A. W. Hensbergen et al. / Tetrahedron Letters 56 (2015) 6478–6483
6483
effects in the submicromolar range.44 Further development of this
new compound class and its application to other biological targets
are currently underway and will be reported in due course.
Conclusions
34. CAUTION: It should be noted that the mixing of formic acid with strong acids
liberates carbon monoxide, as witnessed by the evolution of a gas upon mixing.
In the present Letter, we have identified a straightforward
three-step route to a new class of oxazepino and oxazocino quina-
zolines. We have demonstrated the SNAr of a fluorobenzonitrile
with a range of commercially available aminoalcohols followed
by sequential Niementowski and BOP-mediated ring closure to
afford a collection of rigidified analogues. This remarkable tandem
cyclisation strategy is a new and enabling route to rigidify kinase
inhibitor-like quinazolines and has wide-ranging potential in the
field of medicinal chemistry.
41. Experimental procedure: Synthesis of 8,8a,9,10,11,12-hexahydropyrido
[20,10:3,4][1,4]oxazepino[5,6,7-de]quinazoline (3a) sodium hydride (60% w/w
in oil, 87 mg, 2.28 mmol) was added portion wise to N-Boc-piperidine-2-
methanol (0.49 g, 2.28 mmol) in THF (7.6 mL) at 0 °C over a period of 10 min.
The resulting solution was stirred at 0 °C for 1 h. Then, 2-amino-6-
fluorobenzonitrile (0.28 g, 2.05 mmol) was added in one-portion and the
mixture heated at 85 °C for 2 h. The reaction mixture was quenched with water
(2 mL) and then evaporated. The residue was diluted with ethyl acetate
(30 mL) and washed with a saturated aqueous solution of sodium bicarbonate
(2 ꢀ 30 mL). The organic layer was dried over sodium sulphate, filtered and the
Acknowledgments
The authors thank Manchester Metropolitan University for
funding and Dr. Swee Sharp at the Institute of Cancer Research
(London) for biological evaluation of 3a–d, 3f and 3h using
MCF7, BT474 and MDA-MB231 cancer cell lines. The authors thank
the analytical services at MMU and ICR for performing NMR and
MS analyses. A.W.H. thanks the Erasmus + Scholarship scheme
and the University of Applied Sciences, Utrecht, The Netherlands.
solvent removed in vacuo. The residue was passed through
a SCX-2 ion
exchange column (10 g), eluting the product with 2 M ammonia–methanol.
Purification by flash column chromatography [SiO2, MeOH:DCM, 0–15%]
afforded the corresponding product (1a) as
a white powder (87 mg,
max/cmꢁ1 3311, 2925, 2211, 1577, 1476
Supplementary data
0.38 mmol, 17%). Mp 102–103 °C;
m
and 1456; 1H NMR (500 MHz, CDCl3) d = 7.18 (dd, J = 8.5 Hz, 1H), 6.30 (dd,
J = 8.5, 1.0 Hz, 1H), 6.20 (dd, J = 8.5, 1.0 Hz, 1H), 4.48 (s, 2H), 3.96 (dd, J = 9.0,
3.7 Hz, 1H), 3.86 (dd, J = 9.0, 8.0 Hz, 1H), 3.14 (ddt, J = 11.5, 4.0, 2.0 Hz, 1H),
3.10–2.97 (m, 1H), 2.78 (s, 1H), 2.71 (td, J = 11.9, 2.7 Hz, 1H), 1.96–1.78 (m, 1H),
1.76–1.62 (m, 2H), 1.58–1.26 (m, 3H); 13C NMR (126 MHz, CDCl3) d = 161.0,
151.1, 134.5, 115.4, 107.6, 100.4, 86.7, 73.0, 55.4, 46.4, 28.3, 25.9, 24.1; LC–MS
(TOF, 2.0 min) Rt = 0.59 min; m/z (ESI) 232 (M+H); Hi-Res LC–MS (ESI) m/z
calcd for C13H18N3O (M+H) 232.1450, found 232.1452. 2-Amino-6-(piperidin-
2-ylmethoxy)benzonitrile (1a) (87 mg, 0.38 mmol) was added portion-wise to
a refluxing mixture of formic acid (1.5 mL, 39.1 mmol) and concd sulphuric
acid (0.09 mL, 1.7 mmol). 30 min after the last addition, the mixture was
cooled to 0 °C and poured onto ice-water. The aqueous was made basic with
satd. NaHCO3 (aq) and extracted with ethyl acetate (20 mL ꢀ 3). The organic
layer was dried over sodium sulphate, filtered and the solvent removed in
vacuo. Purification by ion-exchange chromatography [SCX-2, ammonia–
Supplementary data (experimental details and characterization
of novel compounds) associated with this article can be found, in
References and notes
methanol, 2 M] afforded the corresponding product (2a) as
a clear oil
(81 mg, 0.31 mmol, 83%).
m
max/cmꢁ1 2923, 1630, 1603, 1578, 1472 and 1461;
1H NMR (500 MHz, CD3OD) d = 8.05 (s, 1H), 7.65 (dd, J = 8.0 Hz, 1H), 7.22 (dd,
J = 8.0, 1.0 Hz, 1H), 6.98 (dd, J = 8.0, 1.0 Hz, 1H), 4.21 (dd, J = 9.0, 3.5 Hz, 1H),
3.86 (t, J = 9.0 Hz, 1H), 3.20–3.06 (m, 2H), 2.76 (td, J = 12.0, 2.9 Hz, 1H), 1.93–
1.81 (m, 1H), 1.81–1.63 (m, 2H), 1.50 (dddd, J = 25.1, 12.6, 8.0, 3.7 Hz, 2H), 1.35
(tdd, J = 12.6, 11.1, 3.8 Hz, 1H); 13C NMR (126 MHz, CD3OD) d = 163.7, 159.1,
151.3, 148.5, 134.1, 118.4, 112.6, 109.2, 72.9, 55.3, 45.4, 27.2, 25.0, 23.6; LC–MS
(TOF, 2.0 min) Rt = 0.16 min; m/z (ESI) 260 (M+H); Hi-Res LC–MS (ESI) m/z
calcd for C14H18N3O2 (M+H) 260.1399, found 260.0805. A round-bottom flask
was charged with 5-(2-piperidylmethoxy)-3H-quinazolin-4-one (2a) (80 mg,
0.31 mmol,
1.0 equiv)
and
(benzotriazol-1-yloxy)tris(dimethylamino)
phosphonium hexafluorophosphate (BOP) (1.3 equiv) before the addition of
anhydrous acetonitrile (2.5 ml). DBU (2.5 equiv) was added dropwise whilst
stirring at 0 °C. The reaction mixture was stirred at 0 °C for a further 5 min and
then at rt for 19 h. The reaction mixture was evaporated and the residue
purified by flash column chromatography [SiO2, EtOAc:Petrol, 50–80%] to
afford the title compound 3a as a yellow oil (53 mg, 0.22 mmol, 71%). mmax
/
cmꢁ1 2923, 1630, 1603, 1578, 1472 and 1461; 1H NMR (500 MHz, CD3OD)
d = 8.40 (s, 1H), 7.62 (dd, J = 8.0 Hz, 1H), 7.37 (dd, J = 8.3, 1.3 Hz, 1H), 7.04 (dd,
J = 7.9, 1.3 Hz, 1H), 5.28–5.20 (m, 1H), 4.41 (dd, J = 13.2, 2.8 Hz, 1H), 4.30 (dd,
J = 13.3, 5.5 Hz, 1H), 3.90 (ddt, J = 10.7, 5.1, 2.5 Hz, 1H), 3.01 (td, J = 12.9, 2.4 Hz,
1H), 2.00 (dtd, J = 10.1, 4.1, 2.3 Hz, 1H), 1.91–1.55 (m, 5H); 13C NMR (126 MHz,
CD3OD) d = 159.9, 158.9, 157.6, 153.9, 132.6, 120.3, 114.6, 109.8, 73.3, 63.5,
49.2, 29.2, 25.2, 24.2; LC–MS (TOF, 4.0 min) Rt = 1.59 min; m/z (ESI) 242 (M+H);
Hi-Res LC–MS (ESI) m/z calcd for C14H16N3O (M+H) 244.1345, found 244.1346.
19. Bradbury, R. H.; Kettle, J. G.; Scott, J. S.; Barlaam, B. C. PCT Patent, WO 2005/
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44. MCF7 cell line GI50 > 10 lM