Development and Cycloaddition Reactivity of a New Class of Pyridine-Based Mesoionic 1,3-Dipole

Article abstract of DOI:10.1002/anie.201609726

We describe here the development and structural characterization of a new type of mesoionic 1,3-dipole, which can be generated in the one-step reaction of imines with pyridine- or quinoline-based acid chlorides. Coupling the formation of these dipoles with alkyne cycloaddition can open a general and modular route to synthesize indolizines from combinations of available and diversifiable building blocks.

Full text of DOI:10.1002/anie.201609726

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Communications
Chemie
International Edition: DOI: 10.1002/anie.201609726
German Edition: DOI: 10.1002/ange.201609726
Mesoionic Dipoles
Development and Cycloaddition Reactivity of a New Class of Pyridine-
Based Mesoionic 1,3-Dipole
Huseyin Erguven, David C. Leitch, Evan N. Keyzer, and Bruce A. Arndtsen*
Abstract: We describe here the development and structural
characterization of a new type of mesoionic 1,3-dipole, which
can be generated in the one-step reaction of imines with
pyridine- or quinoline-based acid chlorides. Coupling the
formation of these dipoles with alkyne cycloaddition can open
a general and modular route to synthesize indolizines from
combinations of available and diversifiable building blocks.
1,3-Dipolar cycloaddition has become one of the central
synthetic approaches to construct five-membered ring hetero-
cycles.[1] Relative to the more classical assembly of hetero-
cycles by cyclization of pre-synthesized substrates, dipolar
cycloadditions can provide access to these products in
a convergent fashion, where one reactant is often a readily
available unsaturated dipolarophile (alkyne, alkene, imine,
etc). These cycloadditions can also be rapid reactions, which,
when coupled with the orthogonality of this chemistry to
more traditional organic reactions, has opened its application
in a diverse array of areas (i.e. a variant of “click” reactions).[2]
Examples include not just organic heterocycle synthesis, but
also biochemical studies,[3] polymer chemistry,[4] materials
Scheme 1. Mesoionic 1,3-dipoles and cycloaddition.
science,[5] and many other topics.
Key to the utility of 1,3-dipolar cycloaddition is access to
these reactive dipoles, many of which were pioneered through
the early work of Huisgen and others.[6] One notable class are
mesoionic heterocycles (e.g. Scheme 1a).[7] In contrast to
many 1,3-dipoles, mesoionic dipoles can be considered of
“intermediate” ionicity, and multiple aromatic resonance
structures can be drawn for each of these compounds. An
important feature of mesoionic heterocycles is their stability,
where resonance can make many of these reagents suffi-
ciently robust for isolation. Nevertheless, the use of many
variants of mesoionics can be limited by the required steps
needed to build-up their structure, which can detract from
their utility in heterocycle synthesis.
We have recently become interested in the design of new
classes of mesoionic dipoles, and in particular those that might
be more easily generated from available substrates.[8] In
considering potential structures, we noted that one of the
earliest isolated mesoionic heterocycles was quinoline-based
compound 1 (Scheme 1a), commonly known as Besthornꢀs
Red. This red pigment was generated by Besthorn in 1894,[9]
with subsequent studies by Krollpfeiffer[10] demonstrating it
to contain the now accepted mesoionic structure. Besthornꢀs
Red has not been shown to participate in 1,3-dipolar cyclo-
addition reactivity, presumably due to its extended conjuga-
tion and resonance stabilization. Nevertheless, in light of its
facile synthesis from quinolines, we questioned if this plat-
form might be modified to access to an alternative class of
mesoionic 1,3-dipolar cycloaddition reagents. We describe
here our studies towards this goal. These demonstrate that the
reaction of imines with pyridine-based acid chlorides can
allow the generation of a new type of 1,3-dipolar cyclo-
addition reagent 2 (Scheme 1b). Compounds 2 undergo rapid
1,3-dipolar cycloaddition reactions with alkynes. The latter
opens a route to construct families of pharmaceutically
relevant indolizines,[11] where this structure is generated in
one pot from simply imines, heterocyclic acid chlorides, and
alkynes.
Our initial studies probed the reaction of the acid chloride
=
of picolinic acid (3a) with the imine p-tolyl(H)C NBn
(Scheme 2). Combining these reagents at 808C leads to
formation of a green solution over the course of 12 h,
suggestive of the potential formation of the chromophoric
1,3-dipole. However, 1H NMR analysis shows this reaction is
not clean, and includes the formation of significant amounts
of protonated imine and other products. After testing several
reaction conditions, it was found that simple Et3N can serve as
an effective base for this transformation, and leads to the near
[*] H. Erguven, D. C. Leitch, E. N. Keyzer, Prof. B. A. Arndtsen
Department of Chemistry, McGill University
801 Sherbrooke St. W, Montreal, Quebec, H3A 0B8 (Canada)
E-mail: bruce.arndtsen@mcgill.ca
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201609726.
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delocalization of charge onto the carbonyl oxygen and
pyridine (see below).
A feature of 2a is its generation from available acid
chlorides and imines. As such, it is straightforward to prepare
a range of new variants of this dipole. Table 1 demonstrates
the substrate scope for this transformation. For example, the
imine can be systematically varied to incorporate a number of
different nitrogen substituents, such as N-benzyl (2b) or
-aromatic (2 f) units. Similarly, the imine carbon can be
modulated to include various substituted aromatics with
electron withdrawing (2i) or donor (2d,m) groups. Hetero-
aromatic substituents are also well tolerated (2g,h), as are
more sensitive enolizable alkyl-substituted imines (2e,f). The
pyridine can be replaced with a diacid chloride (2n,o), and
a quinoline (2j–m). The former react rapidly with imines (3 h
at ambient temperature) and can be further derivatized to
access other dipoles (2p,q). Notably, many of these modifi-
cations leads to a significant color change, and can allow the
formation of dipoles with colors ranging from red (2j–m) to
blue (2n,o) to green (2a–i).[12]
Scheme 2. Synthesis of pyridine-based 1,3-dipole 2a.
quantitative formation of 2a. Dipole 2a can be isolated as
a green solid in 87% yield by extraction with toluene. 1H and
13C NMR analysis are consistent with the structure shown,
including upfield shifts in the pyridinyl hydrogens (to d 6.0–
7.5 ppm) and carbonyl carbon (d 150.6 ppm), indicative of
Table 1: Substrate scope for 1,3-dipole 2 formation.
In the case of dipole 2n, crystals suitable for X-ray
structural analysis can be obtained by crystallization from
dichloromethane/ pentane. The crystal structure of 2n is
shown in Figure 1, and demonstrates it is indeed a new
Figure 1. Crystal structure of 2n. Select bond lengths [ꢀ]: N1–C1
1.343(2), N2–C1 1.376(2), O1–C2 1.228(2), C3–C2 1.428(2), C3–C4
1.370(2), C2–N2 1.402(2), Cl1–C8 1.8035(17), O2–C8 1.197(2).
mesoionic heterocycle.[12] Of note, the N1 C1 (1.343(2) ꢁ)
À
À
and N2 C1 (1.376(2) ꢁ) bonds in 2n are close to symmetrical,
and intermediate between single and double bonds. In
À
addition, the C2 O1 bond length (1.228(2) ꢁ) is similar to
[13]
=
that in typical amides (PhCONMe2, C O 1.231 ꢁ). This,
À
together with a C2 C3 length between a single and double
bond (1.428(2) ꢁ) and upfield pyridinyl 1H NMR resonances,
suggests the formal negative charge is likely delocalized
throughout the carbonyl and heterocyclic system.
With the ability to form these mesoionic heterocycles in
hand, we next questioned if the 1,3-dipole core of 2 can allow
their participation in cycloaddition chemistry. For this, it was
envisioned that the reduced aromaticity of 2 relative to
Besthornꢀs Red could allow alkyne cycloaddition across the
carbon skeleton to be followed by irreversible isocyanate
[a] Acid chloride (0.3 mmol), imine (0.3 mmol) and Et3N (90 mg,
0.9 mmol) in 3 mL CHCl3 for 12 h at 808C. [b] 3 h at RT. [c] Et3N (60 mg,
0.6 mmol).
2
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Table 2: Modular synthesis of indolizines via mesoionic 1,3-dipoles 2.
liberation (which cannot occur with 1) as a route to build-up
indolizines. Initial studies with the crystallographically char-
acterized 2n show that while it does react sluggishly with the
electron poor alkyne dimethylacetylene dicarboxylate
(DMAD), it forms indolizine in very low yield [Eq. (1)].
However, removing the electron withdrawing acid chloride
functionality on the pyridine (e.g. dipole 2b), which presum-
ably creates a more nucleophilic dipole, leads to a rapid
cycloaddition with the electron poor DMAD within less than
1 h at ambient temperature, and the formation of indolizine
4a in good yield (75%).
As illustrated in Table 2, the generation of 2 can be
coupled with alkyne cycloaddition to create a modular syn-
thesis of indolizines. A range of alkynes can participate in
cycloaddition with in situ generated 2. While electron poor
alkynes undergo most rapid reaction (e.g. methyl propiolate,
DMAD, and diketoalkynes), mild heating can also allow
reactions to proceed with more electron rich alkynes, such as
phenylacetylene (4b,t), those with functional groups (4j), and
even TMS acetylene (4k).[14] In the case of terminal alkynes,
only one regioisomeric product is isolated, wherein the alkyne
substituent is directed away from the 2-carbon of the
imidazolinium core. As this selectivity is consistent with
both electron poor and electron rich alkynes, it presumably
arises from steric interactions with the R1 substituent in the
imidazolium dipole 2.
The dipole 2 can also be tuned. In the case of the pyridinyl
unit, this can allow the synthesis of various quinoline-based
heterocycles (4l–p), and functionalized pyridine derivatives
(4q–t). The cycloaddition reactivity shows a strong depend-
ence upon the electronics of these substituents. While the
simple pyridine- and quinoline-derived dipoles react within
30 min at ambient temperature with DMAD, the more
electron deficient dipoles 2p and 2q require 10 h, and the
most electron poor 2o does not react at all. As with the trends
in alkyne substituents, this is consistent with the dipole 2
behaving as the electron-rich component in the cycloaddition
reaction, similar to that noted with related N-alkylated
pyridinium 1,3-dipoles.[15] Finally, the imine unit in 2 can
also be modified to tune the 2-substituent in the indolizine.
This includes the incorporation of functionalized aromatics
with electron donor or withdrawing substituents (4c,i), alkyl
units (4d,g), and even other heterocycles (4e,h). Overall
combining the formation of 2 with alkyne cycloaddition can
provide a novel method to build-up families of indolizines,
wherein any of the pyridinyl, imine and alkyne substituents
can be systematically modified.
[a] 2 formed as in Table 2, alkyne (0.3 mmol) in 2 mL CHCl3, 1 h at
ambient temperatue. [b] 658C, 24 h. [c] 10 h.
synthetic approaches to these products include cyclizations
with synthetic pyridine or pyrrole derivatives,[17–19] substitu-
tion on preformed indolizines,[20] or 1,3-dipolar cycloaddition
with pyridinium ylides.[21] 2 can be considered a stabilized,
mesoionic analogue to these latter 1,3-dipoles, and offers the
ability to incorporate a range of aryl, heteroaryl and alkyl
units into the 3-indolizine position from simple imines. As an
illustration of the utility of this approach, ester-substituted
indolizines such as 5 (Scheme 3) has been shown by Lan and
You to be strong blue emitting materials of use in fluores-
cence imaging.[20a] In contrast to its synthesis by substitution
Indolizines are present in a range of pharmaceutically
relevant products as well as electronic materials.[11,16] Typical
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Acknowledgements
We thank NSERC and the FRQNT Centre for Green
Chemistry and Catalysis for support of this research.
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Conflict of interest
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observed with Mꢂnchnones (Ref. [7]), although slower than with
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The authors declare no conflict of interest.
Keywords: 1,3 dipolar cycloaddition · heterocycles · indolizines ·
mesoionic dipoles · multicomponent reactions
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Manuscript received: October 4, 2016
Final Article published: && &&, &&&&
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Communications
Mesoionic Dipoles
H. Erguven, D. C. Leitch, E. N. Keyzer,
B. A. Arndtsen*
&&&& — &&&&
Development and Cycloaddition
Reactivity of a New Class of Pyridine-
Based Mesoionic 1,3-Dipole
Modular approach: A new class of mes-
oionic 1,3-dipole has been formed by
reaction of pyridinyl-acid chlorides and
imines. The modularity of this synthesis
can be employed to build-up families of
dipoles where every substituent can be
modified in one step. Reactivity studies
show these dipoles undergo facile 1,3-
dipolar cycloaddition with alkynes to form
indolizines.
6
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