An efficient synthesis of nitrile, tetrazole and urea from carbonyl compounds

Article abstract of DOI:10.1039/c6nj03860c

An efficient conversion of carbonyl compounds (aldehydes and ketones) to nitrile, tetrazole, and urea was developed with the use of a POCl₃ and sodium azide mixture using a convergent and microwave method. This is the first report on the direct conversion of ketone to urea. The synthesized compounds were characterized by ¹H NMR, ¹³C NMR, mass and IR spectroscopies and were found to be in agreement with reported compounds.

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An efficient synthesis of nitrile, tetrazole and urea
from carbonyl compounds†
Cite this:DOI: 10.1039/c6nj03860c
Rajendran Sribalan, Arumugam Sangili, Govindharasu Banuppriya and
Vediappen Padmini
*
An efficient conversion of carbonyl compounds (aldehydes and ketones) to nitrile, tetrazole, and urea
was developed with the use of a POCl3 and sodium azide mixture using a convergent and microwave
method. This is the first report on the direct conversion of ketone to urea. The synthesized compounds
were characterized by 1H NMR, 13C NMR, mass and IR spectroscopies and were found to be in
agreement with reported compounds.
Received 9th December 2016,
Accepted 22nd March 2017
DOI: 10.1039/c6nj03860c
rsc.li/njc
used as a precursor for synthesizing various functionalities such as
amines,22 carbamates,23 isocyanates24 and imides.25 Urea deriva-
Introduction
Carbonyl conversions are important processes in organic syntheses/ tives have also shown many applications in the fields of materials
preparations. They have been used to synthesize various effective chemistry,26 electrochemistry,27 crystallography,28 catalyses,29 photo-
intermediates such as amides,1 oximes,2 imines,3 alcohols4 and chemistry,30 polymer chemistry31 and medicinal chemistry.32 In
tetrazoles.5 Many scientists have developed various synthetic particular, in the medicinal chemistry field, urea-based compounds
methods starting from carbonyl precursors.6 The Schmidt reaction have shown various bioactivities such as antibacterial,33 anti-
is one of the well-known methods for carbonyl conversions.7 In this inflammatory,34 anticancer,35 antidiabetic,36 and anti-HIV37 activities.
process, carbonyl compounds were converted into carboxamides in Urea denatures nucleobases38 and proteins39 and has been reported
the presence of an acid/Lewis acid catalyst and an azide source.8,9 as a Rho kinase inhibitor.40 To the best of our knowledge, there are no
Further, the carboxamides can be converted into tetrazoles with the reports available on these conversions (nitrile, tetrazole, and urea)
use of sodium azide and a halogenating agent.10 In our previous with POCl3 and NaN3 mixtures. Few reports are available on the
report, we developed the methodology for direct conversion of amide synthesis of urea by Curtius rearrangement,41 and the reaction of
to tetrazole with the use of POCl3 and NaN3.11 Phosphoryl chloride is isocyanates/phosgenes with an amine.42,43 But there are no reports
a well-known halogenating agent which can also act as an acid catalyst. available on the conversion of carbonyl compounds to urea. In
So the direct conversion of carbonyl to tetrazole can be achieved with particular, this is the first report on the direct conversion of ketone
the use of POCl3 and sodium azide via amide formation.
to urea. The conversion of an aldehyde to nitrile has been reported
The actual research is planned to synthesize tetrazole from with a long reaction time.44–49 But there are no reports available on
carbonyl compounds because tetrazole has numerous applica- the conversion of an aldehyde to nitrile within a minute at room
tions in the field of chemistry.12–15 Three different precursors temperature. Thus the research is continued to develop the conver-
such as benzaldehyde, acetophenone, and benzophenone have sion of carbonyls to nitrile, tetrazole, and urea with the use of a POCl3
been chosen and the reaction methodology has been followed and NaN3 mixture. Furthermore, these conversions were developed in
as per Sribalan et al.11 As expected, acetophenone converted a microwave synthesizer for reducing the reaction time. The merits of
into tetrazole and the other precursors gave different unexpected this method include less reaction time, low-cost reagents, easily
products. The unexpected products were isolated and identified available precursors, single step conversion, reagents as solvents
as benzonitrile and diphenylurea. These products are valuable and good yields. Overall, the conversion of carbonyls to various
intermediates having various synthetic applications. Nitrile functionalities is presented in Scheme 1.
compounds are very good precursors for synthesizing various
functional groups such as carboxylic acids,16 oximes,17 tetrazoles,18
amines,19 imidazoles20 and carboxamides.21 Similarly, urea can be
Experimental section
General consideration
Department of Organic Chemistry, Madurai Kamaraj University, Madurai-625 021,
All the reactions were carried out with the use of a guard tube
Tamil Nadu, India. E-mail: padimini_tamilenthi@yahoo.co.in
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c6nj03860c set-up and nitrogen gas was purged into the reaction set-up
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gas was purged into the reaction mixture for 5 min. The
reaction mixture was heated to 80 1C for 9 h. The completion
of the reaction was monitored by TLC. Then the reaction
mixture was allowed to attain room temperature and carefully
quenched with crushed ice. Then the reaction mixture was
extracted with ethyl acetate, and washed with sodium bicarbonate
solution (50 mL), water (50 mL) and brine solution (50 mL). The
organic layer was separated and dried over anhydrous sodium
sulfate. The solvent was evaporated under reduced pressure, and
finally, the product was purified by column chromatography with
ethyl acetate and petroleum ether as an eluent.
Microwave method. In a 10 mL double neck RB flask, aceto-
phenone (1 mmol), phosphorus oxychloride (2 mmol) and
sodium azide (2 mmol) were added and one neck is connected
to a reflux condenser with a guard tube and the other neck is
connected to a nitrogen inlet. The nitrogen gas is purged into
the reaction mixture for 10 min. Then the nitrogen inlet was
removed and immediately closed with a stopper. The reaction
setup was fixed in a microwave synthesizer (better to avoid
sealed tube microwave irradiation). The reaction mixture was
subjected to microwave irradiation at 120 W at 90 1C for 20 min.
Then the reaction mixture was allowed to attain room temperature.
Then the reaction mixture was quenched with crushed ice. The
mixture was neutralized with sodium bicarbonate solution. The
product was extracted with ethyl acetate (50 mL), and washed with
water (50 mL) and brine solution (50 mL). The organic layer was
separated and dried over anhydrous Na2SO4 and concentrated under
reduced pressure. Finally, the product was purified by column
chromatography petether and ethlyl acetate with as an eluent.
General procedure for the conversion of benzophenones
to diphenyl urea derivatives (6a–l)
Thermal method. To benzophenone (1 mmol), sodium azide
(2 mmol) and phosphorus oxychloride (5 mmol) were added (in
the open vessel with a guard tube). Before starting the reaction,
nitrogen gas was purged into the reaction mixture for 5 min.
The reaction mixture was heated to 80 1C for 24 h. The comple-
tion of the reaction was monitored by TLC. Then the reaction
mixture was allowed to attain room temperature and carefully
quenched with crushed ice. Then the reaction mixture was
extracted with ethyl acetate and washed with sodium bicarbonate
solution (50 mL), water (50 mL) and brine solution (50 mL). The
Scheme 1 Schematic representation of various carbonyl conversions.
before starting the reaction (to avoid moisture contact). All the
reagents were purchased from Sigma-Aldrich/Spectrochem.
Phosphoryl chloride was used from a freshly opened bottle or
a distilled one (to avoid moisture contact in the reaction). The
reactions were tested up to a 5 g scale in the thermal method
and a 3 g scale in the microwave method (for safety purposes).
(Caution: Generally, azides are explosives. So the personal
protective equipment (PPE) like face shields has to be worn
before starting the reactions.) IR spectra were recorded on a
JASCO FT-IR410 using the KBr pellet method. 1H NMR and 13
C
NMR spectra were recorded on Bruker 300 MHz and 75 MHz
instruments in CDCl3 with TMS as an internal standard.
Chemical shift values are mentioned in d (ppm) and coupling
constants are given in Hz. Mass spectra were recorded on an AB
SCIEX 3000 LC-MS. The progress of all reactions was monitored
by TLC on 2 Â 5 cm pre-coated silica gel 60 F254 plates with a
thickness of 0.25 mm (Merck). The chromatograms were visualized
under UV 254–366 nm and iodine. All the reactions (both thermal
and microwave reactions) were carried out in an open vessel with a
guard tube set-up for the safer method.
Chemistry
General procedure for the conversion of aldehydes to nitriles organic layer was separated and dried over anhydrous sodium
(2a–n). To a stirred mixture of aldehyde (1 mmol) and sodium sulfate. The solvent was evaporated under reduced pressure, and
azide (1 mmol), phosphorus oxychloride was added (in the finally, the product was purified by column chromatography with
open vessel with a guard tube) and the reaction mixture was ethyl acetate and petroleum ether as an eluent.
quenched with crushed ice. Then the reaction mixture was
extracted with ethyl acetate (50 mL), and washed with sodium
Microwave method. In a 10 mL double neck RB flask,
bicarbonate solution (50 mL), water (50 mL) and brine solution benzophenones (1 mmol), phosphorus oxychloride (5 mmol)
(50 mL). The organic layer was separated and dried over anhydrous and sodium azide (2 mmol) were added and one neck is
Na2SO4. The evaporation of the solvent afforded the product.
General procedure for the conversion of acetophenones other neck is connected to a nitrogen inlet. The nitrogen gas is
to 5-methyltetrazoles (4a–j) purged into the reaction mixture for 10 min. Then the nitrogen
connected to a reflux condenser with a guard tube and the
Thermal method. To acetophenone (1 mmol), sodium azide inlet was removed and immediately closed with a stopper. The
(2 mmol) and phosphorus oxychloride were added (in the open reaction setup was fixed in a microwave synthesizer (better to
vessel with a guard tube). Before starting the reaction, nitrogen avoid sealed tube microwave irradiation). The reaction mixture
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Table 2 Optimization of the reaction conditions for conversion of aceto-
phenone to 5-methyltetrazole
was subjected to microwave irradiation at 120 W at 90 1C for
30 min. Then the reaction mixture was allowed to attain room
temperature. Then the reaction mixture was quenched with
crushed ice. The mixture was neutralized with sodium bicarbonate
solution. The product was extracted with ethyl acetate (50 mL), and
washed with water (50 mL) and brine solution (50 mL). The organic
layer was separated and dried over anhydrous Na2SO4 and con-
centrated under reduced pressure. Finally, the product was purified
by column chromatography with pet etheracetate as an eluent.
S. No. POCl3 (eq.) NaN3 (eq.) Temperature (1C) Time (h) Yield (%)
1
2
3
4
5
6
7
1.0
2.0
2.0
2.0
2.0
5.0
10.0
2.0
2.0
2.0
2.0
3.0
2.0
2.0
60
60
80
95
80
80
80
12
11
9
8
9
10
10
50
82
87
75
80
84
75
Results and discussion
Initially, the conversion of an aldehyde to nitrile was carried out
in the presence of a POCl3 and NaN3 mixture and benzaldehyde
was chosen as a model substrate for optimization. The best
solvents for dissolving sodium azide were water, DMF, and
DMSO. The selection of these solvents was not advisable for our
reaction conditions, because these solvents readily react with
POCl3 and generate by-products such as phosphoric acid,
Vilsmeier formulating agents and Swern oxidizing agents.50,51
So the reaction was started with toluene, THF, 1,4-dioxane, and
acetonitrile and carried out with equimolar amounts of POCl3
and NaN3 at room temperature. Depending on the polarity of
the solvents, the reaction time was varied and yields achieved
were from moderate to good (Table 1, entries 1–4). The pre-
liminary results suggested that acetonitrile is a good solvent
because its reaction time and yields are better than those of the
others. When temperature was increased to 80 1C the reaction
time was reduced to 30 min and the yield of the reaction was
increased to 86% (Table 1, entry 5). Even though the reaction
was complete in 30 minutes with a good solvent, the research
was continued to develop better optimization. Since our previous
report suggested that only POCl3 and NaN3 were better than
solvent used methodologies, optimization was continued with
excessive POCl3 (5 eq.) and equimolar sodium azide at room
temperature (Table 1, entry 6). Unexpectedly, the reaction was
complete within a minute and the reaction yield was increased to
92%. Furthermore, the reaction was repeated for its development
from the previous optimization with equimolar POCl3 and NaN3
(Table 1, entry 7). The same results were obtained with 95% yield.
Thus, the optimized results revealed that equimolar sodium azide
and POCl3 were the best conditions for the conversion of an
aldehyde to nitrile. The list of these optimized conditions for this
conversion is presented in Table 1.
Based on the above-optimized results, the conversion of
acetophenone to tetrazole was started with neat POCl3 and
sodium azide. The first reaction was carried out with equimolar
POCl3 and NaN3 at 60 1C (Table 2, entry 1). The reaction was
complete in 12 h and the yield was 50% correspondingly.
Furthermore, for improving the yield of the reaction, the
quantity of POCl3 was increased to 2 eq. and the reaction was
repeated at 60 1C. The reaction was complete in 11 h and its
yield was improved to 82% (Table 2, entry 2). To identify the
best optimized conditions the reaction was repeated under
several reaction conditions and reagent quantities (Table 2,
entries 3–7). Among the various conditions, 2 eq. of POCl3 with
equimolar sodium azide (2 eq.) at 80 1C for 9 h with 87% yield
were identified as the best optimized conditions (Table 2, entry 3).
Upon continuation, the same method was developed in the
microwave synthesizer (open vessel method).
The best conditions in the thermal method (Table 2, entry 3)
were chosen for optimization in a microwave synthesizer for the
conversion of acetophenone to tetrazole. To optimize the best
reaction conditions different microwave powers (80 to 120 W),
temperatures (80 to 100 1C) and reaction times (5 to 30 min)
were applied (Table 3, entries 1–7). Among these conditions,
2 eq. of POCl3, 2 eq. of NaN3 at 90 1C, and 120 W for 20 min
were identified as the best optimized conditions with 82% yield
of the product (Table 3, entry 6). The list of optimized conditions
for the conversion of acetophenone to 5-methyltetrazole using both
thermal and microwave methods is presented in Tables 2 and 3.
Similarly, neat POCl3 and NaN3 were chosen for the conver-
sion of benzophenone to diphenylurea. Initially, the reaction was
carried out with 1–2 eq. of POCl3 and 1–2 eq. of NaN3 for 12 h at
60 1C. The reactions yielded a trace amount of diphenylurea
(Table 4, entries 1 and 2). To optimize the best conditions, the
reaction was repeated with different equivalents of reagents,
reaction times and temperatures (Table 4, entries 3–10). Finally,
the optimized reaction conditions were identified as 5 eq. of
Table 1 Optimization of the reaction conditions for conversion of an
aldehyde to nitrile
POCl3
(eq.)
NaN3
(eq.)
Temp.
(1C)
Yield
(%)
S. No.
Solvent
Time
1
2
3
4
5
6
7
Toluene
THF
1,4-Dioxane
ACN
ACN
POCl3
Nil
1.0
1.0
1.0
1.0
1.0
5.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
RT
RT
RT
RT
80 1C
RT
RT
8 h
6 h
5 h
4.5 h
30 min
o1 min
o1 min
70
75
79
81
86
92
95
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Table 3 Optimization of the reaction conditions for conversion of aceto-
Table 5 Optimization of the reaction conditions for conversion of benzo-
phenone to 5-methyltetrazole using the microwave method
phenone to diphenyl urea using the microwave method
S. No. MW power (W) Temperature (1C) Reaction time (min) Yield (%)
S. No. MW power (W) Temperature (1C) Reaction time (min) Yield (%)
1
3
4
5
6
7
8
9
80
80
80
80
80
90
90
90
90
90
10
20
20
20
20
20
30
40
Trace
10
15
53
59
64
73
66
1
2
3
4
5
6
7
80
80
80
100
100
120
120
80
80
80
80
90
90
100
5
20
30
20
20
20
20
o5
22
28
35
43
82
74
100
100
110
120
120
120
electron donating groups like methoxy and methyl on the para
positions gave good yields when compared to the parent substrate
(85–88%). Similarly, a chloro substituent on the para position gave
84% tetrazole. But an electron withdrawing group (–NO2) on the
para position affected the yield of the reaction, which afforded
62–63% of the product. Similarly, ortho substituents also affect the
yield of the reaction. For instance, ortho methoxy acetophenone
gave 53–55% tetrazole. The meta substituent gave a moderate yield
(73–75%). Bulky substituents like naphthalene and biphenyl and
Table
4
Optimization of the reaction conditions for conversion of
benzophenone to diphenylurea using the thermal method
S. No. POCl3 (eq.) NaN3 (eq.) Temperature (1C) Time (h) Yield (%)
1
2
3
4
5
6
7
8
9
10
1.0
2.0
2.0
2.0
2.0
5.0
5.0
5.0
5.0
10.0
2.0
2.0
2.0
2.0
3.0
2.0
2.0
2.0
2.0
2.0
60
60
80
95
80
80
80
80
80
80
12
12
12
12
15
15
20
24
36
24
Trace
Trace
o5
o5
o5
25
52
75
70
68
POCl3, 2 eq. of NaN3 at 80 1C for 24 h with 75% yield of
diphenylurea. During the course of the reaction, there was the
formation of diphenyltetrazole as a by-product (15%) which was
inevitable. When the quantity of NaN3 was high, tetrazole
formation also increased. The usage of 2 eq. of NaN3 resulted
in a maximum yield of urea. Furthermore, the same reaction was
developed in a microwave synthesizer (open vessel method).
The best conditions in the thermal method were chosen for
the microwave synthetic method during the conversion of
benzophenone to diphenylurea. To optimize the best reaction
conditions, the microwave power (80 to 120 W), temperature
(80 to 90 1C) and reaction time (10 to 40 min) were changed
(Table 5, entries 1–9). Among these conditions, 5 eq. of POCl3,
2 eq. of NaN3 at 90 1C, and 120 W for 30 min were identified as
the best optimized conditions with 82% yield of the product
(Table 5, entry 8). The list of optimized conditions for the
conversion of benzophenone to diphenylurea by both thermal
and microwave methods is presented in Tables 4 and 5.
The scope of these conversions was examined with various
substrates like electron withdrawing, electron donating and
sterically hindered precursors. Negligible yield variations were
identified in the conversion of an aldehyde to nitrile (84–96%).
In the case of conversion of acetophenones to 5-methyltetrazoles,
Fig. 1 List of synthesized nitriles.
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Fig. 2 List of synthesized tetrazoles.
heterocycles like thiophene also gave a good yield of products
(80–84%).
In the conversion of acetophenone to tetrazole, the addition
of carbonyl to phosphoryl chloride gives vinyl chloride IV. The
Similar to acetophenone conversion, the substrate scope affects nucleophilic addition of an azide anion to vinyl chloride gave
the conversion of benzophenones to diphenylureas. Substituents vinyl azide V. Furthermore, nucleophilic addition of an azide
like methyl and chloro on the para position gave 70–73% yields of anion to vinyl azide gave intermediate VII via intermediate VI.
urea. An electron withdrawing group like nitro on the para position Finally, tetrazole VIII was obtained via internal cyclization of
gave a very poor yield (50–52%). Similarly, substituents on the intermediate VII.
ortho position gave a poor yield of the product (54–56%). The meta
In the conversion of benzophenone to urea, the intra-
substitution and bulky units such as phenoxyphenyl and naphtha- molecular rearrangement of R2 in intermediate II gave inter-
lene gave 60–69% of products. Aliphatic substituents containing mediate IX. The nucleophilic addition of an azide anion to
substrate tert-butyl phenyl ketone gave their corresponding urea intermediate IX gave intermediate X. X gave carbodiimide XII
with 61–62% yield. The little yield variations were identified with the elimination of nitrogen molecules followed by the
between thermal and microwave conversions. The list of synthe- rearrangement.11 The carbodiimide gave the corresponding
sized products and their yields is presented in Fig. 1–3.
urea XIII upon the addition of water (while quenching).11
Plausible mechanisms for the formation of products were During this conversion, the minor product tetrazole is formed
proposed from their corresponding precursors (Fig. 4). For from the internal cyclization of intermediate X. The tetrazole
proposing the mechanism for these conversions, the intermediates and intermediate X are in equilibrium with each other and lead to
were isolated (intermediates IV and XII, which are presented in the tetrazole formation.52 Upon increasing the sodium azide quantity,
ESI†). Based on the intermediate and product formation, the the equilibrium is shifted towards tetrazole formation.
plausible mechanism for these conversions was proposed.
From the above conversions, it is clear that the carbonyl
In the conversion of an aldehyde to nitrile, the lone pair of compounds containing the a-hydrogen are ready to convert into
oxygen of carbonyl attacks the phosphoryl chloride, giving vinyl chloride with phosphoryl chloride. It further reacts with
intermediate I. Intermediate I gave intermediate II. The final sodium azide and gives tetrazoles.53 But the benzophenone
product III was obtained from intermediate II via the elimination based compound does not have a-hydrogen and follow a different
of H+ and nitrogen molecules.
reaction pathway with the same reagents and conditions. So it
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Fig. 3 List of synthesized diphenyl urea derivatives.
Fig. 4 Plausible mechanism for the formation of nitrile, tetrazole, and urea.
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13 M. V. Werrett, S. Muzzioli, P. J. Wright, A. Palazzi, P. Raiteri,
S. Zacchini, M. Massi and S. Stagni, Inorg. Chem., 2014, 53,
229–243.
14 M. Tariluzzi, A. S. Hameed, I. H. Bechtold, A. J. Bortluzzi
and A. A. Merlo, J. Mater. Chem. C, 2013, 1, 5583–5593.
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R. G. Picther and M. J. Kramer, J. Med. Chem., 1976, 19,
286–290.
afforded urea as the major product. The NMR spectra of
intermediates IV and XII and minor product XI are presented
in the ESI.†
All the synthesized compounds were characterized by 1H NMR,
13C NMR, mass and IR spectroscopies. The compounds were
matched with previously reported compounds which clearly con-
firm the product formations. The model spectra are provided in
the ESI.†
16 P. Lignier, J. Estager, N. Kardos, L. Gravouil, J. Gazza and
E. Naffrecjpix, Ultrason. Sonochem., 2011, 18, 28–31.
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Conclusion
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50, 3525–3528.
19 H. Goksu, S. F. Ho, O. Metin, K. Korkmaz, A. M. Garcia,
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20 E. Galeazzi, A. Guzman and J. L. Nava, J. Org. Chem., 1995,
60, 1090–1092.
New efficient synthetic methods were developed from the
unprecedented conversion of carbonyl compounds with eco-
nomically cheaper reagents. A plausible mechanism for the
formation of their corresponding products was proposed and
explained. The ongoing research is on synthesizing biologically
active nitrile, tetrazole, and urea based derivatives.
21 P. Marce, J. Lynch, A. J. Blacker and J. M. J. Williams, Chem.
Commun., 2016, 52, 1436–1438.
22 N. A. Stephenson, S. H. Gellman and S. S. Stahl, RSC Adv.,
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Acknowledgements
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The authors are grateful to UGC and DST, New Delhi, India, for
financial support and the DST-IRHPA program for providing
the high resolution NMR facility and acknowledge a UGC-Non-
Net fellowship for financial support.
26 E. I. Pereira, F. B. Minussi, C. C. da Cruz, A. C. Bernardi and
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