Synergistic Photoredox/Nickel Coupling of Acyl Chlorides with Secondary Alkyltrifluoroborates: Dialkyl Ketone Synthesis

Article abstract of DOI:10.1021/acs.joc.6b02897

Visible light photoredox/nickel dual catalysis has been employed in the cross-coupling of acyl chlorides with potassium alkyltrifluoroborates. This protocol, based on single-electron-mediated alkyl transfer, circumvents the restriction of using reactive alkylmetallic nucleophiles in transition-metal-catalyzed acylation and achieves a mild and efficient method for the synthesis of unsymmetrical alkyl ketones. In this approach, a variety of acyl chlorides have been successfully coupled with structurally diverse potassium alkyltrifluoroborates, generating the corresponding ketones with good yields.

Full text of DOI:10.1021/acs.joc.6b02897

Note
pubs.acs.org/joc
Synergistic Photoredox/Nickel Coupling of Acyl Chlorides with
Secondary Alkyltrifluoroborates: Dialkyl Ketone Synthesis
Javad Amani 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: Visible light photoredox/nickel dual catalysis
has been employed in the cross-coupling of acyl chlorides with
potassium alkyltrifluoroborates. This protocol, based on single-
electron-mediated alkyl transfer, circumvents the restriction of
using reactive alkylmetallic nucleophiles in transition-metal-
catalyzed acylation and achieves a mild and efficient method
for the synthesis of unsymmetrical alkyl ketones. In this
approach, a variety of acyl chlorides have been successfully
coupled with structurally diverse potassium alkyltrifluorobo-
rates, generating the corresponding ketones with good yields.
etones, widespread in nature and in pharmaceuticals,1 are
among the most important and versatile functional groups
in organic molecules and have long been used as important
intermediates for the synthesis of complex structures. Because
of their ubiquity, the development of diverse synthetic methods
to prepare these compounds has been the subject of intense
research.
This synergistic catalysis approach via the simultaneous
activation and engagement of two separate coupling partners
with two distinct catalysts through low-barrier, open-shell
processes, has had a profound impact on C(sp3)−C(sp2) bond
formations under mild conditions. In this protocol, complica-
tions associated with the transmetalation of alkylmetallic
reagents in conventional cross-coupling methods, which are
mainly a consequence of the two-electron nature of the
transmetalation step, are avoided. The Doyle group has
employed a related strategy for acylation using anhydride
electrophiles (eq 1).7 This method was restricted to α-amino
radical precursors, and in fact acyl chlorides could not be used
in the protocol developed. Our group subsequently investigated
the photoredox/Ni dual catalyzed approach to α-alkoxy ketones
using α-alkoxyalkyltrifluoroborates as the radical precursor in
conjunction with carboxylic acid chloride electrophiles (eq 2).8
To achieve an efficient protocol for the general synthesis of
aliphatic ketones and in an effort to broaden the range of
electrophiles to which the photoredox/Ni dual catalysis
activation mode could be applied, we investigated the potential
of this method for the cross-coupling of acyl chlorides with
potassium secondary alkyltrifluoroborates to generate alkyl−
alkyl and alkyl−aryl ketones (Figure 1).
K
In principle, one of the most straightforward methods for the
synthesis of alkyl ketones is the reaction of acyl halides with
alkylmetallic reagents.2 However, the addition of highly reactive
alkylmetallic reagents (e.g., alkyllithium or Grignard reagents)
typically generates tertiary alcohols, and the enolization of the
produced ketones in these reactions cannot be repressed
completely. The use of low temperatures or less reactive
nucleophiles such as alkylcopper, alkylmanganese, alkylzinc, or
alkylzirconium reagents can be used to generate the ketones
without undesired over-reaction, but many of these reagents are
prepared from alkyllithium or Grignard reagents and thus are
often minimally functionalized.3 Furthermore, these reagents
are not shelf-stable, and many alkylzinc and alkylstannane
reagents lack atom economy because only one alkyl group on
the metal is transferred.
To overcome these problems, significant progress has been
made in the development of transition-metal-catalyzed
acylation of alkyl nucleophiles using acyl halides.4 In general,
however, metal-catalyzed ketone formation employing aliphatic
nucleophiles with carboxylic acid chlorides has been the least
explored, perhaps owing to the slow transmetalation of the
alkylmetallic nucleophiles and the susceptibility of the resulting
transition metal intermediates to undergo β-hydride elimi-
nation.5
To validate the strategy outlined in Figure 1 through the
conversion of acyl chlorides to aliphatic ketones, the cross-
coupling of hydrocinnamoyl chloride with i-PrBF3K was
evaluated as a model reaction under a variety of conditions
(e.g., varying solvents, Ni catalysts, ligands, and additives). The
investigation commenced with the evaluation of an extensive
array of Ni sources and ligands (L1−L8) by means of
microscale high-throughput experimentation (HTE, Figure
Recently, our group has developed an efficient photoredox/
Ni dual catalysis paradigm for transition-metal-catalyzed cross-
couplings of alkylboron reagents with halide electrophiles based
on a single-electron transfer (SET) transmetalation pathway.6
Received: December 2, 2016
© XXXX American Chemical Society
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acylated in 78% and 77% isolated yields, respectively (entries 1
and 2). In these reactions only the desired regioisomers were
obtained. Although alkyltrifluoroborates possessing various ring
sizes were coupled in good yields (entries 3−5), the reaction
with potassium cyclopropyltrifluoroborate did not produce the
desired product owing to the high s character of the hybrid
orbitals, which destabilizes the incipient radical and engenders
an unfavorable redox potential on the trifluoroborate. The
products derived from sterically hindered structures such as 2-
methylcyclopentyl and pinanyl substrates were also isolated in
good yields (entries 6 and 8). In contrast to the reported
procedures using Pd catalysis,10 no isomerization was observed
for these substrates, and trans-diastereomers were the major
products formed in these cross-coupling reactions. The reaction
with aliphatic, heterocyclic compounds containing oxygen or
protected nitrogen atoms produced the coupled products with
moderate to good yields under this protocol (entries 9−12),
illustrating the versatility of this method. Moreover, β-
trifluoroboratoketones and -esters were successfully coupled
to generate the corresponding 1,4-diketones (entries 13−15),
which are useful precursors to generate substituted furans,
pyrroles, and thiophenes via the Paal−Knorr synthesis.11 The
scalable nature of this coupling was demonstrated by
performing the reaction on 6.0 mmol scale (entry 3). In this
reaction, using half of the catalyst loadings (1.5 mol % of I and
3 mol % of NiCl2·dme/L1) afforded the desired product in
69% yield.
To investigate the applicability of this method to other
electrophiles, potassium cyclohexyltrifluoroborate was coupled
with various acyl halides (Table 2). We found that a broad
range of aliphatic and aromatic acyl chlorides participated in the
cross-coupling reaction with great efficiency. In these reactions,
the desired products 2a−o were obtained with yields up to
88%. The reaction proceeded well with cyclopropane- and
cyclobutanecarbonyl chlorides, resulting in 78% and 79% yields,
respectively (entries 1 and 2). Both electron-rich and electron-
poor aromatic acyl chlorides were coupled using the optimal
conditions with 53−88% yields (entries 8−10). Remarkably,
the sterically hindered 1-adamantanecarbonyl chloride provided
the desired cross-coupled product with 60% yield (entry 6).
The success of the reaction with 4-cyanobenzoyl chloride
(entry 9) and 1-chlorocarbonyl-1-methylethyl acetate (entry
14) further demonstrates the functional group compatibility of
this method. Finally, the reaction with 4-morpholinecarbonyl
Figure 1. Photoredox/Ni dual catalysis cross-coupling of acyl chlorides
with secondary R−BF3K.
2).9 After addition of an internal standard to the reaction
mixtures in these screens, the results were analyzed by UPLC.
Then, to determine the relative amount of product formed in
each microscale reaction, the product to internal standard (P/
IS) ratios were calculated. The P/IS ratios of the first screen are
shown in Figure 2.
In this screen, with hydrocinnamoyl chloride and i-PrBF3K
(1.5 equiv) as the coupling partners, using Ir[dF(CF3)ppy]2-
(bpy)PF6 (1) [dF(CF3)ppy = 2-(2,4-difluorophenyl)-5-
(trifluoromethyl)pyridine, bpy = 2,2′-bipyridine] as the photo-
catalyst, NiCl2·dme (6 mol %)/4,4′-di-tert-butyl-2,2′-dipyridyl,
L1, (6 mol %) as the cross-coupling catalyst, and lutidine (1
equiv) as a base in THF at room temperature provided the best
yield.
Control experiments revealed that all of the reaction
parameters (photocatalyst, Ni source, and ligand) are essential
for efficient coupling, in agreement with our mechanistic
proposal. Additionally, without added base, the product to
internal standard ratio noticeably decreased. Considering the
important role of the base, which is ascribed to sequestration of
the BF3 generated upon oxidation of the alkyltrifluoroborate, an
extensive screening of various bases in different solvents was
carried out (Figure 3). The investigations revealed that using
KF instead of lutidine and DME instead of THF provided a
substantial improvement and afforded the highest P/IS ratio.
Further investigations demonstrated that lower concentra-
tions (0.05 M) increased the yield of the reaction, while higher
molarities (0.2 M) resulted in diminished yields. To explore the
generality of this transformation, the developed conditions were
applied to the cross-coupling of hydrocinnamoyl chloride with
a variety of structurally diverse, secondary alkyltrifluoroborates.
As demonstrated in Table 1, all the secondary alkyltrifluor-
oborates function efficiently in this transition-metal-catalyzed
acylation protocol. Isopropyl- and sec-butyltrifluoroborates were
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Figure 2. Graphical chart of P/IS ratios of the cross-coupling reactions using different Ni sources and ligands. Reaction conditions: 0.01 mmol of
hydrocinnamoyl chloride, 1.5 equiv of i-PrBF3K, 3 mol % Ir[dF(CF3)ppy]2(bpy)PF6, 6 mol % Ni source, 6 mol % ligand, 1.0 equiv of lutidine, rt,
blue LEDs, 24 h in THF (0.1 M).
chloride to generate cyclohexyl(morpholino)methanone in 74%
yield (entry 15) shows the extension of this protocol to
carbamoyl chloride cross-coupling.
It is important to note that primary alkyltrifluoroborates are
not suitable substrates for these processes owing to an
unfavorable redox potential. Additionally, preliminary results
indicate that a different set of conditions are required for
reaction of tertiary alkyltrifluoroborates, and research along this
line of investigation continues.
In conclusion, the first visible light photoredox cross-
coupling of acyl chlorides with potassium secondary
alkyltrifluoroborates has been developed to access a variety of
dialkyl- and alkyl-aryl ketones in high yields. This efficient
protocol establishes one of the few catalytic methods to
generate 2° alkyl ketones from acyl chlorides. It extends
photoredox/Ni dual catalytic cross-coupling of secondary
alkylboron reagents to catalytic acylation approaches. Finally,
the ability to employ bench-stable, storable nucleophiles, the
mild conditions, high functional group tolerance, and the
operational simplicity of this protocol lend themselves favorably
to the facile synthesis of unsymmetrical alkyl ketones.
EXPERIMENTAL SECTION
■
General Considerations. All reactions were carried out under an
inert atmosphere of nitrogen or argon unless otherwise noted. THF
was dried over activated alumina. DME (99.5%, anhydrous) was used
as received. IrCl3·xH2O and NiCl2·dme were purchased from
commercial sources. All other reagents were purchased commercially
and used as received. Photoredox reactions were irradiated with two or
three standard 26 W compact fluorescent light bulbs. Melting points
(°C) are uncorrected. NMR spectra were recorded on a 400 or 500
MHz spectrometer. Data are presented as follows: chemical shift
(ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet,
br = broad), coupling constant J (Hz), and integration. Analytical thin-
layer chromatography (TLC) was performed on TLC silica gel plates
(0.25 mm) precoated with a fluorescent indicator. Visualization of the
TLC plates was effected with ultraviolet light. HRMS data were
obtained by either ESI or CI using a TOF mass spectrometer.
Synthesis of Potassium Secondary Alkyltrifluoroborates.
Most of the potassium alkyltrifluoroborates were purchased
commercially. In cases where the desired potassium organo-
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Figure 3. Graphical chart of P/IS ratios of the cross-coupling reactions using different bases and solvents. Reaction conditions: 0.01 mmol of
hydrocinnamoyl chloride, 1.5 equiv of i-PrBF3K, 3 mol % Ir[dF(CF3)ppy]2(bpy)PF6, 6 mol % NiCl2·dme, 6 mol % L1, 1.0 equiv of base, rt, blue
LEDs, 24 h (0.1 M).
Table 1. Scope of Secondary R−BF3K in Cross-Coupling with Hydrocinnamoyl Chloride
a
Reaction completed on 6.0 mmol scale with 1.5 mol % Ir photocatalyst 1 and 3 mol % NiCl2·dme/L1.
D
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Table 2. Scope of the Cross-Coupling with Acyl Chlorides
trifluoroborate was not available, the corresponding boronic acid
derivative was converted to the trifluoroborate by the following
procedure.
hydrocinnamoyl chloride, and photocatalyst 1 in a desired solvent was
added to each vial. The vials were sealed and stirred over blue LED
lights. After 24 h the reactions were opened to air, 1 μmol of 4,4′-di-
tert-butylbiphenyl (500 μL of a 0.002 μM solution in MeCN) was
added to each vial as an internal standard, and the reaction mixtures
were diluted with MeCN. The reaction mixtures were then analyzed
by UPLC to obtain product-to-internal standard (P/IS) ratios for
different conditions.
General Procedure for the Photoredox Cross-Coupling
Reaction of Acyl Chlorides with Potassium Alkyltrifluoro-
borates. To a long, thin glass vial (∼20 mL) equipped with a Teflon-
coated magnetic stir bar was added NiCl2·dme (6.6 mg, 0.03 mmol)
and 4,4′-di-tert-butyl-2,2′-bipyridine L1 (8.1 mg, 0.03 mmol). The vial
was sealed, evacuated under vacuum, and purged with Ar three times.
Anhydrous degassed THF (∼1 mL) was added by syringe under an
inert atmosphere, and the resulting mixture was stirred until it
appeared as a pale green suspension. Then, the solvent was removed
under vacuum. Once dry, potassium alkyltrifluoroborate (0.75 mmol,
1.5 equiv), Ir[dFCF3ppy]2(bpy)PF6 (15.1 mg, 0.015 mmol), and KF
(29.1 mg, 0.5 mmol) were added. Next, the vial was sealed, evacuated,
and purged four times. Anhydrous degassed DME (10 mL) was then
added by syringe under an inert atmosphere followed by the
corresponding acyl halide (0.5 mmol). The resulting mixture was
stirred for 24 h in the presence of two 26 W fluorescent light bulbs
while a fan was blown across the reaction setup to suppress the heat
and maintain an ambient temperature of 24 °C. After completion, the
General Procedure for Conversion of Boronic Acids to
Trifluoroborates. To a solution of boronic acid derivative in MeOH
(0.1 M) at 0 °C saturated aq KHF2 (4.5 M) was added dropwise over
30 min. After completion of the reaction, followed by 11B NMR, the
resulting suspension was concentrated under reduced pressure. H2O
was removed by lyophilizer. The remaining solid was suspended in hot
acetone (3 × 100 mL) and filtered. The filtrate was concentrated to a
minimal volume (5−20 mL), and hexane or Et2O (∼200 mL) was
added to yield a white precipitate. The precipitate was isolated by
filtration, washing with hexanes (∼30 mL) and CH2Cl2 (∼30 mL), to
afford the desired secondary alkyltrifluoroborate.
Synthesis of Ir[dF(CF3)ppy]2(bpy)PF6 as the Photocatalyst 1.
Photocatalyst 1 was synthesized according to the literature procedure.6
High-Throughput Experiments in the Design and Optimi-
zation of the Photoredox Cross-Coupling Reaction of Hydro-
cinnamoyl Chloride with Potassium Isoropyltrifluoroborate as
Model Coupling Partners. High Throughput Experimentation
(HTE) was performed at the Penn/Merck Center for High
Throughput Experimentation at the University of Pennsylvania. The
screens were performed on a 10 μmol scale. To reaction vials equipped
with a Teflon coated magnetic stir bar in a glovebox was added a
solution of the Ni source and ligand [1:1] dissolved in THF. The
solvent was removed in vacuo under an inert atmosphere. Then a
solution of a desired additive, potassium isopropyltrifluoroborate,
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crude reaction mixture was filtered through a plug of silica and rinsed
with EtOAc (20 mL). The resulting solution was concentrated, and
the residue was purified by column chromatography on silica gel,
eluting with EtOAc and hexanes, to obtain products in pure form.
Gram Scale Reaction. 1-Cyclohexyl-3-phenylpropan-1-one (1c).
To a long, thin-walled vacuum flask equipped with a Teflon-coated
magnetic stir bar was added NiCl2·dme (39.5 mg, 0.18 mmol, 3.0 mol
%) and 4,4′-di-tert-butyl-2,2′-bipyridine L1 (48.3 mg, 0.18, 3.0 mol %).
Anhydrous degassed THF (∼5 mL) was added by syringe under Ar,
and the resulting mixture was stirred until it appeared as a pale green
suspension. The solvent was then removed under vacuum. Once dry,
potassium cyclohexyltrifluoroborate (1.71 g, 9.0 mmol, 1.5 equiv),
Ir[dFCF3ppy]2(bpy)PF6 1 (90.8 mg, 0.09 mmol, 1.5 mol %), and
anhydrous KF (348.6 mg, 6.0 mmol, 1.0 equiv) were added. The vial
was then capped with a rubber septum and purged and evacuated four
times. Under an inert atmosphere, DME (120 mL, 0.05 M) was
introduced followed by hydrocinnamoyl chloride (1.012 g, 6.0 mmol).
The resulting mixture was stirred vigorously for 48 h in the presence of
three 26 W fluorescent light bulbs while a fan was blown across the
reaction setup to maintain an ambient temperature of 24 °C. After
completion, the crude reaction mixture was filtered through an
approximately 4 cm × 2 cm cylindrical plug of silica, washing with
EtOAc (60 mL). The resulting solution was concentrated, and the
residue was purified by column chromatography on silica gel, eluting
with EtOAc and hexanes, to obtain 895.5 mg (69% yield) of the
product as a colorless liquid.
HRMS (ES+) m/z calcd for C15H20ONa [M + Na]+ 239.1412, found
239.1414.
2-Methyl-1,5-diphenylpentan-3-one (1g).15 The title compound
1
was obtained as a liquid in 83% yield (0.5 mmol scale, 104.7 mg). H
NMR (500 MHz, CDCl3): δ 7.25−7.21 (m, 4H), 7.18−7.13 (m, 2H),
7.09−7.08 (m, 4H), 2.95−2.91 (m, 1H), 2.82−2.66 (m, 4H), 2.56−
2.51 (m, 2H), 1.03 (d, J = 7.0 Hz, 3H); 13C NMR (125.8 MHz,
CDCl3): δ 213.2, 141.4, 139.9, 129.1, 128.6, 128.5, 126.4, 126.2, 48.5,
43.8, 39.3, 29.8, 16.5.
3-Phenyl-1-(2,6,6-trimethylbicyclo[3.1.1]heptan-3-yl)propan-1-
one (1h). The title compound was obtained as a liquid in 82% yield
1
(0.5 mmol scale, 110.9 mg). H NMR (500 MHz, CDCl3): δ 7.30−
7.27 (m, 2H), 7.21−7.18 (m, 3H), 2.96−2.70 (m, 5H), 2.43−2.39 (m,
1H), 2.30−2.26 (m, 1H), 2.20−2.14 (m, 1H), 1.95−1.91 (m, 1H),
1.84−1.79 (m, 2H), 1.21 (s, 3H), 1.03−1.01 (m, 6H), 0.87 (d, J = 10.0
Hz, 1H); 13C NMR (125.8 MHz, CDCl3): δ 212.4, 141.6, 128.7,
128.6, 126.3, 49.6, 47.4, 43.9, 41.0, 38.8, 36.8, 32.9, 30.4, 29.9, 28.1,
23.1, 22.6; FT-IR (neat): 1709, 1453, 1368, 909, 731, 698 cm−1;
HRMS (ES+) m/z calcd for C19H26ONa [M + Na]+ 293.1881, found
293.1879.
3-Phenyl-1-(tetrahydro-2H-pyran-4-yl)propan-1-one (1i). The
title compound was obtained as a liquid in 75% yield (0.5 mmol
1
scale, 81.9 mg). H NMR (500 MHz, CDCl3): δ 7.26−7.23 (m, 2H),
7.17−7.14 (m, 3H), 3.95−3.92 (m, 2H), 3.35 (dt, J = 11.5, 3.0 Hz,
2H), 2.87 (t, J = 7.5 Hz, 2H), 2.74 (t, J = 7.5 Hz, 2H), 2.49−2.44 (m,
1H), 1.69−1.58 (m, 4H); 13C NMR (125.8 MHz, CDCl3): δ 211.1,
141.3, 128.7, 128.5, 126.3, 67.4, 47.8, 42.1, 29.8, 28.2; FT-IR (neat):
1705, 1444, 1240, 1112, 1090, 1015, 749, 698 cm−1; HRMS (CI+) m/
z calcd for C14H19O2 [M + H]+ 219.1385, found 219.1381.
4-Methyl-1-phenylpentan-3-one (1a).12 The title compound was
obtained as a liquid in 78% yield (0.5 mmol scale, 70.5 mg). 1H NMR
(500 MHz, CDCl3): δ 7.30−7.27 (m, 2H), 7.20−7.18 (m, 3H), 2.90
(t, J = 8.0 Hz, 2H), 2.77 (t, J = 8.0 Hz, 2H), 2.60−2.54 (m, 1H), 1.08
(d, J = 6.5 Hz, 6H); 13C NMR (125.8 MHz, CDCl3): δ 213.9, 141.6,
128.7, 128.5, 126.2, 42.2, 41.2, 30.0, 18.3.
3-Phenyl-1-(tetrahydrofuran-3-yl)propan-1-one (1j). The title
compound was obtained as a liquid in 69% yield (0.5 mmol scale,
70.5 mg). 1H NMR (500 MHz, CDCl3): δ 7.27−7.23 (m, 2H), 7.19−
7.14 (m, 3H), 3.87−3.79 (m, 3H), 3.75−3.71 (m, 1H), 3.16−3.10 (m,
1H), 2.89 (t, J = 7.5 Hz, 2H), 2.79−2.74 (m, 2H), 2.03−1.99 (m, 2H);
13C NMR (125.8 MHz, CDCl3): δ 209.2, 141.1, 128.7, 128.5, 126.4,
69.4, 68.5, 51.3, 43.8, 29.9, 28.9; FT-IR (neat): 1709, 1453, 1102,
1066, 913, 749, 698 cm−1; HRMS (ES+) m/z calcd for C13H16O2Na
[M + Na]+ 227.1048, found 227.1051.
4-Methyl-1-phenylhexan-3-one (1b).12 The title compound was
obtained as a liquid in 77% yield (0.5 mmol scale, 73.3 mg). 1H NMR
(500 MHz, CDCl3): δ 7.29−7.26 (m, 2H), 7.20−7.17 (m, 3H), 2.90
(t, J = 7.5 Hz, 2H), 2.81−2.70 (m, 2H), 2.47−2.40 (m, 1H), 1.71−
1.62 (m, 1H), 1.41−1.33 (m, 1H), 1.04 (d, J = 7.0 Hz, 3H), 0.85 (t, J =
7.5 Hz, 3H); 13C NMR (125.8 MHz, CDCl3): δ 213.9, 141.6, 128.7,
128.6, 126.3, 48.2, 43.0, 29.9, 26.1, 16.0, 11.9.
tert-Butyl 3-(3-Phenylpropanoyl)pyrrolidine-1-carboxylate (1k).
The title compound was obtained as a liquid in 63% yield (0.5 mmol
1-Cyclohexyl-3-phenylpropan-1-one (1c).13 The title compound
1
scale, 95.6 mg). H NMR (500 MHz, CDCl3): δ 7.25−7.22 (m, 2H),
1
was obtained as a liquid in 79% yield (0.5 mmol scale, 85.4 mg). H
7.16−7.12 (m, 3H), 3.49−3.40 (m, 3H), 3.30−3.25 (m, 1H), 3.06−
3.00 (m, 1H), 2.92−2.84 (m, 2H), 2.81−2.70 (m, 2H), 1.99−1.96 (m,
2H), 1.43 (s, 9H); 13C NMR (125.8 MHz, CDCl3): δ 208.5, 154.6,
141.2, 128.8, 128.5, 126.5, 79.6, 47.4, 45.6, 43.5, 30.0, 28.8, 28.5, 28.1;
FT-IR (neat): 1687, 1453, 1401, 1365, 1166, 1116, 879, 731, 699
cm−1; HRMS (ES+) m/z calcd for C18H25NO3Na [M + Na]+
326.1732, found 326.1740.
NMR (500 MHz, CDCl3): δ 7.29−7.23 (m, 2H), 7.17−7.15 (m, 3H),
2.86 (t, J = 7.5 Hz, 2H), 2.74 (t, J = 7.5 Hz, 2H), 2.31−2.26 (m, 1H),
1.80−1.73 (m, 4H), 1.65−1.62 (m, 1H), 1.33−1.22 (m, 5H); 13C
NMR (125.8 MHz, CDCl3): δ 213.4, 141.7, 128.7, 128.6, 126.2, 51.2,
42.5, 30.0, 28.6, 26.1, 25.9.
1-Cyclopentyl-3-phenylpropan-1-one (1d).14 The title compound
1
was obtained as a liquid in 72% yield (0.5 mmol scale, 72.8 mg). H
tert-Butyl 3-(3-Phenylpropanoyl)azetidine-1-carboxylate (1l).
The title compound was obtained as a liquid in 55% yield (0.5
mmol scale, 79.6 mg). 1H NMR (500 MHz, CDCl3): δ 7.27−7.24 (m,
2H), 7.19−7.14 (m, 3H), 3.99−3.94 (m, 4H), 3.37−3.31 (m, 1H),
2.91 (t, J = 7.0 Hz, 2H), 2.72 (t, J = 7.0 Hz, 2H), 1.42 (s, 9H); 13C
NMR (125.8 MHz, CDCl3): δ 207.1, 156.4, 140.9, 128.8, 128.5, 126.5,
79.9, 50.8, 42.5, 39.1, 29.8, 28.6; FT-IR (neat): 1694, 1454, 1392,
1365, 1131, 770, 730, 699 cm−1; HRMS (ES+) m/z calcd for
C17H24NO3 [M + H]+ 290.1756, found 290.1761.
NMR (500 MHz, CDCl3): δ 7.29−7.26 (m, 2H), 7.20−7.17 (m, 3H),
2.91 (t, J = 7.5 Hz, 2H), 2.87−2.81 (m, 1H), 2.78 (t, J = 7.5 Hz, 2H),
1.82−1.54 (m, 8H); 13C NMR (125.8 MHz, CDCl3): δ 212.5, 141.6,
128.7, 128.6, 126.2, 51.8, 43.6, 30.1, 29.0, 26.2.
1-Cyclobutyl-3-phenylpropan-1-one (1e). The title compound was
obtained as a liquid in 70% yield (0.5 mmol scale, 65.8 mg). 1H NMR
(500 MHz, CDCl3): δ 7.29−7.26 (m, 2H), 7.20−7.17 (m, 3H), 3.26−
3.19 (m, 1H), 2.90 (t, J = 7.5 Hz, 2H), 2.67 (t, J = 7.5 Hz, 2H), 2.22−
2.07 (m, 4H), 1.99−1.90 (m, 1H), 1.83−1.76 (m, 1H); 13C NMR
(125.8 MHz, CDCl3): δ 211.2, 141.6, 128.7, 128.6, 126.3, 45.7, 41.8,
30.0, 24.5, 18.0; FT-IR (neat): 1704, 1453, 1366, 1121, 978, 747, 698
cm−1; HRMS (ES+) m/z calcd for C13H16ONa [M + Na]+ 211.1099,
found 211.1108.
1-(2-Methylcyclopentyl)-3-phenylpropan-1-one (1f). The title
compound was obtained as a liquid in 78% yield (0.5 mmol scale,
84.4 mg). 1H NMR (500 MHz, CDCl3): δ 7.30−7.27 (m, 2H), 7.20−
7.18 (m, 3H), 2.91 (t, J = 7.5 Hz, 2H), 2.82−2.73 (m, 2H), 2.43−2.38
(m, 1H), 2.17−2.11 (m, 1H), 1.91−1.82 (m, 2H), 1.74−1.61 (m, 3H),
1.24−1.16 (m, 1H), 1.00 (d, J = 6.5 Hz, 3H); 13C NMR (125.8 MHz,
CDCl3): δ 212.6, 141.6, 128.6, 128.5, 126.2, 59.8, 44.1, 37.9, 35.1, 30.0,
29.9, 24.9, 20.2; FT-IR (neat): 1705, 1453, 1374, 748, 698 cm−1;
4-Methyl-1-phenyloctane-3,6-dione (1m). The title compound
1
was obtained as a liquid in 68% yield (0.5 mmol scale, 78.9 mg). H
NMR (500 MHz, CDCl3): δ 7.28−7.25 (m, 2H), 7.19−7.15 (m, 3H),
3.05−3.00 (m, 1H), 2.96−2.85 (m, 5H), 2.46−2.33 (m, 3H), 1.04−
1.01 (m, 6H); 13C NMR (125.8 MHz, CDCl3): δ 212.8, 210.3, 141.6,
128.7, 128.6, 126.2, 45.4, 43.2, 41.3, 36.1, 29.9, 16.8, 7.9; FT-IR (neat):
1707, 1454, 1376, 1361, 1112, 749, 699 cm−1; HRMS (ES+) m/z calcd
for C15H20O2Na [M + Na]+ 255.1361, found 255.1358.
3-Methyl-1,6-diphenylhexane-1,4-dione (1n). The title compound
1
was obtained as a liquid in 66% yield (0.5 mmol scale, 92.5 mg). H
NMR (500 MHz, CDCl3): δ 7.96−7.94 (m, 2H), 7.57−7.54 (m, 1H),
7.47−7.44 (m 2H), 7.31−7.28 (m, 2H), 7.25−7.18 (m, 3H), 3.57−
3.52 (m, 1H), 3.26−3.19 (m, 1H), 3.03−2.91 (m, 5H), 1.14 (dd, J =
F
DOI: 10.1021/acs.joc.6b02897
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The Journal of Organic Chemistry
Note
7.0, 0.5 Hz, 3H); 13C NMR (125.8 MHz, CDCl3): δ 212.7, 198.7,
141.6, 136.8, 133.4, 128.8, 128.7, 128.6, 128.2, 126.2, 43.3, 42.1, 41.4,
29.9, 16.9; FT-IR (neat): 1711, 1681, 1449, 1356, 1216, 1003, 748,
689 cm−1; HRMS (ES+) m/z calcd for C19H21O2 [M + H]+ 281.1542,
found 281.1532.
(125.8 MHz, CDCl3): δ 202.7, 139.7, 132.7, 128.9, 118.3, 116.2, 46.2,
29.4, 26.1, 25.9.
Cyclohexyl(3-fluorophenyl)methanone (2j). The title compound
1
was obtained as a liquid in 86% yield (0.5 mmol scale, 88.7 mg). H
NMR (500 MHz, CDCl3): δ 7.70 (dd, J = 7.5, 1.0 Hz, 1H), 7.61−7.58
(m, 1H), 7.44−7.39 (m, 1H), 7.24−7.20 (m, 1H), 3.21−3.15 (m, 1H),
1.87−1.81 (m, 4H), 1.74−1.70 (m, 1H), 1.51−1.33 (m, 4H), 1.29−
1.23 (m, 1H); 13C NMR (125.8 MHz, CDCl3): δ 202.7, 164.1 (d, J =
247.7 Hz, 1C), 138.7 (d, J = 5.7 Hz, 1C), 130.4 (d, J = 7.8 Hz, 1C),
124.1 (d, J = 2.7 Hz, 1C), 119.9 (d, J = 21.5 Hz, 1C), 115.2 (d, J = 22.0
Hz, 1C), 46.0, 29.6, 26.1, 26.0 ; FT-IR (neat): 1681, 1587, 1440, 1254,
1226, 1164, 1154, 896, 768 cm−1; HRMS (ES+) m/z calcd for
C13H15OFNa [M + Na]+ 229.1005, found 229.1001.
Ethyl 3-Methyl-4-oxo-6-phenylhexanoate (1o).16 The title com-
pound was obtained as a liquid in 64% yield (0.5 mmol scale, 79.4
1
mg). H NMR (500 MHz, CDCl3): δ 7.28−7.25 (m, 2H), 7.19−7.16
(m, 3H), 4.09 (q, J = 7.0 Hz, 2H), 3.00−2.94 (m, 1H), 2.92−2.89 (m,
2H), 2.88−2.81 (m, 2H), 2.78−2.73 (m, 1H), 2.30−2.26 (m, 1H),
1.22 (t, J = 7.0 Hz, 3H), 1.07 (d, J = 7.0 Hz, 3H); 13C NMR (125.8
MHz, CDCl3): δ 212.0, 172.4, 141.4, 128.6, 128.5, 126.2, 60.7, 43.0,
42.3, 37.2, 29.8, 16.7, 14.4.
Cyclohexyl(cyclopropyl)methanone (2a).17 The title compound
Benzo[d][1,3]dioxol-5-yl(cyclohexyl)methanone (2k). The title
1
compound was obtained as a white solid in 73% yield (0.5 mmol
was obtained as a liquid in 78% yield (0.5 mmol scale, 59.3 mg). H
1
scale, 84.7 mg). Mp 68−69 °C; H NMR (500 MHz, CDCl3): δ 7.53
NMR (500 MHz, CDCl3): δ 2.46−2.42 (m, 1H), 1.94−1.84 (m, 3H),
1.74−1.72 (m, 2H), 1.63−1.60 (m, 1H), 1.35−1.13 (m, 5H), 0.92−
0.89 (m, 2H), 0.78−0.75 (m, 2H); 13C NMR (125.8 MHz, CDCl3): δ
214.1, 51.7, 28.7, 26.2, 26.0, 19.1, 10.7.
(dd, J = 8.0, 1.5 Hz, 1H), 7.40 (d, J = 1.5 Hz, 1H), 6.82 (d, J = 8.5 Hz,
1H), 6.00 (s, 2H), 3.17−3.11 (m, 1H), 1.84−1.79 (m, 4H), 1.72−1.68
(m, 1H), 1.50−1.42 (m, 2H), 1.39−1.30 (m, 2H), 1.27−1.9 (m, 1H);
13C NMR (125.8 MHz, CDCl3): δ 202.1, 151.7, 148.4, 131.3, 124.5,
108.4, 108.1, 102.0, 45.7, 29.8, 26.2, 26.1; FT-IR (neat): 1656, 1602,
1447, 1107, 1035, 936, 900, 743 cm−1; HRMS (ES+) m/z calcd for
C14H17O3 [M + H]+ 233.1178, found 233.1168.
Cyclobutyl(cyclohexyl)methanone (2b).17 The title compound was
obtained as a liquid in 79% yield (0.5 mmol scale, 65.7 mg). 1H NMR
(500 MHz, CDCl3): δ 3.39−3.32 (m, 1H), 2.32−2.27 (m, 1H), 2.23−
2.15 (m, 2H), 2.09−2.02 (m, 2H), 1.97−1.87 (m, 1H), 1.79−1.71 (m,
5H), 1.63−1.61 (m, 1H), 1.32−1.14 (m, 5H); 13C NMR (125.8 MHz,
CDCl3): δ 215.0, 49.1, 44.0, 28.8, 26.1, 26.0, 24.8, 18.1.
Cyclohexyl(furan-2-yl)methanone (2l).21 The title compound was
obtained as a liquid in 52% yield (0.5 mmol scale, 46.3 mg). 1H NMR
(500 MHz, CDCl3): δ 7.56−7.55 (m, 1H), 7.16−7.15 (m, 1H), 6.50−
6.49 (m, 1H), 3.06−3.00 (m, 1H), 1.85−1.79 (m, 4H), 1.70−1.68 (m,
1H), 1.51−1.44 (m, 2H), 1.37−1.29 (m, 2H), 1.26−1.20 (m, 1H); 13C
NMR (125.8 MHz, CDCl3): δ 193.1, 152.5, 146.4, 117.2, 112.3, 46.6,
29.2, 26.1, 26.0.
Cyclohexyl(cyclopentyl)methanone (2c).17 The title compound
1
was obtained as a liquid in 83% yield (0.5 mmol scale, 74.8 mg). H
NMR (500 MHz, CDCl3): δ 2.99−2.93 (m, 1H), 2.44−2.38 (m, 1H),
1.79−1.62 (m, 11H), 1.54−1.51 (m, 2H), 1.34−1.15 (m, 5H); 13C
NMR (125.8 MHz, CDCl3): δ 216.9, 50.5, 49.7, 29.6, 28.9, 26.3, 26.1,
26.0.
Cyclohexyl(thiophen-2-yl)methanone (2m).21 The title compound
1
was obtained as a liquid in 48% yield (0.5 mmol scale, 46.6 mg). H
Dicyclohexylmethanone (2d).17 The title compound was obtained
NMR (500 MHz, CDCl3): δ 7.69 (dd, J = 3.5, 0.5 Hz, 1H), 7.59 (dd, J
= 5.0, 0.5 Hz, 1H), 7.10 (dd, J = 3.5, 5.0 Hz, 1H), 3.10−3.04 (m, 1H),
1.89−1.80 (m, 4H), 1.72−1.69 (m, 1H), 1.56−1.48 (m, 2H), 1.39−
1.30 (m, 2H), 1.28−1.20 (m, 1H); 13C NMR (125.8 MHz, CDCl3): δ
197.0, 144.1, 133.6, 131.7, 128.3, 47.7, 29.9, 26.1, 26.0.
1
as a liquid in 84% yield (0.5 mmol scale, 81.6 mg). H NMR (500
MHz, CDCl3): δ 2.47−2.41 (m, 2H), 1.74−1.72 (m, 8H), 1.64−1.61
(m, 2H), 1.32−1.14 (m, 10H); 13C NMR (125.8 MHz, CDCl3): δ
217.3, 49.4, 28.8, 26.1, 26.0.
1-Cyclohexyl-3,3-dimethylbutan-1-one (2e). The title compound
1-Cyclohexyl-2-methyl-1-oxopropan-2-yl Acetate (2n). The title
1
was obtained as a liquid in 72% yield (0.5 mmol scale, 65.6 mg). H
compound was obtained as a liquid in 85% yield (0.5 mmol scale, 90.2
NMR (500 MHz, CDCl3): δ 2.28−2.23 (m, 3H), 1.77−1.73 (m, 4H),
1.64−1.61 (m, 1H), 1.28−1.13 (m, 5H), 0.97 (s, 9H); 13C NMR
(125.8 MHz, CDCl3): δ 214.4, 53.1, 52.6, 31.2, 30.0, 28.5, 26.1, 26.0;
FT-IR (neat): 1705, 1449, 1364, 712 cm−1; HRMS (ES+) m/z calcd
for C12H22ONa [M + Na]+ 205.1568, found 205.1569.
1
mg). H NMR (500 MHz, CDCl3): δ 2.69−2.63 (m, 1H), 2.02 (s,
3H), 1.74−1.62 (m, 5H), 1.45 (s, 6H), 1.40−1.32 (m, 2H), 1.24−1.17
(m, 3H); 13C NMR (125.8 MHz, CDCl3): δ 212.5, 170.4, 84.0, 45.1,
30.1, 26.0, 24.2, 21.5; FT-IR (neat): 1735, 1713, 1369, 1251, 1150,
1134, 1018, 990, 964 cm−1; HRMS (ES+) m/z calcd for C12H20O3Na
[M + Na]+ 235.1310, found 235.1307.
(Adamantan-1-yl)(cyclohexyl)methanone (2f). The title com-
pound was obtained as a white solid in 60% yield (0.5 mmol scale,
73.9 mg). Mp 80−81 °C; 1H NMR (500 MHz, CDCl3): δ 2.86−2.80
(m, 1H), 2.02 (s, 3H), 1.78−1.65 (m, 15H), 1.57−1.53 (m, 2H),
1.38−1.19 (m, 5H); 13C NMR (125.8 MHz, CDCl3): δ 218.7, 47.2,
44.3, 38.1, 37.0, 30.1, 28.3, 26.2; FT-IR (neat): 1695, 1450, 1244,
1196, 1162, 996, 967 cm−1; HRMS (CI+) m/z calcd for C17H26O
[M]+ 246.1984, found 246.1978.
Cyclohexyl(morpholino)methanone (2o).22 The title compound
1
was obtained as a liquid in 74% yield (0.5 mmol scale, 73.0 mg). H
NMR (500 MHz, CDCl3): δ 3.65−3.60 (m, 6H), 3.48 (s, 2H), 2.44−
2.39 (m, 1H), 1.80−1.78 (m, 2H), 1.71−1.68 (m, 3H), 1.56−1.48 (m,
2H), 1.27−1.23 (m, 3H); 13C NMR (125.8 MHz, CDCl3): δ 174.8,
67.1, 66.9, 46.0, 42.0, 40.3, 29.4, 25.9.
Cyclohexyl(phenyl)methanone (2g).18 The title compound was
obtained as a liquid in 75% yield (0.5 mmol scale, 70.6 mg). 1H NMR
(500 MHz, CDCl3): δ 7.92−7.91 (m, 2H), 7.52−7.49 (m, 1H), 7.44−
7.41 (m, 2H), 3.26−3.21 (m, 1H), 1.88−1.79 (m, 4H), 1.73−1.69 (m,
1H), 1.46−1.20 (m, 5H); 13C NMR (125.8 MHz, CDCl3): δ 204.0,
136.5, 132.9, 128.8, 128.4, 45.8, 29.6, 26.2, 26.1.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.6b02897.
Cyclohexyl(4-methoxyphenyl)methanone (2h).19 The title com-
pound was obtained as a white solid in 88% yield (0.5 mmol scale, 96.1
NMR spectra for all compounds (PDF)
1
mg). Mp 59−60 °C; H NMR (500 MHz, CDCl3): δ 7.92 (dd, J =
AUTHOR INFORMATION
11.5, 2.5 Hz, 2H), 6.91 (dd, J = 11.5, 2.5 Hz, 2H), 3.84 (s, 3H), 3.22−
3.17 (m, 1H), 1.86−1.80 (m, 4H), 1.72−1.70 (m, 1H), 1.52−1.44 (m,
2H), 1.41−1.32 (m, 2H), 1.29−1.22 (m, 1H); 13C NMR (125.8 MHz,
CDCl3): δ 202.6, 163.4, 130.7, 129.4, 113.9, 55.6, 45.5, 29.8, 26.2, 26.1.
4-(Cyclohexanecarbonyl)benzonitrile (2i).20 The title compound
was obtained as a white solid in 53% yield (0.5 mmol scale, 56.5 mg).
■
Corresponding Author
*E-mail: gmolandr@sas.upenn.edu.
ORCID
Gary A. Molander: 0000-0002-9114-5584
1
Mp 60−61 °C; H NMR (500 MHz, CDCl3): δ 7.98−7.97 (m, 2H),
Notes
7.73−7.72 (m, 2H), 3.21−3.16 (m, 1H), 1.85−1.79 (m, 4H), 1.72−
1.68 (m, 1H), 1.48−1.31 (m, 4H), 1.27−1.19 (m, 1H); 13C NMR
The authors declare no competing financial interest.
G
DOI: 10.1021/acs.joc.6b02897
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(21) Kondo, T.; Akazome, M.; Tsuji, Y.; Watanabe, Y. J. Org. Chem.
1990, 55, 1286.
(22) Tillack, A.; Rudloff, I.; Beller, M. Eur. J. Org. Chem. 2001, 2001,
523.
ACKNOWLEDGMENTS
■
This research was supported by the NIGMS (R01 GM-
113878). Frontier Scientific is thanked for the donation of
boron compounds used in this investigation. Johnson-Matthey
is acknowledged for the donation of IrCl3 used for the synthesis
of the photocatalyst. Dr. Rakesh Kohli (University of
Pennsylvania) is acknowledged for obtaining HRMS data.
REFERENCES
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DOI: 10.1021/acs.joc.6b02897
J. Org. Chem. XXXX, XXX, XXX−XXX