Chemistry of 1,2,4-trioxanes: Base-mediated formation of highly reactive electrophiles and their entrapment with amines and thiols

Article abstract of DOI:10.1055/s-2006-950233

6-(1-Arylvinyl)-substituted 1,2,4-trioxanes undergo a highly facile fragmentation under mild basic conditions to furnish 3-aryl-1-hydroxybut-3-en-2- ones, which react very efficiently with various amines and thiols to give Michael adducts. Both the formation of the reactive 3-aryl-1-hydroxybut-3-en-2- ones and their subsequent reaction with amines and thiols can be achieved in one pot. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-950233

PAPER
3485
Chemistry of 1,2,4-Trioxanes: Base-Mediated Formation of Highly Reactive
Electrophiles and Their Entrapment with Amines and Thiols1
F
ormation and Tr
h
apping of
H
i
ghly React
n
ive Electroph
d
iles
f
rom 1,2
a
, 4-Trioxan
n
es Singh,* Heetika Malik
Division of Medicinal & Process Chemistry, Central Drug Research Institute, Lucknow 226001, India
Fax +91(522)2223405; E-mail: chandancdri@yahoo.com
Received 13 March 2006; revised 19 June 2006
Several 1,2,4-trioxanes prepared by this method have
Abstract: 6-(1-Arylvinyl)-substituted 1,2,4-trioxanes undergo a
highly facile fragmentation under mild basic conditions to furnish
3-aryl-1-hydroxybut-3-en-2-ones, which react very efficiently with
various amines and thiols to give Michael adducts. Both the forma-
shown promising antimalarial activity.6 A unique feature
of these trioxanes is the presence of a 1-aryl-substituted
vinyl group at C-6 of the trioxane, which together with the
tion of the reactive 3-aryl-1-hydroxybut-3-en-2-ones and their sub- peroxy group makes H-6 quite acidic. In fact, these triox-
sequent reaction with amines and thiols can be achieved in one pot.
anes undergo a facile cleavage under mild basic condi-
tions to regenerate the carbonyl compounds and give 3-
aryl-1-hydroxybut-3-en-2-ones (Scheme 2).
Key words: 1,2,4-trioxanes, hydroxy enones, Michael additions,
thiols, amines
R1
R2
O O
O
R1
R2
O O
O
R1
R2
Base
O
+
Artemisinin (1), a naturally occurring 1,2,4-trioxane from
Artemisia annua, and its semisynthetic derivatives arte-
mether (2), arteether (3), and artesunic acid (4) (Figure 1)
O
Ar
Ar
H
Ar
B:
OH
are highly effective against both chloroquine-sensitive Scheme 2 Cleavage of trioxanes to regenerate carbonyl compounds
and -resistant malaria.2 The essentiality of a peroxy link-
and give 3-aryl-1-hydroxybut-3-en-2-ones
age in the form of the 1,2,4-trioxane ring system as the an-
timalarial pharmacophore of artemisinin has led to the
current interest in the synthesis3 and bioevaluation4 of
structurally simple 1,2,4-trioxanes.
Building on this reaction, we earlier developed 1,2,4-tri-
oxane as a new base-cleavable protecting group for the
carbonyl group.7 Our further investigations in this area
have shown that these 3-aryl-1-hydroxybut-3-en-2-ones
react very efficiently with various amines and thiols to
furnish the corresponding Michael adducts.
H
H
H
O
O
O
O
O
O
O
Thus the reaction of trioxane 5 with sodium bicarbonate,
n-butylamine, and diisopropylamine in hexamethylphos-
phoramide at room temperature furnished 3-aryl-1-hy-
droxybut-3-en-2-one 9 and adamantan-2-one (13) in 34%
and 66% yields, respectively. Similarly, trioxanes 6–8, on
reaction with n-butylamine in hexamethylphosphoramide
at room temperature, furnished 3-aryl-1-hydroxybut-3-
en-2-ones 10–12 in 36–38% yields (Scheme 3, Table 1).8
O
O
H
H
H
O
O
O
O
O
O
OR
OH
2; R = Me
3; R = Et
O
1
4
Figure 1 Artemisinin and semisynthetic derivatives thereof
We earlier reported a novel photooxygenation route for
the synthesis of 1,2,4-trioxanes. Preparation of b-hydroxy
hydroperoxides by photooxygenation of allylic alcohols
and the acid-catalyzed reaction of these hydroperoxides
with aldehydes or ketones are the key steps of this method
(Scheme 1).5
R1
R2
O O
O
O
Base, HMPA, r.t.
OH
X
X
9-12
5-8
5 X = Cl, R1, R2
=
9 X = Cl
10 X = H
11 X = Ph
R1
R2
H+
O
1O2
O OH
OH
O O
O
R1
R2
12 X = OMe
Ar
Ar
OH
Ar
6 X= H, R1, R2
=
Scheme 1 Synthesis of 1,2,4-trioxanes by a photooxygenation route
7 X = Ph, R1 = R2 = Me
8 X = OMe, R1, R2
=
SYNTHESIS 2006, No. 20, pp 3485–3489
Advanced online publication: 10.10.2006
DOI: 10.1055/s-2006-950233; Art ID: T03906SS
1
7.
1
0
.
2
0
0
6
Scheme 3 Synthesis of 3-aryl-1-hydroxybut-3-en-2-ones from
trioxanes
© Georg Thieme Verlag Stuttgart · New York

3486
C. Singh, H. Malik
PAPER
Table 1 Conditions and Yields of Base-Mediated Synthesis of
Table 2 Conditions and Yields of Conjugate Additions of Amines
3-Aryl-1-hydroxybut-3-en-2-ones from 1,2,4-Trioxanesa
and Thiols to 3-Aryl-1-hydroxybut-3-en-2-onesa
Entry Trioxane Base
Time (h) Product Yield (%)
Entry Keto Nucleophile
alcohol (equiv)
Time (h)Product Yield
(%)
1
2
3
4
5
6
5
5
5
6
7
8
NaHCO3
n-BuNH2
i-Pr2NH
8 h
7 h
7 h
7 h
7 h
7 h
9
9
34
40
39
38
36
37
1
2
3
4
5
6
7
8
9
9
PhNH2 (1.5)
4 h
3 h
4 h
4 h
4 h
2 h
2.5 h
14
15
16
17
18
19
20
21
81
84
83
80
86
84
82
81
PMPNH2 (1.5)
PhNH2 (1.5)
9
10
10
11
9
n-BuNH2
n-BuNH2
n-BuNH2
10
11
12
p-ClC6H4NH2 (1.5)
PhNH2 (1.5)
TolSH (1.5)
a Reagents and conditions: trioxane, base, HMPA, r.t.
9
Me(CH2)6SH (1.5)
3-Aryl-1-hydroxybut-3-en-2-ones 9–12 undergo facile re-
actions with aniline, p-chloroaniline, and p-methoxy-
aniline in hexamethylphosphoramide at room temperature
to give amino derivatives 14–18 in 80–86% yields, while
similar reactions with p-thiocresol, heptane-1-thiol, and
N-acetyl-L-cysteine furnish thiol derivatives 19–21 in 81–
84% yields (Scheme 4, Table 2). Treatment of N-acetyl-L-
cysteine adduct 21 with diazomethane in diethyl ether
gave the corresponding methyl ester 22 (Scheme 4),
whose purification by column chromatography gave a
diastereomeric mixture (1:1, by 1H NMR), which was ful-
ly characterized by 1H and 13C NMR spectroscopy.
9
N-acetyl-L-cysteine (1.5) 1 h
a Reagents and conditions: keto alcohol, nucleophile, HMPA, r.t.
When keto alcohol 5 was treated with glutathione (re-
duced) in tetrahydrofuran, the Michael addition product 1-
hydroxy-4-sulfanylbutan-2-one 23 formed as a diastereo-
meric mixture (Scheme 5). The two isomers were separat-
ed by high-performance liquid chromatography and
characterized by high-resolution electron-impact mass
spectrometry.
To achieve the formation of the 3-aryl-1-hydroxybut-3-
en-2-ones and their subsequent reactions with amines and
thiols in one pot, we examined the reaction of trioxane 5
with aniline and various thiols in the presence of n-butyl-
amine in hexamethylphosphoramide at room temperature
(Table 3). Thus, reaction of trioxane 5 with aniline in the
presence of n-butylamine at room temperature for eight
hours furnished 4-amino-1-hydroxybutan-2-one 14 in
42% yield (Table 3, entry 1). Similar reactions of trioxane
5 with p-thiocresol (Table 3, entry 2), 1-heptanethiol (en-
try 3), and N-acetyl-L-cysteine (entry 4) furnished 1-
hydroxy-4-sulfanylbutan-2-ones 19, 20, and 21, respec-
tively, in 60–63% yields. In these experiments, the 3-aryl-
1-hydroxybut-3-en-2-one 9 generated by reaction of tri-
oxane 5 with n-butylamine reacts in situ with aniline and
the various thiols to give Michael adducts 14, 19, 20, and
21 (Table 3).9 Compound 21 was obtained as an insepara-
ble mixture of diastereomers (ratio 1:1) and was converted
into its methyl ester 22 by reaction with diazomethane.
O
OH
HMPA, r.t.
X
9–12
R'
RH
NH2
SR
NH
R
O
O
OH
X
OH
X
19–21
14–18
14 X = Cl, R = H
15 X = Cl, R = OMe
16 X = H, R = H
17 X = H, R = Cl
18 X = Ph, R = H
Me
19 X = Cl, R =
20 X = Cl, R =
(CH2)6Me
NHCOMe
S
S
21 X = Cl, R =
22 X = Cl, R =
COOH
NHCOMe
In conclusion, we have investigated the reactions of sev-
eral 1,2,4-trioxanes with various amines and thiols under
mild basic conditions. These trioxanes undergo a very fac-
ile base-catalyzed fragmentation to generate highly reac-
COOMe
Scheme 4 Synthesis of 4-sulfanyl- and 4-amino-substituted 3-aryl-
1-hydroxybutan-2-ones from 3-aryl-1-hydroxybut-3-en-2-ones
NHCOCH2CH2CH(NH2)COOH
S
CONHCH2CO2H
O
O
O
NaHCO3, HMPA, r.t.
glutathione, THF, r.t.
O
Cl
OH
Cl
5
23
Scheme 5 Synthesis of a 3-aryl-1-hydroxy-4-sulfanylbutan-2-one amino acid derivative from a trioxane and glutathione
Synthesis 2006, No. 20, 3485–3489 © Thieme Stuttgart · New York

PAPER
Formation and Trapping of Highly Reactive Electrophiles from 1,2,4-Trioxanes
Oil; yield: 0.045 g (40%).
3487
tive 3-aryl-1-hydroxybut-3-en-2-ones,10 which react very
efficiently with various nucleophiles. The chemistry dis-
cussed here allows easy access to highly functionalized
molecules such as 4-sulfanyl- and 4-amino-substituted 3-
aryl-1-hydroxybutan-2-ones 14–21 from easily available
1,2,4-trioxanes.
IR (neat): 1491, 1690, 3432 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.30 (t, J = 4.8 Hz, 1 H, OH), 4.64
(d, J = 4.8 Hz, 2 H), 6.09 and 6.19 (2 × s, 2 H), 7.29 (d, J = 8.7 Hz,
2 H), 7.65 (d, J = 8.7 Hz, 2 H).
FAB-MS: m/z = 197, 199 [M + H+].
Anal. Calcd for C10H9ClO2: C, 61.08; H, 4.61. Found: C, 61.42; H,
4.87.
Table 3 Tandem Fragmentation and Conjugate Addition of Triox-
ane 5 to Amines and Thiolsa
1-Hydroxy-3-phenylbut-3-en-2-one (10)
Entry Nucleophile (equiv)
Time (h) Product Yield (%)
Keto alcohol 10 was prepared by the same procedure described for
9 in which n-BuNH2 was used as base (Method B).
1
2
3
4
PhNH2 (1.5)
8 h
7 h
8 h
7 h
14
19
20
21
42
61
60
63
Oil; yield: 38%.
IR (neat): 1598, 1683, 3416 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.38 (br s, 1 H, OH), 4.66 (s, 2 H),
6.03 and 6.17 (2 × s, 2 H), 7.28–7.38 (m, 5 H).
TolSH (1.5)
Me(CH2)6SH (2.0)
N-acetyl-L-cysteine (1.5)
FAB-MS: m/z = 163 [M + H+].
a Reagents and conditions: trioxane 5, n-BuNH2 (cat.), nucleophile,
HMPA, r.t.
Anal. Calcd for C10H10O2: C, 74.06; H, 6.21. Found: C, 73.99; H,
6.14.
3-Biphenyl-4-yl-1-hydroxybut-3-en-2-one (11)
Keto alcohol 11 was prepared by the same procedure described for
9 in which n-BuNH2 was used as base (Method B).
All glassware were oven-dried prior to use. Melting points were de-
termined on a COMPLAB melting point apparatus and are uncor-
rected. IR spectra were recorded on a Perkin-Elmer FT-IR RXI
spectrophotometer. 1H NMR and 13C NMR spectra were recorded
on a Bruker DPX-200 (operating at 200 MHz for 1H and at 50 MHz
for 13C) or DRX-300 (operating at 300 MHz for 1H and at 75 MHz
for 13C) spectrometer, with CDCl3 used as solvent. TMS (0.00 ppm)
served as an internal standard in 1H NMR and CDCl3 (77.0 ppm) in
13C NMR spectra. A JEOL SX 102 spectrometer was used for FAB-
MS, for which argon/xenon (6 kV, 10 mA) was used as the FAB
gas. Glycerol or m-nitrobenzyl alcohol was used as matrix. Elemen-
tal analyses were carried out on a Vario EL-III CHNS analyzer
(Germany). HRMS (EI) was performed on a JEOL MS route 600H
instrument. Reactions were monitored by TLC (TLC-grade silica
gel, Merck). Detecting agents used for TLC were: I2 vapour and/or
spraying with an aq. soln of vanillin in 10% H2SO4 followed by
heating at 150 °C. Silica gel (60–120 mesh, Qualigens, India) and
freshly distilled solvents were used for column chromatography. All
chemicals and reagents were obtained from Aldrich (USA), Lan-
caster (England), or Spectrochem (India) and were used without
further purification.
Yield: 36%; mp 115–117 °C.
IR (KBr): 1598, 1683, 3416 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.34 (br s, 1 H, OH), 4.64 (d,
J = 2.9 Hz, 2 H), 6.09 and 6.17 (2 × s, 2 H), 7.32–7.62 (m, 9 H).
FAB-MS: m/z = 239 [M + H+].
Anal. Calcd for C16H14O2: C, 80.65; H, 5.92. Found: C, 80.41; H,
5.76.
1-Hydroxy-3-(4-methoxyphenyl)but-3-en-2-one (12)
Keto alcohol 12 was prepared by the same procedure described for
9 in which n-BuNH2 was used as base (Method B).
Oil; yield: 37%.
IR (neat): 1598, 1721, 3426 cm–1.
1H NMR (200 MHz, CDCl3): d = 3.35 (br s, 1 H, OH), 3.82 (s, 3 H),
4.60 (d, J = 3.0 Hz, 2 H), 5.97 and 6.06 (2 × s, 2 H), 6.90 (d, J = 8.7
Hz, 2 H), 7.27 (d, J = 8.7 Hz, 2 H).
FAB-MS: m/z = 193 [M + H+].
3-(4-Chlorophenyl)-1-hydroxybut-3-en-2-one (9); Typical
Procedures
Method A (Sodium Bicarbonate as Base)
Anal. Calcd for C11H12O3: C, 68.74; H, 6.29. Found: C, 68.66; H,
6.18.
NaHCO3 (0.04 g, 0.57 mmol) was added to a soln of trioxane 5
(0.20 g, 0.58 mmol) in HMPA (4 mL), and the mixture was stirred
at r.t. for 8 h. The reaction mixture was diluted with H2O (10 mL)
and extracted with Et2O (2 × 15 mL). The combined organic layer
was washed successively with H2O (2 × 5 mL) and brine (5 mL),
dried (Na2SO4), and concentrated. This gave 9 as a crude product
which was purified by column chromatography (silica gel, EtOAc–
hexane, 0.5:10).
4-Anilino-3-(4-chlorophenyl)-1-hydroxybutan-2-one (14);
Typical Procedures
Method A (from 9)
To a soln of keto alcohol 9 (0.05 g, 0.25 mmol) in HMPA (3 mL)
was added aniline (0.03 g, 0.38 mmol). The mixture was stirred at
r.t. for 4 h, and then diluted with H2O (5 mL) and extracted with
Et2O (2 × 10 mL). The combined organic layer was washed succes-
sively with H2O (5 mL) and brine (5 mL), dried (Na2SO4), and con-
centrated. This gave crude product 14, which was purified by
column chromatography (silica gel, EtOAc–hexane, 0.5:10).
Oil; yield: 0.038 g (34%).
Method B (n-Butylamine as Base)
n-BuNH2 (0.04 g, 0.57 mmol) was added to a soln of trioxane 5
(0.20 g, 0.58 mmol) in HMPA (4 mL). The mixture was stirred at
r.t. for 7 h, then diluted with H2O (10 mL), and extracted with Et2O
(2 × 15 mL). The combined organic layer was washed successively
with H2O (2 × 5 mL) and brine (5 mL), dried (Na2SO4), and concen-
trated. This gave crude product 9, which was purified by column
chromatography (silica gel, EtOAc–hexane, 0.5:10).
Oil; yield: 0.059 g (81%).
Method B (One-Pot Procedure from 5)
To a soln of trioxane 5 (0.1 g, 0.29 mmol) in HMPA (4 mL) was
added n-BuNH2 (0.02 g, 0.28 mmol) and aniline (0.03 g, 0.36
mmol). The mixture was stirred at r.t. for 8 h, and then diluted with
H2O (10 mL) and extracted with Et2O (2 × 15 mL). The combined
Synthesis 2006, No. 20, 3485–3489 © Thieme Stuttgart · New York

3488
C. Singh, H. Malik
PAPER
organic layer was washed successively with H2O (2 × 5 mL) and
brine (5 mL), dried (Na2SO4), and concentrated. This gave crude
product 14, which was purified by column chromatography (silica
gel, EtOAc–hexane, 0.5:10).
IR (KBr): 1720, 3458 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.96 (br s, 1 H, OH), 3.52 (dd,
J = 13.5, 5.7 Hz, 1 H), 3.97 (dd, J = 13.5, 8.1 Hz, 1 H), 4.11 (dd,
J = 8.1, 5.7 Hz, 1 H), 4.22 (d, J = 7.8 Hz, 2 H), 6.62 (d, J = 7.6 Hz,
2 H), 6.76 (t, J = 7.6 Hz, 1 H), 7.18–7.62 (m, 11 H).
13C NMR (50 MHz, CDCl3): d = 45.7 (t), 53.5 (d), 67.8 (t), 113.0 (d,
2 C), 118.0 (d), 127.0 (d, 2 C), 127.5 (d), 128.0 (d, 2 C), 128.5 (d, 2
C), 128.8 (d, 2 C), 129.4 (d, 2 C), 134.4 (s), 140.1 (s), 141.1 (s),
147.0 (s), 209.2 (s).
Oil; yield: 0.035 g (42%).
IR (neat): 1719, 3398 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.96 (br s, 2 H, NH, OH), 3.44 (dd,
J = 13.4, 5.6 Hz, 1 H), 3.90 (dd, J = 13.4, 8.1 Hz, 1 H), 4.04 (dd,
J = 8.1, 5.6 Hz, 1 H), 4.17 (s, 2 H), 6.57 (d, J = 7.9 Hz, 2 H), 6.74–
6.78 (m, 1 H), 7.15–7.37 (m, 6 H).
FAB-MS: m/z = 332 [M + H+].
FAB-MS: m/z = 290, 292 [M + H+].
HRMS (EI): m/z calcd for C22H21NO2: 331.1572; found: 331.1569.
Anal. Calcd for C16H16ClNO2: C, 66.32; H, 5.57; N, 4.83. Found: C,
66.49; H, 5.46; N, 4.64.
3-(4-Chlorophenyl)-1-hydroxy-4-(4-tolylsulfanyl)butan-2-one
(19); Typical Procedures
Method A (from 9)
3-(4-Chlorophenyl)-1-hydroxy-4-(4-methoxyanilino)butan-2-
To a soln of keto alcohol 9 (0.09 g, 0.46 mmol) in HMPA (5 mL)
was added p-thiocresol (0.079 g, 0.56 mmol). The mixture was
stirred at r.t. for 2 h, then diluted with H2O (5 mL), and extracted
with Et2O (2 × 10 mL). The combined organic layer was washed
successively with H2O (5 mL) and brine (5 mL), dried (Na2SO4),
and concentrated. This gave crude product 19, which was purified
by column chromatography (silica gel, EtOAc–hexane, 0.5:10).
one (15)
Compound 15 was prepared by Method A used for the preparation
of compound 14.
Oil; yield: 84%.
IR (neat): 1720, 3386 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.95 (br s, 2 H, NH, OH), 3.38 (dd,
J = 13.4, 6.0 Hz, 1 H), 3.74 (s, 3 H), 3.83 (dd, J = 13.4, 8.0 Hz, 1 H),
4.01 (dd, J = 8.0, 6.0 Hz, 1 H), 4.15 (s, 2 H), 6.54 (dd, J = 6.6, 2.2
Hz, 2 H), 6.77 (dd, J = 6.6, 2.2 Hz, 2 H), 7.16 (dd, J = 6.6, 1.9 Hz,
2 H), 7.33 (dd, J = 6.6, 1.9 Hz, 2 H).
Oil; yield: 0.12 g (84%).
Method B (One-Pot Procedure from 5)
To a soln of trioxane 5 (0.1 g, 0.29 mmol) in HMPA (5 mL) was
added n-BuNH2 (0.02 g, 0.28 mmol) and p-thiocresol (0.05 g, 0.43
mmol). The mixture was stirred at r.t. for 7 h, diluted with H2O (10
mL), and extracted with Et2O (2 × 15 mL). The combined organic
layer was washed successively with H2O (2 × 5 mL) and brine (5
mL), dried (Na2SO4), and concentrated. This gave crude product 19,
which was purified by column chromatography (silica gel, EtOAc–
hexane, 0.5:10).
FAB-MS: m/z = 320, 322 [M + H+].
Anal. Calcd for C17H18ClNO3: C, 63.85; H, 5.67; N, 4.38. Found: C,
63.49; H, 5.43; N, 4.64.
1-Hydroxy-3-phenyl-4-anilinobutan-2-one (16)
Compound 16 was prepared by Method A used for the preparation
of compound 14.
Oil; yield: 0.056 g (61%).
Oil; yield: 83%.
IR (neat): 1712, 3440 cm–1.
1H NMR (200 MHz, CDCl3): d = 2.98 (br s, 1 H, OH), 3.46 (dd,
J = 13.1, 5.3 Hz, 1 H), 3.87–4.07 (m, 2 H), 4.15 and 4.16 (2 × s, 2
H), 6.58 (d, J = 7.7 Hz, 2 H), 6.73 (t, J = 7.2 Hz, 1 H), 7.14–7.40
(m, 7 H).
IR (neat): 1720, 2363, 3508 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.34 (s, 3 H), 2.90 (t, J = 4.9 Hz,
1 H, OH), 3.15 (dd, J = 13.5, 6.3 Hz, 1 H), 3.58 (dd, J = 13.5, 8.7
Hz, 1 H), 3.81 (dd, J = 8.7, 6.3 Hz, 1 H), 4.18 (d, J = 4.8 Hz, 2 H),
7.09–7.12 (m, 4 H), 7.24–7.31 (m, 4 H).
FAB-MS: m/z = 321, 323 [M + H+].
FAB-MS: m/z = 256 [M + H+].
Anal. Calcd for C17H17ClO2S: C, 63.64; H, 5.34; S, 9.99. Found: C,
63.84; H, 4.98; S, 9.79.
Anal. Calcd for C16H17NO2: C, 75.27; H, 6.71; N, 5.49. Found: C,
75.38; H, 6.43; N, 5.42.
3-(4-Chlorophenyl)-4-(heptylsulfanyl)-1-hydroxybutan-2-one
(20)
Compound 20 could be prepared as an oil by Method A (yield: 82%)
or Method B (yield: 60%) described for the preparation of com-
pound 19.
IR (neat): 1720, 2363, 3506 cm–1.
4-(4-Chloroanilino)-1-hydroxy-3-phenylbutan-2-one (17)
Compound 17 was prepared by Method A used for the preparation
of compound 14.
Oil; yield: 80%.
IR (neat): 1716, 3445 cm–1.
1H NMR (200 MHz, CDCl3): d = 0.87 (t, J = 6.4 Hz, 3 H), 1.26–1.61
(m, 10 H), 2.46 (t, J = 7.4 Hz, 2 H), 2.81 (dd, J = 13.0, 6.3 Hz, 1 H),
2.94 (t, J = 4.8 Hz, 1 H, OH), 3.22 (dd, J = 13.0, 8.6 Hz, 1 H), 3.85
(dd, J = 8.6, 6.3 Hz, 1 H), 4.26 (d, J = 4.8 Hz, 2 H), 7.18 (d, J = 8.4
Hz, 2 H), 7.32 (d, J = 8.4 Hz, 2 H).
1H NMR (200 MHz, CDCl3): d = 2.98 (br s, 1 H, OH), 3.43 (dd,
J = 13.0, 5.3 Hz, 1 H) 3.83–4.06 (m, 2 H), 4.16 (s, 2 H), 6.49 (d,
J = 8.7 Hz, 2 H), 7.11 (d, J = 8.7 Hz, 2 H), 7.19–7.41 (m, 5 H).
FAB-MS: m/z = 290, 292 [M + H+].
13C NMR (50 MHz, CDCl3): d = 14.46 (q), 22.99 (t), 29.13 (t), 29.24
(t), 29.96 (t), 32.09 (t), 33.56 (t), 34.64 (t), 55.02 (d), 68.55 (t),
129.75 (d, 4 C), 134.59 (s), 135.62 (s), 208.71 (s).
Anal. Calcd for C16H16ClNO2: C, 66.32; H, 5.57; N, 4.83. Found: C,
66.54; H, 5.68; N, 4.73.
3-Biphenyl-4-yl-1-hydroxy-4-anilinobutan-2-one (18)
Compound 18 was prepared by Method A used for the preparation
of compound 14.
FAB-MS: m/z = 329, 331 [M + H+].
Anal. Calcd for C17H25ClO2S: C, 62.08; H, 7.66; S, 9.75. Found: C,
62.42; H, 7.32; S, 9.51.
Yield: 86%; mp 106–108 °C.
Synthesis 2006, No. 20, 3485–3489 © Thieme Stuttgart · New York

PAPER
Formation and Trapping of Highly Reactive Electrophiles from 1,2,4-Trioxanes
3489
Methyl N-Acetyl-S-[2-(4-chlorophenyl)-4-hydroxy-3-oxobu-
tyl]cysteinate (22)
Compound 21 could be prepared by Method A (yield: 81%) or
Method B (yield: 63%) described for the preparation of compound
19. Ester 22 was prepared from compound 21 by reaction with
CH2N2 in Et2O.
(3) (a) O’Neill, P. M.; Mukhtar, A.; Ward, S. A.; Bickley, J. F.;
Davies, J.; Bachi, M. D.; Stocks, P. A. Org. Lett. 2004, 6,
3035. (b) O’Neill, P. M.; Pugh, M.; Davies, J.; Ward, S. A.;
Park, B. K. Tetrahedron Lett. 2001, 42, 4569.
(c) Bloodworth, A. J.; Johnson, K. A. Tetrahedron Lett.
1994, 35, 8057. (d) Posner, G. H.; Oh, C. H.; Milhous, W. K.
Tetrahedron Lett. 1991, 32, 4235. (e) Bunnelle, W. H.;
Isbell, T. A.; Barnes, C. L.; Qualls, S. J. Am. Chem. Soc.
1991, 113, 8168. (f) Avery, M. A.; Chong, W. K. M.; Detre,
G. Tetrahedron Lett. 1990, 31, 1799. (g) Kepler, J. A.;
Philip, A.; Lee, Y. W.; Morey, M. C.; Caroll, F. I. J. Med.
Chem. 1988, 31, 713. (h) Jefford, C. W.; Jaggi, D.;
Boukouvalas, J.; Kohmoto, S. J. Am. Chem. Soc. 1983, 105,
6497.
Oil; yield: quantitative.
IR (neat): 1740, 2927, 3309 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.01 and 2.03 (2 × s, 3 H), 2.77–
3.05 (m, 3 H), 3.24 (dd, J = 12.9, 9.0 Hz, 1 H), 3.74 and 3.75 (2 × s,
3 H), 3.92 (dd, J = 15.6, 9.0 Hz, 1 H), 4.23 (d, J = 3.9 Hz, 2 H),
4.76–4.83 (m, 1 H), 6.40 and 6.48 (2 × d, J = 7.2 Hz, 1 H, NH),
7.14–7.18 (m, 2 H), 7.32 (d, J = 8.4 Hz, 2 H).
(4) (a) Peters, W.; Robinson, B. L.; Tovey, G.; Rossier, J. C.;
Jefford, C. W. Ann. Trop. Med. Parasitol. 1993, 87, 1.
(b) Peters, W.; Robinson, B. L.; Rossier, J. C.; Jefford, C. W.
Ann. Trop. Med. Parasitol. 1993, 87, 9. (c) Peters, W.;
Robinson, B. L.; Tovey, G.; Rossier, J. C.; Jefford, C. W.
Ann. Trop. Med. Parasitol. 1993, 87, 111. (d) Kepler, J. A.;
Philip, A.; Lee, Y. W.; Morey, M. C.; Carroll, F. I. J. Med.
Chem. 1988, 31, 713. (e) Posner, G. H.; Maxwell, J. P.;
O’Dowd, H.; Krasavin, M.; Xie, S.; Shapiro, T. A. Bioorg.
Med. Chem. 2000, 8, 1361. (f) Posner, G. H.; Jeon, H. B.;
Parker, M. H.; Krasavin, M.; Paik, I.-H.; Shapiro, T. A. J.
Med. Chem. 2001, 44, 3054. (g) Posner, G. H.; Jeon, H. B.;
Polypradith, P.; Paik, I.-H.; Borstnik, K.; Xie, S.; Shapiro, T.
A. J. Med. Chem. 2002, 45, 3824. (h) Griesbeck, A. G.; El-
Idreesy, T. T.; Fiege, M.; Brun, R. Org. Lett. 2002, 24,
4193. (i) O’Neill, P. M.; Mukhtar, A.; Ward, S. A.; Bickley,
J. F.; Davies, J.; Bachi, M. D.; Stocks, P. A. Org. Lett. 2004,
18, 3035. (j) Griesbeck, A. G.; El-Idreesy, T. T.; Hoinck, L.
O.; Lex, J.; Brun, R. Bioorg. Med. Chem. Lett. 2005, 15, 595.
(5) (a) Singh, C. Tetrahedron Lett. 1990, 31, 6901. (b) Singh,
C.; Gupta, N.; Puri, S. K. Tetrahedron Lett. 2005, 46, 205.
(6) (a) Singh, C.; Misra, D.; Saxena, G.; Chandra, S. Bioorg.
Med. Chem. Lett. 1992, 2, 497. (b) Singh, C.; Misra, D.;
Saxena, G.; Chandra, S. Bioorg. Med. Chem. Lett. 1995, 5,
1913. (c) Singh, C.; Gupta, N.; Puri, S. K. Bioorg. Med.
Chem. Lett. 2003, 13, 3447. (d) Singh, C.; Malik, H.; Puri,
S. K. Bioorg. Med. Chem. 2004, 14, 459. (e) Singh, C.;
Malik, H.; Puri, S. K. Bioorg. Med. Chem. Lett. 2005, 15,
4484. (f) Singh, C.; Tiwari, P.; Puri, S. K. US Patent
6737438 B2, 2004; Chem. Abstr. 2004, 140, 270882j.
(7) Singh, C.; Malik, H. Org. Lett. 2005, 25, 5673.
(8) The stability of 3-aryl-1-hydroxybut-3-en-2-ones 9–12 is
low, and this could be one of the reasons why they are
obtained in such poor yields.
13C NMR (75 MHz, CDCl3): d = 22.9 (q), 34.4 (t), 34.7 and 34.9 (t),
51.8 and 52.1 (d), 52.5 and 52.7 (q), 53.9 and 54.0 (d), 68.0 (t),
129.30 (d, 4 C), 134.1 (s), 134.8 (s), 170.1 (s), 171.1 (s), 208.2 and
208.3 (s).
FAB-MS: m/z = 375, 377 [M + H+].
HRMS (EI): m/z calcd for C16H20ClNO5S: 374.0829; found:
374.0830.
2-Amino-4-{1-[(carboxymethyl)carbamoyl]-2-[2-(4-chloro-
phenyl)-4-hydroxy-3-oxobutylsulfanyl]ethylcarbamoyl}butyric
Acid (23)
To a soln of trioxane 5 (0.5 g, 1.44 mmol) in HMPA (7 mL) was
added NaHCO3 (0.12 g, 1.44 mmol). The mixture was allowed to
stir at r.t. for 8 h, then diluted with H2O (15 mL) and extracted with
Et2O (2 × 25 mL). The combined organic layer was washed succes-
sively with H2O (2 × 7 mL) and brine (7 mL), dried (Na2SO4), and
concentrated. This furnished 9, which was dissolved in THF (10
mL). Glutathione (reduced, 0.15 g, 0.51 mmol) was added, and the
reaction mixture was stirred at r.t. overnight. THF was evaporated,
and the residue was dissolved in H2O (10 mL) and washed with
Et2O (2 × 5 mL). The aqueous layer was concentrated; this provided
23 as a mixture of diastereomers; yield: 0.24 g (97% based on glu-
tathione). A part of the product was separated by HPLC (RP-18,
MeOH–H2O, 80:20) to give two pure isomers, both of which gave
correct ES-MS spectra.
ES-MS (ES+): m/z = 504, 506.
Acknowledgment
Heetika Malik is grateful to the Council of Scientific and Industrial
Research (CSIR), New Delhi for the award of a Senior Research
Fellowship.
(9) We suggest that this facile formation of 3-aryl-1-
hydroxybut-3-en-2-one systems from the trioxanes on
reaction with weak bases such as n-butylamine and the equal
facile entrapment of these reactive species with amines and
thiols may have relevance to the mechanism of the
antimalarial action of these trioxanes. n-Butylamine is
similar to the lysine side chain of lysine-containing proteins
and an appropriate protein can generate the reactive species
which could alkylate thiol residues of the same or a nearby
protein, vital for the survival of the malarial parasite.
(10) For similar base-catalyzed fragmentation of
References
(1) CDRI Communication No: 6850.
(2) (a) Klayman, D. L. Science 1985, 228, 1049.
(b) Bhattacharya, A. K.; Sharma, R. P. Heterocycles 1999,
51, 1651. (c) Borstnik, K.; Paik, I.; Shapiro, T. A.; Posner,
G. H. Int. J. Parasitol. 2002, 32, 1661. (d) Ploypradith, P.
Acta Trop. 2004, 89, 329. (e) O’Neill, P. M.; Posner, G. H.
J. Med. Chem. 2004, 47, 2945.
dialkylperoxides and bicyclic endoperoxide, see:
(a) Kornblum, N.; Delamare, H. E. J. Am. Chem. Soc. 1951,
73, 880. (b) Mete, E.; Altundas, E.; Secen, H. Turk. J. Chem.
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Synthesis 2006, No. 20, 3485–3489 © Thieme Stuttgart · New York