Straightforward Stereoselective Synthesis of Seven-Membered Oxa-Bridged Rings through in Situ Generated Cycloheptenol Derivatives

Mengdan Wang, Liqiang Yin, Lu Cheng, Yajie Yang, and Yanzhong Li*

Article

Straightforward Stereoselective Synthesis of Seven-Membered Oxa-

Bridged Rings through In Situ Generated Cycloheptenol Derivatives

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Cite This: https://doi.org/10.1021/acs.joc.1c01648

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sı Supporting Information

ABSTRACT: An iodine-mediated stereoselective synthesis of

seven-membered oxa-bridged rings via in situ generated cyclo-

heptenols was reported. This process was realized through the

combination of C−C σ-bond cleavage and C−O bond-forming

reactions in a one-pot fashion from simple and easily accessible raw

materials. The formation of carbon radicals initiated by I was the

key to the reaction.

INTRODUCTION

Scheme 1. Synthesis of the Seven-Membered Oxa-Bridged

Ring

■

Oxa-bridged heterocyclic scaﬀolds, especially the seven-

membered oxa-bridged rings (OBC), are widely found in

many natural products and synthetic molecules with important

biological activities (Figure 1 ). Due to their special biological

Figure 1. Some natural products with oxa-bridged bicyclic skeletons.

importance, these seven-membered oxa-bridged carbocycles

have attracted great attention from synthetic chemists. So far, a

large number of methods have been developed to synthesize

seven-membered oxa-bridged ring compounds. The reported

methods predominantly rely on cycloaddition reaction, such as

in the presence of hypervalent iodine PhI(OAc) was described

by the Sarpong group (Scheme 1b). Nevertheless, these

the [4 + 3] cycloaddition of allyl cations with furans, [4 + 3]

protocols usually relied on cycloheptenols as starting materials,

and the range of commercially available cycloheptenol

substrates greatly limited its application of this type of

transformation. Consequently, there is still an urgent need to

develop novel methodologies for the construction of cyclo-

heptenols from simple and easily available reactants; if

achieved, it may provide a platform for the direct assembling

of seven-membered oxa-bridged rings.

cycloaddition between 1,4-dicarbonyls and 1,3-bis(trimethyl-

silyl)oxy dienes, [5 + 2] annulations between oxidopyrylium

and alkenes, etc. These transformations usually require noble

metal catalysis. Intramolecular cyclization is also an eﬃcient

method, which typically involves multistep reactions in the

elaboration of substrates. Another straightforward way to

construct seven-membered oxa-bridged rings is the installing of

a bridged oxygen atom on cycloheptane or cycloheptene

As part of our ongoing interest in C−C σ-bond cleavage

derivatives. However, there are two challenges: (1) The

chemistry, we have developed eﬃcient base-promoted

diastereoselective functionalization of a cycloheptene deriva-

tive is diﬃcult owing to the inherent conformational

uncertainties. (2) The molecular structure of bridge-containing

fragments is less ﬂexible compared to their homologous

counterparts, and this strategy is rarely reported.

Received: July 12, 2021

Iwabuchi et al. developed a novel oxidative cyclo-ether-

iﬁcation of 4-hydroxycyclohept-2-enone using PhI(OH)OTs

(

Scheme 1a). A tandem oxidative dearomatization/cyclization

XXXX American Chemical Society

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

approaches for the preparation of cycloheptenols. It could be

nice precursors of oxa-bridged ring compounds via intra-

molecular C−O bond formation reactions. We envisaged that

the construction of such seven-membered oxa-bridged ring

compounds might be realized through the combination of C−

C σ-bond cleavage and C−O bond-forming reactions in a one-

pot fashion by tuning the reaction parameters from simple and

easily accessible raw materials. Herein, we report an iodine-

mediated stereoselective synthesis of seven-membered oxa-

bridged rings (Scheme 1c).

TsOH·H O and 50 mol % of I at 100 °C for 6 h (Table 1,

2 2

entry 9).

After obtaining the optimal reaction conditions, the

substrate range was investigated (Scheme 2). Regarding the

Scheme 2. Substrate Scope for the Synthesis of 3

RESULTS AND DISCUSSION

The reaction of 1-phenyl-3-(p-tolyl)prop-2-yn-1-one (1a) with

H-indene-1,3(2H)-dione (2a) was chosen as a template

■

reaction to test our hypothesis and optimize experimental

conditions. First, the reaction of 1a with 2a was carried out

using Cs CO (3.0 equiv) as the base and DMSO as the

solvent at 110 °C under N , as previously reported. Next, we

attempted to add iodine into the reaction system at 100 °C for

h. Regrettably, no desired C−O bond-forming product could

be observed (Table 1, entry 1). Then HCl (6 M) was added to

Table 1. Optimization Studies for the Synthesis of 3a

catalyst

(mol %)

(°C)

yield

(%)

entry

acid (equiv)

t (h)

I₂(50)

I₂(25)

I₂(50)

100

6 M HCI (6.0)

CH COOH (6.0)

TfOH (6.0)

trace

TsOH·H O (6.0)

6 M HCI (6.0)

6 M HCI (8.0)

6 M HCI (4.0)

TsOH·H O (8.0)

TsOH·H O (10.0)

Reaction conditions: 0.3 mmol scale, 3 mL of DMSO, 1/2a = 1:1.4.

TsOH·H O (8.0)

120

R¹substituent, no matter it has an electron-donating group or

an electron-withdrawing group at the para position, the target

products were obtained in moderate to good yields (3a−3f).

When the electron-withdrawing group (−Cl) was in the meta-

position, it provided a lower yield than in the para-position

Isolated yield, 1a (0.2 mmol), 2a (0.28 mmol), DMSO (5 mL). 2

mL of DMSO. No product. Heating mantle.

neutralize the reaction system, and it was interesting that the

desired oxa-bridged product 3a was obtained in 62% yield

(49% vs 62%). For the R substituent, it could tolerate various

(

Table 1, entry 2). Considering the importance of acid,

substituents such as 4-Me, 4-OMe, 3,4-(OMe) , 4-F, and 4-Cl,

diﬀerent acids were used to increase the yield, but there was no

improvement (Table 1, entries 3−5). Reducing the volume of

solvent to 2 mL resulted in a slightly higher yield (63%, entry

and the target products (3h−3m) were generated in 35−83%

yields. It was worth noting that when the −F was in the para

position, the yield of 3l was only 35%. Other aryl substituents

were also suitable for this reaction (such as naphthalene ring,

2-furyl) to provide corresponding products with yields of 62%

). Increasing or decreasing the amount of HCl (6 M) both

gave lower yields (entries 7 and 8). We were pleased to ﬁnd

that the yield of 3a could be increased to 70% by further

and 71%, respectively. When both R and R were other

heteroaryls, such as thiophene-2-yl or N-Ts-pyrrole-2-yl, the

corresponding products (3p−3q) were also well aﬀorded. The

increasing the amount of TsOH·H O to 8.0 equiv (entry 9);

0.0 equiv of TsOH·H O gave almost the same result as that of

.0 equiv (entry 10 vs entry 9). When the amount of iodine

structure of 3q was fully conﬁrmed by X-ray crystallography.

was reduced to 25 mol %, the yield of 3a was decreased to 63%

entry 11). The strategy of raising or lowering the temperature

to increase the yield was ineﬀective (entries 12 and 13).

Interestingly, alkyl-substituted alkynones could also react with

2a to give 3r−3t in moderate yields. Notably, alkynyl ester

could also be employed in the reaction to aﬀord 3u in a 44%

yield.

(

Therefore, the optimized reaction condition is 8.0 equiv of

J. Org. Chem. XXXX, XXX, XXX−XXX

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Article

Scheme 4. ¹⁸O-Labeled Experiments^a

Some control experiments were conducted to explore the

reaction mechanism (Scheme 3). The reaction of 1h with 2a

Scheme 3. Control Experiments

^a¹⁸O determined by ESI-MS.

under the same reaction conditions, it was found that three

O-labeled atoms were incorporated to give O -3h (Scheme

b). This result suggested that O exchange could take place

between H₂O and the three O atoms of the bridged

compound 3h (see Scheme 4b, O, O, and O) in the

presence of I₂.

Based on the experimental results and previous re-

10,11,13

ports,

a plausible mechanism for the formation of 3h

was proposed in Scheme 5. First, 1h and 2a generated M-h

Scheme 5. Possible Reaction Mechanism

was carried out under the optimized reaction conditions for the

ﬁrst step, providing a ring expansion product M-h in a yield of

6% (Scheme 3a). When M-h was subjected to the general

reaction conditions of the second step, the desired product 3h

was obtained 85% yield within 6 h (Scheme 3b). There was no

Cs CO in the conversion from M-h to 3h, so there was no

need to add acid to neutralize the system. This result indicates

that M-h is an intermediate for the formation of 3h in the one-

pot process. When M-h was treated with I in the presence of

Cs CO , a complex reaction mixture was observed (Scheme

c). Adding TsOH·H O to the system under the standard

conditions of the second step aﬀorded 3h in 84% yield

Scheme 3d). These results suggested that the oxa-bridged

product could not be formed under basic conditions. When

,2,6,6-tetramethyl-1-piperinedinyloxy (TEMPO) was added,

through C−C bond insertion reaction in the presence of bases.

Tautomerization of M-h gave A. Free radical intermediate B

was obtained under iodine. Intermediate B was oxidized to

form C, which was hydrolyzed to produce D. Then, D was

oxidized to form a triketone intermediate E. Subsequently, E

was hydrolyzed to give F. Dehydration of F gave G. Finally, an

intramolecular attack of OH to aﬀord product 3h.

In conclusion, an iodine-mediated protocol for the stereo-

selective synthesis of seven-membered oxa-bridged rings via in

situ generated cycloheptenols has been developed. Cascade

(

the radical trapping product 4h was obtained in 35% yield with

a trace amount of 3h (Scheme 3e), which might suggest a

radical process. The radical trapping product 4h was processed

underthe general reaction conditions of the second step to

obtain the desired product 3h in 60% yield (Scheme 3f). When

h was treated in the absence of I , 3h was isolated with a yield

of 50%. This result indicates that iodine was not required for

cyclization reactions.

reactions of Cs

-promoted C−C bond cleavage and I -

mediated C−O bond formation were involved in this process.

It is anticipated that the eﬀective combination of C−O bond

formation and C−C bond cleavage reactions may be an

attractive choice for the construction of complex molecular

skeletons from readily available starting materials.

In order to explore the source of oxygen, ¹⁸O isotopic

labeling experiments were carried out under the standard

reaction conditions. When the seven-membered ring M-h was

treated with I in the presence of H₂O, O -3h was obtained

with a yield of 87%. There are four labeled O atoms in O -3h

EXPERIMENTAL SECTION

General Information. All reactions under N₂were

performed in ﬂame-dried glassware under an atmosphere of

(Scheme 4a). These results indicated that two additional

■

oxygen atoms (one from the bridged “O” and the other from

the OH group) might come from water. Treatment of 3h

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

dry nitrogen, unless otherwise noted. Column chromato-

graphic puriﬁcation of products was carried out using silica gel

(10 mL × 3). The combined organic layers were washed with

brine, dried over anhydrous Na SO , ﬁltered, and concentrated

(

200−300 mesh). The reagents were used without further

under reduced pressure. Puriﬁcation by chromatography on

silica gel (petroleum ether/ethyl acetate = 2:1) aﬀorded

desired compound 3b (light yellow solid, 84.8 mg, 74% yield).

1.0 mmol Scale Reaction for 1b with 2a. A mixture of

1,3-diphenylprop-2-yn-1-one 1b (1.0 mmol, 206.2 mg), 1H-

indene-1,3(2H)-dione 2a (1.4 mmol, 204.6 mg), Cs CO (3.0

puriﬁcation. H NMR spectra were recorded at 400 or 500

MHz, and C NMR spectra were recorded at 100 or 125

MHz, in CDCl (containing 0.03% TMS) or in DMSO-d

solutions. H NMR spectra were recorded with tetramethylsi-

lane (δ = 0.00 ppm) as an internal reference. C NMR spectra

were recorded with CDCl (δ = 77.00 ppm) as an internal

mmol, 977.5 mg), and DMSO (10.0 mL) in a Schlenk tube

reference, or C NMR spectra were recorded with DMSO-d₆

δ = 39.50 ppm) as an internal reference. High-resolution mass

spectra were performed on a mass spectrometer with a TOF

for EI or ESI) or FT-ICR (for MALDI) analyzer. The crystal

was stirred at 110 °C under N . After the reaction was

(

completed as monitored by thin-layer chromatography (1 h),

the reaction system was cooled to room temperature. The

(

reaction mixture was then quenched by TsOH·H O (8.0

preparation and measurement methods of 3q are as follows: 50

mg of 3q was placed in a 50 mL round-bottom ﬂask, and 3q

was dissolved in 2 mL of dichloromethane. Then, 6 mL of

petroleum ether was added, and the solution was mixed well

and left to stand still at room temperature until crystals

precipitated out. Single-crystal X-ray diﬀraction data was

collected in Bruker SMARTAPEX diﬀractiometers with

molybdenum cathodes.

mmol, 1521.8 mg), then I (0.5 mmol, 126.9 mg) was added,

and the reaction temperature was increased to 100 °C for 5 h.

The reaction mixture was then quenched by water, and the

water layers were extracted with ethyl acetate (20 mL × 3).

The combined organic layers were washed with brine, dried

over anhydrous Na SO , ﬁltered, and concentrated under

reduced pressure. Puriﬁcation by chromatography on silica gel

(petroleum ether/ethyl acetate = 2:1) aﬀorded desired

compound 3b (light yellow solid, 249.5 mg, 65% yield).

Radical Trapping Experiment. In a Schlenk tube, 9-

hydroxy-8-(4-methylbenzoyl)-7-phenyl-5H-benzo[7]annulen-

Synthesis of 1: Preparation of 1a−1s. To a solution of

the alkyne (12 mmol) in anhydrous THF (30 mL), n-BuLi

(

2.5M, 10 mmol, 4 mL) was added at −78 °C. The resulting

mixture was stirred at −78 °C for 1 h, then the aldehyde (10

mmol) was added, and the reaction temperature was raised to

room temperature until the aldehyde disappeared by TLC

analysis. The resulting mixture was quenched with a saturated

5-one M-h (0.20 mmol, 73.2 mg), I (0.1 mmol, 25.4 mg), and

TEMPO (0.4 mmol, 62.5 mg) were dissolved in DMSO (2.0

mL), and the mixture was stirred at 100 °C for 5 h. The

reaction mixture was then quenched by water, and the water

layers were extracted with ethyl acetate (10 mL × 3). The

combined organic layers were washed with brine, dried over

anhydrous Na SO , ﬁltered, and concentrated under reduced

solution of NH Cl and extracted with ethyl acetate (20 mL ×

). The combined organic layers were washed with brine and

dried over anhydrous Na SO , ﬁltered, and concentrated under

pressure. Puriﬁcation by chromatography on silica gel

(petroleum ether/ethyl acetate = 20:1) aﬀorded the desired

compound 4h (light yellow solid, 47.1 mg, 45%).

(5R)-6-Benzoyl-5,8-dihydroxy-7-(p-tolyl)-5,8-dihydro-9H-

5,8-epoxybenzo[7]annulen-9-one (3a): light yellow solid,

petroleum ether/ethyl acetate = 2:1, 83.3 mg, 70% yield; mp

160−161 °C; H NMR (400 MHz, CDCl ) δ 8.09−8.06 (m,

1H), 7.46−7.39 (m, 3H), 7.36−7.31 (m, 3H), 7.10−7.05 (m,

4H), 6.90−6.87 (m, 2H), 5.84 (s, 1H), 5.70 (s, 1H), 2.17 (s,

3H); C{ H} NMR (100 MHz, CDCl ) δ 195.0, 191.1, 145.9,

145.1, 143.6, 140.1, 134.9, 134.5, 134.5, 129.7, 129.3, 128.7,

128.7, 126.7, 126.1, 123.1, 105.4, 104.0, 21.0; HRMS (ESI) m/

z [M + Na] calcd for C H NaO 421.1046, found 421.1046.

(5R)-6-Benzoyl-5,8-dihydroxy-7-phenyl-5,8-dihydro-9H-

5,8-epoxybenzo[7]annulen-9-one (3b): light yellow solid,

petroleum ether/ethyl acetate = 2:1, 84.8 mg, 74% yield; mp

142−143 °C; H NMR (500 MHz, DMSO-d ) δ 8.59 (s, 1H),

8.51 (s, 1H), 7.90−7.88 (m, 1H), 7.60−7.56 (m, 3H), 7.52−

7.49 (m, 2H), 7.40−7.38 (m, 1H), 7.35−7.31 (m, 2H), 7.23−

7.16 (m, 5H); C{ H} NMR (125 MHz, CDCl ) δ 194.3,

190.5, 145.5, 144.7, 144.5, 134.6, 134.3, 134.2, 129.5, 129.4,

129.4, 129.4, 128.5, 128.5, 128.4, 128.3, 125.8, 123.0, 105.3,

104.0; HRMS (ESI) m/z [M + Na] calcd for C H O Na

mmol, 61.4 mg), Cs CO (0.9 mmol, 293.2 mg), and DMSO

407.0890, found 407.0889.

(5R)-6-Benzoyl-5,8-dihydroxy-7-(4-methoxyphenyl)-5,8-

dihydro-9H-5,8-epoxybenzo[7]annulen-9-one (3c): yellow

(

3.0 mL) in a Schlenk tube was stirred at 110 °C under N₂.

After the reaction was completed as monitored by thin-layer

chromatography (1 h), the reaction system was cooled to room

temperature. The reaction mixture was then quenched by

TsOH·H O (2.4 mmol, 456.5 mg), then I (0.15 mmol, 38.1

solid, petroleum ether/ethyl acetate = 2:1, 52.3 mg, 63%

yield; mp 163−164 °C; H NMR (500 MHz, DMSO-d ) δ

8.56−8.55 (m, 1H), 8.42−8.41 (m, 1H), 7.87−7.85 (m, 1H),

7.62−7.58 (m, 2H), 7.58−7.55 (m, 1H), 7.54−7.46 (m, 2H),

7.40−7.37 (m, 1H), 7.36−7.32 (m, 2H), 7.21−7.18 (m, 2H),

mg) was added, and the reaction temperature was increased to

00 °C for 5 h. The reaction mixture was then quenched by

water, and the water layers were extracted with ethyl acetate

6.76−6.73 (m, 2H), 3.64 (s, 3H); C{ H} NMR (125 MHz,

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Article

CDCl ) δ 194.3, 191.0, 160.5, 146.0, 144.9, 141.9, 134.9,

(5R)-5,8-Dihydroxy-6-(4-methoxybenzoyl)-7-phenyl-5,8-

dihydro-9H-5,8-epoxybenzo[7]annulen-9-one (3i): light yel-

34.4, 134.1, 130.3, 129.4, 129.4, 128.5, 128.5, 125.8, 122.9,

21.9, 113.9, 105.1, 103.7, 55.2; HRMS (ESI) m/z [M + Na]⁺

low solid, petroleum ether/ethyl acetate = 3:1, 74.2 mg, 60%

calcd for C H O Na 437.0996, found 437.0996.

yield; mp 162−163 °C; H NMR (500 MHz, CDCl ) δ 8.10−

(5R)-6-Benzoyl-7-(4-ﬂuorophenyl)-5,8-dihydroxy-5,8-dihy-

8.07 (m, 1H), 7.45−7.36 (m, 3H), 7.27−7.24 (m, 2H), 7.22−

7.19 (m, 2H), 7.16−7.07 (m, 3H), 6.53−6.50 (m, 2H), 6.26

(brs, 1H), 6.20 (brs, 1H), 3.67 (s, 3H); C{ H} NMR (125

dro-9H-5,8-epoxybenzo[7]annulen-9-one (3d): light yellow

solid, petroleum ether/ethyl acetate = 2:1, 50.8 mg, 63% yield;

mp 144−145 °C; H NMR (500 MHz, DMSO-d ) δ 8.65 (s,

MHz, CDCl ) δ 192.7, 190.4, 164.6, 145.3, 144.8, 143.3, 134.1,

H), 8.54 (s, 1H), 7.90−7.87 (m, 1H), 7.62−7.56 (m, 3H),

.54−7.49 (m, 2H), 7.43−7.40 (m, 1H), 7.36−7.32 (m, 2H),

132.1, 129.5, 129.4, 129.3, 128.5, 128.4, 128.4, 127.4, 126.0,

122.9, 113.8, 105.4, 104.0, 55.4; HRMS (ESI) m/z [M + H]

.28−7.23 (m, 2H), 7.07−7.01 (m, 2H); C{ H} NMR (125

calcd for C25

5R)-6-(3,4-Dimethoxybenzoyl)-5,8-dihydroxy-7-phenyl-

,8-dihydro-9H-5,8-epoxybenzo[7]annulen-9-one (3j): light

yellow solid, petroleum ether/ethyl acetate = 3:1, 95.4 mg,

H O 415.1176, found 415.1176.

19 6

(

MHz, DMSO-d ) δ 193.0, 190.3, 163.3, 161.3, 147.0, 146.8,

42.8, 135.5, 134.0, 133.3, 130.7, 130.6, 129.1, 129.0, 128.6,

27.2, 126.8, 126.5, 126.5, 123.4, 115.5, 115.3, 106.2, 103.8;

2% yield; mp 117−118 °C; H NMR (500 MHz, CDCl ) δ

HRMS (ESI) m/z [M + Na] calcd for C H FO Na

.09−8.06 (m, 1H), 7.45−7.40 (m, 3H), 7.24−7.21 (m, 2H),

.17−7.08 (m, 3H), 6.98−6.97 (m, 1H), 6.83−6.80 (m, 1H),

.42−6.40 (m, 1H), 6.31 (brs, 1H), 6.23 (brs, 1H), 3.74 (s,

25.0796, found 425.0796.

(

5R)-6-Benzoyl-7-(4-chlorophenyl)-5,8-dihydroxy-5,8-di-

hydro-9H-5,8-epoxybenzo[7]annulen-9-one (3e): light yel-

H), 3.57 (s, 3H); C{ H} NMR (125 MHz, CDCl ) δ 192.7,

low solid, petroleum ether/ethyl acetate = 2:1, 77.5 mg, 62%

190.3, 154.4, 148.7, 145.4, 144.8, 143.3, 134.2, 129.5, 129.4,

yield; mp 166−167 °C; H NMR (500 MHz, CDCl ) δ 8.10−

29.3, 128.4, 128.3, 127.3, 126.0, 125.4, 123.0, 110.7, 110.0,

.07 (m, 1H), 7.51−7.48 (m, 2H), 7.48−7.44 (m, 1H), 7.41−

.37 (m, 1H), 7.36−7.33 (m, 2H), 7.16−7.07 (m, 6H), 5.52

05.3, 104.0, 55.9, 55.5; HRMS (ESI) m/z [M + H] calcd for

(

_b_r_s_,₁_H₎_,₅_.₃₅₍_b_r_s_,₁_H₎_;₁3C{ H} NMR (125 MHz, CDCl )

C H O 445.1282, found 445.1282.

26 21 7

(

5R)-5,8-Dihydroxy-7-phenyl-6-(3,4,5-trimethoxybenzoyl)-

,8-dihydro-9H-5,8-epoxybenzo[7]annulen-9-one (3k): light

yellow solid, petroleum ether/ethyl acetate = 2:1, 81.1 mg,

δ 193.6, 190.8, 145.6, 144.7, 143.8, 135.7, 134.7, 134.6, 134.5,

29.8, 129.7, 129.3, 128.7, 128.7, 128.6, 128.0, 125.6, 123.1,

₀₄_.₉_,₁₀₃_.₈_;_H_R_M_S₍_E_S_I₎_m_/_z_[_M₊_N_a_]+ calcd for

4% yield; mp 161−162 °C; H NMR (500 MHz, DMSO-d )

C H ClO Na 441.0500, found 441.0500.

δ 8.59 (s, 1H), 8.54 (s, 1H), 7.94−7.92 (m, 1H), 7.61−7.56

(

5R)-6-Benzoyl-7-(4-bromophenyl)-5,8-dihydroxy-5,8-di-

(

m, 1H), 7.53−7.49 (m, 1H), 7.41−7.39 (m, 1H), 7.25−7.21

hydro-9H-5,8-epoxybenzo[7]annulen-9-one (3f): light yellow

13 1

m, 5H), 6.79 (s, 2H), 3.64 (s, 3H), 3.56 (s, 6H); C{ H}

solid, petroleum ether/ethyl acetate = 3:1, 54.7 mg, 59% yield;

NMR (125 MHz, DMSO-d ) δ 191.4, 190.6, 152.5, 147.1,

mp 166−167 °C; H NMR (500 MHz, CDCl ) δ 8.10−8.07

46.7, 143.4, 142.4, 133.5, 130.5, 130.4, 129.2, 129.1, 128.4,

(

m, 1H), 7.52−7.48 (m, 2H), 7.48−7.44 (m, 1H), 7.42−7.38

28.2, 127.3, 126.9, 123.4, 106.5, 106.1, 103.8, 60.1, 55.7;

m, 1H), 7.36−7.33 (m, 2H), 7.27−7.23 (m, 2H), 7.16−7.12

HRMS (ESI) m/z [M + Na] calcd for C H O Na 497.1207,

m, 2H), 7.05−7.01 (m, 2H), 5.51 (brs, 1H), 5.34 (brs, 1H);

found 497.1207.

5R)-6-(4-Fluorobenzoyl)-5,8-dihydroxy-7-phenyl-5,8-di-

C{ H} NMR (125 MHz, CDCl ) δ 193.7, 190.8, 145.5,

(

44.8, 143.7, 134.6, 134.6, 134.5, 131.7, 130.0, 129.7, 129.3,

hydro-9H-5,8-epoxybenzo[7]annulen-9-one (3l): light yellow

28.7, 128.6, 128.4, 125.6, 124.1, 123.1, 104.9, 103.8; HRMS

solid, petroleum ether/ethyl acetate = 3:1, 28.4 mg, 35% yield;

(

ESI) m/z [M + Na] calcd for C H BrO Na 484.9995,

mp 121−122 °C; H NMR (500 MHz, DMSO-d ) δ 8.63 (s,

found 484.9995.

H), 8.56 (s, 1H), 7.89−7.86 (m, 1H), 7.67−7.63 (m, 2H),

(

5R)-6-Benzoyl-7-(3-chlorophenyl)-5,8-dihydroxy-5,8-di-

.63−7.58 (m, 1H), 7.53−7.49 (m, 1H), 7.43−7.40 (m, 1H),

hydro-9H-5,8-epoxybenzo[7]annulen-9-one (3g): light yel-

.23−7.17 (m, 7H); C{ H} NMR (125 MHz, DMSO-d ) δ

low solid, petroleum ether/ethyl acetate = 3:1, 62.0 mg, 49%

91.6, 190.3, 166.3, 164.3, 146.9 (d, J = 47.3 Hz), 144.1, 133.4,

32.4 (d, J = 2.5 Hz), 132.1, (d, J = 9.8 Hz), 130.0, 129.2 (d, J

yield; mp 162−163 °C; H NMR (500 MHz, DMSO-d ) δ

.72 (s, 1H), 8.62 (s, 1H), 7.92−7.90 (m, 1H), 7.62−7.50 (m,

9.7 Hz), 128.4 (d, J = 2.3 Hz), 127.2, 126.9, 123.4, 115.8 (d,

H), 7.42−7.33 (m, 4H), 7.30−7.27 (m, 1H), 7.21−7.17 (m,

J = 22.3 Hz), 106.3, 103.8, 54.9; HRMS (ESI) m/z [M + Na]

H), 7.06−7.03 (m, 1H); C{ H} NMR (125 MHz, DMSO-

calcd for C H FO Na 425.0797, found 425.0797.

d ) δ 192.8, 190.2, 148.3, 146.8, 142.1, 135.4, 134.1, 133.4,

(5R)-6-(4-Chlorobenzoyl)-5,8-dihydroxy-7-phenyl-5,8-di-

hydro-9H-5,8-epoxybenzo[7]annulen-9-one (3m): light yel-

32.9, 132.0, 130.3, 129.2, 129.0, 128.6, 127.7, 127.3, 126.9,

26.7, 123.4, 106.1, 103.9; HRMS (ESI) m/z [M + Na] calcd

low solid, petroleum ether/ethyl acetate = 2:1, 104.0 mg, 83%

for C H ClO Na 441.0500, found 441.0500.

yield; mp 156−157 °C; H NMR (500 MHz, DMSO-d ) δ

(

5R)-5,8-Dihydroxy-6-(4-methylbenzoyl)-7-phenyl-5,8-di-

.61 (s, 1H), 8.55 (s, 1H), 7.89−7.86 (m, 1H), 7.63−7.56 (m,

hydro-9H-5,8-epoxybenzo[7]annulen-9-one (3h): light yel-

H), 7.53−7.48 (m, 1H), 7.45−7.40 (m, 3H), 7.24−7.16 (m,

low solid, petroleum ether/ethyl acetate = 3:1, 87.9 mg, 74%

H); C{ H} NMR (125 MHz, DMSO) δ 191.9, 190.2,

yield; mp 164−165 °C; H NMR (500 MHz, DMSO-d ) δ

147.0, 146.5, 144.5, 138.8, 134.4, 133.4, 130.8, 129.9, 129.3,

29.1, 128.7, 128.4, 128.3, 127.2, 126.8, 123.4, 106.3, 103.7;

.56 (s, 1H), 8.47 (s, 1H), 7.91−7.89 (m, 1H), 7.59−7.55 (m,

H), 7.52−7.48 (m, 3H), 7.38−7.35 (m, 1H), 7.25−7.21 (m,

HRMS (ESI) m/z [M + Na] calcd for C H ClO Na

H), 7.21−7.17 (m, 3H), 7.16−7.13 (m, 2H), 2.27 (s, 3H);

41.0497, found 441.0499.

(5R)-6-(2-Naphthoyl)-5,8-dihydroxy-7-phenyl-5,8-dihy-

dro-9H-5,8-epoxybenzo[7]annulen-9-one (3n): light yellow

C{ H} NMR (125 MHz, DMSO-d ) δ 192.7, 190.5, 147.1,

47.1, 144.7, 142.6, 133.3, 133.1, 130.2, 129.2, 129.1, 129.0,

28.3, 128.1, 127.2, 126.9, 123.3, 106.3, 103.8, 21.2; HRMS

solid, petroleum ether/ethyl acetate = 2:1, 81.3 mg, 62% yield;

(

ESI) m/z [M + Na] calcd for C H O Na 421.1046, found

mp 165−166 °C; H NMR (500 MHz, DMSO-d ) δ 8.65 (s,

21.1046.

1H), 8.59 (s, 1H), 8.01−7.96 (m, 2H), 7.93−7.88 (m, 2H),

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

https://pubs.acs.org/doi/10.1021/acs.joc.1c01648.

Article

.78−7.74 (m, 2H), 7.65−7.60 (m, 1H), 7.58−7.51 (m, 3H),

2.18−2.11 (m, 1H), 1.88−1.81 (m, 1H), 1.13−1.03 (m, 2H),

0.99−0.88 (m, 3H), 0.84−0.79 (m, 2H), 0.69−0.64 (m, 1H),

.42−7.39 (m, 1H), 7.30−7.27 (m, 2H), 7.17−7.09 (m, 3H);

C{ H} NMR (125 MHz, DMSO-d ) δ 192.9, 190.5, 147.3,

0.62 (t, J = 7.5 Hz, 3H); C{ H} NMR (125 MHz, DMSO-

^d6⁾^δ¹⁹²^.⁵^,¹⁹⁰^.⁷^,¹⁵⁰^.⁰^,¹⁴⁷^.⁹^,¹⁴⁵^.⁴^,¹³⁷^.⁴^,¹³³^.⁷^,¹³³^.⁰^,

47.1, 143.6, 135.3, 133.4, 132.9, 132.3, 131.6, 130.3, 129.5,

29.2, 129.0, 128.4, 128.3, 128.2, 127.7, 127.3, 127.1, 127.0,

23.4, 123.4, 106.4, 103.9; HRMS (ESI) m/z [M + Na] calcd

28.9, 128.7, 128.6, 127.2, 126.5, 123.8, 106.0, 104.1, 30.3,

7.8, 26.3, 25.3, 21.6, 13.6; HRMS (ESI) m/z [M + Na] calcd

for C H O Na 415.1516, found 415.1520.

for C H O Na 457.1046, found 457.1046.

24 24

(

5R)-5,8-Dihydroxy-7-phenyl-6-pivaloyl-5,8-dihydro-9H-

(5R)-6-(Furan-2-carbonyl)-5,8-dihydroxy-7-phenyl-5,8-di-

,8-epoxybenzo[7]annulen-9-one (3t): yellow liquid, petro-

leum ether/ethyl acetate = 4:1, 71.9 mg, 66%); H NMR (500

hydro-9H-5,8-epoxybenzo[7]annulen-9-one (3o): white

solid, petroleum ether/ethyl acetate = 1:1, 79.5 mg, 71%

MHz, DMSO-d ) δ 8.44 (s, 1H), 7.40 (s, 1H), 7.86−7.84 (m,

yield; mp 159−160 °C; H NMR (500 MHz, CDCl ) δ 8.07−

H), 7.66−7.62 (m, 1H), 7.53−7.49 (m, 1H), 7.42−7.40 (m,

.04 (m, 1H), 7.52−7.44 (m, 3H), 7.33−7.31 (m, 1H), 7.24−

.16 (m, 5H), 6.34−6.33 (m, 1H), 6.16−6.15 (m, 1H), 5.73

H), 7.37−7.33 (m, 3H), 7.22−7.18 (m, 2H), 0.80 (s, 9H);

brs, 1H), 5.57 (brs, 1H); ¹³C{ H} NMR (125 MHz, CDCl )

C{ H} NMR (125 MHz, DMSO-d ) 211.3, 191.1, 150.0,

(

47.5, 140.1, 133.7, 131.8, 129.6, 129.6, 128.9, 128.6, 127.6,

δ 190.6, 179.7, 150.9, 148.5, 145.9, 145.5, 143.8, 134.3, 129.7,

27.4, 123.7, 106.8, 104.2, 44.4, 26.7; HRMS (ESI) m/z [M +

29.6, 129.5, 128.5, 128.5, 128.4, 125.7, 123.0, 122.2, 112.7,

05.2, 103.8; HRMS (ESI) m/z [M + Na]⁺calcd for

Na] calcd for C H O Na 387.1203, found 387.1209.

22 20

Methyl (5R)-5,8-Dihydroxy-9-oxo-7-phenyl-8,9-dihydro-

H-5,8-epoxybenzo[7]annulene-6-carboxylate (3u): light

C H O Na 397.0683, found 397.0683.

(

5R)-5,8-Dihydroxy-6-(4-methylbenzoyl)-7-(thiophen-2-

yellow solid, petroleum ether/ethyl acetate = 4:1, 44.5 mg,

yl)-5,8-dihydro-9H-5,8-epoxybenzo[7]annulen-9-one (3p):

light yellow solid, petroleum ether/ethyl acetate = 2:1, 75.4

4% yield; mp 165−166 °C; H NMR (500 MHz, DMSO-d )

δ 8.52 (s, 1H), 8.40 (s, 1H), 7.87−7.84 (m, 1H), 7.67−7.62

mg, 62% yield; mp 117−118 °C; H NMR (500 MHz, DMSO-

(

m, 1H), 7.59−7.57 (m, 1H), 7.52−7.47 (m, 1H), 7.45−7.41

d ) δ 8.79 (s, 1H), 8.45 (s, 1H), 7.85−7.83 (m, 1H), 7.72−

13 1

m, 2H), 7.39−7.35 (m, 3H), 3.59 (s, 3H); C{ H} NMR

.69 (m, 2H), 7.63−7.59 (m, 1H), 7.53−7.47 (m, 2H), 7.43−

125 MHz, DMSO-d ) 190.7, 163.6, 148.7, 146.9, 140.3,

.40 (m, 1H), 7.29−7.27 (m, 2H), 7.24−7.22 (m, 1H), 6.94−

_.₉₂₍_m_,₁_H₎_,₂_.₃₄₍_s_,₃_H₎_;1 C{ H} NMR (125 MHz,

133.4, 130.3, 129.4, 129.0, 128.7, 128.0, 127.0, 126.8, 123.7,

06.0, 102.9, 51.8; HRMS (ESI) m/z [M + Na] calcd for

DMSO-d ) δ 192.6, 189.7, 147.5, 145.0, 143.5, 136.8, 133.4,

C H O Na 361.0683, found 361.0681.

³³^.²^,¹³⁰^.⁸^,¹³⁰^.²^,¹³⁰^.¹^,¹²⁹^.⁴^,¹²⁹^.³^,¹²⁹^.⁰^,¹²⁷^.⁴^,¹²⁷^.⁰+^,

8-(4-Methylbenzoyl)-7-phenyl-6-((2,2,6,6-tetramethylpi-

peridin-1-yl)oxy)-5H-benzo[7]annulene-5,9(6H)-dione (4h):

26.8, 123.5, 105.9, 104.2, 21.3; HRMS (ESI) m/z [M + H]

calcd for C H O S 405.0792, found 405.0792.

light yellow solid, petroleum ether/ethyl acetate = 20:1, 47.1

(

5R)-5,8-Dihydroxy-7-(p-tolyl)-6-(1-tosyl-1H-pyrrole-2-car-

bonyl)-5,8-dihydro-9H-5,8-epoxybenzo[7]annulen-9-one

3q): light yellow solid, petroleum ether/ethyl acetate = 2:1,

mg, 45% yield; mp 108−109 °C; H NMR (500 MHz,

CDCl3) δ 8.03−8.00 (m, 1H), 7.93−7.91 (m, 1H), 7.74−7.64

(

m, 2H), 7.60−7.58 (m, 2H), 7.42−7.40 (m, 2H), 7.24−7.22

m, 3H), 7.07−7.05 (m, 2H), 5.22 (s, 1H), 2.30 (s, 3H),

2.8 mg, 45% yield; mp 187−188 °C; H NMR (500 MHz,

CDCl ) δ 8.07−8.04 (m, 1H), 7.87−7.84 (m, 2H), 7.60−7.58

.52−1.49 (m, 1H), 1.39−1.35 (m, 2H), 1.34 (s, 3H), 1.07 (s,

(

m, 1H), 7.46−7.39 (m, 2H), 7.37−7.35 (m, 2H), 7.29−7.27

13 1

H), 0.85 (s, 3H), 0.56 (s, 3H); C{ H} NMR (125 MHz,

m, 1H), 7.06−7.04 (m, 2H), 6.96−6.93 (m, 2H), 5.78−5.76

CDCl3) δ 194.9, 193.1, 190.9, 146.0, 144.4, 143.8, 137.6,

m, 1H), 5.56−5.54 (m, 1H), 2.47 (s, 3H), 2.24 (s, 3H);

35.2, 134.0, 133.3, 133.2, 132.5, 129.5, 129.4, 129.4, 129.3,

29.2, 128.6, 128.5, 96.9, 60.6, 60.2, 39.8, 39.7, 33.8, 33.2, 21.6,

1.1, 20.4, 16.8; HRMS (ESI) m/z [M + H] calcd for

C{ H} NMR (125 MHz, CDCl ) δ 190.2, 180.0, 145.5,

45.4, 145.3, 143.1, 139.8, 135.0, 134.0, 131.8, 131.7, 129.5,

29.5, 129.1, 128.7, 128.7, 128.5, 127.6, 126.2, 125.9, 122.9₊,

10.8, 105.2, 103.8, 21.7, 21.3; HRMS (ESI) m/z [M + Na]

C H NO 522.2639, found 522.2639.

calcd for C H NO SNa 497.1207, found 497.1207.

ASSOCIATED CONTENT

sı Supporting Information

The Supporting Information is available free of charge at

■

(5R)-6-Benzoyl-7-butyl-5,8-dihydroxy-5,8-dihydro-9H-5,8-

epoxybenzo[7]annulen-9-one (3r): light yellow solid, petro-

leum ether/ethyl acetate = 4:1, 42.9 mg, 39% yield; mp 168−

69 °C; H NMR (500 MHz, DMSO-d ) δ 8.25 (s, 1H), 8.21

Experimental procedures, characterization data, and

spectra of new compounds (PDF)

(

s, 1H), 7.83−7.81 (m, 1H), 7.74−7.72 (m, 2H), 7.69−7.65

m, 1H), 7.63−7.59 (m, 1H), 7.57−7.52 (m, 3H), 7.49−7.44

m, 1H), 2.16−2.10 (m, 1H), 1.88−1.81 (m, 1H), 1.12−1.03

m, 1H), 0.99−0.89 (m, 1H), 0.75−0.65 (m, 2H), 0.46 (t, J =

Accession Codes

CCDC 2080094 contains the supplementary crystallographic

data for this paper. These data can be obtained free of charge

via www.ccdc.cam.ac.uk/data_request/cif , or by emailing

data_request@ccdc.cam.ac.uk , or by contacting The Cam-

bridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

.5 Hz, 3H); C{ H} NMR (125 MHz, DMSO-d ) δ 193.1,

91.2, 150.4, 148.4, 145.8, 137.8, 134.2, 133.5, 129.4, 129.2,

29.1, 127.6, 127.0, 124.2, 106.5, 104.6, 29.0, 25.6, 21.9, 13.5;

HRMS (ESI) m/z [M + Na] calcd for C H O Na 387.1203,

found 387.1207.

5R)-6-Benzoyl-7-hexyl-5,8-dihydroxy-5,8-dihydro-9H-5,8-

(

epoxybenzo[7]annulen-9-one (3s): brown solid, petroleum

AUTHOR INFORMATION

Corresponding Author

■

ether/ethyl acetate = 4:1, 37.6 mg, 32% yield; mp 88−89 °C;

H NMR (500 MHz, DMSO-d ) δ 8.25 (s, 1H), 8.21 (s, 1H),

Yanzhong Li − School of Chemistry and Molecular

Engineering, East China Normal University, Shanghai

200241, China; Key Laboratory of Polar Materials and

.83−7.81 (m, 1H), 7.75−7.72 (m, 2H), 7.69−7.64 (m, 1H),

.63−7.59 (m, 1H), 7.56−7.52 (m, 3H), 7.48−7.44 (m, 1H),

J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry

Kirchhoefer, P. Asymmetric Organocatalysis of 4 + 3 Cycloaddition

Article

Devices, Ministry of Education, Shanghai 200241, China;

orcid.org/0000-0002-2898-3075; Email: yzli@

chem.ecnu.edu.cn

(d) Harmata, M.; Ghosh, S. K.; Hong, X.; Wacharasindhu, S.;

Reactions. J. Am. Chem. Soc. 2003 , 125 , 2058 −2059. (e) Lo, B.; Lam,

S.; Wong, W. T.; Chiu, P. Asymmetric (4 + 3) cycloadditions of

enantiomerically enriched epoxy enolsilanes. Angew. Chem., Int. Ed.

Authors

012 , 51 , 12120 −12123. (f) Hartung, I. V.; Hoffmann, H. M. R. 8-

Mengdan Wang − School of Chemistry and Molecular

Engineering, East China Normal University, Shanghai

Oxabicyclo[3.2.1]oct-6-en-3-ones: Application to the Asymmetric

Synthesis of Polyoxygenated Building Blocks. Angew. Chem., Int. Ed.

00241, China; orcid.org/0000-0002-9840-5924

004, 43, 1934−1949. (g) Di, X.; Wang, Y.; Wu, L.; Zhang, Z. M.;

Liqiang Yin − School of Chemistry and Molecular Engineering,

East China Normal University, Shanghai 200241, China

Lu Cheng − School of Chemistry and Molecular Engineering,

East China Normal University, Shanghai 200241, China

Yajie Yang − School of Chemistry and Molecular Engineering,

East China Normal University, Shanghai 200241, China;

orcid.org/0000-0002-3782-1131

Dai, Q.; Li, W.; Zhang, J. Enantioselective Gold(I)-Catalyzed

Heterocyclization-Intermolecular Exo [4 + 3]-Cycloaddition Reac-

tions for the Synthesis of Chiral Oxa-Bridged Benzocycloheptanes.

Org. Lett. 2019, 21, 3018−3022.

3) (a) Molander, G. A.; Cameron, K. O. A novel concept for

regiochemical and stereochemical control in Lewis acid promoted [3

+ 4] annulation reactions. J. Org. Chem. 1991 , 56 , 2617 −2619.

b) Molander, G. A.; Cameron, K. O. Neighboring group

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c01648

participation in Lewis acid-promoted [3 + 4] and [3 + 5] annulations.

The synthesis of oxabicyclo[3.n.1]alkan-3-ones. J. Am. Chem. Soc.

4) (a) Iwasawa, N.; Shido, M.; Kusama, H. Generation and

993, 115, 830−846.

Author Contributions

M.W. and L.Y. contributed equally to this work.

Notes

∥

Reaction of Metal-Containing Carbonyl Ylides: Tandem [3 + 2]-

Cycloaddition-Carbene Insertion Leading to Novel Polycyclic

Compounds. J. Am. Chem. Soc. 2001 , 123 , 5814 −5815. (b) Burns,

N. Z.; Witten, M. R.; Jacobsen, E. N. Dual catalysis in enantioselective

oxidopyrylium-based [5 + 2] cycloadditions. J. Am. Chem. Soc. 2011 ,

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

We thank the National Natural Science Foundation of China (

1871087) and the Open Research Fund of Key Laboratory of

■

33 , 14578 −14581. (c) Witten, M. R.; Jacobsen, E. N. Catalytic

asymmetric synthesis of 8-oxabicyclooctanes by intermolecular [5 +

] pyrylium cycloadditions. Angew. Chem., Int. Ed. 2014, 53, 5912−

5916.

(5) (a) Jimenez-Nun

Polar Materials and Devices, Ministry of Education for

ﬁnancial support.

ez, E.; Claverie, C. K.; Nieto-Oberhuber, C.;

Echavarren, A. M. Prins Cyclizations in Au-Catalyzed Reactions of

Enynes. Angew. Chem., Int. Ed. 2006, 45, 5452 −5455. (b) Oh, C. H.;

Lee, J. H.; Lee, S. J.; Kim, J. I.; Hong, C. S. Intramolecular Huisgen-

Type Cyclization of Platinum-Bound Pyrylium Ions with Alkenes and

Subsequent Insertion into a Benzylic C-H Bond. Angew. Chem., Int.

Ed. 2008 , 47 , 7505 −7507. (c) Oh, C. H.; Yi, H. J.; Lee, J. H.; Lim, D.

H. Stereocontrolled synthesis of oxygen-bridged polycycles via

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alkenes. Chem. Commun. 2010 , 46 , 3007 −3009. (d) Li, B.; Zhao, Y. J.;

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