A simple synthesis of dimethyl 2-[(Z)-3-amino-1-oxo-1-(substituted)but-2-en-2-yl]fumarates: Potential intermediates in the synthesis of polysubstituted five- and six-membered heterocycles

Article abstract of DOI:10.1515/znb-2016-0017

In this communication, a simple synthesis of dimethyl 2-[(Z)-3-amino-1-oxo-1-(substituted)but-2-en-2-yl] fumarates is described. Methyl ketones were transformed by treatment with N,N-dimethylacetamide dimethyl acetal (DMADMA) into 3-dimethylamino-1-(subst

Full text of DOI:10.1515/znb-2016-0017

Z. Naturforsch. 2016; aop
Rok Šinkovec, Uroš Grošelj, Benjamin Prek, Marta Počkaj, Sebastijan Ričko, Jurij Svete
aAndsBiramnkopSlteanosvnyikn* thesis of dimethyl 2-[(Z)-3-amino-
1-oxo-1-(substituted)but-2-en-2-yl]fumarates:
potential intermediates in the synthesis
of polysubstituted five- and six-membered
heterocycles
DOI 10.1515/znb-2016-0017
Recently, polysubstituted butadienes have been prepared
by microwave-assisted [2+2] cycloadditions of enami-
nones to electron-poor acetylenes [13, 14].
Received January 15, 2016; accepted February 2, 2016
Abstract: In this communication, a simple synthesis of
dimethyl 2-[(Z)-3-amino-1-oxo-1-(substituted)but-2-en-2-yl]
fumarates is described. Methyl ketones were transformed
by treatment with N,N-dimethylacetamide dimethyl acetal
(DMADMA) into 3-dimethylamino-1-(substituted)but-2-en-
1-ones, followed by treatment with ammonium acetate
into (Z)-3-amino-1-(substituted)but-2-en-1-ones and addi-
tion to dimethyl acetylenedicarboxylate. These novel
polysubstituted butadienes are potential intermediates
for the metal-free preparation of polysubstituted five- and
six-membered heterocycles.
Polysubstituted aminobutadienes prepared by this
procedure are suitable for the preparation of polysub-
stituted pyridine derivatives. They also represent a
group of isomeric intermediates in regard to the amin-
obutadienes prepared via Michael addition in the Bohl-
mann-Rahtz synthesis of pyridine derivatives [15, 16].
On this basis, a simple metal-free synthesis of 2-alkyl-,
2-cycloalkyl-, 2-aryl-, and 2-heteroaryl-substituted pyr-
idine-3,4-dicarboxylates and their N-oxides has been
developed [17].
The electron-poor propyne iminium triflates, pre-
Keywords: enaminones; methyl ketones; polysubsti- pared from 3-trifloxypropene iminium triflates by
tuted butadienes; (Z)-3-amino-1-(substituted)but-2-en-1- elimination of triflic acid, underwent [2+2] and [2+4]
ones;
2-[(Z)-3-amino-1-oxo-1-(substituted)but-2-en-2-yl] cycloadditions with enamines [18]. Their reactivity
toward imines has been also reported [19, 20]. Recently,
fumarates.
we reported on a simple one-pot metal-free synthesis
of 2,4,5-trisubstituted pyridine derivatives and their
N-oxides by [2+2] cycloaddition of propyne iminium salts
1 Introduction
as electron-poor acetylenes to enaminones as an exten-
sion of the research recently developed in our laboratory
[21]. We also recently reported on a simple, metal-free
synthesis of polysubstituted benzene derivatives, where
N,N-dimethylacetamide dimethyl acetal (DMADMA)
served as the reagent and building block for generating
aromatic final products [22].
3-Dimethylaminopropenoates and related enaminones
have been demonstrated to exhibit a broad applicability
in heterocyclic synthesis [1–5], including the preparation
of natural products and their analogues, such as aplysin-
opsins [6, 7], meridianines [8, 9], and dipodazines [10–12].
We have reported on another application of the enami-
none system in the synthesis of heterocyclic compounds.
We have expanded the DMADMA methodology on aryl- and
(hetero)aryl-enaminone systems, as well as on aromatic
and heteroaromatic carboxamides, to prepare N,N,6-tri-
methyl-4-(substituted)pyridin-2-amines and N2,N2,N4,N4-
tetramethyl-6-(substituted) pyridine-2,4-diamines as the
final products [23].
*Corresponding author: Branko Stanovnik, Faculty of Chemistry and
Chemical Technology, University of Ljubljana, P.O. Box 537,
Večna pot 113, 1000 Ljubljana, Slovenia,
e-mail: branko.stanovnik@fkkt.uni-lj.si
Rok Šinkovec, Uroš Grošelj, Benjamin Prek, Marta Počkaj,
Sebastijan Ričko and Jurij Svete: Faculty of Chemistry and Chemical
Technology, University of Ljubljana, P.O. Box 537, Večna pot 113,
1000 Ljubljana, Slovenia
Unauthenticated
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ꢀꢀꢀꢁ
2ꢀ ꢀR. Šinkovec et al.: Dimethyl 2-[(Z)-3-amino-1-oxo-1-(substituted)but-2-en-2-yl]fumarates
2 Results and discussion
acetate to substitute the N,N-dimethylamino group with
an amino group to give (Z)-3-amino-1-(substituted)but-2-
It has been reported that enaminones 2, which are easily en-1-ones 3a–i as was reported earlier [23]. Enaminones
prepared from methyl ketones 1 using amide acetals, such 2a–i did not react in [2+2] cycloaddition reaction with
as N,N-dimethylformamide dimethyl acetal (DMFDMA), acetylenedicarboxylate either under normal thermal con-
undergo self-condensation in the presence of ammo- ditions or under microwave irradiation. The enaminones
nium acetate affording 2,5-disubstituted pyridine deriva- 3a–i reacted with dimethyl acetylenedicarboxylate by
tives [24, 25]. Meanwhile, when using DMADMA, the heating in acetonitrile at reflux temperature for 2.5–4.5 h
enaminone products of the condensation reaction do not or by microwave irradiation for 20–30 min. The [2-(Z)-3-
undergo self-condensation in acidic media. Therefore, amino-1-oxo-1-(substituted)but-2-en-2yl]fumarates 4a–i,
the dimethylamino group can be readily replaced with a new type of polysubstituted butadienes, were formed
the amino group, using ammonium acetate as an active in 30%–65% yields (Scheme 1). The formation of these
form of ammonia [26]. It is known that the methyl group polysubstituted butadienes is not a result of [2+2]cycload-
attached to the enaminone system is acidic and is capable dition according to the sequence A → B → C as shown
of participating in condensation reactions [22, 27].
on Scheme 2 reported earlier for a series of enaminones
Ketones 1a–i were transformed with DMADMA into without a methyl group at position 3 [28]. They are formed
enaminones 2a–i, which were treated with ammonium according to the reaction sequence D → E → F.
H
O
DMADMA
O
Me
NMe2
O
NH
Me
NH4OAc
R
Me
MeOH, r. t.
R
R
toluene, reflux
1
3
2
MW
100−110°C
20−30 min.
DMAD
R = a) phenyl
b) 4-methylphenyl
c) 4-bromophenyl
d) 4-chlorophenyl
e) 4-fluorophenyl
H
O
R
NH
f) 4-methoxyphenyl
g) 3-(trifluoromethyl)phenyl
h) 3-nitrophenyl
Me
CO2Me
i) pyrazin-2-yl
MeO2C
4
Scheme 1:ꢀFormation of [2-(Z)-3-amino-1-oxo-1-(substituted)but-2-en-2-yl]fumarates 4a–i.
O
C
H
O
C
O
C
NH2
Me
R
Me
H
R
NH2
R
NH2
Me
H
MeO2C
CO2Me
CO2Me
MeO2C
CO2Me
MeO2C
A
D
C
B
H2N
O
NH2
O
NH2
Me
C
R
H
Me
ROC
R
Me
CO2Me
CO2Me
MeO2C
MeO2C
MeO2C
CO2Me
H
E
F
Scheme 2:ꢀProposed mechanism for the formation of 4a–i.
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ꢁꢀꢀꢀ
R. Šinkovec et al.: Dimethyl 2-[(Z)-3-amino-1-oxo-1-(substituted)but-2-en-2-yl]fumaratesꢂ ꢂ3
2.1 Structure determination
but-2-en-1-ones. This novel polysubstituted butadienes are
potential intermediates for the metal-free preparation of
The structures of new compounds were determined on the polysubstituted five- and six-membered heterocycles.
basis of 1H and 13C NMR, IR, HRMS spectra, and microanal-
yses for C, H, and N. The structures of compounds 4a and
4e were confirmed by X-ray crystal structure determina-
4 Experimental section
tions (Figs. 1 and 2).
Melting points were determined on a Stanford Research
Systems MPA100 OptiMelt automated melting point
3 Conclusion
system.TheNMRspectrawereobtainedonaBrukerAvance
DPX 300 at 300 MHz for 1H and 75.5 MHz for 13C and on a
1
In conclusion, we have described a simple synthesis of Bruker Avance III UltraShield 500 plus at 500 MHz for H
dimethyl
2-[(Z)-3-amino-1-oxo-1-(substituted)but-2-en-2-yl] and 126 MHz for 13C, using CDCl3 and [D6]DMSO with Me4Si
fumarates from methyl ketones via 3-dimethylamino- as the internal standard, as solvents. Mass spectra were
1-(substituted)but-2-en-1-ones and (Z)-3-amino-1-(substituted) recorded on an Agilent 6224 Accurate Mass TOF LC/MS
spectrometer, IR spectra on a Perkin Elmer Spectrum BX
FTIR spectrophotometer. Microanalyses were performed
N1
O1
on a Perkin-Elmer CHN Analyzer 2400 II. Column chroma-
tography (CC) was performed on silica gel (silica gel 60,
particle size 35–70 μm; Fluka). Compounds 2z–i and 3a–i
C9
C7
C8
were prepared according to the procedure described in the
C1
C10
C6
C5
literature [23].
C2
O4
O2
C11
4.1 General procedure for the preparation
of dimethyl 2-[(Z)-3-amino-1-oxo-1-
C15
C13
C3
C4
C12
O5
(substituted)but-2-en-2-yl]fumarates 4a–i
C16
O3
A solution of 3-amino-1-(substituted)but-2-en-1-ones (3a–i,
1 mmol) and dimethyl acetylenedicarboxylate (2 mmol)
in acetonitrile (2 mL) was placed in a microwave tube
equippedwithamagneticstirringbar.Thereactionmixture
was then heated via microwave irradiation (300 W) in a
closed vessel at an automatically controlled constant tem-
perature (CEM Corporation Discover microwave unit). The
reaction temperatures were between 100°C and 110°C, and
the reaction times were 20–30 min. After the completion
of the reaction, the volatile components were evaporated
in vacuo and the product was washed with diethyl ether or
purified by column chromatography ethyl acetate/petro-
leum ether 1:2.
C14
Fig. 1:ꢀOrtep representation of 4a. Displacement ellipsoids drawn
at the 30% probability level, H atoms as spheres with arbitrary radii
N1
O1
C7
C9
C5
C2
C6
C8
C4
O4
C10
O3
The following compounds were prepared in this manner.
C1
C15
C11
C13
C3
F1
C12
4.1.1 Dimethyl 2-[(Z)-3-amino-1-oxo-1-phenylbut-2-en-
C14
2-yl]fumarate (4a)
C16
O2
O5
Prepared from 3a (330 mg, 2 mmol) and DMAD (568 mg,
4 mmol). Yield: 392 mg (65%) of a yellow crystalline solid;
Fig. 2:ꢀOrtep representation of 4e. Displacement ellipsoids drawn
1
at the 30% probability level, H atoms as spheres with arbitrary radii. m.p. 147°C–149°C. – H NMR (CDCl3, 500 MHz): δ ꢀ=ꢀ 1.91
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ꢀꢀꢀꢁ
4ꢀ ꢀR. Šinkovec et al.: Dimethyl 2-[(Z)-3-amino-1-oxo-1-(substituted)but-2-en-2-yl]fumarates
(3H, s, Me), 3.62 (3H, s, COOMe), 3.69 (3H, s, COOMe), 5.55 4.1.4 Dimethyl 2-[(Z)-3-amino-1-oxo-1-(4-chlorophenyl)
(1H, br. s, NH2), 6.70 (1H, s, CH), 7.23–7.32 (5H, m, Ph), 10.95
but-2-en-2-yl]fumarate (4d)
(1H, br. s, NH2) ppm. – 13C NMR (CDCl3, 125 MHz): δ ꢀ=ꢀ 21.9,
52.0, 52.9, 101.5, 127.2, 127.7, 129.2, 129.4, 142.4, 144.0, 163.1, Prepared from 3d (700 mg, 3.60 mmol) and DMAD (1022
165.8, 168.2, 193.3 ppm. – IR (KBr): ν ꢀ=ꢀ 3271, 3130, 1715, mg, 7.20 mmol). Yield: 674 mg, (55%) of a yellow solid; m.p.
1602, 1471, 1433, 1376, 1300, 1283, 1247, 1215, 1168, 1146, 158°C–160°C. – 1H NMR (CDCl3, 500 MHz): δ ꢀ=ꢀ 1.93 (3H, s,
1054, 1025, 990, 942, 900, 863, 779, 743, 706 cm−1. – HRMS: Me), 3.69 (3H, s, COOMe), 3.71 (3H, s, COOMe), 5.65 (1H,
+
m/z ꢀ=ꢀ 304.1180 (calcd. 304.1179 for C16H18NO5, [M+H] ). br. s, NH2), 6.74 (1H, s, CH), 7.23–7.26 (2H, m, Ph), 7.28–7.30
– C16H17NO5 (303.1): calcd. C 63.36, H 5.65, N 4.62; found C (2H, m, Ph), 10.94 (1H, br. s, NH2) ppm. – 13C NMR (CDCl3,
63.24, H 5.63, N 4.61.
125 MHz): δ ꢀ=ꢀ 21.9, 52.0, 53.0, 101.1, 128.0, 128.7, 129.6, 135.4,
140.8, 143.8, 163.4, 165.7 168.1; 191.9 ppm. – IR (KBr): ν ꢀ=ꢀ
3257, 2946, 1718, 1639, 1583, 1469, 1431, 1246, 1194, 1170,
1140, 1086, 1055, 1029, 1014, 906, 868, 835, 771, 709 cm−1.
– HRMS: m/z ꢀ=ꢀ 338.0788 (calcd. 338.0790 for C16H17NO5,
4.1.2 Dimethyl 2-[(Z)-3-amino-1-oxo-1-(p-tolyl)but-2-en-
2-yl]fumarate (4b)
+
[M+H] ). – C16H16ClNO5 (337.1): calcd. C 56.90, H 4.78, N 4.15;
found C 57.00, H 4.77, N 4.23.
Prepared from 3b (87 mg, 0.5 mmol) and DMAD (142
mg, 1 mmol). Yield: 90 mg (57%) of a yellow solid; m.p.
1
137°C–139°C. – H NMR (CDCl3, 500 MHz): δ ꢀ=ꢀ 1.90 (3H,
4.1.5 Dimethyl 2-[(Z)-3-amino-1-oxo-1-(4-fluorophenyl)
s, Me), 2.30 (3H, s, Me), 3.62 (3H, s, COOMe), 3.69 (3H, s,
COOMe), 5.53 (1H, br. s, NH2), 6.70 (1H, s, CH), 7.03–7.06
(2H, m, Ph), 7.19–7.22 (2H, m, Ph), 10.92 (1H, br. s, NH2)
ppm. – 13C NMR (CDCl3, 125 MHz): δ ꢀ=ꢀ 21.5, 21.9, 52.0; 52.8,
101.5, 127.3, 128.4, 128.9, 139.5, 139.7, 144.2, 162.9, 165.8,
168.3, 193.4 ppm. – IR (KBr): ν ꢀ=ꢀ 3263, 3117, 2945, 1718,
1637, 1582, 1562, 1466, 1430, 1375, 1245, 1169, 1140, 1055,
1027, 868, 829, 787, 767, 712 cm−1. – HRMS: m/z ꢀ=ꢀ 318.1331
but-2-en-2-yl]fumarate (4e)
Prepared from 3e (90 mg, 0.5 mmol) and DMAD (142 mg,
1.0 mmol). Yield: 84 mg (52%) of a yellow precipitate;
m.p. 142–144°C. – 1H NMR (CDCl3, 500 MHz): δ ꢀ=ꢀ 1.92 (3H,
s, Me), 3.66 (3H, s, COOMe), 3.69 (3H, s, COOMe), 5.53
(1H, br. s., NH2), 6.71 (1H, s, CH), 6.91–6.96 (2H, m, C6H4),
13
7.32–7.36 (2H, m, C6H4), 10.92 (1H, br. s., NH2) ppm. – C
+
(calcd. 318.1336 for C17H20NO5, [M+H] ). – C17H19NO5 (317.1):
calcd. C 64.34, H 6.04, N 4.41; found C 64.20, H 6.07,
N 4.40.
NMR (CDCl3, 125 MHz): δ = 21.9, 52.0, 52.9, 101.2, 114.7 (d, J
= 21.6 Hz), 129.3, 129.4 (d, J = 8.8 Hz), 138.6 (d, J = 3.2 Hz),
144.0, 163.3, 163.3 (d, J = 249 Hz), 165.8, 168.2, 192.0 ppm.
– IR(KBr): ν = 3391, 2947, 1718, 1698, 1595, 1478, 1435, 1377,
1257, 1216, 1174, 1135, 1093, 1037, 1019, 908, 881, 866, 848,
787, 762, 718 cm−1. – HRMS: m/z = 322.1088 (calc. 322.1085
4.1.3 Dimethyl 2-[(Z)-3-amino-1-oxo-1-(4-bromophenyl)
+
but-2-en-2-yl]fumarate (4c)
for C16H17FNO5, [M+H] ). – C16H16FNO5 (321.1): calc. C 59.81,
H 5.02, N 4.36; found C 59.53, H 5.11, N 4.21.
Prepared from 3c (239 mg, 1 mmol) and DMAD (284 mg,
2 mmol). Yield: 200 mg (52%) of a yellow solid; m.p.
154°C–157°C. – 1H NMR (CDCl3, 500 MHz): δ ꢀ=ꢀ 1.89 (3H, s, 4.1.6 Dimethyl 2-[(Z)-3-amino-1-oxo-1-(4-
Me), 3.66 (3H, s, COOMe), 3.67 (3H, s, COOMe), 5.73 (1H,
methoxyphenyl)but-2-en-2-yl]fumarate (4f)
br. s, NH2), 6.70 (1H, s, CH), 7.17–7.21 (2H, m, Ph), 7.36–
13
7.39 (2H, m, Ph), 10.90 (1H, br. s, NH2) ppm. – C NMR Prepared from 3f (600 mg, 3.14 mmol) and DMAD (1022 mg,
(CDCl3, 125 MHz): δ ꢀ=ꢀ 21.9, 52.0, 53.0, 101.0, 123.7, 128.9, 7.20 mmol). Yield: 778 mg (74%) of a yellow precipitate;
1
129.6, 130.9, 141.2, 143.7, 163.6, 165.7, 168.1, 191.9 ppm. m.p. 136°C–138°C. – H NMR (CDCl3, 500 MHz): δ ꢀ=ꢀ 1.91
– IR (KBr): ν ꢀ=ꢀ 3257, 3116, 2945, 1717, 1638, 1583, 1467, (3H, s, Me), 3.63 (3H, s, COOMe), 3.69 (3H, s, COOMe), 3.79
1431, 1390, 1246, 1193, 1170, 1139, 1067, 1028, 1010, 906, (3H, s, OMe), 5.52 (1H, br. s, NH2), 6.72 (1H, s, CH), 6.75–6.78
880, 867, 831, 770, 708 cm−1. – HRMS: m/z ꢀ=ꢀ 382.0280 (2H, m, Ph), 7.30–7.34 (2H, m, Ph), 10.88 (1H, br. s, NH2)
+
(calcd. 382.0285 for C16H17BrNO5, [M+H] ). – C16H16BrNO5 ppm. – 13C NMR (CDCl3, 125 MHz): δ ꢀ=ꢀ 21.9, 51.9, 52.9, 101.5,
(381.0): calcd. C 50.28, H 4.22, N 3.66; found C 50.14, H 113.0, 128.6, 129.2, 135.1, 144.4, 160.6, 162.7, 165.9, 168.4,
4.21, N 3.69.
192.8 ppm. – IR (KBr): ν ꢀ=ꢀ 3415, 2943, 1723, 1702, 1591,
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ꢁꢀꢀꢀ
R. Šinkovec et al.: Dimethyl 2-[(Z)-3-amino-1-oxo-1-(substituted)but-2-en-2-yl]fumaratesꢂ ꢂ5
1567, 1475, 1433, 1243, 1169, 1023, 914, 881, 862, 790 cm−1. (1H, br. s, NH2), 6.78 (1H, s, CH), 8.32–8.34 (1H, m, Ar),
– C17H19NO6 (333.1): calcd. C 61.25, H 5.75, N 4.20; found C 8.50–8.51 (1H, m, Ar), 9.06 (1H, m, Ar), 11.17 (1H, br. s, NH2)
61.08, H 5.77, N 4.17.
ppm. – 13C NMR (CDCl3, 125 MHz): δ ꢀ=ꢀ 22.0, 51.9, 52.9, 100.3,
128.0, 141.2, 144.0, 144.9, 145.1, 152.0, 165.2, 165.9, 168.0,
185.4 ppm. – IR (KBr): ν ꢀ=ꢀ 3355, 2950, 1732, 1702, 1592, 1560,
4.1.7 Dimethyl 2-{(Z)-3-amino-1-oxo-1-[3-(trifluoromethyl) 1471, 1433, 1301, 1256, 1138, 1201, 861, 772 cm−1. – HRMS:
+
phenyl]but-2-en-2-yl}fumarate (4g)
m/z ꢀ=ꢀ 306.1086 (calcd. 306.1084 for C14H16N3O5, [M+H] ). –
C14H15N3O5 (305.1): calcd. C 55.08, H 4.95, N 13.76; found C
Prepared from 3g (573 mg, 2.5 mmol) and DMAD (710 mg, 54.03, H 4.84, N 12.96.
5.0 mmol). Yield: 277 mg (30%) of a yellow precipitate;
1
m.p. 130°C–132°C. – H NMR (CDCl3, 500 MHz): δ ꢀ=ꢀ 1.93
(3H, s, CH3), 3.67 (3H, s, COOMe), 3.69 (3H, s, COOMe), 4.2 Crystal structure determinations
5.63 (1H, br. s, NH2), 6.70 (1H, s, CH), 7.36–7.39 (1H, m, Ph),
7.48–7.49 (1H, m, Ph), 7.54–7.55 (1H, m, Ph), 10.92 (1H, br. s, Single crystal X-ray diffraction data of compounds 4a
NH2) ppm. – 13C NMR (CDCl3, 125 MHz): δ ꢀ=ꢀ 22.0, 52.0, 53.0, and 4e were collected at room temperature on an Agilent
101.0, 124.0 (q, J ꢀ=ꢀ 27.0 Hz), 124.2 (q, J ꢀ=ꢀ 3.9 Hz), 125.9 (q, SuperNova diffractometer (Dual, Cu at zero, Atlas) using
J ꢀ=ꢀ 3.6 Hz), 128.3, 130.1 (q, J ꢀ=ꢀ 32.5 Hz), 130.2, 143.0, 143.5, MoK (λ ꢀ=ꢀ 0.71073 Å) radiation at ambient temperature.
163.7, 165.6, 168.0, 191.5 ppm. – IR (KBr): ν ꢀ=ꢀ 3343, 2956, Dataαreduction and integration were performed with the
1717, 1613, 1582, 1467, 1431, 1386, 1332, 1278, 1248, 1157, 1124, software package Crysalis Pro [29]. Both structures were
1069, 1049, 1021, 939, 908, 876, 815, 788, 772, 702 cm−1. – solved by direct methods with the program Sir97 [30, 31].
HRMS: m/z ꢀ=ꢀ 372.1050 (calcd. 372.1053 for C17H17F3NO5, Full-matrix least-squares refinement on F2 with anisotropic
+
[M+H] ). – C17H16F3NO5 (371.1): calcd. C 54.99, H 4.34, N 3.77; displacement parameters for all non-hydrogen atoms
found C 54.89, H 4.35, N 3.75.
using Shelxl2013 [32, 33] was employed. All hydrogen
atoms were initially located in the difference Fourier maps.
Carbon-attached hydrogens were subsequently treated
as riding atoms in geometrically idealized positions with
bond lengths C–H of 0.96 Å for methyl and 0.93 Å for
aromatic C–H bonds. The corresponding displacement
4.1.8 Dimethyl 2-[(Z)-3-amino-1-oxo-1-(3-nitrophenyl)
but-2-en-2-yl]fumarate (4h)
Prepared from 3h (103 mg, 0.5 mmol) and DMAD (142 mg, parameters Uiso(H) were 1.5 times higher than those of the
1.0 mmol). Yield: 66 mg (38%) of a yellow precipitate; m.p. carrier methyl carbons and 1.2 times higher than aromatic
140°C–142°C. – 1H NMR (CDCl3, 500 MHz): δ ꢀ=ꢀ 1.94 (3H, s, carbon atoms. The hydrogen atoms of the amino group
Me), 3.68 (3H, s, COOMe), 3.75 (3H, s, COOMe), 5.73 (1H, were refined isotropically and without any restraints in 4e,
br. s, NH2), 6.72 (1H, s, CH), 7.43–7.46 (1H, t, J ꢀ=ꢀ 5 Hz, Ph), whereas in 4a, both N–H bonds were restrained to 0.87(2)
7.65–7.68 (1H, m, Ph), 8.13–8.20 (2H, m, Ph), 10.89 (1H, br. Å. In 4a, due to a more pronounced disorder of the termi-
13
s, NH2) ppm. – C NMR (CDCl3, 125 MHz): δ ꢀ=ꢀ 22.0, 52.2, nal groups the phenyl carbon atoms (with exceptions of C6
53.2, 100.6, 122.2, 124.0, 129.0, 130.7, 133.1, 143.2, 143.8, 147.6, attached to the rest of molecule) were restrained during
164.1, 165.5, 167.9, 190.1 ppm. – IR (KBr): ν ꢀ=ꢀ 3398, 2949, refinement (EADP restraints). Similarly, EADP restraints
1726, 1709, 1607, 1529, 1476, 1435, 1349, 1299, 1246, 1214, were also used for C12 and C13. Figures depicting the struc-
1175, 1146, 1092, 1077, 1042, 1017, 903, 877, 840, 810, 791, tures were prepared with Ortep [34, 35].
773, 745, 714 cm−1. – HRMS: m/z ꢀ=ꢀ 349.1032 (calcd. 349.1030
+
for C16H17N2O7, [M+H] ). – C16H16N2O7 (348.1): calcd. C 55.17,
H 4.63, N 8.04; found C 55.25, H 4.60, N 7.96.
4.2.1 Crystallographic data
For 4a: C16H17NO5, Mr ꢀ=ꢀ 303.30, orange prisms, 0.15 ꢀ×ꢀ
0.25 ꢀ×ꢀ 0.30 mm3, orthorhombic, space group P212121 (no.
19), a ꢀ=ꢀ 16.7212(8) Å, b ꢀ=ꢀ 10.6319(7) Å, c ꢀ=ꢀ 9.2340(5) Å, V ꢀ=ꢀ
1641.60(16) Å3, Z ꢀ=ꢀ 4, Dx ꢀ=ꢀ 1.227 Mg m−3, F(000) ꢀ=ꢀ 640 e,
4.1.9 Dimethyl 2-[(Z)-3-amino-1-oxo-1-(1-pyrazin-2-yl)
but-2-en-2-yl]fumarate (4i)
Prepared from 3i (89 mg, 0.55 mmol) and DMAD (120 mg, μ ꢀ=ꢀ 0.09 mm−1, T ꢀ=ꢀ 293(2) K, MoK radiation, λ ꢀ=ꢀ 0.71073 Å,
0825 mmol). Yield: 104 mg (62%) of a brown precipitate; ω scans, θ range 2.92–30.36°; hklαrange: –17 ꢀ<ꢀ h ꢀ<ꢀ 23, –14 ꢀ<ꢀ
1
m.p. 113°C–115°C. – H NMR (CDCl3, 500 MHz): δ ꢀ=ꢀ 1.97 k ꢀ<ꢀ 14, –10 ꢀ<ꢀ l ꢀ<ꢀ 12; 10242 measured, 4335 independent
(3H, s, Me), 3.62 (3H, s, COOMe), 3.81 (3H, s, COOMe), 5.97 and 2340 observed reflections, Rint ꢀ=ꢀ 0.0681, multi-scan
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ꢀꢀꢀꢁ
6ꢀ ꢀR. Šinkovec et al.: Dimethyl 2-[(Z)-3-amino-1-oxo-1-(substituted)but-2-en-2-yl]fumarates
absorption correction, refinement on F2, R(F) [F2 ꢀ>ꢀ 2
σ(F2)] ꢀ=ꢀ 0.0990, wR(F2) (all data) ꢀ=ꢀ 0.2917, 4335 contribut-
ing reflections, 175 parameters, 2 restraints, Shelxl2013
weighting scheme, absolute structure could not be deter-
mined reliably (x(Flack) ꢀ=ꢀ 2.2(10)), Δρmax ꢀ=ꢀ 0.53 e Å−3,
Δρmin ꢀ=ꢀ –0.30 e Å−3.
[10] J. Wagger, D. Bevk, A. Meden, J. Svete, B. Stanovnik, Helv.
Chim. Acta 2006, 89, 240.
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B. Stanovnik, Tetrahedron: Asymmetry 2007, 18, 464.
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dron 2008, 64, 2801.
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B. Stanovnik, Curr. Org. Chem. 2011, 15, 2530.
For 4e: C16H16FNO5, Mr ꢀ=ꢀ 321.30, yellow prisms,
[14] J. Bezenšek, T. Koleša, U. Grošelj, J. Wagger, K. Stare, A.
Meden, J. Svete, B. Stanovnik, Tetrahedron Lett. 2010, 51, 3392.
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Stanovnik, Tetrahedron 2012, 68, 4719.
0.30 ꢀ×ꢀ 0.30 ꢀ×ꢀ 0.45 mm3, triclinic, space group Pꢀ1
̅
(no. 2),
a ꢀ=ꢀ 8.0223(8) Å, b ꢀ=ꢀ 9.5519(11) Å, c ꢀ=ꢀ 11.1434(9) Å, α ꢀ=ꢀ
69.294(9)°, β ꢀ=ꢀ 87.285(7)°, γ ꢀ=ꢀ 83.598(9)°, V ꢀ=ꢀ 793.73(14) Å3,
Z ꢀ=ꢀ 2, Dx ꢀ=ꢀ 1.344 Mg m−3, F(000) ꢀ=ꢀ 336 e, μ ꢀ=ꢀ 0.11 mm−1, T ꢀ=ꢀ
293(2) K, MoK radiation, λ ꢀ=ꢀ 0.71073 Å, ω scans, θ range
3.20–30.44°; hαkl range: –11 ꢀ<ꢀ h ꢀ<ꢀ 10, –12 ꢀ<ꢀ k ꢀ<ꢀ 11, –15 ꢀ<ꢀ l ꢀ<ꢀ
10; 6919 measured, 4134 independent and 2377 observed
reflections, Rint ꢀ=ꢀ 0.0450, multi-scan absorption correc-
tion, refinement on F2, R(F) [F2 ꢀ>ꢀ 2 σ(F2)] ꢀ=ꢀ 0.0676, wR(F2)
(all data) ꢀ=ꢀ 0.2169, 4134 contributing reflections, 219
parameters, 0 restraints, Shelxl2013 weighting scheme,
Δρmax ꢀ=ꢀ 0.24 e Å−3, Δρmin ꢀ=ꢀ –0.23 e Å−3.
[18] G. Maas, B. Singer, P. Wald, M. Gimmy, Chem. Ber. 1988, 121,
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69b, 554.
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Stanovnik, Tetrahedron 2014, 70, 2359.
CCDC 1446156 and 1446157 contain the supplemen-
tary 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.
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[29] CrysAlis Pro Software System, Intelligent Data Collection and
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Acknowledgments: We are grateful for the financial
support from the Slovenian Research Agency, Slovenia,
through grant P1-0179. We thank EN-FIST Centre of Excel-
lence, Trg OF 13, 1000 Ljubljana, Slovenia, for the use of
the SuperNova diffractometer.
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Z. Naturforsch.ꢂ
ꢂ2016 | Volume x | Issue x(b)
Graphical synopsis
Rok Šinkovec, Uroš Grošelj, Benjamin
Prek, Marta Počkaj, Sebastijan Ričko,
Jurij Svete and Branko Stanovnik
A simple synthesis of dimethyl 2-[(Z)-
3-amino-1-oxo-1-(substituted)but-2-en-
2-yl]fumarates: potential intermediates
in the synthesis of polysubstituted five-
and six-membered heterocycles
DOI 10.1515/znb-2016-0017
Z. Naturforsch. 2016; x(x)b: xxx–xxx
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