HCl·DMPU-assisted one-pot and metal-free conversion of aldehydes to nitriles

Article abstract of DOI:10.1039/d0gc00757a

We report an efficient HCl·DMPU assisted one-pot conversion of aldehydes into nitriles. The use of HCl·DMPU as both an acidic source as well as a non-nucleophilic base constitutes an environmentally mild alternative for the preparation of nitriles. Our protocol proceeds smoothly without the use of toxic reagents and metal catalysts. Diverse functionalized aromatic, aliphatic and allylic aldehydes incorporating various functional groups were successfully converted to nitriles in excellent to quantitative yields. This protocol is characterized by a broad substrate scope, mild reaction conditions, and high scalability. This journal is

Full text of DOI:10.1039/d0gc00757a

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DOI: 10.1039/D0GC00757A
COMMUNICATION
HCl•DMPU-Assisted One-pot and Metal-free Conversion of
Aldehydes to Nitriles
a
a
b
a,*
Sagar R. Mudshinge, Chinmay S. Potnis, Bo Xu, Gerald B. Hammond
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
We report an efficient HCl•DMPU assisted one-pot conversion of aldehydes
into nitriles. The use of HCl•DMPU as both an acidic source as well as a non-
nucleophilic base constitutes an environmentally mild alternative for the
preparation of nitriles. Our protocol proceeds smoothly without the use of
toxic reagents and metal catalysts. Diverse functionalized aromatic, aliphatic
and allylic aldehydes incorporating various functional groups were
successfully converted to nitriles in excellent to quantitative yields. This
protocol is characterized by a broad substrate scope, mild reaction
conditions, and high scalability.
O
O
O
CN
N
HN
O2N
HO
N
N
NH2
CN
OH
Vilazodone
1
Entacapone
2
CN
CN
O
O
O
O
S
HO
OH
N
N
Introduction
H
H
N
HO
O
Cl
O
With the increasing awareness of sustainable chemistry
principles, much effort is devoted to reducing the toxicity and
harsh conditions of the reactions. In this context, an oxidant-
and metal-free synthesis represent the ideal strategy for
sustainable chemistry. The nitrile group is one of the most
important functionalities found in natural products, biologically
Febuxostat
4
Lodoxamide
3
Due to these significant applications, a need to develop a more
efficient and sustainable methodology has been pursued in the
last few decades. There are various traditional methods that are
frequently used for the construction of the nitrile moiety.
Typical methods include the Sandmeyer reaction ,
Rosenmund-von Braun reaction11,12, transoximation of
1
-
relevant compounds, agrochemicals, dyes, or material science
4
.
They are also used as building blocks in a variety of functional
groups such as amides, carboxylic acids, ketones, amines, and
10
5
esters . Many nitrile-containing pharmacophores are present in
numerous pharmaceutically active drug molecules. Examples
13
14
aldehydes , Kolbe’s nitrile synthesis and cyanide-halide
include vilazodone (1),
antidepressant that has completed phase III clinical trials;
a
dual-acting serotonergic
15-17
exchange reactions
. But most of these methodologies suffer
from the use of highly toxic reagents, complicated operations,
harsh reaction conditions, and heavy metal waste.
Of the various starting materials for nitrile synthesis--
, alcohols , and amines aldehydes are easily
available, inexpensive and environmentally benign. Selected
2
, 6
7
entacapone (2), which is used for treating Parkinson’s disease;
Lodoxamide (3), a histamine inhibitor that is used as ocular anti-
8
inflammatory agent; and febuxostat (4) which is a non-purine
13, 18-31
32
33
aldehydes
9
xanthine oxidase inhibitor used to treat gout (Figure 1).
nitrile synthesis from aldehydes are depicted in Figure 2.
Figure 1. Nitrile containing pharmaceutical drugs.
1
3, 18, 20, 24, 25, 27, 30
Different nitrogen
sources have been used.
Despite the tremendous progress made in the synthesis of
nitriles, there are still drawbacks in terms of toxicity of
2
0-22
23
reagents
, harsh reaction conditions or substrate scope. To
a. Department of Chemistry, University of Louisville, Louisville, Kentucky 40292,
United States.
College of Chemistry, Chemical Engineering and Biotechnology, Donghua
address the drawbacks of the current methods, we designed an
environmentally friendly alternative using HCl•DMPU.
reagent is highly concentrated, easily prepared and bench
stable. We found that HCl•DMPU plays a dual role as a proton
source as well as a non-nucleophilic base, obviating the need for
b.
34-37
This
University, 2999 North Renmin Lu, Shanghai, China
Electronic Supplementary Information (ESI) available: [details of any
c.
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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COMMUNICATION
Journal Name
*All reactions were performed on 0.5 mmol scale at 60 C for 4 h.
o
a
any external base or metal catalyst. We are pleased to report a
HCl•DMPU-mediated one-pot synthesis of nitriles from
aldehydes. Our protocol eliminates the use of metal catalysts
and external oxidants.
View Article Online
b
Determined by GC–MS with dodecane as the internal standard. Formation
DOI: 10.1039/D0GC00757A
of oxime.
With optimal conditions in hand, the substrate scope of the
reaction was assessed using several allylic and aliphatic
aldehydes (Table 2). We were pleased to observe tolerance to
various functional groups. Notably, an array of aliphatic
aldehydes such as (1a) to (1h), (1k) and (1m) underwent this
protocol smoothly giving the corresponding nitrile products in
Figure 2. Methods for preparing nitriles.
NaN3, TfOH
R
CN
CN
(Prabhu, 2012)
(Nantz, 2012)
DPPH, Toluene
R
R
R
7
6-92% yields. Branched aliphatic aldehydes, (1b) and (1l) also
worked very well. Substrates bearing naphthalene, (1c) and
diarylmethane (1d) units delivered nitrile analogs in excellent
yields. Aldehydes such as (1i) and (1j) were successfully
converted to nitrile analogs in 79% and 80% yields respectively
with complete retention of the double bond geometry.
R
CHO
Acetic acid, 50 o
CN (Gustavo,2016)
CN (Fokin, 2019)
C
NH2OH.HCl, SO2F2,Et3N
NH2OH.HCl
Na2CO3,DMSO
R
CN (Hua-Li Qin, 2019)
Table 2. Scope of aliphatic aldehydes.a
.
This work
R-CHO
NH OH.HCl
HCl DMPU (0.5 mmol)
2
R-CN
3
.
HCl DMPU,MeCN
(0.5 mmol)
(0.7 mmol)
MeCN,
3-4 hrs, 60o
C
R
CHO
NH OH.HCl
R
CN
2
2
-4 hrs, 60 o
C
1
3
CN
CN
CN
CN
CN
Results and discussion
3
a, 85%
3b, 84%
3c, 88%
CN
3d, 92%
3h, 81%
We initially investigated the reaction of benzaldehyde (1 equiv)
with HCl•DMPU (1 equiv) and hydroxylamine hydrochloride (1.2
Br
Br
CN
NC
o
equiv) at 60 C with acetonitrile as the solvent. To our delight,
3
e, 76%
3f, 80%
3j, 80%
3g, 76%
the desired product was formed in 98% yield. None of the other
solvents screened (Table 1) were superior to acetonitrile. We
tried the reaction in the absence of HCl•DMPU, but the reaction
did not proceed further after yielding the oxime. In order to
check the reactivity of the oxime with our standard conditions,
we synthesized oxime (20) and treated it with our standard
conditions, and we were pleased to observe the desired nitrile
product (5f) in 95%. (refer SI for more details).
CN
CN
CN
CN
N
3i, 79%
3k, 83%
3l, 75%
N
3
9
CN
3
m, 84%
.
a
Table 1. HCl DMPU assisted one pot conversion of aldehydes to
All yields are isolated yields.
nitriles
O
CN
H
.
HCl DMPU (1 equiv)
MeCN, 4h, 60 o
NH OH HCl
2
C
1
equiv.
1.2 equiv.
Entry
Change from standard conditions
% Conversiona
1
2
3
4
5
6
7
8
9
none
98
0b
0b
.
without HCl DMPU
.
DMPU instead of HCl DMPU
MeOH instead of MeCN
EtOH instead of MeCN
DCM instead of MeCN
EtOAc instead of MeCN
DCE instead of MeCN
Toluene instead of MeCN
rt instead of 60 oC
10
12
20
18
23
21
29
1
0
2
| J. Name., 2012, 00, 1-3
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Journal Name
COMMUNICATION
Table:3 Scope of aromatic and heteroaromatic aldehydes. a
ester (4x) also delivered corresponding nitriles in quantitative
yields.
View Article Online
DOI: 10.1039/D0GC00757A
.
NH2OH.HCl
(0.7 mmol)
HCl DMPU
(
0.5 mmol)
R-CHO
R-CN
5
(
0.5 mmol)
A plausible mechanism for this nitrile synthesis is illustrated in
Scheme 1. Initially, the attack of hydroxylamine hydrochloride
to aldehyde a gives intermediate oxime b, which then
undergoes an HCl•DMPU assisted dehydration to give the
desired nitrile product d. In this process there is no need for an
exogenous base because DMPU itself acts as a non-nucleophilic
base assisting the proton abstraction from oxime derivatives.
The ability of DMPU in the proton abstraction step was
MeCN,
3-4 hrs, 60o
C
4
2
CN
CN
CN
CN
O
5a, 98%
5b, 95%
5c, 93%
5d, 96%
O
CN
CN
CN
3
8
demonstrated in our group’s previous publication.
O2N
S
I
CN
5e, 89%
5f, 94%
5g, 92%
5h, 93%
Scheme 1. Proposed reaction mechanism.
O
CN
CN
CN
H
CN
N
N
HCl
O
H
OH
H
O
a
.
N
b
N
NH2OH HCl
Cl
CF3
N
R
H
R
R
H
MeCN
MeCN
5i, 94%
5j, 92%
5k, 97%
5l, 92%
c
O
Br
CN
CN
CN
N
N
NC
O
O
HCl
N
O
F
O
5
p, 98%
5
m, 94%
5n, 95%
5o, 96%
R
O
CF3
O
CN
S
d
NC
O
NC
N
HO
CN
5s, 90%
To further demonstrate the utility of this protocol, we
performed several gram-scale synthesis for a series of
precursors of drug molecules (Scheme 2). 3,4-Bis(2-
methoxyethoxy)benzaldehyde (8) derived from aldehyde (6)
was subjected to our standard protocol and provided the
corresponding nitrile product, (9) in 98% yield. Nitrile (9) is the
key precursor in the synthesis of a cancer treatment drug -
5
q, 72%
5r, 92%
5t, 98%
H
N
CN
CN
HO
CN
N
O
O
N
H
O
CN
v, 95%
O
5
5
u, 94%
5w, 92%
5x, 95%
a
All yields are isolated yields.
40
Erlotinib 10. We also examined the synthesis of Fluanxol (13)
(
an antipsychotic drug) by subjecting 2-chloro-5-
We expanded the substrate scope to include electron-donating
and electron-withdrawing groups on aromatic aldehydes (4a-
(trifluoromethyl)benzaldehyde (11) to our standard protocol
and obtained the nitrile precursor (12) in 98% yield. In addition,
starting from 3-bromo-4-hydroxybenzaldehyde (14), we
obtained the nitrile precursor (15) in 95% yield in the formal
synthesis of Febuxostat (17), which is used to treat gout.
4
x) (Table 3). The corresponding nitriles were obtained in
excellent to quantitative yields. To investigate the effect of
steric hindrance we evaluated ortho-substituted aldehydes
such as (4l) and (4m), which gave the corresponding 2-
(trifluoromethyl) benzonitrile (5l) and 2-fluorobenzonitrile (5m)
Scheme 2. Gram scale synthesis of precursors for drug molecules.
in 92% and 94%, respectively. These results indicated that the
steric hindrance of the ortho position did not influence the
reactivity of trifluoromethyl benzaldehyde and fluoro
benzaldehyde substrates. Several para-substituted aldehydes
incorporating methoxy (4d), nitro (4f), thio (4g), iodo (4h),
chloro(4i) and cyano (4j) substituents were tolerated, delivering
the nitrile products in excellent yields of 92-96% as compared
to ortho-substituted aldehydes. Naphthalene (4k) and
anthracene (4n) derivatives were successfully transformed,
giving 97% and 95% yields, respectively. Given the importance
and broad application of heterocyclic molecules in the
pharmaceutical sector and medicinal chemistry, we also
examined various heterocyclic aldehydes (Table 2). A wide
range of aldehydes incorporating sulfur (4s) oxygen (4p, 4t, 4u)
and nitrogen atoms (4q and 4v) in aromatic rings were
efficiently converted to their nitrile analogs in quantitative
yields. Various other functionalities such as amide (4w) and
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COMMUNICATION
Journal Name
O
O
Br
Conflicts of interest
The authors declare no competing financial interests.
View Article Online
DOI: 10.1039/D0GC00757A
K2CO3 (3.0 equiv)
DMF, 95 oC, 6 h
O
O
.
H2N OH HCl(1.2 equiv)
HO
HO
O
O
+
.
HCl DMPU( 1.0 equiv)
MeCN, 60 oC, 5 h
O
8
6
7
O
O
N
O
O
O
O
CN
Acknowledgements
O
O
N
NH
9, 98%
We are grateful to the National Institutes of Health for financial
support (R01GM121660). We are grateful to Dr. Ricardo A.
Angnes (University of São Paulo, Brazil) for scientific support
and discussions.
1
0
Erlotinib
OH
N
N
CF3
Cl
CF3
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