Synthesis of new substituted 2,2-bis-(3,5-di-t-butyl-4-hydroxybenzyl) benzocycloalkanones, bromopropiophenones, and their alcohol analogs

Article abstract of DOI:10.3906/kim-1012-878

A new series of substituted 2,2-bis-(3,5-di-t-butyl-4-hydroxybenzyl) benzocycloalkanones, bromopropiophenones, and their alcohol analogs were synthesized. The corresponding alcohols may act as potential allosteric modulators of GABA_B receptors. TUeBITAK.

Full text of DOI:10.3906/kim-1012-878

Turk J Chem
35 (2011) , 543 – 552.
¨
˙
c
ꢀ TUBITAK
doi:10.3906/kim-1012-878
Synthesis of new substituted 2,2-bis-(3,5-di-t-butyl-4-
hydroxybenzyl)benzocycloalkanones,
bromopropiophenones, and their alcohol analogs
Jabbar KHALAFY1,∗, Mehdi RIMAZ1, Sara TAGHINEJHAD1,2
Mirzagha BABAZADEH2
,
1Chemistry Department, Urmia University, P. O. Box 57154, Urmia-IRAN
e-mails: j.khalafi@mail.urmia.ac.ir, jkhalafi@yahoo.com
2Department of Chemistry, Faculty of Science, Tabriz Branch,
Islamic Azad University, Tabriz-IRAN
Received: 18.12.2010
A new series of substituted 2,2-bis-(3,5-di-t-butyl-4-hydroxybenzyl) benzocycloalkanones, bromopropio-
phenones, and their alcohol analogs were synthesized. The corresponding alcohols may act as potential
allosteric modulators of GABAB receptors.
Key Words: Benzocycloalkanone, allosteric modulator, GABAB receptor, propiophenone
Introduction
γ-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the central nervous system.1,2 GABA
is involved in the regulation of a variety of physiological mechanisms3,4 and is implicated in the pathophysiology
of several central nervous system diseases.5 Therefore, a variety of GABA analogs have been investigated,6−8
essentially GABA agonists, GABA antagonists, and GABA uptake inhibitors. Two subclasses of receptors
for GABA have been defined and designated as GABAA and GABAB receptors.9,10 GABAA receptors
are selectively activated by the GABA analog muscimol and blocked by convulsants such as bicuculline or
picrotoxin. A selective agonist for the GABAB receptor is β-p-chlorophenyl-GABA 1 (baclofen, Figure 1).10
Until recently, investigation has concentrated on agonists and antagonists for the GABAA receptor; by contrast,
∗Corresponding author
543

Synthesis of new substituted 2,2-bis-(3,5-di-t-butyl-4-hydroxybenzyl)..., J. KHALAFY, et al.,
few compounds have been studied for the GABAB receptor, and its activities and consequently its structure-
activity relationships have remained practically unknown.11
Cl
H2N
CO2H
1
Figure 1. Structure of baclofen.
Following a random mass screening, Urwyler et al.12 recently reported that 2,6-di-t-butyl-4-(3-hydroxyp-
henyl)-2,2-dimethylpropionaldehyde, CGP 13501, 2 (R1 , R2 = Me), acted as a positive allosteric modulator
for GABAB receptors,13,14 and its reduction product, the corresponding alcohol CGP 7930 3 (R1 , R2 = Me),
regarded as a hybrid of propofol 4 and γ-hydroxybutyric acid (GHB, 5) was found to be even more potent
(Figure 2). Propofol15,16 is a short-acting hypnotic agent (GABAA modulator), effective for induction and
maintenance of anesthesia when administered intravenously either as repeated bolus injections or by continuous
infusion. GHB is best known as a drug of abuse17 and is a GABA analog.
OH
HO
HO
R1
R1
R2
R2
HO
CO2H
CHO
CH2OH
5
3
4
2
Figure 2. Structures of CGP 13501, CGP 7930, propofol, and GHB.
Accordingly, we recently synthesized a series of modifications of structure 3, all of which acted as positive
modulators at GABAB receptors.18,19 The present paper describes the synthesis of new substituted 2,2-bis-
(3,5-di-t-butyl-4-hydroxybenzyl) benzocycloalkanones (6), bromopropiophenones (7), and their alcohol analogs
(8-9) as potential allosteric modulators of GABAB receptors (Figure 3). The basic synthetic approach continues
to be basically that of Urwyler et al.12
Experimental
All solvents used were freshly distilled and dried according to the methods of Perrin and Armarego.20 Melting
points were determined on a Reichert hot-stage microscope. 1 H-NMR (300 MHz) and 13 C-NMR (75.5 MHz)
spectra were recorded on a Bruker 300 spectrometer in deuteriochloroform with tetramethylsilane as the internal
standard. Infrared spectra were recorded on a Thermo Nicolet (Nexus 670) FT-infrared spectrophotometer,
measured as films or KBr disks. Microanalyses were performed on a LECO Analyzer 932.
544

Synthesis of new substituted 2,2-bis-(3,5-di-t-butyl-4-hydroxybenzyl)..., J. KHALAFY, et al.,
Synthesis of 2,6-(di-t-butyl-4-methoxymethyl)phenol (10)
2,6-Di-t-butylphenol 11 (5.2 g, 0.025 mol), 36% formaldehyde (5 mL), and absolute methanol (50 mL) were
dissolved in a 3-necked round-bottom flask, and a solution of potassium hydroxide (2 g) in water (2 mL) was
added under a nitrogen atmosphere. The solution was refluxed for 30 min under an atmosphere of nitrogen,
and it turned deep purple. After the mixture had cooled to room temperature, the precipitate was collected
and washed with cold water. The pale yellow product was recrystallized several times from methanol to yield
colorless crystalline plates (5.01 g), mp 99-100 ◦ C (lit. mp 99.5 ◦ C). 211 H-NMR (CDCl3): δ 1.44 (s, 18H,
t-Bu), 3.40 (s, 3H, CH3), 4.34 (s, 2H, CH2), 5.10 (s, 1H, OH), 7.14 (s, 2H, Ar) ppm. 13 C-NMR (CDCl3): δ
30.21, 34.37, 58.10, 75.54, 125.29, 128.65, 135.84, 153.01 ppm.
OH
Br
O
O
Z
OH
OH
HO
HO
(CH2)n
Y
OH
X
7
6
Br
OH
HO
OH
(CH2)n
Z
Y
OH
X
9
8
Figure 3. Structures of benzocycloalkanones, bromopropiophenones, and their alcohol analogs.
Typical procedure for synthesis of 2,2-bis-(3,5-di-t-butyl-4-hydroxybenzyl) benzo-
cycloalkanones
A solution of 2,6-(di-t-butyl-4-methoxymethyl)phenol 10 (1 g, 4 mmol) and potassium hydroxide (0.04 g) in
methanol (4 mL) was heated to 60 ◦ C. The corresponding benzocycloalkanone (2 mmol) was then added to
the solution over a period of 10 min and the reaction mixture was refluxed for 4 h. The mixture was cooled to
room temperature and poured into 1% acetic acid (10 mL) to solidify. The resulting solids were washed with
water and dried. Recrystallization from n-hexane gave the final products in good yields.
2,2-Bis(3,5-di-t-butyl-4-hydroxybenzyl)-4-chloro-2,3-dihydroinden-1-one (17) Yellow solid, 93%,
mp 224-225 ◦ C. Anal calcd for C39 H51 ClO3 : C 77.65%; H 8.52%. Found: C 77.76%, H 8.60%. 1 H-NMR
(CDCl3): δ 1.34 (s, 36H, 12 × CH3), 2.79 (d, J = 13.5 Hz, 2H, CH2), 3.03 (s, 2H, CH2), 3.24 (d, J = 13.5
Hz, 2H, CH2), 4.95 (s, 2H, 2 × OH), 6.87 (s, 4H, Ar), 7.06 (t, J = 7.8 Hz, 1H, Ar), 7.26 (d, J = 7.5 Hz, 1H,
545

Synthesis of new substituted 2,2-bis-(3,5-di-t-butyl-4-hydroxybenzyl)..., J. KHALAFY, et al.,
Ar), 7.39 (d, J = 7.5, 1H, Ar) ppm. 13 C-NMR (CDCl3): δ 30.17, 34.10, 34.26, 44.19, 56.36, 121.13, 126.39,
127.47, 128.02, 131.85, 133.48, 135.34, 139.34, 150.97, 152.23, 210.55 ppm. FT-IR (KBr): υ 3642, 2954, 2911,
2872, 1712, 1599, 1460, 1435, 1391, 1360, 1318, 1248, 1235, 1213, 1153, 1122, 960, 881, 770, 758 cm−1
.
2,2-Bis(3,5-di-t-butyl-4-hydroxybenzyl)-6-methoxy-2,3-dihydroinden-1-one (18) Yellow solid,
92%, mp 194-195 ◦ C. Anal calcd for C40 H54 O4 : C 80.22%, H 9.09%. Found: C 80.17%, H 9.16%. 1 H-NMR
(CDCl3): δ 1.34 (s, 36H, 12 × CH3), 2.78 (d, J = 13.5 Hz, 2H, CH2), 2.93 (s, 2H, CH2), 3.21 (d, J =
13.5 Hz, 2H, CH2), 3.74 (s, 3H, CH3), 4.95 (s, 2H, 2 × OH), 6.86 (s, 4H, Ar), 6.92-7.00 (m, 3H, Ar) ppm.
13 C-NMR (CDCl3): δ 30.25, 34.10, 34.56, 44.14, 55.42, 56.69, 104.22, 123.42, 126.43, 126.46, 127.95, 135.19,
138.91, 146.50, 152.12, 158.76, 211.30 ppm. FT-IR (KBr): υ 3642, 3551, 2955, 2920, 2873, 1740, 1666, 1501,
1435, 1261, 1256, 1215, 1121, 844 cm−1
.
2,2-Bis(3,5-di-t-butyl-4-hydroxybenzyl)-6-methoxy-3,4-dihydronaphthalen-1(2H)-one (19)
White solid, 81%, mp 214-215 ◦ C. Anal calcd for C41 H56 O4 : C 80.35%, H 9.21%. Found: C 80.45%, H 9.31%.
1 H-NMR (CDCl3): δ 1.39 (s, 36H, 12 × CH3), 1.89 (t, J = 7 Hz, 1H, CH), 2.06 (d, J = 7 Hz, 1H, CH),
2.55 (d, J = 13.5 Hz, 2H, CH2), 2.82 (t, J = 7 Hz, 2H, CH2), 3.28 (d, J = 13.5 Hz, 2H, CH2), 3.82 (s, 3H,
CH3), 5.04 (s, 2H, 2 × OH), 6.58 (d, J = 2.4 Hz, 1H, Ar), 6.80 (dd, J1 = 8.4 Hz, J2 = 1.2 Hz, 1H, Ar), 6.94
(s, 4H, Ar), 8.03 (d, J = 8.7 Hz, 1H, Ar) ppm. 13 C-NMR (CDCl3): δ 25.87, 28.66, 30.25, 34.19, 42.76, 50.80,
55.35, 111.96, 113.15, 125.16, 127.41, 128.29, 130.18, 135.15, 145.81, 152.18, 163.18, 200.65 ppm. FT-IR (KBr):
υ 3642, 3551, 2955, 2920, 2873, 1740, 1666, 1601, 1435, 1261, 1256, 1215, 1121, 844 cm−1
.
2,2-Bis(3,5-di-t-butyl-4-hydroxybenzyl)-7-methoxy-3,4-dihydronaphthalen-1(2H)-one (20)
White solid, 86%, mp 215-217 ◦ C. Anal calcd for C41 H56 O4 : C 80.35%, H 9.21%. Found: C 80.43%, H 9.26%.
1 H-NMR (CDCl3): δ 1.41 (s, 36H, 12 × CH3), 1.91 (t, J = 6 Hz, 2H, CH2), 2.62 (d, J = 13.5 Hz, 2H, CH2),
2.85 (t, J = 6 Hz, 2H, CH2), 3.27 (d, J = 13.5 Hz, 2H, CH2), 3.85 (s, 3H, CH3), 5.06 (s, 2H, 2 × OH), 6.95
(s, 4H, Ar), 6.99-7.08 (m, 2H, Ar), 7.55 (d, J = 2.4 Hz, 1H, Ar) ppm. 13 C-NMR (CDCl3): δ 24.67, 29.03,
30.36, 34.20, 42.56, 50.92, 55.47, 109.62, 121.33, 127.41, 128.15, 129.69, 133.92, 135.20, 135.90, 152.22, 158.2,
201.69 ppm. FT-IR (KBr): υ 3637, 3568, 2954, 1655, 1495, 1434, 1237, 1199, 1097, 1033, 882, 776 cm−1
.
2,2-Bis(3,5-di-t-butyl-4-hydroxybenzyl)benzosuberone (21) Yellow solid, 83%, mp 195-196 ◦ C.
Anal calcd for C41 H56 O3 : C 82.50%, H 9.46%. Found: C 82.62%, H 9.55%. 1 H-NMR (CDCl3): δ 1.42 (s,
36H, 12 × CH3), 1.71 (t, J = 6 Hz, 2H, CH2), 2.06 (m, 2H, CH2), 2.73-2.78 (m, 4H, CH), 3.08 (d, J = 13.5
Hz, 2H, CH2), 5.07 (s, 2H, 2 × OH), 6.58 (d, J = 7.5 Hz, 1H, Ar), 6.91-6.98 (m, 6H, Ar), 7.17 (dd, J1 = 7.5
Hz, J2 = 2.7 Hz, 1H, Ar) ppm. 13 C-NMR (CDCl3): δ 23.41, 28.21, 30.33, 31.14, 34.21, 43.29, 54.61, 125.91,
126.73, 127.36, 127.53, 127.57, 130.32, 135.21, 136.65, 141.92, 152.33, 214.98 ppm. FT-IR (KBr): υ 3638, 3584,
2955, 2866, 1669, 1434, 1377, 1358, 1235, 1213, 1155, 1113, 957, 757 cm−1
.
Typical procedure for synthesis of 2-(3,5-di-t-butyl-4-hydroxybenzyl) bromopro-
piophenones
A solution of 2,6-(di-t-butyl-4-methoxymethyl)phenol 10 (1 g, 4 mmol) and potassium hydroxide (0.04 g) in
methanol (4 mL) was heated to 60 ◦ C. The corresponding bromopropiophenone (4 mmol) was then added to
the solution over a period of 10 min and the reaction mixture was refluxed for 3 h. The mixture was cooled to
room temperature and poured into 1% acetic acid (10 mL) to solidify. The resulting solids were washed with
546

Synthesis of new substituted 2,2-bis-(3,5-di-t-butyl-4-hydroxybenzyl)..., J. KHALAFY, et al.,
water and dried. Recrystallization from n-hexane gave the final products in good yields.
2-(3,5-Di-t-butyl-4-hydroxybenzyl)-1-(4-bromophenyl)propan-1-one (24) Yellow solid, 86%,
mp 83-84 ◦ C. Anal calcd for C24 H31 BrO2 : C 66.82%, H 7.24%. Found: C 66.72%, H 7.22%. 1 H-NMR
(CDCl3): δ 1.24 (d, J = 6.9 Hz, 3H, CH3), 1.38 (s, 18H, 6 × CH3), 2.68 (dd, J1 = 13.8 Hz, J2 = 7.5 Hz, 1H,
CH), 3.01 (dd, J1 = 13.8 Hz, J2 = 7.5 Hz, 1H, CH), 3.64 (sex., J = 6.9 Hz, 1H, CH), 5.03 (s, 1H, OH), 6.90
(s, 2H, Ar), 7.53 (d, J = 8.4 Hz, 2H, Ar), 7.68 (d, J = 8.4 Hz, 2H, Ar) ppm. 13 C-NMR (CDCl3): δ 17.52,
30.32, 34.18, 40.23, 43.02, 125.42, 127.78, 129.77, 130.11, 131.68, 135.71, 135.79, 152.15, 203.53 ppm. FT-IR
(KBr): υ 3569, 2957, 2870, 1683, 1584, 1434, 1238, 1216, 1133, 974, 754 cm−1
.
2-(3,5-Di-t-butyl-4-hydroxybenzyl)-1-(3-bromophenyl)propan-1-one (25) Yellow solid, 88%,
mp 76-77 ◦ C. Anal calcd for C24 H31 BrO2 : C 66.82%, H 7.24%. Found: C 66.75%, H 7.20%. 1 H-NMR
(CDCl3): δ 1.25 (d, J = 6.9 Hz, 3H, CH3), 1.38 (s, 18H, 6 × CH3), 2.69 (dd, J1 = 13.5 Hz, J2 = 7.5 Hz,
1H, CH), 3.01 (dd,J1 = 13.5 Hz,J2 = 7.5 Hz, 1H, CH), 3.64 (sex., J = 6.9 Hz, 1H, CH), 5.03 (s, 1H, OH),
6.90 (s, 2H, Ar), 7.26 (t, J = 7.50 Hz, 1H, Ar), 7.62 (d, J = 7.8 Hz, 1H, Ar), 7.74 (d, J = 7.8 Hz, 1H, Ar),
7.90 (d, J = 1.8 Hz, 1H, Ar) ppm. 13 C-NMR (CDCl3): δ 17.49, 30.26, 34.19, 40.38, 43.26, 122.78, 125.42,
126.68, 127.31, 129.98, 131.36, 135.44, 135.82, 138.87, 152.19, 203.33 ppm. FT-IR (KBr): υ 3576, 2957, 1684,
1566, 1433, 1359, 1203, 1118, 987, 733, 667 cm−1
.
Typical procedure for synthesis of 2,2-bis(3,5-di-t-butyl-4-hydroxybenzyl) bromo-
propiophenones
A solution of 2,6-(di-t-butyl-4-methoxymethyl)phenol 10 (0.25 g, 1 mmol) and potassium hydroxide (0.02 g) in
methanol (2 mL) was heated to 60 ◦ C. The corresponding 2-(3,5-di-t-butyl-4-hydroxybenzyl)bromopropiophenone
(1 mmol) was then added to the solution over a period of 10 min and the reaction mixture was refluxed for
4 h. The mixture was cooled to room temperature and poured into 1% acetic acid (10 mL) to solidify. The
resulting solids were washed with water and dried. Recrystallization from n-hexane gave the final products in
good yields.
2,2-Bis(3,5-di-t-butyl-4-hydroxybenzyl)-1-(4-bromophenyl)propan-1-one (26) White needles,
92%, mp 76-77 ◦ C. Anal calcd for C39 H53 BrO3 : C 72.09%, H 8.22%. Found: C 72.19%, H 8.29%. 1 H-NMR
(CDCl3): δ 1.14 (s, 3H, CH3), 1.39 (s, 36H, 12 × CH3), 2.67 (d, J = 13.2 Hz, 2H, CH2), 3.42 (d, J = 13.2
Hz, 2H, CH2), 5.10 (s, 2H, 2 × OH), 6.27 (d, J = 8.4 Hz, 2H), 6.92 (s, 4H, Ar), 7.20 (d, J = 8.4 Hz, 2H, Ar)
ppm. 13 C-NMR (CDCl3): δ 22.22, 30.27, 34.2, 47.88, 54.84, 123.94, 127.25, 127.51, 128.03, 130.50, 135.65,
140.37, 152.52, 211.12 ppm. FT-IR (KBr): υ 3635, 2056, 1698, 1583, 1434, 1363, 1237, 1154, 1120, 1065, 967,
937, 824, 771 cm−1
.
2,2-Bis(3,5-di-t-butyl-4-hydroxybenzyl)-1-(3-bromophenyl)propan-1-one (27) White needles,
84%, mp 229-230 ◦ C. Anal calcd for C39 H53 BrO3 : C 72.09%, H 8.22%. Found: C 72.04%, H 8.26%. 1 H-NMR
(CDCl3): δ 1.15 (s, 3H, CH3), 1.41 (s, 36H, 12 × CH3), 2.66 (d, J = 12.9 Hz, 2H, CH2), 3.42 (d, J = 12.9
Hz, 2H, CH2), 5.13 (s, 2H, 2 × OH), 6.11 (d, J = 1.5 Hz, 1H, Ar), 6.20 (dd, J1 = 7.5 Hz, J2 = 0.9 Hz, 1H,
Ar), 6.90 (d, J = 7.8 Hz, 1H, Ar), 6.95 (s, 4H, Ar), 7.29 (d, J = 8.1 Hz, 1H, Ar) ppm. 13 C-NMR (CDCl3): δ
22.15, 30.30, 34.21, 48.07, 55.00, 121.69, 123.72, 127.31, 127.93, 128.24, 128.94, 132.07, 135.76, 143.74, 152.63,
211.42 ppm. FT-IR (KBr): υ 3631, 2955, 2910, 1697, 1466, 1434, 1236, 1148, 1119, 974, 888, 771, 731 cm−1
.
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Synthesis of new substituted 2,2-bis-(3,5-di-t-butyl-4-hydroxybenzyl)..., J. KHALAFY, et al.,
Typical procedure for preparation of alcohol analogs of 2,2-bis-(3,5-di-t-butyl-4-
hydroxybenzyl)benzocycloalkanones and 2,2-bis(3,5-di-t-butyl-4-hydroxybenzyl)
bromopropiophenones
A mixture of 2,2-bis-(3,5-di-t-butyl-4-hydroxybenzyl)benzocycloalkanone or 2,2-bis(3,5-di-t-butyl-4-hydroxy-
benzyl)bromopropiophenone (1 mmol) and lithium aluminum hydride (4 mmol) in dry THF (5 mL) was refluxed
for 1 h under a nitrogen atmosphere. After cooling the mixture to room temperature, water (10 mL) was added
and then the mixture was extracted with dichloromethane (20 mL), which was dried over sodium sulfate.
Removal of the solvent gave the corresponding alcohols in good yields.
2,2-Bis(3,5-di-t-butyl-4-hydroxybenzyl)-4-chloro-2,3-dihydro-1H-inden-1-ol (32) Colorless crys-
tals, 96%, mp 187-188 ◦ C. Anal calcd for C39 H53 ClO3 : C 77.39%, H 8.83%. Found: C 77.50%, H 8.90%.
1 H-NMR (CDCl3): δ 1.46 (s, 36H, 12 × CH3), 2.51-2.83 (m, 4H), 2.95-3.05 (m, 2H), 5.08 (s, 1H, CH), 5.12
(s, 1H, OH), 5.18 (s, 1H, OH), 6.94-7.14 (m, 7H, Ar) ppm. 13 C-NMR (CDCl3): δ 30.19, 30.34, 30.36, 34.22,
34.27, 37.13, 38.19, 42.54, 53.44, 80.52, 121.68, 126.89, 127.30, 127.49, 128.00, 128.89, 129.03, 135.25, 135.92,
138.53, 146.70, 152.05, 152.33 ppm. FT-IR (KBr): υ 3630, 2955, 2870, 1434, 1232, 1212, 1148, 1120, 882, 775
cm−1
.
2,2-Bis(3,5-di-t-butyl-4-hydroxybenzyl)-6-methoxy-2,3-dihydro-1H-inden-1-ol (33) Colorless
crystals, 79%, mp 164-165 ◦ C. Anal calcd for C40 H56 O4 : C 79.96%, H 9.39%. Found: C 80.03%, H 9.32%.
1 H-NMR (CDCl3): δ 1.42 (s, 18H, 6 × CH3), 1.46 (s, 18H, 6 × CH3), 2.49-2.79 (m, 5H), 2.98 (d, J = 13.8
Hz, 1H, CH), 3.80 (s, 3H, CH3), 5.08 (s, 1H, CH), 5.11 (s, 2H, 2 × OH), 6.73 (dd, J1 = 8.1 Hz, J2 = 2.4 Hz,
1H, Ar), 6.89 (d, J = 2.1 Hz, 1H, Ar), 6.97-7.00 (m, 3H, Ar), 7.05 (s, 2H, Ar) ppm. 13 C-NMR (CDCl3): δ
29.72, 30.40, 34.24, 34.27, 37.31, 37.47, 41.87, 54.26, 55.37, 80.21, 108.73, 113.90, 125.11, 127.03, 127.31, 129.33,
129.36, 132.28, 135.20, 135.82, 145.95, 151.97, 152.22, 158.83 ppm. FT-IR (KBr): υ 3643, 3568, 2955, 1613,
1489, 1434, 1390, 1361, 1315, 1282, 1234, 1214, 1152, 1120, 1030, 885, 757 cm−1
.
2,2-Bis-(3,5-di-t-butyl-4-hydroxybenzyl)-6-methoxy-1,2,3,4 tetrahydronaphthalen-1-ol (34)
Viscous colorless oil, 69%. Anal calcd for C41 H58 O4 : C 80.08%, H 9.51%. Found: C 80.20%, H 9.58%. 1 H-
NMR (CDCl3): δ 1.46 (s, 18H, 6 × CH3), 1.49 (s, 18H, 6 × CH3), 1.89 (t, J = 6.3 Hz, 2H, CH2), 2.33 (s,
1H, OH), 2.45-3.07 (m, 5H), 3.83 (s, 3H, CH3), 4.42 (s, 1H, CH), 5.10 (s, 1H, OH), 5.15 (s, 1H, OH), 6.70 (s,
1H, Ar), 6.81 (d, J = 8.4 Hz, 1H, Ar), 7.03 (s, 2H, Ar), 7.10 (s, 2H, Ar), 7.45 (d, J = 8.4 Hz, 1H, Ar) ppm.
13 C-NMR (CDCl3): δ 26.03, 27.80, 30.37, 30.44, 34.24, 34.34, 37.59, 41.10, 41.36, 55.26, 72.56, 112.23, 113.22,
125.54, 127.38, 128.53, 128.73, 129.14, 131.79, 135.26, 135.51, 137.00, 152.11, 152.22, 158.53 ppm. FT-IR (KBr):
υ 3630, 2955, 2870, 1434, 1232, 1212, 1148, 1120, 882, 775 cm−1
.
2,2-Bis(3,5-di-t-butyl-4-hydroxybenzyl)-7-methoxy-1,2,3,4-tetrahydronaphthalen-1-ol (35)
Viscous colorless oil, 69%. Anal calcd for C41 H58 O4 : C 80.08%, H 9.51%. Found: C 80.15%, H 9.60%. 1 H-
NMR (CDCl3): δ 1.47 (s, 18H, 6 × CH3), 1.48 (s, 18H, 6 × CH3), 1.64 (t, J = 6.6 Hz, 2H, CH2), 2.50
(d, J = 12.9 Hz, 1H, CH), 2.65 (d, J = 13.5 Hz, 1H, CH), 2.75-3.16 (m, 4H), 3.85 (s, 3H, CH3), 4.45 (s, 1H,
CH), 5.10 (s, 1H, OH), 5.15 (s, 1H, OH), 6.81 (d, J = 8.1 Hz, 1H, Ar), 7.06-7.14 (m, 6H, Ar) ppm. 13 C-NMR
(CDCl3): δ 24.91, 28.44, 29.72, 30.44, 34.24, 34.32, 37.50, 41.30, 41.73, 55.29, 73.08, 111.30, 113.38, 125.54,
127.34, 127.41, 128.60, 129.05, 129.56, 135.30, 135.59, 140.84, 152.14, 152.28, 158.14 ppm. FT-IR (KBr): υ
3566, 3547, 3448, 2955, 2926, 2869, 1434, 1377, 1236, 1096, 872 cm−1
.
548

Synthesis of new substituted 2,2-bis-(3,5-di-t-butyl-4-hydroxybenzyl)..., J. KHALAFY, et al.,
2,2-Bis(3,5-di-t-butyl-4-hydroxybenzyl)benzosuberol (36) Viscous colorless oil, 89%. Anal calcd
for C41 H58 O3 : C 82.22%, H 9.76%. Found: C 82.33%, H 9.74%. 1 H-NMR (CDCl3): δ 1.45 (s, 36H, 12 ×
CH3), 1.62-2.62 (m, 10H), 4.74 (s, 1H, CH), 5.08 (s, 1H, OH), 5.12 (s, 1H, OH), 7.04-7.35 (m, 8H, Ar) ppm.
13 C-NMR (CDCl3): δ 24.23, 29.72, 30.41, 30.45, 34.29, 34.31, 35.12, 44.06, 125.73, 126.99, 127.32, 127.44,
129.11, 129.39, 129.57, 135.13, 135.71, 152.00 ppm. FT-IR (KBr): υ 3641, 3501, 2955, 2870, 1434, 1235, 1214,
1154, 1121, 1024, 756 cm−1
.
2,2-Bis(3,5-di-t-butyl-4-hydroxybenzyl)-1-(4-bromophenyl)propan-1-ol (37) Viscous colorless
oil, 88%. Anal calcd for C39 H55 BrO3 : C 71.87%, H 8.51%. Found: C 71.94%, H 8.55%. 1 H-NMR (CDCl3):
δ 0.76 (s, 3H, CH3), 1.27 (s, 18H, 6 × CH3), 1.44 (s, 18H, 6 × CH3), 2.26-2.40 (m, 2H, CH2), 2.89-2.98 (m,
2H, CH2), 4.41 (s, 1H, CH), 5.08 (s, 2H, 2 × OH), 6.93 (s, 2H, Ar), 7.03 (s, 2H, Ar), 7.21 (d, J = 7.5 Hz, 2H,
Ar), 7.42 (d, J = 7.5 Hz, 2H, Ar) ppm. 13 C-NMR (CDCl3): δ 14.10, 21.05, 22.67, 29.49, 30.42, 31.43, 34.25,
40.74, 42.32, 126.95, 127.29, 127.51, 128.81, 128.50, 129.11, 130.34, 131.27, 135.33, 142.14, 144.47, 153.00 ppm.
FT-IR (KBr): υ 3641, 3421, 2058, 1484, 1435, 1362, 1234, 1213, 1157, 1120, 1072, 1010, 874, 770 cm−1
.
2,2-Bis(3,5-di-t-butyl-4-hydroxybenzyl)-1-(3-bromophenyl)propan-1-ol (38) Viscous colorless
oil, 80%. Anal calcd for C39 H55 BrO3 : C 71.87%, H 8.51%. Found: C 71.87%, H 8.51%. 1 H-NMR (CDCl3):
δ 0.79 (s, 3H, CH3), 1.46 (s, 36H, 6 × CH3), 2.29-2.43 (m, 2H, CH2), 2.91-3.01 (m, 2H, CH2), 4.43 (s, 1H,
CH), 5.10 (s, 2H, 2 × OH), 6.95 (s, 2H, Ar), 7.05 (s, 2H, Ar), 7.18-7.29 (m, 2H, Ar), 7.43 (d, J = 7.5 Hz, 2H,
Ar) ppm. 13 C-NMR (CDCl3): δ 21.09, 29.70, 30.45, 30.48, 34.27, 40.79, 42.37, 42.59, 76.59, 121.90, 125.68,
126.96, 127.31, 127.52, 128.63, 128.84, 129.13, 130.36, 131.29, 135.30, 135.37, 144.49, 152.14 ppm. FT-IR (KBr):
υ 3643, 3422, 2923, 2855, 1462, 1434, 1363, 1234, 1213, 1158, 1120, 883, 783 cm−1
.
Results and discussion
2,6-Di-t-butyl-4-methoxymethylphenol 1021 was prepared by the reaction of 2,6-di-t-butylphenol 11 and
formaldehyde in the presence of potassium hydroxide in methanol at reflux conditions (Scheme 1).
OH
OH
CH2O, MeOH
KOH, reflux
OMe
11
10
Scheme 1.
As shown in Schemes 2 and 3, compound 10, presumably a precursor of p-quinonemethide, was reacted
with a number of substituted benzocycloalkanones and bromopropiophenones in the presence of potassium
hydroxide in methanol at 65 ◦ C. For cyclic ketones, i.e. indanones 12-13, tetralones 14-15, and benzosuberone
16, the resulting products were the substituted 2,2-bis-(3,5-di-t-butyl-4-hydroxybenzyl) benzocycloalkanones
17-21, whereas in the case of acyclic ketones, i.e. p- and m- bromopropiophenones 22-23, the 2-(3,5-di-
t−butyl-4-hydroxybenzyl)propanones 24-25 were formed initially, but further reaction with compound 10 gave
the bis products 26-27.
549

Synthesis of new substituted 2,2-bis-(3,5-di-t-butyl-4-hydroxybenzyl)..., J. KHALAFY, et al.,
OH
O
O
Z
Z
KOH, MeOH
reflux
1/2
+
10
(CH2)n
(CH2)n
Y
Y
OH
X
X
12, n=1, X=Cl, Y=Z=H
13, n=1, X=Y=H, Z=OCH3
14, n=2, X=Z=H, Y=OCH3
15, n=2, X=Y=H, Z=OCH3
16, n=3, X=Y=Z=H
17, n=1, X=Cl, Y=Z=H
18, n=1, X=Y=H, Z=OCH3
19, n=2, X=Z=H, Y=OCH3
20, n=2, X=Y=H, Z=OCH3
21, n=3, X=Y=Z=H
Scheme 2.
OH
OH
O
O
O
10
KOH, MeOH
X
10
+
reflux
KOH, MeOH
Y
reflux
X
X
22, X=Br, Y=H
23, X=H, Y=Br
Y
Y
24, X=Br, Y=H
25, X=H, Y=Br
OH
26, X=Br, Y=H
27, X=H, Y=Br
Scheme 3.
The proposed mechanism for the formation of bis product 17 involves in situ formation of p-quinonemethide
28, then the nucleophilic attack by the preformed enolate 29 to form the mono-substituted ketone 30 and the
subsequent nucleophilic attack of its enolate 31 on a second molecule of p-quinonemethide 28 to afford the
final product 17, as shown in Scheme 4.
It is notable that all of the cycloalkanone derivatives reacted with 2 equivalents of p-quinonemethide
28 and directly formed the bis alkylated products; we were unable to isolate any mono-substituted products
even under moderate reaction conditions. This was probably because of the high reactivity of the remaining
alpha hydrogen on the mono-substituted cycloalkanone intermediates (e.g. 30), which is easily removed with
KOH to form a reactive enolate that readily reacts with a second molecule of quinonemethide. In contrast with
the cyclic ketones, with acyclic ketones the initial mono-substituted ketones 24-25 were unreactive, even under
harsh reaction conditions.
All of these alkylated ketones were reduced to their corresponding alcohols (Schemes 5 and 6). As
mentioned previously, it is hoped that such alcohols will act as positive allosteric modulators of GABAB
receptors as propofol analogs, with the hydroxyphenyl group corresponding to the carboxyl group of γ-
hydroxybutyric acid.
550

Synthesis of new substituted 2,2-bis-(3,5-di-t-butyl-4-hydroxybenzyl)..., J. KHALAFY, et al.,
OH
OH
H
H
O
O
O
O
OH
-OCH3
OH
-H2O
31
H
CH2
OCH3
Cl
CH2
Cl
28
10
30
O
O
OH
OH
-H2O
H
O
H
O
Cl
12
Cl
28
29
17
Cl
OH
Scheme 4.
OH
OH
O
OH
(CH2)n
Z
Z
LiAlH4
THF, reflux
(CH2)n
Y
OH
Y
OH
X
X
17, n=1, X=Cl, Y=Z=H
18, n=1, X=Y=H, Z=OCH3
19, n=2, X=Z=H, Y=OCH3
20, n=2, X=Y=H, Z=OCH3
21, n=3, X=Y=Z=H
32, n=1, X=Cl, Y=Z=H
33, n=1, X=Y=H, Z=OCH3
34, n=2, X=Z=H, Y=OCH3
35, n=2, X=Y=H, Z=OCH3
36, n=3, X=Y=Z=H
Scheme 5.
OH
OH
OH
O
LiAlH4
THF, reflux
X
X
Y
Y
OH
OH
26, X=Br, Y=H
37, X=Br, Y=H
27, X=H, Y=Br
38, X=H, Y=Br
Scheme 6.
551

Synthesis of new substituted 2,2-bis-(3,5-di-t-butyl-4-hydroxybenzyl)..., J. KHALAFY, et al.,
Conclusion
In conclusion, we have synthesized a series of new substituted 2,2-bis-(3,5-di-t-butyl-4-hydroxybenzyl)indanones,
tetralones, propiophenones, and benzosuberone, and their alcohol analogs. These alcohols are potential allosteric
modulators of GABAB receptors. Due to the presence of 2 phenolic hydroxyl groups in these derivatives, they
may exhibit better binding properties than those previously synthesized.
Acknowledgements
We thank the Urmia University Research Council for financial support of this work. We also thank Professor
R. H. Prager for proofreading this article.
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