Self-condensation of β-(isoxazol-5-yl) enamines under treatment with acetyl chloride and acids. Synthesis of novel 1,3-diisoxazolyl-1,3-dieneamines and 1,3,5-triisoxazolyl benzenes

Article abstract of DOI:10.1016/j.tet.2014.04.015

Two directions for self-condensation of β-(isoxazol-5-yl) enamines under treatment with either acetyl chloride or acids were found leading to new 1,3-diisoxazolyl-1,3-dieneamines and 1,3,5-triisoxazolyl benzenes. The effect of solvent, acid, temperature and the reaction time on the ratio of reaction products were investigated. Trans-E-cis configuration of prepared 1,3-diisoxazolyl-1,3-dieneamines was unambiguously confirmed by 2D NMR spectra and X-ray analysis. A new mechanism of 1,3-diisoxazolyl-1,3-dieneamines formation was proposed.

Full text of DOI:10.1016/j.tet.2014.04.015

Tetrahedron xxx (2014) 1e9
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Self-condensation of
b
-(isoxazol-5-yl) enamines under treatment
with acetyl chloride and acids. Synthesis of novel 1,3-diisoxazolyl-
1,3-dieneamines and 1,3,5-triisoxazolyl benzenes
Tetyana V. Beryozkina a, Sergey S. Zhidovinov a, Yuri M. Shafran a, Oleg S. Eltsov a,
,
Pavel A. Slepukhin b, Johann Leban c, Javier Marquez d, Vasiliy A. Bakulev a
*
a TOS Department, Ural Federal University named after the first President of Russia B. N. Yeltsin, 19 Mira str., 620002 Ekaterinburg, Russia
b I. Ya. Postovsky Institute of Organic Synthesis, Ural Branch of Russian Academy of Science, 20 S. Kovalevskaya str., 620990 Ekaterinburg, Russia
c Medicinal University of Vienna, Gert Lubec Proteomics Laboratory, 14 Lazarettgasse, 1090 Vienna, Austria
d Department of Molecular Biology and Biochemistry, Faculty of Sciences, University of Malaga, 29071 Malaga, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Two directions for self-condensation of b-(isoxazol-5-yl) enamines under treatment with either acetyl
Received 31 December 2013
Received in revised form 26 March 2014
Accepted 7 April 2014
chloride or acids were found leading to new 1,3-diisoxazolyl-1,3-dieneamines and 1,3,5-triisoxazolyl
benzenes. The effect of solvent, acid, temperature and the reaction time on the ratio of reaction prod-
ucts were investigated. Trans-E-cis configuration of prepared 1,3-diisoxazolyl-1,3-dieneamines was un-
ambiguously confirmed by 2D NMR spectra and X-ray analysis. A new mechanism of 1,3-diisoxazolyl-1,3-
dieneamines formation was proposed.
Available online xxx
Keywords:
Isoxazoles
Ó 2014 Elsevier Ltd. All rights reserved.
Enamines
Dieneamines
1,3,5-Triisoxazolyl benzenes
Self-condensation
1. Introduction
condensation of b
-azolyl enamines mediated by acetylation.9 The
scope and limitations of this method are not known. Also it is not
clear whether the other compounds can catalyze the process of the
formation of 1,3-dieneamines from b-enamines.
Dieneamines due to their similarity to both enamines and di-
enes are prospective substrates for cycloaddition reactions and
other type cyclization processes.1e4 They are also known to be used
in the strategy for HOMO activation via amine organo-catalysis of
asymmetric DielseAlder reaction.5 Therefore reactions of diene-
amines could find wide application in modification of natural
compounds and interesting intermediates in drug discovery. The
known methods for the synthesis of dieneamines are not numerous
and include reactions of acroleine with secondary amines,1e4 1,1-
dimethyl-3-acetyleneamine with malononitrile,6 enamines with
The isoxazole ring is an important pharmacophore in modern
drug discovery. Isoxazoles are known to show anticancer,10,11 an-
tibacterial,12 antiplatelet activity,13 activity on human
b-adrenergic
receptors,14 analgesic and antimicrobial activity,15 miscellaneous
activity,16,17 anti-inflammatory, and immunomodulatory activity.18
Therefore our initial efforts to expand the scope of the self-
condensation of dieneamines were focused on the synthesis of
1,3-dieneamines bearing isoxazole rings at positions 2 and 4 of the
molecule. Data on the ability of sulfonyl chlorides, hydrochloric and
p-toluene sulfonic acid, and BF3 to mediate self-condensation of
dieneamines are also reported.
b
-trifluoroacetylvinyl ether,7 and 2-methyleneindolines with
b-
nitroenamines8 catalyzed by cerium chloride. Because they have
some limitations and are not applicable for the synthesis of large
series of compounds, the search of new stereoselective routes to
dieneamines remains a synthetic challenge. Quite recently, we have
found a new approach to 1,3-diazolyl dieneamines in 1,2,3-triazol-
5-yl and thiadiazol-5-yl series based on the novel self-
2. Results and discussion
The starting enamines 2aei were prepared from alkyl 5-methyl-
3-arylisoxazole-4-carboxylates 1aei by the reaction with dimethyl
formamide dimethyl acetal (DMFeDMA) in the presence of N-
methylimidazole at 80 ꢀC.18e20 Enamines formation was shown to
* Corresponding author. E-mail addresses: tetber@mail.ru (T.V. Beryozkina), v.a.
bakulev@urfu.ru (V.A. Bakulev).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.04.015
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2
T.V. Beryozkina et al. / Tetrahedron xxx (2014) 1e9
proceed in stereospecific manner to give the single reaction prod-
ucts (E)-alkyl-3-(2-aryl)-5-(2-(dimethylamino)vinyl)isoxazole-4-
carboxylates 2aei in high yields (Scheme 1). Their assigned struc-
ture as the trans-isomers is deduced from the coupling constant
(J¼12.0e16.0 Hz) for protons of ene fragment in 1H NMR spectra
(see Experimental section and Supplementary data).
3h at room temperature and compound 4h as a single product at
50 ꢀC and long period of the reaction (Table 1, entry 8). It looks like
dieneamines 3 are kinetic and benzenes of type 4 are thermody-
namic products of the reaction.
The structures of dieneamines 3aeh were confirmed by the
combination of 1H and 13C NMR spectroscopy, mass-spectrometry,
and X-ray analysis. The NMR spectra for products 3aeh demon-
strate that all of the compounds belong to the same structural type.
Thus, the 1H NMR spectra contain doublets of the C1eH protons at
6.30e6.43 ppm, singlets of the C4eH protons at 6.95e7.03 ppm,
doublets of C2eH protons at 7.50e7.70 ppm, broad singlets of the
protons of N(CH3)2 groups at 2.74e2.95 ppm, and signals of the
protons of alkoxycarbonile groups and aromatic rings in the cor-
responding areas. The presence of a diene fragment in compounds
3aeh was confirmed by the 2D HMBC and HSQC NMR experiments
for products 3f and 3h where cross-peaks were registered between
four ethylene type carbons S1eS4 and three hydrogens atoms H1,
H2, H4: atom H1 has cross-peaks with C1, C2, and C3; H2dwith C1, C2,
C3, and C4; H4dwith C4, C3, and C2 (see Supplementary data). The
connections of the diene system with the isoxazole rings 0are con-
0
firmed by cross-peaks between H1 with both C5 and C4 and H4
00
00
with C5 and C4 also. The coupling constants for protons of C1H]
C2H double bonds are 15.2e16.0 Hz that is in accordance with
trans-configuration of C1]C2 bond and allowed one to rule out
from consideration the four isomers bearing this fragment with the
cis configuration of protons.
Scheme 1. Synthesis of enamines 2aei.
The prepared isoxazolyl enamines 2aeh were examined for
ability to undergo self-condensation reaction in the presence of
acetyl chloride in anhydrous 1,4-dioxane in the conditions found
earlier for the syntheses of 1,2,3-triazolyl and 1,2,3-thiadiazolyl
dieneamines.9 To our delight the novel diethyl 5,50-((1E,3Z)-4-
(dimethylamino)buta-1,3-diene-1,3-diyl)bis(3-phenylisoxazole-4-
carboxylate) 3a was stereoselectively produced in 80% isolated
yield (Table 1, entry 1). In contrast to results found for 2a, self-
condensation of enamine 2b underwent via two directions to
form the mixture of dieneamine 3b and the new product of the
reaction, 1,3,5-triisoxazolyl benzene 4b in 1:1 ratio in 79% total
yield (Table 1, entry 2). The ratio of the compounds 3 and 4 depends
on both nature of aryl and on the temperature used. Generally the
increase of temperature leads to increase of the yield of tri-
substituted benzenes 4. Remarkably, that 2,6-dichloroaryl de-
rivative 2e afforded the single product 3e both at room temperature
and at 50 ꢀC while 2-chloro-6-fluoro derivative 2h furnished diene
The 13C NMR spectra contain signals of C3 at 93.6e94.0 ppm, C1
at 102.2e102.4 ppm, C2 at 141.7e142.0 ppm, C]O at
161.0e162.0 ppm and this is in agreement with literature data for
these groups in similar compounds.9 Signals of carbon atoms in 13
C
NMR spectra for N(CH3)2 groups of compounds 3 were not
decoupled but revealed from HSQC spectra.
The configuration of the prepared compounds as trans-E-cis
isomers was also confirmed by NOESY experiments with diene-
amine 3f where the interaction of C4eH with both C2eH and pro-
tons of (CH3)2N group were registered as cross-peaks (see
Supplementary data). The structure of dieneamines 3aeh is further
supported by X-ray analysis (Fig.1) for the crystal of dieneamine 3e.
According to the X-ray data, compound 3e is crystallized in
centrosymmetric space group. The molecule is non-planar (Fig. 1),
it has an S-trans-configuration of its diene moiety, a planar con-
figuration of its enamine moiety and is characterized by disordering
Table 1
Self-condensation of enamines 2aeh to dienes 3aeh and benzenes 4aee,h under action of acetyl chloride
Entry
Enamine
Diene 3a, yield
Benzene 4a, yield
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
3a, Ar¼Ph, R¼Et, 80%
4a, Ar¼Ph, R¼Et, 16%b
3b, Ar¼2-CleC6H4, R¼Me, 40%
3c, Ar¼2-FeC6H4, R¼Et, 30%
4b, Ar¼2-CleC6H4, R¼Me, 39%
4c, Ar¼2-FeC6H4, R¼Et, 9%
4d, Ar¼4-CleC6H4, R¼Et, 35%
4e, Ar¼2,4-(Cl)2eC6H4, R¼Et, 12%
The product was not formed
The product was not formed
4hb, Ar¼2-Cle6-FeC6H3, R¼Me, 55%
3d, Ar¼4-CleC6H4, R¼Et, 54%
3e, Ar¼2,4-(Cl)2eC6H3, R¼Et, 64%
3f, Ar¼2,6-(Cl)2eC6H3, R¼Me, 61%, (96%b)
3g, Ar¼2,6-(Cl)2eC6H3, R¼Et, 81%
3h, Ar¼2-Cle6-FeC6H3, R¼Me, 80%
2g
2h
a
Reactions were carried out with 1.0 mmol of enamines 2 and 3.0 mmol of acetyl chloride in anhydrous 1,4-dioxane (4 mL) at room temperature for 20e22 h.
The reaction was carried out at 50 ꢀC for 8 h (3f), 25 h (4a), and 9 days (4h).
b
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T.V. Beryozkina et al. / Tetrahedron xxx (2014) 1e9
3
The most closely related published work to this was reported by
Elnagdi22 and Elgharmy,23 in their synthesis of 1,3,5-triaroyl ben-
zenes by the condensation of enaminones (3-(dimethylamino)-1-
phenylprop-2-en-1-one) in acetic acid. Interestingly, one of the
mechanisms proposed by Elgharmy includes the formation of in-
termediate 1,3-dibenzoyl dieneamines, which were neither iso-
lated nor spectroscopy identified.
In contrast, dieneamines 3 were found to be rather stable
products. We have involved 3b in reaction with enamines 2b in the
presence of acetyl chloride to form compound 4b in 60% yield
(Scheme 2).
Monitoring of the transformation of various enamines 2 at 50 ꢀC
by TLC has shown the initial fast formation of dieneamines 3 fol-
lowed by a slow formation of compounds 4 and disappearance of 2.
Both of these experiments are in a good agreement with [4þ2]
cycloaddition mechanism of the reaction.
Fig. 1. X-ray structure of compound 3e..
It should be specially noted the method found here for the
synthesis of trisubstituted benzenes 4 can be used in supramo-
lecular chemistry for the preparation of dendrimers.24e27 To find
optimal conditions for the syntheses of amino dienes 3 and 1,3,5-
trisubstituted benzenes 4 we have studied the ratio of products
3a to 4a formed from enamine 2a depending on the nature of the
solvent, catalyst, temperature and time of the reaction (see the
full report in Table 1 of the Supplementary data). Tosyl chloride
and thionyl chloride were found inactive. On the contrary,
hydrochloric and p-toluene sulfonic acids (PTSA), and tri-
fluoroborane (BF3) were shown to mediate self-condensation of
enamines 2a. Albeit, the use of 2 equiv of PTSA led to formation
of benzene 4a in low yield accompanied by tar-like impurities.
On the other hand the use of 2.2 equiv of HCl led to 3a in 70%
yield along to 10% of benzene 4a. Reaction of enamine 2i with
1.2 equiv of BF3 methyl etherate at 70 ꢀC afforded benzene 4i in
80% yield.
The use of acetyl chloride is the most effective for the synthesis
of both dieneamine 3a and benzene 4a. The best results for the
synthesis of dieneamine 3a were obtained in anhydrous 1,4-
dioxane in the presence of 3 equiv of acetyl chloride. Benzene 4a
was obtained in highest yield either with the use of 3 equiv of acetyl
chloride in anhydrous 1,4-dioxane or in neat acetyl chloride. Re-
placement of 1,4-dioxane by other solvents and increase of the
temperature led to decrease of the yield for compounds 3, 4 due to
the formation of the tar-like products.
of m-dichlorophenyl in positions 2 with a coefficient of occupancy
0.93/0.07. Molecular packing is formed without any shortened in-
termolecular contacts (see Supplementary data).
The structures of the 1,3,5-triisoxazolyl benzenes 4 were de-
duced from their 1H and 13C NMR and mass spectra. Further con-
firmation of the structure of 4 came from the analysis of single-
crystal X-ray data of 4h (Fig. 2). The 1H NMR spectra of benzenes
4aee,h,i revealed three kinds of protons: three protons singlet in
the range of 8.74e8.98 ppm corresponding to three protons at
2,4,6-positions of the benzene ring, multiplets at 7.20e7.70 ppm
belonging to aromatic protons of aryls at position 3 of isoxazole
rings, and signals of protons corresponding alkoxy groups in up-
field. The 13C NMR spectra of benzenes 4aee,h,i show signals of
carbon atoms of aromatic rings at 109.8e163.6 ppm including two
types of signals of carbons of symmetrically substituted benzene
ring, carbons atoms of alkoxy groups at 13.6e61.8 (OCH2CH3) ppm
and 52.4e52.8 (OCH3) ppm, and characteristic signals of the C]O
the carbons atoms at 170.3e170.6 ppm.
To expand the reaction of self-condensation to enamines of
isothiazole series we treated (E)-5-(2-(dimethylamino)vinyl)-3-
phenylisothiazole-4-carbonitrile 5a28 with acetyl chloride at
50e55ꢀS for 16 h. In contrast to the self-condensation of
b
-iso-
xazolyl enamines the reaction of
b-isothiazolyl enamine 5a led to
a mixture of a several compounds that after separation by column
chromatography and further double crystallization afforded buta-
dieneamine 6 in 25% yield (Scheme 3). Furthermore, reaction of (E)-
5-(2-(dimethylamino)vinyl)-3-phenylisothiazole-4-carbonitrile 5b
with acetyl chloride gave a complex mixture of inseparable
compounds.
The structure of compound 6 was confirmed by 1H and 13C NMR
spectroscopy, mass-spectrometry, and X-ray analysis.
Fig. 2. X-ray structure of compound 4h.
In contrast to dieneamines 3f,g, which were prepared in high
yields from enamines 2f,g, all our attempts to prepare benzenes
4f,g failed (Table 1, entries 6 and 7).
The signals for dieneamine fragment in their 13C NMR spectra
are similar to those of isoxazole derivatives 3 but shifted up-field:
signals for C1eH and C2eH by 0.05 and 0.48 ppm, respectively,
and signal of C4eH is shifted down-field by 0.04 ppm. The coupling
constants for protons of C1H]C2H double bonds are 15.6 Hz that is
in accordance with trans-configuration of C1]C2 bond.
Final confirmation of the structure of 6 came from the analysis
of single-crystal X-ray data of 6.
According to the X-ray diffraction data the compound 4h is
crystallized in centrosymmetric space group. Molecule of the
compound 4h is placed in partial position on threefold axis (Fig. 2).
Cl- and F-substituents of arene fragment are disordered in two
positions with coefficients of occupancy 0.75/0.25. Bond distances
and angles are typical for these compounds. The molecular packing
has disordered solvent voids included in the refinement by
SQUEEZE procedure of program PLATON.21
According to the X-ray data, compound 9 is crystallized in
centrosymmetric space group. A general view of the molecule and
numeration of atoms is presented in Fig. 3.
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T.V. Beryozkina et al. / Tetrahedron xxx (2014) 1e9
Scheme 2. [4þ2] Cycloaddition of enamine 2b to dieneamine 3b leading to benzene 4b.
Scheme 3. Transformation of enamines 5a,b under action of acetyl chloride.
Scheme 4. Failed attempt for the preparation of dieneamine 9.
involve the interaction of lone pair of electrons of carbonyl oxygen
atom with electrophilic specie E no matter whether it is acetyl
cation, proton from a mineral acid or a Lewis acid. Further in-
teraction of cationic specie C derived from enamine 2A with intact
enamine 2A leads to formation of a new s-bond to afford specie D
Fig. 3. View of molecule 6 according to X-ray data.
bearing a positive charge at another nitrogen atom. The latter can
undergo an elimination of dimethyl amine that is favored by the
presence of an acid/acetyl chloride, in medium. Most probably this
step is rate-limiting one of the overall process. It is believed that
elimination of dimethyl amine is also enhanced by formation of
Bonds distances and angles are typical for this class of com-
pound. In particular, length of sp2esp2 bond in S-trans-diene sys-
ꢀ
tem C(10)C(11) 1.436(3) A is typical for conjugated system.
Dimethyl amine moiety has strong conjugation with diene system
and exists in planar geometry: deviation of N(5) atom from plane
a long p
-conjugated system in specie E. The elimination of Eþ can
automatically occur to form the final product 3 (Scheme 5). We
have proved that dieneamines 3 are intermediates in the synthesis
of benzenes 4 from enamines 2 (see above). In their turn reactions
of dieneamines 3 with enamines 2 can undergo via two different
mechanisms to furnish first either cyclohexenes F (by [4þ2] cy-
cloaddition) or trienes G (similar to formation of dieneamines 3
from enamines). Elimination of two molecules of dimethyl amine
from cyclohexene F can finalize the transformation of dienes 3 to
benzenes 4. Alternatively, trienes G can afford benzenes 4 by
elimination of dimethyl amine via two-step process involving 1,6-
electrocyclic reaction.
ꢀ
C(24)C(25)C(26) is 0.062 A. Angle between plane of diene system
and thiazole ring at C(10) in compound is 73.3ꢀ, while for thiazole
in compound at C(12) it is 9.5ꢀ. However, no significant distinction
in the bond distance and the angle between similar moieties are
observed, suggesting that conjugation of the thiazole at C(12) atom
also is not significant. The molecular packing has no any specific
intermolecular contacts or stereometry.
All our attempts to prepare 2,4-di-(oxazole-5-yl)dienamine 9 by
self-condensations of enamine 8 using the optimal conditions
found for the synthesis of dienamines 3 failed (Scheme 4). Starting
1,2,4-oxadiazol-5-yl-ethenamine 8 was recovered from the re-
action mixture only.
Obviously the presence of a carbonyl group in the
g-position
3. Conclusions
relative to tert-amine is required for the self-condensation into
dieneamines to proceed. The fact that the self-condensation of
enamines is mediated, not only with acetyl chloride (described
earlier9) but with acids and Lewis acids as well expands our
knowledge of this process and of mechanism of the reaction
(Scheme 5). Therefore we assume the first step of the reaction to
The unusual reactivity of
chloride, hydrochloric, and p-toluene sulfonic acid and tri-
fluoroboran methyl etherate is described. -Azolyl enamines when
treated with these reagents undergo self-condensation to form
either single 1,3-diazolyl dieneamines and 1,3,5-triazolyl benzenes
b-azolyl enamines in respect to acetyl
b
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T.V. Beryozkina et al. / Tetrahedron xxx (2014) 1e9
5
Scheme 5. Plausible mechanisms for the formation of dieneamine 3 and benzenes 4.
or their mixtures depending on the both nature of azole ring and
conditions of the reaction.
carboxylates 1aeh or 5-methyl-3-phenylisoxazole-4-carbonitrile
(1.0 equiv, 1.0e10.0 mmol) was heated for 6 h at 80 ꢀC. The re-
action mixture was concentrated in vacuo to dryness, and the
residue was purified by flash chromatography over silica gel
(60e120) using EtOAc/hexane (1:2) as eluent to give the enamines
2aei, 5b in 70e85% yield.19,28
4. Experimental section
4.1. General
Enamines 2a,h synthesized by this method have identical ana-
lytical characteristics with the products described earlier.18,20
1H and 13C NMR spectra were recorded on Bruker Avance II
spectrometer in CDCl3 or DMSO-d6 (400 and 100 MHz, respectively)
using Me4Si as an internal standard. Mass spectrometric data (MS)
were obtained on Bruker Daltonics MicrOTOF-Q II with an elec-
trospray ionization source (ESI-MS). UV spectra were recorded with
a PerkineElmer Lambda 50 UV/VIS spectrometer. Microanalyses
were performed on PerkineElmer Series II CHNS/O 2400 elemental
analyzer. Single-crystal X-ray diffraction analysis was performed at
295(2) K on an Xcalibur 3 diffractometer equipped with a CCD
4.2.1. (E)-Methyl 3-(2-chlorophenyl)-5-(2-(dimethylamino)vinyl)iso-
xazole-4-carboxylate (2b). Light yellow solid, yield 80%, mp
149e151 ꢀC; Rf¼0.47 (EtOAc/hexane 1:1); 1H NMR (CDCl3):
d 3.01
(6H, br s, N(Me)2), 3.60 (3H, s, COOMe), 5.71 (1H, d, J 13.6 Hz, CH]),
7.30e7.45 (4H, m, AreH), 7.53 (1H, d, J 13.6 Hz, ]CH); UV (iPrOH)
l,
nm (log 50.9, 82.3, 100.6, 126.3,
3
) 345 (4.57); 13S NMR (CDCl3):
d
129.2, 129.7, 130.2, 130.8, 134.1, 148.4, 160.9, 163.2, 171.7; ESI-MS: m/
z¼307.08 [MþH]þ; Anal. Calcd (%) for C15H15ClN2O3: C, 58.73; H,
4.93; N, 9.13. Found: C, 58.64; H, 4.54; N, 9.09.
detector (
crystal-detector distance 50 mm, Mo K
u
-scanning at 1ꢀ step and 20-s exposure per frame,
-irradiation). The progress
a
of the reactions and the purity of the compounds were monitored
by TLC on TLC Silica gel 60F245 Aluminum sheets (Merck KGaA).
4.2.2. (E)-Ethyl 3-(2-fluorophenyl)-5-(2-(dimethylamino)vinyl)iso-
xazole-4-carboxylate (2c). Yellow solid, yield 80%; mp 53e55 ꢀC;
Rf¼0.40 (EtOAc/hexane 1:1); 1H NMR (CDCl3):
d 1.06 (3H, t, J 7.0 Hz,
4.2. General procedure for the preparation of enamines 2aei,
5b
OCH2CH3), 3.00 (6H, br s, N(Me)2), 4.10 (2H, q, J 7.0 Hz, OCH2CH3),
5.73 (1H, d, J 16.0 Hz, CH]), 7.11 (1H, t, J 8.0 Hz, AreH), 7.19 (1H, t, J
8.0 Hz, AreH), 7.39e7.47 (2H, m, AreH), 7.51 (1H, d, J 16.0 Hz,
The mixture of DMFeDMA (3.0 equiv), N-methylimidazole
(3.0 equiv), and corresponding alkyl 5-methyl-3-arylisoxazole-4-
CH]); 13S NMR (CDCl3):
d 13.9, 59.8, 82.4, 100.8, 115.4 (d, JC,F
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6
T.V. Beryozkina et al. / Tetrahedron xxx (2014) 1e9
21.0 Hz), 118.7 (d, JC,F 16.0 Hz), 123.7 (d, JC,F 3.0 Hz), 131.0 (d, JC,F
3.0 Hz), 131.1 (d, JC,F 8.0 Hz), 148.4, 158.2, 160.7 (d, JC,F 249.0 Hz),
(log
3
) 342 (4.95); ESI-MS: m/z¼239.11 [MþH]þ; Anal. Calcd (%) for
C
15H14N2O: C, 75.61; H, 5.92; N, 11.76. Found: C, 75.70; H, 5.99; N,
163.0, 175.0; UV (iPrOH)
l
, nm (log
3
) 345 (4.60); ESI-MS: m/
11.70.
z¼305.12 [MþH]þ; Anal. Calcd (%) for C16H17FN2O3: C, 63.15; H,
5.63; N, 9.21. Found: C, 63.54; H, 5.47; N, 9.16.
4.3. General procedure for the preparation of dienamines
3a,f,g,h
4.2.3. (E)-Ethyl 3-(4-chlorophenyl)-5-(2-(dimethylamino)vinyl)iso-
xazole-4-carboxylate (2d). Yellow solid, yield 70%, mp 65e68 ꢀC;
To a solution of the corresponding enamine 2 (1.0 mmol,
1.0 equiv) in anhydrous 1,4-dioxane (4 mL) was added acetyl
chloride (3.0 mmol, 3.0 equiv) and the reaction mixture was
stirred at room temperature for 20e22 h. The resulting mixture
was evaporated under reduced pressure to dryness and residue
was purified by column chromatography over silica gel (60e120)
using EtOAc/hexane (1:2) as eluent to give the products 3 as yel-
low solids.
Rf¼0.41 (EtOAc/hexane 1:1); 1H NMR (CDCl3):
d 1.18 (3H, t, J 7.0 Hz,
OCH2CH3), 3.01 (6H, br s, N(Me)2), 4.17 (2H, q, J 7.0 Hz, OCH2CH3),
5.73 (1H, d, J 13.2 Hz, CH]), 7.40 (2H, d, J 8.1 Hz, AreH), 7.57 (2H, d, J
8.1 Hz, AreH), 7.63 (1H, d, J 13.2 Hz, ]CH); 13S NMR (CDCl3):
d 14.0,
59.0, 82.4, 99.3, 127.9, 128.3, 130.9, 135.1, 148.2, 161.7, 162.8, 175.4;
UV (iPrOH)
l, nm (log
3
) 346 (4.65); ESI-MS: m/z¼321.09 [MþH]þ;
Anal. Calcd (%) for C16H17ClN2O3: C, 59.91; H, 5.34; N, 8.73. Found: C,
59.53; H, 5.21; N, 8.62.
4.3.1. Diethyl 5,50-((1E,3Z)-4-(dimethylamino)buta-1,3-diene-1,3-
4.2.4. (E)-Ethyl 3-(2,4-dichlorophenyl)-5-(2-(dimethylamino)vi-
diyl)bis(3-phenylisoxazole-4-carboxylate) (3a). Yield 80%; mp
nyl)isoxazole-4-carboxylate (2e). Yellow solid, yield 70%, mp
121e123 ꢀC; Rf¼0.35 (EtOAc/hexane 1:1); 1H NMR (CDCl3):
d 1.12
80e82 ꢀC; Rf¼0.38 (EtOAc/hexane 1:1); 1H NMR (CDCl3):
d
1.04
(6H, m, 2OCH2CH3), 2.91 (6H, br s, N(CH3)2), 4.17 (4H, dd, J 6.6 Hz,
2OCH2CH3), 6.33 (1H, d, J 15.6 Hz, C1eH), 6.95 (1H, s, C4eH),
7.41e7.62 (10H, m, AreH), 7.70 (1H, d, J 15.6 Hz, C2eH); 13C NMR
(3H, t, J 7.0 Hz, OCH2CH3), 3.02 (6H, br s, N(Me)2), 4.08 (2H, q, J
7.0 Hz, OCH2CH3), 5.73 (1H, d, J 13.2 Hz, CH]), 7.29e7.32 (2H, m,
AreH), 7.47 (1H, s, AreH), 7.53 (1H, d, J 13.2 Hz, ]CH); 13S NMR
(CDCl3): d 13.7, 13.8, 60.7, 61.8, 94.4, 102.3, 127.9, 128.3, 128.9, 129.1,
(CDCl3):
d
13.9, 59.9, 82.3, 100.7, 126.7, 128.7, 129.1, 131.7, 135.2,
129.3, 129.5, 130.0, 141.3, 151.1, 162.6, 162.7, 163.1, 171.9, 172.9; UV
135.6, 148.5, 160.1, 162.6, 174.9; UV (iPrOH)
l
, nm (log
3 ) 346
(iPrOH):
l, nm (log
3
)¼392 (4.60); ESI-MS: m/z 528.21 [MþH]þ;
(4.58); ESI-MS: m/z¼355.05 [MþH]þ; Anal. Calcd (%) for
Anal. Calcd (%) for C30H29N3O6: C, 68.30; H, 5.54; N, 7.96. Found: C,
68.51, H, 5.32; N, 7.84.
C
16H16Cl2N2O3: C, 54.10; H, 4.54; N, 7.89. Found: C, 54.19; H, 4.50;
N, 7.78.
4.3.2. Dimethyl 5,50-((1E,3Z)-4-(dimethylamino)buta-1,3-diene-1,3-
diyl)bis(3-(2,6-dichlorophenyl)isoxazole-4-carboxylate) (3f). Yield
61%; mp 251e253 ꢀC; Rf¼0.40 (EtOAc/hexane 1:1); 1H NMR
4.2.5. (E)-Methyl 3-(2,6-dichlorophenyl)-5-(2-(dimethylamino)vinyl)
isoxazole-4-carboxylate (2f). Yellow solid, yield 80%, mp
157e160 ꢀC; Rf¼0.38 (EtOAc/hexane 1:1); 1H NMR (CDCl3):
d
3.02
(CDCl3): d 2.74 (6H, br s, N(CH3)2), 3.61 (3H, s, OCH3), 3.64 (3H, s,
(6H, br s, N(Me)2), 3.60 (3H, s, COOMe), 5.73 (1H, d, J 13.2 Hz, CH]),
7.28e7.31 (1H, m, AreH), 7.36e7.38 (2H, m, AreH), 7.56 (1H, d,
OCH3), 6.32 (1H, d, J 15.2 Hz, C1eH), 7.01 (1H, s, C4eH), 7.28e7.45
(6H, m, AreH), 7.50 (1H, d, J 15.2 Hz, C2eH); 13C NMR (CDCl3):
51.6,
d
J¼13.2 Hz, ]CH); 13S NMR (CDCl3):
d
51.0, 82.3, 100.1, 127.6, 129.4,
52.01, 94.04, 102.4, 112.6, 127.8, 128.0, 128.2, 128.7, 130.9, 131.2,
135.4, 135.5, 141.7, 151.5, 159.2, 159.5, 161.0, 161.9, 172.1, 172.6; UV
130.5, 135.3, 148.6, 158.6, 162.8, 174.9; UV (iPrOH)
l
, nm (log ) 346
3
(3.99); ESI-MS: m/z¼341.04 [MþH]þ; Anal. Calcd (%) for
(iPrOH):
l, nm (log
3
)¼392 (4.48); ESI-MS: m/z 636.02 [MþH]þ;
C
15H14Cl2N2O3: C, 52.80; H, 4.14; N, 8.21. Found: C, 53.39; H, 4.01; N,
Anal. Calcd (%) for C28H21Cl4N3O6: C, 52.77; H, 3.32; N, 6.59. Found:
C, 52.53; H, 3.44; N, 6.52.
8.68.
4.2.6. (E)-Ethyl 3-(2,6-dichlorophenyl)-5-(2-(dimethylamino)vinyl)
4.3.3. Diethyl 5,50-((1E,3Z)-4-(dimethylamino)buta-1,3-diene-1,3-
diyl)bis(3-(2,6-dichlorophenyl)isoxazole-4-carboxylate) (3g). Yield
81%; mp 192e195 ꢀC; Rf¼0.37 (EtOAc/hexane 1:1); 1H NMR
isoxazole-4-carboxylate (2g). Yellow solid, yield 77%, mp 95e97 ꢀC;
Rf¼0.38 (EtOAc/hexane 1:1); 1H NMR (CDCl3):
d 0.95 (3H, t, J 7.2 Hz,
OCH2CH3), 3.02 (6H, br s, N(Me)2), 4.03 (2H, q, J 7.2 Hz, OCH2CH3),
5.76 (1H, d, J 13.2 Hz, CH]), 7.28e7.30 (1H, m, AreH), 7.37 (2H, d, J
(CDCl3): d 0.96 (3H, t, J 7.2 Hz, OCH2CH3), 1.02 (3H, t, J 7.2 Hz,
OCH2CH3), 2.93 (6H, br s, N(CH3)2), 4.03e4.10 (4H, m, 2OCH2CH3),
8.4 Hz, AreH), 7.57 (1H, d, J 13.2 Hz, ]CH); UV (iPrOH)
l
, nm (log )
3
6.43 (1H, d, J 15.2 Hz, C1eH), 7.03 (1H, s, C4eH), 7.29e7.44 (6H, m,
346 (4.38); ESI-MS: m/z¼355.05 [MþH]þ; Anal. Calcd (%) for
AreH), 7.52 (1H, d, J 15.2 Hz, C2eH); 13C NMR (CDCl3):
d 13.5, 13.8,
C
16H16Cl2N2O3: C, 54.10; H, 4.54; N, 7.89. Found: C, 54.37; H, 4.47; N,
42.9, 60.1, 60.6, 93.8, 102.3, 112.3, 127.6, 127.7, 128.5, 129.0, 130.6,
131.0, 135.5, 141.6, 151.5, 159.0, 159.1, 160.3, 161.2, 172.0, 172.7; UV
7.96.
(iPrOH)
l, nm (log
3
) 391 (4.57); ESI-MS: m/z 664.04 [MþH]þ; Anal.
4.2.7. (E)-Methyl 5-(2-(dimethylamino)vinyl)-3-phenylisoxazole-4-
Calcd (%) for C28H21Cl4N3O6: C, 54.16; H, 3.79; N, 6.32; Found: C,
54.31; H, 3.55; N, 6.26.
carboxylate (2i). Yellow solid, yield 70%, mp 85e87; Rf¼0.55
(EtOAc/hexane 1:1); 1H NMR (CDCl3):
d 3.01 (6H, br s, N(Me)2), 3.68
(3H, s, COOMe), 5.73 (1H, d, J 12.0 Hz, CH]), 7.38e7.43 (3H, m,
4.3.4. Dimethyl 5,50-((1E,3Z)-4-(dimethylamino)buta-1,3-diene-1,3-
diyl)bis(3-(2-chloro-6-fluorophenyl)isoxazole-4-carboxylate)
(3h). Yield 80%; mp 219e220 ꢀC, Rf¼0.36 (EtOAc/hexane 1:1); 1H
AreH), 7.50 (1H, d, J 12.0 Hz, ]CH), 7.57e7.59 (2H, m, AreH); 13S
NMR (CDCl3):
d 50.8, 82.5, 99.3, 127.7, 129.1, 129.3, 129.6, 148.3,
162.6, 163.5, 175.3; UV (iPrOH)
l, nm (log
3 ) 346 (4.55); ESI-MS: m/
NMR (DMSO-d6): d 2.95 (6H, br s, N(CH3)2), 3.53 (3H, s, OCH3), 3.60
z¼273.12 [MþH]þ; Anal. Calcd (%) for C15H16N2O3: C, 66.16; H, 5.92;
(3H, s, OCH3), 6.10 (1H, d, J 15.6 Hz, C1eH); 7.26 (1H, t, J 8.4 Hz,
N, 10.29. Found: C, 66.27; H, 5.99; N, 10.20.
AreH), 7.34 (1H, t, J 8.4 Hz, AreH), 7.44 (1H, s, C4eH), 7.45 (1H, d, J
15.6 Hz, C2eH), 7.51e7.64 (4H, m, AreH); 13C NMR (CDCl3):
d 42.9,
4.2.8. (E)-5-(2-(Dimethylamino)vinyl)-3-phenylisoxazole-4-
51.3, 51.9, 93.9, 102.3, 104.8 (d, JC,F 2.4 Hz), 114.0 (d, JC,F 21.0 Hz),
114.2 (d, JC,F 21.0 Hz), 118.0 (d, JC,F 19.0 Hz), 125.1 (d, JC,F 3.3 Hz),
125.2 (d, JC,F 3.3 Hz), 131.2 (d, JC,F 9.3 Hz), 131.6 (d, JC,F 9.3 Hz), 135.1
(d, JC,F 4.0 Hz),135.2 (d, JC,F 4.0 Hz),141.4,151.3,156.0,156.2,160.7 (d,
carbonitrile (5b). Yellow solid, yield 83%, mp 136e138 ꢀC; Rf¼0.39
(EtOAc/hexane 1:1); 1H NMR (CDCl3):
d 3.02 (6H, br s, N(Me)2),
5.16 (1H, d, J 12.0 Hz, CH]), 7.47e7.53 (4H, m, HeArþCH]),
7.92e7.93 (2H, m, HeAr); 13S NMR (CDCl3):
78.5, 80.1, 114.6,
127.2, 127.4, 129.0, 130.6, 148.5, 160.8, 177.9; UV (iPrOH)
, nm
d
JC,F 251.8 Hz),161.8 (d, JC,F 251.8 Hz), 161.8, 172.3; UV (iPrOH):
l, nm
l
(log
3
)¼392 (4.62); ESI-MS: m/z 604.08 (MþH)þ; Anal. Calcd (%) for
Please cite this article in press as: Beryozkina, T. V.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.015

T.V. Beryozkina et al. / Tetrahedron xxx (2014) 1e9
7
C28H21Cl2F2N3O6: C, 55.64; H, 3.50; N, 6.95. Found: C, 55.48; H, 3.41;
N, 6.89.
131.0 (d, JC,F 2.4 Hz), 132.1 (d, JC,F 4.2 Hz), 132.2, 159.4, 161.4, 160.5 (d,
JC,F 250.0 Hz), 170.3; UV (iPrOH):
l
, nm (log
3
)¼272 (4.54); ESI-MS:
m/z 778.19 [MþH]þ; Anal. Calcd (%) for C42H30F3N3O9: C, 64.86; H,
4.4. General procedure for the preparation of dienes 3bee
and benzenes 4bee
3.89; N, 5.40. Found: C, 64.94; H, 3.84; N, 5.42.
4.4.5. Diethyl 5,50-(4-(dimethylamino)buta-1,3-diene-1,3-diyl)bis(3-
To a solution of corresponding enamine 2 (1.0 mmol, 1.0 equiv)
in anhydrous 1,4-dioxane (4 mL) was added acetyl chloride
(3.0 mmol, 3.0 equiv) and the reaction mixture was stirred at room
temperature for 20e22 h. The resulting mixture was evaporated
under reduced pressure to dryness and residue was purified by
column chromatography over silica gel (60e120) using EtOAc/
hexane (1:2) as eluent to give the dienes 3bee as major product (Rf
0.15e0.20) and benzenes 4bee as minor products (Rf 0.45e0.54).
(4-chlorophenyl)isoxazole-4-carboxylate) (3d). Yield 54%, mp
128e130 ꢀC; Rf¼0.40 (EtOAc/hexane 1:1); 1H NMR (CDCl3):
d 1.11
(3H, t, J 7.2 Hz, OCH2CH3), 1.17 (3H, t, J 7.2 Hz, OCH2CH3), 2.92 (6H,
br s, N(CH3)2), 4.12 (2H, q, J 7.2 Hz, OCH2CH3), 4.21 (2H, q, J 7.2 Hz,
OCH2CH3), 6.30 (1H, d, J 15.6 Hz, C1eH), 6.96 (1H, s, C4eH),
7.38e7.46 (5H, m, AreHþC2eH), 7.57 (2H, d, J 8.4 Hz, AreH), 7.68
(2H, d, J 8.0 Hz, AreH); 13C NMR (CDCl3):
d 13.9, 60.4, 61.1, 94.5, 99.8,
111.5, 126.8, 127.4, 128.1, 128.5, 130.4, 130.7, 135.8, 136.2, 151.4, 161.4,
161.7, 162.0, 162.3, 172.4, 173.0; UV (iPrOH):
l
, nm (log
3
)¼392
4.4.1. Dimethyl
5,50-(4-(dimethylamino)buta-1,3-diene-1,3-diyl)
(4.57); ESI-MS: m/z 596.13 [MþH]þ; Anal. Calcd (%) for
bis(3-(2-chlorophenyl)isoxazole-4-carboxylate) (3b). Yield 40%; mp
C30H27Cl2N3O6: C, 60.41; H, 4.56; N, 7.04. Found: 60.50; H, 4.61; N,
160e161 ꢀC; Rf¼0.30 (EtOAc/hexane 1:1); 1H NMR (CDCl3):
d
2.94
7.00.
(6H, s, N(CH3)2), 3.61 (3H, s, OCH3), 3.64 (3H, s, OCH3), 6.32 (1H, d, J
15.6 Hz, C1eH), 7.02 (1H, s, C4eH), 7.31e7.50 (8H, m, AreH), 7.55
4.4.6. Triethyl
5,50,500-(benzene-1,3,5-triyl)tris(3-(4-chlorophenyl)
(1H, d, J 15.6 Hz, C2eH); 13C NMR (CDCl3):
d
51.4, 52.0, 94.0, 102.2,
isoxazole-4-carboxylate) (4d). Yellow solid; yield 35%; mp
126.6,126.9,129.2,129.5,129.6,130.7, 131.0, 131.1,134.0,134.2,141.7,
130e131 ꢀC, Rf¼0.56 (EtOAc/hexane 1:1); 1H NMR (CDCl3):
d 1.15
151.5, 161.3, 161.4, 161.7, 162.3, 172.1, 172.5; UV (iPrOH):
l, nm
(9H, t, J 7.2 Hz, 3OCH2CH3), 4.27 (6H, q, J 7.2 Hz, 3OCH2CH3), 7.48
(6H, d, J 8.4 Hz, AreH), 7.64 (6H, d, J 8.4 Hz, AreH), 8.74 (3H, s,
(log
3
)¼392 (4.64); ESI-MS: m/z 568.10 (MþH)þ; Anal. Calcd (%) for
C
28H23Cl2N3O6: C, 59.17; H, 4.08; N, 7.39. Found: 59.28; H, 4.00; N,
HeAr); 13C NMR (CDCl3):
d 13.7, 61.8, 109.6, 126.7, 127.9, 128.6,
7.44.
130.5, 131.5, 136.4, 161.5, 162.5, 170.5; UV (iPrOH):
l, nm (log
3 )¼267
(4.76); ESI-MS: m/z 826.10 [MþH]þ; Anal. Calcd (%) for
4.4.2. Trimethyl 5,50,500-(benzene-1,3,5-triyl)tris(3-(2-chlorophenyl)
C42H30Cl3N3O9: C, 60.99; H, 3.66; N, 5.08. Found: C, 60.91; H, 3.58;
isoxazole-4-carboxylate) (4b). Yellow solid; yield 39%; mp
N, 5.02.
155e158 ꢀC; Rf¼0.56 (EtOAc/hexane 1:1); 1H NMR (CDCl3):
d 3.72
(9H, s, OCH3), 7.40e7.57 (12H, m, AreH), 8.96 (3H, s, AreH); 13C
4.4.7. Diethyl 5,50-(4-(dimethylamino)buta-1,3-diene-1,3-diyl)bis(3-
(2,4-dichlorophenyl)isoxazole-4-carboxylate) (3e). Yield 64%, mp
152e155 ꢀC; Rf¼0.42 (EtOAc/hexane 1:1); 1H NMR (CDCl3):
NMR (CDCl3):
d 52.4, 110.6, 127.0, 127.9, 128.3, 129.7, 131.3, 132.2,
134.0, 161.8, 162.0, 170.4; UV (iPrOH):
l, nm (log
3 )¼272 (4.71); ESI-
MS: m/z 784.06 (MþH)þ; Anal. Calcd (%) for C39H24Cl3N3O9: C,
d 1.02e1.09 (6H, m, 2OCH2CH3), 2.94 (6H, br s, N(CH3)2), 4.06e4.14
59.67; H, 3.08; N, 5.35. Found: C, 59.74; H, 3.03; N, 5.30.
(4H, m, 2OCH2CH3), 6.36 (1H, d, J 15.2 Hz, C1eH), 7.03 (1H, s, C4eH),
7. 33 (2H, s, AreH), 7.36e7.52 (5H, m, AreHþC2eH); 13C NMR
Compound 4b can be prepared also by the cycloaddition of
dieneamine 3b to enamine 2b. A solution of enamine 2b (0.016 g,
0.053 mmol, 1.0 equiv), dieneamine 3b (0.03 g, 0.053 mmol,
1.0 equiv), acetyl chloride (0.011 mL, 0.16 mmol, 3.0 equiv) in an-
hydrous benzene (2 mL) was stirred at room temperature for 5
days. The resulting mixture was evaporated under reduced pres-
sure to dryness and the residue was purified by flash column
chromatography over silica gel (60e120) using EtOAc/hexane (1:3)
as eluent to give benzene 4b in 60% (0.024 g) yield.
(CDCl3): d 13.7, 13.8, 60.3, 60.9, 93.6, 102.3, 126.8, 127.2, 129.2, 129.3,
131.7, 134.8, 135.0, 135.9, 136.4, 141.6, 141.7, 151.7, 160.4, 160.5, 161.6,
172.5; UV (iPrOH):
l
, nm (log
3
)¼393 (4.61); ESI-MS: m/z 664.05
[MþH]þ; Anal. Calcd (%) for C30H25Cl4N3O6: C, 54.16; H, 3.79; N,
6.32. Found: C, 54.30; H, 3.91; N, 6.26.
4.4.8. Triethyl 5,50,500-(benzene-1,3,5-triyl)tris(3-(2,4-dichlorophenyl)
isoxazole-4-carboxylate) (4e). Light yellow; yield 12%; mp
190e192 ꢀC; Rf¼0.58 (EtOAc/hexane 1:1); 1H NMR (CDCl3):
d 1.06
4.4.3. Diethyl 5,50-(4-(dimethylamino)buta-1,3-diene-1,3-diyl)bis(3-
(9H, t, J 7.1 Hz, 3OCH2CH3), 4.19 (6H, q, J 7.1 Hz, 3OCH2CH3), 7.40 (1H,
d, J 7.1 Hz, AreH), 7.42 (2H, d, J 7.1 Hz, AreH), 7.46 (2H, s, AreH), 7.48
(1H, s, AreH), 7.55 (3H, d, J 7.1 Hz, AreH), 8.98 (3H, s, AreH); 13C
(2-fluorophenyl)isoxazole-4-carboxylate) (3c). Yield 30%; mp
167e169 ꢀC; Rf¼0.36 (EtOAc/hexane 1:1); 1H NMR (CDCl3):
d 1.08
(6H, m, 2OCH2CH3), 2.92 (6H, br s, N(CH3)2), 4.08e4.17 (4H, m,
2OCH2CH3), 6.35 (1H, d, J 16.0 Hz, C1eH), 7.00 (1H, s, C4eH),
7.10e7.22 (4H, m, AreH), 7.41e7.63 (5H, m, HeArþC2eH); 13C NMR
NMR (CDCl3): d 13.7, 61.7, 110.8, 127.3, 127.4, 127.8, 129.6, 132.0,
132.4, 135.0, 136.8, 161.0, 161.5, 170.6; UV (iPrOH):
l
, nm (log
3
)¼273
(4.77); ESI-MS: m/z 927.99 [MþH]þ; Anal. Calcd (%) for
(CDCl3):
d
13.8, 13.9, 43.0, 60.4, 61.0, 93.9, 102.3, 108.5, 115.5 (d, JC,F
C42H27Cl6N3O9: C, 54.22; H, 2.93; N, 4.52. Found: C, 54.63; H, 2.99;
21.0 Hz), 115.6 (d, JC,F 22.0 Hz), 117.9 (d, JC,F 18.0 Hz), 123.9 (d, JC,F
3.5 Hz), 130.9 (d, JC,F 21.8 Hz), 131.2 (d, JC,F 8.2 Hz), 131.5 (d, JC,F
8.2 Hz), 141.7, 151.6, 158.4, 158.8, 160.5 (d, JC,F 250.0 Hz), 160.6 (d, JC,F
N, 4.31.
4.5. General procedure for the preparation of benzene 4a in
different solvents
250.0 Hz), 161.9, 172.5; UV (iPrOH):
l
, nm (log
3
)¼392 (4.57); ESI-
MS: m/z 664.19 [MþH]þ; Anal. Calcd (%) for C30H27F2N3O6: C,
63.94; H, 4.83; N, 7.46. Found: 64.10; H, 4.89; N, 7.42.
To a solution of enamine 2a (0.7 mmol, 1.0 equiv) in the corre-
spondent solvent (4 mL) (see Table 1 in the Supplementary data),
acetyl chloride (2.1 mmol, 3.0 equiv) was added and the reaction
mixture was stirred at room temperature until the starting en-
amine 2a and intermediate diene 3a disappeared according to TLC
analysis (from 20 h to 22 days). The resulting mixture was evapo-
rated under reduced pressure to dryness and the residue was pu-
rified by column chromatography over silica gel (60e120) using
EtOAc/hexane (1:2) as eluent to give benzene 4a in 36e65% yield.
4.4.4. Triethyl 5,50,500-(benzene-1,3,5-triyl)tris(3-(2-fluorophenyl)iso-
xazole-4-carboxylate) (4c). Yellow solid; yield 9%; mp 125e127 ꢀC;
Rf¼0.60 (EtOAc/hexane 1:1); 1H NMR (CDCl3):
d 1.06 (9H, t, J 7.2 Hz,
3OCH2CH3), 4.23 (6H, q, J 7.2 Hz, 3OCH2CH3), 7.20 (3H, t, J 8.6 Hz,
AreH), 7.30 (3H, t, J 8.0 Hz, AreH), 7.49e7.55 (3H, m, AreH), 7.64
(3H, t, J 8.7 Hz, AreH), 8.93 (3H, s, HeAr); 13C NMR (CDCl3):
d
13.6,
61.6, 110.7, 115.7, 117.2 (d, JC,F 14.5 Hz), 124.4 (d, JC,F 3.4 Hz), 127.8,
Please cite this article in press as: Beryozkina, T. V.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.015

8
T.V. Beryozkina et al. / Tetrahedron xxx (2014) 1e9
4.5.1. Triethyl 5,50,500-(benzene-1,3,5-triyl)tris(3-phenylisoxazole-4-
C, 67.07; H, 4.11; N, 15.04, S, 13.77. Found: C, 67.01; H, 4.15; N, 15.00,
S, 13.69.
carboxylate) (4a). Colorless solid; mp 128e130 ꢀC; Rf¼0.67
(EtOAc/hexane 1:1); 1H NMR (CDCl3):
d 1.12 (9H, t, J 7.2 Hz,
3OCH2CH3), 4.26 (6H, q, J 7.2 Hz, 3OCH2CH3), 7.49e7.51 (9H, m,
4.9. X-ray diffraction study
AreH), 7.67e7.70 (6H, m, AreH), 8.76 (3H, s, AreH); 13C NMR
(CDCl3):
d
13.8, 61.8, 109.8, 128.1, 128.4, 128.4, 129.3, 130.2, 131.5,
4.9.1. X-ray diffraction study of 3e. X-ray intensity data were col-
161.9, 163.6,170.3; UV (iPrOH):
l, nm (log
3 )¼270 (4.79); ESI-MS: m/
lected with a Xcalibur S diffractometer using standard procedure
z 724.22 [MþH]þ; Anal. Calcd (%) for C42H33N3O9: C, 69.70; H, 4.60;
(l
(Mo Ka)¼0.71069 A radiation, T¼295(2) K,
u-scanning with step
m
ꢀ
N, 5.81. Found: C, 69.93; H, 4.71; N, 5.75.
1ꢀ). Absorption correction was not applied (
angles 2.65<
¼0.426 mmꢁ1). On
q
<26.37ꢀ 14,453 reflections were collected, 6122
4.6. Trimethyl 5,50,500-(benzene-1,3,5-triyl)tris(3-(2-chloro-6-
fluorophenyl)isoxazole-4-carboxylate) (4h)
(Rint¼0.0579) independent reflections, 2340 reflections with
I>2
s
(I). Completeness to
q
¼26.37ꢀ 95.5%. Unit cell parameters were
refined using all collected spots after the integration process.
ꢀ
A solution of enamine 2h (0.162 g, 0.5 mmol, 1.0 equiv) and
acetyl chloride (0.236 g, 3.0 mmol, 6.0 equiv) in anhydrous 1,4-
dioxane (4 mL) was kept at 50 ꢀC for 9 days. After that the vola-
tiles were evaporated, the residue was treated with boiling water.
The residue was extracted with several portions of boiling heptane
to get free of tars and the extract was concentrated. The solid thus
formed was purified by column chromatography on silica gel, elu-
ent EtOAc/heptanes (1:2) to give benzene 4h. Colorless solid; yield
55% (0.077 g); mp 181e183 ꢀC; Rf¼0.58 (EtOAc/hexane 1:1); 1H
Crystal is triclinic, space group Pꢁ1, a¼6.7961(8) A,
b¼13.1361(14) A, c¼17.9928(10) A,
a
¼82.653(7)ꢀ,
b
¼80.199(7)ꢀ,
ꢀ
ꢀ
3
ꢀ
ꢀ
g
¼83.538(9) , V¼1563.1(3) A . For compound C30H25Cl4N3O6, Z¼2,
r
(calcd)¼1.414 g/cm3. SHELXTL program28 was used for solution
and refinement of structure. Structure was refined in anisotropic
approximation for non-hydrogen atoms, hydrogen atoms were
placed in calculated positions and refined in isotropic approxima-
tion in ‘riding’ model. The details of the refinement and the final R
indices: R1 [I>2
s
(I)]¼0.0471, R1 (all data)¼0.1567, wR2 [I>2 (I)]¼
s
NMR (CDCl3):
d
3.73 (9H, s, OCH3), 7.17 (3H, td, J 8.5 Hz, 1.0 Hz,
0.0759, wR2 (all data)¼0.0851, S¼1.005. Largest diffraction peak and
3
ꢀ
ꢁ
AreH), 7.33e7.39 (3H, m, AreH), 7.45 (3H, td, J 8.2, 5.9 Hz, AreH)
hole 0.274 and ꢁ0.400 e/A .
8.98 (3H, s, AreH); 13C NMR (DMSO-d6):
d 52.8, 110.7, 115.2 (d, JC,F
2
21.6 Hz), 116.7 (d, JC,F 18.3 Hz), 126.1, 127.3, 133.1, 133.6 (d, JC,F
9.6 Hz), 134.3 (d, JC,F 3.7 Hz), 156.7, 160.6 (d, JC,F 251.8 Hz), 160.8,
4.9.2. X-ray diffraction study of 4h. Single-crystal X-ray diffraction
analysis was performed at 295(2) K on an Xcalibur 3 diffractometer
171.1; 19F NMR (376 MHz, CDCl3):
d
ꢁ109.54 (s, 1F); ESI-MS, m/z
equipped with a CCD detector (
exposure per frame, crystal-detector distance 50 mm, Mo Ka-irra-
u
-scanning at 1ꢀ step and 20-s
838.03 [MþH]þ; Anal. Calcd (%) for C39H21Cl3F3N3O9: C, 55.83; H,
2.52; N, 5.01. Found: C, 55.71; H, 2.27; N, 5.07.
diation). Colorless prismatic crystals of 4h belong to the trigonal
ꢀ
system, space group Rꢁ3. Unit cell parameters: a¼b¼16.7694(4) A,
3
4.7. Trimethyl 5,50,500-(benzene-1,3,5-triyl)tris(3-
phenylisoxazole-4-carboxylate) (4i)
c¼24.3406(9) A,
a
¼
b
¼90ꢀ,
g
¼120 , V¼5927.8(3) A ,
r
(calcd)¼
ꢀ
ꢀ
ꢀ
1.410 g/cm3,
m
¼0.304 mmꢁ1, Z¼6. To collect and edit the experi-
mental data and refine the unit cell parameters, we used the Cry-
The solution of enamine 2i (0.3 g, 1.1 mmol, 1.0 equiv) and
BF3$O(CH3)2 (60% solution) (0.2 mL, 1.3 mmol, 1.18 equiv) in an-
hydrous 1,4-dioxane (2 mL) was stirred at 60e70 ꢀC for 12 h until
TLC does not show the presence of starting enamine and in-
termediate dieneamine in the reaction mixture. The reaction mix-
ture was concentrated under reduced pressure and the residue was
purified by column chromatography on silica gel (60e120) using
EtOAc/hexane (1:3) as eluent to give product 4i. Colorless solid;
yield 80% (0.20 g); mp 152e155 ꢀC; Rf¼0.64 (EtOAc/hexane 1:1); 1H
sAlis CCD program.29 At 3.49<
collected, 3251 independent reflections (Rint¼0.0175), 2209 re-
flections with I>2 (I). The experiment completeness at
<28.30ꢀ
q
<28.30ꢀ 13,293 reflections were
s
q
was 99.2%. The structure was solved and refined using the SHELX
program package.29 The refinement was carried out by the full
matrix least-squares method by F2 with all non-hydrogen atoms
taken in the anisotropic approximation. The hydrogen atoms were
placed in calculated positions and included in refinement in the
‘rider’ model in the isotropic approximation with dependent ther-
mal parameters. Final parameters of refinement: R1¼0.0492,
NMR (CDCl3):
d 3.80 (9H, s, OCH3), 7.47e7.55 (9H, m, AreH),
7.68e7.70 (6H, m, AreH), 8.72 (3H, s, AreH); 13C NMR (CDCl3): 52.6,
109.5, 128.2, 128.3, 128.6, 129.1, 130.3, 131.3, 162.4, 163.4, 170.3; ESI-
MS, m/z 682.17 [MþH]þ; Anal. Calcd (%) for C39H27N3O9: C, 68.72; H,
3.99; N, 6.16. Found: C, 68.81; H, 3.92; N, 6.09.
wR2¼0.1560 (for reflections with I>2 (I)), R1¼0.0667, wR2¼0.1646
s
(for all data), S¼1.017. Largest diffraction peak and hole 0.407 and
ꢀꢁ3
ꢁ
ꢁ0.295 eA
.
4.9.3. X-ray diffraction study of 6. Single-crystal X-ray diffraction
4.8. 5,50-((1E,3Z)-4-(Dimethylamino)buta-1,3-diene-1,3-diyl)
bis(3-phenylisothiazole-4-carbonitrile) (6)
analysis was performed at 295(2) K on an Xcalibur 3 diffractometer
equipped with a CCD detector (
exposure per frame, crystal-detector distance 50 mm, Mo K
u
-scanning at 1ꢀ step and 20-s
a
-irra-
To a solution of enamine 5a (0.18 g, 0.705 mmol) in anhydrous
1,4-dioxane (3 mL) was added acetyl chloride (0.11 mL, 1.55 mmol)
and the reaction mixture was stirred at 50e55ꢀS for 16 h. The dark
yellow precipitate obtained was filtered off, washed with ether, and
dried. The product was purified through silica gel column chro-
matography by eluting with EtOAc/hexane (1:2) and further double
recrystallization with EtOAc/hexane to give the diene 6. Yellow
solid; yield 25% (0.041 g); mp 208e210 ꢀC; Rf¼0.37 (EtOAc/hexane
diation). Orange plates of crystals belong to monoclinic system,
space group P21/c. Unit cell parameters: a¼19.9068(9) A,
ꢀ
ꢀ
ꢀ
b¼7.4737(3) A, c¼15.8609(7) A,
a
¼
g
¼90ꢀ,
b
¼96.935(4)ꢀ.
3
V¼2342.48(18) A ,
r
(calcd)¼1.320 g/cm3,
m
¼0.252 mmꢁ1, Z¼4. To
ꢀ
collect and edit the experimental data and refine the unit cell pa-
rameters, we used the CrysAlis CCD program.30 At 2.90<
11,166 reflections were collected, 5626 independent reflections
(Rint¼0.0341), 2294 reflections with I>2 (I). The experiment com-
pleteness at
<26.00ꢀ was 98.0%. The structure was solved and
q
<28.29ꢀ
s
1:1); 1H NMR (CDCl3):
d
2.97 (6H, br s, N(CH3)2), 6.28 (1H, d, J
15.2 Hz, C1eH), 6.99 (1H, s, C4eH), 7.22 (1H, d, J 15.2 Hz, C2eH),
7.47e7.56 (10H, m, AreH); 13C NMR (CDCl3):
45.0, 94.2, 105.9,
108.1, 114.2, 115.4, 127.8, 127.9, 128.9, 129.1, 130.3, 130.7, 132.9, 133.3,
q
refined using the SHELX program package.29 The refinement was
carried out by the full matrix least-squares method by F2 with all
non-hydrogen atoms taken in the anisotropic approximation. The
hydrogen atoms were placed in calculated positions and included
in refinement in the ‘rider’ model in the isotropic approximation
d
141.4, 150.0, 167.4, 167.9, 173.9, 175.7; UV (iPrOH):
l
, nm (log
3
)¼252
(6.10), ESI-MS: m/z 466.11 [MþH]þ; Anal. Calcd (%) for C26H19N5S2:
Please cite this article in press as: Beryozkina, T. V.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.015

T.V. Beryozkina et al. / Tetrahedron xxx (2014) 1e9
9
7. Volochnyuk, D. M.; Kostyuk, A. N.; Sibgatulin, D. A.; Chernega, A. N.; Pinchuk, A.
M.; Tolmachev, A. A. Tetrahedron 2004, 60, 2361.
with dependent thermal parameters. Final parameters of re-
(I)),
finement: R1¼0.0376, wR2¼0.0721 (for reflections with I>2
s
8. Attanasi, O. A.; Favi, G.; Filippone, P.; Forzato, C.; Giorgi, G.; Morganti, S.; Nitti,
P.; Pitacco, G.; Rizzato, E.; Spinelli, D.; Valentin, E. Tetrahedron 2006, 62, 6420.
9. Shafran, Y.; Rozin, Y.; Beryozkina, T.; Zhidovinov, S.; Eltsov, O.; Subbotina, Y.;
Leban, J.; Novikova, R.; Bakulev, V. Org. Biomol. Chem. 2012, 10, 5795.
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11. Pengler, W. A.; Schulte, J.; Berger, D. P.; Mertelsmann, R.; Fiebig, H. H. Anti-
Cancer Drugs 1995, 6, 522.
R1¼0.1049, wR2¼0.0757 (for all data), S¼1.001. Largest diffraction
ꢀꢁ3
ꢁ
peak and hole 0.243 and ꢁ0.175 eA
.
Deposition numbers for compounds 3e (CCDC 978581), 4h
(CCDC 978580), and 6 (CCDC 978582) contain the supplementary
crystallographic data for this paper. These data can be obtained free
of charge from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
12. Roth, T.; Berger, A. M.; Dengler, W.; Willmann, H.; Fiebig, H. H. Contrib. Oncol.
1999, 54, 145.
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Biomol. Chem. 2012, 10, 281.
Acknowledgements
This work was supported by the Russian Foundation for Basic
Research (grant no. 14-03-01033).
Supplementary data
20. Bakulev, V. A.; Efimov, I. V.; Belyaev, N. A.; Rozin, Y. A.; Volkova, N. N.; El’tsov, O.
S. Chem. Heterocycl. Compd. 2012, 47, 1593.
21. Spek, A. L. J. Appl. Crystallogr. 2003, 36, 7.
22. Almazroa, S.; Elnagdi, M. H.; Salah El-Din, A. M. J. Heterocycl. Chem. 2004, 41,
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2014.04.015.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
267.
23. Elgharmy, I. Synthesis 2003, 15, 2301.
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29. Sheldrick, G. M. Acta Crystallogr., Sect. A 2008, 64, 112.
30. CrysAlis CCD. Version 1.171.29.9 (release 23-03-2006 CrysAlis171.NET). Oxford
Diffraction Ltd.
Please cite this article in press as: Beryozkina, T. V.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.04.015