A new efficient deprotection of azines, hydrazones and oximes. An excellent route for exchanging oxygen isotopes in carbonyls

Article abstract of DOI:10.1016/j.tetlet.2005.11.090

Carbonyls, protected as azines or other C=N derivatives can be deprotected by HOF·CH₃CN in seconds to the corresponding ketone or aldehyde in very good yields. This reaction also offers a very efficient route for replacing the oxygen atom of most carbonyls with any other oxygen isotope, for example, [18]O.

Full text of DOI:10.1016/j.tetlet.2005.11.090

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 763–766
A new efficient deprotection of azines, hydrazones and oximes.
An excellent route for exchanging oxygen isotopes in carbonyls
Mira Carmeli and Shlomo Rozen*
School of Chemistry, Tel-Aviv University, Tel-Aviv 69978, Israel
Received 16 October 2005; revised 9 November 2005; accepted 18 November 2005
Available online 9 December 2005
Abstract—Carbonyls, protected as azines or other C@N derivatives can be deprotected by HOFÆCH3CN in seconds to the corre-
sponding ketone or aldehyde in very good yields. This reaction also offers a very efficient route for replacing the oxygen atom of
most carbonyls with any other oxygen isotope, for example, [18]O.
Ó 2005 Elsevier Ltd. All rights reserved.
1. Introduction
obtained from carbonyls and hydrazine hydrate forming
stable derivatives. However, their resistance to conver-
sion back to the original carbonyl compound has ex-
cluded them from being a popular strategy. There have
been several attempts to decompose azines to the corre-
sponding ketones or aldehydes, but prolonged reaction
times (up to 3 days), high temperatures, polluting
reagents based on heavy metals, inseparable mixtures
and low yields, rendered these methods impractical.4
The notion of protecting various functional groups in a
molecule is almost as old as organic chemistry itself. One
of the conditions for a moiety to assume the role of pro-
tecting group has to be the ease and efficiency of its
removal when its purpose has been fulfilled. When it
comes to carbonyls there is practically one exclusive
protective family consisting of various acetals and thio-
acetals. The first category is stable to bases but very
sensitive to acids, a disadvantage if the protected com-
pound has to encounter acidic media and an advantage
since it is easy to remove.1 Thioacetals are more stable in
general, and hence have gained considerable popular-
ity,1,2 but their removal is more difficult. In both cases
the protected products are rarely crystalline making
their purification somewhat tedious.
The HOFÆCH3CN complex is readily made by passing
commercial dilute fluorine through aqueous acetonitrile.
It is an excellent oxygen transfer agent,5 which can oxi-
dize alcohols, ketones6 and ethers.7 It is able to trans-
form aliphatic and aromatic amines, including amino
acids, into the corresponding nitro derivatives8 and
can hydroxylate sp3 tertiary carbon centres.9 This agent
was also used for other oxygen transfer reactions such as
epoxidation of olefins10,11 and aromatic rings,12 trans-
forming azides and vicinal diamines into the corre-
sponding nitro13 and dinitro derivatives,14 forming
various N-oxides15 and much more.16 A few experiments
convinced us that HOFÆCH3CN can be the reagent of
choice for transferring oxygen to azines and other
C@N containing compounds as well, regenerating the
carbonyl moiety, with molecular nitrogen being the only
noticeable by-product.
In general, most types of azines, various hydrazones and
oxime ethers are readily formed in excellent yields.
Semicarbazones, hydrazones and alike are stable com-
pounds and have had an important role in synthesis
and analysis in addition to their frequent use as protect-
ing groups.1–3 With azines the situation is different and
one can only occasionally find this group used for pro-
tecting carbonyls, mainly because the deprotection step
is quite problematic.
In many cases azines are considered to be a synthetically
ꢀdead endꢁ. They are easily, and usually quantitatively,
2. Discussion
Reacting adamantylazine (1) with a slight excess of
HOFÆCH3CN at 0 °C for a few seconds produced
adamantanone (2) in 98% yield. Parallel reactions with
*
Corresponding author. Tel.: +972 3 6408378; fax: +972 3 6409293;
e-mail: rozens@post.tau.ac.il
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.090

764
M. Carmeli, S. Rozen / Tetrahedron Letters 47 (2006) 763–766
4d
all the other azines tested by us, also proceeded with
very good yields. Cyclic and straight chain ketones also
underwent oxygen transfer, for example, cyclohexanone
azine (3) was converted to cyclohexanone (4) in a few
seconds and in 88% yield. Cyclooctanone azine (5), 4-
methylcyclohexanone azine (6), cholestanone azine (7)
and 5-nonanone azine (8), were all transformed to the
corresponding ketones (9, 10, 11 and 12) in 80%, 80%,
92% and 75% yields, respectively (Scheme 1).
MCPBA,
(17%)
high temp. hours
DMDO
4d
hours,
(33%)
HOF•CH CN
3
PhCHO
PhCH=N-N=CHPh
(90%)
seconds,
21
Ce(NH ) (NO )
4 2
3 6
4c
18 hours,
(65%)
Potential complications may arise with aromatic azines,
since HOFÆCH3CN is also capable of epoxidizing aro-
matic rings.12 However, since the initial attack of the
reagent on the carbon–nitrogen double bond is so fast,
the aromatic ring remains intact as demonstrated by
propiophenone (15) and 4-nitroacetophenone (16) which
were obtained in a matter of seconds in excellent yields
from their corresponding azines 13 and 14. Aldehydes
are of no exception, although special care has to be
taken not to use a large excess of the reagent in order
to avoid further oxidation to the corresponding acids.
Hexylazine (17) and anisazine (18) were both reacted
with HOFÆCH3CN for a few seconds at low tempera-
ture. Hexanal (19) and anisaldehyde (20) were obtained
in 60% and 70% yields, respectively (Scheme 1).
3-Carboxypyridinium
chlorochromate
4b
hours,
(70%)
Scheme 2. From benzalazine to benzaldehyde using various oxidation
agents.
It was of interest to compare carbonyl regeneration from
the corresponding azines using some of the published
methods. The following scheme, using benzalazine (21)
as a model compound, depicts the differences (Scheme 2).
We believe that the reaction proceeds via initial attack
of the electrophilic oxygen on the relatively electron rich
double bond of the azine, resulting in the formation of
the unstable bis-oxaziridine intermediate (A) and HF,
the latter being the driving force of the whole process.
The intermediate A may decompose via two consecutive
N–O bond cleavages forming a ketone or an aldehyde
along with nitrogen elimination (Scheme 3).
N
O
HOF•CH CN
3
(98%)
2
1
2
An especially interesting situation arises when more
than one carbonyl group is found in a molecule. It is
possible to protect one of them as a dimethyleneketal
(e.g., 24) or dimethyltrimethyleneketal (e.g., 25) while
the other carbonyl is protected as an azine (e.g., 22
and 23). Despite the sensitivity of the ketals to acid,
the azine group could be quickly and efficiently removed
without affecting the ketal moieties, producing the mono
protected diketones 24 and 25 in 95% and 80% yields
(Scheme 4).
N
R
O
HOF•CH CN
3
(CH )
(CH )
2 n
2 n
2
R
4
9
(88%)
(80%)
(80%)
3
5
6
R = H; n = 1
R = H; n = 3
R = Me; n = 1
10
This behaviour offers an array of possibilities for differ-
entiating two carbonyl groups for different reactions. An
illuminating example is the alkylation of the ketoester
ethyl 4-ketocyclohexanoate 26. Although the four
hydrogen atoms a to the ketone are more acidic than
the single one a to the ester group, protecting the car-
N
H
2
7
HOF•CH CN
3
(92%)
O
11
O
R
R
R'
F
R
H
HOF•CH CN
3
R
C
N
N
C
C
N
N
C
R'
R'
R
R
R'
HOF•CH CN
3
O:
O:
F
C
N
C
R'
2
H
R'
H
R = R' = Bu
(75%)
(90%)
(90%)
(60%)
(70%)
8
12
15
16
19
20
O
O
R
+
N
+
R
R
-2HF
R
C
N
C
13
R = Ph; R' = Et
C
N
A
N
C
R'
R'
R'
R'
-
14
17
18
-O
R = 4-NO C H ; R' = Me
O
2
6 4
R = CH (CH ) ; R' = H
R
3
2 4
+
N
C
O
2
R = 4-MeOC H ; R' = H
R'
6
4
Scheme 1. Deprotection of azines using the HOFÆCH3CN complex.
Scheme 3. The proposed mechanism of azine deprotection.

M. Carmeli, S. Rozen / Tetrahedron Letters 47 (2006) 763–766
765
R
R
HOF•CH CN
3
O
O
O
HOF•CH CN
>90%
O
C
C
N X
3
O
N
R'
R'
seconds
O
2
24
22
R = Ph, R' = H
R = R' = cyclo-(CH )
(95%)
2 7
X = NH (as pure derivatives or as mixtures
2
O
with azines) OMe, NHCONH , NHPh
2
O
O
HOF•CH CN
3
N
Scheme 6. Converting the C@N moiety to a carbonyl.
2
23
O
O
R
R
H NNH
2
16
2
C
O
C
N
25
R'
2
R'
(80%)
18
H
O + CH CN + F
3
2
2
R
18
Scheme 4. Selective azine deprotection.
C
O
R'
18
H
OF•CH CN
3
6: R = R' =
17: R = CH (CH ) ; R' = H
C
O
N
3
2 4
H NNH •H O
2
2
2
1. LDA
2. MeI
Scheme 7. Direct synthesis of a ketone and aldehyde containing the
18[O] isotope.
COOEt
COOEt
2
26
27
is the best source for all oxygen isotopes. Passing fluo-
rine through acetonitrile and H218O produces
H18OFÆCH3CN. When this reagent was reacted with
either 6 or 17 the carboxylic oxygen atom in the corre-
sponding product (10 or 19) was found to be the 18O iso-
tope (Scheme 7). The only other way to exchange
oxygen isotopes in a carbonyl compound is to treat
the molecule with an acid and a large excess of the very
expensive H218O. The HRMS (CI) of [18]O-4-methyl
cyclohexanone (10-[18]O) and of [18]O-hexanal (19-
[18]O) were recorded to be m/z = 115.100769, calcd for
C7H1218O (M+1): 115.100885, and m/z = 103.100535,
calcd for C6H1218O (M+1): 103.100885, respectively.
N
O
HOF•CH CN
3
Me
COOEt
COOEt
2
28
29
(85%)
Scheme 5. Alkylation a to an ester in the presence of an a-keto moiety.
bonyl by forming the corresponding azine 27, enabled us
to abstract the a ester hydrogen using a strong base and
alkylate the resulting anion with MeI. The stable new
azine of ethyl 4-keto-1-methylcyclohexanoate (28) was
rapidly deprotected using HOFÆCH3CN to give ethyl
4-keto-1-methylcyclohexanoate (29)17 in 85% yield
(from 26) with no detectable amount of ester hydrolysis
(Scheme 5).
In conclusion, new possibilities for using azines, hydraz-
ones and other C@N derivatives as protecting groups
for carbonyl compounds have been described, since their
removal with HOFÆCH3CN is very easy and efficient.
This reagent also provides an excellent route for replac-
ing a carbonyl oxygen with [18]O or any other oxygen
isotope. It also should be stressed that the preparation
of HOFÆCH3CN from dilute F2 and water is as easy as
turning a valve on and off (see also Ref. 15b). Today,
working with dilute fluorine is not as exotic an adven-
ture as it used to be 20 years ago and many laboratories
have already used this element without any reported
incidents. It is predicted that in 20 years every semicon-
ductor and LCD plant, for example, will have its own F2
generator.18
Azine is not the only protecting group which could be
readily removed by HOFÆCH3CN. Practically any
R2C@NR0 moiety is suitable for this reaction. We trea-
ted hydrazones, methyl oxime ethers, semicarbazones
and phenyl hydrazones with the acetonitrile complex
of hypofluorous acid and obtained the corresponding
carbonyls in yields of 90% and higher in a matter of a
few seconds. These results help to circumvent an addi-
tional potential problem. Usually, when an azine is used
as a protecting group, a small but noticeable amount of
a hydrazone is also formed. Similarly, when a hydrazone
is the desired derivative, formation of some azine is
almost unavoidable. Usually, separation of these prod-
ucts is a time consuming process, but the present depro-
tection method does not require any separation, as it is
equally effective for both types of compounds even as a
mixture (Scheme 6).
3. Experimental
For general procedures concerning working with
fluorine, as well as for generating HOFÆCH3CN and
working with it, see Ref. 15b. The physical and spectro-
scopic data for all final products are in perfect agree-
ment with the proposed structures and were found to
be identical to the respective authentic samples. For
more details see also Supplementary data.
One of the advantages of the HOFÆCH3CN complex is
that the origin of its electrophilic oxygen is water, which

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1988, 44, 6821–6830; (e) Trudell, L. M.; Fukada, N.;
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This work was supported by the Israel Science Founda-
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