Conformationally constrained 1,4-DHPs. A convenient route to bis-1,4-DHPs as a novel class of nitrogen compounds

Article abstract of DOI:10.1016/S0040-4020(02)00542-2

2-Formyl-1,4-DHP derivatives 2 undergo the tandem Knoevenagel condensation/amino-nitrile cyclisation with activated methylene reagents to afford high functionalised indolizines. However, in the absence of this tandem, the Knoevenagel condensation intermediate leads to bis-1,4-DHPs as a new class of nitrogen compounds.

Full text of DOI:10.1016/S0040-4020(02)00542-2

TETRAHEDRON
Pergamon
Tetrahedron 58 42002) 5747±5754
Conformationally constrained 1,4-DHPs. A convenient route
to bis-1,4-DHPs as a novel class of nitrogen compounds
a
Stefan Marchalõn, Miloslav Chudõk, Katarõna Cvopova, Jozef Kozõsek, Jan Lesko
a
a
b
c
Ï
Â
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and Adam Daõch
Â
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d,p
È
aDepartment of Organic Chemistry, Faculty of Chemical Technology, Slovak University of Technology,
SK-81237 Bratislava, Slovak Republic
bDepartment of Physical Chemistry and Central Laboratory, Faculty of Chemical Technology, Slovak University of Technology,
SK-81237 Bratislava, Slovak Republic
cCentral Laboratory, Faculty of Chemical Technology, Slovak University of Technology, SK-81237 Bratislava, Slovak Republic
d
 Â
Laboratoire de Chimie de l'Universite du Havre, Faculte des Sciences and Techniques, URCOM, EA 3221,
25 rue Philippe Lebon, B.P: 540, F-76058 Le Havre Cedex, France
Received 10 December 2001; revised 21 January 2002; accepted 5 February 2002
AbstractÐ2-Formyl-1,4-DHP derivatives 2 undergo the tandem Knoevenagel condensation/amino-nitrile cyclisation with activated
methylene reagents to afford high functionalised indolizines. However, in the absence of this tandem, the Knoevenagel condensation
intermediate leads to bis-1,4-DHPs as a new class of nitrogen compounds. q 2002 Elsevier Science Ltd. All rights reserved.
1. Introduction
2. Results and discussion
To begin our study, a series of 2-formyl-1,4-DHP reagents
2a±g with substituents of different bulk at C4 and C5 DHP
positions was easily prepared in a three-step sequence
according to our reported procedure. In fact, this synthetic
scheme starts with condensation of aromatic carboxalde-
hyde with methyl 4,4-dimethoxy-3-oxo-butanoate 1 fol-
lowed by thermal cyclisation in the presence of enamine
derivatives and acidic hydrolysis 4Scheme 1). In all cases
the resulting 2-formyl-1,4-DHP derivatives 2a±g were
solids and isolated in a range of 63±95% yields after
recrystallisation from absolute ethanol.6
As a part of our research program directed towards the
synthesis and the biological evaluation of the 1,4-dihydro-
pyridines 41,4-DHPs) polyheterocycles,1 we have recently
explored the utility of 2-formyl-1,4-DHP derivatives 22,3 as
remarkable synthons for the synthesis of various pyrrolo-
[3,4-b]-1,4-DHPs,3 high functionalised indolizines,2,4
and corresponding dihydroindolizines and tetrahydroindo-
lizines.4 These last compounds 2 are obtained by basic
amino-ester cyclisation,2 thermal amino-ester cyclisation3
or by the tandem Knoevenagel condensation/amino-nitrile
cyclisation in alkaline conditions,4 respectively.
In the ®rst set of our Knoevenagel condensation experi-
ments 4Scheme 1), a 2-formyl-1,4-DHP 2a was subjected
to 1 equiv. of methyl acetoacetate 43a) in acetic acid at
This tandem, which uses 2-formyl-1,4-DHP substrates and
activated methylene reagents in a basic medium, constitutes
a new and competitive methodology to access ef®ciently to
indolizines with different degrees of unsaturation.5 Because
of the exceptional biological potential of theses species
allied with our great interest to develop this chemistry
fully, we decided to investigate, evaluate and compare the
regiocontrol features of this process in acidic conditions.
1
re¯ux for 30 min. The H NMR and GC±MS analysis of
crude reaction products indicated the presence of one single
compound. This compound was then isolated by recrystal-
lisation from ethanol in 65% yield, and its structure was
established as 4a by an array of classical monodimensional
NMR experiments including 1H NMR, 13C NMR and DEPT
program as well as by its elemental analysis and by compar-
ison to related structures described earlier.7 In the same
manner as above, 2-formyl-1,4-DHP 2f with 1 equiv. of
freshly distilled methyl acetoacetate 43a) or benzoylaceto-
nitrile 43b), led to indolizine 4f or 5f as a sole reaction
product in 79 and 88% yields, respectively 4see Table 1).
Keywords: 1,4-DHP; bis-1,4-DHP; tandem; Knoevenagel; indolizine; intra-
molecular cyclisation; [1,3]-hydrogen transfer.
p
Corresponding author. Tel.: 133-2-32-74-44-03; fax: 133-2-32-74-43-
91; e-mail: adam.daich@univ-lehavre.fr
0040±4020/02/$ - see front matter q 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020402)00542-2

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S. Marchalõn et al. / Tetrahedron 58 ;2002) 5747±5754
5748
Scheme 1. Key: 4i) See Refs. 2,3; 4ii) 1 equiv. of methyl acetoacetate 43a), AcOH; 4iii) 1 equiv. of benzoylacetonitrile 43b), AcOH; 4iv) 1 equiv. of
3-aminocrotonitrile 43c), AcOH; 4v) 2 equiv. of 3-aminocrotonitrile 43c), AcOH. See Tables 1 and 2 for aryl and R groups.
Table 1. Synthesis of functionalised indolizines 4±6 in a one-pot procedure
from 2-formyl-1,4-DHP derivatives 2
conformation,1 the migration of the proton H4 could be
performed with acetic acid assistance as indicated in the
plausible model depicted in Scheme 2. Furthermore, during
the course of this migration process, the transferring proton
remains associated with the same face of the p-system. This
phenomenon is similar to that commonly known as a supra-
facial process. At this present time, the resulting ion C is
converted to D in the same manner by proton transfer.
Entrya
Aryl group
R group Product Yield 4%)b Mp 48C)
1
2
3
4
5
5-NO2-2-C4H2O Ac
4a
4f
65
79
88
±
192±199
174±177
146±148
±
3-NO2-C6H4
3-NO2-C6H4
2-C4H3S
CO2iPr
CO2iPr
CO2Me
CO2Me
5f
6,7gc
d
2-C4H3S
±
±
±
a
The reactions were performed in equimolar amount.
b
c
The indicated yields were obtained after recrystallisation from ethanol.
Under conditions iv cited above 4Scheme 1), a mixture of indolizine 6g
and bis-1,4-DHP 7g was obtained.
This ion D was, in turn, capable of an intramolecular amino-
ketone cyclisation with a nitrogen atom as an internal
nucleophile into E. Under this sequential set, followed by
departure of one molecule of water, the reaction produced
azabicyclic systems 4 and 5. In our conditions, it is worth
mentioning that:
d
See Table 2 for bis-1,4-DHPs 7a±g.
Interestingly, the 2-enone-1,4-DHP A 4Scheme 2) as the
Knoevenagel condensation intermediate8 was protonated
in acetic medium to give the oxonium ion B. This ion,
under an acidic catalysis 4AcOH), underwent two consecu-
tive [1,3]-hydrogen transfer reactions9 to produce the
dihydro-pyridinium salt C then D. In fact, because the
proton at C4 position of the intermediate B is acid and taking
into account that the DHP nucleus could take a chairlike
18Ðthe regioselectivity was inverted in comparison with
earlier study using basic conditions from 2-formyl-1,4-
DHPs,10 and Lewis acids as catalysts from 3-42-pyridyl)-
2-propenols;11 and ®nally
28Ðthe reaction proceeded cleanly and selectively in a
one-pot procedure.
Scheme 2. Plausible mechanism leading to functionalised indolizines 4 and 5. Key: 4i) Knoevenagel condensation;8 4ii) Two consecutive acid catalysed proton
transfer reactions were required, see also Refs. 4,9.

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S. Marchalõn et al. / Tetrahedron 58 ;2002) 5747±5754
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5749
Table 2. Bis-1,4-DHPs 7a±g obtained in a one-pot procedure by reaction of
2-formyl-1,4-DHPs 2a±g with enamine derivatives
at C4 and C5 positions of the 1,4-DHP ring in the cyclisation
step. So, in a similar manner as above 4i.e. 2 equiv. of 3c,
AcOH, re¯ux, 30 min) 2-formyl-1,4-DHPs 2a±f prepared as
outlined in Scheme 1 4conditions i),6 afforded the bis-1,4-
DHP products 7a±f in a range of 50±82% yields 4see Table
2). It is important to notice that there was no discernible
preference for the nature and the range of the substituents R
and aryl groups since the indolizine skeletons 6a±f were
observed in comparable yields, as indicated above.13,14
Entry
Aryl group
R group Product Yield 4%)a Mp 48C)b
1
2
3
4
5
6
7
5-NO2-2-C4H2O
5-NO2-2-C4H2O
5-CN-2-C4H2O
5-CN-2-C4H2O
5-CO2Me-2-C4H2O CN
3-NO2-C6H4
2-C4H3S
Ac
CN
Ac
CN
7a
7b
7c
7d
7e
79
53
50
82
80
73
56
293±295
335±338
296±299
298±300
255±258
176±178
159±160
CO2iPr 7f
CO2Me 7g
As shown in Scheme 3, the described transformations could
possibly be rationalised by two consecutive [1,3]-hydrogen
transfer processes as outlined above in Scheme 2 from
the common intermediates E. This was obtained by the
Knoevenagel condensation of formyl derivatives 2a±g
with activated methylene 3c 4conditions i, Scheme 3). At
this stage, the resulting non-isolated imino-nitrile F could be
protonated at cyano group 4path a) followed by the favoured
intramolecular amino-nitrile cyclisation into G. This latter,
in the ®nal imino-amine tautomerism, could furnish indo-
lizines 8a±g. Because we have never detected the formation
of these species in the reaction medium, combined with the
fact that the imino function of the imino-nitrile F could be
hydrolysed easily 4path b),15 the resulting keto-nitrile A
similar to that proposed as intermediate in Scheme 2 4with
R4ˆMe and EWGˆCN) might open up an ef®cient entry to
indolizines 6a±g as discussed above for related products 4
and 5.
The reactions were performed on 1±3 mmol using 2 equiv. of enamine
derivative.
The indicated yields were obtained after recrystallisation from ethanol.
In general, the mp measurements were accompanied with the decompo-
sition of the products.
a
b
On the other hand, when the 2-formyl-1,4-DHP 2g inter-
acted with 3-aminocrotonitrile 3c12 4entry 4, Table 1) in
equimolar amount under acidic conditions as underlined
above, the reaction after 30 min to 1 h of re¯ux produced
three compounds: 18Ðthe unreacted starting material 2g;
28Ðthe indolizine 6g; and 38Ðthe azabicyclic structure 7g
as the main component. The both unexpected and new
products were separated by chromatography on a silica
gel column 4dichloromethane/ethyl acetate 49.5/0.5)), and
their structure was identi®ed as 6g and 7g by spectroscopic
analyses. In the case of 7g, monodimensional and bidimen-
sional NMR experiments including techniques like homo-
1
1
correlation H±1H and 13C±13C, heterocorrelation H±13C,
DEPT, HMQC, and HMBC were necessary.
Otherwise, predominant production of 7 could be explained
by assuming that the condensation product E takes another
course with a more reactive 3c involving initial C-alkylation
to form the dienamino-derivative H. This latter, after an
intramolecular cyclisation with elimination of ammonia,
would afford the corresponding bis-1,4-DHPs 7a±g. This
process also appears to follow the Hantzsch type reaction
pattern leading to 1,4-DHP systems.
In view of the fact that reaction of arylcarboxaldehyde
with enamine derivatives could bring about the formation
of 1,4-DHP nucleus by a modi®ed Hantzsch type reaction,
we anticipated the subjection of 2-formyl-1,4-DHP deriva-
tive 2g to 2 equiv. of 3c under same conditions as outlined
4entry 5, Table 1). In this case, interestingly, all starting
material was consumed after 30 min of reaction and the
novel bis-1,4-DHP component 7g was obtained in 56%
yield after ®ltration off followed by recrystallisation from
absolute ethanol.13
The structure elucidation of bis-1,4-DHPs 7a±g was estab-
lished by spectroscopic analyses. By comparison of 1H
NMR spectra of 7a±g with that of their 2-formyl congeners
2a±g, we found that protons H4 and NH signals are shifted
to up®eld 4Ddˆ0.19±0.54 ppm) and to down®eld 4Ddˆ
0.43±1.35 ppm), respectively. For other signals, no
We then examined the generalisation of this reaction by
evaluation of the effect of the substituent R and aryl groups
Scheme 3. Probable mechanism leading to bis-1,4-DHPs 7a±g. Key: 4i) Knoevenagel condensation with 3-aminocrotonitrile 3c as active methylene;8 4ii) See
also Scheme 2 for the proposed mechanism leading to indolizines related to 6a±g.

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S. Marchalõn et al. / Tetrahedron 58 ;2002) 5747±5754
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4. Experimental
4.1. General
All melting points were measured on a Boetius micro hot-
stage and are uncorrected. The infrared spectra of solids
4potassium bromide) were recorded on a Perkin±Elmer
1
FT-IR paragon 1000 spectrometer. The H and 13C NMR
spectra were recorded on a Bruker AC-200 MHz and
300 MHz instruments in deuteriochloroform unless other
indicated solvent and chemical shifts 4d) are expressed
in ppm relative to TMS as internal standard. Ascending
thin layer chromatography was performed on precoated
plates of silica gel 60 F 254 4Merck) and the spots visualised
using an ultraviolet lamp or iodine vapor. Mass spectral
measurements were recorded on a AEI MS 902 S spectro-
photometer. The elemental analyses were carried out by the
microanalysis laboratory of INSA, F-76130 Mt St Aignan,
France.
Figure 1. ORTEP view of the molecular structure of the bis-1,4-DHP 7b.
Thermal ellipsoids are at 50% probability level.
4.2. General procedure for preparation of 1,4-DHP
derivatives 2a±g
signi®cant alterations were observed. Furthermore, the 13C
NMR spectra of bis-1,4-DHPs 7a±g showed typical signals
for C2±C6 and for nitrile groups at dˆ111.8±119.3 ppm.16
Their distribution was also unambiguously performed by
off-resonance, DEPT, HMQC, and HMBC techniques.
From these experiments it should be pointed out that:
A mixture of arylcarboxaldehyde 410 mmol), methyl 4,4-di-
methoxy-3-oxo-butanoate 1 41.76 g, 10 mmol) and piperi-
dine 490 mg, 1 mmol) in benzene 410 ml) was re¯uxed with
a Dean±Stark for 5 h. The solvent was evaporated under
reduced pressure to give an oil ole®n, which was used for
the next step without any additional puri®cation. To this
oily residue, enamine derivative 44-aminopent-3-en-2-one,
3-aminocrotonitrile or alkyl 3-aminocrotonate) 410 mmol)
was added and the resulting mixture was stirred at 100±
1208 for 3 h. After cooling, viscous oil was dissolved in
acetone 437 ml) and 6N hydrochloric acid 46.5 ml) was
added dropwise. The solution was stirred at room tempera-
ture for 3 h. The organic solvent was removed under vacuo
and the residue was poured onto water 410 ml) and neutra-
lised with 10% solution of NaHCO3. After classical workup,
the solid residue was puri®ed by recrystallisation from
ethanol and gave suitable 2-formyl-1,4-DHPs 2a±g in
63±95% yield.
18Ðonly C2 signal did not show any interaction;
0
28Ðthe H4 signal appears as broadband at dˆ5.88±
5.94 ppm; and ®nally
38Ðthe 13C NMR spectra showed broadband signals with
low intensity. These facts were the consequence of the
0
slow rotation around the C2±C4 bond 4see also Fig. 1).
These data, the microanalyses and the coupling GC±MS
clearly con®rm the proposed structure of products 7a±g
and suggest the existence of the bis-1,4-DHP system in
constrained conformation. Finally, the identity of these
non symmetrical bis-1,4-DHP components 7a±g was
secured through an X-ray crystallographic determination.
In fact, an ORTEP view of representative derivative
7b, namely methyl 5,30,50-tricyano-6,20,60-trimethyl-4-45-
nitrofuran-2-yl)-1,4,10,40-tetrahydro[2,40]bipyridinyl-3-carb-
oxylate is shown in Fig. 1.17,18
4.2.1. Methyl 5-acetyl-2-formyl-6-methyl-4-05-nitro-
furan-2-yl)-1,4-dihydropyridine-3-carboxylate
02a).
Yieldˆ65%; mp 156±1578C; IR n/cm21: 3321 4NH),
2953 4CH), 1707 4CvO), 1506 4NO2); 1H NMR 4300
MHz): d 2.38 4s, 3H, Ac), 2.53 4s, 3H, Me), 3.86 4s, 3H,
0
0
0
OMe), 5.49 4s, 1H, H4), 6.50 4d, 1H, H3 , J3 ,4 ˆ3.5 Hz), 7.38
0
0
0
4d, 1H, H4 , J3 ,4 ˆ3.5 Hz), 8.47 4s, 1H, NH), 10.43 4s, 1H,
CHO); 13C NMR 480 MHz): d 20.5 4Me), 30.2 4Ac), 35.1
3. Conclusion
0
4C4), 52.6 4OMe), 107.2 4C5), 109.6 4C3 ), 110.0 4C3), 112.7
In conclusion, the synthesis in one step of polysubstituted
indolizines 4 and 5 by ring transformation of the formyl
containing 1,4-DHPs 2 by reaction with two active methyl-
ene reactants in acidic medium has been reported. These
1,4-DHPs 2 have also been allowed to react with 3-amino-
crotonitrile and, to our surprise, afforded bis-1,4-DHPs 7
accompanied with indolizines 6 as minor products. A
mechanism performing these transformations was proposed
and discussed. Finally, because of the novelty and potential
of these tandem reactions, extension to other activated
methylene reactants is possible. Investigation in this way
is underway.
0
0
0
4C4 ), 139.7 4C2), 145.7 4C6), 151.9 4C5 ), 159.2 4C2 ), 165.1
4CO2), 185.8 4CHO), 195.7 4CO); EIMS m/z 4%): 334 4Mz1,
14), 317 443), 285 422), 275 412), 244 427), 190 412), 43
4100); Anal. Calcd for C15H14N2O7 4334.08): C, 53.88; H,
4.22; N, 8.38. Found: C, 53.99; H, 4.31; N, 8.34%.
4.2.2. Methyl 5-cyano-2-formyl-6-methyl-4-05-nitro-
furan-2-yl)-1,4-dihydropyridine-3-carboxylate
02b).
Yieldˆ63%; mp 160±1618C; IR n/cm21: 3330 4NH),
2958 4CH), 2201 4CN), 1718 4CvO), 1512 4NO2); 1H
NMR 4300 MHz): d 2.29 4s, 3H, Me), 3.97 4s, 3H, OMe),
0
0
0
5.06 4s, 1H, H4), 6.72 4d, 1H, H3 , J3 ,4 ˆ3.9 Hz), 7.48 4d, 1H,

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S. Marchalõn et al. / Tetrahedron 58 ;2002) 5747±5754
Â
5751
0
0
0
H4 , J3 ,4 ˆ3.9 Hz), 8.83 4s, 1H, NH), 10.41 4s, 1H, CHO);
4.2.6. Methyl-isopropyl 2-formyl-6-methyl-4-03-nitro-
phenyl)-1,4-dihydropyridine-3,5-dicarboxylate 02f).
13C NMR 480 MHz): d 18.5 4Me), 36.3 4C4), 52.8 4OMe),
Yieldˆ91%; mp 147±1498C; IR n/cm21: 3366 4NH),
2963 4CH), 1701 4CvO), 1518 4NO2); 1H NMR 4300
MHz): d 1.27 4d, 6H, Me2CH, Jˆ6.7 Hz), 2.44 4s, 3H,
Me), 3.78 4s, 3H, OMe), 4.98 4sept, 1H, Me2CH, Jˆ
6.7 Hz), 5.23 4s, 1H, H4), 7.43±8.12 4m, 4H, H-aromatic),
7.00 4s, 1H, NH), 10.49 4s, 1H, CHO); 13C NMR 480 MHz):
d 19.6 4Me), 22.1 4Me), 22.8 4Me), 40.9 4C4), 52.4 4OMe),
0
81.2 4C5), 108.1 4C3), 110.2 4C3 ), 112.6 4C4 ), 117.8 4CN),
0
0
0
139.4 4C2), 147.6 4C6), 152.0 4C5 ), 157.3 4C2 ), 164.8 4CO2),
185.7 4CHO); EIMS m/z 4%): 317 4Mz1, 51), 300 477), 298
422), 288 433), 272 427), 268 4100), 258 427), 255 440), 227
422), 214 422), 211 417), 205 422), 199 416), 184 433), 177
417), 173 479), 155 442), 145 458), 118 426), 117 455), 101
416), 91 437), 77 419), 76 419), 75 416), 63 435), 59 430), 51
430), 45 466), 42 463), 39 443), 38 431); Anal. Calcd for
C14H11N3O6 4317.06): C, 53.00; H, 3.49; N, 13.24. Found:
C, 53.41; H, 3.76; N, 12.96%.
0
67.8 4OCHMe2), 102.5 4C5), 114.5 4C3), 122.1 4C4 ), 123.1
0
4C2 ), 129.2 4C5 ), 134.3 4C6 ), 139.1 4C2), 144.6 4C6), 147.9
0
0
0
0
4C1 ), 148.3 4C3 ), 165.8 4CO2), 166.1 4CO2), 186.5 4CHO);
EIMS m/z 4%): 388 4Mz1, 14), 371 418), 359 47), 345 420),
329 416), 313 418), 301 418), 280 464), 266 4100), 238 416),
234 411), 224 464), 196 411), 192 477), 164 432), 75 414), 44
432), 32 420), 28 470); Anal. Calcd for C19H20N2O7 4388.13):
C, 58.76; H, 5.19; N, 7.21. Found: C, 58.78; H, 5.11; N,
7.15%.
4.2.3. Methyl 5-acetyl-4-05-cyanofuran-2-yl)-2-formyl-6-
methyl-1,4-dihydropyridine-3-carboxylate 02c). Yieldˆ
80%; mp 140±1428C; IR n/cm21: 3351 4NH), 2959 4CH),
1
2227 4CN), 1702 4CvO); H NMR 4300 MHz): d 2.33 4s,
3H, Ac), 2.51 4s, 3H, Me), 3.85 4s, 3H, OMe), 5.45 4s, 1H,
0
0
0
0
H4), 6.36 4d, 1H, H3 , J3 ,4 ˆ3.1 Hz), 7.27 4d, 1H, H4 ,
J3 ,4 ˆ3.1 Hz), 8.40 4s, 1H, NH), 10.42 4s, 1H, CHO); 13C
0
0
4.2.7. Dimethyl 2-formyl-6-methyl-4-thiophen-2-yl-1,4-
dihydropyridine-3,5-dicarboxylate 02g). Yieldˆ95%;
mp 152±1548C; IR n/cm21: 3344 4NH), 2952 4CH), 1705
NMR 480 MHz): d 20.4 4Me), 30.0 4Ac), 35.0 4C4), 52.5
0
4OMe), 107.4 4C5), 107.8 4C3 ), 110.4 4C3), 111.5 4CN),
1
0
0
123.1 4C4 ), 125.1 4C5 ), 139.5 4C2), 145.4 4C6), 161.3
4CvO); H NMR 4300 MHz): d 2.44 4s, 3H, Me), 3.72 4s,
3H, OMe), 3.85 4s, 3H, OMe), 5.45 4s, 1H, H4), 6.81±7.14
0
4C2 ), 165.2 4CO2), 185.9 4CHO), 195.9 4CO); EIMS m/z
4%): 314 4Mz1, 80), 282 418), 271 424), 260 430), 255
422), 254 434), 240 435), 239 457), 212 423), 211 429), 190
417), 45 475), 43 4100); Anal. Calcd for C16H14N2O5
4314.09): C, 61.14; H, 4.49; N, 8.91. Found: C, 61.46; H,
4.62; N, 8.88%.
0
0
0
00 00
00 00
4m, 3H, H3 , H4 and H5 , J3 ,5 ˆ1.3 Hz, J3 ,4 ˆ3.3 Hz and
J4 ,5 ˆ5.2 Hz), 7.18 4s, 1H, NH), 10.50 4s, 1H, CHO); 13C
00 00
NMR 480 MHz): d 19.3 4Me), 35.1 4C4), 51.3 4OMe), 52.2
0
0
4OMe), 102.0 4C5), 114.5 4C3), 124.0 4C4 ), 124.3 4C5 ),
0
0
126.8 4C3 ), 138.6 4C2), 144.9 4C6), 148.4 4C2 ), 165.9
4CO2), 167.0 4CO2), 186.6 4CHO); EIMS m/z 4%): 321
4Mz1, 34), 292 416), 289 410), 262 4100), 246 428), 238
416), 230 428), 206 430), 202 415), 178 424), 172 415), 147
414), 111 410), 75 416), 59 412), 44 410), 43 426), 38 414), 28
415); Anal. Calcd for C15H15NO5S 4321.07): C, 56.06; H,
4.70; N, 4.36; S, 9.98. Found: C, 56.01; H, 4.76; N, 4.33; S,
10.01%.
4.2.4. Methyl 5-cyano-4-05-cyanofuran-2-yl)-2-formyl-6-
methyl-1,4-dihydropyridine-3-carboxylate 02d). Yieldˆ
73%; mp 169±1718C; IR n/cm21: 3291 4NH), 2962 4CH),
2229, 2201 4CN), 1709 4CvO); H NMR 4300 MHz): d
2.27 4s, 3H, Me), 3.80 4s, 3H, OMe), 5.01 4s, 1H, H4),
1
0
0
0
0
0
0
6.57 4d, 1H, H3 , J3 ,4 ˆ3.7 Hz), 7.38 4d, 1H, H4 , J3 ,4
ˆ
3.7 Hz), 8.75 4s, 1H, NH), 10.40 4s, 1H, CHO); 13C NMR
480 MHz): d 18.4 4Me), 35.9 4C4), 52.5 4OMe), 81.5 4C5),
4.3. General procedure for synthesis of indolizines 4a, 4f
and 5f
0
0
108.3 4C3 ), 108.4 4C3), 111.3 4CN), 118.0 4CN), 123.2 4C4 ),
0
0
125.9 4C5 ), 139.3 4C2), 147.3 4C6), 159.5 4C2 ), 164.8 4CO2),
185.8 4CHO); EIMS m/z 4%): 297 4Mz1, 88), 268 439), 265
449), 254 425), 236 471), 237 4100), 211 420), 210 434), 209
453), 205 418), 177 416), 173 451), 155 417), 145 434), 118
417), 117 429), 90 420), 64 420), 63 420), 59 414), 53 413), 52
413), 42 429), 39 418); Anal. Calcd for C15H11N3O4 4297.07):
C, 60.61; H, 3.73; N, 14.14. Found: C, 60.38; H, 3.77; N,
14.11%.
A solution of 2-formyl-1,4-DHP derivative 2a or 2f
43 mmol) and methyl acetoacetate 43a, 0.35 g, 3 mmol) or
benzoylacetonitrile 43b, 0.44 g, 3 mmol) in glacial acetic
acid 415 ml) was re¯uxed for 30 min. After cooling, 10 ml
of water was added and the solid material which began to
precipitate was collected by suction washed with water and
air dried. An analytical sample of 4a, 4f or 5f was obtained
after recrystallisation from ethanol.
4.2.5. Methyl 5-cyano-2-formyl-4-05-methoxycarbonyl-
furan-2-yl)-6-methyl-1,4-dihydropyridine-3-carboxylate
02e). Yieldˆ79%; mp 156±1588C; IR n/cm21: 3325 4NH),
2952 4CH), 2200 4CN), 1712 4CvO); 1H NMR 4300 MHz):
d 2.27 4s, 3H, Me), 3.78 4s, 3H, OMe), 3.81 4s, 3H, OMe),
4.3.1. Dimethyl 6-acetyl-3,5-dimethyl-7-05-nitrofuryl)-
indolizin-2,8-dicarboxylate 04a). Yieldˆ65% 40.80 g);
mp 169±1728C; IR n/cm21: 3136, 2953 4CH), 1732
4CvO), 1508, 1473 4NO2); H NMR 4300 MHz, DMSO-
d6): d 2.41 4s, 3H, Ac), 2.88 4s, 3H, Me5), 3.16 4s, 3H, Me3),
1
0
0
0
4.98 4s, 1H, H4), 6.47 4d, 1H, H3 , J3 ,4 ˆ3.2 Hz), 7.16 4d, 1H,
0
0
0
H4 , J3 ,4 ˆ3.2 Hz), 8.66 4s, 1H, NH), 10.39 4s, 1H, CHO);
0
3.82±3.83 4s-board, 3H, OMe), 6.74 4d, 1H, H3 , J3 ,4
0
0
ˆ
13C NMR 480 MHz): d 18.2 4Me), 35.8 4C4), 51.7 4OMe),
0
0
0
3.9 Hz), 7.03 4s, 1H, H1), 7.77 4d, 1H, H4 , J3 ,4 ˆ3.9 Hz);
13C NMR 480 MHz, DMSO-d6): d 14.4 4Me3), 18.5 4Me3),
32.7 4Ac), 51.6±53.2 4OMe), 105.0 4C1), 113.2 4C6), 114.0
0
52.5 4OMe), 81.7 4C5), 108.9 4C3 ), 109.2 4C3), 118.2 4CN),
0
0
0
119.0 4C4 ), 139.2 4C2), 144.2 4C5 ), 147.1 4C6), 158.5 4C2 ),
158.5 4CO2), 165.1 4CO2), 185.9 4CHO); EIMS m/z 4%): 330
4Mz1, 22), 298 443), 271 431), 270 436), 255 431), 239 436),
184 411), 183 419), 173 424), 155 422), 149 421), 145 417), 45
4100), 43 421); Anal. Calcd for C16H12N2O6 4330.09): C,
58.18; H, 4.27; N, 8.48. Found: C, 58.09; H, 4.12; N, 8.25%.
0
0
4C3 ), 114.6 4C4 ), 119.4 4C2), 123.8 4C8), 125.2 4C3), 127.9
0
0
4C7), 132.1 4C5), 135.3 4C8a), 150.9 4C2 ), 151.3 4C5 ),
165.3±164.6 4CO2Me), 203.3 4Ac); EIMS m/z 4%): 414
4Mz1, 92), 399 45), 383 415), 368 435), 353 45), 336 410),
324 412), 309 4100), 308 433), 294 415), 250 410), 184 48), 45

Ï
Â
S. Marchalõn et al. / Tetrahedron 58 ;2002) 5747±5754
5752
1
4CN), 1726 4CvO); H NMR 4300 MHz): d 2.85 4s, 3H,
417), 44 413), 43 423), 31 431), 28 423); Anal. Calcd for
C20H18N2O8 4414.37): C, 57.97; H, 4.38; N, 6.76. Found:
C, 58.03; H, 4.45; N, 6.59%.
Me), 3.01 4s, 3H, Me), 3.60 4s, 3H, OMe), 3.69 4s, 3H,
0
0
0
OMe), 6,83 4s, 1H, H1), 6.97 4dd, 1H, H3 , J3 ,5 ˆ1.2 Hz
0
0
0
0
0
and J3 ,4 ˆ3.6 Hz), 7.02 4dd, 1H, H4 , J3 ,4 ˆ3.6 Hz and
4.3.2. Dimethyl-2-propyl 3,5-dimethyl-7-03-nitrophenyl)-
indolizin-2,6,8-tricarboxylate 04f). Yieldˆ79% 41.11 g);
mp 174±1778C; IR n/cm21: 2988, 2951 4CH), 1713
0
0
0
0
0
0
0
J4 ,5 ˆ5.1 Hz), 7.36 4dd, 1H, H5 , J3 ,5 ˆ1.2 Hz and J4 ,5
ˆ
5.1 Hz); 1H NMR 480 MHz): d 16.3, 18.8, 52.5, 52.6, 101.9,
103.9, 115.9, 122.5, 123.0, 123.8, 126.9, 127.0, 128.0,
130.6, 131.1, 134.8, 136.8, 165.9, 167.6; EIMS m/z 368
4Mz1, 15); Anal. Calcd for C19H16N2O4S 4368.41): C,
61.94; H, 4.38; N, 7.60; S, 8.70. Found: C, 61.87; H, 4.19;
N, 7.55; S, 8.61%.
1
4CvO), 1533, 1450 4NO2); H NMR 4300 MHz, DMSO-
d6): d 0.90 4d, 6H, Me2CH, Jˆ6.3 Hz), 2.91 4s, 3H, Me5),
3.17 4s, 3H, Me3), 3.57±3.81 4s-board, 3H, OMe), 4.74
4sept, 1H, Me2CH, Jˆ6.3 Hz), 6.97 4s, 1H, H1), 7.64 4d,
0
0
0
0
0
0
1H, H6 , J5 ,6 ˆ8.1 Hz), 7.73 4dd, 1H, H5 , and J4 ,5 and
4.4.2. Methyl 5-acetyl-30,50-dicyano-6,20,60-trimethyl-4-
05-nitrofuran-2-yl)-1,4,10,40-tetrahydro[2,40]bipyridinyl-
3-carboxylate 07a). Yieldˆ79%; mp 293±2958C 4decom-
position); IR n/cm21: 3321 4NH), 3009, 2953 4CH), 2204
4CN), 1701, 1662 4CvO), 1508 4NO2); 1H NMR 4300 MHz,
DMSO-d6): d 1.98 4s, 3H, Me), 1.99 4s, 3H, Me), 2.34 4s,
3H, Ac), 2.42 4s, 3H, Me), 3.68 4s, 3H, OMe), 5.30 4s, 1H,
0
0
0
0
0
0
J5 ,6 ˆ8.1 Hz), 7.98 4s, 1H, H2 ), 8.28 4d, 1H, H4 , J4 ,5
ˆ
8.1 Hz); 13C NMR 480 MHz, DMSO-d6): d 14.3 4Me3),
18.8 4Me5), 20.8 4Me2CH), 51.5±52.5 4OMe), 69.4
4Me2CH), 103.3 4C1), 118.7 4C2), 120.5 4C6), 121.8 4C8),
0
122.9 4C4 ), 123.0 4C2 ), 126.7 4C3), 128.3 4C7), 130.0
0
0
0
0
4C5 ), 130.7 4C5), 135.3 4C6 ), 137.2 4C8a), 138.5 4C1 ),
0
147.3 4C3 ), 164.9±165.3 4CO2Me), 166.6 4CO2iPr); EIMS
m/z 4%): 468 4Mz1, 96), 438 411), 437 410), 426 4100), 411
434), 409 418), 379 418), 45 414), 44 414), 31 421), 28 436);
Anal. Calcd for C24H24N2O8 4468.46): C, 61.53; H, 5.16; N,
5.98. Found: C, 61.43; H, 5.09; N, 6.05%.
0
00
00 00
H4), 5.90 4s, 1H, H4 6.43 4d, 1H, H3 , J3 ,4 ˆ3.3 Hz), 7.50
00
00 00
4d, 1H, H4 , J3 ,4 ˆ3.3 Hz), 8.90 4s, 1H, NH), 9.52 4s, 1H,
1
NH); H NMR 480 MHz, DMSO-d6): d 18.0 4Me), 18.1
0
4Me), 19.0 4Me), 30.2 4Ac), 34.1 4C4 ), 34.1 4C4), 51.5
0
4OMe), 78.3 4C3 ), 78.6 4C5 ), 99.3 4C3), 107.3 4C5), 109.2
0
4.3.3. Dimethyl-2-propyl 2-cyano-5-methyl-3-phenyl-7-
03-nitrophenyl)indolizin-6,8-dicarboxylate 05f). Yieldˆ
88% 41.31 g); mp 146±1488C 4decomposition); IR
n/cm21: 2984, 2949 4CH), 2231 4CN), 1722 4CvO), 1527
00
00
4C3 ), 113.9 4C4 ), 118.2 4CN), 118.3 4CN), 147.7 4C2),
00
147.7 4C6), 148.8 4C5 ), 149.5 4C2 ), 149.5 4C6 ), 161.7
0
0
z1
4C2 ), 165.9 4CO2), 195.3 4CO); EIMS m/z 463 4M ,12);
00
Anal. Calcd for C23H21N5O6 4463.15): C, 59.61; H, 4.57; N,
15.11. Found: C, 59.73; H, 4.61; N, 15.20%.
1
4NO2); H NMR 4300 MHz, DMSO-d6): d 0.87 4d, 6H,
Me2CH, Jˆ6.3 Hz), 2.08 4s, 3H, Me5), 3.65 4s, 3H, OMe),
4.4.3. Methyl 5,30,50-tricyano-6,20,60-trimethyl-4-05-
nitrofuran-2-yl)-1,4,10,40-tetrahydro[2,40]bipyridinyl-3-
carboxylate 07b). Yieldˆ53%; mp 335±3388C 4decompo-
sition); IR n/cm21: 3301 4NH), 3000, 2954 4CH), 2203
4CN), 1715, 1666 4CvO), 1506 4NO2); 1H NMR
4300 MHz, DMSO-d6): d 2.01 4s, 6H, 2xMe), 2.18 4s, 3H,
4.71 4sept, 1H, Me2CH, Jˆ6.3 Hz), 7.35 4s, 1H, H1), 7.51±
0
0
0
7.66 4m, 5H, H-aromatic), 7.68 4d, 1H, H6 , J5 ,6 ˆ7.8 Hz),
0
0
0
0
0
0
7.76 4dd, 1H, H5 , J4 ,5 and J5 ,6 ˆ8.1 Hz), 8.03 4s, 1H, H2 ),
8.31 4d, 1H, H4 , J4 ,5 ˆ7.8 Hz); 13C NMR 480 MHz, DMSO-
d6): d 19.8 4Me5), 20.7 4Me2CH), 52.7 4OMe), 69.6
4Me2CH), 101.8 4C2), 105.0 4C1), 115.6 4CN), 121.5 4C6),
0
0
0
0
121.6 4C8), 122.9 4C4 ), 123.2 4C2 ), 127.9 4C2 ), 128.7 4C3),
0
00
0
Me), 3.61 4s, 3H, OMe), 4.89 4s, 1H, H4), 5.94 4s, 1H, H4 ),
00
0
129.6 4C7), 129.8 4C4 ), 130.0 4C5 ), 130.9 4C5), 131.3 4C3 ),
00
00
00 00
00
1
00 00
6.62 4d, 1H, H3 , J3 ,4 ˆ3.5 Hz), 7.63 4d, 1H, H4 , J3 ,4
ˆ
00
0
0
0
134.2 4C1 ), 135.3 4C6 ), 136.2 4C8a), 138.1 4C1 ), 147.3 4C3 ),
164.7 4CO2Me), 165.3 4CO2iPr); EIMS m/z 4%): 497 4Mz1,
100), 467 411), 455 498), 438 415), 408 422), 303 49), 45 49),
44 413), 28 444); Anal. Calcd for C28H23N3O6 4497.50): C,
67.60; H, 4.66; N, 8.45. Found: C, 67.48; H, 4.59; N, 8.63%.
3.5 Hz), 9.39 4s, 1H, NH), 9.60 4s, 1H, NH); H NMR
480 MHz, DMSO-d6): d 17.8 4Me), 18.2 4Me), 18.2 4Me),
0
35.2 4C4 ), 35.2 4C4), 51.8 4OMe), 78.2 4C3 ), 78.3 4C5 ), 79.9
00
4C5), 97.9 4C3), 110.0 4C3 ), 114.2 4C4 ), 118.3 4CN), 118.5
0
4CN), 118.9 4CN), 148.7 4C5 ), 149.9 4C2 ), 149.9 4C6 ),
0
0
00
00
0
00
150.1 4C2), 150.1 4C6), 160.5 4C2 ), 165.7 4CO2); EIMS
m/z 446 4Mz1,12) 429 426), 334 412), 333 453), 274 418),
273 412), 177 414), 159 411), 158 4100), 157 413), 73 411);
Anal. Calcd for C22H18N6O5 4446.13): C, 59.19; H, 4.06; N,
18.83. Found: C, 58.98; H, 3.99; N, 18.71%.
4.4. General procedure for synthesis of indolizines 6 and
bis-1,4-DHPs 7
A solution of 2-formyl-1,4-DHP derivatives 2a±g 43 mmol)
and 3-aminocrotonitrile 3c 40.5 g, 6 mmol) in glacial acetic
acid 410 ml) was re¯uxed under magnetical stirring for
30 min 4the reaction was monitored by TLC). After cooling,
the solid material which began to precipitate was collected
by suction washed with water and air dried. An analytical
analysis of bis-1,4-DHPs 7a±g was obtained after recrystal-
lisation from ethanol. For example, in the case of the
substrate 2g, the resulting mother liquor obtained after ®ltra-
tion of the solid 7g, after concentration, classical workup
and puri®cation by ¯ash chromatography on silica gel
column, gave the indolizine 6g as colourless solid.
4.4.4. Methyl 5-acetyl-30,50-dicyano-4-05-cyanofuran-2-
yl)-6,20,60-trimethyl-1,4,10,40-tetrahydro[2,40]bipyridinyl-
3-carboxylate 07c). Yieldˆ50%; mp 296±2998C 4decom-
position); IR n/cm21: 3323 4NH), 3012, 2956 4CH), 2233,
2204 4CN), 1666 4CvO); 1H NMR 4300 MHz, DMSO-d6):
d 1.98 4s, 3H, Me), 2.00 4s, 3H, Me), 2.31 4s, 3H, Ac), 2.40
4s, 3H, Me), 3.66 4s, 3H, OMe), 5.27 4s, 1H, H4), 5.89 4s, 1H,
0
00
00 00
00
H4 ), 6.30 4d, 1H, H3 , J3 ,4 ˆ3.6 Hz), 7.37 4d, 1H, H4 ,
1
00 00
J3 ,4 ˆ3.6 Hz), 8.75 4s, 1H, NH), 9.51 4s, 1H, NH); H
NMR 480 MHz, DMSO-d6): d 18.0 4Me), 18.2 4Me), 19.0
0
4Me), 30.2 4Ac), 33.8 4C4 ), 33.8 4C4), 51.5 4OMe), 78.5
0
0
4C3 ), 78.5 4C5 ), 100.4 4C3), 107.9 4C5), 107.1 4C3 ), 112.1
00
4.4.1. Dimethyl 2-cyano-3,5-dimethyl-7-thiophen-2-yl-
indolizine-6,8-dicarboxylate 06g). 5%; mp 190±1938C
4decomposition); IR n/cm21: 3009, 2987 4CH), 2221
00
4CN), 118.3 4CN), 118.3 4CN), 123.4 4C5 ), 124.2 4C4 ),
0
147.5 4C6), 148.3 4C2), 149.4 4C2 ), 149.4 4C6 ), 163.6
00
0

Ï
S. Marchalõn et al. / Tetrahedron 58 ;2002) 5747±5754
Â
5753
z1
4C2 ), 166.0 4CO2), 195.3 4CO); EIMS m/z 443 4M ,18),
517 4Mz1, 10), 486 428), 485 470), 474 422), 458 447), 457
439), 395 432), 393 440), 351 432), 196 4100), 158 468); Anal.
Calcd for C27H27N5O6 4517.53): C, 62.66; H, 5.26; N, 13.53.
Found: C, 62.54; H, 5.16; N, 13.36%.
00
412 421), 411 466), 400 421), 384 424), 368 432), 350 419),
194 420), 158 4100), 43 449); Anal. Calcd for C24H21N5O4
4443.16): C, 65.00; H, 4.77; N, 15.79. Found: C, 64.79; H,
4.63; N, 15.61%.
4.4.8. Dimethyl 30,50-dicyano-6,20,60-trimethyl-4-thio-
phen-2-yl-1,4,10,40-tetrahydro[2,40]bipyridinyl-3,5-dicarb-
oxylate 07g). Yieldˆ56%; mp 159±1608C 4decomposition);
IR n/cm21: 3300, 3226 4NH), 3012, 2990 4CH), 2210, 2197
4CN), 1683, 1668 4CvO); 1H NMR 4300 MHz, DMSO-d6):
d 2.00 4s, 3H, Me), 2.02 4s, 3H, Me), 2.34 4s, 3H, Me), 3.62
4s, 3H, OMe), 3.66 4s, 3H, OMe), 5.27 4s, 1H, H4), 5.90 4s,
4.4.5. Methyl 5,30,50-tricyano-4-05-cyanofuran-2-yl)-
6,20,60-trimethyl-1,4,10,40-tetrahydro[2,40]bipyridinyl-3-
carboxylate 07d). Yieldˆ82%; mp 298±3008C 4decompo-
sition); IR n/cm21: 3311 4NH), 3009, 2953 4CH), 2235,
2202 4CN), 1698 4CvO); H NMR 4300 MHz, DMSO-
d6): d 2.00 4s, 3H, Me), 2.01 4s, 3H, Me), 2.16 4s, 3H,
Me), 3.59 4s, 3H, OMe), 4.83 4s, 1H, H4), 5.91 4s, 1H,
1
0
00
00
00 00
1H, H4 ), 6.79±6.82 4m, 2H, H3 and H4 , J3 ,5 ˆ1.2 Hz and
00 00
00
00 00
0
00
00 00
00
J3 ,4 ˆ3.8 Hz), 7.22 4d, 1H, H5 , J4 ,5 ˆ5.1 Hz), 8.55 4s, 1H,
H4 ), 6.48 4d, 1H, H3 , J3 ,4 ˆ3.4 Hz), 7.49 4d, 1H, H4 ,
1
NH), 9.50 4s, 1H, NH); H NMR 480 MHz, DMSO-d6): d
1
00 00
J3 ,4 ˆ3.4 Hz), 9.25 4s, 1H, NH), 9.55 4s, 1H, NH); H
0
18.1 4Me), 18.2 4Me), 18.3 4Me), 34.5 4C4), 34.5 4C4 ), 50.9
NMR 480 MHz, DMSO-d6): d 17.7 4Me), 18.1 4Me), 18.1
0 0
4OMe), 51.4 4OMe), 78.1 4C3 ), 79.3 4C5 ), 101.7 4C3), 103.7
0
0
4Me), 35.1 4C4 ), 35.1 4C4), 51.6 4OMe), 78.3 4C3 ), 78.3
00 00
4C5), 118.3 4CN), 118.7 4CN), 123.3 4C2 ), 124.0 4C4 ),
0
4C5 ), 80.2 4C5), 98.3 4C3), 107.8 4C3 ), 111.8 4CN), 118.0
00
00 00
126.3 4C3 ), 147.2 4C5 ), 148.3 4C2), 149.1 4C6), 149.8
00
4CN), 118.4 4CN), 119.0 4CN), 124.0 4C5 ), 124.5 4C4 );
00
00
00
0
148.3 4C2), 149.5 4C2 ), 149.5 4C6 ), 149.6 4C6), 162.5
0
4C2 ), 149.8 4C6 ), 166.6 4CO2), 166.9 4CO); EIMS m/z
450 4Mz1, 12); Anal. Calcd for C23H22N4O4S 4450.51): C,
61.17; H, 4.77; N, 12.40; S, 7.06. Found: C, 61.32; H, 4.92;
N, 12.44; S, 7.11%.
z1
4C2 ), 165.7 4CO2); EIMS m/z 426 4M ,20), 394 413), 368
00
417), 367 464), 365 414), 333 413), 274 424), 177 414), 158
4100), 42 423); Anal. Calcd for C23H18N6O3 4426.14): C,
64.78; H, 4.25; N, 19.71. Found: C, 64.63; H, 4.24; N,
19.83%.
Acknowledgements
4.4.6. Methyl 5,30,50-tricyano-4-05-methoxycarbonyl-
furan-2-yl)-6,20,60-trimethyl-1,4,10,40-tetrahydro[2,40]-
bipyridinyl-3-carboxylate 07e). Yieldˆ80%; mp 255±
2588C 4decomposition); IR n/cm21: 3457 4NH), 3011,
2954 4CH), 2228, 2202 4CN), 1683, 1663 4CvO); 1H
NMR 4300 MHz, DMSO-d6): d 2.00 4s, 3H, Me), 2.02 4s,
3H, Me), 2.13 4s, 3H, Me), 3.57 4s, 3H, OMe), 3.78 4s, 3H,
The authors thank the Grant Agency of Slovak Republic,
Grant No.1/9249/2002 and the Scienti®c Council of
University of Le Havre, France, for their ®nancial support
for this research. We also thank Professor Bernard Decroix
for helpful comments and discussions made during the
course of this work.
0
OMe), 4.80 4s, 1H, H4), 5.92 4s, 1H, H4 ), 6.41 4d, 1H, H3 ,
00
00 00
00
00 00
J3 ,4 ˆ3.7 Hz), 7.21 4d, 1H, H4 , J3 ,4 ˆ3.7 Hz), 9.20 4s, 1H,
1
NH), 9.58 4s, 1H, NH); H NMR 480 MHz, DMSO-d6): d
References
0
17.8 4Me), 18.1 4Me), 18.2 4Me), 35.2 4C4 ), 35.2 4C4), 51.7
0
4OMe), 51.8 4OMe), 78.1 4C3 ), 78.5 4C5 ), 80.9 4C5), 98.8
00
4C3), 108.4 4C3 ), 118.3 4CN), 118.8 4CN), 119.3 4CN),
0
1. 4a) Bossert, F.; Vater, W. Med. Res. Rev. 1989, 9, 291.
4b) Goldmann, S.; Stoltefuss, J. Angew. Chem., Int. Ed.
Engl. 1991, 30, 1559. 4c) Sausins, A.; Duburs, G. Khim.
00
119.7 4C4 ), 142.9 4C5 ), 148.1 4C2), 149.2 4C2 ), 149.6
00
0
Ï
0
00
4C6 ), 149.8 4C6), 158.4 4CO2), 161.8 4C2 ), 166.0 4CO2);
EIMS m/z 459 4Mz1, 46), 427 424), 401 419), 400 468),
340 422), 333 417), 320 432), 312 421), 274 429), 158
4100); Anal. Calcd for C24H21N5O5 4459.15): C, 62.74; H,
4.61; N, 15.24. Found: C, 62.69; H, 4.72; N, 15.28%.
Â
Â
Geterotsikl. Soedin. 1992, 4, 435. 4d) Marchalõn, S.; Chudõk,
M.; Mastihuba, V.; Decroix, B. Heterocycles 1998, 48, 1943
and references therein.
Ï
  Â
2. 4a) Chudõk, M.; Marchalõn, S.; Havrilova, K. Collect. Czech.
Ï
Chem. Commun. 1998, 63, 826. 4b) Chudõk, M.; Marchalõn, S.;
Â
Â
Pham-Huu, D.-P.; Humpa, O.; Friedl, Z. Monatsh. Chem.
1999, 130, 1241.
4.4.7. Methyl-isopropyl 30,50-dicyano-6,20,60-trimethyl-
4-03-nitrophenyl)-1,4,10,40-tetrahydro[2,40]bipyridinyl-3,
5-dicarboxylate 07f). Yieldˆ73%; mp 176±1788C 4decom-
position); IR n/cm21: 3369 4NH), 3015, 2989 4CH), 2206
4CN), 1681, 1669 4CvO), 1553 4NO2); 1H NMR 4300 MHz,
DMSO-d6): d 1.61 4d, 6H, Me2CH, Jˆ6.5 Hz), 2.02 4s, 3H,
Me), 2.10 4s, 3H, Me), 2.15 4s, 3H, Me), 3.61 4s, 3H, OMe),
4.19 4sept, 1H, Me2CH, Jˆ6.5 Hz), 4.69 4s, 1H, H4), 5.72 4s,
Ï
3. 4a) Chudõk, M.; Marchalõn, S.; Knesl, P.; Daõch, A.; Decroix,
Â
Â
È
B. J. Heterocycl. Chem. 2000, 37, 1549. 4b) Chudõk, M.;
Â
Ï
Marchalõn, S.; Daõch, A.; Decroix, B. Res. Adv. Synth. Org.
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Chem. 2000, 1, 1.
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4. Marchalõn, S.; Cvopova, K.; Pham-Huu, D.-P.; Chudõk, M.;
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Kozõsek, J.; Svoboda, I.; Daõch, A. Tetrahedron Lett. 2001, 42,
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5663.
0
00
00
1H, H4 ), 7.99 4s, 1H, NH), 7.15±7.45 4m, 3H, H2 , H5 and
5. Only three general methods have been reported for the
preparation of indolizines and in all these cases, substituted
pyridine was used as a starting material. For recent article see
the following reference: Katritzky, A. R.; Qiu, G.; Yang, B.;
He, H. Y. J. Org. Chem. 1999, 64, 7618 and most references
therein.
00
00
0
0
0
0
H6 ), 8.01±8.15 4dd, 1H, H4 , J4 ,5 ˆ7.8 Hz and J4 ,6
ˆ
1
1.9 Hz), 8.98 4s, 1H, NH); H NMR 480 MHz, DMSO-d6):
d 18.0 4Me), 18.1 4Me), 18.6 4Me), 21.5 4Me), 21.5 4Me),
0
32.2 4C4 ), 33.9 4C4), 51.4 4OMe), 68.5 4OCHMe2), 78.4
0
4C3 ), 78.6 4C5 ), 98.6 4C3), 101.5 4C5), 118.1 4CN), 118.9
0
00
4CN), 119.8 4C4 ), 122.3 4C2 ), 131.5 4C5 ), 135.1 4C6 ),
00
00
00
6. 4a) The oily residue used as intermediates during the synthesis
of 2-formyl-1,4-DHPs 2a±g, was isolated and identi®ed as the
2-dimethylacetal-1,4-DHPs 20a±g. 4b) See in the following,
00
138.1 4C1 ), 147.6 4C2), 148.6 4C6), 148.9 4C2 ), 149.1
0
0
00
4C6 ), 149.2 4C2 ), 164.6 4CO2), 165.8 4CO2); EIMS m/z

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S. Marchalõn et al. / Tetrahedron 58 ;2002) 5747±5754
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selected data for 2-dimethylacetal 20a: methyl 5-acetyl-2-
alkoyl, or aroyl)indolizines were observed. See also Refs.
2,4 for this end.
dimethoxymethyl-6-methyl-4-;5-nitrofuran-2-yl)-1,4-dihydro-
pyridine-3-carboxylate ;20a). Yieldˆ70%; mp 120±1228C; IR
4KBr), n/cm21: 3353 4NH), 2960 4CH), 1682 4CvO), 1512
4NO2); 1H NMR 4300 MHz, CDCl3): d 2.37 4s, 3H, Ac), 2.39
4s, 3H, Me), 3.44 4s, 3H, OMe), 3.51 4s, 3H, OMe), 3.77 4s, 3H,
11. Abe, Y.; Ohsawa, A.; Igeta, H. Chem. Pharm. Bull. 1982, 30,
881.
12. The 3-aminocrotonitrile reagent constitutes an activated
methylene after an enamino-imine tautomerism.
13. Since our ®rst attention was focused on the bis-1,4-DHP
systems, indolizines 6a±f were not systematically isolated
and identi®ed. For clarity, only indolizine 6g was isolated
but its yield did not exceed 5%.
0
CO2Me), 5.36 4s, 1H, H4), 6.00 4s, 1H, CH), 6.31 4d, 1H, H3 ,
0
0
0
0
0
J3 ,4 ˆ4.0 Hz), 7.17 4s, 1H, NH), 7.20 4d, 1H, H4 , J3 ,4
ˆ
4.0 Hz); 13C NMR 480 MHz, CDCl3): d 20.6 4Me), 30.1
4Ac), 34.1 4C4), 51.7 4CO2Me), 54.4 4OMe), 55.8 4OMe),
0
98.1 4CH), 100.1 4C5), 108.0 4C3), 108.9 4C3 ), 112.9 4C4 ),
0
14. The reaction was monitored by TLC 4silica gel, dichloro-
methane/ethyl acetate: 9.5/0.5) and the ratios of products
6a±f and 7a±f were determined by the coupling GC±MS
analyses.
0
0
145.5 4C2), 145.5 4C6), 151.1 4C5 ), 161.0 4C2 ), 165.7 4CO2),
195.9 4CO); EIMS m/z 4%): 380 4Mz1, 17), 363 415), 348 431),
331 4100), 321 410), 317 417), 305 446), 301 426), 289 454),
275 410), 274 413), 260 426), 255 417), 241 423), 236 444), 228
428), 208 428), 198 418), 75 496), 59 423), 43 494); Anal. Calcd
for C17H20N2O8 4380.12): C, 53.68; H, 5.30; N, 7.37. Found:
C, 53.79; H, 5.14; N, 7.44%. 4c) All other acetals 20b±g, have
similar characteristics.
15. Water was liberated in the medium during the Knoevenagel
condensation between 2-formyl-1,4-DHPs 2 and 3-amino-
crotonitrile 3c.
16. KurfuÈrt, A.; Trska, P.; Goljer, I. Collect. Czech. Chem.
Commun. 1984, 49, 2393.
17. Crystallographic structure of methyl 5,30,50-tricyano-6,20,60-
trimethyl-4-45-nitrofuran-2-yl)-1,4,10,40-tetrahydro[2,40]bi-
pyridinyl-3-carboxylate 47b): colourless, 0.80£0.40£0.06 mm3
7. A few analogous types of products were described in poor to
moderate yields 49±58%) by another pathway, see for exam-
ple: 4a) Uchida, T.; Matsumoto, K. Synthesis 1972, 209 and
references therein. 4b) Hurst, J.; Melton, T.; Wibberley, D. G.
J. Chem. Soc. 1965, 2948. 4c) Pohjala, E. K. J. Heterocycl.
Chem. 1977, 14, 273 and references therein.
Ê
block, C25H25N7O6, triclinic, P-1, aˆ9.017041) A, bˆ
Ê
11.459942) A,
Ê
cˆ12.826841) A,
aˆ93.8741)8,
bˆ
102.64041)8, gˆ96.04041)8, Zˆ2. Stoe Stadi-4 diffractometer
using Mo Ka radiation, Tˆ18342) K, 19715 re¯ections
measured up to 2u ˆ 65:628; 8770 independent data 4Rintˆ
1.93%) for 374 re®ned parameters. The structure was re®ned
on the basis of absorption-corrected data 4Tminˆ0.9248,
Tmaxˆ0.9941), using standard methods18 with constraints for
hydrogen atoms. Final R indices: R1ˆ4.51% for 6945 data
having I . 2sꢀI† and wR2ˆ12.08% for all data.
8. For more details of the Knoevenagel condensation mecha-
nism, see the following reference: Jones, G. Org. React.
1967, 15, 204.
9. For recent advances in the [1,n]-hydrogen transfer study,
see: 4a) Jensen, F. J. Am. Chem. Soc. 1995, 117, 7487.
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4b) Hussenius, A.; Matsson, O.; Bergson, G. Chem. Commun.
1998, 2693.
18. Sheldrick, G. N. SHELX-97 User's Manual; University of
10. Using same 2-formyl-1,4-DHP precursors 2 but under basic
conditions, only the formation of 3-amino-2-alkyl4aryl,
È
Gottingen: Germany, 1997.