From aldehydes to nitriles, a general and high yielding transformation using HOF·CH3CN complex

Article abstract of DOI:10.1016/j.tetlet.2006.10.014

N,N-Dimethylhydrazones of aldehydes undergo a rapid oxidative cleavage to form nitriles in very high yields on reaction with HOF·CH₃CN under mild conditions. The reaction is chemoselective and proceeds rapidly without racemization. The nitriles were resistant to further oxidation, even when a large excess of the reagent was employed.

Full text of DOI:10.1016/j.tetlet.2006.10.014

Tetrahedron Letters 47 (2006) 8969–8972
From aldehydes to nitriles, a general and high
yielding transformation using HOFÆCH3CN complex
Mira Carmeli, Neta Shefer and Shlomo Rozen*
School of Chemistry, Tel-Aviv University, Tel-Aviv 69978, Israel
Received 17 July 2006; revised 27 September 2006; accepted 4 October 2006
Available online 30 October 2006
Abstract—N,N-Dimethylhydrazones of aldehydes undergo a rapid oxidative cleavage to form nitriles in very high yields on reaction
with HOFÆCH3CN under mild conditions. The reaction is chemoselective and proceeds rapidly without racemization. The nitriles
were resistant to further oxidation, even when a large excess of the reagent was employed.
Ó 2006 Elsevier Ltd. All rights reserved.
The transformation of aldehydes to nitriles by reacting
imines with certain oxidizing agents (Scheme 1) is an
important topic in organic chemistry. Each of the proce-
dures developed has its advantages and disadvantages.
On the positive side most oxidants are commercial, how-
ever, not all reagents can be applied to all imines. The
reactions are usually slow and certain oxidants are asso-
ciated with health hazards as for example reactions with
MCPBA or SeO2,1 heavy polluting metals such as
molybdenum and tungsten2 or expensive metals like
rhenium.3
tion of HOFÆCH3CN with N,N0-dimethylhydrazones of
various aldehydes. This reagent, readily prepared from
acetonitrile, water, and F2,8 is a powerful oxygen transfer
agent. This stands alone in its ability to oxidize azides
and vicinal diamines into the corresponding nitro9 and
dinitro10 derivatives, forming a variety of N-oxides,11
including the 1,10-phenanthroline-N,N0-dioxide deriva-
tives which eluded chemists for so many decades,12 quin-
oxalines,13 and thiazoles.14 This is also able to transfer
oxygen atoms to episulfides,15 thiophenes,16 polythioph-
enes,17 and can oxidize C@N-containing compounds,18
among others.19 The reaction with imines, which is the
subject of this report, is general in nature and proceeds
well with dimethylhydrazones of any aldehyde, being
aromatic, heterocyclic, benzylic, aliphatic, or part of a
sugar molecule. This is completed after a few seconds
and the corresponding nitriles were formed under mild
conditions and in almost quantitative yields.20
Dimethyldioxirane was employed using large quantities
of organic solvents which generated large volumes of
effluents.4 Oxone supported on wet Al2O3 is an efficient
reagent for this reaction too, providing microwave irra-
diation in dry media is used.5 N,N-Dimethylhydrazones
of aldehydes6 could also be converted to the respective
nitriles as well as the corresponding N,N,N-tri-
methylhydrazonium salts in basic media, using high
temperatures and long reaction times.7
Reacting straight chain or cyclic N,N0-dimethylhydraz-
ones such as 1a, 1b, and 1c, obtained quantitatively from
the corresponding aldehydes, with about 2.5 mol equiv
of HOFÆCH3CN at 0 °C produced the corresponding
nitriles 2a, 2b, and 2c in a few seconds in 95%, 98%,
and 94% yields, respectively (Scheme 2).
We present here an additional route for the transforma-
tion of aldehydes to nitriles based on the very fast reac-
O
NR'
[O]
R C
R C
R C N
Potential complications might have been expected with
aromatic N,N-dimethylhydrazones, since HOFÆCH3CN
is also capable of epoxidizing aromatic rings.21 How-
ever, the initial attack of the reagent on the carbon–
nitrogen double bond was fast enough to prevent any at-
tack on the aromatic ring. This was demonstrated by the
formation of benzonitrile 2d, obtained in a few seconds
H
H
Scheme 1. Oxidation of imines to nitriles.
*
Corresponding author. Tel.: +972 3 6408378; fax: +972 3 6409293;
e-mail: rozens@post.tau.ac.il
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.10.014

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M. Carmeli et al. / Tetrahedron Letters 47 (2006) 8969–8972
furonitriles, (2l) and (2m), in 91% and 80% yields,
N
Me2N
F2 + H2O + CH3CN
HOF•CH3CN
respectively. We had doubts on the behavior of the thio-
phene ring since we had already shown that it could
react with the acetonitrile complex of hypofluorous acid
to produce the corresponding S,S-dioxides.16,17 Fortu-
nately, however, the dimethylhydrazone moiety reacted
faster than the sulfur atom, and if one adheres strictly
to 2.5 mol equiv of HOFÆCH3CN, the dimethylhydr-
azone of 2-thiophenecarboxaldehyde 1n could be con-
verted to 2-cyanothiophene (2n) in a few seconds at
0 °C in a 96% yield. If larger excess of the reagent was
used, then the sulfur atom also reacted.
R C
H
R C N
RCHO
2.5 equiv, few seconds
R =
2a (95%)
2b (98%)
1a
CH3(CH2)4
1b
1c
1d
R = CH3(CH2)10
R = cyclo-C5H9
(94%)
(97%)
2c
2d
R = C6H5
1e
1f
2e (93%)
2f (95%)
R = 4-CH3OC6H4
R =
2-NO2C6H4
As mentioned above the oxidation of 1 required at least
2 mol equiv of HOFÆCH3CN. This fact supports the
general mechanism proposed by Curci4 and Rudler3b
and involves an electrophilic oxygen (Scheme 3). The
factor that makes a substantial difference as far as speed,
yields and employment of mild conditions are concerned
is the formation of HF along with oxide 3, which is a
very strong driving force for the reaction. It is thermo-
dynamically favorable for 3 to transform immediately
to nitrile 2 and dimethylhydroxylamine (4), which in
turn is further oxidized by an additional molecule of
HOFÆCH3CN, to N-oxide 5 and HF, this once again
being a strong driving force for the whole process. We
were able to detect both dimethylhydroxylamine (4)
and N-oxide 5 by MS (EI) m/z = 61 (M)+ for
C2H7NO and m/z = 59 (M)+ for C2H5NO. This proce-
dure was not feasible for ketohydrazones.18
1g
(93%)
R = CH3COC6H4
R = 2,4-(NO2)2C6H3
R = 3,4,5-(OCH3)3C6H2
2g
1h
1i
(98%)
2h
2i (96%)
R =
1j
4-Me2NN CHC6H4
1,4-C6H4(CN)2
2j (98%)
(96%)
(91%)
(80%)
2k
2l
R =
O
1k
1l
R =
R =
O
2m
2n
1m
1n
O
(96%)
R =
S
Scheme 2. Conversion of aldehyde N,N-dimethyl hydrazones to
nitriles.
Transforming the N,N-dimethylhydrazone group to a
nitrile moiety did not affect the stereochemistry around
the nitrogen bonded carbon (Scheme 4). We have
reacted dimethylhydrazone 6 (derived from (1S,2S,
5S)-(ꢀ)-myrtanal) and the N,N-dimethylhydrazone of
(R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxaldehyde (7)
with HOFÆCH3CN for a few seconds and obtained the
corresponding nitriles 824 and 94 without any racemiza-
tion. It is worth noting that these reactions are fast
enough such that rearrangement to the corresponding
menthol derivatives did not occur as is usually the situ-
ation with this bicyclic system.
in a 97% yield, from benzaldehyde N,N-dimethylhydraz-
one 1d.
Electron-donating or electron-withdrawing groups on
the aromatic rings did not affect the speed of the reac-
tion and nitriles 2e–i were obtained from the corre-
sponding N,N-dimethylhydrazones 1e–i again in a few
seconds and in excellent yields. No problems were
encountered with the bifunctional 1,4-benzdialdehyde,
which was converted almost instantaneously, via its
bis(dimethylhydrazone) 1j to 1,4-dicyanobenzene (2j)
again in a practically quantitative yield.
The retention of configuration and the chemoselectivity
of this oxidation process, prompted us to explore the
It was of interest to expand the study to molecules with
more than one potential reactive center. Aldehydes con-
taining double bonds presented such an opportunity
since the olefin function is known to undergo ready
epoxidation.22 Thus, reacting 3-cyclohexene N,N-di-
methylhydrazone (1k) with 1 mol equiv of HOFÆCH3CN
produced a mixture of products arising from an attack
on both the nitrogen atom and the double bond. The
addition of 4 mol equiv of the oxidizing agent resulted
in the epoxynitrile 2k23 in a 96% yield.
N
N
O
N N
R C
R C
HF
HOF•CH3CN
H
H
3
1
Me
Me
HOF•CH3CN
R C
N
N OH
Heterocyclic aldehydes have potentially more than one
reactive center and the question was whether these could
be differentiated between to give clean products. Grati-
fyingly, furan derivatives such as the dimethylhydr-
azones of 2- and 3-furan aldehydes (1l) and (1m) were
smoothly converted into the corresponding nitriles with
HOFÆCH3CN in a few seconds at 0 °C forming 2- and 3-
2
4
H2C
+ H2O + HF
O
N
Me
5
Scheme 3. The mechanistic route to nitrile formation.

1,2:3,4-di-O-isopropylidene-a-D
-galacturononitrile (13)26
M. Carmeli et al. / Tetrahedron Letters 47 (2006) 8969–8972
8971
was smoothly obtained (see Scheme 5).
HOF•CH CN
3
In conclusion, we have described a method for convert-
ing aldehyde hydrazones to nitriles using HOFÆCH3CN,
which is rapid, high yielding and ecofriendly (the re-
leased HF could be easily trapped by a base to produce
a salt). Considering the commercial availability of pre-
mixed fluorine/nitrogen mixtures and the technical ease
of the reaction (no special equipment is needed)27, this
method may become a method of choice for the above
transformation.
H
CN
(98%)
N N
8
6
25
[α] D = -8.4
(c 1.3, benzene)
lit.[α] D = -7.5
(c 1, benzene)
25
[α] D = -4.5
(c 1.3, benzene)
25
N N
H
CN
HOF•CH CN
3
O
O
O
O
Acknowledgment
(95%)
7
9
This work was supported by the Israel Science
Foundation.
25
25
[α] D = -4.7
(c 1.3, CH Cl )
[α] D = 1.5
(c 2.2, CHCl )
2
2
3
25
25
lit.[α] D = -4
(c 1.19, CH Cl )
lit.[α] D = 1.5
References and notes
(c 2.2, CHCl )
2
2
3
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Scheme 4. Synthesis of chiral nitriles using HOFÆCH3CN.
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xylopentodialdofuranose (1,4) (10) was reacted with
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in 30 mL EtOH, N,N-dimethylhydrazine (12–45 mmol)
was added in one portion and then stirred for 1 h. The
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H
O
O
HOF•CH CN
3
N N
H CO
O
3
O
N
O
10
[α] D = 31.6
C
25
O
(c 0.6, CH Cl )
2
2
H CO
3
11
25
[α] D = -43
(c 0.6, CH Cl )
2
2
25
Lit [α] D = -44
N N
O
Yield 98%
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O
O
HOF•CH CN
3
8. General procedure for working with fluorine. Fluorine is a
strong oxidant and a corrosive material. It should be used
only with an appropriate vacuum line.11 For the occa-
sional user, however, various premixed mixtures of F2 in
inert gases are commercially available, thereby simplifying
the process. Unreacted fluorine should be captured by a
simple trap containing a solid base such as sodalime
located at the outlet of the glass reactor. If elementary
precautions are taken, the work with fluorine is relatively
simple and we had never experienced difficulties working
with it.
O
O
12
NC
25
O
[α] D = -96
(c 1.5, MeOH)
O
O
O
O
13
25
[α] D = -105
(c 1.6, MeOH)
20
Lit [α] D = -103
(c 1.0, MeOH)
Yield 92%
General procedure for producing HOFÆCH3CN. The mix-
tures of 10–20% F2 in nitrogen were used throughout this
work. The gas mixture was prepared in a secondary
container prior to the reaction11 and passed at a rate of
Scheme 5. Synthesis of chiral sugar nitriles using HOFÆCH3CN.

8972
M. Carmeli et al. / Tetrahedron Letters 47 (2006) 8969–8972
about 400 mL per minute through a cold (ꢀ15 °C) mixture
CHCl3 solution on an FTIR spectrophotometer. The MS
were measured under CI, EI or FAB conditions. The
typical spectroscopic data for the nitriles: IR (CN): 2250–
of 100 mL CH3CN and 10 mL H2O in a regular glass
reactor. The development of the oxidizing power was
monitored by reacting aliquots with an acidic aqueous
solution of KI. The liberated iodine was then titrated with
thiosulfate. The typical concentrations of the oxidizing
reagent were around 0.4–0.6 mol/L.
2400 cmꢀ1 13C NMR (CN): 115–125 ppm.
;
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50 MHz, respectively, with CDCl3 as a solvent and Me4Si
as an internal standard. The IR spectra were recorded in a
27. One of the referees who had very positive and constructive
remarks, still expressed unfortunate common feelings
amongst chemists regarding fluorine saying that it is
‘surely one of the more evil reagents available’. We would
like to differ. In our opinion and experience, comparing
work with 10–15% F2 in N2, to chlorine reveals that it is
more complicated to work with the latter since it tends to
corrode the cylinders’ heads. Working with bromine is
associated with many accidents and fatalities. Experiment-
ing with the widely used HCN, HF, perchlorates and alike
is surely more dangerous. Diluted fluorine can be passed
through copper, monel, stainless steel, or Teflon tubes
without much trouble.