Preparation of hexafluoroisopropyl esters by oxidative esterification of aldehydes using sodium persulfate

Article abstract of DOI:10.1039/d1ob00251a

A simple, metal-free route for the oxidative esterification of aldehydes to yield hexafluoroisopropyl esters is reported. The methodology employs sodium persulfate and a catalytic quantity of a nitroxide and is applicable to aromatic, heteroaromatic, and aliphatic aldehydes.

Full text of DOI:10.1039/d1ob00251a

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PAPER
Preparation of hexafluoroisopropyl esters by
oxidative esterification of aldehydes using
sodium persulfate†
Cite this: Org. Biomol. Chem., 2021,
19, 2986
Arturo León Sandoval,
Nicholas E. Leadbeater
Fabrizio Politano,
*
Mason L. Witko and
Received 8th February 2021,
Accepted 15th March 2021
A simple, metal-free route for the oxidative esterification of aldehydes to yield hexafluoroisopropyl esters
is reported. The methodology employs sodium persulfate and a catalytic quantity of a nitroxide and is
applicable to aromatic, heteroaromatic, and aliphatic aldehydes.
DOI: 10.1039/d1ob00251a
rsc.li/obc
materials for organocatalytic asymmetric reactions.9,10
Additionally, they are themselves more lipophilic than their
Introduction
Of the oxidants in the synthetic chemist’s toolkit, oxoammo- non-fluorinated analogues11 and have other unique properties
nium salts such as 4-acetamido-2,2,6,6-tetramethylpiperidine- (e.g. they can be readily reduced with NaBH4).12 Other routes
1-oxoammonium tetrafluoroborate (AcNH-TEMPO+BF4−, 1) are to HFIP esters include organocatalytic cross-coupling of alde-
attractive. They are shelf-stable, metal-free, recyclable, and can hydes with hexafluoroisopropyl alcohol (HFIP),13 palladium-
be used under mild conditions.1 They and their nitroxide ana- catalysed alkoxycarbonylation,14 or in a two-step process via
logues, such as ACT (AcNH-TEMPO, 2), have been employed the intermediacy of an acid anhydride.15
extensively for the oxidation of alcohols to aldehydes, ketones,
While successful and operationally simple, our route to
and carboxylic acids.2 Moving beyond simple alcohol oxi- HFIP esters does suffer from one significant drawback; a
dation, oxoammonium salts can also be used as reagents for a superstiochiometric quantity of 1 is required. In the presence
range of oxidative functionalisation reactions. This includes of base, the hydroxylamine byproduct 3 initially formed under-
the preparation of nitriles3 and amides4 from aldehydes, as goes a comproportionation reaction with a further aliquot of 1
well as an array of C–H functionalisation processes.5 Another to generate two equivalents of nitroxide 2.16,17 Thus a sacrifi-
example is the oxidative esterification of aldehydes (Fig. 1a).6 cial equivalent of 1 is required to achieve complete esterifica-
When performing this transformation, the nature of the coup- tion of the aldehyde substrate. To overcome this challenge, we
ling partner is important. It is not possible to use a simple wanted to turn to a method we have used for other oxidative
alcohol since there is a propensity for it to undergo oxidation
in the presence of the oxoammonium salt. One solution is to
use a tertiary alcohol which could not itself be oxidised but
previous methods have shown this to be difficult, due to the
steric bulk of such species.7 Under appropriate conditions,
α-trifluoromethyl alcohols fail to oxidise when exposed to 1
and, based on this observation, we developed a methodology
for the preparation of perfluoro esters from aldehydes and an
excess of the requisite perfluoro alcohol (Fig. 1b).6 Our atten-
tion focused primarily on the generation of hexafluoroisopro-
pyl esters (HFIP esters). These compounds are valuable syn-
thons that can easily be converted to other types of esters or to
amides under mild conditions,6,8 and can be used as starting
Department of Chemistry, University of Connecticut, 55 North Eagleville Road,
Storrs, Connecticut 06269, USA. E-mail: nicholas.leadbeater@uconn.edu
†Electronic supplementary information (ESI) available: Experimental details and
spectral characterisation. See DOI: 10.1039/d1ob00251a
Fig. 1 Oxidative esterification of aldehydes.
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Fig. 3 Employing visible-light photoredox catalysis to prepare HFIP
esters.
light. Surprisingly, we obtained a 75% conversion to 5a. This
result showed that the reaction was not wholly photomediated
and motivated us to develop a simpler approach for the
reaction.
Fig. 2 Merger of oxoammonium cations and visible-light photoredox
We first re-ran the reaction in the absence of light having
removed the ruthenium photocatalyst and obtained an identi-
cal result (Table 1, entry 1). We next removed the lithium
tetrafluoroborate additive and again obtained a comparable
conversion to the HFIP ester (entry 2). Extending the reaction
time from 24 h to 48 h led to an improved conversion (entry
3). Operating for 24 h but reducing the quantity of sodium
persulfate used had a deleterious effect on product conver-
sion, showing that 5 eq. was optimal (entries 4 and 5). The
same was true when we attempted to reduce the amount of
pyridine used (entry 6). Increasing the loading of 2 to
30 mol% did improve the outcome of the reaction (entry 7),
but changing the persulfate salt to the potassium analogue
did not (entry 8). Returning to sodium persulfate as the term-
inal oxidant, and using 20 mol% 2, we next probed the effect
of increasing the temperature at which the reaction was per-
formed (entries 9 and 10). Operating at 50 °C proved to be
optimal, especially if the loading of 2 is increased to 30 mol%
(entry 10). To confirm that the nitroxide, 2, plays a key role
in the reaction, we performed a trial in its absence. While
we did obtain some product, this came at the cost of selecti-
vity; a significant amount of off-target carboxylic acid (6c)
being formed (entry 11). In some of our previous work,
catalysis.
functionalisation processes; namely merging oxoammonium-
cations and visible-light photocatalysis.18 We employed a dual
catalytic system comprising of Ru(bpy)3(PF6)2 as a photo-
catalyst and 2 as the primary oxidant.19 Cheap, readily avail-
able sodium persulfate is used as a terminal oxidant.20 This
approach proved successful for the preparation of nitriles and
amides from alcohols and aldehydes,21 and for the oxidation
of alcohols to ketones, and carboxylic acids (Fig. 2).22 We
believed that such an approach might allow us to prepare a
series of HFIP esters from aldehyde precursors. We therefore
embarked on a program of study focused on this transform-
ation. We report here how we started this endeavour and
how it led to a simpler, easier approach that does not
require photocatalysis but instead simply uses sodium persul-
fate as a primary oxidant, in conjunction with a catalytic quan-
tity of 2.
Results and discussion
With development of a photocatalytic route to HFIP esters in and in other literature reports, the use of lutidine as a base
mind, we embarked on reaction optimisation. Using 4-tert- was advantageous,6,17,23 but in this case changing from
butylbenzaldehyde (4a) as a test substrate, we used as our start- pyridine to 3,5-lutidine did not improve the outcome of this
ing point the reaction conditions developed previously by our reaction (entry 12). Returning to pyridine as the base but
group for the photoamidation of alcohols.22 This involved reducing the reaction time showed us that
a good
employing Ru(bpy)3(PF6)2 as the photocatalyst and 2 as the conversion to 5 could be obtained after 3.5 h at 50 °C
pro-oxidant that would be converted to the active oxoammo- (entries 13–15).
nium cation oxidant (1) in situ. Pyridine was used as the base,
We turned our attention next to isolating the HFIP ester
and lithium tetrafluoroborate as an additive to activate the product. This proved challenging since it is necessary to
aldehyde towards nucleophilic attack by pyridine. Using remove any unspent aldehyde starting material as well as the
sodium persulfate as the terminal oxidant resulted in a corresponding carboxylic acid formed as a byproduct. In
mixture of the desired HFIP ester (5a, 92%) and 4-tert-butyl- addition, HFIP esters are generally volatile and prone to hydro-
benzoic acid (6a, 4%) after irradiating with blue LED light for lysis in an aqueous acidic environment. Exploring a number of
24 h (Fig. 3). Buoyed by this encouraging result, we moved to product isolation protocols, isolation of the HFIP ester from
explore the effects of changing the parameters of the reaction. the aldehyde starting material proved particularly trouble-
As part of this, we undertook a series of baseline experiments some. Using a standard method involving washing with
to confirm the need for each component in the reaction. One sodium bisulfite to remove unreacted aldehyde impacted the
such trial involved performing the reaction in the absence of recovery of the desired ester product.24 We decided to return to
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Table 1 Optimisation of reaction conditionsa
Entry
Conditionsb
4a (%)
5a (%)
6a (%)
1
2
3
4
5
6
7
8
Na2S2O8 (5 eq.), 2 (0.2 eq.), LiBF4 (0.3 eq.), pyridine (5 eq.), 25 °C, 24 h
Na2S2O8 (5 eq.), 2 (0.2 eq.), no LiBF4, pyridine (5 eq.), 25 °C, 24 h
Na2S2O8 (5 eq.), 2 (0.2 eq.), no LiBF4, pyridine (5 eq.), 25 °C, 48 h
Na2S2O8 (2.5 eq.), 2 (0.2 eq.), no LiBF4, pyridine (5 eq.), 25 °C, 24 h
Na2S2O8 (4 eq.), 2 (0.2 eq.), no LiBF4, pyridine (5 eq.), 25 °C, 24 h
Na2S2O8 (5 eq.), 2 (0.2 eq.), no LiBF4, pyridine (2.5 eq.), 25 °C, 24 h
Na2S2O8 (5 eq.), 2 (0.3 eq.), no LiBF4, pyridine (5 eq.), 25 °C, 24 h
K2S2O8 (5 eq.), 2 (0.2 eq.), no LiBF4, pyridine (5 eq.), 25 °C, 24 h
Na2S2O8 (5 eq.), 2 (0.2 eq.), no LiBF4, pyridine (5 eq.), 30 °C, 24 h
Na2S2O8 (5 eq.), 2 (0.3 eq.), no LiBF4, pyridine (5 eq.), 50 °C, 24 h – optimised conditions taken forward
Na2S2O8 (5 eq.), no 2, no LiBF4, pyridine (5 eq.), 50 °C, 24 h
23
28
7
60
50
33
13
48
17
0
75
71
90
39
50
59
87
52
81
88
60
63
81
55
91
2
1
3
1
0
8
0
0
9
2
10
11
12
13
14
15
12
40
0
0
Na2S2O8 (5 eq.), 2 (0.2 eq.), no LiBF4, 3,5-lutidine (5 eq.), 50 °C, 24 h
Na2S2O8 (5 eq.), 2 (0.2 eq.), no LiBF4, pyridine (5 eq.), 50 °C, 3.5 h
Na2S2O8 (5 eq.), 2 (0.2 eq.), no LiBF4, pyridine (5 eq.), 50 °C, 1 h
Na2S2O8 (5 eq.), 2 (0.3 eq.), no LiBF4, pyridine (5 eq.), 50 °C, 3.5 h
37
16
44
6
3
Trace
3
a Reactions performed in acetonitrile (2 mL) using 3a (1 mmol, 1 eq.) and 2.5 eq. HFIP in a sealed vial; conversion determined by GC-MS.
b Conditions changed from entry 1 are highlighted in bold.
Table 2 Scope of the oxidative esterification protocola
running the reaction for 24 h rather than the shorter time
because at this juncture all the aldehyde was consumed
(Table 1, entry 10). Therefore, our optimal reaction conditions
were: HFIP (2.5 eq.), 2 (30 mol%), pyridine (5 eq.), Na2S2O8 (5
eq.), in acetonitrile at 50 °C for 24 h.
With the optimised reaction conditions in hand, we moved
to assessing the substrate scope of the methodology with
respect to aldehydes that varied in electronic properties as well
as substitution patterns (Table 2). We were pleased to find that
the oxidative esterification was effective for both electron rich
and electron poor ortho-, meta-, and para-substituted benzal-
dehydes (5a–j), polysubstituted benzaldehydes (5k and 5l), as
well as representative heteroaromatic substrates (5m–o) and an
extended aromatic example (5p). While aliphatic aldehydes
could be converted to the corresponding HFIP esters, product
isolation proved problematic due to the volatility of the ester
products (5q and 5r). Substrate screening was performed on
the 1 mmol scale. To show the scalability of the reaction, we
performed the reaction using 4a at a tenfold scale. A 91% iso-
lated yield of the desired HFIP ester, 5a, was obtained.
From a mechanistic standpoint (Fig. 4), the initial step of
the reaction in likely the thermally-mediated homolytic clea-
vage of sodium persulfate to yield two equivalents of the
a Reactions performed on the 1 mmol scale; isolated yield after purifi-
oxygen-centred sulfate radical anion for which there is litera-
cation unless noted otherwise. b Reaction performed on the 10 mmol
ture precedent in other classes of reaction.25,26 This radical
anion can then oxidise nitroxide A in a single-electron transfer
(SET) process to yield the oxoammonium cation B which then
performs the oxidative esterification process. In so doing,
scale. c Product conversion determined by GC-MS.
hydroxylamine C is formed and then A can be regenerated by intermediacy of an acyl pyridinium ion. Such intermediates
hydrogen-atom transfer (HAT) to another sulfate radical anion. have been identified previously when performing oxidative
The oxidative esterification process itself take place via the functionalisation reactions using 1.4,6,17
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Fig. 4 Envisioned catalytic cycle for oxidative esterification.
Conclusion
In summary, a simple, metal-free route for the oxidative esteri-
fication of aldehydes to yield hexafluoroisopropyl esters is pre-
sented. The methodology employs sodium persulfate as the
primary oxidant and a catalytic quantity of a nitroxide as an
additive. It can be applied to aromatic, heteroaromatic, and
aliphatic aldehyde substrates.
13 B. Tan, N. Toda and C. F. Barbas, Angew. Chem., Int. Ed.,
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Conflicts of interest
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3191.
There are no conflicts to declare.
15 K. Imai, Z. Tamura, F. Mashige and T. Osuga,
J. Chromatogr., 1976, 120, 181.
Acknowledgements
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This research was funded by the University of Connecticut
Research Enhancement Program (FP) and Office of
Undergraduate Research (MLW).
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