New strategy to construct fused/bridged/spiro carbocyclic scaffolds based on the design of novel 6-C synthon precursor

Article abstract of DOI:10.1039/c0ob00660b

In this article we report a new strategy to build fused/spiro/bridged carbocyclic systems with a novel 6-C synthon from readily available diallyl diacetates through the sequential Pd-catalyzed double allyl alkylation and Diels-Alder annulation. Further ex

Full text of DOI:10.1039/c0ob00660b

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PAPER
New strategy to construct fused/bridged/spiro carbocyclic scaffolds based on
the design of novel 6-C synthon precursor†
Jia Liu,a,b Xi Wang,b Chang-Liang Sun,b Bi-Jie Li,b Zhang-Jie shib and Min Wang*a
Received 3rd September 2010, Accepted 22nd November 2010
DOI: 10.1039/c0ob00660b
In this article we report a new strategy to build fused/spiro/bridged carbocyclic systems with a novel
6-C synthon from readily available diallyl diacetates through the sequential Pd-catalyzed double allyl
alkylation and Diels–Alder annulation. Further exploration on the application of this strategy can
construct useful complex scaffolds.
Introduction
Fused/bridged/spiro carbocyclic ring scaffolds are one of most
important motifs in the natural and synthetic organic world.1
Many efforts have been made to construct such structural units
and various methods have been developed and successfully
implemented into organic synthesis.2 For instance, Diels–Alder
reactions have been employed as a very successful and efficient
strategy and unique natural products were synthesized using this
approach.3 The strategy to construct such polycarb carbocyclic
systems was mainly built from the existing carbon rings to the
other.4 For example, the bicyclic ring system could be constructed
from ring A or ring B (Path a, Scheme 1). In this paper, we show
a new 6-C synthon, which could be applied to construct complex
fused-, bridge and spiro- systems through the simple sequential
Scheme 2 Initiated design on 6-C TMDM synthon inspired by p–allyl
and TMM.
chemical transformations from an acyclic precursor by a one-pot
strategy from both different directions (Path b, Scheme 1).
generated from allyl acetate and its derivatives, which then under-
went further transformations to produce the designed products,
leaving an activated double bond for further functionalization.
From this point, we proposed that linking together two allyl
acetates would introduce the dienyl adducts (3) into the product
after Pd-catalyzed transformations, which could be a Diels–Alder
precursor for the subsequent ring construction. As envisioned, a
6-C synthon (tetramethylenedimethyne, TMDM 3¢) was designed
for the construction of bi-/poly-cyclic system.
Scheme 1 New strategy for the construction of bi-/poly-cyclic systems.
Our design was initially inspired by p-allyl species and
trimethylenemethane (TMM) in palladium chemistry, which have
been well studied and broadly applied in organic synthesis (Scheme
2).5 In previous studies, p-allyl-Pd and TMM-Pd species were
Results and discussion
Construction of fused/bridged/spiro carbocyclic scaffolds by
Pd-catalyzed based on novel 6-C synthon precursor
Many methods have been reported to efficiently construct diallyl
diacetates 3.6 The en-yne metathesis procedure was selected to
make 3 due to its efficiency and step economy.6a We initiated our
studies with simple dinucleophiles to build the first carbocycles
via Pd-based catalysis. After the systematical screening, we found
that the desired five-membered adduct 5a was obtained in an
excellent isolated yield when dimethyl malonate 4a was employed
as a substrate in the presence of Pd(OAc)2 (2.5 mol%), and DPPF
(5.0 mol%) as ligand, and DBU as base (Eq. 1, Table 1). This
aDepartment of Applied Chemistry, China Agricultural University, Beijing
100193, PR China. E-mail: wangmin@cau.edu.cn; Tel: 86-010-62731356
bBeijing National Laboratory of Molecular Sciences (BNLMS) and Key
Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry
of Education, Peking University, Beijing, PR China. E-mail: zshi@
pku.edu.cn; Fax: 86-010-62760890; Tel: 86-010-62760890
† Electronic supplementary information (ESI) available: Experimental
procedures as well as X-ray datas of 11 and 17. CCDC reference numbers:
777559 and 777560. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0ob00660b
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Table 1 Double substitution of diallyl diacetate
3 with various
The subsequent Diels–Alder annualtion was studied with the
bridged product 9a. When N-phenylmaleimide 10 was used, the
complicated fused/bridged cyclic compound 11 was produced in
an excellent yield under simple reaction conditions (eqn (4)). The
structure of the product was determined by X-ray crystallography
(Fig. 1), which indicates that the carbonyl group and two hydrogen
atoms locate at the trans position.
nucleophilesa
(4)
Fig. 1 X-Ray structure of compound 11 with toluene. ORTEP diagram
with ellipsoide drawn at the 30% probability.
Notably, this sequential two-step procedure could be simplified
in one-pot. Starting from diallyl diacetate 3, with either dinu-
cleophilie 4a or dimethyl 2-oxocyclohexane-1,3-dicarboxylate 8b,
and dimethyl acetylene dicarboxylate (DMAD) 12, two separate
reactions were carried out in different solvents in one pot without
additional purification. The 5,6-fused ring system 13 and a bridged
system 14 were constructed in one pot in excellent yields (eqn (5)
and 6).
a All the reactions were carried out in the scale of 0.2 mmol of 3 and
0.24 mmol of dinucleophile in the presence of 2.5 mol% of Pd(OAc)2 and
5.0 mol% of DPPF, 2.5 eq. of DBU in 2.5 mL of CH2Cl2 and isolate yields
were reported. 5h and 5i were obtained at 40 ◦C.
(5)
idea could also be extended to construct the spirocarbocycle 7a
with 1,3-cyclohexadione 6a as a dinucleophile. Most importantly,
when 1,3-dinucleophile 8a was surveyed, a complex bridged ring
system 9a was constructed in one step with excellent efficiency. It
is important to note that the dienyl motif is untouched under such
conditions.
To explore the substrate scope, various dinucleophiles were
tested (Table 1). Different electron withdrawing groups were
investigated to replace the ester group of malonate to activate
the C–Hs of methylene group. The desired products were ob-
tained in good to excellent yields (5a–5i). Notably, the use of
the phenylsulfonyl group offers the possibility of subsequently
desulfonylation of the products 5h and 5i to produce other
substituted cyclopentanes.7 For the production of the spiro ring
system, different sized diketones were tested and the desired
products 7a–7c were obtained in good yields. Furthermore, a cyclic
1,3,5-tricarbonyl reagent 8a was subjected to such transformation,
and the desired bridged product 9a was produced in 76% isolated
yield.
(6)
It is important to note that, with the use of linear 1,3,5-
tricarbonyl compound 15, the bridged compound 16 was produced
in a good yield through four rounds of nucleophilic substitutions
with four carbon-carbon bond formations, while avoiding the
formation of linear by-products (eqn (7)). Furthermore, double
Diels–Alder annulations induced the formation of a complicated
fused scaffold 17, whose structure was also successfully determined
by X-ray crystallography (Fig. 2).
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and DBU (99% pure) was purchased from Alfa. CH2Cl2 was
distilled over CaH2. 1H NMR (300 MHz) and 13C NMR (50 MHz)
was recorded on Varian Inc spectrometers or 13C NMR (60 MHz)
was registered on Jeol spectrometers with CDCl3 as solvent and
tetramethylsilane (TMS) as the internal standard. Chemical shifts
are reported in ppm by assigning TMS resonance in the 1H
spectrum as 0.00 ppm and CDCl3 resonance in the 13C spectrum
as 77.0 ppm. All coupling constants (J values) are reported in
Hertz (Hz). Column chromatography was performed on silica
gel 200–300 mesh. IR, GC, MS, and HRMS were performed
by the State-authorized Analytical Center in Peking University.
The following compounds were prepared according to known
literature procedures: 3,9 8a,10 8b.11
(7)
Experimental procedure for synthesis of
2,3-dimethylenebutane-1,4-diyl diacetate (3):9
To a three-necked flask (250 mL) equipped with a magnetic stir
bar was added 2.12 g (2.5 mmol, 5 mol%) of 1,3-dimesityl-4,5-
dihydroimidazol-2-ylidenetricyclohexylphosphine
benzylidene
ruthenium dichloride (Grubbs II catalyst)12 under an ethylene
balloon. A solution of 8.5 g of but-2-yne-1,4-diyl diacetate
(50 mmol) in 200 mL of CH2Cl2 was added to the flask. The
mixture was stirred at room temperature for 12 h. The reaction
mixture was purified by silica gel column chromatography with
ether/petroleum ether = 1/4 to afford compound 3 as a white
solid (8.11 g, 82% yield). 1H NMR (CDCl3, 300 MHz): d 5.34 (bs,
2H), 5.31 (bs, 2H), 4.78 (s, 4H), 2.10 (s, 6H). 13C NMR (CDCl3,
50 MHz): d 170.5, 139.3, 115.8, 64.9, 20.9. MS (C10H14O4): 198
(M+). HRMS (EI): Anal. Calcd. (M+) 198.08, Found: 198.1. IR
(cm-1): n 1742, 1405, 1318, 1260, 1178.
Fig. 2 X-Ray structure of compound 17 with dichloromethane. ORTEP
diagram with ellipsoide drawn at the 30% probability.
Further investigations indicated that the carbonyl bridged ring
system could also be transformed into complicated fused ring
systems. Starting from DMAD 12, the extrusion of carbon
monoxide (CO) was facilitated in a high efficiency by a light
induced photoreaction (eqn (8)).8 This study provided a potential
strategy to construct fused ring scaffolds from the same 6-C
synthon through a different pathway.
General procedure for the cycloaddition reaction of diyl diacetate
with nucleophile by Pd catalysis:
To an oven dried Schlenk tube was added 2,3-dimethylenebutane-
1,4-diyl diacetate 3 (39.6 mg, 0.20 mmol), nucleophile (0.24 mmol),
Pd(OAc)2 (1.12 mg, 0.005 mmol), DPPF (5.54 mg, 0.01 mmol),
DBU (76 mg, 0.50 mmol). The tube was evacuated and refilled
with N2, and this process was repeated 3 times. Then 2.5 mL
of CH2Cl2 was added into the tube by syringe. The mixture was
stirred at room temperature for 24 h. The mixture was applied to
flash column chromatography eluting with ether and petroleum
ether.
(8)
Conclusions
Dimethyl 3,4-dimethylenecyclopentane-1,1-dicarboxylate (5a):
In summary, we have designed
a new strategy to build
Following the general procedure, starting from 32 mg (0.24 mmol)
of dimethyl malonate 4a, product 5a was obtained using
ether/petroleum ether (1 : 4) as the eluant. Yield: 33.4 mg, 79%,
fused/bridged/spiro carbocyclic systems with a novel 6-C synthon
from readily available diallyl diacetates through the sequential
Pd-catalyzed double allyl alkylation and Diels Alder annulation.
This strategy could also be applied to construct various conserved
structural units in the synthetic world. Further exploration on the
application of this strategy is underway.
1
colorless oil. H NMR (CDCl3, 300 MHz): d 5.40 (s, 2H), 4.96
(s, 2H), 3.73 (s, 6H), 3.04 (s, 4H). 13C NMR (CDCl3, 50 MHz):
d 171.6, 144.4, 105.6, 57.6, 52.8, 41.2. MS (C11H14O4): 210
(M+). HRMS (ESI): Anal. Calcd. (M+Na+) 233.07843, Found:
233.07831. IR (cm-1): n 1735, 1435, 1288, 1247, 1178.
Experimental section
Ethyl 1-acetyl-3,4-dimethylenecyclopentanecarboxylate (5b):
All the reactions were carried out under a nitrogen atmosphere
using standard Schlenk techniques. Pd(OAc)2 (99.99% pure) was
purchased from Alfa, DPPF (99% pure) was purchased from Zilai
Following the general procedure, starting from 32 mg (0.24 mmol)
of ethyl acetoacetate 4b, product 5b was obtained using
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ether/petroleum ether (1 : 4) as the eluant. Yield: 35.4 mg, 85%,
colorless oil. 1H NMR (CDCl3, 300 MHz): d 5.39 (s, 2H), 4.96 (s,
2H), 4.24–4.16 (m, 2H), 3.04–2.91 (m, 4H), 2.19 (s, 3H), 1.26 (t,
3H, J = 7.2 Hz). 13C NMR (CDCl3, 50 MHz): d 203.2, 171.9,
144.6, 105.6, 64.0, 61.7, 39.9, 26.3, 14.0. MS (C12H16O3): 208
(M+). HRMS (ESI): Anal. Calcd. (M+Na+) 231.09917, Found:
231.09911. IR (cm-1): n 1713, 1357, 1235, 1180, 1151.
ether/petroleum ether (1 : 4) as the eluant. Yield: 55.4 mg, 88%,
pale yellow sticky oil. 1H NMR (CDCl3, 300 MHz): d 8.30 (d, 2H,
J = 4.5 Hz), 8.04 (d, 2H, J = 4.5 Hz), 5.4 (s, 2H), 4.99 (s, 2H),
4.17–4.10 (m, 2H), 3.20 (s, 4H), 1.06 (t, 3H, J = 7.2 Hz). 13C NMR
(CDCl3, 50 MHz): d 193.7, 172.5, 150.1, 144.0, 139.7, 129.6, 123.7,
105.9, 62.1, 61.4, 41.2, 13.8. MS (C17H17NO5): 315 (M+). HRMS
(ESI): Anal. Calcd. (M+Na+) 338.09989, Found: 338.10013. IR
(cm-1): n 1738,1693, 1521, 1349, 1280, 1203.
1,1¢-(3,4-Dimethylenecyclopentane-1,1-diyl)diethanone (5c):
Following the general procedure, starting from 24 mg (0.24 mmol)
of pentane-2,4-dione 4c, product 5c was obtained using
ether/petroleum ether (1 : 4) as the eluant. Yield: 29.2 mg, 82%,
Methyl 3,4-dimethylene-1-(phenylsulfonyl)cyclopentanecarbo
xylate (5h):
Following the general procedure, starting from 51 mg (0.24 mmol)
of methyl phenylsulfonylacetate 4h, product 5h was obtained using
ether/petroleum ether (1 : 4) as the eluant. Yield: 41.5 mg, 71%,
colorless oil. 1H NMR (CDCl3, 300 MHz): d 7.85–7.82 (m, 2H),
7.72–7.67 (m, 1H), 7.59–7.54 (m, 2H), 5.39 (s, 2H), 4.96 (s, 2H),
3.66 (s, 3H), 3.27 (d, 2H, J = 8.3 Hz), 3.15 (d, 2H, J = 8.3 Hz).
13C NMR (CDCl3, 50 MHz): d 168.0, 142.8, 134.3, 129.8, 128.9,
128.8, 106.4, 76.0, 53.3, 38.9. MS (C15H16O4S): 292 (M+). HRMS
(ESI): Anal. Calcd. (M+Na+) 315.06615, Found: 315.06527. IR
(cm-1): n 1742,1680, 1540, 1470, 1280.
1
colorless oil. H NMR (CDCl3, 300 MHz): d 5.39 (s, 2H), 4.98
(s, 2H), 2.97 (s, 4H), 2.14 (s, 6H). 13C NMR (CDCl3, 50 MHz):
d 205.0, 144.4, 105.9, 71.7, 38.8, 26.6. MS (C11H14O2): 178
(M+). HRMS (ESI): Anal. Calcd. (M+H+) 179.10666, Found:
179.10634. IR (cm-1): n 1718, 1699, 1421, 1356, 1210.
Ethyl 1-cyano-3,4-dimethylenecyclopentanecarboxylate (5d):
Following the general procedure, starting from 27 mg (0.24 mmol)
of ethyl cyanoacetate 4d, product 5d was obtained using
ether/petroleum ether (1 : 4) as the eluant. Yield: 34.8 mg, 91%,
colorless oil. 1H NMR (CDCl3, 300 MHz): d 5.52 (s, 2H), 5.07 (s,
2H), 4.32–4.25 (m, 2H), 3.07 (dd, 4H, J1 = 28.5 Hz, J2 = 15.9 Hz),
1.33 (t, 3H, J = 7.2 Hz). 13C NMR (CDCl3, 50 MHz): d 168.0,
142.1, 119.5, 107.3, 63.1, 45.5, 43.3, 13.9. MS (C11H13NO2): 191
(M+). HRMS (ESI): Anal. Calcd. (M+Na+) 214.08385, Found:
214.08361. IR (cm-1): n 1743, 1239, 1069, 1023, 907.
1,1-Biphenylsulfonyl-3,4-dimethylenecyclopentane (5i):
Following the general procedure, starting from 71 mg (0.24 mmol)
of bis(phenylsulfonyl)methane 4i, product 5i was obtained using
ether/petroleum ether (1 : 4) as the eluant. Yield: 48.6 mg, 65%,
white solid, mp 123–124 ◦C. 1H NMR (CDCl3, 300 MHz): d 8.03–
8.01 (m, 4H), 7.74–7.69 (m, 2H), 7.59–7.54 (m, 4H), 5.29 (s, 2H),
4.84 (s, 2H), 3.40 (s, 4H). 13C NMR (CDCl3, 50 MHz): d 142.5,
136.6, 134.7, 131.1, 128.7, 106.3, 90.2, 38.4. MS (C19H18O4S2):
374 (M+). HRMS (ESI): Anal. Calcd. (M+H+) 375.15909, Found:
375.15869. IR (cm-1): n 1740, 1603, 1374, 1224, 1028.
3,4-Dimethylene-1-nitrocyclopentanecarboxylate (5e):
Following the general procedure, starting from 32 mg (0.24 mmol)
of ethyl nitroacetate 4e, product 5e was obtained using
ether/petroleum ether (1 : 4) as the eluant. Yield: 21.5 mg, 51%,
pale yellow oil. 1H NMR (CDCl3, 300 MHz): d 5.48 (s, 2H), 5.05
(s, 2H), 4.32–4.25 (m, 2H), 3.48 (d, 2H, J = 8.7 Hz), 3.26 (d, 2H,
J = 8.7 Hz), 1.29 (t, 3H, J = 7.2 Hz). 13C NMR (CDCl3, 50 MHz):
d 166.3, 141.8, 107.2, 96.7, 63.2, 42.5, 13.8. MS (C10H13NO4): 234
(M+). HRMS (ESI): Anal. Calcd. (M+Na+) 234.07368, Found:
234.07362. IR (cm-1): n 1749, 1554, 1414, 1369, 1240.
2,3-Dimethylenespiro[4.5]decane-6,10-dione (7a):
Following the general procedure, starting from 27 mg (0.24 mmol)
of 1,3-cyclohexanedione 6a, product 5a was obtained using
ether/petroleum ether (1 : 2) as the eluant. Yield: 33.1 mg, 87%,
colorless oil. 1H NMR (CDCl3, 300 MHz): d 5.39 (s, 2H), 4.94 (s,
2H), 2.93 (t, 4H, J = 1.8 Hz), 2.71 (t, 4H, J = 6.6 Hz), 2.03–1.94
(m, 2H). 13C NMR (CDCl3, 50 MHz): d 207.3, 144.6, 105,5, 69.8,
39.7, 37.8, 17.9. MS (C12H14O2): 190 (M+). HRMS (ESI): Anal.
Calcd. (M+H+) 191.10666, Found: 191.10626. IR (cm-1): n 1727,
1695, 1423, 866, 713.
(3,4-Dimethylenecyclopentane-1,1-diyl)bis(phenylmethanone) (5f):
Following the general procedure, starting from 54 mg (0.24 mmol)
of 1,3-diphenylpropane-1,3-dione 4f, product 5f was obtained
using ether/petroleum ether (1 : 4) as the eluant. Yield: 54.4 mg,
◦
1
90%, white solid; mp: 73–74 C. H NMR (CDCl3, 300 MHz):
d 7.86 (d, 4H, J = 3.9 Hz), 7.42 (t, 2H, J = 7.5 Hz), 7.31 (t,
4H, J = 7.5 Hz), 5.42 (s, 2H), 4.96 (s, 2H), 3.40 (s, 4H). 13C NMR
(CDCl3, 50 MHz): d 197.6, 144.9, 135.5, 133.2, 129.2, 128.6, 105.5,
67.4, 41.9. MS (C21H18O2): 302 (M+). HRMS (ESI): Anal. Calcd.
(M+H+) 303.13796, Found: 303.13820. IR (cm-1): n 1725, 1682,
1427, 1325, 1210.
7,8-Dimethylenespiro[4.4]nonane-1,4-dione (7b):
Following the general procedure, starting from 20 mg (0.24 mmol)
of 1,3-cyclopentanedione 6b, product 7b was obtained using
ether/petroleum ether (1 : 2) as the eluant. Yield: 24.7 mg, 70%,
◦
1
white solid, mp: 83–84 C. H NMR (CDCl3, 300 MHz): d 5.46
(s, 2H), 4.97 (s, 2H), 2.82 (s, 4H), 2.70 (t, 4H, J = 1.8 Hz). 13C
NMR (CDCl3, 50 MHz): d 214.2, 144.3, 106.0, 59.8, 40.5, 35.0.
MS (C11H12O2): 176 (M+). HRMS (ESI): Anal. Calcd. (M+H+)
177.09101, Found: 177.09059. IR (cm-1): n 1720, 1420, 1297, 1205,
937.
Ethyl 3,4-dimethylene-1-(4-nitrobenzoyl)cyclopentanecarboxylate
(5g):
Following the general procedure, starting from 50 mg (0.24 mmol)
of ethyl 4-nitrophenylacetate 4g, product 5g was obtained using
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8,8-Dimethyl-2,3-dimethylenespiro[4.5]decane-6,10-dione (7c):
column chromatography with EtOAc/petroleum ether = 1 : 4 to
afford compound 11 a◦s a white solid (79.7 mg, 84% yield, dr >
Following the general procedure, starting from 34 mg (0.24 mmol)
of dimedone 6c, product 7c was obtained using ether/petroleum
ether (1 : 3) as the eluant. Yield: 31.0 mg, 71%, white solid, mp:
103–104% ◦C. 1H NMR (CDCl3, 300 MHz): d 5.38 (s, 2H), 4.93
(s, 2H), 2.91 (s, 4H), 2.63 (s, 4H), 1.01 (s, 6H). 13C NMR (CDCl3,
50 MHz): d 207.0, 144.6, 105.4, 68.5, 51.6, 39.6, 30.7, 28.4.
MS (C14H18O2): 218 (M+). HRMS (ESI): Anal. Calcd. (M+H+)
219.13796, Found: 219.13773. IR (cm-1): n 1720, 1696, 1422, 1327,
1239.
1
20: 1), mp: 273–274% C. H NMR (CDCl3, 300 MHz): d 7.41–
7.33 (m, 3H), 7.30– 7.27 (m, 2H), 7.20– 7.16 (m, 2H), 7.10– 7.02
(m, 2H), 3.81 (s, 6H), 3.48 (s, 1H), 3.43 (s, 1H), 3.16– 3.14 (m,
2H), 3.06 (s, 1H), 3.00 (s, 1H), 2.67–2.49 (m, 6H), 2.22 (s, 1H),
2.18 (s, 1H). 13C NMR (CDCl3, 60 MHz): d 206.6, 178.9, 172.7,
135.9, 134.0, 131.8, 131.7, 128.9, 128.3, 128.0, 126.1, 63.2, 52.4,
39.7, 39.3, 35.8, 31.5. MS (C31H29NO7): 527 (M+). HRMS (ESI):
Anal. Calcd. (M+H+) 528.20168, Found: 528.20046. IR (cm-1): n
2923, 2852, 1738, 1708, 1476, 1285.
3,4-Dimethylenespiro[cyclopentane-1,2¢-indene]¢1¢,3¢-dione (7d):
Synthesis of compound 13 (eqn (5))
Following the general procedure, starting from 34 mg (0.24 mmol)
of 35 mg (0.24 mmol) of 1,3-indanedione 6d, product 7d was
obtained using ether/petroleum ether (1 : 3) as the eluant. Yield:
43.0 mg, 96%, white solid, mp: 70–71 ◦C. 1H NMR (CDCl3,
300 MHz): d 8.00–7.98 (m, 2H), 7.88–7.85 (m, 2H), 5.53 (s, 2H),
5.01 (s, 2H), 2.83 (s, 4H). 13C NMR (CDCl3, 50 MHz): d 202.6,
145.2, 141.2, 135.8, 123.5, 105.6, 56.8, 40.7. MS (C15H12O2): 224
(M+). HRMS (ESI): Anal. Calcd. (M+H+) 225.09101, Found:
225.09088. IR (cm-1): n 1739, 1701, 1593, 1333, 1232.
To an oven dried Schlenk tube was added 2,3-dimethylenebutane-
1,4-diyl diacetate 3 (39.6 mg, 0.20 mmol), dimethyl malonate 4a
(0.24 mmol), Pd(OAc)2 (1.12 mg, 0.005 mmol), DPPF (5.54 mg,
0.01 mmol), and DBU (76 mg, 0.50 mmol). The tube was evacuated
and refilled with N2, and this process was repeated 3 times. Then
2.5 mL of CH2Cl2 was added into the tube by syringe. The
mixture was stirred at room temperature for 24 h. After removing
the solvent under vacuum, a solution of DMAD 12 (170.4 mg,
1.2 mmol) in ether (5 mL) was add to the reaction mixture. After
refluxing for 4 h, the solvent was removed under vacuum. the
residue was purified by silica gel column chromatography with
EtOAc/petroleum ether = 1 : 1 to afford compound 13 as a white
solid (51.9 mg, 74% yield), mp: 117–118 C. H NMR (CDCl3,
300 MHz): d 3.78 (s, 6H), 3.75 (s, 6H), 2.99 (s, 4H), 2.98 (s, 4H).
13C NMR (CDCl3, 60 MHz): d 172.4, 166.3, 132.8, 127.8, 57.6,
52.8, 52.1, 42.7, 28.3. MS (C17H20O8): 352 (M+). HRMS (ESI):
Anal. Calcd. (M+H+) 353.12309, Found: 353.12280. IR (cm-1): n
1730, 1647, 1434, 1317, 1255, 1202, 1152.
Dimethyl 8,9-benzo-3,4-dimethylene-11-
oxobicyclo[4.3.1]undecane-1,6-dicarboxylate (9a):
◦
1
Following the general procedure, starting from 66 mg (0.24 mmol)
of dimethyl 3-oxo-1,2,4,5-tetrahydrobenzo[d]cycloheptene-2,4-
dicarboxylate 8a, product 9a was obtained using ether/petroleum
ether (◦1 : 4) as the eluant. Yield: 65.2 mg, 92%, white solid, mp:
94–95 C. 1H NMR (CDCl3, 300 MHz): d 7.27–7.20 (m, 4H), 5.58
(s, 2H), 5.04 (s, 2H), 3.73 (s, 6H), 3.22 (dd, 4H, J1 = 23.4 Hz, J2 =
14.7 Hz), 2.90 (d, 2H, J = 7.5 Hz), 2.55 (d, 2H, J = 7.5 Hz). 13C
NMR (CDCl3, 50 MHz): d 206.0, 172.6, 142.2, 137.0, 131.1, 127.3,
115.7, 63.5, 52.2, 38.4, 37.4. MS (C21H22O5): 354 (M+). HRMS
(ESI): Anal. Calcd. (M+H+) 355.15400, Found: 355.15369. IR
(cm-1): n 1735, 1696, 1433, 1268, 1237, 1202, 1180.
Synthesis of compound 14 (eqn (6))
To an oven dried Schlenk tube was added 2,3-dimethylenebutane-
1,4-diyl diacetate 3 (39.6 mg, 0.20 mmol), nucleophile (0.24 mmol),
Pd(OAc)2 (1.12 mg, 0.005 mmol), DPPF (5.54 mg, 0.01 mmol),
and DBU (76 mg, 0.50 mmol). The tube was evacuated and refilled
with N2, and this process was repeated 3 times. Then 2.5 mL of
CH2Cl2 was added into the tube by syringe. The mixture was
stirred at room temperature for 24 h. After removing the solvent
under vacuum, a solution of DMAD 12 (170.4 mg, 1.2 mmol) in
ether (5 mL) was add to the reaction mixture. The mixture was
refluxed for 4 h. After removing the solvent under vacuum, the
residue was purified by silica gel column chromatography with
EtOAc/petroleum ether = 1 : 1 to afford compound 14 as a white
3,4-Dimethylene-11-oxobicyclo[4.4.1]decane-1,6-dicarboxylate
(9b):
Following the general procedure, starting from dimethyl
cyclohexanone-2,6-dicaboxylate 8b, product 9d was obtained
using ether/petroleum ether (1 : 4) as the eluant. Yield: 44.4 mg,
1
76%, colorless oil. H NMR (CDCl3, 300 MHz): d 5.48 (s, 2H),
5.11 (s, 2H), 3.74 (s, 6H), 2.92 (s, 4H), 2.55–2.45 (m, 2H), 2.26–2.17
(m, 1H), 2.12–2.01 (m, 2H), 1.97–1.83 (m, 1H). 13C NMR (CDCl3,
60 MHz): d 206.2, 172.8, 142.1, 114.4, 61.1, 52.3, 37.5, 34.8, 17.1.
MS (C16H20O5): 292 (M+). HRMS (ESI): Anal. Calcd. (M+Na+)
315.12029, Found: 315.11968. IR (cm-1): n 1735, 1706, 1458, 1431,
1277, 1214, 1139.
◦
1
solid (59.4 mg, 69% yield), mp: 122–123 C. H NMR (CDCl3,
300 MHz): d 3.77 (s, 6H), 3.75 (s, 6H), 3.53–3.43 (m, 2H), 3.04–
2.95 (m, 4H), 2.53–2.47 (m, 2H), 2.42–2.37 (m, 2H), 2.02–1.97 (m,
2H), 1.86–1.80 (m, 2H). 13C NMR (CDCl3, 60 MHz): d 205.6,
172.8, 168.1, 132.4, 128.7, 61.0, 52.4, 52.0, 35.3, 34.1, 33.4, 16.7.
MS (C22H26O9): 434 (M+). HRMS (ESI): Anal. Calcd. (M+Na+)
457.14690, Found: 457.14691. IR (cm-1): n 1734, 1434, 1286, 1249,
1071.
Synthesis of compound 11 (eqn (4))
A
solution of dimethyl 8,9-benzo-3,4-dimethylene-11-
oxobicyclo[4.3.1]undecane-1,6-dicarboxylate 9a (65 mg,
Synthesis of compounds 16 and 17 (eqn (7))
0.184 mmol), N-phenylmaleimide 10 (34.6 mg, 0.2 mol) in
acetone (5.0 mL) was stirred for 12 h at rt. After removing the
solvent under vacuum, the residue was purified by silica gel
To an oven dried Schlenk tube was added 2,3-dimethylenebutane-
1,4-diyl diacetate 3 (99 mg, 0.50 mmol), dimethyl acetone-1,
1576 | Org. Biomol. Chem., 2011, 9, 1572–1577
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◦
18 is a white solid (yield > 95%), mp: 261–262 C.1H NMR
Table 2 Crystal Data of compounds 11 and 17
(CDCl3, 300 MHz): d 7.33–7.23 (m, 5H), 7.16–6.99 (m, 4H), 3.77
(s, 6H), 3.44 (s, 1H), 3.39 (s, 1H), 3.11– 3.05 (m, 2H), 3.02 (s,
1H), 3.00 (s, 1H), 2.62–2.45 (m, 6H), 2.19 (s, 1H), 2.14 (s, 1H).
13C NMR (CDCl3, 60 MHz): d 179.2, 173.0, 136.1, 134.3, 132.0,
131.6, 129.1, 128.6, 128.3, 126.3, 63.3, 52.5, 39.8, 39.4, 35.9, 31.4.
MS (C30H29NO6): 499 (M+). HRMS (ESI): Anal. Calcd. (M+)
499.19894, Found: 499.20023. IR (cm-1): n 2904, 1710, 1699, 1480,
1206.
11
17
Formula
fw
Cryst. syst.
C31H29NO7, C7H8
618.68
C31H34O13
614.58
Monoclinic
Triclinic
¯
Space group
P1
P21/n
˚
a/A
9.851(2)
11.303(2)
15.868(3)
82.36(3)
76.88(3)
64.54(3)
1552.4(5)
2
12.624(3)
10.895(2)
21.852(4)
90.00
˚
b/A
˚
c/A
a (◦)
b (◦)
g (◦)
104.90(3)
90.00
2904.7(10)
4
1.405
0.110
1296
0.40 ¥ 0.40 ¥ 0.30
55.0
6634
2441/0.0903
404
0.990
0.0649, 0.0734
0.1659, 0.0734
Acknowledgements
3
˚
V/A
Support of this work by the grant from NSFC (No. 20872104,
20832002, 20925207 and 20821062) and the “973” program from
MOST of China (2009CB825300) and Fok Ying Tung Education
Foundation is gratefully acknowledged.
Z
Dc/g cm-3
1.324
0.091
645
0.19 ¥ 0.18¥ 0.10
50.0
5470
4872/0.0457
417
m/mm-1
F(000)
Cryst size/mm
Max. 2q/deg
No. of reflns collected
No. of indep reflns/Rint
No. of params
Goodness-of-fit on F2
R1, wR2 (I > 2s(I))
R1, wR2 (all data)
Notes and references
1 (a) D. P. Curran, Advances in Cycloaddition, D. P. Curran, Ed.: JAI
Press: Greenwich, CT, 1988; (b) A. Padwa, A. M. Schoffstall, Advances
in Cycloaddition, D. P. Curran, Ed.: JAI Press: Greenwich, CT, 1988;
(c) M. Sainsbury, Comprehensive Organic Synthesis, B. M. Trost, I.
Fleming, ed.: Pergamon Press: Oxford, 1991; (d) K. C. Nicolaou, E. J.
Sorensen, Classics in Total Synthesis, VCH: Weinheim, 1996.
2 (a) E. J. Corey, Angew. Chem. Int. Ed., 1998, 53, 6031; (b) M. Sannigrahi,
Tetrahedron, 1999, 55, 9007; (c) K. I. Tadano, K. I. Takao and R.
Munakata, Chem. Rev., 2005, 105, 4779; (d) W. Zhao, Chem. Rev.,
2010, 110, 1706.
3 (a) M. Lautens, W. Klute and W. Tam, Chem. Rev., 1996, 96, 49; (b) H.-
W. F u¨hauf, Chem. Rev., 1997, 97, 523; (c) F. Fringuelli, A. Taticchi,
The Diels–Alder Reaction: Selected Practical Methods, John Wiley and
Sons: Chichester, U.K., 2002; (d) N. Dennis, Org. React. Mech., 2004,
499.
1.211
0.0775, 0.1767
0.0883, 0.1831
3-dicarboxylate 15 (0.2 mmol), Pd(OAc)2 (2.24 mg, 0.01 mmol),
DPPF (11.8 mg, 0.02 mmol), DBU (182.4 mg, 1.2 mmol). The tube
was evacuated and refilled with N2, and this process was repeated
3 times. Then 5 mL of CH2Cl2 was added into the tube by syringe.
The mixture was stirred at room temperature for 24 h. The reaction
mixture was purified by silica gel column chromatography with
ether/petroleum ether = 1 : 4 to afford compound 16 as colorless
oil (51.1 mg, 74% yield). 1H NMR (CDCl3, 300 MHz): d 5.45 (s,
4H), 5.00 (s, 4H), 3.72 (s, 6H), 2.82 (d, 8H, J = 1.7 Hz). 13C NMR
(CDCl3, 60 MHz): d 206.8, 172.7, 143.9, 115.8, 63.3, 52.3, 37.8.
MS (C19H22O5): 330 (M+). HRMS (ESI): Anal. Calcd. (M+Na+)
353.13594, Found: 353.13586. IR (cm-1): n 1735, 1696, 1432, 1269,
1209.
4 (a) K. C. Nicolaou, E. J. Sorensen, Classics in Total Synthesis, VCH:
Weinheim, 1996, p 55–64, p 153–166.
5 (a) J. Tsuji and M. Tak Morikawa, Tetrahedron Lett., 1965, 6, 4387;
(b) B. M. Trost and D. M. T. Chan, J. Am. Chem. Soc., 1979, 101, 6429;
(c) B. M. Trost, T. N. Nanninga and T. Satoh, J. Am. Chem. Soc., 1985,
107, 721; (d) B. M. Trost and D. T. MacPherson, J. Am. Chem. Soc.,
1987, 109, 3483; (e) B. M. Trost, Pure Appl. Chem., 1988, 60, 1615;
(f) H. Nakamura, K. Nakamura and Y. Yamamoto, J. Am. Chem. Soc.,
1998, 120, 4242; (g) P. W. N. W. Van Leeuwen, P. C. J. Kamer and J.
N. H. Reek, Chem. Rev., 2000, 100, 2741; (h) B. M. Trost, C. Lee, In
Catalytic Asymmetric Synthesis, I. Ojima, Ed.; Wiley-VCH: New York,
2000; p 593; (i) E. Negishi, A. de Meijre, Organopalladium Chemistry
for Organic Synthesis, Wiley: New York, 2002; (j) J. Tsuji, Palladium
Reagents and Catalysis. New Perspectives for the 21st Century, Wiley:
Chichester, U.K., 2004.
6 (a) W. R. Sorrnson and W. J. Bailey, J. Am. Chem. Soc., 1956, 78, 2287;
(b) Y. Gaoni and S. Sdeh, J. Org. Chem., 1980, 45, 870; (c) S. T. Diver
and J. A. Smulik, Org. Lett., 2000, 2, 2271.
7 (a) M. Ihara, Y. Ishida, K. Fukumoto and T. Kametani, Chem. Pharm.
Bull., 1985, 33, 4102; (b) A. B. Smith, K. J. Hale and J. P. McCauley,
Tetrahedron Lett., 1989, 30, 5579; (c) H. Kuenzer, M. Stahnke, G. Sauer
and R. Wiechert, Tetrahedron Lett., 1991, 32, 1949.
A solution of 16 (66 mg, 0.2 mmol), DMAD 12 (71 mg, 0.5 mol)
in CH2Cl2/ether = 1 : 1 (5.0 mL) was stirred for 12 h in reflux. After
removing the solvent under vacuum, the residue was purified by
silica gel column chromatography with EtOAc/petroleum ether =
2 : 1 to afford compound 17 as a white solid (105.6 mg, 86% yield),
◦
1
mp: 253–254 C. H NMR (CDCl3, 300 MHz): d 3.79 (s, 12H),
3.76 (s, 6H), 3.40–3.30 (m, 4H), 3.03–2.92 (m, 4H), 2.58 (s, 8H). 13
C
NMR (CDCl3, 50 MHz): d 205.6, 172.7, 167.8, 132.2, 128.0, 62.5,
52.5, 52.3, 35.5, 34.8. MS (C31H34O13): 614 (M+). HRMS (ESI):
Anal. Calcd. (M+Na+) 637.18818, Found: 637.18916. IR (cm-1):
n 2952, 1734, 1696, 1434, 1271, 1235, 1066.
The crystal data for compounds 11 and 17 are summarized in
8 M. A. Garcia-Garibay and T. Choe, Photochem. Photobiol. Sci., 2006,
5, 449.
Table 2.
9 (a) Yehiel Gaoni and Shoshana Sadeh, J. Org. Chem., 1980, 45, 870;
(b) K. Atsushi, S. Norikazu and M. Miwako, Tetrahedron, 1999, 55,
8155.
Synthesis of compound 18 (eqn (8))
10 Mataka Shuntaro, J. Org. Chem., 1989, 54, 5237.
Compound 18 was obtained from CH2Cl2 by slow solvent
evaporation with using compound sample obtained by irradiation
of 11 in the solid state with k > 290 nm (Pyrex filter). Compound
11 F. F. Blicke and F. J. McCarty, J. Org. Chem., 1959, 24, 1069.
12 M. Scholl, S. Ding, C. W. Lee and R. H. Grubbs, Org. Lett., 1999, 1,
953.
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The Royal Society of Chemistry 2011
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