A Mild Strategy for the Preparation of Phenols via the Ligand-Free Copper-Catalyzed O-Arylation of para -Toluenesulfonic Acid

Article abstract of DOI:10.1055/s-0035-1561623

A facile and simple ligand-free copper-catalyzed reaction to synthesize substituted phenols is reported. The reaction presumably proceeds via an O-arylsulfonate intermediate that is hydrolyzed to afford good to excellent yields of up to 88%. This protocol provides an alternative to existing reports which use strong hydroxide salts as the direct hydroxylation partner. Demonstrating a wide substrate scope and functional group tolerance, this protocol can also be applied to inexpensive and commercially available carboxylic acids to yield phenols.

Full text of DOI:10.1055/s-0035-1561623

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–F
letter
A
B. Y.-H. Tan, Y.-C. Teo
Letter
Synlett
A Mild Strategy for the Preparation of Phenols via the Ligand-Free
Copper-Catalyzed O-Arylation of para-Toluenesulfonic Acid
Bryan Yong-Hao Tan
Yong-Chua Teo*
O-arylsulfonate intermediate
Cu2O (10 mol%)
Cs2CO3 (2 equiv)
O
basic hydrolysis
I
S
O
HO
water (0.2 mL)
TsOH solution
(0.3 mL, 2.45 M)
120 °C, 24 h
R
R
Natural Sciences and Science Education, National Institute
of Education, Nanyang Technological University, Nanyang
Walk, Singapore 637616, Singapore
R
O
R = F, Cl, Br,
17 examples
up to 88% yield
OMe, CF3, NO2,
Ac etc.
yongchua.teo@nie.edu.sg
Received: 11.01.2016
Accepted after revision: 24.03.2016
Published online: 25.04.2016
ligand systems.10 Nevertheless, both sets of reactions are ef-
ficient and straightforward C–O cross-couplings of hydrox-
ide and aryl halides, affording good to excellent yields of the
desired products. Despite significant advances, some lim-
itations still remained; the abovementioned reports em-
ployed a large excess (3 equiv and above) of strong bases
such as NaOH, KOH, and CsOH as the nucleophilic partner
(Scheme 1). This greatly harshens the reaction conditions
and diminishes the synthetic utility. Furthermore, the re-
quirement of assisting ligands to increase the yields and
generality of the reactions entails to increase the overall
operating costs.8,9a–d,9f–h,9k Therefore, from a practical and
industrial point of view, the development of new sustain-
able and experimentally simple ligand-free catalytic system
for the preparation of phenols which excludes the direct
hydroxylation of aryl halides using strong basic hydroxide
salts would represent a significant progress for the synthet-
ic community.
Encouraged by our endeavors in ligand-free copper-cat-
alyzed cross-coupling reactions in water,11 we envisaged
the application of a milder nucleophile for the C–O bond
formation with aryl halides in the lead up to the synthesis
of phenols. We report herein a facile and simple ligand-free
copper-catalyzed synthesis of phenols through the in situ
hydrolysis of the O-arylated products generated by the re-
action between p-toluenesulfonic acid (TsOH) and iodoben-
zenes. With the use of catalytic amounts of TsOH as the nu-
cleophile, this protocol eliminates the need of basic hydrox-
ide salts, hence creating a milder reaction environment.
Furthermore, unlike many of the previously reported proto-
cols where intricately balanced water–organic solvent sys-
tems were crucial for the success of the reaction,8a–c,9a–g,9l
water is used solely. Therefore, this reaction is more sus-
tainable from an industrial standpoint.12
DOI: 10.1055/s-0035-1561623; Art ID: st-2016-b0021-l
Abstract A facile and simple ligand-free copper-catalyzed reaction to
synthesize substituted phenols is reported. The reaction presumably
proceeds via an O-arylsulfonate intermediate that is hydrolyzed to af-
ford good to excellent yields of up to 88%. This protocol provides an al-
ternative to existing reports which use strong hydroxide salts as the di-
rect hydroxylation partner. Demonstrating a wide substrate scope and
functional group tolerance, this protocol can also be applied to inex-
pensive and commercially available carboxylic acids to yield phenols.
Key words phenol, copper, ligand-free, water, p-toluenesulfonic acid
Phenols are valuable synthetic building blocks for the
chemical,1 materials2 and pharmaceutical industries.3 To-
day, about 90% of this demand is met by the classical cu-
mene–phenol process, an oxidative approach based on the
decomposition of cumene hydroperoxide with sulfuric ac-
id.4 However, this method suffers from low efficiency even
under harsh reaction conditions.5 Functionalized phenols,
on the other hand, are typically prepared using non-oxida-
tive methods, including reactions of diazoarenes,6 and nu-
cleophilic aromatic substitution of benzene and aryl ha-
lides.7 Nevertheless, problems associated with these meth-
ods include the limited substrate scope and harsh reaction
conditions. As a result, significant effort has been focused
onto the development of the phenol motif.
Lately, several different reports on palladium-8 and cop-
per-catalyzed9 direct hydroxylation of aryl halides for the
synthesis of phenol and its derivatives have emerged
(Scheme 1). Where the former stood out with greater cata-
lytic efficiency and milder conditions, the latter compensat-
ed through the low toxicity and cost of the copper catalyst–
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

B
B. Y.-H. Tan, Y.-C. Teo
Letter
Synlett
reaction was evaluated. A volume of 0.5 mL water was de-
termined to be optimal, while any deviation from this led to
a decrease in phenol yield (see Supporting Information for
comprehensive study and table). This is possibly due to the
need to strike an intricate balance between the necessity
for water in the proposed hydrolysis step as well as in the
dilution effect. To enhance the practicality of the protocol,
we attempted the same reaction through separate additions
of water and a prepared 2.45 M stock solution of TsOH. It
was observed that effervescence and heat produced
through this staggered addition were considerably reduced,
at a small compensation of 2% yield (Table 1, entry 15). To
conclude the optimization studies, the reactions were car-
ried out using CsOH, KOH, or NaOH (Table 1, entries 16–18);
essential components of previously reported procedures for
the formation of phenols.8,9 Only up to 9% yield was ob-
Reported protocols:
[Cu] or [Pd]
OH– salts
X
HO
R
R
O-arylsulfonate intermediate
O
[Cu]
catalytic TsOH
S
O
I
R
R
O
This work
HO
R
Scheme 1 Metal-catalyzed synthesis of phenols using aryl halides
We initiated our investigations by using iodobenzene (1
equiv) and TsOH (1.5 equiv) as the model substrates for the
O-arylation reaction (Table 1). To the best of our knowledge,
there was no prior study focused on the C–O bond forma-
tion between aryl halides and TsOH. Drawing cue from our
Table 1 Optimization Studies on the Cu-Catalyzed Cross-Coupling of
Sulfonic Acids and Iodobenzene for the Synthesis of Phenola
[Cu] (10 mol%)
base (2 equiv)
previous carbon–heteroatom cross-coupling protocol,11c
a
I
HO
TsOH (0.5 equiv)
solvent
120 °C, 24 h
combination of Cu2O (10 mol%), Cs2CO3 (2 equiv), and water
at 120 °C for 24 hours was used. An encouraging yield of
52% phenol, rather than the O-arylated product, was ob-
tained (Table 1, entry 1). Through this result, we hypothe-
size that the synthesis of phenol was achieved through a
two-step mechanism: 1) the cross-coupling of TsOH and io-
dobenzene, followed by 2) the hydrolysis of the O-arylated
product to produce phenol, concurrently regenerating
TsOH. To support our hypothesis, the effect of different
amounts of TsOH on the yield of phenol was investigated
(see Supporting Information for comprehensive study and
table). To our delight, catalytic amounts of TsOH were able
to produce excellent yields of up to 90%, with 0.5 equiva-
lents being the optimal value (Table 1, entry 2). However,
we observed significantly lower yields of phenol with 0.2
equivalents of TsOH (Table 1, entry 3). This is possibly due
to the inefficient initial cross-coupling of aryl iodide and
nucleophile at low concentrations of TsOH.
With these promising results, we proceeded to evaluate
the influence of bases on the reaction efficiency. All bases
screened, namely K2CO3, K3PO4, Na2CO3 and CsOAc, proved
to be ineffective for the reaction, affording only trace yields.
Among the copper sources, the copper(I) halides screened
were inferior to Cu2O, giving yields of up to 72%, while CuO
was unable to catalyze the reaction (Table 1, entries 4–7).
Control experiments confirmed that no product was ob-
tained in the absence of the catalysts, base, or the nucleo-
philic partner (Table 1, entries 8–10). Following that, a
range of protic and polar organic solvent was examined to
probe on the solvent effect on this reaction (Table 1, entries
11–14). Interestingly, low yields were obtained, leading to
the conclusion that water is essential for the success of the
reaction. Thereafter, the impact of the water volume on the
Entry
Catalyst
Base
Solvent
Yield (%)b
1
2
Cu2O
Cu2O
Cu2O
CuI
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
–
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
MeOH
EtOH
DMF
DMSO
H2O
H2O
H2O
H2O
52c
90
40d
65
72
54
0
3
4
5
CuBr
CuCl
CuO
–
6
7
8
0
9
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
0
10
11
12
13
14
15
16
17
18
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CsOH
0e
20
10
26
0
88f
9
KOH
6
NaOH
0
a Reaction conditions: copper salt (10 mol%), base (2.94 mmol), sulfonic
acid (0.735 mmol), solvent (0.5 mL), iodobenzene (1.47 mmol), 120 °C for
24 h.
b Average GC yield of two runs, with m-cresol as internal standard.
c Amount of TsOH used was 1.5 equiv.
d Amount of TsOH used was 0.2 equiv.
e No TsOH was added.
f Reaction was carried out with Cu2O (10 mol%), Cs2CO3 (2.94 mmol), H2O
(0.2 mL), iodobenzene (1.47 mmol) followed by 2.45 M TsOH (0.3 mL)
solution.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

C
B. Y.-H. Tan, Y.-C. Teo
Letter
Synlett
tained. In summary, in our protocol we eliminated the need
to use strong basic hydroxide salts in the direct hydroxyl-
ation of aryl halides. The synthesis of phenol in water was
achieved by using a combination of Cu2O (10 mol%) and
Cs2CO3 (2 equiv), TsOH solution (0.5 equiv), and iodoben-
zene (1.0 equiv), which was stirred at 120 °C for 24 hours
without the need for stringent inert conditions.
With this set of optimized conditions, we proceeded to
explore the breadth of application of this protocol through
the use of a wide range of substituted aryl halides. The re-
sults are summarized in Table 2.
ent substituents at the meta and para positions were well
tolerated by the reaction conditions, and good yields of up
to 87% of substituted phenols were obtained (Table 2, en-
tries 6–17). Unfortunately, the synthesis of phenols or het-
eroaryl alcohols were not achieved using aryl bromides, a
less reactive electrophile (Table 2, entry 18), and iodopyri-
dines. Reactions using iodophenols and iodoanilines did
not proceed either, due to the acidity and basicity of the
substituents, respectively.
In order to achieve a more comprehensive understand-
ing of the reaction route, experiments involving the hydro-
lysis of the proposed intermediate, an O-arylated sulfonate,
were carried out (Scheme 2). Interestingly, under standard
conditions, a high base-to-intermediate ratio was essential
for 100% conversion of the intermediate into phenol (see
Supporting Information). Next, 1H NMR analysis of the
crude reaction mixtures involving iodobenzene and TsOH
was done under optimized conditions and shortened reac-
tion times (0–2 h). Although phenol was formed within an
hour, 1H NMR analysis showed no accumulation of the pro-
posed intermediate (See Supporting Information). With the
help of the observations above, we postulate the rapid suc-
cession of O-arylation and basic hydrolysis.
Table 2 O-Arylation of p-Toluenesulfonic Acid with Various Substitut-
ed Aryl Halides for the Synthesis of Substituted Phenolsa
Cu2O (10 mol%)
Cs2CO3 (2 equiv)
R
R
I
HO
H2O (0.20 mL)
TsOH solution (0.30 mL)
120 °C, 24 h
Entry
ArX
PhI
Product
Yield (%)b
1
2
2a
2b
2c
2d
2e
2f
88
2-FC6H4I
40
3
2-AcC6H4I
2-MeC6H4I
2-Naphthyl-C6H4I
3-FC6H4I
70
HO
4
30
Cu2O (10 mol%)
Cs2CO3 (2 equiv)
O
S
5
43
O
+
H2O (0.50 mL)
120 °C, 24 h
O
O
S
6
87
HO
proposed O-arylsulfonate
intermediate
(1.96–0.0147 mmol)
7
3-ClC6H4I
3-CF3C6H4I
3-OMeC6H4I
3-NO2C6H4I
3-AcC6H4I
3-MeC6H4I
4-FC6H4I
2g
2h
2i
75
O
8
70
Scheme 2 Hydrolysis of proposed O-arylated sulfonate
9
70c)
85
10
11
12
13
14
15
16
17
18
2j
Taking into consideration the data in Tables 1 and 2
along with reported chemistry of copper-catalyzed cross-
coupling reactions,14 a mechanism for the reaction is pro-
posed (Scheme 3). The ligand-free synthesis of the O-ary-
lated sulfonate intermediate can be achieved by a three-
step mechanism: coordination of TsO–, obtained through
the reaction of TsOH with Cs2CO3, to the CuI metal center,
followed by the oxidative addition of the aryl iodide to form
the CuIII intermediate, and concluded with the reductive
elimination of the O-arylated intermediate to regenerate
the active catalytic CuI species. The pathway is succeeded
by a reversible hydrolysis of the intermediate to produce
phenol and regenerate TsO–. The presence of more TsO–
would likely reverse the equilibrium, leading to lower yields
of phenol, and this expectation is consistent with data in
Table 1 (entry 1), where the use of larger amount of TsOH
led to a significantly lower yield of phenol. Meanwhile, the
inability of other organic solvents to facilitate the reaction
(Table 1, entries 11–14) illustrates the crucial role of water
in the hydrolysis step, in tandem with the proposed mecha-
nism. Nevertheless, more mechanistic studies are necessary
to further elucidate the catalytic cycle and the reaction
pathway.
2k
2l
72
74
2m
2n
2o
2p
2q
2a
71
4-Cl C6H4I
4-NO2C6H4I
4-AcC6H4I
4-MeC6H4I
PhBr
70
70c)
80
67
tracec
a Reaction conditions: Cu2O (10 mol%), Cs2CO3 (2.94 mmol), H2O (0.2 mL),
iodobenzene (1.47 mmol) followed by 2.45 M TsOH (0.3 mL) solution,
stirred at 120 °C for 24 h.
b Isolated yield.
c Reactions were carried out at 130 °C.
In most cases, good to excellent yields of substituted
phenols were obtained. Lower yields were observed for or-
tho-substituted aryl iodides (Table 2, entries 2–5). This set
of results supported the hypothesis of an O-arylated TsOH
intermediate, as it corresponds to the trend observed in
various metal-catalyzed C–O cross-coupling reactions,
where the reaction is hampered by sterically hindered
ortho-substituted aryl iodides.13 Electronic effects of differ-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

D
B. Y.-H. Tan, Y.-C. Teo
Letter
Synlett
OH
O
O
S
O
Hydrolysis/Catalyst regeneration
O
S
O
O
O
S
H2O
O
O
CuI
Ester coordination
Reductive elimination
O
CuIII
O
S
O
CuI
O
S
O
O
Oxidative addition
I
I
CsI
CuIII
Cs+
O
S
O
O
Scheme 3 Proposed mechanism for the synthesis of phenol through hydrolysis of an O-arylsulfonate intermediate
In view of our proposed mechanism and existing litera-
ture of cross-coupling reaction between iodobenzene and
carboxylic acids,15 we envision the application of various
inexpensive and commercially available organic acids as the
nucleophile of this protocol. Intriguingly, a wide range of al-
iphatic (Table 3, entries 1–6) and aromatic carboxylic acids
(Table 3, entries 7 and 8) were successfully applied in cata-
lytic amounts to afford good yields of phenol.
Table 3 O-Arylation of Various Organic Acids with Iodobenzene for the
Synthesis of Phenolsa
Cu2O (10 mol%)
Cs2CO3 (2 equiv)
I
HO
organic acid (0.5 equiv)
water (0.50 mL)
120 °C, 24 h
Entry
Organic acid
Yield (%)b
A small amount (<10%) of aniline was also detected with
the use of benzhydroxamic acid, possibly due to further hy-
drolysis of the present amide linkage. Furthermore, meth-
anesulfonic acid and camphosulfonic acid can also be uti-
lized as the nucleophile to derive 34% and 70% phenol, re-
spectively (Table 3, entries 9 and 10).
In conclusion, a facile, simple and practical ligand-free
copper-catalyzed protocol for the synthesis of phenols
through O-arylation using catalytic amounts of TsOH has
been successfully developed.16 Due to its exclusion of strong
hydroxide salts and assisting ligands, the reaction provides
a plausible alternative to previously established metal-cata-
lyzed hydroxylation of aryl halides. Interestingly, a wide
range of carboxylic acids have also been successfully em-
ployed as the O-arylation partner to afford good yields of
1
2
formic acid
65
70
68
70
65
67
79
60
34
70
acetic acid
3
pivalic acid
4
hexanoic acid
octanoic acid
5
6
decanoic acid
benzoic acid
7
8
benzhydroxamic acid
methanesulfonic acid
camphorsulfonic acid
9
10
a Reaction conditions: Cu2O (10 mol%), Cs2CO3 (2.94 mmol), organic acid
(0.735 mmol), H2O (0.5 mL), iodobenzene (1.47 mmol) stirred at 120 °C for
24 h.
b Average GC yield of two runs, with m-cresol as internal standard.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

E
B. Y.-H. Tan, Y.-C. Teo
Letter
Synlett
phenols. With its tolerance towards different functional
groups present in iodobenzene, this protocol is expected to
be particularly useful in industrial applications.
315. (g) Thakur, K. G.; Sekar, G. Chem. Commun. 2011, 47, 6692.
(h) Ding, G.; Han, H.; Jiang, T.; Wu, T.; Han, B. Chem. Commun.
2014, 50, 9072. (i) Jing, L.; Wei, J.; Zhou, L.; Huang, Z.; Li, Z.;
Zhou, X. Chem. Commun. 2010, 46, 4767. (j) Chen, J.; Yuan, T.;
Hao, W.; Cai, M. Catal. Commun. 2011, 12, 1463. (k) Yang, K.; Li,
Z.; Wang, Z.; Yao, Z.; Jiang, S. Org. Lett. 2011, 13, 4340.
Acknowledgment
(10) For reports on low toxicity of copper catalyst, see: (a) Gujadhur,
R.; Venkataraman, D.; Kintigh, J. T. Tetrahedron Lett. 2001, 42,
4791. (b) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed. 2003,
42, 5400. (c) Beletskaya, I. P.; Cheprakov, A. V. Coord. Chem. Rev.
2004, 248, 2337.
We would like to thank the National Institute of Education and
Nanyang Technological University (RP 5/13 TYC) for the funding of
this work.
(11) For our group’s published ligand-free copper catalysis, see:
(a) Yong, F.-F.; Teo, Y.-C.; Tay, S.-H.; Tan, B. Y.-H.; Lim, K.-H. Tet-
rahedron Lett. 2011, 52, 1161. (b) Yong, F.-F.; Teo, Y.-C.; Chua, G.-
L.; Lim, G. S.; Lin, Y. Tetrahedron Lett. 2011, 52, 1169. (c) Tan, B.
Y.-H.; Teo, Y.-C.; Seow, A.-H. Eur. J. Org. Chem. 2014, 1541.
(12) For reports on sustainable solvents in organic reactions, see:
(a) Li, C.-J.; Trost, B. M. Proc. Natl. Acad. Sci. U.S.A. 2008, 105,
13197. (b) DeSimone, J. M. Science 2002, 297, 799. (c) Capello,
C.; Fischer, U.; Hungerbühler, K. Green Chem. 2007, 9, 927.
(13) For C–O cross-coupling reactions which encountered low yields
with sterically hindered aryl halides, see: (a) Yong, F.-F.; Teo, Y.-
C.; Yan, Y.-K.; Chua, G.-L. Synlett 2012, 101. (b) Yang, H.; Xi, C.;
Miao, Z.; Chen, R. Eur. J. Org. Chem. 2011, 3353. (c) Cristau, H.-J.;
Cellier, P. P.; Hamada, S.; Spindler, J.-F.; Taillefer, M. Org. Lett.
2004, 6, 913.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561623.
S
u
p
p
ortioInfgrmoaitn
S
u
p
p
ortiInfogrmoaitn
References and Notes
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(16) General Procedure for the Synthesis of Substituted Phenols
via O-Arylation of p-Toluenesulfonic Acid: A mixture of Cu2O
(Sigma-Aldrich, 99.99% purity, 0.147 mmol), Cs2CO3 (2.94
mmol), distilled H2O (0.2 mL), aryl halide (1.47 mmol) and p-
toluenesulfonic acid (TsOH) solution (0.3 mL, 2.45 mol/dm3)
were added to a reaction vial and a screw cap was fitted to it.
The reaction mixture was stirred under air in a closed system at
120 °C for 24 h, following which the heterogeneous mixture
was cooled to r.t. and diluted with CH2Cl2. The combined
organic extracts were dried with anhyd Na2SO4 and the solvent
was removed under reduced pressure. The crude product was
loaded onto the silica gel column using minimal amounts of
CH2Cl2 and was purified by silica gel column chromatography to
afford the N-arylated product.
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Phenol (2a): Following the general procedure using p-toluene-
sulfonic acid solution (0.3 mL, 2.45 mol/dm3) and iodobenzene
(0.165 mL, 1.47 mmol), the product (122 mg, 89% yield) was
obtained as a colorless oil after purification by flash chromatog-
raphy (hexane–EtOAc, 80:20). 1H NMR (400 MHz, CDCl3): δ =
7.23 (t, J = 8.6 Hz, 2 H), 6.92 (t, J = 7.6 Hz, 1 H), 6.83 (d, J = 7.6 Hz,
2 H), 5.67 (br s, 1 H). 13C NMR (100 MHz, CDCl3): δ = 155.3,
129.7, 120.9, 115.3. GC–MS: tR = 4.91 min, M/Z = 94. HRMS: m/z
[M+] calcd for C6H6O: 95.0495; found: 95.0500.
2-Fluorophenol (2b): Following the general procedure using p-
toluenesulfonic acid solution (0.3 mL, 2.45 mol/dm3) and 2-fluo-
roiodobenzene (0.172 mL, 1.47 mmol), the product (66 mg, 40%
yield) was obtained as a colorless oil after purification by flash
chromatography (hexane–EtOAc, 80:20). 1H NMR (400 MHz,
CDCl3): δ = 7.02–7.17 (m, 3 H), 6.85–6.90 (m, 1 H), 5.59 (br s, 1
H). 13C NMR (100 MHz, CDCl3): δ = 151.1 (J = 236.2 Hz), 143.4
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F

F
B. Y.-H. Tan, Y.-C. Teo
Letter
Synlett
(J = 14.5 Hz), 124.8 (J = 3.1 Hz), 120.9 (J = 6.1 Hz), 117.4 (J = 2.2
Hz), 115.5 (J = 17.5 Hz). HRMS: m/z [M+] calcd for C6H5OF:
113.0400; found: 113.0393.
204.5, 162.3, 136.4, 130.7, 119.7, 118.9, 118.3, 26.6. HRMS: m/z
[M+] calcd for C8H8O2: 137.0600; found: 137.0598.
O-Cresol (2d): Following the general procedure using p-tolue-
nesulfonic acid solution (0.3 mL, 2.45 mol/dm3) and 2-
methyliodobenzene (0.188 mL, 1.47 mmol), the product (48
mg, 30% yield) was obtained as a colorless oil after purification
2′-Hydroxyacetophenone (2c): Following the general proce-
dure using p-toluenesulfonic acid solution (0.3 mL, 2.45
mol/dm3) and 2′-iodoacetophenone (0.210 mL, 1.47 mmol), the
product (140 mg, 70% yield) was obtained as a colorless oil after
purification by flash chromatography (hexane–EtOAc, 90:10).
1H NMR (400 MHz, CDCl3): δ = 12.26 (br s, 1 H), 7.71 (d, J = 8.4
Hz, 1 H), 7.45 (t, J = 8.4 Hz, 1 H), 6.96 (d, J = 8.0 Hz, 1 H), 6.89 (t,
J = 8.0 Hz, 1 H), 2.61 (s, 3 H). 13C NMR (100 MHz, CDCl3): δ =
1
by flash chromatography (hexane–EtOAc, 85:15). H NMR (400
MHz, CDCl3): δ = 7.09–7.17 (m, 2 H), 6.89 (t, J = 7.2 Hz, 1 H), 6.79
(d, J = 7.6 Hz, 1 H), 4.88 (br s, 1 H), 2.28 (s, 3 H). 13C NMR (100
MHz, CDCl3): δ = 153.7, 131.0, 127.1, 123.8, 120.8, 114.9, 15.7.
HRMS: m/z [M+] calcd for C7H8O: 109.0651; found: 109.0655.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–F