Copper-Catalyzed [2 + 2 + 3] Annulation of 1,6-Enynes with α-Bromo-1,3-Dicarbonyl Compounds: Synthesis of Dihydrooxepines

Article abstract of DOI:10.1021/acs.joc.7b00879

Copper-catalyzed [2 + 2 + 3] annulation of 1,6-enynes with α-bromo-1,3-dicarbonyl compounds is described. This reaction provides facile access to seven-membered dihydrooxepines for epidithiodiketopiperazines with two newly formed C-C bonds and one C-O bon

Full text of DOI:10.1021/acs.joc.7b00879

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Note
Copper-Catalyzed [2+2+3] Annulation of 1,6-Enynes with #-
Bromo-1,3-Dicarbonyl Compounds: Synthesis of Dihydrooxepines
Lan Zheng, and Yong-Min Liang
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 07 Jun 2017
Downloaded from http://pubs.acs.org on June 7, 2017
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Copper-Catalyzed
[2+2+3]
Annulation
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with
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α-Bromo-1,3-Dicarbonyl Compounds: Synthesis of Dihydrooxepines
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Lan Zheng, † and Yong‐Min Liang*†‡
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†State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P.R. China
E‐mail: liangym@lzu.edu.cn
‡State Key Laboratory of Solid Lubrication, Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou, 730000, P.R. China
Abstract: A copper‐catalyzed [2+2+3] annulation of 1,6‐enynes with α‐bromo‐1,3‐dicarbonyl
compounds is described. This reaction provides a facile access to seven‐membered
dihydrooxepines for epidithiodiketopiperazines (ETPs) with newly formed two C‐C bonds and one
C‐O bond.
The seven‐membered dihydrooxepine subunit is found in a wide variety of nature products,
in which epidithiodiketopiperazines (ETPs) have generally attracted much attention from many
research groups for valuable synthetic significance.1 Classical ETPs, such as, (–)‐emethallicin A
(1),2 acetylapoaranotin (2),3 (–)‐acetylaranotin (3),4 (–)‐SCH 64874 (4),5 hirsutellomycin (5),6
(+)‐MPC 1001 (6),7 and (+)‐Emestrin (7)8 are recognized as biological properties relevant to the
treatment of cancer cell line and strong antifungal activities (Figure 1). In these reports, the
synthesis of dihydrooxepines subunit generally needs several steps from commercially available
starting materials. The further interest in new routes to construct dihydrooxepines ring system
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further stimulates studies in this area.
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Figure 1. Representative Active Molecule Possessing Dihydrooxepine Moiety.
The construction of C‐O bond is one of the most widely used methods in producing
alcohols, ethers, and esters for the synthesis of biologically active molecules, materials, and
natural products.9 In recent years, great progress has been made in C‐O bond formation from
carbon‐halide bonds which is limited by tedious prefunctionalization of substrates10 or reductive
elimination from PdIV species.11 Most widely used traditional atom‐economical method to
prepare oxygen‐containing heterocycles is the catalytic hydroalkoxylation of alkenes or alkynes,
which remains a challenge due to the relatively high bond enthalpies of most O‐H bonds and the
modest reactivity of electron‐rich olefins with nucleophiles.12 Additionally, 1,3‐dicarbonyl
compounds are usually employed to build C‐O bonds with alkynes, functional olefins13 or
cinnamaldehyde14 for the synthesis of furans or dihydropyranones, respectively.
Seven‐membered lactone was produced through cascade esterification‐alkylation reaction in the
presence of copper(I)‐TPMA catalyst system followed by hydrolysis to give various Z‐olefin
compounds.15 To the best of our knowledge, despite that the C‐O bond formation has been
widely used in nature products synthesis, a convenient route to construct C‐O bond in
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seven‐membered dihydrooxepines is scarcely reported.16 In present work, an atom‐economical
approach to seven‐membered dihydrooxepines unit with new C‐O bond formation via radical
annulation of 1,6‐enynes 1 with α‐bromo‐1,3‐dicarbonyl compounds 2 is described. In this
reaction, a new type of the formation of C(sp2)‐O bond in the seven‐membered dihydrooxepines
is presented through enolate coupling with vinylic bromide in the presence of Cu‐catalyst.
By taking consideration of catalytic ability of copper complexes17 in the enyne‐cyclization,
we started to explore the possibility of copper catalyst for this enyne radical cyclization to give
seven‐membered heterocycles. The treatment of 1,6‐enynes 1a with 2‐bromo keto esters 2a in
the presence of CuCl (10 mol %) and Na2CO3 (2.5 equiv) in DCE at 120 °C under N2 for 24 h, gave
the desired product 3a smoothly in 24% yield (Table 1, entry 1, for details in the Supporting
Information). A short survey on solvents showed that toluene was the most efficient one (entries
2‐5). And Cu(CH3CN)4ClO4 performed with a slight advantage than other Cu salt (entries 6‐15).
Base played an important role in this reaction: DBU, CsF, and t‐BuOLi, were totally inactive
whereas NaOAc, NaHCO3, Na2CO3 showed positive effects (entries 17‐23). Both Cu and base were
necessary for this transformation (entries 16, 24). When one and a half equivalents NaHCO3 were
added to the reaction system, a yield of 48% was achieved (entry 25). To our delight, the addition
of diisopropyl azodicarboxylate (DIAD) or diethyl azodicarboxylate (DEAD) could be benifted for
this reaction as a reagent to promote the regeneration of Cu(I) species18 (entries 26‐27). The
reaction could not to be carried out at other temperature as efficiently as 120 °C (entries 28‐31).
The increase of Na2CO3 or NaHCO3 to 4.0 equivalents led to a similar effect compared to a
mixture of those two bases (entries 32‐33). Since CO2 would be released from NaHCO3 at 120 °C,
Na2CO3 was identified as the best chioce.
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Reaction conditions: 1 (0.2 mmol), 2a (0.5 mmol), Cu(CH3CN)4ClO4 (10 mol %), Na2CO3 (4.0 equiv), DIAD (10 mol %),
toluene (2 mL), 120 °C, 24 h, under N2.
Scheme 1. Reaction of 1,6-Enynes 1 with 2-Bromo-3-oxobutanoate 2a.
With the optimal reaction conditions in hand, the scope of 1,6‐enyne substrates was then
investigated. As shown in Scheme 1, malonate‐tethered enynes with several substituents, such as,
Br, Cl, CN, Ph, and OMe on para position of aromatic ring were well‐tolerated, and gave desired
products 3b‐3f in good yields. A key character is that the electron‐withdrawing groups showed
more compatibilities. Enynes bearing two substituent groups on the aryl were proceeded
smoothly to afford the corresponding products 3g–3j in this transformation. Moreover, the
reaction of ester‐tethered 1,6‐enynes with 2‐bromo‐3‐oxobutanoate would lead to respective
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product under the optimized conditions in excellent yields (3k‐3p). The N‐tethered 1,6‐enynes
gave declined yields due to slight decomposition as observation (3q‐3u). Gratifyingly, the
aliphatic 1,6‐enynes showed compatibility to this transformation and gave desired products in
satisfactory yields (3v‐3x). When no methyl substituent was connected with the vinyl moiety,
there was only trace for the desired product 3y. Either Ph or CO2Et substituent enynes had
slightly lower yield than the methyl substituent one (3z‐3ab). The structure of 3a and 3r were
confirmed by X‐ray crystal structure analysis.19
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Reaction conditions: 1a (0.2 mmol), 2 (0.5 mmol), Cu(CH3CN)4ClO4 (10 mol %), Na2CO3 (4.0 equiv), DIAD (10 mol %),
toluene (2 mL), 120 °C, 24 h, under N2.
Scheme 2. Reaction of 1a with α-Bromo-1,3-Dicarbonyl Compounds 2.
Next, the scope of the α‐bromo‐1,3‐dicarbonyl compounds 2 was examined (Scheme 2).
Under the standard conditions, alkyl‐substituted α‐bromo‐1,3‐dicarbonyl compounds underwent
this radical cyclization with ester‐tethered enyne 1k smoothly providing the cyclic products in
good yields (3ac‐3ag). Similarly, chloroethane substituted keto esters also furnished the reaction
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in 41% yield (3ah). Substituted α‐bromo‐1,3‐dicarbonyl compounds of propylene lowered the
efficiency of this transformation, and 3ai was produced in 72% yield. Product 3aj could be
obtained by using α‐bromo‐1,3‐indanedione through annulation in morderate yields, which was
confirmed by X‐ray crystal structure analysis.19 It was showed low yield when enyne reacted with
3‐bromopentane‐2,4‐dione due to unstabled than other (3ak).
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Scheme 3. Investingation for Reaction Mechanism.
To gain further mechanistic insights for this reaction, some necessary control experiments
were carried out (Scheme 3). The reaction was absolutely suppressed by the radical scavenger of
TEMPO (2,2,6,6‐tetramethyl‐1‐piperidinyloxy). When BHT (2,6‐di‐tert‐butyl‐4‐methyl‐phenol) was
added into the optimal conditions, the desired product was obtained in a very low yield. These
results suggested that the reaction may proceed through a free‐radical pathway. When ethyl
2‐bromo‐2‐methyl‐3‐oxobutanoate was employed, the enyne 1k was recovered in 83% yield,
indicated that the proton is necessary in this reaction.
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Scheme 4. Plausible Mechanism.
On the basis of the present results, a plausible mechanistic for this reaction is proposed in
Scheme 4. Initially, radical intermediate A is formed via the activation of 2‐bromo keto esters in
the present of Cu(I) speices. The addition of intermediate A to 1,6‐enynes 1 generated
intermediate B, followed by cyclization with C‐C triple bond to afford the alkene adduct C. The
intermediate C undergoes 7‐endo‐trig annulation to afford intermediate D.20 Then D is oxidized
by copper catalyst to offord the oxonium cation E with DIAD as the reducing regent for the
regeneration of Cu(I) species.18,21 Finally, deprotonation of E gave the radical cyclization product
3.21
In conclusion, we have accomplished a Cu‐catalyzed [2+2+3] annulation of 1,6‐enynes with
α‐bromo‐1,3‐dicarbonyl compounds for the synthesis of dihydrooxepines, in which two new C‐C
bonds and one C‐O bond were formed through radical process in one step. The seven‐membered
dihydrooxepine is indentified to be significant scaffold in the epidithiodiketopiperazines and
widely existed in a class of important natural products. Further inverstigations on the mechanistic
pathway and the synthesis of backbones for some important natural products are underway in
our laboratory and will be reported elsewhere.
Experimental Section
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General Methods. Unless otherwise noted, reactions were carried out under an argon
atmosphere. For Column chromatography, 200‐300 mesh silica gel was employed. Analytical TLC
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was performed with silica gel GF254 plates. H NMR (400 MHz) and 13C NMR (100 MHz) were
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recorded in CDCl3 using TMS as internal standard. 1H NMR spectra were recorded on 400 MHz in
CDCl3 and 13C NMR spectra were recorded on 100 MHz 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), dq (doublet of quartets), q (quartet)
or m (multiplet). HR‐MS was obtained using a Q‐TOF instrument equipped with ESI source. Data
collections for crystal structure were performed at room temperature (293 K) using MoKα
radiation on a Bruker APEXII diffractometer. All compounds were copies of their 1H NMR and 13
C
NMR spectra are provided in the Supporting Information.
General Procedures for the Synthesis of Substrate 1.
All of 1,6‐enynes were synthesized according to the previous literatures, and the NMR
spectroscopy and GC‐MS data were in full accordance with the data in the reported literatures.22
To a solution of 4‐methyl‐N‐(prop‐2‐ynyl)benzenesulfonamide (1.0 mmol) in CH2Cl2 (5 mL)
was added iPr2NEt (1.5 mmol) and then cooled to 0 °C in the ice water bath. Methacryloyl
chloride (1.2 mmol) was slowly added to the solution at 0 °C and then the mixture was stirred at
room temperature for 1 h. The reaction was quenched by water and the aqueous layer was
extracted with CH2Cl2 (10 mL x 3). The combined organic layers were washed with brine, dried
over Na2SO4 and concentrated in vacuo. The residue was purified by flash column
chromatography to afford product C as a white solid.
To a dried schlenk flask was added Pd(PPh3)2Cl2 (0.2 mmol), CuI (0.2 mmol), Iodobenzene
(11.0 mmol), C (10.0 mmol) and freshly distilled Et3N under argon. The resulting mixture was
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stirred for 16 h at 50 °C. 50 mL of MTBE were added and the mixture filtered. After removal of
solvent using rotary evaporator, the residue was purified by flash column chromatography to
afford 1.
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General Procedures for the Synthesis of the Products 3.
In an oven‐dried tube, enynes 1 (0.2 mmol), Cu(CH3CN)4ClO4 (10 mol %), and Na2CO3 (0.8
mmol) were added and charged with nitrogen more than three times. α‐bromo‐1,3‐dicarbonyl
compounds 2 (0.5 mmol) and toluene (2.0 mL) were added and the DIAD (10 mol %) was
subsequent injected into the tube. Afterwards, the mixture was allowed to stir at 120 °C for 24 h.
When the reaction was considered complete, the solvent was removed under vacuo, and the
residue was purified with chromatography column (PE‐EtOAc, 10:1) on silica gel and recrystallized
to afford the product 3.
4‐ethyl 7,7‐dimethyl 3,5a‐dimethyl‐1‐phenyl‐5a,6‐dihydro‐5H‐cyclopenta[c]oxepine‐4,7,7
1
(8H)‐tricarboxylate (3a); (54.0 mg, 63% yield); yellow solid; mp 110‐112°C; H NMR (400 MHz,
CDCl3, δ ppm): 1.26 (s, 3H), 1.30 (t, J = 7.2Hz, 3H), 2.25 (d, J = 1.2 Hz, 3H), 2.39‐2.46 (m, 2H),
2.55 (d, J = 15.2 Hz, 1H), 2.74 (d, J = 15.2 Hz, 1H), 3.01 (d, J = 16.4 Hz, 1H), 3.26 (d, J = 16.0 Hz, 1H),
3.67 (s, 3H), 3.74 (s, 3H), 4.17‐4.22 (m, 2H), 7.28‐7.33 (m, 1H), 7.35‐7.40 (m, 4H); 13C NMR (100
MHz, CDCl3, δ ppm): 172.3, 172.1, 169.5, 162.3, 145.4, 137.0, 128.2, 128.0, 127.6, 110.0, 60.4,
57.7, 52.9, 52.8, 48.8, 44.0, 39.9, 39.5, 25.5, 22.0, 14.3; HRMS (ESI‐TOF) m/z: [M + Na]+ Calcd for
C24H28O7Na 451.1727; Found 451.1733.
4‐ethyl 7,7‐dimethyl 1‐(4‐bromophenyl)‐3,5a‐dimethyl‐5a,6‐dihydro‐5H‐cyclopenta[c]
oxepine‐4,7,7(8H)‐tricarboxylate (3b); (73.8 mg, 73% yield); yellow oil; 1H NMR (400 MHz, CDCl3,
δ ppm): 1.24 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H), 2.23 (d, J = 1.2 Hz, 3H), 2.42 (dd, J = 13.6, J = 23.2 Hz,
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2H), 2.54 (d, J =16.0 Hz, 1H), 2.74 (d, J = 15.2 Hz, 1H), 2.95 (d, J = 16.0 Hz, 1H), 3.23 (d, J = 16.4 Hz,
1H), 3.68 (s, 3H), 3.74 (s, 3H), 4.19 (q, J = 7.2 Hz, 2H), 7.26 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz,
2H); 13C NMR (100 MHz, CDCl3, δ ppm): 172.1, 172.0, 169.3, 162.1, 144.3, 135.8, 131.1, 129.8,
128.2, 122.0, 110.2, 60.5, 57.6, 52.9, 52.9, 48.6, 44.1, 39.7, 39.5, 25.4, 21.9, 14.2; HRMS (ESI‐TOF)
m/z: [M + Na]+ Calcd for C24H27BrO7Na 529.0832; Found 529.0838.
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4‐ethyl 7‐methyl 7‐acetoxy‐1‐(4‐chlorophenyl)‐3,5a‐dimethyl‐5a,6,7,8‐tetrahydro‐5H‐
cyclopenta‐[c]oxepine‐4,7‐dicarboxylate (3c): (61.9 mg, 67% yield); yellow oil; 1H NMR (400 MHz,
CDCl3, δ ppm): 1.24 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H), 2.23 (d, J = 1.2 Hz, 3H), 2.37‐2.46 (m, 2H), 2.54
(d, J = 15.2 Hz, 1H), 2.74 (d, J = 15.2 Hz, 1H), 2.96 (d, J = 16.0 Hz, 1H), 3.23 (d, J = 16.0 Hz, 1H),
3.68 (s, 3H), 3.74 (s, 3H), 4.17‐4.22 (m, 2H), 7.32 (s, 4H); 13C NMR (100 MHz, CDCl3, δ ppm): 172.2,
172.0, 169.4, 162.1, 144.3, 135.4, 133.8, 129.6, 128.2, 128.0, 110.2, 60.5, 57.6, 53.0, 52.9, 48.7,
44.1, 39.8, 39.5, 25.4, 22.0, 14.2; HRMS (ESI‐TOF) m/z: [M + Na]+ Calcd for C24H27ClO7Na 485.1338;
Found 485.1345.
4‐ethyl 7‐methyl 7‐acetoxy‐1‐(4‐cyanophenyl)‐3,5a‐dimethyl‐5a,6,7,8‐tetrahydro‐5H‐
cyclopenta[c]oxepine‐4,7‐dicarboxylate (3d): (44.4 mg, 49% yield); yellow solid; mp 118‐120°C; 1H
NMR (400 MHz, CDCl3, δ ppm): 1.27 (s, 3H), 1.29‐1.32 (m, 3H), 2.25 (s, 3H), 2.44 (dd, J = 13.6 Hz, J
= 35.2 Hz, 2H), 2.54 (d, J = 15.6 Hz, 1H), 2.75 (d, J = 15.2 Hz, 1H), 2.98 (d, J = 16.0 Hz, 1H), 3.25 (d,
J = 16.0 Hz, 1H), 3.69 (s, 3H), 3.75 (s, 3H), 4.20 (q, J = 7.2 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.66 (d, J
= 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3, δ ppm): 171.9, 171.8, 169.1, 161.8, 143.6, 141.2, 131.8,
130.5, 128.7, 118.5, 111.5, 110.6, 60.5, 57.6, 52.9, 52.9, 48.5, 44.4, 39.6, 39.4, 25.3, 21.8, 14.2;
HRMS (ESI‐TOF) m/z: [M + Na]+ Calcd for C25H27NO7Na 476.1680; Found 476.1682.
4‐ethyl 7‐methyl 1‐([1,1'‐biphenyl]‐4‐yl)‐7‐acetoxy‐3,5a‐dimethyl‐5a,6,7,8‐tetrahydro‐5H‐
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cyclopenta[c]oxepine‐4,7‐dicarboxylate (3e): (51.0 mg, 51% yield); white solid; mp 122‐125°C; 1H
NMR (400 MHz, CDCl3, δ ppm): 1.28 (s, 3H), 1.28‐1.32 (m, 3H), 2.28 (s, 3H), 2.44 (dd, J = 13.6 Hz, J
= 18.0 Hz, 2H), 2.58 (d, J = 15.2 Hz, 1H), 2.75 (d, J = 15.2 Hz, 1H), 3.07 (d, J = 15.2 Hz, 1H), 3.32 (d,
J = 16.4 Hz, 1H), 3.68 (s, 3H), 3.74 (s, 3H), 4.17‐4.23 (m, 2H), 7.34 (t, J = 7.2 Hz, 1H), 7.44 (dd, J =
8.0 Hz, J = 14.8 Hz, 4H), 7.57‐7.61 (m, 4H); 13C NMR (100 MHz, CDCl3, δ ppm): 172.2, 172.1, 169.4,
162.2, 145.1, 140.7, 140.5, 135.9, 128.7, 128.6, 128.0, 127.4, 127.0, 126.6, 110.0, 60.3, 57.7, 52.8,
52.8, 48.8, 44.1, 39.9, 39.6, 25.4, 22.0, 14.2; HRMS (ESI‐TOF) m/z: [M + Na]+ Calcd for C30H32O7Na
527.2040; Found 527.2045.
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4‐ethyl 7‐methyl 7‐acetoxy‐1‐(4‐methoxyphenyl)‐3,5a‐dimethyl‐5a,6,7,8‐tetrahydro‐5H‐
cyclopenta[c]oxepine‐4,7‐dicarboxylate (3f): (47.6 mg, 52% yield); yellow solid; mp 116‐118°C; 1H
NMR (400 MHz, CDCl3, δ ppm): 1.25 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H), 2.24 (d, J = 1.2 Hz, 3H),
2.38‐2.46 (m, 2H), 2.54 (d, J = 15.2 Hz, 1H), 2.72 (d, J = 15.2 Hz, 1H), 3.00 (d, J = 16.0 Hz, 1H), 3.24
(d, J = 16.0 Hz, 1H), 3.68 (s, 3H), 3.73 (s, 3H), 3.82 (s, 3H), 4.16‐4.22 (m, 2H), 6.87 (d, J = 8.8 Hz,
2H), 7.32 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3, δ ppm): 172.3, 172.1, 169.5, 162.3, 159.2,
145.2, 129.6, 129.5, 126.7, 113.3, 109.9, 60.3, 57.7, 55.2, 52.8, 52.8, 48.8, 43.9, 40.0, 39.6, 25.4,
22.0, 14.2; HRMS (ESI‐TOF) m/z: [M + Na]+ Calcd for C25H30O8Na 481.1833; Found 481.1838.
4‐ethyl 7‐methyl 7‐acetoxy‐1‐(3,5‐dichlorophenyl)‐3,5a‐dimethyl‐5a,6,7,8‐tetrahydro‐5H‐
cyclopenta[c]oxepine‐4,7‐dicarboxylate (3g): (58.5 mg, 59% yield)；yellow solid; mp 107‐109°C; 1H
NMR (400 MHz, CDCl3, δ ppm): 1.23 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H), 2.23 (d, J = 0.8 Hz, 3H), 2.42
(dd, J = 13.6 Hz, J = 18.0 Hz, 2H), 2.53 (d, J = 14.8 Hz, 1H), 2.74 (d, J = 15.2 Hz, 1H), 2.95 (d, J =
16.0 Hz, 1H), 3.23 (d, J =16.4 Hz, 1H), 3.71 (s, 3H), 3.75 (s, 3H), 4.17‐4.23 (m,2H), 7.26‐7.27 (m,
2H), 7.30 (d, J = 1.6 Hz, 1H); 13C NMR (100 MHz, CDCl3, δ ppm): 172.0, 171.9, 169.1, 162.0, 142.9,
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139.7, 134.6, 129.5, 128.1, 126.7, 110.8, 60.5, 57.5, 53.0, 48.6, 44.3, 39.5, 39.4, 30.9, 25.5, 21.8,
14.2; HRMS (ESI‐TOF) m/z: [M + Na]+ Calcd for C24H26Cl2O7Na 519.0948; Found 519.0955.
4‐ethyl 7‐methyl 7‐acetoxy‐1‐(3,5‐difluorophenyl)‐3,5a‐dimethyl‐5a,6,7,8‐tetrahydro‐5H‐
cyclopenta[c]oxepine‐4,7‐dicarboxylate (3h): (58.5 mg, 63% yield); white solid; mp 111‐114°C; 1H
NMR (400 MHz, CDCl3, δ ppm): 1.25 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H), 2.25 (s, 3H), 2.42 (dd, J = 13.6
Hz, J = 26.0 Hz, 2H), 2.53 (d, J = 15.2 Hz, 1H), 2.73 (d, J = 15.2 Hz, 1H), 3.02 (d, J = 16.4 Hz, 1H),
3.24 (d, J = 16.4 Hz, 1H), 3.70 (s, 3H), 3.75 (s, 3H), 4.20 (q, J = 7.2 Hz, 2H), 6.73‐6.79 (m, 1H),
6.92‐6.94 (m, 2H); 13C NMR (100 MHz, CDCl3, δ ppm): 172.0 , 171.9 , 169.2 , 162.5 (dd, J = 246.5
Hz, J = 12.9 Hz), 161.8 , 143.2 (t, J = 2.8 Hz), 139.9 (t, J = 9.5 Hz), 129.7 , 111.2 (d, J = 25.8 Hz),
110.5 , 103.4 (t, J = 25.1 Hz), 60.6, 57.7, 53.0, 52.9, 48.6, 44.3, 39.7, 39.5, 25.3, 21.9, 14.2; HRMS
(ESI‐TOF) m/z: [M + Na]+ Calcd for C24H26F2O7Na 487.1539; Found 487.1548.
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4‐ethyl 7‐methyl 7‐acetoxy‐1‐(3,5‐dimethylphenyl)‐3,5a‐dimethyl‐5a,6,7,8‐tetrahydro‐5H‐
cyclopenta[c]oxepine‐4,7‐dicarboxylate (3i): (62.0 mg, 68% yield); yellow solid; mp 112‐114°C; 1H
NMR (400 MHz, CDCl3, δ ppm): 1.24 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H), 2.24 (d, J = 1.2 Hz, 3H), 2.32 (s,
6H), 2.42 (d, J = 1.6 Hz, 2H), 2.55 (d, J = 14.8 Hz, 1H), 2.74 (d, J = 15.2 Hz, 1H), 2.95 (d, J = 16.0 Hz,
1H), 3.24 (d, J = 16.0 Hz, 1H), 3.68 (s, 3H), 3.73 (s, 3H), 4.17‐4.22 (m, 2H), 6.95 (d, J = 14.8 Hz, 3H);
13C NMR (100 MHz, CDCl3, δ ppm): 172.3, 172.1, 169.4, 162.5, 145.6, 137.4, 136.9, 129.6, 126.9,
126.0, 110.0, 60.3, 57.6, 52.8, 52.7, 48.8, 43.9, 39.8, 39.5, 25.5, 22.0, 21.2, 14.2; HRMS (ESI‐TOF)
m/z: [M + Na]+ Calcd for C26H32O7Na 479.2040; Found 479.2046.
4‐ethyl 7‐methyl 7‐acetoxy‐1‐(3,5‐dimethoxyphenyl)‐3,5a‐dimethyl‐5a,6,7,8‐tetrahydro‐5H
‐cyclo‐penta[c]oxepine‐4,7‐dicarboxylate (3j): (49.0 mg, 50% yield); yellow solid; mp 106‐108°C;
1H NMR (400 MHz, CDCl3, δ ppm): 1.22 (s, 3H), 1.29‐1.32 (m, 3H), 2.21 (d, J = 1.2 Hz, 3H), 2.41 (s,
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2H), 2.61 (d, J = 14.4 Hz, 1H), 2.70 (d, J = 16.4 Hz, 1H), 2.77 (d, J = 14.4 Hz, 1H), 3.08 (d, J = 16.4 Hz,
1H), 3.68 (s. 3H), 3.72 (s, 3H), 3.76 (s, 3H), 3.79 (s, 3H), 4.16‐4.24 (m, 2H), 6.84 (s, 2H), 6.85 (d, J =
2.4 Hz, 1H); 13C NMR (100 MHz, CDCl3, δ ppm): 172.5, 172.3 169.5, 153.3, 151.5, 142.2, 127.8,
126.9, 116.3, 114.9, 112.9, 60.3, 57.0, 56.4, 55.8, 52.8, 52.7, 48.9, 43.8, 39.3, 38.9, 25.6, 21.8,
14.3; HRMS (ESI‐TOF) m/z: [M + Na]+ Calcd for C26H32O9Na 511.1939; Found 511.1952.
ethyl 6,8a‐dimethyl‐3‐oxo‐4‐phenyl‐1,3,8,8a‐tetrahydrofuro[3,4‐c]oxepine‐7‐carboxylate (3k):
(53.0 mg, 81% yield)；white solid; mp 94‐96°C; 1H NMR (400 MHz, CDCl3, δ ppm): 1.31 (s, 3H),
1.33‐1.36 (m, 3H), 2.36 (d, J = 1.2 Hz, 3H), 2.72 (d, J = 13.6 Hz, 1H), 2.88 (d, J = 14.4 Hz, 1H), 3.97
(d, J = 8.4 Hz, 1H), 4.05 (d, J = 8.4 Hz, 1H), 4.22‐4.28 (m, 2H), 7.37‐7.45 (m, 5H); 13C NMR (100
MHz, CDCl3, δ ppm): 170.0, 167.9, 162.2, 160.1, 133.4, 130.1, 129.1, 127.7, 113.2, 112.6, 61.0,
45.4, 36.1, 25.1, 21.5, 14.1; HRMS (ESI‐TOF) m/z: [M + Na]+ Calcd for C19H20O5Na 351.1203;
Found 351.1209.
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ethyl 4‐(4‐chlorophenyl)‐6,8a‐dimethyl‐3‐oxo‐1,3,8,8a‐tetrahydrofuro[3,4‐c]oxepine‐7‐
carboxylate (3l): (64.0 mg, 88% yield); yellow solid; mp 95‐97°C; 1H NMR (400 MHz, CDCl3, δ ppm):
1.31‐1.35 (m, 3H), 1.37 (s, 3H), 2.35 (d, J = 1.6 Hz, 3H), 2.71 (d, J = 14.4 Hz, 1H), 2.88 (d, J = 14.4
Hz, 1H), 3.97 (d, J = 8.4 Hz, 1H), 4.06 (d, J = 8.4 Hz, 1H), 4.22‐4.28 (m, 2H), 7.35‐7.40 (m, 4H); 13
C
NMR (100 MHz, CDCl3, δ ppm): 169.6, 167.9, 162.0, 158.9, 136.1, 131.8, 130.6, 128.1, 113.7,
112.7, 75.7, 61.1, 45.3, 36.1, 25.2, 21.5, 14.1; HRMS (ESI‐TOF) m/z: [M + Na]+ Calcd for
C19H19ClO5Na 385.0813; Found 385.0820.
ethyl
6,8a‐dimethyl‐3‐oxo‐4‐(p‐tolyl)‐1,3,8,8a‐tetrahydrofuro[3,4‐c]oxepine‐7‐carboxylate
(3m): (57.5 mg, 84% yield); white solid; mp 99‐101°C; 1H NMR (400 MHz, CDCl3, δ ppm): 1.33 (t, J
= 7.2 Hz, 3H), 1.36 (s, 3H), 2.36 (d, J = 1.2 Hz, 3H), 2.38 (s, 3H), 2.70 (d, J = 14.0 Hz, 1H), 2.86 (d, J
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= 14.0 Hz, 1H), 3.96 (d, J = 8.4 Hz, 1H), 4.04 (d, J = 8.4 Hz, 1H), 4.21‐4.29 (m, 2H), 7.19 (d, J = 8.4
Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3, δ ppm): 169.8, 168.0, 162.1, 160.4,
140.4, 130.5, 129.1, 128.5, 112.9, 112.5, 75.7, 61.0, 45.3, 36.1, 25.1, 21.5, 21.4, 14.1; HRMS
(ESI‐TOF) m/z: [M + Na]+ Calcd for C20H22O5Na 365.1359; Found 365.1362.
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ethyl 4‐(4‐methoxyphenyl)‐6,8a‐dimethyl‐3‐oxo‐1,3,8,8a‐tetrahydrofuro[3,4‐c]oxepine
‐7‐carboxylate (3n); (56.0 mg, 78% yield); yellow solid; mp 103‐106°C; 1H NMR (400 MHz, CDCl3,
δ ppm): 1.33 (t, J = 7.2 Hz, 3H), 1.36 (s, 3H), 2.36 (d, J = 1.2 Hz, 3H), 2.70 (d, J = 14.4 Hz, 1H), 2.85
(d, J = 14.4 Hz, 1H), 3.83 (s, 3H), 3.97 (d, J = 8.4 Hz, 1H), 4.05 (d, J = 8.0 Hz, 1H), 4.22‐4.28 (m, 2H),
6.90 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3, δ ppm): 170.0, 168.1,
161.9, 161.2, 160.4, 131.0, 125.5, 113.2, 112.5, 112.5, 75.7, 61.0, 55.2, 45.2, 36.3, 25.0, 21.6,
14.2; HRMS (ESI‐TOF) m/z: [M + Na]+ Calcd for C20H22O6Na 381.1309; Found 381.1317.
ethyl 4‐(4‐(tert‐butyl)phenyl)‐6,8a‐dimethyl‐3‐oxo‐1,3,8,8a‐tetrahydrofuro[3,4‐c]oxepine
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‐7‐carboxylate (3o): (60.0 mg, 79% yield); white solid; mp 95‐97°C; H NMR (400 MHz, CDCl3, δ
ppm): 1.31‐1.34 (m, 12H), 1.36 (s, 3H), 2.37 (d, J = 1.6 Hz, 3H), 2.71 (d, J = 14.4 Hz, 1H), 2.86 (d, J
= 14.0 Hz, 1H), 3.97 (d, J = 8.0 Hz, 1H), 4.05 (d, J = 8.4 Hz, 1H), 4.21‐4.29 (m, 2H), 7.41 (s, 4H); 13
C
NMR (100 MHz, CDCl3, δ ppm): 169.8, 168.0, 162.2, 160.4, 153.4, 130.4, 129.0, 124.7, 112.9,
112.6, 75.7, 61.0, 45.4, 36.1, 34.7, 31.1, 25.0, 21.5, 14.1; HRMS (ESI‐TOF) m/z: [M + Na]+ Calcd for
C23H28O5Na 407.1829; Found 407.1836.
ethyl 6,8a‐dimethyl‐3‐oxo‐4‐(m‐tolyl)‐1,3,8,8a‐tetrahydrofuro[3,4‐c]oxepine‐7‐carboxylate
(3p): (56.0 mg, 82% yield); white solid; mp 103‐105°C; 1H NMR (400 MHz, CDCl3, δ ppm): 1.33 (d,
J = 7.2 Hz, 3H), 1.36 (s, 3H), 2.36 (d, J = 1.2 Hz, 3H), 2.37 (s, 3H), 2.71 (d, J = 14.4 Hz, 1H), 2.87 (d, J
= 14.4 Hz, 1H), 3.96 (d, J = 8.4 Hz, 1H), 4.05 (d, J = 8.4 Hz, 1H), 4.22‐4.29 (m, 2H), 7.22‐7.28 (m,
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4H); 13C NMR (100 MHz, CDCl3, δ ppm): 169.7, 167.9, 162.2, 160.3, 137.4, 133.4, 130.9, 129.6,
127.7, 126.3, 113.1, 112.6, 75.6, 61.0, 45.4, 36.0, 25.1, 21.5, 21.2, 14.1; HRMS (ESI‐TOF) m/z: [M
+ Na]+ Calcd for C20H22O5Na 365.1359; Found 365.1361.
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ethyl 6,8a‐dimethyl‐4‐phenyl‐2‐tosyl‐2,3,8,8a‐tetrahydro‐1H‐oxepino[3,4‐c]pyrrole
‐7‐carboxylate (3q); (29.0 mg, 31% yield); white solid; mp 110‐112°C; 1H NMR (400 MHz, CDCl3, δ
ppm): 1.21 (s, 3H), 1.28‐1.32 (m, 3H), 2.25 (s, 3H), 2.44 (s, 3H), 2.62 (d, J = 14.4 Hz, 1H), 2.73 (d, J
= 14.4 Hz, 1H), 3.01 (d, J = 9.2 Hz, 1H), 3.17 (d, J = 9.2 Hz, 1H), 3.83 (d, J = 13.2 Hz, 1H), 4.02 (d, J =
13.2 Hz, 1H), 4.17‐4.23 (m, 2H), 7.18‐7.21 (m, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.34‐7.36 (m, 3H), 7.65
(d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3, δ ppm): 168.7, 163.6, 145.9, 143.7, 135.9, 132.7,
129.7, 128.6, 128.2, 127.7, 127.5, 123.0, 111.1, 60.6, 60.4, 51.3, 44.0, 36.7, 23.7, 21.8, 21.5, 14.2;
HRMS (ESI‐TOF) m/z: [M + Na]+ Calcd for C26H29NO5SNa 490.1659; Found 490.1664.
ethyl 4‐(4‐bromophenyl)‐6,8a‐dimethyl‐2‐tosyl‐2,3,8,8a‐tetrahydro‐1H‐oxepino[3,4‐c]pyrrole
‐7‐carboxylate (3r): (47.0 mg, 43% yield); yellow solid; mp 117‐119°C; 1H NMR (400 MHz, CDCl3, δ
ppm): 1.20 (s, 3H), 1.28‐1.32 (m, 3H), 2.24 (s, 3H), 2.44 (s, 3H), 2.60 (d, J = 14.8 Hz, 1H), 2.73 (d, J
= 14.4 Hz, 1H), 2.99 (d, J = 9.2 Hz, 1H), 3.18 (d, J = 8.8 Hz, 1H), 3.76 (d, J = 13.2 Hz, 1H), 4.02 (d, J =
13.2 Hz, 1H), 4.17‐4.22 (m, 2H), 7.07 (d, J = 8.8 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.4 Hz,
2H), 7.66 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3, δ ppm): 168.6, 163.4, 144.9, 143.8, 134.8,
132.7, 131.4, 129.7, 129.1, 127.7, 123.5, 122.7, 111.4, 60.7, 60.3, 51.2, 44.1, 36.5, 23.8, 21.7,
21.5, 14.2; HRMS (ESI‐TOF) m/z: [M + Na]+ Calcd for C26H28BrNO5SNa 568.0764; Found 568.0774.
ethyl 4‐(4‐chlorophenyl)‐6,8a‐dimethyl‐2‐tosyl‐2,3,8,8a‐tetrahydro‐1H‐oxepino[3,4‐c]pyrrole
‐7‐carboxylate (3s): (32.0 mg, 32% yield); yellow solid; mp 112‐114°C; 1H NMR (400 MHz, CDCl3, δ
ppm): 1.20 (s, 3H), 1.28‐1.32 (m, 3H), 2.23 (d, J = 0.8 Hz, 3H), 2.44 (s, 3H), 2.58‐2.62 (m, 1H), 2.73
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(d, J = 14.8 Hz, 1H), 3.00 (d, J = 9.2 Hz, 1H), 3.18 (d, J = 9.2 Hz, 1H), 3.77 (d, J = 13.2 Hz, 1H), 4.02
(d, J = 13.2 Hz, 1H), 4.17‐4.23 (m, 2H), 7.14 (d, J = 8.4 Hz, 2H), 7.31‐7.34 (m, 4H), 7.65 (d, J = 8.4
Hz, 2H); 13C NMR (100 MHz, CDCl3, δ ppm): 168.9, 163.7, 145.2, 144.1, 134.8, 134.7, 133.2, 130.0,
129.2, 128.8, 128.0, 123.8, 111.7, 61.0, 60.6, 51.5, 44.5, 36.9, 24.1, 22.0, 21.8, 14.5; HRMS
(ESI‐TOF) m/z: [M + Na]+ Calcd for C26H28ClNO5SNa 524.1269; Found 524.1274.
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ethyl 4‐(4‐methoxyphenyl)‐6,8a‐dimethyl‐2‐tosyl‐2,3,8,8a‐tetrahydro‐1H‐oxepino[3,4‐c]
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pyrrole‐7‐carboxylate (3t): (31.0 mg, 31% yield); white solid; mp 119‐121°C; H NMR (400 MHz,
CDCl3, δ ppm): 1.20 (s, 3H), 1.30 (t, J = 7.2 Hz, 3H), 2.25 (s, 3H), 2.44 (s, 3H), 2.61 (d, J = 14.4 Hz,
1H), 2.72 (d, J = 14.8 Hz, 1H), 3.01 (d, J = 9.2 Hz, 1H), 3.15 (d, J = 8.8 Hz, 1H), 3.82 (d, J = 12.8 Hz,
1H), 3.83 (s, 3H), 4.01 (d, J = 13.2 Hz, 1H), 4.19 (dd, J = 7.2 Hz, J = 14.0 Hz, 2H), 6.87 (d, J = 8.4 Hz,
2H), 7.13 (d, J = 8.8 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 7.66 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz,
CDCl3, δ ppm): 168.8, 163.6, 159.6, 145.8, 143.6, 132.9, 129.7, 128.9, 128.5, 127.7, 122.1, 113.5,
111.1, 60.5, 60.4, 55.3, 51.4, 44.0, 36.8, 23.7, 21.8, 21.5, 14.2; HRMS (ESI‐TOF) m/z: [M + Na]+
Calcd for C27H31NO6SNa 520.1764; Found 520.1771.
ethyl 4‐(2‐cyanophenyl)‐6,8a‐dimethyl‐1‐oxo‐2‐tosyl‐2,3,8,8a‐tetrahydro‐1H‐oxepino[3,4‐c]
pyrrole‐7‐carboxylate (3u): (40.5 mg, 40% yield); white solid; mp 117‐119°C; 1H NMR (400 MHz,
CDCl3, δ ppm): 1.23 (s, 3H), 1.29 (d, J = 7.2 Hz, 3H), 2.26 (d, J = 1.2 Hz, 3H), 2.45 (s, 3H), 2.57 (d, J
= 14.8 Hz, 1H), 3.10 (d, J = 14.8 Hz, 1H), 4.03 (d, J = 13.2 Hz, 1H), 4.17‐4.22 (m, 2H), 4.41 (d, J =
13.2 Hz, 1H), 7.34 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 7.6 Hz, 1H), 7.55‐7.59 (m, 1H), 7.68‐7.72 (m, 1H),
7.77 (d, J = 7.6 Hz, 1H), 7.89 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3, δ ppm): 174.6, 168.1,
162.4, 145.6, 144.4, 138.1, 134.4, 133.3, 133.1, 129.9, 129.7, 129.4, 128.0, 116.9, 116.5, 112.4,
109.7, 60.8, 48.4, 47.3, 33.7, 22.4, 21.6, 21.2, 14.1; HRMS (ESI‐TOF) m/z: [M + Na]+ Calcd for
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C27H26N2O6S Na 529.1404; Found 529.1414.
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ethyl 4,6,8a‐trimethyl‐3‐oxo‐1,3,8,8a‐tetrahydrofuro[3,4‐c]oxepine‐7‐carboxylate (3v): (43.6
mg, 82% yield); white oil; 1H NMR (400 MHz, CDCl3, δ ppm): 1.24 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H),
2.29 (d, J = 2.0 Hz, 3H), 2.34 (s, 3H), 2.52 (d, J = 14.0 Hz, 1H), 2.78 (d, J = 14.0 Hz, 1H), 3.85 (d, J =
8.4 Hz, 1H), 4.00 (d, J = 8.4 Hz, 1H), 4.20‐4.26 (m, 2H); 13C NMR (100 MHz, CDCl3, δ ppm): 171.4,
168.2, 161.8, 160.9, 111.9, 111.8, 75.9, 61.0, 44.4, 36.3, 25.6, 21.6, 18.9, 14.2; HRMS (ESI‐TOF)
m/z: [M + Na]+ Calcd for C14H18O5Na 289.1046; Found 289.1054.
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ethyl 4‐ethyl‐6,8a‐dimethyl‐3‐oxo‐1,3,8,8a‐tetrahydrofuro[3,4‐c]oxepine‐7‐carboxylate (3w):
(47.0 mg, 84% yield); white oil; 1H NMR (400 MHz, CDCl3, δ ppm): 1.13‐1.17 (m, 3H), 1.24 (s,
3H), 1.32 (t, J = 7.2 Hz, 3H), 2.30 (d, J = 1.6 Hz, 3H), 2.52 (d, J = 14.4 Hz, 1H), 2.63‐2.72 (m, 1H),
2.79 (d, J = 14.0 Hz, 1H), 2.83‐2.92 (m, 1H), 3.85 (d, J = 8.0 Hz, 1H), 3.99 (d, J = 8.4 Hz, 1H),
4.20‐4.25 (m, 2H); 13C NMR (100 MHz, CDCl3, δ ppm): 171.0, 168.2, 165.9, 162.1, 112.0, 111.2,
75.9, 61.0, 44.3, 36.2, 25.6, 25.1, 21.3, 14.2, 12.1; HRMS (ESI‐TOF) m/z: [M + Na]+ Calcd for
C15H20O5Na 303.1203; Found 303.1201.
ethyl 6,8a‐dimethyl‐3‐oxo‐4‐propyl‐1,3,8,8a‐tetrahydrofuro[3,4‐c]oxepine‐7‐carboxylate (3x):
(51.7 mg, 88% yield); white oil; 1H NMR (400 MHz, CDCl3, δ ppm): 0.94‐0.98 (m, 3H), 1.25 (s, 3H),
1.30‐1.34 (m, 3H), 1.57‐1.66 (m, 2H), 2.30 (s, 3H), 2.52 (d, J = 14.0 Hz, 1H), 2.64‐2.71 (m, 1H),
2.78‐2.86 (m, 2H), 3.85 (d, J = 8.4 Hz, 1H), 3.99 (d, J = 8.4 Hz, 1H), 4.20‐4.26 (m, 2H); 13C NMR
(100 MHz, CDCl3, δ ppm): 171.0, 168.1, 164.5, 162.1, 112.0, 111.9, 75.8, 60.9, 44.3, 36.2, 33.1,
25.6, 21.3, 20.8, 14.2, 13.3; HRMS (ESI‐TOF) m/z: [M + Na]+ Calcd for C16H22O5Na 317.1359;
Found 317.1356.
diethyl 6‐methyl‐3‐oxo‐4‐phenyl‐1H,3H‐furo[3,4‐c]oxepine‐7,8a(8H)‐dicarboxylate (3z): (33.1
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mg, 43% yield); white oil; 1H NMR (400 MHz, CDCl3, δ ppm):1.24 (t, J = 7.2 Hz, 3H), 1.31‐1.35 (m,
3H), 2.31 (d, J = 1.6 Hz, 3H), 2.73 (dd, J = 1.6 Hz, J = 14.4 Hz, 1H), 3.40 (d, J = 14.0 Hz, 1H), 4.03 (d,
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J = 9.2 Hz, 1H), 4.11‐4.25 (m, 4H), 4.57 (d, J = 9.2Hz, 1H), 7.40‐7.43 (m, 2H), 7.44‐7.51(m, 3H); 13
C
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NMR (100 MHz, CDCl3, δ ppm): 171.7, 168.6, 167.2, 162.4, 162.1, 133.1, 130.5, 129.2, 127.8,
112.0, 107.3, 71.5, 62.2, 61.1, 55.9, 34.0, 21.4, 14.2, 14.0; HRMS (ESI‐TOF) m/z: [M + Na]+ Calcd
for C21H22O7Na 409.1258; Found 409.1261.
4‐ethyl 7,7‐dimethyl 3‐methyl‐1,5a‐diphenyl‐5a,6‐dihydro‐5H‐cyclopenta[c]oxepine‐
4,7,7(8H)‐tricarboxylate (3aa): (44.0 mg, 45% yield); yellow oil; 1H NMR (400 MHz, CDCl3, δ ppm):
1.11‐1.15 (m, 3H), 2.05 (d, J = 0.8 Hz, 3H), 2.71 (d, J = 13.2 Hz, 1H), 2.84 (dd, J = 1.2 Hz, J = 14.4 Hz,
1H), 2.92‐3.00 (m, 2H), 3.30 (s, 3H), 3.39 (d, J = 9.2 Hz, 1H), 3.43 (d, J = 11.2 Hz, 1H), 3.66 (s, 3H),
3.89‐3.95 (m, 2H), 7.11‐7.16 (m, 1H), 7.23‐7.26 (m, 4H), 7.36 (d, J = 7.2 Hz, 1H), 7.41 (t, J = 7.2 Hz,
2H), 7.50‐7.52 (m, 2H); 13C NMR (100 MHz, CDCl3, δ ppm): 172.1 , 171.1 , 168.1 , 163.8 , 146.7 ,
144.2 , 137.1 , 128.4 , 128.2 , 128.1 , 127.8 , 127.1 , 126.3 , 123.0 , 110.8 , 60.0 , 57.4 , 53.8 , 52.9 ,
52.4 , 48.9 , 39.8 , 39.5 , 21.6 , 14.1 . HRMS (ESI‐TOF) m/z: [M + Na]+ Calcd for C29H30O7Na
513.1884; Found 513.1890.
ethyl 6‐methyl‐4,8a‐diphenyl‐2‐tosyl‐2,3,8,8a‐tetrahydro‐1H‐oxepino[3,4‐c]pyrrole‐7‐
carboxylate(3ab): (32.0 mg, 30% yield); yellow oil; 1H NMR (400 MHz, CDCl3, δ ppm): 1.15 (t,
J = 7.2 Hz, 3H), 2.06 (d, J = 0.8 Hz, 3H), 2.38 (s, 3H), 2.88‐2.92 (m, 1H), 3.33 (d, J = 14.4 Hz, 1H),
3.42 (d, J = 9.6 Hz, 1H), 3.68 (d, J = 9.6 Hz, 1H), 3.94 (dd, J = 4.8 Hz, J = 7.2 Hz, 2H), 4.01 (d, J = 4.8
Hz, 2H), 7.15 (d, J = 7.6 Hz, 3H), 7.17‐7.19(m, 3H), 7.20 (d, J = 9.2 Hz, 1H), 7.30‐7.33 (m, 2H),
7.40‐7.41 (m, 3H), 7.47 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3, δ ppm):167.8 , 164.0 , 147.8 ,
143.4 , 142.6 , 135.9 , 132.9 , 129.5 , 128.9 , 128.4 , 128.3 , 127.7 , 127.5 , 126.7 , 126.7 , 120.5 ,
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111.3 , 61.1 , 60.3 , 53.1 , 51.9 , 36.8 , 21.5 , 14.1. HRMS (ESI‐TOF) m/z: [M + Na]+ Calcd for
C31H31NO5SNa 552.1815; Found 552.1819.
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methyl 6,8a‐dimethyl‐3‐oxo‐4‐phenyl‐1,3,8,8a‐tetrahydrofuro[3,4‐c]oxepine‐7‐carboxylate
(3ac): (47.7 mg, 76% yield); yellow oil; 1H NMR (400 MHz, CDCl3, δ ppm): 1.36 (s, 3H), 2,37 (d, J =
1.6 Hz, 3H), 2.72 (d, J = 13.6 Hz, 1H), 2.89 (d, J = 14.4 Hz, 1H), 3.79 (s, 3H), 3.97 (d, J = 8.4 Hz, 1H),
4.06 (d, J = 8.0 Hz, 1H), 7.38‐7.46 (m, 5H); 13C NMR (100 MHz, CDCl3, δ ppm): 169.7, 168.4, 162.6,
160.1, 133.4, 130.2, 129.2, 127.8, 113.3, 112.2, 75.7, 52.1, 45.4, 36.1, 25.2, 21.6; HRMS (ESI‐TOF)
m/z: [M + Na]+ Calcd for C18H18O5Na 337.1046; Found 337.1048.
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tert‐butyl 6,8a‐dimethyl‐3‐oxo‐4‐phenyl‐1,3,8,8a‐tetrahydrofuro[3,4‐c]oxepine‐7‐carboxylate
(3ad): (51.0 mg, 72% yield); white solid; mp 111‐113°C; 1H NMR (400 MHz, CDCl3, δ ppm): 1.37 (s,
3H), 1.53 (s, 9H), 2.31 (d, J = 1.2 Hz, 3H), 2.69 (d, J = 14.0 Hz, 1H), 2.80 (d, J = 14.0 Hz, 1H), 3.97 (d,
J = 8.4 Hz, 1H), 4.05 (d, J = 8.4 Hz, 1H), 7.37‐7.46 (m, 5H); 13C NMR (100 MHz, CDCl3, δ ppm):
169.9, 167.4, 160.8, 160.4, 133.6, 130.1, 129.2, 127.8, 114.4, 113.0, 81.6, 75.8, 45.6, 36.3, 28.1,
25.2, 21.4; HRMS (ESI‐TOF) m/z: [M + Na]+ Calcd for C21H24O5Na 379.1516; Found 379.1520.
ethyl 6‐ethyl‐8a‐methyl‐3‐oxo‐4‐phenyl‐1,3,8,8a‐tetrahydrofuro[3,4‐c]oxepine‐7‐carboxylate
(3ae): (52.0 mg, 76% yield); white oil; 1H NMR (400 MHz, CDCl3, δ ppm): 1.19‐1.23 (m, 3H), 1.33 (t,
J = 7.2 Hz, 3H), 1.36 (s, 3H), 2.49‐2.58 (m, 1H), 2.72‐2.78 (m, 1H), 2.80‐2.87 (m, 2H), 3.97 (d, J =
8.4 Hz, 1H), 4.05 (d, J = 8.4 Hz, 1H), 4.23‐4.28 (m, 2H), 7.38‐7.46 (m, 5H); 13C NMR (100 MHz,
CDCl3, δ ppm): 169.8, 168.0, 166.6, 160.5, 133.6, 130.1, 129.1, 127.8, 113.0, 112.2, 75.7, 61.1,
45.5, 36.2, 28.2, 25.2, 14.1, 12.1; HRMS (ESI‐TOF) m/z: [M + Na]+ Calcd for C20H22O5Na 365.1359;
Found 365.1364.
ethyl 8a‐methyl‐3‐oxo‐4‐phenyl‐6‐propyl‐1,3,8,8a‐tetrahydrofuro[3,4‐c]oxepine
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‐7‐carboxylate (3af): (41.3 mg, 58% yield); white oil; 1H NMR (400 MHz, CDCl3, δ ppm): 0.96‐1.00
(m, 3H), 1.33 (t, J = 7.2 Hz, 3H), 1.37 (s, 3H), 1.66 (dd, J = 7.6 Hz, J = 14.8 Hz, 2H), 2.46‐2.53 (m,
1H), 2.72‐2.79 (m, 1H), 2.81‐2.87 (m, 2H), 3.96 (d, J = 8.4 Hz, 1H), 4.05 (d, J = 8.4 Hz, 1H),
4.22‐4.28 (m, 2H), 7.38‐7.46 (m, 5H); 13C NMR (100 MHz, CDCl3, δ ppm): 169.9, 167.9, 165.5,
160.3, 133.6, 130.0, 129.0, 127.8, 113.0, 112.9, 75.6, 61.0, 45.6, 36.2, 36.1, 25.2, 21.0, 14.1, 13.8;
HRMS (ESI‐TOF) m/z: [M + Na]+ Calcd for C21H24O5Na 379.1516; Found 379.1525.
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methyl 6‐isopropyl‐8a‐methyl‐3‐oxo‐4‐phenyl‐1,3,8,8a‐tetrahydrofuro[3,4‐c]oxepine‐7‐
carboxylate (3ag): (50.6 mg, 74% yield); white oil; 1H NMR (400 MHz, CDCl3, δ ppm): 1.30 (s, 3H),
1.32 (s, 3H), 1.36 (s, 3H), 2.35 (d, J = 1.6 Hz, 3H), 2.71 (d, J = 14.0 Hz, 1H), 2.86 (d, J = 14.0 Hz, 1H),
3.97 (d, J = 8.4 Hz, 1H), 4.05 (d, J = 8.4 Hz, 1H), 5.09‐5.15 (m, 1H), 7.37‐7.46 (m, 5H); 13C NMR
(100 MHz, CDCl3, δ ppm): 169.8, 167.5, 161.9, 160.2, 133.4, 130.1, 129.1, 127.8, 113.1, 113.1,
75.7, 68.6, 45.5, 36.0, 25.1, 21.7, 21.4; HRMS (ESI‐TOF) m/z: [M + Na]+ Calcd for C20H22O5Na
365.1359; Found 365.1363.
ethyl 6‐(chloromethyl)‐8a‐methyl‐3‐oxo‐4‐phenyl‐1,3,8,8a‐tetrahydrofuro[3,4‐c]oxepine‐
7‐carboxylate (3ah): (30.0 mg, 41% yield); yellow oil; 1H NMR (400 MHz, CDCl3, δ ppm): 1.37 (t, J
= 7.2 Hz, 3H), 1.39 (s, 3H), 2.78 (d, J = 14.4 Hz, 1H), 2.94 (d, J = 14.0 Hz, 1H), 3.99 (d, J = 8.4 Hz,
1H), 4.08 (d, J = 8.0 Hz, 1H), 4.22(d, J = 11.2 Hz, 1H), 4.28‐4.34 (m, 2H), 5.00 (d, J = 11.6 Hz, 1H),
7.39‐7.46 (m, 3H), 7.53‐7.55 (m, 2H); 13C NMR (100 MHz, CDCl3, δ ppm): 169.4, 166.5, 160.4,
158.7, 132.9, 130.4, 129.3, 127.9, 116.5, 113.4, 75.5, 61.9, 45.2, 42.7, 36.1, 25.2, 14.1; HRMS
(ESI‐TOF) m/z: [M + Na]+ Calcd for C19H19ClO5Na 385.0813; Found 385.0818.
ethyl 6‐cyclopropyl‐8a‐methyl‐3‐oxo‐4‐phenyl‐1,3,8,8a‐tetrahydrofuro[3,4‐c]oxepine‐
7‐carboxylate (3ai): (51.0 mg, 72% yield); yellow oil; 1H NMR (400 MHz, CDCl3, δ ppm): 0.72‐0.75
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(m, 2H), 0.77‐0.86 (m, 1 H), 0.93‐0.98 (m, 1H), 1.32‐1.35 (m, 3H), 1.36 (s, 3H), 2.73 (d, J = 14.0,
1H), 2.82‐2.88 (m, 1H), 2.92 (d, J = 14.0 Hz, 1H), 3.94 (d, J = 8.4 Hz, 1H), 4.04 (d, J = 8.0 Hz, 1H),
4.25‐4.31 (m, 2H), 7.34‐7.43 (m, 5H); 13C NMR (100 MHz, CDCl3, δ ppm): 169.6, 168.2, 165.7,
159.9, 133.3, 130.0, 128.7, 127.9, 113.9, 112.2, 75.7, 60.9, 45.5, 36.1, 25.3, 14.2, 13.5, 7.16, 6.26;
HRMS (ESI‐TOF) m/z: [M + Na]+ Calcd for C21H22O5Na 377.1359; Found 377.1361.
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11a‐methyl‐4‐phenyl‐11,11a‐dihydro‐1H‐furo[3,4‐e]indeno[1,2‐b]oxepine‐3,10‐dione (3aj):
(45.0 mg, 65% yield); yellow solid; mp 142‐144°C; 1H NMR (400 MHz, CDCl3, δ ppm): 1.46 (s, 3H),
2.63 (d, J = 15.6 Hz, 1H), 2.78 (d, J = 16.0 Hz, 1H), 4.20 (dd, J = 8.8 Hz, J = 13.2 Hz, 2H), 7.22 (d, J =
6.8 Hz, 1H), 7.31 (t, J = 7.2 Hz, 1H), 7.37‐7.40 (m, 1H), 7.45‐7.48 (m, 3H), 7.50‐7.55 (m, 3H); 13C
NMR (100 MHz, CDCl3, δ ppm): 168.8, 166.5, 162.1, 139.7, 133.1, 132.5, 131.0, 130.6, 129.8,
129.8, 128.0, 122.0, 118.5, 115.8, 111.5, 76.5, 42.6, 33.5, 25.4; HRMS (ESI‐TOF) m/z: [M + Na]+
Calcd for C22H16O4Na 367.0941; Found 367.0947.
dimethyl 4‐acetyl‐3,5a‐dimethyl‐1‐phenyl‐5a,6‐dihydro‐5H‐cyclopenta[c]oxepine‐7,7(8H)‐
1
dicarboxylate (3ak): (24.7 mg, 31% yield); white oil; H NMR (400 MHz, CDCl3, δ ppm): 1.27 (s,
3H), 2.13 (d, J = 1.2 Hz, 3H), 2.30 (s, 3H), 2.44 (s, 2H), 2.56 (d, J = 14.8 Hz, 1H), 2.65 (d, J = 15.2 Hz,
1H), 3.00 (d, J = 16.0 Hz, 1H), 3.28 (d, J = 16.4 Hz, 1H), 3.67 (s, 3H), 3.74 (s, 3H), 7.28‐7.32 (m, 1H),
7.32‐7.41(m, 4H); 13C NMR (100 MHz, CDCl3, δ ppm): 202.3, 172.1, 172.0, 159.3, 145.5, 136.9,
128.2, 128.0, 127.9, 127.2, 118.8, 57.8, 52.9, 52.8, 48.9, 44.2, 40.5, 39.6, 30.2, 25.7, 21.8. HRMS
(ESI‐TOF) m/z: [M + Na]+ Calcd for C23H26O6Na 421.1627; Found 421.1622.
ASSOCIATED CONTENT
Notes
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The authors declare no competing financial interest.
Acknowledgment
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Financial support was received from the National Natural Science Foundation (NSF21472073,
NSF21532001) and the “111” project.
Supporting Information
X‐ray structures, copies of 1H NMR, 13C NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org/.
Reference
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van den Hende, J. H. J. Am. Chem. Soc. 1968, 90, 6519. (g) Murdock, K. C. J. Med. Chem. 1974, 17, 827.
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