Transition-metal-free hydration of nitriles using potassium tert -butoxide under anhydrous conditions

Article abstract of DOI:10.1021/jo502752u

Potassium tert-butoxide acts as a nucleophilic oxygen source during the hydration of nitriles to give the corresponding amides under anhydrous conditions. The reaction proceeds smoothly for a broad range of substrates under mild conditions, providing an efficient and economically affordable synthetic route to the amides in excellent yields. This protocol does not need any transition-metal catalyst or any special experimental setup and is easily scalable to bulk scale synthesis. A single-electron-transfer radical mechanism as well as an ionic mechanism have been proposed for the hydration process.

Full text of DOI:10.1021/jo502752u

Note
pubs.acs.org/joc
Transition-Metal-Free Hydration of Nitriles Using Potassium tert-
Butoxide under Anhydrous Conditions
Ganesh Chandra Midya, Ajoy Kapat, Subhadip Maiti, and Jyotirmayee Dash*
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur, Kolkata 700032, India
S
* Supporting Information
ABSTRACT: Potassium tert-butoxide acts as a nucleophilic
oxygen source during the hydration of nitriles to give the
corresponding amides under anhydrous conditions. The
reaction proceeds smoothly for a broad range of substrates
under mild conditions, providing an efficient and economically
affordable synthetic route to the amides in excellent yields. This protocol does not need any transition-metal catalyst or any
special experimental setup and is easily scalable to bulk scale synthesis. A single-electron-transfer radical mechanism as well as an
ionic mechanism have been proposed for the hydration process.
he amide functional group is present in proteins and is
essential for sustaining life. It is a synthetically versatile
To circumvent these problems, several catalytic hydration of
nitriles have been devised utilizing enzyme catalysis,7 transition-
metal-mediated homogeneous catalysis,8 heterogeneous catal-
ysis,9 and nanocatalysis.10 Various green approaches such as
microwave-assisted hydration of nitriles,11 super basic system
DMSO−CsOH,12 chitosan-supported ruthenium catalyst,13
and hydroxide-promoted14 hydrolysis of nitriles have been
reported. Although these processes offer improved yields and
selectivity, each of these protocols has its own set of
disadvantages. There is a need for the development of an
ideal reaction condition, which can be performed at room
temperature in a metal-free environment and scalable for
industrial applications. As part of our ongoing research program
toward the development of economically sustainable green
synthetic methodologies,15 we herein report an efficient
hydration of organonitriles to the corresponding amides using
potassium tertiary butoxide (KOtBu) as an oxygen source
(Scheme 1).
T
synthon distributed in several biologically active molecules.1
Amides have also been extensively used in industrial
applications.1,2 One of the most straightforward and atom-
economical ways to synthesize amides is the hydration of the
corresponding organonitriles. The nitrile group is mechanisti-
cally intriguing as it is kinetically inert and thermodynamically
unstable.3 Further, the rate of amide hydrolysis to the
corresponding acid is much faster than the rate of hydrolysis
of nitrile to the corresponding amide (Scheme 1).4 These
Scheme 1. Hydration of the Nitriles to the Amides
Recently, KOtBu-promoted synthesis of biaryls has been
reported by the groups of Itami, Shi, Lei, and Hayashi.16
Hartwig and co-workers reported that the nitrile group can be
activated via coordination with the potassium ion.16e We
perceived the possibility of nucleophilic addition of tertiary
butoxide to the electrophilic carbon atom of the activated nitrile
group. We are delighted to observe the formation of amide (2)
in 42% yield, when KOtBu (0.5 equiv) was added to the
solution of benzonitrile (1) in toluene at room temperature
under anhydrous conditions (Table 1, entry 1). This
preliminary result inspired us to investigate the reaction in
detail. The yield was significantly improved by increasing the
amount of base (entries 2−4). Benzamide 2 was isolated in
91% using 3 equiv of KOtBu for 5 h (entry 4). A slight
improvement in yield (96%) with shorter reaction time (3 h)
was observed when the reaction temperature was raised to 60
inherent properties make selective hydrolysis of nitriles to the
corresponding amides much more challenging. Classically,
hydration of nitriles was carried out under acid- and base-
catalyzed conditions. However, major limitations of these
hydration protocols include (a) the formation of corresponding
acids by overhydrolysis, (b) requirement of high temperature
and pressure, (c) poor functional group tolerance and narrow
substrate scope, and (d) the inability to hydrolyze substrates
having more than one nitrile functional group.5,6
Received: December 5, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/jo502752u
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The Journal of Organic Chemistry
Note
a
Table 1. Hydration of Benzonitrile
Table 2. KOtBu-Promoted Hydration of the Nitriles
a
entry
base (equiv)
solvent
toluene
yield (%)
1
KOtBu (0.5)
KOtBu (1.0)
KOtBu (2.0)
KOtBu(3.0)
42
60
80
2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
xylene
3
b
4
91 (96)
c
5
KOtBu (3.0)
NaOtBu (3.0)
LiOtBu (3.0)
K2CO3 (3.0)
Cs2CO3 (3.0)
K3PO4 (3.0)
KOtBu (3.0)
KOtBu (3.0)
KOtBu (3.0)
KOtBu (3.0)
KOtBu (3.0)
KOtBu (3.0)
KOtBu (3.0)
KOtBu (3.0)
KOtBu (3.0)
KOtBu (3.0)
KOtBu (3.0)
KOtBu (3.0)
15
6
NR
NR
7
d
8
NR
d
9
NR
d
10
11
12
13
14
15
16
17
18
19
20
21
22
23
NR
55
THF
55
dioxane
DMF
27
NR
NR
NR
NR
traces
NR
65
DMSO
DMAc
ClCH2CH2Cl
CH2Cl2
CHCl3
EtOH
iPrOH
tBuOH
tBuOH
75
e
>99
c
KOtBu (3.0)
51
a
All reactions were carried out under nitrogen atmosphere.
b
c
d
Performed at 60 °C for 3 h. 2% H2O(v/v) was added. Heating
a
b
c
e
See general procedure A. See general procedure B. 5 h, 60 °C,
at 135 °C did not improve the result. 4 h.
d
toluene. 130 °C, toluene.
°C (entry 4). Only a trace amount of the product (15%) was
isolated in the presence of water (entry 5). To investigate the
positive counteranion effect, sodium and lithium tert-butoxides
were used, which fail to give the desired product (entries 6 and
7). These results suggest that potassium cation plays an
important role in this transformation. No reaction was observed
using inorganic bases (K2CO3, Cs2CO3, K3PO4) containing
different counteranions at room temperature or higher
temperature (entries 8−10). Systematic screening of bases
and temperature revealed that KOtBu is the only base, which
can promote the hydration at room temperature (entries 6−
10). Next, sets of representative protic solvents (EtOH, iPrOH,
tBuOH) and polar solvents (DMSO, MeCN, DMF, and
DMAc) were screened (Table 1). Moderate yield (55%) was
obtained in aprotic solvents like THF and xylene. The reaction
proceeded in toluene and tBuOH, but higher yield with shorter
benzonitriles takes place in relatively slower rate (9−12 h) with
comparable yields (3, 5b, 6b, 7a). o-Dichlorobenzonitrile
afforded the corresponding amide 8 in nearly quantitative yield
after the reaction was run for 12 h. As expected, electron-rich
benzonitriles afforded the corresponding amides (9−12) in
t
realtively lower yields (55−85%) in both BuOH and toluene.
This protocol was successfully applied for the hydration of p-
and m-cyanopyridines to give the desired amides 14 and 15 in
97% and 84% yields, respectively. Antitubercular agent
pyrazinamide 16 was prepared in 95% yield by hydration of
the corresponding nitrile. Aliphatic nitriles were found to be
less reactive compared to the aromatic nitriles. The desired
amides 17 and 18 were obtained in 55% and 60% yields in
tBuOH. The aliphatic amide 17 did not form in toluene at
room temperature and formed in moderate yield by performing
the reaction at 130 °C (Table S1, Supporting Information). We
were delighted to observe the formation of the desired
dicarboxamide 19 as a single product from the dicyanobenzene
in 78% yield. These results indicate that the hydration
methodology exhibits general substrate scope; electron-rich
and electron-deficient aromatic, heteroaromatic nitriles, ali-
phatic nitriles, and dinitrile afforded high yields of the desired
amide. The outcome of this protocol depends on both the
electronic nature as well as the sterics of the substrates. It is
worth mentioning that meta- and ortho-substituted halobenzo-
nitriles reacted slowly with lower yields in toluene compared to
tBuOH.
t
reaction time was obtained using BuOH as the solvent. To
avoid contamination from the glassware and reagents, hydration
of benzonitrile was performed using 99.99% pure KOtBu
(Sigma-Aldrich) in thoroughly clean glassware. The benzamide
t
was obtained in similar yield in toluene and BuOH.
With the optimized reaction conditions (1 equiv nitrile, 3
t
equiv KOtBu, 4 mL/mmol BuOH) in hand, the scope of this
hydration was then evaluated using different nitriles (Table 2).
The yield of each of these substrates was also determined in
toluene (Supporting Information, Table S1). The reactions are
extremely efficient and high yielding in tBuOH, when
benzonitriles are appended with electron-withdrawing group
at the ortho- and para-position to give the corresponding
amides 4, 5a, 5c, 6a, 6c, and 7b. Hydration of meta-substituted
To gain mechanistic insights, radical-quenching experiments
t
were performed in both toluene and BuOH. Hydration of
B
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Note
benzonitrile in the presence of radical traps 2,2,6,6-
tetramethylpiperidine-1-oxyl and 1,1-diphenylethylene (DPE)
proceeded with a diminished yield of the product (Scheme 2).
Scheme 3. Proposed Mechanism
Scheme 2. Hydration of Nitriles in the Presence of Radical
Scavengers
A complete inhibition of the reaction was observed in toluene
t
using galvinoxyl as the radical scavenger. In BuOH, 20−30%
inhibition of product formation was observed using 1 equiv of
TEMPO and DPE. By increasing the amount of galvinoxyl in
tBuOH, the yield of amide 2 was decreased and the reaction
was completely inhibited using 3 equiv of galvinoxyl. These
experiments suggest that radical intermediates are involved
during the hydration process. Electron paramagnetic resonance
(EPR) studies indicated the formation of a strong EPR signal
with a g value of 1.98 for the reaction mixture containing
t
of BuOH with the heteroatom present in the aryl moiety (see
the Supporting Information for further explanation, Figure S3).
However, we cannot rule out the possibility of a nucleophilic
addition of tert-butoxy anion to the electrophilic carbon atom of
the nitrile (as shown in B1) to generate the iminyl anion
intermediate C2. Subsequent deprotonation of C2 followed by
elimination of 2-methylpropene may lead to the formation of
the amidate D.
t
benzonitrile (0.5 mmol) and BuOK (1.5 mmol) after stirring
in toluene (3.0 mL) for 2 h, while a very weak EPR signal was
detected in the absence of nitrile (Figure S1, Supporting
Information).17 This result is suggestive of an electron-transfer
process between KOtBu and nitrile.
In conclusion, we have developed an efficient potassium tert-
butoxide-mediated hydration of organonitriles to prepare the
corresponding amides in excellent yields under mild reaction
conditions. The method has a broad scope. No overhydrolysis
with high selectivity was observed for the double hydration of
dicyanobenzene. This protocol does not need any metal
catalyst or any special experimental setup and is easily scalable
to bulk scale synthesis.
We propose that Lewis basic nitrile coordinates with the
potassium cation in the presence of KOtBu to form complex A,
which is stabilized by intermolecular cation−π as well as π−π*
stacking interactions (Scheme 3).18 On the basis of the EPR
evidence, a single electron transfer (SET) may occur between
the cationic complex A and tertiary butoxide anion to generate
the radical ion pair B. Next, the tert-butoxy radical adds to the
electrophilic carbon atom of the nitrile to form the iminyl
radical intermediate C. The lower reactivity of aliphatic nitriles
compared to the aromatic nitriles (Table 2) suggests that
cation−π interaction plays a key role in aromatic nitriles. The
intermediate C subsequently gives potassium amidate D via 1,5-
hydrogen abstraction followed by elimination of 2-methyl-
propene. The formation of 2-methylpropene from the reaction
mixture was detected by GC−MS analysis (Figure S2,
Supporting Information). Finally, protonation of D affords
the desired amide.
In case of ortho-substituted aryl nitriles, the formation of
intermediate C1 is unfavorable due to the steric interaction
between the ortho-substituents and the 6-membered cyclic
intermediate. This explains why the hydration of ortho-
substituted aryl nitriles does not proceed at room temperature
in toluene and occurs at 60 °C to give moderate yields of the
desired products. The improved reactivity in tBuOH compared
to toluene could be due to the strong hydrogen-bonding ability
EXPERIMENTAL SECTION
■
General Information. All starting materials were obtained from
commercial suppliers and used as received. Products were purified by
flash chromatography on silica gel (100−200 mesh, Merck). Unless
otherwise stated, yields refer to analytical pure samples. NMR spectra
1
were recorded in DMSO-d6. H NMR spectra were recorded at 500
and 400 MHz instruments at 278 K. Data are reported as follows:
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q =
quartet, m = multiplet, br = broad), coupling constants (Hz), and
integration. 13C NMR spectra were recorded on either 100 or 125
MHz with complete proton decoupling. Chemical shifts (δ) are
reported in ppm. Infrared (FTIR) spectra were recorded with the KBr
disk and KBr plate techniques for solid and liquid samples, νmax
(cm−1).
General Procedure A (GP-A): Hydration of m-Nitrobenzoni-
trile. A flame-dried flask fitted with magnetic stir bar was charged with
m-nitrobenzonitrile (148 mg, 1.0 mmol, 1.0 equiv) and KOtBu (336
mg, 3.0 mmol, 3.0 equiv), and dry tert-butyl alcohol (4 mL/mmol) was
added. The reaction mixture was stirred at room temperature for 12 h
under nitrogen atmosphere, and progress of the reaction was
monitored by TLC. Upon completion, the reaction mixture was
C
DOI: 10.1021/jo502752u
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The Journal of Organic Chemistry
Note
treated with water (10 mL). The solid amide product was filtered,
washed with water, and dried under vacuum to provide the
corresponding amide 3 in 99% (164 mg, 0.99 mmol) as a light yellow
solid.
General Procedure B (GP-B): Hydration of Benzonitrile. A
flame-dried flask fitted with a magnetic stir bar was charged with
benzonitrile (103 mg, 1.0 mmol, 1.0 equiv) and KOtBu (336 mg, 3.0
mmol, 3.0 equiv), and dry toluene (4 mL/mmol) was added. The
reaction mixture was stirred at room temperature for 5 h under
nitrogen atmosphere, and progress of the reaction was monitored by
TLC. Upon completion, the reaction mixture was treated with water
(10 mL). The solid amide product was filtered, washed with water, and
dried under vacuum to provide the corresponding amide 2 in 91%
(110 mg, 0.91 mmol) as a white solid.
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1
yields and purities. The H and 13C NMR spectroscopic data of the
amides 2,18 3,9d 4,6 5a,18 5b,18 5c,18,9d 6a,19 6b,20 6c,11 7a,11 7b,19,9d
23
9d,21
9a,18,21 9b,19,21 9c,19,21 10,22 11,19,9d 12,6 13, 14,19,6 15,
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b
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ASSOCIATED CONTENT
■
S
* Supporting Information
EPR, GC−MS, 1H NMR, and 13C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: ocjd@iacs.res.in.
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank DST India for research funding. G.C.M. thanks
CSIR-India for a research fellowship. We thank Dr. Tapan
Kanti Paine for useful discussions.
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DOI: 10.1021/jo502752u
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