Synthesis of Chromone-Containing Allylmorpholines through a Morita–Baylis–Hillman-Type Reaction

Article abstract of DOI:10.1002/ejoc.201801159

The first example of an unusual addition of chromone-substituted acrylic acid to enamines is described. The process shows high versatility concerning both enamines and chromones. The reaction is catalyzed by tertiary amines and is highly likely of Morita–

Full text of DOI:10.1002/ejoc.201801159

A Journal of
Accepted Article
Title: Synthesis of chromone-containing allylmorpholines through
Morita-Baylis-Hillman-type reaction
Authors: Nikita M Chernov, Roman Shutov, Oleg I Barygin, Mikhail
Y Dron, Galina L Starova, Nikolay N Kuz’mich, and Igor P
Yakovlev
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801159
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10.1002/ejoc.201801159
European Journal of Organic Chemistry
FULL PAPER
Synthesis of chromone-containing allylmorpholines through
Morita-Baylis-Hillman-type reaction
Dr. Nikita M. Chernov,[a] Dr. Roman V. Shutov,*[a] Dr. Oleg I. Barygin,[b] Mikhail Y. Dron,[b] Dr. Galina L.
Starova,[c] Dr. Nikolay N. Kuz’mich[d,e] and Prof. Dr. Igor P. Yakovlev[a]
Abstract: The first example of an unusual addition of chromone-
substituted acrylic acid to enamines is described. The process
shows high versatility concerning both enamines and chromones.
The reaction is catalyzed by tertiary amines and is highly likely of
Morita-Baylis-Hillman-type. The described compounds show
combined moderate inhibitory action on BChE and antagonism
towards NMDA receptors which makes them a perspective group for
the development of anti-Alzheimer drugs.
Introduction
Chromone's scaffold is a privileged structure for the creation of
drugs [1]. A significant number of biologically active substances
of both synthetic and natural origin belong to this group of
compounds [2]. An important feature of the chromone system is
Scheme 1. Results of previous works with chromone-fused dienes 1
its electron-deficiency and powerful synthetic potential, and
because of that they are widely used as precursors of azoles,
Present work is a continuation of these studies, where we
azines, pyrroles [3] and polycyclic O-containing heterocycles
demonstrate a new way of chromone-fused dienes 1 reaction
with enamines resembling a Morita-Baylis-Hillman type (MBH
reaction).
such as xanthones [4].
Currently one area of research is the use of chromone-fused
dienes 1 in [4+2] cycloaddition reactions [5, 6]. As shown by
Results and Discussion
Bodwell's group, dienes 1 (R2=Et) react with enamines 2 to give
3,4-dihydroxanthones 4 and benzophenones 5 (scheme 1).
Later on we have shown that the dienes 1 with carboxyl group
(R2=H) mostly form 4,4a-dihydroxanthones 6 and to a lesser
extent – 3,4-dihydroisomers 4.
We discovered that upon replacement of pyrrolidine in enamine
2 with low-nucleophilic morpholine 8 it reacts with the chromone-
fused diene 7a to form an unusual product – allylmorpholine 9a
in 52% yield (table 1). This compound was characterized by a
complex of NMR spectra (see Supporting information), and X-
ray analysis ([7], figure 1). During the TLC run of the reaction
mixture a conventional product of the [4+2] cycloaddition – 4,4a-
dihydroxanthone 10a was seen as a by-product, and it only
became the principal one after performing the reaction in
methanol or when using the ester 7a' instead of acid 7a (entries
3, 11, 12). The exclusive [4+2] cycloaddition reaction in case of
the ester diene obviously indicates the importance of carboxyl
groups in the mechanism of formation of allylmorpholine 9a.
[a]
N.M. Chernov, R.V. Shutov, I.P. Yakovlev
Organic Chemistry Department
Saint-Petersburg State Chemical Pharmaceutical University
Prof. Popov st. 14, Saint-Petersburg, 197376, Russian Federation
E-mail: h4o2@yandex.ru
http://spcpu.ru/english/
[b]
[c]
O.I. Barygin, M.Y. Dron
I.M. Sechenov Institute of Evolutionary Physiology and Biochemistry
RAS
Torez pr. 44, Saint-Petersburg, 194223, Russian Federation
G.L. Starova
Department of Chemistry
Saint-Petersburg State University
Universitetskii pr. 26, Petrodvorets, Saint-Petersburg, 198504,
Russian Federation
[d]
[e]
N.N. Kuz’mich
Department of Drug Safety
Research Institute of Influenza, WHO National Influenza Centre of
Russia
Prof. Popov st. 15/17, Saint-Petersburg 197376, Russian Federation
N.N. Kuz’mich
Laboratory of Bioinformatics
Institute of Biotechnology and Translational medicine, I. M.
Sechenov, First Moscow State Medical University
Trubetskaya st. 8-2, Moscow 119991, Russian Federation
Supporting information for this article is given via a link at the end of
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10.1002/ejoc.201801159
European Journal of Organic Chemistry
FULL PAPER
Table 1. Reaction of chromone-fused diene 7a/7a’ with enamine 8
Entry
7a or 7a’
Conditions
Catalyst
Time
Preparative yield, % for compound
9
10a or 10a’
1
2
3
4
5
6
7
8
9
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a
7a’
7a’
DCM, 20°C
THF, 20°C
MeOH, 20°C
EtOAc, 80°C
DCM, 20°C
DCM, 20°C
DCM, 20°C
DCM, 20°C
DCM, 20°C
DCM, 20°C
DCM, 20°C
DCM, 20°C
-
-
-
-
5 days
48 h
36 h
6 h
12 h
8 h
14 h
48 h
48 h
52
58
14
63
72
69
68
65
-
-
47
-
-
-
-
-
-
0.5 equiv Et3N
1.0 equiv Et3N
0.5 equiv DIPEA
0.5 equiv Pr3N
0.5 equiv DABCO
0.5 equiv DBU
-
61
10
11
12
no reaction
-
-
5 days
5 days
65
61
0.5 equiv Et3N
Figure 1. ORTEP structure of allylmorpholine 9a.
One can easily see that the formation of allylmorpholine 9a is
the interaction of electron-deficient alkene with an aldehyde
derivative (enamine 8), which makes the process similar to MBH
reaction [8]. The similarity is improved by the fact that the
studied reaction is catalyzed by organic bases (table 1, entry 5-
10) resulting in a higher product yield of 9a (up to 72%) and
significantly shorter the reaction time. Despite the fact that MBH
reaction is one of the most actively studied modern chemical
processes, we have not found any references in the literature
concerning the use of acrylic acids in it in contrast to the
extensive use of their esters and amides [9]. Also, there are no
data on the use of enamines in this reaction, although aza-MBH
reactions with N-aryl-, N-alkoxycarbonyl- and N-tosylaldimines
are widely known [10]).
At the same time, Ghosh et al. [11] and Terzidis et al. [12]
described the application of 3-formylchromone in MBH reaction.
In these works the authors point to the ability of the chromone to
add amine to the position 2 of the cycle forming a reactive
zwitterion. Based on this, we propose a possible mechanism of
the studied reaction (scheme 2). It starts with an attack of a
catalyst (e.g., triethylamine) at the position 2 of the chromone 7a.
A zwitterion A is formed, where the negative charge is
delocalized over the π-bond system. Further the intermediate A
is added to the enamine
8 followed by simultaneous
decarboxylation and extrusion of the catalyst, thus forming the
allylmorpholine 9a.
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10.1002/ejoc.201801159
European Journal of Organic Chemistry
FULL PAPER
Scheme 2. Possible mechanism for the formation of allylmorpholine 9a
The proposed mechanism explains, in particular, low efficiency
of DBU as a catalyst (table 1, entry 10). This is probably due to
the fact that DBU is a strong base, which forms a stable salt with
the carboxyl group of the chromone 7a, making the reaction
difficult to proceed. In addition DBU is a bulky base, hence its
nucleophilic attack at the chromone double bond maybe
sterically hindered. In contrast to this, another often used non-
nucleophilic base – DIPEA – possessed excellent catalytic
activity (table 1, entry 7) equivalent to triethylamine. A side
reaction of the catalyst with the carboxyl group might be the
reason for having yet not used acids in MBH reaction. In
agreement with the proposed mechanism is also the fact that the
ester 7a’ forms exclusively a [4+2]-cycloaddition product 10a’
(table 1, entry 11, 12). As can be seen from scheme 2, carboxyl
group plays important role by stabilizing the anion center in the
intermediate B, which is then transformed into a more stable
adduct C.
morpholine leads exclusively to the cycloaddition products –
dihydroxanthones 4 and 6 [6]. Apparently, this is due to the fact
that the enamine in the studied MBH-type reaction should act as
an electrophile, which is supported by low nucleophilicity of
morpholine. This assumption is confirmed by the fact that the
reported aza-MBH reactions always use not aldimines
themselves but their more electrophilic N-carboxy- or N-tosyl-
derivatives.
Our next task was to determine the limits of applicability of the
studied reaction, namely the influence of the structure of acrylic
acid 7 and N-alkenylmorpholines on the process. Thus, the
reaction of unsubstituted and methylsubstituted chromones 7b,c
(table 2, entry 1,2) without a basic catalyst results in the
exclusive formation of the competing [4+2] cycloaddition
products 10b,c. As the rate of reaction in case of
methoxysubstituted chromone 7d is low even in presence of 1
equiv of triethylamine, it can be assumed that the introduction of
donor substitutes reduces the speed of the process.
The role of the morpholine in the reaction is also unusual. As we
shown earlier (scheme 1), using pyrrolidine instead of
Table 2. Influence of the chromones 7b-m structure on the reaction process
Entry
7
R1
R2
R3
Time
Preparative yield, % for compound
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10.1002/ejoc.201801159
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9
10a
1[a]
2[a]
3
7b
7c
7b
7c
7d
7e
7f
7g
7h
7i
H
Me
H
Me
MeO
Br
F
NO2
H
Me
Me
Cl
F
Br
H
H
H
H
H
H
H
H
Me
Me
H
H
F
H
H
H
H
H
H
H
H
H
H
Br
Br
H
H
6 days
8 days
72 h
72 h
6 days
6 h
-
-
29
34
-
-
-
-
-
-
-
-
-
-
-
31
52
33
68
69
47
54
48
63
59
65
46
4
5[b]
6
7
8
9
10
11
12
13
14
8 h
1 h
72 h
5 days
24 h
5 h
10 h
12 h
7j
7k
7l
7m
MeO
-
[a] Without triethylamine
[b] With 1.0 equiv of triethylamine
Next, we chose a series of enamines 11-23, which were
generated in the reaction mixture from morpholine and
corresponding aldehyde (table 3). Lower aldehydes (C2 and C3,
and C4 without a catalyst) formed allylmorpholines 24a-35a
along with [4+2] cycloaddition products – benzophenones 36a-
38a. As the aliphatic chain length grew, the yield of
system. This is supported by theoretical calculation at P2(full)/6-
31+G**//M062X/6-31+G** theory level performed with Gaussian
16 (tables S2, S3) [13]. The reaction free energy ΔG of
benzophenone 36а formation was 92.43 kJ·mol-1 lower than for
the 4,4а-dihydroxanthone 10a. As a result, for the lower
aldehydes the reaction of [4+2] cycloaddition was
thermodynamically more favorable. Formation of the
phenylbenzophenone 39а as a major product may be explained
by the fact that its calculated reaction free energy is lower than
for the benzophenone 36а for even more 37.53 kJ·mol-1, which
might be a result of conjugation between two benzene systems
in compound 39a.
allylmorpholines
increased
up
to
71%
for
the
cyclohexanecarboxaldehyde derivative 33a. Unexpectedly
phenylacetaldehyde (table 3, entry 14) failed to form the
corresponding allylmorpholine, and the main product was
phenylbenzophenone 39a. The formation of benzophenones
36a-39a appears to be associated with a significant change in
the reaction free energy due to the closure of the aromatic
Table 3. Influence of the alkenylmorpholines 11-23 structure on the reaction
Entry
1
2
Enamine[a]
R4
H
Me
Et
R5
H
H
H
Time, h
Product (preparative yield, %)
11
12
13
13
14
15
16
17
18
19
20
21
22
23
12
12
8
28
7
6
6
4
10
4
24а (21)
25a (34)
26a (58)
26a (34)
27a (55)
28a (66)
29a (61)
30a (64)
31a (59)
32a (63)
33a (71)
34a (64)
35a (24)
-
36a (35)
37a (47)
3
-
4[b]
5
Et
H
38a (30)
-CH2CH2-
-
-
-
-
-
-
-
-
6
7
8
9
10
11
12
13
14
Pr
iPr
Bu
Et
H
H
H
Et
H
Pen
-(CH2)5-
6
6
14
48
n-C8H17
PhCH2
Ph
H
H
H
-
39a (53)
[a] Generated in situ from corresponding aldehyde and morpholine
[b] Without triethylamine
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10.1002/ejoc.201801159
European Journal of Organic Chemistry
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Thus, as shown above, the studied reaction allows obtaining a
fairly wide range of chromone-containing allylmorpholines, which
can be of interest as biologically active substances. In particular,
compounds comprising an aromatic system in combination with
cyclic amine, e.g. derivatives of chromone [14] and indanone
[15] (including donepezil) (figure 2) are known to inhibit
acetylcholinesterase (AChE).
Figure 2. Compounds inhibiting AChE.
Donepezil is one of a few drugs approved by the FDA for the
treatment of the Alzheimer’s disease (AD), in which
neurodegeneration, among other, strongly affects the cholinergic
system [16]. In recent years, more and more data indicate the
special role of butyrylcholinesterase (BChE) in the pathogenesis
of AD [17, 18].
Based on the aforementioned, we investigated the inhibitory
activity of the prepared allylmorpholines 9a-m, 24-35a against
the horse butyrylcholinesterase (eqBChE) (table 4). The
compounds generally shown a moderate level of activity, but the
inhibition ability significantly increases upon the introduction of
bromine in the position 8 of the chromone ring. In addition, the
activity is influenced by the length and branching of the alkyl
substituent R4(R5): in a series of unbranched alkyls the activity
increases up to R4=Pr (28a), and then begins to fall. However,
the replacement of 1-pentyl with a more compact 3-pentyl (30a
and 31a) restores the activity. This is even more evident when
changing from hexyl to cyclohexyl (32a and 33a), which
indicates the importance of non-bulky alkyls in the structure.
With respect to the inhibition of electric eel AChE (eeAChE), the
pattern of structure-activity relationship (SAR) is more complex,
but 8-bromo-substituent similarly enhances inhibition. In general,
the synthesized substances are moderate selective inhibitors of
BChE, apart from donepezil which is much more active towards
AChE.
Given the found SAR, we synthesized the allylmorpholine 33b
that combined 8-bromochromone core and cyclohexyl alkyl in
the side chain. This assumption proved to be fruitful, the
compound did possess the highest activity (0,42 µM) against
BChE from the entire series of allylmorpholines.
Table 4. AChE and BChE inhibition results and NMDA antagonism activity of allylmorpholines
IC50, µM or % inhibition at 24 µM
Compound
R1-3
R4
R5
eqBChE
14.5±0.4
14.7±0.5
12±2
22±1
9±1
EeAChE
15%
18%
31%
15%
36%
30%
4.0±0.1
34%
23±3
7±1
11±1
6.4±0.2
40%
15±1
47%
43%
19±3
38%
13%
46%
21%
42%
14%
7±1
NMDA
28±6
nd
nd
nd
nd
nd
nd
nd
nd
51±12
nd
nd
nd
nd
nd
nd
nd
nd
nd
nd
25±5
nd
15±4
8±3
nd
9a
9b
9c
9d
9e
9f
9g
9h
9i
6-Cl
-
6-Me
6-MeO
6-Br
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
6-F
15±1
8±1
6-NO2
7-Me
6,7-diMe
6-Me-8-Br
6-Cl-8-Br
6,7-diF
6-Br-7-MeO
6-Cl
7.6±0.1
4.8±0.3
1.2±0.1
4.0±0.6
17%
9j
9k
9l
9m
24а
25a
26a
27a
28a
29a
30a
31a
32a
33a
33b
34a
35a
24±2
28%
6-Cl
6-Cl
6-Cl
6-Cl
6-Cl
6-Cl
6-Cl
6-Cl
H
H
23.6±0.4
19.5±0.1
16±2
5.0±0.8
46%
12.8±0.5
4.9±0.3
25.9±0.5
1.6±0.1
0.42±0.03
15%
-CH2CH2-
Pr
H
H
H
Et
H
iPr
Bu
Et
Pen
-(CH2)5-
-(CH2)5-
n-C8H17
PhCH2
6-Cl
6-Me-8-Br
6-Cl
H
H
33%
28%
6-Cl
24.1±0.7
nd
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10.1002/ejoc.201801159
European Journal of Organic Chemistry
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Donepezil
3.8±0.1
0.05±0.01
>100
Memantine
nd
nd
1.1±0.3
nd = not determined
General procedure for the synthesis of chromone-containing
allylmorpholines 9a-m (tables 1, 2). A mixture of acrylic acid 7a-m (4
mmole), enamine 8 (846 mg, 6 mmole, 1.5 eq.) and triethylamine (200
mg, 2 mmole, 0.5 eq.; or other catalyst, see table 1) was stirred in DCM
(10 ml; or other solvent, see table 1). The end of the reaction was
determined by TLC (ethyl acetate, detected by UV-light). Then 10 ml of
2M hydrochloric acid were added to the reaction mixture, the emulsion
was stirred for 1 hour. The resulting precipitate (dihydroxanthones 10a-c)
was filtered off, washed with water and dried. The organic layer of the
biphasic filtrate was separated and evaporated under reduced pressure.
Ethyl acetate (10 ml) was added to the residue; the resulting product
(allylmorpholines 9a-m) was filtered, washed with ethyl acetate and dried.
The multifactor nature of the AD and its various cerebral
mechanisms of pathogenesis lead to an idea of multi-target-
directed ligands [19]. Usually, the targets are a combination of
AChE/BChE inhibition with optionally MAO-B inhibition [20],
reduction of oxidative stress [21], inhibition of aggregation of
beta-amyloid [22], antagonism with H3 receptors [23], and 5НТ6
receptors [24]. NMDA receptors are of particular interest since
memantine is the only NMDA receptor antagonist approved by
the FDA for use in patients with moderate-to-severe AD [25]. Its
important features are low affinity, uncompetitive nature and fast
off-rate kinetics, that’s why the receptors retain their functions
[26]. In view of this concept, we tested the antagonistic activity of
the same key compounds (9a,j, 31a, 33a,b) against NMDA
receptors in a patch-clamp test. The highest activity was shown
by compound 33b with IC50 of 8±3 µM, which is comparable to
that of memantine. It is worth mentioning that donepezil did not
demonstrate substantial activity against NMDA receptors even
at 100 µM concentration.
Allylmorpholines 9a,e,f,j-l usually precipitated immediately after
acidification, then the precipitate was filtered off, washed with DCM and
dried. The filtrate treatment as described above gave an additional
amount of the product (10-15%).
Dihydroxanthones 10a-c were crystallized from ethanol, allylmorpholines
9a-m were crystallized from water or 0.1M hydrochloric acid.
(E)-4-[1-(6-chloro-4-oxo-4H-chromen-3-yl)-4-methylpent-1-en-3-
yl]morpholin-4-ium chloride (9a). White needles (H2O), mp 204-206 °C.
1H NMR (400 MHz, DMSO-d6): δH ppm 0.93 (d, J = 6.8 Hz, 3H, Me), 1.06
(d, J = 6.5 Hz, 3H, Me), 2.42 (m, 1H, CHMe2), 3.07 (m, 2H, NCH2CH2O),
3.42 (m, 2H, NCH2CH2O), 3.75 (m, 1H, CHN), 3.92 (m, 2H, NCH2CH2O),
4.07 (m, 2H, NCH2CH2O), 6.57 (d, J = 15.8 Hz, 1H, CH=CH), 6.82 (dd, J
= 10.0, 15.8 Hz, 1H, CH=CH),7.74 (d, J = 9.0 Hz, 1H, C8H), 7.83 (dd, J =
2.3, 9.0 Hz, 1H, C7H), 7.98 (d, J = 2.3 Hz, 1H, C5H), 8.72 (s, 1H, C2H),
11.27 (br.s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): δC ppm 17.20,
21.02, 26.48, 49.92, 50.71, 63.32, 63.38, 74.97, 119.63, 121.46, 122.91,
124.63, 124.97, 130.05, 130.64, 134.62, 154.25, 157.22, 174.67. HRMS-
ESI: m/z calcd. for C19H23ClNO3 [M+H]+ 348.1361, found 348.1343.
Conclusions
In conclusion, we have described a new and efficient method of
synthesis of chromone-containing allylmorpholines, which highly
likely proceeds via MBH-type mechanism. For best results
catalysis with nucleophilic tertial amines, such as TEA and
DIPEA, is required. The method has been optimized to generate
the enamine in the reaction mixture from aldehyde and
morpholine and can be easily applied to various aldehydes and
substituted chromones. In some cases a side reaction of [4+2]-
cycloaddition occurs. The resultant allylmorpholines show
moderate inhibitory activity towards eqBChE with good
selectivity in relation to EeAChE, which is combined with
moderate antagonism towards NMDA receptors similar to the
reference substance memantine. Altogether this makes them a
perspective group for drug design in neurodegenerative
diseases therapy.
X-ray analysis of compound 9a. Single crystals of allylmorpholine 9a
were grown from acetonitrile. A suitable crystal was selected and studied
on a SuperNova (Dual, Cu at zero, Atlas) diffractometer. The crystal was
kept at 100(2) K during data collection. Using Olex2 [26], the structure
was solved with the Superflip [27] structure solution program using
«сharge flipping» and refined with the ShelXL [28] refinement package
using least squares minimization. Crystallographic data have been
deposited in the Cambridge Crystallographic Data Center [7].
Crystal data for compound 9a. C19H23O3Cl2N, M =384.28, monoclinic,
a = 11.7616(4) Å, b = 7.6304(4) Å, c = 42.125(2) Å, β = 92.252(4)°, V =
3777.7(3) Å3, T = 100(2), space group C2/c (no. 15), Z = 8, μ(Cu Kα) =
3.238, 11244 reflections measured, 3497 unique (Rint = 0.0984) which
were used in all calculations. The final wR2 was 0.1664 (all data) and R1
was 0.0660 (>2sigma(I)).
Experimental Section
General methods. Commercial grade reagents and solvents were used
without further purification. Reactions were monitored by thin layer
chromatography using Merck silica gel 60 F254 aluminum sheets,
visualization of the compounds was achieved by UV. NMR spectra were
recorded on Bruker Avance III (1Н – 400 MHz, 13С – 100 MHz). NMR
spectra were calibrated to the solvent signals of DMSO-d6 or D2O.
HRMS-ESI were recorded on a Bruker micrOTOF mass-spectrometer.
Melting points were determined on a capillary point apparatus and are
uncorrected.
(E)-4-[1-(4-oxo-4H-chromen-3-yl)-4-methylpent-1-en-3-yl]morpholin-
4-ium chloride (9b). White needles (H2O), mp 188-190 °C. 1H NMR (400
MHz, DMSO-d6): δH ppm 0.93 (d, J = 6.8 Hz, 3H, Me), 1.05 (d, J = 6.5 Hz,
3H, Me), 2.41 (m, 1H, CHMe2), 3.06 (m, 2H, NCH2CH2O), 3.40 (m, 2H,
NCH2CH2O), 3.73 (m, 1H, CHN), 3.92 (m, 2H, NCH2CH2O), 4.04 (m, 2H,
NCH2CH2O), 6.57 (d, J = 15.8 Hz, 1H, CH=CH), 6.81 (dd, J = 10.0, 15.8
Hz, 1H, CH=CH),7.53 (t, J = 7.5 Hz, 1H, C6H), 7.69 (d, J = 8.5 Hz, 1H,
C8H), 7.83 (m, 1H, C7H), 8.12 (d, J = 8.0 Hz, 1H, C5H), 8.69 (s, 1H, C2H),
11.09 (br.s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): δC ppm 17.17,
Dienes 7a-m were prepared from corresponding phenols through a four-
step synthesis (see Supporting information).
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10.1002/ejoc.201801159
European Journal of Organic Chemistry
FULL PAPER
21.00, 26.47, 49.92, 50.67, 63.36, 63.42, 75.04, 118.93, 119.58, 122.36,
123.90, 125.74, 126.26, 130.50, 134.81, 155.70, 157.04, 175.82. HRMS-
ESI: m/z calcd. for C19H24NO3 [M+H]+ 314.1751, found 314.1744.
CH=CH),7.97 (d, J = 9.3 Hz, 1H, C8H), 8.59 (dd, J = 2.8, 9.3 Hz, 1H,
C7H), 8.78 (d, J = 2.8 Hz, 1H, C5H), 8.82 (s, 1H, C2H), 10.67 (br.s, 1H,
NH). 13C NMR (100 MHz, DMSO-d6): δC ppm 16.95, 20.84, 26.37, 49.87,
50.81, 63.49, 74.83, 119.95, 121.37, 121.84, 123.53, 123.89, 128.93,
129.85, 144.99, 157.71, 158.67, 175.11. HRMS-ESI: m/z calcd. for
C19H23N2O5 [M+H]+ 359.1601, found 359.1597.
(E)-4-[1-(6-methyl-4-oxo-4H-chromen-3-yl)-4-methylpent-1-en-3-
yl]morpholin-4-ium chloride (9c). White needles (H2O), mp 196-198 °C.
1H NMR (400 MHz, DMSO-d6): δH ppm 0.93 (d, J = 6.5 Hz, 3H, Me), 1.04
(d, J = 6.5 Hz, 3H, Me), 2.42 (m, 1H, CHMe2), 2.44 (s, 3H, Me), 3.06 (m,
2H, NCH2CH2O), 3.37 (m, 1H, NCH2CH2O), 3.48 (m, 1H, NCH2CH2O),
3.72 (m, 1H, CHN), 3.97 (m, 4H, NCH2CH2O), 6.58 (d, J = 15.7 Hz, 1H,
CH=CH), 6.78 (dd, J = 10.0, 15.7 Hz, 1H, CH=CH),7.59 (d, J = 8.5 Hz,
1H, C8H), 7.65 (dd, J = 2.0, 8.5 Hz, 1H, C7H), 7.89 (d, J = 2.0 Hz, 1H,
C5H), 8.66 (s, 1H, C2H), 10.90 (br.s, 1H, NH). 13C NMR (100 MHz,
DMSO-d6): δC ppm 17.11, 20.96, 20.98, 26.45, 49.92, 50.66, 63.39,
63.46, 75.04, 118.74, 119.40, 122.00, 123.63, 124.94, 130.67, 135.85,
135.88, 154.05, 156.88, 175.76. HRMS-ESI: m/z calcd. for C20H26NO3
[M+H]+ 328.1907, found 328.1921.
(E)-4-[1-(7-methyl-4-oxo-4H-chromen-3-yl)-4-methylpent-1-en-3-
yl]morpholin-4-ium chloride (9h). White needles (H2O), mp 236-238 °C.
1H NMR (400 MHz, D2O): δH ppm 0.89 (d, J = 5.4 Hz, 3H, Me), 0.91 (d, J
= 5.6 Hz, 3H, Me), 2.20 (s, 3H, Me), 2.32 (m, 1H, CHMe2), 3.09 (m, 2H,
NCH2CH2O), 3.47 (m, 2H, NCH2CH2O), 3.59 (m, 1H, CHN), 3.77 (m, 2H,
NCH2CH2O), 4.01 (m, 2H, NCH2CH2O), 6.40 (m, 2H, CH=CH), 6.88 (s,
1H, C8H), 6.92 (d, J = 8.3 Hz, 1H, C6H), 7.40 (d, J = 8.3 Hz, 1H, C5H),
7.98 (s, 1H, C2H). 13C NMR (100 MHz, D2O): δC ppm 15.65, 19.32, 20.92,
26.25, 49.88, 50.00, 63.56, 63.64, 75.81, 117.52, 118.64, 120.02, 120.87,
124.34, 127.16, 131.46, 146.60, 155.24, 156.61, 177.64. HRMS-ESI: m/z
calcd. for C20H26NO3 [M+H]+ 328.1907, found 328.1895.
(E)-4-[1-(6-methoxy-4-oxo-4H-chromen-3-yl)-4-methylpent-1-en-3-
yl]morpholin-4-ium chloride (9d). White needles (H2O), mp 178-180 °C.
1H NMR (400 MHz, DMSO-d6): δH ppm 0.92 (d, J = 6.8 Hz, 3H, Me), 1.03
(d, J = 6.8 Hz, 3H, Me), 2.40 (m, 1H, CHMe2), 3.06 (m, 2H, NCH2CH2O),
3.38 (m, 1H, NCH2CH2O), 3.49 (m, 1H, NCH2CH2O), 3.73 (m, 1H, CHN),
3.86 (s, 3H, MeO), 3.96 (m, 4H, NCH2CH2O), 6.58 (d, J = 15.8 Hz, 1H,
CH=CH), 6.80 (dd, J = 10.3, 15.8 Hz, 1H, CH=CH),7.42 (dd, J = 3.0, 9.0
Hz, 1H, C7H), 7.47 (d, J = 3.0, 1H, C5H), 7.66 (d, J = 9.0 Hz, 1H, C8H),
8.67 (s, 1H, C2H), 10.74 (br.s, 1H, NH). 13C NMR (100 MHz, DMSO-d6):
δC ppm 17.00, 20.90, 26.39, 49.86, 50.72, 56.20, 63.48, 75.03, 105.48,
118.66, 120.56, 122.08, 123.84, 124.59, 130.71, 150.45, 156.92, 157.19,
175.54. HRMS-ESI: m/z calcd. for C20H26NO4 [M+H]+ 344.1856, found
344.1853.
(E)-4-[1-(6,7-dimethyl-4-oxo-4H-chromen-3-yl)-4-methylpent-1-en-3-
yl]morpholin-4-ium chloride (9i). White needles (H2O), mp 213-215 °C.
1H NMR (400 MHz, DMSO-d6): δH ppm 0.92 (d, J = 6.8 Hz, 3H, Me), 1.03
(d, J = 6.8 Hz, 3H, Me), 2.32 (s, 3H, Me), 2.35 (s, 3H, Me), 2.39 (m, 1H,
CHMe2), 3.06 (m, 2H, NCH2CH2O), 3.37 (m, 1H, NCH2CH2O), 3.47 (m,
1H, NCH2CH2O), 3.72 (m, 1H, CHN), 3.95 (m, 4H, NCH2CH2O), 6.57 (d,
J = 15.6 Hz, 1H, CH=CH), 6.76 (dd, J = 10.3, 15.6 Hz, 1H, CH=CH),7.46
(s, 1H, C8H), 7.81 (s, 1H, C5H), 8.62 (s, 1H, C2H), 10.77 (br.s, 1H, NH).
13C NMR (100 MHz, DMSO-d6): δC ppm 17.04, 19.47, 20.30, 20.92,
26.41, 49.87, 50.70, 63.48, 75.04, 118.71, 119.30, 121.71, 121.74,
125.09, 130.81, 135.31, 145.10, 154.24, 156.61, 175.60. HRMS-ESI: m/z
calcd. for C21H28NO3 [M+H]+ 342.2064, found 342.2077.
(E)-4-[1-(6-bromo-4-oxo-4H-chromen-3-yl)-4-methylpent-1-en-3-
yl]morpholin-4-ium chloride (9e). White needles (H2O), mp 196-197 °C.
1H NMR (400 MHz, DMSO-d6): δH ppm 0.93 (d, J = 6.8 Hz, 3H, Me), 1.04
(d, J = 6.5 Hz, 3H, Me), 2.41 (m, 1H, CHMe2), 3.07 (m, 2H, NCH2CH2O),
3.44 (m, 2H, NCH2CH2O), 3.74 (m, 1H, CHN), 3.97 (m, 4H, NCH2CH2O),
6.56 (d, J = 15.8 Hz, 1H, CH=CH), 6.80 (dd, J = 10.0, 15.8 Hz, 1H,
CH=CH),7.70 (d, J = 8.8 Hz, 1H, C8H), 7.98 (dd, J = 2.0, 8.8 Hz, 1H,
C7H), 8.16 (d, J = 2.0 Hz, 1H, C5H), 8.73 (s, 1H, C2H), 10.93 (br.s, 1H,
NH). 13C NMR (100 MHz, DMSO-d6): δC ppm 17.14, 20.96, 26.48, 49.96,
50.70, 63.44, 74.98, 118.64, 119.71, 121.67, 122.81, 125.41, 127.82,
130.18, 137.39, 154.69, 157.28, 174.65. HRMS-ESI: m/z calcd. for
C19H23BrNO3 [M+H]+ 392.0856, found 392.0847.
(E)-4-[1-(8-bromo-6-methyl-4-oxo-4H-chromen-3-yl)-4-methylpent-1-
en-3-yl]morpholin-4-ium chloride (9j). White needles (H2O), mp 190-
192 °C. H NMR (400 MHz, DMSO-d6): δH ppm 0.92 (d, J = 6.8 Hz, 3H,
1
Me), 1.05 (d, J = 6.8 Hz, 3H, Me), 2.41 (m, 4H, CHMe2, Me), 3.07 (m, 2H,
NCH2CH2O), 3.38 (m, 1H, NCH2CH2O), 3.49 (m, 1H, NCH2CH2O), 3.75
(m, 1H, CHN), 3.98 (m, 4H, NCH2CH2O), 6.56 (d, J = 15.8 Hz, 1H,
CH=CH), 6.80 (dd, J = 10.3, 15.8 Hz, 1H, CH=CH),7.81 (d, J = 2.8 Hz,
1H, C8H), 7.94 (d, J = 2.8 Hz, 1H, C5H), 8.76 (s, 1H, C2H), 11.03 (br.s,
1H, NH). 13C NMR (100 MHz, DMSO-d6): δC ppm 17.07, 20.66, 20.96,
26.42, 49.86, 50.76, 63.42, 74.89, 111.20, 119.57, 122.85, 124.80,
130.11, 137.04, 138.61, 150.36, 156.79, 175.21. HRMS-ESI: m/z calcd.
for C20H25BrNO3 [M+H]+ 406.1012, found 406.1009.
(E)-4-[1-(6-fluoro-4-oxo-4H-chromen-3-yl)-4-methylpent-1-en-3-
yl]morpholin-4-ium chloride (9f). White needles (H2O), mp 206-207 °C.
1H NMR (400 MHz, DMSO-d6): δH ppm 0.91 (d, J = 6.3 Hz, 3H, Me), 1.05
(d, J = 5.8 Hz, 3H, Me), 2.40 (m, 1H, CHMe2), 3.06 (m, 2H, NCH2CH2O),
3.41 (m, 2H, NCH2CH2O), 3.74 (m, 1H, CHN), 3.92 (m, 2H, NCH2CH2O),
4.03 (m, 2H, NCH2CH2O), 6.57 (d, J = 15.8 Hz, 1H, CH=CH), 6.83 (dd, J
= 10.3, 15.8 Hz, 1H, CH=CH),7.78 (m, 3H, Ar), 8.74 (s, 1H, C2H), 11.08
(br.s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): δC ppm 17.00, 20.90,
26.38, 49.87, 50.73, 63.48, 74.95, 110.30 (d, JCF = 24.2 Hz), 118.84,
121.84 (d, JCF = 8.1 Hz), 122.64, 123.02 (d, JCF = 25.6 Hz), 125.10 (d,
JCF = 7.4 Hz), 130.36, 152.19, 157.53, 159.59 (d, JCF = 244.4 Hz), 175.23.
HRMS-ESI: m/z calcd. for C19H23FNO3 [M+H]+ 332.1656, found 332.1640.
(E)-4-[1-(8-bromo-6-chloro-4-oxo-4H-chromen-3-yl)-4-methylpent-1-
en-3-yl]morpholin-4-ium chloride (9k). White needles (H2O), mp 195-
197 °C. H NMR (400 MHz, DMSO-d6): δH ppm 0.92 (d, J = 6.8 Hz, 3H,
1
Me), 1.03 (d, J = 6.5 Hz, 3H, Me), 2.40 (m, 1H, CHMe2), 3.07 (m, 2H,
NCH2CH2O), 3.37 (m, 1H, NCH2CH2O), 3.49 (m, 1H, NCH2CH2O), 3.75
(m, 1H, CHN), 3.95 (m, 4H, NCH2CH2O), 6.56 (d, J = 15.8 Hz, 1H,
CH=CH), 6.82 (dd, J = 10.0, 15.8 Hz, 1H, CH=CH),8.03 (d, J = 2.5 Hz,
1H, C8H), 8.32 (d, J = 2.5 Hz, 1H, C5H), 8.84 (s, 1H, C2H), 10.75 (br.s,
1H, NH). 13C NMR (100 MHz, DMSO-d6): δC ppm 16.95, 20.87, 26.38,
49.86, 50.80, 63.47, 63.65, 74.81, 113.45, 119.67, 123.45, 124.50,
125.82, 129.86, 130.84, 137.12, 151.28, 157.43, 174.43. HRMS-ESI: m/z
calcd. for C10H22BrClNO3 [M+H]+ 426.0466, found 426.0449.
(E)-4-[1-(6-nitro-4-oxo-4H-chromen-3-yl)-4-methylpent-1-en-3-
(E)-4-[1-(6,7-difluoro-4-oxo-4H-chromen-3-yl)-4-methylpent-1-en-3-
yl]morpholin-4-ium chloride (9l). White needles (H2O), mp 244-246 °C.
1H NMR (400 MHz, DMSO-d6): δH ppm 0.91 (d, J = 6.8 Hz, 3H, Me), 1.03
(d, J = 6.8 Hz, 3H, Me), 2.40 (m, 1H, CHMe2), 3.06 (m, 2H, NCH2CH2O),
3.35 (m, 1H, NCH2CH2O), 3.48 (m, 1H, NCH2CH2O), 3.74 (m, 1H, CHN),
3.94 (m, 4H, NCH2CH2O), 6.55 (d, J = 15.8 Hz, 1H, CH=CH), 6.80 (dd, J
yl]morpholin-4-ium chloride (9g). White needles (H2O), mp 212-214 °C.
1H NMR (400 MHz, DMSO-d6): δH ppm 0.93 (d, J = 6.5 Hz, 3H, Me), 1.03
(d, J = 6.5 Hz, 3H, Me), 2.41 (m, 1H, CHMe2), 3.07 (m, 2H, NCH2CH2O),
3.43 (m, 2H, NCH2CH2O), 3.77 (m, 1H, CHN), 3.94 (m, 4H, NCH2CH2O),
6.59 (d, J = 15.8 Hz, 1H, CH=CH), 6.83 (dd, J = 10.0, 15.8 Hz, 1H,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801159
European Journal of Organic Chemistry
FULL PAPER
= 10.0, 15.8 Hz, 1H, CH=CH), 8.03 (m, 3H, Ar), 8.74 (s, 1H, C2H), 10.77
(br.s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): δC ppm 16.98, 20.87,
26.37, 49.85, 50.76, 63.42, 63.47, 74.98, 108.80 (d, JCF = 21.6 Hz),
113.00 (d, JCF = 19.4 Hz), 119.12, 121.24 (dd, JCF = 2.4, 5.6 Hz), 122.99,
130.07, 148.35 (dd, JCF = 13.8, 247.9 Hz), 152.32 (d, JCF = 11.8 Hz),
153.52 (dd, JCF = 15.4, 255.3 Hz), 157.63, 174.54. HRMS-ESI: m/z calcd.
for C19H22F2NO3 [M+H]+ 350.1562, found 350.1571.
1H, COOH). 13C NMR (100 MHz, DMSO-d6): δC ppm 17.47, 20.44, 25.87,
38.60, 81.82, 118.47, 121.13, 126.39, 126.74, 126.78, 130.61, 131.48,
137.73, 152.55, 158.53, 165.85, 179.25. HRMS-ESI: m/z calcd. for
C17H15O4 [M-H]- 283.0976, found 283.0981.
General procedure for synthesis of chromone-containing
allylmorpholines 24a-35a (table 3). A mixture of morpholine (6 mmole),
corresponding aldehyde (6 mmole) and molecular sieves 4Å (0.5 g) was
stirred in DCM (10 ml) for 12-24 hour. The solution of enamine was
filtered, and acrylic acid 7a (1.0 g, 4 mmole) and triethylamine (200 mg, 2
mmole, 0.5 eq.) were added. The end of the reaction was determined by
TLC (ethyl acetate, detected by UV-light). Then 10 ml of 2M hydrochloric
acid were added to the reaction mixture, the emulsion was stirred for 1
hour. The resulting precipitate (benzophenones 36a-39a) was filtered by
water and dried. The organic layer of the biphasic filtrate was separated
and evaporated under reduced pressure. Ethyl acetate (10 ml) was
added to the residue; the resulting product (allylmorpholines 24a-35a)
was filtered, washed with ethyl acetate and dried.
(E)-4-[1-(6-bromo-7-methoxy-4-oxo-4H-chromen-3-yl)-4-methylpent-
1-en-3-yl]morpholin-4-ium chloride (9m). White needles (H2O), mp
230-232 (dec.) °C. 1H NMR (400 MHz, DMSO-d6): δH ppm 0.92 (d, J =
4.8 Hz, 3H, Me), 1.03 (d, J = 4.8 Hz, 3H, Me), 2.39 (m, 1H, CHMe2), 3.07
(m, 2H, NCH2CH2O), 3.47 (m, 2H, NCH2CH2O), 3.73 (m, 1H, CHN), 3.94
(m, 4H, NCH2CH2O), 4.01 (s, 3H, MeO), 6.55 (d, J = 15.7 Hz, 1H,
CH=CH), 6.79 (dd, J = 10.5, 15.7 Hz, 1H, CH=CH),7.40 (s, 1H, C8H),
8.19 (s, 1H, C5H), 8.68 (s, 1H, C2H), 10.64 (br.s, 1H, NH). 13C NMR (100
MHz, DMSO-d6): δC ppm 16.95, 20.88, 26.37, 49.86, 50.73, 57.96, 63.52,
74.94, 102.02, 110.03, 118.48, 119.43, 122.42, 129.26, 130.47, 156.66,
157.01, 160.05, 174.21. HRMS-ESI: m/z calcd. for C20H25BrNO4 [M+H]+
422.0961, found 422.0963.
Allylmorpholines 30a, 33a usually precipitated immediately after
acidification, and then the precipitate was filtered off, washed with DCM
and dried. The filtrate treatment gave an additional portion of the product
(5-15%).
7-Chloro-4,4-dimethyl-9-oxo-4,4a-dihydro-9H-xanthen-2-carboxylic
acid (10a). Pale yellow needles (EtOH), mp 243-245 °C. 1H NMR (400
MHz, DMSO-d6): δH ppm 1.05 (s, 3H, Me), 1.44 (s, 3H, Me), 5.33 (dd, J =
1.5, 3.0 Hz, 1H, C4aH), 7.08 (t, J = 1.5 Hz, 1H, C3H), 7.13 (d, J = 8.8 Hz,
1H, C5H), 7.33 (dd, J = 1.5, 3.0 Hz, 1H, C1H), 7.61 (dd, J = 2.8, 8.8 Hz,
1H, C6H), 7.72 (d, J = 2.8 Hz, 1H, C8H), 13.07 (s, 1H, COOH). 13C NMR
(100 MHz, DMSO-d6): δC ppm 17.50, 25.80, 38.68, 82.32, 121.06, 122.36,
126.15, 126.35, 126.53, 127.71, 129.66, 136.39, 153.02, 159.12, 165.75,
178.34. HRMS-ESI: m/z calcd. for C16H13ClO4 [M-H]- 303.0430, found
303.0444.
Benzophenones 36a-39a were crystallized from ethanol, allylmorpholines
24a-35a were crystallized from water or 0.1M hydrochloric acid.
(E)-4-[4-(6-chloro-4-oxo-4H-chromen-3-yl)-but-3-en-2-yl]morpholin-4-
ium chloride (24a). White needles (H2O), mp 225-226 °C. 1H NMR (400
MHz, D2O): δH ppm 1.44 (d, J = 6.8 Hz, 3H, Me), 3.10 (m, 2H,
NCH2CH2O), 3.43 (d, J = 12.6 Hz, 2H, NCH2CH2O), 3.70 (m, 2H,
NCH2CH2O), 3.93 (m, 1H, CHN), 4.04 (d, J = 13.1 Hz, 2H, NCH2CH2O),
6.41 (m, 2H, CH=CH), 7.20 (d, J = 9.0 Hz, 1H, C8H), 7.43 (dd, J = 2.5,
9.0 Hz, 1H, C7H), 7.46 (d, J = 2.5 Hz, 1H, C5H), 8.07 (s, 1H, C2H). 13C
NMR (100 MHz, D2O): δC ppm 15.04, 48.27, 49.36, 63.79, 63.89, 65.40,
118.81, 120.24, 123.27, 123.82, 125.11, 128.63, 131.06, 134.55, 153.61,
157.00, 176.30. HRMS-ESI: m/z calcd. for C17H19ClNO3 [M+H]+ 320.1048,
found 320.1036.
Ethyl
7-chloro-4,4-dimethyl-9-oxo-4,4a-dihydro-9H-xanthen-2-
carboxylate (10a’). Compound 10a’ was synthesized according to the
general procedure with the following modification: after acidification the
organic layer was separated and evaporated under reduced pressure.
Ethanol was added to the residue; the resulting precipitate was filtered,
washed with ethanol and dried. The resulting product was crystallized
1
from ethanol. Pale yellow needles (EtOH), mp 126-127 °C. H NMR (400
MHz, DMSO-d6): δH ppm 1.06 (s, 3H, Me), 1.28 (t, J = 7.0 Hz, CH3CH2),
1.46 (s, 3H, Me), 4.23 (q, J = 7.0 Hz, CH3CH2), 5.35 (dd, J = 1.4, 3.1 Hz,
1H, C4aH), 7.13 (t, J = 1.5 Hz, 1H, C3H), 7.15 (d, J = 8.8 Hz, 1H, C5H),
7.31 (dd, J = 1.8, 3.3 Hz, 1H, C1H), 7.64 (dd, J = 2.8, 9.0 Hz, 1H, C6H),
7.73 (d, J = 2.8 Hz, 1H, C8H). 13C NMR (100 MHz, DMSO-d6): δC ppm
14.51, 17.41, 25.72, 38.75, 61.50, 82.18, 121.12, 122.32, 125.74, 126.14,
126.57, 127.04, 129.94, 136.51, 153.41, 159.14, 164.13, 178.31. HRMS-
ESI: m/z calcd. for C18H17ClNaO4 [M+Na]+ 355.0708, found 355.0711.
(E)-4-[1-(6-chloro-4-oxo-4H-chromen-3-yl)-pent-1-en-3-yl]morpholin-
4-ium chloride (25a). White needles (H2O), mp 215-217 °C. 1H NMR
(400 MHz, D2O): δH ppm 0.84 (t, J = 7.3 Hz, 3H, Me), 1.69 (m, 1H, CH2),
1.90 (m, 1H, CH2), 3.09 (m, 2H, NCH2CH2O), 3.42 (d, J = 13.1 Hz, 2H,
NCH2CH2O), 3.70 (m, 3H, NCH2CH2O, CHN), 4.02 (d, J = 13.1 Hz, 2H,
NCH2CH2O), 6.33 (dd, J = 9.8, 15.8 Hz, 1H, CH=CH), 6.44 (d, J = 15.8
Hz, 1H, CH=CH), 7.15 (d, J = 9.8 Hz, 1H, C8H), 7.38 (m, 2H, C7H, C5H),
8.08 (s, 1H, C2H). 13C NMR (100 MHz, D2O): δC ppm 9.60, 22.17, 48.14,
49.96, 63.77, 63.88, 71.44, 118.84, 120.18, 123.21, 123.58, 123.73,
130.51, 130.98, 134.43, 153.51, 156.98, 176.12. HRMS-ESI: m/z calcd.
for C18H21ClNO3 [M+H]+ 334.1204, found 334.1194.
4,4-Dimethyl-9-oxo-4,4a-dihydro-9H-xanthen-2-carboxylic acid (10b).
Pale yellow needles (EtOH), mp 186-188 °C. 1H NMR (400 MHz, DMSO-
d6): δH ppm 1.06 (s, 3H, Me), 1.46 (s, 3H, Me), 5.33 (dd, J = 1.6, 3.1 Hz,
1H, C4aH), 7.07 (t, J = 1.6 Hz, 1H, C3H), 7.09 (d, J = 8.5 Hz, 1H, C5H),
7.12 (t, J = 7.5 Hz, 1H, C7H), 7.33 (dd, J = 1.6, 3.1 Hz, 1H, C1H), 7.59-
7.63 (m, 1H, C6H), 7.83 (dd, J = 1.8, 7.8 Hz, 1H, C8H), 13.05 (s, 1H,
COOH). 13C NMR (100 MHz, DMSO-d6): δC ppm 17.51, 25.87, 38.67,
81.99, 118.73, 121.46, 122.51, 126.36, 126.88, 127.34, 130.52, 136.96,
152.79, 160.52, 165.87, 179.36. HRMS-ESI: m/z calcd. for C16H14O4 [M-
H]- 269.0819, found 269.0832.
(E)-4-[1-(6-chloro-4-oxo-4H-chromen-3-yl)-hex-1-en-3-yl]morpholin-
4-ium chloride (26a). White needles (H2O), mp 212-213 °C. 1H NMR
(400 MHz, D2O): δH ppm 0.83 (t, J = 7.4 Hz, 3H, Me), 1.20 (m, 1H, CH2),
1.30 (m, 1H, CH2), 1.69 (m, 1H, CH2), 1.80 (m, 1H, CH2), 3.09 (m, 2H,
NCH2CH2O), 3.42 (d, J = 12.8 Hz, 2H, NCH2CH2O), 3.73 (m, 3H,
NCH2CH2O, CHN), 4.02 (d, J = 13.1 Hz, 2H, NCH2CH2O), 6.35 (dd, J =
9.5, 15.8 Hz, 1H, CH=CH), 6.45 (d, J = 15.8 Hz, 1H, CH=CH), 7.16 (d, J
= 8.3 Hz, 1H, C8H), 7.40 (m, 2H, C7H, C5H), 8.08 (s, 1H, C2H). 13C NMR
(100 MHz, D2O): δC ppm 12.63, 18.56, 30.63, 48.09, 49.92, 63.77, 63.89,
69.85, 118.84, 120.19, 123.27, 123.76, 123.82, 130.32, 130.99, 134.43,
153.53, 157.00, 176.13. HRMS-ESI: m/z calcd. for C19H23ClNO3 [M+H]+
348.1361, found 348.1372.
4,4,7-Trimethyl-9-oxo-4,4a-dihydro-9H-xanthen-2-carboxylic
acid
(10c). Pale yellow needles (EtOH), mp 225-226 °C. 1H NMR (400 MHz,
DMSO-d6): δH ppm 1.02 (s, 3H, Me), 1.42 (s, 3H, Me), 2.26 (s, 3H, Me),
5.17 (s, 1H, C4aH), 6.94 (d, J = 8.3 Hz, 1H, C5H), 7.03 (s, 1H, C3H), 7.29
(s, 1H, C1H), 7.36 (d, J = 8.3 Hz, 1H, C6H), 7.58 (s, 1H, C8H), 13.00 (s,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801159
European Journal of Organic Chemistry
FULL PAPER
(E)-4-[3-(6-chloro-4-oxo-4H-chromen-3-yl)-1-
157.18, 176.44. HRMS-ESI: m/z calcd. for C21H27ClNO3 [M+H]+ 376.1674,
cyclopropylallyl]morpholin-4-ium chloride (27a). White needles (H2O),
mp 214-215 °C. 1H NMR (400 MHz, DMSO-d6): δH ppm 0.24 (m, 1H, cPr),
0.68 (m, 2H, cPr), 0.81 (m, 1H, cPr), 1.34 (m, 1H, cPr), 3.07 (m, 2H,
NCH2CH2O), 3.37 (m, 2H, NCH2CH2O), 3.65 (m, 1H, CHN), 3.95 (m, 4H,
NCH2CH2O), 6.53 (d, J = 15.8 Hz, 1H, CH=CH), 6.93 (dd, J = 9.5, 15.8
Hz, 1H, CH=CH),7.76 (d, J = 9.0 Hz, 1H, C8H), 7.86 (dd, J = 2.5, 9.0 Hz,
1H, C7H), 8.00 (d, J = 2.5 Hz, 1H, C5H), 8.70 (s, 1H, C2H), 11.64 (br.s,
1H, NH). 13C NMR (100 MHz, DMSO-d6): δC ppm 3.29, 7.35, 11.22,
49.74, 63.73, 73.27, 119.51, 121.53, 124.65, 124.99, 125.64, 128.06,
130.67, 134.68, 154.27, 157.40, 174.75. HRMS-ESI: m/z calcd. for
C19H21ClNO3 [M+H]+ 346.1204, found 346.1212.
found 376.1686.
(E)-4-[1-(6-chloro-4-oxo-4H-chromen-3-yl)-non-1-en-3-yl]morpholin-
4-ium chloride (32a). White needles (H2O), mp 171-173 °C. 1H NMR
(400 MHz, DMSO-d6): δH ppm 0.83 (t, J = 6.8 Hz, 3H, Me), 1.23 (m, 8H,
CH2), 1.75 (m, 1H, CH2), 2.09 (m, 1H, CH2), 3.02 (m, 2H, NCH2CH2O),
3.43 (m, 2H, NCH2CH2O), 3.93 (m, 5H, NCH2CH2O, CHN), 6.66 (m, 2H,
CH=CH), 7.77 (d, J = 9.0 Hz, 1H, C8H), 7.87 (dd, J = 2.5, 9.0 Hz, 1H,
C7H), 8.00 (d, J = 2.5 Hz, 1H, C5H), 8.76 (s, 1H, C2H), 11.64 (br.s, 1H,
NH). 13C NMR (100 MHz, DMSO-d6): δC ppm 14.37, 22.48, 25.93, 28.65,
31.47, 48.04, 50.08, 63.58, 63.71, 69.06, 119.53, 121.54, 124.64, 124.97,
125.07, 129.79, 130.67, 134.70, 154.31, 157.34, 174.74. HRMS-ESI: m/z
calcd. for C22H29ClNO3 [M+H]+ 390.1830, found 390.1826.
(E)-4-[1-(6-chloro-4-oxo-4H-chromen-3-yl)-hept-1-en-3-yl]morpholin-
4-ium chloride (28a). White needles (H2O), mp 209-211 °C. 1H NMR
(400 MHz, D2O): δH ppm 0.84 (t, J = 6.8 Hz, 3H, Me), 1.29 (m, 4H, CH2),
1.77 (m, 1H, CH2), 1.91 (m, 1H, CH2), 3.17 (m, 2H, NCH2CH2O), 3.49 (d,
J = 11.3 Hz, 2H, NCH2CH2O), 3.81 (m, 3H, NCH2CH2O, CHN), 4.09 (d, J
= 13.1 Hz, 2H, NCH2CH2O), 6.45 (dd, J = 9.5, 15.8 Hz, 1H, CH=CH),
6.53 (d, J = 15.8 Hz, 1H, CH=CH), 7.27 (d, J = 9.0 Hz, 1H, C8H), 7.49 (dd,
J = 2.5, 9.0 Hz, 1H, C7H), 7.55 (d, J = 2.5 Hz, 1H, C5H), 8.18 (s, 1H, C2H).
13C NMR (100 MHz, D2O): δC ppm 13.17, 21.49, 27.35, 28.40, 48.26,
49.97, 63.87, 63.97, 70.24, 119.01, 120.34, 123.53, 123.98, 130.44,
131.10, 134.56, 153.79, 157.16, 176.48. HRMS-ESI: m/z calcd. for
C20H25ClNO3 [M+H]+ 362.1517, found 362.1501.
(E)-4-[3-(6-chloro-4-oxo-4H-chromen-3-yl)-1-
cyclohexylallyl]morpholin-4-ium chloride (33a). White needles (H2O),
mp 217-219 °C. 1H NMR (400 MHz, DMSO-d6): δH ppm 1.04 (m, 3H,
cHex), 1.27 (m, 2H, cHex), 1.61 (d, J = 12.1 Hz, 2H, cHex), 1.71 (d, J =
12.6 Hz, 2H, cHex), 2.02 (m, 2H, cHex), 3.06 (m, 2H, NCH2CH2O), 3.35
(m, 1H, NCH2CH2O), 3.47 (m, 1H, NCH2CH2O), 3.71 (m, 1H, CHN), 3.97
(m, 4H, NCH2CH2O), 6.53 (d, J = 15.8 Hz, 1H, CH=CH), 6.84 (dd, J =
10.0, 15.8 Hz, 1H, CH=CH), 7.78 (d, J = 9.0 Hz, 1H, C8H), 7.87 (dd, J =
2.5, 9.0 Hz, 1H, C7H), 8.02 (d, J = 2.5 Hz, 1H, C5H), 8.74 (s, 1H, C2H),
10.97 (br.s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): δC ppm 25.65,
26.02, 26.06, 27.37, 30.81, 36.34, 48.95, 50.50, 63.40, 63.46, 74.60,
119.51, 121.53, 123.80, 124.67, 125.01, 129.72, 130.66, 134.68, 154.28,
157.43, 174.79. HRMS-ESI: m/z calcd. for C22H27ClNO3 [M+H]+ 388.1674,
found 388.1659.
(E)-4-[1-(6-chloro-4-oxo-4H-chromen-3-yl)-5-methylhex-1-en-3-
yl]morpholin-4-ium chloride (29a). White needles (H2O), mp 226-
1
228 °C. H NMR (400 MHz, D2O): δH ppm 0.87 (d, J = 6.3 Hz, 3H, Me),
0.94 (d, J = 6.5 Hz, 3H, Me), 1.57 (m, 1H, CHMe2), 1.65 (pseudo-dt, J =
3.0, 11.5×2 Hz, 1H, CH2), 1.80 (pseudo-dt, J = 3.0, 10.0×2 Hz, 1H, CH2),
3.18 (m, 2H, NCH2CH2O), 3.49 (d, J = 12.3 Hz, 2H, NCH2CH2O), 3.77 (m,
2H, NCH2CH2O) 3.89 (pseudo-dt, J = 3.0, 10.0×2 Hz, 1H, CHN), 4.09 (d,
J = 13.1 Hz, 2H, NCH2CH2O), 6.45 (dd, J = 10.0, 15.8 Hz, 1H, CH=CH),
6.59 (d, J = 15.8 Hz, 1H, CH=CH), 7.28 (d, J = 9.0 Hz, 1H, C8H), 7.49 (dd,
J = 2.5, 9.0 Hz, 1H, C7H), 7.55 (d, J = 2.5 Hz, 1H, C5H), 8.19 (s, 1H, C2H).
13C NMR (100 MHz, D2O): δC ppm 19.81, 22.91, 24.49, 37.40, 48.14,
50.00, 63.88, 64.00, 68.87, 118.99, 120.32, 123.50, 123.93, 130.47,
131.09, 134.54, 153.74, 157.17, 176.40. HRMS-ESI: m/z calcd. for
C20H25ClNO3 [M+H]+ 362.1517, found 362.1510.
(E)-4-[3-(8-bromo-6-methyl-4-oxo-4H-chromen-3-yl)-1-
cyclohexylallyl]morpholin-4-ium chloride (33b). White needles (H2O),
mp 221-222 °C. 1H NMR (400 MHz, DMSO-d6): δH ppm 1.05 (m, 3H,
cHex), 1.27 (m, 2H, cHex), 1.62 (d, J = 12.3 Hz, 2H, cHex), 1.72 (d, J =
12.6 Hz, 2H, cHex), 2.01 (m, 2H, cHex), 2.43 (s, 3H, Me), 3.05 (m, 2H,
NCH2CH2O), 3.35 (m, 1H, NCH2CH2O), 3.47 (m, 1H, NCH2CH2O), 3.72
(m, 1H, CHN), 3.96 (m, 4H, NCH2CH2O), 6.53 (d, J = 15.8 Hz, 1H,
CH=CH), 6.82 (dd, J = 10.3, 15.8 Hz, 1H, CH=CH), 7.85 (s, 1H, C7H),
7.98 (s, 1H, C5H), 8.77 (s, 1H, C2H), 10.91 (br.s, 1H, NH). 13C NMR (100
MHz, DMSO-d6): δC ppm 20.66, 25.67, 26.00, 26.08, 27.33, 30.80, 36.35,
49.96, 50.50, 63.42, 63.48, 74.54, 111.23, 119.53, 123.80, 124.85,
129.70, 137.08, 138.66, 150.42, 156.89, 175.28. HRMS-ESI: m/z calcd.
for C23H29BrNO3 [M+H]+ 446.1325, found 446.1318.
(E)-4-[1-(6-chloro-4-oxo-4H-chromen-3-yl)-oct-1-en-3-yl]morpholin-4-
ium chloride (30a). White needles (H2O), mp 197-198 °C. 1H NMR (400
MHz, DMSO-d6): δH ppm 0.85 (t, J = 6.3 Hz, 3H, Me), 1.27 (m, 6H, CH2),
1.74 (m, 1H, CH2), 2.06 (m, 1H, CH2), 3.02 (m, 2H, NCH2CH2O), 3.43 (m,
2H, NCH2CH2O), 3.90 (m, 5H, NCH2CH2O, CHN), 6.66 (m, 2H, CH=CH),
7.79 (d, J = 9.0 Hz, 1H, C8H), 7.88 (dd, J = 2.5, 9.0 Hz, 1H, C7H), 8.03 (d,
J = 2.5 Hz, 1H, C5H), 8.76 (s, 1H, C2H), 11.45 (br.s, 1H, NH). 13C NMR
(100 MHz, DMSO-d6): δC ppm 14.34, 22.32, 25.59, 28.59, 31.13, 48.07,
50.07, 63.61, 63.74, 69.04, 119.52, 121.57, 124.67, 125.01, 129.82,
130.69, 134.72, 154.33, 157.40, 174.79. HRMS-ESI: m/z calcd. for
C21H27ClNO3 [M+H]+ 376.1674, found 376.1671.
(E)-4-[1-(6-chloro-4-oxo-4H-chromen-3-yl)-dodec-1-en-3-
yl]morpholin-4-ium chloride (34a). White solid (ethyl acetate), mp 148-
150 °C. 1H NMR (400 MHz, DMSO-d6): δH ppm 0.79 (t, J = 7.0 Hz, 3H,
Me), 1.18 (m, 14H, CH2), 1.75 (m, 1H, CH2), 2.09 (m, 1H, CH2), 3.05 (m,
2H, NCH2CH2O), 3.42 (m, 2H, NCH2CH2O), 3.90 (m, 5H, NCH2CH2O,
CHN), 6.66 (m, 2H, CH=CH), 7.77 (d, J = 9.0 Hz, 1H, C8H), 7.87 (dd, J =
2.5, 9.0 Hz, 1H, C7H), 8.00 (d, J = 2.5 Hz, 1H, C5H), 8.76 (s, 1H, C2H),
11.69 (br.s, 1H, NH). 13C NMR (100 MHz, DMSO-d6): δC ppm 14.39,
22.55, 25.92, 28.60, 28.91, 29.13, 29.24, 29.34, 31.75, 48.05, 50.09,
63.61, 63.69, 69.07, 119.54, 121.53, 124.63, 124.96, 125.10, 129.73,
130.68, 134.69, 154.29, 157.32, 174.70. HRMS-ESI: m/z calcd. for
C25H35ClNO3 [M+H]+ 432.2300, found 432.2294.
(E)-4-[1-(6-chloro-4-oxo-4H-chromen-3-yl)-4-ethylhex-1-en-3-
yl]morpholin-4-ium chloride (31a). White needles (H2O), mp 219-
220 °C. 1H NMR (400 MHz, D2O): δH ppm 0.83 (t, J = 7.3 Hz, 3H, Me),
0.90 (t, J = 6.8 Hz, 3H, Me), 1.13-1.48 (m, 3H, CH2), 2.06 (m, 1H, CH2),
3.10 (m, 2H, NCH2CH2O), 3.50 (m, 2H, NCH2CH2O), 3.75 (m, 3H,
NCH2CH2O, CHN), 4.00 (m, 2H, NCH2CH2O), 6.45 (m, 2H, CH=CH),
7.21 (d, J = 9.0 Hz, 1H, C8H), 7.42 (dd, J = 2.5, 9.0 Hz, 1H, C7H), 7.78 (d,
J = 2.5 Hz, 1H, C5H), 8.11 (s, 1H, C2H). 13C NMR (100 MHz, D2O): δC
ppm 10.61, 12.66, 15.34, 26.72, 32.65, 49.57, 50.87, 63.62, 74.48,
118.92, 120.24, 121.57, 123.41, 123.84, 130.73, 131.03, 134.47, 153.65,
(E)-4-[1-(6-chloro-4-oxo-4H-chromen-3-yl)-5-phenylpent-1-en-3-
yl]morpholin-4-ium chloride (35a). White solid (ethyl acetate), mp 175-
177 °C. 1H NMR (400 MHz, DMSO-d6): δH ppm 2.09 (m, 1H, CH2), 2.45-
2.62 (m, 3H, CH2), 3.04 (m, 2H, NCH2CH2O), 3.44 (m, 2H, NCH2CH2O),
3.91 (m, 5H, NCH2CH2O, CHN), 6.69 (m, 2H, CH=CH), 7.24 (m, 5H, Ph),
7.79 (d, J = 9.0 Hz, 1H, C8H), 7.89 (dd, J = 2.5, 9.0 Hz, 1H, C7H), 8.04 (d,
J = 2.5 Hz, 1H, C5H), 8.77 (s, 1H, C2H), 11.36 (br.s, 1H, NH). 13C NMR
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201801159
European Journal of Organic Chemistry
FULL PAPER
(100 MHz, DMSO-d6): δC ppm 30.42, 31.93, 48.20, 50.15, 63.76, 68.88,
119.61, 121.58, 124.68, 125.00, 126.61, 128.77, 128.89, 130.28, 130.73,
134.76, 140.85, 154.37, 157.36, 174.81. HRMS-ESI: m/z calcd. for
C24H25ClNO3 [M+H]+ 410.1517, found 410.1529.
of Evolutionary Physiology and Biochemistry of the Russian Academy of
Sciences. Outbred male Wistar rats of 13–18 days old and 25–35 g were
obtained from local (IEPHB) facility. Maximum efforts were made to
minimize the number of animals used and to minimize discomfort. Rats
were anesthetized with urethane and then decapitated. Brains were
removed quickly and cooled to 2–4 C. Transverse hippocampal and
striatal slices were prepared using a vibratome (Campden Instr.) and
single neurons were freed from slices by vibrodissociation [31]. All
experiments were performed at room temperature. The whole-cell patch
clamp technique was used for recording membrane currents in response
to applications of an agonist. Series resistance of about 20 MΩ was
compensated by 70–80% and monitored during experiments. Currents
were recorded using an EPC-8 amplifier (HEKA Electronics, Lambrecht,
Germany), filtered at 5 kHz, sampled and stored on a personal computer.
Drugs were applied using RSC-200 (BioLogic) perfusion system under
computer control. The extracellular solution contained (in mM): NaCl 143,
KCl 5, CaCl2 2.5, D-glucose 18, HEPES 10 (pH was adjusted to 7.4 with
NaOH). The pipette solution contained (in mM): CsF 100, CsCl 40, NaCl
5, CaCl2 0.5, EGTA 5, HEPES 10 (pH was adjusted to 7.2 with CsOH).
Drugs were purchased from Tocris Bioscience (Bristol, UK) and Sigma
(St Louis, MO, USA). Experiments were conducted on hippocampal
pyramidal neurons (CA1 area). NMDA receptors were activated by 100
µM NMDA plus 10 µM glycine. The percentage of block of the steady-
state current by different drug concentrations was measured at -80mV
holding potential and IC50 values were obtained from fits by the Hill
equation of concentration-inhibition relationships. All data are presented
as means ± SD estimated from at least four experiments.
3-(5-Chloro-2-hydroxybenzoyl)benzoic acid (36a). White solid
(ethanol), mp 209-210 °C. 1H NMR (400 MHz, DMSO-d6): δH ppm 7.01 (d,
J = 8.8 Hz, 1H, C3’H), 7.29 (d, J = 2.5 Hz, 1H, C6’H), 7.47 (dd, J = 2.5, 8.8
Hz, 1H, C4’H), 7.67 (pseudo-t, J = 7.8 Hz, 1H, C5H), 7.99 (d, J = 7.8 Hz,
1H, C6H), 8.20 (d, J = 7.8 Hz, 1H, C4H), 8.23 (s, 1H, C2H), 10.43 (s, 1H,
OH), 13.34 (br.s, 1H, COOH). 13C NMR (100 MHz, DMSO-d6): δC ppm
118.76, 123.27, 127.58, 129.38, 129.65, 130.55, 131.54, 132.75, 133.70,
134.15, 137.65, 155.04, 167.07, 194.84. HRMS-ESI: m/z calcd. for
C14H8ClO4 [M-H]- 275.0117, found 275.0104.
3-(5-Chloro-2-hydroxybenzoyl)-5-methylbenzoic acid (37a). White
solid (ethanol), mp 238-240 °C. 1H NMR (400 MHz, DMSO-d6): δH ppm
2.43 (s, 3H, Me), 7.01 (d, J = 8.8 Hz, 1H, C3’H), 7.36 (d, J = 2.8 Hz, 1H,
C6’H), 7.45 (dd, J = 2.8, 8.8 Hz, 1H, C4’H), 7.80 (s, 1H, C6H), 8.02 (s, 2H,
C4H, C2H), 10.40 (s, 1H, OH), 13.22 (br.s, 1H, COOH). 13C NMR (100
MHz, DMSO-d6): δC ppm 21.10, 118.81, 123.24, 127.70, 128.10, 129.30,
131.54, 132.67, 133.79, 134.64, 137.77, 139.22, 155.11, 167.13, 195.01.
HRMS-ESI: m/z calcd. for C15H10ClO4 [M-H]- 289.0273, found 289.0288.
3-(5-Chloro-2-hydroxybenzoyl)-5-ethylbenzoic acid (38a). White solid
(ethanol), mp 229-231 °C. 1H NMR (400 MHz, DMSO-d6): δH ppm 1.21 (t,
J = 7.5 Hz, 3H, Me), 2.74 (q, J = 7.5 Hz, 2H, CH2), 7.01 (d, J = 8.5 Hz,
1H, C3’H), 7.36 (d, J = 2.5 Hz, 1H, C6’H), 7.45 (dd, J = 2.5, 8.5 Hz, 1H,
C4’H), 7.84 (s, 1H, C6H), 8.03 (s, 1H, C4H), 8.04 (s, 1H, C2H), 10.40 (s,
1H, OH), 13.18 (br.s, 1H, COOH). 13C NMR (100 MHz, DMSO-d6): δC
ppm 15.78, 28.16, 118.81, 123.27, 127.62, 128.50, 129.38, 131.65,
132.65, 132.72, 133.49, 137.80, 145.34, 155.15, 167.15, 194.99. HRMS-
ESI: m/z calcd. for C16H12ClO4 [M-H]- 303.0430, found 303.0411.
Computation. All calculations were performed using Gaussian 16 [13]
software. Geometry optimisation was conducted using meta-hybrid M06-
2X density functional [32] on 6-31+G** level. For all the optimized
structures the frequency calculations were conducted to verify the nature
of stationary points. For the stationary points involved the single-point
energy calculations were performed at MP2(full)/6-31+G** level. Thermal
corrections to free energy were calculated at M06-2X/6-31+G** level.
3-(5-Chloro-2-hydroxybenzoyl)-5-phenylbenzoic acid (39a). White
solid (ethanol), mp 205-207 °C. 1H NMR (400 MHz, DMSO-d6): δH ppm
7.03 (d, J = 8.8 Hz, 1H, C3’H), 7.43-7.54 (m, 5H, C6’H, C4’H, Ph), 7.72 (d,
J = 7.3 Hz, 2H, Ph), 8.19 (s, 1H, C6H), 8.21 (s, 1H, C4H), 8.40 (s, 1H,
C2H), 10.47 (s, 1H, OH), 13.41 (br.s, 1H, COOH). 13C NMR (100 MHz,
DMSO-d6): δC ppm 118.93, 123.41, 127.38, 128.84, 129.48, 129.66,
129.73, 131.49, 131.97, 132.44, 133.05, 138.51, 138.87, 141.48, 155.26,
166.96, 194.68. HRMS-ESI: m/z calcd. for C20H12ClO4 [M-H]- 351.0430,
found 351.0440.
Acknowledgements
We thank the management of the Saint-Petersburg State
Chemical Pharmaceutical University and personally its rector Dr.
I.A. Narkevich for the financial and organizational support of this
research. We thank Dr. V.I. Zakharov for the registration of NMR
spectra. The project was partially supported by FASO program
for IEPhB RAS and Russian Science Foundation grant 17-74-
10117.
EeAChE and eqBChE inhibition assays. Enzyme inhibition assays
were performed on AChE from electric eel (C3389-1KU; Sigma) and
BChE from equine serum (C7512-6KU; Sigma), according to the
spectrophotometric Ellman method as previously described [30]. The
experiment was performed in 96-well plates with a final volume 250 μL.
Each well contained 0.08 U/mL of EeAChE or eqBChE, and 0.1 M of pH
8 phosphate buffer. The plates were incubated for 20 min at different
compound concentrations at 37ºC. Then 0.35 mM acetylthiocholine
iodide (ATCh; A5751-1G; Sigma) or 0.35 mM butyrylthiocholine iodide
(20820-5G; Sigma) and 0.35 mM 5,5’-dithiobis-2-nitrobenzoic acid
(DTNB; D218200-1G; Sigma) were added. Change in absorbance was
measured at 410 nm in a kinetic mode for 10 min every 60 s at Tecan
Infinite M200 Pro reader. The IC50 values were determined graphically
from inhibition curves (log inhibitor concentration vs percent of inhibition).
A control experiment was performed under the same conditions without
inhibitor and the blank contained buffer, DMSO, DTNB, and substrate.
Keywords: chromone • enamine • morpholine • allylamine •
Morita-Baylis-Hillman reaction
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Heterocyclic chemistry*
Nikita M. Chernov, Roman V. Shutov,*
Oleg I. Barygin, Mikhail Y. Dron, Galina
L. Starova, Nikolay N. Kuz’mich and Igor
P. Yakovlev
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An unusual addition of enamines to chromone-substituted acrylic acid is an efficient
and versatile method of synthesis of allylamine derivatives. The reaction is
catalyzed by amines and is highly likely of Morita-Baylis-Hillman-type. The
described compounds show combined moderate inhibitory action on BChE and
antagonism towards NMDA receptors
Synthesis of chromone-containing
allylmorpholines through Morita-
Baylis-Hillman-type reaction
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