First synthesis of α,β-unsaturated lactones with high diversity through the Passerini reaction and ring-closing metathesis (RCM)

Article abstract of DOI:10.1002/ejoc.201100160

A new class of α,β-unsaturated pyran-2-carboxamides was easily accessed by a multicomponent reaction (MCR), followed by a ring-closing metathesis (RCM) using a ruthenium catalyst. In the first step, α-acyloxy carboxamides with two terminal double bonds were formed from terminal unsaturated carboxylic acids, allyl ketones, and isocyanides (Passerini reaction, P-3CR). A new class of α,β-unsaturated pyran-2-carboxamides was easily accessed by amulticomponent reaction (MCR), followedby a ring-closing metathesis (RCM) using a ruthenium catalyst.

Full text of DOI:10.1002/ejoc.201100160

FULL PAPER
DOI: 10.1002/ejoc.201100160
First Synthesis of α,β-Unsaturated Lactones with High Diversity through the
Passerini Reaction and Ring-Closing Metathesis (RCM)[‡]
Almuth Schwäblein[a] and Jürgen Martens*[a]
Keywords: Synthetic methods / Multicomponent reactions / Passerini reaction / Ring-closing metathesis / Ruthenium /
Lactones
A new class of α,β-unsaturated pyran-2-carboxamides was
easily accessed by a multicomponent reaction (MCR), fol-
lowed by a ring-closing metathesis (RCM) using a ruthenium
catalyst. In the first step, α-acyloxy carboxamides with two
terminal double bonds were formed from terminal unsatu-
rated carboxylic acids, allyl ketones, and isocyanides (Pass-
erini reaction, P-3CR).
In connection with our interest in the synthesis of new
heterocyclic structures, we describe the formation of a new
class of α,β-unsaturated-δ-oxacaprolactams from cyclic im-
ines as starting materials.[11] α,β-Unsaturated lactams are
present in many biologically active molecules.[12] However,
the α,β-unsaturated-δ-oxacaprolactams are almost un-
known in the literature.[11] The synthetic procedure is based
on a sequence involving the Asinger four-component reac-
tion (A-4CR),[13,14] followed by an acid chloride addition
in the second step.[15,16] Finally a ring-closing metathesis
is carried out using a ruthenium catalyst. The metathesis
reactions proceed in moderate to very good yields using a
Grubbs II catalyst.[6] The reported metathesis-based capro-
lactam synthesis is moderately optimized for solvent and
temperature with respect to the catalysts. The described
synthesis is of great value and it provides information about
this potentially important class of molecules.
Introduction
One-pot multicomponent reactions (MCRs) have
emerged as powerful tools in organic synthesis because they
offer significant advantages, such as the construction of
complex molecules from readily available building blocks,
the realization of higher yields than almost any sequential
synthesis of the same target, the need for a single purifica-
tion step, and the easy adaptation to combinatorial synthe-
sis.[1] MCRs provide significant advantages over traditional
stepwise strategies in terms of cost, waste, time, and atom
economy, and these reactions constitute an extremely popu-
lar field of research within both academic and industrial
domains.[2] Interest in the Passerini three-component reac-
tion (P-3CR), which involves an isocyanide, a carbonyl
compound, and a carboxylic acid, is growing because of its
efficiency in the syntheses of diverse products.[3] As a result
of the discovery of efficient catalysts,[4] ring-closing metath-
esis (RCM) is currently one of the best methods to create
cyclic substructures from unsaturated substrates.[5,6]
In this paper, we investigate the P-3CR of isocyanides 1,
allyl ketones 2, and carboxylic acids 3, which give α-acyloxy
carboxamides 4 with two terminal double bonds. Further-
more, we report the preparation of a new family of α,β-
unsaturated pyran-2-carboxamides 5 through a ruthenium-
catalyzed ring-closing metathesis (Scheme 1).
The sequential combination of a MCR and a RCM pro-
vides even more complex structural types.[7,8] However,
there are just a few examples found in the literature. For
instance, the combination of an Ugi four-component reac-
tion (U-4CR) and a RCM can produce a new class of bicy-
clic lactams.[9] The combination of the P-3CR and a RCM
can successfully build macrocycles as well.[10]
Results and Discussion
The Passerini three-component reaction, first described
in 1921,[2] is a reaction between carboxylic acids, oxo-com-
pounds, and isocyanides that provides α-acyloxy carbox-
amides 4 in one step (Scheme 1).[17,18] This group of com-
pounds is present in the structures of many natural prod-
ucts.[15,19] The Passerini reaction is an inexpensive and rapid
way to generate compound libraries.
[‡] Sequential Multicomponent Reaction and Ring-Closing
Metathesis in the Synthesis of New Heterocycles, 4.
Part 1–3: Ref.[11]
[a] Universität Oldenburg, Institut für Reine und Angewandte
Chemie,
26129 Oldenburg, Germany
Fax: +49-441-798-3757
E-mail: juergen.martens@uni-oldenburg.de
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A. Schwäblein, J. Martens
FULL PAPER
Scheme 1. Synthesis of α,β-unsaturated lactones 5. R1 = CH2Ph,
Cy, CH2CO2CH3, CH2CO2CH2CH3; R2 = H, CH3; R3 = CH2Ph,
CH2CO2CH2CH3.
Passerini Reaction with Allyl Ketones
Rarely investigated is the use of allyl ketones in MCRs,
as allyl ketones may isomerize easily to α,β-unsaturated
ketones (Michael acceptor), which cannot be used in Ugi
or Passerini reactions.[20] For the construction of new cyclic
structures through a ring-closing metathesis, it is necessary
to build a molecule with two terminal olefin groups. Pro-
duced in excellent yields, 1-phenylpent-4-en-2-one (2a) and
ethyl 3-oxohex-5-enoate (2b) were synthesized from the
mixture of zinc, nitrile, and allyl bromide in the presence
of the Lewis acid AlCl3 through a Barbier-type reaction
(Scheme 2).[21]
Scheme 2. Synthesis of allyl ketones 2a and 2b.
Figure 1. Products 4 obtained by the P-3CR (cf. Scheme 1). All
yields are isolated yields.
The known compound 3-allylcyclohexanone (6) was syn-
thesized from cyclohexenone and allyltrimethylsilane with
titanium tetrachloride (1 equiv.) by a Sakurai reaction
(Scheme 3).[22,23]
We obtained single crystals of 4h from a mixture of hex-
ane and ethyl acetate, and its structure was further con-
firmed by X-ray crystallographic analysis (Figure 2).
Scheme 3. Synthesis of 3-allyl ketone 6.
To avoid the isomerization of the freshly prepared allyl
ketones, they were used directly. Thus, the target molecules
4 were obtained in good to moderate yields. Acrylic acid or
metacrylic acid were used to provide a second C=C bond
in carboxamide 4. Using this approach, various precursors
(i.e., 4) for ring-closing metathesis have been prepared.
Furthermore, structure 4 bears elements of destruxin, which
is an inducer of erythropoietin.[24] Details of the prepared
Figure 2. X-ray crystal structure of the racemic α-acyloxy carbox-
amide 4h.
By using the 3-allylcyclohexanone (6), it was also pos-
carboxamides 4 and the reaction yields are summarized in sible to build the three structures 7a–c in moderate yields
Figure 1.
from 27 to 41% (Scheme 4).
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Synthesis of α,β-Unsaturated Lactones with High Diversity
Scheme 4. Synthesized structures by using 3-allylcyclohexanone (6).
Ring-Closing Metathesis (RCM)
The synthesis of new heterocycles through a ring-closing
metathesis can be found in the literature.[25] As an extension
of previous investigations,[6] we decided to employ the
Evonik benzylidene ruthenium catalyst in the metathesis re-
action (Figure 3).
Figure 3. Metathesis catalyst used for RCM reactions.
With the expected ten dienes 4a–j in hand, we next inves-
tigated the ring-closing metathesis. α-Acyloxy carbox-
amides 4 and the catalyst, in a ratio of 20:1, were dissolved
in toluene and heated to approximately 70 °C. The reaction
was monitored by TLC and stopped when the starting ma-
terial (i.e., 4) was no longer detected. With these reaction
conditions, it was possible to obtain the desired α,β-unsatu-
rated pyran-2-carboxamides 5 in good to excellent yields up
to 97% (Figure 4). Furthermore, the ring-closing metathesis
of α-acyloxy carboxamides 7a–c was attempted under iden-
tical conditions, but the resultant 12-membered ring was
not obtained. This could be due to the rigidity of the cyclo-
hexane ring.
Figure 4. α,β-unsaturated pyran-2-carboxamides 5 obtained by
RCM (cf. Scheme 1). All yields are isolated yields.
We obtained single crystals of 5g from a mixture of hex-
ane and ethyl acetate, and its structure was further con-
firmed by X-ray crystallographic analysis (Figure 5).
Finally the potential for the α,β-unsaturated pyran-2-
carboxamides 5 as a Michael acceptor was demonstrated
by an initial experiment adding thioacetic acid to give a
sulfur atom attached to the β-C atom of the carbonyl com-
pound.[26,27] Using the methods of Brown, Jones and
Pinder,[26] a derivative of compound 5g was synthesized by
the addition of thioacetic acid in the presence of AIBN
[azobis(isobutyronitrile), Scheme 5].
Figure 5. X-ray crystal structure of the racemic N,2-dibenzyl-6-oxo-
3,6-dihydro-2H-pyran-2-carboxamide (5g).
We obtained single crystals of new compound 8 from a
mixture of hexane and ethyl acetate, and its structure was
further confirmed by X-ray crystallographic analysis (Fig-
ure 6). The structure shows a trans-configuration between
the proton attached to the C-1 position and the benzyl
group connected to C-4.
Scheme 5. Derivatization of the racemic α,β-unsaturated pyran-2-
carboxamide 5g.
Eur. J. Org. Chem. 2011, 4335–4344
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A. Schwäblein, J. Martens
FULL PAPER
Ethyl 3-Oxohex-5-enoate (2b): To a suspension of zinc powder
(2.615 g, 40 mmol) in anhydrous THF (10 mL), a solution of benzyl
cyanide (1.130 g, 10 mmol) in anhydrous THF (30 mL) and allyl
bromide (1.815 g, 15 mmol) were added under an argon atmo-
sphere. The mixture was cooled to 0 °C. Aluminium trichloride
(0.533 g, 4 mmol) was dissolved in cold anhydrous THF (exother-
mic reaction) and then slowly added to the reaction mixture. The
suspension was warmed to room temperature and stirred for 18 h.
After the reaction was completed (monitored by TLC), HCl (2 m
aqueous solution, 50 mL) was added, and the reaction mixture was
stirred at room temperature for 5 min. The mixture was passed
through a short silica gel column. The phases were separated, and
the aqueous layer was extracted with ethyl acetate (3ϫ50 mL). The
combined organic layers were dried with magnesium sulfate, and
Figure 6. X-ray crystal structure of derivative 8 (only one enantio-
mer shown). The numbering of the atoms in the X-ray structure
does not follow the IUPAC nomenclature.
Conclusions
We succeeded in the syntheses of a new class of α-acyloxy the solvent was removed under reduced pressure using a rotary
evaporator. The product was a yellow oil and was used without
further purification (1.53 g, 9.8 mmol, 98%). 1H NMR
(500.1 MHz, CDCl3): δ = 1.28 (t, 3J = 3.2 Hz, 3 H, CH2CH3), 3.31
carboxamides 4 through a Passerini reaction involving allyl
ketones. Furthermore, we created a new class of α,β-unsatu-
rated pyran-2-carboxamides 5 in good to moderate yields
through a ring-closing metathesis using a ruthenium cata-
lyst in hot toluene. Because of the large number of known
isocyanides, this reaction can be applied to build plenty of
new α,β-unsaturated pyran-2-carboxamides 5. In addition,
the double bond in the α,β-unsaturated pyran-2-carbox-
amides 5 offers a great opportunity for further functionali-
zations.
3
(d, J = 6.8 Hz, 2 H, CH2CH=CH2), 3.47 (s, 2 H, CH2), 4.20 (q,
3
3
3J = 7.2 Hz, 2 H, CH2CH3), 5.20 (dd, J = 10.2 Hz, J = 17.1 Hz,
2 H, CH2CH=CH2), 5.87–5.95 (m, 1 H, CH2CH=CH2) ppm.[19,20]
General Procedure (GP A): Under an argon atmosphere, the respec-
tive allyl ketone (1 equiv.) and the respective acid (1 equiv.) were
dissolved in anhydrous dichloromethane. After stirring for 30 min
at room temperature, the respective isocyanide (1 equiv.) was added
dropwise to the mixture. The mixture was stirred at room tempera-
ture until the reaction was complete (detected by TLC). The solvent
was removed under reduced pressure. Purification of the crude
product is described in the experiments.
Experimental Section
rac-3-Acroloxy-3-benzylaminocarbonyl-1-ethoxy-1-oxohex-5-ene
(4a): Following GP A, ethyl 3-oxohex-5-enoate (2b, 160 mg,
1.026 mmol), acrylic acid (73.90 mg, 1.026 mmol), benzyl isocya-
nide (120.19 mg, 1.026 mmol), and anhydrous dichloromethane
(5.0 mL) were used. The crude product was purified by column
chromatography on silica gel (n-hexane/ethyl acetate, 7:3; Rf = 0.35)
and obtained as a colorless solid (170 mg, 0.490 mmol, 48%), m.p.
General Methods: All reagents and solvents were commercial grade
and were purified prior to use when necessary. Preparative column
chromatography was carried out using Grace SiO2 (0.035–
0.070 mm, type KG 60). TLC was performed on Merck SiO2 F254
plates on aluminum sheets. 1H and 13C NMR spectra were re-
corded with Bruker Avance DRX 500 and Avance DPX 300 spec-
trometers. Assignments of the signals in the 13C NMR spectrum
were supported by measurements applying DEPT and COSY tech-
niques. EI-MS, CI-MS and HRMS spectra were obtained with a
Finnigan MAT 95 spectrometer. IR spectra were recorded with a
Bruker Tensor 27 spectrometer equipped with a “GoldenGate” dia-
mond-ATR (attenuated total reflection) unit.
3
42–43 °C. 1H NMR (500.1 MHz, CDCl3): δ = 1.18 (t, J = 7.1 Hz,
3 H, CH2CH3), 2.81 (dd, 2J = 14.0 Hz, 3J = 6.7 Hz, 1 H,
CH2CH=CH2), 3.11 (dd, 2J = 14.1 Hz, 3J = 8.0 Hz, 1 H,
2
2
CH2CH=CH2), 3.28 (d, J = 16.2 Hz, 1 H, CH2CO), 3.54 (d, J =
16.3 Hz, 1 H, CH2CO), 4.06 (dq, 2J = 2.1, 3J = 7.1 Hz, 2 H,
CH2CH3), 4.48 (dd, J = 14.8 Hz, J = 5.5 Hz, 1 H, CH2Ph), 4.57
2
3
1-Phenylpent-4-en-2-one (2a): To a suspension of zinc powder
(2.615 g, 40 mmol) in anhydrous THF (tetrahydrofuran, 10 mL), a
solution of benzyl cyanide (1.171 g, 10 mmol) in anhydrous THF
(10 mL) and allyl bromide (1.815 g, 15 mmol) were added under an
argon atmosphere. The mixture was cooled to 0 °C. Aluminium
trichloride (0.533 g, 4 mmol) was dissolved in cold anhydrous THF
(exothermic reaction) and then slowly added to the reaction mix-
ture. The suspension was warmed to room temperature and stirred
for 30 min. After the reaction was completed (monitored by TLC),
HCl (2 m aqueous solution, 50 mL) was added, and the reaction
mixture was stirred at room temperature for 5 min. The mixture
was passed through a short silica gel column. The phases were sep-
arated, and the aqueous layer was extracted with ethyl acetate
(3ϫ50 mL). The combined organic layers were dried with magne-
sium sulfate, and the solvent was removed under reduced pressure
using a rotary evaporator. The product was a colorless oil and was
used without further purification (1.58 g, 9.9 mmol, 99%). 1H
2
3
2
3
(dd, J = 14.8, J = 6.6 Hz, 1 H, CH2Ph), 5.10 (dd, J = 14.3, J
= 8.6 Hz, 2 H, CH2CH=CH2), 5.62–5.64 (m, 1 H, CH2CH=CH2),
5.84 (d, 3J = 10.4 Hz, 1 H, CH=CH2), 6.09 (dd, 3J = 10.4, 3J =
17.6 Hz, 1 H, CH=CH2), 6.37 (d, 3J = 17.4 Hz, 1 H, CH=CH2),
6.82 (br. s, 1 H, NH), 7.26–7.35 (m, 5 H, ArCH) ppm. 13C NMR
(126 MHz, CDCl3): δ = 14.07 (CH2CH3), 39.55 (CH2CO), 40.04
(CH2CH=CH2), 43.65 (CH2Ph), 60.62 (CH2CH3), 84.13
(CCH2CO), 120.10 (CH2CH=CH2), 127.53, 127.77 (ArCH), 128.26
(CH=CH2), 128.67 (ArCH), 130.53 (CH2CH=CH2), 131.80
(CH=CH ), 137.89 (ArC), 163.96, 169.33, 170.30 (CO) ppm. IR: ν
˜
2
= 3341, 2980, 1738, 1651, 1175, 698 cm–1. TOF MS (ESI+): m/z
(%) = 368.1 (100) [M + Na]+ . TOF HRMS: calcd. for
C19H23NO5Na [M + Na]+ 368.1417; found 368.1483.
rac-3-Acryloxy-3-cyclohexylaminocarbonyl-1-ethoxy-1-oxohex-5-
ene (4b): Following GP A, ethyl 3-oxohex-5-enoate (2b, 216.5 mg,
1.390 mmol), acrylic acid (100.0 mg, 1.390 mmol), cyclohexyl iso-
NMR (500.1 MHz, CDCl3): δ = 3.21 (d, 3J = 3.2 Hz, 2 H, cyanide (151.7 mg, 1.390 mmol), and anhydrous dichloromethane
CH2CH=CH2), 3.68 (s,
2
H, CH2Ph), 5.08–5.21 (m,
2
H,
(5.0 mL) were used. The crude product was purified by column
chromatography on silica gel (n-hexane/ethyl acetate, 8:2; Rf = 0.20)
and obtained as a colorless oil (170 mg, 0.504 mmol, 30%). 1H
CH2CH=CH2), 5.83–5.97 (m, 1 H, CH2CH=CH2), 7.31–7.34 (m,
5 H, ArCH) ppm.[15,28]
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Synthesis of α,β-Unsaturated Lactones with High Diversity
NMR (500.1 MHz, CDCl3): δ = 1.19 (t, 3J = 7.1 Hz, 3 H,
CH2CH3), 1.16–1.28, 1.35–1.42, 1.60–1.72, 1.90–1.96 (4m, 10 H,
CyCH), 2.75 (dd, J = 14.1 Hz, J = 6.4 Hz, 1 H, CH2CH=CH2),
(CH2CH3), 83.96 (CCH2CO), 120.00 (CH2CH=CH2), 126.12
(C=CH2), 127.46, 127.52, 127.61, 128.68 (ArCH), 130.53
(CH2CH=CH2), 136.33 (C=CH2), 137.90 (ArC), 165.28, 169.35,
2
3
2
3
3.07 (dd, J = 14.1 Hz, J = 8.2 Hz, 1 H, CH2CH=CH2), 3.23 (d,
170.50 (CO) ppm. IR: ν = 3447, 2982, 1725, 1670, 1164, 699 cm–1.
˜
2J = 16.2 Hz, 1 H, CH2CO), 3.48 (d, J = 16.2 Hz, 1 H, CH2CO),
TOF MS (ESI+): m/z (%) = 382.2 (100) [M + Na]+. TOF MS
2
3.78–3.85 (m, 1 H, CHNH), 4.07 (q, J = 7.1 Hz, 2 H, CH2CH3), (ESI+): calcd. for C20H25NO5Na [M + Na]+ 382.1630; found
3
5.09 (dd, 2J = 18.6 Hz, 3J = 9.3 Hz, 2 H, CH2CH=CH2), 5.57–5.66
(m, 1 H, CH2CH=CH2), 5.87 (d, 3J = 10.4 Hz, 1 H, CH=CH2),
382.1629.
rac-3-Cyclohexylaminocarbonyl-1-ethyloxy-3-methacryloxy-1-
oxohex-5-ene (4e): Following GP A, ethyl 3-oxohex-5-enoate (2b,
72.5 mg, 0.465 mmol), methacrylic acid (40.0 mg, 0.465 mmol), cy-
clohexyl isocyanide (50.7 mg, 0.465 mmol), and anhydrous dichlo-
romethane (5.0 mL) were used. The crude product was purified by
column chromatography on silica gel (n-hexane/ethyl acetate, 8:2;
Rf = 0.36) and obtained as a colorless solid (88.0 mg, 0.250 mmol,
3
3
6.13 (dd, J = 10.4 Hz, J = 17.3 Hz, 1 H, CH=CH2), 6.36 (br. s,
1 H, NH), 6.38 (d, J = 17.1 Hz, 1 H, CH=CH2) ppm. 13C NMR
3
(126 MHz, CDCl3): δ = 14.10 (CH2CH3), 24.71, 24.73, 25.49,
32.72, 33.04 (CyCH), 39.48 (CH2CO), 39.95 (CH2CH=CH2), 48.31
(CHNH), 60.50 (CH2 CH3 ), 83.86 ( CCH2 CO), 119. 85
(CH2CH=CH2), 128.46 (CH=CH2), 130.63 (CH2CH=CH2), 131.48
(CH=CH ), 163.89, 169.33, 170.30 (CO) ppm. IR: ν = 3347, 2931,
˜
2
1
54%), m.p. 58–63 °C. H NMR (500.1 MHz, CDCl3): δ = 1.19 (t,
1734, 1661, 1174 cm–1. TOF MS (ESI+): m/z (%) = 360.1 (100) [M
+ Na]+. TOF HRMS: calcd. for C18H27NO5Na [M + Na]+
360.1787; found 360.1779.
3J = 7.1 Hz, 3 H, CH2CH3), 1.35–1.43, 1.58–1.61, 1.67–1.70, 1.89–
1.92 (4m, 10 H, CyCH), 1.95 (s, 3 H, CCH3), 2.75 (dd, 2J =
3
2
14.1 Hz, J = 6.5 Hz, 1 H, CH2CH=CH2), 3.07 (dd, J = 14.1 Hz,
3J = 8.2 Hz, 1 H, CH2CH=CH2), 3.22 (d, 2J = 16.2 Hz, 1 H,
rac-3-Acryloxy-1-ethoxy-3-(2-methoxy-2-oxoethylaminocarbonyl)-1-
oxohex-5-ene (4c): Following GP A, ethyl 3-oxohex-5-enoate (2b,
130.0 mg, 0.833 mmol), acrylic acid (60.0 mg, 0.833 mmol), methyl
isocyanoacetate (71.7 mg, 0.833 mmol), and anhydrous dichloro-
methane (5.0 mL) were used. The crude product was purified by
column chromatography on silica gel (n-hexane/ethyl acetate, 7:3;
Rf = 0.10) and obtained as a colorless oil (160 mg, 0.511 mmol,
2
CH2CO), 3.48 (d, J = 16.2 Hz, 1 H, CH2CO), 3.78–3.85 (m, 1 H,
CHNH), 4.06 (q, 3J = 7.1 Hz, 2 H, CH2CH3), 5.09 (dd, 2J =
17.8 Hz, 3J = 8.1 Hz, 2 H, CH2CH=CH2), 5.57–5.65 (m, 1 H,
CH2CH=CH2), 5.59 (s, 1 H, C=CH2), 6.05 (s, 1 H, C=CH2), 6.38
(d, 3J = 7.7 Hz, 1 H, NH) ppm. 13C NMR (126 MHz, CDCl3): δ =
14.12 (CH2CH3), 18.39 (CCH3), 24.57, 25.51, 32.71, 33.02 (CyCH),
39.48 (CH2CO), 39.89 (CH2CH=CH2), 48.10 (CHNH), 60.53
(CH2CH3), 83.80 (CCH2CO), 119.81 (CH2CH=CH2), 126.06
(C=CH2), 130.72 (CH2CH=CH2), 136.42 (C=CH2), 165.17, 169.22,
1
3
61%). H NMR (500.1 MHz, CDCl3): δ = 1.19 (t, J = 7.1 Hz, 3
H, CH2CH3), 2.75–2.79 (m, 1 H, CH2NH), 3.09–3.13 (m, 1 H,
CH2NH), 3.23 (d, 2J = 16.2 Hz, 1 H, CH2CO), 3.53 (d, 2J =
16.2 Hz, 1 H, CH2CO), 3.78 (s, 3 H, OCH3), 4.03 (dd, 2J = 18.6 Hz,
3J = 4.6 Hz, 1 H, CH2CH=CH2), 4.08 (q, 3J = 6.4 Hz, 2 H,
CH2CH3), 4.18 (dd, 2J = 18.4 Hz, 3J = 5.5 Hz, 1 H, CH2CH=CH2),
5.10–5.12 (m, 2 H, CH2 CH=CH2 ), 5.65–5.75 (m, 1 H,
CH2CH=CH2), 5.90 (d, 3J = 10.3 Hz, 1 H, CH=CH2), 6.14 (dd, 3J
169.33 (CO) ppm. IR: ν = 3334, 2936, 1718, 1650, 1145 cm–1. TOF
˜
MS (ESI+): m/z (%) = 374.2 (100) [M + Na]+. TOF MS (ESI+):
calcd. for C19H29NO5Na [M + Na]+ 374.1943; found 374.1942.
rac-1-Ethyloxy-3-(2-ethoxy-2-oxoethylaminocarbonyl)-3-methacryl-
oxy-1-oxohex-5-ene (4f): Following GP A, ethyl 3-oxohex-5-enoate
(2b, 110.0 mg, 0.710 mmol), methacrylic acid (61.0 mg,
0.710 mmol), ethyl isocyanoacetate (80.7 mg, 0.710 mmol), and an-
hydrous dichloromethane (5.0 mL) were used. The crude product
was purified by column chromatography on silica gel (n-hexane/
ethyl acetate, 8:2; Rf = 0.10) and obtained as a colorless oil
3
3
= 10.4 Hz, J = 17.4 Hz, 1 H, CH=CH2), 6.43 (d, J = 17.4 Hz, 1
H, CH=CH2), 7.10 (br. s, 1 H, NH) ppm. 13C NMR (126 MHz,
CDCl3): δ = 14.72 (CH2CH3), 39.50 (CH2CO), 40.06 (CH2NH),
41.33 (CH2CH=CH2), 52.41 (OCH3), 60.67 (CH2CH3), 83.96
(CCH2CO), 120.10 (CH2CH=CH2), 128.29 (CH=CH2), 130.41
(CH2CH=CH2), 131.79 (CH=CH2), 163.85, 169.22, 170.03, 170.68
1
(CO) ppm. IR: ν = 3405, 2956, 1734, 1672, 1169 cm–1. MS (ESI+):
(70.0 mg, 0.197 mmol, 28%). H NMR (500.1 MHz, CDCl3): δ =
˜
1.19 (t, 3J = 7.1 Hz, 3 H, CH2CH3), 1.30 (t, 3J = 7.1 Hz, 3 H,
CH2CH3), 1.99 (s, 3 H, CCH3), 2.76 (dd, 3J = 14.1 Hz, 3J = 6.4 Hz,
m/z (%) = 354.1 (100) [M + Na]+. MS (CI, isobutane): m/z (%) =
332.1 (100) [M + H]+. HRMS (CI, isobutane): calcd. for
C18H22NO5 [M]+ 332.1498; found 332.1500. TOF MS (ESI+):
calcd. for C21H27NO3Na [M + Na]+ 364.1472; found 364.1471. MS
(CI, isobutane): m/z (%) = 328.2 (100) [M + H]+. HRMS (CI, iso-
butane): calcd. for C15H22NO7 [M]+ 328.1396; found 328.1406.
3
1 H, CH2NH), 3.12 (dd, 3J = 14.1 Hz, J = 8.3 Hz, 1 H, CH2NH),
2
2
3.23 (d, J = 16.2 Hz, 1 H, CH2CO), 3.53 (d, J = 16.2 Hz, 1 H,
3
CH2CO), 4.03–4.16 (m, 4 H, CH2CH=CH2, CH2CH3), 4.24 (q, J
= 7.1 Hz, 2 H, CH2CH3), 5.09–5.12 (m, 2 H, CH2CH=CH2), 5.63
(s, 1 H, C=CH2), 5.65–5.72 (m, 1 H, CH2CH=CH2), 6.13 (s, 1 H,
C=CH2), 7.11 (br. s, 1 H, NH) ppm. 13C NMR (126 MHz, CDCl3):
δ = 14.01 (CH2CH3), 14.10 (CH2CH3), 18.36 (CH3), 39.52
(CH2CO), 39.95 (CH2NH), 41.59 (CH2CH=CH2), 60.63
(CH2 CH3 ), 61.63 (CH2 CH3 ), 83.88 (CCH2 CO), 119.97
(CH2CH=CH2), 126.39 (C=CH2), 130.50 (CH2CH=CH2), 136.23
rac-3-Benzylaminocarbonyl-1-ethyloxy-3-methacryloxy-1-oxohex-5-
ene (4d): Following GP A, ethyl 3-oxohex-5-enoate (2b, 138.0 mg,
0.885 mmol), methacrylic acid (76.0 mg, 0.885 mmol), benzyl iso-
cyanide (103.7 mg, 0.885 mmol), and anhydrous dichloromethane
(5.0 mL) were used. The crude product was purified by column
chromatography on silica gel (n-hexane/ethyl acetate, 7:3; Rf = 0.42)
and obtained as a colorless oil (270 mg, 0.750 mmol, 85 %). 1H
NMR (500.1 MHz, CDCl3): δ = 1.18 (t, 3J = 7.1 Hz, 3 H,
CH2CH3), 1.89 (s, 3 H, CCH3), 2.81 (dd, 2J = 14.0 Hz, 3J = 6.7 Hz,
1 H, CH2CH=CH2), 3.09 (dd, 2J = 14.1 Hz, 3J = 8.0 Hz, 1 H,
(C=CH ), 165.19, 169.54, 170.72 (CO) ppm. IR: ν = 3441, 2983,
˜
2
1733, 1677, 1148 cm–1. MS (CI, isobutane): m/z (%) = 356.2 (100)
[M + H]+. HRMS (CI, isobutane): calcd. for C17H26NO7 [M]+
356.1709; found 356.1716.
2
2
CH2CH=CH2), 3.27 (d, J = 16.2 Hz, 1 H, CH2CO), 3.51 (d, J =
rac-2-Acryloxy-2-benzyl-1-benzylamino-1-oxopent-4-ene (4g): Fol-
3
16.2 Hz, 1 H, CH2CO), 4.05 (q, J = 7.1 Hz, 2 H, CH2CH3), 4.47– lowing GP A, 1-phenylpent-4-en-2-one (2a, 250.0 mg, 1.560 mmol),
4.56 (m, 2 H, CH2Ph), 5.08–5.12 (m, 2 H, CH2CH=CH2), 5.55 (s, acrylic acid (112.0 mg, 1.560 mmol), benzyl isocyanide (182.0 mg,
1 H, C=CH2), 5.59–5.67 (m, 1 H, CH2CH=CH2), 6.00 (s, 1 H, 1.560 mmol), and anhydrous dichloromethane (5.0 mL) were used.
C=CH2), 6.74 (br. s, 1 H, NH), 7.26–7.35 (m, 5 H, ArCH) ppm. The crude product was purified by column chromatography on sil-
13C NMR (126 MHz, CDCl3): δ = 14.05 (CH2CH3), 18.29 (CCH3), ica gel (n-hexane/ethyl acetate, 8:2; Rf = 0.34) and obtained as a
1
39.49 (CH2CO), 40.03 (CH2CH=CH2), 43.72 (CH2Ph), 60.59 colorless oil (470.0 mg, 1.346 mmol, 86%). H NMR (500.1 MHz,
Eur. J. Org. Chem. 2011, 4335–4344
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4339

A. Schwäblein, J. Martens
FULL PAPER
CDCl3 ): δ = 2. 97 (dd, 2 J = 14. 1 Hz, 3 J = 6.4 Hz, 1 H,
165.41, 170.58 (CO) ppm. IR: ν = 3433, 3085, 2926, 1720, 1672,
˜
CH2CH=CH2), 3.25 (dd, 2J = 14.1 Hz, 3J = 8.3 Hz, 1 H,
1153, 699 cm–1. MS (ESI+): m/z (%) = 386.2 (100) [M + Na]+. TOF
3
3
CH2CH=CH2), 3.32 (d, J = 13.8 Hz, 1 H, CH2Ph), 3.65 (d, J = MS (ESI+): calcd. for C23H25NO3Na [M + Na]+ 386.1732; found
2
13.8 Hz, 1 H, CH2Ph), 4.29 (m, 2 H, CH2NH), 4.99, 5.06 (2d, J 386.1738.
3
= 17.0 Hz, J = 10.9 Hz, 2 H, CH2CH=CH2), 5.52–5.60 (m, 1 H,
rac-2-Benzyl-2-methacryloxy-1-(2-methoxy-2-oxoethylamino)-1-
CH2CH=CH2), 5.70 (dd, 3J = 10.4 Hz, 3J = 1.1 Hz, 1 H,
oxopent-4-ene (4j): Following GP A, 1-phenylpent-4-en-2-one (2a,
3
3
CH=CH2), 5.92 (dd, J = 10.4 Hz, J = 17.3 Hz, 1 H, CH=CH2),
1.090 g, 7.500 mmol), methacrylic acid (0.645 g, 7.500 mmol),
methyl isocyanoacetate (0.743 g, 7.500 mmol), and anhydrous
dichloromethane (15.0 mL) were used. The crude product was puri-
fied by column chromatography on silica gel (n-hexane/ethyl acet-
ate, 8:2; Rf = 0.21) and obtained as a colorless solid (1.440 g,
4.056 mmol, 65%), m.p. 48–54 °C. 1H NMR (500.1 MHz, CDCl3):
3
3
6.23 (dd, J = 17.3 Hz, J = 1.1 Hz, 1 H, CH=CH2), 6.26 (br. s, 1
H, NH), 6.95–7.18 (m, 10 H, ArCH) ppm. 13C NMR (126 MHz,
CDCl3): δ = 39.70 (CH2CH=CH2), 40.65 (CH2Ph), 43.35
(CH2NH), 88.75 (CCH2Ph), 119.46 (CH2CH=CH2), 126.81,
127.41, 127.61, 128.18, 128.56 (ArCH), 129.98, 130.05 (ArCH),
131.33 (CH=CH2), 131.38 (CH2CH=CH2), 135.49, 137.67 (ArC),
2
3
δ = 1.86 (s, 3 H, CH3), 2.97 (dd, J = 14.2 Hz, J = 6.2 Hz, 1 H,
164.05, 170.36 (CO) ppm. IR: ν = 3355, 3029, 2934, 1730, 1655,
˜
CH2CH=CH2), 3.30 (dd, 2J = 14.4 Hz, 3J = 8.4 Hz, 1 H,
CH2CH=CH2), 3.34 (d, J = 13.9 Hz, 1 H, CH2Ph), 3.69 (d, J =
14.2 Hz, 1 H, CH2Ph), 3.71 (s, 3 H, OCH3), 3.80 (dd, 2J = 18.6 Hz,
1175, 698 cm–1. MS (ESI+): m/z (%) = 372.2 (100) [M + Na]+. TOF
MS (ESI+): calcd. for C22H23NO3Na [M + Na]+ 372.1576; found
372.1577.
3
3
3J = 4.3 Hz, 1 H, CH2NH), 4.07 (dd, J = 18.7 Hz, J = 5.5 Hz, 1
H, CH2 NH), 5.09 (dd, 2 J = 20.5 Hz, 3 J = 10.1 Hz, 2 H,
CH2CH=CH2), 5.52 (s, 1 H, C=CH2), 5.60–5.68 (m, 1 H,
CH2CH=CH2), 5.96 (s, 1 H, C=CH2), 6.63 (br. s, 1 H, NH), 7.04–
7.06 (m, 2 H, ArCH), 7.17–7.19 (m, 3 H, ArCH) ppm. 13C NMR
(126 MHz, CDCl3): δ = 18.31 (CH3), 39.57 (CH2CH=CH2), 40.48
(CH2Ph), 41.13 (CH2NH), 52.35 (OCH3), 88.34 (CCH2Ph), 119.38
(CH2CH=CH2), 125.89 (C=CH2), 126.84, 128.07, 129.76 (ArCH),
131.25 (CH2CH=CH2), 135.32 (ArC), 136.51 (C=CH2), 165.39,
2
3
rac-2-Acryloxy-2-benzyl-1-(2-methoxy-2-oxoethylamino)-1-oxopent-
4-ene (4h): Following GP A, 1-phenyl-pent-4-en-2-one (2a,
280.0 mg, 1.750 mmol), acrylic acid (126.0 mg, 1.750 mmol),
methyl isocyanoacetate (551.0 mg, 1.750 mmol), and anhydrous
dichloromethane (5.0 mL) were used. The crude product was puri-
fied by column chromatography on silica gel (n-hexane/ethyl acet-
ate, 8:2; Rf = 0.13) and obtained as a colorless oil (180.0 mg,
0.543 mmol, 31%). 1H NMR (500.1 MHz, CDCl3): δ = 3.01 (dd,
2J = 14.2 Hz, 3J = 6.2 Hz, 1 H, CH2CH=CH2), 3.32 (dd, 2J =
14.2 Hz, 3J = 8.5 Hz, 1 H, CH2CH=CH2), 3.39 (d, 2J = 13.9 Hz, 1
H, CH2Ph), 3.75 (s, 3 H, OCH3), 3.82 (dd, 2J = 18.3 Hz, 3J =
169.77, 170.95 (CO) ppm. IR: ν = 3395, 3038, 1717, 1657, 1153,
˜
706 cm–1. MS (ESI+): m/z (%) = 368.1 (100) [M + Na]+. MS (CI,
isobutane): m/z (%) = 346.2 (10) [M + H]+, 327.2 (100). HRMS (CI,
isobutane): calcd. for C19H24NO5 [M]+ 346.1654; found 346.1663.
3
4.4 Hz, 1 H, CH2NH), 4.12 (dd, 2J = 18.7 Hz, J = 5.6 Hz, 1 H,
CH2NH), 5.13 (dd, 2J = 18.3 Hz, 3J = 5.6 Hz, 2 H, CH2CH=CH2),
5.60–5.68 (m, 1 H, CH2CH=CH2), 5.85 (d, 3J = 11.4 Hz, 1 H,
rac-2-Acryloxy-2-benzyl-1-cyclohexylamino-1-oxopent-4-ene (4k):
Following GP A, 1-phenylpent-4-en-2-one (2a, 810.0 mg,
5.050 mmol), acrylic acid (364.0 mg, 5.050 mmol), cyclohexyl iso-
cyanide (551.0 mg, 5.050 mmol), and anhydrous dichloromethane
(5.0 mL) were used. The crude product was purified by column
chromatography on silica gel (n-hexane/ethyl acetate, 8:2; Rf = 0.29)
and obtained as a colorless oil (190.0 mg, 0.556 mmol, 11%). 1H
NMR (500.1 MHz, CDCl3): δ = 0.86–0.89, 1.06–1.16, 1.33–1.43,
3
3
CH=CH2), 6.07 (dd, J = 10.4 Hz, J = 17.2 Hz, 1 H, CH=CH2),
6.37 (d, 3J = 17.2 Hz, 1 H, CH=CH2), 6.63 (br. s, 1 H, NH), 7.04–
7.06 (m, 2 H, ArCH), 7.17–7.19 (m, 3 H, ArCH) ppm. 13C NMR
(126 MHz, CDCl3): δ = 39.72 (CH2CH=CH2), 40.58 (CH2Ph),
41.08 (CH2NH), 52.30 (OCH3), 88.45 (CCH2Ph), 119.44
(CH2CH=CH2), 126.84, 128.05 (ArCH), 128.11 (CH=CH2),
128.63, 129.79 (ArCH), 129.86 (ArC), 131.21 (CH=CH2), 131.31
(CH2CH=CH2), 135.29 (ArC), 163.98, 169.76, 170.85 (CO) ppm.
2
3
1.59–1.68, 1.82–1.86 (5m, 10 H, CyH2), 3.01 (dd, J = 14.2 Hz, J
= 6.0 Hz, 1 H, CH2CH=CH2), 3.26 (dd, 2J = 14.2 Hz, 3J = 8.7 Hz,
1 H, CH2CH=CH2), 3.40 (d, J = 13.8 Hz, 1 H, CH2Ph), 3.64 (d,
IR: ν = 3424, 3085, 2947, 1725, 1671, 1176, 700 cm–1. MS (ESI+):
˜
3
m/z (%) = 354.1 (100) [M + Na]+. MS (CI, isobutane): m/z (%) =
332.1 (100) [M + H]+. HRMS (CI, isobutane): calcd. for
C18H22NO5 [M]+ 332.1498; found 332.1500. TOF MS (ESI+):
calcd. for C21H27NO3Na [M + Na]+ 364.1472; found 364.1471.
3J = 13.8 Hz, 1 H, CH2Ph), 3.73–3.80 (m, 1 H, CyH), 5.07, 5.13
(2d, 2J = 17.0 Hz, 3J = 10.9 Hz, 2 H, CH2CH=CH2), 5.57–5.63 (m,
1 H, CH2CH=CH2), 5.88 (dd, 2J = 1.4 Hz, 3J = 10.4 Hz, 1 H,
CH=CH2), 6.01 (br. s, 1 H, NH), 6.10 (dd, 3J = 10.4 Hz, 3J =
rac-2-Benzyl-1-benzylamino-2-methacryloxy-1-oxopent-4-ene (4i):
Following GP A, 1-phenylpent-4-en-2-one (2a, 260.0 mg,
1.620 mmol), methacrylic acid (139.0 mg, 1.620 mmol), benzyl iso-
cyanide (189.0 mg, 1.620 mmol), and anhydrous dichloromethane
(5.0 mL) were used. The crude product was purified by column
chromatography on silica gel (n-hexane/ethyl acetate, 8:2; Rf = 0.42)
and obtained as a colorless solid (400.0 mg, 1.100 mmol, 68%),
m.p. 42–45 °C. 1H NMR (500.1 MHz, CDCl3): δ = 1.70 (s, 3 H,
CH3), 2.97 (dd, 2J = 14.2 Hz, 3J = 6.4 Hz, 1 H, CH2CH=CH2),
3
17.3 Hz, 1 H, CH=CH2), 6.42 (dd, 3J = 10.4 Hz, J = 1.4 Hz, 1 H,
CH=CH2), 7.11–7.13, 7.20–7.26 (2m, 5 H, ArCH) ppm. 13C NMR
(126 MHz, CDCl3): δ = 24.74, 25.44, 32.51, 32.99, 34.91 (CyCH2),
39.69 (CH2CH=CH2), 40.59 (CH2Ph), 48.16 (CyC), 88.76
(CCH2Ph), 119.10 (CH2CH=CH2), 126.84, 127.95, 128.09, 129.89
(ArCH), 131.39 (CH=CH2), 131.60 (CH2CH=CH2), 135.56 (ArC),
165.75, 168.25 (CO) ppm. IR: ν = 3445, 3065, 2931, 1726, 1670,
˜
1168, 702 cm–1. MS (ESI+): m/z (%) = 364.2 (100) [M + Na]+. TOF
MS (ESI+): calcd. for C21H27NO3Na [M + Na]+ 364.1472; found
364.1471.
2
3
3.24 (dd, J = 14.1 Hz, J = 8.3 Hz, 1 H, CH2CH=CH2), 3.31 (d,
3J = 13.8 Hz, 1 H, CH2Ph), 3.63 (d, J = 13.8 Hz, 1 H, CH2Ph),
3
3
2
4.29 (d, J = 5.7 Hz, 2 H, CH2NH), 5.00, 5.06 (2d, J = 17.0 Hz, rac-2-Benzyl-1-cyclohexylamino-2-methacryloxy-1-oxopent-4-ene
3J = 10.2 Hz, 2 H, CH2CH=CH2), 5.39 (s, 1 H, C=CH2), 5.52–5.60
(m, 1 H, CH2CH=CH2), 5.76 (s, 1 H, C=CH2), 6.19 (br. s, 1 H,
NH), 6.92–7.18 (m, 10 H, ArCH) ppm. 13C NMR (126 MHz,
(4l): Following GP A, 1-phenylpent-4-en-2-one (2a, 170.0 mg,
1.060 mmol), methacrylic acid (91.35 mg, 1.060 mmol), cyclohexyl
isocyanide (115.72 mg, 1.060 mmol), and anhydrous dichlorometh-
CDCl3): δ = 18.33 (CH3), 39.57 (CH2CH=CH2), 40.55 (CH2Ph), ane (5.0 mL) were used. The crude product was purified by column
43.34 (CH2NH), 88.52 (CCH2Ph), 119.44 (CH2CH=CH2), 125.73 chromatography on silica gel (n-hexane/ethyl acetate, 9:1; Rf = 0.36)
(C=CH2), 126.81, 127.36, 128.15, 128.56, 129.98 (ArCH), 131.38 and obtained as a colorless oil (200.0 mg, 0.563 mmol, 53%). 1H
(CH2CH=CH2), 135.49 (ArC), 136.52 (C=CH2), 137.57 (ArC),
NMR (500.1 MHz, CDCl3): δ = 0.75–0.83, 0.95–1.32, 1.40–1.56
4340
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4335–4344

Synthesis of α,β-Unsaturated Lactones with High Diversity
2
3
(m, 1H, CyCH2), 1.75 (s, 3 H, CH3), 2.93 (dd, J = 14.1 Hz, J = 8.6 μmol) were used. The crude product was purified by column
2
3
6.2 Hz, 1 H, CH2CH=CH2), 3.20 (dd, J = 14.1 Hz, J = 8.4 Hz,
chromatography on silica gel (n-hexane/ethyl acetate, 1:1; Rf = 0.16)
and obtained as a colorless oil (31 mg, 0.103 mmol, 60 %). 1H
NMR (500.1 MHz, CDCl3): δ = 1.23 (t, 3J = 7.2 Hz, 3 H,
3
1 H, CH2CH=CH2), 3.28 (d, J = 13.8 Hz, 1 H, CH2Ph), 3.58 (d,
3J = 13.8 Hz, 1 H, CH2Ph), 3.63–3.70 (m, 1 H, CHNH), 4.97, 5.03
(2d, J = 16.8 Hz, J = 10.1 Hz, 2 H, CH2CH=CH2), 5.42 (s, 1 H, CH2CH3), 2.88–2.93 (m, 1 H, CH2CH=CH), 2.89 (d, 3J = 15.2 Hz,
2
3
3
C=CH2), 5.49–5.57 (m, 1 H, CH2CH=CH2), 5.81 (s, 1 H, C=CH2), 1 H, CH2CO), 3.00 (d, J = 15.2 Hz, 1 H, CH2CO), 3.01–3.06 (m,
5.87 (br. s, 1 H, CHNH), 7.01–7.13 (m, 5 H, ArCH) ppm. 13C 1 H, CH2CH=CH), 3.74 (s, 3 H, OCH3), 3.99 (dd, J = 15.2 Hz,
2
NMR (126 MHz, CDCl3): δ = 18.31 (CH3), 24.34, 24.38, 25.42, 3J = 5.4 Hz, 1 H, CH2NH), 4.10 (dd, J = 15.6 Hz, J = 5.9 Hz, 1
2
3
3
32.40, 32.91 (CyCH), 39.49 (CH2CH=CH2), 40.52 (CH2Ph), 47.56 H, CH2NH), 4.13 (q, J = 7.1 Hz, 2 H, CH2CH3), 6.04–6.06 (m, 1
(CHNH), 88.28 (CCH2Ph), 119.09 (CH2CH=CH2), 125.45 H, CH2CH=CH), 6.83–6.87 (m, 1 H, CH2CH=CH), 7.11 (br. t, 1
(C=CH2), 126.71, 127.97, 128.64, 129.39, 129.93 (ArCH), 131.54 H, NH) ppm. 13C NMR (126 MHz, CDCl3): δ = 13.98 (CH2CH3),
(CH2CH=CH2), 135.59 (ArC), 136.76 (C=CH2), 165.29, 169.35 30.12 (CH2CH=CH), 41.22 (CH2NH), 41.63 (CH2CO), 52.37
(CO) ppm. IR: ν = 3445, 3031, 2930, 1723, 1675, 1153, 701 cm–1.
(OCH3), 61.16 (CH2CH3), 82.31 (CCH2CH=CH), 120.32
(CH2CH=CH), 144.35 (CH2CH=CH), 161.04, 167.96, 169.33,
˜
MS (ESI+): m/z (%) = 378.2 (100) [M + Na]+. TOF MS (ESI+):
calcd. for C22H29NO3Na [M + Na]+ 378.2045; found 378.2051.
170.88 (CO) ppm. IR: ν = 3366, 2924, 1720, 1674, 1043 cm–1. MS
˜
(CI, isobutane): m/z (%) = 300.1 (100) [M + H]+. HRMS (CI, iso-
General Procedure (GP B): The α-acyloxy carboxamides 4
(1 equiv.), synthesized according to GP A, and the ruthenium cata-
lyst (0.05 equiv., Figure 3) in toluene (10 mL) were slowly heated
to 70 °C until the reaction was complete (monitored by TLC). The
solvent was removed under reduced pressure. Purification of the
crude product is described in the experiments.
butane): calcd. for C13H18NO7 [M]+ 300.1083; found 300.1076.
rac-Ethyl 2-[2-(Benzylcarbamoyl)-5-methyl-6-oxo-3,6-dihydro-2H-
pyran-2-yl]acetate (5d): Following GP B, α-acyloxy carboxamide 4d
(85 mg, 0.237 mmol) and the ruthenium catalyst (11.2 mg, 11 μmol)
were used. The crude product was purified by column chromatog-
raphy on silica gel (n-hexane/ethyl acetate, 1:1; Rf = 0.35) and ob-
tained as a colorless oil (20 mg, 0.060 mmol, 25 %). 1H NMR
(500.1 MHz, CDCl3): δ = 1.22 (t, 3J = 7.1 Hz, 3 H, CH2CH3), 1.88
(s, 3 H, CH3), 2.82–3.10 (m, 4 H, CH2CH=C, CH2CO), 4.11 (q, 3J
= 7.1 Hz, 2 H, CH2CH3), 4.39 (dd, 2J = 14.7 Hz, 3J = 5.5 Hz, 1 H,
rac-Ethyl 2-[2-(Benzylcarbamoyl)-6-oxo-3,6-dihydro-2H-pyran-2-yl]-
acetate (5a): Following GP B, α-acyloxy carboxamide 4a (72 mg,
0.208 mmol) and the ruthenium catalyst (9.88 mg, 10 μmol) were
used. The crude product was purified by column chromatography
on silica gel (n-hexane/ethyl acetate, 1:1; Rf = 0.30) and obtained
2
3
CH2Ph), 4.52 (dd, J = 14.7 Hz, J = 6.2 Hz, 1 H, CH2Ph), 6.52–
6.56 (m, 1 H, CH2CH=C), 6.91 (br. s, 1 H, NH), 7.23–7.33 (m, 5
H, ArCH) ppm. 13C NMR (126 MHz, CDCl3): δ = 14.03
(CH2CH3), 16.82 (CH3), 30.87 (CH2CH=C), 41.96 (CH2CO), 43.70
(CH2Ph), 61.07 (CH2CH3), 82.45 (CCH2CH=C), 127.62, 127.64,
128.69 (ArCH), 137.47 (ArC), 138.13 (CH2CH=C), 162.95, 168.03,
1
as a colorless solid (60 mg, 0.189 mmol, 90%), m.p. 77–79 °C. H
NMR (500.1 MHz, CDCl3): δ = 1.22 (t, 3J = 7.1 Hz, 3 H,
3
CH2CH3), 2.88–3.07 (m, 4 H, CH2CH=CH2, CH2CO), 4.12 (q, J
3
= 7.1 Hz, 2 H, CH2CH3), 4.46 (d, J = 5.8 Hz, 2 H, CH2Ph), 6.04
(d, 3 J = 9.8 Hz, 1 H, CH2 CH=CH), 6.48–6.88 (m, 1 H,
CH2CH=CH), 6.90 (br. s, 1 H, NH), 7.25–7.34 (m, 5 H,
ArCH) ppm. 13C NMR (126 MHz, CDCl3): δ = 14.04 (CH3), 30.51
(CH2CH=CH), 41.96 (CH2CO), 43.84 (CH2Ph), 61.15 (CH2CH3),
82.44 (CCH2CH=CH), 120.34 (CH2CH=CH), 127.69, 127.74,
128.74, (ArCH), 137.31 (ArC), 144.51 (CH2CH=CH), 161.13,
170.50 (CO) ppm. IR: ν = 3362, 2982, 1723, 1673, 1091 cm–1. TOF
˜
MS (ESI+): m/z (%) = 354.2 (100) [M + Na]+. TOF MS (ESI+):
calcd. for C18H21NO5Na [M + Na]+ 354.1317; found 354.1322.
rac-Ethyl 2-[2-(Cyclohexylcarbamoyl)-5-methyl-6-oxo-3,6-dihydro-
2H-pyran-2-yl]acetate (5e): Following GP B, α-acyloxy carbox-
amide 4e (88 mg, 0.251 mmol) and the ruthenium catalyst (11.9 mg,
13 μmol) were used. The crude product was purified by column
chromatography on silica gel (dichloromethane/ethyl acetate, 8:2;
Rf = 0.52) and obtained as a colorless solid (50 mg, 0.155 mmol,
62%), m.p. 88–89 °C. 1H NMR (500.1 MHz, CDCl3): δ = 1.12–
167.93, 170.26 (CO) ppm. IR: ν = 3356, 2982, 1730, 1671,
˜
1188 cm–1. TOF MS (ESI+): m/z (%) = 340.1 (100) [M + Na]+.
TOF MS (ESI+): calcd. for C17H19NO5Na [M + Na]+ 340.1161;
found 340.1164.
rac-Ethyl 2-[2-(Cyclohexylcarbamoyl)-6-oxo-3,6-dihydro-2H-pyran-
2-yl]acetate (5b): Following GP B, α-acyloxy carboxamide 4b
(135 mg, 0.400 mmol) and the ruthenium catalyst (18.9 mg,
20 μmol) were used. The crude product was purified by column
chromatography on silica gel (n-hexane/ethyl acetate, 6:4; Rf = 0.16)
and obtained as a colorless oil (106 mg, 0.343 mmol, 85 %). 1H
NMR (500.1 MHz, CDCl3): δ = 1.16–1.21 (m, 3 H, CyCH2), 1.25
(t, 3J = 7.1 Hz, 3 H, CH2CH3), 1.30–1.39, 1.59–1.95 (2m, 7 H,
CyCH2), 2.85–3.03 (m, 4 H, CH2CH=CH, CH2CO), 3.71–3.77 (m,
3
1.20 (m, 3 H, CyCH2), 1.25 (t, J = 7.2 Hz, 3 H, CH2CH3), 1.29–
1.40, 1.59–1.81 (2m, 7 H, CyCH2), 1.91 (s, 3 H, CH3), 2.79–2.96
(m, 4 H, CH2CH=C, CH2CO), 3.70–3.78 (m, 1 H, CHNH), 4.13
(q, 3J = 7.2 Hz, 2 H, CH2CH3), 6.39–6.41 (m, 1 H, CH2CH=C),
6.54 (br. s, 1 H, NH) ppm. 13C NMR (126 MHz, CDCl3): δ = 14.02
(CH2CH3), 16.81 (CH3), 24.67, 25.28, 32.46, 32.80 (CyCH2), 30.79
(CH2CH=C), 41.73 (CH2CO), 48.53 (CHNH), 60.96 (CH2CH3),
82.25 (CCH2CH=C), 127.52 (CH2CH=C), 138.20 (CH2CH=C),
3
3
1 H, CHNH), 4.14 (q, J = 6.9 Hz, 2 H, CH2CH3), 6.04 (d, J =
9.9 Hz, 1 H, CH2CH=CH), 6.41 (d, 3J = 7.7 Hz, 1 H, CHNH),
6.84–6.87 (m, 1 H, CH2CH=CH) ppm. 13C NMR (126 MHz,
CDCl3): δ = 14.07 (CH2CH3), 24.72, 25.34 (CyCH2), 30.44
(CH2CH=CH), 32.51, 32.81 (CyCH2), 41.86 (CH2CO), 48.73
(CHNH), 61.09 (CH2CH3), 82.27 (CCH2CH=CH), 120.20
(CH2CH=CH), 144.69 (CH2CH=CH), 161.43, 167.98, 169.16
163.18, 168.04, 169.39 (CO) ppm. IR: ν = 3346, 2938, 1717, 1651,
˜
1051 cm–1. MS (CI, isobutane): m/z (%) = 324.5 (100) [M + H]+.
HRMS (CI, isobutane): calcd. for C17H26NO5 [M]+ 324.1811;
found 324.1816.
rac-Ethyl 2-[2-(2-Ethoxy-2-oxoethyl)-5-methyl-6-oxo-3,6-dihydro-
2H-pyran-2-carboxamido]acetate (5f): Following GP B, α-acyloxy
carboxamide 4f (56 mg, 0.157 mmol) and the ruthenium catalyst
(7.5 mg, 79 μmol) were used. The crude product was purified by
column chromatography on silica gel (n-hexane/ethyl acetate, 7:3;
Rf = 0.22) and obtained as a colorless oil (20 mg, 0.061 mmol,
39%). 1H NMR (500.1 MHz, CDCl3): δ = 1.23–1.30 (m, 8 H, 2
(CO) ppm. IR: ν = 3345, 2931, 1731, 1666, 1187, 1053 cm–1. MS
˜
(CI, isobutane): m/z (%) = 310.2 (100) [M + H]+. HRMS (CI, iso-
butane): calcd. for C16H24NO5 [M]+ 310.1654; found 310.1648.
rac-Ethyl 2-[2-(2-Methoxy-2-oxoethylcarbamoyl)-6-oxo-3,6-dihydro-
2H-pyran-2-yl]acetate (5c): Following GP B, α-acyloxy carboxam-
ide 4c (54 mg, 0.172 mmol) and the ruthenium catalyst (8.2 mg,
3
CH2CH3, CH2CH=C), 1.93 (s, 3 H, CH3), 2.99 (d, J = 15.1 Hz, 2
Eur. J. Org. Chem. 2011, 4335–4344
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4341

A. Schwäblein, J. Martens
FULL PAPER
2
3
H, CH2CO), 3.95 (dd, J = 18.1 Hz, J = 5.2 Hz, 1 H, CH2NH),
130.48, 134.19, 137.16 (ArCH), 139.05 (CH=C), 163.88, 170.88
(CO) ppm. IR: ν = 3389, 3006, 2927, 1712, 1670, 1127, 1047,
˜
2
3
3
4.12 (dd, J = 18.1 Hz, J = 6.1 Hz, 1 H, CH2NH), 4.14 (q, J =
7.1 Hz, 2 H, CH2CH3), 4.21 (q, J = 7.1 Hz, 2 H, CH2CH3), 6.52 700 cm–1. MS (ESI+): m/z (%) = 692.7 (100) [2M + Na]+. TOF
(m, 1 H, CHNH), 7.02 (m, 1 H, CH=C) ppm. 13 C NMR MS (ESI+): calcd. for C21H21NO6Na [M + Na]+ 358.1419; found
(126 MHz, CDCl3): δ = 14.03, 14.11 (2 CH2CH3), 16.96 (CH3), 358.1413.
3
29.94 (CH2CH=C), 30.53 (CH2CO), 41.37 (CH2NH), 61.16, 61.57
rac-Methyl 2-(2-Benzyl-5-methyl-6-oxo-3,6-dihydro-2H-pyran-2-
carboxamido)acetate (5j): Following GP B, α-acyloxy carboxamide
4j (82 mg, 0.237 mmol) and the ruthenium catalyst (23.75 mg,
22 μmol) were used. The crude product was purified by column
chromatography on silica gel (n-hexane/ethyl acetate, 7:3; Rf = 0.07)
and obtained as a colorless oil (10 mg, 0.032 mmol, 13 %). 1H
(2 CH2CH3), 82.35 (CCH2NH), 127.81 (CH2CH=C), 137.90
(CH CH=C), 162. 87, 168.11, 168.87, 171.13 (CO) ppm. IR: ν =
˜
2
3441, 2983, 1733, 1677, 1148 cm–1. MS (CI, isobutane): m/z (%) =
328.1 (100) [M + H]+. HRMS (CI, isobutane): calcd. for
C15H22NO7 [M]+ 328.1396; found 328.1400.
rac-N,2-Dibenzyl-6-oxo-3,6-dihydro-2H-pyran-2-carboxamide (5g):
Following GP B, α-acyloxy carboxamide 4g (81 mg, 0.232 mmol)
and the ruthenium catalyst (11.0 mg, 11 μmol) were used. The
crude product was purified by column chromatography on silica
gel (n-hexane/ethyl acetate, 6:4; Rf = 0.24) and obtained as a color-
less solid (19 mg, 0.059 mmol, 97%), m.p. 100–101 °C. 1H NMR
(500.1 MHz, CDCl3): δ = 2.51–2.56 (dm, 1 H, CH2CH=CH), 3.06–
3.10 (dm, 1 H, CH2CH=CH), 3.11 (s, 2 H, CH2Ph), 4.14–4.22 (m,
2 H, CH2NH), 5.90–5.94 (m, 1 H, CH2CH=CH), 6.38 (br. s, 1 H,
NH), 6.77–6.81 (m, 1 H, CH2CH=CH), 6.87–6.89, 7.12–7.19 (m,
10 H, ArCH) ppm. 13C NMR (126 MHz, CDCl3): δ = 30.60
(CH2CH=CH), 43.53 (CH2NH), 43.86 (CH2Ph), 85.48 (CCH2Ph),
120.27 (CH=CH), 127.27, 127.48, 127.53, 128.36, 128.56, 130.49
(ArCH), 133.97, 136.95 (ArC), 145.32 (CH=CH), 162.08, 170.55
4
NMR (500.1 MHz, CDCl3): δ = 1.79 (d, J = 1.7 Hz, 3 H, CH3),
2.42–2.48 (dm, 1 H, CH2CH=C), 2.94–2.99 (dm, 1 H, CH2CH=C),
2
3
3.08 (dd, J = 33.6 Hz, J = 14.1 Hz, 2 H, CH2Ph), 3.62 (s, 3 H,
2
3
OCH3), 3.69 (dd, J = 17.9 Hz, J = 5.3 Hz, 1 H, CH2NH), 3.94
2
3
(dd, J = 17.9 Hz, J = 6.1 Hz, 1 H, CH2NH), 6.40–6.42 (m, 1 H,
CH2CH=C), 6.58 (br. s, 1 H, NH), 7.13–7.21 (m, 5 H, ArCH) ppm.
1 3 C NMR (126 MHz, CDCl3 ): δ = 16.84 (CH3 ) , 30. 17
(CH2CH=C), 41.02 (CH2NH), 43.93 (CH2Ph), 52.29 (OCH3),
85.53 (CCH2Ph), 127.29 (ArCH), 127.73 (CH=C), 128.32, 130.54
(ArCH), 134.21 (ArC), 138.64 (CH=C), 163.78, 169.13, 171.78
(CO) ppm. IR: ν = 3366, 2924, 1720, 1674, 1202, 1043, 701 cm–1.
˜
MS (ESI+): m/z (%) = 324.2 (100) [M + Li]+. HRMS (CI, isobut-
ane): calcd. for C17H20NO5 [M]+ 318.1341; found 318.1337.
(CO) ppm. IR: ν = 3379, 3030, 2942, 1714, 1661, 1241, 1055,
˜
3-Allylcyclohexanone (6): Under an argon atmosphere, to a solution
of cyclohexenone (0.97 mL, 10 mmol) in anhydrous dichlorometh-
ane (15 mL) was added titanium tetrachloride (1.09 mL, 10 mmol)
at –78 °C. At this point, the mixture had a dark red color. A solu-
tion of allyltrimethylsilane (1.75 mL, 11 mmol) in anhydrous
dichloromethane was added dropwise with a syringe. The mixture
was stirred at –30 °C for 3 h. After that time, water (20 mL) was
added very carefully. The organic layer was separated, and the inor-
ganic layer was extracted with diethyl ether (3ϫ40 mL). The com-
bined layers were dried with magnesium sulfate. The crude product
was purified by column chromatography on silica gel (n-hexane/
ethyl acetate, 7:3; Rf = 0.72). The product was obtained as a color-
less oil (550 mg, 3.98 mmol, 40%). 1H NMR (500.1 MHz, CDCl3):
δ = 1.31–1.38, 1.59–1.67, 1.84–1.91, 2.02–2.08, 2.21–2.27, 2.33–2.42
(6m, 11 H, CyCH2, CyH, CH2CH=CH2), 5.00–5.03 (m, 2 H,
CH2CH=CH2), 5.69–5.77 (m, 1 H, CH2CH=CH2) ppm.[29]
699 cm–1. MS (ESI+): m/z (%) = 344.1 (100) [M + Na]+. TOF MS
(ESI+): calcd. for C19H29NO5Na [M + Na]+ 374.1943; found
374.1942.
rac-Methyl 2-(2-Benzyl-6-oxo-3,6-dihydro-2H-pyran-2-carbox-
amido)acetate (5h): Following GP B, α-acyloxy carboxamide 4h
(81 mg, 0.244 mmol) and the ruthenium catalyst (14.0 mg, 12 μmol)
were used. The crude product was purified by column chromatog-
raphy on silica gel (n-hexane/ethyl acetate, 6:4; Rf = 0.10) and ob-
tained as colorless oil (20 mg, 0.065 mmol, 26 %). 1H NMR
(500.1 MHz, CDCl3): δ = 2.45–2.50 (dm, 1 H, CH2CH=CH), 3.01–
3.05 (dm, 1 H, CH2CH=CH), 3.11 (dd, 2J = 37.4 Hz, 3J = 14.1 Hz,
2 H, CH2Ph), 3.63 (s, 3 H, OCH3), 3.74 (dd, 2J = 17.9 Hz, 3J =
3
5.4 Hz, 1 H, CH2NH), 3.91 (dd, 2J = 18.0 Hz, J = 5.8 Hz, 1 H,
CH2NH), 5.90–5.92 (m, 1 H, CH=CH), 6.63 (br. s, 1 H, NH), 6.73–
6.77 (m, 1 H, CH=CH), 7.14–7.23 (m, 5 H, ArCH) ppm. 13C NMR
(126 MHz, CDCl3): δ = 30.29 (CH2CH=CH), 41.51 (CH2NH),
44.32 (CH2Ph), 52.81 (OCH3), 85.94 (CCH2Ph), 120.76 (CH=CH),
127.81, 128.80, 130.99 (ArCH), 134.38 (ArC), 145.60 (CH=CH),
rac-Allyl N-{[1-(Acetyloxy)-3-allylcyclohexyl]carbonyl}glycinate
(7a): Following GP A, 3-allylcyclohexanone 6 (110.0 mg,
0.80 mmol), acetic acid (48.0 mg, 0.80 mmol), allyl isocyanoacetate
(100.0 mg, 0.80 mmol), and anhydrous dichloromethane (5.0 mL)
were used. The crude product was purified by column chromatog-
raphy on silica gel (n-hexane/ethyl acetate, 7:3; Rf = 0.19) and ob-
tained as a colorless oil (95.0 mg, 0.290 mmol, 37%). 1H NMR
(500.1 MHz, CDCl3): δ = 1.26–1.31, 2.42–2.48 (5 m, 11 H, CyCH2,
162.49, 169.58, 171.89 (CO) ppm. IR: ν = 3366, 3031, 2952, 1731,
˜
1673, 1205, 1046, 603 cm–1. MS (CI, isobutane): m/z (%) = 304.1
(100) [M + H]+. HRMS (CI, isobutane): calcd. for C16H18NO5
[M]+ 304.1185; found 304.1189.
rac-N,2-Dibenzyl-5-methyl-6-oxo-3,6-dihydro-2H-pyran-2-carb-
oxamide (5i): Following GP B, α-acyloxy carboxamide 4i (94 mg, CH2CH=CH2), 2.05 (s, 3 H, CH3), 4.06–4.08 (m, 2 H, CH2NH),
3
3
0.258 mmol) and the ruthenium catalyst (13.3 mg, 12 μmol) were 4.65 (d, J = 5.9 Hz, 2 H, OCH2CH=CH2), 4.99 (dd, J = 7.7 Hz,
used. The crude product was purified by column chromatography
on silica gel (n-hexane/ethyl acetate, 6:4; Rf = 0.32) and obtained
as a colorless solid (25 mg, 0.075 mmol, 28%), m.p. 114–120 °C.
1H NMR (500.1 MHz, CDCl3): δ = 1.77 (s, 3 H, CH3), 2.48–2.52
3J = 10.3 Hz, 2 H, CH2CH=CH2), 5.31 (dd, 3J = 10.3 Hz, 3J =
17.3 Hz, 2 H, CH2CH=CH2), 5.71–5.79 (m, 1 H, CH2CH=CH2),
5.87–5.95 (m, 1 H, OCH2CH=CH2), 6.33 (br. s, 1 H, NH) ppm.
13C NMR (126 MHz, CDCl3): δ = 21.36 (CyCH2), 21.94 (CH3),
(dm, 1 H, CH2CH=C), 3.00–3.06 (dm, 1 H, CH2CH=C), 3.09 (s, 31.18 (CyCH2), 33.45 (CyCH), 34.00 (CH2CH=CH2), 39.63
2
3
2 H, CH2Ph), 4.12 (dd, J = 14.6 Hz, J = 5.8 Hz, 1 H, CH2NH),
(CH2NH), 41.04, 41.18 (CyCH2), 66.08 (OCH2CH=CH2), 82.48
2
3
4.25 (dd, J = 14.8 Hz, J = 5.9 Hz, 1 H, CH2NH), 6.40 (br. s, 1 (CyC), 116.51 (CH2CH=CH2), 119.09 (OCH2CH=CH2), 131.02
H, NH), 6.47 (s, 1 H, CH2CH=C), 6.88–6.90, 7.12–7.18 (2m, 10 H, (OCH2CH=CH2), 136.92 (CH2CH=CH2), 169.67, 171.15, 172.13
ArCH) ppm. 13C NMR (126 MHz, CDCl3): δ = 16.82 (CH3), 30.79
(CO) ppm. IR: ν = 3354, 2935, 1740, 1668, 1181 cm–1. MS (ESI+):
˜
(CH2CH=C), 43.39 (CH2NH), 43.82 (CH2Ph), 85.55 (CCH2Ph), m/z (%) = 346.1 (100) [M + Na]+. TOF MS (ESI+): calcd. for
127.20, 127.44 (ArCH), 127.52 (CH=C), 128.32, 128.45, 128.54,
C17H25NO5Na [M + Na]+ 346.1630; found 346.1627.
4342
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 4335–4344

Synthesis of α,β-Unsaturated Lactones with High Diversity
rac-3-Allyl-1-[2-(allyloxy)-2-oxoethylcarbamoyl]cyclohexyl Prop- 1 H, NH), 7.01–7.02, 7.19–7.28 (2m, 10 H, ArCH) ppm. 13C NMR
ionate (7b): Following GP A, 3-allylcyclohexanone 6 (70.0 mg,
0.51 mmol), propionic acid (38.0 mg, 0.51 mmol), allyl isocy-
anoacetate (64.0 mg, 0.51 mmol), and anhydrous dichloromethane
(5.0 mL) were used. The crude product was purified by column
chromatography on silica gel (n-hexane/ethyl acetate, 7:3; Rf = 0.26)
and obtained as a colorless oil (46.0 mg, 0.126 mmol, 27%). 1H
NMR (500.1 MHz, CDCl3): δ = 1.09 (t, 3J = 7.5 Hz, 3 H,
(126 MHz, CDCl3): δ = 30.53 (CH3), 32.66 (CyCH), 34.31, 36.83
(CyCH2), 43.76 (CH2Ph), 45.27 (CH2NH), 87.46 (CyC), 127.35,
127.57, 127.62, 128.38, 128.68, 130.62, 133.67, 136.99 (ArC),
167.41, 170.12 (CO), 193.58 (SCO) ppm. IR: ν = 3316, 2933, 1738,
˜
1651, 1083, 694 cm–1. MS (CI, isobutane): m/z (%) = 398.2 (100)
[M + H]+. HRMS (CI, isobutane): calcd. for C22H24NO4S [M]+
398.1426; found 398.1437. The minor diastereoisomer (2S*,4S*)-8
CH2CH3), 1.23–2.03, 2.32–2.45 (5m, 11 H, CyCH2, CH2CH=CH2),
2.30 (q, J = 7.5 Hz, 2 H, CH2CH3), 4.03–4.05 (m, 2 H, CH2NH), 33%). H NMR (500.1 MHz, CDCl3): δ = 2.30 (s, 3 H, CH3), 2.39
(Rf = 0.17) was obtained as a colorless oil (33 mg, 0.083 mmol,
3
1
3
3
4.62 (d, J = 5.9 Hz, 2 H, OCH2CH=CH2), 4.97 (dd, J = 7.0 Hz,
3J = 10.1 Hz, 2 H, CH2CH=CH2), 5.27 (dd, 3J = 10.4 Hz, 3J =
17.1 Hz, 2 H, OCH2CH=CH2), 5.69–5.77 (m, 1 H, CH2CH=CH2),
(dd, 2J = 14.4 Hz, 3J = 9.5 Hz, 1 H, CyCH2), 2.50 (dd, 2J =
3
17.8 Hz, J = 8.9 Hz, 1 H, CyCH2), 2.53 (dd, 2J = 14.8 Hz, 3J =
4.9 Hz, 1 H, CyCH2), 2.82 (dd, 2J = 17.7 Hz, 3J = 5.5 Hz, 1 H,
5.84–5.92 (1 H, OCH2CH=CH2), 6.35 (br. s, 1 H, NH) ppm. 13C CyCH2), 3.15 (d, 2J = 13.9 Hz, 1 H, CH2Ph), 3.25 (d, 2J = 13.9 Hz,
2
NMR (126 MHz, CDCl3): δ = 8.93 (CH2CH3), 21.87 (CyCH2), 1 H, CH2Ph), 3.91–3.96 (m, 1 H, CyCH), 4.22 (dd, J = 14.7 Hz,
28.05 (CH2 CH3 ), 31.21 (CyCH2 ), 33.70 (CyCH), 33.39 3J = 5.3 Hz, 1 H, CH2NH), 4.32 (dd, J = 14.6 Hz, J = 6.3 Hz, 1
2
3
3
(CH2CH=CH2), 39.74 (CH2NH), 41.04, 41.17 (CyCH2), 66.01 H, CH2NH), 6.59 (t, J = 5.4 Hz, 1 H, NH), 6.96–6.98, 7.18–7.27
(OCH2CH=CH2), 82.22 (CyC), 116.04 (CH2CH=CH2), 119.02 (2m, 10 H, ArCH) ppm. 13C NMR (126 MHz, CDCl3): δ = 30.61
( O C H 2 C H = C H 2 ) , 1 3 1 . 3 6 ( O C H 2 C H = C H 2 ) , 1 3 6 . 6 0 (CH3), 33.05 (CyCH), 34.63, 35.94 (CyCH2), 43.41 (CH2Ph), 44.80
(CH CH=CH ), 169.63, 172.19, 173.06 (CO) ppm. IR: ν = 3352, (CH2NH), 86.31 (CyC), 127.35, 127.49, 127.79, 128.42, 128.62,
˜
2
2
2937, 1740, 1668, 1177 cm–1. TOF MS (ESI+): m/z (%) = 398.3 130.60, 133.73, 136.98 (ArC), 166.99, 170.07 (CO), 193.84
(100) [M + Na]+. TOF MS (ESI+): calcd. for C18H27NO5Na [M +
Na]+ 360.1787; found 360.1783.
(SCO) ppm. IR: ν = 3316, 2933, 1738, 1651, 1083, 694 cm–1. MS
˜
(CI, isobutane): m/z (%) = 398.5 (100) [M + H]+. HRMS (CI, iso-
butane): calcd. for C22H24NO4S [M]+ 398.1426; found 398.1435.
rac-3-Allyl-1-[2-(allyloxy)-2-oxoethylcarbamoyl]cyclohexyl 4-Meth-
oxybenzoate (7c): Following GP A, 3-allylcyclohexanone 6
(104.0 mg, 0.76 mmol), 4-methoxybenzoic acid (115.0 mg,
0.76 mmol), allyl isocyanoacetate (95.0 mg, 0.76 mmol), and anhy-
drous dichloromethane (5.0 mL) were used. The crude product was
purified by column chromatography on silica gel (n-hexane/ethyl
acetate, 7:3; Rf = 0.37) and obtained as a colorless oil (130.0 mg,
X-ray Crystallographic Study
Crystal Data for 4c: C18H21NO5, M = 331.36, T = 153(2) K, ortho-
rhombic, space group P212121, a = 8.4092(3) Å, b = 16.8186(5) Å,
c = 25.1187(8) Å, β = 90°, V = 3552.6(2) Å3, ρcalcd. = 1.239 Mg/m3,
Z = 8, R(int) = 0.0326 [for 4414 reflections with IϾ2.0σ(I)], wR2
= 0.0902 (all data), GOF = 1.019.
1
0.313 mmol, 41%). H NMR (500.1 MHz, CDCl3): δ = 1.35–1.56
Crystal Data for 5g: C20H19NO3, M = 321.36, T = 153(2) K, tri-
(5m, 11 H, CyCH2, CH2CH=CH2), 3.80 (s, 3 H, OCH3), 3.96–4.06
(m, 2 H, CH2NH), 4.53 (d, 3J = 5.7 Hz, 2 H, OCH2CH=CH2),
¯
clinic, space group P1, a = 6.1078(3) Å, b = 10.1201(6) Å, c =
13.7540(8) Å, β = 82.531(3)°, V = 838.00(8) Å3, ρcalcd. = 1.274 Mg/
m3, Z = 2, R(int) = 0.0343 [for 4954 reflections with IϾ2.0σ(I)],
wR2 = 0.1433 (all data), GOF = 0.923.
3
3
4.92 (dd, J = 6.0 Hz, J = 10.6 Hz, 2 H, CH2CH=CH2), 5.19 (dd,
3J = 10.3 Hz, J = 17.2 Hz, 2 H, OCH2CH=CH2), 5.64–5.88 (m, 2
3
H, CH2CH=CH2, OCH2CH=CH2), 6.36 (br. s, 1 H, NH), 6.87 (d,
3
3J = 8.8 Hz, 2 H, ArCH), 7.98 (d, J = 8.8 Hz, 2 H, ArCH) ppm.
Crystal Data for 8: C22H23NO4S, M = 397.47, T = 153(2) K, mono-
clinic, space group P21/n, a = 17.6264(7) Å, b = 13.6851(6) Å, c =
13C NMR (126 MHz, CDCl3): δ = 21.96, 31.31 (CyCH2), 33.85
(CyCH), 34.33 (CH2CH=CH2), 39.90 (CH2NH), 41.11, 41.26
(CyCH2), 55.46 (OCH3), 67.13 (OCH2CH=CH2), 82.70 (CyC),
113.69 (ArCH), 116.05 (CH2CH=CH2), 119.90 (OCH2CH=CH2),
122.55 (ArC), 130.69 (OCH2CH=CH2), 131.85 (ArCH), 136.72
(CH2CH=CH2), 163.67 (ArC), 164.81, 169.59, 172.34 (CO) ppm.
25.3138(10) Å,
β = 100.641(2)°, V = =
6001.2(4) Å3, ρcalcd.
1.320 Mg/m3, Z = 12, R(int) = 0.0731[for 8170 reflections with
IϾ2.0σ(I)], wR2 = 0.1557 (all data), GOF = 1.003.
CCDC-827416, -827417, and -827418 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
IR: ν = 3345, 2923, 1715, 1606, 1254 cm–1. TOF MS (ESI+): m/z
˜
(%) = 438.3 (100) [M + Na]+. TOF MS (ESI+): calcd. for
C23H29NO6Na [M + Na]+ 438.1893; found 438.1902.
(2S*,4R*)- and (2S*,4S*)-S-2-Benzyl-2-(benzylcarbamoyl)-6-oxo-
tetrahydro-2H-pyran-4-yl Ethanethioate (8): For the derivatization,
racemic α,β-unsaturated pyran-2-carboxamide 5g (80 mg,
0.249 mmol) was dissolved in 0.9 mL thioacetic acid. A pinch of
AIBN was added, and the mixture was heated to 100 °C for 6 h.
Then the thioacetic acid was removed under reduced pressure. The
diastereomers were separated by column chromatography on silica
gel (dichloromethane/ethyl acetate, 7:3), with a diastereomeric ratio
(dr) = 56:44. The major diastereoisomer (2S*,4R*)-8 (Rf = 0.26)
was obtained as a colorless solid (35 mg, 0.088 mmol, 35%), m.p.
109–110 °C. 1H NMR (500.1 MHz, CDCl3): δ = 1.74 (t, 3J =
13.3 Hz, 1 H, CyCH2), 2.31 (s, 3 H, CH3), 2.31–2.37 (m, 1 H,
Acknowledgments
We are indebted to Ludmila Hermann for the preparative assist-
ance. The ruthenium catalyst was generously supplied to us by
Evonik Degussa GmbH, and the silica gel was supplied by Grace
GmbH & Co. KG. A. S. gratefully acknowledges the Heinz-
Neumüller-Stiftung for a doctoral fellowship.
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Received: February 3, 2011
Published Online: June 7, 2011
4344
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Eur. J. Org. Chem. 2011, 4335–4344