Titania-promoted carboxylic acid alkylations of alkenes and cascade addition-cyclizations

Article abstract of DOI:10.1021/jo4027929

Photochemical reactions employing TiO₂ and carboxylic acids under dry anaerobic conditions led to several types of C-C bond-forming processes with electron-deficient alkenes. The efficiency of alkylation varied appreciably with substituents in the carboxylic acids. The reactions of aryloxyacetic acids with maleimides resulted in a cascade process in which a pyrrolochromene derivative accompanied the alkylated succinimide. The selectivity for one or other of these products could be tuned to some extent by employing the photoredox catalyst under different conditions. Aryloxyacetic acids adapted for intramolecular ring closures by inclusion of 2-alkenyl, 2-aryl, or 2-oximinyl functionality reacted rather poorly. Profiles of reactant consumption and product formation for these systems were obtained by an in situ NMR monitoring technique. An array of different catalyst forms were tested for efficiency and ease of use. The proposed mechanism, involving hole capture at the TiO₂ surface by the carboxylates followed by CO₂ loss, was supported by EPR spectroscopic evidence of the intermediates. Deuterium labeling indicated that the titania likely donates protons from surface hydroxyl groups as well as supplying electrons and holes, thus acting as both a catalyst and a reaction partner.

Full text of DOI:10.1021/jo4027929

Article
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Titania-Promoted Carboxylic Acid Alkylations of Alkenes and
Cascade Addition−Cyclizations
David W. Manley,* Roy T. McBurney, Phillip Miller, and John C. Walton*
EaStCHEM School of Chemistry, University of St. Andrews, St. Andrews, Fife KY16 9ST, United Kingdom
Andrew Mills and Christopher O’Rourke
School of Chemistry and Chemical Engineering, Queens University Belfast, Stranmillis Road, Belfast BT9 5AG, United Kingdom
S
* Supporting Information
ABSTRACT: Photochemical reactions employing TiO2 and
carboxylic acids under dry anaerobic conditions led to several
types of C−C bond-forming processes with electron-deficient
alkenes. The efficiency of alkylation varied appreciably with
substituents in the carboxylic acids. The reactions of
aryloxyacetic acids with maleimides resulted in a cascade
process in which a pyrrolochromene derivative accompanied
the alkylated succinimide. The selectivity for one or other of
these products could be tuned to some extent by employing
the photoredox catalyst under different conditions. Aryloxy-
acetic acids adapted for intramolecular ring closures by
inclusion of 2-alkenyl, 2-aryl, or 2-oximinyl functionality
reacted rather poorly. Profiles of reactant consumption and
product formation for these systems were obtained by an in
situ NMR monitoring technique. An array of different catalyst forms were tested for efficiency and ease of use. The proposed
mechanism, involving hole capture at the TiO2 surface by the carboxylates followed by CO2 loss, was supported by EPR
spectroscopic evidence of the intermediates. Deuterium labeling indicated that the titania likely donates protons from surface
hydroxyl groups as well as supplying electrons and holes, thus acting as both a catalyst and a reaction partner.
organic substrates11 or more complete substrate mineraliza-
INTRODUCTION
■
tions.12 Under anhydrous, anaerobic conditions and with
Carboxylic acids are pervasive in nature and are produced
industrially on a large scale. Therefore, methods of employing
certain substrates, TiO2 SCPC can lead to the generation of
specific radicals adapted for molecular assembly applications.
To date, however, only a modest number of such processes
have been identified and developed.13 Notably, SCPC additions
of enol ethers to various acceptors have been investigated,14
and successful additions of tertiary amines to electron-deficient
alkenes, some bearing chiral auxiliaries, have been described.15
We recently discovered that under dry, anaerobic conditions,
TiO2 mediation with carboxylic acid precursors could result in
carbon−carbon bond-forming processes. Alkylations and
annulations were achieved when photolyses of certain acid
precursors were carried out in the presence of suitable electron-
deficient alkenes.16 This paper reports advances in crucial
aspects of this process in the following areas: (1) structural
features in the carboxylic acids that are necessary and sufficient;
(2) the range of functionality in the alkene acceptors that can
be tolerated; (3) how the reactions respond to modifications to
them in organic preparations have received a lot of attention.
Hard UV (λ ≤ 250 nm) irradiations generate carbon-centered
radicals but also induce much degradation.1,2 Conventionally,
decarboxylative alkylations have relied on preparations of
unappealing precursors such as peroxides,3 Barton esters,4 or
Hunsdieker salts.5 Recently attention shifted toward discover-
ing catalytic systems capable of utilizing them in target-oriented
syntheses. Decarboxylative copper-catalyzed reactions of
carboxylic acids with carbonyls6 and with aldimines,7 and of
amino acids with alkynes8 have been reported. Photoredox
methods have also been used for this purpose9 but can suffer
from difficulties in removing the catalyst. Interest in
heterogeneous photoredox methods for carboxylates dates
back to the 1970s and the photo-Kolbe
́
reaction.10
Semiconductor photoredox catalysis (SCPC) offers tangible
advantages for organic preparations. The chosen semiconductor
can be nontoxic and can easily be removed by filtration, and
when visible or soft UVA light is used, the procedure can be
convenient and benign. Most applications of TiO2 SCPC have
utilized aerobic conditions, resulting in selective oxidations of
Received: December 17, 2013
Published: January 17, 2014
© 2014 American Chemical Society
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the catalyst form and the catalyst support; and (4) the
mechanism followed by the reaction.
The efficiency of the process evidently increased as the
stabilization energy of the released radical increased (see the
Supporting Information for a plot of radical stabilization energy
vs yield). The observation of a significant amount of 4 in each
case suggested that alkene 2 plays the role of an electron sink,
consuming electrons in two sequential reduction−protonations.
2. Additions of Stabilized Radicals to N-Phenyl-
maleimide. We next examined a set of addition reactions
with N-phenylmaleimide involving more diverse carboxylic
acids (Scheme 2). Primary alkyl radicals stabilized by α-alkoxy
RESULTS AND DISCUSSION
■
In our preliminary study,16 we discovered an experimental
protocol with reasonably wide applicability utilizing Degussa
(Evonik) P25 as a 1−5 mg mL−1 dispersion in dried
acetonitrile. This dispersion, with added carboxylic acid and
substrate, in an oven-dried Pyrex tube was purged with argon
and then irradiated by two face-to-face sunlamp arrays (UVA)
at ambient temperature. After photolysis, the catalyst was
removed by filtration and the products were isolated by
conventional organic techniques.
Scheme 2. P25-Promoted Alkylations of N-Phenylmaleimide
with Diverse Carboxylic Acids
1. Alkylations of Maleimide with Aliphatic Carboxylic
Acids. During initial investigations, N-phenylmaleimide (2)
was found to be an ideal radical acceptor in this system, as it is
symmetrical and photostable, its photodimerization is negligible
(under our experimental conditions), and its electron-with-
drawing character favors addition by weakly nucleophilic
radicals. This alkene was therefore chosen to test the
applicabliity of our process with simple aliphatic carboxylic
acids 1. Standard unoptimized conditions were adopted so a
clear comparison of behavior from acid to acid could be
obtained (Table 1). In all instances, 0.1 mmol of 1 and 0.2
Table 1. TiO2-Promoted Reactions of N-Phenylmaleimide
with Aliphatic Carboxylic Acids
a
yield (%)
entry
R in 1
Me
adduct 3
4
1
2
3
4
5
6
23
4
41
Me(CH2)4
t-BuCH2
i-Pr
2
18
25
38
∼1
40
25
31
trace
t-Bu
a
b
Accompanied by dimers (see the text). Obtained as a 1:1 mixture of
CF3
a
two diastereoisomers.
NMR yields.
groups proved to be a good deal more reactive than the simple
alkyl radicals. Methoxy- and tert-butoxyacetic acids gave the
corresponding adducts (3g and 3h) in reasonable yields of 54%
and 57%, respectively, while 2-tetrahydrofuroic acid furnished a
1:1 mixture of the two diastereomers of 3i in a very pleasing
yield of 75%. However, methylthioacetic acid returned only a
disappointing 34% yield of the desired product 3j. Moderate
and poor yields were obtained with benzyl (57%) and 2-
thienylmethyl acids (22%), but these adducts (3k and 3l) were
accompanied by the dimers bibenzyl (18%) and 1,2-bis-
(thiophen-2-yl)ethane (27%), respectively.
mmol of 2 were photolyzed in a suspension of the P25 catalyst
(12 mg, 0.15 mmol) in CH3CN (12 mL) for 18 h. The
reactions did indeed lead to the formation of adducts 3
incorporating the R moiety of the carboxylic acid and an
additional H atom, together with significant amounts of
succinimide 4 (Scheme 1).
For acids that decarboxylated to give methyl (entry 1) or
primary radicals (entries 2 and 3), the yields were low;
however, increased yields were obtained with secondary and
tertiary radicals (entries 4 and 5). Negligible adduct was
detected for the destabilized, σ-type CF3 radical (entry 6).
Decarboxylative additions also worked with Boc-protected α-
amino acids, and the bottom row in Scheme 2 displays the
adducts and the useful yields obtained. While Boc-proline was
transformed into adduct 3n in a fine yield of 75%, Boc-alanine
and the unnatural α-amino acid Boc-piperidinecarboxylic acid
gave much more modest yields of 38% and 29%, respectively.
As expected, these adducts were 1:1 mixtures of stereoisomers.
No retention of chirality was observed when optically pure
amino acids were employed because the released radicals have
planar, or close to planar, configurations at their reactive
centers. Surprisingly, vinylacetic, ethynylacetic, and cyanoacetic
acids failed to react, even though the released radicals would be
strongly stabilized.
Scheme 1. P25-Promoted Alkylations of N-Phenylmaleimide
with Simple Carboxylic Acids
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3. Comparison of Catalyst Efficiencies. To compare the
efficiencies of different forms of the titania catalyst, the reaction
of phenoxyacetic acid with acrylamide, which was clean and
efficient (82% adduct isolated)16 was chosen. For each
photolysis, suboptimum conditions of phenoxyacetic acid (0.1
mmol) and acrylamide (0.2 mmol) with irradiation for 17 h in
anhydrous CH3CN (12 mL) were employed. Where applicable,
TiO2 (12 mg) was employed in a 1 mg mL−1 dispersion (see
the Supporting Information for full details). With P25 itself
(Table 2, entry 1), a 47% yield of the 4-phenoxybutanamide
Scheme 3. Titania-Promoted Reactions of Aryloxyacetic
Acids with N-Substituted Maleimides
Table 2. Comparison of TiO2 Catalysts for the Reaction of
Phenoxyacetic Acid with Acrylamide
a
entry
catalyst
P25
PC500
sol−gel tube
yield of adduct (%)
b
1
2
3
4
47 (82 )
c
39
d
e
Table 3. Titania-Promoted Reactions of Aryloxyacetic Acids
with Maleimides
73 (68 )
f
Photospheres
9
a
b
NMR yields. Isolated yield from 5:1 acid/acrylamide irradiated for
a
b
entry
R1 R2 (a−f)
conditions
P25, 20 h
P25 dd, 45 h
yield (%)
75
6:7 ratio
c
62 h. Millenium PC500 (anatase, surface area ∼300 m2 g−1, particle
d
1
2
H Me (a)
2.38:1.0
10:1
size 5−10 nm). Schlenk tubes coated internally with P25 by a sol−gel
c
e
f
H Me (a)
75
process. Yield of the isolated product. Hollow glass spheres (mean
diameter 45 μm, density 0.22 g/mL) coated with TiO2, from
Microsphere Technology.
c
3
H Me (a)
coated tube, 22 h
P25, 11 h
75
0.25:1.0
1.0:1.0
0.18:1.0
4.20:1.0
4
H Ph (b)
79
c
5
H Ph (b)
coated tube, 22 h
P25, 22 h
85
d
adduct was recorded. With Millenium PC500 titania, having
about 6 times the surface area,17 the yield dropped slightly
(entry 2). Reactions were also carried out in Schlenk tubes
coated with a fine internal layer of TiO2 by a sol−gel process
(see the Supporting Information for details). These proved to
be very efficient and led to the best yield (entry 3). TiO2
Photospheres consisting of hollow Pyrex beads coated
externally with rutile titania18 delivered lower conversion and
adduct yields (entry 4). This was attributed to difficulties in
dispersing the Photospheres satisfactorily throughout the
reaction flask. Because of their buoyancy, they tended to
accumulate at the top, and this was compounded by the fact
that the high rate of magnetic stirring used in attempts to
overcome this tended to result in their becoming damaged. An
isolated yield of 68% was achieved upon scale-up of the
reaction in the coated tube (entry 3). Incorporation of 4-tert-
butyl and 4-trifluoromethyl substituents in the aryl ring of the
acid component furnished the corresponding adducts in
similarly pleasing yields of 68% and 66%, respectively. Although
the sol−gel-coated tubes gave the best yields and conversions,
the coatings tended to detach, so they could only be used about
three times. We therefore concluded that for ease of handling
with conventional organic techniques, scale-up, and efficient
product formation, the orthodox P25 catalyst was the best
compromise.
6
t-Bu Me (c)
t-Bu Me (c)
t-Bu Ph (d)
t-Bu Ph (d)
CF3 Me (e)
CF3 Me (e)
CF3 Ph (f)
CF3 Ph (f)
57
c
e
7
P25 dd, 42 h
P25, 18 h
56
>10:1.0
8
74
1.64:1.0
0.82:1.0
1.10:1.0
1.70:1.0
0.57:1.0
0.38:1.0
c
9
coated tube, 19 h
P25, 16 h
51
10
11
12
13
61
c
P25 dd, 42 h
P25, 16 h
62
63
c
coated tube, 17 h
93
a
Dispersion of 1 mg mL−1 except for dd = dense dispersion of 5 mg
b
c
d
mL−1. mol % isolated products, except as noted. NMR yield. 15% 6
was obtained in the absence of P25. Only 6 was observed.
e
aromatic ring and for methyl- and phenyl-substituted
maleimides. The reactions with just P25 generally gave a slight
excess of the chromenopyrrole 6 (entries 1, 4, 6, 8, and 10),
except in the case of the CF3 substituent (entry 12), for which
an excess of adduct 7 was observed. The selectivity for
chromenopyrroles 6 was improved by using a more dense
dispersion of P25 (entries 2, 7, and 11). On the other hand,
photolyses in the sol−gel TiO2-coated tubes (entries 3, 5, 9,
and 13) led to a reversal in selectivity with predominant
formation of adduct 7. The possibility to tune the selectivity of
reactions in this manner is an advantage of the technique. The
1H NMR spectra of all 6 had 3JH−H coupling constants between
the two protons at the junction of the pyran and dihydropyrrole
rings within the range of 9.2−9.3 Hz. This indicated a cis
arrangement,19 in agreement with the conclusion that the
reaction selectively formed the cis isomer in every case. Very
few syntheses of dihydrochromeno[3,4]pyrrole-1,3-diones 6
have been reported,20 but compounds with the corresponding
reduced ring system, chromenopyrrolidines, are well-known
biologically active species.21
4. Addition−Cyclizations with Aryloxyacetic Acids.
The reaction of aryloxyacetic acids (5) with N-substituted
maleimides (2) led to N-substituted-3,4-dihydrochromeno-
[3,4]pyrrole-1,3-dione derivatives 6, each accompanied by a
significant amount of the expected adduct 7 (Scheme 3).
Tricyclics 6 presumably resulted from cyclization of the initial
adduct radical onto the aryl ring followed by rearomatization.
Good to excellent overall yields were obtained under all
conditions (Table 3). A moderate amount of succinimide (11−
43% yield) was also formed in each case.
5. Intramolecular Ring Closures with Acceptor-
Functionalized Aryloxyacetic Acids. Three types of acid
framework with different acceptor groups were prepared to test
the applicability of P25-mediated ring closures. 2-(2-
Vinylphenoxy)acetic acids having alkene acceptors with ester
Table 3 shows that the process worked well with both
electron-releasing and electron-withdrawing substituents in the
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(8a), nitrile (8b), and ketone (8c) substituents (Scheme 4)
were obtained by treatment of 2-formylphenoxyacetic acid with
mediated reactions, 8a−c all gave rather complex product
mixtures containing unreacted alkene as a mixture of E and Z
isomers (8/9) as well as the 5-exo ring-closed dihydrobenzo-
furans 10. None of the 4-substituted chroman derivatives from
6-endo cyclizations were detected. Disappointing yields of 10a
and 10b were isolated. The acids with aromatic acceptors 11a−
c all reacted very poorly under both sets of conditions. NMR
and GC−MS analyses showed complex product mixtures
containing possible trace amounts of the cyclized 6H-
benzo[c]chromenes 12a−c. The 2,3-dihydrobenzofuran core
of 10 is found in many natural products and pharmaceutically
relevant molecules and has generated much interest.22
Scheme 4. Substrates and Products for Intramolecular
Reactions
The reaction profile from irradiation of acid 8a in a sol−gel-
coated tube obtained by NMR monitoring (Figure 1) shows
Figure 1. Reaction profile for acid 8a obtained by NMR monitoring.
the sharp decrease in 8a (the E isomer), which was all
consumed in <150 min. The Z isomer 9a initially increased,
passed through a maximum at about 25 min, and then steadily
decreased as it too was converted to cyclic product 10a. The
latter steadily increased, reaching a plateau by about 200 min.
Analogous reaction profiles were obtained for the sol−gel tube
reactions of 8a−c, 11b, and 13a. No cyclized product was
identified in the sol−gel tube reactions of 11a and 11b. A
significant yield (28%) of the cyclized product N-(2,3-
dihydrobenzofuranyl)-O-methylhydroxylamine (14a) was
found in the sol−gel tube reaction of oxime ether-function-
alized acid 13a (Scheme 4). However, attempts to isolate and
fully characterize this alkoxyamine were not successful.
a
Yields in brackets are maximum yields from NMR monitoring of sol−
b
1
gel tube reactions. Yield estimated by H NMR analysis (nd = not
determined).
the appropriate phosphorane (see the Experimental Section). 2-
(Biphenyl-2-yloxy)acetic acids 11a−c having aromatic accept-
ors were prepared by coupling of the appropriate 1,1′-biphenyl-
2-ol with methyl bromoacetate and subsequent hydrolysis of
the ester with LiOH in MeOH/H2O. Acids 13a and 13b having
oxime ether acceptor groups were prepared by condensation of
2-formylphenoxyacetic acid with the appropriate alkoxylamine
hydrochloride. Reactions with these acids were carried out in
two ways. The first used P25 under standard conditions as
described above. The second used 1 mL aliquots of acid
solutions (10 mM) in CD3CN (5 mL) in sol−gel-coated NMR
tubes. The tubes were purged with argon and then placed in an
overhead stirrer (turned on its side), which was then spun at
250 rpm. The tube was held at a slight angle with respect to
horizontal in the “chuck” of the overhead stirrer so that, when
rotated, it described a small (ca. 2 cm) circle at its non-chuck-
held end so as to agitate the reaction solution. Irradiation was
performed using a photoreactor with twelve 8 W black light
blue (BLB) UV lamps (λmax = 365 nm) (see the Supporting
Information for a graphic). Periodically the tube was removed
for NMR analysis. This was repeated until all of the starting
material had been consumed or the product concentration
plateaued. For acids 8a−c with alkene acceptors, control
photolyses in the absence of TiO2 showed that E/Z
isomerization was significant (52−79%). In conventional P25-
6. Mechanism of the Reaction. Hole capture at the TiO2
surface by a carboxylate creates the corresponding acyloxyl
radical. Decarboxylation of this species furnishes the corre-
sponding alkyl radical. Radicals of this type were directly
observed by CW X-band EPR spectroscopy of frozen
suspensions of P25 and t-BuCO2H in CH3CN.16 Transient t-
Bu• radicals and PhOCH2 radicals were observed during UV
•
irradiation of the acids t-BuCO2H and PhOCH2CO2H,
respectively, with PC-50023 in fluid PhH at 300 K.16 In similar
EPR experiments with vinylacetic acid and 2,2,2-triphenylacetic
acid, we were also able to detect and characterize allyl and
triphenylmethyl radicals, respectively (see the Supporting
Information). The isotropic character of the solution EPR
•
spectra of all the RXCH2 radicals established that in the main
they were freely tumbling and not attached to the TiO2 surface
(Scheme 5).
Literature precedents imply that weakly nucleophilic
•
RXCH2 radicals should add rapidly to the electron-deficient
double bonds of maleimides (and similar acceptors).24 Most
likely the resulting adduct radicals 15 will be converted to
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valence-band holes.29 Electron transfer from the π system of the
Scheme 5. Proposed Mechanism for TiO2-Promoted
Reactions of Carboxylic Acids and Maleimides
carboxylate to a hole trap site furnishes the surface-bound
•
RXCH2−CO2 radical. We propose that a competition exists
between β-scission of this surface-bound species to yield the
•
desired free RXCH2 radical and back transfer of the electron,
either from the trap site or from trapped conduction-band
electrons, to the carboxylate. For acid precursors that generate
stabilized RXCH2• radicals, such as those depicted in Scheme 2,
the decarboxylation step is more favorable, thus explaining the
improved yields and conversions recorded. Conversely, for the
simple aliphatic acids of Table 1, the radical stabilization energy
from the RX groups is minimal, so back transfer of an electron
to the TiO2 will take precedence over the loss of CO2. This is
illustrated in Scheme 6.
Scheme 6. SET Photoxidation Events Taking Place between
Carboxylic Acids RXCH2CO2H and the TiO2 Surface
enolates 16 by electron transfer from the TiO2 particles. Ready
protonation25 will afford adducts 3, 7, etc. (Scheme 5). For
ArOCH2• radicals containing aromatic rings, addition produces
electrophilic imidoalkyl radicals 15, for which a competition
exists between reduction to adducts 7 or homolytic closure (6-
endo-trig) onto the aryl ring. As radicals 15 are weakly
electrophilic in character, this annulation should be favored by
increasing the electron density in the ring and, conversely,
disfavored by decreasing it.26 In agreement with this, the
proportion of 6 increased when an electron-releasing tert-butyl
group was introduced to the ring, whereas it decreased when an
electron-withdrawing trifluoromethyl group was introduced.
The resonance-stabilized cyclohexadienyl-type radicals 17 will
rearomatize to yield the functionalized chromenes 6. This
aromatization could result from hole capture from TiO2 by the
radicals 17 and subsequent proton loss as shown. Alternatively,
electron transfer to maleimide might take place, as suggested in
related work by Hoffmann.15b,c Protonation of the resulting
maleimide radical anions, followed by further electron capture
and protonation steps, would explain the significant yields of
succinimides obtained in our reactions. However, as greater
amounts of succinimides than cyclized products 6 were
generally formed, it is thought that direct reduction of the
maleimide acceptor by the conduction band of the P25 also
initiates this process.
It should be noted that while we believe radical stability to be
a key aspect in this system, it is clear that there are other factors
at play as well and that these take precedence in deciding the
reaction outcome in a few instances. For example, vinylacetic
acid would be expected to generate the allyl radical very readily
in the presence of photoexcited TiO2. While we did observe the
allyl radical in our EPR experiments, no products at all were
observed in the preparative photolysis involving vinylacetic acid
and 2. In this case, other as yet unknown factors at the TiO2
surface must come into play.
A crucial feature of the process is that in the formation of
adducts 3 and 7 a hydrogen atom is gained from some source
within the dispersion. This is not the proton lost from the
aromatic ring because reduced adducts were formed equally well
from acids lacking aromatic rings. Several deuterium labeling
experiments were carried out to try to identify the source. The
reaction of phenoxyacetic acid with acrylamide was again
chosen as a test-bed process (Scheme 7) because it was clean
and practically quantitative.
From the results described in Schemes 1 and 2 and Table 1,
it can be deduced that the stability of the initial radicals is an
important factor in this system. Carboxylic acids dissociate on
the TiO2 surface to give the corresponding surface-bound
carboxylate and a proton.27 Photolysis with UVA and resultant
photoexcitation generates an electron−hole pair, which can
migrate through the bulk of the semiconductor to the surface.
The TiO2 surface is extensively hydroxylated,28 and it is
thought that these species act as surface trapping sites for the
When this reaction was carried out in d3-CH3CN solvent, the
isolated adduct was screened for D incorporation by 1H and 2H
NMR spectroscopy and GC−MS. However, no deuterium
could be detected in the 4-phenoxybutanamide (19H).
Reaction with d1-phenoxyacetic acid also yielded adduct with
no detectable D incorporation. Thus, unless the acidic D atom
of 5a rapidly and completely exchanges, the source of the
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hydroxyl groups, thus acting as both a catalyst and a reaction
partner.
Scheme 7. Deuterium Labeling Test Reactions
These photoredox reactions are cleanly, safely, and cheaply
carried out in the laboratory, and the heterogeneous catalyst is
simply filtered off during workup. Thus, with the exception
mentioned above, they constitute a useful synthetic protocol.
EXPERIMENTAL SECTION
■
General Procedure for TiO2 Photoredox Experiments. To a
suspension of semiconductor (1−5 mg mL−1) in MeCN (freshly
distilled over CaH2) in an oven-dried Pyrex tube were added known
amounts of the desired carboxylic acid and alkene. The resulting
suspension was degassed by bubbling with argon for 20 min. The
mixture was then irradiated with eight 29 cm 15 W Philips Cleo tubes
(λ = 350 nm) for the desired reaction time at ambient temperature.
Following irradiation, the semiconductor powder was removed by
filtration through a Celite pad. The solvent was removed under
reduced pressure, and the reaction mixture was purified by
chromatography. Yields were determined from the amounts of isolated
products and/or from the 1H NMR spectra by reference to CH2Br2 as
an internal standard. Additional general procedures are described in
the Supporting Information.
additional H atom is neither the acid nor the solvent. The most
likely source therefore is the P25 semiconductor. Obviously it is
counterintuitive that a metal oxide would supply protons.
However, it is well-established that H2O molecules and HO
groups are attached to the surface of the TiO2 particles.28a
Drying P25 in a vacuum at 150 °C removes a significant
amount of the surface H2O while leaving the chemically
attached HO groups. When P25 dried in this way was used, the
yield of 18 was scarcely reduced, suggesting that the OH groups
were likely the proton donors. Attempts were made to
deuterate the H2O and OH groups on the P25 surface by
refluxing in degassed D2O in a glovebox. However, it was found
that back exchange occurred immediately upon exposure to air
and rapidly with any moisture traces in solvents or on surfaces.
Only partly deuterated P25 (ca. 80% as judged by IR) could be
obtained. Definitive experiments were difficult to achieve
because of this. When the partly deuterated P25D was
photolyzed with the undeuterated acid, the phenoxybutanamide
product contained no deuterium. It seemed possible, however,
that P25 surface OD groups could have rapidly exchanged with
protons from the COOH groups of 5a. Experiments with partly
deuterated P25D and 5a-COOD were also carried out, but
deuterated 19D was again not found. In view of the partially
deuterated nature of the P25D and the ease with which it
reverts to the protiated form, making handling difficult, our
tentative conclusion is still that the P25 is the source of the H
atoms.
NMR Tube Irradiations. Irradiations were carried out using titania
sol−gel-coated NMR tubes. A photoreactor consisting of two lots of
six 8 W BLB UV lamps (emission λmax = 365 nm), each arranged in a
semicylinder with an aluminum reflector, was used to irradiate the
contents of the NMR tube. The two photoreactor semicylinders were
brought together to surround the NMR tube (see the Supporting
Information for a graphic). For a typical reaction, a stock solution
comprising acid (10 mM) in d3-CH3CN was prepared. This solution
was purged with argon for 5 min, and then 1 mL was pipetted into an
argon-flushed sol−gel-coated NMR tube. The cap was quickly
replaced on the tube and sealed with Parafilm. The loaded NMR
tube was placed in an overhead stirrer (turned on its side), which was
spun at 250 rpm. The tube was held at a slight angle with respect to
horizontal in the chuck of the overhead stirrer so that, when rotated, it
described a small (ca. 2 cm) circle at its non-chuck-held end so as to
agitate the reaction solution. Once the NMR tube was in place, the
irradiation was started, and the tube was periodically removed and
analyzed by NMR.
Deuterium Labeling Experiments. These experiments were
carried out in a similar fashion to the photoredox experiments outlined
above. Following photolysis, the reaction mixtures were scrutinized for
CONCLUSIONS
■
We have found that photochemical reactions employing P25
and carboxylic acids under dry anaerobic conditions generate
C-centered radicals that can be deployed in several types of C−
C bond-forming processes. Simple aliphatic carboxylic acids
alkylated N-phenylmaleimide, albeit rather inefficiently. Acids
that yielded alkoxyalkyl, alkylthioalkyl, and benzyl radicals
alkylated electron-deficient alkenes in moderate to good yields.
Boc-protected amino acids furnished aminoalkyl radicals that
alkylated N-phenylmaleimide in useful yields. The reactions of
aryloxyacetic acids with maleimides resulted in a cascade
process in which a pyrrolochromene derivative accompanied
the alkylated succinimide. Selectivity for one or other of these
products could be tuned to some extent by employing the TiO2
catalyst under different conditions. Aryloxyacetic acids adapted
for intramolecular ring closures by the inclusion of 2-alkenyl, 2-
aryl, or 2-oximinyl functionality reacted rather poorly, especially
the 2-aryl acceptor types.
1
2
deuterium incorporation by H and H NMR spectroscopy and GC−
MS. Further details of these experiments are provided in the
Supporting Information.
3-Methyl-1-phenylpyrrolidine-2,5-dione (3a). Acetic acid (6
mg, 0.1 mmol), N-phenylmaleimide (34.7 mg, 0.2 mmol), and TiO2
(12 mg, 0.15 mmol) were reacted in accordance with the general
procedure to yield 3a (24% by NMR) as a white solid. Mp: 94−96 °C.
1H NMR (400 MHz, CDCl3, 296 K): δ 1.44 (d, J = 7.2 Hz, 3H),
2.47−2.54 (m, 1H), 2.97−3.14 (m, 2H), 7.27−7.30 (m, 2H), 7.36−
7.42 (m, 1H), 7.44−7.50 (m, 2H). 13C NMR (100 MHz, CDCl3, 297
K): δ 16.9, 34.9, 36.7, 126.4, 128.6, 129.2, 132.0, 175.5, 179.6. LR-
ESIMS: m/z 190 [M + H]+. HR-ESIMS: m/z 190.0861 (calcd for
C11H12NO2, 190.0863). Also observed was N-phenylsuccinimide (41%
by NMR).
3-Pentyl-1-phenylpyrrolidine-2,5-dione (3b). n-Hexanoic acid
(11.6 mg, 0.1 mmol), N-phenylmaleimide (34.7 mg, 0.2 mmol), and
TiO2 (12 mg, 0.15 mmol) were reacted in accordance with the general
procedure. Following irradiation, a yield of 4% (0.04 mmol) was
determined for 3b. Yields were determined by assigning peaks “a” and
“b” by analogy with the previously characterized 3-ethyl adduct.30 1H
NMR (500 MHz, CDCl3, 295 K): δ 2.60 (dd, J = 3.3, 17.0 Hz, 1H),
2.97−3.07 (m, 1H). Also observed were N-phenylsuccinimide (4% by
NMR) and unreacted n-hexanoic acid (65% conversion by NMR).
3-Neopentyl-1-phenylpyrrolidine-2,5-dione (3c). tert-Butyl-
acetic acid (11.6 mg, 0.1 mmol), N-phenylmaleimide (34.7 mg, 0.2
mmol), and TiO2 (12 mg, 0.15 mmol) were reacted in accordance
The mechanism (Scheme 5) is supported by EPR
spectroscopic evidence of the intermediates. An intriguing
aspect of the process is the identity of the proton donor.
Experiments with deuterium-labeled solvent and reactants
implied that this was the hydroxyl groups on the surface of
the P25. It appears that the titania supplies electrons and holes
upon photostimulation but also donates protons from surface
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with the general procedure to yield 3c (18% by NMR) as a white solid.
Mp: sample decomposed at >250 °C. H NMR (400 MHz, CDCl3,
ESIMS: m/z 262 [M + H]+. HR-ESIMS: m/z 262.1440 (calcd for
C15H20NO3, 262.1438).
1
1-Phenyl-3-(tetrahydrofuran-2-yl)-pyrrolidine-2,5-dione (3i).
2-Tetrahydrofuroic acid (76.6 mg, 0.66 mmol), N-phenylmaleimide
(462.3 mg, 2.67 mmol), and TiO2 (80 mg, 1.00 mmol) were reacted in
accordance with the general procedure. Following irradiation for 18 h,
the reaction mixture was purified by column chromatography on silica
gel (eluent: Et2O) to yield a 1:1 mixture of the two diastereoisomers of
296 K): δ 0.94 (s, 9H), 1.36 (dd, J = 10.7, 14.0 Hz, 1H), 2.12 (dd, J =
2.0, 13.9 Hz, 1H), 2.54 (dd, J = 5.3, 18.1 Hz, 1H), 3.03 (dd, J = 9.1,
18.1 Hz, 1H), 2.84−2.92 (m, 1H), 7.19−7.22 (m, 2H), 7.29−7.34 (m,
1H), 7.37−7.42 (m, 2H). 13C NMR (100 MHz, CDCl3, 297 K): δ
29.6, 29.7, 31.0, 37.6, 45.9, 126.4, 128.6, 129.2, 132.1, 175.8, 179.8. LR-
ESIMS: m/z 246 [M + H]+. HR-ESIMS: m/z 246.1486 (calcd for
C15H20NO2, 246.1489). Also observed was N-phenylsuccinimide (40%
by NMR).
3-Isopropyl-1-phenylpyrrolidine-2,5-dione (3d). Isobutyric
acid (8.1 mg, 0.1 mmol), N-phenylmaleimide (34.7 mg, 0.2 mmol),
and TiO2 (12 mg, 0.15 mmol) were reacted in accordance with the
general procedure to yield 3d (25% by NMR) as a white solid. Mp:
90−92 °C. 1H NMR (400 MHz, CDCl3, 297 K): δ 0.99 (d, J = 6.8 Hz,
3H), 1.07 (d, J = 6.9 Hz, 3H), 2.32−2.40 (m, 1H), 2.56 (dd, J = 4.4,
18.3 Hz, 1H), 2.79 (dd, J = 9.4, 18.3 Hz, 1H), 2.87−2.92 (m, 1H),
7.18−7.21 (m, 2H), 7.29−7.34 (m, 1H), 7.37−7.43 (m, 2H). 13C
NMR (100 MHz, CDCl3, 300 K): δ 17.3, 20.0, 29.2, 30.6, 45.8, 126.5,
128.6, 129.2, 131.9, 175.9, 178.4. LR-ESIMS: m/z 218 [M + H]+. HR-
ESIMS: m/z 218.1178 (calcd for C13H16NO2, 218.1176). Also
observed was N-phenylsuccinimide (25% by NMR).
1
3i as a yellow oil (121.8 mg, 75%). Diastereomer 1: H NMR (400
MHz, CDCl3, 295 K): δ 1.92−2.02 (m, 2H), 2.02−2.12 (m, 2H),
2.79−2.84 (m, 1H), 2.99 (dd, J = 9.3, 18.3 Hz, 1H), 3.26−3.30 (m,
1H), 3.76−3.84 (m, 2H), 4.23−4.27 (m, 1H), 7.26−7.32 (m, 2H),
7.37−7.42 (m, 1H), 7.45−7.51 (m, 2H). 13C NMR (100 MHz, CDCl3,
297 K): δ 25.9, 27.9, 32.7, 43.4, 68.8, 79.1, 126.6, 128.6, 129.1, 132.0,
1
175.7, 175.9. Diastereomer 2: H NMR (500 MHz, CDCl3, 295 K): δ
1.63−1.71 (m, 1H), 1.92−2.02 (m, 2H), 2.10−2.19 (m, 1H), 2.79−
2.84 (m, 2H), 3.08−3.12 (m, 1H), 3.86−3.94 (m, 2H), 4.39−4.44 (m,
1H), 7.26−7.32 (m, 2H), 7.37−7.42 (m, 1H), 7.45−7.51 (m, 2H). 13C
NMR (100 MHz, CDCl3, 297 K): δ 25.9, 29.7, 29.8, 44.4, 68.8, 77.3,
126.6, 128.6, 129.1, 132.0, 176.5, 177.4. GC−MS: for tR = 15.75 min,
m/z (%) 245 (38), 217 (10), 202 (58), 175 (100), 147 (10), 119 (28),
111 (11), 71 (98); for tR = 16.20 min, m/z (%) 245 (51), 217 (11),
202 (33), 175 (81), 147 (6), 119 (22), 111 (12), 71 (100). LR-
ESIMS: m/z 246 [M + H]+. HR-ESIMS: m/z 246.1127 (calcd for
C14H16NO3, 246.1125).
3-(Methylthiomethyl)-1-phenylpyrrolidine-2,5-dione (3j).
Methylthioacetic acid (70.8 mg, 0.67 mmol), N-phenylmaleimide
(462.3 mg, 2.67 mmol), and TiO2 (80 mg, 1.00 mmol) were reacted in
accordance with the general procedure. Following irradiation for 42 h,
the reaction mixture was purified by column chromatography on silica
gel (eluent: gradient of 20−40% EtOAc in petroleum ether 40−60) to
yield 3j as a white powder (53.6 mg, 34%). Mp: 90−94 °C. 1H NMR
(500 MHz, CDCl3, 299 K): δ 2.14 (s, 3H), 2.84 (dd, 1H, J = 5.0, 18.4
Hz), 2.92 (dd, 1H, J = 7.4, 13.5 Hz), 3.01 (dd, 1H, J = 9.2, 18.4 Hz),
3.04 (dd, 1H, J = 4.1, 13.5 Hz), 3.21−3.28 (m, 1H), 7.22−7.27 (m,
2H), 7.35−7.39 (m, 1H), 7.42−7.47 (m, 2H). 13C NMR (75 MHz,
CDCl3, 297 K): δ 16.5, 33.7, 35.5, 40.1, 126.5, 128.7, 129.2, 131.9,
175.2, 177.5. LR-ESIMS: m/z 236 [M + H]+. HR-ESIMS: m/z
236.0741 (calcd for C12H14NO2S, 236.0740).
3-tert-Butyl-1-phenylpyrrolidine-2,5-dione (3e). Pivalic acid
(10.2 mg, 0.1 mmol), N-phenylmaleimide (34.7 mg, 0.2 mmol), and
TiO2 (12 mg, 0.15 mmol) were reacted in accordance with the general
procedure to yield 3e (38% by NMR) as a white solid. Mp: 101−103
1
°C. H NMR (400 MHz, CDCl3, 300 K): δ 1.12 (s, 9H), 2.67−2.80
(m, 2H), 2.89 (dd, J = 8.8, 17.6 Hz, 1H), 7.24−7.26 (m, 2H), 7.36−
7.41 (m, 1H), 7.45−7.49 (m, 2H). 13C NMR (100 MHz, CDCl3, 300
K): δ 27.2, 32.0, 33.8, 49.9, 126.6, 128.6, 129.2, 132.0, 175.6, 177.4.
LR-ESIMS: m/z 232 [M + H]+. HR-ESIMS: m/z 232.1326 (calcd for
C14H18NO2, 232.1332). Also observed was N-phenylsuccinimide (31%
by NMR).
3-(Trifluoromethyl)-1-phenylpyrrolidine-2,5-dione (3f). Tri-
fluoroacetic acid (11.4 mg, 0.1 mmol), N-phenylmaleimide (34.7 mg,
0.2 mmol), and TiO2 (12 mg, 0.15 mmol) were reacted in accordance
with the general procedure to yield 3f (∼1% by NMR). 1H NMR (400
MHz, CDCl3, 295 K): δ 2.86 (dd, J = 5.5, 18.6 Hz, 1H), 2.99 (dd, J =
9.5, 18.6 Hz, 1H), 3.61 (m, 1H), 7.10 (m, 2H), 7.39 (m, 3H). 19F
NMR (375 MHz, CDCl3, 296 K): δ −69.3 (s, 3F). Data are consistent
with literature values.31 Also observed was N-phenylsuccinimide
(trace).
1-Phenyl-3-(thiophen-2-ylmethyl)pyrrolidine-2,5-dione (3k).
2-Thiopheneacetic acid (93.9 mg, 0.66 mmol), N-phenylmaleimide
(462.3 mg, 2.67 mmol), and TiO2 (80 mg, 1.00 mmol) were reacted in
accordance with the general procedure. Following irradiation for 17 h,
the reaction mixture was purified by column chromatography on silica
gel (eluent: 20% EtOAc in pentanes) to yield 3k as a yellow oil (45.9
3-(Methoxymethyl)-1-phenylpyrrolidine-2,5-dione (3g). Me-
thoxyacetic acid (54.4 mg, 0.63 mmol), N-phenylmaleimide (433.6
mg, 2.50 mmol), and TiO2 (75 mg, 0.94 mmol) were reacted in
accordance with the general procedure. Following irradiation for 18 h,
the reaction mixture was purified by column chromatography on silica
gel (eluent: 30% EtOAc in petroleum ether 40−60) to yield 3g as a
white powder (74.4 mg, 54%). Mp: 109−111 °C. 1H NMR (400 MHz,
CDCl3, 299 K): δ 2.86−2.99 (m, 2H), 3.08−3.15 (m, 1H), 3.38 (s,
3H), 3.36 (dd, J = 3.3, 9.1 Hz, 1H), 3.91 (dd, J = 3.9, 9.1 Hz, 1H),
7.26−7.30 (m, 2H), 7.36−7.41 (m, 1H), 7.44−7.49 (m, 2H). 13C
NMR (75 MHz, CDCl3, 298 K): δ 31.9, 41.2, 59.3, 70.8, 126.6, 128.6,
129.1, 132.1, 175.8, 177.3. Data are consistent with literature values.16
3-(tert-Butoxymethyl)-1-phenylpyrrolidine-2,5-dione (3h).
tert-Butoxyacetic acid (87.3 mg, 0.66 mmol), N-phenylmaleimide
(462.3 mg, 2.67 mmol), and TiO2 (80 mg, 1.0 mmol) were reacted in
accordance with the general procedure. Following irradiation for 17 h,
1H NMR analysis revealed that N-phenylmaleimide had been
consumed entirely while a significant quantity of tert-butoxyacetic
acid remained. A further 462.3 mg of N-phenylmaleimide was hence
added, and the reaction was photolyzed for another 18 h. The reaction
mixture was then purified by column chromatography on silica gel
(eluent: 25% EtOAc in pentanes) to yield 3h as a yellow oil (97.8 mg,
57%). 1H NMR (500 MHz, CDCl3, 295 K): δ 1.18 (s, 9H), 2.85−2.89
(m, 2H), 3.07−3.11 (m, 1H), 3.59 (dd, J = 2.9, 8.5 Hz, 1H), 3.91 (dd,
J = 3.5, 8.5 Hz, 1H), 7.27 (d, J = 7.4 Hz, 2H), 7.39 (t, J = 7.4 Hz, 1H),
7.48 (t, J = 7.4 Hz, 2H). 13C NMR (75 MHz, CDCl3, 297 K): δ 27.4,
32.3, 41.3, 60.7, 73.3, 126.6, 128.6, 129.2, 134.2, 176.3, 178.0. LR-
1
mg, 26%). H NMR (500 MHz, CDCl3, 295 K): δ 2.72 (dd, J = 4.8,
18.4 Hz, 1H), 2.98 (dd, J = 9.2, 18.4 Hz, 1H), 3.30−3.35 (m, 1H),
3.37−3.45 (m, 2H), 6.89 (m, 1H), 6.98 (m, 1H), 7.20 (m, 2H), 7.39
(m, 1H), 7.46 (m, 2H). 13C NMR (75 MHz, CDCl3, 297 K) 30.7,
33.4, 41.3, 125.0, 126.5, 127.0, 127.3, 128.7, 129.2, 131.8, 138.2, 175.2,
177.8, 177.5. LR-ESIMS: m/z 272 [M + H]+. HR-ESIMS: m/z
272.0743 (calcd for C15H14NO2S, 272.0740). 1,2-Bis(thiophen-2-
1
yl)ethane was also isolated as a clear oil (14.1 mg, 22%). H NMR
(500 MHz, CDCl3, 295 K): δ 3.20 (s, 4H), 6.80 (d, J = 3.4 Hz, 2H),
6.91−6.94 (m, 2H), 7.14 (d, J = 5.2 Hz, 2H). Data are consistent with
literature values.32
3-Benzyl-1-phenylpyrrolidine-2,5-dione (3l). Phenylacetic acid
(89.9 mg, 0.66 mmol), N-phenylmaleimide (462.3 mg, 2.67 mmol),
and TiO2 (80 mg, 1.00 mmol) were reacted in accordance with the
general procedure. Following irradiation for 22 h, the reaction mixture
was purified by dry flash chromatography on silica gel (eluent: gradient
of 10−20% EtOAc in CH2Cl2) to yield 3l as a white powder (99.3 mg,
1
57%). H NMR (500 MHz, CDCl3, 295 K): δ 2.65 (dd, J = 4.7, 18.5
Hz, 1H), 2.88 (dd, J = 9.2, 18.5 Hz, 1H), 3.08 (dd, J = 8.0, 13.8 Hz,
1H), 3.25 (dd, J = 4.4, 13.8 Hz, 1H), 3.30−3.35 (m, 1H), 7.17 (m,
2H), 7.22 (m, 2H), 7.29 (m, 1H), 7.34 (m, 2H), 7.39 (m, 1H), 7.46
(m, 2H). 13C NMR (75 MHz, CDCl3, 297 K): δ 33.5, 36.7, 41.4, 77.2,
126.6, 127.4, 128.8, 129.0, 129.3, 129.4, 132.0, 136.8, 175.4, 178.4.
Data are consistent with literature values.33 Bibenzyl (10.9 mg, 18%)
was observed by NMR prior to purification of the reaction mixture. 1H
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NMR (500 MHz, CDCl3, 298 K): δ 2.95 (s, 4H), 7.21−7.24 (m, 6H),
7.30−7.33 (m, 4H). Data are consistent with literature values.34
tert-Butyl (1-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)ethyl)-
carbamate (3m). N-Boc-L-alanine (126.2 mg, 0.67 mmol), N-
phenylmaleimide (462.3 mg, 2.67 mmol), and TiO2 (80 mg, 1.00
mmol) were reacted in accordance with the general procedure.
Following irradiation for 18 h, the mixture was purified by column
chromatography on silica gel (eluent: gradient of 20−40% EtOAc in
petroleum ether 40−60) to yield two diastereomers of 3m.
Diastereomer 1 was isolated as a white powder (36.7 mg, 18%). Mp:
155−157 °C. 1H NMR (400 MHz, CDCl3, 296 K): δ 1.29 (d, J = 6.9
Hz, 3H), 1.38 (s, 9H), 2.78 (dd, J = 4.8, 18.6 Hz, 1H), 2.89 (dd, J =
9.1, 18.5 Hz, 1H), 3.15−3.20 (m, 1H), 4.08−4.18 (m, 1H), 4.53 (bs,
1H), 7.18−7.22 (m, 2H), 7.30−7.35 (m, 1H), 7.38−7.43 (m, 2H). 13C
NMR (75 MHz, CDCl3, 297 K): δ 18.7, 28.3, 32.2, 45.3, 47.7, 80.2,
126.5, 128.7, 129.2, 131.8, 155.5, 175.3, 176.6. LR-ESIMS: m/z 341
[M + Na]+. HR-ESIMS: m/z 341.1467 (calcd for C17H22O4N2Na,
341.1472). Diastereomer 2 (20% wrt CH2Br2 standard) was obtained as
a 1:1 mixture with N-phenylsuccinimide. 1H NMR (500 MHz, CDCl3,
297 K): δ 1.25 (d, J = 6.8 Hz, 3H), 1.44 (s, 9H), 2.63 (dd, J = 4.5, 18.6
Hz, 1H), 3.00 (dd, J = 9.6, 18.5 Hz, 1H), 3.17−3.23 (m, 1H), 4.13−
4.17 (m, 1H), 5.20 (bs, 1H), 7.27−7.30 (m, 2H), 7.39−7.42 (m, 1H),
7.46−7.50 (m, 2H). 13C NMR (75 MHz, CDCl3, 297 K): δ 17.1, 28.5,
31.9, 45.1, 47.1, 80.0, 126.6, 128.8, 129.3, 131.8, 155.2, 175.2, 177.5.
LR-ESIMS: m/z 341 [M + Na]+. HR-ESIMS: m/z 341.1475 (calcd for
C17H22O4N2Na, 341.1472).
tert-Butyl 2′,5′-Dioxo-1′-phenyl-[2,3′-bipyrrolidine]-1-car-
boxylate (3n). N-Boc-L-proline (144.3 mg, 0.67 mmol), N-phenyl-
maleimide (462.3 mg, 2.67 mmol), and TiO2 (80 mg, 1.00 mmol)
were reacted in accordance with the general procedure. Following
irradiation for 17 h, the crude mixture was purified by dry flash
chromatography on silica gel (eluent: gradient of 20−60% EtOAc in
petroleum ether 40−60) to yield an inseparable mixture of two
diastereomers of 3n (171 mg, 75%, 1:1 ratio) that also contained 7%
N-phenylsuccinimide. 1H NMR (500 MHz, CDCl3, 326 K):
diastereomer 1 δ 1.44 (s, 9H), 1.94−1.99 (m, 2H), 2.18−2.24 (m,
2H), 2.73−2.75 (m, 1H), 2.83 (dd, J = 3.8, 9.4 Hz, 1H), 3.53 (dd, J =
7.3, 11.1 Hz, 1H), 3.79−3.85 (m, 2H), 4.34−4.39 (m, 2H), 7.27−7.47
(m, 5H); diastereomer 2 δ 1.49 (s, 9H), 2.14−2.17 (m, 2H), 1.66−1.71
(m, 2H), 2.69−2.71 (m, 1H), 2.86 (dd, J = 4.3, 9.7 Hz, 1H), 3.30 (dd,
J = 3.4, 7.8 Hz, 1H), 3.95−3.99 (m, 2H), 4.31−4.35 (m, 2H), 7.27−
7.47 (m, 5H). 13C NMR (75 MHz, CDCl3, 300 K): δ 23.3−24.0, 27.9,
28.4, 28.5, 29.7−30.1, 31.8, 43.7−44.1, 47.2−47.8, 57.1−57.8, 79.9−
80.5, 126.5−126.8, 128.4−129.2, 131.2−132.0, 155.0−156.0, 174.1−
177.3. GC−MS: for tR = 19.81 min, m/z (%) 344 (2), 288 (19), 271
(17), 243 (48), 175 (16), 114 (50), 70 (100) 57 (41); for tR = 20.09
min, m/z (%) 344 (2), 288 (19), 271 (17), 243 (48), 175 (16), 114
(50), 70 (100) 57 (41). LR-ESIMS: m/z 367 [M + Na]+. HR-ESIMS:
m/z 367.1632 (calcd for C19H24N2O4Na, 367.1628).
19.0 Hz, 1H), 3.35 (dd, J = 6.3, 17.6 Hz, 1H), 3.37−3.42 (m, 1H),
3.94−3.98 (m, 1H), 7.38−7.42 (m, 3H), 7.44−7.49 (m, 2H). 13C
NMR (125 MHz, CDCl3, 295 K): δ 19.6, 24.4, 24.6, 28.3, 33.4, 37.8,
39.5, 46.1, 82.5, 126.4, 128.5, 129.1, 131.4, 152.6, 175.2, 175.5. LR-
ESIMS: m/z 381 [M + Na]+. HR-ESIMS: m/z 381.1787 (calcd for
C20H26N2O4Na, 381.1785).
Attempted Preparation of 2-(2,5-Dioxo-1-phenylpyrrolidin-
3-yl)acetonitrile. Cyanoacetic acid (56.2 mg, 0.67 mmol), N-
phenylmaleimide (462.3 mg, 2.67 mmol), and TiO2 (80 mg, 1.00
mmol) were reacted in accordance with the general procedure.
Following irradiation for 18 h, the reaction mixture was scrutinized by
1H NMR and GC−MS, but none of the desired product was obtained.
N-Methyl-3-(phenoxymethyl)pyrrolidine-2,5-dione (7a) and
N-Methyl-3a,4-dihydrochromeno[3,4-c]pyrrole-1,3(2H,9bH)-
dione (6a). Phenoxyacetic acid (100 mg, 0.65 mmol), N-
methylmaleimide (145 mg, 1.3 mmol), and TiO2 (75 mg, 0.98
mmol) were reacted in accordance with the general procedure.
Following irradiation for 20 h, the crude mixture was purified by
column chromatography on silica gel (eluent: 20% EtOAc in
petroleum ether 40−60) to yield 7a as a colorless oil (32.6 mg,
1
23%). H NMR (400 MHz, CDCl3, 297 K): δ 2.88−2.90 (m, 2H),
3.04 (s, 3H), 3.17−3.23 (m, 1H), 4.17 (dd, J = 3.4, 9.2 Hz, 1H), 4.40
(dd, J = 4.4, 9.2 Hz, 1H), 6.87 (d, J = 8.8 Hz, 2H), 6.98 (t, J = 7.4 Hz,
1H), 7.28 (t, J = 7.4 Hz, 2H). 13C NMR (75 MHz, CDCl3, 297 K): δ
25.4, 32.1, 41.1, 66.4, 115.1, 122.0, 130.0, 158.5, 177.0 178.0. 6a was
also obtained as a white powder (77.8 mg, 55%). 1H NMR (400 MHz,
CDCl3, 296 K): δ 3.00 (s, 3H), 3.36−3.40 (m, 1H), 4.01 (dd, J = 4.2,
11.4 Hz, 1H), 4.07 (d, J = 9.2 Hz, 1H), 4.62 (dd, J = 2.9, 11.4 Hz, 1H),
6.89 (d, J = 8.2 Hz, 1H), 7.05 (t, J = 7.5 Hz, 1H), 7.21 (t, J = 7.7 Hz,
1H), 7.58 (d, J = 7.4 Hz, 1H). 13C NMR (75 MHz, CDCl3, 297 K): δ
27.8, 40.1, 42.7, 64.3, 118.1, 118.3, 123.2, 129.4, 130.5, 155.7, 176.6,
177.2. Data are consistent with literature values.16
3-(Phenoxymethyl)-1-phenylpyrrolidine-2,5-dione (7b) and
N-Phenyl-3a,4-dihydrochromeno[3,4-c]pyrrole-1,3(2H,9bH)-
dione (6b). Phenoxyacetic acid (100 mg, 0.65 mmol), N-phenyl-
maleimide (230 mg, 1.3 mmol), and TiO2 (75 mg, 0.98 mmol) were
reacted in accordance with the general procedure. Following
irradiation for 11 h, the crude mixture was purified by column
chromatography on silica gel (eluent: 20% EtOAc in petroleum ether
1
40−60) to yield 7b as a yellow oil (71.5 mg, 39%). H NMR (400
MHz, CDCl3, 297 K): δ 3.01−3.07 (m, 2H), 3.33−3.39 (m, 1H), 4.28
(dd, J = 3.2, 9.0 Hz, 1H), 4.55 (dd, J = 4.1, 9.1 Hz, 1H), 6.91 (d, J =
8.8 Hz, 2H), 7.00 (t, J = 7.3 Hz, 1H), 7.28−7.33 (m, 2H), 7.41 (t, J =
7.4 Hz, 1H), 7.48 (d, J = 7.2, 2H). 13C NMR (75 MHz, CDCl3, 297
K): δ 32.4, 41.1, 66.9, 115.1, 122.1, 127.0, 129.2, 129.7, 130.0, 132.4,
158.5, 175.9, 177.1. 6b was also obtained as a white powder (72.8 mg,
1
40%). H NMR (400 MHz, CDCl3, 297 K): δ 3.54−3.58 (m, 1H),
4.11, (dd, J = 4.4, 11.4 Hz, 1H), 4.23 (d, J = 9.3 Hz, 1H), 4.7 (dd, J =
3.3, 11.4 Hz, 1H), 6.94 (d, J = 8.2 Hz, 1H), 7.07 (t, J = 7.5 Hz, 1H),
7.22−7.27 (m, 2H), 7.37 (t, J = 7.4 Hz, 2H), 7.44 (t, J = 7.1 Hz, 1H),
7.63 (d, J = 7.4 Hz, 1H). 13C NMR (75 MHz, CDCl3, 297 K): δ 40.2,
42.6, 64.4, 77.1, 77.5, 77.9, 117.7, 118.3, 123.3, 126.7, 129.2, 129.5,
129.6, 130.7, 132.1 155.7 175.5, 176.1. Data are consistent with
literature values.16
tert-Butyl 2-(2,5-Dioxo-1-phenylpyrrolidin-3-yl)piperidine-1-
carboxylate (3o). N-Boc-D/L-2-piperidinecarboxylic acid (151.4 mg,
0.67 mmol), N-phenylmaleimide (462.3 mg, 2.67 mmol), and TiO2
(80 mg, 1.00 mmol) were reacted in accordance with the general
procedure. Following irradiation for 18 h, the crude mixture was
purified by column chromatography on silica gel (eluent: 30% EtOAc
in pentanes) to yield two diastereomers of 3o. Diastereomer 1 was
3-((4-(tert-Butyl)phenoxy)methyl)-1-methylpyrrolidine-2,5-
dione (7c) and 8-(tert-Butyl)-2-methyl-3a,4-dihydrochromeno-
[3,4-c]pyrrole-1,3(2H,9bH)-dione (6c). 4-(tert-Butyl)phenoxyacetic
acid (130.3 mg, 0.62 mmol), N-methylmaleimide (275.6 mg, 2.48
mmol), and TiO2 (75 mg, 0.98 mmol) were reacted in accordance
with the general procedure. Following irradiation for 22 h, the reaction
mixture was purified by column chromatography on silica gel (eluent:
20% EtOAc in petroleum ether 40−60) to yield 7c as a clear oil (18.4
mg, 11%). 1H NMR (400 MHz, CDCl3, 296 K): δ 1.29 (s, 9H), 2.84−
2.89 (m, 2H), 3.03 (s, 3H), 3.21−3.16 (m, 1H), 4.16 (dd, J = 3.4, 9.2
Hz, 1H), 4.39 (dd, J = 4.4, 9.2 Hz, 1H), 6.81 (d, J = 8.8 Hz, 2H), 7.29
(d, J = 8.8 Hz, 2H). 13C NMR (100 MHz, CDCl3, 296 K): δ 25.0,
29.7, 31.5, 34.1, 40.7, 66.1, 114.2, 126.4, 144.4, 155.8, 176.6, 177.6. LR-
ESIMS: m/z 276 [M + H]+. HR-ESIMS: m/z 276.1599 (calcd for
C16H22NO3, 276.1594). 6c was also obtained as a white powder (77.2
mg, 46%). Mp: 134−137 °C. 1H NMR (400 MHz, CDCl3, 296 K): δ
1
isolated as an off-white solid (32.7 mg, 14%). Mp: 107−110 °C. H
NMR (500 MHz, CDCl3, 295 K): δ 1.39 (s, 9H), 1.46−1.59 (bm,
2H), 1.67−1.79 (bm, 4H), 2.52 (dd, J = 3.0, 18.2 Hz, 1H), 2.98 (dd, J
= 8.9, 18.2 Hz, 1H), 3.04 (t, J = 13.2 Hz, 1H), 3.26−3.30 (m, 1H),
4.06 (d, J = 13.2 Hz, 1H), 4.34−4.37 (m, 1H), 7.32−7.36 (m, 3H),
7.41−7.45 (m, 2H). 13C NMR (75 MHz, CDCl3, 297 K): δ 18.9, 24.8,
27.0, 28.4, 34.2, 38.1, 40.2, 53.3, 79.9, 126.7, 128.4, 128.9, 132.1, 155.5,
174.9, 176.1. LR-ESIMS: m/z 381 [M + Na]+. HR-ESIMS: m/z
381.1787 (calcd for C20H26N2O4Na, 381.1785). Diastereomer 2 (15%
wrt CH2Br2 standard) was obtained as a 1:2 mixture with N-
1
phenylsuccinimide. H NMR (500 MHz, CDCl3, 295 K): δ 1.42 (s,
9H), 1.53 (m, 1H), 1.68−1.72 (m, 1H), 1.90−1.96 (m, 1H), 2.21−
2.23 (m, 1H), 2.40−2.45 (m, 1H), 2.54−2.58 (m, 1H), 2.95 (dd, J =
4.4, 19.0 Hz, 1H), 3.05 (dd, J = 9.6, 17.6 Hz, 1H), 3.26 (dd, J = 9.1,
1393
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1.32 (s, 9H), 2.98 (s, 3H), 3.33−3.37 (m, 1H), 3.98 (dd, J = 4.1, 11.3
Hz, 1H), 4.05 (d, J = 9.2 Hz, 1H), 4.59 (dd, J = 3.0, 11.3 Hz, 1H), 6.82
(d, J = 8.6 Hz, 1H), 7.23 (dd, J = 2.4, 8.6 Hz, 1H), 7.58 (d, J = 2.4 Hz,
1H). 13C NMR (75 MHz, CDCl3, 296 K): δ 25.8, 31.9, 34.8, 40.3,
42.7, 64.3, 117.1, 117.6, 126.5, 127.3, 146.0, 153.3, 176.7, 177.3. LR-
ESIMS: m/z 274 [M + H]+. HR-ESIMS: m/z 274.1442 (calcd for
C16H20NO3, 274.1438).
66.6, 114.7, 124.0 (q, 2JC−F = 32.8 Hz, 1C), 124.3 (q, 1JC−F = 271.1 Hz,
3
1C), 126.5, 127.1 (q, JC−F = 3.7 Hz, 2C), 128.8, 129.3, 131.9, 160.4,
175.2, 176.3. 19F NMR (376 MHz, CDCl3, 297 K): δ −62.1. LR-
ESIMS: m/z 367 [M + NH4]+. HR-ESIMS: m/z 367.1269 (calcd for
C18H18N2O3F3, 367.1275). 6f was also obtained as a yellow oil (90 mg,
1
23%). H NMR (400 MHz, CDCl3, 297 K): δ 3.57−3.61 (m, 1H),
4.15 (dd, J = 4.2, 11.4 Hz, 1H), 4.25 (d, J = 9.3 Hz, 1H), 4.71 (dd, J =
3.4, 11.4 Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 7.24−7.27 (m, 2H), 7.36−
7.51 (m, 4H), 7.93 (s, 1H). 13C NMR (75 MHz, CDCl3, 297 K): δ
3-((4-(tert-Butyl)phenoxy)methyl)-1-phenylpyrrolidine-2,5-
dione (7d) and 8-(tert-Butyl)-2-phenyl-3a,4-dihydrochromeno-
[3,4-c]pyrrole-1,3(2H,9bH)-dione (6d). 4-(tert-Butyl)phenoxyacetic
acid (70 mg, 0.33 mmol), N-phenylmaleimide (117 mg, 0.66 mmol),
and TiO2 (40 mg, 0.5 mmol) were reacted in accordance with the
general procedure. Following irradiation for 19 h, the crude mixture
was purified by column chromatography on silica gel (eluent: 20%
EtOAc in petroleum ether 40−60) to yield 7d as a clear oil (31.2 mg,
28%). 1H NMR (300 MHz, CDCl3, 295 K): δ 1.30 (s, 9H), 2.98−3.13
(m, 2H), 3.30−3.37 (m, 1H), 4.23 (dd, J = 3.2, 9.1 Hz, 1H), 4.53 (dd,
J = 3.9, 9.1 Hz, 1H), 6.85 (d, J = 8.9 Hz, 2H), 7.27−7.33 (m, 3H),
7.40−7.51 (m, 4H). 13C NMR (75 MHz, CDCl3, 297 K): δ 29.7, 31.5,
34.2, 40.8, 66.6, 114.2, 126.4, 126.6, 128.7, 129.2, 132.0, 144.6, 155.8,
175.6, 176.8. LR-ESIMS: m/z 338 [M + H]+. HR-ESIMS: m/z
338.1755 (calcd for C21H24NO3, 338.1751). 6d was also obtained as a
clear oil (50.3 mg, 46%). 1H NMR (300 MHz, CDCl3, 296 K): δ 1.32
(s, 9H), 3.51−3.56 (m, 1H), 4.10 (dd, J = 4.3, 11.4 Hz, 1H), 4.23 (d, J
= 7.3 Hz, 1H), 4.66 (dd, J = 3.3, 11.5 Hz, 1H), 6.87 (d, J = 8.1 Hz,
1H), 7.24−7.29 (m, 2H), 7.33−7.48 (m, 4H). 13C NMR (75 MHz,
CDCl3, 297 K): δ 31.5, 34.4, 40.0, 42.3, 64.1, 116.4, 117.3, 126.3,
127.0, 128.7, 129.1, 131.8, 134.2, 145.7, 153.0, 175.2, 175.7. LR-
ESIMS: m/z 336 [M + H]+. HR-ESIMS: m/z 336.1598 (calcd for
C21H22NO3, 336.1600).
1
39.5, 41.7, 64.1, 117.7, 118.5, 123.9 (q, JC3−F = 271.8 Hz, 1C), 125.2
2
(q, JC−F = 33.0 Hz, 1C), 126.2, 126.4 (q, JC−F = 3.5 Hz, 1C), 127.7
3
(q, JC−F = 3.7 Hz, 1C), 128.9, 129.2, 131.5, 157.8, 174.3, 175.0. 19F
NMR (376 MHz, CDCl3, 297 K): δ −62.3. LR-ESIMS: m/z 365 [M +
NH4]+. HR-ESIMS: m/z 365.1114 (calcd for C18H16N2O3F3,
365.1108).
(E)-2-(2-(3-Methoxy-3-oxoprop-1-en-1-yl)phenoxy)acetic
Acid (8a). A THF (60 mL) solution of methyl bromoacetate (0.62
mL, 6.54 mmol, 1.0 equiv) and triphenylphosphine (1.715 g, 6.54
mmol, 1.0 equiv) was heated at reflux for 4 h until a white precipitate
formed. The suspension was allowed to cool to room temperature
before filtration; the precipitate was washed with Et2O (3 × 50 mL),
and the precipitate was then redissolved in CH2Cl2 (30 mL) and H2O
(20 mL). Then 2 M NaOH (10 mL) was added, and the biphasic
mixture was stirred overnight. The reaction mixture was extracted with
CH2Cl2 (3 × 100 mL), and the combined organic layers were washed
with brine, dried (MgSO4), and concentrated under reduced pressure
1
to yield the phosphorane as a colorless powder (1.923 g, 88%). H
NMR (400 MHz, CDCl3, 295 K): δ 2.90 and 3.51 (br, 3H), 7.43−7.48
(m, 6H), 7.52−7.57 (m, 3H), 7.62−7.70 (m, 6H). 13C NMR (100
MHz, CDCl3, 298 K): δ 49.9, 128.5 (d, J = 12.0 Hz), 128.8 (d, J = 12.2
Hz), 131.9 (d, J = 2.7 Hz), 132.1 (d, J = 9.8 Hz), 132.9, 133.0 (d, J =
10.2 Hz). 31P NMR (161 MHz, CDCl3, 295 K): δ 17.73. LR-ESIMS:
m/z 335 [M + H]+. HR-ESIMS: m/z 335.1200 (calcd for C21H20O2P,
335.1195). A CHCl3 (200 mL) solution of phosphorane (1.893 g, 5.66
mmol, 1.1 equiv) and 2-formylphenoxyacetic acid (0.927 g, 5.15 mmol,
1.0 equiv) was heated at reflux for 18 h. The solvent was removed
under reduced pressure, and the crude residue was purified by column
chromatography (eluent: gradient of petroleum ether to 1:1 EtOAc/
petroleum ether) to yield 8a as a colorless powder (1.037 g, 85%).
Mp: 96 °C. 1H NMR (300 MHz, CDCl3, 295 K): δ 3.80 (s, 3H), 4.77
(s, 2H), 6.61 (d, J = 16.2 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 7.03 (t, J =
7.6 Hz, 1H), 7.33 (td, J = 1.7, 7.5 Hz, 1H), 7.54 (dd, J = 1.6, 7.7 Hz,
1H), 8.04 (d, J = 16.2 Hz, 1H), 8.89−9.30 (br, 1H). 13C NMR (75
MHz, CDCl3, 298 K): δ 52.2, 65.4, 112.5, 119.5, 122.5, 124.4, 129.8,
131.8, 140.4, 156.7, 168.6, 173.8. LR-ESIMS: m/z 235 [M − H]−. HR-
ESIMS: m/z 235.0610 (calcd for C12H11O5, 235.0612).
1-Methyl-3-((4-(trifluoromethyl)phenoxy)methyl)-
pyrrolidine-2,5-dione (7e) and 2-Methyl-8-(trifluoromethyl)-
3a,4-dihydrochromeno[3,4-c]pyrrole-1,3(2H,9bH)-dione (6e).
4-(Trifluoromethyl)phenoxyacetic acid (143 mg, 0.65 mmol), N-
methylmaleimide (145 mg, 1.3 mmol), and TiO2 (75 mg, 0.98 mmol)
were reacted in accordance with the general procedure. Following
irradiation for 16 h, the reaction mixture was purified by two rounds of
column chromatography on silica gel (eluent: 20% EtOAc in
petroleum ether 40−60 and subsequently 10% EtOAc in CH2Cl2)
to yield 7e as a clear oil (54.7 mg, 29%). 1H NMR (400 MHz, CDCl3,
300 K): δ 2.82−2.96 (m, 2H), 3.05 (s, 3H), 3.20−3.26 (m, 1H), 4.22
(dd, J = 3.4, 9.2 Hz, 1H), 4.46 (dd, J = 4.3, 9.2 Hz, 1H), 6.94 (d, J =
8.5 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H). 13C NMR (75 MHz, CDCl3,
300 K): δ 25.1, 31.6, 40.5, 66.1, 114.6, 123.9 (q, 2JC−F = 32.9 Hz, 1C),
124.4 (q, 3JC−F = 271.2 Hz, 2C), 127.0 (q, 1JC−F = 3.7 Hz, 1C), 160.4,
176.2, 177.1. 19F NMR (376 MHz, CDCl3, 300 K): δ −62.1. LR-
ESIMS: m/z 288 [M + H]+. HR-ESIMS: m/z 288.0838 (calcd for
C13H13NO3F3, 288.0842). 6e was also obtained as a clear oil (60.1 mg,
32%). 1H NMR (400 MHz, CDCl3, 298 K): δ 3.01 (s, 3H), 3.40−3.44
(m, 1H), 4.04−4.10 (m, 2H), 4.64 (dd, J = 3.2, 11.5 Hz, 1H), 6.98 (d,
J = 8.6 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.87 (s, 1H). 13C NMR (75
MHz, CDCl3, 298 K): δ 25.5, 39.4, 41.8, 64.0, 117.9, 118.4, 123.9 (q,
1JC−F = 271.7 Hz, 1C), 125.1 (q, 2JC−F = 33.1 Hz, 1C), 127.2 (q, 3JC−F
(E)-2-(2-(2-Cyanovinyl)phenoxy)acetic Acid (8b). Prepared in
the same manner as 8a. Bromoacetonitrile (0.88 mL, 12.5 mmol) and
PPh3 (3.28 g, 12.5 mL) were reacted to give the salt (4.580 g, 96%).
The phosphorane was prepared as before to give a colorless powder
(3.422 g, 91%). 1H NMR (300 MHz, CDCl3, 297 K): δ 7.45−7.70 (m,
15H). 13C NMR (121 MHz, CDCl3, 297 K): δ 128.9 (d, J = 12.1 Hz),
129.5 (d, J = 12.4 Hz), 132.3 (d, J = 2.6 Hz), 132.5 (d, J = 9.9 Hz),
133.0 (d, J = 2.1 Hz), 133.2 (d, J = 10.1 Hz). 31P NMR (121 MHz,
CDCl3, 295 K): δ 23.3. 8b was prepared from the phosphorane (3.346
g, 11.11 mmol) and 2-formylphenoxyacetic acid (1.819 g, 10.10
3
= 3.5 Hz, 1C), 127.6 (q, JC−F = 3.8 Hz, 1C), 157.7, 175.3, 176.1. 19F
NMR (376 MHz, CDCl3, 298 K): δ −62.3. LR-ESIMS: m/z 286 [M +
H]+. HR-ESIMS: m/z 286.0687 (calcd for C13H11NO3F3, 286.0686).
1-Phenyl-3-((4-(trifluoromethyl)phenoxy)methyl)-
pyrrolidine-2,5-dione (7f) and 8-(Trifluoromethyl)-2-phenyl-
3a,4-dihydrochromeno[3,4-c]pyrrole-1,3(2H,9bH)-dione (6f). 4-
(Trifluoromethyl)phenoxyacetic acid (143 mg, 0.65 mmol), N-
phenylmaleimide (230 mg, 1.3 mmol), and TiO2 (75 mg, 0.98
mmol) were reacted in accordance with the general procedure.
Following irradiation for 16 h, the reaction mixture was purified by
column chromatography on silica gel (eluent: 25% EtOAc in
petroleum ether 40−60) to yield 7f as a colorless solid (52.9 mg,
1
mmol) to give a colorless powder (1.477 g, 72%). Mp: 118 C°. H
NMR (400 MHz, CDCl3, 297 K): δ 4.67 (s, 3H), 6.31 (d, J = 16.8 Hz,
1H), 6.83 (d, J = 1.1 Hz, 1H), 7.01 (t, J = 7.6 Hz, 1H), 7.33−7.39 (m,
2H), 7.62 (d, J = 16.8 Hz, 1H). 13C NMR (100 MHz, CDCl3, 297 K):
δ 65.1, 98.0, 112.2, 119.1, 121.9, 123.0, 129.8, 132.2, 146.5, 156.5,
170.5. LR-ESIMS: m/z 202 [M − H]−. HR-ESIMS: m/z 202.0511
(calcd for C11H8O3N1, 202.0510).
(E)-2-(2-(3-Oxopent-1-en-1-yl)phenoxy)acetic Acid (8c). Pre-
pared in the same manner as 8a. 1-Bromo-2-butanone (1.0 g, 6.62
mmol) and PPh3 (1.737 g, 6.62 mmol) were reacted to give the salt
(2.613 g, 96%). The phosphorane was prepared as before (2.051 g,
93%). 1H NMR (500 MHz, CDCl3, 295 K): δ 1.18 (t, J = 7.6 Hz, 3H),
2.33 (qd, J = 1.3, 7.6 Hz, 2H), 7.43−7.47 (m, 6H), 7.52−7.56 (m,
3H), 7.62−7.67 (m, 6H). 8c was prepared from the phosphorane
1
40%). Mp: 121−124 °C. H NMR (400 MHz, CDCl3, 297 K): δ
2.98−3.13 (m, 2H), 3.35−3.40 (m, 1H), 4.28 (dd, J = 3.1, 9.1 Hz,
1H), 4.57 (dd, J = 4.0, 9.1 Hz, 1H), 6.97 (d, J = 8.5 Hz, 2H), 7.29 (d, J
= 7.2 Hz, 2H), 7.41 (t, J = 7.3 Hz, 1H), 7.49 (t, J = 7.2 Hz, 2H), 7.56
(d, J = 8.6 Hz, 2H). 13C NMR (75 MHz, CDCl3, 297 K): δ 31.9, 40.6,
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(1.712 g, 5.15 mmol) and 2-formylphenoxyacetic acid (0.843 g, 4.70
mmol) to give a colorless powder (0.829 g, 75%). Mp: 125 °C. H
294 K): δ 4.63 (s, 2H), 6.92 (dd, J = 1.1, 8.2 Hz, 1H), 7.13 (td, J = 1.1,
7.5 Hz, 1H), 7.29−7.46 (m, 5H), 7.57 (dd, J = 1.5, 8.4 Hz, 2H), 8.80−
10.10 (br, 1H). 13C NMR (75 MHz, CDCl3, 295 K): δ 65.9, 113.4,
123.1, 127.7, 128.7, 129.1, 129.9, 131.8, 131.9, 138.3, 154.6, 173.7. LR-
ESIMS: m/z 227 [M − H]−. HR-ESIMS: m/z 227.0707 (calcd for
C14H11O3, 227.0714).
2-((3′-(Trifluoromethyl)-[1,1′-biphenyl]-2-yl)oxy)acetic Acid
(11b). Prepared in the same manner as 11a. (2-Bromophenoxy)-
(tert-butyl)dimethylsilane (0.95 g, 3.3 mmol), 4-(trifluoromethyl)-
phenylboronic acid (0.75 g, 4.0 mmol), Pd[P(Ph)3]4 (0.38 g, 0.33
mmol), and K2CO3 (1.2 g, 9.9 mmol) were reacted and then
columned on silica gel (eluent: 25% CH2Cl2 in petroleum ether 40−
60) to afford 3′-(trifluoromethyl)-[1,1′-biphenyl]-2-ol (0.13 g, 14%).
1H NMR (400 MHz, CDCl3, 296 K): δ 4.98−5.10 (br, 1H), 6.96 (d, J
1
NMR (400 MHz, CDCl3, 295 K): δ 1.17 (t, J = 7.3 Hz, 3H), 2.73 (q, J
= 7.3 Hz, 2H), 4.78 (s, 2H), 6.82 (d, J = 6.82 Hz, 1H), 6.90 (d, J =
16.4 Hz, 1H), 7.04 (t, J = 7.1 Hz, 1H), 7.35 (td, J = 1.7, 7.4 Hz, 1H),
7.58 (dd, J = 1.7, 7.7 Hz, 1H), 7.96 (d, J = 16.4 Hz, 1H). 13C NMR
(100 MHz, CDCl3, 298 K): δ 8.3, 33.5, 65.4, 112.2, 121.8, 124.0,
127.2, 128.9, 131.5, 137.8, 156.7, 170.6, 202.5. LR-ESIMS: m/z 233
[M − H]−. HR-ESIMS: m/z 233.0820 (calcd for C13H13O4,
233.0819).
2-([1,1′-Biphenyl]-2-yloxy)acetic Acid (11a). 2-Bromophenol
(6.4 mL, 60.5 mmol), tert-butyldimethylsilyl chloride (10.0 g, 66.5
mmol), and imidazole (8.23 g, 121.0 mmol) were dissolved in the
minimum volume of DMF, and the mixture was allowed to stir at
room temperature overnight. The DMF was removed under reduced
pressure, and the resultant residue was taken up in EtOAc and washed
with 1 M HCl, sat. NaHCO3, and sat. LiCl before being dried over
MgSO4. The solvent was then removed under reduced pressure to
= 8.5 Hz, 1H), 7.03 (td, J = 1.1, 7.5 Hz, 1H), 7.26−7.31 (m, 2H),
7.57−7.65 (m, 2H), 7.71 (d, J = 7.5 Hz, 1H), 7.78 (s, 1H). 19F NMR
(376 MHz, CDCl3, 296 K): δ −63.0. 13C NMR (100 MHz, CDCl3,
297 K): δ 116.2, 121.3, 126.9, 129.3, 129.7, 130.5, 132.5, 138.3, 152.4.
LR-ESIMS: m/z 237 [M − H]−. HR-ESIMS: m/z 237.0526 (calcd for
C13H8OF3, 237.0533). The aforementioned biphenyl alcohol (0.13 g,
0.55 mmol) was alkylated as before with methyl bromoacetate (0.1
mL, 1.1 mmol) and K2CO3 (0.38 g, 2.7 mmol) and columned on silica
gel (eluent: 50% CH2Cl2 in petroleum ether 40−60) to afford methyl
2-((3′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)oxy)acetate (0.14 g,
1
yield (2-bromophenoxy)(tert-butyl)dimethylsilane (17.29 g, 99%). H
NMR (400 MHz, CDCl3, 296 K): δ 0.25 (s, 6H), 1.05 (s, 9H), 6.80−
6.84 (m, 1H), 6.87 (dd, J = 1.5, 8.1 Hz, 1H), 7.14−7.19 (m, 1H), 7.51
(dd, J = 1.7, 7.9 Hz, 1H). 13C NMR (100 MHz, CDCl3, 297 K): δ
−4.2, 18.4, 25.8, 115.4, 120.3, 122.4, 128.2, 133.4, 152.6. LR-ESIMS:
m/z 287 [M + H]+. HR-ESIMS: m/z 287.0461 (calcd for
C12H20OBrSi, 287.0461). The aforementioned silane (0.54 g, 1.9
mmol) was coupled with phenylboronic acid (0.27 g, 2.2 mmol) by
refluxing overnight in toluene (20 mL) and ethanol (5 mL) with
Pd[P(Ph)3]4 (0.2 g, 0.2 mmol) and K2CO3 (0.9 g, 6.5 mmol). The
solvent was then removed under reduced pressure, and the reaction
mixture was taken up in H2O before being extracted with EtOAc. The
combined extracts were dried over MgSO4 before being concentrated
under reduced pressure. The resultant mixture was subjected to
column chromatography on silica gel (eluent: 25% CH2Cl2 in
petroleum ether 40−60) to yield [1,1′-biphenyl]-2-yloxy)(tert-butyl)-
dimethylsilane (0.39 g, 73%). 1H NMR (400 MHz, CDCl3, 296 K): δ
−0.05 (s, 6H), 0.83 (s, 9H), 6.92 (dd, J = 1.2, 8.0 Hz, 1H), 7.04 (td, J
= 1.2, 7.5 Hz, 1H), 7.21−7.24 (m, 1H), 7.30−7.33 (m, 2H), 7.36−7.40
(m, 2H), 7.50 (dd, J = 1.5, 8.5 Hz, 1H). 13C NMR (100 MHz, CDCl3,
297 K): δ −4.6, 18.1, 25.6, 120.4, 121.6, 126.7, 127.8, 128.3, 129.8,
130.9, 133.6, 139.2, 152.6. The aforementioned biphenylsilane (0.36 g,
1.3 mmol) was treated overnight with acetyl chloride (0.3 mL, 0.4
mmol) in methanol (15 mL). Following removal of the solvent under
reduced pressure, the reaction mixture was subjected to column
chromatography on silica gel (eluent: CH2Cl2) to yield [1,1′-
1
84%). H NMR (400 MHz, CDCl3, 296 K): δ 3.79 (s, 3H), 4.65 (s,
2H), 6.89 (d, J = 7.7 Hz, 1H), 7.12 (td, J = 1.0, 7.5 Hz), 7.32−7.39 (m,
2H), 7.54 (t, J = 7.7 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.81 (d, J = 7.6
Hz, 1H), 7.92 (s, 1H). 19F NMR (376 MHz, CDCl3, 296 K): δ −62.9.
13C NMR (100 MHz, CDCl3, 297 K): δ 52.3, 65.5, 112.3, 122.3, 123.8
(q, 3JCF = 3.7 Hz), 124.4 (q, 1JCF = 272.2 Hz), 126.5 (q, 3JCF = 3.7 Hz),
2
128.5, 129.4, 129.7, 130.4 (q, JCF = 32.1 Hz), 131.2, 133.0, 138.8,
154.6, 169.2. LR-ESIMS: m/z 328 [M + NH4]+. HR-ESIMS: m/z
328.1162 (calcd for C16H17NO3F3, 328.1155). The aforementioned
ester (0.14 g, 0.5 mmol) was hydrolyzed with LiOH (0.08 g, 1.8
1
mmol) to afford 11b (0.13g, 95%). H NMR (400 MHz, CDCl3, 296
K): δ 4.68 (s, 2H), 6.91 (d, J = 8.2 Hz, 1H), 7.14 (td, J = 1.0, 7.5 Hz,
1H), 7.34−7.39 (m, 2H), 7.54 (t, J = 7.7 Hz, 1H), 7.60 (d, J = 7.8 Hz,
1H), 7.76 (d, J = 7.6 Hz, 1H), 7.87 (s, 1H). 19F NMR (376 MHz,
CDCl3, 296 K): δ −63.0. 13C NMR (100 MHz, CDCl3, 297 K): δ 65.0,
3
1
112.4, 122.6, 123.9 (q, JCF = 3.3 Hz), 124.2 (q, JCF = 272.4 Hz),
126.4 (q, 3JCF = 3.6 Hz), 128.5, 129.4, 129.7, 130.6 (q, 2JCF = 32.5 Hz),
131.2, 132.8, 138.6, 154.1, 173.0. LR-ESIMS: m/z 314 [M + NH4]+.
HR-ESIMS: m/z 314.1001 (calcd for C15H15NO3F3, 314.0999).
2-((4′-(Trifluoromethyl)-[1,1′-biphenyl]-2-yl)oxy)acetic Acid
(11c). Prepared in the same manner as 11a. (2-Bromophenoxy)-
(tert-butyl)dimethylsilane (0.63 g, 2.2 mmol), 4-(trifluoromethyl)-
phenylboronic acid (0.5 g, 2.6 mmol), Pd[P(Ph)3]4 (0.22 g, 0.22
mmol), and K2CO3 (0.9 g, 6.5 mmol) were reacted and then
columned on silica gel (eluent: 25% CH2Cl2 in petroleum ether 40−
60) to afford 4′-(trifluoromethyl)-[1,1′-biphenyl]-2-ol (0.43 g, 82%).
Mp: 99 °C. 1H NMR (400 MHz, CDCl3, 296 K): δ 4.99 (s, 1H), 6.97
(dd, J = 0.5, 8.1 Hz, 1H), 7.04 (td, J = 1.1, 7.5 Hz, 1H), 7.26−7.32 (m,
2H), 7.64 (d, J = 8.6 Hz, 2H), 7.74 (d, J = 8.6 Hz, 2H). 19F NMR (376
MHz, CDCl3, 296 K): δ −63.05. 13C NMR (100 MHz, CDCl3, 297
1
biphenyl]-2-ol (0.19 g, 86%). H NMR (400 MHz, CDCl3, 296 K):
δ 5.13 (bs, 1H), 6.88−6.92 (m, 2H), 7.14−7.19 (m, 2H), 7.28−7.32
(m, 1H), 7.36−7.42 (m, 4H). The aforementioned biphenyl alcohol
(0.19 g, 1.11 mmol), methyl bromoacetate (0.16 mL, 0.26 mmol), and
K2CO3 (0.76 g, 5.5 mmol) were refluxed overnight in THF (20 mL).
The solvent was then removed under reduced pressure, and the
resultant residue was taken up in CH2Cl2 before being washed with
H2O and dried over MgSO4. The solvent was removed under reduced
pressure, and the resultant mixture was subjected to column
chromatography on silica gel (eluent: 25% CH2Cl2 in petroleum
ether 40−60) to afford methyl 2-([1,1′-biphenyl]-2-yloxy)acetate
(0.25 g, 94%). 1H NMR (300 MHz, CDCl3, 294 K): δ 3.82 (s,
3H), 4.66 (s, 2H), 6.94 (d, J = 8.3 Hz, 1H), 7.15 (td, J = 1.0, 7.5 Hz,
1H), 7.33−7.51 (m, 5H), 7.69 (dd, J = 1.4, 8.4 Hz, 1H). 13C NMR (75
MHz, CDCl3, 295 K): δ 52.2, 65.8, 112.8, 122.2, 127.1, 128.1, 128.6,
129.7, 131.3, 131.4, 138.1, 154.8, 169.6. LR-ESIMS: m/z 243 [M +
H]+. HR-ESIMS: m/z 243.1020 (calcd for C15H15O3, 243.1016). The
aforementioned ester (0.19 g, 0.8 mmol) was hydrolyzed with LiOH
(0.13 g, 3.2 mmol) in a 3:1 mixture of MeOH and H2O. Following
overnight stirring at room temperature, the reaction mixture was
concentrated to ca. 10% of its original volume, diluted with sat.
(NH3)2SO4 (30 mL), adjusted to pH 3 with conc. H2SO4, and
extracted with EtOAc (3 × 30 mL). The combined extracts were dried
over MgSO4 and concentrated under reduced pressure, and the
resultant residue was chromatographed on silica gel (eluent: CH2Cl2)
1
3
K): δ 116.2, 121.3, 124.1 (q, JCF = 272.0 Hz), 125.9 (q, JCF = 3.7
Hz), 126.9, 129.4 (q, 2JCF = 32.4 Hz), 129.6, 129.8, 130.4, 141.1, 152.3.
LR-ESIMS: m/z 237 [M − H]−. HR-ESIMS: m/z 237.0539 (calcd for
C13H8OF3, 237.0533). The aforementioned biphenyl alcohol (0.4 g,
1.66 mmol) was alkylated as before with methyl bromoacetate (0.24
mL, 2.5 mmol) and K2CO3 (1.15 g, 8.3 mmol) and columned on silica
gel (eluent: 25% CH2Cl2 in petroleum ether 40−60) to afford methyl
2-((4′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)oxy)acetate (0.529 g,
1
99%). H NMR (400 MHz, CDCl3, 296 K): δ 3.78 (s, 3H), 4.64 (s,
2H), 6.88 (d, J = 8.2 Hz, 1H), 7.10 (td, J = 1.0, 7.5 Hz, 1H), 7.32−7.36
(m, 2H), 7.67 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H). 19F NMR
(376 MHz, CDCl3, 296 K): δ −62.9. 13C NMR (100 MHz, CDCl3,
297 K): δ 52.2, 65.5, 112.3, 122.2, 124.4 (q, 1JCF = 271.6 Hz), 124.9 (q,
2
3JCF = 3.7 Hz), 129.1 (q, JCF = 32.4 Hz), 129.4, 129.8, 129.9, 131.2,
141.7, 154.6, 169.2. LR-ESIMS: m/z 328 [M + NH4]+. HR-ESIMS: m/
z 328.1158 (calcd for C16H17NO3F3, 328.1155). The aforementioned
1
to yield 11a (0.13 g, 73%). Mp: 84 °C. H NMR (300 MHz, CDCl3,
1395
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ester (0.49 g, 1.6 mmol) was hydrolyzed with LiOH (0.26 g, 6.3
mmol) to afford 11c (0.44g, 95%). Mp: 126 °C. 1H NMR (400 MHz,
CDCl3, 296 K): δ 4.68 (s, 2H), 6.91 (dd, J = 1.1, 8.9 Hz, 1H), 7.13 (td,
J = 1.0, 7.6 Hz, 1H), 7.33−7.39 (m, 2H), 7.66−7.72 (m, 4H). 19F
NMR (376 MHz, CDCl3, 296 K): δ −62.9. 13C NMR (100 MHz,
CDCl3, 297 K): δ 65.5, 112.9, 123.0, 125.0 (q, 1JCF = 273.5 Hz), 125.4
(q, 3JCF = 3.9 Hz), 129.7 (q, 2JCF = 31.2 Hz), 129.9, 130.3 (×2), 131.7,
142.0, 154.6, 173.2. LR-ESIMS: m/z 295 [M − H]−. HR-ESIMS: m/z
295.0592 (calcd for C15H10O3F3, 295.0588).
procedure in a TiO2 sol−gel-coated tube. Following irradiation for 30
h, the reaction mixture was purified by dry flash chromatography on
silica gel (eluent: gradient of 2−7.5% MeOH in CH2Cl2) to yield the
title compound as an off-white solid (105.4 mg, 68%) containing ∼5%
1
4-(tert-butyl)phenol. Mp: 85−88 °C. H NMR (400 MHz, CD3OD,
297 K): δ 1.30 (s, 9H), 2.04−2.11 (m, 2H), 2.43 (t, J = 7.3 Hz, 2H),
4.00 (t, J = 6.3 Hz, 2H), 6.85 (d, J = 8.9 Hz, 2H), 7.30 (dd, J = 3.2,
11.5 Hz, 1H). 13C NMR (75 MHz, CDCl3, 297 K): δ 27.0, 32.4, 33.4,
35.3, 68.5, 115.5, 127.6, 144.8, 158.5, 179.0. LR-ESIMS: m/z 236 [M +
H]+. HR-ESIMS: m/z 236.1647 (calcd for C14H22NO2, 236.1645).
4-(Trifluoromethyl)phenoxybutanamide. 4-(Trifluoromethyl)-
phenoxyacetic acid (145.3 mg, 0.66 mmol) and acrylamide (93.9 mg,
1.32 mmol) in MeCN (45 mL) were reacted in accordance with the
general procedure in a TiO2 sol−gel-coated tube. Following irradiation
for 24 h, the reaction mixture was purified by dry flash
chromatography on silica gel (eluent: 5% MeOH in CH2Cl2) to
yield the title compound as an off-white solid (108.4 mg, 66%). Mp:
93−94 °C. 1H NMR (500 MHz, d6-acetone, 295 K): δ 2.06−2.11 (m,
2H), 2.41 (t, J = 7.2 Hz, 2H), 4.14 (t, J = 5.9 Hz, 2H), 6.30 (bs, 1H),
6.86 (bs, 1H), 7.14 (d, J = 8.7 Hz, 2H), 7.63 (d, J = 8.7 Hz, 2H). 13C
NMR (75 MHz, d6-acetone, 297 K): δ 29.9, 36.3, 72.7, 120.0, 127.2 (q,
2JC−F = 33.1 Hz, 1C), 130.0 (q, 1JC−F = 271.1 Hz, 1C), 132.0 (q, 3JC−F
2-(2-((Methoxyimino)methyl)phenoxy)acetic Acid (13a). A
suspension of 2-formylphenoxyacetic acid (0.515 g, 2.86 mmol, 1.0
equiv), methoxylamine hydrochloride (0.478 g, 5.72 mmol, 2.0 equiv),
and sodium acetate (0.469 g, 5.72 mmol, 2.0 equiv) in ethanol (30
mL) was heated at reflux for 18 h. The solvent was removed under
reduced pressure, and the crude residue was redissolved in H2O (100
mL) and extracted into CH2Cl2 (3 × 100 mL). The combined organic
layers were dried (MgSO4), concentrated under reduced pressure, and
purified by column chromatography (5% EtOAc/CH2Cl2) to yield 13a
1
as a colorless solid (0.390 g, 65%). H NMR (300 MHz, CDCl3, 294
K): δ 4.01 (s, 3H), 4.72 (s, 2H), 6.91 (d, J = 8.2 Hz, 1H), 7.12 (m,
1H), 7.34 (d, J = 7.6 Hz, 1H), 7.40 (m, 1H), 8.15 (s, 1H). 13C NMR
(75 MHz, CDCl3, 295 K): δ 61.9, 66.6, 114.2, 120.6, 123.0, 131.7,
132.4, 148.8, 155.4, 169.5. LR-ESIMS: m/z 208 [M − H]−. HR-
ESIMS: m/z 208.0614 (calcd for C10H10NO4, 208.0615).
= 3.6 Hz, 2C), 167.2, 178.9. 19F NMR (470 MHz, d6-acetone, 295 K):
δ −61.8. LR-ESIMS: m/z 248 [M + H]+. HR-ESIMS: m/z 248.0896
(calcd for C11H13NO2F3, 248.0896).
2-(2-(((Benzyloxy)imino)methyl)phenoxy)acetic Acid (13b).
A suspension of 2-formylphenoxyacetic acid (1.00 g, 5.55 mmol, 1.0
equiv), benzoxylamine hydrochloride (1.773 g, 11.11 mmol, 2.0
equiv), and sodium acetate (0.911 g, 11.11 mmol, 2.0 equiv) in ethanol
(60 mL) was heated at reflux for 18 h. The solvent was removed under
reduced pressure, and the crude residue was redissolved in H2O (100
mL) and extracted into CH2Cl2 (3 × 100 mL). The combined organic
layers were dried (MgSO4), concentrated under reduced pressure, and
purified by column chromatography (5% EtOAc/CH2Cl2) to yield
Photocatalyzed Reaction of (E)-2-(2-(3-oxopent-1-en-1-yl)-
phenoxy)acetic Acid (8c). A suspension of 8c (0.050 g, 0.21 mmol,
1.0 equiv) and TiO2 (P25, 0.025 g, 0.32 mmol, 1.5 equiv) in MeCN
(20 mL) was reacted in accordance with the general procedure for 9 h.
Following removal of the solvent under reduced pressure, the mixture
1
1
was subjected to analysis by H NMR and GC−MS. The H NMR
spectrum showed a complex array of components. GC−MS indicated
four major components, and one of these (tR = 10.7 min) had the
correct mass and fragmentation pattern for the cyclized product 10c:
m/z (%): 190 (40), 161 (36), 146 (18), 133 (23), 119 (38), 118
1
13b as a colorless solid (0.422 g, 26%). H NMR (300 MHz, CDCl3,
294 K): δ 4.70 (s, 2H), 5.25 (s, 2H), 6.90 (d, J = 8.2 Hz, 1H), 7.11 (t, J
= 6.6 Hz, 1H), 7.32−7.44 (m, 7H), 8.26 (s, 1H). 13C NMR (75 MHz,
CDCl3, 295 K): δ 66.5, 76.2, 114.0, 120.6, 122.9, 128.2, 128.5, 128.5,
131.7, 132.2, 136.6, 149.3, 155.3, 169.5. LR-ESIMS: m/z 284 [M −
H]−. HR-ESIMS: m/z 284.0923 (calcd for C16H14NO4, 284.0928).
d1-Phenoxyacetic Acid (5aD). Phenoxyacetic acid (304 mg, 2.0
mmol) and SOCl2 (0.74 mL, 10.0 mmol) were refluxed in CHCl3 for
72 h. The volatiles were removed under reduced pressure to yield
1
(100), 91 (41). H NMR (400 MHz, CD3CN, 298 K): δ 0.98 (t, J =
7.3 Hz, 3H), 2.47 (q, J = 7.3 Hz, 2H), 3.26−3.29 (m, 1H), 4.37 (dd, J
= 2.3, 8.4 Hz, 1H), 4.94 (dd, J = 5.2, 9.4 Hz, 1H), 7.03−7.17 (m, 2H,),
7.50−7.54 (m, 2H). Attempts to isolate and thoroughly characterize
10c were not successful. Photoisomerization of 8c to its Z isomer was
1
observed during the course of this experiment. H NMR (400 MHz,
1
CD3CN, 298 K): δ 7.38 (d, J = 7.3 Hz, 1H), 7.30 (t, J = 7.3 Hz, 1H),
7.02 (d, J = 12.0 Hz, 1H), 6.95 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 8.3 Hz,
1H), 6.28 (d, J = 12.5 Hz, 1H), 4.69 (s, 2H), 2.47 (q, J = 7.3 Hz, 2H),
0.97 (t, J = 7.3 Hz, 3H).
phenoxyacetyl chloride. H NMR (400 MHz, CDCl3, 296 K): δ 4.95
(s, 2H), 6.93 (m, 2H), 7.09 (m, 1H), 7.35 (m, 2H). 13C NMR (75
MHz, CDCl3, 297 K): δ 64.9, 77.2, 114.8, 122.3, 129.9, 157.5, 174.2.
This compound was immediately treated with D2O (0.9 mL, 5.0
mmol) in anhydrous CH3CN (10 mL), and the mixture was allowed
to stir overnight under an argon atmosphere. The solvent was removed
under reduced pressure, and the resultant residue was recrystallized
from anhydrous Et2O to yield 5aD as a white crystalline solid (141 mg,
Photocatalyzed Reaction of 2-([1,1′-Biphenyl]-2-yloxy)acetic
Acid (11a). A suspension of 11a (0.052 g, 0.23 mmol, 1.0 equiv) and
TiO2 (P25, 0.027 g, 0.34 mmol, 1.5 equiv) in MeCN (20 mL) was
reacted in accordance with the general procedure for 18 h. Following
1
1
removal of the solvent under reduced pressure, H NMR analysis of
46%). H NMR (500 MHz, CDCl3, 295 K): δ 4.70 (s, 2H), 6.93 (m,
2H), 7.03 (m, 1H), 7.32 (m, 2H). 2H NMR (76 MHz, CHCl3, 315 K):
δ 10.13 (bs, 1D). 13C NMR (75 MHz, CDCl3, 297 K): δ 64.9, 114.8,
122.4, 129.9, 157.4, 172.8. LR-ESIMS: m/z 153 [M]+. HR-ESIMS: m/
z 153.0543 (calcd for C8H8O3D, 153.0513).
the reaction mixture showed mainly unreacted 11a together with a
small amount of the cyclized product 12a (0.01 mmol, 5% wrt
CH2Br2). 1H NMR (400 MHz, CDCl3, 296 K): δ 5.05 (s, 2H), 6.90−
6.95 (m, 2H), 7.00−7.10 (m, obscured by SM), 7.60−7.70 (m, 3H).
Attempts to isolate and thoroughly characterize 12a were unsuccessful.
Methyl 2-(2,3-Dihydrobenzofuran-3-yl)acetate (10a). A sus-
pension of 8a (0.050 g, 0.21 mmol, 1.0 equiv) and TiO2 (P25, 0.025 g,
0.32 mmol, 1.5 equiv) in MeCN (20 mL) was reacted according to the
general procedure for 9 h to yield 10a as a colorless powder (20% by
NMR). 1H NMR (400 MHz, CDCl3, 294 K): δ 2.52 (dd, J = 9.5, 16.5
Hz, 1H), 2.73 (dd, J = 5.3, 16.5 Hz, 1H), 3.72 (s, 3H), 3.84−3.91 (m,
1H), 4.18 (dd, J = 6.3, 9.2 Hz, 1H), 4.68 (t, J = 9.0 Hz, 1H), 6.80 (d, J
= 7.7 Hz, 1H), 6.86 (t, J = 8.3 Hz, 1H), 7.08−7.17 (m, 2H). 13C NMR
(75 MHz, CDCl3, 295 K): δ 38.7, 39.7, 52.3, 110.2, 114.1, 121.0,
124.6, 129.1, 129.5, 160.2, 172.7. LR-ESIMS: m/z 215 [M + Na]+.
HR-ESIMS: m/z 215.0674 (calcd for C11H12O3Na, 215.0679).
Photoisomerization of 8a to its Z isomer was observed during the
4-Phenoxybutanamide (19H). Phenoxyacetic acid (100 mg, 0.66
mmol) and acrylamide (93.9 mg, 1.32 mmol) in MeCN (45 mL) were
reacted in accordance with the general procedure in a TiO2 sol−gel-
coated tube. Following irradiation for 24 h, the reaction mixture was
purified by dry flash chromatography on silica gel (eluent: gradient of
2−10% MeOH in CH2Cl2) to yield 19H as an off-white solid (79.8
mg, 68%). 1H NMR (300 MHz, CDCl3, 294 K): δ 2.13 (m, 2H), 2.45
(t, J = 7.2 Hz, 2H), 4.02 (t, J = 6.0 Hz, 2H), 5.63 (bs, 1H), 5.82 (bs,
1H), 6.90 (d, J = 8.8 Hz, 2H), 6.95 (t, J = 7.4 Hz, 1H), 7.29 (t, J = 7.4
Hz, 2H). 13C NMR (75 MHz, CDCl3, 295 K): δ 25.4, 32.6, 67.1,
114.9, 121.2, 129.9, 159.2, 175.4. Data are consistent with literature
values.16
4-(tert-Butyl)phenoxybutanamide. 4-(tert-Butyl)phenoxyacetic
acid (137.5 mg, 0.66 mmol) and acrylamide (93.9 mg, 1.32 mmol) in
MeCN (45 mL) were reacted in accordance with the general
1
course of this experiment. H NMR (400 MHz, CD3CN, 298 K): δ
7.48 (dd, J = 7.6, 1.8 Hz, 1H), 7.31 (t, J = 7.8 Hz, 1H), 7.19 (d, J =
1396
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12.5 Hz, 1H), 6.97 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.01
(d, J = 12.3 Hz, 1H), 4.69 (s, 2H), 3.63 (s, 3H).
SCPC Reaction of Phenoxyacetic Acid with Acrylamide and
P25 Vacuum-Dried at 150 °C. TiO2 (12 mg, 0.15 mmol) was dried
overnight at 150 °C under a continuous vacuum in an oven-dried
Schlenk tube. Phenoxyacetic acid (15.2 mg, 0.1 mmol) and acrylamide
(14.2 mg, 0.2 mmol) in MeCN (12 mL) were added via syringe, and
the resultant mixture was irradiated for 18 h. H NMR analysis of the
resultant mixture revealed 19H (39% by NMR).
SCPC Reaction in Deuterated Acetonitrile (d3-MeCN).
Phenoxyacetic acid (15.2 mg, 0.1 mmol), acrylamide (14.2 mg, 0.2
mmol), and TiO2 (12 mg, 0.15 mmol) in d3-MeCN (12 mL) were
irradiated for 18 h. 1H NMR analysis of the resultant mixture revealed
19H (55% by NMR). Any deuterium incorporation was below the
NMR and MS detection limits.
2-(2,3-Dihydrobenzofuran-3-yl)acetonitrile (10b). A solution
of 8b (0.050 g, 0.246 mmol) in MeCN (15 mL) in a TiO2 sol−gel-
coated tube was reacted according to the general procedure. The
solvent was removed under reduced pressure, and the crude residue
was purified by column chromatography (CH2Cl2) to yield 10b as a
1
1
colorless powder (0.007 g, 28%). H NMR (400 MHz, CDCl3, 296
K): δ 2.58−2.71 (m, 2H), 3.74−3.82 (m, 1H), 4.34 (dd, J = 4.8, 9.6
Hz, 1H), 4.69 (dd, J = 8.7, 9.6 Hz, 1H). 6.84 (d, J = 8.1 Hz, 1H), 6.93
(td, J = 1.0, 7.5 Hz, 1H), 7.22 (m, 1H), 7.32 (d, J = 7.5 Hz, 1H). 13C
NMR (75 MHz, CDCl3, 295 K): δ 22.8, 38.8, 75.4, 110.3, 117.7, 121.2,
124.4, 127.1, 129.7, 159.7. LR-ESIMS: m/z 159 [M]+. HR-ESIMS: m/
z 159.0676 (calcd for C10H9NO, 159.0679). Photoisomerization of 8b
SCPC Reaction with Deuterated Phenoxyacetic Acid. d1-
Phenoxyacetic acid (15.3 mg, 0.1 mmol), acrylamide (14.2 mg, 0.2
mmol), and TiO2 (12 mg, 0.15 mmol) in MeCN (12 mL) were
1
to its Z isomer was observed during the course of this experiment. H
NMR (400 MHz, CD3CN, 298 K): δ 8.01 (dd, J = 7.6, 1.6 Hz, 1H),
7.66 (d, J = 12.5 Hz, 1H), 7.44 (t, J = 8.0 Hz, 1H), 7.11 (t, J = 7.5 Hz,
1H), 6.97 (d, J = 8.3 Hz, 1H), 5.64 (d, J = 12.3 Hz, 1H), 4.74 (s, 2H).
Photocatalyzed Reaction of 2-((4′-(Trifluoromethyl)-[1,1′-
biphenyl]-2-yl)oxy)acetic Acid (11c). A suspension of 11c (59
mg, 0.20 mmol, 1.0 equiv) and TiO2 (P25, 0.024 g, 0.30 mmol, 1.5
equiv) in MeCN (20 mL) was reacted in accordance with the general
procedure for 18 h. Following removal of the solvent under reduced
1
irradiated for 19 h. H NMR analysis (wrt CH2Br2 standard) of the
resultant mixture revealed 19H (49% by NMR). Any deuterium
incorporation was below the NMR and MS detection limits.
SCPC Reaction with Deuterated P25. An oven-dried Schlenk
tube, complete with magnetic stirrer, was connected to a vacuum line,
evacuated, and then back-filled with argon while still hot from the
oven. In a glovebox, TiO2 (P25, 0.15 mmol, 12 mg) was added, and
the tube was then heated at 150 °C for 3 h under vacuum. In a
separate oven-dried vessel, 10 mL of D2O (freshly opened) was
degassed by three freeze−pump−thaw cycles before being transferred
by cannula to the tube containing the TiO2 once it had cooled to
ambient temperature. The resultant mixture was allowed to stir
overnight before the D2O was removed under reduced pressure. At
this point the TiO2 was again dried for 3 h at 150 °C under vacuum. In
a separate oven-dried vessel, phenoxyacetic acid (0.1 mmol, 15.2 mg)
and acrylamide (0.2 mmol, 14.2 mg) were dissolved in MeCN (12
mL) that had been freshly collected after distillation over calcium
hydride. The resultant mixture was degassed for 15 min by bubbling
with argon and then transferred via cannula to the tube containing the
TiO2 once it had cooled to ambient temperature. The resultant
mixture was then irradiated in accordance with the general procedure
for 19 h. 1H NMR analysis of the resultant mixture revealed 19H (58%
by NMR). Any deuterium incorporation was below the NMR and MS
detection limits.
1
pressure, H NMR analysis of the reaction mixture showed mainly
unreacted acid (79%) together with a small amount of the cyclized
product 12c (0.01 mmol, 5% wrt CH2Br2). 1H NMR (400 MHz,
CDCl3, 296 K): δ 5.07 (s, 2H), 6.93−6.96 (m, 2H), 6.98−7.04 (m;
obscured by SM), 7.72−7.65 (m, 3H). GC−MS analysis of the
reaction mixture showed 12c as the main product: tR = 11.76 min; m/z
(%) 250 (58), 249 (100), 231 (6), 201 (10), 181 (10), 152 (16). Also
observed was a trace of what was probably the direct reduction
product 2-methoxy-4′-(trifluoromethyl)-1,1′-biphenyl: tR = 11.84 min;
m/z (%) 252 (82), 251 (48), 250 (61), 249 (100), 237 (20), 201 (16),
183 (26), 152 (32). Attempts to isolate and thoroughly characterize
12c were unsuccessful.
Photocatalyzed Reaction of 2-(2-((Methoxyimino)methyl)-
phenoxy)acetic Acid (13a). A suspension of 13a (51 mg, 0.24
mmol, 1.0 equiv) and TiO2 (P25, 0.029 g, 0.36 mmol, 1.5 equiv) in
MeCN (29 mL) was reacted in accordance with the general procedure
for 24 h. Following removal of the solvent under reduced pressure, 1H
NMR analysis of the reaction mixture showed that 13a had been
entirely consumed and that a complex mixture of products had been
formed. GC−MS analysis of the mixture revealed that 14a had been
formed: tR = 8.15 min; m/z (%) 165 (29), 133 (12), 119 (100), 91
(77) 77 (26). Also observed were benzofuran-3(2H)-one O-methyl
oxime [tR = 7.93 min; m/z (%) 163 (100), 118 (91), 91 (52)], 2,3-
dihydrobenzofuran [tR = 7.87 min; m/z (%) 120 (27), 119 (100), 91
(57)], 2,3-dihydrobenzofuran-3-amine [tR = 5.06 min; m/z (%) 135
(7), 134 (74), 119 (100), 117 (11)], and benzofuran [tR = 3.43 min;
m/z (%) 118 (100), 90 (22), 84 (30)]. Attempts to isolate and
thoroughly characterize 14a, or any other products, were unsuccessful.
Photocatalyzed Reaction of 2-(2-(((Benzyloxy)imino)-
methyl)phenoxy)acetic Acid (13b). A suspension of 13b (62 mg,
0.22 mmol, 1.0 equiv) and TiO2 (P25, 0.026 g, 0.33 mmol, 1.5 equiv)
in MeCN (26 mL) was reacted in accordance with the general
procedure for 24 h. Following removal of solvent under reduced
SCPC Reaction with Deuterated Phenoxyacetic Acid and
Deuterated P25. This reaction was performed as above using d1-
phenoxyacetic acid (15.3 mg, 0.1 mmol) for 19 h. 1H NMR analysis of
the resultant mixture revealed no clear signals indicating the formation
of 19H or 19D.
ASSOCIATED CONTENT
■
S
* Supporting Information
General procedures, EPR spectra, NMR monitoring of coated
tube reactions, and 1H and 13C NMR spectra for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Authors
1
pressure, H NMR analysis of the reaction mixture showed that 13b
*E-mail: dm53@st-andrews.ac.uk.
*Tel: 44 (0)1334 463864. Fax: 44 (0)1334 463808. E-mail:
jcw@st-and.ac.uk.
had been entirely consumed and that a complex mixture of products
had been formed. GC−MS analysis of the mixture revealed that 14b
had been formed: tR = 15.53 min; m/z (%) 241 (9), 210 (9), 133 (6),
91 (100), 77 (14). Also observed were benzofuran-3(2H)-one O-
benzyl oxime [tR = 15.37 min; m/z (%) 239 (37), 222 (4), 148 (3),
119 (7), 91 (100), 77 (12)], 2,3-dihydrobenzofuran-3-amine [tR = 5.04
min; m/z (%) 135 (7), 134 (74), 119 (100), 117 (11)], benzyl alcohol
[tR = 3.77 min; m/z (%) 108 (100), 107 (73), 79 (76)], benzofuran
[tR = 3.41 min; m/z (%) 118 (100), 90 (22), 84 (30)], and
benzaldehyde [tR = 2.90 min; m/z (%) 106 (87), 105 (100), 77 (66)].
Attempts to isolate and thoroughly characterize 14b or any other
product were unsuccessful.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the EPSRC for funding (Grants EP/I003479/1 and
EP/I003800/2), the EPSRC National Mass Spectrometry
Service, Swansea, and Prof. Russell Howe and Shona
Rhydderch for help with deuterium labeling of P25.
1397
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The Journal of Organic Chemistry
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