C–N Bond Formation by the Oxidative Alkylamination of Azines
FULL PAPER
M.p. 116–118 °C (ref.[17] 116 °C). 1H NMR (400 MHz, CDCl3, 30 °C): δ = 8.71 (s, 1 H, 2-H), 7.87 (d, J = 8.3 Hz, 1 H, 5-H), 7.86
30 °C): δ = 8.67 (s, 1 H, 2-H), 7.83 (d, J = 8.3 Hz, 1 H, 8-H), 7.75 (d, J = 8.3 Hz, 1 H, 8-H), 7.70 (dd, J = 7.1, 8.3 Hz, 1 H, 6-H), 7.42
(d, J = 8.3 Hz, 1 H, 5-H), 7.71 (t, J = 7.6 Hz, 1 H, 6-H), 7.44 (t, J (dd, J = 7.1, 8.3 Hz, 1 H, 7-H), 3.71 (m, 4 H, α-CH2 piperidino),
= 7.6 Hz, 1 H, 7-H), 6.00 (br. s, 1 H, NH), 3.67 (m, 2 H, 1.75 ppm (m, 6 H, β-CH2 and γ-CH2 piperidino). 13C NMR
CH2CH2CH2CH3), 1.72 (m, 2 H, CH2CH2CH2CH3), 1.47 (m, 2 H, (400 MHz, CDCl3, 30 °C): δ = 164.9, 154.1, 151.7, 132.3, 128.5,
CH2CH2CH2CH3), 0.98 ppm (t,
J
=
7.4 Hz,
3
H, 125.2, 125.0, 116.8, 51.0, 26.0, 24.8 ppm. HRMS (ESI): calcd. for
C13H16N3 [M + H]+ 214.1344; found 214.1353. C13H15N3 (213.3):
calcd. C 73.21, H 7.09, N 19.70; found C 73.23, H 6.87, N 19.91.
CH2CH2CH2CH3). 13C NMR (400 MHz, CDCl3, 30 °C): δ =
158.6, 154.4, 148.2, 131.5, 127.4, 124.9, 119.6, 114.0, 40.2, 30.4,
19.2, 12.8 ppm. HRMS (ESI): calcd. for C12H16N3 [M + H]+
202.1344; found 202.1345. C12H15N3 (201.3): calcd. C 71.61, H
7.51, N 20.88; found C 71.92, H 7.69, N 21.03.
4-Morpholinoquinazoline (4h): Yield 5 mg, 2% (method A); 207 mg,
96% (method C). Yellow solid. M.p. 92–93 °C (ref.[13c] 93–94 °C).
1H NMR (400 MHz, CDCl3, 30 °C): δ = 8.76 (s, 1 H, 2-H), 7.93
(d, J = 8.4 Hz, 1 H, 5-H), 7.87 (dd, J = 8.3, 1.0 Hz, 1 H, 8-H), 7.75
(ddd, J = 7.0, 8.4, 1.0 Hz, 1 H, 6-H), 7.47 (ddd, J = 7.0, 8.3, 1.2 Hz,
1 H, 7-H), 3.90 [t, J = 4.7 Hz, 4 H, O(CH2)2 morpholino], 3.79 ppm
[t, J = 4.7 Hz, 4 H, N(CH2)2 morpholino]. 13C NMR (400 MHz,
CDCl3, 30 °C): δ = 164.7, 154.0, 151.7, 132.6, 128.8, 125.6, 124.7,
116.6, 66.8, 50.3 ppm. HRMS (ESI): calcd. for C12H14N3O [M +
4-Amylaminoquinazoline (4c): Yield 13 mg, 6% (method A);
207 mg, 96% (method B). White solid. M.p. 109–110 °C (heptane)
1
(ref.[17] 110 °C). H NMR (400 MHz, CDCl3, 30 °C): δ = 8.66 (s, 1
H, 2-H), 7.85 (d, J = 8.2 Hz, 1 H, 8-H), 7.75 (d, J = 8.2 Hz, 1 H,
5-H), 7.72 (ddd, J = 7.0, 8.2, 1.3 Hz, 1 H, 6-H), 7.46 (ddd, J = 7.0,
8.2, 1.3 Hz, 1 H, 7-H), 5.95 (br. s, 1 H, NH), 3.67 (dt, J = 5.5,
H]+ 216.1137; found 216.1132. C12H13N3 (215.2): calcd. C 66.96,
H 6.09, N 19.52; found C 67.23, H 5.85, N 19.34.
7.2 Hz,
2
H, CH2CH2CH2CH2CH3), 1.74 (m,
2
H,
CH2CH2CH2CH2CH3), 1.42 (m, 4 H, CH2CH2CH2CH2CH3),
0.93 ppm (t, J = 7.1 Hz, 3 H, CH2CH2CH2CH2CH3). 13C NMR
(400 MHz, CDCl3, 30 °C): δ = 159.6, 155.5, 149.3, 132.5, 128.4,
125.9, 120.7, 115.1, 41.4, 29.2, 29.0, 22.4, 14.0 ppm. HRMS (ESI):
calcd. for C13H18N3 [M + H]+ 216.1501; found 216.1502. C13H17N3
(215.3): calcd. C 72.52, H 7.96, N 19.52; found C 72.32, H 8.14, N
19.33.
4-Hexamethyleneiminoquinazoline (4i): Yield 73 mg, 32% (method
1
C). Yellow oil. H NMR (400 MHz, CDCl3, 30 °C): δ = 8.60 (s, 1
H, 2-H), 7.99 (dd, J = 8.3, 1.3 Hz, 1 H, 5-H), 7.87 (dd, J = 8.3,
1.3 Hz, 1 H, 8-H), 7.68 (ddd, J = 7.0, 8.3, 1.3 Hz, 1 H, 6-H), 7.37
(ddd, J = 7.0, 8.3, 1.3 Hz, 1 H, 7-H), 3.95 (t, J = 5.8 Hz, 4 H, α-
CH2 hexamethyleneimino), 1.98 (m, 4 H, β-CH2 hexamethyl-
eneimino), 1.68 ppm (dt, J = 6.9, 2.6 Hz, 4 H, γ-CH2 hexamethyl-
eneimino). 13C NMR (400 MHz, CDCl3, 30 °C): δ = 162.6, 153.8,
152.1, 131.8, 128.2, 125.5, 124.2, 115.9, 51.3, 28.5, 27.5 ppm.
HRMS (ESI): calcd. for C14H18N3 [M + H]+ 228.1501; found
228.1500. C14H17N3 (227.3): calcd. C 73.98, H 7.54, N 18.49; found
C 74.05, H 7.77, N 18.31.
4-Cyclohexylaminoquinazoline (4d): Yield 12 mg, 5% (method A);
198 mg, 87% (method B). White solid. M.p. 146–148 °C (heptane)
(ref.[13c] 148–149 °C). 1H NMR (400 MHz, CDCl3, 30 °C): δ = 8.66
(s, 1 H, 2-H), 7.81 (d, J = 8.2 Hz, 1 H, 8-H), 7.73 (d, J = 8.3 Hz,
1 H, 5-H), 7.69 (ddd, J = 7.0, 8.3, 1.2 Hz, 1 H, 6-H), 7.42 (ddd, J
= 7.0, 8.2, 1.1 Hz, 1 H, 7-H), 5.63 (d, J = 6.9 Hz, 1 H, NH), 4.27
[m, 1 H, H(1Ј) c-C6H11], 2.15 (m, 2 H, CH2, c-C6H11), 1.80 (m, 2
H, CH2, c-C6H11), 1.50 (m, 2 H, CH2, c-C6H11), 1.29 ppm (m, 4
H, CH2, c-C6H11). 13C NMR (400 MHz, CDCl3, 30 °C): δ = 158.7,
155.6, 149.6, 132.4, 128.7, 125.8, 120.4, 115.0, 49.7, 33.1, 25.7,
25.0 ppm. HRMS (ESI): calcd. for C14H18N3 [M + H]+ 228.1501;
found 228.1495. C14H17N3 (227.3): calcd. C 73.98, H 7.54, N 18.49;
found C 73.77, H 7.21, N 18.52.
4-Diethylaminoquinazoline (4j): Yield 56 mg, 28% (method C). Yel-
1
low oil (ref.[13f] oil). H NMR (400 MHz, CDCl3, 30 °C): δ = 8.54
(s, 1 H, 2-H), 7.81 (d, J = 8.3 Hz, 1 H, 5-H), 7.76 (d, J = 8.3 Hz,
1 H, 8-H), 7.60 (ddd, J = 7.2, 8.3, 1.0 Hz, 1 H, 6-H), 7.30
(ddd, J = 7.2, 8.3, 1.0 Hz, 1 H, 7-H), 3.66 [q, J = 7.0 Hz, 4 H,
N(CH2CH3)2], 1.31 ppm [t, J = 7.0 Hz, 6 H, N(CH2CH3)2]. 13C
NMR (400 MHz, CDCl3, 30 °C): δ = 162.5, 153.9, 151.7, 131.9,
128.3, 124.7, 124.5, 116.2, 45.0, 13.0 ppm. HRMS (ESI): calcd. for
C12H16N3 [M + H]+ 202.1344; found 202.1345. C12H15N3 (201.3):
calcd. C 71.61, H 7.51, N 20.88; found C 71.50, H 7.22, N 20.64.
4-Benzylaminoquinazoline (4e): Yield 214 mg, 91% (method C);
183 mg, 78% (method D). White solid. M.p. 167–168 °C (ref.[13c]
1
169 °C). H NMR (400 MHz, CDCl3, 30 °C): δ = 8.67 (s, 1 H, 2-
H), 7.84 (d, J = 8.3 Hz, 1 H, 8-H), 7.77 (d, J = 8.3 Hz, 1 H, 5-H),
7.71 (ddd, J = 7.1, 8.3, 1.3 Hz, 1 H, 6-H), 7.45–7.31 (m, 6 H, 7-H
and C6H5), 6.35 (br. s, 1 H, NH), 4.87 ppm (d, J = 5.4 Hz, 2 H,
CH2C6H5). 13C NMR (400 MHz, CDCl3, 30 °C): δ = 159.4, 155.3,
149.3, 138.1, 132.7, 128.8, 128.6, 128.4, 127.9, 127.3, 127.0, 126.1,
120.8, 114.9, 45.3 ppm. HRMS (ESI): calcd. for C15H14N3 [M +
H]+ 236.1188; found 236.1187. C15H13N3 (235.3): calcd. C 76.57,
H 5.57, N 17.86; found C 76.82, H 5.69, N 17.54.
Acknowledgments
A.V.G. thanks the University of Antwerp (BOF Visiting Postdoc-
toral Researcher) for a scholarship. The authors acknowledge the
financial support of the Flemish Government which enabled the
purchase of NMR and supercomputing facilities (Impulsfinancier-
ing van de Vlaamse Overheid voor Strategisch Basisonderzoek
PFEU 2003) as well as the technical assistance of J. Aerts, W.
Van Dongen and J. Verreydt. We would like to thank Prof. Dr. F.
Lemière for HRMS measurements and Prof. Dr. R. Dommisse for
NMR spectra.
4-Pyrrolidinoquinazoline (4f): Yield 62 mg, 31% (method C). Yellow
solid. M.p. 56–57 °C (ref.[13d] 57–58 °C). 1H NMR (400 MHz,
CDCl3, 30 °C): δ = 8.59 (s, 1 H, 2-H), 8.14 (d, J = 8.3 Hz, 1 H, 5-
H), 7.82 (d, J = 8.3 Hz, 1 H, 8-H), 7.67 (ddd, J = 7.1, 8.3, 1.2 Hz,
1 H, 6-H), 7.36 (ddd, J = 7.1, 8.3, 1.2 Hz, 1 H, 7-H), 3.92 (t, J =
6.6 Hz, 4 H, α-CH2 pyrrolidino), 2.05 ppm (m, 4 H, β-CH2 pyrroli-
dino). 13C NMR (400 MHz, CDCl3, 30 °C): δ = 159.8, 154.4, 151.4,
131.9, 128.0, 125.3, 124.4, 116.5, 51.0, 25.7 ppm. HRMS (ESI):
calcd. for C12H14N3 [M + H]+ 200.1188; found 200.1184. C12H13N3
(199.2): calcd. C 72.33, H 6.58, N 21.09; found C 72.12, H 6.90, N
21.15.
[1] For reviews, see a) O. N. Chupakhin, V. N. Charushin, H. C.
van der Plas, Nucleophilic Aromatic Substitution of Hydrogen,
Academic Press, San Diego, 1994; b) F. Terrier, Nucleophilic
Aromatic Displacement, The Influence of Nitro Group, VCH,
New York, 1991; c) M. Makosza, Uspekhi Khimii 1989, 58,
1298–1317 (in Russian); d) M. Makosza, Russ. Chem. Rev.
1996, 45, 491–504; e) O. N. Chupakhin, D. G. Beresnev, Russ.
Chem. Rev. 2002, 71, 707–720; f) H. C. van der Plas in Ad-
˛
˛
4-Piperidinoquinazoline (4g): Yield 145 mg, 68% (method C). Yel-
low oil. [ref.[13c] 193–194 °C (picrate)]. 1H NMR (400 MHz, CDCl3,
Eur. J. Org. Chem. 2006, 5305–5314
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