Straightforward Access to 2-Iodoindolizines via Iodine-Mediated Cyclization of 2-Pyridylallenes

Article abstract of DOI:10.1021/acs.oprd.9b00418

A metal-free access to 2-iodo-1,3-disubstituted indolizines has been developed. The proposed synthesis is relatively simple and efficient and involves the iodine-triggered 5-endo-trig cyclization of 2-pyridylallene precursors. While it can be conducted on

Full text of DOI:10.1021/acs.oprd.9b00418

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Communication
Straightforward Access to 2-Iodoindolizines via
Iodine-Mediated Cyclization of 2-Pyridylallenes
Thibaut Martinez, Ismail Alahyen, gilles Lemiere, Virginie Mouriès-Mansuy, and Louis Fensterbank
Org. Process Res. Dev., Just Accepted Manuscript • Publication Date (Web): 10 Jan 2020
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Straightforward Access to 2-Iodoindolizines via Iodine-Mediated
Cyclization of 2-Pyridylallenes
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Thibaut Martinez, Ismail Alahyen, Gilles Lemière*, Virginie Mouriès-Mansuy* and Louis Fensterbank*
Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire, IPCM, 75005 Paris, France
Supporting Information Placeholder
indolizines after elimination of one of the groups present on the
newly formed quaternary carbon center (Scheme 1).
ABSTRACT: A metal-free access to 2-iodo-1,3-
disubstituted indolizines has been developed. The
proposed synthesis is relatively simple and
efficient and involves the iodine-triggered 5-
Scheme 1. Electrophile-induced cyclization reactions of
arylallenes
endo-trig
cyclization
of
2-pyridylallene
precursors. While it can be conducted on a gram
scale, the preparation of the precursors is
straightforward and does not always require
intermediate purifications. The obtained 2-
iodoindolizines can be further functionalized
through cross coupling reactions.
Keywords: allenes, indolizines, iodine, cyclization, pyridine
INTRODUCTION
Indolizines are key motifs in organic chemistry present in a
myriad of biologically active compounds1 and used as precursors
of valuable organic materials.2 In the latter case, tuning of the
properties can be achieved via variation of the substituents of the
two rings. Logically, this has elicited a strong attention in
developing new synthetic pathways to these compounds.
Originally synthetized by Scholtz3 and Chichibabin4 at the
beginning of the XXth century through condensation reactions,
new methods, essentially dipolar cycloaddition and
cycloisomerization reactions have been developed since then,
giving access to a plethora of polysubstituted indolizine rings5 as
well as indolizines bearing a halogen at position 2.6 Although
there is a growing interest in accessing 1,2,3-trisubstituted
indolizines,7 to the best of our knowledge, only Kim and coll.
have proposed a method to synthetize 1,3-disubstituted 2-
iodoindolizines from propargylic acetates.8,9 The position 2 being
iodinated, it should allow post-functionalization through
commonly used transition metal cross-coupling reactions or a
radical pathway. Also, a brief literature survey shows that
pyridylallenes are valuable intermediates for the synthesis of
indolizines via 5-endo-trig cyclisation reaction under electrophilic
activation.10,11
In 2015, our group has reported on the cyclization of 2-
pyridylallenes using dimethyl sulfide gold (I) chloride as -Lewis
acid to provide a new family of gold complexes (Scheme 1).12
Also relevant to our project, Michelet and Toullec described in
2016 the synthesis of 2-iodoindenes by activation of arylallenes
using N-iodosuccinimide (NIS) as iodonium source.13 We
surmised that if the cyclization of 2-pyridylallenes can also be
triggered by such electrophiles, the resulting indoliziniums could
evolve towards the formation of 2-iodo-1,3-disubstituted
RESULT AND DISCUSSION
The retrosynthetic analysis led us to consider the C3-N4
disconnection: we reasoned that the key cyclization/elimination
sequence of B would provide indolizine A (Scheme 2). The
required tetrasubstituted allenic precursors B of indolizines A
would be readily accessed from propargylic acetate C via SN2’
type reaction. The latter can be obtained through a 1,2-
addition/acetylation sequence from 2-pyridyl ketone and alkyne
derivatives D.
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Scheme 2. Retrosynthetic analysis for the synthesis of
1,2,3-trisubstituted indolizines
Scheme 4. Synthesis of 2-pyridylallenes 2
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Following this strategy, nine propargylic acetates were obtained
(1a-i) in high yields over two steps (Scheme 3).
Scheme 3. Synthesis of propargylic acetates 1
Next, we investigated the cyclisation reaction, starting initially
with NIS as an electrophilic iodine source. When conducted at
room temperature, a significant quantity of starting material
remained untouched after two hours with no evolution of the
reaction. Increasing the temperature to 60°C led to the full
conversion of 2-pyridylallene 2a to afford the desired 2-
iodoindolizine 3a along with the succinimide adduct 4.
Iodoindolizine 3a results as expected from the loss of the tert-
butyl group on the cyclic indolizinium intermediate 6 (Scheme 5),
itself originating from the cyclization of iodonium 5. The
formation of 4 could be rationalized by considering the N-addition
of the succinimidate on the activated
α position of the
iodopyridinium 6 to give adduct 7. The latter would rearomatize
after oxidation to 815 and -adduct 4 is generated via 9. Another
pathway transiting via an iodopyridinium, generated by iodination
of the pyridine nitrogen, and -addition was discarded since
model 2-vinylpyridine remained intact in the reaction conditions.
This suggests that the preliminary activation of the allene as in 5
is required for the addition of the succinimidate.16 The formation
of 3a validated our strategy and we then pursued on the
optimization of the reaction conditions in order to suppress the
formation of the undesired product 4.
Propargylic acetates 1 were then converted into tetrasubstituted
allenes 2 bearing a tert-butyl group at the C3 position using the
tert-butylcyanocuprate reagent following Krause’s procedure14
(Scheme 4). This reaction quickly showed high efficiency on
propargylic acetate 1a since a quantitative yield was observed for
the formation of 2a. It was then extended to the other propargylic
acetates 1b-i to obtain the corresponding seven tetrasubstituted
allenes 2a-i even when R1 are a hydrogen or a methyl instead of a
phenyl group. We found out that the temperature needed to be
carefully controlled to obtain the desired products. While 2f, 2h
and 2i were obtained in excellent yield, the reaction showed less
efficiency on other substrates, especially from 1d and 1e.
Moreover, each of these allenes and intermediates were found to
be perfectly stable under bench conditions and no purification was
required until the final allene compound was obtained.
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1,2
equiv.
1
2
3
4
80°C
60°C
70°C
70°C
-
-
43%a
48% a
84%
18% a
12% a
Traces
-
1
2
3
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5
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8
Scheme 5. Cyclization of 2a using NIS
1,2
equiv.
2
-
equiv.
2
2
92%
equiv. equiv.
a yields calculated from a mixture of 3a/10.
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We then extended this iodocyclization reaction to other 2-
pyridylallenes using the optimized conditions (Scheme 6). 3-
arylindolizines 3b, 3c and 3i were obtained very efficiently from
2b, 2c and 2i, respectively, while the yield was slightly lower
from electrodeficient aromatic ring 2d bearing a trifluoromethyl
group. Alkylindolizines 3f and 3g were also obtained albeit with
moderate yield, maybe due to a lower stabilization of the cationic
charge that is developing on 5. Also with precursors bearing an
alkyl chain (2f and 2g), we suspect that decumulation of the allene
takes place. We could show that the cyclization process was not
restricted to substrates bearing a phenyl group at the allenic
position (R1) with engaging trisubstituted allene 1h and
methylated derivative 1i. While the expected 2-iodoindolizine 3h
was obtained in a good yield (78%) accompanied by a side
product (see SI), the introduction of a methyl at that position
proved very rewarding since 3i was obtained in quantitative yield.
We also reasoned that a TMS group could be a better leaving
group than the tert-butyl group. Gratifyingly, when TMS-
substituted 2-pyridylallene 2e was used as substrate, tert-butyl
substituted 2-iodoindolizine 3e was selectively obtained in
satisfactory yield (74%).
When 1.2 equivalents of iodine were employed as the
electrophilic halogen source instead of NIS (Table 1), 43% yield
of 2-iodoindolizine 3a was obtained along with the 1,3-
disubsubstituted indolizine 10 in a 80/20 ratio (Table 1, entry 1).
This latter compound is suspected to originate from the
cyclization reaction of 2-pyridylallene 2a promoted by hydroiodic
acid generated in situ after the cyclization/elimination process.
Interestingly, 3a was formed in greater proportion by decreasing
the temperature to 60°C (entry 2). Using two equivalents of iodine
and setting the temperature to 70°C proved to be beneficial since
3a was obtained in 84% with only traces of indolizine 10 (entry
3). Running the reaction in basic conditions using potassium
carbonate as an acid scavenger allowed to avoid totally the
formation of the undesired product 10 and afforded 3a in
excellent yield (entry 4). This reaction turned out to be very
convenient from a practical point of view since it could be run on
the gram scale (see Scheme 6) and pure material was recovered
from the simple filtration of the greenish solid formed while the
excess of iodine was neutralized. Moreover, the structure of 2-
iodoindolizine 3a was unambiguously confirmed by X-ray
diffraction (Figure 1).17
Figure 1. Crystal structure of compound 3a (H atoms are omitted
for clarity).
Scheme 6. Synthesis of 2-iodoindolizines
Table 1. Conditions optimization for the iodocyclization
Entry
3
T°C
I2
K2CO3 Yield of 3aa
Yield of 10a
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This reaction gives access to 1,2,3-trisubstituted indolizines
pyridylallene precursors. An example of this cyclization was
conducted on the gram scale with high efficiency and convenient
purification procedure. The presence of the iodo group at the
position 2 allows for late 2-fonctionalization steps which have
been barely described in the literature. Three common transition
metal-catalyzed cross-coupling reactions were given as examples
but the iodo group should be useful for other types of 2-
substitution. An example of activation of a 2-pyridylallene with
electrophilic fluorine to deliver a 2-fluoroindolizine was also
performed. As an extension of this work, different azacycles-
allene cyclisations using various electrophiles are currently
underway and should allow access to other unprecedented
indolizine type scaffolds.
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7
8
bearing an iodine atom at position 2 which can then be
functionalized. Inspired by the work of Kim,8 we investigated
further functionalization with widely employed pallado-catalyzed
cross coupling reactions such as Sonogashira, Suzuki and Heck
reactions using 3a as model substrate (Scheme 7). The
Sonogashira cross coupling was conducted with phenylacetylene
to yield 1,2,3-trisubstituted indolizine 11 in moderate yield.
Compound 12 and 13 were synthesized using a Suzuki and a Heck
coupling with phenylboronic acid and methylacrylate,
respectively. NMR yields for those two coupling reactions were
excellent while isolated yield turned out to be lower than expected
due to possible degradation during purification which was not
optimized.
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ASSOCIATED CONTENT
Supporting Information
Scheme 7. Palladium-catalyzed cross-coupling reactions of
2-iodoindolizines
The Supporting Information is available free of charge on the
ACS Publications website.
Experimental procedures, characterization data for all new
compounds, 1H, 13C and 19F NMR specta.
AUTHOR INFORMATION
Corresponding Author
gilles.lemiere@sorbonne-universite.fr;
virginie.mansuy@sorbonne-universite.fr;
louis.fensterbank@sorbonne-universite.fr
Author Contributions
TM did some experimental work and contributed to the writing of
the article. IA did some experimental work. GL, VMM and LF
designed the reactions and wrote the article.
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
The authors are grateful to Sorbonne Université (PhD grant to
TM) and CNRS for funding of this work. They also thank
Geoffrey Gontard for the XRD analysis of 3a.
Furthermore, since fluorinated aromatic compounds show
interesting properties in medicinal chemistry18 we extended the
reaction using Selectfluor as an electrophilic fluorine source. In
that case, the 2-fluoroindolizine 14 was obtained.
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Scheme 8. Synthesis of 2-fluorindolizine
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R3
I
R1
R1
Pd-catalyzed cross coupling
for post-functionalization
R1
R2
I2
•
R2
R2
LG
N
N
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N
R1, R2 = Ar, alkyl
LG : electrofuge
R3 = Ar, alkene, alkyne
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