A convenient synthesis of phenols

Article abstract of DOI:10.1080/00397911.2018.1496263

Anilines are rapidly, often within 60 minutes, converted into the corresponding phenols in up to 87% isolated yield. The presented experimentally simple protocol display broad compatibility with a variety of functional groups, and in particular, well suited for the preparation of methyl-substituted phenols. Such phenols are not easily available by other synthetic approaches. The formation of phenolic radical coupling products was not observed even for activated anilines using this open flask method.

Full text of DOI:10.1080/00397911.2018.1496263

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
A convenient synthesis of phenols
Renate Kristianslund, Anders Vik & Trond V. Hansen
To cite this article: Renate Kristianslund, Anders Vik & Trond V. Hansen (2018): A convenient
synthesis of phenols, Synthetic Communications, DOI: 10.1080/00397911.2018.1496263
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https://doi.org/10.1080/00397911.2018.1496263
A convenient synthesis of phenols
Renate Kristianslund, Anders Vik, and Trond V. Hansen
School of Pharmacy, Department of Pharmaceutical Chemistry, University of Oslo, Oslo, Norway
ABSTRACT
ARTICLE HISTORY
Anilines are rapidly, often within 60 minutes, converted into the cor-
responding phenols in up to 87% isolated yield. The presented
experimentally simple protocol display broad compatibility with a
variety of functional groups, and in particular, well suited for the
preparation of methyl-substituted phenols. Such phenols are not eas-
ily available by other synthetic approaches. The formation of phen-
olic radical coupling products was not observed even for activated
anilines using this open flask method.
Received 21 June 2018
Accepted 29 June 2018
KEYWORDS
Anilines; copper sulfate;
diazotization; 3-iodo
catechol; phenols
GRAPHICAL ABSTRACT
Introduction
Phenols and hydroxylated heteroarenes are important structural elements in pharma-
[
1]
ceuticals and natural products. These aromatic compounds and derivatives are often
utilized as starting materials or intermediates in synthesis. Hence, this field of synthetic
[
2,3]
organic chemistry continues to remain an area of active investigation.
Substituted phenols have traditionally been synthesized by nucleophilic aromatic sub-
[
4]
[5]
stitution or hydrolysis of arenediazonium salts. These reactions are often hampered
by several drawbacks, such as limited substrate scope and harsh reaction conditions for
[
6]
the formation of potential explosive arenediazonium salts. The use of boronic acids or
[
7]
silanes in oxidative protocols, but also transition metal catalyzed C–H activation/oxi-
[
8]
dation methodology, has emerged recently. Moreover, aryl or heteroaryl halides under
Cu-catalysis have also been utilized for making phenols and hydroxylated heteroar-
enes. These methods often require multi-step protocols for making the desired start-
ing materials. Moreover, the cost of the transition metals and phosphine ligands, as well
as their sensitivity to air and moisture, limit their large-scale applications. Alternatively,
Friedel–Crafts chemistry may also be used for the synthesis of alkyl substituted phenols.
[
9]
CONTACT Trond V. Hansen
t.v.hansen@farmasi.uio.no
School of Pharmacy, Department of Pharmaceutical
Chemistry, University of Oslo, PO Box 1068, Blindern, Oslo, N-0316, Norway.
Color versions of one or more of the figures in the article can be found online at www.tandfonline.com/lsyc.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2018 Taylor & Francis

2
R. KRISTIANSLUND ET AL.
Scheme 1. The last step in the synthesis of (–)-sielboldianin A.
However, problems with regioselectivity, polyalkylation, or rearrangements of intermedi-
[
10]
ates are often observed.
Therefore, the development of benign, regioselective, and
experimentally simple synthetic protocols are of interest.
Two mechanistically different transformations exist for converting an aniline to the
corresponding phenol through its diazonium salt. Thermal hydrolysis of the acidic
aqueous solution leads to the formation of an aryl cation intermediate that is converted
[
1]
into the corresponding phenol. A milder alternative is a Sandmeyer type redox reac-
[
11]
tion, reported by Cohen et al.,
in which an aryl radical is formed from the diazo-
nium ion by Cu O, and oxidized to the phenol by hydrated cupric ions. During our
2
efforts towards the total synthesis of the sesquiterpenoid (–)-sielboldianin (1) A, the
[
12]
conversion of aniline 2 to 1 was needed, see Scheme 1.
When the classical conditions for the Sandmeyer type reaction were applied to com-
[
11]
pound 2,
product 3 was formed in 42% isolated yield. As expected, the aniline func-
tionality in 2 was converted to the phenol. However, nitration of the activated para-
position of the formed phenol functionality was also observed. Accordingly, replacing
Cu(NO ) with CuSO yielded (–)-sielboldianin A (1) after chromatographic purifica-
3
2
4
tion (Scheme 1). There are a few reported examples of these reaction conditions in the
[
13]
literature.
In order to further investigate the generality and applicability of this
method, we set out to broaden its substrate scope. Herein, we reveal the results from
our studies extending this cheap, practical, and convenient experimental protocol.
Results and discussion
The substrate scope using commercially available functionalized anilines was evaluated.
In most cases, the products were obtained in moderate to good yields (Table 1).
Accordingly, methyl-substituted phenols not easily obtained by the Friedel–Crafts proto-
col were obtained in good yields (Table 1, entries 1–5). For the four examples with
yields below 40% (Table 1, entries 6–9), this straightforward method using cheap and
commercially available reagents is still a convenient alternative for the preparation of
these types of compounds. For instance, the alkyne substituted phenol product in entry
[
14]
7
is a precursor in the synthesis of combretastatin A-4 and analogs.
Some of the

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Table 1. Synthesis of substituted phenols.
a
a
Entry
1
Product
Yield (%)
40
Entry
10
Product
Yield (%)
66
2
3
4
5
6
7
8
9
53
61
67
86
30
30
36
18
11
12
13
14
15
16
17
18
69
87
76
44
50
65
39
b
50
a
The yields are the average of two experiments of isolated and purified material.
See reference.
b
[11]
anilines were also subjected to the original protocol using Cu(NO ) for comparison of
3
2
the methods. Performing the reaction in the presence of Cu(NO ) with 3-methoxyani-
3
2
line yielded the nitrated phenol product, whereas employing 2-aminophenol and 3,4-
dimethoxyaniline, neither the desired phenol nor the nitrated phenol was obtained
(determined by NMR and MS). However, when subjecting these anilines to the modi-
fied method using CuSO (Table 1, entries 8–10), the desired phenol products were
4
obtained in 36, 18, and 66% yields, respectively. Several different functional groups were
tolerated, such as hydroxyl, methoxy, ester, nitro, isoxazole, tetrahydrofuran, sulfona-
mide, halogens, and amide substituents (Table 1, entries 10–18). Regarding electronics,
anilines containing either electron donating, -withdrawing, and/or -neutral substituents

4
R. KRISTIANSLUND ET AL.
Figure 1. Examples of pharmaceuticals and phenolic natural products.
gave the desired products. Of great synthetic interest, 3-iodocatechol was formed in a
[
15]
reasonable yield of 40%, which compares well with earlier reported enzymatic
synthetic\cenveospan{ }
and
[
16]
protocols. Of note, aniline 2 (Scheme 1, Table 1, entry 18)
was cleanly converted to the phenol using this method, even with several acid sensitive
functionalities present in the molecule. Other sources of Cu(II) have been reported to
[
5,12]
induce phenolic radical coupling reactions.
Hence, for the preparation of activated
and methyl substituted phenols, the presented protocol is attractive.
Conclusions
The results of the modified protocol have been demonstrated for the preparation of
substituted phenols and catechols. The reaction takes place at ambient temperature
resulting in good yields of the products. In particular, methyl substituted phenols are
readily available using this practical and simple protocol. Of note, the formation of
phenolic radical coupling products was not observed using this open flask procedure.
The diazonium salts are prepared in situ making this protocol rather safe. Nevertheless,
[
17]
care should always be taken when handling diazonium compounds.
Experimental
Typical experimental procedure for the synthesis of phenols: Water (4 mL) and HBF4
(
ꢀ48–50% aq. sol., 4 mL) was added to the aniline (0.50 mmol, 1.0 equiv.) and stirred
for a couple of minutes at room temperature in an open reaction flask. NaNO (0.038 g,
1
2
ꢁ
.1 equiv.) in water (2.8 mL) was added dropwise at 0 C and stirred for 30 minutes. To
the cold solution of the resulting diazonium salt was added sat. aq. copper(II)sulfate
50 mL), followed by copper(I)oxide (1.0 equiv., 0.072 g), and stirred at room tempera-
ture for 30 minutes. The reaction mixture was extracted with CH Cl , dried (MgSO )
(
2
2
4
and evaporated in vacuo. The crude products were purified by silica gel chromatog-
raphy. Potential hazard note: Diazonium compounds can be explosive, however, the risk

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5
[
17]
is greatly reduced by following several rules for precaution.
Additional points that
render the experimental procedure reported herein safer is that the diazonium salt is
prepared in situ under dilute conditions and is not isolated, the reaction is performed
ꢁ
-
open to air, the reaction temperature is 0 C to ambient, HBF is used as the counter-
4
ion in this procedure, and arene diazonium tetra-fluoroborates, in contrast to the chlor-
ide salts, are renowned in general for their enhanced thermal stability and shock-
insensitivity. Nevertheless, care should always be taken when handling diazo-
nium compounds.
5
-Methoxy-2-methylphenol
1
Prepared according to the general procedure. Yield: 46 mg (67%). H NMR (400 MHz,
CDCl ) d 7.01 (d, J ¼ 8.2 Hz, 1H), 6.43 (dd, J ¼ 8.2, 2.5 Hz, 1H), 6.40 (d, J ¼ 2.5 Hz, 1H),
3
1
3
5
.00 (s, 1H), 3.76 (s, 3H), 2.18 (s, 3H); C NMR (101 MHz, CDCl ) d 158.9, 154.5,
3
131.2, 115.8, 105.9, 101.4, 55.3, 14.7.
Disclosure statement
No potential conflict of interest was reported by the authors.{AQ8}
Funding
The Research Council of Norway is gratefully acknowledged for funding of a doctoral fellowship
to R. K. (FRIPRO-FRINATEK 230470). Generous support from the Norwegian Ph.D. School in
Pharmacy (Nasjonal forskerskole i Farmasi, NFIF) for a travel grant to R. K. is also appreciated.
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