Synthesis of 5,6,7,8-tetrahydroindolizines via a domino-type transformation based on the rhodium catalyzed hydroformylation of N-(β-methallyl)pyrroles

Article abstract of DOI:10.1002/jhet.5570440234

(Chemical Equation Presented) Variously substituted 5,6,7,8- tetrahydroindolizines can be easily synthesized via a domino reactions sequence under rhodium catalyzed hydroformylation of N-(β-methallyl)pyrroles. The later are readily prepared from properly functionalized pyrroles via phase-transfer N-allylation in the presence of 18-crown-6 and potassium tert-butoxide.

Full text of DOI:10.1002/jhet.5570440234

Mar-Apr 2007
479
Synthesis of 5,6,7,8-Tetrahydroindolizines via a Domino-Type
Transformation Based on the Rhodium Catalyzed Hydroformylation
of N-(β-Methallyl)pyrroles
a
a
a
b*
Silvia Rocchiccioli , Giuditta Guazzelli, Raffaello Lazzaroni, Roberta Settambolo
a
Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via Risorgimento 35, 56126 Pisa, Italy.
ICCOM- CNR, Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via Risorgimento 35,
b
5
6126 Pisa, Italy.E-mail: settambolo@dcci.unipi.it.
Received May 12, 2006
Z
O
Z
Z
X
Rh (CO)
4
12
Y
Y
N
Y
N
CO/H2
N
X
X
Variously substituted 5,6,7,8-tetrahydroindolizines can be easily synthesized via a domino reactions
sequence under rhodium catalyzed hydroformylation of N-(β-methallyl)pyrroles. The later are readily
prepared from properly functionalized pyrroles via phase-transfer N-allylation in the presence of 18-
crown-6 and potassium tert-butoxide.
J. Heterocyclic Chem., 44, 479 (2007).
INTRODUCTION
fine chemistry [7-8], we found a general domino protocol
to 5,6,7,8-tetrahydroindolizines. It is based on the
rhodium catalyzed hydroformylation of the differently
substituted N-(β-methallyl)pyrroles (2): under these
conditions the formed 4-(pyrrol-1-yl)butanals (3) undergo
an in situ intramolecular cyclization followed by
hydrogenation of the six membered ring to selectively
give the 6-methyltetrahydroindolizines (4) (Scheme 1).
8
1
7
6
2
N
5
3
1
The tetrahydroindolizine framework 1 and its oxidized
and reduced forms are frequently found in a wide array of
alkaloids and other pharmaceutically important natural
and synthetic compounds. The base-structure 1 is present
in (-)-rhazinilam, an alkaloid isolated from different
Apocynaceae species, and inhibits disassembly of
microtubole [1].
Variously substituted 5,6,7,8-tetrahydroindolizines are
dopaminergic ligands [2], anti-TNF agents [3], as well as
useful intermediates in the synthesis of the corresponding
Scheme 1
Z
O
Z
X
Z
i
Y
Y
N
Y
N
N
X
X
2
3
4
fully
unsaturated
indolizines
or
hydrogenated
4 2
i: Rh (CO)12, 130 atm, CO/H =1/1, 140°C, toluene, 10- 72 h
indolizidines [4]. Although 5,6,7,8-tetrahydroindolizine
has been obtained many years ago by catalyzed
hydrogenation of indolizine [5], the isolation from natural
sources, synthesis, and the study of the biological
properties of analogous molecules is still a research field
of great interest and continuous evolution.
RESULTS AND DISCUSSION
The differently substituted N-allylpyrroles (2a-d) were
prepared via N-allylation of the proper pyrroles (1a-d)
Scheme 2). This step was accomplished in diethyl ether
(
Among the synthetic approaches starting from pyrrole
derivatives, radical or cationic cycloadditions [6a,2] and
intramolecular cyclizations based on benzotriazole-
methodology have been recently reported [6b]. With
respect to multi-steps reactions, domino-type sequences
are very powerful synthetic tools because they rapidly
increase the complexity of a substrate while at the same
time make economical use of available functional groups
via a phase-transfer process in which 18-crown-6 was
employed as the catalyst and potassium tert-butoxide was
employed as the base [9]. In this way 2a was obtained in a
higher yield with respect to the previous one reported
[
7c]. In the case of the preparation of 2a-c the proper
pyrroles were commercially available. In contrast in the
case of the preparation of 2d, 2-i-propyl-3-acetylpyrrole
was obtained from 3-acetylpyrrole [10a] via alkylation on
the 2-pyrrole position with isopropyl chloride at 50 °C,
according to a method reported in literature [10b].
[
6c]. In the frame of our studies on the rhodium catalyzed
hydroformylation of olefins as synthetic instrument for

4
80
S. Rocchiccioli, G. Guazzelli, R. Lazzaroni, R. Settambolo
Vol 44
Scheme 2
Y
Z
Y
Z
Y
Z
OH
X
N
X
N
1
X
N
H
II
III
1
8-crown-6
Cl
tert-BuOK
a X=Y=Z=H
2
c X=H Y=Z= COOCH CH3
b X=Et, Y=Z=H d X=i-Pr, Y= H, Z=COCH3
Y=H
X=(CH ) CH
X=Y=Z=H
Y=Z=H X=CH CH
X=H Y=Z=COOCH2CH3
2
3
3 2
Z=COCH3
An intermediate of the III type has been evidenced in
the case of 2d [14]: this structure could be favoured by an
intramolecular hydrogen bond between the hydrogen of
the hydroxyl group and the carbonyl substituent on the β-
pyrrole position.
O
O
O
O
O
N
N
N
N
All synthesized tetrahydroindolizines 4 are new
compounds: they have been isolated and characterized
and can be stored at 0 °C for long periods of time without
decomposition.
2
a
2b
2c
2d
To sum up, starting from N-β-methallylpyrroles the
corresponding 6-methyl-5,6,7,8-tetrahydroindolizines have
been obtained under rhodium-catalyzed hydroformylation
conditions in a one-pot domino operation. Electron-
withdrawing or electron-donating substituents on both
pyrrole ring or alkyl chain do not affect the sequence
selectivity and the good yield of the final products. All
transformations employ inexpensive reagents and provide
pure products after a simple purification process. It is
worth noting that indolizines with various degrees of
unsaturation are common in nature and they are
characterized by different physiological activities [2,3].
On this light we think that the domino-type
transformation described by us represents a convenient
addition to the pyrrole chemistry.
With respect to a typical hydroformylation experiment
7c,11] stressed temperature and pressure values were
[
applied together with longer reaction times. The substrates
a-d were inserted into a 25 ml stainless autoclave in the
2
presence of Rh (CO)12 as the catalyst precursor, at 140 °C,
4
under a pressure of 130 atm (CO:H 1:1), in toluene as a
2
solvent. Under the above conditions the sole formed
aldehydes 3 (Scheme 1) evolve to the indolizine skeleton via
an in situ intramolecular cyclization on the α-pyrrole
position by the carbonyl carbon atom followed by reduction
of the six membered ring. Very different reaction times were
necessary in dependence on the substituents nature. For 2c,
bearing two electron-withdrawing groups on the pyrrole
ring, 72 h were necessary in order to observe a complete
conversion into 4c. On the contrary 2b, characterized by the
presence of the electron-donating ethyl group on the 2-
pyrrole position, was converted into 4b within 10 hours.
Intermediate values of reaction time were observed for 2a
and 2d. The cyclization step conditions the global process
rate. It is greater when no groups or an electron-donating
group are present on the pyrrole ring (case of 2a-b): thus no
traces of the pyrrolylbutanals 3a-b were observed at all
conversions but directly the corresponding 5,6-
dihydroindolizine intermediates IIa-b (GC-MS control) [12]
deriving from an intramolecular cyclodehydration [7a] of
Table 1
Entry
a
4
Yield %
Purification
process
N
63
Colorless oil
2 3
Al O ; hexane
b
c
N
60
75
Colorless oil
Al ; hexane
2
O
3
3a-b. The successive hydrogenation of the double bond in
O
O
the six membered ring gave rise to the structures 4a-b. In
the case of 2c and 2d, the evolution of the corresponding
aldehydes 3c and 3d to 4c and 4d respectively is slower and
via two possible intermediates: the 5,6-dihydroindolizines
IIc-d, as for 2a and 2b, or the bicyclic alcohols IIIc-d as
evidenced in the case of the hydroformylation of 3-acetyl-1-
β-methallylpyrrole [13]. Thus 4 could form from II via a
double bond hydrogenation or from III via a direct
hydrogenolysis of the hydroxyl group.
Yellow oil
Al
O
O
2
3
O ;
N
hexane/acetone
(70/30)
O
Yellow oil
Al O ,
d
70
2
3
N
benzene/AcOEt
80/20)
(

Mar-Apr 2007
Synthesis of 5,6,7,8-Tetrahydroindolizines via a Domino-Type Transformation
481
EXPERIMENTAL
Hz, 1H, CH), 4.35 (s, 2H, CH
2
-N), 4.53 (s, 1H, CH
2
=), 4.91 (s,
1
H, CH =), 6.37 (d, J=1.8 Hz, 1H, Pyr), 7.15 (d, J=1.8 Hz, 1H,
2
1
3
Pyr). C nmr δ 20.1, 23.3 (2 CH of i-Pr), 25.5, 38.7, 53.0,
3
All reagents were of commercial quality. TLC analyses were
performed on aluminum oxide 60 F254 neutral plates from
Merck. For preparative chromatography Merck aluminum oxide
1
03.2, 104.1, 112.9, 126.5, 132.2, 141.4, 192.7. MS m/z 205
+
(M , 31), 190 (100), 162 (19), 148 (38), 120 (25), 77 (18), 55
(71). Anal. Calcd for C H NO: C, 78.79; H, 8.22; N, 6.06.
1
3
19
9
0 active (neutral, 70-230 mesh) was used. Toluene was dried
1
Found: C, 78.86; H, 8.21; N, 6.05.
Typical Procedure for the Preparation of 5,6,7,8-
Tetrahydroindolizines 4. A solution of 2 (0.8 mmole) and
over molecular sieves and distilled under nitrogen. H NMR
spectra were recorded on a Varian Gemini 200 at 200 MHz for
1
13
H and 50 MHz for C with TMS as internal standard and
-3
Rh (CO) (5 mg, 7x10 mmole, substrate/Rh= 115/1) in toluene
4
12
CDCl as the solvent. GC analyses were performed on a Perkin
3
(5 ml) was introduced by suction into an evacuated 25 ml
Elmer 8700 chromatograph equipped with a 15 m x 0.25 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 x 0.25 mm apolar BP1 capillary column, using
helium as carrier gas. Microanalyses were performed at
Laboratorio di Microanalisi, Istituto di Chimica Organica,
stainless steel reaction vessel. Carbon monoxide was introduced,
the autoclave was then rocked, heated to 140 °C and hydrogen
was rapidly introduced to 130 atm (CO/H =1:1) total pressure.
The degree of conversion and the product distributions were
determined by GC/GC-MS (in the case of 2a-b and 2d) with use
2
1
of n-decane as internal standard or H NMR (case of 2c). Then
the reaction mixture was siphoned out, the solvent was
evaporated under reduced pressure and the residue was eluted on
chromatographic column (Table 1).
Facoltà di Farmacia, Università di Pisa. Rh (CO)12 was prepared
4
according to a known procedure [15].
Typical Procedure for the Preparation of the Pyrroles 2.
To a solution of 18-crown-6 (0.25 mmoles) in 20 ml of
6
-Methyl-5,6,7,8-tetrahydroindolizine (4a). Colorless oil.
1
H nmr δ 1.13 (d, J=6.6 Hz, 3H, CH ), 1.50 (m1H, CH -CH),
3
2
anhydrous Et O was added potassium tert-butoxide (2.8
2
1
.98 (m, 1H, CH -CH), 2.12 (m, 1H, CH), 2.70-3.02 (m, 2H,
2
mmoles). The mixture was stirred magnetically while the pyrrole
derivative 1 (2.4 mmoles) was introduced in a single portion.
Stirring was continued for 15 min and then 3-chloro-2-methyl-1-
CH -C=, CH -N), 3.45 (t, J=11.5 Hz, 1H, CH -C=), 4.05 (dd,
J=5.5; 11.1 Hz, 1H, CH -N), 5.90 (bs, 1H, Pyr), 6.19 (m, 1H,
Pyr), 6.55 (m, 1H, Pyr). C nmr δ 19.4, 23.2, 30.2, 30.4, 52.5,
1
2
2
2
2
13
propene (2.8 moles) dissolved in 10 ml of anhydrous Et O was
+
2
03.9, 107.9, 118.6, 129.0. MS m/z 135 (M , 92), 134 (100), 120
added dropwise to the reaction mixture cooled in an ice bath.
The mixture was then allowed to warm up to room temperature
and, after complete conversion of the reagent was achieved
(32), 106 (18), 93 (71), 80 (25). Anal. Calcd for C H N: C,
9 13
8
0.00; H, 9.63; N, 10.37. Found: C, 80.24; H, 9.65; N, 10.38.
-Ethyl-6-methyl-5,6,7,8-tetrahydroindolizidine (4b).
3
(GC), water was added to the reaction mixture. The layers were
1
Colorless oil. H nmr δ 1.18 (d, J=6.6 Hz, 3H, CH ), 1.33 (t,
J=7.5 Hz, 3H, CH -CH ), 1.50 (m, 1H, CH -CH), 1.92-2.24 (m,
2
3
separated and the aqueous layer was extracted with Et O. The
2
3
2
2
combined organic solution was dried over anhydrous Na SO
2
4
H, CH -CH, CH), 2.56 (q, 2H, J=7.5 Hz, CH -CH ), 2.75-3.03
2
2
3
and evaporated in vacuo to give 2 as crude products.
-Methyl-3-(pyrrol-1-yl)prop-1-ene (2a). 75 % yield.
(m, 2H, CH -C=, CH -N), 3.27 (t, J=11.1 Hz, 1H, CH -C=), 3.97
2 2 2
2
13
(dd, J= 5.1; 14.0 Hz; 1H, CH -N), 5.93 (bs, 2H, Pyr). C nmr δ
2
1
Colorless liquid; bp 32 °C, 1.5 mmHg. H nmr δ 6.67 (t, J=2.1
1
2.9, 19.5, 19.5, 23.4, 29.8, 29.9, 49.7, 102.8, 103.7, 128.1,
Hz, 2H, Pyr), 6.19 (t, J=2.1 Hz, 2H, Pyr), 4.92 (s, 1H, CH =),
+
2
1
132.9. MS m/z 163 (M , 34), 148 (100), 134 (7), 106 (12), 93
(7). Anal. Calcd for C H N: C, 80.98; H, 10.43; N, 8.59.
Found: C, 81.30; H, 10.40; N, 8.60.
3
4
.77 (s, 1H, CH =), 4.43 (s, 2H, CH -N), 1.68 (s, 3H, CH ). C
2 2 3
1
1
17
nmr δ 19.8, 55.9, 108.2 (2 Cβpyr), 112.8, 121.2 (2Cαpyr), 142.3.
+
MS m/z 121 (M , 68), 120 (65), 106 (100), 80 (99), 53 (16).
Diethyl6-methyl-1,2-(5,6,7,8-tetrahydroindolizine)dicar-
Anal. Calcd for C H N: C, 79.34; H, 9.10; N, 11.57. Found: C,
1
8
11
boxylate (4c). Colorless oil. H nmr δ 1.07 (d, J=6.6 Hz, 3H,
CH ), 1.31 (t, J=6.6 Hz, 6H, CH ), 1.40 (m, 1H, CH -CH), 1.94-
2.04 (m, 2H, CH -CH, CH), 2.81 (m, 1H, CH -C=). 3.21 (m, 1H,
2 2
CH -N), 3.42 (t, J=11.2 Hz, 1H, CH -C=), 3.95 (dd, J=5.4; 12.6
2 2
7
9.45; H, 9.12; N, 11.59.
-Methyl-3-(2-ethylpyrrol-1-yl)prop-1-ene (2b). 70 % yield,
3
3
2
2
1
as a yellow oil. H nmr δ 6.55 (t, J=1.6 Hz, 1H, Pyr), 6.09 (t,
J=3.1 Hz, 1H, Pyr), 5.92 (m, 1H, Pyr), 4.83 (m, 1H, CH =), 4.48
Hz, CH -N), 4.27 (q, J=6.6 Hz, 4H, CH -CH ), 6.99 (s, 1H, Pyr).
2 2 3
13
2
(
s, 1H, CH =), 4.30 (s, 2H, CH -N), 2.50 (q, J=7.4 Hz, 2H, CH -
C nmr δ 14.7 (2 CH ), 18.9, 23.1, 29.1, 30.0, 52.8, 60.4 (2
3
2
2
2
1
3
CH ), 1.69 (s, 3H, CH ), 1.24 (t, J=7.4 Hz, 3H, CH -CH ).
C
CH -O), 107.4, 108.2, 124.9, 136.0, 164.9 (2 CO). Anal. Calcd
3
3
2
3
2
nmr δ 13.0, 19.4, 20.0, 52.6, 104.8, 106.8, 111.7, 120.8, 135.2,
for C H N: C, 64.52; H, 7.53; N, 5.02. Found: C, 64.48; H,
7.52; N, 5.00.
1
5
21
+
1
42.3. MS m/z 149 (M , 60), 134 (100), 120 (39), 93 (18), 80
(
9
27), 55 (41). Anal. Calcd for C H N: C, 80.54; H, 10.07; N,
.40. Found: C, 80.70; H, 10.08; N, 9.42.
1-(3-iPropyl-6-methyl-5,6,7,8-tetrahydroindolizin-1-yl)eth-
10
15
1
anone (4d). Colorless oil. H nmr δ 1.18 (d, J=6.6 Hz, 3H, CH ),
3
Diethyl 1-(2-methylprop-2-enyl)-3,4-pyrroledicarboxylate
2c). 75% yield, as a yellowish oil. H nmr δ 1.39 (t, J=7.1 Hz,
1.33 (d, J=6.8 Hz, 6H, CH
(m, 2H, CH, CH -CH), 2.45 (s, 3H, CH
CH(CH , CH -C=), 3.35-3.54 (m, 2H, CH
(dd, J=4.3; 11.9 Hz, 1H, CH -N), 6.32 (s, 1H, Pyr). C nmr δ
19.3, 22.9 (2 CH ), 23.0, 24.5, 25.4, 28.6, 29.1, 49.9, 104.8,
105.4, 138.5, 138.9, 196.5. MS m/z 219 (M , 25), 205 (33), 204
(100), 176 (11). Anal. Calcd for C14 21N: C, 76.71; H, 9.59; N,
3
), 1.47 (m, 1H, CH
CO), 2.86-3.05 (m, 2H,
-C=, CH -N), 4.04
2
-CH), 1.90-2.19
1
(
2
3
6
4
7
H, CH ), 1.73 (s, 3H, CH ), 4.36 (q, J=7.1 Hz, 4H, CH -CH ),
3
)
3
2
2
2
3
3
2
3
1
3
.42 (s, 2H, CH -N), 4.91 (s, 1H, CH =), 5.05 (s, 1H, CH =),
2
2
2
2
13
.27 (s, 2H, Pyr). C nmr δ 14.5 (2 CH ), 19.8, 56.7, 60.4 (2
3
3
+
CH -O), 115.0, 116.5 (2 C
β
pyr), 128.2 (2 C
α
pyr), 140.2, 163.9 (2
2
CO). Anal. Calcd for C H NO : C, 63.40; H, 7.17; N, 5.28.
H
1
4
19
4
Found: C, 63.32; H, 7.15; N, 5.26.
-[5-iPropyl-1-(2-methylallyl)pyrrol-3-yl]ethanone (2d). 78
6.39. Found: C, 76.55; H, 9.58; N, 6.41.
1
Acknowledgments. Financial support by MIUR
Programma di Ricerca Scientifica di Rilevante Interesse
Nazionale is gratefully acknowledged.
–
1
%
yield, as a yellowish oil. H nmr δ 1.21 (d, J=7.1 Hz, 6H,
CH ), 1.71 (s, 3H, CH ), 2.36 (s, 3H, CH CO), 2.75 (sept, J=7.1
3
3
3

4
82
S. Rocchiccioli, G. Guazzelli, R. Lazzaroni, R. Settambolo
Vol 44
[7a] R. Lazzaroni, R. Settambolo, A. Caiazzo and L. Pontorno, J.
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9
2
Catalyzed Hydroformylation, P. van Leeuwen and C. Claver, ed.,
[
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+
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1
18 (100), 117 (50), 91 (20). Typical GC-MS data for IIb: MS m/z 161
+
[
(M , 48), 146 (100), 144 (9).
[13] R. Settambolo, S. Rocchiccioli, R. Lazzaroni and G.
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[
+
[14] Typical GC-MS data of IIId: Ms m/e 235 (M , 39), 220
(48), 217 (43), 202 (100), 192 (45), 160 (20), 144 (24), 77 (15). The
precursor 3d shows the same significant fragments. In the case of 2c the
GC-MS analysis was unsuccessful and the conversion into 4c was
monitored via TLC on Al O by eluting with hexane/acetone (70:30).
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2
3