Efficient, transition metal mediated, sequential, two- and three-component coupling reactions for the synthesis of highly substituted five-membered ring carbocycles

Article abstract of DOI:10.1002/ejoc.200700197

A Cu-catalysed method for the preparation of highly substituted methylenecyclopentanes, through a sequence involving a Michael addition of stabilized enolates to activated enynes followed by an intramolecular carbocupration reaction, is presented. This me

Full text of DOI:10.1002/ejoc.200700197

FULL PAPER
DOI: 10.1002/ejoc.200700197
Efficient, Transition Metal Mediated, Sequential, Two- and Three-Component
Coupling Reactions for the Synthesis of Highly Substituted Five-Membered
Ring Carbocycles
Nicolas Coia,[a] Didier Bouyssi,[a] and Geneviève Balme*[a]
Keywords: Synthetic design / Multicomponent reactions / Methylenecyclopentanes / Arylidenecyclopentanes / Copper
iodide / Palladium
A Cu-catalysed method for the preparation of highly substi-
with a Pd-mediated coupling reaction to perform a new
tuted methylenecyclopentanes, through a sequence involv- three-component reaction through a transmetallation path-
ing a Michael addition of stabilized enolates to activated en-
ynes followed by an intramolecular carbocupration reaction,
is presented. This method was also successfully combined
way on the vinylcopper intermediate.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
dition of an active methylene compound of type 1 such as
malonate, malononitrile or methylcyanoacetate to the acti-
vated olefin 2 would lead to the expected stabilized interme-
diate 3 by proton transfer. This would be followed by a Cu-
mediated cycloisomerisation of the resulting functionalised
unactivated alkynes, leading to highly substituted methyl-
enecyclopentanes 5.
Introduction
The importance of natural products and pharmaceuticals
containing the cyclopentyl moiety has led to the develop-
ment of numerous synthetic methods to construct such
structures in recent years.[1] In these synthetic approaches,
several procedures based on the cyclisation of acetylenic
substrates bearing a pendant nucleophile and leading to
functionalised methylenecyclopentanes have been re-
ported.[2] Among them, our group has recently developed a
general method allowing for the cyclisation of a variety of
δ-acetylenic stabilized carbanions with catalytic amounts of
base and copper salts.[3] It occurred to us that the combina-
tion of this intramolecular cupration with an initial inter-
molecular Michael addition of a stabilized enolate 1 to an
activated olefin such as 2 would provide a new procedure
for the highly flexible synthesis of substituted methylenecy-
clopentanes. Another advantage of this [4+1] annulation
approach is that, by the appropriate choice of the different
electron-withdrawing substituents groups, the resulting cy-
clopentane derivatives could then be subjected to a number
of further transformations.[4]
Scheme 1. Cu-catalysed synthesis of functionalised methylenecyclo-
pentanes.
Results and Discussion
The two Michael acceptors 2a,b were readily prepared in
good yields by the reaction of the anions of the β-keto ester
6a and the β-keto sulfone 6b, respectively, with paraformal-
dehyde followed by an in situ deacylation according to a
slight modification of known procedures (Scheme 2).[5]
First of all, we studied the [4+1] annulation reaction of
unsaturated ester 2a with the malonic enolate prepared
from dimethyl malonate (1a) and potassium tert-butoxide
in THF. The Michael addition was nearly complete, as ob-
served by GC, after 3 h at 68 °C. However, a subsequent
This [4+1] annulation strategy utilizes 1 and 2 as the one-
and four-carbon components, respectively, and is based on
a
sequential Michael addition-cyclisation reaction
(Scheme 1). Indeed, we envisioned that the Michael ad-
[a] ICBMS, Institut de Chimie et Biochimie Moléculaires et Supra-
moléculaires, Université Lyon 1, CPE,
43 Boulevard du 11 Novembre 1918, 69622 Villeurbanne,
France
Fax: +33-4-72431214
E-mail: balme@univ-lyon1.fr
3158
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Highly Substituted Five-Membered Ring Carbocycles
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Table 1. Cu-mediated Michael addition-cyclisation.
Scheme 2. Synthesis of Michael acceptors.
addition of a catalytic amount of CuI (10 mol-%) to the
reaction mixture only resulted in a low conversion to 5a
even after prolonged heating at reflux temperature. When
the same reaction was performed in the presence of stoi-
chiometric amounts of CuI, the annulation process took
place, and the resulting functionalised methylenecyclopen-
tane 5a was obtained in 53% isolated yield (Table 1, Entry
1). The addition of methylcyanoacetate (1b) to 2a under
identical reaction conditions gave 5b in 48% yield as a mix-
ture of diastereomers (Table 1, Entry 2). The major draw-
back of this procedure is that a stoichiometric amount of
CuI was required. As a consequence, we started a system-
atic study concerning the development of a catalytic process
for the Cu-mediated cyclisation reaction that was capable
of producing a comparable yield of 5a to that obtained by
the stoichiometric route. Therefore, different bases
(Cs2CO3, DBU, K2CO3, NaH, KH and nBuLi) and sol-
vents (CH3CN, DMSO and THF) were screened. The best
results were obtained by the addition of 2a to a CH3CN
solution of the preformed enolate [1.2 equiv. of dimethyl
malonate (1a) and 1 equiv. of NaH]. After 5 h at 50 °C, CuI
(10 mol-%) was added to the resulting Michael adduct. The
reaction required 5 h to reach completion and gave rise to
5a in 60% isolated yield (Table 1, Entry 3). These optimised
conditions, applied to malononitrile (1c), afforded the re-
lated methylenecyclopentane analogue 5c in 55% yield
(Table 1, Entry 4). However, the reaction of ethyl cyanoace-
tate (1d) with 2a gave rise to two different cyclised com-
pounds, identified as the expected diastereomeric products
5d and 5dЈ and the decarboxylated[6] product 7 in 54% com-
bined yield (1:1:1 mixture, Table 1, Entry 5). The isomeric
1
ratios were based on the integrals of the H NMR signals
corresponding to the two exocyclic methylene protons ob-
served in the crude reaction mixture.
[a] All reactions were performed with 10 mol-% of CuI as the cata-
lyst, except for entries 1 and 2, where a stoichiometric quantity of
CuI was added to the reaction medium. [b] Isolated as a mixture
of three compounds [two diastereomers (5d and 5dЈ) and 7 in a
1:1:1 ratio]. [c] Only one diastereomer was obtained.
The above conditions, applied to (phenylsulfonyl)aceto-
nitrile (1e), resulted predominantly in the trienic dinitrile 8,
which probably results from the dimerisation of a vinylcar-
bene, which, in turn, arises from the vinylic copper interme-
diate 4e (Scheme 3).[7] However, under a different set of
conditions (with THF and DBU), the expected methylene-
cyclopentane 5e was formed in 69% yield (Table 1, Entry
6).
The Michael addition-cyclisation process was also tested
with nitronate anions derived from phenylnitroethane (1f)
and ethyl nitroacetate (1g). The Michael addition of the so-
dium salt of 1f to 2a in CH3CN containing 1 equiv. of tri-
ethylbenzylammonium (TEBA) chloride followed by the Scheme 3. Dimerisation of the vinylcopper intermediate.
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N. Coia, D. Bouyssi, G. Balme
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addition of CuI afforded 5f in 65% yield (Table 1, Entry 7). ful. Therefore, to test the feasibility of the overall transfor-
The presence of an ammonium salt, such as TEBA chloride, mation, we chose to examine the Pd-mediated cyclisation
to dissolve the nitronate anion, was critical for the success process on the isolated open-chain Michael adduct 11a with
of this reaction.
an aryl iodide. After screening various solvents and bases,
The attempted condensation of 2a with ethyl nitroacetate we found that the best results in this cyclisation-coupling
(1g) as the nucleophilic moiety under the various reaction reaction were achieved when the reaction of 11a with 9a
conditions described above failed to effect the desired was conducted in THF at 50 °C with PdCl2(PPh3)2/nBuLi
Michael addition-cyclisation tandem reaction. Interestingly, as the catalytic system and with NaH. The expected cyclised
with CH3CN and the reaction conditions recently reported product 10a was then isolated in 52% yield (Table 2, Entry
by Hammer and coworkers for the Michael addition of 1). When these conditions were applied to 11a and 1-iodo-
alkyl nitroacetates (DIPEA in the presence of a catalytic 4-methoxybenzene (9b), 10b was obtained in 62% yield
amount of tetraalkylammonium salt to increase the reactiv- (Table 2, Entry 2). In this last case, the yield was improved
ity of the anion),[8] functionalised methylenecyclopentane to 94% yield with a slow addition procedure (syringe pump
5g was obtained in 55% yield (Table 1, Entry 8).
addition of the preformed sodium enolate derived from 11a
Since vinylic sulfones are versatile precursors for various to 2.5 equiv. of 9b in the presence of 5 mol-% of the Pd
functionalities,[9] this Michael addition-cyclisation tandem catalyst in THF at 50 °C, Table 2, Entry 3).
reaction was also developed on the unsaturated sulfone 2b.
Optimum conditions with dimethyl malonate (1a), ma-
lononitrile (1c) or methyl (diethoxyphoshoryl)acetate (1h)
as nucleophilic moieties involved the Michael addition of a
Table 2. Pd-mediated cyclisation-coupling reaction.
THF solution of the preformed enolate (2 equiv. of 1a or
1h or 3 equiv. of 1c and 1 equiv. of NaH) to 2b at 50 °C.
The addition of 10 mol-% of CuI to the resulting Michael
adduct gave rise to 5h, 5i and 5j in 89%, 46% and 65%
yield, respectively (Table 1, Entries 9–11).
Having succeeded in the preparation of various function-
alised methylenecyclopentanes, we next turned our atten-
tion to the development of a new three-component, dom-
ino, Michael addition-cyclisation-coupling process involv-
ing an organopalladium species as the promoter of the
cyclisation reaction so as to introduce diversity onto the
exocyclic unsaturation of the final ring (Scheme 4).[10]
[a] Slow addition of sodium enolate with a syringe pump.
With these results in hand, we next attempted to effect
the Michael addition and the subsequent cyclisation-coup-
ling reaction in one operation with the precursors 1a, 2a
Scheme 4. Pd-mediated Michael addition-cyclisation-coupling re-
and 9a. After considerable experimentation, with slow ad-
action.
dition techniques and varying the order of introduction of
each starting material and the solvent, we found that the
We first attempted the sequential Michael addition- highest yield of cycloadduct 10a that could be obtained
cyclisation-coupling reaction in a one-pot procedure, with from this one-pot cascade process was only 35%. The op-
active methylene compound 1a, unsaturated alkyne 2a and timised reaction conditions involve the slow addition of the
iodobenzene (9a) as the precursor of the organopalladium intermediate Michael adduct enolate (1 equiv.) at 50 °C to
species. Thus, the intermediate Michael adduct enolate 3a a THF solution of iodobenzene (1.2 equiv.) in the presence
(Z1 = CO2Et and Z2, Z3 = CO2Me) was generated by the of dichlorobis(triphenylarsane)palladium [PdCl2(AsPh3)2]
addition of 1 equiv. of dimethyl sodium malonate in as the catalyst (10 mol-%). Following these unfruitful ef-
CH3CN to 2a, followed by stirring of the mixture at 50 °C forts, we decided to investigate another strategy to access
for 5 h. This was followed by the addition of iodobenzene the targeted three-component adduct 10a in a single opera-
9a (1.2 equiv.) and 5 mol-% of a Pd0 complex, generated by tion. In our earlier studies, we had developed an efficient
the reduction of PdCl2(PPh3)2 with nBuLi.[11] After 15 h at Pd/CuI-cocatalysed cyclisation-coupling reaction of linear
this temperature, the desired cycloadduct 10a was isolated unactivated alkynes bearing a stabilized nucleophile with 1-
in low yield (17%) along with 5a (17% yield). The at- halogeno-1-alkynes.[12] The mechanism for this transforma-
tempted modification of this standard protocol to achieve tion was not clear but one could speculate that the cycli-
acceptable yields of the desired cycloadduct was unsuccess- sation-coupling reaction proceeds through the formation of
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Highly Substituted Five-Membered Ring Carbocycles
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Scheme 5. Proposed mechanism for the Pd/Cu-mediated three-component condensation reaction.
a vinylcopper intermediate followed by a transmetallation Table 3. Pd/Cu-cocatalysed three-component condensation reac-
tion.
pathway. On the basis of this study and of the successful
results from the Cu-promoted Michael addition-cyclisation
reaction described above, we decided to extend this Pd/Cu-
cocatalysed methodology to the one-step preparation of
compounds of type 10 (Scheme 5).
We were pleased to see that, in this way, it was possible
to reach satisfactory results, and the highest yield was ob-
tained with a slight excess of malonate. Thus, compound
10a was obtained in 80% yield by the slow addition (over
2 h) of enyne 2a (1 equiv.) to iodobenzene (9a, 1.2 equiv.),
dimethyl malonate (1a, 2.5 equiv.), NaH (2.3 equiv.),
(Pd(PPh3)4) as the catalyst (3 mol-%) and CuI (6 mol-%,
Table 3, Entry 1). Having optimized conditions in hand, the
generality of this process was investigated. In most entries,
good yields were obtained for the Pd/Cu-cocatalysed three-
component reaction with a wide range of electronically var-
ied aryl iodides; no appreciable difference in the yield for
the three-component reaction was observed with electron-
donating groups or electron-withdrawing substituents on
the aryl iodides (Table 3, Entries 2–5). We also investigated
this Pd/Cu-cocatalysed three-component condensation re-
action with benzyl chloride (9f) as the coupling reagent un-
der our optimized reactions. We were pleased to observe a
50% yield of the desired three-component coupling product
10f (Table 3, Entry 6). No trace of the benzylmalonate re-
sulting from the reaction of the malonate anion with the
chlorine derivative was isolated.[13] We have also examined
the three-component reaction of iodobenzene (9a) and the
unsaturated ester 2a with (phenylsulfonyl)acetonitrile (1e)
as the nucleophile. Under the optimal conditions described
above, the reaction proceeded to give the target arylidenecy-
clopentane 10g along with the undesired cyclic product 5e
resulting from the competitive two-component process. Sev-
eral experiments indicated that the solvent was very impor-
tant for this particular three-component condensation reac-
tion. Thus, effecting the three-component reaction in a 2:1
mixture of THF/DMSO suppressed the formation of 5e
dramatically, and 10g was isolated as an inseparable 7:3
[a] All reactions were performed with 3 mol-% of Pd(PPh3)4 and
6 mol-% of CuI as the catalyst with NaH and THF except for Entry
7, where a 2:1 mixture of THF/DMSO was used.
Conclusions
In summary, we have developed efficient methods for the
mixture of two diastereomers in 50% yield (Table 3, Entry one-pot synthesis of a variety of methylenecyclopentanes
7). This three-component condensation reaction was then and (arylmethylene)cyclopentanes containing useful func-
extended to unsaturated sulfone 2b, and the corresponding tionalities from readily or commercially available starting
functionalised arylidenecyclopentanes were isolated in good materials. Further work is in progress to study the synthetic
to excellent yields with neutral, electron-rich or electron- application of these new two-component and three-compo-
deficient aryl iodides (Table 3, Entries 8–10).
nent condensation reactions.
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flash chromatography on silica gel with petroleum ether/diethyl
Experimental Section
ether (7:3) containing 4% Et3N, to afford pure 5a as a pale yellow
All reactions were carried out under a nitrogen atmosphere. 1H and
13C NMR spectra were recorded with a Bruker DRX 300 spectrom-
eter. Chemical shifts are reported in δ values (ppm) relative to TMS
1
oil (116 mg, 60% yield). H NMR (300 MHz, CDCl3): δ = 1.28 (t,
J = 7.1 Hz, 3 H, CH3), 2.51 (dd, J = 10.7 Hz, J = 13.5 Hz, 1 H,
CH), 2.73–2.78 (m, 3 H, CH), 2.97 (m, 1 H, CH), 3.77 (s, 3 H,
OCH3), 3.78 (s, 3 H, OCH3), 4.16 (q, J = 7.1 Hz, 2 H, OCH2), 5.25
1
for H and to CDCl3 for 13C. Mass spectra were recorded with a
(d, J = 2.15Hz, 1 H, CH), 5.30 (d, J = 2.15Hz, 1 H, CH) ppm. 13
C
Thermoquest Finnigan MAT 95 XL. In the case of diastereoiso-
meric mixtures, the chemical shifts for the minor isomer where de-
termined from the relative intensities, and corresponding shifts are
given in brackets.
NMR (75 MHz, CDCl3): δ = 14.1 (CH3), 36.8 (CH2), 38.4 (CH2),
41.7 (CH), 52.8 (OCH3), 52.9 (OCH3), 60.6 (Cquat.), 62.9 (OCH2),
113.2 (CH2), 145.4 (Cquat.), 170.2 (Cquat.), 170.4 (Cquat.), 173.6
(Cquat.) ppm. HRMS (ESI): calcd. for C13H18NaO6 [M + Na]+
293.1001; found 206.1002.
Ethyl 2-Methylenepent-4-yn-1-oate (2a): Based on the protocol of
Queignec et al.,[5b] in a 100 mL round-bottomed flask, propargyl
bromide (80% in toluene, 7.1 mL, 63.7 mmol), NaI (2.17 g,
14.5 mmol) and ethyl benzoylacetate (10 mL, 58 mmol) were
mixed, and K2CO3 (12 g, 86.9 mmol) was then added quickly. The
resulting heterogeneous mixture was vigorously stirred for 24 h at
room temp., giving a thick orange gum. Once diluted in dry THF
(50 mL), this gum was mixed with paraformaldehyde (2.96 g,
96.4 mmol) and additional K2CO3 (8 g, 58 mmol), and the mixture
was stirred for 9 d at 40 °C. The mixture was extracted by ethyl
acetate (3ϫ150 mL), and the organic layers were concentrated, giv-
ing the crude product, which was distilled under vacuum (35 °C/
3 Torr) to afford pure 2a as a pale yellow oil (6.27 g, 78% yield).
NMR analysis was in accordance with literature data.
Ethyl 3,3-Dicyano-4-methylenecyclopentane-1-carboxylate (5c):
With the same procedure as was described for the synthesis of 5a,
the reaction was performed with Michael acceptor 2a (100 mg,
0.72 mmol). Purification by chromatography with petroleum ether/
ethyl acetate (8:2) containing 2% of Et3N afforded 4c as a colour-
1
less oil (82 mg, 55% yield). H NMR (300 MHz, CDCl3): δ = 1.28
(t, J = 7.1 Hz, 3 H, CH3), 2.68 (dd, J = 9.7 Hz, J = 13.3 Hz, 1 H,
CH), 2.85 (m, 3 H, CH), 3.20 (m, 1 H, CH), 4.19 (q, J = 7.1 Hz,
2 H, OCH2), 5.49 (d, J = 2.0 Hz, 1 H, CH), 5.69 (d, J = 2.0 Hz, 1
H, CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.1 (CH3), 33.7
(CH2), 38.1 (Cquat.), 41.3 (CH2), 41.5 (CH), 61.7 (OCH2), 114.6
(CN), 114.7 (CN), 116.2 (CH2), 142.6 (Cquat.), 171.6 (Cquat.) ppm.
HRMS (EI): calcd. for C11H12N2O2 [M]+ 204.0899; found
204.0899.
1-[(Pent-1-en-4-yn-2-yl)sulfonyl]benzene (2b): (Phenylsulfonyl)ace-
tophenone (4 g, 15.4 mmol) and NaH (60% oil dispersion, 614 mg,
15.35 mmol) were mixed in CH3CN (80 mL). Once the evolution
of gas had stopped, propargyl bromide (80% in toluene, 2 mL,
18 mmol) and NaI (576 mg, 3.8 mmol) were added. The reaction
mixture was then stirred at room temp. for 24 h before being con-
centrated under vacuum. The resulting gum was then diluted with
dry THF (60 mL) and dry CH2Cl2 (20 mL), and NaH (60% oil
dispersion, 614 mg, 15.35 mmol) was then added. Once gaseous
evolution stopped, paraformaldehyde (1.4 g, 46.63 mmol) was
added with vigorous stirring to avoid instant clotting. The resulting
solution was stirred at room temp. for 48 h. The mixture was ex-
tracted with diethyl ether (4ϫ200 mL), the organic layers were
washed with brine (100 mL) and concentrated under vacuum, and
the crude product was purified by flash chromatography on silica
gel with petroleum ether/ethyl acetate (8:2) containing 4% of Et3N
to ensure good separation. Pure 2b was obtained as a pale yellow
oil, which turned brown rapidly (2.15 g, 68% yield). 1H NMR
(300 MHz, CDCl3): δ = 2.21 (t, J = 2.5 Hz, 1 H, CH), 3.18 (td, J
= 1.8 Hz, J = 2.5 Hz, 2 H, CH2), 6.22 (dt, J = 0.6 Hz, J = 1.8 Hz,
1 H, CH), 6.50 (dt, J = 0.6 Hz, J = 1.8 Hz, 1 H, CH), 7.56 (tt, J
= 1.4 Hz, J = 7.5 Hz, 2 H, CH), 7.63 (tt, J = 1.4 Hz, J = 7.5 Hz,
1 H, CH), 7.87 (dt, J = 7.5 Hz, J = 1.4 Hz, 2 H, CH) ppm. 13C
NMR (75 MHz, CDCl3): δ = 20.2 (CH2), 73.5 (CH), 77.4 (Cquat.),
125.4 (CH2), 128.3 (CH), 129.4 (CH), 133.9 (CH), 138.2 (Cquat.),
145.5 (Cquat.) ppm. HRMS (EI): calcd. for C11H10O2S [M]+
206.0402; found 206.0402.
Diethyl 1-Cyano-5-methylenecyclopentane-1,3-dicarboxylate (5d):
With the same procedure as was described for the synthesis of 5a,
the Michael acceptor 2a (200 mg, 1.45 mmol) was employed as the
starting material. Purification of the reaction mixture by flash
chromatography on silica gel with petroleum ether/CH2Cl2 (7:3)
led to a 1:1:1 mixture of cyclisation diastereomers 5d and 5dЈ and
monoester 7 (177 mg, 54% overall yield for the cyclization) as a
colourless oil. 1H NMR (300 MHz, CDCl3, mixture of 5d and 5dЈ):
δ = 1.19–1.27 (m, 6 H, CH3), 2.50 (m, 2 H, CH), 2.66–2.90 (m, 3
H, CH), 3.00–3.22 (m, 3 H, CH), 4.18 (q, J = 7.1 Hz, J = 7.1 Hz,
4 H, 2 H, OCH2), 4.28 (q, J = 7.1 Hz, J = 7.1 Hz, 2 H, OCH2),
5.27 (s, 1 H, CH), 5.28 (s, 1 H, CH), 5.38 (s, 1 H, CH), 5.48 (s, 1
H, CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.7 (13.7) [CH3],
14.5 (CH3), 35.9 (CH2), 39.7 (CH2), 42.6 (CH), 61.5 (OCH2), 63.6
(63.7) [OCH2], 114.0 (114.2) [CN], 146.3 (Cquat.), 167.4 (Cquat.),
175.2 (Cquat.) ppm. HRMS (ESI): calcd. for C13H17NO4 [M]+
251.1158; found 251.1155.
Ethyl 3-Cyano-4-methylcyclopent-3-ene-1-carboxylate (7): Com-
pound 7 was isolated from an earlier attempt at the synthesis of 5d
with 2a (200 mg, 1.45 mmol), Cs2CO3 (472 mg, 1.45 mmol), methyl
cyanoacetate (1b, 128 µL, 1.45 mmol) and CuI (28 mg, 0.15 mmol)
in dry DMF (3 mL). The reaction was stirred at 50 °C for 14 h.
Purification by chromatography with petroleum ether/ethyl acetate
(7:3) afforded pure 7 as a colourless oil (43 mg, 17% yield). 1H
NMR (300 MHz, CDCl3): δ = 1.27 (t, J = 7.1 Hz, 3 H, CH3), 1.93
(s, 3 H, CH3), 2.65–2.85 (m, 2 H, CH), 3.04 (m, 1 H, CH), 3.22
(m, 1 H, CH), 4.08 (q, J = 7.1 Hz, 2 H, CH2) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.1 (CH3), 16.3 (CH3), 37.2 (CH2), 40.7
(CH2), 50.0 (CH), 61.0 (CH2), 106.8 (Cquat.), 116.0 (CN), 158.8
(Cquat.), 174.0 (Cquat.) ppm.
1-Ethyl 3,3-Dimethyl 4-Methylenecyclopentane-1,3,3-tricarboxylate
(5a): Under a nitrogen atmosphere, dimethylmalonate (1a, 100 µL,
0.868 mmol) and NaH (60% oil dispersion, 29 mg, 0.724 mmol)
were mixed in CH3CN (2 mL). The reaction mixture was vigor-
ously stirred until hydrogen evolution stopped. Ethyl 2-methyl-
enepent-4-yn-1-oic acid (2a, 100 mg, 0.724 mmol) was added, and
the resulting solution was stirred at 50 °C for 5 h (TLC monitor-
ing). CuI (13.8 mg, 0.072 mmol) was then added, and the reaction
mixture was stirred for an additional 5 h at 50 °C. After removal
of CuI by filtration through a short pad of silica gel (CH2Cl2) and
concentration of the mixture, the crude product was purified by
Ethyl 3-Cyano-4-methylene-3-(phenylsulfonyl)cyclopentanecarboxyl-
ate (5e): Michael acceptor 2a (400 mg, 2.89 mmol), (phenylsulfo-
nyl)acetonitrile (1e, 630 mg, 3.48 mmol) and DBU (436 µL,
2.89 mmol) were stirred together at 50 °C for 4 h under a nitrogen
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FULL PAPER
atmosphere. CuI (55 mg, 0.29 mmol) was then added, and the reac-
tion mixture was stirred overnight at 50 °C. After removal of CuI
by filtration through a short pad of silica gel (CH2Cl2) and concen-
tration of the resulting filtrate, the crude product was purified by
flash chromatography on silica gel with petroleum ether/diethyl
ether (8:2) to afford 5e as a 3:5 mixture of two diastereomers
(635.2 mg, 69% yield) and as a pale yellow oil. 1H NMR
(300 MHz, CDCl3 mixture of the two diastereomers): δ = 1.28 (q,
J = 7.1 Hz, 3 H, CH3), 2.53–2.62 (m, 0.5 H, CH), 2.68–2.93 (m, 2
H, CH2), 2.95–3.14, (m, 2 H, CH2), 3.38–3.51 (m, 0.5 H, CH), 4.17
(q, J = 7.1 Hz, 1.2 H, OCH2), 4.20 (q, J = 7.1 Hz, 0.8 H, OCH2),
5.15–5.19 (m, 0.6 H, CH), 5.30 (m, 0.3 H, CH), 5.45 (m, 0.6 H,
CH), 5.49 (m, 0.3 H, CH), 7.60–7.68 (m, 2 H, CH), 7.74–7.81 (m,
1 H, CH), 7.99–8.06 (m, 2 H, CH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.2 (14.3) [CH3], 37.1 (35.8) [CH2], 36.9 (36.8) [CH2],
41.6 (41.9) [CH], 61.4 (61.5) [OCH2], 69.5 (68.2) [Cquat.], 116.8
(113.4) [CN], 118.9 (118.8) [CH2] 129.2 (129.3) [CH], 131.3 (131.2)
[CH], 133.0 (133.7) [Cquat.], 135.4 (135.3) [CH], 141.4 (141.6)
(161.9) [Cquat.], 172.9 (172.3) [Cquat.] ppm. HRMS (ESI): calcd. for
C15H17NNaO4 [M + Na]+ 294.0954; found 294.0955.
Dimethyl 2-Methylene-4-(phenylsulfonyl)cyclopentane-1,1-dicarbox-
ylate (5h): Compound 5h was prepared by a procedure analogous
to that used for 4a except that 2 equiv. of the nucleophile in THF
were used. The reaction was performed with the Michael acceptor
2b (500 mg, 2.42 mmol). Purification by chromatography with pe-
troleum ether/ethyl acetate (8:2) afforded 5h as a pale yellow oil
1
(709 mg, 86% yield). H NMR (300 MHz, CDCl3): δ = 1.23 (dt, J
= 1.3 Hz, J = 7.3 Hz, 1 H, CH), 2.67 (m, 3 H, CH), 2.93 (m, 1 H,
CH), 3.69 (s, 3 H, OCH3), 3.75 (s, 3 H, OCH3), 5.29 (s, 1 H, CH),
5.39 (s, 1 H, CH), 7.57 (t, J = 7.4 Hz, 2 H, CH), 7.67 (t, J = 7.4 Hz,
1 H, CH), 7.89 (d, J = 8.1 Hz, 2 H, CH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 33.9 (CH2), 34.0 (CH2), 52.9 (OCH2), 53.1 (OCH2),
61.0 (CH2), 62.5 (Cquat.), 114.5 (CH2), 128.2 (CH), 129.2 (CH),
133.9 (CH), 137.9 (Cquat.), 142.7 (Cquat.), 169.0 (Cquat.), 169.6
(Cquat.) ppm. HRMS (ESI): calcd. for C16H18NaO6S [M + Na]+
361.0722; found 361.07219.
[Cquat.], 173.0 (171.8) [Cquat.
] ppm. HRMS (EI): calcd. for
C16H17NO4S [M]+ 319.0878; found 319.0879.
2-Methylene-4-(phenylsulfonyl)cyclopentane-1,1-dicarbonitrile (5i):
Compound 5i was prepared with the same procedure as was de-
scribed for the synthesis of 5a except that 2 equiv. of the nucleo-
phile in THF were used. The reaction was performed with Michael
acceptor 2b (150 mg, 0.73 mmol) and gave pure product (197 mg,
3-Benzyl-4-methylene-3-nitrocyclopentyl Propionate (5f): With the
same procedure as was described for the synthesis of 5a, the
Michael acceptor 2a (200 mg, 1.45 mmol) was employed as the
starting material. The Michael addition step was performed with
additional TEBA chloride (330 mg, 1.45 mmol). Purification by
chromatography with petroleum ether/diethyl ether (9:1) containing
4% of Et3N afforded 5f as an inseparable 3:1 mixture of two dia-
stereomers (210 mg, 50% yield) and as a yellow oil. 1H NMR
(300 MHz, CDCl3 mixture of the two diastereomers): δ = 1.16 (t,
J = 7.1 Hz, 1 H, CH3), 1.18 (t, J = 7.2 Hz, 3 H, CH3), 2.09 (dd, J
= 11.5 Hz, J = 14.6 Hz, 1 H, CH), 2.27–2.38 (m, 3.3 H, CH), 2.41–
2.81 (m, 4.2 H, CH), 2.97 (d, J = 14.3 Hz, 1 H, CH), 3.05–3.10 (m,
1 H, CH), 3.63 (pseudo-t, J = 12.9 Hz, 0.33 H, CH), 3.79 (d, J =
14.3 Hz, 1.3 H, CH), 4.05 (q, J = 7.1 Hz, 0.3 H, OCH2), 4.07 (q,
J = 7.2 Hz, 2 H, OCH2), 5.33 (dd, J = 1.9 Hz, J = 2.5 Hz, 1.33 H,
CH), 5.56 (m, 0.33 H, CH), 5.66 (ddd, J = 0.6 Hz, J = 1.9 Hz, J =
2.8 Hz, 1 H, CH), 7.06 (m, 2.5 H, CH), 7.20 (m, 3.9 H, CH) ppm.
13C NMR (75 MHz, CDCl3): δ = 14.1 (14.0) [CH3], 36.1 (35.3)
[CH2], 38.5 (37.4) [CH2], 41.1 (40.2) [Cquat.], 43.9 (44.2) [CH2], 60.7
(60.8) [OCH2], 97.9 (96.6) [Cquat.], 113.5 (112.7) [CH2], 127.4
(127.5) [CH], 128.5 (CH), 129.6 (129.9) [CH], 134.6 (134.3) [Cquat.],
148.1 (Cquat.), 173.9 (173.1) [Cquat.] ppm. HRMS (EI): calcd. for
C16H19NO4 [M]+ 290.1392; found 290.1390.
1
46% yield) as a colourless oil. H NMR (300 MHz, CDCl3): δ =
2.87 (tdd, J = 2.1 Hz, J = 9.0 Hz, J = 17.4 Hz, 2 H, CH), 3.08 (tdd,
J = 2.4 Hz, J = 9.0 Hz, J = 17.4 Hz, 1 H, CH), 3.8 (m, 1 H, CH),
5.53 (q, J = 2.2 Hz, 1 H, CH), 5.73 (q, J = 2.2 Hz, 1 H, CH), 7.63
(td, J = 3.8 Hz, J = 7.2 Hz, 2 H, CH), 7.73 (dd, J = 7.0 Hz, J =
14.0 Hz, 1 H, CH), 7.90 (dd, J = 2.3 Hz, J = 7.9 Hz, 2 H, CH)
ppm. 13C NMR (75 MHz, CDCl3): δ = 31.1 (CH2), 38.3 (CH2),
38.4 (Cquat.), 60.5 (CH), 113.6 (CN), 113.9 (CN), 117.4 (CH2),
128.5 (CH), 129.9 (CH), 134.8 (CH), 137.2 (Cquat.), 140.3 (Cquat.
)
ppm. HRMS (EI): calcd. for [C14H12N2O2S]+ 272.0619; found
272.0619.
Ethyl 1-(Diethoxyphosphoryl)-2-methylene-4-(phenylsulfonyl)cyclo-
pentane-1-carboxylate (5j): Compound 5j was prepared with the
same procedure as was described for the synthesis of 5a except that
2 equiv. of the nucleophile in THF were used. The reaction was
performed with Michael acceptor 2b. Purification by chromatog-
raphy with petroleum ether/acetone (9:1) afforded 5j as an insepa-
rable 5:1 mixture of two diastereomers (135 mg, 65% yield) and as
a colourless oil. 1H NMR (300 MHz, CDCl3): δ = 1.23 (m, 9 H,
phosphoryl-CH3 and carboxy-CH3), 2.62 (dd, J = 9.4 Hz, J =
14.0 Hz, 2.6 H, CH2), 2.88 (m, 1.2 H, CH), 3.65 (m, 0.8 H, CH),
3.88 (m, 0.2 H, CH), 4.12 (dd, J = 5.4 Hz, J = 8.9 Hz, 6 H, OCH2),
3-Ethyl 1-Ethyl 5-Methylene-1-nitrocyclopentane-1,3-dicarboxylate
(5g): Michael acceptor 2a (200 mg, 1.45 mmol), ethyl nitroacetate
(1g, 482 µL, 4.34 mmol), DIPEA (720 µL, 4.34 mmol) and tetraeth- 5.23 (s, 1 H, CH), 5.51 (s, 0.8 H, CH), 5.59 (s, 0.2 H, CH), 7.54
ylammonium bromide (31.5 mg, 0.15 mmol) were mixed together
in CH3CN (6 mL) and stirred at room temp. for 24 h under a nitro-
gen atmosphere. CuI (28 mg, 0.15 mmol) was then added, and the
mixture was stirred at room temp. for an additional 24 h. The reac-
tion mixture was then filtered through silica gel and purified by
chromatography with petroleum ether/diethyl ether (8:2) to afford
5g as a single diastereomer (216 mg, 55% yield) and as a yellow
(dd, J = 7.0 Hz, J = 1.3 Hz, 2 H, CH), 7.63 (dd, J = 7.0 Hz, J =
7.4 Hz, 1 H, CH), 7.86 (dd, J = 1.3 Hz, J = 7.4 Hz, 2 H, CH) ppm.
13C NMR (75 MHz, CDCl3, major isomer): δ = 13.8 (CH3), 16.2
(d, J = 6.29 Hz, CH3), 16.3 (d, J = 6.1 Hz, CH3), 34.0 (d, J =
0.5 Hz, CH2), 35.3 (d, J = 5.8 Hz, CH2) 56.7 (d, J = 146 Hz, Cquat.),
62.2 (CH), 62.9 (d, J = 7.2 Hz, OCH2), 63.8 (d, J = 6.8 Hz, OCH2),
114.5 (d, J = 6.38 Hz, CH2), 128.3 (CH), 129.3 (CH), 133.9 (CH),
oil. 1H NMR (300 MHz, CDCl3): δ = 1.25 (dt, J = 0.5 Hz, J = 138.0 (Cquat.), 142.4 (d, J = 6.15 Hz, Cquat.), 168.9 (d, J = 1.2 Hz,
7.1 Hz, 3 H, CH3), 1.28 (dt, J = 0.5 Hz, J = 7.1 Hz, 3 H, CH3),
Cquat.) ppm. 13C NMR (75 MHz, CDCl3, minor isomer): δ = 13.9
2.74 (m, 2 H, CH2), 2.89 (m, 1 H, CH), 3.02 (m, 2 H, CH2), 4.15 (CH3), 16.2 (d, J = 6.29 Hz, CH3), 16.3 (d, J = 6.1 Hz, CH3), 33.4
(dq, J = 0.5 Hz, J = 7.2 Hz, 2 H, OCH2), 4.28 (dq, J = 0.5 Hz, J
= 7.1 Hz, 2 H, OCH2), 5.52 (t, J = 2.1 Hz, 1 H, CH), 5.63 (d, J =
2.1 Hz, 1 H, CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.9
(d, J = 3.4 Hz, CH2), 34.4 (d, J = 3.2 Hz, CH2), 57.9 (d, J =
137.9 Hz, Cquat.), 61.2 (CH), 63.3 (d, J = 7.4 Hz, OCH2), 64.0 (d,
J = 7.4 Hz, OCH2), 114.5 (d, J = 8.47 Hz, CH2), 128.3 (CH), 129.3
(13.9) [CH3], 14.2 (14.2) [CH3], 35.8 (33.8) [CH2], 40.2 (39.2) [CH2], (CH), 133.8 (CH), 138.2 (Cquat.), 141.4 (d, J = 9.9 Hz, Cquat.), 168.1
41.0 (39.7) [CH], 61.2 (61.4) [OCH2], 63.2 (63.3) [OCH2], 98.7 (d, J = 3.6 Hz, Cquat.) ppm. HRMS (ESI): calcd. for C19H27Na-
(100.8) [Cquat.], 118.0 (118.0) [CH2], 142.6 (142.5) [Cquat.], 165.2 O7PS [M + Na]+ 453.1113; found 453.1114.
Eur. J. Org. Chem. 2007, 3158–3165
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3163

N. Coia, D. Bouyssi, G. Balme
FULL PAPER
General Procedure for the Three-Component Reactions: In a round-
bottomed flask, the nucleophile (2.5 equiv.) was deprotonated by
NaH (60% oil dispersion, 2.3 equiv.) in dry THF (2.4 mL/mmol of
NaH). Once the gaseous evolution stopped, the mixture was de-
gassed by sparging with nitrogen. Aryl iodide (1.2 equiv.), CuI
(0.06 equiv.) and Pd(PPh3)4 (0.03 equiv.) were then added, and the
mixture was stirred at 50 °C. A solution of the Michael acceptor
(1 equiv.) in THF (3 mL/mmol of acceptor) was then added over
2 h at 50 °C. Once the addition was complete, the mixture was
heated for an additional 12 h at 50 °C. After filtration of the mix-
ture through silica gel, the filtrate was concentrated under vacuum,
and the crude material was purified by chromatography on silica
gel with the appropriate solvent (see the details for each compound
below).
with Michael acceptor 2a (200 mg, 1.45 mmol). Purification by
chromatography with petroleum ether/ethyl acetate (85:15) gave
10d (441 mg, 75% yield) as a dark red oil. 1H NMR (300 MHz,
CDCl3): δ = 1.27 (t, J = 7.1 Hz, 3 H, CH3), 2.52 (ddd, J = 1.0 Hz,
J = 9.0 Hz, J = 12.8 Hz, 1 H, CH), 2.78 (m, 1 H, CH), 3.00 (m, 3
H, CH), 3.79 (s, 6 H, OCH3), 3.91 (s, 3 H, OCH3), 4.16 (dq, J =
1.2 Hz, J = 7.1 Hz, 2 H, OCH2), 6.78 (s, 1 H, CH), 7.38 (d, J =
8.4 Hz, 2 H, CH), 8.00 (d, J = 8.4 Hz, 2 H, CH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 14.3 (CH3), 35.4 (CH2), 38.1 (CH2), 42.8
(CH), 52.2 (OCH3), 53.2 (OCH3), 53.3 (OCH3), 61.1 (OCH2), 70.3
(Cquat.), 128.0 (CH), 128.6 (CH), 128.8 (Cquat.), 129.7 (CH), 140.7
(Cquat.), 141.6 (Cquat.), 166.9 (Cquat.), 170.4 (Cquat.), 170.6 (Cquat.),
173.8 (Cquat.) ppm. HRMS (ESI): calcd. for C21H24NaO8 [M + Na]
+
427.1369; found 427.1367.
(E)-1-Ethyl 3,3-Dimethyl 4-Benzylidenecyclopentane-1,3,3-tricar-
boxylate (10a): The reaction was performed with Michael acceptor
2a (100 mg, 0.72 mmol). Purification by chromatography with pe-
troleum ether/diethyl ether (8:2) containing 4% of Et3N gave 10a
(200.5 mg, 80% yield) as a pale yellow oil. 1H NMR (300 MHz,
CDCl3): δ = 1.27 (t, J = 7.1 Hz, 3 H, CH3), 2.52 (dd, J = 10.6 Hz,
J = 13.0 Hz, 1 H, CH), 2.77 (m, 1 H, CH), 2.90–3.10 (m, 3 H,
CH), 3.78 (s, 6 H, OCH3), 4.16 (q, J = 7.1 Hz, 2 H, OCH2), 6.74
(m, 1 H, CH), 7.25 (m, 1 H, CH), 7.32–7.35 (m, 4 H, CH) ppm.
13C NMR (75 MHz, CDCl3): δ = 14.3 (CH3), 35.3 (CH2), 38.2
(CH2), 42.9 (CH), 53.1 (OCH3), 53.2 (OCH3), 61.0 (OCH2), 64.8
(Cquat.), 127.3 (CH), 128.4 (CH), 128.8 (CH), 128.9 (CH), 137.1
(E)-1-Ethyl 3,3-Dimethyl 4-[4-(Trifluoromethyl)benzylidene]cyclo-
pentane-1,3,3-tricarboxylate (10e): The reaction was performed
with Michael acceptor 2a (200 mg, 1.45 mmol). Purification by
chromatography with petroleum ether/ethyl acetate (9:1) gave 10e
(332 mg, 55% yield) as a pale yellow oil. 1H NMR (300 MHz,
CDCl3): δ = 1.20 (t, J = 7.2 Hz, 3 H, CH3), 2.50 (dd, J = 10.0 Hz,
J = 12.8 Hz, 1 H, CH), 2.72 (m, 2 H, CH), 2.94 (m, 2 H, CH), 3.72
(s, 6 H, OCH3), 4.10 (q, J = 7.2 Hz, 2 H, OCH2), 6.75 (s, 1 H,
CH), 7.39 (d, J = 7.5 Hz, 2 H, CH), 7.52 (d, J = 7.5 Hz, 2 H, CH)
ppm. 13C NMR (75 MHz, CDCl3): δ = 14.2 (CH3), 35.2 (CH2),
38.1 (CH2), 42.7 (CH), 53.1 (OCH3), 53.3 (OCH3), 61.0 (OCH2),
64.8 (Cquat.), 123.8 (dd, J = 241.2 Hz, J = 513.1 Hz, CF3), 125.3
(q, J = 3.8 Hz, CH), 127.7 (CH), 128.9 (Cquat.), 140.6 (q, J =
1.4 Hz, CH), 140.8 (Cquat.), 146.0 (Cquat.), 170.4 (Cquat.), 170.5
(Cquat.), 138.0 (Cquat.), 170.7 (Cquat.), 170.9 (Cquat.), 173.9 (Cquat.
)
ppm. HRMS (ESI): calcd. for C19H22NaO6 [M + Na]+ 369.1314;
found 369.1313.
(Cquat.), 173.6 (Cquat.
)
ppm. HRMS (ESI): calcd. for
C20H21F3NaO6 [M + Na]+ 415.1368; found 415.1368.
(E)-1-Ethyl 3,3-Dimethyl 4-(4-Methoxybenzylidene)cyclopentane-
1,3,3-tricarboxylate (10b): The reaction was performed with
Michael acceptor 2a (100 mg, 0.72 mmol). Purification by
chromatography with petroleum ether/diethyl ether (9:1) containing
4% of Et3N gave 10b (200 mg, 80% yield) as an orange oil. 1H
NMR (300 MHz, CDCl3): δ = 1.27 (t, J = 7.1 Hz, 3 H, CH3), 2.50
(dd, J = 10.5 Hz, J = 13.1 Hz, 1 H, CH), 2.75 (ddd, J = 1.6 Hz, J
= 6.1 Hz, J = 13.1 Hz, 1 H, CH), 2.97 (m, 3 H, CH), 3.77 (s, 6 H),
3.81 (s, 3 H, OCH3), 4.17 (dq, J = 1.6 Hz, J = 7.1 Hz, 2 H, OCH2),
6.67 (s, 1 H, CH), 6.88 (d, J = 8.8 Hz, 2 H, CH), 7.27 (d, J =
8.8 Hz, 2 H, CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.3
(CH3), 35.2 (CH2), 38.2 (CH2), 42.9 (CH), 53.1 (OCH3), 53.2
(OCH3), 55.4 (OCH3), 60.9 (OCH2), 64.7 (Cquat.), 113.8 (CH),
128.2 (CH), 129.9 (Cquat.), 130.2 (CH), 135.7 (Cquat.), 158.8 (Cquat.)
, 170.9 5 (Cquat.), 171.0 (Cquat.), 174.0 (Cquat.) ppm. HRMS (ESI):
calcd. for C20H24NaO7 [M + Na]+ 399.1420; found 399.1420.
(E)-1-Ethyl 3,3-Dimethyl 4-(2-Phenylethylidene)cyclopentane-1,3,3-
tricarboxylate (10f): The reaction was performed with Michael ac-
ceptor 2a (150 mg, 1.1 mmol). Purification by chromatography
with petroleum ether/diethyl ether (8:2) gave 10f (196 mg, 50%
1
yield) as an orange oil. H NMR (300 MHz, CDCl3): δ = 1.33 (t,
J = 7.1 Hz, 3 H, CH3), 2.58 (dd, J = 11.1 Hz, J = 13.0 Hz, 1 H,
CH), 2.68–2.95 (m, 3 H, CH), 3.07 (m, 1 H, CH), 3.49 (s, 1 H,
CH), 3.51 (s, 1 H, CH), 3.79 (s, 6 H, OCH3), 4.22 (q, J = 7.1 Hz,
2 H, OCH2), 6.00 (m, J = 7.4 Hz, 1 H, CH), 7.24 (m, J = 1.6 Hz,
2 H, CH), 7.34 (m, J = 7.1 Hz, J = 7.8 Hz, 3 H, CH) ppm. 13C
NMR (75 MHz, CDCl3): δ = 14.2 (CH3), 33.0 (CH2), 35.6 (CH2),
38.4 (CH2), 41.8 (CH), 52.8 (OCH3), 52.9 (OCH3), 60.7 (CH2), 63.4
(Cquat.), 126.0 (CH), 127.3 (CH), 128.2 (CH), 128.4 (CH), 137.6
(Cquat.), 139.8 (Cquat.), 170.6 (Cquat.), 170.9 (Cquat.), 173.9 (Cquat.
)
ppm. HRMS (ESI): calcd. for C20H24O6 [M + Na]+ 360.1573;
found 360.1570.
(E)-1-Ethyl 3,3-Dimethyl 4-(3,4,5-Trimethoxybenzylidene)cyclopen-
tane-1,3,3-tricarboxylate (10c): The reaction was performed with
Michael acceptor 2a (200 mg, 1.45 mmol). Purification by
chromatography with petroleum ether/ethyl acetate (7:3) gave 10c
(585 mg, 92% yield) as a dark red oil. 1H NMR (300 MHz,
CDCl3): δ = 1.21 (t, J = 7.1 Hz, 3 H, CH3), 2.47 (dd, J = 10.3 Hz,
J = 13.1 Hz, 1 H, CH), 2.71 (m, 1 H, CH), 2.93 (m, 3 H, CH), 3.72
(s, 6 H, OCH3), 3.78 (s, 3 H, OCH3), 3.80 (s, 6 H, OCH3), 4.10 (q,
J = 7.1 Hz, 2 H, OCH2), 6.49 (s, 2 H, CH), 6.61 (s, 1 H, CH) ppm.
13C NMR (75 MHz, CDCl3): δ = 14.1 (CH3), 35.0 (CH2), 38.0
(CH2), 42.6 (CH), 53.0 (OCH3), 53.1 (OCH3), 56.1 (OCH3), 60.8
(OCH3), 64.6 (OCH3), 106.0 (CH), 128.6 (CH), 132.7 (Cquat.), 137.2
(Cquat.), 137.3 (Cquat.), 149.8 (Cquat.), 152.9 (Cquat.), 170.5 (Cquat.),
(E)-Ethyl 4-Benzylidene-3-cyano-3-(phenylsulfonyl)cyclopentanecar-
boxylate (10g): The reaction was performed with Michael acceptor
2a (100 mg, 0.48 mmol). THF/DMSO (2:1) was used instead of
pure THF. Purification by chromatography with petroleum ether/
ethyl acetate (8:2) afforded 10g as a 0.45:1 mixture of diastereomers
(143 mg, 50% yield) and as a brown oil. 1H NMR (300 MHz,
CDCl3): δ = 1.15 (t, J = 7.1 Hz, 1.35 H, CH3), 1.19 (t, J = 7.1 Hz,
3 H, CH3), 2.53 (dd, J = 5.8 Hz, J = 12.0 Hz, 1 H, CH), 2.63 (dd,
J = 9.7 Hz, J = 14.9 Hz, 0.45 H, CH), 2.89–3.08 (m, 4.35 H, CH),
3.19 (ddd, J = 2.6 Hz, J = 9.5 Hz, J = 17.4 Hz, 1 H, CH), 3.53 (tt,
J = 7.5 Hz, J = 9.6 Hz, 0.45 H, CH), 4.01 (dd, J = 6.2 Hz, J =
13.3 Hz, 1.0 H, 0.9 H, OCH2), 4.11 (t, J = 7.1 Hz, 2 H, OCH2),
6.24 (t, J = 2.5 Hz, 0.45 H, CH), 6.51 (s, 1 H, CH), 7.12–7.30 (m,
7.25 H, CH), 7.46–7.53 (m, 2.9 H, CH), 7.62–7.68 (m, 1.45 H, CH),
7.89–7.96 (m, 2.9 H, CH) ppm. 13C NMR (75 MHz, CDCl3): δ =
14.1 (14.1) [CH3], 34.2 (34.1) [CH2], 35.5 (35.5) [CH2], 42.7 (42.2)
170.7 (Cquat.), 173.7 (Cquat.
) ppm. HRMS (ESI): calcd. for
C22H28NaO9 [M + Na]+ 459.1631; found 459.1629.
(E)-1-Ethyl 3,3-Dimethyl 4-[4-(Methoxycarbonyl)benzylidene]cyclo-
pentane-1,3,3-tricarboxylate (10d): The reaction was performed
3164
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 3158–3165

Highly Substituted Five-Membered Ring Carbocycles
FULL PAPER
ito, A. L. Rheingold, J. Am. Chem. Soc. 1998, 120, 13285; c)
G. A. Molander, E. D. Dowdy, H. Schumann, J. Org. Chem.
1998, 63, 3386; d) A. Hassner, E. Ghera, T. Yechezkel, V. Klei-
man, T. Balasubramanian, D. Ostercamp, Pure Appl. Chem.
2000, 72, 1671; e) M. Mikolajczyk, M. Mikina, R. Zurawinski,
Pure Appl. Chem. 1999, 71, 473.
[CH], 61.4 (61.3) [OCH2], 70.2 (71.9) [Cquat.], 117.0 (116.8) [CN],
128.5 (128.6) [CH], 128.6 (128.6) [CH], 129.1 (129.0) [CH], 129.2
(129.1) [CH], 131.0 (131.1) [CH], 132.8 (132.6) [Cquat.], 133.1
(133.2) [Cquat.], 133.4 (133.3) [CH], 135.0 (134.9) [Cquat.], 135.3
(135.2) [CH], 171.8 (173.0) [Cquat.] ppm. HRMS (ESI): calcd. for
C22H21NNaO4S [M + Na]+ 418.1089; found 418.1089.
[2] a) Palladium-catalyzed: N. Monteiro, J. Gore, G. Balme, Tetra-
hedron 1992, 48, 10103; b) Molybdenum-catalyzed: F. E. Mc-
Donald, T. C. Olson, Tetrahedron Lett. 1997, 38, 7691; c) Co-
balt/light-catalyzed: J.-L. Renaud, C. Aubert, M. Malacria,
Tetrahedron 1999, 55, 5113; d) Gold(I)-catalyzed: J. Kennedy-
Smith, S. T. Staben, F. D. Toste, J. Am. Chem. Soc. 2004, 126,
4526; e) Rhenium-catalyzed: Y. Kuninobu, A. Kawata, K.
Takai, Org. Lett. 2005, 7, 4823; f) Nickel(II)-catalyzed: Q. Gao,
B.-F. Zheng, J.-H. Li, D. Yang, Org. Lett. 2005, 7, 2185.
[3] D. Bouyssi, N. Monteiro, G. Balme, Tetrahedron Lett. 1999,
40, 1297.
[4] Only a few [4+1] annulation strategies have been reported. For
example, see:a) J. L. Loebach, D. M. Bennet, R. L. Danheiser,
J. Am. Chem. Soc. 1998, 120, 9690; b) T. Hudlicky, M. G.
Natchus, G. Sinai-Zingde, J. Org. Chem. 1987, 52, 4641; c) K.
Takasu, H. Ohsato, J.-I. Kuroyanagi, M. Ihara, J. Org. Chem.
2002, 67, 6001; d) M. Murakami, K. Itami, Y. Ito, J. Am.
Chem. Soc. 1999, 121, 4130; e) S. V. Gagnier, R. C. Larock, J.
Am. Chem. Soc. 2003, 125, 4804.
(E)-Dimethyl 2-Benzylidene-4-(phenylsulfonyl)cyclopentane-1,1-di-
carboxylate (10h): The reaction was performed with Michael ac-
ceptor 2b (300 mg, 2.2 mmol). Purification by chromatography
with petroleum ether/ethyl acetate (8:2) gave 10h (427 mg, 71%
1
yield) as a brown oil. H NMR (300 MHz, CDCl3): δ = 2.6 (d, J
= 10 Hz, 1 H, CH), 2.95 (ddd, J = 1.3 Hz, J = 7.7 Hz, J = 16.5 Hz,
1 H, CH), 3.11 (ddd, J = 3.1 Hz, J = 10 Hz, J = 16.5 Hz, 1 H,
CH), 3.66 (s, 3 H, OCH3), 3.69 (m, 1 H, CH), 3.71 (s, 3 H, OCH3),
6.73 (t, J = 1.9 Hz, 1 H, CH), 7.16–7.23 (m, 3 H, CH), 7.27 (m, 2
H, CH), 7.50 (m, 1 H, CH), 7.60 (m, 2 H, CH), 7.85 (m, 2 H, CH)
ppm. 13C NMR (75 MHz, CDCl3): δ = 32.0 (CH2), 35.3 (CH2),
53.2 (OCH3), 53.3 (OCH3), 62.1 (Cquat.), 64.1 (CH), 127.5 (CH),
128.3 (CH), 128.4 (CH), 128.6 (CH), 129.4 (CH), 129.9 (CH), 134.0
(CH), 134.9 (Cquat.), 136.3 (Cquat.), 138.1 (Cquat.), 169.5 (Cquat.),
170.2 (Cquat.) ppm. HRMS (ESI): calcd. for C22H22NaO6S [M +
Na]+ 437.1035; found 437.1034.
[5] a) V. T. Ravikumar, S. Swaminathan, K. Rajagopalan, Tetrahe-
dron Lett. 1984, 25, 6045; b) R. Gueignec, B. Kirschleger, F.
Lambert, M. Aboutaj, Synth. Commun. 1988, 18, 1213.
[6] A similar demethoxycarbonylation was recently observed dur-
ing a Pd-catalyzed tandem cyclization-coupling reaction of
conjugated enynes bearing a methyl cyanoacetate as the nucleo-
phile. See: T. Lomberget, D. Bouyssi, G. Balme, Synlett 2002,
1439.
[7] N. Monteiro, G. Balme, J. Gore, Synlett 1992, 227.
[8] Y. Fu, L. G. J. Hammarström, T. J. Miller, F. R. Fronczek,
M. L. McLaughlin, R. P. Hammer, J. Org. Chem. 2001, 66,
7118.
(E)-Dimethyl 2-(3,4,5-Trimethoxybenzylidene)-4-(phenylsulfonyl)cy-
clopentane-1,1-dicarboxylate (10i): The reaction was performed
with Michael acceptor 2b (200 mg, 1 mmol). Purification by
chromatography with petroleum ether/ethyl acetate (7:3) gave 10i
1
(319 mg, 65% yield) as a brown oil. H NMR (300 MHz, CDCl3):
δ = 2.64 (d, J = 9.1 Hz, 2 H, CH), 2.88 (dd, J = 7.1 Hz, J = 16.5 Hz,
1 H, CH), 3.07 (ddd, J = 2.9 Hz, J = 10.4 Hz, J = 16.2 Hz, 1 H,
CH), 3.67 (s, 3 H), 3.70 (m, 1 H, CH), 3.72 (s, 3 H), 3.74 (pseudo-
s, 9 H, OCH3), 6.40 (s, 2 H, CH), 6.65 (s, 1 H, CH), 7.49 (t, J =
7.5 Hz, 1 H, CH), 7.59 (t, J = 7.4 Hz, 1 H, CH), 7.84 (d, J = 7.3 Hz,
1 H, CH) ppm. 13C NMR (75 MHz, CDCl3): δ = 32.4 (CH2), 34.6
(CH2), 53.0 (OCH3), 53.2 (OCH3), 55.8 (OCH3), 60.6 (OCH3), 61.9
(OCH3), 63.9 (Cquat.), 105.7 (CH), 128.0 (CH), 129.2 (CH), 129.6
(CH), 131.8 (Cquat.), 133.9 (CH), 134.1 (Cquat.), 137.3 (Cquat.), 138.0
(Cquat.), 152.8 (Cquat.), 169.3 (Cquat.), 169.9 (Cquat.) ppm.
[9] For reviews on the chemistry of sulfones:a) S. Patai, Z. Rappo-
port, C. Stirling in The Chemistry of sulfones and sulfoxides,
Wiley, Chichester, 1988; b) B. M. Trost, Bull. Chem. Soc. Jpn.
1988, 61, 107; c) N. S. Simpkins in Sulfones in Organic Synthe-
sis, Pergamon Press, Oxford, 1993; d) S. Patei, Z. Rappoport
in The Synthesis of sulfones, Sulfoxides and Cyclic Sulphides,
Wiley, Chichester, 1994; e) C. M. Rayner, Contemp. Org. Synth.
1994, 1, 191; f) C. M. Rayner, Contemp. Org. Synth. 1995, 2,
409; g) C. M. Rayner, Contemp. Org. Synth. 1996, 3, 499; h) R.
Chinchilla, C. Nájera, Recent Res. Devel. Org. Chem. 1997, 1,
437; i) Nájera, J. M. Sansano, Recent Res. Devel. Org. Chem.
1998, 2, 637; j) C. Nájera, M. Yus, Tetrahedron 1999, 55, 10547;
k) E. N. Prilezhaeva, Russ. Chem. Rev. 2000, 69, 367.
[10] a) G. Balme, D. Bouyssi, T. Lomberget, N. Monteiro, Synthesis
2003, 2115; b) G. Balme, E. Bossharth, N. Monteiro, Eur. J.
Org. Chem. 2003, 4101; c) G. Balme, D. Bouyssi, N. Monteiro,
in Handbook of Organopalladium Chemistry for Organic Syn-
thesis (Ed.: E.-I. Negishi), Wiley, New York, 2002, vol. 2, pp.
2245–2265; d) G. Balme, D. Bouyssi, N. Monteiro, Pure Appl.
Chem. 2006, 78, 231.
(E)-Dimethyl 2-[4-(Methoxycarbonyl)benzylidene]-4-(phenylsulfonyl)-
cyclopentane-1,1 dicarboxylate (10j): The reaction was performed
with Michael acceptor 2b (200 mg, 1 mmol). Purification by
chromatography with petroleum ether/ethyl acetate (7:3) gave 10j
(325 mg, 71% yield) as an orange oil. 1H NMR (300 MHz, CDCl3):
δ = 2.62 (d, J = 9.0 Hz, 2 H, CH), 2.92 (m, 1 H, CH), 3.15 (ddd,
J = 2.3 Hz, J = 10.1 Hz, J = 16.2 Hz, 1 H, CH), 3.68 (s, 3 H,
OCH3), 3.70 (m, 1 H, CH), 3.73 (s, 3 H, OCH3), 3.84 (s, 3 H,
OCH3), 6.79 (s, 1 H), 7.28 (d, J = 8.3 Hz, 2 H), 7.56 (td, J = 7.1 Hz,
J = 14.8 Hz, 3 H), 7.85 (d, J = 7.6 Hz, 2 H), 7.94 (d, J = 7.6 Hz,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 32.0 (CH2), 35.0
(CH2), 52.0 (OCH3), 53.2 (OCH3), 53.3 (OCH3), 61.9 (CH), 64.1
(Cquat.), 128.2 (CH), 128.4 (CH), 128.9 (CH), 129.4 (CH), 129.5
(CH), 134.0 (CH), 137.4 (Cquat.), 137.9 (Cquat.), 140.6 (Cquat.), 166.4
(Cquat.), 169.1 (Cquat.), 169.8 (Cquat.) ppm.
[11] We have already reported the high efficiency of this Pd0 source
in a related cyclisation-coupling reaction; see: M. Bottex, M.
Cavicchioli, B. Hartmann, N. Monteiro, G. Balme, J. Org.
Chem. 2001, 66, 175.
[12] D. Bouyssi, G. Balme, J. Gore, Tetrahedron Lett. 1991, 32,
6541.
Acknowledgments
[13] A subsequent control experiment revealed that treatment of
the preformed enolate of 1a with 1 equiv. of NaH with benzyl
chloride in THF at 50 °C for 7 h led mainly to the recovery of
unreacted substrates.
N. C. wishes to thank the Ministère de l’Education Nationale, de
la Recherche et de la Technologie for a fellowship.
[1] For selected references, see:a) B. M. Trost, A. B. Pinkerton, J.
Org. Chem. 2001, 66, 7714; b) D. F. Taber, H. Yu, C. D. Incarv-
Received: March 6, 2007
Published Online: May 22, 2007
Eur. J. Org. Chem. 2007, 3158–3165
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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