Interaction of 2-piperazinobenzaldehyde with cyanoacet(thio)amide: Stereoselective cyclization by the "tert-amino effect" mechanism

Full text of DOI:10.1007/s10593-008-0097-2

Chemistry of Heterocyclic Compounds, Vol. 44, No. 6, 2008
LETTERS TO THE EDITOR
INTERACTION OF 2-PIPERAZINOBENZ-
ALDEHYDE WITH CYANOACET(THIO)AMIDE:
STEREOSELECTIVE CYCLIZATION BY
THE "tert-AMINO EFFECT" MECHANISM
T. V. Glukharev, E. P. Klimova, A. Yu. Platonova, and Yu. Yu. Morzherin
Keywords: tert-aminoeffect, Knoevenagel condensation, diastereomers.
In continuing our research on the interaction of 2-dialkylaminobenzaldehydes with unsymmetrical CH-
active compounds we have carried out the reaction of 2-piperazinobenzaldehyde 1 with cyanothioacetamide 2a
and cyanoacetamide 2b. It was shown that the reaction of 2-piperazinobenzaldehyde 1 with cyanothioacetamide
2a in butanol for 2 h the product of tandem reactions [2], the Knoevenagel condensation and cyclization by the
"tert-amino effect" mechanism [3-6], 2,3,4,41,5,6-hexahydro-1H-pyrazin[1,2-a]quinoline 3 was formed, while
reaction of benzaldehyde 1 with cyanoacetamide 2b stopped at the stage of formation of the Knoevenagel
CHO
for Х = S – toluene,
for Х = О – butanol
NC
CXNH2
2a,b
+
N
N
X
10
N
1
2
1
NH2
OMe
5
4
3
6
7
H
11
butanol
Х = S
9
12
N
8
14
13
N
15
16
N
10
S
4a,b
butanol
17
NH2
4a
OMe
1
3
2
15
14
12
5
7
17
OMe
11
4
N
N
6
13
16
9
18
19
8
a X = S, b X = O
3
__________________________________________________________________________________________
Ural State Technical University-UPI, Ekaterinburg 620002, Russia; e-mail: morzherin@mail.ustu.ru.
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, 942-944, June, 2008. Original article
submitted April 8, 2008.
0009-3122/08/4406-0759©2008 Springer Science+Business Media, Inc.
759

condensation product 4b which did not cyclize on prolonged heating. When the reaction of 2-pipera-
zinobenzaldehyde 1 with cyanothioacetamide 2a was carried out in toluene the vinyl derivative 4a was isolated,
which on heating in butanol cyclized to the pyrazinoquinoline 3. The starting materials were recovered when the
benzaldehyde 1 was boiled with cyanoacetamide 2b in toluene.
It should be noted that compound 4a contains two asymmetric centers, consequently it is possible to
form two diastereoisomers. It was shown that the reaction occurs stereospecifically and leads predominantly to a
single diastereomer in 95-98% yield. The proton in position 11 (see scheme) is axial, which is confirmed by its
1
coupling constant in the H NMR spectrum (J =14.5 Hz). In the 13C NMR spectrum the signal of the carbon
atom of the thiocarbamide group occurs at 199.88 ppm in the form of a triplet (J ~ 7.7 Hz, coupling with two
axial protons), which indicates its axial position.
Thus we have shown that cyclization of the thioamide 4a leads selectively to the (4aR*,5R*)-isomer 3,
whereas under analogous conditions the amide 4b does not cyclize at all: a Lewis acid catalyst [7] is necessary
for cyclization.
1H and 13C NMR spectra of DMSO-d6 solutions with TMS as internal standard were recorded on a
Bruker DRX instrument (400 and 100 MHz respectively).
(4aR*,5R*)-5-Cyano-3-(4-methoxyphenyl)-2,3,4,4a,5,6-hexahydro-1H-pyrazin[1,2-a]quinoline-
5-carbothioamide (3). Yield 69%; mp 193°C. 1H NMR spectrum, δ, ppm (J, Hz): 10.41 (1H, s, NH); 9.39 (1H,
s, NH); 7.17 (1H, dd, J = 8.2, 8.3, ArH); 7.11 (1H, d, J = 8.3, ArH); 7.08 (1H, d, J = 7.8, ArH); 6.91 and 6.88
(4H, AB, J = 9.2, C6H4); 6.78 (1H, dd, J = 7.8, J = 8.2, ArH); 4.09 (1H, ddd, J = 11.2, J = 2.6, J = 2.1, H-18e);
3.71 (1H, d, J = 16.4, H-3e); 3.70 (3H, s, CH3); 3.69 (1H, dd, J = 11.0, J = 3.0, H-12e); 3.64 (1H, dd, J = 10.8,
J = 3.0, H-11a); 3.54 (1H, ddd, J = 11.8, J = 3.0, J = 2.1, H-19e); 3.20 (1H, d, J =16.4, H-3a); 2.91 (1H, ddd,
J = 11.9, J = 11.5, J = 3.0, H-18a); 2.80 (1H, ddd, J = 11.9, J = 11.8, J = 2.6, H-19a); 2.64 (1H, dd, J =11.0,
J = 10.8, H-12a). 13C NMR spectrum, δ, ppm: 199-88 (C-1); 153.77 (C-16); 144.55 (C-13); 144.04 (C-9);
129.15 (C-7); 127.85 (C-9); 119.04 (C-6); 118.68 (C-10); 118.26 (C-15); 117.98 (C-4); 114.51 (C-14); 113.44
(C-8); 58.44 (C-11); 55.20 (C-16); 53.90 (C-2); 52.00 (C-18); 50.13 (C-12); 46.12 (C-19); 38.54 (C-3). Found,
%: C 66.81; H 5.92; N 14.99. C21H22N4OS. Calculated, %: C 66.64; H 5.86; N 14.80.
2-Cyano-3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)thioacrylamide (4a). Yield 81%; mp
1
186°C. H NMR spectrum, δ, ppm (J, Hz): 10.12 (1H, s, NH); 9.49 (1H, s, NH); 8.49 (1H, s, CH=); 7.93 (1H,
dd, J = 7.6, J =1.5, ArH); 7.57 (1H, ddd, J = 8.5, J = 8.3, J = 1.5, ArH); 7.24 (1H, d, J = 8.3, ArH); 7.21 (1H, dd,
J =7.6, J = 6.5, ArH); 6.95 (2H, d, J = 9.1, C6H4); 6.85 (2H, d, J = 9.1, C6H4); 3.70 (3H, s, CH3); 3.20-3.25 (4H,
m, 2NCH2); 3.06-3.10 (4H, m, 2NCH2). 13C NMR spectrum, δ, ppm: 191.93 (C-1); 153.44 (C-16); 153.06 (C-9);
147.89 (C-3); 145.11 (C-13); 133.13 (C-5); 128.99 (C-7); 125.26 (C-4); 122.53 (C-6); 118.90 (C-8); 117.43
(C-15); 116.14 (C-10); 114.29 (C-14); 111.58 (C-2); 55.17 (C-17); 52.88 (C-11); 49.84 (C-12). Found, %:
C 76.21; H 8.03; N 7.55. C12H15NO. Calculated, %: C 76.16; H 7.99; N 7.40.
2-Cyano-3-(2-(4-(4-methoxyphenyl)piperazin-1-yl)phenyl)acrylamide (4b). Yield 86%; mp 210°C.
1H NMR spectrum, δ, ppm (J, Hz): 8.35 (1H,s, CH=); 7.91 (1H, dd, J = 7.9, J = 1.3, ArH); 7.90 (1H, s, NH);
7.72 (1H, s, NH), 7.56 ddd, J = 8.5, J = 7.5, J = 1.3, ArH), 7.25 (1H, d, J = 7.5, ArH), 7.22 (1H, dd, J = 7.3,
J = 8.5, ArH); 6.95 (2H, d, J = 9.1, C6H4); 6.84 (2H, d, J = 9.1, C6H4); 3.70 (3H, s, CH3); 3.18-3.22 (4H, m,
2NCH2); 3.05-3.10 (4H, m, 2NCH2). Found, %: C 76.21; H 8.03; N 7.55. C12H15NO. Calculated, %: C 76.16;
H 7.99; N 7.40.
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