Direct phthalimidomethylation of 2,6-dialkylphenols. Reactions of N-(4-hydroxybenzyl)phthalimides with electrophiles and nucleophiles

Article abstract of DOI:10.1007/s11172-012-0041-6

Reactions of 2,6-dialkylphenols with N-(N′,N′- diethylaminomethyl)phthalimide gave the corresponding 4-phthaloylmethylphenols, in which the phthaloyl group can be replaced by an alkylsulfanyl substituent via reactions with thiols. Phthaloylmethylphenols containing the tert-butyl groups that are ortho to the OH group can undergo acid-catalyzed de-tert-butylation.

Full text of DOI:10.1007/s11172-012-0041-6

Russian Chemical Bulletin, International Edition, Vol. 61, No. 2, pp. 298—302, February, 2012
298
Direct phthalimidomethylation of 2,6ꢀdialkylphenols.
Reactions of Nꢀ(4ꢀhydroxybenzyl)phthalimides
with electrophiles and nucleophiles
I. M. Bugaev,† A. I. Dmitriev, and A. E. Prosenko
Research Institute of Antioxidant Chemistry, Novosibirsk State Pedagogical University,
28 ul. Vilyuiskaya, 630126 Novosibirsk, Russian Federation.
Fax: +7 (383) 244 1856. Eꢀmail: bugaev@mail.com
Reactions of 2,6ꢀdialkylphenols with Nꢀ(N´,N´ꢀdiethylaminomethyl)phthalimide gave the
corresponding 4ꢀphthaloylmethylphenols, in which the phthaloyl group can be replaced by an
alkylsulfanyl substituent via reactions with thiols. Phthaloylmethylphenols containing the
tertꢀbutyl groups that are ortho to the OH group can undergo acidꢀcatalyzed deꢀtertꢀbutylation.
Key words: phenols, phthalimides, phthalimidomethylation, alkylthiomethylphenols.
Scheme 1
Various Nꢀsubstituted phthalimides are widely emꢀ
ployed in synthetic practice (the Gabriel synthesis,1 proꢀ
tection of primary amines,2 etc.). Some phthalimide deꢀ
rivatives exhibit pharmacological activity. For instance,
thalidomide has found use in the last few decades for the
treatment of grave forms of multiple myeloma and other
cancers;3 some of its analogs are under clinical trials.4
Nꢀ(4ꢀHydroxybenzyl)phthalimides have attracted our
attention as potential building blocks for regioselective
synthesis of new representatives of pꢀthiomethylphenols,
which are promising antioxidants5,6 and bioantioxidants.7
A general route to Nꢀsubstituted phthalimides involves
reactions of electrophilic reagents with phthalimide or poꢀ
tassium phthalimide (Scheme 1). Alkylation of potassium
phthalimide with [3,5ꢀdi(tertꢀbutyl)ꢀ4ꢀhydroxybenzyl]
bromide produces Nꢀ[3,5ꢀdi(tertꢀbutyl)ꢀ4ꢀhydroxybenzꢀ
yl]phthalimide (1).8 Compound 1 as well as a number of its
analogs can be obtained from appropriate 4ꢀ(N,Nꢀdiꢀ
methylaminomethyl)phenols of the type 2 and phthalimide.9
i. C6H4Me2, D, 3 h; ii. DMF, 140 C, 5 h.
Results and Discussion
30 min. The yield of product 1 was 70% (GLC); note that
the peak corresponding to an authentic sample of 2,6ꢀdiꢀ
(tertꢀbutyl)ꢀ4ꢀ(N,Nꢀdiethylaminomethyl)phenol was abꢀ
sent. An analogous reaction in the absence of diethylamine
did not give compound 1, which suggests a catalytic role
of Et2NH. Theoretically, the process could also proceed
through Nꢀaminomethylation of phthalimide. To verify
this conjecture, we obtained Nꢀ(N´,N´ꢀdiethylaminoꢀ
methyl)phthalimide (3) (Scheme 2).
A reaction of compound 3 with 2,6ꢀdi(tertꢀbutyl)ꢀ
phenol in DMF at 160 C for 15 min gave crude product 1
in 95% yield (GLC); its preparative yield upon purificaꢀ
tion was 81%. Analogous reactions with 2ꢀ(tertꢀbutyl)ꢀ6ꢀ
It can be seen in Scheme 1 that the synthesis of comꢀ
pound 1 from aminomethylphenol 2 is accompanied by
elimination of dimethylamine. At the same time, comꢀ
pound 2 is easily formed in the Mannich reaction of 2,6ꢀdiꢀ
(tertꢀbutyl)phenol with formaldehyde and dimethylamine.
We tried to combine both steps in a "one pot" synthesis.
Instead of dimethylamine, we used less volatile diethylꢀ
amine, which was added in catalytic amounts (10 mol.%)
to a mixture of a phenol, phthalimide, paraformaldehyde,
and DMF. The reaction mixture was heated at 150 C for
†
Deceased.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 2, pp. 297—301, February, 2012.
1066ꢀ5285/12/6102ꢀ298 © 2012 Springer Science+Business Media, Inc.

Nꢀ(4ꢀHydroxybenzyl)phthalimides
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 2, February, 2012
299
Scheme 2
context, compounds 1 and 4 are protected derivatives of
Nꢀ[3ꢀ(tertꢀbutyl)ꢀ4ꢀhydroxybenzyl]phthalimide (6) and
Nꢀ(4ꢀhydroxyꢀ3ꢀmethylbenzyl)phthalimide (7). It is known
that compounds in which the hydroxybenzyl substituent is
bound to a heteroatom tend to undergo fragmentation in
the presence of acids and electrophiles. However, since
the phthalimide N atom in compounds 1 and 4 is only
slightly basic and nucleophilic, we succeeded in removing
the tertꢀbutyl groups and obtained unprotected phthalꢀ
imides 6 and 7 in acceptable yields (Scheme 3).
Scheme 3
i. EtOH, 50 C, 10 min; ii. DMF, 160 C, 15 min.
1: R1 = R2 = But, 81%; 4: R1 = But, R2 = Me, 72%;
5: R1 = R2 = Me, 49%
Product
6
R
HX
Yield (%)
methylphenol and 2,6ꢀdimethylphenol produced phthalꢀ
imides 4 and 5, respectively. Diminution of the steric hinꢀ
drance around the OH group of the starting phenol lowers
the yields of the target products (see Scheme 2; hereafter,
their preparative yields are given).
But
HClO4
TsOH
HClO4
57
73
66
7
Me
When the reaction was carried out in the system
HClO4—AcOH, the yield of compound 6 decreased beꢀ
cause of further dealkylation. A somewhat better result
was achieved with TsOH instead of HClO4.
Baseꢀcatalyzed reactions of compounds 6 and 7 with
thiols afforded the target pꢀthiomethylphenols 8—10,
which are not easily accessible via other methods (Scheme 4).
According to the literature data, the reactions in which
the phthalimide substituent acts as a leaving group are
mostly characteristic of Nꢀhaloꢀ and Nꢀchalcophthalꢀ
In contrast to 2,6ꢀdialkylphenols, reactions of comꢀ
pound 3 with 2,4ꢀdimethylphenol and 2,4ꢀdi(tertꢀbutyl)ꢀ
phenol gave unsubstituted phthalimide and the correꢀ
sponding diethylaminomethylphenols. The same result was
obtained with 2,6ꢀdi(tertꢀbutyl)phenol when no solvent
was used or when DMF was replaced by acetic acid.
The literature data on reactions of phenols with aminoꢀ
methylphthalimides are lacking. We have retrieved only
one reference10 to aminomethylphthalimides as phthalꢀ
imidomethylating agents: heating of indole with Nꢀ(N´,N´ꢀ
dimethylaminomethyl)phthalimide and a catalytic amount
of NaOH gives 3ꢀ(phthalimidomethyl)indole in 65% yield.
However, this process is more likely to proceed through
intermediate aminomethylation of indole: a reaction of
gramine with phthalimide under the same conditions gives
3ꢀ(phthalimidomethyl)indole in 82% yield.
Scheme 4
Direct amidoꢀ and imidomethylation of aromatic comꢀ
pounds, which is also known as the Tscherniac—Einhorn
reaction, can be accomplished through the use of Nꢀhydrꢀ
oxymethyl amides and imides, including Nꢀ(hydroxyꢀ
methyl)phthalimide.11 It should be noted that this apꢀ
proach is unsuitable for the synthesis of compounds 1 and
4 because of strongly acidic media required for this reacꢀ
tion to occur.
Product
8
9
10
R
R´
nꢀC12H25
CH2CH2COOH
nꢀC12H25
Yield (%)
65
But
But
Me
A common practice in the protection of the aromatic
C—H bonds is introduction of tertꢀbutyl groups.12 In this
80
54

300
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 2, February, 2012
Bugaev et al.
Scheme 5
NPhth =
i. Br2, CHCl3; ii. CH2O, TsOH, AcOH; iii. Et2NCH2SC12H25, AcOH; iv. RSH, NaOH, DMF.
imides,13 while the fragments PhthN—C are either inert
to nucleophiles or attacked by them at the carbonyl
C atoms, except for a number of specific cases.14 Apꢀ
parently, Nꢀ(4ꢀhydroxybenzyl)phthalimides lose the
phthalimide anion through 1,6ꢀelimination leading to
a quinone methide intermediate to which a thiolate beꢀ
comes added.
act as a leaving group in reactions with Sꢀnucleophiles.
Based on the aforesaid transformations, we proposed a new
route to pꢀthiomethylphenols.
Experimental
1
H NMR spectra were recorded on a Bruker AVꢀ600 instruꢀ
Following preliminary functionalization of the phenol
ring in compound 7, we obtained a number of 2,6ꢀdisubꢀ
stituted 4ꢀthiomethylphenols, for which currently availꢀ
able routes are also unsuitable. Compound 7 was convertꢀ
ed into bromo derivative 11 by bromination and into meꢀ
thylenebisphenol 12 by condensation with formaldehyde;
sulfide 13 was obtained as described earlier15 (Scheme 5).
Products 11—13 were further converted into the target
compounds 14—16.
To sum up, we were the first to carry out direct phthalꢀ
imidomethylation of 2,6ꢀdialkylphenols. We also demonꢀ
strated that the phthalimidomethyl fragment of Nꢀ(4ꢀ
hydroxybenzyl)phthalimides is stable under the SEAr reꢀ
action conditions and that the phthalimide fragment can
ment. Melting points were determined on a PTP instrument.
Elemental analysis was carried out at the check analysis laboraꢀ
tory of the Research Institute of Antioxidant Chemistry of the
Novosibirsk State Pedagogical University. GLC data were colꢀ
lected on an LKhMꢀ80 instrument.
Nꢀ[3,5ꢀDi(tertꢀbutyl)ꢀ4ꢀhydroxybenzyl]phthalimide (1). A mixꢀ
ture of 2,6ꢀdi(tertꢀbutyl)phenol (72.21 g, 0.35 mmol) and
Nꢀ(N´,N´ꢀdiethylaminomethyl)phthalimide (90.59 g, 0.39 mmol)
was heated in DMF (75 mL) at 160 C for 15 min, with removal
of liberated diethylamine. The reaction mixture was treated with
water and the precipitate that formed was twice recrystallized
from toluene—light petroleum. The yield of compound 1 was
1
105.05 g (81%), white crystalline solid, m.p. 164 C. H NMR
(CDCl3), : 1.42 (s, 18 H, CMe3); 4.68 (s, 2 H, NCH2Ar); 5.10
(s, 1 H, OH); 7.26 (s, 2 H, ArH); 7.62 (m, 2 H, ArH); 7.78 (m, 2 H,

Nꢀ(4ꢀHydroxybenzyl)phthalimides
Russ.Chem.Bull., Int.Ed., Vol. 61, No. 2, February, 2012
301
ArH). Found (%): C, 75.63; H, 7.41; N, 3.85. C23H27NO3. Calꢀ
culated (%): C, 75.59; H, 7.45; N, 3.83.
1 h, diluted with water (10 mL), and acidified with conc. HCl (3
mL). The product was extracted with toluene (25 mL). The orꢀ
ganic layer was washed with water, dried, and concentrated.
Crude product 8 was recrystallized three times from light petroꢀ
leum. The yield was 2.37 g (65%), white crystalline solid, m.p.
Nꢀ(N´,N´ꢀDiethylaminomethyl)phthalimide (3). Ethanol
(75 mL) and diethylamine (43.88 g, 0.60 mmol) were added to
a mixture of phthalimide (73.57 g, 0.50 mmol) and paraformalꢀ
dehyde (18.01 g, 0.60 mmol). The reaction mixture was stirred at
50 C for 10 min and diluted with water. The product was exꢀ
tracted with light petroleum, washed with water, dried over
Na2SO4, and concentrated. The yield of compound 3 was 98.24 g
(85%), a yellow liquid crystallizing on cooling, m.p. 29—30 C.
1H NMR (CDCl3), : 1.01 (t, 6 H, CH3CH2, J = 7.2 Hz); 2.47
(q, 4 H, MeCH2, J = 7.2 Hz); 4.50 (s, 2 H, NCH2N); 7.58 (m, 2 H,
ArH); 7.69 (m, 2 H, ArH). Found (%): C, 67.20; H, 6.99; N, 12.10.
C13H16N2O2. Calculated (%): C, 67.22; H, 6.94; N, 12.06.
Nꢀ[3ꢀ(tertꢀButyl)ꢀ4ꢀhydroxyꢀ5ꢀmethylbenzyl]phthalimide (4)
was obtained as described for compound 1 from 2ꢀ(tertꢀbutyl)ꢀ6ꢀ
methylphenol (41.06 g, 0.25 mmol) and compound 3 (63.88 g,
0.275 mmol) in DMF (50 mL). Crude product 4 was twice reꢀ
crystallized from toluene. The yield was 45.43 g (72%), white
crystalline solid, m.p. 184 C. 1H NMR (CDCl3), : 1.38 (s, 9 H,
CMe3); 2.21 (s, 3 H, ArMe); 4.65 (s, 2 H, NCH2Ar); 4.69 (s, 1 H,
OH); 7.03 (d, 1 H, ArH, J = 1.8 Hz); 7.20 (d, 1 H, ArH, J = 1.8 Hz);
7.64 (m, 2 H, ArH); 7.79 (m, 2 H, ArH). Found (%): C, 74.30;
H, 6.51; N, 4.34. C20H21NO3. Calculated (%): C, 74.28; H, 6.55;
N, 4.33.
39—40 C. 1H NMR (CDCl3), : 0.89 (t, 3 H, CH3(CH2)11
,
J = 7.2 Hz); 1.25—1.33 (m, 18 H, (CH2)9); 1.39 (s, 9 H, CMe3);
1.52 (m, 2 H, CH2CH2S); 2.33 (t, 2 H, CH2CH2S, J = 7.2 Hz);
3.56 (s, 2 H, SCH2Ar); 4.63 (br.s, 1 H, OH); 6.48 (d, 1 H, ArH,
J = 7.8 Hz); 6.90 (dd, 1 H, ArH, J = 7.8 Hz, J = 2.4 Hz); 7.10
(d, 1 H, ArH, J = 2.4 Hz). Found (%): C, 75.71; H, 11.10;
S, 8.83. C23H40OS. Calculated (%): C, 75.76; H, 11.06; S, 8.79.
3ꢀ[3ꢀ(tertꢀButyl)ꢀ4ꢀhydroxybenzylthio]propionic acid (9) was
obtained as described for compound 8 from phthalimide 6 (10.05 g,
32 mmol), 3ꢀmercaptopropionic acid (3.45 g, 32 mmol), and
NaOH (3.89 g, 97 mmol) in DMF (20 mL). The reaction mixꢀ
ture was diluted with water and acidified. The product was exꢀ
tracted with toluene and the extract was concentrated. The yield
of compound 9 was 6.98 g (80%), yellowish resin. 1H NMR
(CDCl3), : 1.42 (s, 9 H, CMe3); 2.52 (t, 2 H, CH2COOH,
J = 7.2 Hz); 2.61 (t, 2 H, CH2CH2S, J = 7.2 Hz); 3.62 (s, 2 H,
SCH2Ar); 5.12 (br.s, 1 H, OH); 6.50 (d, 1 H, ArH, J = 7.8 Hz);
6.91 (dd, 1 H, ArH, J = 7.8 Hz, J = 2.4 Hz); 7.11 (d, 1 H, ArH,
J = 2.4 Hz); 10.78 (br.s, 1 H, COOH). Found (%): C, 62.62;
H, 7.48; S, 11.98. C14H20O3S. Calculated (%): C, 62.66; H, 7.51;
S, 11.95.
Nꢀ(4ꢀHydroxyꢀ3,5ꢀdimethylbenzyl)phthalimide (5) was obꢀ
tained as described for compound 1 from 2,6ꢀdimethylphenol
(12.21 g, 0.10 mmol) and compound 3 (25.55 g, 0.11 mmol) in
DMF (20 mL). Crude product 5 was twice recrystallized from
toluene. The yield was 13.76 g (49%), white crystalline solid,
4ꢀDodecylthiomethylꢀ2ꢀmethylphenol (10) was obtained and
isolated as described for compound 8. The starting reagents were
phthalimide 7 (5.35 g, 20 mmol), dodecanethiol (4.05 g,
20 mmol), and NaOH (1.60 g, 40 mmol) in DMF (10 mL). The
yield of compound 10 was 3.74 g (54%), white crystalline solid,
1
m.p. 177—180 C. H NMR (CDCl3), : 2.19 (s, 6 H, ArMe);
4.42 (s, 1 H, OH); 4.62 (s, 2 H, NCH2Ar); 7.00 (s, 2 H, ArH);
7.65 (m, 2 H, ArH); 7.80 (m, 2 H, ArH). Found (%): C, 72.59;
H, 5.35; N, 5.00. C17H15NO3. Calculated (%): C, 72.58; H, 5.37;
N, 4.98.
m.p. 28—29 C. 1H NMR (CDCl3), : 0.89 (t, 3 H, CH3(CH2)11
,
J = 7.2 Hz); 1.25—1.33 (m, 18 H, (CH2)9); 1.52 (m, 2 H,
CH2CH2S); 2.20 (s, 3 H, ArMe); 2.33 (t, 2 H, CH2CH2S,
J = 7.2 Hz); 3.54 (s, 2 H, SCH2Ar); 4.95 (br.s, 1 H, OH); 6.58
(d, 1 H, ArH, J = 7.8 Hz); 6.90 (dd, 1 H, ArH, J = 7.8 Hz,
J = 1.8 Hz); 6.98 (d, 1 H, ArH, J = 1.8 Hz). Found (%): C, 74.44;
H, 10.63; S, 9.98. C20H34OS. Calculated (%): C, 74.47; H, 10.62;
S, 9.94.
Nꢀ(3ꢀBromoꢀ4ꢀhydroxyꢀ5ꢀmethylbenzyl)phthalimide (11).
A solution of bromine (0.84 g, 5.25 mmol) in CHCl3 (3 mL) was
added dropwise to a solution of compound 7 (1.34 g, 5.00 mmol)
in CHCl3 (15 mL). The reaction mixture was stirred for 2 h,
washed with water, and concentrated. The residue was recrystalꢀ
lized from ethanol. The yield of compound 11 was 1.38 g (80%),
white crystalline solid, m.p. 180—182 C. 1H NMR (CDCl3), :
2.25 (s, 3 H, ArMe); 4.64 (s, 2 H, NCH2Ar); 5.45 (s, 1 H, OH);
7.12 (d, 1 H, ArH, J = 1.8 Hz); 7.36 (d, 1 H, ArH, J = 1.8 Hz);
7.67 (m, 2 H, ArH); 7.80 (m, 2 H, ArH). Found (%): C, 55.48;
H, 3.43; N, 4.04. C16H12BrNO3. Calculated (%): C, 55.51;
H, 3.49; N, 4.05.
Nꢀ[3ꢀ(tertꢀButyl)ꢀ4ꢀhydroxybenzyl]phthalimide (6). A mixꢀ
ture of compound 1 (48.00 g, 131.34 mmol), toluenesulfonic
acid monohydrate (10.00 g, 52.57 mmol), and acetic acid (50 mL)
was refluxed for 2.5 h and treated with water. The precipitate
that formed was recrystallized from toluene. The yield of comꢀ
pound 6 was 29.66 g (73%), white crystalline solid, m.p.
168—169 C. 1H NMR (CDCl3), : 1.38 (s, 9 H, CMe3); 4.69
(s, 2 H, NCH2Ar); 5.23 (br.s, 1 H, OH); 6.50 (d, 1 H, ArH,
J = 8.4 Hz); 7.08 (dd, 1 H, ArH, J = 8.4 Hz, J = 1.8 Hz); 7.31
(d, 1 H, ArH, J = 1.8 Hz); 7.64 (m, 2 H, ArH); 7.80 (m, 2 H, ArH).
Found (%): C, 73.74; H, 6.15; N, 4.58. C19H19NO3. Calculatꢀ
ed (%): C, 73.77; H, 6.19; N, 4.53.
Nꢀ(4ꢀHydroxyꢀ3ꢀmethylbenzyl)phthalimide (7). A mixture of
compound 4 (40.00 g, 123.69 mmol) and 57% HClO4 (4 mL) in
acetic acid (80 mL) was refluxed for 2 h and treated with water.
The precipitate that formed was recrystallized from toluene. The
yield of compound 7 was 21.72 g (66%), white crystalline solid,
6,6´ꢀMethylenebis(2ꢀmethylꢀ4ꢀphthalimidomethylphenol)
(12). A mixture of compound 7 (10.00 g, 37 mmol), tolueneꢀ
sulfonic acid monohydrate (7.12 g, 37 mmol), and acetic acid
(25 mL) was heated to 100 C. Then 31% formalin (3.3 mL,
37 mmol) was added dropwise with stirring. The precipitate
that formed was washed with acetone and recrystallized from
DMF—acetone. The yield of compound 12 was 6.02 g (59%),
1
m.p. 173—174 C. H NMR (CDCl3), : 2.19 (s, 3 H, ArMe);
4.67 (s, 2 H, NCH2Ar); 4.74 (br.s, 1 H, OH); 6.59 (d, 1 H, ArH,
J = 7.8 Hz); 7.10 (dd, 1 H, ArH, J = 7.8 Hz, J = 1.8 Hz); 7.15
(d, 1 H, ArH, J = 1.8 Hz); 7.65 (m, 2 H, ArH); 7.80 (m, 2 H, ArH).
Found (%): C, 71.97; H, 4.93; N, 5.20. C16H13NO3. Calculatꢀ
ed (%): C, 71.90; H, 4.90; N, 5.24.
2ꢀ(tertꢀButyl)ꢀ4ꢀdodecylthiomethylphenol (8). A mixture of
compound 6 (3.09 g, 10 mmol), dodecanethiol (2.02 g, 10 mmol),
and NaOH (0.80 g, 20 mmol) was refluxed in DMF (5 mL) for
1
white crystalline solid, m.p. 232—237 C. H NMR (DMFꢀd6),
: 2.19 (s, 6 H, ArMe); 3.93 (s, 2 H, ArCH2Ar); 4.64 (s, 4 H,
NCH2Ar); 6.97 (m, 4 H, ArH); 7.90 (m, 8 H, ArH); 8.04 (s, 2 H,

Russian Chemical Bulletin, International Edition, Vol. 61, No. 2, pp. 302—302, February, 2012
302
OH). Found (%): C, 72.48; H, 4.75; N, 5.19. C33H26N2O6. Calꢀ
culated (%): C, 72.52; H, 4.79; N, 5.13.
compound 16 was 3.92 g (48%), white crystalline solid, m.p.
45—46 C. 1H NMR (CDCl3), : 0.88 (t, 3 H, CH3(CH2)11
,
Nꢀ(3ꢀDodecylthiomethylꢀ4ꢀhydroxyꢀ5ꢀmethylbenzyl)phthalꢀ
imide (13). A mixture of compound 7 (10.00 g, 37 mmol) and
N,Nꢀdiethylaminomethyl dodecyl sulfide15 (10.76 g, 37 mmol)
was refluxed in acetic acid (25 mL) for 1 h and treated with
water. The precipitate that formed was filtered off, washed with
water on the filter, and sequentially recrystallized from ethanol
and light petroleum. The yield of compound 13 was 10.51 g
(58%), white crystalline solid, m.p. 98—100 C. 1H NMR
(CDCl3), : 0.88 (t, 3 H, CH3(CH2)11, J = 7.2 Hz); 1.21—1.29
(m, 18 H, (CH2)9); 1.49 (m, 2 H, CH2CH2S); 2.19 (s, 3H,
ArMe); 2.29 (t, 2 H, CH2CH2S, J = 7.2 Hz); 3.71 (s, 2 H,
SCH2Ar); 4.63 (s, 2 H, NCH2Ar); 6.75 (s, 1 H, OH); 6.94 (d, 1 H,
ArH, J = 1.8 Hz); 7.11 (d, 1 H, ArH, J = 1.8 Hz); 7.65 (m, 2 H,
ArH); 7.78 (m, 2 H, ArH). Found (%): C, 72.29; H, 8.17; N, 2.88;
S, 6.69. C29H39NO3S. Calculated (%): C, 72.31; H, 8.16; N, 2.91;
S, 6.66.
2ꢀBromoꢀ4ꢀdodecylthiomethylꢀ6ꢀmethylphenol (14) was obꢀ
tained and isolated as described for compound 8. The starting
reagents were phthalimide 11 (1.04 g, 3 mmol), dodecanethiol
(0.91 g, 4.5 mmol), and NaOH (0.30 g, 7.5 mmol) in DMF
(3 mL). The yield of compound 14 was 0.55 g (46%), white
crystalline solid, m.p. 37—38 C. 1H NMR (CDCl3), : 0.88
(t, 3 H, CH3(CH2)11, J = 7.2 Hz); 1.25—1.33 (m, 18 H, (CH2)9);
1.51 (m, 2 H, CH2CH2S); 2.26 (s, 3 H, ArMe); 2.33 (t, 2 H,
CH2CH2S, J = 7.2 Hz); 3.51 (s, 2 H, SCH2Ar); 5.40 (s, 1 H,
OH); 6.96 (d, 1 H, ArH, J = 1.8 Hz); 7.18 (d, 1 H, ArH, J = 1.8 Hz).
Found (%): C, 59.85; H, 8.31; S, 8.02. C20H33BrOS. Calculatꢀ
ed (%): C, 59.84; H, 8.29; S, 7.99.
6,6´ꢀMethylenebis(4ꢀdodecylthiomethylꢀ2ꢀmethylphenol) (15)
was obtained as described for compound 8 from bisphthalimide
12 (6.02 g, 11 mmol), dodecanethiol (6.69 g, 33 mmol), and
NaOH (2.20 g, 50 mmol) in DMF (15 mL). The reaction mixꢀ
ture was treated with water and the product was extracted with
toluene. The extract was concentrated and the residue was recrysꢀ
tallized from acetone—acetonitrile. The yield of compound 15
was 1.80 g (25%), white crystalline solid, m.p. 92—94 C.
1H NMR (CDCl3), : 0.88 (t, 6 H, CH3(CH2)11, J = 7.2 Hz);
1.23—1.31 (m, 36 H, (CH2)9); 1.51 (m, 4 H, CH2CH2S); 2.18
(s, 6 H, ArMe); 2.31 (t, 4 H, CH2CH2S, J = 7.2 Hz); 3.51
(s, 4 H, SCH2Ar); 3.82 (s, 2 H, ArCH2Ar); 5.98 (br.s, 2 H, OH);
6.85 (d, 2 H, ArH, J = 1.8 Hz); 6.96 (d, 2 H, ArH, J = 1.8 Hz).
Found (%): C, 74.98; H, 10.39; S, 9.71. C41H68O2S2. Calculatꢀ
ed (%): C, 74.94; H, 10.43; S, 9.76.
J = 7.2 Hz); 1.23—1.31 (m, 18 H, (CH2)9); 1.52 (m, 2 H,
CH2CH2S); 2.21 (s, 3 H, ArMe); 2.33 (t, 2 H, CH2CH2S,
J = 7.2 Hz); 2.52 (t, 2 H, CH2CH2COOH, J = 7.2 Hz); 2.59
(t, 2 H, CH2CH2COOH, J = 7.2 Hz); 3.57 (s, 2 H, SCH2Ar);
3.71 (s, 2 H, SCH2Ar); 6.78 (d, 1 H, ArH, J = 1.8 Hz); 6.96 (d, 1 H,
ArH, J = 1.8 Hz); 11.25 (br.s, 2 H, OH). Found (%): C, 65.40;
H, 9.11; S, 14.60. C24H40O3S2. Calculated (%): C, 65.41;
H, 9.15; S, 14.55.
References
1. M. S. Gibson, R. W. Bradshaw, Angew. Chem., Int. Ed., 1968,
7, 919.
2. P. G. M. Wuts, T. W. Greene, Greene´s Protective Groups
in Organic Synthesis, 4th ed., Wiley and Sons, Inc., Hoboꢀ
ken, 2006.
3. N. Raje, K. Anderson, N. Engl. J. Med., 1999, 341, 1606.
4. A. F. List, Semin. Oncol., 2005, 32, Suppl. 5, 31.
5. A. E. Prosenko, O. I. Dyubchenko, E. I. Terakh, A. F. Marꢀ
kov, E. A. Gorokh, M. A. Boiko, Neftekhimiya, 2006, 46, 1
[Petroleum Chem. (Engl. Transl.), 2006, 46].
6. H. Meier, H. Kuenzi, G. Knobloch, G. Rist, M. Szelaꢀ
giewicz, Phosphorus, Sulfur, Silicon, Relat. Elem., 1999,
153—154, 275.
7. E. A. Kemeleva, E. A. Vasyunina, O. I. Sinitsina, A. S.
Khomchenko, M. A. Gross, N. V. Kandalintseva, A. E.
Prosenko, G. A. Nevinskii, Bioorg. Khim., 2008, 34, 558
[Russ. J. Bioorg. Chem. (Engl. Transl.), 2008, 34].
8. A. A. Volod´kin, V. V. Ershov, Izv. Akad. Nauk SSSR, Otd.
Khim. Nauk, 1962, 342 [Bull. Acad. Sci. USSR, Div. Chem.
Sci. (Engl. Transl.), 1962, 11, 317].
9. F. B. Gershanov, G. A. Tolstikov, A. G. Liakumovich, V. N.
Vorontsova, in Khimiya i fizicheskaya khimiya monomerov
[The Chemistry and Physical Chemistry of Monomers], Ufa,
1975, 207 (in Russian).
10. R. O. Atkinson, J. Chem. Soc., 1954, 1329.
11. H. E. Zaugg, R. W. Denet, J. E. Fraser, A. M. Kotre, J. Org.
Chem., 1969, 34, 14.
12. Protective Groups in Organic Chemistry, Ed. J. F. W. McOmie,
Plenum Press, London—New York, 1973.
13. K. C. Nicolaou, N. A. Petasis, D. A. Claremon, Tetrahedron,
1985, 41, 4835.
14. M. Sekiya, Y. Terao, Chem. Pharm. Bull., 1970, 18, 947.
15. I. M. Bugaev, A. E. Prosenko, Izv. Akad. Nauk, Ser. Khim.,
2010, 843 [Russ. Chem. Bull., Int. Ed., 2010, 59, 861].
3ꢀ(3ꢀDodecylthiomethylꢀ4ꢀhydroxyꢀ5ꢀmethylbenzylthio)propꢀ
ionic acid (16) was obtained as described for compound 8 from
phthalimide 13 (9.00 g, 19 mmol), 3ꢀmercaptopropionic acid
(2.97 g, 28 mmol), and NaOH (3.00 g, 75 mmol) in DMF
(15 mL). The reaction mixture was diluted with water (25 mL)
and neutralized with conc. HCl (10 mL). The product was exꢀ
tracted with toluene and the extract was concentrated. The resiꢀ
due was twice recrystallized from light petroleum. The yield of
Received July 25, 2011;
in revised form November 17, 2011