A mild and one-step synthesis of 2,8-dioxabicyclo [3.3.1] nonane derivatives via classical Knoevenagel condensation

Article abstract of DOI:10.1016/j.tet.2017.07.054

Utilizing simple and readily available 2-hydroxy benzaldehydes and 1,3-diketones or 1,3-cyclohexanediones as raw materials, complex 2,8-dioxabicyclo [3.3.1] nonane derivatives were synthesized in one-step via classical Knoevenagel condensation. The reaction was simply conducted under solvent-free and mild conditions, which showed good tolerance to a variety of functional groups. This atom-economical approach delivers an attractive synthetic protocol for 2,8-dioxabicyclo [3.3.1] nonane derivatives.

Full text of DOI:10.1016/j.tet.2017.07.054

Tetrahedron xxx (2017) 1e6
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A mild and one-step synthesis of 2,8-dioxabicyclo [3.3.1] nonane
derivatives via classical Knoevenagel condensation
De-Suo Yang*, Sen Ke, Xin Du, Peng Gao, Hai-Tao Zhu, Ming-Jin Fan**
Shaanxi Key Laboratory of Phytochemistry, College of Chemistry and Chemical Engineering, Baoji University of Arts and Sciences, Baoji, 721013, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Utilizing simple and readily available 2-hydroxy benzaldehydes and 1,3-diketones or 1,3-
cyclohexanediones as raw materials, complex 2,8-dioxabicyclo [3.3.1] nonane derivatives were synthe-
sized in one-step via classical Knoevenagel condensation. The reaction was simply conducted under
solvent-free and mild conditions, which showed good tolerance to a variety of functional groups. This
atom-economical approach delivers an attractive synthetic protocol for 2,8-dioxabicyclo [3.3.1] nonane
derivatives.
Received 22 May 2017
Received in revised form
26 July 2017
Accepted 28 July 2017
Available online xxx
© 2017 Published by Elsevier Ltd.
Keywords:
2,8-Dioxabicyclo [3.3.1] nonane
Knoevenagel condensation
V-shaped rigid framework
1. Introduction
diketones/1,3-cyclohexanediones could also be used as raw mate-
rials to construct 2,8-dioxabicyclo [3.3.1] nonane derivatives via
2,8-Dioxabicyclo [3.3.1] nonane skeletons are precious in natu-
ral compounds because of their elaborate V-shaped rigid frame-
works and structural complexities.1 These skeletons have been
shown to possess a number of biological and pharmacological ac-
tivities.2,3 For example, the flavonoid proanthocyanidin A1 and A2,4
dracoflavan C and D,5 ephedrannin A and B,6 diinsininol (5) and (4)
isolated from natural compounds,7 all exhibit a wide range of bio-
logical and pharmacological properties including anti-inflamma-
tory,8 antimicrobial,9 antiviral activities,10 anticoagulant and so on
(Fig. 1). Therefore, they have drawn enormous attention and
stimulated organic chemists to design strategies for assembling
these challenging structures in recent years.11e13 Manolov and co-
workers illustrated a base-catalyzed condensation between 3-
benzoylcoumarin and 4-hydroxycoumarin to afford the corre-
sponding 1-phenyl 2,8-dioxabicyclo [3.3.1] nonanes.14 Yang re-
ported that these molecules could be achieved through the reaction
of 2-phenylchroman-4-ol with 4-hydroxycoumarin in the presence
of aluminum chloride.15 Wu and Ganguly described the synthesis of
cascade Knoevenagel/hetero-Dielse-Alder reactions catalyzed by
AuBr3 and
D
-proline.17 In fact, all these strategies possess short-
comings of harsh reaction conditions, expensive catalysts or
complicated starting materials. The development of efficient and
metal free catalytic methods toward 2,8-dioxabicyclo [3.3.1] non-
anes from simple starting materials is still of significant interest and
also represents one of the most challenging goals in organic
synthesis.18
As we all know that benzaldehyde can react with 1,3-diketones
to afford condensation products in the presence of piperidine/
acetic acid and this reaction was called Knoevenagel condensation
reaction. It is a versatile, convenient and extensively used reaction,
which represents one of the most fundamental bond-forming
protocol in organic synthesis.19 However, during our research, we
are surprised to find that 2,8-dioxabicyclo [3.3.1] nonanes can be
produced by the reaction of 2-hydroxybenzaldehyde with 1,3-
diketones under classical Knoevenagel condensation conditions.
Herein, we report this efficient synthesis of diverse 1-aryl-
substituted 2,8-dioxabicyclo [3.3.1] nonane derivatives from cheap
2-hydroxybenzaldehyde and 1,3-diketones.
2,8-dioxabicyclo
[3.3.1]
nonanes
derivatives
from
2-
hydroxychalcone-a,b-enones and 4-hydroxycoumarin respec-
tively.16 Aldehyde-substituted vinylogous carbonates and 1,3-
2. Results and discussion
For the initial feasibility studies, 2-hydroxybenzaldehyde (1a)
and 2,4-pentanedione (2a) were selected as model substrates to
study the cycloaddition. 1a (1 mmol) and 2a (2.0 mmol) were
* Corresponding author.
** Corresponding author.
E-mail address: yangdesuo@163.com (D.-S. Yang).
http://dx.doi.org/10.1016/j.tet.2017.07.054
0040-4020/© 2017 Published by Elsevier Ltd.
Please cite this article in press as: Yang D-S, et al., A mild and one-step synthesis of 2,8-dioxabicyclo [3.3.1] nonane derivatives via classical
Knoevenagel condensation, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.07.054

2
D.-S. Yang et al. / Tetrahedron xxx (2017) 1e6
Table 1
Optimization studies for the synthesis of 2,8-dioxabicyclo [3.3.1] nonane derivative
3a.a
Entry
1a:2a
Base
Acid
Solvent
T/ꢀC
Yield/%b
1
2
3
4
5
6
7
8
1: 2
1: 2.5
1: 3
1: 3.5
1: 3
1: 3
1: 3
1: 3
1: 3
1: 3
1: 3
1: 3
1: 3
1: 3
1: 3
1: 3
1: 3
1: 3
1: 3
1: 3
1: 3
1: 3
1: 3
1: 3
1: 3
1: 3
1: 3
1: 3
1: 3
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
Piperidine
DABCO
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
Ac2O
TsOH
CF3CO2H
AcOH
AcOH
AcOH
AcOHf
AcOHg
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
Ac2O
toluene
toluene
toluene
toluene
THF
CH3CN
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
e
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
75
65
70
80
70
70
70
70
70
70
70
16
17
27
23
22
28
45
36
NR
trace
NR
NR
NR
40
50
26
38
41
9
Pyridine
DBU
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Piperidine
Piperidine
Piperidine
Piperidinec
Piperidined
Piperidinee
Piperidined
Piperidined
Piperidined
Piperidined
Piperidined
Piperidined
DABCO
Pyridine
DBU
Piperidine
Piperidine
Piperidine
Piperidine
Fig. 1. Biologically interesting natural products containing 2,8-dioxabicyclo [3.3.1]
non-3-ene skeleton.
78
57
89
77
e
e
treated with piperidine (0.6 eq.) and acetic acid (1.1 eq.) in toluene
at 75 ꢀC under argon atmosphere for 20 h. It was found that the
expected 1-phenyl 2,8-dioxabicyclo [3.3.1] nonane (3a) was ob-
tained only in 16% yield (Table 1, entry 1). The structure of 3a was
unambiguously confirmed by its 1H NMR, 13C NMR, HRMS spectra
and X-ray crystallographic analysis (see Fig. 2 and the corre-
sponding datablock was in the Supporting Information).20 A brief
survey on the proportion of 1a and 2a indicated that appropriately
excessive 2a was favorable to the transformation (entries 1e4). 3a
was obtained in relatively higher yield in dichloroethane (DCE)
according to the screen of solvents (entries 5e7). The trans-
formation was also attempted under catalysis of other bases and
acids, such as DABCO, pyridine, DBU, Ac2O, TsOH and CF3CO2H, but
3a wasn't isolated in higher yields (entries 8e13). Also, no
increasing yield was obtained after increasing the amount of
piperidine to 1.0 eq. (entry 14). Next, by decreasing the dosage of
piperidine to 0.3 eq., higher yield of 50% was achieved (entry 15).
But the yield decreased obviously after continuing decreasing the
dosage of piperidine (entry 16). The amount of acetic acid was also
explored, but no better results were given (entries 17 and 18).
Finally, to our excitement, the product was obtained in excellent
yield under solvent-free condition (entry 19). Additionally, slight
decreasing in the reaction temperature was favorable to increase
the yield, but continuous decreasing the reaction temperature gave
the opposite result (entries 21 and 22). After sifting different bases
and acids, the optimal conditions were identified as the use of 1a
(1 mmol), piperidine (0.3 eq.), acetic acid (1.1 eq.) under argon at-
mosphere and solvent-free conditions at 70 ꢀC for 20 h (entry 21 is
shown in Table 1 boldly).
e
e
39
e
NR
trace
NR
NR
NR
NR
e
e
TsOH
CF3CO2H
e
e
e
a
All reactions were conducted under the following conditions unless otherwise
indicated: 1a (1 mmol), base (0.6 eq.) and acid (1.1 eq.) in anhydrous solvent (2 mL)
under argon atmosphere for 20 h.
b
Isolated yield.
1.0 eq. piperidine was used.
0.3 eq. piperidine was used.
0.2 eq. piperidine was used.
1.0 eq. AcOH was used.
1.2 eq. AcOH was used.
c
d
e
f
g
Under the optimal conditions, the generality of the reaction was
explored for the synthesis of diverse 1-aryl-substituted 2,8-dioxa-
bicyclo [3.3.1] nonanes. Primarily, 1,3-diketone 2a was used to react
with a variety of 2-hydroxybenzaldehyde derivatives (1). In all
these reactions, products 3 were produced in moderate to good
yields (Table 2). The substrates bearing electron-withdrawing
substituent such as -F, -Cl, -Br on C-4 or C-5 position of the
Fig. 2. X-ray crystallography of 3a.
phenyl ring could react smoothly with 2a to deliver the corre-
sponding 3b, 3c, 3e, 3g in excellent yields (70e85%) (entries 2, 3, 5
and 7). However, the halogen atom on the C-3 position was found to
be unfavorable for this transformation due to steric hindrance
Please cite this article in press as: Yang D-S, et al., A mild and one-step synthesis of 2,8-dioxabicyclo [3.3.1] nonane derivatives via classical
Knoevenagel condensation, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.07.054

D.-S. Yang et al. / Tetrahedron xxx (2017) 1e6
3
Table 2
the reaction and applied to react with 1,3-diketones. It was found
that compound C could react smoothly with 1,3-diketones 2a and
generate 3a in 80% yield under the standard reaction conditions
(Scheme 1, path a). It proved that 2,8-dioxabicyclo [3.3.1] nonanes
are most likely synthesized via this unsaturated condensation in-
termediate. When the reaction was performed under the same
conditions in the absence of acetic acid, 3a was obtained in a lower
yield of 66% (path b). On contrary, when the reaction was per-
formed in the absence of piperidine, 3a could not be obtained (path
c). Therefore, the following cyclization was proved to be carried
under base-acid catalyzing condition.
Substrate scope of the synthesis of 2,8-dioxabicyclo [3.3.1] nonane derivatives
3a¡o.a
Entry
Substrate
Product
Yield/%a
On the basis of the previous reports and the experiment results
obtained above, a tentative mechanism was proposed in Scheme
1
2
3
4
5
6
7
8
R ¼ H, 1a
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
89
80
70
45
73
23
85
30
70
87
25
50
78b
75b
20
2.13d,
Initially, 2-hydroxybenzaldehyde 1a reacts with piperi-
R ¼ 5-Br, 1b
16a
R ¼ 4-Br, 1c
dine via known mechanism of Knoevenagel condensation to give
the intermediate A, which can react with another deprotonated
substrate 2a via Michael addition and generates intermediate B. In
the following process, the phenolic hydroxyl group of intermediate
B is deprotonated by piperidine, meanwhile, the continuous
nucleophilic addition reaction happens to give intermediate E.
Finally, the desired product 3a is formed through the elimination of
water from intermediate E.
R ¼ 3-Br, 1d
R ¼ 5-Cl, 1e
R ¼ 3, 5-Cl, 1f
R ¼ 5-F, 1g
R ¼ 5-NO2, 1h
R ¼ 5-Me, 1i
9
10
11
12
13
14
15
R ¼ 3-Me, 1j
R ¼ 4-OMe,1k
R ¼ 5-OMe, 1l
R ¼ 3-OH, 1m
R ¼ 2-NH2, 1n
2-hydroxy-1-naphthaldehyde, 1o
3. Conclusions
a
Isolated yield.
Only condensation products were generated.
In summary, a novel and efficient approach to synthesize 2,8-
dioxabicyclo [3.3.1] nonane derivatives from readily accessible 2-
hydroxybenzaldehydes and 1,3-diketones under mild reaction
conditions have been developed. Four chemical bonds (two CꢁC
bond and two CꢁO bonds) and two six-member cycles were
formed in this one-pot operation. The use of toxic and expensive
transition-metal catalysts were completely avoided in this process.
This atom-economical and mild approach delivers an attractive
synthetic protocol for complex 2,8-dioxabicyclo [3.3.1] nonane
derivatives, which are important motifs in many natural and
pharmaceutical products.
b
(entries 4 and 6). The extremely strong electron-withdrawing
substituent like nitryl on the phenyl ring (3h) was also found to
be unfavorable for this transformation (entry 8). The electron-
donating substituents on the aromatic ring were found to be un-
favorable to this reaction, because these substituents make the
double bond of the reaction intermediate a bad Michael acceptor in
the reaction process (see the following mechanistic study section).
For examples, the substrates bearing methoxyl groups (-OMe) on
the phenyl ring were found to give the corresponding products 3k
and 3l in poor yields of 25% and 50%. It is worthy of note that the
substrates bearing small and weak electron-donating substituent
like methyl group could afford the corresponding products 3i and
3j in good yields (70% and 87%). Subsequently, the substrates
bearing hydroxy group at C-3 position or amino group at C-2 po-
sition of the phenyl ring could only afford condensation products
(3m and 3n). The substrate 2-hydroxy-1-naphthaldehyde (1o) can
also provide the corresponding products 3o in 20% yield.
Next, 2-hydroxybenzaldehyde (1a) was employed to react with
a variety of diketones 2 under standard reaction conditions. As
shown in Table 3, diketone derivatives 2,5-hexanedione (2p) and 3-
pentylpentane-2,4-dione (2q) couldn't react with 1a. When the
reaction was conducted with substrates 2r and 2s, the desired
products 3r and 3s could be generated smoothly in moderate yields
(Table 3, 3r and 3s, 40% and 50%). The same result was also obtained
when compound 2t was applied as the substrate (3t). It is pleased
to find that 1,3-cyclohexanedione (2u) could also react with 1a to
give more complex polycyclic 2,8-dioxabicyclo [3.3.1] nonane
compounds (3u) in good yields of 70%. Overall, these results
highlight the great potential and versatility of the present method,
which provides a direct and practical access to highly valuable 2,8-
dioxabicyclo [3.3.1] nonane derivatives from readily accessible
starting materials.
4. Experimental section
4.1. General experimental detials
Product purification was realized by flash column chromatog-
raphy. 1H NMR and 13C NMR spectra were recorded on an Agilent
400 MHz nuclear magnetic resonance spectrometer in CDCl3.
Chemical shifts (ppm) were recorded with tetramethylsilane (TMS)
as the internal reference standard. Multiplicities are given as: s
(singlet), d (doublet), t (triplet), dd (doublet of doublets), q (quartet)
or m (multiplet). IR spectra were recorded on a FT-IR spectrometer
and only major peaks are reported in cmꢁ1. HR-MS was obtained
using a Q-TOF instrument equipped with ESI source. Copies of the
1H NMR and 13C NMR spectra are provided. Commercially available
reagents were used without further purification. All solvents were
dried before using.
4.2. General reaction procedures
Piperidine (25.5 mg, 0.3 eq.) and acetic acid (66 mg, 1.1 eq.) were
added to a mixture of 2-hydroxybenzaldehyde (120 mg, 1 mmol)
and 1,3-diketones derivatives (300 mg, 3 mmol), which was then
heated at 70 ꢀC under argon atmosphere for 20 h until no starting
material remained (monitored by thin layer chromatography). The
reaction mixture was diluted with ethyl acetate (10 mL) and water
(5 mL). The aqueous layer was extracted with ethyl acetate
(3*15 mL), the combined organic layers were washed in turn with
water and saturated brine, dried over Na2SO4 and evaporated under
During the following study, the experiments for mechanistic
studies on this reaction were performed and the results are pre-
sented in Scheme 1.
a,b-Unsaturated condensation compound C
was firstly prepared, which was presumed to be an intermediate of
Please cite this article in press as: Yang D-S, et al., A mild and one-step synthesis of 2,8-dioxabicyclo [3.3.1] nonane derivatives via classical
Knoevenagel condensation, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.07.054

4
D.-S. Yang et al. / Tetrahedron xxx (2017) 1e6
Table 3
Substrate scope of the synthesis of 2,8-Dioxabicyclo [3.3.1] nonane derivatives 3rꢁu.a
reduced pressure. The residue was purified by chromatography on
silica gel to afford the corresponding 3a.
Compound 3a: yield 0.2546 g (89%); mp 159e161 ꢀC; IR (neat,
cmꢁ1): 3566.8, 3400.7, 2982.3, 2946.6, 1457.8, 1377.2; 1H NMR
(400 MHz, CDCl3)
d
ppm 7.28 (dd, J ¼ 7.5, 1.3 Hz, 1H), 7.10e7.06 (m,
1H), 6.86e6.81 (m, 2H), 4.63 (d, J ¼ 2.4 Hz, 1H), 3.07 (d, J ¼ 2.6 Hz,
1H), 2.29 (s, 3H), 2.21 (s, 3H), 2.20 (s, 3H), 1.82 (s, 3H); 13C NMR
(100 MHz,CDCl3) d ppm 203.3,195.3,164.2,150.3,127.9,127.5,126.3,
121.2, 115.9, 114.9, 97.8, 49.3, 31.2, 31.0, 29.5, 24.2, 21.0; HRMS (ESI)
Calcd for C17H18O4: [MþNa] ¼ 309.1103. Found: 309.1105.
Compound 3b: yield 0.2908 g (80%); mp 159e160 ꢀC; IR (neat,
cmꢁ1): 3256.0, 2994.8, 2257.6, 1973.4, 1709.1, 1358.5; 1H NMR
(400 MHz, CDCl3)
d
ppm 7.45 (d, J ¼ 2.4 Hz, 1H), 7.19 (dd, J ¼ 8.6,
2.4 Hz, 1H), 6.72 (d, J ¼ 8.6 Hz, 1H), 4.62 (d, J ¼ 2.5 Hz, 1H), 3.04 (d,
J ¼ 2.6 Hz, 1H), 2.32 (s, 3H), 2.24 (s, 3H), 2.21 (s, 3H), 1.82 (s, 3H); 13
C
Scheme 1. Experiments for mechanistic studies.
Scheme 2. Plausible mechanism for the synthesis of 2,8-dioxabicyclo [3.3.1] nonanes.
Please cite this article in press as: Yang D-S, et al., A mild and one-step synthesis of 2,8-dioxabicyclo [3.3.1] nonane derivatives via classical
Knoevenagel condensation, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.07.054

D.-S. Yang et al. / Tetrahedron xxx (2017) 1e6
5
NMR (100 MHz, CDCl3)
d
ppm 203.1, 195.3, 164.6, 149.7, 130.9, 130.3,
(400 MHz, CDCl3)
d
ppm 7.15 (d, J ¼ 7.5 Hz, 1H), 6.97 (d, J ¼ 7.4 Hz,
128.5, 117.9, 114.8, 113.6, 98.1, 49.1, 31.4, 30.9, 29.7, 24.3, 21.2; HRMS
(ESI) Calcd for C17H17BrO4: [MþNa] ¼ 387.0208. Found: 387.0215.
Compound 3c: yield 0.2548 g (70%); mp 141e143 ꢀC; IR (neat,
cmꢁ1): 3256.5, 2984.1, 2315.5, 1766.8, 1707.7, 1376.5; 1H NMR
1H), 6.77 (t, J ¼ 7.5 Hz, 1H), 4.64 (d, J ¼ 2.5 Hz, 1H), 3.06 (d,
J ¼ 2.6 Hz, 1H), 2.31 (s, 3H), 2.23 (s, 3H), 2.22 (s, 3H), 2.19 (s, 3H) 1.86
(s, 3H); 13C NMR (100 MHz, CDCl3)
d ppm 203.7, 195.6, 164.3, 148.6,
129.4, 126.0, 125.4, 125.2, 120.9, 115.1, 97.8, 49.9, 31.4, 31.3, 29.7,
24.5, 21.3,15.9; HRMS (ESI) Calcd for C18H20O4: [MþNa] ¼ 323.1259.
Found: 323.1263.
(400 MHz, CDCl3)
4.62 (d, J ¼ 2.4 Hz, 1H), 3.04 (d, J ¼ 2.6 Hz, 1H), 2.30 (s, 3H), 2.23 (s,
3H), 2.22 (s, 3H), 1.82 (s, 3H); 13C NMR (100 MHz, CDCl3)
ppm
d
ppm 7.18 (d, J ¼ 8.1 Hz, 1H), 7.02e6.97 (m, 2H),
d
Compound 3k: yield 0.0790 g (25%); Liquid; IR (neat, cmꢁ1):
203.1, 195.4, 164.5, 151.4, 128.9, 125.6, 124.5, 120.9, 119.3, 115.0, 98.1,
49.2, 31.4, 30.8, 29.7, 24.3, 21.2; HRMS (ESI) Calcd for C17H17BrO4:
[MþNa] ¼ 387.0208. Found: 387.0210.
3674.5, 2966.1, 2245.8, 1760.2, 1502.3, 1376.0; 1H NMR (400 MHz,
CDCl3)
J ¼ 2.5 Hz, 1H), 3.73 (s, 3H), 3.07 (d, J ¼ 2.6 Hz, 1H), 2.31 (s, 3H), 2.23
(s, 3H), 2.22 (s, 3H), 1.83 (s, 3H); 13C NMR (100 MHz, CDCl3)
ppm
d
ppm 7.20 (d, J ¼ 8.3 Hz, 1H), 6.46e6.41 (m, 2H), 4.59 (d,
Compound 3d: yield 0.1637 g (45%); mp 167e169 ꢀC; IR (neat,
cmꢁ1): 3241.7, 3016.5, 2883.7, 2367.8, 1712.4, 1329.8; 1H NMR
d
203.7, 195.7, 164.2, 159.7, 151.4, 128.2, 118.9, 115.6, 107.8, 101.4, 98.0,
55.5, 49.8, 31.4, 30.7, 29.7, 24.4, 21.2; HRMS (ESI) Calcd for C18H20O5:
[MþNa] ¼ 339.1208. Found: 339.1213.
(400 MHz, CDCl3)
d
ppm 7.34 (dd, J ¼ 8.0, 1.5 Hz, 1H), 7.27 (dd,
J ¼ 7.4, 1.6 Hz, 1H), 6.24 (t, J ¼ 7.8 Hz, 1H), 4.67 (d, J ¼ 2.5 Hz, 1H),
3.06 (d, J ¼ 2.6 Hz, 1H), 2.31 (s, 3H), 2.25 (s, 3H), 2.22 (s, 3H), 1.91 (s,
Compound 3l: yield 0.1580 g (50%); mp 100e102 ꢀC; IR (neat,
cmꢁ1): 2944.1, 2833.1, 2214.0, 1712.5, 1492.2, 1378.5; 1H NMR
3H); 13C NMR (100 MHz, CDCl3)
d ppm 203.0, 195.4, 164.4, 147.7,
131.8, 128.1, 126.9, 122.3, 114.9, 109.9, 98.5, 49.3, 31.4, 31.3, 29.8,
24.3, 21.2; HRMS (ESI) Calcd for C17H17BrO4: [MþNa] ¼ 387.0208.
Found: 387.0222.
(400 MHz, CDCl3)
d
ppm 6.85 (d, J ¼ 3.0 Hz, 1H), 6.76 (d, J ¼ 8.8 Hz,
1H), 6.66 (dd, J ¼ 8.8, 3.0 Hz,1H), 4.61 (d, J ¼ 2.6 Hz,1H), 3.72 (s, 3H),
3.08 (d, J ¼ 2.7 Hz, 1H), 2.31 (s, 3H), 2.23 (s, 3H), 2.21 (s, 3H), 1.81 (s,
Compound 3e: yield 0.2340 g (73%); mp 152e154 ꢀC; IR (neat,
3H); 13C NMR (100 MHz, CDCl3)
d ppm 203.6, 195.5, 164.8, 154.0,
cmꢁ1): 2982.1, 2355.5, 2328.9, 2048.5, 1709.4, 1369.9; 1H NMR
144.3,126.9,116.8,114.9,114.3,112.0, 97.9, 55.9, 49.5, 31.4, 31.3, 29.7,
24.3, 21.3; HRMS (ESI) Calcd for C18H20O5: [MþNa] ¼ 339.1208.
Found: 339.1218.
(400 MHz, CDCl3)
d
ppm 7.30 (d, J ¼ 2.5 Hz, 1H), 7.05 (dd, J ¼ 8.7,
2.6 Hz, 1H), 6.76 (d, J ¼ 8.7 Hz, 1H), 4.62 (d, J ¼ 2.5 Hz, 1H), 3.05 (d,
J ¼ 2.6 Hz, 1H), 2.32 (s, 3H), 2.24 (s, 3H), 2.21 (s, 3H), 1.82 (s, 3H); 13
C
Compound 3o: yield 0.0672 g (20%); mp 160e162 ꢀC; IR (neat,
NMR (100 MHz, CDCl3) d ppm 203.1, 195.3, 164.7, 149.2, 128.0, 127.9,
cmꢁ1): 2924.6, 2204.6, 2179.1, 1713.0, 1604.8, 1352.2; 1H NMR
127.4, 126.2, 117.4, 114.8, 98.1, 49.2, 31.4, 30.9, 29.7, 24.3, 21.2; HRMS
(ESI) Calcd for C17H17ClO4: [MþNa] ¼ 343.0713. Found: 343.0720.
Compound 3f: yield 0.0814 g (23%); mp 171e173 ꢀC; IR (neat,
cmꢁ1): 3073.1, 2952.8, 2985.2, 1709.0, 1369.2, 1222.9; 1H NMR
(400 MHz, CDCl3)
d
ppm 8.25 (d, J ¼ 8.5 Hz, 1H), 7.74 (d, J ¼ 8.1 Hz,
1H), 7.64 (d, J ¼ 8.8 Hz, 1H), 7.55e7.51 (m, 1H), 7.37e7.33 (m, 1H),
7.09 (d, J ¼ 8.9 Hz, 1H), 5.44 (d, J ¼ 2.7 Hz, 1H), 3.18 (d, J ¼ 2.8 Hz,
1H), 2.32 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H), 1.92 (s, 3H); 13C NMR
(400 MHz, CDCl3)
1H), 4.62 (d, J ¼ 2.5 Hz, 1H), 3.03 (d, J ¼ 2.6 Hz, 1H), 2.29 (s, 3H), 2.23
(s, 3H), 2.19 (s, 3H), 1.87 (s, 3H); 13C NMR (100 MHz, CDCl3)
ppm
d
ppm 7.21 (d, J ¼ 2.4 Hz, 1H), 7.13 (d, J ¼ 2.5 Hz,
(100 MHz, CDCl3)
128.9, 128.4, 127.2, 124.1, 123.8, 118.9, 117.9, 115.2, 98.1, 49.8, 31.5,
29.7, 27.6, 24.0, 21.1; HRMS (ESI) Calcd for
d ppm 203.9, 196.9, 164.4, 148.7, 131.3, 129.6,
d
C21H20O4:
202.6, 195.1, 164.6, 145.5, 128.9,128.3,126.0,125.9,121.6, 114.4, 98.5,
48.8, 31.3, 30.9, 29.7, 24.1, 21.1; HRMS (ESI) Calcd for C17H16Cl2O4:
[MþNa] ¼ 377.0323. Found: 377.0340.
[MþNa] ¼ 359.1259. Found: 359.1273.
Compound 3r: yield 0.1592 g (40%); mp 115e117 ꢀC; IR (neat,
cmꢁ1): 2968.0, 2873.2, 2196.8, 1725.7, 1382.8, 1233.9; 1H NMR
(400 MHz, CDCl3) d ppm 7.23e7.19 (m, 1H), 7.08e7.07 (m, 1H),
Compound 3g: yield 0.2585 g (85%); mp 149e151 ꢀC; IR (neat,
cmꢁ1): 2987.3, 2945.6, 2158.8, 2018.1, 1706.2, 1328.9; 1H NMR
7.06e7.04 (m, 1H), 7.02e7.00 (m, 1H), 4.65 (d, J ¼ 9.5 Hz, 1H), 4.27
(d, J ¼ 9.5 Hz, 1H), 3.33 (dt, J ¼ 13.8, 6.9 Hz, 1H), 3.23e3.16 (m, 1H),
2.48 (dt, J ¼ 13.7, 6.9 Hz, 1H), 2.15 (dt, J ¼ 13.8, 6.9 Hz, 1H), 1.26 (d,
J ¼ 6.9 Hz, 3H),1.13 (d, J ¼ 6.5 Hz, 3H),1.06 (d, J ¼ 7.0 Hz, 3H),1.00 (d,
J ¼ 3.0 Hz, 3H), 0.98 (d, J ¼ 3.1 Hz, 3H), 0.93 (d, J ¼ 2.4 Hz, 3H), 0.92
(d, J ¼ 1.9 Hz, 3H), 0.46 (d, J ¼ 6.9 Hz, 3H); 13C NMR (100 MHz,
(400 MHz, CDCl3)
d
ppm 7.02 (d, J ¼ 8.3, 2.3 Hz, 1H), 6.79e6.76 (m,
2H), 4.60 (d, J ¼ 2.5 Hz, 1H), 3.06 (d, J ¼ 2.6 Hz, 1H), 2.31 (s, 3H), 2.23
(s, 3H), 2.21 (s, 3H), 1.81 (s, 3H); 13C NMR (100 MHz, CDCl3)
d ppm
203.3, 195.3, 164.8, 157.2 (d, 1JCF ¼ 240.2 Hz), 146.5 (d, 6JCF ¼ 2.3 Hz),
5
127.5 (d, JCF ¼ 7.7 Hz), 116.9 (d,4 JCF ¼ 8.2 Hz), 114.6 (d,
3JCF ¼ 23.5 Hz), 114.0 (d, JCF ¼ 23.8 Hz), 98.0, 49.2, 31.3, 31.1, 31.0,
CDCl3)
d ppm 206.9, 206.7, 206.1, 163,9, 153.2, 128.8, 128.2, 124.3,
2
29.7, 24.3, 21.2; HRMS (ESI) Calcd for C17H17FO4:
[MþNa] ¼ 327.1009. Found: 327.1014.
123.6, 115.9, 114.2, 69.0, 42.9, 42.3, 38.1, 37.0, 29.3, 20.1, 19.8, 19.5,
17.9, 17.7, 17.5, 17.3, 16.7; HRMS (ESI) Calcd for
C25H34O4:
Compound 3h: yield 0.0993 g (30%); mp 135e137 ꢀC; IR (neat,
cmꢁ1): 3069.3, 2928.5, 2853.4, 2156.4, 1982.7, 1359.9; 1H NMR
[MþNa] ¼ 421.2355. Found: 421.2364.
Compound 3s: yield 0.2670 g (50%); mp 162e164 ꢀC; IR (neat,
(400 MHz, CDCl3)
d
ppm 8.22 (d, J ¼ 2.7 Hz, 1H), 7.98 (dd, J ¼ 9.0,
cmꢁ1): 3058.6, 2921.0, 2157.8, 1981.2, 1374.2, 1205.2; 1H NMR
2.7 Hz, 1H), 6.90 (d, J ¼ 9.0 Hz, 1H), 4.73 (d, J ¼ 2.4 Hz, 1H), 3.08 (d,
(400 MHz, CDCl3) d ppm 8.03e8.01 (m, 2H), 7.76e7.74 (m, 2H),
J ¼ 2.5 Hz, 1H), 2.32 (s, 3H), 2.25 (s, 3H), 2.24 (s, 3H), 1.87 (s, 3H); 13
C
7.45e7.41 (m, 3H), 7.36e7.24 (m, 4H), 7.20e7.15 (m, 2H), 7.13e7.08
(m, 4H), 7.01e6.99 (m, 3H), 6.98e6.92 (m, 4H), 6.37 (d, J ¼ 4.3 Hz,
NMR (100 MHz, CDCl3) d ppm 202.5, 195.1, 164.3, 156.0, 141.1, 127.3,
124.1, 123.8, 116.7, 114.5, 98.7, 48.8, 31.4, 30.9, 29.7, 24.2, 21.0; HRMS
(ESI) Calcd for C17H17NO4: [MþNa] ¼ 354.0954. Found: 354.0963.
Compound 3i: yield 0.2100 g (70%); mp 127e129 ꢀC; IR (neat,
cmꢁ1): 2922.9, 2340.5, 2152.4, 2072.8, 1760.8, 1328.3; 1H NMR
1H), 4.99 (d, J ¼ 4.3 Hz,1H); 13C NMR (100 MHz, CDCl3)
d ppm 197.8,
195.6, 195.2, 160.2, 152.6, 138.2, 137.2, 136.6, 133.4, 133.3, 132.2,
132.1, 130.2, 130.1, 129.6, 129.4, 128.9, 128.8, 128.6, 128.5, 127.9,
127.8, 124.5, 121.9, 116.2, 111.3, 61.8, 38.3, 27.0; HRMS (ESI) Calcd for
(400 MHz, CDCl3)
d
ppm 7.10 (d, J ¼ 1.8 Hz, 1H), 6.90 (dd, J ¼ 8.1,
C
37H26O4: [MþNa] ¼ 557.1729. Found: 557.1742.
1.8 Hz, 1H), 6.73 (d, J ¼ 8.2 Hz, 1H), 4.61 (d, J ¼ 2.5 Hz, 1H), 3.07 (d,
Compound 3t: total yield 0.2296 g (56%); mp 152e154 ꢀC; IR
J ¼ 2.6 Hz, 1H), 2.31 (s, 3H), 2.23 (s, 3H), 2.22 (s, 3H), 2.20 (s, 3H),
(neat, cmꢁ1): 2945.3, 2920.6, 1687.0, 1594.3, 1374.3, 1152.2; 1H NMR
(400 MHz, CDCl3) d ppm 7.93e7.91 (m, 2H), 7.63e7.59 (m, 1H),
1.81 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
ppm 203.6, 195.5, 164.5,
148.2,130.7,128.6,127.9,126.1,115.8,115.1, 97.9, 49.6, 31.4, 31.1, 29.6,
24.3, 21.2, 20.1; HRMS (ESI) Calcd for 18H20O4:
7.51e7.43 (m, 3H), 7.40e7.38 (m, 2H), 7.33 (t, J ¼ 7.5 Hz, 2H),
7.16e7.12 (m, 1H), 7.03 (d, J ¼ 7.7 Hz, 1H), 6.80 (dd, J ¼ 7.5, 1.6 Hz,
1H), 6.71 (td, J ¼ 7.4, 1.1 Hz, 1H), 4.57 (d, J ¼ 2.4 Hz, 1H), 4.01 (d,
J ¼ 2.7 Hz, 1H), 1.91 (s, 3H), 1.64 (s, 3H); 13C NMR (100 MHz, CDCl3)
C
[MþNa] ¼ 323.1259. Found: 323.1261.
Compound 3j: yield 0.2611 g (87%); mp 178e179 ꢀC; IR (neat,
cmꢁ1): 3249.3, 2980.7, 2274.8, 2160.1, 1708.6, 1377.1; 1H NMR
d ppm 196.4, 195.2, 158.7, 152.1, 140.6, 136.0, 133.7, 132.2, 129.1,
Please cite this article in press as: Yang D-S, et al., A mild and one-step synthesis of 2,8-dioxabicyclo [3.3.1] nonane derivatives via classical
Knoevenagel condensation, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.07.054

6
D.-S. Yang et al. / Tetrahedron xxx (2017) 1e6
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128.6, 128.5, 128.4, 128.3, 127.2, 122.0, 121.5, 117.5, 115.7, 98.9, 45.3,
35.2, 24.7, 20.3; HRMS (ESI) Calcd for 27H22O4:
C
[MþNa] ¼ 433.1416. Found: 433.1414.
Compound 3u: yield 0.2170 g (70%); mp 150e152 ꢀC; IR (neat,
cmꢁ1): 2957.7, 2327.3, 2028.6, 1716.5, 1621.8, 1378.6; 1H NMR
5. (a) Arnone A, Nasini G, de Pava OV, Merlini L. J Nat Prod. 1997;60:971;
(b) Dumontet V, van Hung N, Adeline MT, et al. J Nat Prod. 2004;67:858.
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587.
(400 MHz, CDCl3)
d ppm 7.38e7.35 (m, 1H), 7.11e7.07 (m, 1H), 6.87
(dd, J ¼ 10.8, 4.4 Hz, 2H), 4.45 (d, J ¼ 1.9 Hz, 1H), 2.86 (d, J ¼ 2.2 Hz,
1H), 2.64 (d, J ¼ 13.8 Hz, 1H), 2.49e2.45 (m, 1H), 2.40e2.33 (m, 1H),
2.32e2.29 (m, 3H), 2.26e2.18 (m, 2H), 2.11e2.05 (m, 1H), 1.92e1.80
~
8. Ignoato MC, Fabrao RM, Schuquel ITA, et al. Quím Nova. 2012;35:2241.
(m, 3H); 13C NMR (100 MHz, CDCl3)
d
ppm 203.5,195.8,166.9,150.9,
9. Cheng VJ, Bekhit AEDA, McConnell M, Mros S, Zhao J. Food Chem. 2012;134:474.
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4224;
128.6, 127.8, 126.5, 121.8, 115.7, 115.2, 100.9, 49.5, 40.4, 36.4, 35.1,
27.4, 24.3, 20.8, 20.6; HRMS (ESI) Calcd for
C19H18O4:
[MþNa] ¼ 333.1103. Found: 333.1106.
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12. (a) Ren HL, Wu CR, Ding XX, Chen XG, Shi F. Org Biomol Chem. 2012;10:8975;
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Acknowledgments
€
(c) Vervisch K, D'hooghe M, Tornroos KW, Kimpe ND. J Org Chem. 2010;75:
7734;
The authors gratefully acknowledge the financial support for
this work from the National Natural Science Fund (51675006), the
project of Science and Technology Department of Shaanxi Province
(2016JZ017) and the PhD research startup foundation of Baoji
University of Arts and Sciences (ZK15047).
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20. The structure of 3a was characterized by X-ray studies (see the Supporting
Information for details; CCDC 153840).
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2017.07.054.
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Please cite this article in press as: Yang D-S, et al., A mild and one-step synthesis of 2,8-dioxabicyclo [3.3.1] nonane derivatives via classical
Knoevenagel condensation, Tetrahedron (2017), http://dx.doi.org/10.1016/j.tet.2017.07.054