A one-pot electrophilic cyanation–functionalization strategy for the synthesis of disubstituted malononitriles

Article abstract of DOI:10.1016/j.tet.2019.05.004

Malononitriles are valuable synthetic intermediates for many applications, including the synthesis of herbicides and other biologically active molecules, and the synthesis of chiral ligands for asymmetric catalysis. This article describes the development of a procedure for the conversion of primary nitriles to malononitriles using dimethylmalononitrile, a commercial, non-toxic, carbon-bound source of electrophilic cyanide. This procedure avoids the use of toxic cyanide or malononitrile as a starting material. This protocol is further applied to the dicyanation of benzyl Grignard reagents, generated from benzyl bromides, yielding fully functionalized malononitriles from a nitrile-free precursor.

Full text of DOI:10.1016/j.tet.2019.05.004

Accepted Manuscript
A one-pot electrophilic cyanation–functionalization strategy for the synthesis of
disubstituted malononitriles
L. Reginald Mills, Sophie A.L. Rousseaux
PII:
S0040-4020(19)30511-3
https://doi.org/10.1016/j.tet.2019.05.004
TET 30325
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 18 March 2019
Revised Date: 26 April 2019
Accepted Date: 1 May 2019
Please cite this article as: Mills LR, Rousseaux SAL, A one-pot electrophilic cyanation–functionalization
strategy for the synthesis of disubstituted malononitriles, Tetrahedron (2019), doi: https://
doi.org/10.1016/j.tet.2019.05.004.
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ACCEPTED MANUSCRIPT
A one-pot electrophilic cyanation–
Leave this area blank for abstract info.
functionalization strategy for the synthesis of
disubstituted malononitriles
L. Reginald Mills and Sophie A. L. Rousseaux
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George St., Toronto,
ON M5S 3H6

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
A one-pot electrophilic cyanation–functionalization strategy for the synthesis of
disubstituted malononitriles
L. Reginald Millsa and Sophie A. L. Rousseauxa*
aDavenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Malononitriles are valuable synthetic intermediates for many applications, including the
synthesis of herbicides and other biologically active molecules, and the synthesis of chiral
ligands for asymmetric catalysis. This article describes the development of a procedure for the
conversion of primary nitriles to malononitriles using dimethylmalononitrile, a commercial,
non-toxic, carbon-bound source of electrophilic cyanide. This procedure avoids the use of toxic
cyanide or malononitrile as a starting material. This protocol is further applied to the dicyanation
of benzyl Grignard reagents, generated from benzyl bromides, yielding fully functionalized
malononitriles from a nitrile-free precursor.
Available online
Keywords:
Malononitrile
Electrophilic cyanation
Transnitrilation
2009 Elsevier Ltd. All rights reserved
.
Organometallic chemistry
1. Introduction
presence of two equivalents of N,N-dimethylcyanamide, via two
transnitrilation events. Since then, much work has gone into the
design of mild and safe electrophilic cyanating reagents for the
synthesis of malononitriles from primary nitriles (Scheme 1a,
Malononitriles are important reaction partners and synthetic
building blocks for a variety of applications.1 Arylmalononitriles
are key intermediates in the synthesis of oxopyrazoline
herbicides such as pinoxaden.2 Arylmalononitriles have been
used as intermediates in the synthesis of the 2-amino-
pyrazolo[1,5-a]pyrimidine class of molecules, which are
inhibitors for JAK2,3 and in the synthesis of a series of ERα and
ERβ ligands.4 Disubstituted malononitriles have been used as
antiparasitic agents in mammals.5 They are also presursors to
bisoxazoline (BOX) ligands, a popular class of chiral ligands for
asymmetric catalysis.6 Substituted malononitriles can be quickly
accessed in one or two steps from malononitrile,7,8 which is
commercially available and inexpensive. However, malononitrile
is toxic9 and has a low melting point of 30–32 ºC, making it a
less than ideal reagent. Further, the synthesis of aryl-substituted
malononitrile derivatives can sometimes require forcing
conditions10,2b or reactive reagents.11,12
bottom
arrow),
including
cyanamides,18
cyanates,19
thiocyanates,20 and 1-cyanobenzotriazole.21,22
In 2015, Reeves and coworkers reported that
dimethylmalononitrile (DMMN) could be used as a reagent for
the electrophilic cyanation of aryllithium and aryl Grignard
reagents.14,23 DMMN is a commercially available bench-stable
solid, which has a health rating of 2 in HMIS and NFPA rating
systems. The electrophilic nitrile is carbon-bound, imparting
stability compared to some of the previously used heteroatom-
bound electrophilic cyanating reagents. Its reactivity as an
efficient transnitrilation reagent has been known since work
reported by Erickson in 1935.24 Reeves and coworkers have also
reported that other derivatives, such as dibenzylmalononitrile
(DBMN), are competent electrophilic cyanation reagents.23
One approach towards the synthesis of substituted
malononitriles which avoids the use of toxic malononitrile is the
electrophilic cyanation of primary nitriles (Scheme 1a).
Electrophilic cyanation is a well-established strategy to access
myriad
nitrile-containing
compounds,13,14
including
malononitriles.15 For example, one industrial route for the
preparation of malononitrile includes electrophilic cyanation of
acetonitrile using cyanogen chloride at high temperature (Scheme
1a, top arrow).16 The generation of substituted malononitriles via
electrophilic cyanation has also been known since 1927 (Scheme
1a, middle arrow).17 Vuylsteke and coworkers observed that
Grignard reagents could be converted to malononitriles in the

2
Tetrahedron
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2. Results and Discussion
We imagined a two-step, one-pot process for the cyanation
and functionalization of primary nitriles: 1) transnitrilation in
order to generate intermediate D, and 2) electrophilic
functionalization of D. Thus, we set out to optimize each step
independently with the goal of later merging them into a one-pot
transformation.
For the optimization of the first step of the reaction, we used
methylmagnesium bromide as
a
base, knowing that
magnesium(II) anions are competent for transnitrilation
chemistry.23 Thus, a solution of benzyl cyanide (1a) in THF was
stirred in the presence of methylmagnesium bromide for 30 min
to afford the deprotonated α-anion, which was then treated with
1.1 equiv of DMMN (Table 1). Lithium chloride (1.1 equiv) was
included to improve the solubility of the organomagnesium
species in THF. After 1 h at room temperature, 43% yield of
desired 2-phenylmalononitrile (2a) was observed (Table 1, Entry
1). By heating the reaction mixture at 80 ºC for 1 h, the yield
could be increased to 91% (Entry 2). Stirring at 80 ºC for 6 h
gave an optimal yield of 99% (Entry 3). The viability of
n-butyllithium in this reaction was probed as well. By using
n-butyllithium as a base, 89% of 2a could be obtained after
stirring at 80 ºC for 1 h (Entry 4). If the reaction was stirred for
longer (6 h), slightly greater conversion of 1a was observed
(Entry 5). However, the yield of 2a varied in these trials, and we
often observed the product of nucleophilic addition of α-anion C
to 2a in varying amounts, which affected the reproducibility of
the transformation using n-BuLi.
Table 1. Optimization of the transnitrilation stepa
Scheme 1. (a) Examples of electrophilic cyanation for accessing
malononitriles; (b) Reaction design: Tandem electrophilic
cyanation–functionalization with DMMN or DBMN to
synthesize disubstituted malononitriles. DMMN =
dimethylmalononitrile; DBMN = dibenzylmalononitrile.
Entry
Temp. (ºC)
Time (h)
Yield 2a (%)b
Inspired by this work on the electrophilic cyanation of C(sp2)
centers, we were interested in probing the use of DMMN and
DBMN as safe reagents for the cyanation of primary nitriles,
which would generate malononitriles via transnitrilation (Scheme
1b). Thus, upon deprotonation with base, a primary nitrile could
undergo addition to DMMN to form metal imine intermediate A.
This intermediate would undergo retro-Thorpe fragmentation25 to
generate the desired transnitrilated malononitrile (B) and the
corresponding nitrile α-anion (C). At this stage, due to the low
pKa of newly formed malononitrile B, α-anion C would
deprotonate B to form the more stable α-anion D. Conveniently,
this α-anion is primed for functionalization, and can be trapped
with an appropriate electrophile (E–X) to yield the disubstituted
malononitrile.26 Alternately, rather than using an electrophile, the
monosubstituted malononitrile could be obtained via acidic
quench of the reaction. Since cyanide salts are never present in
the reaction mixture, the generation of HCN gas is not a concern.
1
2
r.t.
80
80
80
80
1
1
6
1
6
43
91
3
99
4c
5c
89
30–99d
aReaction conditions: 1a (46 ꢀL, 0.40 mmol, 1.0 equiv),
MeMgBr (1.1 equiv), LiCl (1.1 equiv), THF (0.40 mL,
1.0 M), DMMN (1.1 equiv). DMMN = dimethylmalononitrile.
bGC-MS yield based on n-dodecane as internal standard.
cUsing n-BuLi (1.1 equiv) instead of MeMgBr and LiCl.
dThe major observed side-product was the imine resulting
from nucleophilic addition of α-anion intermediate C to 2a.
This strategy represents
a facile method for accessing
Next, we probed the electrophilic functionalization step of
our one-pot process (Table 2). 2-Phenylmalononitrile (2a) was
used as a malononitrile α-anion precursor. Deprotonation of 2a
using methylmagnesium bromide generates intermediate D,
which was then treated with iodobutane in various solvents.
When THF was used as the solvent, product 2b was not observed
after 1 h at room temperature (Entry 1). The alkylation reaction
was observed when a polar co-solvent (DMF) was used (1:1
THF/DMF mixture, Entry 2). If the reaction was stirred at 80 ºC
malononitriles from primary nitriles without the use of highly
toxic cyanating reagents or malononitrile. Herein, we describe
the development of a one-pot protocol for the formation of
disubstituted malononitriles from primary nitriles using the
electrophilic cyanating reagent DMMN, as well as the application
of this strategy to the dicyanation of benzyl bromide.

3
for 1 h, 30% of 2b was observed (Entry 3). Finally, when the
reaction was left for 16 h, high conversion to 2b was achieved
(Entry 4). n-Butyllithium was found to be viable for the
functionalization step as well, delivering 2b in 24% and 93%
yields at r.t. and 80 ºC, respectively, after only 1 h (Entries 5 and
6). However, due to the inconsistent formation of side-products
when lithium α-anions are generated in the first step of our
desired transformation (Table 1, Entry 5), methylmagnesium
bromide was chosen as the optimal base for the combined one-
pot protocol.
longer transnitrilation times (24 h) were required in this case.
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The procedure also translated well to a larger scale reaction,
delivering 1.48 g of 2c (95%) on 10-mmol scale.
Table 3. Scope of the one-pot transnitrilation–functionalization
reaction for primary nitrilesa
Table 2. Optimization of the electrophilic functionalization stepa
Temp.
(ºC)
Yield 2b
Entry
Solvent
Time (h)
(%)b
THF
1
2
r.t.
r.t.
80
80
r.t.
80
1
1
0
THF/DMF (1:1)
THF/DMF (1:1)
THF/DMF (1:1)
6
3
1
30
87
24
93
4
16
1
5c
6c
THF/DMF (1:1)
THF/DMF (1:1)
1
aReaction conditions: Nitrile (0.40 mmol, 1.0 equiv), methylmagnesium
bromide (1.1 equiv), lithium chloride (1.1 equiv), THF (1.0 M); then DMMN
(1.1 equiv) or DBMN (1.1 equiv), THF (0.5 M); then electrophile (1.2 equiv),
aReaction conditions: 2a (46 ꢀL, 0.40 mmol, 1.0 equiv),
MeMgBr (1.1 equiv), LiCl (1.1 equiv), solvent (0.80 mL,
0.50 M), n-BuI (1.2 equiv).
THF/DMF (1:1, 0.25 M). Yields are isolated. DMMN
dimethylmalononitrile; DBMN = dibenzylmalononitrile.
bUsing DBMN (1.1 equiv) instead of DMMN.
=
bGC-MS yield based on n-dodecane as internal standard.
cUsing n-BuLi (1.1 equiv) instead of MeMgBr and LiCl.
cTransnitrilation was performed at 80 ºC for 24 h instead of 6 h.
Having determined optimal conditions for each individual step
of this process, we next combined them into a one-pot protocol
by adding DMF after transnitrilation to bring the reaction solvent
to a 1:1 THF/DMF mixture. As designed, this protocol was
viable for a variety of substrates (Table 3). Thus, primary nitriles
(1) could be deprotonated using methylmagnesium bromide
(1.1 equiv) in the presence of lithium chloride (1.1 equiv) in THF
over 30 min. Transnitrilation was achieved in the presence of
DMMN (1.1 equiv) by stirring at 80 ºC for 6 h, generating the
malononitrile α-anion intermediate. Then, the desired electrophile
(1.2 equiv) could be added with DMF to obtain disubstituted
malononitriles (2) in moderate to excellent yields. A variety of
primary alkyl halides (2b, 2c, and 2e) were viable electrophiles,
as well as benzyl, allyl, and propargyl bromides (2d, 2f–2h).
Alternately, the monosubstituted malononitrile 2a could be
isolated if HCl was used to quench the reaction. Arylation could
be achieved using aryl fluorides that were sufficiently activated
(2i). Finally, a variety of primary benzylic nitriles could be used
as starting materials, including electron-rich (2j), electron-
deficient (2k), electron-neutral (2l), and heterocyclic derivatives
(2n, 2o). The formation of ortho-pyridine derivative 2o is
noteworthy since the Lewis basic nitrogen in the pyridine ring
does not appear to significantly retard transnitrilation via
formation of a magnesium chelate, as has been previously
observed in related transnitrilation processes.14 A sterically
hindered substrate (2m) was also obtained, although slightly
Primary alkyl nitriles are often prepared via nucleophilic
cyanation of alkyl halides with toxic cyanide salts such as NaCN
or KCN.27 We therefore wondered if benzyl bromides could be
directly converted to malononitriles via formation of a Grignard
reagent and a double transnitrilation strategy (Table 4). This
protocol represents a rapid and convenient way to access
disubstituted malononitriles from
a nitrile-free precursor,
generating three new C−C bonds in the process.
As demonstrated in Table 4, benzyl bromide (3) was
converted to benzylmagnesium bromide, which was then treated
with DBMN (2.2 equiv)28 for 1 h at r.t. to allow the first
transnitrilation even to take place. Conversion to the
malononitrile was achieved by then stirring the reaction mixture
at 80 ºC for 6 h. The resulting α-magnesiated malononitrile could
then be functionalized with a variety of electrophiles in a 1:1
THF/DMF solvent mixture, affording malononitriles 2p–2r in
good yields over two steps.
Table 4. Scope of the cyanation–functionalization reaction using
benzylmagnesium bromidea

4
Tetrahedron
purchased as HPLC-grade (inhibitor-free) from Caledon or
ACCEPTED MANUSCRIPT
Sigma–Aldrich, were dried using a PureSolv MD 5 solvent
purification system, and were used without further manipulation.
DMF was purchased from Acros as Extra Dry over molecular
sieves and was used as received. Methylmagnesium bromide and
n-butyllithium solutions were purchased from Sigma–Aldrich
and were titrated with I2 on a weekly basis.29 All other
commercial reagents and starting materials were used as
received. Compounds were purified by flash column
chromatography using SiliCycle SilicaFlash P60 silica gel.
1H and 13C NMR spectra were recorded on Varian MercuryPlus
400 MHz, Agilent DD2 500 MHz, or Bruker AvanceIII 400 MHz
spectrometers. TLC samples were run on EMD Millipore TLC
Silica gel 60 F254 plates and were visualized by UV or by staining
with standard KMnO4, phosphomolybdic acid (PMA), or p-
anisaldehyde stains. IR spectra were obtained on a Perkin-Elmer
aReaction conditions: 1. Benzyl bromide (20 mmol), Mg(0) turnings (1.2
equiv), Et2O (1.0 M). 2. Benzylmagnesium bromide (0.40 mmol of a solution
in Et2O), lithium chloride (1.1 equiv), DBMN (2.2 equiv), THF (0.50 M);
then electrophile (1.2 equiv), THF/DMF (1:1, 0.25 M). Yields are isolated
and represent the combined yield over two steps. DBMN
dibenzylmalononitrile.
=
Spectrum 100 instrument equipped with
a single-bounce
The transnitrilation–functionalization strategy could be
applied to primary alkyl nitriles as well, but with a slight
modification. When alkylnitriles were employed in the optimized
diamond/ZnSe ATR accessory as solids or thin films. Melting
points were obtained on a Fisher-Johns Melting Point Apparatus.
High-resolution mass spectra (HRMS) were recorded on a JEOL
AccuTOF JMS-T1000LV mass spectrometer equipped with a
Direct Analysis in Real Time (DART) ion source.
conditions using methylmagnesium bromide as
a
base,
unselective deprotonation of the α position was observed, which
resulted in a mixture of products. This selectivity issue could be
circumvented if lithium diisopropylamide (LDA) was used as the
base and if the deprotonation was performed at −78 ºC instead of
r.t. (Table 5). Thus, the transnitrilation–functionalization
procedure was used to generate dialkyl-substituted malononitriles
2s and 2t in good yield.
4.2 Experimental Procedures and Product Characterization
4.2.1 2,2-Dimethylmalononitrile (DMMN): To a flame-dried 250-
mL round-bottom flask with stir bar was added MeCN (100 mL,
0.5 M), malononitrile (4.0 g, 50 mmol, 1.0 equiv), iodomethane
(6.8 mL, 110 mmol, 2.2 equiv), and potassium carbonate (17 g,
125 mmol, 2.5 equiv). The reaction was stirred at r.t. for 16 h
under N2. The reaction was opened to air, diluted with DCM (100
mL), filtered using a fritted funnel, and the filtrate was
concentrated. The concentrate was purified by flash column
chromatography (gradient of 0–40% EtOAc/hexanes) to yield
Table 5. Cyanation–functionalization of alkyl nitriles using
LDAa
1
DMMN as a white solid (2.4 g, 26 mmol, 52%). H NMR (400
MHz, CDCl3, 298 K): δH 1.82 (s, 6H) ppm; 13C NMR (100 MHz,
CDCl3, 298 K): δc 116.9, 26.5, 26.4 ppm; Rf (8:2 hexanes/EtOAc;
KMnO4): 0.43.
4.2.2 2,2-Dibenzylmalononitrile (DBMN): To a flame-dried 500-
mL round-bottom flask with stir bar was added MeCN (200 mL,
0.5 M), malononitrile (6.6 g, 100 mmol, 1.0 equiv), benzyl
bromide (26 mL, 220 mmol, 2.2 equiv), and potassium carbonate
(35 g, 250 mmol, 2.5 equiv). The reaction was stirred at r.t. for
16 h under N2. The reaction was opened to air, diluted with
EtOAc (200 mL), filtered using a fritted funnel, and the filtrate
was concentrated. The concentrate was purified by
recrystallization (DCM/pentane) to yield DBMN as a white solid
aReaction conditions: Alkyl nitrile (0.40 mmol, 1.0 equiv), diisopropylamine
(1.2 equiv), n-BuLi (1.1 equiv), THF (1.0 M); then DMMN (1.1 equiv), THF
(0.5 M); then electrophile (1.2 equiv), THF/DMF (1:1, 0.25 M). Yields are
isolated. DMMN = dimethylmalononitrile.
1
(19 g, 77 mmol, 77%). H NMR (400 MHz, CDCl3, 298 K): δH
7.48–7.30 (m, 10H), 3.25 (s, 4H) ppm; 13C NMR (100 MHz,
CDCl3, 298 K): δC 132.0, 130.3, 129.0, 128.9, 114.9, 43.5, 41.2
ppm; Rf (9:1 hexanes/EtOAc; KMnO4): 0.33.
3. Conclusion
In conclusion, we have developed a transnitrilation strategy
for the synthesis of disubstituted malononitriles from primary
nitriles using transnitrilation reagents DMMN and DBMN. This
protocol avoids the use of toxic malononitrile or other toxic
cyanating reagents. Additionally, this strategy can be applied to
the dicyanation of benzylmagnesium bromide to rapidly form
disubstituted malononitriles. Further work on transnitrilation
chemistry is ongoing in our laboratory.
4.2.3 General Procedure A: Synthesis of malononitriles from
primary nitriles using MeMgBr: Step 1: To an 8-mL culture tube
with stir bar was added lithium chloride (1.1 equiv) and the flask
was flame-dried under vacuum and cooled under an atmosphere
of N2. THF (1.0 M) was added, followed by the appropriate
nitrile (1.0 equiv). While stirring, methylmagnesium bromide
(1.1 equiv of a solution in Et2O) was added dropwise at r.t., and
the solution was stirred at r.t. for 30 min under an atmosphere of
N2. A 1.1 M stock solution of dimethylmanononitrile (DMMN)
or dibenzylmalononitrile (DBMN) in THF was prepared and
added at r.t. (1.1 equiv of a 1.1 M solution in THF, reaction
volume = 0.50 M with respect to nitrile starting material). The
reaction was stirred at 80 ºC for 6 h under an atmosphere of N2.
Step 2: The reaction was cooled to r.t. and DMF was added to
4. Experimental Section
4.1 General Information
Unless otherwise noted, all reactions were set up on the benchtop
and run under an atmosphere of Ar or N2 using flame-dried
glassware and anhydrous solvents. THF, Et2O, and MeCN were

5
bring the reaction solvent to a 1:1 THF/DMF ratio (0.25 M of a
1:1 THF/DMF mixture with respect to nitrile starting material).
The desired electrophile (1.2 equiv) was added in a single
portion. If the electrophile was a solid, it was added with the
DMF as a 0.60 M stock solution. The reaction was stirred at 80
ºC for 16 h, or until complete conversion was achieved as judged
by TLC. The reaction was cooled to r.t., opened to air, quenched
with 1 M aq. HCl, and extracted with EtOAc (×3). The organic
fractions were combined, dried over MgSO4, and concentrated.
The crude residue was purified by flash column chromatography
to yield the desired malononitrile.
methylmagnesium bromide (0.21 mL of a 2.1 M solution in
ACCEPTED MANUSCRIPT
Et2O, 0.44 mmol, 1.1 equiv), and dimethylmalononitrile (0.40
mL of a 1.1 M solution in THF, 0.44 mmol, 1.1 equiv). Step 2:
DMF (0.80 mL; total reaction solvent = 1.6 mL of a 1:1
DMF/THF mixture, 0.25 M) and benzyl bromide (57 ꢀL, 0.48
mmol, 1.2 equiv). The crude residue was purified by flash
column chromatography (gradient of 0–15% EtOAc/hexanes) to
yield 2d as a white solid (93 mg, 0.40 mmol, 99%). Analytical
data:12 1H NMR (400 MHz, CDCl3, 298 K): δH 7.52–7.43 (m,
5H), 7.39–7.26 (m, 3H), 7.17–7.10 (m, 2H), 3.46 (s, 2H) ppm;
13C NMR (100 MHz, CDCl3, 298 K): δC 131.7, 131.6, 130.6,
130.1, 129.7, 129.0, 128.8, 126.3, 114.8, 48.7, 44.2 ppm; Rf (9:1
hexanes/EtOAc): 0.41.
4.2.4 2-Phenylmalononitrile (2a): According to General
Procedure A, 2a was prepared using the following amounts of
reagent: lithium chloride (19 mg, 0.44 mmol, 1.1 equiv), THF
(0.40 mL), benzyl cyanide (46 ꢀL, 0.40 mmol, 1.0 equiv),
methylmagnesium bromide (0.21 mL of a 2.1 M solution in Et2O,
0.44 mmol, 1.1 equiv), and dimethylmalononitrile (0.40 mL of a
1.1 M solution in THF, 0.44 mmol, 1.1 equiv) (total reaction
volume = 0.80 mL of THF, 0.50 M). After transnitrilation, the
reaction was cooled to r.t., quenched with 1 M aq. HCl, and
worked up as outlined in the general procedure. The crude
residue was purified by flash column chromatography (gradient
of 0–30% EtOAc/hexanes) to yield 2a as a white solid (39 mg,
0.27 mmol, 68%). Analytical data:20 1H NMR (400 MHz, CDCl3,
298 K): δH 7.62–7.42 (m, 5H), 5.07 (s, 1H) ppm; 13C NMR (100
MHz, CDCl3, 298 K): δC 130.4, 130.2, 127.2, 126.2, 111.7, 28.1
ppm; Rf (9:1 hexanes/EtOAc; KMnO4/PMA): 0.16.
4.2.8 2-Phenyl-2-(3-phenylpropyl)malononitrile (2e): According
to General Procedure A, 2e was prepared using the following
amounts of reagent: Step 1: lithium chloride (19 mg, 0.44 mmol,
1.1 equiv), THF (0.40 mL), benzyl cyanide (46 ꢀL, 0.40 mmol,
1.0 equiv), methylmagnesium bromide (0.23 mL of a 1.9 M
solution in Et2O, 0.44 mmol, 1.1 equiv), and
dimethylmalononitrile (0.40 mL of a 1.1 M solution in THF, 0.44
mmol, 1.1 equiv). Step 2: DMF (0.80 mL; total reaction solvent =
1.6 mL of a 1:1 DMF/THF mixture, 0.25 M) and 1-bromo-3-
phenylpropane (73 ꢀL, 0.48 mmol, 1.2 equiv). The crude residue
was purified by flash column chromatography (gradient of 0–
10% EtOAc/hexanes) to yield 2e as a white solid (59 mg, 0.23
mmol, 58%). 7.56–7.42 (m, 5H), 7.33–7.25 (m, 2H), 7.25–7.18
(m, 1H), 7.17–7.10 (m, 2H), 2.70 (t, J = 7.4 Hz, 2H), 2.28–2.18
(m, 2H), 2.02–1.91 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3,
298 K): δC 140.0, 132.0, 129.9, 129.7, 128.6, 128.3, 126.4, 125.7,
115.0, 42.2, 41.9, 34.5, 26.9 ppm; HRMS m/z (DART): calcd for
C18H17N2 (M+H) 261.1392; found 261.1398; IR (neat): 3028,
2943, 2931, 2863, 2180, 2169, 2030, 1979, 1884, 1601, 1493,
1453, 1339, 1203, 1156, 1101, 1084, 1029, 1002, 982, 755, 695
cm–1; Rf (9:1 hexanes/EtOAc; UV/KMnO4): 0.58.
4.2.5 2-Butyl-2-phenylmalononitrile (2b): According to General
Procedure A, 2b was prepared using the following amounts of
reagent: Step 1: lithium chloride (19 mg, 0.44 mmol, 1.1 equiv),
THF (0.40 mL), benzyl cyanide (46 ꢀL, 0.40 mmol, 1.0 equiv),
methylmagnesium bromide (0.21 mL of a 2.1 M solution in Et2O,
0.44 mmol, 1.1 equiv), and dimethylmalononitrile (0.40 mL of a
1.1 M solution in THF, 0.44 mmol, 1.1 equiv). Step 2: DMF
(0.80 mL; total reaction solvent = 1.6 mL of a 1:1 DMF/THF
mixture, 0.25 M) and iodobutane (55 ꢀL, 0.48 mmol, 1.2 equiv).
The crude residue was purified by flash column chromatography
(gradient of 0–10% EtOAc/hexanes) to yield 2b as a colourless
oil (37 mg, 0.19 mmol, 48%). Analytical data:12 1H NMR (400
MHz, CDCl3, 298 K): δH 7.64–7.45 (m, 5H), 2.30–2.20 (m, 2H),
1.71–1.58 (m, 2H), 1.43 (h, J = 7.3 Hz, 2H), 0.96 (t, J = 7.3 Hz,
3H) ppm; 13C NMR (100 MHz, CDCl3, 298 K): δC 132.3, 129.8,
129.7, 125.7, 115.1, 42.5, 42.4, 27.6, 21.9, 13.6 ppm; Rf (9:1
hexanes/EtOAc; UV/KMnO4): 0.61.
4.2.9 2-Allyl-2-phenylmalononitrile (2f): According to General
Procedure A, 2f was prepared using the following amounts of
reagent: Step 1: lithium chloride (19 mg, 0.44 mmol, 1.1 equiv),
THF (0.40 mL), benzyl cyanide (46 ꢀL, 0.40 mmol, 1.0 equiv),
methylmagnesium bromide (0.23 mL of a 1.9 M solution in Et2O,
0.44 mmol, 1.1 equiv), and dimethylmalononitrile (0.40 mL of a
1.1 M stock solution in THF, 0.44 mmol, 1.1 equiv). Step 2:
DMF (0.80 mL; total reaction solvent = 1.6 mL of a 1:1
DMF/THF mixture, 0.25 M) and allyl bromide (42 ꢀL, 0.48
mmol, 1.2 equiv). The crude residue was purified by flash
column chromatography (gradient of 0–15% EtOAc/hexanes) to
4.2.6 2-Methyl-2-phenylmalononitrile (2c): According to General
Procedure A, 2c was prepared using the following amounts of
reagent: Step 1: lithium chloride (19 mg, 0.44 mmol, 1.1 equiv),
THF (0.40 mL), benzyl cyanide (46 ꢀL, 0.40 mmol, 1.0 equiv),
methylmagnesium bromide (0.21 mL of a 2.1 M solution in Et2O,
0.44 mmol, 1.1 equiv), and dimethylmalononitrile (0.40 mL of a
1.1 M solution in THF, 0.44 mmol, 1.1 equiv). Step 2: DMF
(0.80 mL; total reaction solvent = 1.6 mL of a 1:1 DMF/THF
mixture, 0.25 M) and iodomethane (30 ꢀL, 0.48 mmol, 1.2
equiv). The crude residue was purified by flash column
chromatography (gradient of 0–30% EtOAc/hexanes) to yield 2c
as a colourless oil (53 mg, 0.34 mmol, 85%). Analytical data:30
1H NMR (400 MHz, CDCl3, 298 K): δH 7.64–7.42 (m, 5H), 2.13
(s, 3H) ppm; 13C NMR (100 MHz, CDCl3, 298 K): δC 131.1,
130.0, 129.8, 129.3, 115.7, 36.4, 29.5 ppm; Rf (9:1
hexanes/EtOAc; UV): 0.39.
1
yield 2f as a colourless oil (35 mg, 0.19 mmol, 48%). H NMR
(400 MHz, CDCl3, 298 K): δH 7.60–7.54 (m, 2H), 7.53–7.44 (m,
3H), 5.88–5.74 (m, 1H), 5.44–5.31 (m, 2H), 2.97–2.90 (m,
2H) ppm; 13C NMR (100 MHz, CDCl3, 298 K): δC 131.7, 130.1,
129.8, 128.5, 126.0, 123.8, 114.7, 46.7, 42.6 ppm; IR (neat):
3091, 3085, 3070, 2990, 2928, 2357, 2254, 1881, 1645, 1600,
1495, 1452, 1441, 1418, 1027, 990, 934, 759, 715, 694, 655 cm–
1; Rf (9:1 hexanes/EtOAc; UV/KMnO4): 0.44.
4.2.10 2-Phenyl-2-(prop-2-yn-1-yl)malononitrile (2g): According
to General Procedure A, 2g was prepared using the following
amounts of reagent: Step 1: lithium chloride (19 mg, 0.44 mmol,
1.1 equiv), THF (0.40 mL), benzyl cyanide (46 ꢀL, 0.40 mmol,
1.0 equiv), methylmagnesium bromide (0.23 mL of a 1.9 M
solution in Et2O, 0.44 mmol, 1.1 equiv), and
dibenzylmalononitrile (0.40 mL of a 1.1 M solution in THF, 0.44
mmol, 1.1 equiv). Step 2: DMF (0.80 mL; total reaction solvent =
1.6 mL of a 1:1 DMF/THF mixture, 0.25 M) and propargyl
bromide (53 ꢀL of a 80% w/w solution in PhMe, 0.48 mmol, 1.2
equiv). The crude residue was purified by flash column
4.2.7 2-Benzyl-2-phenylmalononitrile (2d): According to General
Procedure A, 2d was prepared using the following amounts of
reagent: Step 1: lithium chloride (19 mg, 0.44 mmol, 1.1 equiv),
THF (0.40 mL), benzyl cyanide (46 ꢀL, 0.40 mmol, 1.0 equiv),

6
Tetrahedron
ACCEPTED MANUSCRIPT
chromatography (gradient of 0–20% EtOAc/hexanes) to yield
127.1, 124.0, 115.3, 114.9, 55.5, 42.4, 41.7, 27.5, 21.8, 13.6 ppm;
1
2g as a colourless oil (64 mg, 0.36 mmol, 90%). H NMR (400
MHz, CDCl3, 298 K): δH 7.66–7.58 (m, 2H), 7.55–7.48 (m, 3H),
3.15 (d, J = 2.6 Hz, 2H), 2.37 (t, J = 2.6 Hz, 1H) ppm; 13C NMR
(100 MHz, CDCl3, 298 K): δC 130.8, 130.6, 129.9, 126.1, 114.1,
75.7, 74.7, 42.1, 33.7 ppm; HRMS m/z (DART) calcd for
C12H9N2 (M+H) 181.0766; found 181.0763; IR (neat): 3293 (br),
3069, 3040, 2966, 2935, 2255, 2249, 2132, 1960, 1600, 1494,
1452, 1428, 1338, 1257, 1192, 1069, 1028, 1003, 757, 694, 666,
650 cm–1; Rf (9:1 hexanes/EtOAc; UV/KMnO4): 0.26.
HRMS m/z (DART): calcd for C14H17N2O1 (M+H) 229.1341;
found 229.1345; IR (neat): 3006, 2962, 2935, 2876, 2867, 2841,
2251, 2055, 1609, 1585, 1512, 1463, 1444, 1423, 1306, 1256,
1184, 1120, 1031, 829, 813, 798, 733, 662, 634, 604 cm–1; Rf
(9:1 hexanes/EtOAc; UV/KMnO4): 0.47.
4.2.14
2-(4-Fluorophenyl)-2-methylmalononitrile
(2k):
Following General Procedure A, 2k was prepared using the
following amounts of reagent: Step 1: lithium chloride (19 mg,
0.44 mmol, 1.1 equiv), THF (0.40 mL), 4-fluorobenzyl cyanide
(48 ꢀL, 0.40 mmol, 1.0 equiv), methylmagnesium bromide (0.21
mL of a 2.1 M solution in Et2O, 0.44 mmol, 1.1 equiv), and
dimethylmalononitrile (0.40 mL of a 1.1 M solution in THF, 0.44
mmol, 1.1 equiv). Step 2: DMF (0.80 mL; total reaction solvent =
1.6 mL of a 1:1 DMF/THF mixture, 0.25 M) and iodomethane
(30 ꢀL, 0.48 mmol, 1.2 equiv). The crude residue was purified by
4.2.11 2-(Nitrobenzyl)-2-phenylmalononitrile (2h): According to
General Procedure A, 2h was prepared using the following
amounts of reagent: Step 1: lithium chloride (19 mg, 0.44 mmol,
1.1 equiv), THF (0.40 mL), benzyl cyanide (46 ꢀL, 0.40 mmol,
1.0 equiv), methylmagnesium bromide (0.23 mL of a 1.9 M
solution in Et2O, 0.44 mmol, 1.1 equiv), and
dimethylmalononitrile (0.40 mL of a 1.1 M stock solution in
THF, 0.44 mmol, 1.1 equiv). Step 2: 2-nitrobenzyl bromide (0.10
g in 0.80 mL of DMF, 0.48 mmol, 1.2 equiv) (total reaction
solvent = 1.6 mL of a 1:1 DMF/THF mixture, 0.25 M). The crude
residue was purified by flash column chromatography (gradient
of 10–40% EtOAc/hexanes) to yield 2h as a yellow solid (77 mg,
0.28 mmol, 70%). Analytical data:12 1H NMR (400 MHz, CDCl3,
298 K): δH 8.15–8.03 (m, 1H), 7.74–7.64 (m, 1H), 7.64–7.42 (m,
6H), 7.35–7.20 (m, 1H), 4.06 (s, 2H) ppm; 13C NMR (100 MHz,
CDCl3, 298 K): δC 149.3, 133.9, 133.6, 131.2, 130.43, 130.36,
130.0, 127.1, 126.12, 126.07, 114.4, 43.9, 43.5 ppm; Rf (9:1
hexanes/EtOAc; UV/KMnO4): 0.13.
flash
column
chromatography (gradient
of
0–15%
EtOAc/hexanes) to yield 2k as a colourless oil (62 mg, 0.36
mmol, 90%). H NMR (500 MHz, CDCl3, 298 K): δH 7.63–7.54
1
(m, 2H), 7.24–7.15 (m, 2H), 2.11 (s, 3H) ppm; 13C NMR
(125 MHz, CDCl3, 298 K): δC 163.5 (d, J = 250.0 Hz), 129.1 (d,
J = 3.5 Hz), 127.6 (d, J = 8.7 Hz), 117.1 (d, J = 22.4 Hz), 115.6,
36.0, 29.6 ppm; 19F NMR (376 MHz, CDCl3, 298 K):
−110.3 ppm; HRMS m/z (DART): calcd for C10H8F1N2 (M+H)
175.0672; found 175.0665; IR (neat): 3083, 3008, 2252, 1898,
1603, 1509, 1454, 1415, 1385, 1309, 1238, 1167, 1107, 1096,
1015, 879, 834, 813, 719, 632 cm–1; Rf (9:1 hexanes/EtOAc):
0.42.
4.2.12 2-(4-Cyano-2,3,5,6-tetrafluorophenyl)-2-
4.2.15 2-Ethyl-2-(p-tolyl)malononitrile (2l): According to
General Procedure A, 2l was prepared using the following
amounts of reagent: Step 1: lithium chloride (19 mg, 0.44 mmol,
1.1 equiv), THF (0.40 mL), 4-methylbenzyl cyanide (53 ꢀL, 0.40
mmol, 1.0 equiv), methylmagnesium bromide (0.21 mL of a 2.1
phenylmalononitrile (2i): According to General Procedure A, 2i
was prepared using the following amounts of reagent: Step 1:
lithium chloride (19 mg, 0.44 mmol, 1.1 equiv), THF (0.40 mL),
benzyl cyanide (46 ꢀL, 0.40 mmol, 1.0 equiv), methylmagnesium
bromide (0.23 mL of a 1.9 M solution in Et2O, 0.44 mmol, 1.1
equiv), and dimethylmalononitrile (0.40 mL of a 1.1 M stock
solution in THF, 0.44 mmol, 1.1 equiv). Step 2: DMF (0.80 mL;
total reaction solvent = 1.6 mL of a 1:1 DMF/THF mixture, 0.25
M) and 2,3,4,5,6-pentafluorobenzonitrile (60 ꢀL, 0.48 mmol, 1.2
equiv). The crude residue was purified by flash column
chromatography (gradient of 0–20% hexanes/EtOAc) to yield 2i
M
solution in Et2O, 0.44 mmol, 1.1 equiv), and
dimethylmalononitrile (0.40 mL of a 1.1 M solution in THF, 0.44
mmol, 1.1 equiv). Step 2: DMF (0.80 mL; total reaction solvent =
1.6 mL of a 1:1 DMF/THF mixture, 0.25 M) and iodoethane (39
ꢀL, 0.48 mmol, 1.2 equiv). The crude residue was purified by
flash
column
chromatography (gradient
of
0–15%
EtOAc/hexanes) to yield 2l as a colourless oil (47 mg, 0.26
1
1
as a red oil (86 mg, 0.27 mmol, 68%). H NMR (400 MHz,
mmol, 65%). H NMR (400 MHz, CDCl3, 298 K): δH 7.46–7.41
CDCl3, 298 K): δH 7.67–7.59 (m, 2H), 7.59–7.40 (m, 3H) ppm;
13C NMR (100 MHz, CDCl3, 298 K): 149.4–142.2 (m), 131.4,
130.6, 130.1, 126.8, 126.0 (t, J = 1.2 Hz), 118.9 (t, J = 10.6),
111.2, 106.2 (t, J = 3.7 Hz), 38.9 ppm; 19F NMR (376 MHz,
CDCl3, 298 K): −128.4, −133.3 ppm; IR (neat): 2924, 2854,
2250, 1653, 1490, 1453, 1307, 1260, 1002, 978, 919, 813, 784,
751, 709, 693, 673, 637 cm–1; Rf (9:1 hexanes/EtOAc; UV): 0.28.
(m, 2H), 7.31–7.26 (m, 2H), 2.39 (s, 3H), 2.27 (q, J = 7.4 Hz,
2H), 1.22 (t, J = 7.3 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3,
298 K): δC 140.2, 130.4, 129.1, 125.8, 115.2, 43.0, 36.6, 21.2,
10.1 ppm; HRMS m/z (DART): calcd for C12H13N2 (M+H)
185.1079; found 185.1084; IR (neat): 3303, 2981, 2942, 2928,
2883, 2252, 1908, 1615, 1513, 1459, 1414, 1387, 1192, 1128,
1097, 1044, 1021, 937, 905, 811, 714 cm–1; Rf (9:1
hexanes/EtOAc; UV/KMnO4) 0.55.
4.2.13 2-Butyl-2-(4-methoxyphenyl)malononitrile (2j): According
to General Following General Procedure A, 2j was prepared
using the following amounts of reagent: Step 1: lithium chloride
(19 mg, 0.44 mmol, 1.1 equiv), THF (0.40 mL), 4-
methoxyphenylacetonitrile (54 ꢀL, 0.40 mmol, 1.0 equiv),
methylmagnesium bromide (0.16 mL of a 2.7 M solution in Et2O,
0.44 mmol, 1.1 equiv), and dimethylmalononitrile (0.40 mL of a
1.1 M solution in THF, 0.44 mmol, 1.1 equiv). Step 2: DMF
(0.80 mL; total reaction solvent = 1.6 mL of a 1:1 DMF/THF
mixture, 0.25 M) and iodobutane (55 ꢀL, 0.48 mmol, 1.2 equiv).
The crude residue was purified by flash column chromatography
(gradient of 0–15% EtOAc/hexanes) to yield 2j as a colourless
4.2.16 2-(2-Bromophenyl)malononitrile (2m): According to
General Procedure A, 2m was prepared using the following
amounts of reagent: Step 1: lithium chloride (19 mg, 0.44 mmol,
1.1 equiv), THF (0.40 mL), 2-bromophenylacetonitrile (52 ꢀL,
0.40 mmol, 1.0 equiv), methylmagnesium bromide (0.16 mL of a
2.7 M solution in Et2O, 0.44 mmol, 1.1 equiv), and
dibenzylmalononitrile (0.40 mL of a 1.1 M stock solution in
THF, 0.44 mmol, 1.1 equiv). The reaction mixture was stirred at
80 ºC for 24 h for the transnitrilation step. After transnitrilation,
the reaction was cooled to r.t. and quenched with 10% aq. H2SO4
and worked up following the procedure outlined in General
Procedure A. The crude residue was purified by flash column
chromatography (gradient of 0–20% EtOAc/hexanes) to yield 2m
as a white solid (64 mg, 0.29 mmol, 73%), which contained some
remaining dibenzylmalononitrile (10 mg, 0.041 mmol).
1
oil (84 mg, 0.37 mmol, 93%). H NMR (500 MHz, CDCl3, 298
K): δH 7.49–7.44 (m, 2H), 7.01–6.95 (m, 2H), 3.84 (s, 3H), 2.21–
2.15 (m, 2H), 1.63–1.56 (m, 2H), 1.44–1.34 (m, 2H), 0.93 (t, J =
7.4 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3, 298 K): δC 160.5,

7
Analytical data:31 1H NMR (400 MHz, CDCl3, 298 K): δH 7.78–
7.66 (m, 2H), 7.55–7.46 (m, 1H), 7.44–7.35 (m, 1H), 5.39 (s, 2H)
ppm; 134.1, 132.3, 129.6, 129.2, 126.5, 123.2, 111.1, 29.2 ppm;
Rf (9:1 hexanes/EtOAc; UV/KMnO4): 0.13.
in THF was prepared and was added at r.t. (2.2 equiv of a 2.2 M
ACCEPTED MANUSCRIPT
solution in THF; reaction volume = 0.50 M with respect to
benzylmagnesium bromide). The reaction was stirred under an
atmosphere of N2 at r.t. for 1 h, then was moved to a pre-heated
80 ºC oil bath and was stirred for an additional 6 h. Step 2: The
reaction was cooled to r.t. and DMF was added to bring the
reaction solvent to a 1:1 THF/DMF ratio (0.25 M of a 1:1
THF/DMF mixture with respect to benzylmagnesium bromide
starting material). The desired electrophile (1.2 equiv) was added
in a single portion. If the electrophile was a solid, it was added
with the DMF as a 0.60 M stock solution. The reaction was
stirred at 80 ºC for 16 h, or until complete conversion was
achieved as judged by TLC. The reaction was cooled to r.t.,
opened to air, quenched with 1 M aq. HCl, and extracted with
EtOAc (×3). The organic fractions were combined, dried over
MgSO4, and concentrated. The crude residue was purified by
flash column chromatography to yield the desired malononitrile.
4.2.17 2-Methyl-2-(thiophen-2-yl)malononitrile (2n): According
to General Procedure A, 2n was prepared using the following
amounts of reagent: Step 1: lithium chloride (19 mg, 0.44 mmol,
1.1 equiv), THF (0.40 mL), 2-thiopheneacetonitrile (43 ꢀL, 0.40
mmol, 1.0 equiv), methylmagnesium bromide (0.16 mL of a
2.7 M solution in Et2O, 0.44 mmol, 1.1 equiv), and
dibenzylmalononitrile (0.40 mL of a 1.1 M stock solution in
THF, 0.44 mmol, 1.1 equiv). Step 2: DMF (0.80 mL; total
reaction solvent = 1.6 mL of a 1:1 DMF/THF mixture, 0.25 M)
and iodomethane (30 ꢀL, 0.48 mmol, 1.2 equiv). The crude
residue was purified by flash column chromatography (gradient
of 0–20% EtOAc/hexanes) to yield 2n as an orange oil (51 mg,
1
0.21 mmol, 78%). H NMR (500 MHz, CDCl3, 298 K): δH 7.44
(dd, J = 5.2, 1.2 Hz, 1H), 7.34 (dd, J = 3.6, 1.3 Hz, 1H), 7.06 (dd,
J = 5.2, 3.6 Hz, 1H), 2.23 (s, 3H) ppm; 13C NMR (125 MHz,
CDCl3, 298 K): δC 135.2, 127.9, 127.6, 127.5, 115.0, 32.4, 29.0
ppm; HRMS m/z (DART): calcd for C8H7N2S (M+H) 163.0330;
found 163.0334; IR (neat): 3115, 3005, 2945, 2253, 2099, 1498,
1452, 1430, 1383, 1355, 1345, 1209, 1165, 1089, 1074, 1044,
927, 858, 831, 704, 653, 617 cm–1; Rf (9:1 hexanes/EtOAc;
UV/KMnO4/p-anisaldehyde): 0.25.
4.2.21 2-Ethyl-2-phenylmalononitrile (2p): According to General
Procedure B, 2p was prepared using the following amounts of
reagent: Step 1: lithium chloride (19 mg, 0.44 mmol, 1.1 equiv),
benzylmagnesium bromide (3) (0.47 mL of a 0.85 M solution in
Et2O, 0.40 mmol, 1.0 equiv), and DBMN (0.80 mL of a 1.1 M
stock solution in THF, 0.88 mmol, 2.2 equiv). Step 2: DMF (0.80
mL; total reaction solvent = 1.6 mL of a 1:1 DMF/THF mixture,
0.25 M) and iodoethane (39 ꢀL, 0.48 mmol, 1.2 equiv). The
crude residue was purified by flash column chromatography
(gradient of 0–10% EtOAc/hexanes) to yield 2p as a colourless
oil (65 mg, 0.38 mmol, 95%; 81% from benzyl bromide).
Analytical data:12 1H NMR (400 MHz, CDCl3, 298 K): δH 7.59–
7.54 (m, 2H), 7.53–7.43 (m, 3H), 2.29 (q, J = 7.4 Hz, 2H), 1.24
(t, J = 7.3 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3, 298 K): δC
132.1, 130.0, 129.8, 125.9, 115.1, 43.4, 36.7, 10.1 ppm; Rf (9:1
hexanes/EtOAc; UV/KMnO4): 0.41.
4.2.18 2-Methyl-2-(pyridin-2-yl)malononitrile (2o): Following
General Procedure A, 2o was prepared using the following
amounts of reagent: Step 1: lithium chloride (19 mg, 0.44 mmol,
1.1 equiv), THF (0.40 mL), 2-pyridylacetonitrile (45 ꢀL, 0.40
mmol, 1.0 equiv), methylmagnesium bromide (0.21 mL of a 2.1
M
solution in Et2O, 0.44 mmol, 1.1 equiv), and
dimethylmalononitrile (0.40 mL of a 1.1 M solution in THF, 0.44
mmol, 1.1 equiv). Step 2: DMF (0.80 mL; total reaction solvent =
1.6 mL of a 1:1 DMF/THF mixture, 0.25 M) and iodomethane
(30 ꢀL, 0.48 mmol, 1.2 equiv). The crude residue was purified by
flash column chromatography (gradient of 10–50%
EtOAc/hexanes) to yield 2o as a yellow oil (38 mg, 0.24 mmol,
4.2.22 2-Phenethyl-2-phenylmalononitrile (2q): According to
General Procedure B, 2q was prepared using the following
amounts of reagent: Step 1: lithium chloride (19 mg, 0.44 mmol,
1.1 equiv), benzylmagnesium bromide (3) (0.47 mL of a 0.85 M
solution in Et2O, 0.40 mmol, 1.0 equiv), and DBMN (0.80 mL of
a 1.1 M stock solution in THF, 0.88 mmol, 2.2 equiv). Step 2:
DMF (0.80 mL; total reaction solvent = 1.6 mL of a 1:1
DMF/THF mixture, 0.25 M) and (2-bromoethyl)benzene (68 ꢀL,
0.48 mmol, 1.2 equiv). The crude residue was purified by flash
column chromatography (gradient of 0–10% EtOAc/hexanes) to
yield 2q as a colourless oil (73 mg, 0.30 mmol, 75%; 64% from
1
60%). H NMR (400 MHz, CDCl3, 298 K): δH 8.74–8.66 (m,
1H), 7.91–7.82 (m, 1H), 7.75–7.67 (m, 1H), 7.46–7.38 (m, 1H),
2.19 (s, 3H) ppm; 13C NMR (100 MHz, CDCl3, 298 K): δC 151.6,
150.5, 138.3, 124.7, 120.2, 115.3, 38.5, 27.3 ppm; HRMS m/z
(DART) calcd for C9H8N3 (M+H) 158.0718; found 158.0718; IR
(neat): 3081, 3060, 3004, 2256, 2196, 1588, 1577, 1468, 1435,
1379, 1303, 1182, 1113, 1097, 1050, 994, 781, 747, 622, 615 cm–
1; Rf (9:1 hexanes/EtOAc; UV/KMnO4): 0.13.
1
benzyl bromide). H NMR (400 MHz, CDCl3, 298 K): δH 7.64–
7.58 (m, 2H), 7.55–7.46 (m, 2H), 7.36–7.20 (m, 4H), 7.20–7.14
(m, 2H), 2.99–2.89 (m, 2H), 2.54–2.44 (m, 2H) ppm; 13C NMR
(100 MHz, CDCl3, 298 K): δC 138.3, 132.1, 130.2, 130.0, 129.0,
128.5, 127.1, 125.9, 115.0, 44.5, 32.1 ppm; HRMS m/z (DART):
calcd for C17H15N2 (M+H) 247.1235; found 247.1237; IR (neat):
3088, 3066, 3030, 2933, 2250, 2158, 1978, 1969, 1604, 1589,
1495, 1452, 1340, 1281, 1216, 1160, 1068, 1030, 1005, 915, 867,
762, 749, 694, 638 cm–1; Rf (9:1 hexanes/EtOAc; UV/KMnO4):
0.47.
4.2.19 Benzylmagnesium bromide: To a 25-mL pear-shaped flask
with stir bar were added magnesium(0) turnings (0.58 g, 24
mmol, 1.2 equiv). The flask was sealed and was flame-dried and
cooled under vacuum. The flask was backfilled with N2 and Et2O
(20 mL, 1.0 M) was added. The magnesium(0) turnings were
activated with 1,2-dibromoethane (ca. 0.050 mmol, 0.58 mmol,
0.029 equiv) and benzyl bromide (3) (2.4 mL, 20 mmol, 1.0
equiv) was added portionwise over 2 h at r.t. The reaction was
stirred for an additional 1 h at r.t. then was allowed to stand for
1 h at r.t. to yield benzylmagnesium bromide as a grey solution.
The solution was titrated with I2 and was found to have a
concentration of 0.85 M (17 mmol, 85%).
4.2.23 2-Hexadecyl-2-phenylmalononitrile (2r): According to
General Procedure B, 2r was prepared using the following
amounts of reagent: Step 1: lithium chloride (19 mg, 0.44 mmol,
1.1 equiv), benzylmagnesium bromide (3) (0.47 mL of a 0.85 M
solution in Et2O, 0.40 mmol, 1.0 equiv), and DBMN (0.80 mL of
a 1.1 M stock solution in THF, 0.88 mmol, 2.2 equiv). Step 2:
iodohexadecane (0.80 mL of a 0.60 M stock solution in DMF,
0.48 mmol, 1.2 equiv; total reaction solvent = 1.6 mL of a 1:1
DMF/THF mixture, 0.25 M). The crude residue was purified by
4.2.20 General Procedure B: Synthesis of malononitriles from
benzylmagnesium bromide: Step 1: To an 8-mL culture tube with
stir bar was added lithium chloride (1.1 equiv) and the flask was
flame-dried under vacuum and cooled under an atmosphere of
N2. THF (1.0 M) was added, followed by benzylmagnesium
bromide (0.47 mL of a 0.85 M solution in Et2O, 0.40 mmol, 1.0
equiv). A 2.2 M stock solution of dibenzylmalononitrile (DBMN)
flash
column
chromatography
(gradient
of
0–5%

8
Tetrahedron
ACCEPTED MANUSCRIPT
EtOAc/hexanes) to yield 2r as a colourless oil (0.10 g, 0.27
phenylpropane (73 ꢀL, 0.48 mmol, 1.2 equiv) and DMF
1
mmol, 70%; 60% from benzyl bromide). H NMR (400 MHz,
CDCl3, 298 K): δH 7.60–7.53 (m, 2H), 7.52–7.42 (m, 3H), 2.26–
2.13 (m, 2H), 1.69–1.55 (m, 2H), 1.47–1.07 (m, 26H), 0.94–0.73
(m, 3H) ppm; HRMS m/z (DART): calcd for C25H42N3 (M+NH4)
384.3379; found 384.3376; IR (neat): 2955, 2923, 2853, 2370,
2251, 1602, 1495, 1467, 1452, 1378, 1034, 1004, 917, 758, 695
cm–1; Rf (9:1 hexanes/EtOAc; UV/KMnO4): 0.66.
(0.80 mL; total reaction solvent = 1.6 mL of a 1:1 THF/DMF
mixture, 0.25 M with respect to the alkyl nitrile). The crude
residue was purified by flash column chromatography (gradient
of 0–20% hexanes/EtOAc) to yield 2t as a colourless oil (76 mg,
0.34 mmol, 85%). 7.36–7.13 (m, 5H), 2.74 (t, J = 7.0 Hz, 2H),
2.08–1.97 (m, 2H), 1.96–1.82 (m, 4H), 1.75–1.62 (m, 2H), 1.03
(t, J = 7.3 Hz, 3H) ppm; 13C NMR (100 MHz, CDCl3, 298 K): δC
140.2, 128.7, 128.3, 126.4, 115.7, 39.7, 37.6, 37.2, 34.8, 27.0,
19.1, 13.4 ppm; HRMS m/z (DART): calcd for C15H19N2 (M+H)
227.1548; found 227.1549; IR (neat): 3063, 3029, 2966, 2936,
2877, 2870, 2249, 1736, 1605, 1497, 1461, 1455, 1384, 1244,
1032, 750, 745, 700 cm–1; TLC Rf (9:1 hexanes/EtOAc;
UV/KMnO4): 0.30.
4.2.24 General Procedure C: Synthesis of malononitriles from
alkyl nitriles using LDA: Step 1: To a flame-dried 8-mL culture
tube with stir bar was added THF (0.40 mL) and
diisopropylamine (67 ꢀL, 0.48 mmol, 1.2 equiv). The solution
was cooled to 0 ºC and n-BuLi (0.28 mL of a 1.6 M solution in
hexanes, 0.44 mmol, 1.1 equiv) was added, dropwise, and the
reaction was stirred at 0 ºC for 10 min. The solution was cooled
to −78 ºC and the desired alkyl nitrile was added neat, dropwise
(0.40 mmol, 1.0 equiv), and the reaction was stirred at −78 ºC for
1 h. The reaction was warmed to r.t. and a stock solution of
dimethylmalononitrile (DMMN) in THF was added (1.1 equiv of
a 1.1 M solution in THF; reaction volume = 0.50 M with respect
to alkyl nitrile). The reaction was stirred at 80 ºC for 6 h under an
atmosphere of N2. Step 2: The reaction was cooled to r.t. and
DMF was added to bring the reaction solvent to a 1:1 THF/DMF
ratio (0.25 M of a 1:1 THF/DMF mixture with respect to alkyl
nitrile). The desired electrophile (1.2 equiv) was added in a single
portion. If the electrophile was a solid, it was added with the
DMF as a 0.60 M stock solution. The reaction was stirred at 80
ºC for 16 h, or until complete conversion was achieved as judged
by TLC. The reaction was cooled to r.t., opened to air, quenched
with 1 M aq. HCl, and extracted with EtOAc (×3). The organic
fractions were combined, dried over MgSO4, and concentrated.
The crude residue was purified by flash column chromatography
to yield the desired malononitrile.
4.2.27
Gram-scale
preparation
of
2-methyl-2-
phenylmalononitrile (2c): According to General Procedure A, 2c
was prepared using the following amounts of reagent: Step 1:
benzyl cyanide (1.2 mL, 10 mmol, 1.0 equiv), lithium chloride
(0.46 g, 11 mmol, 1.1 equiv), THF (10 mL), methylmagnesium
bromide (4.1 mL of a 2.7 M solution in Et2O, 11 mmol, 1.1
equiv), and DMMN (10 mL of a 1.1 M stock solution in THF, 11
mmol, 1.1 equiv); Step 2: iodomethane (0.75 mL, 12 mmol, 1.2
equiv) and DMF (20 mL). The crude residue was purified by
flash
column
chromatography (gradient
of
0–20%
EtOAc/hexanes) to yield 2c (1.48 g, 9.5 mmol, 95%). The
analytical data matched that of 2c prepared on 0.40-mmol scale.
4.2.28 Large-scale preparation of 2-phenylmalononitrile (2a):32
To a flame-dried 500-mL flask was added copper(I) iodide (1.9
g, 10 mmol, 20 mol %), L-proline (1.2 g, 10 mmol, 20 mol %),
potassium carbonate (28 g, 200 mmol,
4 equiv), and
malononitrile (9.9 g, 150 mmol, 3.0 equiv). The flask was sealed,
evacuated and backfilled with N2 (×3), and DMSO was added
(250 mL, 0.20 M). Iodobenzene (5.6 mL, 50 mmol, 1.0 equiv)
was added and the reaction was stirred at 90 ºC for 18 h under
N2. The flask was cooled to 0 ºC, opened to air, and 1 M HCl was
added to bring the solution to pH 2–3. The solution was extracted
with EtOAc (×3) and the organic fractions were combined,
washed with brine (×3), dried over MgSO4, and concentrated.
The crude residue was purified by flash column chromatography
(gradient of 10–20% EtOAc/hexanes) to yield 2a as an off-white
solid (6.2 g, 44 mmol, 88%). The characterization data matched
that of 2a prepared using General Procedure A.
4.2.25 2-Benzyl-2-propylmalononitrile (2s): According to
General Procedure C, malononitrile 2s was prepared using the
following amounts of reagent: Step 1: THF (0.40 mL),
diisopropylamine (67 ꢀL, 0.48 mmol, 1.2 equiv), n-butyllithium
(0.28 mL of a 1.6 M solution in hexanes, 0.44 mmol, 1.1 equiv),
valeronitrile (42 ꢀL, 0.40 mmol, 1.0 equiv), and DMMN (0.40
mL of a 1.1 M stock solution in THF, 0.44 mmol, 1.1 equiv).
Step 2: benzyl bromide (57 ꢀL, 0.48 mmol, 1.2 equiv) and DMF
(0.80 mL; total reaction solvent = 1.6 mL of a 1:1 THF/DMF
mixture, 0.25 M with respect to the alkyl nitrile). The crude
residue was purified by flash column chromatography (gradient
of 0–20% hexanes/EtOAc) to yield 2s as a white solid (78 mg,
0.39 mmol, 98%). 7.45–7.32 (m, 5H), 3.21 (s, 2H), 1.97–1.86 (m,
2H), 1.83–1.69 (m, 2H), 1.05 (t, J = 7.3 Hz, 3H) ppm; 13C NMR
(100 MHz, CDCl3, 298 K): δC 132.1, 130.2, 129.0, 128.8, 115.4,
43.4, 39.4, 39.3, 19.2, 13.4 ppm; HRMS m/z (DART): calcd for
C13H18N3 (M+NH4) 216.1501; found 216.1505; IR (neat): 3070,
3037, 2990, 2966, 2951, 2937, 2924, 2870, 2881, 2249, 1606,
1498, 1469, 1458, 1450, 1274, 1141, 1011, 760, 702, 666 cm–1;
TLC Rf (9:1 hexanes/EtOAc; UV/KMnO4): 0.39.
Acknowledgements
We thank NSERC (Discovery Grants and Canada Research
Chair programs), the Canada Foundation for Innovation (project
number 35261), the Ontario Research Fund and the University of
Toronto for generous financial support of this work. The authors
also wish to acknowledge the Canada Foundation for Innovation
(project number 19119) and the Ontario Research Fund for
funding the Centre for Spectroscopic Investigation of Complex
Organic Molecules and Polymers. L. R. M. thanks NSERC for a
graduate scholarship (PGS D).
4.2.26 2-(3-phenylpropyl)-2-propylmalononitrile (2t): According
to General Procedure C, 2t was prepared using the following
amounts of reagent: Step 1: THF (0.40 mL), diisopropylamine
(67 ꢀL, 0.48 mmol, 1.2 equiv), n-butyllithium (0.28 mL of a 1.6
M solution in hexanes, 0.44 mmol, 1.1 equiv), valeronitrile (42
ꢀL, 0.40 mmol, 1.0 equiv), and DMMN (0.40 mL of a 1.1 M
stock solution in THF, 0.44 mmol, 1.1 equiv). Step 2: 1-bromo-3-
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9
ACCEPTED MANUSCRIPT
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