Synthesis of 1,2,4-trioxepanes and 1,2,4-trioxanes via Hmediated reaction of tertiary carbinols

Article abstract of DOI:10.1055/s-0032-1317958

A facile and efficient method for the synthesis of 1,2,4-trioxepanes and 1,2,4-trioxanes from different carbinols having cyclopropyl and phenyl substituents has been developed. The corresponding hydroxyhydroperoxides were synthesized from 30% Hmediated reaction of carbinols in acidic conditions. This method provided access to novel 6,6-diaryl-substituted 1,2,4-trioxanes derived from benzilic acid. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317958

LETTER
▌173
lSetyternthesis of 1,2,4-Trioxepanes and 1,2,4-Trioxanes via H2O2-Mediated
Reaction of Tertiary Carbinols
Synthesis of 1,2,4-Trioxepanes and 1,2,4-Trioxanes
Makthala Ravi,a Devireddy Anand,a Ranjani Maurya,a Parul Chauhan,a Niraj K. Naikade,a Sanjeev K. Shukla,b Prem
P. Yadav*a
a
Divisions of Medicinal and Process Chemistry, CSIR-Central Drug Research Institute, Lucknow 226001, India
Fax +91(522)2623405; Fax +91(522)2623938; E-mail: pp_yadav@cdri.res.in; E-mail: ppy_cdri@yahoo.co.in
b
Sophisticated Analytical Instrument Facility, CSIR-Central Drug Research Institute, Lucknow 226001, India
Received: 29.10.2012; Accepted after revision: 08.12.2012
H
R1
R2
O
O
O
Abstract: A facile and efficient method for the synthesis of 1,2,4-
trioxepanes and 1,2,4-trioxanes from different carbinols having cy-
clopropyl and phenyl substituents has been developed. The corre-
sponding hydroxyhydroperoxides were synthesized from 30%
H2O2 mediated reaction of carbinols in acidic conditions. This
method provided access to novel 6,6-diaryl-substituted 1,2,4-triox-
anes derived from benzilic acid.
O
O
O
n
H
R3
O
n = 1, 1,2,4-trioxane
n = 2, 1,2,4-trioxepane
by Singh et al.
O
artemisinin
Key words: 1,2,4-trioxanes, 1,2,4-trioxepanes, hydrogen peroxide,
carbinols, antimalarial
O
O
O
S
Ar
O
O
O
O
C6H11
O
Malaria is a major parasitic disease of the tropics, around
215 million people are affected and an estimated 655000
people died of malaria in 2010.1 Currently, artemisinin
and its derivatives are the drugs of choice to treat multi-
drug-resistant malaria. The antimalarial activity of arte-
misinin and its clinically useful derivatives such as
artemether and arteether is due to the presence of the
1,2,4-trioxane moiety in their molecular structure. Several
structurally simple synthetic 1,2,4-trioxanes and 1,2,4-tri-
oxepanes (Figure 1) have shown promising antimalarial
activity.2–5
1,2,4-trioxepane by Dussault
1,2,4-trioxepane by O'Neill et al.
literature reports
1
O
R1
1
O
O
R1
O
O
6
R2
7
R2
O
4
4
1,2,4-trioxanes
1,2,4-trioxepanes
present work
The key step in the synthesis of these oxygen heterocycles
is the introduction of the hydroperoxy group. In the re-
ported methods, this has been achieved by H2O2-mediated
reaction of acetophenone-derived carbinols,6 photooxy-
genation of allylic or homoallylic alcohols,7 Lewis acid
catalyzed opening of oxetanes by hydrogen peroxide,8 and
ozonolysis of enol ethers.9 Taking into consideration the
importance of phenyl substituents on the 1,2,4-trioxanes
and trioxepanes evident from work by Singh et al.,10 we
have investigated a new route for 1,2,4-trioxepanes pos-
sessing an aryl substituent at C-7 and 1,2,4-trioxanes pos-
sessing diaryl substituents at C-6 to assess their
antimalarial potential.
Figure 1
therefore provide a π cloud which stabilizes the positive
charge on the adjacent carbon atom.11
Thus, we devised our synthetic strategy for the generation
of γ-hydroxyhydroperoxides from cyclopropyl-substitut-
ed diols (Scheme 1).
R2
R3
O
O
O
OH
OH
OH
O
Ph
R1
Ph
R1
Ph
OH
n
R1
n
n
It was reported that cyclopropyl-substituted alcohols react
efficiently with 30% H2O2 in the presence of concentrated
H2SO4 to furnish cyclopropyl-substituted hydroperox-
ides.12 The greater stability of the cyclopropyl methyl car-
bocation is due to the fact that the bonds in the
cyclopropane ring have considerable sp2 character and
n = 2, R1 = c-Pr
1,2,4-trioxepanes
n = 1, R1 = Ph
1,2,4-trioxanes
Scheme 1
The cyclopropyl-substituted diol 4 was readily accessible
by reaction of the corresponding cyclopropyl phenyl ke-
tone with an α-halo ester in the presence of zinc, followed
by reduction with lithium aluminum hydride. The 1,3-diol
SYNLETT 2013, 24, 0173–0176
Advanced online publication: 21.12.2012
DOI: 10.1055/s-0032-1317958; Art ID: ST-2012-D0926-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

174
M. Ravi et al.
LETTER
OH
OH
O
O
(b)
(a)
+
Br
O
OH
O
O
1
2
3
4
(c)
R1
R2
O
O
O
OH
(d)
O
OH
5 R1CR2 = cyclohexyl
6 R1CR2 = adamantyl
7 R1CR2 = cyclopentyl
8 R1 = R2 = Me
Scheme 2 Reagents and conditions: (a) Zn, benzene, reflux, 2–7 h; (b) LiAlH4, Et2O, 0 °C, 1 h; (c) 30% H2O2, concd H2SO4, CH2Cl2, 0–5 °C,
3 h; (d) cyclic ketones, PTSA (20 mol%), CH2Cl2, 0–5 °C, 1.5–2.5 h.
4 was treated with 30% H2O2 in the presence of H2SO4 in
dichloromethane to furnish γ-hydroxyhydroperoxide.
Subsequent acid-catalyzed condensation of the hydroxy-
hydroperoxide with various ketones afforded the corre-
sponding 1,2,4-trioxepanes 5–8 in good yields (Scheme 2,
Table 1).
OH
(b)
(a)
OH
OH
O
OH
O
O
OH
9
10
11
(c)
In the initial synthesis of 1,2,4-trioxepanes, diol 4 was re-
acted with three equivalents of 30% H2O2 in the presence
of concentrated H2SO4 (1 equiv) in dichloromethane. Sub-
sequently, it was observed that a combination of four
equivalents of 30% H2O2, 0.5 equivalents of concentrated
H2SO4, and dichloromethane as solvent was optimal for
the hydroperoxidation. For the peroxyketalization, we
used 10 mol% of PTSA with a further increase in catalyst
loading to 20 mol% leading to marginal improvement in
the yield.
O
OH
OH
R1
R2
O
O
O
(d)
We also observed that diphenyl-substituted diols react ef-
ficiently with 30% H2O2 in the presence of concentrated
H2SO4. This strategy was used to prepare β-hydroxyhy-
droperoxides to furnish 1,2,4-trioxanes in good yields
(Table 1). To the best of our knowledge this is the first re-
port of the synthesis of C-6 diaryl-substituted 1,2,4-triox-
anes. In the case of diphenyl-substituted diols, the doubly
benzylic carbocation is the more stable and hence can be
trapped to form the corresponding hydroperoxide. The di-
phenyl-substituted diol 11 was easily accessible by reduc-
tion of benzilic acid ethyl ester (10). The diol 11 was
further treated with 30% H2O2 in the presence of concen-
trated H2SO4 to furnish β-hydroxyhydroperoxide. The
acid-catalyzed peroxyketalization of β-hydroxyhydroper-
oxide with different ketones furnished 1,2,4-trioxanes 12
and 13 (Scheme 3). All the synthesized compounds were
characterized by spectroscopic analyses. A representative
synthetic procedure for the synthesis of compound 5 and
representative data for compounds 5 and 13 are provided
in the references.13–15
12 R1CR2 = adamantyl
13 R1CR2 = cyclohexyl
Scheme 3 Reagents and conditions: (a) EtOH, concd HCl, reflux,
80 °C, 4–5 h; (b) LiAlH4, Et2O, 0 °C, 45 min; (c) 30% H2O2, concd
H2SO4, CH2Cl2, 0–5 °C, 2.5 h; (d) cyclic ketone, PTSA (20 mol%),
CH2Cl2, 0–5 °C, 1.5 h.
In summary we have developed a simple and efficient
method for the synthesis of 1,2,4-trioxanes and 1,2,4-tri-
oxepanes in good to moderate yields. The reactions pro-
ceed under mild conditions and short reaction times.
Further modifications of the benzilic acid derived 1,2,4-
trioxanes having different degrees of substitution are in
progress.
Acknowledgment
We thank SAIF-CDRI, Lucknow for providing spectroscopic and
analytical data. M.R, D.R, R.M and P.C are thankful to the Council
of Scientific and Industrial Research (CSIR), New Delhi, for Fel-
lowship. Authors are also thankful to Mr. Anoop K. Srivastava for
providing technical support during the course of work. This is CDRI
communication No. 8369.
Synlett 2013, 24, 173–176
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of 1,2,4-Trioxepanes and 1,2,4-Trioxanes
175
Table 1 Synthesized 1,2,4,-Trioxepanes 5–8 and 1,2,4,-Trioxanes 12 and 13
30% H2O2 (4 equiv)
concd H2SO4 (0.5 equiv), CH2Cl2
OH
OH
O
R2
R3
OH
O
O
O
Ph
Ph
R1
Ph
R1
PTSA (20 mol%), CH2Cl2
step 2
OH
R1
step 1
n
n
n
Step 1
n
Step 2
R2COR3
R1
Time (h)
Product
Time (h)
1.5
Yield (%)a
Mp (°C)
O
O
O
2
c-Pr
3
cyclohexanone
adamantanone
65
94–95
5
O
O
O
O
O
O
O
O
O
2
2
2
c-Pr
c-Pr
c-Pr
3
3
3
1.5
62
55
50
103–105
79–80
oil
6
7
8
cyclopentanone
2
acetone
2.5
O
O
1
1
Ph
Ph
2.5
2.5
adamantanone
cyclohexanone
1.5
1.5
63
62
108–110
100–101
O
12
13
O
O
O
a Overall yield for two steps.
1988, 31, 713. (c) Fujisaku, T.; Miura, M.; Nojima, M.;
Kasabayashi, S. J. Chem. Soc., Perkin Trans. 1 1989, 1031.
(d) Bloodworth, A. J.; Shah, A. J. Chem. Soc., Chem.
Commun. 1991, 947. (e) Bunelle, W. H.; Isbell, T. A.;
Barnes, C. L.; Qualls, S. J. Am. Chem. Soc. 1991, 113, 8168.
(f) Bloodworth, A. J.; Johnson, K. A. Tetrahedron Lett.
1994, 35, 8057. (g) O’Neill, P. M.; Pugh, M.; Davies, J.;
Ward, S. A.; Park, B. K. Tetrahedron Lett. 2001, 42, 4569.
(h) 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.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
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ungIifoop
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References and Notes
(1) World Malaria Report; World Health Organization: Geneva,
2011, ; http://www.who.int/-
malaria/world_malaria_report_2011/en/.
(2) Klayman, D. L. Science 1985, 228, 1049.
(3) (a) Jefford, C. W.; Jaggi, D.; Boukouvalas, J.; Kohmoto, S.
J. Am. Chem. Soc. 1983, 105, 6498. (b) Kepler, J. A.; Philip,
A.; Lee, Y. W.; Morey, M. C.; Caroll, F. I. J. Med. Chem.
(4) Singh, C.; Verma, V. P.; Naikade, N. K.; Singh, A. S.;
Hassam, M.; Puri, S. K. J. Med. Chem. 2008, 51, 7581.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 173–176

176
M. Ravi et al.
LETTER
(5) Singh, C.; Pandey, S.; Sharma, M.; Puri, S. K. Bioorg. Med.
Chem. 2008, 16, 1816.
(6) Adam, W.; Duran, N. J. Chem. Soc., Chem. Commun. 1972,
798.
(7) Singh, C. Tetrahedron Lett. 1990, 31, 6901.
(8) Dussault, P. H.; Trullinger, T. K.; Noor-e-Ain, F. Org. Lett.
2002, 4, 4591.
(9) (a) Dussault, P. H.; Davies, D. R. Tetrahedron Lett. 1996,
37, 463. (b) Ushigoe, Y.; Torao, Y.; Masuyama, A.; Nojima,
M. J. Org. Chem. 1997, 62, 4949. (c) Ushigoe, Y.; Kano, Y.;
Nojima, M. J. Chem. Soc., Perkin Trans. 1 1997, 5.
(d) Ahmed, A.; Dussault, P. H. Org. Lett. 2004, 6, 3609.
(10) (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.; Malik, H.; Puri, S. K. Bioorg. Med.
Chem. Lett. 2004, 14, 459. (d) Singh, C.; Malik, H.; Puri, S.
K. J. Med. Chem. 2006, 49, 2794. (e) Singh, C.; Kanchan,
R.; Sharma, U.; Puri, S. K. J. Med. Chem. 2007, 50, 521.
(11) Wong, H. N. C.; Hon, M. Y.; Tse, C. W.; Yip, Y. C.; Tanko,
J.; Hudlicky, T. Chem. Rev. 1989, 89, 165.
extracted with CH2Cl2 (3 × 25 mL). The combined organic
layers were washed with sat. aq NaHSO3 solution (25 mL)
and H2O (2 × 25 mL). The combined organic layer was dried
(Na2SO4), the solution reduced to 50 mL under reduced
pressure, and the crude hydroxyhydroperoxide was reacted
with cyclohexanone (0.74 mL, 7.2 mmol) in the presence of
PTSA (0.2 g, 1 mmol) with stirring for 1.5 h at 0–5 °C. The
reaction mixture was concentrated in vacuo at r.t., and the
crude product was purified by column chromatography over
silica gel using 1.0% EtOAc–hexane as eluent to furnish
0.97g (65%) of 5 as a white solid.
(14) Compound 5: mp 94–95 °C. FT-IR (KBr): 2933.9, 1659.3,
755.6 cm–1. 1H NMR (300 MHz, CDCl3): δ = 0.14–0.37 (m,
4 H), 1.03 (br s, 1 H), 1.33–1.57 (m, 8 H), 1.96 (br d, 2 H),
2.28 (br d, 1 H), 2.57 (br d, 1 H), 3.73–3.85 (m, 2 H), 7.25–
7.37 (m, 5 H). 13C NMR (75 MHz, CDCl3): δ = 1.02 (CH2),
1.36 (CH2), 20.43 (CH), 22.81 (CH2), 23.07 (CH2), 25.5
(2 × CH2), 32.73 (CH2), 41.12 (CH2), 59.17 (CH2), 87.86
(C), 106.19 (C),126.85 (CH), 127.05 (CH), 127.64 (CH),
141.31 (C). APCI-MS: m/z = 287 [M + H+]. Anal. Calcd for
C18H24O3: C, 74.97; H, 8.39. Found: C, 74.91; H, 8.43.
(15) Compound 13: yield 62%, white solid, mp 100–101 °C. FT-
IR (KBr): 2937, 1661.2, 764.9 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 1.46–1.76 (m, 10 H), 4.54 (s, 2 H), 7.26–7.37
(m, 6 H), 7.43–7.46 (m, 4 H). 13C NMR (75MHz, CDCl3): δ
= 24.01 (2 × CH2), 25.23 (CH2), 36.12 (2 × CH2), 74.80
(CH2), 85.72 (C), 111.33 (C), 126.22 (4 × CH), 127.16
(2 × CH), 128.16 (4 × CH), 144.88 (2 × C). APCI-MS: m/z
= 311 [M + H]+. Anal. Calcd for C20H22O3: C, 77.39; H, 7.14.
Found: C, 77.43; H, 7.20.
(12) Singh, C.; Srivastav, N. C.; Srivastav, N.; Puri, S. K.
Tetrahedron Lett. 2005, 46, 2757.
(13) Representative Procedure for the Synthesis of 1,2,4-
Trioxepane 5
To an ice-cooled (0–5 °C) solution of 1,3-diol 4 (1.00 g, 5.2
mmol) in CH2Cl2 (50 mL) was added 30% H2O2 (0.64 mL,
20.8 mmol) followed by dropwise addition of concd H2SO4
(0.14 mL, 2.6 mmol) with constant stirring, and the mixture
was stirred at 0–5 °C for 3 h. The reaction mixture was
diluted with cold H2O (25 mL), and the aqueous layer was
Synlett 2013, 24, 173–176
© Georg Thieme Verlag Stuttgart · New York