New application of triphosgene in a convenient synthesis of 3-aryl-1,3-benzoxazine-2,4-diones from anacardic acids

Article abstract of DOI:10.3987/COM-04-10261

In conjunction with a search program focused on utilization of cashew (Anacardium occidentale) nut shell liquid (CNSL) as starting material for the preparation of useful compounds, a convenient synthesis of novel series of 3-aryl-1, 3-benzoxazine-2, 4-diones was prepared from anacardic acids by using of the triphosgene.

Full text of DOI:10.3987/COM-04-10261

HETEROCYCLES, Vol. 65, No. 2, 2005
311
HETEROCYCLES, Vol. 65, No. 2, 2005, pp. 311 - 318
Received, 25th October, 2004, Accepted, 20th December, 2004, Published Online, 21st December, 2004
NEW APPLICATION OF TRIPHOSGENE IN A CONVENIENT SYNTHESIS
OF 3-ARYL-1,3-BENZOXAZINE-2,4-DIONES FROM ANACARDIC ACIDS
Inês Sabioni Resck,1* Maria Lucilia dos Santos,1 and Luiz Antonio
Soares Romeiro2
1.Institute of Chemistry, University of Brasilia, Campus Darcy Ribeiro,
Brasilia-DF, Brazil, 70919-970 – isresck@unb.br
2.Center of Bioorganic and Medicinal Chemistry, Catholic University of
Brasilia, QS 07, Lot 01, Taguatinga-DF, Brazil, 71966-700
Abstract – In conjunction with a search program focused on utilization of
cashew (Anacardium occidentale) nut shell liquid (CNSL) as starting
material for the preparation of useful compounds, a convenient synthesis of
novel series of 3-aryl-1,3-benzoxazine-2,4-diones was prepared from
anacardic acids by using of the triphosgene.
INTRODUCTION
Benzoxazines, an important class of heterocyclic compounds which exhibit a wide range of
biological activity, have attracted the attention of many researchers. On the other hand, 1,3-
benzoxazine-2,4-diones, which exhibit promising antimycobacterial1 and antifungal2 properties,
no considerable synthetic pathway have been described to them. The preparation of the 3-aryl-
1,3-benzoxazine-2,4-diones was primarily reported in 1960s from salicylanilide and ethyl
chloroformate.3 Others synthetic procedures to construction of this class of compounds include
cyclization of salicylamide with 1,1’-carbonyldiimidazole4 and 2-hydroxybenzonitrile with
phenylisocyanate, followed by hydrolytic cleavage.5
In the past ten years, the preparation of several substituted 3-phenylbenzoxazine-2,4-diones
thioxo analogues by using ethyl chloroformate as synthetic tool for insertion of C-O unit have
been described.1,6 Structure-activity relationship studies based in activity against atypical
strains including M. tuberculosis have showed that the antimycobacterial activity increases with
electron-accepting ability and hydrophobicity of the substituents on the phenyl ring,1 where the
in vitro activity of some of them exceeds that of commercial tuberculostactics used as
standards.7 Nowadays, bis(trichloromethyl)carbonate (triphosgene) is recognized not only as
synthetic auxiliary8 but also for insertion of C=O moiety.9 Recently, it was successfully

312
HETEROCYCLES, Vol. 65, No. 2, 2005
employed for one-step cycloaddition reactions of spiro 1,3-benzoxazine dimers10 and 4-
methylene-1,3-benzoxazinones from arylhidrazones.11 This latter prompted us to speculate the
application of triphosgene in the direct construction of 3-aryl-1,3-benzoxazine-2,4-dione system.
In connection with our ongoing program aiming to the development of bioactive heterocyclic
compounds using as starting material non-isoprenoid phenolic lipids from Anacardium
occidentale we became interested in the preparation of new substituted 5-pentadecyl-3-phenyl-
1,3-benzoxazine-2,4-diones (1) from anacardic acids (2), the major component of natural
CNSL,12 an inexpensive Brazilian starting material (Figure 1).
OH
G
COOH
R
O
O
N
2
O
2a
2b
2c
1
8
8
C15H31
R =
11
11
14
8
G = H; Cl; Br; NO2; OMe; Me
2d
Figure 1. 5-Pentadecyl-3-aryl-1,3-benzoxazine-2,4-diones (1) and anacardic acids (2).
Apart from industrial use, anacardic acids have been described as potent fungicide13 and
bactericide.14 Several analogues of well-known drugs have been prepared using 2a and
suggested fields of application are given based on their prototype currently in use.15 These
novel 3-phenyl-1,3-benzoxazine-2,4-diones (1) were structurally planned by maintenance of the
1,3-benzoxazine-2,4-diones subunit, a chemically hydrophilic moiety, which would retain high
intrinsic activity of the well-known prototypes having no long alkyl side chain. The second
structural feature consists in the presence of a C15 side chain group, which provide a
hydrophobic character to the new compounds, so that would play an important role to bioactivity.
Further structural modifications were replacement of the hydrogen atom at the G-position, for
electron-withdrawing groups e.g. chlorine, bromine, nitro, as well as electron-donating groups
e.g. methyl and methoxy, both elected in order to investigate the eventual electronic and
hydrophobic contribution in assisting the enhanced activities of the analogues with long side
chain.

HETEROCYCLES, Vol. 65, No. 2, 2005
313
RESULTS AND DISCUSSION
As outlined in Scheme 1, our approach for the synthesis of the title compounds involves the use
of inexpensive anacardic acids (2) and features the use of triphosgene for one-step
cycloaddition. Initially, the heterogeneous mixture of anacardic acids was quantitatively
converted by conventionally catalytic hydrogenation into saturated anacardic acid (2a). This was
converted to the corresponding anilides (3a-f) by heating with PCl3 followed by treatment with
appropriated anilines according to standard.16 In this step the yields were very much influenced
by the pureness of the commercially available anilines.
OH
OH
OH
O
COOH
R
COOH
C15H31
a
b
NH
G
C15H31
2
2a
3
G
O
a = H
b = Cl
c = Br
c
O
N
G =
d = NO2
e = OCH3
f = CH3
O
C15H31
1
Scheme 1 - a) H2, 10 % Pd-C, EtOH, 60 psi, rt, 2 h, 86%; b) PCl3, PhCl, reflux, appropriated
aniline, 40-80%; c) triphosgene, pyridine, CH2Cl2, rt, 12 h or overnight, 85-91%.
By analogy with the previous method for preparation of 3-phenyl-1,3-benzoxazines-1,4-dione
which characterised by using of salicylanilide and ethyl chloroformate as synthetic tool for
insertion of C=O unit, we decided that such a direct transformation could be possible by
replacing the chloroformate reagent by triphosgene, a solid safe and convenient phosgene.18 In
this way, salicycilic acid was used primarily as model study and triphosgene as a reagent for
one-pot preparation of the 3-phenyl-1,3-benzoxazine-2,4-dione in 81% yield. Attempts to
promote the ring closure of the salicylanilide with ethyl chloroformate instead of triphosgene led
to the 3-phenyl-1,3-benzoxazine-2,4-dione in 70% yield. Furthermore, by using triphogene was
found simplicity of the work-up procedure. In light of the above experiments, the present
methodology was applied for preparation of the 5-pentadecyl-3-phenyl-1,3-benzoxazine-2,4-
diones (1a-f) from the corresponding anilides. The ring closure was smoothly promoted by

314
HETEROCYCLES, Vol. 65, No. 2, 2005
triphosgene in presence of pyridine, under very mild reaction conditions (Scheme 1). In the
most cases the target compounds were obtained in high yield ca. 90%.
Interestingly, the presence of the alkyl side chain did not affect the reactivity of the anilides in
the cyclization step, since 1a was obtained in 81% from the 3a similar to the model study.
According to our current investigation, no influence related to the electronic effects of both
electron-withdrawing and electron-donating groups was observed.
In conclusion, we have shown that triphosgene can be used for direct and mild conversion of
salicylanilide into the 3-phenyl-1,3-benzoxazine-2,4-dione. The reaction also proved to be
successful for preparation of novel substituted 3-phenyl-1,3-benzoxazine-2,4-diones from
anacardic acids. This procedure can be used to promote cycloaddition in both electron-rich and
electron-deficient with comparable very high yields. Noteworthy, we register here of the high
efficiency and ready availability of the starting material, allied the structural features and
potential activity of the title compounds.
EXPERIMENTAL
General Procedures. IR spectra were recorded on a Bomem Hartmann & Braun (MB – 100)
1
spectrometer. H and 13C-NMR spectra were recorded on Varian Gemini and Mercury plus
1
spectrophotometers (300 MHz) using CDCl3/TMS. H and 13C chemical shifts are reported in
parts per million (ppm) relative to TMS. The assignments of some 13C-NMR signals were made
with the aid of APT experiments. HRMS were obtained by electronic ionization (IE). Analytical
TLC was performed on silica gel plates Merck (60F254/0.2 mm), using 5% ethanolic
phosphomolybidic acid or iodine vapors to visualize the spots. Melting points were obtained on
a Köffler apparatus.
Preparation of 3-phenyl-1,3-benzoxazine-2,4-diones. A solution of the appropriated
salicylanilide (0.5 mmol) in methylene chloride (15 mL), were added pyridine (0.15 mL) and
triphosgene (250 mg; 1.0 mmol). The cloudy reaction mixture was stirred overnight at rt, under
argon atmosphere. The reaction was diluted with ethyl acetate (20 mL) then, washed with brine.
The organic phase was dried with sodium sulfate and the solvent was removed to furnish a solid,
which was recrystallized from hexane-acetone to afford the corresponding benzoxazines (85-
91%) as white or pale yellow crystals.

HETEROCYCLES, Vol. 65, No. 2, 2005
315
Physical Data
5-Pentadecyl-3-phenyl-1,3-benzoxazine-2,4-dione (1a): Yield 90%; Rf = 0.48 (4:1, hexane:ethyl
acetate); mp 123-124oC (hexane-acetone); IR (KBr) cm-1: 1764, 1696. 1H NMR (CDCl3) δ: 0.88
(3H, t, J = 6.4 Hz, CH3), 1.18-1.40 (24H, m, CH2), 1.53-1.63 (2H, m, CH2), 3.13-3.17 (2H, m,
CH2), 7.21 (2H, d, J = 7.8 Hz, Ar-H), 7.31 (2H, d, J = 7.0 Hz, Ar-H’), 7.47-7.58 (3H, m, Ar-H’),
7.62 (1H, t, J = 7.9 Hz, Ar-H). 13C NMR (CDCl3) δ: 14.1 (CH3), 22.7 (CH2), 29.4 (CH2), 29.5
(CH2), 29.7 (CH2), 31.2 (CH2), 31.9 (CH2), 34.5 (CH2), 112.0 (C), 114.7 (CH), 128.1 (CH), 128.2
(CH), 129.3 (CH), 129.6 (CH), 134.5 (C), 135.3 (CH), 148.1 (C), 154.0 (C), 160.8 (C). HRMS-IE
m/z = 449.2930 (Calcd 449.2929). Anal. Calcd for C29H39NO3: C, 77.47; H, 8.74; N, 3.12.
Found: C, 77.52; H, 8.60; N, 3.03.
3-(4-Chlorophenyl)-5-pentadecyl-1,3-benzoxazine-2,4-dione (1b): Yield 89%; Rf = 0.51 (4:1,
1
hexane:ethyl acetate); mp 115-116oC (hexane-acetone); IR (KBr) cm-1: 1762, 1698. H NMR
(CDCl3) δ: 0.88 (3H, t, J = 6.6 Hz, CH3), 1.20-1.35 (24H, m, CH2), 1.47-1.62 (2H, m, CH2), 3.14
(2H, t, J = 7.7 Hz, CH2), 7.20 (2H, d, J = 8.2 Hz, Ar-H’), 7.25 (2H, d, J = 8.8 Hz, Ar-H), 7.51 (2H,
13
d, J = 8.5, Ar-H’), 7.61 (1H, t, J = 8.0 Hz, Ar-H). C NMR (CDCl3) δ: 14.4 (CH3), 22.9 (CH2),
29.6 (CH2), 29.9 (CH2), 31.4 (CH2), 32.1 (CH2), 34.8 (CH2), 112.0 (C), 114.8 (CH), 129.3 (CH),
129.8 (CH), 130.0 (CH), 133.1(C), 135.5 (C), 135.6 (CH), 147.8 (C), 148.4 (C), 154.2 (C), 160.3
(C). HRMS-EI: m/z = 483.2540 (Calcd 483.2540). Anal. Calcd for C29H38NO3Cl: C, 71.96; H,
7.32; N, 2.89. Found: C, 69.39; H, 7.59; N, 2.73.
3-(4-Bromophenyl)-5-pentadecyl-3-phenyl-1,3-benzoxazine-2,4-dione (1c): Yield 91%; Rf = 0.51
1
(4:1, hexane:ethyl acetate); mp 103-104oC (hexane-acetone); IR (KBr) cm-1: 1763, 1698. H
NMR (CDCl3) δ: 0.88 (3H, t, J = 6.6 Hz, CH3), 1.20-1.40 (24H, m, CH2), 1.50-1.62 (2H, m, CH2),
3.11-3.20 (2H, m, J = 7.8 Hz, CH2), 7.18-7.21 (4H, m, Ar-H’), 7.60-7.68 (3H, m, Ar-H). 13C NMR
(CDCl3) δ: 14.1 (CH3), 22.7 (CH2), 29.4 (CH2), 29.7 (CH2), 31.1 (CH2), 31.9 (CH2), 34.5 (CH2),
111.8 (C), 114.7 (CH), 123.4 (CH), 128.0 (CH), 130.0 (CH), 133.3 (C), 135.5 (C), 147.6 (C),
148.2 (C), 154.0 (C), 160.5 (C). HRMS-EI: m/z = 529.2020 (M+2) (Calcd 527.2035). Anal. Calcd
for C29H38NO3Br: C, 65.90; H, 7.25; N, 2.65. Found: C, 65.76; H, 7.18; N, 2.43.
3-(4-Nitrophenyl)-5-pentadecyl-1,3-benzoxazine-2,4-dione (1d): Yield 95%; Rf = 0.36 (4:1,
hexane:ethyl acetate); mp 126-127oC (hexane-acetone); IR (KBr) cm-1: 1767, 1698, 1521, 1350;
1H NMR (CDCl3) δ: 1.08 (3H, t, J = 6.6 Hz, CH3), 1.40-1.60 (24H, m, CH2), 1.72-1.82 (2H, m,

316
HETEROCYCLES, Vol. 65, No. 2, 2005
CH2), 3.33 (2H, t, J = 7.7 Hz, CH2), 7.43 (2H, d, J = 8.2 Hz, Ar-H), 7.73 (2H, d, J = 9.0 Hz, Ar-H’),
7.84 (1H, t, J = 8.0, Ar-H), 8.60 (2H, d, J = 8.8 Hz, Ar-H’); 13C NMR (CDCl3) δ: 14.3 (CH3), 22.9
(CH2), 29.5 (CH2), 29.6 (CH2), 29.7 (CH2), 31.3 (CH2), 32.1 (CH2), 34.7 (CH2), 111.8 (C), 115.0
(CH), 125.0 (CH), 128.5 (CH), 130.0 (CH), 135.9 (CH), 140.2 (C), 147.3 (C), 148.1 (C), 148.5
(C), 154.2 (C), 160.4 (C). HRMS: m/z = 495.2859 (M+1) (Calcd 494.2781). Anal. Calcd for
C29H38N2O5: C, 70.42; H, 7.74; N, 5.66. Found: C, 70.86; H, 7.66; N, 5.88.
3-(4-Methylphenyl)-5-pentadecyl-1,3-benzoxazine-2,4-dione (1e): Yield 90%; Rf = 0.48 (4:1,
1
hexane:ethyl acetate); mp 129-130 oC (hexane-acetone); IR (KBr) cm-1: 1767, 1688; H NMR
(CDCl3) δ: 0.88 (3H, t, J = 6.3 Hz, CH3), 0.95-1.41(24H, m, CH2), 1.43-1.66 (2H, m, CH2), 2.42
(3H, s, ArCH3), 3.14 (2H, t, J=7.5, ArCH3), 7.18 (4H, d, J = 8.4, ArH'), 7.34 (2H, d, J = 8.4 Hz,
Ar-H), 7.59 (1H, t, J = 7.8 Hz, Ar-H); 13C NMR (CDCl3) δ: 14.1(CH3), 21.2 (CH3), 22.6 (CH2),
29.3 (CH2), 29.4 (CH2), 29.6 (CH2), 31.1 (CH2), 31.8 (CH2), 34.5 (CH2), 111.9 (C), 114.5 (CH),
127.7 (CH), 127.8 (CH), 130.3 (CH), 131.8 (C), 135.5 (CH), 135.1 (CH), 139.2 (C), 147.9 (C),
148.0 (C), 153.9 (C), 160.7 (C); HRMS: m/z = 463.3079 (Calcd 463.3086). Anal. Calcd for
C30H41NO3: C, 77.71; H, 8.91; N, 3.02. Found: C, 77.68; H, 8.68; N, 3.19.
3-(4-Methoxyphenyl)-5-pentadecyl-1,3-benzoxazine-2,4-dione (1f): Yield 85%; Rf = 0.40 (4:1,
1
hexane:ethyl acetate); mp 132-133 oC (hexane-acetone); IR (KBr) cm-1: 1773, 1688. H NMR
(CDCl3) δ: 0.88 (3H, t, J = 6.3 Hz, CH3), 0.93-142 (24H, m, CH2), 1.58 (2H, q, J =7.5, CH2), 3.15
(2H, t, J = 7.5 Hz, CH2), 3.85 (3H, s, OCH3), 7.05 (2H, d, J = 9.0 Hz, Ar-H'), 7.18 (2H, d, J = 8.7,
13
Ar-H'), 7.22 (2H, d, J = 9.0 Hz, Ar-H), 7.61 (1H, t, J = 8.1 Hz, Ar-H); C NMR (CDCl3) δ: 14.1
(CH3), 22.6 (CH2), 29.2 (CH2), 29.3 (CH2), 29.5 (CH2), 29.6 (CH2), 31.1 (CH2), 32.9 (CH2), 34.5
(CH2), 55.5 (OCH3), 111.9 (C), 114.2 (CH), 114.6 (CH), 114.9 (CH), 126.9 (C), 127.9 (CH),
129.1 (CH), 135.1(CH), 148.1 (C), 154.0 (C), 159.9 (C), 160.9 (C); HRMS: m/z = 479.3033
(Calcd 479.3039). Anal. Calcd for C30H41NO4: C, 75.12; H, 8.62; N, 2.92. Found: C, 74.83; H,8.5
8.53; N, 3.13.
ACKNOWLEDGMENTS
Financial support from the CNPq and FINEP (Process CT-INFRA 970/2001), both research
foundations subordinated to the Ministry of Education of Brazil, University of Brasilia, and
Catholic University of Brasilia are gratefully acknowledged. The authors are indebted with to
Professor Dr. T. Hudlicky, University of Florida, Ms. Angelo H. L. Machado, and Professor Dr.

HETEROCYCLES, Vol. 65, No. 2, 2005
317
Carlos Roque, University of Campinas (UNICAMP) for mass spectral data of the title
compounds. The authors also thank Professor Dr. Helena M. C. Ferraz, University of São Paulo
(USP), for the microanalysis data.
REFERENCES
1. K. Waisser, O. Bures, P. Holy, J. Kunes, R. Oswald, L. Jiraskova, M. Pour, V. Klimesova, K.
Palat, J. Kaustova, H. M. Danse, and U. Mollmann, Pharmazie, 2003, 58, 83; K. Waisser, J.
Hladuvkova, P. Holy, M. Machacek, P. Karajannis, L. Kubicova, V. Klimesova, J. Kunes, and
J. Kaustova, Chem. Pap-Chem. Zvesti., 2001, 55, 323; K. Waisser, M. Machacek, H. Dostal,
J. Gregor, L. Kubicova, V. Klimesova, J. Kunes, K. Palat, J. Hladuvkova, J. Kaustova, and U.
Mollmann, Collect. Czech. Chem. Commun., 1999, 64, 1902; K. Waisser, J. Hladuvkova, J.
Gregor, T. Rada, L. Kubicova, V. Klimesova, and J. Kaustova, Arch. Pharm., 1998, 331, 3.
2. K. Waisser, L. Kubicova, V. Buchta, P. Kubanova, K. Bajerova, L. Jiraskova, O. Bednarik, O.
Bures, and P. Holy, Folia Microb., 2002, 47, 488.
3. J. D. Crum and D. A. Franks Jr., J. Heterocycl. Chem., 1965, 2, 37; R. E. Stenseth, J. W.
Baker, and D. P. Roman, J. Med. Chem., 1963, 6, 212; B. S. Joshi, R. Srinivasan, R. V.
Talavdekar, and K. Venkataraman, Tetrahedron, 1960, 11, 133; S. L. Shapiro, I. M. Rose,
and L. Freedman, J. Am. Chem. Soc., 1957, 79, 2811.
4. D. Geffken, Liebigs Ann. Chem., 1981, 1513.
5. J. Petridou-Fischer and E. P. Papadopoulos, J. Heterocyclic. Chem., 1983, 20, 1159.
6. K. Waisser, J. Gregor, L. Kubicova, V. Klimesova, J. Kunes, M. Machacek, and J. Kaustova,
Eur. J. Med. Chem., 2000, 35, 733.
7. K. Waisser, L. Kubicova, V. Klimesova, and Z. Odlerova, Collect. Czech. Chem. Commun.,
1993, 58, 2977.
8. R. T. Patil, G. Parveen, V. K. Gumaste, B. M. Bhawal, and A. R. A. S. Deshmukh, Synlett,
2002, 1455; D. Krishanaswamy, B. M. Bhawal, and A. R. A. S. Deshmukh, Tetrahedron Lett.,
2000, 41, 417.
9. X. Peng, J. Wang, J. Cui, R. Zhang, and Y. Yan, Synth. Commun., 2002, 32, 2361; M. Kluge
and D. Sicker, J. Nat. Prod., 1998, 61, 821; R. Di Santo, R. Costi, and M. Artico, Il Farmaco,
1997, 52, 375.
10. H. Z. Alkhathlan, M. A. Al-Saad, H. M. Al-Hazimi, and K. A. Al-Farhan, J. Chem. Research
(S), 2002, 473; H. Z. Alkhathlan, Tetrahedron, 2003, 59, 8163; H. Z. Alkhathlan, Synth.
Commun., 2004, 34, 71.

318
HETEROCYCLES, Vol. 65, No. 2, 2005
11. H. Z. Alkhathlan, Synth. Commun., 2004, 34, 71; H. Z. Alkathalan, Tetrahedron, 2003, 59,
8163.
12. J. H. P. Tyman, ‘Studies in Natural Products Chemistry: The chemistry of non-isoprenoid
phenolic lipids,’ Vol. 9, ed. by Atta-ur-Rahan, Elservier Science Publisher, Armsterdam, 1991,
pp. 313-381.
13. B. Prithiviraj, M. Manickam, V. P. Singh, and A. B. Ray, Can. J. Bot., 1997, 75, 207.
14. H. Muroi and I. Kubo, J. Appl. Bacteriology, 1996, 80, 387; J. Kubo, J. R. Lee, and I. Kubo,
J. Agric. Food Chem., 1999, 47, 533.
15. R. Paramashivappa, P. P. Kumar, P. V. Subba Rao, and A. Srinivasa Rao, Bioorg. Med.
Chem. Lett., 2003, 13, 657; R. Paramashivappa, P. P. Kumar, P. V. Subba Rao, and A.
Srinivasa Rao, J. Agric. Food Chem., 2002, 50, 7709; M. A. ElSholy, P. D. Adawadkar, D. A.
Beniggni, E. S. Watson, and T. L. Little, Jr., J. Med. Chem., 1986, 29, 606; A. S. Gulati and
B. C. S. Subba Rao, Indian J. Chem., 1964, 2, 337.
16. H. Lemaire, C. H. Schramm, and A. Cahn, J. Pharm. Sci., 1961, 50, 831.
17. H. Eckert and M. Forster, Angew. Chem., Int. Ed. Engl., 1987, 26, 894.