Iron-Catalyzed Indolizine Synthesis from Pyridines, Diazo Compounds, and Alkynes

Article abstract of DOI:10.1021/acs.orglett.7b03252

The iron(III)-catalyzed synthesis of indolizines from commercially available alkyne, pyridine, and diazo precursors is reported. This mild, expedient method is tolerant of various solvents and proceeds with as little as 0.25 mol % [Fe(TPP)Cl]. Significant

Full text of DOI:10.1021/acs.orglett.7b03252

Letter
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
pubs.acs.org/OrgLett
Iron-Catalyzed Indolizine Synthesis from Pyridines, Diazo
Compounds, and Alkynes
Tim Douglas, Anca Pordea,‡ and James Dowden*,†
†
,‡
†
‡
School of Chemistry and Department of Chemical and Environmental Engineering, University of Nottingham, University Park,
Nottingham NG7 2RD, United Kingdom
*
S Supporting Information
ABSTRACT: The iron(III)-catalyzed synthesis of indolizines from
commercially available alkyne, pyridine, and diazo precursors is reported.
This mild, expedient method is tolerant of various solvents and proceeds
with as little as 0.25 mol % [Fe(TPP)Cl]. Significantly, this multicomponent
reaction is compatible with electrophilic alkynes; control experiments
demonstrate the importance of the catalyst in promoting pyridinium ylide
formation over background reactivity.
atalytic multicomponent reactions that give direct access
to indolizines from commercially available precursors are
Scheme 1. Envisaged Reaction Pathway for Indolizine
Synthesis via Catalytically Generated Pyridinium Ylides
C
highly desirable. The strong demand for this heterocycle
1
−5
reflects its versatile photochemical properties
and biological
6
,7
activity. In turn, this has stimulated much innovation in
indolizine synthesis.
8
−11
Exploiting the abundance of commer-
cially available pyridines would be attractive, especially if they
are used directly without the need for prior functionalization.
An initial report of rhodium(II)-catalyzed indolizine synthesis
involved transformation of pyridine-tethered diazo precursors
via metal carbenoids and ylides in the presence of electrophilic
alkynes; just one example from this report involved a three-
12
component transformation from a simple pyridine. The
synthesis of indolizines by combination of alkenes, diazo
reagents, and quinolines or pyridines was described very
recently, although a large amount of catalyst (20 mol % CuF2
and PPh ) was required and poor yields were obtained from
3
13
alkyne, and diazo ester precursors. The commercially available
reactions involving pyridines. A general method involving
alkynes and catalytically generated pyridinium ylides is yet to be
reported.
[
Fe(TPP)Cl] (TPP = tetraphenylporphyrin) catalyst is derived
from cheap and abundant iron and successfully operates with
loadings as low as 0.25 mol % at mild temperatures in various
solvents. Characterization of background reaction products
underlines the remarkable capacity of this catalyst to promote a
pathway via highly reactive metal carbenoid and pyridinium
ylides.
We recently described the efficient synthesis of alkaloid-
inspired spirotetrahydroindolizines by combination of pyr-
idines, diazo compounds, and alkenes using an iron(III)
1
4
catalyst. We were keen to investigate whether indolizines
could be accessed by performing the related reaction with
electrophilic alkynes. Marshaling the greater reactivity of these
dipolarophiles is a potential challenge, however. In the ideal
reaction pathway (Scheme 1), diazo precursor A is converted to
electrophilic metal carbenoid B, which is intercepted by the
pyridine to give ylide C. Subsequent addition to the
electrophilic alkyne and cyclization give dihydroindolizine D,
which undergoes aromatization to generate the target indolizine
E. Clearly, direct addition of the pyridine to the alkyne is a
potential competing pathway, but once formed, pyridinium
ylides are expected to be significantly more nucleophilic than
Initially, reaction of pyridine (3 equiv), ethyl diazoacetate
EDA) (1.5 equiv), and ethyl propiolate (1 equiv) using
(
[Fe(TPP)Cl] as the catalyst (1 mol %) at ambient temperature
was investigated. Reagents were combined in a vessel open to
air without additional oxidant. To our satisfaction, these
reaction conditions returned an excellent yield of the target
indolizine 1 (89%; Table 1, entry 1). The same reaction was
performed in a variety of solvents (e.g., acetone, ethyl acetate,
toluene, etc.), from which consistently good yields of indolizine
16
1
were obtained (70−82%; entries 2−5).
1
5
pyridines.
Herein we report the catalytic synthesis of indolizines by
one-pot condensation of commercially available pyridine,
Received: October 18, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03252
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Initial Reaction Optimization
Table 2. Further Optimization of Indolizine Synthesis
pyridine
(equiv)
Fe(TPP)Cl
(mol %)
yield
a
entry
solvent
CH Cl
(%)
1
2
3
4
5
6
7
8
9
3
3
3
3
3
3
3
1
1
1
1
89
80
82
79
70
13
82
87
82
27
2
2
1
CH CN
3
1
acetone
toluene
EtOAc
1
1
1
H O
2
1
H O/EtOH (2:8)
2
1
CH Cl
2
2
2
2
0.25
0.1
CH Cl
2
1
0
CH Cl
2
a
Isolated yields after column chromatography.
The yield of indolizine 1 was not significantly reduced when
pyridine was used in a 1:1 ratio to alkyne (87%; Table 1, entry
). Subsequently, reducing the amount of catalyst to 0.25 mol
also gave 1 in good yield (82%; entry 9), but a poor yield
27%) was obtained if the catalyst was used at 0.1 mol % (entry
0). For the rest of this study, reactions were compared using
8
%
(
1
the most productive conditions, specifically 1 mol % catalyst in
dichloromethane.
In the absence of catalyst, the same combination of reagents
furnished 3H-pyrazole derivative 2 in significant yield (49%;
Table 2, entry 1). Presumably, cycloaddition between EDA and
the alkyne gives an initial 1H-pyrazole product, which
undergoes subsequent 1,4-conjugate addition with a further
equivalent of ethyl propiolate. The lack of product 2 when
a
1
7
Reactions were performed by addition of EDA (1.5 equiv) to a
solution of pyridine (as specified), alkyne (1.0 equiv), and [Fe(TPP)-
Cl] (1 mol %) in CH Cl at room temperature. EDA (1.5 equiv) and
pyridine (1.0 equiv, 0.6 mmol) were added to a solution of alkyne (1.0
equiv) and [Fe(TPP)Cl] (1 mol %) in CH Cl2 at the specified
b
2
2
[
Fe(TPP)Cl] (1 mol %) was present reinforces the notion of a
2
catalytic pathway via metal carbenoid and pyridinium ylide.
When ethyl propiolate was replaced with more electrophilic
dimethyl acetylenedicarboxylate, an exothermic reaction
occurred prior to addition of EDA, which may be identified
as the deleterious reaction between alkyne and pyridine.
Specifically, 4H-quinolizine 3 (66%, entry 2) was isolated as the
main product from this reaction mixture, which is consistent
with reported preparation of this molecule. Indolizine 4 was
obtained in 4% yield from the same reaction. The yield of 4
improved to 53% upon coaddition of pyridine and EDA to a
mixture of catalyst and alkyne at −20 °C and subsequent
warming to room temperature (entry 3). Methyl 2-butynoate,
pyridine, and EDA gave indolizine 5 in 34% yield using these
conditions (entry 4).
Indolizines were readily obtained using these improved
reaction conditions and a variety of commercially available
pyridines. For example, reaction of 4-methoxypyridine gave
indolizine 6 in excellent yield (77%; Scheme 2). Pyridines with
various 4-substitutents also gave indolizine products. 4-
Acetylpyridine gave the corresponding indolizine 7 in excellent
yield (75%). Reaction of 4-pyridines with other electron-
temperature.
4-phenylpyridine precursors, respectively. 2-Methylpyridine
also reacted well to give indolizine 12 in 58% yield.
3-Substituted pyridines also reacted in good yields, and the
resulting indolizine products were obtained as mixtures of
regioisomers corresponding to substitution at either the 6- or 8-
position. 3-Formylpyridine gave a 1:1 mixture of indolizine
regioisomers 13a and 13b in 51% yield. Indolizines were
produced with a slight preference for substitution at the 8-
position from reaction of either 3-methylpyridine (69% yield;
14a:14b = 5:3) or 3-fluoropyridine (15a 33% and 15b 19%). A
more significant preference was observed in the reaction of 3-
methoxypyridine, from which the 8-methoxyindolizine isomer
16a was obtained as the major product (68%), whereas 6-
methoxyindolizine 16b was isolated from the same reaction in
4% yield. The influence of electron-donating substituents on
the products of addition to pyridinium species has been noted
18
1
9
previously. Interestingly, reaction of 3-bromopyridine gave
the indolizine product arising from protodebromination, 1
(60%; Scheme 3A).
withdrawing substituents (CF , CN) gave the corresponding
3
indolizines 8 (57%) and 9 (45%), respectively. Indolizines 10
We sought to further explore this dehalogenation. The same
indolizine product 1 was obtained in the noncatalyzed route
(74%) and 11 (59%) were obtained from 4-methylpyridine and
B
DOI: 10.1021/acs.orglett.7b03252
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Indolizine Products Incorporating Various Pyridines
a
Reactions were performed using pyridines (1.0 equiv, 0.6 mmol), ethyl propiolate (1.0 equiv), EDA (1.5 equiv), and [Fe(TPP)Cl] (1 mol %) in
b
CH Cl at −20 °C followed by warming to room temperature for 16 h. Yields after chromatography are shown. Product ratios were estimated by
relative integration of peaks corresponding to the indolizine 6- or 8-position by H NMR spectroscopy. 5 equiv of 2-methylpyridine was used.
2
2
1
c
a
Scheme 3. Dehalogenation Observed During the Reaction of
-Bromopyridine in (A) CH Cl or (B) CH Cl /D O (3:1);
Scheme 4. Indolizine Products of Various Alkynes
3
2
2
2
2
2
(C) Proposed Debromination Mechanism to Form 1 or 18a
a
Reactions were performed using 4-acetylpyridine (1.0 equiv, 0.6
mmol), alkynes (1.0 equiv), EDA (1.5 equiv), and [Fe(TPP)Cl] (1
mol %) in CH Cl2 at −20 °C followed by warming to room
2
temperature for 16 h. Yields after chromatography are shown.
a
Reaction conditions: 3-bromopyridine (1.0 equiv, 1.74 mmol), ethyl
similar ratio (18a:18b = 5:3) to the brominated coproducts
propiolate (1.0 equiv), EDA (1.5 equiv), and [Fe(TPP)Cl] (1 mol %)
(
17a and 17b). On the basis of these observations, we speculate
in CH Cl /D O (3:1) at room temperature for 16 h; the combined
2
2
2
b
that the initial dihydropyridine cycloadduct undergoes
tautomerization and deuterium exchange to form an
intermediate (e.g., [19a]) from which bromine is collected by
an external nucleophile (e.g., pyridinium ylide) to furnish 1 or
deuterated analogue 18a (Scheme 3C). Formation of 18b from
the dihydropyiridine precursor of 17b via an analogous pathway
yield for the inseparable mixture of 1 and 18ab is shown. The
product ratio was estimated by relative integration of protons at the
1
indolizine 5-, 6-, and 8-positions by H NMR spectroscopy.
using K CO to generate the ylide by deprotonation of a
2
3
20,21
20
pyridinium salt (40%; Scheme S1A),
absolving the iron
is envisaged (Scheme S2). A related dehalogenation
mechanism has been noted for other N-heterocycles.
22,23
catalyst from involvement in this process. Performing the
catalytic reaction in a biphasic mixture of CH Cl and D O
Generally, electron-deficient alkynes were required to
produce indolizines in acceptable yields. For example, methyl
propiolate and phenylsulfonylacetylene reacted with 4-
acetylpyridine to give indolizines 20 and 21 in 85% and 41%
yield, respectively (Scheme 4), but the target heterocycles (22,
2
2
2
(3:1) gave indolizine products with bromine at the 6- or 8-
position (17a 37% and 17b 25%, respectively; Scheme 3B)
along with a mixture of proto- and deuterodebrominated
products (1 and 18ab, 14%); deuterium was incorporated in a
C
DOI: 10.1021/acs.orglett.7b03252
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
3) were not obtained from the reaction with trimethylsilyla-
Letter
2
(7) Hay, D. A.; Rogers, C. M.; Fedorov, O.; Tallant, C.; Martin, S.;
Monteiro, O. P.; Muller, S.; Knapp, S.; Schofield, C. J.; Brennan, P. E.
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cetylene or phenylacetylene.
Disubstituted alkynes such as dimethyl acetylenedicarbox-
ylate or ethyl 3-trifluoromethylpropiolate gave the correspond-
ing indolizines 24 in 60% yield and 25 in 65% yield. Alternative
benzyl diazoacetate ester performed equally well in the reaction
with ethyl propiolate to produce indolizine 26 in 64% yield.
In conclusion, a general and expedient one-pot synthesis of
indolizines has been developed. The reaction uses commercially
available pyridine, alkyne and diazo ester precursors, while the
catalyst is derived from cheap and abundant iron. Significantly,
the iron-catalyzed route via pyridinium ylides is compatible
with electrophilic alkynes by outcompeting potentially
significant background reactions.
(
(
(
Chem., Int. Ed. 2017, 56, 6078−6082.
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ASSOCIATED CONTENT
■
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(
with [Fe(TPP)Cl] (Table S1).
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Chem. 2009, 11, 156−159.
(
(
*
S
Supporting Information
16) Other catalysts were evaluated but gave inferior yields compared
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03252.
20
17) Vuluga, D.; Legros, J.; Crousse, B.; Bonnet-Delpon, D. Green
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Supplementary tables and schemes and detailed exper-
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Supporting Information.
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(
AUTHOR INFORMATION
■
*
(
Corresponding Author
̌
́ ́ ́
kova, H.; Sustkova, A.;
E-mail: james.dowden@nottingham.ac.uk;
́
́
́
̌
ORCID
(
Anca Pordea: 0000-0001-8453-0743
James Dowden: 0000-0002-7825-8971
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support from the EPSRC Centre for Doctoral Training in
Sustainable Chemistry (Grant EP/L015633/1) and the EPSRC
(EP/J021008/1) is acknowledged.
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DOI: 10.1021/acs.orglett.7b03252
Org. Lett. XXXX, XXX, XXX−XXX