?-C(sp2)-H alkylation of enamides using xanthate chemistry

Article abstract of DOI:10.1039/d0nj01209b

Access to the ?-amino-?,?-unsaturated acyl scaffold was established by applying xanthate chemistry to enamides. This original ?-C(sp²)-H alkylation is regioselective and exhibits broad substrate scope and good functional group tolerance. The la

Full text of DOI:10.1039/d0nj01209b

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-C(sp2)‒H Alkylation of enamides using xanthate chemistry
Sylvain Bertho,a Ismaël Dondasse,a Pascal Retailleau,b Cyril Nicolas,a and Isabelle Gillaizeau*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
An access to the -amino-,-unsaturated acyl scaffold was biological interest and a polyvalent building block that can be
developed by applying xanthate chemistry to enamides. This readily derivatized under a variety of conditions (Figure 1).4 As a
original -C(sp2)-H alkylation is regioselective and exhibits broad result,
substrate scope and good functional group tolerance. The large intermolecular
availability of xanthates is advantageous to the scope of the reported (Scheme 1).3a-b,5 Most of them were triggered by the
a
series of interesting methods on the direct

-C(sp2)‒H alkylation of enamides has been
reaction which combines a radical process and a polar reaction.
addition of an alkyl radical which is mainly generated by direct
radical initiation6 or a single electron-transfer (SET) process.
Renaud and Schubert studied the stereocontrolled addition of
sulfonylmethyl radicals to chiral enamines followed by H-atom
transfers (path. (a)).7 Curran et al. described the addition of
methyl malononitrile radicals to N-vinylpyrrolidinones as part of
a broader study of phenylselenenyl group transfer additions to
electron-rich alkene acceptors.8 Friestad reported an unusual
Introduction
Due to the importance of electron-rich C(sp3)‒H bonds found in
many biologically active natural products and pharmaceuticals,1
the development of methods that allow the coupling of sp3
centers represents a great challenge in organic synthesis.
Recent advances have permitted significant progress in sp3‒sp2
cross coupling particularly in those involving single-electron
pathways.2,3
non-reductive coupling of N-vinyloxazolidinones with
-
haloesters and iodoacetonitrile in presence of tri-n-
butylstannane and AIBN as radical precursor.6 Visible-light
iridium photoredox-catalysis was highlighted by Yu and co-
workers using electron-deficient bromides as alkylating agents
(path. (b)).9
Figure 1. Representative bioactive compounds containing the
unsaturated acyl scaffold.
-amino-,-
The

-C(sp2)‒H alkylation of electron-rich olefins such as
-amino-,-
enamides has attracted particular attention, as the

unsaturated acyl moiety is a unique structural framework of
a.Institute of Organic and Analytical Chemistry, ICOA UMR 7311 CNRS, Université
d’Orléans, rue de Chartres, 45100 Orléans, France.
E-mail: Isabelle.gillaizeau@univ-orleans.fr.
b.Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex,
France.
Scheme 1. Strategies for direct intermolecular
-C(sp2)-H alkylation of enamide
and access to the -amino- -unsaturated systems.

,
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Loh’s group elegantly described a palladium-catalyzed strategy 8-9) but little by the stoichiometry of the xanthate derivative
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for the branch-selective alkylation of enamides (path. (c)).10 Li (entries 6-7), demonstrating that 2 equiv.DoOfI:210a.1n0d391/.D20eNqJ0u1i2v0. 9oBf
and co-workers developed an efficient MnIII-mediated cross DLP was mandatory. The decomposition half-life for a given
dehydrogenation coupling reaction between enamides and 1,3- radical precursor at an operating temperature is often of great
dicarbonyl compounds.11 Another approach involved
-diazo significance. Lastly, portionwise (a portion every 90 min)
compounds as reported by Maas and Muller12 or Yan13 through addition of the DLP initiator was compared with its addition in
a CuII-catalyzed process and more recently upon RhII-catalysis a single portion (entry 10). As expected, the direct addition of
by Musaev and France.5b Although some of these methods DLP proved to be the optimum choice. Polar effects in radical
show high efficiency and good functional group tolerance, there mediated processes are much less important than in ionic
is still great room for improvement with the perspective of processes, allowing a much wider choice of solvents. The next
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developing an efficient, generally applicable method.
step was therefore to screen common solvents for radical
Complementarily, xanthates14 have emerged as attractive reactions. Of note, less polar aprotic solvents such as 1,4-
feedstocks in radical coupling reactions and in promoting the dioxane (entry 11) or the bio-renewable 2-Me-THF (entry 12)
direct alkylation of olefins, as elegantly developed by Zard,15 were capable of performing the transformation, albeit with
Miranda16 or Landais.17 It has been demonstrated that lower efficiencies, whereas with ethyl acetate (entry 13) the
xanthates display an inherent advantage in the oxidative radical addition proceeded well and product 3a was isolated with the
substitution of het(aryl) compounds. Zard reported the C-2 same yield as previously observed with 1,2-DCE. We avoided
alkylation of t-butyl 3-indolecarboxylate15a using such
a
using 1,2-DCE for environmental reasons. Acetonitrile proved
strategy. The oxidative direct intermolecular alkylation of less effective (44%, entry 14). In addition, it is noteworthy that
several heteroaromatic systems (i.e. indoles, pyrroles, furans, degradation was observed when conventional heating was
and thiophenes) was observed by Miranda.16b Furthermore, the replaced by microwave heating.
same group demonstrated that xanthate-based radical
chemistry could be used for the intermolecular alkylation of 1,3-
dimethyluracil.16 Of particular interest, the addition of a radical
Table 1. Optimization of the -C(sp2)-H alkylation of enamide 1a using xanthate 2a.
species derived from xanthate was highlighted by Zard on
azetines,15b also once on the N-vinylpyrolidone15c, and by
Landais17 in the carbo-alkenylation of enamides. Apart from
these examples, and to the best of our knowledge, no study has
showcased to date the applicability of xanthate in the direct
intermolecular C(sp2)‒H alkylation of electron-rich olefins such
as enamides. Following our interest in radical processes to
promote the selective functionalization of nitrogen-containing
heterocycles, we report here the application of xanthate
Entry
Radical
initiator
DLP
DTBP
AIBN
PhI(OAc)2
t-BuOOH [5M]
DLP
Equiv.
Solvent
Yield [%]
of 3ab
62
1
2
3
4
5
6c
7d
8
1.2
1.2
1.2
1.2
1.2
1.2
1.2
0.5
1
1.2
1.2
1.2
1.2
1.2
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
AcOEt
0
0
10
0
58
62
30
50
35
32
31
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chemistry to the
aromatic enamides to synthesize new

-C(sp2)‒H alkylation of a range of non-
-amino- -unsaturated

,
systems which are envisioned to be useful for further
elaboration.
DLP
DLP
DLP
DLP
DLP
DLP
DLP
DLP
AcOEt
1,2-DCE
1,2-DCE
1,2-DCE
1,4-Dioxane
2-Me-THF
AcOEt
9
Results and discussion
10e
11
12
13
14
At the outset of our study, we chose the commercially
available N-vinylpyrrolidinone 1a and xanthate of ethyl acetate
2a as the coupling partner for our model reaction (Table 1). By
applying Zard’s guidelines,15 we began the optimization
conditions by performing the reaction with enamide 1a (1
equiv.) and 2a (2 equiv.) in 1,2-dichloroethane (1,2-DCE) using
readily biodegradable lauroyl peroxide (DLP, 1.2 equiv.) as the
radical precursor. The reaction mixture was refluxed until the
starting material 1a had been consumed (TLC monitoring). The
MeCN
44
a Typical reaction conditions: Argon-free oxygen atmosphere, compound 1a (56
mg, 1 equiv.), xanthate 2a (2 equiv.), radical initiator (1.2 equiv.), solvent (1.5
mL), heating under reflux for 4h30. b Isolated yield after purification by column
chromatography (SiO2, petroleum ether/EtOAc). c 1.5 equiv. of xanthate 2a was
used. d 2.5 equiv. of xanthate 2a was used. e A portion (0.4 equiv.) of the radical
initiator was added every 90 min.
related -amino-,-unsaturated ester 3a was obtained in good
yield (e.g., 62%, entry 1) after 4h30. The E geometry of 3a was
assigned on the basis of NMR data.18 Other radical initiators
such as di-tert-butyl peroxide (DTBP), azobisisobutyronitrile
(AIBN), iodobenzene diacetate or tert-butyl hydroperoxide
were next studied. In most instances, the reaction did not
proceed or a dramatic decrease in yield was observed (entries
2‒5). The yield of 3a was affected by the amount of DLP (entries
On the basis of literature precedent, the following mechanism
can be proposed (Figure 2). The thermal decomposition of
lauroyl peroxide (DLP) initiates first the radical addition of
enamide
1 by the electrophilic alkyl radical A to provide the
amido radical
B
. As observed with (het)aromatic systems and
the uracil system,16 lauroyl peroxide induces the oxidation of
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the latter into the corresponding cation
C
and its resonance of the reaction mixture. As previously observed by us,21 when
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DOI: 10.1039/D0NJ01209B
structure
transfer-xanthate product resulting from the trapping of the morpholin-2-ones 4p
amido radical by the xanthate was not observed. However, in isomer mixture (45:55 ratio). In this case, we assume that no
some specific cases with more electron-rich enamides, the elimination step occurred as the electron donor property of the
D. A proton elimination generated the enamide 3. The more electron-rich enamides were used, the di-functionalized
‒q were originally isolated as a cis:trans
B
iminium species
D
can be trapped by a nucleophile (i.e. the oxygen atom lowers the acidity of the nearby proton in 4p
‒
q.
-
released carboxylate C11H23CO2 ) leading to the difunctionalized The latter two examples illustrate in an interesting way the
adduct 4
, isolated as a mixture of cis-trans diastereoisomers. oxyalkylation reaction of enamides.22
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This mechanism demonstrated the need for a stoechiometric
amount of lauryl peroxide for the reaction to succeed.
Figure 2. Proposed mechanism.
With the optimized conditions in hand, we next examined the

-C(sp2)‒H alkylation of various enamides 1a-q with 2a
(Scheme 2). To our delight, a series of cyclic and acyclic
enamides were successfully converted to the corresponding
-alkylated enamides . Monosubstituted 5- or 7-membered
ring tertiary enamides 1a worked well, giving the new
alkylated product 3a
as a unique E stereoisomer.18 The
1

3
‒
b
‒
b
secondary enamide 1c was also suitable for this alkylation
reaction and provided 3c in good yield. Cyclic (i.e. 6- or 7-
membered rings) di-substituted enamides 1d‒i bearing various
electron-withdrawing N-protecting groups were also good
substrates in this reaction and led to the desired alkylated
products 3d‒i with moderate to good yields. It is worth noting
that no alkylated product was observed in the case of the
corresponding ene-sulfonamide.19 The alkylation of 3j bearing
an ester group at the C-2 position, which could serve as a
valuable synthetic intermediate was tolerated. Furthermore,
the reaction turned out to be compatible with other functional
groups such as a hydroxyl group (3k), which was amenable to
Scheme 2
Reaction conditions: Argon-free oxygen atmosphere, enamide
xanthate 2a (2 equiv.), DLP (1.2 equiv.), AcOEt, heating under reflux for 4h30.
brsm: based on recovered starting material.
.

-C(sp2)-H Alkylation of diverse enamides 1a-q using xanthate 2a.
1
(1 equiv., 0.33 ),
M
further useful transformations. Notably, the vinylogous
-
To ascertain the scope of this reaction, various xanthates 2b
‒
alkylester enamide 3l and pyridones 3m were isolated in
‒
n
f
(Scheme 3) were prepared by substitution of the
moderate yields accompanied, in the case of 3m, with
unreacted starting material. It is noteworthy that functionalized
pyridones are useful partners in Diels-Alder cycloadditions.20
Interestingly, no chemoselectivity was observed starting from
the N-allyl enamide 1o; a xanthate transfer was indeed
additionally observed onto the allylic olefin allowing the
implementation of a potential second radical sequence (3o).
The observed low yields are due mainly to a slight degradation
corresponding halo derivative with commercially available
potassium ethyl xanthogenate.23 Remarkably, a variety of
electron-deficient primary and secondary alkyl groups
successfully underwent this transformation to give a range of
new substituted acyclic enamides 3ab‒af bearing an -ester or

-nitrile function in moderate to good yields (39‒72%).
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With the objective of increasing the molecular diversity, and
based on the proposed mechanism depicted in Figure 2, we next
envisaged that a nucleophile introduced into the reaction
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DOI: 10.1039/D0NJ01209B
mixture could be trapped by the iminium species of type
D
(Figure 2), leading to enamides in good yields. Intra- and
5
intermolecular processes can be envisioned (Scheme 4, (a) and
(b)). The tandem difunctionalization of enamides involving the
simultaneous formation of C(sp3)‒C(sp3) and C‒O or C‒CN
bonds has proven to be a powerful tool for the synthesis of
various motifs.24,25a Firstly, starting from 5- or 7-membered
exocyclic enamides 1a‒b and through a sequential one-pot
reaction, 10 equivalents of ethanol or phenol were used to
intermolecularly trap the iminium ion intermediate leading to
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5a‒h in good yields. In addition to this oxyalkylation reaction,
cyanoalkylation was observed using TMSCN as the
nucleophile.25
Scheme 3. Alkylation reactions of enamide 1a with diverse xanthates 2b-f
.
Reaction conditions: Argon-free oxygen atmosphere, enamide 1a (1 equiv., 0.33
M
), xanthate 2b‒f (2 equiv.), DLP (1.2 equiv.), AcOEt, heating under reflux for 4h30.
A large array of transformations can thus be envisaged to
introduce further diversity and complexity into the structures.
Starting from the enamide 1s bearing a chain with a pendant
dimethoxyphenyl group as the nucleophile, spontaneous
cyclization occurred, leading directly to the new tricyclic
enamide 5i with an overall yield of 30% for the three-step
sequence. As the limiting step is the intramolecular addition of
the nucleophilic aryl moiety onto the iminium ion intermediate,
conducting the reaction in the absence of ethanol resulted in
the degradation of the reaction mixture. Additionally, a two-
step sequence can be achieved by taking advantage of the
iminium ion intermediate reactivity in acidic media (Scheme 4,
(c)) from 4r allowing the formation of the original tricyclic and
diversely substituted morpholine derivative 5j. The compound
5j was isolated as a unique trans diastereoisomer; The relative
stereochemistry was unambiguously confirmed by X-ray
Scheme 4. (a) and (b) Difunctionalization of enamide 1a or 1b with xanthate 2a or
2b in presence of nucleophiles. Reaction conditions: Argon-free oxygen
atmosphere, enamide1a or 1b (1 equiv., 0.33 M), xanthate 2a or 2b (2 equiv.), DLP
(1.2 equiv.), related nucleophile (10 equiv.), AcOEt, heating under reflux for 4h30
to 18h. (c) Cyclization of 4r to 5j in presence of trifluoroacetic acid. Ortep view of
the crystal structure 5j (CCDC NUKBAZ). Displacement ellipsoids are drawn at the
30% probability level and hydrogen atoms with an arbitrary radius size. (d)
Reduction of the -amino-,-unsaturated ester 3h to the primary alcohol 6.
Conclusions
In summary, we have developed a mild, simple and efficient
access to the -amino- -unsaturated acyl scaffold by applying
crystallography.26 Furthermore, the
enamide 3h was reduced with good yields in the corresponding
primary alcohol in presence of LiAlH4. This approach thus
-ester function in the

,
xanthate chemistry to enamide. This original reaction is totally
regioselective and exhibits broad substrate scope, good
functional group tolerance and thus demonstrates its potent
application in the synthesis of versatile N-containing building
blocks. The large availability of xanthates is advantageous to the
scope of the reaction which combines a radical process and a
6
illustrated the potential of this strategy to provide access to a
wide range of nitrogen containing heterocycles decorated with
various functional groups.
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polar reaction. Further applications based on this chemistry are h under argon atmosphere. After cooling to rt (ca. 20 °C), the
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in progress in our laboratory.
solvent was concentrated under reducedDpOrIe: s1s0u.1r0e3.9T/Dh0eNrJe0s1i2d0u9eB
was taken up in dichloromethane and dry silica was added
(approximately 10 times the mass of the sample). The solvents
were evaporated in vacuo until the silica is dry and free-flowing
and the coated support was packed on top of a silica gel column.
The crude product was purified (SiO2) to give the desired
monoalkylated enamide derivative in moderate to good yield.
Experimental
General information
Unless otherwise noted, all reagents and solvents were
purchased from commercial sources and used as received. All
manipulations were conducted under argon. The reactions
were monitored by thin-layer chromatography (TLC) using silica
gel (60 F254) plates. Compounds were visualized using a UV
lamp (254 nm) and/or by potassium permanganate stain. Flash
column chromatography was carried out on silica gel 60 (230-
400 mesh, 0.040-0.063 mm). Melting points (mp [°C]) were
taken on samples in open capillary tubes and are uncorrected.
The infrared spectra of compounds were recorded on a Thermo
Scientific Nicolet iS10. 1H, 13C and 19F NMR spectra were
recorded on a spectrometer at 250 MHz (13C, 62.9 MHz) or 400
MHz (13C, 100 MHz; 19F: 376 MHz CPD). High-resolution accurate
mass measurements (HRAM) were recorded with a Maxis
Bruker 4G instrument and were performed in positive mode
with an ESI source on a Q-TOF mass spectrometer with an
accuracy tolerance of 2 ppm by the “Fédération de Recherche”
ICOA/CBM (FR2708) platform.
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General Procedure for the Radical Difunctionalisation of
Enamides With Xanthates in Presence of a Nucleophile (G.P.
C). An oven-dried 2‒5 mL microwave vial under argon
atmosphere was charged with the enamide substrate (1.0
equiv., 0.33 M), related xanthate derivative (2.0 equiv., 0.66 M),
ethyl acetate and a magnetic stir bar. The solution was degassed
3 times (vacuum/argon cycles), the reaction vessel was capped
and it was placed in a pre-heated oil bath for 5 min at 90 °C.
Next, the vial was uncapped and DLP (1.2 equiv.) followed by
corresponding nucleophile (10 equiv.) were added. The vessel
was sealed and the reaction mixture was heated at 78 °C for 4.5
h under argon atmosphere. After cooling to rt (ca. 20 °C), the
solvent was concentrated under reduced pressure. The residue
was taken up in dichloromethane and dry silica was added
(approximately 10 times the mass of the sample). The solvents
were evaporated in vacuo until the silica is dry and free-flowing
and the coated support was packed on top of a silica gel column.
The crude product was purified (SiO2) to give the desired
dialkylated enamide compound in moderate to good yield.
General Procedure for the Synthesis of Enamides 1d‒i, 1k, 1l
and 1o‒1q (G.P. A). An oven-dried single-necked round-
bottomed flask under argon atmosphere was charged with dry
toluene, the related imide
stir bar. The reaction vessel was cooled to ‒78 °C (dry
ice/acetone bath) and a 1 solution of LiEt3BH in THF (1.1
equiv.) was then added dropwise. The mixture was stirred
further at ‒78 °C for 1 h. Next, N,N-Diisopropylethylamine
1 (1.0 equiv., 0.49 M) and a magnetic
General procedure D (G.P. D). Alternatively, after solvent
concentration in G.P. B and G.P. C, addition of cold acetonitrile
could be performed at 0 °C, leaving decomposition products
from DLP undissolved. The precipitate was filtered through a
sintered glass Büchner funnel and the mother liquor was
recovered. Then, the acetonitrile was removed by rotary
evaporation and the product residue was purified further by
flash SiO2‒column chromatography.
M
(DIPEA, 5.7 equiv.) and
a
catalytic amount of 4-
Dimethylaminopyridine (DMAP, 0.03 equiv.) were added,
followed by the dropwise addition of Trifluoroacetic anhydride
(TFAA, 1.2 equiv.) and the reaction mixture was allowed to
warm up to room temperature (ca. 20 °C). The mixture was
stirred for 3 h at the same temperature and it was quenched by
the addition of water. The aqueous phase was then extracted
twice with EtOAc, combined organic phases were washed (sat.
aq. NaCl), dried over MgSO4 and filtered through a cotton plug.
The solvents were evaporated under reduced pressure and the
resulting crude enamide derivative was purified by column
chromatography (SiO2).
4-(3,4-Dimethoxyphenethyl)-1,4-oxazin-3-one (1q). The titled
compound was obtained following G.P. A. Purification by flash
chromatography using petroleum ether/EtOAc (8:2, v/v) gave
1q as a yellow oil (632.0 mg, 48%). Rf 0.1 (SiO2, petroleum
1
ether/EtOAc 8:2, v/v). M.p. < 40 °C. H NMR (400 MHz, CDCl3):
δ 6.80 (d, J = 8.0 Hz, 1 H, HAr), 6.77–6.70 (po, 2 H, HAr), 6.11 (d, J
= 4.3 Hz, 1 H, H-6), 5.46 (d, J = 4.3 Hz, 1 H, H-5), 4.39 (s, 2 H, H-
2), 3.87 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3), 3.68 (t, J = 7.4 Hz, 2
H, NCH2), 2.83 (t, J = 7.4 Hz, 2 H, NCH2CH2) ppm. 13C NMR (101
MHz, CDCl3): δ 162.5 (C, C-3), 149.1 (C, CAr), 147.9 (C, CAr), 130.7
(C, CAr), 130.5 (CH, C-6), 120.9 (CH, CHAr), 112.2 (CH, CHAr), 111.5
(CH, CHAr), 111.0 (CH, C-5), 67.7 (CH2, C-2), 56.0 (CH3, OCH3),
56.0 (CH3, OCH3), 47.3 (CH2, NCH2), 34.1 (CH2, NCH2CH2) ppm.
HRMS (ESI): m/z calcd. for C14H18NO4 [M + H]+ 264.123034,
found 264.123098.
General Procedure for the Direct Oxidative Radical β-C(sp2)‒H
Monoalkylation of Enamides (G.P. B). An oven-dried 2‒5 mL
microwave vial under argon atmosphere was charged with the
enamide substrate (1.0 equiv., 0.33
corresponding xanthate (2.0 equiv., 0.66
M
), ethyl acetate,
M
) and a magnetic stir
bar. The solution was degassed 3 times (vacuum/argon cycles),
the reaction vessel was capped and it was placed in a pre-
heated oil bath for 5 min at 90 °C. Next, the vial was uncapped
and dilauroyl peroxide (DLP, 1.2 equiv.) was added. The vessel
was sealed and the reaction mixture was heated at 78 °C for 4.5
Ethyl (E)-4-(2-oxopyrrolidin-1-yl)but-3-enoate (3a). According
to G.P. B, the reaction was performed with enamide 1a (56 mg,
0.50 mmol), ethyl 2-ethoxycarbothioylsulfanylacetate (210 mg,
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1.0 mmol), DLP (239 mg, 0.60 mmol) and EtOAc (1.5 mL). The CHAr maj.), 61.3 (CH2, OCH2CH3 min.), 61.2 (CH2, OCH2CH3 maj.),
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crude product was purified by column chromatography (SiO2, 39.3 (CH2, C-2 maj.), 38.5 (CH2, C-2 min.)D, 2O8I:.160.(1C0H392/,DC0-N3J’0m12a0j9.)B,
petroleum ether/EtOAc 75:25 to 70:30, v/v) to afford 3a as a 28.2 (CH2, C-3’ min.), 27.7 (CH2, C-4’ maj.), 27.5 (CH2, C-4’ min.),
colourless oil (61 mg, 62%). Rf 0.2 (SiO2, petroleum ether/EtOAc 23.4 (CH3, CH3CO maj.), 20.3 (CH3, CH3CO min.), 14.3 (CH3,
5:5, v/v). 1H NMR (400 MHz, CDCl3/TMS): δ 6.97 (d, J = 14.6 Hz, OCH2CH3 maj. + OCH2CH3 min.) ppm. IR (neat): ṽ = 3244 (N‒H),
1 H, H-4), 5.03 (dt, J = 14.6, 7.3 Hz, 1 H, H-3), 4.15 (q, J = 7.1 Hz, 1725 (C=O), 1641 (C=O) cm‒1. HRMS (ESI): m/z calcd. for
2 H, OCH2CH3), 3.54 (t, J = 7.2 Hz, 2 H, H-5’), 3.10 (d, J = 7.3 Hz, C16H20NO3 [M + H]+ 274.143770 found, 274.143607.
2 H, H-2), 2.48 (t, J = 8.1 Hz, 2 H, H-3’), 2.18–2.04 (m, 2 H, H-4’),
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1.27 (t, J = 7.1 Hz, 3 H, OCH2CH3) ppm. 13C NMR (101 MHz, Ethyl 2-(1-benzyl-2-oxo-3,4-dihydropyridin-3-yl)acetate (3d)
CDCl3): δ 173.2 (C, CO), 172.1 (C, CO), 126.6 (CH, C-4), 103.6 (CH, According to G.P. B, the reaction was performed with enamide
C-3), 60.9 (CH2, OCH2CH3), 45.3 (CH2, C-5’), 35.7 (CH2, C-2), 31.3 1d (94 mg, 0.50 mmol), ethyl 2-
.
(CH2, C-3’), 17.6 (CH2, C-4’), 14.3 (OCH2CH3) ppm. IR (neat): ṽ = ethoxycarbothioylsulfanylacetate (210 mg, 1.0 mmol), DLP (239
1728 (C=O), 1653 (C=O) cm‒1. HRMS (ESI): m/z calcd. for mg, 0.60 mmol) and EtOAc (1.5 mL). The crude product was
C10H16NO3 [M + H]+ 198.112470, found 198.112227.
purified by column chromatography (SiO2, petroleum
ether/EtOAc 85:15 to 80:20, v/v) to give 3d as a colourless oil
Ethyl (E)-4-(2-oxoazepan-1-yl)but-3-enoate (3b). According to (98 mg, 72%). Rf 0.1 (SiO2, petroleum ether/EtOAc 75:25, v/v).
G.P. B, the reaction was performed with enamide 1b (70 mg, 1H NMR (400 MHz, CDCl3/TMS): δ 7.37–7.09 (po, 5 H, HAr), 5.97–
0.50 mmol), ethyl 2-ethoxycarbothioylsulfanylacetate (210 mg, 5.88 (m, 1 H, H-6’), 4.67 (s, 2 H, CH2Ph), 4.13 (q, J = 7.1 Hz, 2 H,
1.0 mmol), DLP (239 mg, 0.60 mmol) and EtOAc (1.5 mL). The OCH2), 2.99 (s, 2 H, H-2), 2.62 (dd, J = 8.8, 7.2 Hz, 2 H, H-3’), 2.38
crude product was purified by column chromatography (SiO2, (t, J = 8.1 Hz, 2 H, H-4’), 1.24 (t, J = 7.1 Hz, 3 H, OCH2CH3) ppm.
petroleum ether/EtOAc 85:15 to 75:25, v/v) to afford 3b as a 13C NMR (101 MHz, CDCl3/TMS): δ 171.0 (C, C-1), 168.9 (CH2, C-
colourless oil (80 mg, 71%). Rf 0.14 (SiO2, petroleum 2’), 137.0 (C, CAr), 128.6 (CH, CHAr), 127.5 (CH, CHAr), 127.4 (CH,
ether/EtOAc 75:25, v/v). 1H NMR (400 MHz, CDCl3/TMS): δ 7.24 CHAr), 127.2 (CH, C-6’), 112.9 (C, C-5’), 60.7 (CH2, OCH2), 48.8
(d, J = 14.6 Hz, 1 H, H-4), 5.13 (dt, J = 14.6, 7.2 Hz, 1 H, H-3), 4.14 (CH2, NCH2Ph), 39.0 (CH2, C-2), 31.0 (CH2, C-3’), 24.2 (CH2, C-4’),
(q, J = 7.1 Hz, 2 H, OCH2CH3), 3.63–3.56 (m, 2 H, H-7’), 3.10 (dd, 14.1 (CH3, OCH2CH3) ppm. IR (neat): ṽ = 2926 (C-H), 1732 (C=O),
J = 7.2, 1.2 Hz, 2 H, H-2), 2.65–2.58 (m, 2 H, H-3’), 1.79–1.60 (po, 1643 (C=O), 1563 (C=C) cm‒1. HRMS (ESI): m/z calcd. for
6 H, H-6’ + H-5’ + H-4’), 1.26 (t, J = 7.1 Hz, 3 H, OCH2CH3) ppm. C16H20NO3 [M + H]+ 274.143770, found 274.143849.
13C NMR (101 MHz, CDCl3): δ 174.3 (C, CO), 172.4 (C, CO), 129.6
(CH, C-4), 102.4 (CH, C-3), 60.8 (CH2, OCH2CH3), 45.5 (CH2, C-7’), Ethyl
2-[1-[(4-methoxyphenyl)methyl]-2-oxo-3,4-
37.2 (CH2, C-3’), 35.8 (CH2, C-2), 29.5 (CH2, C-6’), 27.4 (CH2, C- dihydropyridin-5-yl]acetate (3e). According to G.P. B, the
5’), 23.5 (CH2, C-4’), 14.3 (CH3, OCH2CH3) ppm. IR (neat): ṽ = 1690 reaction was performed with enamide 1e (109 mg, 0.50 mmol),
(C=O), 1652 (C=O) cm‒1. HRMS (ESI): m/z calcd. for C12H20NO3 ethyl 2-ethoxycarbothioylsulfanylacetate (210 mg, 1.0 mmol),
[M + H]+ 226.143770 found, 226.143888.
DLP (239 mg, 0.60 mmol) and EtOAc (1.5 mL). The crude product
was purified by column chromatography (SiO2, petroleum
Ethyl
(3c). Compound 3c was prepared according to G.P. B, using (77 mg, 51%). Rf 0.14 (SiO2, petroleum ether/EtOAc 75:25, v/v).
enamide 1c (94 mg, 0.50 mmol), ethyl
2- 1H NMR (400 MHz, CDCl3): δ 7.17 (d, J = 8.7 Hz, 2 H, HAr), 6.85
2-(1-acetamido-3,4-dihydronaphthalen-2-yl)acetate ether/EtOAc 85:15 to 75:25, v/v) to afford 3e as a colourless oil
ethoxycarbothioylsulfanylacetate (210 mg, 1.0 mmol), DLP (239 (d, J = 8.7 Hz, 2 H, HAr), 5.92 (s, 1 H, H-6’), 4.60 (s, 2 H, NCH2Ph),
mg, 0.60 mmol) and EtOAc (1.5 mL). The crude product was 4.13 (q, J = 7.1 Hz, 2 H, OCH2CH3), 3.79 (s, 3 H, OCH3), 2.98 (s, 2
purified by passage though SiO2‒column chromatography H, H-2), 2.60 (t, J = 8.0 Hz, 2 H, H-3’), 2.36 (t, J = 8.1 Hz, 2 H, H-
(petroleum ether/EtOAc 70/30 to 50/50 v/v) and was obtained 4’), 1.24 (t, J = 7.1 Hz, 3 H, OCH2CH3) ppm. 13C NMR (101 MHz,
in moderate yield (87 mg, 64%) as a mixture of rotamers (ca. CDCl3/TMS): δ 171.1 (C, CO), 168.8 (C, CO), 159.0 (C, CAr), 129.2
65:35). Rf 0.16 (SiO2, petroleum ether/EtOAc 5:5, v/v). M.p. (C, CAr), 129.1 (CH, CHAr), 127.1 (CH, C-6’), 114.0 (CH, CHAr),
107‒109 °C. 1H NMR (400 MHz, CDCl3): δ 7.25–7.06 (po, 4 H, HAr 112.7 (C, C-5’), 60.8 (CH2, OCH2CH3), 55.2 (CH3, OCH3), 48.3 (CH2,
maj. + HAr min.), 6.71 (s, 0.35 H, NH min.), 4.16 (po, 2 H, OCH2CH3 NCH2), 39.1 (CH2, C-2), 31.1 (CH2, C-3’), 24.3 (CH2, C-4’), 14.2
min. + OCH2CH3 maj.), 3.36 (s, 0.75 H, H-2 min.), 3.27 (s, 1.25 H, (CH3, OCH2CH3) ppm. IR (neat): ṽ = 1724 (C=O), 1659 (C=O) cm‒
H-2 maj.), 2.85 (t, J = 8.0 Hz, 2 H, H-3’ maj. + H-3’ min. or H-4’ 1. HRMS (ESI): m/z calcd. for C17H22NO4 [M + H]+ 304.154335,
maj. + H-4’ min.), 2.46 (t, J = 8.0 Hz, 2 H, H-4’ maj. + H-4’ min. or found 304.154465.
H-3’ maj. + H-3’ min.), 2.20 (s, 1.87 H, CH3CO maj.), 1.83 (s, 1.13
H, CH3COmin.), 1.27 (t, J = 7.1 Hz, 3 H, OCH2CH3 maj. + OCH2CH3 Ethyl 2-[1-(2-ethoxy-2-oxoethyl)-2-oxo-3,4-dihydropyridin-5-
min.) ppm. 13C NMR (101 MHz, CDCl3): δ 174.0 (C, CO min.), yl]acetate (3f). The titled compound was synthesized according
171.5 (C, CO maj.), 170.4 (C, CO min.), 169.3 (C, CO maj.), 135.8 to G.P. B, using enamide 1f (92 mg, 0.50 mmol), ethyl 2-
(C, CAr min.), 135.7 (C, CAr maj.), 133.1 (C, CIV min.), 132.2 (C, CIV ethoxycarbothioylsulfanylacetate (210 mg, 1.0 mmol), DLP (239
maj.), 131.7 (C, CIV min.), 131.0 (C, CIV min.), 130.2 (C, CIV maj.), mg, 0.60 mmol) and EtOAc (1.5 mL). The crude product was
129.2 (C, CIV min.), 128.0 (CH, CHAr min.), 127.7 (CH, CHAr min.), purified by column chromatography (SiO2, petroleum
127.6 (CH, CHAr maj.), 127.5 (CH, CHAr maj.), 127.0 (CH, CHAr ether/EtOAc 80:20 to 70:30 v/v) to provide 3f as a colourless oil
min.), 126.6 (CH, CHAr maj.), 122.7 (CH, CHAr min.), 122.6 (CH, (82 mg, 61%). Rf 0.07 (SiO2, petroleum ether/EtOAc 75:25, v/v).
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1H NMR (400 MHz, CDCl3): δ 5.91 (s, 1 H, H-6’), 4.25–4.10 (po, 6 maj.), 121.6 (CH, CHAr min.), 113.4 (C, C-5 min.), V1ie1w2A.8rtic(leCO, nCli-n5e
H, CH2N + 2 × OCH2CH3), 3.03 (s, 2 H, H-2), 2.65–2.55 (m, 2 H, H- maj.), 60.7 (CH2, OCH2CH3 maj.), 60.6 (CHD2,OOI:C10H.120C3H93/Dm0iNnJ.0),124029.B4
3’), 2.39 (t, J = 7.9 Hz, 2 H, H-4’), 1.26 (t, J = 7.2 Hz, 3 H, OCH2CH3), (CH2, C-2 min.), 41.9
1.25 (t, J = 7.2 Hz, 3 H, OCH2CH3) ppm. 13C NMR (101 MHz, (CH2, C-1’ min.), 25.3 (CH2, C-4 maj.), 25.0
CDCl3): δ 171.1 (C, CO), 169.3 (C, CO), 168.8 (C, CO), 127.9 (CH, (CH2, C-3 min.), 21.4 CH2, C-3 maj.), 14.2 (CH3, OCH2CH3 maj. +
(CH2, C-2 maj.), 40.8 (CH2, C-1’ maj.), 40.7
(CH2, C-4 min.), 21.6
(
C-6’), 113.0 (C, C-5’), 61.5 (CH2, OCH2CH3), 61.0 (CH2, OCH2CH3), OCH2CH3 min.) ppm. IR (neat): ṽ = 1716 (C=O), 1674 (C=O) cm‒1.
47.4 (CH2, NCH2), 39.2 (CH2, C-2), 30.8 (CH2, C-3’), 24.3 (CH2, C- HRMS (ESI): m/z calcd. for C16H20NO4 [M + H]+ 290.138685
4’), 14.3 (CH3, OCH2CH3), 14.2 (CH3, OCH2CH3) ppm. IR (neat): ṽ found, 290.138613.
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= 1732 (C=O), 1672 (C=O) cm‒1. HRMS (ESI): m/z calcd. for
C13H20NO5 [M + H]+ 270.133599 found, 270.133791.
tert-Butyl 6-(2-ethoxy-2-oxoethyl)-2,3,4,5-tetrahydroazepine-
1-carboxylate (3i). The titled compound was synthesized
tert-Butyl 5-(2-ethoxy-2-oxoethyl)-3,4-dihydro-2H-pyridine-1- according to G.P. B, using enamide 1i (198 mg, 1.0 mmol), ethyl
carboxylate (3g). According to G.P. B, the reaction was 2-ethoxycarbothioylsulfanylacetate (420 mg, 2.0 mmol), DLP
performed with enamide 1g (93 mg, 0.51 mmol), ethyl 2- (478 mg, 1.2 mmol) and EtOAc (3.0 mL). The crude product was
ethoxycarbothioylsulfanylacetate (210 mg, 1.0 mmol), DLP (239 purified by column chromatography (SiO2, petroleum
mg, 0.60 mmol) and EtOAc (1.5 mL). The crude product was ether/EtOAc 97:3 to 95:5 v/v) to give 3i as a colourless oil (173
purified by column chromatography (SiO2, petroleum mg, 61%). Mixture of rotamers ca. 6:4. Rf 0.3 (SiO2, petroleum
ether/EtOAc 98:2 to 97:3, v/v) to afford 3g as a colourless oil (88 ether/EtOAc 85:15, v/v). 1H NMR (400 MHz, CDCl3): δ 6.50 (br s,
mg, 64%). Mixture of rotamers ca. 6:4. Rf 0.6 (SiO2, petroleum 0.4 H, H-7 min.), 6.37 (br s, 0.6 H, H-7 maj.), 4.14 (q, J = 7.1 Hz,
ether/EtOAc 75:25, v/v). 1H NMR (400 MHz, CDCl3/TMS): δ 6.80 2 H, OCH2CH3 maj. + OCH2CH3 min.), 3.68–3.59 (br m, 2 H, H-2
(br s, 0.4 H, H-6 min.), 6.65 (br s, 0.6 H, H-6 maj.) 4.23–4.06 (m, maj. + H-2 min.), 2.97 (br s, 2 H, H-1’ maj. + H-1’ min.), 2.31–2.18
2 H, CH2, OCH2CH3 maj. + OCH2CH3 min.), 3.58–3.43 (m, 2 H, H- (br m, 2 H, H-5 maj. + H-5 min.), 1.84–1.67 (po, 4 H, H-3 maj. +
2 maj. + H-2 min.), 2.95 (s, 2 H, H-1’ maj. + H-1’ min.), 2.04 (t, J H-4 maj. + H-3 min. + H-4 min.), 1.47 (s, 9 H, C(CH3)3 maj. +
= 6.1 Hz, 2 H, H-4 maj. + H-4 min.), 1.88–1.77 (m, 2 H, H-3 maj. C(CH3)3 min.), 1.26 (t, J = 7.1 Hz, 3 H, OCH2CH3 maj. + OCH2CH3
+ H-3 min.), 1.46 (s, 9 H, C(CH3)3 maj. + C(CH3)3 min.), 1.33–1.21 min.) ppm. 13C NMR (101 MHz, CDCl3): δ 172.1 (C, C-2’ maj. + C-
(m, 3 H, OCH2CH3 maj. + OCH2CH3 min.) ppm. 13C NMR (101 2’ min.), 153.8 (C, NCO maj. + NCO min.), 129.9 (CH, C-7 maj. +
MHz, CDCl3): δ 172.0 (C, C-2’ maj. + C-2’ min.), 152.8 (C, NCO C-7 min.), 121.0 (C, C-6 maj. + C-6 min.), 80.5 (C, C(CH3)3 maj. +
min.), 152.3 (C, NCO maj.), 124.1 (CH, C-6 maj.), 123.8 (CH, C-6 C(CH3)3 min.), 60.7 (CH2, OCH2CH3 maj. + CH2, OCH2CH3 min.),
min.), 111.1 (C, C-5 min.), 110.5 (C, C-5 maj.), 80.8 (C, C(CH3)3 47.9 (CH2, C-2 min.), 47.0 (CH2, C-2 maj.), 42.9 (C, C-1’ maj. + C-
maj.), 80.6(C, C(CH3)3 min.), 60.7 (CH2, OCH2CH3 maj.), 60.6 (CH2, 1’ min.), 31.0 (CH2, C-5 maj.), 30.7 (CH2, C-5 min.), 28.2 (CH3,
OCH2CH3 min.), 42.1 (CH2, C-2 min.), 41.1 (CH2, C-1’ min.), 41.0 C(CH3)3 maj. + C(CH3)3 min.), 28.1 (CH2, C-3 maj. + C-3 min.), 24.3
(CH2, C-2 maj.), 41.0 (CH2, C-1’ maj.), 28.4 (CH3, C(CH3)3 maj. + (CH2, C-4 maj. + C-4 min.), 14.4 (CH3, OCH2CH3 maj. + OCH2CH3
C(CH3)3 min.), 25.4 (CH2, C-4 maj.), 25.2 (CH2, C-4 min.), 21.8 min.) ppm. IR (neat): ṽ = 1762 (C=O), 1682 (C=O) cm‒1. HRMS
(CH2, C-3 min.), 21.6 (CH2, C-3 maj.), 14.3 (CH3, OCH2CH3 maj. + (ESI): m/z calcd. for C15H26NO4 [M + H]+ 284.185635 found,
OCH2CH3 min.) ppm. HRMS (ESI): m/z calcd. for C14H24NO4 [M + 284.185824.
H]+ 270.169985 found, 270.170411.
1-O-tert-Butyl
5-(2-ethoxy-2-oxoethyl)-3,4-dihydro-2H-pyridine-1- dihydro-2H-pyridine-1,6-dicarboxylate (3j)
carboxylate (3h). The reaction was performed according to G.P. compound was synthesized according to G.P. B, using enamide
using enamide 1h (102 mg, 0.50 mmol), ethyl 2- 1j (121 mg, 0.50 mmol), ethyl 2-
6-O-methyl
5-(2-ethoxy-2-oxoethyl)-3,4-
Phenyl
.
The titled
B,
ethoxycarbothioylsulfanylacetate (210 mg, 1.0 mmol), DLP (239 ethoxycarbothioylsulfanylacetate (210 mg, 1.0 mmol), DLP (239
mg, 0.60 mmol) and EtOAc (1.5 mL). The crude titled product mg, 0.60 mmol) and EtOAc (1.5 mL). The crude product was
was purified by column chromatography (SiO2, petroleum purified by column chromatography (SiO2, petroleum
ether/EtOAc 95:5 to 90:10 v/v) to afford 3h as a colourless oil ether/EtOAc 93:7 to 95:5 v/v) to give 3j as a colourless oil (41
(82 mg, 57%). Mixture of rotamers ca. 6:4. Rf 0.2 (SiO2, mg, 25%). Rf 0.17 (SiO2, petroleum ether/EtOAc 85:15, v/v). 1H
1
petroleum ether/EtOAc 85:15, v/v). H NMR (400 MHz, CDCl3): NMR (400 MHz, CDCl3): δ 4.14 (q, J = 7.1 Hz, 2 H, OCH2CH3), 3.75
δ 7.36 (br t, J = 7.7 Hz, 2 H, HAr), 7.21 (t, J = 7.4 Hz, 1 H, HAr), 7.12 (s, 3 H, OCH3), 3.60–3.50 (m, 2 H, H-2), 3.32 (s, 2 H, H-1’), 2.23
(d, J = 7.7 Hz, 2 H, HAr), 6.94 (br s, 0.6 H, H-6 maj.), 6.87 (br s, 0.4 (t, J = 6.7 Hz, 2 H, H-4), 1.86–1.79 (m, 2 H, H-3), 1.43 (s, 9 H,
H, H-6 min.), 4.17 (m, 2 H, OCH2CH3 maj. + OCH2CH3 min.), 3.81– C(CH3)3), 1.24 (t, J = 7.1 Hz, 3 H, OCH2CH3) ppm. IR (neat): ṽ =
3.74 (m, 0.8 H, H-2 min.), 3.71–3.64 (m, 1.2 H, H-2 maj.), 3.03 (s, 1731 (C=O), 1702 (C=O) cm‒1. HRMS (ESI): m/z calcd. for
2 H, H-1’ maj. + H-1’ min.), 2.15 (t, J = 6.1 Hz, 2 H, H-4 maj. + H- C16H26NO6 [M + H]+ 328.175464 found, 328.176091.
4 min.), 1.99–1.88 (m, 2 H, H-3 maj. + H-3 min.), 1.30–1.21 (m,
3 H, OCH2CH3 maj. + OCH2CH3 min.) ppm. 13C NMR (101 MHz, (rac)-Phenyl 5-(2-ethoxy-2-oxoethyl)-3-hydroxy-3,4-dihydro-
CDCl3): δ 171.5 (C, C-2’ maj.), 171.6 (C, C-2’ min.), 152.0 (C, NCO 2H-pyridine-1-carboxylate (3k). Compound 3k was prepared
min.), 151.5 (C, NCO maj.), 151.1 (C, CAr maj.), 151.0 (C, CAr min.), according to G.P. B, using enamide 1k (110 mg, 0.50 mmol),
129.3 (CH, CHAr maj. + CHAr min.), 125.5 (CH, CHAr maj. + CHAr ethyl 2-ethoxycarbothioylsulfanylacetate (210 mg, 1.0 mmol),
min.), 123.5 (CH, C-6 min.), 123.2 (CH, C-6 maj.), 121.7 (CH, CHAr DLP (239 mg, 0.60 mmol) and EtOAc (1.5 mL). The crude product
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was purified by column chromatography (SiO2, petroleum colourless oil (83 mg, 61%, (88% brsm)). Rf 0.4 (SiO2, petroleum
View Article Online
DOI: 10.1039/D0NJ01209B
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ether/EtOAc 85/15 to 75/25 v/v) to provide 3k as a colourless ether/EtOAc 5:5, v/v). H NMR (400 MHz, CDCl3/TMS): δ 7.36–
oil (63 mg, 41%) and a mixture of rotamers (ca. 55:45). Rf 0.2 7.26 (po, 6 H, HAr + H-6’), 7.22 (dd, J = 6.8, 2.0 Hz, 1 H, H-4’), 6.13
(SiO2, petroleum ether/EtOAc 6:4, v/v). 1H NMR (400 MHz, (t, J = 6.8 Hz, 1 H, H-5’), 5.15 (s, 2 H, NCH2Ph), 4.18 (q, J = 7.1 Hz,
CDCl3): δ 7.41–7.33 (m, 2 H, HAr maj. + HAr min.), 7.25–7.20 (m, 2 H, OCH2CH3), 3.56 (s, 2 H, H-2), 1.26 (t, J = 7.1 Hz, 3 H,
1 H, HAr maj. + HAr min.), 7.16–7.10 (m, 2 H, HAr maj. + HAr min.), OCH2CH3) ppm. 13C NMR (101 MHz, CDCl3): δ 171.3 (C, C-1),
6.99 (br s, 0.55 H, H-6 maj.), 6.93 (br s, 0.45 H, H-6 min.), 4.27 162.3 (C, C-2’), 138.4 (CH, C-6’), 136.5 (C, CAr), 136.2 (CH, C-4’),
(br s, 1 H, H-3 maj. + H-3 min.), 4.21–4.11 (m, 2 H, OCH2CH3 maj. 129.0 (CH, CHAr), 128.3 (CH, CHAr), 128.1 (CH, CHAr), 126.9 (C, C-
+ OCH2CH3 min.), 3.95 (dd, J = 12.7, 4.1 Hz, 0.45 H, H-2a min.), 3’), 105.9 (CH, C-5’), 61.0 (CH2, OCH2CH3), 52.4 (CH2, NCH2Ph),
3.81 (dd, J = 12.7, 4.8 Hz, 0.55 H, H-2a maj.), 3.63 (br d, J = 12.5 36.5 (CH2, C-2), 14.3 (CH3, OCH2CH3) ppm. IR (neat): ṽ = 1730
Hz, 0.45 H, H-2b min.), 3.56 (br d, J = 12.7 Hz, 0.55 H, H-2b maj.), (C=O), 1651 (C=O) cm‒1. HRMS (ESI): m/z calcd. for C16H18NO3
3.06 (s, 2 H, H-1’ maj. + H-1’ min.), 2.48 (br dd, J = 17.0, 4.0 Hz, [M + H]+ 272.128120 found, 272.128007.
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1 H, H-4a maj. + H-4a min.), 2.41 (br s, 0.45 H, OH min.), 2.30 (br
s, 0.55 H, OH maj.), 2.22–2.13 (m, 1 H, H-4b maj. + H-4b min.), Ethyl
2-(1-benzyl-4-methoxy-6-methyl-2-oxo-3-
1.28 (td, J = 7.2, 2.4 Hz, 3 H OCH2CH3 maj. + OCH2CH3 min.) ppm. pyridyl)acetate (3n). Compound 3n was prepared according to
13C NMR (101 MHz, CDCl3): δ 171.9 (C, C-2’ maj.), 171.8 (C, C-2’ G.P. B, using pyridone 1n (150 mg, 0.654 mmol), ethyl 2-
min.), 152.7 (C, NCO maj.), 152.1 (C, NCO min.), 151.1 (C, CAr ethoxycarbothioylsulfanylacetate (271 mg, 1.30 mmol), DLP
maj.), 151.0 (C, CAr min.), 129.5 (CH, CHAr maj. + CHAr min.), (311 mg, 0.78 mmol) and EtOAc (2.2 mL). The crude product was
125.8 (CH, CHAr maj. + CHAr min.), 123.9 (CH, C-6 min.), 123.4 purified by column chromatography (SiO2, petroleum
(CH, C-6 maj.), 121.8 (CH, CHAr maj.), 121.5 (CH, CHAr min.), ether/EtOAc 75/25 to 40/60 v/v) to give 3n as a colourless oil
109.2 (C, C-5 maj. + C-5 min.), 63.0 (CH, C-3 maj. + C-3 min.), (80 mg, 39% (49% brsm)). Rf 0.25 (SiO2, petroleum ether/EtOAc
61.1 (CH2, OCH2CH3 maj. + OCH2CH3 min.), 48.4 (CH2, C-2 min.), 5:5, v/v). M.p. 94‒95 °C. 1H NMR (400 MHz, CDCl3/TMS): δ 7.32–
47.8 (CH2, C-2 maj.), 40.3 (CH2, C-1’ maj.), 40.1 (CH2, C-1’ min.), 7.22 (po, 3 H, HAr), 7.13 (d, J = 7.1 Hz, 2 H, HAr), 5.94 (s, 1 H, H-
33.9 (CH2, C-4 maj.), 33.7 (CH2, C-4 min.), 14.3 (CH3, OCH2CH3 5’), 5.34 (s, 2 H, NCH2Ph), 4.15 (q, J = 7.1 Hz, 2 H, OCH2CH3), 3.83
maj. + OCH2CH3 min.) ppm. IR (neat): ṽ = 1716 (C=O), 1070 (C‒ (s, 3 H, OCH3), 3.61 (s, 2 H, H-2), 2.28 (s, 3 H, CH3), 1.24 (d, J =
OH), 1563 cm‒1. HRMS (ESI): m/z calcd. for C16H20NO5 [M + H]+ 7.1 Hz, 3 H, OCH2CH3) ppm. 13C NMR (101 MHz, CDCl3): δ 171.9
306.133599 found, 306.133786.
(C, C-1), 164.1 (C, C-2’ or C-4’), 163.9 (C, C-4’ or C-2’), 146.0 (C,
C-6’)), 136.7 (C, CAr), 128.7 (CH, CHAr), 127.2 (CH, CHAr), 126.4
1-O-Benzyl 4-O-ethyl
(2E)-2-[(1-benzyl-2-oxo-3,4- (CH, CHAr), 105.1 (C, C-3’), 95.5 (C, C-5’), 60.4 (CH2, OCH2CH3),
dihydropyridin-5-yl)methylene]butanedioate (3l). Compound 55.7 (CH3, OCH3), 47.2 (CH2, NCH2Ph), 29.6 (CH2, C-2), 21.0 (CH3,
3l was synthesized according to G.P. B, using enamide 1l (348 CH3), 14.2 (CH3, OCH2CH3) ppm. IR (neat): ṽ = 2930 (C‒H), 1732
mg, 1.0 mmol), ethyl 2-ethoxycarbothioylsulfanylacetate (420 (C=O), 1672 (C=O), 1644 (C=C), 1563 cm‒1. HRMS (ESI): m/z
mg, 2.0 mmol), DLP (478 mg, 1.2 mmol) and EtOAc (3.0 mL). The calcd. for C18H22NO4 [M + H]+ 316.154335 found, 316.154606.
crude product was obtained as a single diastereomer. It was
purified by column chromatography (SiO2, petroleum Ethyl 4-ethoxycarbothioylsulfanyl-5-[5-(2-ethoxy-2-oxoethyl)-
ether/EtOAc 85/15 to 75/25 v/v) to give 3l as a colourless oil 2-oxo-3,4-dihydropyridin-1-yl]pentanoate (3o). Compound 3o
(152 mg, 35%). Rf 0.5 (SiO2, petroleum ether/EtOAc 6:4, v/v). 1H was prepared according to G.P. B, using N-allyl enamide 1o (69
NMR (400 MHz, CDCl3/TMS): δ 7.41–7.11 (po, 11 H, HAr + H-6’), mg, 0.50 mmol), ethyl 2-ethoxycarbothioylsulfanylacetate (210
6.50 (s, 1 H, C-5’‒CH), 5.18 (s, 2 H, OCH2Ph), 4.71 (s, 2 H, mg, 1.0 mmol), DLP (239 mg, 0.60 mmol) and EtOAc (1.5 mL).
NCH2Ph), 4.08 (q, J = 7.1 Hz, 2 H, OCH2CH3), 3.46 (s, 2 H, H-3), The crude product was purified by passage though SiO2‒column
2.64 (s, 4 H, H-3’ + H-4’), 1.18 (t, J = 7.1 Hz, 3 H, OCH2CH3) ppm. chromatography (petroleum ether/EtOAc 85/15 to 75/25 v/v)
13C NMR (101 MHz, CDCl3): δ 171.3 (C, C-4), 168.8 (C, C-2’), 167.6 and was obtained in moderate yield (86 mg, 40%). Rf 0.44 (SiO2,
1
(C, C-1), 140.6 (CH, C-6’), 136.6 (C, CAr), 136.3 (CH, C-5’‒CH), petroleum ether/EtOAc 5:5, v/v). H NMR (400 MHz, CDCl3): δ
136.2 (C, CAr), 129.0 (CH, CHAr), 128.6 (CH, CHAr), 128.3 (CH, 6.10 (s, 1 H, H-6’), 4.64 (d, J = 7.0 Hz, 2 H, SCOCH2CH3), 4.20–
CHAr), 128.2 (CH, CHAr), 128.0 (CH, CHAr), 127.9 (CH, CHAr), 120.6 4.07 (po, 4 H, 2 × OCH2CH3), 4.02–3.93 (po, 2 H, H-4 + H-5a),
(C, C-2), 115.9 (C, C-5’), 66.9 (CH2, OCH2Ph), 61.1 (CH2, 3.50–3.41 (m, 1 H, H-5b), 3.05 (s, 2 H, H-1”), 2.60–2.50 (po, 3 H,
OCH2CH3), 49.6 (CH2, NCH2Ph), 33.8 (CH2, C-3), 31.0 (CH2, C-3’), H-3’ + H-2a), 2.48–2.40 (m, 1 H, H-2b), 2.40–2.30 (m, 2 H, H-4’),
23.4 (CH2, C-4’), 14.2 (CH3, OCH2CH3) ppm. IR (neat): ṽ = 1732 2.15–2.04 (m, 1 H, H-3a), 1.89–1.76 (m, 1 H, H-3b), 1.43 (t, J =
(C=O), 1682 (C=O), 1619 (C=O) cm‒1. HRMS (ESI): m/z calcd. for 7.1 Hz, 3 H, SCOCH2CH3), 1.26 (t, J = 7.1 Hz, 3 H, OCH2CH3), 1.26
C26H28NO5 [M + H]+ 434.196199 found, 434.196219.
(t, J = 7.1 Hz, 3 H, OCH2CH3) ppm. 13C NMR (101 MHz, CDCl3): δ
213.4 (C, CS), 172.7 (C, C-1), 171.2 (C, C-2”), 169.3 (C, C-2’),
Ethyl 2-(1-benzyl-2-oxo-3-pyridyl)acetate (3m). Compound 3m 127.7 (CH, C-6’), 112.9 (C, C-5’), 70.4 (CH2, SCOCH2CH3), 61.0
was synthesized according to G.P. B, using pyridone 1n (93 mg, (CH2, OCH2CH3), 60.7 (CH2, OCH2CH3), 49.6 (CH, C-4), 48.9 (CH2,
0.50 mmol), ethyl 2-ethoxycarbothioylsulfanylacetate (210 mg, C-5), 39.3 (CH2, C-1”), 31.6 (CH2, C-2), 31.2 (CH2, C-3’), 26.2 (CH2,
1.0 mmol), DLP (239 mg, 0.60 mmol) and EtOAc (1.5 mL). The C-3), 24.2 (CH2, C-4’), 14.3 (CH3, OCH2CH3), 14.3 (CH3, OCH2CH3),
crude product was purified by column chromatography (SiO2, 13.9 (CH3, SCOCH2CH3) ppm. IR (neat): ṽ = 2923 (C‒H), 1763
petroleum ether/EtOAc 75/25 to 40/60 v/v) to give 3m as a
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(C=O), 1683 (C=O), 1663 (C=O) cm‒1. HRMS (ESI): m/z calcd. for (287 mg, 0.72 mmol) and EtOAc (2.0 mL). The crude product was
View Article Online
DOI: 10.1039/D0NJ01209B
C19H30NO6S2 [M + H]+ 432.150906 found, 432.151189.
purified by passage though SiO2‒column chromatography
(petroleum ether/EtOAc 85:15 to 75:25 v/v) and was obtained
Cis-
and
trans-[4-benzyl-2-(2-ethoxy-2-oxoethyl)-5-oxo- in moderate yield (184 mg, 56%) as a mixture of diastereomers
(trans:cis 55:45).
morpholin-3-yl] dodecanoate (4p). Prepared following G.P. B
,
1
using enamide 1p (189 mg, 1.0 mmol), ethyl 2- 2,3-cis-4q. Rf 0.27 (SiO2, petroleum ether/EtOAc 5:5, v/v). H
ethoxycarbothioylsulfanylacetate (420 mg, 2.0 mmol), DLP (478 NMR (400 MHz, CDCl3): δ 6.84–6.71 (po, 3 H, HAr), 5.88 (d, J =
mg, 1.2 mmol) and EtOAc (3.0 mL). The crude product was 1.5 Hz, 1 H, H-3), 4.37–4.11 (po, 5 H, H-2 + H-6 + OCH2CH3), 4.02–
obtained as a mixture of diastereomers (trans:cis 55:45). It was 3.93 (m, 1 H, 0.5 × NCH2), 3.89 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3),
purified by SiO2‒column chromatography (petroleum 3.25–3.14 (m, 1 H, 0.5 × NCH2), 2.97–2.86 (m, 1 H, 0.5 × CH2Ph),
ether/EtOAc 90:10 to 85:15 v/v) to give 2,3-cis-4p (105 mg, 22%) 2.85–2.72 (m, 1 H, 0.5 × CH2Ph), 2.52 (dd, J = 16.3, 7.8 Hz, 1 H,
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and 2,3-trans-4p (124 mg, 26%).
H-1’a), 2.41–2.35 (po, 3 H, H-1’b + CH2(CO)O), 1.75–1.53 (m, 2
2,3-cis-4p. Colourless oil. Rf 0.3 (SiO2, petroleum ether/EtOAc H, CH2CH2(CO)O), 1.37–1.15 (po, 19 H, OCH2CH3 + (CH2)8), 0.88
8:2, v/v). 1H NMR (400 MHz, CDCl3/TMS): δ 7.35–7.25 (po, 5 H, (t, J = 6.7 Hz, 3 H, (CH2)8CH3) ppm. 13C NMR (101 MHz, CDCl3): δ
HAr), 6.05 (d, J = 1.2 Hz, 1 H, H-3), 4.94 (d, J = 14.8 Hz, 1 H, 0.5 × 173.6 (C, CO), 169.5 (C, CO), 167.0 (C, CO), 149.2 (C, CAr), 147.9
NCH2Ph), 4.44 (d, J = 16.9 Hz, 1 H, H-6a), 4.30 (d, J = 16.9 Hz, 1 (C, CAr), 130.7 (C, CAr), 121.0 (CH, CHAr), 112.1 (CH, CHAr), 111.4
H, H-6b), 4.28–4.21 (po, 2 H, H-2 + 0.5 × NCH2Ph), 4.13 (q, J = 7.1 (CH, CHAr), 78.3 (CH, C-3), 72.4 (CH, C-2), 68.2 (CH, C-6), 61.3
Hz, 2 H, OCH2CH3), 2.51 (dd, J = 16.4, 8.2 Hz, 1 H, H-1’a), 2.40 (CH2, OCH2CH3), 56.0 (CH3, OCH3), 56.0 (CH3, OCH3), 46.9 (CH2,
(dd, J = 16.4, 5.0 Hz, 1 H, H-1’b), 2.30–2.10 (m, 2 H, CH2(CO)O), NCH2), 35.9 (CH2, C-1’), 34.4 (CH2, CH2(CO)O), 33.6 (CH2, CH2Ph),
1.60–1.49 (m, 2 H, CH2CH2(CO)O), 1.27 (s, 16 H, (CH2)8), 1.22 (t, 32.0 (CH2, (CH2)8), 29.7 (CH2, (CH2)8), 29.7 (CH2, (CH2)8), 29.6
J = 7.1 Hz, 3 H, OCH2CH3), 0.88 (t, J = 6.8 Hz, 3 H, (CH2)8CH3) ppm. (CH2, (CH2)8), 29.5 (CH2, (CH2)8), 29.3 (CH2, (CH2)8), 29.3 (CH2,
13C NMR (101 MHz, CDCl3): δ 173.4 (C, CO), 169.5 (C, CO), 167.0 (CH2)8), 25.0 (CH2, CH2CH2(CO)O), 22.8 (CH2, (CH2)8), 14.2 (CH3,
(C, CO), 136.3 (C, CAr), 128.8 (CH, CHAr), 128.5 (CH, CHAr), 128.0 (CH2)8CH3), 14.2 (CH3, OCH2CH3) ppm. IR (neat): ṽ = 2924 (C‒H),
(CH, CHAr), 77.7 (CH, C-3), 72.6 (CH, C-2), 68.2 (CH2, C-6), 61.3 2864 (C‒H), 1736 (C=O), 1680 (C=O) cm‒1. HRMS (ESI): m/z
(CH2, OCH2CH3), 47.8 (CH2, NCH2Ph), 35.8 (CH2, C-1’), 33.9 (CH2, calcd. for C30H47NNaO8 [M
CH2(CO)O), 32.0 (CH2, (CH2)8), 29.7 (CH2, (CH2)8), 29.7 (CH2, 572.318643.
(CH2)8), 29.6 (CH2, (CH2)8), 29.4 (CH2, (CH2)8), 29.3 (CH2, (CH2)8),
+
Na]+ 572.319388 found,
29.2 (CH2, (CH2)8), 24.7 (CH2, CH2CH2(CO)O), 22.8 (CH2, (CH2)8), 2,3-trans-4q. Rf 0.34 (SiO2, petroleum ether/EtOAc 5:5, v/v). 1H
14.2 (CH3, (CH2)8CH3), 14.2 (CH3, OCH2CH3) ppm. IR (neat): ṽ = NMR (400 MHz, CDCl3): δ 6.85–6.69 (po, 3 H, HAr), 5.90 (d, J =
2922 (C‒H), 2852 (C‒H), 1735 (C=O), 1672 (C=O) cm‒1. HRMS 3.7 Hz, 1 H, H-3), 4.25–4.11 (po, 5 H, H-2 + H-6 + OCH2CH3), 4.08–
(ESI): m/z calcd. for C27H41NNaO6 [M + Na]+ 498.282609 found, 3.95 (m, 1 H, 0.5 × NCH2), 3.88 (s, 3 H, OCH3), 3.86 (s, 3 H, OCH3),
498.282760.
3.23–3.12 (m, 1 H, 0.5 × NCH2), 2.95–2.87 (m, 1 H, 0.5 × CH2Ph),
2.83–2.73 (m, 1 H, 0.5 × CH2Ph), 2.53 (dd, J = 15.7, 8.6 Hz, 1 H,
2,3-trans-4p
.
Colourless oil. Rf
0.4 (SiO2, petroleum H-1’a), 2.41–2.29 (po, 3 H, H-1’b + CH2(CO)O), 1.68–1.59 (m, 2
1
ether/EtOAc 8:2, v/v). H NMR (400 MHz, CDCl3/TMS): δ 7.38– H, CH2CH2(CO)O), 1.36–1.20 (po, 19 H, OCH2CH3 + (CH2)8), 0.88
7.21 (po, 5 H, HAr), 5.93 (d, J = 3.7 Hz, 1 H, H-3), 4.99 (d, J = 14.8 (t, J = 6.7 Hz, 3 H, (CH2)8CH3) ppm. 13C NMR (101 MHz, CDCl3): δ
Hz, 1 H, 0.5 × NCH2Ph), 4.36–4.27 (po, 2 H, H-6a + H-6b), 4.26– 173.4 (C, CO), 169.5 (C, CO), 167.8 (C, CO), 149.2 (C, CAr), 147.9
4.20 (po, 2 H, H-2 + 0.5 × NCH2Ph), 4.15–4.07 (m, 2 H, OCH2CH3), (C, CAr), 130.6 (C, CAr), 121.0 (CH, CHAr), 112.0 (CH, CHAr), 111.4
2.57 (dd, J = 15.7, 8.6 Hz, 1 H, H-1’a), 2.38 (dd, J = 15.7, 5.1 Hz, (CH, CHAr), 80.1 (CH, C-3), 72.4 (CH, C-2), 64.9 (CH2, C-6), 61.3
1 H, H-1’b), 2.27–2.08 (m, 2 H, CH2(CO)O), 1.59–1.49 (m, 2 H, (CH2, OCH2CH3), 56.0 (CH3, OCH3), 56.0 (CH3, OCH3), 45.6 (CH2,
CH2CH2(CO)O), 1.26 (br s, 16 H, (CH2)8), 1.22 (t, J = 7.1 Hz, 3 H, NCH2), 35.5 (CH2, C-1’), 34.3 (CH2, CH2(CO)O), 33.4 (CH2, CH2Ph),
OCH2CH3), 0.88 (t, J = 6.8 Hz, 3 H, (CH2)8CH3) ppm. 13C NMR (101 32.0 (CH2, (CH2)8), 29.7 (CH2, (CH2)8), 29.7 (CH2, (CH2)8), 29.6
MHz, CDCl3): δ 173.1 (C, CO), 169.4 (C, CO), 167.7 (C, CO), 136.2 (CH2, (CH2)8), 29.4 (CH2, (CH2)8), 29.3 (CH2, (CH2)8), 29.2 (CH2,
(C, CAr), 128.9 (CH, CHAr), 128.5 (CH, CHAr), 128.0 (CH, CHAr), 79.2 (CH2)8), 24.9 (CH2, CH2CH2(CO)O), 22.8 (CH2, (CH2)8), 14.2 (CH3,
(CH, C-3), 72.5 (CH, C-2), 65.0 (CH2, C-6), 61.3 (CH2, OCH2CH3), (CH2)8CH3), 14.2 (CH3, OCH2CH3) ppm. IR (neat): ṽ = 2924 (C‒H),
47.2 (CH2, NCH2Ph), 35.4 (CH2, C-1’), 34.1 (CH2, CH2(CO)O), 32.0 2864 (C‒H), 1736 (C=O), 1680 (C=O) cm‒1. HRMS (ESI): m/z
(CH2, (CH2)8), 29.7 (CH2, (CH2)8), 29.7 (CH2, (CH2)8), 29.6 (CH2, calcd. for C30H47NNaO8 [M
(CH2)8), 29.5 (CH2, (CH2)8), 29.3 (CH2, (CH2)8), 29.2 (CH2, (CH2)8), 572.318643.
24.7 (CH2, CH2CH2(CO)O), 22.8 (CH2, (CH2)8), 14.2 (CH3,
+
Na]+ 572.319388 found,
(CH2)8CH3), 14.2 (CH3, OCH2CH3). IR (neat): ṽ = 2922 (C‒H), 2852 Methyl
(E)-4-(2-oxopyrrolidinyl)but-3-enoate
(3ab).
(C‒H), 1735 (C=O), 1672 (C=O) cm‒1. HRMS (ESI): m/z calcd. for Compound 3ab was prepared according to G.P. B, using
C27H41NNaO6 [M + Na]+ 498.282609 found, 498.282760.
enamide 1a (56 mg, 0.50 mmol), methyl 2-
ethoxycarbothioylsulfanylacetate 2b (198 mg, 1.0 mmol), DLP
Cis- and trans [4-(3,4-dimethoxyphenethyl)-2-(2-ethoxy-2- (239 mg, 0.60 mmol) and EtOAc (1.5 mL). The crude product was
oxoethyl)-5-oxo-morpholin-3-yl] dodecanoate (4q). Prepared purified by passage though SiO2‒column chromatography
following G.P. B, using enamide 1q (158 mg, 0.60 mmol), ethyl (petroleum ether/EtOAc 75/25 to 60/40 v/v) and was obtained
2-ethoxycarbothioylsulfanylacetate (253 mg, 1.2 mmol), DLP as colourless oil (41 mg, 45%). Rf 0.1 (SiO2, petroleum
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ether/EtOAc 6:4, v/v). M.p. < 40 °C. H NMR (400 MHz, CDCl3): to afford compound 3ae (42 mg, 39%). Rf 0.14 (SiO2, petroleum
View Article Online
δ 6.98 (d, J = 14.5 Hz, 1 H, H-4), 5.02 (dt, J = 14.5, 7.3 Hz, 1 H, H- ether/EtOAc 5:5, v/v). 1H NMR (400 MHz,DCODIC: 1l30/.1T0M39S/)D:0δN6J0.91270(9dB,
3), 3.69 (s, 3 H, OCH3), 3.54 (d, J = 7.2 Hz, 2 H, H-5’), 3.11 (dd, J J = 14.8 Hz, 1 H, H-4), 5.17 (d, J = 14.8 Hz, 1 H, H-3), 4.12 (q, J =
= 7.3, 1.1 Hz, 2 H, H-2), 2.48 (t, J = 8.1 Hz, 2H, H-3’), 2.18–2.06 7.1 Hz, 2 H, OCH2CH3), 3.52 (t, J = 7.2 Hz, 2 H, H-5’), 2.49 (t, J =
(m, 2 H, H-4’) ppm. 13C NMR (101 MHz, CDCl3): δ 173.3 (C, CO), 8.1 Hz, 2 H, H-3’), 2.17–2.01 (m, 2 H, H-4’), 1.35 (s, 6 H, 2 × CH3),
172.5 (C, CO), 126.8 (CH, C-4), 103.4 (CH, C-3), 52.1 (CH3, OCH3), 1.25 (t, J = 7.1 Hz, 3 H, OCH2CH3) ppm. 13C NMR (101 MHz,
45.3 (CH2, C-5’), 35.4 (CH2, C-2), 31.3 (CH2, C-3’), 17.6 (CH2, C-4’) CDCl3): δ 176.6 (C, CO), 173.3 (C, CO), 123.1 (CH, C-4), 116.9 (CH,
ppm. IR (neat): ṽ = 2952 (C‒H), 1724 (C=O), 1686 (C=O), 1661 C-3), 60.9 (CH2, OCH2CH3), 45.3 (CH2, C-5’), 43.0 (C, C-2), 31.4
(C=C) cm‒1. HRMS (ESI): m/z calcd. for C9H14NO3 [M + H]+ (CH2, C-3’), 25.6 (CH3), 25.6 (CH3), 17.5 (CH2, C-4’), 14.2 (CH3,
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184.096820 found, 184.096651.
OCH2CH3) ppm. IR (neat): ṽ = 2926 (C‒H), 1731 (C=O), 1683
(C=O), 1515 (C=C) cm‒1. HRMS (ESI): m/z calcd. for C12H20NO3 [M
(E)-4-(2-oxopyrrolidinyl)but-3-enenitrile (3ac). According to + H]+ 226.143770 found, 226.143487.
G.P. B, the reaction was performed, using N-vinylpyrrolidone 1a
(56
mg,
0.50
mmol),
O-ethyl 1-[(E)-2-(2-oxotetrahydrofuran-3-yl)vinyl]pyrrolidin-2-one
cyanomethylsulfanylmethanethioate 2c (162 mg, 1.0 mmol), (3af). The reaction was performed according to G.P. B, using N-
DLP (239 mg, 0.60 mmol) and EtOAc (1.5 mL). The crude product vinylpyrrolidone 1a (56 mg, 0.50 mmol), O-ethyl (2-
was purified by passage though SiO2‒column chromatography oxotetrahydrofuran-3-yl)sulfanylmethanethioate 2f (207 mg,
(petroleum ether/EtOAc 60/40 to 40/60 v/v) and was isolated 1.0 mmol), DLP (239 mg, 0.60 mmol) and EtOAc (1.5 mL). The
as a beige solid (45 mg, 60%). Rf 0.03 (SiO2, petroleum crude product was purified by passage though SiO2‒column
ether/EtOAc 6:4, v/v). M.p. 75‒78 °C. 1H NMR (400 MHz, CDCl3): chromatography (petroleum ether/EtOAc 50/50 to 25/75 v/v)
δ 7.13 (br d, J = 14.2 Hz, 1 H, H-4), 4.83 (dt, J = 14.2, 6.6 Hz, 1 H, and was isolated as a colourless oil (70 mg, 71%). Rf 0.1 (SiO2,
1
H-3), 3.51 (t, J = 7.2 Hz, 2 H, H-5’), 3.15 (dd, J = 6.6, 1.2 Hz, 2 H, petroleum ether/EtOAc 1:3, v/v). H NMR (400 MHz, CDCl3): δ
H-2), 2.50 (t, J = 8.2 Hz, 2 H, H-3’), 2.19–2.07 (m, 2 H, H-4’) ppm. 7.04 (d, J = 14.5 Hz, 1 H, H-3’), 5.01 (dd, J = 14.5, 6.9 Hz, 1 H, H-
13C NMR (101 MHz, CDCl3): δ 173.5 (C, C-2’), 128.3 (CH, C-4), 2’), 4.41 (td, J = 8.7, 2.4 Hz, 1 H, 0.5 × OCH2), 4.24 (ddd, J = 10.3,
117.9 (C, C-1), 98.9 (CH, C-3), 45.2 (CH2, C-5’), 31.1 (CH2, C-3’), 9.1, 6.3 Hz, 1 H, 0.5 × OCH2), 3.59‒3.46 (m, 2 H, H-5), 3.36–3.23
18.6 (CH2, C-2 or C-4’), 17.6 (CH2, C-4’ or C-2) ppm. IR (neat): ṽ = (m, 1 H, H-1’), 2.56–2.45 (po, 3 H, H-3 + 0.5 × OCH2CH2), 2.27–
2954 (C‒H), 2240 (C≡N), 1690 (C=O), 1652 (C=C) cm‒1. HRMS 2.14 (m, 1 H, 0.5 × OCH2CH2), 2.16–2.08 (m, 2 H, H-4) ppm. 13
(ESI): m/z calcd. for C8H11N2O [M + H]+ 151.086589 found, NMR (101 MHz, CDCl3): δ 177.8 (C, CO(O)), 173.4 (C, C-2), 127.0
C
151.086535.
(CH, C-3’), 105.9 (CH, C-2’), 66.7 (CH2, OCH2), 45.2 (CH2, C-5),
40.9 (CH, C-1’), 31.2 (CH2, C-3), 29.7 (CH2, OCH2CH2), 17.6 (CH2,
C-4) ppm. IR (neat): ṽ = 2919 (C‒H), 1762 (C=O), 1683 (C=O),
Ethyl (E)-2-methyl-4-(2-oxopyrrolidinyl)but-3-enoate (3ad)
Following G.P. B, the reaction was performed with enamide 1a 1661 (C=C) cm‒1. HRMS (ESI): m/z calcd. for C10H14NO3 [M + H]+
.
(56
mg,
0.50
mmol),
ethyl
2- 196.096820 found: 196.096790.
ethoxycarbothioylsulfanylpropanoate 2d (222 mg, 1.0 mmol),
DLP (239 mg, 0.60 mmol) and EtOAc (1.5 mL). The crude product Ethyl
4-(2-oxopyrrolidinyl)-4-phenoxy-butanoate
(5a).
was purified by passage though SiO2‒column chromatography According to G.P. C, the reaction was performed with enamide
(petroleum ether/EtOAc 75/25 to 65/35 v/v) and was obtained 1a (56 mg, 0.5 mmol), ethyl 2-ethoxycarbothioylsulfanylacetate
as a colourless oil (79 mg, 72%). Rf 0.24 (SiO2, petroleum (210 mg, 1 mmol), DLP (239 mg, 0.6 mmol), phenol (470 mg, 5
ether/EtOAc 5:5, v/v). 1H NMR (400 MHz, CDCl3/TMS): δ 6.99 (d, mmol) and EtOAc (1.5 mL). The crude product was purified by
J = 14.5 Hz, 1 H, H-4), 5.02 (dd, J = 14.5, 8.4 Hz, 1 H , H-3), 4.13 column chromatography (SiO2, petroleum ether/EtOAc 80:20 to
(qd, J = 7.1, 1.5 Hz, 2 H, OCH2CH3), 3.52 (t, J = 7.2 Hz, 2 H, H-5’), 70:30, v/v) to give 5a as a yellow oil (60 mg, 40%). Rf 0.27 (SiO2,
3.22–3.11 (m, 1 H, H-2), 2.48 (t, J = 8.1 Hz, 2 H, H-3’), 2.14–2.05 petroleum ether/EtOAc 8:2, v/v). 1H NMR (400 MHz,
(m, 2 H, H-4’), 1.30 (d, J = 7.1 Hz, 3 H, CH3), 1.26 (t, J = 7.1 Hz, 3 CDCl3/TMS): δ 7.26 (t, J = 7.8 Hz, 2 H, HAr), 6.99‒6.94 (po, 3 H,
H, OCH2CH3) ppm. 13C NMR (101 MHz, CDCl3): δ 175.0 (C, CO), HAr), 6.04 (t, J = 6.5 Hz, 1 H, H-4), 4.14 (q, J = 7.1 Hz, 2 H,
173.3 (C, CO), 125.0 (CH, C-4), 111.0 (CH, C-3), 60.8 (CH2, OCH2CH3), 3.45‒3.39 (m, 1H, H-5’a), 3.32‒3.27 (m, 1 H, H-5’b),
OCH2CH3), 45.3 (CH2, C-5’), 41.0 (CH, C-2), 31.3 (CH2, C-3’), 18.3 2.55–2.25 (po, 5 H, H-3’ + H-3a + H-2), 2.15–1.80 (po, 3 H, H-4’
(CH3), 17.6 (CH2, C-4’), 14.3 (CH3, OCH2CH3) ppm. HRMS (ESI): + H-3b), 1.26 (t, J = 6.5 Hz, 3 H, OCH2CH3) ppm. 13C NMR (101
m/z calcd. for C11H18NO3 [M + H]+ 212.128120 found, MHz, CDCl3): δ 175.6 (C, CO), 172.7 (C, CO), 155.9 (C, CAr), 129.8
212.128116.
(CH, CHAr), 121.9 (CH, CHAr), 115.7 (CH, CHAr), 78.3 (CH, C-4),
60.8 (CH2, OCH2CH3), 41.3 (CH2, C-5’), 31.3 (CH2, C-2), 29.9 (CH2,
Ethyl
(3ae). Following G.P. B, the reaction was performed with IR (neat): ṽ = 1740 ( C=O), 1603 (C=O) cm‒1. HRMS (ESI): m/z
enamide 1a (56 mg, 0.50 mmol), ethyl 2- calcd. for C16H21NNaO4 [M
Na]+ 314.135680 found,
(E)-2,2-dimethyl-4-(2-oxopyrrolidinyl)but-3-enoate C-3’), 28.0 (CH2, C-3), 18.1 (CH2, C-4’), 14.2 (CH3, OCH2CH3) ppm.
+
ethoxycarbothioylsulfanyl-2-methyl-propanoate 2e (236 mg, 314.136279.
1.0 mmol), DLP (239 mg, 0.60 mmol) and EtOAc (1.5 mL). The
crude residue was purified though SiO2‒column Ethyl 4-ethoxy-4-(2-oxopyrrolidinyl)butanoate (5b). According
chromatography (petroleum ether/EtOAc 75/25 to 65/35 v/v) to G.P. C, the reaction was performed with enamide 1a (56 mg,
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0.5 mmol), ethyl 2-ethoxycarbothioylsulfanylacetate (210 mg, 1 C-2), 30.3 (CH2, C-5’ or C-6’), 29.4 (CH2, C-6’ or C-5’), 28.6 (CH2,
View Article Online
mmol), DLP (239 mg, 0.6 mmol), EtOH (300 µl, 5 mmol) and C-3), 23.8 (CH2, C-4’), 15.1 (CH3, OCH2CH3D),O1I:41.03.1(0C3H9/3D, 0ONCJH0122C0H93B)
EtOAc (1.5 mL). The crude product was purified by column ppm. IR (neat): ṽ = 1735 (C=O), 1645 (C=O) cm‒1. HRMS (ESI):
chromatography (SiO2, petroleum ether/EtOAc 70:30 to 60:40, m/z calcd. for C14H26NO4 [M + H]+ 272.185396 found,
v/v) to provide 5b as a yellow oil (26 mg, 51%). Rf 0.2 (SiO2, 272.185635; m/z calcd. for C14H25NNaO4 [M + Na]+ 294.167609
1
petroleum ether/EtOAc 5:5, v/v). H NMR (400 MHz, CDCl3): δ found, 294.167579.
5.30–5.21 (br t, J = 6.8 Hz, 1 H, H-4), 4.13 (q, J = 7.1 Hz, 2 H,
(OC)OCH2CH3), 3.46–3.27 (po, 4 H, OCH2CH3 + H-5’), 2.48–2.37 Methyl 4-ethoxy-4-(2-oxoazepanyl)butanoate (5e). According
(po, 3 H, H-2a + H-3’), 2.33–2.22 (m, 1 H, H-2b), 2.12–1.94 (po, to G.P. C, the reaction was performed with enamide 1b (100 mg,
3 H, H-4’ + H-3a), 1.88–1.77 (m, 1 H, H-3b), 1.24 (t, J = 7.1 Hz, 3 0.71 mmol), methyl 2-ethoxycarbothioylsulfanylacetate (277
H, (OC)OCH2CH3), 1.17 (t, J = 7.0 Hz, 3 H, OCH2CH3) ppm. 13C mg, 1.42 mmol), DLP (342 mg, 0.86 mmol), EtOH (400 µL, 7.2
NMR (101 MHz, CDCl3): δ 176.0 (C, C-2’), 172.9 (C, C-1), 80.4 (CH, mmol) and EtOAc (1.5 mL). The crude product was purified by
C-4), 63.6 (CH2, OCH2CH3), 60.6 (CH2, (OC)OCH2CH3) 41.2(CH2, C- column chromatography (SiO2, petroleum ether/EtOAc 80:20 to
5’), 31.7 (CH2, C-3’), 30.3 (CH2, C-2), 28.1 (CH2, C-3),18.4 (CH2, C- 70:30, v/v) to provide 5e as a yellow oil (100 mg, 54%). Rf 0.3
4’), 15.0 (CH3, (OC)OCH2CH3), 14.3 (CH3, OCH2CH3) ppm. HRMS (SiO2, petroleum ether/EtOAc 8:2, v/v). 1H NMR (400 MHz,
(ESI): m/z calcd. for C12H21NNaO4 [M + Na]+ 266.136279 found, CDCl3): δ 5.69–5.65 (m, 1 H, H-4), 3.66 (s, 3 H, OCH3), 3.48‒3.16
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266.136185.
(po, 4 H, H-7’ + OCH2CH3), 2.62–2.36 (m, 3 H, H-3’ + H-2a), 2.36–
2.21 (m, 1 H, H-2b), 2.04–1.90 (m, 1 H, H-3a), 1.99–1.48 (m, 7 H,
(5c). H-4’ + H-5’ + H-6’ + H-3b), 1.15 (t, J = 7.0, 1.1 Hz, 3 H, OCH2CH3)
Methyl
4-(2-oxoazepanyl)-4-phenoxy-butanoate
According to G.P. C, the reaction was performed with enamide ppm. 13C NMR (101 MHz, CDCl3): δ 177.0 (C, CO), 173.6 (C, CO),
1b
(100
mg,
0.71
mmol),
methyl
2- 82.4 (CH, C-4), 63.7 (CH2, OCH2CH3), 51.8 (CH3, OCH3), 41.4 (CH2,
ethoxycarbothioylsulfanylacetate (277 mg, 1.42 mmol), DLP C-7’), 37.9 (CH2, C-3’), 30.3 (CH2, C-2), 30.3 (CH2, C-6’ or C-5’)
(342 mg, 0.86 mmol), phenol (671 mg, 7.2 mmol) and EtOAc (1.5 29.4 (CH2, C-5’ or C-6’), 28.7 (CH2, C-3), 23.8 (CH2, C-4’), 15.1
mL). The crude product was purified by column (CH3, OCH2CH3) ppm. IR (neat): ṽ = 1727 (C=O), 1688 (C=O) cm‒
chromatography (SiO2, petroleum ether/EtOAc 80:20 to 70:30, 1. HRMS (ESI): m/z calcd. for C13H24NO4 [M + H]+ 258.169826
v/v) to provide 5c as a yellow oil (120 mg, 55%). Rf 0.25 (SiO2, found, 258.169985; m/z calcd. for C13H23NaNO4 [M + Na]+
petroleum ether/EtOAc 8:2, v/v). 1H NMR (400 MHz, 280.151725 found 280.151929.
CDCl3/TMS): δ 7.26 (t, J = 7.4 Hz, 2 H, HAr), 6.96 (t, J = 7.4 Hz, 1
H, HAr), 6.91 (br d, J = 8.1 Hz, 2 H, HAr), 6.46 (t, J = 6.7 Hz, 1 H, H- Ethyl 4-cyano-4-(2-oxopyrrolidinyl)butanoate (5f). According
4), 3.68 (s, 3 H, OCH3), 3.40‒3.20 (m, 2 H, H-7’), 2.58‒2.45 (po, to G.P. C, the reaction was performed with enamide 1a (56 mg,
3 H, H-2a + H-3’), 2.45‒2.35 (m, 1 H, H-2b), 2.30‒2.20 (m, 1 H, 0.5 mmol), ethyl 2-ethoxycarbothioylsulfanylacetate (210 mg, 1
H-3a), 2.06‒1.97 (m, 1 H, H-3b), 1.70‒1.50 (po, 5 H, H-4’ + H-5’ mmol), DLP (239 mg, 0.6 mmol), TMSCN (625 µl, 5 mmol) and
+ H-6’a), 1.31‒1.21 (m, 1 H, H-6’b) ppm. 13C NMR (101 MHz, EtOAc (1.5 mL). The crude product was purified by column
CDCl3): δ 176.4 (C, CO), 173.3 (C, CO), 156.3 (C, CAr), 129.7 (CH, chromatography (SiO2, petroleum ether/EtOAc 80:20 to 70:30,
CHAr), 121.7 (CH, CHAr), 115.3 (CH, CHAr), 79.6 (CH, C-4), 51.9 v/v) to provide 5f as a yellow oil (50 mg, 40%). Rf 0.3 (SiO2,
1
(CH3, OCH3), 41.9 (CH2, C-7’), 37.8 (CH2, C-3’), 30.1 (CH2, C-5’), petroleum ether/EtOAc 8:2, v/v). H NMR (400 MHz, CDCl3): δ
29.9 (CH2, C-2), 28.9 (CH2, C-6’), 28.6 (CH2, C-3), 23.4 (CH2, C-4’) 5.18 (t, J = 8.0 Hz, 1 H, H-4), 4.16 (q, J = 7.1 Hz, 2 H, OCH2CH3),
ppm. IR (neat): ṽ = 1739 (C=O), 1645 (C=O) cm‒1. HRMS (ESI): 3.54‒3.37 (m, 2 H, H-5’), 2.46–2.25 (po, 4 H, H-2 + H-3’), 2.25–
m/z calcd. for C17H24NO4 [M + H]+ 306.169896 found, 1.90 (po, 4 H, H-4’ + H-3), 1.27 (t, J = 7.1 Hz, 3 H, OCH2CH3) ppm.
306.169985; m/z calcd. for C17H23NNaO4 [M + Na]+ 328.151955 13C NMR (101 MHz, CDCl3): δ 174.8 (C, CO), 171.3 (C, CO), 116.4
found 328.151929.
(C, CN), 61.9 (CH2, OCH2CH3), 43.4 (CH, C-4), 42.1 (CH2, C-5’),
30.2 (CH2 C-3’ or C-2), 29.9 (CH2, C-2 or C-3’), 26.3 (CH2, C-3),
Ethyl 4-ethoxy-4-(2-oxoazepanyl)butanoate (5d). According to 17.7 (CH2, C-4’), 14.1 (CH3, OCH2CH3) ppm. IR (neat): ṽ = 1750
G.P. C, the reaction was performed with enamide 1b (100 mg, (C=O), 1640 (C=O) cm‒1. HRMS (ESI): m/z calcd. for C11H17N2O3
0.71 mmol)), ethyl 2-ethoxycarbothioylsulfanylacetate (300 mg, [M + H]+ 225.123214 found, 225.123369; m/z calcd. for
1.44 mmol), DLP (342 mg, 0.86 mmol), EtOH (41 µl, 7.2 mmol) C11H16N2NaO3 [M + Na]+ 247.12105210 found, 247.12105313.
and EtOAc (1.5 mL). The crude product was purified by column
chromatography (SiO2, petroleum ether/EtOAc 80:20 to 70:30, Ethyl 4-cyano-4-(2-oxoazepan-1-yl)butanoate (5g). According
v/v) to afford 5d as a yellow oil (121 mg, 63%). Rf 0.25 (SiO2, to G.P. C, the reaction was performed with enamide 1b (100 mg,
1
petroleum ether/EtOAc 8:2, v/v). H NMR (400 MHz, CDCl3): δ 0.71 mmol)), ethyl 2-ethoxycarbothioylsulfanylacetate (300 mg,
5.70–5.65 (dd, J = 7.5, 6.0 Hz, 1 H, H-4), 4.13 (q, J = 7.1 Hz, 2 H, 1.44 mmol), DLP (342 mg, 0.86 mmol), TMSCN (900 μL, 7.2
OCH2CH3), 3.55–3.15 (po, 4 H, OCH2CH3 + H-7’), 2.63–2.20 (po, mmol) and EtOAc (1.5 mL). The crude product was purified by
4 H, H-3’ + H-2), 2.05‒1.90 (m, 1 H, H-3a), 1.90‒1.50 (po, 7 H, H- column chromatography (SiO2, petroleum ether/EtOAc 80:20 to
4’ + H-5’ + H-6’+H-3b), 1.25 (t, J = 7.1 Hz, 3 H, OCH2CH3), 1.15 (t, 70:30, v/v) to give 5g as a yellow oil (100 mg, 55%). Rf 0.2 (SiO2,
1
J = 7.0 Hz, 3 H, OCH2CH3) ppm. 13C NMR (101 MHz, CDCl3): δ petroleum ether/EtOAc 8:2, v/v). H NMR (400 MHz, CDCl3): δ
177.0 (C, CO), 173.1 (C, CO), 81.4 (CH, C-4), 63.7 (CH2, OCH2CH3), 5.66 (t, J = 8.0 Hz, 1 H, H-4), 4.16 (q, J = 7.1 Hz, 2 H, OCH2CH3),
60.6 (CH2, OCH2CH3), 41.5 (CH2, C-7’), 38.0 (CH2, C-3’), 30.5 (CH2, 3.47 (t, J = 9.1 Hz, 2 H, H-7’), 2.65–2.49 (m, 2 H, H-3’), 2.49–2.31
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(m, 2 H, H-2), 2.23‒2.11 (m, 1 H, H-3a), 2.10‒1.98 (m, 1 H, H- round-bottomed flask under argon atmosphere was charged
3b), 1.90‒1.62 (po, 6 H, H-4’ + H-5’+ H-6’), 1.27 (t, J = 7.1 Hz, 3 with compound 4q (33 mg, 0.060 mmol, cis:trans 45:55), dry
View Article Online
DOI: 10.1039/D0NJ01209B
H, OCH2CH3) ppm. 13C NMR (101 MHz, CDCl3): δ 175.6 (C, CO), CH2Cl2 (1.0 mL) and a magnetic stir bar. Trifluoroacetic acid (10
171.7 (C, CO), 117.7 (C, CN), 61.1 (CH2, OCH2CH3), 46.1 (CH2, C- µL, 0.14 mmol) was then added and the solution mixture was
7’), 45.0 (CH, C-4), 36.9 (CH2, C-3’), 30.3 (CH2, C-2), 29.9 (CH2, C- stirred at rt for 18 h. Next, the solution was diluted (CH2Cl2) and
6’ or C-5’), 28.8 (CH2, C-5’ or C-6’), 27.0 (CH2, C-3), 23.2 (CH2, C- the organic phase was washed with aqueous NaHCO3 and brine.
4’), 14.3 (CH3, OCH2CH3) ppm. IR (neat): ṽ = 1739 (C=O), 1654 The organic phase was dried (MgSO4), filtered through a cotton
(C=O) cm‒1. HRMS (ESI): m/z calcd. for C13H21N2O3 [M + H]+ plug and evaporated under reduced pressure. The crude
253.154708 found, 253.154669; m/z calcd. for C13H20N2NaO3 [M product was obtained as a single diastereomer; purification of
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+ Na]+ 275.136713 found, 275.1376613.
which (SiO2, petroleum ether/EtOAc 85/15 to 75/25) afforded
trans-5j as a white solid (11 mg, 52%). Rf 0.2 (SiO2, petroleum
Methyl 4-cyano-4-(2-oxoazepanyl)butanoate (5h). According ether/EtOAc 3:7, v/v). M.p. 110‒112 °C. 1H NMR (400 MHz,
to G.P. C, the reaction was performed with enamide 1b (100 mg, CDCl3): δ 6.75 (s, 1 H, HAr), 6.70 (s, 1 H, HAr), 4.66 (d, J = 8.4 Hz, 1
0.71 mmol), methyl 2-ethoxycarbothioylsulfanylacetate (277 H, H-11’b), 4.48–4.42 (m, 1 H, H-6’a), 4.38 (d, J = 16.7 Hz, 1 H, H-
mg, 1.42 mmol), DLP (342 mg, 0.86 mmol), TMSCN (900 μL, 7.2 3’a), 4.25–4.16 (po, 4 H, H-1’ + H-3’b+ OCH2CH3), 3.88 (s, 3 H,
mmol) and EtOAc (1.5 mL). The crude product was purified by OCH3), 3.86 (s, 3 H, OCH3), 3.09–2.99 (m, 1 H, H-6’b), 2.95–2.87
column chromatography (SiO2, petroleum ether/EtOAc 80:20 to (po, 2 H, H-7’a + H-2a), 2.79 (dd, J = 15.6, 7.9 Hz, 1 H, H-2b),
70:30, v/v) to provide 5h as a yellow oil (90 mg, 52%). Rf 0.25 2.76–2.67 (dt, J = 15.8, 4.8 Hz, 1 H, H-7’b), 1.28 (t, J = 7.1 Hz, 3
(SiO2, petroleum ether/EtOAc 8:2, v/v). 1H NMR (400 MHz, H, OCH2CH3) ppm. 13C NMR (101 MHz, CDCl3): δ 170.5 (C, CO),
CDCl3): δ 5.63 (t, J = 7.9 Hz, 1 H, H-4), 3.70 (s, 3 H, OCH3), 3.48 166.7 (C, CO), 148.7 (C, CAr), 147.7 (C, CAr), 130.1 (C, CAr), 124.2
(m, 2 H, H-7’), 2.62–2.47 (m, 2 H, H-3’), 2.46–2.28 (m, 2 H, H-2), (C, CAr), 112.0 (CH, CHAr), 109.6 (CH, CHAr), 75.1 (CH, C-1’), 67.5
2.21–2.10 (m, 1 H, H-3a), 2.09–1.97 (m, 1 H, H-3b), 1.81 (po, 6 (CH2, C-3’), 61.3 (CH2, OCH2CH3), 58.2 (CH, C-11’b), 56.3 (CH3,
H, H-4’ + H-5’ + H-6’) ppm. 13C NMR (101 MHz, CDCl3): δ 175.6 OCH3), 56.1 (CH3, OCH3), 40.5 (CH2, C-6’), 38.8 (CH2, C-2), 28.9
(C, CO), 172.1 (C, CO), 117.6 (C, CN), 52.1 (CH3, OCH3), 46.0 (CH2, (CH2, C-7’), 14.3 (CH3, OCH2CH3) ppm. IR (neat): ṽ = 2979 (C‒H),
C-7’), 44.9 (CH, C-4), 36.8(CH2, C-3’), 29.9 (CH2, C-5’ or C-2), 29.8 2939 (C‒H), 1717 (C=O), 1636 (C=O), 1522 (C=C) cm‒1. HRMS
(CH2, C-2 or C-5’), 28.7 (CH2, C-6’), 27.0 (CH2, C-3), 23.2 (CH2, C- (ESI): m/z calcd. for C18H24NO6 [M + H]+ 350.159814 found,
4’) ppm. IR (neat): ṽ = 1735 (C=O), 1652 (C=O) cm‒1. HRMS (ESI): 350.160181.
m/z calcd. for C12H19N2O3 [M + H]+ 239.138817 found,
239.139019; m/z calcd. for C12H18N2NaO3 [M + Na]+ 261.120838 Phenyl
5-(2-hydroxyethyl)-3,4-dihydro-2H-pyridine-1-
found, 261.120963.
carboxylate (6).
An oven-dried roundbottomed flask under argon atmosphere
Ethyl
2-(9,10-dimethoxy-4-oxo-2,3,6,7- was charged with ester 3h (55 mg, 0.19 mmol), anhydrous THF
tetrahydrobenzo[a]quinolizinyl)acetate (5i). The titled (1.5 mL) and a magnetic stir bar. The solution was cooled to 0
compound was prepared according to G.P. C, using enamide 1r °C (ice-water bath) and LiAlH4 (80 mg, 11 equiv) was added
(500 mg, 1.8 mmol), ethyl 2-ethoxycarbothioylsulfanylacetate portionwise. The mixture was stirred at rt for 16 h and then
(749mg, 3.6 mmol), DLP (861 mg, 2.16 mmol), EtOH (1.04 mL, heated under reflux for 3 h (reaction monitored by TLC using
18.0 mmol) and EtOAc (3.6 mL). The crude product was purified EP/EtOAc 5/5 as eluent). After cooling at 0 °C (ice-water bath),
by column chromatography (SiO2, petroleum ether/EtOAc the mixture was then hydrolysed (H2O, 0.5 mL), the suspension
80:20 to 70:30, v/v) to provide 5i as a yellow oil (186 mg, 30%). was filtered through a pad of celite® and the cake rinsed with
1
Rf 0.6 (SiO2, petroleum ether/EtOAc 8:2, v/v). H NMR (400 CH2Cl2. Next, the aqueous phase was discarded, the organic
MHz, CDCl3): δ 7.62 (s, 1 H, HAr), 6.68 (s, 1 H, HAr), 4.15 (q, J = 7.1, layer was dried (MgSO4), filtered through a cotton plug and
2 H, OCH2CH3), 3.90–3.85 (t, 2 H, J = 6.2 Hz, H-6’), 3.95 (s, 3 H, evaporated under reduced pressure. The crude product was
OCH3), 3.93 (s, 3 H, OCH3), 3.37 (t, J = 6.4 Hz, 2 H, H-3’), 2.93 (t, purified by column chromatography over silica gel (petroleum
J = 6.2 Hz, 2 H, H-7’), 2.75–2.66 (t, J = 6.4 Hz, 2 H, H-2’), 1.28– ether/EtOAc: 50/50) to give
6 as a 6:4 mixture of rotamers
1.23 (m, 5 H, H-2 + OCH2CH3) ppm. 13C NMR (101 MHz, CDCl3): (colourless oil, 31 mg, 66%). Rf 0.36 (SiO2, petroleum
1
δ 175.6 (C, CO), 173.0 (C, CO), 165.7 (C, C=C), 153.6 (C, CIV), ether/EtOAc 6:4, v/v). H NMR (400 MHz, CDCl3): δ 7.37 (t, J =
148.6 (C, CIV), 134.9 (C, CIV), 121.4 (C, CAr), 111.2 (CH, CHAr), 7.9 Hz, 2 H, HAr maj. + HAr min.), 7.21 (t, J = 7.4 Hz, 1 H, HAr maj.
109.4 (CH, CHAr), 60.7 (CH2, OCH2CH3), 56.3 (CH3, OCH3), 56.3 + HAr min.), 7.13 (br s, 0.56 H, HAr maj. + HAr min.), 6.89 (br s, 0.6
(CH3, OCH3), 42.4 (CH2, C-6’), 34.7 (CH2, C-3’), 29.7 (CH2, C-2’), H, H-6 maj.), 6.82 (br s, 0.4 H, H-6 min.), 3.85–3.60 (m, 4 H, H-2
29.7 (CH2, C-2), 28.0 (CH2, C-7’), 14.4 (CH3, OCH2CH3) ppm. IR maj. + H-2 min. + H-2’ maj. + H-2’ min.), 2.30 (t, J = 6.2 Hz, 2 H,
(neat): ṽ = 1726 (C=O), 1688 (C=O) cm‒1. HRMS (ESI): m/z calcd. H-1’ maj. + H-1’ min.), 2.09 (t, J = 6.0 Hz, 2 H, H-4 maj. + H-4
for C17H22NO6 [M ‒ C2H5 + H3O+ + H]+ 336.144391 found, min.), 1.93 (p, J = 6.0 Hz, 2 H, H-3 maj. + H-3 min.), 1.55 (br s, 1
336.1444164; m/z calcd. for C17H21NNaO6 [M ‒ C2H5 + H3O+ + H, OH maj. + OH min.) ppm. 13C NMR (101 MHz, CDCl3): δ 152.2
Na]+ 358.126130 found, 358.126108.
(C, CO min.), 151.7 (C, CO maj.), 151.3 (C, CAr maj.), 151.2 (C, CAr
min.), 129.5 (CH, CHAr maj. + CHAr min.), 125.6 (CH, CHAr maj. +
Trans- Ethyl 2-(9,10-dimethoxy-4-oxo-1,6,7,11b-tetrahydro- CHAr min.), 122.3 (CH, C-6 min.), 122.0 (CH, C-6 maj.), 121.8 (CH,
[1,4]oxazino[3,4-a]isoquinolinyl)acetate (5j). An oven-dried CHAr maj.) 121.8 (CH, CHAr min.), 116.7 (C, C-5 min.), 116.1 (C, C-
12 | J. Name., 2012, 00, 1-3
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5 maj.), 60.7 (CH2, C-2’ min.), 60.6 (CH2, C-2’ maj.), 42.7 (CH2, C-
2 min.), 42.2 (CH2, C-2 maj.), 38.7 (CH2, C-1’ maj.), 38.6 (CH2, C-
13 a) W.-J. Zhao, M. Yan, D. Huang and S.-J. Ji, Tetrahedron, 2005,
DOI: 10.1039/D0NJ01209B
61, 5585; b) M. Yan, W.-J. Zhao, D. Huang and S.-J. Ji,
Tetrahedron Lett., 2004, 45, 6365.
1’ min.), 25.0 (CH2, C-4 maj.), 24.9 (CH2, C-4 min.), 21.9 (CH2, C-
3 min.), 21.7 (CH2, C-3 maj.) ppm. IR (neat): ṽ = 3112 (br, O‒H),
2933 (C‒H), 1715 (C=O), 1260 (O‒H), 1043 (C‒OH) cm‒1. HRMS
(ESI): m/z calcd. for C14H18NO3 [M + H]+ 248.128120 found,
248.127933.
14 For reviews of the xanthate transfer chemistry, see: a) S. Z.
Zard, Angew. Chem., Int. Ed. Engl., 1997, 36, 672; b) S. Z. Zard,
In Radicals in Organic Synthesis; P. Renaud, M. P. Sibi, Eds;
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Conflicts of interest
There are no conflicts of interest to declare.
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3554; b) S. Han and S. Z. Zard, Org. Lett., 2014, 16, 1992; c) F.
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Acknowledgements
The authors thank the Labex SynOrg ANR-11-LABX-0029 and the
Region Centre-Val de Loire for financial support and fellowships
(S.B., I.D.).
16 a) P. E. Reyes-Gutiérrez, R. O. Torres-Ochoa, R. Martínez and
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18 A trans coupling constant J3= 14.6 Hz was observed on 1H
NMR.
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26 CCDC NUKBAZ
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This journal is © The Royal Society of Chemistry 20xx
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R
R'
EWG2
R3
N
H
R3
N
R
R'
S
DLP (1.2 equiv)
R1
R1
+
EWG2
S
OEt
R2
EWG1
R2
EtOAc
reflux, 4h30
EWG1
6
7
8
9
or
EWG1
Free radical process
Mild reaction conditions
Yields up to 72%
30 examples
R3
EWG2
Nu
N
R1
10
11
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