A convenient approach to the synthesis of 2-(2-aminoethyl)pyrroles and their heterocyclization into hydrogenated pyrrolopyridines and related pyrroloindolizines

Article abstract of DOI:10.1016/S0040-4020(03)00777-4

2-(2-Aminoethyl)pyrroles and 2-(2-succinimidoethyl)pyrroles were prepared from acetals of ethyl 4-oxoalkanoates via latent vinyl 1,4-dicarbonyl compounds as the key intermediates. The Pictet-Spengler condensation of 2-(2-aminoethyl)pyrroles with aromatic aldehydes gave 4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridines in good yields. 4,5,7,8,9,9a-Hexahydro-3H-pyrrolo[2,3-g]indolizines were prepared in a similar way starting from 2-(2-succinimidoethyl)pyrroles.

Full text of DOI:10.1016/S0040-4020(03)00777-4

Tetrahedron 59 (2003) 5265–5272
A convenient approach to the synthesis of
2-(2-aminoethyl)pyrroles and their heterocyclization into
hydrogenated pyrrolopyridines and related pyrroloindolizines
Marina V. Raiman,a Aleksei V. Pukin,a Vladimir I. Tyvorskii,a Norbert De Kimpeb
and Oleg G. Kulinkovicha
,
*
aDepartment of Organic Chemistry, Belarusian State University, Fr. Scorina Avenue, 4, 220050 Minsk, Belarus
bDepartment of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University, Coupure Links 653,
B-9000 Ghent, Belgium
Received 17 January 2003; revised 15 April 2003; accepted 16 May 2003
Abstract—2-(2-Aminoethyl)pyrroles and 2-(2-succinimidoethyl)pyrroles were prepared from acetals of ethyl 4-oxoalkanoates via latent
vinyl 1,4-dicarbonyl compounds as the key intermediates. The Pictet–Spengler condensation of 2-(2-aminoethyl)pyrroles with aromatic
aldehydes gave 4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridines in good yields. 4,5,7,8,9,9a-Hexahydro-3H-pyrrolo[2,3-g]indolizines were
prepared in a similar way starting from 2-(2-succinimidoethyl)pyrroles. q 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
magnesium bromide in the presence of titanium(IV) iso-
propoxide8 followed by brominative ring opening of the three-
membered ring in cyclopropanols 2a,b.9 Compounds 7a–c
were smoothly converted into 4,5,6,7-tetrahydro-1H-
pyrrolo[3,2-c]pyridines 10a–i by reaction with aromatic
aldehydes in i-PrOH (Scheme 3). The related tricyclic
compounds 13a–c, bearing the pharmacophoric indolizine
fragment were accessible similarly from compounds 7d–f
(Scheme 4).10 Herein we describe our results.
Pyrrolopyridines with different types of ring fusions and
their partially hydrogenated derivatives are of great interest
as aza-analogues of indole.1 Methods for the synthesis of
4,5,6,7-tetrahydropyrrolo[3,2-c]pyridines, which show
interesting biological activity and which have found
application as synthetic building blocks, were summarized
in a recent review.2 The most important of them are based
on the pyrrole annelation onto the corresponding piperidin-
4-one framework, as well as on the formation of a
hydrogenated pyridine ring by means of cyclisation of
2-(2-aminoethyl)pyrroles.3,4 The latter approach appeared
to be effective in the synthesis of previously unknown
octahydropyridopyrrolopyridines in the acid-catalysed
Pictet–Spengler reaction.5 Similar non-catalytic hetero-
cyclisations have been also accomplished in the series of
tryptamine derivatives and have preparative importance for
acidophobic pyrrole and indole systems.6,7
2. Results and discussion
6-Bromo-4-oxohexanal 4a was obtained in three preparative
steps in an overall yield of 67% starting from ethyl 4,4-
diethoxybutanoate 1a via the cyclopropanol intermediate 2a
as a key product (Scheme 1). Deprotection of aldehyde
group was performed after bromination of the substituted
cyclopropanol 2a, since hydrolysis of the latter led to the
formation of the cyclic acetal 611 which was stable under
bromination conditions. In contrast, deprotection of the
ketone group in cyclopropanol derivative 2b proceeded with
formation of monocyclic acetonylmethylcyclopropanol 3,8e
and bromination of the latter led to 7-bromoheptan-2,5-
dione 4b in good yield (Scheme 1). The resulting
b-bromoketones 4a,b and 5a,b were not stable and readily
lost hydrogen bromide, merely upon contact with a
adsorbent for chromatography. Therefore, these compounds
were used for further transformations without purification
In the present work a convenient approach to the synthesis
of 2-(2-aminoethyl)pyrroles 7a–c and their succinimide
analogues 7d–f, starting from carbonyl-protected esters of
g-oxocarboxylic acids 1a,b, is demonstrated (Schemes 1 and
2). The key precursors of compounds 7 were b-bromoketones
4, 5 prepared by cyclopropanation of esters 1 with ethyl-
Keywords: cyclopropanols; 2-aminoethylpyrroles; pyrrolopyridines;
pyrroloindolizines; Pictet–Spengler reaction.
*
Corresponding author. Tel.: þ375-17-2095190; fax: þ375-17-2265609;
1
e-mail: kulinkovich@bsu.by
(purity .98%; H NMR spectroscopy).
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4020(03)00777-4

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M. V. Raiman et al. / Tetrahedron 59 (2003) 5265–5272
Scheme 1.
Scheme 2.

M. V. Raiman et al. / Tetrahedron 59 (2003) 5265–5272
5267
Scheme 3.
7-Bromoheptan-2,5-dione 4b and 6-bromo-4-oxohexanal
4a reacted readily with three equivalents of benzylamine in
diethyl ether at room temperature to produce pyrroles 7a,b
in high yields. The corresponding N-methyl compound 7c
was obtained in moderate yield upon bubbling of gaseous
methylamine through an ethereal solution of 7-bromo-
heptan-2,5-dione 4b.
in the presence of p-toluenesulfonic acid or cation exchange
resin (in Hþ-form). The use of the latter in the synthesis of
9a allows simplification of the work-up procedure and an
increase in the yield of the product. To obtain the pyrroles
7d–f, the corresponding dicarbonyl compounds 9a,b were
involved in a heterocyclization reaction with benzylamine
or methylamine.
2-(2-Succinimido)pyrroles 7d–f were prepared in a similar
way to that of compounds 7a–c (Scheme 2). However, the
use of b-bromoketones 4a,b as precursors of pyrroles 7d–f
resulted only in moderate yields of the target products.
Better results were achieved by preliminary transformation
of the protected bromoketones 5a,b into the corresponding
vinyl ketones 8a,b followed by reaction of the latter enones
with equimolar quantities of succinimide and catalytic
amounts of K2CO3 and triethylamine. The use of either of
these catalysts separately, led to an extension of the reaction
time which may be due to the non-sufficient solubility of
potassium carbonate and deficient basicity of triethylamine.
Combined use of these bases probably evoked phase
transfer catalytic processes. To remove the acetal protecting
group, the resulting crude product was treated with acetone
N,N0-Dialkyl-2-(2-aminoethyl)pyrroles 7a–c were con-
verted into the target fused compounds 10a–i by Pictet–
Spengler condensation with aromatic aldehydes in i-PrOH
(Scheme 3). The reaction was complete within 2–4 h at
room temperature, and tetrahydropyrrolopyridines 10a–g
precipitated from the reaction mixture as crystalline
products (80–90% yield after recrystallisation from
i-PrOH). Pyrrolopyridines 10h,i having no substituents at
the a-position of the pyrrole ring, were obtained in similar
manner at 08C, and were isolated by column chromato-
graphy with somewhat lower yields. It should be noted that
in contrast to the reported procedure,5 a non-catalytic
variant of the Pictet–Spengler reaction was used which
allowed us to isolate acidophobic compounds 10h,i as free
bases in good yields.
Scheme 4.

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M. V. Raiman et al. / Tetrahedron 59 (2003) 5265–5272
2-(2-Succinimidoethyl)pyrroles 7d–f were converted into
the corresponding pyrroloindolizines 13a–c by a modified
Pictet–Spengler reaction in which the heterocyclization
steps were achieved by the intramolecular electrophilic
addition of N-acyliminium ion generated from the partially
reduced succinimide fragment of compounds 11a–c
(Scheme 4). The latter were obtained in quantitative yields
by treatment of pyrroles 7d–f with sodium borohydride in a
CH3OH-THF mixture at 2108C.12
The cyclopropanols 2b, 3 were prepared according to the
known procedures.8e
3.1.1. 1-(3,3-Diethoxypropyl)-1-cyclopropanol (2a). A
solution of ethylmagnesium bromide in Et2O (5 mL of
3.2 M solution, 16 mmol) was added to a stirred solution of
ethyl 4,4-diethoxybutanoate 1a (1 g, 4.9 mmol) and Ti(OPr-
i)4 (0.15 mL, 0.49 mmol) in dry Et2O (10 mL) at room
temperature over 10 min. The reaction mixture was stirred
for 1 h and quenched with an ice-cold saturated aqueous
solution of NH4Cl (10 mL). After filtration, the organic
layer was separated and the aqueous phase was extracted
with Et2O (3£3 mL). The organic phases were combined,
washed with brine, dried with Na2SO4 and evaporated in
vacuo. The crude product was purified by column
chromatography on silica gel (Et2O–cyclohexane, 1:3) to
give 0.78 g (85%) of cyclopropanol 2a as a colorless oil. 1H
NMR (400 MHz, CDCl3): d 0.38–0.41 (m, 2H), 0.69–0.72
(m, 2H), 1.18 (t, J¼7.2 Hz, 6H), 1.62 (t, J¼7.2 Hz, 2H),
1.85 (dt, J¼7.2, 5.1 Hz, 2H), 3.48 (dq, J¼9.2, 7.2 Hz, 2H),
3.64 (dq, J¼9.2, 7.2 Hz, 2H), 3.80 (bs, 1H), 4.56 (t,
J¼5.1 Hz, 1H). 13C NMR (CDCl3): d 13.5, 15.1, 30.5, 33.4,
55.0, 61.1, 102.9. Anal. calcd for C10H20O3: C, 63.83; H,
10.64. Found: C, 63.88; H, 10.63.
The formation of the hemiaminals 11a–c was supported
spectroscopically by the appearance of the characteristic
multiplet of the methine proton at 4.86–4.98 ppm in the 1H
NMR spectra (CDCl3). The hemiaminals 11b,c, without
purification, were cyclized upon reaction with mesyl
chloride in dichloromethane in the presence of triethylamine
to give tricyclic pyrrolopyridine derivatives 12b,c in good
yields, whereas the less substituted pyrrole 11a turned into a
resin-like product under these conditions. The conversion of
hemiaminal 11a into pyrroloindolizidine 12a was success-
fully achieved by treatment with oxalic acid on silica in
diethyl ether. The structure of compounds 12a–c was
confirmed by the 1H NMR spectra (CDCl3), which revealed
a characteristic triplet of doublets at 2.86–3.06 (Jgem
<
Jaa¼12.0 Hz; Jae¼5.5 Hz) for the axial 5-H proton and a
doublet of doublets at 4.32–4.48 (Jgem¼12.0 Hz;
Jea¼5.5 Hz; Jee¼0 Hz) for the equatorial 5-H proton
deshielded due to the anisotropic effect of the amide
carbonyl.13
3.1.2. 1-Benzyl-2-[2-(benzylamino)ethyl]pyrrole (7a).
Bromine-pyridine complex (0.99 g, 4.15 mmol) was added
portionwise to a stirred solution of cyclopropanol 2a
(0.78 g, 4.15 mmol) in dry Et2O (10 mL) at 108C over
10 min. The precipitate was removed by filtration and the
solvent evaporated in vacuo to give the crude b-bromo-
ketone 5a. The latter was dissolved in 15 mL of acetone and
0.4 g of cation exchange resin in Hþ-form was added. After
stirring for 2 h the cation exchange resin was removed by
filtration and the solvent was evaporated. The residue was
dissolved in 15 mL of ether and the resulting solution of
b-bromoketone 4a was added dropwise to a vigorously
stirred solution of benzylamine (1.36 mL, 12.45 mmol) in
15 mL of diethyl ether over 30 min. The precipitate was
filtered, the solution washed with water, brine, filtered
through a thick layer of alumina and dried over Na2SO4.
Evaporation of the solvent followed by purification of the
crude product on a column of silica (Et2O–petroleum ether,
1:1) gave 0.92 g (76%) of b-(aminoethyl)pyrrole 7a as a
The amide moiety of compounds 12a–c was reduced using
1 M borane in tetrahyrofuran,14 and the resulting com-
pounds 13a–c were purified by column chromatography.
The NMR spectra (CDCl3) of the products 13a–c showed
an upfield shift of the equatorial 5-H proton signal (4.32–
4.48 ppm in the spectra of 12a–c).
In conclusion, an effective route to substituted 4,5,6,7-
tetrahydro-1H-pyrrolo[3,2-c]pyridines
and
related
4,5,7,8,9,9a-hexahydro-3H-pyrrolo[2,3-g]indolizines was
developed, starting from acetals of ethyl 4-oxoalkanoates
via the preparation of latent vinyl 1,4-dicarbonyl com-
pounds as the key intermediates.
yellowish oil. IR (CHCl3): nmax 3346 cm21 1H NMR
.
(400 MHz, CDCl3): d 1.54 (bs, 1H), 2.69 (t, J¼7.2 Hz, 2H),
2.80 (t, J¼7.2 Hz, 2H), 3.71 (s, 2H), 5.03 (s, 2H), 5.88–6.00
(m, 1H), 6.12–6.14 (m, 1H), 6.62–6.64 (m, 1H), 6.94–6.97
(m, 2H), 7.20–7.33 (m, 8H). 13C NMR (CDCl3): d 26.8,
48.25, 50.3, 53.8, 107.1, 107.7, 121.3, 126.2, 126.85, 127.3,
128.0, 128.3, 128.7, 138.4. Anal. calcd for C20H22N2: C,
82.76; H, 7.59. Found: C, 83.15H, 7.56.
3. Experimental
3.1. General
IR spectra were measured on a Specord 75 IR spectro-
1
photometer. H NMR spectra were recorded at 60 MHz
(Tesla BS-467) in CCl4 with hexamethyldisiloxane as
the internal standard, or 200 MHz (Bruker-200) with
TMS as the internal standard, or 400 MHz (Bruker Avance
400) with CDCl3 as the solvent. 13C NMR spectra were
recorded with a Bruker Avance 400 at 100.6 MHz with
CDCl3 as solvent. Melting points were determined in open
capillaries and are uncorrected. Preparative column
chromatography was carried out on silica gel (Merck;
70–230 Mesh). All chemicals were reagent grade; solvents
were dried and distilled prior to use. The cation exchanger
resin (in Hþ-form) was obtained from the Reakhim
Company.
3.1.3. 1-Benzyl-2-[2-(benzylamino)ethyl]-5-methylpyr-
role (7b). NBS (1.78 g, 10 mmol) was added in three
portions to an ice-cold solution of cyclopropanol 38e (1.28 g,
10 mmol) in CCl4 (25 mL). After stirring for 1 h the
precipitate was filtered off, and the filtrate was evaporated in
vacuo to give 2 g of the crude b-bromoketone 4b as a
yellowish liquid (100%). Owing to the lability of this
compound, it was used further without purification.
Benzylamine (3.33 mL, 30 mmol) was added to a solution
of b-bromoketone 4b in Et2O (25 mL). The reaction

M. V. Raiman et al. / Tetrahedron 59 (2003) 5265–5272
5269
mixture was stirred at room temperature for 2 h and
evaporated in vacuo. Column chromatography of the
residue on alumina (EtOAc–cyclohexane, 1:1) led to
2.74 g (90%) of aminoethylpyrrole 7b as a yellowish oil.
IR (CHCl3): nmax 3327 cm21. 1H NMR (200 MHz, CDCl3):
d 1.77 (bs, 1H), 2.14 (s, 3H), 2.62–2.84 (m, 4H), 3.68 (s,
2H), 5.02 (s, 2H), 5.84–5.88 (m, 2H), 6.76–6.92 (m, 2H),
7.14–7.36 (m, 8H). 13C NMR (CDCl3): d 12.2, 26.7, 46.4,
48.2, 53.6, 105.2, 105.6, 125.3, 126.7, 126.8, 127.9, 128.1,
128.2, 128.5, 129.8, 138.4, 140.1. Anal. calcd for C21H24N2:
C, 82.84; H, 7.96. Found: C, 82.70; H, 7.78.
199.9. Anal. calcd for C9H14O3: C, 63.50; H, 8.31. Found:
C, 63.59; H, 8.26.
3.1.7. 4-Oxo-6-succinimidohexanal (9a). K2CO3 (0.07 g,
0.5 mmol) and triethylamine (0.07 mL, 0.5 mmol) were
added to a solution of 6,6-diethoxy-1-hexen-3-one 8a
(0.94 g, 5 mmol) and succinimide (0.5 g, 5 mmol) in
i-PrOH (10 mL). The reaction mixture was refluxed for
1 h, cooled to room temperature and evaporated in vacuo.
The residue was dissolved in Et2O (15 mL), washed with
water (2£3 mL) and brine (3 mL), and dried over Na2SO4.
The solvent was removed in vacuo, the residue was
dissolved in acetone (10 mL) and cation exchange resin in
Hþ-form (0.3 g) was added to the solution. After stirring for
2 h the cation exchange resin was removed by filtration and
the solvent was evaporated. The residue was purified by
recrystallisation from i-PrOH to give 0.85 g (80%) of
aldehyde 9a as white needles. Mp 858C. IR (CHCl3): nmax
3.1.4. 1,5-Dimethyl-2-[2-(methylamino)ethyl]pyrrole
(7c). Through a solution of the crude b-bromoketone 4b
(2.1 g, 10 mmol), in benzene (25 mL) methylamine
(5–7 equiv.) was bubbled during 15 min. The reaction
mixture was stirred at room temperature for 8 h and
evaporated in vacuo. The aminoethylpyrrole 7c was isolated
as a yellowish oil by column chromatography on alumina
(EtOAc–cyclohexane, 1:1). Yield: 0.99 g (65%). IR
1
1689 cm21. H NMR (400 MHz, CDCl3): d 2.72 (bs, 4H),
2.74- 2.79 (m, 4H), 2.84 (t, J¼7.2 Hz, 2H), 3.81 (t,
J¼7.2 Hz, 2H), 9.76 (s, 1H). 13C NMR (CDCl3): d 28.1,
33.8, 34.6, 37.4, 39.6, 176.9, 200.0, 205.7. Anal. calcd for
C10H13NO4: C, 56.87; H, 6.16. Found: C, 57.11; H, 6.14.
1
(CHCl3): nmax 3360 cm21. H NMR (400 MHz, CCl4): d
2.11 (bs, 1H); 2.25 (s, 3H); 2.50 (s, 3H); 2.72–2.90 (m, 4H);
3.45 (s, 3H); 5.78–5.92 (m, 2H). 13C NMR (CDCl3): d 12.3,
26.9, 29.9, 36.1, 50.7, 104.4, 104.8, 128.1, 128.6. Anal.
calcd for C9H16N2: C, 70.99; H, 10.61. Found: C, 71.07; H,
10.44.
3.1.8. 7-Succinimido-2,5-heptanedione (9b). K2CO3
(0.1 g, 0.7 mmol) and triethylamine (0.1 mL, 0.72 mmol)
were added to a solution of ketone 8b (1.7 g, 10 mmol) and
succinimide (0.99 g, 10 mmol) in i-PrOH (20 mL). The
reaction mixture was refluxed for 1 h. The volatile
compounds were removed in vacuo, water (20 mL) was
added to the residue, and the mixture was extracted with
dichloromethane (3£15 mL). The organic phase was
washed with brine (15 mL), dried over Na2SO4 and
evaporated. To the residue was added acetone (10 mL),
CH2Cl2 (20 mL) and p-toluenesulfonic acid (0.02 g,
0.1 mmol), and the mixture was refluxed for 1.5 h. After
evaporation of the solvent in vacuo the residue was
dissolved in CH2Cl2 (20 mL), washed with brine
(3£10 mL) and dried over Na2SO4. The solvent was
removed and the product was recrystallised from i-PrOH
to give 2.08 g (92%) of compound 9b as white needles. Mp
3.1.5. 6,6-Diethoxy-1-hexen-3-one (8a). Bromine-pyridine
complex (1.5 g, 6.3 mmol) was added portionwise over
20 min to a stirred solution of cyclopropanol 2a (1.18 g,
6.3 mmol) in dry Et2O (20 mL) at 108C. The precipitate was
removed by filtration, and triethylamine (0.92 mL,
6.6 mmol) was added dropwise to the filtrate. After stirring
for 3 h at room temperature followed by filtration of the
precipitate, the reaction mixture was evaporated in vacuo.
The crude product was purified by column chromatography
on silica gel (Et2O–petroleum ether, 35:65) to give 0.97 g
(83%) of compound 8a as a colorless oil. IR (CHCl3): nmax
1
1673, 1612 cm21. H NMR (400 MHz, CDCl3): d 1.16 (t,
J¼7.2 Hz, 6H), 1.91 (dt, J¼7.2, 5.1 Hz, 2H), 2.65 (t,
J¼7.2 Hz, 2H), 3.45 (dq, J¼9.2, 7.2 Hz, 2H), 3.61 (dq,
J¼9.2, 7.2 Hz, 2H), 4.48 (t, J¼5.1 Hz, 1H), 5.79 (dd,
J¼10.8, 1.5 Hz, 1H), 6.20 (dd, J¼17.4, 1.5 Hz, 1H), 6.32
(dd, J¼17.4, 10.8 Hz, 1H). 13C NMR (CDCl3): d 15.2, 27.8,
34.4, 61.6, 102.0, 127.7, 136.5, 200.0. Anal. calcd for
C10H18O3: C, 64.52; H, 9.68. Found: C, 64.75; H, 9.66.
65–688C. IR (CHCl3): nmax 1707 cm21
.
1H NMR
(200 MHz, CDCl3): d 2.20 (s, 3H), 2.62–2.78 (m, 8H),
2.82 (t, J¼7.0 Hz, 2H), 3.78 (t, J¼7.0 Hz, 2H). 13C NMR
(CDCl3): d 28.1, 29.8, 33.8, 36.0, 36.8, 39.6, 176.9, 206.4,
206.8. Anal. calcd for C11H15NO4: C, 58.65; H, 6.73.
Found: C, 58.44; H, 6.60.
3.1.6. 5-(2-Methyl-1,3-dioxolan-2-yl)-1-penten-3-one
(8b). NBS (1.78 g, 10 mmol) was added in three portions
to an ice-cold solution of cyclopropanol 2b8e (1.72 g,
10 mmol) in CCl4 (25 mL). After stirring for 1 h followed
by filtration of precipitate, the reaction mixture was
evaporated in vacuo. The crude b-bromoketone 5b was
dissolved in Et2O (25 mL) and triethylamine (4.25 mL,
30 mmol) was added. The reaction mixture was refluxed for
1 h, the precipitate was filtered off, the solution was washed
with brine (15 mL), dried (Na2SO4) and evaporated. The
product was purified by distillation in vacuo to give 1.36 g
(80%) of ketone 8b as a colorless liquid. Bp 78–808C/
3.1.9. 1-Benzyl-2-(2-succinimidoethyl)pyrrole (7d).
Benzylamine (0.1 mL, 0.9 mmol) was added to a stirred
solution of ketoaldehyde 9a (0.19 g, 0.9 mmol) in methanol
(5 mL) at 308C. The reaction mixture was stirred for 10 min
and the solvent was evaporated in vacuo. Column
chromatography of the residue on silica gel (Et2O–
petroleum ether; 35:65) gave 0.23 g (91%) of compound
7d as white crystals. Mp 1078C. IR (CHCl3): nmax
1
1680 cm21. H NMR (400 MHz, CDCl3): d 2.64 (bs, 4H),
2.76 (t, J¼7.7 Hz, 2H), 3.67 (t, J¼7.7 Hz, 2H), 5.12 (s, 2H),
6.01 (m, 1H), 6.11 (dd, J¼3.5, 2.8 Hz, 1H), 6.64 (dd, J¼2.8,
1.8 Hz, 1H), 7.01–7.03 (m, 2H), 7.23–7.32 (m, 3H). 13C
NMR (CDCl3): d 24.2, 28.0, 38.0, 50.2, 107.2, 107.7, 121.8,
126.3, 127.3, 128.3, 128.6, 138.2, 176.8. Anal. calcd for
C17H18N2O2: C, 72.34; H, 6.38. Found: C, 72.58; H, 6.32.
2 Torr. IR (CHCl3): nmax 1680, 1627 cm21 1H NMR
.
(60 MHz, CDCl3): d 1.25 (s, 3H), 2.0 (t, J¼7.0 Hz, 2H),
2.60 (t, J¼7.0 Hz, 2H), 3.87 (s, 4H), 5.64–6.40 (m, 3H). 13C
NMR (CDCl3): d 23.7, 32.6, 33.9, 64.4, 109.0, 127.5, 136.2,

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M. V. Raiman et al. / Tetrahedron 59 (2003) 5265–5272
3.1.10. 1-Benzyl-5-methyl-2-(2-succinimidoethyl)pyrrole
(7e). Diketone 9b (2.25 g, 10 mmol) was dissolved in i-
PrOH (20 mL) and benzylamine (1.08 mL, 10 mmol) was
added. The resulting solution was stirred at room tempera-
ture for 2 h. The precipitate was separated by filtration and
recrystallised from i-PrOH to give 2.56 g (97%) of
compound 7e as white needles. Mp 104–1058C. IR
47.8, 58.3, 64.5, 104.5, 118.7, 125.2, 125.8, 126.8, 127.1,
127.8, 128.1, 128.3, 128.6, 128.7, 129.9, 132.4, 138.5,
139.7, 143.4. Anal. calcd for C28H27N2Cl: C, 78.75; H, 6.39.
Found: C, 78.93; H, 6.11.
3.2.3. 1,5-Dibenzyl-4-(4-fluorophenyl)-2-methyl-4,5,6,7-
tetrahydro-1H-pyrrolo[3,2-c]pyridine (10c). Yield:
65%; colorless solid. Mp 728C. 1H NMR (200 MHz,
CDCl3): d 2.04 (s, 3H), 2.36–2.74 (m, 3H), 3.00–3.14
(m, 1H), 3.23 (d, J¼13.5 Hz, 1H), 3.81 (d, J¼13.5 Hz, 1H),
4.46 (s, 1H), 4.96 (s, 2H), 5.34 (s, 1H), 6.84–7.48 (m, 14H).
13C NMR (CDCl3): 12.0, 22.2, 46.5, 47.9, 58.2, 64.4, 104.5,
114.9 (HC¼CF, d, J¼21 Hz), 119.1, 125.1, 125.7, 126.7,
127.0, 127.7, 128.1, 128.6, 128.7, 130.0 (Cmeta, d, J¼7 Hz),
138.5, 139.9, 140.5 (Cpara, d, J¼2 Hz), 161.8 (CF, d,
J¼244 Hz). Anal. calcd for C28H27N2F: C, 81.91; H, 6.64.
Found: C, 81.78; H, 6.42.
1
(CHCl3): nmax 1691 cm21. H NMR (200 MHz, CDCl3): d
2.12 (s, 3H), 2.62 (s, 4H), 2.72 (t, J¼8.0 Hz, 2H), 3.63 (t,
J¼8.0 Hz, 2H), 5.10 (s, 2H), 5.88 (d, J¼3.5 Hz, 1H), 5.94
(d, J¼3.5 Hz, 1H), 6.84–6.92 (m, 2H), 7.18–7.32 (m, 3H).
13C NMR (CDCl3): d 12.3, 24.8, 28.1, 38.4, 46.6, 105.9,
106.4, 125.6, 127.0, 127.7, 128.7, 129.0, 138.5, 176.9. Anal.
calcd for C18H20N2O2: C, 72.94; H, 6.82. Found: C, 72.78;
H, 6.76.
3.1.11. 1,5-Dimethyl-2-(2-succinimidoethyl)pyrrole (7f).
Dry methylamine (50 mmol) was bubbled through a
solution of diketone 9b (2.25 g, 10 mmol) in i-PrOH
(20 mL) at 408C for 15 min. The reaction mixture was
stirred at room temperature for 2 h, the precipitate was
separated by filtration and recrystallised from i-PrOH to
give 1.62 g (86%) of compound 7f as yellowish crystals. Mp
3.2.4. 1,5-Dibenzyl-2-methyl-4-(3-nitrophenyl)-4,5,6,7-
tetrahydro-1H-pyrrolo[3,2-c]pyridine (10d). Yield:
75%; colorless solid. Mp 588C. IR (CHCl3): nmax 1530,
1
1346 cm21. H NMR (200 MHz, CDCl3): d 2.06 (s, 3H),
2.32–2.72 (m, 3H), 2.96–3.12 (m, 1H), 3.34 (d, J¼13.5 Hz,
1H), 3.80 (d, J¼13.5 Hz, 1H), 4.60 (s, 1H), 4.98 (s, 2H),
5.36 (s, 1H), 6.91 (d, J¼7.5 Hz, 2H), 7.14–7.40 (m, 8H),
7.48 (t, J¼7.5 Hz, 1H), 7.80 (d, J¼7.5 Hz, 1H), 8.11 (d,
J¼7.5 Hz, 1H), 8.36 (s, 1H). 13C NMR (CDCl3): d 12.0,
21.8, 46.6, 47.4, 58.4, 64.1, 104.4, 117.6, 122.0, 123.5,
125.5, 125.7, 127.0, 127.2, 128.3, 128.6, 128.8, 129.0,
134.7, 138.4, 139.4, 147.5. Anal. calcd for C28H27N3O2: C,
76.85; H, 6.23. Found: C, 76.60; H, 6.44.
108–1108C. IR (CHCl3): nmax 1680 cm21 1H NMR
.
(200 MHz, CDCl3): d 2.22 (s, 3H), 2.68 (s, 4H), 2.84 (t,
J¼8.0 Hz, 2H), 3.46 (s, 3H), 3.70 (t, J¼8.0 Hz, 2H), 5.76 (d,
J¼3.0 Hz, 1H), 5.82 (d, J¼3.0 Hz, 1H). 13C NMR (CDCl3):
d 12.4, 24.9, 28.1, 30.0, 38.0, 105.0, 105.7, 127.3, 129.0,
176.9. Anal. calcd for C12H16N2O2: C, 65.42; H, 7.34.
Found: C, 65.49; H, 7.27.
3.2. General procedure for the synthesis of tetrahydro-
1H-pyrrolo[3,2-c]pyridines 10a–i
3.2.5. 1,5-Dibenzyl-4-(2-hydroxy-5-nitrophenyl)-2-
methyl-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine
(10e). Yield: 63%; yiellowish solid. Mp 120–1228C. IR
(CHCl3): nmax 3360 (br), 1597, 1349 cm1. 1H NMR
(200 MHz, CDCl3): d 2.06 (s, 3H), 2.34–2.72 (m, 3H),
3.06–3.24 (m, 1H), 3.45 (d, J¼13.0 Hz, 1H), 4.03 (d,
J¼13.0 Hz, 1H), 4.80 (s, 1H), 4.94 (s, 2H), 5.50 (s, 1H),
6.78–7.56 (m, 13H), 14.72 (bs, 1H). 13C NMR (CDCl3): d
12.0, 21.0, 46.4, 46.7, 58.2, 64.6, 104.7, 114.1, 116.9, 124.4,
124.9, 125.2, 125.6, 127.1, 127.3, 127.9, 128.7, 128.8,
129.0, 129.5, 136.2, 138.0, 140.1, 163.7. Anal. calcd for
C28H27N3O3: C, 73.17; H, 5.93. Found: C, 73.33; H, 6.01.
Arylcarboxaldehyde (benzaldehyde, 4-chloro-, 4-fluoro-,
3-nitrobenzaldehyde or 2-hydroxy-5-nitrobenzaldehyde)
(1.3 mmol) was added to a solution of aminoethylpyrrole
7a–c (1.3 mmol) in i-PrOH (2 mL). The reaction mixture
was stirred at 508C for 15 min and then kept at room
temperature overnight. The precipitate was separated by
filtration and compounds 10a–e,g–i were recrystallised
from i-PrOH. Compound 10f was isolated by column
chromatography (EtOAc–cyclohexane, 1:1).
3.2.1. 1,5-Dibenzyl-2-methyl-4-phenyl-4,5,6,7-tetra-
hydro-1H-pyrrolo[3,2-c]pyridine (10a). Yield: 80%;
colorless solid. Mp 1358C. H NMR (200 MHz, CDCl3): d
3.2.6. 4-Phenyl-1,2,5-trimethyl-4,5,6,7-tetrahydro-1H-
pyrrolo[3,2-c]pyridine (10f). Yield: 50%; colorless oil.
1H NMR (200 MHz, CDCl3): d 2.10 (s, 3H), 2.24 (s, 3H),
2.50–2.76 (m, 2H), 2.84–3.04 (m, 1H), 3.10–3.26 (m, 1H),
3.34 (s, 3H), 4.02 (s, 1H), 5.16 (s, 1H), 7.16–7.38 (m, 5H).
13C NMR (CDCl3): d12.0, 22.8, 29.5, 43.6, 53.2, 68.1,
103.4, 119.2, 124.7, 126.9, 127.5, 128.0, 128.6, 144.2. Anal.
calcd for C16H20N2: C, 79.94; H, 8.40. Found: C, 79.76; H,
8.25.
1
2.04 (s, 3H), 2.32–2.74 (m, 3H), 3.00–3.14 (m, 1H), 3.24
(d, J¼13.5 Hz, 1H), 3.86 (d, J¼13.5 Hz, 1H), 4.46 (s, 1H),
4.94 (s, 2H), 5.34 (s, 1H), 6.84–6.98 (m, 2H), 7.08- 7.54 (m,
13H). 13C NMR (CDCl3): d 12.0, 22.3, 46.5, 47.9, 58.3,
65.3, 104.6, 119.3, 125.1, 125.8, 126.6, 126.8, 127.0, 127.6,
128.0, 128.1, 128.6, 128.7, 137.9, 138.62, 140.0, 144.7.
Anal. calcd for C28H28N2: C, 85.66; H, 7.20. Found: C,
85.42; H, 7.00.
3.2.7. 4-(3-Nitrophenyl)-1,2,5-trimethyl-4,5,6,7-tetra-
hydro-1H-pyrrolo[3,2-c]pyridine (10g). Yield: 63%;
yellow solid. Mp 120–1228C. IR (CHCl3): nmax 1533,
3.2.2. 1,5-Dibenzyl-4-(4-chlorophenyl)-2-methyl-4,5,6,7-
tetrahydro-1H-pyrrolo[3,2-c]pyridine (10b). Yield: 78%;
colorless solid. Mp 103–1048C. 1H NMR (200 MHz,
CDCl3): d 2.04 (s, 3H), 2.36–2.74 (m, 3H), 2.98–3.14
(m, 1H), 3.23 (d, J¼13.5 Hz, 1H), 3.81 (d, J¼13.5 Hz, 1H),
4.44 (s, 1H), 4.96 (s, 2H), 5.36 (s, 1H), 6.84–6.96 (m, 2H),
7.12–7.50 (m, 12H). 13C NMR (CDCl3): 12.0, 22.2, 46.6,
1
1353 cm21. H NMR (200 MHz, CDCl3): d 2.08 (s, 3H),
2.24 (s, 3H), 2.52–2.82 (m, 2H), 2.84–3.04 (m, 1H), 3.10–
3.24 (m, 1H), 3.38 (s, 3H), 4.18 (s, 1H), 5.14 (s, 1H), 7.24–
9.26 (m, 4H). 13C NMR (CDCl3): d 12.0, 22.6, 29.6, 43.5,
52.7, 67.2, 103.1, 117.8, 122.0, 123.4, 124.9, 128.0, 128.9,

M. V. Raiman et al. / Tetrahedron 59 (2003) 5265–5272
5271
134.7, 147.2, 148.4. Anal. calcd for C16H19N3O2: C, 67.33;
H, 6.72. Found: C, 67.58; H, 6.54.
(m, 1H); 5.06 (s, 2H); 5.86–5.98 (m, 2H); 6.84–6.96 (m,
2H); 7.14–7.28 (m, 3H). 13C NMR (CDCl3): d 12.3, 25.2,
28.3, 28.8, 40.6, 46.6, 83.8, 105.7, 106.0, 125.6, 127.1,
128.7, 128.9, 129.2, 138.5, 174.7. Anal. calcd for
C18H22N2O2: C, 72.44; H, 7.45. Found: C, 72.16; H, 7.58.
3.2.8. 1,5-Dibenzyl-4-phenyl-4,5,6,7-tetrahydro-1H-pyr-
rolo[3,2-c]pyridine (10h). Yield: 77%; colorless solid. Mp
1178C. 1H NMR (200 MHz, CDCl3): d 2.36–2.74 (m, 3H);
3.00–3.12 (m, 1H); 3.23 (d, J¼13.5 Hz, 1H); 3.85 (d,
J¼13.5 Hz, 1H); 4.48 (s, 1H); 4.92 (s, 2H); 5.57 (d,
J¼2.5 Hz, 1H); 6.49 (d, J¼2.5 Hz, 1H); 6.96–7.50 (m,
15H). 13C NMR (CDCl3): d 22.4, 48.1, 50.3, 58.6, 65.7,
106.3, 120.4, 121.1, 126.3, 126.9, 127.0, 127.2, 127.6,
128.4, 128.5, 128.9, 129.0, 138.7, 140.3, 144.9. Anal. calcd
for C27H26N2: C, 85.71; H, 6.88. Found: C, 86.02; H, 6.86.
3.2.12. 1,5-Dimethyl-2-[2-(5-hydroxy-2-oxopyrrolidino)-
ethyl]pyrrole (11c). The title compound was obtained in
quantitative yield from succinimidopyrrole 7f by a similar
way. Mp 132–1348C. IR (CHCl3): nmax 3600, 3300 (br),
1687 cm21. 1H NMR (200 MHz, CDCl3): d 1.68–1.98 (m,
2H); 2.16 (s, 3H); 2.14–2.34 (m, 2H); 2.40–2.64 (m, 1H);
2.68–2.94 (m, 2H); 3.40 (s, 3H); 3.46–3.58 (m, 2H); 4.88–
5.06 (m, 1H); 5.66–5.88 (m, 2H). 13C NMR (CDCl3): d
12.4, 25.3, 28.9, 30.1, 31.9, 41.0, 84.3, 105.0, 105.1, 129.0,
129.1, 174.8. Anal. calcd for C12H18N2O2: C, 64.83; H,
8.18. Found: C, 64.76; H, 8.25.
3.2.9. 1,5-Dibenzyl-4-(4-chlorophenyl)-4,5,6,7-tetra-
hydro-1H-pyrrolo[3,2-c]pyridine (10i). Yield: 70%;
1
colorless solid. Mp 1058C. H NMR (200 MHz, CDCl3): d
2.36–2.72 (m, 3H), 2.98–3.12 (m, 1H), 3.23 (d, J¼14.0 Hz,
1H), 3.81 (d, J¼14.0 Hz, 1H), 4.46 (s, 1H), 4.94 (s, 2H),
5.56 (d, J¼3.0 Hz, 1H), 6.50 (d, J¼3.0 Hz, 1H), 6.96–7.46
(m, 14H). Anal. calcd for C27H25N2Cl: C, 78.55; H, 6.06.
Found: C, 78.82; H, 5.88.
3.2.13. 3-Benzyl-4,5,7,8,9,9a-hexahydro-3H-pyrrolo[2,3-
g]indolizin-7-one (12a). Silica (1 g) containing 1% of
oxalic acid15 was added to a stirred solution of hemiaminale
11a (0.5 g) in Et2O (20 mL). The reaction mixture was
stirred for 90 min and then filtered. The filtrate was washed
with saturated aqueous NaHCO3 (3 mL), brine (3 mL), and
then dried over Na2SO4. The solution was evaporated in
vacuo and the crude product was purified by column
chromatography on silica gel (Et2O) to give 0.4 g (85%) of
pyrroloindolizinone 12a as a colorless oil. IR (CHCl3): nmax
1686 cm21. 1H NMR (400 MHz, CDCl3): d 1.73–1.84 (m,
1H), 2.39–2.67 (m, 5H), 2.89–2.96 (m, 1H), 4.40 (dd,
J¼12.0, 5.5 Hz, 1H), 4.69–4.72 (m, 1H), 4.96 (s, 2H), 6.0
(d, J¼2.56, 1H), 6.63 (d, J¼2.56, 1H), 6.97–7.01 (m, 2H),
7.23–7.32 (m, 3H). 13C NMR (CDCl3): d 21.6, 27.1, 31.7,
36.5, 50.1, 55.1, 103.1, 119.8, 121.1, 124.7, 126.4, 127.5,
128.7, 137.6, 173.5. Anal. calcd for C17H18N2O: C, 76.69;
H, 6.77. Found: C, 76.76; H, 6.76.
3.2.10. 1-Benzyl-2-[2-(5-hydroxy-2-oxopyrrolidino)-
ethyl]pyrrole (11a). Sodium borohydride (0.68 g,
17.9 mmol) was added portionwise over 15 min to a
solution of succinimidopyrrole 7d (0.5 g, 1.77 mmol) in a
mixture of methanol (6 mL) and THF (2 mL), cooled to
248C. The reaction mixture was stirred at room temperature
overnight and then poured into a vigorously stirred mixture
of saturated aqueous NaHCO3 (10 mL) and Et2O (10 mL),
cooled in an ice-water bath. The aqueous layer was
separated and extracted with Et2O (3£3 mL). The combined
organic layers were washed with brine, dried (Na2SO4) and
evaporated in vacuo to give 0.50 g (100%) hemiaminal 11a
as white crystals. Compound 11a was used without
1
purification. IR (CHCl3): nmax 3600, 1686 cm21. H NMR
(400 MHz, CDCl3): d 1.63 (bs, 1H), 1.70–1.83 (m, 1H),
2.16–2.28 (m, 2H), 2.45–2.54 (m, 1H), 2.72–2.84 (m, 2H),
3.38–3.46 (m, 2H), 4.83–4.86 (m, 1H), 5.08 (s, 2H), 6.00–
6.02 (m, 1H), 6.14 (dd, J¼3.5, 2.8 Hz, 1H), 6.67 (dd, J¼2.8,
1.8 Hz, 1H), 7.05–7.07 (m, 2H), 7.26–7.33 (m, 3H). 13C
NMR (CDCl3): d 24.7, 28.3, 28.8, 40.4, 50.4, 83.8, 107.1,
107.4, 121.8, 126.4, 127.4, 128.7, 129.9, 138.3, 174.8.
3.2.14. 3-Benzyl-2-methyl-4,5,7,8,9,9a-hexahydro-3H-
pyrrolo[2,3-g]indolizin-7-one (12b). To a stirred solution
of hemiaminal 11b (1.19 g, 4 mmol) in CH2Cl2 (63 mL),
cooled to 2208C (bath temperature), triethylamine
(1.67 mL, 12 mmol) and methanesulfonyl chloride
(0.46 mL, 6 mmol) were added. The reaction mixture was
stirred at room temperature for 15 min and was quenched
with saturated aqueous NaHCO3 (100 mL). The aqueous
phase was separated, extracted with CH2Cl2 (3£70 mL) and
the combined organic phases were washed with brine, dried
(Na2SO4) and evaporated in vacuo. The crude product was
purified by column chromatography on silica gel (Et2O) to
give 1.0 g (90%) of pyrroloindolizinone 12b as white
3.2.11. 1-Benzyl-2-[2-(5-hydroxy-2-oxopyrrolidino)-
ethyl]-5-methylpyrrole (11b). Sodium borohydride
(0.38 g, 10 mmol) was added in one portion to a solution
of succinimidopyrrole 7e (0.30 g, 1 mmol) in a mixture of
methanol (8 mL) and THF (2 mL), cooled to 2258C. The
reaction mixture was stirred at temperature below 2108C
for 1 h and then poured into a vigorously stirred mixture of
saturated aqueous NaHCO3 (10 mL) and CH2Cl2 (10 mL),
cooled in an ice-water bath. The aqueous layer was
separated and extracted with CH2Cl2 (3£3 mL). The
combined organic layers were washed with brine, dried
over Na2SO4 and concentrated in vacuo to give 0.30 g
(100%) of crude hemiaminal 11b as white crystals which
were used without further purification in next step. Mp
1
crystals. Mp 97–988C. IR (CHCl3): nmax 1680 cm21. H
NMR (200 MHz, CDCl3): d 1.64–1.86 (m, 1H), 2.16 (s,
3H), 2.38–2.74 (m, 5H), 2.95 (td, J¼12.0, 5.5 Hz, 1H), 4.40
(dd, J¼12.0, 5.5 Hz, 1H), 4.64–4.78 (m, 1H), 4.96 (s, 2H),
5.78 (s, 1H), 6.82–6.96 (m, 2H), 7.18–7.36 (m, 3H). 13C
NMR (CDCl3): d 12.0, 21.9, 27.4, 31.5, 36.8, 46.7, 55.1,
101.9, 118.6, 125.6, 125.7, 127.3, 128.7, 128.9, 137.9,
173.8. Anal. calcd for C18H20N2O: C, 77.10; H, 7.20.
Found: C, 77.17; H, 7.24.
120–1228C. IR (CHCl3): nmax 3599, 3320 (br), 1689 cm21
.
1H NMR (200 MHz, CDCl3): d 1.66–1.86 (m, 2H); 2.18 (s,
3H); 2.18–2.34 (m, 1H); 2.40–2.52 (m, 1H), 2.54–2.68 (m,
1H), 2.68–2.82, (m, 2H); 3.34–3.48 (m, 2H); 4.86–4.98
3.2.15. 2,3-Dimethyl-4,5,7,8,9,9a-hexahydro-3H-
pyrrolo[2,3-g]indolizin-7-one (12c). The title compound
was obtained from succinimidopyrrole 11c in 90% yield by

5272
M. V. Raiman et al. / Tetrahedron 59 (2003) 5265–5272
a similar way. Mp 120–1218C. IR (CHCl3): nmax
1687 cm21 1H NMR (200 MHz, CDCl3): d 1.60–1.84
57.5, 66.4, 102.9, 116.2, 121.7, 129.5. Anal. calcd for
C12H18N2: C, 75.73; H, 9.55. Found: C, 75.88; H, 9.37.
.
(m, 1H), 2.20 (s, 3H), 2.28–2.84 (m, 5H), 2.96 (td, J¼12.0,
5.5 Hz, 1H), 3.38 (s, 3H), 4.49 (dd, J¼12.0, 5.5 Hz, 1H),
4.66–4.88 (m, 1H), 5.72 (s, 1H). 13C NMR (CDCl3): d 12.4,
21.8, 28.0, 32.8, 33.8, 37.2, 55.1, 101.7, 118.3, 125.7, 129.2,
173.9. Anal. calcd for C12H16N2O: C, 70.54; H, 7.91.
Found: C, 70.69; H, 7.87.
Acknowledgements
The authors are grateful to the Ministry of Education of
Belarus and the INTAS program of the European Union.
3.3. General procedure for the reduction of hexahydro-
3H-pyrrolo[2,3-g]indolizin-7-ones (12a–c) to 4,5,7,8,
9,9a-hexahydro[2,3-g]indolizines (13)
References
BH3 (7 mL of 1.7 M solution in THF, 11.3 mmol) was
added dropwise over 20 min to a stirred solution of
compounds 12a–c (1.13 mmol) in dry THF (7 mL) at
2208C, and the mixture was stirred overnight. Methanol
(5 mL) and saturated aqueous NaHCO3 (8 mL) were added
to the mixture, and the precipitate was filtered off, the filtrate
was diluted with Et2O (40 mL), the organic layer was
separated, washed with saturated aqueous NaHCO3 (8 mL),
brine (40 mL), and dried over Na2SO4. The solution was
evaporated in vacuo and the crude product was purified by
column chromatography on silica gel (cyclohexane–ether,
99:1) to give crystalline products 13a–c.
1. Yakhontov, L. N.; Prokopov, A. A. Russ. Chem. Rev. 1980, 49,
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3.3.1. 3-Benzyl-4,5,7,8,9,9a-hexahydro-3H-pyrrolo[2,3-
g]indolizine (13a). Yield: 87%. Mp 968C. 1H NMR
(400 MHz, CDCl3): d 1.81–1.95 (m, 2H), 2.10–2.18 (m,
1H), 2.48–2.55 (m, 1H), 2.61–2.72 (m, 2H), 2.91–2.97 (m,
1H), 3.17–3.28 (m, 3H), 4.38 (dd, J¼7.5, 4.5 Hz, 1H), 4.98
(s, 2H), 5.95 (d, J¼3.0 Hz, 1H), 6.64 (d, J¼2.6 Hz, 1H),
6.98 (d, J¼7.0 Hz, 2H), 7.25–7.34 (m, 3H). 13C NMR
(CDCl3): d 18.4, 21.8, 31.5, 50.15, 53.3, 57.6, 66.2, 104.7,
117.7, 121.6, 122.5, 126.3, 127.6, 128.8, 137.7. Anal. calcd
for C17H20N2: C, 80.95; H, 7.94. Found: C, 81.16; H, 7.92.
3.3.2. 3-Benzyl-2-methyl-4,5,7,8,9,9a-hexahydro-3H-
pyrrolo[2,3-g]indolizine (13b). Yield: 78%. Mp 78–
798C. H NMR (200 MHz, CDCl3): d 1.80–1.95 (m, 3H),
2.12 (s, 3H), 2.44–2.78 (m, 3H), 2.88–3.02 (m, 1H), 3.10–
3.28 (m, 3H), 4.39 (dd, J¼7.5, 4.5 Hz, 1H), 4.96 (s, 2H),
5.70 (s, 1H), 6.82–6.94 (m, 2H), 7.18–7.40 (m, 3H). 13C
NMR (CDCl3): d 12.0, 18.6, 21.7, 31.4, 46.5, 53.3, 57.5,
66.1, 103.3, 116.1, 121.6, 125.5, 127.2, 128.7, 129.2, 137.9.
Anal. calcd for C18H22N2: C, 81.14; H, 8.34. Found: C,
80.97; H, 8.14.
9. Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A. Zh.
Org. Khim. 1991, 27, 1431.
1
10. (a) Michael, J. P. Nat. Prod. Rep. 1999, 16, 675. (b) Carson,
J. R.; Maryanoff, B. E. US Patent, 4, 572, 911, 1986.
11. Spirocompound, 6 was obtained in 95% yield merely by
distillation of 2a in vacuo. Bp 608C (12 Torr). 1H NMR
(200 MHz, CDCl3): d 0.42–0.60 (m, 2H), 0.76–0.94 (m, 2H),
1.20 (t, J¼7.0 Hz, 3H), 1.86–2.26 (m, 4H), 3.42 (dq, J¼9.8,
7.0 Hz, 1H), 3.68 (dq, J¼9.8, 7.0 Hz, 1H), 5.14 (dd, J¼4.5,
1.5 Hz, 1H).
12. Tanis, S. P.; Deaton, M. V.; Dixon, L. A.; McMills, M. C.;
Raggon, J. W.; Collins, M. A. J. Org. Chem. 1998, 63, 6914.
13. cf. Schoemaker, H. E.; Boer-Terpstra, Tj.; Dijkink, J.;
Speckamp, W. N. Tetrahedron 1980, 36, 143.
3.3.3. 2,3-Dimethyl-4,5,7,8,9,9a-hexahydro-3H-pyr-
rolo[2,3-g]indolizine (13c). Yield: 65 %. Mp 83–848C.
1H NMR (200 MHz, CDCl3): d 1.80–1.96 (m, 3H), 2.18 (s,
3H), 2.52–2.88 (m, 3H), 2.90–3.08 (m, 1H), 3.12–3.30 (m,
3H), 3.38 (s, 3H), 4.32 (dd, J¼7.5, 4.5 Hz, 1H), 5.64 (bs,
1H). 13C NMR (CDCl3): d 12.4, 19.0, 22.1, 31.8, 35.9, 53.8,
14. Okano, T.; Sakaida, T.; Eguchi, S. Heterocycles 1997, 44, 227.
15. Huet, F.; Lechevallier, A.; Pellet, M.; Conia, J. M. Synthesis
1978, 63.