The first general route for efficient synthesis of 18O labelled alcohols using the HOF·CH3CN complex

Article abstract of DOI:10.1039/c3cc42337a

A mild and very efficient method for converting boronic acids to alcohols has been developed using the acetonitrile complex of hypofluorous acid HOF·CH₃CN. Employing ¹⁸O-labeled water results in alcohols containing a heavy oxygen isotope. The reactions were performed at room temperature, within a few minutes and in excellent yields.

Full text of DOI:10.1039/c3cc42337a

Chemical Communications
www.rsc.org/chemcomm
Volume 49 | Number 67 | 28 August 2013 | Pages 7363–7462
ISSN 1359-7345
COMMUNICATION
Shlomo Rozen et al.
The first general route for efficient synthesis of 18O labelled alcohols
using the HOF⋅CH3CN complex
1359-7345(2013)49:67;1-S

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18
The first general route for efficient synthesis of O
labelled alcohols using the HOFÁCH3CN complex†
Julia Gatenyo, Inna Vints and Shlomo Rozen*
Cite this: Chem. Commun., 2013,
49, 7379
Received 31st March 2013,
Accepted 13th May 2013
DOI: 10.1039/c3cc42337a
www.rsc.org/chemcomm
A mild and very efficient method for converting boronic acids to alcohols. An old paper describes the transformation of very
alcohols has been developed using the acetonitrile complex of few alkylboronic acids with 30% H2O2 using a quite cumber-
hypofluorous acid HOFÁCH3CN. Employing 18O-labeled water some procedure, which the authors admit is mainly suitable for
results in alcohols containing a heavy oxygen isotope. The reac-
tions were performed at room temperature, within a few minutes
and in excellent yields.
Table 1 Hydroxylation of arylboronic acids
Phenols are ubiquitous in medicinal and natural product
chemistry whereas the hydroxyl function is essential in numer-
ous aromatic ring functionalizations as well as in biological
activities.1 Despite their importance, classical phenolation
methods, which include various nucleophilic aromatic substi-
tutions of aryl halides, can be limited by the harsh reaction
conditions required for non-activated substrates which may
cause incompatibility with sensitive functions.2 Needless to say,
numerous aliphatic and alicyclic alcohols also play very impor-
tant roles in natural and synthetic organic chemistry. Labeling
all these alcohols with the heavy 18O isotope can be very useful
in tracking their fate in living cells.
Substrate (1)
Product (2)
Yield (%)
95
a
>95
>95
b
c
Aromatic boronic acids are readily available either commer-
cially or through the corresponding halides and have found
broad applications in synthetic chemistry. Several procedures for
hydroxylation of arylboronic acids using transition metal cata-
lysts or a copper/strong base combination have recently been
d
e
f
92
90
93
introduced, providing mild and efficient access to phenols.3,4
A
base free or palladium-catalyzed environment was developed as
well.5 As the pharmaceutical industry prefers metal free pro-
cesses, aromatic hydroxylation via hydrogen peroxide,6 oxone7
and N-oxides was also developed.8 It should be pointed out that
g
>95
>95
none of those methods is suitable for introducing the heavy 18
isotope in the aromatic hydroxyl function.
O
The hydroxylation with alkylboronic acids is less accessible
as only two or three works deal with their conversion to
h
School of Chemistry, Tel-Aviv University, Tel-Aviv 69978, Israel.
E-mail: rozens@post.tau.ac.il; Fax: +972 3640 9293; Tel: +972 3640 8378
† Electronic supplementary information (ESI) available: Working with F2 and
HOFÁCH3CN including the synthesis of alcohols with the 18O isotope is described.
Preparation and characterisation of all alcohols is presented. See DOI: 10.1039/
c3cc42337a
i
j
>95
90
c
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Chem. Commun., 2013, 49, 7379--7381 7379

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liquid materials such as propanol and butanol.9 A recent work
describes the conversion of cyclohexylboronic acid (the only
non-aromatic example in this paper) to cyclohexanol in 60%
yield by an electrochemical method.10 Another procedure made
use of oxone as an oxidant, but the starting materials were the
trifluoroborates, R-BF3K,11 imposing an additional synthetic
step since they are usually prepared from the corresponding
boronic acids. Here again, it should be pointed out that none of
the above methods is suitable for synthesizing alcohols with
the heavy 18O isotope.
Table 2 Hydroxylation of alkylboronic acids
Substrate (3)
Product (4)
Yield (%)
80
a
b
90
Alcohols labeled with 18O are very valuable as biological probes
for a variety of studies which are often limited by the availability of
labeled precursors for the preparation of the compounds of inter-
est. Low oxygen-18 enrichment of phenols by an isotopic exchange
reaction under drastic conditions has been reported.12 Using the
prohibitively expensive 18O2 was also reported for phenols.13 Some
specific compounds bearing an aromatic nitro group undergo
exchange of the phenolic oxygen atom with 18O-labeled water in
basic solution.14 As a matter of fact there is no good general
method available for obtaining 18O containing alcohols.
The HOFÁCH3CN complex is one of the several reagents
produced from F2. By itself fluorine has been used to activate
remote tertiary CH bonds,15 while trifluoroacetyl hypofluorite
and acetyl hypofluorite, CF3COOF and CH3COOF, two secondary
reagents, were employed for various fluorination processes.16
Elemental fluorine is also the source of reagents leading to
fluorine free products, the unique MeOF17 and IF18 being only
two examples. The most useful reagent, however, was found to
be the HOFÁCH3CN complex, easily prepared by bubbling dilute
fluorine through aqueous acetonitrile,19 and which is considered
to be one of the best oxygen transfer agents in chemistry today.20
Unlike all other oxygen transfer reagents, HOFÁCH3CN is a
unique source of a permanent electrophilic oxygen species since
it is bound to the only atom more electronegative than itself –
fluorine. This facilitates the transfer of the oxygen atom to most
nucleophilic sites under mild conditions (e.g., room temperature
and reaction times of seconds or minutes).
c
92
93
d
Br(CH2)6B(OH)2
Br(CH2)6OH
acid (1e), which are transformed into 2,6-dimethylphenol (2d)
and 2-naphthol (2e). Electron-donating or withdrawing groups on
the aromatic ring did not affect the efficiency of the reaction.
4-Methoxyphenol (2f), 4-hydroxyacetophenone (2g) and 3-hydroxy-
acetophenone (2h) were obtained from the corresponding boronic
acids 1f, 1g and 1h in a few seconds in 93%, >95% and >95%
yields, respectively. Halogenated boronic acids 1i and 1j also
provide the corresponding phenols in excellent yields (Table 1).
With aliphatic and alicyclic alcohols the picture is similar.
2-Methylpropylboronic acid (3a) was converted to 2-methyl-
Table 3 Synthesis of oxygen-18 labeled alcohols
Product (5)
MS m/za
Calcd. for C6H518O: 95.0383
a
[MÀH]-found: 95.0384
The present study offers easy and convenient access to both
aromatic and aliphatic alcohols via readily performed, high
yield and fast reactions between any boronic acid and
HOFÁCH3CN. The same procedure leads to oxygen-18 labeled
alcohols by using the most readily available source of
this isotope, namely H218O, which is used for producing
H18OFÁCH3CN in very good yield based on the H218O used.
Hydroxylations with the HOFÁCH3CN complex were applied
to a wide selection of aromatic and aliphatic boronic acids
forming the corresponding alcohols in a few seconds to a few
minutes in almost quantitative yields. Tables 1 and 2 summar-
ize these results.
Calcd. for C8H716O18O: 137.0483
[MÀH]-found: 137.0487
b
Calcd. for C8H6N18O: 134.0492
[MÀH]-found: 134.0499
c
Calcd. for C4H1018O: 76.1
[MÀH]-found: 76.1
d
e
Calcd. for C6H1218O: 102.1
[MÀH]-found: 102.1
Reacting phenylboronic acid (1a) with HOFÁCH3CN at room
temperature produced the corresponding phenol (2a) in a few
seconds and in 95% yield. Similar results were observed with
p-tolylboronic acid (1b) and p-t-butylphenylboronic acid (1c),
which are converted to the corresponding phenols 2b and 2c in
quantitative yields. The reaction provided excellent yields
also for substrates containing meta or ortho substituents as in
Calcd. for C8H1018O: 124.1
[MÀH]-found: 124.1
Calcd. for C6H14Br18O: 183.0
[MÀH]-found: 183.1
f
g
Br(CH2)618OH
a
HRMS of phenols was measured under ESI (negative mode) condi-
tions. MS of aliphatic alcohols was measured via a methanol cluster-
based chemical ionization method through a supersonic molecular
2,6-dimethylphenylboronic acid (1d) and 2-naphthylboronic beam interface.21
c
7380 Chem. Commun., 2013, 49, 7379--7381
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propanol (4a) in 80% isolated yield. The yield of the less volatile
cyclohexanol (4b) obtained from cyclohexylboronic acid (3b)
was 90% and the 2-phenylethylboronic acid (3c) produced
2-phenylethanol (4c) in higher than 90% yield. The reaction is
tolerant of halogens as evident from the reaction of 6-bromo-
hexylboronic acid (3d) which upon treatment with HOFÁCH3CN
resulted in 6-bromohexanol (4d) (Table 2).
As stated above, the origin of the electrophilic oxygen in the
HOFÁCH3CN complex is water. This allowed us to prepare any
alcohol we wished, be it aromatic (5a–5c) or aliphatic (5d–5g),
with the 18O isotope using H18OFÁCH3CN prepared readily by
bubbling dilute F2 through acetonitrile and H218O. When this
labeled reagent was reacted with a variety of boronic acids it
produced the corresponding oxygen-18 labeled alcohols with
identical yields to the reactions with the oxygen-16 isotope. MS
of the final product indicates the expected isotopic enrichment
(Table 3). It should be noted that although during the reaction
the solution is somewhat acidic (HF is released when F2 reacts
with water) the hydroxylic 18O was not exchanged with the
common 16O found in air and water even after several days.
In conclusion, this work offers for the first time a general
route for producing various alcohols, and in particular 18O
labelled alcohols. It is done with the help of dilute fluorine
(10% F2 in N2) which, for example, is much less dangerous and
easier to work with than chlorine (it is less toxic than Cl2
(ref. 22)). Diluted fluorine is commercially available, requiring
a simple soda-lime trap at the reaction outlet, or technical
(>95%) F2 could be diluted on the spot to whatever degree
desired by using a simple vacuum line.23
Notes and references
1 (a) J. H. P. Tyman, Synthetic and Natural Phenols, Elsevier, New York,
1996; (b) Z. Rappoporto, The Chemistry of Phenols, Wiley-VCH, 21 For more information on this unique method see: Aviv Analytical
Weinheim, 2003. Ltd. Tel Aviv Israel – www.avivanalytical.com.
2 (a) C. Hoarau and T. R. R. Pettus, Synlett, 2003, 127–137; 22 American Environmental Group Ltd, AEGL (Acute Exposure Guide-
(b) P. Hanson, J. R. Jones, A. B. Taylor, P. H. Walton and line Level) (50) October 2, 2009.
A. W. Timms, J. Chem. Soc., Perkin Trans. 2, 2002, 1135–1150; 23 S. Dayan, M. Kol and S. Rozen, Synthesis, 1999, 1427–1430.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 7379--7381 7381