Reactions of resorcinols with ketones

Full text of DOI:10.1070/MC2003v013n04ABEH001687

, 2003, 13(4), 194–197
Reactions of resorcinols with ketones
Sergei I. Filimonov,*a Nikolai G. Savinskyb and Elena M. Evstigneevac
a Yaroslavl State Pedagogical University, 150000 Yaroslavl, Russian Federation. E-mail: filim@nordnet.ru
b Yaroslavl Institute of Microelectronics, Russian Academy of Sciences, 150007 Yaroslavl, Russian Federation
c M. V. Lomonosov Moscow State Academy of Fine Chemical Technology, 117571 Moscow, Russian Federation
10.1070/MC2003v013n04ABEH001687
New products of the condensation of resorcinols with ketones under conditions of mild acid catalysis were studied.
The synthesis of chromans and flavans based on the interaction
of di- and trihydroxybenzenes with ketones is of considerable
interest.1,2 Thus, Livant et al.3 studied in detail only the con-
densation products of acetone and resorcinol. The aim of this
work was to study in detail the concentration of various ketones
(acetone, cyclopentanone, and substituted cyclohexanones) with
substituted resorcinols (4-chloro, 2-methyl, monomethyl ether
and pyrogallol) under conditions of mild acid catalysis.
The condensation of ketones with resorcinols under condi-
tions of acid catalysis is a complex multicomponent process,
which includes aldol condensation, crotonization and electro-
philic alkylation of polyphenol. It can result in the formation of
the following products: chromans 3, bisphenols 4, spirobichro-
mans 5, and highly condensed compounds (Schemes 1 and 2).
cyclohexanone reacted with resorcinol, 4-chlororesorcinol,
2-methylresorcinol, 3-methoxyphenol and pyrogallol with the
formation of corresponding compounds 3a–r† (Schemes 1 and 2).
The yields of resulting compounds were no higher than 30–60%
except for compound 3a obtained in 90% yield. The initial
components and highly condensed compounds (oligomers) were
the main impurities. As a rule, our attempts to improve the yield
by increasing reaction time or temperature resulted in an increase
in the oligomer content of the reaction mixture; because of this,
the main product is difficult to isolate. The pure (> 95%) con-
densation products are difficult to separate even by chromato-
graphy because chroman derivatives are prone to form inclusion
compounds3 (for example, with diethyl ether, up to 20 mol%).
Therefore, it is more convenient to analyse them in an acylated
form.
X
OH
OH
X
HO
X
R2
R
O
∆
2
2
R1
O
Y
O
(CH2)n
OH
X
R2
X
Y
OH
(CH2)n
R
1a,c,e
2a
3a,b
∆
2
2
R
(CH2)n
OH
a X = R2 = H
c
a X = H
b X = Cl
R1
OH
O
X = Cl, R2 = H
X = H, R2 = OH
R1
X
R2
1a e
–
2b f
–
e
R2
HO
OH
O
HO
OH HO
OH
Y
O
OH
3c–r
HO
1: a Y = OH, X = R1 = R2 = H
b Y = OMe, X = R1 = R2 = H
c Y = OH, X = Cl, R1 = R2 = H
d Y = OH, X = R1 = H, R2 = Me
e Y = OH, X = R1 = H, R2 = OH
2: b n = 1, R = H
c n = 2, R = H
d n = 2, R = Me
e n = 2, R = But
f n = 2, R = Ph
4
5
Scheme 1
General reaction conditions were determined based on the
studies of the condensation products of acetone and resorcinol.
Sulfuric, hydrochloric and toluenesulfonic acids, which are most
frequently used for the synthesis of bisphenols, were tested as
catalysts. The analysis of reaction mixtures demonstrated that
chroman 3 was predominant in all cases; spirobichroman 5 was
formed in considerable amounts (20%) only in the catalysis
with sulfuric acid. A bisphenol derivative was not isolated. The
catalyst concentration strongly affected the formation of highly
condensed compounds, and it should be minimum; 0.1–0.3 M
per mole of a ketone is sufficient. The solvent plays only an
important role; thus, the yield of chroman increased and the
reaction time shortened in the order methanol, toluene and
chloroform. We found that an optimum temperature for aldol
condensation is no higher than 40 °C at the beginning of the
synthesis and 60–70 °C at the final stage (condensation pro-
cesses).
3: c Y = OH, X = R = R1 = R2 = H, n = 1
d Y = OMe, X = R = R1 = R2 = H, n = 1
e Y = OH, X = Cl, R = R1 = R2 = H, n = 1
f Y = OH, X = R = R1 = H, R2 = Me, n = 1
g Y = OH, X = R = R1 = R2 = H, n = 2
h Y = OMe, X = R = R1 = R2 = H, n = 2
i Y = OH, X = Cl, R = R1 = R2 = H, n = 2
j Y = OH, X = R = R1 = H, R2 = Me, n = 2
k Y = OH, X = R = R1 = H, R2 = OH, n = 2
l Y = OH, X = Cl, R = Me, R1 = R2 = H, n = 2
m Y = OMe, X = R1 = R2 = H, R = Me, n = 2
n Y = OH, X = R1 = H, R = Me, R2 = OH, n = 2
o Y = OH, X = R1 = R2 = H, R = But, n = 2
p Y = OMe, X = R1 = R2 = H, R = But, n = 2
q Y = OH, X = R1 = R2 = H, R = Ph, n = 2
r Y = OMe, X = R1 = R2 = H, R = Ph, n = 2
Scheme 2
In contrast to published data,3 we found no detectable effect
of an excess of resorcinol on the yield of chroman 3. Resorcinol
was always present as an impurity in the reaction products even
at a 1:1 ratio between components. As acetone was replaced
with diacetone alcohol, the product yield noticeably decreased,
whereas with mesityl oxide chroman 3a was not formed. This
fact may be explained by the difficulty of double bond protona-
tion under these conditions.
†
General synthetic procedure. A solution of 10 mmol of ketone 1,
15 mmol of di- or trihydroxybenzene 2 and 1 mmol of p-toluenesulfonic
acid monohydrate in 20–30 ml of chloroform was heated to 40 °C and
stirred for 4–6 h until the formation of a viscous oil. Next, the mixture
was heated to boiling, refluxed for 0.5–3 h and cooled. The formed
precipitate was filtered off. If the product was not crystallised, 30–50 ml
of water were added, and the contents were heated with stirring. Next,
the aqueous layer was separated; the organic layer was evaporated to
dryness, and the residue was crystallised from diethyl ether–hexane.
We found that acetone, cyclopentanone, cyclohexanone,
4-methylcyclohexanone, 4-tert-butylcyclohexanone and 4-phenyl-
– 194 –

, 2003, 13(4), 194–197
The structures of compounds 3 were determined based on
spectroscopic data and the chemical behaviours of chroman
hydroxyl groups in acylation reactions.†,‡ The signals of aliphatic
protons in chromans 3c–r are difficult to attribute accurately
because they appear as a continuous multiplet in the region
2.5–0.8 ppm. The upfield signals (3.5–2.5 ppm) of protons at
C3 and the CH2 group closest to C3 (particularly, for five-
membered rings) can be distinguished. The signal due to C–O
(90–80 ppm) in the 13C NMR spectra is typical of chromans.
The mass spectra of compounds 3 are characterised by the
low-intensity peaks of molecular ions. Scheme 3 illustrates
the main direction of molecular fragmentation (the most intense
signals) under electron ionisation using compound 3i as an
†
1H NMR spectra of the test compounds were recorded on a Bruker
DPX 300 spectrometer at 300 MHz using 3–5% solutions in [2H6]DMSO.
The chemical shifts of protons were measured with reference to an
internal standard of HMDS (0.055 ppm).
Mass spectra were measured on an MX-1321 mass spectrometer with
direct sample injection at 100–150 °C with an ionisation energy of 70 eV.
Reversed-phase high-performance liquid chromatography was performed
on a Perkin-Elmer instrument (mobile phase: acetonitrile–water, 70:30;
stationary phase: C-18).
3k: yield 49%, mp 205–206 °C, M+ 412. 1H NMR, d: 8.82 (s, 1H,
OH), 8.45 (s, 1H, OH), 8.18 (s, 1H, OH), 8.12 (s, 1H, OH), 7.75 (s, 1H,
OH), 6.39 (d, 1H, 6'-H, J 8.8 Hz), 6.24 (d, 1H, 5-H, J 8.8 Hz), 6.18 (d,
1H, 6-H, J 8.8 Hz), 6.02 (d, 1H, 5'-H, J 8.8 Hz), 3.21 (d, 1H, 3-H,
J 13.9 Hz), 2.49 (d, 1H, CH2, J 13.9 Hz), 0.6–1.8 (m, 16H, CH2).
3l: yield 20%, mp 158–160 °C (inclusion compound with diethyl
‡
3a: yield 87%; mp 223–224 °C. 1H NMR, d: 9.31 (s, 1H, OH), 9.07 (s,
1H, OH), 8.98 (s, 1H, OH), 6.97 (d, 1H, 6'-H, J 8.5 Hz), 6.82 (d, 1H,
5-H, J 8.5 Hz), 6.25 (m, 3H), 6.02 (dd, 1H, 5-H', J 8.5 Hz, J 2.3 Hz),
2.90 (d, 1H, 3-He, J 13.9 Hz), 1.64 (d, 1H, 3-Ha, J 13.9 Hz), 1.54 (s, 3H,
4-Me), 1.17 (s, 3H, 4-Me), 0.63 (s, 3H, 2-Me).
3b: yield 61%, mp 131–132 °C, M+ 369.24. 1H NMR, d: 9.82 (s, 1H,
OH), 9.69 (s, 1H, OH), 9.64 (s, 1H, OH), 7.12 (s, 1H, 6'-H), 6.9 (s, 1H,
5-H), 6.54 (s, 1H, 8-H), 6.48 (s, 1H, 3'-H), 2.9 (d, 1H, 3-He, J 14.1 Hz),
1.75 (d, 1H, 3-Ha, J 14.1 Hz), 1.58 (s, 3H, 4-Me), 1.17 (s, 3H, 4-Me),
0.73 (s, 3H, 2-Me) (inclusion compound with diethyl ether).
1
ether). H NMR (C3D5OD) d: 8.84 (s, 1H, OH), 8.57 (s, 1H, OH), 8.37
(s, 1H, OH), 7.17 (s, 1H, 6'-H), 7.01 (s, 1H, 8-H), 6.64 (s, 1H, 6'-H),
6.53 (s, 1H, 3'-H), 2.63 (ddd, 1H, 3-H, J 4.3 Hz, J 13.1 Hz, J 13.5 Hz),
1.85–0.85 (m, 16H, CH2), 0.93 (d, 9H, 4-Me, J 6.4 Hz), 0.90 (d, 9H,
4-Me, J 6.4 Hz). 13C NMR (C3D5OD) d: 154.05 (C-9), 153.95 (C-2'),
152.87 (C-7'), 152.54 (C-4'), 128.86 (C-10), 128.74 (C-8), 128.02 (C-3'),
124.93 (C-5), 124.52 (C-6'), 108.40 (C-1'), 105.93 (C-5'), 104.90 (C-6),
82.24 (C-2), 40.57 (C-3), 38.87 (C-4), 36.37 (CH2), 35.00 (CH2), 34.71
(CH2), 34.54 (CH2), 33.30 (CH2), 32.75 (CH2), 31.72 (CH2), 28.34
(CH2), 23.27 (CH2), 23.07 (Me), 15.67 (Me).
3c: yield 27%; mp 193–194 °C. 1H NMR, d: 8.88 (s, 1H, OH), 8.61 (s,
1H, OH), 8.56 (s, 1H, OH), 6.92 (d, 1H, 6'-H, J 8.5 Hz), 6.83 (d, 1H,
H-5, J 8.5 Hz), 6.25 (m, 3H), 6.05 (dd, 1H, 5'-H, J 8.5 Hz, J 2.5 Hz),
3.12 (dd, 1H, 3-H, J 14.1 Hz, J 6.5 Hz), 2.58 (d, 1H, J 14.1 Hz, J 3.8 Hz),
1.8–0.8 (m, 13H, CH2). MS, m/z: M+ 352 (29), 309 (4), 295 (8), 281 (3),
242 (4), 213 (8), 201 (7), 187 (4), 177 (100), 176 (69), 161 (17), 147
(21), 123 (23), 115 (6), 91 (5), 77 (4), 41 (3), 28 (9).
1
3m: yield 20%, mp 140–142 °C. H NMR, d: 9.58 (s, 1H, OH), 7.03
(d, 1H, 6'-H, J 8.5 Hz), 6.85 (d, 1H, 5-H, J 8.5 Hz), 6.48 (d, 1H, 8-H,
J 2.5 Hz), 6.39 (dd, 1H, 6-H, J 8.5 Hz, J 2.5 Hz), 6.31 (d, 1H, 3'-H,
J 2.5 Hz), 6.16 (dd, 1H, 5'-H, J 8.5 Hz, J 2.5 Hz), 3.73 (s, 3H, OMe),
3.58 (s, 3H, OMe), 1.85–0.85 (m, 17H, CH2), 0.82 (d, 3H, 4-Me, J
6.5 Hz), 0.80 (d, 3H, 4-Me, J 6.5 Hz).
1
3d: yield 24%, mp 150–152 °C. H NMR, d: 9.12 (s, 1H, OH), 7.06
(d, 1H, 6'-H, J 8.6 Hz), 7.01 (d, 1H, 5-H, J 8.6 Hz), 6.52 (dd, 1H, 6-H,
J 2.6 Hz, J 8.6 Hz), 6.50 (d, 1H, 8-H, J 2.6 Hz), 6.39 (dd, 1H, 5'-H,
J 8.6 Hz, J 2.6 Hz), 6.35 (d, 1H, 3'-H, J 2.6 Hz), 3.76 (s, 3H, OMe),
3.74 (s, 3H, OMe), 2.84 (dd, 1H, 3-H, J 9.3 Hz, J 9.2 Hz), 2.27 (ddd,
1H, 1''-H, J 13.6 Hz, J 6.8 Hz, J 6.8 Hz), 2.2–1.15 (m, 13H, CH2).
13C NMR (CDCl3) d: 158.83 (C-9), 158.04 (C-4'), 155.01 (C-7), 151.33
(C-2'), 126.38 (C-10), 126.31 (C-5), 122.94 (C-6'), 121.62 (C-1'),
106.95 (C-5'), 104.95 (C-6), 101.52 (C-3'), 101.47 (C-8), 92.55 (C-2),
54.39 (OMe), 54.26 (OMe), 51.70 (C-4), 45.06 (C-3), 43.48 (C-11),
39.28 (C-14), 36.03 (C-17), 28.00 (C-12), 23.30 (C-16), 22.86 (C-17),
21.42 (C-13). MS, m/z: M+ 380, 366, 337, 323, 257, 227, 215, 191, 175,
161, 159, 137, 115, 103, 91, 77, 28.
3n: yield 39%, mp 138–140 °C, M+ 440. 1H NMR, d: 8.50 (s, 3H,
OH), 7.82 (s, 2H, OH), 6.49 (d, 1H, 6'-H, J 8.6 Hz), 6.29 (d, 1H, 5-H,
J 8.6 Hz), 6.28 (d, 1H, 6-H, J 8.6 Hz), 6.07 (d, 1H, 5'-H, J 8.6 Hz), 3.22
(dd, 1H, 3-H, J 14.1 Hz, J 6.1 Hz), 2.53 (dd, 1H, CH2, J 14.1 Hz,
J 6.1 Hz), 1.1–1.9 (m, 12H, CH2), 1.1 (m, 2H), 0.97 (d, 3H, Me, J
6.8 Hz), 0.88 (d, 3H, Me, J 6.8 Hz), 0.75 (m, 2H).
1
3o: yield 43%, mp 188–190 °C. H NMR (C3D5OD) d: 8.76 (s, 1H,
OH), 8.56 (s, 1H, OH), 8.38 (s, 1H, OH), 7.43 (s, 1H, 6'-H), 7.12 (s, 1H,
5-H), 6.70 (s, 1H, 8-H), 6.51 (s, 1H, 3'-H), 2.89 (dd, 1H, 3-H, J 4.1 Hz,
J 12.3 Hz), 2.40 (ddd, 1H, CH2, J 4.3 Hz, J 13.5 Hz, J 13.6 Hz), 2.0–0.9
(m, 15H, CH2), 0.86 (s, 9H, But), 0.83 (s, 9H, But). 13C NMR (C3D5OD)
d: 153.75 (C-9), 53.40 (C-7), 152.86 (C-4'), 152.66 (C-2'), 130.39
(C-10), 129.10 (C-5), 127,52 (C-6'), 124.45 (C-1'), 112.06 (C-6), 111.80
(C-5'), 105.99 (C-8), 105.29 (C-3'), 80.25 (C-O), 48.37 (C-4), 47.17
(C-3), 40.21 (CH2), 39.79 (CH2), 37.63 (CH2), 37.25 (CH2), 33.16 (CH2),
33.03 (CH2), 27.89 (CBut), 27.76 (CBut), 26.69 (CH2), 26.48 (CH2),
23.48 (CH2), 22.93 (Me), 15.66 (Me).
1
3e: yield 21%, mp 185–187 °C, M+ 421.32. H NMR, d: 9.35 (s, 1H,
OH), 9.25 (s, 2H, OH), 6.95 (s, 1H, H-6'), 6.94 (s, 1H, 5-H), 6.52 (s, 1H,
8-H), 6.49 (s, 1H, 3'-H), 3.35 (dd, 1H, 3-H, J 11.0 Hz, J 7.9 Hz), 3.18 (d,
1H, H-11, J 12.8 Hz, J 9.1 Hz), 1.8–0.8 (m, 13H, CH2).
1
3f: yield 31%, mp 213–215 °C, M+ 380.49. H NMR, d: 8.48 (s, 1H,
OH), 8.45 (s, 1H, OH), 8.09 (s, 1H, OH), 6.73 (d, 1H, 6'-H, J 8.5 Hz),
6.67 (d, 1H, 5-H, J 8.5 Hz), 6.32 (d, 1H, 6-H, J 8.5 Hz), 6.20 (d, 1H,
5'-H, J 8.5 Hz), 3.16 (dd, 1H, 3-H, J 14.1 Hz, J 6.5 Hz), 2.61 (d, 1H,
CH2, J 14.1 Hz, J 3.8 Hz), 2.13 (s, 3H, Me), 2.01 (s, 3H, Me), 1.8–0.8
(m, 13H, CH2).
1
3p: yield 43%, mp 148–150 °C. H NMR, d: 9.28 (s, 1H, OH), 7.28
(d, 1H, 6'-H, J 8.5 Hz), 7.04 (d, 1H, 5-H, J 8.5 Hz), 6.53 (d, 1H, 8-H,
J 2.5 Hz), 6.42 (dd, 1H, 6-H, J 8.5 Hz, J 2.5 Hz), 6.35 (d, 1H, 3'-H,
J 2.5 Hz), 6.24 (dd, 1H, 5'-H, J 8.5 Hz, J 2.5 Hz), 3.76 (s, 3H, OMe),
3.65 (s, 3H, OMe), 2.83 (dd, 1H, CH2, J 12.8 Hz, J 4.8 Hz), 2.36 (ddd,
1H, J 12.5 Hz, J 12.1 Hz, J 3.8 Hz), 1.85–0.85 (m, 15H, CH2), 0.82 (s,
9H, But), 0.80 (s, 9H, But).
1
3g: yield 55%, mp 233–234 °C. H NMR, d: 9.23 (s, 1H, OH), 8.95
(s, 1H, OH), 8.83 (s, 1H, OH), 6.92 (d, 1H, 6'-H, J 8.5 Hz), 6.75 (d, 1H,
5-H, J 8.5 Hz), 6.29 (d, 1H, 8-H, J 2.5 Hz), 6.25 (dd, 1H, 6-H, J 8.5 Hz,
J 2.5 Hz), 6.23 (d, 1H, 3'-H, J 2.5 Hz), 5.98 (dd, 1H, 5'-H, J 8.5 Hz,
J 2.5 Hz), 3.28 (dd, 1H, 3-H, J 14.0 Hz, J 3.5 Hz), 2.55 (ddd, 1H, CH2),
J 14.0 Hz, J 6.8 Hz, J 3.8 Hz), 1.8–0.8 (m, 17H, CH2).
3q: yield 34%, mp 175–176 °C. 1H NMR, d: 8.66 (s, 1H, OH), 8.15 (s,
1H, OH), 8.07 (s, 1H, OH), 7.35–7.1 (m, 10H, 2Ph), 7.10 (d, 1H, 6'-H,
J 8.5 Hz), 7.02 (d, 1H, 5-H, J 8.5 Hz), 6.54 (d, 1H, 8-H, J 2.5 Hz), 6.41
(dd, 1H, 6-H, J 2.5 Hz, J 8.5 Hz), 6.36 (d, 1H, 3'-H, J 2.5 Hz), 6.18 (dd,
1H, 5'-H, J 2.5 Hz, J 8.5 Hz), 3.73 (dd, 1H, 3-H, J 12.3 Hz, J 4.0 Hz),
2.89 (m, 4H, CH2), 2.59 (br. s, 1H), 2.2–1.1 (m, 11H, CH2). MS, m/z:
M+ 532, 506, 421, 413, 385, 381, 331, 303, 281, 268, 267, 251, 199, 173,
162, 147, 123, 104, 91, 77, 51, 27.
1
3h: yield 53%, mp 160–162 °C, M+ 408.5. H NMR, d: 9.52 (s, 1H,
OH), 7.05 (d, 1H, 6'-H, J 8.5 Hz), 6.89 (d, 1H, 5-H, J 8.5 Hz), 6.50 (d,
1H, 8-H, J 2.5 Hz), 6.42 (dd, 1H, 6-H, J 8.5 Hz, J 2.5 Hz), 6.34 (d, 1H,
3'-H, J 2.5 Hz), 6.18 (dd, 1H, 5'-H, J 8.5 Hz, J 2.5 Hz), 3.74 (s, 3H,
OMe), 3.62 (s, 3H, OMe), 3.23 (dd, 1H, 3-H, J 12.8 Hz, J 4.8 Hz), 2.53
(ddd, 1H, CH2, J 12.8 Hz, J 12.5 Hz, J 4.8 Hz), 1.8–0.8 (m, 17H, CH2).
3i: yield 43%, mp 263–265 °C. 1H NMR, d: 9.62 (s, 1H, OH), 9.54 (s,
1H, OH), 9.47 (s, 1H, OH), 7.06 (s, 1H, 6'-H), 6.81 (s, 1H, 5-H), 6.54
(s,1H, 8-H), 6.48 (s, 1H, 3'-H), 3.23 (dd, 1H, 3-H, J 12.4 Hz, J 4.5 Hz),
3.48 (ddd, 1H, CH2, J 12.4 Hz, J 12.8 Hz, J 4.5 Hz), 1.8–0.8 (m, 17H,
CH2). MS, m/z: M+ 449 (18), 448 (24), 349 (6), 303 (4), 261 (3), 249 (4),
225 (100), 224 (96), 209 (16), 196 (19), 181 (25), 157 (79), 148 (7), 115
(6), 91 (4), 77 (7), 41 (8), 28 (16).
1
3r: yield 43%, mp 142–144 °C, M+ 560.7. H NMR, d: 9.73 (s, 1H,
OH), 7.25 (m, 10H, 2Ph), 6.97 (d, 1H, 6'-H, J 8.5 Hz), 6.85 (d, 1H, 5-H,
J 8.5 Hz), 6.57 (d, 1H, 8-H, J 2.5 Hz), 6.40 (d, 1H, 3'-H, J 2.5 Hz), 6.37
(dd, 1H, 6-H, J 8.5 Hz, J 2.5 Hz), 6.21 (dd, 1H, 5-H, J 8.5 Hz, J 2.5 Hz),
3.70 (s, 3H, OMe), 3.58 (s, 3H, OMe), 3.46 (dd, 1H, 3-H, J 12.8 Hz,
J 4.8 Hz), 2.8 (m, 3H, CH2), 2.1–0.9 (m, 13H, CH2).
4: yield 39%, mp 137–140 °C, M+ 292. 1H NMR, d: 8.35 (s, 2H, OH),
7.7 (s, 2H, OH), 6.83 (s, 2H, OH), 6.49 (d, 2H, H-Ar, J 8.8 Hz), 6.21 (d,
2H, H-Ar, J 8.8 Hz), 1.65 (s, 6H, Me).
1
3j: yield 45%, mp 243–245 °C, M+ 408.54. H NMR, d: 8.63 (s, 1H,
OH), 8.58 (s, 1H, OH), 7.98 (s, 1H, OH), 6.76 (d, 1H, 6'-H, J 8.5 Hz),
6.46 (d, 1H, 5-H, J 8.5 Hz), 6.32 (d, 1H, 6-H, J 8.5 Hz), 6.10 (d, 1H,
5'-H, J 8.5 Hz), 3.32 (dd, 1H, 3-H, J 12.1 Hz, J 3.8 Hz), 2.62 (ddd, 1H,
CH2, J 12.5 Hz, J 12.1 Hz, J 3.8 Hz), 2.12 (s, 3H, Me), 1.97 (s, 3H, Me),
1.8–0.8 (m, 17H, CH2).
1
5: yield 20%, mp 195–196 °C. H NMR, d: 9.0 (s, 2H, OH), 7.14 (d,
2H, 6-H, J 8.4 Hz), 6.37 (dd, 2H, 7-H, J 8.4 Hz, J 2.7 Hz), 5.98 (d, 2H,
8-H, J 2.7 Hz), 2.06 (d, 2H, CH2, J 13.8 Hz), 1.91 (d, 2H, CH2, J
13.8 Hz), 1.48 (s, 3H, Me), 1.26 (s, 3H, Me).
– 195 –

, 2003, 13(4), 194–197
tions. Our attempts to perform the condensation of ketones with
monoacylated and monobenzylated resorcinol were unsuccess-
ful, probably, because of steric and deactivating properties of
these substituents.
OH
Cl
It is beyond the scope of this work to study the structure of
highly condensed products (oligomers). However, it is reason-
able to assume that their constituents are chroman condensation
products because the molecules contained resorcinol units,
which can also enter condensation reactions. Thus, the mass
spectrum of acylated chroman 3c exhibited an impurity with
M+ 762, which can be identified as a bichroman (4-acyl
groups). According to 1H NMR spectroscopic data, the con-
centration of this impurity was about 10%.
HO
O
OH
Cl
OH
m/z 157
Cl
OH
M+ m/z 448
Cl
H
O
O
OH
Cl
HO
Cl
O
OH
O
O
O
H
O
m/z 378
O
O
O
O
m/z 225
O
O
Scheme 3
example. Additional signals due to carbene elimination appear
in the mass spectra of acylated chromans (m/z 42).
An anomalous result was obtained in the reaction of acetone
with pyrogallol: bisphenol 4 was formed. Moreover, ketones with
substituents at the α-position (2-methylcyclohexanone and
α-tetralone) incompletely condensed with resorcinol to form
xanthenes 6a,b as the main products. N-methylpiperidone reacted
with resorcinol to give 4-(4-hydroxy-1-methyl-4-piperidyl)-1,3-
benzdiol 7a as the main product. The condensation of cyclo-
hexen-2-one with chlororesorcinol afforded 3-(5-chloro-2,4-di-
hydroxyphenyl)-1-cyclohexanone 7b.
The structure of compounds 3 assumes the occurrence of
stereoisomers; however, the presence of stereoisomers was not
detected in the isolated products. The methoxy group in com-
pounds 3d,h,m,p,r can occur in either ortho or para positions
with respect to the chroman ring. The fact that these com-
pounds were not acylated with acetic anhydride under mild
conditions suggests that the OH group is at the ortho position
and the OMe group is at the para position to the chroman ring
(the effect of a sterically hindered group, which is better pro-
nounced in compounds 3f,j). The observed downfield shift of
the signal due to the hydroxyl group in compounds 3d,h,p,r,
as compared with the chemical shifts of hydroxyl protons in
unmethylated chroman 3c,g,o,q can be due to the occurrence
of a hydrogen bond. This is indirect evidence for the proposed
structural formula for compounds 3d,h,p,r. The results suggest
the steroselective and regioselective formation of chromans.
Note that 4-chlororesorcinol reacted with ketones much more
slowly than resorcinol, whereas resorcylic acids and resorcyl-
aldehyde almost not reacted with ketones under these condi-
O
OH
O
OH
OH
6a
6a: separated as a yellow oil by chromatography on silica gel; eluent:
ethyl acetate–hexane, 30:70. Yield 20%. 1H NMR, d: cyclic: 9.08 (s, 1H,
OH), 6.86 (d, 1H, 5-H, J 8.8 Hz), 6.21 (d, 1H, 6-H, J 8.8 Hz, J 2.5 Hz),
6.12 (d, 1H, 8-H, J 2.5 Hz), 2.92 (m, 2H, CH2), 1.98 (m, 2H, CH2), 1.8–
1.0 (m, 20H, CH2); acyclic: 8.95 (s, 1H, OH), 8.59 (s, 1H, OH), 6.62
(d, 1H, 5-H, J 8.8 Hz), 6.24 (d, 1H, 8-H, J 2.8 Hz), 6.14 (d, 1H, 6-H,
J 8.8 Hz, J 2.8 Hz), 2.92 (m, 2H, CH2), 1.98 (m, 2H, CH2), 1.8–1.0 (m,
20H, CH2).
6b: mp 138–140 °C, yield 10%, M+ 408. 1H NMR, d: 7.55 (d, 1H,
H-Ar, J 8.8 Hz), 7.50 (d, 1H, H-Ar, J 9.0 Hz), 7.25 (m, 6H, H-Ar), 7.13
(t, 1H, H-Ar), 6.75 (dd, 1H, H-Ar, J 8.8 Hz, J 2.4 Hz), 6.65 (d, 1H,
H-Ar, J 2.4 Hz), 2.85 (m, 2H, CH2), 2.66 (m, 2H, CH2), 2.26 (m, 4H,
CH2 + Ac), 2.0–1.75 (m, 5H, CH2).
HO
O
6b
O
O
O
OH
O
HO
Cl
OH
7a: 4-(4-hydroxy-1-methyl-4-piperidyl)-1,3-benzenediol. 1H NMR, d:
9.08 (s, 1H, OH), 6.98 (d, 1H, H-Ar, J 8.5 Hz), 6.18 (s, 1H, H-Ar), 6.16
(d, 1H, H-Ar, J 8.5 Hz), 3.35 (s, 2H, OH), 2.52 (d, 2H, CH2, J 12.5 Hz),
2.32 (t, 2H, CH2, J 12.5 Hz), 2.28 (s, 3H, N–Me), 2.10 (sex, 2H, CH2,
J 3.5 Hz, J 12.5 Hz), 1.61 (d, 2H, CH2, J 12.5 Hz). MS, m/z: M+ 223
(22), 205 (100), 161 (40), 147 (64), 96 (20), 83 (45), 70 (28), 44 (24), 42
(36), 28 (20).
7b: 5-(acetyloxy)-2-chloro-4-(3-oxocyclohexyl)phenyl acetate. 1H NMR,
d: 7.60 (s, 1H, 3-H), 7.08 (s, 1H, 6-H), 3.18 [m, 1H, 1'-H(C–H)], 2.66
(ddd, 1H, CH2, J 13.3 Hz, J 13.2 Hz, J 1.0 Hz), 2.44 (1H, ddd, CH2,
J 13.3 Hz, J 6.0 Hz, J 1.0 Hz), 2.31 (s, 6H, Ac), 2.28 (m, 2H, CH2),
2.11 (ddd, 1H, CH2, J 13.3 Hz, J 13.2 Hz, J 6.0 Hz), 1.94 (m, 2H, CH2),
1.77 (m, 1H, CH2). 13C NMR (C3D5OD) d: 208.9 (C-3', C=O), 169.67
(Ac), 168.66 (Ac), 148.12 (C-1), 146.49 (C-5), 137.34 (C-4), 129.06
(C-3), 124.9 (C-2), 119.81 (C-6), 47.9 (C-2'), 41.44 (C-4'), 38.38 (C-6'),
32.23 (C-1'), 26.11 (C-5').
O
N
7a
7b
Scheme 4 demonstrates the sequence of reactions leading to
chromans 3. These are (i) aldol condensation of two ketone
molecules, (ii) addition of a resorcinol molecule to the resulting
aldol, (iii) intramolecular condensation to form 2-hydroxy-
chroman, and addition of a second resorcinol molecule to (iv)
2-hydroxychroman or (v) its dehydration product.
The proposed scheme was supported by the condensation
products of 2-methylcyclohexanone and α-tetralone with resor-
cinol: xanthenes 6a,b, which contain only one resorcinol frag-
ment. In the case of 2-methylcyclohexanone, we isolated xanthene
– 196 –

, 2003, 13(4), 194–197
6 and its acyclic precursor, which was formed at step (ii)
(Scheme 2), in a 3:1 ratio from the reaction solution.
OH
Based on the experimental data, we can draw the following
conclusions: (1) The formation of chromans 3 was predominant
in the condensation of ketones with resorcinols bearing donor
substituents under mild acid conditions; the formation of bis-
phenols 4 was an exception. (2) The formation of chromans 3
was stereoselective and regioselective. (3) Ketones that are
prone to self-condensation formed spirochroman 5 under more
severe conditions. (4) Ketones that are not prone to self-con-
densation mainly formed 1:1 alkylation products 7.
O
OH
O
i
ii
OH
iii
References
HO
O
OH
HO
O
OH
1 S. Smolinski, in Chem. Heterocycl. Comp. Ser. Monograph., John
Wiley–Interscience, New York, 1981, vol. 36.
OH
2 J. D. Hepworth, in Comprehensive Heterocycl. Chem., ed. A. R. Katritzky,
Pergamon, Oxford, 1997, vol. 3, pp. 778–787.
3 P. Livant, T. R. Webb and Weizheng Xu, J. Org. Chem., 1997, 62, 737.
iv
OH
OH
OH
v
HO
HO
O
O
OH
OH
Scheme 4
Received: 12th November 2002; Com. 02/2013
– 197 –