T3P mediated intramolecular rearrangement of o-aminobenzamide to o-ureidobenzonitrile using isothiocyanates

Article abstract of DOI:10.1080/00397911.2021.1873384

Current work describes the environmentally benign approach for the synthesis of o-ureidobenzonitriles, from o-aminobenzamides and isothiocyanates using T3P. Here, the conversion of thiourea to urea and amide to nitrile take place simultaneously via unprec

Full text of DOI:10.1080/00397911.2021.1873384

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
T3P mediated intramolecular rearrangement of
o-aminobenzamide to o-ureidobenzonitrile using
isothiocyanates
Sadashivamurthy Shamanth, Sandhya C. Nagarakere, Kunigal S. Sagar,
Yatheesh Narayana, Mahesha Mamatha, Kanchugarakoppal S. Rangappa &
Mantelingu Kempegowda
To cite this article: Sadashivamurthy Shamanth, Sandhya C. Nagarakere, Kunigal S. Sagar,
Yatheesh Narayana, Mahesha Mamatha, Kanchugarakoppal S. Rangappa & Mantelingu
Kempegowda (2021) T3P mediated intramolecular rearrangement of o-aminobenzamide to o-
ureidobenzonitrile using isothiocyanates, Synthetic Communications, 51:8, 1197-1205, DOI:
10.1080/00397911.2021.1873384
To link to this article: https://doi.org/10.1080/00397911.2021.1873384
Published online: 09 Feb 2021.
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2021, VOL. 51, NO. 8, 1197–1205
https://doi.org/10.1080/00397911.2021.1873384
T3P mediated intramolecular rearrangement of
o-aminobenzamide to o-ureidobenzonitrile using
isothiocyanates
a
b
a
Ã
Ã
Sadashivamurthy Shamanth , Sandhya C. Nagarakere , Kunigal S. Sagar ,
Yatheesh Narayanaa, Mahesha Mamathac, Kanchugarakoppal S. Rangappaa , and
Mantelingu Kempegowdaa
b
aDOS in Chemistry, Manasagangotri, University of Mysore, Mysuru, India; PG Department of Studies in
c
Chemistry and Research Centre, St. Philomena’s College, Mysuru, India; SRSMN Government First Grade
College, Barkur, India
ABSTRACT
ARTICLE HISTORY
Received 4 November 2020
Current work describes the environmentally benign approach for the
synthesis of o-ureidobenzonitriles, from o-aminobenzamides and iso-
thiocyanates using T3P. Here, the conversion of thiourea to urea and
amide to nitrile take place simultaneously via unprecedented intra-
molecular rearrangement. This protocol is operationally facile and
offers wide variety of o-ureidobenzonitriles at room temperature in
good to excellent yields.
KEYWORDS
Intramolecular rearrange-
ment, isothiocyanates, o-
ureidobenzonitrile, T3P
GRAPHICAL ABSTRACT
Introduction
T3P (Propane phosphonic acid anhydride) (Figure 1), is a versatile and unique reagent
that is being used in many organic reactions like functional group transformations, con-
densation, acylation, oxidation reactions. It is an excellent dehydrating agent and cou-
pling reagent in peptide synthesis.[1] Compared to other traditional reagents, T3P is
eco-friendly, less allergic, less toxic and can be easily removed from the reaction mixture
as it is highly soluble in aqueous solutions.
CONTACT Kanchugarakoppal S. Rangappa
rangappaks@gmail.com; Kempegowda Mantelingu
kmlingu@gmail.com
Equal first authors.
DOS in Chemistry, Manasagangotri, University of Mysore, Mysuru, 570006 Karnataka, India.
Ã
Supplemental data for this article can be accessed on the publisher’s website.
ß 2021 Taylor & Francis Group, LLC

1198
S. SHAMANTH ET AL.
Figure 1. T3P structure.
Figure 2. Bioactive molecules containing urea moiety.
Urea and its derivatives have a broad range of biochemical effects and pharmaceutical
applications for their unique ability to form hydrogen bonds with proteins and receptor
targets.[2,3] They also have extensive applications in agrochemicals. Some of the
urea derivatives have been found to exhibit anti-diabetic, antibacterial[4a], antiviral[4b]
,
anti-HIV[4c], anti-cancer[4d], hypnotic and sedative activities[4e]. Among those many are
clinically approved drugs, such as glyburide (anti-diabetic), sorafenib and linifanib (anti-
cancer) (Figure 2) bearing urea as key moiety.[5] In recent years, intense research have
been focused on the design and synthesis of urea derivatives of biological interest.
Traditional methods for the synthesis of urea involve the reaction of amines with iso-
cyanate, CO and phosgene. Ureas are also synthesized using activated carbamates, car-
bonates, carbon monoxide, carbon dioxide at elevated temperatures.[6]
Nearly 30 pharmaceuticals containing nitrile as core motif are recommended for a
diverse variety of medicinal indications.[7] Saxagliptin,[8a] cimetidine[8b] and anastrozo-
le[8c] are the nitrile-containing drugs prescribed for the treatment of type 2 diabetes,
peptic ulcer and breast cancer respectively. In addition they also have applications in
dyes, agrochemicals and are also synthetic intermediates for the preparation of amines,
amides, alcohols, ketones, carboxylic acids, oxazolines, some polymers and many hetero-
cycles.[9] Therefore, the development of methods for the synthesis of nitriles is one of
the most important task in organic chemistry. Nitriles are generally synthesized by the
dehydration of primary amides and aldoximes. The functional group conversion of

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Scheme 1. Previous works for the synthesis of o-ureidobenzonitriles.
amide to nitrile is a difficult task, which requires acidic dehydrating reagents such as
POCl3, P2O5, TFAA, TiCl4 or SOCl2.[10] Recently, Imen Talbi et al. developed a method
for the conversion of amides to nitriles using phosphorus-III reagents P(NMe2)3, PCl3
and P(OPh)3 as dehydrating agents.[11] Wan-Yin Fang and Hua-Li Qin et al. have
developed some methods which are mediated by SO2F2 to convert primary alcohols,
phenols and aldehydes into corresponding nitriles.[12]
Again, only few methods have been reported for the synthesis of o-ureidobenzoni-
triles (Scheme 1). The traditional method involves the reaction between o-aminobenzo-
nitrile and isocyanates in presence of base. The method developed by Pedro Molina
et al is a three steps process, starting with o-aminobenzamide.[13] Recently we estab-
lished a new protocol using o-aminobenzamides and isothiocyanates catalyzed by
molecular iodine.[14] All the above discussed methods have tremendous toxicological
and environmental problems, suffers from narrow scope and lower yield.
Here, we are reporting a simple and straight forward method for the synthesis of o-
ureidobenzonitriles, which has many advantages than the existing protocols. This
method requires readily available inexpensive starting materials o-aminobenzamides, iso-
thiocyanates, and T3P as reagent. The metal free route achieved here requires less time,
works at room temperature, has easy work up procedure and exceptional functional
group tolerance. The substrate scope for this method is very broad which includes phe-
nyl, benzyl and aliphatic moieties and are synthesized in outstanding yields.
Furthermore, the title compounds can serve as starting materials for many heterocycles
like quinazolines and quinazolinones.[15]
Result and discussion
In continuation of our work on the synthesis of heterocycles via novel methodolo-
gies,[16] we designed a scheme to synthesis quinazolinones (Scheme 2). Initially we
treated the mixture of o-aminobenzamide 1a and phenyl isothiocyanate 2a with one
equivalent of T3P and DMSO in DMF solvent at room temperature for 12 h. The start-
ing materials were consumed partially and a new non-polar spot was observed in TLC,
which then isolated through column chromatography with 43% yield. Analysis of the

1200
S. SHAMANTH ET AL.
Scheme 2. Reaction between o-aminobenzamide and phenylisothiocyanate—expected and
obtained products.
Figure 3. ORTEP diagram of 1-(2-cyanophenyl)-3-phenylurea (3a): CCDC number-2005876.
isolated product confirmed that, we have not got the expected product 2(phenylamino)-
quinazolin-4(3H)-one but the 1-(2-cyanophenyl)-3-phenylurea, 3a has been formed
(Figure 3).
After the confirmation of structure, we initiated to optimize the reaction conditions
to synthesize compound 3a in an improved yield and the results obtained are summar-
ized in Table 1. No desired product was observed in the absence of T3P or DMSO or
both (Table 1, Entries 1–3). We then carried out the reaction using one equivalence of
T3P and DMSO and obtained the product 3a with 46% yield (Table 1, Entry 4).
Increase in the loading of DMSO to 1.5, 2.0 and 2.5 equiv. and using one equiv. of
T3P, yielded 68, 86 and 84% of the product respectively (Table 1, Entries 5–7). Now, by
fixing DMSO quantity to 2.0 equiv., we used 0.5 and 1.5 equiv. of T3P and got 40 and
85% yields respectively (Table 1, Entries 8 and 9). So, in terms of yield, use of one
equiv. of T3P and two equiv. of DMSO as additives was found to be the best among all
the experimented ratios. Elapsing more time with these quantities of additives didn’t

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Table 1. Optimization of the reaction conditions.a
Entry
T3P (equiv.)
DMSO (equiv.)
Solvent
Temp. ꢀC
Time h
Yield %b
1
2
3
4
5
6
7
8
0.0
0.0
1.0
1.0
1.0
1.0
1.0
0.5
1.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.0
1.0
0.0
1.0
1.5
2.0
2.5
2.0
2.0
2.0
–
2.0
2.0
2.0
2.0
2.0
2.0
2.0
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
40
60
24
24
24
4
4
4
4
4
4
10
4
4
4
4
4
4
4
4
–
–
–
46
68
86
84
40
85
82
89
63
68
73
–
9
10
11
12
13
14
15
16
17
18
DMF
DMSO
EtOAc
EtOH
THF
H2O
Toluene
DMSO
DMSO
51
71
58
aOptimal reaction conditions: 1a (1 mmol), 2a (1 mmol) and T3P (1.0 mmol) in DMSO solvent (1 ml) at room temperature
for 4 h.
bIsolated yield.
improve the yield considerably (Table 1, Entry 10). We further screened the reaction
using solvents DMSO, EtOAc, EtOH, THF, H2O and toluene (Table 1, Entries 11–16).
The use of DMSO solvent, which is also an additive was found to be most favored,
among the solvents employed (Table 1, Entry 11). The increase of temperature didn’t
facilitate the reaction in terms of yield (Table 1, Entry 17, 18). In conclusion, we found
that, the reaction of o-aminobenzamide (1a) (1 mmol) and phenyl isothiocyanate (2a)
(1 mmol) with T3P (1 mmol) in DMSO solvent at room temperature for 4 h was the
ideal condition (Table 1, Entry 11) to synthesize 1-(2-cyanophenyl)-3-phenylurea, 3a.
Using the best optimized condition, we further proceeded to synthesize a library of o-
ureidobenzonitriles, using different combinations of o-aminobenzamide and isothiocya-
nates. We successfully synthesized twenty title compounds with excellent yields, which
include phenyl, benzyl and aliphatic moieties of isothiocyanates with o-aminobenza-
mides (Table 2). The substituents on phenyl ring of isothiocyanates includes electron
donating groups (–Me, –OMe), electron-withdrawing groups (–NO2, –CF3) and halo-
gens (–F, –Cl, –Br). The yields of the reaction were not much dependent on the nature
of the substituents as well as their positions on the benzene ring of isothiocyanates.
However, in case of electron-withdrawing groups, like nitro and trifluromethyl, which
are at ortho positions, the yields are a little better. This may be attributed to the fact
that the electron-withdrawing groups may facilitate the nucleophilic attack of amine
group of o-aminobenzamide on the carbon atom of isothiocyanate. The yields obtained
in case of benzyl and aliphatic isothiocyanates are little less when compared to phenyl
isothiocyanates. All these examples clearly illustrate the utility of the protocol for wider

1202
S. SHAMANTH ET AL.
Table 2. Substrate scope of the reaction.a
aReactions were performed with 1 (1 mmol) and 2 (1 mmol) using T3P (1.0 mmol) in DMSO solvent (1 ml) at room tem-
perature for 4 h.
Scheme 3. Plausible mechanism for the formation of o-ureidobenzonitrile.

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applicability. We synthesized 3a in 2.0 g scale and procured 85% yield which was 89%
when synthesized in mmol scale.
A probable mechanism has been proposed for the synthesis of o-ureidobenzonitriles
displayed in Scheme 3. The reaction between o-aminobenzamide 1a and phenyl isothio-
cyanate 2a first produces thiourea intermediate A. The interaction between T3P and
sulfur atom of the thiocarbonyl group,[1c] trailed by the nucleophilic attack of carbonyl
oxygen on the thiocarbonyl carbon leads to the formation of cyclized intermediate B.
Deprotonation of amide group is done by DMSO. The unstable intermediate B further
undergoes intramolecular rearrangement and generates stable o-ureidobenzonitrile 3a.
Conclusion
Herein, we disclose a new and efficient method for the synthesis of o-ureidobenzoni-
triles under metal, ligand and acid-free conditions using nontoxic and eco-friendly
reagent T3P via unique intramolecular rearrangement. The unexpected rearrangement
involves the conversion of thiourea to urea and amide to nitrile simultaneously. We
were able to synthesize a variety of o-ureidobenzonitriles, which are the precursors for
the synthesis of heterocycles like quinazolines and quinazolinones. The unique reaction
path observed here is employing to explore some new kind of reactions. Further exten-
sion of the substrate scope in synthesizing urea derivatives of biological interest and the
study of their pharmacological and agro-chemical applications are under progress.
Experimental section
General procedure for the synthesis of o-ureidobenzonitriles (3a–3t)
The mixture of o-aminobenzamide (1) (1 mmol) and isothiocyanates (2) (1 mmol) was
allowed to stir in DMSO solvent (1 ml) and T3P (Propane phosphonic acid anhydride
solution: 50 wt. % in ethyl acetate) reagent (1 mmol, 0.7 g) at room temperature for 4 h
in a round-bottomed flask. After that, the contents of the flask were poured into 15 ml
of water taken in separating funnel and extracted to 15 ml ethyl acetate. The ethyl acet-
ate extract was separated and dried over anhydrous sodium sulfate. The solvent was
then removed under reduced pressure to afford corresponding crude o-ureidobenzoni-
trile (3). The crude residue thus obtained was purified by column chromatography over
silica gel using 10% ethyl acetate in hexane as eluent to afford the pure o-ureidobenzo-
nitrile with 80–95% yields.
General experimental protocols, characterization details, 1H-NMR, 13C-NMR and
HRMS spectra of compounds and crystal analysis details are in the supporting informa-
tion file.
Funding
The author S.S. thank the UGC, New Delhi for the financial support in the form of UGC-JRF/
SRF fellowship [Order no. 143540]. Financial support from the VGST Project [Grant No. Ksteps/
VGST/GRD-681/KFIST(L1)/2018, dated: 27-08-2018] and PURSE grant [Grant No. PURSE/Phase
2/27(C), dated: 13/09/2019 and PURSE/Phase 2/27(G), dated: 01/10/2019] are also gratefully
acknowledged.

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S. SHAMANTH ET AL.
ORCID
Kanchugarakoppal S. Rangappa
http://orcid.org/0000-0003-0572-6305
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