Friedel-crafts arylation of α-hydroxy ketones: Synthesis of 1,2,2,2-tetraarylethanones

Article abstract of DOI:10.1002/ejoc.201403438

Friedel-Crafts arylation of α-hydroxy ketones such as 2-hydroxy-1,2,2-triarylethanones has been achieved with a variety of arenes and heteroarenes in the presence of Lewis or Bronsted acids. Both sterically hindered and unhindered 1,2,2,2-tetrarylethanone

Full text of DOI:10.1002/ejoc.201403438

Job/Unit: O43438
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Date: 12-01-15 15:55:32
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FULL PAPER
DOI: 10.1002/ejoc.201403438
Friedel–Crafts Arylation of α-Hydroxy Ketones: Synthesis of 1,2,2,2-
Tetraarylethanones
Anil Kumar,[a][‡] Tej V. Singh,*[a] and Sajesh P. Thomas,[b][‡‡] and Paloth Venugopalan*[a]
Keywords: Synthetic methods / Arylation / Ketones / Carbocations
Friedel–Crafts arylation of α-hydroxy ketones such as 2-hy-
droxy-1,2,2-triarylethanones has been achieved with a vari-
ety of arenes and heteroarenes in the presence of Lewis or
Brønsted acids. Both sterically hindered and unhindered
1,2,2,2-tetrarylethanones are formed in good to excellent
yields by using a stoichiometric amount of triflic acid. The
intermediacy of an α-keto carbenium ion has been proposed.
Introduction
of ligands,[6] the economic viability of the method is debat-
able.[7] Moreover, a strong base is required to generate the
ketone enolate and the coupling partner has to be an aryl
halide.
α-Aryl carbonyl compounds are one of the most impor-
tant synthetic targets for the production of pharmaceuti-
cals.[1] A number of nonsteroidal anti-inflammatory drugs
such as (S)-(+)-ibuprofen and dichlofenac contain α-aryl
carbonyl moieties.[2] The α,α-diarylethanone moiety has
been uncovered during the synthesis of skeletal analogues
of Tamoxifen, a drug used for the treatment of estrogen
receptor-positive breast cancer,[3] and the α,α,α-triaryl carb-
onyl compound triphenylmethylamide has been shown to
exhibit anticancer activity against metastatic melanoma.[4]
Considering the importance of α-arylated carbonyl com-
pounds, arylation at the α-position to the carbonyl group is
clearly important. Various methods are in use for the α-
arylation of carbonyl compounds.[5] The synthetic pro-
cedures of α-aryl and α,α-diaryl carbonyl compounds are
well documented and include sp3C–H monoarylation and
diarylation.[6] In this case, the reaction of the enolate of the
ketone with aryl halide is carried out in the presence of
palladium catalyst to give the α-arylated product. The aryl
halide acts as electrophile and the enolate behaves as a nu-
cleophile. However, given that this strategy involves the
combination of costly palladium as catalyst and a variety
Friedel–Crafts reaction of alcohols is another method
that can be used to introduce an aryl group.[8] In this case,
the role of the reactant is the reverse of that described
above. Substrates behave as electrophile and the arylating
reagent acts as nucleophile. This method is in line with
green chemistry principles because water is the only side
product. The principal intermediate in such a reaction is a
carbocation, therefore, electron-releasing groups can en-
hance the rate of reaction by stabilising the carbocation in-
termediate.[9] This method is thus generally applicable to
electron-rich alcohols only. Recently, we have developed a
strategy for the synthesis of α-functionalised ketones such
as α-fluoro ketones[10] and α-azido ketones[11] from tertiary
α-hydroxy ketones. It has been shown in these conversions
that alcohols are activated toward nucleophilic substitution
by the interaction of Lewis acid or Brønsted acid. Treat-
ment of 2-hydroxy-1,2,2-triarylethanones with a selected
acid can cleave the hydroxyl group to form an α-keto carb-
enium ion. Such intermediates have been trapped by nucleo-
philes such as fluoride and azide ions. From these results,
it has been conclusively shown that electron-releasing
groups at the cationic centre are not essential for the reac-
tion. In this context, we felt that it was worth exploring the
[a] Department of Chemistry and Centre of Advanced Studies in
Chemistry, Panjab University,
Chandigarh 160014, India
E-mail: tvs@pu.ac.in
Friedel–Crafts
arylation
of
2-hydroxy-1,2,2-triaryl-
venu@pu.ac.in
ethanones to obtain 1,2,2,2-tetraarylethanones.
http://chemistry.puchd.ac.in/show-biodata.php?
qstrempid=5000&qstrempdesigcode=67
[b] Solid State and Structural Chemistry Unit, Indian Institute of
Science,
1,2,2,2-Tetraarylethanones belong to the category of α-
triaryl-substituted ketones/α-quaternary ketones. The
method used to synthesise α-quaternary centres mainly in-
volves acid catalysed nucleophilic substitution of tertiary
alcohols through Friedel–Crafts reactions.[12] However, re-
ported methods for the synthesis of 1,2,2,2-tetraaryl-
ethanones are scant.[13] Indeed, to our knowledge, there is
only a single method available in literature; Zhou et al. has
Bangalore 560012, India
[‡] Present address: University Institute of Engineering and
Technology, Panjab University,
Chandigarh 160014, India
[‡‡] Present address: School of Chemistry and Biochemistry,
University of Western Australia, Crawley, WA 6009, Australia
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403438.
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A. Kumar, T. V. Singh, S. P. Thomas, P. Venugopalan
FULL PAPER
reported a contemporaneous work to synthesise α-quater- product was characterised as 2-(4-methoxyphenyl)-1,2,2-tri-
nary ketones by Friedel–Crafts reaction of tertiary α-hy- phenylethanone (2a).
droxy ketones.[14] In this case also, the strong stabilising ef-
To study the effect of temperature on arylation, the reac-
fect of the electron-releasing group was crucial for the suc- tion was carried out at 40 °C by using 10 mol-% TfOH
cess of the reaction. Therefore, the substrate scope of the (Table 1, entry 2). The reaction mixture was heated to reflux
reaction was limited to α-hydroxy ketones having a p-meth- for 5 h, whereupon TLC analyses of the contents showed
oxyphenyl ring at the carbon bearing the hydroxyl group. the complete disappearance of 1a. The product 2a was iso-
To circumvent this limitation, we herein report an efficient lated in 92% yield after standard workup and purification.
method for the Friedel–Crafts reaction of tertiary α- In another experiment, when the reaction was carried out
hydroxy ketones without any restriction on the aryl substi- with one equivalent of TfOH at room temperature, it was
tution, to furnish a broader class of α-triaryl-substituted complete in five minutes (entry 3). Therefore an equimolar
ketones.
stoichiometric ratio of the substrate to acid was selected for
all other acids (entries 4–11). The reaction showed efficient
conversion of the substrate into the product. Other acids
such as TiCl4, BF3·OEt2, TMSOTf and H2SO4 were equally
effective, albeit after a slightly increased reaction time. In
the case of PTSA, ZnCl2 and H3PO4, the reaction did not
occur and the starting material was recovered unchanged.
It seems that these acids are not efficient for generating the
α-keto carbenium ion. These results, summarised in Table 1,
show that use of one equivalent of TfOH at room tempera-
ture is optimal (entry 3); these conditions are also appropri-
ate in the context of green chemistry.
After optimising the reaction conditions, a variety of ar-
ene nucleophiles including phenol, toluene, azulene, o-xyl-
ene, 1,4-dimethoxybenzene, triptycene, and heteroarene nu-
cleophiles such as furan and indole were used. Treatment
of 2-hydroxy-1,2,2-triphenylethanone (1a) with these nu-
cleophiles using one equivalent of triflic acid at room tem-
Results and Discussion
Brønsted or Lewis acids can cleave the C–OH bond in
2-hydroxy-1,2,2-triarylethanone to form the 1,2,2-triaryl-α-
keto carbenium ion. The carbenium ion behaves as an elec-
trophile, reacting with the arene nucleophile to produce
1,2,2,2-tetraarylethanones. A variety of Brønsted acids such
as trifluoromethanesulfonic acid (triflic acid or TfOH), p-
toluenesulfonic acid (PTSA), sulfuric acid (H2SO4), tri-
fluoroacetic acid (TFA), phosphoric acid (H3PO4), and
Lewis acids such as titanium tetrachloride (TiCl4), boron
trifluoride etherate (BF3·OEt2), trimethylsilyl trifluoro-
methanesulfonate (TMSOTf) and zinc chloride (ZnCl2) were
selected for the above reaction. In a preliminary experi-
ment, a solution of 2-hydroxy-1,2,2-triphenylethanone (1a)
in anhydrous CH2Cl2 containing anisole was used in the
presence of trifluoromethanesulfonic acid (10 mol-%)
(Table 1, entry 1). The reaction mixture became red imme-
diately. After stirring at room temperature for 72 h, the re-
action was quenched with water, and standard workup and
purification by flash chromatography gave the product
(68% yield). Based on a range of spectroscopic data, the
Table 2. Reaction of 2-hydroxy-1,2,2-triphenylethaone (1a) with
different nucleophiles.[a]
Table 1. Optimisation of reaction conditions for the arylation of 2-
hydroxy-1,2,2-triphenylethanone with anisole.[a]
Entry Acid (quantity)
Time
Temp. [°C] Yield [%][b]
1
2
3
4
5
6
7
8
TfOH (10 mol-%)
TfOH (10 mol-%)
TfOH (1 equiv.)
TMSOTf (1 equiv.)
TiCl4 (1 equiv.)
BF3OEt2 (1 equiv.)
H2SO4 (1 equiv.)
TFA (1 equiv.)
72 h
5 h
25
40
25
25
25
25
25
25
25
25
25
68
92
94
89
88
91
85
24
0
5 min
15 min
15 min
10 min
20 min
12 h
12 h
12 h
12 h
9
10
11
PTSA (1 equiv.)
ZnCl2 (1 equiv.)
H3PO4 (1 equiv.)
0
0
[a] Reactions were performed on 0.35 mmol scale of 2-hydroxy- [a] Reactions were performed on 0.35 mmol scale of 2-hydroxy-
1,2,2-triphenylethanone in CH2Cl2 (5 mL) and anisole
(0.52 mmol). [b] Isolated yield after flash chromatography.
1,2,2-triphenylethanone in CH2Cl2 (5 mL) and anisole
(0.52 mmol). Isolated yields after flash chromatography.
2
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Friedel–Crafts Arylation of α-Hydroxy Ketones
perature gave products 3–10 (Table 2). All arenes, including
heteroarenes, were well tolerated, and could be used to con-
vert 1a into a variety of arylated products in moderate to
good yields. Lower yields of 3, 6 and 8 were recorded, which
may be because, compared with anisole, phenol, toluene
and o-xylene are weak nucleophiles. The lower yield of 5
may be due to the interaction of acid with the heteroarene
indole. All new compounds were characterised based on
their spectroscopic data.
Ketones 3, 7 and 10, with α-substituents such as 4-
hydroxyphenyl, azulenyl and triptycenyl, are high-melting
solids because of the presence of strong intermolecular
hydrogen bonds, π interactions and symmetric structure in
their packing, respectively (vide infra). The carbonyl
stretching frequencies in all ketones are characteristic of
conjugated aryl ketones in the range of 1672–1693 cm–1.
The very low carbonyl frequency at 1662 cm–1 observed for
3 is unusual. The higher value for νC=O in 4 (1689 cm–1)
and 9 (1693 cm–1) clearly shows that the α-substituents lead
to a significantly reduced conjugation with the phenyl
group and/or an electronic effect of the added substituent.
The 1H NMR spectra of 3–10 displayed signals in the range
of δ = 7.4–7.9 ppm for aromatic protons and peaks for
other substituents at expected chemical shifts. The 13C
NMR spectra of these ketones showed carbonyl carbon sig-
nals in the range δ = 197 and 200.4 ppm. Interestingly, com-
pound 9 displayed higher δ values (200.4 ppm) for 13C
NMR chemical shifts (C=O) and also showed higher IR
νC=O frequency. This suggests that the substituent 2,5-di-
methoxyphenyl in 9 has a significant and similar effect in
IR and 13C NMR spectroscopy.
Figure 2. ORTEP of 2-(2-azulenyl)-1,2,2-triphenylethanone (7).
Electrospray ionisation (ESI) mass spectra of 2a and 3–
10 were also recorded (Figure 1). The spectra of all the
ketones showed either no [M + 1] ion peak or a very weak
signal; except for 7, which has a stable azulenyl substituent.
The MS of the latter compound showed a very strong [M
+ 1] ion (49%) at m/z 399, probably due to its high energy
Figure 3. ORTEP of 2-(2-triptycenyl)-1,2,2-triphenylethanone (10).
In the case of 10, molecules of ethyl acetate and water as
of decomposition. Ketones, except 2a, showed a base peak solvent of crystallisation were included in the crystal lattice.
for the triaryl keto carbenium ion (A) formed by the neutral It is interesting to note that the phenyl group attached to
loss of the nucleophile (Figure 1). Ketone 2a showed a base the carbonyl moiety is nearly in plane with the carbonyl
peak at m/z 243, suggesting a facile loss of the p-anisyl ring group, which allows maximum resonance stabilisation en-
followed by CO to give stable triphenylmethyl carbocation ergy to be derived, as evidenced from the torsion angle of
B (Figure 1).
–12.73° (C3–C2–C1-O1) in 7 and 18.15° (C4–C3–C2-O1) in
10 (see Figures 2 and 3). The deviation from the ideal angle
of zero degrees is due to the packing constrains of the re-
spective lattices.
Although there is a strong hydrogen-bond acceptor moi-
ety (ϾC=O) present in 7, the lack of any strong hydrogen-
bond donor groups (such as –NH2, –OH etc.) allows only
interactions of the type C–H···O and C–H···π to operate
and stabilise the lattice. Indeed, two molecules of 7, related
Figure 1. Mass spectral fragments of 1,2,2,2-tetraarylethanones.
To unambiguously characterise the products 7 and 10, by inversion symmetry, form a centrosymmetric dimer with
good-quality crystals were obtained, and single-crystal X- C–H···O interactions [H(26A)···O1 2.667 Å, C26–
=
ray structure analyses were performed. Both compounds 7 H(26A)···O1 = 124.3°] as shown in Figure 4. In addition to
and 10 crystallised as triclinic crystal systems (space group this weak C–H···O hydrogen bond, a C–H···π interaction is
¯
P1) with two molecules in the unit cell. Their ORTEP dia- also observed between the phenyl ring (C19–C24) and
grams with atom numbering scheme employed are shown H(28A) [H(28A)···centroid of C19–24 ring = 3.070 Å and
in Figures 2 and 3 respectively.
C28–H(28A)···centroid = 154.4°].
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A. Kumar, T. V. Singh, S. P. Thomas, P. Venugopalan
FULL PAPER
triflic
acid
(1 equiv.)
to
give
1,2,2,2-tetraaryl-
ethanones 2b–j (Table 3).
α-Hydroxy ketones except 1h and 1i gave tetraaryl-
ethanones in very good yield. In the case of 1h and 1i, for-
mation of the corresponding benzofuran derivatives 11
(63%) and 12 (46%) was observed (Scheme 1). The naph-
thyl ring with extended conjugation and anisyl ring (elec-
tron rich) are present at the carbon bearing the hydroxy
group in 1h and 1i, respectively. These two rings stabilise
the α-keto carbenium ion effectively. Therefore such α-keto
carbenium ions underwent intramolecular rearrangement
(4π cyclisation) to give benzofuran derivatives as shown in
Scheme 2. This conclusion finds support from the fact that
formation of the benzofuran derivative did not occur in 1f,
having an anisyl ring on the carbonyl carbon. In the case
of 1j, the conformation of the carbenium may be such that
the intramolecular arylation (4π cyclisation) to give the cor-
responding benzofuran is not feasible.
The high yield of benzofuran derivatives prompted us to
study the reactivity of α-hydroxy ketone 1i with nucleo-
philes other than anisole. Thus, instead of anisole, furan
was selected as the nucleophile for the dehydrative nucleo-
philic substitution of 1i. Interestingly, the reaction of 1i
with furan yielded only furyl-substituted ethanone 13, and
formation of the corresponding benzofuran 12 was not ob-
served (Scheme 3). From this experiment, it was inferred
that the reactivity of 1i can be tuned by appropriate choice
of the nucleophile.
Figure 4. Centrosymmetric dimer formation in 7 through C–H···O
interaction.
In the case of 10, the carbonyl moiety is engaged in O–
H···O hydrogen-bonding with the occluded water molecule
(O1···O4 distance 2.911 Å). Because of the tripodal fan-like
disposition of the three benzene rings in 10, channels run-
ning parallel to the bc plane are formed during its crystalli-
sation, which are occupied by ethyl acetate and water mol-
ecules as shown in Figure 5. As the molecule is endowed
with many aromatic rings, multiple lattice-stabilising C–
H···π interactions are observed. H(25A) makes a contact of
2.939 Å with the centroid of the C19–C24 aromatic ring
(respective C–H···π angle 171.3°). The centroid of aromatic
ring C21–C34 has a contact of 2.939 Å with H(5A) [C5–
H(5A)···centroid angle 153.8°]. The third C–H···π interac-
tion is between the centroid of the C9–C14 ring and H(30A)
with a distance of 2.526 Å and an angle of 137.8°. No π···π
interactions were observed in these molecules.
Tetraarylethanones 2b–j and benzofuran derivatives 11
and 12 were characterised based on their physical and spec-
troscopic data (see Exp. Section). The benzofuran deriva-
tives 11 and 12 have melting points that are consistent with
the reported values. Ketones 2b–j melt in the range of 53–
80 °C, whereas compound 2h has a melting point of 148–
149 °C. The higher melting point of the latter may be due
to π stacking in tight molecular packing of the naphthyl
ring in 2h. The νC=O absorptions in all ketones are in the
range 1671–1691 cm–1. Although aryl ketones have absorp-
tions in the IR spectrum at 1680 cm–1, the lowest frequency
for the carbonyl group at 1671 cm–1 for 2f suggests a promi-
nent resonance effect of the p-OMe group, bringing con-
1
siderable single bond character to the C=O group. The H
NMR spectra of all ketones displayed signals in the range
of δ = 7.5–7.7 ppm for aromatic protons and peaks for
other substituents at expected δ values. Similarly, the 13C
NMR spectra showed expected signals in the range of δ =
197–201 ppm for carbonyl carbon atoms. In the ESI mass
spectra of 2b–j, the [M + 1] ion was absent in all ketones
except for ketones 2f and 2g, for which it was 4.5 and 3.0%,
respectively. Interestingly, all ketones except 2h showed their
base peak by the loss of anisole ring to form triaryl-α-keto
Figure 5. Packing of molecules of 10 down the a axis. Note the
channel in the middle of the diagram, which is occupied by disor-
dered ethyl acetate and water.
With a view to study the substrate scope of this reaction, carbenium ion A (Figure 1). In the case of 2h, the base peak
a range of 2-hydroxy-1,2,2-triarylethanones 1b–j were syn- is formed by the loss of the larger naphthyl ring.
thesised from symmetrical and unsymmetrical benzils. The
Although the stoichiometric amount of water produced
reaction of α-hydroxy ketones 1b–j with arene or heteroar- in the reaction can deactivate the catalyst and retard the
ene expands the scope of the Friedel–Crafts arylation reac- rate of reaction, the time taken to complete the reaction
tion to give tetraarylethanones. Various α-hydroxy ketones was much less (maximum 40 min). From a standpoint of
were treated with anisole (1.5 equiv.) in the presence of applicability, it is important to note that the method allows
4
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Friedel–Crafts Arylation of α-Hydroxy Ketones
Table 3. Friedel–Crafts arylation of 2-hydroxy-1,2,2-triarylethanones with anisole.[a]
[a] Reactions were performed on 100 mg scale of 2-hydroxy-1,2,2-triarylethanones in CH2Cl2 (5 mL) and anisole (1.5 equiv.). [b] Isolated
yield after flash chromatography. [c] The corresponding rearranged benzofuran derivatives 11 (63%) and 12 (46%) are also formed (see
Scheme 2).
Scheme 1. Reaction of 1h and 1i with anisole using CF3SO3H.
the use of an electron-withdrawing carbonyl group bonded keto carbenium ion was first reported by Karavan and Tem-
to the carbon bearing a hydroxyl group. There is no need nikova during the solvolysis of 2-bromo-1,2,2-triphenyl-
to overcome, neutralise or compensate this effect by placing ethanone in methanol to give 2-methoxy-1,2,2-triphenyl-
an electron-releasing group at the cationic centre. Thus, it ethanone.[16] Its isolation as a carbonyl-substituted carb-
is significant that 2-hydroxy-1,2,2-triarylethanones can be enium ion salt was reported by Takeuchi and co-workers.[17]
arylated at the α-position, despite the decreased stability of The formation of a α-keto carbenium ion may occur cata-
the α-keto carbenium ion.[15] The intermediacy of the α- lytically by the interaction of acid (CF3SO3H) with α-hy-
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A. Kumar, T. V. Singh, S. P. Thomas, P. Venugopalan
FULL PAPER
strate and nucleophiles work well without the presence of
electron-releasing groups. This method is practical and con-
venient because it requires no additional catalyst (ligand)
and works in the presence of atmospheric oxygen. The con-
ditions are mild (room temperature) and the reactions reach
completion in short reaction times. Thus, an efficient strat-
egy for the synthesis of an important class of α-triaryl-
carbonyl compounds has been put forward.
Experimental Section
General: Melting points were recorded in open capillaries and are
uncorrected. IR spectra were recorded with a Perkin–Elmer IR
1
1800 spectrophotometer. H and 13C NMR spectra were recorded
in CDCl3 solutions with a Bruker Avance 400 spectrometer op-
erating at 400 and 100.52 MHz, respectively. Chemical shifts (δ) are
reported in parts per million downfield from internal tetramethyl-
silane. Coupling constants (J) are in Hertz (Hz). Mass spectra were
obtained with a Waters Q-ToF Micro mass spectrometer running
under Mass Lynx version 4.0 software and equipped with an ESI
source. CHN analyses were estimated with a Flash 2000 series
CHNS-O Analyser from Thermo Scientific. X-ray crystallography
was performed with an Oxford Xcalibur (Mova) diffractometer
equipped with an Eos CCD detector using Mo-Kα radiation of
wavelength 0.71073 Å. TLC analyses were carried out by using alu-
minium-backed plates pre-coated with silica gel purchased from
Merck and examined under UV florescence. All the compounds
were purified by preparative flash chromatography using hexane
and ethyl acetate as eluent. Flash chromatography was performed
by using 40–63 μm silica gel (230–400 mesh) and applying nitrogen
pressure from the top of the column.[20]
Scheme 2. Formation of benzofuran derivative from α-keto carb-
enium ion.
Scheme 3. Dehydrative nucleophilic substitution of 1i with furan as
nucleophile.
droxy ketones, which would cleave the hydroxyl group as
water. Subsequent reaction with nucleophile (ArH) would
give the product, α-substituted ketones and release the mo-
lecule of CF3SO3H. This stepwise mechanism is shown in
Scheme 4.[18] It is noteworthy that such an α-keto carb-
enium ion has been observed by reacting 2-hydroxy-1,2,2-
triphenylethanone with chlorosulfonic acid at –60 °C in
CDCl3 or CD2Cl2.[19]
General Procedure for the Optimisation of Lewis/Brønsted Acid; Ini-
tial Reaction Conditions for the Reaction of α-Hydroxy Ketones (1a)
with Anisole: A solution of 2-hydroxy-1,2,2-triphenylethanone (1a;
100 mg, 0.35 mmol) in anhydrous CH2Cl2 (5 mL) and anisole
(56 mg, 0.52 mmol) were placed in a 25 mL round-bottomed flask
fitted with guard tube. An appropriate amount of Lewis acid or
Brønsted acid (as detailed in Table 1) was added. The contents were
stirred at room temperature and the progress of reaction was moni-
tored by TLC analyses. After stirring the contents for the appropri-
ate time period, the reaction was quenched with water (1 mL). The
product was extracted with CH2Cl2 (3ϫ 15 mL), washed with 10%
Na2CO3 (20 mL), water (20 mL) and dried with anhydrous
Na2SO4. The solvent was removed under reduced pressure to give
a brownish oil. Isolation by flash chromatography afforded 2-(4-
methoxyphenyl)-1,2,2-triphenylethanone (2a; 24–94% yield) as a
white solid (mp. 134–135 °C). The identity of the product was con-
firmed based on its spectroscopic data.
Substitution of 1a with Arenes and Heteroarenes. General Procedure:
A
solution of 2-hydroxy-1,2,2-triphenylethanone (1a; 100 mg,
Scheme 4. Proposed mechanism for the arylaion of α-hydroxy
ketones.
0.35 mmol) in anhydrous CH2Cl2 (5 mL) and nucleophile
(1.5 equiv.) were placed in a 25 mL round-bottomed flask fitted
with
a guard tube. Trifluoromethanesulfonic acid (52.5 mg,
0.35 mmol, 1 equiv.) was added and the contents were stirred at
room temperature. The progress of the reaction was monitored by
TLC analysis. After stirring the contents for the appropriate time
period, the reaction was quenched with water (1 mL). The product
was extracted with CH2Cl2 (3ϫ 15 mL), washed with 10% Na2CO3
(20 mL), water (20 mL) and dried with anhydrous Na2SO4. Solvent
was removed under reduced pressure to give a brownish oil. Purifi-
cation and isolation by flash chromatography afforded the products
Conclusions
We have described an efficient protocol for the replace-
ment of the hydroxyl group in 2-hydroxy-1,2,2-triaryl-
ethanones with a variety of nucleophiles by using the Frie-
del–Crafts reaction. The approach provides a simple route
through which to access a broader class of α,α,α-triaryl-
substituted ketones in good to excellent yields. Both sub- 2a and 3–10 in 45–94% yield.
6
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Date: 12-01-15 15:55:33
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Friedel–Crafts Arylation of α-Hydroxy Ketones
2-(4-Methoxyphenyl)-1,2,2-triphenylethanone (2a): Yield 125 mg
2-(2-Azulenyl)-1,2,2-triphenylethanone (7): Yield 115 mg (83%);
bluish solid; m.p. 174–175 °C; Rf = 0.39 (hexane/ethyl acetate,
(94%); white solid; m.p. 134–135 °C (ref.[21] m.p. 135.0–135.5 °C);
R = 0.43 (hexane/ethyl acetate, 90:10). FTIR (KBr): ν = 3057,
10%). FTIR (KBr): ν = 3054, 3030, 2929, 1677 (CO), 1592, 1568,
˜
˜
f
3029, 2932, 2838, 1675 (CO), 1603, 1578, 1509, 1444, 1296, 1182,
1491, 1400, 1213, 1199, 1179 cm–1. 1H NMR (400 MHz, CDCl3):
1
1032 cm–1. H NMR (400 MHz, CDCl3): δ = 3.8 (s, 3 H, OCH3), δ = 6.81 (t, J = 9.9 Hz, 1 H, ArH), 6.94 (t, J = 7.8 Hz, 2 H, ArH),
6.83 (d, J = 8.9 Hz, 2 H, ArH), 7.15–7.35 (m, 15 H, ArH), 7.71 (d,
7.02 (t, J = 9.6 Hz, 1 H, ArH), 7.07–7.20 (m, 11 H, ArH), 7.26 (d,
J = 7.4 Hz, 2 H, ArH) ppm. 13C NMR (100.53 MHz, CDCl3): δ = J = 4.0 Hz, 1 H, ArH), 7.38 (t, J = 9.8 Hz, 1 H, ArH), 7.55 (d, J
55.2, 70.4, 113.2, 126.6, 127.6, 127.7, 130.8, 131.0, 131.6, 131.9,
135.1, 137.4, 143.5, 158.0, 199.0 ppm. ESI-MS: m/z (%) = 401 (3.1)
[M + Na], 379 (Ͼ1) [M + 1], 272 (17.3), 271 (90.1), 244 (17.9), 243
(100), 228 (3.4), 165 (17). C27H22O2: C, 85.69; H, 5.86; found C,
85.71; H, 5.84.
= 7.4 Hz, 2 H, ArH), 7.75 (d, J = 9.9 Hz, 1 H, ArH), 7.91 (d, J =
3.9 Hz, 1 H, ArH), 8.18 (d, J = 9.5 Hz, 1 H, ArH) ppm. 13C NMR
(100.53 MHz, CDCl3): δ = 68.1, 116.9, 122.9, 123.7, 126.3, 127.3,
127.6, 128.9, 130.6, 130.7, 131.4, 136.5, 137.2, 137.4, 137.6, 137.9,
139.7, 142.4, 144.4, 198.4 ppm. ESI-MS: m/z (%) = 421 (5.9) [M +
Na], 399 (48.7) [M + 1], 272 (18.2), 271 (100), 257 (5), 244 (8.9),
243 (50.3), 165 (6). C30H22O: C, 90.42; H, 5.56; found C, 90.52; H,
5.55.
2-(4-Hydroxyphenyl)-1,2,2-triphenyl Ethanone (3): Yield 70 mg
(56%); white solid; m.p. 171–172 °C; Rf = 0.24 (hexane/ethyl acet-
ate, 20%). FTIR (KBr): ν = 3542, 3053, 3029, 1662 (CO), 1595,
˜
1578, 1511, 1493, 1444, 1270, 1177, 1013 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 4.94 (br. s, 1 H, OH), 6.62 (d, J = 8.8 Hz,
2 H, ArH), 6.99 (d, J = 8.8 Hz, 2 H, ArH), 7.06–7.19 (m, 12 H,
ArH), 7.22 (t, J = 7.4 Hz, 1 H, ArH), 7.59 (d, J = 7.3 Hz, 2 H,
ArH) ppm. 13C NMR (100.53 MHz, CDCl3): δ = 70.4, 114.7,
126.6, 127.6, 127.8, 130.8, 131.1, 131.7, 132.1, 135.2, 137.4, 143.4,
154.2, 199.3 ppm. ESI-MS: m/z (%) = 387 (32.3) [M + Na], 365(3.4)
[M + 1], 272 (22), 271 (100), 244 (12.1), 243 (72.4), 165 (8.2).
C26H20O2: C, 85.69; H, 5.53; found C, 85.74; H, 5.54.
2-(3,4-Dimethylphenyl)-1,2,2-triphenylethanone (8): Yield 70 mg
(54%); white solid; m.p. 98–99 °C; Rf = 0.53 (hexane/ethyl acetate,
10%). FTIR (KBr): ν = 3057, 3022, 2955, 2923, 2870, 1682 (CO),
˜
1596, 1579, 1494, 1445, 1217, 1181, 1018 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 2.03 (s, 3 H, CH3), 2.10 (s, 3 H, CH3),
6.86–7.93 (m, 3 H, ArH), 7.01–7.05 (m, 2 H, ArH), 7.06–7.10 (m,
2 H, ArH), 7.11–7.18 (m, 9 H, ArH), 7.59 (d, J = 7.4 Hz, 2 H,
ArH) ppm. 13C NMR (100.53 MHz, CDCl3): δ = 19.4, 20.1, 70.8,
126.6, 127.6, 127.7, 128.3, 129.1, 130.9, 131.1, 131.6, 132.2, 135.1,
135.9, 137.6, 140.3, 143.5, 199.1 ppm. ESI-MS: m/z (%) = 399
(41.8) [M + Na], 377(6.0) [M + 1], 299 (6.2), 272 (21.9), 271 (100),
244 (4.6), 243 (33.8), 165 (2). C28H24O: C, 89.33; H, 6.43; found C,
89.35; H, 6.45.
2-(2-Furyl)-1,2,2-triphenyl Ethanone (4): Yield 105 mg (90%); white
solid; m.p. 114–115 °C; Rf = 0.51 (hexane/ethyl acetate, 10%).
FTIR (KBr): ν = 3061, 3034, 1689 (CO), 1592, 1577, 1493, 1445,
˜
1
1222, 1209, 1019 cm–1. H NMR (400 MHz, CDCl3): δ = 6.24 (d,
2-(2,5-Dimethoxyphenyl)-1,2,2-triphenylethanone (9): Yield 130 mg
(92%); white solid; m.p. 135–136 °C; Rf = 0.29 (hexane/ethyl acet-
J = 3.3 Hz, 2 H, ArH), 6.38 (dd, J = 3.3, 0.8 Hz, 2 H, ArH), 7.18–
7.21 (m, 4 H, ArH), 7.23–7.28 (m, 2 H, ArH), 7.30–7.36 (m, 6 H,
ArH), 7.39–7.43 (m, 2 H, ArH), 7.73 (d, J = 7.3 Hz, 2 H,
ArH) ppm. 13C NMR (100.53 MHz, CDCl3): δ = 67.0, 110.4,
111.0, 127.2, 127.8, 128.0, 129.8, 130.4, 132.1, 137.5, 142.1, 142.6,
154.9, 197.3 ppm. ESI-MS: m/z (%) = 361(7.2) [M + Na], 339 (Ͼ1)
[M + 1], 272 (20.2), 271 (100), 244 (13.4), 243 (83.1), 165 (7.9), 105
(4.8). C24H18O2: C, 85.18; H, 5.36; found C, 85.20; H, 5.37.
ate, 10%). FTIR (KBr): ν = 3058, 3032, 2957, 2935, 2835, 1693
˜
(CO), 1592, 1493, 1442, 1226, 1183, 1043 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 3.1 (s, 3 H, OCH3), 3.6 (s, 3 H, OCH3),
6.51 (d, J = 8.8 Hz, 1 H, ArH), 6.69 (dd, J = 8.8, 3.0 Hz, 1 H,
ArH), 6.81 (d, J = 3.0 Hz, 1 H, ArH), 7.03–7.07 (m, 6 H, ArH),
7.11–7.17 (m, 6 H, ArH), 7.20 (t, J = 7.3 Hz, 1 H, ArH), 7.47 (d,
J = 7.4 Hz, 2 H, ArH) ppm. 13C NMR (100.53 MHz, CDCl3): δ =
55.0, 55.5, 67.8, 111.9, 112.0, 117.2, 126.5, 127.1, 127.2, 129.5,
130.9, 131.3, 133.5, 138.9, 143.6, 151.5, 153.6, 200.4 ppm. ESI-MS:
m/z (%) = 431 (4.2) [M + Na], 409 (2.0) [M + 1], 272 (24), 271
(100), 244 (9.6), 243 (58.3), 165 (6.4). C28H24O3: C, 82.33; H, 5.92;
found C, 82.37; H, 5.91.
2-(1H-Indol-3-yl)-1,2,2-triphenyl Ethanone (5): Yield 60 mg (45%);
white solid; m.p. 118–119 °C; Rf = 0.35 (20%, hexane/ethyl acet-
ate). FTIR (KBr): ν = 3399, 3055, 1672 (CO), 1595, 1491, 1445,
˜
1243, 1216, 1180, 1035 cm–1. 1H NMR (400 MHz, CDCl3): δ =
6.77 (t, J = 7.4 Hz, 1 H, ArH), 6.76–6.81 (m, 2 H, ArH), 6.96 (t,
J = 7.4 Hz, 1 H, ArH), 7.02 (t, J = 7.7 Hz, 2 H, ArH), 7.06–7.20
(m, 12 H, ArH), 7.64 (d, J = 7.3 Hz, 2 H, ArH), 8.04 (br. s, 1 H,
NH) ppm. 13C NMR (100.53 MHz, CDCl3): δ = 66.2, 111.2, 118.4,
119.6, 122.1, 122.2, 125.0, 126.7, 127.3, 127.6, 127.8, 130.4, 131.0,
131.8, 136.4, 137.7, 142.9, 199.1 ppm. ESI-MS: m/z (%) = 410 (3.0)
[M + Na], 388 (2.0) [M + 1] 272 (18.7), 271 (100), 244 (11.8), 243
(72), 165 (8.5). C28H21NO: C, 86.79; H, 5.46; N, 3.61; found C,
86.78; H, 5.48; N, 3.60.
2-(2-Triptycenyl)-1,2,2-triphenylethanone (10): Yield 110 mg (60%);
white solid; m.p. 219–220 °C; Rf = 0.31 (hexane/ethyl acetate, 10%).
FTIR (KBr): ν = 3062, 3022, 2962, 2924, 1685 (CO), 1595, 1491,
˜
1468, 1457, 1444, 1211, 1181 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 5.17 (s, 1 H, -CH), 5.29 (s, 1 H, -CH), 6.72 (dd, J = 7.8, 1.8 Hz,
1 H, ArH), 6.86–6.92 (m, 4 H, ArH), 6.97 (t, J = 7.8 Hz, 2 H,
ArH), 7.06–7.17 (m, 13 H, ArH), 7.20–7.23 (m, 2 H, ArH), 7.24–
7.27 (m, 2 H, ArH), 7.47 (d, J = 7.4 Hz, 2 H, ArH) ppm. 13C NMR
(100.53 MHz, CDCl3): δ = 53.6, 54.0, 71.0, 122.8, 123.6, 123.7,
125.0, 125.1, 126.0, 126.6, 127.5, 127.7, 128.1, 130.9, 131.0, 131.5,
137.6, 140.3, 143.1, 143.5, 144.6, 145.3, 145.4, 199.3 ppm. ESI-MS:
m/z (%) = 547 (31.1) [M + Na], 525 (6.4) [M + 1], 272 (19.4), 271
(100), 244 (9.6), 243 (50.5), 165 (3.7). C40H28O: C, 91.57; H, 5.38;
found C, 91.58; H, 5.37.
2-(4-Methylphenyl)-1,2,2-triphenylethanone (6): Yield 120 mg
(48%); white solid; m.p. 107–108 °C; Rf = 0.56 (hexane/ethyl acet-
ate, 10%). FTIR (KBr): ν = 3055, 3023, 2921, 2866, 1675 (CO),
˜
1594, 1578, 1491, 1443, 1214, 1183, 1034 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 2.22 (s, 3 H, CH3), 6.97–7.02 (m, 3 H,
ArH), 7.04–7.09 (m, 3 H, ArH), 7.10–7.18 (m, 10 H, ArH), 7.19–
7.23 (m, 1 H, ArH), 7.60 (d, J = 8.0 Hz, 2 H, ArH) ppm. 13C NMR Arylation of α-Hydroxy Ketones Using Anisole (Scope of α-Hydroxy
(100.53 MHz, CDCl3): δ = 21.0, 70.8, 126.6, 127.6, 127.8, 128.6,
136.3, 137.4, 140.1, 143.4, 198.9 ppm. ESI-MS: m/z (%) = 385 (3.4)
[M + Na], 363(6.0) [M + 1], 285 (14.9), 272 (20.8), 271 (100), 244
(6.8), 243 (42), 165 (4.7). C27H22O: C, 89.47; H, 6.12; found C,
89.50; H, 6.11.
Ketones). General Procedure: A solution of 2-hydroxy-1,2,2-triar-
ylethanone 1b–j (100 mg, 0.29–0.33 mmol) in anhydrous CH2Cl2
(5 mL) and nucleophile (1.5 equiv.) were placed in a 25 mL round-
bottomed flask fitted with a guard tube. Trifluoromethanesulfonic
acid (1 equiv) was added. The contents were stirred at room tem-
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O43438
/KAP1
Date: 12-01-15 15:55:33
Pages: 10
A. Kumar, T. V. Singh, S. P. Thomas, P. Venugopalan
FULL PAPER
perature and the progress of reaction was monitored by TLC analy-
ses. After stirring the contents for the appropriate time, the reaction
was quenched with water (1 mL). The product was extracted with
1,2-Bis(4-methoxyphenyl)-2,2-diphenylethanone (2f): Yield 105 mg
(82%); white solid; m.p. 68–69 °C; Rf = 0.32 (hexane/ethyl acetate,
10%). FTIR (KBr): ν = 3058, 3032, 2957, 2935, 2835, 1671 (CO),
˜
CH2Cl2 (3ϫ 15 mL), washed with 10% Na2CO3 (20 mL), water 1592, 1493, 1442, 1226, 1183, 1043 cm–1. 1H NMR (400 MHz,
(20 mL) and dried with anhydrous Na2SO4. The solvent was re-
moved under reduced pressure to give brownish oil. Purification by
flash chromatography afforded the products 2b–j and 11–13 in 24–
94% yield.
CDCl3): δ = 3.65 (s, 3 H, OCH3), 3.68 (s, 3 H, OCH3), 6.56 (d, J
= 9.0 Hz, 2 H, ArH), 6.70 (d, J = 8.8 Hz, 2 H, ArH), 7.03 (d, J =
8.8 Hz, 2 H, ArH), 7.10–7.17 (m, 10 H, ArH), 7.60 (d, J = 9.0 Hz,
2 H, ArH) ppm. 13C NMR (100.53 MHz, CDCl3): δ = 55.1, 55.2,
70.2, 112.8, 113.1, 126.5, 127.7, 130.0, 130.8, 131.9, 133.5, 135.3,
143.7, 157.9, 162.1, 197.3 ppm. ESI-MS: m/z (%) = 431(4) [M +
Na], 409(4.5) [M + 1], 302 (21.4), 301 (100), 274 (13.6), 273 (70.4),
195 (3.0). C28H24O3: C, 82.33; H, 5.92; found C, 82.37; H, 5.92.
2-(4-Methoxyphenyl)-2-(2-methylphenyl)-1,2-diphenylethanone (2b):
Yield 115 mg (89%); white solid; m.p. 68–69 °C; Rf = 0.57 (hexane/
ethyl acetate, 10%). FTIR (KBr): ν = 3056, 3017, 2929, 2835, 1680
˜
(CO), 1598, 1508, 1443, 1296, 1252, 1181, 1033 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 1.70 (s, 3 H, CH3), 3.68 (s, 3 H, OCH3),
6.69 (d, J = 9 Hz, 2 H, ArH), 6.94–6.96 (m, 1 H, ArH), 6.99–7.04
(m, 2 H, ArH), 7.05–7.14 (m, 9 H, ArH), 7.18 (t, J = 7.4 Hz, 1 H,
ArH), 7.24–7.26 (m, 1 H, ArH), 7.51 (d, J = 8.2 Hz, 2 H,
ArH) ppm. 13C NMR (100.53 MHz, CDCl3): δ = 22.4, 55.2, 70.1,
112.9, 125.7, 126.5, 127.4, 127.5, 128.5, 129.9, 130.7, 131.3, 131.5,
132.3, 132.4, 135.0, 138.7, 138.9, 141.8, 143.3, 157.9, 200.5 ppm.
ESI-MS: m/z (%) = 301 (6.4), 286 (24.3), 285 (100), 258 (9.4), 257
(55.4), 195 (3.2), 179 (4.8). C28H24O2: C, 85.68; H, 6.16; found C,
85.70; H, 6.18.
2-(4-Methoxyphenyl)-1,2-bis(4-methylphenyl)-2-phenylethanone
(2g): Yield 120 mg (89%); white solid; m.p. 53–54 °C; Rf = 0.33
(hexane/ethyl acetate, 10%). FTIR (KBr): ν = 3055, 3025, 2921,
˜
2855, 2835, 1677 (CO), 1604, 1509, 1443, 1252, 1223, 1181,
1
1035 cm–1. H NMR (400 MHz, CDCl3): δ = 2.14 (s, 3 H, CH3),
2.18 (s, 3 H, CH3), 3.63 (s, 3 H, OCH3), 6.77 (d, J = 8.6 Hz, 2 H,
ArH), 6.84 (d, J = 8.0 Hz, 2 H, ArH), 6.95–7.04 (m, 6 H, ArH),
7.11 (s, 5 H, ArH), 7.51 (d, J = 8.0 Hz, 2 H, ArH) ppm. 13C NMR
(100.53 MHz, CDCl3): δ = 21.0, 21.5, 55.1, 70.0, 113.1, 126.5,
127.7, 128.4, 128.5, 130.7, 130.8, 131.3, 131.9, 134.8, 135.5, 136.1,
140.6, 142.3, 143.9, 158.0, 198.5 ppm. ESI-MS: m/z (%) = 429 (40)
[M + Na], 407 (3) [M + 1], 300 (22), 299 (100), 272 (8), 271 (40.5).
C29H26O2: C, 85.68; H, 6.45; found C, 85.70; H, 6.49.
2-(4-Methoxyphenyl)-2-(3-methylphenyl)-1,2-diphenylethanone (2c):
Yield 108 mg (83%); white solid; m.p. 59–60 °C; Rf = 0.51 (hexane/
ethyl acetate, 10%). FTIR (KBr): ν = 3055, 3032, 2951, 2929, 2835,
˜
2-(4-Methoxyphenyl)-2-(1-naphthyl)-1,2-diphenylethanone (2h):
Yield 30 mg (24%); white solid; m.p. 148–149 °C; Rf = 0.40 (hex-
1680 (CO), 1605, 1578, 1508, 1489, 1444, 1252, 1213, 1181,
1
1033 cm–1. H NMR (400 MHz, CDCl3): δ = 2.28 (s, 3 H, CH3),
ane/ethyl acetate, 10%). FTIR (KBr): ν = 3054, 2925, 2852, 1682
˜
3.80 (s, 3 H, OCH3), 6.83 (d, J = 8.8 Hz, 2 H, ArH), 7.05–7.08 (m,
3 H, ArH), 7.17–7.21 (m, 4 H, ArH), 7.23–7.28 (m, 6 H, ArH),
7.30–7.35 (m, 1 H, ArH), 7.72 (d, J = 7.4 Hz, 2 H, ArH) ppm. 13C
NMR (100.53 MHz, CDCl3): δ = 21.7, 55.2, 70.4, 113.1, 126.5,
127.4, 127.5, 127.6, 127.7, 127.9, 130.8, 131.0, 131.5, 131.6, 132.0,
135.3, 137.3, 137.6, 143.2, 143.7, 158.0, 199.2 ppm. ESI-MS: m/z
(%) = 415 (8.9) [M + Na], 286 (23.7), 285 (100), 258 (7.4), 257
(45.6), 179 (3.5). C28H24O2: C, 85.68; H, 6.16; found C, 85.73; H,
6.15.
(CO), 1596, 1508, 1461, 1444, 1251, 1182, 1032 cm–1. 1H NMR
(400 MHz, CDCl3): δ = 3.68 (s, 3 H, OCH3), 6.68 (d, J = 9 Hz, 2
H, ArH), 6.90 (t, J = 7.8 Hz, 1 H, ArH), 7.01–7.08 (m, 4 H, ArH),
7.13–7.21 (m, 6 H, ArH), 7.32 (t, J = 7.8 Hz, 1 H), 7.43–7.46 (m,
3 H, ArH), 7.54 (d, J = 7.4 Hz, 1 H, ArH), 7.63 (d, J = 8 Hz, 1 H,
ArH), 7.67 (d, J = 8.2 Hz, 2 H, ArH) ppm. 1 3 C N MR
(100.53 MHz, CDCl3): δ = 55.2, 70.1, 112.9, 124.8, 125.1, 125.2,
126.5, 127.1, 127.5, 127.7, 128.7, 128.8, 129.6, 130.2, 131.2, 131.4,
132.6, 132.7, 134.3, 135.6, 138.9, 139.2, 143.8, 157.9, 201.7 ppm.
ESI-MS: m/z (%) = 322 (16.3), 321 (77), 302 (19.3), 301 (100), 293
(12.2), 273 (42.8), 195 (12.4), 167 (7.1), 149 (8). C31H24O2: C, 86.89;
H, 5.65; found C, 86.95; H, 5.68.
2-(4-Methoxyphenyl)-2-(4-methylphenyl)-1,2-diphenylethanone (2d):
Yield 120 mg (93%); white solid; m.p. 79–80 °C; Rf = 0.45 (hexane/
ethyl acetate, 10%). FTIR (KBr): ν = 3055, 3022, 2951, 2928, 2834,
˜
1677 (CO), 1606, 1596, 1508, 1461, 1444, 1252, 1215, 1182,
1
3-(1-Naphthyl)-2-phenylbenzofuran (11): Yield 60 mg (63%); white
solid: m.p. 92–93 °C (ref.[10] m.p. 94–95 °C); Rf = 0.57 (hexane/ethyl
acetate, 10%). 1H NMR (400 MHz, CDCl3): δ = 7.14–7.21 (m, 4
H, ArH), 7.28–7.32 (m, 1 H, ArH), 7.44–7.48 (m, 8 H, ArH), 7.63–
7.68 (m, 2 H, ArH), 7.83 (d, J = 8.1 Hz, 1 H, ArH) ppm. 13C NMR
(100.53 MHz, CDCl3): δ = 112.2, 119.5, 123.1, 123.6, 124.2, 126.0,
126.2, 127.8, 128.2, 128.3, 128.4, 128.9, 129.4, 130.6, 130.9, 131.0,
134.7, 150.1, 151.4 ppm.
1033 cm–1. H NMR (400 MHz, CDCl3): δ = 2.29 (s, 3 H, CH3),
3.75 (s, 3 H, OCH3), 6.77 (d, J = 8.8 Hz, 2 H, ArH), 7.04–7.28
(m, 14 H, ArH), 7.67 (d, J = 7.4 Hz, 2 H, ArH) ppm. 13C NMR
(100.53 MHz, CDCl3): δ = 21.0, 55.2, 70.1, 113.1, 126.5, 127.6,
127.7, 128.5, 130.6, 130.7, 131.1, 131.6, 131.9, 135.3, 136.2, 137.5,
140.4, 143.7, 158.0, 199.2 ppm. ESI-MS: m/z (%) = 415 (3.6) [M +
Na], 286 (23.6), 285 (100), 258 (8.8), 257 (52.7), 179 (3.8).
C28H24O2: C, 85.68; H, 6.16; found C, 85.70; H, 6.11.
2,2-Bis(4-methoxyphenyl)-1,2-diphenylethanone (2i): Yield 65 mg
(52%); white solid; m.p. 119–120 °C; Rf = 0.43 (hexane/ethyl acet-
1,2-Bis(4-fluorophenyl)-2-(4-methoxyphenyl)-2-phenylethanone (2e):
Yield 120 mg (94%); white solid; m.p. 71–72 °C; Rf = 0.45 (hexane/
ate, 10%). FTIR (KBr): ν = 3058, 3032, 2934, 2836, 1679 (CO),
˜
ethyl acetate, 10%). FTIR (KBr): ν = 3059, 3034, 2955, 2836, 1681
˜
1605, 1582, 1508, 1460, 1447, 1297, 1252, 1181, 1115, 1037 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.68 (s, 6 H, OCH3), 6.68–6.72
(m, 4 H, ArH), 7.02–7.05 (m, 4 H, ArH), 7.07–7.23 (m, 8 H, ArH),
7.59 (d, J = 7.4 Hz, 2 H, ArH) ppm. 13C NMR (100.53 MHz,
CDCl3): δ = 55.2, 69.8, 113.1, 126.5, 127.6, 127.7, 130.7, 131.1,
131.6, 131.8, 135.4, 137.5, 143.8, 158.0, 199.3 ppm. ESI-MS: m/z
(%) = 302 (20.9), 301 (100), 274 (13.8), 273 (67.8), 195 (12.7), 167
(13.8), 165 (3). C28H24O3: C, 82.33; H, 5.92; found C, 82.34; H,
5.91.
(CO), 1595, 1505, 1462, 1443, 1253, 1230, 1184, 1156, 1033 cm–1.
1H NMR (400 MHz, CDCl3): δ = 3.69 (s, 3 H, OCH3), 6.71–6.78
(m, 4 H, ArH), 6.82–6.88 (m, 2 H, ArH), 7.02–7.05 (m, 4 H, ArH),
7.10–7.21 (m, 5 H, ArH), 7.59–7.64 (m, 2 H, ArH) ppm. 13C NMR
(100.53 MHz, CDCl3): δ = 55.2, 69.7, 113.4, 114.4 (d, J = 21 Hz),
114.8 (d, J = 22 Hz), 126.9, 128.0, 130.5, 131.7, 132.3 (d, J = 8 Hz),
133.4 (d, J = 3 Hz), 133.7 (d, J = 8 Hz), 134.4, 139.7 (d, J = 3 Hz),
142.9, 158.2, 161.3 (d, J = 246 Hz), 164.5 (d, J = 254 Hz),
197.2 ppm. ESI-MS: m/z (%) = 437 (5.2) [M + Na], 308 (18), 307
(100), 280 (8.4), 279 (45.7). C27H20F2O2: C, 78.25; H, 4.86; found 6-Methoxy-2,3-diphenylbenzofuran (12): Yield 43 mg (46%); white
C, 78.30; H, 4.89.
solid; m.p. 119–120 °C (ref.[22] m.p. 120–121 °C); Rf = 0.48 (hexane/
8
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Pages: 10
Friedel–Crafts Arylation of α-Hydroxy Ketones
ethyl acetate, 10%). FTIR (KBr): ν = 3055, 2956, 2834, 1610, 1591,
[3]
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˜
1508, 1486, 1439, 1296, 1271, 1192, 1151, 1060, 1023 cm–1 1H
.
NMR (400 MHz, CDCl3): δ = 3.79 (s, 3 H, OCH3), 6.79 (dd, J =
8.5, 2.2 Hz, 1 H, ArH), 7.01 (d, J = 2.1 Hz, 1 H, ArH), 7.15–7.23
(m, 3 H, ArH), 7.26–7.34 (m, 2 H, ArH), 7.36–7.42 (m, 4 H, ArH),
7.52–7.54 (m, 2 H, ArH) ppm. 13C NMR (100.53 MHz, CDCl3): δ
= 55.8, 95.7, 111.9, 117.4, 120.2, 123.7, 126.6, 127.6, 127.9, 128.4,
128.9, 129.7, 130.9, 132.9, 149.6, 155.0, 158.4 ppm.
2-(2-Methoxyphenyl)-2-(4-methoxyphenyl)-1,2-diphenylethanone
(2j): Yield 114 mg (89%); white solid; m.p. 121–122 °C; Rf = 0.30
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(hexane/ethyl acetate, 10%). FTIR (KBr): ν = 3056, 3000, 2930,
˜
2835, 1691 (CO), 1596, 1486, 1461, 1289, 1112, 1029 cm–1 1H
.
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NMR (400 MHz, CDCl3): δ = 3.18 (s, 3 H, OCH3), 3.69 (s, 3 H,
OCH3), 6.58 (d, J = 7.4 Hz, 1 H, ArH), 6.68 (d, J = 8.9 Hz, 2 H,
ArH), 6.86 (dt, J = 7.5, 1 Hz, 1 H, ArH), 6.98 (d, J = 89 Hz, 2 H,
ArH), 7.01–7.07 (m, 4 H, ArH), 7.11–7.21 (m, 6 H, ArH), 7.44 (d,
J = 8.2 Hz, 2 H, ArH) ppm. 13C NMR (100.53 MHz, CDCl3): δ =
54.6, 55.1, 67.2, 111.3, 112.5, 120.8, 126.3, 127.0, 127.1, 128.9,
129.5, 129.7, 130.8, 131.2, 132.3, 132.6, 135.7, 138.9, 144.0, 157.2,
157.9, 200.9 ppm. ESI-MS: m/z (%) = 431(100) [M + Na], 302
(20.9), 301 (44.6), 274 (13.6), 273 (29.8), 195 (5.5), 167 (9.5).
C28H24O3: C, 82.33; H, 5.92; found C, 82.34; H, 5.90.
2-(2-Furyl)-2-(4-methoxyphenyl)-1,2-diphenylethanone (13): Yield
105 mg (92%); white solid; m.p. 29–30 °C; Rf = 0.40 (hexane/ethyl
acetate, 10%). FTIR (KBr): ν = 3060, 2940, 2839, 1685 (CO), 1602,
˜
[7]
[8]
1503, 1452, 1445, 1295, 1251, 1181, 1029 cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 3.62 (s, 3 H, OCH3), 6.05 (d, J = 3.3 Hz,
1 H, ArH), 6.19 (dd, J = 3.3, 0.8 Hz, 2 H, ArH), 6.70 (d, J =
8.8 Hz, 2 H, ArH), 6.97 (d, J = 8.8 Hz, 2 H, ArH), 7.03–7.09 (m,
4 H, ArH), 7.11–7.17 (m, 3 H, ArH), 7.20–7.24 (m, 2 H, ArH), 7.57
(d, J = 8.2 Hz, 2 H, ArH) ppm. 13C NMR (100.53 MHz, CDCl3): δ
= 55.2, 66.5, 110.4, 110.9, 113.4, 127.1, 127.8, 128.0, 129.8, 130.4,
130.9, 132.1, 134.1, 137.6, 142.4, 142.5, 155.2, 155.5, 197.5 ppm.
ESI-MS: m/z (%) = 391(39.9) [M + Na], 301 (17.8), 273 (15.9), 261
(91.6), 233 (100), 215 (6.6), 205 (4.2). C25H20O3: C, 81.50; H, 5.47;
found C, 81.52; H, 5.46.
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CCDC-1029526 (for 7) and -1029481 (for 10) contain the supple-
mentary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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Supporting Information (see footnote on the first page of this arti-
1
cle): X-ray diffraction data, and H and 13C NMR spectra for all
new compounds.
[18] Although stoichiometric amount of the triflic acid is used with
respect to the substrate, the mechanism shown in Scheme 4 is
a catalytic one.
Acknowledgments
The authors are grateful to the University Grants Commission
(UGC), New Delhi for providing financial support (grant number
36-194/2008-SR). One of the authors (A. K.) thanks the Council of
Scientific and Industrial Research (CSIR), New Delhi for a senior
research fellowship [09/135 (0604)/2010-EMR-I].
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[1] For a review on α-arylation, see: D. A. Culkin, J. F. Hartwig,
Acc. Chem. Res. 2003, 36, 234–245.
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Received: November 5, 2014
Published Online: ᭿
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9

Job/Unit: O43438
/KAP1
Date: 12-01-15 15:55:33
Pages: 10
A. Kumar, T. V. Singh, S. P. Thomas, P. Venugopalan
FULL PAPER
Friedel–Crafts Arylation
An efficient Friedel–Crafts arylation of α-
hydroxy ketones has been developed that
allows access to a broader class of α-triaryl-
substituted ketones. 2-Hydroxy-1,2,2-tri-
arylethanones have been converted into
1,2,2,2-tetraarylethanones by using tri-
fluoromethanesulfonic acid as Brønsted
acid and arenes/heteroarenes as nucleo-
philes.
A. Kumar, T. V. Singh,* S. P. Thomas,
P. Venugopalan* .............................. 1–10
Friedel–Crafts Arylation of α-Hydroxy
Ketones: Synthesis of 1,2,2,2-Tetraaryl-
ethanones
Keywords: Synthetic methods / Arylation /
Ketones / Carbocations
10
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