Synthesis of Nitrile-Bearing Quaternary Centers by an Equilibrium-Driven Transnitrilation and Anion-Relay Strategy

Article abstract of DOI:10.1002/anie.201903215

The efficient preparation of nitrile-containing building blocks is of interest due to their utility as synthetic intermediates and their prevalence in pharmaceuticals. As a result, significant efforts have been made to develop methods to access these motifs which rely on safer and non-toxic sources of CN. Herein, we report that 2-methyl-2-phenylpropanenitrile is an efficient, non-toxic, electrophilic CN source for the synthesis of nitrile-bearing quaternary centers by a thermodynamic transnitrilation and anion-relay strategy. This one-pot process leads to nitrile products resulting from the gem-difunctionalization of alkyl lithium reagents.

Full text of DOI:10.1002/anie.201903215

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Accepted Article
Title: Synthesis of nitrile-bearing quaternary centers via an equilibrium-
driven transnitrilation and anion-relay strategy
Authors: Sébastien Alazet, Michael S West, Purvish Patel, and Sophie
Rousseaux
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10.1002/anie.201903215
Angewandte Chemie International Edition
COMMUNICATION
Synthesis of Nitrile-Bearing Quaternary Centers by an
Equilibrium-Driven Transnitrilation and Anion-Relay Strategy
Sébastien Alazet,[a] Michael S. West,[a] Purvish Patel,[a] and Sophie A. L. Rousseaux*[a]
Abstract: The efficient preparation of nitrile-containing building
blocks is of interest due to their utility as synthetic intermediates and
their prevalence in pharmaceuticals. As a result, significant efforts
have been made to develop methods to access these motifs which
rely on safer and non-toxic sources of CN. Herein, we report that 2-
methyl-2-phenylpropanenitrile is an efficient, non-toxic, electrophilic
CN source for the synthesis of nitrile-bearing quaternary centers via
a thermodynamic transnitrilation and anion-relay strategy. This one-
pot process leads to nitrile products resulting from the gem-
difunctionalization of alkyl lithium reagents.
reversible)[9] and that tuning the basicity of the leaving group in
the electrophilic CN source is crucial for pushing the equilibrium
towards transnitrilated organolithium intermediate D, which can
be trapped with an electrophile to generate the gem-
difunctionalized product. With a more reactive transnitrilation
reagent such as dimethylmalononitrile,[5b] the leaving group is
not basic enough for complete conversion to D, and subsequent
electrophile-trapping leads to mixtures of products.
a) Nitrile-containing pharmaceuticals
OMe
OMe
MeO
NC
CN
O
NC
The rapid generation of molecular complexity is a long-standing
objective in organic chemistry.[1] One-pot transformations, which
avoid the purification of synthetic intermediates, not only
accelerate the synthesis of complex molecules but also minimize
the amount of waste generated in the process. Complex nitrile-
containing molecules are of interest to the community due to
their versatility as synthetic intermediates for the generation of
amines, ketones, carboxylic acids and aldehydes.[2] They are
also found in numerous pharmaceuticals (Scheme 1a).[3] As a
result, a wide variety of methods for the preparation of nitrile-
containing building blocks have been developed with recent
efforts focusing on the use of safer and non-toxic sources of
CN.[4] Of particular interest are reactions that avoid the use or
generation of cyanide ions.[5] Herein, we report a method for the
generation of all-carbon quaternary centers bearing a nitrile
group from secondary alkyl lithiums (or halides) using a one-pot
transnitrilation, anion-relay[6] and electrophile-trapping strategy
(Scheme 1c). This method uses 2-methyl-2-phenylpropanenitrile
as a non-toxic electrophilic CN source, avoiding the use of
cyanide salts that are typically involved in the synthesis of
alkylnitriles from alkyl halides.
We were inspired by a recent report by Reeves and co-
workers who have demonstrated that dimethylmalononitrile is an
efficient, non-toxic, carbon-bound electrophilic CN source for the
transnitrilation of aryl Grignard reagents and aryllithiums
(Scheme 1b).[5a, b] The reaction is proposed to occur via addition
of the organometallic reagent to a nitrile group and retro-Thorpe
fragmentation to yield the corresponding aryl nitriles. Given our
interest in the synthesis of nitrile-containing molecules,[7] we
wondered if a similar strategy could be applied for the gem-
difunctionalization of alkyl lithium reagents via an equilibrium-
driven transnitrilation and anion-relay process (Scheme 1c).
Addition of the organometallic reagent to an appropriately
functionalized electrophilic CN source would yield lithium imine
A, which fragments to generate nitrile intermediate B along with
tertiary organolithium intermediate C.[8] It should be noted that
this transnitrilation process is under thermodynamic control (i.e.
i-Pr
NC
Me
OMe
OMe
N
N
N
N
CO2H
Anastrazole
Verapamil
Cilomilast
b) Transnitrilation for Ar–CN synthesis
M
N
NC CN
N
M
+
CN
Ar
Ar
Ar
Me
Me
Me Me
M = MgX, Li
c) Thermodynamic transnitrilation and anion-relay strategy for the
synthesis of nitrile-bearing quaternary centers (this work)
E+
NC
E
Li
NC Li
NC
Ph
+
D
R1 R2
R1 R2
Me Me
R1 R2
thermodynamic
transnitrilation
and anion-relay
Me Me
Ph
CN
Li
N
non-toxic
electrophilic CN
reagent
NC
H
Li
Ph
R1
Ph
R1 R2
Me Me
C
R2
Me Me
A
B
Scheme 1. Transnitrilation strategies for the synthesis of pharmaceutically-
relevant nitrile-containing building blocks. E+ = electrophile.
We initiated our study by evaluating the transnitrilation of
s-BuLi (1a) with various electrophilic nitrile sources (2). Benzyl
bromide was chosen as a terminal electrophile to trap the anion
resulting from fragmentation of the lithium imine intermediate
(Scheme 2). We began by examining a range of nitrile sources
(2a-2e) with varying electronic properties. Trimethylacetonitrile
2a is not an efficient transnitrilation reagent since none of the
desired product 3a was observed in this transformation. Only the
imine, resulting from addition of 1a to 2a, was obtained. We
hypothesized that fragmentation of the lithium imine A to release
t-BuLi was too challenging and that a transnitrilation reagent
containing a better leaving group would be more efficient for this
transformation. While dimethylmalononitrile would be efficient for
the transnitrilation process, as reported by Reeves and
coworkers,[5b] the anion resulting from the retro-Thorpe
fragmentation would not be basic enough to drive the anion-
relay process. With these considerations in mind, we examined
[a]
Dr. S. Alazet, M. S. West, P. Patel. Prof. Dr. S. A. L. Rousseaux
Davenport Research Laboratories, Department of Chemistry
University of Toronto
80 St George Street, Toronto, Ontario, M5S 3H6 (Canada)
E-mail: sophie.rousseaux@utoronto.ca
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201903215
Angewandte Chemie International Edition
COMMUNICATION
Table 1. Optimization of the reaction conditions for imine fragmentation.
the use of benzylic nitrile 2b as an electrophilic CN source in our
reaction. Product 3a was obtained in 85% from 2b after a brief
optimization of the reaction conditions, which revealed that
addition of s-BuLi to the electrophilic nitrile source and
subsequent fragmentation of the lithium imine intermediate (A)
i) base (1.3 equiv)
solvent, 0 °C, 5 min;
then RT, 2 h
NH
NC Bn
Me
Me
Ph
Me
Me
ii) BnBr (2.0 equiv)
RT, 1 h
Me Me
was efficient in THF at room temperature in
1
hour.
4
3a
Transnitrilation reagents 2c and 2d afforded the desired product
but in low yields. In both cases, formation of the lithium imine (A)
was efficient, however fragmentation of this intermediate was
inefficient for 2d while anion-relay and alkylation by benzyl
bromide was low yielding for the reaction using 2c. This
demonstrates the need to subtly tune the electronic properties of
the transnitrilation reagent to observe the desired
thermodynamic gem-difunctionalized product. Finally, the
reaction of 1a with 2e led to a complex mixture of products,
possibly due to the poor stability of the highly electron-deficient
lithium imine intermediate. It is interesting to note that Grignard
reagents did not react with 2b at room temperature. High
temperatures (refluxing in THF) were required for metal imine
formation, but the product resulting from the nitrile transfer
process was not obtained.
Entry
Base
Solvent
Yield (%)[a]
1
2
3
4
5
6
7
n-BuLi
NaHMDS
KHMDS
Et2Zn
THF
THF
69
65
75
0
THF
THF
MeMgBr
n-BuLi
THF
0
Et2O
0
n-BuLi
Dioxane
0
[a] Determined by 1H NMR using CH2Br2 as an internal standard. HMDS =
hexamethyldisilazane.
R
2 R3
R1
2 (1.0 equiv)
i)
CN
Li
N
Li
THF, 1 h, RT
NC Bn
R3
Me
Me
Having determined that 2b is an optimal reagent for
transnitrilation and anion-relay functionalization of alkyllithiums,
we next explored the scope of electrophiles that can be used in
this transformation.[11] A commercially available solution of
s-BuLi (1.4 M in cyclohexane) was used as the model substrate
(Scheme 3). Alkyl halides were efficient electrophiles in this
transformation, affording products 3a, 3b and 3f in good yields.
Carbonyl-based electrophiles, such as benzoyl chloride, N-tosyl
imine, an aldehyde and a ketone, provided gem-difunctionalized
products 3c, 3d, 3e and 3i, respectively, in good yields. Tertiary
Me
Me
Me
Me
ii) BnBr
(3.0 equiv)
R1 R2
1a (1.0 equiv)
3a
A
Me Me
Me Me
Ph
CN
Ph Me
Ph
CN
Me Me
F5C6
Me
CN
CN
2d, 10%
CN
N
2a, 0%
2b, 85%
2c, 25%
2e, 0%
Scheme 2. Evaluation of electrophilic CN sources. Yields determined by 1H
NMR using CH2Br2 as an internal standard. THF = tetrahydrofuran.
epoxide 3j was obtained in
a
58% yield using 2-
bromoacetophenone as the electrophile. Products 3g and 3h
were obtained via nucleophilic aromatic substitution of the
corresponding 2-chlorobenzoxazole and 2-chlorobenzothioazole
in 75% and 73% yield, respectively. Finally, trapping the
To better understand the conditions required for
fragmentation of the metal imine intermediate, imine 4 was
treated with various bases and subsequently treated with benzyl
bromide to yield 3a (Table 1). n-BuLi, NaHMDS and KHMDS
(entries 1-3) efficiently enabled the formation of 3a in 69%, 65%
and 75% yield, respectively, using THF as the solvent mixture.
Treating imine 4 with Et2Zn or MeMgBr did not result in
fragmentation, and 4 was recovered (entries 4-5). Other ethereal
solvents were also examined in the fragmentation of 4 with n-
BuLi since the alkyllithium reagents that will be used for this
transnitrilation and anion-relay process are generally prepared in
Et2O or in Et2O/hydrocarbon solvent mixtures.[10] The imine
fragmentation process appears to be highly solvent-dependent.
Product 3a was not observed in reactions performed in Et2O or
1,4-dioxane, as well as in other ethereal solvents besides THF
(entries 6-7 and Table S1). Thus, a solvent switch to THF may
be necessary when exploring the reaction scope with respect to
various alkyllithium reagents (see Scheme 4).
transnitrilated
organolithium
intermediate
with
methyl
benzenesulfinate or phenyl disulfide yielded products 3k and 3l
in 61% and 72%, respectively.
The scope of this reaction with respect to the alkyllithium
reagent is shown in Scheme 4. Starting from alkyl iodides,
various substituted organolithium reagents were prepared via
lithium-halogen exchange.[10] Using Knochel’s procedure,[12]
alkyllithiums were prepared in situ and trapped with the
electrophilic CN source 2b. Since the alkyllithium reagents in
these reactions are generated in a mixture of Et2O and n-hexane,
the resulting lithium imines A do not fragment to initiate the
anion-relay process. Removing the solvent and dissolving A in
THF leads to fragmentation and deprotonation to generate the
transnitrilated organolithium intermediates (D in Scheme 1),
which can be trapped with various electrophiles. Various
secondary alkyl iodides were successfully converted to the
corresponding functionalized nitrile derivatives 6a-6j in moderate
to good yields (Scheme 4). Various electrophiles, including
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10.1002/anie.201903215
Angewandte Chemie International Edition
COMMUNICATION
Me Me
i)
required to obtain products 6c and 6d in 54% and 41%,
respectively.
Ph
CN (2b)
Li
NC
Me
E
THF, 1 h, RT
Me
Me
ii) E+
Me
i) t-BuLi (2.0 equiv)
n-hexane / Et2O (3:2), -100 °C
1a (1.0 equiv)
3
Me Me
Li
N
Ph
Ph
NC
Ph
NC
I
ii)
R1
Ph
CN
(2b, 1.2 equiv)
NC
E
NC Bn
NC
O
Me
NHTs
Me
Ph
Me
Me
R1 R2
iii) solvent switch to THF;
then 1 h, RT
R1 R2
R2
Me
Me
Me
Me
Me Me
5 (1.0 equiv)
6
A
iv) E+ (2.0 equiv)
3a, 76%
3b, 69%
3c, 73%
3d, 74%
1.2:1 d.r.
O
O
O
O
O
O
N
N
NC
NC
OH
O
S
NC
Me
3e, 76%
OH
Me
NC
Me
NC
Me
NC
Me
3h, 73%
NC
Me
Me
Me
Me
Me
3f, 70%
3g, 75%
1:1 d.r.
6a, 46%
6b, 48%
6c, 54%
1.5:1 d.r.
Ph OH
Ph
NC
O
O
NC Bn
Me
Ph
NC
CF2Cl
Me
NC
S
Ph
Me
NC
Me
3l, 72%
S
Ph
Me
NC
NC
Ph
Me
Me
Me
Me
Me
Me
Me
Me
6f, 44%
3i, 61%
1:1 d.r.
3j, 58%
1:1 d.r.
3k, 61%
1.5:1 d.r.
6d, 41%
6e, 58%
Me
Scheme 3. Reaction scope for the tandem transnitrilation and electrophilic
gem-difunctionalization of s-BuLi. Reported yields are isolated yields for an
average of two reactions. See the Supporting Information for experimental
details. Ts = tosyl or toluenesulfonyl.
Me
Me
NC
N
S
H
H
O
H
Me
H
NC
Me
O
Ph
Me
6g, 58%
6h, 60%
F3C
aldehydes (6c, 6j) and 2-chlorobenzothioazole (6g), were also
used in these reactions, generating diverse products. Functional
groups including an acetal (6a, 6h), allyl (6c, 6d), benzyl-
protected alcohol (6i) and aryl bromide (6j) provide handles for
Br
NC Bn
Me
HO
NC
BnO
OH
CN
Ph
Me
Me
Me
HO
further
product
diversification.
A
reaction
with
an
6i, 61%
6j, 60%
2.3:1 d.r.
6k, 61%
1:1 d.r.
1.5:1 d.r.
HO
enantioenriched alkyl iodide led to racemic product, and
transnitrilation adjacent to heteroatoms (oxygen and nitrogen)
are not successful since the directing groups used for the
lithiation reaction make the intermediate too stable to react with
reagent 2b.
CF3
F
O
CN
O
CN
Me
CN
6m, 62%
Overall, these reactions lead to the formation of two new C–
C bonds and the generation of an all-carbon quaternary center
bearing a nitrile functional group. This 4-step, one-pot sequence
occurs in good yields from readily available secondary alkyl
halide starting materials. Most notably, in comparison with
traditional synthetic sequences involving the nucleophilic
cyanation of alkyl halides, this transformation avoids the use of
hazardous cyanide anions and is not plagued by elimination
side-reactions as is often observed with secondary alkyl
halides.[13], [14] Using our transnitrilation and anion relay strategy,
the direct cyanation and functionalization of iodocyclohexyl
derivatives was achieved with good yields. Simple cyclic building
block 6a or natural product analogue 6h were obtained in this
one-pot protocol in 61% and 60% yield, respectively. The
formation of products 6c and 6d was more challenging due to
low conversion of the alkyl iodide to the corresponding
organolithium during the first step of the reaction. Side-products
6l, 64%
1.5:1 d.r.
6n, 59%
2.3:1 d.r.
Scheme 4. Reaction scope for the tandem transnitrilation and electrophilic
gem-difunctionalization of alkyllithium reagents. Reported yields are isolated
yields for an average of two reactions. See the Supporting Information for
experimental details.
The synthesis of nitrile-bearing tertiary centers was achieved
using primary alkyl lithium reagents (Scheme 4, 6k-6n). Using
n-BuLi (6k), we found that the fragmentation of imine A (where
R1 = C3H7 and R2 = H) required higher dilution in THF (0.25 M)
and a longer time reaction (2 h).[16] Primary alkyl iodides also
participated in the one-pot lithium-halogen exchange,
transnitrilation, anion-relay and electrophile trapping reaction.
Nitriles 6l-6n were obtained in good yields using this sequence.
resulting from elimination and reduction reactions during the Li-
15]
halogen exchange protocol were also observed.[12,
A slight
excess of iodoalkane (2.0 equiv) and t-BuLi relative to 2b was
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10.1002/anie.201903215
Angewandte Chemie International Edition
COMMUNICATION
relay reaction, as the deprotonation could take place in THF,
which avoids a solvent switch step in the process. Using this
strategy, α-arylnitriles 10a-10e were prepared from very simple
starting materials. For example, p-xylene was converted to
product 10a in 70% yield, and 10b was obtained selectively from
p-butyltoluene in 61% yield. Benzyl cyanide derivatives are
generally obtained from the corresponding benzyl halides using
nucleophilic cyanide salts. These benzyl halides are typically
prepared from the corresponding toluene derivatives via radical
halogenation, which can lead to regioselectivity challenges in
more substituted derivatives. Using our method, complete
selectivity for the transnitrilated products 10a and 10b is
observed. Products resulting from dicyanation or regioisomers
(in the case of 10b) are not observed. For the synthesis of 10c
and 10d, TMPH (2,2,6,6-tetramethylpiperidine) was used as an
additive to generate a potassium/lithium amide. This helps to
a) via carbolithiation of styrene
i) RLi (1.2 equiv), Et2O
-78 °C, 1 h; then RT, 30 min
Me Me
ii)
Ph
RT, 1 h
CN
(2b, 1.2 equiv)
Li
NC
Ph
Ph
R
R
Ph
iii) solvent switch to THF;
then RT, 2 h
iv) allyl bromide
7 (1.0 equiv)
8
Me
Me
CN
CN
CN
Me
Me
C4H9
Me
Ph
Ph
Ph
8a, 69%
8b, 79%
8c, 83%
1.2:1 d.r.
b) via benzylic deprotonation
i) t-BuOK, t-BuLi
THF, -78 °C, 1 h
K/Li
NC
Ar
E
avoid the formation of side-products resulting from directed ortho
Ar
R
d]
metalation by the OMe group.[18b,
Complete selectivity for
ii) 2b (1.2 equiv)
RT, 2 h
R
Ar
R
9 (1.0 equiv)
10
iii) E+
deprotonation of the methyl group was observed and the
corresponding secondary benzylic nitriles were synthesized in
excellent yields. Product 10d is an intermediate in the synthesis
of verapamil, a drug on the World Health Organization’s List of
Essential Medicines (Scheme 1a). Finally, using a method
reported by Strohmann and coworkers for the direct metalation
of sensitive benzyl derivatives such as (2-phenylethyl)-
dimethylamine,[18c] product 10e was obtained in 46% yield. While
the secondary benzyllithium intermediate in this reaction is
known to undergo β-elimination reactions,[18c] this side reaction
can be avoided by using a mixture of t-BuOK and t-BuLi in THF
at -78 °C.
S
SMe
CN
SPh
HO
CN
CN
n-Bu
MeO
Me
10a, 70%, 2.3:1 d.r.
(from p-xylene)
10b, 61%
10c, 77%
Me
Me
CN
NC
MeO
MeO
NMe2
10d, 73%
10e, 46%
In summary, we have developed a one-pot method for the
synthesis of various nitrile-containing building blocks based on
an equilibrium driven transnitrilation and anion-relay strategy. A
broad range of electrophiles and alkyl lithium reagents,
generated via lithium-halogen exchange, carbolithiation or
benzylic deprotonation, participate in this reaction. The nature of
the transnitrilation reagent is crucial for the success of this one-
pot gem-difunctionalization process; not only must it readily
generate lithium imine adducts (A) under mild conditions, but it
must also fragment to generate a base responsible for anion-
relay. Other applications of transnitrilation strategies for the
synthesis of nitrile-containing building blocks are currently being
explored in our laboratory.
Scheme 5. Synthesis of α-arylnitriles via a) carbolithiation of styrene and b)
selective deprotonation of toluene derivatives. Reported yields are isolated
yields for an average of two reactions. See the Supporting Information for
experimental details.
Diverse α-arylnitriles, which are not only versatile synthetic
intermediates but are also prevalent in pharmaceuticals,[3] could
be prepared using our transnitrilation strategy (Scheme 5). Two
strategies for the generation of benzylithium reagents were
investigated: carbolithiation of styrene (Scheme 5a)[17] and
selective deprotonation of toluene derivatives (Scheme 5b).[18]
Using the carbolithiation protocol, three new C–C bonds can be
formed in
a one-pot process to generate functionalized
Acknowledgements
α-arylnitriles from styrene and 2b as the electrophilic CN source.
As a proof of concept, products 8a-8c were prepared in 69-80%
using n-BuLi, s-BuLi and t-BuLi as nucleophiles. A solvent
switch to THF was required here too to initiate fragmentation of
the lithium imine intermediate.
We thank NSERC (Discovery Grants and Canada Research
Chairs 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.
Selective benzylic deprotonation using
a
superbase,
generated by the addition of t-BuOK to an alkyllithium (n-BuLi or
t-BuLi),[18a] was also explored as a means to access α-arylnitriles
from toluene derivatives (Scheme 5b). The addition of t-BuOK
increases the basicity of the organolithium species, which can
efficiently deprotonate benzylic positions. We chose to use this
metalation protocol for our one-pot transnitrilation and anion-
Conflict of interest
The authors declare no conflict of interest.
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10.1002/anie.201903215
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COMMUNICATION
Steward, F. F. Fleming, Angew. Chem. Int. Ed. 2017,
56, 7257-7260.
S. Seel, G. Dagousset, T. Thaler, A. Frischmuth, K.
Karaghiosoff, H. Zipse, P. Knochel, Chem. Eur. J.
2013, 19, 4614-4622.
Keywords: transnitrilation • anion-relay strategy • alkyl nitriles •
alkyl lithium reagents • fragmentation
[12]
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G. S. Parries, T. K. Sawyer, J. Org. Chem. 1978, 43,
1017-1018.
For comparison, (3-iodobutyl)benzene 5e was
converted to (3-cyanobutyl)benzene in 50% yield via
nucleophilic cyanation using NaCN. This nitrile product
could be converted to 6e via deprotonation/alkylation.
The overall yield for the synthetic sequence is 45%.
See the Supporting Information for details.
[1]
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See the Supporting Information for details.
[16]
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a) A. Gómez-SanJuan, N. Sotomayor, E. Lete,
Beilstein J. Org. Chem. 2013, 9, 313-322; b) S.
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10.1002/anie.201903215
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
A one-pot thermodynamic
transnitrilation and anion-relay
strategy has been developed
for the preparation of nitrile-
R1 R2
bearing quaternary centers
Me Me
Sébastien Alazet, Michael S.
West, Purvish Patel, Sophie A. L.
Rousseaux*
I
Page No. – Page No.
Li
from simple building blocks.
NC
E
i)
Ph
CN
Synthesis of Nitrile-Bearing
Quaternary Centers by an
Equilibrium-Driven
Transnitrilation and Anion-
Relay Strategy
Ar
This one-pot transformation
forms up to 3 new C–C bonds
and involves transfer of a nitrile
group from a non-toxic
R1 R2
R1 R2
ii) E+
H
Nitrile-bearing
quaternary
centers
Ar
R2
cyanating reagent.
This article is protected by copyright. All rights reserved.