−: 179.1072. Found: 179.1074.
Salicyl alcohol 2b. Light yellow solid; m.p. = 83–84 °C (lit.,6a
199.0754. Found: 199.0752.
1
Salicyl alcohol 2i. Light yellow solid; m.p. = 135–136 °C; H
83 °C); 1H NMR (400 MHz, DMSO-d6) δ 8.95 (s, br, 1H), 7.07 (d, NMR (400 MHz, DMSO-d6) δ 8.89 (s, br, 1H), 7.45–7.31 (m,
1H, J = 2.8 Hz), 6.80 (d, 1H, J = 8.0 Hz), 6.63 (dd, 1H, J = 8.0, 5H), 7.03 (s, br, 1H), 6.72 (s, br, 2H), 5.00 (s, br, 3H), 4.51 (s,
2.8 Hz), 4.85 (s, br, 1H), 4.44 (d, 2H, J = 3.6 Hz), 2.44 (q, 2H, J = 2H); 13C NMR (100 MHz, DMSO-d6) δ 151.2, 148.0, 137.6,
7.6 Hz), 1.08 (t, 3H, J = 7.6 Hz); 13C NMR (100 MHz, DMSO-d6) 129.5, 128.2, 127.5, 127.4, 115.0, 114.0, 113.2, 69.7, 58.3; FTIR
δ 152.1, 133.6, 128.0, 126.7, 126.3, 114.4, 58.4, 27.5, 15.9; FTIR (film): 3436, 3158, 1513, 1256, 838, 778 cm−1. HRMS (ESI) m/z:
(film): 3435, 3157, 1517, 1272, 1236, 852, 819, 794 cm−1
.
calcd for C14H13O3 [M − H]−: 229.0865. Found: 229.0868.
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Salicyl alcohol 2j. Light yellow solid; m.p. = 74–76 °C (lit.,19
Salicyl alcohol 2q. Light yellow solid; m.p. = 78–80 °C; 1H
75–76 °C); 1H NMR (300 MHz, CDCl3) δ 7.08 (s, br, 1H), NMR (400 MHz, DMSO-d6) δ 7.95 (s, OH), 7.28 (d, 1H, J =
6.78–6.70 (m, 2H), 6.59 (d, 1H, J = 2.4 Hz), 4.74 (s, 2H), 3.72 (s, 8.2 Hz), 6.82 (s, 1H), 6.74 (d, 1H, J = 8.2 Hz), 4.57 (s, OH), 4.43
3H), 2.98 (s, br, 1H); 13C NMR (75 MHz, CDCl3) δ 153.1, 149.5, (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 157.4, 131.4,
125.8, 116.9, 114.3, 113.6, 64.0, 55.8; FTIR (film): 3181, 2961, 129.3, 129.1, 115.4, 114.1, 59.8; FTIR (film): 3418, 2944, 1610,
1516, 1461, 1412, 1316, 1280, 1211, 1164, 1041, 1009, 999, 930, 1502, 1389, 1267, 1101, 1031, 907, 703 cm−1. HRMS (ESI) m/z:
865, 819, 758, 701 cm−1. HRMS (ESI) m/z: calcd for C8H9O3 calcd for C7H6ClO2 [M − H]−: 157.0056. Found: 157.0058.
1
[M − H]−: 153.0546. Found: 153.0543.
Salicyl alcohol 2r. Light yellow solid; m.p. = 100–101 °C; H
Salicyl alcohol 2k. Light yellow solid; m.p. = 110–112 °C NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1H), 7.31 (d, 1H, J =
(lit.,4b 112–113 °C); 1H NMR (300 MHz, CDCl3) δ 8.05 (s, br, 8.4 Hz), 6.97 (d, 1H, J = 1.6 Hz), 6.79 (dd, 2H, J = 8.4, 1.6 Hz),
1H), 6.77 (s, 1H), 6.62 (s, 1H), 4.66 (s, 2H), 4.03 (s, br, 1H), 2.14 5.14 (s, br, 1H), 4.43 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ
(s, 3H), 2.11 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 153.6, 136.9, 157.0, 131.1, 129.4, 121.5, 118.6, 114.6, 62.3; FTIR (film): 3185,
129.0, 127.1, 122.9, 117.2, 63.0, 19.4, 18.4; FTIR (film): 3179, 2958, 1582, 1445, 1400, 1284, 1264, 1179, 1154, 1048, 992, 889,
2935, 1460, 1407, 1311, 1280, 1203, 1022, 988, 891, 861, 759, 857, 812, 694 cm−1. HRMS (ESI) m/z: calcd for C7H6O2Br
706, 686 cm−1. HRMS (ESI) m/z: calcd for C9H11O2 [M − H]−: [M − H]−: 200.9546. Found: 200.9545.
1
151.0754. Found: 151.0751.
Salicyl alcohol 2s. Light yellow solid; m.p. = 129–131 °C; H
Salicyl alcohol 2l. Light yellow solid; m.p. = 125–129 °C; NMR (400 MHz, DMSO-d6) δ 10.4 (s, br, 1H), 7.00 (t, 1H, J =
1
[α]2D5 = 10.6 (c = 0.8, CH3CO2H); H NMR (400 MHz, DMSO-d6) 8.0 Hz), 6.82 (d, 1H, J = 8.0 Hz), 5.19 (s, br, 1H), 4.43 (s, 2H);
δ 12.67 (s, br, 1H), 9.19 (s, 1H), 7.59 (d, 1H, J = 8.4 Hz), 13C NMR (100 MHz, DMSO-d6) δ 148.5 (d, 1C, JC–F = 242.4 Hz),
7.36–7.18 (m, 6H), 6.92 (d, 1H, J = 8.4 Hz), 6.66 (d, 1H, J = 8.0 148.4 (d, 1C, JC–F = 242.5 Hz), 145.6 (d, 1C, JC–F = 8.9 Hz), 138.1
Hz), 4.98 (t, 1H, J = 2.4 Hz), 4.98 (d, 2H, J = 2.4 Hz), 4.45 (s, (d, 1C, JC–F = 14.6 Hz), 123.0 (dd, 1C, JC–F = 9.9, 4.5 Hz), 112.3
2H), 4.12–4.08 (m, 1H), 2.94 (dd, 1H, J = 13.6, 4.0 Hz), 2.72 (dd, (d, 1C, JC–F = 7.4 Hz), 56.3; FTIR (film): 3413, 2959, 1523, 1489,
1H, J = 13.6, 10.4 Hz); HRMS (ESI) m/z: calcd for C18H18NO6 1416, 1372, 1309, 1060, 998, 954, 931, 874, 812, 769, 675 cm−1
.
[M − H]−: 344.1134. Found: 344.1136. The analytical data were HRMS (ESI) m/z: calcd for C7H5F2O2 [M − H]−: 159.0258.
the same as the reported results.3a,c,d
Salicyl alcohol 2m. Light yellow solid; m.p. = 105–106 °C;
Found: 159.0254.
Salicyl alcohol 2t. Light yellow solid; m.p. = 132–134 °C; H
1
1H NMR (400 MHz, DMSO-d6) δ 9.03 (s, 2H), 7.16 (d, 2H, J = NMR (400 MHz, DMSO-d6) δ 10.45 (s, br, 1H), 7.14 (dd, 1H, J =
2.4 Hz), 6.85 (dd, 2H, J = 8.4, 2.4 Hz), 6.63 (d, 2H, J = 8.4 Hz), 11.16, 7.4 Hz), 6.79 (dd, 1H, J = 11.16, 7.4 Hz), 5.30 (s, br, 1H),
4.86 (t, 2H, J = 5.6 Hz), 4.43 (d, 4H, J = 5.6 Hz), 3.33 (s, 6H); 13
C
4.39 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ 155.0 (d, 1C, JC–F
NMR (100 MHz, DMSO-d6) δ 151.6, 140.9, 127.3, 125.2, 125.1, = 236.5 Hz), 147.3 (d, 1C, JC–F = 235.3 Hz), 144.7 (dd, 1C, JC–F
=
113.8, 58.4, 30.9; FTIR (film): 3435, 3157, 1445, 1293, 987, 25.8, 11.7 Hz), 119.1 (dd, 1C, JC–F = 17.9, 5.4 Hz), 115.6 (dd, 1C,
743 cm−1. HRMS (ESI) m/z: calcd for C17H19O4 [M − H]−: JC–F = 20.7, 7.1 Hz), 104.4 (dd, 1C, JC–F = 26.4, 2.9 Hz), 55.9 (d,
287.1283. Found: 287.1285.
1C, JC–F = 3.0 Hz); FTIR (film): 3418, 2959, 2920, 1637, 1518,
Salicyl alcohol 2n. Light yellow solid; m.p. = 60–61 °C (lit.,15 1442, 1325, 1231, 1181, 1150, 1101, 1080, 1024, 997, 877, 844,
1
60–61 °C); H NMR (400 MHz, DMSO-d6) δ 6.90 (d, 1H, J = 7.6 751 cm−1. HRMS (ESI) m/z: calcd for C7H5F2O2 [M − H]−:
Hz), 6.82 (d, 1H, J = 7.6 Hz), 6.73 (t, 2H, J = 7.6 Hz), 4.49 (s, 159.0258. Found: 159.0256.
2H), 3.76 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 147.0, 143.1,
Bishydroxymethylated product 3a. Light yellow solid; m.p. =
1
129.0, 119.4, 118.3, 110.2, 58.1, 55.7; FTIR (film): 3439, 3161, 115–116 °C; H NMR (300 MHz, CDCl3) δ 8.05 (s, br, 1H), 7.06
1496, 1202, 1101, 768, 723 cm−1. HRMS (ESI) m/z: calcd for (s, 2H), 4.74 (d, 2H, J = 3.9 Hz), 3.05 (s, br, 2H), 1.27 (s, 9H);
C8H9O3 [M − H]−: 153.0546. Found: 153.0543.
13C NMR (75 MHz, CDCl3) δ 152.3, 142.6, 125.4, 124.8, 63.6,
Salicyl alcohol 2o. Light yellow solid; m.p. = 36–38 °C (lit.,2b 34.0, 31.4; FTIR (film): 3366, 3006, 1483, 1225, 1154, 1071,
1
35–36 °C); H NMR (400 MHz, DMSO-d6) δ 7.04 (d, 1H, J = 7.6 929, 860 cm−1. HRMS (ESI) m/z: calcd for C12H17O3 [M − H]−:
Hz), 6.96 (d, 1H, J = 7.6 Hz), 6.70 (t, 2H, J = 7.6 Hz), 4.56 (s, 209.1178. Found: 209.1180.
2H), 2.15 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 152.6, 128.9,
Bishydroxymethylated product 3i. Light yellow solid; m.p. =
127.9, 125.0, 124.1, 118.8, 59.8, 16.0; FTIR (film): 3438, 3151, 159–160 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.06 (s, 1H),
1448, 1299, 1087, 760, 721 cm−1. HRMS (ESI) m/z: calcd for 7.44–7.31 (m, 5H), 6.84 (s, 2H), 5.19 (t, 2H, J = 5.6 Hz), 5.00 (s,
C8H9O2 [M − H]−: 137.0597. Found: 137.0595.
2H), 4.53 (d, 4H, J = 5.6 Hz); 13C NMR (100 MHz, DMSO-d6)
1
Salicyl alcohol 2p. Light yellow solid; m.p. = 98–100 °C; H δ 151.4, 145.1, 137.6, 129.6, 128.2, 127.4, 127.3, 111.9, 69.5,
NMR (400 MHz, DMSO-d6) δ 7.10–6.85 (m, 3H), 4.36 (s, 3H); 59.0; FTIR (film): 3368, 3008, 1510, 1255, 1172, 937, 838 cm−1
.
13C NMR (100 MHz, DMSO-d6) δ 150.8 (d, 1C, JC–F = 238.7 Hz), HRMS (ESI) m/z: calcd for C15H15O4 [M − H]−: 259.0970.
143.6 (d, 1C, JC–F = 12.0 Hz), 133.8 (d, 1C, JC–F = 5.2 Hz), 122.5 Found: 259.0973.
(d, 1C, JC–F = 3.0 Hz), 117.3, 114.2 (d, 1C, JC–F = 18.1 Hz), 62.1;
FTIR (film): 3419, 2959, 1622, 1602, 1523, 1479, 1443, 1384, m.p. = 117–118 °C; H NMR (400 MHz, DMSO-d6) δ 9.41 (s, br,
1294, 1262, 1202, 1112, 1020, 933, 870, 819, 789, 741 cm−1
1H), 7.09 (d, 1H, J = 8.0 Hz), 6.72 (d, 1H, J = 8.0 Hz), 5.00 (s, br,
HRMS (ESI) m/z: calcd for C7H6FO2 [M − H]−: 141.0352. 1H), 4.53 (d, 2H); 13C NMR (100 MHz, DMSO-d6) δ 156.2,
para-Hydroxymethylated product 4d. Light yellow solid;
1
.
Found: 141.0349.
132.6, 127.9, 114.7, 62.7; FTIR (film): 3396, 3135, 1615, 1600,
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1517, 1232, 1202, 987, 830 cm−1. HRMS (ESI) m/z: calcd for
C7H7O2 [M − H]−: 123.0441. Found: 123.0439.
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Acknowledgements
This work was supported by the Science and Technology Devel-
opment Project of Weihai (2011DXGJ13, 2012DXGJ02), the
Natural Science Foundation of Shandong Province
(ZR2012BM002), and the National Natural Science Foundation
of China (21202028, 21372054).
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