Synthesis of Aminoindolizidines through the Chemoselective and Diastereoselective Catalytic Hydrogenation of Indolizines

Article abstract of DOI:10.1021/acs.joc.6b01782

Indolizidines are bioactive heterocyclic compounds of great potential normally prepared following multistep routes. However, to the best of our knowledge, the synthesis of 1-aminoindolizidines has never been reported. Herein, 1-(dialkylamino)-3-substitute

Full text of DOI:10.1021/acs.joc.6b01782

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Article
Synthesis of Amino Indolizidines through the Chemoselective
and Diastereoselective Catalytic Hydrogenation of Indolizines
María José Albaladejo, María José González-Soria, and Francisco Alonso
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b01782 • Publication Date (Web): 29 Sep 2016
Downloaded from http://pubs.acs.org on September 30, 2016
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Synthesis of Amino Indolizidines through the Chemoselective and
Diastereoselective Catalytic Hydrogenation of Indolizines
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María José Albaladejo, María José González-Soria and Francisco Alonso*
Instituto de Síntesis Orgánica (ISO) and Departamento de Química Orgánica, Facultad de Ciencias,
Universidad de Alicante, Apdo. 99, 03080 Alicante (Spain)
Eꢀmail: falonso@ua.es
Abstract: Indolizidines are greatꢀpotential bioactive heterocyclic compounds normally prepared
following multiꢀstep routes. However, to the best of our knowledge, the synthesis of 1ꢀamino
indolizidines has never been reported. Herein, 1ꢀdialkylaminoꢀ3ꢀsubstituted indolizidines have been
straightforwardly synthesized using an atomꢀeconomy protocol which involves a copperꢀcatalyzed
threeꢀcomponent synthesis of indolizines followed by heterogeneous catalytic hydrogenation. The latter
was found to be chemoselective using platinum(IV) oxide as the catalyst at 3.7 atm, providing the
amino indolizidines in modestꢀtoꢀhigh yields (31–95%) and high diastereoselectivity (92:8 to > 99:1).
It has been experimentally demonstrated that the hydrogenation occurs through the intermediate
5,6,7,8ꢀtetrahydroindolizine, which contains a pyrrole moiety. Moreover, the diastereomerically pure 1ꢀ
dibenzylaminoꢀ3ꢀsubstituted indolizidines could be further transformed into the corresponding monoꢀ
benzylated or fully debenzylated amino indolizidines by selective hydrogenolysis catalyzed by Pt/C or
Pd/C, respectively, under ambient conditions.
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INTRODUCTION
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There is a general upsurge of interest in developing new strategies to effectively obtain saturated Nꢀ
heterocycles from readily accessible starting materials. This demand is supported by the potential
development of new pharmaceuticals related to this type of heterocycles and their natural abundance.1
Among them, indolizidine alkaloids are widespread in nature and have attracted a great deal of
attention because of their structural diversity and varied biological activity (Chart 1).2 For instance,
indolizidine 167B was first found as a minor constituent in the skin secretions of a batrachian of the
genus Dendrobates,3 whereas (+)ꢀmonomorine I was isolated from both Pharaoh’s ant Monomorium
pharaonis and from bufonid toads of the Melanopbryniscus genus.4 (–)ꢀTashiromine was first isolated
from the stems of Maackia Tashiroi (Leguminosae),5a a bush from subtropical Asia, and later on from
leaves and seeds of the Poecilanthe5b genus and from Ethiopian Crotalaria species.5c Swainsonine was
first identified in the Australian legume Swainsona canescens6a and, subsequently, as the toxin in
Astragalus and Oxytropis species that cause locoism in livestock.6b In contrast, the significance of
swainsonine in the treatment of cancer and in immunology has been reported.6c Indolizidines have also
played an important role in the synthesis of other natural products.7
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Chart 1. Structure of some naturally occurring indolizidines.
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Different synthetic strategies have been developed to construct the indolizidine skeleton according
to the substitution pattern pursued,8 including: (a) the use of pyrroles as building blocks,9 (b) from αꢀ
aminoacids via stereocontrolled rhodiumꢀcatalyzed hydroformylation of Nꢀallylpyrroles,10 (c) based on
organosulfur and selenium chemistry (i.e., conjugate addition of nitrogen nucleophiles containing ester
or chloroalkyl substituents to acetylenic sulfones, followed by baseꢀmediated intramolecular alkylation
or acylation),11 (d) by stereocontrolled cyclic nitrone cycloaddition,12 (e) by addition of allylsilanes to
Nꢀacyliminium ions,13 (f) by stereoselective conjugate addition reactions,14 (g) through radical
azidation reactions,15 and (h) through chiral oxazolopiperidone lactams.16 However, despite the
synthesis of indolizidines by the reduction of indolizines seems to be a direct approach, it has been
barely documented and limited to some isolated examples.17 Other few reports describe the synthesis of
indolizidines by heterogeneous catalytic hydrogenation of the pyrrole ring of 5,6,7,8ꢀ
tetrahydroindolizines.18 To the best of our knowledge, there is only one systematic study on the
synthesis of indolizidines by full hydrogenation of indolizidines, recently reported by Coelho et al.19 At
any rate, partial reduction is a common problem encountered, which together with a desirable higher
diastereoselectivity,20 make the selective hydrogenation of indolizines a challenging objective.
On the other hand, multicomponent heterocyclic synthesis is a effectual strategy to build diverse and
complex structures in a sole operation and atomꢀeconomy fashion.21 Due to our interest and
commitment to comprehend the reactivity of transition metal colloids,22 we presented a catalyst
comprised of oxidized copper nanoparticles supported on activated carbon (CuNPs/C), which was
easily obtained under soft conditions and highly versatile in the multicomponent click synthesis of
1,2,3ꢀtriazoles in water, using different azido precursors.23 More recently, the same catalyst was shown
to be effective in the multicomponent synthesis of indolizines from pyridineꢀ2ꢀcarbaldehyde
derivatives, secondary amines and terminal alkynes.24 In this work we also introduce what is, to the
best of our knowledge, the first example of a 1,3ꢀdisubstituted indolizidine bearing an amino group at
the 1 position, obtained by catalytic hydrogenation of the corresponding indolizine.24a Herein, we wish
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to present a complete survey on our efforts to develop a straightforward synthesis of 1ꢀaminoꢀ3ꢀ
substituted indolizidines based on the chemoꢀ and diastereoselective catalytic hydrogenation of
indolizines (Scheme 1).
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Scheme 1. Synthetic sequence towards 1-amino-3-substituted indolizidines.
R1
R2
R3
N
H
+
+
N
CHO
3
2
1
Cu-catalyzed
indolizine synthesis
R1
R2
N
N
R3
4
catalytic
hydrogenation
R1
R2
N
N
R3
5
RESULTS AND DISCUSSION
First, we optimized the catalyst and reaction conditions for the catalytic hydrogenation of indolizines.
N,NꢀDibenzylꢀ3ꢀphenylindolizinꢀ1ꢀamine (4h) was chosen as the model substrate because its
hydrogenation was considered more challenging, due to the presence of three carbonꢀnitrogen bonds
prone to undergo hydrogenolysis. In addition, the different hydrogenation degree for the five and sixꢀ
membered rings of the indolizine nucleus made the desired transformation more difficult to achieve. In
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Table 1. Hydrogenation of indolizine 4h using platinum catalysts.a
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Entry
Catalyst
Solvent
P (H2, atm)
t (h)
5h/6h/7h/8h (%)b
c
c
1
PtO2
PtO2
PtO2
PtO2
PtO2
PtO2
PtO2
PtO2
PtO2
PtO2
MeOHꢀCH2Cl2
MeOHꢀCH2Cl2
EtOH
1.0
3.7
3.7
3.7
3.7
3.7
1.0
3.7
3.7
5.1
3.7
1.0e
3.7
3.7
3.7
3.7
1.0e
3.7
3.7
1.0e
3.7
3.7
3.7
3.7
3.7
1.0e
1.0e
1.0e
3.7
72
2
47/ꢀ/ꢀ/ꢀ
44/7/ꢀ/6
8/2/ꢀ/ꢀ
2
3
8
4
CH2Cl2
EtOAc
2
8/ꢀ/ꢀ/ꢀ
5
2
23/ꢀ/ꢀ/ꢀ
6
EtOAc
9
26/ꢀ/ꢀ/ꢀ
7
HOAc
24
2
39/ꢀ/ꢀ/ꢀ
8
HOAc
65/2/-/21
26/10/ꢀ/5
48/ꢀ/ꢀ/ꢀ
9
HOAc
8
10
11
12
13
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20
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22
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24
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HOAc
1
d
PtO2
HOAc
2
40/ꢀ/ꢀ/12
19/24/ꢀ/25
53/ꢀ/ꢀ/20
65/13/ꢀ/10
31/ꢀ/ꢀ/ꢀ
PtO2
PtO2
HOAc
23
2
MeOHꢀHOAcf
CH2Cl2ꢀHOAcf
PtO2
2
c
Pt(1 wt%)/Al2O3
Pt(1 wt%)/Al2O3
Pt(5 wt%)/Al2O3
Pt(5 wt%)/CaCO3
MeOHꢀCH2Cl2
HOAc
2
2
55/ꢀ/ꢀ/ꢀ
HOAc
20
3
ꢀ/ꢀ/ꢀ/ꢀ
HOAc
62/14/-/14
57/7/ꢀ/30
10/23/ꢀ/36
ꢀ/ꢀ/ꢀ/ꢀ
d
Pt(5 wt%)/CaCO3
HOAc
3
Pt(5 wt%)/CaCO3
Pt(5 wt%)/SiO2
Pt(10 wt%)/C
Pt(10 wt%)/C
Pt(5 wt%)/C
Pt(5 wt%)/Cd
Pt(5 wt%)/C
HOAc
20
3
HOAc
c
MeOHꢀCH2Cl2
HOAc
4
24/ꢀ/ꢀ/ꢀ
2
56/ꢀ/ꢀ/ꢀ
HOAc
3
68/6/-/8
52/7/ꢀ/15
16/19/ꢀ/9
30/14/ꢀ/26
22/46/ꢀ/ꢀ
HOAc
3
HOAc
23
7g
48g
3
Pt(5 wt%)/C
HOAc
Pt(5 wt%)/C
HOAc
MeOHꢀHOAcc
Pt(5 wt%)/C
9/5/ꢀ/ꢀ
aReaction conditions: 4h (0.3 mmol), catalyst (10 mol%), solvent (3.0 mL) and H2 at rt. Conversion
determined by GLC. c3:1 v/v. d5 mol%. eIn balloon. f1:1 v/v. gReaction at 50 ºC.
b
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principle, all reactions were carried out at room temperature with 10 mol% of a platinum catalyst in
different solvents or mixtures of solvents at various hydrogen pressures (Table 1); MeOHꢀCH2Cl2 or
MeOHꢀHOAc mixtures favored solubilization of the starting indolizine with respect to the use of only
MeOH. As regards the use of PtO2 as catalyst (Table 1, entries 1–14), higher pressure (3.7 atm) and
shorter reaction time (2 h) increased the conversion into the desired indolizidine 5h, particularly in the
presence of HOAc as solvent (Table 1, entry 8); variable amounts of the monoꢀdebenzylated
indolizidine 6h and a semihydrogenation product (at this stage postulated to be 8h) were also formed.
Longer reaction time (8 h) at the same pressure had a detrimental effect on the conversion due to
additional byꢀproduct formation (Table 1, compare entries 8 and 9). The combination of HOAc with
either MeOH or CH2Cl2 gave quite good results but did not improve those reached with PtO2 (Table 1,
entries 13 and 14). Then, we explored the behavior of different platinumꢀbased supported catalysts. The
highest conversions were achieved with Pt(5 wt%)/CaCO3 and Pt(5 wt%)/C (Table 2, entries 18 and
24, respectively), likewise as above, when pressure (3.7 atm) and short reactions time (3 h) were
applied in HOAc, with the concomitant formation of 6h and 8h. As in the case of PtO2 (Table 1, entry
11), lower catalyst loading (5 mol%) in the supported catalysts led to a decrease in the conversion
though of a lower magnitude compared to the former (Table 1, entries 19 and 25).
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Other metal catalysts were also tested with the aim to minimize byꢀproduct formation (Table 2). Pd(10
wt%)/C provided a moderate conversion into 5h at ambient pressure and prolonged stirring in MeOH,
together with a substantial amount of monoꢀdebenzylated 6h (Table 2, entry 1); higher hydrogen
pressure shortened the reaction time but did not improve the conversion (Table 2, entry 2). An
interesting effect of the pressure was noticed with Pd(20 wt%)/C in HOAc, leading to 6h at 3.7 atm or
7h at ambient pressure with some selectivity (Table 2, entries 4 and 5). Unfortunately, any possibility
for directly transforming the starting indolizine 4h into 6h or 7h by the choice of the pressure vanished
because of the low diastereoselectivity attained in both cases (Table 2, footnotes d and g). This lack of
diastereoselectivity was also manifested with the deployment of Pd(5 wt%)/CaCO3 which, conversely,
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was highly chemoselective towards the formation of 6h (Table 2, entry 7). Other catalysts, either
heterogeneous [Pd(OH)2/C, Rh(5 wt%)/C and Ru(5 wt%)/C] or homogeneous {[Rh(COD)Cl]2,
[RuCl2(pꢀcymene)]2 and [Ir(COD)Cl]2}, and/or reaction conditions furnished complex reaction
mixtures (Table 2, entries 6, 8, 9 and 11), no product (Table 2, entries 12–14) or a certain amount of Nꢀ
benzylideneꢀ3ꢀphenylindolizinꢀ1ꢀamine, i.e. the imine of monoꢀdebenzylated 6h (Table 2, entries 3, 16
and 17).
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Table 2. Hydrogenation of indolizine 4h using other metal catalysts.a
Entry
Catalyst
Solvent
P (H2, atm)
t (h)
5h/6h/7h/8h (%)b
1
2
Pd(10 wt%)/C
Pd(10 wt%)/C
Pd(10 wt%)/C
Pd(20 wt%)/C
Pd(20 wt%)/C
Pd(5 wt%)/CaCO3
Pd(5 wt%)/CaCO3
Pd(OH)2/C
MeOH
MeOH
1.0
3.7
3.7
3.7
1.0e
3.7
1.0e
1.0
1.0
3.7
1.0
1.0e
3.7
3.7
3.7
3.7
3.7
48
7
64/19/ꢀ/ꢀ
48/4/ꢀ/ꢀ
3
HOAc
2
ꢀc
4
HOAc
3
ꢀ/92d/8/ꢀ
5
HOAc
23
3
ꢀ/16f/64g/ꢀ
6
HOAc
ꢀh
7
HOAc
20
22
13
6
ꢀ/81i/ꢀ/ꢀ
8
MeOH
ꢀh
ꢀh
j
j
9
Pd(OH)2/C
MeOHꢀCH2Cl2
MeOHꢀCH2Cl2
10
11
12
13
14
15
16
17
Pd(OH)2/C
ꢀ/27/ꢀ/ꢀ
k
Pd(OH)2/C
MeOHꢀCH2Cl2
HOAc
15
20
3.5
4
ꢀh
Rh(5 wt%)/C
Rh(5 wt%)/C
Ru(5 wt%)/C
[Rh(COD)Cl]2
[RuCl2(pꢀcymene)]2
[Ir(COD)Cl]2
ꢀ
HOAc
ꢀ
HOAc
ꢀ
j
MeOHꢀCH2Cl2
iꢀPrOH
10
8
ꢀl
ꢀm
HOAc
8
ꢀn
b
aReaction conditions: 4h (0.3 mmol), catalyst (10 mol%), solvent (3.0 mL) and H2 at rt. Conversion
c
d
e
determined by GLC. Monodebenzylated 4h (25%) and its imine (35%). 55:45 dr. In balloon.
g
h
i
j
k
f62:38dr. 64:19:17 dr. Complex mixture. 47:44:9 dr. MeOHꢀCH2Cl2 (3:1 v/v). MeOHꢀCH2Cl2 (1:1
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v/v). lUnidentified product (29%). mImine of monodebenzylated 4h (12%). nImine of
monodebenzylated 4h (4%).
5
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7
8
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From this optimization study it can be concluded that PtO2 and Pt(5 wt%)/C are the best catalysts in
terms of conversion and selectivity (Table 1, entries 8 and 24, respectively). Given the heterogeneous
nature of both catalysts, they are potentially recoverable and recyclable.25 PtO2 could be easily reused
by decantation, supernatant removal and catalyst washing in the same hydrogenation flask. In contrast,
further manipulation and centrifugation were required for Pt(5 wt%)/C. For comparative purposes, all
recycling experiments were conducted at 3.7 atm for 2 h (Figure 1). Catalyst reutilization was found to
be more efficient with PtO2 than with Pt(5 wt%)/C (60% versus 36% in the second cycle). The catalytic
activity of both catalysts decreased in subsequent cycles: 35 and 30% for PtO2 and <10% for Pt(5
wt%)/C, albeit better conversions would be expected for longer reaction times. In addition to this, we
also observed that the catalytic performance of Pt(5 wt%)/C with substrates other than 4h was lower
than with PtO2.26 In view of the aforementioned results, the catalytic system of choice was that
composed of PtO2 (10 mol%) in HOAc at 3.7 atm H2 (Table 1, entry 8).
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FIGURE 1. Catalyst recycling experiments in the hydrogenation of 4 h (3.7 atm H2, 2 h).
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In order to study the substrate scope, the optimized catalyst and reaction conditions were applied to a
variety of indolizines 4, derived from pyridineꢀ2ꢀcarbaldehyde (1a), secondary amines (2) and terminal
alkynes (3), producing the expected indolizidines 5 in modestꢀtoꢀhigh yields and with highꢀtoꢀexcellent
diastereoselectivity (Table 3). The yield and diastereoselectivity were found to be dependent on the
substituents at the 1 and 3 positions, with the amino group at the 1 position apparently exerting a
stronger effect. For instance, the indolizines derived from piperidine and arylacetylenes were isolated
in lower yields, with the lowest diastereoselectivity been recorded for the phenylacetylene derivative
(5a). The diastereomeric ratio was improved when a para substituent was present in the arylacetyleneꢀ
derived moiety while at the same time maintaining the 1ꢀpiperidinyl group (Table 3, compare 5a with
5b and 5c). Fortunately, purification by column chromatography allowed the isolation of 5a and 5b as
single diastereoisomers. Better yield and excellent diastereoselectivity were observed when changing
the 1ꢀpiperidinyl into a 1ꢀmorpholino group (Table 3, compare 5a with 5d). In general, the results with
acyclic amines were better than those with the cyclic counterparts concerning all, the yield, the
diastereoselectivity and the reaction time. The diastereoselectivity increased when increasing the steric
hindrance of the secondary amine (Table 3, compare 5e and 5f with 5g and 5h). The indolizidines
derived from dibenzylamine followed a similar trend to that of dibutylamine (5g), being generally
obtained in relatively short hydrogenation reaction times and as single diastereoisomers (Table 3, 5hꢀ
5m). This remarkable behavior was displayed irrespective of the substituent at the 3 position of the
indolizidine nucleus, including aryl substituents with electronꢀneutral (Table 3, 5h and 5i), ꢀreleasing
(Table 3, 5j) and ꢀwithdrawing groups (Table 3, 5k and 5l), as well as aliphatic substituents (Table 3,
5m).
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We endeavored to extend this method to more demanding indolizines in order to validate its
applicability. Such is the case of N,Nꢀdibutylꢀ1ꢀphenylpyrrolo[1,2ꢀa]quinolinꢀ3ꢀamine (4n), a benzoꢀ
fused indolizine coming from the coupling of quinolineꢀ2ꢀcarbaldehyde (1b), dibutylamine (2e) and
phenylacetylene (3a). It is worthy of note that its catalytic hydrogenation failed under the standard
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Table 3. Synthesis of the indolizidines 5.a
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8
9
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O
N
N
H
N
H
N
Me
H
N
N
N
Ph
H
N
H
N
N
Ph
Ph
Ph
5e (3 h, 60%)
[98:2 dr] (>99:1 dr)b
5a (6 h, 58%)
[92:8 dr] (>99:1 dr)b
Me
OMe
5d (6 h, 68%)
[>99:1 dr]
5c (4 h, 45%)
[>99:1 dr]
5b (5 h, 35%)
[98:2 dr] (>99:1 dr)b
NBn2
H
NBn2
H
Me
N
NBu2
H
NBn2
H
H
Ph
N
N
N
N
N
Ph
Ph
Ph
5f (5 h, 61%)
[97:3 dr] (>99:1 dr)b
5g (3 h, 66%)
[>99:1 dr]
5h (2 h, 65%)
[>99:1 dr]
Me
OMe
5i (3 h, 58%)
[>99:1 dr]
5j (1.5 h, 86%)
[>99:1 dr]
NBn2
H
NBn2
H
NBu2
H
NBn2
H
NBn2
H
N
N
N
N
N
Ph
Ph
9
5n (4 h, 45%)c
[97:3 dr] (>99:1 dr)b
CO2Me
CF3
5o (15 min, 40%)
[>99:1 dr]
5m (3 h, 72%)
[>99:1 dr]
5k (5.5 h, 95%)
[>99:1 dr]
5l (1.5 h, 55%)
[>99:1 dr]
aReaction conditions: 4 (0.5 mmol), PtO2 (10 mol%), HOAc (3 mL), H2 (3.7 atm), rt; reaction time and
isolated yield in parentheses; diastereomeric ratio in brackets determined by GCꢀMS from the reaction
crude. bDiastereomeric ratio after purification by column chromatography. cReaction at 4.1 atm.
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pressure and that a slightly higher pressure was necessary to initiate the reaction. Consequently, the
latter was found to be more chemoselective at lower than at higher conversions, with an increase of byꢀ
product formation in the second case. The scant yield of the expected hexahydropyrrolo[1,2ꢀa]quinolinꢀ
3ꢀamine 5n was compensated for the high diastereomeric ratio reached; the presence of the fused
benzene in the tricyclic indolizine core did not vary the stereochemical outcome with respect to the
bicyclic counterparts. We went one step further by dealing with the hydrogenation of the trisubstituted
indolizine 4o, the precursors of which were 6ꢀmethylpyridineꢀ2ꢀcarbaldehyde (1c), dibenzylamine (2f)
and phenylacetylene (3a). In this case, a short reaction time was more convenient to minimize byꢀ
product formation. It was gratifying to know that, though in modest isolated yield, the fourꢀstereocenter
indolizidine 5o could be obtained with very high diastereoselectivity.
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In some cases, byꢀproducts derived from the partial hydrogenation of the indolizine nucleus were
detected in minor amounts. This fact, together with the relative high polarity of the indolizidines, made
purification by column chromatography troublesome and accounted for some of the lower isolated
yields recorded.
We were delighted to confirm that the indolizidine 5h could be obtained from pyridineꢀ2ꢀ
carbaldehyde (1), dibenzylamine (2f) and phenylacetylene (3a), without the need to isolate the
intermediate indolizine (avoiding the corresponding workꢀup and purification) in a slightly higher yield
than that obtained from the isolated indolizine (70 versus 65%, Scheme 2). Therefore, this method
represents a straightforward access into a new type of stereodefined indolizidines with three (or four)
stereocenters.
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Scheme 2. One-pot type synthesis of indolizidine 5h.
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Secondary amines are versatile nitrogenated compounds with multiple applications in organic
chemistry, such as, as organocatalysts,27 as Lewis bases (e.g., for the activation of electronꢀdeficient
olefins)28 or as building scaffolds for multicomponent reactions,29 among many others. On the other
hand, in organic chemistry, it is desirable that the selective conversion of a single starting material into
two or more different products can be accomplished by the selection of the catalyst.30 In this vein,
attempts to directly transform indolizine 4h into the monoꢀbenzylated secondary amine 6h were found
to be successful in terms of conversion under palladium catalysis; regretfully, the diastereoselectivity of
these reactions was too low (Table 2, entries 4 and 7, footnotes d and i). Then, we decided to take
advantage of the presence of two benzyl groups in the indolizidines 5hꢀ5m and 5o to investigate the
possibilities of effecting selective hydrogenolyses, leading to secondary amines 6 or primary amines 7,
through monoꢀ and diꢀdebenzylation processes, respectively.
Taking into account the information in tables 1 and 2, four catalysts were considered for this study,
including platinum and palladium catalysts, using indolizidine 5h as the starting material (Table 4). As
a general trend, platinum catalysts provided the monoꢀdebenzylated product 6h whereas the palladium
catalyst favoured the full debenzylated product 7h. A significant effect of the hydrogen pressure was
also discerned, with ambient pressure resulting in higher conversions and less formation of side
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products. Prolonged stirring was recommended in both cases because did not alter the high selectivity
attained with the platinum catalysts [Pt(5 wt%)/C and PtO2] (Table 4, entries 3 and 4) and guaranteed
the full hydrogenolysis with Pd(20 wt%)/C (Table 4, compare entries 7 and 8).
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Table 4. Optimization of the hydrogenolysis of 5h.
Entry
Catalyst
P (H2, atm)
t (h)
6h/7h (%)b
1
2
3
4
5
6
7
8
Pt(5 wt%)/C
Pt(5 wt%)/C
Pt(5 wt%)/C
PtO2
3.7
3.7
1.0c
1.0c
1.0c
3.7
2
6
15/ꢀ
31/ꢀ
61/-
83/-
59/ꢀ
31/ꢀ
6/77
-/82
22
17
16
2
Pt(5 wt%)/CaCO3
Pd(20 wt%)/C
Pd(20 wt%)/C
Pd(20 wt%)/C
1.0c
1.0c
7
23
aReaction conditions: 5h (0.3 mmol), catalyst (10 mol%), HOAc (3.0 mL) and H2 at rt. Conversion
b
determined by GLC. cIn balloon.
The optimized conditions were first applied to the selective monoꢀdebenzylation of some of the
indolizidines 5hꢀ5m. As representative examples, indolizidines derived from aromatic alkynes of
diverse electronic nature (neutral, rich and deficient ones), as well as from aliphatic alkynes, were
converted into the monobenzylated counterparts 6 in moderateꢀtoꢀhigh yields (Table 5). Although both
catalysts, Pt(5 wt%)/C and PtO2, selectively catalyzed the monoꢀdebenzylation reaction at ambient
hydrogen pressure and temperature, the yields were slightly higher when the former was utilized for 5h
and 5j, and the latter for 5l and 5m.
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Table 5. Mono-debenzylation of indolizidines 5.a
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5
6
7
Bn
Bn
Bn
H
N
N
H
H
10 mol% Pt/C or PtO2
HOAc, H2 (1 atm), rt
8
N
N
9
R3
R3
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5
6
NHBn
NHBn
Ph
H
N
H
N
6h
17 h, 68%b
>99:1 dr
OMe
6j
24 h, 72%b
NHBn
H
N
>99:1 dr
NHBn
H
N
CF3
9
6l
6m
23 h, 81%c
19 h, 65%c
>99:1 dr
>99:1 dr
aReaction conditions: 5 (0.3 mmol), catalyst (10 mol%), HOAc (3.0 mL) and H2 (1 atm) at rt; isolated
yield after purification by preparative TLC (hexane/EtOAc 6:4); conversions into 6 were in the range
82ꢀ>99%); diastereomeric ratio determined by GCꢀMS from the reaction crude. bReaction catalyzed by
PtO2. cReaction catalyzed by Pt(5 wt%)/C.
When the same substrates, as above, were submitted to hydrogenolysis catalyzed by Pd(20 wt%)/C at
ambient hydrogen pressure and temperature, the corresponding free amino indolizidines 7 were
produced in high yields as a result of a diꢀdebenzylation process (Table 6). It is noteworthy that the
original stereochemical integrity of the indolizidines was unaffected during the hydrogenolyses leading
to the desired products as single diastereomers.
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Table 6. Di-debenzylation of indolizidines 5.a
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7
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aConversions into 6 were in the range 73ꢀ>99%. Compounds 7h and 7l were purified by preparative
TLC (EtOAc). Compounds 7j and 7m did not require any further purification. Diastereomeric ratio
determined by GCꢀMS from the reaction crude.
The stereochemistry of the indolizidines 5 was originally proposed on the basis of 2DꢀNMR
experiments conducted for 5d, 5h, 5n and 5o (Figure 2) and, later on, unequivocally established by Xꢀ
ray crystallographic analysis of compound 5a (Figure 3).31 In view of these data, the major
diastereoisomer obtained in the catalytic hydrogenation of the indolizines is that resulting from the
addition of hydrogen to the same face of the indolizine nucleus.
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O
4
5
6
7
8
9
NBn2
H
H
N
N
H
N
H
H
H
Ph
Ph
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5h
5d
NBn2
H
NBu2
H
H
H
N
N
H
H
Ph
Ph
H
5n
5o
FIGURE 2. Selected 1H-1H correlations from NOESY experiments.
FIGURE 3. X-ray structure of compound 5a.
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Finally, we were intrigued to know about the hydrogenation pathway and the structure of any possible
semihydrogenated intermediate. With this purpose in mind, indolizine 4a was hydrogenated under the
standard conditions but for a shorter reaction time. These intermediates were found to be rather elusive
because of their minor formation and high tendency to overꢀhydrogenation. Notwithstanding these
added difficulties, we managed to isolate a certain amount of the 5,6,7,8ꢀtetrahydroindolizine 8a, which
confirmed the preferential hydrogenation of the sixꢀmembered ring of the indolizine nucleus. Further
hydrogenation of 8a gave rise to the fully reduced indolizidine 5a with the same stereoselectivity as
above. These results lend weight to the argument that the stereochemistry of the indolizidines is fixed
in a second stage, where all hydrogen atoms are delivered from the catalyst to the same face of the
pyrrole ring in 8a (Scheme 3).
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Scheme 3. Sequential hydrogenation of the indolizine 4a and hydrogenation model of 8a.
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CONCLUSION
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A series of 1ꢀamino substituted indolizidines have been synthesized from readily available indolizines
by heterogeneous catalytic hydrogenation. By the choice of the catalyst (PtO2, Pt/C or Pd/C), tertiary,
secondary or primary aminoꢀsubstituted indolizidines are selectively produced in modestꢀtoꢀexcellent
yields (35–95%), mostly, as single diastereomers (with three or four stereocenters). Experimental
evidence supports the indolizine hydrogenation occurring through the pyrrolic intermediate 5,6,7,8ꢀ
tetrahydroindolizine. Furthermore, the indolizidine synthesis can be sequentially and successfully
implemented by the copperꢀcatalyzed multicomponent synthesis of the indolizine nucleus followed by
the platinumꢀcatalyzed heterogeneous hydrogenation, without the need to isolate the intermediate
indolizine. This approach represents a direct pathway to a new type of indolizidines.
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EXPERIMENTAL SECTION
General: Platinum(IV) oxide (Acros), Pt(5 wt%)/C (Evonik) and Pd(20 wt%)/C (Evonik) were
commercially available. Catalytic hydrogenation was carried out in a Parr hydrogenation apparatus
using a 500 mL flask. Melting points are uncorrected. Infrared analysis was performed with a FTꢀIR
spectrophotometer equipped with an ATR component; wavenumbers are given in cm–1. NMR spectra
were recorded at 300 or 400 MHz for 1H NMR and 75 and 101 MHz for 13C NMR; chemical shifts are
given in (δ) parts per million and coupling constants (J) in Hertz. Mass spectra (EI) were obtained at 70
eV with a GCꢀMS apparatus; fragment ions in m/z with relative intensities (%) in parentheses. HRMS
analyses were carried out in the electron impact mode (EI) at 70 eV using a quadrupole analyzer or
with a LCꢀESIꢀTOF system. Elemental analysis was performed on a CHNS microanalyzer. Xꢀray data
collection was based on three
ω
ꢀscan runs (starting
ω
φ
= –34°) at the values of
φ = 0°, 120°, 240° with
the detector at 2 = –32°. An additional run at
θ
= 0° of 100 frames was collected to improve
redundancy. The diffraction frames were integrated using the SAINT program and the integrated
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intensities were corrected for Lorentzꢀpolarization effects with SADABS.32 The purity of volatile
compounds and the chromatographic analyses (GLC) were determined with a gas chromatograph
equipped with a flame ionization detector and a 30 m capillary column (0.32 mm diameter, 0.25 ꢀm
film thickness), using nitrogen (2 mL/min) as carrier gas, Tinjector = 270 ºC, Tcolumn = 60 ºC (3 min) and
60–270 ºC (15 ºC/min); retention times (tR) are given in min. Thinꢀlayer chromatography was carried
out on TLC aluminum sheets covered with silica gel. Column chromatography was performed using
silica gel of 40–60 microns (hexane/EtOAc as eluent). Preparative thinꢀlayer chromatography was
carried on laboratoryꢀmade TLC glass plates with silica gel 60 PF254 (hexane/EtOAc or EtOAc).
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General procedure for the synthesis of the indolizines 4: The indolizines 4 were prepared from
pyridineꢀ2ꢀcarbaldehyde derivatives, secondary amines and terminal alkynes according to our
previously published procedure.24 The aldehyde (1, 0.5 mmol), amine (2, 0.5 mmol) and alkyne (3, 0.5
mmol) were added to a reactor tube containing CuNPs/C (20 mg, ca. 0.5 mol%) and dichloromethane
(1.0 mL). The reaction mixture was warmed to 70 ºC without the exclusion of air and monitored by
TLC and/or GLC until total or steady conversion of the starting materials. The solvent was removed in
vacuo; EtOAc (2 mL) was added to the resulting mixture followed by filtration through Celite and
washing with additional EtOAc (4 mL). The reaction crude obtained after evaporation of the solvent
was purified by column chromatography (silica gel, hexane/EtOAc) to give the corresponding
indolizine 4. The physical and spectroscopic data of the new indolizine 4o follows:
N,N-Dibenzyl-5-methyl-3-phenylindolizin-1-amine (4o): yellow oil (247 mg, 61%); tR 29.11; Rf 0.73
(hexane/EtOAc, 8:2); IR (neat) ν 3079, 3066, 3027, 2925, 2827, 1599, 1492, 1472, 1451, 1292, 1070,
748, 696; 1H NMR (300 MHz, CDCl3) δ 2.01(s, 3H), 4.17 (s, 4H), 6.13 (d, J = 6.5 Hz, 1H), 6.48 (dd, J
= 8.8, 6.5 Hz, 1H), 6.55 (s, 1H), 7.14–7.29 (m, 11H), 7.37 (d, J = 7.0 Hz, 1H), 7.49 (d, J = 8.9 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 23.0, 59.4, 111.4, 111.9, 114.7, 115.6, 126.7, 126.8, 127.0, 128.0, 128.6,
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130.9, 123.5, 127.2, 134.0, 136.0, 139.6; MS (EI) m/z 402 (M+, 0.3), 311 (23), 310 (99), 309 (39), 295
(10), 281 (18), 221 (10), 209 (13), 208 (24), 207 (100), 191 (17), 91 (26); HRMS (ESI) m/z: [M]+ Calcd
for C29H26N2 402.2096; Found 402.2093.
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General procedure for the optimization of the catalytic hydrogenation: A suspension of the
indolizine 4h (0.3 mmol) and catalyst (0.03 mmol) in glacial HOAc (3 mL) was hydrogenated at
different pressures and reaction times, at room temperature, as indicated in Tables 1 and 2. The catalyst
was removed by filtration and the resulting mixture was diluted with EtOAc and analyzed by GLC,
TLC and GCꢀMS.
General procedure for the hydrogenation of indolizines 4 catalyzed by PtO2: The indolizine 4 (0.5
mmol) was poured into the hydrogenation flask, followed by the addition of PtO2 (11.4 mg, 10 mol%)
and glacial HOAc (3 mL), with this mixture being subjected to hydrogenation at 3.74 atm (55 psi) and
ambient temperature. The reaction was monitored by TLC and/or GLC until total or steady conversion
of the starting material (see Table 2). The catalyst was separated by filtration and the solvent was
removed under vacuum. Purification of the reaction crude by column chromatography (silica gel,
hexane/EtOAc) afforded the pure indolizidines 5 as single diastereoisomers.
(1R*,3R*,8aR*)-3-Phenyl-1-(piperidin-1-yl)octahydroindolizine (5a): yellow solid (83 mg, 58%); tR
12.62; Rf 0.40 (hexane/EtOAc, 4:6); mp 68.9–70.9 ºC (EtOH); IR (neat) ν 3084, 3050, 3030, 2929,
1
2851, 2789, 2789, 1601, 1439, 1364, 1260, 1142, 1126, 1105, 863, 755, 698; H NMR (400 MHz,
CDCl3) δ 1.13–1.26, 1.34–1.66, 1.71–1.85, 1.98–2.11, 2.29–2.40, 2.67–2.86, 3.11–3.32 (7m, 22H),
13
2.96 (t, J = 8.7 Hz, 1H), 7.19–7.25, 7.28–7.44 (2m, 5H); C NMR (101 MHz, CDCl3) δ 24.7, 24.8,
25.6, 26.3, 26.6, 31.7, 51.7, 52.9, 65.3, 68.9, 70.2, 126.8, 127.4, 128.4, 143.8; MS (EI) m/z 284 (M+, 9),
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201 (13), 174 (10), 173 (76), 172 (100), 110 (44); HRMS (ESI) m/z: [M + H]+ Calcd for C19H29N2
4
5
285.2341; Found 285.2331.
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9
(1R*,3R*,8aR*)-1-(Piperidin-1-yl)-3-(p-tolyl)octahydroindolizine (5b): brown oil (52 mg, 35%); tR
13.14; Rf 0.40 (hexane/EtOAc, 1:1); IR (neat) ν 3046, 3009, 2927, 2851, 2786, 2747, 1512, 1439, 1260,
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1
1143, 1126, 1105, 1036, 863, 813, 797, 735; H NMR (300 MHz, CDCl3) δ 1.15–1.86 (m, 14H), 1.92–
2.08 (m, 2H), 2.27–2.40 (m, 5H), 2.63–2.86 (m, 3H), 2.92 (t, J = 8.7Hz, 1H), 3.16 (ddd, m, J = 9.0 Hz,
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7.4, 3.8, 1H), 7.12 (d, J = 7.8 Hz, 2H), 7.23 (d, J = 7.8 Hz, 2H); C NMR (75 MHz, CDCl3) δ 21.2,
24.8, 24.9, 25.6, 26.4, 26.6, 31.7, 51.8, 52.9, 65.4, 69.0, 70.0, 127.3, 129.1, 136.3, 140.9; MS (EI) m/z
298 (M+, 6), 215 (12), 188 (10), 187 (71), 186 (100), 110 (45); HRMS (ESI) m/z: [M + H]+ Calcd for
C20H31N2 299.2487; Found 299.2500.
(1R*,3R*,8aR*)-3-(4-Methoxyphenyl)-1-(piperidin-1-yl)octahydroindolizine (5c): this compound
was isolated together with an inseparable impurity as a brown oil (71 mg, aprox. 45%); tR 14.20; Rf
0.42 (hexane/EtOAc, 4:6); IR (neat) ν 3060, 2991, 2930, 2852, 2785, 2749, 1611, 1509, 1439, 1300,
1242, 1179, 1170, 1143, 1126, 1101, 1036, 828, 798; Selected NMR data: 1H NMR (400 MHz, CDCl3)
δ 1.06–1.91 (m, 15H), 1.94–2.09 (m, 2H), 2.26–2.49 (m, 2H), 2.73–2.81 (m, 2H), 2.91 (t, J = 8.7 Hz,
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1H), 3.12–3.30 (m, 1H), 3.80 (s, 3H), 6.84–6.89 (m, 2H), 7.21–7.32 (m, 2H); CNMR (101 MHz,
CDCl3) δ 24.7, 24.8, 25.6, 26.2, 26.6, 31.7, 51.7, 52.8, 55.4, 65.2, 68.9, 69.7, 113.8, 128.4, 135.8,
158.6; MS (EI) m/z 314 (M+, 6), 231 (15), 204 (11), 203 (76), 202 (100), 110 (47); HRMS (ESI) m/z:
[M + H]+ Calcd for C20H31N2O 315.2436; Found 315.2435.
4-[(1R*,3R*,8aR*)-3-Phenyloctahydroindolizin-1-yl]morpholine (5d): yellow solid (97 mg, 68%); tR
12.69; Rf 0.34 (hexane/EtOAc, 8:2); mp 53.7–55.7 ºC (EtOH); IR (neat) ν 3079, 3060, 3030, 2939,
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2849, 2802, 2749, 1603, 1448, 1258, 1136, 1114, 998, 866, 755, 699; H NMR (300 MHz, CDCl3) δ
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1.16–1.28, 1.34–1.38, 1.50–1.69, 1.71–1.88, 2.00–2.12, 2.31–2.51, 2.73–2.91 (7m, 15H; 7 × CH2, CH),
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2.30 (t, J = 8.7 Hz, 1H; CH), 3.06–3.23 (m, 1H; CH), 3.66–3.77 (m, 4H; 2 × CH2), 7.21–7.36 (m, 5H; 5
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× ArH); C NMR (75 MHz, CDCl3) δ 24.6, 25.6, 26.7, 31.8, 51.1, 52.9, 67.4 (9 × CH2), 65.1, 68.9,
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70.2 (3 × CH), 126.9, 127.3, 128.5 (5 × ArCH), 143.5 (ArC); MS (EI) m/z 286 (M+, 3), 203 (14), 173
(71), 172 (100), 112 (41), 104 (10); Anal. Calcd for C18H26N2O: C, 75.48; H, 9.15; N, 9.78. Found: C,
75.88; H, 9.28; N 9.94.
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(1R*,3R*,8aR*)-N-Benzyl-N-methyl-3-phenyloctahydroindolizin-1-amine (5e): brown oil; tR 14.14
(96 mg, 60%); Rf 0.57 (hexane/EtOAc, 8:2); IR (neat) ν 3084, 3065, 3025, 2934, 2858, 2784, 1599,
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1492, 1449, 1361, 1262, 1147, 1099, 1071, 1019, 867, 755, 731, 697; H NMR (400 MHz, CDCl3) δ
1.14–1.27, 1.36–1.48, 1.49–1.61, 1.69–1.80, 1.81–1.95, 2.10–2.19 (6m, 10H), 2.33 (s, 3H), 2.84 (d, J =
10.6 Hz, 1H), 3.02 (t, J = 8.7 Hz, 1H), 3.34–3.47 (d, m, J = 13.8 Hz, 2H), 4.10 (d, J = 13.8 Hz, 1H),
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7.22–7.26, 7.28–7.40 (2m, 10H); C NMR (101 MHz, CDCl3) δ 24.8, 25.5, 26.7, 32.1, 52.8, 59.0,
39.9, 63.1, 69.0, 70.1, 126.9, 127.0, 127.4, 128.4, 128.5, 128.9, 139.4, 143.5; MS (EI) m/z 320 (M+, 2),
237 (13), 173 (76), 172 (100), 146 (46), 91 (35); HRMS (ESI) m/z: [M + H]+ Calcd for C22H29N2
321.2335; Found 321.2331.
(1R*,3R*,8aR*)-N-Methyl-N-phenethyl-3-phenyloctahydroindolizin-1-amine (5f): brown oil; tR
15.50 (102 mg, 61%); Rf 0.66 (hexane/EtOAc, 4:6); IR (neat) ν 3084, 3065, 3025, 2933, 2848, 2784,
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2749, 1603, 1493, 1451, 1362, 1262, 1144, 1100, 1029, 934, 867, 802, 755, 697; H NMR (300 MHz,
CDCl3) δ 1.19–1.89, 2.04–2.18 (2m, 10H), 2.42 (s, 3H), 2.44–2.63, 2.73–2.85, 2.94–3.11, 3.25–3.42
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(4m, 7H), 7.15–7.36 (m, 10H); C NMR (101 MHz, CDCl3) δ 24.8, 25.7, 26.9, 32.8, 35.0, 52.8, 57.2,
40.1, 64.1, 69.2, 70.1, 125.9, 126.9, 127.4, 128.3, 128.4, 128.9, 141.1, 143.6; MS (EI) m/z 334 (M+, 1),
251 (11), 243 (39), 173 (70), 172 (100), 160 (42), 139 (10), 91 (11); HRMS (ESI) m/z: [M + H]+ Calcd
for C23H31N2 335.2487; Found 335.2490.
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(1R*,3R*,8aR*)-N,N-Dibutyl-3-phenyloctahydroindolizin-1-amine (5g): brown oil (108 mg, 66%); tR
12.74; Rf 0.54 (hexane/EtOAc, 8:2); IR (neat) ν 3060, 3025, 2936, 2852, 2792, 1601, 1492, 1451, 1363,
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1263, 1145, 1027, 976, 755, 741, 731, 696; H NMR (300 MHz, CDCl3) δ 0.92 (t, J = 7.2 Hz, 6H),
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1.14–1.87, 2.01–2.15, 2.18–2.36, 2.75–2.86, (4m, 23H), 2.94 (t, J = 8.7 Hz, 1H), 3.29–3.45 (m, 1H),
7.19–7.25 (m, 1H), 7.28–7.38 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 14.4, 20.9, 25.0, 25.8, 27.1, 31.1,
34.1, 52.2, 52.8, 60.7, 69.5, 70.3, 126.8, 127.5, 128.4, 144.0; MS (EI) m/z 328 (M+, 4), 174 (10), 173
(84), 172 (100), 154 (40), 140 (10), 117 (10), 91 (11); HRMS (ESI) m/z: [M + H]+ Calcd for C22H37N2
329.2961; Found 329.2957.
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(1R*,3R*,8aR*)-N,N-Dibenzyl-3-phenyloctahydroindolizin-1-amine (5h):
brown oil (129 mg, 65%); tR 21.06; Rf 0.89 (hexane/EtOAc, 8:2); IR ν 3060,
3025, 2936, 2852, 2792, 1601, 1492, 1451, 1363, 1263, 1145, 1027, 976,
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755, 741, 731, 696; HNMR (300 MHz, CDCl3) δ 1.14–1.25 (m, 1H; Hf),
1.34–1.44 (m, 1H; He’), 1.46–1.59 (m, 2H; He, Hd’), 1.75–1.87 (m, 3H; Hb, Hf’, Hg), 1.88–1.95 (m, 1H;
Hg’), 1.99–2.08 (m, 1H; Hh), 2.08–2.19 (m, 1H; Hb’), 2.81 (d, J = 10.4 Hz, 1H; Hd), 2.98 (t, J = 8.8 Hz,
1H; Hc), 3.28 (d, J = 14.8 Hz, 2H; 2 × Hi), 3.36 (td, J = 8.8, 4.0 Hz, 1H; Ha), 4.20 (br s, 2H; 2 × Hi’),
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7.19–7.27 (m, 3H; 3 × ArH), 7.28–7.40 (m, 8H; 8 × ArH), 7.41–7.51 (m, 4H; 4 × ArH); C NMR (75
MHz, CDCl3) δ 24.8 (Cꢀ6), 25.6 (Cꢀ7), 27.0 (Cꢀ8), 32.4 (Cꢀ2), 52.9 (Cꢀ5), 56.1 (2 × Cꢀ9), 58.5 (Cꢀ1),
69.1 (Cꢀ8a), 70.2 (Cꢀ3), 126.7, 126.9, 127.4, 128.4, 128.5 (15 × ArCH), 140.8, 143.7 (3 × ArC); MS
(EI) m/z 396 (M+, 0.3), 306 (14), 305 (59), 222 (51), 174 (10), 173 (79), 172 (100), 117 (12), 91 (72);
HRMS (ESI) m/z: [M + H]+ Calcd for C28H32N2 396.2565; Found 396.2585.
(1R*,3R*,8aR*)-N,N-Dibenzyl-3-(p-tolyl)octahydroindolizin-1-amine (5i): brown oil (119 mg, 58%);
tR 22.80; Rf 0.86 (hexane/EtOAc, 8:2); IR (neat) ν 3079, 3060, 3030, 2935, 2858, 2794, 2754, 1603,
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1493, 1451, 1362, 1263, 1145, 813, 770, 740, 728, 696; H NMR (400 MHz, CDCl3) δ 1.14–1.56,
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1.75–1.96, 1.99–2.16 (3 m, 10H), 2.35 (s, 3H), 2.80 (d, J = 10.6 Hz, 1H), 2.94 (t, J = 8.7 Hz, 1H), 3.28
(d, J = 14.5 Hz, 2H), 3.31–3.40 (m, 1H), 4.19 (broad s, 2H), 7.12–7.16, 7.19–7.25, 7.25–7.34, 7.41–
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7.53 (4m, 14H); C NMR (101 MHz, CDCl3) δ 21.3, 24.8, 25.6, 27.0, 32.4, 52.9, 56.1, 58.5, 69.1,
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69.9, 126.7, 127.3, 128.3, 128.5, 129.2, 136.5, 140.7, 140.8; MS (EI) m/z 410 (M+, 0.2), 320 (10), 319
(41), 236 (31), 222 (10), 188 (11), 187 (77), 186 (97), 131 (12), 118 (14), 117 (11), 106 (10), 105 (27),
91 (100); HRMS (ESI) m/z: [M + H]+ Calcd for C29H35N2 411.2800; Found 411.2813.
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(1R*,3R*,8aR*)-N,N-Dibenzyl-3-(4-methoxyphenyl)octahydroindolizin-1-amine (5j): brown oil
(183 mg, 86%); tR 31.39; Rf 0.26 (hexane/EtOAc, 8:2); IR (neat) ν 3060, 3025, 2934, 2851, 2832, 2791,
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2752, 1610, 1509, 1242, 1170, 1145, 1101, 1036, 828, 740, 728, 697; H NMR (300 MHz, CDCl3) δ
1.11–1.55, 1.76–2.15 (2m, 10H), 2.79 (d, J = 10.4 Hz, 1H), 2.91 (t, J = 8.7 Hz, 1H), 3.20–3.43 (d, m,
J= 14.4 Hz, 3H), 3.81 (s, 3H), 3.93–4.45 (m, 2H), 6.86–6.92, 7.18–7.26, 7.28–7.36, 7.42–7.54 (4m,
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14H); C NMR (75 MHz, CDCl3) δ 24.9, 25.6, 27.0, 32.3, 52.8, 56.1, 55.4, 58.4, 69.1, 69.6, 113.9,
126.7, 128.3, 128.4, 128.5, 135.7, 140.8, 158.7; MS (EI) m/z 426 (M+, 0.3), 343 (10), 336 (18), 335
(74), 252 (35), 222 (23), 204 (13), 203 (91), 202 (100), 134 (10), 121 (47), 91 (75); HRMS (ESI) m/z:
[M + H]+ Calcd for C29H35N2O 427.2749; Found 427.2763.
Methyl 4-[(1R*,3R*,8aR*)-1-(dibenzylamino)octahydroindolizin-3-yl)]benzoate (5k): white solid
(216 mg, 95%); Rf 0.60 (hexane/EtOAc, 8:2); mp 144.5–147.6; IR (neat) ν 3058, 2945, 2792, 1719,
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1274, 1110, 1097, 769, 733, 697; H NMR (300 MHz, CDCl3) δ 1.16–1.61 (m, 4H), 1.76–1.95 (m,
4H), 2.04–2.19 (m, 2H), 2.79 (d, J = 10.7 Hz, 1H), 3.06 (t, J = 8.7 Hz, 1H), 3.24 (d, J = 14.4 Hz, 2H),
3.39 (td, J = 8.7, 3.9 Hz, 1H), 3.92 (s, 3H), 4.17 (br s, 2H), 7.23 (t, J = 7.3 Hz, 2H), 7.32 (t, J = 7.5 Hz,
4H), 7.45 (m, 6H), 8.02 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 24.6, 25.4, 26.8, 32.1, 52.0, 52.8, 55.8,
58.5, 69.0, 69.6, 126.6, 127.1, 128.2, 128.3, 129.8, 128.7, 140.4, 149.2, 167.1; MS (EI) m/z 454 (M+,
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0.4), 364 (18), 363 (72), 281 (13), 280 (65), 232 (14), 231 (100), 230 (96), 222 (10), 216 (20), 91 (70);
Anal. Calcd for C30H34N2O2: C, 79.26; H, 7.54; N, 6.16. Found: C, 78.80; H, 7.48; N, 6.11.
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(1R*,3R*,8aR*)-N,N-Dibenzyl-3-[4-(trifluoromethyl)phenyl]octahydroindolizin-1-amine (5l): beige
solid (128 mg, 55%); tR 19.28; Rf 0.80 (hexane/EtOAc, 7:3); mp 141.6–144.4 ºC; IR (neat) ν 3079,
3060, 3030, 2937, 2853, 2792, 2754, 1617, 1322, 1161, 1121, 1102, 1066, 1018, 834, 739, 729, 697;
1H NMR (300 MHz, CDCl3) δ 1.13–1.64, 1.74–1.99, 2.05–2.22 (3m, 10H), 2.79 (d, J = 10.5 Hz, 1H),
3.06 (t, J = 8.7 Hz, 1H), 3.24 (d, J = 14.4 Hz, 2H), 3.32–3.49 (m, 1H), 3.97–4.42 (m, 2H), 7.20–7.26,
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7.29–7.36, 7.43–7.52, 7.58–7.63 (4m, 14H); CNMR (75 MHz, CDCl3) δ 24.7, 25.5, 27.0, 32.3, 52.9,
56.0, 58.6, 69.1, 69.7, 124.4 (q, 1JCꢀF = 271.9 Hz), 125.5 (q, 3JCꢀF = 3.8 Hz), 126.8, 127.6, 128.4, 128.5,
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129.1 (q, JCꢀF = 32.1 Hz), 140.5, 148.0; MS (EI) m/z 464 (M+, 0.1), 373 (39), 291 (10), 290 (54), 242
(11), 241 (78), 240 (100), 172 (11), 91 (82); Anal. Calcd for C29H31F3N2: C, 74.98; H, 6.73; N, 6.03.
Found: C, 74.95; H, 6.75; N, 5.90.
(1R*,3S*,8aR*)-N,N-Dibenzyl-3-decyloctahydroindolizin-1-amine (5m): brown oil (166 mg, 72%);
tR 25.57; Rf 0.83 (hexane/EtOAc, 7:3); IR ν 3079, 3060, 3020, 2922, 2852, 2791, 2754, 1603, 1493,
1452, 1364, 1263, 1148, 1027, 981, 938, 771, 733, 696; 1H NMR (300 MHz, CDCl3) δ 0.89 (t, J = 6.7
Hz, 3H), 1.07–1.45, 1.47–1.89 (2m, 29H), 3.08–3.16, 3.17–3.25 (2m, 2H), 3.29 (d, J = 14.6 Hz, 2H),
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3.84–4.29 (m, 2H), 7.17–7.23, 7.26–7.33, 7.39–7.50 (3m, 10H); CNMR (75 MHz, CDCl3) δ 14.3,
22.9, 25.1, 25.7, 26.8, 27.0, 28.0, 29.5, 29.8, 29.9, 30.3, 32.1, 32.8, 53.0, 56.1, 58.0, 65.6, 69.8, 126.6,
128.3, 128.4, 140.9; MS (EI) m/z 460 (M+, 0.4), 370 (20), 369 (71), 238 (18), 237 (100), 236 (50), 166
(12), 138 (12), 124 (42), 122 (18), 111 (17), 110 (51), 98 (11), 97 (21), 96 (13), 91 (72), 84 (12); Anal.
Calcd for C32H48N2: C, 83.42; H, 10.50; N, 6.08. Found: C, 83.81; H, 10.23; N, 5.73.
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(1R*,3R*,8aR*)-N,N-Dibutyl-1-phenyl-1,2,3,3a,4,5-hexahydropyrrolo[1,2-a]quinolin-3-amine (5n):
yellow oil (85 mg, 45%), tR 21.37; Rf 0.75(hexane/EtOAc, 9:1); IR (neat) ν 3021, 2957, 2921, 2856,
2816, 1598, 1491, 1455, 1320, 1097, 1079, 1029, 803, 751, 703; 1H NMR (300 MHz, CDCl3) δ 0.87 (t,
J = 7.2 Hz, 6H; 2 × CH3), 1.14–1.43 (m, 8H; 4 × CH2), 1.94 (ddd, J = 14.0, 6.5, 3.6 Hz, 1H; CH), 2.06–
2.19 (m, 4H; 2 × CH2), 2.52–2.65 (m, 3H), 2.92–3.00 (m, 2H), 3.36–3.52 (m, 2H), 4.35 (dd, J = 9.8,
6.5 Hz, 1H; CH), 6.14 (dd, J = 8.1, 0.9 Hz, 1H; ArH), 6.64 (td, J = 7.3, 1.1 Hz, 1H; ArH), 6.79 (td, J =
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8.2, 1.7 Hz, 1H; ArH), 7.05 (dd, J = 7.4, 1.2 Hz, 1H; ArH), 7.17–7.29 (m, 5H; ArH); C NMR (75
MHz, CDCl3) δ 14.2 (2 × CH3), 20.6, 24.5, 27.9, 30.3, 36.1, 51.8 (9 × CH2), 60.7, 63.2, 64.2 (3 × CH),
114.9, 117.9, 125.9, 126.3, 128.1, 128.3, 128.7 (9 × ArCH), 125.6, 144.0, 146.9 (3 × ArC); MS (EI)
m/z 376 (M+, 18), 329 (9), 247 (11), 246 (12), 245 (20), 244 (30), 221 (55), 220 (100), 202 (20), 155
(11), 154 (72), 117 (25), 115 (12), 91 (11); HRMS (ESI) m/z: [M+] Calcd for C26H36N2 376.2878;
Found 376.2889.
(1R*,3R*,5R*,8aR*)-N,N-Dibenzyl-5-methyl-3-phenyloctahydroindolizin-1-amine (5o): yellow oil
(82 mg, 40%), tR 28.22; Rf 0.83 (hexane/EtOAc, 8:2); IR (neat) ν 3027, 2926, 2849, 2797, 1492, 1452,
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1140, 993, 732, 697, 617; H NMR (300 MHz, CDCl3) δ 0.54 (d, J = 6.4 Hz, 3H), 1.18–1.44 (m, 5H),
1.72–1.95 (m, 5H), 2.14–2.25 (m, 2H), 3.21 (d, J = 14.2 Hz, 2H; CH2), 3.23 (t, J = 4.4 Hz, 1H), 3.28
(ddd, J = 9.5, 7.9, 3.6 Hz, 1H), 4.23 (d, J = 14.2 Hz, 2H; CH2), 7.18–7.25 (m, 3H; 3 × ArH), 7.29–7.34
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(m, J = 7.5 Hz, 8H; 8 × ArH), 7.46 (d, J = 7.5 Hz, 4H; 4 × ArH); C NMR (75 MHz, CDCl3) δ 23.3
(CH3), 25.3, 27.3, 34.2, 35.6 (4 × CH2), 55.9 (2 × CH2N), 58.5, 62.9, 69.8, 70.8 (4 × CH), 126.2, 126.6,
126.7, 128.1, 128.4 (15 × ArCH), 140.1, 148.0 (3 × ArC); MS (EI) m/z 319 (73), 222 (49), 207 (20),
187 (64), 186 (89), 117 (14), 106 (10), 104 (12), 92 (11), 91 (100); HRMS (ESI) m/z: [M+] Calcd for
C29H34N2 410.2722, [M – Bn]+ 319.2174; Found 319.2195.
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General procedure for the hydrogenolysis of indolizines 5 to monobenzylated indolizidines 6: The
indolizine 5 (0.3 mmol) was poured into the hydrogenation flask, followed by the addition of Pt(5
wt%)/C (117 mg, 10 mol%) or PtO2 (11.4 mg, 10 mol%) and glacial HOAc (3 mL), with this mixture
being subjected to hydrogenation at ca. 1 atm (balloon) and ambient temperature. The reaction was
monitored by TLC and/or GLC until total or steady conversion of the starting material (see Table 3).
The catalyst was separated by filtration and the glacial HOAc was neutralized with 2M NaOH,
followed by extraction with EtOAc, drying of the organic phase with Na2SO4 and solvent evaporation
under vacuum. Purification of the reaction crude by preparative TLC (silica gel, hexane/EtOAc 6:4)
afforded the pure indolizidines 6 as single diastereoisomers.
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(1R*,3R*,8aR*)-N-Benzyl-3-phenyloctahydroindolizin-1-amine (6h): brown oil (63 mg, 68%); tR
15.38; Rf 0.44 (hexane/EtOAc, 3:7); IR (neat) ν 3029, 2935, 2851, 2789, 1603, 1492, 1451, 1145, 1117,
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754, 731, 609; H NMR (300 MHz, CDCl3) δ 1.15–1.31 (m, 1H), 1.38–1.86 (m, 8H), 2.06–2.15 (m,
1H), 2.43 (dt, J = 13.5, 8.0 Hz, 1H), 2.83, (d, J = 10.7 Hz, 1H), 3.07 (t, J = 8.4 Hz, 1H), 3.14 (ddd, J =
13
7.9, 6.1, 3.1 Hz, 1H), 3.68, 3.86 (AB system, J = 13.4 Hz, 2H), 7.20–7.37 (m, 10H); C NMR (75
MHz, CDCl3) δ 24.4, 25.4, 26.4, 41.7, 51.4, 52.1, 57.5, 68.8, 69.9, 126.8, 126.9, 127.6, 128.1, 128.3,
140.7, 143.3; MS (70 eV) m/z (%) 306 (M+, 3), 223 (20), 197 (21), 196 (20), 173 (61), 172 (100), 168
(11), 132 (29), 91 (25); HRMS (EI) m/z: Calcd for C21H26N2 306.2096; Found 306.2092.
(1R*,3R*,8aR*)-N-Benzyl-3-(4-methoxyphenyl)octahydroindolizin-1-amine (6j): brown oil; (73 mg,
72%); tR 18.52; Rf 0.13 (hexane/EtOAc, 6:4); IR (neat) ν 3060, 2951, 2851, 1509, 1426, 1301, 1259,
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1112, 896, 734, 698; H NMR (300 MHz, CDCl3) δ 1.19–1.92 (m, 9H), 2.02–2.13 (m, 1H), 2.41 (dt, J
= 13.5, 8.0 Hz, 1H), 2.81 (d, J = 10.7 Hz, 1H), 3.02 (t, J = 8.4 Hz, 1H), 3.14 (ddd, J = 7.8, 6.1, 3.1 Hz,
1H), 3.69, 3.87 (AB system, J = 13.4 Hz, 2H), 3.80 (s, 3H), 6.86 (d, J = 8.4 Hz, 2H), 7.21–7.36 (m,
13
7H); C NMR (75 MHz, CDCl3) δ 24.3, 25.3, 26.3, 41.6, 51.4, 52.0, 55.2, 57.4, 68.8, 69.4, 113.7,
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126.8, 128.1, 128.3, 128.7, 135.0, 140.6, 158.6; MS (70 eV) m/z (%) 336 (M+, 2), 253 (21), 252 (10),
231 (10), 227 (39), 226 (13), 212 (17), 207 (13), 203 (58), 202 (100), 162 (34), 135 (12), 134 (20), 132
(39), 106 (16), 92 (10), 91 (66), 84 (12), 77 (14), 65 (10); HRMS (EI) m/z: Calcd for C22H28N2O
336.2202; Found 336.2185.
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(1R*,3R*,8aR*)-N-Benzyl-3-[4-(trifluoromethyl)phenyl]octahydroindolizin-1-amine (6l): brown oil
(73 mg, 65%); tR 15.06; Rf 0.48 (hexane/EtOAc, 6:4); IR (neat) ν 3029, 2934, 2852, 2789, 2753, 1509,
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1325, 1162, 1119, 1018, 837, 731, 697; H NMR (300 MHz, CDCl3) δ 1.08–1.99 (m, 9H), 2.07–2.29
(m, 1H), 2.34–2.61 (m, 1H), 2.80 (d, J = 10.7 Hz, 1H), 3.08–3.21 (m, 2H), 3.67, 3.84 (AB system, J =
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13.3 Hz, 2H), 7.20–7.35 (m, 5H), 7.47, 7.56 (AA’BB’system, J = 8.2 Hz, 4H); C NMR (75 MHz,
CDCl3) δ 24.2, 25.3, 26.4, 41.8, 51.5, 52.1, 57.7, 68.7, 69.3, 124.3 (q, J = 271.8 Hz) 125.3 (q, J = 3.7
Hz), 126.8, 127.8, 128.1, 128.3, 129.1 (q, J = 32.2 Hz) 140.7, 147.9; MS (70 eV) m/z (%) 374 (M+, 2),
291 (8), 269 (11), 242 (10), 241 (62), 240 (100), 172 (11), 132 (20), 91 (38), 84 (27); HRMS (EI) m/z:
Calcd for C22H25F3N2 374.1970; Found 374.1967.
(1R*,3R*,8aR*)-N-Benzyl-3-decyloctahydroindolizin-1-amine (6m): brown oil (90 mg, 81%); tR
19.19; Rf 0.20 (hexane/EtOAc, 3:7); IR (neat) ν 3029, 2922, 2852, 2817, 1566, 1454, 1145, 980, 743,
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698; H NMR (300 MHz, CDCl3) δ 0.88 (t, J = 6.7 Hz, 3H), 1.09–1.40 (m, 20H), 1.43–2.04 (m, 9H),
2.2 (dt, J = 13.1, 7.8 Hz, 1H), 2.96–3.07 (m, 1H), 3.19 (d, J = 10.5 Hz, 1H), 3.65, 3.84 (AB system, J =
13.4 Hz, 2H), 7.17–7.35 (m, 5H); 13C NMR (75 MHz, CDCl3) δ 14.1, 22.7, 24.6, 25.2, 26.2, 26.6, 29.3,
29.6, 30.0, 31.9, 38.0, 51.6, 52.2, 56.9, 65.3, 69.4, 126.6, 128.1, 128.2, 140.7; MS (70 eV) m/z (%) 370
(M+, 3), 261 (9), 238 (13), 237 (49), 236 (23), 229 (28), 135 (14), 134 (100), 132 (12), 124 (27), 111
(10), 110 (27), 97 (11), 91 (25); HRMS (EI) m/z: Calcd for C25H42N2 370.3348; Found 370.3337.
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General procedure for the hydrogenolysis of indolizines 5 to debenzylated indolizidines 7: The
indolizine 5 (0.3 mmol) was poured into the hydrogenation flask, followed by the addition of Pd(20
wt%)/C (16 mg, 10 mol%) and glacial HOAc (3 mL), with this mixture being subjected to
hydrogenation at ca. 1 atm (balloon) and ambient temperature. The reaction was monitored by TLC
and/or GLC until total or steady conversion of the starting material (see Table 3). The catalyst was
separated by filtration and the glacial HOAc was neutralized with 2M NaOH, followed by extraction
with EtOAc, drying of the organic phase with Na2SO4 and solvent evaporation under vacuum.
Compounds 7j and 7m did not require any further purification; compounds 7h and 7l were purified by
preparative TLC (EtOAc). In all cases, the pure indolizidines 7 were obtained as single
diastereoisomers.
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(1R*,3R*,8aR*)-3-Phenyloctahydroindolizin-1-amine (7h): yellow oil (55 mg, 85%); tR 11.11; Rf 0.20
(EtOAc/MeOH, 8:2); IR (neat) ν 3038, 2932, 2854, 1555, 1455, 1388, 1311, 1145, 754, 698; 1H NMR
(300 MHz, CDCl3) δ 1.21–1.62 (m, 6H), 1.63–1.88 (m, 3H), 2.02 (ddd, J = 7.5, 5.4, 2.7 Hz, 2H), 2.62
(ddd, J = 14.0, 8.8, 8.0 Hz, 1H), 2.83 (d, J = 10.8 Hz, 1H), 3.07 (t, J = 8.4 Hz, 1H), 3.27 (ddd, J = 7.7,
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5.1, 2.4 Hz, 1H), 7.15–7.26 (m, 1H), 7.28–7.36 (m, 4H); C NMR (75 MHz, CDCl3) δ 23.9, 25.2,
26.0, 43.9, 51.7, 52.3, 68.6, 69.4, 126.8, 127.4, 128.2, 143.2; MS (70 eV) m/z (%) 217 (M++1, 1), 216
(M+, 8), 173 (51), 172 (100), 132 (8), 104 (7), 84 (15); HRMS (EI) m/z: Calcd for C14H20N2 216.1626,
C14H17N [M+ – NH3] 199.1361; Found 199.1356.
(1R*,3R*,8aR*)-3-(4-Methoxyphenyl)octahydroindolizin-1-amine (7j): brown oil (57 mg, 77%); tR
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12.59; Rf 0.17 (acetone); IR(neat) ν 2933, 2851, 1583, 1242, 1035, 828, 626; H NMR (300 MHz,
CDCl3) δ 0.95–2.01 (m, 9H), 2.57 (dt, J = 13.9, 8.4 Hz, 1H), 2.73 (s, 2H), 2.8 (d, J = 10.8 Hz, 1H),
2.99 (t, J = 8.4 Hz, 1H), 3.27 (ddd, J = 7.9, 5.2, 2.5 Hz, 1H), 3.78 (s, 3H), 6.85, 7.24 (AA’XX’, J = 8.7
Hz, 4H); 13C NMR (75 MHz, CDCl3) δ 23.9, 25.2, 25.9, 43.7, 51.6, 52.1, 55.1, 68.6, 69.0, 113.6, 128.5,
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