An original approach to 5,6-dihydroindolizines from 1-allylpyrroles by a tandem hydroformylation/cyclization/dehydration sequence

Article abstract of DOI:10.1016/S0040-4039(01)00625-6

6-Methyl-5,6-dihydroindolizine and 3- or 2-ethyl derivatives were obtained via a one-pot hydroformylation/cyclization/dehydration sequence starting from 1-(2-methyl-2-propenyl)pyrroles. 7-Phenyl-5,6-dihydroindolizine and 5-methyl-5,6-dihydroindolizine were similarly synthesized. An easily occurring electrophilic aromatic substitution by the carbon atom of the carbonyl group on the α-position of the pyrrole ring with the formation of the six-membered ring is the key-step of the process.

Full text of DOI:10.1016/S0040-4039(01)00625-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4045–4048
An original approach to 5,6-dihydroindolizines from
1-allylpyrroles by a tandem
hydroformylation/cyclization/dehydration sequence
Roberta Settambolo,a Aldo Caiazzob and Raffaello Lazzaronib,*
aIstituto di Chimica Quantistica ed Energetica Molecolare del CNR, Via Alfieri 1, 56010 Ghezzano (PI), Italy
bDipartimento di Chimica e Chimica Industriale, Via Risorgimento 35, 56126 Pisa, Italy
Received 2 February 2001; accepted 11 April 2001
Abstract—6-Methyl-5,6-dihydroindolizine and 3- or 2-ethyl derivatives were obtained via a one-pot hydroformylation/cyclization/
dehydration sequence starting from 1-(2-methyl-2-propenyl)pyrroles. 7-Phenyl-5,6-dihydroindolizine and 5-methyl-5,6-dihydro-
indolizine were similarly synthesized. An easily occurring electrophilic aromatic substitution by the carbon atom of the carbonyl
group on the a-position of the pyrrole ring with the formation of the six-membered ring is the key-step of the process. © 2001
Elsevier Science Ltd. All rights reserved.
The hydroformylation of functionalized unsaturated
substrates, especially when involved in tandem or
domino reaction sequences, constitutes a very versatile
tool for the synthesis of fine chemicals.1 Thus, reduc-
tion, nucleophilic addition or aldol condensation can be
achieved directly under the reaction conditions of the
oxo process.1
of vinyl2 and allyl3 heteroaromatic substrates, we found
that 4-(pyrrol-1-yl)butanal, obtained as the minor
product (20%) in the 1-allylpyrrole hydroformylation,
surprisingly gave 5,6-dihydroindolizine via a one-pot
cyclization/dehydration process.3
5,6-Dihydro- and 5,6,7,8-tetrahydroindolizines are
some of the most intriguing fused pyrrole derivatives,
because they constitute the basic skeleton of many
natural alkaloids and possess pharmacological proper-
During our studies on the factors affecting the regio-
selectivity of the rhodium-catalyzed hydroformylation
Scheme 1.
Keywords: hydroformylation; indolizine; rhodium; catalyst.
* Corresponding author. Tel.: (050) 918227; fax: (050) 918260; e-mail: lazza@dcci.unipi.it
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00625-6

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R. Settambolo et al. / Tetrahedron Letters 42 (2001) 4045–4048
ties.4 Thus, the design of new synthetic methods for
this class of compound is an interesting and topical
subject. The unexpected result obtained in the hydro-
formylation of 1-allylpyrrole prompted us to investi-
gate the synthetic potentiality of this method by
ring, we submitted to hydroformylation 2- or 3-ethyl-
1-(2-methyl-2-propenyl)pyrroles 1c–d (Scheme 1): with
these substrates 5,6-dihydroindolizines 3c–d were also
obtained with very high chemo- and regioselectivity
(Scheme 1). In the case of 1c, 3-ethyl-6-methyl-5,6-
dihydroindolizine (3c) was formed as the sole reaction
product. In the case of 1d, both the 2 and 5 positions
of the pyrrole ring were involved in the cyclization
process, but the 2-ethyl-6-methyl-5,6-dihydroindolizine
3d, coming from annulation on the pyrrole C5 carbon
atom, was largely prevalent with respect to the 1-
ethyl-6-methyl-5,6-dihydroindolizine 3%d, which had
involved the pyrrole C2 carbon atom (3d/3%d=90:10).
It is worth noting that no traces of the expected oxo
pyrrolylbutanals, precursors to the dihydroindolizines
3c–d, were found in the crude reaction mixtures at
any degree of conversion: these aldehydes, as they
form, immediately react with the cyclization process.
submitting
to
hydroformylation
suitable
1-
allylpyrroles which are able to generate 4-(pyrrol-1-
yl)butanals or, more generally, 4-(pyrrol-1-yl)alkanals,
possible precursors of 5,6-dihydroindolizines. We
found and report here that when the easily available
1-(2-methyl-2-propenyl)pyrrole (1a) and 1-(3-phenyl-2-
propenyl)pyrrole (1b) are submitted to rhodium-cata-
lyzed hydroformylation, 5,6-dihydroindolizines 3a–b
substituted on the six-membered ring are obtained as
the exclusive products (Scheme 1).
Under the same experimental conditions, 2-ethyl-1-(2-
methyl-2-propenyl)pyrrole (1c) and 3-ethyl-1-(2-methyl-
2-propenyl)pyrrole (1d) selectively give 5,6-dihydroin-
dolizines 3c–d, substituted on both the rings of the
indolizine moiety (Scheme 1), while the vinyl sub-
strate 1-(1-methyl-2-propenyl)pyrrole (1e) gives 5-
methyl-5,6-dihydroindolizine (3e) (Scheme 1).
The hydroformylation of the vinyl substrate 1-(1-
methyl-2-propenyl)pyrrole (1e) under the same experi-
mental
conditions
gives,
in
addition
to
2-methyl-3-(pyrrol-1-yl)butanal (2%e),13 5-methyl-5,6-
dihydroindolizine (3e) in a 3e/2%e=59/41 molar ratio.
The linear aldehyde 2e, the precursor to 3e, was
present only in traces in the reaction mixture both at
partial and complete substrate conversion. On carry-
ing out the hydroformylation of 1e at a higher tem-
perature (120°C) and lower pressure (30 atm
CO/H2=1:1), the molar ratio 3e/2%e conveniently
increased to 78/22, according to the well documented
behavior of vinyl and allyl substrates.3,12 Interestingly
5-methyl-5,6-dihydroindolizine (3e) is a suitable pre-
cursor to 5-methyloctahydroindolizine, the simplest 5-
1-Allylpyrroles5 1a–e were easily prepared from the
reaction between the corresponding pyrrole compound
and the appropriate allyl halide in the KOH/DMSO
system.3,6 The hydroformylation of the substrates 1a–e
was carried out in the presence of Rh4(CO)12 as
catalyst precursor7,8 according to a typical procedure.9
By using a Rh/substrate ratio of 1:100, the olefin 1a
was totally converted into 6-methyl-5,6-dihydro-
indolizine (3a) in a short time (0.5 h) (Scheme 1). In
order to slow down the reaction, a Rh/substrate ratio
of 1:1000 was employed: at 10% conversion, a small
amount of aldehyde 2a was detected in the reaction
mixture,10 the indolizine formation still being a fast
process with respect to the oxo one. On the other
hand, attempts to carry out the reaction at lower
temperatures were unsuccessful, 1a remaining unre-
acted.
alkylsubstituted
indolizidine,14
which
are
a
well-known family of natural indolizidine alkaloids.15
The dihydroindolizines 3a–e are new compounds and
1
were isolated and characterized by H and 13C NMR
spectroscopy, GC–MS, melting point and elemental
analysis.16 They are stable enough to be handled eas-
ily at room temperature without any decomposition
and can be stored at 0°C for long periods.
When 1b was submitted to rhodium-catalyzed hydro-
formylation under the same conditions as for 1a, 7-
phenyl-5,6-dihydroindolizine 3b was obtained as the
exclusive product (Scheme 1). In this case no traces
of 2-phenyl-4-(pyrrol-1-yl)butanal (2b), the precursor
to 3b, were observed even at very low conversions,
the cyclization/dehydration being very fast with
respect to the hydroformylation reaction. It is worth
noting that in both cases the hydroformylation occurs
with complete regioselectivity. In the presence of 1a,
the exclusive addition of the formyl group to the ter-
minal carbon atom takes place according to behavior
typical of disubstituted terminal olefins.11 In the case
of 1b, exclusive addition of the formyl group to the
carbon atom directly bonded to the phenyl group
occurs, the pyrrolyl olefin 1b showing behavior typi-
cal of styrene.12
In conclusion, the chemistry reported here is an inter-
esting application of the rhodium-catalyzed hydro-
formylation providing a concise synthesis of alkyl
substituted 5,6-dihydroindolizines starting from easily
available allylpyrroles via
a one-pot 4-(pyrrol-1-
yl)butanal formation and intramolecular cyclization.
The key-step of the sequence consists of an
intramolecular electrophilic aromatic substitution pro-
moted by the carbon atom of the carbonyl group on
the C2 (5) carbon atom of the pyrrole ring. The reac-
tion occurs under mild conditions even in the absence
of classical Lewis acids, likely due to the strong
nucleophilic character of the pyrrole carbon atom a
to the nitrogen. It is worth remarking that, while the
intramolecular cyclization of 4-(pyrrol-1-yl)alkanoic
acids or alkanoates is a well-known process catalyzed
by Lewis acid,4b,14 the construction of the indolizine
skeleton via annulation of 4-(pyrrol-1-yl)butanals has
been reported here for the first time.
In order to explore the possibility of obtaining dihy-
droindolizines selectively functionalized on the pyrrole

R. Settambolo et al. / Tetrahedron Letters 42 (2001) 4045–4048
4047
Acknowledgements
introduced to 100 atm (CO/H2=1/1) total pressure.
After 0.5 h at 100°C the reaction was completed and
formation of a single product was observed. From the
reaction mixture 6-methyl-5,6-dihydroindolizine (3a)
was obtained as a red oil (SiO2; hexane/EtOAc=4:1)
This work was partially supported by the Ministero
dell’Universita` e della Ricerca Scientifica e Tecnologica
(40% funds).
1
(0.41 g, 75% yield); H NMR l 6.56 (bs, 1H), 6.37 (dd,
J=9.9; 2.1 Hz, 1H), 6.11 (t, J=3.0 Hz, 1H), 6.02 (m,
1H), 5.55 (dd, J=9.9; 3.6 Hz, 1H), 3.95 (dd, J=12.0;
6.0 Hz, 1H), 3.51 (dd, J=12.0; 9.6 Hz, 1H), 2.75 (m,
1H), 1.15 (d, J=6.9 Hz, 3H); 13C NMR l 128.1, 126.0,
121.0, 119.0, 108.0, 105.5, 51.0, 29.8, 18.2. MS m/e 133
(M+, 45), 132 (23), 118 (100), 117 (50), 91 (20). Anal.
calcd for C9H11N: C, 81.20; H, 8.27; N, 10.53. Found:
C, 81.35; H, 8.22; N, 10.55.
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5. 1a (63% yield), colorless liquid. Bp 31°C, P 1.5 mmHg.
1H NMR l 6.67 (t, J=2.1 Hz, 2H), 6.19 (t, J=2.1 Hz,
2H), 4.92 (s, 1H), 4.77 (s, 1H), 4.43 (s, 2H), 1.68 (s,
3H). MS m/e 121 (M+, 68), 120 (65), 106 (100), 80
(99), 53 (16). 1b (40% yield), yellow oil. 1H NMR l
7.50–7.20 (m, 5H), 6.71 (t, J=2.1 Hz, 2H), 6.49 (d,
J=15.8 Hz, 1H), 6.30 (m, 1H), 6.16 (t, J=2.1 Hz, 2H),
4.64 (d, J=5.9 Hz, 2H). MS m/e 183 (M+, 52), 118
(10), 117 (100), 115 (76). 1c (68% yield), yellow oil. 1H
NMR l 6.55 (t, J=1.6 Hz, 1H), 6.09 (t, J=3.1 Hz,
1H), 5.92 (m, 1H), 4.83 (m, 1H), 4.48 (s, 1H), 4.30 (s,
2H), 2.50 (q, J=7.4 Hz, 2H), 1.69 (s, 3H), 1.24 (t,
J=7.4 Hz, 3H). MS m/e 149 (M+, 60), 134 (100), 120
(39), 93 (18), 80 (27), 55 (41). 1d (65% yield), yellow
oil. 1H NMR l 6.55 (m, 1H), 6.40 (s, 1H), 6.00 (m,
1H), 4.85 (s, 1H), 4.75 (s, 1H), 4.30 (s, 2H), 2.45 (q,
J=5.0 Hz, 2H), 1.65 (s, 3H), 1.20 (t, J=5.0 Hz, 3H).
MS m/e 149 (M+, 65), 134 (100), 120 (37), 93 (18), 80
(24), 55 (38). 1e (68% yield), colorless liquid. 1H NMR
l 6.72 (t, J=2.1 Hz, 2H), 6.16 (t, J=2.1 Hz, 2H), 5.98
(m, 1H), 5.02–5.20 (m, 2H), 4.65 (m, 1H), 1.55 (d,
J=7.0 Hz, 3H). MS m/e 121 (M+, 74), 106 (95), 79
(27), 67 (100), 55 (54).
12. Lazzaroni, R.; Raffaelli, A.; Settambolo, R.; Bertozzi,
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16. 7-Phenyl-5,6-dihydroindolizine (3b). Prepared as a yel-
low solid according to the general procedure starting
from 1b (80% yield). Mp 75°C. 1H NMR l 7.50–7.15
(m, 5H), 6.83 (s, 1H), 6.62 (s, 1H), 6.15 (m, 2H), 4.07
(t, J=6.9 Hz, 2H), 2.89 (t, J=6.9 Hz, 2H). MS m/e
195 (M+, 100), 194 (68), 118 (25), 117 (16), 104 (92).
Anal. calcd for C14H13N: C, 86.15; H, 6.67; N, 7.18.
Found: C, 86.70; H, 6.70; N, 7.22. 3-Ethyl-6-methyl-
5,6-dihydroindolizine (3c). Prepared as
a yellow oil
according to the general procedure starting from 1c
(72% yield). 1H NMR l 6.38 (d, J=9.0 Hz, 1H), 6.18
(d, J=3.2 Hz, 1H), 6.10 (d, J=3.2 Hz, 1H), 5.60 (dd,
J=9.0; 3.1 Hz, 1H), 3.52 (d, J=5.0 Hz, 1H), 3.47 (d,
J=5.0 Hz, 1H), 2.68 (m, 1H), 2.42 (q, J=7.5 Hz, 2H),
1.25 (t, J=7.5 Hz, 3H), 0.71 (d, J=8.3 Hz, 3H). MS
m/e 161 (M+, 48), 146 (100), 144 (9). Anal. calcd for
C11H15N: C, 81.99; H, 9.32; N, 8.70. Found: C, 82.30;
H, 9.29; N, 8.72. 2-Ethyl-6-methyl-5,6-dihydroindolizine
(3d). Prepared as a yellow oil according to the general
procedure starting from 1d (75% yield). The product
was eluted with SiO2; hexane/EtOAc=9:1; 1H NMR l
6.48 (d, J=2.3 Hz, 1H), 6.40 (d, J=9.0 Hz, 1H), 6.00
(d, J=2.3 Hz, 1H), 5.50 (dd, J=9.0; 3.3 Hz, 1H), 3.92
(dd, J=12.0; 6.4 Hz, 1H), 3.50 (dd, J=12.0; 10 Hz,
1H), 2.75 (m, 1H), 2.46 (q, J=7.5 Hz, 2H), 1.2 (d,
J=8.0 Hz, 3H), 1.10 (t, J=7.5 Hz, 3H). MS m/e 161
(M+, 70), 146 (100), 131 (16), 117 (13). Anal. calcd for
C11H15N: C, 81.99; H, 9.32; N, 8.70. Found: C, 81.85;
6. (a) Heaney, H.; Ley, S. V. J. Chem. Soc., Perkin Trans.
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9. Hydroformylation of 1-allylpyrroles 1a–e. General proce-
dure. Preparation of 6-methyl-5,6-dihydroindolizine (3a).
A solution of 1-(2-methyl-2-propenyl)pyrrole (1a) (0.5
g, 4.13 mmol) and Rh4(CO)12 (7.5 mg, substrate/Rh=
100/1) in toluene (10 ml) was introduced by suction
into an evacuated 25 ml stainless steel reaction vessel.
Carbon monoxide was introduced, the autoclave was
then rocked, heated to 100°C and hydrogen was rapidly

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R. Settambolo et al. / Tetrahedron Letters 42 (2001) 4045–4048
H, 9.28; N, 8.76. 1-Ethyl-6-methyl-5,6-dihydroindolizine
1H), 2.53 (m, 1H), 2.20 (m, 1H), 1.43 (d, J=6.5 Hz, 1H);
13C NMR l 128.5, 120.1, 118.4, 117.9, 108.0, 106.2, 49.6,
32.2, 20.2. MS m/e 133 (M+, 63), 132 (19), 118 (100), 117
(44), 91 (23). Anal. calcd for C9H11N: C, 81.20; H, 8.27;
N, 10.53. Found: C, 81.30; H, 8.21; N, 10.48. The dihy-
droindolizine 3%d was characterized via GC–MS analysis
in the mixture with the regioisomer 3d.
(3%d). MS m/e 161 (M+, 72), 146 (100), 131 (20). 5-
Methyl-5,6-dihydroindolizine (3e). Prepared as a yellow
oil according to the general procedure starting from 1e.
The product was eluted with SiO2; hexane/EtOAc=4:1
1
(62% yield). H NMR l 6.70 (m, 1H), 6.42 (d, J=9.8 Hz,
1H), 6.14 (m, 1H), 6.03 (m, 1H), 5.65 (m, 1H), 4.10 (m,
.