Synthesis of 3,6-epoxy[1,5]dioxocines from 2-hydroxyaromatic benzaldehydes

Article abstract of DOI:10.1016/j.tetlet.2011.08.095

Convenient and facile one step synthesis of medicinally relevant new 3,6-epoxy[1,5]dioxocines from 2-hydroxyaromatic benzaldehydes is described. The scope of the method was validated by examining the use of both electron rich and electron-deficient 2-hydroxyaromatic benzaldehydes.

Full text of DOI:10.1016/j.tetlet.2011.08.095

Tetrahedron Letters 52 (2011) 5659–5663
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Synthesis of 3,6-epoxy[1,5]dioxocines from 2-hydroxyaromatic benzaldehydes q
⇑
Koneni V. Sashidhara , Abdhesh Kumar, K. Bhaskara Rao
Medicinal and Process Chemistry Division, Central Drug Research Institute, CSIR-CDRI, Lucknow 226 001, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Convenient and facile one step synthesis of medicinally relevant new 3,6-epoxy[1,5]dioxocines from
2-hydroxyaromatic benzaldehydes is described. The scope of the method was validated by examining
the use of both electron rich and electron-deficient 2-hydroxyaromatic benzaldehydes.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 13 July 2011
Revised 14 August 2011
Accepted 17 August 2011
Available online 23 August 2011
Keywords:
Synthesis
3,6-Epoxy[1,5]dioxocines
2-Hydroxyaromatic benzaldehydes
Triethylamine
Dioxocines are synthetic intermediates in the preparation of a
variety of organic compounds of medicinal interest. The dehydrat-
ing dimerization of salicylaldehydes is known to furnish 6H,
12H-6,12-epoxydibenzo[b,f][1,5]dioxocins1 which upon further
functionalization, could be converted to preussomerin family of
natural products, which were first isolated from the coprophilous
fungus Preuussia Isomera.2 Furthermore, some 12H-dibenzo[d,g]
[1,3]dioxocin derivatives have also been investigated for their anti-
dyslipidemic activity. In fact, it is interesting to note that such a
structure, is necessarily related to their pharmacological activity
and is present in many biologically active natural products. Figure
1 shows the chemical structures of some naturally occurring
potent dioxocine derivatives.3,4
Due to their interesting biological activities, various diverse
synthetic strategies have been developed for the synthesis of these
compounds.5–8 Their synthesis is associated with many drawbacks
such as the use of potentially hazardous catalyst, application of
costly reagents, sophisticated reaction conditions, unwanted side
products, poor yield and some starting materials that are not read-
ily available. On the other hand, recently Getautis co-workers have
reported an one-pot method for the synthesis of 3,6-epoxy
[1,5]dioxocines, catalysed by the phase transfer catalyst (benzyl
triethylammonium chloride) condensation of electron-deficient
salicylaldehydes with epichlorohydrin, but this method has limita-
tions like longer reaction times (60 h) and is applicable for elec-
tron-deficient salicylaldehydes only.9 So there is scope to develop
a convenient and general approach towards the synthesis of
3,6-epoxy[1,5]dioxocines. Herein, we wish to report a facile and
general method for the preparation of new substituted 3,6-
epoxy[1,5]dioxocines in good yields by the Et3N catalysed reaction
of epichlorohydrin with both electron rich and electron-deficient
salicyl aldehydes.
Et3N is quite economical, eco-friendly and a mild base that can
also avoid the problem of side reactions in base-sensitive sub-
strates. It has been demonstrated that this commercially available
base could be used as an efficient catalyst for the synthesis of a
wide variety of organic compounds.10–24
An initial study was performed by the treatment of 4-hydroxy-
5-methylisophthalaldehyde 1a, with epichlorohydrin in the pres-
ence of a catalytic amount of potassium carbonate at ambient
temperature. Initially, we observed the formation of two products
(TLC monitoring during the course of the reaction) that differed
slightly in their polarity. As the reaction time increased, the more
polar product gradually got converted (TLC monitoring) in to the
less polar one. It is apparent that compound 1aa undergoes intra-
molecular cyclization, which results in the formation of the stable
3,6-epoxy[1,5]dioxocines 2a. Complete conversion and 80% iso-
lated yield were obtained after 8 h. The synthetic approach is
depicted in Scheme 1.
Encouraged by these results, we screened several different
bases (organic and inorganic) as catalyst for the reaction of 4-hy-
droxy-5-methylisophthalaldehyde 1a, with epichlorohydrin. The
results are shown in Table 1. Much to our delight, Et3N was found
to be an excellent catalyst to catalyse the reaction. It not only
shortens the reaction time but also provides excellent yields. To
the best of our knowledge, there are no reports of Et3N-catalysed
synthesis of 3,6-epoxy[1,5]dioxocines.
q
Part VI in the series, ‘Studies on Novel Synthetic Methodologies’.
⇑
Corresponding author. Tel.: +91 9919317940; fax: +91 522 2623405.
E-mail addresses: sashidhar123@gmail.com, kv_sashidhara@cdri.res.in (K.V.
To optimize the Et3N requirements, 0.5, 0.75, 1.0 and 1.5 mmol
(entries 5–8 in Table 1) were employed, and the best results were
Sashidhara).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.095

5660
K. V. Sashidhara et al. / Tetrahedron Letters 52 (2011) 5659–5663
OH
O
OH
O
O
OH
O
O
O
O
OH
HO
O
O
O
OH
O
O
O
O
O
O
OMe
O
HO
HO
Penicillidine3
OH
Preussomerin A2
O
Preussomerin I2
Pestalotiollide A4
Figure 1. Structures of some naturally occurring potent dioxocine derivatives.
Table 1
Optimization of reaction conditions for the synthesis of 3,6-epoxy[1,5]dioxocines 2a
O
O
Cl
O
OH
O
O
O
Cl
O
OH
O
H
H
O
O
O
CHO
Base, reflux, time
O
K2CO3, reflux
H
O
H
O
H
O
CHO
CHO
1aa
2a
1a
1a
2a
Scheme 1. Synthesis of 3,6-epoxy[1,5]dioxocines 2a.
Entry
Product
Base (mmol)
Time (h)
Yield (%)
obtained with 0.75 mol of Et3N at reflux in terms of yield and time
duration (entry 7 in Table 1). In the absence of Et3N, the reaction
did not proceed. Initially, the reaction was attempted with differ-
ent solvents (ethanol, DCM, DMF) but the yields were found to
be better in the absence of any solvent as shown in Table 2 (entry
4).
With this finding, we examined the applicability of this catalytic
system to various substituted 2-hydroxyaromatic benzaldehydes,
possessing electron-donating or electron-withdrawing substitu-
ents and all afforded the desired products in very satisfactory
yields. A variety of new 3,6-epoxy[1,5]dioxocines were synthesized
in a one-step process in good to high yields in the presence of Et3N
under reflux to afford the respective products. The representative
results are shown in Table 3. Substituents on the salicylaldehydes
had little influence both on the yield and the time of the reaction.
Interestingly, electron-deficient 2-hydroxyaromatic benzalde-
hydes underwent faster condensation with epichlorohydrin
compared to neutral and electron rich 2-hydroxyaromatic benzal-
dehydes to afford the respective products.
1
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2a
2a
2a
K2CO3 (1.0)
KOH (1.0)
NaHCO3 (1.0)
DABCO (1.0)
Et3N (1.5)
Et3N (1.0)
Et3N (0.75)
Et3N (0.5)
N-Methylmorpholine (1.0)
8.0
6.0
30.0
2.0
0.8
1.0
1.0
1.2
1.1
80
72
65
84
84
88
93
86
92
Table 2
Optimization of reaction solvents
Entry
Product
Solvent
Time (h)
Yield (%)
1
2
3
4
2a
2a
2a
2a
Ethanol
DCM
DMF
3.5
2.5
3.0
1.0
72
76
68
93
Neat
To demonstrate the generality and the applicability of the opti-
mized reaction conditions to other more complex molecules, that
is, electron rich 2-hydroxyaromatic benzaldehydes containing
chalcone moiety at para-position was utilized for the reaction.
These derivatives (1k–p) readily condensed with epichlorohydrin
to form their corresponding 3,6-epoxy[1,5]dioxocines (2k–p) in
good to excellent yields, indicating that this reaction is quite
general and has very broad substrate scopes. These chalcones
(1k–p) were obtained from the condensation reaction of respec-
tive 2-hydroxyaromatic dicarbaldehydes with acetophenones
(Table 3).25
This reaction is clean and free from side reactions, such as self-
condensation of aldehydes, which are normally observed under
basic conditions. It is apparent that the polycyclic compound
formed is the result of intramolecular cyclization of the initial ad-
duct formed by the reaction of epichlorohydrin on the phenol. This
was also confirmed by the fact that we could isolate the interme-
diate formed during the early course of the reaction. The structures
of the products were established from their spectroscopic (IR, 1H
NMR, 13C NMR, 2D NMR and elemental analysis or HRMS) data.26
The isolated product was found to be a mixture of two enantio-
mers, in which the chiral centres have R,S and S,R configuration.9
To the best of our knowledge, there is only one report of the
condensation of salicylaldehydes and epichlorohydrin, using
benzyl triethylammonium chloride as PTC to form 3,6-epoxy[1,5]
dioxocines.9 The reaction was conducted in the presence of PTC
and required a long time (60 h). Moreover, electron rich salicylal-
dehydes failed to give the desired product under the reaction
conditions employed.
In conclusion, we have demonstrated here a simple, and effi-
cient route for the synthesis of 3,6-epoxy[1,5]dioxocines utilizing
Et3N as a catalyst. This method not only provides an excellent com-
plement to dioxocines synthesis, but also avoids the use of hazard-
ous acids or bases and harsh reaction conditions. The advantages of
this method include good substrate generality, the use of inexpen-
sive reagents/catalyst and experimental operational ease. The
functional groups such as aldehyde and a–b unsaturated carbonyl

K. V. Sashidhara et al. / Tetrahedron Letters 52 (2011) 5659–5663
5661
Table 3
Et3N mediated general synthesis of 3,6-epoxy[1,5]dioxocines
OH
O
OH
O
OH
O
O
O
O
O
H
a
b
a
H
H
R
CHO
R
1a
j
2a−p
−
1a, 1f
R1
R = H, Br, CHO, .Butyl, CH=CHCOAr
t
R1 = H, CH3, OCH3
1k p
−
Entry
1
Reactant
Product
Time (min)
Yielda (%)
Mp (°C)
OH
O
CHO
O
O
60
93
98–100
98–100
CHO
CHO
O
1a
2a
OH
CHO
CHO
O
O
O
2
3
4
5
65
65
70
70
91
92
91
92
CHO
OH
CHO
1b
2b
O
O
80–82
CHO
CHO
O
1c
2c
OH
CHO
O
O
78–80
CHO
1d
CHO
O
2d
OH
O
CHO
O
O
105–107
CHO
OH
CHO
1e
1f
2e
2f
O
CHO
O
H
6
70
90
182–183
CHO
O
OH
O
O
O
O
H
7
8
85
90
89
88
145–147
1g
2g
OH
O
H
O
O
O
140–142
1h
2h
(continued on next page)

5662
K. V. Sashidhara et al. / Tetrahedron Letters 52 (2011) 5659–5663
Table 3 (continued)
Entry
Reactant
Product
Time (min)
75
Yielda (%)
Mp (°C)
OH
O
O
O
O
H
9
90
Oily
1i
2i
OH
Br
O
O
O
O
H
10
45
93
Oily
1j
Br
2j
OH
O
CHO
O
O
11
65
92
120–122
O
O
1k
2k
OH
O
CHO
O
O
12
65
90
142–143
O
O
1l
2l
OH
O
CHO
O
O
13
65
91
140–142
O
O
OCH3
1m
OCH3
2m
OH
O
CHO
O
O
14
70
89
132–134
O
O
1n
2n
OH
O
CHO
O
O
15
70
90
137–138
O
O
1o
2o

K. V. Sashidhara et al. / Tetrahedron Letters 52 (2011) 5659–5663
5663
Table 3 (continued)
Entry
Reactant
OH
Product
Time (min)
Yielda (%)
Mp (°C)
O
CHO
O
O
16
70
87
174–175
O
O
O
1p
O
2p
Reagents and conditions: (a) Epichlorohydrin, Et3N, reflux, 45–90 min; (b) concd HCl, p-R1C6H4COCH3, dioxane, 80–90 °C, 2.5–3.5 h.
a
Isolated yields.
9. Janeliunas, D.; Daskeviciene, M.; Malinauskas, T.; Getautis, V. Tetrahedron 2009,
65, 8407–8411.
10. Roh, J.; Vavrova, K.; Hrabalek, A. Tetrahedron Lett. 2010, 51, 1411–1414.
11. Chen, J.; Shum, W. Tetrahedron Lett. 1995, 36, 2379–2380.
12. Sun, J.; Xia, E. Y.; Wu, Q.; Yan, C. G. Org. Lett. 2010, 12, 3678–3681.
13. Hari, A.; Miller, B. L. Org. Lett. 1999, 1, 2109–2111.
groups are tolerated under the reaction conditions to provide
structurally interesting 3,6-epoxy[1,5]dioxocines in high yields.
Acknowledgments
14. Parcher, B. W.; Erion, D. M.; Dang, Q. Tetrahedron Lett. 2004, 45, 2677–2679.
15. Wang, B.; Bonin, M.; Micouin, L. Org. Lett. 2004, 6, 3481–3484.
16. Ajiki, K.; Hirano, M.; Tanaka, K. Org. Lett. 2005, 7, 4193–4195.
17. Yamanoi, Y.; Taira, T.; Sato, J.; Nakamula, I.; Nishihara, H. Org. Lett. 2007, 9,
4543–4546.
18. Murata, M.; Ishikura, M.; Nagata, M.; Watanabe, S.; Masuda, Y. Org. Lett. 2002,
4, 1843–1845.
19. Li, M.; Hou, Y. L.; Wen, L. R.; Gong, F. M. J. Org. Chem. 2010, 75, 8522–8532.
20. Williams, G. D.; Pike, R. A.; Wade, C. E.; Wills, M. Org. Lett. 2003, 5, 4227–4230.
21. Tejedor, D.; Lo´pez-Tosco, S.; Gonza´lez-Platas, J.; Garc´ıa-Tellado, F. J. Org. Chem.
2007, 72, 5454–5456.
22. Kumar, V.; Nair, V. A. Tetrahedron Lett. 2010, 51, 966–969.
23. Sengiil, M. E.; Ceylan, Z.; Balcl, M. Tetrahedron 1997, 53, 10401–10408.
24. Li, H.; Yan, C. G. Tetrahedron 2011, 67, 2863–2869.
25. Sashidhara, K. V.; Kumar, A.; Kumar, M.; Sarkar, J.; Sinha, S. Bioorg. Med. Chem.
Lett. 2010, 20, 7205–7211.
Authors acknowledge the SAIF Division for providing the spec-
troscopic and analytical data. We are also thankful to Dr. T.K. Cha-
kraborty (Director, CDRI) for his constant support and
encouragement. A.K. and K.B.R. are thankful to CSIR, New Delhi, In-
dia for the financial support. This is CSIR-CDRI contribution num-
ber 8117.
Supplementary data
Supplementary data (spectral data of all the compounds) asso-
ciated with this article can be found, in the online version, at
doi:10.1016/j.tetlet.2011.08.095.
26. General procedure for the synthesis of 3,6-epoxy[1,5]dioxocines (2a–p): A solution
of 2-hydroxyaromatic benzaldehydes (3.0 mmol) was dissolved in excess of
epichlorohydrin to which Et3N (2.3 mmol) was added and the reaction mixture
was then refluxed for 45–90 min. After completion of the reaction, excess of
epichlorohydrin was removed under reduced pressure. The solid residue was
poured in water and extracted threefold with 20 mL of CHCl3. The combined
organic layers were dried on Na2SO4, filtered, and concentrated to dryness
under reduced pressure. The crude products were purified over column
chromatography (60–120 mesh) to afford final compounds. The representaive
spectral data of the compound (2a) is given: white solid; mp 98–100 °C; 1H
NMR (CDCl3, 300 MHz): d 9.88 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 6.10 (s, 1H),
4.72–4.69 (m, 1H), 4.47–4.42 (m, 1H), 4.31 (d, J = 6.8 Hz, 1H), 4.04–3.96 (m,
2H), 2.30 (s, 3H); 13C NMR (CDCl3, 75 MHz): d 191.0, 160.1 133.2, 133.1, 131.6,
130.8, 128.4, 105.8, 75.4, 74.1, 66.0, 16.6; IR (KBr): 3015, 1690, 1597,
References and notes
1. Grisar, J. M.; Parker, R. A.; Kariya, T.; Blohm, T. R.; Fleming, R. W.; Petrow, V. J.
Med. Chem. 1972, 15, 1273–1278.
2. Ragot, J. P.; Prime, M. E.; Archibald, S. J.; Taylor, R. J. K. Org. Lett. 2000, 2,
1613–1616.
3. Brückner, D.; Hafner, F. T.; Li, V.; Schmeck, C.; Telser, J.; Vakalopoulos, A.; Wirtz,
G. Bioorg. Med. Chem. Lett. 2005, 15, 3611–3614.
4. Xu, J.; Aly, A. H.; Wray, V.; Proksch, P. Tetrahedron Lett. 2011, 52, 21–25.
5. Liang, J. C.; Yeh, J. L.; Wang, C. S.; Liou, S. F.; Tsai, C. H.; Chen, I. J. Bioorg. Med.
Chem. 2002, 10, 719–730.
6. Stephenson, O. J. Chem. Soc. 1954, 1571–1577.
7. Birch, A.; Bradley, P.; Gill, J.; Kerrigan, F.; Needham, P. J. Med. Chem. 1999, 42,
3342–3355.
1068 cmÀ1
;
ESI-MS (m/z): 221 (M+H)+. HRMS calcd for C12H12O4 (M+H)+
221.0814. Found: 221.0815.
8. Hennis, H. E.; Thompson, L. R.; Wang, C. S.; Priddy, D. B. J. Org. Chem. 1970, 56,
3127–3129.