A simplified method for the efficient preparation of pivaloylacetonitrile

Full text of DOI:10.1080/00304948.2014.922386

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A Simplified Method for the Efficient
Preparation of Pivaloylacetonitrile
Karel Zelinkaa, Jan Simberaab & Pavel Pazderab
a Lucebni Zavody Draslovka Co. Kolin, Havlickova 605 Kolin, Czech
Republic
b Centre for Syntheses at Sustainable Conditions and their
Management, Masaryk University, Faculty of Science, Department of
Chemistry, Kotlarska 2, Brno, Czech Republic
Published online: 10 Jul 2014.
To cite this article: Karel Zelinka, Jan Simbera & Pavel Pazdera (2014) A Simplified Method for the
Efficient Preparation of Pivaloylacetonitrile, Organic Preparations and Procedures International: The
New Journal for Organic Synthesis, 46:4, 386-389, DOI: 10.1080/00304948.2014.922386
To link to this article: http://dx.doi.org/10.1080/00304948.2014.922386
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Organic Preparations and Procedures International, 46:386–389, 2014
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2014.922386
OPPI BRIEF
A Simplified Method for the Efficient Preparation
of Pivaloylacetonitrile
Karel Zelinka,1 Jan Simbera,1,2 and Pavel Pazdera2
1Lucebni Zavody Draslovka Co. Kolin, Havlickova 605 Kolin, Czech Republic
2Centre for Syntheses at Sustainable Conditions and their Management, Masaryk
University, Faculty of Science, Department of Chemistry, Kotlarska 2, Brno,
Czech Republic
Pivaloylacetonitrile (2, cyanopinacolone or 4,4-dimethyl-3-oxopentanenitrile) is a crucial
intermediate for the synthesis of the isoxazole skeleton of the selective herbicide isouron
and for the construction of inhibitors of p38 MAP kinase based on pyrazolyl ureas.1
There are three methods for the preparation of pivaloylacetonitrile. The first is based on the
reaction of methyl or ethyl pivaloate with the anion of acetonitrile2–7 generated through an
electrochemical process2 or under strongly basic conditions with bases such as alkali metal
hydride or alkoxide.3–6 The process is carried out at very low temperatures in inert solvents
such as bromobenzene or THF, for example. An alternate process involves the nucleophilic
substitution of halogen of 1-chloro- or 1-bromopinacolone by alkali metal cyanide in
protic solvents.8–10 The third route involves the reaction of ethyl cyanoacetate with tert-
butyllithium at –70◦C in pentane.11 However, these three methods are not readily applicable
on an industrial scale as they involve difficult reaction conditions (very low temperatures),
poor selectivity, low conversion of the starting materials, long reaction times and relatively
moderate yields (60–78%). Furthermore, some of the starting materials are expensive
and/or dangerous to use. We now report a modification of the nucleophilic substitution
Submitted by February 27, 2014.
Address correspondence to Pavel Pazdera, Centre for Syntheses at Sustainable Conditions and
their Management, Masaryk University, Faculty of Science, Department of Chemistry, Kotlarska 2,
Brno, Czech Republic. E-mail: pazdera@chemi.muni.cz
386

Efficient Preparation of Pivaloylacetonitrile
387
conditions of 1-chloropinacolone with sodium cyanide that removes all disadvantages
of these methods. The reaction proceeds more rapidly in increased yields, diminished
formation of by-products and waste and with limited use of expensive and dangerous
solvents. The effect of the cyanide anion acting as a base or nucleophile on the course of
the reaction is illustrated in Scheme 1.
Scheme 1
The main problem of the published routes is the purity of final product because of
low-reaction regioselectivity. As described in the literature,8–12 the target product, pivaloyl-
acetonitrile (2), is contaminated by up to 20–35% of the oxirane 5 and polymeric by-
products (Scheme 1). The formation of 5 may be explained by nucleophilic addition of
cyanide ion to the carbonyl group of 1-chloropinacolone followed by an intramolecular
nucleophilic substitution of the chlorine atom to provide the oxirane 5. The generation
of polymer by-products may be the result of intermolecular nucleophilic displacement of
the chlorine of the starting material initiated by the carbon atom of the deprotonated (by
cyanide ion) cyanomethylene group 3 (or the starting material itself) or by the oxygen atom
in an intermediary alcoholate 4. Carbanion 3 may be generated by removal of a proton by
cyanide ion acting as a base on cyanomethylene group of 2 or of the starting material to
generate carbanions that undergo further undesirable addition and substitution reactions.
Our simple solution to these difficulties is based on the addition of catalytic amounts of
iodide ion (Finkelstein reaction)13 to a reaction mixture containing 1-chloropinacolone (1),
sodium cyanide and methanol as a solvent. The changes in the reaction pathway resulting
from the addition of iodide ion are shown in Scheme 2. The iodo intermediate 6 generated
in situ is not only more reactive than 1 toward the nucleophilic substitution reaction with
cyanide ion but its methylene hydrogens are less acidic than those of 1. Most importantly,
nucleophilic attack of the iodide ion of the putative oxirane (5) would in effect regenerate
the iodo intermediate 6.
Thus, the Finkelstein procedure using only catalytic amount of iodide ion, is an ex-
cellent method for a very simple yet an effective process on an industrial scale.14,15 The
advantages of method are its simplicity, the high conversion of substrate 1 through a
highly selective synthesis, mild reaction conditions [temperature 60◦C, shorter reaction time
(3 h instead of usual 6 h)] and use of a recyclable solvent. Product 2 is easily isolated by

388
Pazdera et al.
Scheme 2
acidification of the reaction mixture with dilute hydrochloric acid to afford pure 2. The only
waste is the sodium chloride solution in the filtrate after collection of the product.
Experimental Section
1
The H NMR spectrum was recorded in CDCl3 on a Bruker Avance 300 MHz NMR
spectrometer. Chemical shifts are reported in δ values, using TMS an internal standard.
Melting points were determined on a Boetius microscope with digital thermometer and are
uncorrected. GC-MS was acquired on a HP 6890 plus/MS 5973N apparatus (Agilent Tech-
nologies). Comparison of all date obtained with those reported in the literature confirmed
the identity of the product. 1-Chloropinacolone and sodium cyanide were obtained from
Fluka and Lucebni zavody Draslovka a.s. Kolin (Czech Republic), respectively.
4,4-Dimethyl-3-oxopentanenitrile (Pivaloylacetonitrile, 2)
To a stirred and cooled (below 30◦C) suspension of finely powdered sodium cyanide
(50.5 g, 1.01 mol, 98% purity), sodium carbonate (10.6 g, 0.10 mol) and sodium iodide
(3.0 g, 0.02 mol) in methanol (450 ml) in a 1000 ml round bottom flask fitted with a
condenser and a magnetic stir bar, was added dropwise (30 minutes) 1-chloropinacolone
(134.6 g, 1.0 mol). After 15 min stirring, the reaction mixture was heated to 60◦C and
stirred for 3 h. The inorganic salts, which precipitated after cooling, were filtered off using
suction, washed with 50 ml of methanol and the pH value of filtrate was adjusted to neutral
by addition of dil. hydrochloric acid (vol. 1:1). The additional amount of precipitated salts
were filtered off using suction again and washed with 50 ml of methanol. The combined
methanol solution (300 ml) was evaporated in vacuum and 300 ml of hot water (80–85◦C)
was added to the oily distillation residue. This heterogeneous two-phase mixture was cooled
below 20◦C and mixed intensively. The pure solid product formed directly was collected
as a colorless crystallic mass to yield 118.9 g (95%) of 99% pure (GC) 2, mp. 68–69◦,

Efficient Preparation of Pivaloylacetonitrile
389
lit.12 70◦, after a drying in vacuum. 1H NMR: δ 1.24 (s, 9H, 3 × CH3), 3.50 (s, 2H, CH2).
GC-MS, m/z, M+ Calcd for C7H11NO: 125.168. Found 126.166.
Acknowledgment
This work was supported by a grant of the Technology Agency of the Czech Republic (The
ALFA program, Grant No. TA03010633).
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