Transition metal-free sodium borohydride promoted controlled hydration of nitriles to amides

Article abstract of DOI:10.1080/00397911.2012.745566

A transition metal-free process, promoted by sodium borohydride, has been developed for convenient and selective hydration of nitriles to corresponding amides. The present process converts the aromatic, aliphatic, and heteroaromatic nitriles with wide functional group tolerance. The regioselective hydration of one nitrile moiety in the presence of an other nitrile group makes high impact in the present protocol.

Full text of DOI:10.1080/00397911.2012.745566

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Transition Metal-Free Sodium Borohydride Promoted
Controlled Hydration of Nitriles to Amides
Praveen Kumar Verma a , Neeraj Kumar a , Upendra Sharma a , Manju Bala a , Vishal Kumar a
& Bikram Singh a
a Natural Plant Products Division, CSIR-Institute of Himalayan Bioresource Technology
(Council of Scientific and Industrial Research) , Palampur , Himachal Pradesh-176 061 , INDIA
Accepted author version posted online: 31 May 2013.
To cite this article: Praveen Kumar Verma , Neeraj Kumar , Upendra Sharma , Manju Bala , Vishal Kumar & Bikram
Singh (2013): Transition Metal-Free Sodium Borohydride Promoted Controlled Hydration of Nitriles to Amides,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
DOI:10.1080/00397911.2012.745566
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Transition Metal-Free Sodium Borohydride Promoted Controlled Hydration of
Nitriles to Amides
Praveen Kumar Verma1, Neeraj Kumar1, Upendra Sharma1, Manju Bala1, Vishal Kumar1,
Bikram Singh1
1Natural Plant Products Division, CSIR-Institute of Himalayan Bioresource Technology
(Council of Scientific and Industrial Research), Palampur, Himachal Pradesh-176 061,
INDIA
Dr. Neeraj Kumar, Dr. Bikram Singh, Scientist, Natural Plant Products Division, CSIR-
Institute of Himalayan Bioresource Technology Palampur, H.P., 176 061, INDIA. Tel.:
91-1894-230426; Fax: 91-1894-230433. E-mail: neerajnpp@rediffmail.com;
bikram_npp@rediffmail.com
†IHBT Communication No. 2369
Abstract
A transition metal-free process, promoted by sodium borohydride, has been developed
for convenient and selective hydration of nitriles to corresponding amides. The present
process converts the aromatic, aliphatic, and heteroaromatic nitriles with wide functional
group tolerance. The regioselective hydration of one nitrile moiety in the presence of
other nitrile group makes high impact in the present protocol.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications® for the following free supplemental resource(s):
Full experimental and spectral details.]
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CN
CONH2
NaBH4 (0.75 equiv)
EtOH:H2O (1:1), 5 mL
80 oC
R
R
Yield = 85-99%
R = H, F, Cl, Br, I, OH, NO2, CN,
Heteroaromatic Nitriles, Aliphatic Nitriles
CN
CONH2
NaBH4 (0.75 equiv)
EtOH:H2O (1:1), 5 mL
80 oC
CN
CN
Yield = 98%
KEYWORDS: Nitrile hydration; amide synthesis; sodium borohydride
INTRODUCTION
Amides exhibit a broad range of industrial and pharmacological applications.[1] Hydration
of nitriles is the sustainable and ideal atom economical reaction for the synthesis of
amides. Hydration of acrylonitrile produces more than 2x105 tons acrylamide per year.[2]
Traditionally, the hydration of nitriles was accomplished with strong acidic or basic
conditions.[3] These procedures are associated with the serious drawback of over
hydrolysis to carboxylic acids. To overcome these problems many efficient methods have
been developed including enzymatic hydration of nitriles,[4] complexes of transition
metals[5] such as Ni,[6] Pt,[7] Rh,[8] Ir,[9] Mo,[10] Au,[11] Cu,[12] Co,[13] Pd,[14] Ru,[15] Ag,[16]
and CeO2[17] catalyzed reactions. However, these systems have disadvantages like
necessity of special handling of microorganisms (enzymes), difficulty in catalyst/product
separation and use of costly transition metal complexes. Hence, the development of an
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enzymes and transition metal free method is highly desirable. Although hydration of
nitriles was carried out using TFA-H2SO4 or AcOH-H2SO4[18] mixtures, the method was
not general i.e., different reaction conditions were required to afford the desired product
for different substrates. Furthermore, the use of highly toxic acids limits the scope of the
methods.
In continuation to our work on catalysis,[19] recently, while carrying out the reduction of
nitro group in case of 4-nitrobenzonitrile,[19d] instead of nitro reduction hydration of
nitrile moiety to amide was observed with NaBH4 in EtOH : H2O (1:1). Hence, we
thought to optimize the conditions for the selective hydration of nitrile to corresponding
amides. In this context, herein, we report a general and highly selective method for the
controlled hydration of nitriles using NaBH4 in a mixture of EtOH : H2O (1:1).
RESULTS AND DISCUSSION
Initially, to optimize the best reaction conditions the hydration of 4-nitrobenzonitrile was
carried out with 1 equiv of NaBH4 in the mixture of ethanol and water (1:1), no
conversion was observed at room temperature (Table 1, entry 5). However, on increasing
the temperature up to 80 oC, full conversion was observed (Table 1, entry 6).
Furthermore, to optimize the minimum amount of NaBH4 required for the complete
hydration, various equivalents of NaBH4 were tested (Fig. 1). At low amount (0.1-0.5
equiv) of NaBH4 reactions start to give desired products along with traces of side
products (Table 1, entries 1, 2 and 3). The increase in quantity of NaBH4 (0.75 and 1
equiv) resulted in full conversion with excellent selectivity towards desired amide (Table
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1, entries 4 and 6). Further increase in the quantity of NaBH4 resulted in the formation of
mixture of products (Table 1, entries 7-11). Hence, 0.75 equiv of NaBH4 was the
optimized amount for the reaction.
To check the scope of the present method, the hydration of various substituted nitriles
was carried out. Excellent yield (95%) was observed for the reaction of benzonitrile to
form benzamide (Table 2, entry 1).
Halogenated benzonitriles were hydrated to corresponding amides with high to excellent
yield (89-93%) in short time (Table 2, entries 2-6). Present catalytic system efficiently
catalyzes the hydration of rarely reported 4-cyanophenol[15i] to corresponding amide with
high yield (89%, Table 2, entry 7). In case of 3-cyanobenzaldehyde, the reduction of
carbonyl moiety also occurred along with the hydration of nitrile group (Table 2, entry 8).
In case of 4-carboxylic acid benzonitrile reaction was not preceded and reactant was
recovered as such up to 99% (Table 2, entry 9). The hydration of 4-nitrobenzonitrile
afforded corresponding amide with excellent yield (94%, Table 2, entry 10). In case of 1-
cyanonaphthalene, 5 equiv of NaBH4 was used to afford the corresponding amide with
87% yield in 12 h (Table 2, entry 11). 3-Aminobenzonitrile was observed as the main
product for the reaction of 3-cyanobenzoisothiocyanate in excellent yield (Table 2, entry
12).
The present method also efficiently performed the hydration of industrially important
acrylonitrile in good yield (88%). Neither reduction of double bond nor polymerization of
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the product occurred (Table 2, entry 13). The hydration of phenylacetonitrile afforded the
corresponding amides in good yield (Table 2, entry 14).
Generally, the hydration of heteroaromatic nitriles by transition metal based methods is
more difficult due to their strong coordination to the metal centers. Here, nitrogen,
oxygen and sulphur containing heterocyclic nitriles were successfully converted into
corresponding amides. Excellent yields were observed for the hydration of 4-
cyanopyridine, 2-thiophenecarbonitrile, 3-cyanoindole and 5-cyanophthalide without
affecting the heterocyclic ring system (Table 3, entries 1-4).
One of the significant challenges in the hydration of nitriles is the selective hydration of
one nitrile group in the presence of other nitrile group.[11,18] The most important finding
of present method is the regioselective hydration of the one nitrile moiety in case of 1,3-
and 1,4-benzenedinitriles with excellent yields (Table 4, entries 2 and 3). However, in
case of 1,2-benzenedinitriles both the nitrile functional groups were hydrated and further
cyclized to corresponding phthalimides (Table 4, entries 1and 4).
From the mechanistic point of view it is well reported that bases catalyze the hydration of
nitriles.[20] Therefore, we proposed that NaBH4 abstract proton from water to give
hydroxide ions which promoted the hydration of nitriles.
CONCLUSIONS
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In summary, an efficient, transition metal free and sustainable process have been
developed for the selective hydration of nitriles under mild conditions. This process
tolerated various functional groups including halides, hydroxyl, nitro and C-C double
bond. Present protocol is applicable to aromatic and heteroaromatic nitriles. To the best
of our knowledge, this study constitutes the first nitrile hydration promoted by NaBH4,
which, till date, was otherwise used as dehydrating agent for the conversion of amides
into nitriles. The present process is complementary to the many practical methods that
use transition metals and microorganisms for hydration of nitriles under ambient
conditions.
EXPERIMENTAL
Materials And Instrumentation
Silica gel (60-120 mesh) used for column chromatography was purchased from Sisco
Research Laboratories Pvt. Ltd. India and all other chemicals were purchased from
Spectrochem, India, Merck, Germany, and Sigma-Aldrich, USA, and were used without
further purification. NMR spectra were recorded on a Bruker Avance-300 spectrometer.
Mass spectra were recorded on QTOF-Micro of Waters Micromass and Maxis-Bruker.
The GC-MS analysis was carried out on a Shimadzu (QP 2010) series Gas
Chromatogram-Mass Spectrometer (Tokyo, Japan), AOC-20i auto-sampler coupled, and
a DB-5MS capillary column, (30 m x 0.25 mm i.d., 0.25µm). The initial temperature of
column was 70 °C held for 4 min. and was programmed to 230 °C at 4 °C/min., then held
for 15 min. at 230 °C; the sample injection volume was 2 µL in GC grade
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dichloromethane. Helium was used as carrier gas at a flow rate of 1.1 mL min-1 on split
mode (1:50).
General Procedure For Controlled Hydration Of Nitriles To Corresponding Amides
To a mixture of nitrile (1 mmol) and EtOH : H2O (1:1, 5mL), sodium borohydride (0.75
equiv) was added. The reaction solution was stirred at 80 oC and the progress of the
reaction was monitored by TLC (silica gel; hexane/ethyl acetate) and GC-MS. After
completion, the reaction mixture was diluted with MeOH to dissolve all the precipitate.
The entire mixture was transferred into a 50 mL round-bottom flask, evaporated in vacuo,
and concentrated. The residue was purified by column chromatography on silica gel
(hexane/ethyl acetate) to give amide.
Please see the Supplementary Material, available online, for complete experimental and
spectral details.
ACKNOWLEDGEMENTS
Authors are grateful to Dr. P. S. Ahuja, Director of the institute for providing necessary
facility and encouragement. Mr. P. K. V. and Mr. U. S. are thankful to CSIR for SRF
fellowship and Mr. V. K is thankful to UGC for SRF fellowship.
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Table 1. Effect of NaBH4 loading on reaction productsa
Entry NaBH4 Conversion
(equiv) (%)
Yield (%)b
A
B
0
C
2
D E F G
1
0.1
0.25
0.5
0.75
1
48
45
80
0
0
0 0 0
0 0 0
2
81
0
1
3
95
94 0.5 0.5 0 0 0 0
4
>99
0
>99 0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0
0 0 0
0 0 0
0 0 0
0 0 3
0 0 0
0 0 1
0 0 8
0 0 0
5c
0
0
6
1
>99
>99
>99
>99
>99
>99
>99 0
7
1.5
2
97
96
0
4
8
9
5
84 15
21 71
10
11
10
25
0
87 13
aReaction conditions: 4-nitrobenzonitrile (1 mmol), NaBH4 (0.1 to 25 equiv), EtOH :
H2O (1:1, 5 mL), 80 oC temperature, 4 h.
bGC-MS yield.
cReaction at room temperature.
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Table 2. Scope of nitriles for NaBH4 promoted hydrationa
NaBH4
R CONH2
R CN
EtOH + H O (1:1), 5 mL
2
80 O
C
Entry
1
Substrate
Time
(h)
2.5
Product
Yield (%)b
>99 (95)
CONH2
CN
CONH
CN
2
2
3
4
5
2.5
2.5
2.5
4
92
F
F
CONH2
CONH2
CONH2
CN
95 (90)
97 (93)
92 (89)
Cl
Cl
Br
CN
Br
CN
I
I
CONH2
CN
6
7
8
2.5
8
91
94 (89)
87
I
I
CONH2
CN
HO
HO
CN
CONH 2
5
CHO
CH2OH
CN
9
12
-
0
HOOC
O2N
CN
CONH2
10
11
4
>99 (94)
87c
O2N
CONH 2
CN
12
CN
CN
12
4
93
NH 2
NCS
CONH2
CN
13
14
5.5
5
88
89
CN
CONH2
aReaction conditions: nitrile (1 mmol), NaBH4 (0.75 equiv), EtOH : H2O (1:1, 5 mL), 80
oC temperature.
bGC-MS yield, isolated yields are given in parentheses.
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c5 equiv of NaBH4 was used.
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Table 3. Hydration of various heteroaromatic nitriles using NaBH4
a
NaBH4
R
CONH2
R
CN
EtOH + H2O (1:1), 5 mL
80 O
C
Entry
1
Substrate
Time (h)
Product
Yield (%)b
>99 (94)
CN
CONH 2
2
N
N
S
S
2
3
3
>99 (96)
97 (93)
CN
CONH2
CONH 2
CN
2
N
N
H
H
NC
H2NOC
4
1.5
92
O
O
O
aReaction conditions: nitrile (1 mmol), NaBH4 (0.7O5 equiv), EtOH : H2O (1:1, 5 mL), 80
oC temperature.
bGC-MS yield, isolated yields are given in parentheses.
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Table 4. Regioselective hydration of various benzenedinitriles using NaBH4
a
NaBH4
R
CONH2
R
CN
EtOH + H2O (1:1), 5 mL
80 O
C
Entry
1
Substrate
Time (h)
4
Product
Yield (%)b
94
CN
O
NH
CN
CN
O
CONH2
2
4
91
CN
CN
CN
CONH2
3
4
4
5
98 (94)
85
NC
NC
t-Bu
CN
CN
t-Bu
O
NH
O
aReaction conditions: nitrile (1 mmol), NaBH4 (0.75 equiv), EtOH : H2O (1:1, 5 mL), 80
oC temperature.
bGC-MS yield, isolated yields are given in parentheses.
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Scheme 1. Plausible reaction pathway for base (NaBH4) promoted nitrile hydration
reaction.
NaBH4
H2O (excess)
+
NaB(OH)4
H2
_
+
_
_
_
R
C
O
NH
R
C
N
R
C
N
+
OH
OH
H2O
R
C
O
NH2
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Figure 1. Effect of NaBH4 quantity on hydration of nitrile to amide.
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19