Quantitative α-alkylation of primary nitriles

Article abstract of DOI:10.1080/00397910701572456

A synthetic pathway that produces alkyl α,ω-cyanodiolefins in quantitative yield is described, applying chemistry that is based on simple α-alkylation of alkyl nitriles. Three amide bases, lithium 2,2,6,6-tetramethylpiperidide, lithium diisopropylamide, and sodium amide, are used to create the α-carbanions that undergo substitution with various alkylating agents. Optimization leads to essentially quantitative conversions for every substrate/example reported herein, which will prove useful in many synthetic schemes. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701572456

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Quantitative α‐Alkylation of Primary Nitriles
Giovanni Rojas a , Travis W. Baughman b & Kenneth B. Wagener a
a George and Josephine Butler Polymer Research Laboratory, Department of
Chemistry , University of Florida , Gainesville, Florida, USA
b Eindhoven University of Technology, Macromolecular and Organic
Chemistry, Department of Chemical Engineering , Eindhoven, The
Netherlands
Published online: 19 Nov 2007.
To cite this article: Giovanni Rojas , Travis W. Baughman & Kenneth B. Wagener (2007) Quantitative
α‐Alkylation of Primary Nitriles, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 37:22, 3923-3931, DOI: 10.1080/00397910701572456
To link to this article: http://dx.doi.org/10.1080/00397910701572456
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Synthetic Communicationsw, 37: 3923–3931, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701572456
Quantitative a-Alkylation of Primary
Nitriles
Giovanni Rojas
George and Josephine Butler Polymer Research Laboratory, Department
of Chemistry, University of Florida, Gainesville, Florida, USA
Travis W. Baughman
Department of Chemical Engineering, Eindhoven University of
Technology, Macromolecular and Organic Chemistry, Eindhoven,
The Netherlands
Kenneth B. Wagener
George and Josephine Butler Polymer Research Laboratory, Department
of Chemistry, University of Florida, Gainesville, Florida, USA
Abstract: A synthetic pathway that produces alkyl a,v-cyanodiolefins in quantitative
yield is described, applying chemistry that is based on simple a-alkylation of alkyl
nitriles. Three amide bases, lithium 2,2,6,6-tetramethylpiperidide, lithium diisopropy-
lamide, and sodium amide, are used to create the a-carbanions that undergo substi-
tution with various alkylating agents. Optimization leads to essentially quantitative
conversions for every substrate/example reported herein, which will prove useful in
many synthetic schemes.
Keywords: a-Alkylation, isomerization, LDA, nitriles, terminal olefin
We report quantitative conversions of organonitriles to a,v-cyanodiolefins,
using rather conventional chemistry and manipulating simple concepts such
Received in the USA April 25, 2007
Address correspondence to Kenneth B. Wagener, Department of Chemistry, Center
of Macromolecular Science and Engineering, University of Florida, P. O. Box 1172,
Gainesville, FL 32611. E-mail: wagener@chem.ufl.edu
3923

3924
G. Rojas, T. W. Baughman, and K. B. Wagener
as basicity while focusing on the elimination of competing reactions, struc-
tural isomerization in particular.
Organonitriles long have been used for the preparation of numerous organic
structures because of the ease and variety of synthetic transformations that can be
performed with them.[1–9] a-Alkylation of aliphatic nitriles is often employed in
synthetic strategies, because a-anions are easily generated with common bases
such as sodium amide,[2,9–11] n-butyl lithium,[12] lithium diethylamide,[2,13]
potassium hexamethyl disilazane,[14] lithium 2,2,6,6-tetramethylpiperidide
(LTMP),[15] and lithium diisopropylamide (LDA).[2,9,16] Once a-alkylation is
completed, further chemical modification can be performed on the remaining
nitrile functionality. The literature is robust, detailing such transformations in
multistep syntheses; however, to our knowledge, none of the a,v-cynodiolefins
presented in here have been prepared before, although similar products have
been reported in low yield.[10,13,17–21]
Current synthetic approaches to alkyl a,v-diolefins are based on diethyl
malonate chemistry involving multiple steps, resulting in 10–60% product
yields.[22–26] Herein, we report essentially quantitative (96–99%) alkylation
of a family of primary alkyl nitriles using a variety of bromide and tosylate
alkenyl substrates in the presence of various amide bases. In many cases,
structural isomerization of the olefin occurs in these transformations as a detri-
mental side reaction, not only reducing yield but also rendering product
a-olefin purification difficult. We describe the reaction conditions necessary
to avoid this side reaction, a result that is particularly useful when preparing
a,v-diolefins used in metathesis chemistry.[27,28]
Scheme 1 shows the a,a-dialkylation of hexanenitrile, our test reaction for
the development of this chemistry. Once deprotonated, the a-anion nucleophile
monoalkylates either brominated or tosylated a-olefin; a second alkylation
followed to yield the desired tertiary nitrile. Although the chemistry appears
straightforward, achieving quantitative conversions yielding a,v-cyanodiolefins
has not been the reported until now.
Table 1 illustrates the effect of different reaction temperatures and three
bases on reaction yield. Using freshly prepared LTMP (pKa ¼ 37) or LDA
(pKa ¼ 36) in THF, 3c is quantitatively produced at low temperature
(2788C) after 3 h, whereas a weaker base, sodium amide (pKa ¼ 33), leads
to no reaction whatsoever even at room temperature. At 1108C, sodium
amide results in considerably lower yields than for the lithium bases, plus
performs undesired olefin isomerization as described in Scheme 2. Ultimately,
this side reaction causes double-bond “walking” along the aliphatic chain,
Scheme 1. General a,a-dialkylation of hexanenitrile.

Quantitative a-Alkylation of Primary Nitriles
3925
Table 1. Dialkylation of hexanenitrile initiated by different bases
Reaction
time (h)
Isomerization
(%)b
Base
Solvent
Temp (8C)
Yield (%)a
LTMP
LDA
THF
THF
3
3
278
278
278
0
99
99
0
0
0
NaNH2
NaNH2
NaNH2
NaNH2
THF
THF
6
N/A
N/A
N/A
7
6
0
THF
Toluene
6
12
25
110
0
57
aIsolated yield after purification by column chromatography.
bPercentage of olefin isomerization detected by NMR.
Scheme 2. General olefin isomerization side reaction.
generating more stable 1,2-disubstituted olefins, a transformation facilitated
by higher reaction temperature and a less selective base.
Various alkylating agents (2c–f) were also introduced to verify the adap-
tability of the reaction while probing functional group tolerance (Table 2,
entries 6–9). Dialkylation of 1a with benzylbromide produced 3e in 98%
yield, demonstrating that the substitution initiated by the a-anion is not
limited to alkenyl bromides; additionally, no length dependence was
observed during the alkylation of 1a that can be afforded with long-chain
alkenyl substituents 2a or short-chain alkenyl substituents 2d, as is shown
in Table 2, entries 1 and 7. The effect of the a-anion formation in the
presence of a different functionality a to the nitrile group was examined
(Table 2, entry 10); dialkylation yields were 97%, demonstrating that an
adjacent carbonyl group does not interfere with this reaction. We believe
this optimized methodology for preparing alkyl a,v-cyanodiolefins in quanti-
tative yields will prove useful in many synthetic schemes. The versatility of
this transformation is shown by the use of common reagents such as LTMP
and LDA and the prevention of olefin isomerization.
EXPERIMENTAL
General Procedure for Dialkylation of Nitriles using LDA or LTMP,
Synthesis of 2-Butyl-2-(undec-10-enyl)tridec-12-enenitrile (3c)
A 1 M solution of hexanenitrile (1.733 g, 18 mmol) in dry THF (17.8 mL) was
prepared in a three-necked, round-bottomed flask equipped with a stir bar and

3926
G. Rojas, T. W. Baughman, and K. B. Wagener
Table 2. Dialkylation of nitriles with LDA
Alkylating
substrate
Dialkylation
product
Overall yield
(%)a
Entry
1
Primary nitrile
99
99
96
99
2
3
4
5
6
99
98
7
8
9
98
97
99
10
97
aIsolated yield after purification by column chromatography.
argon inlet adaptor. The solution was cooled to 2788C, and a freshly prepared
solution of lithium diisopropylamide (LDA) (2.18 g, 22 mmol) or lithium
2,2,6,6-tetramethylpiperidide (LTMP) (3.11 g, 22 mmol) in THF (21.5 mL)
was added via cannula transfer. The mixture was warmed to 08C and stirred
for 30 min, then cooled to 2788C. The alkylating agent 11-bromoundec-1-
ene (5 g, 22 mmol) was added at 2788C, then stirred at 08C for 30 min.
After the first alkylation, the solution was cooled to 2788C, followed by
the addition of LDA (2.18 g, 22 mmol) or LTMP (3.11 g, 22 mmol) in THF
(21.5 mL) via cannula transfer. The mixture was warmed to 08C and stirred
for 30 min, then cooled to 2788C. The second alkylation was performed by

Quantitative a-Alkylation of Primary Nitriles
3927
addition of 11-bromoundec-1-ene (5 g, 22 mmol) while stirring the solution at
08C for 30 min, followed by stirring for 3 h at room temperature. The reaction
was quenched with water (100 mL), extracted three times with ether
(200 mL), and washed with brine (50 mL). After drying over MgSO4, the
solution was filtered, concentrated by rotary evaporation, and purified by
flash-column chromatography (5% v/v ethyl acetate/hexane). After purifi-
cation, 7.16 g (99% yield) of a pale yellow liquid were collected. The
following spectral properties were observed: 1HNMR (CDCl3): d (ppm)
0.94 (t, 3H, CH3), 1.23–1.56 (m, 39H), 2.04 (q, 4H), 4.97 (m, 4H, vinyl
CH2), 5.82 (m, 2H, vinyl CH); 13CNMR (CDCl3): d (ppm) 14.18 (CH3),
23.12, 24.50, 26.66, 29.15, 29.34, 29.67, 29.73, 30.00, 34.04, 36.05, 36.33,
40.82, 114.32 (vinyl CH2), 124.71 (-CN), 139.39 (vinyl CH); EI/HRMS:
[M]þ calculated for C28H51N: 401.4022; found: 401.4031. Elemental
analysis calculated for C28H51N: 83.72 C, 12.80 H, 3.49 N; found 83.71 C,
12.81 H, 3.48 N.
2-Methyl-2-(undec-10-enyl)tridec-12-enenitrile (3a)
After purification, 6.41 g (99% yield) of a pale yellow liquid were collected.
The following spectral properties were observed: 1HNMR (CDCl3): d (ppm),
1.20–1.64 (m, 33H), 2.04 (q, 4H), 4.96 (m, 4H, vinyl CH2), 5.81 (m, 2H, vinyl
CH); 13CNMR (CDCl3): d (ppm) 24.77 (CH3), 23.95, 28.88, 29.06, 29.40,
29.45, 29.66, 33.77, 36.66, 39.41, 114.08 (vinyl CH2), 124.68 (-CN), 139.13
(vinyl CH); EI/HRMS: [M]þ calculated for C25H45N: 359.3552; found:
359.3697. Elemental analysis calculated for C25H45N: 83.49 C, 12.61 H,
3.89 N; found 83.23 C, 12.59 H, 4.18 N.
2-Ethyl-2-(undec-10-enyl)tridec-12-enenitrile (3b)
After purification, 6.46 g (96% yield) of a pale yellow liquid were collected.
1
The following spectral properties were observed: HNMR (CDCl3): d (ppm)
0.99 (t, 3H, -CH3), 1.29–1.56 (m, 35H), 2.04 (q, 4H), 4.97 (m, 4H, vinyl
CH2), 5.82 (m, 2H, vinyl CH); 13CNMR (CDCl3): d (ppm) 8.89 (CH3),
14.33, 22.87, 24.46, 29.13, 29.32, 29.63, 29.65, 29.71, 29.98, 31.81, 34.01,
35.83, 41.31, 114.33 (vinyl CH2), 124.52 (-CN), 139.39 (vinyl CH); EI/
HRMS: [M]þ calculated for C26H47N: 373.3709; found: 373.3710.
Elemental analysis calculated for C26H47N: 83.57 C, 12.68 H, 3.75 N;
found 83.59 C, 12.67 H, 3.74 N.
2-Hexyl-2-(undec-10-enyl)tridec-12-enenitrile from LTMP (3d)
After purification, 7.66 g (99% yield) of a pale yellow liquid were collected.
1
The following spectral properties were observed: HNMR (CDCl3): d (ppm)

3928
G. Rojas, T. W. Baughman, and K. B. Wagener
0.90 (t, 3H, -CH3), 1.29–1.56 (m, 42H), 2.04 (q, 4H), 4.97 (m, 4H, vinyl CH2),
5.82 (m, 2H, vinyl CH); 13CNMR (CDCl3): d (ppm) 14.24 (CH3), 22.80,
24.48, 24.51, 29.15, 29.33, 29.62, 29.66, 29.71, 29.99, 31.83, 34.01, 36.38,
40.88, 114.34 (vinyl CH2), 124.69 (-CN), 139.41 (vinyl CH); EI/HRMS:
[M]þ calculated for C30H55N: 429.4335; found: 429.4346. Elemental
analysis calculated for C30H55N: 83.84 C, 12.90 H, 3.26 N; found 83.41 C,
13.37 H, 3.49 N.
2-Benzyl-2-methyl-3-phenylpropanenitrile (3e)
After purification, 4.19 g (98% yield) of a pale yellow liquid were collected.
1
The following spectral properties were observed: HNMR (CDCl3): d (ppm)
1.50 (s, 3H, -CH3), 2.83 (s, 4H), 7.40 (m, 10H); 13CNMR (CDCl3): d (ppm)
22.12 (CH3), 30.81 (quaternary carbon), 41.56 (CH2), 120.91 (-CN), 125.51,
128.11, 128.91, 140.32 (aromatic carbon); EI/HRMS: [M]þ calculated for
C17H17N: 235.1361; found: 235.1309. Elemental analysis calculated for
C17H17N: 86.77 C, 7.28 H, 5.95 N; found 86.59 C, 5.41 H, 5.99 N.
2-Allyl-2-methylpent-4-enenitrile (3f)
After purification, 2.41 g (98% yield) of a pale yellow liquid were collected.
1
The following spectral properties were observed: HNMR (CDCl3): d (ppm)
1.53 (s, 3H, -CH3), 2.27 (d, 4H, CH2), 5.01 (m, 4H, vinyl CH2), 5.82
(m, 2H, vinyl CH); 13CNMR (CDCl3): d (ppm) 23.41 (CH3), 25.65 (quatern-
ary carbon), 41.35 (CH2), 115.33 (vinyl CH2), 124.51 (-CN), 136.39 (vinyl
CH); EI/HRMS: [M]þ calculated for C9H13N: 135.1048; found: 135.1059.
Elemental analysis calculated for C9H13N: 79.95 C, 9.69 H, 10.36 N; found
79.99 C, 9.61 H, 11.39 N.
2-Methyl-2-propylpentanenitrile (3g)
After purification, 2.45 g (97% yield) of a pale yellow liquid were collected.
1
The following spectral properties were observed: HNMR (CDCl3): d (ppm)
0.98 (t, 6H, -CH3), 1.29-1.56 (m, 4H, CH2), 1.53 (s, 3H, -CH3) 1.61 (t, 4H,
CH2); 13CNMR (CDCl3): d (ppm) 10.89 (CH3), 15.33, 24.87, 25.46, 46.48
(C-CH2), 122.9 (CN); EI/HRMS: [M]þ calculated for C9H17N: 139.1361;
found: 139.1321. Elemental analysis calculated for C9H17N: 77.63 C,
12.31 H, 10.06 N; found 77.48 C, 12.41 H, 10.11 N.

Quantitative a-Alkylation of Primary Nitriles
3929
2-Methyl-2-pentylheptanenitrile (3h)
After purification, 3.51 g (99% yield) of a pale yellow liquid were collected.
1
The following spectral properties were observed: HNMR (CDCl3): d (ppm)
0.99 (t, 6H, -CH3), 1.29–1.56 (m, 12H), 1.61 (s, 3H, -CH3), 1.72 (t, 4H,
C-CH2-CH2); 13CNMR (CDCl3): d (ppm) 13.12 (CH3), 22.71, 23.57, 24.56,
28.23, 31.65, 43.25, 124.50 (-CN); EI/HRMS: [M]þ calculated for
C13H25N: 195.1987; found: 195.1877. Elemental analysis calculated for
C13H25N: 79.83 C, 12.90 H, 7.17 N; found 79.54 C, 12.99 H, 7.46 N.
Ethyl 2-Cyano-2-(undec-10-enyl)tridec-12-enoate (3i)
After purification, 3.58 g (97% yield) of a pale yellow liquid were collected.
1
The following spectral properties were observed: HNMR (CDCl3): d (ppm)
1.29–1.56 (m, 31H), 2.04 (t, 4H), 2.21 (m, 4H, vinyl CH2), 4.15 (q, 2H,
O-CH2-CH3), 5.01 (m, 4H, vinyl CH2), 5.82 (m, 2H, vinyl CH); 13CNMR
(CDCl3): d (ppm) 14.13 (CH3), 22.87, 24.46, 29.13, 29.32, 29.63, 29.65,
29.71, 29.98, 33.81, 38.01, 61.15 (O-CH2-CH3), 114.33 (vinyl CH2), 124.51
(-CN), 139.39 (vinyl CH), 173.85 (C55O); EI/HRMS: [M]þ calculated for
C27H47NO2: 417.3607; found: 417.3594. Elemental analysis calculated for
C27H47NO2: 77.64 C, 11.34 H, 3.35 N, 7.66 O; found 77.61 C, 11.41 H,
3.28 N, 7.70 O.
General Procedure for Dialkylation of Nitriles using Sodium Amide,
Synthesis of 2-Butyl-2-(undec-10-enyl)tridec-12-enenitrile (3b)
A 1M solution of nitrile (hexanenitrile, 1.50 g, 15 mmol) in dry THF
(15.4 mL) was prepared in a three-necked, round-bottomed flask equipped
with a stir bar, condenser, and argon inlet adaptor. The reaction flask was
loaded with NaNH2 (1.44 g, 37 mmol) and the alkylating 11-bromoundec-1-
ene (8.630 g, 37 mmol). The mixture was refluxed for 12 h and then
quenched with 1 M HCl (100 mL), extracted three times with ether
(500 mL), and washed with brine (100 mL). After drying over MgSO4, the
solution was filtered, concentrated by rotary evaporation, and purified by
flash-column chromatography (5% v/v ethyl acetate/hexane). After purifi-
cation, 3.19 g (57% yield) of a pale yellow liquid were collected. The
following spectral properties were observed: 1HNMR (CDCl3): d (ppm)
0.94 (t, 3H, -CH3), 1.23–1.56 (m, 41H), 2.04 (q, 4H), 4.97 (m, 4H, vinyl
CH2), 5.42 (m, 0.30H, internal olefin CH), 5.82 (m, 2H, vinyl CH);
13CNMR (CDCl3): d (ppm) 14.39 (CH3), 23.34, 24.74, 26.90, 29.39, 29.57,
29.68, 29.90, 29.96, 30.23, 34.26, 36.31, 36.58, 41.05, 114.55 (vinyl CH2),
124.88 (-CN), 139.58 (vinyl CH); EI/HRMS: [M]þ calculated for
C28H51N: 401.4022; found: 404.4029. Elemental analysis calculated for

3930
G. Rojas, T. W. Baughman, and K. B. Wagener
C28H51N: 83.72 C, 12.80 H, 3.49 N; found 83.71 C, 12.81 H, 3.49 N. The
olefin isomerization was quantified by relating the integrals of the isomerized
olefin at 5.42 ppm and the terminal olefin at 4.90–5.04 ppm, and the percen-
tage of isomerization is then given by the formula: 100 ꢀ [Integral at
5.42 ppm/(integral at 5.42 þ integral at 4.90–5.04 ppm)].
ACKNOWLEDGMENTS
The authors express thanks to Yuki Iseki at the Petrochemicals Research Lab-
oratory, Sumitomo Chemical Co., Lisa S. Baugh at ExxonMobil Corporation,
the National Science Foundation (NSF), and the Florida Space Grant Consor-
tium (NASA-FSGC) for supporting this research.
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