Reactions of 2-aryl-1,1-dicyanoethenes with L-proline and aldehydes

Article abstract of DOI:10.1134/S1070428010050131

Three-component heterocyclization of 2-aryl-1,1-dicyanoethenes with L-proline and aldehydes leads to the formation of 1-aryltetrahydro-1H- pyrrolysines that under acid (alkaline) hydrolysis conditions are converted into derivatives of 6-carboxy-7-phenyl-2

Full text of DOI:10.1134/S1070428010050131

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2010, Vol. 46, No. 5, pp. 674−677. © Pleiades Publishing, Ltd., 2010.
Original Russian Text © S.B. Nosachev, O.Yu. Poddubnyi, A.V. Velikorodov, A.G. Tyrkov, 2010, published in Zhurnal Organicheskoi Khimii, 2010,
Vol. 46, No. 5, pp. 683−686.
Reactions of 2-Aryl-1,1-dicyanoethenes with L-Proline
andAldehydes
S. B. Nosachev, O. Yu. Poddubnyi,A. V. Velikorodov, andA. G. Tyrkov
Astrakhan’ State University, Astrakhan, 414000 Russia
e-mail: tyrkov@rambler.ru
Received November 17, 2009
Abstract—Three-component heterocyclization of 2-aryl-1,1-dicyanoethenes with L-proline and aldehydes leads
to the formation of 1-aryltetrahydro-1H-pyrrolysines that under acid (alkaline) hydrolysis conditions are converted
into derivatives of 6-carboxy-7-phenyl-2,3,5,7a- or 1,3-diaryl-2-carboxy-5,6,7,7a-tetrahydro-1H-pyrrolysine.
DOI: 10.1134/S1070428010050131
The development of preparation methods for aza-
heterocyclic systems, of introduction and transformation
of substituents is an urgent problem of the modern organic
chemistry. The 1,3-dipolar cycloaddition remains the most
important route to five-membered heterocyclic com-
pounds, for instance, to pyrrolines and pyrrolidines [1–
3] convenient for the synthesis of the libraries of peptido-
mimetics [4–6], biologically active substances.
cyclization of ethenes Ia–Id with L-proline (II) and
aldehydes IIIa–IIId proceeded at heating in dry toluene
and afforded in moderate yields previously unknown
pyrrolysine derivatives, substituted 1-aryl-tetrahydro-1H-
pyrrolysine-2,2(3H)-dicarbonitriles IVa–IVd.
It is presumable that under heating the paraform-
aldehyde (IIIa) or aromatic aldehydes IIIb–IIId with
L-proline (II) generate the corresponding azomethine
ylides A [7]. The latter by 1,3-dipolar cycloaddition to the
molecules of dipolarophiles Ia–Id are stabilized as sub-
stituted 1H-pyrrolysines IVa–IVd. The passive behavior
of the cyano group of compounds Ia–Id in this process
shows the regioselective character of the reaction in
question.
The treatment of N-substituted α-amino acids with
arenecarbaldehydes is known to result in highly reactive
azomethine ylides that in reaction with quinones are
stabilized as 1-aryl-2H-isoindole-4,7-diones [7].
In order to estimate the range of applicability of this
reaction we extended it to a new type of dipolarophile,
2-phenyl-1,1-dicyanoethene (Ia), and also to its analogs,
2-(4-chlorophenyl)- (Ib), 2-(4-methoxyphenyl)- (Ic), and
2-(4-dimethylaminophenyl)-1,1-dicyanoethenes (Id).
The structure of pyrrolysines IVa–IVd was established
1
from IR, H, 13C NMR, and mass spectra, and the
composition, from elemental analyses. The IR spectra of
cycloadducts contain absorption bands of the stretching
We established that the three-component hetero-
Scheme 1.
Ar
CN
CN
Ar
_
Δ, PhMe
RCOH
+
Iа_г
+
CO2H
+
_CO2, H2O
N
N
H
II
R
N
+CHR
NC
CN
Iа_Id
IVа_IVd
IIIа_IIId
A
Ar = Ph (Ia, IVa), 4-ClC6H4 (Ib, IVb), 4-MeOC6H4 (Ic, IVc), 4-Me2C6H4 (Id, IVd); R = H (IIIa, IVa), 3-PhOC6H4 (IIIb, IVb), 2,4-
Cl2C6H3 (IIIc, IVc), 3,4-(MeO)2C6H3 (IIId, IVd).
674

REACTIONS OF 2-ARYL-1,1-DICYANOETHENES
675
vibrations of the cyano groups shifted to the longwave
region (2245–2247 cm–1) compared with their position
in initial gem-dicyanoethenes Ia–Id (2209 cm–1) and with
lower intensity presumably because of increased spatial
hydroxide. The boiling of pyrrolysines IVa–IVc with
concn. HCl for 10 h gave ambiguous result: The obtained
products were 6-carboxy-7-phenyl-2,3,5,7a-tetrahydro-
1H-pyrrolysine (Va) or 1,3-diaryl-2-carboxy-5,6,7,7a-
tetrahydro-1H-pyrrolysines Vb and Vc. The direction of
the hydrolysis was defined apparently by the formation
of structures with the most efficient conjugation.
1
hindrances in the pyrrolysines. H NMR spectra of
compounds IVa–IVd are consistent with the assumed
structures and are analogous to the spectra of model
compounds with the similar structure [8]. In the spectra
alongside the multiplets of protons of the aryl rings the
signals are observed from the protons of the pyrrolysine
cycle in the region 2.81–4.05 ppm, and the upfield signals
in the region 1.41–3.19 ppm are assigned to six protons
of the proline ring. The 13C NMR spectra besides the
peaks from the carbon atoms of the benzene ring contain
the peaks of the carbon atoms of the pyrrolysine ring in
the range 40–74 ppm, and the signals of the carbon atoms
belonging to proline ring in the region 22–53 ppm.
It is presumable that the process involves either HCN
elimination or the hydrolysis of the cyano to the carboxy
group in the presence of the hydrochloric acid. The
subsequent treatment of pyrrolysines Va–Vc with
alcoholic solution of potassium hydroxide at room
temperature provided the corresponding potassium salts
VIa–VIc. Similarly compounds IVa–IVd reacted with
the alcoholic solution of KOH (boiling for 10 h). The
structure of compounds Va–Vc was established from the
1
IR and H NMR spectra, and the composition of salts
VIa–VIc was proved by elemental analysis.
The mass spectra of obtained products contain
molecular ion peaks, and fragment ions formed by
dissociative ionization by the type of retro-1,3-dipolar
cycloaddition occurring with the rupture of C1–C7a and
C2–C3 bonds of the heterocycle. Fragment peaks of low
intensity result from the rupture of the pyrrolysine ring at
the bonds C1–C2 and C3–N4, and also peaks are present
from the products of decomposition by “benzyl type” of
[C7H7]+. Besides the pyrrolysines mass spectra contain
additionally peaks of ions, which can be described by
several empirical formulas, and that complicates a more
detailed interpretation of the spectra.
Thus the three-component heterocyclization that we
investigated made it possible to obtain previously unknown
pyrrolysines which might be regarded as adducts
promising for further functionalization.
EXPERIMENTAL
IR spectra were recorded on a spectrophotometer
IKS-29 in chloroform solutions of concentration 40 mg/ml,
cell thickness l 0.1 mm. 1H NMR spectra were registered
on a spectrometer DRX500 SF (500 MHz) in DMSO-d6,
internal reference HMDS. 13C NMR spectra were taken
on a spectrometer Tesla BS-567A (25 MHz) in acetone-
d6, internal reference HMDS. Mass spectra were
measured on a Finnigan SSQ-7000 instrument in a direct
The presence of a cyano group in pyrrolysines IVa–
IVd suggested the study of their behavior with respect
to hydrochloric acid and alcoholic solution of potassium
Scheme 2.
Ph
CO2H
Ph
CO_2 K+
KON
EtOH
Δ, HCl
H2O
IVa
N
N
Va
VIa
Ar
CO2H
R
Ar
CO_2 K+
R
KON
EtOH
Δ, HCl
H2O
IVb, IVc
N
N
Vb, Vc
Ar = 4-ClC6H4 (b), 4-MeOC6H4 (c), R = 3-PhOC6H4 (b), 2,4-Cl2C6H3 (c).
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 5 2010
VIb, VIc

NOSACHEV et al.
676
(IVc). Yield 3.543 g (86%), mp 142–143°C. IR spectrum,
ν, cm–1: 2247, 2245 (C≡N). 1H NMR spectrum, δ, ppm:
1.75–2.08 m (4H, C6H2, C7H2), 2.92 d (1H, H1), 3.18 t
(2H, C5H2), 3.45 s (1H, H3), 3.78 s (3H, CH3O), 3.98 q
(1H, H7a), 6.90–7.52 m (4Harom, C6H4), 7.30–7.76 m
(3Harom, C6H3). 13C NMR spectrum, δ, ppm: 43.82 (C2),
46.51 (C1), 22.62–53.40 (C5–7), 55.88 (CH3O), 61.19
(C3), 74.93 (C7a), 120.68, 122.60 (CN), 112.16–151.85
(Carom). Mass spectrum, m/z (Irel, %): 411 (36) [M]+, 227
(25), 121 (42), 107 (23). Found, %: C 63.92; H 4.42;
N 10.03. C22H19Cl2N3O. Calculated, %: C 64.08; H 4.61;
N 10.19. M 412.34.
admission mode, ionizing electrons energy 70 eV,
evaporation of samples at 90–150°C. The reaction
progress was monitored and the homogeneity of com-
pounds obtained was checked by TLC on Silufol UV-
254 plates, eluent acetone–hexane, 2:3, development in
iodine vapor.
2-Aryl-1,1-dicyanoethenes Ia–Id were obtained by
the condensation of malonodinitrile with substituted
aromatic aldehydes in ethanol in the presence of catalytic
amounts of piperidine [9].
1-Aryltetrahydro-1H-pyrrolysine-2,2(3H)-di-
carbonitriles IVa–IVd. To a dispersion of 10 mmol of
compound Ia–Id in 100 ml of dry toluene was added
10 mmol of L-proline (II) and 10 mmol of aldehyde IIIa–
IIId. The reaction mixture was boiled at reflux for 17 h
collecting water in a Dean-Stark trap. After the end of
water liberation the solvent was evaporated in a vacuum,
the residue was extracted with 25 ml of ethyl ether, the
insoluble residue was subjected to descending
chromatography on glass column filled with activated
silica gel Silicagel 100/400 m, eluent chloroform.
3-(3,4-Dimethoxyphenyl)-1-[4-(dimethylamino)-
phenyl]tetrahydro-1H-pyrrolysine-2,2(3H)di-
carbonitrile (IVd). Yield 3.702 g (89%), mp 168–170°C.
1
IR spectrum, ν, cm–1: 2247, 2245 (C≡N). H NMR
spectrum, δ, ppm: 1.42–2.07 m (4H, C6H2, C7H2), 2.43 s
(6H, 2CH3), 2.91 d (1H, H1), 3.19 t (2H, C5H2), 3.46 s
(1H, H3), 3.77, 3.80 s (3H, CH3O), 3.99 q (1H, H7a),
6.87–7.04 m (3Harom, C6H3), 7.37–7.65 m (4Harom, C6H4).
13C NMR spectrum, δ, ppm: 38.72 (CH3N), 44.45 (C2),
46.58 (C1), 22.60-53.98 (C5–7), 55.88, 55.92 (CH3O),
65.41 (C3), 74.95 (C7a), 120.15, 122.63 (CN), 111.20–
151.76 (Carom). Mass spectrum, m/z (Irel, %): 416 (9) [M]+,
347 (5), 219 (100), 204 (22), 164 (27), 93 (27). Found, %:
C 71.82; H 6.51; N 13.27. C25H28N4O2. Calculated, %:
C 64.08; H 4.61; N 10.19. M 416.57.
1-Phenyltetrahydro-1H-pyrrolysine-2,2(3H)di-
carbonitrile (IVa). Yield 1.967 g (83%), mp 176–177°C.
1
IR spectrum, ν, cm–1: 2247, 2245 m (C≡N). H NMR
spectrum, δ, ppm: 1.73–2.02 m (4H, C6H2,C7H2), 2.91 d
(1H, H1), 3.20 t (2H, C5H2), 3.53 s (2H, C3H2), 3.94 q
(1H, H7a), 7.32–7.67 m (5Harom). 13C NMR spectrum, δ,
ppm: 40.17 (C2), 46.21 (C1), 26.42–52.55 (C5–7), 60.63
(C3), 74.56 (C7a), 114.95, 116.81 (CN), 127.52–135.03
(Carom). Mass spectrum, m/z (Irel, %): 237 (31) [M]+, 236
(4) [M –1]+, 154 (8), 91 (29), 84 (100), 77 (44). Found,
%: C 75.78; H 6.12; N 17.56. C15H15N3. Calculated, %:
C 75.95; H 6.33; N 17.72. M 237.33.
Hydrolysis of 1-aryltetrahydro-1H-pyrrolysine-
2,2(3H)-dicarbonitriles IVa–IVc.Asolution of 5 mmol
of compounds IVa–IVc in 50 ml of concn. HCl was boiled
for 10 h. The solvent was evaporated, the residue was
subjected to chromatography as described above, eluent
chloroform.
6-Carboxy-7-phenyl-2,3,5,7a-tetrahydro-1H-pyr-
rolysine (Va). Yield 0.604 g (57%), mp 105–107°C. IR
spectrum, ν, cm–1: 3540 br (OH), 1730 s (C=O). 1H NMR
spectrum, δ, ppm: 1.75–2.04 m (4H, C1H2, C2H2), 3.25 t
(2H, C3H2), 3.91 s (2H, C5H2), 4.06 t (1H, H7a), 7.72 m
(5Harom), 13.85 s (OH). Found, %: C 73.19; H 6.37; N 5.97.
C14H15NO2. Calculated, %: C 73.36; H 6.55; N 6.11.
2-Carboxy-3-(3-phenoxyphenyl)-1-(4-chloro-
phenyl)-5,6,7,7a-tetrahydro-1H-pyrrolysine (Vb).
Yield 1.382 g (64%), mp 110–113°C. IR spectrum, ν, cm–1:
3540 br (OH), 1730 s (C=O). 1H NMR spectrum, δ, ppm:
1.71–2.03 m (4H, C6H2, C7H2), 3.05 d (1H, H1), 3.26 t
(2H, C5H2), 4.05 q (1H, H7a), 7.10–7.55 m (9Harom),
7.36–7.78 m (4Harom), 13.85 s (OH). Found, %: C 72.13;
H 4.96; N 3.08. C26H22ClNO3. Calculated, %: C 72.31;
H 5.10; N 3.24.
1-(4-Chlorophenyl)-3-(3-phenoxyphenyl)-
tetrahydro-1H-pyrrolysine-2,2(3H)-dicarbonitrile
(IVb). Yield 3.424 g (78%), mp 128–130°C. IR spectrum,
1
ν, cm–1: 2247, 2245 m (C≡N). H NMR spectrum, δ,
ppm: 1.76–2.06 m (4H, C6H2, C7H2), 2.95 d (1H, H1),
3.17 t (2H, C5H2), 3.46 s (1H, H3), 3.96 q (1H, H7a),
7.35–7.54 m (9Harom), 7.35–7.72 m (4Harom). 13C NMR
spectrum, δ, ppm: 41.45 (C2), 46.58 (C1), 25.62–53.98
(C5–7), 65.41 (C3), 74.95 (C7a), 115.68, 117.32 (CN),
118.94–137.95 (Carom). Mass spectrum, m/z (Irel, %): 439
(28) [M]+, 188 (12), 125 (35), 93 (57), 84 (100). Found,
%: C 73.56; H 4.82; N 2.38. C27H22ClN3O. Calculated,
%: C 73.72; H 5.01; N 9.56. M 439.97.
3-(2,4-Dichlorophenyl)-1-(4-methoxyphenyl)-
tetrahydro-1H-pyrrolysine-2,2(3H)-dicarbonitrile
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 5 2010

REACTIONS OF 2-ARYL-1,1-DICYANOETHENES
677
(5 mmol) of 3-(3,4-dimethoxyphenyl)-1-[4-(dimethyl-
amino)phenyl]tetrahydro-1H-pyrrolysine-2,2(3H)-di-
carbonitrile (IVd) with 50 ml of 1 M solution of potassium
hydroxide in ethanol was boiled for 10 h. The solvent
was evaporated, the residue was subjected to
chromatography, eluent acetone. Yield 1.365 g (65%), t.
decomp. 215–217°C. Found, %: N 6.08. C24H27KN2O4.
Calculated, %: N 6.28.
2-Carboxy-1-(4-methoxyphenyl)-3-(2,4-dichloro-
phenyl)-5,6,7,7a-tetrahydro-1H-pyrrolysine (Vc).
Yield 1.414 g (70%), mp 120–122°C. IR spectrum, ν,
cm–1: 3540 br (OH), 1730 s (C=O). 1H NMR spectrum,
δ, ppm: 1.70–2.03 m (4H, C6H2, C7H2), 3.09 d (1H, H1),
3.28 t (2H, C5H2), 3.78 s (3H, CH3O), 4.03 q (1H, H7a),
6.95–7.53 m (4Harom, C6H4), 7.32-7.75 m (3Harom, C6H3),
13.85 s (OH). Found, %: C 62.21; H 4.55; N 3.30.
C21H19Cl2NO3. Calculated, %: C 62.38; H 4.70; N 3.47.
REFERENCES
Potassium salts of 6-carboxy-2,3,5,7a- or 2-
carboxy-5,6,7,7a-tetrahydro-1H-pyrrolysines VIa–
VIc. To a solution of 5 mmol of pyrrolysines Va–Vc in a
minimum volume of ethanol at 25°C was poured an
alcoholic solution of potassium hydroxide till pH 9, the
mixture was kept for 10 min, cooled to 0°C, the precipitate
was filtered off and recrystallized from ethanol.
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Trost, B.M. and Eleming, J., Eds., Oxford: Pergamon, Press,
1991, p. 252.
3. Tsude, O. and Kanemasa, S., Adv. Heterocycl. Chem.,
1989, vol. 45, p. 231.
4. Boger, D.L., Tetrahedron, 1983, vol. 39, p. 2869.
5. Feng, Z. and Lubell, W.D., J. Org. Chem., 2001, vol. 66,
p. 1181.
6-Carboxy-7-phenyl-2,3,5,7a-tetrahydro-1H-pyr-
rolysine potassium salt (VIa). Yield 1.165 g (91%), t.
decomp. 253°C. Found, %: N 5.08. C14H14KNO2. Cal-
culated, %: N 5.24.
2-Carboxy-3-(3-phenoxyphenyl)-1-(4-chloro-
phenyl)-5,6,7,7a-tetrahydro-1H-pyrrolysine potas-
sium salt (VIb). Yield 2.160 g (90%), t. decomp. 260°C.
Found, %: N 2.81. C26H21ClKNO3. Calculated, %: N 2.98.
6. Lubell, W.D., J. Org. Chem., 2001, vol. 66, p. 1171.
7. Schubert-Zsilavecz, M., Michelifsch, A., Likussar, W., and
Guster-huber, D., Lieb. Ann., 1993, vol. 2, p. 147.
8. Poddubnyi, O.Yu., Velikorodov,A.V., and Krivosheev, O.O.,
Abstracts of Papers, III Mezhdunar. Nauchn. Konf.
Fundamental’nye i prikladnye problemy polucheniya
novykh materialov (3rd Int. Sci. Conf. on Fundamental and
Applied Problems of Synthesis of New Materials),
Astrakhan, 2009, p. 60.
2-Carboxy-1-(4-methoxyphenyl)-3-(2,4-dichloro-
phenyl)-5,6,7,7a-tetrahydro-1H-pyrrolysine potas-
sium salt (VIc). Yield 2.116 g (92%), t. decomp. 235–
237°C. Found, %: N 3.02. C21H18Cl2KNO3. Calculated,
%: N 3.17.
9. Praktikum po organicheskoi khimii (Workshop on Organic
Chemistry), Potapova, V.M., Ed., Moscow: Mir, 1979, vol. 2,
p. 150.
2-Carboxy-1-(4-dimethylamino-phenyl)-3-(3,4-
dimethoxyphenyl)-5,6,7,7a-tetrahydro-1H-
pyrrolysine potassium salt (VId). A mixture of 2.02 g
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 46 No. 5 2010