[3+3] Cyclization reactions of β-nitroenamines and β-enaminonitriles with α,β-unsaturated carboxylic acid chlorides

Article abstract of DOI:10.1016/j.tet.2008.03.090

New indolizidines, quinolizidines, and octahydro-pyrido[1,2-a]azepines of lactam type were synthesized from 2-nitromethylene-pyrrolidine, -piperidine, and -hexahydroazepine, respectively, by [3+3] cyclizations with α,β-unsaturated carboxylic acid chlorides. In the case of quinolizidines, a double bond migration was observed, and explained in terms of amidity percentage. Cyanomethylene-pyrrolidine gave indolizidines of lactam type, while transformations of 1-cyanomethylene-tetrahydoisoquinoline resulted in lactams as well as ketones, when simple open-chain acid chlorides or cinnamoyl chloride were used, respectively.

Full text of DOI:10.1016/j.tet.2008.03.090

Tetrahedron 64 (2008) 5545–5550
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[3þ3] Cyclization reactions of b-nitroenamines and b-enaminonitriles
with a,b-unsaturated carboxylic acid chlorides
*
´
´
´
´
´
Mihaly V. Pilipecz, Tamas R. Varga, Zoltan Mucsi, Pal Scheiber, Peter Nemes
´
Department of Chemistry, Faculty of Veterinary Science, Szent Istvan University, H-1400 Budapest, PO Box 2, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
New indolizidines, quinolizidines, and octahydro-pyrido[1,2-a]azepines of lactam type were synthesized
from 2-nitromethylene-pyrrolidine, -piperidine, and -hexahydroazepine, respectively, by [3þ3] cycliza-
tions with a,b-unsaturated carboxylic acid chlorides. In the case of quinolizidines, a double bond
migration was observed, and explained in terms of amidity percentage. Cyanomethylene-pyrrolidine
gave indolizidines of lactam type, while transformations of 1-cyanomethylene-tetrahydoisoquinoline
resulted in lactams as well as ketones, when simple open-chain acid chlorides or cinnamoyl chloride
were used, respectively.
Received 20 October 2007
Received in revised form 13 March 2008
Accepted 27 March 2008
Available online 1 April 2008
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
Piperidine, indolizidine, and quinolizidine are common skele-
tons in both natural and synthetic products1,2 that possess a wide
range of biological activities. Accordingly, and because of their
scarce occurrence in exotic organisms, novel strategies for the
synthesis of these N-heterocycles have received considerable at-
tention in the past decades.3 Heterocyclic enamines are versatile
building blocks for the synthesis of various bicyclic and tricyclic
structures bearing a bridgehead nitrogen atom (Fig.1). These highly
reactive compounds include a unique push–pull bonding structure
and readily react with different bis-electrophiles resulting in
substituted indolizidines and quinolizidines. The cyclizations of
easily accessible b-enaminonitriles and b-enaminoesters are well
documented in the literature.4 Their acylations either with acyl
chlorides or esters have been described5 as well. It can be assumed
that replacement of the nitrile group of the enaminonitriles with
another strongly electron withdrawing group such as NO2 will also
provide compounds of high reactivity. Although several nitroen-
amines have been known for a long time, apart from a few re-
actions6 they have not been used in organic synthesis. These
observations prompted us to investigate the acylation reactions of
some b-nitroenamines and b-enaminonitriles.
b-Substituted enamines (1, EWG¼NO2, CN, COOEt) and a,b-
unsaturated carboxylic acid chlorides can theoretically result in
regioisomeric 3,4-dihydro-2-pyridones 2 and 2,3-dihydro-4-pyr-
idones 3 in [3þ3] cyclizations (Scheme 1). Reactions of cyclic b-
enaminoesters with a,b-unsaturated carboxylic acid chlorides 2a–d
published earlier,2 lead to 3,4-dihydro-2-pyridones 3 exclusively.
These transformations were catalyzed by simple tertiary amines,
e.g., pyridine, triethylamine. On the other hand, both regioisomeric
benzoquinolizines have been prepared7 with a,b-unsaturated car-
bonyls from 1-cyanomethylene-tetrahydoisoquinoline (13).
In this paper, we describe the transformations of compounds of
general formula 1, EWG¼NO2, CN with carboxylic acid chlorides.
Using the simple amine catalysts mentioned above, very poor
conversions were unfortunately observed. To find more efficient
catalysts a series of other compounds were tested in model re-
actions between nitroenamine 5 or enaminonitrile 13 and croto-
noyl chloride (2b) at room temperature. The conversion of the
reactants and the degree of side-reaction (e.g., polymerization)
were semi-quantitatively monitored by TLC.
Since the aza-Michael addition can also be catalyzed by Lew-
is-acids,8 our attention turned to ionic compounds showing
mild-to-moderate Lewis-acidic and moderate-to-strong Brønsted/
Lewis-basic properties together. Such catalysts (single or compos-
ite), such as Ca(OH)2, Ba(OH)2, LiBr/Et3N, MgBr2/Et3N, Mg(OCH3)2
or Zr(Oi-Pr)4 are well known in carbonyl chemistry.9 Considering
the conversion, the reaction time, and the work-up procedure,
La(OH)3 and some carbonates MnCO3 (M¼Li, Mg, Ca, Ba) were found
to catalyze our reactions most efficiently, although LiF, LiOAc,
Mg(OAc)2$4H2O also worked well for b-nitroenamines. Since these
ionic compounds are sparingly soluble in acetonitrile, and the
( )n
N
Figure 1.
* Corresponding author. Tel.: þ36 1 4784176; fax: þ36 1 4784268.
E-mail address: nemes.peter@aotk.szie.hu (P. Nemes).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.03.090

5546
M.V. Pilipecz et al. / Tetrahedron 64 (2008) 5545–5550
O
2a: R1 = R2 = H
NH
+ 2a-c
N
O
Cl
R1
NH
+
2b: R1 = CH3, R2 = H
CaCO3 or La(OH)3/MeCN
reflux
R2
2c: R1 = H, R2 = CH3
EWG
O2N
R2
NO2
2d: R1 = C6H5, R2 = H
2e: R1 = 4-CH3OC6H4, R2 = H
R1
EWG = NO2, CN, COOEt
2
1
7
8
N
R1
R2
N
O
N
O
N
O
*
R2
O2N
R2
*
R1
EWG
EWG
O2N
R2
R1
3
O
4
R1
8c, d: R1 = CH3, R2 = H 24%, 23%
8a: R1 = R2 = H
61%
8b: R1 = H, R2 = CH3 28%
Scheme 1.
Scheme 3.
reactions certainly proceed on the surface of the catalysts, they
were employed in 4–6 equimolar amounts. Some other ionic
compounds, like AlF3$3H2O, ZrF4, Ca(OH)2, and LiOH$H2O, and LiBr/
Et3N gave poor yields. It was noteworthy, that neutral, strong ox-
ygen-donor Lewis-bases, such as HMPA or TMU (1,1,3,3-tetrame-
thylurea) efficiently catalyzed the cyclization, providing good-to-
excellent conversions, but due to difficulties in the work-up they
were disregarded.
(2b) the diastereomers 8c and 8d were separated and character-
ized. It might be assumed that they were formed in an isomeriza-
tion process from 8, which could be neither isolated nor detected.
The new position of the double bond in products 8a–d was proven
by their NMR spectra.
The unexpected double bond migration can be interpreted in
terms of amidity values.12 In order to measure the amide bond re-
activity, a general, quick, and simple protocol was recently quanti-
fied for the extent of conjugation, based on the hydrogenation
enthalpy. The parameter obtained was labeled ‘amidity’, analogous
to the terms ‘aromaticity and antiaromaticity’.13–15 On this linear
scale, N,N-dimethylacetamide was denoted as having 100% amidity,
and a 0% amidity was assigned to azaadamantan-2-one.
Amidity values for the structures 8, 8a–d were obtained from
the B3LYP/6-31G(d,p) geometry-optimized structures. While the
supposed product 8 possesses only 72% of amidity, due to the
strongly conjugated amide bond, for 8a,b and 8c,d 81% and 99%
were calculated,16–18 respectively, showing their favored formation.
The lower amidity of 8a,b can be attributed to its twisted, therefore
strained conformation, which hinders the delocalization. The high
amidity value of 8c,d reflects their very stable, completely planar
amide bond.
With cinnamoyl chloride (2d) no isolable product was formed.
The reaction of 2-nitromethylene-azepine4a (9) with acryloyl
chloride (2a) without catalyst gave the isomeric pyrido[1,2-a]aze-
pine derivatives 10a and 10b differing in the position of the double
bond (Scheme 4). Using other unsaturated acid chlorides (2b–d)
2.1. Reactions of nitroenamines with a,b-unsaturated
carbonyl chlorides
The reaction of 2-nitromethylene-pyrrolidine10 (5) with differ-
ent acid chlorides resulted in various indolizidine derivatives 6a–c
(Scheme 2). In the case of acryloyl chloride the reaction took place
even at room temperature without any catalyst, giving 6a in good
yield. The reactions with crotonoyl (2b) and methacryloyl chlorides
(2c) proceeded in refluxing acetonitrile, in the presence of CaCO3 or
La(OH)3 catalyst. In the transformation with methacryloyl chloride,
the non-cyclized by-product 6d was also isolated (6c/6d¼3:1).
Using cinnamoyl chloride (2d) no cyclized product was formed, and
the amide 6e was obtained. The acylation was accompanied by the
isomerization of the nitromethylene moiety, indicated by the sig-
nificant downfield shift of H-3 of 5 (from 2.70 to 3.35 ppm).
Quinolizidine derivatives were produced when 2-nitro-
methylene piperidine11 (7) was subjected to reactions with acid
chlorides. Acryloyl chloride (2a) and methacryloyl chloride (2c)
gave 8a and 8b, respectively (Scheme 3). Using crotonoyl chloride
+ 2d
1
N
2
3
CaCO3 or La(OH)3/MeCN
reflux
O
O2N
NH
6e 19%
NO2
5
CH2
CH3
+ 2a-c
N
O
N
+
CaCO3 or La(OH)3/MeCN
reflux
O2N
R2
O
O2N
R1
6a: R1 = R2 = H
56%
6d: 12%
6b: R1 = CH3, R2 = H 21%
6c: R1 = H, R2 = CH3 36%
Scheme 2.

M.V. Pilipecz et al. / Tetrahedron 64 (2008) 5545–5550
5547
H3CO
H3CO
+ 2d
+ 2a
NH
La(OH)3/MeCN
rt
N
O
Ph
N
O
N
O
CaCO3 or La(OH)3/MeCN
reflux
+
H3CO
H3CO
NO2
NC
14d 55%
H3CO
H3CO
O2N
10a: 25%
Scheme 4.
O2N
10b: 37%
NH
CN
9
13
+ 2a-c
La(OH)3/MeCN
rt
N
O
the reactions did not result in cyclized or other identifiable prod-
ucts displaying the moderate reactivity of 9 to a,b-unsaturated
carbonyl chlorides.
NC
R2
R1
14a: R1 = R2 = H
73%
14b: R1 = CH3, R2 = H 57%
14c: R1 = H, R2 = CH3 58%
2.2. Reactions of enaminonitriles with a,b-unsaturated acid
chlorides
Scheme 6.
b-Enaminonitriles 11 and 13 were also tested with the acid
chlorides used in the above transformations. Reaction of 11 with
2a–c gave the expected cyclic compounds 12a,b,d and the open-
chain products 12c,e were also isolated (Scheme 5). Using cin-
namoyl chloride (2d), only the non-cyclized product 12f was
formed.
H3CO
H3CO
pyridine
rt, 96 h
OCH3
NH
+
13
2e
NC
In the presence of BaCO3 or La(OH)3 catalyst, the reaction
of b-enaminonitrile 13 with the non-aromatic a,b-unsaturated
carboxylic acid chlorides 2a–c in acetonitrile led to 3,4-dihydro-2-
pyridones 14a–c. On the other hand, in the reaction with cinnamoyl
chloride (2d) the 2,3-dihydro-4-pyridone 14d was produced pre-
dominantly (Scheme 6).
The reaction of b-enaminonitrile 13 with p-methoxycinnamoyl
chloride (2e) in pyridine gave the ketone 15, which did not undergo
ring closure even at reflux temperature. The aza-Michael cycliza-
tion of 15 was effected in boiling methanol with Cs2CO3 catalyst
(Scheme 7) affording 16.
O
15 62%
CsCO3/MeOH
reflux, 24 h
H3CO
H3CO
OCH3
N
O
NC
16 90%
Scheme 7.
3. Conclusion
4. Experimental
4.1. General
In summary, this work demonstrates the synthetic usefulness of
nitroenamines, that are able to undergo regioselective cyclizations
with a,b-unsaturated carboxylic acid chlorides. It was established
that lanthanum(III) hydroxide and some carbonates catalyze these
reactions efficiently. Depending on the ring size of the cyclic
nitroenamines, various new indolizines, quinolizines, and octahy-
dro-pyrido[1,2-a]azepines have been prepared in acceptable to
good yield. The position of the carbon–carbon double bond in these
compounds is determined by the ring strain, expressed in the
amidity percentage quantitatively.
All melting points were measured with a Bu¨chi SMP-20 appa-
ratus and are uncorrected. NMR spectra were recorded with
a Bruker Avance 400 DRX spectrometer (1H: 400 MHz; 13C:
100 MHz). The HRMS analyses were performed with a Waters LCT
Premier XE apparatus. IR spectra were recorded with a Perkin–
Elmer 1600 FT/IR spectrometer. Column chromatography was
conducted with Merck Kieselgel 60 (0.063–0.200 mm). Analytical
+ 2d
N
O
CaCO3 or La(OH)3/MeCN
reflux
NC
NH
CN
12f 29%
R1
11
N
O
+ 2a-c
N
R2
+
CaCO3 or La(OH)3/MeCN
reflux
NC
R2
O
R1
NC
12c: R1 = R2 = H
12a: R1 = R2 = H
78%
36%
12e: R1 = H, R2 = CH3 27%
12b: R1 = CH3, R2 = H 20%
12d: R1 = H, R2 = CH3 24%
Scheme 5.

5548
M.V. Pilipecz et al. / Tetrahedron 64 (2008) 5545–5550
TLC was carried out on precoated plates (Merck silica gel 60, F254).
Solvents were dried and freshly distilled according to the common
practice.
1320, 1240, 1217, 1166 cmꢁ1; dH (DMSO-d6) 1.93 (3H, s), 1.95 (2H, q,
J¼7.6 Hz), 3.32 (2H, t, J¼7.6 Hz), 3.88 (2H, t, J¼7.6 Hz), 5.38 (2H, d,
J¼16.6 Hz), 8.41 (1H, s); d (DMSO-d6) 19.8, 21.9, 33.4, 47.4, 118.9,
C
123.0, 125.0, 156.5, 166.5; HRMS (ESI-TOF) calcd for C9H13N2O3:
4.2. General procedures
197.0926 ([MþH]þ), found: 197.0924 ([MþH]þ).
4.2.1. Method A (for the synthesis of the compounds 6a, 8a, 10a,
10b, 12a)
4.2.3.5. 1-(2-Nitromethylene-pyrrolidin-1-yl)-3-phenyl-propenone
(6e). Purification of the product by column chromatography
(dichloromethane) gave the title compound 6e (147 mg, 19%) as
a white solid, mp 170–172 ꢀC; Rf (dichloromethane) 0.68; nmax (KBr)
Nitroenamine (5, 7, 9) or enaminonitrile (11) (3 mmol) and
acryloyl chloride (CAUTION: Lachrymator!) 2a (3.6 mmol,
1.2 equiv) were stirred in acetonitrile (50 mL) at ambient temper-
ature. After 12 h the mixture was concentrated and the crude oil
was crystallized from EtOAc or purified by column chromatography.
1670, 1618, 1484, 1389, 1300, 1285, 1216, 1190 cmꢁ1; d (DMSO-d6)
H
2.02 (2H, q, J¼7.4 Hz), 3.35 (2H, dt, J¼7.4 Hz), 4.15 (2H, t, J¼7.4 Hz),
7.15 (1H, d, J¼15.4 Hz), 7.44 (2H, m), 7.44 (1H, m), 7.79 (1H, d,
J¼15.4 Hz), 8.63 (1H, s); dC (DMSO-d6) 21.2, 33.2, 51.3, 119.7, 123.3,
129.1, 129.2, 131.0, 134.6, 145.7, 157.9, 166.6; HRMS (ESI-TOF) calcd
for C14H15N2O3: 259.1083 ([MþH]þ), found: 259.1085 ([MþH]þ).
4.2.2. Method B (for the synthesis of the compounds 6b–e,
8b–d, 12b–f)
Nitroenamine (5, 7, 9) or enaminonitrile (11) (3 mmol), calcium
carbonate or lanthanum(III) hydroxide (12 mmol, 4 equiv), and
carboxylic acid chlorides (CAUTION: Lachrymator!) 2b–d
(3.6 mmol,1.2 equiv) were refluxed in acetonitrile (50 mL) for 3–6 h.
The catalyst was filtered, and the solvent was removed in vacuo. The
crude oil was purified by column chromatography.
4.2.3.6. 1-Nitro-3,6,7,8,9,9a-hexahydro-quinolizin-4-one (8a). Re-
crystallization of the crude product (EtOAc) gave 8a (426 mg, 61%)
as a white solid, mp 98–99 ꢀC; Rf (EtOAc) 0.56; nmax (KBr) 2960,
1637, 1548, 1387, 1251, 1206, 1179, 1074, 783 cmꢁ1; d (DMSO-d6)
H
1.76 (2H, m), 2.14 (2H, m), 2.25 (1H, m), 2.25 (1H, m), 2.45 (1H, m),
2.45 (1H, m), 3.30 (1H, ddd, J1¼0.6 Hz, J2¼6.0 Hz, J3¼17.4 Hz), 4.0
(1H, ddd, J1¼0.6 Hz, J2¼6.0 Hz, J3¼17.4 Hz), 5.29 (1H, t, J¼4.0 Hz),
4.2.3. Method C (for the synthesis of the compounds 14a–d)
To the solution of b-enaminonitrile 13 (0.10 g, 0.43 mmol) in
acetonitrile (8 mL) La(OH)3 (0.33 g, 1.74 mmol, 4.05 equiv) and
carboxylic acid chlorides (2a–d) (0.50 mmol, 1.15 equiv) were added.
The reaction mixture was stirred for 1–120 h at room temperature
and monitored by TLC. The catalyst was filtered off, then the solvent
was removed under reduced pressure at 40 ꢀC, and the crude
product was purified by column chromatography or recrystallization.
5.60 (1H, t, J¼1.0 Hz); d (DMSO-d6) 20.8, 22.3, 23.8, 27.7, 39.9, 83.2,
C
113.13, 130.4, 165.5; HRMS (ESI-TOF) calcd for C9H13N2O3: 197.0926
([MþH]þ), found: 197.0924 ([MþH]þ).
4.2.3.7. 3-Methyl-1-nitro-3,6,7,8,9,9a-hexahydro-quinolizin-4-one
(8b). Purification of the product by column chromatography
(diethyl ether) gave the title compound 8b (176 mg, 28%) as a white
solid, mp 70–71 ꢀC; Rf (EtOAc) 0.77; n
(KBr) 2959, 1636, 1549,
max
4.2.3.1. 8-Nitro-2,3,6,7-tetrahydro-1H-indolizin-5-one (6a). Recrys-
tallization of the crude product (EtOAc) gave 6a (306 mg, 56%) as
a white solid, mp 101–102 ꢀC; Rf (EtOAc) 0.67; nmax (KBr) 1688,
1388, 1258, 1187, 1124, 995 cmꢁ1; dH (DMSO-d6) 1.13 (3H, d,
J¼6.6 Hz), 1.75 (2H, m), 2.10 (2H, m), 2.10 (1H, m), 2.25 (1H, m), 2.53
(1H, m), 3.36 (1H, m), 3.93 (1H, m), 5.26 (1H, t, J¼6.2 Hz), 5.62 (1H,
1638, 1487, 1364, 1300, 1256, 1204, 1116 cmꢁ1; d (DMSO-d6) 1.98
dd, J1¼3.2 Hz, J2¼6.2 Hz); d (DMSO-d6) 16.8, 20.9, 22.2, 31.5, 32.0,
H
C
(2H, q, J¼7.6 Hz), 2.65 (2H, t, J¼8.0 Hz), 2.90 (2H, dt, J¼8.0 Hz), 3.32
40.3, 83.4, 113.1, 130.5, 168.7; HRMS (ESI-TOF) calcd for C10H15N2O3:
(2H, t, J¼7.6 Hz), 3.68 (2H t, J¼7.6 Hz); d (DMSO-d6) 20.7; 21.8, 30.4,
211.1083 ([MþH]þ), found: 211.1081 ([MþH]þ).
C
33.8, 42.9, 124.3, 155.4, 169.3; HRMS (ESI-TOF) calcd for C8H11N2O3:
183.0770 ([MþH]þ), found: 183.0765 ([MþH]þ).
4.2.3.8. 2-Methyl-1-nitro-1,2,3,6,7,8-hexahydro-quinolizin-4-one
(8c). Purification of the product by column chromatography
(diethyl ether) gave the title compound 8c (151 mg, 24%) as a white
solid, mp 94–95 ꢀC; Rf (Et2O) 0.60; nmax (KBr) 2962, 1674, 1649,
1545, 1386, 1353, 1255, 1204, 1111 cmꢁ1; dH (DMSO-d6) 1.12 (3H, d,
J¼7.0 Hz), 1.76 (2H, m), 2.12 (2H, m), 2.28 (1H, m), 2.43 (1H, m), 2.71
(1H, m), 3.35 (1H, m), 3.98 (1H, m), 5.28 (1H, t, J¼1.2 Hz), 5.42 (1H,
d, J¼2.8 Hz); dC (DMSO-d6) 17.8, 20.9, 22.4, 29.4, 34.7, 39.4, 88.1,
114.4, 128.8, 164.8; HRMS (ESI-TOF) calcd for C10H15N2O3: 211.1083
([MþH]þ), found: 211.1082 ([MþH]þ).
4.2.3.2. 7-Methyl-8-nitro-2,3,6,7-tetrahydro-1H-indolizin-5-one
(6b). Purification of the product by column chromatography
(EtOAc) gave the title compound 6b (124 mg, 21%) as a colorless oil;
Rf (EtOAc) 0.73; nmax (KBr) 2960, 1700, 1638, 1477, 1385, 1300, 1249,
1196 cmꢁ1; d (DMSO-d6) 1.05 (3H, t, J¼6.8 Hz), 2.00 (2H, q,
H
J¼7.6 Hz), 2.43 (1H, t, J¼13.4 Hz), 2.96 (1H, dd, J¼16.8 Hz), 3.32 (2H,
t, J¼7.6 Hz), 3.71 (2H, t, J¼7.6 Hz); d (DMSO-d6) 18.0, 20.7, 28.2,
C
33.8, 38.2, 47.2, 129.2, 154.6, 168.2; HRMS (ESI-TOF) calcd for
C9H13N2O3: 197.0926 ([MþH]þ), found: 197.0923 ([MþH]þ).
4.2.3.9. 2-Methyl-1-nitro-1,2,3,6,7,8-hexahydro-quinolizin-4-one
(8d). Purification of the product by column chromatography
(diethyl ether) gave the title compound 8d (124 mg, 23%) as a white
4.2.3.3. 6-Methyl-8-nitro-2,3,6,7-tetrahydro-1H-indolizin-5-one
(6c). Purification of the product by column chromatography
(diethyl ether) gave the title compound 6c (212 mg, 36%) as a white
solid, mp 63–65 ꢀC; Rf (Et2O) 0.43; n
(KBr) 2969, 2370, 1638,
max
solid, mp 78–79 ꢀC; Rf (EtOAc) 0.77; n
(KBr) 2970, 2348, 1685,
1544, 1385, 1259, 1204 cmꢁ1; dH (DMSO-d6) 0.98 (3H, d, J¼6.4 Hz),
1.72 (2H, m), 2.11 (2H, m), 2.14 (1H, m), 2.51 (1H, m), 2.51 (1H, m),
3.31 (1H, m), 4.00 (1H, m), 5.29 (1H, t, J¼4.0 Hz), 5.54 (1H, d,
1638, 1445, 1320, 1240, 1217, 1166 cmꢁm1;axd (DMSO-d6) 1.18 (3H, t,
H
J¼6.6 Hz), 1.99 (2H, q, J¼7.6 Hz), 2.60 (1H, dd, J1¼14.8 Hz, J2¼2 Hz),
2.73 (1H, m), 3.11 (1H, dd, J¼6.6 Hz), 3.32 (2H, t, J¼7.6 Hz), 3.69 (2H,
J¼3.4 Hz); d (DMSO-d6) 17.0, 20.8, 22.3, 29.1, 35.0, 39.5, 88.4, 112.1,
C
t, J¼7.6 Hz); d (DMSO-d6) 15.5, 20.8, 29.4, 33.7, 35.0, 47.4, 123.8,
131.0, 165.8; HRMS (ESI-TOF) calcd for C10H15N2O3: 211.1083
C
155.4, 171.4; HRMS (ESI-TOF) calcd for C9H13N2O3: 197.0926
([MþH]þ), found: 211.1081 ([MþH]þ).
([MþH]þ), found: 197.0923 ([MþH]þ).
4.2.3.10. 1-Nitro-2,6,7,8,9,10-hexahydro-3H-pyrido[1,2-a]azepin-4-
one (10a). Purification of the product by column chromatography
(diethyl ether) gave the title compound 10a (158 mg, 25%) as
a yellow oil; Rf (EtOAc) 0.80; nmax (KBr) 2931, 2858,1694, 1621, 1494,
1439, 1298, 1194, 1152 cmꢁ1; dH (DMSO-d6) 1.60 (2H, m), 1.60 (2H,
4.2.3.4. 2-Methyl-1-(2-nitromethylene-pyrrolidin-1-yl)-propenone
(6d). Purification of the product by column chromatography
(diethyl ether) gave the title compound 6d (71 mg, 12%) as a color-
less oil; Rf (EtOAc) 0.60; nmax (KBr) 2970, 2348, 1685, 1638, 1445,

M.V. Pilipecz et al. / Tetrahedron 64 (2008) 5545–5550
5549
m), 1.69 (2H, m), 2.61 (1H, t, J¼8.1 Hz), 2.61 (1H, t, J¼8.1 Hz), 2.90
(1H, t, J¼8.1 Hz), 2.90 (1H, t, J¼8.1 Hz), 3.10 (2H, m), 3.91 (2H, m); dC
(DMSO-d6) 22.2, 26.0, 28.0, 28.0, 28.1, 30.6, 42.1, 130.6, 152.9, 169.3;
HRMS (ESI-TOF) calcd for C10H15N2O3: 211.1083 ([MþH]þ), found:
211.1082 ([MþH]þ).
(DMSO-d6) 1.90 (3H, d, J¼6.2 Hz), 1.94 (2H, q, J¼6.8 Hz), 2.87 (2H,
dt, J1¼1.8 Hz, J2¼7.0 Hz), 3.85 (2H, t, J¼6.8 Hz), 5.27 (1H, s), 5.36 (1H,
q, J¼0.6 Hz), 6.18 (1H, t, J¼1.8 Hz); d (DMSO-d6) 19.6, 21.7, 33.1,
C
53.4, 76.1, 118.0, 119.4, 140.8, 171.7; HRMS (ESI-TOF) calcd for
C
10H13N2O: 177.1028 ([MþH]þ), found: 177.1026 ([MþH]þ).
4.2.3.11. 1-Nitro-6,7,8,9,10,10a-hexahydro-3H-pyrido[1,2-a]azepin-
4-one (10b). Purification of the product by column chromatogra-
phy (diethyl ether) gave the title compound 10b (233 mg, 37%) as
a colorless oil; Rf (EtOAc) 0.61; nmax (KBr) 2958, 2360, 1646, 1544,
1396, 1349, 1329, 1220, 1173 cmꢁ1; dH (DMSO-d6) 1.65 (1H, m), 1.65
(1H, m), 1.70 (2H, m), 2.30 (1H, m), 2.30 (1H, m), 2.35 (2H, m), 2.35
(2H, m), 3.02 (1H, dt, J1¼4.0 Hz, J2¼12.8 Hz), 4.30 (1H, dt, J1¼7.0 Hz,
J2¼12.8 Hz), 5.46 (1H, dd, J1¼6.0 Hz, J2¼6.4 Hz), 5.58 (1H, t,
4.2.3.17. [1-(3-Phenyl-acryloyl)-pyrrolidin-2-ylidene]-acetonitrile
(12f). Purification of the product by column chromatography
(dichloromethane) gave the title compound 12f (207 mg, 29%) as
a white solid, mp 164–165 ꢀC; Rf (dichloromethane) 0.33; nmax (KBr)
3108, 2360, 2197, 1670, 1617, 1396, 1340, 1245 cmꢁ1; dH (DMSO-d6)
1.97 (2H, q, J¼7.0 Hz), 2.87 (2H, dt, J1¼1.4 Hz, J2¼7.0 Hz), 4.10 (2H, t,
J¼7.0 Hz), 6.35 (1H, s), 7.08 (1H, d, J¼15 Hz), 7.43 (2H, m), 7.43 (1H,
m), 7.64 (1H, d, J¼15 Hz), 7.76 (2H, m); dC (DMSO-d6) 21.0, 32.9, 51.7,
75.7, 119.5, 119.7, 128.9, 129.2, 130.8, 134.7, 144.8, 161.4, 166.3; HRMS
(ESI-TOF) calcd for C15H15N2O: 239.1184 ([MþH]þ), found: 239.1186
([MþH]þ).
J¼3.2 Hz); d (DMSO-d6) 24.0, 24.1, 25.8, 26.9, 28.9, 28.1, 45.5, 84.2,
C
121.1, 135.4, 167.7; HRMS (ESI-TOF) calcd for C10H15N2O3: 211.1083
([MþH]þ), found: 211.1083 ([MþH]þ).
4.2.3.12. 5-Oxo-1,2,3,5,6,7-hexahydro-indolizine-8-carbonitrile
(12a). Purification of the product by column chromatography (tert-
butyl methyl ether) gave the title compound 12a (379 mg, 78%) as
a white solid, mp 50–52 ꢀC; Rf (EtOAc) 0.60; nmax (KBr) 2902, 2359,
4.2.3.18. 9,10-Dimethoxy-4-oxo-3,4,6,7-tetrahydro-2H-pyrido[2,1-
a]isoquinoline-1-carbonitrile (14a). Recrystallization from 2-
propanol gave 14a (89 mg, 73%) as a pale yellow solid, mp 151–
152 ꢀC; Rf (EtOAc) 0.57; n
(KBr) 2946, 2192, 1689, 1515, 1374,
max
2201, 1685, 1654, 1387, 1317, 1275 cmꢁ1; d (DMSO-d6) 1.93 (2H, q,
1282, 1131 cmꢁ1; dH 2.69 (4H, s), 2.81 (2H, t, J¼6.0 Hz), 3.85 (2H, t,
H
J¼7.0 Hz), 2.48 (2H, s), 2.48 (2H, s), 2.83 (2H, t, J¼7.0 Hz), 3.62 (2H, t,
J¼6.0 Hz), 3.93 (3H, s), 3.96 (3H, s), 6.70 (1H, s), 7.77 (1H, s); d
C
J¼7.0 Hz); d (DMSO-d6) 20.7, 20.9, 30.1, 30.6, 46.9, 78.2,119.6,156.7,
(CDCl3) 23.1, 28.4, 30.4, 39.2, 55.9, 56.2, 83.0, 110.1, 110.7, 119, 9,
120.8, 130.5, 147.6, 147.9, 151.0, 169.1; HRMS (ESI-TOF) calcd for
C
167.7; HRMS (ESI-TOF) calcd for C9H11N2O: 163.0871 ([MþH]þ),
found: 163.0867 ([MþH]þ).
C
16H17N2O3: 285.1239 ([MþH]þ), found: 285.1242 ([MþH]þ).
4.2.3.13. 7-Methyl-5-oxo-1,2,3,5,6,7-hexahydro-indolizine-8-carbo-
nitrile (12b). Purification of the product by column chromatogra-
phy (diethyl ether) gave the title compound 12b (106 mg, 20%) as
a white solid, mp 118–120 ꢀC; Rf (Et2O) 0.55; nmax (KBr) 2197, 1686,
1646, 1387, 1351, 1319, 1276, 1194 cmꢁ1; dH (DMSO-d6) 1.09 (3H, t,
J¼6.6 Hz), 1.94 (2H, q, J¼7.2 Hz), 2.48 (1H, dd, J1¼6.6 Hz, J2¼8.6 Hz),
2.65 (1H, dd, J1¼8.6 Hz, J2¼16.2 Hz), 2.73 (1H, m), 2.82 (2H, t,
4.2.3.19. 9,10-Dimethoxy-2-methyl-4-oxo-3,4,6,7-tetrahydro-2H-
pyrido[2,1-a]isoquinoline-1-carbonitrile (14b). Purification of the
product by column chromatography (isobutyl acetate) gave the title
compound 14b (73 mg, 57%) as a pale yellow solid, mp 176–177 ꢀC;
Rf (isobutyl acetate) 0.43; nmax (KBr) 2964, 2188, 1682, 1515, 1379,
1285, 1144 cmꢁ1; d (CDCl3) 1.20 (3H, d, J¼6.8 Hz), 2.36 (1H, dd,
H
J1¼7.6 Hz, J2¼7.4 Hz), 2.70 (1H, m), 2.74 (1H, m), 2.77 (2H, t,
J¼6.2 Hz), 3.71 (2H, t, J¼6.2 Hz), 3.80 (3H, s), 3.83 (3H, s), 6.82 (1H,
s), 7.62 (1H, s); dC (CDCl3) 18.5, 28.1, 38.0, 55.9, 89.0, 110.8, 111.2,
120.0, 120.3, 131.3, 147.1, 147.1, 151.0, 168.2; HRMS (ESI-TOF) calcd
for C17H19N2O3: 299.1396 ([MþH]þ), found: 299.1389 ([MþH]þ).
J¼7.2 Hz), 3.62 (2H, t, J¼7.2 Hz); d (DMSO-d6) 19.3, 21.0, 28.0, 30.6,
C
38.2, 46.9, 84.6, 118.9, 156.0, 167.4; HRMS (ESI-TOF) calcd for
C
10H13N2O: 177.1028 ([MþH]þ), found: 177.1025 ([MþH]þ).
4.2.3.14. (1-But-2-enoyl-pyrrolidin-2-ylidene)-acetonitrile (12c). Pu-
rification of the product by column chromatography (diethyl ether)
gave the title compound 12c (190 mg, 36%) as a white solid, mp
108–109 ꢀC; Rf (Et2O); 0.26; nmax (KBr) 2202, 1676, 1633, 1600, 1396,
4.2.3.20. 9,10-Dimethoxy-3-methyl-4-oxo-3,4,6,7-tetrahydro-2H-
pyrido[2,1-a]isoquinoline-1-carbonitrile (14c). Recrystallization
from 2-propanol gave 14c (74 mg, 58%) as a pale yellow solid, mp
168–169 ꢀC; Rf (50% methyl tert-butyl ether/chloroform) 0.60;
nmax (KBr) 2187, 1684, 1600, 1513, 1380, 1250, 1206, 1134 cmꢁ1; dH
(CDCl3) 1.50 (3H, d, J¼6.2 Hz), 2.53 (2H, dd, J1¼5.6 Hz,
J2¼16.0 Hz), 2.63 (1H, m), 2.79 (2H, m), 3.53 (1H, m), 3.78 (3H, s),
1340, 1312, 1246 cmꢁ1; d (DMSO-d6) 1.91 (2H, q, J¼7.6 Hz), 1.91
H
(3H, d, J¼3 Hz), 2.84 (2H, t, J¼7.6 Hz), 3.90 (2H, t, J¼7.6 Hz), 6.26 (1H,
s), 6.41 (1H, d, J¼14,0 Hz), 6.83 (1H, dq, J1¼3.0 Hz, J2¼14.0 Hz); d
C
(DMSO-d6) 18.3, 21.0, 32.9, 51.5, 75.4,119.7,123.8,145.4,161.3,166.1;
HRMS (ESI-TOF) calcd for C10H13N2O: 177.1028 ([MþH]þ), found:
177.1025 ([MþH]þ).
3.80 (1H, m), 3.81 (3H, s), 6.98 (1H, s), 7.66 (1H, s); d (CDCl3)
C
15.3, 28.0, 30.2, 34.0, 40.3, 56.0, 56.1, 82.0, 111.1, 111.3, 119.9, 121.4,
131.6, 147.2, 147.7, 151.1, 172.0; HRMS (ESI-TOF) calcd for
4.2.3.15. 6-Methyl-5-oxo-1,2,3,5,6,7-hexahydro-indolizine-8-carbo-
nitrile (12d). Purification of the product by column chromatogra-
phy (diisopropyl ether/dichloromethane 4:1) gave the title
compound 12d (127 mg, 24%) as a white solid, mp 103–104 ꢀC; Rf
(Et2O) 0.46; nmax (KBr) 2198, 1683, 1656, 1456, 1390, 1328,
1284 cmꢁ1; dH (DMSO-d6) 1.19 (3H,d, J¼6.2 Hz),1.94 (2H, q, J¼7 Hz),
2.25 (1H, m), 2.55 (1H, m), 2.55 (1H, m), 2.83 (2H, t, J¼7 Hz), 3.62
C
17H19N2O: 299.1396 ([MþH]þ), found: 299.1400 ([MþH]þ).
4.2.3.21. 9,10-Dimethoxy-4-oxo-2-phenyl-3,4,6,7-tetrahydro-2H-pyr-
ido[2,1-a]isoquinoline-1-carbonitrile (14d). Recrystallization from
2-propanol gave 14d (85 mg, 55%) as a yellow solid, mp 173–174 ꢀC;
Rf (EtOAc) 0.50; n
(KBr disc) 2189, 1641, 1596, 1555, 1462,
max
1273 cmꢁ1; dH (CDCl3) 2.89–3.06 (3H, m), 3.53 (2H, t, J¼6.2 Hz), 3.96
(2H, t, J¼7.0 Hz); d (DMSO-d6) 15.4, 21.1, 29.5, 30.6, 34.7, 47.1, 77.7,
(2H, m), 3.96 (3H, s), 4.00 (3H, s), 6.75 (1H, s), 7.38 (5H, m), 8.03 (1H,
C
119.5, 155.7, 170.8; HRMS (ESI-TOF) calcd for C10H13N2O: 177.1028
s); d (CDCl3) 27.83, 38.85, 56.02, 56.21, 78.90, 110.10, 110.39, 111.89,
C
([MþH]þ), found: 177.1026 ([MþH]þ).
118.51, 122.81, 124.05, 126.84, 128.26, 128.68, 129.05, 129.83, 131.88,
135.09, 141.32, 147.50, 152.56, 164.11, 187.63; HRMS (ESI-TOF) calcd
for C22H21N2O3: 361.1552 ([MþH]þ), found: 361.1560 ([MþH]þ).
4.2.3.16. [1-(2-Methyl-acryloyl)-pyrrolidin-2-ylidene]-acetonitrile
(12e). Purification of the product by column chromatography
(diisopropyl ether/dichloromethane 4:1) gave the title compound
12e (143 mg, 27%) as a white solid, mp 92–94 ꢀC; Rf (Et2O) 0.67;
nmax (KBr) 3108, 2202, 1668, 1610, 1383, 1343, 1232 cmꢁ1; dH
4.2.3.22. 2-(6,7-Dimethoxy-3,4-dihydro-2H-isoquinolin-1-ylidene)-
5-(4-methoxy-phenyl)-3-oxo-pent-4-enenitrile (15). The solution of
b-enaminonitrile 13 (1.0 g, 4.3 mmol) and 4-methoxycinnamoyl

5550
M.V. Pilipecz et al. / Tetrahedron 64 (2008) 5545–5550
chloride (2e) in pyridine (30 mL) was stirred at ambient tempera-
ture. After 96 h the mixture was concentrated and the crude
product was recrystallized from EtOAc/isopropyl ether to give
a white solid (1040 mg, 62%), mp 197–198 ꢀC; Rf (30% hexane/ac-
References and notes
1. (a) Gilchrist, T. L. Heterocyclic Chemistry; Adison Wesley Longman: Essex, UK,
1997; (b) Daly, J. W.; Spande, T. F.; Garraffo, H. M. J. Nat. Prod. 2005, 68,
1556–1575; (c) Robinson, R. S.; Dovey, M. C.; Gravestock, D. Eur. J. Org. Chem.
2005, 505–511; (d) Nukui, S.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Org.
Chem. 1995, 398–404.
2. Michael, J. P. Nat. Prod. Rep. 2000, 17, 579–602.
3. Tehrani, K. A.; D’hooghe, M.; De Kimpe, N. Tetrahedron 2003, 59, 3099–3108 and
references therein.
4. (a) Cheng, Y.; Huang, Z. T.; Wang, M. X. Curr. Org. Chem. 2004, 8, 325–351
and references therein; (b) Cheng, Y.; Yang, H. B.; Huang, Z. T.; Wang, M. X.
Tetrahedron Lett. 2001, 42, 1757–1759; (c) Mahalanabis, K. K.; Sarkar, M.;
Dutta Chowdhury, S. K.; Dutta-Bose, S. Indian J. Chem. 1998, 37B, 1234–
1238.
etone) 0.68; n
(KBr) 2185, 1593, 1550, 1510, 1435, 1288, 1223,
1169, 832 cmꢁm1;axdH (CDCl3) 2.87 (2H, qv, J¼6.4 Hz), 3.51 (2H, dt,
J1¼7.4 Hz, J2¼3.0 Hz), 3.85 (3H, s), 3.95 (3H, s), 4.00 (3H, s), 6.74 (1H,
s), 6.89 (1H, s), 6.93 (1H, s), 7.40–7.70 (4H, m), 8.02 (1H, s); dc
(CDCl3) 27.9, 38.8, 55.2, 56.0, 56.2, 78.7, 110.4, 111.9, 114.2, 118.6,
121.8, 123.0, 127.8, 129.9, 131.9, 141.1, 147.5, 152.4, 161.1, 164.0, 187.8;
HRMS (ESI-TOF) calcd for C23H22N2O4: 391.1658 ([MþH]þ), found:
391.1664 ([MþH]þ).
´ ´
´
5. Brunerie, P.; Celerier, J. P.; Huche, M.; Lhomet, G. Synthesis 1985, 735–738.
6. (a) Rajappa, S. Tetrahedron 1981, 37, 1453–1480; (b) Efremov, D. A.; Perekalin, V.
V.; Lipina, E. S.; Berestovitskaya, V. M. Nitroalkenes; John Wiley and Sons: New
York, NY, 1994 and references therein.
4.2.3.23. 9,10-Dimethoxy-4-(4-methoxy-phenyl)-2-oxo-3,4,6,7-tet-
rahydro-2H-pyrido[2,1-a]isoquinoline-1-carbonitrile (16). A mixture
of 15 (0.1 g, 0.26 mmol) and Cs2CO3 (0.34 g, 1.4 mmol, 4 equiv) in
methanol (25 mL) was stirred and heated to reflux for 24 h. The
cooled solution was acidified with concd hydrochloric acid (0.2 mL)
and evaporated under reduced pressure at 40 ꢀC. After removal of
cesium chloride the residue was treated with isopropyl ether
yielding 16 (91 mg, 90%) as a pale yellow solid, which was recrys-
7. Nemes, P.; Vincze, Z.; Bala´zs, B.; To´th, G.; Scheiber, P. Synlett 2003, 250–252.
8. Ranu, B. C.; Banerjee, S. Tetrahedron Lett. 2007, 48, 141–143, and references
therein.
9. Handbook of Reagents for Organic Synthesis: Acidic and Basic Reagents; Reich, H. J.,
Rigby, J., Eds.; John Wiley and Sons: New York, NY, 2000 and references
therein.
10. Pilipecz, M. V.; Mucsi, Z.; Nemes, P.; Scheiber, P. Heterocycles 2007, 9, 1919–
1928.
11. Hutchinson, H. I.; Matlin, S. A.; Mete, A. Tetrahedron Lett. 2001, 42, 1773–
1776.
tallized from 2-propanol, mp 221–222 ꢀC; Rf (EtOAc) 0.17; n
max
(KBr) 2196, 1635, 1610, 1586, 1535, 1253 cmꢁ1; dH (CDCl3) 1.12 (1H,
qv, J¼6.2 Hz), 2.71–2.85 (2H, m), 3.15 (1H, dd, J1¼7.4 Hz, J2¼16 Hz),
3.3–365 (2H, m), 3.80 (3H, s), 3.95 (3H, s), 3.99 (3H, s), 4.82 (1H, dd,
J1¼5.6 Hz, J2¼7.2 Hz), 6.72 (1H, s), 6.87 (2H, d, J1¼8.4 Hz), 7.22 (1H,
12. Mucsi, Z.; Tsai, A.; Szori, M.; Chass, G. A.; Viskolcz, B.; Csizmadia, I. G. J. Phys.
Chem. 2007, 111, 13245–13254.
13. Mucsi, Z.; Viskolcz, B.; Csizmadia, I. G. J. Phys. Chem A 2007, 111, 1123–1132.
´
´
14. Mucsi, Z.; Ko¨rtvelyesi, T.; Viskolcz, B.; Csizmadia, I. G.; Novak, T.; Keglevich, G.
Eur. J. Org. Chem. 2007, 1759–1767.
d, J1¼8.4 Hz), 7.94 (1H, s); d (CDCl3) 22.7, 28.6, 42.5, 47.0, 55.3, 56.1,
15. Mucsi, Z.; Keglevich, G. Eur. J. Org. Chem. 2007, 4765–4771.
C
16. Amidities were calculated at B3LYP/6-31G(d,p) level of theory11 using G03
program.
56.3, 62.9, 81.6, 110.0, 112.8, 114.6, 119.0, 127.6, 129.0, 131.1, 147.6,
152.9, 159.8, 160.9, 187.2; HRMS (ESI-TOF) calcd for C23H23N2O4:
391.1658 ([MþH]þ), found: 391.1659 ([MþH]þ).
17. Beke, A. D. J. Chem. Phys. 1993, 98, 5648–5656.
18. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A.; Stratmann, R. E., Jr.;
Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.;
Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.;
Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Mo-
rokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;
Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-
Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. Gaussian 03 6.0; Gaussian: Pittsburgh, PA, 2003.
Acknowledgements
´
´
´
The authors are indebted to Dr. Laszlo Balazs for the HRMS
´
measurements and to Ms. Maria Kuti for her technical assistance.
´
The Ph.D. scholarship from Szent Istvan University to M.V.P. is
gratefully acknowledged.