Study of the interaction of salicyl aldehydes with epichlorohydrin: a simple, convenient, and efficient method for the synthesis of 3,6-epoxy[1,5]dioxocines

Article abstract of DOI:10.1016/j.tet.2009.07.093

An efficient synthetic method for 3,6-epoxy[1,5]dioxocines via the condensation of salicyl aldehydes and epichlorohydrin, using benzyl triethylammonium chloride as catalyst, is described. The use of neutral or electron-deficient salicyl aldehydes in all c

Full text of DOI:10.1016/j.tet.2009.07.093

Tetrahedron 65 (2009) 8407–8411
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Study of the interaction of salicyl aldehydes with epichlorohydrin:
a simple, convenient, and efficient method for the synthesis
of 3,6-epoxy[1,5]dioxocines
*
Dainius Janeliunas, Maryte Daskeviciene, Tadas Malinauskas, Vytautas Getautis
Department of Chemical Technology, Kaunas University of Technology, Radvilenu pl. 19, LT-50270 Kaunas, Lithuania
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 18 May 2009
Received in revised form 11 July 2009
Accepted 30 July 2009
Available online 3 August 2009
An efficient synthetic method for 3,6-epoxy[1,5]dioxocines via the condensation of salicyl aldehydes and
epichlorohydrin, using benzyl triethylammonium chloride as catalyst, is described. The use of neutral or
electron-deficient salicyl aldehydes in all cases was found to give 3,6-epoxy[1,5]dioxocine derivatives in
good yields. The structural features were resolved by IR, NMR spectroscopy, mass spectrometry, and
ultimately proved by X-ray crystallographic analysis.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Dioxocine
Epichlorohydrin
Salicyl aldehydes
Intramolecular cyclization
1. Introduction
may be partially solved by addition of a phase transfer catalyst (PTC)
to the aqueous solution of base (K2CO3 or similar).5a,c,f,h,6a,e How-
Epoxides have become very popular in organic synthesis not
only as building blocks but also as synthesis intermediates.1 They
can be easily prepared from a variety of substrates and are easily
opened under a broad range of conditions giving a wide spectrum
of materials. Particularly, O-alkylation reactions of various
substituted phenols with epichlorohydrin are of great interest as
the products obtained are of value in both industrial and academic
applications.2 Consequently, synthetic methodologies for preparing
glycidyl ethers have attracted considerable interest and several
methods offering good results have been reported.2e,3
ever, excellent yields of glycidyl ethers were obtained only when the
compounds investigated contained electron-donating groups,
while presence of electron-withdrawing ones led to formation of
1-chloro-3-aryloxypropan-2-ols in large amounts as unwanted
by-products.7
The reaction of epichlorohydrin with compounds possessing the
salicyl aldehyde core has not been thoroughly investigateddonly
a limited number of papers were published to this date.2b,4b,c
2. Results and discussion
The simplest and most popular method for preparation of
3-aryloxy-1,2-epoxypropanes consists of the one-step O-alkylation
of the suitable phenol with epichlorohydrin in the presence of
a base.2b,4 Generally, in all the procedures described, the epichlo-
rohydrin is used in a significant excess and the reaction is carried out
in an aqueous solution of a base, or in an organic solvent containing
pyridine or piperidine.5,6 Depending on the substituent position and
nature of the phenol, it takes 6–20 h at reflux or 24–26 h at room
temperature to complete the reaction. However, classical methods
possess a number of drawbacks, such as: moderate yields, moderate
purity of products, and poor reaction selectivity.4,5a These problems
During our ongoing research program on the study of epichloro-
hydrin interactions with various substrates, we found that
2-hydroxybenzaldehyde (1a) and epichlorohydrin afforded the
glycidyl ether 2a in high yield in the presence of benzyl triethy-
lammonium chloride as a PTC. The reaction was carried out at the
reflux temperature (125 ꢀC) of epichlorohydrin and under these
conditions reaction duration was 10 min (Scheme 1).
An increase in reaction time resulted in formation of the new
product (TLC monitoring, during the course of the reaction, showed
two products, one of them gradually fading in favor of the other).
Utilizing spectroscopic and elemental analysis data
a new
compound was identified as 3,4-dihydro-2H,6H-3,6-epoxy-benzo-
[1,5]dioxocine (3a). It is apparent that 2-(2-oxiranylmethoxy)-
benzaldehyde (2a) undergoes intramolecular cyclization, which
* Corresponding author. Tel.: þ370 37 300196; fax: þ370 37 300152.
E-mail address: vgetaut@ktu.lt (V. Getautis).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.07.093

8408
D. Janeliunas et al. / Tetrahedron 65 (2009) 8407–8411
O
O
O
O
OH
O
Cl
Table 1
, cat.
R
R
Reaction products, times, and yields
2a-d
reflux
1a-i
Entry
Product
Time
Yield (%)
86
cat.
O
reflux
One Pot Reaction
O
O
O
2a
10 min
O
O
R
Catalyst is PhCH2Et3N+Cl–.
Scheme 1. Reactions of salicyl aldehydes with EPH.
3a-h
O
O
O
2b
2c
15 min
15 min
79
86
results in the formation of 3,6-epoxy[1,5]dioxocine based polycyclic
compound. To generalize the methodology, we investigated
a number of different salicyl aldehydes possessing electron-do-
nating or electron-withdrawing substituents. As seen from the
results presented in Table 1, this method is most effective for
electron-deficient salicyl aldehydes. The reaction time is strongly
influenced by the relative strength of the electron-withdrawing
group. 1i with a nitro group, at the m-position relative to the car-
bonyl moiety, reacts in 30 min while halogen containing ones 1d–f
take 20 h. Neutral salicyl aldehydes 1a, b react even slower (60 h);
meanwhile, compound 1c, containing an electron-donating dieth-
ylamino moiety, does not form the desired product at all and only
glycidyl ether 2c is obtained. Nonetheless, despite significantly
increased reaction times all the products were isolated in good to
excellent yields. In order to confirm the assumption that the de-
sired products 3a–h are obtained via an intramolecular cyclization
of corresponding glycidyl ethers, a number of intermediate com-
pounds 2a, b, d were isolated and their structures confirmed (Table 1).
This relatively simple and easy synthesis method of 3,6-epoxy[1,5]-
dioxocine derivatives could be of particular interest in the field of
medicinal chemistry, as dioxocine derivatives are important in
pharmaceutical and agricultural applications.8 It is also noteworthy
that the variety of functional groups available could make these
compounds appealing intermediate materials for the synthesis of
other new and important derivatives.
O
O
O
N
O
O
O
2d
3a
15 min
60 h
81
74
Cl
O
O
O
O
O
3b
60 h
72
O
O
O
3c
3d
3e
3f
20 h
20 h
20 h
10 h
82
73
71
77
O
F
The structures of the goal products are confirmed by the spectral
analysis. In Figure 1 a typical exampled(3,4-dihydro-2H,6H-3,6-
epoxy-8-nitro-benzo[1,5]dioxocine (3h)) is analyzed.
O
O
O
O
Thus, a singlet of the CH group attached to the phenyl ring ap-
pears at 6.05 ppm and can be easily explained by deshielding
effects due to its neighboring aromatic fragment and two oxygen
atoms. The other aliphatic protons, of the isolated product, yield
a set of signals for five not equivalent protons. They were analyzed
as two spin–spin systems with one generic proton: AMX and A0M0X.
The resonances of CH2 protons (labeled HA and HM in Fig. 1) appear
as a triplet and doublet of doublets positioned at 4.01 and
4.30 ppm, respectively (JAM¼6.9 Hz, JAx¼6.9 Hz, and JMx¼1.3 Hz).
This is due to the coupling with CH (labeled Hx), which in turn is
observed as a multiplet at 4.78–4.71 ppm. The A0M0X system, on the
Cl
O
O
Br
O
O
O
O
0
other hand, is not typical. HM appears as a doublet of doublets at
0
0
0
0
4.43 ppm (JA M ¼13.2 Hz, JM x¼2.6 Hz), while HA is observed as
a doublet centered at 4.09 ppm. This phenomenon can be explained
by the fact that a vicinal coupling constant between protons Hx and
O
O
3g
3h
30 min
89
89
O
0
HA is 0 Hz. It means there is no interaction between these two
protons, consequently the dihedral angle between vicinal protons
Hx and HA tends to be ca. 90ꢀ. MO calculations confirm this as-
Br
Br
0
0
sumption, as the dihedral angle for HA –C–C–Hx obtained from
O
MM3 optimized structure is 88ꢀ. The crystallographic data showed
that the investigated compound 3,4-dihydro-2H,6H-3,6-epoxy-8-
nitro-benzo[1,5]dioxocine (3h) was isolated as a mixture of two
enantiomers, in which chiral centers have R,S and S,R configuration
with dihedral angles 93.4ꢀ and 96.3ꢀ for H(42)–C(25)–C(20)–H(38) and
H(49)–C(31)–C(29)–H(48), respectively (Fig. 2).
O
30 min
O
O N
2

D. Janeliunas et al. / Tetrahedron 65 (2009) 8407–8411
8409
Figure 1. 1H NMR spectra fragment of 3h (300 MHz, CDCl3).
compounds. Furthermore, the variety of functional groups available
makes these compounds appealing intermediate materials for the
synthesis of other new and important derivatives.
4. Experimental section
4.1. General
All chemicals were purchased from Aldrich and used as received
without further purification. The 1H NMR spectra were taken on
Varian Unity Inova (300 MHz) and Varian Mercury 200 (500 MHz)
spectrometers at room temperature. All the data are given as
chemical shifts in
d (ppm), (CH3)4Si (TMS, 0 ppm) was used as an
internal standard. The course of the reaction products was moni-
tored by TLC on ALUGRAM SIL G/UV254 or Silufol UV-254 plates
and developed with I2 or UV light. Silica gel (grade 62, 60–200
mesh, 150 Å, Aldrich) was used for column chromatography. Ele-
mental analysis was performed with an Exeter Analytical CE-440
Elemental. IR spectroscopy was performed on a Perkin Elmer
Spectrum BX II FT-IR System, using KBr pellets or coated on KRS5
discs. Melting points were determined using Electrothermal Mel-
Temp melting point apparatus. Mass spectra (MS) were recorded on
an Agilent 110 (series MS with VL) apparatus. X-ray crystallography
analysis was carried out utilizing Bruker-Nonius Kappa CCD single
Figure 2. Molecular structure of 3h. Displacement ellipsoids are drawn at 50% prob-
ability level.
3. Conclusion
In summary, we demonstrated that salicyl aldehydes with
electron-withdrawing substituents, as well as without any addi-
tional functional groups, react with epichlorohydrin in the presence
of quaternary ammonium halide (under reflux conditions) yielding
3,6-epoxy[1,5]dioxocine based polycyclic compounds in good
yields. The reaction rate is highly dependent on the nature of the
substituent. Salicyl aldehydes possessing electron-withdrawing
fragments react considerably faster then those with no additional
substituents. The strength of the electron-withdrawing moieties is
also an important factor. This relatively simple and easy one pot
synthesis method of 3,6-epoxy[1,5]dioxocine derivatives could be
of particular interest in the field of medicinal chemistry, as dioxo-
cine derivatives are important in the synthesis of biologically active
crystal diffractometer, using Mo K
crystal data was processed using maXus, SIR 97, ORTEP, SHELXL-97
software.
a
radiation (
l
¼0.71073 Å). Single
4.2. General procedure for the alkylation of salicyl aldehydes
with epichlorohydrin
The corresponding salicyl aldehyde was dissolved in epichloro-
hydrin, heated to reflux, and then 10 mol % of benzyl triethyl-
ammonium chloride was added to the reaction mixture. It was then
vigorously stirred at the reflux temperature. After termi-
nation of the reaction, the reaction mixture was diluted with

8410
D. Janeliunas et al. / Tetrahedron 65 (2009) 8407–8411
chloroform and washed with distilled water. The organic layer
was dried over anhydrous MgSO4, filtered, and solvents were
removed.
H, 4.27%]; Rf (acetone/n-hexane, 1:4, v/v) 0.3; nmax (KBr) 3101,
3070, 2999, 2927, 2886, 1678, 1268, 1250 cmꢁ1
dH (300 MHz,
;
CDCl3) 10.44 (s, 1H), 7.78 (d, J¼2.7 Hz, 1H), 7.48 (dd, J¼2.7 Hz,
J¼8.9 Hz, 1H), 6.97 (d, J¼8.9 Hz, 1H), 4.41 (dd, J¼2.7 Hz, J¼11.4 Hz,
1H), 4.03 (dd, J¼5.9 Hz, J¼11.4 Hz, 1H), 3.43–3.37 (m, 5H), 2.95
(t, J¼4.2 Hz, 1H), 2.78 (dd, J¼2.6 Hz, J¼4.2 Hz, 1H); dC (75 MHz,
CDCl3) 188.1, 159.1, 135.3, 127.9, 126.9, 125.9, 114.4, 69.7, 49.7,
44.3; MS (APCIþ, 20 V), m/z: 213 ([MþH]þ).
4.2.1. 2-(2-Oxiranylmethoxy)benzaldehyde (2a). 2-Hydroxybenzal-
dehyde (1a) (1 g, 8.1 mmol), epichlorohydrin (32 mL; 409 mmol),
and benzyl triethylammonium chloride (0.186 g; 0.81 mmol). Re-
action duration 10 min (TLC, acetone/n-hexane, 1:4). Obtained
product was purified by column chromatography using 1:24 ace-
tone/n-hexane as the eluent to yield colorless oil (1.25 g, 86%);
[Found: C, 67.22; H, 5.80. C10H10O3 requires C, 67.41; H, 5.66%]; Rf
(acetone/n-hexane, 1:4, v/v) 0.3; nmax (on KRS5 disc) 3072, 3005,
2929, 2867, 2763, 1688, 1599, 1484, 1458, 1396, 1288, 1240, 1024,
4.2.5. 3,4-Dihydro-2H,6H-3,6-epoxy-benzo[1,5]dioxocine (3a). 2-
Hydroxybenzaldehyde (1a) (1 g, 8.1 mmol), epichlorohydrin
(32 mL, 409 mmol), and benzyl triethylammonium chloride
(0.186 g, 0.81 mmol). Reaction duration 60 h (TLC, acetone/
n-hexane, 1:4). Obtained product was purified by column chromato-
graphy using 1:24 acetone/n-hexane as the eluent to yield
yellow oil (1.08 g, 74%); [Found: C, 67.53; H, 5.57. C10H10O3 re-
quires C, 67.41; H, 5.66%]; Rf (acetone/n-hexane, 1:4, v/v) 0.36;
841, 760 cmꢁ1
;
dH (300 MHz, CDCl3) 10.48 (d, J¼0.8 Hz, 1H), 7.80
(ddd, J¼0.3 Hz, J¼1.8 Hz, J¼5.7 Hz, 1H), 7.57–7.49 (m, 1H), 7.05–6.94
(m, 2H), 4.34 (dd, J¼2.8 Hz, J¼11.1 Hz, 1H), 4.01 (dd, J¼5.7 Hz,
J¼11.1 Hz, 1H), 3.40–3.35 (m, 1H), 2.94 (dd, J¼4.2 Hz, J¼4.8 Hz, 1H),
2.76 (dd, J¼2.8 Hz, J¼4.8 Hz, 1H); dC (52 MHz, CDCl3) 189.5, 160.8,
136.0, 128.4, 125.1, 121.3, 112.8, 69.3, 49.9, 44.5; MS (APCIþ, 20 V),
m/z: 179 ([MþH]þ).
nmax (on KRS5 disc) 3057, 2965, 2923, 2896, 1221, 1105 cmꢁ1
; dH
(300 MHz, CDCl3) 7.28–7.18 (m, 2H), 7.08–6.97 (m, 2H), 6.03 (s,
1H), 4.68–4.62 (m, 1H), 4.34–4.23 (m, 2H), 4.04–3.95 (m, 2H); dC
(75 MHz, CDCl3) 156.4, 132.7, 129.9, 128.4, 122.7, 121.1, 106.1, 75.5,
73.6, 65.7; MS (APCIþ, 20 V), m/z: 179 ([MþH]þ).
4.2.2. 2-(2-Oxiranylmethoxy)-1-naphthaldehyde (2b). 2-Hydroxy-
1-napthaldehyde (1b) (1 g, 5.8 mmol), epichlorohydrin (23 mL,
290 mmol), and benzyl triethylammonium chloride (0.132 g,
0.58 mmol). Reaction duration 15 min (TLC, acetone/n-hexane,
7:18). The residue was dissolved in 2-propanol. Obtained crystals
were filtered off and washed with 2-propanol to yield (1.1 g, 79%)
2b as light brown powder, mp: 102–104 ꢀC (recrystallized from
2-propanol); [Found: C, 73.55; H, 5.10. C14H12O3 requires C,
73.67; H, 5.30%]; Rf (acetone/n-hexane, 7:18, v/v) 0.36; nmax (KBr)
3064, 2997, 2926, 2878, 2799, 1667, 1618, 1592, 1513, 1268,
4.2.6. 3,4-Dihydro-1H,3H-3,6-epoxy-naphtho[2,1-b][1,5]dioxocine
(3b). 2-Hydroxy-1-napthaldehyde (1b) (1 g, 5.8 mmol), epichloro-
hydrin (23 mL, 290 mmol), and benzyl triethylammonium chloride
(0.132 g, 0.58 mmol). Reaction duration 60 h (TLC, acetone/n-hex-
ane, 1:4). Obtained product was purified by column chromatogra-
phy using 1:24 acetone/n-hexane as the eluent to yield yellow oil
(0.95 g, 72%); [Found: C, 73.61; H, 5.36. C14H12O3 requires C, 73.67;
H, 5.30%]; Rf (acetone/n-hexane, 1:4, v/v) 0.33; nmax (on KRS5 disc)
1250 cmꢁ1
;
dH (300 MHz, CDCl3) 10.91 (s, 1H), 9.25 (d, J¼8.5 Hz,
3059, 2964, 2923, 2892, 1231, 1116 cmꢁ1
; dH (300 MHz, CDCl3) 8.18
1H), 8.01 (d, J¼9.2 Hz, 1H), 7.75 (d, J¼8.1 Hz, 1H), 7.64–7.56 (m,
1H), 7.45–7.37 (m, 1H), 7.23 (d, J¼9.2 Hz, 1H), 4.48 (dd, J¼2.9 Hz,
J¼11.2 Hz, 1H), 4.16 (dd, J¼5.7 Hz, J¼11.2 Hz, 1H), 3.45–3.38 (m,
1H), 2.94 (t, J¼4.5 Hz, 1H), 2.79 (dd, J¼2.6 Hz, J¼4.5 Hz, 1H);
dC (52 MHz, CDCl3) 191.6, 162.7, 137.4, 131.3, 129.8, 128.7, 128.1,
124.9, 124.8, 117.0, 113.5, 70.1, 49.8, 44.3; MS (APCIþ, 20 V), m/z:
229 ([MþH]þ).
(d, J¼8.6 Hz, 1H), 7.81 (d, J¼8.1 Hz, 1H), 7.74 (d, J¼8.8 Hz, 1H), 7.56–
7.47 (m, 1H), 7.43–7.35 (m, 1H), 7.25 (d, J¼8.8 Hz, 1H), 7.16 (s, 1H),
4.75–4.68 (m, 1H), 4.42–4.33 (m, 2H), 4.12–3.98 (m, 2H); dC
(75 MHz, CDCl3) 155.6, 131.6, 130.2, 130.0, 128.6, 126.9, 125.4, 124.2,
121.8, 121.4, 100.0, 75.5, 73.9, 66.7; MS (APCIþ, 20 V), m/z: 229
([MþH]þ).
4.2.7. 8-Fluoro-3,4-dihydro-2H,6H-3,6-epoxy-benzo[1,5]dioxocine
(3c). 5-Fluoro-2-hydroxybenzaldehyde (1d) (1 g 7.14 mmol), epi-
chlorohydrin (28 mL, 357 mmol), and benzyl triethylammonium
chloride (0.16 g, 0.714 mmol). Reaction duration 20 h (TLC, ace-
tone/n-hexane, 1:4). Obtained product was purified by column
chromatography using 1:24 acetone/n-hexane as the eluent to
yield colorless oil (1.15 g, 82%); [Found: C, 61.30; H, 4.63. C10H9FO3
requires C, 61.23; H, 4.62%]; Rf (acetone/n-hexane, 1:4, v/v) 0.33;
nmax (on KRS5 disc) 3062, 2964, 2921, 2898, 1258, 1112, 952,
4.2.3. 4-Diethylamino-2-(2-oxiranylmethoxy)benzaldehyde (2c). 4-
Diethylamino-2-hydroxybenzaldehide (1c) (2.5 g, 12.9 mmol), epi-
chlorohydrin (50 mL, 647 mmol), and benzyl triethylammonium
chloride (0.359 g, 1.29 mmol). Reaction duration 15 min (TLC, ace-
tone/n-hexane, 1:4). The residue was dissolved in diethyl ether.
Obtained crystals were filtered off and washed with diethyl ether to
yield (2.5 g, 86%) 2c white powder, mp: 62–63 ꢀC (recrystallized
from diethyl ether); [Found: C, 67.38; H, 7.59; N, 5.42. C14H19NO3
requires C, 67.45; H, 7.68; N, 5.62%]; Rf (acetone/n-hexane, 1:4, v/v)
834 cmꢁ1
; dH (300 MHz, CDCl3) 7.06–6.98 (m, 1H), 6.97–6.88 (m,
0.18; nmax (KBr) 3058, 3015, 2980, 2957, 2921, 1655, 1273, 870 cmꢁ1
;
2H), 5.95 (s, 1H), 4.71–4.65 (m, 1H), 4.37–4.23 (m, 2H), 4.03–3.95
(m, 2H); dC (75 MHz, CDCl3) 156.2, 152.5 (d, J¼2.8 Hz), 134.3 (d,
J¼6.1 Hz), 122.4 (d, J¼7.9 Hz), 116.2 (d, J¼22.7 Hz), 115.1 (d,
J¼23.6 Hz), 105.3 (d, J¼1.4 Hz), 75.8, 73.6, 65.9; MS (APCIþ, 20 V),
m/z: 197 ([MþH]þ).
dH (300 MHz, CDCl3) 10.18 (s, 1H), 7.72 (d, J¼9 Hz, 1H), 6.31 (dd,
J¼2.3 Hz, J¼9 Hz, 1H), 6.11 (d, J¼2.3 Hz, 1H), 4.34 (dd, J¼3 Hz,
J¼11.2 Hz,1H), 4.05 (dd, J¼5.6 Hz, J¼11.2 Hz, 1H), 3.47–3.36 (m, 5H),
2.95 (t, J¼4.5 Hz, 1H), 2.81 (dd, J¼2.7 Hz, J¼4.5 Hz, 1H), 1.22
(t, J¼7.1 Hz, 6H); dC (52 MHz, CDCl3) 186.8, 162.9, 153.7, 130.4, 114.2,
104.7, 93.6, 69.0, 50.1, 44.7, 44.6, 12.4; MS (APCIþ, 20 V), m/z: 250
([MþH]þ).
4.2.8. 8-Chloro-3,4-dihydro-2H,6H-3,6-epoxy-benzo[1,5]dioxocine
(3d). 5-Chloro-2-hydroxybenzaldehyde (1e) (1 g 6.39 mmol), epi-
chlorohydrin (25 mL, 320 mmol), and benzyl triethylammonium
chloride (0.14 g, 0.639 mmol). Reaction duration 20 h (TLC, acetone/
n-hexane, 1:4). Obtained product was purified by column chro-
matography using 1:24 acetone/n-hexane as the eluent to yield
colorless oil (0.99 g, 73%); [Found: C, 56.55; H, 4.33. C10H9ClO3 re-
quires C, 56.49; H, 4.27%]; Rf (acetone/n-hexane, 1:4, v/v) 0.45; nmax
4.2.4. 5-Chloro-2-(2-oxiranylmethoxy)benzaldehyde (2d). 5-Chloro-2-
hydroxybenzaldehyde (1d) (1 g, 6.4 mmol), epichlorohydrin (25 mL,
320 mmol), and benzyl triethylammonium chloride (0.142 g,
0.64 mmol). Reaction duration 20 min (TLC, acetone/n-hexane,
1:4). Obtained colorless oil was purified by column chromato-
graphy using 1:24 acetone/n-hexane as the eluent and crystal-
lized upon standing to yield (1.1 g, 81%) 2d as white powder, mp:
35–36 ꢀC; [Found: C, 56.55; H, 4.18. C10H9ClO3 requires C, 56.49;
(on KRS5 disc) 3058, 2964, 2934, 2897, 1259, 1114, 935, 833 cmꢁ1
;
dH (300 MHz, CDCl3) 7.23–7.17 (m, 2H), 7.02–6.97 (m, 1H), 5.95 (s,
1H), 4.70–4.64 (m, 1H), 4.33–4.24 (m, 2H), 4.03–3.94 (m, 2H); dC

D. Janeliunas et al. / Tetrahedron 65 (2009) 8407–8411
8411
(75 MHz, CDCl3) 155.1, 134.3, 129.5, 128.2, 127.6, 122.6, 105.3, 75.6,
(m, 1H), 4.42 (dd, J¼2.6 Hz, J¼13.2 Hz, 1H), 4.29 (dd, J¼1.3 Hz,
J¼6.9 Hz, 1H), 4.09 (d, J¼13.2 Hz, 1H), 4.00 (t, J¼6.9 Hz, 1H); dC
(75 MHz, CDCl3) 161.8, 142.3, 133.3, 125.4, 124.1, 122.0, 104.8, 75.0,
74.3, 65.6; MS (APCIþ, 20 V), m/z: 225 ([MþH]þ).
73.7, 65.8; MS (APCIþ, 20 V), m/z: 213 ([MþH]þ).
4.2.9. 8-Bromo-3,4-dihydro-2H,6H-3,6-epoxy-benzo[1,5]dioxocine
(3e). 5-Bromo-2-hydroxybenzaldehyde (1f) (1 g 4.97 mmol), epi-
chlorohydrin (19.5 mL, 248 mmol), and benzyl triethylammonium
chloride (0.11 g, 0.49 mmol). Reaction duration 20 h (TLC, acetone/
n-hexane, 1:4). Obtained product was purified by column chro-
matography using 1:24 acetone/n-hexane as the eluent to yield
colorless oil (0.91 g, 71%); [Found: C, 46.65; H, 3.58. C10H9BrO3
requires C, 46.72; H, 3.53%]; Rf (acetone/n-hexane, 1:4, v/v) 0.42;
nmax (on KRS5 disc) 3057, 2964, 2923, 2897, 1259, 1114, 933,
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication number
CCDC 739499. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystal-
lographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax:
þ44 1223 336033.
834 cmꢁ1
; dH (300 MHz, CDCl3) 7.36–7.30 (m, 2H), 6.96–6.90 (m,
1H), 5.93 (s, 1H), 4.69–4.63 (m, 1H), 4.33–4.24 (m, 2H), 4.02–3.95
(m, 2H); dC (75 MHz, CDCl3) 155.6, 134.8, 132.5, 131.1, 123.0, 115.0,
105.2, 75.6, 73.7, 65.8; MS (APCIþ, 20 V), m/z: 258 ([MþH]þ).
Acknowledgements
Financial support of this research by the Lithuanian Science and
Studies Foundation is gratefully acknowledged.
4.2.10. 8-Formyl-3,4-dihydro-2H,6H-3,6-epoxy-benzo[1,5]dioxocine
(3f). 4-Hydroxyisophthalaldehyde (1g) (1 g, 6.66 mmol), epichlo-
rohydrin (26 mL, 333 mmol), and benzyl triethylammonium chlo-
ride (0.15 g, 0.666 mmol). Reaction duration 10 h (TLC, acetone/
n-hexane, 1:4). The residue was dissolved in diethyl ether. Obtained
crystals were filtered off and washed with small amount of diethyl
ether to yield (1.05 g, 77%) 3f as yellow powder, mp: 101.5–103 ꢀC
(recrystallized from diethyl ether); [Found: C, 64.14; H, 4.81.
C11H10O4 requires C, 64.08; H, 4.89%]; Rf (acetone/n-hexane, 1:4,
v/v) 0.21; nmax (KBr) 3048, 2981, 2959, 2904, 1692, 1254, 1111, 952,
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.07.093.
References and notes
1. (a) Bonini, C.; Righi, G. Synthesis 1994, 225; (b) Iranpoor, N.; Mohammadpoor-
Baltork, I. Synth. Commun. 1990, 20, 2789; (c) Tangestaninejad, S.; Moghadam,
M.; Mirkhani, V.; Yadollahi, B.; Mirmohammadi, S. M. R. Monatsh. Chem. 2006,
137, 235; (d) Smith, A. B.; Pitram, S. M.; Boldi, A. M.; Gaunt, M. J.; Sfouggatakis, C.;
Moser, W. H. J. Am. Chem. Soc. 2003, 125, 14435; (e) Iranpoor, N.; Firouzabadi, H.;
Chitsazi, M.; Jafari, A. A. Tetrahedron 2002, 58, 7037; (f) Das, B.; Reddy, V. S.;
Krishnaiah, M. Tetrahedron Lett. 2006, 47, 8471.
2. (a) Sahmetlioglu, E.; Yuruk, H. M. H.; Surme, Y. Chem. Pap. 2006, 60, 65; (b) Liang,
J.-C.; Yeh, J.-L.; Wang, C.-S.; Liou, S.-F.; Tsai, C.-H.; Chen, I.-J. Bioorg. Med. Chem.
2002, 10, 719; (c) Abbas, A. A. Tetrahedron 2004, 60, 1541; (d) Surendra, K.;
Krishnaveni, N. S.; Nageswar, Y. V. D.; Rao, K. R. J. Org. Chem. 2003, 68, 4994;
(e) Liu, Z.-Z.; Chen, H.-C.; Cao, S.-L.; Li, R.-T. Synth. Commun. 1994, 24, 833.
3. (a) Loupy, A.; Bram, G.; Sansoulet, J. New J. Chem. 1992, 16, 233; (b) Toda, F. Synlett
1993, 303; (c) Pilard, J. F.; Klein, B.; Texier-Boullet, F.; Hamelin, J. Synlett 1992,
219; (d) Rechsteiner, B.; Texier-Boullet, F.; Hamelin, J. Tetrahedron Lett. 1993, 34,
5071; (e) Bram, G.; Loupy, A.; Majdoub, M. Synth. Commun. 1990, 20, 125; (f)
Starks, C. M. J. Am. Chem. Soc. 1971, 93, 195; (g) Mac Kenzie, W. M.; Sherrington,
D. C. J. Chem. Soc., Chem. Commun. 1978, 541; (h) Bram, G.; Loupy, A.; Sansoulet,
J.; Strzelecka, H. Synth. Commun. 1984, 14, 889; (i) Kornblum, N.; Seltzer, R.;
Haberfield, P. J. Am. Chem. Soc. 1963, 85, 1148; (j) Deshayes, S.; Liagre, M.; Loupy,
A.; Luche, J. L.; Petit, A. Tetrahedron 1999, 55, 10851.
835 cmꢁ1
; dH (300 MHz, CDCl3) 9.92 (s, 1H), 7.82–7.74 (m, 2H), 7.20
(d, J¼7.9 Hz, 1H), 6.12 (s, 1H), 4.75–4.69 (m, 1H), 4.42 (dd, J¼2.6 Hz,
J¼13.2 Hz, 1H), 4.31 (dd, J¼1.3 Hz, J¼6.8 Hz, 1H), 4.10 (d, J¼13.2 Hz,
1H), 4.00 (t, J¼6.8 Hz, 1H); dC (75 MHz, CDCl3) 190.4, 161.8, 133.4,
131.8, 131.2, 130.0, 122.1, 105.5, 75.2, 74.2, 65.6; MS (APCIþ, 20 V),
m/z: 207 ([MþH]þ).
4.2.11. 8,10-Dibromo-3,4-dihydro-2H,6H-3,6-epoxy-benzo[1,5]di-
oxocine (3g). 3,5-Dibromosalicylaldehyde (1h) (1 g 3.57 mmol),
epichlorohydrin (14 mL, 178 mmol), and benzyl triethylammonium
chloride (0.08 g, 0.357 mmol). Reaction duration 30 min (TLC,
acetone/n-hexane, 1:4). The residue was dissolved in diethyl ether.
Obtained crystals were filtered off and washed with small amount
of diethyl ether to yield (1.07 g, 89%) 3g as white powder, mp: 105–
107 ꢀC (recrystallized from diethyl ether); [Found: C, 35.68; H, 2.34.
C10H8Br2O3 requires C, 35.75; H, 2.40%]; Rf (acetone/n-hexane, 1:4,
4. (a) Bradley, W.; Forest, J.; Stephenson, O. J. Chem. Soc. 1951, 1589; (b) Stephenson,
O. J. Chem. Soc. 1954, 1571; (c) Birch, A.; Bradley, P.; Gill, J.; Kerrigan, F.; Needham,
P. J. Med. Chem. 1999, 42, 3342.
v/v) 0.42; nmax (KBr) 3070, 2950, 2903, 2892, 1257, 1112 cmꢁ1
; dH
(300 MHz, CDCl3) 7.67 (s split, J¼2.3 Hz, 1H), 7.32 (s split, J¼2.3 Hz,
1H), 5.96 (s, 1H), 4.76–4.69 (m, 1H), 4.43 (dd, J¼2.6 Hz, J¼13.3 Hz,
1H), 4.38 (dd, J¼1.3 Hz, J¼6.5 Hz, 1H), 4.08–3.97 (m, 2H); dC
(75 MHz, CDCl3) 152.5, 135.8, 135.6, 130.5, 116.8, 115.2, 105.1, 75.6,
74.1, 66.1; MS (APCIþ, 20 V), m/z: 337 ([MþH]þ).
5. (a) Fischer, E. Chem. Ztg. 1973, 97, 635; Chem. Abstr. 80, 95413; (b) Erhard, P. W.;
Woo, C. M.; Gorczynski, R. J.; Anderson, W. G. J. Med. Chem. 1982, 25, 1402;
(c) Schmolka, S. J.; Zimmer, H. Synthesis 1984, 29; (d) Bevinakatti, H. S.;
Banerji, A. A. J. Org. Chem. 1991, 56, 5372; (e) Crowther, A. F.; Smith, L. H. (ICI
Chem. Ind. Ltd.). U.S. Patent 3,337,628, 1967; (f) Smith, D. R. (Dow Chemical,
USA). Jpn. Patent 5,100,6125, 1976; Chem. Abstr. 85, 178382; (g) DiMenna, W.
S.; Piantadosi, C. J. Med. Chem. 1978, 21, 1073; (h) Lafon, V. (Orsymonde, S. A.,
Fr.). Ger. Offen. 2,166,869, 1976; Chem. Abstr. 85, 62850.
6. (a) Beasley, Y. M.; Petrow, V.; Stephenson, O. J. Pharm. Pharmacol. 1958, 10, 47;
(b) Cvengrosova, Z.; Rattay, V.; Repasova, I.; Spankova, Z.; Fancovic, K. Czech
Patent 200,382, 1983; Chem. Abstr. 100, 68148; (c) Nakayama, K.; Murakami, N.;
Yoshizaki, S.; Tominaga, M.; Movi, H.; Yabkuchi, Y.; Shintani, S. J. Med. Chem.
1974, 17, 52; (d) Li, R.; Yang, J.; Chen, H.; Cao, S. Huaxue Shiji 1995, 17, 7; Chem.
Abstr. 123, 111765; (e) Smith, D. R. (Dow Chemical, USA). Brit. Patent 1,155,543,
1969; Chem. Abstr. 71, 81126.
4.2.12. 3,4-Dihydro-2H,6H-3,6-epoxy-8-nitro-benzo[1,5]dioxocine
(3h). 2-Hydroxy-5-nitrobenzaldehyde (1i) (3 g, 18 mmol), epi-
chlorohydrin (70 mL, 898 mmol), and benzyl triethylammonium
chloride (0.4 g, 1.8 mmol). Reaction duration 30 min (TLC, acetone/
n-hexane, 1:4). The light yellow residue was dissolved in 2-prop-
anol and obtained crystals filtered off to yield (3.56 g, 89%) 3h as
white powder, mp: 145.5–146 ꢀC (recrystallized from toluene);
[Found: C, 53.91; H, 4.07; N, 6.35. C10H9NO5 requires C, 53.82; H,
4.06; N 6.28%]; Rf (acetone/n-hexane, 1:4, v/v) 0.27; nmax (KBr) 3107,
7. Pchelka, B. K.; Loupy, A.; Petit, A. Tetrahedron 2006, 62, 10968.
8. (a) Argyropoulos, D. S.; Jurasek, L.; Kristofova, L.; Xia, Z.-C.; Sun, Y.-J.; Palus, E.
J. Agric. Food Chem. 2002, 50, 658; (b) Tocco, G.; Begala, M.; Delogu, G.; Picciau,
C.; Podda, G. Tetrahedron Lett. 2004, 45, 6909; (c) Borders, D. B.; Lancaster, J. E.
J. Org. Chem. 1974, 39, 435; (d) Yamashita, D. S. J. Peptide Res. 2004, 63, 265; (e)
Ragot, J. P.; Prime, M. E.; Archibald, S. J.; Taylor, R. J. K. Org. Lett. 2000, 2, 1613.
3073, 2968, 2940, 2901, 1586, 1255, 1096 cmꢁ1
CDCl3) 8.16–8.09 (m, 2H), 7.18–7.11 (m, 1H), 6.08 (s, 1H), 4.77–4.70
; dH (300 MHz,