Silver-Catalyzed Cascade 1,6-Addition/Cyclization of para-Quinone Methides with Propargyl Malonates: An Approach to Spiro[4.5]deca-6,9-dien-8-ones

Article abstract of DOI:10.1021/acs.joc.7b01400

An unprecedented silver-catalyzed cascade 1,6-addition/5-exo-dig cyclization reaction between para-quinone methides and propargyl malonates under mild reaction conditions has been described. This reaction provides an efficient method to construct versatile spiro[4.5]cyclohexadienones in moderate to excellent yields with high atom economy and scalability.

Full text of DOI:10.1021/acs.joc.7b01400

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Note
Silver-Catalyzed Cascade 1,6-Addition/Cyclization of para-Quinone Methides
with Propargyl Malonates: An Approach to Spiro[4.5]deca-6,9-dien-8-ones
Zhenbo Yuan, Lina Liu, Rui Pan, Hequan Yao, and Aijun Lin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01400 • Publication Date (Web): 18 Jul 2017
Downloaded from http://pubs.acs.org on July 18, 2017
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Silver-Catalyzed Cascade 1,6-Addition/Cyclization of para-
Quinone Methides with Propargyl Malonates: An Approach
to Spiro[4.5]deca-6,9-dien-8-ones
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Zhenbo Yuan, Lina Liu, Rui Pan, Hequan Yao * and Aijun Lin *
State Key Laboratory of Natural Medicines (SKLNM) and Department of Medicinal
Chemistry, China Pharmaceutical University, Nanjing, 210009, P .R. China
Abstract
An unprecedented silver-catalyzed cascade 1,6-addition/5-exo-dig cyclization
reaction between para-quinone methides and propargyl malonates under mild reaction
conditions has been described. This reaction provides an efficient method to construct
versatile spiro[4.5]cyclohexadienones in moderate to excellent yields with high atom
economy and scalability.
Spiro[4.5]cyclohexadienones are crucial skeletons for their abundant distribution in
natural products and bioactive molecules1 (Scheme 1), and employment as key
intermediates in natural products syntheses.2 As such, developing efficient methods to
construct these frameworks is always a popular topic. Traditional methods included the
intramolecular dearomatization reaction of phenol derivatives catalyzed or mediated by
transition-metals,3 hypervalent iodines4 and strong bases5 (Scheme 2a, eq 1). Rhodium-
catalyzed enyne cycloisomerization reaction as an alternative method has been
disclosed by Nicolaou and co-workers (Scheme 2a, eq 2).6 Recently, palladium-
catalyzed cross-coupling/dearomatization of phenol-based biaryls with internal alkynes
(Scheme 2a, eq 3) or 1,3-dienes (Scheme 2a, eq 4) developed by Luan7 have also been
used to prepare such frameworks. These methods have been extensively explored in
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synthesis despite the fact that well-designed substrates, heavy metal and harsh reaction
conditions are needed.
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Scheme 1. Natural products with spiro[4.5]cyclohexadienones
Scheme 2. Strategies to the construction of spiro[4.5]cyclohexadienones
Recently, para-quinone methides (p-QMs) have been proven as important reactive
intermediates for their unique reactivities of 1,6-conjugated addition8 and
cycloaddition.9 In 2016, our group10a and Zhao’s group10b successively reported
palladium-catalyzed
[3+2]
annulations
of
p-QMs
with
vinyl-
cyclopropanes/aziridines/oxiranes to construct spiro[4.5]cyclohexadienones (Scheme
2a, eq 5). Very recently, our group11a and Fan’s group11b independently reported the
cascade 1,6-addition/VCP rearrangement reactions of vinyl para-quinone methides (p-
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VQMs) with bromomalonates (Scheme 2a, eq 6) or sulfonium salts (Scheme 2a, eq 7)
to synthesize spiro[4.5]deca-6,9-dien-8-ones, respectively. As part of our continuing
interest in characterizing the reactivity of p-QMs12 and preparing spirocyclic
compounds13, herein, we will describe an unprecedented silver-catalyzed cascade 1,6-
addition/5-exo-dig cyclization of p-QMs with propargyl malonates to construct
spiro[4.5]deca-6,9-dien-8-ones (Scheme 2b).
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Table 1. Optimization of Reaction Conditionsa, b, c
entry
1
cat.
CuI
solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Toluene
CH2Cl2
EtOAc
THF
3aa (%)
63
4aa (%)
N.D.
N.D.
N.D.
N.D.
N.D.
33
2
CuBr
22
3
CuOTf·(C6H6)1/2
Cu(OTf)2
PPh3AuCl+AgNTf2
PPh3AuNTf2
AgNTf2
AgOTf
< 5
37
4
5
74
6
8
7
83
N.D.
N.D.
N.D.
N.D.
N.D.
75
8
79
9
AgOMs
AgNO3
76
10
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12
13
14
15
98 (93)
N.D.
11
AgNO3
AgNO3
AgNO3
14
41
AgNO3
6
32
-
DMF
N.D.
94
aAll reactions were performed with 1a (0.10 mmol), 2a (0.15 mmol), catalyst (5.0 mol %) and Cs2CO3 (0.12 mmol)
1
in solvent (1.0 mL) at 60 ºC for 48 h under argon. bThe yields were determined by H NMR analysis with
dibromomethane as an internal standard. cIsolated yield was reported in parenthesis. N.D. = No detection.
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We commenced our study by examining the reaction of p-QM 1a and propargyl
malonate 2a. Initially, we tested various copper salts14 as catalysts for that they are
cheap and abundant on the earth. Encouragingly, the reaction was able to form the
desired spirocyclic product 3aa, although the yields were low to moderate (Table 1,
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13
entries 1–4). The structure of 3aa was confirmed by 1H, C NMR spectra and X-ray
crystallographic analysis.15 To improve the yield, the combination of PPh3AuCl and
AgNTf2 as catalyst was tested, which is a frequently-used catalyst system in
functionalization of alkynes.16 Delightfully, 3aa could be achieved in 74% yield (Table
1, entry 5). However, when PPh3AuNTf2 was solely examined, only 8% yield of 3aa
was obtained with 1,6-addition product 4aa in 33% yield, which suggested that the
silver salt17 might be the authentic catalyst (Table 1, entry 6). Subsequently, several
silver salts were tested (Table 1, entries 7–10), and AgNO3 performed as the most
efficacious catalyst. DMF exhibited good results after the screening of solvents (Table
1, entries 11–14). In the absence of silver catalyst, only 4aa could be detected (Table 1,
entry 15).
With the optimized conditions in hand, we then examined the substrate scope18 of
this silver-catalyzed cascade 1,6-addition/5-exo-dig cyclization and the results are
summarized in Scheme 3. Halogen groups (-F, -Cl, -Br), electron-withdrawing groups
(-CO2Me, -CN, -CF3) or electron-donating groups (-Me, -OMe, -NMe2) at the para-
position of phenyl ring of p-QMs led to the corresponding products 3ba–ja in 77–95%
yields. Spiro[4.5]cyclohexadienones 3ka and 3la with phenyl or alkenyl groups were
achieved in 93 and 94% yield, respectively. Substrates containing bromine group at
either the meta- or ortho-position of the phenyl ring provided 3ma and 3na in 86 and
77% yields. These results indicated that the steric-hindrance played no obvious effect
on the reaction. When the phenyl ring was replaced by 1-naphyl or 2-thiophenyl groups,
the reaction could convert 1oa and 1pa into 3oa and 3pa in 90 and 93% yields. The
transformation could also be extended to 1q with an alkyl group, yielding 3qa in 47%
yield. Meanwhile, vinylogous p-QM 1r could produce 3ra in 51% yield. What is more,
p-QM 1s containing two methyl groups was also tolerated, giving 3sa in 26% yield.
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The substrate scope of propargyl malonates 2 was studied by the reactions with p-QM
1a. Varying the dimethyl ester groups to diethyl, diisopropyl, di-tert-butyl and dibenzyl
groups, 3ab–ae were achieved in excellent yields. Additionally, this method was also
compatible with propargyl p-toluenesulfonamide, delivering 3af in a low yield.
However, no desired products could be detected when the terminal hydrogen atom was
replaced by methyl or phenyl group.
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Scheme 3. Substrate Scope a, b
aAll reactions were performed with 1 (0.10 mmol), 2 (0.15 mmol), AgNO3 (5.0 mol %) and Cs2CO3 (0.12 mmol) in DMF (1.0 mL)
at 60 ºC for 48 h under argon. bIsolated yields.
To gain more insight into the utility of the reaction, the gram-scale experiment and
further transformation of 3aa were carried out. Reducing the amount of silver catalyst
to 2.5 mol %, the reaction of 1a (3.0 mmol, 882 mg) with 2a (3.3 mmol, 765 mg) could
still afford 3aa (1.27 g) in 91% yield (Scheme 4a). Decarboxylation of diester groups
was accomplished using diethylamine under refluxing conditions, furnishing 5aa in 75%
yield (Scheme 4b). Through 1,2-benzyl migration in dienone-phenol rearrangement,
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3aa could be transformed into 7,8-dihydronaphthalen-2-ol derivative 6aa in 76% yield
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(Scheme 4c), which is also a crucial skeleton found in natural products.19
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Scheme 4. Further Study on 3aa
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Control experiments were then carried out to shed some light on the reaction pathway.
As expected, the 1,6-conjugated addition intermediate 4aa could be isolated in 90%
yield under standard conditions without AgNO3 (Scheme 5a). When 4aa was utilized
as the substrate, the 5-exo-dig cyclization reaction proceeded smoothly to deliver 3aa
in 85% yield (Scheme 5b). On the basis of the control experiments and previous
works,20 a proposed mechanism was shown in Scheme 5c. Firstly, in the presence of
Cs2CO3, the nucleophilic 1,6-addition of p-QMs with propargyl malonates takes place
to deliver intermediate I. 4aa could be formed via protonation of I. Intermediate I
coordinates to Ag catalyst, offering the intermediate II, followed by 5-exo-dig
cyclization to give vinyl-silver intermediate III. Finally, protodemetallation of III
delivers the spirocyclic product 3aa and regenerates silver catalyst for a new catalytic
cycle.
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Scheme 5. Mechanistic Insights
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In conclusion, we have described a novel cascade 1,6-addition/5-exo-dig cyclization
reaction between p-QMs and propargyl malonates. The cheap and commercial available
silver nitrate was employed as the catalyst. Spiro[4.5]deca-6,9-diene-8-ones were
efficiently synthesized in high yields with good functional group tolerance and high
atom economy. Through 1,2-benzyl migration in dienone-phenol rearrangement,
spiro[4.5]deca-6,9-diene-8-one could be transformed into 7,8-dihydronaphthalen-2-ol
derivative.
Experimental Section
General Information. NMR spectra were collected on a 300 MHz spectrometer
using CDCl3 as solvent. Infrared (IR) spectra were recorded using a thin film supported
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on KBr disks. High Resolution Mass measurement was performed with electron spray
ionization (ESI) method on a Q-TOF mass spectrometer operating in positive-ion mode.
Melting point (m.p.) was measured on a microscopic melting point apparatus.
Tetrahydrofuran (THF) was distilled from sodium/benzophenone, N, N-dimethyl
formamide (DMF) from calcium hydride and dichloromethane (DCM) from
phosphorus pentoxide. PE refers to petroleum ether (b.p. 60–90 °C) and EA refers to
ethyl acetate. Flash column chromatography was carried out using commercially
available 200–300 mesh under pressure unless otherwise indicated. Gradient flash
chromatography was conducted eluting with PE/EA. All other starting materials and
solvents were commercially available and were used without further purification unless
otherwise stated.
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General Procedure for the Preparation of para-Quinone Methides. Aldehydes (10
mmol) were added to a solution of phenols (10 mmol) in toluene (40 mL). The reaction
mixture was heated in a Dean-Stark apparatus to reflux. Piperidine (20 mmol) was
added drop wisely in 1 h, and the reaction mixture was continued to reflux for 3 h. After
cooling just below the boiling point of toluene, acetic anhydride (20 mmol) was added
and then the solution was stirred for 15 min. The residue was extracted with
dichloromethane for 3 times. The combined organic layers were washed with water and
brine sequentially, dried over Na2SO4, filtered and concentrated. The crude product was
purified by flash chromatography on silica gel (petroleum ether) to afford the
corresponding product. 1a–1p were synthesized by the general procedure.21a 1q,21b
1r11a and 1s21c, were prepared according to corresponding literatures.
General Procedure for the Preparation of Propargyl Malonates. A flame-dried
round bottom flask was charged with NaH (60% in oil, 20 mmol) and THF (10 mL).
The suspension was cooled to 0 °C and dimethyl malonate (15 mmol) in THF (10 mL)
was added dropwise over 1 h. Then propargyl bromide (10 mmol) in THF (10 mL) was
added dropwise over 1 h. The suspension was allowed to warm to room temperature
and stirred overnight. The reaction mixture was added H2O and extracted with EA. The
combined organic layers were washed with H2O, brine, dried over Na2SO4,
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concentrated by rotary evaporation, and purified by column chromatography
(EtOAc/petroleum ether = 1/200) to give corresponding product. 2a–2e22a were
synthesized by the general procedure. 2f22b was prepared according to previous
literature.
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General Procedure for the Preparation of Spiro[2.5]octa-4,7-dien-6-ones. A
sealed tube was charged with para-quinone methide (0.1 mmol, 1 equiv), propargyl
malonates (0.15 mmol, 1.5 equiv), AgNO3 (5 mol %), and Cs2CO3 (1.2 mmol, 1.2
equiv). The vial is thoroughly flushed with argon and dry dimethyl formamide (1.0 mL)
o
was added under argon. Then the reaction mixture was stirred at 60 C for 48 h. After
the reaction vessel was cooled to room temperature, the solution was concentrated in
vacuo and purified by careful chromatography on silica gel (EtOAc/petroleum ether =
1/200) to afford the desired product.
Dimethyl 7,9-di-tert-butyl-4-methylene-8-oxo-1-phenylspiro[4.5]deca-6,9-diene-2,2-
dicarboxylate (3aa) 93% yield (43.3 mg). White solid, m.p. 96 – 97 oC. Rf = 0.5 (1/10
EA/PE). 1H NMR (300 MHz, CDCl3) δ 7.17 – 7.14 (m, 3H), 7.02 – 6.99 (m, 2H), 6.81
(d, J = 2.9 Hz, 1H), 6.47 (d, J = 2.9 Hz, 1H), 4.97 – 4.96 (m, 1H), 4.79 (dd, J = 1.8, 0.6
Hz, 1H), 4.27 (s, 1H), 3.99 (dt, J = 17.6, 2.6 Hz, 1H), 3.76 (s, 3H), 3.39 (s, 3H), 3.09
13
(d, J = 17.6 Hz, 1H), 1.12 (s, 9H), 1.11 (s, 9H) ppm. C NMR (75 MHz, CDCl3) δ
185.9, 172.2, 171.2, 149.5, 147.7, 145.5, 142.5, 140.0, 135.8, 129.6, 127.5, 109.2, 63.0,
61.6, 55.9, 53.2, 52.5, 40.6, 34.9, 34.7, 29.4, 29.1 ppm. IR(KBr): 3000, 2956, 2868,
1727, 1658, 1639, 1458, 1433, 1366, 1250, 1217, 1195, 1172, 1094, 1043, 905, 751,
700, 671, 580, 491 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C29H37O5
465.2636; Found 465.2633.
dimethyl 7,9-di-tert-butyl-1-(4-fluorophenyl)-4-methylene-8-oxospiro[4.5]deca-6,9-
diene-2,2-dicarboxylate (3ba) 87% yield (41.8 mg). White solid, m.p. 80 – 81 oC. Rf =
0.4 (1/10 EA/PE). 1H NMR (300 MHz, CDCl3) δ 7.03 – 6.98 (m, 2H), 6.88 – 6.82 (m,
3H), 6.43 (d, J = 3.0 Hz, 1H), 4.96 (dd, J = 2.5, 1.6 Hz, 1H), 4.80 (dd, J = 2.7, 1.6 Hz,
1H), 4.25 (s, 1H), 3.97 (dt, J = 17.6, 2.6 Hz, 1H), 3.76 (s, 3H), 3.43 (s, 3H), 3.07 (dt, J
= 17.6, 1.6 Hz, 1H), 1.14 (s, 9H), 1.12 (s, 9H) ppm. 13C NMR (75 MHz, CDCl3) δ 185.8,
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172.1, 171.2, 162.0 (d, J = 246.7 Hz), 149.3, 148.2, 146.0, 142.2, 139.5, 131.6 (d, J =
3.5 Hz), 131.3 (d, J = 8.0 Hz), 114.3 (d, J = 21.3 Hz), 109.3, 62.9, 60.8, 55.9, 53.2, 52.6,
40.4, 34.9, 34.7, 29.4, 29.1 ppm. 19F NMR (282 MHz, CDCl3) δ -113.57 ppm. IR(KBr):
2998, 2958, 2869, 1730, 1658, 1638, 1511, 1459, 1436, 1367, 1269, 1253, 1228, 1174,
1164, 1091, 960, 910, 876, 843, 812, 580, 521 cm-1. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C29H36FO5 483.2541; Found 483.2549.
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dimethyl 7,9-di-tert-butyl-1-(4-chlorophenyl)-4-methylene-8-oxospiro[4.5]deca-6,9-
diene-2,2-dicarboxylate (3ca) 89% yield (44.5 mg). White solid, m.p. 115 – 117 oC. Rf
= 0.5 (1/10 EA/PE). 1H NMR (300 MHz, CDCl3) δ 7.09 (d, J = 8.6 Hz, 2H), 6.92 (d, J
= 8.6 Hz, 2H), 6.79 (d, J = 2.9 Hz, 1H), 6.37 (d, J = 2.9 Hz, 1H), 4.92 – 4.90 (m, 1H),
4.74 (dd, J = 2.6, 1.6 Hz, 1H), 4.18 (s, 1H), 3.91 (dt, J = 17.6, 2.6 Hz, 1H), 3.71 (s, 3H),
3.38 (s, 3H), 3.02 (dt, J = 17.6, 1.6 Hz, 1H), 1.09 (s, 9H), 1.07 (s, 9H) ppm. 13C NMR
(75 MHz, CDCl3) δ 185.8, 172.1, 171.1, 149.1, 148.3, 145.9, 142.1, 139.4, 134.3, 133.4,
131.0, 127.6, 109.4, 62.8, 60.9, 55.8, 53.2, 52.7, 40.4, 35.0, 34.7, 29.4, 29.1 ppm.
IR(KBr): 3000, 2956, 2865, 1728, 1656, 1637, 1493, 1435, 1367, 1270, 1254, 1210,
1173, 1092, 955, 910, 873, 808, 710, 580, 506 cm-1. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C29H36ClO5 499.2246; Found 499.2248.
dimethyl 1-(4-bromophenyl)-7,9-di-tert-butyl-4-methylene-8-oxospiro[4.5]deca-6,9-
diene-2,2-dicarboxylate (3da) 85% yield (46.0 mg). White solid, m.p. 122 – 123 oC. Rf
= 0.5 (1/10 EA/PE). 1H NMR (300 MHz, CDCl3) δ 7.29 (d, J = 8.5 Hz, 2H), 6.91 (d, J
= 8.5 Hz, 2H), 6.83 (d, J = 3.0 Hz, 1H), 6.42 (d, J = 2.9 Hz, 1H), 4.97 – 4.95 (m, 1H),
4.79 (dd, J = 2.7, 1.6 Hz, 1H), 4.21 (s, 1H), 3.95 (dt, J = 17.6, 2.6 Hz, 1H), 3.76 (s, 3H),
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3.43 (s, 3H), 3.07 (d, J = 17.7 Hz, 1H), 1.14 (s, 9H), 1.12 (s, 9H) ppm. C NMR (75
MHz, CDCl3) δ 185.8, 172.1, 171.1, 149.2, 148.3, 146.0, 142.1, 139.4, 135.0, 131.3,
130.6, 121.6, 109.4, 62.9, 61.0, 55.8, 53.2, 52.7, 40.5, 35.0, 34.8, 29.4, 29.2 ppm.
IR(KBr): 2991, 2955, 2861, 1727, 1656, 1637, 1489, 1434, 1268, 1254, 1209, 1173,
1090, 907, 886, 810, 580, 503 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C29H36BrO5 543.1741; Found 543.1745.
dimethyl
7,9-di-tert-butyl-1-(4-(methoxycarbonyl)phenyl)-4-methylene-8-
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oxospiro[4.5]deca-6,9-diene-2,2-dicarboxylate (3ea) 80% yield (42.0 mg). White solid,
m.p. 136 – 137 oC. Rf = 0.3 (1/10 EA/PE). 1H NMR (300 MHz, CDCl3) δ 7.85 (d, J =
8.0 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 6.84 (s, 1H), 6.45 (s, 1H), 4.98 (s, 1H), 4.81 (s,
1H), 4.32 (s, 1H), 4.00 (d, J = 17.6 Hz, 1H), 3.88 (s, 3H), 3.77 (s, 3H), 3.40 (s, 3H),
3.10 (d, J = 17.7 Hz, 1H), 1.13 (s, 9H), 1.11 (s, 9H) ppm. 13C NMR (75 MHz, CDCl3)
δ 185.7, 172.0, 171.0, 166.6, 149.1, 148.2, 146.0, 142.0, 141.2, 139.3, 129.7, 129.2,
128.7, 109.5, 62.9, 61.3, 55.8, 53.3, 52.6, 52.0, 40.4, 34.9, 34.7, 29.4, 29.1 ppm.
IR(KBr): 2997, 2955, 2861, 1729, 1658, 1639, 1612, 1436, 1368, 1282, 1252, 1214,
1189, 1172, 1110, 1039, 1016, 933, 874, 768, 709, 580, 491 cm-1. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C31H39O7 523.2690; Found 523.2687.
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dimethyl 7,9-di-tert-butyl-1-(4-cyanophenyl)-4-methylene-8-oxospiro[4.5]deca-6,9-
diene-2,2-dicarboxylate (3fa) 77% yield (37.9 mg). Light yellow solid, m.p. 88 – 89 oC.
Rf = 0.3 (1/10 EA/PE). 1H NMR (300 MHz, CDCl3) δ 7.47 (d, J = 8.4 Hz, 2H), 7.16 (d,
J = 8.4 Hz, 2H), 6.81 (d, J = 3.0 Hz, 1H), 6.42 (d, J = 3.0 Hz, 1H), 5.00 – 4.99 (m, 1H),
4.82 (t, J = 2.1 Hz, 1H), 4.28 (s, 1H), 3.97 (dt, J = 17.7, 2.6 Hz, 1H), 3.77 (s, 3H), 3.43
(s, 3H), 3.09 (d, J = 17.6 Hz, 1H), 1.13 (s, 9H), 1.11 (s, 9H) ppm. 13C NMR (75 MHz,
CDCl3) δ 185.6, 171.8, 170.8, 148.8, 148.7, 146.4, 141.6, 141.5, 138.8, 131.1, 130.5,
118.4, 111.5, 109.8, 62.8, 61.3, 55.8, 53.3, 52.7, 40.4, 35.0, 34.8, 29.4, 29.1 ppm.
IR(KBr): 3003, 2956, 2867, 2224, 1727, 1660, 1643, 1434, 1366, 1271, 1254, 1213,
1173, 1090, 1045, 954, 910, 874, 848, 813, 586, 550, 491 cm-1. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C30H36NO5 490.2588; Found 490.2588.
dimethyl
7,9-di-tert-butyl-4-methylene-8-oxo-1-(4-
(trifluoromethyl)phenyl)spiro[4.5]deca-6,9-diene-2,2-dicarboxylate (3ga) 91% yield
(48.3 mg). White solid, m.p. 87 – 89 oC. Rf = 0.6 (1/10 EA/PE). 1H NMR (300 MHz,
CDCl3) δ 7.43 (d, J = 8.1 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H), 6.81 (d, J = 2.9 Hz, 1H),
6.45 (d, J = 3.0 Hz, 1H), 4.99 – 4.98 (m, 1H), 4.81 (dd, J = 2.6, 1.6 Hz, 1H), 4.32 (s,
1H), 3.98 (dt, J = 17.6, 2.6 Hz, 1H), 3.77 (s, 3H), 3.41 (s, 3H), 3.10 (d, J = 17.6 Hz,
1H), 1.12 (s, 18H) ppm. 13C NMR (75 MHz, CDCl3) δ 185.7, 172.0, 170.9, 149.0, 148.4,
146.1, 141.9, 140.2, 139.3, 130.0, 124.4 (q, J = 3.8 Hz), 109.6, 62.9, 61.1, 55.8, 53.3,
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52.6, 40.5, 35.0, 34.8, 29.4, 29.1 ppm. 19F NMR (282 MHz, CDCl3) δ -36.62 ppm.
IR(KBr): 2996, 2957, 2865, 1732, 1659, 1640, 1459, 1437, 1327, 1269, 1254, 1168,
1128, 1070, 902, 878, 845, 739, 673, 608, 494 cm-1. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C30H36F3O5 533.2509; Found 533.2504.
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dimethyl 7,9-di-tert-butyl-4-methylene-8-oxo-1-(p-tolyl)spiro[4.5]deca-6,9-diene-2,2-
dicarboxylate (3ha) 95% yield (45.7 mg). White solid, m.p. 60 – 61 oC. Rf = 0.6 (1/10
EA/PE). 1H NMR (300 MHz, CDCl3) δ 6.95 (d, J = 8.1 Hz, 2H), 6.88 (d, J = 8.2 Hz,
2H), 6.83 (d, J = 2.9 Hz, 1H), 6.45 (d, J = 2.9 Hz, 1H), 4.95 – 4.94 (m, 1H), 4.78 (dd,
J = 2.7, 1.6 Hz, 1H), 4.22 (s, 1H), 3.96 (dt, J = 17.6, 2.5 Hz, 1H), 3.75 (s, 3H), 3.42 (s,
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3H), 3.07 (dt, J = 17.6, 1.6 Hz, 1H), 2.23 (s, 3H), 1.12 (s, 9H), 1.12 (s, 9H) ppm. C
NMR (75 MHz, CDCl3) δ 186.1, 172.3, 171.3, 149.7, 147.7, 145.4, 142.7, 140.2, 137.0,
132.7, 129.5, 128.1, 109.1, 63.0, 61.4, 56.0, 53.1, 52.5, 40.7, 34.9, 34.7, 29.4, 29.1, 21.0
ppm. IR(KBr): 2997, 2955, 2868, 1731, 1658, 1638, 1514, 1484, 1458, 1435, 1367,
1312, 1263, 1255, 1213, 1171, 1093, 1044, 961, 887, 810, 577, 506 cm-1. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C30H39O5 479.2792; Found 479.2788.
dimethyl 7,9-di-tert-butyl-1-(4-methoxyphenyl)-4-methylene-8-oxospiro[4.5]deca-6,9-
diene-2,2-dicarboxylate (3ia) 87% yield (43.2 mg). White solid, m.p. 120 – 121 oC. Rf
= 0.4 (1/10 EA/PE). 1H NMR (300 MHz, CDCl3) δ 6.94 (d, J = 8.8 Hz, 2H), 6.86 (d, J
= 2.9 Hz, 1H), 6.68 (d, J = 8.8 Hz, 2H), 6.44 (d, J = 2.9 Hz, 1H), 4.95 – 4.94 (m, 1H),
4.79 – 4.77 (m, 1H), 4.22 (s, 1H), 3.97 (dt, J = 17.6, 2.5 Hz, 1H), 3.75 (s, 3H), 3.72 (s,
3H), 3.43 (s, 3H), 3.06 (d, J = 17.5 Hz, 1H), 1.13 (s, 9H), 1.12 (s, 9H) ppm. 13C NMR
(75 MHz, CDCl3) δ 186.0, 172.3, 171.4, 158.8, 149.6, 147.9, 145.6, 142.7, 140.1, 130.8,
127.8, 112.8, 109.1, 63.0, 61.0, 56.1, 55.1, 53.1, 52.6, 40.6, 34.9, 34.7, 29.4, 29.1 ppm.
IR(KBr): 2997, 2952, 2861, 1756, 1726, 1656, 1635, 1614, 1516, 1458, 1439, 1369,
1251, 1184, 1175, 1092, 1032, 912, 874, 821, 706, 577, 527, 488 cm-1. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C30H39O6 495.2741; Found 495.2739.
dimethyl
7,9-di-tert-butyl-1-(4-(dimethylamino)phenyl)-4-methylene-8-
oxospiro[4.5]deca-6,9-diene-2,2-dicarboxylate (3ja) 95% yield (48.2 mg). Brown solid,
m.p. 59 – 61 oC. Rf = 0.4 (1/10 EA/PE).1H NMR (300 MHz, CDCl3) δ 6.90 – 6.84 (m,
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3H), 6.51 – 6.45 (m, 3H), 4.93 (s, 1H), 4.77 (s, 1H), 4.19 (s, 1H), 3.96 (d, J = 17.6 Hz,
1H), 3.74 (s, 3H), 3.45 (s, 3H), 3.05 (d, J = 17.5 Hz, 1H), 2.85 (s, 6H), 1.14 (s, 9H),
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1.13 (s, 9H) ppm. C NMR (75 MHz, CDCl3) δ 186.1, 172.4, 171.5, 149.8, 149.7,
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147.5, 145.1, 143.0, 140.5, 130.3, 123.2, 111.4, 108.8, 63.0, 61.2, 56.3, 53.0, 52.6, 40.6,
40.4, 34.8, 34.6, 29.4, 29.1 ppm. IR(KBr): 3000, 2954, 2867, 2802, 1729, 1658, 1637,
1615, 1524, 1457, 1435, 1367, 1357, 1255, 1169, 1090, 1039, 948, 883, 807, 580, 488
cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C31H42NO5 508.3057; Found
508.3058.
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dimethyl 1-([1,1'-biphenyl]-4-yl)-7,9-di-tert-butyl-4-methylene-8-oxospiro[4.5]deca-
6,9-diene-2,2-dicarboxylate (3ka) 93% yield (50.2 mg). White solid, m.p. 129 – 131
oC. Rf = 0.5 (1/10 EA/PE). 1H NMR (300 MHz, CDCl3) δ 7.53 – 7.50 (m, 2H), 7.43 –
7.38 (m, 4H), 7.34 – 7.29 (m, 1H), 7.08 (d, J = 8.3 Hz, 2H), 6.87 (d, J = 2.9 Hz, 1H),
6.49 (d, J = 2.9 Hz, 1H), 4.99 – 4.97 (m, 1H), 4.81 (dd, J = 2.7, 1.6 Hz, 1H), 4.32 (s,
1H), 4.01 (dt, J = 17.6, 2.6 Hz, 1H), 3.78 (s, 3H), 3.44 (s, 3H), 3.11 (d, J = 17.6 Hz,
1H), 1.13 (s, 18H) ppm. 13C NMR (75 MHz, CDCl3) δ 185.9, 172.3, 171.3, 149.4, 147.9,
145.6, 142.5, 140.5, 140.1, 139.9, 134.9, 130.0, 128.7, 127.3, 126.9, 126.1, 109.3, 62.9,
61.3, 56.0, 53.2, 52.7, 40.6, 34.9, 34.7, 29.4, 29.1 ppm. IR(KBr): 2954, 2925,
2867 ,1730, 1656, 1638, 1617, 1523, 1484, 1458, 1434, 1367, 1315, 1268, 1249, 1214,
1170, 1039, 1007, 957, 901, 886, 848, 759, 695, 503, 488 cm-1. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C35H41O5 541.2949; Found 541.2954.
dimethyl (E)-7,9-di-tert-butyl-4-methylene-8-oxo-1-(4-styrylphenyl)spiro[4.5]deca-
6,9-diene-2,2-dicarboxylate (3la) 94% yield (53.2 mg). Light yellow solid, m.p. 77 –
79 oC. Rf = 0.5 (1/10 EA/PE). 1H NMR (300 MHz, CDCl3) δ 7.48 (d, J = 7.6 Hz, 2H),
7.33 – 7.23 (m, 5H), 7.02 (m, 4H), 6.87 (s, 1H), 6.48 (s, 1H), 4.97 (s, 1H), 4.80 (s, 1H),
4.29 (s, 1H), 4.00 (d, J = 17.6 Hz, 1H), 3.76 (s, 3H), 3.42 (s, 3H), 3.10 (d, J = 17.6 Hz,
1H), 1.14 (s, 18H) ppm. 13C NMR (75 MHz, CDCl3) δ 185.8, 172.2, 171.2, 149.4, 147.8,
145.5, 142.4, 139.9, 137.1, 136.3, 135.2, 129.9, 128.6, 128.5, 128.0, 127.5, 126.4, 125.5,
109.2, 62.9, 61.3, 56.0, 53.2, 52.6, 40.5, 34.9, 34.7, 29.4, 29.1 ppm. IR(KBr): 3027,
2999, 2954, 2866, 1730, 1658, 1638, 1511, 1481, 1450, 1435, 1367, 1267, 1252, 1214,
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1170, 1087, 1044, 963, 874, 807, 757, 692, 580, 533, 488 cm-1. HRMS (ESI-TOF) m/z:
[M + H]+ Calcd for C37H43O5 567.3105; Found 567.3107.
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diene-2,2-dicarboxylate (3ma) 86% yield (46.7 mg). White solid, m.p. 124 – 125 C.
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Rf = 0.5 (1/10 EA/PE). 1H NMR (300 MHz, CDCl3) δ 7.31 (d, J = 7.7 Hz, 1H), 7.13 (s,
1H), 7.08 – 6.98 (m, 2H), 6.90 (d, J = 3.0 Hz, 1H), 6.42 (d, J = 3.0 Hz, 1H), 4.96 (s,
1H), 4.80 (s, 1H), 4.21 (s, 1H), 3.98 (d, J = 17.6 Hz, 1H), 3.76 (s, 3H), 3.50 (s, 3H),
3.05 (d, J = 17.6 Hz, 1H), 1.17 (s, 9H), 1.12 (s, 9H) ppm. 13C NMR (75 MHz, CDCl3)
δ 185.7, 172.0, 171.3, 149.0, 148.6, 146.1, 142.1, 139.0, 137.8, 132.3, 130.6, 129.0,
128.8, 121.2, 109.5, 62.6, 61.1, 55.9, 53.2, 52.7, 40.5, 35.0, 34.7, 29.4, 29.2 ppm.
IR(KBr): 2997, 2955, 2868, 1731, 1658, 1639, 1568, 1458, 1434, 1366, 1269, 1248,
1214, 1172, 954, 884, 774, 701, 586, 491, 438 cm-1. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C29H36BrO5 543.1741; Found 543.1734.
dimethyl 1-(2-bromophenyl)-7,9-di-tert-butyl-4-methylene-8-oxospiro[4.5]deca-6,9-
diene-2,2-dicarboxylate (3na) 77% yield (41.8 mg). White solid, m.p. 157 – 159 oC. Rf
= 0.5 (1/10 EA/PE). 1H NMR (300 MHz, CDCl3) δ 7.50 (d, J = 7.9 Hz, 1H), 7.13 – 6.90
(m, 3H), 6.67 (s, 2H), 5.08 (s, 1H), 5.02 (s, 1H), 4.82 (s, 1H), 3.96 (d, J = 18.2 Hz, 1H),
3.77 (s, 3H), 3.45 (s, 3H), 3.19 (d, J = 17.7 Hz, 1H), 1.17 (s, 9H), 1.08 (s, 9H) ppm. 13C
NMR (75 MHz, CDCl3) δ 185.8, 171.9, 171.2, 149.1, 147.0, 146.0, 141.9, 139.3, 135.2,
133.2, 129.8, 128.8, 127.0, 125.8, 109.8, 63.2, 58.4, 56.2, 53.3, 52.6, 40.8, 34.8, 34.7,
29.2, 29.1 ppm. IR(KBr): 3000, 2955, 2923, 2868, 1735, 1658, 1639, 1459, 1434, 1367,
1266, 1245, 1169, 1024, 906, 882, 808, 755, 490 cm-1. HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C29H36BrO5 543.1741; Found 543.1737.
dimethyl 7,9-di-tert-butyl-4-methylene-1-(naphthalen-1-yl)-8-oxospiro[4.5]deca-6,9-
diene-2,2-dicarboxylate (3oa) 90% yield (46.5 mg). White solid, m.p. 132 –133 oC. Rf
= 0.6 (1/10 EA/PE). 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J = 8.3 Hz, 1H), 7.77 – 7.74
(m, 1H), 7.67 (d, J = 8.1 Hz, 1H), 7.48 – 7.38 (m, 2H), 7.31 – 7.26 (m, 1H), 7.11 (d, J
= 7.2 Hz, 1H), 6.72 (d, J = 3.0 Hz, 1H), 6.43 (d, J = 2.9 Hz, 1H), 5.44 (s, 1H), 5.05 (s,
1H), 4.80 (s, 1H), 4.10 (dt, J = 17.3, 2.6 Hz, 1H), 3.79 (s, 3H), 3.32 – 3.25 (m, 4H),
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1.03 (s, 9H), 0.80 (s, 9H) ppm. 13C NMR (75 MHz, CDCl3) δ 185.5, 172.4, 171.0, 149.5,
146.6, 145.1, 142.5, 140.3, 133.8, 133.0, 132.5, 128.7, 127.9, 126.2, 125.5, 125.3, 123.8,
123.5, 109.9, 63.8, 55.7, 53.4, 52.6, 41.2, 34.5, 34.5, 29.1, 28.8 ppm. IR(KBr): 3049,
2998, 2954, 2867, 1728, 1658, 1641, 1510, 1435, 1366, 1272, 1245, 1209, 1171, 1093,
1045, 963, 886, 800, 777, 731, 629, 576, 527, 494 cm-1. HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C33H39O5 515.2792; Found 515.2795.
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dimethyl
7,9-di-tert-butyl-4-methylene-8-oxo-1-(thiophen-2-yl)spiro[4.5]deca-6,9-
diene-2,2-dicarboxylate (3pa) 93% yield (43.7 mg). White solid, m.p. 81 – 82 oC. Rf =
0.5 (1/10 EA/PE). 1H NMR (300 MHz, CDCl3) δ 7.07 (dd, J = 4.8, 1.5 Hz, 1H), 6.99
(d, J = 3.0 Hz, 1H), 6.85 – 6.82 (m, 2H), 6.41 (d, J = 3.0 Hz, 1H), 4.93 – 4.92 (m, 1H),
4.79 – 4.78 (m, 1H), 4.62 (s, 1H), 3.92 (dt, J = 17.5, 2.6 Hz, 1H), 3.78 (s, 3H), 3.46 (s,
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3H), 3.03 (d, J = 17.5 Hz, 1H), 1.20 (s, 9H), 1.15 (s, 9H) ppm. C NMR (75 MHz,
CDCl3) δ 185.9, 172.0, 171.0, 148.9, 148.7, 146.2, 142.2, 139.3, 137.4, 127.5, 125.9,
124.5, 109.2, 63.4, 56.1, 55.9, 53.2, 52.9, 40.3, 35.0, 34.8, 29.4, 28.9 ppm. IR(KBr):
2999, 2955, 2868, 1731, 1659, 1639, 1484, 1458, 1435, 1367, 1261, 1212, 1172, 1093,
1044, 903, 886, 854, 739, 699, 491 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C27H35O5S 471.2200; Found 471.2195.
dimethyl 7,9-di-tert-butyl-1-methyl-4-methylene-8-oxospiro[4.5]deca-6,9-diene-2,2-
1
dicarboxylate (3qa) 47% yield (18.9 mg). Colorless oil. Rf = 0.5 (1/10 EA/PE). H
NMR (300 MHz, CDCl3) δ 6.57 (d, J = 2.9 Hz, 1H), 6.33 (d, J = 2.9 Hz, 1H), 4.92 (s,
1H), 4.71 (s, 1H), 3.76 (s, 6H), 3.60 (d, J = 17.4 Hz, 1H), 3.00 (q, J = 7.2 Hz, 1H), 2.88
(d, J = 17.4 Hz, 1H), 1.23 (s, 9H), 1.19 (s, 9H), 0.80 (d, J = 7.2 Hz, 3H) ppm. 13C NMR
(75 MHz, CDCl3) δ 186.6, 172.0, 171.6, 149.7, 148.2, 146.1, 143.4, 139.9, 109.6, 61.8,
54.6, 52.9, 52.5, 50.2, 40.7, 35.0, 34.8, 29.6, 29.5, 11.6 ppm. IR(KBr): 2956, 2869,
1734, 1691, 1659, 1639, 1481, 1458, 1435, 1367, 1267, 1200, 1174, 1128, 1098, 1066,
1042, 1004, 960, 936, 880, 810, 777, 739, 494 cm-1. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C24H35O5 403.2479; Found 403.2473.
dimethyl
(E)-7,9-di-tert-butyl-4-methylene-8-oxo-1-styrylspiro[4.5]deca-6,9-diene-
o
2,2-dicarboxylate (3ra) 51% yield (25.1 mg). White solid, m.p. 87 – 88 C. Rf = 0.4
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(1/10 EA/PE). 1H NMR (300 MHz, CDCl3) δ 7.26 – 7.17 (m, 5H), 6.67 (d, J = 2.9 Hz,
1H), 6.42 (d, J = 2.9 Hz, 1H), 6.33 (d, J = 15.5 Hz, 1H), 5.83 (dd, J = 15.6, 9.8 Hz, 1H),
5.00 (s, 1H), 4.79 (s, 1H), 3.77 – 3.63 (m, 8H), 3.02 (d, J = 17.1 Hz, 1H), 1.20 (s, 18H)
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ppm. C NMR (75 MHz, CDCl3) δ 186.3, 171.6, 171.1, 149.4, 148.3, 146.5, 142.5,
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139.2, 136.7, 134.3, 128.4, 127.5, 126.3, 123.1, 110.1, 62.2, 59.5, 55.5, 53.1, 52.7, 41.0,
34.9, 34.7, 29.6, 29.5 ppm. IR(KBr): 3121, 3015, 1729, 1655, 1635, 1400, 1260, 1166,
1072, 986, 945, 860, 748, 695, 547, 521 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C31H39O5 491.2792; Found 491.2796.
dimethyl
7,9-dimethyl-4-methylene-8-oxo-1-phenylspiro[4.5]deca-6,9-diene-2,2-
dicarboxylate(3sa) 26% yield (10.0 mg). White solid, m.p. 83 – 84 oC. Rf = 0.3 (1/10
EA/PE). 1H NMR (300 MHz, CDCl3) δ 7.18 – 7.16 (m, 3H), 7.09 – 7.08 (m, 2H), 7.01
(s, 1H), 6.56 (s, 1H), 4.94 (s, 1H), 4.83 (s, 1H), 4.34 (s, 1H), 3.97 (dd, J = 17.5, 2.1 Hz,
1H), 3.75 (s, 3H), 3.33 (s, 3H), 3.04 (dd, J = 17.3, 1.8 Hz, 1H), 1.82 (s, 6H) ppm. 13C
NMR (75 MHz, CDCl3) δ 187.0, 172.1, 171.2, 148.7, 146.5, 144.0, 136.0, 135.8, 133.8,
129.5, 127.7, 127.6, 109.3, 63.3, 60.9, 56.9, 53.1, 52.5, 40.6, 16.2, 16.1 ppm. IR(KBr):
2953, 2923, 2852, 1729, 1668, 1638, 1602, 1452, 1434, 1376, 1252, 1208, 1159, 1094,
1044, 904, 753, 702, 571, 524, 485, 459 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C23H25O5 381.1697; Found 381.1693.
diethyl
7,9-di-tert-butyl-4-methylene-8-oxo-1-phenylspiro[4.5]deca-6,9-diene-2,2-
dicarboxylate (3ab) 95% yield (46.7 mg). White solid, m.p. 91 – 93 oC. Rf = 0.6 (1/10
EA/PE). 1H NMR (300 MHz, CDCl3) δ 7.16 – 7.13 (m, 3H), 7.05 – 7.02 (m, 2H), 6.73
(d, J = 2.9 Hz, 1H), 6.52 (d, J = 2.9 Hz, 1H), 4.96 (s, 1H), 4.78 (s, 1H), 4.28 – 4.18 (m,
3H), 4.02 – 3.92 (m, 2H), 3.77 – 3.67 (m, 1H), 3.09 (d, J = 17.5 Hz, 1H), 1.25 (t, J =
13
7.1 Hz, 3H), 1.14 (s, 9H), 1.08 (s, 9H), 0.81 (t, J = 7.2 Hz, 3H) ppm. C NMR (75
MHz, CDCl3) δ 185.9, 171.7, 170.5, 149.7, 147.2, 145.3, 142.6, 140.5, 136.3, 129.6,
127.4, 127.3, 109.1, 63.1, 61.9, 61.6, 61.2, 55.8, 40.6, 34.8, 34.6, 29.4, 29.0, 13.9, 13.3
ppm. IR(KBr): 2958, 2868, 1731, 1658, 1638, 1457, 1389, 1367, 1256, 1210, 1178,
1096, 1066, 1044, 1010, 883, 702, 580, 491 cm-1. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C31H41O5 493.2949; Found 493.2956.
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diisopropyl
7,9-di-tert-butyl-4-methylene-8-oxo-1-phenylspiro[4.5]deca-6,9-diene-
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8
o
2,2-dicarboxylate (3ac) 94% yield (48.9 mg). White solid, m.p. 96 – 97 C. Rf = 0.7
(1/10 EA/PE). 1H NMR (300 MHz, CDCl3) δ 7.16 – 7.13 (m, 3H), 7.06 – 7.03 (m, 2H),
6.62 (d, J = 2.9 Hz, 1H), 6.57 (d, J = 2.9 Hz, 1H), 5.14 – 5.03 (m, 1H), 4.96 (s, 1H),
4.76 (s, 1H), 4.73 – 4.62 (m, 1H), 4.29 (s, 1H), 3.96 (dt, J = 17.4, 2.5 Hz, 1H), 3.07 (d,
J = 17.3 Hz, 1H), 1.28 (d, J = 6.3 Hz, 3H), 1.22 (d, J = 6.3 Hz, 3H), 1.16 (s, 9H), 1.07
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(d, J = 6.2 Hz, 3H), 1.04 (s, 9H), 0.50 (d, J = 6.3 Hz, 3H) ppm. C NMR (75 MHz,
CDCl3) δ 186.0, 171.2, 169.7, 149.8, 146.6, 145.1, 142.7, 141.0, 136.8, 129.5, 127.5,
127.2, 109.0, 69.5, 69.4, 63.3, 60.8, 55.7, 40.9, 34.7, 34.6, 29.4, 29.0, 21.6, 21.4, 21.3,
20.4 ppm. IR(KBr): 2958, 2869, 1729, 1658, 1639, 1485, 1456, 1388, 1374, 1266, 1215,
1181, 1147, 1108, 1037, 934, 904, 882, 830, 702, 577, 491, 421 cm-1. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C33H45O5 521.3262; Found 521.3262.
di-tert-butyl 7,9-di-tert-butyl-4-methylene-8-oxo-1-phenylspiro[4.5]deca-6,9-diene-
o
2,2-dicarboxylate (3ad) 96% yield (52.7 mg). White solid, m.p. 93 – 95 C. Rf = 0.5
(1/20 EA/PE). 1H NMR (300 MHz, CDCl3) δ 7.18 – 7.16 (m, 3H), 7.09 – 7.06 (m, 2H),
6.62 (d, J = 2.9 Hz, 1H), 6.33 (d, J = 2.9 Hz, 1H), 4.97 (s, 1H), 4.72 (s, 1H), 4.19 (s,
1H), 3.89 (d, J = 17.7 Hz, 1H), 3.08 (d, J = 17.6 Hz, 1H), 1.49 (s, 9H), 1.19 (s, 9H),
1.03 (s, 9H), 0.98 (s, 9H) ppm. 13C NMR (75 MHz, CDCl3) δ 186.2, 170.8, 168.5, 150.3,
145.2, 145.1, 142.9, 142.0, 137.9, 129.6, 127.7, 127.0, 108.9, 81.9, 81.8, 64.8, 60.4,
55.6, 40.6, 34.7, 34.6, 29.4, 29.0, 27.8, 27.1 ppm. IR(KBr): 3068, 2965, 2870, 1728,
1656, 1634, 1457, 1329, 1370, 1356, 1269, 1259, 1233, 1163, 1140, 1060, 1039, 930,
913, 883, 844, 737, 670, 653, 568, 506, 465 cm-1. HRMS (ESI-TOF) m/z: [M + H]+
Calcd for C35H49O5 549.3575; Found 549.3576.
dibenzyl 7,9-di-tert-butyl-4-methylene-8-oxo-1-phenylspiro[4.5]deca-6,9-diene-2,2-
dicarboxylate(3ae) 90% yield (55.5 mg). White solid, m.p. 114 – 115 oC. Rf = 0.4 (1/20
EA/PE). 1H NMR (300 MHz, CDCl3) δ 7.27 – 7.10 (m, 11H), 7.01 (d, J = 5.0 Hz, 2H),
6.79 – 6.75 (m, 3H), 6.50 (d, J = 2.9 Hz, 1H), 5.09 (q, J = 12.2 Hz, 2H), 4.94 – 4.78 (m,
3H), 4.58 (d, J = 12.2 Hz, 1H), 4.31 (s, 1H), 4.00 (d, J = 17.5 Hz, 1H), 3.10 (d, J = 17.5
13
Hz, 1H), 1.12 (s, 9H), 1.08 (s, 9H) ppm. C NMR (75 MHz, CDCl3) δ 186.0, 171.4,
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170.4, 149.4, 147.5, 145.4, 142.5, 140.3, 136.0, 135.0, 134.4, 129.6, 128.5, 128.4, 128.3,
128.1, 128.1, 128.0, 127.6, 127.5, 109.4, 67.8, 67.5, 63.2, 61.3, 55.9, 40.7, 34.8, 34.7,
29.4, 29.0 ppm. IR(KBr): 3032, 2957, 2867, 1728, 1658, 1638, 1496, 1481, 1456, 1368,
1254, 1167, 1087, 1031, 904, 880, 749, 698, 586, 497 cm-1. HRMS (ESI-TOF) m/z: [M
+ H]+ Calcd for C41H45O5 617.3262; Found 617.3262.
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7,9-di-tert-butyl-4-methylene-1-phenyl-2-tosyl-2-azaspiro[4.5]deca-6,9-dien-8-one
(3af) 23% yield (11.4 mg). brown solid, m.p. 157 – 158 oC. Rf = 0.3 (1/10 EA/PE). 1H
NMR (300 MHz, CDCl3) δ 7.64 (d, J = 8.2 Hz, 2H), 7.30 – 7.23 (m, 5H), 7.07 (m, 2H),
6.14 (d, J = 2.9 Hz, 1H), 5.74 (d, J = 2.9 Hz, 1H), 5.04 (s, 1H), 4.74 (s, 1H), 4.64 (s,
1H), 4.49 (d, J = 14.1 Hz, 1H), 4.38 (d, J = 14.2 Hz, 1H), 2.43 (s, 3H), 1.08 (s, 9H),
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0.97 (s, 9H) ppm. C NMR (75 MHz, CDCl3) δ 185.9, 147.9, 146.3, 145.0, 143.9,
138.6, 138.4, 129.8, 128.0, 128.0, 127.5, 127.0, 110.1, 71.9, 54.6, 52.4, 34.9, 34.6, 29.1,
29.0, 21.5 ppm. IR(KBr): 2958, 2922, 2868, 2852, 1727, 1658, 1640, 1598, 1457, 1366,
1351, 1249, 1216, 1199, 1182, 1163, 1137, 1094, 1059, 1042, 995, 942, 883, 816, 780,
736, 697, 663, 612, 593, 580, 548, 512 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C31H38NO3S 504.2567; Found 504.2571.
General Procedure for the Preparation of Intermediate 4aa.
A sealed tube was charged with para-quinone methide (0.1 mmol, 1 equiv), propargyl
malonates (0.15 mmol, 1.5 equiv) and Cs2CO3 (1.2 mmol, 1.2 equiv). The vial is
thoroughly flushed with argon and dry dimethyl formamide (1.0 mL) was added under
o
argon. Then the reaction mixture was stirred at 60 C. After the reaction vessel was
cooled to room temperature, the solution was concentrated in vacuo and purified by
careful chromatography on silica gel (EtOAc/petroleum ether = 1/50) to afford the
desired product.
dimethyl
2-((3,5-di-tert-butyl-4-hydroxyphenyl)(phenyl)methyl)-2-(prop-2-yn-1-
yl)malonate (4aa) 90% yield (41.9 mg). White solid, m.p. 115 – 117 oC. Rf = 0.4 (1/10
EA/PE). 1H NMR (300 MHz, CDCl3) δ 7.42 (d, J = 7.1 Hz, 2H), 7.28 – 7.23 (m, 2H),
7.19 (m, 3H), 5.09 (s, 1H), 4.90 (s, 1H), 3.63 (s, 6H), 2.87 – 2.74 (m, 2H), 1.98 (t, J =
13
2.6 Hz, 1H), 1.40 (s, 18H) ppm. C NMR (75 MHz, CDCl3) δ 170.5, 170.4, 152.5,
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140.6, 135.0, 129.9, 127.8, 126.7, 126.5, 79.6, 71.1, 62.1, 54.9, 52.5, 52.3, 34.3, 30.3,
26.2 ppm. IR(KBr): 3630, 2955, 2867, 1730, 1638, 1496, 1436, 1363, 1309, 1279, 1227,
1203, 1177, 1122, 1077, 1045, 978, 892, 871, 810, 771, 702, 645, 538 cm-1. HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C29H36O5Na 487.2455; Found 487.2459.
General Procedure for the Decarboxylation of 3aa with Diethylamine.
A sealed tube was charged with 3aa (0.1 mmol, 1 equiv) and diethylamine (1.0 mL).
The reaction mixture was stirred at 80 oC for 24 h. After the reaction vessel was cooled
to room temperature, the solution was concentrated in vacuo and purified by careful
chromatography on silica gel (EtOAc/petroleum ether = 1/200) to afford the desired
product 5aa.
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methyl
7,9-di-tert-butyl-4-methylene-8-oxo-1-phenylspiro[4.5]deca-6,9-diene-2-
carboxylate (5aa) 75% yield (30.5 mg), trans:cis > 20:1. White solid, m.p. 81 – 83 oC.
Rf = 0.7 (1/10 EA/PE). 1H NMR (300 MHz, CDCl3) δ 7.17 – 7.13 (m, 3H), 7.03 – 6.99
(m, 2H), 6.58 (d, J = 2.8 Hz, 1H), 6.28 (d, J = 2.8 Hz, 1H), 5.01 – 5.00 (m, 1H), 4.77 –
4.76 (m, 1H), 3.69 – 3.62 (m, 5H), 3.16 – 3.08 (m, 1H), 3.00 – 2.92 (m, 1H), 1.23 (s,
9H), 0.95 (s, 9H) ppm. 13C NMR (75 MHz, CDCl3) δ 186.0, 174.3, 149.8, 147.7, 145.0,
143.1, 139.1, 135.7, 127.7, 127.3, 110.5, 59.4, 55.9, 52.1, 44.7, 36.3, 34.7, 34.4, 29.5,
28.9 ppm. IR(KBr): 3125, 3005, 2957, 2866, 1731, 1658, 1638, 1481, 1458, 1430, 1392,
1366, 1319, 1267, 1215, 1167, 1134, 1101, 1021, 924, 901, 885, 866, 827, 792, 745,
699, 671, 627, 568, 544, 524, 497, 488 cm-1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C27H35O3 407.2581; Found 407.2582.
General Procedure for the Further Transformation of 3aa with TFA
A sealed tube was charged with 3aa (0.1 mmol, 1 equiv) and dichloromethane (1.0
mL). Trifluoroacetic acid was then added, and the reaction mixture was stirred at
ambient temperature until the reaction was judged to be completed by TLC analysis.
The mixture was extracted by dichloromethane, and the combined organic layers were
washed with H2O, brine, dried over Na2SO4. Then the solution was concentrated in
vacuo and purified by chromatography on silica gel (EtOAc/petroleum ether = 1/50 –
1/20) to afford the desired product 6aa.
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dimethyl
6,8-di-tert-butyl-7-hydroxy-4-methyl-1-phenylnaphthalene-2,2(1H)-
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8
dicarboxylate (6aa) 76% yield (35.5 mg). White solid, m.p. 97 – 98 oC. Rf = 0.4 (1/10
EA/PE). 1H NMR (300 MHz, CDCl3) δ 7.22 (s, 1H), 7.16 – 7.12 (m, 2H), 6.89 – 6.87
(m, 3H), 5.95 (s, 1H), 5.70 (s, 1H), 5.40 (s, 1H), 3.62 (s, 3H), 3.61 (s, 3H), 2.17 (s, 3H),
1.55 (s, 9H), 1.45 (s, 9H) ppm. 13C NMR (75 MHz, CDCl3) δ 170.8, 170.2, 155.3, 138.5,
135.8, 133.9, 133.4, 129.6, 127.8, 126.6, 121.3, 116.8, 61.3, 52.6, 52.4, 44.2, 37.7, 34.3,
32.9, 30.2, 20.7 ppm. IR(KBr): 3622, 2955, 2925, 2867, 1739, 1638, 1493, 1449, 1433,
1361, 1313, 1251, 1210, 1159, 1045, 883, 821, 774, 748, 701, 589 cm-1. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C29H37O5 465.2636; Found 465.2638.
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Associated content
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
1H and 13C NMR spectra for all new compounds (PDF)
X-ray crystallographic data for 3aa (CIF)
Author information
Corresponding Author
*E-mail: ajlin@cpu.edu.cn
*E-mail: hyao@cpu.edu.cn and cpuhyao@126.com
ORCID
Aijun Lin: 0000-0001-5786-4537
Hequan Yao: 0000-0003-4865-820X
Notes
The authors declare no competing financial interest.
Acknowledgments
Generous financial support from the National Natural Science Foundation of China
(NSFC21502232 and NSFC 21572272), the Natural Science Foundation of Jiangsu
Province (BK20140655), the Foundation of State Key Laboratory of Natural Medicines
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(ZZYQ201605) is gratefully acknowledged.
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References
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9
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Fortanet, J.; Del Aguila Sanchez, M. A.; Buchwald, S. L. J. Am. Chem. Soc. 2011, 133,
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James, M. J.; Cuthbertson, J. D.; O ’Brien, P.; Taylor, R. J. K.; Unsworth, W. P. Angew.
Chem., Int. Ed. 2015, 54, 7640, and references cited therein.
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Dohi, T.; Minamitsuji, Y.; Maruyama, A.; Hirose, S.; Kita, Y. Org. Lett. 2008, 10, 3559.
(c) Andrez, J.-C.; Giroux, M.-A.; Lucien, J.; Canesi, S. Org. Lett. 2010, 12, 4368. (d)
Beaulieu, M.-A.; Sabot, C.; Achache, N.; Guérard, K. C.; Canesi, S. Chem.-Eur. J. 2010,
16, 11224.
(5) For selected examples, see: (a) Marx, J. N.; Bih, Q. R. J. Org. Chem. 1987, 52, 336.
(b) Swenton, J. S.; Carpenter, K.; Chen, Y.; Kerns, M. L.; Morrow, G. W. J. Org. Chem.
1993, 58, 3308. (c) Nemoto, T.; Wu, R.; Zhao, Z.; Yokosaka, T.; Hamada, Y.
Tetrahedron 2013, 69, 3403.
(6) Nicolaou, K. C.; Li, A.; Ellery, S. P.; Edmonds, D. J. Angew. Chem., Int. Ed. 2009,
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(8) For selected examples, see: (a) Chu, W.-D.; Zhang, L.-F.; Bao, X.; Zhao, X.-H.;
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(15) Crystallographic data for 3aa have been deposited with the Cambridge
Crystallographic Data Centre as Deposition Numbers CCDC 1539859. Detailed
information of X-ray crystallographic analysis can be found in the Supporting
Information.
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cited therein.
(18) For more details of the structures of all the substrates, see Supporting Inforamtion.
(19) For more details of full spectra of 6aa, see Supporting Information. For selected
examples of the natural products containing the skeletons, see: (a) Meng, Q.; Hesse, M.
Helv. Chim. Acta 1990, 73, 455. (b) Obase, A.; Kageyama, A.; Manabe, Y.; Ozawa, T.;
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