Simple stepwise route to 1-substituted 2-amino-3-ethoxycarbonylindolizines

Article abstract of DOI:10.1016/j.tet.2013.02.049

2-Chloro-N-ethoxycarbonylmethylpyridinium bromide reacts with substituted acetonitriles in two steps; the initially formed pyridine anhydro baseses undergo further ring closure to 2-amino-3-ethoxycarbonylindolizines.

Full text of DOI:10.1016/j.tet.2013.02.049

Accepted Manuscript
Simple stepwise route to 1-substituted 2-amino-3-ethoxycarbonylindolizines
Gennadiy E. Khoroshilov, Natalia M. Tverdokhleb, Vladimir S. Brovarets, Eugene V.
Babaev
PII:
S0040-4020(13)00274-3
10.1016/j.tet.2013.02.049
TET 24044
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 6 September 2012
Revised Date: 29 January 2013
Accepted Date: 18 February 2013
Please cite this article as: Khoroshilov GE, Tverdokhleb NM, Brovarets VS, Babaev EV, Simple
stepwise route to 1-substituted 2-amino-3-ethoxycarbonylindolizines, Tetrahedron (2013), doi: 10.1016/
j.tet.2013.02.049.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Simple stepwise route to 1-substituted 2-
amino-3-ethoxycarbonylindolizines
Gennadiy E. Khoroshilov*, Natalia M. Tverdokhleb, Vladimir S. Brovarets, Eugene V. Babaev
Lugansk Taras Shevchenko National University, Oboronnaya 2, Lugansk, 91011, Ukraine

ACCEPTED MANUSCRIPT
1
Tetrahedron
journal homepage: www.elsevier.com
Simple stepwise route to 1-substituted 2-amino-3-ethoxycarbonylindolizines
Gennadiy E. Khoroshilov*a, Natalia M. Tverdokhleba, Vladimir S. Brovaretsb, Eugene V. Babaevc
a Lugansk Taras Shevchenko National University, Oboronnaya 2, Lugansk, 91011, Ukraine
b Institute of Bioorganic Chemistry and Petrochemistry National Academy of Sciences of Ukraine, 1, Murmanskaya Str., Kiev, 02660, Ukraine
c Moscow State University, Chemistry Department, Mosocow, 119991, Russia
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
2-Chloro-N-ethoxycarbonylmethylpyridinium bromide reacts with substituted acetonitriles in
two steps; the initially formed pyridine anhydro baseses undergo further ring closure to 2-amino-
3-ethoxycarbonylindolizines.
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
2-Aminoindolizine
Pyrrole ring synthesis
CH-acids
2-Chloro-N-ethoxycarbonylmethylpyridinium
bromide
1. Introduction
2-Chloro(bromo)pyridinium salts I with a potentially ylidic N-
CH2COR-group are important precursors of various pyrido-
annelated heterocycles with bridgehead nitrogen atom.1 The
structure of the products formed from these salts strictly depends
on the nature of the CH2COR group. Thus, the salts with
methylketone residue Ia (R=Ar), Scheme 1, smoothly react with
nucleophiles (reactions 1a, 2a)2,3 or dipolarophiles (reaction 3a)4
giving the expected products of ring closure.
Scheme 2
anhydro bases II which may undergo further cyclization to 2-
aminoindolizines III.8 Recently we have expanded this novel
synthetic route to indolizines III by involving salts Ia in
reactions 4a with diversely substituted acetonitriles (R’ = α-
heteroaryl group).9
Similar reaction 4b of the salts Ib towards CH-acidic
acetonitriles may result in the interesting class of bifunctional 2-
aminoindolizines bearing ester groups at position 3. This
reaction, however, was never studied before and is the goal of the
present communication.
Scheme 1
In contrast, analogous salts Ib with more reactive acetic ester
group CH2CO2Et react with the same reagents in a more
complicated way (reactions 1b, 2b, 3b),5-7 see Scheme 2, so that
the products involve two structural units of the parent salt Ib.
2. Results and discussion
We found that 2-chloro-1-(2-ethoxy-2-oxoethyl)pyridinium
bromide 1 readily reacts with various acetonitrile derivatives 2a-e
in the presence of two equivalents of a tertiary amine, and the
structure of product strongly depends on the nature of the CH-
acid (Scheme 3, Tables 1,2). In the case of cyanoacetic ester 2a
Kröhnke demonstrated that the reaction 4a (Scheme 1)
between 2-chloropyridinium salt Ia and either malononitrile or
ethyl cyanoacetate in the presence of Hunig's base yielded

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Tetrahedron
(X = CO2Et) the product was the pyridine anhydro base 3a,
the group (X or CN) located at the end of the double bond.
Therefore, one might expect that in the E-isomers (B on Scheme
4), the signals H-3 should be much more downfielded (due to the
influence of the ester or thiazolyl group X) than in the Z-isomers
A (without such influence from the CN group). This expectation
is completely confirmed (as shown by chemical shifts of the
protons H-3 and H-8 labeled by squares in Scheme 3). Therefore,
the observed high values (δ>8) for H-3 in the spectra of anhydro
bases 3 clearly indicate their E configuration (B). (Since the data
for “ideal” reference dicyano-structure 3f with R=CH2CO2Et
were not available due to its spontaneous ring closure to 4f, the
NMR data were taken for simplest structure 3g with R=Me).11
whereas malononitrile 2f (X = CN) gave aminoindolizine 4f.
Scheme 3
Thiazolyl-substituted acetonitriles 2b-e (X = α-thiazolyl)
gave either pure pyridine anhydro bases 3d,e (in cases 2d,e) or
mixtures of anhydro bases 3b, 3c with minor amounts of
1
indolizines 4b, 4c (3:4 ~ 85:15 by H NMR spectroscopy). All
the anhydro bases 3a-e smoothly underwent ring closure to
indolizines 4a-e upon treatment with 10% KOH in DMF.
In the IR spectra of all of the aminoindolizines 4 the
characteristic frequency of amino group was observed at 3316-
1
3485 cm-1, and in their H NMR spectra a broad singlet for the
NH2-group appeared at ~7 ppm (6.5 for 4a). The signal of proton
H-5, appeared as a doublet (for 4b,c,f J = 6.7-7.2 Hz) or a broad
singlet (for 4a,d,e), and is strongly downshifted (δ = 9.32-9.39)
due to the well-known peri-effect of the magnetically anisotropic
3-CO2Et group, typical for indolizines.10
Additional to peri-effect from position 3 towards proton H-5,
an analogous downfield shift was observed for proton H-8 from
similar groups located at peri-position 1. Thus, the chemical shift
of proton H-8 in the indolizine 4a with 1-CO2Et groups appeared
at 7.94 ppm, whereas in the analogous 1-cyanoderivative 4f
(where the CN group is incapable to peri-effect) the signal for H-
8 is located at 7.36-7.48 ppm. A similar downfield location for
the signal of H-8 in 1-(2-thiazolyl)-derivatives 4b-e (at 7.79-7.85
ppm) clearly indicates the peri-influence of the C=N bond of the
thiazolyl ring, which has the same nature as the C=O bond of the
ester group in the indolizine 4a (see also Scheme 3 and
discussion below).
Scheme 4
The observed Z-configuration of anhydro bases 3 may be
clearly understood for steric reasons, since the less bulky CN
group and NCH2CO2Et residue expected to be cis-oriented to
each other. On the other hand, this spatial vicinity of the CN and
CH2CO2Et groups strongly favor the next step – Thorpe-Ziegler
cyclization to form the pyrrole ring of indolizines 4. Concerning
the differences in behavior of different CH-acids (formation of 3,
4 or their mixtures) one may suppose that the stronger is the
acceptor properties of the groups X in 3, the easier is the final
cyclization step to 4 (cf. where X=CN or nitrophenyl-substituted
thiazole against X=CO2Et and other thiazolyl radicals).
The isomeric anhydro bases 3 can be clearly distinguished
1
from the indolizines 4 by H NMR spectroscopy: in all cases the
One interesting observation on the structure of the parent
pyridinium salt 1 cannot be neglected: its mass spectrum
displayed two peaks of molecular ions corresponding both to 2-
chloro (1a) and 2-bromo (1b) pyridinium cations, Scheme 5. This
effect was also observed in the spectra of the analogous 2-
chloropyridinium bromides Ia,1 and can be rationalized by the
higher nucleophilicity of the bromide ion versus chloride.
singlet of the methylene NCH2 group appeared at δ = 5.18-5.29
ppm for all structures 3 and at δ = 48-50 ppm in the 13C NMR
spectra. Since the CN-group in anhydro bases 3 was preserved, it
can be observed in the IR spectra as a broad vibrational band at
2169-2179 cm-1. The frequency of the non-conjugated carbonyl
function of the ester group (1726-1747 cm-1) in anhydro bases 3
dramatically differed from the frequency of the conjugated
CO2Et group in indolizines 4 (ν 1665-1673 cm-1).
It is an interesting problem to establish the configuration of
the non-symmetrical double bond in anhydro bases 3 only from
their 1H NMR spectra. In our opinion, it is instructive to compare
the isostructutral parts of anhydro bases 3 and of indolizines 4, as
shown on Scheme 4.
Scheme 5
According to the 1H NMR spectra, the ratio 1a:1b (~70:30) is
not influenced by further heating of the parent salt. In our
opinion, this fact does not influence the nature and distribution of
the products 3,4, but may be dramatic if the halogen is preserved
(like in cycloadditions of the ylides from salts I).1,12
As was shown above, the chemical shift of proton H-8 in
indolizines 4 is very sensitive to the nature of the substituent in
position 1 due to the peri-effect. In the isostructural anhydro
bases 3 the proton H-3 (spatially corresponding to proton H-8 in
4) should definitely undergo a similar (“peri-like”) effect from

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Table 1. Characteristics of dihydropyridines 3a-e (Scheme 3)
Compd
Yield (%)
47
X
Product
3a
CO2Et
3b
71
N
S
N
EtO
N
O
3c
42
3d
76
3e
58
To conclude, the reaction of readily available pyridinium salt 1
(having an acetic ester residue at nitrogen atom) with various
acetonitriles 2, provides a smooth route to an interesting
bifunctional scaffold – aminoindolizine esters 4 with various
groups at C-1. In contrast to earlier observed (and somewhat
complex, Scheme 2) behavior of the salts Ib, the discovered
transformation of 1 to 4 occurs smoothly, and in many cases,
interesting stable multifunctional anhydro bases 3 can be isolated
as intermediates.
of the products was monitored by TLC on Silufol UV-254 plates
(acetone-hexane, 3:5). Mass spectra were measured on MX-1321
(EY, 70 eV) mass spectrometer. Melting points were determined
on a Kofler hot stage. The elemental analysis data were obtained
for 3a, 3d, 4d using Carlo Erba 11-06 (±0.01%) and for other
compounds using Euro Vector EA 300 (±0.1%).
A
mixture of 2-chloro-1-(2-ethoxy-2-oxoethyl)pyridinium
bromide 1a and 2-bromo-1-(2-ethoxy-2-oxoethyl)pyridinium
chloride 1b
It should be mentioned that indolizines bearing 2-amino and
3-alkoxycarbonyl groups are poorly investigated; the only known
structure is an indolizine (obttained from α-pyridyl acetonitrile
and bromoacetate) described in patent literature13 as a precursor
of biologically active pyrido[2,3-b]indolizines. Several N-alkyl-
A mixture of 2-chloropyridine (30.0 mmol) and ethyl 2-
bromoacetate (32.0 mmol) was heated without solvent at 80-
85°C for 3h. After cooling, the mixture was diluted with acetone
(40 mL) and kept for 24 h at ambient temperature. The residue
was filtered and washed with acetone. Yield: 2.5 g (30%), white
solid, mp 186 °C; νmax (KBr): 1741 сm-1; δH (400 MHz, DMSO-
d6) 9.25 (1 Н, d, J 6.2 Hz, H-6 (1b)), 9.21 (1 Н, d, J 6.2 Hz, H-6
(1a)), 8.76 (1 Н, td, J 8.2, 1.7 Hz, H-4 (1a)), 8.66-8.56 (2 Н, m,
Н-3,Н-4 (1b)), 8.52 (1 Н, d, J 8.3 Hz, H-3 (1a)), 8.30-8.21 (1 Н,
14,15
and N-tosyl-16 derivatives with a 3-CO2R group were
obtained via cycloaddition to pyridinium ylides (frequently as
side products).
Experimental section
IR spectra were measured with a Perkin-Elmer spectrometer
1
in dry KBr pellets. H and 13C NMR spectra were recorded with
Bruker DRX-200 (200 MHz), Bruker AVANCE II-400 (400
MHz) and Bruker AC-400 (400 MHz) spectrometers. The purity

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Tetrahedron
Table 2. Characteristics of indolizines 4a-f (Scheme 3)
Compd
Yield (%)
69
X
Product
4а
CO2Et
4b
85
86
4c
4d
89
4e
41
4f
CN
67
m, Н-5 (1a+1b)), 5.83 (2 Н, s, NCH2 (1a+1b)), 4.27 (2Н, qd, J
7.1, 2.0 Hz, CH2CH3 (1a+1b)), 1.25 (3 Н, td, J 7.1, 0.9 Hz,
CH2CH3 (1a+1b)); δC (100 MHz, CCl4–DMSO-d6) 164.63,
164.56, 149.3, 149.0, 147.8, 139.8, 139.4, 133.8, 129.9, 126.8,
126.6, 119.1, 62.4, 61.9, 60.6, 59.4, 13.80, 13.76; m/z (EI, 70 eV)
525 (4.2), 481 (4.7), 244 (36, M-1) (1b), 200 (100%, M-1) (1a).
distilled water and kept for 24 hour in the fridge. The residue was
filtered, washed with distilled water, then with ethanol and
recrystallized (for solvent, see Table 1).
Ethyl
(E)-2-cyano-2-[1-(2-ethoxy-2-oxoethyl)pyridin-2(1H)-
ylidene]acetate (3a).
Yellow solid, m.p. 115 °C (MeOH); [Found: C, 60.77; H, 5.82;
N, 10.18. C14H16N2O4 requires C, 60.86; H, 5.84; N, 10.14 %];
νmax (KBr): 2179, 1746, 1655 сm-1; δH (400 MHz, DMSO-d6)
8.10 (2 Н, d, J 8.50 Hz, Н-3, H-6), 7.84-7.75 (1 Н, m, Н-4), 7.11-
7.03 (1 Н, m, Н-5), 5.18 (2 Н, s, NCH2), 4.17 (2 Н, q, J 7.11 Hz,
CH2CH3), 4.04 (2 Н, q, J 7.08 Hz, CH2CH3), 1.13-1.29 (6 Н, m,
CH2CH3); δC (100 MHz, DMSO-d6) 167.3, 166.5, 157.6, 143.5,
138.6, 125.7, 121.6, 115.6, 96.1, 61.9, 59.1, 58.1, 15.0, 14.3; m/z
(EI, 70 eV) 276 (97.5, M+), 158 (87), 132 (100%).
2-[1-(2-Ethoxy-2-oxoethyl)pyridin-2(1H)-ylidene]acetonitriles
(3a-e), 2-amino-1-cyano-3-ethoxycarbonylindolizine (4f)
The salt 1 (2.0 mmol) and corresponding acetonitrile 2 (2.0
mmol) was dissolved in ethanol (15 mL). To the stirred mixture,
2 equiv of triethylamine was added, and the solution was stirred
for 4 hours at RT and kept for 24 hour in the fridge (-10 °C). The
residue was filtered, washed with cold ethanol and recrystallized
(for solvents, see Table 1, 2).
2-Amino-1-(R)-3-ethoxycarbonylindolizine (4a-e)
(E)-2-[1-(2-Ethoxy-2-oxoethyl)pyridin-1(2H)-ylidene]-2-(4-
phenylthiazol-2-yl)acetonitrile (3b).
Anhydro base 3 (1.0 mmol) was dissolved in DMF (5-7 ml). To
stirred solution the aqueous 10% KOH (1,0 mmol) was added.
After stirring for 3-4 hours the mixture was mixed with 5-7 ml of
Orange solid, m.p. 164-165 °C (EtOH); [Found: C, 66.1; H, 4.5;
N, 11.6; S 8.8. C20H17N3O2S requires C, 66.10; H, 4.71; N, 11.56;

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S 8.82 %]; νmax (KBr): 2172, 1726 сm-1; δH (400 MHz, DMSO-
2-Amino-1-(4-phenylthiazol-2-yl)-3-ethoxycarbonylindolizine
(4b).
d6) 8.67 (1 Н, d, J 9.2 Hz, Н-3), 7.95-7.87 (3 Н, m, Н-6, HAr),
7.71 (1 Н, s, Hthiazolyl), 7.69-7.60 (1 H, m, H-4), 7.48 (1 H, t, J 7.5
Hz, HAr), 7.42 (2 H, t, J 7.5 Hz, HAr), 6.86-6.76 (1 Н, m, Н-5),
5.27 (2 Н, s, NCH2), 4.14 (2 Н, q, J 7.1 Hz, CH2CH3), 1.1 (3 Н, t,
J 7.1 Hz, CH2CH3); δC (100 MHz, DMSO-d6) 167.7, 167.1,
153.8, 153.1, 142.8, 137.2, 134.9, 129.0, 128.9, 127.9, 126.5,
126.3, 113.3, 109.1, 62.0, 59.6, 57.7, 14.4; m/z (EI, 70 eV) 363
(100%, M+).
Yellow solid, m.p. 139-140 °C (EtOH); [Found: C, 66.1; H, 5.1;
N, 11.6; S 8.8. C20H17N3O2S requires C, 66.10; H, 4.71; N, 11.56;
S 8.82 %]; νmax (KBr): 3485, 3329, 1668 сm-1; δH (200 MHz,
DMSO-d6) 9.37 (1 Н, d, J 6.8 Hz, Н-5), 8.03 (2 H, d, J 7.0 Hz,
HAr), 7.98 (1 Н, s, Hthiazolyl), 7.81 (1 Н, d, J 8.8 Hz, Н-8), 7.52-
7.31 (4 Н, m, H-7, HAr), 7.07 (2 Н, s, NH2), 6.99 (1 Н, t, J 6.8 Hz,
H-6), 4.36 (2 H, q, J 7.1 Hz, CH2CH3), 1.37 (3Н, t, J 7.1 Hz,
CH2CH3); δC (100 MHz, CDCl3) 170.0, 166.4, 162.0, 153.8,
153.4, 134.5, 134.1, 128.7, 128.0, 126.3, 125.8, 125.4, 118.4,
115.0, 111.5, 107.1, 59.6, 14.8; m/z (EI, 70 eV) 363 (100%, M+).
(E)-2-[4-(4-Methoxyphenyl)thiazol-2-yl-2-[1-(2-ethoxy-2-
oxoethyl)pyridin-2(1H)-ylidene]acetonitrile (3c).
Orange solid, m.p. 158-159 °C (EtOH); [Found: C, 64.1; H, 4.7;
N, 10.7; S 8.1. C21H19N3O3S requires C, 64.10; H, 4.87; N, 10.68;
S 8.15 %]; νmax (KBr): 2171, 1747 сm-1; δH ( 400 MHz, DMSO-
d6) 8.65 (1 H, d, J 9.0 Hz, H-3,), 7.88-7.82 (3 H, m, H-6, HAr),
7.65-7.57 (1 H, m, H-4), 7.54 (1 H, s, Hthiazolyl), 6.97 (2 H, d, J 8.7
Hz, HAr), 6.77 (1 H, t, J 6.7 Hz, H-5), 5.26 (2 H, s, NCH2), 4.15
(2 H, q, J 7.1 Hz, CH2CH3), 3.78 (3 H, s, OCH3), 1.19 (3 H, t, J
7.1 Hz, CH2CH3); δC (100 MHz, DMSO-d6) 171.3, 170.4, 162.7,
157.0, 156.3, 146.3, 141.0, 131.2, 131.0, 127.4, 118.5, 118.0,
117.8, 116.9, 110.7, 65.5, 61.2, 58.9, 17.7; m/z (EI, 70 eV) 393
(100%, M+).
2-Amino-1-(4-methoxyphenylthiazol-2-yl)-3-ethoxycarbonyl-
indolizine (4c).
Yellow solid, m.p. 157 °C (EtOH); [Found: C, 64.1; H, 5.0; N,
10.7; S 8.0. C21H19N3O3S requires C, 64.10; H, 4.87; N, 10.68; S
8.15 %]; νmax (KBr): 3464, 3313, 1670 сm-1; δH (200 MHz,
DMSO-d6)9.36 (1 H, d, J 6.7 Hz, H-5), 7.95 (2 H, d, J 8.8 Hz,
HAr), 7.83-7.79 (2 H, m, H-8, Hthiazolyl), 7.44 (1 H, t, J 9.0 Hz, H-
7), 7.10-6.95 (5 H, m, HAr, NH2, H-6), 4.36 (2 H, q, J 7.1 Hz,
CH2CH3), 3.80 (3 H, s, OCH3), 1.37 (3 H, t, J 7.1 Hz, CH2CH3);
δC (100 MHz, CDCl3) 166.5, 160.8, 158.3, 152.3, 144.5, 133.8,
127.4, 126.4, 124.6, 113.8, 112.8, 110.3, 104.2, 100.0, 99.6, 94.3,
58.4, 54.2, 13.6; m/z (EI, 70 eV) 393 (100%, M+).
(E)-2-[4-(4-Chlorophenyl)thiazol-2-yl-2-[1-(2-ethoxy-2-
oxoethyl)pyridin-2(1H)-ylidene]acetonitrile (3d).
Orange solid, m.p. 183-184 °C (EtOH); [Found: C, 60.41; H,
4.11; N, 10.61. C20H16ClN3O2S requires C, 60.37; H, 4.05; N,
10.56 %]; νmax (KBr): 2173, 1740 сm-1; δH (400 MHz, DMSO-d6)
8.65 (1 Н, d, J 9.3 Hz, Н-3), 7.95-7.87 (3 Н, m, Н-6, HAr), 7.78 (1
H, s, Hthiazolyl), 7.64 (1 Н, dd, J 9.3, 6.7 Hz, Н-4), 7.47 (2 H, d, J
8.5 Hz, HAr), 6.82 (1 H, t, J 6.7 Hz, Н-5), 5.27 (2 Н, s, NCH2),
4.15 (2 Н, q, J 7.1 Hz, CH2CH3), 1.19 (3 Н, t, J = 7.1 Hz,
CH2CH3); δC (100 MHz, DMSO-d6) 167.5, 167.2, 152.6, 152.1,
142.6, 137.5, 133.3, 132.1, 128.7, 127.61, 127.57, 123.6, 123.2,
113.4, 109.5, 61.7, 57.4, 13.9; m/z (EI, 70 eV) 397 (100%, M+).
2-Amino-1-(4-chlorophenylthiazol-2-yl)-3-ethoxycarbonyl-
indolizine (4d).
Yellow solid, m.p. 175-176 °C (EtOH); [Found: C, 60.39; H,
4.10; N, 10.59. C20H16ClN3O2S requires C, 60.37; H, 4.05; N,
10.56 %]; νmax (KBr): 3470, 3316, 1673 сm-1; δH (400 MHz,
DMSO-d6) 9.39 (1 H, s, H-5), 8.10-8. 04 (3 H, m, HAr, Hthiazolyl),
7.83 (1 H, d, J 8.9 Hz, H-8,), 7.53 (2 H, d, J 8.5 Hz, HAr), 7.51-
7.44 (1 H, m, H-7), 7.05 (2 H, s, NH2), 7.01 (1H, t, J 6.5 Hz, H-
6), 4.37 (2 H, q, J 7.1 Hz, CH2CH3), 1.38 (3 H, t, J 7.1 Hz,
CH2CH3); δC (100 MHz, CDCl3) 166.4, 162.2, 161.9, 152.6,
135.4, 133.7, 133.0, 128.8, 128.7, 127.5, 125.9, 115.0, 111.6,
107.5, 106.1, 99.7, 59.6, 14.8; m/z (EI, 70 eV) 397 (100%, M+).
(E)-2-[4-(4-Nitrophenyl)thiazol-2-yl-2-[1-(2-ethoxy-2-
oxoethyl)pyridin-2(1H)-ylidene]acetonitrile (3e).
Orange solid, m.p. 221 °C (EtOH); [Found: C, 58.6; H, 4.2; N,
13.6; S 7.8. C20H16N4O4S requires C, 58.81; H, 3.95; N, 13.72; S
7.85 %]; νmax (KBr): 2169, 1727 сm-1; δH (400 MHz, DMSO-d6)
8.70 (1 Н, d, J 9.5 Hz, Н-3), 8.28 (2 Н, d, J 8.9 Hz, , HAr), 8.17 (2
H, d, J 8.9 Hz, , HAr), 8.09 (1 Н, s, Hthiazolyl), 7.96 (1 H, d, J 7.1
Hz, Н-6), 7.74-7.64 (1 H, m, Н-4), 6.88 (1 H, t, J 7.1 Hz, Н-5),
5.29 (2 Н, s, NCH2), 4.16 (2 Н, q, J 7.2 Hz, CH2CH3), 1.19 (3 Н,
t, J 7.2 Hz, CH2CH3); δC (100 MHz, DMSO-d6) 168.1, 167.7,
153.2, 151.6, 146.7, 143.0, 140.9 137.7, 127.4, 127.1, 124.5,
124.3, 113.9, 113.5, 96.0, 62.1, 57.7, 14.3; m/z (EI, 70 eV) 408
(100%, M+).
2-Amino-1-(4-nitrophenylthiazol-2-yl)-3-ethoxycarbonyl-
indolizine (4e).
Brown solid, m.p. 203-204 °C (EtOH); [Found: C, 58.1; H, 3.6;
N, 13.6; S, 7.7. C20H16N4O4S requires C, 58.81; H, 3.95; N,
13.72; S, 7.85]; νmax (KBr): 3499, 3359, 1667 сm-1; δH (400 MHz,
DMSO-d6) 9.38 (1 Н, s, Н-5), 8.38 (1 Н, s, Hthiazolyl), 8.31 (4 H, s,
HAr), 7.85 (1 Н, d, J 8.9 Hz, Н-8), 7.54-7.44 (1 Н, m, H-7), 7.10-
6.95 (3 Н, m, H-6, NH2), 4.38 (2 H, q, J 7.1 Hz, CH2CH3), 1.39
(3 H, t, J 7.1 Hz, CH2CH3); δC (100 MHz, DMSO-d6) 172.5,
161.1, 158.1, 146.6, 139.8, 138.6, 134.8, 128.2, 126.9, 124.1,
120.3, 114.7, 113.2, 112.5, 109.7, 99.5, 59.4, 14.6; m/z (EI, 70
eV) 408 (100%, M+).
2-Amino-1,3-di(ethoxycarbonyl)indolizine (4a).
White solid, m.p. 113 °C (MeOH); [Found: C, 60.9; H, 5.9; N,
10.1. C14H16N2O4 requires C, 60.86; H, 5.84; N, 10.14 %]; νmax
(KBr): 3515, 3387, 1666 сm-1; δH (400 MHz, DMSO-d6) 9.32 (1
Н, s, Н-5), 7.94 (1 Н, d, J 8.8 Hz, Н-8), 7.41 (1 Н, t, J 7.8 Hz, Н-
7), 7.02 (1 Н, t, J 6.4 Hz, Н-6), 6.48 (2 Н, s, NН2), 4.31 (4 Н, dq,
J 14.3, 7.1 Hz, CH2CH3), 1.34 (6 Н, t, J 7.1 Hz, CH2CH3); δC
(100 MHz, CDCl3) 165.6, 165.5, 161.8, 138.7, 128.2, 126.8,
117.3, 112.8, 99.9, 90.3, 59.6, 59.4, 14.7, 14.6; m/z (EI, 70 eV)
276 (73.2, M+), 158 (100%).
2-Amino-1-cyano-3-ethoxycarbonylindolizine (4f).
Colorless solid, m.p. 151 °C (MeOH); [Found: 62.9; H, 4.9; N,
18.3. C12H11N3O2 requires: C, 62.87; H, 4.84; N, 18.33]; νmax
(KBr): 3469, 3343, 2207, 1675 сm-1; δH (200 MHz, DMSO-d6)
9.25 (1 Н, d, J 7.2 Hz, Н-5), 7.48-7.36 (2 Н, m, Н-7, Н-8), 7.06-
6.98 (1 Н, m, Н-6), 6.49 (2 Н, s, NН2), 4.33 (2 H, q, J 7.0 Hz,
CH2CH3), 1.32 (3 H, t, J 7.0 Hz, CH2CH3); δC (100 MHz, CDCl3)
163.7, 161.2, 139.4, 128.7, 126.9, 115.3, 115.0, 113.3, 100.0,
93.1, 60.1, 14.7; m/z (EI, 70 eV) 229 (100%, M+).

ACCEPTED MANUSCRIPT
6
Tetrahedron
Acknowledgments
EVB thanks Russian Foundation of Basic Research (RFBR
grant No. 12-03-00644a) for support.
References and notes
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