Synthesis of 2-Aryl Acetophenones via Hydrobromination and Oxy-isomerization of (o-Arylethynyl)benzyl Alcohols

Article abstract of DOI:10.1021/acs.joc.1c00294

Hydrobromination and oxy-isomerization of (o-arylethynyl)benzyl alcohols to yield brominated aryl ketones were achieved with bromotrimethylsilane. The substrate scope suggested that vinyl carbocations, stabilized by the conjugated aryl groups, are the rea

Full text of DOI:10.1021/acs.joc.1c00294

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Synthesis of 2‑Aryl Acetophenones via Hydrobromination and Oxy-
isomerization of (o‑Arylethynyl)benzyl Alcohols
Tzu-Hsuan Kuan and Duen-Ren Hou*
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ABSTRACT: Hydrobromination and oxy-isomerization of (o-
arylethynyl)benzyl alcohols to yield brominated aryl ketones were
achieved with bromotrimethylsilane. The substrate scope suggested
that vinyl carbocations, stabilized by the conjugated aryl groups, are
the reaction intermediates. 1H-Isochromene was also detected by
1H NMR, and an isolated 1H-isochromene was converted to the
product when retreated with TMSBr. The formation of 1H-
isochromene is equivalent to a 6-endo-dig cyclization and contrasts with the corresponding reactions under basic conditions, in which
the 5-exo-dig process dominated.
alcohols 1 undergo hydrobromination and oxy-isomerization
to yield 2-aryl acetophenones 2 efficiently.
2-Aryl acetophenones are useful building blocks to access
many heterocycles, including furans,1−11 benzofurans,12−18
pyrroles,19−21 indoles,22−26 imidazoles,27−30 pyridines,31−36
pyrimidines,37−39 quinolines,40−43 quinoxalines,44−46 and
isoxazoles, etc.47−49 Various methods have been developed
to prepare 2-aryl acetophenones; however, hydration of diaryl
acetylenes is a direct and atom-economical pathway to access
this family of compounds, and new development in this
direction continues to receive the attention of chemists.50,51 In
addition to mercury(II), the classical catalyst used to activate
alkynes for hydration,52−55 various metal salts or complexes
have been applied for this purpose, including iron,56−60
copper,61,62 ruthenium,63−65 rhodium,66,67 gold,68−74 plati-
num,75,76 and other metals,18,75,77−79 and significant progress
in the effectiveness of catalysts has been achieved. However,
fewer reports have described the reactions of alkynes catalyzed
by metal-free, Lewis or Brønsted acids/bases, although these
protocols could be more economical, easy to handle, and
environmentally benign.77,80−86 The lack of experimentation in
this area is probably due to the disadvantages of metal-free,
acid/base-catalyzed reactions, such as high temperature,80−83
long reaction time,84,85 and high catalyst loading.86 One way to
increase the reactivities of alkynes is through the participation
of a neighboring group.87−90 Recent progress on intra-
molecular reactions of alkynes with neighboring aldehydes,91,92
ketones,91,93−96 carboxylic acids,97−99 esters,100−102
amides,85,103−107 imidates,108 or alcohols109−112 to yield
various addition products has been reported (Scheme 1).
The issue of regioselectivity, often observed in the reactions of
internal alkynes, is also improved by the participation of
neighboring groups.113−116 It is also interesting to note that
under basic conditions (o-arylethynyl)benzyl alcohols 1
undergo cyclization via a 5-exo-dig pathway.112 Here, we
report that under acidic conditions (o-arylethynyl)benzyl
Table 1 summarizes the reactions of o-phenylethynylbenzyl
alcohol (1a) with various hydrohalic acids. Common hydro-
chloride acid and hydrogen bromide in acetic acid did not yield
any aryl acetophenone (entries 1 and 2) but a trace of 1H-
isochromene 3a and halogenation at the hydroxyl group to
form 4a. Concentrated hydrobromic acid and hydroiodic acid
gave the mixtures of 2-(2-(bromomethyl)phenyl)-1-phenyl-
ethanone 2a and brominated/iodinated product 4a, in nearly
1:1 ratios (entries 3 and 4). The position of the keto group in
2a was identified unambiguously by reducing the bromo group
of product 2a to the known 1-phenyl-2-(o-tolyl)ethan-1-one
(5,eq 1).117 Anhydrous HBr gas provided another mixture of
2a and brominated product 4a (entry 5). The reactions of 1a
with trimethylsilyl halides, which are known to generate
hydrogen halides in situ,118 were then screened. Both TMSCl
and TMSI provided the chlorinated and iodinated products 4a
with 12% and 95% yield, respectively (entries 6 and 7). We
were glad to find that bromotrimethylsilane (TMSBr, 1.2
equiv) gave the desired acetophenone 2a in 91% yield with a
trace of brominated product 4a (entry 8). The byproduct 4a
Received: February 5, 2021
Published: April 14, 2021
https://doi.org/10.1021/acs.joc.1c00294
© 2021 American Chemical Society
J. Org. Chem. 2021, 86, 6907−6917
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Note
the para-position.119 On the other hand, electron-donating
groups including 4-hydroxyl and 4-NHTs gave ketones 2o and
2p in good yields (entries 14 and 15). Excellent yields were
also obtained with 1-naphthyl-, 2-thienyl-, and 2-furyl-
substituted substrates 1q−1s (entries 16−18). The importance
of the conjugation between the alkynyl and aryl groups was
also shown in the reaction of internal arylalkyl alkyne 1t, which
gave a typical Markovnikov hydrobromination product 6t
(entry 19).
Scheme 1. Participation of Neighboring Groups in the
Reactions of Diarylalkynes
The influence of the substituents on the other benzene ring
of 1 was also studied using substrates 1u−1w (eq 2−4). The
reaction of TMSBr and 1u, where the lone pair electrons of the
methoxy group are not delocalized to the alkyne moiety by
resonance, gave the desired phenyl ketone 2u in 80% yield. On
the other hand, the corresponding reaction of 1v gave
hydrobromination product 6v due to the formation of the
carbocation 7, stabilized by the p-methoxy group (relative to
the carbocation). When the methoxy group of 1v was replaced
with a fluorine atom (substrate 1w,eq 4), the formation of
ketone 2w was reinstalled due to the poor carbocation−
stabilization provided by the fluoro group. Secondary alcohol
1x gave the bromide 1y120 due to the formation of a well-
stabilized benzyl carbocation (eq 5).The above results suggest
increased as more TMSBr was applied (entry 9). We noticed
that this reaction is sensitive to solvents: chloroform also gave
2a with an 85% yield (entry 10), but no reaction occurred in
ethyl acetate and DMF (entries 11 and 12). In diethyl ether
and THF, the reactions were sluggish to yield cyclization
product 3a (entries 13 and 14), and only the hydroxyl-
brominated product 4a was formed in acetonitrile and 1,4-
dioxane (entries 15 and 16). With the optimized reaction
conditions in hand (TMSBr, 1.2 equiv, in CH2Cl2, rt, 16 h),
more substrates (1b−1t) were examined for this process
(Table 2). In general, alcohols 1 bearing ortho-, meta-, and
para-substituted methoxy or methyl groups provided the
corresponding aryl ketones (2b−2g) in good to excellent
yields (entries 1−6). The reaction using 3,5-dimethylphenyl-
substituted acetylene 1h also proceeded (68% yield, entry 7);
however, 2,6-dimethyl-substituted substrate 1i did not yield
any ketone 2i but did yield 1H-isochromene 3i (entry 8). The
poor conjugation between the enol ether moiety and 2,6-
dimethyl-substituted benzene of 3i, due to the two o-methyl
groups, prevented further ring-opening reaction (vide infra).
The results derived from m-chloro- and p-nitro-substituted
substrates indicated that the reaction is retarded by electron-
withdrawing groups (1j and 1k, entries 9 and 10). 4-
Halogenated (F-, Cl-, Br-) phenyl compounds gave the
ketones 2l−2n in 74, 19, and 6% yields, respectively (entries
11−13), which correlated well with their electronic effects at
the reaction mechanism shown in Scheme 2. The initial
reaction of TMSBr and alcohol 1 should give the vinyl
carbocations A or B, which were stabilized and dominated by
the adjacent aryl groups; i.e., the more stabilized intermediate
should dictate the product. To have aryl ketones 2,
intermediate B needs to be stabilized by the Ar group and
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Note
a
Table 1. Hydrobromination and Oxy-isomerization of 1a.
yield (%)
entry
reagent
2a
3a
4a
1
2
3
4
5
6
7
8
concd HCl(aq) (37 wt %, 5.0 equiv), X = Cl
0
0
54
57
53
0
11
0
0
0
42
0
2
0
45
42
4
12
95
8
concd HBr (33 wt % in acetic acid, 5.0 equiv), X = Br
concd HBr(aq) (48 wt %, 5.0 equiv), X = Br
concd HI(aq) (57 wt %, 5.0 equiv), X = I
b
HBr(g) (5.0 equiv) , X = Br
TMSCl (5.0 equiv), X = Cl
TMSI (2.0 equiv), X = I
TMSBr (1.2 equiv), X = Br
3
0
0
c
91 (71)
9
TMSBr (2.0 equiv), X = Br
52
85
0
0
0
0
0
0
0
0
0
0
8
26
0
47
0
0
0
0
12
35
51
10
11
12
13
14
15
16
TMSBr (1.2 equiv) in CHCl3, X = Br
TMSBr (1.2 equiv) in ethyl acetate, X = Br
TMSBr (1.2 equiv) in DMF, X = Br
TMSBr (1.2 equiv) in THF, X = Br
TMSBr (1.2 equiv) in diethyl ether, X = Br
TMSBr (1.2 equiv) in acetonitrile, X = Br
TMSBr (1.2 equiv) in 1,4-dioxane, X = Br
0
a
b
(2-(Phenylethynyl)phenyl)methanol (0.05 mmol) and TMSX/HX in CH2Cl2 (1.0 mL) were stirred at rt for 16 h. Generated from
c
tetrahydronaphthalene and bromine. 1.0 mmol of 1a applied.
a
CH2Cl2 and the presence of the trimethylsilyl group should be
helpful to suppress simple halogenations of benzylic alcohols,
observed for the reactions using hydrohalic acids (Table 1).
Indeed, the appearance and disappearance of the proposed
reaction intermediate, 1H-isochromene 3g, was observed by
1H NMR as the reaction proceeded (Figure S1 and Table S1).
Isolated 3a was also converted to 2-arylacetophenone 2a when
treated with TMSBr (eq 6). Synthetic application of the
Table 2. Formation of Various Aryl Ketones
entry
R
product
yield (%)
1
2
3
4
5
6
7
8
9
2-OMe-C6H4
3-OMe-C6H4
4-OMe-C6H4
2-Me-C6H4
3-Me-C6H4
4-Me-C6H4
3,5-(CH3)2-C6H3
2,6-(CH3)2-C6H3
3-Cl-C6H4
2b
2c
2d
2e
2f
2g
2h
3i
88
81
99
83
66
98
68
75
c
brominated aryl ketones was demonstrated in a one-step
synthesis of 2-benzyl-3-phenyl-1,2-dihydroisoquinoline (8)
from acetophenone 2a and benzylamine (eq 7). The
b
0
0
c
10
11
12
13
14
15
16
17
18
19
4-NO2-C6H4
4-F-C6H4
4-Cl-C6H4
2l
74
c
2m
2n
2o
2p
2q
2r
19 (<5)
4-Br-C6H4
6
90
80
90
95
90
90
4-OH-C6H4
4-NHTs-C6H4
1-naphthyl
2-thienyl
2-furyl
t-Bu
2s
6t
a
Alcohol 1 and TMSBr (1.2 equiv) in CH2Cl2 was stirred at rt for 16
b
c
h. Starting material recovered. Reaction conducted in 1,2-dichloro-
isoquinoline skeleton of 8 is found in many natural alkaloids
and biologically active compounds.123−125 Acetophenone 2a
was also converted to 1H-isochromene 3a quantitatively with
triethylamine (eq 8); therefore, 2a and 3a are chemically
interconvertible. In summary, hydrobromination and oxy-
isomerization of 4-alkynyl alcohols to Br-substituted aryl
acetophenones was achieved efficiently with bromotrimethylsi-
lane. Although the outcome of these reactions is equal to a 6-
endo-dig process, the reactions indeed go through the
ethane at 80 °C for 16 h.
undergoes cyclization to form 1H-isochromene 3, addition of
hydrogen bromide,121,122 and ring-opening to yield 2. On the
other hand, the substrates bearing electron-deficient Ar groups
(2j and 2k), lacking an aryl group (2t), or the R substituent
favoring intermediate A (para-OMe, 1v) were either inactive
or gave product 6. The anhydrous condition of TMSBr in
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Note
Scheme 2. Proposed Reaction Mechanism
95.4, 92.0, 77.8, 77.3, 76.9, 63.5, 21.2; HRMS (ESI) m/z [M + H]+
calcd for C17H17O 237.1273, found 237.1269.
formation of vinyl carbocations, which require stabilization
from the conjugated aryl groups, and 1H-isochromenes 3 are
the precursors to yield final aryl ketones. The reactions are
metal-free and easy to apply, and the products, brominated aryl
ketones, are useful synthetic blocks to access various
heterocycles.
4-((2-(Hydroxymethyl)phenyl)ethynyl)phenol (1o). 2-(2-
Ethynylphenyl)methanol135 (100.1 mg, 0.76 mmol) was added to a
suspension of 4-iodophenol (272.8 mg, 1.24 mmol), Pd(PPh3)2Cl2
(10.7 mg, 0.020 mmol), CuI (1.5 mg, 8 μmol), and triethylamine (4
mL). The reaction mixture was stirred and heated in an oil bath (50
°C) for 16 h under an atmosphere of nitrogen, cooled to rt, and
concentrated. The crude product was purified with column
chromatography (SiO2, EtOAc/hexanes, 1:1, Rf 0.35) to give 1o as
EXPERIMENTAL SECTION
■
1
General Information. Dichloromethane and toluene were dried
over calcium hydride and distilled prior to use. Tetrahydrofuran and
diethyl ether were dried over sodium, monitored with benzophenone
ketyl radicals, and distilled prior to use. TLC was conducted using
precoated silica gel 60 F254 plates containing a fluorescent indicator;
purification by chromatography was conducted using silica gel (230−
a light yellow liquid (119.2 mg, 0.53 mmol, 70%): H NMR (300
MHz, CD3CN) δ 7.62−7.27 (m, 7H), 6.89−6.79 (m, 2H), 4.92 (s,
2H); 13C{1H} NMR (75 MHz, CD3CN) δ 158.5, 144.2, 134.0, 132.4,
129.2, 127.9, 127.6, 122.0, 116.6, 115.0, 95.0, 85.9, 63.1; HRMS (ESI)
m/z [M + H]+ calcd for C15H13O2 225.0910, found 225.0903.
N-(4-((2-(Hydroxymethyl)phenyl)ethynyl)phenyl)-4-methylben-
zenesulfonamide (1p). 2-(2-Ethynylphenyl)methanol135 (100.1 mg,
0.76 mmol) was added to a suspension of iodoaniline (271.6 mg, 1.24
mmol), Pd(PPh3)2Cl2 (10.7 mg, 0.020 mmol), CuI (1.5 mg, 8 μmol),
and triethylamine (4 mL). The reaction mixture was stirred and
heated in an oil bath (50 °C) for 16 h under an atmosphere of
nitrogen, cooled to rt, and concentrated. The crude product was
purified with column chromatography (SiO2, EtOAc/hexanes, 1:1, Rf
0.30) to give (2-((4-aminophenyl)ethynyl)phenyl)methanol as a light
1
400 mesh). Chemical shifts for H NMR and 13C{1H} NMR spectra
are reported in δ units (parts per million) with reference to residual
solvent peaks. All spectra were obtained at 25 °C. The multiplicities
are abbreviated as follows: s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, dd = doublet of doublets, td = triplet of
doublets. High-resolution mass spectrometry (HRMS) data were
recorded on a JMS-700 quadrupole mass spectrometer. Compounds
1a,126 1b,127 1d,128 1e−f,127 1g,126 1h,127 1j,127 1k,126 1l,127 1m−
n,128 1q,128 1r,127 1s,129 1t,130 1u,131 1v,132 1w,133 and 1x134 were
prepared according to the literature procedure.
(2-((3-Methoxyphenyl)ethynyl)phenyl)methanol (1c). 2-(2-
Ethynylphenyl)methanol135 (100.1 mg, 0.76 mmol) was added to a
suspension of 1-iodo-3-methoxybenzene (176.5 mg, 0.91 mmol),
Pd(PPh3)2Cl2 (10.5 mg, 0.020 mmol), copper(I) iodide (1.4 mg, 8
μmol), and triethylamine (4 mL). The reaction mixture was stirred
and heated in an oil bath (50 °C) for 16 h under an atmosphere of
nitrogen, cooled to rt, and concentrated. The crude product was
purified with column chromatography (SiO2, EtOAc/hexanes, 1:1, Rf
0.35) to give 1c as a dark brown liquid (105.4 mg, 0.53 mmol, 70%):
1H NMR (300 MHz, CDCl3) δ 7.61−7.46 (m, 2H), 7.44−7.24 (m,
3H), 7.21−7.11 (dt, J = 7.6 Hz, J = 1.2 Hz, 1H), 7.11−7.04 (dd, J =
2.7 Hz, J = 1.4 Hz, 1H), 6.99−6.89 (m, 1H), 4.97−4.91 (s, 2H),
3.88−3.82 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.4, 142.6,
132.2, 129.5, 128.8, 127.5, 127.2, 124.2, 123.9, 121.2, 116.4, 115.1,
94.1, 86.6, 77.5, 77.1, 76.6, 64.0, 55.4; HRMS (ESI) m/z [M + H]+
calcd for C16H15O2 239.1066, found 239.1056.
(2-((2,6-Dimethylphenyl)ethynyl)phenyl)methanol (1i). 2-(2-
Ethynylphenyl)methanol135 (100.1 mg, 0.76 mmol) was added to a
suspension of 2-iodo-1,3-dimethylbenzene (287.6 mg, 1.24 mmol),
Pd(PPh3)2Cl2 (10.7 mg, 0.020 mmol), CuI (1.5 mg, 8 μmol), and
triethylamine (4 mL). The reaction mixture was stirred and heated in
an oil bath (50 °C) for 16 h under an atmosphere of nitrogen, cooled
to rt, and concentrated. The crude product was purified with column
chromatography (SiO2, EtOAc/hexanes, 1:4, Rf 0.45) to give 1i as a
light yellow liquid (134.5 mg, 0.58 mmol, 76%): 1H NMR (300 MHz,
CDCl3) δ 7.64−7.47 (dd, J = 7.6 Hz, J = 1.5 Hz, 2H), 7.44−7.20 (m,
2H), 7.20−7.10 (m, 1H), 7.10−7.02 (d, J = 6.4 Hz, 2H), 4.98−4.91
(m, 2H), 2.56−2.50 (s, 6H); 13C{1H} NMR (75 MHz, CDCl3) δ
142.5, 140.2, 131.8, 128.5, 128.0, 127.1, 126.8, 126.7, 122.9, 121.4,
1
yellow solid (115.2 mg, 0.52 mmol, 68%): mp 105.0−106.5 °C; H
NMR (500 MHz, CDCl3) δ 7.56−7.46 (m, 2H), 7.39−7.27 (m, 4H),
6.67 (d, J = 5.5 Hz, 2H), 4.92 (s, 2H); 13C{1H} NMR (126 MHz,
CDCl3) δ 147.4, 142.2, 132.9, 131.9, 128.1, 127.5, 127.3, 122.1, 114.8,
112.2, 95.1, 84.7, 77.3, 77.0, 76.8, 64.2; HRMS (ESI) m/z [M + H]+
calcd for C15H14NO 224.1069, found 224.1065. p-Toluenesulfonyl
chloride (9.3 mg, 0.05 mmol was added to a solution of 2-((4-
aminophenyl)ethynyl)phenyl)methanol (10.0 mg, 0.040 mmol) and
pyridine (1 mL). The reaction mixture was stirred and heated in an oil
bath (50 °C) for 2 h, concentrated to remove pyridine, diluted with
water (1 mL), and extracted with CH2Cl2 (1 mL × 2). The combined
organic layers were dried over sodium sulfate, filtered and
concentrated. The crude product was purified with column
chromatography (SiO2, EtOAc/hexanes, 1:9, Rf 0.40) to give 1p as
a light yellow solid (13.1 mg, 0.029 mmol, 72%): mp 108.0−109.5
1
°C; H NMR (300 MHz, CDCl3) δ 7.75−7.66 (m, 2H), 7.59−7.46
(m, 2H), 7.42−7.19 (m, 6H), 7.14−6.99 (m, 2H), 4.89 (d, J = 2.7 Hz,
3H), 2.39 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 144.1, 142.4,
137.0, 135.9, 133.3, 132.6, 132.1, 129.8, 128.8, 127.5, 127.3, 121.2,
120.6, 119.3, 93.5, 87.0, 77.5, 77.1, 76.6, 63.9, 21.6; HRMS (ESI) m/z
[M + H]+ calcd for C22H20NO3S 378.1158, found 378.1150.
General Procedure for Hydrobromination and Oxy-isomer-
ization of 4-Alkynyl Alcohols. Bromotrimethylsilane (TMSBr, 37
μL, 42.8 mg, 0.29 mmol) was added to a solution of (2-
(phenylethynyl)phenyl)methanol (1a,50.0 mg, 0.24 mmol) and
CH2Cl2 (5 mL) at 0 °C. The reaction mixture was stirred at rt for
16 h under an atmosphere of nitrogen and concentrated. The crude
product was purified with column chromatography (SiO2, EtOAc/
hexanes, 1:9, Rf 0.20) to give 2-(2-(bromomethyl)phenyl)-1-phenyl-
ethanone (2a, X = Br) as a light yellow oil (63.1 mg, 0.22 mmol,
1
91%): IR (neat) 3029, 1681, 1496, 1446, 1215, 991, 752 cm−1; H
NMR (300 MHz, CDCl3) δ 8.14−8.05 (m, 2H), 7.69−7.59 (m, 1H),
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Note
7.54 (dd, J = 8.2 Hz, J = 6.7 Hz, 2H), 7.47−7.37 (m, 1H), 7.30 (ddd,
J = 7.7 Hz, J = 3.1 Hz, J = 1.9 Hz, 2H), 7.20 (dt, J = 4.9 Hz, J = 3.2
Hz, 1H), 4.53 (s, 2H), 4.52 (s, 2H); 13C{1H} NMR (75 MHz,
CDCl3) δ 197.2, 136.6, 136.4, 134.1, 133.5, 131.4, 130.7, 129.2, 128.8,
128.5, 127.8, 42.5, 32.5; HRMS (ESI) m/z [M + H]+ calcd for
C15H14BrO 289.0222, found 289.0212.
A 1 mmol scale of reaction was conducted by the same procedure
with 1a (210.1 mg, 1.0 mmol), TMSBr (160 μL, 184.9 mg, 1.2
mmol), and CH2Cl2 (20 mL) to yield 2a (202.5 mg, 0.71 mmol,
71%). Compound 2a was also prepared from 3a (10.0 mg, 0.05
mmol) and TMSBr (7.7 μL, 8.8 mg, 0.06 mmol) in CH2Cl2 (1 mL).
After being stirred at rt for 72 h, the reaction mixture was
concentrated, and product 2a (13.1 mg, 0.04 mmol, 92%) was
isolated after column chromatography.
134.3, 131.4, 130.7, 129.2, 129.0, 128.7, 127.8, 126.7, 125.7, 42.5,
32.5, 21.4; HRMS (ESI) m/z [M + H]+ calcd for C16H16BrO
303.0379, found 303.0374.
2-(2-(Bromomethyl)phenyl)-1-(p-tolyl)ethanone (2g). The gen-
eral procedure was followed. Starting with 1g (50.0 mg, 0.23 mmol)
and TMSBr (37 μL, 42.8 mg, 0.28 mmol) in CH2Cl2 (5 mL), 2g
(67.5 mg, 0.22 mmol, 97%) was generated after column
chromatography (SiO2, EtOAc/hexanes, 1:9, Rf 0.20) as a light
yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.04−7.95 (m, 2H), 7.46−
7.37 (m, 1H), 7.37−7.25 (m, 4H), 7.20−7.17 (m, 1H), 4.52 (s, 2H),
4.51 (s, 2H), 2.46 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 196.8,
144.4, 136.4, 134.4, 134.2, 131.4, 130.6, 129.5, 129.2, 128.6, 127.7,
42.3, 32.6, 21.7; HRMS (ESI) m/z [M + H]+ calcd for C16H16BrO
303.0379, found 303.0372.
2-(2-(Bromomethyl)phenyl)-1-(2-methoxyphenyl)ethanone (2b).
The general procedure was followed. Starting with 1b (50.0 mg, 0.21
mmol), TMSBr (33 μL, 37.9 mg, 0.25 mmol) in CH2Cl2 (5 mL), 2b
(58.6 mg, 0.18 mmol, 88%) was generated after column
chromatography (SiO2, EtOAc/hexanes, 1:9, Rf 0.20) as a light
yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.62−7.47 (m, 1H), 7.38−
7.31 (m, 1H), 7.35−7.17 (m, 1H), 7.23−7.03 (m, 2H), 7.08−6.97
(m, 1H), 6.95−6.74 (m, 2H), 4.56 (s, 2H), 4.55 (s, 2H), 4.00 (s,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ 199.6, 158.5, 136.5, 134.7,
133.7, 131.6, 130.5, 129.6, 129.0, 128.2, 127.6, 120.8, 111.6, 55.7,
47.5, 32.7; HRMS (ESI) m/z [M + H]+ calcd for C16H16BrO2
319.0328, found 319.0317.
2-(2-(Bromomethyl)phenyl)-1-(3-methoxyphenyl)ethanone (2c).
The general procedure was followed. Starting with 1c (50.0 mg, 0.21
mmol), TMSBr (33 μL, 37.9 mg, 0.25 mmol) in CH2Cl2 (5 mL), 2c
(54.3 mg, 0.17 mmol, 81%) was generated after column
chromatography (SiO2, EtOAc/hexanes, 1:9, Rf 0.20) as a light
yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.43 (dt, J = 7.6 Hz, J = 1.2
Hz, 1H), 7.32 (dd, J = 2.7 Hz, J = 1.6 Hz, 1H), 7.23−7.11 (m, 2H),
7.16−6.98 (m, 2H), 6.98−6.86 (m, 2H), 4.53 (s, 2H), 4.52 (s, 2H),
3.62 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 197.1, 160.0, 138.0,
136.4, 134.1, 130.9, 130.2, 129.3, 128.7, 127.3, 120.6, 119.5, 112.2,
55.5, 42.6, 32.5; HRMS (ESI) m/z [M + H]+ calcd for C16H16BrO2
319.0328, found 319.0318.
2-(2-(Bromomethyl)phenyl)-1-(4-methoxyphenyl)ethanone (2d).
The general procedure was followed. Starting with 1d (50.0 mg, 0.21
mmol) and TMSBr (33 μL, 37.9 mg, 0.25 mmol) in CH2Cl2 (5 mL),
2d (67.0 mg, 0.21 mmol, 99%) was generated after column
chromatography (SiO2, EtOAc/hexanes, 1:9, Rf 0.20) as a light
yellow oil: 1H NMR (300 MHz, CDCl3) δ 8.13−8.02 (m, 2H), 7.46−
7.35 (m, 1H), 7.32 (dd, J = 6.3 Hz, J = 2.8 Hz, 2H), 7.24−7.14 (m,
1H), 7.05−6.89 (m, 2H), 4.53 (s, 2H), 4.48 (s, 2H), 3.91 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 195.7, 163.8, 136.4, 134.5, 131.4,
130.8, 130.6, 129.7, 129.2, 127.7, 114.0, 77.5, 77.1, 76.6, 55.6, 42.1,
32.6; HRMS (ESI) m/z [M + H]+ calcd for C16H16BrO2 319.0328,
found 319.0319.
2-(2-(Bromomethyl)phenyl)-1-(3,5-dimethylphenyl)ethanone
(2h). The general procedure was followed. Starting with 1h (50.0 mg,
0.21 mmol) and TMSBr (46 μL, 53.6 mg, 0.35 mmol) in CH2Cl2 (5
mL), 2h (45.3 mg, 0.14 mmol, 68%) was generated after column
chromatography (SiO2, EtOAc/hexanes, 1:9, Rf 0.21) as a light yellow
1
oil: H NMR (300 MHz, CDCl3) δ 7.71 (d, J = 1.5 Hz, 2H), 7.49−
7.38 (m, 1H), 7.43−7.21 (m, 3H), 7.25−7.14 (m, 1H), 4.52 (s, 2H),
4.51 (s, 2H), 2.43 (s, 6H); 13C{1H} NMR (75 MHz, CDCl3) δ 197.5,
138.5, 136.8, 136.4, 135.2, 134.4, 131.4, 130.7, 129.2, 127.8, 126.3,
42.6, 32.6, 21.3; HRMS (ESI) m/z [M + H]+ calcd for C17H18BrO
317.0535, found 317.0526.
2-(2-(Bromomethyl)phenyl)-1-(4-fluorophenyl)ethanone (2l).
The general procedure was followed. Starting with 1l (50.0 mg,
0.22 mmol) and TMSBr (35 μL, 40.4 mg, 0.26 mmol) in CH2Cl2 (5
mL), 2l (50.0 mg, 0.16 mmol, 74%) was generated after column
chromatography (SiO2, EtOAc/hexanes, 1:9, Rf 0.21) as a light yellow
1
oil. H NMR (300 MHz, CDCl3) δ 8.17−8.06 (m, 2H), 7.50−7.37
(m, 1H), 7.36−7.26 (m, 2H), 7.25−7.13 (m, 3H), 4.51 (s, 2H), 4.50
(s, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ 195.6, 167.7, 136.3,
131.3, 131.2, 131.1, 130.7, 129.3, 127.9, 116.1, 115.8, 42.4, 32.4;
HRMS (ESI) m/z [M + H]+ calcd for C15H13BrFO 307.0128, found
307.0120.
2-(2-(Bromomethyl)phenyl)-1-(4-chlorophenyl)ethanone (2m).
The general procedure was followed. Starting with 1m (50.0 mg,
0.21 mmol) and TMSBr (35 μL, 40.4 mg, 0.26 mmol) in CH2Cl2 (5
mL), 2m (12.9 mg, 0.04 mmol, 19%) was generated after column
chromatography (SiO2, EtOAc/hexanes, 1:9, Rf 0.20) as a light yellow
1
oil. H NMR (300 MHz, CDCl3) δ 8.08−7.97 (m, 2H), 7.54−7.48
(m, 2H), 7.33−7.29 (m, 2H), 7.19−7.07 (m, 2H), 4.50 (s, 2H), 4.49
(s, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ 196.0, 140.0, 136.3,
131.3, 130.7, 129.9, 129.3, 129.1, 128.6, 128.3, 127.9, 42.4, 32.4;
HRMS (ESI) m/z [M + H]+ calcd for C15H13BrClO 322.9838, found
322.9826.
2-(2-(Bromomethyl)phenyl)-1-(4-bromophenyl)ethanone (2n).
The general procedure was followed. Starting with 1n (100.0 mg,
0.34 mmol) and TMSBr (70 μL, 80.8 mg, 0.42 mmol) in CH2Cl2 (8
mL), 2n (8.1 mg, 0.02 mmol, 6%) was generated after column
chromatography (SiO2, EtOAc/hexanes, 1:9, Rf 0.20) as a light yellow
2-(2-(Bromomethyl)phenyl)-1-(o-tolyl)ethanone (2e). The gen-
eral procedure was followed. Starting with 1e (50.0 mg, 0.23 mmol)
and TMSBr (37 μL, 42.8 mg, 0.28 mmol) in CH2Cl2 (5 mL), 2e
(57.8 mg, 0.19 mmol, 83%) was generated after column
chromatography (SiO2, EtOAc/hexanes, 1:9, Rf 0.20) as a light
1
oil. H NMR (300 MHz, CDCl3) δ7.93−7.91 (m, 2H), 7.67−7.61
(m, 2H), 7.43−7.25 (m, 4H), 4.50 (s, 2H), 4.48 (s, 2H); 13C{1H}
NMR (75 MHz, CDCl3) δ 196.2, 136.3, 135.3, 133.7, 133.0, 132.1,
131.3, 130.7, 129.9, 129.3, 127.9, 42.4, 32.3; HRMS (ESI) m/z [M +
H]+ calcd for C15H13Br2O 366.9333, found 366.9328.
1
yellow oil: H NMR (300 MHz, CDCl3) δ 7.87 (dd, J = 7.7 Hz, J =
1.5 Hz, 1H), 7.50−7.40 (m, 2H), 7.40−7.26 (m, 4H), 7.25−7.14 (m,
1H), 4.52 (s, 2H), 4.47 (s, 2H), 2.50 (s, 3H); 13C{1H} NMR (75
MHz, CDCl3) δ 200.7, 138.7, 137.4, 136.4, 134.1, 132.2, 131.7, 131.5,
130.7, 129.2, 128.7, 127.8, 125.9, 77.5, 77.0, 76.6, 45.3, 32.4, 21.4;
HRMS (ESI) m/z [M + H]+ calcd for C16H16BrO 303.0379, found
303.0367.
2-(2-(Bromomethyl)phenyl)-1-(4-hydroxyphenyl)ethanone (2o).
The general procedure was followed. Starting with 1o (50.0 mg, 0.22
mmol) and TMSBr (35 μL, 40.4 mg, 0.26 mmol) in CH2Cl2 (5 mL),
2o (61.2 mg, 0.20 mmol, 90%) was generated after column
chromatography (SiO2, EtOAc/hexanes, 1:1, Rf 0.50) as a light
yellow viscous liquid: 1H NMR (300 MHz, CD3OD) δ 8.06−7.95 (m,
2H), 7.57−7.32 (m, 1H), 7.28−7.25 (m, 2H), 7.21−7.16 (m, 1H),
6.91−6.88 (m, 2H), 4.57 (s, 2H), 4.48 (s, 2H); 13C{1H} NMR (75
MHz, CD3OD) δ 196.9, 162.7, 136.7, 134.9, 131.1, 130.9, 130.3,
128.6, 128.4, 127.1, 115.0, 41.5, 31.6; HRMS (ESI) m/z [M + H]+
calcd for C15H14BrO2 305.0171, found 305.0167.
2-(2-(Bromomethyl)phenyl)-1-(m-tolyl)ethanone (2f). The gen-
eral procedure was followed. Starting with 1f (50.0 mg, 0.23 mmol)
and TMSBr (37 μL, 42.8 mg, 0.28 mmol) in CH2Cl2 (5 mL), 2f (46.0
mg, 0.15 mmol, 66%) was generated after column chromatography
1
(SiO2, EtOAc/hexanes, 1:9, Rf 0.20) as a light yellow oil: H NMR
(300 MHz, CDCl3) δ 7.94−7.88 (m, 2H), 7.50−7.39 (m, 3H), 7.34−
7.29 (m, 2H), 7.24−7.16 (m, 1H), 4.53 (s, 2H), 4.52 (s, 2H), 2.47 (s,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ 197.4, 138.7, 136.7, 136.4,
N-(4-(2-(2-(Bromomethyl)phenyl)acetyl)phenyl)-4-methylbenze-
nesulfonamide (2p). The general procedure was followed. Starting
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Note
with 1p (50.0 mg, 0.13 mmol) and TMSBr (35 μL, 40.4 mg, 0.26
mmol) in CH2Cl2 (5 mL), 2p (40.1 mg, 0.11 mmol, 80%) was
generated after column chromatography (SiO2, EtOAc/hexanes, 1:1,
mg, 0.22 mmol, 98%) was generated after column chromatography
(SiO2, EtOAc/hexanes, 1:9, Rf 0.60) as a light brown liquid: 1H NMR
(300 MHz, CDCl3) δ 7.71−7.51 (m, 4H), 7.50−7.30 (m, 4H), 7.44−
7.31 (m, 1H), 5.91 (q, J = 7.0 Hz, 1H), 2.16 (d, J = 7.0 Hz, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 144.3, 132.4, 131.7, 129.0, 128.7,
128.6, 128.2, 126.5, 123.1, 121.7, 95.4, 86.6, 46.9, 26.2.
1
Rf 0.41) as a light yellow solid: mp 116.0−117.0 °C; H NMR (300
MHz, CDCl3) δ 7.97−7.88 (m, 2H), 7.84−7.67 (m, 2H), 7.40−7.29
(m, 2H), 7.29−7.23 (m, 2H), 7.19−7.12 (m, 2H), 7.12−7.05 (m,
2H), 4.43 (s, 2H), 4.39 (s, 2H), 2.37 (s, 3H); HRMS (ESI) m/z [M +
H]+ calcd for C22H21BrNO3S 458.0420, found 458.0406.
3-Phenyl-1H-isochromene (3a). Hydrogen bromide gas, generated
from tetrahydronaphthalene (48.4 mg, 1.5 mmol) and bromine (61
μL, 190.8 mg, 1.2 mmol), was bubbled through the solution of 1a
(50.0 mg, 0.24 mmol) and CH2Cl2 (1 mL) at 0 °C. The reaction
mixture was stirred at rt for 16 h and concentrated. The crude product
was purified with column chromatography (SiO2, EtOAc/hexanes,
1:9, Rf 0.50) to yield 3a (20.8 mg, 0.10 mmol, 42%) as a light yellow
2-(2-(Bromomethyl)phenyl)-1-(naphthalen-1-yl)ethanone (2q).
The general procedure was followed. Starting with 1q (50.0 mg,
0.19 mmol) and TMSBr (31 μL, 35.5 mg, 0.23 mmol) in CH2Cl2 (5
mL), 2q (58.0 mg, 0.17 mmol, 90%) was generated after column
chromatography (SiO2, EtOAc/hexanes, 1:9, Rf 0.31) as a light yellow
1
1
liquid: H NMR (300 MHz, CDCl3) δ 8.69−8.57 (m, 1H), 8.16−
liquid: H NMR (300 MHz, CDCl3) δ 7.79−7.75 (m, 2H), 7.45−
7.97 (m, 2H), 7.97−7.86 (m, 1H), 7.75−7.51 (m, 3H), 7.50−7.35
(m, 1H), 7.39−7.21 (m, 3H), 4.64 (s, 2H), 4.59 (s, 2H); 13C{1H}
NMR (75 MHz, CDCl3) δ 200.8, 136.4, 135.3, 134.2, 134.1, 133.2,
131.6, 130.7, 130.2, 129.3, 128.5, 128.2, 128.1, 127.9, 126.6, 125.8,
124.4, 45.8, 32.5; HRMS (ESI) m/z [M + H]+ calcd for C19H16BrO
339.0379, found 339.0366.
7.37 (m, 4H), 7.31−7.01 (m, 3H), 5.31−6.44 (s, 1H), 5.20 (s, 2H).
1
The identity of this product was confirmed by comparison of the H
NMR spectrum to that from a literature report.136 Compound 3a was
also obtained from 2a (30.0 mg, 0.10 mmol) and triethylamine (21.0
mg, 0.21 mmol) in chloroform (1 mL). The reaction mixture was
heated in an oil bath (60 °C) for 14 h, concentrated, diluted with
ethyl acetate (5 mL), and filtered to removed undissolved salt. The
filtrate was concentrated and purified with column chromatography to
yield 3a (21.7 mg, 99%).
2-(2-(Bromomethyl)phenyl)-1-(thiophene-2-yl)ethanone (2r).
The general procedure was followed. Starting with 1r (50.0 mg,
0.23 mmol) and TMSBr (31 μL, 35.5 mg, 0.23 mmol) in CH2Cl2 (5
mL), 2r (64.5 mg, 0.22 mmol, 95%) was generated after column
chromatography (SiO2, EtOAc/hexanes, 1:9, Rf 0.20) as a light yellow
3-(2,6-Dimethylphenyl)-1H-isochromene (3i). Bromotrimethylsi-
lane (TMSBr, 35 μL, 40.2 mg, 0.26 mmol) was added to a solution of
1i (50.0 mg, 0.21 mmol) and CH2Cl2 (5 mL) at 0 °C. The reaction
mixture was stirred at rt for 16 h under an atmosphere of nitrogen and
concentrated. The crude product was purified with column
chromatography (SiO2, EtOAc/hexanes, 1:9, Rf 0.61) to give 3i as a
1
liquid: H NMR (300 MHz, CDCl3) δ 7.90 (dd, J = 3.8 Hz, J = 1.1
Hz, 1H), 7.70 (dd, J = 5.0 Hz, J = 1.1 Hz, 1H), 7.46−7.37 (m, 1H),
7.42−7.24 (m, 2H), 7.29−7.15 (m, 2H), 4.57 (s, 2H), 4.45 (s, 2H);
13C{1H} NMR (75 MHz, CDCl3) δ 189.9, 143.8, 136.5, 134.4, 133.8,
132.7, 131.4, 130.7, 129.2, 128.4, 127.9, 43.1, 32.5; HRMS (ESI) m/z
[M + H]+ calcd for C13H12BrOS 294.9786, found 294.9777.
1
light yellow oil (37.2 mg, 0.16 mmol, 75%): H NMR (300 MHz,
CDCl3) δ 7.33−7.04 (m, 7H), 5.86 (s, 1H), 5.28 (s, 2H), 2.43 (s,
6H); 13C{1H} NMR (75 MHz, CDCl3) δ 154.1, 137.3, 135.4, 131.8,
128.6, 128.2, 127.6, 126.5, 124.0, 123.7, 123.1, 105.8, 68.9, 20.4;
HRMS (ESI) m/z [M + H]+ calcd for C17H17O 237.1273, found
237.1259.
1-(Bromomethyl)-2-(phenylethynyl)benzene (4a). Bromotrime-
thylsilane (TMSBr, 11 μL, 12.2 mg, 0.081 mmol) was added to a
solution of 1a (10.0 mg, 0.04 mmol) and CH2Cl2 (1 mL) at 0 °C.
The reaction mixture was stirred at rt for 16 h under an atmosphere of
nitrogen and concentrated. The crude product was purified with
column chromatography (SiO2, EtOAc/hexanes, 1:9, Rf 0.20) to give
4a (X = Br)as a light yellow oil (5.1 mg, 0.02 mmol, 47%): 1H NMR
(300 MHz, CDCl3) δ 1H NMR (300 MHz, CDCl3) δ 7.66−7.58 (m,
3H), 7.51−7.34 (m, 6H), 4.79 (s, 2H). The identity of this product
was confirmed by comparison of the 1H NMR spectrum to that from
a literature report.130
2-(2-(Bromomethyl)phenyl)-1-(furan-2-yl)ethanone (2s). The
general procedure was followed. Starting with 1s (50.0 mg, 0.25
mmol) and TMSBr (40 μL, 46.5 mg, 0.30 mmol) in CH2Cl2 (5 mL),
2s (63.3 mg, 0.23 mmol, 90%) was generated after column
chromatography (SiO2, EtOAc/hexanes, 1:9, Rf 0.20) as a light
1
yellow liquid. H NMR (300 MHz, CDCl3) δ 7.65 (d, J = 1.7 Hz,
1H), 7.50−7.36 (m, 1H), 7.40−7.22 (m, 4H), 6.59 (dd, J = 3.6 Hz, J
= 1.7 Hz, 1H), 4.60 (s, 2H), 4.37 (s, 2H); 13C{1H} NMR (75 MHz,
CDCl3) δ 186.0, 152.4, 146.8, 136.6, 133.4, 131.5, 130.7, 129.2, 127.9,
118.0, 112.6, 42.2, 32.4; HRMS (ESI) m/z [M + H]+ calcd for
C13H12BrO2 279.0015, found 279.0001.
2-(2-(Bromomethyl)-5-methoxyphenyl)-1-phenylethanone (2u).
The general procedure was followed. Starting with 1u (50.0 mg, 0.21
mmol) and TMSBr (33 μL, 37.9 mg, 0.25 mmol) in CH2Cl2 (5 mL),
2u (53.2 mg, 0.16 mmol, 80%) was generated after column
chromatography (SiO2, EtOAc/hexanes, 1:9, Rf 0.20) as a light
1-Phenyl-2-(o-tolyl)ethanone (5). Benzoyl peroxide (0.5 mg,
0.002 mmol) was added to a mixture of 2a (20.0 mg, 0.07 mmol)
and tributyltin hydride (40.7 mg, 0.14 mmol). The reaction mixture
was stirred in an oil bath (60 °C) for 1 h and concentrated. The crude
product was purified with column chromatography (SiO2, EtOAc/
hexanes, 1:9, Rf 0.61) to give 5 as a light yellow oil (14.7 mg, 0.07
1
yellow liquid: H NMR (300 MHz, CDCl3) δ 7.82−7.66 (m, 1H),
7.57−7.50 (m, 1H), 7.54−7.37 (m, 1H), 7.43−7.23 (m, 2H), 7.27−
7.17 (m, 1H), 7.15−6.94 (m, 2H), 4.46 (s, 2H), 4.45 (s, 2H) 3.90 (s,
3H); 13C{1H} NMR (75 MHz, CDCl3) δ 194.1, 162.2, 134.7, 132.9,
129.7, 129.2, 129.0, 128.0, 127.5, 126.1, 112.3, 75.8, 75.4, 75.0, 53.9,
40.5, 31.0; HRMS (ESI) m/z [M + H]+ calcd for C16H16BrO2
319.0328, found 319.0315.
1
mmol, 95%): H NMR (300 MHz, CDCl3) δ 8.07−8.04 (m, 2H),
7.61−7.53 (m, 1H), 7.51−7.48 (m, 2H), 7.24−7.16 (m, 4H), 4.31−
4.37 (s, 2H), 2.27−2.33 (s, 3H). The identity of this product was
2-(2-(Bromomethyl)-5-fluorophenyl)-1-phenylethanone (2w).
The general procedure was followed. Starting with 1w (50.0 mg,
0.22 mmol) and TMSBr (35 μL, 40.5 mg, 0.26 mmol) in CH2Cl2 (5
mL), 2w (40.8 mg, 0.13 mmol, 60%) was generated after column
chromatography (SiO2, EtOAc/hexanes, 1:9, Rf 0.20) as a light yellow
1
confirmed by comparison of the H NMR spectrum to that from a
literature report.117
(Z)-(2-(1-Bromo-3,3-dimethylbut-1-en-1-yl)phenyl)methanol
(6t). Bromotrimethylsilane (TMSBr, 43 μL, 50.2 mg, 0.33 mmol) was
added to a solution of 1t (50.0 mg, 0.27 mmol) and CH2Cl2 (5 mL)
at 0 °C. The reaction mixture was stirred at rt for 16 h under an
atmosphere of nitrogen and concentrated. The crude product was
purified with column chromatography (SiO2, EtOAc/hexanes, 1:9, Rf
1
liquid: H NMR (300 MHz, CDCl3) δ 8.13−8.04 (m, 2H), 7.73−
7.60 (m, 1H), 7.61−7.43 (m, 2H), 7.21−7.10 (m, 2H), 7.10−6.95
(m, 1H), 4.49 (s, 2H), 4.43 (s, 2H); 13C{1H} NMR (75 MHz,
1
CDCl3) δ 196.8, 161.7(d, JC−F = 245.2 Hz), 138.9, 136.4, 133.6,
1
133.0, 132.9, 128.8, 128.4, 117.3(d, 2JC−F = 21.9 Hz), 116.0(d, 2JC−F
=
0.21) to give 6t as a light yellow oil (64.6 mg, 0.24 mmol, 90%): H
21.0 Hz), 41.7, 31.3; HRMS (ESI) m/z [M + H]+ calcd for
C15H13BrFO 307.0128, found 307.0118.
NMR (300 MHz, CDCl3) δ 7.59−7.49 (m, 1H), 7.38 (td, J = 7.3 Hz,
J = 1.9 Hz, 1H), 7.31−7.20 (m, 2H), 6.30 (s, 1H), 4.93 (d, J = 13.4
Hz, 1H), 4.72 (d, J = 13.4 Hz, 1H), 0.89 (s, 9H); 13C{1H} NMR (75
MHz, CDCl3) δ 145.1, 138.3, 138.3, 129.4, 129.2, 127.7, 127.2, 116.6,
62.6, 36.3, 30.1; HRMS (ESI) m/z [M + H]+ calcd for C13H17BrNaO
291.0355, found 291.0338.
1-(1-Bromoethyl)-2-(phenylethynyl)benzene (1y). 120 The general
procedure to prepare 2a was followed. Starting with 1-(2-
(phenylethynyl)phenyl)ethanol 1x134 (50.0 mg, 0.23 mmol) and
TMSBr (42 μL, 51.6 mg, 0.34 mmol) in CH2Cl2 (5 mL), 1y (62.9
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Note
(Z)-(2-(1-Bromo-2-phenylvinyl)-5-methoxyphenyl)methanol
(6v). Bromotrimethylsilane (TMSBr, 34 μL, 39.2 mg, 0.26 mmol) was
added to a solution of 1v (50.0 mg, 0.21 mmol) and CH2Cl2 (5 mL)
at 0 °C. The reaction mixture was stirred at rt for 16 h under an
atmosphere of nitrogen and concentrated. The crude product was
purified with column chromatography (SiO2, EtOAc/hexanes, 1:9, Rf
yne-1,2-diols to di- and tri-substituted furans. Tetrahedron 2018, 74,
6047−6056.
(4) Yang, Y.; Yao, J.; Zhang, Y. Synthesis of Polysubstituted Furans
via Copper-Mediated Annulation of Alkyl Ketones with α,β-
Unsaturated Carboxylic Acids. Org. Lett. 2013, 15, 3206−3209.
(5) Yuan, Y.; Tan, H.; Kong, L.; Zheng, Z.; Xu, M.; Huang, J.; Li, Y.
Transition-metal-free C-C σ-bond activation of α-aryl ketones and
subsequent Zn-catalyzed intramolecular cyclization: synthesis of
tetrasubstituted furans. Org. Biomol. Chem. 2019, 17, 2725−2733.
(6) Dey, A.; Ali, M. A.; Jana, S.; Hajra, A. Copper-Catalyzed
Regioselective Synthesis of Multisubstituted Furans by Coupling
between Ketones and Aromatic Olefins. J. Org. Chem. 2017, 82,
4812−4818.
1
0.21) to give 6v as a light yellow oil (67.0 mg, 0.21 mmol, 99%): H
NMR (300 MHz, CDCl3) δ 7.28−7.13 (m, 6H), 6.91−6.88 (m, 3H),
4.77 (d, J = 13.7 Hz, 1H), 4.52 (d, J = 13.7 Hz, 1H), 3.87 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 160.2, 139.7, 135.3, 134.6, 130.4,
129.7, 128.3, 127.9, 127.6, 120.8, 113.8, 112.7, 62.1, 55.1; HRMS
(ESI) m/z [M + H]+ calcd for C16H16BrO2 319.0328, found
319.0345.
2-Benzyl-3-phenyl-1,2-dihydroisoquinoline (8).123 A reaction
mixture of 2a (30.0 mg, 0.10 mmol) and benzylamine (11.7 mg,
0.11 mmol) in CH2Cl2 (2 mL) was stirred at 50 °C (oil bath) for 5 h
and concentrated. The crude product was purified with flash column
chromatography (SiO2, hexanes, Rf 0.50) to give 8 as a light yellow
liquid (29.9 mg, 0.10 mmol, 98%). Compound 8 was labile and
decomposed quickly: 1H NMR (300 MHz, CDCl3) δ 7.70 (d, J = 6.3
Hz, 2H), 7.58−7.23 (m, 9H), 7.19−7.11 (m, 2H), 6.98−6.88 (m,
2H), 6.15 (s, 1H), 4.31 (s, 2H), 4.02 (s, 2H); 13C{1H} NMR (75
MHz, CDCl3) δ 149.2, 138.9, 137.5, 134.3, 128.5, 128.4, 127.9, 127.8,
127.8, 127.5, 127.4, 127.0, 125.7, 125.3, 123.1, 107.4, 54.2, 51.2.
(7) Wu, Y.; Huang, Z.; Luo, Y.; Liu, D.; Deng, Y.; Yi, H.; Lee, J.-F.;
Pao, C.-W.; Chen, J.-L.; Lei, A. X-ray Absorption and Electron
Paramagnetic Resonance Guided Discovery of the Cu-Catalyzed
Synthesis of Multiaryl-Substituted Furans from Aryl Styrene and
Ketones Using DMSO as the Oxidant. Org. Lett. 2017, 19, 2330−
2333.
(8) Luo, Z.; Fang, Y.; Zhao, Y.; Liu, P.; Xu, X.; Feng, C.; Li, Z.; He,
J. Synthesis of multisubstituted furans via Cu(i)-catalyzed annulation
of ketones with alkynoate under ligand- and additive-free conditions.
RSC Adv. 2016, 6, 5436−5441.
(9) Naveen, T.; Kancherla, R.; Maiti, D. Radical Based Strategy
toward the Synthesis of 2,3-Dihydrofurans from Aryl Ketones and
Aromatic Olefins. Org. Lett. 2014, 16, 5446−5449.
(10) Ghosh, M.; Mishra, S.; Monir, K.; Hajra, A. Copper-catalyzed
regioselective synthesis of furan via tandem cycloaddition of ketone
with an unsaturated carboxylic acid under air. Org. Biomol. Chem.
2015, 13, 309−314.
(11) Ghosh, M.; Mishra, S.; Hajra, A. Regioselective Synthesis of
Multisubstituted Furans via Copper-Mediated Coupling between
Ketones and β-Nitrostyrenes. J. Org. Chem. 2015, 80, 5364−5368.
(12) Ruan, L.; Shi, M.; Mao, S.; Yu, L.; Yang, F.; Tang, J. An efficient
approach to construct 2-arylbenzo[b]furans from 2-methoxychalcone
epoxides. Tetrahedron 2014, 70, 1065−1070.
(13) Chen, J.; Li, J.; Su, W. Palladium-catalyzed tandem reaction of
2-hydroxyarylacetonitriles with sodium sulfinates: one-pot synthesis of
2-arylbenzofurans. Org. Biomol. Chem. 2014, 12, 4078−4083.
(14) Faragó, J.; Kotschy, A. Synthesis of Benzo[b]furans by
Palladium-NHC Catalyzed Ring Closure of o-Bromobenzyl Ketones.
Synthesis 2009, 2009, 85−90.
(15) Henry, M. C.; Sutherland, A. Synthesis of Benzo[b]furans by
Intramolecular C-O Bond Formation Using Iron and Copper
Catalysis. Org. Lett. 2020, 22, 2766−2770.
(16) Speckmeier, E.; Padié, C.; Zeitler, K. Visible Light Mediated
Reductive Cleavage of C-O Bonds Accessing α-Substituted Aryl
Ketones. Org. Lett. 2015, 17, 4818−4821.
(17) Liang, Z.; Hou, W.; Du, Y.; Zhang, Y.; Pan, Y.; Mao, D.; Zhao,
K. Oxidative Aromatic C-O Bond Formation: Synthesis of 3-
Functionalized Benzo[b]furans by FeCl3-Mediated Ring Closure of
α-Aryl Ketones. Org. Lett. 2009, 11, 4978−4981.
(18) Ackermann, L.; Kaspar, L. T. TiCl4-Catalyzed Indirect Anti-
Markovnikov Hydration of Alkynes: Application to the Synthesis of
Benzo[b]furans. J. Org. Chem. 2007, 72, 6149−6153.
(19) Zhang, M.; Fang, X.; Neumann, H.; Beller, M. General and
Regioselective Synthesis of Pyrroles via Ruthenium-Catalyzed Multi-
component Reactions. J. Am. Chem. Soc. 2013, 135, 11384−11388.
(20) Iida, K.; Miura, T.; Ando, J.; Saito, S. The Dual Role of
Ruthenium and Alkali Base Catalysts in Enabling a Conceptually New
Shortcut to N-Unsubstituted Pyrroles through Unmasked α-Amino
Aldehydes. Org. Lett. 2013, 15, 1436−1439.
(21) Donthiri, R. R.; Samanta, S.; Adimurthy, S. Copper-catalyzed
C(sp3)-H functionalization of ketones with vinyl azides: synthesis of
substituted-1H-pyrroles. Org. Biomol. Chem. 2015, 13, 10113−10116.
(22) Zhang, S.-L.; Yu, Z.-L. Divergent synthesis of indoles,
oxindoles, isocoumarins and isoquinolinones by general Pd-catalyzed
retro-aldol/α-arylation. Org. Biomol. Chem. 2016, 14, 10511−10515.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00294.
1H and 13C{1H} NMR spectra for compounds 2a-2h, 2l-
2s, 2u, 2w, and all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Duen-Ren Hou − Department of Chemistry, National Central
University, Taoyuan 32001, Taiwan; orcid.org/0000-
0003-1072-2915; Email: drhou@ncu.edu.tw
Author
Tzu-Hsuan Kuan − Department of Chemistry, National
Central University, Taoyuan 32001, Taiwan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00294
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from the Ministry of Science and
Technology (MOST 108-2113-M-008-003 and MOST 107-
2113-M-008-014), Taiwan, is gratefully acknowledged. We
thank the Institute of Chemistry, Academia Sinica, and the
Valuable Instrument Center at National Central University for
mass analysis.
REFERENCES
■
(1) Minkler, S. R. K.; Isley, N. A.; Lippincott, D. J.; Krause, N.;
Lipshutz, B. H. Leveraging the Micellar Effect: Gold-Catalyzed
Dehydrative Cyclizations in Water at Room Temperature. Org. Lett.
2014, 16, 724−726.
(2) Chan, C.-K.; Chen, Y.-C.; Chen, Y.-L.; Chang, M.-Y. Synthesis of
substituted phenanthrofurans. Tetrahedron 2015, 71, 9187−9195.
(3) Rao, H. S. P.; Satish, V.; Kanniyappan, S.; Kumari, P. Studies
towards iodine-catalyzed dehydrative-cycloisomerization of pent-4-
6913
https://doi.org/10.1021/acs.joc.1c00294
J. Org. Chem. 2021, 86, 6907−6917

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
(23) Melkonyan, F. S.; Kuznetsov, D. E.; Yurovskaya, M. A.;
Karchava, A. V. One-pot synthesis of substituted indoles via
titanium(iv) alkoxide mediated imine formation - copper-catalyzed
N-arylation. RSC Adv. 2013, 3, 8388−8397.
(24) Yu, S.; Hu, K.; Gong, J.; Qi, L.; Zhu, J.; Zhang, Y.; Cheng, T.;
Chen, J. Palladium-catalyzed tandem addition/cyclization in aqueous
medium: synthesis of 2-arylindoles. Org. Biomol. Chem. 2017, 15,
4300−4307.
(25) Tan, W. W.; Hou, X.; Yoshikai, N. Pd(II)/Bu4NBr/DMSO
Catalytic System for Practical Synthesis of Indoles and Pyrroles from
Imines through Aerobic Dehydrogenative Cyclization. Synthesis 2014,
46, 2727−2733.
(26) Wei, Y.; Deb, I.; Yoshikai, N. Palladium-Catalyzed Aerobic
Oxidative Cyclization of N-Aryl Imines: Indole Synthesis from
Anilines and Ketones. J. Am. Chem. Soc. 2012, 134, 9098−9101.
(27) Dekamin, M. G.; Arefi, E.; Yaghoubi, A. Isocyanurate-based
periodic mesoporous organosilica (PMO-ICS): a highly efficient and
recoverable nanocatalyst for the one-pot synthesis of substituted
imidazoles and benzimidazoles. RSC Adv. 2016, 6, 86982−86988.
(28) Kang, P.; Foote, C. S. Photosensitized Oxidation of 13C,15N-
Labeled Imidazole Derivatives. J. Am. Chem. Soc. 2002, 124, 9629−
9638.
(42) Xi, L.-Y.; Zhang, R.-Y.; Zhang, L.; Chen, S.-Y.; Yu, X.-Q. An
efficient synthesis of quinolines via copper-catalyzed C-N cleavage.
Org. Biomol. Chem. 2015, 13, 3924−3930.
(43) Wu, F.-W.; Hou, R.-S.; Wang, H.-M.; Kang, I.-J.; Chen, L.-C.
̈
Catalyst Free Indirect Friedlander Synthesis of Substituted Quinolines
from Alcohols in PEG-400. J. Chin. Chem. Soc. 2012, 59, 535−539.
(44) Sithambaram, S.; Ding, Y.; Li, W.; Shen, X.; Gaenzler, F.; Suib,
S. L. Manganese octahedral molecular sieves catalyzed tandem
process for synthesis of quinoxalines. Green Chem. 2008, 10, 1029−
1032.
(45) Shaabani, A.; Maleki, A. Green and Efficient Synthesis of
Quinoxaline Derivatives via Ceric Ammonium Nitrate Promoted and
in Situ Aerobic Oxidation of α-Hydroxy Ketones and α-Keto Oximes
in Aqueous Media. Chem. Pharm. Bull. 2008, 56, 79−81.
(46) Song, W.; Liu, P.; Lei, M.; You, H.; Chen, X.; Chen, H.; Ma, L.;
Hu, L. FeCl3 and Morpholine as Efficient Cocatalysts for the One-
Step Synthesis of Quinoxalines from α-Hydroxyketones and 1,2-
Diamines. Synth. Commun. 2012, 42, 236−245.
(47) Dong, K.-Y.; Qin, H.-T.; Bao, X.-X.; Liu, F.; Zhu, C. Oxime-
Mediated Facile Access to 5-Methylisoxazoles and Applications in the
Synthesis of Valdecoxib and Oxacillin. Org. Lett. 2014, 16, 5266−
5268.
(29) Soh, C. H.; Chui, W. K.; Lam, Y. An Efficient and Expeditious
Synthesis of Di- and Monosubstituted 2-Aminoimidazoles. J. Comb.
Chem. 2008, 10, 118−122.
(30) Little, T. L.; Webber, S. E. A Simple and Practical Synthesis of
2-Aminoimidazoles. J. Org. Chem. 1994, 59, 7299−7305.
(31) Xi, L.-Y.; Zhang, R.-Y.; Liang, S.; Chen, S.-Y.; Yu, X.-Q.
Copper-Catalyzed Aerobic Synthesis of 2-Arylpyridines from
Acetophenones and 1,3-Diaminopropane. Org. Lett. 2014, 16,
5269−5271.
(32) Zhang, Z.-W.; Lin, A.; Yang, J. Methyl Ketone Oxime Esters as
Nucleophilic Coupling Partners in Pd-Catalyzed C-H Alkylation and
Application in the Synthesis of Isoquinolines. J. Org. Chem. 2014, 79,
7041−7050.
(33) Liu, W.; Tan, H.; Chen, C.; Pan, Y. A Method to Access
Symmetrical Tetrasubstituted Pyridines via Iodine and Ammonium
Persulfate Mediated [2 + 2+1 + 1]-Cycloaddition Reaction. Adv.
Synth. Catal. 2017, 359, 1594−1598.
(48) Habeeb, A. G.; Rao, P. N. P.; Knaus, E. E. Design and syntheses
of diarylisoxazoles: Novel inhibitors of cyclooxygenase-2 (COX-2)
with analgesic-antiinflammatory activity. Drug Dev. Res. 2000, 51,
273−286.
(49) Zhu, X.; Wang, Y.-F.; Ren, W.; Zhang, F.-L.; Chiba, S.
TEMPO-Mediated Aliphatic C-H Oxidation with Oximes and
Hydrazones. Org. Lett. 2013, 15, 3214−3217.
(50) Alonso, F.; Beletskaya, I. P.; Yus, M. Transition-Metal-
Catalyzed Addition of Heteroatom-Hydrogen Bonds to Alkynes.
Chem. Rev. 2004, 104, 3079−3160.
(51) Hintermann, L.; Labonne, A. Catalytic Hydration of Alkynes
and Its Application in Synthesis. Synthesis 2007, 2007, 1121−1150.
(52) Bassetti, M.; Floris, B. Metalation of alkynes. Part 2. Behaviour
of alkynes with mercury(II) acetate in methanol: a systematic
reinvestigation. J. Chem. Soc., Perkin Trans. 2 1988, 227−233.
(53) Bassetti, M.; Trovato, M. P.; Bocelli, G. Metalation of alkynes.
5. Reaction of diphenylethyne with mercuric salts in alcohols.
Synthesis, stereochemistry, and structure of (.beta.-alkoxyvinyl)
mercury adducts. Organometallics 1990, 9, 2292−2298.
(54) Jung, M. E.; Deng, G. Synthesis of α-Diketones from Alkylaryl-
and Diarylalkynes Using Mercuric Salts. Org. Lett. 2014, 16, 2142−
2145.
(34) Liu, J.; Wang, C.; Wu, L.; Liang, F.; Huang, G. Simple Selective
Synthesis of 2,4- and 2,6-Diarylpyridines through Metal-Free
Cyclocondensation of Aromatic Ketones with Ammonium Acetate.
Synthesis 2010, 2010, 4228−4234.
(35) Hardegger, L. A.; Habegger, J.; Donohoe, T. J. Modular
Synthesis of Highly Substituted Pyridines via Enolate α-Alkenylation.
Org. Lett. 2015, 17, 3222−3225.
(55) Hong, J.-H.; Kurapati, S.; Jo, Y.; Shin, J.-H.; Cho, D.-G.
Accelerated hydration reaction of an unsymmetrical tolan evidenced
by a Hg(ii)-trapped macrocycle and its application as a Hg(ii)-
selective indicator. Chem. Commun. 2016, 52, 10759−10762.
(56) Antenucci, A.; Flamini, P.; Fornaiolo, M. V.; Di Silvio, S.;
Mazzetti, S.; Mencarelli, P.; Salvio, R.; Bassetti, M. Iron(III)-
Catalyzed Hydration of Unactivated Internal Alkynes in Weak Acidic
Medium, under Lewis Acid-Assisted Brønsted Acid Catalysis. Adv.
Synth. Catal. 2019, 361, 4517−4526.
(57) Greenhalgh, M. D.; Frank, D. J.; Thomas, S. P. Iron-Catalysed
Chemo-, Regio-, and Stereoselective Hydrosilylation of Alkenes and
Alkynes using a Bench-Stable Iron(II) Pre-Catalyst. Adv. Synth. Catal.
2014, 356, 584−590.
(36) Jiang, B.; Hao, W.-J.; Wang, X.; Shi, F.; Tu, S.-J. Diversity-
̈
Oriented Synthesis of Krohnke Pyridines. J. Comb. Chem. 2009, 11,
846−850.
(37) Upare, A.; Sathyanarayana, P.; Kore, R.; Sharma, K.; Bathula, S.
R. Catalyst free synthesis of mono- and disubstituted pyrimidines
from O-acyl oximes. Tetrahedron Lett. 2018, 59, 2430−2433.
(38) Shi, T.; Zerio, C.; Sivinski, J.; Ambrose, A. J.; Moore, K. T.;
Buckley, T.; Kaneko, L.; Zhang, M.; Zhang, D. D.; Chapman, E. A
One-Step, Atom Economical Synthesis of Thieno[2,3-d]pyrimidin-4-
amine Derivatives by a Four-Component Reaction. Eur. J. Org. Chem.
2019, 2019, 3269−3272.
(39) Shi, T.; Kaneko, L.; Sandino, M.; Busse, R.; Zhang, M.; Mason,
D.; Machulis, J.; Ambrose, A. J.; Zhang, D. D.; Chapman, E. One-Step
Synthesis of Thieno[2,3-d]pyrimidin-4(3H)-ones via a Catalytic
Four-Component Reaction of Ketones, Ethyl Cyanoacetate, S8, and
Formamide. ACS Sustainable Chem. Eng. 2019, 7, 1524−1528.
(40) Das, J.; Singh, K.; Vellakkaran, M.; Banerjee, D. Nickel-
Catalyzed Hydrogen-Borrowing Strategy for α-Alkylation of Ketones
with Alcohols: A New Route to Branched gem-Bis(alkyl) Ketones.
Org. Lett. 2018, 20, 5587−5591.
(58) Srivastava, A. K.; Ali, M.; Siangwata, S.; Satrawala, N.; Smith, G.
S.; Joshi, R. K. Multitasking FeOCN Composite as an Economic,
Heterogeneous Catalyst for 1-Octene Hydroformylation and Hydra-
tion Reactions. Asian J. Org. Chem. 2020, 9, 377−384.
(59) Cabrero-Antonino, J. R.; Leyva-Pérez, A.; Corma, A.
Regioselective Hydration of Alkynes by Iron(III) Lewis/Brønsted
Catalysis. Chem. - Eur. J. 2012, 18, 11107−11114.
(60) Park, J.; Yeon, J.; Lee, P. H.; Lee, K. Iron-catalyzed indirect
hydration of alkynes in presence of methanesulfonic acid. Tetrahedron
Lett. 2013, 54, 4414−4417.
(41) Luo, W.; Mu, Q.; Qiu, W.; Liu, T.; Yang, F.; Liu, X.; Tang, J. A
novel Friedlander-type synthesis of 3-aryl quinolines from 3-oxo-2,3-
diaryl-propionaldehydes. Tetrahedron 2011, 67, 7090−7095.
(61) Hassam, M.; Li, W.-S. Copper-catalyzed Markovnikov
hydration of alkynes. Tetrahedron 2015, 71, 2719−2723.
6914
https://doi.org/10.1021/acs.joc.1c00294
J. Org. Chem. 2021, 86, 6907−6917

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
(62) Mei, Q.; Liu, H.; Hou, M.; Liu, H.; Han, B. Selective hydration
of asymmetric internal aryl alkynes without directing groups to α-aryl
ketones over Cu-based catalyst. New J. Chem. 2017, 41, 6290−6295.
(63) Grotjahn, D. B.; Lev, D. A. A General Bifunctional Catalyst for
the Anti-Markovnikov Hydration of Terminal Alkynes to Aldehydes
Gives Enzyme-Like Rate and Selectivity Enhancements. J. Am. Chem.
Soc. 2004, 126, 12232−12233.
(64) Tokunaga, M.; Wakatsuki, Y. The First Anti-Markovnikov
Hydration of Terminal Alkynes: Formation of Aldehydes Catalyzed
by a Ruthenium(II)/Phosphane Mixture. Angew. Chem., Int. Ed. 1998,
37, 2867−2869.
(65) Liu, S.; Liu, H.; Zhou, H.; Liu, Q.; Lv, J. Transformation of
Alkynes into Chiral Alcohols via TfOH-Catalyzed Hydration and Ru-
Catalyzed Tandem Asymmetric Hydrogenation. Org. Lett. 2018, 20,
1110−1113.
(66) Ali, M.; Srivastava, A. K.; Siangwata, S.; Smith, G. S.; Joshi, R.
K. Photo induced alkyne hydration reactions mediated by a water
soluble, reusable Rhodium (I) catalyst. Catal. Commun. 2018, 115,
78−81.
(67) James, B. R.; Rempel, G. L. Hydration of acetylenes catalyzed
by rhodium(III) chloride complexes. J. Am. Chem. Soc. 1969, 91,
863−865.
(81) Liu, H.; Wei, Y.; Cai, C. A Combination System of p-
Toluenesulfonic Acid and Acetic Acid for the Hydration of Alkynes.
Synlett 2016, 27, 2378−2383.
(82) Tsuchimoto, T.; Joya, T.; Shirakawa, E.; Kawakami, Y.
Brønsted Acid-Catalyzed Hydration of Alkynes: A Convenient
Route to Diverse Carbonyl Compounds. Synlett 2000, 2000, 1777−
1778.
(83) Menashe, N.; Shvo, Y. Hydration of alkynes in anhydrous
medium with formic acid as water donor. J. Org. Chem. 1993, 58,
7434−7439.
(84) Oss, G.; Ho, J.; Nguyen, T. V. Tropylium Ion Catalyzes
Hydration Reactions of Alkynes. Eur. J. Org. Chem. 2018, 2018,
3974−3981.
(85) Lee, W.-C.; Shen, H.-C.; Hu, W.-P.; Lo, W.-S.; Murali, C.;
Vandavasi, J. K.; Wang, J.-J. Iodine-Catalyzed, Stereo- and
Regioselective Synthesis of 4-Arylidine-4H-benzo[d][1,3]oxazines
and their Applications for the Synthesis of Quinazoline 3-Oxides.
Adv. Synth. Catal. 2012, 354, 2218−2228.
(86) Liu, W.; Wang, H.; Li, C.-J. Metal-Free Markovnikov-Type
Alkyne Hydration under Mild Conditions. Org. Lett. 2016, 18, 2184−
2187.
(87) Asao, N.; Nogami, T.; Takahashi, K.; Yamamoto, Y. Pd(II)
Acts Simultaneously as a Lewis Acid and as a Transition-Metal
Catalyst: Synthesis of Cyclic Alkenyl Ethers from Acetylenic
Aldehydes. J. Am. Chem. Soc. 2002, 124, 764−765.
(88) Barluenga, J.; Vázquez-Villa, H.; Ballesteros, A.; González, J. M.
Cyclization of Carbonyl Groups onto Alkynes upon Reaction with
IPy2BF4 and Their Trapping with Nucleophiles: A Versatile Trigger
for Assembling Oxygen Heterocycles. J. Am. Chem. Soc. 2003, 125,
9028−9029.
(68) Ebule, R. E.; Malhotra, D.; Hammond, G. B.; Xu, B. Ligand
Effects in the Gold Catalyzed Hydration of Alkynes. Adv. Synth. Catal.
2016, 358, 1478−1481.
(69) Bayrakdar, T. A. C. A.; Nahra, F.; Zugazua, O.; Eykens, L.;
Ormerod, D.; Nolan, S. P. Improving process efficiency of gold-
catalyzed hydration of alkynes: merging catalysis with membrane
separation. Green Chem. 2020, 22, 2598−2604.
(70) Dubovtsev, A. Y.; Shcherbakov, N. V.; Dar’in, D. V.;
Kukushkin, V. Y. Nature of the Nucleophilic Oxygenation Reagent
Is Key to Acid-Free Gold-Catalyzed Conversion of Terminal and
Internal Alkynes to 1,2-Dicarbonyls. J. Org. Chem. 2020, 85, 745−757.
(71) Gasperini, D.; Greenhalgh, M. D.; Imad, R.; Siddiqui, S.; Malik,
A.; Arshad, F.; Choudhary, M. I.; Al-Majid, A. M.; Cordes, D. B.;
Slawin, A. M. Z.; Nolan, S. P.; Smith, A. D. Chiral AuI- and AuIII-
Isothiourea Complexes: Synthesis, Characterization and Application.
Chem. - Eur. J. 2019, 25, 1064−1075.
(89) Mondal, S.; Nogami, T.; Asao, N.; Yamamoto, Y. Synthesis of
Novel Antitumor Agent 1-Methoxy-5,10- dioxo-5,10-dihydro-1H-
benzo[g]isochromene Carboxylic Acid (3-Dimethylylaminopropyl)-
amide with a Dual Role Pd(II) Catalyst. J. Org. Chem. 2003, 68,
9496−9498.
(90) Barluenga, J.; Vázquez-Villa, H.; Merino, I.; Ballesteros, A.;
González, J. M. The Reaction of o-Alkynylarene and Heteroarene
Carboxaldehyde Derivatives with Iodonium Ions and Nucleophiles: A
Versatile and Regioselective Synthesis of 1H-Isochromene, Naph-
thalene, Indole, Benzofuran, and Benzothiophene Compounds. Chem.
- Eur. J. 2006, 12, 5790−5805.
(91) Zhang, C.; Wang, G.; Zhan, L.; Yang, X.; Wang, J.; Wei, Y.; Xu,
S.; Shi, M.; Zhang, J. Gold(I) or Gold(III) as Real Intermediate
Species in Gold-Catalyzed Cycloaddition Reactions of Enynal/
Enynone? ACS Catal. 2020, 10, 6682−6690.
(92) Dell’Acqua, M.; Castano, B.; Cecchini, C.; Pedrazzini, T.;
Pirovano, V.; Rossi, E.; Caselli, A.; Abbiati, G. Mild Regiospecific
Synthesis of 1-Alkoxy-isochromenes Catalyzed by Well-Defined
[Silver(I)(Pyridine-Containing Ligand)] Complexes. J. Org. Chem.
2014, 79, 3494−3505.
(93) Terada, M.; Li, F.; Toda, Y. Chiral Silver Phosphate Catalyzed
Transformation of ortho-Alkynylaryl Ketones into 1H-Isochromene
Derivatives through an Intramolecular-Cyclization/Enantioselective-
Reduction Sequence. Angew. Chem., Int. Ed. 2014, 53, 235−239.
(94) Cai, L.; Chen, Y.; Cao, H.; Wei, Q.; Yang, Y.; Ouyang, Q.;
Peng, Y. Asymmetric Cyclization/Nucleophilic Tandem Reaction of
o-Alkynylacetophenone with (Diazomethyl)phosphonate for the
Synthesis of Functional Isochromenes. Org. Lett. 2019, 21, 7597−
7601.
(95) Liu, S.; Chen, K.; Lan, X.-C.; Hao, W.-J.; Li, G.; Tu, S.-J.; Jiang,
B. Synergistic silver/scandium catalysis for divergent synthesis of
skeletally diverse chromene derivatives. Chem. Commun. 2017, 53,
10692−10695.
(96) Liu, S.; Lan, X.-C.; Chen, K.; Hao, W.-J.; Li, G.; Tu, S.-J.; Jiang,
B. Ag/Brønsted Acid Co-Catalyzed Spiroketalization of β-Alkynyl
Ketones toward Spiro[chromane-2,1′-isochromene] Derivatives. Org.
Lett. 2017, 19, 3831−3834.
(97) Zhang, X.; Hou, W.; Zhang-Negrerie, D.; Zhao, K.; Du, Y.
Hypervalent Iodine-Mediated Intramolecular trans-Aminocarboxyla-
(72) Heidrich, M.; Bergmann, M.; Muller-Borges, D.; Plenio, H.
̈
Bispentiptycenyl-N-Heterocyclic Carbene (NHC) Gold Complexes:
Highly Active Catalysts for the Room Temperature Hydration of
Alkynes. Adv. Synth. Catal. 2018, 360, 3572−3578.
(73) Gatto, M.; Del Zotto, A.; Segato, J.; Zuccaccia, D. Hydration of
Alkynes Catalyzed by L-Au-X under Solvent- and Acid-Free
Conditions: New Insights into an Efficient, General, and Green
Methodology. Organometallics 2018, 37, 4685−4691.
(74) Arai, H.; Yoshida, T.; Nagashima, E.; Hatayama, A.; Horie, S.;
Matsunaga, S.; Nomiya, K. Silver- and Acid-Free Catalysis by
Polyoxometalate-Assisted Phosphanegold(I) Species for Hydration
of Diphenylacetylene. Organometallics 2016, 35, 1658−1666.
(75) Baidossi, W.; Lahav, M.; Blum, J. Hydration of Alkynes by a
PtCl4-CO Catalyst. J. Org. Chem. 1997, 62, 669−672.
(76) Hiscox, W.; Jennings, P. W. Catalytic hydration of alkynes with
Zeise’s dimer. Organometallics 1990, 9, 1997−1999.
(77) Liang, S.; Hammond, G. B.; Xu, B. Efficient hydration of
alkynes through acid-assisted Brønsted acid catalysis. Chem. Commun.
2015, 51, 903−906.
(78) Gao, Q.; Li, S.; Pan, Y.; Xu, Y.; Wang, H. The indium-catalysed
hydration of alkynes using substoichiometric amounts of PTSA as
additive. Tetrahedron 2013, 69, 3775−3781.
(79) Kortman, G. D.; Orr, M. J.; Hull, K. L. Synthesis and Reactivity
of Dioxazirconacyclohexenes: Development of a Zirconium-Oxo-
Mediated Alkyne-Aldehyde Coupling Reaction. Organometallics 2015,
34, 1013−1016.
(80) Nairoukh, Z.; Avnir, D.; Blum, J. Acid-Catalyzed Hydration of
Alkynes in Aqueous Microemulsions. ChemSusChem 2013, 6, 430−
432.
6915
https://doi.org/10.1021/acs.joc.1c00294
J. Org. Chem. 2021, 86, 6907−6917

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
tion and Oxoaminocarboxylation of Alkynes: Divergent Cascade
Annulations of Isocoumarins under Metal-Free Conditions. Org. Lett.
2015, 17, 5252−5255.
(98) Hou, Q.; Zhang, Z.; Kong, F.; Wang, S.; Wang, H.; Yao, Z.-J.
Assembly of fused indenes via Au(i)-catalyzed C1-C5 cyclization of
enediynes bearing an internal nucleophile. Chem. Commun. 2013, 49,
695−697.
(115) Nun, P.; Ramón, R. S.; Gaillard, S.; Nolan, S. P. Efficient
silver-free gold(I)-catalyzed hydration of alkynes at low catalyst
loading. J. Organomet. Chem. 2011, 696, 7−11.
(116) Jeong, J.; Ray, D.; Oh, C. H. Cationic Gold-Catalyzed
Regioselective Hydration of 1-Arylalkynes through Carbonyl Group
Participation. Synlett 2012, 23, 897−902.
(117) Landers, B.; Berini, C.; Wang, C.; Navarro, O. (N-
Heterocyclic Carbene)-Pd-Catalyzed Anaerobic Oxidation of Secon-
dary Alcohols and Domino Oxidation-Arylation Re actions. J. Org.
Chem. 2011, 76, 1390−1397.
(118) Lalonde, M.; Chan, T. H. Use of Organosilicon Reagents as
Protective Groups in Organic Synthesis. Synthesis 1985, 1985, 817−
845.
(119) Hansch, C.; Leo, A.; Taft, R. W. A survey of Hammett
substituent constants and resonance and field parameters. Chem. Rev.
1991, 91, 165−195.
(120) Feng, J.; Lv, M.; Lu, G.; Cai, C. Efficient Synthesis of
Isothiochromene Derivatives by Pd-Catalyzed Hydrothiolation
Reaction. Eur. J. Org. Chem. 2014, 2014, 5312−5317.
(121) 1H NMR of a freshly opened, commercial TMSBr indicated a
3:1 ratio of TMSBr and 1,1,1,3,3,3-hexamethyldisiloxane (reference
114), derived from moisture and TMSBr. The presence of excess HBr
seems inevitable while using TMSBr.
(122) Drabowicz, J.; Bujnicki, B.; Mikolajczyk, M. An efficient
procedure for the synthesis of 18O-labelled methanesulfinyl chloride.
J. Labelled Compd. Radiopharm. 2003, 46, 1001−1005.
(123) Ye, Z.-S.; Guo, R.-N.; Cai, X.-F.; Chen, M.-W.; Shi, L.; Zhou,
Y.-G. Enantioselective Iridium-Catalyzed Hydrogenation of 1- and 3-
Substituted Isoquinolinium Salts. Angew. Chem., Int. Ed. 2013, 52,
3685−3689.
(124) Scott, J. D.; Williams, R. M. Chemistry and Biology of the
Tetrahydroisoquinoline Antitumor Antibiotics. Chem. Rev. 2002, 102,
1669−1730.
(125) Bentley, K. W. β-Phenylethylamines and the isoquinoline
alkaloids. Nat. Prod. Rep. 2006, 23, 444−463.
(126) Long, P.-W.; Bai, X.-F.; Ye, F.; Li, L.; Xu, Z.; Yang, K.-F.; Cui,
Y.-M.; Zheng, Z.-J.; Xu, L.-W. Construction of Six-Membered
Silacyclic Skeletons via Platinum-Catalyzed Tandem Hydrosilyla-
tion/Cyclization with Dihydrosilanes. Adv. Synth. Catal. 2018, 360,
2825−2830.
(127) Qiu, Y.-F.; Niu, Y.-J.; Wei, X.; Cao, B.-Q.; Wang, X.-C.; Quan,
Z.-J. AgSCF3/Na2S2O8-Promoted Trifluoromethylthiolation/Cycli-
zation of o-Propargyl Arylazides/o-Alkynyl Benzylazides: Synthesis of
SCF3-Substituted Quinolines and Isoquinolines. J. Org. Chem. 2019,
84, 4165−4178.
(128) Mancuso, R.; Mehta, S.; Gabriele, B.; Salerno, G.; Jenks, W. S.;
Larock, R. C. A Simple and Mild Synthesis of 1H-Isochromenes and
(Z)-1-Alkylidene-1,3-dihydroisobenzofurans by the Iodocyclization of
2-(1-Alkynyl)benzylic Alcohols. J. Org. Chem. 2010, 75, 897−901.
(129) Siyang, H. X.; Ji, X. Y.; Wu, X. R.; Wu, X. Y.; Liu, P. N. Lewis
Acid Catalyzed Tandem Polycyclization of Internal Alkynols and
Vinyl Azides. Org. Lett. 2015, 17, 5220−5223.
(130) Sashida, H.; Ohyanagi, K.; Minoura, M.; Akiba, K.-y. Studies
on tellurium-containing heterocycles. Part 18.1 Preparation and
structure of 2-benzotelluropyrylium salts and 2-benzoselenopyrylium
salts. J. Chem. Soc., Perkin Trans. 1 2002, 606−612.
(99) Zheng, Y.; Liu, M.; Qiu, G.; Xie, W.; Wu, J. Synthesis of 3-
(Bromomethylene)isobenzofuran-1(3H)-ones through regioselective
5-exo-dig bromocyclization of 2-alkynylbenzoic acids. Tetrahedron
2019, 75, 1663−1668.
(100) Hashmi, A. S. K.; Lothschutz, C.; Döpp, R.; Ackermann, M.;
̈
De Buck Becker, J.; Rudolph, M.; Scholz, C.; Rominger, F. On
Homogeneous Gold/Palladium Catalytic Systems. Adv. Synth. Catal.
2012, 354, 133−147.
(101) Komeyama, K.; Takahashi, K.; Takaki, K. Bismuth-Catalyzed
Intramolecular Carbo-oxycarbonylation of 3-Alkynyl Esters. Org. Lett.
2008, 10, 5119−5122.
(102) Soltani, Y.; Wilkins, L. C.; Melen, R. L. Stoichiometric and
Catalytic C-C and C-H Bond Formation with B(C6F5)3 via Cationic
Intermediates. Angew. Chem., Int. Ed. 2017, 56, 11995−11999.
(103) Chary, R. G.; Dhananjaya, G.; Prasad, K. V.; Vaishaly, S.;
Ganesh, Y. S. S.; Dulla, B.; Kumar, K. S.; Pal, M. A simple access to N-
(un)substituted isoquinolin-1(2H)-ones: unusual formation of
regioisomeric isoquinolin-1(4H)-ones. Chem. Commun. 2014, 50,
6797−6800.
(104) Bianchi, G.; Chiarini, M.; Marinelli, F.; Rossi, L.; Arcadi, A.
Product Selectivity Control in the Heteroannulation of o-(1-
Alkynyl)benzamides. Adv. Synth. Catal. 2010, 352, 136−142.
(105) Yang, C.; Zhang, X.; Zhang-Negrerie, D.; Du, Y.; Zhao, K.
PhI(OCOCF3)2-Mediated Cyclization of o-(1-Alkynyl)benzamides:
Metal-Free Synthesis of 3-Hydroxy-2,3-dihydroisoquinoline-1,4-
dione. J. Org. Chem. 2015, 80, 5320−5328.
(106) Wang, R.-X.; Yuan, S.-T.; Liu, J.-B.; Wu, J.; Qiu, G.
Regioselective 5-exo-dig oxy-cyclization of 2-alkynylbenzamide for
the synthesis of isobenzofuran-1-imines and isobenzofuran. Org.
Biomol. Chem. 2018, 16, 4501−4508.
(107) Wang, Y.-H.; Liu, J.-B.; Ouyang, B.; Zhou, H.; Qiu, G. TBAI-
mediated regioselective 5-exo-dig iodinative oxocyclization of 2-
alkynylbenzamides for the synthesis of isobenzofuran-1-imines and
isobenzofurans. Tetrahedron 2018, 74, 4429−4434.
(108) Yao, T.; Liang, X.; Guo, Z.; Yang, D. Highly stereoselective
synthesis of (Z)-3-methoxy-1-methyleneisoindoles via DMAP cata-
lyzed cyclization of methyl 2-alkynylbenzimidates. Tetrahedron 2019,
75, 3088−3100.
(109) Bhunia, S.; Wang, K.-C.; Liu, R.-S. PtII-Catalyzed Synthesis of
9-Oxabicyclo[3.3.1]nona-2,6-dienes from 2-Alkynyl-1-carbonylben-
zenes and Allylsilanes by an Allylation/Annulation Cascade. Angew.
Chem., Int. Ed. 2008, 47, 5063−5066.
(110) Rodríguez, E.; Grayson, M. N.; Asensio, A.; Barrio, P.; Houk,
K. N.; Fustero, S. Chiral Brønsted Acid-Catalyzed Asymmetric
Allyl(propargyl)boration Reaction of ortho-Alkynyl Benzaldehydes:
Synthetic Applications and Factors Governing the Enantioselectivity.
ACS Catal. 2016, 6, 2506−2514.
(111) Sota, Y.; Yamamoto, M.; Murai, M.; Uenishi, J. i.; Uemura, M.
Gold(I)-Catalyzed Asymmetric Desymmetrization of meso-Alkynyl
Diols and Kinetic Resolution of the Corresponding dl-Diols: Effects of
Celite Filtration and Silver Salts. Chem. - Eur. J. 2015, 21, 4398−4404.
(112) Padwa, A.; Krumpe, K. E.; Weingarten, M. D. An Unusual
Example of a 6-Endo-Dig Addition to an Unactivated Carbon-Carbon
Triple Bond. J. Org. Chem. 1995, 60, 5595−5603.
(113) 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.
(131) Jongcharoenkamol, J.; Chuathong, P.; Amako, Y.; Kono, M.;
Poonswat, K.; Ruchirawat, S.; Ploypradith, P. Selective Divergent
Synthesis of Indanols, Indanones, and Indenes via Acid-Mediated
Cyclization of (Z)- and (E)-(2-Stilbenyl)methanols and Its
Application for the Synthesis of Paucifloral F Derivatives. J. Org.
Chem. 2018, 83, 13184−13210.
̌
(132) Hessler, F.; Betík, R.; Kadlcíková, A.; Belle, R.; Kotora, M.
Enantioselective Allylation of Selected ortho-Substituted Benzalde-
hydes: A Comparative Study. Eur. J. Org. Chem. 2014, 2014, 7245−
7252.
(114) Wang, W.; Xu, B.; Hammond, G. B. Efficient Synthesis of γ-
Keto Esters through Neighboring Carbonyl Group-Assisted Regiose-
lective Hydration of 3-Alkynoates. J. Org. Chem. 2009, 74, 1640−
1643.
(133) Li, D. Y.; Shi, K. J.; Mao, X. F.; Chen, G. R.; Liu, P. N.
Transition Metal-Free Cascade Reactions of Alkynols to Afford
6916
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J. Org. Chem. 2021, 86, 6907−6917

The Journal of Organic Chemistry
pubs.acs.org/joc
Note
Isoquinolin-1(2H)-one and Dihydroisobenzofuran Derivatives. J. Org.
Chem. 2014, 79, 4602−4614.
(134) Wang, C.; Xie, X.; Liu, J.; Liu, Y.; Li, Y. Gold(I)-Catalyzed
1,4- and/or 1,5-Heteroaryl Migration Reactions through Regiocon-
trolled Cyclizations. Chem. - Eur. J. 2015, 21, 559−564.
(135) Man, Z.; Dai, H.; Shi, Y.; Yang, D.; Li, C.-Y. Synthesis of 5-
Iodo-1,2,3,4-tetrahydropyridines by Rhodium-Catalyzed Tandem
Nucleophilic Attacks Involving 1-Sulfonyl-1,2,3-triazoles and Iodides.
Org. Lett. 2016, 18, 4962−4965.
(136) Smith, R. E.; Richards, N. G. J. Importance of Steric Effects in
the Photochemical Ring Opening of Isochromenes. J. Org. Chem.
1997, 62, 1183−1187.
6917
https://doi.org/10.1021/acs.joc.1c00294
J. Org. Chem. 2021, 86, 6907−6917