Synthesis of 1-acyl-3,4-dihydroquinazoline-2(1H)-thiones by cyclization of N-[2-(isothiocyanatomethyl)phenyl] amides generated in situ from N-[2-(azidomethyl)phenyl] amides

Article abstract of DOI:10.1002/hlca.201400078

An efficient method for the preparation of 1-acyl-3,4-dihydroquinazoline- 2(1H)-thiones 5 has been developed. The reaction of N-[2-(azidomethyl)phenyl] amides 3, easily prepared by a three-step sequence starting with (2-aminophenyl)methanols, with Ph

Full text of DOI:10.1002/hlca.201400078

Helvetica Chimica Acta – Vol. 97 (2014)
923
Synthesis of 1-Acyl-3,4-dihydroquinazoline-2(1H)-thiones by Cyclization
of N-[2-(Isothiocyanatomethyl)phenyl] Amides Generated in situ from
N-[2-(Azidomethyl)phenyl] Amides
by Kazuhiro Kobayashi* and Naoki Matsumoto
Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of
Engineering, Tottori University, 4-101 Koyama-minami, Tottori 680-8552, Japan
(phone/fax: þ 81-857-315263; e-mail: kkoba@chem.tottori-u.ac.jp)
An efficient method for the preparation of 1-acyl-3,4-dihydroquinazoline-2(1H)-thiones 5 has been
developed. The reaction of N-[2-(azidomethyl)phenyl] amides 3, easily prepared by a three-step
sequence starting with (2-aminophenyl)methanols, with Ph3P, followed by CS2, allowed generation of N-
[2-(isothiocyanatomethyl)phenyl]-amide intermediates 4, which underwent cyclization on treatment
with NaH to furnish the corresponding desired products in generally good yields.
Introduction. – 3,4-Dihydroquinazoline-2(1H)-thione derivatives have attracted
much attention, because some of them have been reported to exhibit biological
activities [1]. This type of heterocycles have commonly been prepared by the reaction
of 2-(aminomethyl)benzenamines with CSCl2 [2]. Recently, a new type of derivatives,
4-alkylidene-3,4-dihydroquinazoline-2(1H)-thiones, have been synthesized by the
reaction of 2-isothiocyanatobenzonitriles with carbon nucleophiles [3]. Some bio-
logically active 1-acyl derivatives have also been prepared [4]. However, no general
methods for the synthesis of 1-acyl derivatives have been reported so far. We envisaged
that N-[2-(azidomethyl)phenyl] amides 3 could generate N-[2-(isothiocyanatomethyl)-
phenyl] amides 4, which would undergo cyclization to 1-acyl-3,4-dihydroquinazoline-
2(1H)-thiones 5 on treatment with a base. Herein, we report the results of our study,
providing a convenient synthetic approach to 5. We have found that the azido
precursors 3 can be easily prepared by a three-step sequence starting with (2-
aminophenyl)methanols, and that the desired product 5 can be obtained form 3 in a
one-pot reaction through treatment of the isothiocyanate intermediates 4 with NaH.
Results and Discussion. – N-[2-(hydroxymethyl)phenyl] amides 1 were readily
prepared in good yields (see Exper. Part) by reacting (2-aminophenyl)methanols
with appropriate acylating agents. These amides 1 were chlorinated with SOCl2 in THF
at ꢀ 408 to room temperature to afford N-[2-(chloromethyl)phenyl] amides 2 in fair-to-
good yields. Replacement of the Cl group of 2 with NaN3 in DMF at room temperature
proceeded smoothly and cleanly to afford the corresponding N-[2-(azidomethyl)-
phenyl] amides 3 in good yields (Table).
The desired products 5 could be obtained in a one-pot reaction from 3, as illustrated
in the Scheme as well. Thus, treatment of 3 with Ph3P in CH2Cl2 at room temperature
afforded the corresponding aza-ylide intermediates. After replacement of the solvent
ꢀ 2014 Verlag Helvetica Chimica Acta AG, Zꢁrich

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Helvetica Chimica Acta – Vol. 97 (2014)
Scheme
Table. Preparation of 3,4-Dihydroquinazoline-2(1H)-thiones 5
Entry
1
2
Yielda) [%]
3
Yielda) [%]
5
Yielda) [%]
1
2
3
4
5
6
7
8
9
1a (R1 ¼ R2 ¼ H, R3 ¼ Me)
2a 87
2b 95
2c 73
2d 71
2e 60
3a 73
3b 82
3c 97
3d 93
3e 78
3f 91
3g 92
3h 97
3i 87
3j 78
5a 64
5b 78
5c 54
5d 81
5e 75
5f 62
5g 86
5h 62
5i 76
5j 74
1b (R1 ¼ R2 ¼ H, R3 ¼ Ph)
1c (R1 ¼ R2 ¼ H, R3 ¼ 2-MeꢀC6H4)
1d (R1 ¼ R2 ¼ H, R3 ¼ 3-ClꢀC6H4)
1e (R1 ¼ R2 ¼ H, R3 ¼ 4-ClꢀC6H4)
1f (R1 ¼ R2 ¼ H, R3 ¼ 4-MeOꢀC6H4) 2f 60
1g (R1 ¼ R2 ¼ H, R3 ¼ EtO)
1h (R1 ¼ H, R2 ¼ Cl, R3 ¼ Me)
1i (R1 ¼ H, R2 ¼ Cl, R3 ¼ Ph)
1j (R1 ¼ R2 ¼ MeO, R3 ¼ Ph)
2g 87
2h 60
2i 59
2j 91
10
a) Yields of isolated products.
by MeCN, the intermediates were reacted with CS2 at reflux temperature to generate
the corresponding isothiocyanato intermediates 4. Subsequently, these intermediates
were treated with NaH. Cyclization took place immediately to give, after usual aqueous
workup and the subsequent purification of the crude products by column chromatog-
raphy on SiO2, the desired products 5. The results compiled in the Table indicate that
the yields of 5 are generally fair-to-good, though the yield of the 1-(2-methylbenzoyl)
derivative 5c is somewhat lower than those of the others, probably due to steric reasons.
It should be noted that the use of ClCOOEt as an acylating agent for the first step of the
present synthetic sequence has proved to be effective. Entry 7 indicates that the yields
of each step of this sequence are comparable to those of the others.
In conclusion, we have developed a convenient sequence for the preparation of 1-
acyl-3,4-dihydroquinazoline-2(1H)-thiones 5 from (2-aminophenyl)methanols. The
present method may be of value in organic synthesis because of the operational
simplicity, as well as the good availability of the starting materials.
Experimental Part
General. All org. solvents were dried over appropriate drying agents and distilled prior to use. All
chemicals were commercially available. TLC: Merck silica gel 60 PF254. Column chromatography (CC):
Wako Gel C-200E. M.p.: Laboratory Devices MEL-TEMP II melting-point apparatus; uncorrected. IR

Helvetica Chimica Acta – Vol. 97 (2014)
Spectra: PerkinElmer Spectrum65 FTIR spectrophotometer; ˜n in cmꢀ1
925
.
1H-NMR Spectra: JEOL
ECP500 FT NMR or JEOL LA400 FT NMR spectrometer (at 500 or 400 MHz, resp.); in CDCl3, d in
ppm rel. to Me4Si as internal standard, J in Hz. 13C-NMR Spectra: JEOL ECP500 FT NMR
spectrometer, at 125 MHz; in CDCl3, d in ppm rel. to Me4Si as internal standard. HR-MS (DART,
positive-ion mode): Thermo Scientific Exactive spectrometer; in m/z.
(2-Amino-4,5-dimethoxyphenyl)methanol. A soln. of (4,5-dimethoxy-2-nitrophenyl)methanol (1.1 g,
5.2 mmol) in AcOEt (30 ml) containing 10% Pd/C (0.19 g, 0.16 mmol) was stirred under H2 at r.t. for 1 d.
After filtration under reduced pressure through a Celite pad, the filtrate was concentrated by evaporation
to give a residue, separation of which by CC (SiO2; AcOEt) afforded the product (0.83 g, 87%). White
1
solid. M.p. 75 – 768 (hexane/Et2O). IR (KBr): 3368, 1619, 1519. H-NMR (500 MHz): 1.60 (br. s, 1 H);
3.79 – 3.86 (including 2 br. s at 3.81, 3.84, 8 H); 4.61 (s, 2 H); 6.32 (s, 1 H); 6.66 (s, 1 H). Anal. calc. for
C9H13NO3 (183.20): C 59.00, H 7.15, N 7.65; found: C 59.03, H 7.22, N 7.42.
N-[2-(Hydroxymethyl)phenyl]acetamide (1a). To a stirred soln. of (2-aminophenyl)methanol
(0.62 g, 5.0 mmol) in Et2O (10 ml) at 08 was added Ac2O (1.5 g, 15 mmol) dropwise. After 5 min stirring
at the same temp., the precipitate was collected by filtration under reduced pressure: 0.72 g (87%).
White solid. M.p. 116 – 1178 (hexane/CH2Cl2) ([5]: 114 – 1158). The IR and 1H-NMR data for this
compound were identical to those reported in [6].
N-[2-(Hydroxymethyl)phenyl]benzamide (1b). To a stirred mixture of 2-(aminophenyl)methanol
(0.31 g, 2,5 mmol) in sat. aq. NaHCO3 (12 ml) at r.t. was added BzCl (0.42 g, 3.0 mmol) dropwise. After
30 min stirring at the same temp., the precipitate was collected by filtration under reduced pressure and
washed with hexane/Et2O 20 :1 to give 1b (0.54 g, 95%). Colorless needles. M.p. 93 – 948 (hexane/
CH2Cl2 ; [7]: 95 – 968). IR (KBr): 3361, 3309, 1645. 1H-NMR (500 MHz): 2.33 (t, J ¼ 5.9, 1 H); 4.81 (d, J ¼
5.9, 2 H); 7.11 (dd, J ¼ 7.8, 6.8, 1 H); 7.21 (d, J ¼ 7.8, 1 H); 7.40 (ddd, J ¼ 7.8, 6.8, 2.0, 1 H); 7.48 – 7.58 (m,
3 H); 7.95 (dd, J ¼ 8.8, 2.0, 2 H); 8.31 (d, J ¼ 7.8, 1 H); 9.57 (br. s, 1 H).
N-[2-(Hydroxymethyl)phenyl]-2-methylbenzamide (1c) was prepared from (2-aminophenyl)metha-
nol and 2-methylbenzoyl chloride as described for 1b. Yield: 73%. Colorless crystals. M.p. 127 – 1288
(hexane/CH2Cl2). IR (KBr): 3249, 1644. 1H-NMR (400 MHz): 2.16 (t, J ¼ 4.9, 1 H); 2.56 (s, 3 H); 4.75 (d,
J ¼ 4.9, 2 H); 7.13 (t, J ¼ 7.8, 1 H); 7.22 – 7.29 (m, 3 H); 7.35 – 7.42 (m, 2 H); 7.55 (d, J ¼ 7.8, 1 H); 8.25 (d,
J ¼ 7.8, 1 H); 8.90 (br. s, 1 H). Anal. calc. for C15H15NO2 (241.29): C 74.67, H 6.27, N 5.81; found: C 74.26,
H 6.31, N 5.52.
3-Chloro-N-[2-(hydroxymethyl)phenyl]benzamide (1d) was prepared from (2-aminophenyl)metha-
nol and 3-chlorobenzoyl chloride as described for 1b. Yield: 86%. Colorless crystals. M.p. 120 – 1218
(hexane/CH2Cl2). IR (KBr): 3251, 1657. 1H-NMR (400 MHz): 2.41 (br. s, 1 H); 4.82 (s, 2 H); 7.11 (dd, J ¼
7.8, 6.8, 1 H); 7.21 (d, J ¼ 7.8, 1 H); 7.39 (t, J ¼ 7.8, 1 H); 7.42 (dd, J ¼ 8.8, 6.8, 1 H); 7.53 (d, J ¼ 6.8, 1 H);
7.79 (d, J ¼ 7.8, 1 H); 7.94 (d, J ¼ 2.0, 1 H); 8.28 (d, J ¼ 7.8, 1 H); 9.63 (br. s, 1 H). Anal. calc. for
C14H12ClNO2 (261.70): C 64.25, H 4.62, N 5.35; found: C 64.20, H 4.50, N 5.32.
4-Chloro-N-[2-(hydroxymethyl)phenyl]benzamide (1e) was prepared from (2-aminophenyl)metha-
nol and 4-chlorobenzoyl chloride as described for 1b. Yield: 92%. Colorless crystals. M.p. 121 – 1248
(hexane/CH2Cl2). IR (KBr): 3284, 1663, 1614. 1H-NMR (500 MHz): 2.32 (t, J ¼ 5.7, 1 H); 4.82 (d, J ¼ 5.7,
2 H); 7.11 (t, J ¼ 7.4, 1 H); 7.21 (d, J ¼ 7.4, 1 H); 7.40 (dd, J ¼ 8.0, 7.4, 1 H); 7.46 (d, J ¼ 8.6, 2 H); 7.88 (d,
J ¼ 8.6, 2 H); 8.30 (d, J ¼ 8.0, 1 H); 9.61 (br. s, 1 H). Anal. calc. for C14H12ClNO2 (261.70): C 64.25, H 4.62,
N 5.35; found: C 64.29, H 4.70, N 5.31.
N-[2-(Hydroxymethyl)phenyl]-4-methoxybenzamide (1f) was prepared from (2-aminophenyl)me-
thanol and 4-methoxybenzoyl chloride as described for 1b. Yield: 71%. Colorless crystals. M.p. 144 – 1468
(hexane/CH2Cl2). IR (KBr): 3264, 1642, 1608. 1H-NMR (500 MHz): 2.39 (t, J ¼ 5.7, 1 H); 3.87 (s, 3 H);
4.80 (d, J ¼ 5.7, 2 H); 6.98 (d, J ¼ 9.2, 2 H); 7.09 (t, J ¼ 7.4, 1 H); 7.20 (d, J ¼ 7.4, 1 H); 7.38 (ddd, J ¼ 8.0, 7.4,
1.1, 1 H); 7.91 (d, J ¼ 9.2, 2 H); 8.28 (d, J ¼ 8.0, 1 H); 9.47 (br. s, 1 H). Anal. calc. for C15H15NO3 (257.28):
C 70.02, H 5.88, N 5.44; found: C 69.74, H 5.90, N 5.26.
Ethyl 2-(Hydroxymethyl)phenylcarbamate (1g) [8] was prepared from (2-aminophenyl)methanol
and ClCOOEt as described for the preparation of 1b. Yield: 95%. Colorless oil. Rf (AcOEt/hexane 3 :2)
0.48. IR (neat): 3352, 1710. 1H-NMR (500 MHz): 1.32 (t, J ¼ 7.4, 3 H); 2.05 (t, J ¼ 5.7, 1 H); 4.22 (q, J ¼ 7.4,
2 H); 4.71 (d, J ¼ 5.7, 2 H); 7.03 (t, J ¼ 7.4, 1 H); 7.17 (d, J ¼ 7.4, 1 H); 7.33 (d, J ¼ 7.4, 1 H); 7.84 (br. s, 1 H);
7.94 (d, J ¼ 7.4, 1 H).

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Helvetica Chimica Acta – Vol. 97 (2014)
N-[5-Chloro-2-(hydroxymethyl)phenyl]acetamide (1h) was prepared from (2-amino-4-chlorophe-
nyl)methanol and Ac2O as described for 1a. Yield: 84%. White solid. M.p. 129 – 1318 (hexane/CH2Cl2).
1
IR (KBr): 3266, 1658, 1605. H-NMR (500 MHz): 2.19 (s, 3 H); 2.20 (t, J ¼ 5.9, 1 H); 4.69 (d, J ¼ 5.9,
2 H); 7.04 (d, J ¼ 8.8, 1 H); 7.09 (d, J ¼ 8.8, 1 H); 8.18 (s, 1 H); 8.61 (br. s, 1 H). Anal. calc. for
C9H10ClNO2 (199.63): C 54.15, H 5.05, N 7.02; found: C 54.18, H 5.34, N 6.80.
N-[5-Chloro-2-(hydroxymethyl)phenyl]benzamide (1i) [9] was prepared from (2-amino-4-chloro-
phenyl)methanol and BzCl as described for 1b. Yield: 87%. White solid. M.p. 129 – 1318 (hexane/
1
CH2Cl2). IR (KBr): 3415, 3312, 1666, 1614. H-NMR (500 MHz): 2.32 (t, J ¼ 5.7, 1 H); 4.80 (d, J ¼ 5.7,
2 H); 7.06 (dd, J ¼ 8.0, 1.7, 1 H); 7.11 (d, J ¼ 8.0, 1 H); 7.50 (dd, J ¼ 8.0, 7.4, 2 H); 7.57 (t, J ¼ 7.4, 1 H); 7.93
(d, J ¼ 8.0, 2 H); 8.45 (s, 1 H); 9.68 (br. s, 1 H). Anal. calc. for C14H12ClNO2 (261.70): C 64.25, H 4.62, N
5.35; found: C 64.19, H 4.78, N 5.30.
N-[2-(Hydroxymethyl)-4,5-dimethoxyphenyl]benzamide (1j) was prepared from (2-amino-4,5-
dimethoxyphenyl)methanol and BzCl as described for 1b. Yield: 83%. White solid. M.p. 138 – 1398
(hexane/CH2Cl2). IR (KBr): 3396, 3292, 1646, 1619. 1H-NMR (500 MHz): 2.39 (t, J ¼ 5.9, 1 H); 3.87 (s,
3 H); 3.94 (s, 3 H); 4.74 (d, J ¼ 5.9, 2 H); 6.73 (s, 1 H); 7.50 (ddd, J ¼ 8.8, 7.6, 2.0, 2 H); 7.56 (td, J ¼ 7.6, 2.0,
1 H); 7.92 (s, 1 H); 7.94 (d, J ¼ 8.8, 2 H); 9.35 (br. s, 1 H). Anal. calc. for C16H17NO4 (287.31): C 66.89, H
5.96, N 4.88; found: C 66.64, H 5.93, N 4.75.
N-[2-(Chloromethyl)phenyl]acetamide (2a) [10]. Representative Procedure. To a stirred soln. of 1a
(0.41 g, 2.5 mmol) in THF (7 ml) at ꢀ 408 was added a soln. of SOCl2 (0.31 g, 2.6 mmol) in THF (1.5 ml)
during 6 min. The temp. was raised gradually to r.t., and stirring was continued overnight, then Na2CO3
(1.5 g) was added. After stirring for 30 min, the mixture was filtered under reduced pressure. The filtrate
was concentrated by evaporation to give a residue, purification of which by CC (SiO2 ; AcOEt/hexane
3 :2) furnished 2a (0.40 g, 88%). Colorless needles. M.p. 114 – 1158 (hexane/CH2Cl2). IR (KBr): 3254,
1654. 1H-NMR (400 MHz): 2.25 (s, 3 H); 4.62 (s, 2 H); 7.15 (t, J ¼ 7.8, 1 H); 7.32 (d, J ¼ 7.8, 1 H); 7.38 (t,
J ¼ 7.8, 1 H); 7.52 (br. s, 1 H); 7.86 (d, J ¼ 7.8, 1 H).
N-[2-(Chloromethyl)phenyl]benzamide (2b). White solid. M.p. 122 – 1248 (hexane/CH2Cl2). IR
(KBr): 3253, 1647, 1601. 1H-NMR (400 MHz): 4.70 (s, 2 H); 7.19 (dd, J ¼ 8.8, 7.8, 1 H); 7.35 (dd, J ¼ 7.8,
2.0, 1 H); 7.45 (t, J ¼ 7.8, 1 H); 7.53 (t, J ¼ 7.8, 2 H); 7.60 (t, J ¼ 7.8, 1 H); 7.96 (dd, J ¼ 7.8, 2.0, 2 H); 8.10 (d,
J ¼ 8.8, 1 H); 8.41 (br. s, 1 H). Anal. calc. for C14H12ClNO (245.70): C 68.44, H 4.92, N 5.70; found: C
68.28, H 4.98, N 5.65.
N-[2-(Chloromethyl)phenyl]-2-methylbenzamide (2c). Colorless crystals. M.p. 148 – 1498 (hexane/
1
CH2Cl2). IR (KBr): 3252, 1648. H-NMR (500 MHz): 2.58 (s, 3 H); 4.67 (s, 2 H); 7.20 (dd, J ¼ 8.0, 7.4,
1 H); 7.29 – 7.32 (m, 2 H); 7.36 (dd, J ¼ 7.4, 1.1, 1 H); 7.41 (t, J ¼ 7.4, 1 H); 7.45 (dd, J ¼ 8.0, 7.4, 1 H); 7.60
(d, J ¼ 8.0, 1 H); 7.91 (br. s, 1 H); 8.09 (d, J ¼ 7.4, 1 H). Anal. calc. for C15H14ClNO (259.73): C 69.36, H
5.43, N 5.39; found: C 69.20, H 5.59, N 5.39.
3-Chloro-N-[2-(chloromethyl)phenyl]benzamide (2d). Colorless crystals. M.p. 121 – 1238 (hexane/
CH2Cl2). IR (KBr): 3236, 1646. 1H-NMR (500 MHz): 4.70 (s, 2 H); 7.21 (t, J ¼ 7.4, 1 H); 7.36 (d, J ¼ 7.4,
1 H); 7.44 – 7.49 (m, 2 H); 7.57 (d, J ¼ 8.0, 1 H); 7.81 (d, J ¼ 8.0, 1 H); 7.97 (s, 1 H); 8.06 (d, J ¼ 8.6, 1 H);
8.36 (br. s, 1 H). Anal. calc. for C14H11Cl2NO (280.15): C 60.02, H 3.96, N 5.00; found: C 59.95, H 3.74, N
5.24.
4-Chloro-N-[2-(chloromethyl)phenyl]benzamide (2e). Colorless crystals. M.p. 128 – 1308 (hexane/
1
CH2Cl2). IR (KBr): 3279, 1648. H-NMR (500 MHz): 4.70 (s, 2 H); 7.19 (td, J ¼ 7.4, 1.1, 1 H); 7.36 (dd,
J ¼ 7.4, 1.1, 1 H); 7.45 (ddd, J ¼ 8.0, 7.4, 1.1, 1 H); 7.50 (d, J ¼ 8.6, 2 H); 7.90 (d, J ¼ 8.6, 2 H); 8.07 (d, J ¼
8.0, 1 H); 8.37 (br. s, 1 H). Anal. calc. for C14H11Cl2NO (280.15): C 60.02, H 3.96, N 5.00; found: C 59.97,
H 4.04, N 4.91.
N-[2-(Chloromethyl)phenyl]-4-methoxybenzamide (2f). Colorless crystals. M.p. 142 – 1448 (hexane/
1
CH2Cl2). IR (KBr): 3269, 1640, 1607. H-NMR (500 MHz): 3.99 (s, 3 H); 4.70 (s, 2 H); 7.02 (d, J ¼ 8.6,
2 H); 7.17 (t, J ¼ 7.8, 1 H); 7.34 (d, J ¼ 7.8, 2.0, 1 H); 7.44 (t, J ¼ 7.8, 1 H); 7.93 (d, J ¼ 8.6, 2 H); 8.09 (d, J ¼
7.8, 1 H); 8.33 (br. s, 1 H). Anal. calc. for C15H14ClNO2 (275.73): C 65.34, H 5.12, N 5.08; found: C 65.26,
H 5.26, N 5.04.
Ethyl 2-(Chloromethyl)phenylcarbamate (2g). White solid. M.p. 86 – 878 (hexane/CH2Cl2). IR
(KBr): 3287, 1691. 1H-NMR (500 MHz): 1.34 (t, J ¼ 7.4, 3 H); 4.25 (q, J ¼ 7.4, 2 H); 4.62 (s, 2 H); 6.89 (br.

Helvetica Chimica Acta – Vol. 97 (2014)
927
s, 1 H); 7.10 (t, J ¼ 7.4, 1 H); 7.29 (d, J ¼ 8.0, 1 H); 7.38 (dd, J ¼ 8.0, 7.4, 1 H); 7.86 (d, J ¼ 7.4, 1 H). Anal.
calc. for C10H12ClNO2 (213.66): C 56.21, H 5.66, N 6.56; found: C 56.06, H 5.78, N 6.32.
N-[5-Chloro-2-(chloromethyl)phenyl]acetamide (2h) [11]. White solid. M.p. 155 – 1568 (hexane/
1
CH2Cl2). IR (KBr): 3259, 1661. H-NMR (500 MHz): 2.25 (s, 3 H); 4.58 (s, 2 H); 7.12 (d, J ¼ 8.6, 1 H);
7.23 (d, J ¼ 8.6, 1 H); 7.53 (br. s, 1 H); 8.01 (br. s, 1 H).
N-[5-Chloro-2-(chloromethyl)phenyl]benzamide (2i). White solid. M.p. 137 – 1398 (hexane/
1
CH2Cl2). IR (KBr) 3265, 1646. H-NMR (400 MHz): 4.66 (s, 2 H); 7.15 (dd, J ¼ 7.8, 2.0, 1 H); 7.28 (d,
J ¼ 7.8, 1 H); 7.54 (t, J ¼ 7.8, 2 H); 7.61 (t, J ¼ 7.8, 1 H); 7.95 (d, J ¼ 7.8, 2 H); 8.24 (d, J ¼ 2.0, 1 H); 8.43 (br.
s, 1 H). Anal. calc. for C14H11Cl2NO (280.15): C 60.02, H 3.96, N 5.00; found: C 59.81, H 4.00, N 4.80.
N-[2-(Chloromethyl)-4,5-dimethoxyphenyl]benzamide (2j). White solid. M.p. 160 – 1628 (hexane/
CH2Cl2). IR (KBr): 3274, 1642, 1612. 1H-NMR (400 MHz): 3.91 (s, 3 H); 3.94 (s, 3 H); 4.68 (s, 2 H); 8.34
(s, 1 H); 7.54 (dd, J ¼ 7.8, 6.9, 2 H); 7.60 (t, J ¼ 6.9, 1 H); 7.67 (s, 1 H); 7.96 (d, J ¼ 7.8, 2 H); 8.26 (br. s,
1 H). Anal. calc. for C16H16ClNO3 (305.76): C 62.85, H 5.27, N 4.58; found: C 62.82, H 5.26, N 4.55.
N-[2-(Azidomethyl)phenyl]acetamide (3a). Representative Procedure. To a stirred soln. of NaN3
(72 mg, 1.1 mmol) in DMF (1 ml) at r.t. was added a soln. of 2a (0.18 g, 1.0 mmol) in DMF (1.5 ml).
Stirring was continued for 1.5 h at the same temp., before H2O (15 ml) was added. The mixture was
extracted with AcOEt (3 ꢁ 10 ml), and the combined extracts were washed with H2O (3 ꢁ 10 ml) and
brine (10 ml), dried (Na2SO4), and concentrated by evaporation. The residual solid was recrystallized
from hexane/CH2Cl2 to give 3a (0.14 g, 73%). White solid. M.p. 92 – 948. IR (KBr): 3275, 2117, 2092, 1657.
1H-NMR (400 MHz): 2.22 (s, 3 H); 4.34 (s, 2 H); 7.16 (dd, J ¼ 7.8, 6.8, 1 H); 7.27 (d, J ¼ 7.8, 1 H); 7.39 (dd,
J ¼ 7.8, 6.8, 1 H); 7.58 (br. s, 1 H); 7.91 (d, J ¼ 7.8, 1 H). Anal. calc. for C9H10N4O (190.20): C 56.83, H 5.30,
N 29.46; found: C 56.70, H 5.59, N 29.17.
N-[2-(Azidomethyl)phenyl]benzamide (3b) [12]. Colorless crystals. M.p. 88 – 898 (hexane/CH2Cl2).
IR (KBr): 3289, 2101, 1654. 1H-NMR (500 MHz): 4.42 (s, 2 H); 7.19 (td, J ¼ 7.4, 1.1, 1 H); 7.30 (dd, J ¼ 7.4,
1.1, 1 H); 7.45 (ddd, J ¼ 8.0, 7.4, 1.1, 1 H); 7.53 (t, J ¼ 7.4, 2 H); 7.59 (tt, J ¼ 7.4, 1.1, 1 H); 7.94 (dd, J ¼ 7.0,
1.1, 2 H); 8.16 (d, J ¼ 8.0, 1 H); 8.50 (br. s, 1 H).
N-[2-(Azidomethyl)phenyl]-2-methylbenzamide (3c). Colorless crystals. M.p. 103 – 1058 (Et2O). IR
(KBr): 3250, 2105, 1650. 1H-NMR (500 MHz): 2.56 (s, 3 H); 4.39 (s, 2 H); 7.20 (t, J ¼ 7.4, 1 H); 7.29 – 7.32
(m, 3 H); 7.40 (dd, J ¼ 7.4, 6.9, 1 H); 7.45 (dd, J ¼ 8.0, 7.4, 1 H); 7.56 (d, J ¼ 7.4, 1 H); 7.97 (br. s, 1 H); 8.14
(d, J ¼ 7.4, 1 H). Anal. calc. for C15H14N4O (266.30): C 67.65, H 5.30, N 21.04; found: C 67.61, H 5.49, N
20.95.
N-[2-(Azidomethyl)phenyl]-3-chlorobenzamide (3d). Colorless crystals. M.p. 96 – 978 (hexane/
Et2O). IR (KBr) 3251, 2102, 1647. 1H-NMR (500 MHz): 4.42 (s, 2 H); 7.21 (dd, J ¼ 7.4, 6.9, 1 H); 7.31 (dd,
J ¼ 7.4, 1.1, 1 H); 7.44 – 7.48 (m, 2 H); 7.56 (dt, J ¼ 8.0, 1.1, 1 H); 7.78 (d, J ¼ 8.0, 1 H); 7.94 (t, J ¼ 1.7, 1 H);
8.12 (d, J ¼ 8.0, 1 H); 8.49 (br. s, 1 H). Anal. calc. for C14H11ClN4O (286.72): C 58.65, H 3.87, N 19.54;
found: C 58.50, H 4.06, N 19.31.
N-[2-(Azidomethyl)phenyl]-4-chlorobenzamide (3e). Colorless needles. M.p. 97 – 998 (hexane/
CH2Cl2). IR (KBr): 3287, 2093, 1650. 1H-NMR (500 MHz): 4.42 (s, 2 H); 7.20 (td, J ¼ 7.4, 1.1, 1 H); 7.30
(dd, J ¼ 7.4, 1.1, 1 H); 7.45 (ddd, J ¼ 8.0, 7.4, 1.1, 1 H); 7.50 (d, J ¼ 8.6, 2 H); 7.87 (d, J ¼ 8.6, 2 H); 8.14 (d,
J ¼ 8.0, 1 H); 8.50 (br. s, 1 H). Anal. calc. for C14H11ClN4O (286.72): C 58.65, H 3.87, N 19.54; found: C
58.53, H 3.97, N 19.49.
N-[2-(Azidomethyl)phenyl]-4-methoxybenzamide (3f). Colorless crystals. M.p. 118 – 1198 (Et2O).
IR (KBr): 3289, 2097, 1641, 1606. 1H-NMR (500 MHz): 3.89 (s, 3 H); 4.42 (s, 2 H); 7.01 (d, J ¼ 8.8, 2 H);
7.17 (dd, J ¼ 8.8, 7.8, 1 H); 7.30 (d, J ¼ 8.8, 1 H); 7.44 (ddd, J ¼ 8.8, 7.8, 2.0, 1 H); 7.90 (d, J ¼ 8.8, 2 H); 8.15
(d, J ¼ 8.8, 1 H); 8.44 (br. s, 1 H). Anal. calc. for C15H14N4O2 (282.30): C 63.82, H 5.00, N 19.85; found: C
63.73, H 5.05, N 19.79.
Ethyl 2-(Azidomethyl)phenylcarbamate (3g). Colorless oil. Rf (AcOEt/hexane 1:4) 0.48. IR (neat):
3320, 2101, 1717. 1H-NMR (500 MHz): 1.33 (t, J ¼ 7.4, 3 H); 4.24 (q, J ¼ 7.4, 2 H); 4.35 (s, 2 H); 6.96 (br. s,
1 H); 7.11 (t, J ¼ 7.4, 1 H); 7.24 (d, J ¼ 7.4, 1 H); 7.38 (t, J ¼ 7.4, 1 H); 7.89 (d, J ¼ 7.4, 1 H). Anal. calc. for
C10H12N4O2 (220.23): C 54.54, H 5.49, N 25.44; found: C 54.40, H 5.53, N 25.31.
N-[2-(Azidomethyl)-5-chlorophenyl]acetamide (3h). White solid. M.p. 105 – 1068 (hexane/CH2Cl2).
IR (KBr): 3245, 2096, 1661. 1H-NMR (500 MHz): 2.23 (s, 3 H); 4.32 (s, 2 H); 7.13 (d, J ¼ 8.0, 1 H); 7.19 (d,

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J ¼ 8.0, 1 H); 7.65 (br. s, 1 H); 8.07 (br. s, 1 H). Anal. calc. for C9H9ClN4O (224.65): C 48.12, H 4.04, N
24.94; found: C 47.97, H 4.07, N 24.77.
N-[2-(Azidomethyl)-5-chlorophenyl]benzamide (3i). White solid. M.p. 94 – 968 (hexane/CH2Cl2).
IR (KBr): 3287, 2104, 1652, 1601. 1H NMR (500 MHz): 4.40 (s, 2 H); 7.15 (dd, J ¼ 8.0, 2.3, 1 H); 7.22 (d,
J ¼ 8.0, 1 H); 7.54 (dd, J ¼ 8.0, 7.4, 2 H); 7.60 (tt, J ¼ 7.4, 1.1, 1 H); 7.92 (dd, J ¼ 8.0, 1.1, 2 H); 8.32 (d, J ¼
2.3, 1 H); 8.59 (br. s, 1 H). Anal. calc. for C14H11ClN4O (286.72): C 58.65, H 3.87, N 19.54; found: C 58.70,
H 3.72, N 19.27.
N-[2-(Azidomethyl)-4,5-dimethoxyphenyl]benzamide (3j). White solid. M.p. 127 – 1298 (hexane/
CH2Cl2). IR (KBr): 3185, 2089, 1634. 1H-NMR (400 MHz): 3.91 (s, 3 H); 3.94 (s, 3 H); 4.37 (s, 2 H); 6.80
(s, 1 H); 7.53 (dd, J ¼ 7.8, 6.8, 2 H): 7.59 (t, J ¼ 6.8, 1 H); 7.72 (s, 1 H); 7.92 (d, J ¼ 7.8, 2 H); 8.35 (br. s,
1 H). Anal. calc. for C16H16N4O3 (312.32): C 61.53, H 5.16, N 17.94; found: C 61.41, H 5.27, N 17.89.
1-(3,4-Dihydro-2-thioxoquinazolin-1(2H)-yl)ethanone (5a). Representative Procedure. A mixture of
3a (0.13 g, 0.70 mmol) and PPh3 (0.19 g, 0.84 mmol) in CH2Cl2 was stirred at r.t. for 2 h. After removal of
CH2Cl2 under reduced pressure, MeCN and CS2 (1.6 ml each) were added. The mixture was heated at
reflux temp. for 1 h, and then it was cooled to 08. NaH (60% in mineral oil; 28 mg, 0.70 mmol) was added,
and stirring was continued for 10 min before sat. aq. NH4Cl (15 ml) was added. The resulting mixture was
extracted with AcOEt (3 ꢁ 10 ml). The combined extracts were washed with brine (10 ml), dried
(Na2SO4), and concentrated by evaporation. The residue was purified by CC (SiO2 ; CH2Cl2) to give 5a
(92 mg, 64%). White solid. M.p. 157 – 1598 (hexane/CH2Cl2). IR (KBr): 3178, 1702, 1621, 1246. 1H-NMR
(500 MHz): 2.76 (s, 3 H); 4.89 (s, 2 H); 6.87 (d, J ¼ 8.0, 1 H); 7.13 (t, J ¼ 7.4, 1 H); 7.21 (d, J ¼ 7.4, 1 H);
7.29 (dd, J ¼ 8.0, 7.4, 1 H); 8.98 (br. s, 1 H). 13C-NMR: 27.8; 44.4; 113.8; 122.0; 125.1; 126.0; 128.9; 134.7;
173.6; 179.6. HR-MS: 207.0585 ([M þ H]þ, C10H11N2OSþ; calc. 207.0587). Anal. calc. for C10H10N2OS
(206.26): C 58.23, H 4.89, N 13.58; found: C 58.12, H 5.03, N 13.42.
(3,4-Dihydro-2-thioxoquinazolin-1(2H)-yl)(phenyl)methanone (5b). Colorless crystals. M.p. 193 –
1
1948 (hexane/CH2Cl2). IR (KBr): 3169, 1691, 1616, 1242. H-NMR (500 MHz): 4.86 (s, 2 H); 6.89 (d,
J ¼ 8.0, 1 H); 7.16 (dd, J ¼ 8.0, 7.4, 1 H); 7.24 (d, J ¼ 7.4, 1 H); 7.32 (t, J ¼ 7.4, 1 H); 7.37 (dd, J ¼ 8.0, 7.4,
2 H); 7.49 (t, J ¼ 7.4, 1 H); 7.69 (dd, J ¼ 8.0, 1.1, 2 H); 9.01 (br. s, 1 H). 13C-NMR: 46.81; 114.25; 121.16;
124.99; 126.05; 128.26; 128.97; 129.04; 132.04; 134.48; 135.64; 173.38; 179.71. HR-MS: 269.0728 ([M þ
H]þ, C15H13N2OSþ; calc. 269.0743). Anal. calc. for C15H12N2OS (268.33): C 67.14, H 4.51, N 10.44;
found: C 67.09, H 4.50, N 10.38.
(3,4-Dihydro-2-thioxoquinazolin-1(2H)-yl)(2-methylphenyl)methanone (5c). Pale-yellow crystals.
1
M.p. 185 – 1878 (hexane/CH2Cl2). IR (KBr) 3170, 1691, 1620, 1251. H-NMR (500 MHz): 2.47 (s, 3 H);
4.90 (s, 2 H); 6.79 (d, J ¼ 8.0, 1 H); 7.08 (t, J ¼ 7.4, 1 H); 7.14 – 7.32 (m, 6 H); 7.59 (br. s, 1 H). 13C-NMR:
20.00; 45.66; 114.17; 121.32; 125.02; 125.25; 126.06; 127.28; 128.93; 130.34; 131.03; 134.39; 136.50; 137.74;
173.25; 179.24. HR-MS: 283.0886 ([M þ H]þ, C16H15N2OSþ; calc. 283.0900). Anal. calc. for C16H14N2OS
(282.36): C 68.06, H 5.00, N 9.92; found: C 67.84, H 5.01, N 9.73.
(3-Chlorophenyl)(3,4-dihydro-2-thioxoquinazolin-1(2H)-yl)methanone (5d). Colorless crystals.
M.p. 195 – 1988 (CHCl3). IR (KBr): 3168, 1704, 1615, 1246. 1H-NMR (500 MHz): 4.86 (s, 2 H); 6.91
(d, J ¼ 8.0, 1 H); 7.18 (td, J ¼ 7.4, 1.1, 1 H); 7.25 (d, J ¼ 7.4, 1 H); 7.30 (dd, J ¼ 8.0, 7.4, 1 H); 7.33 (ddd, J ¼
8.0, 7.4, 1.1, 1 H); 7.44 (dt, J ¼ 8.0, 1.1, 1 H); 7.54 (ddd, J ¼ 8.0, 1.7, 1.1, 1 H); 7.65 (t, J ¼ 1.7, 1 H); 9.17 (br. s,
1 H). 13C-NMR: 46.73; 114.19; 121.08; 125.17; 126.17; 126.97; 128.77; 129.15; 129.49; 131.95; 134.28;
134.31; 137.47; 172.09; 179.42. HR-MS: 303.0357 ([M þ H]þ, C15H12ClN2OSþ; calc. 303.0353). Anal. calc.
for C15H11ClN2OS (302.78): C 59.50, H, 3.66, N 9.25; found: C 59.22, H 3.69, N 9.19.
(4-Chlorophenyl)(3,4-dihydro-2-thioxoquinazolin-1(2H)-yl)methanone (5e). Colorless crystals.
1
M.p. 169 – 1728 (hexane/CHCl3). IR (KBr): 3190, 1696, 1622, 1231. H-NMR (500 MHz): 4.85 (s, 2 H);
6.89 (d, J ¼ 7.4, 1 H); 7.17 (td, J ¼ 7.4, 1.1, 1 H); 7.23 (d, J ¼ 7.4, 1 H); 7.30 – 7.35 (m, 3 H); 7.62 (d, J ¼ 8.0,
2 H); 9.48 (br. s, 1 H). 13C-NMR (125 MHz): 46.79; 114.23; 121.08; 125.15; 126.12; 128.60; 129.10; 130.33;
134.13; 134.33; 138.35; 172.38; 179.54. HR-MS: 303.0344 ([M þ H]þ, C15H12ClN2OSþ; calc. 303.0353).
Anal. calc. for C15H11ClN2OS (302.78): C 59.50, H 3.66, N 9.25; found: C 59.25, H 3.63, N 9.28.
(3,4-Dihydro-2-thioxoquinazolin-1(2H)-yl)(4-methoxyphenyl)methanone (5f). Pale-yellow solid.
M.p. 159 – 1628 (hexane/CH2Cl2). IR (KBr): 3186, 1670, 1623, 1257. 1H-NMR (500 MHz): 3.84 (s,
3 H); 4.81 (s, 2 H); 6.87 (d, J ¼ 9.2, 2 H); 6.89 (d, J ¼ 8.0, 1 H); 7.15 (t, J ¼ 7.4, 1 H); 7.21 (d, J ¼ 7.4, 1 H);
7.31 (dd, J ¼ 8.0, 7.4, 1 H); 7.72 (d, J ¼ 9.2, 2 H); 9.07 (br. s, 1 H). 13C-NMR: 47.15; 55.41; 113.66; 114.00;

Helvetica Chimica Acta – Vol. 97 (2014)
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120.96; 124.84; 126.09; 127.49; 128.97; 131.65; 134.46; 163.20; 172.71; 179.82. HR-MS: 299.0849 ([M þ
H]þ, C16H15N2O2Sþ; calc. 299.0849). Anal. calc. for C16H14N2O2S (298.36): C 64.41, H 4.73, N 9.39;
found: C 64.20, H 4.84, N 9.25.
Ethyl 3,4-Dihydro-2-thioxo-2H-quinazoline-1-carboxylate (5g). White solid. M.p. 128 – 1318 (hex-
ane/CH2Cl2). IR (KBr): 3285, 1713, 1601, 1229. 1H-NMR (500 MHz): 1.45 (t, J ¼ 7.4, 3 H); 4.45 (d, J ¼
2.3, 2 H); 4.49 (q, J ¼ 7.4, 2 H); 7.08 (d, J ¼ 7.4, 1 H); 7.13 (t, J ¼ 7.4, 2 H); 7.27 (t, J ¼ 7.4, 1 H); 7.82 (br.
s, 1 H). 13C-NMR: 13.72; 44.05; 65.07; 116.02; 119.94; 125.13; 125.89; 128.50: 134.07; 152.44; 177.65. HR-
MS: 237.0693 ([M þ H]þ, C11H13N2O2Sþ; calc. 237.0692). Anal. calc. for C11H12N2O2S (236.29): C 55.91, H
5.12, N 11.86; found: C 55.77, H 5.05, N 11.83.
1-(7-Chloro-3,4-dihydro-2-thioxoquinazolin-1(2H)-yl)ethanone (5h). White solid. M.p. 187 – 1898
(hexane/CHCl3). IR (KBr): 3184, 1707, 1614, 1242. 1H-NMR (500 MHz): 2.76 (s, 3 H); 4.85 (s, 2 H); 6.93
(br. s, 1 H); 7.10 (dd, J ¼ 8.0, 1.7, 1 H); 7.14 (d, J ¼ 8.0, 1 H); 9.31 (br. s, 1 H). 13C NMR: 27.7; 44.01;
113.94; 120.20; 124.84; 127.10; 134.53; 135.51; 173.53; 179.68. HR-MS: 241.0189 ([M þ H]þ,
C10H10ClN2OSþ; calc. 241.0197). Anal. calc. for C10H9ClN2OS (240.71): C 49.90, H 3.77, N 11.64; found:
C 49.80, H 3.92, N 11.36.
(7-Chloro-3,4-dihydro-2-thioxoquinazolin-1(2H)-yl)(phenyl)methanone (5i). White solid. M.p.
1
176 – 1788 (hexane/CHCl3). IR (KBr): 3162, 1694, 1611, 1241. H-NMR (500 MHz): 4.82 (s, 2 H); 6.90
(d, J ¼ 1.7, 1 H); 7.14 (dd, J ¼ 8.0, 1.7, 1 H); 7.18 (d, J ¼ 8.0, 1 H); 7.38 (dd, J ¼ 8.0, 7.4, 2 H); 7.50 (t, J ¼ 7.4,
1 H); 7.68 (d, J ¼ 8.0, 2 H); 8.99 (br. s, 1 H). 13C-NMR: 46.41; 114.32; 119.50; 124.88; 127.20; 128.35;
129.02; 132.46; 134.67; 135.27; 135.36; 173.27; 179.84. HR-MS: 303.0348 ([M þ H]þ, C15H12ClN2OSþ;
calc. 303.0353). Anal. calc. for C15H11ClN2OS (302.78): C 59.50, H 3.66, N 9.25; found: C 59.20, H 3.66, N
8.95.
(3,4-Dihydro-6,7-dimethoxy-2-thioxoquinazolin-1(2H)-yl)(phenyl)methanone (5j). Pale-yellow sol-
1
id. M.p. 219 – 2218 (hexane/CH2Cl2). IR (KBr): 3176; 1682; 1629; 1242. H-NMR (500 MHz): 3.82 (s,
3 H); 3.88 (s, 3 H); 4.80 (s, 2 H); 6.48 (s, 1 H); 6.71 (s, 1 H); 7.35 (t, J ¼ 7.4, 2 H); 7.46 (t, J ¼ 7.4, 1 H); 7.68
(d, J ¼ 7.4, 2 H); 9.51 (br. s, 1 H). 13C-NMR: 46.53; 56.22; 56.37; 98.96; 109.02; 112.70; 128.17; 128.98;
132.00; 133.74; 135.81l; 146.49; 149.41; 173.42; 178.85. HR-MS: 329.0947 ([M þ H]þ, C17H17N2O3Sþ; calc.
329.0954). Anal. calc. for C17H16N2O3S (328.39): C 62.18, H 4.91, N 8.53; found: C 62.02, H 4.84, N 8.45.
This work was supported in part by JSPS KAKENHI Grant No. 26410051. We thank Mrs. Miyuki
Tanmatsu of our university for recording mass spectra and performing combustion analyses.
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Received March 5, 2014