Reaction of primary alkylamines, heterocumulenes, and isatoic anhydride, catalyzed by magnetic Fe3O4 nanoparticles in H 2O

Article abstract of DOI:10.1002/hlca.201100071

An efficient protocol for the one-pot reaction of isatoic anhydride (=1,2-dihydro-4H-3,1-benzoxazine-2,4-dione), primary alkylamines, and heterocumulenes (isothiocyanates and isocyanates) in H₂O catalyzed by magnetically recoverable Fe₃O₄ nanoparticles is described. Copyright

Full text of DOI:10.1002/hlca.201100071

Helvetica Chimica Acta – Vol. 94 (2011)
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Reaction of Primary Alkylamines, Heterocumulenes, and Isatoic Anhydride,
Catalyzed by Magnetic Fe3O4 Nanoparticles in H2O
by Issa Yavari* and Saeideh Beheshti
Chemistry Department, Tarbiat Modares University, P.O. Box 14115-175, Tehran, Iran
(phone: þ 98-21-82883465; fax: þ 98-21-82883455; e-mail: yavarisa@modares.ac.ir)
An efficient protocol for the one-pot reaction of isatoic anhydride (¼1,2-dihydro-4H-3,1-
benzoxazine-2,4-dione), primary alkylamines, and heterocumulenes (isothiocyanates and isocyanates)
in H2O catalyzed by magnetically recoverable Fe3O4 nanoparticles is described.
Introduction. – The development of efficient and environmentally benign chemical
processes using recyclable catalysts is one of the major tasks in organic synthesis [1].
Magnetic nanoparticles are of interest because of their high catalytic activities. Among
them, Fe3O4 is the most important one [2 – 7]. Magnetically driven separation makes
the recovery of catalysts in a liquid-phase reaction much easier than filtration or
centrifugation [8].
As part of our current studies on the development of new routes in organic synthesis
[9 – 12], we describe the use of Fe3O4 nanoparticles (NPs) as Lewis acid catalyst, for the
synthesis of 2,3-dihydro-2-thioxoquinazolin-4(1H)-ones via a one-pot, three-compo-
nent reaction of isatoic anhydride (¼1,2-dihydro-4H-3,1-benzoxazine-2,4-dione) with
primary alkylamines and isothiocyanates in H2O (Scheme 1).
Scheme 1
Results and Discussion. – The three-component reaction of MeNH2, isatoic
anhydride, and phenylisothiocyanate as a simple model reaction was investigated to
optimize the reaction conditions (Table). Different amounts of the catalyst were used.
As indicated in the Table, the best result was obtained with 10 mol-% of Fe3O4 NPs, and
ꢀ 2011 Verlag Helvetica Chimica Acta AG, Zꢁrich

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the desired product 4b was obtained in 92% yield. Using a lower amount of catalyst
resulted in lower yields, while a higher amount of catalyst and longer reaction times did
not affect the yields (Table).
Table. Model Reaction of MeNH2, Isatoic Anhydride, and Phenyl Isothiocyanate under Various
Conditions
Catalyst (mol-%)
Time [h]
Yield of 4b [%]
No catalyst
ZnO (20)
24
9
trace
45
Bulk Fe3O4 (20)
Fe3O4 NPs (5)
Fe3O4 NPs (10)
Fe3O4 NPs (15)
3
1
1
1
68
87
92
92
After optimization of the reaction conditions, a variety of isothiocyanates and
amines were employed under similar reaction conditions to evaluate the scope of the
reaction. The results are shown in Scheme 1. All reactions proceeded smoothly, and no
undesirable side reactions were observed. The isothiocyanates carrying either electron-
withdrawing or electron-releasing groups on the aromatic ring were converted to the
corresponding 2,3-dihydro-2-thioxoquinazolin-4(1H)-one derivatives 4a – 4f in good
yields.
A plausible mechanism for this reaction is proposed in Scheme 2. It is conceivable
that the Fe3O4 NPs are coordinated to the O-atom of the CO groups in different stages
of the reaction activating them for the nucleophilic attack of the N-atom. The high
surface area-to-volume ratio of Fe3O4 NPs is mainly responsible for their catalytic
properties [13].
Scheme 2
When the reaction was carried out with bulky alkylamines, the product did not
cyclize. For example, the reaction of 4-methoxybenzylamine, isatoic anhydride, and
phenylisothiocyanate led to N-(4-methoxybenzyl)-2-[(phenylcarbamothioyl)amino]-

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benzamide (8; Fig. 1). The reaction of ethylamine, isatoic anhydride, and 4-nitro-
benzoyl isothiocyanate (9) led to uncyclized product 10 (Fig. 1).
Fig. 1. Structure of Compounds 8 – 10
The reaction of primary alkylamines, isatoic anhydride, and phenylisocyanate led to
phenylurea derivatives 12a – 12c (Scheme 3).
Scheme 3
Fig. 2 shows the XRD pattern of the Fe3O4 NPs. All of the diffraction peaks are in
agreement with the JCPDS file of Fe3O4 (JCPDS No. 19-0629). The morphology and
grain size of the Fe3O4 NPs were investigated by SEM (Fig. 3). They have spherical
morphology including a narrow distribution of sizes, from 32 to 68 nm.
In conclusion, we have developed an efficient method to use Fe3O4 NPs as a Lewis
acid catalyst for the synthesis of 2,3-dihydro-2-thioxoquinazolin-4(1H)-ones by a one-
pot, three-component condensation of isatoic anhydride with amines and isothiocya-
nates in H2O. The Fe3O4 NPs would act as a catalyst to activate the substrate molecules.
Moreover, the catalyst can be recovered conveniently and reused for at least nine
reaction cycles without considerable loss of activity.
Experimental Part
General. All chemicals were obtained commercially and used without further purification. M.p.:
Electrothermal-9100 apparatus. IR Spectra: Shimadzu-IR-460 spectrometer; ˜n in cmꢀ1. 1H- and 13C-NMR
Spectra: Bruker DRX-500 Avance instrument at 500.1 and 125.7 MHz, resp., in CDCl3 with TMS as
internal standard; d in ppm, J in Hz. MS: Finnigan-MAT-8430EI-MS mass spectrometer; at 70 eV; in m/z
(rel. %). Elemental analyses: Vario EL III CHNOS elemental analyzer. Scanning electron microscopy
(SEM) images: Stereo Scan XL30 Philip instrument.

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Fig. 2. XRD Pattern of synthesized Fe3O4 nanoparticles
Fig. 3. SEM Image of the synthesized Fe3O4 nanoparticles
General Procedure. Isatoic anhydride (¼1,2-dihydro-4H-3,1-benzoxazine-2,4-dione; 2; 1 mmol),
amine 1 (1 mmol), isothiocyanate 3 or phenyl isocyanate 11 (1 mmol), and Fe3O4 (0.1 mmol) were mixed
in H2O (5 ml). The mixture was stirred under reflux in an air atmosphere for 1 h. Then, AcOEt (5 ml)
was added. The Fe3O4 nanoparticles were removed with a magnetic stirring bar. The org. and aq. layers
were separated. The org. phase was dried over anh. Na2SO4, and the solvent was evaporated under
vacuum. Pure products were obtained by recrystallization from EtOH.
3-Ethyl-2,3-dihydro-2-thioxoquinazolin-4(1H)-one (4a). Yield: 0.19 g (95%). White powder. M.p.
246 – 2488. IR (KBr): 3232, 2965, 1640, 1522, 1339, 1218. 1H-NMR: 1.28 (t, J ¼ 7.0, Me); 4.55 (q, J ¼ 7.0,
CH2); 7.35 (dd, J ¼ 7.9, 1 arom. H); 7.45 (d, J ¼ 8.1, 1 arom. H); 7.74 (dd, J ¼ 8.2, 1 arom. H); 8.04 (d, J ¼
7.9, 1 arom. H); 11.57 (s, NH). 13C-NMR: 12.2 (Me); 42.1 (CH2); 115.9 (CH); 125.1 (CH); 128.4 (CH);
136.1 (CH); 139.5 (C); 140.5 (C); 160.1 (C¼O); 177.1 (C¼S). EI-MS: 206 (100, Mþ), 166 (27), 145 (13),
119 (25), 92 (16), 77(19). Anal. calc. for C10H10N2OS (206.05): C 58.23, H 4.89, N 13.58, S 15.55; found: C
57.87, H 5.12, N 13.42, S 15.04.
2,3-Dihydro-3-phenyl-2-thioxoquinazolin-4(1H)-one (4b). Yield: 0.23 g (92%). White powder. M.p.
318 – 3208. IR (KBr): 3232, 3040, 2935, 1658, 1519, 1405, 1204. 1H-NMR: 7.26 (d, J ¼ 7.4, 2 arom. H); 7.33

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(dd, J ¼ 7.8, 1 arom. H); 7.39 (dd, J ¼ 7.3, 1 arom. H); 7.43 – 7.48 (m, 3 arom. H); 7.76 (dd, J ¼ 7.2, 1 arom.
H); 7.94 (d, J ¼ 7.8, 1 arom. H); 13.02 (s, NH). 13C-NMR: 115.6 (CH); 116.1 (C); 124.2 (CH); 127.3 (CH);
128.1 (CH); 128.8 (2 CH); 128.9 (2 CH); 135.5 (CH); 139.2 (C); 139.5 (C); 159.7 (C¼O); 176.1 (C¼S).
EI-MS: 254 (100, Mþ), 221 (8), 166 (12), 145 (13), 119 (25), 92 (21), 77 (19). Anal. calc. for C14H10N2OS
(254.05): C 66.12, H 3.96, N 11.02, S 12.61; found: C 66.10, H 3.54, N 10.35, S 11.89.
3-(4-Chlorophenyl)-2,3-dihydro-2-thioxoquinazolin-4(1H)-one (4c). Yield: 0.25 g (89%). White
powder. M.p. 338 – 3408. IR (KBr) : 3244, 3039, 2939, 1667, 1520, 1404, 1202. 1H-NMR: 7.29 – 7.33 (m, 3
arom. H); 7.43 (d, J ¼ 8.1, 1 arom. H); 7.53 (d, J ¼ 8.1, 2 arom. H); 7.76 (dd, J ¼ 7.3, 1 arom. H); 7.94 (d, J ¼
7.6, 1 arom. H); 13.07 (s, NH). 13C-NMR: 115.7 (CH); 116.1 (C); 124.3 (CH); 127.3 (CH); 128.9 (2 CH);
130.7 (2 CH); 132.6 (C); 135.6 (CH); 138.2 (C); 139.5 (C); 159.7 (C¼O); 175.8 (C¼S). EI-MS: 290 (5,
Mþ), 288 (63, Mþ), 253 (34), 152 (26), 92 (100), 77 (41). Anal. calc. for C14H9ClN2OS (288.01): C 58.23, H
3.14, N 9.70, S 11.10; found: C 57.06, H 3.44, N 9.45, S 11.28.
2,3-Dihydro-3-(4-methylphenyl)-2-thioxoquinazolin-4(1H)-one (4d). Yield: 0.34 g (94%). White
powder. M.p. 318 – 3208. IR (KBr): 3233, 3033, 2928, 2350, 1657, 1519, 1403, 1201. 1H-NMR: 2.35 (s, Me);
7.12 (d, J ¼ 7.8, 2 arom. H); 7.25 (d, J ¼ 7.8, 2 arom. H); 7.32 (dd, J ¼ 7.6, 1 arom. H); 7.43 (d, J ¼ 8.2, 1
arom. H); 7.76 (dd, J ¼ 7.6, 1 arom. H); 7.93 (d, J ¼ 7.8, 1 arom. H); 13.01 (s, NH). 13C-NMR: 20.7 (Me);
115.6 (CH); 116.1 (C); 124.2 (CH); 127.3 (CH); 128.6 (2 CH); 129.3 (2 CH); 135.5 (CH); 136.6 (C); 137.3
(C); 139.5 (C); 159.7 (C¼O); 176.1 (C¼S). EI-MS: 268 (13, Mþ), 253 (48), 133 (24), 92 (100), 77 (35).
Anal. calc. for C15H12N2OS (268.07): C 67.14, H 4.51, N 10.44, S 11.95; found: C 66.18, H 4.35, N 10.15, S
11.73.
2,3-Dihydro-3-(4-nitrophenyl)-2-thioxoquinazolin-4(1H)-one (4e). Yield: 0.27 g (90%). Yellow
1
powder. M.p. 330 – 3328. IR (KBr): 3239, 3112, 2930, 2349, 1661, 1523, 1412, 1344. H-NMR: 7.35 (dd,
J ¼ 7.6, 1 arom. H); 7.45 (d, J ¼ 8.2, 1 arom. H); 7.65 (d, J ¼ 8.6, 2 arom. H); 7.79 (dd, J ¼ 7.6, 1 arom. H);
7.96 (d, J ¼ 7.8, 1 arom. H); 8.34 (d, J ¼ 8.6, 2 arom. H); 13.16 (s, NH). 13C-NMR: 115.8 (CH); 116.2 (C);
124.2 (2 CH); 124.4 (CH); 127.3 (CH); 130.9 (2 CH); 135.7 (CH); 139.6 (C); 145.2 (C); 147.1 (C); 159.6
(C¼O); 175.3 (C¼S). EI-MS: 299 (17, Mþ), 253 (54), 164 (45), 92 (100), 77 (28). Anal. calc. for
C14H9N3O3S (299.04): C 56.18, H 3.03, N 14.04, S 10.71; found: C 55.32, H 2.94, N 13.75, S 11.43.
3-(2,4-Dichlorophenyl)-2,3-dihydro-2-thioxoquinazolin-4(1H)-one (4f). Yield: 0.29 g (92%). White
powder. M.p. 254 – 2568. IR (KBr): 3243, 2936, 1659, 1511, 1398, 1202. 1H-NMR: 7.40 (dd, J ¼ 7.7, 1 arom.
H); 7.50 – 7.59 (m, 3 arom. H); 7.68 (s, 1 arom. H); 7.82 (dd, J ¼ 7.8, 1 arom. H); 8.07 (d, J ¼ 7.8, 1 arom. H);
11.90 (s, NH). 13C-NMR: 115.1 (CH); 115.5 (C); 124.1 (CH); 127.4 (CH); 127.7 (CH); 128.9 (CH); 131.9
(CH); 133.1 (C); 133.9 (C); 135.4 (CH); 135.6 (C); 139.3 (C); 158.5 (C¼O); 175.4 (C¼S). EI-MS: 321 (2,
Mþ), 287 (100), 178 (37), 119 (38), 92 (12). Anal. calc. for C14H8Cl2N2OS (321.97): C 52.03, H 2.49, N
8.67, S 9.92; found: C 54.05, H 3.08, N 8.15, S 9.35.
N-(4-Methoxybenzyl)-2-[(phenylcarbamothioyl)amino]benzamide (8). Yield: 0.38 g (97%). White
powder. M.p. 154 – 1568. IR (KBr): 3333, 3182, 3022, 1616, 1518, 1254. 1H-NMR: 3.77 (s, MeO); 4.44 (d,
J ¼ 5.9, CH2); 6.88 (d, J ¼ 8.6, 2 arom. H); 7.13 (dd, J ¼ 7.7, 1 arom. H); 7.23 (dd, J ¼ 7.4, 1 arom. H); 7.27
(d, J ¼ 8.6, 2 arom. H); 7.39 – 7.46 (m, 3 arom. H); 7.52 (d, J ¼ 7.7, 2 arom. H); 7.67 (d, J ¼ 7.8, 1 arom. H);
8.05 (s, NH); 8.54 (d, J ¼ 7.8, 1 arom. H); 9.49 (s, NH); 10.99 (s, NH). 13C-NMR: 43.5 (CH2); 55.6 (MeO);
114.7 (CH); 124.4 (CH); 125.5 (2 CH); 126.1 (CH); 126.6 (CH); 128.2 (2 CH); 129.8 (2 CH); 130.1
(2 CH); 131.3 (CH); 131.9 (C); 136.4 (C); 139.5 (C); 140.7 (C); 160.1 (C); 169.1 (C¼O); 181.1 (C¼S). EI-
MS: 391 (1, Mþ), 298 (12), 272 (11), 253 (70), 135 (95), 121 (86), 93 (100), 77 (70). Anal. calc. for
C22H21N3O2S (391.14): C 67.50, H 5.41, N 10.73, S 8.19; found: C 66.71, H 5.73, N 9.95, S 7.62.
N-Ethyl-2-{[(4-nitrobenzoyl)carbamothioyl]amino}benzamide (10). Yield: 0.33 g (91%). Yellow
powder. M.p. 202 – 2048. IR (KBr): 3439, 2929, 2349, 1639, 1524. 1H-NMR: 1.23 (t, J ¼ 7.3, Me); 3.46 – 3.51
(m, CH2); 6.18 (s, NH); 7.32 (dd, J ¼ 7.5, 1 arom. H); 7.50 – 7.54 (m, 2 arom. H); 8.12 (d, J ¼ 8.6, 2 arom.
H); 8.29 (d, J ¼ 8.1, 1 arom. H); 8.36 (d, J ¼ 8.6, 2 arom. H); 9.19 (s, NH); 13.11 (s, NH). 13C-NMR: 14.7
(Me); 34.9 (CH2); 124.1 (2 CH); 126.8 (CH); 126.9 (CH); 127.1 (CH); 129.1 (CH); 129.3 (C); 130.7
(2 CH); 136.4 (C); 137.3 (C); 150.6 (C); 163.6 (C¼O); 167.2 (C¼O); 178.3 (C¼S). EI-MS: 372 (1, Mþ),
166 (20), 150 (100), 120 (36), 104 (39), 92 (37). Anal. calc. for C17H16N4O4S (372.09): C 54.83, H 4.33, N
15.04, S 8.61; found: C 55.12, H 4.78, N 14.61, S 8.05.
N-Methyl-2-[(phenylcarbamoyl)amino]benzamide (12a). 0.25 g (93%). Yield: White powder. M.p.
318 – 3208. IR (KBr): 3272, 3089, 1686, 1596, 1513, 1444, 1295, 1216. 1H-NMR: 2.90 (d, J ¼ 4.7, Me); 6.97

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(dd, J ¼ 7.6, 2 arom. H); 7.26 (dd, J ¼ 7.8, 2 arom. H); 7.40 (dd, J ¼ 8.4, 1 arom. H); 7.63 – 7.64 (m, 3 arom.
H); 7.89 (s, NH); 8.48 (d, J ¼ 8.4, 1 arom. H); 8.96 (s, NH); 10.68 (s, NH). 13C-NMR: 26.6 (Me); 119.6
(2 CH); 120.7 (C); 121.2 (CH); 121.5 (CH); 122.8 (CH); 127.9 (CH); 129.4 (2 CH); 132.4 (CH); 141.2
(C); 141.9 (C); 153.3 (C¼O); 170.2 (C¼O). EI-MS: 269 (8, Mþ), 177 (18), 150 (53), 120 (33), 93 (100).
Anal. calc. for C15H15N3O2 (269.12): C 66.90, H 5.61, N 15.60; found: C 65.71, H 5.78, N 14.87.
N-Ethyl-2-[(phenylcarbamoyl)amino]benzamide (12b). Yield: 0.27 g (95%). White powder. M.p.
204 – 2068. IR (KBr): 3274, 3084, 2349, 1518, 1447, 1295, 1224. 1H-NMR: 1.21 (t, J ¼ 7.2, Me); 3.38 – 3.44
(m, CH2); 6.95 (dd, J ¼ 7.9, 2 arom. H); 7.26 (dd, J ¼ 7.7, 2 arom. H); 7.41 (dd, J ¼ 8.1, 1 arom. H); 7.62 –
7.65 (m, 3 arom. H); 7.92 (s, NH); 8.48 (d, J ¼ 8.3, 1 arom. H); 8.96 (s, NH); 10.67 (s, NH). 13C-NMR: 14.8
(Me); 35.1 (CH2); 119.6 (2 CH); 120.9 (C); 121.2 (CH); 121.5 (CH); 122.8 (CH); 128.1 (CH); 129.3
(2 CH); 132.3 (CH); 141.2 (C); 142.1 (C); 153.3 (C¼O); 169.6 (C¼O). EI-MS: 283 (15, Mþ), 191 (22),
164 (46), 120 (37), 93 (100). Anal. calc. for C16H17N3O2 (283.13): C 67.83, H 6.05, N 14.83; found: C 67.14,
H 5.43, N 13.92.
N-(4-Methoxybenzyl)-2-[(phenylcarbamoyl)amino]benzamide (12c). Yield: 0.35 g (94%). White
powder. M.p. 178 – 1808. IR (KBr): 3255, 3084, 2928, 1689, 1609, 1526, 1445, 1306, 1239. 1H-NMR: 3.76 (s,
MeO); 4.54 (d, J ¼ 5.9, CH2); 6.90 (d, J ¼ 8.7, 2 arom. H); 6.99 (dd, J ¼ 7.5, 2 arom. H); 7.26 – 7.32 (m, 4
arom. H); 7.43 (dd, J ¼ 8.6, 1 arom. H); 7.64 (d, J ¼ 7.7, 2 arom. H); 7.73 (d, J ¼ 7.9, 1 arom. H); 8.36 (s,
NH); 8.50 (d, J ¼ 8.5, 1 arom. H); 9.01 (s, NH); 10.68 (s, NH). 13C-NMR: 43.5 (CH2); 55.6 (MeO); 114.8
(CH); 119.7 (2 CH); 120.8 (C); 121.5 (CH); 121.7 (CH); 123.1 (2 CH); 128.3 (CH); 129.5 (2 CH); 129.7
(2 CH); 132.1 (C); 132.7 (CH); 141.3 (C); 142.3 (C); 153.4 (C¼O); 160.1 (C); 169.8 (C¼O). EI-MS: 375
(1, Mþ), 282 (22), 256 (25), 136 (79), 121 (100), 93 (70), 77 (23). Anal. calc. for C22H21N3O3 (375.16): C
70.38, H 5.64, N 11.19; found: C 69.10, H 5.12, N 10.34.
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Received February 15, 2011