Direct Photorelease of Alcohols from Boron-Alkylated BODIPY Photocages

Article abstract of DOI:10.1021/acs.joc.0c00044

BODIPY photocages allow the release of substrates using visible light irradiation. They have the drawback of requiring reasonably good leaving groups for photorelease. Photorelease of alcohols is often accomplished by attachment with carbonate linkages, which upon photorelease liberate CO₂ and generate the alcohol. Here, we show that boron-alkylated BODIPY photocages are capable of directly photoreleasing both aliphatic alcohols and phenols upon irradiation via photocleavage of ether linkages. Direct photorelease of a hydroxycoumarin dye was demonstrated in living HeLa cells.

Full text of DOI:10.1021/acs.joc.0c00044

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Note
Direct Photorelease of Alcohols from Boron-Alkylated BODIPY
Photocages
Julie A. Peterson, Logan J. Fischer, Elizabeth J. Gehrmann, Pradeep Shrestha, Ding Yuan,
Chamari S. Wijesooriya, Emily A. Smith,* and Arthur H. Winter*
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ABSTRACT: BODIPY photocages allow the release of substrates
using visible light irradiation. They have the drawback of requiring
reasonably good leaving groups for photorelease. Photorelease of
alcohols is often accomplished by attachment with carbonate
linkages, which upon photorelease liberate CO2 and generate the
alcohol. Here, we show that boron-alkylated BODIPY photocages
are capable of directly photoreleasing both aliphatic alcohols and
phenols upon irradiation via photocleavage of ether linkages.
Direct photorelease of a hydroxycoumarin dye was demonstrated
in living HeLa cells.
hotocages are light-sensitive chemical protecting groups
that can be covalently linked to a substrate of interest,
P
rendering it inactive. Upon irradiation, the bond is cleaved and
the substrate is released, restoring its activity. Photocages are
useful in studies that require the spatial and temporal control
that can be provided by pulsed light irradiation. These include
biological investigations of short-lived species, small molecules,
and signaling agents;1,2 targeted phototherapeutics;3,4 and
microarray synthesis.5−8 Visible light-absorbing photocages
have been an exciting new development as they allow for less
toxic visible light irradiation in biological studies.1,4,9−11 In
particular, our group along with others have developed
BODIPY photocages that can release leaving groups from
the meso position after activation with single photons of green
to near IR light.12−18 Many biological targets (e.g., paclitaxel,
dopamine) have phenolic or aliphatic alcohol functional
groups that remain challenging targets for current photocages.
Previously, meso-substituted BODIPY compounds have been
used to release alcohols and amines via carbonate or carbamate
linkages (Figure 1).13,15−17 While carbonate linkages permit
photorelease of alcohols, they have several potential drawbacks.
First, while they are easy to make in theory, carbonates can be
less synthetically tractable compared to ether linkages.
Moreover, they can, in principle, be cleaved by cellular
esterases, which would yield undesirable background thermal
deprotection, and in some cases, may be less hydrolytically
stable than ethers. In addition, there is a required thermal
decarboxylation step after photolysis, which interferes with the
temporal control that photoactivation allows. Direct photo-
release of alcohols from the corresponding BODIPY ethers
would address these disadvantages.
Figure 1. Photochemical reaction followed by thermal decarbox-
ylation to release alcohols via a carbonate linker (top). Direct
photochemical release of an alcohol via an ether linkage (bottom).
Recently, Weinstain and co-workers demonstrated the direct
release of 2,4-dinitrophenol from a BODIPY photocage, which
has a pKa on par with acetic acid.13 Our group along with
Klan’s and Weinstain’s groups recently conducted a structure−
reactivity investigation of BODIPY photocages and discovered
that boron-alkylation leads to a large increase in quantum
yields of photorelease for carboxylic acids (see 2-PAA in
Received: January 7, 2020
Published: March 27, 2020
https://dx.doi.org/10.1021/acs.joc.0c00044
© XXXX American Chemical Society
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A

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Note
a
Scheme 1. Synthesis of BODIPY Compounds Ether Linkages from Acetyl Chlorides to Investigate the Release of Alcohols
a
Conditions: (a) DCM, reflux, triethyamine, boron trifluoride diethyl etherate; (b) DCM, methylmagnesium bromide, rt; (c) THF, N-
iodosuccinimide, rt. Compound 1-PNP is an example of a carbonate linkage previously published by Weinstain’s group.16 Compound 2-PAA is an
example of a B-methylated derivative published by our group in a collaborative study with Weinstain and Klan.18
Table 1. Photophysical Properties
e
λex (nm) λem (nm) ε × 104 (M−1 cm−1
)
Φ (%)
0.099
5.5 0.02
0.16
0.10 0.02
0.38 0.04
1.0 0.5
1.0 0.1
0.15 0.03
0.8 0.1
photorelease yield (%), (time (h))
remaining ethers (time) εΦ (M−1 cm−1
)
a
b
1-OAc
517
512
547
514
516
510
511
535
537
529
550
7.1
6.9
4.8
6.9
6.6
5.2
5.1
5.7
6.1
70
3800
77
2-PAA
1-PNP
1-OBn
c
>95
d
528
529
528
529
547
560
12 (20)
30 (20)
71 (24)
65 (24)
32 (4)
83 (20)
56 (20)
0 (24)
0 (24)
0 (4)
69
251
340
510
86
d
1-OPh
2-OBn
d
d
2-OPh
3-OBn
d
d
3-OPh
28 (6)
0 (6)
104
a
b
Values taken from a previous study; quantum yields were calculated in methanol.12 Values taken from a previous study; quantum yield was
calculated in methanol.18 Values taken from a previous study; quantum yields were calculated in a pH 7.4 aqueous solution with 5% acetonitrile.16
c
d
Compounds synthesized in this study; quantum yields were calculated in 1:1 CDCl3/CD3OD using quantitative NMR to follow the release of the
e
substrate using dimethyl sulfone as an internal standard and 1-OAc as the actinometer. Chemical yields and remaining ether were determined by
irradiating NMR tubes with 1 mL of 2 mM solutions of substrates dissolved in 1:1 CDCl3/CD3OD with a 500 W halogen lamp. Dimethyl sulfone
was used as an internal standard for quantitative NMR.
Scheme 1 and Table 1).18 We thus considered the possibility
that these improved structures might be able to achieve direct
photorelease of alcohols. We synthesized BODIPY photocages
(Scheme 1) with benzyl and phenyl ethers in the meso
position in order to investigate their ability to release aliphatic
alcohols and phenols, respectively, upon excitation with visible
light.
1-OBn and 1-OPh were formed in a one-pot synthesis first
refluxing 2,4-dimethylpyrrole in dry DCM with benzyloxyace-
tyl chloride for 1-OBn or phenoxyacetyl chloride for 1-OPh.
The reaction was then cooled to room temperature, and
triethylamine and boron trifluoride diethyl etherate were added
sequentially. 1-OBn and 1-OPh were transformed into 2-OBn
and 2-OPh by reaction with excess methylmagnesium
bromide. N-Iodosuccinimide was used to iodinate the
compounds to generate 3-OBn and 3-OPh. These photocages
have high extinction coefficients (>50 000 M−1 cm−1) and λmax
values > 500 nm (Table 1). Photocages were irradiated with a
500 W Halogen lamp, and release of phenol or benzyl alcohol
occurred, as demonstrated by following the photoreaction by
1H NMR (Table 1, Figure S1 and S2). Reactivity of the
fluorinated derivatives was slow, giving less than 50%
conversion when irradiated for 20 h. Interestingly, the
methylated derivatives 2-OBn and 2-OPh seemed to initially
release their respective alcohols quickly; however, over time,
the rate of release slowed down (Figures S8 and S9). This may
be due to photolability of the methyl groups on the boron,
which we have seen in other studies.19
Due to low solubility in methanol, a 1:1 mixture with a
cosolvent was necessary to dissolve the substrates in this study.
Interestingly, in solutions of 2-OBn dissolved using acetonitrile
or DMSO as cosolvents with methanol, benzaldehyde was
observed in the NMR after irradiation with a 532 nm Nd:YAG
laser. However, benzaldehyde formation was not detected with
either a 500 W halogen lamp or a low-intensity green LED
(Figure S5). Additionally, benzaldehyde was not detected
when 2-OBn was irradiated with the 532 nm laser using
chloroform as the cosolvent (Table S1). The mechanism of
this oxidation is currently unknown, and it is unclear why
benzaldehyde is only present under certain conditions. To
avoid this curiosity, quantum yields were determined using
chloroform as the cosolvent for the purpose of this study.
To determine quantum yields of photorelease for the
compounds of this study, samples dissolved in 50:50 CDCl3/
CD3OD were irradiated with a 532 nm Nd:YAG laser. The
amount of release over time was calculated using quantitative
NMR with dimethyl sulfone as an internal standard and using
1-OAc as the actinometer (Φ = 0.099%).12
B
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Note
a
Scheme 2. Synthesis of BODIPY Ethers with Williamson Ether Synthesis From 2-Br
a
Conditions: (a) DCM, methylmagnesium bromide, rt; (b) DCM, pyridine, phosphorous tribromide, 0 °C; (c) ACN, potassium carbonate, rt; (d)
ACN, cesium carbonate, rt.
The boron-fluorinated ethers surprisingly have decent
quantum yields of photorelease in a 50:50 methanol/
chloroform mixture (Table 1). Upon methylating the boron
of the BODIPY ethers, the quantum yield of photorelease
increases 2.5−10-fold compared to the corresponding boron-
fluorinated ethers. We hypothesized that appending iodines to
the BODIPY core would lead to a further increase in the
quantum yield by promoting intersystem crossing to a longer-
lived triplet excited state. This strategy was previously shown
to be effective for increasing the photorelease quantum yields
for carboxylic acids.12,17,18 Curiously, instead of increased
quantum yields of release, we observed a lower quantum yield
of release and an accelerated rate of photodecomposition
compared to the uniodinated derivatives (Figure S6).
cesium carbonate was used instead, the reaction was complete
after stirring overnight. Using the alcohols in excess afforded
fair (67−75%) yields of 2-OEt, 2-OVan, and 2-OCou under
mild conditions. When p-vanillin was reacted with a small
excess of 2-Br, 2-OVan was achieved in a slightly lowered yield
(54%). 2-OEt and 2-OVan released ethanol and vanillin,
respectively, upon irradiation with white light (Figures S3 and
S4). Preliminary data suggests that attachment and photo-
release of secondary alcohols may be possible (Scheme S1,
Figures S10 and S11).
2-OCou was used as a proof of concept to demonstrate the
viability for direct photorelease of alcohols in biological
studies. The fluorescence of 7-hydroxycoumarin (4) is
known to be highly dependent on substitutions on the
hydroxy group. The protected coumarin (2-OCou) should
have a diminished fluorescence, which is recovered after
irradiation. HeLa cells were incubated with 2-OCou and
irradiated. Cells irradiated with a green light for intervals
showed an increase in fluorescence at 450 nm using short 365
nm excitation (Figure S7). In order to obtain the best signal-
to-noise ratio, the cells were irradiated with 350 nm light. This
doubled as the activation wavelength for BODIPY, as well as
the excitation wavelength for 7-hydroxycoumarin so the
fluorescence could be collected continuously at 450 nm
(Figure 2). An increase in fluorescence followed by photo-
bleaching was observed for irradiation of cells incubated with
Direct photorelease of alcohols with a visible light
photoremovable protecting group is an exciting avenue for
studies of biologically relevant alcohols or as protecting groups
for multistep syntheses. There are three obvious synthetic
methods for attaching alcohols to the meso position of
BODIPY. First, as used for the synthesis of 1-OBn and 1-OPh,
the phenoxy or alkyloxy acid chloride could be used for the
BODIPY synthesis (Scheme 1). This method is useful for
simple alcohols that are readily available. However, it may not
be practical to make the acid chloride from sensitive or
expensive alcohols. Another potential method of attaching
alcohols to the meso BODIPY is via Williamson ether
synthesis, using the BODIPY alcohol as the nucleophile and
having the desired alcohol replaced with a good leaving
group.13 While this is a reasonable approach, it would be
difficult to use this method for precious materials, which are
not available with leaving groups in the appropriate positions.
The most generally useful method is to perform a
Williamson ether synthesis using the alcohol of interest as
the nucleophile. We found that the addition of alkoxides to
boron-fluorinated BODIPY can lead to decomposition of the
starting material with very low or no yield. However, first
substituting the boron with methyl groups allowed this
reaction to occur with fair yields (Scheme 2).20 1-OAc was
converted to 2-OH using excess methylmagnesium bromide,
which acted to both methylate the boron and hydrolyze the
acetyl group. Then, 2-Br was synthesized by reacting 2-OH
with phosphorus tribromide at 0 °C. The reaction generally
occurred with a 10−33% yield accompanied by decomposition.
When pyridine is included in the reaction, the yield increased
slightly to 38%, and we were able to recover unreacted 2-OH.
Due to low yields of the bromination, we chose to use excess
alcohol for the Williamson Ether synthesis in order to conserve
2-Br. For the phenolic compounds, potassium carbonate was
used as the base. However, under these conditions, no reaction
was observed between 2-Br and ethanol after 12 h. When
Figure 2. (A) Scheme of 2-OCou, which has a fluorescence increase
upon photorelease of 4. (B) Fluorescence increase in imaging buffer
following the photorelease of 7-hydroxycoumarin upon irradiation
with a green LED. (C−F) Fluorescence images of HeLa cells
incubated with 25 μM compound 2-OCou and continuously
irradiated with 350 nm light while collecting 450 nm emission.
(G−J) Fluorescence images using 25 μM of 4 as a control. (K)
Fluorescence intensity with continuous irradiation of cells incubated
with 2-OCou and 4.
C
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6H), 2.30 (s, 6H); 13C{1H} NMR (93 MHz, CDCl3) δ 158.3, 156.5,
141.7, 134.1, 133.0, 129.8, 122.1, 121.7, 114.1, 60.7, 15.4, 14.7;
HRMS (ESI/QTOF) m/z [M + H]+ calcd for C20H21BF2N2O
355.1793, found 355.1787.
2-OCou, while only a decrease in fluorescence (photo-
bleaching) was measured in a control experiment irradiating
cells incubated only with 7-hydroxycoumarin. These studies
indicate that the use of ethers as a linkage to directly
photorelease alcohols is a viable strategy in biological systems.
In conclusion, the synthesis of meso-substituted BODIPY
ethers was demonstrated, and direct photorelease of the
corresponding alcohols has been reported. Swapping the
fluorines on the boron for methyls effectively increases the
quantum yield of release, while iodination does not. The
Williamson ether synthesis between 2-Br and an alcohol of
interest may be a good path for making these ethers, but more
work needs to be done to find a better path for the synthesis of
2-Br itself. Practical use was demonstrated by direct photo-
release of the fluorescent dye 7-hydroxycoumarin in living
HeLa cells.
8-Benzoxymethyl-1,3,5,7-tetramethyl Pyrromethene Fluorobo-
rate (1-OBn). The compound was obtained from 2,4-dimethyl pyrrole
(400 μL, 3.9 mmol, 2 equiv) and benzyloxyacetyl chloride (310 μL,
1.95 mmol, 1 equiv) as a bright orange solid in 64% yield (447 mg):
1H NMR (400 MHz, CDCl3) δ 7.31−7.37 (m, 5 H), 6.04 (s, 2 H),
4.65 (s, 2 H), 4.61 (s, 2 H), 2.52 (s, 6 H), 2.31 (s, 6 H); 13C{1H}
NMR (93 MHz, CDCl3) δ 155.9, 141.9, 137.1, 136.2, 133.1, 128.6,
128.4, 128.3, 122.0, 73.1, 63.1, 15.4; HRMS (ESI/QTOF) m/z [M +
H]+ calcd for C21H23BF2N2O 369.1944, found 369.1952.
General Procedure for Methylation of BODIPY Etherate
Photocages. To a solution of 1-OBn or 1-OPh in 5 mL of dry
dichloromethane was added 11 equiv of methylmagnesium bromide.
The solutions were stirred for 1 h, quenched with ammonium
chloride, washed 3 times with water and once with brine, and dried
over sodium sulfate. The solvent was removed under a vacuum, and
the mixtures were purified as listed below.
EXPERIMENTAL SECTION
■
1,3,5,7-Tetramethyl-8-phenoxymethyl Pyrromethene Methylbo-
rate (2-OPh). The compound was obtained from 1-OPh (100 mg,
0.28 mmol, 1 equiv) and methylmagnesium bromide (1 mL 3 M
solution in THF, 3.0 mmol, 11 equiv). The crude solid was purified
with silica gel column chromatography using 90:10 hexanes/
methylene chloride as the eluent to give the product as a bright
General Information. Unless otherwise stated, all purchased
chemicals were used without further purification. Solvents were dried
for 3 days over activated 4 Å molecular sieves. Compound 1-OAc was
prepared as previously reported.21 All reactions were done in the dark.
Light Sources. Irradiation with white light was carried out using a
Utilitech brand 500 W model no. MPL1025-C500 K9030 halogen
work lamp. A 500 mL beaker filled with water was placed in front of
the lamp, and a fan was blown on the lamp and the sample to prevent
overheating. Samples were irradiated in NMR tubes approximately 25
cm away from the light source.
1
orange solid in 80% yield (75 mg): H NMR (400 MHz, CDCl3) δ
7.36 (t, J = 8 Hz, 2H), 7.05 (t, J = 8 Hz, 2H), 7.00 (d, J = 8 Hz, 2H),
5.20 (s, 2H), 2.56 (s, 6H), 2.35 (s, 6H), 0.22 (s, 6H); 13C{1H} NMR
(93 MHz, CDCl3) δ 158.5, 153.1, 137.4, 134.2, 131.6, 129.8, 122.6,
121.5, 114.2, 61.3, 16.7, 15.8, 1.2; HRMS (ESI/QTOF) m/z [M +
H]+ calcd for C22H27BN2O 346.2295, found 347.2288.
Irradiation with a green LED was carried out using an Luzchem
EXPO-LED photoreactor equipped with 5 LED-GR (4 W) lamps.
The photoreactor was placed on its side, and samples were irradiated
in NMR tubes approximately 10 cm away from the light source.
Irradiation with a green laser was carried out using a Nd:YAG laser
equipped with a 532 nm crystal. Samples were irradiated in quartz
cuvettes equipped with stir bars.
8-Benzoxymethyl-1,3,5,7-tetramethyl Pyrromethene Methylbo-
rate (2-OBn). The compound was obtained from 1-OBn (100 mg,
0.27 mmol, 1 equiv) and methylmagnesium bromide (1 mL 3 M
solution in THF, 3.0 mmol, 11 equiv). The crude solid was purified
with silica gel column chromatography using 90:10 hexanes/
methylene chloride as the eluent to give the product as a bright
Procedure for Determination of Quantum Yields. BODIPY
compounds (2−20 mg) were dissolved in 5 mL of deuterated
chloroform. The solutions were spiked with a known amount of
dimethylsulfone as an internal standard and diluted to 10 mL with
deuterated methanol. The solutions were checked to ensure that they
had an absorbance of greater than 2 at 532 nm. Three mL of the
solutions were transferred to quartz cuvettes and irradiated with a
ND:YAG 532 nm laser under air. At varying time intervals of
irradiation, 0.6 mL of the samples were transferred to NMR tubes,
and 1H NMR spectra were obtained. The solutions were then
returned to the cuvettes for further irradiation. Photorelease was
monitored at six time points for each compound by 1H NMR,
following the growth of the leaving group. The concentration of the
released compound was calculated using the internal standard, and the
quantum yield was calculated using 1-OAc (8-acetoxymethyl-1,3,5,7-
tetramethyl pyrromethene fluoroborate) as the actinometer. 1-OAc
was irradiated in the same manner as the other photocages.
General Procedure for the Synthesis of 1-OBn and 1-OPh. To a
solution of 2,4-dimethylpyrrole (2 equiv) stirring in 3 mL of dry
dichloromethane in a two-neck flask equipped with a condenser under
argon was added 1 equiv of acid chloride. The mixture was stirred at
reflux in an oil bath for 2 h and turned dark red. The mixture was
cooled to room temperature, and triethylamine was added followed by
boron trifluoride diethyl etherate. The solvent was reduced under a
vacuum to give a dark oily liquid. Methanol was added to precipitate
the product, which was then filtered and washed with methanol until
the solid was bright orange.
1
orange solid in 60% yield (60 mg): H NMR (400 MHz, CDCl3) δ
7.40 (m, 5H), 6.09 (s, 2H), 4.77 (s, 2H), 4.65 (s, 2H), 2.49 (s 6H),
2.40 (s, 6H), 0.24 (s, 6H); 13C{1H} NMR (93 MHz, CDCl3) δ 152.5,
137.4, 137.3, 136.1, 131.7, 128.6, 128.5, 128.2, 122.4, 73.4, 63.9, 16.7,
15.7; HRMS (ESI/QTOF) m/z [M + H]+ calcd for C23H29BN2O
361.2446, found 361.2454.
General Iodination Procedure. To a solution of 2-OBn or 2-OPh
dissolved in 10 mL of dry THF was added 3 equiv of N-
iodosuccinimide. The solution was stirred until the color changed
to dark pink, after which dichloromethane and water were added. The
organic layer was washed with water three times and dried over
sodium sulfate. The solvent was removed under a vacuum, and the
crude product was purified as listed below.
8-Benzoxymethyl-2,6-diiodo-1,3,5,7-tetramethyl pyrromethene
methylborate (3-OBn). The compound was obtained from 2-OBn
(50 mg, 0.14 mmol, 1 equiv) and N-iodosuccinimide (95 mg, 0.42
mmol, 3 equiv). The crude product was purified with silica gel column
chromatography using hexanes to a 90:10 hexanes/dichloromethane
gradient as the eluent to give the product as a red solid in 70% yield
(59 mg): 1H NMR (400 MHz, CDCl3) δ 7.35 (m, 5 H), 4.73 (s, 2H),
4.63 (s, 2H), 2.52 (s, 6H), 2.42 (s, 6H), 0.17 (s, 6H); 13C{1H} NMR
(93 MHz, CDCl3) δ 153.2, 139.9, 136.8, 135.2, 131.6, 128.7, 128.7,
128.5, 87.1, 73.7, 64.5, 18.5, 18.0, 1.2; HRMS (ESI/QTOF) m/z [M
− H]− calcd for C22H25BI2N2O 597.0077, found 597.0059.
2,6-Diiodo-1,3,5,7-tetramethyl-8-Phenoxymethyl pyrromethene
methylborate (3-OPh). The compound was obtained from 2-OPh
(50 mg, 0.14 mmol, 1 equiv) and N-iodosuccinimide (95 mg, 0.42
mmol, 3 equiv). The crude product was purified with silica gel column
chromatography using hexanes to a 90:10 hexanes/dichloromethane
gradient as the eluent to give the product as a red solid in 72% yield
(62 mg): 1H NMR (400 MHz, CDCl3) δ 7.36 (dd, J = 8, 7.6 Hz, 2H),
7.06 (t, J = 7.6 Hz, 1H), 7.00 (d, J = 8 Hz, 2H), 5.20 (s, 2H), 2.56 (s,
8-Phenoxymethyl-1,3,5,7-tetramethyl Pyrromethene Fluorobo-
rate (1-OPh). The compound was obtained from 2,4-dimethyl pyrrole
(400 μL, 3.9 mmol, 2 equiv) and phenoxyacetyl chloride (270 μL,
1.95 mmol, 1 equiv) as a bright orange solid in 73% yield (511 mg):
1H NMR (400 MHz, CDCl3) δ 7.34 (t, J = 6 Hz, 2H), 7.04 (t, J = 6
Hz, 1H), 6.98 (d, J = 6 Hz, 2H), 6.07 (s, 2H), 5.15 (s, 2H), 2.54 (s,
D
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Note
6H), 2.35 (s, 6H), 0.23 (s, 6H); 13C{1H} NMR (93 MHz, CDCl3) δ
158.0, 153.7, 139.8, 133.3, 131.4, 129.9, 121.8, 114.1, 87.3, 61.8, 18.4,
18.1, 1.1; HRMS (ESI/QTOF) m/z [M + H]+ calcd for
C23H27BI2N2O 613.0379, found 613.0380.
2-OCou. To a solution of 7-hydroxycoumarin (20 mg, 0.12 mmol,
1.7 equiv) stirring in 5 mL of acetonitrile was added potassium
carbonate (10 mg, 0.07 mmol, 1 equiv), followed by 2-Br (24 mg,
0.07 mmol, 1 equiv). The solution was stirred until the starting
material was consumed by TLC, after which it was diluted with water
and ethyl acetate. The organic layer was washed with water 10 times
to remove unreacted 7-hydroxycoumarin. The organic layer was dried
over sodium sulfate, and the solvent was removed under a vacuum.
The crude product was purified via silica gel column chromatography
using dichloromethane as the eluent to give the product as a pink
solid in 69% yield (20 mg): 1H NMR (400 MHz, CDCl3): δ 7.67 (d, J
= 8 Hz, 1H), 7.43 (d, J = 8, 1H), 6.96 (m, 2H), 6.30 (d, J = 8 Hz,
1H), 6.09 (s, 2H), 5.27 (s, 2H), 2.48 (s, 6H), 2.29 (s, 6H), 0.22 (s,
6H); 13C{1H} NMR (140 MHz, CDCl3) δ 161.6, 161.1, 156.1, 153.6,
143.4, 137.2, 132.8, 131.6, 129.3, 122.9, 113.8, 112.9, 101.3, 62.3,
16.8, 15.9, 1.2; HRMS (ESI/QTOF) m/z [M + H]+ calcd for
C25H27BN2O3 415.2187, found 415.2197.
8-Hydroxymethyl-1,3,5,7-tetramethyl pyrromethene methylbo-
rate (2-OH). To a solution of 1-OAc (100 mg, 0.31 mmol, 1 equiv)
dissolved in dichloromethane was added 15 equiv of methyl
magnesium bromide (4.7 mL 1 M solution in diethyl ether, 4.7
mmol, 15 equiv). The solution was stirred for 1 h, after which the
reaction was complete by TLC. The reaction was quenched with
ammonium chloride, and ethyl acetate was added. The organic layer
was washed 3 times with ammonium chloride, with brine, and dried
over sodium sulfate. The solvent was reduced under a vacuum, and
the product was purified via silica gel column chromatography using
methylene chloride as the eluent to give 2-OH in an 85% yield (71
mg). Characterization matched those previously reported.21
8-Bromomethyl-1,3,5,7-tetramethyl pyrromethene methylbo-
rate (2-Br). To a solution of 2-OH (100 mg, 0.37 mmol, 1 equiv)
stirring in 5 mL of dry dichloromethane at 0 °C was added pyridine
(60 μL, 0.74 mmol, 2 equiv), followed by phosphorus tribromide (50
μL, 0.55 mmol, 1.5 equiv). The solution was stirred for 30 min, after
which it had turned dark red. Ice water was added, and the organic
layer was extracted with dichloromethane. The organic layer was
washed with saturated sodium carbonate, saturated ammonium
chloride, and brine. The organic layer was dried over sodium sulfate,
and the solvent was removed under a vacuum. The mixture was
purified with column chromatography on silica gel using 90:10
hexanes/dichloromethane as the eluent to give the product as a red-
orange solid in a 38% yield (46 mg): 1H NMR (400 MHz, CDCl3) δ
6.09 (s, 2H), 4.77 (s, 2H), 2.58 (s, 6H), 2.46 (s, 6H), 0.21 (s, 3H),
0.15 (s, 3H); 13C{1H} NMR (93 MHz, CDCl3) δ 153.2, 137.6, 136.7,
129.6, 122.9, 26.1, 16.7, 16.5; HRMS (ESI/QTOF) m/z [M + H]+
calcd for C16H22BN2Br 333.1132, found 333.1133.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c00044.
1H NMR of irradiated samples, additional information
on cell studies, formation of benzaldehyde, percent
release studies, and characterization data of all new
1
compounds including H NMR, 13C{1H} NMR, and
HRMS (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
8-Ethoxymethyl-1,3,5,7-tetramethyl Pyrromethene Methylbo-
rate (2-OEt). To a solution of 1 mL of ethanol in 5 mL of
acetonitrile with stirring with cesium carbonate (5 mg, 0.015 mmol, 1
equiv) was added 2-Br (5 mg, 0.015 mmol, 1 equiv). The solution
was stirred at room temperature overnight. The solvent was
evaporated, and the residue was dissolved in dichloromethane and
washed with water. The organic layer was dried over sodium sulfate,
and the solvent was removed under a vacuum. The residue was
purified by silica gel chromatography using 50:50 hexanes/dichloro-
methane as the eluent to give the product as an orange solid in 67%
Emily A. Smith − Department of Chemistry, Iowa State
University, Ames, Iowa 50010, United States; orcid.org/
0000-0001-7438-7808; Email: esmith1@iastate.edu
Arthur H. Winter − Department of Chemistry, Iowa State
University, Ames, Iowa 50010, United States; orcid.org/
0000-0003-2421-5578; Email: winter@iastate.edu
Authors
1
Julie A. Peterson − Department of Chemistry, Iowa State
University, Ames, Iowa 50010, United States
Logan J. Fischer − Department of Chemistry, Iowa State
University, Ames, Iowa 50010, United States; orcid.org/
0000-0003-1166-2379
Elizabeth J. Gehrmann − Department of Chemistry, Iowa State
University, Ames, Iowa 50010, United States
Pradeep Shrestha − Department of Chemistry, Iowa State
University, Ames, Iowa 50010, United States
Ding Yuan − Department of Chemistry, Iowa State University,
Ames, Iowa 50010, United States
yield (3 mg): H NMR (400 MHz, CDCl3) δ 6.06 (s, 2H), 4.65 (s,
2H), 3.63 (t, J = 7 Hz, 2H), 2.44 (s, 12H), 1.30 (t, J = 7 Hz, 3H), 0.17
(s, 6H); 13C{1H} NMR (93 MHz, CDCl3) δ 152.4, 137.3, 136.0,
131.6, 122.1, 66.5, 64.2, 29.7, 15.6, 15.3, 1.0; HRMS (ESI/QTOF)
m/z [M + H]+ calcd for C18H27BN2O 299.2289, found 299.2299.
2-OVan. (a) Using vanillin in excess, to a solution of 2-Br (15 mg,
0.04 mmol, 1 equiv) stirring in 5 mL of dry acetonitrile was added p-
vanillin (7 mg, 0.046 mmol, 1.1 equiv), followed by potassium
carbonate (10 mg, 0.07 mmol, 1.8 equiv). The solution was stirred
overnight, after which 2-Br had been consumed by TLC. The mixture
was diluted with water and extracted three times with dichloro-
methane. The combined organic layers were dried over sodium
sulfate, and the solvent was removed under a vacuum. The crude
mixture was purified via silica gel column chromatography using 20:80
dichloromethane/hexanes as the eluent to give the product as a pink-
orange solid in a 75% yield (12 mg). (b) Using 2-Br in excess, the
procedure above was used with 40 mg of 2-Br (0.12 mmol, 1.2 equiv),
15 mg of p-vanillin (0.1 mmol, 1 equiv), and potassium carbonate (20
mg, 0.14 mmol, 1.4 equiv). The above work up gave the product in a
54% yield (26 mg): 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 2H), 7.50
(dd, J = 8, 2 Hz, 1H), 7.45 (d, J = 2 Hz, 1H), 7.11 (d, J = 8 Hz, 1H),
6.07 (s, 2H), 5.31 (s, 2H), 3.89 (s, 3H), 2.47 (s, 6H), 2.28 (s, 6H),
0.21 (s, 6H); 13C{1H} NMR (93 MHz, CDCl3) δ 191.0, 153.5, 153.4,
150.2, 137.4, 132.9, 131.9, 131.0, 126.6, 122.8, 111.6, 109.8, 62.0,
56.2, 16.8, 15.7, 1.2; HRMS (ESI/QTOF) m/z [M + H]+ calcd for
C24H29BN2O3 404.238, found 404.2375.
Chamari S. Wijesooriya − Department of Chemistry, Iowa
State University, Ames, Iowa 50010, United States
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c00044
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.H.W. thanks the National Science Foundation (CHE-
1464956) for support. E.A.S. thanks the National Science
Foundation (CHE-1709099).
E
https://dx.doi.org/10.1021/acs.joc.0c00044
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
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