Construction of complex bisether-bridged medium-sized cyclic compounds from o-(1-(acyloxy)propargyl)benzaldehydes under base and acid catalysis

Article abstract of DOI:10.1021/acs.joc.9b01677

We report herein our serendipitous discovery of the rapid and straightforward accesses to unprecedented diverse complex molecular structures from readily available starting materials. Catalyzed by 1,8-diazabicyclo[5.4.0]undec-7-ene under mild conditions, o-(1-(acyloxy)propargyl)benzaldehydes 1 underwent efficient and selective dimerization reactions to produce novel complex bisether-bridged tricyclic products 3 and 4. The reactions proceeded most probably through dimerizations between 3-methylene-3H-isochromene intermediate and its zwitterionic resonance structures which were generated from a concerted 6-πelectrocyclic ring closure reaction from the initially formed (2-formylphenyl)allene intermediates derived directly from o-(1-(acyloxy)propargyl)benzaldehydes. Treatment of the resulting product simply with NaOEt in ethanol and aqueous HCl, respectively, enabled further development of complex molecular diversities.

Full text of DOI:10.1021/acs.joc.9b01677

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Article
Construction of Complex Bisether-bridged
Medium-sized Cyclic Compounds from o-(1-
(Acyloxy)propargyl)benzaldehydes under Base and Acid Catalysis
Yun-Long Zhao, and Ying Cheng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01677 • Publication Date (Web): 16 Aug 2019
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Construction of Complex Bisether-bridged
Medium-sized Cyclic Compounds from
o-(1-(Acyloxy)propargyl)benzaldehydes under Base and
Acid Catalysis
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Yun-Long Zhao and Ying Cheng*
College of Chemistry, Beijing Normal University, Beijing 100875, China
E-mail: ycheng2@bnu.edu.cn
ABSTRACT: We report herein our serendipitous discovery of the rapid and straightforward
accesses to unprecedented diverse complex molecular structures from readily available starting
materials. Catalyzed by 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) under mild conditions,
o-(1-(acyloxy)propargyl)benzaldehydes 1 underwent efficient and selective dimerization reactions
to produce novel complex bisether-bridged tricyclic products 3 and 4. The reactions proceeded
most probably through dimerizations between 3-methylene-3H-isochromene intermediate and its
zwitterionic resonance structures which were generated from a concerted 6-electrocyclic ring
closure reaction from the initially formed (2-formylphenyl)allene intermediates derived directly
from o-(1-(acyloxy)propargyl)benzaldehydes. Treatment of the resulting product simply with
NaOEt in ethanol and aqueous HCl, respectively, enabled further development of complex
molecular diversities.
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INTRODUCTION
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Rapid construction of complex molecules of novel bridge bicyclic and tricyclic structures is
attractive and important as the creation of diverse three-dimensional molecular entities would
provide great opportunity for the discovery of promising drug leads, biological probes and
functional materials. Ether-bridged medium rings, for instance, constitute the core skeletons of a
large number of naturally occurring products including austroliolide (I),1 badgerin (II),1
abyssomicin C (III)2 and abyssomicin 2 (IV),2 which possess attractive antibacterial and antiviral
activities. The synthetic ether-bridged bicyclic structures such as compound V is a potent HIV-1
inhibitor3 while VI-VIII exhibit sedative and analgesic effects in central nervous system4 (Figure
1). Synthesis of the ether-bridged medium ring-bearing natural and unnatural compounds still
remains a formidable challenge. Tedious multistep reactions employing expensive catalysts and
reagents under harsh conditions are usually required. We report herein our serendipitous discovery
of an efficient and practical protocol to synthesize unprecedented ether-bridged tricyclic medium
ring compounds from a very convenient DBU-catalyzed one-pot dimerization of readily available
o-(1-(acyloxy)propargyl)benzaldehydes under very mild conditions.
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Figure 1. Structures of selected bioactive compounds which contain ether-bridged medium rings.
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o-(1-(Acyloxy)propargyl)benzaldehydes are prepared conveniently from commercially available
o-bromobenzaldehydes and ethynyl Grignard reagent.5 Despite their multifunctionality and easy
availability, o-(1-(acyloxy)propargyl)benzaldehydes have been used only scarcely in organic
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synthesis.5-7 In
a
2010 paper, Liu reported
a
gold-catalyzed reaction of
o-(1-acyloxy-2-propynyl)benzaldehydes with vinyl ethers, which proceeded through a formal [4 +
2] cycloaddition between s-trans-methylene(vinyl)oxonium intermediate and electron-rich alkenes
to produce 5,6,7,10-tetrahydro-5,9-epoxybenzo[8]annulene derivatives.6 The other documented
application is the synthesis of indeno[1,2-b]quinolines from the reaction between
o-(1-acyloxy-2-propynyl)benzaldehydes and anilines based on Povarov reaction.7
To continue our recent endeavors in developing new reactions by means of N-heterocyclic
carbene and transition metal cascade catalysis,8 we attempted initially the reaction of
o-(1-(acetyloxy)propargyl)benzaldehyde 1a with N-boc-phenylimine. Upon the treatment of an
NHC catalyst which was generated in situ from the interaction of a triazolium salt and DBU, the
reaction of 1a and imine gave no anticipated azabenzoin product. Occasionally, two product spots
were observed on TLC plate, and they were separated by means of silica gel column
chromatography. To our surprise and pleasure, two products 3a and 4a, whose molecular
structures were determined unambiguously with various spectroscopy and X-ray crystallography,
were stunning bis-ether-bridged tricyclic compounds (Figure 2). Evidently, they were resulted
from distinct dimerization reactions of 1a.
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Figure 2. X-ray molecular structures of products 3a and 4a. The ellipsoid contour probability
level is 50%.
RESULTS AND DISCUSSION
To establish the method for the synthesis of complex bis-ether-bridged medium ring compounds,
we started optimization of reaction conditions. After excluding the involvement of N-heterocyclic
carbene as the catalyst, we then focused on the base-promoted dimerization reactions of 1a. In the
presence of one equivalent of DBU, reactant 1a at ambient temperature (~ 25 oC) in
dichloromethane
(DCM)
was
transformed
within
8
h
into
16-methylene-6,14-epoxy-8,13-(epoxymethano)dibenzo[a,e][10]annulene-5,13-diacetate 3a and
6,16:9,15-diepoxydibenzo[a,e][12]annulene-5,10-diacetate 4a in a total yield of 56% with a 3a :
4a ratio being 4.6 : 1 (Table 1, entry 1). Both chemical yield and selectivity were slightly
improved when DBU was decreased to 50 mol% and 30 mol% (Table 1, entries 2 and 3).
o
DBU-catalyzed reaction of 1a with a 30 mol % catalyst loading at 40 C in DCM led to an even
better conversion in terms of efficiency and selectivity (Table 1, entry 4). It should be addressed
that other organic and inorganic bases including DBN, TDB, DIPEA, DABCO, TMG
(tetramethylguanidine), Cs2CO3 and t-BuOK were not effective to catalyze dimerization reaction
(Table 1, entries 5-11). Noticeably, while it did not influence the total chemical yields considerably,
the reaction media did change the selectivity of dimerization reaction. For example, the combined
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yields for 3a and 4a remained comparable when DCM was replaced by chloroform,
1,2-dichloroethane (DCE), toluene, THF, acetone and acetonitrile, the ratio of 3a over 4a varied
between 6.6 : 1 to 3.2 : 1 with toluene as the least favorably solvent to give the lowest selectivity
(Table 1, entries 12 – 17). To our delight, the total chemical yield increased significantly to 91%
with the selectivity remaining at a satisfactory level (3a : 4a = 5.2 : 1) when the DBU-catalyzed
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dimerization of 1a was conducted at 60 C in chloroform (Table 1, entry 18). Further increase of
o
reaction temperature to 80 C in DCE, however, did not have a beneficial effect (Table 1, entry
19).
Table 1. Development of DBU-catalyzed dimerization reactions.a
yield of
Mol
%
Temp.
(o C)
Entry
Base
solvent
3a : 4ad
3a+4a
(%)c
56
1
2
DBU
DBU
100
50
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
30
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
DCE
rt
4.6 : 1
5 : 1
rt
65
3
DBU
rt
67
5.6 : 1
6 : 1
4
DBU
40
40
40
40
40
40
40
40
40
40
40
40
40
40
60
83
5
DBNb
TBDb
DIPEA
DABCO
TMGb
Cs2CO3
t-BuOK
DBU
13
6
trace
--
7
8
--
9
trace
16
10
11
12
13
14
15
16
17
18
22
84
5.8 : 1
6.6 : 1
3.6 : 1
3.2 : 1
5.8 : 1
4.8 : 1
5.2 : 1
DBU
80
DBU
THF
76
DBU
toluene
CH3CN
Me2CO
CHCl3
73
DBU
74
DBU
67
DBU
91
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DBU
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DCE
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5.4 : 1
a A mixture of 1a (0.5 mmol) and base in solvent (10 mL) was stirred for 8 h at a specified temperature.
b DBN = 2,3,4,6,7,8-hexahydropyrrolo[1,2-a]pyrimidine;
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TBD = 2,3,4,6,7,8-hexahydro-1H-pyrimido[1,2-a]pyrimidine; TMG = tetramethylguanidine.
c Isolated yields. d Determined by 1 H NMR in the mixture of products.
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We prepared various o-(1-(acyloxy)propargyl)benzaldehyde substrates 1 to assess the scope of
dimerization reaction under DBU catalysis (Table 2). It was found that this base-catalyzed reaction
tolerated both electron-donating and electron-withdrawing groups on the aromatic ring of
benzaldehydes. As summarized in Table 2, irrespective of the electronic nature of the substituent
X, all substrates tested underwent transformations to afford the corresponding bis-ether-bridged
tricyclic products 3 and 4. The reactivity and efficiency of transformations were, however,
governed by the electronic nature and substitution pattern of the substituents.
2-(1-(Acetyloxy)propargyl)benzaldehydes 1b-f which bear either an electron-donating group or an
electron-withdrawing substituent at para-position of carbonyl underwent efficient dimerizations
within 5-16 h to afford products 3 and 4 in 70-83% total yields (Table 2, entries 2-6). In the case
of meta-substituted 2-(1-(acetyloxy)propargyl)benzaldehyde substrates 1g-1j, replacement of an
electron-withdrawing group such as chloro and fluoro by an electron-donating methoxy and
methyl group resulted in the decrease of reactivity. A longer reaction time was required and lower
chemical yields were observed for the reactions of 1g and 1h (24-36 h, 69-75% total yields) than
that of 1i and 1j (8-9 h, 83-86% total yields) (Table 2, entries 7-10). It is worth noting that in
comparison to the substituent dependence on reactivity, substituents exhibited a much more
o
pronounced effect on selectivity or the reaction pathways. For example, when reacting at 60 C,
substrate 1a along with its 4-methoxy (1b), 4-fluoro (1e) and 5-chloro (1i) containing analogs
yielded products 3 and 4 in a ratio around 5 : 1 (Table 2, entries 1, 2, 5 and 9). On the contrary,
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virtually no selectivity (3 : 4 ~ 1 : 1) was obtained from the reactions of 4-trifluoromethylated (1f)
and 5-methoxylated (1g) benzaldehydes (Table 2, entries 6 and 7). It should be noted that the
selectivities of the reactions of 1c, 1d and 1j were found to improve slightly from 1 : 1, 3.3 : 1 and
3.3 : 1 to 1.6 : 1, 4.1 : 1 and 5.1 : 1, respectively, when reaction was carried out at a lower
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temperature as 25-30 C with the expense of chemical yields (Table 2, entries 4, 6 and 10). The
DBU catalysis also accepted substrates which contain benzoyl (1k) and t-butoxycarbonyl (Boc)
(1l) in addition to acetyl attached on propargylic alcohol. Reactions produced analogously
bis-oxa-bridged tricyclic products in 82-95% total yields with moderate selectivity (3 : 4 ~ 3 : 1)
(Table 2, entries 11 and 12). The products 3 and 4 have very similar molecular polarities.
Successfully separation between them was achieved only by repetitive column chromatography
using different eluting solvents with the exception of 3b and 4b which were not completely
separated. The isolated yields of products 3 and 4 were 30-70% and 13-35%, respectively. In
addition to the reaction of o-(1-(acyloxy)propargyl)benzaldehydes 1a-1l, the DBU-catalyzed
reactions
of
2-(1-(acetyloxy)propargyl)thiophene-3-carbaldehyde
1m
and
2-(1-(acetyloxy)propargyl)nicotinaldehyde 1n were also examined. Under the similar conditions
as that for benzaldehyde 1a, the DBU-catalyzed reactions of thiophene-3-carbaldehyde 1m and
pyridine-3-carbaldehyde
1n
produced
the
tricyclic
bis-thiophene-
and
bis-pyridine-fused-[10]annulenes 3m and 3n in 52% and 34% yields, respectively (Table 2, entries
13 and 14). No analogous product of 4 was detected in these reactions.
Table 2. Scope of DBU-Catalyzed Reaction of o-(1-(Acyloxy)propargyl) Substituted Aromatic
Aldehydes 1.
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Products 3 and 4
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Entry
1
Substrate 1
Time (h), total yielda, 3 : 4b
2
3
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a Isolated yields. b Determined by 1 H NMR in the mixture of products 3 and 4. c The data in the parentheses were
obtained from the reactions conducted at 25-30 oC.
The formation of two complex bis-ether-bridged tricyclic compounds 3 and 4 from
2-(1-(acyloxy)propargyl)benzaldehydes 1 is very intriguing. To shed light on the reaction
mechanism, the reaction process was carefully monitored with TLC. The reaction was found to
form initially other two products which underwent further transformation or decomposition in a
o
prolonged time either at 25 C or at a higher temperature. To isolate presumably unstable
intermediates
and
to
characterize
their
structures,
the
reaction
of
o
2-(1-(acetyloxy)propargyl)-5-fluorobenzaldehyde 1j was executed at 0 C for a short period of
o
time (2 h). All work-up including silica gel column chromatography at or below 0 C enabled
isolation of compounds 5j and 6j (Scheme 1). Confirmed by spectroscopic data, compounds 5j
(30%) and 6j (17%) turned out to be 1-(4-fluoro-2-formylphenyl)propa-1,2-dienyl acetate and
5-fluoro-3-hydroxy-2-methylene-1-indanone, respectively.
Scheme 1. Isolation of reaction intermediates.
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Base on the formation of allene intermediates 5, we proposed the most plausible reaction
pathways of aldehydes 1 under DBU catalysis which are delineated in Scheme 2. Treated with
DBU, a strong organic base in solution, o-(1-(acyloxy)propargyl)benzaldehydes 1 are transformed
into (2-formylphenyl)allene intermediates 5.9 Under the thermal condition, allenes 5 would
undergo a concerted 6-electrocyclic ring closure reaction to form 3-methylene-3H-isochromene
intermediate A and its resonance structures B and C. Dimerization between B and C gives rise to
the formation of products 3 via intermediate D, while dimerization between A and B furnishes
products 4. Although compounds 3 and 4 contain three and two stereogenic centers, respectively,
no other diastereomeric isomers were observed. It suggested that the dimerization reactions
proceeded in highly diastereoselective manners because of the steric requirement for the assembly
of bis-oxa-bridged tricyclic structures. The 1-indanone derivatives 6, which were unstable in the
presence of DBU, should be derived from the base-catalyzed deacylation of allenes 5, followed by
an intramolecular addition of the enolates to aldehyde group (Scheme 2).
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Scheme 2. Proposed mechanisms for DBU-catalyzed dimerization reactions of
2-(1-(acyloxy)propargyl)benzaldehydes 1.
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To extend the synthetic application of the methods, further transformations of the resulting major
product 3 were attempted. Upon the treatment with one equivalent of sodium ethoxide for 1 h in
ethanol at room temperature, compound 3a underwent selective deacetylation efficiently to afford
bisether-bridged tricyclic ketone 7a in 71% yield (Scheme 3). Employment of an excess amount of
EtONa (3 equiv.) did not cause the cleavage of the other acetyl group. Surprisingly, compound 3a
was transformed into -hydroxylated ketone 8a in 75% yield within 4h at 50 oC under atmosphere.
Under the similar conditions,-hydroxylated ketone 8a was also obtained in 78% yield from
thereaction of ketone 7a with EtONa (Scheme 3). On the contrary, when compound 3a was
reacted with aqueous hydrochloric acid (10 % w/w, 1 equiv. HCl) in THF at room temperature, a
much more sophisticated tri-bridged tetracyclic compound 9a was generated in 74% yield
(Scheme 3) (See X-ray molecular structures of 7a, 8a and 9a in Figure 3).
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Scheme 3. Synthetic applications of the major product 3.
Figure 3. X-ray molecular structures of compounds 7a, 8a and 9a. The ellipsoid contour
probability level is 50%.
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To shed light on the formation of hydroxy group in ketone 8a, both the reactions of compounds 3a
and 7a with EtONa were carried out under strictly oxygen-free condition in a glovebox. In these
cases, no-hydroxyketone 8a was formed. To further trace the origin of the oxygen of hydroxy
group in product 8a, reaction of 7a under strong basic condition was exposed to 18O2. Under this
circumstance, an oxygen-18 labelled product 8a' was yielded, indicating the oxidation of 7a by
molecular oxygen. The -hydroxyketone 8a could be obtained from 7a in the presence of EtONa
and O2 under dark condition excluding the photocatalysis. On the contrary, no-hydroxyketone
8a was formed when 7a was exposed to oxygen gas in the absence of EtONa. Very recently, Yang
and coworkers reported a visible-light-mediated iodine-catalyzed α-hydroxylation of α-methylene
ketones under aerobic conditions.10 They demonstrated that the reaction proceeded via a radical
pathway. Based on our experimental evidences and Yang's report, a most plausible reaction
pathway for the formation of -hydroxyketone 8a was suggested in Scheme 4. In the presence of
EtONa and O2 (air), ketone 7a is converted into a radical intermediate H, probably via a single
electron transfer from the enolate intermediate G to oxygen molecule. The resulting enolate
radical H and hydrogen peroxide radical coupled to form peroxide intermediate J. Alternatively,
the radical H reacts with molecular oxygen to form peroxy radical I which subsequently
abstracted the hydrogen atom from ethanol or ketone 7a to afford peroxide intermediate J.
Decomposition of peroxide J led to the formation of -hydroxyketone 8a (Scheme 4, equ.1). In
the presence of aqueous hydrochloric acid, the formation of tetracyclic compound 9a was most
probably started from the protonation of the methene of 3a followed consecutively by
intramolecular addition of the resulting carbocation L to the enol moiety and the hydroxylation of
the carbocation M (Scheme 4, equ.2).
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Scheme 4. Proposed mechanisms for the formation of compounds 8a and 9a.
CONCLUSION
In conclusion, we have established the DUB-catalyzed reactions of o-(1-(acyloxy)propargyl)
substituted aromatic aldehydes to construct complex molecular structures. The reaction
proceeded most probably through the conversion of the reactant into (2-formylphenyl)allene
intermediates which underwent a concerted 6-electrocyclic ring closure reaction to form
3-methylene-3H-isochromene intermediate A and its zwitterionic resonance structures B and C.
Dimerizations between intermediates B and C and between A and B afforded bis-ether-bridged
tricyclic compounds 3 and 4, respectively. We have also demonstrated that the reactions of 3 with
NaOEt and hydrochloric acid enabled the further development of complex molecule diversities.
The easy availability of starting materials, environmentally benign catalytic reaction without using
any transition metals, and efficient construction of diverse complex molecular structures that are
not accessible by other means would render the method an invaluable tool in study of organic
synthesis and medicinal chemistry.
EXPERIMENTAL SECTION
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1. Preparation of the reactants 1.
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(1). Preparation of 2-(1-(acetyloxy)propargyl)benzaldehydes 1a-1j (see Scheme S1 and Table
S1 in Supporting Information).
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A
typical
experimental
procedure
for
the
synthesis
of
2-(1-(acetyloxy)propargyl)benzaldehyde 1a.5 At room temperature, 2-bromobenzaldehyde Ia
(3.7 g, 20 mmol), triethyl orthoformate (6 g, 40 mmol) and TsOH‧H2O (76 mg, 2 mol%) were
dissolved in anhydrous ethanol (20 mL). The reaction mixture was refluxed in ethanol for 6 h in
an oil bath. After removal of the solvent, the residue was chromatographed on a silica gel column
eluting with a mixture of petroleum ether and ethyl acetate (PE : EA = 30 : 1) to give
1-bromo-2-(diethoxymethyl)benzene IIa as colorless oil (4.96 g, 95 %).
Under nitrogen atmosphere, to a solution of acetal IIa (4.92 g, 19 mmol) in anhydrous THF (40
mL) was added dropwise n-BuLi (2.5 M in hexane, 8.4 mL, 20.9 mmol) at -78 ˚C. After stirring
for 30 min at -78 ˚C, anhydrous DMF (3.47 g, 47.5 mmol) was added dropwise to the solution.
The resulting mixture was kept stirring at -78 ˚C for 30 min and then at room temperature for
another 1 h. The reaction was then quenched by adding a saturated aqueous solution of NH4Cl (20
mL). The resulting mixture was extracted with ethyl acetate (20 × 3 mL). The combined organic
layer was dried over anhydrous MgSO4. After filtration and removal of solvents, the residue was
chromatographed on a silica gel column eluting with a mixture of petroleum ether and ethyl
acetate (PE : EA = 10 : 1) to give 2-(diethoxymethyl)benzaldehyde IIIa as pale yellow oil (3.44 g,
87 %).
Under nitrogen atmosphere and at 0 ˚C, to a solution of 2-(diethoxymethyl)benzaldehyde IIIa
(2.08 g, 10 mmol) in anhydrous THF (30 mL) was added dropwise ethynylmagnesium bromide
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(26 mL, 0.5M in THF, 13 mmol). After the resulting solution was kept stirring at 0 ˚C for 40 min,
acetic anhydride (3.06 g, 30 mmol) was added. The reaction mixture was then warmed to room
temperature and was stirred for another 2 h. The reaction was quenched by the addition of a
saturated aqueous solution of NaHCO3 (30 mL) and the resulting mixture was extracted with ethyl
acetate (20 × 3 mL). The combined organic layer was dried over anhydrous MgSO4. After
filtration and removal of solvents, the residue was chromatographed on a silica gel column eluting
with a mixture of petroleum ether and ethyl acetate (PE : EA = 10 : 1) to give
2-(1-( acetyloxy)propargyl)benzaldehyde diethyl acetal IVa as pale yellow oil (2.51 g, 91 %).
Acetal IVa (2.49 g, 9 mmol) was hydrolyzed with hydrochloric acid (1 mol/L, 27 mL, 27 mmol)
in THF (20 mL) for 3 h at room temperature. The reaction mixture was then neutralized by the
addition of a saturated aqueous solution of NaHCO3 (10 mL) and was extracted with ethyl acetate
(20 × 3 mL). The combined organic layer was dried over anhydrous MgSO4. After filtration and
removal of solvents, the residue was chromatographed on a silica gel column eluting with a
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mixture of petroleum ether and ethyl acetate (PE
:
EA
=
8
:
1) to give
2-(1-( acetyloxy)propargyl)benzaldehyde 1a as pale yellow oil (1.57 g, 86%).
2-(1-(Acetyloxy)propargyl)benzaldehyde 1a6: pale yellow oil, IR v (cm-1) 3285, 2124 (w), 1744,
1
1697, 1599, 1580; H NMR (400 MHz, CD3Cl3) δ (ppm) 10.3 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H),
7.80 (d, J = 7.7 Hz, 1H), 7.63 (dt, J = 7.5, 1.2 Hz, 1H), 7.56 (t, J = 7.5 Hz, 1H), 7.10 (d, J = 2.2 Hz,
1H), 2.68 (d, J = 2.3 Hz, 1H), 2.10 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 191.6,
169.0, 137.5, 133.9, 133.0, 132.6, 129.3, 128.6, 79.8, 76.1, 62.1, 20.6.
Substrates 1b-1j were prepared from the substituted 2-bromobenzaldehydes I using the same
procedures as that for 1a. The chemical yields of 1-bromo-2-(diethoxymethyl)benzenes II,
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2-(diethoxymethyl)benzaldehydes III, 2-(1-(acetyloxy)propargyl)benzaldehyde diethyl acetals IV
and compounds 1a-1j were summarized in Scheme S1 and Table S1 in Supporting Information.
8
9
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2-(1-(Acetyloxy)propargyl)-4-methoxybenzaldehyde 1b: pale yellow solid, mp 51-52 C; IR v
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(cm-1) 3285, 2124 (w), 1746, 1688, 1602, 1570; H NMR (400 MHz, CD3Cl3) δ (ppm) 10.1 (s,
1H), 7.82 (d, J = 8.4 Hz, 1H), 7.30 (d, J = 2.8 Hz, 1H), 7.13 (d, J = 2.0 Hz, 1H), 6.99 (dd, J = 8.8,
2.8 Hz, 1H), 3.90 (s, 3H), 2.65 (d, J = 2.4 Hz, 1H), 2.10 (s, 3H). 13C{1H}NMR (100 MHz, CDCl3)
δ (ppm) 190.2, 168.9, 163.8, 139.7, 136.0, 126.2, 114.7, 113.4, 79.7, 75.8, 61.8, 55.5, 20.6. HRMS
(TOF-ESI): [M + Na]+ calcd for C13H12O4Na: 255.0627, found: 255.0631.
2-(1-(Acetyloxy)propargyl)-4-methylbenzaldehyde 1c: pale yellow oil; IR v (cm-1) 3289, 2124
1
(w), 1748, 1697, 1606; H NMR (400 MHz, CD3Cl3) δ (ppm): 10.2 (s, 1H), 7.77 (d, J = 7.6 Hz,
1H), 7.58 (s, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.08 (d, J = 2.4 Hz, 1H), 2.66 (d, J = 2.4 Hz, 1H), 2.45
(s, 3H), 2.10 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 191.3, 168.9, 145.1, 137.3, 133.1,
130.7, 129.9, 129.2, 79.9, 76.0, 62.0, 21.6, 20.6. HRMS (TOF-ESI): [M + Na]+ calcd for
C13H12O3Na: 239.0678, found: 239.0681.
2-(1-(Acetyloxy)propargyl)-4-chlorobenzaldehyde 1d: pale yellow oil; IR v (cm-1) 3289, 2126
(w), 1746, 1695, 1593, 1566; 1H NMR (400 MHz, CD3Cl3) δ (ppm) 10.3 (s, 1H), 7.84 (d, J = 8.2
Hz, 1H), 7.78 (s, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.08 (d, J = 1.6 Hz, 1H), 2.7 (d, J = 1.8 Hz, 1H),
2.13 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm):190.2, 168.8, 140.3, 139.3, 133.9, 131.3,
129.4, 128.7, 79.2, 76.5, 61.4, 20.6. HRMS (TOF-ESI): [M + Na]+ calcd for C12H9ClO3Na:
259.0132; found: 259.0134.
2-(1-(Acetyloxy)propargyl)-4-fluorobenzaldehyde 1e: pale yellow oil; IR v (cm-1) 3289, 2126
(w), 1746, 1701, 1606, 1587; 1H NMR (400 MHz, CD3Cl3) δ (ppm) 10.2 (s, 1H), 7.92 (dd, J = 8.5,
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5.8 Hz, 1H), 7.52 (dd, J = 9.4, 2.2 Hz, 1H), 7.21-7.26 (m, 1H), 7.12 (d, J = 1.6 Hz, 1H), 2.69 (d, J
= 2.1 Hz, 1H), 2.13 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm): 189.9, 168.8, 165.5 (d, J
= 260 Hz), 140.9 (d, J = 8 Hz), 135.6 (d, J = 9 Hz), 129.5, 116.0 (d, J = 51 Hz), 116.0, 79.2, 76.2,
61.3, 20.5. HRMS (TOF-ESI): [M + Na]+ calcd for C12H9FO3Na: 243.0427; found: 243.0431.
2-(1-(Acetyloxy)propargyl)-4-(trifluoromethyl)benzaldehyde 1f: pale yellow solid, mp 45-46
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oC; IR v (cm-1) 3291, 2126 (w), 1751, 1703; H NMR (400 MHz, CD3Cl3) δ (ppm) 10.4 (s, 1H),
1
8.03 (s, 1H), 8.03 (d, J = 6.5 Hz, 1H), 7.81 (d, J = 8 Hz, 1H), 7.09 (d, J = 2.2 Hz, 1H), 2.73 (d, J =
2.2 Hz, 1H), 2.12 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm): 190.5, 169.0, 138.8, 135.6,
135.2 (q, J = 33 Hz), 132.6, 126.3 (q, J = 4 Hz), 125.7 (q, J = 3 Hz), 123.1 (q, J = 272 Hz), 79.2,
77.0, 61.7, 20.7. HRMS (TOF-ESI): [M + Na]+ calcd for C13H9F3O3Na: 293.0396; found:
293.0400.
o
2-(1-(Acetyloxy)propargyl)-5-methoxybenzaldehyde 1g: pale yellow solid, mp 57-58 C; IR v
1
(cm-1) 3285, 2124 (w), 1744, 1689, 1607, 1576; H NMR (400 MHz, CD3Cl3) δ (ppm) 10.4 (s,
1H), 7.68 (d, J = 8.5 Hz, 1H), 7.39 (d, J = 2.8 Hz, 1H), 7.13 (dd, J = 8.5, 2.8 Hz, 1H), 6.96 (d, J =
2.2 Hz, 1H), 3.86 (s, 3H), 2.70 (d, J = 2.2 Hz, 1H), 2.07 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3)
δ (ppm) 191.0, 169.0, 160.2, 134.5, 130.6, 129.8, 119.6, 115.9, 80.2, 76.1, 61.9, 55.4, 20.6. HRMS
(TOF-ESI): [M + Na]+ calcd for C13H12O4Na: 255.0627, found: 255.0631.
2-(1-(Acetyloxy)propargyl)-5-methylbenzaldehyde 1h: pale yellow oil; IR v (cm-1) 3287, 2124
(w), 1744, 1695, 1609, 1574; 1H NMR (400 MHz, CD3Cl3) δ (ppm): 10.3 (s, 1H), 7.69 (d, J = 1.6
Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 2.4 Hz, 1H), 2.66 (d, J = 2 Hz, 1H), 2.43 (s, 3H),
2.09 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 191.7, 169.0, 139.5, 134.6, 134.5, 133.0,
132.95, 128.7, 80.0, 76.0, 62.0, 20.8, 20.6. HRMS (TOF-ESI): [M + Na]+ calcd for C13H12O3Na:
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239.0678, found: 239.0677.
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2-(1-(Acetyloxy)propargyl)-5-chlorobenzaldehyde 1i: pale yellow oil; IR v (cm-1) 3291, 2126
(w), 1746, 1695, 1593, 1570; 1H NMR (400 MHz, CD3Cl3) δ (ppm) 10.3 (s, 1H), 7.86 (d, J = 2 Hz,
1H), 7.71 (d, J = 7.6 Hz, 1H), 7.59 (dd, J = 8.4, 2.4 Hz, 1H), 6.99 (d, J = 2 Hz, 1H), 2.69 (d, J =
2.4 Hz, 1H), 2.10 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm):189.9, 168.9, 136.0, 135.7,
134.4, 133.6, 131.6, 130.3, 79.4, 76.6, 61.6, 20.6. HRMS (TOF-ESI): [M + Na]+ calcd for
C12H9ClO3Na: 259.0132; found: 259.0135.
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2-(1-(Acetyloxy)propargyl)-5-fluorobenzaldehyde 1j: pale yellow oil; IR v (cm-1) 3291, 2126
(w), 1746, 1695, 1609, 1589; 1H NMR (400 MHz, CD3Cl3) δ (ppm) 10.3 (s, 1H), 7.76 (dd, J = 8.4,
5.1 Hz, 1H), 7.57 (dd, J = 8.4, 1.9 Hz, 1H), 7.27-7.32 (m, 1H), 6.96 (s, 1H), 2.73 (s, 1H), 2.08 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm): 189.8, 168.9, 162.8 (d, J = 251 Hz), 135.2 (d, J =
6 Hz), 133.7,, 131.2 (d, J = 7 Hz), 120.6 (d, J = 21 Hz), 117.8 (d, J = 22 Hz), 79.7, 76.7, 61.6, 20.5.
HRMS (TOF-ESI): [M + Na]+ calcd for C12H9FO3Na 243.0427; found: 243.0426.
(2). Preparation of 2-(1-(benzoyloxy)propargyl)benzaldehyde 1k (see Scheme S2 in
Supporting Information).
To a solution of 2-(diethoxymethyl)benzaldehyde IIIa (1.66 g, 8 mmol) in anhydrous THF (30 mL)
o
at 0 C and under nitrogen protection was added dropwise ethynylmagnesium bromide (21 mL,
0.5 M in THF, 13 mmol). After stirring at 0 ˚C for 40 min, the reaction was quenched by the
addition of a saturated aqueous solution of NH4Cl (20 mL) and the mixture was extracted with
ethyl acetate (20 × 3 mL). The combined organic layer was dried over anhydrous MgSO4. After
filtration and removal of solvents, the residue was dissolved in anhydrous dichloromethane (10
mL). To this solution, benzoyl chloride (1.35 g, 9.6 mmol), DMAP (0.489 g, 4 mmol) and Et3N
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(1.62 g, 16 mmol) were added at 0 oC under nitrogen atmosphere. After the resulting mixture was
stirred for 2 h at ambient temperature, the reaction was then quenched by the addition of water (10
mL). The mixture was extracted with CH2Cl2 (10 × 3 mL) and the combined organic layer was
dried over anhydrous MgSO4. After filtration and removal of solvents, the residue was
chromatographed on a silica gel column eluting with a mixture of petroleum ether and ethyl
acetate (PE : EA = 12 : 1) to give 1-(2-(diethoxymethyl)phenyl)propargyl benzoate IVk as pale
yellow solid (2.19 g, 81 %). The obtained acetal IVk was then hydrolyzed with hydrochloric acid
(1 mol/L, 20 mL) in THF (15 mL) for 3 h at room temperature. The reaction mixture was
neutralized by the addition of a saturated aqueous solution of NaHCO3 (10 mL). After extracting
with ethyl acetate (10 × 3 mL), drying and evaporating of solvent, the residue was
chromatographed on a silica gel column eluting with a mixture of petroleum ether and ethyl
acetate (PE : EA = 20 : 1) to give 2-(1-(benzoyloxy)propargyl)benzaldehyde 1k as a white solid
(1.3 g, 77%).
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2-(1-(Benzoyloxy)propargyl)benzaldehyde 1k: white solid, mp 90-91 C; IR v (cm-1) 3289,
2124 (w), 1722, 1697, 1599, 1580; 1H NMR (600 MHz, CD3Cl3) δ (ppm) 10.4 (s, 1H), 8.04 (dd, J
= 7.8, 1.8 Hz, 2H), 7.92 (dd, J = 7.8, 1.2 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H), 7.65 (dt, J = 7.2, 1.2
Hz, 1H), 7.57 (t, J = 7.8 Hz, 1H), 7.56 (t, J = 7.8 Hz, 1H), 7.42 (t, J = 7.8 Hz, 2H), 7.35 (d, J = 1.8
Hz, 1H), 2.73 (d, J = 1.8 Hz, 1H). 13C{1H} NMR (100 MHz, CDCl3) δ (ppm): 191.6, 164.7, 137.7,
134.0, 133.3, 133.2, 132.5, 129.7, 129.4, 129.1, 128.6, 128.3, 79.9, 76.4, 62.8. HRMS (TOF-ESI):
[M + Na]+ calcd for C17H12O3Na 287.0678; found: 287.0682.
(3). Preparation of 2-(1-((t-butoxycarbonyl)oxy)propargyl)benzaldehyde 1l (see Scheme S3 in
Supporting Information).
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To a solution of 2-(diethoxymethyl)benzaldehyde IIIa (2.08 g, 10 mmol) in anhydrous THF (30
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7
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mL) at 0 C and under nitrogen protection was added dropwise ethynylmagnesium bromide (26
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mL, 0.5 M in THF, 13 mmol). After stirring at 0 ˚C for 40 min, a saturated aqueous solution of
NH4Cl (20 mL) was added, and the resulting mixture was extracted with ethyl acetate (20 × 3 mL).
The combined organic layer was dried over anhydrous MgSO4. After filtration and removal of
solvents, the residue was dissolved in anhydrous acetonitrile (10 mL). To this solution at 0 oC and
under nitrogen protection were added di-t-butyl dicarbonate (2.84 g, 13 mmol) and DMAP (0.122
g, 1 mmol). The resulting mixture was kept stirring at 0 oC for 4 h. The reaction was quenched by
adding water (10 mL). The mixture was extracted with CH2Cl2 (10 × 3 mL) and the combined
organic layer was dried over anhydrous MgSO4. After filtration and removal of solvents, the
residue was chromatographed on a silica gel column eluting with a mixture of petroleum ether and
ethyl acetate (PE : EA = 12 : 1) to give t-butyl (1-(2-(diethoxymethyl)phenyl)propargyl) carbonate
IVl as pale yellow oil (2.41 g, 72 %). The resulting acetal IVl was hydrolyzed with hydrochloric
acid (1 mol/L, 21mL) in THF (15 mL) at room temperature for 6 h. Then the reaction mixture was
neutralized by the addition of a saturated aqueous solution of NaHCO3 (10 mL). After extracting
with ethyl acetate (10 × 3 mL), drying and evaporating of solvent, the residue was
chromatographed on a silica gel column eluting with a mixture of petroleum ether and ethyl
acetate (PE : EA = 15 : 1) to give 2-(1-((t-butoxycarbonyl)oxy)propargyl)benzaldehyde 1l as a
pale yellow solid (1.39 g, 74 %).
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(cm-1) 3288, 2126 (w), 1746, 1697, 1601, 1580; δ (ppm) 10.3 (s, 1H), 7.87 (d, J = 8 Hz, 1H), 7.83
(d, J = 7.6 Hz, 1H), 7.63 (dt, J = 7.6, 1.6 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.0 (d, J = 1.6 Hz, 1H),
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2.69 (d, J = 2.4 Hz, 1H), 1.48 (s, 9H). 13C{1H}NMR (100 MHz, CDCl3) δ (ppm): 191.7, 151.8,
137.2, 133.9, 133.0, 132.9, 129.3, 128.4, 83.1, 79.6, 76.4, 64.5, 27.5. HRMS (TOF-ESI): [M +
Na]+ calcd for C15H17O4 261.1121; found: 261.1118.
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(4) Preparation of 2-(1-(acetyloxy)propargyl)thiophene-3-carbaldehyde 1m (see Scheme S4
in Supporting Information).
Substrate 1m was prepared from thiophene-3-carbaldehyde Im using the similar procedures as
that for substrate 1a. The chemical yields of 3-(diethoxymethyl)thiophene IIm,
3-(diethoxymethyl)thiophene-2-carbaldehyde
IIIm,
2-(1-(acetyloxy)propargyl)thiophene-3-carbaldehyde diethyl acetal IVm and compound 1m were
summarized in Scheme S4 in Supporting Information.
2-(1-(Acetyloxy)propargyl)thiophene-3-carbaldehyde 1m: pale yellow oil; IR v (cm-1) 3287,
2127 (w), 1746, 1685, 1528; 1H NMR (400 MHz, CD3Cl3) δ (ppm) 10.16 (s, 1H), 7.46 (d, J = 4.9
Hz, 1H), 7.33 (d, J = 4.8 Hz, 1H), 7.14 (s, 1H), 2.71 (s, 1H), 2.13 (s, 3H);13C{1H}NMR (100 MHz,
CDCl3) δ (ppm) 184.1, 168.8, 147.8, 137.6, 128.1, 126.0, 78.9, 75.8, 58.3, 20.5. HRMS
(TOF-ESI): [M + Na]+ calcd for C10H8O3SNa: 231.0086, found: 231.0089.
(5) Preparation of 2-(1-(acetyloxy)propargyl)pyridine-3-carbaldehyde 1n (see Scheme S5 in
Supporting Information).
Substrate 1n was prepared from 2-bromopyridine-3-carbaldehyde In using the similar procedures
as that for 1a. The chemical yields of 2-bromo-3-(diethoxymethyl)pyridine IIn,
3-(diethoxymethyl)pyridine-2-carbaldehyde
IIIn,
2-(1-(acetyloxy)propargyl)pyridine-3-carbaldehyde diethyl acetal IVn and compound 1n were
summarized in Scheme S5 in Supporting Information.
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2-(1-(acetyloxy)propargyl)pyridine-3-carbaldehyde 1n：pale yellow solid; mp 48-49 C; IR v
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(cm-1) 3280, 2125 (w), 1700, 1584, 1572; H NMR (400 MHz, CD3Cl3) δ (ppm) 10.56 (s, 1H),
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8.79 (d, J = 2.7 Hz, 1H), 8.25 (d, J = 7.5 Hz, 1H), 7.51 (t, J = 4.9 Hz, 1H), 6.99 (s, 1H), 2.75 (s,
1H), 2.15 (s, 3H);13C{1H}NMR (100 MHz, CDCl3) δ (ppm) 189.9, 168.9, 156.3, 153.0, 138.3,
129.2, 124.1, 78.8, 77.3, 64.7, 20.5. HRMS (TOF-ESI): [M + Na]+ calcd for C11H9NO3SNa:
226.0474, found: 231.0477.
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2. General procedure for the DBU-catalyzed reaction of 2-(1-(acyloxy)propargyl) substituted
aromatic aldehydes 1.
To a solution of aldehyde 1 (1 mmol) in dry chloroform (20 mL) at room temperature and under
nitrogen protection was added DBU (45 μL，0.3 mmol, 30 mol%) through a syringe. The reaction
mixture was warmed up slowly to 60 oC in an oil bath and was then kept stirring for 5 - 36 h. The
reaction was then quenched by removal of the solvent. The residue was chromatographed on a
silica gel column eluting with a mixture of petroleum ether, dichloromethane and ethyl acetate
(PE : DCM : EA from 8 : 1 : 1 to 3 : 1 : 1) to give a mixture of products 3 and 4 in 69-95% total
yields. After determining the ratios of 3 over 4 by 1H NMR, the products 3 and 4 were obtained as
pure products in 30-70% and 11-35% yields after repetitive silica gel column chromatography
eluting with the solvents indicated below. Since compounds 3b and 4b were not completely
separated by column chromatography, pure 3b and 4b were obtained by recrystallization. In the
reaction
of
2-(1-(acyloxy)propargyl)thiophene-3-carbaldehyde
1m
and
and
2-(1-(acyloxy)propargyl)pyridine-3-carbaldehyde
1n, the bis-thiophene-
bis-pyridine-fused-[10]annulene products 3m and 3n were isolated in 52% and 34% yields,
respectively, by silica gel column chromatography eluting with a mixture of solvents (3m: PE :
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DCM : EA = 5 : 1 : 1; 3n: from PE : EA = 1 : 1 to 1 : 3 and then to pure EA), and no analogous
product of 4 was detected.
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Eluting solvents used for silica gel column chromatography to separate products 3 and 4 are as
follows.
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3a and 4a, PE : acetone = 5 : 1; 3c and 4c, PE : DCM : EA = 10 : 1 : 1 − 8 : 1 : 1; 3d and 4d, PE :
acetone = 8 : 1 − 5 : 1; 3e and 4e; PE : acetone = 3:1; 3f and 4f, PE : DCM : EA = 8 : 1 : 1; 3g and
4g, PE : acetone = 3:1; 3h and 4h, PE : DCM : EA = 10 : 1 : 1 − 8 : 1 : 1; 3i and 4i, PE : DCM :
EA = 8 : 1 : 1; 3j and 4j, PE : DCM : EA = 8 : 1 : 1; 3k and 4k, PE : acetone = 8 : 1; 3l and 4l, PE :
DCM : EA = 12 : 1 : 1.
16-Methylene-7,8,13,14-tetrahydro-6,14-epoxy-8,13-(epoxymethano)dibenzo[a,e][10]annulen
e-5,13-diacetate 3a: white solid, 123.3 mg, 61%, mp 193-194 oC (recrystallization from
n-hexane/CH2Cl2); IR v (cm-1) 1761, 1653, 1620; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.47 (dd, J
= 6.1, 2.4 Hz, 1H),7.36-7.44 (m, 4H), 7.33 (d, J = 7.9 Hz, 1H), 7.23 (d, J = 7.2 Hz, 1H), 7.11 (dd,
J = 6.3, 2.2 Hz, 1H), 5.58 (d, J = 5.9 Hz, 1H), 4.69 (s, 1H), 4.08 (d, J = 1.8 Hz, 1H), 3.22 (dd, J =
13.5, 6.1 Hz, 1H), 3.11 (d, J = 1.7 Hz, 1H), 2.49 (d, J = 13.4 Hz, 1H), 2.38 (s, 3H), 2.15 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 169.4, 166.9, 153.9, 139.2, 138.4, 137.3, 132.9, 131.3,
129.8, 128.5, 128.2, 127.8, 127.4, 126.9, 123.9, 122.0, 121.5, 85.4, 81.7, 77.8, 74.9, 38.4, 21.7,
20.6; HRMS (TOF-ESI): [M + H]+ calcd for C24H21O6: 405.1332; found:405.1335.
7,8,15,16-Tetrahydro-6,16:9,15-diepoxydibenzo[a,e][12]annulene-5,10-diacetate 4a: white
o
solid, 28.3 mg, 14%, mp 217-218 C (recrystallization from n-hexane/CH2Cl2); IR v (cm-1) 1759,
1680; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.27 (t, J = 8.9 Hz, 2H), 7.22 (t, J = 7.3 Hz, 2H), 7.0
(d, J = 7.0 Hz, 2H), 6.92 (d, J = 7.4 Hz, 2H), 5.25 (s, 2H), 2.62-2.70 (m, 2H), 2.35 (s, 6H),
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2.31-2.33 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 169.1, 148.5, 133.0, 131.3, 128.3,
127.53, 127.50, 123.9, 119.1, 84.5, 29.0, 20.3; HRMS (TOF-ESI): [M + H]+ calcd for C24H21O6:
405.1332; found:405.1335.
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3,11-Dimethoxy-16-methylene-7,8,13,14-tetrahydro-6,14-epoxy-8,13-(epoxymethano)dibenzo
[a,e][10]annulene-5,13-diacetate 3b: white solid, mp 203-204 oC (recrystallization from
n-hexane/CH2Cl2); IR v (cm-1) 1759, 1755, 1614; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.38 (d, J
= 8.3 Hz, 1H), 7.14 (d, J = 8.3 Hz, 1H), 6.86-6.91 (m, 2H), 6.82 (d, J = 2 Hz, 1H), 6.61 (d, J = 2
Hz, 1H), 5.54 (d, J = 5.7 Hz, 1H), 4.66 (s, 1H), 4.07 (d, J = 1.1 Hz, 1H), 3.84 (s, 3H), 3.83 (s, 3H),
3.16 (dd, J = 13.4, 6 Hz, 1H), 3.12 (d, J = 1.4 Hz, 1H), 2.42 (d, J = 13.4 Hz, 1H), 2.36 (s, 3H),
2.13 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 169.5, 167.0, 159.9, 159.7, 140.0, 138.3,
134.7, 131.3, 129.9, 128.1, 125.2, 123.8, 112.9, 112.4, 108.4, 107.6, 85.5, 81.6, 78.1, 74.8, 55.4,
55.3, 38.8, 21.9, 20.7; HRMS (TOF-ESI): [M + H]+ calcd for C26H25O8: 465.1543; found:
465.1547.
3,12-Dimethoxy-7,8,15,16-tetrahydro-6,16:9,15-diepoxydibenzo[a,e][12]annulene-5,10-diacet
o
ate 4b: white solid, mp 224-225 C (recrystallization from n-hexane/CH2Cl2); IR v (cm-1) 1755,
1682, 1611; 1H NMR (400 MHz, CDCl3) δ (ppm) 6.92 (d, J = 8.2 Hz, 2H), 6.73 (dd, J = 8.2, 2.4
Hz, 2H), 6.46 (d, J = 2.4 Hz, 2H), 5.17 (s, 2H), 3.80 (s, 6H), 2.60-2.68 (m, 2H), 2.34 (s, 6H),
2.26-2.32 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 169.3, 159.8, 149.2, 131.3, 129.0,
125.7, 125.2, 112.0, 105.7, 84.8, 55.4, 29.3, 20.5; HRMS (TOF-ESI): [M + H]+ calcd for C26H25O8:
465.1543; found: 465.1546.
3,11-Dimethyl-16-methylene-7,8,13,14-tetrahydro-6,14-epoxy-8,13-(epoxymethano)dibenzo[a
,e][10]annulene-5,13-diacetate 3c: white solid, 114.6 mg, 53%, mp 211-212 oC (recrystallization
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from n-hexane/CH2Cl2); IR v (cm-1) 1757, 1647; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.35 (d, J =
7.7 Hz, 1H), 7.19 (d, J = 7.7 Hz, 1H), 7.16 (d, J = 7.8 Hz, 1H), 7.11 (d, J = 6.8 Hz, 1H), 7.10 (s,
1H), 6.70 (s, 1H); 5.55 (d, J = 5.8 Hz, 1H), 4.65 (s, 1H), 4.07 (d, J = 1.4 Hz, 1H), 3.19 (dd, J =
13.4, 6 Hz, 1H), 3.11 (d, J = 1.2 Hz, 1H), 2.44 (d, J = 13.5 Hz, 1H), 2.41 (s, 3H), 2.40 (s, 3H),
2.39 (s, 3H), 2.15 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 168.8, 167.2, 154.3, 139.5,
138.63, 138.58, 138.2, 134.7, 133.0, 129.9, 128.8, 128.5, 127.0, 124.0, 122.6, 122.2, 85.4, 81.9,
78.2, 75.1, 38.8, 22.0, 21.7, 21.6, 20.9; HRMS (TOF-ESI): [M + H]+ calcd for C26H25O6: 433.1645;
found: 433.1642.
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3,12-Dimethyl-7,8,15,16-tetrahydro-6,16:9,15-diepoxydibenzo[a,e][12]annulene-5,10-diacetat
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e 4c: white solid, 34.6 mg, 16%, mp 225-226 C (recrystallization from n-hexane/CH2Cl2); IR v
(cm-1) 1753, 1676, 1611; 1H NMR (600 MHz, CDCl3) δ (ppm) 7.0 (d, J = 6.6 Hz, 2H), 6.87 (dd, J
= 7.8 Hz, 2H), 6.69 (s, 2H), 5.17 (s, 2H), 2.59-2.65 (m, 2H), 2.34 (s, 6H), 2.31 (s, 6H), 2.26-2.29
(m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 169.2, 148.5, 138.0, 131.4, 130.4, 128.1,
127.3, 123.8, 119.7, 84.6, 29.0, 21.2, 20.4; HRMS (TOF-ESI): [M + H]+ calcd for C26H25O6:
433.1645; found: 433.1648.
3,11-Dichloro-16-methylene-7,8,13,14-tetrahydro-6,14-epoxy-8,13-(epoxymethano)dibenzo[a,
e][10]annulene-5,13-diacetate 3d: white solid, 108.9 mg, 46%, mp 217-219 oC (recrystallization
1
from n-hexane/CH2Cl2): IR v (cm-1) 1761, 1620; H NMR (400 MHz, CDCl3) δ (ppm) 7.36-7.40
(m, 2H), 7.34 (dd, J = 8.2, 2.0 Hz, 1H), 7.28 (d, J = 1.9 Hz, 1H), 7.17 (d, J = 8.2 Hz, 1H), 7.07 (s,
1H), 5.55 (d, J = 5.8 Hz, 1H), 4.66 (s, 1H), 4.11 (d, J = 2 Hz, 1H), 3.19 (dd, J = 13.4, 6 Hz, 1H),
3.15 (d, J = 2 Hz, 1H), 2.45 (d, J = 13.4 Hz, 1H), 2.39 (s, 3H), 2.16 (s, 3H); 13C{1H} NMR (100
MHz, CD3COCD3) δ (ppm) 168.9, 166.5, 153.9, 140.4, 137.4, 136.6, 135.6, 133.9, 133.2, 131.8,
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129.9, 129.0, 127.7, 127.2, 125.8, 122.5, 121.2, 84.7, 80.5, 76.9, 74.1, 38.0, 20.7, 19.6; HRMS
(TOF-ESI): [M + H]+ calcd for C24H19Cl2O6: 473.0553; found: 473.0556.
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e 4d: white solid, 35.5 mg, 15%, mp 236-238 C (recrystallization from n-hexane/CH2Cl2); IR v
(cm-1) 1774, 1759, 1678; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.18 (dd, J = 7.9, 1.6 Hz, 2H), 6.91
(d, J = 8 Hz, 2H), 6.88 (d, J = 1.3 Hz, 2H), 5.19 (s, 2H), 2.61-2.69 (m, 2H), 2.36 (s, 6H), 2.26-2.32
(m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 168.9, 149.7, 134.5, 130.8, 130.4, 129.4,
127.3, 125.2, 119.3, 84.0, 29.0, 20.3; HRMS (TOF-ESI): [M + H]+ calcd for C24H19Cl2O6:
473.0553; found:473.055.
3,11-Difluoro-16-methylene-7,8,13,14-tetrahydro-6,14-epoxy-8,13-(epoxymethano)dibenzo[a,
e][10]annulene-5,13-diacetate 3e: white solid, 125.5 mg, 57 %, mp 227-228 oC (recrystallization
from n-hexane/CH2Cl2); IR v (cm-1) 1761, 1751, 1616; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.42
(dd, J = 8.3, 5.4 Hz, 1H), 7.20 (dd, J = 8.4, 5.3 Hz, 1H), 7.03-7.11(m, 2H), 7.0 (dd, J = 9.1, 2.3 Hz,
1H), 6.80 (dd, J = 9.1, 2.4 Hz, 1H), 5.57 (d, J = 5.8 Hz, 1H), 4.67 (s, 1H), 4.10 (d, J = 2 Hz, 1H),
3.19 (dd, J = 13.5, 6.0 Hz, 1H), 3.12 (d, J = 1.9 Hz, 1H), 2.44 (d, J = 13.4 Hz, 1H), 2.38 (s, 3H),
2.14 (s, 3H); 13C{1H} NMR (100 MHz, DMSO-d6) δ (ppm) 170.0, 167.6, 162.8 (d, J = 243.4 Hz),
162.5 (d, J = 241.5 Hz), 154.2, 140.7, 137.8, 135.9 (d, J = 7.6 Hz), 134.4, 132.3 (d, J = 9.6 Hz),
130.0 (d, J = 8.6 Hz), 127.5, 126.9 (d, J = 8.6 Hz), 115.3(d, J = 22 Hz), 114.9 (d, J = 21.1 Hz),
110.2 (d, J = 23 Hz), 109.1 (d, J = 23 Hz), 85.3, 80.2, 77.3, 74.1, 39.7, 22.0, 21.2; HRMS
(TOF-ESI): [M + H]+ calcd for C24H19F2O6: 441.1144; found: 441.1142.
3,12-Difluoro-7,8,15,16-tetrahydro-6,16:9,15-diepoxydibenzo[a,e][12]annulene-5,10-diacetate
o
4e: white solid, 24.2 mg, 11%, mp 236-237 C (recrystallization from n-hexane/CH2Cl2); IR v
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(cm-1) 1774, 1751, 1682, 1610; 1H NMR (400 MHz, CDCl3) δ (ppm) 6.87-6.96 (m, 4H) 6.63 (dd,
J = 9.3, 2.2 Hz, 2H), 5.20 (s, 2H), 2.62-2.70 (m, 2H), 2.35 (s, 6H), 2.27-2.33 (m, 2H); 13C{1H}
NMR (100 MHz, CDCl3) δ (ppm) 169.1, 163.0 (d, J = 245 Hz), 149.8, 130.8 (d, J = 2 Hz), 130.0
(d, J = 9 Hz), 128.4 (d, J = 4 Hz), 125.6 (d, J = 9 Hz), 114.1 (d, J = 23 Hz), 106.8 (d, J = 24 Hz),
84.3, 29.2, 20.5; HRMS (TOF-ESI): [M + H]+ calcd for C24H19F2O6: 441.1144; found: 441.1142.
3,11-Di(trfluoromethyl)-16-methylene-7,8,13,14-tetrahydro-6,14-epoxy-8,13-(epoxymethano)
dibenzo[a,e][10]annulene-5,13-diacetate 3f: white solid, 97.3 mg, 36%, mp 205-206 oC
(recrystallization from n-hexane/CH2Cl2); IR v (cm-1) 1761, 1633; 1H NMR (400 MHz,
CD3COCD3) δ (ppm) 7.89 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8 Hz, 1H), 7.76 (s, 1H), 7.71 (d, J =
7.6 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.49 (s, 1H), 5.76 (d, J = 6 Hz, 1H), 5.05 (s, 1H), 3.94 (d, J
= 2 Hz, 1H), 3.32 (dd, J = 14, 6 Hz, 1H), 3.16 (d, J = 1.2 Hz, 1H), 2.52 (d, J = 13.6 Hz, 1H), 2.37
(s, 3H), 2.17 (s, 3H); 13C{1H} NMR (100 MHz, CD3COCD3) δ (ppm) 169.0, 166.8, 154.1, 142.0,
140.7, 137.7, 135.3, 134.7, 131.1, 130.5 (q, J = 32 Hz), 129.8 (q, J = 32 Hz), 128.5, 125.3, 124.8
(q, J = 4 Hz), 124.2 (q, J = 4 Hz), 124.3 (q, J = 270 Hz), 124.2 (q, J = 270 Hz), 119.8 (q, J = 4 Hz),
118.2 (q, J = 4 Hz), 85.1, 80.5, 77.1, 74.4, 38.1, 20.8, 19.8; HRMS (TOF-ESI): [M + H]+ calcd for
C26H19F6O6: 541.108; found: 541.1084.
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3,12-Di(trifluoromethyl)-7,8,15,16-tetrahydro-6,16:9,15-diepoxydibenzo[a,e][12]annulene-5,1
0-diacetate 4f: white solid, 94.6 mg, 35%, mp 261-263 oC (recrystallization from
n-hexane/CH2Cl2); IR v (cm-1) 1778, 1757, 1678; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.49 (d, J
= 7.7 Hz, 2H), 7.14 (s, 2H), 7.11 (d, J = 7.8 Hz, 2H), 5.30 (s, 2H), 2.64-2.72 (m, 2H), 2.38 (s, 6H),
2.31-2.36 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 169.1, 150.2, 135.9, 131.3 (q, J =
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33 Hz), 130.7, 128.9, 124.6 (q, J = 4 Hz), 124.5, 123.7 (q, J = 271 Hz), 116.2 (q, J = 4 Hz), 83.9,
29.1, 20.5; HRMS (TOF-ESI): [M + H]+ calcd for C26H19F6O6: 541.108; found: 541.1083.
2,10-Dimethoxy-16-methylene-7,8,13,14-tetrahydro-6,14-epoxy-8,13-(epoxymethano)dibenzo
[a,e][10]annulene-5,13-diacetate 3g: white solid, 70 mg, 30 %, mp 186-187 oC (recrystallization
from n-hexane/CH2Cl2); IR v (cm-1) 1771, 1612; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.22 (d, J =
8.5 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.95 (dd, J = 8.5, 2.4 Hz, 1H), 6.91
(dd, J = 8.5, 2.5 Hz, 1H), 6.75 (d, J = 2.4 Hz, 1H), 5.49 (d, J = 5.9 Hz, 1H), 4.59 (s, 1H), 4.08 (d, J
= 1.8 Hz, 1H), 3.89 (s, 3H), 3.84 (s, 3H), 3.17 (dd, J = 13.5, 6.1 Hz, 1H), 3.14 (d, J = 1.4 Hz, 1H),
2.47 (d, J = 13.5 Hz, 1H), 2.36 (s, 3H), 2.15 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm)
169.8, 167.1, 159.5, 159.0, 154.1, 138.9, 138.7, 137.5, 133.7, 125.1, 123.6, 123.2, 114.3, 113.5,
113.3, 109.5, 85.7, 82.6, 78.1, 75.2, 55.55, 55.47, 38.4, 22.1, 20.9; HRMS (TOF-ESI): [M + H]+
calcd for C26H25O8: 465.1543; found: 465.1546.
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2,13-Dimethoxy-7,8,15,16-tetrahydro-6,16:9,15-diepoxydibenzo[a,e][12]annulene-5,10-diacet
ate 4g: white solid, 66 mg, 28 %, mp 222 oC (recrystallization from n-hexane/CH2Cl2); IR v (cm-1)
1755, 1610; 1H NMR (400 MHz, CDCl3) δ (ppm) 6.85 (d, J = 8.8 Hz, 2H), 6.76 (dd, J = 8.8, 2.4
Hz, 2H), 6.53 (d, J = 2.8 Hz, 2H), 5.17 (s, 2H), 3.80 (s, 6H), 2.55-2.60 (m, 2H), 2.31 (s, 6H),
2.23-2.28 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 169.5, 159.3, 146.6, 135.2, 131.5,
120.9, 120.8, 112.6, 111.0, 84.3, 55.6, 28.8, 20.6; HRMS (TOF-ESI): [M + H]+ calcd for C26H25O8:
465.1543; found: 465.1546.
2,10-Dimethyl-16-methylene-7,8,13,14-tetrahydro-6,14-epoxy-8,13-(epoxymethano)dibenzo[a
,e][10]annulene-5,13-diacetate 3h: white solid, 101.6 mg, 47 %, mp 226-227 oC
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(recrystallization from n-hexane/CH2Cl2); IR v (cm-1) 1765, 1651, 1618; H NMR (400 MHz,
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CDCl3) δ (ppm) 7.26 (s, 1H), 7.18-7.23 (m, 3H), 7.04 (s, 1H), 6.99 (d, J = 7.8 Hz, 1H), 5.51 (d, J
= 5.9 Hz, 1H), 4.61 (s, 1H), 4.06 (d, J = 1.8 Hz, 1H), 3.18 (dd, J = 13.5, 6.1 Hz, 1H), 3.11 (d, J =
1.8 Hz, 1H), 2.45 (d, J = 12.8 Hz, 1H), 2.44 (s, 3H), 2.39 (s, 3H), 2.36 (s, 3H), 2.14 (s, 3H);
13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 169.7, 167.1, 154.2, 138.7, 138.6, 137.9, 137.4, 137.3,
131.6, 130.2, 129.3, 129.2, 127.8, 127.4, 124.7, 122.0, 121.5, 85.3, 82.1, 78.0, 75.1, 38.6, 21.9,
21.6, 21.2, 20.8; HRMS (TOF-ESI): [M + H]+ calcd for C26H25O6: 433.1645; found:433.1648.
2,13-Dimethyl-7,8,15,16-tetrahydro-6,16:9,15-diepoxydibenzo[a,e][12]annulene-5,10-diacetat
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e 4h: white solid, 28 mg, 13 %, mp 220-221 C (recrystallization from n-hexane/CH2Cl2); IR v
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(cm-1) 1771, 1684; H NMR (400 MHz, CDCl3) δ (ppm) 7.05 (d, J = 7.6 Hz, 2H), 6.81 (s, 2H),
6.80 (d, J = 7.6 Hz, 2H), 5.17 (s, 2H), 2.57-2.65 (m, 2H), 2.35 (s, 6H), 2.32 (s, 6H), 2.23-2.29 (m,
2H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 169.1, 147.6, 137.4, 133.3, 131.5, 128.8, 124.9,
124.6, 119.1, 84.5, 28.8, 21.1, 20.3; HRMS (TOF-ESI): [M + H]+ calcd for C26H25O6: 433.1645;
found: 433.1649.
2,10-Dichloro-16-methylene-7,8,13,14-tetrahydro-6,14-epoxy-8,13-(epoxymethano)dibenzo[a,
o
e][10]annulene-5,13-diacetate 3i: white solid, 142 mg, 60%, mp 195 C (recrystallization from
n-hexane/CH2Cl2); IR v (cm-1) 1769, 1751, 1626; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.42 (d, J
= 1.6 Hz, 1H), 7.34-7.38 (m, 2H), 7.20-7.22 (m, 2H), 7.02 (d, J = 8.4 Hz, 1H), 5.49 (d, J = 6.0 Hz,
1H), 4.58 (s, 1H), 4.09 (d, J = 1.6 Hz, 1H), 3.16 (s, 1H), 3.15-3.20 (m, 1H), 2.45 (d, J = 13.2 Hz,
1H), 3.13 (s, 3H), 3.12 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ (ppm) 169.4, 167.0, 153.6,
139.5, 139.2, 138.1, 133.8, 133.0, 131.6, 129.0, 128.8, 128.6, 127.2, 124.4, 123.9, 123.2, 86.2,
81.3, 77.6, 74.6, 38.4, 21.9, 20.8; HRMS (TOF-ESI): [M + H]+ calcd for C24H19Cl2O6: 473.0553;
found: 473.0551.
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