Silica Gel as a Promoter of Sequential Aza-Michael/Michael Reactions of Amines and Propiolic Esters: Solvent- and Metal-Free Synthesis of Polyfunctionalized Conjugated Dienes

Article abstract of DOI:10.1002/asia.201800645

We present an efficient, simple, metal- and solvent-free silica-gel-promoted synthesis of functionalized conjugated dienes by sequential aza-Michael/Michael reactions by starting from commercially available primary amines and propiolic esters. The scope a

Full text of DOI:10.1002/asia.201800645

CHEMISTRY
AN ASIAN JOURNAL
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Accepted Article
Title: Silica Gel as a Promoter of Sequential Aza-Michael/Michael
Reactions of Amines and Propiolic Esters: Solvent-free and
Metal-free Synthesis of Polyfunctionalized Conjugated Dienes
Authors: Jovana Aleksić, Milovan Stojanović, and Marija Baranac-
Stojanović
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10.1002/asia.201800645
Chemistry - An Asian Journal
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Silica Gel as a Promoter of Sequential Aza-Michael/Michael
Reactions of Amines and Propiolic Esters: Solvent-free and
Metal-free Synthesis of Polyfunctionalized Conjugated Dienes
Jovana Aleksić,[b] Milovan Stojanović[b] and Marija Baranac-Stojanović*[a]
Abstract: We present an efficient and simple, metal-free and
solvent-free silica gel-promoted synthesis of functionalized
conjugated dienes by sequential aza-Michael/Michael reactions
starting from commercially available primary amines and propiolic
esters. The scope and usefulness of the method is demonstrated on
31 examples, including a range of propiolic esters, aliphatic amines
and differently substituted aromatic amines. In the case of aliphatic
amines, the products are obtanied within 0.5-4 h in 52-85% yield
compared with 3.5-22 h under classical solution-phase synthesis,
proceeding in similar or lower yields. Particular usefulness of the
method is found in the case of weakly nucleophilic aromatic amines,
which provide products in 21-73% yield during 2.5-9.5 h compared
with 0-49% during 1-6 days under standard solution-phase
conditions and in the case of more hydrophobic esters yielding
products in 47-79% during 1-3 h compared with 0-45% during 4-114
h in the solvent.
An attractive and simple approach to the highly
functionalized conjugated dienes can be envisioned as a
sequential aza-Michael/Michael reactions of amines with an
activated alkyne, such as propiolic ester (Scheme 1). Even
though this approach was used for the formation of conjugated
dienes,[2c,2g,2j,2k,12] it is mainly unexplored. Thus, the reported
syntheses often require long reaction times (1-3 days),[2c,2j,2k,12]
while product yields are moderate or low when an allylic,
benzylic or weakly nucleophilic aromatic amine is employed as a
substrate (50-60% for the former two and 17-45% for the
latter).[2c,2j,2k,12c,d,13]
Scheme 1. Formation of a conjugated diene motif by the reaction of an amine
with an excess of propiolic ester.
Herein, we re-investigate the environmentally benign
construction of a highly functionalized conjugated diene motif by
the one-pot, two-sequence reaction of a variety of aliphatic and
aromatic amines with excess of propiolic esters. We report a
simple and efficient solvent-free silica gel-promoted approach to
dienes 4, particularly useful in the case of weakly nucleophilic
aromatic amines which, under classical solution-phase
syntheses, require very long reaction times (several days)
providing products 4 in low yields ( 50%). The usefulness of the
method is also demonstrated for more hydrophobic esters,
which, when react with an aromatic amine do not provide dienes
under standard solution-phase conditions and when react with
an aliphatic amine furnish dienes in low yields (18-45%) with no
selectivity with respect to by-products, from which a diene is
hardly separable.
Introduction
The conjugated diene motif is present in many biologically
important natural products[1] and is broadly applied for the
construction of a wide variety of organic compounds.[2] Therefore,
a significant effort has been made to develop new and efficient
methods for its formation. Main strategies for the formation of a
conjugated diene involve the Wittig-type alkenylation of ,-
unsaturated carbonyl compounds,[3] transition metal-catalyzed
CC cross-coupling such as Stille coupling (using
vinylstannanes),[4]
organoboranes),[5,6]
Suzuki-Miyaura
Heck reaction
coupling
(using
vinyl
(using
halides/triflates),[5,7] Negishi coupling (using vinylzincs),[1d,5,8]
transition metal-catalyzed direct oxidative cross-coupling via
double CvinylH bond activation,[9] and ruthenium-mediated
enyne metathesis.[10] Recently, highly functionalized conjugated
dienes were obtained by the base-promoted reaction of
enaminones with ethyl propiolate.[11] Most of these syntheses
require preparation of substrates, some of which are air- and/or
moisture-sensitive, or even toxic (organostannanes), and/or the
use of expensive metal catalysts.
Results and Discussion
We commenced our study by exploring the formation of 4a (R 
Bn, R  Et) from benzylamine (1a) and ethyl propiolate (2a) in
EtOH, in a closed tube at 100 C (Table 1, entry 1). After 10 h
conversion was completed and 4a was isolated in 75% yield,
along with two by-products, 1,4-dihydropyridine 5a and 1,3,5-
trisubstituted benzene 6a, isolated in low yields of 5% and 4%,
respectively. The formation of trisubstituted benzene 6 as a by-
product in the reaction of an amine with propiolic ester was also
observed before.[2g] We tested if other solvents such as MeCN,
PhMe and water could improve the yield of 4a, but all they were
inferior to EtOH (entries 2-4). Although the solvent-free
conditions reduced reaction time to only 1 h, the yield of 4a was
slightly lower than in EtOH (70%) and that of by-products was
increased to 11% and 14% for 5a and 6a, respectively (entry 5).
We next examined the solvent-free synthesis of other two dienes,
[a]
[b]
Prof.Dr. M. Baranac-Stojanović
University of Belgrade – Faculty of Chemistry
Studentski trg 12-16
11000 Belgrade, Serbia
E-mail: mbaranac@chem.bg.ac.rs
Dr. Jovana Aleksić, Dr. Milovan Stoajnović
University of Belgrade, Institute of Chemistry, Technology and
Metallurgy - Center for Chemistry
Njegoševa 12
11000 Belgrade, Serbia
Supporting information for this article is given via a link at the end of
the document.
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10.1002/asia.201800645
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4b and 4c, starting from methylamine (1b) and tert-butylamine
(1c). Both reactions resulted in much lower yields of dienes
(34% 4b and 63% 4c) compared with reactions performed in
EtOH (73% 4b and 82% 4c), with an increased yield of by-
product 6a and detection of unreacted intermediates 3b and 3c
in an NMR spectrum of reaction mixture, with estimated 10%
and 27% yields, respectively (entries 6-9). Therefore, the eco-
friendly EtOH was selected as the solvent to explore diene 4
formation from a series of amines, as is shown in Figure 1
(method A).
dihydropyridines 5' and trisubstituted benzene 6a, was not
detected, whereas the intermediacy of structure 7, previously
suggested in the synthesis of 1,4-dihydropyridines by the Lewis
acid-catalyzed dimerization of enamino esters,[15] has been
proven in our work by its isolation in several cases (see below).
In contrast to aliphatic amines, the aromatic ones 1k-u
were highly unreactive. The reaction times were very long, 30-
144 h (1-6 days), and yields of products 4k-u were low 0-49%. A
significant percent of intermediate enaminoester 3 was isolated
in each case (14-78%), often as the major product or as the sole
product in the case of 4-nitroaniline (1p) (the unreacted 1p
constituted the major part of the reaction mixture). The isolated
dienes 4q and 4u, derived from 3-chloro-4-methylaniline (1q)
and 2-chloro-4-methylaniline (1u) contained the intermediate 7q
and 7u in 12 and 15 weight percent, respectively.
Table 1. Optimization of liquid-phase reaction conditions.[a]
The reactions showed sensitivity to electronic properties of
substituents. For example, t-butylamine (1c) and i-propylamine
(1e) afforded corresponding dienes 4c and 4e in 82% and 81%,
respectively, after 4 h and 3.5 h, while n-propylamine (1d)
reacted during 20 h to give 72% of product 4d. Among aromatic
amines, the most reactive 4-methoxyaniline (1l) gave 4l in the
highest yield of 49% after 30 h, while 3,4-dichloroaniline (1r)
furnished 4r in only 8% yield after 6 days. The least reactive 4-
nitroaniline (1p) gave no trace of diene 4p, only the enamino
ester 3p in low yield of 14%. Steric hindrance from an ortho-
substituent is also in play, increasing reaction time and
decreasing product yield. Thus, while 4-methylaniline (1m)
reacted during 96 h to give 38% of 4m, 2,4-dimethylaniline (1s)
provided 26% of 4s after 120 h. Both steric and electronic
effects reduced the yield further to 18% in the case of 2-chloro-
4-methylaniline (1u).
Obviously, the second step of the reaction (3  4, in
Scheme 1) is highly unfavoured for aromatic amines, and even
the first step (formation of enamino ester 3 from 1 and 2a) in the
case of highly unreactive 4-nitroaniline (1p). Given our fortuitous
discovery that diene 4c (R  Bu-t) was formed as the sole
product upon standing of 1c and 2a at the same spot on TLC
plate overnight, we turned our attention to solvent-free silica gel-
promoted reactions. Silica gel, as an inexpensive, non-toxic and
readily available chemical, has gained popularity as a promoter
of chemical reactions, particularly those which involve poorly
reactive substrates.[16] Aromatic amines, as intrinsically weak
nucleophiles, certainly belong to this kind of partners in an
important chemical reaction, such as Michael addition.[17] While
silica gel has been used as a promoter of Michael addition
reactions onto activated alkenes, with or without a solvent,[18] its
potential to mediate sequential additions onto an activated
alkyne has yet to be disclosed.[19] Thus, we have first performed
all reactions at room temperature by placing the reactants onto
the silica gel to form a homogeneous solid mixture (around 0.5 g
of silica gel is needed for 0.25 mL of reactants), which was
stirred with a magnetic stirrer in a closed tube. The results are
shown in Figure 1, as method B.
entry
amine
solvent
time (h)
yield[b] (%)
4
6a
3
55'
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1b
1b
1c
1c
EtOH
10
8
75
70
59
41
70
73
34
82
63
5
5
4
4
0
0
MeCN
PhMe
12
8
0
15
0
0
H2O
14
11
17[c]
0
0
no solvent
EtOH
1
14
0
0
9
0
no solvent
EtOH
2
13[d]
10[d]
4
0
5
0
no solvent
2
0
13[d]
27[d]
[a] 2a: 3-4 equiv. in a solvent; 2.2-3.0 equiv. without solvent. [b] Yields of
isolated products. [c] Isolated as a mixture of 1,4- and 1,2-isomer 1.7:1. [d]
Estimated on the basis of 1H NMR spectrum of reaction mixture.
Aliphatic amines 1a-j furnished dienes 4a-j in moderate to
good yields (51-86%) within a period of 3.5-20 h. The by-
products' yields, where isolated, were low ( 17% and  10% for
5 and 5', and for 6a, respectively). The dihydropyridine by-
product was isolated either as the single 1,4-isomer (5a and 5h),
or as the mixture of 1,4- and 1,2-isomers (5 and 5', respectively).
To the best of our knowledge, there are only two reports on the
synthesis of 1,4-dihydropyridine from an amine (aniline) and
ethyl propiolate under scandium(III) triflate catalysis[14a] and
organocatalysis,[14b] while formation of 1,2-isomer starting from
an amine and a propiolic ester has never been reported. This
reaction and its regioslectivity will be examined further in our
laboratory. The postulated intermediate 8, leading to 1,2-
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Figure 1. Synthesis of conjugated dienes 4 from various amines and ethyl propiolate (2a). The yields refer to isolated products (for mixtures are based on 1H
NMR). In the case of methods B and C, 0.5 g of silica gel was used for 0.25 mL of reactants. Abbreviation n.i. means formed, but not isolated.
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Next, we tried to improve the yields of dienes 4k-u,
obtained from aromatic amines, and to reduce reaction times
further by performing reactions at an elevated temperature of
100 C (Figure 1, method C). Under these conditions, the
product 4 yields were either similar or higher than at rt (with
exception of 4s) and no enamino esters 3 were isolated.
Importantly, the reaction times were reduced to only several
hours (2.5-9.5 h). The intermediate 7 was not detected as a
contaminant of dienes derived from methyl-substituted aromatic
amines, except in one case (diene 4u). The elevated
temperature, however, also accelerated the side reaction
between diene 4 and 3 or 2a (Figure 1) so that dihydropyridines
5 and 5' were isolated in higher yields (14-37%) compared to
method B (0-15%). Due to this side reaction, the synthesis of
dienes 4a-j, starting from aliphatic amines, was performed at
somewhat lower temperature of 60-65 C (Figure 1, method C).
These conditions significantly reduced reaction times from 15-48
h at rt to only 0.5-4 h, without affecting yields much, except
those of 4b, 4e, 4h and 4j, which were by 16% lower, and that
of 4i, which increased from 72% at rt to 85%. In fact, method C
works well for the synthesis of all but four dienes, 4a, 4b, 4e and
4j for which method A provides better yields in a similar or
longer reaction time.
diene. This is of particular importance because, by now, the
method C presents the only way to obtain the functionalized
conjugated dienes 4, from an aromatic amine and propiolic ester,
in satisfactory yields and in a reasonable time, as is shown by
the results in Figure 1 and the literature data given in the
Introduction.[20]
No propiolic amide was detected as by-product in any of
the performed reaction, suggesting that 1,4-addition of an amine
onto the propiolic ester is much more favoured patway, under
the conditions of methods A, B and C. In fact, synthesis of a
propiolic amide, if carried out from an ester, requires very low
temperatures (30 C to 78 C) to favour 1,2- over 1,4-
addition,[21] or formation of an activated intermediate, such as
propiolyl chloride,[22] anhydride,[23] activated ester (N-
hydroxysuccinimide ester),[23] or the use of enzymes.[24]
The scope of the method C was further tested by varying
the ester component that involved
cyclohexyl and phenyl propiolate 2b-f, four of which are
commercially available.[25] Aniline (1k) was chosen as
n-butyl, allyl, benzyl,
a
representative of aromatic amines and 2-phenylethanamine (1i)
was employed as a representative of aliphatic amines. In the
case of both amines, method C represented a significant
improvement for the synthesis of dienes 4i and 4k with respect
to both the product yields and reduction of reaction times (Figure
1). Figure 2 shows the results of the extension of method C to
esters 2b-f, which are compared with the classical solution-
phase method A. As can be seen, under the conditions of
method A, 2-phenylethanamine (1i) provided dienes 4i(b-f) in
low yields of 18-45% during 4-22 h. Four, out of the five
Substituent effects on reaction rates and product yields
can be seen in method C, but appear to be less pronounced
than in a solvent. Thus, for example, t-butylamine (1c) provided
product 4c after 0.5 h in 80% yield, while n-propylamine (1d)
needed 4 h to give 70% of product 4d. In the case of aromatic
amines, the shortest reaction time was observed for the most
reactive 4-methoxyaniline (1l) which yielded 4l in 64% after 2.5 h. reactions, were also accompanied by the formation of
The reaction involving 4-methylaniline (1m) required longer time,
9 h, giving 4m in 71% yield, while the least reactive 4-nitroaniline
(1p) provided 4p in 21% yield during 9.5 h. Steric hindrance
from an ortho-substituent can affect product yields. For instance,
a shift of chlorine from meta-position in 3-chloro-4-methylaniline
(1q) into ortho-position in 2-chloro-4-methylaniline (1u)
decreases the yield of 4u by 15% with respect to the yield of 4q.
However, it is important to realize that in the case of aromatic
amines the reaction times and product 4 yields are also affected
by the rates of side-reactions that lead to dihydropyridine by-
products 5 and 5.
In both methods B and C the work-up procedure was
simple, as the silica gel adsorbed reaction mixture was directly
transferred to a flash chromatography column. Alternatively,
silica gel may easily be recycled after washing with EtOAc, then
with MeOH and air-drying, and reused with just a slight loss of
catalytic activity, as was shown for substrate 1k: 71%, 68%,
64% and 61% of 4k were isolated by using fresh, the first, the
second and the third recycled silica gel, respectively.
In reactions which lead to several products from the same
starting materials, achievement of good chemoselectivity is an
important task. In the case of our method C, chemoselectivity is
excellent when aliphatic amines are used as substrates, since all
by-products are formed in yields which are  6%. It is worse, but
still satisfactory, in the case of aromatic amines: apart from two
cases (amines 1p and 1s), diene is the main product in all
reactions and its yield exceeds that of 5 and 5 from 18% to pure
dihydropyridine by-products 5 and 5, obtained in similar or
higher yields relative to the yield of the corresponding diene.
Dienes 4i(b-e) and dihydropyridines 5i(b-e) are hardly separable
and are often isolated in a mixture. By contrast, all reactions
were very clean in the solid state providing dienes as the sole
products in improved yields of 53-79% and shorter reaction
times 1-2 h (method C). Only in the case of ester 2c, by-product
5i(c) was isolated in very low yield of 4%.
In the case of aniline (1k), method A failed to provide
dienes 4. This is because the initially formed dienes 4k(b) and
4k(e) cyclized into the quinoline derivatives 9a and 9b,
presumably via the sequence shown in Figure 2. They were
isolated in 21% and 23% yields, respectively. These two
reactions also yielded dihydropyridines 5 and 5 in 13-15% yields.
For 2c and 2d a complex mixtures containing 4, 5 and 5 were
obtained, as deduced on the basis of NMR spectra. Any attempt
to isolate pure compounds failed and their individual yields could
not exceed 30% for 2c and 15% for 2d. The reaction of aniline
(1k) with phenyl propiolate (2f) also resulted in a complex
mixture from which only intermediate enamino ester 3k(f) could
be isolated in pure form, while diene 4k(f) was detected by NMR
spectroscopy and its yield does not exceed 15%. By contrast,
method C provided pure dienes 4 in 47-66% yields after 1-3 h. In
the case of cyclohexyl propiolate (2e), the reaction was
conducted at rt to avoid the formation of 5,[26] form which the
diene is hardly separable. The yields of dihydropyridine by-
products 5 and 5 were low ( 22%).
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Figure 2. Synthesis of conjugated dienes 4i(b-f) and 4k(b-f) from 2-phenylethanamine (1i) and aniline (1k), and propiolic esters 2b-f employing methods A and C.
The yields refer to isolated products (for mixtures are based on 1H NMR). In the case of methods B and C, 0.5 g of silica gel was used for 0.25 mL of reactants.
In these cases, too, chemoselectivity of method C was
excellent for aliphatic amine 1i which yielded diene as the sole
product, except in one case where a trace amount of by-product
5i(c) was isolated. By contrast, the classical solution-phase
synthesis proceeded with almost no selectivity giving 4 and 5 in
approximate yields (4i(b)/5i(b) 25%/29%, 4i(c)/5i(c) 25%/26%
and 4i(e)/5i(e) 28%/21%), or even 5 as the main product
(4i(d)/5i(d) 18%/42%). The selectivity of classical approach was
fine only for ester 2f, but method C provided higher yield of
diene 4i(f) in a shorter reaction time (Figure 2). The success of
method C to yield dienes with good chemoselectivity is of
particular importance for aromatic amine 1k, since the classical
approach to their formation completely failed. In addition,
method
C allows the use of stoichiometric amounts of
reactants.[27]
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While secondary amines easily form enamino esters in the
reaction with a propiolic ester 2,[12c,28] further reaction with 2 to
give a diene was reported in just one case in which enamino
ester derived from ethyl cinnamate and pyrrolidine reacted with
methylpropiolate to yield 50% of the corresponding diene.[12b] We
have tested applicability of methods A, B and C for the synthesis
of dienes from ethyl propiolate (2a) and four secondary amines:
pyrrolidine,
piperidine,
morpholine
and
diethylamine.
Unfortunately, the results were not encouraging. Only one diene
4v, derived from pyrrolidine, was isolated in 70% yield under the
conditions of method A. In the case of other three amines,
method A resulted in inseparable mixtures of enamino esters
and dienes, in which the former significantly prevailed. The
performance of methods B and C was even worse, for all four
amines, because, in these cases, silica gel enhanced the
formation of benzene by-product 6a, while the amount of the
mixture of enamino ester and diene was smaller than that
obtained by method A. In the mixture, enamino ester was the
major component. Thus, a further search for efficient methods
for the synthesis of this type of compounds is needed. Recently,
it has been reported that the metal-catalyzed oxidative amination
of alkenes with secondary amine can give the diene.[29]
Figure 3. Stereochemistry determination of dienes 4.
Mechanistic Investigations
The formation of dienes
4
can proceed via two
mechanisms, as suggested previously.[12b] Both of them involve
the common zwitterionic intermediate 10, formed by the Michael
addition of 3 onto 2 (Scheme 2). This intermediate can be
stabilized in two ways: 1) by proton transfer to give 11 which
tautomerizes to product 4, or 2) by formation of cyclobutene 12
which undergoes a conrotatory ring opening to diene 4. In the
first mechanism the two triple-bonded carbons of 2 ends in the
terminal double bond, having one vinylic hydrogen taken from
the N-H group, while in the second mechanism the two carbons
of 2 are inserted between the  and  carbon atoms of enamino
ester 3. In the two mechanisms, the ester groups originating
from enamino ester and propiolic ester exchange their position
in the product (Scheme 2), thus allowing one to distinguish
between them. Previous mechanistic studies based on
deuterium labeling (ND instead of NH) and cross reactions of
2a/2g (R  Et/Me) with 3 (R  Me/Et) derived from crotonic and
cinnamic esters (Me and Ph, respectively, instead of -H in 3)
went in favour of only the first mechanism (via the intermediate
11). The second one, involving cyclobutene 12, was shown to
operate with secondary amines.[12b] However, the cross
reactions of enamines 3 having acrylic ester moiety, as in our
case, failed, due to complete decomposition of 3 into amine 1
and propiolate ester 2 upon heating in benzene.[12b]
Stereochemistry Determination
The products
4 were isolated as a single 2E,4Z
stereizomer, or as a mixture of 2E,4Z and 2E,4E isomers in the
case of 4l (R  4-methoxyphenyl, 91:9), 4n (R  4-iodophenyl,
91:9), 4o (R  4-fluorophenyl, 91:9), 4p (R  4-nitrophenyl,
50:50), 4q (R  3-chloro-4-methylphenyl, 83:17) and 4r (R  3,4-
dichlorophenyl, 71:29). The 2E stereochemistry for all products
was established on the basis of the large JH,H  15.5-16 Hz
between the two olefinic hydrogen atoms, while the 4Z
stereochemistry was deduced on the basis of the low field
position of NH signal ( 8.7-9.2 ppm when R  aliphatic and 
10.6-11.0 ppm when R  aromatic) and NOE cross-peaks
between the C4H and C3H/C2H (Figure 3a and Figure S1 in the
Supporting Information). The two NOE cross-peaks, where the
former is more intensive, indicate the presence of s-trans/s-cis
equilibrium which is shifted toward the s-trans form. The 4E
stereochemistry was determined on the basis of high field
position of NH signal,  7.6-7.9 ppm, and NOE cross-peaks
between the NH and C3H/C2H (Figure 3b and Figure S1 in the
Supporting Information). The two NOE cross-peaks, where the
former is more intensive, again point to the existence of s-
trans/s-cis equilibrium which is shifted toward the s-trans form.
Scheme 2. Proposed mechanisms for the reaction of enamino ester 3 with propiolate ester 2 to give diene 4.
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We have re-investigated cross experiments under the
conditions of our methods A, B and C. First of all, we have
unequivocally identified the signal position of the two carbonyl
carbon atoms in 13C NMR spectra, by using the HMBC
experiment. Thus, the C2H can give HMBC cross-peak only with
carbonyl carbon of the terminal ester group, via the two bonds,
while the C4H can give HMBC cross-peak only with carbonyl
carbon of internal ester group, over the three bonds (Figure 4).
The remaining vinylic hydrogen attached at C3 can interact with
both carbonyl carbons, over the three bonds. We have chosen
methylamine derivative 4b for mechanistic investigations,
from methyl (3-methylamino)acrylate (3b) and ethyl propiolate
(2a) (reaction (2) in Scheme 3). In all six reactions a mixture of
four products was obtained (4b, 4b, 4b and 4b abbreviated
as EE, MM, EM and ME, Scheme 3), clearly evidenced by the
presence of four signals for C2 and C3 carbon atoms in 13C
NMR spectra of reaction mixtures. A precise determination of
product ratio was not possible due to overlapping of the two OR
1H NMR signals (R  Me or Et) when included in terminal or
internal ester group. The formation of four products indicated
decomposition of enamino ester 3 into amine 1 and propiolate 2,
as was also observed previously.[12b] However, while esters of
type 3 completely decomposed when heated in benzene,[12b]
decomposition was only partial under the conditions of our
method A, where dominant product was EM and ME in reaction
(1) and (2), respectively, determined on the basis of OCH2 and
OCH3 signal positions and intensity in NMR spectra (Scheme 3
and Figures S4 and S6 in the Supporting Information). In case of
complete decomposition, product percent weight would be MM
(56.25%), ME  EM (18.75%) and EE (6.25%) in reaction (1),
and EE (56.25%), ME  EM (18.75%) and MM (6.25%) in
reaction (2), that is, MM and EE would have been the major
compounds in reaction mixtures. The formation of EM and ME
as the main products in reactions (1) and (2) goes in favour of
mechanism involving intermediate 11 (Scheme 2), as the
dominant one. We are currently not able to decide if another
mixed product ME in reaction (1) and EM in reaction (2) results
from the second mechanism going via cyclobutene 12 (Scheme
2), or if it comes from recombination of amine 1 and propiolate 2
and further reaction with propiolate 2. The position of methyl and
ethyl ester groups in ME, where carbonyl carbon signals are
separated by 0.7 ppm, could be determined on the basis of
HMBC cross-peaks (Figure S7 in the Supporting Information),
while for EM the situation is less clear due to small chemical
shift difference of the two carbonyl carbons (0.1 ppm) and cross-
peaks' widening originating from the presence of four
compounds in the mixture (Figure S5 in the Supporting
Information).
1
because of its most simple and well resolved H NMR and 13C
NMR spectra (see Supporting Information for the two spectra, p.
S15). The HMBC experiments were performed on two
derivatives, 4b (R  Me, R  Et) and 4b (R  Me, R  Me), the
latter obtained by the reaction of methylamine (1b) with methyl
1
propiolate (2g). In both cases, the C2H, the H NMR signal of
which is positioned at 6.0 ppm, showed the HMBC cross-peak
with the higher field carbonyl carbon signal, while the C4H at
7.2 ppm showed cross-peak with the lower field, hydrogen-
bonded carbonyl carbon signal (see Figures S2 and S3 in the
Supporting Information). Next, we have determined that OCH2
and OCH3 protons of internal ester group resonate at lower field
with respect to the corresponding protons of terminal ester group
by the presence of 169.4/4.24 ppm and 168.9/4.18 ppm HMBC
cross-peaks for 4b, and 170.9/3.76 ppm and 170.6/3.70 ppm for
4b (Figures S2 and S3 in the Supporting Information).
Figure 4. Possible HMBC interactions between carbonyl carbon atoms and
vinylic hydrogen atoms in dienes 4.
In the case of methods B and C, the cross reaction results,
shown in Scheme 3, indicate a higher extent of enamino ester 3
decomposition into 1 and 2 followed by amine 1/enamino ester 3
reaction with momentarily locally distributed 2a and 2g.
Next, we performed two cross reactions under the
conditions of methods A, B and C. The first one involved ethyl
(3-methylamino)acrylate (3b) and methyl propiolate (2g) as
reactants (reaction (1) in Scheme 3) and the second started
Scheme 3. Cross reactions between ethyl (3-methylamino)acrylate (3b) and methyl propiolate (2g), and between methyl (3-methylamino)acrylate (3b) and ethyl
propiolate (2a).
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Thermo Scientific Nicolet 6700 FT-IR spectrometer using ATR technique.
HRMS spectra were recorded only for new compounds on 6210 Time-of-
Flight LC/MS (G1969A, Agilent Technologies) coupled with 1200 Series
HPLC system (Agilent Technologies) and on LTQ Orbitrap XL mass
spectrometer (ThermoFisher Scientific). When a mixture could not be
separated, quantities and yields are based on 1H NMR.
The mechanism by which silica gel promotes these
sequential aza-Michael/Michael additions onto an activated triple
bond is not clearly understood. Since silica gel contains many
hydroxyl groups on its surface, a reasonable explanation of its
catalytic activity may be the activation of both amine and ester
component by formation of NH...OSi and CO...HOSi
hydrogen bonding interactions. These would increase
nucleophilicity of amino group and electrophilicity of -carbon of
the unsaturated ester component. Since our mechanistic
investigations indicated a high degree of intermediate enamino
ester 3 decomposition into starting compounds 1 and 2 on the
surface of silica gel, we assume that the next step involves the
attack of the hydrogen bonded zwitterionic intermediate 3 onto
the activated 2. The quantitative structure-reactivity relationship
(QSRR) analysis of Michael addition reactions onto enones
highlights the importance of coulombic interactions in the case of
silica gel catalysis.[30] In addition, adsorption of molecules on the
surface of silica gel brings them in close proximity which could
also be responsible for the reaction rate acceleration.
Synthesis of propiolic esters 2b-f
n-Butyl propiolate (2b)
To a solution of propiolic acid (210.0 mg, 3.0 mmol) and n-butanol (267.0
mg, 3.60 mmol) in toluene (5 mL) conc. H2SO4 was added (200 L) and
the mixture was heated at 100 C for 40 min. The solution was cooled to
rt and CH2Cl2 (20 mL) was added. It was then washed with 5% NaHCO3
(aq), water and dried over anh. Na2SO4. The solvent was evaporated and
the residue was subjected to column chromatography on silica gel, using
petrol ether (bp 40-60 C)/EtOAc (100:0 to 95:5), to give 229.0 mg (61%)
of 2b, as a colourless liquid. IR:  3266, 2120, 1716, 1241 cm1; 1H NMR
(500.3 MHz, CDCl3): 0.93 (t, 3H, J  7.5 Hz), 1.40 (sext, 2H, J  7.5 Hz),
1.65 (quint, 2H, J  7.5 Hz), 2.87 (s, 1H), 4.18 (t, 2H, J  6.7 Hz); 13C
NMR (125.8 MHz, CDCl3): 13.5, 18.9, 30.3, 66.1, 74.4, 74.7, 152.8.
Allyl propiolate (2c)
Allyl propiolate (2c) was prepared according to the procedure given in ref.
31. To a solution of propiolic acid (249.0 mg, 3.55 mmol) in DMF (2.0 mL)
NaHCO3 (600.0 mg, 7.14 mmol) was added and the mixture was stirred
at rt for 1 h. Then, allyl bromide (640.0 mg, 5.3 mmol) was added and the
mixture was stirred at rt overnight. The mixture was diluted with ether
(30.0 mL), washed with water (5) and dried over anh. Na2SO4. The
solvent was evaporated under reduced pressure. The ester 2c was
isolated in 82% yield (319.0 mg), as a reddish liquid. IR:  3271, 2120,
Conclusions
In conclusion, we have developed an efficient, metal-free and
solvent-free, silica gel-promoted method for the construction of
functionalized conjugated diene motif by the two-sequence
reaction between commercially available reagents, which can be
used in their stoichiometric amounts. The method is
operationally simple, cheap and environmentally benign. Silica
gel showed its important role in these sequential reactions,
which is reflected in reduction of reaction times and increase in
product yields. This is of particular importance if weakly
nucleophilic aromatic amines or/and more hydrophobic esters
are used as reactants, since they poorly react under standard
solution-state conditions.
1
1717, 1615, 1225 cm1; H NMR (500.3 MHz, CDCl3): 2.90 (s, 1H), 4.68
(dt, 2H, J  1.5 Hz, J  6.0 Hz), 5.28-5.39 (m, 2H), 5.88-5.95 (m, 1H); 13
C
NMR (125.8 MHz, CDCl3): 66.7, 74.5, 74.9, 119.5, 130.8, 152.3.
Benzyl propiolate (2d)
Benzyl propiolate (2d) was prepared according to the procedure given in
ref. 32. A mixture of propiolic acid (208.0 mg, 2.97 mmol), benzyl
bromide (460.0 mg, 2.69 mmol) and K2CO3 (410.0 mg, 2.97 mmol) in
DMF (3.0 mL) was stirred at rt for 14h. Water (10 mL) was added and the
mixture was extracted with EtOAc/n-hexane (1:1). Organic layer was
dried over anh. Na2SO4, solvent was evaporated and the residue was
chromatographed on silica gel, using petrol ether (bp 40-60 C)/EtOAc
(100:0 to 95:5), to give 370.0 mg (86%) of 2d, as a colourless liquid. IR: 
3277, 2121, 1716, 1223 cm1; 1H NMR (500.3 MHz, CDCl3): 2.90 (s, 1H),
5.23 (s, 2H), 7.39-7.40 (m, 5H); 13C NMR (125.8 MHz, CDCl3): 67.9, 74.6,
75.1, 128.6, 128.7, 128.7, 134.6, 152.5.
Experimental Section
General
All reactions were carried out in closed Pyrex glass tubes (26 mm  100
mm) heated in an oil bath. The quoted reaction temperatures refer to the
temperature of the oil bath. All reactions were monitored by TLC and
were conducted until the disappearance of enamino ester intermediate 3,
or until the reaction mixture started to be more complex while 3 was still
present (the latter applies only to methods A and B, and aromatic
amines). Silica gel 60 (0.063-0.200 mm, Merck), was used for solvent-
free reactions and for column chromatography. Thin layer
chromatography was performed on precoated silica gel 60 F254 (Merck)
and on silica gel 60 Å, 12-26 ICN Biomedicals. Visualization of TLC spots
was achieved by UV light and iodine vapour for the former and by iodine
vapour and 50% H2SO4 for the latter. Melting points were determined on
Stuart SMP10 apparatus. NMR spectra were recorded in CDCl3 on
Bruker Avance III spectrometer, operating at 500.3 MHz for 1H and 125.8
MHz for 13C, and on Varian Gemini 2000 spectrometer, operating at 200
Cyclohexyl propiolate (2e)
To a solution of propiolic acid (176.4 mg, 2.52 mmol) and cyclohexanol
(323 mg, 3.22 mmol) in toluene (5 mL) conc. H2SO4 was added (150 L)
and the mixture was heated at 100 C for 30 min. The dark-coloured
solution was cooled to rt and CH2Cl2 (20 mL) was added. It was then
washed with 5% NaHCO3 (aq), water and dried over anh. Na2SO4. The
solvent was evaporated and the residue was subjected to column
chromatography on silica gel, using petrol ether (bp 40-60 C)/EtOAc
(100:0 to 95:5), to give 287.0 mg (75%) of 2e, as a colourless liquid. IR: 
3263, 2118, 1711, 1235 cm1; 1H NMR (500.3 MHz, CDCl3):[33] 1.22-1.56
(m, 6H), 1.73-1.78 (m, 2H), 1.87-1.91 (m, 2H), 2.85 (s, 1H), 4.84-4.89 (m,
1H); 13C NMR (125.8 MHz, CDCl3):2 23.6, 25.1, 31.3, 73.9, 75.2, 75.3,
152.2.
1
MHz for H and 50.3 MHz for 13C. Chemical shifts are given as  values
in ppm and are referenced to TMS, or to the residual proton resonance of
CHCl3 at 7.26 ppm and solvent carbon resonance of CDCl3 at 77.0 ppm.
Coupling constants J are given in Hz. IR spectra were recorded on
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Phenyl propiolate (2f)
4.46 (d, 2H, J  6.0 Hz), 6.05 (d, 1H, J  15.5 Hz), 7.24 (d, 2H, J  6.5
Hz), 2.27 (d, 1H, J  13.5 Hz), 7.30-7.33 (m, 1H), 7.35-7.38 (m, 2H), 7.38
(d, 1H, J  15.5 Hz), 9.19 (broad t, 1H, J  6.5 Hz); 13C NMR (125.8 MHz,
CDCl3): 14.4, 14.4, 52.9, 59.6, 59.9, 95.4, 108.4, 127.3, 128.1, 129.0,
136.8, 143.1, 156.9, 168.8, 169.1.
5a: yellow oil[14b,15] IR:  1730, 1700, 1622, 1583 cm1; 1H NMR (200 MHz,
CDCl3): 1.16 (t, 3H, J  7.1 Hz), 1.27 (t, 6H, J  7.1 Hz), 2.51 (d, 2H, J 
5.0 Hz), 3.99 (q, 2H, J  7.1 Hz), 4.19 (q, 4H, J  7.1 Hz), 4.24 (t, 1H, J 
5.0 Hz), 4.51 (s, 2H), 7.20 (s, 2H), 7.22-7.44 (m, 5H); 13C NMR (50.3
MHz, CDCl3): 14.2, 29.6, 40.8, 58.1, 59.9, 60.1, 106.5, 127.1, 128.2,
129.0, 136.0, 139.5, 166.8, 171.7.
Phenyl propiolate (2f) was obtained according to the procedure given for
the synthesis of aryl alkynoate esters.[34] A solution of DCC (520.0 mg,
2.5 mmol) in CH2Cl2 (2 mL) was added to a solution of propiolic acid
(197.0 mg, 2.8 mmol) in CH2Cl2 (2 mL), at 0 C. After 5 min stirring,
PhOH (225 mg, 2.4 mmol) was added followed by a solution of DMAP
(29.3 mg, 0.24 mmol) in CH2Cl2 (1 mL). The mixture was stirred at 0 C
for additional 3h, the precipitate was filtered off and washed with CH2Cl2.
The filtrate was washed with water and dried over anh. Na2SO4. The
solvent was removed under reduced pressure and the residue was
purified by column chromatography using petrol ether (bp 40-60
C)/EtOAc (100:0 to 95:5) to give 146.0 mg (42%) of 2f, as a colourless
6a: white crystals, mp 134-135 °C (lit.[35] 135-136 C); IR:  1721, 1238
cm1; 1H NMR (200 MHz, CDCl3): 1.41 (t, 9H, J = 7.1 Hz), 4.42 (q, 6H, J
= 7.1 Hz), 8.82 (s, 3H); 13C NMR (50.3 MHz, CDCl3): 14.3, 61.6, 131.4,
134.4, 165.0.
liquid. IR:  3275, 2125, 1732, 1199 cm1; H NMR (500.3 MHz, CDCl3):
3.08 (s, 1H), 7.16 (d, 2H, J  8.0 Hz), 7.28 (t, 1H, J  7.5 Hz), 7.41 (t, 2H,
J  8.0 Hz); 13C NMR (125.8 MHz, CDCl3): 74.2, 76.8, 121.2, 126.6,
129.6, 149.8, 150.9.
1
(2E,4Z)-diethyl 4-((methylamino)methylene)pent-2-enedioate (4b)
Method A: 49.8 mg (73%), obtained as following. To a solution of
methylamine in THF (1.2 M, 0.25 mL, 0.3 mmol of 1b) 2a was added
(35.3 mg, 0.36 mmol) and the mixture was stirred at rt overnight. The
solvent and excess of 2a were removed under reduced pressure, EtOH
(1.5 mL) and 2a (58.9 mg, 0.6 mmol) were added. The mixture was
heated at 100 C during 9 h and chromatographed. One side product
was isolated, 5/5'b (16.9 mg, 17%).
Method B: 46.4 mg (68%), obtained as following. To a solution of
methylamine in THF (1.2 M, 0.25 mL, 0.3 mmol of 1b) 2a was added
(97.0 mg, 0.99 mmol) followed by addition of silica gel. The solvent was
evaporated under reduced pressure and the solid mixture was left at rt
for 16 h. The only side product was 6a (2.7 mg, 3%).
Method C: 71.2 mg (52%), obtained as following. To a solution of
methylamine in THF (1.2 M, 0.5 mL, 0.6 mmol of 1b) 2a was added
(145.0 mg, 1.48 mmol) and the mixture was stirred at rt for 18 h. The
solvent and excess of 2a were removed under reduced pressure and
another quantity of 2a was added (63.0 mg, 0.6 mmol) followed by
addition of silica gel. The solid mixture was kept at 60-65 C for 30 min
and chromatographed. Two side products were isolated, 5b/5'b (9.8 mg,
5%) and 6a (3.5 mg, 6%).
General procedure for preparation of conjugated dienes 4
Method A
Amine 1 (1 mmol) and propiolic ester 2 (3-4 mmol) were heated in abs.
EtOH at 100 C, for 3.5-144 h. After completion of the reaction, the
solvent was removed under reduced pressure and the residue was
purified by flash chromatography on silica gel, using petrol ether (bp 40-
60 C)/EtOAc (100:0 to 80:20 for dienes derived from aliphatic amines
and 100:0 to 90:10 for dienes derived from aromatic amines).
Method B
Silica gel was added to a mixture of amine 1 (1 mmol) and propiolic ester
2 (3-4 mmol) to form a homogeneous solid (0.5 g for 0.25 mL of
reactants), which was kept at r.t. for 15-120 h. The solid mixture was
stirred with a magnetic stirrer. After completion of the reaction the solid
mixture was directly transferred to a flash chromatography column, which
was eluted with petrol ether (bp 40-60 C)/EtOAc (100:0 to 80:20 for
dienes derived from aliphatic amines and 100:0 to 90:10 for dienes
derived from aromatic amines).
Method C
Silica gel was added to a mixture of amine 1 (1 mmol) and propiolic ester
2 (2 mmol) to form a homogeneous solid (0.5 g for 0.25 mL of
reactants), which was heated at 60-65 C for 0.5-4 h in the case of
aliphatic amines, and at 100 C for 1-9.5 h in the case of aromatic
amines. The solid mixture was stirred with a magnetic stirrer. After
completion of the reaction the solid mixture was directly transferred to a
flash chromatography column, which was eluted with petrol ether (bp 40-
60 C)/EtOAc (100:0 to 80:20 for dienes derived from aliphatic amines
and 100:0 to 90:10 for dienes derived from aromatic amines).
Silica gel may also be re-used, after washing with EtOAc, then with
MeOH and air-drying, with no appreciable loss of activity, as was shown
for substrate 1k: 4k (71%) and 5/5k (24%) after the first reaction (Figure
1), 4k (68%) and 5/5k (24%) after the second reaction, 4k (64%) and
5/5k (18%) after the third reaction, 4k (61%) and 5/5k (15%) after the
fourth reaction.
4b: pale yellow solid, mp 77-78 C; IR:  3287, 1690, 1652, 1585 cm1;
1H NMR (500.3 MHz, CDCl3): 1.29 (t, 3H, J  7.2 Hz), 1.35 (t, 3H, J  7.0
Hz), 3.10 (d, 3H, J  5.0 Hz), 4.18 (q, 2H, J  7.2 Hz), 4.25 (q, 2H, J  7.0
Hz), 6.01 (d, 1H, J  15.5 Hz), 7.20 (d, 1H, J  14.0 Hz), 7.39 (d, 1H, J 
15.5 Hz), 8.79 (broad s, 1H); 13C NMR (125.8 MHz, CDCl3): 14.4, 35.6,
59.5, 59.7, 94.6, 107.6, 143.2, 158.3, 168.8, 169.1; HRMS calcd. for
C11H18NO4 [MH]: 228.1236, found: 228.1226.
5b and 5'b: pale yellow amorphous substance; IR:  1724, 1701, 1.630,
1583 cm1; 1H NMR (200 MHz, CDCl3, mixture of 1,4- and 1,2-isomers
1.7:1): 1.18-1.39 (m, 18H, 1,2- and 1,4-isomers), 2.31-2.40 (dd, 1H, J 
4.1 Hz, J  15.0 Hz, 1,2-isomer), 2.47 (d, 2H, J  5.0 Hz, 1,4-isomer),
2.59-2.70 (dd, 1H, J  7.4 Hz, J  15.0 Hz, 1,2-isomer), 3.17 (s, 3H, 1,4-
isomer), 3.25 (s, 3H, 1,2-isomer), 4.04 (q, 4H, J  7.2 Hz, 1,2- and 1,4-
isomer), 4.14-4.25 (m, 9H, 1,2- and 1,4-isomer), 5.00 (dd, 1H, J  4.1 Hz,
J  7.4 Hz, 1,2-isomer), 7.11 (s, 2H, 1,4-isomer), 7.48 (s, 1H, 1,2-isomer),
7.64 (s, 1H, 1,2-isomer); 13C NMR (50.3 MHz, CDCl3, mixture of 1,4- and
1,2-isomers 1.7:1): 14.0, 14.2, 14.5, 29.2 (1,4-isomer), 38.0 (1,2-isomer),
40.8 (1,4-isomer), 55.5 (1,2-isomer), 60.0, 61.0, 99.2 (1,2-isomer), 107.0
(1,4-isomer), 108.9 (1,2-isomer), 133.1 (1,2-isomer), 140.1 (1,4-isomer),
149.7 (1,2-isomer), 165.5, 166.8, 170.9, 171.8; HRMS calcd. for
C16H24NO6 [MH]: 326.1604, found: 326.1594.
(2E,4Z)-diethyl 4-((benzylamino)methylene)pent-2-enedioate (4a)
Method A: 103.8 mg (75%) from 1a (49.0 mg, 0.46 mmol) and 2a (145.5
mg, 1.48 mmol) in EtOH (2.0 mL) during 10 h, along with 5a (10.0 mg,
5%) and 6a (11.0 mg, 8%).
Method B: 295.0 mg (53%) from 1a, (196.0 mg, 1.83 mmol) and 2a
(540.0 mg, 5.50 mmol) during 24 h, along with 5a (22.4 mg, 3%).
Method C: 50.4 mg (52%) from 1a (34.0 mg, 0.32 mmol) and 2a (62.3
mg, 0.64 mmol) during 2 h, along with 5a (5.5 mg, 4%) and 6a (1.3 mg,
2%).
(2E,4Z)-diethyl 4-((tert-butylamino)methylene)pent-2-enedioate (4c)
Method A: 105.5 mg (82%) from 1c (34.8 mg, 0.48 mmol) and 2a (188.4
mg, 1.92 mmol) in EtOH (2.0 mL) during 4 h, along with 6a (9.2 mg, 5%).
Method B: 109.0 mg (85%) from 1c (35.0 mg, 0.48 mmol) and 2a (176.0
mg, 1.79 mmol) during 15 h.
4a: pale yellow solid, mp 107-108 C (lit.[12b] 109 C); IR:  3311, 1697,
1
1653, 1597 cm1; H NMR (500.3 MHz, CDCl3): 1.28 (t, 3H, J  7.2 Hz),
1.35 (t, 3H, J  7.0 Hz), 4.18 (d, 2H, J  7.0 Hz), 4.25 (d, 2H, J  7.2 Hz),
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Method C: 62.2 mg (80%) from 1c (21.0 mg, 0.29 mmol) and 2a (57.0
mg, 0.58 mmol) during 30 min, along with 5c (4.0 mg, 4%) and 6a (1.1
mg, 2%).
(2E,4Z)-diethyl 4-((isobutylamino)methylene)pent-2-enedioate (4f)
Method A: 90.0 mg (66%) from 1f (36.8 mg, 0.50 mmol) and 2a (196.2
mg, 2.0 mmol) in EtOH (1.5 mL) during 7 h, along with 6a (6.0 mg, 3%).
Method B: 105.0 mg (71%) from 1f (40.0 mg, 0.55 mmol) and 2a (214.6
mg, 2.20 mmol) during 48 h, along with 6a (5.5 mg, 3%).
4c: pale yellow solid, mp 77-78 C (previuosly isolated as an oil[36]); IR: 
3265, 1699, 1658, 1621, 1593 cm1; 1H NMR (500.3 MHz, CDCl3): 1.27 (t,
3H, J  7.2 Hz), 1.31 (s, 9H), 1.33 (t, 3H, J  7.2 Hz), 4.16 (q, 2H, J  7.2
Hz), 4.22 (q, 2H, J  7.2 Hz), 5.99 (d, 1H, J  15.5 Hz), 7.34 (d, 1H, J 
14.0 Hz), 7.38 (d, 1H, J  15.5 Hz), 9.19 (d, 1H, J  14.0 Hz); 13C NMR
(125.8 MHz, CDCl3): 14.4, 29.9, 52.9, 59.5, 59.6, 94.2, 107.2, 143.8,
153.1, 167.0, 169.2.
Method C: 55.0 mg (71%) from 1f (21.0 mg, 0.29 mmol) and 2a (56.3
mg, 0.57 mmol) during 3.5 h.
4f: pale yellow oil; IR:  3286, 1697, 1663, 1599 cm1; 1H NMR (500.3
MHz, CDCl3): 0.91 (d, 6H, J = 7.0 Hz), 1.25 (t, 3H, J = 7.0 Hz), 1.32 (t, 3H,
J = 7.0 Hz), 1.79 (sep, 1H, J = 6.5 Hz), 3.08 (t, 2H, J = 6.5 Hz), 4.15 (q,
2H, J = 7.0 Hz), 4.22 (q, 2H, J = 7.0 Hz), 5.99 (d, 1H, J = 15.7 Hz), 7.16
(d, 1H, J = 14.0 Hz), 7.36 (d, 1H, J = 15.7 Hz), 8.97 (broad signal, 1H);
13C NMR (125.8 MHz, CDCl3): 14.4, 19.6, 29.6, 57.2, 59.5, 59.7, 94.3,
107.6, 143.4, 157.6, 168.8, 169.2; HRMS calcd. for C14H24NO4 [M+H] +:
270.1705, found: 270.1693.
1
5c: yellow oil; IR:  1733, 1702, 1663, 1578 cm1; H NMR (500.3 MHz,
CDCl3): 1.21 (t, 3H, J  7.2 Hz), 1.30 (t, 3H, J  7.2 Hz), 1.39 (s, 9H),
2.42 (d, 2H, J  5.0 Hz), 4.02 (q, 2H, J  7.2 Hz), 4.21 (q, 4H, J  7.2 Hz),
(t, 1H is covered by the previous signal), 7.48 (s, 2H); 13C NMR (125.8
MHz, CDCl3): 13.8, 14.0, 28.8, 29.2, 40.6, 57.1, 59.5, 59.6, 106.7, 135.7,
166.8, 171.4; HRMS calcd. for C19H30NO6 [MH]: 368.2073, found:
368.2086.
(2E,4Z)-diethyl 4-((hexylamino)methylene)pent-2-enedioate (4g)
Method A: 105.0 mg (71%) from 1g (50.0 mg, 0.49 mmol) and 2a (192.3
mg, 1.96 mmol) in EtOH (1.5 mL) during 5 h, along with 5g (15.0 mg,
8%) and 6a (7.0 mg, 4%).
Method B: 110.0 mg (75%) from 1g (50.0 mg, 0.49 mmol) and 2a (192.3
mg, 1.96 mmol) during 24 h, along with 6a (5.7 mg, 3%).
(2E,4Z)-diethyl 4-((propylamino)methylene)pent-2-enedioate (4d)
Method A: 225.0 mg (72%) from 1d (72.0 mg, 1.22 mmol) and 2a (478.7
mg, 4.88 mmol) in EtOH (2.5 mL) during 20 h, along with 6a (48.0 mg,
10%).
Method B: 171.0 mg (79%) from 1d (50.0 mg, 0.85 mmol) and 2a (333.5
mg, 3.40 mmol) during 18 h, along with 6a (8.0 mg, 2%).
Method C: 60.0 mg (70%) from 1d (20.0 mg, 0.34 mmol) and 2a (66.4
mg, 0.68 mmol) during 4 h, along with 5/5'd (5.0 mg, 4%).
Method C: 60.0 mg (73%) from 1g (28.0 mg, 0.28 mmol) and 2a (54.3
mg, 0.56 mmol) during 3 h, along with 5g (5.5 mg, 5%).
;
4g: pale yellow oil; IR:  3288, 1696, 1663, 1598 cm1 1H NMR (500.3
MHz, CDCl3): 0.84 (t, 3H, J  7.0 Hz), 1.21-1.28 (m, 6H), 1.24 (t, 3H, J 
7.0 Hz), 1.31 (t, 3H, J  7.2 Hz), 1.54 (quint, 2H, J  7.0 Hz), 3.24 (q, 2H,
J  7.0 Hz), 4.14 (q, 2H, J  7.0 Hz), 4.20 (q, 2H, J  7.2 Hz), 5.97 (d, 2H,
J  15.5 Hz), 7.17 (d, 2H, J  14.0 Hz), 7.34 (d, 2H, J  15.5 Hz), 8.89
(broad signal, 1H); 13C NMR (125.8 MHz, CDCl3): 13.8, 14.4, 14.4, 22.3,
26.0, 30.7, 31.2, 49.4, 59.4, 59.6, 94.2, 107.4, 143.3, 157.2, 168.8,
169.1; HRMS: calcd. for C16H28NO4 [M+H] +: 298.2018, found: 298.2011.
5g and 5'g: yellow oil; IR:  1733, 1702, 1581 cm1; 1H NMR (500.3 MHz,
CDCl3, 1,4- and 1,2-isomers 5:1): 0.84-0.90 (m, 6H, 1,2- and 1,4-isomer),
1.19 (t, 3H, J  7.0 Hz, 1,4-isomer), 1.23 (t, 3H, J  7.0 Hz, 1,2-isomer),
1.28 (t, 3H, J  7.0 Hz, 1,4-isomer), 1.25-1.31 (m, 24H, 1,2- and 1,4-
isomer), 1.60 (quint, 4H, J  7.0 Hz, 1,2- and 1,4-isomer), 2.27-2.31 (dd,
1H, J  4.0 Hz, J  14.5 Hz, 1,2-isomer), 2.44 (d, 2H, J  5.5 Hz, 1,4-
isomer), 2.58-2.62 (dd, 1H, J  7.7 Hz, J  14.5 Hz, 1,2-isomer), 3.28 (t,
2H, J  7.0 Hz, 1,4-isomer), 4.02 (q, 2H, J  7.0 Hz, 1,4-isomer), 4.09 (q,
2H, J  7.0 Hz, 1,2-isomer), 4.16-4.23 (m, 9H, 1,2- and 1,4-isomer), 5.04-
5.06 (m, 1H, 1,2-isomer), 7.11 (s, 2H, 1,4-isomer), 7.49 (s, 1H, 1,2-
isomer), 7.64 (s, 1H, 1,2-isomer); 11C NMR (125.8 MHz, CDCl3, 1,4-
isomer): 13.9, 14.1, 14.4, 22.4, 25.8, 29.5, 30.2, 31.3, 40.9, 54.9, 59.9,
60.0, 106.8, 139.3, 166.9, 171.7; HRMS: calcd. for C21H34NO6 [M+H] +:
396.2386, found: 396.2368.
4d: pale yellow oil; IR:  3288, 1696, 1663, 1622, 1598 cm1; 1H NMR
(500.3 MHz, CDCl3): 0.96 (t, 3H, J = 7.5 Hz), 1.29 (t, 3H, J = 7.2 Hz),
1.36 (t, 3H, J = 7.0 Hz), 1.62 (sext, 2H, J = 7.5 Hz), 3.26 (q, 2H, J = 7.0
Hz), 4.18 (q, 2H, J = 7.0 Hz), 4.25 (q, 2H, J = 7.2 Hz), 6.01 (d, 1H, J =
15.5 Hz), 7.22 (d, 1H, J = 14.0 Hz), 7.39 (d, 1H, J = 15.5 Hz), 8.94 (broad
s, 1H); 13C NMR (125.8 MHz, CDCl3): 10.6, 14.1, 14.1, 23.7, 50.8, 59.2,
59.4, 94.0, 107.2, 143.0, 157.0, 168.6, 168.9; HRMS calcd. for
C13H22NO4 [M+H] +: 256.1549, found: 256.1543.
5d and 5'd: yellow oil; IR:  1732, 1701, 1580 cm1; 1H NMR (500.3 MHz,
CDCl3, mixture of 1,4- and 1,2-isomers 10:1): 0.88 (t, 3H, J = 7.2 Hz, 1,2-
isomer), 0.94 (t, 3H, J = 7.2 Hz, 1,4-isomer), 1.20 (t, 3H, J = 7.0 Hz, 1,4-
isomer), 1.24 (t, 3H, J = 7.2 Hz, 1,2-isomer), 1.28 (t, 6H, J = 7.0 Hz, 1,4-
isomer), 1.65 (sext, 4H, J = 7.2 Hz, 1,2- and 1,4-isomers), 2.27-2.31 (dd,
1H, J = 4.5 Hz, J = 15.0 Hz, 1,2-isomer), 2.45 (d, 2H, J = 5.0 Hz, 1,4-
isomer), 2.59-2.63 (dd, 1H, J = 8.0 Hz, J = 15.0 Hz, 1,2-isomer), 3.26 (t,
4H, J = 7.2 Hz, 1,2- and 1,4-isomers), 4.02 (q, 2H, J = 7.0 Hz, 1,4-
isomer), 4.10 (q, 2H, J = 7.2 Hz, 1,2-isomer), 4.17-4.22 (m, 9H, 1,2- and
1,4-isomers), 5.04-5.06 (m, 1H, 1,2-isomer), 7.12 (s, 2H, 1,4-isomer),
7.49 (s, 1H, 1,2-isomer), 7.65 (s, 1H, 1,2-isomer); 13C NMR (125.8 MHz,
CDCl3, 1,4-isomer): 10.8, 14.2, 14.4, 23.5, 29.5, 40.9, 56.5, 59.9, 60.0,
+
106.8, 139.3, 166.9, 171.7; HRMS calcd. for C18H28NO6 [M+H]
354.1917, found: 354.1924.
:
(2E,4Z)-diethyl
4-((cyclohexylamino)methylene)pent-2-enedioate
(4h)
(2E,4Z)-diethyl 4-((isopropylamino)methylene)pent-2-enedioate (4e)
Method A: 120.0 mg (81%) from 1e (34.5 mg, 0.58 mmol) and 2a (227.6
mg, 2.32 mmol) in EtOH (1.5 mL) during 3.5 h.
Method A: 138.0 mg (77%) from 1h (60.0 mg, 0.60 mmol) and 2a (235.4
mg, 2.40 mmol) in EtOH (1.5 mL) during 5 h, along with 5h (8.0 mg, 3%)
and 6a (13.0 mg, 6%).
Method B: 174.0 mg (81%) from 1e (50.0 mg, 0.85 mmol) and 2a (333.5
mg, 3.40 mmol) during 18 h, along with 6a (7.0 mg, 2%).
Method C: 72.0 mg (67%) from 1e (25.0 mg, 0.42 mmol) and 2a (83.0
mg, 0.84 mmol) during 3.5 h.
Method B: 123.5 mg (83%) from 1h (50.0 mg, 0.5 mmol) and 2a (197.8
mg, 2.02 mmol) during 24 h, along with 6a (5.6 mg, 3%).
Method C: 65.0 mg (70%) from 1h (31.0 mg, 0.31 mmol) and 2a (61.3
mg, 0.62 mmol) during 3 h, along with 6a (6.0 mg, 5%).
4e: pale yellow oil;[36] IR:  3278, 1698, 1661, 1620, 1595 cm1; 1H NMR
(500.3 MHz, CDCl3): 1.25 (d, 6H, J = 6.5 Hz), 1.25 (t, 3H, J = 7.0 Hz),
1.32 (t, 3H, J = 7.5 Hz), 3.51 (m, 1H, J = 6.5 Hz), 4.15 (q, 2H, J = 7.0 Hz),
4.21 (q, 2H, J = 7.5 Hz), 5.98 (d, 1H, J = 15.5 Hz), 7.25 (d, 1H, J = 14.0
Hz), 7.36 (d, 1H, J = 15.5 Hz), 8.88 (broad signal, 1H); 13C NMR (125.8
MHz, CDCl3): 14.1, 23.2, 50.3, 59.1, 59.3, 93.9, 107.1, 143.1, 154.8,
168.5, 168.8.
4h: pale yellow oil; IR:  3278, 1698, 1661, 1596 cm1; 1H NMR (500.3
MHz, CDCl3): 1.16-1.21 (broad m, 1H), 1.24 (t, 3H, J = 7.0 Hz), 1.31 (t,
3H, J = 7.0 Hz), 1.30-1.35 (m, 4H), 1.56-1.58 (broad m, 1H), 1.71-1.74
(broad m, 2H), 1.88-1.90 (broad m, 2H), 3.13 (broad signal, 1H), 4.13 (q,
2H, J = 7.0 Hz), 4.20 (q, 2H, J = 7.0 Hz), 5.96 (d, 1H, J = 15.7 Hz), 7.25
(d, 1H, J = 13.5 Hz), 7.35 (d, 1H, J = 15.7 Hz), 8.95 (broad signal, 1H);
13C NMR (125.8 MHz, CDCl3): 14.4, 24.3, 25.0, 33.8, 57.5, 59.4, 59.6,
This article is protected by copyright. All rights reserved.

10.1002/asia.201800645
Chemistry - An Asian Journal
FULL PAPER
94.1, 107.2, 143.4, 155.2, 168.8, 169.1; HRMS: calcd. for C16H26NO4
[M+H] +: 296.1862, found: 296.1852.
1.25 (t, 3H, J = 7.0 Hz, 1,2-isomer), 1.28 (t, 6H, J = 7.0 Hz, 1,4-isomer),
1.27-1.31 (m, 6H, 1,2-isomer), 2.29-2.33 (dd, 1H, J = 4.0 Hz, J = 15.0 Hz,
1,2-isomer), 2.48 (d, 2H, J = 5.0 Hz, 1,4-isomer), 2.62-2.66 (dd, 1H, J =
8.0 Hz, J = 15.0 Hz, 1,2-isomer), 3.91-3.92 (m, 2H, 1,4-isomer), 4.04 (q,
2H, J = 7.0 Hz, 1,4-isomer), 4.09-4.15 (m, 4H, 1,2-isomer), 4.17-4.23 (m,
9H, 1,2- and 1,4-isomer), 5.03-5.06 (m, 1H, 1,2-isomer), 5.27-5.30 (m,
4H, 1,2- and 1,4-isomer), 5.79-5.86 (m, 2H, 1,2- and 1,4-isomer), 7.12 (s,
2H, 1,4-isomer), 7.50 (s, 1H, 1,2-isomer), 7.66 (s, 1H, 1,2-isomer); 13C
NMR (125.8 MHz, CDCl3, 1,4- and 1,2-isomers 2:1): 14.1, 14.2, 14.4,
14.5, 29.6 (1,4-isomer), 38.3 (1,2-isomer), 40.7 (1,4-isomer), 53.6 (1,2-
isomer), 56.8, 58.1, 59.8, 60.0, 60.1, 60.3, 60.9, 100.2, 106.3, 109.5,
119.0, 119.4, 132.0, 132.5, 133.3, 139.2, 148.6, 165.4, 165.7, 166.8,
170.9, 171.8; HRMS: calcd. for C18H26NO6 [M+H] +: 352.1760, found:
352.1746.
5h: yellow oil; IR:  1734, 1701, 1578 cm1; 1H NMR (500.3 MHz, CDCl3):
1.13-1.19 (m, 1H), 1.20 (t, 3H, J = 7.0 Hz), 1.29 (t, 3H, J = 7.0 Hz), 1.27-
1.30 (m, 1H), 1.42-1.50 (m, 2H), 1.62-1.70 (m, 2H), 1.86-1.90 (m, 4H),
2.44 (d, 2H, J = 5.0 Hz), 3.11-3.15 (m, 1H), 4.01 (q, 2H, J = 7.0 Hz), 4.19
(q, 4H, J = 7.0 Hz), 4.21 (t, 1H, J = 5.0 Hz), 7.21 (s, 2H); 13C NMR (125.8
MHz, CDCl3): 14.2, 14.4, 25.0, 25.6, 30.0, 32.5, 40.8, 59.9, 60.0, 63.6,
+
106.7, 137.7, 167.0, 171.7; HRMS: calcd. for C21H32NO6 [M+H]
394.2230, found: 394.2213.
:
(2E,4Z)-diethyl 4-((phenethylamino)methylene)pent-2-enedioate (4i)
Method A: 90.0 mg (51%) from 1i (68.0 mg, 0.56 mmol) and 2a (219.5
mg, 2.24 mmol) in EtOH (1.5 mL) during 20 h, along with 5/5'i (30.0 mg,
13%) and 6a (20.0 mg, 9%).
Method B: 106.8 mg (72%) from 1i (57.0 mg, 0.47 mmol) and 2a (184.5
mg, 1.88 mmol) during 20 h, along with 6a (13.2, 7%).
Method C: 60.0 mg (85%) from 1i (27.0 mg, 0.22 mmol) and 2a (43.7 mg,
0.44 mmol) during 2 h, along with 5/5'i (5.0, 5%).
(2E,4Z)-diethyl 4-((phenylamino)methylene)pent-2-enedioate (4k)
Method A: 145.0 mg (46%) from 1k (102.2 mg, 1.10 mmol) and 2a
(431.6 mg, 4.40 mmol) in EtOH (2.5 mL) during 72 h, along with 3k (55.0
mg, 26%) and 5k (40.0 mg, 9%).
4i: pale yellow amorphous substance; IR  3325, 1728, 1696, 1665, 1620,
1600 cm1; 1H NMR (500.3 MHz, CDCl3): 1.28 (t, 3H, J  7.0 Hz), 1.33 (t,
3H, J  7.0 Hz), 2.88 (t, 2H, J  7.0 Hz), 3.52 (q, 2H, J  7.0 Hz), 4.17 (q,
2H, J  7.0 Hz), 4.23 (q, 2H, J  7.0 Hz), 5.97 (d, 1H, J  15.5 Hz), 7.06,
(d, 1H, J  13.5 Hz), 7.16 (d, 2H, J  7.5 Hz), 7.25 (t, 1H, J  7.5 Hz),
7.32 (t, 2H, J  7.5 Hz), 7.32 (d, 1H, J  15.5 Hz), 8.91 (broad signal,
1H); 13C NMR (125.8 MHz, CDCl3): 14.1, 14.1, 37.2, 50.6, 59.2, 59.4,
94.4, 107.6, 126.6, 128.4, 128.5, 137.1, 142.9, 156.6, 168.5, 168.7;
HRMS calcd. for C18H24NO4 [M+H] +: 318.1705, found: 318.1705.
5i and 5'i: yellow oil, only 1,4-isomer was already reported;[37] IR  1731,
1700, 1580 cm1; 1H NMR (500.3 MHz, CDCl3, 1,4- and 1,2-isomers 5:1):
1.19 (t, 3H, J  7.0 Hz, 1,4-isomer), 1.21 (t, 3H, J  7.0 Hz, 1,2-isomer),
1.26 (t, 3H, J  7.0 Hz, 1,4-isomer), 1.28 (t, 3H, J  7.0 Hz, 1,2-isomer),
2.21-2.25 (dd, 1H, J  3.7 Hz, J  15.2 Hz, 1,2-isomer), 2.41 (d, 2H, J 
4.5 Hz, 1,4-isomer), 2.57-2.62 (dd, 1H, J  8.2 Hz, J  15.2 Hz, 1,2-
isomer), 2.89 (t, 2H, J  7.5 Hz, 1,4-isomer), 3.52 (t, 2H, J  7.5 Hz, 1,4-
isomer), 4.01 (q, 2H, J  7.0 Hz, 1,4-isomer), 4.08 (q, 2H, J  7.0 Hz, 1,2-
isomer), 4.14-4.18 (m, 9H, 1,2- and 1,4-isomer), 4.93 (dd, 1H, J  3.7 Hz,
J  8.2 Hz, 1,2-isomer), 7.04 (s, 2H, 1,4-isomer), 7.08 (d, 2H, J  7.0 Hz,
1,2-isomer), 7.16 (d, 2H, J  7.0 Hz, 1,4-isomer), 7.22 (t, 1H, J  7.5 Hz,
1,4-isomer), 7.29 (t, 2H, J  7.0 Hz, 1,4-isomer), 7.33 (s, 1H, 1,2-isomer),
7.60 (s, 1H, 1,2-isomer); 13C NMR (125.8 MHz, CDCl3, 1,4- and 1,2-
isomers 5:1): 14.0, 14.1, 14.3, 14.4, 29.3 (1,4-isomer), 36.3, 36.7, 38.2
(1,2-isomer), 40.9 (1,4-isomer), 53.6 (1,2-isomer), 56.2, 57.3, 59.6, 59.9,
60.0, 60.2, 60.7, 100.1, 107.0, 109.1, 126.8, 126.9, 128.6, 128.7, 128.8,
133.2, 137.0, 139.0, 148.3, 165.2, 165.6, 166.7, 170.8, 171.5; HRMS
calcd. for C23H30NO6 [MH]+: 414.1911, found: 414.1901.
Method B: 101.0 mg (64%) 1k (51.0 mg, 0.55 mmol) and 2a (214.9 mg,
2.20 mmol) during 72 h, along with 3k (18.0 mg, 17%) and 5k (12.0 mg,
6%).
Method C: 66.0 mg (71%) from 1k (30.0 mg, 0.32 mmol) and 2a (62.8
mg, 0.64 mmol) during 3 h, along with 5/5'k (30.0 mg, 24%).
4k: pale yellow solid, mp 35-36 C (previously isolated as a yellow oil[15]);
IR  3280, 1670, 1663, 1629, 1596 cm1 1H NMR (500.3 MHz, CDCl3):
;
1.29 (t, 3H, J = 7.5 Hz), 1.38 (t, 3H, J = 7.0 Hz), 4.20 (q, 2H, J = 7.5 Hz),
4.30 (q, 2H, J = 7.0 Hz), 6.16 (d, 1H, J = 15.8 Hz), 7.05 (d, 2H, J = 8.0
Hz), 7.10 (t, 1H, J = 7.5 Hz), 7.34 (t, 2H, J = 8.0 Hz), 7.46 (d, 1H, J = 15.8
Hz), 7.74 (d, 1H, J = 13.0 Hz), 10.75 (d, 1H, J = 13.0 Hz); 13C NMR
(125.8 MHz, CDCl3): 15.9, 16.0, 61.5, 62.0, 100.1, 112.6, 118.2, 125.9,
131.4, 140.9, 143.9, 149.3, 170.0, 170.5.
3k: Z isomer, white solid, mp 95-96 C (previously isolated as a
colourless oil);[15] IR  3316, 1669, 1631, 1602 cm1; 1H NMR (200 MHz,
CDCl3): 1.29 (t, 3H, J = 7.2 Hz), 4.17 (q, 2H, J = 7.2 Hz), 4.83 (d, 1H, J =
8.4 Hz), 6.92-7.02 (m, 3H), 7.18-7.32 (m, 3H), 9.90 (d, 1H, J = 11.6 Hz);
13C NMR (50.3 MHz, CDCl3): 14.3, 59.2, 87.3, 115.2, 122.4, 129.6, 140.6,
142,9, 170.3.
5k: yellow oil;[14b,15] IR (1,4-isomer):  1734, 1705, 1594 cm1; 1H NMR
(500.3 MHz, CDCl3, 1,4-isomer): 1.18 (t, 3H, J = 7.0 Hz), 1.31 (t, 6H, J =
7.0 Hz), 2.60 (d, 2H, J = 5.0 Hz), 4.04 (q, 2H, J = 7.0 Hz), 4.23 (q, 2H, J 
7.0 Hz), 4.24 (q, 2H, J  7.0 Hz), 4.27 (t, 1H, J = 5.0 Hz), 7.22-7.24 (m,
2H), 7.25-7.29 (m, 1H), 7.41-7.44 (m, 2H), 7.58 (s, 2H); 13C NMR (125.8
MHz, CDCl3, 1,4-isomer): 14.2, 14.4, 29.6, 40.6, 60.0, 60.3, 108.3, 120.8,
126.4, 129.8, 137.6, 143.1, 166.7, 171.6.
5k and 5'k: yellow oil; IR (1,4- and 1,2-isomer 1.5:1)  1733, 1704, 1627,
1
1598 cm1; H NMR (500.3 MHz, CDCl3, 1,4- and 1,2-isomer 1.5:1): 1.14
(t, 3H, J = 7.0 Hz, 1,2-isomer), 1.17 (t, 3H, J = 7.0 Hz, 1,4-isomer), 1.29-
1.34 (m, 12H, 1,2- and 1,4-isomers), 2.51-2.55 (dd, 1H, J = 6.5 Hz, J =
13.5 Hz, 1,2-isomer), 2.59 (d, 2H, J = 5.0 Hz), 2.63-2.67 (dd, 1H, J = 6.0
Hz, J = 13.5 Hz, 1,2-isomer), 3.89-3.95 (m, 2H, 1,2-isomer), 4.04 (q, 2H,
J = 7.0 Hz, 1,4-isomer), 4.21-4.27 (m, 9H, 1,2- and 1,4-isomers), 5.68 (dt,
1H, J = 1.5 Hz, J = 6.0 Hz, 1,2-isomer), 7.21-7.23 (m, 2H, 1,4-isomer),
7.25-7.28 (m, 1H, 1,4-isomer), 7.32-7.34 (m, 2H, 1,2-isomer), 7.40-7.43
(m, 4H, 1,2- and 1,4-isomers), 7.57 (s, 2H, 1,4-isomer), 7.73 (d, 1H, J =
0.5 Hz, 1,2-isomer), 7.86 (t, 1H, J = 1.5 Hz, 1,2-isomer); 13C NMR (125.8
MHz, CDCl3): 13.8, 14.1, 14.3, 14.5, 29.6 (1,4-isomer), 38.4 (1,2-isomer),
40.5 (1,4-isomer), 55.0 (1,2-isomer), 60.0, 60.1, 60.3, 60.5, 60.8, 104.3,
108.3, 113.1, 120.8, 121.0, 126.1, 126.3, 129.7, 129.8, 132.1, 137.6,
143.1, 143.7, 144.4, 165.2, 165.5, 166.7, 169.9, 171.6; HRMS calcd. for
C21H26NO6 [M+H] +: 388.1760, found: 388.1783.
(2E,4Z)-diethyl 4-((allylamino)methylene)pent-2-enedioate (4j)
Method A: 190.0 mg (86%) from 1j (50.0 mg, 0.88 mmol) and 2a (345.3
mg, 3.52 mmol) in EtOH (2 mL) during 3.5 h, along with 5/5'j (13.0 mg,
4%) and 6a (10.0 mg, 3%).
Method B: 176.7 mg (80%) from 1j (50.0 mg, 0.88 mmol) and 2a (345.3
mg, 3.52 mmol) during 48 h, along with 6a (8.3 mg, 2%).
Method C: 63.0 mg (68%) from 1j (21.0 mg, 0.37 mmol) and 2a (72.2 mg,
0.74 mmol) during 4 h, along with 5/5'j (5.5 mg, 4%).
1
4j: pale yellow oil;[2c] IR  3290, 1697, 1664, 1597 cm1; H NMR (500.3
MHz, CDCl3): 1.26 (t, 3H, J = 7.0 Hz), 1.33 (t, 3H, J = 7.0 Hz), 3.86-3.89
(m, 2H), 4.16 (q, 2H, J = 7.0 Hz), 4.23 (q, 2H, J = 7.0 Hz), 5.20-5.24 (m,
2H), 5.80-5.88 (m, 1H), 6.01 (d, 1H, J = 15.5 Hz), 7.18 (d, 1H, J = 13.5
Hz), 7.35 (d, 1H, J = 15.5 Hz), 8.92 (broad signal, 1H); 13C NMR (125.8
MHz, CDCl3): 14.4, 51.1, 59.5, 59.8, 95.2, 108.2, 117.8, 133.4, 143.1,
156.9, 168.8, 169.1.
1
5j and 5'j: yellow oil; IR  1732, 1701, 1583 cm1; H NMR (500.3 MHz,
CDCl3, 1,4- and 1,2-isomers 2:1): 1.20 (t, 3H, J = 7.0 Hz, 1,4-isomer),
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10.1002/asia.201800645
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(2E,4Z)- and (2E,4E)-diethyl 4-(((4-methoxyphenyl)amino)methy-
lene)pent-2-enedioate (4l)
Method A: 63.0 mg (49%) from 1l (50.0 mg, 0.41 mmol) and 2a (157.0
mg, 1.60 mmol) in EtOH (1.5 mL) during 30 h, along with 3l (45.0 mg,
50%).
Method B: 90.0 mg (69%) from 1l (50.0 mg, 0.41 mmol) and 2a (159.3
mg, 1.62 mmol) during 30 h, along with 3l (10.0 mg, 11%) and 6a (17.0
mg, 11%).
Method C: 50.0 mg (64%) from 1l (30.0 mg, 0.24 mmol) and 2a (47.1 mg,
0.48 mmol) during 2.5 h.
Hz, 1,2-isomer), 2.59 (d, 2H, J  4.5 Hz, 1,4-isomer), 2.62-2.66 (dd, 1H, J
 6.0 Hz, J  13.5 Hz, 1,2-isomer), 3.90-4.00 (m, 2H, 1,2-isomer), 4.04 (q,
2H, J  7.2 Hz, 1,4-isomer), 4.22-4.29 (m, 9H, 1,2- and 1,4-isomers),
5.64 (dt, 1H, J  1.5 Hz, J  6.0 Hz, 1,2-isomer), 7.12 (d, 2H, J  8.5 Hz,
1,4-isomer), 2.22 (d, 2H, J  8.5 Hz, 1,4-isomer), 7.22 (s, 4H, 1,2-isomer),
7.54 (s, 2H, 1,4-isomer), 7.73 (s, 1H, 1,2-isomer), 7.84 (s, 1H, 1,2-
isomer); 13C NMR (125.8 MHz, CDCl3, 1,4- and 1,2-isomer 1:1.8): 13.5,
13.8, 14.0, 14.2, 20.5 (1,2- and 1,4-isomer), 29.3 (1,4-isomer), 38.0 (1,2-
isomer), 40.3 (1,4-isomer), 55.0 (1,2-isomer), 59.7, 59.9, 60.2, 60.5,
103.3, 107.5, 111.8, 120.5, 120.8, 129.9, 129.9, 132.0, 135.9, 136.0,
137.5, 140.4, 141.0, 144.4, 164.9, 165.3, 166.4, 169.6, 171.3; HRMS
calcd. for C22H28NO6 [M+H] +: 402.1917, found: 402.1925.
4l: pale yellow solid, mp 93-95 C; IR (2E,4Z and 2E,4E 10:1)  3221,
1
3182, 1689, 1655, 1628, 1602 cm1; H NMR (500.3 MHz, CDCl3, 2E,4Z
1
and 2E,4E 10:1): 1.31 (t, 3H, J  7.0 Hz, 2E,4Z), 1.33 (t, 3H, J  7.0 Hz,
2E,4E), 1.39 (t, 3H, J  7.0 Hz, 2E,4Z), 3.80 (s, 3H, 2E,4Z and 2E,4E),
4.21 (q, 2H, J  7.0 Hz, 2E,4Z), 4.26 (q, 2H, J  7.2 Hz, 2E,4E), 4.31 (q,
2H, J  7.2 Hz, 2E,4Z), 6.15 (d, 1H, J  15.5 Hz, 2E,4Z), 6.46 (d, 1H, J 
16.0 Hz, 2E,4E), 6.89 (d, 2H, J  9.0 Hz, 2E,4Z), 7.01 (d, 2H, J  9.0 Hz,
2E,4Z), 7.47 (d, 1H, J  15.5 Hz, 2E,4Z), 7.64 (d, 1H, J  16.0 Hz, 2E,4E),
7.66 (d, 1H, J  13.5 Hz, 2E,4Z), 8.09 (d, 1H, J  14.5 Hz, 2E,4E), 10.73
(d, 1H, J  13.5 Hz, 2E,4Z); 13C NMR (125.8 MHz, CDCl3, 2E,4Z isomer):
7m: 1H NMR (500.3 MHz, CDCl3) H NMR (500.3 MHz, CDCl3): 1.19 (t,
3H, J = 7.0 Hz), 1.24 (t, 6H, J = 7.0 Hz), 2.27 (s, 6H), 2.89 (d, 2H, J = 8.0
Hz), 4.07-4.12 (m, 3H), 6.85 (d, 4H, J = 8.5 Hz), 7.07 (d, 4H, J = 8.5 Hz),
7.38 (d, 2H, J = 13.0 Hz), 9.96 (d, 2H, J = 13.0 Hz); 13C NMR (125.8 MHz,
CDCl3): 14.2, 14.2, 20.5, 37.3, 38.4, 59.4, 99.2, 115.1, 130.0, 131.5,
138.6, 142.7, 169.7, 172.3; HRMS calcd. for C29H36N2NaO6 [M+Na] +:
531.2471, found: 531.2448.
14.4, 14.4, 55.5, 59.8, 60.2, 97.5, 110.1, 115.0, 118.2, 132.9, 142.5,
(2E,4Z)- and (2E,4E)-diethyl 4-(((4-iodophenyl)amino)methylene)-
pent-2-enedioate (4n)
Method A: 23.0 mg (30%) from 1n (40.0 mg, 0.18 mmol) and 2a (70.6
mg, 0.72 mmol) in EtOH (1 mL) during 120 h, along with 3n (30.0 mg,
52%), 5/5'n (7.0 mg, 7%) and 6a (5.0 mg; 7%).
Method B: 35.3 mg (53%) from 1n (35.0 mg, 0.16 mmol) and 2a (62.7
mg, 0.64 mmol) during 72 h, along with 3n (9.0 mg, 18%), 5/5'n (12.0 mg,
15%) and 6a (7.7 mg; 12%).
Method C: 30.2 mg (53%) from 1n (30.0 mg, 0.14 mmol) and 2a (27.5
mg, 0.28 mmol) during 9 h, along with 5/5'n (22.0 mg, 31%) and 6a (5.8
mg; 21%).
+
148.7, 156.8, 168.5, 169.1; HRMS calcd. for C17H22NO5 [M+H]
320.1498, found: 320.1498.
:
3l: Z isomer, yellow solid, mp 81-83 C (previously isolated as a yellow
oil);[15] IR  3304, 3274, 1695, 1612, 1587, 1509 cm1; 1H NMR (500.3
MHz, CDCl3): 1.30 (t, 3H, J = 7.0 Hz), 3.78 (s, 3H), 4.17 (q, 2H, J = 7.0
Hz), 4.77 (d, 1H, J = 8.0 Hz), 6.84-6.86 (m, 2H), 6.90-6.92 (m, 2H), 7.15
(dd, 1H, J = 8.0 Hz, J  12.2 Hz), 9.81 (d, 1H, J = 12.2 Hz); 13C NMR
(125.8 MHz, CDCl3): 14.5, 55.6, 59.1, 86.1, 114.9, 116.9, 134.5, 144.1,
155.5, 170.5.
(2E,4Z)-diethyl 4-((p-tolylamino)methylene)pent-2-enedioate (4m)
Method A: 48.0 mg (38%) from 1m (45.0 mg, 0.42 mmol) and 2a (164.8
mg, 1.68 mmol) in EtOH (1.5 mL) during 96 h, along with 3m (24.0 mg,
28%).
Method B: 71.4 mg (56%), obtained in a mixture with 7m (83.0 mg of the
mixture containing 86% of 4m and 14% of 7m), from 1m (45.0 mg, 0.42
mmol) and 2a (164.8 mg, 1.68 mmol) during 40 h, along with 3m (9.0 mg,
10%) and 5/5'm (10.0 mg, 6%).
4n: pale yellow solid, mp 120-122 C; IR (2E,4Z and 2E,4E 10:1)  3166,
1694, 1633 cm1; 1H NMR (500.3 MHz, CDCl3, 2E,4Z and 2E,4E 10:1):
1.31 (t, 3H, J = 7.0 Hz, 2E,4Z), 1.34 (t, 3H, J = 7.0 Hz, 2E,4E), 1.39 (t, 3H,
J = 7.0 Hz, 2E,4Z), 4.22 (q, 2H, J = 7.0 Hz, 2E,4Z), 4.27 (t, 2H, J = 7.0
Hz, 2E,4E), 4.32 (q, 2H, J = 7.0 Hz, 2E,4Z), 6.19 (d, 1H, J = 16.0 Hz,
2E,4Z), 6.50 (d, 1H, J = 16.0 Hz, 2E,4E), 6.83 (d, 2H, J = 8.5 Hz, 2E,4Z),
7.44 (d, 1H, J = 16.0 Hz, 2E,4Z), 7.64 (d, 2H, J = 8.5 Hz, 2E,4Z), 7.67 (d,
1H, J = 13.0 Hz, 2E,4Z), 8.09 (d, 1H, J = 14.0 Hz, 2E,4E), 10.74 (d, 1H, J
= 13.0 Hz, 2E,4Z); 13C NMR (125.8 MHz, CDCl3, 2E,4Z isomer): 14.3,
14.4, 59.9, 60.5, 87.0, 99.4, 111.8, 118.2, 138.7, 139.1, 141.8, 146.7,
168.2, 168.8; HRMS calcd. for C16H19INO4 [M+H] +: 416.0359, found:
416.0340.
Method C: 60.0 mg (71%) from 1m (30.0 mg, 0.28 mmol) and 2a (54.9
mg, 0.56 mmol) during 9 h, along with 5/5'm (28.0 mg, 25%) and 6a (1.1
mg; 2%).
4m: pale yellow solid, mp 61-63 C; IR  3273, 1694, 1655, 1599 cm1
;
1H NMR (500.3 MHz, CDCl3): 1.29 (t, 3H, J  7.0 Hz), 1.37 (t, 3H, J  7.0
Hz), 2.20 (s, 3H), 4.20 (q, 2H, J  7.0 Hz), 4.30 (q, 2H, J  7.0 Hz), 6.15
(d, 1H, J  15.5 Hz), 6.94 (d, 2H, J  8.2 Hz), 7.13 (d, 2H, J  8.2 Hz),
7.46 (d, 1H, J  15.5 Hz), 7.70 (d, 1H, J  13.5 Hz), 10.72 (d, 1H, J  13.5
Hz); 13C NMR (125.8 MHz, CDCl3): 14.3, 14.4, 20.6, 59.7, 60.2, 97.9,
110.4, 116.5, 130.3, 134.1, 136.9, 142.4, 148.0, 168.4, 168.9; HRMS
calcd. for C17H22NO4 [M+H] +: 304.1549, found: 304.1535.
3n: Z isomer, pale yellow solid, mp 91-93 C (lit.[15] 90-95 C); IR  3363,
1725, 1665, 1620, 1586 cm1; 1H NMR (500.3 MHz, CDCl3) 1.31 (t, 3H, J
= 7.0 Hz), 4.18 (q, 2H, J = 7.0 Hz), 4.88 (d, 1H, J = 8.5 Hz), 6.73 (d, 2H, J
= 8.5 Hz), 7.18 (dd, 1H, J = 8.5 Hz, J = 12.5 Hz), 7.58 (d, 2H, J = 8.5 Hz),
9.90 (broad d, 1H, J = 12.5 Hz), there is also another set of signals of
lower intensity, the origin of which has not been determined: 1.32 (t, 3H,
J = 7.0 Hz), 4.24 (q, 2H, J = 7.0 Hz), 4.99 (d, 1H, J = 8.5 Hz), 7.14 (dd,
1H, J = 8.5 Hz, J = 12.0 Hz), 8.08 (d, 1H, J = 2.0 Hz), 10.16 (broad d, 1H,
J = 12.0 Hz); 13C NMR (125.8 MHz, CDCl3): 14.4, 59.4, 84.6, 88.5, 117.2,
138.4, 140.5, 142.2, 170.3.
3m: pale yellow oil (also reported previoulsy);[19] IR (64% Z and 36% E) 
3300, 3274, 1683, 1613, 1582, 1521 cm1 1H NMR (200 MHz, CDCl3,
;
64% Z and 36% E): Z isomer 1.30 (t, 3H, J = 7.2 Hz), 2.29 (s, 3H), 4.17
(q, 2H, J = 7.2 Hz), 4.79 (d, 1H, J = 8.2 Hz), 6.85 (d, 2H, J = 8.4 Hz), 7.09
(d, 2H, J = 8.4 Hz), 7.21 (dd, 1H, J = 8.2 Hz, J  12.8 Hz), 9.84 (broad d,
1H), E isomer 1.28 (t, 3H, J  7.2 Hz), 2.29 (s, 3H), 4.17 (q, 2H, J = 7.2
Hz), 5.17 (d, 1H, J = 13.0 Hz), 6.85 (d, 2H, J = 8.4 Hz), 7.09 (d, 2H, J =
8.4 Hz), 7.89 (t, 1H, J  13.0 Hz); 13C NMR (50.3 MHz, CDCl3): Z isomer
14.5, 20.6, 59.2, 86.7, 115.4, 130.1, 132.1, 138.3, 143.4, 170.4.
5n and 5'n: yellow solid, only 1,4-isomer was already reported;[15] IR 
1734, 1702, 1627 cm1; 1H NMR (500.3 MHz, CDCl3, 1,4- and 1,2-isomer
1:4): 1.16 (t, 3H, J = 7.0 Hz, 1,2-isomer), 1.17 (t, 3H, J = 7.0 Hz, 1,4-
isomer), 1.29-1.35 (m, 12H, 1,2- and 1,4-isomer), 2.49-2.53 (dd, 1H, J =
6.2 Hz, J = 13.5 Hz, 1,2-isomer), 2.59 (d, 2H, J = 5.0 Hz, 1,4-isomer),
2.0-2.64 (dd, 1H, J = 6.0 Hz, J = 13.5 Hz, 1,2-isomer), 3.91-4.04 (m, 4H,
1,2- and 1,4-isomer), 4.21-4.29 (m, 9H, 1,2- and 1,4-isomer), 5.61 (m, 1H,
1,2-isomer), 6.98 (d, 2H, J = 9.0 Hz, 1,4-isomer), 7.09 (d, 2H, J = 9.0 Hz,
1,2-isomer), 7.52 (s, 2H, 1,4-isomer), 7.7 (s, 1H, 1,2-isomer), 7.72 (d, 2H,
J = 9.0 Hz, 1,2-isomer), 7.72 (d, 2H, J = 9.0 Hz, 1,4-isomer), 7.80 (s, 1H,
1,2-isomer); 13C NMR (125.8 MHz, CDCl3): 13.9, 14.2, 14.3, 14.5, 29.7
5m and 5'm: yellow solid, only 1,4-isomer was already reported;[14b] IR 
1734, 1703, 1626 cm1; 1H NMR (500.3 MHz, CDCl3, 1,4- and 1,2-isomer
1:1.8): 1.16 (t, 3H, J  7.0 Hz, 1,2-isomer), 1.19 (t, 3H, J  7.2 Hz, 1,4-
isomer), 1.30-1.35 (m, 12H, 1,2- and 1,4-isomers), 2.36 (s, 3H, 1,2-
isomer), 2.37 (s, 3H, 1,4-isomer), 2.51-2.55 (dd, 1H, J  6.0 Hz, J  13.5
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10.1002/asia.201800645
Chemistry - An Asian Journal
FULL PAPER
(1,4-isomer), 38.3 (1,2-isomer), 40.3 (1,4-isomer), 54.7 (1,2-isomer), 60.1,
60.3, 60.4, 60.7, 61.0, 89.9, 106.4, 109.0, 113.5, 122.5, 131.8, 137.0,
138.8, 138.9, 143.2, 143.4, 165.0, 165.4, 169.9; HRMS calcd. for
C21H25INO6 [M+H] +: 514.0727, found: 514.0731.
2E,4Z and 2E,4E 1:1): 1.31 (t, 3H, J  7.0 Hz), 1.32 (t, 3H, J  7.5 Hz),
1.36 (t, 3H, J  7.2 Hz), 1.41 (t, 3H, J  7.2 Hz), 4.22 (q, 2H, J  7.5 Hz),
4.24 (q, 2H, J  7.0 Hz), 4.30 (q, 2H, J  7.2 Hz), 4.35 (q, 2H, J  7.2 Hz),
6.27 (d, 1H, J  16.0 Hz, 2E,5Z), 6.59 (d, 1H, J  15.5 Hz, 2E,5E), 7.14
(d, 2H, J  9.5 Hz, 2E,5Z), 7.17 (d, 2H, J  9.0 Hz, 2E,5E), 7.45 (d, 1H, J
 16.0 Hz, 2E,5Z), 7.60 (d, 1H, J  15.5 Hz, 2E,5E), 7.74 (d, 1H, J  13.0
Hz, 2E,5Z), 7.92 (d, 1H, J  14.0 Hz, 2E,5E), 8.14 (d, 1H, J  14.0 Hz,
2E,5E), 8.25 (d, 2H, J  9.5 Hz, 2E,5Z), 8.25 (d, 2H, J  9.0 Hz, 2E,5E),
8.25 (d, 2H, J  9.5 Hz, 2E,5Z), 11.02 (d, 1H, J  13.0 Hz, 2E,5Z); 13C
NMR (125.8 MHz, CDCl3): 14.3, 14.4, 14.4, 60.2, 60.6, 60.8, 61.1, 102.3,
104.4, 114.1 (2E,5Z), 115.4, 115.6, 119.4 (2E,5E), 126.1 (2E,5Z), 126.1
(2E,5E), 134.2 (2E,5E), 140.5 (2E,5E), 140.8 (2E,5Z), 143.1, 143.3,
144.6, 144.7, 145.4, 166.2, 167.8, 168.1, 168.6; HRMS calcd. for
C16H18N2NaO6 [M+Na] +: 357.1063, found: 357.1053.
3p: Z isomer, orange solid, mp 127-129 C; IR  3294, 3112, 1668, 1639,
1600, 1334 cm1; 1H NMR (200 MHz, CDCl3) 1.32 (t, 3H, J = 7.2 Hz),
4.21 (q, 2H, J = 7.2 Hz), 5.06 (d, 1H, J = 8.6 Hz), 7.00 (d, 2H, J = 9.2 Hz),
7.27 (dd, 1H, J = 8.6 Hz, J  12.2 Hz), 8.20 (d, 2H, J = 9.2 Hz), 10.29 (d,
1H, J = 12.2 Hz); 13C NMR (50.3 MHz, CDCl3): 14.1, 59.9, 92.3, 114.1,
126.1, 140.5, 142.0, 146.0, 169.8; HRMS calcd. for C11H13N2O4 [M+H] +:
237.0875, found: 237.0865.
(2E,4Z)- and (2E,4E)-diethyl 4-(((4-fluorophenyl)amino)methylene)-
pent-2-enedioate (4o)
Method A: 46.0 mg (35%) from 1o (48.0 mg, 0.43 mmol) and 2a (168.7
mg, 1.72 mmol) in EtOH (1.5 mL) during 120 h, along with 3o (41.0 mg,
45%) and 5/5'o (10.0 mg, 6%).
Method B: 80.0 mg (60%) from 1o, 48.0 mg, 0.43 mmol) and 2a (168.7
mg, 1.72 mmol) during 72 h, along with 3o (10.0 mg, 11%) and 5/5'o
(17.0 mg, 10%).
Method C: 52.0 mg (63%) from 1o (30.0 mg, 0.27 mmol) and 2a (53.0
mg, 0.54 mmol) during 9 h, along with 5/5'o (23.0 mg, 21%) and 6a (1.1
mg; 2%).
4o: pale yellow solid, mp 70-72 C (lit.12c 74-78 C), IR (2E,4Z and 2E,4E
10:1)  3422, 1676, 1655, 1593 cm1; 1H NMR (500.3 MHz, CDCl3, 2E,4Z
and 2E,4E 10:1): 1.31 (t, 3H, J = 7.0 Hz, 2E,4Z), 1.34 (t, 3H, J = 7.0 Hz,
2E,4E), 1.39 (t, 3H, J = 7.0 Hz, 2E,4Z), 4.21 (q, 2H, J = 7.0 Hz, 2E,4Z),
4.26 (q, 2H, J = 7.0 Hz, 2E,4E), 4.31 (q, 2H, J = Hz, 2E,4Z), 6.18 (d, 1H,
J = 16.0 Hz, 2E,4Z), 6.57 (d, 1H, J = 15.7 Hz, 2E,4E), 7.03-7.07 (m, 4H,
2E,4Z and 2E,4E), 7.32 (d, 1H, J = 12.5 Hz, 2E,4E), 7.46 (d, 1H, J = 16.0
Hz, 2E,4Z), 7.65 (d, 1H, J = 13.0 Hz, 2E,4Z), 7.67 (d, 1H, J = 15.7 Hz,
2E,4E), 10.75 (d, 1H, J = 13.0 Hz, 2E,4Z); 13C NMR (125.8 MHz, CDCl3):
14.3, 14.3, 59.8, 60.4, 98.5, 111.0, 116.5 (d, JC-F  23.1 Hz), 118.1 (d, JC-
F  6.8 Hz), 135.7 (d, JC-F  2.4 Hz), 159.5 (d, JC-F  244.2 Hz), 168.3,
168.9.
5p and 5'p: yellow-brown solid; IR  1710, 1692, 1635, 1596, 1553, 1518,
1
1344 cm1; H NMR (500.3 MHz, CDCl3, mixture of 1,4- and 1,2-isomers
1:4): 1.16 (t, 3H, J = 7.0 Hz, 1,4-isomer), 1.19 (t, 3H, J = 7.0 Hz, 1,2-
isomer), 1.33 (t, 9H, J = 7.0 Hz, 1,2- and 1,4-isomer), 1.36 (t, 3H, J = 7.0
Hz, 1,2-isomer), 2.56-2.60 (dd, 1H, J = 6.5 Hz, J = 14.0 Hz, 1,2-isomer),
2.64 (d, 2H, J = 4.5 Hz, 1,4-isomer), 2.65-2.69 (dd, 1H, J = 6.5 Hz, J =
14.0 Hz, 1,2-isomer), 3.99-4.07 (m, 4H, 1,2- and 1,4-isomer), 4.21-4.33
(m, 9H, 1,2- and 1,4-isomer), 5.71 (dt, 1H, J = 1.5 Hz, J = 6.5 Hz, 1,2-
isomer), 7.36 (d, 2H, J = 9.0 Hz, 1,4-isomer), 7.44 (d, 2H, J = 9.0 Hz, 1,2-
isomer), 7.68 (s, 2H, 1,4-isomer), 7.69 (s, 1H, 1,2-isomer), 7.89 (s, 1H,
1,2-isomer), 8.29 (d, 2H, J = 9.0 Hz, 1,2-isomer), 8.30 (d, 2H, J = 9.0 Hz,
1,4-isomer); 13C NMR (125.8 MHz, CDCl3, 1,4- and 1,2-isomer 1:4): 14.7,
14.9, 15.0, 15.1, 15.2, 30.4 (1,4-isomer), 38.8 (1,2-isomer), 40.5 (1,4-
isomer), 54.4 (1,2-isomer), 60.8, 61.5, 61.7, 61.9, 109.5, 111.8, 117.0,
3o: Z isomer, pale yellow solid, mp 36-38 C (lit.[15] 35-38 C); IR  3366,
1665, 1594, 1512 cm1; 1H NMR (500.3 MHz, CDCl3): 1.30 (t, 3H, J = 7.0
Hz), 4.18 (q, 2H, J = 7.0 Hz), 4.83 (d, 1H, J = 8.5 Hz), 6.90-6.92 (m, 2H),
7.00 (t, 2H, J = 8.5 Hz), 7.14 (dd, 1H, J = 8.5 Hz, J = 12.5 Hz), 9.87
(broad d, 1H, J = 12.5 Hz); 13C NMR (125.8 MHz, CDCl3): 14.4, 59.3,
87.4, 116.3 (d, JC-F  22.6 Hz), 116.7 (d, JC-F  7.5 Hz), 137.1, 143.5,
158.6 (d, JC-F  241.5 Hz), 170.4.
5o and 5'o: yellow solid, only 1,4-isomer was already reported;[15] IR 
1733, 1692, 1628, 1511 cm1; 1H NMR (500.3 MHz, CDCl3, 1,4- and 1,2-
isomer 1:2): 1.15 (t, 3H, J = 7.0 Hz, 1,2-isomer), 1.18 (t, 3H, J = 7.0 Hz,
1,4-isomer), 1.29-1.35 (m, 12H, 1,2- and 1,4-isomers), 2.48-2.52 (dd, 1H,
J = 6.0 Hz, J = 13.7 Hz, 1,2-isomer), 2.60 (d, 2H, J = 5.0 Hz, 1,4-isomer),
2.63-2.67 (dd, 1H, 6.0 Hz, J = 13.7 Hz, 1,2-isomer), 3.91-4.07 (m, 4H,
1,2- and 1,4-isomers), 4.22-4.28 (m, 8H, 1,2- and 1,4-isomers), 5.60 (dt,
1H, J = 1.5 Hz, J = 6.0 Hz, 1,2-isomer), 7.10-7.13 (m, 4H, 1,2- and 1,4-
isomers), 7.20-7.22 (m, 2H, 1,4-isomer), 7.30-7.33 (m, 2H, 1,2-isomer),
7.48 (s, 2H, 1,4-isomer), 7.72 (d, 1H, J = 1.0 Hz, 1,2-isomer), 7.77 (t, 1H,
J = 1.5 Hz, 1,2-isomer); 13C NMR (125.8 MHz, CDCl3, 1,4- and 1,2-
isomer 1:2): 15.5, 15.8, 15.9, 16.1, 31.1 (1,4-isomer), 39.9 (1,2-isomer),
42.0 (1,4-isomer), 57.2 (1,2-isomer), 61.6, 61.8, 61.9, 62.2, 62.5, 106.8,
109.8, 114.1, 118.2 (d, JC-F  23.9 Hz, 1,2-isomer), 118.2 (d, JC-F  22.6
Hz, 1,4-isomer), 124.7 (d, JC-F  8.8 Hz, 1,4-isomer), 125.0 (d, JC-F  7.5
Hz, 1,2-isomer), 133.7, 139.4, 141.1, 141.7, 146.3, 166.7, 167.1, 168.2,
171.6, 173.2; HRMS calcd. for C21H25FNO6 [M+H] +: 406.1666, found:
406.1670.
119.6, 120.1, 126.3, 126.5, 131.7, 136.4, 141.3, 145.0, 149.0, 165.4,
+
165.6, 166.8, 170.4, 172.1; HRMS calcd. for C21H25N2O8 [MH]
:
431.1449, found: 431.1441.
(2E,4Z)- and (2E,4E)-diethyl 4-(((3-chloro-4-methylphenyl)amino)me-
thylene)pent-2-enedioate (4q)
Method A: 25.5 mg (27%), obtained in a mixture with 7q (29.0 mg of the
mixture containing 88% of 4q and 12% of 7q), from 1q (40.0 mg, 0.28
mmol) and 2a (109.9 mg, 1.12 mmol) in EtOH (1.2 mL) during 120 h,
along with 3q (32.0 mg, 47%) and 5/5'q (9.0 mg, 7%).
Method B: 52.4 mg (55%), obtained in a mixture with 7q (57.0 mg of the
mixture containing 92% of 4q and 8% of 7q), from 1q (40.0 mg, 0.28
mmol) and 2a (109.9 mg, 1.12 mmol) during 96 h, along with 3q (9.0 mg,
13%) and 5/5'q (15.0 mg, 12%).
Method C: 41.0 mg (57%) from 1q (30.0 mg, 0.21 mmol) and 2a (41.6
mg, 0.42 mmol) during 7 h, along with 5/5'q (30.0 mg, 32%) and 6a (2.1
mg; 5%).
4q: yellow oil; IR (2E,4Z and 2E,4E 5:1)  3287, 1701, 1664, 1601 cm1
;
1H NMR (500.3 MHz, CDCl3, 2E,4Z and 2E,4E 5:1): 1.31 (t, 3H, J  7.0
Hz, 2E,4Z), 1.34 (t, 3H, J  7.5 Hz, 2E,4E), 1.39 (t, 3H, J  7.0 Hz, 2E,4Z),
2.30 (s, 3H, 2E,4E), 2.33 (s, 3H, 2E,4Z), 4.22 (q, 2H, J  7.0 Hz, 2E,4Z),
4.32 (q, 2H, J  7.0 Hz, 2E,4Z), 6.18 (d, 1H, J  15.7 Hz, 2E,4Z), 6.49 (d,
1H, J  16.0 Hz, 2E,4E), 6.86 (dd, 1H, J  2.5 Hz, J  8.0 Hz, 2E,4Z),
7.08 (d, 1H, J  2.5 Hz, 2E,4Z), 7.11 (d, 1H, J  2.0 Hz, 2E,4E), 7.19 (d,
1H, J  8.0 Hz, 2E,4Z), 7.46 (d, 1H, J  15.7 Hz, 2E,4Z), 7.60 (d, 1H, J 
16.0 Hz, 2E,4E), 7.66 (d, 1H, J  13.0 Hz, 2E,4Z), 8.08 (d, 1H, J  14.0
Hz, 2E,4E), 10.70 (d, 1H, J  13.0 Hz, 2E,4Z); 13C NMR (125.8 MHz,
CDCl3, only signals for 2E,4Z isomer are clearly visible): 14.3, 14.4, 19.3,
59.9, 60.5, 98.9, 111.4, 114.9, 117.0, 131.9, 135.5, 138.3, 141.9, 147.2,
(2E,4Z)- and (2E,4E)-diethyl 4-(((4-nitrophenyl)amino)methylene)-
pent-2-enedioate (4p)
Method A: Only 3p (11.0 mg, 14%) was obtained from 1p (45.0 mg, 0.33
mmol) and 2a (125.6 mg, 1.28 mmol) in EtOH (1.3 mL) during 120 h.
Method B: 20.0 mg (18%) from 1p (45.0 mg, 0.33 mmol) and 2a (125.6
mg, 1.28 mmol) during 120 h, along with 3p (25.0 mg, 32%).
Method C: 15.0 mg (21%) from 1p (30.0 mg, 0.22 mmol) and 2a (42.6
mg, 0.44 mmol) during 9.5 h, along with 5/5'p (20.0 mg, 21%).
4p: pale yellow solid, mp 136-137 C; IR (2E,4Z and 2E,4E 1:1)  3193,
1
1706, 1658, 1620, 1588, 1517, 1331 cm1; H NMR (500.3 MHz, CDCl3,
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10.1002/asia.201800645
Chemistry - An Asian Journal
FULL PAPER
168.3, 168.9; HRMS calcd. for C17H21ClNO4 [M+H] +: 338.1159, found:
338.1152.
2H, J = 7.2 Hz), 4.90 (d, 1H, J = 8.4 Hz), 6.77 (dd, 1H, J = 2.6 Hz, J = 8.6
Hz), 7.05 (d, 1H, J = 2.6 Hz), 7.12 (dd, 1H, J = 8.4 Hz, J = 12.4 Hz), 7.32
(d, 1H, J = 8.6 Hz), 9.92 (d, 1H, J = 12.4 Hz); 13C NMR (50.3 MHz,
3q: Z isomer, pale yellow solid, mp 103-105 C; IR  3296, 3269, 1692,
1666, 1608, 1573 cm1; 1H NMR (200 MHz, CDCl3): 1.31 (t, 3H, J = 7.2
Hz), 2.31 (s, 3H), 4.18 (q, 2H, J = 7.2 Hz), 4.84 (d, 1H, J = 8.4 Hz), 6.75
(dd, 1H, J = 2.4 Hz, J = 8.2 Hz), 6.98 (d, 1H, J = 2.4 Hz), 7.13 (d, 1H, J =
8.2 Hz), 7.16 (dd, 1H, J = 8.4 Hz, J  12.8 Hz), 9.85 (d, 1H, J = 12.8 Hz);
13C NMR (50.3 MHz, CDCl3): 14.2, 19.2, 59.3, 88.0, 113.9, 115.6, 115.7,
129.8, 131.6, 135.2, 139.7, 142.7, 170.3; HRMS calcd. for
C12H14ClNNaO2 [M+Na] +: 262.0611, found: 262.0602.
CDCl3): 14.2, 15.6, 89.5, 114.8, 116.7, 125.3, 131.2, 133.5, 140.3, 141.9,
+
170.2; HRMS calcd. for C11H12Cl2NO2 [M+H]
260.0237.
: 260.0245, found:
5r and 5'r: yellow solid; IR  1731, 1694, 1629, 1592 cm1; 1H NMR
(500.3 MHz, CDCl3, mixture of 1,4- and 1,2-isomers 1:5.6): 1.17 (t, 3H, J
 7.2 Hz, 1,2- and 1,4-isomers), 1.29 (t, 3H, J  7.0 Hz, 1,4-isomer), 1.30
(t, 3H, J  7.2 Hz, 1,2-isomer), 1.32 (t, 3H, J  7.0 Hz, 1,2-isomer), 2.47-
2.51 (dd, 1H, J  6.0 Hz, J  14.0 Hz, 1,2-isomer), 2.58 (d, 2H, J  5.0 Hz,
1,4-isomer), 2.59-2.63 (dd, 1H, J  6.0 Hz, J  14.0 Hz, 1,2-isomer), 3.95-
4.00 (m, 4H, 1,2- and 1,4-isomers), 4.21-4.28 (m, 9H, 1,2- and 1,4-
isomers), 5.56 (dt, 1H, J = 1.5 Hz, J  6.0 Hz, 1,2-isomer), 7.07 (dd, 1H, J
 3.0 Hz, J  9.0 Hz, 1,4-isomer), 7.18 (dd, 1H, J  3.0 Hz, J  9.0 Hz,
1,2-isomer), 7.32 (d, 1H, J  3.0 Hz, 1,4-isomer), 7.41 (d, 1H, J  3.0 Hz,
1,2-isomer), 7.44 (d, 1H, J  9.0 Hz, 1,2-isomer), 7.45 (d, 1H, J  9.0 Hz,
1,4-isomer), 7.48 (s, 2H, 1,4-isomer), 7.66 (d, 1H, J = 1.0 Hz, 1,2-isomer),
7.74 (t, 1H, J = 1.0 Hz, 1,2-isomer); 13C NMR (125.8 MHz, CDCl3,
mixture of 1,4- and 1,2-isomers 1:5.6): 14.6, 14.9, 15.0, 15.2, 30.2 (1,4-
isomer), 38.9 (1,2-isomer), 40.8 (1,4-isomer), 55.4 (1,2-isomer), 60.8,
61.1, 61.2, 61.5, 61.8, 107.0, 110.2, 114.9, 120.4, 120.5, 123.1, 123.2,
5q and 5'q: yellow solid; IR  1734, 1704, 1605 cm1 1H NMR (500.3
;
MHz, CDCl3, mixture of 1,4- and 1,2-isomers 1:3.3): 1.18 (t, 3H, J = 7.2
Hz, 1,2-isomer), 1.18 (t, 3H, J = 7.2 Hz, 1,4-isomer), 1.30-1.35 (m, 12H,
1,2- and 1,4-isomers), 2.37 (s, 3H, 1,2-isomer), 2.37 (s, 3H, 1,4-isomer),
2.49-2.53 (dd, 1H, J = 6.0 Hz, J = 13.7 Hz, 1,2-isomer), 2.59 (d, 2H, J =
5.0 Hz, 1,4-isomer), 2.61-2.65 (dd, 1H, J = 6.0 Hz, J = 13.7 Hz, 1,2-
isomer), 3.94-4.06 (m, 4H, 1,2- and 1,4-isomers), 4.22-4.29 (m, 9H, 1,2-
and 1,4-isomers), 5.60 (dt, 1H, J = 1.5 Hz, J = 6.0 Hz, 1,2-isomer), 7.03
(dd, 1H, J = 2.5 Hz, J = 8.2 Hz, 1,4-isomer), 7.14 (dd, 1H, J = 2.5 Hz, J =
8.5 Hz, 1,2-isomer), 7.23 (d, 1H, J = 2.5 Hz, 1,4-isomer), 7.26 (d, 1H, J =
8.5 Hz, 1,2-isomer), 7.32, (d, 1H, J = 2.5 Hz, 1,2-isomer), 7.51 (s, 2H,
1,4-isomer), 7.70 (s, 1H, 1,2-isomer), 7.79 (s, 1H, 1,2-isomer); 13C NMR
(125.8 MHz, CDCl3, mixture of 1,4- and 1,2-isomers 1:3.3): 13.9, 14.2,
14.3, 14.5, 18.9 (1,4-isomer), 19.5 (1,2-isomer), 29.6 (1,4-isomer), 38.3
(1,2-isomer), 40.4 (1,4-isomer), 55.1 (1,2-isomer), 60.1, 60.2, 60.4, 60.6,
61.0, 104.8, 108.6, 113.1, 113.7, 119.0, 119.1, 121.4, 121.6, 131.3,
131.8, 132.0, 134.0, 135.3, 137.2, 141.8, 142.6, 143.7, 165.1, 165.4,
166.6, 169.9, 171.6; HRMS calcd. for C22H27ClNO6 [M+H] +: 436.1527,
found: 436.1518.
130.3, 132.0, 132.1, 132.2, 134.4, 137.3, 142.9, 143.2, 143.7, 165.6,
+
165.9, 167.1, 170.5, 172.2; HRMS calcd. for C21H24Cl2NO6 [M+H]
456.0981, found: 456.0967.
:
(2E,4Z)-diethyl 4-(((2,4-dimethylphenyl)amino)methylene)pent-2-ene-
dioate (4s)
Method A: 23.4 mg (26%), obtained in a mixture with 6a (26.0 mg of the
mixture containing 90% of 4s and 10% of 6a), from 1s (35.0 mg, 0.29
mmol) and 2a (113.3 mg, 1.16 mmol) in EtOH (1.2 mL) during 120 h,
along with 3s (14.0 mg, 22%).
Method B: 38.2 mg (42%), obtained in a mixture with 7s (46.0 mg of the
mixture containing 83% of 4s and 17% of 7s), from 1s (35.0 mg, 0.29
mmol) and 2a (113.3 mg, 1.16 mmol) during 72 h, along with 3s (4.0 mg,
6%) and 5s (8.0 mg, 7%).
Method C: 26.7 mg (34%), obtained in a mixture with 6a (31.0 mg of the
mixture containing 86% of 4s and 14% of 6), from 1s (30.0 mg, 0.25
mmol) and 2a (48.6 mg, 0.50 mmol) during 3 h, along with 5s (38.0 mg,
37%); 6a (2.0 mg; 4%).
7q: 1H NMR (500.3 MHz, CDCl3): 2.29 (s, 6H), 2.89 (d, 2H, J = 8.0 Hz),
4.00 (t, 1H, J = 8.0 Hz), 7.31 (d, 2H, J = 12.5 Hz), 9.97 (d, 2H, J = 12.5
Hz), assignation of other signals is not safe; due to the low concentration,
signals of 7q are not visible in the 13C NMR spectrum; HRMS calcd. for
C29H34Cl2N2NaO6 [M+Na] +: 599.1692, found: 599.1688.
(2E,4Z)-and (2E,4E)-diethyl 4-(((3,4-dichlorophenyl)amino)methy-
lene)pent-2-enedioate (4r)
Method A: 9.0 mg (8%) from 1r (50.0 mg, 0.31 mmol) and 2a (121.1 mg,
1.23 mmol) in EtOH (1.5 mL) during 144 h, along with 3r (40.0 mg, 50%)
and 5/5'r (6.0 mg, 4%).
Method B: 25.0 mg (21%) from 1r (55.0 mg, 0.34 mmol) and 2a (133.2
mg, 1.36 mmol) during 96 h, along with 3r (31.0 mg, 35%) and 5/5'r (18.0
mg, 12%).
Method C: 35.0 mg (53%) from 1r (30.0 mg, 0.19 mmol) and 2a (36.3
mg, 0.37 mmol) during 9 h, along with 5/5'r (21.0 mg, 25%) and 6a (3.0
mg; 8%).
4s: yellow solid; IR  3427, 3279, 1673, 1656, 1593 cm1; 1H NMR (500.3
MHz, CDCl3): 1.31 (t, 3H, J  7.0 Hz), 1.40 (t, 3H, J  7.0 Hz), 2.30 (s,
3H), 2.32 (s, 3H), 4.22 (q, 2H, J  7.0 Hz), 4.33 (q, 2H, J  7.0 Hz), 6.17
(d, 1H, J  15.5 Hz), 7.02-7.06 (m, 3H), 7.50 (d, 1H, J  15.5 Hz), 7.76 (d,
1H, J  13.0 Hz), 10.83 (d, 1H, J  13.0 Hz); 13C NMR (125.8 MHz,
CDCl3): 14.5, 17.4, 20.7, 59.8, 60.4, 98.1, 110.3, 114.8, 126.8, 127.9,
131.9, 134.4, 135.6, 142.6, 148.5, 168.6, 169.2; HRMS calcd. for
C18H24NO4 [M+H] +: 318.1705, found: 318.1693.
3s: Z isomer, reddish oil; IR  3431, 3277, 1676, 1654, 1622, 1594 cm1;
1H NMR (500.3 MHz, CDCl3): 1.31 (t, 3H, J = 7.0 Hz), 2.28 (s, 3H), 2.30
(s, 3H), 4.20 (q, 2H, J = 7.0 Hz), 4.84 (d, 1H, J = 8.0 Hz), 6.93 (d, 1H, J =
9.0 Hz), 6.98-7.00 (m, 3H), 7.27 (dd, 1H, J = 8.0 Hz, J = 12.5 Hz), 9.92 (d,
1H, J = 12.5 Hz); 13C NMR (125.8 MHz, CDCl3): 14.5, 17.4, 20.6, 59.2,
86.8, 113.2, 125.4, 127.6, 131.7, 131.9, 136.8, 143.8, 170.7; HRMS
calcd. for C13H18NO2 [M+H] +: 220.1338, found: 220.1325.
4r: yellow oil; IR (2E,4Z and 2E,4E 2.5:1)  3416, 1677, 1661, 1630,
1589 cm1; 1H NMR (500.3 MHz, CDCl3, 2E,4Z and 2E,4E 2.5:1): 1.31 (t,
3H, J = 7.2 Hz, 2E,4E), 1.31 (t, 3H, J = 7.2 Hz, 2E,4Z), 1.35 (t, 3H, J =
7.2 Hz, 2E,4E), 1.39 (t, 3H, J = 7.2 Hz, 2E,4Z), 4.22 (q, 2H, 7.2 Hz,
2E,4Z and 2E,4E), 4.28 (q, 2H, J = 7.2 Hz, 2E,4E), 4.32 (q, 2H, J = 7.2
Hz, 2E,4Z), 6.20 (d, 1H, J = 15.5 Hz, 2E,4Z), 6.53 (d, 1H, J = 16.0 Hz,
2E,4E), 6.90 (dd, 1H, J = 2.5 Hz, J = 8.7 Hz, 2E,4Z), 6.94 (dd, 1H, J = 2.5
Hz, J = 8.7 Hz, 2E,4E), 7.18 (d, 1H, J = 2.5 Hz, 2E,4Z), 7.21 (d, 1H, J =
2.5 Hz, 2E,4E), 7.39 (d, 1H, J = 8.7 Hz, 2E,4E), 7.40 (d, 1H, J = 8.7 Hz,
2E,4Z), 7.44 (d, 1H, J = 15.5 Hz, 2E,4Z), 7.58 (d, 1H, J = 16.0 Hz, 2E,4E),
7.62 (d, 1H, J = 12.5 Hz, 2E,4Z), 7.67 (d, 1H, J = 13.7 Hz, 2E,4E), 8.02
(d, 1H, J = 13.7 Hz, 2E,4E), 10.75 (d, 1H, J = 12.5 Hz, 2E,4Z); 13C NMR
(125.8 MHz, CDCl3, only signals for 2E,4Z isomer are clearly visible):
14.3, 14.4, 60.0, 60.7, 100.1, 112.5, 115.8, 118.0, 127.4, 131.4, 133.9,
139.0, 141.4, 146.3, 168.1, 168.8; HRMS calcd. for C16H18Cl2NO4 [M+H]
+: 358.0613, found: 358.0605.
5s: yellow solid, mp 62-64 C (lit.[14b] 76-77 C); IR  1734, 1705, 1588
cm1; 1H NMR (500.3 MHz, CDCl3): 1.23 (t, 3H, J = 7.0 Hz), 1.30 (t, 6H, J
= 7.0 Hz), 2.28 (s, 3H), 2.36 (s, 3H), 2.62 (d, 1H, J = 5.0 Hz), 4.09 (q, 2H,
J = 7.0 Hz), 4.22 (2  q, 4H, J = 7.0 Hz), 4.31 (t, 1H, J = 5.0 Hz), 7.07 (2
 s, 2H), 7.11 (s, 1H), 7.24 (s, 2H); 13C NMR (125.8 MHz, CDCl3): 14.9,
15.1, 18.3, 21.7, 30.2, 41.3, 60.7, 60.8, 107.1, 126.7, 128.6, 132.9, 134.6,
139.0, 140.3, 140.8, 167.6, 172.5.
1
3r: Z isomer, yellow amorphous substance; IR  3313, 1664, 1634, 1598,
7s: H NMR (500.3 MHz, CDCl3): 1.20 (t, 3H, J = 7.0 Hz), 1.26 (t, 3H, J =
1
1568 cm1; H NMR (200 MHz, CDCl3): 1.30 (t, 3H, J = 7.2 Hz), 4.18 (q,
7.0 Hz), 2.27 (s, 12H), 2.92 (d, 2H, J = 8.0 Hz), 4.09 (t, 1H, J = 8.0 Hz),
This article is protected by copyright. All rights reserved.

10.1002/asia.201800645
Chemistry - An Asian Journal
FULL PAPER
4.11 (q, 2H, J = 7.0 Hz), signal of another ester group is covered by the
signal of 4s, 6.95-6.98 (m, 6H), 7.46 (d, 2H, J = 12.5 Hz), 10.01 (d, 2H, J
= 12.5 Hz); 13C NMR (125.8 MHz, CDCl3, not all signals are clearly
Method C: 30.0 mg (42%), obtained in a mixture with 7u (40.0 mg of the
mixture containing 75% of 4u and 25% of 7u), from 1u, 30.0 mg, 0.21
mmol) and 2a (41.6 mg, 0.42 mmol) during 8 h, along with 5/5'u (22.0 mg,
24%).
visible): 14.2, 14.3, 17.5, 20.6, 37.4, 38.5, 59.5, 99.6, 112.7, 127.6, 131.6,
134.4, 137.2, 142.9, 169.9; HRMS calcd. for C31H40N2NaO6 [M+H]
559.2784, found: 559.2764.
:
4u: pale yellow solid; IR  3424, 1664, 1626, 1597 cm1; 1H NMR (500.3
MHz, CDCl3, 4u and 7u 5:1): 1.20 (t, 3H, J = 7.2 Hz, 7u), 1.28 (t, 6H, J =
7.2 Hz, 7u), 1.31 (t, 3H, J = 7.2 Hz, 4u), 1.40 (t, 3H, J = 7.2 Hz, 4u), 2.28
(s, 6H, 7u), 2.31 (s, 3H, 4u), 2.94 (d, 2H, J = 8.0 Hz, 7u), 4.09 (t, 1H, J =
8.0 Hz, 7u), 4.11 (q, 2H, J = 7.2 Hz, 7u), 4.22 (q, J = 7.2 Hz, 4u), 4.21-
4.24 (m, 4H, 7u), 4.36 (q, J = 7.2 Hz, 4u), 6.23 (d, 1H, J = 15.5 Hz, 4u),
7.03 (broad s, 4H, 7u), 7.10 (broad s, 2H, 4u), 7.17 (broad signal, 2H,
7u), 7.22 (broad s, 1H, 4u), 7.42 (d, 2H, J = 12.0 Hz, 7u), 7.47 (d, 1H, J =
15.5 Hz, 4u), 7.71 (d, 1H, J = 13.0 Hz, 4u), 10.25 (broad d, 2H, J = 12.0
Hz, 7u), 11.02 (broad d, 1H, J = 13.0 Hz, 4u); 13C NMR (125.8 MHz,
CDCl3, 4u and 7u 5:1): 14.4, 20.3 (7u), 20.5 (4u), 37.8 (7u), 38.3 (7u),
59.8 (7u), 59.9 (4u), 60.4 (7u), 60.6 (4u), 99.8 (4u), 101.2 (7u), 111.8
(4u), 113.1 (7u), 114.6 (4u), 121.4 (7u), 122.8 (4u), 128.5 (7u), 128.7
(4u), 130.3 (7u), 130.5 (4u), 131.9, 134.0, 134.6, 135.5, 140.9, 142.1
(4u), 146.2 (4u), 168.3 (4u), 168.5 (4u), 169.2 (7u), 172.3 (7u); HRMS
calcd. for 4u C17H21ClNO4 [M+H]+: 338.1159, found: 338.1149; HRMS
calcd. for 7u C29H34Cl2N2NaO6 [M+H] +: 599.1692, found: 599.1678.
3u: pale yellow solid, mp 48-50 C; IR  3275, 3225, 1668, 1623 cm1;1H
NMR (200 MHz, CDCl3): 1.31 (t, 3H, J = 7.2 Hz), 2.27 (s, 3H), 4.22 (q, 2H,
J = 7.2 Hz), 4.91 (d, 1H, J = 8.4 Hz), 6.94-7.04 (m, 2H), 7.17 (s, 1H), 7.21
(dd, 1H, J = 8.4 Hz, J = 12.4 Hz), 10.25 (d, 1H, J = 12.4 Hz); 13C NMR
+
(2E,4Z)-diethyl 4-(((2,3-dimethylphenyl)amino)methylene)pent-2-ene-
dioate (4t)
Method A: 46.0 mg (35%) from 1t (50.0 mg, 0.41 mmol) and 2a (160.9
mg, 1.64 mmol) in EtOH (1.5 mL) during 120 h, along with 3t (50.0 mg,
55%).
Method B: 60 mg (46%), obtained in a mixture with 7t (80.0 mg of the
mixture containing 75% of 4t and 25% of 7t), from 1t, 50.0 mg, 0.41
mmol) and 2a (160.9 mg, 1.64 mmol) during 72 h, along with 3t (20.0 mg,
22%).
Method C: 57.0 mg (73%) from 1t (30.0 mg, 0.25 mmol) and 2a (48.6
mg, 0.50 mmol) during 6 h, along with 5t (14.0 mg, 14%) and 6a (2.0 mg;
4%).
4t: pale yellow solid, mp 70-72 C; IR  3280, 1692, 1657, 1627, 1590
cm1; 1H NMR (500.3 MHz, CDCl3): 1.31 (t, 3H, J = 7.0 Hz), 1.40 (t, 3H, J
= 7.0 Hz), 2.25 (s, 3H), 2.32 (s, 3H), 4.21 (q, 2H, J = 7.0 Hz), 4.33 (q, 2H,
J = 7.0 Hz), 6.17 (d, 1H, J = 15.5 Hz), 6.96 (d, 1H, J = 7.7 Hz), 6.99 (d,
1H, J = 7.7 Hz), 7.13 (t, 1H, J = 7.7 Hz), 7.49 (d, 1H, J = 15.5 Hz), 7.75 (d,
1H, J = 12.5 Hz), 10.90 (d, 1H, J = 12.5 Hz); 13C NMR (125.8 MHz,
CDCl3): 13.1, 14.4, 14.4, 20.5, 59.8, 60.3, 98.3, 110.4, 113.2, 125.6,
126.3, 126.6, 138.1, 138.2, 142.5, 149.0, 168.5, 169.2; HRMS calcd. for
C18H24NO4 [M+H] +: 318.1705, found: 318.1690.
3t: Z isomer, yellow solid, mp 70-72 C; IR  3375, 1691, 1658, 1589
cm1; 1H NMR (200 MHz, CDCl3): 1.31 (t, 3H, J = 7.2 Hz), 2.23 (s, 3H),
2.31 (s, 3H), 4.20 (q, 2H, J = 7.2 Hz), 4.85 (d, 1H, J = 8.2 Hz), 6.86 (d,
1H, J = 7.8 Hz), 6.90 (d, 1H, J = 7.8 Hz), 7.08 (t, 1H, J = 7.8 Hz), 7.27 (dd,
1H, J = 8.2 Hz. J  12.6 Hz), 10.03 (d, 1H, J = 12.6 Hz); 13C NMR (50.3
(50.3 MHz, CDCl3): 14.3, 20.4, 59.4, 89.1, 113.3, 121.5, 128.4, 130.2,
+
132.4, 135.1, 141.6, 170.0; HRMS calcd. for C12H15ClNO2 [M+H]
240.0791, found: 240.0786.
:
5u and 5'u: yellow solid; IR  1731, 1702, 1629, 1597 cm1 1H NMR
;
(500.3 MHz, CDCl3, mixture of 1,4- and 1,2-isomers 2.5:1): 1.07 (t, 3H, J
 7.0 Hz, 1,2-isomer), 1.20 (t, 3H, J  7.2 Hz, 1,4-isomer), 1.27 (t, 3H, J 
7.0 Hz, 1,4-isomer), 1.28 (t, 3H, J  7.2 Hz, 1,2-isomer), 1.31 (t, 3H, J 
7.2 Hz, 1,2-isomer), 2.34 (s, 3H, 1,2-isomer), 2.35 (s, 3H, 1,4-isomer),
2.35-2.39 (dd, 1H, J  4.5 Hz, J  14.5 Hz, 1,2-isomer), 2.58 (d, 2H, J 
5.0 Hz, 1,4-isomer), 2.68-2.72 (dd, 1H, J  7.0 Hz, J  14.5 Hz, 1,2-
isomer), 4.06 (q, 2H, J  7.2 Hz, 1,4-isomer), 4.19 (q, 4H, J  7.0 Hz, 1,4-
isomer), 4.26 (t, 1H, J  5.0 Hz, 1,4-isomer), 5.47 (ddd, 1H, J = 1.0 Hz, J
 4.5 Hz, J  7.0 Hz, 1,2-isomer), 7.11 (d, 1H, J  8.0 Hz, 1,4-isomer),
7.12 (d, 1H, J  8.0 Hz, 1,2-isomer), 7.18 (d, 1H, J  8.0 Hz, 1,4-isomer),
7.24 (s, 2H, 1,4-isomer), 7.28 (s, 1H, 1,2- and 1,4-isomers), 7.31 (d, 1H,
J  8.0 Hz, 1,2-isomer), 7.56 (t, 1H, J = 1.0 Hz, 1,2-isomer), 7.71 (d, 1H,
J = 1.0 Hz, 1,2-isomer); 13C NMR (125.8 MHz, CDCl3, mixture of 1,4- and
1,2-isomers 2.5:1): 14.5, 14.9, 15.0, 15.2, 21.6, 30.1 (1,4-isomer), 39.1
(1,2-isomer), 41.4 (1,4-isomer), 57.0 (1,2-isomer), 60.7, 60.8, 61.0, 61.2,
61.4, 102.4, 107.9, 112.9, 128.0, 129.5, 129.7, 130.5, 130.9, 131.9,
133.4, 138.7, 139.8, 140.0, 140.4, 140.6, 149.4, 165.9, 166.2, 167.4,
170.8, 172.3; HRMS calcd. for C22H27ClNO6 [M+H]+: 436.1527, found:
436.1517.
MHz, CDCl3): 13.0, 14.3, 20.5, 59.2, 87.0, 111.5, 124.1, 124.4, 126.3,
+
137.9, 139.2, 144.1, 170.7; HRMS calcd. for C13H18NO2 [M+H]
220.1338, found: 220.1330.
:
5t: pale yellow solid, mp 103-105 C; IR  1730, 1703, 1665, 1626, 1587
cm1; 1H NMR (500.3 MHz, CDCl3): 1.21 (t, 3H, J = 7.0 Hz), 1.27 (t, 6H, J
= 7.0 Hz), 2.19 (s, 3H), 2.32 (s, 3H), 2.61 (d, 2H, J = 5.0 Hz), 4.07 (q, 2H,
J = 7.0 Hz), 4.20 (2  q, 6H, J = 7.0 Hz), 4.29 (t, 1H, J = 5.0 Hz), 7.02-
7.03 (broad signal, 1H), 7.13-7.16 (m, 2H), 7.22 (s, 2H); 13C NMR (125.8
MHz, CDCl3): 14.4, 14.5, 20.6, 29.7, 40.7, 60.1, 60.3, 97.9, 106.6, 126.7,
129.9, 133.2, 139.3, 139.8, 147.9, 167.0, 172.0; HRMS calcd. for
C23H30NO6 [M+H] +: 416.2073, found: 416.2072.
1
7t: H NMR (500.3 MHz, CDCl3): 1.20 (t, 3H, J = 7.0 Hz), 1.27 (t, 3H, J =
7.0 Hz), 2.20 (s, 6H), 2.30 (s, 6H), 2.93 (d, 2H, J = 8.0 Hz), 4.10 (t, 1H, J
= 8.0 Hz), 4.11 (q, 2H, J = 7.0 Hz), 4.21 (q, 2H, J = 7.0 Hz), 6.82 (d, 2H, J
= 7.5 Hz), 7.08 (t, 2H, J = 7.5 Hz), the third Harom is not visible, 7.48 (d,
2H, J = 12.5 Hz), 10.14 (d, 2H, J = 12.5 Hz); 13C NMR (125.8 MHz,
CDCl3): 12.9, 14.4, 20.5, 37.4, 38.4, 59.4, 99.8, 110.9, 123.7, 123.8,
126.2, 137.6, 139.5, 143.1, 169.8, 172.3; HRMS calcd. for C31H40N2NaO6
[M+H] +: 559.2784, found: 559.2763.
(2E,4Z)-diethyl 4-(pyrrolidin-1-ylmethylene)pent-2-enedioate (4v)
Method A: 139.0 mg (70%) from 1v (53.0 mg, 0.75 mmol) and 2a (220.7
mg, 2.25 mmol) in EtOH (2.0 mL) during 30 h, along with 3v (18.0 mg,
14%) and 6a (27.0 mg, 12%).
Due to overlapping of C(3)H and C(5)H signals, a precise determination
of stereochemistry around the C(4)C(5) double bond was not possible.
4v: pale yellow solid, mp 52-53 C; IR  2984, 1692, 1580, 1416, 1283
cm1; 1H NMR (500.3 MHz, CDCl3): 1.26 (t, 3H, J = 7.2 Hz), 1.30 (t, 3H, J
= 7.2 Hz), 1.95 (broad m, 4H), 3.62-3.64 (broad m, 4H), 4.16 (q, 2H, J =
7.2 Hz), 4.20 (q, 2H, J = 7.2 Hz), 6.26 (d, 1H, J = 15.3 Hz), 7.82 (s, 1H),
7.83 (d, 1H, J = 15.3 Hz); 13C NMR (125.8 MHz, CDCl3): 14.4, 14.5, 25.2
53.2, 59.6, 59.7, 96.4, 112.1, 138.1, 151.2, 168.4, 169.4.
(2E,4Z)-diethyl 4-(((2-chloro-4-methylphenyl)amino)methylene)pent-
2-enedioate (4u)
Method A: 17.0 mg (18%), obtained in a mixture with 7u (20.0 mg of the
mixture containing 85% of 4u and 15% of 7u), from 1u (40.0 mg, 0.28
mmol) and 2a (109.9 mg, 1.12 mmol) in EtOH (1.2 mL) during 120 h,
along with 3u (53.0 mg, 78%).
Method B: 16.0 mg (17%), obtained in a mixture with 7u (28.0 mg of the
mixture containing 57% of 4u and 43% of 7u), from 1u (40.0 mg, 0.28
mmol) and 2a (109.9 mg, 1.12 mmol) during 96 h, along with 3u (48.0 mg,
71%).
3v: E isomer; pale yellow solid, mp 39-40 C (previously isolated as an
oil);[39] IR  2975, 2867, 1686, 1613, 1149 cm1 1H NMR (200 MHz,
;
CDCl3): 1.26 (t, 3H, J = 7.2 Hz), 1.90-1.97 (m, 4H), 3.27 (broad s, 4H),
This article is protected by copyright. All rights reserved.

10.1002/asia.201800645
Chemistry - An Asian Journal
FULL PAPER
4.13 (q, 2H, J = 7.2 Hz), 4.47 (d, 1H, J = 12.8 Hz), 7.65 (d, 1H, J = 12.8
1.34 (sext, 2H, J  7.5 Hz), 1.50 (sext, 2H, J  7.5 Hz), 1.60 (quint, 2H, J
 7.5 Hz), 1.79 (quint, 2H, J  7.5 Hz), 4.12 (t, 2H, J  6.5 Hz), 4.36 (t, 2H,
J  6.5 Hz), 4.46 (s, 2H), 7.60 (t, 1H, J  7.5 Hz), 7.81 (t, 1H, J  7.5 Hz),
7.92 (d, 1H, J  8.5 Hz), 8.10 (d, 1H, J  8.5 Hz), 8.85 (s, 1H); 13C NMR
(125.8 MHz, CDCl3): 13.6, 13.7, 19.0, 19.3, 30.6, 30.7, 44.6, 64.8, 65.5,
121.1, 123.7, 126.3, 127.2, 128.6, 128.9, 131.9, 140.4, 154.6, 166.0,
170.9; HRMS calcd. for C20H26NO4 [M+H]+: 344.1862, found: 344.1846.
Hz); 13C NMR (50.3 MHz, CDCl3): 14.4, 25.2, 58.7, 84.4, 148.6, 169.6.
(2E,4Z)-di-n-butyl
4-((phenetylamino)methylene)pent-2-enedioate
(4i(b))
Method A: 20.4 mg (25%), obtained in a mixture with 5i(b), from 1i (26.0
mg, 0.21 mmol) and 2b, 84.8 mg, 0.67 mmol) in EtOH (1.5 mL) during 17
h; 5i(b) (30.9 mg, 29%).
Method C: 72.6 mg (79%) from 1i (30.0 mg, 0.25 mmol) and 2b (63.1
mg, 0.50 mmol) during 1.5 h.
(2E,4Z)-diallyl 4-((phenetylamino)methylene)pent-2-enedioate (4i(c))
Method A: 20.1 mg (25%) from 1i (29.0 mg, 0.24 mmol) and 2c (104.7
mg, 0.95 mmol) in EtOH (1.5 mL) during 8 h, along with 5i(c) (27.9 mg,
26%).
Method C: 38.2 mg (58%) from 1i (23.4 mg, 0.19 mmol) and 2c (43.0 mg,
0.39 mmol) during 1 h, along with 5i(c) (3.7 mg, 4%).
4i(b): pale orange solid, mp 72-73 C; IR  3287, 1699, 1663, 1598 cm1;
1H NMR (500.3 MHz, CDCl3): 0.94 (t, 3H, J  7.0 Hz), 0.95 (t, 3H, J  7.5
Hz), 1.36-1.45 (m, 4H), 1.60-1.71 (m, 4H), 2.87 (t, 2H, J  7.0 Hz), 3.52
(q, 2H, J  7.0 Hz), 4.11 (t, 2H, J  6.7 Hz), 4.17 (t, 2H, J  6.7 Hz), 5.95
(d, 1H, J  15.5 Hz), 7.06 J  13.5 Hz), 7.15-7.17 (m, 2H), 7.23-7.26 (m,
1H), 7.29-7.33 (m, 2H), 7.32 (d, 1H, J  15.5 Hz), 8.91 (m, 1H); 13C NMR
(125.8 MHz, CDCl3): 13.7, 13.7, 19.2, 19.3, 30.8, 30.9, 37.5, 50.9, 63.5,
63.7, 94.8, 107.9, 126.9, 128.7, 128.8, 137.5, 143.1, 156.8, 168.9, 169.1;
HRMS calcd. for C22H32NO4 [M+H] +: 374.2331, found: 374.2333.
4i(c): pale yellow oil; IR  3288, 1700, 1665, 1596 cm1; 1H NMR (500.3
MHz, CDCl3): 2.81 (t, 2H, J  7.0 Hz), 3.46 (q, 2H, J  7.0 Hz), 4.56 (dt,
2H, J  1.5 Hz, J  5.5 Hz), 4.62 (dt, 2H, J  1.5 Hz, J  5.5 Hz), 5.12-
5.18 (m, 2H), 5.22-5.28 (m, 2H), 5.85-5.94 (m, 2H), 5.92 (d, 1H, J  15.5
Hz), 7.00 (d, 1H, J  13.5 Hz), 7.09 (d, 2H, J  8.0 Hz), 7.18 (t, 1H, J 
7.5 Hz), 7.25 (t, 2H, J  8.0 Hz), 7.29 (d, 1H, J  15.5 Hz), 8.85 (t, 1H, J 
6.5 Hz); 13C NMR (125.8 MHz, CDCl3): 37.7, 51.2, 64.7, 64.8, 94.8, 107.8,
117.7, 118.1, 127.2, 129.0, 129.1, 132.9, 133.3, 137.6, 143.8, 157.4,
168.6, 168.9; HRMS calcd. for C20H24NO4 [M+H] +: 342.1705, found:
342.1704.
5i(b): yellow oil; IR  1732, 1702, 1582 cm1 1H NMR (500.3 MHz,
;
CDCl3): 0.91 (t, 3H, J  7.5 Hz), 0.95 (t, 6H, J  7.5 Hz), 1.31-1.43 (m,
6H), 1.56 (quint, 2H, J  7.0 Hz), 1.63 (quint, 4H, J  7.0 Hz), 2.44 (d, 2H,
J  5.0 Hz), 2.90 (t, 2H, J  7.5 Hz), 3.53 (t, 2H, J  7.5 Hz), 3.96 (t, 2H, J
 7.0 Hz), 4.12 (t, 2H, J  7.0 Hz), 4.13 (t, 2H, J  7.0 Hz), 4.17 (t, 1H, J 
5.0 Hz), 7.04 (s, 2H), 7.17 (d, 2H, J  7.0 Hz), 7.24 (t, 1H, J  7.5 Hz),
7.31 (t, 2H, J  7.0 Hz); 13C NMR (125.8 MHz, CDCl3): 13.8, 14.1 19.1,
19.2, 29.5, 29.7, 30.8, 36.8, 40.8, 56.3, 63.0, 106.1, 126.9, 128.8, 137.1,
139.1, 166.9, 171.7; HRMS calcd. for C29H42NO6 [MH] +: 498.2850,
found: 498.2836.
1
5i(c): pale yellow oil; IR  1732, 1702, 1580 cm1; H NMR (500.3 MHz,
CDCl3): 2.49 (d, 2H, J  5.0 Hz), 2.91 (t, 2H, J  7.2 Hz), 3.54 (t, 2H, J 
7.5 Hz), 4.23 (t, 2H, J  5.0 Hz), 4.48 (dt, 2H, J  1.5 Hz, J  5.5 Hz),
4.63 (d, 4H, J  5.5 Hz), 5.17-5.33 (m, 6H), 5.84-5.98 (m, 3H), 7.08 (s,
2H), 7.17 (d, 2H, J  8.0 Hz), 7.24 (t, 1H, J  7.5 Hz), 7.31 (t, 2H, J  7.5
Hz); 13C NMR (125.8 MHz, CDCl3): 29.4, 36.8, 40.7, 56.4, 64.8, 105.7,
117.6, 117.7, 127.0, 128.8, 128.9, 132.5, 132.6, 137.0, 139.5, 166.3,
171.2; HRMS calcd. for C26H30NO6 [MH] +: 450.1911, found: 450.1896.
(2E,4Z)-di-n-butyl
4-((phenylamino)methylene)pent-2-enedioate
(4k(b))
Method A: Only 5/5k(b) (20.6 mg, 15%) and 9a (21.4 mg, 21%) were
obtained from 1k (28.0 mg, 0.30 mmol) and 2b (151.2 mg, 1.20 mmol) in
EtOH (0.8 mL) during 18 h.
(2E,4Z)-diallyl 4-((phenylamino)methylene)pent-2-enedioate (4k(c))
Method A: The reaction of 1k, 32.0 mg, 0.34 mmol) and 2c (132.4 mg,
1.20 mmol) in EtOH (0.8 mL) during 25 h gave a complex mixture from
which 4k(c) and 5/5k(c), detected by NMR, could not be isolated in pure
form. Their yields do not exceed 30%.
Method C: 60.0 mg (54%) from 1k (30.0 mg, 0.32 mmol) and 2b (81.3
mg, 0.64 mmol) during 1 h, along with 5/5k(b) (24.3 mg, 16%).
4k(b): yellow oil; IR  3286, 1704, 1664, 1628, 1596 cm1 1H NMR
;
(500.3 MHz, CDCl3): 0.96 (t, 3H, J  7.5 Hz), 0.98 (t, 3H, J  7.5 Hz),
1.39-1.51 (m, 4H), 1.67 (quint, 2H, J  7.0 Hz), 1.75 (quint, 2H, J  7.0
Hz), 4.16 (t, 2H, J  6.7 Hz), 4.27 (t, 2H, J  6.7 Hz), 6.17 (d, 1H, J  15.5
Hz), 7.07 (d, 2H, J  7.5 Hz), 7.12 (t, 1H, J  7.5 Hz), 7.36 (t, 2H, J  8.0
Hz), 7.48 (d, 1H, J  15.5 Hz), 7.76 (d, 1H, J  13.0 Hz), 10.76 (d, 1H, J 
13.0 Hz); 13C NMR (125.8 MHz, CDCl3): 13.7, 13.8, 19.2, 19.3, 30.7, 30.9,
63.8, 64.3, 98.6, 111.0, 116.6, 124.4, 129.9, 139.4, 142.2, 147.6, 168.5,
169.0; HRMS calcd. for C20H28NO4 [M+H] +: 346.2018, found: 346.2022.
5k(b) and 5'k(b): yellow oil; IR (1,4- and 1,2-isomer 1:0.25)  1730, 1707,
Method C: 50.5 mg (47%) from 1k (32.0 mg, 0.34 mmol) and 2c (74.9
mg, 0.68 mmol) during 1.5 h, along with 5/5k(c) (32.0 mg, 22%).
4k(c): pale yellow oil; IR  3279, 1704, 1666, 1595 cm1; 1H NMR (500.3
MHz, CDCl3): 4.67 (dt, 2H, J  1.5 Hz, J  5.5 Hz), 4.78 (dt, 2H, J  1.5
Hz, J  5.5 Hz), 5.23-5.40 (m, 4H), 5.95-6.07 (m, 2H), 6.22 (d, 1H, J 
15.7 Hz), 7.08 (d, 2H, J  8.0 Hz), 7.13 (t, 1H, J  7.0 Hz), 7.36 (t, 2H, J 
8.0 Hz), 7.53 (d, 1H, J  15.7 Hz), 7.78 (d, 1H, J  13.0 Hz), 10.74 (d, 1H,
J  13.0 Hz); 13C NMR (125.8 MHz, CDCl3): 64.7, 65.0, 98.3, 110.6,
116.7, 117.8, 118.3, 124.6, 129.9, 132.2, 132.8, 139.2, 142.6, 148.1,
168.0, 168.5; HRMS calcd. for C18H20NO4 [M+H] +: 314.1392, found:
314.1376.
5k(c) and 5'k(c): yellow oil; IR (1,4- and 1,2-isomer 0.5:1)  1734, 1701,
1628, 1597 cm1; 1H NMR (500.3 MHz, CDCl3, 1,4- and 1,2-isomer 0.5:1):
2.56-2.60 (dd, 1H, J  6.5 Hz, J  13.5 Hz, 1,2-isomer), 2.66 (d, 2H, J 
5.0 Hz, 1,4-isomer), 2.67-2.71 (dd, 1H, J  6.0 Hz, J  13.5 Hz, 1,2-
isomer), 4.30 (t, 1H, J  5.0 Hz, 1,4-isomer), 4.31-4.35 (m, 1H, 1,2-
isomer), 4.39-4.43 (m, 1H, 1,2-isomer), 4.48 (dt, 2H, J  1.5 Hz, J  5.5
Hz, 1,4-isomer), 4.63-4.69 (m, 4H, 1,2-isomer), 4.71 (dt, 2H, J  1.5 Hz, J
 5.5 Hz, 1,4-isomer), 5.11-5.37 (m, 12H, 1,2- and 1,4-isomer), 5.70 (dt,
1H, J  1.0 Hz, J  6.5 Hz, 1,2-isomer), 5.75-5.85 (m, 3H, 1,4-isomer),
5.93-6.00 (m, 3H, 1,2-isomer), 7.22 (d, 2H, J  7.5 Hz, 1,4-isomer), 7.24-
7.29 (m, 3H, 1,4-isomer), 7.33 (d, 2H, J  8.0 Hz, 1,2-isomer), 7.42 (t, 3H,
J  7.7 Hz, 1,2-isomer), 7.60 (s, 2H, 1,4-isomer), 7.78 (s, 1H, 1,2-isomer),
7.89 (s, 1H, 1,2-isomer); 13C NMR (125.8 MHz, CDCl3): 29.6 (1.4-isomer),
38.3 (1,2-isomer), 40.3 (1.4-isomer), 55.2 (1.2-isomer), 64.9, 65.0, 65.2,
65.7, 103.9, 107.9, 112.1, 115.4, 117.9, 118.0, 118.0, 118.0 118.6, 120.9,
1626, 1598 cm1 1H NMR (500.3 MHz, CDCl3, 1,4- and 1,2-isomer
;
1:0.25): 0.85 (t, 3H, J  7.5 Hz, 1,4-isomer), 0.95 (t, 6H, J  7.5 Hz, 1,4-
isomer), 1.30 (sext, 2H, J  7.5 Hz, 1,4-isomer), 1.41 (sext, 4H, J  7.5
Hz, 1,4-isomer), 1.52 (quint, 2H, J  7.5 Hz, 1,4-isomer), 1.66 (quint, 4H,
J  7.5 Hz, 1,4-isomer), 2.50-2.54 (dd, 1H, J  6.5 Hz, J  13.5 Hz, 1,2-
isomer), 2.60 (d, 2H, J  4.5 Hz, 1,4-isomer), 2.64-2.68 (dd, 1H, J  6.2
Hz, J  13.5 Hz, 1,2-isomer), 3.96 (t, 2H, J  6.7 Hz, 1,4-isomer), 4.16-
4.21 (m, 4H, 1,4-isomer), 4.25 (t, 1H, J  4.5 Hz, 1,4-isomer), 5.67 (dt, J
 1.0 Hz, J  6.5 Hz, 1,2-isomer), 7.21 (d, 2H, J  7.5 Hz, 1,4-isomer),
7.27 (t, 1H, J  7.5 Hz, 1,4-isomer), 7.42 (t, 2H, J  7.5 Hz, 1,4-isomer),
7.57 (s, 2H, 1,4-isomer), 7.71 (s, 1H, 1,2-isomer), 7.85 (s, 1H, 1,2-
isomer); 13C NMR (125.8 MHz, CDCl3, only signals of 1,4-isomer are
visible): 13.6, 13.8, 19.1, 19.2, 29.8, 30.6, 30.8, 40.4, 64.0, 64.2, 108.3,
120.7, 126.3, 129.8, 137.6, 143.1, 166.8, 171.7; HRMS calcd. for
C27H38NO6 [M+H] +: 470.2537, found: 470.2550.
9a: yellow oil; IR  3062, 2960, 2929, 2872, 1732, 1462 cm1; 1H NMR
(500.3 MHz, CDCl3): 0.90 (t, 3H, J  7.5 Hz), 1.00 (t, 3H, J  7.5 Hz),
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121.2, 126.4, 126.5, 129.6, 129.8, 131.8, 132.3, 132.4, 132.5, 132.6,
132.7, 138.1, 143.0, 143.6, 144.9, 164.7, 165.1, 166.2, 169.5, 171.2;
HRMS calcd. for C24H26NO6 [MH] +: 422.1598, found: 422.1594.
1H, J  13.5 Hz); 13C NMR (125.8 MHz, CDCl3): 65.7, 66.0, 98.2, 110.6,
116.7, 124.5, 127.8, 127.9, 128.0, 128.1, 128.4, 128.6, 129.8, 136.0,
136.6, 139.2, 142.6, 147.9, 168.1, 168.4; HRMS calcd. for C26H24NO4
[M+H] +: 414.1705, found: 414.1702.
3k(d): Z isomer, white solid, mp 157-159 C; IR  3281, 1668, 1621,
1582 cm1; 1H NMR (500.3 MHz, CDCl3): 4.91 (d, 1H, J = 8.0 Hz), 5.19 (s,
2H), 6.97 (d, 2H, J = 8.0 Hz), 7.01 (t, 1H, J = 7.2 Hz), 7.28-7.41 (m, 8H),
9.88 (d, 1H, J = 12 Hz); 13C NMR (125.8 MHz, CDCl3): 65.2, 87.0, 115.4,
122.7, 127.9, 128.0, 128.5, 129.6, 136.7, 140.6, 143.4, 170.0; HRMS
calcd. for C16H16NO2 [M+H] +: 254.1181, found: 254.1169.
(2E,4Z)-dibenzyl
(4i(d))
4-((phenetylamino)methylene)pent-2-enedioate
Method A: 15.5 mg (18%), obtained in a mixture with 5i(d), from 1i (24.0
mg, 0.20 mmol) and 2d (113.6 mg, 0.71 mmol) in EtOH (1.2 mL) during
22 h; 5i(d) (50.1 mg, 42%).
Method A: 10.3 mg (12%), isolated in a mixture with 5i(d), from 1i (24.0
mg, 0.20 mmol) and 2d (64.1 mg, 0.40 mmol) in EtOH (1.2 mL) during 17
h, along with 3i(d) (14.4 mg, 26%) and 5i(d) (26.5 mg, 22%), the latter
isolated in a mixture with 4i(d).
5k(d) and 5'k(d): yellow oil; IR (1,4- and 1,2-isomer 0.5:1)  1731, 1700,
1626, 1595 cm1; 1H NMR (500.3 MHz, CDCl3, 1,4- and 1,2-isomer 0.5:1):
2.60-2.64 (dd, 1H, J = 6.5 Hz, J = 13.5 Hz, 1,2-isomer), 2.71 (d, 2H, J =
4.5 Hz, 1,4-isomer), 2.70-2.74 (dd, 1H, J = 6.0 Hz, J = 13.5 Hz, 1,2-
isomer), 4.35 (t, 1H, J = 4.5 Hz, 1,4-isomer), 4.80 (d, 1H, J = 12.0 Hz,
1,2-isomer), 4.92 (d, 1H, J = 12.0 Hz, 1,2-isomer), 4.99 (s, 2H, 1,4-
isomer), 5.15 (d, 1H, J = 12.5 Hz, 1,2-isomer), 5.19 (d, 1H, J = 12.5 Hz,
1,2-isomer), 5.24 (d, 1H, J = 12.5 Hz, 1,2-isomer), 5.26 (d, 1H, J = 12.5
Hz, 1,2-isomer), 5.26 (s, 2H, 1,4-isomer), 5.74 (dt, 1H, J = 1.0 Hz, J = 6.0
Hz, 1,2-isomer), 7.06-7.40 (m, 40H, 1,2- and 1,4-isomers), 7.50 (s, 2H,
1,4-isomer), 7.82 (s, 1H, 1,2-isomer), 7.88 (s, 1H, 1,2-isomer); 13C NMR
(125.8 MHz, CDCl3): 29.8 (1,4-isomer), 38.4 (1,2-isomer), 40.2 (1,4-
isomer), 55.3 (1,2-isomer), 65.9, 66.1, 66.3, 66.8, 103.8, 107.6, 112.2,
120.1, 121.2, 126.4, 126.5, 127.9, 128.1, 128.2, 128.2, 128.3, 128.3,
128.5, 128.5, 128.5, 129.7, 129.8, 132.8, 135.4, 136.1, 136.2, 136.3,
136.5, 138.2, 142.9, 143.5, 145.1, 164.9, 165.2, 166.4, 169.7, 171.4;
HRMS calcd. for C36H32NO6 [MH] +: 572.2068, found: 572.2076.
Method C: 85.0 mg (76%) from 1i (30.9 mg, 0.25 mmol) and 2d (81.7
mg, 0.50 mmol) during 2 h.
4i(d): pale yellow solid, mp 53-55 C; IR  3288, 1700, 1664, 1596 cm1;
1H NMR (500.3 MHz, CDCl3): 2.88 (t, 2H, J  7.0 Hz), 3.53 (q, 2H, J  7.0
Hz), 5.20 (s, 2H), 5.27 (s, 2H), 6.07 (d, 1H, J  15.5 Hz), 7.10 (d, 1H, J 
13.5 Hz), 7.17 (d, 2H, J  7.5 Hz), 7.27 (t, 1H, J  7.2 Hz), 7.32-7.41 (m,
12H), 7.45 (d, 1H, J  15.5 Hz), 8.95 (m, 1H); 13C NMR (125.8 MHz,
CDCl3): 37.4, 50.9, 65.4, 94.5, 107.5, 126.9, 127.7, 127.8, 127.9, 128.4,
128.5, 128.7, 128.8, 136.4, 136.8, 137.4, 143.5, 157.1, 168.5, 168.6;
HRMS calcd. for C28H28NO4 [M+H] +: 442.2018, found: 442.2000.
3i(d): Z and E isomers, 1:0.4, pale yellow oil; IR  3336, 1666, 1614
cm1 1H NMR (500.3 MHz, CDCl3): 2.83 (t, 2H, J  7.0 Hz, Z isomer),
;
2.87 (t, 2H, J  7.0 Hz, E isomer), 3.32 (q, 2H, J  7.0 Hz, E isomer), 3.40
(q, 2H, J  7.0 Hz), 4.52 (d, 1H, J  8.0 Hz, Z isomer), 4.86 (d, 1H, J 
13.5 Hz, E isomer), 5.12 (s, 2H, Z isomer), 5.15 (s, 2H, E isomer), 6.55
(dd, 1H, J  8.0 Hz, J  13.5 Hz, Z isomer), 7.18-7.40 (m, 20H, Z and E
isomers), 7.51 (dd, 1H, J  8.0 Hz, J  13.5 Hz, E isomer), 7.90 (broad
signal, 1H, Z isomer); 13C NMR (125.8 MHz, CDCl3): 38.0, 50.2, 64.5 (Z
isomer), 64.9 (E isomer), 75.0 (E isomer), 81.7 (Z isomer), 85.8 (E
isomer), 126.6 (Z isomer), 126.7 (E isomer), 127.0, 127.7, 127.8, 128.4,
128.5, 128.6, 128.6, 128.7, 128.7, 128.8, 137.2, 137.3, 138.1, 138.3,
152.4, 169.3, 170.4; HRMS calcd. for C18H20NO2 [M+H] +: 282.1494,
found: 282.1482.
(2E,4Z)-dicyclohexyl
4-((phenethylamino)methylene)pent-2-ene-
dioate (4i(e))
Method A: 27 mg (28%), obtained in a mixture with 5i(e), from 1i (27.0
mg, 0.22 mmol) and 2e (101.7 mg, 0.67 mmol) in EtOH (1.4 mL) during
17 h; 5i(e) (27.0 mg, 21%).
Method C: 60.5 mg (69%) from 1i (25.0 mg, 0.21 mmol) and 2e (64.6 mg,
0.42 mmol) during 2 h.
4i(e): pale yellow oil; IR  3287, 1692, 1659, 1597 cm1; 1H NMR (500.3
MHz, CDCl3): 1.25-1.57 (m, 12H), 1.74-1.78 (m, 4H), 1.86-1.91 (m, 4H),
2.88 (t, 2H, J = 7.0 Hz), 3.53 (q, 2H, J = 7.0 Hz), 4.79-4.90 (m, 2H), 5.96
(d, 1H, J = 15.7 Hz), 7.08 (d, 1H, J = 13.5 Hz), 7.17 (d, 2H, J = 7.0 Hz),
7.25 (t, 1H, J = 7.5 Hz), 7.33 (t, 2H, J = 7.5 Hz), 7.35 (d, 1H, J = 15.7 Hz),
8.87-8.92 (m, 1H); 13C NMR (125.8 MHz, CDCl3): 23.8, 23.8, 25.4, 25.5,
31.7, 31.8, 37.5, 50.8, 71.5, 72.2, 95.1, 108.4, 126.9, 128.7, 128.8, 137.5,
143.0, 156.5, 168.3, 168.5; HRMS calcd. for C26H36NO4 [M+H]+:
426.2644, found: 426.2637.
5i(d): yellow amorphous substance; IR  1730, 1701, 1582 cm1 1H
;
NMR (500.3 MHz, CDCl3): 2.56 (d, 2H, J  5.0 Hz), 2.80 (t, 2H, J  7.5
Hz), 3.39 (t, 2H, J  7.5 Hz), 4.29 (t, 1H, J  5.0 Hz), 4.98 (s, 2H), 5.14 (d,
2H, J  12.5 Hz), 5.19 (d, 2H, J  12.5 Hz), 7.01 (s, 2H), 7.11 (d, 2H, J 
7.0 Hz), 7.20 (t, 1H, J  7.5 Hz), 7.26-7.37 (m, 17H); 13C NMR (125.8
MHz, CDCl3): 29.5, 36.6, 40.7, 56.1, 65.4, 65.0, 106.5, 126.8, 127.8,
127.9, 128.0, 128.1, 128.3, 128.5, 128.8, 136.2, 136.4, 137.0, 139.6,
166.5, 171.4; HRMS calcd. for C38H35NO6 [MH] +: 600.2381, found:
600.2369.
5i(e): 1H NMR (500.3 MHz, CDCl3, from the mixture with 4i(e); only the
most diagnostic signals for the structure of 5i(e) are listed): 2.47 (d, 2H, J
= 4.5 Hz), 4.17 (t, 1H, J = 4.5 Hz), 7.02 (s, 2H); HRMS calcd. for
C35H48NO6 [MH] +: 576.3320, found: 576.3337.
(2E,4Z)-dibenzyl
(4k(d))
4-((phenylamino)methylene)pent-2-enedioate
Method A: The reaction of 1k (30.0 mg, 0.32 mmol) and 2d (205.0 mg,
1.28 mmol) in EtOH (0.8 mL) during 57 h gave a complex mixture from
which 4k(d) and 5/5k(d), detected by NMR, could not be isolated in pure
form. Their yields do not exceed 15%.
Method A: The reaction of 1k (25.0 mg, 0.27 mmol) and 2d (86.0 mg,
0.54 mmol) in EtOH (0.7 mL) during 48 h gave a complex mixtrure from
which only 3k(d) (15.0 mg, 22%) could be isolated in pure form. The
yields of 4k(d) and 5k(d), which were detected by NMR spectroscopy, do
not exceed 30% and 10%, respectively.
Method C: 90.0 mg (63%) from 1k (32.0 mg, 0.34 mmol) and 2d (110.0
mg, 0.68 mmol) during 3 h, along with 3k(d) (3.0 mg, 3%) and 5/5'k(d)
(40.0 mg, 20%).
4k(d): yellow solid, mp 77-79 C; IR  3283, 1705, 1665, 1628, 1595
cm1; 1H NMR (500.3 MHz, CDCl3): 5.11 (s, 2H), 5.23 (s, 2H), 6.18 (d, 1H,
J  15.7 Hz), 6.95 (d, 2H, J  7.5 Hz), 7.02 (t, 1H, J  7.5 Hz), 7.22-7.34
(m, 12H), 7.48 (d, 1H, J  15.7 Hz), 7.68 (d, 1H, J  13.5 Hz), 10.62 (d,
(2E,4Z)-dicyclohexyl 4-((phenylamino)methylene)pent-2-enedioate
(4k(e))
Method A: Only 5k(e) (20.0 mg; 13%) and 9b (26.8 mg; 23%) were
isolated from the reaction of 1k (27.0 mg, 0.29 mmol) and 2e (176.5 mg,
1.16 mmol) in EtOH (0.8 mL) during 6.5 h.
Method C: 13.6 mg (16%), obtained in a mixture with 5k(e), from 1k
(20.0 mg, 0.21 mmol) and 2e (64.0 mg, 0.42 mmol) during 3 h, along with
pure 5k(e) (46.4 mg, 39%; given quantity and yield are based on pure
compound and the mixture with 4k(e)).
Method C: 36.7 mg (34%), obtained in a mixture with 5k(e), from 1k
(25.0 mg, 0.27 mmol) and 2e (81.7 mg, 0.54 mmol) during 2.5 h at 65 C,
along with pure 5k(e) (27.8 mg, 19%; given quantity and yield are
estimated on the basis of pure compound and the mixture).
Method C: 45.0 mg (53%) from 1k (20.0 mg, 0.21 mmol) and 2e (64.0
mg, 0.42 mmol) during 9.5 h at rt.
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10.1002/asia.201800645
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4k(e): yellow oil; IR  3281, 1695, 1660, 1596 cm1; 1H NMR (500.3 MHz,
CDCl3): 1.38-1.47 (m, 8H), 1.57-1.62 (m, 4H), 1.74-1.81 (m, 4H), 1.89-
1.97 (m, 4H), 4.82-4.88 (m, 1H), 4.93-4.98 (m, 1H), 6.17 (d, 1H, J = 16.0
Hz), 7.07 (d, 2H, J = 7.5 Hz), 7.11 (t, 1H, J = 7.5 Hz), 7.35 (t, 2H, J = 7.5
Hz), 7.49 (d, 1H, J = 16.0 Hz), 7.76 (d, 1H, J = 13.0 Hz), 10.77 (d, 1H, J =
13.0 Hz); 13C NMR (125.8 MHz, CDCl3): 23.8, 23.9, 25.4, 25.5, 31.7, 31.8,
71.9, 73.0, 98.9, 111.5, 116.5, 124.2, 129.8, 139.5, 142.0, 147.2, 167.9,
168.4; HRMS calcd. for C24H32NO4 [M+H] +: 398.2331, found: 398.2346.
5k(e): yellow oil; IR  1726, 1704, 1625, 1598 cm1; 1H NMR (500.3 MHz,
CDCl3): 1.28-1.88 (m, 30H), 2.62 (d, 2H, J = 4.5 Hz), 4.25 (t, 1H, J = 4.5
Hz), 4.63-4.67 (m, 1H), 4.87-4.92 (m, 2H), 7.20 (d, 2H, J = 7.5 Hz), 7.25
(t, 1H, J = 7.5 Hz), 7.41 (t, 2H, J = 8.0 Hz), 7.55 (s, 2H); 13C NMR (125.8
MHz, CDCl3): 23.6, 23.7, 25.3, 25.4, 30.0, 31.5, 31.6, 40.3, 72.1, 72.3,
108.6, 120.6, 126.1, 129.8, 137.4, 143.1, 166.2, 171.2; HRMS calcd. for
C33H44NO6 [MH] +: 548.3007, found: 548.2997.
2.98 (dd, 1H, J  6.5 Hz, J  13.5 Hz, 1,2-isomer), 3.00-3.04 (dd, 1H, J 
5.5 Hz, J  13.5 Hz, 1,2-isomer), 3.05 (d, 2H, J  4.5 Hz, 1,4-isomer),
4.64 (t, 1H, J  4.5 Hz, 1,4-isomer), 5.98 (t, 1H, J  6.5 Hz, 1,2-isomer),
6.81-6.98 (m, 4H, 1,2- and 1,4-isomer), 7.06-7.49 (m, 36H, 1,2- and 1,4-
isomer), 7.87 (s, 2H, 1,4-isomer), 8.16 (s, 1H, 1,2-isomer), 8.18 (s, 1H,
1,2-isomer); 13C NMR (125.8 MHz, CDCl3, only signals of 1,4-isomer are
clearly visible): 30.0, 40.3, 107.4, 121.4, 121.6, 121.8, 125.6, 125.7,
129.3, 129.4, 130.0, 139.5, 142.8, 150.8, 165.1, 170.0; HRMS calcd. for
C33H26NO6 [MH] +: 530.1598, found: 530.1592.
6b: 1H NMR (500.3 MHz, CDCl3, from the mixture with 4k(f)):38 9.26 (s,
3H), other signals are covered by those of 4k(f)).
Cross experiments
Synthesis of (2E,4Z)-dimethyl 4-((methylamino)methylene)pent-2-
enedioate (4'b)
1
9b: yellow oil; IR  3060, 2936, 2858, 1725, 1451 cm1; H NMR (500.3
The product 4b (55.0 mg, 69%) was obtained as following. To a solution
of methylamine in THF (1.2 M, 0.33 mL, 0.4 mmol of 1b) methyl
propiolate (2g, 104.0 mg, 1.20 mmol) and EtOH (1 mL) were added and
the mixture heated at 100 C for 9 h. The solvents were removed under
reduced pressure and the residue purified by column chromatography.
Pale yellow crystals, mp 138-140 C (lit.[12a] 143 C); IR  3318, 1699,
1662, 1593 cm1; 1H NMR (500.3 MHz, CDCl3): 3.10 (d, 3H, J  5.0 Hz),
3.71 (s, 3H), 3.76 (s, 3H), 6.00 (d, 1H, J  15.7 Hz), 7.18 (d, 1H, J  14.0
Hz), 7.37 (d, 1H, J  15.7 Hz), 8.76 (broad s, 1H); 13C NMR (125.8 MHz,
CDCl3): 35.7, 50.8, 51.0, 94.6, 107.3, 143.3, 158.4, 169.2, 169.6.
MHz, CDCl3): 1.28-1.50 (m, 8H), 1.58-1.66 (m, 6H), 1.81-1.83 (m, 4H),
1.99-2.02 (m, 2H), 4.46 (s, 2H), 4.79-4.84 (m, 1H), 5.02-5.07 (m, 1H),
7.60 (t, 1H, J  7.5 Hz), 7.81 (t, 1H, J  7.5 Hz), 7.92 (d, 1H, J  8.0 Hz),
8.10 (broad d, 1H), 8.84 (s, 1H); 13C NMR (125.8 MHz, CDCl3): 23.6,
23.9, 25.4, 25.4, 31.5, 31.6, 44.8, 73.2, 74.1, 124.4, 126.4, 127.2, 128.6,
131.8, 140.4, 154.7, 165.3, 170.1; HRMS calcd. for C24H30NO4 [M+H] +:
396.2175, found: 396.2160.
(2E,4Z)-diphenyl
4-((phenethylamino)methylene)pent-2-enedioate
(4i(f))
Method A: 42.5 mg (45%) from 1i (28.0 mg, 0.23 mmol) and 2f (107.6
mg, 0.74 mmol) in EtOH (1.5 mL) during 4 h.
Synthesis of (Z)- and (E)-ethyl 3-(methylamino)acrylate (3b)
To a solution of methylamine in THF (1.2 M, 0.5 mL, 0.6 mmol of 1b)
ethyl propiolate (2a) was added (87.3 mg, 0.89 mmol) and the mixture
was stirred at rt overnight. The solvent and excess of 2a were removed
under reduced pressure to give 3b as a pale yellow oil (47.0 mg, 61%).
1H NMR 1H NMR (500.3 MHz, CDCl3, Z and E 1:0.9): Z isomer 1.20 (t,
3H, J  7.0 Hz), 2.90 (d, 3H, J  5.0 Hz), 4.04 (q, 2H, J  7.0 Hz), 4.40 (d,
1H, J  8.0 Hz), 6.53 (dd, 1H, J  8.0 Hz, J  13.5 Hz), 7.58 (broad s, 1H),
E isomer 1.21 (t, 3H, J  7.0 Hz), 2.70 (d, 3H, J  5.0 Hz), 4.07 (q, 2H, J
 7.0 Hz), 4.63 (d, 1H, J  13.0 Hz), 4.90 (broad s, 1H), 7.51 (dd, 1H, J 
7.5 Hz, J  13.0 Hz); 13C NMR (125.8 MHz, CDCl3): 14.4, 14.4, 34.7,
58.4, 58.7, 81.6 (Z isomer), 85.0 (E isomer), 153.3, 169.6, 170.8.
Method C: 50.4 mg (53%) from 1i (28.0 mg, 0.23 mmol) and 2f (67.9 mg,
0.46 mmol) during 1.5 h.
1
4i(f): pale yellow oil; IR  3292, 1716, 1674, 1593 cm1; H NMR (500.3
MHz, CDCl3): 2.88 (t, 2H, J = 7.0 Hz), 3.58 (q, 2H, J = 7.0 Hz), 6.24 (d,
2H, J = 15.7 Hz), 7.11-7.17 (m, 7H), 7.19 (t, 1H, J = 7.5 Hz), 7.23-7.26
(m, 2H), 7.32 (t, 2H, J = 7.5 Hz), 7.36 (t, 2H, J = 7.5 Hz), 7.41 (t, 2H, J =
7.5 Hz), 7.62 (d, 1H, J = 15.7 Hz), 9.04 (broad m, 1H); 13C NMR (125.8
MHz, CDCl3): 37.3, 51.2, 94.0, 107.4, 121.8, 122.0, 125.2, 125.7, 127.1,
128.7, 128.9, 129.2, 129.4, 137.1, 144.6, 150.4, 151.2, 158.4, 167.1,
167.6; HRMS calcd. for C26H24NO4 [M+H] +: 414.1705, found: 414.1692.
(2E,4Z)-diphenyl 4-((phenylamino)methylene)pent-2-enedioate (4k(f))
Method A: The reaction of 1k (29.0 mg, 0.31 mmol) and 2f (158.3 mg,
1.08 mmol) in EtOH (0.9 mL) during 114 h gave a complex mixture from
which only 3k(f) (10.7 mg, 14%) was isolated, while 4k(d), detected by
NMR spectroscopy, could not be isolated in pure form.
Method C: 73.2 mg (66%) from 1k (27.0 mg, 0.29 mmol) and 2f (84.7
mg, 0.58 mmol) during 1 h, along with 5/5k(f) (18.0 mg, 12%) and 6b
(7.8 mg, 9%; isolated in a mixture with small amount of 4k(f)).
Synthesis of (Z)- and (E)-methyl 3-(methylamino)acrylate (3b)
To a solution of methylamine in THF (1.2 M, 0.5 mL, 0.6 mmol of 1b)
methyl propiolate (2g) was added (76.3 mg, 0.90 mmol) and the mixture
was stirred at rt overnight. The solvent and excess of 2g were removed
under reduced pressure to give 3b as a pale yellow oil (49.2 mg, 71%).
1H NMR (500.3 MHz, CDCl3, Z and E 1.5:1): Z isomer 2.95 (d, 3H, J 
5.0 Hz), 3.63 (s, 3H), 4.46 (d, 1H, J  8.0 Hz), 6.58 (dd, 1H, J  8.0 Hz, J
 13.0 Hz), 7.62 (broad s, 1H), E isomer 2.75 (d, 3H, J  5.0 Hz), 3.65 (s,
3H), 4.55 (broad s, 1H), 4.70 (d, 1H, J  13.0 Hz), 7.55 (dd, 1H, J  7.5
Hz, J  13.0 Hz); 13C NMR (125.8 MHz, CDCl3): 34.8, 50.1 (Z isomer),
50.5 (E isomer), 81.3 (Z isomer), 85.2 (E isomer), 153.4, 169.9 (E
isomer), 171.2 (Z isomer).
4k(f): yellow oil; IR  3284, 1721, 1676, 1629, 1583 cm1; 1H NMR (500.3
MHz, CDCl3): 6.51 (d, 1H, J  15.5 Hz), 7.11 (d, 2H, J  7.5 Hz), 7.16-
7.24 (m, 6H), 7.31 (t, 1H, J  7.5 Hz), 7.37-7.41 (m, 4H), 7.46 (t, 2H, J 
7.5 Hz), 7.81 (d, 1H, J  15.5 Hz), 7.99 (d, 1H, J  13.5 Hz), 10.86 (d, 1H,
J  13.5 Hz); 13C NMR (125.8 MHz, CDCl3): 97.5, 110.3, 116.9, 121.8,
121.9, 125.1, 125.4, 126.1, 129.3, 129.5, 130.0, 138.8, 143.6, 149.6,
+
Cross reaction (1)
Method A
150.2, 151.1, 166.7, 167.7; HRMS calcd. for C24H19NO4 [M+H]
386.1392, found: 386.1405.
:
A mixture of 3b (47.0 mg, 0.36 mmol) and methyl propiolate (2g, 90.8 mg,
1.08 mmol) in EtOH (1.5 mL) was heated at 100 C for 12 h. Solvent was
removed under reduced pressure and the residue chromatographed to
give 35.0 mg of mixture of four dienes. The NMR spectrum of both the
crude reaction mixture and of chromatographed product indicated 4b as
the main compound.
3k(f): Z isomer, white solid, mp 138-140 C; IR  3300, 1692, 1620, 1583
cm1; 1H NMR (500.3 MHz, CDCl3): 5.09 (d, 1H, J  8.5 Hz), 6.98 (d, 2H,
J  8.5 Hz), 7.04 (t, 1H, J  7.5 Hz), 7.15 (m, 2H), 7.24 (t, 1H, J  7.5 Hz),
7.31 (m, 2H), 7.39-7.45 (m, 3H), 9.96 (d, 1H, J  12.5 Hz); 13C NMR
(125.8 MHz, CDCl3): 86.1, 115.6, 121.9, 123.1, 125.5, 129.3, 129.7,
+
140.3, 144.9, 150.8, 168.9; HRMS calcd. for C15H14NO2 [M+H]
240.1025, found: 240.1014.
:
5k(f) and 5'k(f): yellow amorphous substance; IR  1751, 1719, 1626,
(2E,4Z)-5-ethyl 1-methyl 4-((methylamino)methylene)pent-2-ene-
dioate (4b)
1593 cm1; 1H NMR (500.3 MHz, CDCl3, 1,2- and 1,4-isomer 0.6:1): 2.94-
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10.1002/asia.201800645
Chemistry - An Asian Journal
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1H NMR (500.3 MHz, CDCl3): 1.31 (t, 3H, J  7.0 Hz), 3.07 (d, 3H, J  5.0
Hz), 3.68 (s, 3H), 4.21 (q, 2H, J  7.0 Hz), 5.99 (d, 1H, J  16.0 Hz), 7.16
(d, 1H, J  13.5 Hz), 7.35 (d, 1H, J  16.0 Hz), 8.76 (broad s, 1H); 13C
NMR (125.8 MHz, CDCl3): 14.4, 35.6, 50.9, 59.7, 94.6, 107.1, 143.5,
158.4, 169.1, 169.2.
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This work was supported by the Ministry of Education, Science
and Technological Development of the Republic of Serbia,
project No. 172020. The authors acknowledge the support of the
FP7 RegPot project FCUB ERA GA No. 256716, the equipment
of which was used for recording HRMS (LTQ Orbitrap XL). The
EC does not share responsibility for the content of the article.
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Keywords: amines • conjugated dienes • green chemistry •
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10.1002/asia.201800645
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Jovana Aleksić, Milovan Stojanović,
Marija Baranac-Stojanović*
Page No. – Page No.
Silica Gel as a Promoter of Sequential
Aza-Michael/Michael Reactions of
Amines and Propiolic Esters:
Solvent-free and Metal-free Synthesis
of Polyfunctionalized Conjugated
Dienes
A green and simple method for the construction of functionalized conjugated diene
motif has been developed. The reaction takes place on the surface of silica gel, in
the solid state. The method is particularly useful for weakly nucleophilic aromatic
amines and for hydrophobic esters, which poorly react under standard solution-
state conditions.
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