Selective hydrogenation of indolizines: An expeditious approach to derive tetrahydroindolizines and indolizidines from Morita-Baylis-Hillman adducts

Article abstract of DOI:10.1021/jo502471q

In this study, we describe the hydrogenation of indolizines derived from Morita-Baylis-Hillman adducts. We demonstrate that functionalized tetrahydroindolizines and indolizidines can be prepared selectively, at low pressure, by simply adjusting the acidity of the medium. Using this simple and straightforward strategy, substituted tetrahydroindolizines and indolizidines were obtained diastereoselectively in high yield.

Full text of DOI:10.1021/jo502471q

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Article
Selective hydrogenation of indolizines: an expeditious approach to derive
tetrahydroindolizines and indolizidines from Morita-Baylis-Hillman adducts
Bruno Vinicius Motta Teodoro, José Tiago Menezes Correia, and Fernando Coelho
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502471q • Publication Date (Web): 30 Jan 2015
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The Journal of Organic Chemistry
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Selective hydrogenation of indolizines: an expeditious approach to derive
tetrahydroindolizines and indolizidines from Morita-Baylis-Hillman
adducts
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Bruno V. M. Teodoro, José Tiago M. Correia and Fernando Coelho*
Laboratory of Synthesis of Natural Products and Drugs, Institute of Chemistry, University of Campinas,
P. O. Box 6154, 13083-970, Campinas, São Paulo, Brazil
coelho@iqm.unicamp.br
H
R2
R2
R2
Acid Solution
Neutral Solution
R1
R1
R1
N
N
N
PtO2, H2 balloon
rt
PtO2, H2 (5 bar)
rt
12 examples
40-95% yield
5 examples
78-92 % yield
84-95% cis isomer
Indolizines derivated
by MBH adducts
- Commercially available catalyst
- Mild conditions (room temperature, low pressure)
- High diastereoselectivity
Abstract:
In this study, we describe the hydrogenation of indolizines derived from Morita-Baylis-Hillman
adducts. We demonstrate that functionalized tetrahydroindolizines and indolizidines can be prepared
selectively, at low pressure, by simply adjusting acidity of the medium. Using this simple and straight-
forward strategy, substituted tetrahydroindolizines and indolizidines were obtained diastereoselectively
and in high yield.
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INTRODUCTION
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Indolizines and tetrahydroindolizines are polyunsaturated N-heterocycles that have caught the
attention of the chemical community, because of their broad potential in biological and synthetic
applications. Together with the quinolizidine nucleus, it is estimated that these structural moieties are
found in approximately 25% to 30% of known alkaloids.1 Glycosidase inhibitor activity (e.g.,
castanospermine and swainsonine alkaloids, Scheme 1)2 and pheromone activity (e.g., monomorine,
Scheme 1)3 are among the highlighted biological properties of these alkaloids. Some indolizidines
are directly related to the occurrence of diseases. For instance, slaframine is an indolizidine that
causes slobber disease, which negatively impacts the cattle industry.4 Unlike indolizidines,
tetrahydroindolizines are rarely found in alkaloids structures.
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O
H
N
NH
Et
OH
OH
H
HO
HO
O
n-Bu
Me
N
N
(+)-Monomorine
(-)-Rhazinicine
Castanospermine
H
N
O
OH
OH
H
Et
N
OH
N
N
Swainsonine
(-)-Rhazinilam
Et
OAc
H
R
N
O
N
H2N
H
R= n-Pr, Myrmicarine 217
R= (Z)-propenyl, Myrmicarine 215A
R= (E)-propenyl, Myrmicarine 215B
Slaframine
N
RO
R= H, Polygonatine A
R= Et, Polygonatine B
R= n-Bu, Kinganone
Scheme 1. Examples of indolizidinic and tetrahydroindolizinic alkaloids
Anticancer activity (e.g., rhazinilam and rhazinicine (Scheme 1)5 and antimicrobial activity (e.g.,
polygonatine A, polygonatine B and kinganone (Scheme 1)6 are among the biological activities
shown by this class of compounds. Alkaloids isolated from Myrmicaria ants (Myrmicarines 217,
215A and 215B) are interesting examples, because their biological profiles remain poorly
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understood.7 Although several methodologies have been described, these molecules represent a
challenge from a synthetic point of view, because of their low stability in air, silica gel and alumina.
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Many reports focused on the preparation of indolizines8 and tetrahydroindolizines9 can be found in
the literature, with each focusing on specific substitution patterns.
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The synthetic and biological relevance of these molecules justify the interest in the development
and/or improvement of the synthetic methodologies used to prepare them. The rationalization that
tetrahydroindolizines and indolizidines could be obtained by the partial and full hydrogenation of
indolizines, respectively, is reasonable (Scheme 2).
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R2
R1
N
OH
R2
Indolizidines
R2
R1
R1
N
N
MBH adduct
Indolizines
R2
R1
N
Tetrahydroindolizines
Scheme 2. Retrosynthetic analysis for the preparation of indolizidines and tetrahydroindoliz-
ines.
Many methods for the preparation of indolizines are available in the literature.10 Furthermore,
indolizines can be easily accessed, in few steps, by the intramolecular cyclization of Morita-Baylis-
Hillman (MBH) adducts prepared from suitable acrylates or α,β-unsaturated ketones and adequately
substituted 2-pyridinecarboxaldehydes.
Among the strategies based on MBH adducts we have mentioned, acetylation followed by heating11,
allylic bromination12 or direct heating of the MBH adduct under MW conditions afford indolizines.13
Additionally, a recent report by Basavaiah described a one-step autocatalytic methodology for
preparing indolizines using pyridine-2-carboxyaldehydes or 2-acetopyridines and vinylketones,
promoted by TMSOTf.14 Curiously, an in situ cyclization is observed during the preparation of the
MBH adduct from 2-cyclohexenone.12 Although this cyclization occurs without substrate pre-
activation, it can be accelerated in the presence of silica-gel.
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Despite the great number of methodologies used to access tetrahydroindolizines and indolizidines,9
few of them have focused on the preparation of these heterocycles via partial and full hydrogenation,
respectively (Scheme 2). Most data related to this approach are described in the patent literature.15
However, high temperatures and pressures are required and the substitution patterns are limited. For
example, Soldatenkov reported a partial hydrogenation to obtain a unique tetrahydroindolizine using
Re2S7 at 260 °C and 140 atm.16 Recently, the first asymmetric partial hydrogenation of indolizines
was reported by the Glorious group. In this case, a NHC-Ru chiral complex was used as the
catalyst.17 Although high yields and high selectivity were achieved, the scope (i.e., substitution
pattern of indolizines) was relatively limited, showing that much remains to be done in this area.
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The complete hydrogenation of indolizines presents several challenges regarding the aspects of
enantio- and diastereoselectivity. The first study of this type of transformation was reported by
Poponova, in which 10 examples of indolizidines were prepared in moderate yields and poor
diastereoselectivity (1:1.4) in favor of the cis diastereoisomer.18 Recently, Gevorgyan reported a
unique example using Adams's catalyst. In this case, a strong acid (HBr) and a hydrogenation
pressure of 5 atm were used to afford (+/-)-monomorine with moderate diastereoselectivity.19 With
the aim of demonstrating the applicability of indolizines prepared via a multicomponent reaction
catalyzed by a copper nanoparticle, Alonso and Yus, also reported a unique example of the full
hydrogenation of indolizines. In this case, the reaction gave the desired indolizidine with high
diastereoselectivity using Adams catalyst under a pressure of 55 psi with acetic acid as the solvent.20
Driven by the previous data provided in the literature and with the intent of expanding our
understanding of the behavior of indolizines, we explored herein the catalytic heterogeneous
hydrogenation of indolizines derived from Morita-Baylis-Hillman adducts to obtain both 5,6,7,8-
tetrahydroindolizines and indolizidines.
RESULTS AND DISCUSSION
Preparation of Morita-Baylis-Hillman (MBH) adducts and indolizines
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Morita-Baylis-Hillman (MBH) adducts were prepared using a methodology used from our group,21,
22 whereby they were obtained in good to excellent yields (Table 1, part A).
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Table 1. Preparation of MBH adducts
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DABCO (0.65 equiv.)
rt, ultrasound
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9
O
OH
R2
R2
+
R1
R1
2 to 12 h, 50 to 99%
N
N
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4.0 eq.
1a-l
1.0 eq.
OH
OH
OH
CO2Me
CO2Et
CO2n-Bu
N
N
N
1c, 12 h, 96%
1a, 12 h, 93%
1b, 12 h, 96%
OH
OH
O
OH
N
CO2t-Bu
N
N
N
1f, 12 h, 50%
1d, 12 h, 95%
1e, 2 h, 95%
OH
OH
OH
Et
CO2Me
CO2Me
Me
CO2Me
N
N
N
1i, 12 h, 99%
1g, 12 h, 88%
1h, 12 h, 85%
OH
OH
OH
CO2Me
CO2Me
CO2Me
N
N
N
Me
Br
1l, 7 h, 97%
Me
1k, 12 h, 89%
1j, 12 h, 94%
Once the MBH adducts were synthesized, the next step was the optimization of the methodology
used to prepare the indolizines. Among the methods available in literature, we chose acetylation
followed by thermal treatment and allylic bromination to get the desired indolizines.
Table 2. Optimization of the conditions for the preparation of indolizines.
OH
entries 1-4
CO2Me
CO2Me
N
N
1a
2a
Entry Conditions
Yield (%)
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1
PBr3, CH2Cl2, 0 0C
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PPh3, CBr4, CH2Cl2, 0 0C to rt
20
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i) Ac2O, 100 0C; ii) 130 0C
20a
0
i) Py, AcCl, CH2Cl2, 0 C to rt, 30 min; ii) 55a
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toluene, reflux 12 h
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a. Overall yield for two steps
When the allylic bromination using PBr3 was tested, the indolizine was obtained in very low yield
(Entry 1, Table 2). Using the milder Appel reaction conditions,23 the yield increased to 20% (Entry
2, Table 2). A similar result was obtained when the methodology described by Bode was used (Entry
3, Table 2). Modifications of the acetylation conditions and thermal cyclization (Entry 4, Table 2) led
to a net increase in the overall yield, which improved to 55% for the two steps. Using these better
optimization conditions, a set of indolizines were prepared from MBH adducts. Good overall yields
derived from acrylates and cyclopentenone could be obtained, with a yield of up to 65% for two
steps (Table 3).
Table 3. Preparation of indolizines
i) CH2Cl2, pyridine, AcCl, 0 0C to rt
OH
R2
ii) toluene, reflux
R2
R1
R1
N
N
12 h, 30 to 65% (2 steps)
2a-l
1a-l
CO2Me
CO2Et
N
CO2n-Bu
2c, 59%
N
N
2a, 55%
2b, 52%
O
CO2t-Bu
N
N
N
N
2f, 65%
2d, 60%
2e, 30%
Et
Me
CO2Me
CO2Me
CO2Me
N
N
N
2i, 44%
2g, 45%
2h, 39%
CO2Me
CO2Me
CO2Me
N
N
N
Me
Br
Me
2l, 38%
2j, 39%
2k, 41%
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Additionally, indolizines derived from methylvinylketone (MVK) and cyclohexenone were also
prepared. Indolizine 2m was obtained by the treatment of 2-pyridinecarboxaldehyde with TMSOTf
in the presence of MVK in acetonitrile containing 1% water (Scheme 3). Indolizine 2n was prepared
via the reaction between 2-pyridinecarboxaldehyde and 2-cyclohexenone in the presence of DMAP
as the catalyst (Scheme 4). Both methodologies were reproduced from literature and yields and
purities were in accordance with the reported data.
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CH3CN (1% H2O)
TMSOTf (1 eq.)
O
O
O
+
0 0C to rt, 12 h, 35%
N
N
2m
Scheme 3. Preparation of indolizine 2m.
THF/H2O (1:1)
DMAP (0,40 eq.)
O
O
O
+
N
rt, 4 days, 50%
N
2n
Scheme 4. Preparation of indolizine 2n.
Hydrogenation
Once the indolizines were prepared, the performance of the hydrogenation reactions was evaluated
by screening different catalysts. Indolizine 2a was chosen as a model to optimize the reaction
conditions. The following catalysts were tested: Pd/C, PtO2, Rh/Al2O3 and Rh/C.
Notably, no reaction was observed when rhodium catalysts (i.e., Rh/Al2O3 and Rh/C) were used.
Indeed, the starting material was recovered in both cases after 24h. By contrast, partial
hydrogenation was observed when Pd/C and PtO2 were used as the catalysts, affording 5,6,7,8-
tetrahydroindolizine 3a in 90% and 93% yields, respectively. The reaction in the presence of PtO2
was faster than the reaction in the presence of Pd/C. No indolizidine was detected in the reaction
medium, even when the pressure was increased (Entries 1-5, Table 4).
Table 4. Optimization of the conditions for the preparation of tetrahydroindolizines and
indolizidines
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MeOH
H2 (1 bar)
H
1
2
+
CO2Me
CO2Me
CO2Me
N
N
N
catalyst
3
4
4a
3a
2a
5
6
7
Entry
Catalyst
Additive
Time (h)
Yield (%)
3a:4a
8
1
2
3
4
5
6
7
Rh/Al2O3
Rh/C
Pd/C
-
-
-
-
-
12
12
4
-
-
9
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-
-
90
93
92
91
78
100:0
100:0
100:0
99:1
0:100
PtO2
2
PtO2
4
PtO2
AcOH (1 equiv.)
TFA (1 equiv.)
4
PtO2
4
Additional reactions were performed that examined the effect of acids as additives. In these cases,
the same conditions were maintained. When the reaction was performed in the presence of acetic
acid, a tiny amount of the corresponding indolizidine was observed by TLC. However,
tetrahydroindolizine was still obtained as the major product (91% yield). Full hydrogenation was
achieved only when the reaction was performed using TFA as the additive. Under this condition,
only the desired indolizidine was detected by TLC at the end of the reaction. After isolation,
indolizidine 4a was obtained in 78% yield (Entries 6-7, Table 4).
After the procedure had been optimized, the partial hydrogenation was performed (Table 5). The
results showed that indolizines without substituents on six-membered rings gave their corresponding
tetrahydroindolizines in yields varying from 65% to 95%, with short reaction times (up to 4 h,
Entries 1-4, 6, 12 and 13). The presence of a cyano group led to a drastic drop in the yield
(compound 3e, Table 5). Notably, reduction of the cyano group was not detected.
This result is likely associated with the fact that this functional group competes with the aromatic
system under hydrogenation conditions. Indolizines containing substituents on the six-membered
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ring afforded tetrahydroindolizines in yields varying from 67% to 83% with longer reaction times
(up to 48 h). This behavior is likely caused by the increased steric hindrance incurred as a result of
these substituents, which could compromise the adsorption of the substrate on the catalyst surface. In
particular, a slight increase in pressure to 4 bar was necessary for analog 2g to synthesize
tetrahydroindolizine 3g (Table 5).
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Table 5. Synthesis of tetrahydroindolizines by partial hydrogenation of indolizines
R2
R2
CH3OH, PtO2 (10 mol%)
R1
R1
N
N
H2 (1 bar), rt, 40 to 95%
2a-n
3a-m
CO2Me
CO2Et
N
CO2n-Bu
N
N
3c, 2 h, 95%
3a, 2 h, 93%
3b, 2 h, 91%
O
CO2t-Bu
N
N
N
N
3f, 4 h, 91%
3d, 2 h, 95%
3e, 12 h, 40%
Et
Me
CO2Me
CO2Me
CO2Me
N
N
N
3g, 48 h, 67%a
3h, 12 h, 79%
3i, 12 h, 81%
CO2Me
CO2Me
CO2Me
N
N
N
Me
Br
3l, 3 h, 0%b
Me
3j, 13 h, 79%
3k, 15 h, 83%
O
N
3m, 4 h, 90%
a. Reaction was performed with 5 bar pressure of H2.
b. 3a was recovered as unique product in 65% yield.
It is noteworthy that Gevorgyan reported the unique example of hydrogenation of this same substrate
some years ago, using the Birch reaction.24 However, this methodology failed when it was tested
with indolizines structurally similar to those obtained from Morita-Baylis-Hillman adducts leading
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to the decomposition of the starting materials.24 These data show how mild and easy to handle is the
methodology described in this study.
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8
9
Product 3a was obtained when brominated indolizine 2l underwent the same partial hydrogenation
condition. It is likely that an hydrogenolysis of C-Br bond occurred to give indolizine 2a,25 which
then is partially hydrogenated to afford tetrahydroindolizine 3a.
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Full hydrogenation was also investigated and the results are summarized in Table 6. Indolizidines
were obtained in 78% to 95% yield and 84% to 95% d.r. in favor of the cis diastereoisomer. All
indolizidines showed the Bohlmann band between 2725 and 2793 cm-1,26 indicating that they adopt a
conformation where substituents on the six-membered rings are in the equatorial position.27
Table 6. Full hydrogenation of indolizines
H
CH3OH, PtO2 (10 mol%)
R1
R2
R2
R1
N
H2 (5 bar), rt, 4 h, 40 to 95%
N
3a,b,d,h,k
4a-e
H
N
H
H
CO2Me
CO2Et
N
CO2t-Bu
N
(+/-)-4c, 92%, d.r. 93:7
(+/-)-4a, 78%, d.r. 92:8
(+/-)-4b, 80%, d.r. 84:16
H
H
N
Me
CO2Me
N
CO2Me
Me
(+/-)-4e, 95%, d.r. 95:5
(+/-)-4d, 89%, d.r. 89:11
1
Diastereoisomeric ratios were obtained by H NMR analysis and uncoupled 13C NMR analysis
without NOE.28 By extending ¹H NMR spectra in the region between 2.0 and 3.5 ppm, it was
possible to observe the presence of signals with very low intensity, which can possibly be attributed
to a minor diastereoisomer. By integrating the ¹³C NMR without NOE spectra signals, the same ratio
was found. In this way, the d.r. ratio was determined by ¹H NMR analysis followed by confirmation
using ¹³C NMR without NOE analysis (see Figure 86, in supporting information).
To confirm this observation, a GC-MS analysis of ( )-indolizidine 4c was performed, which
detected only two peaks with the same mass spectra. Integration of these peaks showed that same
ratio had occurred as that observed in the analysis of the ¹³C NMR without NOE data (see Figure
112, supporting information).
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Relative configurations of the diastereoisomeric centers 2 and 8a of our indolizidines were
determined via the spatial coupling between hydrogens 2, 3α and 8a observed by NOESY. Hydrogen
H3α couples spatially with H2, whereas H3α couples spatially with H8a. From these observations, a
cis relative configuration of hydrogens 2 and 8a could be determined. This relative stereochemistry
was observed in all indolizines synthesized in this work (Figure 1).
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Figure 1. NOESY data of indolizidines 4c, 4d and 4e.
Relative to indolizidine ( )-4d, a spatial coupling between hydrogens H8a and H7 could be
observed. Thus, a cis relative configuration between hydrogens 2, 7 and 8a could be assigned. For
indolizidine ( )-4e, a coupling between H3α and H5 could be detected, whereas H3β couples with
the methyl group bonded to carbon 5. Thus, a cis relative configuration between hydrogens 2, 5 and
8a could be assigned.
Some additional experiments were performed in this work to understand the participation of a strong
acid, such as TFA on the hydrogenation reactions. It is known that indolizines can be protonated on
carbons 1 and 3, which is associated with the strength and nature of the acid.29 Assuming this
characteristic, two ¹H NMR analyses of indolizine 2a were performed under different acidic
conditions, with CDCl3 as solvent: one analysis used acetic acid (pKa 4.76)30 and the other analysis
used TFA (pKa 0.23).30 In accordance with the obtained NMR spectra, no modification of the
indolizine structure was observed when it was treated by acetic acid (see, Figure 111-B in supporting
information). However, in addition to a rapid change of the solution's color from colorless to
yellowish, a significant modification of the indolidizine structure was observed when it was treated
with TFA, as evidencied by comparison with the ¹H NMR spectra of indolizine in the absence of this
strong acid (see, Figure 111-C in supporting information).
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A drastic alteration of the pattern of the aromatic hydrogens and the appearance of broad bands
downfield, which are superimposed with the hydrogens of the pyridinic ring moiety, were also
observed (see, Figure 111-D supporting information). These modifications can be rationalized by
assuming that the pyrrole portion of indolizine is protonated, as reported in a previous work.31
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Therefore, another ¹H NMR spectrum of 2a was obtained to confirm this protonation, this time using
TFA-d as the solvent. The complete disappearance of hydrogens 1 and 3 was observed because they
were exchanged for deuterium atoms. In this spectrum there were only four hydrogen signals in the
aromatic region beyond the signal of the methyl ester moiety, which refer to the four hydrogen atoms
present on the six-membered ring. In addition, an intensification of TFA residual signal was
observed (see supporting informations).
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From these NMR data, it can be concluded that TFA is sufficiently strong to protonate carbons 1 and
3 on indolizine and that this cationic intermediate is now susceptible to complete hydrogenation,
which can give the desired indolizidines (Scheme 5).
H
R
N
N
H2, PtO2
TFA
R
R
N
N
R
4a
2a
Scheme 5. Proposed pathways for hydrogenation
Another experiment used to understand the interesting behavior of these N-heterocycles was an
evaluation of the reactivity of these substrates against the hydrogenation catalysts used in this work.
Initially, the different behaviors of the catalysts were attributed to electronic factors. To confirm
these effects, indolizine 2a was reduced with LiAlH4 to 2o (83% yield),13 which was then subjected
to hydrogenation conditions using PtO2, Pd/C and Rh/Al2O3 in MeOH under hydrogen atmospheric
pressure. No reaction was observed when PtO2 and Pd/C were used as the catalysts, and the starting
material was recovered. By contrast, when Rh/Al2O3 was used as catalyst, the complete
hydrogenated product ( )-4f was obtained in 98% yield with a 66.5:33.5 cis/trans ratio (Scheme 6).
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The diastereoisomeric ratio was determined by comparing the obtained ¹H NMR spectra with known
spectra present in the literature.32
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These experiments led to the conclusion that the reactivity of indolizines with different
hydrogenation catalysts is also dependent on the electronic density of indolizine itself, which can be
modulated by the rational incorporation of substituents in the indolizine structure.
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Rh/Al2O3 5%
(10% m/m)
MeOH,
H
N
THF
LiAlH4 (1,5 eq.)
H2 (1 bar), 98%.
CO2Me
0 0C to rt, 83%
N
N
OH
OH
2o
2a
(+/-)-4f
66.5:33.5 (cis:trans)
Scheme 6. Full hydrogenation of indolizine mediated by rhodium, without the addition of acid
CONCLUSION
Herein, we described a simple and direct approach to synthesize 5,6,7,8-tetrahydroindolizines and
indolizidines using MBH adducts, as building blocks. During its development, it was discovered that
partial or full hydrogenation product formation could be modulated by a simple pH adjustment of the
reaction media. A special catalyst is not necessary and the reactions occur under low pressure and at
room temperature. Starting from MBH adducts, tetrahydroindolizines with a diverse substitution
pattern were obtained in overall yields ranging from 12% to 57%, whereas indolizidines were
obtained in overall yields ranging from 35% to 43%, with high diastereoselectivity that range from
84% to 95% in favor of cis diastereoisomer.
To more fully comprehend the reactivity and electronic characteristics of such indolizines,
theoretical calculations are currently underway.
EXPERIMENTAL SECTION
General protocol for preparation of MBH adducts (1a-l): To a mixture of aldehyde (5 mmol) and
acrylate or vinylketone (4 eq.) was added DABCO (0.65 eq.) and the solution was sonicated in the
ultrasound bath for 2-12 hours. After, the acrylate was removed and the crude residue was dissolved
in ethyl acetate (30 mL). The resulting solution was washed with distilled water (2 x 30 mL), brine
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(1 x 30 mL) and dried over anhydrous sodium sulfate, filtrated and concentrated. The crude product
was purified by column chromatography (silica flash, ethyl acetate 30 % to 100% in hexane) to give
the MBH adducts as a pure compounds. All adducts are known.
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Methyl 2-[hydroxy(pyridin-2-yl)methyl]prop-2-enoate (1a):9,33 0.89g, 93% yield; yellow oil. H
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NMR (250 MHz, CDCl3): δ 3.69 (s, 3H), 4.84 (sl, 1H), 5.59 (s, 1H), 5.93 (s, 1H), 6.32 (s, 1H), 7.17
(ddd, 1H, J = 0.8 Hz, 4.9 and 7.8 Hz), 7.38 (d, 1H, J = 7.8 Hz), 7.64 (td, 1H, J = 1.7 and 7.8 Hz),
8.50 (d, 1H, J = 4.9 Hz) ppm. 13C NMR (62.5 MHz, CDCl3): δ 52.0, 72.3, 121.5, 122.9, 127.0,
137.0, 141.9, 148.5, 159.7, 166.7 ppm.
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Ethyl 2-[hydroxy(pyridin-2-yl)methyl]prop-2-enoate (1b):11a,34 0.99 g, 96% yield; yellow oil. H
NMR (250 MHz, CDCl3): δ 1.18 (t, 3H, J = 7.1 Hz), 4.13 (q, 2H, J = 7.1 Hz), 4.87 (sl, 1H), 5.25 (s,
1H), 5.58 (s, 1H), 5.90 (s, 1H), 6.31 (s, 1H), 7.15 (ddd, 1H, J = 0.7, 4.8 and 7.7 Hz), 7.37 (d, 1H, J =
7.7 Hz), 7.62 (td, 1H, J = 1.7 and 7.7 Hz), 8.48 (d, 1H, J = 4.8 Hz) ppm. 13C NMR (62.5 MHz,
CDCl3): δ 14.2, 60.9, 72.4, 121.4, 122.7, 126.8, 136.9, 142.2, 148.4, 159.8, 166.2 ppm.
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Butyl 2-[hydroxy(pyridin-2-yl)methyl]prop-2-enoate (1c): 1.09 g, 93% yield; yellow oil. H
NMR (250 MHz, CDCl3): δ 0.83 (t, 3H, J = 7.3 Hz), 1.18-1.32 (m, 2H), 1.46-1.57 (m, 2H), 4.06 (t,
2H, J = 6.6 Hz), 4.93 (sl, 1H), 5.56 (s, 1H), 5.90 (s, 1H), 6.31 (s, 1H), 7.11-7.17 (m, 1H), 7.36 (d,
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1H, J = 7.8 Hz), 7.61 (td, 1H, J = 1.7 and 7.8 Hz), 8.47 (d, 1H, J = 4.2 Hz) ppm. C NMR (62.5
MHz, CDCl3): δ 13.8, 19.2, 30.6, 64.8, 72.4, 121.3, 122.7, 126.8, 136.9, 142.1, 148.3, 159.8, 166.3
ppm. HRMS (FT-MS) calcd. for C13H18NO3 (M+H)+ 236.12812, found: 236.12814.
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tert-Butyl 2-[hydroxy(pyridin-2-yl)methyl]prop-2-enoate (1d): 1.11 g, 95% yield; yellow oil. H
NMR (250 MHz, CDCl3): δ 1.35 (s, 9H), 4.83 (sl, 1H), 5.52 (s, 1H), 5.81 (s, 1H), 6.23 (s, 1H), 7.14
(dd, 1H, J = 4.8 and 7.7 Hz), 7.36 (d, 1H, J = 7.7 Hz), 7.62 (td, 1H, J = 1.7 and 7.7 Hz), 8.48 (d, 1H,
J = 4.8 Hz) ppm. 13C NMR (62.5 MHz, CDCl3): δ 28.1, 72.7, 81.4, 121.2, 122.6, 126.2, 136.9,
143.4, 148.3, 160.2, 165.5 ppm. HRMS (FT-MS) calcd. for C13H18NO3 (M+H)+ 236.12812, found:
236.12786.
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2-[Hydroxy(pyridin-2-yl)methyl]prop-2-enenitrile (1e):11a,21 0.76 g, 95% yield; pale yellow solid.
1H NMR (250 MHz, CDCl3): δ 5.27 (s, 1H), 6.02 (s, 1H), 6.19 (s, 1H), 7.27 (ddd, 1H, J = 0.6, 4.8
and 7.7 Hz), 7.38 (d, 1H, J = 7.7 Hz), 7.74 (td, 1H, J = 1.6 and 7.7 Hz), 8.54 (d, 1H, J = 4.8 Hz)
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ppm. C NMR (62.5 MHz, CDCl3): δ 73.1, 116.9, 121.4, 123.9, 125.9, 131.2, 137.6, 148.6, 156.3
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ppm.
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2-[Hydroxy(pyridin-2-yl)methyl]cyclopent-2-en-1-one (1f): 0.47 g, 50% yield; yellow solid. H
NMR (250 MHz, CDCl3): δ 2.39-2.44 (m, 2H), 2.52-2.60 (m, 2H), 4.99 (sl, 1H), 5.56 (s, 1H), 7.15-
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7.20 (m, 1H), 7.46-7.54 (m, 2H), 7.61-7.67 (m, 1H), 8.49 (d, 1H, J = 4.4 Hz) ppm. C NMR (62.5
MHz, CDCl3): δ 26.9, 35.5, 68.5, 121.5, 123.0, 137.2, 147.8, 148.3, 159.3, 160.2, 209.0 ppm. HRMS
(FT-MS) calcd. for C11H12NO2 (M+H)+ 190.08626, found 190.08615.
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Methyl 2-[hydroxy(quinolin-2-yl)methyl]prop-2-enoate (1g):11a,35 1.07 g, 88% yield; red oil. H
NMR (250 MHz, CDCl3): δ 3.71 (s, 3H), 5.25 (s, 1H), 5.77 (s, 1H), 5.97 (s, 1H), 6.37 (s, 1H), 7.43
(d, 1H, J = 8.4 Hz), 7.47-7.53 (m, 1H), 7.65-7.72 (m, 1H), 7.77 (dd, 1H, J = 0.8 and 8.4 Hz), 8.07 (t,
2H, J = 8.4 Hz) ppm. 13C NMR (62.5 MHz, CDCl3): δ 52.1, 72.0, 119.0, 126.7, 127.7, 129.0, 130.0,
137.2, 141.9, 146.5, 159.5, 166.8 ppm.
Methyl 2-[hydroxy(4-methylpyridin-2-yl)methyl]prop-2-enoate (1h): 0.88 g, 85% yield; white
solid. 1H NMR (250 MHz, CDCl3): δ 2.32 (s, 3H), 3.71 (s, 3H), 4.84 (sl, 1H), 5.54 (s, 1H), 5.92 (s,
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1H), 6.32 (s, 1H), 6.99 (d, 1H, J = 5.1 Hz), 7.18 (s, 1H), 8.35 (d, 1H, J = 5.1 Hz) ppm. C NMR
(62.5 MHz, CDCl3): δ 21.3, 52.1, 72.2, 122.1, 123.9, 127.0, 142.1, 148.1, 148.3, 159.5, 166.8 ppm.
HRMS (FT-MS) calcd. for C11H14NO3 (M+H)+ 208.09682, found: 208.09657.
Methyl 2-[hydroxy(4-ethylpyridin-2-yl)methyl]prop-2-enoate (1i): 1.09 g, 99% yield; colorless
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oil. H NMR (250 MHz, CDCl3): δ 1.21 (t, 3H, J = 7.6 Hz), 2.62 (q, 2H, J = 7.6 Hz). 3.71 (s, 3H),
4.81 (sl, 1H), 5.56 (s, 1H), 5.91 (s, 1H), 6.32 (s, 1H), 7.00-7.03 (m, 1H), 7.21 (s, 1H), 8.38 (d, 1H, J
= 5.0 Hz) 13C NMR (62.5 MHz, CDCl3): δ 14.4, 28.4, 51.9, 72.2, 120.9, 122.5, 126.8, 142.1, 148.2,
154.2, 159.6, 166.7 ppm. HRMS (FT-MS): calcd. for C12H16NO3 (M+H)+ 222.11247, found:
222.11241.
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Methyl 2-[hydroxy(5-methylpyridin-2-yl)methyl]prop-2-enoate (1j): 0.97 g, 94% yield; colorless
oil. 1H NMR (250 MHz, CDCl3): δ 2.30 (s, 3H), 3.71 (s, 3H), 4.72 (d, 1H, J = 6.4 Hz), 5.56 (d, 1H, J
= 6.4 Hz), 5.92 (s, 1H), 6.31 (s, 1H), 7.26-7.29 (m, 1H), 7.45 (dd, 1H, J = 1.5 and 8.0 Hz), 8.34 (s,
1H) ppm. 13C NMR (62.5 MHz, CDCl3): δ 18.2, 52.0, 72.1, 120.9, 126.7, 132.3, 137.6, 142.1, 148.7,
156.8, 166.8 ppm. HRMS (FT-MS) calcd. for C11H14NO3 (M+H)+ 208.09682, found: 208.09673.
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Methyl 2-[hydroxy(6-methylpyridin-2-yl)methyl]prop-2-enoate (1k):11a 0.92 g, 89% yield;
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colorless oil. H NMR (250 MHz, CDCl3): δ 2.53 (s, 3H), 3.72 (s, 3H), 5.16 (sl, 1H), 5.57 (s, 1H),
5.91 (s, 1H), 6.30 (s, 1H), 7.03 (d, 1H, J = 7.6 Hz), 7.13 (d, 1H, J = 7.6 Hz), 7.52 (t, 1H, J = 7.6 Hz)
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ppm. C NMR (62.5 MHz, CDCl3): δ 24.3, 52.0, 71.4, 118.2, 122.3, 126.7, 137.2, 142.3, 157.2,
158.5, 166.8 ppm.
Methyl 2-[(6-bromopyridin-2-yl)(hydroxy)methyl]prop-2-enoate (1l): 1.32 g, 97% yield;
colorless oil. 1H NMR (250 MHz, CDCl3): δ 3.73 (s, 3H), 4.20 (d, 1H, J = 7.0 Hz), 5.56 (d, 1H, J =
7.0 Hz), 5.94 (s, 1H), 6.36 (s, 1H), 7.36-7.41 (m, 1H), 7.49-7.55 (m, 1H) ppm. 13C NMR (62.5 MHz,
CDCl3): δ 52.2, 72.4, 120.3, 127.2, 127.6, 139.3, 141.0, 141.2, 161.5, 166.6 ppm. HRMS (FT-MS)
calcd. for C10H11BrNO3 (M+H)+ 271.99168 (79Br); 273.98963 (81Br), found: 271.9922 (79Br);
273.9902 (81Br)
General protocol for preparation of indolizines (2a-l): To a mixture of adducts 1a-l (3 mmol) and
pyridine (1.5 eq.) in anhydrous CH2Cl2 (5 mL) under nitrogen atmosphere at 0 °C, was added,
dropwise, acetyl chloride (1.5 eq.). The resulting mixture was stirred for 10 minutes at 0 °C. Then,
the reaction was warmed to room temperature and stirred for 1 hour more. After that, a saturated
solution of NaHCO3 (10 mL) was carefully added and the biphasic solution was stirred vigorously
for 30 minutes. Then, the organic layer was separated and the aqueous phase was extracted twice
with CH2Cl2 (10 mL each time). The organic phases were combined, washed with brine (1 x 30 mL),
dried over anhydrous sodium sulfate, filtrate and concentrated. The crude product was refluxed in
toluene (10 mL) for 12 hours. Then, the solvent was removed under reduced pressure, and the crude
product was purified by column chromatography (silica flash, ethyl acetate 10 % to 40% in hexane)
to furnish the corresponding indolizines.
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1
Methyl indolizine-2-carboxylate (2a): 0.29 g, 55 % yield; white solid. m.p. 101-102 °C. H NMR
(250 MHz, CDCl3): δ 3.86 (s, 3H), 6.49 (td, 1H, J = 1.1 and 7.1 Hz), 6.65 (ddd, 1H, J =1.1, 6.5 and
9.1 Hz), 6.79 (s, 1H), 7.32 (d, 1H, J = 9.1 Hz), 7.76 (d, 1H, J = 1.0 Hz), 7.82 (dd, 1H, J = 1.0 and 7.1
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Hz). C NMR (62.5 MHz, CDCl3): δ 51.6, 100.6, 112.4, 116.0, 118.3, 119.8, 120.4, 125.5, 132.9,
165.7. IR (KBr): ν 1713, 1634, 1571, 1541, 1849, 1216 cm-1 HRMS (FT-MS) calcd. for C10H10NO2
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(M+H)+ 176.07061, found: 176.07041.
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Ethyl indolizine-2-carboxylate (2b): 0.29 g, 52 % yield; gray solid, m.p. 63-64 °C. H NMR (250
MHz, CDCl3): δ 1.34 (t, 3H, J = 7.1 Hz), 4.32 (q, 2H, J = 7.1 Hz), 6.44 (t, 1H, J = 6.7 Hz), 6.60 (dd,
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1H, J = 6.7 and 9.1 Hz), 6.79 (s, 1H), 7.29 (d, 1H, J = 9.1 Hz), 7.75-7.79 (m, 2H) C NMR (62.5
MHz, CDCl3): δ 14.5, 60.2, 100.5, 112.2, 115.9, 115.9, 118.1, 120.1, 120.3, 125.4, 132.8, 165.2. IR
(KBr): ν 3123, 3062, 2996, 2979, 1694, 1544, 1519, 1500, 1350, 1304, 1252 cm-1. HRMS (FT-MS)
calcd. for C11H12NO2 (M+H)+ 190.08626, found: 190.08620.
Butyl indolizine-2-carboxylate (2c): 0.38 g, 59 % yield, yellow oil. 1H NMR (250 MHz, CDCl3): δ
0.96 (t, 3H, J = 7.3 Hz) 1.38-1.53 (m, 2H), 1.69-1.77 (m, 2H), 4.27 (t, 3H, J = 6.6 Hz), 6.47 (td, 1H,
J = 1.1 and 7.1 Hz), 6.63 (ddd, 1H, J = 0.9, 7.3 and 9.8 Hz), 6.81 (s, 1H), 7.31 (d, 1H, J = 9.1 Hz),
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7.76 (d, 1H, J = 0.8 Hz), 7.81 (dd, 1H, J = 0.9 and 7.1 Hz). C NMR (62.5 MHz, CDCl3): δ 13.9,
19.4, 31.0, 64.2, 100.5, 112.3, 115.9, 118.2, 120.2, 120.4, 125.5, 132.9, 165.4 ppm. IR (film): ν
3133, 2959, 2872, 1709, 1636, 1544, 1518, 1498, 1458, 1410, 1358, 1304 cm-1. HRMS (FT-MS)
calcd. for C13H16NO2 (M+H)+ 218.11756, found: 218.11781.
tert-Butyl indolizine-2-carboxylate (2d): 0.39 g, 60% yield; yellow solid, m.p: 42-43 °C. 1H NMR
(250 MHz, CDCl3): δ 1.57 (s, 9H), 6.48 (td, 1H, J = 1.2 and 7.0 Hz), 6.63 (ddd, 1H, J = 1.0, 6.5 and
9.0 Hz), 6.75 (s, 1H), 7.31 (d, 1H, J = 9.0 Hz), 7.70 (d, 1H, J = 1.2 Hz), 7.82 (dd, 1H, J = 1.0 and 7.0
Hz) ppm. 13C NMR (62.5 MHz, CDCl3): δ 28.5, 80.4, 100.6, 122.2, 115.8, 118.1, 120.4, 122.0,
125.5, 132.8, 164.7. IR (KBr): ν 3133, 2974, 2929, 1705, 1541, 1499, 1392, 1364, 1353, 1304 cm-1.
HRMS (TOF-MS) calcd. for C13H16NO2 (M+H)+ 218.11756, found: 218.11736.
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1
Indolizine-2-carbonitrile (2e): 0.13 g, 30 % yield; yellow solid, m.p: 69-70 ºC. H NMR (250
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MHz, CDCl3): δ 6.55-6.62 (m, 2H), 6.74 (dd, 1H, J = 7.0 and 9.1 Hz), 7.32 (d, 1H, J = 9.1 Hz), 7,62
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(s, 1H), 7.83 (d, 1H, J = 7.0 Hz). C NMR (62.5 MHz, CDCl3): δ 97.4, 102.6, 113.2, 116.6, 117.6,
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119.6, 119.8, 125.2, 132.8. IR (KBr): ν 2226, 1638, 1520, 1488, 1458, 1369, 1349, 1309, 1250,
1219, 1188, 1141, 1121 cm-1 HRMS (FT-MS): calcd. for C9H7N2 (M+H)+ 143.06037, found:
143.06023.
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1H,2H,3H-cyclopenta[b]indolizin-1-one (2f): 0.33g, 65 % yield; yellow solid, m.p.: 156-157 °C.
1H NMR (250 MHz, CDCl3): δ 2.95-2.99 (m, 2H), 3.03-3.07 (m, 2H), 6.44 (s, 1H), 6.51 (td, 1H, J =
1.1 and 7.0 Hz), 6.65 (ddd, 1H, J = 0.8, 6.6 and 9.3 Hz), 7.31 (d, 1H, J = 9.3 Hz), 7.63 (dd, 1H, J =
1.0 and 7.0 Hz). 13C NMR (62.5 MHz, CDCl3): δ 20.0, 41.4, 92.0, 112.1, 119.0, 121.8, 122.8, 129.5,
139.1, 147.9, 198.8. IR (KBr): ν 3128, 2921, 1678, 1631, 1529, 1472, 1451 cm-1. HRMS (FT-MS):
calcd. for C11H10NO (M+H)+172.07569, found: 172.07581.
Methyl pyrrolo[1,2-a]quinoline-2-carboxylate (2g): 0.30 g, 45 % yield; white solid, m.p. 110-111
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°C. H NMR (250 MHz, CDCl3): δ 3.89 (s, 3H), 6.88 (d, 1H, J = 1.4 Hz), 6.97-7.01 (m, 1H), 7.22-
7.26 (m, 1H), 7.31-7.37 (m, 1H), 7.47-7.54 (m, 1H), 7.61 (dd, 1H, J = 1.1 and 7.7 Hz), 7.88 (d, 1H, J
= 8.5 Hz), 8.36 (s, 1H) ppm. 13C NMR (62.5 MHz, CDCl3): δ 51.7, 103.9, 114.6, 116.1, 119.2,
119.3, 120.5, 124.5, 125.0, 128.5, 129.0, 131.5, 133.2, 165.6. IR (KBr): ν 1711, 1528, 1500, 1435,
1421 cm-1 HRMS (FT-MS): calcd. for C14H12NO2 (M+H)+ 226.08626, found: 226.08634.
Methyl 7-methylindolizine-2-carboxylate (2h): 0.22 g, 39% yield; white solid, m.p. 111-112 °C.
1H NMR (250 MHz, CDCl3): δ 2.22 (s, 3H), 3.85 (s, 3H), 6.33 (dd, 1H, J = 7.2 and 1.1 Hz), 6.64 (s,
1H), 7.06 (s, 1H), 7.64 (d, 1H, J = 1.1 Hz), 7.72 (d, 1H, J = 7.2 Hz). 13C NMR (62.5 MHz, CDCl3):
δ 21.2, 51.6, 98.9, 115.4, 115.4, 115.5, 118.2, 119.8, 125.0, 128.4, 133.3, 165.9. IR (KBr): ν 1716,
1545.9, 1491, 1446, 1403, 1301, 1318, 1215 cm-1 HRMS (FT-MS): calcd. for C11H12NO2 (M+H)+
190.08626, found: 190.08624.
Methyl 7-ethylindolizine-2-carboxylate (2i): 0.27 g, 44% yield; pale yellow solid, m.p. 49-50 °C.
1H NMR (250 MHz, CDCl3): δ 1.20 (t, 3H, J = 7.5 Hz), 2.52 (q, 2H, J = 7.5 Hz), 3.85 (s, 3H), 6.37
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(dd, 1H, J = 1.6 and 7.2 Hz), 6.67 (s, 1H), 7.07 (s, 1H), 7.69-7.70 (m, 1H), 7.74 (d, 1H, J = 7.2 Hz).
13C NMR (62.5 MHz, CDCl3): δ 14.4, 28.3, 51.6, 99.2, 114.4, 115.4, 116.7, 119.8, 125.2, 133.4,
134.6, 165.9. IR (KBr): ν 3133, 2963, 1701, 1544, 1492, 1473, 1459, 1438, 1406, 1359, 1323, 1222
cm-1. HRMS (TOF-MS): calcd. for C12H14NO2 (M+H)+ 204.1024, found: 204.1019.
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Methyl 6-methylindolizine-2-carboxylate (2j): 0.22 g, 39% yield; white solid, m.p. 82-83 °C. H
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NMR (250 MHz, CDCl3): δ 2.18 (s, 3H), 3.85 (s, 3H), 6.51 (d, 1H, J = 9.0 Hz), 6.74 (s, 1H), 7.24 (d,
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1H, 9.0 Hz), 7.61 (s, 1H), 7.68 (s, 1H). C NMR (62.5 MHz, CDCl3): δ 18.5, 51.6, 100.4, 115.7,
119.3, 119.9, 121.9, 122.8, 131.9, 165.9. IR (KBr): ν 1716, 1545, 1491, 1445, 1403, 1300, 1318,
1215, 1096 cm-1 HRMS (FT-MS): calcd. for C11H12NO2 (M+H)+ 190.08626, found: 190.08620.
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Methyl 5-methylindolizine-2-carboxylate (2k): 0.23 g, 41% yield, white solid, m.p. 59-60 °C. H
NMR (250 MHz, CDCl3): δ 2.46 (s, 3H), 3.88 (s, 3H), 6.38 (d, 1H, J = 6.6 Hz), 6.67 (dd, 1H, J = 6.6
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and 9.1 Hz), 6.88 (d, 1H, J = 1.4 Hz), 7.29 (d, 1H, J = 9.1 Hz), 7.69 (s, 1H). C NMR (62.5 MHz,
CDCl3): δ 18.6, 51.6, 101.2, 111.5, 113.2, 118.1, 118.7, 119.7, 133.2, 133.7, 165.9. IR (KBr): ν
1717, 1546, 1500, 1438, 1422, 1382, 1360, 1218, 1154 cm-1 HRMS (TOF-MS): calcd. for
C11H12NO2 (M+H)+ 190.0863, found: 190.0868.
Methyl 5-bromoindolizine-2-carboxylate (2l): 0.29 g, 38% yield; pale yellow solid, m.p. 83-84 °C.
1H NMR (250 MHz, CDCl3): δ 3.88 (s, 3H), 6.55-6.61 (m, 1H), 6.82-6.84 (m, 1H), 6.99 (s, 1H),
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7.37 (d, 1H, J = 8.7 Hz), 8.07 (s, 1H). C NMR (62.5 MHz, CDCl3): δ 51.8, 103.0, 114.8, 116.5,
117.2, 118.5, 119.5, 120.1, 134.5, 165.4. IR (KBr): ν 1723, 1623, 1543, 1506, 1493, 1203, 1230 cm-
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1. HRMS (FT-MS): calcd. for C10H9 BrNO2 (M+H)+ 253.98112 and C10H9 BrNO2 (M+H)+:
255.97907, found: 253.98166 (79Br) and 255.97961 (81Br).
Preparation of 1-(Indolizin-2-yl)ethan-1-one (2m):36 To a solution of pyridine-2-carboxaldehyde
(0.101 g, 1 mmol) and methyl vinyl ketone (0.075 g, 1 mmol) in CH3CN:H2O (2 mL, 99:1 v/v) was
added TMSOTf (1 mmol) at 0 °C. Then, the reaction was raised up to room temperature and was
stirred for 12 hours. After that, the reaction medium was diluted with diethyl ether (10 mL) and was
added saturated solution of NaHCO3 (10 mL). The organic layer was separated and aqueous layer
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was washed twice with diethyl ether (5 mL). The organic layers were combined and washed with
water (2 x 15 mL), brine (1 x 15 mL) and dried over anhydrous sodium sulfate, filtrated and
concentrated. The crude product was purified by column chromatography (silica flash, ethyl acetate
5 % to 40 % in hexane) to furnish a pure material as a white solid. 0.079 g, 35% yield. 1H NMR (250
MHz, CDCl3): δ 2.51 (s, 3H), 6.50 (td, 1H, J = 1.1 and 7.0 Hz), 6.64 (ddd, 1H, J = 0.8, 6.5 and 8.9
Hz), 6.75 (s, 1H), 7.31 (d, 1H, J = 8.9 Hz), 7.72 (d, 1H, J = 1.1 Hz), 7.81 (dd, 1H, J = 0.8 and 7.0
Hz) ppm. 13C NMR (62.5 MHz, CDCl3): δ 27.8, 99.7, 112.8, 115.4, 118.6, 120.7, 125.7, 128.6,
133.3, 195.2.
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Preparation of 6H,7H,8H,9H-pyrido[1,2-a]indol-9-one (2n): To a solution of pyridine-2-
carboxaldehyde (0.107 g, 1 mmol) in THF:H2O (2 mL 1:1 v/v) was added DMAP (0.060 g, 0.49
mmol) and 2-cyclohexenone (0.25 mL, 2.6 mmol). Then the reaction was stirred at room
temperature for 96 h. After that, the solvent was removed under low vaccum pressure and the crude
material was purified by column chromatography (silica flash, ethyl acetate 50 % to 100% in
hexane) to give the desired MBH adduct. 0.092 g, 40% yield; yellow solid, m.p. 87-88 °C. 1H NMR
(250 MHz, CDCl3): δ 2.23-2.33 (m, 2H), 2.58-2.63 (m, 2H), 2.94 (t, 2H, J = 6.2 Hz), 6.54 (td, 1H, J
= 1.0 and 7.0 Hz), 6.64 (ddd, 1H, J = 1.0, 6.4 and 8.9 Hz), 6.73 (s, 1H), 7.34 (d, 1H, J = 8.9 Hz),
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7.61 (dd, 1H, J = 1.0 and 7.0 Hz). C NMR (62.5 MHz, CDCl3): δ 21.2, 23.8, 38.8, 95.5, 112.4,
118.2, 121.2, 122.4, 123.4, 132.2, 133.1, 196.2. IR (KBr): ν 3073, 2944, 2869, 2832, 1661, 1537,
1465, 1448, 1416, 1363, 1331, 1304, 1245, 1214 cm-1. HRMS (FT-MS): calcd. for C12H12NO
(M+H)+ 186.09134, found: 186.09156.
Preparation of indolizin-2-ylmethanol (2o): To a solution of 2a (0.176 g, 1.0 mmol) in dry THF (5
mL) was added LiAlH4 (2.0 mmol) at 0 °C. After 1 hour at 0 °C, the solution was warmed to room
temperature and stirred for 1 hour. Then, distilled water (0.5 mL) was added carefully and the
mixture was filtered in a plug of K2CO3 and celite, and the cake was washed with dry THF. The
solution was concentrated, and the crude material was purified by column chromatography (silica
flash, ethyl acetate 60 % to 100% in hexane) to furnish 2o, as a solid (0.122 g). Yield 83%, white
solid, m.p. 106-107 °C. 1H NMR (250 MHz, DMSO-d6): δ 4.55 (d, 2H, J = 5.5 Hz), 4.91 (t, 1H, J =
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5.5 Hz), 6.29 (s, 1H), 6.45 (td, 1H, J = 0.9 and 6.9 Hz), 6.62 (ddd, 1H, J = 0.9, 6.9 and 9.0 Hz), 7.31
(d, 1H, J = 9.0 Hz), 7.42 (s, 1H), 8.17 (dd, 1H, J = 0.9 and 6.9 Hz) ppm. 13C NMR (62.5 MHz,
CDCl3): δ 59.3, 98.1, 110.5, 110.9, 117.4, 119.2, 125.3, 129.4, 133.3 ppm. IR (film): ν 3407, 2924,
2866, 1685, 1654, 1560, 1541, 1508, 1458, 1362, 1292, 1137 cm-1. HRMS (TOF-MS): calcd. for
C9H10NO (M+H)+ 148.07569, found: 148.07558.
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General procedure for the partial hydrogenation of indolizines: To a mixture of indolizines 2a-n
(0.25 mmol) in CH3OH (5 mL) was added PtO2 (0.02 mmol, 10 mol%) and the atmosphere was
replaced with N2, followed by H2. The reactions wee stirred vigorously for 2-48 hours at room
temperature. Then, the reaction medium was filtrated in a plug of celite and the filtrate was
concentrated. The crude product was purified by column chromatography (silica flash, ethyl acetate
10 % to 40% in hexane) to give the corresponding tetrahydroindolizines.
Methyl 5,6,7,8-tetrahydroindolizine-2-carboxylate (3a): 0.042 g, yield 93 %; white solid, m.p. 73-
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74 °C. H NMR (250 MHz, CDCl3): δ 1.74-1.83 (m, 2H), 1.87-1.96 (m, 2H), 2.72 (t, 2H, J = 6.1
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Hz), 3.75 (s, 3H), 3.91 (t, 2H, J = 12.1 Hz), 6.21 (d, 1H, J = 1.3 Hz), 7.11 (d, 1H, J = 1.3 Hz) C
NMR (62.5 MHz, CDCl3): δ 21.3, 23.3, 23.7, 46.0, 51.1, 105.8, 115.1, 124.4, 130.4, 165.8 IR (KBr):
ν 3122, 2945, 1700, 1559, 1521, 1466, 1437, 1391, 1204 cm-1. HRMS (TOF-MS): calcd. for
C10H14NO2 (M+H)+ 180.1024, found: 180.1020.
Ethyl 5,6,7,8-tetrahydroindolizine-2-carboxylate (3b): 0.044 g, yield 91 %; colorless oil. 1H NMR
(250 MHz, CDCl3): δ 1.29 (t, 3H, J = 7.1 Hz), 1.73-1.83 (m, 2H), 1.86-1.96 (m, 2H), 2.71 (t, 2H, J =
6.5 Hz), 3.90 (t, 2H, J = 12.0 Hz), 4.22 (q, 3H, J = 7.1 Hz), 6.21 (s, 1H), 7.11 (d, 1H, J = 1.7 Hz),
13C NMR (62.5 MHz, CDCl3): δ 14.6, 21.2, 23.2, 23.7, 45.9, 59.6, 115.5, 124.2, 130.3, 165.4, IR
(film): ν 2945, 2868, 1704, 1561, 1519, 1470, 1455, 1406, 1383, 1322 cm-1. HRMS (FT-MS): calcd.
for C11H16NO2 (M+H)+ 194.11756, found: 194.11777.
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Butyl 5,6,7,8-tetrahydroindolizine-2-carboxylate (3c): 0.052 g, yield 95 %; yellow oil. H NMR
(250 MHz, CDCl3): δ 0.92 (t, 3H, J = 7.3 Hz), 1.33-1.48 (m, 2H), 1.59-1.71 (m, 2H), 1.73-1.83 (m,
2H), 1.85-1.95 (m, 2H), 2.71 (t, 2H, J = 6.1 Hz), 3.90 (t, 2H, J = 12.0 Hz), 4.17 (t, 3H, J = 6.6 Hz),
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6.21 (s, 1H), 7.10 (d, 1H, J = 1.7 Hz), 13C NMR (62.5 MHz, CDCl3): δ 13.9, 19.4, 21.2, 23.2, 23.7,
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31.1, 45.9, 63.5, 105.7, 115.5, 124.2, 130.3, 165.4 ppm. IR (film): ν 2955, 2871, 1704, 1561, 1519,
1470, 1456, 1407, 1389, 1322 cm-1. HRMS (ESI): calcd. for C13H20NO2 (M+H)+ 222.14886, found:
222.14897.
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tert-Butyl 5,6,7,8-tetrahydroindolizine-2-carboxylate (3d): 0.052 g, yield 95 %; white solid, 63-
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2H, J = 6.1 Hz), 3.89 (t, 2H, J = 5.9 Hz), 6.17 (s, 1H), 7.04 (s, 1H) ppm.13C NMR (62.5 MHz,
CDCl3): δ 21.3, 23.3, 23.8, 28.6, 46.0, 79.3, 105.8, 117.3, 124.0, 130.1, 164.9 ppm. IR (film): ν
2977, 2964, 2937, 2877, 1697, 1520, 1473, 1457, 1448, 1400, 1390, 1367, 1324, 1222 cm-1. HRMS
(FT-MS): calcd. for C13H20NO2 (M+H)+ 222.14886, found: 222.14864.
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5,6,7,8-Tetrahydroindolizine-2-carbonitrile (3e): 0.016 g, yield 40 %, purple oil. H NMR (250
MHz, CDCl3): δ 1.75-1.85 (m, 2H), 1.88-1.98 (m, 2H), 2.71 (t, 2H, J = 6.1 Hz), 3.91 (t, 2H, J = 12.1
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Hz), 6.04 (s, 1H), 6.95 (d, 1H, J = 1.6 Hz) ppm. C NMR (62.5 MHz, CDCl3): δ 20.9, 23.0, 23.5,
46.1, 92.0, 107.8, 117.6, 126.2, 130.8 ppm. IR (film): ν 3116, 2953, 2897, 2861, 2219, 1556, 1514,
1470, 1455, 1384, 1193, 1153, 1126 cm-1, HRMS (FT-MS): calcd. for C9H11N2 (M+H)+ 147.09168,
found: 147.09166.
1H,2H,3H,5H,6H,7H,8H-cyclopenta[b]indolizin-1-one (3f): 0.040 g, yield 91 %; white solid, m.p.
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141-142 °C. H NMR (250 MHz, CDCl3): δ 1.72-1.81 (m, 2H), 1.88-1.98 (m, 2H), 2.71-2.76 (m,
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6H), 3.81 (t, 2H, J = 6.1 Hz), 5.90 (s, 1H) ppm. C NMR (62.5 MHz, CDCl3): δ 20.2, 20.9, 23.3,
24.2, 41.1, 43.7, 98.4, 126.0, 137.5, 158.6, 196.6 ppm. IR (KBr): ν 2953, 2890, 1661, 1556, 1538,
1517, 1488, 1471, 1455 cm-1. HRMS (FT-MS): calcd. for C11H14NO (M+H)+ 176.10699, found:
176.10690.
Methyl 5H,6H-pyrrolo[1,2-a]quinoline-8-carboxylate (3g): 0.038 g, Yield 67 %. Colorless oil. 1H
NMR (250 MHz, Acetone-d6): δ = 2.91 (s, 4H) 3.76 (s, 3H), 6.36 (s, 1H), 7.15-7.21 (m, 1H), 7.32-
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7.38 (m, 2H), 7.65-7.68 (m, 1H), 7.91 (d, 1H, J = 1.6 Hz) ppm. C NMR (62.5 MHz, CDCl3): δ
22.2, 26.9, 51.4, 106.7, 115.8, 116.9, 119.9, 125.4, 127.9, 128.6, 129.4, 130.8, 136.0, 165.5 ppm. IR
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(film): ν 3054, 2987, 1707, 1524, 1497, 1438, 1422 cm-1 HRMS (FT-MS): calcd. for C14H14NO2
(M+H)+ 228.10191, found: 228.10195 (NOTE: This product and the starting material present the
same Rf).
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1.82-1.92 (m, 2H), 2.21-2.32 (m, 1H), 2.84 (dd, 1H, J = 4.5 and 16.0 Hz), 3.75 (s, 3H), 3.85 (td, 1H,
J = 4.5 and 11.4 Hz), 3.97-4.06 (m, 1H), 6.19 (s, 1H), 7.12 (s, 1H, J = 1,6 Hz) ppm. 13C NMR (62.5
MHz, CDCl3): δ 21.5, 28.0, 31.6, 31.7, 45.4, 51.1, 105.6, 115.4, 124.2, 130.5, 165.8 ppm. IR (KBr):
ν 2954, 2893, 1705, 1517, 1447, 1386 cm-1. HRMS (FT-MS): calcd. for C11H16NO2 (M+H)+
194.11755, found: 194.11762.
Methyl 7-ethyl-5,6,7,8-tetrahydroindolizine-2-carboxylate (3i): 0.042 g, yield 81%; white solid,
m.p. 50-51 °C. 1H NMR (250 MHz, CDCl3): δ 0.94 (t, 3H, J = 7.2 Hz), 1.37-1.43 (m, 2H), 1.60-1.63
(m, 2H), 1.97-2.02 (m, 1H), 2.22-2.32 (m, 1H), 2.85-2.92 (m, 1H), 3.76 (s, 3H), 3.85-3.89 (m, 1H),
4.00-4.05 (m, 1H), 6.20 (s, 1H), 7.12 (s, 1H) ppm. 13C NMR (62.5 MHz, CDCl3): δ 11.5, 28.7, 29.5,
34.7, 45.5, 51.1, 105.7, 115.4, 124.1, 130.6, 165.8 ppm. IR (KBr): ν 2959, 2925, 2961, 2854, 1710,
1559, 1521, 1465, 1437, 1394, 1245, 1207 cm-1. HRMS (TOF-MS): calcd. for C12H18NO2 (M+H)+
208.1333, found: 208.1338.
Methyl 6-methyl-5,6,7,8-tetrahydroindolizine-2-carboxylate (3j): 0.038 g, yield 79%; colorless
oil. 1H NMR (250 MHz, CDCl3): δ 1.05 (d, 3H, J = 6.6 Hz), 1.37-1.48 (m, 1H), 1.87-2.00 (m, 2H),
2.59-2.73 (m, 1H), 2.79-2.89 (m, 1H), 3.37-3.46 (m, 1H), 3,69 (dd, 1H, J = 4.8 and 12.2 Hz), 3.75
(s, 3H), 6.22 (s, 1H), 7.09 (s, 1H) ppm. 13C NMR (62.5 MHz, CDCl3): δ 19.0, 22.7, 29.6, 29.7, 51.1,
52.7, 105.6, 115.3, 124.2, 130.0, 165.8 ppm. IR (KBr): ν 2954, 2928, 2851, 1710, 1561, 1465, 1440,
1394, 1210 cm-1. HRMS (TOF-MS): calcd. for C11H16NO2 (M+H)+ 194.1176, found: 194.1172.
Methyl 5-methyl-5,6,7,8-tetrahydroindolizine-2-carboxylate (3k): 0.039 g, yield 80%, colorless
oil. 1H NMR (250 MHz, CDCl3): δ 1.45 (d, 3H, J = 6.5 Hz), 1.57-1.73 (m, 2H), 1.86-1.95 (m, 1H),
1.98-2.08 (m, 1H), 2.58-2.79 (m, 2H), 3.75 (s, 3H), 3.97-4.10 (m, 1H), 6.19 (s, 1H), 7.26 (d, 1H, J =
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1.8 Hz) ppm. 13C NMR (62.5 MHz, CDCl3): δ 19.7, 22.4, 23.6, 31.8, 51.1, 51.3, 105.6, 115.0, 122.8,
130.8, 165.8 ppm. IR (KBr): ν 2954, 2928, 2851, 1710, 1561, 1465, 1440, 1394, 1210 cm-1. HRMS
(TOF-MS): calcd. for C11H16NO2 (M+H)+ 194.1176, found: 194.1170.
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1-(5,6,7,8-Tetrahydroindolizin-2-yl)ethan-1-one (3l): 0.026 g, yield 65 %, pale yellow solid, m.p.
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57-58 °C. H NMR (250 MHz, CDCl3): δ 1.74-1.82 (m, 2H), 1.91-1.97 (m, 2H), 2.32 (s, 1H), 2.72
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(t, 2H, J = 6.2 Hz), 3.92 (t, 2H, J = 6.0 Hz), 6.22 (s, 1H), 7.09 (d, 1H, J = 1.4 Hz) ppm. C NMR
(62.5 MHz, CDCl3): δ 21.2, 23.2, 23.7, 27.1, 46.1, 104.9, 124.4, 125.4, 131.1, 193.7 ppm. IR
(KBr): ν 2942, 2869, 1649, 1518, 1556, 1469, 1441, 1399, 1383 cm-1. HRMS (FT-MS): calcd. for
C10H14NO (M+H)+ 164.10699, found: 164.10680.
1H,2H,3H,4H,6H,7H,8H,9H-pyrido[1,2-a]indol-9-one (3m): 0.042 g, yield 90 %, white solid,
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m.p. 106-107 °C. H NMR (250 MHz, CDCl3): δ 1.72-1.82 (m, 2H), 1.89-1.99 (m, 2H), 2.04-2.14
(m, 2H), 2.37-2.43 (m, 2H), 2.72 (t, 2H, J = 6.3 Hz), 2.65 (t, 2H, J = 6.2 Hz), 3.76 (t, 2H, J = 6.1
Hz), 6.16 (s, 1H) ppm. 13C NMR (62.5 MHz, CDCl3): δ 21.0, 21.5, 23.4, 23.6, 23.8, 38.1, 43.3,
101.1, 119.9, 131.0, 142.4, 194.2 ppm. IR (KBr): ν 2954, 2890, 1743, 1635, 1592, 1573, 1473, 1438
cm-1. HRMS (ESI): calcd. for C12H16NO (M+H)+ 190.12264, found: 190.12292
General Protocol for the full hydrogenation of indolizines: To a mixture of indolizine (1 mmol) in
CH3OH:TFA (5 mL 1:1 v/v) was added PtO2 (0.1 mmol, 10 mol%) and the solution was placed in a
glass autoclave. The air was removed by flushing a stream of H2. Internal pressure was adjusted to 5
bar of H2, before being reducing to 1 bar by carefully releasing stop valve. This procedure was
repeated for three times and finally the vessel was pressurized to 5 bar. The reaction was stirred
vigorously for 4 hours. After carefully venting the hydrogen gas, the solution was filtrated in a plug
of celite and the solution was concentrated. Then the crude material was diluted with CH2Cl2 (10
mL) and neutralized with satured solution NaHCO3 (10 mL). The aqueous phase was extracted with
CH2Cl2 (3 x 10 mL). The organic phases were combined and washed with brine (1 x 30 mL), dried
with anhydrous sodium sulfate, filtrated and concentrated. The crude product was purified by
column chromatography (silica flash, methanol 0 % to 5% in dichloromethane) to furnish the
required indolizidines.
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Methyl octahydroindolizine-2-carboxylate (4a): 0.143 g, yield 78%; pale green oil. 1H NMR (500
MHz, C6D6): δ 0.98-1.05 (m, 1H), 1.18-1.26 (m, 1H), 1.36-1.39 (m, 1H), 1.49-1.58 (m, 4H), 1.69-
1.74 (m, 1H), 1.88-1.91 (m, 2H), 2.06 (t, 1H, J = 9.1 Hz), 2.60 (qd, 1H, J = 2.1 and 9.1 Hz), 2.88-
2.90 (m, 1H), 3.33 (s, 3H), 3.46 (dd, 1H, J = 2.1 and 9.1 Hz) ppm. 13C NMR (150 MHz, CDCl3): δ
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24.3, 25.2, 30.6, 35.2, 39.8, 52.1, 52.9, 56.8, 64.6, 175.9 ppm. IR (film): ν 2932, 2854, 2785, 2753,
2725, 1739, 1436, 1383, 1341, 1266, 1175 cm-1. HRMS (TOF-MS): calcd. for C10H18NO2 (M+H)+
184.1338, found: 184.1345.
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Ethyl octahydroindolizine-2-carboxylate (4b): 0.158 g, yield 80%, pale green oil. H NMR (600
MHz, C6D6): δ 0.95 (t, 3H, J = 7.2 Hz), 0.98-1.03 (m, 1H), 1.24-1.28 (m, 1H), 1.36-1.39 (m, 1H),
1.52-1.57 (m, 4H), 1.70-1.74 (m, 1H), 1.88-1.96 (m, 2H), 2.08 (t, 1H, J = 9.6 Hz), 2.60-2.65 (m,
1H), 2.91-2.92 (m, 1H), 3.52 (dd, 1H, J = 2.4 and 9.6 Hz), 3.96 (q, 2H, J = 7.2 Hz) ppm. 13C NMR
(125 MHz, CDCl3): δ 14.6, 25.0, 25.9, 31.2, 35.5, 40.4, 53.0, 57.2, 60.8, 64.7, 175.0 ppm. IR (film):
ν 2932, 2856, 2786, 2754, 2726, 1737, 1449, 1384, 1370, 1341, 1278, 1182 cm-1. HRMS (TOF-MS):
calcd. for C11H20NO2 (M+H)+ 198.1489, found: 198.1494.
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tert-Butyl octahydroindolizine-2-carboxylate (4c): 0.207 g, yield 92%; pale green oil. H NMR
(600 MHz, C6D6): δ 0.98-1.05 (m, 1H), 1.22-1.28 (m, 1H), 1.36-1.37 (m, 10H), 1.51-1.58 (m, 4H),
1.71-1.75 (m, 1H), 1.88-1.92 (m, 2H), 2.11 (t, 1H, J = 9.1 Hz), 2.64 (qd, 1H, J = 2.3 and 9.1 Hz),
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2.91-2.92 (m, 1H), 3.52 (dd, 1H, J = 2.3 and 9.1 Hz) ppm. C NMR (125 MHz, CDCl3): δ 24.4,
25.3, 28.3, 30.7, 35.4, 40.7, 53.0, 56.7, 64.6, 80.3, 174.7 ppm. IR (film): ν 2975, 2932, 2857, 2785,
2752, 1732, 1449, 1367, 1331, 1321, 1279, 1262, 1216, 1153 cm-1. HRMS (TOF-MS): calcd. for
C13H24NO2 (M+H)+ 226.1802, found: 226.1807.
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Methyl 7-methyloctahydroindolizine-2-carboxylate (4d): 0.171 g, yield 87%; pale green oil. H
NMR (600 MHz, C6D6): δ 0.83 (d, 3H, J = 6.4 Hz), 0.90-0.99 (m, 2H), 1.21-1.28 (m, 1H), 1.36-1.40
(m, 1H), 1.49-1.60 (m, 2H), 1.74 (td, 1H, J = 2.6 and 11.2 Hz), 1.87-1.90 (m, 2H), 2.06 (t, 1H, J =
9.1 Hz), 2.64 (qd, 1H, J = 2.1 e 9.1 Hz), 2.87-2.90 (m, 1H), 3.46 (dd, 1H, J = 2.1 e 9.1 Hz) ppm. 13C
NMR (125 MHz, CDCl3): δ 22.5, 31.8, 34.7, 35.4, 39.8, 40.8, 51.7, 52,5, 57.0, 64.6, 175.5 ppm. IR
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(film): ν 2950, 2923, 2871, 2850, 2793, 1742, 1456, 1435, 1376, 1333, 1202, 1191 cm-1. HRMS
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(TOF-MS): calcd. for C11H20NO2 (M+H)+ 198.1489, found: 198.1494.
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Methyl 5-methyloctahydroindolizine-2-carboxylate (4e): 0.168 g, yield 85%, pale green oil. H
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NMR (600 MHz, C6D6): δ 1.01 (d, 3H, J = 6.2 Hz) 1.09-1.25 (m, 3H), 1.35-1.38 (m, 1H), 1.53-1.58
(m, 2H), 1.61-1.67 (m, 1H), 1.78-1.83 (m, 1H), 1.88-1.91 (m, 2H), 2.01 (t, 1H, J = 9.2 Hz), 2.61 (qd,
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1H, J = 2.4 and 9.2 Hz), 3.65 (dd, 1H, J = 2.4 and 9.2 Hz) ppm. C NMR (125 MHz, CDCl3): δ
21.6, 25.2, 31.3, 34.7, 35.6, 40.0, 51.7, 54.9, 58.9, 65.0, 175.5 ppm. IR (film): ν 2951, 2930, 2851,
2790, 1750, 1450, 1455, 1370 cm-1. HRMS (ESI): calcd. for C11H20O2N (M+H)+ 198.1489, found:
198.1495.
Preparation of (octahydroindolizin-2-yl)methanol (4f): To a mixture of indolizine 2o (0.029 g,
0.20 mmol) in CH3OH (5 mL) was added Rh/Al2O3 (0.003 g, 10 % m/m) and the atmosphere was
replaced with N2, followed by H2. The reaction was stirred vigorously for 6 hours at room
temperature. Then, the solution was filtrated in a celite plug and the filtrate was concentrated. The
crude product was purified by column chromatography (silica flash, methanol 10 % in
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dichloromethane) to furnish a pure material, as a yellow oil (0.030 g, 98%). H NMR (250 MHz,
CDCl3): δ (Major isomer - cis) 3.02-2.98 (m, 2H), (Minor isomer - trans) 2.86 (d, 2H, J = 8.1 Hz),
3.14-3.20 (m, 1H) ppm. 13C NMR (125 MHz, CDCl3): δ (Major isomer - cis) 25.3, 30.9, 34.2, 36.7,
53.0, 58.4, 64.9, 67.5, (Minor isomer - trans) 25.3, 30.8, 34.4, 37.5, 53.1, 58.4, 63.6, 66.0 ppm. IR
(film): ν 3404, 2932, 2857, 2795, 2730, 1471, 1450, 1385, 1331, 1317, 1272, 1264, 1227, 1190,
1140 cm-1. HRMS (ESI): calcd for C9H18NO (M+H)+ 156.1383, found: 156.1388.
ASSOCIATED CONTENT
Supporting Information
1H and 13C-NMR spectra for all compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
* E-mail: coelho@iqm.unicamp.br.
Author Contributions
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The manuscript was written through contributions of all authors. / All authors have given approval to
the final version of the manuscript. /
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ACKNOWLEDGMENT
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Authors thank Fapesp and CNPq for financial support. BVMT thanks CNPq for fellowship and
JTMC thanks Fapesp for fellowship (Process 2012/21809-0). Authors thank Prof. Cláudio F.
Tormena for NMR suggestions and discussions and for Nicolas Schwab for HRMS analyses.
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REFERENCES
(1) (a) Michael, J. P. Nat. Prod. Rep. 2008, 25, 139-165; (b) Michael, J. P. Nat. Prod. Rep.
2007, 24, 191-222.
(2) (a) Kim, N. –S.; Choi, J. –R.; Cha, J. K. J. Org. Chem. 1993, 58, 7096-7099; (b) Martín,
R.; Murruzzu, C.; Pericàs, M. A.; Riera, A. J. Org. Chem. 2005, 70, 2325-2328.
(3) Zhang, S.; Xu, L.; Miao, L.; Shu, H.; Trudell, M. L. J. Org. Chem. 2007, 72, 3133-3136.
(4) Pourashraf, M.; Delair, P.; Rasmussen, M. O.; Greene, A. E. J. Org. Chem. 2000, 65, 6966-
6972.
(5) Sugimoto, K.; Toyoshima, K.; Nonaka, S.; Kotaki, K.; Ueda, H.; Tokuyama, H. Angew.
Chem. Int. Ed. 2013, 52, 7168-7171.
(6) Dinsmore, A.; Mandy, K.; Michael, J. P. Org. Biomol. Chem. 2006, 4, 1032-1037.
(7) Movassaghi, M.; Ondrus, A. E. Org. Lett. 2005, 7, 4423-4426.
(8) For some recent reviews concerning the synthesis of indolizidines, see: (a) Bhat, C.; Tilve,
S. G. RSC Adv. 2014, 4, 5405-5452; (b) Chakraborty, I.; Jana, S. Synthesis 2013, 3325-
3331; (c) Gómez-SanJuan, A.; Sotomayor, N.; Lete, E. Beilstein J. Org. Chem. 2013, 9,
313-322; (d) Lazzaroni, R.; Settambolo, R. Chirality 2011, 23, 730-735; (e) Brandi, A.;
Cardona, F.; Cicchi, S.; Cordero, F. M.; Goti, A. Chem. Eur. J. 2009, 15, 7808-7821; (f)
Agarwal, S.; Cammerer, S.; Filali, S.; Frohner, W.; Knoll, J.; Krahl, M. P.; Reddy, K. R.;
Knolker, H. J. Curr. Org. Chem. 2005, 9, 1601-1614.
27
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(9) For some examples for the synthesis of tetrahydroindolizidines, see: (a) Bowie Jr., A. L.;
Trauner, D. J. Org. Chem. 2009, 74, 1581-1586; (b) Ghosh, S. K.; Buchanan, S. G.; Long,
Q. A.; Wie, Y.; Al-Rashid, Z. F.; Sklenicka, H. M.; Hsung, R. P. Tetrahedron 2008, 64, 883-
893; (c) Rocchiccioli, S.; Settambolo, R.; Lazzaroni, R. J. Organomet. Chem. 2005, 690,
1866-1870; (d) Marchalin, T.; Cvopova, K.; Pham-Huu, D. P.; Chudik, M.; Kozisek, J.;
Svoboda, I.; Daich, A. Tetrahedron Lett. 2001, 42, 5663-5667; (e) Lehmann, T.; Gmeiner,
P. Heterocycles 2000, 53, 1371-1378; (f) Gmeiner, P.; Lerche, H. Heterocycles 1990, 31, 9-
12; (g) Wang, M. D.; Alper, H. Tetrahedron Lett. 1995, 36, 6855-6858; (h) Tanis, S. P.;
Raggon, J. W. J. Org. Chem. 1987, 52, 819-827.
1
2
3
4
5
6
7
8
9
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12
13
14
15
16
17
18
19
20
21
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25
26
27
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(10) For some examples concerning the preparation of indolizines, see: (a) Pandya, A. N.;
Fletcher, J. T.; Villa, E. M.; Agrawal, D. K. Tetrahedron Lett. 2014, 55, 6922-6924; (b)
Mamedov, V. A.; Kalinin, A. A.; Samigulina, A. I.; Mironova, E. V.; Krivolapov, D. B.;
Gubaidulin, A. T.; Rizvolapov, D. B. Tetrahedron Lett. 2013, 54, 3348-3352; (c) Muthusar-
avanan, S.; Perumal, S.; Yogeeswari, P.; Sriram, D. Tetrahedron Lett. 2010, 51, 6439-6443;
(d) Kucukdisli, M.; Opatz, T. J. Org. Chem. 2013, 78, 6670-6676; (e) Chung, L.-H.; Wong,
C.-Y Organometallics 2013, 32, 3583-3586; (f) Zhang, C.; Zhang, H.; Zhang, L.; Wen, T.
B.; He, X.; Xia, H. Organometallics 2013, 32, 3738-3743; (g) Lee, J. H.; Kim, I. J. Org.
Chem. 2013, 78, 1283-1288; (h) Jung, Y.; Kim, I. Tetrahedron 2012, 68, 8198-8206; (i)
Zhu, H.; Stockigt, J.; Yu, Y.; Zou, H. Org. Lett. 2011, 13, 2792-2794; (j) Smith, C.R.; Bun-
nelle, E. M.; Rhodes, A. J.; Sarpong, R. Org. Lett. 2007, 9, 1169-1171; (k) Rotaru, A. V.;
Druta, I. D.; Oeser, T.; Muller, T. J. J. Helv. Chim. Acta 2005, 88, 1798-1812; (l) Fang, X.;
Wu, Y.-M; Denga, J.; Wang, S.-W. Tetrahedron 2004, 60, 5487-5493; (m) Bora, U.; Saikia,
A.; Boruah, R. C. Org. Lett. 2003, 5, 435-438; (n) Katritzky, A. R.; Qiu, G. F.; Yang, B. Z.;
He, H. Y. J. Org. Chem. 1999, 64, 7618-7621.
(11) (a) Bode, M. L.; Kaye, P. T. J. Chem. Soc., Perkin Trans. 1 1993, 1809-1813; (b) Bode, M.
L.; Kaye, P. T. J. Chem. Soc., Perkin Trans. 1 1990, 2612-2613.
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(12) Singh, V.; Hutait, S.; Batra, S. Eur. J. Org.Chem. 2010, 3684-3691.
1
2
3
4
(13) Cunha, S. M. D.; Oliveira, R. G.; Vasconcellos, M. L. A. A. J. Braz. Chem. Soc. 2013, 24,
5
6
432-438.
7
8
9
(14) (a) Basavaiah, D.; Rao, A. J. Chem. Comm. 2003, 604-605; (b) Basavaiah, D.;
Veeraraghavaiah, G.; Badsara, S. S. Org. Biomol. Chem. 2014, 12, 1551-1556.
10
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17
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57
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59
60
(15) (a) Crawford, J. J.; Young, W. B. Alkylated Piperazine Compounds as Inihibitors of BTK
Activity and Their Preparation. PCT Patent WO 067277, May 10, 2013; SciFinder Scholar
2013:728485; (b) Payne, L. J.; Downham, R.; Sibley, G. E. M.; Edwards, P.; Davies, G. M.
2-Oxo-2-(2-Phenyl-5,6,7,8-tetrahydroindolizin-3-yl)acetamide Derivatives as Antifungal
Agents and Their Preparation. PCT WO 145,968, December 4, 2008; SciFinder Scholar
2008:1450870; (c) Shen, S.; Sun, L.; Xie, Y. Benzimidazolyl-pyridine Compounds for In-
flammation and Immune-related Uses. PCT Patent WO 112,093, October 4, 2007; SciFind-
er Scholar 2007:115254; (d) Gmeiner, P.; Huebner, H.; Bettinetti, L.; Schlotter, K. Prepara-
tion of 2-indolizinecrboxiamides and Related Compounds as Central Nervous System
Agents. PCT Patent WO 015,737, February 16, 2006; SciFinder Scholar 2006:151134; (e)
Mignani, S.; Nemecek, C. Preparation and Antiviral Activity of Indolizine Derivatives, PCT
WO 9,964,419, December 16, 1999; Scinder Scholar 1999:795812; (f) Sabb, A. L. Saturat-
ed and Unsaturated Pyridazino[4,5-b]indolizines Useful as Antidementia Agents, US Patent
5,756,501, May 26, 1998; Scinder Scholar 1998:331565.
(16) Soldatova, S. A.; Alarkon, J. A.; Mamyrbekova, Z. A.; Kryvenko, L. I.; Ntaganda, Z.;
Ryashentseva, M. A.; Soldatenkov, A. T. Chem. Heterocycl. Compd. 1994, 30, 331-334.
(17) Ortega, N.; Tang, D.-T. D; Urban, S.; Zhao, D.; Glorius, F. Angew. Chem. Int. Ed. 2013, 52,
9500-9503.
(18) Zaporozhets, O. B.; Ryashentseva, M. A.; Polosin, V. M.; Poponova, R. V. Russ. Chem.
Bull. 1993, 42, 1209-1210.
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