Selective one-pot synthesis of functionalized cyclopentenones

Article abstract of DOI:10.1021/jo300806y

Double addition (1,2-1,4) of vinyl magnesium bromide to squaric acid derivatives allows the preparation of polyoxygenated cyclopentenones (8) in a one-pot procedure. The reaction occurs through the intermediate formation of octatetraenes (6). Protonation of this latter intermediate at -78 °C with TFE occurs selectively at the vinyl CH₂ closer to the metallic centers. DFT studies of the cyclization step justify the observed diastereoselectivity.

Full text of DOI:10.1021/jo300806y

Note
pubs.acs.org/joc
Selective “One-Pot” Synthesis of Functionalized Cyclopentenones
Teresa Varea,*,† Ana Alcalde,† Carolina Lopez de Dicastillo,† Carmen Ramírez de Arellano,†
́
Fernando P. Cossío,‡ and Gregorio Asensio†
†Departamento de Química Organ
‡Departamento de Química Organ
20018 San Sebastian-Donostia, Spain
́
ica, Universidad de Valencia, 46100 Burjassot, Valencia, Spain
́
ica I, Universidad del País Vasco-Euskal Herriko Unibertsitatea (UPV-EHU), Facultad de Química,
́
S
* Supporting Information
ABSTRACT: Double addition (1,2−1,4) of vinyl magnesium
bromide to squaric acid derivatives allows the preparation of
polyoxygenated cyclopentenones (8) in a “one-pot” procedure.
The reaction occurs through the intermediate formation of
octatetraenes (6). Protonation of this latter intermediate at
−78 °C with TFE occurs selectively at the vinyl CH2 closer to
the metallic centers. DFT studies of the cyclization step justify the observed diastereoselectivity.
he double addition of alkenyl magnesium or lithium
derivatives to squarate esters 1 is a suitable route for the
more complex organic structures such as carbofuranoses4 and a
wide range of derivatives.5
T
preparation of a variety of cyclic compounds containing the
cyclopentenone moiety. The substitution pattern of this ring
depends on the regioselectivity attained in the double 1,2−1,2 or
1,2−1,4 addition process.1,2 Our group has reported that the
addition of vinyl magnesium to 1 leads mainly to the
corresponding bicyclooctenones 4 besides minor amounts of
their regioisomers 5 (Scheme 1). The 4:5 ratio depends on the
In this context, we realized that the regular course of these
reactions after the 1,2−1,2 or 1,2−1,4 double addition to 1 could
be shifted toward the synthesis of different types of monocyclic
cyclopentenones. In this sense, the octatetraene intermediates 6
and 7 resulting from the double addition step should be
protonated before the subsequent cyclization which results in the
formation of cyclooctatrienes 2 and 3, respectively (Scheme 2).
Scheme 1
Scheme 2
size of the alkoxy group in 1 and the reaction conditions, in
particular the solvent and the reaction temperature.1 The
formation of these compounds occurs through the protonation
of an intermediate cyclooctatriene 2 or 3. On the other hand, the
double 1,2-addition of different alkenyl lithium derivatives to 1
has been widely used and applied to the synthesis of a great
variety of compounds related with 5 containing the 4-
hydroxycyclopentenone ring.2
The synthesis of cyclopentenones has been recently subject of
numerous reviews3 in the literature because this structure is
present in a variety of natural products and derivatives of
therapeutic interest and it is also important in the construction of
In this way, new reaction intermediates I−III similar to those
described by Tius6 (Scheme 3) in the Nazarov base catalyzed
cyclization of unsaturated diketones would be obtained.
Nazarov’s reaction is usually carried out in acid medium, and it
is considered an excellent route to generate the cyclopentenone
ring.7
Received: May 2, 2012
Published: June 21, 2012
© 2012 American Chemical Society
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was obtained under similar conditions as a crystalline solid and its
crystal structure determined by X-ray diffraction showing the
relative cis configuration of the 4-vinyl and 5-methyl groups
(Figure 1). The NMR spectra of the compounds obtained from
1a and 1b showed a similar pattern, which allows proposition of
the structure 8a (R = Bu) to the ketone derived from 1a.
Scheme 3
Dialkoxy octatetraene 6 results as the major intermediate
product in the double addition of vinylmagnesium bromide to
squarates 1,1 and it could produce, at first, different isomeric
unsaturated α-hydroxyketones 8−10 due to the presence of two
different enolate groups in this structure (see intermediates I and
II, Scheme 2). On the other hand, the addition of the vinyl
reagent to the carbonyl groups of the squarate 1 would form the
cyclopentenone 11 through the symmetric octatetraene 7. This
could constitute an easy “one pot” synthetically useful route to
oxyfunctionalized cyclopentenones from commercially available
squaric acid esters if the reaction could be conducted in a
regioselective way.
According to this approach, and as it was expected based on
our previous results,1 commercial dibutyl squarate 1a reacted
with 2 equiv of vinyl magnesium bromide in THF at −78 °C to
afford bicyclic compounds 4a and 5a with high regioselectivity
(ratio >9:1) after hydrolysis at room temperature (see entry 1,
Table 1). In aiming to avoid the formation of bicyclooctenones 4
Figure 1. X-ray ellipsoid plot of 8b (one enantiomer) 50% probability
level.
Aiming at a better understanding of the protonation step,
charges and HOMO coefficients in a minimum energy structure
of magnesium dialkoxy octatetraene intermediate 6c (R = Me)
were calculated. The terminal carbon atom next to the alkoxy
groups showed both the highest coefficient and electronic
density in the HOMO, confirming this position as the most
reactive in the protonation step (see Figure 2).
Table 1. Selectivity of the Reactions of Squarates 1 with
Vinylmagnesium bromide in THF at −78°C
b
protonation
a
selectivity
4:5:8
product
c
entry substrate
conditions
(yield)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1b
1c
1a
1a
A
B
92:8 0
d
0:15:85
C
D
D
D
0:9:91
0:8:92
8a (78%)
8b (70%)
8c (84%)
0:20:80
0:7:93
e
D
55:10:35
89:11:0
f
D
a
A: NH4Cl/H2O, rt. B: NH4Cl/H2O, −78 °C. C: TFA/THF, −78 °C.
b
c
D: TFE/THF −78 °C. Based on NMR and/or GC. Determined by
NMR from the crude. Yields of isolated compounds are given in the
d
Experimental Section. NMR spectra showed a complex mixture.
e
Figure 2. Minimum energy structure of magnesium dialkoxy
octatetraene intermediate 6c (R = Me) showing HOMO coefficients
(A) and charges (B) at the terminal CH2.
Before hydrolysis, the reaction mixture was allowed to reach 0 °C,
maintained at this temperature for 2 h, and cooled down again to −78
f
°C. Before hydrolysis, the reaction mixture was allowed to reach room
temperature, maintained at this temperature for several hours, and
cooled down again to −78 °C.
In addition, the formation of 8 occurs with complete
diastereoselectivity because only cyclopentenones with cis
disposition of the 4-vinyl and 5-methyl groups were formed in
all cases. To ascertain this result, we carried out a theoretical
study of the cyclization step (DFT level) from octatetraenes 6.
The cyclization of these intermediates can be viewed as an
intramolecular Michael-type attack of the enolate on the α,β-
unsaturated carbonyl moiety (Figure 3A). This process, however,
should be ascribed to a [5-endotrig] cyclization, an unfavored
transformation according to the Baldwin rules.8 Alternatively, the
cyclization step can be envisaged as a four-electron electro-
cyclization because the in-phase combination of the HOMO of
the enolate (highlighted in red in Figure 3B) and the LUMO of
the acrylic moiety (shown in blue in Figure 3B) yields an orbital
topology that enforces the conrotatory cyclization to yield the
cyclopentenone ring.9 Different aspects of the selectivity in
and 5 by ring closure of the intermediate cyclooctatrienes 2 and
3, in a parallel experiment, the reaction mixture was quenched at
−78 °C with aqueous ammonium chloride (entry 2). NMR
analysis of the crude reaction mixture revealed the formation of a
single vinyl cyclopentenone as the major product besides a minor
amount of bicyclooctenone 5a formed in spite of the low
temperature protonation. Three of the cyclopentenone isomers
shown in Scheme 2 (compounds 8, 10, and 11) meet this
characteristic.
Hydrolysis with trifluoroacetic acid or trifluoroethanol in THF
at −78 °C of a similar reaction mixture obtained from squarate 1a
and vinyl magnesium bromide gave a single cyclopentenone and
less than 10% of 5a (entries 3, 4, Table 1). The reaction product
was hard to purify by column chromatography due to the lack of
stability of vinyl cyclopentenones. Compound ( )-8b (R = iPr)
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inhibited when the temperature of the reaction is maintained at
this value until protonation. Formation of cyclopentenones 11,
which would be derived from intermediate 7, was not observed in
any case. On the other hand, use of vinyl lithium instead of vinyl
magnesium in the preliminary addition steps did not give rise to
the formation of any type of monocyclic cyclopentenones and
only bicycles 5 were obtained.12
Total selectivity toward the formation of cyclopentenones 13
(Scheme 4) was achieved in the addition of vinyl magnesium to
Scheme 4
Figure 3. (A) Cyclization of a model compound possessing an enolate
moiety and an electrophilic α,β-unsaturated carbonyl group. (B)
Frontier molecular orbital (FMO) diagram showing the origin of the
conrotatory topology for this cyclization.
related 4πe− electrocyclic ring closure reactions have been
theoretically studied by De Lera.10
Our calculations (B3LYP/6-31G* level of theory, vide infra)
on the model transition structures gathered in Figure 4 show
unsymmetrically substituted squarates 12 bearing alkyl sub-
stituents. Formation of ketones 13 takes place in nearly
quantitative yield based on the NMR analysis of the crude
reaction product. However, partial decomposition occurs in any
attempt of further purification of these vinyl cyclopentenones by
the usual chromatographic methods. To obtain more stable
derivatives, different methods were tested to protect the enol
group. The best results were obtained upon acylation of the
crude hydroxyketones 13 with p-chlorobenzoyl chloride in the
presence of DMAP and triethylamine. Ester 14b was isolated
after column chromatography in 65% yield from 12b (see 1H and
13C NMR spectra of the crude corresponding to the obtention of
14b from 12b in Supporting Information). Acylation under
similar conditions of the crude reaction from 1a (entry 4, Table1)
gave in 67% yield the p-chlorobenzoyl ester 15a, which is much
more stable than the parent cyclopentenone 8a.
The above results indicate that formation of polysubstituted
cyclopentenones 8 or 13 is completely regioselective, involving a
good selectivity not only in the attack to the squarate of the 2
equiv of vinylmagnesium bromide (first 1,2 and then 1,4) but
also in the protonation step, which occurs exclusively at the vinyl
methylene group adjacent to the alkoxy groups.
In conclusion, highly functionalized cyclopentenones can be
prepared from readily available and convenient cyclobutene-
dione precursors through a 1,2−1,4 double addition of vinyl
magnesium bromide. Regardless of the presence of several
reactive sites in the enol intermediate resulting from the addition
step, the protonation occurs with high regioselectivity to afford a
single α-hydroxy unsaturated vinyl ketone. Selective cyclization
of this later intermediate leads to a single polysubstituted
cyclopentenone.
Figure 4. Fully optimized (B3LYP/6-31G* level of theory) transition
structures associated with the formation of syn- and anti-2-hydroxy-3,4-
dimethoxy-5-methyl-4-vinylcyclopent-2-enone. Bond distances are
given in Å. Numbers in parentheses are the relative energies, computed
at the B3LYP/6-31G*+ΔZPVE level.
́
geometries compatible with conrotatory electrocyclizations. It is
interesting to note that TS1, which has a methyl group in an
equatorial disposition with respect to the cyclopentenone ring
being formed, is ca. 7 kcal/mol more stable than TS2, in which
the methyl group occupies a more sterically demanding axial
position. In addition, the electron-releasing methyl group
occupies an outward disposition in TS1, whereas in TS2 this
methyl group is inward. Because, according the torquoelectronic
theory for conrotatory electrocyclizations,11 electron releasing
groups prefer to be outward, TS1 must be more stable than TS2,
a result in nice agreement with our calculations and with the
experimental findings.
EXPERIMENTAL SECTION
General Procedure 1: Obtaining α-Hydroxycyclopentenones
by Addition of Vinylmagnesium Bromide to Cyclobutene-
diones. A solution of vinylmagnesium bromide (8 mmol) in anhydrous
■
Several additional experiments (Table 1, entries 7−8) showed
that cyclizations to afford bicyclic compounds 4 only occurs at a
feasible reaction rate at temperatures above −78 °C and can be
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THF (40 mL) was cooled and stirred at −78 °C in a jacketed two-neck
round-bottom flask under N2. Then, a solution of the squarate 1 (1
mmol) in anhydrous THF (20 mL), maintained also at −78 °C in a
jacketed addition funnel, was slowly added under N2. Both stirring and
the N2 flow were maintained at this temperature for 4 h before
quenching with a cold solution (−78 °C) of trifluoroethanol (0.73 mL,
10 mmol) in dry THF (10 mL). After 10 min stirring at −78 °C, the
reaction mixture was allowed to reach room temperature and a saturated
sodium bicarbonate solution (5 mL) was added. After 30 min, the
organic layer was separated, and the aqueous layer was extracted three
times with ethyl acetate. The combined organic extracts were washed
with brine, dried over Na2SO4, and filtered. After concentration, the
resulting residue was analyzed by NMR and/or GC before purification
by chromatography. NMR spectra of the crude reaction mixtures
showed in all cases (entries 4−6, Table 1) compounds 8 as the main
products.
Hz), 7.50 (3H, m), 8.05 (2H, m). 13C NMR (CDCl3) δ 13.6, 18.5, 31.9,
75.2, 127.6 (2C), 127.7, 129.1 (2C), 132.6, 173.6, 192.5, 192.8, 194.6. IR
ν (cm−1) 2978, 2955, 2934, 2871, 1782, 1742, 1610, 1599, 1587.
1
MS(EI+) m/z 230 (M+), 202, 145 (100%), 117, 89, 85. ( )-13a: H
NMR (CDCl3) δ 0.82 (3H, t, J = 6.6 Hz), 1.14 (3H, d, J = 6.7 Hz), 1.30
(2H, m), 1.45 (2H, m), 2.9 (1H, q, J = 7.3 Hz), 3.15 (1H, m), 3.30 (1H,
m), 5.23 (1H, dd, J1 = 10.7 Hz, J2 = 1 Hz), 5.32 (1H, dd, J1 = 17.5 Hz, J2 =
1 Hz), 5.82 (1H, dd, J1 = 17.5 Hz, J2 = 10.7 Hz), 7.35 (3H, m), 8.17 (2H,
d, J = 7.3 Hz). 13C NMR (CDCl3) δ 10.3, 13.8, 19.2, 31,9, 45.6, 62.0,
85.1, 115.9, 128.0 (2C), 129.0, 129.6 (2C), 131.9, 137.1, 139.8, 149.2,
202.0. IR ν (cm−1) 3388, 3054, 2954, 2925, 2868, 1705, 1616, 1593,
1490, 1445, 1380, 1355, 1264, 1156. MS(EI+) m/z (relative intensity)
286 (M+, 33%), 258 (15%), 202 (100%), 105 (40%). HRMS: calcd for
C18H22O3, 286.1569; found, 286.1561.
(4S,5S)-2-Hydroxy-4-isopropoxy-5-methyl-3-phenyl-4-vinylcyclo-
pent-2-en-1-one (13b). Following the procedure described in the
literature,13 0.88 g of cyclobutenedione 12b (3.9 mmol, 65% yield) were
obtained as a yellow solid from squarate 1b (6 mmol) after purification
by flash column chromatography (silica gel, 15:1 hexane/ethyl acetate).
General procedure 1 was then applied to 12b (1,2 mmol), and 328 mg
were obtained as an oil were the only product observed by NMR was
cyclopentenone 13b. All our attempts of isolation by column
chromatography led to degradation of 13b, which only could be further
purified after derivatization (see compound 14b). 12b: mp 114 °C (lit
113−114 °C).13 1H NMR (CDCl3) δ 1.54 (6H, d, J = 6.2 Hz), 5.59 (1H,
sept, J = 6.2 Hz), 7.50 (3H, m), 8.02 (2H, m). 13C NMR (CDCl3) δ 22.9,
80.1, 127.5 (2C), 127.8, 129.0 (2C), 132.5, 173.9, 192.4, 192.8, 194.2. IR
ν (cm−1) 2983, 2937, 2780, 1751, 1603, 1587, 1496, 1399, 1340, 1091,
1015, 904, 774, 695. ( )-13b (from crude reaction): 1H NMR (CDCl3)
δ 0,67 (3H, d, J = 6.0 Hz), 1.06 (3H, d, J = 6.0 Hz), 1.07 (3H, d, J = 7.3
Hz), 2.8 (1H, q, J = 7.3 Hz), 3.56 (1H, m), 5.17 (1H, dd, J1 = 10.7 Hz, J2
= 1.1 Hz), 5.20 (1H, dd, J1 = 1.1 Hz, J2 = 17.5 Hz), 5.82 (1H, dd, J1 = 17.5
Hz, J2 = 10.7 Hz), 7.23−7.31 (3H, m), 8.00 (2H, d, J = 8.5 Hz). 13C
NMR (CDCl3) δ 10.0, 23.4, 25.2, 47.5, 65.6, 85.4, 116.0, 127.8 (2C),
128.9, 130.4 (2C), 131.7, 137.5, 140.7, 148.9, 201.4.
(4S,5S)-3,4-Dibutoxy-2-hydroxy-5-methyl-4-vinylcyclopent-2-en-
1-one (8a). Following the general procedure 1, 145 mg (0.52 mmol,
52% yield) of cyclopentenone 8a were obtained as an oil from 1a (1
mmol) after purification by flash chromatography (silica gel, 9:1 hexane/
ethyl acetate). ( )-8a: 1H NMR (CDCl3) δ 0.84 (3H, t, J = 7.4 Hz), 0.86
(3H, t, J = 7.4 Hz), 0.98 (3H, d, J = 7.5 Hz), 1.25−1.42 (4H, m), 1.44−
1.57 (2H, m), 1.60−1.70 (2H, m), 2.60 (1H, q, J = 7.5 Hz), 3.32 (2H,
m), 4.47 (2H, m), 5.24 (1H, dd, J1 = 10.5 Hz, J2 = 1.5 Hz), 5.27 (1H, dd,
J1 = 17.3 Hz, J2 = 1.5 Hz), 5.60 (1H, dd, J1 = 10.5 Hz, J2 = 17.3 Hz). 13
C
NMR (CDCl3) δ 10.8, 13.7, 13.9, 18.7, 19.3, 31.9, 32.2, 45.2, 63.1, 71.6,
82.6, 116.8, 133.0, 136.6, 159.4, 199.5. IR ν (cm−1) 3300, 2959, 2875,
1711, 1633, 1432, 1310. MS (EI+) m/z (relative intensity) 282 (M+,
21%), 208 (14%), 185 (45%), 142 (18%), 129 (56%), 111 (53%), 57
(100%). HRMS: calcd for C16H26O4, 282.1831; found, 282.1838.
(4S,5S)-2-Hydroxy-3,4-diisopropoxy-5-methyl-4-vinylcyclopent-2-
en-1-one (8b). Following the general procedure 1, 179 mg (0.71 mmol,
35% yield) of cyclopentenone 8b were obtained as a white solid from 1b
(2 mmol) after purification by column chromatography (silica gel, 9:1
hexane/ethyl acetate). ( )-8b: mp 78−80 °C. 1H NMR (CDCl3) δ 0.97
(3H, d, J = 7.4 Hz), 1.09 (3H, d, J = 6.1 Hz), 1.11 (3H, d, J = 6.1 Hz),
1.29 (3H, d, J = 6.1 Hz), 1.30 (3H, d, J = 6.1 Hz), 2.57 (1H, q, J = 7.4
Hz), 3.70 (1H, sept, J = 6.1 Hz), 5.18 (1H, d, J = 10.5 Hz), 5.21 (1H, d, J
= 17.5 Hz), 5.31 (1H, sept, J = 6.1 Hz), 5.61 (1H, dd, J = 17.5 Hz, J2 =
10.5 Hz), 6.95 (1H, s, 1 OH). 13C NMR (CDCl3) δ 10.2, 22.6, 22.9,
24.3, 24.8, 46.7, 66.0, 74.4, 82.8, 116.7, 132.1, 137.4, 159.3, 199.6. IR ν
(cm−1) 3292, 2977, 2936, 1703, 1632, 1384, 1304. MS (FAB+) m/z
(relative intensity) 255 ([M + H]+, 52%), 213 (10%), 195 (26%), 169
(21%), 153 (100%). HRMS-FAB: calcd for C14H23O4, 255.1596; found,
255.1628.
General Procedure 2:14 Formation of Benzoylated Deriva-
tives 14 and 15. Triethylamine (0.30 mmol) and 4-nitrobenzoyl
chloride (0.21 mmol) were added under N2 to a solution of the
corresponding hydroxycyclopentenone (0.15 mmol) and DMAP (0.15
mmol) in anhydrous CH2Cl2 (10 mL). After being stirred at rt for 2 h,
the mixture was washed with 5% HCl until pH 2, then with a 1N NaOH
solution until pH 12, and then with a NaHCO3 solution until pH 8−9,
and finally with brine. Then, the organic layer was dried and
concentrated. The residue was purified by flash chromatography on
silica gel (elution with hexane/ethyl acetate)
(3S,4S)-3-Isopropoxy-4-methyl-5-oxo-2-phenyl-3-vinylcyclopent-
1-enyl 4-Chlorobenzoate (14b). Following the general procedure 2
starting from 275 mg of crude 13b, 267 mg (0.65 mmol, 65% yield) of
the OH-protected cyclopentenone 14b were obtained as an oil after
purification by column chromatography (silica gel, 99:1 hexane/ethyl
acetate). ( )-14b: 1H NMR (CDCl3) δ 0.51 (3H, t, J = 6.0 Hz), 1.07
(3H, d, J = 6.0 Hz), 1.08 (3H, d, J = 7.1 Hz), 3.01 (1H, q, J = 7.1 Hz),
3.64 (1H, sept, J = 6.0 Hz), 5.30 (1H, d, J = 11.3 Hz), 5.45 (1H, d, J =
17.1 Hz), 5.83 (1H, dd, J1 = 11.3 Hz, J2 = 17.1 Hz), 7.27 (2H, m), 7.38
(2H, d, J = 8.7 Hz), 7.71 (2H, m), 7.89 (1H, m), 7.99 (2H, d, J = 8.5 Hz).
13C NMR (CDCl3) δ 9.0, 23.1, 25.0, 49.2, 66.5, 85.7, 116.8, 126.6, 128.2
(2C), 129.0 (2C), 129.8 (2C), 131.8 (2C), 140.1, 145.1, 155.0, 162.6,
197.6. IR ν (cm−1) 2959, 2875, 1723, 1633, 1462, 1380. MS (EI+) m/z
(relative intensity) 410 (M+, 5%), 229 (11%), 184 (4%), 141 (32%), 139
(100%), 111 (15%). HRMS: calcd for C24H23O4Cl, 410.1285; found,
410.1279.
(4S,5S)-2-Hydroxy-3,4-dimethoxy-5-methyl-4-vinylcyclopent-2-
en-1-one (8c). Following the general procedure 1, 55.4 mg (0.28 mmol,
28% yield) of cyclopentenone 8c were obtained as an oil from 1c (1
mmol) after purification by column chromatography (calcined silica gel,
12:1 hexane/ethyl acetate,). ( )-8c: 1H NMR (CDCl3) δ 1.00 (3H, d, J
= 7.3 Hz), 2.64 (1H, q, J = 7.3 Hz), 3.23 (3H, s), 4.18 (3H, s), 5.28 (1H,
dd, J1 = 17.5 Hz, J2 = 1.3 Hz), 5.29 (1H, dd, J1 = 10.5 Hz, J2 = 1.3 Hz),
5.59 (1H, dd, J1 = 17.5 Hz, J2 = 10.5 Hz), 6.60 (1H, bs, OH). 13C NMR
(CDCl3) δ 10.8, 44.4, 51.1, 59.4, 83.0, 117.2, 133.7, 135.8, 159.2, 199.4.
IR ν (cm−1) 3357, 2959, 1763, 1711, 1613, 1455, 1380, 1261. MS(EI+)
m/z (relative intensity) 198 (M+, 37%), 183 (17%), 167 (50%), 155
(23%), 138 (43%), 95 (95%), 67 (100%). HRMS: calcd for C10H14O4,
198.0892; found, 198.0900.
(4S,5S)-4-Butoxy-2-hydroxy-5-methyl-3-phenyl-4-vinylcyclopent-
2-en-1-one (13a). Following the procedure described in the literature,13
0.75 g of cyclobutenedione 12a (3.24 mmol, 54% yield) were obtained
as a yellow solid from squarate 1a (6 mmol) after purification by flash
column chromatography (silica gel, 9:1 hexane/ethyl acetate). General
procedure 1 was then applied to 12a (1 mmol), and NMR spectra of the
crude reaction mixture showed 13a as the only product. Isolation by
column chromatography (silica gel, hexane/ethyl acetate, 4:1) was
difficult due to partial decomposition of the product in the column
allowing to isolate 121 mg (0.42 mmol, 42% yield) of cyclopentenone
13a as an oil. 12a: mp 100−102 °C. 1H NMR (CDCl3) δ 0.99 (3H, t, J =
7.4 Hz), 1.45 (2H, m), 1.88 (2H, m), 4.91 (2H, dt, J1 = 6.5 Hz, J2 = 0.6
(3S,4S)-2,3-Dibutoxy-4-methyl-5-oxo-3-vinylcyclopent-1-enyl 4-
Chlorobenzoate (15a). Cyclopentenone 8a was obtained by following
the general procedure 1 from 1a (1 mmol), and the crude reaction was
submitted to the above-described benzoylation conditions (general
procedure 2). 281 mg (0.67 mmol, 67% yield) of cyclopentenone 15a
were obtained as an oil after purification by column chromatography
1
(silica gel, 15:1 hexane/ethyl acetate). ( )-15a: H NMR (CDCl3) δ
0.85 (3H, t, J = 7.4 Hz), 0.92 (3H, t, J = 7.4 Hz), 1.08 (3H, d, J = 7.3 Hz),
1.23−1.40 (4H, m), 1,56−1.67 (4H, m), 2.83 (1H, q, J = 7.3 Hz), 3.40
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(1H, dt, J = 8.9 and 7.4 Hz), 3.60 (1H, dt, dt, J = 8.9 and 7.4 Hz), 4.30
(2H, t, J = 6.5 Hz)), 5.35 (1H, dd, J = 10.8 and 1.2 Hz), 5.45 (1H, dd, J =
17.4 and 1.2 Hz), 5.76 (1H, dd, J = 17.4 and 10.8 Hz), 7.44 (2H, d, J = 8.8
Hz), 8.03 (2H, d, J = 8.8 Hz). 13C NMR (CDCl3) δ 10.2, 13.5, 13.9, 18.7,
19.3, 31.4, 32.2, 45.9, 63.5, 71.8, 83.0, 117.4, 126.7, 127.5, 129.0 (2C),
130.9 (2C), 131.8, 135.9, 140.6, 162.7, 169.6, 195.8. IR ν (cm−1) 2960,
2874, 1747, 1724, 1644, 1594, 1488, 1402, 1323, 1253, 1089. MS
(FAB+) m/z (relative intensity) 421 ([M + H]+, 30%), 139 (100%).
HRMS-FAB: calcd for C23H30O5Cl, 421.1782; found, 421.1789.
Computational Methods. All the calculations reported in this
paper were obtained with the GAUSSIAN 03 suite of programs.15
Electron correlation was partially taken into account using the hybrid
functional usually denoted as B3LYP16 and the standard 6-31G* basis
set.17 Zero point vibrational energy (ZPVE) corrections were computed
at the B3LYP/6-31+G* level and were not scaled. Reaction
intermediates were characterized by frequency calculations,18 and
have positive definite Hessian matrices. Transition structures (TSs)
show only one negative eigenvalue in their diagonalized force constant
matrices, associated with nuclear motion along the reaction coordinate
being studied. Atomic charges were computed using the natural bond
orbital (NBO) method.19
(9) For a related intramolecular enolate−electrophile interaction in the
Staudinger reaction between ketenes and imines see: Cossío, F. P.;
Arrieta, A.; Sierra, M. A. Acc. Chem. Res. 2008, 41, 925.
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(12) The absence of this type of cyclopentenones suggests that these
bicyclic compounds are probably formed by direct 6π electrocyclization
of the cis-1,2−1,2 adduct without opening of the four membered ring.
This type of regioselectivity is usually observed in the addition of alkenyl
lithium derivatives to squarates.2b Alternatively, a fast 8π electro-
cyclization of 7 to 3 at −78 °C prior to protonation would also account
for the formation of 5.
(13) Liebeskind, L. S.; Fengl, R. W.; Wirtz, K. R.; Shawe, T. T. J. Org.
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N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa,
J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.;
Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; and Pople, J. A.;
Gaussian 03, revision C.02; Gaussian, Inc.: Wallingford CT, 2004.
(16) (a) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (b) Lee, C.; Yang,
W.; Parr, R. G. Phys. Rev. B 1998, 37, 785. (c) Vosko, S. H.; Wilk, L.;
Nusair, M. Can. J. Phys. 1980, 58, 1200.
ASSOCIATED CONTENT
■
S
* Supporting Information
General experimental methods, H and 13C NMR spectra of
1
compounds ( )-8a−c, 12a,b, ( )-13a,b, ( )-14b, and ( )-15a,
computational data, and crystallographic information file (CIF)
for compound ( )-8b. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Maria.T.Varea@uv.es
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Consolider-Ingenio 2010
(CSD2007-00006). We acknowledge the SCSIE (Universidad
de Valencia) and SGIker (UPV-EHU) for access to instrumental
and computational facilities, respectively. A.A. thanks the Spanish
(17) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.;Pople, J. A. Ab Initio
Molecular Orbital Theory; Wiley: New York, 1986, page 76 and
references therein.
(18) McIver, J. W.; Komornicki, A. K. J. Am. Chem. Soc. 1972, 94, 2625.
(19) (a) Foster, J. P.; Weinhold, F. J. Am. Chem. Soc. 1980, 102, 7211.
(b) Reed, A. E.; Weinhold, F. J. J. Chem. Phys. 1985, 83, 1736. (c) Reed,
A. E.; Weinstock, R. B.; Weinhold, F. J. Chem. Phys. 1985, 83, 735.
(d) Reed, A. E.; Curtiss, L. A.; Weinhold, F. Chem. Rev. 1988, 88, 899.
́
Ministerio de Educacion for a fellowship.
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