Generalized method for the production of 1,3-benzoxazine, 1,3-benzothiazine, and quinazoline derivatives from 2-(hydroxy, thio, or amino) aromatic acids using triphenylphosphine thiocyanogen

Article abstract of DOI:10.1081/SCC-200061564

A modified one-pot method was developed for the synthesis of 1,3-benzoxazines, in which the preparation of unstable thiocyanogen was omitted. The method was found to be general for substituted (methyl, methoxy, halo, and hydroxy) 2-hydroxy benzoic acids and 2-hydroxy naphthoic acids. The method was extended to 2-thio, 2-amino, and N-methyl aminobenzoic acid with which the synthesis of 1,3-benzothiazine and quinazoline derivatives has been achieved, respectively. It was also found that 3-hydroxypyridine-2-carboxylic acid and 2-hydroxynicotinic acid using a modified method gave 2-thioxo-2,3-dihydro-4H- pyrido[2,3-e][1,3]oxazin-4-one and 2-thioxo-2,3-dihydro-4H-pyrido[3,2-e][1,3] oxazin-4-one, respectively. The structures of the new compounds were confirmed by the analysis of their IR, ¹H, and ¹³C NMR spectra. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200061564

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Generalized Method for the
Production of 1,3‐Benzoxazine,
1,3‐Benzothiazine, and
Quinazoline Derivatives
from 2‐(Hydroxy, Thio,
or Amino) Aromatic Acids
Using Triphenylphosphine
Thiocyanogen
Kaylene M. Pritchard a , Jasim M. Al‐Rawi a &
Andrew B. Hughes b
a School of Pharmacy and Applied Science, La Trobe
University, Bendigo, Australia
b Department of Chemistry, La Trobe University,
Victoria, Australia
Published online: 16 Aug 2006.
To cite this article: Kaylene M. Pritchard , Jasim M. AlRawi & Andrew B. Hughes
(2005) Generalized Method for the Production of 1,3‐Benzoxazine, 1,3‐Benzothiazine,
and Quinazoline Derivatives from 2‐(Hydroxy, Thio, or Amino) Aromatic Acids Using
Triphenylphosphine Thiocyanogen, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 35:12, 1601-1611,
DOI: 10.1081/SCC-200061564
To link to this article: http://dx.doi.org/10.1081/SCC-200061564

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Synthetic Communicationsw, 35: 1601–1611, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200061564
Generalized Method for the Production of
1,3-Benzoxazine, 1,3-Benzothiazine, and
Quinazoline Derivatives from 2-(Hydroxy,
Thio, or Amino) Aromatic Acids Using
Triphenylphosphine Thiocyanogen
Kaylene M. Pritchard and Jasim M. Al-Rawi
School of Pharmacy and Applied Science, La Trobe University,
Bendigo, Australia
Andrew B. Hughes
Department of Chemistry, La Trobe University, Victoria, Australia
Abstract: Amodified one-pot method was developed forthesynthesis of 1,3-benzoxazines,
in which the preparation of unstable thiocyanogen was omitted. The method was
found to be general for substituted (methyl, methoxy, halo, and hydroxy) 2-hydroxy
benzoic acids and 2-hydroxy naphthoic acids. The method was extended to
2-thio, 2-amino, and N-methyl aminobenzoic acid with which the synthesis of
1,3-benzothiazine and quinazoline derivatives has been achieved, respectively. It was
also found that 3-hydroxypyridine-2-carboxylic acid and 2-hydroxynicotinic acid
using a modified method gave 2-thioxo-2,3-dihydro-4H-pyrido[2,3-e][1,3]oxazin-4-one
and 2-thioxo-2,3-dihydro-4H-pyrido[3,2-e][1,3]oxazin-4-one, respectively. The struc-
tures of the new compounds were confirmed by the analysis of their IR, 1H, and
13C NMR spectra.
Keywords: Triphenylphosphine thiocyanogen, modified synthesis of 1,3-benzoxazines,
1,3-benzothiazine, quinazolines
Received in the USA January 27, 2005
Address correspondence to Jasim M. Al-Rawi, School of Pharmacy and Applied
Science, La Trobe University, Bendigo 3550, Australia. E-mail: j.al-rawi@latrobe.
edu.au
1601

1602
K. M. Pritchard, J. M. Al-Rawi, and A. B. Hughes
INTRODUCTION
Researchers have shown the significance of the title compounds in the devel-
opment of antimicrobial, antiviral, and antifungal drugs.[1–3] Presence of a
sulfur group in the C-2 position, which results in the 2-mercapto tautomer,
provides a good leaving group for the reaction of morpholine (secondary
amines) with the title compounds to give 2-morpholinyl antiatherosclerotic
compounds.[4] The 2-mercapto tautomer also reacts with benzylamine
(primary amines) to open the oxazine ring between positions 1 and 2 to
give N-benzylthioureas, which have been found to possess antiviral, antipro-
liferation, and antibacterial properties.[5] Many methods (Scheme 1, methods
1 and 2) have been used in the synthesis of certain 1,3-oxazine derivatives.
This has promoted the need for a general method to produce 1,3-oxazines
and their related derivatives.
Method 1 (Scheme 1) for the synthesis of 1,3-oxazines using substituted
2-hydroxybenzoic acids was reported in 1978.[6] Bromine was added to lead
thiocyanate to produce thiocyanogen. Thiocyanogen was separated from the
reaction mixture and allowed to react with triphenylphosphine at 2408C in
dichloromethane to give triphenylphosphine thiocyanogen 1. The reagent 1
was then allowed to react with 2-hydroxybenzoic acids to give the
1,3-oxazines. Several disadvantages were found with this method. Firstly,
the separation of the thiocyanogen was difficult because this compound is
highly susceptible to polymerization. Other disadvantages included the
reaction conditions, where temperatures of 2408C were required and the
reactions were poorly reproducible. Nine oxazines 2 were prepared using
method 1 (Scheme 1) including where X ¼ H, 6-Cl, 6-Br, 6-OH, 7-Me,
8-Me, 5/6-Ar, 6/7-Ar, and 7/8-Ar.
Scheme 1.

Production of 1,3-Benzoxazine, 1,3-Benzothiazine, and Quinazoline
1603
More recently a modified method (method 2, Scheme 1) was introduced[7]
where bromine was added to triphenylphosphine, followed by the addition of
ammonium thiocyanate, to produce triphenylphosphine thiocyanogen 1 at
room temperature. Then, t-butyldimethylsilyl (TBDMS) or triisopropylsilyl
(TIPS) salicylates were added to afford the 1,3-oxazine. In this method, a
solution of ammonium thiocyanate in acetonitrile was added dropwise to
a solution of the triphenylphosphine dibromide; however, both ammonium
thiocyanate and triphenylphosphine dibromide are poorly soluble in
acetonitrile. Furthermore, the extraction of the 1,3-oxazine (Scheme 1,
method 2) was difficult because of interference by the by-product,
ammonium bromide. This method also brought the need for an extra step in
which the acid was converted to the silyl ester. This extra step was not only
time consuming but also the t-butyldimethylsilyl salicyates are prone to
hydrolysis,[8] leading to poor reproducibility. In method 2 (Scheme 1), only
the oxazine 2 where X ¼ H was prepared.
RESULTS AND DISCUSSION
The aim of this study was to generalize the one-pot method for the production
of 1,3-oxazines from substituted 2-hydroxybenzoic acids. This has been
achieved by simplifying the procedure. The reaction requires the addition of
bromine to triphenylphosphine to give triphenylphosphine dibromide. Lead
thiocyanate was then added to the reaction mixture, followed by a substituted
2-hydroxybenzoic acid, to produce a 1,3-oxazine (Scheme 2). The replacement
of lead thiocyanate with ammonium thiocyanate was attempted because it
would be advantageous to eliminate the use of lead thiocyanate, but it was
found that the yield was decreased because of the difficult workup of the
reaction mixture.
Scheme 2. Compound 2 (Z ¼ O, a X ¼ H; b X ¼ 8-CH3; c X ¼ 8-OCH3; d X ¼
7-OCH3; e X ¼ 8-Cl; f X ¼ 7-Cl; g X ¼ 6-Cl; h X ¼ 7-OH; i X ¼ 7-OH & 8-CH3;
Compound
3
Z ¼ S, X ¼ H; Compound
4
Z ¼ NH, X ¼ H; Compound
5
Z ¼ NCH3, X ¼ H).

1604
K. M. Pritchard, J. M. Al-Rawi, and A. B. Hughes
It was found that the yield of the 1,3-oxazines increased, and the workup
was simplified, if the triphenylphosphine dibromide was first isolated and then
used in the preparation of triphenylphosphine thiocyanogen (Scheme 2).
Indeed, the use of the commercially available triphenylphosphine dibromide
in the 1,3-oxazine synthesis improved the yield and the product purification.
The best reaction temperature was found to be 08C with the 1,3-oxazine
yield decreasing if the temperature of the reaction was above 08C.
It was found that this reaction was general for substituted 2-hydroxyben-
zoic acids, as well as 2-thio, 2-amino, and N-methylamino benzoic acids
(Scheme 2). Furthermore, the reaction was successfully extended to
1-hydroxy-2-naphthoic acid, 3-hydroxy-2-naphthoic acid, 3-hydroxypyri-
dine-2-carboxylic acid, and 2-hydroxynicotinic acid to produce the corre-
sponding 1,3-oxazines 6, 7, 8 and 9, respectively (Figure 1).
Compounds (2a, 2b, 2g, 3, 4, 5, 6, and 7) were characterized by compari-
son of their physical data (mp, IR,1H, and 13C NMR spectra) with literature
values.[6,9–14] The structures of the newly described 1,3-oxazines (2c–f, h,
and i) were confirmed using IR, 1H, and 13C NMR spectroscopy. The
infrared spectra of the new oxazines 2c–f, h, and i showed a strong resem-
blance to those of the previously prepared oxazines 2a, 2b, 2g, 3, 4, 5, 6,
1
and 7. The H NMR spectra of the new oxazines 2c–f, h, and i give strong
support for the proposed structures.
The 13C NMR chemical shift assignment for compounds 2c–f, h, and i
was achieved using the calculated value, starting from the previously
reported chemical shifts of 1,3-oxazine 2a[11] and substitution increments of
the aromatic ring of 2c, 8-OMe; 2d, 7-OMe; 2e, 8-Cl; 2f, 7-Cl; 2h, 7-OH;
and 2i, 7-OH and 8-Me.[15] The structures of the new heteroaromatic 1,3-
oxazine structures 8 and 9 were confirmed by 1H NMR and proton-
decoupled 13C NMR spectra as well as multinuclear two-dimensional NMR.
Figure 1. 1,3-Oxazines (6–9) prepared from 1-hydroxy-2-naphthoic acid, 3-hydroxy-
pyridine-2-carboxylic acid and 2-hydroxynicotinic acid respectively.

Production of 1,3-Benzoxazine, 1,3-Benzothiazine, and Quinazoline
1605
The spectra of compound 8 showed the correct number of signals. Assignment
of the carbon-13 chemical shifts was made as follows: (d6DMSO) d 181.5 and
156.5 were assigned to C-2 and C-4, respectively, by analogy to the corre-
sponding carbons in compound 2a.[11] The assignment of the pyridine ring
carbons C-4a, C-6, C-7, C-8, and C-8a was accomplished using the corre-
sponding aromatic ring carbons chemical shifts of 1,3-oxazine 2a and the
nitrogen insertion effect. (Starting from 128.5 as the carbon chemical shift
for benzene ring and the use of pyridine C-2, C-3, and C-4 carbon chemical
shifts allowed the calculation of the nitrogen insertion effect increments,
with the increments being þ21.7, 24.6 and þ7.4, respectively.) The
observed/calculated values for the oxazine 8 are C-4a 133.2/137.3 (quatern-
ary carbon); C-6 147.9/147.9 (CH); C-7 130.3/131.9 (CH); C-8 125.1/123.8
(CH); and C-8a 153.5/150.7 (quaternary carbon). Similarly, the 13C NMR
spectra of compound 9 also showed the correct number of signals and their
assignment was achieved in a similar manner to that outlined for compound
8 (see Experimental).
The proposed reaction mechanism for 1,3-oxazine synthesis is shown in
Scheme 3. Confirmation of the proposed reaction mechanism was possible
Scheme 3.

1606
K. M. Pritchard, J. M. Al-Rawi, and A. B. Hughes
after the isolation and identification of the by-product triphenylphosphine
oxide 10 (see Experimental).
EXPERIMENTAL
Infrared spectra were obtained using a Perkin Elmer FT-IR spectrometer.
1H NMR and 13C NMR spectra were obtained using a Bruker UX NMR spec-
trometer at 300 MHz and 75.5 MHz, respectively, and HSQC two-dimensional
1
NMR were obtained. All H and 13C NMR spectral results are recorded as
chemical shifts (d) and are relative to the internal TMS. Microanalysis was
measured by CMAS (Chemical and Microanalytical Services), Australia.
Melting point determinations were carried out using a Stuart Scientific
(SMP3) melting point apparatus and all melting points are corrected to +18C.
Starting Materials
All acids (with the exception of 2,4-dihydroxy-3-methylbenzoic acid), lead
thiocyanate, triphenylphosphine, and triphenylphosphine dichloride were
purchased from Aldrich Chemical Company and were used as received.
Bromine was purchased from BDH laboratory supplies and used as
received. Triphenylphosphine dibromide was purchased from Strem
Chemicals (USA) and also used as received.
2,4-Dihydroxy-3-methylbenzoic acid was prepared from 2-methylresor-
cinol[16] to give the acid in 42% yield after recrystalization from ethanol/
water, mp 205–2068C (lit. mp 204–2068C); nmax (KBr) 3500–3300 and
3250–2500w (OH), 1646 and 1622s (C55O) cm21
;
1H (d6-DMSO)
d 14.9, (s, 1H, COOH), 11.6 (s, 1H, 2-OH), 10.2 (s, 1H, 4-OH), 7.5 (d, 1H,
J ¼ 8.6 Hz, 6-H), 6.4 (d, 1H, J ¼ 8.6 Hz, 5-H), 1.9 (s, 3H, 3-CH3); 13C
(d6-DMSO) d 103.9 (C-1), 161.5 and 161.6 (C-2 and C-4), 110.2 (C-3),
107.0 (C-5), 128.5 (C-6), 172.6 (COOH), 7.8 (CH3).
Synthesis of 1,3-Benzoxazines
General Method
Triphenylphosphine dibromide (5 mmol) was weighed out under nitrogen into
a three-necked, round-bottomed flask containing a stirring bar. Dry dichloro-
methane (20 mL) was then added to the flask and the flask was placed into an
ice bath. The reaction vessel was equipped with a nitrogen gas inlet with
bubbling tube as well as a dropping funnel. The other side arm was fitted
with a calcium chloride drying tube. A suspension of lead thiocyanate
(6 mmol) in dry dichloromethane (40 mL) was then added slowly via the

Production of 1,3-Benzoxazine, 1,3-Benzothiazine, and Quinazoline
1607
dropping funnel with stirring. A suspension of 2-hydroxy aromatic/
heteroaromatic acid (4 mmol) in dry dichloromethane (20 mL) was then
added to the reaction mixture. The flask was stoppered and the mixture left
to stir while slowly warming to room temperature. The reaction mixture
was stirred at room temperature for 30 min and then heated at reflux for 3 h.
Some of the acids required the reagent to be in a greater excess and/or
needed a longer reaction time. (Any variation from this general method is
specified with the following details of the prepared oxazine.)
The reaction mixture was then filtered and the filter cake was washed with
dichloromethane. The initial waste solid collected was hot filtered with
acetone or acetic acid to ensure all of the product had been extracted. All
the filtrates were evaporated to dryness in vacuo and toluene was used to
dissolve any oil which accompanied the solid product. The products were
collected and recrystallized from a suitable solvent. The use of triphenylpho-
sphine dichloride was explored with results being comparable to the use of
triphenylphosphine dibromide.
Isolation of triphenylphosphine oxide 10 was achieved when the residual
mother liquor oil, collected from the reaction to prepare 2a, was applied to
a silica-gel column and eluted with acetone. The solid recovered was ident-
ified by melting point and comparison of the IR spectrum to the known
spectrum.
2-Thioxo-2,3-dihydro-4H-1,3-benzoxazin-4-one 2a. Salicylic acid was
allowed to react with 1 as described in the general method to give 2a with
the solid collected from the mother liquor and the acetone hot-filtration
wash of the initial waste solid combined and recrystallized from toluene,
1
80% yield, mp 247–2498C (lit. mp 246–2478C), H (d6-DMSO) d 13.5
(s, 1H, NH), 7.9 (d, 1H, J ¼ 7.5 Hz, H-5), 7.8 (t, 1H, J ¼ 7.5 Hz, H-7), 7.5
(d, 1H, J ¼ 7.5 Hz, H-8), 7.4 (t, 1H, J ¼ 7.5 Hz, H-6).
8-Methyl-2-thioxo-2,3-dihydro-4H-1,3-benzoxazin-4-one 2b. Similarly,
the general method was used for the reaction of 3-methylsalicylic acid with
1 to give 2b with the solid collected from the mother liquor (no solid
collected from the acetone hot-filtration wash of the initial waste solid),
then recrystallized from CHCl3, 68% yield, mp 216–2188C (lit. mp 2138C),
1H (d6-DMSO) d 13.5 (s, 1H, NH), 7.8 (d, 1H, J ¼ 7.1 Hz, H-5), 7.7 (d, 1H,
J ¼ 7.1 Hz, H-7), 7.4 (t, 1H, J ¼ 7.1 Hz, H-6), 2.4 (s, 3H, 8-CH3).
8-Methoxy-2-thioxo-2,3-dihydro-4H-1,3-benzoxazin-4-one 2c. 3-Metho-
xysalicylic acid was allowed to react with 1 as described in the general
method to give 2c. The solid from the mother liquor and the acetone hot-
filtration wash of the initial waste solid were then combined and recrystallized
from toluene, 84% yield, mp 243–2468C; (found C, 51.73; H, 3.49; N, 6.75;
C9H7NO3S requires C, 51.66; H, 3.37; N, 6.69); nmax (KBr) 3191w and 3087w
(N–H), 1718s (4–C55O), 1618m (C55C), 1222s (C55S) cm21
;
1H

1608
K. M. Pritchard, J. M. Al-Rawi, and A. B. Hughes
(d6-DMSO) d 13.5 (s, 1H, NH), 7.5–7.4 (m, 3H, Ar), 3.9 (s, 3H, 8-OCH3);
13C (d6-DMSO) d 181.6 (C-2), 157.5 (C-4), 116.5 (C-4a), 117.3 (C-5),
126.3 (C-6), 118.8 (C-7), 146.5 (C-8), 145.4 (C-8a), 56.8 (8-OCH3).
7-Methoxy-2-thioxo-2,3-dihydro-4H-1,3-benzoxazin-4-one 2d. 4-Methoxy-
salicylic acid was allowed to react with 1 as described in the general method
to give 2d with the solid from the mother liquor (no solid collected from the
acetone hot-filtration wash of the initial waste solid), then recrystallized
from toluene, 97% yield, mp 213–2158C (found C, 51.78; H, 3.38; N, 6.75;
C9H7NO3S requires C, 51.66; H, 3.37; N, 6.69); nmax (KBr) 3203w and
3119w (N–H), 1723s (4–C55O), 1625s (C55C), 1180s (C55S) cm21
;
1H (d6-DMSO) d 13.4 (s, 1H, NH), 7.9 (d, 1H, J ¼ 8.3 Hz, 5-H), 7.1 (s, 1H,
8-H), 7.0 (d, 1H, J ¼ 8.3 Hz, 6-H), 3.9 (s, 3H, 7-OCH3); 13C (d6-DMSO) d
182.2 (C-2), 157.2 (C-4 and C-8a), 108.3 (C-4a), 128.2 (C-5), 114.3 (C-6),
165.7 (C-7), 100.3 (C-8), 56.5 (7-OCH3).
8-Chloro-2-thioxo-2,3-dihydro-4H-1,3-benzoxazin-4-one 2e. The general
method was used for the reaction of 3-chlorosalicylic acid with 1 to give 2e
with the solid collected from the mother liquor (no solid from acetone hot-fil-
tration wash of the initial waste solid), then recrystallized from toluene, 48%
yield, mp 220–2238C (found C, 45.02; H, 1.78; N, 6.47; C8H4ClNO2S
requires C, 44.98; H, 1.89; N, 6.56); nmax (KBr) 3195w and 3098w (N–H),
1
1693s (4–C55O), 1606m (C55C), 1175m (C55S) cm21; H (d6-DMSO) d
13.6 (s, 1, NH), 8.0 (d, 1H, J ¼ 7.6 Hz, H-5), 7.9 (d, 1H, J ¼ 7.6 Hz, H-7),
7.5 (t, 1H, J ¼ 7.6 Hz, H-6); 13C (d6-DMSO) d 181.1 (C-2), 157.1 (C-4),
117.6 (C-4a), 125.7 (C-5), 126.6 (C-6), 136.2 (C-7), 119.6 (C-8), 151.2 (C-8a).
7-Chloro-2-thioxo-2,3-dihydro-4H-1,3-benzoxazin-4-one 2f. 4-Chlorosa-
licylic acid was allowed to react with 1 to give 2f as described in the
general method with the mother liquor solid (no solid obtained from the
acetone hot-filtration wash of the initial waste solid), then recrystallized
from toluene, 90% yield, mp 1948C (found C, 45.01; H, 1.75; N, 6.47;
C8H4ClNO2S requires C, 44.98; H, 1.89; N, 6.56); nmax (KBr) 3198w and
1
3085w (N–H), 1718s (4–C55O), 1611m (C55C), 1165s (C55S) cm21; H
(d6-DMSO) d 13.6 (s, 1H, NH), 7.9 (d, 1H, J ¼ 8.2 Hz, H-5), 7.7 (s, 1H, H-8),
7.5 (d, 1H, J ¼ 8.2 Hz, H-6); 13C (d6-DMSO) d 181.7 (C-2), 156.9 (C-4),
114.8 (C-4a), 128.4 (C-5), 126.5 (C-6), 140.8 (C-7), 116.6 (C-8), 155.7 (C-8a).
6-Chloro-2-thioxo-2,3-dihydro-4H-1,3-benzoxazin-4-one 2g. The general
method was used for the reaction of 5-chlorosalicylic acid with 1 to give
2g. The mother liquor solid and the solid obtained from the acetone hot-
filtration of the initial waste solid were then combined and recrystallized
1
from toluene, 79% yield, mp 239–2428C (lit. mp 2358C), H (d6-DMSO) d
13.6 (s, 1H, NH), 7.9 (s, 1H, H-5), 7.9 (d, 1H, J ¼ 8.8 Hz, H-7), 7.6 (d, 1H,
J ¼ 8.8 Hz, H-8).

Production of 1,3-Benzoxazine, 1,3-Benzothiazine, and Quinazoline
1609
7-Hydroxy-2-thioxo-2,3-dihydro-4H-1,3-benzoxazin-4-one 2h. 2,4-Dihy-
droxybenzoic acid was allowed to react with 1 as described in the general
method to give 2h, then the solid collected from the mother liquor and the
acetone hot-filtration wash of the initial waste solid were combined and
recrystallized from dioxane/dichloromethane (dissolved in minimum hot
dioxane and precipitated after the addition of cold dichloromethane), 90%
yield, mp 2458C decomp. (found C, 49.17; H, 2.49; N, 7.20; C8H5NO3S
requires C, 49.23; H, 2.58; N, 7.18); nmax (KBr) 3200–2700b (O-H), 3255w
and 3078 w (N–H), 1686s (4–C55O), 1626m (C55C), 1180m (C55S)
1
cm21; H (d6-DMSO) d 13.3 (s, 1H, NH), 11.2 (s, 1H, 7-OH), 7.8 (d, 1H,
J ¼ 8.6 Hz, H-5), 6.9 (d, 1H, J ¼ 8.6 Hz, H-6), 6.7 (s, 1H, H-8); 13C (d6-
DMSO) d 182.3 (C-2), 157.2 (C-4 and C-8a), 107.0 (C-4a), 128.6 (C-5),
114.9 (C-6), 164.8 (C-7), 101.6 (C-8).
7-Hydroxy-8-methyl-2-thioxo-2,3-dihydro-4H-1,3-benzoxazin-4-one 2i:
2,4-Dihydroxy-3-methylbenzoic acid was allowed to react with 1 as
described in the general method to give 2i. The solid from the mother
liquor and the acetone hot-filtration wash of the initial waste solid were
then combined and recrystallized from ethyl acetate, 86% yield, mp 2508C
decomp. (found C, 51.69; H, 3.40; N, 6.63; C9H7NO3S requires C, 51.67;
H, 3.37; N, 6.69); nmax (KBr) 3188w and 3085w (N–H), 3250–2900b
(O-H); 1664s (4–C55O), 1619m (C55C), 1223m (C55S) cm21
;
1H
(d6-DMSO) d 13.3 (s, 1H, NH), 11.1 (s, 1H, 7-OH), 7.7 (d, 1H, J ¼ 8.4 Hz,
H-5), 6.9 (d, 1H, J ¼ 8.4 Hz, H-6), 2.1 (s, 3H, 8-CH3); 13C (d6-DMSO)
d 182.3 (C-2), 155.1 (C-4), 106.9 (C-4a), 125.3 (C-5), 113.6 (C-6), 162.6
(C-7), 110.5 (C-8), 157.6 (C-8a), 8.1 (8–CH3).
2-Thioxo-2,3-dihydro-4H-1,3-benzothiazin-4-one 3. Thiosalicylic acid was
allowed to react with 1 as described in the general method to give 3, then the
solid from the mother liquor and the acetone hot-filtration wash of the initial
waste solid were combined and recrystallized from acetonitrile, 55% yield, mp
1
234–2358C (lit. mp 232–2338C), H (d6-DMSO) d 13.6 (s, 1H, NH), 8.2
(d, 1H, J ¼ 7.6 Hz, H-5), 7.8 (t, 1H, J ¼ 7.6 Hz, H-7), 7.6 (t, 1H,
J ¼ 7.6 Hz, H-6), 7.5 (d, 1H, J ¼ 7.6 Hz, H-8); 13C (d6-DMSO) d 192.8
(C-2), 160.5 (C-4), 122.4 (C-4a), 130.0 (C-5/C-6), 128.4 (C-6/C-5), 134.6
(C-7), 123.4 (C-8), 137.0 (C-8a).
2-Thioxo-2,3-dihydroquinazolin-4(1H)-one 4. Anthranilic acid was
allowed to react with 1 as described in the general method and then left to
stir at room temperature overnight to give 4. The solid from the mother
liquor and the acetic acid hot-filtration wash of the initial waste solid were
then combined and recrystallized from acetonitrile, 70% yield, mp 294–
1
2968C (lit. mp 295–2968C), H (d6-DMSO) d 12.6 (bs, 2H, 2 x NH), 7.9
(d, 1H, J ¼ 7.7 Hz, H-5), 7.7 (t, 1H, J ¼ 7.7 Hz, H-7), 7.3 (m, 2H, H-8 and
H-6).

1610
K. M. Pritchard, J. M. Al-Rawi, and A. B. Hughes
1-Methyl-2-thioxo-2,3-dihydroquinazolin-4(1H)-one 5. N-Methylanthrani-
lic acid (3.3 mmol) was allowed to react with 1 as described in the general
method and then left to stir at room temperature overnight to give 5. The
solid from the mother liquor and the acetone hot-filtration wash of the
initial waste solid were then combined and recrystallized from methanol,
81% yield, mp 255–2578C (lit. mp 2538C); nmax (KBr) 3196w and 3082w
(N–H), 1690s (4–C55O), 1610m (C55C), 1202m (C55S) cm21 1H (d6-
;
DMSO) d 12.6 (s, 1H, NH), 8.0 (d, 1H, J ¼ 7.6 Hz, H-5), 7.8 (t, 1H,
J ¼ 7.6 Hz, H-7), 7.6 (d, 1H, J ¼ 7.6 Hz, H-8), 7.4 (t, 1H, J ¼ 7.6 Hz, H-6),
4.0 (s, 3H, N–CH3); 13C (d6-DMSO) d 175.4 (C-2), 157.4 (C-4), 117.2
(C-4a), 126.5 (C-5), 123.7 (C-6), 134.8 (C-7), 115.5 (C-8), 140.8 (C-8a)
36.0 (N–CH3).
2-Thioxo-2,3-dihydro-4H-naphtho[2,1-e][1,3]oxazin-4-one 6. 1-Hydroxy-
2-naphthoic acid was allowed to react with 1 as outlined in the general
method and then left to stir at room temperature overnight to give 6. The
solid from the mother liquor and the acetone hot filtration wash of the
initial waste solid were then combined and recrystallized from acetic acid,
76% yield, mp 2458C decomp. (lit. mp 2428C); nmax (KBr) 3187w and
3079w (N–H), 1684s (4–C55O), 1636m (C55C), 1209m (C55S) cm21
1H (d6-DMSO) d 14.9 (s, 1H, NH), 8.4–7.8 (m, 6H, Ar).
;
2-Thioxo-2,3-dihydro-4H-naphtho[2,3-e][1,3]oxazin-4-one 7. 3-Hydroxy-
2-naphthoic acid was allowed to react with 1 as described in the general
method and then left to stir at room temperature overnight to give 7. The
solid from the mother liquor and the acetic acid hot-filtration wash of the
initial waste solid were then combined and recrystallized from ethanol, 70%
yield, mp 2508C decomp. (lit. mp 2488C); nmax (KBr) 3188w and 3084w
(N–H), 1695s (4–C55O), 1634m (C55C), 1215s (C55S) cm21
;
1H
(d6-DMSO) d 14.9 (s, 1H, NH), 8.7 (s, 1H, H-10), 8.2 (d, 1H, J ¼ 7.1 Hz,
H-5/H-8), 8.1 (d, 1H, J ¼ 7.1 Hz, H-8/H-5), 8.0 (s, 1H, H-9), 7.7 (t, 1H,
J ¼ 7.1 Hz, H-6/H-7), 7.6 (t, 1H, J ¼ 7.1 Hz, H-7/H-6).
2-Thioxo-2,3-dihydro-4H-pyrido[2,3-e][1,3]oxazin-4-one 8. 3-Hydroxy-
picolinic acid (2 mmol) was allowed to react with 1 as outlined in the
general method and then left to stir at room temperature overnight to give
8. The solid from the mother liquor and the acetic acid hot-filtration wash
of the initial waste solid were then combined and recrystallized from ethyl
acetate, 70% yield, mp 1988C decomp. (found C, 46.70; H, 2.16; N, 15.62;
C7H4N2O2S requires C, 46.66; H, 2.24; N, 15.55); nmax (KBr) 3210w
and 3119w (N–H), 1711s (4–C55O), 1605w (C55C), 1585w (C55N), 1232s
;
(C55S) cm21 1H (d6-DMSO) d 13.7 (s, 1H, NH), 8.7 (s (broad-
nitrogen quadruple coupling), 1H, H-6), 8.0 (d, 1H, J ¼ 8.1 Hz, H-8) 7.8 (dd,
1H, JH7,H6 ¼ 8.1 Hz, JH7,H8 ¼ 8.1 Hz, H-7); 13C (d6-DMSO) d 181.5 (C-2),
156.5 (C-4), 133.2 (C-4a), 147.9 (C-6), 130.3 (C-7), 125.1 (C-8), 153.5 (C-8a).

Production of 1,3-Benzoxazine, 1,3-Benzothiazine, and Quinazoline
1611
2-Thioxo-2,3-dihydro-4H-pyrido[3,2-e][1,3]oxazin-4-one 9. 2-Hydroxyni-
cotinic acid (2 mmol) was allowed to react with 1 as outlined in the general
method and then left to stir at room temperature overnight to give 9. The
solid from the mother liquor and the acetone hot-filtration wash of the
initial waste solid were then combined and recrystallized from toluene, 97%
yield, mp 209–2118C; (found C, 46.62; H, 2.23; N, 15.61; C7H4N2O2S
requires C, 46.66; H, 2.24; N, 15.55); nmax (KBr) 3203w and 3101w (N–
H), 1698s (4–C55O), 1610m (C55C), 1587m (C55N), 1212m (C55S) cm21
;
1H (d6-DMSO) d 13.6 (s, 1H, NH), 8.7 (d, 1H, J ¼ 6.7 Hz, H-7), 8.4 (d, 1H,
J ¼ 6.7 Hz, H-5), 7.6 (dd, 1H, JH6,H7 ¼ 6.7 Hz, JH6,H5 ¼ 6.7 Hz, H-6); 13C
(d6-DMSO) d 181.9 (C-2), 160.0 (C-4), 111.7 (C-4a), 137.4 (C-5), 123.0
(C-6), 154.4 (C-7), 158.2 (C-8a).
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