Visible-light-mediated α-arylation of enol acetates using aryl diazonium salts

Article abstract of DOI:10.1021/jo301984p

Visible light mediates efficiently the α-arylation of enol acetates by aryl diazonium salts under mild conditions using [Ru(bpy)₃]Cl ₂ as a photoredox catalyst. The broad scope of the reaction toward various diazonium salts and enol acetates was explored. The application of this reaction in the concise synthesis of 2-substituted indoles was demonstrated

Full text of DOI:10.1021/jo301984p

Article
pubs.acs.org/joc
Visible-Light-Mediated α‑Arylation of Enol Acetates Using Aryl
Diazonium Salts
Thea Hering, Durga Prasad Hari, and Burkhard Konig*
̈
Institut fur Organische Chemie, Universitat Regensburg, Universitatsstrasse 31, D-93053 Regensburg, Germany
̈
̈
̈
S
* Supporting Information
ABSTRACT: Visible light mediates efficiently the α-arylation of enol
acetates by aryl diazonium salts under mild conditions using [Ru(bpy)3]-
Cl2 as a photoredox catalyst. The broad scope of the reaction toward
various diazonium salts and enol acetates was explored. The application
of this reaction in the concise synthesis of 2-substituted indoles was
demonstrated
elaborated this concept to perform intermolecular direct C−H
INTRODUCTION
■
bond arylation of heteroarenes8j and double bonds.8k Herein
we now report a mild method for the α-arylation of ketones in
visible light by PET-mediated arylation of enol acetates
(Scheme 1); the reaction proceeds at room temperature
without the need for any bases or toxic metal enolates.
The catalytic α-arylation of ketones as a method of C−C bond
formation has been extensively studied over the past decades.
This interest arises from the importance of α-aryl carbonyl
moieties in many pharmaceuticals and bioactive molecules,1
including well-known drugs such as ibuprofen and the β-
blocker atenolol. 1,2-Diarylated ethanones (deoxybenzoines)
can serve as valuable building blocks for the synthesis of
heterocycles such as oxazoles,2 pyrazoles,3 diazepines,4 and
indoles,5 which are common functionalities in various drug
molecules.
Scheme 1. Photocatalytic Approach for α-Arylation of
Ketones in Visible Light
In addition to only a few examples for base-promoted
reactions,6 especially transition metal5a,7 (Pd, Ni, Cu, Fe)-
catalyzed reactions proved to be highly effective. In particular
Pd-catalyzed arylations pioneered by Buchwald and Hartwig
offer access to many interesting products.5c,7a,b In the context of
efficient synthesis, visible light can be considered the ideal
“reagent” since it is abundant and nontoxic and generates no
waste. The great potential of photoredox chemistry to perform
essential organic transformations by irradiation with visible light
was impressively demonstrated in recent publications by the
RESULTS AND DISCUSSION
■
Initial studies showed that under irradiation at 440 nm the
reaction of p-nitrobenzenediazonium tetrafluoroborate 1a with
isopropenyl acetate 2a and 1 mol % [Ru(bpy)3]Cl2 in DMSO
gave the α-arylated ketone 3a in high yields. The possibility to
replace [Ru(bpy)3]Cl2 by photocatalytic active organic dyes13
was investigated, and the results of the screening are presented
in Table 1. We observed no catalytic enhancement for 5 mol %
Eosin B or Rose Bengal (entries 5 and 6) compared to the
control reaction without catalyst (entries 3 and 1). Eosin Y (5
mol %) increased the yield slightly, reaching a yield of 50%
(entry 4) with 10 mol % Eosin Y. The much shorter lifetime of
the excited states of the organic dyes13a,14 in comparison to
[Ru(bpy)3]Cl2 may explain why the ruthenium complex is the
best photoredoxcatalyst for the reaction.
groups of MacMillan, Yoon, Ruping, Blechert, Bach,
̈
Stephenson, and others.8
Reactive radical intermediates have unique features and are
therefore widely employed in organic synthesis.9 The highly
reactive aryl radical, for instance, is easily accessible through
one-electron reduction of aryl diazonium salts10 and reacts with
versatile unsaturated compounds.8g Detailed investigations on
these reactions were done by Heinrich et al.,11 who used TiCl3
as a stoichiometric reductant for the generation of the aryl
radical. An elegant and ecofriendly approach to aryl radicals is
the catalytic reduction of aryl diazonium salts by photoinduced
electron transfer (PET) using [Ru(bpy)3]Cl2. This was first
described by Cano-Yelo and Deronzier. They used an
intramolecular cyclization known as the Pschorr reaction for
the synthesis of phenanthrene derivatives.12 Our group has
To optimize the reaction conditions we screened different
solvents, catalyst loadings, and irradiation times (Table 2). Dry
Received: September 21, 2012
Published: October 27, 2012
© 2012 American Chemical Society
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Article
a
Table 1. Screening of Different Photocatalysts
Table 3. Screening of Different Diazonium
Tetrafluoroborates
a
b
entry
catalyst
mol %
yield (%)
b
entry
R1
diazonium salt
product
yield (%)
c
1
2
3
4
5
6
33
1
4-NO2
2-NO2
3-NO2
2-CF3
2-CN
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
90
60
55
59
75
50
61
57
40
47
[Ru(bpy)3]Cl2
Eosin Y
1
5
80
43
50
35
32
2
3
Eosin Y
10
5
4
Eosin B
5
Rose Bengal
5
6
4-COOEt
4-Cl
a
The reaction was performed using 0.3 mmol of 1a, with 15 equiv of
2a in DMSO and irradiation time of 2 h. Yield determined by gas
chromatography. Experiment was conducted in DMF (see ref 8(g) p
7
1g
1h
1i
3g
3h
3i
b
8
4-Br
c
9
4-MeO
4-CH3
775 for details on the background reaction).
10
1j
3j
a
a
The reaction was performed using 0.3 mmol 1 with 10 equiv 2a and
Table 2. Optimization of Reaction Conditions
0.003 mmol of [Ru(bpy)3]Cl2 in DMF and 2 h of irradiation at 440
nm. Yield after purification over silica gel.
b
a
entry
conditions
yield (%)
1
2a (15 equiv), DMSO dry, 2 h
2a (5 equiv), DMSO dry, 2 h
2a (15 equiv), DMSO dry, 6 h
2a (15 equiv), DMSO dry, 2 mol % cat.
2a (15 equiv), 2:1 DMSO/H2O, 2 h
2a (15 equiv), MeCN, 2 h
80
a
Table 4. Scope of Enol Acetates
2
75−70
70
3
4
70
5
47
6
56
7
2a (15 equiv), MeCN dry, 2 h
2a (15 equiv), DMF dry, 2 h
2a (10 equiv), DMF dry, 2 h
2a (5 equiv), DMF dry, 2 h
62
b
entry
R3
R2
enol acetate product
yield (%)
90
8
95−100
93
9
1
2
3
4
5
6
7
Me
H
H
H
H
H
H
2a
2b
2c
2d
2e
2f
3a
10
11
73
tert-butyl
Ph
3k
3l
75
2a (15 equiv), DMF dry, no light, 2 h
15
95
a
4-Br- Ph
4-OMe- Ph
thienyl
Et
3m
3n
3o
3p
3q
3r
92
Yield determined by gas chromatography.
96
79
DMF as a solvent, 2 h irradiation time, and 1 mol %
[Ru(bpy)3]Cl2 provided the highest yields (entry 9). The
excess of the enol acetate 2a was needed for an efficient
product formation (entries 8−10). Most of the unreacted
substrate could be recovered during the workup, and we
assume that the high concentration of 2 is required to trap the
very reactive aryl radical efficiently. We observed no significant
conversion without irradiation (entry 11).
Me
2g
2h
2i
33
c
8
−(CH2)4−
35
9
H
H
H
26
10
C6H13
2j
(3s)
(only traces)
a
The reaction was performed using 0.3 mmol of 1a with 10 equiv of 2
and 0.003 mmol of [Ru(bpy)3]Cl2 in DMF and 2 h of irradiation at
440 nm. Yield after purification over silica gel. Enol acetate derived
b
c
from cyclohexanone.
With these optimized conditions in hand, we explored the
scope of the reaction of 2a with different aryl diazonium salts
(Table 3). A variety of different substituents were tested, and
the desired product 3 was obtained in all cases. In accordance
with their higher reduction potentials10 electron-deficient aryl
diazonium salts (entries 1−5 and 7) showed the highest yields.
However, a strong dependence on the position of the
substituents was observed (entries 1−3), probably due to
steric hindrance. Neutral or electron-donating substituents gave
moderate to good yields. It is advantageous that halogen
substituents are tolerated on the aromatic ring as this opens up
possibilities for facile subsequent synthetic modifications
(entries 7 and 8).
Having established the broad scope of the diazonium salts in
this α-arylation, we varied the substituents on the enol. As
Table 4 shows, the reaction was very effective for terminal enols
regardless of the substituent (entries 1−6). Aliphatic as well as
aromatic and heterocyclic groups are tolerated for terminal
enols. Excellent yields can be obtained with aromatic enol
acetates (entries 3−5), because a well stabilized benzylic radical
is formed upon addition of the aryl radical (see Scheme 3,
intermediate 7). However, a substituent on the enol's double
bond decreases the yield significantly (entries 7 and 8). Due to
subsequent aldol reaction low or no yields are observed with
enol acetates of aldehydes (entries 915 and 10).
Our investigations have shown that visible light photoredox
catalysis can serve as a viable method to promote organic
transformations. To further illustrate its applicability, we
performed the synthesis of 2-substituted indoles. As shown in
Scheme 2 we used the developed photochemical arylation as a
first step, followed by the iron-catalyzed reductive cyclization
described by Raucher et al.5b The ketone 3 carrying an ortho-
NO2-substituted benzene in the α-position is easily accessible
through the photoreaction of 2-nitro aryl diazonium salt 1b
with any enol acetate. In situ reduction of the nitro group leads
to amine 4, which undergoes iron-directed condensation to give
indole 5. This synthesis avoids regioselectivity problems
observed in Fischer indole synthesis16 and allows the
introduction of synthetically valuable halogen substituents on
the indoles benzene ring as well as on the substituent.
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intermediates 7 and 6 in the reaction cycle, we could not
detect compounds arising from acyl cation 9.
Scheme 2. Application of the Photoreaction in the Synthesis
of Substituted Indoles through Photochemical Arylation
Followed by Reductive Cyclization
a
CONCLUSION
■
In conclusion, we described a mild method for the α-arylation
of ketones by reacting aryl diazonium salts with enol acetates
using visible light photoredox catalysis. The reaction proceeds
smoothly at room temperature without the need of bases,
expensive patented ligands, or toxic metal enolates and is
compatible with a broad range of functional groups. Thus it
provides an environmentally benign synthesis of α-arylated
ketones catalyzed by photoinduced electron transfer (PET) as
an alternative to conventional synthetic procedures. Further-
more, we obtained synthetically valuable indoles in a simple
two-step process, introducing first an ortho-nitro-substituted
aryl moiety on a ketone by our photochemical arylation
followed by reductive cyclization to the indole. Further studies
on the exact mechanism of the arylation are ongoing in our
group.
a
Reaction was performed using 0.5 mmol of ketone 3, 3.5 equiv of
iron powder, 1 equiv NaOAc, and 7 equiv HOAc in 4:1 ethanol/
water.5b
b
EXPERIMENTAL SECTION
■
Yield after purification over silica gel.
General Experimental Details. Commercial reagents and starting
materials were purchased and used without further purification.
Solvents were used either as p.a. grade or dried and distilled according
to literature known procedures.19 NMR spectroscopy was carried out
on either a 400 MHz (1H, 400.13 MHz; 13C, 101 MHz, T = 300 K) or
a 300 MHz Spectrometer (1H, 300.13 MHz; 13C, 75 MHz, T = 295
K). GC measurements were done with following parameters: injector
temperature (split injection, 40:1 split) was 250 °C, detection
temperature was 300 °C (FID) with a capillary column 30 m ×
0.25 mm/0.2 μm film. The GC oven temperature program was
adjusted as follows: initial temperature 40 °C was kept for 3 min, the
temperature was increased at a rate of 15 °C/min over a period of 16
min until the final temperature (280 °C) was reached and kept for 5
min. Naphthalene was used as an internal standard. Irradiation was
performed with high power LEDS (blue, λmax = 455 15 nm, 700 mA,
3.0 W) for blue light or (green, λ = 520 15 nm, 145 lm @700 mA,
1.0 W) for green light.
c
Yield determined by NMR.
Scheme 3 depicts a plausible mechanism for the described
arylation based on our investigation and recent literature
Scheme 3. Proposed Mechanism for the Photocatalyzed α-
Arylation of Enol Acetates
General Procedure A: Preparation of Aryl Diazonium
Tetrafluoroborates. Compounds were prepared according to
literature.20 In a mixture of 4 mL of distilled water and 3.4 mL of
50% hydrofluoroboric acid was dissolved 10 mmol of the appropriate
aniline. After the reaction mixture was cooled to 0 °C using an ice
bath, a solution of sodium nitrite in distilled water (0.69 g in 1.5 mL)
was added dropwise. The suspension was stirred for an additional 40
min and then filtered, and the resulting solid was redissolved in a
minimum amount of acetone. Diethyl ether was added until
precipitation of diazonium tetrafluoroborate, which was filtered,
washed several times with diethyl ether, and dried under vacuum.
General Procedure B: Preparation of Enol Acetates.
Compounds were prepared according to literature.7k To a mixture
of the ketone (50 mmol) and 2-propenyl acetate (250 mol) was added
p-toluenesulfonic acid (3.6 mmol). The resulting mixture was refluxed
overnight and afterward cooled to rt. The solvent was evaporated in
vacuo. Diethyl ether (100 mL) was added, and the organic layer was
subsequently washed with H2O (3 × 50 mL), dried over Na2SO4, and
concentrated in vacuo. The resulting crude mixture was purified by
column chromatography on SiO2 (50% CH2Cl2 in hexane) for
aromatic products and by fractionated distillation under reduced
pressure for aliphatic products.
reports.8h,11 The cycle is initiated by photoexcitation of the
catalyst, which is oxidatively quenched by the diazonium salt 1
to give aryl radical 6.17 The radical 6 can attack the enol double
bond to form radical intermediate 7. Compound 7 can be
oxidized to the cationic species 8 by two possible pathways: (a)
single electron transfer (SET) to [Ru(bpy)3]3+ thus closing the
catalytic cycle or (b) reduction of 1 to the aryl radical 6
initiating a radical chain process. To yield the observed product
3, an acyl cation 9 has to be transferred to a nucleophile, e.g.,
the solvent DMF, to give the stable salt 10 in analogy to the
first step of the Vilsmeier−Haack reaction.18 While the
TEMPO adducts 11 and 12 support the presence of
1-Phenylvinyl Acetate (2c).7n 1H NMR (400 MHz, CDCl3) δ
7.52−7.43 (m, 2H), 7.38−7.32 (m, 3H), 5.49 (d, J = 2.2 Hz, 1H), 5.04
(d, J = 2.2 Hz, 1H), 2.28 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
169.1, 153.0, 134.3, 129.0, 128.6, 124.9, 102.2, 21.0.
1-(4-Bromophenyl)vinyl Acetate (2d).7n 1H NMR (400 MHz,
CDCl3) δ 7.55−7.41 (m, 2H), 7.40−7.28 (m, 2H), 5.47 (d, J = 2.4 Hz,
1H), 5.06 (d, J = 2.4 Hz, 1H), 2.27 (s, 3H).
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1-(4-Methoxyphenyl)vinyl Acetate (2e).7n 1H NMR (400
MHz, CDCl3) δ 7.52−7.32 (m, 2H), 6.90−6.73 (m, 2H), 5.35 (d, J
= 2.2 Hz, 1H), 4.91 (d, J = 2.2 Hz, 1H), 3.81 (s, 3H), 2.27 (s, 3H).
1-(Thiophen-2-yl)vinyl Acetate (2f).21 1H NMR (300 MHz,
CDCl3) δ 7.29−7.19 (m, 1H), 7.10 (dd, J = 3.7, 1.2 Hz, 1H), 6.98 (dd,
J = 5.0, 3.7 Hz, 1H), 5.39 (d, J = 2.5 Hz, 1H), 4.94 (d, J = 2.5 Hz, 1H),
2.27 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 168.8, 147.6, 138.2,
127.5, 125.8, 124.7, 101.2, 20.9.
1-(4-Bromophenyl)propan-2-one (3h).25 Yield 57% (40 mg,
1
0.17 mmol). H NMR (400 MHz, CDCl3) δ 7.46−7.35 (m, 2H),
7.06−6.96 (m, 2H), 3.61 (s, 2H), 2.12 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 205.5, 133.1, 131.8, 131.2, 121.1, 50.1, 29.5.
1-(4-Methoxyphenyl)propan-2-one (3i).26 Yield 40% (22 mg,
1
0.13 mmol). H NMR (400 MHz, CDCl3) δ 7.18−7.05 (m, 2H),
6.91−6.82 (m, 2H), 3.79 (s, 3H), 3.63 (s, 2H), 2.13 (s, 3H).
1-(p-Tolyl)propan-2-one (3j).6b Yield 47% (24 mg, 0.16 mmol).
1H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 7.9 Hz, 2H), 7.09 (d, J =
8.0 Hz, 2H), 3.65 (s, 2H), 2.34 (s, 3H), 2.14 (s, 3H). 13C NMR (101
MHz, CDCl3) δ 206.7, 136.7, 131.2, 129.5, 129.3, 50.7, 29.2, 21.1.
3,3-Dimethyl-1-(4-nitrophenyl)butan-2-one (3k). Compound
is an orange oil. Yield 75% (50 mg, 0.23 mmol). 1H NMR (400 MHz,
CDCl3) δ 8.18 (d, J = 8.7 Hz, 2H), 7.34 (d, J = 8.7 Hz, 2H), 3.92 (s,
2H), 1.23 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 211.4, 146.9,
142.5, 130.6, 123.6, 44.9, 42.9, 26.3. HRMS (EI-MS) m/z: [M]+ calcd
for C12H15NO3 221.1052; found 221.1056.
3,3-Dimethylbut-1-en-2-yl Acetate (2b).22 1H NMR (400
MHz, CDCl3) δ 4.87 (d, J = 2.0 Hz, 1H), 4.63 (d, J = 2.0 Hz, 1H),
2.17 (s, 3H), 1.09 (s, 9H).
Pent-2-en-3-yl Acetate (2g).23 1H NMR (400 MHz, CDCl3) δ
5.23−4.96 (m, 1H), 2.41−2.03 (m, 5H), 1.63 (d, J = 7.1 Hz, 1H), 1.47
(dd, J = 6.8, 1.4 Hz, 2H), 1.00 (m, 3H).
Cyclohex-1-en-1-yl Acetate (2h).23 1H NMR (400 MHz,
CDCl3) δ 5.35 (ddd, J = 5.3, 2.6, 1.5 Hz, 1H), 2.16−2.06 (m, 7H),
1.72 (dtd, J = 12.2, 6.3, 2.8 Hz, 2H), 1.58 (dtd, J = 9.2, 6.0, 2.9 Hz,
2H).
2-(4-Nitrophenyl)-1-phenylethanone (3l).27 Yield 95% (69 mg,
0.29 mmol). 1H NMR (400 MHz, CDCl3) δ 8.27−8.16 (m, 2H), 8.01
(dd, J = 8.4, 1.3 Hz, 2H), 7.61 (d, J = 7.4 Hz, 1H), 7.50 (t, J = 7.6 Hz,
2H), 7.44 (d, J = 8.8 Hz, 2H), 4.42 (s, 2H). 13C NMR (101 MHz,
CDCl3) δ 196.0, 142.0, 136.2, 133.8, 130.7, 128.9, 128.5, 123.8, 45.0.
1-(4-Bromophenyl)-2-(4-nitrophenyl)ethanone (3m).28 Yield
Oct-1-en-1-yl Acetate (2j).23 1H NMR (400 MHz, CDCl3) δ
7.05 (dt, J = 12.4, 1.4 Hz,1H), 6.99 (dt, J = 6.4, 1.5 Hz,0.7H), 5.40 (dt,
J = 12.4, 7.5 Hz, 1H), 4.86 (dd, J = 13.9, 7.4 Hz, 0.7H), 2.12 (d, J =
14.9 Hz, 7H), 1.99 (ddd, J = 9.6, 8.8, 5.9 Hz, 2H), 1.45−1.13 (m,
20H), 0.99−0.72 (m, 9H).
General Procedure C: Photocatalytic Arylation of Enol
Acetates. In a 5 mL snap vial 0.3 mmol of the aryl diazonium
tetrafluoroborate, 3.0 mmol (10 equiv) of the enol acetate, and 0.01
equiv [Ru(bpy)3]Cl2 were dissolved in 670 μL dry DMF. The vial was
sealed with a septum and degassed via the “freeze-pump-method”
(3×). The reaction mixture was stirred at 20 °C and irradiated for 2 h
using blue LEDs (440 nm). After the irradiation time the mixture was
diluted with water and washed three times with diethyl ether. The
combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuum. The resulting crude product was further
purified by column chromatography using a 3:1 mixture of petrol
ether/ethyl acetate as an eluent (Rf value changes from 0.4 to 0.6 for
all products). For GC analysis the samples were taken directly after
irradiation, diluted in a 1:1 mixture with the internal standard solution
and submitted to GC without further purification.
1
92% (88 mg, 0.28 mmol). H NMR (400 MHz, CDCl3) δ 8.35−8.05
(m, 2H), 7.96−7.77 (m, 2H), 7.72−7.56 (m, 2H), 7.42 (d, J = 8.8 Hz,
2H), 4.38 (s, 2H). 13C NMR (101 MHz, CDCl3) δ 195.0, 141.5,
134.9, 132.3, 130.6, 130.0, 123.9, 44.9.
1-(4-Methoxyphenyl)-2-(4-nitrophenyl)ethanone (3n).28
Yield 96% (78 mg, 0.29 mmol). 1H NMR (400 MHz, CDCl3) δ
8.25−8.11 (m, 2H), 8.06−7.89 (m, 2H), 7.44−7.35 (m, 2H), 7.05−
6.90 (m, 2H), 4.35 (s, 2H), 3.87 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 194.5, 163.9, 146.9, 142.5, 130.8, 130.5, 129.1, 123.6, 114.0,
55.5, 44.6.
2-(4-Nitrophenyl)-1-(thiophen-2-yl)ethanone (3o).28 Yield
1
79% (0.59 mg, 0.24 mmol). H NMR (400 MHz, CDCl3) δ 8.27−
8.14 (m, 2H), 7.81 (dd, J = 3.8, 1.1 Hz, 1H), 7.71 (dd, J = 5.0, 1.1 Hz,
1H), 7.48 (d, J = 8.8 Hz, 2H), 7.18 (dd, J = 4.9, 3.8 Hz, 1H), 4.32 (s,
2H).
1-(4-Nitrophenyl)propan-2-one (3a).6b Yield 90% (49 mg, 0.27
mmol). 1H NMR (400 MHz, CDCl3) δ 8.23−8.09 (m, 2H), 7.32 (dd,
J = 9.0, 2.2 Hz, 2H), 3.80 (s, 2H), 2.20 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 204.1, 147.1, 141.5, 130.5, 123.8, 50.1, 29.9.
2-(4-Nitrophenyl)pentan-3-one (3p). Compound is a colorless
1
to pale yellow oil. Yield 33% (21 mg, 0,10 mmol). H NMR (400
MHz, CDCl3) δ 8.27−8.10 (m, 2H), 7.47−7.33 (m, 2H), 3.91 (q, J =
7.0 Hz, 1H), 2.42 (qd, J = 7.3, 4.1 Hz, 2H), 1.44 (d, J = 7.0 Hz, 3H),
0.99 (t, J = 7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 209.8, 148.1,
147.1, 128.7, 124.0, 52.3, 34.9, 17.7, 7.8. HRMS (EI-MS) m/z: [M]+
calcd for C11H13NO3 207.0895; found 207.0895.
1-(2-Nitrophenyl)propan-2-one (3b).6b Yield 60% (36 mg, 0.20
mmol). 1H NMR (400 MHz, CDCl3) δ 8.12 (dd, J = 8.2, 1.2 Hz, 1H),
7.60 (td, J = 7.5, 1.2 Hz, 1H), 7.53−7.39 (m, 1H), 7.38−7.17 (m, 1H),
4.12 (s, 2H), 2.33 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 203.6,
133.6, 133.6, 130.4, 128.5, 125.3, 48.6, 30.0.
2-(4-Nitrophenyl)cyclohexanone (3q).5a Yield 35% (23 mg,
1
1-(3-Nitrophenyl)propan-2-one (3c).24 Yield 55% (30 mg, 0.17
0.11 mmol). H NMR (400 MHz, CDCl3) δ 8.23−8.13 (m, 2H),
1
7.36−7.27 (m, 2H), 3.73 (dd, J = 12.6, 5.3 Hz, 1H), 2.61−2.43 (m,
2H), 2.31 (ddd, J = 13.0, 5.5, 3.0 Hz, 1H), 2.26−2.16 (m, 1H), 2.11−
1.94 (m, 2H), 1.93−1.75 (m, 2H). 13C NMR (101 MHz, CDCl3) δ
207.7, 145.9, 145.3, 128.6, 122.5, 56.3, 41.2, 34.2, 26.7, 24.3.
mmol). H NMR (400 MHz, CDCl3) δ 8.18−8.08 (m, 1H), 8.06 (s,
1H), 7.57−7.47 (m, 2H), 3.85 (s, 2H), 2.25 (s, 3H). 13C NMR (101
MHz, CDCl3) δ 204.4, 148.4, 135.9, 135.9, 129.5, 124.5, 122.2, 49.7,
29.9.
2-(4-Nitrophenyl)acetaldehyde (3r).29 Yield 26% (13 mg, 0.08
1-(2-(Trifluoromethyl)phenyl)propan-2-one (3d).6b Yield 59%
1
1
mmol). H NMR (400 MHz, CDCl3) δ 9.78 (s, 1H), 8.19 (d, J = 8.7
(39 mg, 0.19 mmol). H NMR (300 MHz, CDCl3) δ 7.66 (d, J = 7.8
Hz, 2H), 7.35 (d, J = 8.7 Hz, 2H), 3.83 (d, J = 1.6 Hz, 2H). 13C NMR
(101 MHz, CDCl3) δ 197.1, 139.3, 130.6, 124.1, 50.0.
Hz, 1H), 7.52 (t, J = 7.3 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.27 (d, J =
7.4 Hz, 1H), 3.91 (d, J = 0.9 Hz, 2H), 2.21 (s, 3H).
2-(2-Nitrophenyl)-1-phenylethanone (3t).30 Yield 70% (51 mg,
0.21 mmol). 1H NMR (400 MHz, CDCl3) δ 8.16 (d, J = 7.8 Hz, 1H),
8.04 (d, J = 7.4 Hz, 2H), 7.62 (t, J = 7.4 Hz, 2H), 7.50 (dd, J = 14.9,
7.4 Hz, 3H), 7.35 (d, J = 7.5 Hz, 1H), 4.74 (s, 2H). 13C NMR (75
MHz, CDCl3) δ 195.4, 136.5, 134.0, 133.7, 133.5, 130.7, 128.9, 128.8,
128.4, 128.3, 127.8, 125.33, 77.5, 77.0, 76.6, 44.2.
2-(2-Oxopropyl)benzonitrile (3e).6b Yield 75% (36 mg, 0.23
mmol). 1H NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 7.7, 1.1 Hz, 1H),
7.55 (td, J = 7.7, 1.4 Hz, 1H), 7.43−7.33 (m, 1H), 7.33−7.27 (m, 1H),
3.97 (s, 2H), 2.28 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 203.5,
138.2, 132.9, 132.8, 130.9, 127.7, 117.8, 113.4, 48.6, 30.1.
Ethyl 4-(2-Oxopropyl)benzoate (3f).7l Yield 50% (34 mg, 0.15
1
1-(4-Bromophenyl)-2-(2-nitrophenyl)ethanone (3u). Com-
pound is a pale yellow solid. Mp: 83−86 °C. Yield 67% (46 mg,
0.56 mmol). 1H NMR (400 MHz, CDCl3) δ 8.18 (dd, J = 8.2, 1.2 Hz,
1H), 7.95−7.86 (m, 2H), 7.70−7.64 (m, 2H), 7.62 (dd, J = 7.5, 1.3
Hz, 1H), 7.56−7.47 (m, 1H), 7.39−7.31 (m, 1H), 4.69 (s, 2H). 13C
NMR (75 MHz, CDCl3) δ 194.5, 148.9, 135.2, 133.7, 133.66, 132.1,
130.3, 129.8, 128.7, 128.6, 125.4, 44.1. HRMS (ESI-TOF) m/z: [M +
Na]+ calcd for C14H10NO3BrNa 341.9741 ; found 341.9736.
mmol). H NMR (400 MHz, CDCl3) δ 8.11−7.94 (m, 2H), 7.31−
7.17 (m, 2H), 4.36 (q, J = 7.1 Hz, 2H), 3.75 (s, 2H), 2.16 (s, 3H), 1.38
(t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 205.3, 166.4,
139.2, 129.9, 129.5, 129.4, 61.0, 50.7, 29.5, 14.3.
1-(4-Chlorophenyl)propan-2-one (3g).6b Yield 61% (31 mg,
1
0.18 mmol). H NMR (400 MHz, CDCl3) δ 7.33−7.27 (m, 2H),
7.16−7.04 (m, 2H), 3.67 (s, 2H), 2.16 (s, 3H). 13C NMR (101 MHz,
CDCl3) δ 205.6, 133.1, 132.6, 130.8, 128.9, 50.1, 29.4.
10350
dx.doi.org/10.1021/jo301984p | J. Org. Chem. 2012, 77, 10347−10352

The Journal of Organic Chemistry
Article
2-(2-Nitrophenyl)-1-(thiophen-2-yl)ethanone (3v). Com-
pound is an orange oil. Yield 62% (65 mg, 0.20 mmol) H NMR
AUTHOR INFORMATION
Corresponding Author
*E-mail: Burkhard.Koenig@chemie.uni-regensburg.de.
Notes
■
1
(400 MHz, CDCl3) δ 8.15 (dd, J = 8.2, 1.0 Hz, 1H), 7.86 (dd, J = 3.8,
0.8 Hz, 1H), 7.69 (dd, J = 4.9, 0.8 Hz, 1H), 7.62 (m, 1H), 7.56−7.43
(m, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.19 (dd, J = 4.8, 3.9 Hz, 1H), 4.67
(s, 2H). 13C NMR (101 MHz, CDCl3) δ 188.1, 143.3, 134.1, 133.7,
133.5, 132.4, 123.0, 128.6, 128.2, 125.3, 44.4. HRMS (ESI-TOF) m/z:
[M + H]+ calcd for C14H10NO3BrH+ 248.0376 ; found 248.0381.
General Procedure D: Reductive Cyclization. Indoles were
prepared using a procedure described by Raucher and Koolpe.5b In a
50 mL round-bottom flask were dissolved 0.5 mmol of the ketone, 1.7
mmol (3.5 equiv) iron powder, and 0.5 mmol (1 equiv) sodium
acetate in 3.5 mmol (7 equiv) acetic acid and 10 mL of 80:20 (v/v)
ethanol/water. The mixture was heated to reflux under an atmosphere
of nitrogen. After a reaction time of 2 h, the reaction mixture was
cooled to room temperature, ethanol was evaporated, and the residue
was extracted three times with dichloromethane. The organic layer
were combined, washed with water and brine, and dried over
potassium carbonate. Dichloromethane was evaporated, and the crude
product was purified by column chromatography using a 1:1 mixture
of hexane/dichloromethane containing 1−2% triethylamine as an
eluent. To extract the residual triethylamine, the collected fraction was
washed with 2 M HCl.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the GRK 1626 (Chemical
Photocatalysis) of the German Science Foundation (DFG).
T.H. thanks the Max-Weber-Program for a scholarship.
REFERENCES
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