Tertiary amine oxidation using HOF-CH3CN: A novel synthesis of N-oxides

Article abstract of DOI:10.1055/s-1999-6078

HOF·CH₃CN, probably the best oxygen transfer agent organic chemistry has to offer, is easily made by bubbling diluted fluorine (10-15%) through aqueous acetonitrile solution. Used as formed without any isolation or purification, it reacts with various tertiary amines such as pyridine derivatives, polyaromatic nitrogen containing compounds and aliphatic and alicyclic ones to form the corresponding N-oxides. When two nitrogen atoms are present it is possible to make both the N-monoxides and the N,N-dioxides. The reaction times are short (a few minutes), conditions are very mild (0-25 °C) and the yields range from good to excellent (70-95%).

Full text of DOI:10.1055/s-1999-6078

PAPER
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Tertiary Amine Oxidation using HOF◊CH3CN: A Novel Synthesis of N-Oxides
Sharon Dayan, Moshe Kol, Shlomo Rozen*
School of Chemistry, Raymond and Beverly Sackler Faculty of Exact Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel
Fax +972(3)6409293; E-mail: rozens@post.tau.ac.il
Received 4 April 1999
HOF◊CH3CN to form epoxides11 the nitrogen atom of the
Abstract: HOF◊CH3CN, probably the best oxygen transfer agent
pyridine is activated first. Thus 4-vinylpyridine (15) was
converted in 70% yield to the corresponding N-oxide 16
without affecting the alkene. Another interesting example
organic chemistry has to offer, is easily made by bubbling diluted
fluorine (10–15%) through aqueous acetonitrile solution. Used as
formed without any isolation or purification, it reacts with various
tertiary amines such as pyridine derivatives, polyaromatic nitrogen is 4-(N,N-dimethylamino)pyridine (17) with its two tertia-
containing compounds and aliphatic and alicyclic ones to form the
corresponding N-oxides. When two nitrogen atoms are present it is
possible to make both the N-monoxides and the N,N-dioxides. The
4-(N,N-dimethylamino)pyridine oxide (18) in 70%
reaction times are short (a few minutes), conditions are very mild
(0-25 °C) and the yields range from good to excellent (70–95%).
ry nitrogen atoms. Under the mild reaction conditions ap-
plied, only the ring-nitrogen atom was oxidized to give the
yield.14
Key words: oxidation, N-oxides, tertiary amines
Tertiary amine N-oxides are a class of compounds which
assumes increasing importance. They are used in a variety
of processes as well as final products such as fiber prepa-
ration,1 hair tonics,2 topical pharmaceuticals,3 and cellu-
lose solvents.4 The increased attention these compounds
are receiving encouraged us to examine their preparation
by using one of the best oxygen transfer agents organic
chemistry has to offer, the HOF◊CH3CN complex.
The preparation of this reagent, first introduced by us
some years ago,5 is quite simple. Its solution is formed in
good yields by passing nitrogen-diluted fluorine through
aqueous acetonitrile. The HOF◊CH3CN complex is used
as obtained and does not require any isolation or purifica-
tion. It is able to transfer an oxygen atom under mild con-
ditions even to very weak nucleophiles. In the past we
have demonstrated its ability to epoxidize normal6 and
very electron deficient alkenes,7 oxidize amines,8 ethers,9
a variety of sulfides,10 and much more.11 We report here
yet another of its fast and efficient reactions, this time
with tertiary amines forming the corresponding N-oxides.
It should be noted that although some of the N-oxides had
been previously prepared, the combination of the very
mild conditions and short reaction times gave in most cas-
es better results than those reported in the literature.12
Although aromatic rings react with HOF◊CH3CN produc-
ing various phenols epoxides and quinones,15 the nitrogen
atom proved once again more reactive. This is demon-
strated by isoquinoline (19) which produced isoquinoline
N-oxide (20) in good yield without affecting the aromatic-
ity.
More complex polycyclic heteroaromatic derivatives
were also easily converted into their N-oxides. Reacting
1.1 equiv of the HOF◊CH3CN complex with 4,7-phenan-
throline (21), for 10 min, gave the N-monoxide 2216 in
80% yield. Increasing the excess of HOF◊CH3CN com-
plex to 5 mol/equiv resulted in the formation of N,N-diox-
ide 23 in 70% yield.16 Similarly, 2,2-bipyridine (24) was
oxidized to the N,N-dioxide 26 in 80% yield by applying
5 eq of the HOF◊CH3CN complex. The N,N-monoxide
(25)17 can be isolated as the main product in 70% yield if
a smaller amount (about 1.5 mol/equiv) of the
HOF◊CH3CN complex is used.
Pyridines react quickly at temperatures ranging from 0 to
25 °C to produce the N-oxide compounds in good yields.
Pyridine (1) itself was transformed into its N-oxide deriv-
ative 2 in 85% yield within less than five minutes. Simi-
larly 3- and 4-methylpyridines 3 and 4 were converted to
the corresponding N-oxides 5 and 6 in high yields. Rings
substituted with strong electron-donating groups such as
2-methoxypyridine13 (7) or with electron-withdrawing
ones such as 2-cyano- (8), 3-acetyl- (9) and 2-chloropyri-
dine (10) also proved to be excellent substrates producing
the respective N-oxides 11–14 in good yields. Although
we had already demonstrated that double bonds react with
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S. Dayan et al.
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Working with Fluorine; General Procedure
The reaction is by no means restricted to pyridine deriva-
tives. Tertiary aliphatic and alicyclic amines have proved
to be excellent substrates as well. Tributylamine (27) gave
the corresponding N-oxide 2818 in 82% yield. Similar re-
sults were observed with dioctyl methyl amine (29) which
was converted in 95% yield to its N-oxide 30, an impor-
tant industrial chemical whose previous preparation was a
subject of several patents.19 Another interesting amine
successfully reacted was N,N-dicyclohexyl-N-methyl-
amine (31) whose N-oxide 32 is used to dissolve cellu-
lose.20 Anilines are oxidized in this manner as well. N-
Benzyl-N-ethylaniline (33) and N-phenylpiperidine (35)
produced both in 85% yield the corresponding N-oxides
(34 and 36).21
Fluorine is a strong oxidant and a very corrosive material. It should
be used only with an appropriate vacuum line such as outlined in the
following figure and constructed in a well ventilated area. After
evacuation of the line, nitrogen is added up to about 8 psi above at-
mospheric pressure, followed by an appropriate amount of F2, usu-
ally about 10–12 psi. More nitrogen is introduced building up a total
pressure of 60 psi. We assume a rapid mixing of N2 and F2 takes
place in the secondary cylinder B. For the occasional user, however,
various premixed mixtures of F2 in inert gases are commercially
available, simplifying the process. If elementary precautions are
taken, work with fluorine is relatively simple and we have had no
bad experiences working with it.
Producing the Oxidizing Agent, HOF◊CH3CN Complex; Gener-
al Procedure
Mixtures of 15% F2 with nitrogen were used in this work. They
were passed at a rate of about 400 mL per minute through a cold
(–10 °C) mixture of CH3CN (400 mL) and H2O (40 mL). The devel-
opment of the oxidizing power was monitored by reacting aliquots
with an acidic aqueous solution of KI. The liberated iodine was then
titrated with thiosulfate. Typical concentrations of the oxidizing re-
agent were around 0.3–0.4 mol/liter.
General Oxidation Procedure
Tertiary amine or pyridine derivative (5 mmol) were dissolved in
CHCl3 (10–20 mL). The mixture was then cooled to 0 °C and added
to a 1.5–2.5 fold excess of the HOF◊CH3CN complex. After about
5–10 min the mixture was warmed to r.t., neutralized with NaHCO3,
filtered, evaporated, extracted with CHCl3, dried (MgSO4), and then
stripped of the solvent. The crude product was purified either by
chromatography using alumina, or by recrystallization. The spectral
and physical properties of the non-commercial known products,
which we have referred to, were compared with the literature re-
ports. In every case excellent agreement was obtained. The physical
properties of previously not described compounds are given below.
Methyldioctylamine N-Oxide (30)
Obtained as a waxy solid in 95% yield.
1H NMR: d = 0.84–0.90 (m, 6H), 1.20–1.45 (m, 21H), 1.70–1.90
(m, 3H), 3.12 (s, 3H), 3.15–3.30 (m, 4H).
13C NMR: d = 13.9, 22.5, 23.4, 26.6, 29.0, 29.2, 31.6, 55.7, 68.9.
1H NMR spectra were recorded using Bruker AC-200 with CDCl3
or D2O as solvents and Me4Si as an internal standard. The proton
broad band decoupled 13C NMR spectra were recorded at 90.5
MHz. Here too, CDCl3 served as a solvent with TMS as an internal
standard. HRMS were measured with a VG micromass 7070H in-
strument. IR spectra were recorded as neat films, in CHCl3 solution
or in KBr pellets on a Bruker Vector22 FTIR spectrophotometer.
MS (CI): m/z = 272.295340 (M+1)+ Calcd. for C17H37NO
272.295189.
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Tertiary Amine Oxidation using HOF◊CH3CN: A Novel Synthesis of N-Oxides
1429
Figure
Benzylethylaniline N-Oxide (34)
Obtained as an oil in 85% yield.
(Shiseido Co., Ltd.) U.S. Patent US 5,156,836, 1992; Chem.
Abstr. 1993, 118, 260685d.
(3) Johnson, D. L.; Senta, T. A.; Sirvio, L. M.; (Minnesota Mining
and Mfg. Co. ) U.S. Patent, US 4,411,893, 1983; Chem. Abstr.
1984, 100, 39602f.
(4) Berger, W; Philipp, B; Kabbrelian, V; Taeger, E; (Technische
Universität Dresden) Ger (East) DD 298,653, 1992, Chem.
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(5) Rozen, S.; Brand, M. Angew. Chem., Int. Ed. Engl. 1986, 25,
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(10) Rozen, S.; Bareket, Y. J. Org. Chem. 1997, 62, 1457.
(11) Rozen, S. Acc. Chem. Res. 1996, 29, 243.
(12) Coperet, C; Adolfson, H.; Khuong, T.-A. V.; Yudin, A. K.;
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1H NMR: d = 1.17 (t, 3H, J = 7Hz), 3.33 (q, 2H, J = 7Hz), 4.77(s,
2H), 6.95–7.4 (m, 10H).
13C NMR: d = 11.4, 53.2, 75.5, 117.2, 122.25, 128.0, 128.4, 128.8
(x 2), 136.8, 151.4.
MS: m/z = 227.131014 (M)+ Calcd. for C15H17NO 227.129938.
Anal. calcd. for C15H17NO: C, 79.26; H, 7.54; N, 6.16 Found: C,
78.9; H, 7.7; N, 6.07.
Acknowledgment
This research was supported by the USA-Israel Binational Science
Foundation (BSF), Jerusalem, Israel.
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