A novel synthesis of quinazolines by cyclization of 1-(2-isocyanophenyl) alkylideneamines generated by the treatment of 2-(1-azidoalkyl)phenyl isocyanides with NaH

Article abstract of DOI:10.1002/hlca.201300431

A new and efficient method for the synthesis of quinazolines has been developed. Thus, N-[2-(1-azidoalkyl)phenyl]formamides 1 are dehydrated with POCl₃ to give the corresponding 2-(1-azidoalkyl)phenyl isocyanides 2, which are then treated with NaH in DMF at 0° to give quinazolines 6 in satisfactory yields via cyclization of 1-(2-isocyanophenyl)alkylideneamine intermediates 4. This methodology can be applied to the synthesis of the 7-azaanalogs of quinazolines, i.e., pyrido[3,4-d]pyrimidines 9. Copyright

Full text of DOI:10.1002/hlca.201300431

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Helvetica Chimica Acta – Vol. 97 (2014)
A Novel Synthesis of Quinazolines by Cyclization
of 1-(2-Isocyanophenyl)alkylideneamines Generated by the Treatment
of 2-(1-Azidoalkyl)phenyl Isocyanides with NaH
by Kosuke Ezaki and Kazuhiro Kobayashi*
Division of Applied Chemistry, Department of Chemistry and Biotechnology, Graduate School of
Engineering, Tottori University, 4-101 Koyama-minami, Tottori 68-8552, Japan
(phone/fax: þ 81-857-315263; e-mail: kkoba@chem.tottori-u.ac.jp)
A new and efficient method for the synthesis of quinazolines has been developed. Thus, N-[2-(1-
azidoalkyl)phenyl]formamides 1 are dehydrated with POCl3 to give the corresponding 2-(1-azidoalkyl)-
phenyl isocyanides 2, which are then treated with NaH in DMF at 08 to give quinazolines 6 in satisfactory
yields via cyclization of 1-(2-isocyanophenyl)alkylideneamine intermediates 4. This methodology can be
applied to the synthesis of the 7-azaanalogs of quinazolines, i.e., pyrido[3,4-d]pyrimidines 9.
Introduction. – Quinazolines are undoubtedly one of the most important classes of
heterocycles, and they recently attract much attention, because a number of
compounds with the quinazoline skeleton exhibit a variety of biological activities [1].
Quinazoline is a rather expensive chemical, and its new preparation by the reaction of
benzene-1,2-dicarboxamide with iodobenzene diacetate as a key step has been reported
[2]. Moreover, several new methods for the general preparation of quinazoline
derivatives have recently been described [3][4]. For example, Wang and co-workers
have reported a synthesis of 4-substituted quinazolines by the N-iodosuccinimide
(NIS)-catalyzed reaction of 2-aminophenyl ketones with AcNMe2 and NH3 in the
presence of excess t-BuOOH at 1208 [3]. So, we became interested in pursuing a novel
and convenient procedure for the preparation of quinazoline and its derivatives. We
envisaged that the generation of 1-(2-isocyanophenyl)alkylideneamine would lead to
the formation of quinazolines. In the course of our investigations, it was found that the
reaction of 2-(1-azidoalkyl)phenyl isocyanides 2, easily derived from N-[2-(1-
azidoalkyl)phenyl]formamides 1, with NaH could fulfill our expectations. We report
herein the results of our study, which provided an efficient route to quinazolines. We
have found that the present method is also applicable to the synthesis of the 7-
azaanalogs of quinazolines, pyrido[3,4-d]pyrimidines 9, which are of biological interest
as well [5].
Results and Discussion. – The synthesis of quinazolines 6 from azido formamides 1
could be achieved as outlined in Scheme 1. Compounds 1 were easily accessible: N-[2-
(azidomethyl)phenyl]formamide (1a) [6] is a known compound, and N-[2-(azido-
methyl)-5-chlorophenyl]formamide (1e) was prepared from N-[3-chloro-6-(chlorome-
thyl)phenyl]formamide [7] under the conditions for the preparation of 1a. The other
azido formamides 1 were prepared from the respective 2-aminophenyl ketones by easy
ꢀ 2014 Verlag Helvetica Chimica Acta AG, Zꢁrich

Helvetica Chimica Acta – Vol. 97 (2014)
823
Scheme 1
four-step sequences. Thus, these ketones were N-formylated with HCO2H, and
subsequent reduction with NaBH4 afforded the corresponding N-[2-(1-hydroxyalkyl)-
phenyl]formamides. The latter were treated with SOCl2, and the resulting chloro
formamides were converted to 1 on treatment with NaN3 (see Exper. Part).
The azido formamides 1, thus obtained, were dehydrated with POCl3 in the
presence of Et3N in THF at 08 to give the corresponding 2-(azidoethyl)phenyl
isocyanides 2 in relatively good yields (Table; see [6]). When compounds 2 were
treated with 1 equiv. of NaH in DMF at 08, smooth deprotonation of the benzyl group,
giving the benzyl anion intermediate 3, denitrogenation, and subsequent intramolec-
ular cyclization of the resulting alkylideneamine intermediate 3 by the attack of the
anion on the isocyano C-atom took place within 10 min. Aqueous workup, followed by
purification (recrystallization or column chromatography on SiO2) gave the desired
quinazolines 6 in generally good yields as compiled in the Table as well. However, the
yield of product 6b was much lower than those of the others (Entry 2). We speculate
that this poor yield may be attributed to the lower acidity of the benzyl proton of the
respective precursor 2b due to its Me substituent.
Solvents other than DMF were also studied. In THF and 1,2-dimethoxyethane
(DME), the reactions proceeded much slower than those in DMF. However, if the
reactions were allowed to proceed long enough (overnight and ca. 5 h, resp.) at room
Table. Preparation of Quinazolines 6
Entry
1
2
Yielda)
6
Yielda)
1
2
3
4
5
6
7
8
9
1a (R1 ¼ R2 ¼ R3 ¼ H)
2a [6]
2b
2c
2d
2e
2f
2g
2h
2i
86
74
79
76
75
69
76
82
73
6a
6b
6c
6d
6e
6f
6g
6h
6i
69
34
88
87
63
88
85
96
95
1b (R1 ¼ R2 ¼ H, R3 ¼ Me)
1c (R1 ¼ R2 ¼ H, R3 ¼ Ph)
1d (R1 ¼ R2 ¼ H, R3 ¼ 4-ClꢀC6H4)
1e (R1 ¼ H, R2 ¼ Cl, R3 ¼ H)
1f (R1 ¼ H, R2 ¼ Cl, R3 ¼ 4-ClꢀC6H4)
1g (R1 ¼ Cl, R2 ¼ H, R3 ¼ 4-MeꢀC6H4)
1h (R1 ¼ Cl, R2 ¼ H, R3 ¼ 4-ClꢀC6H4)
1i (R1 ¼ MeO, R2 ¼ H, R3 ¼ Ph)
a) Yields of isolated products [%].

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Helvetica Chimica Acta – Vol. 97 (2014)
temperature, the desired products were obtained in slightly lower yields than those in
DMF.
A possible pathway for the production of quinazolines 6 is also shown in Scheme 1.
Trapping of the intermediate 5 by adding electrophiles such as MeI, Me3SiCl, and BzCl
to the reaction mixtures after confirmation of the disappearance of starting materials 1,
it was attempted to introduce a substituent at the 2-position of quinazolines.
Unfortunately, however, all attempts failed; no desired products were obtained at
all. Thus, we considered that deprotonation of 2 by 5 occurs to afford 6 and to
regenerate 3. When 2c was treated with 0.1 equiv. of NaH in DMF at 08, the reaction
was complete in ca. 20 min to give the corresponding desired quinazoline 6c in 75%
yield. This result may support our consideration.
To investigate the utility of the present method, it was applied to the synthesis of 4-
arylpyrido[3,4-d]pyrimidines 9 using N-{[4-aryl(azido)methyl]pyridin-3-yl}formamide
7 as precursors, which could be easily prepared from known (4-aminopyridin-3-
yl)arylmethanones [8][9] by the same sequence as mentioned above for the
preparation of azido formamides 1 from 2-aminophenyl ketones. After transformation
of compounds 7 to the corresponding isocyanides 8, these were subjected to the
treatment with NaH under the same conditions as described for the preparation of
quinazolines 6. Moderate-to-fair yields of the desired products 9 were obtained by a
similar workup and the subsequent purification as described for the isolation of 6.
In conclusion, we have developed a novel method for the preparation of
quinazolines, which can be conducted under mild conditions. The easiness of
experimental operations and the ready availability of the starting materials make the
present method attractive. We are currently exploring the possibility of applying this
methodology to related heterocyclic systems to expand its potential scope.
Scheme 2
Experimental Part
General. All org. solvents used in this study were dried over appropriate drying agents and distilled
prior to use. 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 Spectra: PerkinElmer
.
Spectrum65 FT-IR spectrophotometer; ˜n in cmꢀ1 1H-NMR Spectra: JEOL ECP500 FT NMR
spectrometer or JEOL LA400 FT NMR spectrometer (at 500 or 400 MHz, resp.); 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, pos.): Thermo Scientific
Exactive spectrometer; in m/z.
2-(Aminophenyl)(4-chlorophenyl)methanone [10], (2-amino-5-chlorophenyl)(4-methylphenyl)me-
thanone [11], (2-amino-5-methoxyphenyl)phenylmethanone [12], N-[2-ethanoylphenyl]formamide [13],
N-(2-benzoylphenyl)formamide [14], N-[3-chloro-6-(chloromethyl)phenyl]formamide [7], N-[2-(azido-

Helvetica Chimica Acta – Vol. 97 (2014)
825
methyl)phenyl]formamide (1a) [6], N-(4-benzoylpyridin-3-yl)formamide [8], and N-[4-(4-chloroben-
zoyl)pyridin-3-yl]formamide [9] were prepared according to the reported procedures. All other
chemicals used in this study were commercially available.
Other (2-Aminophenyl)arylmethanones were prepared from appropriate 2-aminobenzonitriles and
arylmagnesium bromide as reported for the preparation of (2-aminophenyl)(4-chlorophenyl)methanone
[10].
(2-Amino-4-chlorophenyl)(4-chlorophenyl)methanone. Yield: 64%. Yellow solid. M.p. 116 – 1188
(hexane/CHCl3). IR (KBr): 3450, 3338, 1629, 1611. 1H-NMR (500 MHz, CDCl3): 6.17 (br. s, 2 H); 6.58
(dd, J ¼ 8.4, 2.3, 1 H); 6.75 (d, J ¼ 2.3, 1 H); 7.33 (d, J ¼ 8.4, 1 H); 7.44 (d, J ¼ 8.4, 2 H); 7.55 (d, J ¼ 8.4,
2 H). Anal. calc. for C13H9Cl2NO (266.12): C 58.67, H 3.41, N 5.26; found: C 58.57, H 3.48, N 5.14.
N-(2-Acylphenyl)formamides were prepared by N-formylation of the respective 2-aminophenyl
ketones with HCO2H as described in [14].
N-[5-Chloro-2-(4-chlorobenzoyl)phenyl]formamide. Yield: 98%. Yellow solid. M.p. 95 – 978 (hex-
ane/CHCl3). IR (KBr): 3307, 1704, 1640. 1H-NMR (500 MHz, CDCl3): 7.12 (d, J ¼ 8.4, 1 H); 7.49 (d, J ¼
8.4, 3 H); 7.63 (d, J ¼ 8.4, 2 H); 8.50 (s, 1 H); 8.79 (s, 1 H); 10.77 (br. s, 1 H). Anal. calc. for C14H9Cl2NO2
(294.13): C 57.17, H 3.08, N 4.76; found: C 57.09, H 3.35, N 4.65.
N-[4-Chloro-2-(4-methylbenzoyl)phenyl]formamide. Yield: 89%. Pale-yellow solid. M.p. 95 – 968
(hexane/CH2Cl2). IR (KBr): 3318, 1702, 1642. 1H-NMR (500 MHz, CDCl3): 2.47 (s, 3 H); 7.32 (d, J ¼ 7.8,
2 H); 7.52 – 7.54 (m, 2 H); 7.63 (d, J ¼ 7.8, 2 H); 8.42 – 10.04 (m, 3 H). Anal. calc. for C15H12ClNO2
(273.71): C 65.82, H 4.42, N 5.12; found: C 65.79, H 4.48, N 5.03.
N-[4-Chloro-2-(4-chlorobenzoyl)phenyl]formamide. Yield: 86%. Yellow solid. M.p. 89 – 918 (hex-
ane/Et2O). IR (KBr): 3367, 1711, 1637. 1H-NMR (500 MHz, CDCl3): 7.49 – 7.52 (m, 3 H); 7.55 (dd, J ¼ 9.2,
2.3, 1 H); 7.67 (d, J ¼ 8.4, 2 H); 8.47 (d, J ¼ 2.3, 1 H); 8.64 (d, J ¼ 9.2, 1 H); 10.43 (s, 1 H). Anal. calc. for
C14H9Cl2NO2 (294.13): C 57.17, H 3.08, N 4.76; found: C 57.15, H 3.24, N 4.76.
N-(2-Benzoyl-4-methoxyphenyl)formamide. Yield: 90%. Yellow oil. Rf (AcOEt/hexane 1:1) 0.22. IR
1
(neat): 3323, 1695, 1645. H-NMR (500 MHz, CDCl3): 3.76, 3.77 (2s, combined 3 H); 7.06 – 10.26 (m,
10 H). Anal. calc. for C15H13NO3 (255.27): C 70.58, H 5.13, N 5.49; found: C 70.52, H 5.13, N 5.30.
N-[2-(Hydroxyalkyl)phenyl]formamides and N-{4-[Aryl(hydroxy)methyl]pyridin-3-yl}formamides
were prepared by the NaBH4 reduction of the respective keto formamides in MeOH at r.t.
N-[2-(1-Hydroxyethyl)phenyl]formamide. Yield: 76%. Pale-yellow oil. Rf (AcOEt/hexane 1:2) 0.11.
1
The H-NMR data were identical to those reported in [15].
N-{2-[Hydroxy(phenyl)methyl]phenyl}formamide. Yield: 68%. White solid. M.p. 120 – 1218 (hex-
ane/THF) ([15]: 121 – 1228). IR (KBr): 3357, 1688. 1H-NMR (500 MHz, CDCl3): 2.38 (s, 1 H); 5.82, 5.92
(2s, combined 1 H); 7.05 – 8.79 (m, 11 H).
N-{2-[(4-Chlorophenyl)(hydroxy)methyl]phenyl}formamide. Yield: 82%. Colorless amorphous. Rf
(AcOEt/hexane 1:2) 0.19, IR (neat): 3319, 1675. 1H-NMR (500 MHz, CDCl3): 2.95, 3.01 (2s, combined
1 H); 5.93 (s, 1 H); 7.05 – 8.58 (m, 10 H). Anal. calc. for C14H12ClNO2 (261.70): C 64.25, H 4.62, N 5.35;
found: C 64.04, H 4.69, N 5.08.
N-{5-Chloro-2-[(4-chlorophenyl)(hydroxy)methyl]phenyl}formamide. Yield: 92%. Colorless amor-
phous. Rf (AcOEt/hexane 1:2) 0.23. IR (neat): 3315, 1682. 1H-NMR (500 MHz, CDCl3): 2.90, 2.99 (2d,
J ¼ 3.1, each, combined 1 H); 5.90 (d, J ¼ 3.1, 1 H); 6.97 – 8.65 (m, 9 H). Anal. calc. for C14H11Cl2NO2
(296.15): C 56.78, H 3.74, N 4.73; found: C 56.73, H 3.81, N 4.80.
N-{4-Chloro-2-[(hydroxy)(4-methylphenyl)methyl]phenyl}formamide. Yield: 85%. Colorless vis-
cous oil. Rf (AcOEt/hexane 1:1) 0.26. IR (neat): 3316, 1681. 1H-NMR (500 MHz, CDCl3): 2.35 (s, 3 H);
3.11, 3.20 (2d, J ¼ 2.9 and 3.4, resp., combined 1 H); 5.83, 5.85 (2d, J ¼ 2.9 and 3.4, resp., combined 1 H);
7.00 – 8.68 (m, 9 H). Anal. calc. for C15H14ClNO2 (275.73): C 65.34, H 5.12, N 5.08; found: C 65.34, H 5.14,
N 5.04.
N-{4-Chloro-2-[(4-chlorophenyl)(hydroxy)methyl]phenyl}formamide. Yield: 77%. White solid.
1
M.p. 117 – 1188 (hexane/Et2O). IR (KBr): 3318, 1680. H-NMR (500 MHz, CDCl3): 3.89, 3.99 (2d, J ¼
3.1 each, combined 1 H); 5.82 (s, 1 H); 7.04 – 8.72 (m, 9 H). Anal. calc. for C14H11Cl2NO2 (296.15): C
56.78, H 3.74, N 4.73; found: C 56.53, H 3.99, N 4.51.
N-{2-[Hydroxy(phenyl)methyl]-4-methoxyphenyl}formamide. Yield: 78%. Colorless viscous oil. Rf
(AcOEt/hexane 2 :3) 0.21. IR (neat): 3331, 1674, 1605. 1H-NMR (500 MHz, CDCl3): 3.34, 3.53 (2d,

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Helvetica Chimica Acta – Vol. 97 (2014)
J ¼ 3.1 each, combined 1 H); 3.73, 3.76 (2s, combined 3 H); 5.857, 5.862 (2s, combined 1 H), 6.66 – 8.33
(m, 10 H). Anal. calc. for C15H15NO3 (257.28): C 70.02, H 5.88, N 5.44; found: C 69.84, H 5.96, N 5.31.
N-{4-[Hydroxy(phenyl)methyl]pyridin-3-yl}formamide. Yield: 65%. White solid. M.p. 143 – 1458
1
(hexane/THF). IR (KBr): 3293, 1678. H-NMR (500 MHz, CDCl3): 3.21, 3.60 (2 br. s. combined 1 H);
5.93, 5.94 (2s, combined 1 H); 7.01 – 9.37 (m, 10 H). Anal. calc. for C13H12N2O2 (228.25): C 68.41, H 5.30,
N 12.27; found: C 68.15, H 5.40, N 12.20.
N-{4-[(4-Chlorophenyl)(hydroxy)methyl]pyridin-3-yl}formamide. Yield: 65%. White solid. M.p.
138 – 1408 (hexane/THF). IR (KBr): 3289, 3249, 1688, 1606. 1H-NMR (500 MHz, (D6)DMSO): 5.94, 6.03
(2s, combined 1 H); 6.43 (br., 1 H); 7.28 – 9.80 (m, 9 H). Anal. calc. for C13H11ClN2O2 (262.69): C 59.44, H
4.22, N 10.66; found: C 59.27, H 4.27, N 10.50.
N-{2-[Azido(phenyl)methyl]phenyl}formamide (1c) (Representative Procedure). To a stirred soln.
of N-{2-[hydroxy(phenyl)methyl]phenyl}formamide (2.0 g, 8.6 mmol) in THF (11 ml) at ꢀ 408 was
added a soln. of SOCl2 (1.1 g, 9.0 mmol) in THF (5 ml) dropwise. After stirring for 30 min at the same
temp., the temp. was raised to ꢀ 208, and stirring was continued for 1.5 h. Na2CO3 (0.3 g) was added, and
the mixture was filtered under reduced pressure. The filtrate was concentrated by evaporation to give a
residue (1.9 g), which was used for the next step without any purification. The residue was dissolved in
DMF, and NaN3 (0.59 g, 9.0 mmol) was added under stirring, which was continued for 7 d at r.t. H2O
(30 ml) was added, and the mixture was extracted with AcOEt (3 ꢁ 20 ml). The combined extracts were
washed with H2O (3 ꢁ 20 ml) and brine (20 ml), and dried (Na2SO4) and concentrated by evaporation.
The residue was purified by CC (SiO2) to give 1c (1.5 g, 70%). White solid. M.p. 103 – 1048 (hexane/
CH2Cl2). IR (KBr): 3314, 2101, 1687. 1H-NMR (500 MHz, CDCl3): 5.82, 5.92 (2s, combined 1 H); 7.05 –
8.80 (m, 11 H). Anal. calc. for C14H12N4O (252.27): C 66.65, H 4.79, N 22.21; found: C 66.65, H 4.77, N
22.15.
N-[2-(1-Azidoethyl)phenyl]formamide (1b). Yield: 71%. Yellow oil. Rf (AcOEt/hexane 1:1) 0.47.
IR (neat): 3287, 2104, 1693, 1604. 1H-NMR (500 MHz, CDCl3): 1.64 (d, J ¼ 6.1, 3 H); 4.64 – 4.72 (m, 1 H);
7.18 – 8.58 (m, 6 H). Anal. calc. for C9H10N4O (190.20): C 56.83, H 5.30, N 29.46; found: C 56.62, H 5.30, N
29.20.
N-{2-[Azido(4-chlorophenyl)methyl]phenyl}formamide (1d). Yield: 60%. White solid. M.p. 100 –
1
1028 (hexane/CH2Cl2). IR (KBr): 3224, 2106, 1656. H-NMR (500 MHz, CDCl3): 5.79 (s, 1 H); 7.05 –
8.38 (m, 10 H). Anal. calc. for C14H11ClN4O (286.72): C 58.65, H 3.87, N 19.54; found: C 58.42, H 3.90,
N 19.40.
N-[2-(Azidomethyl)-5-chlorophenyl]formamide (1e) was prepared from N-[3-chloro-6-(chlorome-
thyl)phenyl]formamide [7] in 87% yield as described for the preparation of N-[2-(azidomethyl)phe-
nyl]formamide (1a) from N-[2-(chloromethyl)phenyl]formamide and NaN3 [6]. Yellow oil. Rf (AcOEt/
hexane 1:5) 0.57. IR (neat): 3288, 2106, 1693. 1H-NMR (500 MHz, CDCl3): 4.34, 4.36 (2s, combined 2 H);
7.18 – 8.56 (m, 5 H). Anal. calc. for C8H7ClN4O (210.62): C 45.62, H 3.35, N 26.60; found: C 45.47, H 3.38,
N 26.48.
N-{2-[Azido(4-chlorophenyl)methyl]-5-chlorophenyl}formamide (1f). Yield: 64%. Yellow oil. Rf
(AcOEt/hexane 1:2) 0.25. IR (neat): 3286, 2102, 1693. 1H-NMR (500 MHz, CDCl3): 5.76, 5.77 (2s,
combined 1 H); 7.18 – 8.39 (m, 9 H). Anal. calc. for C14H10Cl2N4O (321.16): C 52.36, H 3.14, N 17.45;
found: C 52.16, H 3.40, N 17.40.
N-{2-[Azido(4-methylphenyl)methyl]-4-chlorophenyl}formamide (1g). Yield: 67%. Colorless oil. Rf
(AcOEt/hexane 1:1) 0.30. IR (neat): 3292, 2103, 1693. 1H-NMR (500 MHz, CDCl3): 2.36 (s, 3 H); 5.70 (s,
1 H); 7.05 – 8.34 (m, 9 H). Anal. calc. for C15H13ClN4O (300.74): C 59.91, H 4.36, N 18.63; found: C 59.86,
H 4.60, N 18.37.
N-{2-[Azido(4-chlorophenyl)methyl]-4-chlorophenyl}formamide (1h). Yield: 83%. Pale-yellow
1
solid. M.p. 98 – 1008 (hexane/CHCl3). IR (KBr): 3275, 2104, 1694. H-NMR (500 MHz, CDCl3): 5.75,
5.78 (2s, combined 1 H); 7.12 – 8.31 (m, 9 H). Anal. calc. for C14H10Cl2N4O (321.16): C 52.36, H 3.14, N
17.45; found: C 52.35, H 3.28, N 17.40.
N-{2-[Azido(phenyl)methyl]-4-methoxyphenyl}formamide (1i). Yield: 70%. Yellow oil. Rf (AcOEt/
1
hexane 1:1) 0.21. IR (KBr): 3257, 2101, 1689. H-NMR (500 MHz, CDCl3): 3.81, 3.83 (2s, combined,
3 H); 5.78, 5.80 (2s, combined 1 H); 6.86 – 8.17 (m, 10 H). Anal. calc. for C15H14N4O2 (282.30): C 63.82, H
5.00, N 19.85; found: C 63.93, H 5.04, N 20.13.

Helvetica Chimica Acta – Vol. 97 (2014)
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N-{4-[Azido(phenyl)methyl]pyridin-3-yl}formamide (7a). Yield: 60%. Yellow oil. Rf (THF/hexane
1:1) 0.35. IR (neat): 3239, 2103, 1695. 1H-NMR (500 MHz, CDCl3): 5.87 (s, 1 H); 7.23 – 9.02 (m, 10 H).
Anal. calc. for C13H11N5O (253.26): C 61.65, H 4.38, N 27.65; found: C 61.61, H 4.40, N 27.60.
N-{4-[Azido(4-chlorophenyl)methyl]pyridin-3-yl}formamide (7b). Yield: 62%. Yellow oil. Rf (THF/
1
hexane 1:1) 0.24. IR (neat): 3239, 2105, 1695. H-NMR (500 MHz, CDCl3): 5.86, 5.88 (2s, combined
1 H); 7.18 – 8.98 (m, 9 H). Anal. calc. for C13H10ClN5O (287.70): C 54.27, H 3.50, N 24.34; found: C 54.10,
H 3.53, N 24.28.
Isocyanobenzenes 2 were prepared by dehydration of 1 with POCl3 as described in [16].
1
1-(Azidomethy)l-2-isocyanobenzene (2a). Green oil. Rf (CH2Cl2/hexane 1:1) 0.46. H-NMR Data:
identical to those reported in [6].
1-(1-Azidoethyl)-2-isocyanobenzene (2b). Pale-green oil. Rf (CH2Cl2/hexane 1:5) 0.50. IR (neat):
2121, 2101. 1H-NMR (500 MHz, CDCl3): 1.57 (d, J ¼ 6.9, 3 H); 5.09 (q, J ¼ 6.9, 1 H); 7.35 (td, J ¼ 7.6, 1.5,
1 H); 7.41 (d, J ¼ 7.6, 1 H); 7.46 (td, J ¼ 7.6, 1.5, 1 H), 7.52 (d, J ¼ 7.6, 1 H). HR-MS: 173.0806 ([M þ H]þ,
C9H9Nþ4 ; calc. 173.0827).
1-[Azido(phenyl)methyl]-2-isocyanobenzene (2c). Pale-green oil. Rf (CH2Cl2/hexane 1:5) 0.20. IR
1
(neat): 2119, 2102. H-NMR (500 MHz, CDCl3): 6.09 (s, 1 H); 7.32 – 7.35 (m, 3 H); 7.36 – 7.40 (m, 4 H);
7.47 (td, J ¼ 7.6, 1.5, 1 H); 7.62 (d, J ¼ 7.6, 1 H). HR-MS: 235.0982 ([M þ H]þ, C14H11N4þ ; calc. 235.0983).
1-[Azido(4-chlorophenyl)methyl]-2-isocyanobenzene (2d). Pale-green oil. Rf (CH2Cl2/hexane 1:3)
0.47. IR (neat): 2127, 2103. 1H-NMR (500 MHz, CDCl3): 6.07 (s, 1 H); 7.26 – 7.29 (m, 2 H); 7.34 – 7.40 (m,
4 H); 7.48 (td, J ¼ 7.6, 1.5, 1 H); 7.59 (d, J ¼ 7.6, 1 H). HR-MS: 269.0565 ([M þ H]þ, C14H10ClN4þ ; calc.
269.0594).
1-(Azidomethy)l-4-chloro-2-isocyanobenzene (2e). Pale-green liquid. Rf (CH2Cl2/hexane 1:3) 0.18.
IR (neat): 2119. 1H-NMR (500 MHz, CDCl3): 4.55 (s, 2 H); 7.37 – 7.38 (m, 2 H); 7.48 (s, 1 H). HR-MS:
193.0278 ([M þ H]þ, C8H6ClNþ4 ; calc. 193.0281).
1-[Azido(4-chlorophenyl)methyl]-4-chloro-2-isocyanobenzene (2f). Green oil. Rf (CH2Cl2/hexane
1:5) 0.30. IR (neat): 2104. 1H-NMR (500 MHz, CDCl3): 6.00 (s, 1 H); 7.25 (d, J ¼ 8.4, 2 H); 7.36 (d, J ¼
8.4, 2 H); 7.39 (d, J ¼ 2.3, 1 H); 7.46 (dd, J ¼ 8.4, 2.3, 1 H); 7.54 (d, J ¼ 8.4, 1 H). HR-MS: 303.0203 ([M þ
H]þ, C14H9Cl2Nþ4 ; calc. 303.0204).
1-[Azido(4-methylphenyl)methyl]-5-chloro-2-isocyanobenzene (2g). Green oil. Rf (CH2Cl2/hexane
1:3) 0.26. IR (neat): 2128, 2103. 1H-NMR (500 MHz, CDCl3): 2.35 (s, 3 H); 5.98 (s, 1 H); 7.21 (br. s, 4 H);
7.28 – 7.32 (m, 2 H); 7.65 (br. s, 1 H). HR-MS: 283.0729 ([M þ H]þ, C15H12ClN4þ ; calc. 283.0750).
1-[Azido(4-chlorophenyl)methyl]-5-chloro-2-isocyanobenzene (2h). Light-blue solid. M.p. 85 – 868
(hexane/Et2O). IR (KBr): 2106. 1H-NMR (400 MHz, CDCl3): 5.99 (s, 1 H); 7.28 (d, J ¼ 8.3, 2 H); 7.29 –
7.34 (m, 2 H); 7.38 (d, J ¼ 8.3, 2 H); 7.62 (d, J ¼ 2.0, 1 H). HR-MS: 303.0197 ([M þ H]þ, C14H9Cl2N4þ ; calc.
303.0204).
1-[Azido(phenyl)methyl]-5-methoxy-2-isocyanobenzene (2i). Green oil. Rf (CH2Cl2/hexane 1:2)
0.57. IR (neat): 2103, 1607. 1H-NMR (500 MHz, CDCl3): 3.84 (s, 3 H); 6.04 (s, 1 H); 6.82 (dd, J ¼ 9.2, 2.3,
1 H); 7.11 (d, J ¼ 2.3, 1 H); 7.29 – 7.39 (m, 6 H). HR-MS: 265.1088 ([M þ H]þ, C15H13N4Oþ; calc.
265.1089).
4-[Azido(phenyl)methyl]-3-isocyanopyridine (8a). Brown oil. Rf (THF/hexane 1:2) 0.50. IR (neat):
2119, 2106. 1H-NMR (500 MHz, CDCl3): 6.00 (s, 1 H); 7.32 – 7.43 (m, 5 H); 7.66 (d, J ¼ 5.3, 1 H); 8.62 (s,
1 H); 8.69 (d, J ¼ 5.3, 1 H). HR-MS: 236.0928 ([M þ H]þ, C13H10ON5þ ; calc. 236.0936).
4-[Azido(4-chlorophenyl)methyl]-3-isocyanopyridine (8b). Green oil. Rf (THF/hexane 1:4) 0.52. IR
(neat): 2107. 1H-NMR (500 MHz, CDCl3): 5.98 (s, 1 H); 7.27 (d, J ¼ 8.4, 2 H); 7.39 (d, J ¼ 8.4, 2 H); 7.69
(d, J ¼ 5.3, 1 H); 8.65 (s, 1 H); 8.70 (d, J ¼ 5.3, 1 H). HR-MS: 270.0550 ([M þ H]þ, C13H9ClN5þ ; calc.
270.0546).
Quinazoline (6a) (Representative Procedure). To a stirred suspension of NaH (60% in mineral oil;
35 mg, 0.88 mmol) in DMF (2 ml) at 08 was added a soln. of 2a (0.14 g, 0.88 mmol) in DMF (1.5 ml)
dropwise. After stirring for 10 min at the same temp., 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), and dried (Na2SO4) and concentrated by evaporation. The residue was purified by CC (SiO2) to
give 6a (79 mg, 69%). White solid. M.p. 45 – 478 (hexane/CH2Cl2) ([17]: 488). Identified by a direct
comparison with a sample purchased from Tokyo Chemical Industry Co., Ltd.

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Helvetica Chimica Acta – Vol. 97 (2014)
4-Methylquinazoline (6b). White solid. M.p. 34 – 368 (hexane/CH2Cl2) ([18]: 34 – 358). 1H-NMR
Data: identical to those reported in [18].
4-Phenylquinazoline (6c). White solid. M.p. 99 – 1018 (hexane/CH2Cl2) ([18]: 100 – 1018). H- and
13C-NMR data: identical to those reported in [19].
1
4-(4-Chlorophenyl)quinazoline (6d). White solid. M.p. 123 – 1258 (hexane/CH2Cl2) ([17]: 1228).
1H-NMR Data: identical to those reported in [17].
7-Chloroquinazoline (6e). White solid. M.p. 92 – 948 (hexane/CH2Cl2) ([20]: 93 – 948). 1H-NMR
Data: identical to those reported in [21].
7-Chloro-4-(4-chlorophenyl)quinazoline (6f). White solid. M.p. 160 – 1628 (hexane/Et2O). IR
1
(KBr): 3065, 1604, 1557, 1475. H-NMR (500 MHz, CDCl3): 7.57 – 7.59 (m, 3 H); 7.73 (d, J ¼ 8.4, 2 H);
8.03 (d, J ¼ 9.2, 1 H); 8.12 (d, J ¼ 2.3, 1 H); 9.36 (s, 1 H). 13C-NMR: 121.35; 128.09; 128.11; 129.10 (2
overlapped Cs); 131.23; 135.08; 136.81; 140.21; 151.77; 155.55; 167.11. HR-MS: 275.0123 ([M þ H]þ,
C14H9Cl2Nþ2 ; calc. 275.0143). Anal. calc. for C14H8Cl2N2 (275.13): C 61.12, H 2.93, N 10.18; found: C 60.85,
H 2.81, N 10.08.
6-Chloro-4-(4-methylphenyl)quinazoline (6g). White solid. M.p. 163 – 1648 (hexane/CH2Cl2). IR
(KBr): 3065, 1556, 1486. 1H-NMR (500 MHz, CDCl3): 2.49 (s, 3 H); 7.41 (d, J ¼ 7.6, 2 H); 7.68 (d, J ¼ 7.6,
2 H); 7.84 (dd, J ¼ 9.2, 2.3, 1 H); 8.06 (d, J ¼ 9.2, 1 H); 8.13 (d, J ¼ 2.3, 1 H); 9.36 (s, 1 H). 13C-NMR:
21.46; 123.72; 125.91; 129.55; 129.85; 130.62; 133.33; 133.71; 134.55; 140.74; 149.61; 154.83; 167.64. HR-
MS: 255.0688 ([M þ H]þ, C15H12ClN2þ ; calc. 255.0689). Anal. calc. for C15H11ClN2 (254.71): C 70.73, H
4.35, N 11.00; found: C 70.57, H 4.48, N 10.90.
6-Chloro-4-(4-chlorophenyl)quinazoline (6h). Pale-yellow solid. M.p. 125 – 1278 (hexane/Et2O). IR
(KBr): 3037, 1559, 1486. 1H-NMR (500 MHz, CDCl3): 7.59 (d, J ¼ 8.4, 2 H); 7.73 (d, J ¼ 8.4, 2 H); 7.86 (dd,
J ¼ 9.2, 2.3, 1 H); 8.05 (d, J ¼ 2.3, 1 H); 8.08 (d, J ¼ 9.2, 1 H); 9.37 (s, 1 H). 13C-NMR: 123.46; 125.35;
129.17; 130.81; 131.17; 133.75; 134.84; 134.90; 136.83; 149.64; 154.75; 166.31. HR-MS: 275.0128 ([M þ
H]þ, C14H9Cl2N2þ ; calc. 275.0143). Anal. calc. for C14H8Cl2N2 (275.13): C 61.12, H 2.93, N 10.18; found:
C 60.96, H 3.04, N 9.78.
6-Methoxy-4-phenylquinazoline (6i). Yellow solid. M.p. 101 – 1038 (hexane/Et2O). IR (KBr): 3062,
1
1619, 1537, 1504, 1234. H-NMR (500 MHz, CDCl3): 3.85 (s, 3 H); 7.37 (d, J ¼ 2.3, 1 H); 7.55 – 7.61 (m,
4 H); 7.79 – 7.81 (m, 2 H); 8.03 (d, J ¼ 9.2, 1 H); 9.27 (s, 1 H). 13C-NMR: 55.62; 104.10; 124.03; 125.47;
128.70; 129.55; 129.85; 130.37; 137.45; 147.32; 152.88; 158.39; 166.56. HR-MS: 237.1019 ([M þ H]þ,
C15H13N2Oþ; calc. 237.1028). Anal. calc. for C15H12N2O (236.27): C 76.25, H 5.12, N 11.86; found: C 76.04,
H 5.15, N 11.84.
4-Phenylpyrido[3,4-d]pyrimidine (9a). Yellow solid. M.p. 87 – 888 (hexane/CH2Cl2). IR (KBr): 3030,
1
1557, 1542, 1384. H-NMR (500 MHz, CDCl3): 7.61 – 7.64 (m, 3 H); 7.83 – 7.85 (m, 2 H); 7.96 (d, J ¼ 5.4,
1 H); 8.77 (d, J ¼ 5.4, 1 H); 9.54 (s, 1 H); 9.61 (s, 1 H); 13C-NMR: 118.12; 125.51; 128.96; 129.92; 130.87;
135.78; 145.29; 145.40; 154.46; 156.00; 168.24. HR-MS: 208.0864 ([M þ H]þ, C13H10N3þ ; calc. 208.0874).
Anal. calc. for C13H9N3 (207.23): C 75.35, H 4.38, N 20.28; found: C 75.10, H 4.58, N 20.26.
4-(4-Chlorophenyl)pyrido[3,4-d]pyrimidine (9b). Yellow solid. M.p. 141 – 1428 (hexane/CH2Cl2). IR
(KBr): 3061, 1554, 1536, 1381. 1H-NMR (500 MHz, CDCl3): 7.61 (d, J ¼ 8.4, 2 H); 7.80 (d, J ¼ 8.4, 2 H);
7.91 (d, J ¼ 5.4, 1 H); 8.78 (d, J ¼ 5.4, 1 H); 9.52 (s, 1 H); 9.61 (s, 1 H). 13C-NMR: 117.67; 125.31; 129.08;
129.32; 131.24; 134.18; 137.44; 145.45; 154.59; 155.96; 166.97. HR-MS: 242.0481 ([M þ H]þ, C13H9ClN3þ ;
calc. 242.0485). Anal. calc. for C13H8ClN3 (241.68): C 64.61, H 3.34, N 17.39; found: C 64.40, H 3.18, N
17.27.
This work was supported in part by JSPS KAKENHI Grant No. 26410051. Mrs. Miyuki Tanmatsu of
our university is acknowledged for recording mass spectra and performing combustion analyses.
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Received December 6, 2013