Synthesis of polyfunctional aromatic ring systems (phloroglucide analogs) under microwave irradiation

Article abstract of DOI:10.1002/hlca.200390192

An efficient and rapid synthesis of phloroglucide analogs under microwave irradiation is described. The solid-phase condensation reaction of the 4-halo-2,6-bis(hydroxymethyl)phenols 1a,b with other substituted phenols in the presence of ZnCl₂ afforded the target molecules in much higher yields than by classical solution-phase synthesis and allowed us to prepare new phloroglucide analogs possessing sensitive functional groups difficult to access by established means.

Full text of DOI:10.1002/hlca.200390192

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Helvetica Chimica Acta Vol. 86 (2003)
Synthesis of Polyfunctional Aromatic Ring Systems (Phloroglucide Analogs)
under Microwave Irradiation
by Ali Khalafi-Nezhad*a), Mohammad Navid Soltani Rada), and Gholam Hossein Hakimelahib)
a) Department of Chemistry, College of Science, Shiraz University, Shiraz 71454, Iran
(phone: ‡98-711-2282380; fax: ‡98-711-2280926; e-mail: khalafi@chem.susc.ac.ir)
b) TaiGen Biotechnology, Taipei, Taiwan 114, ROC
An efficient and rapid synthesis of phloroglucide analogs under microwave irradiation is described. The
solid-phase condensation reaction of the 4-halo-2,6-bis(hydroxymethyl)phenols 1a,b with other substituted
phenols in the presence of ZnCl2 afforded the target molecules in much higher yields than by classical solution-
phase synthesis and allowed us to prepare new phloroglucide analogs possessing sensitive functional groups
difficult to access by established means.
Introduction. The presence of essential functional groups in a suitable spatial
arrangement for chelating metal ions of enzymes is a feature common to several
antibiotics [1], e.g., triaspedinol (I) [2], cryptosporin (II) [3], and tetracycline (III) [4].
O
Pr
H
O
Me
O
H
O
Me
O
HO
O
OH
O
Et
Et
OH
OH
OH
I
O
NMe2
HO Me
O
OH
O
NH2
OH
OH
OH O
OH
O
OH
OH
O
II
III
We have prepared several antibacterial phloroglucide analogs by classical methods,
and the results were published in this journal [5 9].
The application of microwave technology in organic chemistry has been explored
extensively within the last ten years. Microwave irradiation often leads to a remarkable
decrease in reaction time, increased yields, easier workup, compliance with green-
chemistry protocols, and may enhance the regio- and stereoselectivity of reactions.
These advantages encouraged us to prepare phloroglucide analogs by this technique
[10 14].

Helvetica Chimica Acta Vol. 86 (2003)
2397
Herein, we report the solid-phase synthesis of phloroglucide analogs by condensa-
tion of 4-halo-2,6-bis(hydroxymethyl)phenols (1), prepared according to Scheme 1,
with substituted phenols in the presence of ZnCl2 under microwave irradiation.
Scheme 1
OH
X
OH
X
1. CH2O, NaOH
2. AcOH, H2O
HO
OH
1a X = Cl
1b X = Br
Results and Discussion. 4-Chloro- (1a) and 4-bromo-2,6-bis(hydroxymethyl)-
phenol (1b), [8][15] are precursors for the synthesis of phloroglucide analogs of type 2
(Scheme 2). The halogen substituent in para-position of 1 was found to be essential for
antimicrobial activity [17].
In the mortar, compounds 1a or 1b were mixed with substituted phenols, and ZnCl2
was added as a Lewis-acid catalyst. The compounds were crushed to a −homogeneous×
solid mixture, which was then irradiated in a microwave oven at 400 700 W until a
Scheme 2
W
Z
OH
OH
Y
OH
OH
Y
Y
OH
Z
Z
HO
OH
ZnCl2
W
W
Microwave irradiation
X
X
1a X = Cl
1b X = Br
2
Y
Z
Y
Z
X
W
X
W
2a
2b
2c
2d
2e
2f
Cl
Br
Cl
Cl
Br
Cl
Cl
Cl
Cl
Br
H
Br
Cl
Me
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
2h
2i
2j
2k
2l
Cl
Cl
Cl
Cl
Cl
Br
Cl
NO2
CHO
OH
Ph
allyl
allyl
Cl
H
H
H
H
MeO
MeO
H
H
H
H
H
H
H
Me
2m
2n
2g
OH
OH
OH
N
N
Cl
3

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Helvetica Chimica Acta Vol. 86 (2003)
Table 1. Comparison of Solution-Phase and Microwave-Assisted Solid-Phase Syntheses of Phloroglucide
Analogs
Product
Conventional Methoda)
Microwave-Assisted Methodb)
Yieldc)
[%]
Reaction time
[h]
Yieldc)
[%]
Reaction time
[s]
Irradiation power
[W]
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
3
56d)
77d)
60d)
37d)
54
20
60
0
30
71
53
43
39
36
0
12
12
12
18
10
24
10
72
18
9
13
10
9
15
72
92
92
90
73
86
95
85
96
75
93
82
85
80
84
90
40
45
42
40
50
35
40
25
30
50
50
50
40
40
40
600
500
600
400
700
500
600
500
600
600
500
500
500
400
500
a) In HCl/MeOH solution [19]. b) In the solid phase with an excess of ZnCl2. c) Isolated yields. d) Literature
values [8].
color change was observed. The yields increased greatly with respect to the classical
method [5 9], as shown in a comparative study (Table 1).
As substrates, substituted phenols with different electron-releasing and electron-
withdrawing groups were subjected to the coupling, as well as phenols that showed
biological activity to some extent. With regard to the data in Table 1, the isolated yields
cannot be rationalized simply on the basis of substituent effects, since compounds with
higher dipole moments generate more heat under microwave irradiation (−microwave
effect×) [10].
One remarkable advantage of microwave-assisted solid-phase synthesis of phlor-
oglucide analogs is the possibility of introducing acid-sensitive functional groups.
Compounds 2l and 2m, e.g., are derived from eugenol (essential oil of clove [18]) and
would be difficult to prepare by classical methods [19] in which the allyl moiety is
altered. In the literature [19], electrophilic substitutions with eugenol are performed
with a protected allyl group, which otherwise reacts with electrophiles, leading to loss of
biological activity. Under −classical× conditions (HCl/MeOH solution), side reactions
dominate, as shown in Scheme 3.
Scheme 3
OH
OH
OH
OH
MeO
R
MeO
R
MeO
R
MeO
R
H+ / Nu−
+
+
Nu
Nu

Helvetica Chimica Acta Vol. 86 (2003)
2399
The solution-phase syntheses of 2i and 2n were also beset with problems. The
formyl group of 4-hydroxybenzaldehyde is sensitive toward HCl (conc.) in MeOH and
tends to polymerize.
4-Hydroxypyridine used for the preparation of the phloroglucide analog 3 was
deactivated in HCl/MeOH solution (salt formation by protonation), but readily
reacted in the solid phase under microwave irradiation.
Because of technical problems, concentrated HCl cannot be used under microwave
conditions. However, suitable solid Lewis acids can be selected. We compared several
Lewis acids in the solid-phase reaction leading to phloroglucide 2c as a model
compound [8]. The results are summarized in Table 2.
Table 2. Effect of Different Lewis Acid Catalysts in the Microwave-Assisted Solid-Phase Reaction Leading to the
Formation of Compound 2c
Catalyst
Yield [%]
Catalyst
Yield [%]
Catalyst
Yield [%]
TsOH
CuCl2
SnCl2
SnCl4
FeCl3
10
CdCl2
LiBr
MgCl2
NiCl2
MnCl2
22
CoCl3
HgCl2
Zn(OAc)2
ZnBr2
ZnCl2
n.r.a)
10
50
74
90
n.r.a)
20
n.r.a)
n.r.a)
n.r.a)
n.r.a)
10
n.i.b)
a) No reaction observed. b) Product(s) not identified.
Clearly, Zn2‡ salts are especially versatile as Lewis acids in the synthesis of
phloroglucide analogs under microwave irradiation. This may be due to the special
chelating properties of Zn2‡ with the reactants (suitable spatial arrangement, so-called
Symphoria effect [21]). The phloroglucide analogs 2d and 2n are good examples to
demonstrate the special role of Zn2‡. In the case of 2d, there is a higher tendency for
ortho rather than para condensation with respect to solution-phase synthesis (Table 1).
In the condensation of 1a with 4-chloro-3-methylphenol leading to 2n, there are two
nonequivalent ortho positions in the substrate, yet the less-hindered ortho position was
preferred under microwave conditions, as confirmed by 1H-NMR and 13C-NMR
spectroscopy. The observed regioselectivity was rationalized in the case of 2d by means
of consisted-valance-force-field (CVFF) calculations. The most-stable conformer exists
in a cis-syn-syn geometry in front of the metal ion, forming a cavity (half-calix) [22]. We
also used AM1 semi-empirical quantum-mechanic calculations to optimize the
structure of 2a, which also suggested −cavity× formation in the presence of Zn2‡, as
shown in the Figure.
Conclusions. Microwave-assisted syntheses of phloroglucide analogs 2a n and 3
has several advantages over classical solution-phase methods. It reduces the reaction
time and increases the yields considerably, even in the case of phenols that hardly react
in solution. This seems to contradict the classical rule, according to which electrophilic
aromatic substitution of phenols containing electron-withdrawing groups results in
lower yields due to deactivation of the phenolic ring. Also, several acid-sensitive
functional groups remain unchanged in the solid-phase reaction under microwave
irradiation (2f, 2i, 2l, 2m, and 3). As Lewis acid catalysts, Zn2‡ salts seem to be crucial

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Helvetica Chimica Acta Vol. 86 (2003)
Fig. 1. cis-syn-cis Conformer of the Phloroglucide Analog 2a
for the success of the reactions, probably due to their ability to form complexes with the
reactants.
We appreciate financial support of the Shiraz University Research Council. We also thank Sajedian Fard for
recording the NMR spectra.
Experimental Part
General. All chemicals were obtained from Fluka or Merck. Solvents were purified according to reported
methods and stored over molecular sieves. Compounds 1a and 1b were prepared according to [8][15]. TLC:
Silica gel SILG/UV 254 plates. Melting points were recorded on a B¸chi 510 apparatus in open capillary tubes
and are uncorrected. IR spectra were run on a Perkin-Elmer 781 spectrophotometer; in cmÀ1. 1H- and 13C-NMR
Spectra were run on a Bruker Advance DPX-250 spectrometer; d in ppm, J in Hz. Mass spectra were recorded
on a Shimadzu GC MS-QP 1000EX apparatus. Microanalyses were performed on a Perkin-Elmer 240-B
microanalyzer. Microwave oven: MB 245 from Butane Industrial Co.
General Procedure for the Preparation of Phloroglucide Analogs under Microwave Irradiation. In a mortar
containing 2.7 mmol of 1 were added 4 equiv. of substituted phenol, and the mixture was crushed to a
homogeneous mass. Then, ZnCl2 (10 mmol) was added, and crushing was continued for one min. The mixture
was transferred to a test tube and irradiated in the microwave oven for 25 50 s (cf. Table 1). The crude products
were suspended in boiling H2O to dissolve ZnCl2 and unreacted phenols. The mixture was evaporated and
purified as specified.
4-Chloro-2,6-bis[(5-chloro-2-hydroxyphenyl)methyl]phenol (2a). Sublimation at 200 2108, 0.01 Torr, gave
white crystals (1.01 g, 92%). M.p. 232 2348. Rf (CH2Cl2) 0.2. IR (KBr): 3150w, 3010m, 2980m, 1610s, 1220m.
1H-NMR ((D6)DMSO, 250 MHz): 9.7 (br., 2 OH); 8.95 (br., OH); 7.75 6.54 (m, 8 arom. H); 3.88 (s, 2 CH2).
13C-NMR ((D6)DMSO, 62.5 MHz): 154.85; 154.53; 129.60; 128.03; 127.62; 124.26; 123.01; 120.05; 118.02; 114.51;

Helvetica Chimica Acta Vol. 86 (2003)
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15.58 (2 CH2). MS (m/z): 409. Anal. calc. for C20H15Cl3O3: C 58.63, H 3.69, Cl 25.96; found: C 58.60, H 3.73,
Cl 26.03.
4-Bromo-2,6-bis[(5-chloro-2-hydroxyphenyl)methyl]phenol (2b). CC on SiO2 (CHCl3/hexane 1:3) gave
pale yellow crystals (1.10 g, 92%). M.p. 234 2388 (dec.). Rf (CH2Cl2) 0.25. IR (KBr): 3150w, 3050m, 2950m,
1
1600s, 1220m. H-NMR ((D6)DMSO, 250 MHz): 9.84 (br., 2 OH); 8.88 (br., OH); 7.07 6.08 (m, 8 arom. H);
3.81 (s, 2 CH2). 13C-NMR ((D6)DMSO, 62.5 MHz): 154.76; 154.23; 132.28; 129.57; 127.69; 124.03; 123.44;
118.03; 116.22; 112.27; 16.04 (2 CH2). MS (m/z): 454. Anal. calc. for C20H15BrCl2O3: C 52.89, H 3.33, Br 17.59,
Cl 15.61; found: C 52.83, H 3.32, Br 17.61, Cl 15.59.
4-Chloro-2,6-bis[(5-bromo-2-hydroxyphenyl)methyl]phenol (2c). Recrystallization from benzene (15 ml)
or CH2Cl2 (20 ml) gave white crystals (1.2 g, 90%). M.p. >2508. Rf (CH2Cl2) 0.23. IR (KBr): 3150w, 3020m,
2990m, 1600s, 1220m. 1H-NMR ((D6)DMSO, 250 MHz): 9.91 (br., 2 OH); 8.78 (br., OH); 7.34 6.69
(m, 8 arom. H); 3.81 (s, 2 CH2). 13C-NMR ((D6)DMSO, 62.5 MHz): 155.32; 152.09; 131.75; 131.40; 128.14;
124.55; 122.93; 122.43; 118.01; 100.66; 15.06 (2 CH2); MS (m/z): 498. Anal. calc. for C20H15Br2ClO3: C 48.18,
H 3.03, Br 32.05, Cl 7.11; found: C 48.20, H 3.05, Br 32.00, Cl 7.09.
4-Chloro-2,6-bis[(2-hydroxyphenyl)methyl]phenol (2d). CC on SiO2 (AcOEt/hexane 1:3) gave white
crystals (0.67 g, 73%). M.p. 180 1828. Rf (CH2Cl2) 0.28. IR (KBr): 3300w, 3010m, 2900m, 1600s, 1200m.
1H-NMR ((D6)DMSO, 250 MHz): 9.53 (s, 2 OH); 8.88 (s, OH); 7.33 6.65 (m, 10 arom. H); 3.84 (s, 2 CH2).
13C-NMR ((D6)DMSO, 62.5 MHz): 155.34; 153.01; 133.44; 128.34; 127.80; 124.52; 121.02; 120.32; 119.23; 115.42;
16.02 (2 CH2). MS (m/z): 340. Anal. calc. for C20H17ClO3: C 70.49, H 5.03, Cl 10.40; found: C 70.52, H 5.05,
Cl 10.37.
4-Bromo-2,6-bis[(5-bromo-2-hydroxyphenyl)methyl]phenol (2e). CC on SiO2 (CHCl3/hexane 1:3) gave
yellow crystals (1 g, 86%). M.p. 235 2368. Rf (CH2Cl2) 0.27. IR (KBr): 3200w, 3010m, 2950m, 1600s, 1250m.
1H-NMR ((D6)DMSO, 250 MHz): 9.76 8.28 (br., 3 OH); 7.30 6.72 (m, 8 arom. H); 3.81 (s, 2 CH2). 13C-NMR
((D6)DMSO, 62.5 MHz): 154.74; 153.02; 132.02; 131.98; 131.33; 124.52; 120.18; 117.41; 113.48; 100.72; 14.09
( 2 CH). MS (m/z): 543. Anal. calc. for C20H15Br3O3: C 44.23, H 2.78, Br 44.14; found: C 44.21, H 2.76, Br 44.16.
2
4-Chloro-2,6-bis[(3,5-dichloro-2-hydroxyphenyl)methyl])phenol (2f). CC on SiO2 (CH2Cl2) gave white
pungent crystals (1.17 g, 95%). M.p. 156 1608. Rf (CH2Cl2) 0.33. IR (KBr): 3350w, 3100w, 2920m, 1490s, 1590m,
1180s, 1230m, 850s. 1H-NMR ((D6)DMSO, 250 MHz): 10.52 9.73 (br., 3 OH); 7.42 6.92 (m, 6 arom. H); 3.97
(s, 2 CH2). 13C-NMR ((D6)DMSO, 62.5 MHz): 157.32; 150.21; 136.02; 129.23; 128.31; 127.66; 124.85; 124.23;
120.91; 116.32; 15.61 (2 CH2). MS (m/z): 478. Anal. calc. for C20H13Cl5O3: C 50.19, H 2.74, Cl 37.04; found:
C 50.16, H 2.78, Cl 37.05.
4-Chloro-2,6-bis[(2-hydroxy-5-methylphenyl)methyl]phenol (2g). Recrystallization from hexane (20 ml)
gave white crystals (0.86 g, 85%). M.p. 136 1408. Rf (CH2Cl2) 0.45. IR (KBr): 3200w, 3020m, 2920m, 2880m,
1600m, 1450m, 1210s, 810s. 1H-NMR ((D6)DMSO, 250 MHz): 9.38 (s, 2 OH); 9.06 (s, OH); 7.04 6.41
(m, 8 arom. H); 4.02 (s, 2 CH2); 2.15 (s, 2 Me). 13C-NMR ((D6)DMSO, 62.5 MHz): 155.02; 153.61; 133.61;
128.33; 127.70; 127.61; 123.61; 118.58; 114.31; 113.62; 31.48 (2 CH2); 20.07 (2 Me). MS (m/z): 368. Anal. calc. for
C22H21ClO3: C 71.64, H 5.74, Cl 9.61; found: C 71.62, H 5.79, Cl 9.59.
4-Chloro-2,6-bis[(2-hydroxy-5-nitrophenyl)methyl]phenol (2h). CC on SiO2 (CHCl3) gave yellow-orange
needles (1.12 g, 96%). M.p. 220 2258 (dec.). Rf (CH2Cl2) 0.15. IR (KBr): 3400w, 3090m, 2920m, 1630s, 1590s,
1500s, 1300s, 1250s, 1300m, 1080m. 1H-NMR ((D6)DMSO, 250 MHz): 11.15 (br., 2 OH); 8.86 (br., OH); 8.77
6.67 (m, 8 arom. H); 3.86 (s, 2 CH2). 13C-NMR ((D6)DMSO, 62.5 MHz): 161.56; 151.02; 140.91; 130.21; 129.61;
125.32; 123.40; 122.81; 117.21; 112.36; 17.65 (2 CH2). MS (m/z): 430. Anal. calc. for C20H15ClN2O7: C 55.76,
H 3.51, Cl 8.23, N 6.50; found: C 55.80, H 3.46, Cl 8.22, N 6.52.
4-Chloro-2,6-bis[(5-formyl-2-hydroxyphenyl)methyl]phenol (2i). CC on SiO2 (CHCl3) gave yellow crystals
(0.8 g, 75%). M.p. 200 2058. Rf (CH2Cl2) 0.1. IR (KBr): 3200w, 3020w, 2950w, 2850m, 2750m, 1690s, 1600s,
1210m. 1H-NMR ((D6)DMSO, 250 MHz): 10.59 8.07 (br., 3 OH); 9.86 (s, 2 CHO); 7.87 6.65 (m, 8 arom. H);
3.90 (s, 2 CH2). 13C-NMR ((D6)DMSO, 62.5 MHz): 196.63 (2 CHO); 156.22; 154.23; 132.61; 132.57; 128.01;
123.11; 118.32; 116.64; 114.62; 112.36; 18.62 (2 CH2). MS (m/z): 396. Anal. calc. for C22H17ClO5: C 66.59, H 4.32,
Cl 8.93; found: C 66.53, H 4.36, Cl 8.90.
4-Chloro-2,6-bis[(2,5-dihydroxyphenyl)methyl]phenol (2j). Recrystallization from MeOH/H2O 1:5 gave
light-brown crystals (0.94 g, 93%). M.p. 178 1808 (dec.). Rf (CH2Cl2) 0.05. IR (KBr): 3200w, 3020m, 2990m,
1
1600s, 1610s, 1500s, 1450m, 1250m, 850s. H-NMR ((D6)DMSO, 250 MHz): 8.93 8.62 (br., 5 OH); 6.79 6.32
(m, 8 arom. H); 3.76 (s, 2 CH2). 13C-NMR ((D6)DMSO, 62.5 MHz): 156.23; 150.56; 150.31; 132.01; 128.36;
125.91; 123.91; 116.36; 116.21; 114.61; 15.73 (2 CH2). MS (m/z): 372. Anal. calc. for C20H17ClO5: C 64.44, H 4.60,
Cl 9.51; found: C 64.44, H 4.65, Cl 9.48.

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Helvetica Chimica Acta Vol. 86 (2003)
4-Chloro-2,6-bis[(4-hydroxy-1,1'-biphenyl-3-yl)methyl]phenol (2k). CC on SiO2 (AcOEt/hexane 1 :5) gave
white crystals (1.1 g, 82%). M.p. 143 1458. Rf (CH2Cl2) 0.64. IR (KBr): 3200w, 3030m, 2910m, 1610s, 1600s,
1520s, 1490m, 1220s, 820s. 1H-NMR ((D6)DMSO, 250 MHz): 9.79 (s, 2 OH); 8.82 (s, OH); 7.59 6.84
(m, 18 arom. H); 3.91 (s, 2 CH2). 13C-NMR ((D6)DMSO, 62.5MHz): 158.62; 154.32; 149.21; 135.39; 134.01;
133.62; 128.71; 128.31, 125.60; 123.31; 120.45; 117.61; 116.62; 114.35; 31.41 (2 CH2). MS (m/z): 492. Anal. calc.
for C32H25ClO3: C 77.96, H 5.11, Cl 7.19; found: C 78.02, H 5.08, Cl 7.22.
4-Chloro-2,6-bis{[2-hydroxy-3-methoxy-5-(prop-2-en-1-yl)phenyl]methyl}phenol (2l). CC on SiO2
(AcOEt/hexane 1:3) gave light-yellow crystals (1.1 g, 85%). M.p. 54 568. Rf (CHCl3) 0.66. IR (KBr): 3450w,
3090m, 2950m, 2985m, 1600m, 1510m, 1450m, 1410m, 1210w, 1200s. 1H-NMR (CDCl3, 250 MHz): 7.49 6.54
(m, 6 arom. H); 5.70 (m, 2 H, ˆC(H)ÀC); 5.16 (br., 3 OH); 4.81 (dd, J ˆ 10.3, 16.5, 2 H2CˆC); 3.67 (s, MeO);
3.61 (s, 2 CH2); 3.11 (d, J ˆ 6.6, 2 CH2). 13C-NMR ((D6)DMSO, 62.5 MHz): 156.37; 143.02; 141.69; 138.81;
134.01; 128.65; 125.81; 122.67; 124.61; 117.52; 115.36; 111.36; 56.34 (MeO); 40.01 (2 CH2); 30.02 (2 CH2). MS
(m/z): 480. Anal. calc. for C28H29ClO5: C 69.92, H 6.08, Cl 7.37; found: C 69.96, H 6.12, Cl 7.40.
4-Bromo-2,6-bis{[2-hydroxy-3-methoxy-5-(prop-2-en-1-yl)phenyl]methyl}phenol (2m). CC on SiO2
(AcOEt/hexane 1 :3) gave light-brown crystals (0.92 g, 80%); M.p. 58 608. Rf (CHCl3) 0.67. IR (KBr):
3450w, 3090m, 2950m, 2985m, 1600m, 1520m, 1430s, 1420m, 1200w. 1H-NMR (CDCl3, 250 MHz): 7.28 6.46
(m, 6 arom. H); 5.90 (m, 2 ˆC(H)ÀC); 5.10 (br., 3 OH); 4.97 (dd, J ˆ 10.3, 16.8, 2 H2CˆC); 43.8 (s, 2 MeO);
3.84 (s, 2 CH2); 3.34 (d, J ˆ 6.3, 4 H, 2 CH2). 13C-NMR ((D6)DMSO, 62.5 MHz): 154.33; 143.19; 142.21; 138.23;
134.51; 128.68; 125.75; 124.33; 122.63; 117.65; 115.33; 111.39; 56.41 (MeO); 40.32 (2 CH2; 29.63 (2 CH2). MS (m/
z): 525. Anal. calc. for C28H29BrO5: C 64.00, H 5.56, Br 15.21; found: C 64.05, H 5.58, Br 15.19.
4-Chloro-2,6-bis[(5-chloro-2-hydroxy-4-methylphenyl)methyl]phenol (2n). CC on SiO2 (AcOEt/hexane
1:3) gave white crystals (0.99 g, 84%). M.p. 178 1808. Rf (CH2Cl2) 0.66. IR (KBr): 3350w, 3100m, 2950m,
1650m, 1620m, 1460s, 1225m, 1170m. 1H-NMR ((D6)DMSO, 250 MHz): 9.75 (br., 2 OH); 8.88 (br., OH); 7.19
6.27 (m, 6 arom. H); 3.89 (s, 2 CH2); 2.12 (s, 2 Me). 13C-NMR ((D6)DMSO, 62.5 MHz): 154.61; 153.22; 136.32;
130.81; 128.46; 126.21; 124.61; 120.01; 116.32; 112.22; 31.21 (2 CH2), 20.06 (2 Me). MS (m/z): 437. Anal. calc. for
C22H19Cl3O3: C 60.36, H 4.37, Cl 24.30; found: C 60.40, H 4.41, Cl 24.27.
4-Chloro-2,6-bis[(4-hydroxypyridin-3-yl)methyl]phenol (3). Recrystallization from MeOH (20 ml) afford-
ed orange crystals (0.83 g, 90%). M.p. >2708. Rf (CH2Cl2) 0.07. IR (KBr): 3200w, 3030m, 2910m, 1650s, 1550s,
1220m. 1H-NMR ((D6)DMSO, 250 MHz): 9.91 (br., 2 OH); 8.78 (br., OH); 7.34 6.69 (m, 8 arom. H); 3.89
(s, 2 CH2). 13C-NMR ((D6)DMSO, 62.5 MHz): 156.96; 156.35; 150.01; 147.02; 132.61; 126.02; 123.92; 122.02;
114.54; 29.36 (2 CH2). MS (m/z): 342. Anal. calc. for C18H15ClN2O3: C 63.07, H 4.41, Cl 10.34, N 8.17; found:
C 63.08, H 4.36, Cl 10.35, N 8.13.
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Received January 8, 2003