Cu(I)- and Cu(II)-catalyzed cyclo- and michael addition reactions of unsaturated β-ketoesters

Article abstract of DOI:10.1021/jo200776c

The α-alkylidene β-ketoesters 2-carbethoxycyclopentenone (1a) and ethyl 2-benzoylacrylate (1b) react with 1,2-dimethylbutadiene (2) (Diels - Alder), N-benzyl-N-(cyclohexylethynyl)-4-methylbenzenesulfonamide (3) (Ficini reaction), ethynyl(phenyl)sulfane (4

Full text of DOI:10.1021/jo200776c

NOTE
pubs.acs.org/joc
Cu(I)- and Cu(II)-Catalyzed Cyclo- and Michael Addition Reactions of
Unsaturated β-Ketoesters
Christoph Schotes and Antonio Mezzetti*
Department of Chemistry and Applied Biosciences, ETH Z€urich, CH-8093 Z€urich, Switzerland
S Supporting Information
b
ABSTRACT: The R-alkylidene β-ketoesters 2-carbethoxycyclopentenone (1a)
and ethyl 2-benzoylacrylate (1b) react with 1,2-dimethylbutadiene (2) (Dielsꢀ
Alder), N-benzyl-N-(cyclohexylethynyl)-4-methylbenzenesulfonamide (3)
(Ficini reaction), ethynyl(phenyl)sulfane (4) ([2 + 2] cycloaddition), and 1,2,5-
trimethyl-1H-pyrrole (5) (Michael addition) in the presence of copper(I) (6) or
copper(II) triflate (7) (1ꢀ2 mol %) in dichloromethane. This convenient
protocol converts 1a and 1b to the corresponding cycloaddition (8ꢀ10) or
Michael addition (11) products in good yields after reaction times of 0.5ꢀ3 h
without requiring purified solvents or inert gas atmosphere.
β-Ketoesters are versatile reagents in organic synthesis and
find widespread application,1 particularly in the formation of all-
carbon quaternary centers.2 In the transformations of their
unsaturated, R-alkylidene analogues, DielsꢀAlder and cycloaddi-
tion reactions play a major role.3 However, R-unsaturated
β-ketoesters are challenging substrates because of their tendency
for polymerization and ketoꢀenol tautomerization.4 Consequently,
they react under harsh conditions and usually give low yields,5 with
the notable exception of alkoxycarbonylquinones, which are more
reactive and easier to handle and have been applied in a number of
highly efficient catalytic reactions.6
Scheme 1. Asymmetric DielsꢀAlder and Ficini Reaction of
Alkylidene β-Ketoesters
We have recently developed dicationic catalysts derived from
the chiral complex [RuCl2(PNNP)] for the functionalization of
2-ethoxycarbonyl-2-cyclopenten-1-one (1a) and related sub-
strates (PNNP is N,N0-bis[o-(diphenylphosphino)benzylidene]-
(1S,2S)-diaminocyclohexane). This system efficiently catalyzes
the DielsꢀAlder reaction of 1a with dienes such as 2,3-dimethyl-
buta-1,3-diene (2)7 to give, among others, alkoxycarbonyltetra-
hydro-1-indanones 8 in excellent yield (Scheme 1a). High enan-
tioselectivity was achieved with the tert-butyl ester analogue of
1a. With the same catalyst and class of substrates, we also reported
the Ficini [2 + 2] cycloaddition reaction8 with ynamides9 like
N-benzyl-N-(cyclohexylethynyl)-4-methylbenzenesulfonamide
(3) to give cyclobuteneamides 9 (Scheme 1b).10
The above results are a breakthrough in the application of
alkylidene β-ketoesters in cycloaddition reactions, for which no
simple and straightforward protocols were available. As an illus-
trative example, the screening of a number of Lewis acids in the
reaction of 2-methoxycarbonyl-2-cyclohexen-1-one with various
dienes gave the best results with SnCl4 (0.5 equiv), which is toxic,
inconvenient to handle, and requires anhydrous solvents, and the
yields were only moderate.11 In an alternative approach that
compensates for the low reactivity of alkylidene β-ketoesters as
dienophiles, 1-methylbuta-1,3-diene has been activated with a
stoichiometric amount of a cobalt complex and refluxed in THF
during 72 h in the presence of a large excess (4 equiv) of
2-methoxycarbonyl-2-cyclohexen-1-one, followed by the cleavage
of the resulting cobalt complex.12 As for the Ficini reaction of
ynamides onto unsaturated β-ketoesters, it is unprecedented
with the exception of our report, the closest analogue being
Hsung’s recently developed reaction of cyclohexenone with
ynamides, which was the first example of its class.13 However,
the catalyst system based on a combination of copper(II) chloride
(20 mol %) and silver(I) hexafluoroantimonate (60 mol %) uses
high catalyst loading and gives moderate yields.
Received: April 15, 2011
Published: June 03, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo200776c J. Org. Chem. 2011, 76, 5862–5866
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NOTE
Scheme 2. Synthesis of 8ꢀ11 Catalyzed by 6 (Yields with 7 in Parentheses)
In view of the lack of simple and efficient nonenantioselective
synthetic methods, we were confronted with the necessity of
developing a new method to prepare racemic reference substances
such as 1-ethoxycarbonyl-3,4-dimethyl-9-oxobicyclo[4.3.0]oct-
3-ene (8a) and ethyl-8-[N-benzyl-4-methylphenylsulfonamido]-
7-cyclohexyl-2-oxobicyclo[4.2.0]oct-7-ene-1-carboxylate (9a) for
the determination of the enantioselectivity of the [RuCl2(PNNP)]
system during our previous studies.7,10 Thus, we tested the
copper(I) triflate benzene complex [Cu2(μ2-O3SCF3)2(μ2-η2-
C6H6)]n (6) as a mild Lewis acid, as copper-based catalysts are
commonly used Lewis-acidic catalysts and have found applica-
tion in related reactions with R-thioacrylates14 and alkylidene
malonates.15 In fact, complex 6 turned out to catalyze the Dielsꢀ
Alder and Ficini reactions with a number of cyclic alkylidene
β-ketoesters. At this stage, the copper-catalyzed reaction was not
optimized, and its products were not isolated but rather used as
racemic references for chiral HPLC analysis.7,10 The present paper
describes a protocol developed from these preliminary experi-
ments for which we chose 1a and 1b as representative examples of
cyclic and acyclic R-alkylidene β-ketoesters (Scheme 2).16
We also extended the study to other reactions of alkylidene
β-ketoesters. In particular, ethynyl(phenyl)sulfane (4), which is
known to react with unsaturated β-ketoesters in the presence of a
high catalytic loading of copper(II) triflate (7) (30 mol %),17 was
chosen as alternative [2 + 2] cycloaddition reagent. Finally, we
studied the Michael addition of 1,2,5-trimethyl-1H-pyrrole (5)
(Scheme 2), as there is some precedent with furan derivatives.18
For the sake of comparison, selected reactions were run with cop-
per(II) triflate (7) as catalyst. Both 6 and 7, as well as the saturated
precursors of the ethyl esters 1a and 1b, are commercially available.
In the standard procedure, β-ketoesters 1a or 1b, reagents
2ꢀ5 (1.1 equiv), and the Cu(I) complex 6 (1ꢀ2 mol %) were
stirred in CH2Cl2 until TLC analysis showed that the β-ketoester
had been quantitatively converted. Total reaction times were
between 30 min and 3 h (Table 1). Copper(I) triflate 6 is only
moderately soluble in CH2Cl2 and does not dissolve completely
under these reaction conditions, which is probably due to its
polymeric structure.19 In the case of diene 2, 5 equiv was required
to drive the reaction to completion because of the low reactivity
of 2,3-dimethylbuta-1,3-diene. The above protocol gives the
desired products in 48ꢀ99% yield without the need for anhy-
drous solvents or protective gas atmosphere.
Table 1. Reactions of β-Ketoesters 1a and 1b Catalyzed by
6 and 7
β-ketoester/
catalyst/
loading
time
(h)
isol yield
(%)
entry
reagent
product
8a
1
2
1a/2
1a/2
1a/3
1a/3
1a/4
1a/4
1a/5
1b/2
1b/3
1b/4
1b/5
6 (2 mol %)
7 (1 mol %)
6 (1 mol %)
7 (1 mol %)
6 (1 mol %)
7 (1 mol %)
6 (1 mol %)
6 (2 mol %)
6 (2 mol %)
6 (2 mol %)
6 (1 mol %)
3
94
95
99
52
70
79
99
96
99
48a
64
0.5 8a
0.5 9a
0.5 9a
0.5 10a
0.5 10a
0.5 11a
3
4
5
6
7
8
3
3
3
8b
9
9b
10b0/10b
10
11
0.5 11b
a Total yield of 10b0 and 10b (4:1 ratio).
Cyclic and acyclic β-ketoesters are converted under mild
conditions in short reaction times and, apart from flash column
chromatography, no workup of the reaction solution is required.
The copper(I) catalyst 6 is much more active than the [RuCl2-
(PNNP)]-based system,7,10 and the catalyst loading can be reduced
to 1 or 2 mol % while maintaining full conversion after 0.5ꢀ3 h.
This is remarkable in particular for the cycloaddition reactions,
which involve the formation of a sterically crowded quaternary
all-carbon center.
In the Ficini reaction, both the cyclic (1a) and acyclic (1b)
unsaturated β-ketoesters give the regioisomer expected on the
basis of electronic preference (9a and 9b, respectively) as the
only product. In contrast, the [2 + 2] cycloaddition of ethynyl-
(phenyl)sulfane (4) onto 1b gives a 4:1 mixture of the regio-
isomers 10b and 10b0, in which the sterically favored isomer 10b0
is the major component. This is unusual, since sulfanes and
ynamides are nucleophilic at the β-position to the heteroatom,
which normally efficientlydirectstheregioselectivityoftheseformal
[2 + 2] cycloadditions notwithstanding the steric situation. The
inversed regioselectivity is probably caused by the lower electro-
nic induction of the sulfane as compared to ynamide, in
combination with the substantial steric difference between the
doubly substituted R- and the unsubstituted β-position of 1b.
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NOTE
Table 2. Synthesis of 8a with Different Catalystsa
was observed, but the enantioselectivity was low (19ꢀ23% ee)
and the yields were only moderate (47ꢀ66%). Thus, the [RuCl2-
(PNNP)]-based catalyst7 remains unchallenged in terms of
enantioselective catalysis, although the results with copper may
possibly be improved by investigating a larger array of ligands.
In conclusion, we have described a convenient, inexpensive,
and fast protocol for Lewis acid-catalyzed reactions of represen-
tative examples of alkylidene β-ketoesters. Good yields are obtained
in a variety of reactions using commercially available copper(I) or
copper(II) triflate, which represents a major advantage to previously
reported literature procedures. As for the scope of the reaction,
we notice that a number of products with different dienes7 and
ynamides,10 as well as with a six-membered alylidene β-ketoester,16
have been prepared in preliminary experiments with the nonopti-
mized protocol as mentioned above (Scheme 1). Therefore, we are
confident that the method may find wide application.
entry
catalyst
isol yield (%)
ee (%)
1
2
3
SnCl4 (50 mol %)
55
95
88
6 (2 mol %), in air
[Cu2(μ2-OTf)2(μ2ꢀη2-CH3C6H5)]n
(2 mol %), under argon
Cu(II)(OTf)2 (7) (1 mol %)
6 + Ph-box (20 mol %)
4
5
6
94
47
66
23
19
7 + Ph-box (20 mol %)
a See the Experimental Section for reaction conditions.
This difference is smaller in 1a, in which the β-position is part of
the 5-membered ring, and hence, only the electronically
favored regioisomer 10a is formed. In comparison to the
reported protocol,17 the Cu(I)-catalyzed reaction of 1a with 4
is run at room temperature (instead of 0 °C), and a much smaller
catalyst loading is applied (1% instead of 30 mol %).
’ EXPERIMENTAL SECTION
For comparison, we also tested copper(II) triflate (7) in
selected instances, such as the DielsꢀAlder reaction of 1a, which
gives 8a in excellent yield (Table 1, entry 2). Monitoring of the
reaction course by TLC analysis showed that, overall, the reactions
with Cu(OTf)2 (7) are complete after a shorter reaction time than
with the less Lewis-acidic Cu(I) complex 6 (even with a catalytic
loading of 1 mol %). Also, 7 gives a slightly higher yield with the
less reactive ethynyl(phenyl)sulfane 4 than Cu(I) (70 and 79%,
respectively, entries 5 and 6). On the other hand, the mild
copper(I) catalyst 6 gives much better yields in combination with
acid-sensitive substrates, such as ynamide 3, whose reaction with
1a gives 9a in 99% yield with 6 but only 52% yield with 7.
A comparison of the copper(I) catalyst 6 with the best
literature protocol11 for the DielsꢀAlder reaction of unsaturated
β-ketoesters with 2 shows that the much stronger Lewis acid
SnCl4 (in anhydrous diethylether) gives a significantly lower
yield of 8a (55 vs 95% with 6), which is probably due to partial
polymerization of 1a under these conditions (Table 2, entries
1 and 2).
To test whether small amounts of a copper(II) species, formed
by oxidation or dismutation of 6, may account for catalytic activity,
we repeated the reaction between 1a and diene 2 with [Cu2(μ2-
O3SCF3)2(μ2-η2-CH3C6H5)]n, the toluene analogue of 6. The
latter complex is commercially available in 99.9% purity, whereas
the batch of 6 used in this study was of technical grade (90%).
The reaction was carried out under argon in the dark, and the
solution remained colorless throughout the reaction, which
indicates that no sizable amounts of Cu(II) are formed. As the
yield obtained under these conditions (88%) is similar to that
observed with 6 (95%) (Table 2, entries 2 and 3), we conclude
that Cu(I) is competent for the catalytic reaction.
General Procedures. Reactions were generally performed in air
with synthesis grade solvents. Reactions involving the phenyl-box ligand
were carried out under an argon atmosphere using Schlenk techniques in
dry CH2Cl2 (distilled over CaH2). 2-Carbethoxycyclopentenone (1a)
was obtained from its saturated analogue using a selenide oxida-
tionꢀelimination reaction.20 Ethyl 2-benzoylacrylate (1b) was prepared
by a slightly modified literature procedure.21 Ethyl 3-oxo-3-phenylpro-
panoate and paraformaldehyde (3 equiv) were heated at reflux under a
protective gas atmosphere for 2 h and then for an additional 2 h after
addition of 2 equiv of paraformaldehyde. N-Benzyl-N-(cyclohexylet-
hynyl)-4-methylbenzenesulfonamide (3)10 and ethynyl(phenyl)sulfane
(4)22 were prepared as reported. All other reagents, including complex 6
(90%, technical grade), Cu(OTf)2 (7) (98%), [Cu2(μ2-O3SCF3)2(μ2-
η2-CH3C6H5)]n (99.9%), and Ph-box (g96%), are commercially avail-
able and were used as received. 1H and 13C positive chemical shifts δ (in
ppm) are downfield from tetramethylsilane and are referenced to the
residual solvent signal. The enantiomeric excess was determined by GC
analysis on a β-DEX column (30 m ꢁ 0.25 mm, film 0.25 μm).
General Procedure for Catalytic Reactions. A CH2Cl2 solu-
tion (1.5 mL) of the unsaturated β-ketoester 1a or 1b (0.15 mmol,
1 equiv), the appropriate reagent 2ꢀ5 (1.1 equiv, 5 equiv for 2,3-
dimethylbutadiene 2), and copper(I) triflate benzene complex (6) or
copper(II) triflate (7) (0.015 or 0.03 mmol, 0.01 or 0.02 equiv) was
stirred at room temperature for 0.5ꢀ3 h, until TLC analysis showed that
the unsaturated β-ketoester was fully converted. The solvent was removed
under reduced pressure, and the oily residue was subjected to flash
column chromatography on silica.
1-Ethoxycarbonyl-3,4-dimethyl-9-oxobicyclo[4.3.0]oct-3-
ene (8a). The reaction of 1a and 2,3-dimethylbutadiene (2) with
copper(I) triflate benzene complex (6) (0.02 equiv) gave 8a as a colorless
oil after 3 h. Yield (isolated): 33.7 mg, 0.143 mmol, 95%. This material was
identical with the known compound based on 1H NMR spectra data.7
Ethyl 8-[N-Benzyl-4-methylphenylsulfonamido]-7-cyclo-
hexyl-2-oxobicyclo[4.2.0]oct-7-ene-1-carboxylate (9a). The
reaction of 1a and N-benzyl-N-(cyclohexylethynyl)-4-methylbenzene-
sulfonamide (3) with catalyst 6 (0.01 equiv) gave 9a as a colorless oil
after 30 min. Yield (isolated): 78.0 mg, 0.15 mmol, >99%. This material
Finally, for the sake of comparison with the Ru/PNNP catalyst,7
we tested (S,S)-2,20-isopropylidenebis(4-phenyl-2-oxazoline)
(Ph-Box) as chiral ligand in combination with Cu(I) and Cu(II)
in the DielsꢀAlder reaction of 1a with diene 2. Copper(I) or
copper(II) triflate (20 mol %), ligand Ph-box (1.1 equiv vs metal),
and 1a were dissolved in dichloromethane under argon, and 2 (1.5
equiv) was added thereto. Copper(II) gives full conversion after
1 h at room temperature, whereas the reaction with the copper(I)
system 6 reaches completion upon stirring overnight (Table 2,
entries 6 and 5). A reasonable explanation is that the ligand further
reduces the already modest Lewis acidity of copper(I) and thus
deactivates the system considerably. Some asymmetric induction
1
was identical with the known compound based on H NMR spectra
data.10
Ethyl 2-Oxo-7-(phenylthio)bicyclo[3.2.0]hept-6-ene-1-
carboxylate (10a). The reaction of 1a and ethynyl(phenyl)sulfane
(4) in the presence of 6(0.01 equiv)gave10aasacolorlessoil after30min.
Yield (isolated): 32.0 mg, 0.111 mmol, 74%. 1H NMR (400 MHz, CDCl3):
δ7.64ꢀ7.47(m, 2H), 7.45ꢀ7.30(m, 3H), 5.88(s,1H), 4.23(q, J=7.1Hz,
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NOTE
2H), 3.68 (d, J = 6.9 Hz, 1H), 3.03 (ddd, J = 18.4, 11.9, 9.2 Hz, 1H),
2.40 (dd, J = 18.3, 8.5 Hz, 1H), 2.26ꢀ2.06 (m, 1H), 1.90 (dd, J = 13.4, 9.1
Hz, 1H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3): δ 208.9,
167.7, 141.0, 134.1, 133.2, 130.3, 129.8, 129.1, 66.7, 61.8, 48.7, 35.3, 22.8,
14.6. IR (liquid film, cmꢀ1): 1719.7 (s, carbonyl CꢀO), 1736.7 (s, carbonyl
CꢀO). HRMS (ESI): calcd for C16H17O3S m/z 289.0893, found m/z
289.0889.
Ethyl 3-Oxo-3-phenyl-2-((1,2,5-trimethyl-1H-pyrrol-3-yl)-
methyl)propanoate (11b). The reaction of 1b and 1,2,5-trimethyl-
1H-pyrrole (5) with 6 (0.01 equiv) as catalyst gave 11b as a slightly
yellow oil after 30 min. Yield (isolated): 30.0 mg, 0.096 mmol, 64%. 1H
NMR (700 MHz, CD2Cl2): δ 8.07ꢀ7.92 (m, 2H), 7.63ꢀ7.54 (m, 1H),
7.48 (t, J = 7.8 Hz, 2H), 5.71 (s, 1H), 4.54 (t, J = 7.1 Hz, 1H), 4.28ꢀ4.04
(m, 2H), 3.32 (s, 3H), 3.15 (dd, J = 14.6, 7.6 Hz, 1H), 3.10 (dd, J = 14.6,
6.7 Hz, 1H), 2.16 (s, 3H), 2.13 (s, 3H), 1.19 (t, J = 7.1 Hz, 3H). 13C
NMR (176 MHz, CDCl3): δ 195.5, 169.9, 136.5, 133.2, 128.7, 128.5,
127.0, 124.6, 114.4, 105.4, 61.2, 56.4, 30.1, 25.8, 14.0, 12.3, 10.0. IR
(liquid film, cmꢀ1): 1682.2 (s, carbonyl CꢀO), 1731.8 (s, carbonyl
CꢀO). HRMS (ESI): calcd for C19H24NO3 m/z 314.1751, found m/z
314.1746.
Cu(I) and Cu(II) Ph-Box Catalysts. The reactions were performed
in close analogy to a procedure published by Aggarwal.14 The catalyst was
prepared by stirring copper(I) triflate benzene complex (6) or copper(II)
triflate (7) (0.03mmol, 0.2equiv) and Ph-Box (11.5 mg, 0.033 mmol, 0.22
equiv, Ph-Box is (4S,40S)-2,20-(propane-2,2-diyl)bis(4-phenyl-4,5-dihy-
drooxazole)) in freshly distilled CH2Cl2 (0.5 mL) for 3 h. After the
solution was cooled to ꢀ78 °C, substrate 1a (23.1 mg, 0.15 mmol,
1 equiv) in CH2Cl2 (1 mL) was added thereto. After 5 min, 2,3-dimethyl-
butadiene (2) (25.5 μL, 0.225 mmol, 1.5 equiv) was slowly added to the
reaction solution, and stirring was continued for 2 h at ꢀ78 °C, afterwhich
neither catalyst gave detectable conversion (by TLC analysis). Cu(II)
triflate (7) gave about20%conversion after1 h at0 °C, andthe conversion
was quantitative after 1 h at room temperature. With Cu(I) triflate (6), no
conversion was observed after1 h at 0 °C, and the reactionrequired24 h at
room temperature to achieve completion. In both reactions, the solvent
was removed under reduced pressure and the oily residue was subjected to
flash column chromatography on silica. Compound 8a was obtained in
47% yield with 6 and in 65% yield with copper(II) triflate (7). Chiral GC:
β-DEX column, 120 °C isotherm, retention times tR (major) = 164.1 min,
tR (minor) = 167.3 min; 19% ee for copper(I) triflate (6) and 23% ee for
copper(II) triflate (7).
Ethyl 2-Oxo-5-(1,2,5-trimethyl-1H-pyrrol-3-yl)cyclopenta-
necarboxylate (11a). The reaction of 1a and 1,2,5-trimethyl-1H-
pyrrole (5) in the presence of 6 (0.01 equiv) gave 11a as a slightly red oil
after 30 min. Yield (isolated): 39.0 mg, 0.148 mmol, 99%. 1H NMR (400
MHz, CDCl3): δ 5.74 (s, 1H), 4.30ꢀ4.07 (m, 2H), 3.71 (td, J = 11.6, 6.4
Hz, 1H), 3.38 (s, 3H), 3.21 (d, J = 11.5 Hz, 1H), 2.64ꢀ2.36 (m, 2H),
2.35ꢀ2.25 (m, 1H), 2.21 (s, 3H), 2.19 (s, 3H), 2.02ꢀ1.81 (m, 1H), 1.28
(t, J = 7.1 Hz, 4H). 13C NMR (101 MHz, CDCl3): δ 212.5, 169.6, 128.0,
124.9, 118.5, 102.6, 63.7, 61.6, 39.4, 38.8, 30.6, 29.9, 14.6, 12.9, 10.5. IR
(liquid film, cmꢀ1): 1720.5 (s, carbonyl CꢀO), 1750.1 (s, carbonyl CꢀO).
HRMS (ESI): calcd for C15H22NO3 m/z 264.1594, found m/z 264.1588.
Ethyl 1-Benzoyl-3,4-dimethylcyclohex-3-enecarboxylate
(8b). The reaction of 1b and 2,3-dimethylbutadiene (2) with 6 (0.02
equiv) as catalyst gave 8b as a colorless oil after 3 h. Yield (isolated): 41.4
mg, 0.145 mmol, 96%. 1H NMR (400 MHz, CDCl3): δ 7.84 (d, J = 7.9
Hz, 2H), 7.53 (t, J = 7.2 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 4.15 (q, J = 7.1
Hz, 2H), 2.53 (s, 2H), 2.38ꢀ2.18 (m, 2H), 2.00ꢀ1.79 (m, 2H), 1.66
(s, 3H), 1.61 (s, 3H), 1.11 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz,
CDCl3): δ 197.5, 174.0, 136.3, 132.9, 128.8, 124.9, 123.2, 61.7, 57.8,
38.0, 29.4, 28.7, 19.2, 14.3, 14.3. IR (liquid film, cmꢀ1): 1681.2
(s, carbonyl CꢀO), 1731.4 (s, carbonyl CꢀO). HRMS (ESI): calcd
for C18H23O3 m/z 287.1642, found m/z 287.1634.
Ethyl 1 -Benzoyl-2-(N-benzyl-4-methylphenylsulfon-
amido)-3-cyclohexylcyclobut-2-enecarboxylate (9b). The reac-
tion of 1b and N-benzyl-N-(cyclohexylethynyl)-4-methylbenzenesulfona-
mide (3) with 6 (0.02 equiv) as catalyst gave 9b as a colorless oil after 3 h.
Yield (isolated): 85.0 mg, 0.149 mmol, 99%. 1H NMR (400 MHz,
CDCl3): δ 7.85 (d, J = 7.6 Hz, 2H), 7.77 (d, J = 8.1 Hz, 2H), 7.54 (t,
J = 7.3 Hz, 1H), 7.48ꢀ7.37 (m, 4H), 7.31ꢀ7.21 (m, 5H), 4.98 (d, J =
14.9 Hz, 1H), 4.81 (d, J = 14.9 Hz, 1H), 4.17ꢀ4.05 (m, 1H), 4.04ꢀ3.91
(m, 1H), 3.02 (d, J = 12.7 Hz, 1H), 2.43 (s, 3H), 2.48ꢀ2.36 (m, 1H),
1.63ꢀ1.32 (m, 5H), 0.99 (t, J = 7.1 Hz, 3H), 1.03ꢀ0.73 (m, 6H). 13C
NMR (101 MHz, CDCl3):δ195.2, 170.5, 158.3, 143.7, 138.2, 137.9, 136.0,
133.5, 129.8, 128.9, 128.8, 128.7, 128.5, 128.4, 128.3, 127.9, 127.1, 67.7,
62.1, 52.8, 52.8, 37.2, 32.7, 30.1, 29.9, 26.1, 25.9, 21.9, 21.9, 14.0. IR (liquid
film, cmꢀ1): 1680.6 (s, carbonyl CꢀO), 1734.0 (s, carbonyl CꢀO).
HRMS (ESI): calcd for C34H38NO5S m/z 572.2465, found m/z 572.2472.
Ethyl 1-Benzoyl-3-(phenylthio)cyclobut-2-enecarboxylate
(10b0) and Ethyl 1-Benzoyl-2-(phenylthio)cyclobut-2-ene-
carboxylate (10b). The reaction of 1b and ethynyl(phenyl)sulfane
(4) in the presence of 6 (0.02 equiv) as catalyst gave a mixture of the two
regioisomers 10b0:10b (4:1) as a slightly yellow oil after 3 h. Yield
SnCl4-Catalyzed DielsꢀAlder Reactions. Following the proce-
dure published by Browne,11 the reaction of 1a (23.1 mg, 0.15 mmol,
1 equiv) and 2,3-dimethylbutadiene (2) (85 μL, 0.750 mmol, 5 equiv)
with SnCl4 (9 μL, 0.075 mmol, 0.5 equiv) gave ethoxycarbonyl-3,4-
dimethyl-9-oxo-bicyclo[4.3.0]oct-3-ene (8a) as a colorless oil. Yield
(isolated): 19.4 mg, 0.082 mmol, 55%.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra
S
b
1
for all new compounds and H NMR spectra of 8a and 9a.
This material is available free of charge via the Internet at
http://pubs.acs.org.
1
(isolated): 24.4 mg, 0.072 mmol, 48%. H NMR (700 MHz, CDCl3):
’ AUTHOR INFORMATION
δ 8.10ꢀ8.05 (m, 2H, 10b), 7.93ꢀ7.87 (m, 2H. 10b0), 7.65ꢀ7.61 (m, 1H,
10b), 7.60ꢀ7.55 (m, 3H, 10b0), 7.54ꢀ7.50 (m, 2H, 10b), 7.49ꢀ7.45 (m,
2H, 10b0), 7.38ꢀ7.29 (m, 7H, 3H from 10b0 and 4H from 10b),
7.23ꢀ7.19 (m, 1H, 10b), 6.03 (t, J = 1.0 Hz, 1H, 10b0), 4.68 (t, J = 7.4
Hz, 1H, 10b), 4.23ꢀ4.17 (m, 2H, 10b), 4.16ꢀ4.07 (m, 2H, 10b0), 3.41
(dd, J = 12.8, 1.1 Hz, 1H, 10b0), 3.23 (dd, J = 17.2, 7.6 Hz, 1H, 10b), 3.15
(dd, J = 17.2, 7.2 Hz, 1H, 10b), 2.95 (dd, J = 12.8, 1.1 Hz, 1H, 10b0), 1.20
(t, J = 7.1 Hz, 3H, 10b), 1.08 (t, J = 7.1 Hz, 3H, 10b0). 13C NMR
(126 MHz, CD2Cl2): δ 193.9, 193.7, 170.0, 168.7, 140.1, 136.3, 135.5,
134.2, 133.7, 133.1, 133.1, 131.8, 129.6, 129.5, 129.3, 129.2, 129.1, 128.9,
128.5, 126.7, 126.4, 96.1, 68.2, 66.7, 62.3, 53.8, 37.2, 30.1, 20.7, 14.4, 14.3.
IR (liquid film, cmꢀ1): 1680.8 (s, carbonyl CꢀO), 1731.7 (s, carbonyl
CꢀO). HRMS (ESI): Calcd. for C20H19O3S m/z 339.1049, found m/z
339.1050.
Corresponding Author
*E-mail: mezzetti@inorg.chem.ethz.ch.
’ REFERENCES
(1) Benetti, S.; Romagnoli, R.; De Risi, C.; Spalluto, G.; Zanirato, V.
Chem. Rev. 1995, 95, 1065.
(2) Trost, B. M.; Jiang, C. Synthesis 2006, 369.
(3) Kobayashi, S.; Jorgensen, K. A. Cycloaddition Reactions in Organic
Synthesis; Wiley-VCH: Weinheim, 2001.
(4) Bernardi, A.; Colombo, G.; Scolastico, C. Tetrahedron Lett. 1996,
37, 8921.
(5) Marx, J. N.; Cox, J. H.; Norman, L. R. J. Org. Chem. 1972,
37, 4489.
5865
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The Journal of Organic Chemistry
NOTE
(6) Selected papers: (a) Evans, D. A.; Wu, J. J. Am. Chem. Soc. 2003,
125, 10162. (b) Mikami, K.; Motoyama, Y.; Terada, M. J. Chem. Am. Soc.
1994, 116, 2812.
(7) (a) Schotes, C.; Mezzetti, A. J. Am. Chem. Soc. 2010, 132, 3652.
(b) Schotes, C.; Mezzetti, A. Chimia 2011, 65, 231.
(8) Ficini, J. Tetrahedron 1976, 32, 1449.
(9) Recent review articles on ynamides: (a) Evano, G.; Coste, A.;
Jouvin, K. Angew. Chem., Int. Ed. 2010, 49, 2840. (b) DeKorver, K. A.; Li,
H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.; Hsung, R. P. Chem. Rev.
2010, 110, 5064.
(10) Schotes, C.; Mezzetti, A. Angew. Chem., Int. Ed. 2011, 50, 3072.
(11) Liu, H.-J.; Ngooi, T. K.; Browne, E. N. C. Can. J. Chem. 1988,
66, 3143.
(12) Richardson, B. M.; Welker, M. E. J. Org. Chem. 1997, 62, 1299.
(13) Li, H.; Hsung, R. P.; DeKorver, K. A.; Wei, Y. Org. Lett. 2010,
12, 3780.
(14) Aggarwal, V. K.; Jones, D. E.; Martin-Castro, A. M. Eur. J. Org.
Chem. 2000, 2939.
(15) (a) Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Tedrow, J. S.
J. Am. Chem. Soc. 1999, 121, 1994. (b) Evans, D. A.; Rovis, T.; Kozlowski,
M. C.; Downey, C. W.; Tedrow, J. S. J. Am. Chem. Soc. 2000, 122, 9134.
(16) In addition to 1a and 1b, we have previously shown that the six-
membered substrate 2-ethoxycarbonyl-2-cyclohexen-1-one undergoes
Ficini reaction with ynamide 3 (nonoptimized protocol with 10 mol % of
catalyst; see ref 10).
(17) Ito, H.; Kobayashi, T.; Hasegawa, M.; Kazuo, I. Tetrahedron
Lett. 2003, 44, 1259.
(18) Liu, H.-J.; Ulibarri, G.; Browne, E. N. C. Can. J. Chem. 1992,
70, 1545.
(19) Hubig, S. S.; Lindeman, S. V.; Kochi, J. K. Coord. Chem. Rev.
2000, 200 ꢀ 202, 831 and reference 33 therein..
(20) Baker, R.; Selwood, D. L.; Swain, C. J.; Webster, N. M. H.
J. Chem. Soc., Perkin Trans. 1 1988, 3, 471.
(21) Bugarin, A.; Jones, K. D.; Connell, B. T. Chem. Commun. 2010,
46, 1715.
(22) Miura, K.; Saito, H.; Fujisawa, N.; Wang, D.; Nishikori, H.;
Hosomi, A. Org. Lett. 2001, 3, 4055.
5866
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