A General and Practical Approach for the Synthesis of 1,2,4-Trioxanes Catalyzed by Silica-Ferric Chloride

Article abstract of DOI:10.1002/adsc.201700671

An efficient and practical method has been developed for the facile synthesis of 1,2,4-trioxanes by the condensation of β-hydroperoxy alcohols and carbonyl compounds in the presence of a catalytic amount of silica-supported ferric chloride (FeCl₃/SiO₂) at room temperature. The method has the benefits of operational simplicity, high yields and potential large-scale application. Moreover, the catalyst can be readily recovered by simple filtration and reused up to five times while almost maintaining its catalytic activity. (Figure presented.).

Full text of DOI:10.1002/adsc.201700671

Title: A General and Practical Approach for Synthesis of 1,2,4-
Trioxanes Catalyzed by Silica-Ferric Chloride
Authors: Mo Zhang, Yi Han, Jia-Liang Niu, and Zhan-Hui Zhang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700671
Link to VoR: http://dx.doi.org/10.1002/adsc.201700671

10.1002/adsc.201700671
Advanced Synthesis & Catalysis
Advanced Synthesis & Catalysis
A General and Practical Approach for Synthesis of 1,2,4-Trioxanes
Catalyzed by Silica-Ferric Chloride
Mo Zhang, Yi Han, Jia-Liang Niu, and Zhan-Hui Zhang*
National Demonstration Center for Experimental Chemistry Education, College of Chemistry
and Material Science, Hebei Normal University, Shijiazhuang 050024, China
Fax: +(86)-311-80787431; e-mail: zhanhui@mail.nankai.edu.cn
Abstract: An efficient and practical synthetic method has been developed for the facile synthesis of
1,2,4-trioxanes by the condensation of -hydroperoxy alcohols and carbonyl compounds in the presence of a
catalytic amount of silica-supported FeCl3 (FeCl3/SiO2) at room temperature. The method has the benefits of
operational simplicity, high yields and potentially large-scale application. Moreover, the catalyst can be readily
recovered by simple filtration and reused up to five times with almost maintained its catalytic activity.
Keywords: 1,2,4-trioxanes; -hydroperoxy alcohols; carbonyl compounds; silica-supported FeCl3
1
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Introduction
Organic peroxides are found in an extensive number of structurally diverse natural products and biologically
active compounds and have been explored extensively as antimalarial agents, anthelmintics, and antitumor
drugs.[1] Among them, 1,2,4-trioxanes have been attracting considerable interest of researchers in the fields of
medicinal chemistry and pharmacology since 1,2,4-trioxane structural motif was found to be core structure in
artemisinin as the active pharmacophore against both chloroquinine-sensitive and chloroquinine-resistant malaria
(Figure 1).[2] Due to the fascinating biological activities of these structural compounds, some synthetic method
have been developed to construct 1,2,4-trioxanes,[3] for example (i) rearrangements of ketodioxetanes;[4] (ii)
photochemical reaction of -ionone derivatives in the presence of oxygen;[5] (iii) the reaction of endoperoxides
with cyclohexanones;[6] (iv) ) the photooxidation of enol ethers with oxygen followed by the rearrangement the
resulting 1,2-dioxetanes in the presence of trialkylsilyl triflates;[7] (iv) the photo-oxygenation of dihydropyrans;[8]
and (v) the condensation of the -hydroxy hydroperoxides with carbonyl compounds in the presence of acid
catalysts such as hydrochloric acid,[9] p-toluenesulfonic acid (p-TSA),[10] 10-camphorsulfonicacid (CSA),[11]
pyridinium p-toluenesulfonate (PPTS)[12] and boron trifluoride.[13] However, some of these synthetic methods
suffer from certain constraints such as use of large amounts of strong acid, unsatisfactory yields, long reaction
times, poorly accessible starting materials or narrow substrate scope, and this limits the application of these
methods for large-scale synthesis for 1,2,4-trioxanes. Therefore, the development of an efficient, general and
practical approach for the straightforward construction of 1,2,4-trioxanes from simple and readily available
starting materials is still highly desirable.
Figure 1. Examples of biologically active 1,2,4-trioxanes
Recently, the use of silica supported reagents as reusable and efficient heterogeneous catalysts in
organic syntheses is still emerging due to their ease of preparation, increased reaction rate, better selectivity,
2
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10.1002/adsc.201700671
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Advanced Synthesis & Catalysis
simple workup, low cost and recyclability of the catalyst.[14] Over the past few years, as the most abundant
transition metal on earth, iron compounds have drawn much attention toward various organic reactions and
synthesis of functionalized heterocycles because of their low toxicity, outstanding catalytic activity, ready
availability, inexpensive and environ-mentally friendly properties.[15] In addition, silica-supported FeCl3
has been used as the catalyst for a wide range of organic transformations including Diels-Alder reactions,[16]
synthesis of aminals,[17] nitriles,[18] 2-aminocyclohex-1-ene-1-carboxylic esters,[19] 2-substituted
benzimidazole,[20] 4(3H)-quinazolinones,[21] 1,2,4-triazines[22] and 1,5-benzodiazepine derivatives.[23]
Previously, we have established an efficient method for the preparation of -hydroperoxy alcohols.[24] As
part of our ongoing effort in the development of environmental benign synthetic methodologies for heterocyclic
compounds,[25] herein, we wish to report a direct synthesis of 1,2,4-trioxanes by the condensation of
-hydroperoxy alcohols and carbonyl compounds in the presence of a catalytic amount of silica-supported FeCl3
(FeCl3/SiO2) at room temperature (Scheme 1).
Scheme 1. Silica-ferric chloride catalyzed synthesis of 1,2,4-trioxanes.
Results and Discussion
At the onset, the reaction of 2-hydroperoxy-2-phenylethan-1-ol and benzaldehyde was selected as
model reaction for optimizing the reaction condition, and the results are summarized in Table 1. When the
reaction was attempted without
a
catalyst, it was found that only
a
trace amount of
3,6-diphenyl-1,2,4-trioxane (3a) was obtained (Table 1, entry 1). This result suggests that a catalyst plays a
critical role in this transformation. It is noteworthy that 3a was formed in medium yields when the reaction
was carried out using proton acid such as HCl, H2SO4 or organic acid such as p-TSA in CH2Cl2 at room
temperature (entries 2-4). It is noteworthy that FeCl3 resulted in noticeable improvement for this reaction,
but it is difficult for separating out the sticky iron-derived solid from the product due to hygroscopic nature
of FeCl3. It was envisioned that silica gel could act as water absorbent and thereby assist the dehydration
reaction step while enabling the convenient removal of the catalyst via a simple filtration. We examined
various silica-supported catalysts such as BF3/SiO2, SbCl3/SiO2, HClO4/SiO2 and FeCl3/SiO2. To our
3
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10.1002/adsc.201700671
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Advanced Synthesis & Catalysis
delight, FeCl3/SiO2 is indeed an effective catalyst and gave target product in 91% yield (entry 9). At the
same time, the amount of the FeCl3/SiO2 was investigated, it was indicted that 10 mol% FeCl3/SiO2 gives
excellent result as compared to the other runs under similar conditions. When the amount of FeCl3/SiO2 is
decreased to 5 mol%, slightly lower yield was obtained and reaction time was prolonged (entry 9).
However, further increasing the amount of FeCl3/SiO2 (15 mol%) showed no significant beneficial effect
on the reaction (entry 11). The reaction showed a strong dependence on the solvent. When the reaction was
performed under solvent-free condition, almost no conversion was observed (Table 1, entry 12). It was
found that dichloromethane was superior to other solvents including tetrahydrofuran (THF), diethyl ether,
acetonitrile and n-hexane (Table 1, entries 13-16).
In order to expand the synthetic competence of this novel method, a gram-scale synthesis of
3,6-diphenyl-1,2,4-trioxane
(
3a
)
was performed under the optimal reaction conditions.
2-Hydroperoxy-2-phenylethan-1-ol (7.7 g, 50 mmol) was reacted with benzaldehyde (5.30 g, 50 mmol) in
CH2Cl2 (100 ml) in the presence of FeCl3/SiO2 (5 mmol FeCl3, 15.0 g) at room temperature for 2.5 h. The
expected 3a was obtained in 92% yield (entry 17). After the completion of the reaction, the catalyst can be
easily recovered quantitatively by simple filtration due to the fact that the catalyst was insoluble in CH2Cl2.
The recovered catalyst could be reused for five consecutive runs without any significant loss of its activity
(Table 1, entry 18). The amount of leaching of the Fe from the FeCl3/SiO2 was also investigated by
inductively coupled plasma-atomic emission spectroscopy (ICP-AES) and found that the Fe content after
fifth cycles were 8.5 ppm in CH2Cl2. This result confirmed that only a slight loss of the catalyst occurred
during the course of work-up process. We think the possible reason for the extreme stability of the
FeCl3/SiO2 may be due to the immobilization of FeCl3 on the surface of SiO2 by bonding of FeCl3 and
silicon hydroxyl groups (Si-OH) in forming the new Lewis acid sites of Si-O-Fe-Cl2.[26] These satisfying
results of gram-scale reaction and recyclable catalyst highlight that it is interest for a potential industrial
application.
Table 1. Optimization study for synthesis of 3,6-diphenyl-1,2,4-trioxanea[a]
Entry
Catalyst
Solvent
4
Time (h)
Yield (%)
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Advanced Synthesis & Catalysis
1
no
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
no
5.0
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
3.0
2.5
5.0
3.0
3.0
3.0
3.0
2.5
2.5
trace
51
70
63
80
50
46
59
91
84
91
trace
6
2
HCl
3
H2SO4
4
p-TSA
5
FeCl3
6
BF3/SiO2
SbCl3/SiO2
HClO4/SiO2
FeCl3/SiO2
FeCl3/SiO2
FeCl3/SiO2
FeCl3/SiO2
FeCl3/SiO2
FeCl3/SiO2
FeCl3/SiO2
FeCl3/SiO2
FeCl3/SiO2
FeCl3/SiO2
7
8
9
10[b]
11[c]
12
13
14
15
16
17[d]
THF
Et2O
12
21
8
MeCN
n-Hexane
CH2Cl2
CH2Cl2
92
18[e]
91, 90, 90, 89, 88
[a]
Reaction condition: 2-hydroperoxy-2-phenylethan-1-ol (1 mmol), benzaldehyde (1 mmol), catalyst (10
mol%), solvent (2 ml), room temperature, unless otherwise mentioned.
5 mol% catalyst.
[b]
[c]
[d]
[e]
15 mol% catalyst.
The reaction was carried out in 50.0 mmol scale.
The catalyst was reused for five consecutive runs.
After determining the optimized conditions, we then turned our attention toward investigating the
substrate scope of the method using FeCl3/SiO2 as the catalyst and CH2Cl2 as the solvent. As shown in
Table 2, various substituted benzaldehyde containing both electron-donating and electron-withdrawing
s
groups underwent the reaction smoothly, giving the expected products in high yield. It was noteworthy that
heteroaryl aldehydes such as thiophene-2-carbaldehyde was also successfully utilised for the formation of
corresponding 1,2,4-trioxane 3k, however, affording relatively low yield. Aliphatic aldehydes such as
cyclohexanecarbaldehyde was also tested for this reaction, the resulted 1,2,4-trioxane 3n was obtained in a
5
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10.1002/adsc.201700671
Advanced Synthesis & Catalysis
Advanced Synthesis & Catalysis
moderate yield. In addition to aryl

-hydroxy hydroperoxides, different alkyl

-hydroxy hydroperoxides
such
as
2-hydroperoxy-3-phenoxypropan-1-ol,
2-hydroperoxy-3-(o-tolyloxy)propan-1-ol,
2-hydroperoxy-3-(4-methoxyphenoxy)propan-1-ol as well as 2-hydroperoxycyclohexan-1-ol could also be
used for this condensation reaction and gave the corresponding 1,2,4-trioxanes 3i-3q in good yields.
Table 2. Synthesis of 1,2,4-trioxane from aldehydesa
6
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[a] Reaction condition: -hydroperoxy alcohols (1 mmol), aldehyde (1 mmol) in CH2Cl2 (2 ml), FeCl3/SiO2
(10 mol%, 0.3 g), 2.5 h, room temperature.
Encouraged by these results, we next applied this protocol to less electrophilic ketones. Without any
optimization, we were pleased to find that alkyl-alkyl ketone such as acetone as well as cyclic ketones such as
cyclopentanone, cyclohexanone and adamantan-2-one also underwent this conversion to afford the respective
1,2,4-trioxanes in high yields under these conditions. Unfortunately, aryl-alkyl ketones such as acetophenone
failed to undergo this reaction.
Table 3. Synthesis of 1,2,4-trioxane from ketones[a]
[a]
Reaction condition: -hydroperoxy alcohols (1 mmol), ketone (1 mmol) in CH2Cl2 (2 ml), FeCl3/SiO2 (10
mol%), 1.5 h, room temperature.
Conclusion
7
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Advanced Synthesis & Catalysis
In summary, we have successfully developed a novel, practical highly and general approach for the
synthesis of 1,2,4-trioxanes by the condensation of -hydroperoxy alcohols and carbonyl compounds in

the presence of a catalytic amount of FeCl3/SiO2. This method is high efficient and provides rapid access
to valuable 1,2,4-trioxanes in high to excellent yield. Moreover, this reaction can be effectively scale up
and the catalyst can be easily recovered and reused at least five times without apparent loss of its
catalytic activity. These features make this method an attractive choice for the synthesis of
1,2,4-trioxanes.
Experimental Section
All commercially available chemicals and solvents were used as received without further purification. -
Hydroperoxy alcohols were prepared according to our previous development method.[24] Melting points were
measured on an X-5 digital melting point apparatus without correction. IR spectra were recorded in the range
4000-600 cm-1 either as neat for liquid or KBr pellets for solid samples using a Thermo Fisher is50 spectrometer
1
instrument. H NMR and 13C NMR spectra were recorded on Bruker DRX-500 spectrometer at 500 MHz and
125 MHz respectively, using CDCl3 as the solvent and TMS as an internal standard. High-resolution mass
spectra (HRMS) were recorded on waters GCT Premier mass spectrometer.
Preparation of ferric chloride adsorbed on silica gel (FeCl3/SiO2)
The preparation of FeCl3/SiO2 was carried out according to a reported procedure with modification.[20] FeCl3 (1.6
g, 10 mmol) was added to a suspension of SiO2 (300-400 mesh, 28.4 g) in EtOH (50.0 mL). The mixture was
stirred at room temperature for 1 h then the solvent was removed with a rotary evaporator and the residue was
heated at 100 °C under vacuum for 5 h to furnish FeCl3/SiO2 as a free-flowing powder. The amount of iron
loading in FeCl3/SiO2 catalyst was about 0.33 mmol·g-1.
Typical procedure for synthesis of 1,2,4-trioxanes
To a solution of -hydroperoxy alcohols (1 mmol) and carbonyl compounds (1 mmol) in CH2Cl2 (2 ml),
FeCl3/SiO2 (0.3 g) was added and the mixture was stirred at room temperature. Progress of the reaction was
monitored by thin-layer chromatography. After completion of the reaction, the catalyst was filtered and
washed with CH2Cl2. The combined filtrate was dried over Na2SO4 and the solvent was removed under
reduced pressure. The crude product was purified by flash chromatography using the mixture of petroleum
ether and ethyl acetate as the eluting solvent to give the pure product
.
8
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o
3,6-Diphenyl-1,2,4-trioxane (3a). White solid, m.p. 142-143 C; IR (KBr): 3383, 3084, 2982, 2916, 1718,
1456, 1379, 1313, 1205, 1105, 1049, 974, 910, 746, 694 cm-1; 1H NMR (CDCl3, 500 MHz): δ 4.12 (dd, J = 12.0,
10.5 Hz, 1H), 4.29 (dd, J = 12.0, 3.0 Hz, 1H), 5.53 (dd, J = 10.5, 3.0 Hz, 1H), 6.29 (s, 1H), 7.43-7.37 (m, 8H),
7.55-7.57 (m, 2H) ppm; 13C NMR (CDCl3, 125 MHz): δ 70.3, 81.9, 104.1, 127.1, 127.4, 128.6, 128.8, 129.5,
130.1, 134.2, 134.4 ppm; HRMS (EI, m/z): calcd. for C15H14O3 (M)+: 242.0943, found: 242.0948.
6-Phenyl-3-(p-tolyl)-1,2,4-trioxane (3b). White solid, m.p. 139-140 °C; IR (KBr): 3421, 3385, 2924, 2899,
2916, 2856, 1612, 1452, 1373, 1205, 1180, 1105, 1051, 925, 808, 754, 698 cm-1. 1H NMR (CDCl3, 500 MHz) δ:
2.37 (s, 3H), 4.10 (dd, J = 12.0, 11.0 Hz, 1H), 4.27 (dd, J = 12.0, 2.5 Hz, 1H), 5.52 (dd, J = 10.5, 2.5 Hz, 1H),
6.25 (s, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.36-7.40(m, 5H), 7.40 (d, J = 8.0 Hz, 2H) ppm; 13C NMR (CDCl3, 125
MHz) δ: 21.4, 70.3, 81.8, 104.2, 127.0, 127.4, 128.8, 129.2, 129.4, 131.3, 134.5, 140.1 ppm; HRMS (EI, m/z):
calcd. for C16H16O3 (M)+: 256.1099, found: 256.1103.
3-(4-Fluorophenyl)-6-phenyl-1,2,4-trioxane (3c). White solid, 162-164 °C; IR (KBr): 3385, 2924, 2852,
1608, 1514, 1454, 1377, 1230, 1112, 1082, 920, 808, 752, 696 cm-1; 1H NMR (CDCl3, 500 MHz) δ: 4.11 (dd, J =
12.0, 10.5 Hz, 1H), 4.28 (dd, J = 12.0, 2.5 Hz, 1H), 5.52 (dd, J = 10.5, 2.5 Hz, 1H), 7.10 (t, J = 8.5 Hz, 2H), 6.26
(s, 1H), 7.36-7.41 (m, 5H), 7.55 (dd, J = 8.5, 5.5 Hz, 2H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 70.3, 81.8, 103.3,
2
115.5 (d, JCF = 21.8 Hz), 127.4, 128.8, 129.1 (d, 3JCF = 8.1 Hz), 129.5, 130.1(d, 4JCF = 2.6 Hz), 134.2, 163.7(d,
1JCF = 247.1 Hz) ppm; HRMS (EI, m/z): calcd. for C15H13FO3 (M)+: 260.0849, found: 260.0843.
3-(4-Chlorophenyl)-6-phenyl-1,2,4-trioxane (3d). White solid, 167-168 °C; IR (KBr): 3421, 3367, 2924,
2852, 1600, 1521, 1456, 1375, 1201, 1089, 922, 808, 756, 696 cm-1; 1H NMR (CDCl3, 500 MHz) δ: 4.11 (dd, J =
12.0, 10.5 Hz, 1H), 4.28 (dd, J = 12.0, 2.5 Hz, 1H), 5.51 (dd, J = 10.5, 2.5 Hz, 1H), 6.26 (s, 1H), 7.35-7.42 (m,
7H), 7.49 (d, J = 8.5 Hz, 2H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 70.2, 81.9, 103.3, 127.4, 128.5, 128.7, 128.8,
129.5, 132.6, 134.2, 136.0 ppm; HRMS (EI, m/z): calcd. for C15H13ClO3 (M)+: 276.0553, found: 276.0557.
2-(6-Phenyl-1,2,4-trioxan-3-yl)benzonitrile (3e). White solid, 145-146°C; IR (KBr): 3446, 3421, 2974,
2866, 1705, 1662, 1521, 1384, 1280, 1114, 1084, 974, 746, 680 cm-1; 1H NMR (CDCl3, 500 MHz) δ: 4.12 (dd, J
= 12.0, 10.5 Hz, 1H), 4.29 (dd, J = 12.0, 3.0 Hz, 1H), 5.38 (dd, J = 10.5 2.5 Hz, 1H), 6.29 (s, 1H), 7.37-7.44 (m,
7H), 7.55-7.57 (m, 2H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 70.3, 81.8, 104.1, 126.2, 127.1, 127.4, 128.5, 128.7,
128.8, 129.4, 129.7, 130.1, 134.1, 134.4 ppm; HRMS (EI, m/z): calcd. for C16H13NO3 (M)+: 267.0895, found:
267.0890.
3-(4-Nitrophenyl)-6-phenyl-1,2,4-trioxane (3f). White solid, 84-85°C; IR (KBr): 3446, 3385, 2926, 2845,
9
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1
1616, 1521, 1458, 1065, 979, 854, 763, 702 cm-1; H NMR (CDCl3, 500 MHz) δ: 3.85 (t, J = 7.5 Hz, 1H), 4.44
(dd, J = 8.5, 6.5 Hz, 1H), 5.11 (t, J = 6.5 Hz, 1H), 6.20 (s, 1H), 7.28-7.34(m, 5H), 7.66 (d, J = 8.5 Hz, 2H), 8.20
(d, J = 8.5 Hz, 2H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 72.8, 78.2, 103.1, 123.7, 126.1, 127.4, 128.5, 128.8,
138.5, 145.3, 148.4 ppm; HRMS (EI, m/z): calcd. for C15H13NO5 (M)+: 287.0794, found: 287.0798.
6-Phenyl-3-(4-(trifluoromethyl)phenyl)-1,2,4-trioxane (3g). White solid, 180-181°C; IR (KBr): 3446,
3421, 3367, 2924, 2852, 1521, 1473, 1330, 1122, 989, 840, 756, 695 cm-1; 1H NMR (CDCl3, 500 MHz) δ: 4.14
(dd, J = 12.0, 10.5 Hz, 1H), 4.30 (dd, J = 12.0, 2.5 Hz, 1H), 5.53 (dd, J = 10.5, 2.5 Hz, 1H), 6.34 (s, 1H),
1
7.36-7.43 (m, 5H), 7.68 (s, 4H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 70.2, 81.9, 103.0, 123.8 (q, JFC = 270.8
Hz), 125.5 (q, 3JFC =3.8 Hz), 127.4, 127.5, 128.7 (q, 2JFC =37.1 Hz), 128.9, 129.6, 134.1, 137.7 ppm; HRMS (EI,
m/z): calcd. for C16H13F3O3 (M)+: 310.0817, found: 310.0813.
6-(4-Chlorophenyl)-3-(4-(trifluoromethyl)phenyl)-1,2,4-trioxane (3h). White solid, 179-180 °C; IR (KBr):
3446, 2874, 2553, 1695, 1593, 1496, 1417, 1323, 1170, 1124, 1066, 1016, 927, 835, 640 cm-1; 1H NMR (CDCl3,
500 MHz) δ: 4.08 (dd, J = 12.0, 10.5 Hz, 1H), 4.28 (dd, J = 12.0, 3.0 Hz, 1H), 5.50 (dd, J = 10.5, 3.0 Hz, 1H),
6.31 (s, 1H), 7.31 (d, J = 8.5 Hz, 2H), 7.39 (d, J = 8.5 Hz, 2H), 7.66-7.70 (m, 4H) ppm; 13C NMR (CDCl3, 125
MHz) δ: 70.0, 81.2, 103.0, 123.8 (q, 1JFC = 270.8 Hz), 125.5 (q, 3JFC =3.6 Hz), 127.5, 128.7, 129.1, 132.1 (q, 2JFC
=32.3 Hz), 132.5, 135.6, 137.5 ppm; HRMS (EI, m/z): calcd. for C16H12ClF3O3 (M)+: 344.0427, found:
344.0432.
5-(Phenoxymethyl)-3-(p-tolyl)-1,2,4-trioxane (3i). White solid, 70-71°C; IR (KBr): 3414, 2922, 2852,
1
1600, 1491, 1383, 1244, 1107, 1051, 977, 750 cm-1; H NMR (CDCl3, 500 MHz) δ: 2.36 (s, 3H), 4.08-4.11 (m,
1H), 4.23-4.31 (m, 2H), 4.49-4.55 (m, 2H), 6.25 (s, 1H), 6.93 (d, J = 8.0 Hz, 2H), 6.99 (t, J = 7.5 Hz, 1H), 7.19
(d, J = 8.0 Hz, 2H), 7.30 (t, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 2H) ppm; 13C NMR (CDCl3, 125 MHz) δ:
21.4, 67.2, 72.5, 73.8, 104.3, 114.6, 121.4, 127.0, 129.1, 129.6, 131.3, 140.1, 158.3 ppm; HRMS (EI, m/z): calcd.
for C17H18O4 (M)+: 286.1205, found: 286.1201.
5-(Phenoxymethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,4-trioxane (3j). White solid, 72-73°C; IR (KBr):
1
3414, 2924, 2852, 1599, 1377, 1325, 1244, 1168, 1068, 991, 839, 750 cm-1; H NMR (CDCl3, 500 MHz) δ:
4.10-4.13 (m, 1H), 4.24-4.27 (m, 1H), 4.29-4.31 (m, 1H), 4.55-4.57 (m, 2H), 6.34 (s, 1H), 6.94 (d, J = 8.0 Hz,
1H), 7.00 (t, J = 7.5 Hz, 2H), 7.32 (dd, J = 8.5, 7.5 Hz, 2H), 7.64 (dd, J = 15.0, 8.5 Hz, 1H) ppm; 13C NMR
1
3
(CDCl3, 125 MHz) δ: 67.0, 72.7, 73.8, 103.1, 114.6, 121.5, 123.8 (q, JFC = 270.8 Hz), 125.4 (q, JFC =3.6 Hz),
2
127.5, 129.7, 132.1 (q, JFC =32.4 Hz), 137.6, 158.3 ppm; HRMS (EI, m/z): calcd. for C17H15F3O4 (M)+:
340.0922, found: 340.0926.
10
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5-(Phenoxymethyl)-3-(thiophen-2-yl)-1,2,4-trioxane (3k). White solid, 59-60°C; IR (KBr): 3414, 3099,
1
2926, 2852, 1597, 1456, 1379, 1249, 1120, 1051, 991, 756, 721 cm-1; H NMR (CDCl3, 500 MHz) δ: 4.07-4.10
(m, 1H), 4.23-4.26 (m, 1H), 4.28-4.30 (m, 1H), 4.50-4.54 (m, 2H), 6.51 (s, 1H), 6.93 (d, J = 8.5 Hz, 2H), 6.99 (t,
J = 7.5 Hz, 1H), 7.04 (t, J = 5.0 Hz, 1H), 7.25 (d, J = 5.0 Hz, 1H), 7.31 (t, J = 8.0 Hz, 2H), 7.39 (d, J = 5.0 Hz,
1H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 66.9, 72.9, 73.8, 100.6, 114.5, 121.5, 126.8, 127.4, 127.5, 129.6, 135.9,
158.2 ppm; HRMS (EI, m/z): calcd. for C14H14O4S (M)+: 278.0613, found: 278.0616.
3-(p-Tolyl)-5-((o-tolyloxy)methyl)-1,2,4-trioxane (3l). White solid, 45-46°C; IR (KBr): 3421, 2924, 2854,
1
1600, 1496, 1375, 1240, 1118, 1049, 1003, 906, 746 cm-1; H NMR (CDCl3, 500 MHz) δ: 2.24 (s, 3H), 2.36 (s,
3H), 4.10 (dd, J = 10.0, 6.0 Hz, 1H), 4.26 (dd, J = 10.0, 4.5 Hz, 1H), 4.30 (d, J = 10.0 Hz, 1H), 4.52-4.60 (m,
2H), 6.26 (s, 1H), 6.84 (d, J = 8.0 Hz, 1H), 6.90 (t, J = 7.5 Hz, 1H), 7.16 (d, J = 7.5 Hz, 2H), 7.20 (d, J = 8.0 Hz,
2H), 7.39 (d, J = 8.0 Hz, 2H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 16.2, 21.4, 67.2, 72.6, 74.0, 104.3, 111.0,
121.1, 126.9, 127.0, 129.2, 130.9, 131.4, 140.2, 156.4 ppm; HRMS (EI, m/z): calcd. for C18H20O4 (M)+:
300.1362, found: 300.1366.
5-((4-Methoxyphenoxy)methyl)-3-(p-tolyl)-1,2,4-trioxane (3m). White solid, 87-88°C; IR (KBr): 3385,
1
2962, 2841, 1600, 1510, 1236, 1062, 827, 752 cm-1; H NMR (CDCl3, 500 MHz) δ: 2.36 (s, 3H), 3.78 (s, 3H),
3.85 (dd, J = 15.0, 8.0 Hz, 4H), 4.04 (dd, J = 10.0, 6.0 Hz, 1H), 4.19 (dd, J = 10.0, 4.5 Hz, 1H), 4.27 (d, J = 10.0
Hz, 1H), 4.47-4.54 (m, 2H), 6.24 (s, 1H), 7.19 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 8.0 Hz, 2H) ppm; 13C NMR
(CDCl3, 125 MHz) δ: 21.4, 55.7, 67.9, 72.6, 73.8, 104.2, 114.7, 115.6, 127.0, 129.2, 131.3, 140.2, 152.5, 154.3
ppm; HRMS (EI, m/z): calcd. for C18H20O5 (M)+: 316.1311, found: 316.1316.
3-Cyclohexyl-5-(phenoxymethyl)-1,2,4-trioxane (3n). White solid, 66-67°C; IR (KBr): 3414, 2928, 2850,
1
1599, 1500, 1249, 1120, 1001, 752 cm-1; H NMR (CDCl3, 500 MHz) δ: 1.09-1.26 (m, 6H), 1.64-1.66 (m, 1H),
1.72-1.83 (m, 4H), 3.97 (dd, J = 10.0, 6.0 Hz, 1H), 4.12-4.17 (m, 2H), 4.25-4.30 (m, 1H), 4.32-4.36 (m, 1H),
5.09 (d, J = 5.5 Hz, 1H), 6.90 (d, J = 8.5 Hz, 2H), 6.98 (t, J = 8.0 Hz, 1H), 7.29 (t, J = 8.0 Hz, 2H) ppm; 13C
NMR (CDCl3, 125 MHz) δ: 25.6, 25.7, 26.2, 27.0, 27.1, 40.7, 67.3, 71.9, 73.9, 107.3, 114.6, 121.3, 129.5, 158.4
ppm; HRMS (EI, m/z): calcd. for C16H22O4 (M)+: 278.1518, found: 278.1513.
3-Cyclohexyl-5-((o-tolyloxy)methyl)-1,2,4-trioxane (3o). White solid, 50-51 °C; IR (KBr): 3414, 2922,
2854, 1591, 1473, 1384, 1247, 1120, 987, 754 cm-1; 1H NMR (CDCl3, 500 MHz) δ: 1.11-1.25 (m, 5H), 1.59-1.65
(m, 2H), 1.72-1.83 (m, 4H), 2.20 (s, 3H), 3.98 (dd, J = 9.5, 6.5 Hz, 1H), 4.13-4.19 (m, 2H), 4.28-4.32 (m, 1H),
4.38 (t, J = 11.0 Hz, 1H), 5.10 (d, J = 6.0 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.89 (t, J = 7.5 Hz, 1H), 7.15 (t, J =
8.5 Hz, 2H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 16.2, 25.6, 25.7, 26.2, 27.1, 40.7, 67.3, 71.9, 74.1, 107.3,
11
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110.9, 120.9, 126.9, 130.8, 156.4 ppm; HRMS (EI, m/z): calcd. for C17H24O4 (M)+: 292.1675, found: 292.1679.
3-Phenylhexahydrobenzo[e][1,2,4]trioxine (3p). White solid, 65-66°C; IR (KBr): 3414, 2949, 2862, 1452,
1
1381, 1161, 1091, 1043, 974, 750 cm-1; H NMR (CDCl3, 500 MHz) δ: 1.21-1.29 (m, 1H), 1.37-1.46 (m, 2H),
1.52-1.60 (m, 1H), 1.84-1.90 (m, 3H), 2.03-2.06 (m, 1H), 3.70 (ddd, J = 12.0, 8.5, 4.0 Hz, 1H), 4.22 (ddd, J =
12.0, 8.5, 4.0 Hz, 1H), 6.29 (s, 1H), 7.38-7.39 (m, 3H), 7.50-7.52 (m, 2H) ppm; 13C NMR (CDCl3, 125 MHz) δ:
23.9, 24.0, 26.9, 29.1, 79.8, 89.6, 103.5, 123.6, 128.1, 140.7, 148.7 ppm; HRMS (EI, m/z): calcd. for C13H16O3
(M)+: 220.1099, found: 220.1103.
3-(4-Nitrophenyl)hexahydrobenzo[e][1,2,4]trioxine (3q). White solid, 107-108°C; IR (KBr): 3385, 2945,
1
2864, 1608, 1518, 1329, 1166, 1070, 989, 854, 746 cm-1; H NMR (CDCl3, 500 MHz) δ: 1.24-1.27 (m, 1H),
1.39-1.47 (m, 2H), 1.55-1.61 (m, 1H), 1.84-1.91 (m, 3H), 2.05-2.08 (m, 1H), 3.73 (ddd, J = 12.0, 8.5, 4.0 Hz,
1H), 4.23 (ddd, J = 12.0, 9.0, 4.0 Hz, 1H), 6.36 (s, 1H), 7.68 (d, J = 8.5 Hz, 2H), 8.24 (d, J = 8.5 Hz, 2H) ppm;
13C NMR (CDCl3, 125 MHz) δ: 23.9, 24.1, 26.9, 29.2, 79.6, 84.3, 105.2, 127.1, 128.4, 129.9, 134.5 ppm; HRMS
(EI, m/z): calcd. for C13H15NO5 (M)+: 265.0950, found: 265.0955.
3,3-Dimethyl-6-phenyl-1,2,4-trioxane (5a). Colorless oil; IR (KBr): 3385, 2997, 2941, 2872, 1496, 1454,
1205, 1163, 1099, 1047, 900, 831, 756, 698, 526 cm-1; 1H NMR (CDCl3, 500 MHz) δ: 1.44 (s, 3H), 1.75 (s, 3H),
3.85 (dd, J = 12.0, 3.0 Hz, 1H), 4.11 (t, J = 11.0 Hz, 1H), 5.28 (dd, J = 10.5, 3.0 Hz, 1H), 7.38-7.32 (m, 5H) ppm;
13C NMR (CDCl3, 125 MHz) δ: 20.1, 25.6, 64.1, 81.3, 102.3, 127.2, 128.7, 129.2, 135.2 ppm; HRMS (EI, m/z):
calcd. for C11H14O3 (M)+: 194.0943, found: 194.0947.
8-Phenyl-6,7,10-trioxaspiro[4.5]decane (5b). Colorless oil; IR (KBr): 3421, 2989, 2924, 2858, 1647, 1508,
1384, 1080, 991, 871, 785, 688, 542 cm-1; 1H NMR (CDCl3, 500 MHz) δ: 1.80-1.68 (m, 4H), 2.05-1.84 (m, 4H),
3.69 (t, J = 7.8 Hz, 1H), 4.27 (dd, J = 8.3, 6.3 Hz, 1H), 5.01 (t, J = 7.0 Hz, 1H), 7.38-7.28 (m, 5H) ppm; 13C
NMR (CDCl3, 125 MHz) δ: 23.4, 23.7, 36.5, 36.8, 71.6, 77.8, 119.8, 126.3, 128.0, 128.6, 139.5 ppm; HRMS (EI,
m/z): calcd. for C13H16O3 (M)+: 220.1099, found: 220.1103.
3-Phenyl-1,2,5-trioxaspiro[5.5]undecane (5c). Colorless oil; IR (KBr): 3385, 3064, 2935, 2862, 1718, 1635,
1
1494, 1448, 1384, 1276, 1161, 1103, 929, 758, 698 cm-1; H NMR (CDCl3, 500 MHz) δ: 1.44-1.47 (m, 2H),
1.60-1.84 (m, 8H), 3.69 (t, J = 8.0 Hz, 1H), 4.29 (dd, J = 8.0, 6.5 Hz, 1H), 5.07 (t, J = 8.0 Hz, 1H), 7.28-7.38 (m,
5H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 23.9, 24.0, 25.2, 35.6, 36.2, 71.5, 77.6, 110.3, 126.3, 128.0, 128.5,
139.3 ppm; HRMS (EI, m/z): calcd. for C14H18O3 (M)+: 234.1256, found: 234.1261.
(1R,2R,5S)-6'-Phenylspiro[adamantane-2,3'-[1,2,4]trioxane] (5d). Colorless oil; IR (KBr): 3421, 3064,
2931, 2856, 1718, 1635, 1452, 1384, 1219, 1128, 1045, 999, 929, 752, 698 cm-1; 1H NMR (CDCl3, 500 MHz) δ:
12
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1.70-1.83 (m, 8H) 1.97-2.17 (m, 6H), 3.69 (t, J = 8.3 Hz, 1H), 4.31 (dd, J = 8.0, 6.0 Hz, 1H), 5.08 (dd, J = 8.0,
6.5 Hz, 1H), 7.39-7.27 (m, 5H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 27.0, 27.1, 34.7, 34.8, 35.1, 35.3, 36.9,
37.3, 37.5, 71.6, 77.7, 112.8, 126.2, 127.9, 128.5, 139.8 ppm; HRMS (EI, m/z): calcd. for C18H22O3 (M)+:
286.1569, found: 286.1575.
4-(Phenoxymethyl)-1,2,5-trioxaspiro[5.5]undecane (5e). White solid, 64-65°C; IR (KBr): 3423, 2939,
1
2850, 1600, 1500, 1249, 1105, 752 cm-1; H NMR (CDCl3, 500 MHz) δ: 1.47-1.63 (m, 8H), 1.99-2.04 (m, 1H),
2.24-2.29 (m, 1H), 3.90 (dd, J = 9.5, 7.0 Hz, 1H), 4.09 (dd, J = 9.5, 4.5 Hz, 1H), 4.17 (dd, J = 12.0, 3.0 Hz, 1H),
4.25 (t, J = 11.0 Hz, 1H), 4.51-4.56 (m, 1H), 6.90 (d, J = 8.0 Hz, 2H), 6.97 (t, J = 7.5 Hz, 1H), 7.29 (t, J = 8.0 Hz,
2H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 22.1, 22.4, 25.6, 29.3, 35.2, 65.1, 67.9, 73.8, 103.4, 114.5, 121.3,
129.5, 158.4 ppm; HRMS (EI, m/z): calcd. for C15H20O4 (M)+: 264.1362, found: 264.1366.
4-((o-Tolyloxy)methyl)-1,2,5-trioxaspiro[5.5]undecane (5f). Colorless oil; IR (KBr): 3419, 2933, 2860,
1
1591, 1496, 1384, 1244, 1079, 991, 750 cm-1; H NMR (CDCl3, 500 MHz) δ: 1.44-1.52 (m, 2H), 1.56-1.67 (m,
6H), 2.06-2.12 (m, 1H), 2.22 (s, 3H), 2.24-2.28 (m, 1H), 3.92 (dd, J = 9.5, 7.0 Hz, 1H), 4.10 (dd, J = 9.5, 4.5 Hz,
1H), 4.19 (dd, J = 12.0, 3.5 Hz, 1H), 4.30 (t, J = 11.5 Hz, 1H), 4.54-4.59 (m, 1H), 6.82 (d, J = 8.0 Hz, 1H), 6.89
(t, J = 7.5 Hz, 1H), 7.16 (t, J = 8.5 Hz, 2H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 16.2, 22.2, 22.4, 25.6, 29.3,
35.2, 65.2, 68.0, 73.9, 103.4, 110.9, 120.9, 126.8, 126.9, 130.8, 156.5 ppm; HRMS (EI, m/z): calcd. for C16H22O4
(M)+: 278.1518, found: 278.1523.
(5r,7r)-5'-(Phenoxymethyl)spiro[adamantane-2,3'-[1,2,4]trioxane] (5g). White solid, 99-100°C; IR (KBr):
1
3421, 2928, 2848, 1599, 1500, 1238, 1122, 1000, 756 cm-1; H NMR (CDCl3, 500 MHz) δ: 1.57-1.62 (m, 2H),
1.70-1.72 (m, 4H), 1.82-1.84 (m, 3H), 1.91 (t, J = 15.0 Hz, 2H), 1.98 (d, J = 12.5 Hz, 1H), 2.10 (d, J = 13.0 Hz,
1H), 3.92 (dd, J = 10.0, 7.0 Hz, 1H), 2.98 (d, J = 1.5 Hz, 1H), 4.10 (dd, J = 9.5, 4.5 Hz, 1H), 4.17 (dd, J = 12.0,
3.0 Hz, 1H), 4.25 (t, J = 11.0 Hz, 1H), 4.49-4.54 (m, 1H), 6.90 (d, J = 8.0 Hz, 2H), 6.97 (t, J = 7.5 Hz, 1H), 7.29
(t, J = 7.5 Hz, 2H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 27.1, 27.2, 29.6, 33.0, 33.2, 33.3, 33.4, 36.6, 37.2, 64.6,
68.0, 73.7, 105.5, 114.5, 121.2, 129.5, 158.4 ppm; HRMS (EI, m/z): calcd. for C19H24O4 (M)+: 316.1675, found:
316.1679.
(5r,7r)-5'-((o-Tolyloxy)methyl)spiro[adamantane-2,3'-[1,2,4]trioxane] (5h). White solid, 49-51°C; IR
1
(KBr): 3367, 2922, 2852, 1600, 1496, 1400, 1242, 1122, 1047, 925, 752 cm-1; H NMR (CDCl3, 500 MHz) δ:
1.58-1.62 (m, 2H), 1.70-1.73 (m, 4H), 1.82-1.85 (m, 3H), 1.93 (t, J = 10.0 Hz, 2H), 1.99 (d, J = 12.5 Hz, 1H),
2.06 (d, J = 12.5 Hz, 1H), 2.20 (s, 3H), 3.00 (s, 1H), 3.93 (dd, J = 9.5, 7.0 Hz, 1H), 4.09 (dd, J = 9.5, 5.0 Hz, 1H),
4.17 (dd, J = 12.0, 3.5 Hz, 1H), 4.28 (t, J = 10.5 Hz, 1H), 4.53-4.58 (m, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.88 (t, J =
13
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10.1002/adsc.201700671
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7.5 Hz, 1H), 7.15 (dd, J = 10.0, 7.5 Hz, 2H) ppm; 13C NMR (CDCl3, 125 MHz) δ: 16.2, 27.1, 27.2, 29.6, 33.0,
33.2, 33.3, 33.4, 36.6, 37.2, 64.7, 67.9, 73.7, 105.5, 110.8, 120.9, 126.8, 126.9, 130.8, 156.5 ppm; HRMS (EI,
m/z): calcd. for C20H26O4 (M)+: 330.1831, found: 330.1837.
Acknowledgements
This work was financially supported by the National Natural Science Foundation of China (21272053) and
Nature Science Foundation of Hebei Province (B2015205182).
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