Organic Letters
Letter
offer milder conditions and higher degrees of control.9b−d
Photocatalytic RAFT polymerizations are often performed in
continuous flow conditions, due to the benefits of microflow
chemistry in this area.8a−c,10
Pyrylium photocatalysts have been recently used in cationic
photoinduced electron/energy transfer RAFT processes (PET-
RAFT10c,11) for the polymerization of vinyl ethers,2e,f not
always easy to achieve with traditional RAFT.12 Here, we
report investigations on the use of pyrylium salts for the
photchemical RAFT polymerization of vinyl ethers in flow and
comparison with the corresponding batch process. The use of
microflow chemistry allowed for much shorter reaction time,
higher molecular weight, and lower polydispersity of the
polymeric materials.
Pyrylium salts are typically prepared by reaction of an
acetophenone and a chalcone derivative in the presence of an
acid. This protocol comprises the use of simple starting
materials and allows for the synthesis of both symmetrical and
unsymmetrical triarylpyryliums, and was therefore chosen for
our investigations in flow. As tetrafluoroborate salts are
commonly used for both pyryliums and Katritzky salts
applications, we focused on these salts.
We started our investigation by performing the reaction
between chalcone (1), acetophenone (2), and HBF4·Et2O
under flow conditions for the synthesis of 2,4,6-triphenylpyry-
lium tetrafluoroborate (3) in DCE. The reaction was then
optimized with respect to temperature and residence time.
Reactions were performed above the boiling point of the
solvent (82 °C) using a back-pressure regulator set at 3.4 bar at
the end of the reactor coil. Screening of temperature showed
110 °C as the optimal temperature for the reaction, giving up
to 74% yield over 5 min residence time (entry 3, Table 1).
However, reactions conducted at 130 °C over 3 min residence
time gave comparable results (entry 9, Table 1).
substituted chalcones could be used in the reaction, furnishing
halogenated or methoxylated pyryliums 4−8. Different
acetophenones, including substituents such as phenyl,
methoxy, methylthio, chloro, and bromo, also reacted well,
giving products 9−15. Heteroaromatic ketones could also be
efficiently employed, and the reaction of chalcones with
acetylbenzofuran and acetylbenzothiophene led to pyryliums
16−18. Differently substituted pyrliums, containing alkyl
moieties, were then investigated (Scheme 2). Tetrasubstituted
and polycyclic pyrylium salts can be prepared by reaction of
chalcones with linear or cyclic ketones. For example, indanone,
cyclohexa/heptenone, and valerophenone gave pyryliums 19−
22 in 68−76% yield.
The yields obtained for the pyrylium salts 3−22 reflect the
electronic properties of the reagents, and analogous trends are
observed in the literature for batch reactions.13 Reactions
under batch conditions (same scale, higher concentration, 1 h
reaction time) for a few of the salts were performed for the
sake of comparison and provided similar yields to the flow
protocol, further demonstrating the electronic limitations of
the synthesis.
We then set out to investigate the continuous-flow synthesis
of N-alkyl triphenylpyridinium compounds (Katritzky salts) in
a “one-flow” fashion.14 These compounds are typically
prepared in batch by reaction of pyrylium salts with a primary
amine in refluxing ethanol for a few hours.5a,d,7a A one-pot
process in batch, starting from the synthesis of triphenylpyry-
lium 3, followed by addition of an amine solution after 1 h of
reflux, resulted in the immediate formation of smoke and
deposition of amine salts on the walls of flask and condenser
and resulted in a complex mixture of salts, making this process
cumbersome and unpractical. A telescoped flow synthesis was
therefore envisaged, starting with the initial synthesis of
pyrylium, followed by immediate reaction with the desired
amine.
The use of DCE for both steps resulted in heavy reactor
clogging. Ethanol was therefore selected as the solvent of
choice for the second step, as it provides a good medium for
the synthesis of pyridinium salts, good miscibility with DCE,
and a comparable boiling point.15 The temperature and
residence time for the second reactor coil were set respectively
at 130 °C and 15 min, making the overall residence time for
the two-step process 18 min.
The flow protocol was tested for the synthesis of a variety of
triarylpyrylium tetrafluoroborates (Scheme 2). Differently
Table 1. Selected Optimization for the Synthesis of
a
Triphenylpyrylium Tetrafluoroborate in Flow
The telescoped protocol was applied to the synthesis of
different pyridinium salts (Scheme 3). Pyridinium salts
containing linear, primary alkyl chains (23−25) were obtained
smoothly in 41−59% yield. Allyl- and benzylamines also
reacted with comparable yields (26−28, 44−54%). The
reaction with cyclopropylmethyl-, isopropyl-, cyclobutyl-, and
cyclohexylamine delivered compounds 29−32, albeit in lower
yields (25−37%). As the yield for the triphenylpyrylium
precursor 3 (first step) is in average 71%, the second step of
the telescoped process results in yields of 58−83% for
compounds 23−28. For compounds 29−32, this translates
to 35−52% yield. As the reaction of secondary alkyl amines
with pyrylium salts (30−32) is known to be much slower than
the reaction of primary alkyl amines,15 we suspect individual
optimization might be necessary for these compounds, as well
as for 29.
entry
T (°C)
res time (min)
yield (%)
57
Temperature Screening
1
2
3
4
5
90
100
110
120
130
5
5
5
5
5
b
65−69
b
69−74
b
57−67
63
Residence Time Screening
6
7
8
9
110
110
110
130
2
3
7
3
57
64
70
69
a
Conditions: Feed 1: 2.5−5 mmol of acetophenone, 5−10 mmol of
chalcone, diluted with DCE to 2−4 mL. Feed 2: 5−10 mmol HBF4·
Et2O, diluted with DCE to 2−4 mL. Isolated yields from direct
b
Having established the efficiency of the microflow method
for the fast preparation of pyrylium salts, we set out to
investigate their use in the photopolymerization of vinyl ethers
via cationic RAFT.2e,f We thus selected differently substituted
precipitation into Et2O at the outlet of the reactor. The reported
range represent the variation observed within at least two runs.
Conditions in entry 3 were run several times, with results always in
the reported range.
2043
Org. Lett. 2021, 23, 2042−2047