Tropylium salts as efficient organic Lewis acid catalysts for acetalization and transacetalization reactions in batch and flow

Article abstract of DOI:10.1039/c7gc01519d

Acetalization reactions play significant roles in the synthetically important masking chemistry of carbonyl compounds. Herein we demonstrate for the first time that tropylium salts can act as organic Lewis acid catalysts to facilitate acetalization and transacetalization reactions of a wide range of aldehyde substrates. This metal-free method works efficiently in both batch and flow conditions, prompting further future applications of tropylium organocatalysts in green synthesis.

Full text of DOI:10.1039/c7gc01519d

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DOI: 10.1039/C7GC01519D
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COMMUNICATION
Tropylium Salts as Efficient Organic Lewis Acid Catalysts for
Acetalization and Transacetalization Reactions in Batch and Flow
D. J. M. Lyons,a,† R. D. Crocker,a,† Dieter Endersb and T. V. Nguyena,*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Previously
Acetalization reactions play significant roles in the synthetically
important masking chemistry of carbonyl compounds. Herein we
demonstrate for the first time that tropylium salts can act as
organic Lewis acid catalysts to facilitate acetalization and
R1
R1
cat. = Brønsted or metal-Lewis acid
ROH or HC(OR)3
OR
OR
R2
R2
O
This work: tropylium salts as organo-Lewis acid catalysts
transacetalization reactions of
a wide range of aldehyde
substrates. This metal-free method works efficiently in both batch
and flow conditions, prompting further future applications of
tropylium organocatalysts in green synthesis.
R1
R1
X
cat.
(1-5 mol%)
OR
OR
R2
R2
O
ROH or HC(OR)3
30 examples
67-99% yields
in batch or flow
Carbonyl compounds are among the most synthetically
important classes of organic substrates owing to their
ubiquitous and versatile chemical reactivity in redox and
nucleophilic addition or substitution reactions.1 The highly
reactive carbonyl functionality, however, requires masking or
protection to survive multi-step chemical processes frequently
found in modern laboratory and industrial syntheses.1
Acetalization reaction is probably the most popular masking
method for aldehydes and ketones.1 This type of reaction
typically involves condensation processes promoted by
Brønsted/Lewis acids or combined Lewis/Brønsted assisted
acids.1-2 Most of the previously employed Lewis acid catalysts
are metal salts,1 which might pose significant issues in the
purification process.3 Herein, we introduce the utilization of
tropylium salts as organic Lewis acids to efficiently catalyze
acetalization reactions of a wide range of carbonyl compounds
with orthoformates and 1,2-diols (Scheme 1). Similarly,
transacetalization from acyclic to cyclic acetal systems can also
be promoted by these catalysts with excellent outcomes.
Scheme 1. Tropylium-catalyzed acetalization reactions
scope.5a,5c,5f To the best of our knowledge, salts of the
aromatic tropylium ion,6 though recognized as stable
analogues of tritylium salts,7 have never been employed as
Lewis acid catalysts.7e Based on our previous works with
tropylium-promoted chemistry8 and carbonyl compounds,9 we
envisioned that the aromatic tropylium ion,10 possessing one
positive charge delocalized over a fully conjugated 6π-electron
seven-carbon system,7e could serve as a soft Lewis catalyst.
Thus, this work demonstrates for the first time that tropylium
salts can be used in this role for acetalization and
transacetalization reactions. The successful implementation of
this method in a simple flow setup also pave way for further
applications of tropylium catalysts in green chemistry.
Our initial investigation using 10 mol% of tropylium
tetrafluoroborate to catalyze acetal formation reaction
between p-tolualdehyde (1a) and triethylorthoformate (2a)
was instantly met with very positive outcomes (entry 1, Table
1). NMR monitoring study of the reaction showed complete
conversion of the aldehyde to the product within hours with
high yield after chromatography isolation. Variation of reaction
conditions and catalyst loading revealed that the reaction was
optimal with 5 mol% TropBF4 catalyst in acetonitrile (entries 5-
10); the reaction however also worked effectively in other
solvent systems or neat conditions at lower catalyst loadings
(entries 1-4, Table 1). We did not further investigate the
reaction in neat conditions as the use of a small amount of
solvent facilitated the stirring of reaction mixtures. Elevated
temperature reduced reaction time significantly, although
The concept of using salts of stable carbocations as organic
Lewis acids4 has been reported in literature with tritylium salts
as catalysts for a number of chemical transformations.5
Applications of these methods in organic synthesis, however,
are still limited due to their issues with efficiency and reaction
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Green Chemistry
Having the optimized reaction conditions in hand, we
subsequently carried out a substrate scope investigation with a
Table 1. Optimization of tropylium-promoted acetalization reaction[a]
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DOI: 10.1039/C7GC01519D
O
broad range of aldehydes (Scheme 2) and orthoesters. The
reaction worked smoothly with all tested benzaldehydes to
give diethyl and dimethyl acetal products in good to excellent
yields. The stereoelectronic properties of substituents on the
aromatic rings of benzaldehydes seemed to have little effect
on reaction outcomes (4a-l, Scheme 2). Aliphatic aldehydes
also reacted to give products in moderate yields (4n, 4o, 4v).
Interestingly, heteroaromatic aldehydes were only either
partially converted to the products or not acetalized at all
under these reaction conditions (4p-s). Presumably, the
heteroatom centres are usually more Lewis basic than the oxo
moieties, thus the unwanted coordination of tropylium to
these heteroatoms deactivated its catalytic efficiency. This
fascinating phenomenon could be exploited in selective acetal
protection of a mixture of p-nitrobenzaldehyde and 4-pyridine
carboxaldehyde.13 Similarly, the ketone functional group is
presumably not reactive enough for this type of tropylium-
catalyzed reaction, thus the ketalization did not proceed
efficiently (4t, Scheme 2). Therefore, the aldehyde moiety
could be chemoselectively protected in the presence of ketone
functionality using our reaction settings (4u-v).
EtO OEt
H
cat.
X
(3)
H
+
HC(OEt)3
2a
Me
Me
solvent, T
1a
4a
Entry
X
mol% cat.
solvent
T (°C) time[b] Yield[c]
1
2
3
4
5
BF4
BF4
BF4
BF4
BF4
BF4
BF4
BF4
BF4
-
5
5
5
2.5
5
5
5
2.5
1
0
5
DCM
toluene
neat
rt/70
rt/70
70
24
24
24
5
83/74
56/69
46
80
63/61
99
89
84
75
12
neat
70
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
rt/reflux 24/5
6
70
70
70
70
70
70
70
70
70
5
5
5
5
24
5
5
5
5
7[d]
8
9
10
11
12
13
14[e]
Br
OTf
BPh4
BF4
81
88
90
96
5
5
5
[a] Conditions: aldehyde 1a (0.5 mmol), triethyl orthoformate 2a (1.0 mmol), cat. 3
in dry solvent (0.6 mL) under Ar atmosphere. [b] Reaction time (hour) for total
consumption of aldehyde 1a. [c] Yield of the isolated product. [d] Reaction flask
opened to air. [e] 10 mol% of DTBMP added in extra-dry MeCN solvent.11
A plausible mechanism for this reaction was proposed in
Scheme 2. While we believe that tropylium ion acted as a
Lewis acid to activate the carbonyl moiety (A, Scheme 2) for
nucleophilic addition reaction with trialkyl orthoformate (B,
Scheme 2), what happened afterwards could be quite
complicated with many electron-rich oxygen centres on the
prolonged heating led to decomposition of the product
(entries 1-6, Table 1). Tropylium salts with other counterions
also promoted this reaction efficiently (entries 11-13, Table 1)
but tropylium tetrafluoroborate was the catalyst of choice due
to its superior stability and availability.12 On the other hand, a
control reaction with 2,6-di-tert-butyl-4-methylpyridine
(DTBMP, entry 14) and extra-dry solvent confirmed that this
reaction does not follow a Lewis-acid assisted Brønsted acid
catalytic pathway. The reaction also seemed to tolerate
aerobic environments (entries 6-7, Table 1).
reactive intermediate. In
a simplified hypothesis, the
methyl/ethyl group could be transferred intramolecularly or
intermolecularly along with elimination of the alkyl formate,
which proceeded through intermediates C/D to the product
with loss of the tropylium ion to another catalytic cycle. We
cannot rule out the possibility that the tropylium catalyst also
activates the orthoformate to promote the reaction.
Proposed (simplified) mechanism
cat.
BF4 (Trop+BF4-, 5 mol%)
OR
CHO
O
OR
OR
+
HC(OR)3
R1
OR
R1
reaction
conditions
MeCN, 70 ∞C
R1
1
2
4
R1
1
R
O
R
O
R
O
4
O
R
O
R
O
R
O
O
MeO
MeO
R
O
O
O
R
Cl
R
R
O
Trop+
O
- Trop+
O
O2N
R = Me: 4dM, 91%
R = Et: 4cE, 89% R = Et: 4dE, 95% (0.5 mmol scale) R = Et: 4eE, 86%
R = Et: 4dE, 99% (5.0 mmol scale)
Me
OMe
Br
R = Me: 4gM, 75%
R = Et: 4gE, 71%
4a, 99%
R = Me: 4cM, 89%
R = Me: 4eM, 98% R = Me: 4fM, 90%
4b, 92%
Trop
R = Et: 4fE, 95%
Trop
R
O
O
R
R1
O
O
O
R1
O
O
O
A
O
O
O
O
D
O
O
O
O
O
HO
OR
O
Br
F3C
NO2
OMe
4h, 85%
MeO
OMe
O
R
H
4i, 95%
4j, 75%
4k, 89%
4l, 69%
4m, 66%
4n, 36%
-
OR
RO
H
H
2
O
O
O
O
Trop
Trop
R
O
O
O
O
O
O
O
O
O
R
H
N
O
O
O
O
O
O
O
Me
RO
H
R1
R1
O
O
O
O
N
O
O
O
N
OR
R
R
4u, 44%
4v, 69%
B
4o, 15%
4p, no reaction
4q, no reaction
4r, trace
4s, 9%
4t, trace
C
Scheme 2. (left) Substrate scope of acetalization reaction; (right) proposed mechanism of the reaction. Reaction conditions: carbonyl compound 1 (0.5 mmol), triethyl or trimethyl
orthoformate 2 (1.0 mmol), catalyst tropylium tetrafluoroborate (0.025 mmol, 5 mol%) in dry acetonitrile (0.6 mL) under Ar atmosphere.
2 | Green Chem., 2017, 00, 1-4
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Green Chemistry
COMMUNICATION
Scheme 3a
ethylene glycol acetals also work effectively usiVniegw AthrtieclesOanmlinee
catalytic conditions, offering a convenient method to switch
masking groups on carbonyl functionality (Scheme 3b).
O
O
R2
cat.
BF4 (5 mol%)
R2
DOI: 10.1039/C7GC01519D
HO
H
O
+
Na2SO4 (5 equiv)
MeCN, 70 °C
HO
We subsequently focused on adapting this newly developed
batch method to a flow chemistry approach for practical
synthesis of acetal products. As outlined in Scheme 4, our
simple flow system comprised of a syringe pump connected to
a heated tubular reactor coil fitted with a back-pressure
regulator.14 The flow protocol mirrored batch conditions but
was implemented at higher temperature to further reduce
reaction/residence time. Gratifyingly, this rudimentary flow
setup efficiently mediated the acetalization reactions of
benzaldehyde to afford the desired products in high to
excellent yields. A quick optimization study demonstrated that
the tropylium tetrafluoroborate catalyst loading could be
reduced to 1 mol% without affecting these remarkable
reaction outcomes.11 The tropylium catalyst remained mostly
unchanged after the reaction and could be isolated for
recycling purpose (see page S25 in the ESI).11
6
1
5 (2 equiv)
O
O
O
O
O
Cl
O
O
O
O2N
O2N
Br
6c, 72%
6a, 79%
6b, 99%
6d, 91%
O
MeO
O
O
O
O
MeO
OMe
O
6e, 74%
6f, 81%
6g, 66%
Scheme 3b
O
pinacol
(2 equiv)
O
BF4 (5 mol%)
6b, quant.
O2N
O
O
O
O
MeCN, 70 °C
O2N
4dE
ethylene glycol
(2 equiv)
O2N
6c, 99%
The optimized flow settings were subsequently employed to
allow highly efficient multiple-gram synthesis of a range of
acyclic acetals (Scheme 4), even with very volatile substrates
such as acetaldehyde. Most interestingly, this tropylium-
catalyzed flow procedure can also be applied to promote
acetalization of aldehydes with ethylene epoxide,15 which
might be difficult in batch with this gaseous reagent. The
simplicity and efficiency of this metal-free flow protocol offer a
new practical approach to acetalization reactions of aldehyde
compounds on large scales.
Scheme 3. (a) Cyclic acetalization and (b) transacetalization reactions.
Replacement of orthoesters with 1,2-diols and Na2SO4 as
dehydrating agent also produced cyclic acetals in high to
excellent yields (Scheme 3a). Surprisingly, the bulky pinacol
proved to be more efficient than the commonly used ethylene
glycol for 1,3-dioxolane formation reactions. We believe that
the steric hindrance posed by four methyl substituents on
pinacol helps to prevent unwanted coordination of tropylium
ion to the hydroxyl groups of this diol. The transacetalization
reactions from acyclic diethyl acetals to cyclic pinacol or
CHO
CHO
HC(OR)3
+
R1
+
R1
O
BPR
(1 equiv)
BPR
(2 equiv)
OR
OR
O
(1 equiv)
(~ 4 equiv)
O
R1
R1
BF4
BF4
MeCN, 90 °C
MeCN, 90 °C
(1 mol%)
(1 mol%)
O
O
O
O
O
O
O
O
O
O
O
O
O2N
4dM, 96% (2.84 g)
O2N
O2N
6c, 83% (1.61 g)
4b, 99% (12.05 g)
4dE, 98% (3.31 g)
4fM, 94% (0.38 g)
6g, 71% (1.16 g)
O
O
Scheme& 4.! Tropylium+promoted! acetalization! reactions! in! flow.! Conditions:!
tropylium! tetrafluoroborate! (0.01! equiv,! 1! mol%),! aldehyde! 1! (1.0! equiv),!
orthoester!2!(2.0!equiv)!or!ethylene!epoxide!(~!4!equiv)!in!acetonitrile!(0.08!M),
0.1!mL/min,!T!=!90!°C,!PTFE!tubing!(0.8!mm!ID)!reactor!volume!=!4.5!mL.
O
Me
O
O
O
O
O
MeO
4w, 72% (0.85 g)
4i, 95% (0.40 g)
4n, 80% (0.31 g)
4gM, 86% (0.77 g)
batch and flow conditions, offering a convenient protocol to
mask aldehyde functional groups in organic chemistry. This
work also prompts further studies to develop future applications of
tropylium organocatalysts in green synthesis. Other tropylium-
catalyzed chemical reactions are currently under investigation in
our group and will be reported in due course.
Conclusions
In conclusion, we have demonstrated for the first time that
tropylium salts can act as organic Lewis acid catalysts to facilitate
the acetalization and transacetalization reactions on a wide range
of aldehydes. This metal-free method works efficiently in both
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Lett., 2014, 55, 6895-6898; (c) T. V. Nguyen and D. J. M.
DOI: 10.1039/C7GC01519D
Lyons, Chem. Commun., 2015, 51, 3131-3134.
This work is financially supported by Australian Research
Council (grant DE150100517) and UNSW Faculty of Science.
DJML and RDC gratefully acknowledge UA-DAAD Researcher
Exchange Scheme for providing travel grant to RWTH Aachen.
Inspirational discussions from Hon. Assoc. Prof. Roger Read
(UNSW) and Prof. Bradley Williams (UTS) are greatly
appreciated.
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9.
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53, 2091-2095; (b) M. Blümel, J.-M. Noy, D. Enders, M. H.
Stenzel and T. V. Nguyen, Org. Lett., 2016, 18, 2208-2211;
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R. V. Williams, W. D. Edwards, P. Zhang, D. J. Berg and R.
H. Mitchell, J. Am. Chem. Soc., 2012, 134, 16742-16752.
See the ESI for more details.
Tropylium tetrafluoborate used in this project can either
be purchased from chemical suppliers or synthesized in
multiple-gram scale with an experimental protocol
suitable for undergraduate laboratory; see: K. Conrow,
Org. Synth., 1963, 43, 101.
A 1:1 mixture of p-nitrobenzaldehyde and 4-pyridine
carboxaldehyde was subjected to the reaction conditions
with 5 mol% tropylium tetrafluoroborate catalyst and 2.0
equiv of triethyl orthoformate. The reaction resulted in ~
91% p-nitrobenzaldehyde diethylacetal and almost
unreacted 4-pyridine carboxaldehyde.
Notes and references
11.
12.
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4 | Green Chem., 2017, 00, 1-4
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DOI: 10.1039/C7GC01519D
TOC: Tropylium salts were reported as organic-Lewis acids to efficiently catalyze
acetalization reactions in batch and flow.