Chemoselective reaction of benzoylisothiocyanates with hydroxyl group of salicylamide: A new and convenient entry into 2-Aryl-4 H -benzo[e][1,3]oxazin-4- ones

Article abstract of DOI:10.1080/10426507.2012.755974

The reactions of benzoylisothiocyanates with salicylamide in pyridine-xylene solution occurs chemoselectively at the hydroxyl group of the salicylamide to afford the corresponding O-benzoyl derivatives. The latter products, on prolonged heating in pyridin

Full text of DOI:10.1080/10426507.2012.755974

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Phosphorus, Sulfur, and Silicon and the
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Chemoselective Reaction of
Benzoylisothiocyanates with Hydroxyl
Group of Salicylamide: a New and
Convenient Entry Into 2-Aryl-4H-
benzo[e][1,3]oxazin-4-ones
Tarjeet Singh a , Girija S. Singh b & Ram Lakhan a
a Department of Chemistry , Banaras Hindu University , Varanasi ,
221 005 , India
b Department of Chemistry, University of Botswana , Private Bag
0022, Gaborone , Botswana
Accepted author version posted online: 02 Jan 2013.Published
online: 06 Sep 2013.
To cite this article: Tarjeet Singh , Girija S. Singh & Ram Lakhan (2013) Chemoselective Reaction
of Benzoylisothiocyanates with Hydroxyl Group of Salicylamide: a New and Convenient Entry Into 2-
Aryl-4H-benzo[e][1,3]oxazin-4-ones, Phosphorus, Sulfur, and Silicon and the Related Elements, 188:10,
1442-1448, DOI: 10.1080/10426507.2012.755974
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Phosphorus, Sulfur, and Silicon, 188:1442–1448, 2013
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426507.2012.755974
CHEMOSELECTIVE REACTION OF
BENZOYLISOTHIOCYANATES WITH HYDROXYL GROUP
OF SALICYLAMIDE: A NEW AND CONVENIENT ENTRY
INTO 2-ARYL-4H-BENZO[E][1,3]OXAZIN-4-ONES
Tarjeet Singh,1 Girija S. Singh,2 and Ram Lakhan1
1Department of Chemistry, Banaras Hindu University, Varanasi-221 005, India
2Department of Chemistry, University of Botswana, Private Bag 0022, Gaborone,
Botswana
GRAPHICAL ABSTRACT
Abstract The reactions of benzoylisothiocyanates with salicylamide in pyridine-xylene solu-
tion occurs chemoselectively at the hydroxyl group of the salicylamide to afford the correspond-
ing O-benzoyl derivatives. The latter products, on prolonged heating in pyridine-xylene solu-
tion, undergo cyclodehydration to give 2-aryl-4H-benzo[e][1,3]oxazin-4-ones in good yields.
These compounds could also be synthesized by a direct one-pot reaction of benzoylisoth-
iocyanates with salicylamide by slow addition of benzoylisothiocyanates into a solution of
salicylamide in xylene-pyridine solution under reflux. The products have been characterized
on the basis of satisfactory analytical and spectral data.
Keywords Benzoylisothiocyanates; salicylamide; bezoxazinones; cyclodehydration
INTRODUCTION
The reactions of heterocumulenes are of interest to organic chemists from a synthetic
and mechanistic point of view. Our group is involved in the investigation of the reactivity of
heterocumulenes, especially ketenes (C C O), with substrates having a nitrogen atom in
different structural environments.1 The reactions of ketenes often depend on the electronic
environments of the nitrogen nucleophilic center in the molecule. For example, the reac-
tion of diarylketenes with N-salicylideneamines containing two reactive sites, a hydroxyl
group and an imine linkage, is observed to occur at the hydroxyl group in a chemoselective
manner.2 A similar reaction with benzophenone N-diphenylacyl hydrazones has been ob-
served to take place at imino nitrogen but not at amidic nitrogen.3 However, the reaction of
Received 5 October 2012; accepted 14 November 2012.
Address correspondence to Professor Girija Shankar Singh, PhD, Department of Chemistry, University of
Botswana, Private Bag 0022, Notwane Road, Gaborone, Botswana. E-mail: singhgs@mopipi.ub.bw
1442

CHEMOSELECTIVE REACTION OF BENZOYLISOTHIOCYANATES
1443
diphenylketene with 3-iminoisatins, which contain both amido nitrogen and imine linkage,
occurs at amido nitrogen in the molecule.4
In continuation of these studies, we considered it pertinent to extend these investi-
gations using heterocumulenes that contain C N and C S groups besides C O such as
benzoylisothiocyanates [ArC(O)N C S]. The latter compounds are easily accessible in
the laboratory by reaction of the corresponding acyl chloride with ammonium thiocyanate.
We envisioned that such isothiocyanates could show an even more interesting reactivity
profile toward different nucleophiles that can be exploited for the synthesis of hetero-
cyclic systems. A literature survey revealed that the reactions of benzoylisothiocyanates
have drawn attention of organic chemists for applications in organic synthesis and medicinal
chemistry.5 It has been observed that the reactivity of such isothiocyanates often depends on
structure of isothiocyanates besides the other substrate in the reaction, solvents, and reaction
conditions.6 Recently, the reaction of benzoylisothiocyanate with 2-aminobenzothiophenes
has been employed in the synthesis of annulated thiophene derivatives.7 Our group recently
carried out the reactions of differently substituted benzoylisothiocyanates with symmetri-
cal bis-nucleophiles 1,2-phenylenediamines forming 2-arylbenzimidazoles.8 The usual bis-
thiourea products were cyclized by refluxing in pyridine to afford the 2-arylbenzimidazoles
(Scheme 1). In the present paper, we wish to report the reactions of benzoylisothiocyanates
with an unsymmetrical bis-nucleophile salicylamide leading to the formation of 2-aryl-4H-
benzo[e][1,3]oxazin-4-ones. The reaction of benzoylisothiocyanates occurs chemoselec-
tively at the hydroxyl group of salicylamide affording 2-(O-benzoyl)benzamides. The latter
compounds cyclize on prolonged heating to afford the 2-aryl-4H-benzo[e][1,3]oxazin-4-
ones.
Scheme 1
Benzoxazinones constitute an important class of heterocyclic compounds and have
been extensively explored as pharmaceuticals and agrochemicals.9 A few earlier studies
on the synthesis of 2-aryl-4H-benzo[e][1,3]oxazin-4-ones using salicylamide involve its
reaction with carbonyl compounds such as acid chlorides and ethyl chloroformate.10,11,12
A reaction of 1-aryl-1-chloro-2,2,2-trifluoromethylisocyanate with phenols is reported to
yield 2-aryl-2-trifluoromethyl-2,3-dihydro-4H-benzo[e][1,3]oxazin-4-ones via cyclization
of an iminoester intermediate.13 This paper is, to the best of our knowledge, the first entry
to a benzoxazinone system employing a sulfur-containing reagent.
RESULTS AND DISCUSSION
An equimolar reaction of benzoylisothiocyanate 1a with salicylamide 2 by refluxing
in xylene-pyridine (5:1) for 1 h afforded a white crystalline product. This product was
characterized as O-benzoyl derivative 3a of salicylamide on the basis of satisfactory ana-
lytical and spectral data discussed briefly in the succeeding paragraph. The use of a base,

1444
T. SINGH ET AL.
pyridine in this case, was a necessity for the reaction of isothiocyanates with a phenolic
hydroxyl group.14 The xylene-pyridine ratio was optimized by carrying out the reaction in
three different ratios of xylene-pyridine (5:0.5, 5:1, and 5:2). The maximum yield could be
obtained in minimum time using the xylene-pyridine ratio of 5:1.
The IR spectrum of the product 3a showed strong absorption bands at 1717 cm−1
1
and 1670 cm−1 corresponding to ester and amide carbonyls, respectively. The H NMR
spectra showed signals corresponding to nine aromatic protons besides a D2O-exchangeable
downfield signal at δ = 10.34 ppm accounting for two amido nitrogen protons.
A similar reaction of salicylamide with differently substituted benzoylisothiocyanates
1b–g afforded the corresponding O-benzoyl derivatives 3b–g (Scheme 2), identified on the
basis of their analytical and spectral data (see Experimental). The reactions of 4-chloro-
and 4-nitrobenzoylisothiocyanates 1f,g containing electron-withdrawing groups required
more time (2 h) in comparison with other isothiocyanates. Anticipated adducts 4 could not
be isolated in any case because of an easy elimination of thiocyanic acid in pyridine.
-
–
Scheme 2
The formation of only one product in these reactions clearly demonstrates the higher
reactivity of isothiocyanates toward the hydroxyl group. It is worth mentioning here that the
chemoselective reactions are of immense importance for the synthetic organic chemists to
avoid unnecessary protection and deprotection steps, and also to reduce the cost of overall

CHEMOSELECTIVE REACTION OF BENZOYLISOTHIOCYANATES
1445
synthetic processes. The reaction of a particular functional group, selectively, in complex
molecules containing more than one functional group is a challenging endeavor in organic
chemistry.
With seven O-aroyl derivatives of salicylamide in hand, it was considered useful to
extend the scope of the reaction for the synthesis of heterocyclic compounds. With this ob-
jective, the pyridine solution of compound 3a was added slowly over 6 h in refluxing xylene.
The reaction mixture was refluxed for an additional 2 h. It resulted into cyclodehydration of
3a to afford the crystalline product characterized as 2-aryl-4H-benzo[e][1,3]oxazin-4-one
5a (Scheme 3) on the basis of satisfactory analytical and spectral data and by comparison
with an authentic sample. The observation that cyclodehydration of 3a took place easily
affording the heterocyclic system prompted us to develop a one-pot method for synthe-
sis of compounds 5a–g from the reaction of salicylamide 2 with benzoylisothiocyanates
1a–g. A slow addition (6 h) of the appropriate benzoylisothiocyanate to salicylamide 2 in
xylene-pyridine solution followed by an additional reflux for 2 h afforded products 5a–g
(Scheme 3) in good yields (see Experimental). This direct synthesis of benzoxazinones,
however, was unsuccessful in either xylene or pyridine alone.
O
NH2
OH
O
2
xylene-
pyridine
O
O
R
xylene-pyridine
N
R
N
C
O
Δ, 8 h
Δ, 8 h
O
S
CONH2
3a
R
1a–g
5
R = 5a. H, 5b. 2-Me, 5c. 3-Me, 5d. 4-Me, 5e. 4-MeO, 5f. 4-Cl, 5g. 4-O2N
Scheme 3
CONCLUSION
The study reports a chemoselective reaction of benzoylisothiocyanates with the hy-
droxyl group of the salicylamide forming the corresponding 2-(O-aroyl)benzamides. This
finding led us to develop a new and convenient one-pot method for the synthesis of 2-aryl-
4H-benzo[e][1,3]oxazin-4-ones through the cyclodehydration of 2-(O-aroyl)benzamides in
pyridine-xylene solution. An easy work-up and relatively good yields of the products make
this method a useful addition to the arsenal of synthetic methods for such compounds.
EXPERIMENTAL
Melting points have been recorded on a Gallenkamp melting point apparatus and are
uncorrected. The IR spectra were recorded on a Jasco FT-IR 5300 IR spectrophotometer
using nujol mull of the sample. The 1H NMR spectra were recorded in a DMSO-d6 solution
at 90 MHz on a Jeol FX-90Q 90 MHz spectrometer. The elemental analyses have been
carried out on a Perkin–Elmer CHN Analyzer 240 C. Salicylamide was procured from the

1446
T. SINGH ET AL.
Aldrich Chemicals, and benzoylisothiocynates were prepared by reactions of acid chlorides
with potassium thiocyante according to the reported methods.15
General Procedure for the Preparation of 2-(O-aroyl)Benzamides 3a–g
An appropriate benzoylisothiocyanate (10 mmol) was added to a solution of salicy-
lamide (10 mmol) in xylene (10.0 mL) and pyridine (2.0 mL). The reaction mixture was
refluxed for 1–2 h and the progress of reaction was monitored by thin layer chromatography
(TLC). After the completion of the reaction, the reaction flask was allowed to cool to room
temperature. The solid product that appeared in the flask was filtered and recrystallized
with ethanol.
Compound 3a: White crystalline solid; yield: 86%; mp 143–144 ◦C (lit mp
143–144 ◦C)16; IR (Nujol, ν cm−1): 3400, 3200, 1717, 1670, 1600, 1518, 1481; 1H NMR
(DMSO-d6, 90 MHz) δ: 7.51 (9H, ArH), 10.34 (bs, 2H, CONH2); found: C 69.42, H 4.74,
N 5.60% (calculated for C14H11NO3: C 69.70, H 4.60, N 5.81%).
Compound 3b: White crystalline solid; yield: 74%; mp 201–202 ◦C; IR (Nujol, ν
cm−1): 3420, 3246, 1720, 16780, 1590, 1500, 1465; 1H NMR (DMSO-d6, 90 MHz) δ: 2.64
(s, 3H, CH3), 7.65 (8H, ArH), 10.09 (bs, 2H, CONH2); found: C 70.25, H 5.37, N 5.36%
(calculated for C15H13NO3: C 70.58, H 5.13, N 5.49%).
Compound 3c: White crystalline solid; yield: 79%; mp 210–212 ◦C; IR (Nujol, ν
cm−1): 3410, 3240, 1715, 1675, 1590, 1520, 1470; 1H NMR (DMSO-d6, 90 MHz) δ: 2.41
(s, 3H, CH3), 7.62 (8H, ArH), 10.42 (bs, 2H, CONH2); found: C 70.20, H 5.45, N 5.38%
(calculated for C15H13NO3: C 70.58, H 5.13, N 5.49%).
Compound 3d: White crystalline solid; yield: 83%; mp 240–241 ◦C; IR (Nujol, ν
1
cm−1): 3420, 3250, 1717, 1680, 1600, 1480; H NMR (DMSO-d6, 90 MHz) δ: 2.22 (s,
3H, CH3), 7.64 (8H, ArH), 10.41 (bs, 2H, CONH2); found: C 70.33, H 5.32, N 5.25%
(calculated for C15H13NO3: C 70.58, H 5.13, N 5.49%).
Compound 3e: White crystalline solid; yield: 80%; mp 166–167 ◦C (lit mp
166–167 ◦C)16; IR (Nujol, ν cm−1): 3420, 3250, 1720, 1680, 1590, 1520, 1454; 1H NMR
(DMSO-d6, 90 MHz) δ: 3.91 (s, 3H, OCH3), 7.52 (8H, ArH), 10.51 (bs, 2H, CONH2);
found: C 66.00, H 5.12, N 4.89% (calculated for C15H13NO4: C 66.41, H 4.83, N 5.16%).
Compound 3f: White crystalline solid; yield: 75%; mp 225–227 ◦C (lit mp
225–227 ◦C)16; IR (Nujol, ν cm−1): 3425, 3240, 1715, 1680, 1580, 1550, 1500; 1H NMR
(DMSO-d6, 90 MHz) δ: 7.58 (8H, ArH), 10.42 (bs, 2H, CONH2); found: C 60.65, H 3.90,
N 5.12% (calculated for C14H10NO3Cl: C 60.99, H 3.66, N 5.08%).
Compound 3g: Light yellow crystals; yield: 73%; mp 212–214 ◦C (lit mp
212–214 ◦C)16; IR (Nujol, ν cm−1): 3420, 3235, 1715, 1675, 1610, 1580, 1550; 1H NMR
(DMSO-d6, 90 MHz) δ: 7.56 (8H, ArH), 10.28 (bs, 2H, CONH2); found: C 58.30, H 3.78,
N 9.50% (calculated for C14H10N2O5: C 58.74, H 3.52, N 9.79%).
General Procedures for the Synthesis of Oxazin-4-Ones 5a–g
By cyclodehydration of 2-(O-aroyl)benzamides 3a: A solution of appropriate 2-(O-
aroyl)benzamides (5 mmol) in pyridine (5.0 mL) was added drop-wise over 6 h to refluxing
xylene (15.0 mL) in an oil bath at 145 ◦C. The solution was refluxed for an additional 2 h.
Removal of pyridine and xylene under reduced pressure afforded a solid product that was
washed with water, dried, and recrystallized with ethanol.

CHEMOSELECTIVE REACTION OF BENZOYLISOTHIOCYANATES
1447
Compound 5a: Brown solid; yield: 60%; mp 102–103 ◦C; IR (Nujol, ν cm−1): 1755,
1
1660, 1600, 1450; H NMR (DMSO-d6, 90 MHz) δ: 7.54 (9H, ArH), found: C 74.95, H
4.35, N 6.00% (calculated for C14H9NO2: C 75.33, H 4.06, N 6.27%).
By one-pot reaction of benzoylisothiocyanates 1a–g with salicylamide 2: An ap-
propriate benzoylisothiocynate (10 mmol) was added drop-wise during 8 h to a refluxing
solution of salicylamide (10 mmol) in xylene (10.0 mL) and pyridine (2.0 mL) in an oil bath
at 145 ◦C. Pyridine (2.0 mL) was added again and refluxing was continued for additional
2 h. Removal of pyridine and xylene under reduced pressure afforded a solid product that
was washed with water, dried, and recrystallized with ethanol.
Compound 5a: Brown solid; yield: 55%; mp 102–103 ◦C (undepressed mixed melt-
ing point with the compound 5a prepared by cyclodehydration of 2-(O-aroyl)benzamides
3a).
Compound 5b: Reddish brown solid; yield: 57%; mp 178–180 ◦C; IR (Nujol, ν
cm−1): 1740, 1650, 1590, 1470; 1H NMR (DMSO-d6, 90 MHz) δ: 2.82 (s, 3H, CH3), 7.56
(8H, ArH), found: C 76.22, H 4.52, N 5.82% (calculated for C15H11NO2: C 75.93, H 4.67,
N 5.90%).
Compound 5c: White solid; yield: 60%; mp 170–171 ◦C; IR (Nujol, ν cm−1): 1760,
1
1650, 1590, 1460; H NMR (DMSO-d6, 90 MHz) δ: 2.63 (s, 3H, CH3), 7.55 (8H, ArH),
found: C 75.74, H 4.38, N 5.81% (calculated for C15H11NO2: C 75.93, H 4.67, N 5.90%).
Compound 5d: White solid; yield: 65%; mp 201–203 ◦C; IR (Nujol, ν cm−1): 1760,
1
1650, 1590, 1460; H NMR (DMSO-d6, 90 MHz) δ: 2.42 (s, 3H, CH3), 7.47 (8H, ArH),
found: C 75.66, H 4.53, N 6.12% (calculated for C15H11NO2: C 75.93, H 4.67, N 5.90%).
Compound 5e: White solid; yield: 67%; mp 185–186 ◦C (lit. mp 184–186 ◦C);16 IR
1
(Nujol, ν cm−1): 1755, 1670, 1590, 1465; H NMR (DMSO-d6, 90 MHz) δ: 3.84 (s, 3H,
OCH3), 7.54 (8H, ArH), found: C 70.82, H 4.60, N 5.60% (calculated for C15H11NO3: C
71.14, H 4.38, N 5.53%).
Compound 5f: White solid; yield: 60%; mp 171–172 ◦C (lit. mp 172 ◦C);16IR (Nujol,
ν cm−1): 1730, 1650, 1600, 1500; 1H NMR (DMSO-d6, 90 MHz) δ: 7.48 (8H, ArH), found:
C 64.95, H 3.38, N 5.66% (calculated for C14H8NO2Cl: C 65.26, H 3.13, N 5.44%).
Compound 5g: Red needles; yield: 55%; mp 192–194 ◦C; IR (Nujol, ν cm−1): 1750,
1
1650, 1590, 1520; H NMR (DMSO-d6, 90 MHz) δ: 7.56 (8H, ArH), found: C 62.35, H
3.30, N 10.65% (calculated for C14H8N2O4: C 62.68, H 3.00, N 10.44%).
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