A shortcut hydroformylation route to 7-formyl-5,6-dihydroindolizine from 1-allyl-2-formylpyrrole

Article abstract of DOI:10.1016/S0022-328X(00)00658-6

When 1-allyl-2-formylpyrrole (1) was subject to hydroformylation conditions with Rh₄(CO)₁₂ as catalyst precursor, at 100 atm total pressure and 100°C, 7-formyl-5,6-dihydroindolizine (2′) was produced together with the expected branched aldehyde (3), the linear isomer (2) being obtained in traces only. An intramolecular aldol condensation between the carbon atom adjacent to the formyl group in the chain and the carbonyl group directly bonded to pyrrole ring most likely generates the indolizine structure.

Full text of DOI:10.1016/S0022-328X(00)00658-6

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Journal of Organometallic Chemistry 619 (2001) 241–244
A shortcut hydroformylation route to
7
-formyl-5,6-dihydroindolizine from 1-allyl-2-formylpyrrole
a
b
b
b,
Roberta Settambolo , Stefania Savi , Aldo Caiazzo , Raffaello Lazzaroni *
a
Istituto di Chimica Quantistica ed Energetica Molecolare del CNR, 6ia Alfieri 1, 56010 Ghezzano, Pisa, Italy
b
Centro di Studio CNR per le Macromolecole Stereordinate ed Otticamente Atti6e, Dipartimento di Chimica e Chimica Industriale,
6
ia Risorgimento 35, 56126 Pisa, Italy
Received 4 July 2000; accepted 6 September 2000
Abstract
When 1-allyl-2-formylpyrrole (1) was subject to hydroformylation conditions with Rh (CO)12 as catalyst precursor, at 100 atm
4
total pressure and 100°C, 7-formyl-5,6-dihydroindolizine (2%) was produced together with the expected branched aldehyde (3), the
linear isomer (2) being obtained in traces only. An intramolecular aldol condensation between the carbon atom adjacent to the
formyl group in the chain and the carbonyl group directly bonded to pyrrole ring most likely generates the indolizine structure.
©
2001 Elsevier Science B.V. All rights reserved.
Keywords: Hydroformylation; 1-Allyl-2-formylpyrrole; Rhodium; Catalysis; Indolizine
The hydroformylation experiments on 1-allyl-2-
formylpyrrole (1) were carried out in a stainless steel
autoclave, in toluene, with Rh (CO) as catalyst pre-
1
. Introduction
4
12
Aldehydes produced via hydroformylation are not
cursor, at 100°C, at 100 atm total pressure (CO:H =
2
always the final products. Due to the versatile chem-
istry of the formyl group, hydroformylation can also be
integrated in tandem or domino reaction sequences [1].
Recently we found that tandem hydroformylation–cy-
clization–dehydration sequence of 1-allylpyrrole very
easily occurs giving 5,6-dihydroindolizine [2]. In an
extension of these studies to the hydroformylation of
1
:1), using a 100:1 substrate:rhodium ratio. The
substrate conversion and the composition of the reac-
tion mixture were analysed at different times by GC
and GC–MS, using acetophenone as internal standard.
The regioisomeric 3:2 ratio was 54:46 at partial con-
version (Table 1, entry 1). This value was very similar
to that observed in the case of unsubstituted 1-al-
lylpyrrole (59:41 at the same temperature [2]), the pres-
ence of a formyl group on aromatic ring weakly
affecting the regioselectivity of the reaction.
After 1 h at 100°C (Table 1, entry 2), the conversion
was complete and the oxo-dialdehydes 4-(2-
formylpyrrol-1-yl)butanal (2) and 2-methyl-3-(2-
formylpyrrol-1-yl)propanal (3) were the almost
exclusive isomeric products (97%). A low amount of
7-formyl-5,6-dihydroindolizine (2%) (B3%) was also ob-
served. When the crude reaction mixture was allowed
to stand under CO:H2 pressure for longer reaction
times, an increase of the dihydroindolizine 2% was ob-
served together with the reduction of the carbonyl
group of both the branched and the linear dialdehydes
3 and 2 to the corresponding hydroxyl groups. When,
1-allylpyrroles substituted on aromatic rings, we investi-
gated the easily available 1-allyl-2-formylpyrrole (1).
We found and report here that when 1 was submitted
to hydroformylation in the presence of Rh (CO) as
catalyst precursor, at complete substrate conversion, a
mixture of the isomeric oxo-dialdehydes 2 and 3 (2:3=
4
12
4
6:54) was found as almost exclusive product. By heat-
ing the reaction mixture for longer times, the linear
aldehyde 2 disappeared and 7-formyl-5,6-dihydroin-
dolizine (2%) was obtained, whereas the branched alde-
hyde 3 remained unchanged (Scheme 1).
*
Corresponding author. Tel.: +39-50-918227; fax: +39-50-
9
0
18260.
E-mail address: lazza@dcci.unipi.it (R. Lazzaroni).
022-328X/01/$ - see front matter © 2001 Elsevier Science B.V. All rights reserved.
PII: S0022-328X(00)00658-6

2
42
R. Settambolo et al. / Journal of Organometallic Chemistry 619 (2001) 241–244
Scheme 1. (i) Rh (CO) , 100 atm CO:H =1:1, 100°C, toluene, 1 h. (ii) The same conditions as (i), 72 h under N atmosphere, after CO and H
2
4
12
2
2
removal.
at complete substrate conversion, the CO:H gas mix-
ture was removed and the autoclave was heated at
The above findings suggest that the indolizine struc-
ture 2% comes from 2 likely via an intramolecular aldol
addition between the carbon atom adjacent to the
formyl group in the alkyl chain and the carbonyl group
directly bonded to pyrrole ring. Then a bicyclic hydrox-
yaldehyde should form (Scheme 1), which very easily
undergoes water elimination to give a double bond
conjugated with both the pyrrole and the formyl group.
In order to verify this hypothesis a sample of pure
dialdehyde 2 was submitted to typical aldol condensa-
tion conditions with EtONa in absolute EtOH, at room
temperature: selective formation of 7-formyl-5,6-dihy-
droindolizine was immediately observed, the precursor
2 resulting completely transformed into 2%. In contrast,
in absence of rhodium-catalyst, no traces of 2% were
observed by heating 2 in toluene at 100°C. On this light
we can hypothesise that under hydroformylation condi-
2
100°C for additional 72 h (Table 1, entry 3c), the
dialdehyde 2 disappeared and 2% was 46% of the total
products, the branched dialdehyde 3 (54%) staying un-
reacted during all the reaction time.
Aldehydes 2 and 3 and dihydroindolizine 2% are all
new compounds and are obtained as isolated products
via elution on column chromatography. The two alde-
hydes were separated one from each other on SiO2
(
(
hexane:AcOEt=2:1) from a 1 h time reaction mixture
Table 1, entry 2), while 7-formyl-5,6-dihydroindolizine
was separated from aldehyde 3 on Al O (hex-
2
3
ane:AcOEt=9:1) from a 72 h time reaction mixture
(
Table 1, entry 3). The compounds 2, 3 and 2% were
1
characterised by GC–MS and IR analyses [3–5], H-
and C-NMR spectroscopy (Table 2).
1
3
Table 1
a
Composition of the crude reaction mixtures resulting from 1-allyl-2-formylpyrrole (1) in the presence of Rh (CO)12, at 100°C, with or without
4
CO:H2 gas pressure

R. Settambolo et al. / Journal of Organometallic Chemistry 619 (2001) 241–244
243

2
44
R. Settambolo et al. / Journal of Organometallic Chemistry 619 (2001) 241–244
tions the aldol condensation is promoted by a rhodium
carbonyl, although at a very low rate. It is to remark that,
the 3-formyl-5,6-dihydroindolizine, arising from an in-
tramolecular attack of C5 pyrrole carbon atom on the
carbonyl group of the alkyl chain of the dialdehyde 2,
previously observed in the case of simple 1-allylpyrrole
hydroformylation [2], does not form, the above described
aldol condensation being the exclusive process. Because
of the presence of electron-withdrawing group on the
pyrrole C2 carbon atom, the C5 carbon atom is not
nucleophilic enough to bear the electrophilic attack of the
carbonyl moiety.
Aldol condensations of oxo aldehydes under hydro-
formylation conditions have been often observed [6–8].
Recently several efforts have been reported in literature
to combine hydroformylation with a consecutive aldol
reaction in a one pot sequence [9–12]. As far as we know,
the process here described constitutes the first example
of tandem hydroformylation–aldol condensation se-
quence devoted to the synthesis of indolizine moiety.
Hydro derivatives of indolizine are an interesting and
topical subject because some of these occur in natural
products [13]. The rhodium-catalysed hydroformylation
of appropriate 1-allyl-2-formylpyrroles could be a conve-
nientprotocolforthesynthesisofthisclassofcompounds.
and evaporated in vacuo to give 3.4 g (25.3 mmol, 80%
yield) of 1 as a orange oil. H-NMR: l 9.55 (s, 1H), 6.96
1
(m, 2H), 6.26 (t, 1H), 5.98 (m, 1H), 5.17 (d, 1H), 5.04–4.95
13
(m, 3H). C-NMR: 179.5, 134.0, 131.0, 124.3, 116.9,
110.0, 51.0.
2.2. Hydroformylation of 1-allyl-2-formylpyrrole (1)
2.2.1. General procedure
A solution of 1-allyl-2-formylpyrrole (1) (0.5 g, 3.7
mmol) and Rh (CO) (7 mg) in toluene (11 ml) was
4
12
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 introduced to 100 atm (CO:H =
2
1:1) total pressure. When the gas absorption reached the
value corresponding to the fixed conversion, the reaction
mixture was siphoned out; the degree of conversion and
the products distributions were determined by GC/GC–
MS control, by using acetophenone as internal standard.
Acknowledgements
This work was supported by the Ministero dell’
Universit a` e della Ricerca Scientifica e Tecnologica
(
Murst, Roma), Programmi di Ricerca di Interesse
Nazionale (2000–2002).
2. Experimental
References
All reagents were of commercial quality. Silica gel and
aluminium oxide (70–230 mesh) were purchased from
Merck. Toluene was dried over molecular sieves and
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CDCl on a Varian Gemini 200 at 200 MHz for H and
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3
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3
0 MHz for C. Chemical shifts (l) were referred to TMS.
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chromatograph equipped with a 12 m×0.22 mm BP5
capillary column, using nitrogen as carrier gas. GC–MS
analyses were performed on a Perkin Elmer Q-Mass 910
interfaced with a Perkin Elmer 8500 chromatograph
equipped with a 30 m×0.25 mm apolar BP1 capillary
column, using helium as carrier gas. IR spectra were
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+
4] 3: MS m/e 137 (M −28, 40), 118 (43), 108 (31), 104 (38), 94 (100),
8
0 (40). IR neat 1723.9 (wcꢀo), 1659.6 (wcꢀo).
+
5] 2%: MS m/e 147 (M , 66), 146 (61), 118 (100), 117 (58), 91 (19).
−1
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4 12
1
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2
.1. Preparation of 1-allyl-2-formylpyrrole (1)
[
[
(
1
To a stirred mixture of 50% aqueous NaOH (20 ml)
solution, 2-formylpyrrole (3.0 g, 31.6 mmol) and tetra-
butylammonium hydrogen sulfate (1.2 g, 3.5 mmol) in
toluene (50 ml), was added 3-chloro-1-propene (2.7 ml,
[12] (a) C. Hollmann, P. Eilbracht, Tetrahedron Letters 40 (1999) 4313.
b) C. Hollmann, P. Eilbracht, Tetrahedron Letters 56 (2000) 1685.
(
[
13] (a) A.R. Katritzky, C.N. Fali, J. Li, J. Org. Chem. 62 (1997) 4148,
and references cited therein. (b) B. Sayah, N. Pelloux-L e´ on, Y.
Vall e´ e, J. Org. Chem. 65 (2000) 2824.
2.5 g, 32.7 mmol). The mixture was then heated at 70°C,
with vigorous stirring, for 1 h. The cooled mixture was
dilutedwithwaterandextractedwithether. Thecombined
[
14] J.A. McCleverty, G. Wilkinson, Inorg. Synth. 8 (1966) 211.
organic extracts were washed with water, dried (Na
.
SO4),
[15] P.E. Cattermole, G.A. Osborne, Inorg. Synth. 17 (1977) 115.
2