Industrially viable preparation of 2,2-diisopropylpropionitrile, a key intermediate of physiological coolant WS-23 (2-isopropyl-n,2,3- trimethylbutyramide)

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Organic Preparations and Procedures
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Industrially Viable Preparation of
2,2-Diisopropylpropionitrile, a
Key Intermediate of Physiological
Coolant WS-23 (2-Isopropyl-N,2,3-
trimethylbutyramide)
Ramadas Chavakulaa, Narayana Rao Mutyalaa & Srinivasa Rao
Chennupatia
a Tyche Industries Limited, H. No. C-21/A, Road No. 9, Film Nagar,
Jubilee Hills, Hyderabad, 500093, India
Published online: 27 May 2014.
To cite this article: Ramadas Chavakula, Narayana Rao Mutyala & Srinivasa Rao Chennupati
(2014) Industrially Viable Preparation of 2,2-Diisopropylpropionitrile, a Key Intermediate of
Physiological Coolant WS-23 (2-Isopropyl-N,2,3-trimethylbutyramide), Organic Preparations
and Procedures International: The New Journal for Organic Synthesis, 46:3, 277-279, DOI:
10.1080/00304948.2014.903147
To link to this article: http://dx.doi.org/10.1080/00304948.2014.903147
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Organic Preparations and Procedures International, 46:277–279, 2014
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2014.903147
OPPI BRIEF
Industrially Viable Preparation
of 2,2-Diisopropylpropionitrile, a Key Intermediate
of Physiological Coolant WS-23
(2-Isopropyl-N,2,3-trimethylbutyramide)
Ramadas Chavakula, Narayana Rao Mutyala,
and Srinivasa Rao Chennupati
Tyche Industries Limited, H. No. C-21/A, Road No. 9, Film Nagar, Jubilee Hills,
Hyderabad, 500093, India
Readily synthesized monosubstituted aliphatic acyclic carboxamides have a physiolog-
ical cooling effect similar to that obtained with menthol. Among the monosubstituted
aliphatic acyclic carboxamides, WS-231 (2-isopropyl-N,2,3-trimethylbutyramide, (2) is a
nearly odorless white powder, characterized by a high cooling capacity with no side ef-
fects such as burning, stinging, or tingling sensations. It has been used as a coolant in
medicinal preparations, oral care products, foodstuffs, drinks, tobacco products, cosmetics,
toiletries, and confectionery products. It has been synthesized2 by the Ritter reaction of 2,2-
diisopropylpropionitrile (1) with methanol in the presence of acid (Scheme 1). Although
2,2-diisopropylpropionitrile (1) is commercially available, it is very expensive, hence, it
was our endeavor to develop an eco-friendly methodology for its preparation in good yields.
CH3
CN
CH3
1. MeOH, H2SO4
2. H2O
(Me2CH)2C
1
(Me2CH)2C
2
CONHMe
(WS-23)
Scheme 1
Submitted by August16, 2013.
Address correspondence to Ramadas Chavakula, Tyche Industries Limited, H. No. C-21/A, Road
No. 9, Film Nagar, Jubilee Hills, Hyderabad, 500093, India. E-mail: das.krishnac@gmail.com
277

278
Chavakula et al.
Previous methods3,4 used to synthesize 1, by dialkylation of propionitrile with isopropyl
bromide, require long reaction times at −60◦C to −65◦C and involve tedious work-up pro-
cedures. In addition, the solvents used in these methods such as liquid ammonia and THF
are toxic and not eco-friendly. This communication reports a simple, efficient, economi-
cal single-pot synthesis for the large-scale preparation of 2,2-diisopropylpropionitrile (1).
Method 1 (Scheme 2) is of significance because it does not require any cryogenic conditions,
expensive toxic reagents, or harsh reaction conditions and is simpler than other strategies.
In our approach, dialkylation of propionitrile with isopropyl bromide in the presence of a
sodamide at 0◦C–5◦C in a minimum amount of tetrahydro-furan afforded 1 in 90% yield.
Method 2 (Scheme 2), utilizing the desired product as solvent (either prepared by Method 1
or purchased) for the diisopropylation of propionitrile is carried out at 30◦C–35◦C, avoids
the use of expensive THF and the product is easier to isolate i (92%).
Method 1:
CH3CH2CN
NaNH2, 0oC, THF
3
CH3
CN
(Me2CH)2C
1
+
Method 2:
NaNH2, 30-35oC, 1
(CH3)2CHBr
4
Scheme 2
Experimental Section
All chemicals were reagent grade and available commercially. 2,2-Diisopropylpropionitrile
(1) may be purchased from Chem-Impex International, Inc. (935 Dillon Drive, Wood Dale,
IL, 60191).1H NMR spectra were recorded on a Bruker AVANCE 400 MHz spectrometer,
using CDCl3 as solvent and TMS as internal standard. Infrared spectra were obtained
on a Perkin-Elmer Spectrum 100 FT-IR spectrophotometer. Electrospray ionization mass
spectroscopy was performed using an ion trap mass spectrometer (Model 6310 Agilent).
Gas chromatographic analysis was carried out using a Shimadzu GC-2010 Plus instrument
equipped with an Alltech poly(dimethoxysiloxane) 30 m capillary DB-1 column.
Preparation of 2,2-Diisopropylpropionitrile (1) (Method 1)
Sodamide (270.0 g, 6.92 mol) and THF (540 ml) were mixed at 30◦C–35◦C, and the mixture
was cooled to 0◦C–5◦C (under nitrogen). Then a mixture of propionitrile (3) (150.0 g,
2.72 mol) and isopropyl bromide (4) (705.0 g, 5.73 mol) was added to the reaction mixture
over 3–4 h at 0◦C–5◦C under mechanical stirring. The reaction mixture was stirred for an
additional 6 h at 0◦C–5◦C, completion of reaction being monitored by gas chromatography
(GC). The reaction mixture was cooled to 0◦C, and chilled water (600 ml) was added over
60 min. After the addition was complete, the solution was stirred at 30◦C–35◦C for 30 min.
The mixture was concentrated under atmospheric pressure below 95◦C to remove most of
the tetrahydrofuran. The top organic layer was washed with water (100 ml), 10% aqueous

Preparation of 2,2-Diisopropylpropionitrile
279
NaCl and dried over solid sodium sulfate and distilled in vacuo to give 1 (341.0 g, 90%) as
a colorless oil, bp. 110◦C–120◦C/600 mmHg, lit.3 186◦C–187◦C/760 mmHg.1H NMR: δ
0.96 (6H, d), 1.05 (6H, d), 1.17 (3H, s), 1.95 (2H, m).
Preparation of 2,2-Diisopropylpropionitrile (1) (Method 2)
Sodamide (270.0 g, 6.92 mol) and 1 (240.0 g) were mixed at 30◦C–35◦C, and the mixture
was stirred at 30◦C–35◦C (under nitrogen) for 30 min. Then a mixture of propionitrile (3)
(150.0 g, 2.72 mol) and isopropyl bromide (4) (705.0 g, 5.73 mol) was added to the reaction
mixture over 3–4 h at 30◦C–35◦C. The temperature of reaction mixture was then maintained
at 30◦C–35◦C for 6 h; completion of reaction was monitored by gas chromatography (GC).
The reaction mixture was cooled to 0◦C, and chilled water (600 ml) was added over 60 min.
After the addition was complete, the solution was stirred at 30◦C–35◦C for 30 min. The top
organic layer was washed with water (100 ml) and with 10% aqueous NaCl. The organic
layer was dried over anhydrous sodium sulfate and distilled in vacuo to give 1 (588.0 g,
92%) as a colorless oil, bp. 110◦C–120◦C/600 mmHg.
Acknowledgement
The authors are thankful to Tyche Industries Limited for financial assistance.
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