Surprising and Highly Efficient Use of Methylmagnesium Chloride as a Non-Nucleophilic Base in the Deprotonation and Alkylation of sp3 Centres Adjacent to Nitriles

Article abstract of DOI:10.1002/ejoc.201801462

Methylmagnesium chloride (MeMgCl) is a key reagent in research and industry typically as a nucleophile. In this article we develop the use of MeMgCl as a non-nucleophilic base in conjunction with catalytic amounts of an amine mediator. Specifically, we use the base to deprotonate α to a variety of nitriles in alkylation reactions, applying it to the synthesis of a wide variety of tertiary and quaternary nitriles, including examples where we successively and successfully added three different substituents on the carbon α to the nitrile. This method is generally applicable, high yielding and much greener than existing methods, and it has considerable advantages for industrial application.

Full text of DOI:10.1002/ejoc.201801462

A Journal of
Accepted Article
Title: Surprising and highly efficient use of methylmagnesium chloride
as a non-nucleophilic base in the deprotonation and alkylation of
sp3 centres adjacent to nitriles
Authors: Omolola Gbadebo, Dennis Smith, Ger Harnett, Gregory
Donegan, and Patrick O'Leary
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801462
Link to VoR: http://dx.doi.org/10.1002/ejoc.201801462
Supported by

10.1002/ejoc.201801462
European Journal of Organic Chemistry
FULL
PAPER
Surprising and highly efficient use of methylmagnesium
chloride as a non-nucleophilic base in the deprotonation
and alkylation of sp3 centres adjacent to nitriles.
Omolola Gbadebo,[a] Dennis Smith, [a] Ger Harnett,[b] Gregory Donegan [b] and Patrick O’Leary *[a]
aSMACT, School of Chemistry, National University of Ireland Galway, Ireland, bRoche Ireland Ltd, Clarecastle, Co.
Clare, Ireland
Abstract: Methylmagnesium chloride (MeMgCl) is a key reagent in
research and industry typically as a nucleophilic reagent. In this
article we develop the use of MeMgCl as a non-nucleophilic base in
conjunction with catalytic amounts of an amine mediator. Specifically
we use the base to deprotonate  to a variety of nitriles in alkylation
reactions applying it to the synthesis of a wide variety of tertiary and
quaternary nitriles, including examples where we successively and
successfully added three different substituents on the carbon  to the
nitrile. This method is generally applicable, high yielding, is much
greener than existing methods and has considerable advantages for
application industrially.
reaction of esters with aminodimethylalane[4] and amide
dehydration.[5]
Figure 1. Nitrile pharmaceutical compounds.
Syntheses of many nitrile-containing pharmaceuticals typically
involve elaboration of a simpler nitrile using multiple alkylations or
arylations. This is particularly true in the synthesis of those
bearing quaternary centres, such as anastrozole, and the
cyclohexylnitriles cilomilast and levocabastine (Figure 1).
Introduction
The nitrile functional group is highly versatile synthetically. Some
of the multitude of different functional groups that can be
accessed from nitrile precursors (amides, carboxylic acids,
imines, amines, etc) are discussed in Wang’s recent review.[1]
Wang's publication also demonstrated that chiral derivatives can
be accessed from racemic nitriles via biotransformations using
different enzymes. To exploit these transformations to full effect
we need reliable versatile methods for the synthesis of nitriles and
their elaboration and functionalisation. Synthetically, nitriles can
be accessed via numerous routes such as substitution reactions
of alkyl halides with cyanide salts,[2] dehydration of aldoximines,[3]
Existing nitriles can be elaborated via deprotonation α to the nitrile
using a strong base and alkylation of the resulting anion or using
other methods involving catalytic generation of metalated
alkylnitriles which can be further alkylated.[6] Nitriles are present
in many pharmaceutically active compounds and are hence of
great interest both in research and industrially.[7]
Our work has concentrated on the elaboration of existing nitriles.
We sought to develop easily scalable green synthetic methods
which would lead to the maximum amount of diversity in potential
products from simple easily available starting materials.
[a]
[b]
O.Gbadebo, Prof. D. Smith, Dr. P. O’Leary
SMACT, School of Chemistry
National University of Ireland Galway
University Road, Galway, Ireland
E-mail:patrick.oleary@nuigalway.ie
Homepage: http://www.nuigalway.ie/science/school-of-
chemistry/staffprofiles/patrickoleary/
Dr. G. Harnett, Dr. G Donegan
Roche Ireland Ltd.
Clarecastle
Co Clare, Ireland
Scheme 1. Roche 2012 patent on alkylation of
cyclohexanecarbonitrile 1.
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201801462
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such deprotonations and the question arises how does Roche’s
MeMgCl chemistry compare with existing technology?
In 2009 and 2012 Roche published patents in which they
described the use of methylmagnesium chloride with a catalytic
MeMgCl offers many advantages over LDA at manufacturing
scale, whether LDA is sourced commercially or manufactured in-
house using n-BuLi. The manufacturing process for MeMgCl is
atom efficient and simpler than that for LDA or n-BuLi; magnesium
is cheaper and more naturally abundant than lithium; and
magnesium presents fewer environmental issues than lithium.
Another environmental advantage is that the reduction in amine
loading from 1 equivalent with LDA to 0.05 equivalent in the “late
MeMgCl” process simplifies management of waste streams.
At commercial scale recycling of solvents is an economic and
environmental essential. MeMgCl is commercially available in
neat THF and this simplifies solvent recycling in THF-based
processes. Commercial LDA is only available in mixtures of
solvents (typically THF, ethyl benzene and heptane) and n-BuLi
is usually only available in alkanes. Recovery of THF from the
mixture of solvents from processes involving LDA is often not
feasible without incurring excessive cost.
amount
of
an
amine
mediator
to
deprotonate
cyclohexanecarbonitrile 1, the resulting anion being successfully
alkylated (Scheme 1).[8] The two patents dealt with the same
reaction, the difference being whether the Grignard was added
prior to the alkylating agent resulting in formation of the anion
first[8a] or whether the Grignard was added last in a so-called ‘late
addition’ method (Scheme 1).[8b] The advantages of the “late
addition” method were that it simplified manufacturing operations
and minimized formation of by-products arising from reaction of
the preformed anion with the precursor nitrile. [8c]
Another “green” advantage of the reported MeMgCl alkylation is
that energy requirements are lower because extreme
temperatures are not required. The chemistry works well between
ambient temperatures and 70 °C whereas organolithium reagents
and LDA often require sub-zero temperatures.
Scheme 2. Coldham et al’s deprotonation with a Grignard and
reaction with an electrophile. [9]
MeMgCl in THF is also more stable than commercial
preparations of LDA, which are reported to decompose by 1%
over 1.5 weeks at 20 oC.[12] The decomposition of LDA
complicates supply chain management at industrial scale and
disposal of the decomposition product lithium hydride can be
highly hazardous.
Also, the fact that MeMgCl is available commercially in 3.0 M
solutions compared to 2.0 M for LDA helps process intensification.
The cost of commercial MeMgCl per mole of active base is around
The use of Grignard reagents or organometallics derived
therefrom as bases is known in different contexts. For instance
Kerr’s group have used such reagents in the functionalisation of
ketones via their enol ethers.[10]
There are isolated examples in the literature of the use of
Grignard reagents in deprotonation adjacent to nitriles but these
have been in cases where adjacent groups activate the reaction
site for deprotonation.[9] One example is shown in Scheme 2. In
this work Coldham reported the rapid deprotonation of a pipecolic
acid-derived nitrile and its quenching with acetone with very little
scrambling of the chirality. He also reported a similar reaction with
ester activating groups on the nitrile and different electrophiles.
Roche’s report interested us for its simplicity, scalability and the
fact that the alkylation did not appear to be complicated by
addition of MeMgCl to the nitrile group. The presence of catalytic
amounts of the amine modifier seems to play a key role. Hauser
et al reported reaction of nitriles with Gringard reagents without a
modifier where they observed two competing reactions, direct
Grignard addition to the nitrile and deprotonation alpha to the
40% that of LDA.
The Roche patents
[8a, 8b]
report the transformation outlined in
Scheme 1 being carried out in three ways via ‘preforming’ the
anion prior to addition of the alkylating agent, via ‘late addition’ of
the Grignard to all other reagents and via a traditional method
involving the use of LDA.[13] Using the scales reported by Roche
we calculated the E Factors for each method as LDA 13.9,
‘preforming’ 12.9 and ‘late addition’ 9.7.
Methylmagnesium chloride chemistry and particularly the Roche
‘late MeMgCl’ method are well aligned with Paul Anastas’s 12
Principles of Green Chemistry.[14]
In this paper with the
nitrile followed by reaction of the anion with another molecule of
11]
the nitrile.[8c,
Despite using a wide variety of nitriles and
developments we have made we can see prevention of waste
generation, atom economy increase, use of less hazardous
reactions and reagents using inherently safer chemistry,
increased energy efficiency, safer solvents and use of catalytic
amounts of the amine additive.
Grignards no great control over the product produced was
achieved. Another report where nitriles RCN are treated with
R1CH2MgX and the alkylating agents BuI, BuBr, and BuCl, gave
mixtures of ketones RCOCH2R1 and α-substituted ketones
RCOCHBuR1 showing reaction of the Grignard with the nitrile
group.[8c, 11]
Results and Discussion
We are not aware of Roche’s patent being cited in other work and
we wanted to further study this methodology, particularly, the ‘late
addition’ method, to see if we could apply it more generally than
the one example reported by Roche. This method obviously fits
into the realm of ‘deprotonation α to the nitrile using a strong base
and alkylation of the resulting anion’ as mentioned above. Lithium
diisopropylamide (LDA) and similar bases are typically used in
We started our study by looking at the same nitrile 1 used by
Roche (Table 1). Initially we looked at straightforward alkylation
using an alkyl bromide and late addition of methylmagnesium
chloride to a solution of the other reagents at room temperature.
No external heating or cooling were applied. Alkylation using the
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10.1002/ejoc.201801462
European Journal of Organic Chemistry
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same alkyl halide as Roche proceeded well with 100% conversion
to nitrile 2a according to GC analysis and an isolated yield of 63%.
There was no evidence of reaction of the Grignard reagent with
the nitrile group or the alkyl halide. Reactions were conducted on
a relatively small scale and as a result isolated yields are not as
high as the initial report by Roche which were optimised and on
large scale. For that reason the conversion values we report are
more significant in terms of assessing the efficiency of the
reaction.
wanted to check the process would work using other reagents
also. On repeating the reaction to form nitrile 4b using
phenylmagnesium chloride as the Grignard the crude reaction
mixture had the same product distribution and we isolated the
product in a comparable 74% yield.
Table 2. Alkylation reactions of phenylacetonitrile
Table 1. Alkylation reactions of cyclohexanecarbonitrile 1.
Entry
(product)
R[a]
Ratio[b] (%)
SM:Mono:Di
Yield
%
[c]
1 (4a)
2 (4b)
3 (4c)
Me
Et
11:82:7
3:96:1
8:91:1
66[d]
73
Electrophile
Product structure
Product
Number
Conv
%
Yield
%
[a]
[b]
70
2a
2b
100
100
63
81
4 (4d)
13:78:9
45
[a] X= I for entries 1 and 2 and X= Br for entries 3 and 4 [b] Based on GC-MS.
Starting material (SM): Monoalkylated:Dialkylated product [c]Based on isolated
yield for monoalkylation [d] Yield of monoalkylated product based on crude
weight isolated and composition by GC-MS.
[a] Based on GC-MS [b] Based on isolated yield
We now knew we could achieve a reasonable level of control in
the monoalkylation of phenylacetonitrile and that we could isolate
the monoalkylated product. We also knew that some dialkylation
was seen. This led us to speculate as to whether we could gain
control over the dialkylation reaction. This would lead to the
possibility of producing quaternary nitriles which would be
synthetically useful. The natural progression from here would
then involve developing routes which would allow dialkylation with
different alkyl groups (heterodialkylation). This would open
synthetic routes to many different nitriles of interest. A review of
the literature revealed that heterodialkylation of phenylacetonitrile
using alkyl halides has been reported very rarely and for a limited
number of molecules.[15] With one exception involving ephedrine,
the reported methods involve the use of sodamide as the base. A
generally applicable method which could synthesise multiple
nitriles from common starting materials would certainly be a useful
addition to synthetic methodology.
n-Butyl bromide also reacted well giving compound 2b in 100%
conversion and 81% isolated yield.
When the reaction to produce product 2a was repeated without
the amine modifier the reaction gave a mixture of alkyl halide,
nitrile SM 1, ketone, product 2a in the ratio 66:26:2:6 after 2 hours.
With a longer reaction time (18 hours) it was found that the
conversion to the product 2a had increased to 60%. It does
however appear that the amine modifier is key to achieving
selective alkylation in high conversions rapidly.
Having established that we could deprotonate and functionalize
the methine carbon we next decided to investigate if the
methodology could be employed in the functionalization of
methylene carbons.
We chose to attempt alkylation of
phenylacetonitrile 3 with alkyl halides using the same reaction
conditions as above (Table 2). This also allowed us to evaluate
whether an adjacent aromatic group changed the reaction
outcome. GC-MS allowed us to identify the ratio of unreacted
starting material to the monoalkylated product. A small amount of
dialkylated product was also present in the reaction products. The
monoalkylation product could be separated successfully from the
starting material and the dialkylated product by chromatography
giving yields ranging from 45 to 73% of the monoalkylated product
representing a reasonable return on the 78 to 96% conversions.
Though MeMgCl is the most convenient Grignard to use we
We started this aspect of the study by looking at the
monoalkylation reactions which produced dialkyl products as side
products. In one-pot reactions using 3 equivalents of the Grignard
reagent and the alkyl halide but maintaining the amount of amine
modifier at 0.05 equivalents we achieved essentially complete
conversion to the quaternary nitrile after three hours at reflux
(Scheme 3). This reaction worked for alkylation with simple
methyl groups leading to 5a, ethyl groups leading to 5b or the
more complex 2-ethylbutyl groups giving nitrile 5c.
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with the two-step method where the tertiary nitrile is isolated
before being reacted on to give the quaternary nitrile which gave
a conversion of 96% and an isolated yield of 71%. Obviously
carrying out the transformation in one pot involved one fewer step,
lower inputs and time savings. When we formed the same product
but reversing the order in which the alkyl groups were added the
product was isolated in the same yield with similar compound
distribution in the crude reaction mixture. The same reaction with
ethyl and methyl additions was also successful with 94%
conversion to nitrile 5f.
Scheme 3. Dialkylation reactions of phenylacetonitrile
Table 3. One pot hetero-dialkylation of phenylacetonitrile
Scheme 4. Sequential hetero-dialkylation reactions of
phenylacetonitrile
We then investigated ways in which we might make
heterosubstituted quaternary nitriles. The work preparing the
homosubstituted quaternary nitriles in a one pot reaction (Scheme
3) established that there did not seem to be a barrier to formation
of quaternary nitriles so we decided to start with tertiary nitriles
(prepared as in Table 2) and attempt the deprotonation and
alkylation to produce the quaternary product in a sequential
alkylation route. Two examples are shown in Scheme 4. Starting
from the 2-allyl-2-phenylacetonitrile 4d using our standard
conditions and refluxing for two hours we managed to
successfully add the 2-ethylbutyl group with 96% conversion and
isolated the product 5d in 78% yield. This was very encouraging.
Adding the same group to the 2-ethyl-2-phenylacetonitrile was
also successful giving 94% conversion to nitrile 5e and 71%
isolated yield. The remainder of the starting material was
unchanged.
R1
R2
MeMgCl/Alkyl
Product
Conv
(%)[b]
Yield
(%)[c]
halide[a]
/Amine
/
1.2 eq/1.2eq/ 0.05
eq (addn R1)
Et
5e
96%
76%
1.2 eq/1.2eq/ 0.05
eq (addn R2)
1.2 eq/1.2eq/0.05 eq
(addn R1)
Et
1.2 eq/ 1.2eq/
5e
95%
94%
79%
29%
residual amine from
first addn (addn R2)
1.2 eq/1.2eq/0.05 eq
(addn R1)
We wanted to go directly from phenylacetonitrile to the
heterosubstituted quaternary nitrile in
a one-pot hetero-
Me
dialkylation (Table 3). We essentially carried out these reactions
by doing an initial monoalkylation at room temperature to
minimise formation of dialkylation product. This reaction was not
worked up but the second different alkyl halide was added
followed by a second portion of Grignard. The second alkylation
reaction was conducted at elevated temperature. Exploratory
work indicated that for heteroalkylation of phenylacetonitrile with
ethyl and 2-ethylbutyl groups it was better to install the ethyl group
first. This sequence gave a 94% conversion to the product 5e and
a 76% isolated yield. The one-pot method compares favourably
Et
5f
2.0 eq/2.0 eq/0.05
eq (addn R2)
[a]Ethyl iodide, methyl iodide, allyl bromide, 2-ethylbutyl bromide [b] Percentage
of targeted product in final reaction mixture by GC-MS [c] Isolated yield
The main side product was the diethylated product 5b at 5%. A
chromatographic separation to produce an analytical sample
proved difficult and the isolated yield of 5f was only 29%.
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In general, for this one pot procedure where we installed two
different alkyl groups we included a second charge of 0.05 eq of
the amine in the second alkylation step. As the amine has a
catalytic role this second charge should not be necessary and
when the reaction to produce the product 5e was repeated (ethyl
addition followed by 2-ethylbutyl) without the second charge of
amine the outcome was unaffected (95% conversion, 79%
isolated yield).
2-Methyl-THF as greener alternative reaction solvent
During our development studies as part of the workup process we
had used diethyl ether as a diluent of the reaction mixture to allow
for water extraction. This was necessary as the THF solvent is
substantially soluble in water. We wanted to make the process
more environmentally friendly and thus turned to the greener
solvent 2-methyl-tetrahydrofuran (2-Me-THF).
2-Me-THF is
considered to be the greenest of the widely available ether
solvents.[17] Its low water solubility allowed us to complete the
work-up without addition of diethyl ether. We initially used the
new solvent in the reaction to add an n-butyl group to
cyclohexanecarbonitrile 1 to give compound 2b (see table 1 for
comparison). The reaction worked well and the product was
isolated in 77% yield with >99% purity without a purification step.
This compares well with the same reaction using THF which gave
81% yield with >99% purity. Part of our standard diethyl ether
work-up had been a sodium sulfate drying step but we found it
was unnecessary to dry the 2-Me-THF extract with sodium sulfate
prior to solvent removal as any water present (up to 4.5%) is
removed during distillation as an azeotrope (10.5% water) with
the solvent.[18] When the preparation of 2b was repeated with no
drying agent the product was isolated in 79% yield.
Alkylation of acetonitrile
Scheme 5. Synthetic elaboration of acetonitrile
Having successfully alkylated methine and methylene carbons we
decided to challenge the method further by using the simplest
available alkyl nitrile as the starting material. Publications on the
alkylation of acetonitrile are quite rare although Taber reported
moderate yields for the alkylation of lithioacetonitrile at -78 °C.[16]
Using acetonitrile 6 we could potentially add three alkyl groups via
either sequential or one-pot processes. We found that trying to
add the three alkyl groups in a ‘one-pot’ manner to acetonitrile did
lead to the product however a lot of side products were also
produced. Simplifying the sequence somewhat we initially
alkylated acetonitrile 6 with one equivalent of benzyl bromide to
give the nitrile 7 and followed this initial alkylation, after isolation,
by addition of an ethyl group and a 2-ethylbutyl group in a one-pot
procedure (Scheme 5). Reaction of acetonitrile with benzyl
bromide at 0 °C gave a crude mixture which contained a mixture
of benzyl bromide SM, product 7 and N,N-diethylbenzylamine
(possibly via reaction of a magnesium diethylamide species with
benzyl bromide) in the ratio 6:92:2 as measured by GC-MS. The
alkylated product 7 was isolated in 80% yield after column
chromatography. The isolated product was then alkylated in a
one pot process initially with ethyl iodide at room temperature and
then with 2-ethylbutyl bromide at reflux in both cases amine (0.05
eq) and MeMgCl (1.2eq) effected the required deprotonation. The
trisubstituted product 8 made up 98% of the crude product with
the other product being nitrile that had been disubstituted by the
ethyl group. Following chromatography the required product 8
was isolated in 86% yield. The overall yield from acetonitrile was
thus 69%.
Conclusions
In this publication we report on the use of methylmagnesium
chloride with a catalytic amount of an amine modifier as a non-
nucleophilic base in the alkylation of nitrile compounds. The
reaction can be applied to form tertiary or quaternary nitrile
compounds and used to add one or two alkyl groups to methine
(one addition) and methylene (one or two additions, identical or
different) carbons. Even though the nitrile, alkyl halide and
Grignard reagent are present in the reaction mixture
simultaneously, direct reaction of the Grignard with the nitrile or
the alkyl halide is not seen and the alkylation product is formed in
high yields. We have also successfully alkylated acetonitrile with
controlled addition of one alkyl group and further elaboration to a
quaternary nitrile
This methodology is applicable from the small scale we have used
(15 mmol) to the industrial scale used by Roche in their one
example (4700 mol). It avoids the hazards associated with alkyl
lithiums and the consequent purchase, storage and handling
costs. It avoids the use of alkane solvents and facilitates the use
and recovery of “greener” ether solvents. Another green
advantage is that extreme temperatures are not required, all
reactions being run between 0oC and 70 °C. The operational
simplicity of the “late addition” methodology makes it ideally suited
for continuous processing.
We have successfully carried out the reactions in 2-Me-THF
which is derived from renewable sources and is the greenest of
the ether solvents and the reactions work equally well as our initial
studies with THF.
We are currently working on the extension of this methodology
with continuing focus on the ‘greenness’ of the process while also
A literature search of alkylations of acetonitrile returned no
reported reactions involving trialkylation of acetonitrile. We are
continuing to explore the versatility of this method to produce a
diversity of nitrile compounds using the safer and greener
methodology.
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2H, CH2CH3), 1.24-1.08 (m, 3H, 3 x cyclohexyl-H). 0.82 (t, J = 7.3 Hz, 3H,
CH3).13C NMR (100 MHz, CDCl3) δ 124.0 (CN), 40.4, 39.1 (CCN), 35.8,
26.6, 25.6, 23.2, 22.9, 14.0. IR: max /cm-1: 2937, 2232 (conj.CN), 1451.
seeking to exploit the versatile nature of the nitrile functionality to
synthesise molecules of biological interest.
Spectral data is consistent with literature values.[19]
Experimental Section
Preparation of 2b using 2-Me-THF as solvent and drying via azeotrope
General experimental information is given in the supporting information
including details of analysis methods and setup. All reactions conducted
under nitrogen atmosphere.
To a stirring solution of cyclohexanecarbonitrile 1 (1.8 mL, 15 mmol) in
anhydrous 2-Me-THF (15 mL) was added diethylamine (80 µL, 0.75 mmol)
and 1-bromobutane (1.6 mL, 15 mmol). MeMgCl (6 mL, 3 M in THF, 18
mmol) was added dropwise at rt over a minute and the reaction was left to
stir for 2 hours at rt at which stage all starting material (SM) had been
consumed (GC-MS monitoring). The reaction was quenched with 1M HCl
(15 mL). The organic layer was separated and washed with H2O (2 x 10
mL). The organic solution was concentrated to afford the title compound
2b as a yellow oil (>99% pure GC-MS) (1.95 g, 79% yield).
1-(2-Ethylbutyl)cyclohexane-1-carbonitrile 2a.[8a,8b]
To a stirring solution of cyclohexanecarbonitrile 1 (1.8 mL, 15 mmol) in
anhydrous THF (10 mL) was added diethylamine (80 µL, 0.75 mmol) and
1-bromo-2-ethylbutane (2.1 mL, 15 mmol). MeMgCl (6 mL, 3 M in THF, 18
mmol) was added dropwise at rt over a minute* and the reaction was left
to stir for 2 hours at rt at which stage all starting material (SM) had been
consumed (GC-MS monitoring). The reaction was quenched with 1M HCl
(15 mL) followed by the addition of diethyl ether (15 mL). The organic layer
was separated and washed with H2O (2 x 15 mL) and then brine (10 mL).
The organic solution was dried over Na2SO4, filtered and concentrated to
afford the alkylated product. The title compound 2a was recovered as a
yellow oil (>99% pure GC-MS) (1.82 g, 63% yield). 1H NMR (400 MHz,
CDCl3): δ 1.97 (d, J = 12.9 Hz, 2H, CNCCH2CH), 1.76 – 1.56 (m, 5H, 5 x
cyclohexyl-H), 1.50 – 1.34 (m, 7H, 2 x CHCH2CH3 and 3 x cyclohexyl-H),
1.25 – 1.08 (m, 3H, CHCH2 and 2 x cyclohexyl-H), 0.87 (t, J = 7.3, 6H, 2 x
CH3).13C NMR (100 MHz, CDCl3) δ 124.3 (CN), 44.2, 38.5(C), 36.7, 36.4,
26.6, 25.4, 23.0, 10.9. IR max /cm-1: 2961, 2861, 2229 (conj. CN) 1450;
GC-MS m/z: 192 (5), 178 (9), 164 (64), 138 (100), 123 (45), 95 (20); HRMS
(ESI) m/z: Calcd for C13H24N [M+H+]: 194.1909, found 194.1911.
The spectral data was consistent with that described for 2b above.
2-Phenylpropionitrile 4a.
This was prepared according to the procedure described for compound 2a
using phenylacetonitrile 3 (15 mmol) and iodomethane (15 mmol).
A
mixture of starting material (SM), mono- and dialkylated product was
obtained in the ratio 11:82:7 (measured by GC-MS) (1.58 g, 80%). This
mixture proved difficult to separate but based on the recovery and crude
product ratio it represents 66% crude yield of the product 4a.1H NMR (400
MHz, CDCl3) δ 7.45 – 7.26 (m, 5H, Ar-H), 3.90 (q, J = 7.3 Hz, 1H, CH),
1.62 (d, J = 7.3 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ 137.2, 129.3,
128.0, 126.8, 121.7 (CN), 31.4, 21.6. IR: max /cm-1: 3033, 2963, 2934,
2241 (conj. CN), 1601.
* Upon addition of MeMgCl the temperature rose to 70 °C. After 30 mins,
the temperature had returned to rt and the reaction was left to stir for 2
hours at which time full conversion was obtained (GC-MS monitoring). No
external heating or cooling were applied.
Spectral data is consistent with literature values .[20]
2-Phenylbutyronitrile 4b
Preparation of 2a with no amine mediator
This was prepared according to the procedure described for compound 2a
using phenylacetonitrile 3 (10 mmol) and iodoethane (10 mmol). A mixture
of SM, mono- and dialkylated product was obtained in the ratio 3: 96: 1
(measured by GC-MS). The crude mixture was purified by column
chromatography (PE: Et2O, 99:1) to afford the product 4b as a yellow oil
(1.06 g, 73% yield).1H NMR (400 MHz, CDCl3) δ 7.55 – 7.25 (m, 5H, Ar-
H), 3.74 (t, J = 7.2 Hz, 1H, CHCH2), 2.08 - 1.72 (m, 2H, CHCH2CH3), 1.08
(t, J = 7.4 Hz, 3H, CH2CH3). 13C NMR (100 MHz, CDCl3) δ 135.8, 129.1,
128.1, 127.4, 120.9 (CN), 39.0, 29.3, 11.6. IR: max /cm-1: 3033, 2963,
2936, 2240 (conj. CN), 1601.
To a stirring solution of cyclohexanecarbonitrile 1 (0.3 mL, 2.5 mmol) in
anhydrous THF (10 mL) was added 1-bromo-2-ethylbutane (0.35 mL, 2.5
mmol). MeMgCl (1 mL, 3M in THF, 3 mmol) was added dropwise at rt over
a minute and the reaction was left to stir for 2 hours at rt at which stage
there was a mixture of alkyl halide, nitrile 1, 1-cyclohexylethanone and
alkylated product 2a in the ratio 66:26:2:6 (GC-MS monitoring). The
reaction was then left to stir further overnight at rt before being quenched
with 1M HCl (15 mL) followed by the addition of diethyl ether (15 mL). The
organic layer was separated and washed with H2O (2 x 15 mL) and then
brine (10 mL). The organic solution was dried over Na2SO4, filtered and
concentrated. At this stage the ratio of the mixtures had changed to
28:10:2:60 for alkyl halide, nitrile 1, 1-cyclohexylethanone and alkylated
product 2a respectively.
Spectral data is consistent with literature values.[21]
2-Phenylbutyronitrile 4b (use of PhMgCl as an alternative Grignard
reagent)
*The product was not isolated and only GC-MS was used in
characterization by comparison to previous reaction outcomes.
This was prepared according to the procedure described for compound 2a
with the substitution of the PhMgCl for the MeMgCl and a change in scale
and concentration. The reaction was conducted using phenylacetonitrile
3 (2.5 mmol), diethylamine (0.125 mmol), iodoethane (2.5 mmol) and
PhMgCl (1.5 mL, 2M in THF, 3 mmol). A mixture of SM, mono- and
dialkylated product was obtained in the ratio 3: 93: 4 (measured by GC-
MS). The crude mixture was purified by column chromatography (PE:
Et2O, 99:1) to afford the product 4b as a yellow oil (74% yield).
1-Butylcyclohexanecarbonitrile 2b.
This was prepared according to the procedure described for compound 2a
using cyclohexanecarbonitrile 1 (15 mmol) and 1-bromobutane (15 mmol).
The title compound 2b was recovered as a yellow oil (>99% pure GC-MS)
(1.99 g, 81% yield). 1H NMR (400 MHz, CDCl3): δ 1.85 (d, J = 12.8 Hz,
2H, CH2), 1.78 – 1.70 (m, 3H, 3 x cyclohexyl-H), 1.56 – 1.42 (m, 2H, 2 x
cyclohexyl-H), 1.43 – 1.30 (m, 4H, CH2CH2CH2 CH3), 1.24 (q, J = 6.8 Hz,
The spectral data was consistent with that described for 4b above.
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10.1002/ejoc.201801462
European Journal of Organic Chemistry
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Preparation of 4b using 2-Me-THF as solvent
15mL) and then with brine (10 mL). The organic solution was dried over
Na2SO4, filtered and concentrated to afford the alkylated product. The
product was obtained with a purity >99% by GC-MS. The product 5a was
To a stirring solution of phenylacetonitrile 3 (0.3 mL, 2.5 mmol) in
anhydrous 2-MeTHF (10 mL) was added diethylamine (14 µL, 0.125 mmol)
and iodoethane (0.2 mL, 2.5 mmol). MeMgCl (1 mL, 3 mmol) was added
dropwise over a minute at rt and the reaction was left to stir for 2 hours at
rt. After 2 hours, a mixture of SM, mono- and di-alkylated product was
obtained in the ratio 3: 95: 2 (measured by GC-MS).The reaction was
quenched with 1M HCl (15 mL). The organic layer was separated and
washed with H2O (2 x 10 mL). The organic solution was dried over Na2SO4
and, filtered. The Na2SO4 was washed with EtOAc the combined filtrate
and washes were concentrated to afford the alkylated product.The crude
mixture was purified by column chromatography (PE: Et2O, 99:1) to afford
the product 4b as a yellow oil (0.25 g, 70% yield).
1
isolated as an oil (0.28g, 77% yield). H NMR (400 MHz, CDCl3): δ 7.49-
7.45 (m, 2H, Ar-H). 7.41-7.33 (m, 2H, Ar-H), 7.32-7.26 (m, 1H, Ar-H), 1.73
(s, 6H, 2 x CH3).13C NMR (100 MHz, CDCl3): 141.5, 129.0, 127. 9, 125.2,
124.6, 37.3, 29.3. IR: max /cm-1: 3032, 2234 (conj. CN), 1601.
Spectral data is consistent with literature values[23]
2-Ethyl-2-phenylbutyronitrile 5b
This was prepared according to the procedure described for compound 5a
using phenylacetonitrile 3 (2.5 mmol) and iodoethane (7.5 mmol). The
product was obtained with a purity of >99% assessed by GC-MS. The
product 5b was isolated as an oil (0.33g, 75% yield).1H NMR (400 MHz,
CDCl3): δ 7.39-7.25 (m, 5H, Ar-H). 2.04 (dq, J = 14.7, 7.4 Hz, 2H, CH2),
1.91 (dq, J = 14.7, 7.4 Hz, 2H, CH2), 0.90 (t, 6H, J = 7.3 Hz, 6H, 2 x CH3).
13C NMR (100 MHz, CDCl3): δ 138.1, 128.9, 127.7, 126.2, 122.4 (CN),
49.9, 33.9, 9.8. IR: max /cm-1: 3062, 2963, 2936, 2234 (CN), 1601.
The spectral data was consistent with that described for 4b above.
4-Ethyl-2-phenylhexanenitrile 4c
This was prepared according to the procedure described for compound 2a
using phenylacetonitrile 3 (30 mmol), 1-bromo-2-ethylbutane (30 mmol)
and THF (20 mL). A crude mixture of SM, mono- and dialkylated product
was obtained in the ratio 9:91:1 (measured by GC-MS). The crude mixture
was purified by column chromatography on silica (PE: Et2O, 99:1) giving
the product 4c as a clear oil (4.25 g, 70% yield).1H NMR (400 MHz, CDCl3):
δ 7.41 – 7.27 (m, 5H, Ar-H), 3.80 (dd, J = 10.0, 6.2 Hz, 1H, PhCHCN), 1.92
(ddd, J = 13.8, 10.0, 5.0 Hz, 1H of CH2), 1.69 (ddd, J = 14.0, 8.2, 6.2 Hz,
1H of CH2), 1.54 – 1.21 (m, 5H, CHCH2CH3 and 2 x CH2), 0.89, 0.86 (2 x
overlapping t, J = 7.3 Hz, 2 x 3H, 2 x CH3 ), 13C NMR (100 MHz, CDCl3):
δ 136.7, 129.2, 128.1, 127.3, 121.2 (CN), 39.9, 38.0, 35.5, 25.2, 24.4, 10.7,
10.1. IR: max /cm-1: 3033, 2971, 2936, 2240 (conj. CN), 1602. GC-MS m/z:
Spectral data is consistent with literature values.[23]
4-Ethyl-2-(2-ethylbutyl)-2-phenylhexanenitrile 5c
This was prepared according to the procedure described for compound 5a
using phenylacetonitrile 3 (2.5 mmol) and 1-bromo-2-ethylbutane (7.5
mmol). The product was obtained with a purity of >99% assessed by GC-
MS. The product 5c was isolated as a yellow oil (0.56g, 79% yield).1H NMR
(400 MHz, CDCl3) δ 7.47 – 7.21 (m, 5H, Ar-H), 1.95 – 1.68 (m, 4H, 2 of
CH2), 1.5-1.33 (m, 4H, 2 of CH2CH3), 1.32 – 1.17 (m, 2H, 2 x CH), 0.99
(app p, J = 7.3 Hz, 4H, 2 of CH2CH3), 0.83 (t, J = 8.0 Hz, 6H, 2 x CH3),
0.60 (t, J = 7.4 Hz, 6H, 2 x CH3). 13C NMR (100 MHz, CDCl3) δ 138.9,
128.7, 127.5, 126.4, 123.2 (CN), 46.8 (CCN), 45.5 (2 x CCH2), 37.2, 25.8,
10.4, 10.2. IR: max /cm-1: 2962, 2244, 1601. GC-MS m/z: 285 (8), 201
(100), 172 (85), 145 (16) 130 (80), 103 (58), 85 (16). HRMS (ESI) m/z:
Calcd for C20H32N [M+H+]: 286.2535 found 286.2536.
201 (38), 117 (100), 89 (85), 57 (35). HRMS (ESI) m/z: Calcd for C14H18
[M-H+]: 200.1439 found 200.1431.
N
2-Phenylpent-4-ene-1-nitrile 4d
This was prepared according to the procedure described for compound 2a
with a change in scale and concentration using phenylacetonitrile 3 (2.5
mmol), allyl bromide (2.5 mmol) and THF (10 mL). Upon addition of
MeMgCl (3 mmol) at this scale and concentration the temperature rose to
40 °C then returned to rt after 20 mins. A crude mixture of SM, mono- and
di-alkylated product was obtained in the ratio of 13: 77: 10 (measured by
GC-MS). The crude mixture was purified by column chromatography (PE:
Et2O, 90:10) giving the product 4d as a clear oil (0.17 g, 45% yield).1H
NMR (400 MHz, CDCl3) δ 7.48-7.25 (m, 5 H, Ar-H), 5.86-5.70 (m, 1H,
CH=CH2), 5.29 – 5.14 (m, 2H, CH=CH2), 3.85 (t, J = 7.2 Hz, 1H, CH), 2.68-
2.50 (m, 2H, CHCH2). 13C NMR (100 MHz, CDCl3) δ 135.3, 132.7, 129.2,
128.3, 127.4, 120.4 (CN), 119.5, 40.0, 37.6. IR: max /cm-1: 2924, 2851,
2241 (conj. CN), 1601.
2-Allyl-4-ethyl-2-phenylhexanitrile 5d
This was prepared according to the procedure described for compound 2a
albeit at a smaller scale using 2-phenylpent-4-enenitrile 4d (0.86 mmol),
1-bromo-2-ethylbutane (0.86 mmol) and THF (10 mL). The reaction was
left to reflux for 2 hours.The reaction mixture contained SM and product in
the ratio 4:96 (measured by GC-MS). On workup, a 1H NMR spectrum
showed only the product 5d which was isolated as a yellow oil (0.141g,
78% yield). 1H NMR (400 MHz, CDCl3): δ 7.48 – 7.33 (m, 4H, Ar-H), 7.32
– 7.19 (m, 1H, Ar-H), 5.76 – 5.55 (m, 1H, CH=CH2), 5.15 – 4.93 (m, 2H,
CH2=CH), 2.67 (d, J = 6.8 Hz, 2H, CH2CH=CH2), 1.94 (dd, J = 14.4, 6.3
Hz, 1H of CH2), 1.82 (dd, J = 14.3, 4.9 Hz, 1H of CH2), 1.49-1.30 (m, 2H,
2 of CH2CH3), 1.29-1.22 (m, 1H, CH), 1.04 (app p, J = 7.1 Hz, 2H, 2 of
CH2CH3), 0.82 (t, J = 7.4 Hz, 3H, CH3), 0.62 (t, J = 7.4 Hz, 3H, CH3). 13C
NMR (100 MHz, CDCl3): δ 138.4, 132.0 (=CH2), 128.8, 127.7, 126.3,
122.5 (CN), 120.0 (=CH), 47.4, 46.5, 43.6, 37.3, 25.9, 25.6, 10.3. IR: max
/cm-1: 2962, 2238 (conj.CN), 1643. GC-MS m/z: 241(20), 200 (13), 170
(16), 130 (100), 103 (20), 77 (10), 55 (9). HRMS (ESI) m/z: Calcd for
C17H24N [M+H+]: 242.1909 found 242.1909.
Spectral data is consistent with literature values.[22]
2-Methyl-2-phenylpropionitrile 5a
To a stirring solution of phenylacetonitrile 3 (0.3 mL, 2.5 mmol) in
anhydrous THF (10 mL) was added diethylamine (14 µL, 0.125 mmol) and
iodomethane (0.45 mL, 7.5 mmol). MeMgCl (2.5 mL, 7.5 mmol) was added
dropwise over a minute at rt. Upon addition of MeMgCl the temperature
rose to 45°C. The reaction was then left to stir for 3 hours at reflux by which
time full conversion was obtained (GC-MS monitoring). The reaction was
quenched with 1M HCl (15 mL) followed by the addition of diethyl ether
(15 mL). The organic layer was separated and washed with H2O (2 x
2,4-Diethyl-2-phenylhexanenitrile 5e
Preparation of 5e by one-pot heterodialkylation of phenylacetonitrile
(addition of ethyl group first)
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10.1002/ejoc.201801462
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To a stirring solution of phenylacetonitrile 3 (0.3 mL, 2.5 mmol) in
anhydrous THF (10 mL) was added diethylamine (14 µL, 0.125 mmol) and
iodoethane (0.2 mL, 2.5 mmol). MeMgCl (1 mL, 3 M in THF, 3 mmol) was
added dropwise over a minute and the reaction was left to stir for 2 hours
at rt. After 2 hours, a mixture of SM, mono- and dialkyated product was
obtained in the ratio 3:96:1 (measured by GC-MS). In the same pot, 1-
bromo-2-ethylbutane (0.35 mL, 2.5 mmol) and diethylamine (14 µL, 0.125
mmol) were then added followed by MeMgCl (1 mL, 3 mmol and the
reaction was left to stir at reflux for 3 hours. The reaction was quenched
with 1M HCl (15 mL) followed by diethyl ether (15 mL). The organic layer
was separated, washed with H2O (2 x 15 mL) and then with brine (10 mL).
The organic solution was dried over Na2SO4, filtered and concentrated to
afford the alkylated product. A mixture of ethyl monoalkylated 5b and di-
hetero product 5e was obtained in the ratio 6:94 (measured by GC-MS).
The crude mixture was purified by column chromatography (PE: Et2O,
99:1) to afford nitrile 5e as a colourless oil (0.435 g, 76% yield).1H NMR
(400 MHz, CDCl3): δ 7.42-7.22 (m, 5H, Ar-H), 2.09–1.98 (m, 1H of CCH2),
1.97 – 1.86 (m, 2H, 2 of CHCH2CH3), 1.80 (dd, J = 14.3, 4.9 Hz, 1H, 1 of
CCH2), 1.51 – 1.28 (m, 2H, 2 of CHCH2CH3), 1.27 – 1.13 (m, 1H,
CH2CHCH2CH2), 1.03 (app p, J = 6.8 Hz, 2H, CCH2CH3), 0.87 (t, 7.4 Hz,
3H, CH3), 0.83 (t, 7.4 Hz, 3H, CH3), 0.62 (t, J = 7.4 Hz, 3H, CH3). 13C NMR
(100 MHz, CDCl3): δ138.5, 128.8, 127.6, 126.3, 122.8 (CN), 48.3, 44.4,
37.4, 35.2, 25.9, 25.7, 10.3, 9.7. IR: max /cm-1: 3023, 2964, 2921, 2242
(conj.CN). GC-MS m/z: 229 (7), 200 (6), 145 (100), 130 (82), 103 (53), 77
(22), 55 (13). HRMS (ESI) m/z: Calcd for C16H24N [M+H+]: 230.1909, found
230.1915.
purified by column chromatography (PE: Et2O, 99:1) to afford the product
5e as a colourless oil (0.82 g, 71% yield).
The spectral data was consistent with that described above for 4c.
2-Methyl-2-phenylbutyronitrile 5f
Preparation of 5f by one-pot heterodialkylation of phenylacetonitrile
(addition of ethyl group first)
To a stirring solution of phenylacetonitrile 3 (0.6 mL, 5 mmol) in anhydrous
THF (10 mL) was added diethylamine (30 µL, 0.25 mmol), iodoethane (0.4
mL, 5 mmol). MeMgCl (2 mL, 3 M in THF, 6 mmol) was added dropwise
over a minute. Upon addition of MeMgCl (6 mmol) at this scale,
temperature rose to 40 °C. After 20 mins, the reaction temperature
returned to rt and the reaction was left to stir for 2 hours. After 2 hours, a
mixture of SM 3, monoethylated product 4b and diethylated product 5b
was obtained in the ratio 1:94:5 (measured by GC-MS). In the same pot,
diethylamine (30 µL, 0.25 mmol), iodomethane (0.6 mL, 10 mmol), and
MeMgCl (3.4 mL, 10 mmol) were then added and the reaction was left to
stir at reflux for 3 hours. The reaction was quenched with 1M HCl (15 mL)
followed by diethyl ether (15 mL). The organic layer was separated,
washed with H2O (2 x 15 mL) and then with brine (10 mL). The organic
solution was dried over Na2SO4, filtered and concentrated to afford the
alkylated product. A mixture of dimethylated 5a, diethylated 5b and
methyl-ethyl product 5f was obtained in the ratio 1:5:94 (measured by GC-
MS). This mixture proved difficult to separate. The crude mixture was
purified by column chromatography (PE: Et2O, 90:10) to afford nitrile 5f as
a pale-yellow oil (0.23g, 29% yield). 1H NMR (400 MHz, CDCl3) δ 7.44 -
7.36 (m, 4H, Ar-H), 7.32 -7.25 (m, 1H, Ar-H), 2.01 – 1.87 (m, 2H, CH2),
1.70 (s, 3H, CH3), 0.96 (t, J = 7.4 Hz, 3H, CH2CH3). 13C NMR (100 MHz,
CDCl3): 140.2, 128.9, 127.8, 125.6, 123.5, 43.3, 35.4, 27.4, 10.0. IR:
Preparation of 5e by one-pot heterodialkylation of phenylacetonitrile
(addition of ethyl group first) with no amine addition before second
alkylation
To a stirring solution of phenylacetonitrile 3 (0.3 mL, 2.5 mmol) in
anhydrous THF (10 mL) was added diethylamine (14 µL, 0.125 mmol) and
iodoethane (0.2 mL, 2.5 mmol). MeMgCl (1 mL, 3 M in THF, 3 mmol) was
added dropwise over a minute and the reaction was left to stir for 2 hours
at rt. After 2 hours, a mixture of SM, mono- and dialkylated product was
obtained in the ratio 4:95:1 (measured by GC-MS). In the same pot, 1-
bromo-2-ethylbutane (0.35 mL, 2.5 mmol) was then added followed by
MeMgCl (1 mL, 3 mmol) and the reaction was left to stir at reflux for 3
hours. The reaction was quenched with 1M HCl (15 mL) followed by
diethyl ether (15 mL). The organic layer was separated, washed with H2O
(2 x 15 mL) and then with brine (10 mL). The organic solution was dried
over Na2SO4, filtered and concentrated to afford the alkylated product. A
mixture of 1-bromo-2-ethylbutane SM: ethyl monoalkylated 4b, di-hetero
product 5e and 2-ethylbutyl dialkylated product 5c was obtained in the ratio
1:1:97:1 (measured by GC-MS). The crude mixture was purified by column
chromatography (PE: Et2O, 99:1) to afford nitrile 5e as a colourless oil
(0.45 g, 79% yield).

max/cm-1: 2974, 2238 (conj.CN) 1602.
Spectral data is consistent with literature values.[24]
3-Phenylpropionitrile 7 by alkylation of acetonitrile
To a stirring solution of acetonitrile 6 (0.78 mL, 15 mmol) in anhydrous THF
(10 mL) was added diethylamine (80 µL, 0.75 mmol) and benzyl bromide
(1.8 mL, 15 mmol). MeMgCl (6 mL, 3 M in THF, 18 mmol) was added
dropwise over a minute and the reaction was left to stir at 0 °C for 1 hour.
The reaction was quenched with 1M HCl (15 mL) followed by diethyl ether
(15 mL). The organic layer was separated, washed with H2O (2 x 15 mL)
and then with brine (10 mL). The organic solution was dried over Na2SO4,
filtered and concentrated to afford the alkylated product.
The spectral data was consistent with that described above for 5e.
A mixture of benzyl bromide SM, product 7 and N-benzyl-diethylamine
(from the reaction of diethylamine and benzyl bromide) was obtained in the
ratio 6:92:2 (measured by GC-MS). The crude mixture was purified by
column chromatography on silica (PE: Et2O, 90:10) to give the product 7
(1.6 g, 80% yield). 1H NMR (400 MHz, CDCl3): δ 7.39-7.20 (m, 5H, Ar- H),
2.94 (t, J = 7.8 Hz, 2H, CH2CN), 2.60 (t, J = 7.6 Hz, 2H, ArCH2), 13C NMR
(100 MHz, CDCl3): δ138.2, 129.0, 128.4, 127.3, 119.4, 31.6, 19.4. IR: max
/cm-1: 2976, 2240 (conj.CN)
Preparation of 5e by sequential addition from previously prepared 4-ethyl-
2-phenylhexanenitrile 4c.
To a stirring solution of 4-ethyl-2-phenylhexanenitrile 4c (1.01 g, 5 mmol)
in anhydrous THF (10 mL) was added diethylamine (40 µL, 0.38 mmol)
and iodoethane (0.4 mL, 5 mmol). MeMgCl (1.7 mL, 3 M in THF, 5 mmol)
was added dropwise over a minute and the reaction was left to stir for 2
hours at reflux. Upon cooling, the reaction was quenched with 1M HCl (10
mL) followed by diethyl ether (10 mL). The organic layer was separated,
washed with H2O (2 x 10 mL) and then with brine (10 mL). The organic
solution was dried over Na2SO4, filtered and concentrated to afford the
alkylated product. A mixture of starting material 4c and product 5e was
obtained in the ratio 4:94 (measured by GC-MS). The crude mixture was
Spectral data is consistent with literature values.[25]
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10.1002/ejoc.201801462
European Journal of Organic Chemistry
FULL PAPER
Chem. 2008, 6, 1238-1243; (c) W. J. Kerr, A. J. B. Watson, D.
Hayes, Synlett 2008, 2008, 1386-1390.
2-Benzyl-2,4-diethyl-hexanenitrile 8 by one-pot hetero dialkylation of 3-
phenylpropionitrile 7
[11]
[12]
[13]
T. Cuvigny, H. Normant, Bull. Soc. Chim. Fr. 1968, 4990-4997.
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preparation of 1-alkylcyclohexanecarboxylic acid derivatives from
1-alkylcyclohexanecarbonitriles via the corresponding
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To a stirring solution of 3-phenylpropionitrile 7 (0.327 g, 0.33 mL, 2.5
mmol) in anhydrous THF (10mL) was added diethylamine (14 µL, 0.125
mmol) and iodoethane (0.2 mL, 2.5mmol). MeMgCl (1 mL, 3 M in THF, 3
mmol) was added dropwise at rt over a minute and the reaction was stirred
for 2 hours at rt. After 2 hours, a mixture of SM, mono- and diethylated
product was obtained in the ratio 1:96:3 (measured by GC-MS). In the
same pot, diethylamine (14 µL, 0.125 mmol), 1-bromo-2-ethylbutane (0.35
mL, 2.5 mmol), and MeMgCl (1 mL, 3 mmol) were then added and the
reaction was left to stir at reflux for 3 hours. The reaction was quenched
with 1M HCl (15 mL) followed by diethyl ether (15 mL). The organic layer
was separated, washed with H2O (2 x 15 mL) and then with brine (10 mL).
The organic solution was dried over Na2SO4, filtered and concentrated to
afford the alkylated product. A mixture of di-hetero product 8 and the
diethylated product was obtained in the ratio 98: 2 (measured by GC-MS).
The crude mixture was purified by column chromatography on silica (PE:
Et2O, 90:10) to yield the product 8 (0.53 g, 86% yield). 1H NMR (400 MHz,
CDCl3): δ 7.35-7.22 (m, 5H, Ar-H), 2.85 – 2.70 (ABq, 2H, CH2Ph), 1.63 –
1.55 (m, 2H, CH2CH3), 1.54 –1.35 (m, 7H, 3 x CH2 and CH), 1.06 (t, J =
7.4 Hz, 3H, CH3), 0.86 (t, J = 7.4 Hz, 3H, CH3), 0.82 (t, J = 7.4 Hz, 3H,
CH3). 13C NMR (100 MHz, CDCl3): δ135.7, 130.5, 128.4, 127.3, 123.5,
42.9, 41.8, 39.9, 36.8, 29.8, 26.5, 10.7, 9.1. IR: max /cm-1: 3031, 2963,
2231 (conj.CN). GC-MS m/z: 243(50), 215(86), 186 (83), 171 (57), 115
(29), 91 (100), 65 (64). HRMS (ESI) m/z: Calcd for C17H24N [M-H+]:
242.1909 found 242.1902.
[14]
[15]
[16]
[17]
[18]
[19]
[20]
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Acknowledgements
The authors acknowledge the support of the Irish Research
Council and Roche Clarecastle for the Postgraduate Scholarship
to OG
under
the
Enterprise Partnership Scheme
EPSPG/2014/93. We further thank Prof. John O’Reilly for his
valuable advice re analytical work.
Keywords: Nitrile • alkylation • Magnesium base • Synthesis •
Grignard
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10.1002/ejoc.201801462
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