One-pot synthesis of 3,3-dimethylpyrrolidine-2-carbonitriles from 4-chloro-2,2-dimethylbutanal in water

Article abstract of DOI:10.3987/COM-08-S(F)1

Treatment of 4-chloro-2,2-dimethylbutanal, prepared in high yield by means of a three-step procedure starting from ethyl isobutyrate, with successively sodium bisulphite, a primary amine and potassium cyanide in water afforded novel 1-alkyl- and l-aryl-3,

Full text of DOI:10.3987/COM-08-S(F)1

HETEROCYCLES, Vol. 77, No. 1, 2009
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HETEROCYCLES, Vol. 77, No. 1, 2009, pp. 255 - 261. © The Japan Institute of Heterocyclic Chemistry
Received, 30th January, 2008, Accepted, 8th April, 2008, Published online, 11th April, 2008.
DOI: 10.3987/COM-08-S(F)1
ONE-POT SYNTHESIS OF 3,3-DIMETHYLPYRROLIDINE-2-CARBO-
NITRILES FROM 4-CHLORO-2,2-DIMETHYLBUTANAL IN WATER
Matthias D’hooghe, Berten Van Driessche, and Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Bioscience Engineering, Ghent
University, Coupure Links 653, B-9000 Ghent, Belgium
norbert.dekimpe@UGent.be
Abstract – Treatment of 4-chloro-2,2-dimethylbutanal, prepared in high yield by
means of a three-step procedure starting from ethyl isobutyrate, with successively
sodium bisulphite, a primary amine and potassium cyanide in water afforded
novel 1-alkyl- and 1-aryl-3,3-dimethylpyrrolidin-2-carbonitriles in a convenient
and environmentally benign way.
INTRODUCTION
In recent years, pyrrolidine-2-carbonitriles have attracted considerable attention from medicinal chemists
due to their diverse biological activities. In particular, many efforts have been devoted to the synthesis of
novel 2-cyanopyrrolidines as dipeptidyl peptidase IV inhibitors, which are of importance for the treatment
of type II diabetes.1 The most advanced 2-cyanopyrrolidine, vildagliptin 1, is now even on the verge of
entering the market. Furthermore, pyrrolidine-2-carbonitriles are of interest as building blocks in
synthetic organic chemistry, especially as precursors for the preparation of proline analogues.2 Also other
applications have been reported, such as the synthesis of biologically relevant alkaloids and cage
compounds.3 Consequently, the development of new and efficient entries towards 2-cyanopyrrolidines
remains of significant importance from both a biological and a synthetic point of view.
OH
N
N
H
CN
O
1
vildagliptin
This paper is dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

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HETEROCYCLES, Vol. 77, No. 1, 2009
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In
the
literature,
few
general
procedures
for
the
preparation
of
monocyclic
1-alkylpyrrolidine-2-carbonitriles are available. For example, 1-alkyl-2-cyanopyrrolidines have been
prepared via transformation of 2-carbamoyl-4 and 2-(alkoxycarbonyl)pyrrolidines,5 via indium-promoted
conjugate addition-cyclization reactions of ethenetricarboxylates with propargylamines,6 via reductive
cyanation of pyrrolidin-2-ones through acyliminium intermediates,7 and via oxidation of
1-alkylpyrrolidines with ClO2 followed by the in situ reaction of intermediate iminium ions with cyanide.8
As for the synthesis of 1-arylpyrrolidin-2-carbonitriles, an electrochemical cyanation9 and a
ruthenium-catalyzed oxidative cyanation of 1-arylpyrrolidines10 have been reported. From this overview,
it is clear that the lack of simple and general approaches towards 1-alkyl- and
1-arylpyrrolidin-2-carbonitriles impedes the study of this type of heterocycles as substrates for further
elaboration or as relevant target compounds.
In the present paper, a novel and elegant protocol for the preparation of a variety of 1-substituted
3,3-dimethylpyrrolidin-2-carbonitriles will be discussed, based on the cyclization of γ-chloroimines in
water triggered by the addition of cyanide across the imino moiety. In recent years, the demand for
environmentally benign processes has become an important element in the design of new synthetic
methodologies. In this respect, organic reactions in aqueous media constitute an attractive alternative for
the use of classical solvents.11 Despite of the simplicity, only one report is available in the literature based
on this approach, affording an elegant entry into 1-(1-phenylethyl)pyrrolidine-2-carbonitriles through
cyclization of γ-chloroimines. For this purpose, 2-methyl-2-[(1-phenylethyl)amino]propanenitrile was
used as an in situ source of α-phenylethylamine and hydrogen cyanide, resulting in the formation of
intermediate (4-chlorobutylidene)-N-(1-phenylethyl)amines from the corresponding aldehydes, followed
by cyclization upon nucleophilic addition of cyanide in acetonitrile.12 Also α,α,γ-trichlorinated aldehydes
have been used previously for the synthesis of intermediate α,α,γ-trichlorinated imines, which were
subsequently cyclised towards pyrrolidine13 or pyrroline14 derivatives. The analogous reductive
cyclization of δ-haloimines towards the corresponding piperidines has been studied in more detail in the
past,15 although in only one case the synthesis of 2-cyanopiperidines has been reported.16
RESULTS AND DISCUSSION
4-Chloro-2,2-dimethylbutanal 5 was chosen as a substrate for the synthesis of a variety of corresponding
imines by condensation with the appropriate primary amines. The cyclization of the latter γ-chloroimines
would then be evaluated as a new approach towards 2-cyanopyrrolidines.
Based on literature data, 4-chloro-2,2-dimethylbutan-1-ol 4 was prepared on a large scale upon alkylation
of ethyl isobutyrate 2 with one equivalent of 1-bromo-2-chloroethane in THF in the presence of 1.1

HETEROCYCLES, Vol. 77, No. 1, 2009
257
equivalent of LDA (lithium diisopropylamide) affording ethyl 4-chloro-2,2-dimethylbutyrate 3 in 95%
yield, followed by reduction of the latter ester 3 using 1.5 equivalents of lithium borohydride (LiBH4) in
dichloromethane upon reflux for 16 hours (Scheme 1).17 The desired 4-chloro-2,2-dimethylbutanal 518
could then easily be prepared by oxidation of alcohol 4 utilizing two equivalents of pyridinium
chlorochromate (PCC) coated on silicagel in dichloromethane at room temperature for 2 hours (Scheme
1).19 The application of Swern oxidation conditions was unsuccessful and yielded only the starting
compound.
O
O
Br
1 equiv
Cl
Cl
O
O
1.1 equiv LDA, THF
-78 °C to rt, 2 h
2
3 (95%)
1.5 equiv LiBH4
CH2Cl2, Δ, 16 h
O
OH
2 equiv PCC
Cl
Cl
H
SiO2, CH2Cl2, rt, 2 h
5 (63%)
4 (89%)
Scheme 1
The condensation of β-chloroimines with primary amines (e.g. tert-butylamine, isopropylamine,
benzylamine, aniline, 1-amino-2,2-dimethylcyclopropanecarbonitrile) towards the corresponding imines
by means of standard conditions (MgSO4/CH2Cl2, TiCl4/Et2O or MgSO4/Et2O) has been studied before.20
In analogy, aldehyde 5 was treated with different primary amines in order to synthesize the corresponding
γ-chloroimines 6 as substrates for further elaboration. However, in some cases the attempts to isolate the
desired γ-chloroimines 6 in a pure state failed, and rather complex reaction mixtures were obtained. These
observations prompted us to investigate an alternative one-pot approach without the isolation of the
intermediate imines 6. Thus, the consecutive treatment of 4-chloro-2,2-dimethylbutanal 5 with one
equivalent of sodium bisulphite, two equivalents of an amine and two equivalents of potassium cyanide in
water afforded novel 3,3-dimethylpyrrolidin-2-carbonitriles 7 in acceptable yields, taking into account the
difficulty to generate the intermediate reactive aldimines 6. The pyrrolidine-2-carbonitriles 7 were
purified by means of column chromatography in order to obtain analytically pure samples (Scheme 2,
isolated yields after column chromatography). In this way, 1-alkyl-, 1-allyl-, 1-benzyl- and
1-phenylpyrrolidin-2-carbonitriles were prepared for the first time via a convenient and straightforward
approach. As described before, the cyclization of δ-chloroimines to piperidines through addition of
potassium cyanide only occurred upon heating under reflux,15b,16 whereas pyrrolidines 7 were formed
smoothly at room temperature. The fact that water is used as an alternative for classical organic solvents

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HETEROCYCLES, Vol. 77, No. 1, 2009
258
clearly adds value to this methodology from an environmental point of view. To underline the importance
of the solvent, it is interesting to note that with the use of methanol as solvent, only complex reaction
mixtures were obtained. Remarkably, the omission of sodium bisulphite in the three-step sequence from 5
to 7 resulted in a significant decrease of the yield, e.g. 13% instead of 36% for
1-allyl-3,3-dimethylpyrrolidine-2-carbonitrile 7a, pointing to the peculiar role of the inorganic salt in this
transformation (stable adduct formation).
1) 1 equiv NaHSO3
H2O, rt, 2 h
2) 2 equiv RNH2
H2O, rt, 2 h
R
O
N
NC
Cl
H
3) 2 equiv KCN
H2O, rt, 18 h
5
7
7a R = Allyl (36%)
7b R = Bn (16%)
7c R = Ph (24%)
7d R = iPr (13%)
7e R = tert-Bu (17%)
R
N
Cl
H
6
Scheme 2
In summary, an easy and straightforward one-pot approach for the preparation of 1-alkyl- and
1-aryl-3,3-dimethylpyrrolidin-2-carbonitriles has been described involving the consecutive treatment of
4-chloro-2,2-dimethylbutanal with sodium bisulphite, an amine and potassium cyanide in water.
EXPERIMENTAL
1H NMR spectra were recorded at 300 MHz (JEOL ECLIPSE+) with CDCl3 as solvent and
13
tetramethylsilane as internal standard. C NMR spectra were recorded at 75 MHz (JEOL ECLIPSE+)
with CDCl3 as solvent. Mass spectra were obtained with an AGILENT 1100, 70 eV. IR spectra were
measured with a Spectrum One FT-IR spectrophotometer. Tetrahydrofuran was distilled over sodium
benzophenone ketyl and dichloromethane was distilled over calcium hydride. Other solvents were used as
received from the supplier. Elemental analyses were performed with a PerkinElmer Series II CHNS/O
Analyzer 2400.
Synthesis of 3,3-dimethylpyrrolidine-2-carbonitriles 7
The synthesis of 1-allyl-3,3-dimethylpyrolidine-2-carbonitrile 7a is described here as a representative
example for the synthesis of 3,3-dimethylpyrrolidine-2-carbonitriles 7. A solution of sodium bisulphite
(1.41 g, 7.43 mmol, 1 equiv) in water (10 mL) was added dropwise to a stirred solution of
4-chloro-2,2-dimethylbutanal 5 (1.00 g, 7.43 mmol) in water (10 mL) at rt. The resulting mixture was

HETEROCYCLES, Vol. 77, No. 1, 2009
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stirred for 2 h at rt, after which allylamine (0.85 g, 14.87 mmol, 2 equiv) was added. This mixture was
again stirred for 2 h at rt and subsequently treated with potassium cyanide (0.96 g, 14.87 mmol, 2 equiv)
in water (10 mL). After stirring overnight (18 h) at rt, the aqueous phase was extracted with Et2O (3×30
mL). Drying (MgSO4), filtration of the drying agent, evaporation of the solvent in vacuo and purification
by
means
of
column
chromatography
(hexane/EtOAc
10/1)
yielded
pure
1-allyl-3,3-dimethylpyrolidine-2-carbonitrile 7a (0.12 g, 2.67 mmol, 36%).
1-Allyl-3,3-dimethylpyrrolidine-2-carbonitrile 7a. Yield 36%. Colorless oil. Column chromatography:
1
hexane/EtOAc 10/1, Rf = 0.33. H NMR (300 MHz, CDCl3): δ 1.20 and 1.28 (2×3H, 2×s, 2×CH3),
1.58-1.78 (2H, m, CH2C(CH3)2), 2.71 (1H, ~t×d, J = 9.2 Hz, J = 6.1 Hz, C(H)HN), 2.81-2.89 (1H, m,
C(H)HN), 3.14 (1H, d×d, J = 13.3 Hz, J = 7.3 Hz, C(H)HCH=CH2), 3.35 (1H, s, CHCN), 3.38 (1H,
d×d×t, J = 13.3 Hz, J = 5.5 Hz, J = 1.4 Hz, C(H)HCH=CH2), 5.14-5.33 (2H, m, CH=CH2), 5.78-5.91 (1H,
m, CH=CH2). 13C NMR (75 MHz, CDCl3): δ 26.24 and 29.94 (2×CH3), 37.89 (CH2C(CH3)2), 41.80
(C(CH3)2), 50.94 (CH2CH2N), 55.86 (CH2CH=CH2), 65.43 (CHCN), 116.98 (CN), 118.14 (CH=CH2),
134.52 (CH=CH2). IR (NaCl, cm-1): νCN = 2221. MS (70 eV): m/z (%): 165 (M+1+, 100). Anal. Calcd for
C10H16N2: C 73.13, H 9.82, N 17.06. Found: C 73.28, H 10.09, N 16.92.
1-Benzyl-3,3-dimethylpyrrolidine-2-carbonitrile 7b. Yield 16%. Colorless oil. Column
1
chromatography: hexane/EtOAc 10/1, Rf = 0.50. H NMR (300 MHz, CDCl3): δ 1.20 and 1.28 (2×3H,
2×s, 2×CH3), 1.61-1.80 (2H, m, CH2C(CH3)2), 2.69 (1H, ~t×d, J = 9.6 Hz, J = 6.2 Hz, C(H)HN),
2.87-2.95 (1H, m, C(H)HN), 3.28 (1H, s, CHCN), 3.63 (1H, d, J = 13.2 Hz, C(H)HC5H6), 3.93 (1H, d, J =
13.2 Hz, C(H)HC5H6), 7.23-7.56 (5H, m, C6H5). 13C NMR (75 MHz, CDCl3): δ 26.05 and 28.92 (2×CH3),
37.64 (CH2C(CH3)2), 41.76 (C(CH3)2), 50.78 (CH2N), 56.74 (CH2C6H5), 65.23 (CHCN), 116.68 (CN),
127.35, 128.44 and 128.66 (CHarom), 137.80 (NCH2Cq). IR (NaCl, cm-1): νCN = 2210. MS (70 eV): m/z
(%): 215 (M+1+, 100). Anal. Calcd for C14H18N2: C 78.46, H 8.47, N 13.07. Found: C 78.31, H 8.71, N
12.94.
3,3-Dimethyl-1-phenylpyrrolidine-2-carbonitrile 7c. Yield 24%. White crystals. Mp 67 °C. Column
chromatography: hexane/EtOAc 10/1, Rf = 0.26. 1H NMR (300 MHz, CDCl3): δ 1.16 en 1.43 (2×3H, 2×s,
2×CH3), 1.82-1.89 (1H, m, C(H)HC(CH3)2), 2.04-2.14 (1H, m, C(H)HC(CH3)2), 3.47 (2H, d×d, J = 9.1
Hz, J = 4.7 Hz, CH2N), 4.03 (1H, s, CHCN), 6.65-6.68, 6.79-6.84 and 7.25-7.32 (2H, 1H and 2H, 3×m,
C6H5). 13C NMR (75 MHz, CDCl3): δ 24.60 and 26.11 (2×CH3), 37.47 (CH2C(CH3)2), 42.38 (C(CH3)2),
46.51 (CH2N), 60.13 (CHCN), 112.31, 117.93 and 129.44 (CHarom), 117.69 (CN), 145.49 (CqN). IR
(NaCl, cm-1): νCN = 2217. MS (70 eV): m/z (%): 201 (M+1+, 100). Anal. Calcd for C13H16N2: C 77.96, H
8.05, N 13.99. Found: C 77.78, H 8.23, N 14.11.
3,3-Dimethyl-1-isopropylpyrrolidine-2-carbonitrile 7d. Yield 13%. Colorless oil. Column
1
chromatography: hexane/EtOAc 10/1, Rf = 0.42. H NMR (300 MHz, CDCl3): δ 1.08 and 1.12 (2×3H,

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HETEROCYCLES, Vol. 77, No. 1, 2009
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2×d, J = 6.3 Hz, CH(CH3)2), 1.19 and 1.28 (2×3H, 2×s, C(CH3)2), 1.57-1.85 (2H, m, CH2C(CH3)2), 2.61
(1H, ~t×d, J = 9.3 Hz, J = 6.1 Hz, C(H)HN), 2.77 (1H, sept, J = 6.3 Hz, CH(CH3)2), 3.04 (1H, ~t×d, J =
9.3 Hz, J = 5.4 Hz, C(H)HN), 3.50 (1H, s, CHCN). 13C NMR (75 MHz, CDCl3): δ 19.68 and 21.76
(CH(CH3)2), 25.88 and 28.84 (C(CH3)2), 37.53 (CH2C(CH3)2), 42.45 (C(CH3)2), 48.31 (CH2N), 51.47
(CHCH3)2), 63.81 (CHCN), 117.26 (CN). IR (NaCl, cm-1): νCN = 2229. MS (70 eV): m/z (%): 167 (M+1+,
10). Anal. Calcd for C10H18N2: C 72.24, H 10.91, N 16.85. Found: C 72.40, H 11.13, N 16.71.
1-tert-Butyl-3,3-dimethylpyrrolidine-2-carbonitrile 7e. Yield 17%. Colorless oil. Column
1
chromatography: hexane/EtOAc 10/1, Rf = 0.41. H NMR (300 MHz, CDCl3): δ 1.08 and 1.28 (2×3H,
2×s, CH(CH3)2), 1.15 (3×3H, s, C(CH3)3), 1.56 (1H, d×d×d, J = 12.3 Hz, J = 6.9 Hz, J = 3.4 Hz,
C(H)HC(CH3)2), 1.74-1.83 (1H, m, C(H)HC(CH3)2), 2.85 (1H, ~t×d, J = 8.5 Hz, J = 7.0 Hz, C(H)HN),
13
2.99 (1H, t×d, J = 8.5 Hz, J = 3.5 Hz, C(H)HN), 3.43 (1H, s, CHCN). C NMR (75 MHz, CDCl3): δ
25.72 and 27.37 (C(CH3)2), 26.73 (C(CH3)3), 38.56 (CH2C(CH3)2), 41.86 (C(CH3)2), 44.70 (CH2N), 53.33
(C(CH3)3), 59.59 (CHCN), 121.48 (CN). IR (NaCl, cm-1): νCN = 2231. MS (70 eV): m/z (%): 181 (M+1+,
80). Anal. Calcd for C11H20N2: C 73.28, H 11.18, N 15.54. Found: C 73.46, H 11.37, N 15.71.
ACKNOWLEDGEMENTS
The authors are indebted to the “Fund for Scientific Research - Flanders (Belgium)” (F.W.O.-Vlaanderen)
and to Ghent University (GOA) for financial support.
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