Iron(III)-catalyzed Conia-ene cyclization of 2-alkynic 1,3-dicarbonyl compounds

Article abstract of DOI:10.1021/jo300957q

A cheap, simple, and effective FeCl₃-catalyzed Conia-ene cyclization of 2-alkynic 1,3-dicarbonyl compounds was stereospecific to afford alkylidenecyclopentanes in (E)-isomers via the 5-exo-dig pathway. The 5-endo-dig and 6-exo-dig cyclizations were also possible, depending on the structure of the substrates.

Full text of DOI:10.1021/jo300957q

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Iron(III)-Catalyzed Conia−Ene Cyclization of 2-Alkynic 1,3-Dicarbonyl
Compounds
Li Yan Chan,† Sunggak Kim,*,† Youngchul Park,‡ and Phil Ho Lee*,‡
†Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637371, Singapore
‡Department of Chemistry, Kangwon National University, Chuncheon 200-701, Republic of Korea
S
* Supporting Information
ABSTRACT: A cheap, simple, and effective FeCl3-catalyzed Conia−ene cyclization of 2-alkynic 1,3-dicarbonyl compounds was
stereospecific to afford alkylidenecyclopentanes in (E)-isomers via the 5-exo-dig pathway. The 5-endo-dig and 6-exo-dig
cyclizations were also possible, depending on the structure of the substrates.
Table 1. Optimizing Reaction Conditions for Conia−Ene
INTRODUCTION
■
a
Cyclization
The growth of organic chemistry has been fueled by the
increasing interest in researching the biological properties of
natural products, thus leading to the constant development of
new and novel synthetic methodologies. A motif common in
natural products is 5-membered rings, which include cyclo-
pentanes and heterocyclic rings such as furans, pyrroles, and
indoles.1
Among various reactions to form cyclic structures, the
Conia−ene reaction is a powerful method for forming cyclized
compounds,2 the intramolecular cyclization of acetylenic
ketones and aldehydes. Various transition metals such as
Au(I),3 In(III),4 Cu(I),5 Ni(II),6 Zr(II),7 etc. have been
extensively studied for such Conia−ene reactions.8 Never-
theless, minimum studies were carried out using iron catalysts,9
though it is noteworthy that iron salts are naturally abundant,
cheap, and easy to handle with low toxicity. Thus, we have
explored the catalytic ability of iron salts in the Conia−ene
cyclizations.
yield (%)
temp
time
(h)
entry
Fe (mol %)
FeBr2 (10)
solvent
(°C)
2
3
1
2
DCE
70
70
70
70
70
rt
5
6
65
72
53
FeCl2 (10)
Fe(acac)3 (10)
Fe2O3 (10)
Fe(OTf)3 (10)
FeCl3 (10)
FeCl3 (5)
DCE
3
DCE
18
18
24
1.5
1.5
1
4
DCE
5
DCE
47
76
65
54
46
30
50
63
6
DCE
7
DCE
rt
8
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
FeCl3 (20)
DCE
rt
18
19
9
toluene
CH3NO2
CH3CN
DCE
70
70
70
rt
5
10
11
12
18
18
2.5
RESULTS AND DISCUSSION
■
FeCl3 (10) +
Na2CO3 (1 equiv)
The Conia−ene cyclization was carried out using the ketoester
1 as the standard substrate to optimize the reaction conditions.
As exemplified in Table 1, 1 underwent 5-exo-dig cyclization in
the presence of various Fe catalysts. Most Fe catalysts
employed required heating at 70 °C and produced only a
moderate yield (47−72% yield) (entries 1−5), whereas FeCl3
could catalyze the Conia−ene cyclization effectively at room
temperature (entries 6−8 and 12). Fe2O3 was basically inert to
such reactions (entry 4). In addition, it is noteworthy that
Fe(OTf)3 is much less efficient than FeCl3 (entry 5). Varying
the catalyst loading changed the results to some extent. As seen
in entry 8, 1 readily cyclized to give methylenecyclopentane 2
a
Conditions: 1 (0.3 mmol) and Fe (5−20 mol %) in 2 mL of solvent
at respective temperature.
in 72% yield, which isomerized partially to 3. This isomer-
ization could be easily avoided by decreasing the amount of
FeCl3 from 20 mol % (entry 8) to either 10 mol % (entry 6) or
5 mol % (entry 7), with which 10 mol % of FeCl3 gave the best
Received: May 10, 2012
© XXXX American Chemical Society
A
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a
Table 2. Conia−Ene Cyclization of 4 or 6 Using FeCl3 as Catalyst
a
b
c
Conditions: 4, 6, or 8 (0.3 mmol) and FeCl3 (10 mol %) in 2 mL of DCE at room temperature. Reaction was carried out at 70 °C. Reaction was
d
e
carried out at 80 °C. Recovery yield of the starting material. 9a:9b = 1:1.8.
result. When solvents such as nitromethane (entry 10) and
acetonitrile (entry 11) were used, the reaction proceeded much
less efficiently, even under prolonged heating at 70 °C. When
the reaction was carried out in toluene (entry 9), 1 cyclized at
70 °C to give 65% yield after 5 h. However, the exo-
methylenecyclopentane 2 again further isomerized to its
thermodynamically more stable 3 to some extent. Addition of
Na2CO3 did not facilitate the reaction at all (entry 12).
the R group was changed from a methyl group to a phenyl
group (4a), the reaction proceeded cleanly at room temper-
ature to furnish the desired 5a in 77%, but at an extended time
of 29 h (entry 1). The introduction of an electron-donating
methyl (4b) group at the para position of the phenyl R group
decreased the reactivity of the Fe catalyst, thus requiring
heating and a longer reaction time for the cyclization to afford
5b in 73% yield (entry 2). Nonetheless, the addition of a bulky
tert-butyl group at the R1 position (4c) also cyclized smoothly
to deliver the desired 5-membered olefin 5c in 70% yield after
Table 2 summarizes the results of the Conia−ene cyclization
achieved using 10 mol % of FeCl3 in 1,2-dichloroethane. When
B
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14 h (entry 3). Cyclization reaction also occurred smoothly
with alkyl-substituted alkynes, yielding stereoselective (E)-5d
isomer in 72% yield (entry 4). Substrate 4e bearing a pyrrole
moiety required heating at 70 °C for 23 h to afford 5e in 73%
yield (entry 5). This catalytic system can also be utilized in
diketone derivative 4f, but the cyclization was slower (entry 6).
We also explored the possibility of 5-endo-dig cyclization by
reducing one carbon at the alkynyl chain (Table 2, entries 7−
9). When 6a was subjected to the standard conditions, the
cyclization was very slow and required heating at 80 °C for a
long period of time (48 h) to give the desired product in 51%
yield together with the recovery of the starting material (38%)
(entry 7). However, ethyl-substituted alkynes 6b and 6c were
more reactive, and the alkynes proceeded at room temperature
(entries 8 and 9). In the case where the alkynyl chain was
extended by one more carbon, 8 underwent cyclization slowly
to give 9a via 6-exo-dig, which isomerized to a more stable 9b
(ratio of 9a:9b = 1.0:1.8) (entry 10).
then discovered that upon treatment with FeX3 (X = Cl, OTf),
intermediate 14 was formed at room temperature, which
underwent cyclization at 80 °C. Intermediate 14 was
successfully isolated, and treating it with Fe(OTf)3 again
eventually resulted in the same (E)-15 in 91% yield.
In Scheme 3, (E)-15 was readily converted to its iodide
derivative 16a and deuterated 16b,10 and subjected to the NOE
Scheme 3. Further Transformation of 15
experiment. Compounds 16a and 16b were also compared to
similar previously known compounds3a,5d,11 before the
sterostructure was assigned.
Alternatively, as illustrated in Scheme 1, when 10 was
subjected to the standard cyclization conditions, trisubstituted
furan ring 11 was isolated in 76% yield, which is in line with the
previously reported result.9f
Further studies on such stannyl Conia−ene experiments are
represented in Table 3. The reactions for 5-endo-dig cyclization
for synthesizing 18a−c gave moderate yields of 63−66%
(entries 1−3). In entry 4, a similar observation from Scheme 2
was seen when 19a was cyclized to yield selectively bicyclic (E)-
20a. By replacing the ester group with a sulfonyl group, 19b not
only underwent cyclization via the usual 5-exo-dig cyclization to
yield (E)-20b but also via 6-endo-dig cyclization, whereby
SO2Ph was eliminated to give a more stable naphthalene
derivative 20b′ (entry 5).
Scheme 1. Formation of Trisubstituted Furan 11 via FeCl3
Catalysis of 10
To confirm that the cyclization did not proceed via a radical
intermediate (Scheme 4), substrate 1 was subjected to the
standard cyclization conditions in the presence of a radical
scavenger, TEMPO. However, the reaction did not proceed as
expected. Nonetheless, this finding was not very conclusive, as
previous reports have shown possible formation of metal
complexes with TEMPO,12 which would in turn mask the
catalytic properties of Fe, thus inhibiting the reaction. When
alkene 21 was treated with FeCl3 overnight at 80 °C, no
reaction was observed and the starting material was recovered
unchanged. This result clearly indicates that the reaction was
unlikely to go through a radical mechanism since alkyne and
alkene are both susceptible toward radical attack.13
Additional stannyl Conia−ene-type experiments were carried
out using tin enolate 13 as shown in Scheme 2. The ketoester 1
a
Scheme 2. Stannyl Conia−Ene-Type Cyclization
On the basis of experimental results obtained in this study, a
plausible mechanism might involve an enol−alkyne iron
complex, which undergoes a 5-exo-dig cyclization to yield
stereospecific product in exclusive (E)-isomer after protonation
of a vinyl iron intermediate (Scheme 5).
CONCLUSIONS
■
Iron(III) salts such as FeCl3 and Fe(OTf)3 were found to be
very mild and effective catalysts in promoting the Conia−ene
cyclizations in 5-exo-dig, 5-endo-dig, and 6-exo-dig manners,
especially in the formation of 5-membered rings. With its
naturally cheap and abundant properties, FeCl3 will be a very
useful catalytic source for such reactions. Synthetically useful
vinylstannanes synthesized could be further utilized, especially
in the application of coupling reactions.
a
Ac2O (1.2 equiv) and pyridine (1.5 equiv) in CH2Cl2.
b
Bu3SnOMe (1.05 equiv) under neat conditions.
c
Fe(OTf)3 (5 mol %) in DCE.
was first treated with Ac2O to give its acetate 12, which was
converted to 13 by stirring with Bu3SnOMe under neat
conditions. When the reaction mixture was subjected to the
cyclization condition, the cyclized stannane product 15 was
obtained exclusively as its (E)-isomer, however, in a low yield of
only 23% when FeCl3 was used. The yield was greatly improved
to 94% when Fe(OTf)3 was used instead, giving (E)-15. We
EXPERIMENTAL SECTION
■
General Methods. A variety of chemical reagents were
commercially purchased and used without further purification.
Analytical TLC was carried out on precoated plates and visualized
with UV light or stained with potassium permanganate. H and 13C
1
NMR spectra were measured at 298 K on a 400 Fourier transform
C
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a
Table 3. Stanyl Conia−Ene Cyclization
a
b
Conditions: 17 or 19 (0.3 mmol) and Fe(OTf)3 (5 mol %) in 2 mL of DCE at 80 °C. 20b:20b′ = 1.38:1.
NMR spectrometer. Chemical shifts are reported in δ (ppm), relative
to the internal standard of TMS. The signals observed were described
as: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplets). The
number of protons (n) for a given resonance is indicated as nH.
Coupling constants are reported as J in Hz. 13C NMR are reported as δ
(ppm) in downfield from TMS and relative to the signal of
chloroform-d (δ 77.00, triplet). Mass spectrometry was performed
on a GC/HRMS spectrometer under electron impact (EI) ionization
technique (mass analyzer: magnetic sector−electric sector). FeCl2
(99.5%), FeBr2 (98%), Fe(acac)2 (99.9%), Fe2O3 (99.99%), Fe(OTf)3
(90%), and FeCl3 (98%), purchased from commercial suppliers, were
used.
Scheme 4. Exploring Possible Reaction Mechanism
General Experimental Procedure for the Conia−Ene
Cyclization. Anhydrous FeCl3 (4.9 mg, 0.03 mmol, 10 mol %
equiv) was carefully weighed and stirred in 1,2-dichloroethane (2 mL).
1,3-Dicarbonyl (0.3 mmol, 1.0 equiv) was then added, and the mixture
was either stirred at room temperature or heated to the respective
temperature. The residual crude product was concentrated in vacuo
and purified by flash chromatography to afford the desired cyclized
product.
Scheme 5. Proposed Reaction Mechanism
Methyl 1-acetyl-2-methylenecyclopentanecarboxylate
(2):.3a,5a (Table 1, entry 6) 41.5 mg, 76% yield; yellow liquid; H
1
NMR (400 MHz, CDCl3) δ 5.30 (t, J = 2.1 Hz, 1H), 5.23 (t, J = 2.3
Hz, 1H), 3.75 (s, 3H), 2.48−2.38 (m, 3H), 2.25−2.16 (m, 4H), 1.76−
1.62 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 203.6, 171.7, 148.7,
112.2, 70.42, 52.7, 35.0, 33.9, 26.6, 24.1.
Methyl 1-acetyl-2-methylcyclopent-2-enecarboxylate (3):
1
(Table 1, entry 9) 10.4 mg, 19% yield; yellow liquid; H NMR (400
MHz, CDCl3) δ 5.71 (d, J = 1.2 Hz, 1H), 3.76 (s, 3H), 2.69−2.61 (m,
1H), 2.61−2.32 (m, 2H), 2.29−2.19 (m, 1H), 2.18 (s, 3H), 1.82 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 205.1, 172.2, 137.4, 132.2, 74.7,
52.3, 32.8, 30.4, 26.6, 14.8; FTIR (NaCl, neat) ν 1703, 1647 cm−1;
HRMS (EI, C10H15O3 (M + 1)) calcd 183.1021, found 183.1028.
Ethyl 1-benzoyl-2-methylenecyclopentanecarboxylate
(5a):.3a,6 (Table 2, entry 1) 60.0 mg, 77% yield; yellow liquid; H
1
D
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NMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.4 Hz, 2H), 7.53 (t, J = 7.4
Hz, 1H), 7.42 (t, J = 7.4 Hz, 2H), 5.36 (t, J = 2.0 Hz, 1H), 5.22 (t, J =
2.1 Hz, 1H), 4.13 (m, 2H), 2.86 (dt, J = 13.2, 7.0 Hz, 1H), 2.52 (m,
2H), 2.19 (dt, J = 13.2, 7.0 Hz, 1H), 1.86 (m, 1H), 1.71 (m, 1H), 1.06
(t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 195.4, 171.8,
149.5, 135.4, 132.7, 128.8, 128.4, 111.8, 67.5, 61.6, 36.8, 34.4, 24.4,
13.7.
Methyl 1-(4-methylbenzoyl)-2-methylenecyclopentanecar-
boxylate (5b):4d (Table 2, entry 2) 57 mg, 73% yield; yellow liquid;
1H NMR (400 MHz, CDCl3) δ 7.75 (d, J = 8.24 Hz, 2H), 7.22 (d, J =
8.14 Hz, 2H), 5.35 (t, J = 1.95 Hz, 1H), 5.18 (t, J = 2.16 Hz, 1H), 3.66
(s, 3H), 2.83 (td, J = 13.3, 6.77 Hz, 1H), 2.51 (m, 2H), 2.40 (s, 3H),
2.18 (td, J = 13.3, 6.90 Hz, 1H), 1.85 (m, 1H), 1.70 (m, 1H); 13C
NMR (100 MHz, CDCl3) δ 195.1, 172.9, 149.8, 143.9, 133.0, 129.6,
129.4, 112.3, 67.8, 53.1, 37.3, 34.7, 24.7, 22.0.
2, entry 10) 30.3 mg, 48% combined yield, ratio of 9a:9b = 1.0:1.8;
yellow liquid; 1H NMR (400 MHz, CDCl3) δ 5.77 (br s, 1.80H), 5.05
(s, 1H), 4.65 (s, 1H), 4.33−4.16 (m, 5.6H), 2.41−2.29 (m, 2.8H), 2.25
(s, 3H), 2.19 (s, 5.4H), 2.11−2.01 (m, 5.8H), 1.98−1.88 (m, 1.8H),
1.76 (dd, J = 3.4, 1.9 Hz, 5.4H), 1.62−1.52 (m, 8.4H), 1.33−1.25 (m,
8.4H); 13C NMR (100 MHz, CDCl3) δ 206.4 (9b), 205.4 (9a), 171.9
(9a and 9b), 129.7 (9a and 9b), 128.2 (9b), 112.0 (9a and 9b), 65.4
(9a and 9b), 61.4 (9a), 61.2 (9b), 34.6 (9a), 32.3 (9a), 29.9 (9b), 27.6
(9a), 27.3 (9a), 26.7 (9b), 25.1 (9b), 22.5 (9a), 21.7 (9b), 18.6 (9b),
14.1 (9b), 14.0 (9a); FTIR (NaCl, neat) ν 1699, 1641 cm−1; HRMS
(EI, C12H19O3 (M + 1)) calcd 211.1334, found 211.1355.
Methyl 2,5-dimethylfuran-3-carboxylate (11):15 (Scheme 1)
46.2 mg, 76% yield; yellow liquid; 1H NMR (400 MHz, CDCl3) δ 6.20
(s, 1H), 3.80 (s, 3H), 2.52 (s, 3H), 2.24 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 164.7, 157.7, 149.9, 113.7, 106.1, 51.1, 13.6, 13.2.
Methyl 2-(1-acetoxyethylidene)hept-6-ynoate (12): (Scheme
2) 91.9 mg, 82% yield; yellow liquid; H NMR (400 MHz, CDCl3) δ
tert-Butyl 1-acetyl-2-methylenecyclopentanecarboxylate
(5c):.3a,6 (Table 2, entry 3) 47.1 mg, 70% yield; yellow liquid; H
1
1
NMR (400 MHz, CDCl3) δ 5.18 (t, J = 2.0 Hz, 1H), 5.13 (t, J = 2.19
Hz, 1H), 2.29 (m, 3H), 2.11 (s, 3H), 2.01 (m, 1H), 1.58 (m, 2H), 1.36
(s, 9H); 13C NMR (100 MHz, CDCl3) δ 203.6, 170.1, 148.9, 111.6,
81.9, 71.1, 35.0, 34.1, 27.8, 26.8, 23.9.
(E)-Ethyl 1-acetyl-2-ethylidenecyclopentanecarboxylate
(5d): (Table 2, entry 4) 45.4 mg, 72% yield; yellow liquid; 1H
NMR (400 MHz, CDCl3) δ 5.70−5.61 (m, 1H), 4.20 (q, J = 7.1 Hz,
2H), 2.46−2.26 (m, 3H), 2.22−2.12 (m, 4H), 1.84−1.45 (m, 5H),
1.26 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 204.5, 171.6,
140.2, 122.2, 70.6, 61.3, 35.0, 29.5, 26.8, 23.7, 15.3, 14.0; FTIR (NaCl,
neat): ν 1699, 1630 cm−1; HRMS (EI, C12H19O3 (M + 1)) calcd
211.1334, found 211.1348.
Ethyl 2-methylene-1-(1H-pyrrole-2-carbonyl)-
cyclopentanecarboxylate (5e): (Table 2, entry 5) 54.1 mg, 73%
yield; yellow liquid; 1H NMR (400 MHz, CDCl3) δ 9.48 (s, 1H), 6.99
(m, 1H), 6.75 (m, 1H), 6.25 (m, 1H), 5.36 (t, J = 2.0 Hz, 1H), 5.29 (t,
J = 2.2 Hz, 1H), 4.17 (m, 2H), 2.76 (dt, J = 13.2, 6.6 Hz, 1H), 2.50 (m,
2H), 2.25 (m, 1H), 1.76 (m, 2H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 186.7, 172.2, 148.9, 129.9, 124.4, 116.5, 112.8,
111.2, 67.4, 61.9, 38.1, 34.7, 24.7, 14.3; FTIR (NaCl, neat) ν 3292,
1733, 1641 cm−1; HRMS (EI, C14H17NO3 (M + 1)) calcd 247.1208,
found 247.1206.
3.76 (s, 3H), 2.35 (t, J = 7.8 Hz, 2H), 2.27 (s, 3H), 2.21 (s, 3H), 2.20−
2.13 (m, 2H), 1.95 (t, J = 2.4 Hz, 1H), 1.81−1.51 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 168.2, 167.9, 157.3, 121.4, 84.3, 68.4, 51.7, 27.3,
26.2, 20.9, 19.4, 18.1; FTIR (NaCl, neat) ν 21156, 1759, 1717, 1647
cm−1; HRMS (EI, C12H17O4 (M + 1)) calcd 225.1127, found
225.1114.
Methyl 2-acetyl-7-(tributylstannyl)hept-6-ynoate (14):
1
(Scheme 2) 97.6 mg, 69% yield; yellow liquid; H NMR (400 MHz,
CDCl3) δ 3.74 (s, 3H), 3.47 (t, J = 7.4 Hz, 1H), 2.28 (dd, J = 9.5, 4.5
Hz, 2H), 2.24 (s, 3H), 1.98 (dd, J = 15.4, 7.8 Hz, 2H), 1.64−1.43 (m,
8H), 1.42−1.23 (m, 6H), 1.05−0.81 (m, 15H); 13C NMR (100 MHz,
CDCl3) δ 202.9, 170.1, 110.3, 82.5, 59.2, 52.3, 28.8, 28.7, 27.2, 26.9,
19.8, 13.6, 10.9; FTIR (NaCl, neat) ν 2999, 2955, 2930, 2879, 2118,
1715, 1647, 1435, 1246, 1057, 646 cm−1; HRMS (EI, C22H41O3Sn (M
+ 1)) calcd 473.2078, found 473.2120.
(E)-Methyl 1-acetyl-2-((tributylstannyl)methylene)cyclo-
pentanecarboxylate (15): (Scheme 2) 132.9 mg, 94% yield; yellow
liquid; 1H NMR (400 MHz, CDCl3) δ 6.12 (dt, 2JSn−H = 57.6, J = 2.0
Hz, 1H), 3.72 (s, 3H), 2.51−2.32 (m, 3H), 2.26 (dd, J = 13.2, 6.6 Hz,
1H), 2.21 (s, 3H), 1.82−1.68 (m, 2H), 1.58−1.39 (m, 6H), 1.38−1.24
(m, 6H), 1.06−0.75 (m, 15H); 13C NMR (100 MHz, CDCl3) δ 204.3,
171.8, 156.6, 126.3, 72.7, 52.4, 35.8, 34.9, 29.1, 27.2, 26.6, 24.3, 13.7,
9.9; FTIR (NaCl, neat) ν 2957, 2926, 2872, 2853, 1710, 1638, 1458,
1233, 1072, 667 cm−1; HRMS (EI, C22H41O3Sn (M + 1)) calcd
473.2078, found 473.2083.
(E)-Methyl 1-acetyl-2-(iodomethylene)cyclopentane-
carboxylate (16a): (Scheme 3) 87.8 mg, 95% yield; yellow liquid;
1H NMR (400 MHz, CDCl3) δ 6.51 (t, J = 2.6 Hz, 1H), 3.77 (s, 3H),
2.62−2.50 (m, 1H), 2.50−2.39 (m, 2H), 2.32 (dt, J = 13.1, 6.6 Hz,
1H), 2.19 (s, 3H), 1.88−1.70 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 201.9, 170.2, 150.3, 78.2, 71.9, 53.0, 38.1, 36.3, 26.6, 22.9; FTIR
(NaCl, neat): ν 1705, 1636 cm−1; HRMS (ESI, C10H14O3I (M + 1))
calcd 308.9988, found 308.9993.
(2-Methylenecyclopentane-1,1-diyl)bis(phenylmethanone)
1
(5f): (Table 2, entry 6) 50.5 mg, 58% yield; yellow liquid; H NMR
(400 MHz, CDCl3) δ 7.81 (app d, J = 8.0 Hz, 4H), 7.44 (tt, J = 7.43
Hz, 2H), 7.34 (app t, J = 7.45 Hz, 4H), 5.39 (t, J = 1.91 Hz, 1H), 4.96
(t, J = 2.0 Hz, 1H), 2.65 (m, 4H), 1.83 (m, 2H)); 13C NMR (100
MHz, CDCl3) δ 198.5, 150.8, 136.4, 133.1, 129.9, 128.8, 113.7, 74.0,
38.0, 35.2, 24.0.; FTIR (NaCl, neat) ν 1687, 1681 cm−1; HRMS (EI,
C20H18O2 (M)) calcd 290.1307, found 290.1305.
Methyl 1-acetylcyclopent-2-enecarboxylate (7a):14 (Table 2,
1
entry 7) 25.7 mg, 51% yield; yellow liquid; H NMR (400 MHz,
CDCl3) δ 6.08−6.00 (m, 1H), 5.92−5.82 (m, 1H), 3.74 (s, 3H),
2.55−2.33 (m, 4H), 2.18 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
203.9, 172.3, 136.4, 128.6, 73.5, 52.6, 31.9, 30.1, 26.4.
(E)-Methyl 1-acetyl-2-(deuteromethylene)cyclopentane-
carboxylate (16b):2 (Scheme 3) 47.8 mg, 87% yield, 84% deuterium
Methyl 1-acetyl-2-ethylcyclopent-2-enecarboxylate (7b):3b
1
incorporation; yellow liquid; 84% deuterium incorporation; H NMR
1
(Table 2, entry 8) 41.8 mg, 71% yield; yellow liquid; H NMR (400
(400 MHz, CDCl3) δ 5.30 (t, J = 2.1 Hz, 0.16H), 5.21 (t, J = 2.3 Hz,
1H), 3.75 (s, 3H), 2.53−2.35 (m, 3H), 2.25−2.13 (m, 4H), 1.83−1.65
(m, 2H).
MHz, CDCl3) δ 5.74 (m, 1H), 3.75 (s, 3H), 2.62 (m, 1H), 2.41 (m,
2H), 2.22 (m, 1H), 2.17 (s, 3H), 2.13 (m, 2H), 1.10 (t, J = 7.36 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 205.4, 172.5, 143.9, 129.4, 74.9,
52.3, 32.9, 30.5, 26.7, 21.7, 12.4.
Methyl 1-acetyl-2-methyl-3-(tributylstannyl)cyclopent-2-
enecarboxylate (18a): (Table 3, entry 1) 88.9 mg, 63% yield;
colorless liquid; 1H NMR (400 MHz, CDCl3) δ 3.74 (s, 3H), 2.53 (m,
3H), 2.23 (m, 1H), 2.15 (s, 3H), 1.85 (s, 3H), 1.48 (m, 6H), 1.32 (m,
6H), 0.95 (m, 15H); 13C NMR (100 MHz, CDCl3) δ 205.9, 172.8,
146.5, 144.4, 77.2, 52.5, 38.7, 34.5, 29.6, 28.2, 27.7, 27.3, 26.9, 17.9,
17.2, 14.1, 14.0, 10.0; FTIR (NaCl, neat) ν 2955, 2925, 2871, 2851,
1741, 1717, 1462, 1249, 1072, 691 cm−1; HRMS (FAB,
C22H40O3NaSn (M+ + Na)) calcd 495.1987, found 495.1989.
Ethyl 1-benzoyl-2-ethyl-3-(tributylstannyl)cyclopent-2-ene-
carboxylate (18b): (Table 3, entry 2) 111.2 mg, 66% yield; colorless
liquid; 1H NMR (400 MHz, CDCl3) δ 7.82 (app d, J = 7.08 Hz, 2H),
7.50 (tt, J = 7.44, J = 1.0 Hz, 1H), 7.41 (app t, J = 6.85 Hz, 2H), 4.10
(m, 2H), 3.03 (m, 1H), 2.61 (m, 1H), 2.42 (m, 1H), 2.29 (m, 3H),
Ethyl 1-benzoyl-2-ethylcyclopent-2-enecarboxylate (7c):
1
(Table 2, entry 9) 61.3 mg, 75% yield; yellow liquid; H NMR (400
MHz, CDCl3) δ 7.83 (app d, J = 7.07 Hz, 2H), 7.52 (tt, J = 6.8, 1.9 Hz,
1H), 7.42 (app t, J = 6.8, 1.8 Hz, 2H), 5.78 (t, J = 2.05 Hz, 1H), 4.10
(q, J = 7.12 Hz, 2H), 3.09 (m, 1H), 2.55 (m, 1H), 2.40 (m, 1H), 2.29
(m, 2H), 2.01 (m, 1H), 1.14 (t, J = 7.38 Hz, 3H), 1.03 (t, J = 7.19 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 197.3, 172.5, 144.4, 135.7,
132.6, 128.8, 128.6, 128.4, 72.4, 34.0, 30.9, 21.7, 13.8, 12.5; FTIR
(NaCl, neat) ν 1733, 1684 cm−1; HRMS (EI, C17H20O3 (M)) calcd
272.1412, found 272.1414.
Ethyl 1-acetyl-2-methylenecyclohexanecarboxylate (9a) and
ethyl 1-acetyl-2-methylcyclohex-2-enecarboxylate (9b): (Table
E
dx.doi.org/10.1021/jo300957q | J. Org. Chem. XXXX, XXX, XXX−XXX

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1.52 (m, 6H), 1.33 (m, 6H), 0.97 (m, 21H); 13C NMR (100 MHz,
CDCl3) δ 197.8, 151.4, 145.3, 136.4, 132.7, 129.0, 128.7, 74.1, 61.7,
38.9, 35.8, 29.6, 27.8, 24.7, 15.9, 14.1, 10.1; FTIR (NaCl, neat) ν 2956,
2927, 2871, 2853, 1734, 1684, 1447, 1254, 693 cm−1; HRMS (EI,
C29H46O3Sn (M)) calcd 562.2471, found 562.2469.
(3) (a) Kennedy-Smith, J. J.; Staben, S. T.; Toste, F. D. J. Am. Chem.
Soc. 2004, 126, 4526. (b) Staben, S. T.; Kennedy-Smith, J. J.; Toste, F.
D. Angew. Chem., Int. Ed. 2004, 43, 5350. (c) Pan, J. H.; Yang, M.;
Gao, Q.; Zhu, N. Y.; Yang, D. Synthesis 2007, 2539. (d) Ochida, A.;
Ito, H.; Sawamura, M. J. Am. Chem. Soc. 2006, 128, 16486. (e) Ito, H.;
Makida, Y.; Ochida, A.; Ohmiya, H.; Sawamura, M. Org. Lett. 2008,
5051.
(4) (a) Tsuji, H.; Yamagata, K.; Itoh, Y.; Endo, K.; Nakamura, M.;
Nakamura, E. Angew. Chem., Int. Ed. 2007, 46, 8060. (b) Huang, S.;
Du, G.; Lee, C. S. J. Org. Chem. 2011, 76, 6534. (c) Takahashi, K.;
Midori, M.; Kawano, K.; Ishihara, J.; Hatakeyama, S. Angew. Chem., Int.
Ed. 2008, 47, 6244. (d) Itoh, Y.; Tsuji, H.; Yamagata, K.; Endo, K.; Iku
Tanaka, I.; Nakamura, M.; Nakamura, E. J. Am. Chem. Soc. 2008, 130,
17161.
(5) (a) Deng, C. L.; Zou, T.; Wang, Z. Q.; Song, R. J.; Li, J. H. J. Org.
Chem. 2009, 74, 412. (b) Deng, C. L.; Song, R. J.; Guo, S. M.; Wang,
Z. Q.; Li, J. H. Org. Lett. 2007, 9, 5111. (c) Montel, S.; Bouyssi, D.;
Balme, G. Adv. Synth. Catal. 2010, 352, 2315. (d) Yang, T.; Ferrali, A.;
Sladojevich, F.; Campbell, L.; Dixon, D. J. J. Am. Chem. Soc. 2009, 131,
9140.
(6) Gao, Q.; Zheng, B. F.; Li, J. H.; Yang, D. Org. Lett. 2005, 7, 2185.
(7) (a) Morikawa, S.; Yamazaki, S.; Tsukada, M.; Izuhara, S.;
Morimoto, T.; Kakiuchi, K. J. Org. Chem. 2007, 72, 6459.
(b) Morikawa, S.; Yamazaki, S.; Furusaki, Y.; Amano, N.; Zenke, K.;
Kakiuchi, K. J. Org. Chem. 2006, 71, 3540. (c) Nakamura, M.; Liang,
C.; Nakamura, E. Org. Lett. 2004, 6, 2015. (d) Deng, C.-L.; Song, R.-J.;
Liu, Y.-L.; Lia, J.-H. Adv. Synth. Catal. 2009, 351, 3096.
Ethyl 2-ethyl-1-isobutyryl-3-(tributylstannyl)cyclopent-2-
enecarboxylate (18c): (Table 3, entry 3) 103.0 mg, 65% yield;
1
colorless liquid; H NMR (400 MHz, CDCl3) δ 4.20 (m, 2H), 2.84
(m, 1H), 2.61 (m, 1H), 2.50 (m, 1H), 2.35 (m, 1H), 2.21 (m, 3H),
1.49 (m, 6H), 1.31 (m, 9H), 1.11 (d, J = 6.75 Hz, 3H), 1.09 (d, J = 6.8
Hz, 3H), 0.92 (m, 18H); 13C NMR (100 MHz, CDCl3) δ 212.7, 172.8,
151.6, 145.3, 76.7, 38.4, 38.1, 34.7, 29.7, 29.6, 29.5, 27.8, 27.7, 24.8,
21.0, 20.8, 15.9, 14.4, 14.1, 10.1; FTIR (NaCl, neat) ν 2957, 2927,
2871, 2853, 1740, 1712, 1462, 1238, 1070, 690 cm−1; HRMS (EI,
C22H39O3Sn (M − C4H9)) calcd 471.1921, found 471.1922.
(E)-Methyl 3-oxo-4-((tributylstannyl)methylene) octahydro-
pentalene-3a-carboxylate (20a): (Table 3, entry 4) 98.6 mg, 65%
yield; colorless liquid; 1H NMR (400 MHz, CDCl3) δ 6.29 (t, J = 29.0
Hz, 1H), 3.70 (s, 3H), 3.22 (m, 1H), 2.41 (m, 4H), 2.08 (m, 2H), 1.61
(m, 2H), 1.47 (m, 6H), 1.29 (m, 6H), 0.90 (m, 15H); 13C NMR (100
MHz, CDCl3) δ 210.1, 170.2, 153.6, 126.6, 71.6, 52.6, 48.5, 37.9, 33.9,
29.4, 29.1, 27.2, 24.5, 13.7, 9.9; FTIR (NaCl, neat) ν 2954, 2927, 2870,
2853, 1737, 1705, 1452, 1246, 1066, 665 cm−1; HRMS (EI,
C19H31O3Sn (M − Bu)) calcd for C19H31O3Sn (M − Bu) 427.1295,
found 427.1297.
(E)-1-(2-(Phenylsulfonyl)-1-((tributylstannyl)methylene)-2,3-
dihydro-1H-inden-2-yl)ethanone (20b): (Table 3, entry 5) 90.2
1
mg, 50% yield; white solid; mp = 41−45 °C; H NMR (400 MHz,
́ ̀ ́
(8) For other metal-catalyzed reactions, see: (a) Denes, F.; Perez-
CDCl3) δ 7.92−7.84 (m, 2H), 7.51 (t, J = 7.5 Hz, 1H), 7.43−7.28 (m,
Luna, A.; Chemla, F. Chem. Rev. 2010, 110, 2366. (b) Corkey, B. K.;
Toste, F. D. J. Am. Chem. Soc. 2005, 127, 17168. (c) Kuninobu, Y.;
Kawata, A.; Takai, K. Org. Lett. 2005, 7, 4823. (d) Matsuzawa, A.;
Mashiko, T.; Kumagai, N.; Shibasaki, M. Angew. Chem., Int. Ed. 2011,
50, 7616.
2
3H), 7.24−7.15 (m, 3H), 6.30 (d, JSn−H = 31.6 Hz, 1H), 3.91 (d, J =
18.2 Hz, 1H), 3.68 (d, J = 18.2 Hz, 1H), 2.29 (s, 3H), 1.55−1.42 (m,
6H), 1.36−1.22 (m, 6H), 1.14−0.94 (m, 6H), 0.87 (t, J = 7.3 Hz, 9H);
13C NMR (100 MHz, CDCl3) δ 199.6, 150.1, 142.7, 140.1, 136.1,
133.6, 132.4, 131.4, 129.3, 127.9, 127.1, 125.0, 121.5, 86.9, 36.9, 29.1,
29.0, 28.9, 27.4, 27.2, 13.6, 10.8; FTIR (NaCl, neat) ν 2957, 2928,
2870, 2853, 1715, 1636, 1447, 1240, 1082, 687 cm−1; HRMS (EI,
C30H43O3SSn (M + 1)) calcd 603.1955, found 603.1943.
(9) For reviews and recent iron-catalyzed reactions, see: (a) Iron
Catalysis in Organic Chemistry; Plietker, B., Ed.; Wiley-VCH:
Weinheim, 2008. (b) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L.
Chem. Rev. 2004, 104, 6217. (c) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem.
Rev. 2011, 111, 1293. (d) Kohno, K.; Nakagawa, K.; Yahagi, T.; Choi,
J.-C.; Yasuda, H.; Sakakura, T. J. Am. Chem. Soc. 2009, 131, 2784.
(e) Hatakeyama, T.; Hashimoto, S.; Ishizuka, K.; Nakamura, M. J. Am.
Chem. Soc. 2009, 131, 11949. (f) Ji, W.-H.; Pan, Y.-M.; Zhao, S.-Y.;
Zhan, Z.-P. Synlett 2008, 3046. (g) Chan, L. Y.; Kim, S.; Chung, W. T.;
Long, C.; Kim, S. Synlett 2011, 415. (h) Chan, L. Y.; Lim, J. S. K.; Kim,
S. Synlett 2011, 2862. (i) Kischel, J.; Michalik, D.; Zapf, A.; Beller, M.
Chem. Asian. J. 2007, 2, 909. (j) Li, R.; Wang, S. R.; Lu, W. Org. Lett.
2007, 9, 2219. (k) Dal Zotto, C.; Wehbe, J.; Virieux, D.; Campagne, J.-
M. Synlett 2008, 2033. (l) Correa, A.; Mancheno, O. G.; Bolm, C.
Chem. Soc. Rev. 2008, 37, 1108.
1-(3-(Tributylstannyl)naphthalen-2-yl)ethanone (20b′):
1
(Table 3, entry 5) 49.6 mg, 36% yield; yellow liquid; H NMR (400
MHz, CDCl3) δ 8.40 (s, 1H), 8.17 (dd, 2JSn−H = 48.0, J = 1.7 Hz, 1H),
7.97 (d, J = 7.8 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.61 (dd, J = 11.0,
4.1 Hz, 1H), 7.54 (dd, J = 8.6, 5.1 Hz, 1H), 2.73 (s, 3H), 1.59−1.51
(m, 6H), 1.33 (dt, J = 14.7, 7.4 Hz, 6H), 1.27−1.19 (m, 6H), 0.87 (t, J
= 7.3 Hz, 9H); 13C NMR (100 MHz, CDCl3) δ 198.6, 144.2, 141.2,
133.4, 132.7, 130.8, 130.6, 130.0, 128.2, 126.2, 29.1, 27.3, 26.7, 13.6,
10.5; FTIR (NaCl, neat) ν 2957, 2928, 2870, 2855, 1638, 1449, 1271,
1072, 746 cm−1; HRMS (EI, C24H37OSn (M + 1)) calcd 461.1866,
found 461.1880.
(10) For synthesis of deuterated 16b: Porcel, S.; Echavarren, A. M.
Angew. Chem., Int. Ed. 2007, 46, 2672.
(11) Chen, J.; Ma, S. J. Org. Chem. 2009, 74, 5595.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
(12) Humbeck, J. F. V.; Simonovich, S. P.; Knowles, R. R.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132, 10012.
(13) (a) Cabri, W.; Borghi, D.; Arlandini, E.; Sbraletta, P.; Bedeschi,
A. Tetrahedron 1993, 49, 6837. (b) Booker-Milburn, K. I.; Thompson,
D. F. J. Chem. Soc., Perkin Trans. 1 1995, 2315. (c) Taniguchi, T.;
Goto, N.; Nishibata, A.; Ishibashi, H. Org. Lett. 2010, 12, 112.
(d) Taniguchi, T.; Ishibashi, H. Org. Lett. 2010, 12, 124.
(e) Prateeptongkum, S.; Jovel, I.; Jackstell, R.; Vogl, N.;
Weckbecker, C.; Beller, M. Chem. Commun. 2009, 45, 1990.
(14) McDonald, F. E.; Olson, T. C. Tetrahedron Lett. 1997, 38, 7691.
(15) Peng, W.; Hirabaru, T.; Inokuchi, T.; Kawafuchi, H. Eur. J. Org.
Chem. 2011, 5469.
AUTHOR INFORMATION
Corresponding Author
*E-mail: sgkim@ntu.edu.sg, phlee@kangwon.ac.kr.
■
ACKNOWLEDGMENTS
■
S.K. gratefully acknowledges financial support from Nanyang
Technological University, and P.H.L. acknowledges financial
support from the National Research Foundation of Korea (CRI
Program 2012-0001245).
REFERENCES
■
(1) Nicolaou, K. C.; Vourloumis, D.; Winssinger, N.; Baran, P. S.
Angew. Chem., Int. Ed. 2000, 39, 44.
(2) Conia, J. M.; Perchec, P. L. Synthesis 1975, 1.
F
dx.doi.org/10.1021/jo300957q | J. Org. Chem. XXXX, XXX, XXX−XXX