Highly regio-and stereoselective addition of ethyl 3-aminobut-2-enoates to 2-substituted 3-nitro-2H-chromenes

Article abstract of DOI:10.1016/j.mencom.2013.05.010

Ethyl 3-aminobut-2-enoates MeC(NHR)=CHCO₂Et (R = H, Me, Bn) whose reaction site is C(2) atom add to 2-R-3-nitro-2H-chromenes at their C(4) atom to give the corresponding trans,trans-2,3,4-trisubstituted chromanes. Analogous substrates MeC(NR

Full text of DOI:10.1016/j.mencom.2013.05.010

Mendeleev
Communications
Mendeleev Commun., 2013, 23, 150–152
Highly regio- and stereoselective addition of ethyl 3-aminobut-2-enoates
to 2-substituted 3-nitro-2H-chromenes
Vladislav Yu. Korotaev, Alexey Yu. Barkov, Anna A. Sokovnina and Vyacheslav Ya. Sosnovskikh*
Department of Chemistry, Ural Federal University, 620000 Ekaterinburg, Russian Federation.
Fax: +7 343 261 5978; e-mail: vyacheslav.sosnovskikh@usu.ru
DOI: 10.1016/j.mencom.2013.05.010
Ethyl 3-aminobut-2-enoates MeC(NHR)=CHCO2Et (R = H, Me, Bn) whose reaction site is C(2) atom add to 2-R-3-nitro-2H-chromenes
at their C(4) atom to give the corresponding trans,trans-2,3,4-trisubstituted chromanes. Analogous substrates MeC(NR2)=CHCO2Et
(NR2 is piperidin-1-yl or morpholin-4-yl) react by their C(4) methyl group to afford cis,trans-2,3,4-trisubstituted chromanes. The
stereochemistry of the products was established by X-ray diffraction analysis.
2H-Chromene (2H-1-benzopyran) and its derivatives being an
important class of oxygen-containing heterocyclic compounds
that are widespread in the plant world1 show various types of
biological activity and can serve as starting compounds in syn-
theses of more complex molecules.2 In this respect, 3-nitro-
2H-chromenes, that are related to conjugated nitroalkenes, are
of particular interest.3 The reactions of 3-nitro-2H-chromenes
with C-, N- and S-nucleophiles, which occur at the activated
double bond and give various chromane derivatives, have been
studied in sufficient detail.4 However, reactions of these com-
pounds with push-pull enamines have nearly not been covered.
Only one paper is known5 reporting the reaction of 2-aryl-
3-nitro-2H-chromenes with methyl ester of b-methylamino-
crotonic acid to give mixtures of the addition product and the
corresponding pyrrole formed from it by the Grob reaction. Here,
we have studied the reactions of 2-trifluoromethyl-, 2-trichloro-
methyl- and 2-phenyl-3-nitro-2H-chromenes with ethyl 3-amino-
but-2-enoates MeC(NR1R2)=CHCO2Et derived from ethyl aceto-
acetate and amino compounds such as ammonia, methyl- and
benzylamines, morpholine and piperidine, and shown that transi-
tion from primary and secondary enamines to tertiary ones results
in changes in both the regio- and stereochemistry of the addition
product.
secondary amino groups (Scheme 1). The reaction takes two
days and gives Michael C-adducts 3a–h as colourless crystals
in 37–83% yields. The structures of the latter were determined
by elemental analyses, IR, 1H, 19F NMR spectroscopy and X-ray
diffraction data.† The addition occurred at the chromene C-4
atom without elimination of the nitro group and with involvement
of the most nucleophilic enamine a-C atom to give only one
trans,trans-diastereomer (tt) with Z-configuration of the double
bond stabilised by an intramolecular hydrogen bond. All the three
bulky substituents in the benzopyran system occupy equatorial
positions, as indicated by the high coupling constants between
the H-2, H-3 and H-4 protons located in axial positions (3JH-2,H-3
3
7.9–10.1 Hz, JH-3,H-4 10.1–10.8 Hz in CDCl3). The stereo-
†
NMR spectra were recorded for solutions of compounds in CDCl3 at
400 or 500 MHz for 1H and 376 MHz for 19F.
Synthesis of compounds 3 and 6 (general procedure). A mixture of the
corresponding chromene 1 (1 mmol) and enamine 2 (1 mmol) was kept in
dry acetonitrile (0.2 ml) for several hours at ~20°C. The precipitate was
filtered off and recrystallized from dichloromethane–hexane (1:2).
Ethyl (2S*,3S*,4S*)-(Z)-3-amino-2-[3-nitro-2-(trifluoromethyl)-3,4-di-
hydro-2H-chromen-4-yl]-2-butenoate 3a. Yield 0.33 g (83%), mp 162–
163°C (decomp.), colourless prisms. IR (KBr, n/cm–1): 3403, 3315,
1
3328, 1652, 1633, 1570, 1555, 1529, 1484, 1455, 1371. H NMR (500
It has been found that 3-nitrochromenes 1 smoothly react in
acetonitrile at ~20°C with enamines 2 bearing primary or
MHz, CDCl3) d: 0.83 (t, 3H, Me, J 7.1 Hz), 2.05 (s, 3H, Me), 3.87 (dq,
1H, OCHH, J 10.7 and 7.1 Hz), 3.94 (dq, 1H, OCHH, J 10.7 and 7.1 Hz),
4.56 (d, 1H, H-4, J 10.4 Hz), 4.7–4.9 (br.s, 1H, NHH), 4.87 (dq, 1H, H-2,
J 10.3 and 5.3 Hz), 5.53 (t, 1H, H-3, J 10.3 Hz), 6.96 (td, 1H, H-6, J 7.5
and 1.1 Hz), 6.97 (d, 1H, H-8, J 7.8 Hz), 7.03 (dt, 1H, H-5, J 8.0 and 1.3
Hz), 7.17 (dddd, 1H, H-7, J 8.3, 7.2, 1.7 and 0.9 Hz), 9.0 (br.s, 1H,
NHH). 19F NMR (471 MHz, CDCl3) d: 84.5 (d, CF3, J 5.3 Hz). Found
(%): C, 51.19; H, 4.54; N, 7.58. Calc. for C16H17F3N2O5 (%): C, 51.34;
H, 4.58; N, 7.48.
H
NO2
R'
N
O
+
O
R
Me
OEt
1
2
EtOH
R = Ph, R' = Me
MeCN
room
temperature
Ethyl 2,3-dimethyl-4-phenyl-3,4-dihydrochromeno[3,4-b]pyrrole-1-carb-
oxylate 4. A mixture of 3-nitro-2-phenyl-2H-chromene (0.25 g, 1.0 mmol)
and ethyl b-methylaminocrotonate (0.14 g, 1.0 mmol) in ethanol (2 ml)
was refluxed for 6 h. After that, the mixture was concentrated under
reduced pressure and the remaining oil was purified by flash chromato-
graphy on silica gel (eluent – chloroform). The solid that formed was
recrystallized from dichloromethane–hexane (1:2). Yield 0.17 g (48%),
mp 143–144°C, white powder. IR (KBr, n/cm–1): 1693, 1521, 1496, 1467,
1442, 1414. 1H NMR (400 MHz, CDCl3) d: 1.42 (t, 3H, Me, J 7.1 Hz),
2.52 (s, 3H, Me-2), 3.26 (s, 3H, NMe), 4.37 (dq, 1H, OCHH, J 10.7 and
7.1 Hz), 4.41 (dq, 1H, OCHH, J 10.7 and 7.1 Hz), 6.28 (s, 1H, H-4), 6.77
(dd, 1H, H-6, J 7.8 and 1.4 Hz), 6.92 (td, 1H, H-8, J 7.8 and 1.4 Hz), 6.97
(td, 1H, H-7, J 7.5 and 1.7 Hz), 7.17–7.22 (m, 2H, Ph), 7.24–7.29 (m, 3H,
Ph), 8.14 (dd, 1H, H-9, J 7.5 and 1.7 Hz). Found (%): C, 74.12; H, 5.92;
N, 3.88. Calc. for C22H21NO3·0.5H2O (%): C, 74.14; H, 6.22; N, 3.93.
H
O
R'
N
O
Me
EtO2C
Me
OEt
N
NO2
Me
O
Ph
R
4
tt-3a–h
a R = CF3, R' = H (83%)
b R = CF3, R' = Me (38%)
c R = CF3, R' = Bn (70%)
d R = CCl3, R' = H (58%)
e R = CCl3, R' = Me (76%)
R = CCl3, R' = Bn (73%)
g R = Ph, R' = Me (64%)
h R = Ph, R' = Bn (37%)
f
Scheme 1
© 2013 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2013, 23, 150–152
R'
O(4)
X
NO2
R
C(15)
C(14)
MeCN
C(16)
N(2)
N
OEt
+
C(12)
room
temperature
O
Me
O
O(5)
C(7)
N(1)
C(8)
C(9)
C(11)
1
5
C(4)
C(13)
C(5)
O(2)
O(3)
C(6)
O(1)
X
C(2)
C(1)
C(3)
O
N
O
CO2Et
Me
R'
NO2
R'
NO2
H3O+
F(1)
F(2)
F(3)
C(10)
R
O
R
ct-6a–d
ct-7a–c
Figure 1 Molecular structure of chromane tt-3a (thermal ellipsoids at 50%
probability level).
a R = CF3, R' = H, X = O (79%)
b R = CCl3, R' = Br, X = O (56%)
c R = CCl3, R' = H, X = CH2 (54%)
d R = Ph, R' = H, X = O (63%)
a R = CF3 (44%)
b R = CCl3 (56%)
c R = Ph (82%)
chemistry of compound 3a was ultimately proven by X-ray
diffraction study (Figure 1).‡
Ethyl (2S*,3R*,4S*)-(E)-4-[6-bromo-3-nitro-2-(trichloromethyl)-3,4-di-
hydro-2H-chromen-4-yl]-3-morpholino-2-butenoate 6b. Yield 0.32 g
(56%), mp 209–210°C (decomp.), colourless crystals. IR (KBr, n/cm–1):
1673, 1583, 1556, 1480, 1449, 1400, 1354. 1H NMR (400 MHz, CDCl3)
d: 1.24 (t, 3H, Me, J 7.1 Hz), 2.85 (dd, 1H, H-4'a, J 15.2 and 5.4 Hz), 3.19
[dt, 2H, N(CHH)2, J 12.8 and 4.9 Hz], 3.27 [dt, 2H, N(CHH)2, J 12.8 and
4.8 Hz], 3.36 (dd, 1H, H-4, J 11.6 and 5.4 Hz), 3.73 [t, 4H, O(CH2)2, J
4.8 Hz], 4.06 (dq, 1H, OCHH, J 10.9 and 7.1 Hz), 4.10 (dq, 1H, OCHH,
J 10.9 and 7.1 Hz), 4.31 (br.t, 1H, H-4'b, J 13.4 Hz), 5.08 (s, 1H, H-2'),
5.18 (d, 1H, H-2, J 1.4 Hz), 5.56 (br.s, 1H, H-3), 7.03 (d, 1H, H-8, J 8.8
Hz), 7.28 (d, 1H, H-5, J 2.2 Hz), 7.38 (dd, 1H, H-7, J 8.8 and 2.2 Hz). 1H
NMR (400 MHz, C6D6) d: 1.05 (t, 3H, Me, J 7.1 Hz), 2.21–2.38 [m, 5H,
H-4'a, N(CH2)2], 3.07 [t, 4H, O(CH2)2, J 4.8 Hz], 3.12 (dd, 1H, H-4, J
11.4 and 5.9 Hz), 3.96–4.08 (m, 3H, H-4'b, OCH2), 4.86 (s, 1H, H-2'),
5.43 (d, 1H, H-2, J 1.0 Hz), 5.76 (br.s, 1H, H-3), 6.69 (d, 1H, H-8, J 8.8
Hz), 6.96 (dd, 1H, H-7, J 8.8 and 2.2 Hz), 7.11 (d, 1H, H-5, J 2.2 Hz). Found
(%): C, 41.78; H, 3.74; N, 4.95. Calc. for C20H22BrCl3N2O6 (%): C, 41.95; H,
3.87; N, 4.89.
Scheme 2
Refluxing of 2-phenyl-3-nitro-2H-chromene with methyl
b-methylaminocrotonate in ethanol resulted in chromeno[3,4-b]-
pyrrole 4 in 48% yield,† which agrees with literature data,5 but
the reaction with methyl b-benzylaminocrotonate under the
same conditions ceased at the stage of adduct 3h. In the case of
2-trifluoromethyl- and 2-trichloromethyl-3-nitro-2H-chromenes,
the reaction always gave only adducts 3, irrespective of the solvent,
whereas formation of chromenopyrroles was not observed at all.
It is interesting that on moving from primary and secondary
Z-enamines 2, which are stabilised by an intramolecular hydro-
gen bond, to tertiary E-enamines 5 obtained from ethyl aceto-
acetate and morpholine or piperidine, the reaction with nitro-
chromenes 1 under the same conditions occurred differently to
afford ethyl 3-amino-4-(3-nitrochroman-4-yl)-2-butenoates 6a–d
in 41–79% yields (Scheme 2).† In this case, the reaction site of
enamines 5 was the vinylogous b-Me group, whereas products 6
Synthesis of compounds 7 (general procedure). A mixture of the cor-
responding chromane 6 (1.0 mmol), H2O (1.0 ml), EtOH (4.0 ml) and
concentrated HCl (0.2 ml) was refluxed for 6 h. After cooling, the solid
was separated by filtering, washed with water (2×1 ml), dried and
recrystallized from an appropriate solvent.
are formed as one cis,trans-diastereomer (ct) (3JH-2,H-3 ≈ 3JH-3,H-4
≈
≈ 1.5 Hz) with E-configuration of the double bond. This can be
explained by the E-configuration of enamines 5 and, hence, steric
constraints at the a-C atom. Note that enamines 5 react with
a-(trichloroethylidene)nitroalkanes in a similar way.6 The stereo-
chemistry of product 6b was confirmed by an X-ray diffraction
study (Figure 2).‡ The CF3 group in the 19F NMR spectra of
trifluoromethylated chromanes 3 and 6 in CDCl3 manifests itself
as a doublet at d 84.5 (J 5.2 Hz) and 86.7 (J 6.0 Hz), respectively.
Hydrolysis of esters 6a,c,d on refluxing in 70% ethanol in the
presence of concentrated HCl is accompanied by decarboxyla-
tion to give acetonyl derivatives 7a–c with the same configura-
tion (3JH-2,H-3 ≈ 3JH-3,H-4 ≈ 2.0 Hz). We also obtained compounds
(2S*,3R*,4S*)-1-[3-Nitro-2-(trifluoromethyl)-3,4-dihydro-2H-chromen-
4-yl]acetone 7a. Yield 0.13 g (44%), mp 109–110°C (dichloromethane–
hexane, 1:1), white powder. IR (KBr, n/cm–1): 1719, 1585, 1564, 1490,
1
1375. H NMR (400 MHz, CDCl3) d: 2.23 (s, 3H, Me), 2.80 (dd, 1H,
CHHAc, J 18.8 and 9.7 Hz), 3.05 (dd, 1H, CHHAc, J 18.8 and 3.8 Hz),
3.97 (br.d, 1H, H-4, J 8.8 Hz), 4.52 (qd, 1H, H-2, J 5.9 and 2.2 Hz), 5.16
(t, 1H, H-3, J 2.0 Hz), 7.02 (dd, 1H, H-8, J 8.3 and 1.0 Hz), 7.06 (td, 1H,
H-6, J 7.3 and 1.0 Hz), 7.13 (dd, 1H, H-5, J 7.7 and 1.3 Hz), 7.24 (td, 1H,
H-7, J 7.6 and 1.3 Hz). 19F NMR (376 MHz, CDCl3) d: 87.0 (d, CF3, J
5.9 Hz). Found (%): C, 51.62; H, 4.03; N, 4.49. Calc. for C13H12F3NO4
(%): C, 51.49; H, 3.99; N, 4.62.
‡
X-Ray diffraction data for 3a and 6b.
At 295 K, the crystals of 3a (C16H17F3N2O5) are monoclinic, space
group P21/c, a = 9.5731(11), b = 10.0413(9) and c = 18.4072(12) Å,
b = 92.103(7)°, V = 1768.2(3) Å3, Z = 4, dcalc = 1.406 g cm–3, m = 0.125 mm–1,
F(000) = 776.
At 295 K, the crystals of 6b (C20H22BrCl3N2O6) are monoclinic, space
group P21/n, a = 12.0862(11), b = 12.0044(7) and c = 17.4391(16) Å, b =
= 106.161(8)°, V = 2430.2(3) Å3, Z = 4, dcalc = 1.565 g cm–3, m = 2.059 mm–1,
F(000) = 1160.
Br(1)
C(4)
O(6)
C(17)
C(20)
C(15)
C(5)
N(2)
C(12)
C(13)
C(14)
C(11)
O(2)
C(3)
C(7)
C(10)
C(6)
O(3)
C(18)
C(19)
O(1)
Diffraction data were collected on an Xcalibur 3 automatic single-
C(8)
O(4)
C(2)
crystal diffractometer (graphite-monochromated MoKa radiation, w-scans).
N(1)
O(5)
C(9)
The structures were solved by direct methods and refined by the full-
matrix least-squares method using the SHELX-97 program package.7
The H atoms were located geometrically using the riding model.
CCDC 915041 and 915042 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.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2013.
C(16)
Cl(3)
C(1)
Cl(2)
Cl(1)
Figure 2 Molecular structure of chromane ct-6b (thermal ellipsoids at 50%
probability level).
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Mendeleev Commun., 2013, 23, 150–152
References
O
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(ct + tt)-7a (37%)
Me
Et3N
NO2
+
X3C
CH2Cl2 (tc + tt)-7b (55%)
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OH
20 °C,
6 h
Scheme 3
7a,b in a different way, viz., by tandem condensation of o-hydroxy-
benzylideneacetone with (E)-1-nitro-3,3,3-trifluoro(trichloro)-
propenes (Scheme 3). However, the reaction was less stereoselec-
tive in this case, and chromanes 7a,b were formed as a mixture
of two diastereomers (ct: tt = 80:20 for 7a and tc: tt = 72:28
for 7b).
Thus, the reaction of 2-substituted 3-nitro-2H-chromenes
with push-pull enamines depending on their structure, gives
either trans,trans-3-amino-2-(3-nitrochroman-4-yl)-2-butenoates
or cis,trans-3-amino-4-(3-nitrochroman-4-yl)-2-butenoates. The
polyfunctional products described above can serve for the pre-
paration of more complex heterocyclic compounds, including
those containing CF3 and CCl3 groups.
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This work was carried out in terms of Ural Federal University
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Online Supplementary Materials
Supplementarydataassociatedwiththisarticle(characteristics
of compounds tt-3b–h, ct-6a,c,d and ct-7b,c) can be found in the
online version at doi:10.1016/j.mencom.2013.05.010.
Received: 11th December 2012; Com. 12/4034
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