C. G. Saluste et al. / Tetrahedron Letters 42 (2001) 6191–6194
6193
5 mol% PdCl2
10 mol% dppf
dioxane, 98oC
128.76 (CH), 128.15 (CH), 67.33 (CH2), 58.71 (CH),
46.87 (CH2), 35.76 (CH2), 26.15 (CH2), 25.23 (CH2);
MS (electrospray): m/z 273.1 ((M+H)+, 100%); IR
(neat): w 2955 (m), 2930 (m), 2879 (m), 1608 (s), 1586
(m), 1407 (m), 1337 (m), 719 (m). Elemental analysis
(%) calcd for C17H24N2O: C, 74.96; H, 8.88; N, 10.28.
Found: C, 74.89; H, 8.96; N, 10.11%.
ArBr + PhONa + R1NC
(3)
NR1
OPh
NR1
NHR2R3, AcOH
Ar
Ar
NR2R3
7a-e
dioxane,
98 oC.
Acknowledgements
Table 2. Synthesis of amidines via imidates
ArX
Amine R2, R3
R1NC
7
Yield of 7 (%)a
We thank AstraZeneca Charnwood for funding this
work.
C6H5Br
p-MeCOC6H4Br Ph, H
C6H5Br
C6H5Br
3-Bromopyridine -(CH2)4-
C6H5Br PhCH2, H
-(CH2)4-
CyNC
CyNC
a
b
c
d
e
f
60
84b
56
64
83
49
-(CH2)2O(CH2)2- BuNC
-(CH2)2O(CH2)2- CyNC
References
CyNC
BuNC
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a Isolated yield. Conditions: 1.0 equiv. aryl bromide, 1.5 equiv.
R2NC, 5 mol% PdCl2, 10 mol% dppf, 5.0 equiv. NaOPh, dioxane,
98°C, 4 h. Addition of 5.0 equiv. amine and 3.0 equiv. of AcOH.
Heating at 98°C for 2 h.
b Aniline required heating for 74 h in the amidine formation step.
Experimental
Compound 7d: To a 50 mL Schlenk flask with a reflux
condenser under argon at room temperature was added
dppf (0.12 g, 0.22 mmol), sodium phenoxide (6 mL of a
1.7 M soln. in THF, 10 mmol), bromobenzene (0.324 g,
2.1 mmol) in dioxane (2 mL), and cyclohexyl isocyanide
(380 mL, 3.0 mmol). Palladium(II) chloride (19.1 mg,
0.11 mmol) was then added against a counterflow of
argon; then dry and deoxygenated dioxane (13 mL) was
used to wash all solids from the sides of the flask. The
flask was then heated at 98°C (oil bath temp, the
internal temp was 92°C) for 3 h, when GC indicated
complete loss of bromobenzene. The reaction mixture
was allowed to cool to room temperature before mor-
pholine (0.88 g, 10 mmol) and glacial acetic acid (0.24
g, 4.0 mmol) in dioxane (2×1 mL) were added. After
heating for 8 h at 98°C, GC indicated complete loss of
the intermediate imidate. After cooling to room temper-
ature diethyl ether (20 mL) was added and the resulting
slurry extracted with aqueous hydrochloric acid (6×10
mL, 0.2 M). The combined aqueous layers were washed
with ether (6×15 mL) then made strongly basic by
addition of KOH pellets. The aqueous layer was then
extracted with diethyl ether (6×30 mL), the ethereal
layer dried over MgSO4 filtered and evaporated to give
brown–greyish crystals which were Kugelrohr distilled
(oven temp. 120–130°C/1 mmHg) to give white crystals
of the amidine 7d (0.348 g, 64%); mp 74–76°C; 1H
NMR (400 MHz, CDCl3): l 7.35–7.42 (3H, m), 7.149
(2H, dd, J=7.8, 2 Hz), 3.640 (4H, t, J=4.8 Hz), 3.148
(4H, t, J=4.8 Hz), 2.752 (1H, tt, J=10.2, 4.1 Hz),
1.646 (2H, d pentet, J=13, 3.7 Hz), 1.46–1.50 (3H, m),
1.343 (2H, qd, J=11.7, 3.3 Hz), 1.147 (1H, qt, J=12.0,
3.5 Hz), 1.038 (2H, qt, J=12.2, 3.4 Hz); 13C NMR (100
MHz, CDCl3): l 160.41 (C), 135.07 (C), 128.91 (CH),
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