Domino reaction sequences in the rhodium-catalyzed hydroformylation of 3-acetyl-1-allylpyrrole: A short route to 5,6,7,8-tetrahydroindolizines

Article abstract of DOI:10.1016/j.jorganchem.2005.01.018

When 3-acetyl-1-allylpyrrole (1) was subjected under hydroformylation conditions, with Rh₄(CO)₁₂ as catalyst precursor, to 30 atm CO/H₂ (1:1) total pressure and 140°C, an equimolar mixture of the isomeric 5,6,7,8-tetrahydroindolizines 4′ and 5′ was obtained as the almost exclusive product. In both cases a domino hydroformylation/ cyclization on the α pyrrole positions by the aldehyde 3 carbonyl group occurs which involves different intermediates: while 4′ is generated via the dihydroindolizine 4, 5′ forms via direct reduction of 8-hydroxytetrahydroindolizine 5, a structure that has never been observed before from 1-allylpyrroles under oxo conditions.

Full text of DOI:10.1016/j.jorganchem.2005.01.018

Journal of Organometallic Chemistry 690 (2005) 1866–1870
www.elsevier.com/locate/jorganchem
Note
Domino reaction sequences in the rhodium-catalyzed
hydroformylation of 3-acetyl-1-allylpyrrole: a short route
to 5,6,7,8-tetrahydroindolizines
a
Silvia Rocchiccioli , Roberta Settambolo , Raffaello Lazzaroni
b
a,
*
a
`
Dipartimento di Chimica e Chimica Industriale, Universita di Pisa, Via Risorgimento 35, 56126 Pisa, Italy
b
ICCOM-CNR, Sezione di Pisa, Dipartimento di Chimica e Chimica Industriale, Via Risorgimento 35, 56126 Pisa, Italy
Received 22 November 2004; accepted 12 January 2005
Available online 22 February 2005
Abstract
When 3-acetyl-1-allylpyrrole (1) was subjected under hydroformylation conditions, with Rh4(CO)12 as catalyst precursor, to 30 atm
CO/H2 (1:1) total pressure and 140 ꢀC, an equimolar mixture of the isomeric 5,6,7,8-tetrahydroindolizines 40 and 50 was obtained as the
almost exclusive product. In both cases a domino hydroformylation/cyclization on the a pyrrole positions by the aldehyde 3 carbonyl
group occurs which involves different intermediates: while 40 is generated via the dihydroindolizine 4, 50 forms via direct reduction of 8-
hydroxytetrahydroindolizine 5, a structure that has never been observed before from 1-allylpyrroles under oxo conditions.
ꢁ 2005 Published by Elsevier B.V.
Keywords: Hydroformylation; 3-Acetyl-1-allylpyrrole; Rhodium; Catalysis; 5,6,7,8-Tetrahydroindolizines
1. Introduction
present at the a pyrrole position, the above cyclization
does not occur but a dihydroindolizine derivative is never-
theless formed via an aldol condensation involving the
pyrrole formyl group and the C2 butanal carbon atom
[3]. In order to extend the investigation of the rhodium cat-
alyzed hydroformylation of N-allylpyrroles to those
substituted with electron-withdrawing groups on b
pyrrole position, 3-acetyl-1-allylpyrrole (1) was subjected
to oxo conditions. We found that the linear aldehyde 3,
the main oxo product (Scheme 1), gives, under reaction
conditions, the new isomeric acetyl substituted 5,6,7,8-tet-
rahydroindolizines 40 and 50 (1:1) (Scheme 2). Interest-
ingly, the aldehyde 3, in the presence only of CO and the
rhodium catalyst, gives the tricyclic alcoholic species 5 in
addition to dihydroindolizine 4 (Scheme 2). Although a
structure of type 5 has been frequently invoked as part
of the cyclization mechanism, 5 is the first 8-hydroxytetra-
hydroindolizine identified under rhodium-catalyzed hyd-
roformylation of N-allylpyrroles.
Domino reaction sequences are of great interest
because they enable the atom-economic formation of
C–C bonds, thus providing relatively easy access to com-
plex molecular architectures [1]. Recently, we found a
domino process in the intramolecular cyclodehydration
of 4-pyrrolylbutanals generated by rhodium-catalyzed
hydroformylation of 1-allylpyrroles: the aldehyde
carbonyl group attacks the pyrrole position giving a
8-hydroxytetrahydroindolizine which immediately under-
goes water elimination to a 5,6-dihydroindolizine. This
process occurs very easily with unsubstituted 1-allylpyr-
roles or with 1-allylpyrroles having an electron-donor
group at the a- or b-position [2]. In contrast, when an elec-
tron-withdrawing group (a formyl or an acetyl group) is
*
Corresponding author. Tel.: +39 50 918227; fax: +39 50 918260.
E-mail address: lazza@dcci.unipi.it (R. Lazzaroni).
0022-328X/$ - see front matter ꢁ 2005 Published by Elsevier B.V.
doi:10.1016/j.jorganchem.2005.01.018

S. Rocchiccioli et al. / Journal of Organometallic Chemistry 690 (2005) 1866–1870
1867
was present in very small amount, did not give cycliza-
tion products but only reduction to the corresponding
alcohol.
O
O
O
i
+
N
N
According to the previous report [2], the formation of
40 is explainable by an electrophilic attack of the car-
bonyl group of 3 on the C5 pyrrole carbon atom (route
a, Scheme 2) via the conjugated dihydroindolizine 4,
which was identified in the crude reaction mixture at
intermediate times (Table 1, entry 1). An analogous at-
tack on pyrrole carbon atom C2 (route b, Scheme 2) in-
stead of C5 occurs for the formation of 50: in this case
the bicyclic alcohol 5 was found as a transient species
(Table 1, entry 1 and 2). Note that 5 does not undergo
water elimination but is converted into the tetrahydro-
indolizine 50 via a direct reduction of the hydroxyl group
(Table 1, entry 3). Indeed the corresponding dihydroind-
olizine has never been found in the crude reaction mix-
ture. It is to be pointed out that the reduction of 4 to 40
is faster than the transformation of tetrahydroindolizine
5 into the corresponding compound 50. However, it is
possible to stop the reaction at the stage of formation
of 4 and 5 by removing the CO/H2 gas mixture after
the complete conversion of 1 to 3 and by pressuring
the reactor with CO only. In this way after 48 h the alde-
hyde 3 was quantitatively converted into an equimolar
mixture of 4 and 5 (Table 1, entry 5). Reduction prod-
ucts 40 and 50 could not be detected. 4 and 5 were easily
separated by column chromatography and character-
ized. The hydroxylated indolizidines have attracted
special interest by virtue of their varied and pharmaceu-
tically useful biological actions as potential antiviral,
antitumor, and immunomodulating agents [4]. In partic-
ular, tetrahydroindolizines bearing both an acetyl group
at C1 and a hydroxyl group at C8 show antithrombotic
activity or are intermediates for the preparation of anti-
thrombotic derivatives. They also show anti-TNF activ-
ity [5]. 5 is likely to be stabilized by an intramolecular
N
τ = 1h
O
O
3
(85%)
1
2 (15%)
(i) Rh4(CO)12, CO/H2 1:1, 30 atm, 140 ˚C, toluene.
Scheme 1.
2. Results and discussion
The hydroformylation experiments on 1-allyl-3-acet-
ylpyrrole (1) were carried out in a stainless steel auto-
clave, in toluene, with Rh4(CO)12 as catalyst precursor,
at 30 atm total pressure (CO/H2 = 1:1) and 140 ꢀC, using
a 200:1 substrate:Rh ratio. The substrate conversion was
analysed by GC using acetophenone as internal
standard.
After 1 h the starting olefin 1 was completely con-
verted into the corresponding aldehydes, the linear iso-
mer 3 being strongly favoured with respect to the
branched one 2 (regioisomeric 3:2 molar ratio 85:15)
(Scheme 1). This value was very similar to that observed
for other 1-allylpyrroles under the above experimental
conditions [2]: under these drastic conditions (high tem-
perature, low pressure), no trace of the isomeric olefin 1-
(pyrrol-1-yl)propene was found in the crude reaction
mixture, at all conversions.
For long reaction times (s = 48 h) (Table 1, entry 3),
the linear aldehyde was completely transformed into two
products, i.e., 2-acetyl-5,6,7,8-tetrahydroindolizine 40
and 1-acetyl-5,6,7,8-tetrahydroindolizine 50 in a 1:1
molar ratio. In contrast, the branched aldehyde 2, which
O
O
a
N
N
O
4
N
4’
i
b
a
+
+
O
O
O
H
3
O
b
N
N
5
5’
Scheme 2. (i) Rh4(CO)12, CO/H2 1:1, 30 atm, 140 ꢀC, toluene.

1868
S. Rocchiccioli et al. / Journal of Organometallic Chemistry 690 (2005) 1866–1870
Table 1
Distribution of the cyclization products resulting from 4-(3-acetylpyrrol-1-yl)butanal (3)a in the presence of Rh4(CO)12, with CO/H2 or CO only gas
pressure
Entry
CO
(atm)
H2
(atm)
Reaction
Time
(h)
Conv.
(%)b
O
N
O
O
3
O
O
O
OH
N
N
N
N
4
4'
5
5’
(%)b
(%)b
(%)b
(%)b
1
2
3
4
5
15
15
15
30
30
15
15
15
-
11
24
48
23
48
58
100
100
50
16
5
15
6
-
45
45
-
30
-
25
55
-
-
25
25
100
50
-
50
-
-
a Reaction conditions: 0.2 g (1.34 mmol) of 3-acetyl-1-allylpyrrole (1) as the starting material, 5 ml toluene, 3 mg Rh4(CO)12 (7x10-3 mmol, substrate/
Rh = 200/1), 140 ˚C, autoclave volume 25 ml.
b Determined by GLC using acetophenone as internal standard.
hydrogen bond between the hydroxylic hydrogen and
the carbonyl oxygen atom with consequent formation
of a tricyclic structure. This factor could be the driving
force for the formation of 5 in an amount (1:1 molar ra-
tio with respect 4) that would not be expected on the ba-
sis of otherwise unfavourable steric and electronic
effects. In accord with this structural hypothesis, the
IR spectrum showed a band due to OH stretching at
an unexpectedly low frequency (3037 cmꢀ1). This value
was independent of concentration (10ꢀ2, 10ꢀ3, 10ꢀ4 M
solution in CCl4) as expected for an intramolecular,
rather than intermolecular, hydrogen bond.
In conclusion, the hydroformylation of 3-acetyl-1-
allylpyrrole reported here constitutes an interesting
extension of the reactivity of 1-allylpyrroles substi-
tuted with electron-withdrawing groups. Unlike the
analogous 2-acetyl-1-allylpyrrole [3], which undergoes
no electrophilic substitution but only aldol condensa-
tion (Scheme 3), the presence of the acetyl group on
the b pyrrole position makes the a pyrrole positions
N
O
X=H
Y=COCH
3
X
O
O
X=COCH
X=COCH
Y=H
3
3
OH
Y
N
N
Y=H
N
O
Scheme 3.

S. Rocchiccioli et al. / Journal of Organometallic Chemistry 690 (2005) 1866–1870
1869
still available for the electrophilic attack of the car-
3.2. Hydroformylation of 1-allyl-3-acetylpyrrole (1).
General procedure
bonyl moiety. Interestingly, cyclization is much slower
than hydroformylation, thus allowing either the alde-
hydes or the corresponding cyclization products to
be recovered as required. Of these last, tetrahydroind-
olizines can be obtained at long reaction times under
a CO/H2 gas mixture, dihydroindolizine or 8-hydroxy-
tetrahydroindolizine being the exclusive products un-
der CO pressure only. Because of the interest in the
hydroxylated indolizines, the rhodium-catalyzed hyd-
roformylation of appropriate 3-carbonylsubstituted-1-
allylpyrroles could be a convenient protocol for the
synthesis of this class of compounds.
A
solution of 1-allyl-3-acetylpyrrole (1) (0.2 g,
1.34 mmol) and Rh4(CO)12 (3 mg, 7 · 10ꢀ3 mmol, sub-
strate/Rh = 200/1) in toluene (5 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 140 ꢀC and hydrogen was
rapidly introduced to 30 atm (CO/H2 = 1:1) total pres-
sure. When the gas absorption reached the value corre-
sponding to the fixed conversion, the reaction mixture
was siphoned out; the degree of conversion and the
product distributions were determined by GC/GC-MS
with use of acetophenone as internal standard.
3. Experimental
Selected data for 4-(3-acetylpyrrol-1-yl)butanal (3). As
a yellow oil (Al2O3; benzene/EtOAc = 70/30). 1H NMR d
9.69 (t, J = 0.6 Hz, 1H, COH), 7.21 (t, J = 2.4 Hz, 1H,
pyr-H), 6.60 (m, 2H, pyr-H), 4.25 (dd, J = 6.8; 14.4 Hz,
2H, CH2–N), 2.41 (t, J = 7.6 Hz, 2H, CH2–CO), 2.30 (s,
3H, CH3CO), 2.10 (m, 2H, CH2). MS m/e 179 (M+ 14),
164 (10), 161 (16), 151 (54), 146 (30), 136 (82), 94 (100),
80 (40), 71 (46), 66 (7). Selected data for 2-methyl-3-(3-
acetylpyrrol-1-yl)propanal (2). As a yellow oil (Al2O3;
benzene/EtOAc = 70/30). 1H NMR d 9.62 (d, J =
1.1 Hz, 1H, COH), 7.18 (t, J = 2.0 Hz, 1H, pyr-H), 6.51
(m, 2H, pyr-H), 3.90 (dd, J = 6.8; 13.8 Hz, 2H, CH2–N),
2.81 (q, J = 7.0 Hz, 1H, CH–), 2.30 (s, 3H, CH3CO),
1.11 (d, J = 7.0 Hz, 3H, CH3–). MS m/e 179 (M+ 7), 164
(70), 151 (66), 136 (54), 122 (5), 109 (10), 108 (24), 94
(100), 93 (19), 80 (19), 66 (13), 52 (5). Selected data for
2-acetyl-5,6,7,8-tetrahydroindolizine (40). As a yellowish
oil (Al2O3, benzene/EtOAc = 70/30). 1H NMR d 6.50 (d,
J = 3.0 Hz, 1H, pyr-H), 6.47 (d, J = 3.0 Hz, 1H, pyr-H),
3.90 (m, 2H, CH2–N), 2.59 (m, 2H, CH2–), 2.30 (s, 3H,
CH3CO), 1.77 (m, 2H, CH2), 1.53 (m, 2H, CH2). MS
m/e 163 (M+ 60), 148 (100), 120 (30), 106 (10).
All reagents were of commercial quality. Silica gel and
alumina (70–230 mesh) were purchased from Merck.
Toluene was dried over molecular sieves and distilled
under nitrogen. NMR spectra were recorded in CDCl3
on a Varian Gemini 200 at 200 MHz for 1H and
50 MHz for 13C. Chemical shifts (d) were referred to
TMS. GC analyses were performed on a Perkin–Elmer
8700 chromatograph equipped with a 12 m · 0.22 mm
BP1 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 recorded on a Perkin–Elmer FT-IR spectro-
photometer 1760X. Rh4(CO)12 was prepared according
to a well-known procedure [6,7]. 3-acetylpyrrole was pre-
pared as reported in the literature [8].
3.1. Preparation of 1-allyl-3-acetylpyrrole (1)
To a stirred mixture of 50% aqueous NaOH (13 ml)
solution, 3-acetylpyrrole (2.5 g, 0.027 mol) and tetrabu-
tylammonium hydrogen sulfate (1.0 g, 3.0 mmol) in tol-
uene (80 ml), was added 3-bromo-1-propene (2.4 ml,
0.027 mol). The mixture was then heated at 70 ꢀC, with
vigorous stirring, for 1 h. The cooled mixture was di-
luted with water and extracted with ether. The combined
organic extracts were washed with water, dried
(Na2SO4), and evaporated in vacuo to give a residue
which was distilled at reduced pressure (T = 40 ꢀC;
P = 0.3 mmHg) giving 3.23 g (0.02 mol, 87% yield) of
1 as a yellowish oil. 1H NMR d 7.29 (t, J = 2.0 Hz,
1H, pyr-H), 6.63 (m, 2H, pyr-H), 5.89–6.05 (m, 1H,
CH@), 5.12–5.32 (m, 2H, N-CH2), 4.52 (dd, J = 6.0;
4.0; 1.4 Hz, 2H, CH2@), 2.42 (s, 3H, CH3CO). 13C
NMR d 193.1 (CO), 133.0 (CH@), 125.8 (pyr-H),
122.2 (pyr-H), 118.3 (CH2@), 109.1 (pyr-H), 52.3 (C–
N), 26.9 (CH3–). MS m/e 149 (M+ 40), 134 (100), 106
(20), 94 (25), 79 (19), 66 (15), 51 (15), 41 (35).
Selected data for 1-acetyl-5,6,7,8-tetrahydroindoli-
1
zine (50). H NMR d 6.99 (s, 1H, pyr-H), 6.35 (s, 1H,
pyr-H), 3.90 (m, 2H, CH2–N), 2.59 (m, 2H, CH2–),
2.30 (s, 3H, CH3CO), 1.85 (m, 2H, CH2), 1.56 (m, 2H,
CH2). MS m/e 163 (M+ 50), 148 (100), 120 (10), 106 (30).
Selected data for 2-acetyl-5,6-dihydroindolizine (4).
1
As a yellowish oil (Al2O3, benzene/EtOAc = 70/30). H
NMR d 7.25 (s, 1H, pyr-H), 6.50 (t, J = 1.2 Hz, 1H,
pyr-H), 6.48 (d, J = 9.7 Hz, 1H, CH@), 5.74 (dt,
J = 10.0; 4.5 Hz, 1H, CH@), 3.91 (t, J = 7.5 Hz, 2H,
CH2–N), 2.52 (m, 2H, CH2–C@), 2.30 (s, 3H, CH3CO).
MS m/e 161 (M+ 55), 147 (8), 146 (100), 118 (10), 117
(15), 91 (13). Selected data for 1-acetyl-8-hydroxy-
5,6,7,8-tetraidroindolizine (5). 1H NMR d 6.54 (d,
J = 3.0 Hz, 1H, pyr-H), 6.47 (d, J = 3.0 Hz, 1H, pyr-
H), 5.95 (d, J = 1.8 Hz, 1H, –OH), 4.95 (q, J = 6.0 Hz,
1H, CH-O), 3.90 (m, 2H, CH2–N), 2.41 (s, 3H, CH3CO),
2.13 (m, 2H, CH2–), 1.90 (m, 2H, CH2–). 13C NMR
d 196.7 (CO), 164.4 (pyr-H), 146.6 (pyr-H), 119.6

1870
S. Rocchiccioli et al. / Journal of Organometallic Chemistry 690 (2005) 1866–1870
[2] (a) R. Lazzaroni, R. Settambolo, A. Caiazzo, L. Pontorno, J.
Organomet. Chem. 601 (2000) 320;
(pyr-H), 111.3 (pyr-H), 62.4 (CH-O), 45.8 (C–N), 29.7
(CH2–), 28.3 (CH2–), 27.6 (CH3–). MS m/e 179 (m+
38), 164 (23), 161 (58), 160 (9), 146 (100), 136 (24), 120
(10), 118 (14), 117 (15), 108 (31), 80 (16).
(b) R. Settambolo, A. Caiazzo, R. Lazzaroni, Tetrahedron Lett. 42
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Acknowledgement
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This work was supported by the Ministero dellÕ
`
Universita e della Ricerca Scientifica e Tecnologica
(60% funds).
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