Azodicarboxylate-free esterification with triphenylphosphine mediated by flavin and visible light: method development and stereoselectivity control

Article abstract of DOI:10.1039/c8ob01822g

Triphenylphosphine (Ph₃P) activated by various electrophiles (e.g., alkyl diazocarboxylates) represents an effective mediator of esterification and other nucleophilic substitution reactions. We report herein an aza-reagent-free procedure using flavin catalyst (3-methyl riboflavin tetraacetate), triphenylphosphine, and visible light (448 nm), which allows effective esterification of aromatic and aliphatic carboxylic acids with alcohols. Mechanistic study confirmed that photoinduced electron transfer from triphenylphosphine to excited flavin with the formation of Ph₃P⁺ is a crucial step in the catalytic cycle. This allows reactive alkoxyphosphonium species to be generated by reaction of an alcohol with Ph₃P⁺ followed by single-electron oxidation. Unexpected stereoselectivity control by the solvent was observed, allowing switching from inversion to retention of configuration during esterification of (S)- or (R)-1-phenylethanol; for example with phenylacetic acid, the ratio shifting from 10?:?90 (retention?:?inversion) in trifluoromethylbenzene to 99.9?:?0.1 in acetonitrile. Our method uses nitrobenzene to regenerate the flavin photocatalyst. This new approach to flavin re-oxidation has also been successfully proved in benzyl alcohol oxidation, which is a “standard” process among flavin-mediated photooxidations.

Full text of DOI:10.1039/c8ob01822g

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Azodicarboxylate-free esterification with triphenylphosphine
mediated by flavin and visible light: method development and
stereoselectivity control
Received 00th January 20xx,
Accepted 00th January 20xx
Michal März,*a Michal Kohout,a Tomáš Neveselý,a Josef Chudoba,b Dorota Pruka
ł
a,c Stanislaw
DOI: 10.1039/x0xx00000x
Niziński,d Marek Sikorski,c Gotard Burdziński,d and Radek Cibulka*a
www.rsc.org/
Triphenylphosphine (Ph3P) activated by various electrophiles (e.g., alkyl diazocarboxylates) represents an effective
mediator of esterification and other nucleophilic substitution reactions. We report herein an aza-reagent-free procedure
using flavin catalyst (3-methyl riboflavin tetraacetate), triphenylphosphine, and visible light (448 nm), which allows
effective esterification of aromatic and aliphatic carboxylic acids with alcohols. Mechanistic study confirmed that
+
photoinduced electron transfer from triphenylphosphine to excited flavin with the formation of Ph3P● is a crucial step in
+
the catalytic cycle. This allows reactive alkoxyphosphonium species to be generated by reaction of an alcohol with Ph3P●
followed by single-electron oxidation. Unexpected stereoselectivity control by the solvent was observed, allowing
switching from inversion to retention of configuration during esterification of (S)- or (R)-1-phenylethanol; for example with
phenylacetic acid, the ratio shifting from 10:90 (retention:inversion) in trifluoromethylbenzene to 99.9:0.1 in acetonitrile.
Our method uses nitrobenzene to regenerate the flavin photocatalyst. This new approach to flavin re-oxidation has also
been successfully proved in benzyl alcohol oxidation, which is
photooxidations.
a “standard” process among flavin-mediated
of
the
Mitsunobu
esterification.
Usually,
an
Introduction
alkoxyphosphonium species is employed, which results in
inversion of configuration of the chiral alcohol. In some cases,
the acyloxyphosphonium species prevails, which leads to
Nucleophilic substitution of a hydroxy function mediated by
triphenylphosphine (Ph3P) is among the most powerful tools in
organic synthesis.1 Such substitution is allowed as an alcohol
molecule is transformed into an alkoxytriphenylphosphonium
intermediate, which reacts smoothly with nucleophiles by
virtue of the energetically favourable formation of phosphine
oxide with a strong P=O bond (540 kJ mol−1). Alcohols do not
react with triphenylphosphine directly. For the formation of
alkoxyphosphonium species, triphenylphosphine must be
activated with an electrophile/oxidant, for example with a
tetrahalomethane in the Appel reaction2 or with a dialkyl
azodicarboxylate in Mitsunobu esterification1c,3 (see
Scheme 1A). Under certain conditions, the carboxylic function
can be activated analogously, resulting in the formation of
acyloxyphosphonium species capable of undergoing acyl
substitution reaction.3b,4 Whether the hydroxy or the carboxy
group is activated significantly influences the stereoselectivity
retention of configuration.5,6
+
One-electron oxidation to Ph3P● could be
a novel
straightforward way to activate Ph3P for substitution reactions.
Such an approach would not require a dialkyl azadicarboxylate
(or a tetrahalomethane), thus avoiding safety and stability
problems and making the triphenylphosphine-mediated
procedure more sustainable.‡2a,7
+
There are several indications that Ph3P● has the required
properties to mediate substitutions of the OH group.
+
Electrochemically generated Ph3P● has been shown to react
+
with alcohols to form alkoxyphosphonium species.8 Ph3P●
generated from Ph3P by photoinduced electron transfer to an
excited acridinium salt, dicyanoanthracene, pyrylium salts, or
Eosin Y has been proved to form triphenylphosphine oxide by
reaction with oxygen or water.9 Despite these promising
observations, to the best of our knowledge neither
+
electrochemically nor photochemically generated Ph3P● has
hitherto been utilized in organic synthesis. The only exception
is a “dark” aerobic esterification reaction mediated by an iron
phthalocyanine catalyst and 4-methoxypyridine N-oxide (MPO)
as co-catalyst, as reported by Taniguchi (Scheme 1B),10 in
+
which the carboxylic function is activated by Ph3P● , thus
affording an ester with retention of configuration.
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Scheme 1 Activation of triphenylphosphine (Ph3P) for esterification reactions.
We started with simple model substrates, 3-nitrobenzoic acid
and benzyl alcohol, using 2 equivalents of triphenylphosphine
Herein, we report the first azodicarboxylate-free esterification
procedure based on photocatalytic activation of Ph3P. We use
and 10 mol% of
1 (entry 1). An interesting result was that
almost the same ester conversion was obtained under argon
atmosphere as under oxygen, showing that the flavin catalyst
must have been regenerated in another way (cf. entries 1 and
2). The aromatic nitro group seemed to be responsible for this
process, which was confirmed by the following results: (i)
significantly more than 10% of the ester (expected amount
when 10 mol% of flavin is used and it is not regenerated) was
formed when the nitro group was part of a benzyl alcohol,
benzoic acid or externally added in the form of nitrobenzene
3-methyl riboflavin tetraacetate (1) as a photoredox catalyst
and visible light (Scheme 1c). It is shown that this esterification
allows switching from retention to inversion of configuration
of chiral alcohols, depending on the structure and acidity of
the acid and alcohol and on the solvent used.
Results and discussion
Catalytic system design
The design of the photocatalytic system for photoesterification
Table 1. Preliminary results and selected optimization studies for photocatalytic
reaction was inspired by our preliminary observations during esterification.a
development of the photocatalytic Mitsunobu reaction.11 In
that case, a dialkyl azodicarboxylate was used in a catalytic
amount and regenerated by aerial oxidation mediated by
flavin photocatalyst
1 and visible light (448 nm) in the
presence of molecular sieves 4A (MS 4A).§ Surprisingly, we
also observed remarkable ester formation when a mixture of
carboxylic acid, alcohol, triphenylphosphine, and a catalytic
Entry R1
R2
Atmosphere
(temperature)
O2 (25 °C)
Ar (25 °C)
Ar (25 °C)
Ar (25 °C)
Ar (25 °C)
Ar (25 °C)
Ar (25 °C)
Ar (25 °C)
Ar (25 °C)
Ar (25 °C)
Ar (40 °C)
Ar (40 °C)
Ar (40 °C)
Ar (40 °C)
Additive Solvent Conversion
[%]
amount of flavin
1 was irradiated under oxygen in the absence
1
NO2
Cl
Cl
NO2
Cl
H
-
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
90c
80d
33e
5
of a dialkyl azodicarboxylate or its precursor, dialkyl hydrazine-
1,2-dicarboxylate. This led us to investigate the
azodicarboxylate-free system in more detail (Table 1).
2
NO2
H
-
3
-
4
H
-
5
H
-
3
6
H
H
PhNO2
PhNO2
PhNO2
PhNO2
PhNO2
PhNO2
PhNO2
PhNO2
PhNO2
32
32
OAc
7
H
H
λ
λ
λ
E
max = 443nm (acetonitrile)
F = 524 nm (acetonitrile)
P = 599 nm (acetonitrile)
8
H
H
toluene 38
AcO
N
OAc
OAc
9
H
H
THF
BTF
BTF
BTF
BTF
BTF
15
47
66
10
84
95
10
11
12 b
13
14
H
H
H
H
(1/1 ) = -0.82 V SCE
v s
H3C
H3C
N
O
H
H
E*red(S) = 1.76 V vs SCE
E*red(T) = 1.25 V vs SCE
N
CF3
CF3
H
N
CH3
Cl
1
O
a
Conditions: n(alcohol) = 0.15 mmol, n(acid) = 0.18 mmol, n(1) = 0.015 mmol,
n(PhNO2) = 0.15 mmol, n(Ph3P) = 0.3 mmol, MS 4 Å (150 mg), 2 mL solvent, 448
c
nm, 24 h; conversion was determined by 1H NMR. b in the absence of MS
.
4-
Figure 1 Catalyst 1 and its characteristics. Catalyts 1 was selected since flavins
are known versatile catalysts12 and photocatalysts13 in oxidation reactions
absorbing in visible region and being of appropriate redox properties. Derivative
d
Chlorobenzyl 3-nitrobenzoate was observed as
a
sole product. Beside 4-
1
is known for photostability among flavins.13k For the characteristics
measurements, see ESI.
chlorobenzyl 3-nitrobenzoate (main product) formation of N-(3-carboxyphenyl) 3-
e
nitrobenzamide was also observed.
Beside 4-nitrobenzyl benzoate (main
product) formation of N-[4-(hydroxymethyl)phenyl] benzamide was observed.
2 | J. Name., 2012, 00, 1-3
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(entries 2, 3, and 6); (ii) reduction products of nitro We found that benzyl alcohols react with 3-
compounds were observed in the reaction mixtures: N-3- trifluoromethylbenzoic acid to provide esters in moderate
3–9
carboxyphenyl 3-nitrobenzamide – condensation product of to good yields regardless of the nature and position of the
the reduced 3-aminobenzoic acid (Entry 2) and N-[4- substituent. Aliphatic alcohols react smoothly under our
(hydroxymethyl)phenyl] benzamide – condensation product of conditions (see entries for esters 10 and 11). Besides aromatic
the reduced 4-nitrobenzyl alcohol; (iii) less than 10 mol% of acids (see entries for esters
ester was formed in the absence of an aromatic nitro group also proved to react with 4-chlorobenzyl alcohol (see entries
(entries 4 and 5). Thus, nitrobenzene was used as a sacrificial for esters 14 16). The formation of ester 16 is especially
oxidant in the next experiments. noteworthy as it was achieved with significantly higher
2, 12, and 13), aliphatic acids were
–
Optimizing the solvent and temperature (see entries 7–11 and conversion (62%) compared to the previously described11
the ESI for details), we found trifluoromethylbenzene (BTF) aerial photocatalytic Mitsunobu reaction (16%).
and elevated temperature (40 °C) to be the best reaction Special attention was paid to the stereoselectivity of the new
conditions, giving almost quantitative conversion when 3- esterification with chiral secondary alcohols, (R)- and (S)-1-
trifluoromethylbenzoic acid was used as a redox-inactive phenylethan-1-ol and (R)- and (S)-ethyl lactate (Table 3,
alternative to electron-poor 3-nitrobenzoic acid (cf. entries 1 method A, first column). Interestingly, the stereoselective
vs. 13 and 14). Modification of nitrobenzene (stoichiometric course varied significantly depending on the acidity and steric
oxidant) by substitution had only a small effect on the ester hindrance of the acid, shifting from dominant retention for
conversion (see the ESI). Blank experiments (performed with ester 21 (90:10, entry 5) to highly selective inversion for 17
all substrates in Table 1) showed that esterification did not (0.1:99.1, entry 1). It was found that higher acidity of the
proceed in the absence of either
1, Ph3P, or light. In the carboxylic acid favoured production of the ester with retention
absence of molecular sieves (MS), ester
2
was formed with of configuration (cf. entries 2–4), whereas sterically
only 10% conversion (entry 12), probably because of the demanding acids favoured inversion of configuration (entry 1).
negative effect of water formed during flavin re-oxidation with These results can be explained in terms of two mechanistic
nitrobenzene.
pathways
involving
either
alkoxyphosphonium
or
acyloxyphosphonium intermediates, which have been proved
to be in equilibrium by several studies.3b,4,5c,6 Most probably,
for more acidic acids, acyloxyphosphonium prevails, thus
favouring acyl substitution, which results in the product with
retention of configuration (see entries 2–4). Formation of the
acyloxyphosphonium species and thus higher selectivity for
retention of configuration seems to be supported when the
nucleophilicity of the hydroxy function is decreased by the
Substrate scope and stereoselectivity
Having established the optimized conditions, the scope of the
reaction with respect to the structures of the alcohol and acid
was investigated through preparative experiments (Table 2).
Table 2. Substrate scope for photocatalytic esterification mediated by 1 and Ph3P.a
a Conditions: n(alcohol) = 0.15 mmol, n(acid) = 0.18 mmol, n(1) = 0.015 mmol,
n(PhNO2) = 0.15 mmol, n(Ph3P) = 0.3 mmol, MS 4 Å (150 mg), 2ml BTF, 40 °C, 448
nm, 24 h; conversion was determined by 1H NMR. b Aldehyde conv. 51 %.
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Table 3 Stereoselectivity of ester formation with chiral non-racemic alcohols.
Results with trifluorobenzoic acid and (S)-1-phenylethan-1-ol
generating ester 19 (Table 4, first column) confirmed this
premise, showing the stereochemistry of the new
esterification (method A) to significantly vary with the solvent.
In polar solvents such as acetonitrile or acetone, the reaction
predominantly proceeded with retention of configuration,
whereas in non-polar solvents, inversion of configuration
prevailed. An even more significant effect of the solvent was
observed with phenylacetic acid in forming ester 18, for which
the stereoselectivity shifted from 99.9:0.1 in acetonitrile to
10:90 in BTF. On the contrary, the stereoselectivity of the
“dark” Mitsunobu reaction leading to ester 19 was found to be
unaffected by solvent (er 13:87 and 7:93 in acetonitrile and
BTF, respectively) and thus our photocatalytic process remains
unique in this respect.
Method Bb
Method Cc
Method Aa
(according to
(non-catalytic
M.R.)
(from this work)
ref.11
)
Entry
Product
Yieldd
ere
Yieldd
[%]
Yieldd
ere
ere
[%]
[%]
1
2
33 0.1:99.9
0
-
38
1
10:90
10:90
19
52
10:90
40:60
23 99.9:0.1
3
4
5
28 99.9:0.1 65
13:87
9:91
Mechanistic investigation
The key step of the photoesterification is oxidation of Ph3P to
+
Ph3P● by single-electron transfer to the excited flavin
1
(Fl*;
42
24
68:32
90:10
50
99:1
63
see Scheme 2 for the proposed mechanism). Flavin
1 in the
singlet excited state (1Fl*) is strong enough (Ered*(S) = 1.76 V
vs. SCE) to induce the oxidation of Ph3P (Eox = 1.0 V vs. SCE,
ref.9c). This process was confirmed by the observation of
efficient quenching of the steady-state fluorescence emission
19 99.1:0.1 43 0.1:99.9
of
1
upon addition of Ph3P. The value of the quenching rate
-1 s-1) was obtained both from
constant (kq = 6 × 109
M
a For conditions, see Table 2; b n(alcohol) = 0.15 mmol, n(acid) = 0.18 mmol, n(1) =
0.015 mmol, n(DIADH2) = 0.015 mmol, n(Ph3P) = 0.3 mmol, MS 4 Å (150 mg), 2 mL
fluorescence intensity as well as lifetime measurements in the
presence of various amounts of Ph3P (for the Stern–Volmer
plots, see ESI).
c
CH3CN, 50 °C, 448 nm, 72 h. condition of non-catalytic reaction: n(alcohol) =
0.15 mmol, n(acid) = 0.18 mmol, n(DIAD) = 0.2 mmol, n(Ph3P) = 0.3 mmol, 2 ml
d
e
CH3CN, 25 °C, 24 h. Preparative yields. Retention : inversion from HPLC,
average value from experiments with (S)- and (R)- alcohol, see ESI.
Table 4 Effect of solvent on the stereoselectivity of ester formation using method A.a
electron-withdrawing ethoxycarbonyl group (entry 5). With
less acidic and/or sterically hindered acids, the
alkyloxyphosphonium species is preferred, which results in
inversion of configuration with very good to excellent
stereoselectivities (entries 1 and 2). The esterification of non-
chiral benzyl alcohol and benzoic acid was inspected by an
experiment with 18O-labelled acid, which showed the ester to
be formed by acyl vs. alcohol activation in a ratio varying from
25:75 in BTF to 66:34 in acetonitrile (see the ESI).
Solvent
Yieldb
[%]
Yieldb
[%]
erc
erc
CH3CN
acetone
THF
35
20
18
36
33
53
93:7
40
-
99.9:0.1
The steric effect of the alcohol and/or acid structure on the
stereoselectivity of Mitsunobu esterification has previously
been observed in a few studies.1a,5c,6 Nevertheless, the results
obtained by this new azocarboxylate-free photoesterification
(Table 3, method A) are surprising compared to those from
flavin-based photocatalytic esterification under Mitsunobu
conditions with a catalytic amount of dialkyl azodicarboxylate
(method B) and those from “dark” stoichiometric Mitsunobu
reaction (method C), which clearly showed either retention or
inversion of configuration, respectively, with all investigated
substrates. The question then arose as to the origin of this
difference. Although solvent has never been observed as the
dominant factor in determining the stereochemistry of
Mitsunobu esterification, we firstly examined whether
substitution of acetonitrile (used in method B) by BTF (used
inmethod A) could play a role in defining the stereochemistry.
90:10
55:45
38:62
40:60
40:60
-
-
-
PhCl
-
-
-
toluene
BTF
-
19
10:90
a
b
c
For conditions, see Table 2. Preparative yields. Retention : inversion from
HPLC, see ESI.
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transfer. Although the excited triplet state of flavin exists in
dry acetonitrile for tens of microseconds, with an estimated
0.04
0.03
0.02
0.01
0.00
-0.01
-0.02
T1 Tn
lifetime of 68 ꢁs (Figure 2A), this is significantly shortened by
the addition of Ph3P (Figure 2B). The quenching rate of the
A
triplet excited state of flavin by Ph3P was estimated to be 4.1 ×
109 -1 s-1 from a Stern–Volmer plot (Figure 2C). The reaction
M
pathway of photoinduced ET from Ph3P to 3Fl* can be
expected to predominate under conditions of esterification
t [ꢁs]:
because of the much longer intrinsic lifetime of 3Fl* (68
ꢁs)
0.22
flavin 1
3
6
compared to that of 1Fl*(5.7 ns). For instance, at the Ph3P
concentration of 10-2 M, over 99% of 3Fl* undergoes
12
24
48
96
192
1
quenching, while only approximately 20% in the case of Fl*.
-0.03
300
S0 bleaching
Electron transfer from Ph3P to flavin
-
1 in an excited state leads
to flavin radical anion Fl● , formation of which was detected by
400
500
600
700
800
nm
+
transient spectra (see ESI). Unfortunately, Ph3P● was not
clearly observed in our transient spectroscopy experiments,
most probably because of its very low molar absorption
coefficient (see ref.9c) and overlap with the signals of flavin
anion species (see ESI).
0.04
0.03
0.02
0.01
0.00
-0.01
-0.02
B
Additionally, we observed Ph3P to react with water under
argon atmosphere or with oxygen under air in dry solvent to
form triphenylphosphine oxide in acetonitrile or BTF in the
presence of 10 mol% of flavin
1 when the solution was
t [ꢁs]:
irradiated (see Scheme 3). Under argon atmosphere in the
absence of water (in dry solvent) or in the dark, oxidation
reaction was not observed. These results provide further
evidence that excited flavin is able to generate Ph3P●+, which
can then react with an oxygen source or a nucleophile. It
should be noted that the formation of triphenylphosphine
oxide from Ph3P has been proved several times to occur
0.08
0.5
1
2
4
flavin
1
+ Ph3P
-0.03
300
400
500
600
700
800
nm
+
through Ph3P● , which is believed to react smoothly with water
or oxygen.9
O
C
PPh3
PPh3
R2OH
R2O
R1COOH
or
R1
OR2
40
20
0
Fl*
Fl
H+
R2OH
retention
product
+
450 nm
Ph3P OCOR1
1/2Fl
Ph3P=O
Ph3P OCOR1
or
Ph3P OR2
FlH
ox
1/2 FlH
O
C
Ph3P OR2
R1COO
R1
OR2
ArNO2
- H2O
ArNH2
inversion
product
+
H+
R1COOH
Ph3P=O
0.000
0.005
phosphine concentration [M]
0.010
Scheme
2
Proposed mechanism of flavin- and Ph3P-mediated photocatalytic
esterification. In the scheme, flavin 1 is labeled as Fl as the mechanism is expected as
general for flavin derivatives.
Figure 2. Transient absorption spectra of 1 (c = 5.8 × 10-5 mol L-1) in the absence (A) and
in the presence (B) of Ph3P (c = 7 × 10-4 mol L-1) in various times after laser pulse
Scheme 3 Flavin-mediated photocatalytic oxidations of triphenylphosphine in the
excitation (λ
= 355 nm, 1 mJ) and Stern-Volmer dependence at various Ph3P
concentrations (C). Dry acetonitrile has been used as a solvent.
The driving force for photoinduced electron transfer from Ph3P
to the flavin triplet state (3Fl*) estimated from corresponding
redox potentials (ꢀ
Get = Eox(Ph3P)–Ered*(3Fl) = 1.00 – 1.25 = –
0.25 eV) shows that it is also an exergonic process and, indeed,
laser-flash photolysis experiments gave direct evidence that
flavin in its triplet excited state participates in electron
presence of oxygen or water.
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It is reasonable to assume that flavin radical anion Fl●ꢀ (pKa of
conjugated acid is 8.4, ref.14) will be immediately protonated
by
a
carboxylic acid to form radical FlH● (Scheme 2).
Subsequently, Ph3P●+ can react with an alcohol (analogously to
the abovementioned reaction with water) or carboxylate to
form a phosphoranyl radical Ph3P●-X, which is likely to be
rapidly
oxidized
to
corresponding
alkyloxy-
or
acyloxyphosphonium species. The redox potential of the Ph3P+-
X/Ph3P●-X redox couple can be estimated based on reduction
half-wave
potentials
of
related
compounds,
tetraphenylphosphonium (E0
=
–2.16 V vs. SCE) or
methyltriphenylphosphonium (E0 = –2.22 V vs. SCE).15 Several
agents in the reaction mixture are sufficiently oxidizing to
●-
induce this oxidation, e.g. nitrobenzene (NB; E(PhNO2/PhNO2
) = –1.22 V vs. SCE, ref.16) or flavin
1, even in its ground state
(E(1/1●-) = –0.82 V vs. SCE).
In
a
separate experiment, we confirmed that an
Figure 3 31P NMR spectrum of Ph3P irradiated in the presence of 1 in CH3OH (A),
spectrum of Ph3P=O (B, standard); spectrum of Ph3P in the presence of CH3I (C) and
spectrum of Ph3P (D, standard containing traces of Ph3P=O).
alkoxyphosphonium species is formed from Ph3P in the
presence of an alcohol and flavin, as evidenced by the 31P NMR
spectrum of the mixture following irradiation with visible light.
Only a low concentration of alkoxyphosphonium species was
observed under conditions of photoesterification, showing
that this reactive species reacts smoothly with a nucleophile.
In an excess of alcohol (experiment performed in methanol), a
significant amount of alkoxyphosphonium salt was detected
together with methyltriphenylphosphonium, the product of
alkylation of Ph3P with methoxytriphenylphosphonium (see
Figure 3).
O
COOH
flavin 1 (10%)
PPh3 (2 equiv.)
448 nm
O
+
OH
22%
A
NH2
1.1
:
BTF, Ar
MS 4A
PhNO2
O
1
N
H
1
: 1
CF3
A final question remained unanswered about functioning of
nitrobenzene in the photocatalytic esterification. In studying
the reaction of 3-trifluoromethylbenzoic acid with benzyl
alcohol in the absence of nitrobenzene using various amounts
of flavins (0–20 mol% with respect to the substrate), we
observed ester formation in slightly lower amounts (possibly
as a result of flavin bleaching) than might have been expected
by taking into account the amount of flavin that was not
O
F3C
F3C
F3C
B
COOH
flavin 1 (10%)
PPh3 (2 equiv.)
448 nm
N
H
71%
+
BTF, Ar
MS 4A
PhNO2
O
H2N
N
H
CF3
25%
(from PhNO2)
regenerated; e.g. 5% or 7% ester employing 10% and 20% of 1,
Scheme 4 Competitive reaction of benzoic acid with benzyl alcohol and aniline (A) and
respectively (see the ESI). Thus, nitrobenzene seems to be
crucial for flavin re-oxidation, allowing 84% of the ester to be
formed under the same conditions. On the other hand, the
fact that some ester is also formed in the absence of
nitrobenzene shows that its side-role, if indeed there is one, is
rather minor; e.g. nitrobenzene could participate in the
oxidation of Ph3P●-X to Ph3P+-X.
controlled amide formation by flavin-Ph3P-mediated photocatalytic process (B).
A more substantial amount of amide was also formed when an
aniline was present in an excess; for example competitive
reaction of benzoic acid with benzyl alcohol and aniline
(alcohol-aniline ratio 1:1) afforded mixture of corresponding
ester and amide in the ratio around 1:1 though conversion of
alcohol to ester was only 22% (Scheme 4A); most importantly,
reaction of trifluorobenzoic acid with 4-trifluoromethylaniline
(instead of an alcohol) under our conditions in the presence of
In looking for products of nitrobenzene reduction during
esterification under common conditions, we invariably
detected only
a small amount of the amide of the
corresponding acid (1–5% with respect to the amount
expected) and unreacted nitrobenzene (up to 15%) as the only
compounds containing nitrogen. Interestingly, a significant
amount (48%) of amide was found in the reaction mixture
when an excess (2 equiv.) of carboxylic acid was added. Most
probably, aniline formed as a final product of nitrobenzene
reduction was trapped by acyloxyphosphonium to form an
amide. If there is insufficient amount of acid, aniline will
probably polymerize under the reaction conditions (e.g., on
the surface of molecular sieves).17
nitrobenzene
as
oxidant
provided
71%
of
trifluoromethylanilide and only a small amount (25%) of amide
with aniline being slowly released by nitrobenzene reduction
during the catalytic process (Scheme 4B). This result suggests
that our photocatalytic procedure may eventually be used for
amide synthesis.
Not only aniline, but also other intermediates of nitrobenzene
reduction can undergo polymerization reactions. Moreover,
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Table 5 Photocatalytic aerial oxidation of benzylalcohol in the presence of nitrogen
oxidants.a
nitrobenzene and nitrosobenzene are reported to be
deoxygenated with Ph3P with the formation of Ph3P=O.18 This
undesired process also occurs under our conditions, as
evidenced by a blank experiment conducted in the absence of
alcohol and carboxylic acid (see the ESI). Deoxygenation of
nitrobenzene and nitrosobenzene explains why an excess of
nitrobenzene is necessary in our photocatalytic system and
also the fact that 48% of aniline (see above) was captured in
the form of amide in esterification with an excess of carboxylic
acid which is remarkably more than expected amount 33%
(relative to amount ester formed). Theoretically, only one-
third of an equivalent of nitrobenzene could be enough,
considering that all reduction intermediates, nitrosobenzene
(E(PhNO/PhNO●-) = –1.07 V vs. SCE, ref.16), azoxybenzene
(E(PhN=N(O)Ph/PhN=N(O)Ph●-) = –1.44 V vs. SCE, ref.16), and
azobenzene (E(PhN=NPh/PhN=NPh●) = –1.42 V vs. SCE, ref.16),
could participate in flavin re-oxidation, based on their
MeO
MeO
MeO
flavin 1 (10%)
450 nm
+
CH3CN
oxidant
O
N
OH
Ph
Entry
Oxidant
Conv. to aldehyde (or imine)
[%]
1
2
3
4
5
6
7
-
20
PhNO2 (1 equiv.)
PhNO2 (2 equiv.)
PhNO2 (5 equiv.)
PhNO (5 equiv.)
66
80
quant.b
quant.
quant.
67
PhN(O)=NPh (5 equiv.)
PhN=NPh (5 equiv.)
a
Conditions: n(alcohol) = 0.15 mmol, n(1) = 0.015 mmol, 2ml BTF, 40 °C, 24 h;
conversion was determined by 1H NMR. b Aldehyde and imine was present in the
reduction potentials. Indeed, the high conversion to ester
3
reaction mixture in the ratio 8:2.
corroborated flavin catalyst recycling by these agents
(Scheme 5). It should be noted that by using 1 equivalent of
nitrobenzene relative to alcohol (triple excess relative to
theoretical amount) we always observed nitrobenzene (up to
15%) remaining in
the reaction mixture
after
photoesterification. However any attempt to reduce
nitrobenzene loading led to lower ester yields (see the ESI).
The use of a nitro compound as a sacrificial oxidizing agent in
flavin catalysis is still unknown in artificial systems.19 To gain Scheme 6 Schematic description of redox behaviour of flavin 1 (Fl) and nitrobenzene.
insight into this process, we investigated it in flavin-mediated
4-methoxybenzyl alcohol oxidation, which is a “standard”
oxidation process studied by many authors.20 Whereas in the
absence of a sacrificial oxidant, a small amount of aldehyde
was formed in an irradiated mixture containing a catalytic
Finally, to gain direct evidence concerning flavin re-oxidation
with nitrobenzene, we generated the reduced flavin by
1
catalytic hydrogenation (see the ESI). After filtering off
palladium and addition of 1 equivalent of nitrobenzene (all
operations performed in a glove-box), we did not observe the
formation of oxidized flavin by 1H NMR. On the other hand,
after adding 50 equivalents (corresponding to the amount of
nitrobenzene used in flavin-catalyzed benzyl alcohol
oxidations), we observed a fast colour change and green
fluorescence typical for the oxidized form of flavins. 1H NMR
analysis showed that besides nitrobenzene and a product of its
amount of flavin
1 (Table 5, entry 1), nitrobenzene
substantially increased the amount of aldehyde formed
(entries 2 and 3). With an excess of nitrobenzene, quantitative
chemoselective formation of aldehyde (no overoxidation) was
observed (entry 4). In this case, approximately 20% of
benzaldehyde was transformed to an imine by aniline formed
from nitrobenzene. Importantly, similar results were obtained
when nitrosobenzene, azoxide, and azobenzene (entries 5–7)
were used instead, thus confirming their possible participation
in the flavin regeneration process.
reduction, only oxidized flavin
1 was present in the mixture
and not its reduced form (see the ESI). Inspecting the redox
potentials of participating species, nitrobenzene (and its
reduction products) can oxidize fully reduced flavin to radical
species, but it is not strong enough to oxidize the flavin radical
to the fully oxidized form (Scheme 6). This can be explained in
terms of the re-oxidation of fully reduced flavin (FlH-) to radical
,
FlH● which then disproportionates to the reduced FlH- and
oxidized flavin Fl (cf. Scheme 2). Similar disproportionation was
proved to occur in flavin-mediated benzyl alcohol
photooxidations.20b
O
flavin 1 (10%)
PPh3 (2 equiv.)
448 nm
F3C
COOH
F3C
O
Ph
+
HO
BTF, Ar
MS 4A
oxidant
oxidant (conversion):
PhNO2 (84%) PhNO (30%)
O
(53%)
Ph N=N Ph
Ph N=N Ph (38%)
Scheme 5 Photocatalytic esterification using various oxidizing agents.
Conclusions
We have proved that the triphenylphosphine radical cation
Ph3P●+, generated by photoinduced electron transfer to flavin
1, can be utilized for the activation of alcohols or acids to
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Journal Name
Lambert and E. D. Nacsa, Org. Biomol. Chem., 2014, 12
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promote ester formation by nucleophilic substitution reaction
(both SN or SNAc). It should be noted that photooxidation to
phosphine oxides has hitherto been the sole reported
photoredox procedure with triphenylphosphine.9 Thus, our
finding could provide impetus for the design of other methods
utilizing photoactivated phosphine in various organic
transformations. It could be expected that not only flavins, but
also other dyes, might be suitable for this purpose. In the
present case, application of this new approach has led to the
development of an effective esterification method based on
flavin photocatalyst, triphenylphosphine, and visible light,
which has proved applicable to a broad range of substrates,
including less reactive aliphatic acids and alcohols. Regarding
stereoselectivity, we observed an unusual switch from
preferential inversion to retention of configuration in the
esterification of chiral alcohols which was caused merely by
changing the solvent. Previously, such a change has been
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8
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mainly associated with
a change of alcohol or acid
structure.1a,5c,6 It should be noted that also such a preferential
inversion of configuration in aza-reagent-free esterification is
unique.10 The presented method uses nitrobenzene as a novel
sacrificial oxidant to regenerate the flavin catalyst. It could also
be helpful in other flavin-based oxidative procedures,
especially with substrates sensitive to oxygen, which has
hitherto been the sole stoichiometric oxidant used in flavin
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Conflicts of interest
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Soc. Jpn., 2006, 79, 1489-1500; c) M. Nakamura, M. Miki and
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There are no conflicts to declare.
G. X. Gu and H. Guo, RSC Adv., 2017,
Bonesi, S. Protti and A. Albini, J. Org. Chem., 2016, 81
11678-11685; g) S. Yasui, S. Tojo and T. Majima, Org. Biomol.
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Acknowledgements
,
This project was supported by the Czech Science Foundation
(Grant No. 16-09436S), and Ministry of Education, Youth and
Sports of the Czech Republic (Specific university research No
4
10 T. Taniguchi, D. Hirose and H. Ishibashi, ACS Catal., 2011, 1,
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11 M. März, J. Chudoba, M. Kohout and R. Cibulka, Org. Biomol.
Chem., 2017, 15, 1970-1975.
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Tanaka, N. Haraguchi, S. Itsuno and Y. Imada, Chem. Sci.,
2017, 8, 5468-5475; b) H. Iida, Y. Imada and S. I. Murahashi,
21-SVV/2018). M.S. would like to thank support by the
research grant 2017/27/B/ST4/02494 from the National
Science Centre, Poland (NCN). Authors thank Pavlína Kyjaková
for chiral-GC experiments.
Org. Biomol. Chem., 2015, 13, 7599-7613; c) R. Cibulka, Eur.
J. Org. Chem., 2015, 2015, 915-932; d) T. Ishikawa, M.
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Notes and references
‡
It should be noted that Mitsunobu reactions catalytic in the
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2018, 59, 658-662; b) V. Mojr, G. Pitrová, K. Straková, D.
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ChemCatChem, 2018, 10, 849-858; c) B. Mühldorf and R.
dialkyl azadicarboxylate represents an alternative way how to
reduce its amount.7
§ Molecular sieves were needed to decompose hydrogen peroxide
(a possible substrate for Mitsunobu reaction) formed during aerial
flavin re-oxidation and, consequently, to remove water generated
by H2O2 decomposition.
Wolf, ChemCatChem, 2017, 9, 920-923; d) J. B. Metternich,
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Text:
Photoredox catalysis: new way how to induce triphenylphosphine to be able to mediate nucleophilic
substitution reactions of alcohols and acids
TOC: