Communication
ture was dry loaded onto silica gel and purified by flash-column
chromatography eluting with 10% methanol in dichloromethane
to afford the quinazoline product (67 mg, 89%). M.p. 157–1588C;
1H NMR (400 MHz, [D6]DMSO): d=8.44 (1H, s, N=CH), 8.27 (1H, s,
NH), 8.24 (1H, dd, J=8.5, 1.0 Hz, CHar), 7.75 (1H, ddd, J=8.5, 7.0,
1.0 Hz, CHar), 7.67 (1H, dd, J=8.5, 1.0 Hz, CHar), 7.50 (1H, ddd, J=
8.5, 7.0, 1.0 Hz, CHar), 4.81 (1H, t, J=5.5 Hz, OH), 3.67–3.57 ppm
(4H, m, (CH2)2); 13C NMR (100.6 MHz, [D6]DMSO): d=159.5, 155.0,
149.1, 132.5, 127.5, 125.5, 122.7, 115.0, 59.2, 43.3 ppm; FTIR: v˜max
(neat) = 3233 (m), 3021 (w), 2961 (w), 1584 (s), 1319 (s), 1064 (s),
771 cmÀ1 (s); HRMS: m/z [MH]+ calcd for C10H12N3O: 190.0980;
found: 190.0973.
Acknowledgements
Scheme 6. Synthetic route to erlotinib. a) (COCl)2, cat. DMF, CH2Cl2;
HO(CH2)2NH2, Et3N (79%); b) TsCl, Et3N, cat. DMAP, CH2Cl2; NaOH, MeOH
(62%); c) H2NCOCF3, 2.5 mol% [Cp*RhCl2]2, 10 mol%, AgSbF6, PhI(OAc)2,
CH2Cl2, 408C, 16 h (86%); d) NaOH, EtOH; H2NCHNH.HOAc, EtOH, reflux
(82%); e) 6m HCl, reflux (71%); f) POCl3, PhMe, reflux; iPrOH, pyridine, 28,
reflux (69%).
We gratefully acknowledge GlaxoSmithKline and the EPSRC for
financial support. We also thank Ms. Rachel Armstrong for her
assistance in the optimization of the Rh-catalyzed amidation
step.
Keywords: amidation · cyclization · homogeneous catalysis ·
oxazolines · quinazolines
Experimental Section
Typical CÀH amidation procedure as exemplified by the for-
mation of 2
[1] For recent examples of bioactive quinazolines and quinazolinones see:
[2] For representative approaches to the synthesis of quinazolines and qui-
nazolinones see: a) J. B. Jiang, D. P. Hesson, B. A. Dusak, D. L. Dexter,
Wang, Tetrahedron Lett. 2012, 53, 6571; e) H. Li, L. He, H. Neumann, M.
L. Kou, S. Ma, K. M. Engle, J.-Q. Yu, Synthesis 2012, 1778; c) M.-L. Louillat,
[4] Quinazolinones and related heterocycles have been prepared by cycli-
zation reactions involving C-H amidation: a) W. C. P. Tsang, N. Zheng,
Wang, G. Liu, F.-K. Meng, J.-H. Chen, Z. Yang, Z.-J. Shi, Chem. Eur. J.
76, 6362. For C-H-carboxylation approaches see: R. Giri, J. K. Lam, J.-Q.
[8] K. Schwekendiek, F. Glorius, Synthesis 2006, 2996.
[12] The use of excess oxazoline prevents di-amidation occurring. For exam-
ple, conducting the reaction under optimized catalytic conditions using
a 1:1 mixture of CF3CONH2 and 2-phenyl oxazoline gave 2 in 80% yield,
together with 2-(2,6-ditrifluoroacetamidophenyl) oxazoline in 7% yield.
[13] For details of the synthesis of oxazoline substrates, see the Supporting
Information.
To a flame-dried Schlenk tube was added [Cp*RhCl2]2 (3 mg,
0.005 mmol), AgSbF6 (7 mg, 0.02 mmol), PhI(OAc)2 (97 mg,
0.30 mmol) and trifluoroacetamide (23 mg, 0.20 mmol). The tube
was fitted with a rubber septum, and placed under an atmosphere
of nitrogen. 2-Phenyl-2-oxazoline (59 mg, 0.40 mmol) was then
added, followed by dry dichloromethane (2.0 mL). The septum was
replaced by a Teflon screw cap under nitrogen flow. The reaction
mixture was stirred at 408C for 16 h. After cooling to RT, the sol-
vent was removed in vacuo and the residue was purified by flash
column chromatography on silica gel eluting with dichlorome-
thane to afford the aminated product as a colourless solid (48 mg,
92%). M.p. 74–758C; 1H NMR (400 MHz, CDCl3): d=13.69 (1H, s,
NH), 8.68 (1H, dd, J=8.5 and 1.0 Hz, CHar), 7.90 (1H, dd, J=8.5 and
1.0 Hz, CHar), 7.52 (1H, t, J=8.5 Hz, CHar), 7.21 (1H, t, J=8.5 Hz,
CHar), 4.43 (2H, t, J=9.5 Hz, CH2), 4.16 ppm (2H, t, J=9.5 Hz, CH2);
13C NMR (100.6 MHz, CDCl3): d=164.7, 155.7 (q, J=37.5 Hz), 137.7,
132.9, 129.4, 124.5, 120.3, 116.1 (q, J=288.5 Hz), 114.5, 66.8,
54.5 ppm; 19F NMR (376.5 MHz, CDCl3): d=À76.0 ppm; FTIR: v˜max
(neat) = 3054 (w), 2915 (w), 1734 (s), 1260 cmÀ1 (s); HRMS: m/z
calcd for C11H10N2O2F3: 259.0694 [MH]+; found 259.0704.
Typical cyclization procedure as exemplified by the forma-
tion of 15
Substrate
2 (103 mg, 0.400 mmol) was dissolved in ethanol
(4.0 mL), NaOH pellets (320 mg, 8.00 mmol) were added and the
reaction mixture was stirred at RT. The reaction was monitored by
TLC analysis until complete conversion of the starting material was
observed; upon completion, the solvent was removed in vacuo.
The residue was dissolved in water and ethyl acetate, and trans-
ferred to a separating funnel. The layers were partitioned, followed
by further extraction of the aqueous layer with ethyl acetate. The
combined organics were then washed with brine, followed by
drying over anhydrous MgSO4, filtered and the solvent removed in
vacuo. The residue was then dissolved in ethanol (4.0 mL) and for-
mamidine acetate (125 mg, 1.20 mmol) was added and the mixture
was heated at reflux for 1 h. After cooling to RT, the reaction mix-
Chem. Eur. J. 2015, 21, 14342 – 14346
14345
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