A new synthetic approach to pyrrolo[3,4-a]indolizines

Article abstract of DOI:10.1055/s-2005-918510

2-Pyridineacetonitrile was found to react with 1,3-dichloro-2-propanone in the presence of chlorotrimethylsilane yielding 2-chloromethyl-1- indolizinecarbonitrile. The chlorine atom in the prepared indolizine was replaced by various nucleophiles including

Full text of DOI:10.1055/s-2005-918510

PAPER
349
A New Synthetic Approach to Pyrrolo[3,4-a]indolizines
P
yrrolo[3,4-
a
]indo
l
lizine
s
exander D. Tereshchenko,a Dmitry A. Sysoiev,b Anton V. Tverdokhlebov,*a Andrey A. Tolmachevb
a
Enamine Ltd., Alexandra Matrosova str. 23, 01103 Kiev, Ukraine
Fax +380(44)5373253; E-mail: atver@univ.kiev.ua
Kiev National Taras Shevchenko University, Volodimirska str. 62, 01033 Kiev, Ukraine
b
Received 29 June 2005; revised 26 July 2005
give cyclic amidines 2 (Figure 1) or their salts.6 Recently,
Abstract: 2-Pyridineacetonitrile was found to react with 1,3-
dichloro-2-propanone in the presence of chlorotrimethylsilane
yielding 2-chloromethyl-1-indolizinecarbonitrile. The chlorine
atom in the prepared indolizine was replaced by various nucleo-
a similar pyrrole annulation has been reported by us for
fused
pyridine
derivatives.7
Continuing
our
investigations7,8 on the amination of heterocycles contain-
philes including substituted anilines. Treatment of 2-(arylami- ing a 4-halonitrile moiety, we were interested to prepare
no)methyl-1-indolizinecarbonitriles with hydrochloric acid resulted
in 2-aryl-2,3-dihydro-1H-pyrrolo[3,4-a]indolizine-1-iminium chlo-
rides.
2-(chloromethyl)indolizine-1-carbonitrile (4) as a precur-
sor of target pyrroloindolizines. Since certain amidines
derived from structure 2 were claimed as anesthetic, anti-
arrhythmic, antihypertensive, and antiinflammatory
Key words: alkylations, amidines, chlorotrimethylsilane, nitriles,
agents,9 the synthesis of pyrroloindolizine amidines on the
ultrasound
basis of compound 4 leads to the combination of the active
fragments4,9 and, therefore, is promising from a biological
viewpoint.
Pyrrolo[3,4-a]indolizine chemistry was developed inten-
sively in the 1980s as a part of general investigations on
ylide cycloaddition reactions. Thus, maleimides were
found to be suitable traps for ylides and, as the result, var-
ious pyrrolo[3,4-a]indolizines were obtained by addition
of pyridinium ylides to maleimides.1 Moreover, a number
of hydrogenated pyrroloindolizines was prepared nearly
at the same time by reaction of certain piperidine-derived
azomethine ylides with maleimides.2 Along with the syn-
thesis some properties of pyrroloindolizines were also
studied.3 In particular, potent thrombin inhibitors with
high selectivity for thrombin over trypsin have been dis-
covered recently among pyrrolo[3,4-a]indolizines.4 This
finding stimulated new researches on their synthesis.5
However, all further investigations5 exploited the old cy-
cloaddition strategy for pyrroloindolizine skeleton con-
struction and were rather devoted to novel ylides and
methods of their generation, whereas the trapping agents
remained to be maleimides. As the result a curious situa-
tion appeared when almost all pyrrolo[3,4-a]indolizines
known to date are 1,3-dioxo derivatives of type 1
(Figure 1). A few compounds with another substitution
pattern of the pyrrole moiety exhibiting the highest bio-
logical activity4b were obtained by further transformations
of dioxo derivatives 1. Hence, elaboration of an alterna-
tive approach to pyrrolo[3,4-a]indolizines providing an-
other substitution pattern at positions 1 and 3 is of great
interest.
Figure 1
Pyridin-2-ylacetonitrile (3) was described to react with a-
haloketones yielding indolizine-1-carbonitriles.10 The use
of 1,3-dichloroacetone in this reaction should afford chlo-
romethyl derivative 4 (Scheme 1). However, attempts to
perform the condensation of compound 3 with 1,3-dichlo-
roacetone under the conditions reported10 for other ha-
loketones gave unsatisfactory results. According to the
literature,10 the indolizine formation occurs via initial N-
alkylation of pyridine 3 with haloketone and further in-
tramolecular condensation. In the case of 1,3-dichloroac-
etone there are two pathways for further transformations
of the appropriate alkylated intermediate, namely the in-
tramolecular condensation with the carbonyl group and
the intramolecular alkylation with the second CH2Cl
group. This vague behavior is believed to be a reason of
the failure. Therefore, inversion of the reaction sequence
during the indolizine synthesis was assumed to facilitate
the preparation of compound 4. Indeed, if the reaction
starts from a Knoevenagel-type condensation of pyridine
3 with 1,3-dichloroacetone, the following intramolecular
alkylation should proceed clearly because of the absence
of any alternative. Hence, the problem was to achieve
firstly condensation and to suppress initial alkylation. It
was solved using chlorotrimethylsilane (TMSCl) as con-
densing agent. Thus, TMSCl and related halosilanes were
reported to promote certain condensation reactions in-
cluding those with unusual methylene and carbonyl com-
A well-known method of pyrrole ring annulation is the re-
action of vicinal halomethyl-substituted nitriles with
primary amines. Thus, amination of 2-(chloro-
methyl)benzonitrile and related compounds has shown to
SYNTHESIS 2006, No. 2, pp 0349–0353
x
x
.
x
x
.2
0
0
5
Advanced online publication: 21.12.2005
DOI: 10.1055/s-2005-918510; Art ID: Z12605SS
© Georg Thieme Verlag Stuttgart · New York

350
A. D. Tereshchenko et al.
PAPER
Scheme 1
ponents.11 Treatment of pyridine
3
with 1,3- spectra of compounds 7 clearly indicated the ring closure
dichloroacetone in the presence of an excess of TMSCl al- with its participation. A very characteristic signal of the
lowed to obtain the desired indolizine 4 in 65% isolated amidinium carbon atom appeared in the 13C NMR spectra
yield.
of derivatives 7 at 156–158 ppm. The signals of the immo-
nium group hydrogen atoms were observed as two broad
one-proton singlets at 9.6–9.7 and 8.4–8.6 ppm. The one-
proton doublet of 9-H of compounds 7 was present in the
spectra at 8.5–8.6 ppm, whereas for their precursors 6 the
same atom (8-H) signal was observed at 7.5–7.6 ppm.
This 1 ppm shift is the remarkable attribute of the cycliza-
tion and is explained by deshielding of 9-H by the neigh-
boring magnetically anisotropic immonium group in
derivatives 7, which is absent for compounds 6. In addi-
tion, it is interesting to note that for the naphthyl-substitut-
ed derivative 7d the signal of the methylene hydrogen
atoms appeared as two one-proton doublets at 4.75 ppm
and 4.68 ppm with a geminal coupling constant of
J = 15.3 Hz. It is probably the restricted rotation of the
naphthyl moiety around the C–N bond that brings in an
axial chirality to molecule 7d and makes the hydrogen at-
oms of the methylene group magnetically non-equivalent.
A similar effect was reported previously for certain N-(1-
naphthyl)-substituted pyrrole derivatives.13
As expected, a nucleophilic substitution of the chlorine in
compound 4 proceeded smoothly yielding the corre-
sponding derivatives 5a–e. When anilines were employed
as nucleophiles a concomitant bis-alkylation process was
observed. Therefore, the reaction conditions were opti-
mized in order to obtain pure mono-alkylated products
6a–d. Aprotic solvents were found to facilitate bis-alkyla-
tion, whereas the starting chloride 4 was less soluble in al-
cohols. Nevertheless, compounds 6a–d were obtained in
50–80% yields when the reaction was carried out hetero-
geneously in i-PrOH in the presence of triethylamine and
using ultrasonic irradiation12 as a high effective stirring
equivalent. Application of these conditions to the prepara-
tion of derivatives 5a–e also gave better results and,
hence, we accepted it as the standard for chlorine substi-
tution in compound 4.
Upon reflux in ethanol in the presence of aqueous hydro-
chloric acid, compounds 6a–d underwent cyclization to
form the target pyrrolo[3,4-a]indolizine amidinium salts
7a–d. It should be noted that, during amination of the 2-
(chloromethyl)benzonitrile, amidinium salts 2 were al-
ways formed directly without isolation of the alkylated in-
termediate.6 Probably, the ring closure was accomplished
at the expense of HCl liberated during the alkylation step.
In the present case we failed to achieve a direct conversion
of the indolizine 4 into derivatives 7a–d. Furthermore, the
cyclization reaction of compounds 6a–d hardly proceeded
and the yields of salts 7a–d were only moderate (~50%).
Perhaps this could be explained by the lower reactivity of
the nitrile group in compound 4 compared to the corre-
sponding benzonitrile analogue.
To resume, the present investigation has resulted in a new
approach to pyrrolo[3,4-a]indolizine framework con-
struction. It includes pyrrole annulation to the indolizine
nucleus whereas the previously reported methods1–5 are
based on formation of the central ring of the system by
means of cycloaddition reactions. Thus, this work extends
the scope of available pyrroloindolizines and diversifies
the substitution pattern at positions 1 and 3, which hitherto
has been limited to 1,3-dioxo compounds 1.
All starting materials were commercially available. Melting points
were determined in open capillary tubes in a Thiele apparatus and
are uncorrected. 1H and 13C NMR spectra were recorded on a Varian
UNITYplus 400 (400 MHz for 1H and 100 MHz for 13C) spectrom-
eter in DMSO-d6 solutions. Chemical shifts (d) are given in ppm
downfield from internal Me4Si. The purity of all compounds pre-
The structures of the prepared compounds 4–7 were con-
firmed by 1H and 13C NMR spectroscopic data. Thus, ab-
sence of the nitrile absorption both in IR and 13C NMR
Synthesis 2006, No. 2, 349–353 © Thieme Stuttgart · New York

PAPER
Pyrrolo[3,4-a]indolizines
351
pared was verified by 1H NMR spectroscopy and LC/MS on an Ag-
ilent 1100 instrument.
13C NMR: d = 28.1 (CH2), 80.2 (1-C), 113.0 (6-C), 114.4 (8-C),
115.7 (CN), 116.5 (3-C), 123.6 (7-C), 127.2 (1-CNu), 127.5 (2-C),
128.9 (3,5-CNu), 130.2 (2,6-CNu), 130.8 (5-C), 134.7 (4-CNu), 137.3
(8a-C).
2-(Chloromethyl)indolizine-1-carbonitrile (4)
TMSCl (1.09 g, 100 mmol) was added to a solution of pyridin-2-
ylacetonitrile (3, 3.00 g, 25.4 mmol) and 1,3-dichloroacetone (3.87
g, 30.5 mmol) in anhyd DMF (10 mL) in a 50 mL flask. The flask
was sealed thoroughly with a rubber stopper and heated in a boiling
water bath for 4 h. After cooling it was opened (Caution! There is
excessive pressure inside!) and the reaction mixture was poured into
H2O (100 mL). The solid formed was filtered off, washed with H2O,
dried, and recrystallized from i-PrOH to give 3.15 g (65%) of com-
pound 4 as colorless crystals.
Anal. Calcd for C16H11ClN2S: C, 64.32; H, 3.71; N, 9.38; Cl, 11.87;
S, 10.73. Found: C, 64.39; H, 3.73; N, 9.49; Cl, 11.92; S, 10.87.
2-{[(2-Aminophenyl)thio]methyl}indolizine-1-carbonitrile (5d)
Yield: 2.02 g (81%); mp 60 °C.
1H NMR: d = 4.05 (s, 2 H, CH2), 5.35 (s, 2 H, NH2), 6.45 (t, J = 7.6
Hz, 1 H, 5-HNu), 6.71 (d, J = 7.6 Hz, 1 H, 3-HNu), 6.85 (dd, J = 6.8,
7.2 Hz, 1 H, 6-H), 7.02 (dd, J = 6.8, 9.2 Hz, 1 H, 7-H), 7.15 (m, 2
H, 4,6-HNu), 7.47 (s, 1 H, 3-H), 7.55 (d, J = 9.2 Hz, 1 H, 8-H), 8.40
(d, J = 7.2 Hz, 1 H, 5-H).
13C NMR: d = 29.8 (CH2), 81.0 (1-C), 111.5 (6-C), 112.2 (8-C),
112.7 (3-CNu), 115.0 (CN), 116.0 (3-C), 117.2 (5-CNu), 118.5 (1-
Mp 140 °C.
1H NMR: d = 4.82 (s, 2 H, CH2), 6.83 (t, J = 9.0 Hz, 1 H, 6-H), 7.15
(t, J = 9.0 Hz, 1 H, 7-H), 7.56 (d, J = 9.0 Hz, 1 H, 8-H), 7.74 (s, 1
H, 3-H), 8.42 (d, J = 9.0 Hz, 1 H, 5-H).
13C NMR: d = 37.9 (CH2), 80.6 (1-C), 113.9 (6-C), 115.5 (8-C),
115.9 (CN), 117.2 (3-C), 124.7 (7-C), 127.9 (2-C), 128.3 (5-C),
138.1 (8a-C).
CNu), 124.7 (7-C), 128.2 (2-C), 129.1 (5-C), 129.9 (6-CNu), 131.6 (4-
CNu), 135.4 (8a-C), 154.7 (2-CNu).
Anal. Calcd for C16H13N3S: C, 68.79; H, 4.69; N, 15.04; S, 11.48.
Found: C, 68.93; H, 4.73; N, 14.94; S, 11.40.
Anal. Calcd for C10H7ClN2: C, 63.01; H, 3.70; N, 14.69; Cl 18.60.
Found: C, 63.15; H, 3.81; N, 14.72; Cl 18.70.
2-[(1,3-Benzothiazol-2-ylthio)methyl]indolizine-1-carbonitrile
(5e)
Indolizine-1-carbonitriles 5a–e; General Procedure
Yield: 2.26 g (79%); mp 125 °C.
An appropriate amine or thiol (8.92 mmol) and Et3N (0.91 g, 9.0
mmol) were added to a suspension of compound 4 (1.7 g, 8.92
mmol) in i-PrOH (10 mL). The resulting mixture was heated at 60–
70 °C with simultaneous ultrasonic irradiation for 7 h. Then the
mixture was cooled to 4 °C, the solid was filtered off and washed
with cold i-PrOH and H2O. Recrystallization from i-PrOH afforded
derivatives 5a–e as white powders.
1H NMR: d = 4.77 (s, 2 H, CH2), 6.88 (dd, J = 6.8, 7.8 Hz, 1 H, 6-
H), 7.18 (dd, J = 8.8, 7.8 Hz, 1 H, 7-H), 7.36 (t, J = 7.6 Hz, 1 H, 5-
HNu), 7.48 (t, J = 7.6 Hz, 1 H, 6-HNu), 7.59 (d, J = 8.8 Hz, 1 H, 8-H),
7.79 (s, 1 H, 3-H), 7.91 (d, J = 7.6 Hz, 1 H, 7-HNu), 8.01 (d, J = 7.6
Hz, 1 H, 4-HNu), 8.47 (d, J = 6.8 Hz, 1 H, 5-H).
13C NMR: d = 29.9 (CH2), 77.3 (1-C), 114.0 (6-C), 114.7 (8-C),
115.2 (CN), 117.4 (3-C), 118.6 (7-CNu), 119.2 (4-CNu), 122.8 (7-C),
124.8 (5-CNu), 125.7 (2-C), 126.6 (6-CNu), 131.0 (5-C), 134.8 (7a-
2-(Morpholin-4-ylmethyl)indolizine-1-carbonitrile (5a)
Yield: 1.66 g (77%); mp 76 °C.
CNu), 138.4 (8a-C), 152.0 (3a-CNu), 164.3 (2-CNu).
1H NMR: d = 2.95 (m, 4 H, NCH2), 3.61 (m, 6 H, 2-CH2, OCH2),
6.75 (t, J = 6.9 Hz, 1 H, 6-H), 7.05 (t, J = 6.9 Hz, 1 H, 7-H), 7.48 (s,
1 H, 3-H), 7.51 (d, J = 6.9 Hz, 1 H, 8-H), 8.31 (d, J = 6.9 Hz, 1 H,
5-H).
13C NMR: d = 42.8 (CH2), 54.1 (NCH2), 68.2 (OCH2), 79.5 (1-C),
113.6 (6-C), 115.2 (3-C), 117.6 (8-C), 117.8 (CN), 125.6 (7-C),
126.1 (2-C), 127.3 (5-C), 136.4 (8a-C).
Anal. Calcd for C17H11N3S2: C, 63.53; H, 3.45; N, 13.07; S, 19.95.
Found: C, 63.60; H, 3.61; N, 13.16; S, 20.06.
2-Anilinomethylindolizine-1-carbonitriles 6a–d; General Pro-
cedure
An appropriate aniline (10.7 mmol) and Et3N (0.91 g, 9.0 mmol)
were added to a suspension of compound 4 (1.7 g, 8.92 mmol) in i-
PrOH (10 mL). The resulting mixture was heated at 60–70 °C with
simultaneous ultrasonic irradiation for 7 h and then was cooled to 4
°C. The precipitate was filtered off, washed with cold i-PrOH and
H2O, and recrystallized from i-PrOH to yield derivatives 6a–d as
white powders.
Anal. Calcd for C14H15N3O: C, 69.69; H, 6.27; N, 17.41. Found: C,
69.67; H, 6.15; N, 17.47.
2-(Piperidin-1-ylmethyl)indolizine-1-carbonitrile (5b)
Yield: 1.47 g (69%); mp 68 °C.
2-{[(4-Ethylphenyl)amino]methyl}indolizine-1-carbonitrile
(6a)
Yield: 1.77 g (72%); mp 105 °C.
1H NMR: d = 1.41 (m, 2 H, 4-HNu), 1.54 (m, 4 H, 3,5-HNu), 2.40 (m,
4 H, 2,6-HNu), 3.57 (s, 2 H, 2-CH2), 6.74 (dd, J = 6.9, 7.8 Hz, 1 H,
6-H), 7.04 (dd, J = 9.0, 7.8 Hz, 1 H, 7-H), 7.44 (s, 1 H, 3-H), 7.50
(d, J = 9.0 Hz, 1 H, 8-H), 8.30 (d, J = 6.9 Hz, 1 H, 5-H).
13C NMR: d = 23.9 (CH2), 29.3 (2 CH2), 47.9 (2-CH2), 58.6
(NCH2), 79.6 (1-C), 114.0 (8-C), 115.9 (6-C), 116.0 (CN), 116.1 (3-
C), 122.7 (7-C), 126.8 (2-C), 128.0 (5-C), 139.4 (8a-C).
1H NMR: d = 1.09 (t, J = 7.2 Hz, 3 H, CH3), 2.42 (q, J = 7.2 Hz, 2
H, CH2), 4.35 (s, 2 H, 2-CH2), 5.98 (br s, 1 H, NH), 6.55 (d, J = 8.0
Hz, 2 H, 2,6-HAr), 6.85 (dd, J = 6.8, 7.2 Hz, 1 H, 6-H), 6.90 (d,
J = 8.0 Hz, 2 H, 3,5-HAr), 7.15 (dd, J = 8.0, 7.2 Hz, 1 H, 7-H), 7.57
(m, 2 H, 3-H, 8-H), 8.45 (d, J = 6.8 Hz, 1 H, 5-H).
13C NMR: d = 8.4 (CH3), 27.3 (CH2), 45.2 (2-CH2), 79.5 (1-C),
112.4 (2,6-CAr), 112.8 (6-C), 113.5 (8-C), 116.1 (CN), 116.4 (3-C),
123.2 (7-C), 127.5 (2-C), 128.1 (3,5-CAr), 131.0 (5-C), 131.3 (4-
CAr), 137.2 (8a-C), 146.4 (1-CAr).
Anal. Calcd for C15H17N3: C, 75.28; H, 7.16; N, 17.56. Found: C,
75.39; H, 7.37; N, 17.49.
2-{[(4-Chlorophenyl)thio]methyl}indolizine-1-carbonitrile (5c)
Yield: 2.29 g (86%); mp 88 °C.
Anal. Calcd for C18H17N3: C, 78.52; H, 6.22; N, 15.26. Found: C,
78.39; H, 6.30; N, 15.30.
1H NMR: d = 4.33 (s, 2 H, CH2), 6.84 (dd, J = 6.9, 7.8 Hz, 1 H, 6-
H), 7.14 (dd, J = 9.0, 7.8 Hz, 1 H, 7-H), 7.37 (m, 4 H, HNu), 7.54 (d,
J = 9.0 Hz, 1 H, 8-H), 7.58 (s, 1 H, 3-H), 8.41 (d, J = 6.9 Hz, 1 H,
5-H).
Synthesis 2006, No. 2, 349–353 © Thieme Stuttgart · New York

352
A. D. Tereshchenko et al.
PAPER
2-{[(4-Ethoxyphenyl)amino]methyl}indolizine-1-carbonitrile
(6b)
Yield: 1.77 g (68%); mp 109 °C.
7.53 (d, J = 8.0 Hz, 2 H, HAr), 7.83 (s, 1 H, 4-H), 8.53 (d, J = 8.8 Hz,
1 H, 9-H), 8.58 (br s, 1 H, NH), 8.71 (d, J = 7.2 Hz, 1 H, 6-H), 9.64
(br s, 1 H, NH).
1H NMR: d = 1.25 (t, J = 6.8 Hz, 3 H, CH3), 3.86 (q, J = 6.8 Hz, 2
H, OCH2), 4.32 (s, 2 H, 2-CH2), 5.76 (br s, 1 H, NH), 6.56 (d, J = 8.8
Hz, 2 H, 2,6-HAr), 6.69 (d, J = 8.8 Hz, 2 H, 3,5-HAr), 6.85 (dd,
J = 6.8, 7.2 Hz, 1 H, 6-H), 7.15 (dd, J = 8.0, 7.2 Hz, 1 H, 7-H), 7.58
(m, 2 H, 3-H, 8-H), 8.47 (d, J = 6.8 Hz, 1 H, 5-H).
13C NMR: d = 14.1 (CH3), 44.2 (2-CH2), 64.0 (OCH2), 78.7 (1-C),
112.7 (8-C), 113.0 (6-C), 116.3 (3-C), 118.9 (3,5-CAr), 119.1 (CN),
119.2 (2,6-CAr), 124.9 (7-C), 127.9 (2-C), 131.0 (5-C), 137.5 (8a-
C), 142.4 (1-CAr), 156.7 (4-CAr).
13C NMR: d = 8.3 (CH3), 27.8 (CH2), 45.1 (3-C), 105.4 (9b-C),
107.4 (9-C), 113.9 (7-C), 118.4 (4-C), 123.6 (8-C), 126.3 (2,6-CAr),
128.2 (6-C), 128.3 (3a-C), 129.3 (3,5-CAr), 132.4 (4-CAr), 134.2 (9a-
C), 144.4 (1-CAr), 157.0 (1-C).
Anal. Calcd for C18H18ClN3: C, 69.34; H, 5.82; N, 13.48; Cl, 11.37.
Found: C, 69.25; H, 5.83; N, 13.61; Cl, 11.31.
2-(4-Ethoxyphenyl)-2,3-dihydro-1H-pyrrolo[3,4-a]indolizin-1-
iminium Chloride (7b)
Yield: 0.28 g (57%); mp 254 °C.
Anal. Calcd for C18H17N3O: C, 74.21; H, 5.88; N, 14.42. Found: C,
73.99; H, 5.80; N, 14.40.
1H NMR: d = 1.37 (t, J = 6.9 Hz, 3 H, CH3), 4.12 (q, J = 6.9 Hz, 2
H, CH2), 5.06 (s, 2 H, CH2), 7.05 (dd, J = 6.9, 7.8 Hz, 1 H, 7-H),
7.13 (d, J = 8.7 Hz, 2 H, HAr), 7.32 (dd, J = 9.0, 7.8 Hz, 1 H, 8-H),
7.52 (d, J = 8.7 Hz, 2 H, HAr), 7.81 (s, 1 H, 4-H), 8.41 (br s, 1 H,
NH), 8.53 (d, J = 9.0 Hz, 1 H, 9-H), 8.70 (d, J = 6.9 Hz, 1 H, 6-H),
9.58 (br s, 1 H, NH).
13C NMR: d = 13.7 (CH3), 43.9 (3-C), 59.7 (OCH2), 106.1 (9b-C),
107.0 (9-C), 114.7 (7-C), 118.2 (4-C), 121.2 (3,5-CAr), 124.6 (8-C),
127.3 (6-C), 129.2 (3a-C), 130.5 (2,6-CAr), 133.8 (9a-C), 134.4 (1-
CAr), 156.0 (4-CAr), 157.2 (1-C).
2-{[(3,5-Dimethylphenyl)amino]methyl}indolizine-1-carbo-
nitrile (6c)
Yield: 2.04 g (83%); mp 133 °C.
1H NMR: d = 2.08 (s, 6 H, 2 CH3), 4.34 (d, J = 6.0 Hz, 2 H, CH2),
5.98 (t, J = 6.0 Hz, 1 H, NH), 6.19 (s, 1 H, 4-HAr), 6.25 (s, 2 H, 2,6-
HAr), 6.85 (dd, J = 6.8, 7.2 Hz, 1 H, 6-H), 7.15 (dd, J = 7.6, 7.2 Hz,
1 H, 7-H), 7.57 (m, 2 H, 3-H, 8-H), 8.48 (d, J = 6.8 Hz, 1 H, 5-H).
13C NMR: d = 21.3 (2 CH3), 45.3 (CH2), 79.6 (1-C), 110.3 (2,6-
CAr), 112.8 (6-C), 113.5 (8-C), 116.1 (CN), 116.4 (3-C), 118.2 (4-
CAr), 123.2 (7-C), 127.5 (2-C), 130.9 (5-C), 137.2 (8a-C), 137.6
(3,5-CAr), 148.5 (1-CAr).
Anal. Calcd for C18H18ClN3O: C, 65.95; H, 5.53; N, 12.82; Cl,
10.81. Found: C, 65.74; H, 5.55; N, 12.70; Cl, 10.63.
2-(3,5-Dimethylphenyl)-2,3-dihydro-1H-pyrrolo[3,4-a]indoliz-
in-1-iminium Chloride (7c)
Yield: 0.33 g (71%); mp 187 °C.
Anal. Calcd for C18H17N3: C, 78.52; H, 6.22; N, 15.26. Found: C,
78.60; H, 6.32; N, 15.05.
2-[(1-Naphthylamino)methyl]indolizine-1-carbonitrile (6d)
Yield: 1.38 g (52%); mp 160 °C.
1H NMR: d = 2.36 (s, 6 H, 2 CH3), 5.11 (s, 2 H, CH2), 7.07 (dd,
J = 6.8, 8.4 Hz, 1 H, 7-H), 7.15 (s, 1 H, 4-HAr), 7.23 (s, 2 H, 2,6-
HAr), 7.34 (dd, J = 8.8, 8.4 Hz, 1 H, 8-H), 7.82 (s, 1 H, 4-H), 8.54
(d, J = 8.8 Hz, 1 H, 9-H), 8.57 (br s, 1 H, NH), 8.70 (d, J = 6.8 Hz,
1 H, 6-H), 9.62 (br s, 1 H, NH).
13C NMR: d = 20.9 (2 CH3), 53.8 (CH2), 105.4 (9b-C), 107.4 (9-C),
113.9 (7-C), 118.5 (4-C), 123.6 (2,6-CAr), 126.0 (8-C), 128.2 (6-C),
128.3 (3a-C), 129.9 (4-CAr), 132.3 (9a-C), 136.4 (1-CAr), 139.4 (3,5-
CAr), 156.8 (1-C).
1H NMR: d = 4.62 (d, J = 5.6 Hz, 2 H, CH2), 6.48 (d, J = 7.6 Hz, 1
H, HAr), 6.86 (m, 2 H, NH, 6-H), 7.10–7.23 (m, 3 H, 7-H, 2 HAr),
7.43 (m, 2 H, HAr), 7.58 (d. J = 9.2 Hz, 1 H, 8-H), 7.61 (s, 1 H, 3-
H), 7.76 (d, J = 8.8 Hz, 1 H, HAr), 8.22 (d, J = 7.7 Hz, 1 H, HAr), 8.44
(d, J = 6.9 Hz, 1 H, 5-H).
13C NMR: d = 39.0 (CH2), 79.5 (1-C), 103.5 (4-CAr), 112.8 (6-C),
113.4 (8-C), 115.9 (2-CAr), 116.2 (CN), 116.4 (3-C), 121.8 (3-CAr),
123.1 (8a-CAr), 123.2 (7-C), 124.1 (7-CAr), 125.7 (6-CAr), 126.7 (8-
CAr), 127.5 (2-C), 128.0 (5-CAr), 130.7 (5-C), 134.1 (4a-CAr), 137.3
(8a-C), 143.5 (1-CAr).
Anal. Calcd. for C18H18ClN3: C, 69.34; H, 5.82; N, 13.48; Cl, 11.37.
Found: C, 69.52; H, 5.63; N, 13.69; Cl, 11.27.
2-(1-Naphthyl)-2,3-dihydro-1H-pyrrolo[3,4-a]indolizin-1-imin-
ium Chloride (7d)
Yield: 0.24 g (47%); mp 301 °C.
Anal. Calcd for C20H15N3: C, 80.78; H, 5.08; N, 14.13. Found: C,
80.89; H, 4.91; N, 13.97.
Pyrrolo[3,4-a]indolizines 7a–d; General Procedure
Concd aq HCl (0.5 mL) was added to a solution of compounds 6a–
d (1.5 mmol) in EtOH (15 mL) and the mixture was refluxed for 7
h. The solvent was removed in vacuo, the residue was treated with
acetone, filtered off, washed with Et2O and dried to give analytical-
ly pure salts 7a–d as yellowish powders. If necessary, compounds
7a–d can be purified by recrystallization from a small amount of i-
PrOH.
1H NMR: d = 4.68 (d, J = 15.3 Hz, 1 H, 3-H), 4.75 (d, J = 15.3 Hz,
1 H, 3-H), 6.95 (m, 1 H, HAr), 7.10 (dd, J = 6.8, 7.2 Hz, 1 H, 7-H),
7.27–7.39 (m, 2 H, 8-H, HAr), 7.63–7.75 (m, 3 H, HAr), 7.87 (s, 1 H,
4-H), 8.16 (d, J = 7.6 Hz, 1 H, HAr), 8.20 (d, J = 8.0 Hz, 1 H, HAr),
8.42 (br s, 1 H, NH), 8.59 (d, J = 8.8 Hz, 1 H, 9-H), 8.77 (d, J = 6.8
Hz, 1 H, 6-H), 9.73 (br s, 1 H, NH).
13C NMR: d = 54.7 (CH2), 104.9 (9b-C), 107.6 (9-C), 114.0 (7-C),
118.4 (4-C), 121.8 (2-CAr), 123.8 (8-C), 126.2 (7-CAr), 127.0 (6-
CAr), 127.4 (3-CAr), 127.9 (4-CAr), 128.4 (6-C), 128.5 (3a-C), 128.9
(5-CAr), 129.5 (8-CAr), 130.3 (8a-CAr), 132.4 (9a-C), 133.0 (4a-CAr),
134.4 (1-CAr), 158.4 (1-C).
2-(4-Ethylphenyl)-2,3-dihydro-1H-pyrrolo[3,4-a]indolizin-1-
iminium Chloride (7a)
Yield: 0.23 g (50%); mp 242 °C.
1H NMR: d = 1.24 (t, J = 7.6 Hz, 3 H, CH3), 2.71 (q, J = 7.6 Hz, 2
H, CH2), 5.11 (s, 2 H, CH2), 7.07 (dd, J = 6.8, 8.8 Hz, 1 H, 7-H),
7.34 (dd, J = 6.8, 7.2 Hz, 1 H, 8-H), 7.45 (d, J = 8.0 Hz, 2 H, HAr),
Anal. Calcd for C20H16ClN3: C, 71.96; H, 4.83; N, 12.59; Cl, 10.62.
Found: C, 72.03; H, 4.80; N, 12.68; Cl, 10.67.
Synthesis 2006, No. 2, 349–353 © Thieme Stuttgart · New York

PAPER
Pyrrolo[3,4-a]indolizines
353
Shirayama, K. J. Heterocycl. Chem. 1978, 15, 369.
References
(d) Nannini, G.; Giraldi, P. N.; Molgora, G.; Biasoli, G.;
Spinelli, F.; Logemann, W.; Dradi, E.; Zanni, G.; Buttinoni,
A.; Tommasini, R. Arzneim.-Forsch. 1973, 23, 1090.
(e) Grochowski, E.; Boleslawska, T. Bull. Acad. Pol. Sci.,
Ser. Sci. Chim. 1972, 20, 405. (f) Babichev, F. S.; Tyltin, A.
K. Ukr. Khim. Zh. (Russ. Ed.) 1970, 36, 62; Chem. Abstr.
1970, 72, 132428.
(1) (a) Tsuge, O.; Kanemasa, S.; Takenaka, S. Bull. Chem. Soc.
Jpn. 1985, 58, 3320. (b) Tsuge, O.; Kanemasa, S.;
Takenaka, S. J. Org. Chem. 1986, 51, 1853. (c) Tsuge, O.;
Kanemasa, S.; Takenaka, S. Heterocycles 1983, 20, 1907.
(d) Tsuge, O.; Kanemasa, S.; Takenaka, S. Bull. Chem. Soc.
Jpn. 1985, 58, 3137. (e) Dragota, I.; Caprosu, M.; Druta, I.;
Petrovanu, M. Bul. Inst. Politeh. Iasi, Sect. 2 1978, 24, 103;
Chem. Abstr. 1980, 92, 58540.
(2) (a) Joucla, M.; Mortier, J.; Hamelin, J.; Toupet, L. Bull. Soc.
Chim. Fr. 1988, 143. (b) Grigg, R.; Surendrakumar, S.;
Thianpatanagul, S.; Vipond, D. J. Chem. Soc., Chem.
Commun. 1987, 47. (c) Joucla, M.; Mortier, J.; Hamelin, J.
Tetrahedron Lett. 1985, 26, 2775. (d) Grigg, R.;
Surendrakumar, S.; Thianpatanagul, S.; Vipond, D. J. Chem.
Soc., Perkin Trans. 1 1988, 2693. (e) Terao, Y.; Imai, N.;
Achiwa, K.; Sekiya, M. Chem. Pharm. Bull. 1982, 30, 3167.
(3) (a) Tsuge, O.; Kanemasa, S.; Takenaka, S. Bull. Chem. Soc.
Jpn. 1986, 59, 3631. (b) Tsuge, O.; Kanemasa, S.;
Takenaka, S. Bull. Chem. Soc. Jpn. 1987, 60, 1489.
(c) Kanemasa, S.; Takenaka, S.; Watanabe, H.; Tsuge, O. J.
Org. Chem. 1989, 54, 420. (d) Tsuge, O.; Kanemasa, S.;
Takenaka, S.; Kuraoka, S. Chem. Lett. 1984, 465.
(e) Grigg, R.; Jones, M. F.; McTiernan, M.; Sridharan, V.
Tetrahedron 2001, 57, 7979.
(4) (a) Obst, U.; Gramlich, V.; Diederich, F.; Weber, L.; Banner,
D. W. Angew. Chem., Int. Ed. Engl. 1995, 34, 1739; Angew.
Chem. 1995, 107, 1874. (b) Obst, U.; Betschmann, P.;
Lerner, C.; Seiler, P.; Diederich, F.; Gramlich, V.; Weber,
L.; Banner, D. W.; Schonholzer, P. Helv. Chim. Acta 2000,
83, 855.
(7) Tereshchenko, A. D.; Tolmachev, A. A.; Tverdokhlebov, A.
V. Synthesis 2004, 373.
(8) (a) Volovenko, Yu. M.; Tverdokhlebov, A. V.; Gorulya, A.
P.; Shishkina, S. V.; Zubatyuk, R. I.; Shishkin, O. V. Eur. J.
Org. Chem. 2002, 663. (b) Tverdokhlebov, A. V.;
Tolmachev, A. A.; Volovenko, Yu. M. Collect. Czech.
Chem. Commun. 2004, 69, 414. (c) Volovenko, Yu. M.;
Volovnenko, T. A.; Tverdokhlebov, A. V.; Ryabokon, I. G.
Russ. J. Org. Chem. 2001, 37, 1323. (d) Tverdokhlebov, A.
V.; Volovenko, Yu. M.; Shokol, T. V. Chem. Heterocycl.
Compd. (Engl. Transl.) 1998, 34, 44; Khim. Geterotsikl.
Soedin. 1998, 50.
(9) (a) Diana, G. D. DE 2140099, 1972; Chem. Abstr. 1972, 76,
140565. (b) May, H. J.; Kretzschmar, R.; Neumann, W. DE
2430354, 1976; Chem. Abstr. 1976, 84, 164602. (c) May,
H. J.; Kretzschmar, R.; Neumann, W.; Gries, J. Arzneim.-
Forsch. 1980, 30, 1487.
(10) (a) Ogata, K. Yakugaku Zasshi 1969, 89, 1020; Chem. Abstr.
1969, 71, 101636. (b) Bragg, D. R.; Wibberley, D. G. J.
Chem. Soc. 1963, 3277. (c) Hurst, J.;Melton, T.; Wibberley,
D. G. J. Chem. Soc. 1965, 2948. (d) Bragg, D. R.;
Wibberley, D. G. J. Chem. Soc. 1962, 2627.
(11) (a) Ryabukhin, S. V.; Plaskon, A. S.; Tverdokhlebov, A. V.;
Tolmachev, A. A. Synth. Commun. 2004, 34, 1483.
(b) Anderson, R. Synthesis 1985, 717. (c) Brownbridge, P.
Synthesis 1983, 85. (d) Poirier, J. M. Org. Prep. Proced. Int.
1988, 20, 317.
(5) (a) Laduron, F.; Viehe, H. G. Tetrahedron 2002, 58, 3543.
(b) Hart, D. J.; Huang, Y. Synth. Commun. 2000, 30, 3203.
(c) Pearson, W. H.; Mi, Yu. Tetrahedron Lett. 1997, 38,
5441. (d) Bicknell, A. J.; Hird, N. W.; Readshaw, S. A.
Tetrahedron Lett. 1998, 39, 5869.
(6) (a) Babichev, F. S.; Tyltin, A. K.; Shevchuk, L. I. Ukr. Khim.
Zh. (Russ. Ed.) 1973, 39, 348; Chem. Abstr. 1973, 79,
66289. (b) Giraldi, P. N.; Nannini, G.; Logemann, W.;
Tommasini, R.; Buttinoni, A.; Biasoli, G. DE 2154525,
1972; Chem. Abstr. 1972, 77, 88292. (c) Kametani, T.;
Kigasawa, K.; Hiiragi, M.; Ishimaru, H.; Haga, S.;
(12) (a) Einhorn, C.; Einhorn, J.; Luche, J. L. Synthesis 1989,
787. (b) Goldberg, Y.; Styrkovich, R.; Lukevics, E.
Heterocycles 1989, 29, 597. (c) Mason, T. J. Chem. Soc.
Rev. 1997, 26, 443.
(13) (a) Resnyanskaya, E. V.; Tverdokhlebov, A. V.; Volovenko,
Yu. M.; Shishkin, O. V.; Zubatyuk, R. I. Synthesis 2002,
2717. (b) Resnyanskaya, E. V.; Tverdokhlebov, A. V.;
Tolmachev, A. A.; Volovenko, Yu. M. Russ. J. Org. Chem.
2005, 41, 257.
Synthesis 2006, No. 2, 349–353 © Thieme Stuttgart · New York