Direct Synthesis of Secondary Benzylic Alcohols Enabled by Photoredox/Ni Dual-Catalyzed Cross-Coupling

Article abstract of DOI:10.1021/acs.joc.7b02589

An operationally simple, mild, redox-neutral method for the cross-coupling of α-hydroxyalkyltrifluoroborates is reported. Utilizing an Ir photocatalyst, α-hydroxyalkyl radicals are generated from the single-electron oxidation of the trifluoroborates, and these radicals are subsequently engaged in a nickel-catalyzed C-C bond-forming reaction with aryl halides. The process is highly selective, functional group tolerant, and step economical, which allows the direct synthesis of secondary benzylic alcohol motifs.

Full text of DOI:10.1021/acs.joc.7b02589

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pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX-XXX
Direct Synthesis of Secondary Benzylic Alcohols Enabled by
Photoredox/Ni Dual-Catalyzed Cross-Coupling
Rauful Alam and Gary A. Molander*
Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street, Philadelphia,
Pennsylvania 19104-6323, United States
S
* Supporting Information
ABSTRACT: An operationally simple, mild, redox-neutral
method for the cross-coupling of α-hydroxyalkyltrifluoroborates
is reported. Utilizing an Ir photocatalyst, α-hydroxyalkyl radicals
are generated from the single-electron oxidation of the
trifluoroborates, and these radicals are subsequently engaged in a
nickel-catalyzed C−C bond-forming reaction with aryl halides.
The process is highly selective, functional group tolerant, and step
economical, which allows the direct synthesis of secondary benzylic alcohol motifs.
he importance of the secondary benzylic alcohol motif is
clearly evident from its presence in pharmaceutically and
biologically active compounds, and its application as an
intermediate in numerous organic syntheses.1 Syntheses of
this class of compounds are primarily dependent on the
nucleophilic addition of organometallic reagents to carbonyl
compounds or the reduction of suitable ketones (Figure 1).1b
T
Figure 1. Disconnection approaches for the synthesis of secondary
benzylic alcohols.
Despite considerable advances in the addition of organometallic
reagents to aldehydes, most of these methods suffer from
limitations such as sensitivity to air and moisture, toxicity of the
organometallic reagents, poor functional group compatibility,
and/or the use of harsh reaction conditions. Moreover, the
reduction of a ketone can be associated with challenging
chemoselectivity issues when the target compound is furnished
with multiple electrophilic functional groups.1a
Transition-metal-catalyzed cross-coupling of an α-hydrox-
yalkylmetallic reagent with an aryl halide would represent an
attractive alternative strategy for the direct synthesis of
protected secondary benzylic alcohol derivatives. Approaches
to this transformation have been realized through the efforts of
Falck2 and Molander,3 who have reported the cross-coupling of
protecting-group-dependent α-alkoxyalkylstannane and -boron
nucleophiles, respectively (Figure 2A). Although these
protocols are useful to synthesize secondary benzylic alkoxy
compounds, protection followed by subsequent deprotection steps
are involved for the isolation of the corresponding alcohols. In
fact, very few methods permit direct synthesis of unprotected
secondary benzylic alcohols without the intermediacy of an
Figure 2. (A) Previously reported methods for the cross-coupling of
α-alkoxyalkylmetallic reagents via Pd- and Ir/Ni-catalysis. (B)
Presented protocol: protecting-group-free, direct cross-coupling of α-
hydroxyalkylmetallic reagents via photoredox/Ni-dual catalysis.
unprotected derivative.4 To the best of our knowledge there is
no general report in the literature regarding the direct cross-
coupling of unprotected α-hydroxyalkylmetallic nucleophiles
with aryl halides.
Recently, our group and others have developed powerful
methods for engaging Csp3-centered radicals in a dual-catalytic,
photoredox/Ni cross-coupling system.5 The identification of
benchtop stable precursors from which radicals can be
photocatalytically generated via single electron transfer (SET)
oxidation or reduction is an underlying hurdle that must be
overcome in the development of this type of catalysis. In our
Received: October 11, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b02589
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Note
investigations, alkyltrifluoroborates have been employed based
on favorable SET potentials under photoredox conditions.5f,6
However, it remains of importance to introduce new classes
of radical precursor reagents to demonstrate advantages over
standard two-electron cross-coupling protocols. In this
connection, we envisioned coupling α-hydroxyalkyltrifluoro-
borates and aryl halides, which would offer an umpolung
disconnection approach for the direct synthesis of secondary
benzylic alcohols (Figure 1).
potassium trifluoroborate 3a were chosen as model coupling
partners in the presence of {Ir[dF(CF3)ppy]2(bpy)}PF6
1
(E*1/2= 1.32 V vs SCE)10 as a photocatalyst. An extensive
screening of various reaction parameters (e.g., solvent, Ni
catalyst, ligand, and base) was carried out to determine suitable
conditions for the desired cross-coupling as summarized in
Table 1. A variety of photocatalysts were screened that
a
Table 1. Optimization of the Reaction Conditions
This transformation is highly desirable because an α-
hydroxyalkyl group can be directly installed through the
construction of a new Csp2−Csp3 bond. Recently, it has been
reported that the α-hydroxyalkyl radical can be generated from
alcohols, with subsequent trapping of the generated radical with
a Michael acceptor.7 An alternative approach to generate the
hydroxy radical would be the reduction of carbonyl compounds
by a photocatalytic proton coupled electron transfer process.8
However, the direct cross-coupling of α-hydroxyalkyl radicals
with aryl halides remains unexplored at this point in time.
Therefore, we set out to use α-hydroxyalkyltrifluoroborates as
radical precursors, generating α-hydroxyalkyl radicals under
suitable photoredox/Ni dual catalytic conditions (Figure 2B).
We initiated our study using 3a as a representative radical
precursor, which was easily prepared from a commercially
available aldehyde. At the outset, the ease of single electron
oxidation of the reagent was evaluated. Gratifyingly, cyclic
voltammetric analysis of the alkyltrifluoroborate 3a (Eox
=
+1.22 V vs SCE) confirmed the viability of this oxidation. A
mechanistic scenario was envisioned (Scheme 1) based on our
Scheme 1. Plausible Mechanism
a
General reaction conditions: Ar−Br (1.0 equiv, 0.1 mmol),
trifluoroborate (1.3 equiv, 0.13 mmol), Ir catalyst (2 mol %), 1,4-
dioxane (0.2 M), rt, 24 h. Yield was determined by H NMR using
1,3,5-trimethoxybenzene as an internal standard.
b
1
possessed sufficiently high excited-state redox potentials to
oxidize the trifluoroborate 3a. Although 4CzIPN (E*1/2= 1.35
V vs SCE)11 proved to be a viable catalyst, the Ir catalyst 1
provided superior yields (entries 1−2). MesAcr (mesitylacridi-
nium) has a sufficiently high oxidation potential (E*1/2= 2.2 V
vs SCE),12 but it did not give any desired product 6a (entry 4),
previous studies,5a,9 in which the excited state of a suitable
photocatalyst possessed a redox potential sufficiently high to
induce a single-electron oxidation of the trifluoroborate 3,
affording the α-hydroxyalkyl radical 4 upon fragmentation.
Subsequent capture of the stabilized alkyl radical by Ni(0)
species 2a would then yield Ni(I) species 2b, which could
oxidatively add to aryl halides to generate the high-valent
Ni(III) species 2c. Diorgano Ni(III) intermediate 2c was
expected to undergo reductive elimination to give the desired
cross-coupled product 6 and Ni(I) species 2d. From here,
reduction of 2d by the reduced of photocatalyst (1b) would
regenerate both the Ni(0) species 2a and Ir catalyst 1, closing
the dual catalytic cycle.
likely because of its inability to reduce the putative Ni(I) (Ered
>
−1.1 V)5a intermediate (Scheme 1, 2d). Other organo-
photocatalysts such as Eosin Y were also ineffective under
these reaction conditions (entry 3), most likely because of their
low redox potential (E*1/2= 0.79 V vs SCE).13 The reaction was
also unsuccessful in the absence of an Ir photocatalyst or a Ni
catalyst (entries 5−6). A control experiment was run in the
absence of light (entry 7) to demonstrate that the catalyst is
active only in its photoexcited state. Of those additives
screened, K2HPO4 was the best for maximizing the cross-
coupling reaction. The yield was diminished in the absence of
base (entry 8) indicating that BF3 may interfere with the
To validate the cross-coupling of α-hydroxyalkyltrifluoro-
borates with aryl halides, 4-bromobenzonitrile (5a) and
B
DOI: 10.1021/acs.joc.7b02589
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Note
reaction, requiring sequestration by a base. Although different
aprotic solvents were examined for the cross-coupling reaction,
1,4-dioxane was found to be superior to DME, MeCN, and
DMF (entries 8−10). Moreover, application of the dtbbpy
(4,4′-di-tert-butyl-2,2′-dipyridyl) ligand was the most efficient
compared to other bipyridyl ligands. As anticipated, control
experiments showed that all parameters were essential for the
reaction to proceed.
With suitable reaction conditions in hand, the scope of the
cross-coupling reaction was explored in the context of various
aryl bromides using α-hydroxyalkyltrifluoroborate 3a. As
illustrated in Table 2, different electron-poor aryl bromides
leading to 6e. Aryl bromides containing multiple different
substituents can also be used for the cross-coupling, as
demonstrated by the reaction of substrates affording 6g−h.
A bromo sulfonamide can also be engaged in the coupling to
give 6i. Not only electron-withdrawing but also electron-
donating aryl bromides can be employed for the cross-coupling.
For example, 4-bromoanisole can be cross-coupled with an
extended reaction time (36 h) affording the compound 6l in
moderate yield. Furthermore, the pinacol ester of 4-
bromophenylboronic acid reacted smoothly to afford arylbor-
onate product 6m, thereby permitting potentially powerful
sequential cross-coupling sequences with either nucleophilic or
electrophilic partners.16 Unfortunately, attempts to use 4-
bromophenol and 4-bromobenzoic acid were not met with
success (6n−o). At this time, we surmise that the phenol and
carboxylic acid functional groups undergo rapid deprotonation
in the presence of base to form the oxyanions, which may
strongly coordinate the Ni catalyst and thus diminish the
catalyst activity. Moreover, the desired coupling product 6a was
not observed when the aryl bromide 5a was replaced with 4-
chlorobenzonitrile, which indicates the incompatibility of aryl
chlorides as a coupling partner under these reaction conditions.
A similar trend was observed in previously reported photo-
redox/Ni-dual catalyzed cross-coupling reactions.5f,6
Table 2. Evaluation of Aryl Bromides Under Photoredox
a
Conditions Using 3a
Once the versatility of the protocol was demonstrated against
different aryl bromides, we turned our attention to both the
alkyltrifluoroborate radical precursors and the aryl bromide
partners simultaneously to show the utility of this cross-
coupling in cases where both the nucleophilic and electrophilic
partner present structural and/or electronic challenges (Table
3). Notably, the alkyltrifluoroborates are easily synthesized
from readily available aldehydes following the previously
described procedures.3a,17
The developed reaction conditions were quite general, and
various substitution patterns were well accommodated. A
Table 3. Photoredox Cross-Coupling Using Various
a
Hydroxyalkyltrifluoroborates
a
General reaction conditions: Ar−Br (1.0 equiv, 0.5 mmol),
trifluoroborate (1.3 equiv, 0.65 mmol), Ir catalyst (2 mol %), 1,4-
dioxane (0.2 M), rt, 24−36 h. Yield in parentheses indicates yield on
a 5.5 mmol scale. Reaction time 36 h.
b
c
provided moderate to high yields of the desired products (6a−
k). Of note, a number of electrophilic functional groups that are
intolerant to Grignard reactions14 or even reducing con-
ditions15 could be employed to afford nitrile (6a), aldehyde
(6b),8a ketone (6c), ester (6f), and lactone (6g)-containing
secondary benzylic alcohols. Furthermore, the reaction is also
scalable; on scaling the reaction 11-fold to 5.50 mmol, the
coupling of 4-bromobenzonitrile (5a) and 3a afforded an
uncompromised yield under the same reaction time. The
trifluoromethyl ketone group could also be incorporated within
reaction partners as demonstrated by the transformation
a
General reaction conditions: Ar−Br (1.0 equiv, 0.5 mmol),
trifluoroborate (1.3 equiv, 0.65 mmol), Ir catalyst (2 mol %), 1,4-
dioxane (0.2 M), rt, 24 h.
C
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diverse range of alkylated benzylic alcohols were isolated in
modest to high yields (6p−x). α-Hydroxyalkyltrifluoroborates
containing stereocenters were cross-coupled with moderate
diastereoselectivity (6r). Notably, the starting boryl nucleophile
in this case was isolated in a 3:1 diastereomeric ratio. Isopropyl-
and 3-pentyl-substituted trifluoroborates were also well suited
to the reaction (6s−w). Compound 6v demonstrates electronic
tolerance of meta-substitution in the aryl ring, although the
reaction was not suitable for ortho-substituted aryl bromides.
For example, the reaction between 2-bromobenzonitrile and 3e
afforded trace product. Electron-deficient N-heteroaromatic
halides such as 2-trifluoromethyl-5-bromopyridine could also
be used under the reaction conditions, although affording a
moderate yield of the desired product (6w). Finally, tert-butyl-
substituted trifluoroborate 3f also reacted smoothly to afford a
sterically crowded benzylic alcohol 6x in good yield.
Unfortunately, electron-neutral N-heteroaryl bromides were
ineffective under the coupling conditions. We speculate that the
nitrogen in the aromatic ring serves to ligate the metal center
competitively, inhibiting the active catalyst. Similar reactivity
was observed in a previously reported reaction describing cross-
coupling between 3°-alkyltrifluoroborates and aryl halides
under photoredox/Ni dual catalysis.5d
our knowledge, this reaction is the first example of direct cross-
coupling of α-hydroxyalkyl nucleophiles with aryl halides under
transition metal catalysis. This method avoids protection−
deprotection strategies and therefore offers a step-economical,
direct route to a variety of secondary benzylic alcohols. The
mild reaction conditions tolerate a number of electrophilically
sensitive functional groups such as aldehydes, ketones, esters,
lactones, and boronates. Furthermore, the excellent functional
group compatibility and mild reaction conditions favor
employment in late-stage functionalization of complex
structural motifs. The reported protocol represents a significant
advance in the cross-coupling of α-hydroxyalkyl nucleophiles
and enables the rapid synthesis of an important class of
compounds.
EXPERIMENTAL SECTION
■
General Consideration. NMR spectra (1H, 13C, 19F, 11B) were
performed at 298 K. 1H NMR and 13C NMR spectra were recorded in
CDCl3 (internal standard: 7.26 ppm, H; 77.16 ppm, 13C), DMSO-d6
1
1
(internal standard: 2.50 ppm, H), and MeCN-d6 (internal standard:
1.32 ppm, 13C) using 500 MHz spectrometers. Accurate mass
measurement analyses were conducted on either a time-of-flight
GCMS with electron ionization (EI) or a time-of-flight LCMS with
electrospray ionization (ESI). Samples were taken up in a suitable
solvent for analysis. The signals were mass measured against an
internal lock mass reference of perfluorotributylamine (PFTBA) for
EI-GCMS and leucine enkephalin for ESI-LCMS. The software
calibrates the instruments and reports measurements by use of neutral
atomic masses. The mass of the electron is not included. IR spectra
were recorded using an FTIR-ATR of the neat oil or solid products.
During our study, we also observed the formation of
aldehyde as a side product. In particular, the coupling of
trifluoroborate 3a generated 15−20% of aldehyde. Notably,
aldehyde formation was only observed in the presence of a
nickel catalyst. To understand the formation of aldehyde, we
hypothesized two plausible pathways (I−II) depicted in Figure
3. According to pathway I, a hydroxyalkyl-radical-captured Ni
1
Reactions were monitored by H NMR, and/or by TLC on silica gel
plates (60 Å porosity, 250 μm thickness). TLC analysis was performed
using hexanes/EtOAc as the eluent and visualized using UV light.
Silica plugs utilized flash silica gel (60 Å porosity, 32−63 μm). Flash
chromatography was accomplished using an automated system
(visualizing at 254 nm, monitoring at 280 nm) with silica cartridges
(60 Å porosity, 20−40 μm). Solvents were purified by use of drying
cartridges through a solvent delivery system. Melting points (°C) are
uncorrected. Deuterated NMR solvents were either used as purchased
or stored over 4 Å molecular sieves. NiBr2·dme, 4,4′-di-tert-butyl-2,2′-
dipyridine (dtbbpy), K2HPO4, and 1,4-dioxane were used as
purchased. Aryl bromides were purchased from commercial suppliers
and used without further purification. Aldehydes were distilled and
freshly used. The Cu catalyst (ICyCuCl) and NaOtBu were stored in a
N2 filled glovebox. Before use, dioxane was degassed thoroughly with
N2 and stored under N2 and molecular sieves. The Ir photocatalyst and
4CzIPN were synthesized according to the described procedure.5a,11,20
Synthesis of α-Hydroxyalkyltrifluoroborate Compounds
(3a−f). Potassium α-hydroxyalkyltrifluoroborate compounds (3a−f)
were synthesized according to previously described methods.3,21
Compounds were benchtop stable and stored under ambient
conditions.
General Procedure for the Cross-Coupling of α-Hydroxy-
alkyltrifluoroborate and Ar−Br (Tables 2−3). To a two dram (8
mL) borosilicate glass vial equipped with a Teflon-coated magnetic stir
bar was added NiBr2·dme (8.0 mg, 0.025 mmol), the corresponding
Ar−Br (0.5 mmol), dtbbpy (7.0 mg, 0.025 mmol), Ir[dFCF3ppy]2-
(bpy)PF6 1 (10.0 mg, 0.01 mmol), potassium hydroxyalkyltrifluoro-
borate (0.65 mmol, 1.3 equiv), and K2HPO4 (175.0 mg, 1.0 mmol, 2
equiv). The vial was sealed with a cap containing a TFE-lined silicone
septa and placed under a N2 atmosphere through evacuating and
purging with nitrogen three times via an inlet needle. The vial was then
charged with anhydrous and degassed 1,4-dioxane (2.5 mL) via a
syringe. The cap was sealed with Parafilm, and the solution was
irradiated with blue LEDs. The temperature of the reaction was
maintained at approximately 25−27 °C via a fan. The solution was
stirred vigorously while being irradiated. After completion, the crude
reaction mixture was filtered through a plug of Celite and rinsed with
Figure 3. Plausible mechanism for the formation of aldehyde as side
product.
species 2e could undergo β-hydride elimination to afford an
enol (7a), which subsequently forms aldehyde 7b. On the other
hand, β-hydride elimination from the hydroxyl group would
also lead to the same aldehyde 7b (pathway II), which is very
unlikely.18 Pathway II is independent of substrates bearing β-
hydrogens in the hydroxyalkyltrifluoroborates. We reasoned
that trifluoroborate 3f, which lacks β-hydrogens, might provide
insight into the process by which aldehyde is generated. Indeed,
aldehyde formation was not observed when 3f was employed in
the cross-coupling reaction with 4-bromoacetophenone 5c,
indicating that aldehyde formation most likely follows pathway
I, where the β-hydride elimination leads to the formation of
enol, with subsequent tautomerization providing the alde-
hyde.19
CONCLUSIONS
■
In summary, an operationally simple, scalable, and efficient
method for the direct synthesis of secondary benzyl alcohols
under photoredox/Ni dual catalysis is described. To the best of
D
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EtOAc. The resulting solution was concentrated, and the residue was
purified by silica gel column chromatography using EtOAc/hexane
mixtures as the eluent to obtain products in pure form.
as a colorless oil using a gradient of 0% to 30% EtOAc/hexane for
silica gel chromatography. 1H NMR (500 MHz, CDCl3): δ 8.06 (d, J =
8.0 Hz, 2H), 7.53 (d, J = 8.3 Hz, 2H), 7.31−7.28 (m, 2H), 7.22−7.19
(m, 3H), 4.83−4.79 (m, 1H), 2.81−2.70 (m, 2H), 2.15−2.00 (m, 2H),
1.97 (d, J = 4.0 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 180.3 (q, J
= 35.1 Hz), 152.9, 141.3, 130.6, 129.2, 128.7, 128.5, 126.6, 126.3,
116.8 (q, J = 290.9 Hz), 73.2, 40.7, 31.9; 19F NMR (470 MHz,
CDCl3): δ −71.39; FT-IR (cm−1, neat, ATR) 3341, 1716, 1607, 1196,
942; HRMS (EI+) m/z: calcd for C17H15F3O2 [M], 308.1024; found,
308.1025.
Gram Scale Reaction for the Synthesis of 6a. To an ∼125 mL
Schlenk tube equipped with a Teflon-coated magnetic stir bar was
added NiBr2·dme (0.24 mmol, 77.0 mg), Ir[dFCF3ppy]2(bpy)PF6 1
(0.11 mmol, 109.0 mg), dtbbpy (0.24 mmol, 66.0 mg), 4-
bromobenzonitrile 5a (5.5 mmol, 1.00 g), hydroxyalkyltrifluoroborate
3a (7.14 mmol, 1.73 g, 1.3 equiv), and K2HPO4 (11 mmol, 1.9 g, 2
equiv). The vial was sealed and subsequently purged and evacuated
three times with N2. Anhydrous and degassed 1,4-dioxane (28 mL)
was then added by syringe under N2. The resulting mixture was stirred
vigorously for 5−7 min. The Schlenk tube was then placed in a blue
LED chamber (Supporting Information, Figure A3), and the mixture
was stirred for 24 h. A fan was blown across the reaction setup to
maintain an ambient temperature. After completion, the crude reaction
mixture was filtered through a plug of Celite and rinsed with EtOAc
(8−10 mL). The resulting solution was concentrated, and the residue
was purified by automated column chromatography on silica gel with
EtOAc/hexane mixtures as the eluent, to obtain 73% (950 mg, 4.0
mmol) product in pure form (Supporting Information, Figure A5).
4-(1-Hydroxy-3-phenylpropyl)benzonitrile (6a). The compound
was prepared according to the general procedure. Product 6a was
isolated in 72% yield (85.0 mg, 0.36 mmol) as a light-yellow oil using a
gradient of 0%% to 20% EtOAc/hexane for silica gel chromatography.
1H NMR (500 MHz, CDCl3): δ 7.64 (d, J = 8.2 Hz, 2H), 7.46 (d, J =
8.3 Hz, 2H), 7.30−7.27 (m, 2H), 7.22−7.17 (m, 3H), 4.78−4.74 (m,
1H), 2.79−2.68 (m, 2H), 2.12−1.98 (m, 2H), 1.94 (d, J = 4.0 Hz,
1H); 13C NMR (125 MHz, CDCl3): δ 150.1, 141.3, 132.5, 128.7,
128.5, 126.7, 126.3, 118.9, 111.4, 73.1, 40.7, 31.9; FT-IR (cm−1, neat,
ATR) 3431, 2228, 1608, 1496; HRMS (pos. ESI) m/z: calcd for
C16H16NO [M + H]+, 238.1226; found, 238.1237.
4-(1-Hydroxy-3-phenylpropyl)benzaldehyde (6b). The compound
was prepared according to the general procedure. Product 6b was
isolated in 65% yield (78.0 mg, 0.32 mmol) as a light-yellow oil using a
gradient of 0% to 30% EtOAc/hexane for silica gel chromatography.
1H NMR (500 MHz, CDCl3): δ 10.00 (s, 1H), 7.87 (d, J = 8.20 Hz,
2H), 7.52 (d, J = 8.11 Hz, 2H), 7.30−7.27 (m, 2H), 7.21−7.18 (m,
3H), 4.80−4.78 (m, 1H), 2.80−2.68 (m, 2H), 2.16−2.00 (m, 2H),
1.97 (bs, 1H); 13C NMR (125 MHz, CDCl3): δ 191.1, 150.7, 140.4,
134.9, 129.1, 127.6, 127.5, 125.5, 125.2, 72.4, 39.7, 31.0; FT-IR (cm−1,
neat, ATR) 3400, 1694, 1606, 1577, 1209; HRMS (EI+) m/z: calcd for
C16H16O2 [M], 240.1150; found, 240.1153.
1-(4-(1-Hydroxy-3-phenylpropyl)phenyl)ethan-1-one (6c). The
compound was prepared according to the general procedure. Product
6c was isolated in 71% yield (91.0 mg, 0.035 mmol) as a pale-yellow
oil using a gradient of 0% to 30% EtOAc/hexane for silica gel
chromatography. 1H NMR (500 MHz, CDCl3): δ 7.94 (d, J = 8.21 Hz,
2H), 7.45 (d, J = 8.61 Hz, 2H), 7.30−7.27 (m, 2H), 7.21−7.18 (m,
3H), 4.78−4.75 (m, 1H), 2.79−2.65 (m, 2H), 2.60 (s, 3H), 2.16−2.00
(m, 2H), 1.93 (d, J = 3.20 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ
198.0, 150.1, 141.5, 136.6, 128.7, 128.6, 128.5, 126.1(4), 126.1(2),
73.4, 40.7, 32.0, 26.8; FT-IR (cm−1, neat, ATR) 3450, 1673, 1607,
1496, 1267; HRMS (pos. ESI) m/z: calcd for C17H19O2 [M + H]+,
255.1380; found, 255.1380.
3-Chloro-1-(4-(1-hydroxy-3-phenylpropyl)phenyl)propan-1-one
(6d). The compound was prepared according to the general procedure.
Product 6d was isolated in 69% yield (106.0 mg, 0.35 mmol) as a pale-
yellow oil using a gradient of 0% to 30% EtOAc/hexane for silica gel
chromatography. 1H NMR (500 MHz, CDCl3): δ 7.94 (d, J = 8.26 Hz,
2H), 7.46 (d, J = 8.36 Hz, 2H), 7.30−7.27 (m, 2H), 7.21−7.18 (m,
3H), 4.79−4.76 (m, 1H), 3.92 (t, J = 6.81 Hz, 2H), 3.45 (t, J = 6.81
Hz, 2H), 2.79−2.67 (m, 2H), 2.15−2.00 (m, 2H), 1.94 (d, J = 4.0 Hz,
1H); 13C NMR (125 MHz, CDCl3): δ 196.5, 150.6, 141.5, 135.7,
128.6, 128.5, 128.5, 126.3, 126.2, 73.3, 41.4, 40.6, 38.8, 32.0; FT-IR
(cm−1, neat, ATR) 3450, 1679, 1606, 699; HRMS (pos. ESI) m/z:
calcd for C18H20ClO2 [M + H]+, 303.1146; found, 303.1162.
2,2,2-Trifluoro-1-(4-(1-hydroxy-3-phenylpropyl)phenyl)ethan-1-
one (6e). The compound was prepared according to the general
procedure. Product 6e was isolated in 47% yield (73.0 mg, 0.24 mmol)
Methyl 4-(1-Hydroxy-3-phenylpropyl)benzoate (6f). The com-
pound was prepared according to the general procedure. Product 6f
was isolated in 74% yield (100.0 mg, 0.37 mmol) as a light-yellow oil
using a gradient of 0% to 30% EtOAc/hexane for silica gel
1
chromatography. H NMR (500 MHz, CDCl3): δ 8.01 (d, J = 8.41
Hz, 2H), 7.41 (d, J = 8.21 Hz, 2H), 7.30−7.27 (m, 2H), 7.20−7.17
(m, 3H), 4.77−4.74 (m, 1H), 3.91 (s, 3H), 2.78−2.66 (m, 2H), 2.15−
2.00 (m, 2H), 1.98 (bs, 1H); 13C NMR (125 MHz, CDCl3): δ 167.1,
149.9, 141.6, 129.9, 129.4, 128.6, 128.5, 126.1, 125.9, 73.4, 52.2, 40.6,
32.0; FT-IR (cm−1, neat, ATR) 3450, 1720, 1703, 1611, 1276; HRMS
(EI+) m/z: calcd for C17H18O3 [M], 270.1256; found, 270.1266
5-(1-Hydroxy-3-phenylpropyl)isobenzofuran-1(3H)-one (6g). The
compound was prepared according to the general procedure. Product
6g was isolated in 68% yield (91.0 mg, 0.34 mmol) as a light-yellow oil
using a gradient of 0% to 30% EtOAc/hexane for silica gel
1
chromatography. H NMR (500 MHz, CDCl3): δ 7.88 (d, J = 7.86
Hz, 1H), 7.51 (s, 1H), 7.49 (d, J = 7.91 Hz, 1H), 7.31−7.28 (m, 2H),
7.22−7.19 (m, 3H), 5.30 (s, 2H), 4.86−4.83 (m, 1H), 2.82−2.70 (m,
2H), 2.16−2.02 (m, 3H); 13C NMR (125 MHz, CDCl3): δ 171.1,
152.0, 147.2, 141.3, 128.7, 128.5, 127.1, 126.2, 125.9, 125.0, 119.4,
73.4, 69.8, 41.0, 32.0; FT-IR (cm−1, neat, ATR) 3444, 1745, 1619,
1048; HRMS (EI+) m/z: calcd for C17H16O3 [M], 268.1099; found,
268.1097.
Methyl 4-(1-Hydroxy-3-phenylpropyl)-2-methoxybenzoate (6h).
The compound was prepared according to the general procedure.
Product 6h was isolated in 64% yield (96.0 mg, 0.32 mmol) as a light-
yellow oil using a gradient of 0% to 40% EtOAc/hexane for silica gel
chromatography. 1H NMR (500 MHz, CDCl3): δ 7.77 (d, J = 7.96 Hz,
1H), 7.30−7.27 (m, 2H), 7.21−7.18 (m, 3H), 7.00 (s, 1H), 6.93−6.91
(m, 1H), 4.73−4.70 (m, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 2.79−2.67
(m, 2H), 2.15−2.00 (m, 2H), 1.98 (d, J = 4.0 Hz, 1H); 13C NMR (125
MHz, CDCl3): δ 166.6, 159.6, 151.0, 141.6, 132.0, 128.6, 128.5(6),
126.1, 119.1, 117.7, 109.5, 73.5, 56.2, 52.1, 40.6, 32.0; FT-IR (cm−1,
neat, ATR) 3450, 1708, 1610, 1496, 1245, 1085; HRMS (EI+) m/z:
calcd for C18H20O4 [M], 300.1362; found, 300.1359.
4-(1-Hydroxy-3-phenylpropyl)benzenesulfonamide (6i). The
compound was prepared according to the general procedure. Product
6i was isolated in 48% yield (70.0 mg, 0.24 mmol) as a light yellow
solid (mp: 98−100 °C) using a gradient of 0% to 50% EtOAc/hexane
1
for silica gel chromatography. H NMR (500 MHz, DMSO): δ 7.78
(d, J = 8.30 Hz, 2H), 7.51 (d, J = 8.31 Hz, 2H), 7.28−7.25 (m, 4H),
7.19−7.15 (m, 3H), 5.44 (d, J = 4.30 Hz, 1H), 4.62 (bs, 1H), 2.69−
2.57 (m, 2H), 1.91−1.87 (m, 2H); 13C NMR (125 MHz, CD3CN): δ
151.9, 143.6, 143.3, 129.8(4), 129.8(1), 127.9, 127.4, 127.2, 73.5, 42.2,
33.0; FT-IR (cm−1, neat, ATR) 3264, 3086, 1495, 1326, 1157; HRMS
(EI+) m/z: calcd for C15H15NO2S [M − H2O], 273.0819; found,
273.0823.
1-(4-(Methylsulfonyl)phenyl)-3-phenylpropan-1-ol (6j). The com-
pound was prepared according to the general procedure. Product 6j
was isolated in 72% yield (104.0 mg, 0.36 mmol) as a light-yellow oil
using a gradient of 0% to 50% EtOAc/hexane for silica gel
1
chromatography. H NMR (500 MHz, CDCl3): δ 7.90 (d, J = 8.40
Hz, 2H), 7.55 (d, J = 8.30 Hz, 2H), 7.30−7.27 (m, 2H), 7.21−7.18
(m, 3H), 4.81−4.79 (m, 1H), 3.04 (s, 3H), 2.80−2.69 (m, 2H), 2.14−
2.00 (m, 3H); 13C NMR (125 MHz, CDCl3): δ 151.3, 141.3, 139.5,
128.6, 128.5, 127.6, 126.9, 126.2, 73.0, 44.6, 40.7, 31.9; FT-IR (cm−1,
neat, ATR) 3492, 1600, 1300, 1143, 1088; HRMS (EI+) m/z: calcd for
C16H18O3S [M], 290.0977; found, 290.0967.
3-Phenyl-1-(4-(trifluoromethyl)phenyl)propan-1-ol (6k). The
compound was prepared according to the general procedure. Product
E
DOI: 10.1021/acs.joc.7b02589
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The Journal of Organic Chemistry
Note
6k was isolated in 71% yield (99.0 mg, 0.35 mmol) as a colorless oil
48.2, 18.0; FT-IR (cm−1, neat, ATR) 3468, 2228, 1608; HRMS (EI+)
m/z: calcd for C16H15NO [M], 237.1154; found, 237.1156.
using a gradient of 0% to 20% EtOAc/hexane for silica gel
1
chromatography. H NMR (500 MHz, CDCl3): δ 7.61 (d, J = 8.20
4-(1-Hydroxy-2-methylpropyl)benzonitrile (6s). The compound
was prepared according to the general procedure. Product 6s was
isolated in 75% yield (66.0 mg, 0.37 mmol) as a colorless oil using a
gradient of 0% to 20% EtOAc/hexane for silica gel chromatography.
1H NMR (500 MHz, CDCl3): δ 7.63 (d, J = 8.16 Hz, 2H), 7.43 (d, J =
8.26 Hz, 2H), 4.49 (dd, J = 5.91, 3.50 Hz, 1H), 2.05 (d, J = 3.40 Hz,
1H), 1.98−1.91 (m, 1H), 0.94 (d, J = 6.71 Hz, 3H), 0.85 (d, J = 6.81
Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 149.1, 132.1, 127.3, 119.0,
111.2, 74.0, 35.4, 19.0, 17.6; FT-IR (cm−1, neat, ATR) 3454, 2963,
2229, 1016; HRMS (EI+) m/z: calcd for C11H13NO [M], 175.0997;
found, 175.0996.
Hz, 2H), 7.46 (d, J = 8.10 Hz, 2H), 7.30−7.27 (m, 2H), 7.21−7.18
(m, 3H), 4.78−4.75 (m, 1H), 2.79−2.67 (m, 2H), 2.15−2.00 (m, 2H),
1.91 (d, J = 4.0 Hz, 1H); 13C NMR (125 MHz, CDCl3): δ 148.7,
141.5, 129.9 (q, J = 32.4 Hz), 128.6, 128.5, 126.3, 126.2, 125.6, 124.3
(q, J = 271.9), 73.3, 40.7, 32.0; 19F NMR (470 MHz, CDCl3): δ
−62.46; FT-IR (cm−1, neat, ATR) 3369, 1323, 1110, 1066; HRMS
(EI+) m/z: calcd for C16H15F3O [M], 280.1075; found, 280.1093.
1-(4-Methoxyphenyl)-3-phenylpropan-1-ol (6l). The compound
was prepared according to the general procedure. Product 6l was
isolated in 54% yield (65.0 mg, 0.27 mmol) as a colorless oil using a
gradient of 0% to 30% EtOAc/hexane for silica gel chromatography.
1H NMR (500 MHz, CDCl3): δ 7.29−7.25 (m, 4H), 7.19−7.16 (m,
3H), 6.89−6.87 (d, J = 8.66 Hz, 2H), 4.65−4.61 (m, 1H), 3.80 (s,
3H), 2.75−2.69 (m, 1H), 2.66−2.61 (m, 1H), 2.17−2.09 (m, 1H),
2.03−1.96 (m, 1H), 1.81 (d, J = 3.2 Hz, 1H); 13C NMR (125 MHz,
CDCl3): δ 159.2, 142.0, 136.8, 128.6, 128.5, 127.3, 126.0, 114.0, 73.6,
55.4, 40.5, 32.3; FT-IR (cm−1, neat, ATR) 3350, 1610, 1496, 1244;
HRMS (EI+) m/z: calcd for C16H18O2 [M], 242.1307; found,
242.1295.
3-Phenyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenyl)propan-1-ol (6m). The compound was prepared according to
the general procedure. Product 6m was isolated in 52% yield (88.0 mg,
0.26 mmol) as a light-yellow oil using a gradient of 0% to 30% EtOAc/
hexane for silica gel chromatography. 1H NMR (500 MHz, CDCl3): δ
7.80 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.29−7.25 (m, 2H),
7.19−7.16 (m, 3H), 4.70 (bs, 1H), 2.76−2.63 (m, 2H), 2.16−2.08 (m,
1H), 2.06−1.99 (m, 1H), 1.85 (bs, 1H), 1.34 (s, 12H); 13C NMR (125
MHz, CDCl3): δ 147.8, 141.9, 135.2, 128.6, 128.5, 126.0, 125.4, 83.9,
73.9, 40.5, 32.1, 25.0; 11B NMR (160 MHz, CDCl3): 30.94; FT-IR
(cm−1, neat, ATR) 3450, 1612, 1398, 1358, 1187, 1142; HRMS (pos.
ESI) m/z: calcd for C21H27BO3Na [M + Na]+, 361.1945; found,
361.1964.
Methyl 4-(1-Hydroxy-2-methylpropyl)benzoate (6t). The com-
pound was prepared according to the general procedure. Product 6t
was isolated in 64% yield (56.0 mg, 0.32 mmol) as a colorless oil using
a gradient of 0% to 30% EtOAc/hexane for silica gel chromatography.
1H NMR (500 MHz, CDCl3): δ 8.00 (d, J = 8.36 Hz, 2H), 7.38 (d, J =
8.16 Hz, 2H), 4.46 (dd, J = 6.30, 3.25 Hz, 1H), 3.91 (s, 3H), 2.00−
1.93 (m, 2H), 0.97 (d, J = 6.71 Hz, 3H), 0.83 (d, J = 6.86 Hz, 3H); 13
C
NMR (125 MHz, CDCl3): δ 167.1, 148.9, 129.6, 129.4, 126.6, 79.5,
52.2, 35.5, 19.0, 17.9; FT-IR (cm−1, neat, ATR) 3348, 1722, 1706,
1436; HRMS (EI+) m/z: calcd for C12H16O3 [M], 208.1099; found,
208.1104.
4-(2-Ethyl-1-hydroxybutyl)benzonitrile (6u). The compound was
prepared according to the general procedure. Product 6u was isolated
in 61% yield (62.0 mg, 0.31 mmol) as a colorless oil using a gradient of
1
0% to 20% EtOAc/hexane for silica gel chromatography. H NMR
(500 MHz, CDCl3): δ 7.63 (d, J = 8.40 Hz, 2H), 7.45 (d, J = 8.11 Hz,
2H), 4.77−4.75 (m, 1H), 1.85 (d, J = 4.0 Hz 1H), 1.56−1.49 (m, 1H),
1.42−1.35 (m, 2H), 1.34−1.22 (m, 2H), 0.90 (t, J = 7.46 Hz, 3H),
0.85 (t, J = 7.50 Hz, 3H); 13C NMR (125 MHz, CDCl3): δ 149.7,
132.1, 127.2, 119.1, 110.9, 74.9, 48.2, 22.0, 20.5, 11.6, 11.3; FT-IR
(cm−1, neat, ATR) 3454, 2228, 1462, 1017; HRMS (EI+) m/z: calcd
for C13H17NO [M], 203.1310; found, 203.1301.
4-(1-Hydroxy-2-phenylethyl)benzonitrile (6p). The compound was
prepared according to the general procedure. Product 6p was isolated
in 54% yield (60.0 mg, 0.27 mmol) as a light-yellow oil using a
gradient of 0% to 20% EtOAc/hexane for silica gel chromatography.
1H NMR (500 MHz, CDCl3): δ 7.63 (d, J = 8.16 Hz, 2H), 7.45 (d, J =
3-(2-Ethyl-1-hydroxybutyl)benzonitrile (6v). The compound was
prepared according to the general procedure. Product 6v was isolated
in 65% yield (66.0 mg, 0.33 mmol) as a colorless oil using a gradient of
1
0% to 20% EtOAc/hexane for silica gel chromatography. H NMR
(500 MHz, CDCl3): δ 7.65 (s, 1H), 7.58−7.55 (m, 2H), 7.45 (t, J =
7.76 Hz, 1H), 7.67 (d, J = 8.10 Hz, 2H), 4.75−4.73 (m, 1H), 1.82 (d, J
= 4.0 Hz 1H), 1.54−1.49 (m, 1H), 1.43−1.37 (m, 2H), 1.35−1.20 (m,
2H), 0.91−0.85 (m, 6H); 13C NMR (125 MHz, CDCl3): δ 145.7,
131.0, 131.0, 130.2, 129.1, 119.1, 112.3, 74.7, 48.2, 22.0, 20.5, 11.6,
11.2; FT-IR (cm−1, neat, ATR) 3454, 2230, 1461, 801, 695; HRMS
(EI+) m/z: calcd for C13H15N [M − H2O], 185.1204; found, 185.1209.
2-Ethyl-1-(6-(trifluoromethyl)pyridin-3-yl)butan-1-ol (6w). The
compound was prepared according to the general procedure. Product
6w was isolated in 45% yield (55.0 mg, 0.22 mmol) as a light-yellow oil
using a gradient of 0% to 30% EtOAc/hexane with Et3N (1%) for silica
8.36 Hz, 2H), 7.33−7.30 (m, 2H), 7.28−7.25 (m, 1H), 7.16−7.15 (m,
2H), 4.98−4.95 (m, 1H), 3.04 (dd, J = 13.64, 4.73 Hz, 1H), 2.94 (dd, J
= 13.59, 8.53 Hz, 1H), 2.06 (d, J = 3.0 Hz, 1H); 13C NMR (125 MHz,
CDCl3): δ 149.1, 137.0, 132.3, 129.6, 128.8, 127.1, 126.7, 119.0, 111.3,
74.6, 46.2; FT-IR (cm−1, neat, ATR) 3433, 2228, 1608, 1495; HRMS
(EI+) m/z: calcd for C15H13NO [M], 223.0997; found, 223.1000.
Methyl 4-(1-Hydroxy-2-phenylethyl)benzoate (6q). The com-
pound was prepared according to the general procedure. Product 6q
was isolated in 58% yield (74.0 mg, 0.29 mmol) as a light-yellow oil
using a gradient of 0% to 30% EtOAc/hexane for silica gel
1
chromatography. H NMR (500 MHz, CDCl3): δ 8.00 (d, J = 8.21
1
gel chromatography. H NMR (500 MHz, CDCl3): δ 8.66 (s, 1H),
Hz, 2H), 7.40 (d, J = 8.16 Hz, 2H), 7.31−7.28 (m, 2H), 7.25−7.23
(m, 1H), 7.17−7.15 (m, 2H), 4.98−4.95 (m, 1H), 3.91 (s, 3H), 3.06−
2.94 (m, 2H), 2.11 (bs, 1H); FT-IR (cm−1, neat, ATR) 3512, 1724,
1699, 1282; 13C NMR (125 MHz, CDCl3): δ 167.1, 149.0, 137.5,
129.8, 129.6, 129.4, 128.7, 126.9, 126.0, 75.0, 52.2, 46.2; HRMS (EI+)
m/z: calcd for C16H16O3 [M], 256.1099; found, 256.1089.
7.87 (d, J = 8.10 Hz, 1H), 7.67 (d, J = 8.10 Hz, 1H), 4.85 (bs, 1H),
1.95 (bs, 1H), 1.59−1.54 (s, 1H), 1.45−1.38 (m, 2H), 1.36−1.23 (m,
2H), 0.94−0.87 (m, 6H); 13C NMR (125 MHz, CDCl3): δ 148.5,
147.1 (q, J = 34.8 Hz), 142.8, 135.5, 121.7 (q, J = 273.7 Hz), 120.2,
73.1, 48.2, 21.9, 20.5, 11.5, 11.2; 19F NMR (470 MHz, CDCl3): δ
−67.75; FT-IR (cm−1, neat, ATR) 3372, 1335, 1136, 1085; HRMS
(EI+) m/z: calcd for C12H16F3NO [M], 247.1184; found, 247.1189.
1-(4-(1-Hydroxy-2, 2-dimethylpropyl)phenyl)ethan-1-one (6x).
The compound was prepared according to the general procedure.
Product 6x was isolated in 60% yield (62.0 mg, 0.3 mmol) as a
colorless oil using a gradient of 0% to 30% EtOAc/hexane for silica gel
chromatography. 1H NMR (500 MHz, CDCl3): δ 7.91 (d, J = 8.31 Hz,
2H), 7.41 (d, J = 8.26 Hz, 2H), 4.46 (d, J = 3.10 Hz, 1H), 2.60 (s, 3H),
1.92 (d, J = 3.20 Hz, 1H), 0.93 (s, 9H); 13C NMR (125 MHz, CDCl3):
δ 198.1, 147.7, 136.4, 128.0, 127.8, 82.1, 35.9, 26.7, 26.0; FT-IR (cm−1,
neat, ATR) 3473, 2954, 1675, 1361, 1270; HRMS (EI+) m/z: calcd for
C12H15O2 [M − CH3]+, 191.1067; found, 191.1053
4-(1-Hydroxy-2-phenylpropyl)benzonitrile (6r). The compound
was prepared according to the above general procedure. The crude
product was purified by silica gel chromatography eluting with a
gradient of 0% to 20% EtOAc/hexane, and 6r was isolated in 80%
yield (95.0 mg, 0.4 mmol) as a light-yellow oil with a dr = 70:30 as
1
1
determined by H NMR of the crude mixture. H NMR (500 MHz,
CDCl3): (major isomer) δ 7.54 (d, J = 8.36 Hz, 2H), 7.37−7.34 (m,
1H), 7.32−7.26 (m, 4H), 7.13−7.11 (m, 2H), 4.85−4.83 (m, 1H),
3.10−3.05 (m, 1H), 2.02 (d, J = 3.4 Hz, 1H), 1.29 (d, J = 7.1 Hz, 3H);
13C NMR (125 MHz, CDCl3): (major isomer) δ 148.3, 142.7, 131.9,
128.9, 128.1, 127.8, 127.1, 119.0, 111.1, 78.2, 47.3, 14.8; (minor
isomer) δ 147.9, 142.1, 132.1, 128.6, 128.2, 127.4, 119.0, 111.6, 79.0,
F
DOI: 10.1021/acs.joc.7b02589
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The Journal of Organic Chemistry
Note
(14) Keh, C. C. K.; Wei, C.; Li, C.-J. J. Am. Chem. Soc. 2003, 125,
4062−4063.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b02589.
■
S
(15) Panahi, F.; Bahmani, M.; Iranpoor, N. Adv. Synth. Catal. 2015,
357, 1211−1220.
(16) Yamashita, Y.; Tellis, J. C.; Molander, G. A. Proc. Natl. Acad. Sci.
U. S. A. 2015, 112, 12026−12029.
Experimental setup for gram scale reaction, cyclic
voltammogram of compound 3a, and copies of H, 13C,
1
(17) Laitar, D. S.; Tsui, E. Y.; Sadighi, J. P. J. Am. Chem. Soc. 2006,
128, 11036−11037.
11B, and 19F spectra (PDF)
(18) Keith, J. A.; Oxgaard, J.; Goddard, W. A. J. Am. Chem. Soc. 2006,
128, 3132−3133.
AUTHOR INFORMATION
Corresponding Author
*E-mail: gmolandr@sas.upenn.edu.
ORCID
Gary A. Molander: 0000-0002-9114-5584
Notes
The authors declare no competing financial interest.
(19) (a) Mei, T.-S.; Werner, E. W.; Burckle, A. J.; Sigman, M. S. J.
Am. Chem. Soc. 2013, 135, 6830−6833. (b) Race, N. J.; Schwalm, C.
S.; Nakamuro, T.; Sigman, M. S. J. Am. Chem. Soc. 2016, 138, 15881−
15884.
■
(20) Kelly, C. B.; Patel, N. R.; Primer, D. N.; Jouffroy, M.; Tellis, J.
C.; Molander, G. A. Nat. Protoc. 2017, 12, 472−492.
(21) McIntosh, M. L.; Moore, C. M.; Clark, T. B. Org. Lett. 2010, 12,
1996−1999.
ACKNOWLEDGMENTS
■
The authors are grateful for the financial support provided by
NIGMS (R01 GM 113878). R.A. is thankful to the Swedish
Chemical Society for a postdoctoral fellowship. We thank J. K.
Matsui of the University of Pennsylvania for helpful input. We
thank Dr. Charles W. Ross, III (UPenn) for assistance in
obtaining HRMS.
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DOI: 10.1021/acs.joc.7b02589
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