The catalytic versatility of low toxicity dialkyltriazolium salts: In situ modification facilitates diametrically opposed catalysis modes in one pot

Article abstract of DOI:10.1039/c3cc41588k

The ability of triazolium salts to serve as a precatalyst for both an acid and a powerful base/nucleophile (controlled by additives) has been exploited in a process characterised by a unique in situ catalyst modification strategy. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc41588k

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The catalytic versatility of low toxicity
dialkyltriazolium salts: in situ modification facilitates
diametrically opposed catalysis modes in one pot†
Lauren Myles,a Nicholas Gathergood*b and Stephen J. Connon*a
Cite this: DOI: 10.1039/c3cc41588k
Received 1st March 2013,
Accepted 24th April 2013
DOI: 10.1039/c3cc41588k
www.rsc.org/chemcomm
The ability of triazolium salts to serve as a precatalyst for both an
acid and a powerful base/nucleophile (controlled by additives) has
been exploited in a process characterised by a unique in situ
catalyst modification strategy.
There has been considerable recent interest in the design of novel
Brønsted Acidic Ionic Liquids (BAILS) as conveniently handled, non-
volatile acidic materials for a variety of synthetic applications. Four
general strategies have emerged (Fig. 1): A: the covalent attachment of
an acidic moiety (e.g. 1, Fig. 1A),1,2 use of protic (acidic) imidazolium
ions (e.g. 2),3 incorporation of an acidic counterion (e.g. 3)4 and non-
protic ionic liquids, which become acidic only upon addition of a
protic additive (e.g. 4).5 We began our studies into the latter class of
catalysts with the goal of designing low toxicity materials which would
serve as powerful acid catalysts only in the presence of a protic
additive. These catalysts are not only non-volatile, they also do not
have the safety and environmental hazards associated with their
storage which are a characteristic of other strongly acidic materials.
For instance, the non protic catalyst 4 could promote the conversion
of 5 to the corresponding acetal (6) in good yield at room temperature
(Fig. 1B)5b and was shown to be of low antimicrobial toxicity. The
more electrophilic pyridinium ion 7 exhibited enhanced activity and
Fig. 1 (A) Examples of catalytically active BAILs. (B) The acetalisation of benz-
aldehyde catalysed by non-protic acid equivalents 4 and 7. (C) Proposed mode of
action of 4. (D) Proposed in situ catalyst modification.
can be recycled,5a however its synthesis is not ideal from an environ- additional endocyclic, aromaticity-lowering heteroatom – could serve
mental standpoint, and on prolonged storage its activity diminishes. as a more active, highly accessible, non-toxic analogue of the
It was proposed that the activity of these aprotic catalysts derives from imidazolium ion series of catalysts (e.g. 4). Thus 9 could represent
the formation of the active species 8/8a (Fig. 1C) after reversible a compromise between the stability of 4 and the activity of 7, while
addition of the protic additive to 4, and as such the acidity of these being easier to prepare (multigram scale) than either.
catalysts is controllable by the practitioner in an ‘on–off’ fashion.5
Another potential advantage associated with the use of 9
Since we had shown that the activity of 7 is related to the would be the development of a new paradigm in ‘bifunctional
influence of the substituents at C-3 and C-5, we speculated catalysis’. Conventionally this term has described the activation
that a 1,2,4-triazolium ion (e.g. 9, Fig. 1D) – which incorporates an of two distinct reaction components simultaneously (e.g. via
general acid/base catalysis6). However, the use of 9 potentially
a School of Chemistry, Centre for Synthesis and Chemical Biology, Trinity
Biomedical Sciences Institute, University of Dublin, Trinity College, Dublin 2,
Ireland. E-mail: connons@tcd.ie; Fax: +353 16712826
allows an unprecedented in situ catalyst modification: i.e. 9
could first act as a promoter of a reaction traditionally involving
specific acid catalysis (e.g. acetalisation), then, on addition of
base, deprotonation to the corresponding carbene 10 would
allow subsequent NHC-catalysed reactions7 (e.g. the benzoin
condensation – which under other circumstances would be
completely incompatible with specific acid catalysis) to occur.
b School of Chemical Sciences and National Institute for Cellular Biotechnology,
Dublin City University, Glasnevin, Dublin 9, Ireland.
E-mail: Nick.Gathergood@dcu.ie; Fax: +353 17005503
† Electronic supplementary information (ESI) available: Procedures, characterisa-
tion data, toxicity screening. See DOI: 10.1039/c3cc41588k
c
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Table 1 Preliminary catalyst evaluation: acetalisation
Table 2 Acetalisation catalysed by 11h: substrate scope
Yielda (%)
Entry
Substrate (Ar=)
Loading (mol%)
Yielda (%)
Entry
Catalyst (X=)
1
2
3
4
5
6
7
8
9
5 (R = C6H5)
13a (R = 2-Cl–C6H4)
13b (R = 3-Cl–C6H4)
13c (R = 4-Cl–C6H4)
13d (R = 2-Me–C6H4)
13e (R = 4-OMe–C6H4)
13f (R = 2-furanyl)
13h (R = cinnamyl)
15
1
1
1
1
2
2
2
2
10
98
96
95
98
91
91
92
90
32
1
2
3
4
5
6
7
8
9
11a (X = ClO4)
11b (X = AcO)
11c (X = MeOSO3)
11d (X = BF4)b
11e (X = Cl)
11f (X = OTs)
11g (X = OTf)
11h (X = I)
81
82
86
86
90
97
>98
>98
37
12
a
a
Determined by 1H NMR spectroscopy using (E)-stilbene as an internal
Isolated yield.
b
standard. Catalyst unstable on storage (light sensitive).
Thus the practitioner would have access to diametrically
opposed modes of catalysis from a single species, in the same
flask, depending on the choice of additive: protic (acid catalysis)
or base (basic/nucleophilic/NHC-mediated catalysis).
In order to test this hypothesis, an examination of the catalytic
competence of species such as 9 in acetalisation and benzoin Scheme 1 Dithiane, dithiolane and dioxane formation.
condensations (chosen as representative of acid-catalysed and NHC-
catalysed reactions respectively) was necessary. Our study began with
1910 – which has been shown to serve as an excellent BC
precatalyst for the BC (Table 3).11
the acetalisation of 5 by methanol under conditions previously utilised
in catalysis by 4.5c We chose the prototype triazolium species most
simple to prepare: the dimethyl azolium ions 11a–h (Table 1). As we
found to be the case with pyridinium- and imidazolium-ion-based
materials, the counteranion directly influences catalysis. An immediate
improvement in activity relative to imidazolium ions is apparent: use of
even the least efficient catalysts in the triazolium series (i.e. 11a–d,
entries 1–4) at 1 mol% loading facilitated the formation of 6 in
comparable yield to that obtained using 4 at 5 mol% levels
(cf. Fig. 1B). Gratifyingly, the chloride, tosylate, triflate and iodide ions
11e–h exhibited excellent activity (entries 5–8), with 11h (readily
obtained from the dialkylation of inexpensive 1,2,4-triazole with MeI)
able to mediate the formation of 6 in quantitative yield at 1 mol%
loading. To facilitate some perspective – this is a considerably higher
level of activity than that exhibited by the benzoic acid 12 (entry 9).5a
Next, the question of substrate scope was investigated (Table 2).
Catalyst 11h (at 1–2% levels) performed consistently across a range of
substrates – allowing the isolation of acetals derived from electron
neutral (i.e. 5, entry 1), activated- (13a–c, entries 2–4), hindered- (13d,
entry 5), deactivated- (13e, entry 6), heterocyclic- (13f, entry 7) and
a,b-unsaturated (13g, entry 8) aldehydes in uniformly excellent yields.
Ketalisation of 15 (entry, 9; a consistently problematic substrate 5)
proved difficult, however an appreciable yield was obtained. We also
found that 11h (at low loading) promoted smooth dithiane, dithiolane
and dioxane protection (i.e. 16–18, Scheme 1) at room temperature.
With the superiority of 11h over 4 established, our attention
turned to the benzoin condensation (BC). While the use of 11h
as a precatalyst in NHC-mediated chemistry is well prece-
dented,8 we were surprised to find that a detailed, systematic
study of the utility of this simple system in the archetypal
BC has not been reported.9 We therefore compared the
performance of 11f–h with the pentafluorophenyl-substituted
Catalysts 11f–h all promoted the BC of 5 with excellent
isolated product yield comparable to that obtained using the bench-
mark precatalyst 19 under literature conditions (entries 1–5).11e
From a substrate scope standpoint, the carbene derived from 11h
responded to changes in the steric and electronic characteristics of
the substrate in the same manner as 19 (entries 6–13); i.e. excellent
yields using electron neutral-, activated, heterocyclic and mildly
deactivated-aldehydes, and less efficient catalysis using either
hindered or highly deactivated substrates (which pose a serious
challenge for all triazolium catalyst systems). Since 11h is
considerably more straightforward and less expensive to prepare
Table 3 BC reactions by 11h: catalyst evaluation and substrate scope
Entry
Catalyst
Substrate (Ar=)
Yielda (%)
1
2
11f
11g
11h
11h
19
11h
11h
11h
11h
11h
11h
11h
11h
5 (R = C6H5)
5 (R = C6H5)
5 (R = C6H5)
5 (R = C6H5)
5 (R = C6H5)
96
97
96
96
97
91
27
92
93
18
89
35
93
3
4b
5
6
7
8
9
10
11
12
13
13i (R = 2-naphthyl)
13a (R = 2-Cl–C6H4)
13b (R = 3-Cl–C6H4)
13c (R = 4-Cl–C6H4)
13d (R = 2-Me–C6H4)
13j (R = 4-Me–C6H4)
13e (R = 4-OMe–C6H4)
13f (R = 2-furanyl)
a
b
Isolated yield. Using DBU (4 mol%) as the base.
c
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the potential of this and related strategies in chemoselective
tandem processes are underway.
Financial support from the Environmental Protection
Agency (EPA) is gratefully acknowledged. We thank C. McGlinchey
for preliminary experiments and M. Spulak, M. Pour and B. Quilty
for toxicity screening.
Notes and references
1 A. C. Cole, J. L. Jensen, I. Ntai, K. L. T. Tran, K. J. Weaver,
D. C. Forbes and J. H. Davis, J. Am. Chem. Soc., 2002, 124, 5962.
2 For representative recent examples using this strategy see:
(a) D. C. Forbes and K. J. Weaver, J. Mol. Catal. A: Chem., 2004,
214, 129; (b) D.-Q. Xu, J. Wu, S.-P. Luo, J.-X. Zhang, J.-Y. Wu, X.-H. Du
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H. Panga and Q. X. Guo, Green Chem., 2013, 15, 81.
3 For representative recent examples see: (a) H.-P. Zhu, F. Yang,
J. Tang and M.-Y. He, Green Chem., 2003, 5, 38; (b) H. Li, Y. Qiao,
L. Hua, Z. Hou, B. Feng, Z. Pan, Y. Hu, X. Wang, X. Zhao and Y. Yu,
ChemCatChem, 2010, 2, 1165.
4 For representative recent examples of this strategy see: (a) A. Arfan
and J. P. Bazureau, Org. Process Res. Dev., 2005, 9, 743; (b) D.-Q. Xu,
W.-L. Yang, S.-P. Luo, B.-T. Wang, J. Wu and Z.-Y. Xu, Eur. J. Org.
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5 (a) B. Procuranti and S. J. Connon, Org. Lett., 2008, 10, 4935;
(b) B. Procuranti, L. Myles, N. Gathergood and S. J. Connon,
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Scheme 2 In situ catalyst modification allows a chemoselective synthesis.
than 19 (or variants thereof), we would suggest that it represents an
attractive general system for use in the BC.
A key objective of this study was to ensure that the catalysts
are of low antimicrobial toxicity. We screened 11h for toxicity
against 12 representative fungi and 8 bacteria (both Gram
positive and Gram negative). The salt was found to be of low
toxicity to all the microorganisms up to 2 mM concentration.
The ability of 11h to inhibit bacterial growth was also evaluated
using 5 bacterial strains – IC50 values ranged from 50 to
>100 mM, indicating that 11h has low antibacterial toxicity
and would not be harmful to microbial life in the environment
(see the ESI† for details).
Finally, the bis-aldehyde 21 was selected as a candidate
substrate to demonstrate an in situ catalyst modification
strategy. The aldehyde, when treated with 1h and base, furnishes
oligiomeric products due to uncontrolled BC chemistry, with
only 7% of the dimeric benzoin 22 isolable (Scheme 2). We
therefore treated 21 with MeOH in the presence of 11h, which
resulted in the quantitative formation of mono-acetal 21a.
Subsequent addition of DBU to generate the carbene derivative
of 11h and THF solvent led to the isolation of the protected
benzoin product 23 in good yield. It is noteworthy that only
2.2 equivalents of methanol (usually used as solvent) are
required for the acetalisation (no reaction was detected in the
absence of 11h).
In summary, it has been shown that simple, stable, low
toxicity and readily prepared triazolium salts are highly active
promoters of a specific acid-catalysed reaction – allowing the
room temperature protection of a broad range of aldehydes in
excellent yield at low catalyst loadings. While it was previously
known that these materials are precursors to NHCs, a syste-
matic study revealed that these materials are actually optimal
for the promotion of the BC reaction; affording the practitioner
an identical activity profile to the literature benchmark system
6 For a review of one representative class of such catalysts see:
S. J. Connon, Chem. Commun., 2008, 2499.
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conditions, isolating benzoin from 5 in 69% yield. Curiously, 11h
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both a strong acid and a powerful base/nucleophile was
exploited in a unique in situ modification in which the role
played by the triazolium salt is completely controlled by the
addition of either methanol or a base. Studies to further explore
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c
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