Synthesis of Highly Substituted Biaryls by the Construction of a Benzene Ring via in Situ Formed Acetals

Article abstract of DOI:10.1021/acs.joc.1c01277

Herein, we present an interesting method for the construction of a benzene ring using propargylic alcohols and 1,3-dicarbonyls, which involves three new C-C bond formations via cascade alkylation, formylation, annulation, and aromatization to make substituted biaryls. This one-pot Br?nsted acid-promoted protocol utilizes the unique reactivity of the acetal formed under the reaction conditions. Alkynyl methyl ketones could be employed instead of 1,3-dicarbonyls as they are converted to 1,3-dicarbonyls by hydration under the reaction conditions.

Full text of DOI:10.1021/acs.joc.1c01277

pubs.acs.org/joc
Article
Synthesis of Highly Substituted Biaryls by the Construction of a
Benzene Ring via In Situ Formed Acetals
Chandrahas Tarigopula, Seetharaman Manojveer, and Rengarajan Balamurugan*
Cite This: https://doi.org/10.1021/acs.joc.1c01277
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Herein, we present an interesting method for the construction of a benzene ring using propargylic alcohols and 1,3-
dicarbonyls, which involves three new C−C bond formations via cascade alkylation, formylation, annulation, and aromatization to
make substituted biaryls. This one-pot Brønsted acid-promoted protocol utilizes the unique reactivity of the acetal formed under the
reaction conditions. Alkynyl methyl ketones could be employed instead of 1,3-dicarbonyls as they are converted to 1,3-dicarbonyls
by hydration under the reaction conditions.
substituted biaryls.16a Stoichiometric phosphine-promoted
annulations of δ-acetoxy alleonates with α-hydroxy-β-carbonyl
ester derivatives result in biaryls by the construction of
INTRODUCTION
■
Biaryl compounds are key structural feature of numerous
functional molecules, such as natural products,1 biologically
tetrasubstituted benzenes.16b The visible-light photocatalyzed
annulation of thiophene with arylalkynes results in biaryls at
room temperature.16c Syntheses of maleimide-fused biaryls
have been reported using a copper-catalyzed cyclization of
oximes and maleimides.16d A rhodium(III)-catalyzed directed
C−H activation strategy has been reported for the synthesis of
aryl-substituted salicylaldehydes.16e A [3 + 3] cycloaddition
protocol for the construction of biaryls from atropaldehyde
acetal and 1,3-bisnucleophiles in the presence of a Brønsted or
active compounds,2 organic materials,3 pharmaceuticals,4 and
catalysts (Figure 1).5 A straightforward strategy to make biaryls
is the coupling of two aryl rings. Among such strategies,
classical transition metal-catalyzed cross-coupling reactions
occupy a prominent position (Figure 1).6 Recently, the C−H
bond arylation of arenes has gathered a certain attention.7
Other methods include the arylation of arynes,8 oxidative
coupling,9 arylation using organic radicals,10 coupling phenols
by activating them with sulfoxides,11 electrochemical oxidative
intramolecular coupling,12 the cross-coupling of diazoquinones
with arylboronic esters,13 and the decarbonylative coupling of
arylaldehydes with arenes.14 The requirement of expensive
rare-earth element-based catalysts, issues with substituent
placements and their influence in the success of the reactions,
and the need for a high temperature are definite concern in
these methods. The construction of benzene rings from acyclic
or cyclic precursors has attracted the synthetic community for
quite some time as it offers better prospects for placing
multiple substituents.15 In this regard, the synthesis of biaryls
via the construction of a benzene ring has been pursued by
different groups in the recent years.16
Lewis acid and an oxidizing agent has also been reported.16f
A
two-step procedure involving the[4 + 2] cycloaddition of a
diene generated in situ from benzylideneacetone and methyl
propiolate under high pressure, followed by DDQ oxidation,
results in biaryls.16g An one-pot sequential Pd-catalyzed
Sonogashira coupling/cyclization/aromatization procedure
Received: June 1, 2021
The cycloaddition of pyrones and nitrostyrenes, followed by
the elimination of CO2 and NO2 at 150 °C, affords highly
https://doi.org/10.1021/acs.joc.1c01277
J. Org. Chem. XXXX, XXX, XXX−XXX
© XXXX American Chemical Society
A

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Figure 1. Representative important biaryl compounds and approaches to access biaryls.
Scheme 1. Acid-Promoted Reaction of 1,3-Dicarbonyls with Propargyl Alcohols
results in biaryls.16h The synthesis of biaryls has also been
reported by the reaction of β-iodo-β-silylstyrenes and terminal
alkynes under palladium catalysis.16i Still, there is a scope for
developing strategies for the synthesis of biaryls via the
B
https://doi.org/10.1021/acs.joc.1c01277
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
construction of a benzene ring using easily accessible starting
materials and ambient reaction conditions.
Then, an equal amount of TMOF was added to effect the
conversion of the propargylated benzoylacetone 5 into the
biaryl derivative. We conducted most of the reaction
optimization following the above protocol.
RESULTS DISCUSSION
■
It is anticipated that propargylation at the active methylene
carbon, followed by formylation20 at the methyl and
cyclization, would lead to a cyclohexadiene system, which
may undergo double bond migrations under acidic conditions
to effect the conjugation of double bonds with the available
carbonyl groups. Therefore, conducting the reaction in the
presence of 1 equiv of DDQ to aromatize the products and get
better yields of the product was considered (Table 1, entries 1
and 3−8). Interestingly, CuCl as an additive facilitated a
smooth reaction, resulting in the desired product in a good
yield (Table 1, entries 10, 11, and 13−17). Being alkynophilic,
perhaps, it facilitated the alkyne−carbonyl metathesis.21 Also,
its additional role in aromatization in the final step might not
be ruled out, since this reaction does not require DDQ to
furnish the product. CuCl2 as additive was not effective, as it
resulted in a complex product mixture (Table 1, entry 9).
Overall, the formation of the biaryl involves propargylation,
formylation, cyclization or [2 + 2] alkyne−carbonyl metathesis,
and aromatization all in one-pot, as shown in Scheme 3.
The condition mentioned in entry 13 of the Table 1 was
used for subsequent evaluation of the scope of the reaction.
Different aryoylacetone derivatives were treated with a number
of aryl propargyl alcohols. The reactions resulted in the
expected biaryl products with moderate to good yields (Table
2). Aryl groups having substituents such as F, Cl, Br, I, OMe,
and CF3 could tolerate the reaction conditions very well.
Heterocycles such as furan and thiophene containing 1,3-
dicarbonyl reacted smoothly to give the biaryls attached to
heterocycles (3p and 3q, respectively). On the other hand,
propargyl alcohols having furan or thiophene rings decom-
posed under the reaction conditions. Sterically bulky
naphthalene could be accommodated in both 1,3-dicarbonyl
and propargyl alcohol to get their respective biaryl products
(3r and 3s). A 1,3-ketoester such as ethyl acetoacetate could
also be employed to get diaryls with an ester substituent (3t−
3x). 1,3-Dicarbonyl compounds with longer alkyl groups in the
place of methyl, nonbenzylic, and aliphatic propargyl alcohols
did not result the desired products. 1,3-Ketoamides such as
aceto acetamide and N-benzyl-3-oxobutanamide underwent
decomposition under the reaction conditions. When reacted
with the phenyl propargyl alcohol 2a, a 1,2-diketone, such as
butan-2,3-dione did not take part in the reaction even at a
reflux temperature, and the methyl ether of 2a was obtained in
more than a 95% yield.
Herein, we report the synthesis of substituted biaryls by taking
advantage of the reactivity of acetals generated in situ. We have
developed a number of transformations using in situ formed
acetals by reacting their parent carbonyl compounds with
trimethyl orthoformate (TMOF) and a Lewis or Brønsted
acid.17 Thus, formed acetals promote certain reactions to occur
that are otherwise not possible directly from the parent
carbonyl compounds. Particularly, unactivated ketones in the
presence of trimethyl orthoformate and a Lewis or Brønsted
acid generate enol ethers, which are used as nucleophiles in the
α-functionalization of unactivated ketones.17c−f,20a In this
context, we wished to check the reactivity of 1,3-dicarbonyls
with a methyl group in the presence trimethyl orthoformate
and an acid catalyst, as it bears both the active methylene and
the less reactive α-methyl group. Specifically, propargyl
alcohols were chosen as electrophiles as they would lead to
propargylated products that could undergo further cyclization
by making use of the alkyne functionality under the reaction
conditions. It has been reported that 1,3-dicarbonyl com-
pounds undergo PTS-catalyzed propargylation at the active
methylene position upon their reaction with benzylic propargyl
alcohols (Scheme 1).18 In our initial studies, we took the
propargylated benzoylacetone 5 and attempted its cyclization
in the presence of a Brønsted acid or Lewis acid and trimethyl
orthoformate (Supporting Information (SI)). It is known that
propargylated bezoylacetone gives a trisubstituted furan
derivative under an acid catalyst.19 Interestingly, the reaction
of propargylated benzoylacetone 5 in the presence of trimethyl
orthoformate and an acid catalyst gave a substituted biaryl
compound. Among the acids tried, HClO4 promoted the
formation of the biaryl 3a, and a maximum yield of 58% of 3a
was obtained when the reaction was carried out using 2 equiv
of HClO4 and 1 equiv of DDQ in TMOF (Scheme 2). It has to
Scheme 2. Construction of Biaryl from Propargylated
Benzoylacetone
Syntheses of 1,3-dicarbonyls, apart from trivial Claisen
condensation, have been achieved by the regioselective
hydration of alkynones using gold catalysts.22 However, the
efficient Brønsted acid-promoted regioselective hydration of
alkynones has not been explored systematically.22c,d In this
context, it was anticipated that treating an alkynone with
trimethyl orthoformate in the presence of a HClO4 might lead
to the regioselective addition of a methoxy group at the β-
carbon. The hydrolysis of the enol ether might occur under the
reaction conditions to generate a 1,3-diketone, as HClO4 used
in this work is an aqueous solution. Gratifyingly, the reaction of
1,3-diphenylprop-2-yn-1-one with trimethyl orthoformate (2
equiv) in the presence of HClO4 (1 equiv) in DCE at room
temperature resulted in the smooth formation of 1,3-
diphenylpropane-1,3-dione in a 93% yield. It has to be noted
be mentioned that the reaction became clean only when a
stoichiometric amount of the oxidant DDQ was used as an
additive in the reaction. It is believed that the biaryl formation
happened via α-formylation,20 annulation, and aromatization.
It is reiterated that the presence of trimethyl orthoformate
makes the reaction to take a different pathway, resulting in
biaryl compounds involving three new C−C bond formation
steps (Scheme 1). This prompted us to try and optimize the
condition for the formation a biaryl compound by the reaction
between 1a and 2a in one pot, as propargylation is possible
under acidic conditions. However, it was found that TMOF
alone as a solvent was not suitable for promoting the
propargylation. Therefore, the HClO4-promoted propargyla-
tion was carried out first using nitromethane as the solvent.
C
https://doi.org/10.1021/acs.joc.1c01277
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
a
Table 1. Optimization of Reaction Conditions
b
entry
acid (equiv)
HClO4 (2)
additive
solvent
yield (%)
1
2
3
4
5
6
7
8
DDQ (1)
TMOF/CH3NO2 (1:1)
TMOF/CH3NO2 (1:1)
TMOF/CH3NO2 (1:1)
TMOF/toluene (1:1)
TMOF/CCl4 (1:1)
TMOF/CH3NO2 (1:1)
TMOF/CH3NO2 (1:1)
TMOF/CH3NO2 (1:1)
TMOF/CH3NO2 (1:1)
TMOF/CH3NO2 (1:1)
TMOF/CH3NO2 (1:1)
TMOF/CH3NO2 (1:1)
TMOF/CH3NO2 (1:1)
TMOF/CH3NO2 (1:1)
TMOF/CH3NO2 (1:1)
TMOF/CH3NO2 (1:1)
48
trace
30
20
25
HClO4 (2)
HClO4 (2)
HClO4 (2)
HClO4 (2)
HClO4 (1)
HClO4 (2)
HClO4 (2)
HClO4 (2)
HClO4 (2)
HClO4 (2)
HClO4 (2)
HClO4 (1)
HClO4 (0.5)
NHTf2 (10 mol %)
pTSA (1)
DDQ (1)
DDQ (1)
DDQ (1)
DDQ (1)
DDQ (0.5)
DDQ (1)
CuCl2 (1)
CuCl (1)
CuCl (0.2)
CuI (0.2)
CuCl (0.2)
CuCl (0.2)
CuCl (0.2)
CuCl (0.2)
CuCl (0.2)
40
30
20
n.a.
c
9
10
11
12
13
14
15
16
17
73
68
65
73
72
n.a.
n.a.
n.r.
c
c
HClO4 (0.5)
TMOF
a
b
c
All the reactions were carried out using 1 equiv of 1a and 1 equiv of 2a. Isolated yield. Complex mixture.
Scheme 3. Plausible Mechanism for Biaryl Formation
D
https://doi.org/10.1021/acs.joc.1c01277
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Table 2. Substrate Scope for the Synthesis of Biaryls from 1,3-Dicarbonyls
that the conversion did not occur when the reaction was
conducted using an excess of water in the place of TMOF. The
better nucleophilicity of the OMe group in TMOF due to the
formation of a stabilized carbenium ion after the transfer
MeO− might be a reason for the fruitful reaction with TMOF.
The scope of the reaction was evaluated with a few more
alkynones, which smoothly transformed into their correspond-
ing 1,3-dicarbonyl compounds (Table 3). Thus, this protocol
serves as a simple and metal-free transformation of alkynones
into 1,3-diketones.
CH3NO2) and 20 mol % CuCl were added to the reaction
mixture, and stirring was continued for another 24 h to ensure
the formation of the biaryl product. The results of this one-pot
sequential hydration, propargylation, formylation, cyclization,
and aromatization are provided in Table 4. Although the yields
were slightly less (3a, 61% vs 72% and 3e, 57% vs 62%) when
compared to those for the reaction of 1,3-diketones, the
annexation of one more step (hydration) in the reaction of
alkynones makes it attractive.
The success of the hydration of alkynones using HClO4/
TMOF prompted us to carry out the hydration of 4-arylbut-3-
yn-2-one and the subsequent reaction of the resulting 1,3-
diketone with an aryl propargyl alcohol in one pot. For this,
alkynone 4 was treated with 1 equiv of HClO4 and 2 equiv of
TMOF in a nitromethane solvent. The smooth completion of
the hydration reaction was noted within 4 h. Then, benzylic
propargyl alcohol 2 (0.83 equiv with respect to 4) and 0.5
equiv of HClO4 were added to effect propargylation. Generally,
the propargylation reaction was fast and completed in less than
5 min. Then, TMOF (equal amount (v/v) with respect to
To evaluate the source of oxygen in the product, a reaction
was conducted using the substrate 5 in the presence of 5 equiv
of H218O. HRMS analysis of the product revealed very little
incorporation of 18O in the product, suggesting trimethyl
orthoformate as its source (Scheme 2). The OMe group can
easily be deprotected using BBr3 to get o,p-diacyl-m-aryl
phenols, whose skeleton is present in biologically important
compounds.23 For example, upon reaction with BBr3, 3a
resulted in a 92% yield of the phenol derivative 6 (Scheme 4)
E
https://doi.org/10.1021/acs.joc.1c01277
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Table 3. TMOF-Assisted HClO4-Promoted Conversion of Alkynones into 1,3-Diketones
Table 4. Synthesis of Biaryls from Alkynones
reaction of alkynones with benzylic propargyl alcohols to make
substituted biaryls.
CONCLUSION
■
In conclusion, we have developed a new method for the
synthesis of highly substituted biaryls from propargylic alcohols
and aryoylacetones/ethyl acetoacetate, which involves sequen-
tial propargylation, formylation, annulation, and aromatization,
by exploiting the unique reactivity of an in situ formed acetal.
The metal-free regioselective hydation of alkynones has been
evaluated using perchloric acid and has been employed in the
EXPERIMENTAL SECTION
■
General. Chemicals and solvents were obtained from various
commercial sources. Starting materials were prepared following
known literature procedures. Trimethyl orthoformate and nitro-
methane were obtained from SRL and Finar chemicals, respectively,
and 70% HClO4 was purchased from Merck. THF was dried over
sodium and freshly distilled before use. 1H and 13C spectra were
F
https://doi.org/10.1021/acs.joc.1c01277
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Scheme 4. Control Experiment, Synthesis of the Substituted Phenol, and the One-Gram-Scale Reaction
recorded on a Bruker Avance 400 and 500 MHz spectrometer using
solution in CDCl3 with tetramethylsilane (TMS) as an internal
standard. IR spectra were recorded on a JASCO FT-IR-5300
spectrometer. High-resolution mass spectra (HRMS) were recorded
using electrospray ionization on a Bruker Maxis instrument. Melting
points were determined by using a MR-VIS visual melting range
apparatus and are uncorrected. For TLC, silica gel plates 60 F254
were used, and compounds were visualized by UV light or by
treatment with a Seebach solution (phosphomolybdic acid (2.5 g),
Ce(SO4)2 (1 g), conc. H2SO4 (6 mL), and H2O (94 mL)) followed
by heating. Column chromatography was performed on silica gel
(100−200 mesh) with an ethyl acetate and hexanes mixture as the
eluent.
Representative Procedure for the Synthesis of 1,3-
Diketones 1a−1i. 1,3-Dicarbonyl compounds were prepared by
Claisen condensation. 2,4-Dichloroacetophenone (500 mg, 2.67
mmol, 1 equiv) was dissolved in dry ethyl acetate (5 mL). To this
was added 60% NaH (121 mg, 3.2 mmol, 1.2 equiv) at 0 °C with
constant stirring. The reaction mixture was allowed to stir for 12 h for
the completion of the reaction. Then, a saturated aqueous NH4Cl
solution (10 mL) was added carefully, and the reaction mixture was
acidified to pH 5 with an aqueous HCl solution. The aqueous phase
was separated and extracted with ethyl acetate (3 × 10 mL), the
combined organic phase was dried over anhydrous sodium sulfate,
and the solvent was evaporated under reduced pressure. The residue
was purified by column chromatography with 5% EtOAc/hexanes to
get 1-(2,4-dichlorophenyl)butane-1,3-dione 1b as a yellow solid (513
mg, 84%); mp 40−42 °C); compound existed in the enolic form. IR
(neat): 2952, 1748, 1655, 1216, 1076, 926, 694 cm−1. 1H NMR (500
MHz, CDCl3): δ 15.68 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.47 (d, J =
2.0 Hz, 1H), 7.33 (dd, J = 8.0, 2.0 Hz, 1H), 6.05 (s, 1H), 2.20 (s,
3H). 13C{1H} NMR (125 MHz, CDCl3): δ 192.8, 183.3, 137.0, 133.9,
132.6, 130.9, 130.5, 127.3, 101.7, 25.4. HRMS (ESI) m/z: [M + Na]+
Calcd for C10H8Cl2O2Na 252.9799, found 252.9795. The 1,3-
diketones 1a and 1c have already been reported in the literature.24,22
TMOF-Assisted and HClO4-Promoted Hydration of Alkynones.
To a solution of 1,3-diphenylprop-2-yn-1-one (100 mg, 0.48 mmol, 1
equiv) in DCE (2 mL) in a round-bottom flask were added trimethyl
orthoformate (104 μL, 0.96 mmol, 2 equiv) and HClO4 (0.48 mmol,
48 μL, 1 equiv), and the mixture was stirred at room temperature.
The reaction completed in 4 h as indicated by TLC. Then, solvent
DCE was evaporated, and the residue was loaded on a silica gel
column and eluted with mixtures of EtOAc/hexanes to get pure 1,3-
diphenyl-1,3-propanedione 1d as a yellow solid (99 mg, 93%).24 1H
NMR (500 MHz, CDCl3): δ 8.00 (d, J = 7.2 Hz, 4H) 7.56 (t, J = 7.2
Hz, 2H), 7.49(d, J = 7.2 Hz, 4H). 6.86 (s, 1H).
1-(4-Methoxyphenyl)-3-phenylpropane-1,3-dione (1e).24 Pre-
pared from 50 mg of 1-(4-methoxyphenyl)-3-phenylprop-2-yn-1-one
as a white solid (46 mg, 89%). 1H NMR (500 MHz, CDCl3): δ 8.01−
7.98 (m, 4H), 7.57−7.55 (m, 1H), 7.52−7.47 (m, 2H), 7.01−6.99
(m, 2H), 6.82 (s, 1H), 3.91 (s, 3H).
1-(2-Bromophenyl)-3-phenylpropane-1,3-dione (1f).24 Prepared
from 50 mg of 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one as a
colorless oil (41 mg, 81%). 1H NMR (500 MHz, CDCl3): δ 7.94 (d, J
= 7.2 Hz, 2H), 7.67 (d, J = 7.6 Hz, 1H), 7.61 (d, J = 7.6 Hz, 1H), 7.55
(t, J = 7.6 Hz, 1H), 7.48 (t, J = 7.6 Hz, 2H), 7.41 (t, J = 7.6 Hz, 1H),
7.32 (t, J = 7.2 Hz, 1H), 6.67 (s, 1H).
1-Phenyl-3-(4-(trifluoromethyl)phenyl)propane-1,3-dione (1g).24
Prepared from 50 mg of 3-phenyl-1-(4-(trifluoromethyl)phenyl)prop-
2-yn-1-one as a white solid (42 mg, 81%). 1H NMR (500 MHz,
CDCl3): δ 8.09 (d, J = 7.6 Hz, 2H), 7.99 (d, J = 7.4 Hz, 2H), 7.75 (d,
J = 8.0 Hz, 2H), 7.59 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.2 Hz, 2H),
6.87 (s, 1H).
1-(4-Fluorophenyl)butane-1,3-dione (1h).24 Prepared from 50 mg
of 4-(4-fluorophenyl)but-3-yn-2-one as a white solid (45 mg, 85%).
1H NMR (500 MHz, CDCl3): δ 7.91−7.88 (m, 2 H), 7.15−7.11 (m,
2 H), 6.13 (s, 1 H), 2.20 (s, 3 H).
G
https://doi.org/10.1021/acs.joc.1c01277
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
1-Phenylpentane-1,3-dione (1i).24 Prepared from 50 mg of 1-
phenylpent-1-yn-3-one as a brown-colored liquid (42 mg, 80%). H
NMR (500 MHz, CDCl3): δ 7.88−7.87 (m, 2H), 7.51 (t, J = 7.5 Hz,
1H), 7.46−7.43 (m, 2H), 6.18 (s, 1H), 2.47 (q, J = 7.5 Hz, 2H), 1.21
(t, J = 7.5 Hz, 3H).
129.8, 129.5, 129.4, 129.0, 128.1, 127.8, 127.4, 127.3, 109.4, 55.9.
HRMS (ESI) m/z: [M + H]+ Calcd for C27H21O3 393.1491, found
393.1492. Compounds 3b−3x were synthesized following the above
general procedure.
1
(6-Benzoyl-3-methoxy-[1,1′-biphenyl]-2-yl)(2,4-dichlorophenyl)-
methanone 3b. The product was obtained as a brown liquid in a 47%
yield (51 mg). Rf = 0.56 (20% EtOAc/hexanes). IR (neat): 3059,
Representative Procedure for the Synthesis of Propargylic
Alcohols 2a−2h.25a−d n-BuLi in hexane (1.6 M solution, 3.3 mL,
5.2 mmol, 2.5 equiv) was added to phenylacetylene (340 μL, 3.16
mmol, 1.5 equiv) in THF (5 mL) at −78 °C under N2. The mixture
was stirred for 1 h at the same temperature and then 2,4-
difluorobenzaldehyde (300 mg, 2.11 mmol, 1 equiv) was added.
The reaction mixture was warmed to room temperature and stirred
overnight. The reaction was quenched with a saturated aqueous
NH4Cl solution (10 mL). The aqueous layer was extracted with
EtOAc (3 × 10 mL), and the combined organic layers were washed
with a saturated aqueous brine solution. The organic layer was dried
with anhydrous Na2SO4, and the solvents were removed under
reduced pressure. The residue was purified using silica gel
chromatography with 10% EtOAc/hexanes to get the pure 1-(2,4-
difluorophenyl)-3-phenylprop-2-yn-1-ol 2b as a yellow oil (368 mg,
1
2925, 1725, 1670, 1221, 1009, 916, 694 cm−1. H NMR (400 MHz,
CDCl3): δ 7.63 (d, J = 8.5 Hz, 1H), 7.53−7.51 (m, 2H), 7.38−7.30
(m, 1H), 7.27−7.7.19 (m, 3H), 7.21 (d, J = 2.0 Hz, 1H) 7.08 (d, J =
8.5 Hz, 1H) 7.04−7.01 (m, 1H), 6.94−6.94 (m, 5H), 3.90 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 197.4, 193.8, 158.3, 140.2,
138.0, 137.8, 136.5, 135.1, 134.0, 132.7, 132.6, 132.5, 131.7, 130.5,
130.1, 129.7, 129.6, 128.0, 127.9, 127.7, 127.6, 126.6, 109.7, 56.1.
HRMS (ESI) m/z: [M + H]+ Calcd for C27H19Cl2O3 461.0711, found
461.0710.
(6-Benzoyl-3-methoxy-[1,1′-biphenyl]-2-yl)(4-iodophenyl)-
methanone 3c. The product was obtained as a brown liquid in a 68%
yield (84 mg). Rf = 0.45 (20% EtOAc/hexanes). IR (neat): 3054,
1
2853, 1722, 1665, 1271,1126, 1081, 921, 694 cm−1. H NMR (400
1
72%). IR (neat): 3054, 1216, 1076, 876, 694 cm−1. H NMR (500
MHz, CDCl3): δ 7.68−7.65 (m, 3H), 7.58−7.56 (m, 2H), 7.40−7.37
(m, 1H), 7.34−7.32 (m, 2H), 7.28−7.24 (m, 2H), 7.08 (d, J = 8.5 Hz,
1H), 6.99−6.94 (m, 5H), 3.84 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 197.6, 195.4, 157.9, 140.3, 137.8, 137.5, 136.6, 136.4,
133.0, 132.6, 131.3, 130.4, 129.9, 129.6, 128.9, 127.9, 127.7, 127.6,
109.5, 56.0. HRMS (ESI) m/z: [M + H]+ Calcd for C27H20IO3
519.0457, found 519.0456.
MHz, CDCl3): δ 7.73−7.68 (m, 1H), 7.46−7.44 (m, 2H), 7.32−7.30
(m, 3H), 6.92−6.88 (m, 1H), 6.85−6.81 (m, 1H), 5.92 (s, 1H), 2.65
(br s, OH). 13C{1H} NMR (125 MHz, CDCl3): δ 164.0, 161.9, 161.3,
159.3, 131.7, 129.5, 128.7, 128.2, 114.4, 104.0, 90.2, 87.2, 86.7, 82.6,
58.9. HRMS (ESI) m/z: [M + H]+ Calcd for C15H11F2O 245.0778,
found 245.0780. Compounds 2a and 2c−2h have already been
reported in the literature.25a−d
(6-Benzoyl-3-methoxy-[1,1′-biphenyl]-2-yl)(4-methoxyphenyl)-
methanone 3d. The product was obtained as a brown liquid in a 63%
yield (62 mg). Rf = 0.51 (20% EtOAc/hexanes). IR (neat): 3059,
Representative Procedure for the Synthesis of Alkynones
4a−4c and 4h. Pd(PPh3)2Cl2 (11 mg, 0.016 mmol, 0.4 mol %) and
CuI (30 mg, 0.16 mmol, 4 mol %) were added sequentially to a
solution of but-3-yn-2-ol (308 mg, 4 mmol, 1 equiv) and 1-iodo-3-
nitrobenzene (1 g, 4 mmol, 1 equiv) in Et3N (10 mL) at room
temperature. The contents were stirred at the same temperature for 5
h. Then, the solvent was removed by filtration through a Celite pad.
The resulting crude product was oxidized using PCC (350 mg, 5
equiv) in acetone (10 mL) at room temperature. The completion of
the reaction took 4 h. The evaporation of solvents, followed by
purification by column chromatography (20% EtOAc/hexanes),
resulted in 4-(3-nitrophenyl)but-3-yn-2-one 4b as a brown solid
(574 mg, 76% over two steps); (mp 89−91 °C). IR (neat): 3054,
2930, 1717, 1216, 1076, 926, 694 cm−1. 1H NMR (400 MHz,
CDCl3): δ 8.35 (s, 1H), 8.27 (d, J = 7.6 Hz, 1H), 7.85 (d, J = 7.6 Hz,
1H), 7.60 (t, J = 7.6 Hz, 1H), 2. 47(s, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 183.9, 147.9, 138.2, 129.7, 127.3, 125.0, 121.5, 89.0,
86.2, 32.5. HRMS (ESI) m/z: [M + H]+ Calcd for C10H7NO3
190.0504, found 190.0500. Compounds 4a, 4c, and 4h have already
been reported in the literature.24
1
2837, 1722, 1660, 1257, 1123, 1019, 916, 766, 601 cm−1. H NMR
(400 MHz, CDCl3): δ 7.63 (d, J = 8.5 Hz, 1H), 7.60−7.57 (m, 2H),
7.56−7.54 (m, 2H), 7.36−7.34 (m, 1H), 7.23−7.20 (m, 2H), 7.08 (d,
J = 8.5 Hz, 1H) 7.07−7.04 (m, 2H), 7.03−6.91 (m, 3H), 6.90−6.73
(m, 2H), 3.83 (s, 3H), 3.77 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 198.0. 194.6, 163.5, 158.0, 140.1, 138.0, 136.8, 133.0,
132.4, 131.6, 131.0, 130.5, 130.0, 129.7, 129.6, 127.8, 127.5, 127.4,
113.4, 109.4, 56.0, 55.3. HRMS (ESI) m/z: [M + H]+ Calcd for
C28H23O4 423.1596, found 423.1597.
(2′-Chloro-3-methoxy-[1,1′-biphenyl]-2,6-diyl)bis-
(phenylmethanone) 3e. The product was obtained as a brown-
colored liquid in a 62% yield (86 mg). Rf = 0.55 (20% EtOAc/
hexanes). IR (neat): 3059, 2930, 1732, 1665, 1252,1179, 1066, 916,
771, 622 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.72−7.64 (m, 5H),
7.48−7.42 (m, 2H), 7.36−7.25 (m, 5H), 7.18−7.16 (m, 1H), 7.08 (d,
J = 8.5 Hz, 1H), 6.98−6.96 (m, 2H), 3.82 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 195.7, 195.5, 158.6, 138.40, 137.6, 137.0,
135.2, 133.8, 132.6, 132.5, 132.4, 131.8, 130.5, 130.0, 129.1, 128.8,
128.0, 128.9, 125.7, 109.4, 56.0. HRMS (ESI) m/z: [M + H]+ Calcd
for C27H2035ClO3 427.1101, found 427.1102.
(6-Benzoyl-2′-chloro-3-methoxy-[1,1′-biphenyl]-2-yl)(4-
iodophenyl)methanone 3f. The product was obtained as a brown
liquid in a 75% yield (84 mg). Rf = 0.54 (20% EtOAc/hexanes). IR
(neat): 3054, 2920, 1722, 1665, 1262,1123, 1061, 911, 756, 627 cm−1.
1H NMR (400 MHz, CDCl3): δ 7.71−7.64 (m, 5H), 7.49−7.45 (m,
1H), 7.38−7.23 (m, 4H), 7.16−7.15 (m, 1H), 7.07−6.98 (m, 4H),
3.82 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 195.6, 194.7,
158.5, 138.4, 137.6, 137.4, 136.3, 135.1, 132.6, 132.4, 132.0, 130.4,
130.0, 129.8, 129.1, 128.9, 128.0, 125.8, 109.3, 101.5, 56.0. HRMS
(ESI) m/z: [M + H]+ Calcd for C27H1935ClIO3 553.0067, found
553.0070.
Representative Procedure for the Synthesis of Biaryls from
Propargylic Alcohols and 1,3-Diketones and Analytical Data
of Compounds 3a−3x. A reaction flask (10 mL) was charged with
propargylic alcohol 2a (50 mg, 0.24 mmol, 1 equiv), benzoyl acetone
1a (49 mg, 0.24 mmol, 1 equiv), and HClO4 (70% aqueous solution,
16 μL, 0.24 mmol, 1 equiv) in nitromethane (1 mL) as a solvent.
After 15 min, trimethyl orthoformate (1 mL) and CuCl (5 mg, 0.048
mmol, 20 mol %) were added to the mixture, and the flask was sealed
with a stopper. The reaction mixture was stirred at room temperature
for 24 h. Solvents were evaporated in a rotary evaporator. The residue
was diluted with ethyl acetate and washed with water. The aqueous
layer was extracted twice with ethyl acetate, and the combined organic
layers were dried over sodium sulfate. After the evaporation of
solvents, the crude product was purified by column chromatography
(20% EtOAc/hexanes) to afford (3-methoxy-[1,1′-biphenyl]-2,6-
diyl)bis(phenylmethanone) 3a as a brown liquid (68 mg, 72%). Rf
= 0.54 (in 20% EtOAc/hexanes). IR (neat): 3054, 2930, 1717, 1655,
(6-Benzoyl-2′-chloro-3-methoxy-[1,1′-biphenyl]-2-yl)(2,4-
dichlorophenyl)methanone 3g. The product was obtained as a
brown liquid in a 63% yield (62 mg). Rf = 0.55 (20% EtOAc/
hexanes). IR (neat): 3054, 2925, 1722, 1660, 1262, 1123, 1061, 921,
870, 740 cm−1. 1H NMR (400 MHz, CDCl3): δ 7.67−7.64 (m, 3H),
7.48−7.45 (m, 1H), 7.35−7.32 (m, 2H), 7.26−7.22 (m, 2H), 7.12−
7.10 (m, 1H), 7.07−6.97 (m, 5H), 3.82 (s, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 195.6, 192.6, 159.0, 138.2, 137.8,137.7, 135.5, 135.3,
133.7, 133.0, 132.8, 132.5, 132.3, 132.2, 132.0, 130.8, 130.4, 130.0,
1
1216, 1076, 926, 694 cm−1. H NMR (400 MHz, CDCl3): δ 7.66−
7.59 (m, 3H), 7.58−7.53 (m, 2H), 7.43−7.34 (m, 3H), 7.26−7.24
(m, 2H), 7.23−7.16 (m, 3H), 7.07 (d, J = 8.0 Hz, 1H), 6.87−6.86 (m,
3H), 3.83 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 197.6,
196.1, 157.9, 140.2, 137.7, 137.2, 136.5, 133.0, 132.7, 132.4, 131.0,
H
https://doi.org/10.1021/acs.joc.1c01277
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
129.1, 128.9, 128.0, 126.6, 126.1, 109.7, 56.2. HRMS (ESI) m/z: [M
+ H]+ Calcd for C27H1835Cl3O3 495.0322, found 495.0320.
101.9, 56.0. HRMS (ESI) m/z: [M + H]+ Calcd for C27H1835Cl2IO3
586.9678, found 586.9679.
(2′-Bromo-3-methoxy-[1,1′-biphenyl]-2,6-diyl)bis-
(phenylmethanone) 3n. The product was obtained as a brown liquid
in a d63% yield (74 mg). Rf = 0.52 (20% EtOAc/hexanes). IR (neat):
(2′,4′-Difluoro-3-methoxy-[1,1′-biphenyl]-2,6-diyl)bis-
(phenylmethanone) 3h. The product was obtained as a brown liquid
in a 72% yield (63 mg). Rf = 0.52 (20% EtOAc/hexanes). IR (neat):
1
3054, 2925, 1727, 1665, 1252, 1164, 1055, 911, 709 cm−1. H NMR
1
3054, 2961, 1722, 1660, 1257, 1092, 1004, 962, 797, 622 cm−1. H
(400 MHz, CDCl3): δ 7.74 (d, J = 7.1 Hz, 2H), 7.67 (d, J = 7.6 Hz,
3H), 7.50−7.44 (m, 2H), 7.38−7.30 (m, 4H), 7.19 (d, J = 7.1 Hz,
2H), 7.07−7.04 (m, 2H), 6.90−6.87 (m, 1H), 3.84 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 197.5, 195.5, 158.6, 140.1, 137.7, 137.1,
133.2, 132.7, 132.6, 132.3, 132.0, 131.6, 130.5, 130.2, 129.2, 129.0,
128.1, 127.9, 126.4, 123.1, 109.2, 56.0. HRMS (ESI) m/z: [M + H]+
Calcd for C27H2079BrO3 471.0596, found 471.0595.
NMR (400 MHz, CDCl3): δ 7.67−7.63 (m, 5H), 7.49−7.46 (m, 2H),
7.36−7.31 (m, 4H), 7.09 (d, J = 8.0 Hz, 1H), 7.06−7.02 (m, 1H),
6.57 (dt, J = 8.0, 2.0 Hz, 1H) 6.38 (dt, J = 8.0, 2.0 Hz, 1H), 3.84 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ 196.3, 195.4, 162.3 (dd, J
= 247.8, 11.8 Hz), 159.7 (dd, J = 247.6, 12.3 Hz), 158.1, 137.8, 137.1,
133.8, 133.4, 132.9, 132.7, 132.6, 131.9, 130.8, 129.7, 129.1, 128.3,
128.1, 120.5, (dd, J = 16.2, 4.1 Hz), 110.8 (dd, J = 21.8, 3.5 Hz),
109.9, 103.3 (t, J = 25.5 Hz), 56.7. HRMS (ESI) m/z: [M + H]+
Calcd for C27H19F2O3 429.1302, found 429.1295.
(3-Ethoxy-[1,1′-biphenyl]-2,6-diyl)bis(phenylmethanone) 3o.
The product was obtained as a brown liquid in a 73% yield (68
mg). Rf = 0.58 (20% EtOAc/hexanes). IR (neat): 3411, 3054, 2925,
(6-Benzoyl-2′,4′-difluoro-3-methoxy-[1,1′-biphenyl]-2-yl)(4-
iodophenyl)methanone 3i. The product was obtained as a brown
liquid in a 49% yield (54 mg). Rf = 0.52 (20% EtOAc/hexanes). IR
1
1722, 1670, 1247, 1045, 946, 808, 694 cm−1. H NMR (400 MHz,
CDCl3): δ 7.62−7.55 (m, 5H), 7.43−7.37 (m, 1H), 7.35−7.27 (m,
1H), 7.26−7.20 (m, 5H), 7.07 (d, J = 8.0 Hz, 2H), 6.99−6.89 (m,
3H), 3.77 (q, J = 8.0 Hz, 2H), 1.23 (t, J = 8.0 Hz, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 197.6, 196.1, 157.9, 140.2, 137.7, 137.2,
136.5, 133.0, 132.7, 132.4, 131.0, 129.8, 129.5, 129.4, 129.0, 128.1,
127.8, 127.4, 127.3, 110.3, 64.4, 14.3. HRMS (ESI) m/z: [M + H]+
Calcd for C28H23O3 407.1647, found 407.1648.
1
(neat): 3065, 2920, 1722, 1660, 1092, 1004, 965, 730, 616 cm−1. H
NMR (400 MHz, CDCl3): δ 7.71−7.65 (m, 5H), 7.48−7.47 (m, 1H),
7.36−7.35 (m, 4H), 7.09−7.01 (m, 2H), 6.61 (s, 1H), 6.41 (m, 1H),
3.82 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 196.1, 194.6,
162.6 (dd, J = 249.1, 11.9 Hz), 159.7 (dd, J = 247.8, 11.7 Hz), 158.4,
137.8, 137.7, 136.9, 136.3, 133.8, 132.7, 132.1, 130.3, 130.1, 129.7,
128.1, 120.4 (dd, J = 16.1, 3.8 Hz), 110.8 (dd, J = 21.3, 3.4 Hz),
109.9, 103.5 (t, J = 25.8 Hz), 101.7, 56.0. HRMS (ESI) m/z: [M +
H]+ Calcd for C27H18F2IO3 555.0269, found 555.0267.
(6-Benzoyl-4-methoxy-[1,1′-biphenyl]-2-yl)(5-bromothiophen-2-
yl)methanone 3p. The product was obtained as a pale brown liquid
in a 68% yield (78 mg). Rf = 0.54 (20% EtOAc/hexanes). IR (neat):
1
3056, 2839, 1650, 1567, 1406, 1264, 1016, 987, 731 cm−1. H NMR
(3-Methoxy-4′-(trifluoromethyl)-[1,1′-biphenyl]-2,6-diyl)bis-
(phenylmethanone) 3j. The product was obtained as a brown liquid
in a 74% yield (86 mg); Rf = 0.53 (20% EtOAc/hexanes). IR (neat):
(500 MHz, CDCl3): δ 7.66 (d, J = 8.6 Hz, 1H), 7.54 (dd, J = 9.2, 1.5
Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.23 (t, J = 8.2 Hz, 2H), 7.09 (d, J =
8.6 Hz, 3H), 7.00−6.99 (m, 3H), 6.96 (d, J = 4.6 Hz, 1H), 6.90 (d, J
= 4.2 Hz, 1H), 3.88 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
197.6, 186.7, 157.9, 146.0, 140.2, 137.7, 136.4, 134.4, 132.8, 132.5,
131.5, 131.0, 130.0, 129.9, 128.4, 128.3, 127.8, 127.7, 127.6, 123.4,
109.5, 50.8. HRMS (ESI) m/z: [M + H]+ Calcd for C25H1879BrO3S
477.0160, found 477.0163.
1
3065, 2920, 1737, 1670, 1272, 1169, 1009, 916, 715, 622 cm−1. H
NMR (400 MHz, CDCl3): δ 7.67 (d, J = 8.0 Hz, 1H), 7.61 (dd, J =
7.8, 1.3 Hz, 2H), 7.57 (dd, J = 7.8, 1.4 Hz, 2H), 7.48−7.41 (m, 3H),
7.33−7.27 (m, 4H), 7.21−7.18 (m, 2H), 7.12 (m, 2H), 3.84 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 197.1, 195.7, 158.1, 140.4,
139.2, 138.0, 137.3, 133.4, 132.8, 132.6, 131.5, 130.3, 130.2, 129.8,
129.6, 129.3, 129.1, 128.4, 128.1, 124.4 (q, J = 3.6 Hz), 123.7 (q, J =
270.5 Hz), 121.6, 109.8, 56.1. HRMS (ESI) m/z: [M + H]+ Calcd for
C28H20F3O3 461.1365, found 461.1366.
(6-Benzoyl-4-methoxy-[1,1′-biphenyl]-2-yl)(furan-2-yl)-
methanone 3q. The product was obtained as a pale brown liquid in a
59% yield (54 mg). Rf = 0.56 (20% EtOAc/hexanes). IR (neat): 3005,
1
2915, 1709, 1687, 1564, 1389, 1273, 1017, 942, 823 cm−1. H NMR
(6-Benzoyl-3-methoxy-4′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)-
(4iodophenyl)methanone 3k. The product was obtained as a brown
liquid in a 58% yield (61 mg). Rf = 0.54 (20% EtOAc/hexanes). IR
(neat): 3065, 2920, 1732, 1670, 1272, 1164, 1009, 916, 715, 611
cm−1. 1H NMR (400 MHz, CDCl3): δ 7.71−7.59 (m, 3H), 7.58−7.47
(m, 2H), 7.47−7.45 (m, 1H), 7.44−7.32 (m, 6H), 7.31−7.12 (m,
3H), 3.85 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 196.7,
195.0, 158.0, 140.3, 139.7, 137.9, 137.8, 136.6, 132.9, 132.8, 131.7,
130.4, 130.2, 129.7, 129.2, 128.1, 124.8 (q, J = 3.5 Hz), 123.8 (q, J =
270.6 Hz) 109.1, 101.9, 56.1. HRMS (ESI) m/z: [M + H]+ Calcd for
C28H19F3IO3 587.0331, found 587.0330.
(500 MHz, CDCl3): δ 7.63 (d, J = 8.6 Hz, 1H), 7.52 (dd, J = 9.2, 1.9
Hz, 2H), 7.41 (d, J = 1.2 Hz, 1H), 7.34 (t, J = 7.3 Hz, 1H), 7.21 (t, J =
7.5 Hz, 2H), 7.06 (d, J = 8.6 Hz, 3H), 6.95−6.94 (m, 3H), 6.76 (d, J
= 3.6 Hz, 1H), 6.32 (dd, J = 5.2 1.4 Hz, 1H), 3.86 (s, 3H). 13C{1H}
NMR (100 MHz, CDCl3): δ 197.7, 183.0, 158.1, 153.0, 146.9, 140.5,
137.8, 136.5, 132.7, 132.4, 131.4, 129.8, 129.5, 128.3, 127.8, 127.6,
127.5, 119.7, 112.4, 109.5, 56.0. HRMS (ESI) m/z: [M + H]+ Calcd
for C25H19O4 383.1283, found 383.1288.
(4-Methoxy-2-(naphthalen-1-yl)-1,3-phenylene)bis-
(phenylmethanone) 3r. The product was obtained as a pale brown
liquid in a 66% yield (89 mg). Rf = 0.46 (20% EtOAc/hexanes). IR
(neat): 3243, 2925, 1665, 1594, 1385, 1254, 1053, 981, 797 cm−1. 1H
NMR (500 MHz, CDCl3): δ 7.76 (d, J = 8.6 Hz, 1H), 7.56 (d, J = 7.9
Hz, 1H), 7.50−7.46 (m, 3H), 7.38 (d, J = 8.6 Hz, 1H), 7.33 (d, J =
7.6 Hz, 2H), 7.25−7.20 (m, 5H), 7.17 (d, J = 8.4 Hz, 1H), 7.10 (t, J =
7.8 Hz, 2H), 7.06 (t, J = 8.0 Hz, 2H), 6.99 (t, J = 8.1 Hz, 1H), 3.86 (s,
3H). 13C{1H} NMR (125 MHz, CDCl3): δ 197.1, 195.6, 158.4, 138.8,
137.8, 137.1, 133.7, 133.6, 132.8, 132.7, 131.9, 131.7, 131.6, 130.7,
129.0, 128.8, 128.1, 127.8, 127.6, 127.4, 126.3, 125.6, 125.4, 124.0,
109.7, 56.0. HRMS (ESI) m/z: [M + H]+ Calcd for C31H23O3
443.1647, found 443.1651.
(2′,4′-Dichloro-3-methoxy-[1,1′-biphenyl]-2,6-diyl)bis-
(phenylmethanone) 3l. The product was obtained as a brown liquid
in a 68% yield (54 mg). Rf = 0.54 (20% EtOAc/hexanes). IR (neat):
1
3059, 2915, 1722, 1665, 1241, 1055, 1009, 916, 704, 622 cm.−1; H
NMR (400 MHz, CDCl3): δ 7.70−7.63 (m, 2H), 7.53−7.50 (m, 3H),
7.48−7.39 (m, 2H), 7.25−7.20 (m, 4H), 7.06−7.68 (m, 4H), 3.83 (s,
3H). 13C{1H} NMR (100 MHz, CDCl3): δ 195.6, 195.3, 158.8, 137.6,
137.5, 137.0, 134.2, 134.0, 133.5, 133.2, 132.7, 132.6, 130.7, 130.1,
129.2, 128.8, 128.3, 128.2, 126.2, 126.1, 109.5, 56.9. HRMS (ESI) m/
z: [M + H]+ Calcd for C27H19Cl2O3 461.0711, found 461.0709.
(6-Benzoyl-2′,4′-dichloro-3-methoxy-[1,1′-biphenyl]-2-yl)(4-
iodophenyl)methanone 3m. The product was obtained as a brown
liquid in a 62% yield (66 mg). Rf = 0.55 (20% EtOAc/hexanes). IR
(neat): 3054, 2920, 1732, 1670, 1262, 1179, 1066, 999, 740 cm−1. 1H
NMR (400 MHz, CDCl3): δ 7.72−7.69 (m, 4H), 7.66 (d, J = 8.8 Hz,
1H), 7.53 (tt, J = 8.7, 2.0 Hz, 1H), 7.41−7.37 (m, 4H), 7.12−7.02
(m, 4H), 3.83 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 195.4,
194.5, 158.6, 137.6, 137.5, 137.4, 136.2, 134.3, 133.8, 133.4, 133.2,
132.8, 132.7, 131.9, 130.5, 130.1, 130.0, 128.9, 128.1, 126.3, 109.5,
(6-(1-Naphthoyl)-5-methoxy-[1,1′-biphenyl]-2-yl)(phenyl)-
methanone 3s. The product was obtained as a pale brown liquid in a
60% yield (64 mg). Rf = 0.49 (20% EtOAc/hexanes). IR (neat): 3062,
1
2928, 1713, 1663, 1464, 1361, 1106, 914, 731 cm−1. H NMR (500
MHz, CDCl3): δ 8.85 (d, J = 8.3 Hz, 1H), 7.81 (d, J = 7.9 Hz, 1H),
7.70 (d, J = 7.9 Hz, 1H), 7.63 (d, J = 8.3 Hz, 1H), 7.54 (dd, J = 8.3,
1.2 Hz, 2H), 7.49 (tt, J = 8.3, 1.2 Hz, 1H), 7.41 (tt, J = 8.3, 1.2 Hz,
2H), 7.32 (tt, J = 7.4, 1.2 Hz, 2H), 7.19 (d, J = 7.9 Hz, 2H), 7.08 (d, J
= 8.3 Hz, 1H), 7.00 (d, J = 8.3 Hz, 2H), 6.75 (t, J = 7.5 Hz, 2H), 6.68
I
https://doi.org/10.1021/acs.joc.1c01277
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
(tt, J = 7.3, 1.3 Hz, 1H), 3.88 (s, 3H). 13C{1H} NMR (125 MHz,
CDCl3): δ 197.7, 197.5, 158.0, 140.3, 137.9, 136.8, 134.2, 133.7,
133.5, 132.9, 132.4, 132.0, 131.3, 130.9, 130.4, 129.8, 129.5, 127.9,
127.8, 127.3, 127.0, 126.1, 126.0, 123.9, 109.6, 56.0. HRMS (ESI) m/
z: [M + H]+ Calcd for C31H23O3 443.1647, found 443.1649.
mmol, 2 equiv), and HClO4 (24 μL, 0.36 mmol, 1.5 equiv) in
nitromethane (1 mL). The reaction mixture was stirred at ambient
temperature. The alkynone was converted to its corresponding 1,3-
diketone derivative in 4 h. Then, propargylic alcohol derivative 2a (50
mg, 0.24 mmol, 1 equiv) was added to the reaction mixture. After
then 15 min, TMOF (1 mL) and CuCl (5 mg, 0.048 mmol, 20 mol
%) were added to the mixture. and the flask was sealed with a stopper.
The reaction mixture was stirred at room temperature for 24 h.
Solvents were evaporated using a rotary evaporator. The resulting
residue was diluted with ethyl acetate and washed with water. The
aqueous layer extracted twice with ethyl acetate, and the combined
organic phase was dried over anhydrous sodium sulfate. After the
evaporation of the solvents, the crude product was purified by column
chromatography (20% EtOAc/hexanes) to get the biaryl product 3y
as a yellow colored liquid (60 mg, 58%). Rf = 0.56 (20% EtOAc/
hexanes). IR (neat): 3085, 2943, 1680, 1665, 1283,1123, 1086, 704,
Ethyl 6-Benzoyl-3-methoxy-[1,1′-biphenyl]-2-carboxylate 3t.
The product was obtained as a pale brown liquid in a 78% yield
(68 mg). Rf = 0.60 (20% EtOAc/hexanes). IR (neat): 3431, 3059,
1
2977, 1732, 1587, 1272, 1014, 973, 694 cm−1. H NMR (400 MHz,
CDCl3): δ 7.56−7.54 (m, 3H), 7.40−7.36 (m, 1H), 7.26−7.22 (m,
2H), 7.17−7.11 (m, 5H), 7.02 (d, J = 8.0 Hz, 1H), 4.03 (q, J = 8.0
Hz, 2H), 3.94 (s, 3H), 0.89 (t, J = 8.0 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 197.2, 166.8, 157.5, 140.4, 137.9, 137.3, 132.5,
132.4, 131.2, 129.6, 129.2, 127.9, 127.7, 127.6, 124.9, 109.4, 61.1,
56.1, 13.5. HRMS (ESI) m/z: [M + H]+ Calcd for C23H21O4
361.1440, found 361.1441.
1
658 cm−1. H NMR (400 MHz, CDCl3): δ 8.38 (t, J = 1.7 Hz, 1H),
Ethyl 6-Benzoyl-4′-bromo-3-methoxy-[1,1′-biphenyl]-2-carboxy-
late 3u. The product was obtained as a yellow liquid in a 61% yield
(46 mg). Rf = 0.62 (20% EtOAc/hexanes). IR (neat): 3059, 2977,
8.25 (qt, J = 8.0, Hz, 1.7 Hz, 1H), 7.89 (td, J = 7.7, 1.7 Hz, 1H), 7.70
(d, J = 8.7 Hz, 1H), 7.58−7.56 (m, 2H), 7.46 (t, J = 8.0 Hz, 1H), 7.38
(tt, J = 1.7, 3.0 Hz, 1H), 7.27−7.23 (m, 2H), 7.14 (d, J = 8.7 Hz, 1H),
6.99−6.97 (m, 2H), 6.93−6.90 (m, 3H), 3.86 (s, 3H). 13C{1H} NMR
(100 MHz, CDCl3): δ 197.2, 194.0, 158.0, 148.1, 140.5, 138.5, 137.7,
136.3, 134.4, 133.0, 132.6, 132.0, 129.8, 129.6, 129.4, 128.0, 127.9,
127.8, 127.2, 123.8, 109.5, 56.1. HRMS (ESI) m/z: [M + H]+ Calcd
for C27H20NO5 438.1341, found 438.1340. Compounds 3y−3ad were
synthesized following the above general procedure.
1
1732, 1577, 1272, 1097, 978, 828, 709 cm−1. H NMR (400 MHz,
CDCl3): δ 7.58−7.53 (m, 3H), 7.47−7.43 (m, 1H), 7.31−7.27 (m,
4H), 7.06−7.01 (m, 3H), 4.05 (q, J = 7.0 Hz, 2H), 3.95 (s, 3H), 0.97
(t, J = 7.0 Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 196.8,
166.6, 157.6, 139.2, 137.8, 136.2, 132.8, 132.1, 131.5, 131.0, 130.9,
129.7, 128.1, 125.0. 122.0, 109.6, 61.3, 56.2, 13.7. HRMS (ESI) m/z:
[M + H]+ Calcd for C23H20BrO4 439.0545, found 439.0549.
Ethyl 6-Benzoyl-2′,4′-difluoro-3-methoxy-[1,1′-biphenyl]-2-car-
boxylate 3v. The product was obtained as a pale yellow liquid in a
67% yield (53 mg). Rf = 0.63 (20% EtOAc/hexanes). IR (neat): 3059,
(6-Benzoyl-4′-bromo-3-methoxy-[1,1′-biphenyl]-2-yl)(3-
nitrophenyl)methanone 3z. The product was obtained as a brown
liquid in a 57% yield (49 mg). Rf = 0.55 (20 EtOAc/hexanes). IR
(neat): 3085, 2961, 1686, 1660, 1273,1173, 1081, 880, 715 cm−1. 1H
NMR (400 MHz, CDCl3): δ 8.40 (t, J = 1.7 Hz, 1H), 8.32−8.30 (m,
1H), 7.94 (d, J = 7.9 Hz, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.61−7.59
(m, 2H), 7.53 (t, J = 7.8 Hz, 1H), 7.49−7.44 (m, 2H), 7.31 (t, J = 7.9
Hz, 1H), 7.13 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 8.6 Hz, 2H), 6.87 (d, J
= 8.6 Hz, 2H), 3.58 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ
196.8, 193.7, 158.0, 148.3, 139.5, 138.4, 137.7, 135.3, 134.3, 133.6,
133.0, 132.9, 132.1, 131.8, 131.3, 131.0, 130.5, 129.8, 129.6, 128.5,
128.2, 128.1, 128.0, 127.8, 127.5, 123.9, 122.3, 109.9, 56.1. HRMS
(ESI) m/z: [M + H]+ Calcd for C27H19BrNO5 516.0447, found
516.0447.
(6-Benzoyl-2′-bromo-3-methoxy-[1,1′-biphenyl]-2-yl)(3-
nitrophenyl)methanone 3aa. The product was obtained as brown
liquid in a 55% yield (47 mg). Rf = 0.54 (20% EtOAc/hexanes). IR
(neat): 3085, 2941, 1686, 1660, 1272,1174, 1081, 859, 720 cm−1. 1H
NMR (400 MHz, CDCl3): δ 8.46 (t, J = 1.7 Hz, 1H), 8.30 (qt, J = 8.0,
1.7 Hz, 1H), 7.98−7.96 (m, 1H), 7.73 (t, J = 8.0, Hz, 3H), 7.52−7.48
(m, 2H), 7.38 (t, J = 8.0, Hz, 2H), 7.21 (dd, J = 7.6, 1.7 Hz, 1H), 7.15
(dd, J = 7.6, 1.7 Hz, 1H), 7.12−7.09 (m, 2H), 6.92 (dt, J = 7.6, 1.7
Hz, 1H), 387 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 195.2,
193.4, 158.6, 148.0, 140.4, 138.4, 137.5, 136.8, 134.4, 133.4, 132.8,
132.6, 132.2, 132.0, 130.2, 130.1, 129.4, 129.3, 129.1, 128.4, 128.0,
127.3, 126.5, 124.0, 123.0, 109.6, 56.1. HRMS (ESI) m/z: [M + H]+
Calcd for C27H1979BrNO5 516.0447, found 516.0451.
1
2977, 1727, 1598, 1267, 1019, 968, 849, 730 cm−1. H NMR (400
MHz, CDCl3): δ 7.64−7.62 (m, 2H), 7.57 (d, J = 8.7 Hz, 1H), 7.51−
7.47 (m, 1H), 7.35 (t, J = 7.5 Hz, 2H), 7.23−7.17 (m, 1H), 7.03 (d, J
= 8.7 Hz, 1H), 6.77 (dt, J = 9.0, 2.0 Hz, 1H), 6.64 (dt, J = 9.0, 2.0 Hz,
1H), 4.07 (q, J = 7.2 Hz, 2H), 3.95 (s, 3H), 0.99 (t, J = 7.2 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 196.0, 166.2, 162.2 (dd, J =
249.1, 12.3 Hz), 159.4 (dd, J = 253.2, 12.6 Hz), 158.0, 137.7, 133.8,
132.7, 132.2, 132.1, 129.7, 128.9, 128.6, 128.1, 126.0, 121.2 (dd, J =
17.0, 4.3 Hz), 110.7 (dd, J = 21.4, 3.2 Hz), 110.9, 103.7 (t, J = 25.9
Hz), 61.3, 56.1, 13.7. 19F NMR (470 MHz, CDCl3): δ −108.8 (d, J =
9.4 Hz), −109 (d, J = 9.4 Hz). HRMS (ESI) m/z: [M + H]+ Calcd
for C23H19F2O4 397.1251, found 397.1256.
Ethyl 6-Benzoyl-3-methoxy-4′-(trifluoromethyl)-[1,1′-biphenyl]-
2-carboxylate 3w. The product was obtained as a yellow-colored
liquid in a 53% yield (41 mg). Rf = 0.63 (20% EtOAc/hexanes). IR
1
(neat): 3059, 2977, 1727, 1598, 1267, 1019, 968, 849, 730 cm−1. H
NMR (400 MHz, CDCl3): δ 7.59−7.55 (m, 3H), 7.44−7.41 (m, 3H),
7.31−7.29 (m, 4H), 7.05 (d, J = 8.7 Hz, 1H), 4.03 (q, J = 7.2 Hz,
2H), 3.96 (s, 3H), 0.90 (t, J = 7.2 Hz, 3H). 13C{1H} NMR (100
MHz, CDCl3): δ 196.6, 166.4, 157.7, 141.1, 139.2, 137.9, 132.9,
132.0, 131.7, 129.9, 129.7, 128.6, 128.2, 128.0, 125.1, 125.0, 124.6 (q,
J = 3.6 Hz), 123.9 (q, J = 270.6 Hz) 109.9, 61.4, 58.2, 13.5. 19F NMR
(470 MHz, CDCl3): δ −62.8. HRMS (ESI) m/z: [M + H]+ Calcd for
C24H20F3O4 429.1314, found 429.1316.
(6-Benzoyl-2′-chloro-3-methoxy-[1,1′-biphenyl]-2-yl)(3-
nitrophenyl)methanone 3ab. The product was obtained brown
liquid in a 58% yield (66 mg). Rf = 0.55 (20% EtOAc/hexanes). IR
(neat): 3080, 2925, 1727, 1660, 1267, 1174, 1086, 864, 715 cm−1. 1H
NMR (400 MHz, CDCl3): δ 8.44 (s, 1H), 8.30 (d, J = 9.6 Hz, 1H),
7.96 (d, J = 8.5 Hz, 1H), 7.72−7.71 (m, 3H), 7.52−7.48 (m, 2H),
7.37 (t, J = 8.5 Hz, 2H), 7.18 (d, J = 9.6 Hz, 1H), 7.12 (d, J = 8.5 Hz,
1H), 7.04 (t, J = 7.5 Hz, 1H), 7.00−6.94 (m, 2H), 3.86 (s, 3H).
13C{1H} NMR (100 MHz, CDCl3): δ 195.4, 193.3, 158.6, 148.1,
138.8, 138.5, 137.5, 135.0, 134.4, 133.2, 132.6, 132.2, 130.0, 129.3,
129.1, 129.0, 128.5, 128.0, 127.4, 126.0, 123.9, 109.7, 56.1. HRMS
(ESI) m/z: [M + H]+ Calcd for C27H1935ClNO5 472.0952, found
472.0952.
Ethyl 6-Benzoyl-2′-bromo-3-methoxy-[1,1′-biphenyl]-2-carboxy-
late 3x. The product was obtained as a pale yellow liquid in a 68%
yield (51 mg). Rf = 0.62 (20% EtOAc/hexanes). IR (neat): 3416,
1
2917, 1727, 1577, 1272, 1009, 978, 828, 715 cm−1. H NMR (400
MHz, CDCl3): δ 7.70−7.68 (m, 2H), 7.58 (d, J = 8.6 Hz, 1H), 7.51−
7.47 (m, 1H), 7.46−7.43 (m, 1H), 7.38−7.34 (m, 2H), 7.31−7.28
(m, 1H), 7.24−7.22 (m, 1H), 7.10 (dt, J = 8.2, 2.4 Hz, 1H), 7.01 (d, J
= 8.6 Hz, 1H), 4.01 (q, J = 7.2 Hz, 2H), 3.95 (s, 3H), 0.90 (t, J = 7.2
Hz, 3H). 13C{1H} NMR (100 MHz, CDCl3): δ 195.4, 166.1, 158.1,
140.4, 138.1, 137.7, 133.0, 132.7, 132.6, 132.3, 132.1, 132.0, 131.7,
131.5, 131.0, 130.2, 130.1, 129.3, 129.0, 128.1, 127.8, 125.4, 123.3,
109.4, 109.1, 61.2, 56.2, 13.6. HRMS (ESI) m/z: [M + H]+ Calcd for
C23H2079BrO4 439.0545, found 439.0551.
(6-Benzoyl-2′-chloro-3-methoxy-[1,1′-biphenyl]-2-yl)(4-
fluorophenyl)methanone 3ac. The product was obtained as a yellow
liquid in a 57% yield (50 mg). Rf = 0.54 (20% EtOAc/hexanes). IR
(neat): 3049, 2920, 1722, 1665, 1262, 1148, 1061, 914, 746 cm−1. 1H
Representative Procedure for the Synthesis of Biaryls from
Alkynones and Propargylic Alcohols and Analytical Data of
Compounds 3y−3ad. A 10 mL reaction flask was charged with
alkynone 4b (68 mg, 0.36 mmol, 1.5 equiv), TMOF (57 μL, 0.72
J
https://doi.org/10.1021/acs.joc.1c01277
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
NMR (400 MHz, CDCl3): δ 7.72−7.66 (m, 5H), 7.50−7.46 (m, 1H),
7.35 (t, J = 7.5 Hz, 2H), 7.17 (d, J = 6.5 Hz, 1H), 7.07 (4, J = 7.5 Hz,
1H), 7.06−6.95 (m, 5H), 385 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 195.7, 193.5, 167.5 (d, J = 253.8 Hz), 158.5, 138.4, 137.6,
135.1, 133.6, 132.6, 132.5, 132.4, 132.0, 131.9, 131.7, 130.2, 130.0,
129.1, 129.0, 128.0, 125.9, 115.3 (d, J = 21.8 Hz), 109.3, 56.4. HRMS
(ESI) m/z: [M + H]+ Calcd for C27H1935ClFO3 445.1007, found
445.1006.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c01277
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(6-Benzoyl-4′-bromo-3-methoxy-[1,1′-biphenyl]-2-yl)(4-
chlorophenyl)methanone 3ad. The product was obtained as a
yellow liquid in a 59% yield (52 mg). Rf = 0.52 (20% EtOAc/
hexanes). IR (neat): 3059, 2925, 1722, 1665, 1278, 1174, 1092, 916,
The work was supported SERB India. The authors thank
financial support to UoH-IoE by MHRD (F11/9/2019-
U3(A)). T.C. and S.M. are thankful to UGC, India and
CSIR, India, respectively, for their fellowship.
1
839, 720 cm−1. H NMR (400 MHz, CDCl3): δ 7.64 (d, J = 8.5 Hz,
1H), 7.58- 7.54 (m, 4H), 7.45−7.42 (m, 1H), 7.30−7.27 (m, 4H),
7.09 (m, 3H), 6.67 (m, 2H), 3.83 (s, 3H). 13C{1H} NMR (100 MHz,
CDCl3): δ 197.2, 194.6, 158.0, 140.0, 139.2, 137.7, 135.6, 135.4,
132.9, 132.8, 131.5, 131.4, 130.9, 130.5, 129.7, 129.1, 128.8, 128.1,
122.1, 109.7, 56.1. HRMS (ESI) m/z: [M + H]+ Calcd for
C27H1979BrClO3 505.0206, found 505.0209.
REFERENCES
■
(1) (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Palladium-
Catalyzed Cross-Coupling Reactions in TotalSynthesis. Angew. Chem.,
Int. Ed. 2005, 44, 4442−4489. (b) Bringmann, G.; Mortimer, A. J. P.;
Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M. Atroposelective
Synthesis of Axially Chiral Biaryl Compounds. Angew. Chem., Int. Ed.
2005, 44, 5384−5427.
(2) (a) Sharpe, M.; Jarvis, B.; Goa, K. L. Telmisartan: A Review of its
Use in Hypertension. Drugs 2001, 61, 1501−1529. (b) Yusuf, S. From
the Hope to the Ontarget and the Transcend Studies: Challenges in
Improving Prognosis. Am. J. Cardiol. 2002, 89, 18−25.
(3) (a) Cammidge, A. N.; Crepy, K. V. L. Application of the Suzuki
Reaction as the Key Step in the Synthesis of a Novel Atropisomeric
Biphenyl Derivative for Use as a Liquid Crystal Dopant. J. Org. Chem.
2003, 68, 6832−6835. (b) Cepanec, I. Synthesis of Biaryls; Elsevier:
New York, NY, 2004. (c) Su, S.-J.; Tanaka, D.; Li, Y.-J.; Sasabe, H.;
Takeda, T.; Kido, J. Novel Four-Pyridylbenzene-Armed Biphenyls as
Electron-Transport Materials for Phosphorescent OLEDs. Org. Lett.
2008, 10, 941−944.
(3-Hydroxy-[1,1′-biphenyl]-2,6-diyl)bis(phenylmethanone) 6.
BBr3 (1.0 M solution in CH2Cl2, 20 μL, 0.28 mmol) was charged
to a stirring solution of CHCl3 (1 mL) and compound 3a (57 mg,
0.14 mmol) in a 5 mL round-bottom flask at ambient temperature
under N2. After 4 h, water was added to the reaction mixture and was
then extracted with chloroform. The organic phase was separated,
then washed with an aqueous NH4Cl solution and dried over
anhydrous Na2SO4. Solvents were evaporated under reduced pressure,
and the resultant residue was purified by column chromatography
with 30% EtOAc/hexanes to afford product 6 as a yellow liquid (50
mg, 92%). Rf = 0.39 (30% EtOAc/hexanes). IR (neat): 3049, 2920,
1
1722, 1665, 1262, 1148, 1061, 914, 715 cm−1. H NMR (400 MHz,
CDCl3): δ 8.50−8.02 (m, 2H), 7.63−7.59 (m, 1H), 7.58−7.54 (m,
5H), 7.50−7.47 (m, 3H) 7.33 (d, J = 9.6 Hz, 1H), 7.23−7.21 (m,
1H), 7.12−7.08 (m, 1H), 6.99−6.97 (m, 2H), 6.19 (d, J = 9.6 Hz,
1H). 13C{1H} NMR (100 MHz, CDCl3): δ 195.4, 186.3, 154.2, 146.7,
143.3, 136.2, 135.9, 134.4, 134.2, 133.9, 131.7, 130.4, 130.1, 129.8,
129.5, 129.1, 128.9, 128.8, 127.1, 125.3, 124.4. HRMS (ESI) m/z: [M
+ Na]+ Calcd for C26H18O3Na 401.1154, found 401.1151
(4) (a) Nicolaou, K. C.; Boddy, C. N. C.; Brase, S.; Winssinger, N.
Chemistry, Biology, and Medicine of the Glycopeptide Antibiotics.
Angew. Chem., Int. Ed. 1999, 38, 2096−2152. (b) Boisnard, S.;
Carbonnelle, A. C.; Zhu, J. Studies on the Total Synthesis of RP
66453: Synthesis of Fully Functionalized 15-Membered Biaryl-
Containing Macrocycle. Org. Lett. 2001, 3, 2061−2064. (c) Croom,
K. F.; Keating, G. M. Valsartan: A Review of Its Use in Patients with
Heart Failure and/or Left Ventricular Systolic Dysfunction after
Myocardial Infarction. Am. J. Cardiovasc. Drugs 2004, 4, 395−404.
(d) Goossen, L. J.; Melzer, B. Synthesis of Valsartan via
Decarboxylative Biaryl Coupling. J. Org. Chem. 2007, 72, 7473−
7476. (e) Yamaguchi, J.; Yamaguchi, A. D.; Itami, K. C-H Bond
Functionalization: Emerging Synthetic Tools for Natural Products
and Pharmaceuticals. Angew. Chem., Int. Ed. 2012, 51, 8960−9009.
(5) For reviews for catalysis and biaryl systems, see: (a) Hassan, J.;
Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Aryl−Aryl Bond
Formation One Century after the Discovery of the Ullmann Reaction.
Chem. Rev. 2002, 102, 1359−1469. (b) Lloyd-Williams, P.; Giralt, E.
Atropisomerism, Biphenyls and the Suzuki Coupling: Peptide
Antibiotics. Chem. Soc. Rev. 2001, 30, 145−157. (c) Brunel, J. M.
BINOL: A Versatile Chiral Reagent. Chem. Rev. 2005, 105, 857−898.
(d) Corbet, J.-P.; Mignani, G. Selected Patented Cross-Coupling
Reaction Technologies. Chem. Rev. 2006, 106, 2651−2710.
(e) Ashenhurst, J. A. Intermolecular Oxidative Cross-Coupling of
Arenes. Chem. Soc. Rev. 2010, 39, 540−548. (f) Bringmann, G.;
Gulder, T.; Gulder, T. A. M.; Breuning, M. Atroposelective Total
Synthesis of Axially Chiral Biaryl Natural Products. Chem. Rev. 2011,
111, 563−639. (g) van Leeuwen, P. W. N. M.; Kamer, P. C. J.; Claver,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c01277.
■
sı
Copies of NMR spectra, HRMS analysis reports of the
all new compounds, and X-ray crystallographic data of
the compound 3i(PDF)
Accession Codes
CCDC 2031090 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK. fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
Rengarajan Balamurugan − School of Chemistry, University of
Hyderabad, Gachibowli, Hyderabad, India 500046;
orcid.org/0000-0002-8373-5736; Email: bala@
uohyd.ac.in
̀
C.; Pamies, O.; Diéguez, M. Phosphite-Containing Ligands for
Asymmetric Catalysis. Chem. Rev. 2011, 111, 2077−2118. (h) Wen-
cel-Delord, J.; Panossian, A.; Leroux, F. R.; Colobert, F. Recent
Advances and New Concepts for the Synthesis of Axially Stereo-
enriched Biaryls. Chem. Soc. Rev. 2015, 44, 3418−3430.
Authors
Chandrahas Tarigopula − School of Chemistry, University of
Hyderabad, Gachibowli, Hyderabad, India 500046
Seetharaman Manojveer − School of Chemistry, University of
Hyderabad, Gachibowli, Hyderabad, India 500046
(6) (a) Metal-Catalyzed Cross-Coupling Reactions; de Meijere, A.,
Diederich, F., Eds.; Wiley-VCH: Weinheim, Germany, 2004. (b)
Modern Arylation Methods; Ackermann, L., Ed.; Wiley-VCH:
Weinheim, Germany, 2009. (c) Transition Metals for Organic
K
https://doi.org/10.1021/acs.joc.1c01277
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Synthesis; Beller, M., Bolm, C., Eds.; Wiley-VCH: Weinheim,
Germany, 2004. (d) Hartwig, J. F. Organotransition Metal Chemistry;
University Science Books: Sausalito, CA, 2010.
(7) (a) Lou, S.-J.; Mao, Y.-J.; Xu, D.-Q.; He, J.-Q.; Chen, Q.; Xu, Z.-
U. Fast and Selective Dehydrogenative C−H/C−H Arylation Using
Mechanochemistry. ACS Catal. 2016, 6, 3890−3894. (b) Paira, R.;
Singh, B.; Hota, P. K.; Ahmed, J.; Sau, S. C.; Johnpeter, J. P.; Mandal,
S. K. Open-Shell Phenalenyl in Transition Metal-Free Catalytic C−H
Functionalization. J. Org. Chem. 2016, 81, 2432−2441.
(8) (a) Garcia-López, J.-A.; Greaney, M. F. Synthesis of biaryls using
aryne intermediates. Chem. Soc. Rev. 2016, 45, 6766−6798.
(b) Zhang, J.; Niu, D.; Brinker, V. A.; Hoye, T. R. The Phenol−
Ene Reaction: Biaryl Synthesis via Trapping Reactions between
HDDA-Generated Benzynes and Phenolics. Org. Lett. 2016, 18,
5596−5599. (c) Lee, N. K.; Yun, S. Y.; Mamidipalli, P.; Salzman, R.
M.; Lee, D.; Zhou, T.; Xia, T. Hydroarylation of Arynes Catalyzed by
Silver for Biaryl Synthesis. J. Am. Chem. Soc. 2014, 136, 4363−4368.
(9) (a) Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef,
B. C−C Bond Formation via Double C−H Functionalization: Aerobic
Oxidative Coupling as a Method for Synthesizing Heterocoupled
Biaryls. Org. Lett. 2007, 9, 3137−3139. (b) Laha, J. K.; Jethava, K. P.;
Dayal, N. Palladium-Catalyzed Intramolecular Oxidative Coupling
Involving Double C(sp2)−H Bonds for the Synthesis of Annulated
Biaryl Sultams. J. Org. Chem. 2014, 79, 8010−8019.
(10) (a) Yong, G.-P.; She, W.-L.; Zhang, Y.-M.; Li, Y.-Z. Direct
Arylation of Unactivated Aromatic C−H Bonds Catalyzed by a Stable
Organic Radical. Chem. Commun. 2011, 47, 11766−11768.
(11) (a) He, Z.; Perry, G. J. P.; Procter, D. J. Sulfoxide-mediated
oxidative cross-coupling of phenols. Chem. Sci. 2020, 11 (11), 2001−
2005. (b) Pulis, A. P.; Procter, D. J. C-H Coupling Reactions Directed
by Sulfoxides: Teaching an Old Functional Group New Tricks. Angew.
Chem., Int. Ed. 2016, 55, 9842−9860.
(12) Music, A.; Baumann, A. N.; Spieß, P.; Plantefol, A.; Jagau, T.
C.; Didier, D. Electrochemical Synthesis of Biaryls via Oxidative
Intramolecular Coupling of Tetra(hetero)arylborates. J. Am. Chem.
Soc. 2020, 142, 4341−4348.
(13) Wu, K.; Wu, L. L.; Zhou, C. Y.; Che, C. M. Transition-Metal-
Free C(sp2)−C(sp2) Cross-Coupling of Diazo Quinones with
Catechol Boronic Esters. Angew. Chem., Int. Ed. 2020, 59, 16202−
16208.
Acetals with 1,3-Bisnucleophiles: An Efficient Method of Construct-
ing Six-Membered Aromatic Rings, Including Salicylates and
Carbazoles. Adv. Synth. Catal. 2018, 360, 2727−2741. (g) Minuti,
L.; Temperini, A.; Ballerini, E. High-Pressure-Promoted Diels−Alder
Approach to Biaryls: Application to the Synthesis of the Cannabinols
Family. J. Org. Chem. 2012, 77, 7923−7931. (h) Xi, C.; Chen, C.; Lin,
J.; Hong, X. Pd-Catalyzed One-Pot Multicomponent Coupling
Reaction for the Highly Regioselective Synthesis of Polysubstituted
Benzenes. Org. Lett. 2005, 7, 347−349. (i) Kinoshita, H.; Takahashi,
H.; Miura, K. Regioselective Synthesis of Multisubstituted Benzenes
by Palladium-Catalyzed Intermolecular Reaction of β-Iodo-β-
silylstyrenes with Alkynes. Org. Lett. 2013, 15, 2962−2965.
(17) For recent works, see: (a) Mandal, M.; Sakthivel, S.;
Balamurugan, R. Brønsted/Lewis Acid-Promoted Site-Selective Intra-
molecular Cycloisomerizations of Aryl-Fused 1,6-Diyn-3-ones for
Diversity Oriented Synthesis of Benzo-Fused Fluorenes and
Fluorenones and Naphthyl Ketones. J. Org. Chem. 2021, 86, 333−
351. (b) Mandal, M.; Balamurugan, R. Triflic acid-Mediated
Expedient Synthesis of Benzo[a]fluorenes and Fluorescent Benzo[a]-
fluorenones. Adv. Synth. Catal. 2018, 360, 1453−1465. For works
involving the activation of the α-carbon of unactivated ketones using
in situ formed acetals, see: (c) Koppolu, S. R.; Balamurugan, R. In situ
formed acetals facilitated direct Michael addition of unactivated
ketones. New J. Chem. 2017, 41, 1186−1192. (d) Manojveer, S.;
Balamurugan, R. In Situ Formed Acetal-Facilitated Synthesis of
Substituted Indene Derivatives from o-Alkenylbenzaldehydes. Org.
Lett. 2015, 17, 3600−3603. (e) Naveen, N.; Koppolu, S. R.;
Balamurugan, R. Silver Hexafluoroantimonate-Catalyzed Direct α-
Alkylation of Unactivated Ketones. Adv. Synth. Catal. 2015, 357,
1463−1473. (f) Koppolu, S. R.; Naveen, N.; Balamurugan, R. Triflic
Acid Promoted Direct α-Alkylation of Unactivated Ketones Using
Benzylic Alcohols via in Situ Formed Acetals. J. Org. Chem. 2014, 79,
6069−6078.
(18) Sanz, R.; Miguel, D.; Martınez, A.; Alvarez Gutierrez, J. M.;
Rodriguez, F. Brønsted Acid Catalyzed Propargylation of 1,3-
Dicarbonyl Derivatives. Synthesis of Tetrasubstituted Furans. Org.
Lett. 2007, 9, 727−730.
(19) (a) Chang, M. Y.; Cheng, Y. C.; Lu, Y. J. Bi(OTf)3-Mediated
Cycloisomerization of γ-Alkynyl Arylketones: Application to the
Synthesis of Substituted Furans. Org. Lett. 2015, 17, 1264−1267.
(b) Lei, J.; Xu, Z. G.; Tang, D. Y.; Li, Y.; Xu, J.; Li, H.; Zhu, J.; Chen,
Z. Z. Acid-Promoted One-Pot Synthesis of Substituted Furan and 6-
Methylpyrazin-2(1H)-one Derivatives via Allene Intermediate
Formed in Situ. ACS Comb. Sci. 2018, 20, 292−297.
(20) (a) Manojveer, S.; Balamurugan, R. Synthesis of Naphthalene
Derivatives from orthoAlkynylacetophenone Derivatives via Tandem
in Situ Incorporation of Acetal and Intramolecular Heteroalkyne
Metathesis/Annulation. Org. Lett. 2014, 16, 1712−1715. (b) Ghosh,
S.; Ghatak, U. R. Carbon-carbon bond formation and annulation
reactions using trimethyl and triethyl orthoformates. Indian Acad. Sci.
(Chem. Sci.). 1988, 100, 235−252. (c) Chakraborti, R.; Ranu, C. B.;
Ghatak, U. R. A Formylation-Cyclization Method of Synthesis of
Cycloalkenones from Unsaturated Ketones. 2.1 Simple Synthesis of
Some Functionalized Bicyclo[3.3.1]nonane Derivative. J. Org. Chem.
1985, 50, 5268−5271.
(21) Das, A.; Sarkar, S.; Chakraborty, B.; Kar, A.; Jana, U. Catalytic
Alkyne/Alkene-Carbonyl Metathesis: Towards the Development of
Green Organic Synthesis. Current Green Chemistry 2020, 7, 5−39.
(22) (a) Tarigopula, C.; Thota, G. K.; Balamurugan, R. Efficient
Synthesis of Functionalized β-Keto Esters and β-Diketones through
Regioselective Hydration of Alkynyl Esters and Alkynyl Ketones by
Use of a Cationic NHC−AuI Catalyst. Eur. J. Org. Chem. 2016, 2016,
5855−5861. (b) Kuang, J.; Zhou, T.; You, T.; Chen, J.; Su, C.; Xia, Y.
Facile access to 1,3-diketones by gold(I)-catalyzed regioselective
hydration of ynones. Org. Biomol. Chem. 2019, 17, 3940−3944. For
the hydration of alkynone using concentrated H2SO4 as the solvent,
see: (c) Bickel, C. L. o-Chlorophenylbenzoylacetylene. J. Am. Chem.
Soc. 1947, 69, 73−74. For TfOH-catalyzed hydration, see:
(d) Tsuchimoto, T.; Joya, T.; Shirakawa, E.; Kawakami, Y. Brønsted
(14) Tang, R. J.; He, Q.; Yang, L. Metal-Free Oxidative
Decarbonylative Coupling of Aromatic Aldehydes with Arenes: Direct
Access to Biaryls. Chem. Commun. 2015, 51, 5925−5928.
(15) (a) Zhang, X.; Beaudry, C. M. Synthesis of Highly Substituted
Phenols and Benzenes with Complete Regiochemical Control. Org.
Lett. 2020, 22, 6086−6090. (b) Zhu, P.; Sun, J.; Yang, G.; Liu, G.;
Zhang, P.; Yoneyama, Y.; Tsubaki, N. Tandem Catalytic Synthesis of
Benzene from CO2 and H2. Catal. Sci. Technol. 2017, 7, 2695−2699.
(c) Obydennov, D. L.; Chernyshova, E. V.; Sosnovskikh, V. Y. Self-
Condensation of Enaminodiones as a Method for Benzene Ring
Construction: Synthesis of Diacyl-Substituted Phenols and Catechols.
J. Org. Chem. 2019, 84, 6491−6501.
(16) (a) Zhang, X.; Beaudry, C. M. Synthesis of Highly Substituted
Phenols and Benzenes with Complete Regiochemical Control. Org.
Lett. 2020, 22, 6086−6090. (b) Xu, T.; Wang, D.; Liu, W.; Tong, X.
Phosphine-Promoted Divergent Annulations of δ-Acetoxy Allenoates
with α-Hydroxy-β-carbonyl Ester Derivatives: Synthesis of Tetrasub-
stituted Cyclopentadienes and Benzenes. Org. Lett. 2019, 21, 1944−
1947. (c) Song, C.; Dong, X.; Wang, Z.; Liu, K.; Chiang, C. W.; Lei,
A. Visible-Light-Induced [4 + 2] Annulation of Thiophenes and
Alkynes to Construct Benzene Rings. Angew. Chem., Int. Ed. 2019, 58,
12206−12210. (d) Yang, J.; Zhao, B.; Xi, Y.; Sun, S.; Yang, Z.; Ye, Y.;
Jiang, K.; Wei, Y. Construction of Benzene Rings by Copper-
Catalyzed Cycloaddition Reactions of Oximes and Maleimides: An
Access to Fused Phthalimides. Org. Lett. 2018, 20, 1216−1219.
(e) Qi, B.; Guo, S.; Zhang, W.; Yu, X.; Song, C.; Zhu, J. Rh(III)-
Catalyzed Enaminone-Directed Alkenyl C−H Activation for the
Synthesis of Salicylaldehydes. Org. Lett. 2018, 20, 3996−3999. (f) Gu,
Y.; Wu, F.; Yang, J. Oxidative [3 + 3] Annulation of Atropaldehyde
L
https://doi.org/10.1021/acs.joc.1c01277
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
Acid-Catalyzed Hydration of Alkynes: A Convenient Route to Diverse
Carbonyl Compounds. Synlett 2000, 12, 1777−1778.
́
́
(23) (a) Basaric, N.; Cindro, N.; Bobinac, D.; Uzelac, L.; Mlinaric-
Majerski, K.; Kralj, M.; Wan, P. Zwitterionic Biphenyl Quinone
Methides in Photodehydration Reactions of 3-Hydroxybiphenyl
Derivatives: Laser Flash Photolysis and Antiproliferation Study.
Photochem. Photobiol. Sci. 2012, 11, 381−396. (b) Higson, F. K.;
Focht, D. D. Bacterial metabolism of hydroxylated biphenyls. Appl.
Environ. Microbiol. 1989, 55, 946−952. (c) Von Geldern, T. W.; Brun,
R. P.; Kalmanovich, M.; Wilcox, D.; Jacobson, P. B. The Synthesis and
Characterization of a Novel Insulin Sensitizing Agent. Synlett 2004, 8,
1446−1448.
(24) (a) Inagaki, S.; Saito, K.; Suto, S.; Aihara, H.; Sugawara, A.;
Tamura, S.; Kawano, T. Synthesis of 5-Aryl-3(2H)-furanones Using
Intramolecular Cyclization of Sulfonium Salts. J. Org. Chem. 2018, 83,
13834−13846. (b) He, Z.; Qi, X.; Li, S.; Zhao, Y.; Gao, G.; Lan, Y.;
Wu, Y.; Lan, J.; You, J. Transition-Metal-Free Formal Decarboxylative
Coupling of α-Oxocarboxylates with a-Bromoketones under Neutral
Conditions: A Simple Access to 1,3-Diketones. Angew. Chem. 2015,
127, 869−873. (c) Zhang, H.; Feng, D.; Sheng, H.; Ma, X.; Wan, X.;
Tang, Q. Asymmetric transfer hydrogenation of unsymmetrical
benzils. RSC Adv. 2014, 4, 6417−6423. (d) Sada, M.; Matsubara, S.
A Tandem Reaction Initiated by 1,4-Addition of Bis(iodozincio)-
methane for 1,3-Diketone Formation. J. Am. Chem. Soc. 2010, 132,
432−433.
(25) (a) Jónsson, H. F.; Evjen, S.; Fiksdahl, A. Gold(I)-Catalyzed [2
+ 2 + 2] Cyclotrimerization of 1,3-Diarylpropargyl Acetals. Org. Lett.
2017, 19, 2202−2205. (b) Hamel, J. D.; Hayashi, T.; Cloutier, M.;
Savoie, P. R.; Thibeault, O.; Beaudoin, M.; Paquin, J. F. Highly
regioselective gold-catalyzed formal hydration of propargylic gem-
difluorides. Org. Biomol. Chem. 2017, 15, 9830−9836. (c) Yu, M.;
Wang, Y.; Sun, W.; Yao, X. A Mild, Highly Efficient Addition of
Alkynes to Aldehydes Catalyzed by Titanium Dioxide-Supported
Silver Nanoparticles. Adv. Synth. Catal. 2012, 354, 71−76. (d) Liu, P.;
Deng, C. L.; Lei, X.; Lin, G. Q. Tandem Amination/Cyclo-
isomerization of Aryl Propargylic Alcohols with 2-Aminopyridines
as an Expedient Route to Imidazo[1,2-a]pyridines. Eur. J. Org. Chem.
2011, 2011, 7308−7316.
M
https://doi.org/10.1021/acs.joc.1c01277
J. Org. Chem. XXXX, XXX, XXX−XXX