Synthesis of Nitriles from Aldehydes with Elongation of the Molecule with Two Carbon Atoms

Article abstract of DOI:10.1002/ejoc.201801412

A new protocol for the synthesis of nitriles from carbonyl compounds with elongation of the molecule with two carbon atoms was developed. It involves a reaction of ethyl cyanoacetate with different aldehydes in the presence of iron pentacarbonyl as a redu

Full text of DOI:10.1002/ejoc.201801412

A Journal of
Accepted Article
Title: Synthesis of nitriles from aldehydes with elongation of the
molecule with two carbon atoms
Authors: Oleg I. Afanasyev, Alexander Zarochintsev, Tatiana
Petrushina, Anastasia Cherkasova, Gleb Denisov, Ilia
Cherkashchenko, Olga Chusova, Oh Jinho, Chun Man-Seog,
Dmitry L. Usanov, Sergei E. Semenov, and Denis Chusov
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201801412
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Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201801412
COMMUNICATION
Synthesis of nitriles from aldehydes with elongation of the
molecule with two carbon atoms
a
b, §
b, §
b, §
Oleg I. Afanasyev, Alexander Zarochintsev, Tatiana Petrushina, Anastasia Cherkasova, Gf leb
a
c
d
e
e
Denisov, Ilia Cherkashchenko, Olga Chusova, Jinho Oh, Man-Seog Chun, Dmitry L. Usanov,
Sergei E. Semenov, and Denis Chusov*
b
,a
Abstract: A new protocol for the synthesis of nitriles from carbonyl
compounds with elongation of the molecule with two carbon atoms
was developed. It involves a reaction of ethyl cyanoacetate with
different aldehydes in the presence of iron pentacarbonyl as a
reducing agent. This protocol is very simple and requires only
commonly available reagents, with no catalyst or complicated ligands
being employed.
great interest for chemists. There is only one described approach
for the preparation of nitriles mentioned above from aldehydes,
which is carried out in one step without isolation of intermediates.3
This reaction is based on reductive addition, which takes
advantage of the unique reductive potential of carbon monoxide.4
Reductive alkylation of carbonyl compounds with methyl
cyanoacetate in the presence of carbon monoxide, followed by
hydrolysis and decarboxylation of carboxyl group, leads to
desired nitriles with elongation of carbon chain with two atoms in
one step. (Scheme 2).
Introduction
Nitriles are important building blocks in organic synthesis,1
and various approaches to their synthesis are known. Aliphatic
2 2
nitriles, bound to an organic core with a –CH CH – bridge can be
utilized in the preparation of various natural compounds, including,
for example, potential HIV-therapy drug candidates or dopamine
2
analogs. Their conventional synthesis from carbonyl compounds
includes two or more steps (Scheme 1). Generally, the first step
is Wittig or Knoevenagel reaction, leading to the formation of
intermediate A with a double carbon-carbon bond. The second
step involves reduction of the double bond with conventional
reducing agents, e.g. hydrogen to give product B. A number of
factors can reduce the yield of this reaction sequence. For
instance, the intermediate Knoevenagel adduct can react with
another equivalent of CH-acid, giving Michael addition product C.
Furthermore, reduction with hydrogen can lead to degradation of
some functional groups. These factors together create challenges
in the preparation of libraries of such nitriles, which are required
for biological activity screening.
Atom and step-economical approach for synthesis of
complex molecules from readily available starting materials is of
[
a]
Dr. Oleg I. Afanasyev, Gleb Denisov, Dr. Denis Chusov
Nesmeyanov Institute of Organoelement Compounds of Russian
Academy of Sciences
Scheme 1. The classical approach for nitrile synthesis from aldehydes.
119991, Vavilova St. 28, Moscow, Russian Federation
www.ChemistryFor.Me
E-mail: denis.chusov@gmail.com
[
[
b]
Alexander Zarochintsev, Tatiana Petrushina,Anastasia Cherkasova,
Sergei E. Semenov Moscow South-Eastern School named after V.I.
Chuikov (Moscow Chemical Lyceum), 111033, Tamozhenniy proezd
Results and Discussion
Carbon monoxide has its limitations in laboratory
applications since oftentimes it requires the use of special
equipment, such as autoclaves. In addition, it usually requires
rhodium or ruthenium catalysis, which adds a special purification
step for pharmaceutical synthesis to match heavy metal content
specifications. Some CO surrogates are known, and their
efficiency in carbonylation and reduction processes has been
successfully demonstrated.5 Among them iron pentacarbonyl
attracts special attention due to its low price and availability.
4, Moscow, Russian Federation
с]
Ilia Cherkashchenko M. V. Lomonosov Moscow State University,
Department of Chemistry, Leninskie Gory 1, Moscow, 119991,
Russian Federation
Dr. Olga Chusova Faculty of Science, RUDN University, 6 Miklukho-
Maklaya St., Moscow 117198, Russian Federation
Dr. Jinho Oh, Dr. Man-Seog Chun Korea Science Academy of
KAIST, 105-47, Baegyanggwanmun-ro, Busanjin-gu, 614-822
Busan, Republic of Korea.
Dr. Dmitry L. Usanov Broad Institute of MIT and Harvard, 415 Main
Street, Cambridge, MA 02142, United States
Supporting information for this article is given via a link at the end of
the document
[
d]
e]
[
[f]
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European Journal of Organic Chemistry
10.1002/ejoc.201801412
COMMUNICATION
Iron pentacarbonyl6 and its derivatives, such as sodium
Fe(CO) + 3NaOH → NaHFe(CO) + Na CO + H O
5
4
2
3
2
4
tetracarbonylhydridoferrate NaHFe(CO) , are known as reducing
agents in reductive amination reactions,7 but to the best of our
knowledge they have not been employed in reductive alkylation
reactions, such as the one shown in Scheme 2.
Scheme 3. Tetracarbonylhydridoferrate anion generation
Table 1. Optimization of the reaction conditions.
Entry[a]
X
Y
Temperature,
NaHFe(CO)
generation
time[
Yield, %[c ]
4
°C
b]
Scheme 2. One-pot nitrile synthesis from aldehydes and methyl cyanoacetate.
Complex
mixture
1
9
9
3
3
140
140
140
140
140
140
120
140
140
140
140
<1 min
15 min
30 min
1 h
Complex
mixture
2
Standard conditions for iron carbonyl hydride generation
involves a reaction of iron pentacarbonyl with hydroxide anion
3
9
3
40
54
63
52
29
43
87
83
84
(
Scheme 3).8
4
9
3
We assumed that the above-mentioned conditions might be
5
9
3
2 h
suitable for reductive alkylation occurring in tandem with
hydrolysis and decarboxylation, which would eliminate the need
for gaseous reducing agents. The standard protocol for reductive
amination reactions using tetracarbonylhydridoferrate involves
6[d]
7
9
3
2 h
9
3
2 h
the initial formation of NaHFe(CO)
4
via the reaction of iron
8
3
3
2 h
pentacarbonyl with sodium hydroxide in an alcoholic medium
followed by the addition of substrates. Notably, this reaction
produces water, which is required for the subsequent hydrolysis
step (Scheme 2).
9
9
2
2 h
1
0
1
9
1.5
1.5
2 h
We investigated the influence of temperature, reactant ratios,
1
4.5
2 h
and the length of NaHFe(CO)
4
generation on the product yield
(
Table 1). Based on previous investigations of reductive alkylation
a
0
.9 mmol scale, 1 eq. of aldehyde (108 mg) and
1
eq. of ethyl
3
reactions 140°C was chosen as appropriate temperature to
generate tetracarbonylhydridoferrate and allow reductive
Knoevenagel addition followed by hydrolisys. It was found that
immediate addition of organic compounds to the mixture of iron
pentacarbonyl and an alcoholic solution of sodium hydroxide does
not lead to the formation of the desired product. The same
outcome was observed for 15 minutes of reactive agent
cyanoacetate (102 mg), 4 ml of ethanol were used.
b
the time before addition of organic compounds
c
NMR yield,
d
1.2 equivalents of ethyl cyanoacetate were used
With these results in hand, we proceeded to investigation of
the substrate scope of the developed methodology under the
optimized reaction conditions (Scheme 4). A wide range of
aldehydes could be successfully employed, including those
containing various functional groups prone to reduction by
dihydrogen.9 Ortho-, meta- and para- substituted aldehydes
formed nitriles in good yields (1a, 1f, 1i). Electronic properties of
substituents in the aromatic rings do not have a substantial
influence on the reaction yield: 2,3,4-trimethoxybenzaldehyde
and p-fluorobenzaldehyde gave corresponding products 1p and
1e in similar yields. Halogen-containing aromatic compounds
survive under these conditions (1b, 1d, 1e, 1j), allowing further
functionalization via cross-coupling reactions. Both aromatic and
aliphatic (1h, 1l) aldehydes can be employed. It is known that
aldehydes with a CH-fragment in α-position to the carbonyl group
can undergo self-aldol condensation under basic conditions; no
evidence of this reaction was found during preparation of products
generation. One hour of incubation of NaOH with Fe(CO)
5
followed by addition of substrates provided a moderate yield of
the desired product. Two hours of incubation were chosen as a
good balance between the reaction time and the product yield.
We tried to decrease the reaction temperature, however, a steep
decrease of the amount of the isolated product was detected
(
entry 7). Surprisingly, excess of ethyl cyanoacetate also leads to
decreased yield (entry 6). This phenomenon might be associated
with Michael addition to the intermediate Knoevenagel product
(
reaction mixture. Decreasing the ratio of sodium hydroxide and
iron pentacarbonyl to 1:1 lead to a substantially inferior yield
(
Scheme 1, C); the corresponding products were detected in
entry 8). Notably, the use of lower amounts of iron pentacarbonyl
leads to superior results (entries 10-11).
1h and 1l. The developed protocol tolerates even keto-group (1o)
and hemiaminal moiety (1m), demonstrating its high selectivity.
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European Journal of Organic Chemistry
10.1002/ejoc.201801412
COMMUNICATION
We have shown, that different heterocycles like pyrazoles and
pyridines (1k, 1m) can also be employed in this reaction, which is
notable in light of the presence of these fragments in a large
number of pharmaceutical products. The protocol does not allow
an aromatic nitro group to stay intact: the reaction with p-
nitrobenzaldehyde lead to the corresponding aminoderivative in
40% yield (Scheme 5). This fact is in agreement with early works
on tetracarbonylhydridoferrate applications in organic chemistry
and therefore.10
Scheme 5. Nitro-group reduction.
Conclusions
We developed a novel one-step preparation of aliphatic
nitriles from readily available aldehydes using iron pentacarbonyl
as a reducing agent. The protocol requires only commonly
accessible chemicals and glassware and no noble-metal catalysis
is required. The reaction products represent important building
blocks in medicinal chemistry. Given the fact that these
compounds are usually prepared in two or more steps and often
require special equipment, this protocol serves as a highly
advantageous and convenient alternative.
Experimental Section
General procedure for reductive alkylation
A dry high pressure Schlenk tube from borosilicate glass for 50 ml with a
magnetic stirrer was flushed with argon. The indicated amounts of iron
pentacarbonyl, sodium hydroxide and ethanol were added. The Schlenk
tube was sealed and placed into a preheated oil bath at 140°C (protected
with safety shield). After two hours of heating the Schlenk tube was cooled
to room temperature, opened in argon flow and charged with indicated
amounts of ethyl cyanoacetate and carbonyl compound. The Schlenk tube
was sealed, and heating was continued for indicated time (usually 6 hours).
The resulting reaction mixture was suspended in 3 ml of methanol, 2 ml of
triethylamine were added, suspension was filtered off, liquid phase was
evaporated with triethylamine to dryness. Solids were dissolved in 2M HCl,
and product was extracted with dichloromethane. Extract was combined
with residue of evaporation, followed by removing of volatile compounds
on rotary evaporator. Resulting crude product can be purified by column
chromatography.
Acknowledgments
The reported study was funded by RFBR within research project
18-33-00037. O.C. is grateful to the generous support of RUDN
Pregeneration of NaHFe(CO)
Most substrates were prepared on 0.9 mmol scale. Isolated yield with 3
4
for two hours. Yield was determined by NMR.
«5-100» program. J.O and M.S.C. are grateful to the Korea
Science Academy of KAIST with funds from the Ministry of
Science and ICT. The contribution from the Center of molecular
composition studies of INEOS RAS is gratefully acknowledged.
a
b
equivalents of Fe(CO)
equivalents of Fe(CO)
5
and 9 equivalents of NaOH. Isolated yield with 1.5
and 4.5 equivalents of NaOH
5
Scheme 4. Substrate scope of nitriles synthesis using iron pentacarbonyl as a
Keywords: Aldehyde• Nitrile • Iron carbonyl• CO surrogate •
reducing agent.
Reductive alkylation, Reduction, Carbonyl ligands
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European Journal of Organic Chemistry
10.1002/ejoc.201801412
COMMUNICATION
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European Journal of Organic Chemistry
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COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
COMMUNICATION
Synthetic methods
Oleg I. Afanasyev, Alexander
Zarochintsev, Anastasia Cherkasova,
Tatiana Petrushina, Gleb Denisov, Ilia
Cherkashchenko, Olga Chusova, Jinho
Oh, Man-Seog Chun, Dmitry L. Usanov,
Sergei E. Semenov, Denis Chusov*
A new protocol for the synthesis of nitriles from carbonyl compounds with
elongation of the molecule with two carbon atoms was developed. It involves a
reaction of ethyl cyanoacetate with different aldehydes in the presence of iron
pentacarbonyl as a reducing agent. This protocol is very simple and requires only
commonly available reagents, with no catalyst or complicated ligands being
employed.
Synthesis of nitriles from aldehydes
with elongation of the molecule with
two carbon atoms
Aldehydes to nitriles +2 carbon atoms
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