Synthesis and Evaluation of Azolium-Based Halogen-Bond Donors

Article abstract of DOI:10.1002/chem.201902298

A method for the synthesis of iodinated imidazolium and triazolium N-heterocyclic halogen-bond-donor catalysts has been developed. This approach was applied to the synthesis of a variety of 1,2,4-triazolium salts to prepare a series of novel chiral haloge

Full text of DOI:10.1002/chem.201902298

A Journal of
Accepted Article
Title: Synthesis and Evaluation of Azolium-Based Halogen Bond
Donors
Authors: Karl Scheidt, Richard Squitieri, Keegan Fitzpatrick, and
Ashley Jaworski
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To be cited as: Chem. Eur. J. 10.1002/chem.201902298
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Synthesis and Evaluation of Azolium-Based Halogen Bond
Donors†
Richard A. Squitieri,[a] Keegan P. Fitzpatrick,[a] Ashley A. Jaworski,[a] and Karl A. Scheidt [a]*
Abstract: A method for the synthesis of iodinated imidazolium and
triazolium N-heterocyclic halogen bond donor catalysts has been
developed. This approach was applied to the synthesis of a variety of
1,2,4-triazolium salts to prepare a series of novel chiral halogen bond
donor catalysts. The counterions of the iodinated triazoliums can be
readily exchanged with chiral and achiral non-coordinating
counterions to produce unique scaffolds. Their ability to
promote/catalyse a conjugate addition reaction with indole was
investigated. Through these initial studies, a set of general guidelines
and considerations for the application of these halogen bond donors
in organocatalysis have been established.
halogen-bonding effects by organocatalysts could potentially
provide sufficient energetic bias to promote a selective reaction.
However, the actual energetic effects imparted by halogen-
bonding motifs embedded in organic molecules have been
difficult to disentangle from other dominant energetic
considerations (e.g., H-bonding, pi-stacking, ionic pairing).[9] To
date, there are no known examples of asymmetric organic
reactions employing halogen bonding catalysts. A single chiral
halogen bonding catalyst has been described previously, but it
was not effective in promoting an enantioslective reaction.[10]
Most examples of electrophilic halogen bonding applied to
organocatalysis have utilized monovalent halogen species, with a
notable exception reported by Huber employing iodine(III)
derivatives embedded in cyclic iodolium salts.[11] The majority of
known halogen bonding organocatalysts are based on an
iodinated imidazolium or 1,2,3- triazolium organic scaffolds
(Figure 1B). These heterocyclic substructures are widely used as
N-heterocyclic carbene (NHC) catalyst precursors. Isomeric
1,2,4-triazolium salts have also been studied extensively in the
context of NHC catalysis, since the modular nature of their
synthesis allows for incorporation of chiral motifs and tuning of the
steric and electronic properties of the catalysts. Despite the wide
diversity of 1,2,4-triazoliums available for NHC catalysis, the
corresponding halogenated derivatives have not been reported as
potential halogen-bonding organocatalysts to date. Herein, we
report the synthesis of novel chiral and achiral 3-iodo-1,2,4-
triazolium salts from readily available (3-H)-1,2,4-triazolium
precursors, and an in-depth evaluation of their structure and
activity as halogen bonding catalysts.
Organocatalytic reactions employing unactivated Lewis basic
substrates have traditionally used Lewis or Brønsted acidic
additives to coordinate and activate the electrophile (e.g.,
carbonyl electrophiles, Figure 1A).[1] Recently, the use of halogen-
bonding additives to coordinate unactivated electrophiles has
emerged as a potential alternative to conventional acid-catalyzed
approaches. Specifically, iodine-containing organic molecules
have been shown to promote reactions of Lewis basic substrates
due to the highly polarized nature of the carbon-iodine bond,
which creates an electrophilic -hole which can act similarly to a
Lewis acid.[2] Currently halogen bonds have been widely applied
to anion recognition chemistry, but the extension of their utility to
organocatalysis as an alternative mode of electrophilic activation
is underdeveloped. Huber first demonstrated that halogen-
containing organocatalysts were competent activators of carbon-
heteroatom bonds towards nucleophilic displacement in 2011.[3]
Following this disclosure, reports on a variety of other reactions
promoted by iodine containing halogen bond catalysts including
(aza)-Diels-Alder,[4] Michael addition,[5] halide abstraction,[6]
semipinacol rearrangement,[7] and cooperative catalysis by silica
activation[8] have also appeared. These examples highlight the
potential of halogen-bonding organocatalysts to facilitate known
acid-promoted reactions, but at a more fundamental level, a clear
model for their mode of action remains undefined.
Since halogen bonding by molecular I2 has been shown to
lower reaction barriers up to ~7 kcal/mol, the extension of
[a]
Dr. R. A. Squitieri, K. P. Fitzpatrick, A. A. Jaworski, and Prof. Dr. K.
A. Scheidt*
Department of Chemistry, Center for Molecular Innovation and Drug
Discovery, Northwestern University
Silverman Hall, Evanston, Illinois 60208
*scheidt@northwestern.edu
†
Support for this work was provided by NIGMS R01-GM073072.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/chem.201902298
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R3
Figure 1. A) Traditional modes of carbonyl activation and halogen bonding. B)
Scaffolds of previously synthesized halogen bonding catalysts and novel 1,2,4-
triazolium halogen bonding catalysts.
R3
R2
Y
NIS (5 equiv)
R2
R1
BF4
R4
Y
R4
N
MeCN
N
N
R1
N
ꢀ W 175 °C, 1 h
I
I
Our initial goal was to develop a broadly applicable method
that could convert a library of previously synthesized azolium salts
(NHC precursors) to their corresponding XB donors. Our
preliminary studies were aimed at effecting the iodination of
triazolium salt 4.[12] Starting from the conditions developed by
Huber for imidazole iodination,[13] we explored a series of modified
conditions using N-iodosuccinimide (NIS) as an iodinating
reagent with 1,2,4-triazolium 4 (Table 1). Subjecting the triazolium
precursor to NIS in CH2Cl2 and CH3CN at room temperature
offered no conversion to the iodinated product (Table 1, entries 1
and 2). Heating the reaction 60 °C in toluene also offered no
conversion (Table 1, entry 3). However, under microwave
irradiation in toluene at 150 °C we observed 60% conversion to
the desired product (Table 1, entry 4). Nearly full conversion was
obtained when the reaction was heated to 175 °C in CH3CN, and
by using an excess of NIS (5 equivalents) we observed
quantitative conversion to iodinated triazolium product 5 (Table 1,
entries 5 and 6).
N
N
N
Mes
N
Ar
N
N
≡
≡
I
I
Ph
I
I
5, 98%
Ar = Mes; 7, 96%
ORTEP 5
N
O
N
Mes
N
I
I
6, 99%
ORTEP 6
N
Ar
N
Ph
i-Pr
N
Mes
Ar
N
N
I
N
Me
I
I
I
I
Ar = (2,6-iPr)Ph; 9, 95%
Ar = Mes; 10, 100%
I
8, 91%
11, 98%
Table 2. Synthesis of iodinated imidazolium and 1,2,4-triazolium salts by
microwave conditions.
Compounds 5, 6, and 10 were additionally characterized by
X-ray crystallography, and the structures all featured a close
coordination of the iodide counterion to the -hole of the
heteroaromatic 2-iodo substituent, an interaction similar to one
which was observed by Huber with imidazolium counterparts.[13]
Due to this presumably strong association, we hypothesized that
less coordinating counterions would be necessary to facilitate the
possible coordination to a Lewis basic substrate for activation
(Table 3). Thus, azolium 5 underwent anion exchange with silver
or sodium salts of BF4 , PBF6 , SbF6 , and BArF4-, producing the
new iodinated triazolium salts (12–15) in high yields and with a
facile isolation by simple filtration. Chiral triazolium iodides 6 and
7 were also exchanged to produce their non-coordinating chiral
salts in high yield. Finally, achiral triazolium iodide 5 underwent
salt metathesis with the sodium salts of three chiral phosphoric
acids, producing three achiral iodinated triazoliums with chiral
counterions (20-22). The further inspection of the crystal
structures for catalysts 15 and 20 confirmed that the counterions
were not tightly associated with the -hole as was observed for
the corresponding iodides which is also a feature shared with
iodinated imidazoles (Figure 2).[13] We observed no additional
solid state interactions with the triazolium cores of all compounds
characterized, suggesting that replacement of the imidazolium C4
with nitrogen is an effective means to suppress previously
observed competitive H-bonding with C4/C5 C-H bonds. These
undesired interactions in previous azolium-I structures required
blocking substituents at these positions.[13]
Table 1. Optimization of conditions for the iodination of 1,2,4-triazolium
scaffolds.
-
-
-
With the optimized conditions for the iodination of 1,2,4-
triazoles in hand, we synthesized electronically and sterically
differentiated chiral and achiral triazolium and imidazolium salts
(Table 2). Several chiral triazolium salts that are prominent in
NHC catalysis were iodinated in high yields, including the widely-
used aminoindanol scaffold (6), as well as sterically hindered
chiral catalysts (7), which are known to possess vastly different
electronic properties.[14] Additionally, we found the method to be
general to convert other N-heterocyclic scaffolds used in NHC
catalysis to their iodinated derivatives, for example
benzimidazolium (9) and imidazopyridinium (10) derivatives were
also synthesized in excellent yields using our protocol (>95%).
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studied their ability to promote the conjugate addition of indole to
crotonophenone (23), as this process has been shown to be
promoted by related halogen-bond donor catalysts previously
(Figure 3).[5a] Our initial observations indicated that catalyst 5 was
also effective for promoting the conjugate addition. A survey of
counterion effects showed unsurprisingly, catalyst 5 with the
coordinated iodide counterion gave sluggish reactivity with only
65% conversion over 24h. The use of catalysts possessing non-
-
-
coordinating counterions BF4 and SbF6 improved the reaction,
giving 73% and 85% conversion respectively over 24h. Catalyst
-
13 with a PF6 counterion facilitated the conjugate addition in
-
100% conversion over 4 hours. Finally, catalyst 15 with a BArF4
counterion was the most active, providing full conversion to
product 25 in less than 1 hour. These results mirrored
observations reported in Huber’s imidazolium halogen bond
donor-catalyzed conjugate addition, which showed a similar trend
of increasing reactivity with the use of less coordinating
counterions. Notably, we observed rapid and full conversions in
these studies whereas their best catalyst is reported to facilitate
the title reaction in 58% conversion after 3h and when allowed to
react for several days a maximum conversion of 71% was
reported.[5a] The superior reactivity of the 1,2,4-triazolium iodide
-
catalysts when employing the highly non-coordinating BArF4
counterion might be leveraged to maximize the relatively weak
halogen bonding interaction between the catalyst and substrate
in other reactions employing less reactive partners. Therefore, we
proceeded to investigate this reaction in more detail to determine
the basis of the observed catalytic activity of triazoliums 12-15.
Table 3. Synthesis of 1,2,4-triazolium salts with non-coordinating anions by
anion exchange.
With a variety of new iodinated triazolium derivatives, we
turned our focus to surveying their catalytic properties. We first
Figure 2. Crystal structure of 5,5-Mes-I with noncoordinating counterions (ORTEP 15 and 20).
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coordination to a variety of Lewis bases and π systems such as
cyclohexene, trans-stilbene, diphenyl acetylene, styrene, and
substituted benzylic carbonyls. These combined results show that
the halogen bond donor is likely only sufficient enough to interact
with sterically accessible Lewis bases and not π systems,
establishing the substrate limitations of iodoazolium-type halogen
bonding organocatalysts.
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
BF4
PF6
SBF6
I
BArF
0
5
10
15
20
25
Time (Hours)
Figure 3. Kinetics plot of conjugate addition reaction using 5,5-Mes-derived
iodinated catalysts with various counterions.
With an apparently very active halogen-bond donor catalyst,
we began to explore the limits of its catalytic activity through
presumed halogen-bonding interactions. Catalyst 15 in
conjunction with a variety of pi-nucleophiles was ineffective at
promoting 1,2 additions to some carbonyl and imine electrophilic
partners. We also briefly examined conjugate additions of amines
with maleimide, lactonizations of styrene with CO2, hypervalent
iodide-promoted aziridinations, and hetero Diels-Alder reactions
using 15 with no success.
While the superior reactivity of catalyst 15 to promote a known
process had been established, reaction screening of conceptually
related processes did not provide satisfactory insight to formulate
a hypothesis regarding the narrow substrate tolerance of this and
related halogen-bonding catalysts. To better understand which
potential electrophiles might best interact with these -hole
azolium species, a 13C nuclear magnetic resonance experiment
(NMR) was designed to probe the coordinating effects of catalyst
15 relative to a variety of Lewis basic substrates. The goal of this
study was to benchmark the limits of Lewis basicity required to
observe an interaction (halogen-bonding or otherwise) with the
catalyst and the results are depicted in Figure 4. We observed
that the C-2 carbon of the triazolium resonates at 166.4 ppm,
whereas in the presence of triphenyl phosphine and DABCO a
strong coordination with the catalyst was observed, resulting in a
2.5- 2.6 ppm upfield shift at C-2. Benzophenone imine showed a
substantial upfield shifts of C-2 by 1.6 ppm. Dimethylacetamide
resulted in a moderate shift of 0.9 ppm and benzyl methyl ether
and 4-methoxy benzoate showed a small shift of 0.5 ppm. When
DBMP was allowed to equilibrate with the catalyst in the NMR no
upfield shift was observed (Figure 2B). The catalyst showed no
Figure 4. 13C NMR shifts of catalyst 13 in the presence of a variety of
electronically differentiated π bonds and Lewis bases.
The application of our iodotriazolium catalysts to novel
reactions seemed somewhat implausible given the results of our
13C NMR studies. We next revisited the conjugate addition
reaction of indoles with enones to evaluate chiral 1,2,4-triazolium
based halogen bonding scaffolds, since no one has reported
enantioinduction using chiral halogen bonding catalysis. While
these chiral motifs have been very successful for asymmetric
NHC catalysis, compounds 6, 7, 8, 16, 17 and 18 all failed to
promote the conjugate addition reaction (Catalyst 18 produced an
analytically observable amount of product which was verified as
racemic).
Next, triazolium salts with chiral phosphoric acid counterions
were tested in the conjugate addition reaction (Table 4). Catalyst
20 and 21 also gave no conversion to the desired product (Table
2, entries 1 & 2), whereas catalyst 22 facilitated the reaction with
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95% conversion and slight enantioenrichment (Table 4, entry 3).
A brief temperature screen on this surprising result revealed that
reducing the temperature shut down catalyst activity completely
(Table 4, entries 4 & 5).
Scheme 4. Chiral phosphoric acid counter anion control.
A new method for the preparation of iodinated imidazolium
and 1,2,4-triazolium scaffolds has been developed and applied to
a variety of chiral and achiral azolium salts. The counterions of
the iodinated triazoliums can be readily exchanged with chiral and
achiral non-coordinating counterions to produce unique scaffolds.
Kinetic analysis of a variety of counterions shows that a BArF
counterion improves the overall catalytic activity of the halogen
bonding catalyst. 13C NMR spectroscopic analysis of catalyst 15
indicates that the halogen bond donor is able to coordinate to
several lone pair donors on the NMR time scale, but not many π
bond systems. A closer inspection whether iodinated azoliums
are the active catalysts in the conjugate additions investigated
herein strongly indicates these specific reactions are likely
promoted through a Brønsted acid pathway vs. the halogen bond
donor activation. However, the overall mechanistic details for all
transformations promoted by these interesting catalysts reported
have yet to be fully delineated. While there are interesting and
possibly unique opportunities for -hole interactions in catalysis,
a challenge moving forward for enantioselective variants will be to
be aware of and then avoid these unselective pathways (e.g.,
achiral Brønsted acid).
Table 4. Chiral phosphoric acid counter anion screening.
To further examine this result, a control reaction using just the
parent chiral phosphoric acid as the catalyst facilitated the
conjugate addition with similar conversion, yield and
enantioselectivity as was observed using the triazolium CPA
complex 22 (Scheme 4). This result indicated that the chiral
counterion, not the halogen bond donor, was most likely the
catalyst for this system if adventitious water was present under
the reaction conditions (e.g., “hidden Bronsted acid catalysis”).[15]
To test this hypothesis, the reaction with catalyst 22 was repeated
in the presence of proton scavengers/bases (proton sponge and
2,6-di-tert-butyl-4-methylpyridine (DBMP, 27). In both cases, no
reactivity was observed supporting the hypothesis that this
reaction is actually catalysed by adventitious acid. Chiral
phosphoric acids are well-known Bronsted acid catalysts, so the
observation that catalyst 22’s activity and asymmetric induction
can be attributed solely to the counterion if adventitious water is
present was unsurprising. However, based on this finding, we
were compelled to revisit our results using active catalyst 15.
When DBMP was added to the reaction using catalyst 15 no
reactivity was observed.
Keywords: Lewis base, catalysis, conjugate addition, halogen
bonding
While it is possible that the use of Brønsted basic additives
may also interrupt halogen-bonding effects,[5b, 15] DBMP shows no
interaction with our azolium iodides by 13C NMR spectroscopy
(Figure 4). While not definitive, these results support that DBMP
does not poison the catalyst, but is primarily acting as a Bronsted
acid scavenger. Finally, as has been noted previously, this
reaction is also efficiently catalysed by molecular iodine, and the
possibility that the activity of catalysts such as 26 may also be due
to the formation of trace amounts of I2 from the parent aryl iodides
and cannot be ruled out. The possibility that the combination of
halogen-bond donating motifs in the presence of adventitious acid
can act in a cooperative fashion may also explain of the limited
examples of halogen bonding organocatalysts known to date.
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Squitieri, Richard A., Fitzpatrick, Keegan
P., Jaworski, Ashley A., Scheidt, Karl A.*
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Synthesis and Evaluation of Azolium-
Based Halogen Bond Donors
I
· novel Azole-I · chiral derivatives · efficient access · Lewis acidity benchmarked
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