344
I. A. S. Walters / Tetrahedron Letters 47 (2006) 341–344
(CDCl3, 300 MHz): d 7.81 (1H, s), 7.79 (1H, s), 4.47 (2H,
br s), 2.58 (2H, t, J = 7.5 Hz), 1.78–1.65 (2H, m), 0.97 (3H,
t, J = 7.4 Hz); 13C NMR (CDCl3, 300 MHz): 154.88,
153.75, 133.50, 129.47, 37.21, 22.56, 13.79; HRMS
calcd for C7H11N3: 138.1031 [M+H]+, found 138.1029
[M+H]+. 2-Amino-6-cyclopentylpyrazine 5: mp 122–
124 °C; 1H NMR (CDCl3, 300 MHz): d 7.82 (1H, s),
7.78 (1H, s), 4.45 (2H, br s), 3.07–2.96 (1H, m), 2.04–1.95
(2H, m), 1.84–1.64 (6H, m); 13C NMR (CDCl3, 300 MHz):
d 158.41, 153.78, 132.69, 129.33, 44.96, 33.00, 25.76;
HRMS calcd for C9H13N3: 164.1187 [M+H]+, found
164.1187 [M+H]+. 2-Amino-6-(2-phenylethyl)pyrazine 6:
mp 108–110 °C; 1H NMR (CDCl3, 300 MHz) 7.80 (2H, br
s), 7.31–7.16 (5H, m), 4.50 (2H, br s), 3.04–2.89 (4H, m);
13C NMR (CDCl3, 300 MHz): d 153.86, 141.20, 133.44,
129.76, 128.40, 128.38, 126.06, 36.95, 35.34; HRMS calcd
for C12H13N3: 200.1187 [M+H]+, found 200.1194
[M+H]+. 4-Amino-5-methyl-2-(2-phenylethyl)pyrimidine
4–7). The reaction also worked with an amino-heteroa-
ryl bromide (Table 2, entry 8), but afforded poor yields
with an iodide (Table 2, entry 9), and gave no product at
all with 3-chloro- or 3-iodoaniline or 4-chloro-2-amino-
thiazole. The reaction conditions are tolerant of several
useful functional groups in the alkyl halide coupling
partner (Table 2, entries 11–13).
In conclusion, a practical Ni-catalysed one-pot coupling
of amino-heteroaryl chlorides and alkylzinc reagents has
been demonstrated. The alkylzinc reagents can be com-
mercially available dialkylzincs or alkylzinc halides, or
can be conveniently generated in situ from diethylzinc
and primary alkyl bromides in the presence of the same
inexpensive Ni catalyst used to effect the subsequent
coupling reaction.
1
11: mp 126–128 °C; H NMR (CDCl3, 300 MHz): d 8.04
(1H, s), 7.30–7.16 (5H, m), 4.80 (2H, br s), 3.12–2.99 (4H,
m), 2.06 (3H, s); 13C NMR (CDCl3, 300 MHz) d: 168.07,
161.75, 155.22, 141.81, 128.41, 128.29, 125.80, 110.14,
40.78, 34.71, 13.39. Anal. Found: C, 73.00; H, 6.99; N,
19.90. Calcd for C13H15N3: C, 73.21; H, 7.09; N, 19.70. 2-
References and notes
1. (a) Sato, N. J. Heterocycl. Chem. 1980, 17, 143–147; (b)
Lutz, W. B.; Lazarus, S.; Klutchko, S.; Meltzer, R. I. J.
Org. Chem. 1964, 29, 415–418; (c) Weijlard, J.; Tishler, M.;
Erickson, A. E. J. Am. Chem. Soc. 1945, 67, 802–806.
2. For a review, see: Negishi, E. In Metal-Catalysed Cross-
Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: New York, 1998, Chapter 1.
1
Amino-4-(2-phenylethyl)quinoline 12: mp 156–159 °C; H
NMR (CDCl3, 300 MHz): d 7.88 (1H, d, J = 8.2 Hz), 7.70
(1H, d, J = 8.5 Hz), 7.57 (1H, t, J = 8.2 Hz), 7.34–7.21
(6H, m), 6.52 (1H, s), 4.74 (2H, br s), 3.28–3.24 (2H, m),
3.06–3.02 (2H, m); 13C NMR (CDCl3, 300 MHz): d
156.74, 149.00, 148.09, 141.13, 129.41, 128.50, 128.35,
126.80, 126.25, 123.18, 122.96, 122.55, 110.91, 35.83,
34.07. Anal. Found: C, 82.06; H, 6.49; N, 11.33. Calcd
for C17H16N2: C, 82.23; H, 6.49; N, 11.28. 3-[(6-amino-
3-pyridazinyl)methyl]-benzoic acid methyl ester 16: mp
3. Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem.
1977, 42, 1821–1823.
4. (a) Rosowsky, A.; Chen, H. J. Org. Chem. 2001, 66, 7522–
7526; (b) Jackson, R. F. W.; Moore, R. J.; Dexter, C. S. J.
Org. Chem. 1998, 63, 7875–7884; (c) Jensen, J.; Skjærbæk,
N.; Vedsø, P. Synthesis 2001, 128–134; (d) Campbell, J. B.;
Firor, J. W.; Davenport, T. W. Synth. Commun. 1989, 19,
2265–2272; (e) Russell, C. E.; Hegedus, L. S. J. Am. Chem.
Soc. 1983, 105, 943–949.
1
214–216 °C; H NMR(CDCl3, 300 MHz): d 7.94 (1H, s),
7.91 (1H, d, J = 7.6 Hz), 7.46 (1H, d, J = 7.6 Hz), 7.37
(1H, t, J = 7.6 Hz), 7.02 (1H, d, J = 9.1 Hz), 6.67 (1H, d,
J = 9.1 Hz), 4.67 (2H, br s), 4.24 (2H, s), 3.90 (3H, s); 13C
NMR (CDCl3, 300 MHz): d 166.16, 159.44, 152.35,
140.65, 133.66, 129.77, 129.23, 128.91, 127.90, 127.06,
114.53, 52.09, 40.39. Anal. Found: C, 64.00; H, 5.47; N,
17.00. Calcd for C13H13N3O2: C, 64.19; H, 5.39; N, 17.27.
9. Vettel, S.; Vaupel, A.; Knochel, P. J. Org. Chem. 1996, 61,
7473–7481.
5. (a) Miller, J. A.; Farrell, R. P. Tetrahedron Lett. 1998, 39,
6441–6444; (b) Janiak, C.; Deblon, S.; Wu, H.-P. Synth.
Commun. 1999, 29, 3341–3352; (c) Adonin, N. Y.; Rya-
binin, V. A.; Starichenko, V. F. Russ. J. Org. Chem. 1999,
ˇ
35, 913–915; (d) Cesnek, M.; Hocek, M.; Holy´, A. Collect.
Czech. Chem. Commun. 2000, 65, 1357–1373.
6. Sato, N.; Matsuura, T. J. Chem. Soc., Perkin Trans. 1
1996, 2345–2350.
10. General procedure: Diethylzinc (5 mmol of a 1.1 M
solution in toluene) was added to a solution of [1,3-
bis(diphenylphosphino)propane]nickel(II) chloride (0.2
mmol) in dry dioxane (5 mL) under an atmosphere of
nitrogen. The reaction mixture was stirred at room
temperature for 10 min before addition of the alkyl halide
(6 mmol). Stirring was continued at 65 °C for 4 h, then the
amino-heteroaryl halide (1 mmol) was added as a solid (or
solution in 2 mL dioxane if soluble) and the reaction
mixture heated at reflux for 2 h. The reaction was
quenched with methanol and concentrated in vacuo. The
residue was diluted with methanol (3 mL) and concen-
trated hydrochloric acid (3 mL) was added. The mixture
was then basified with concentrated ammonia and parti-
tioned between ethyl acetate and brine. The organic phase
was dried over magnesium sulfate, filtered and evaporated.
The crude product was purified by silica gel chromatog-
raphy, eluting with dichloromethane/methanol, to afford
the alkyl aminoheterocycles in >95% purity.
7. General procedure: A 1 M THF or toluene solution of the
organozinc reagent (2 mmol if diorganozinc or 4 mmol if
alkylzinc halide) was added to a solution of 6-chloro-2-
aminopyrazine (1 mmol) and [1,3-bis(diphenylphosph-
ino)propane]nickel(II) chloride (0.1 mmol) in dry dioxane
(5 mL) under an atmosphere of nitrogen. The reaction
mixture was heated at reflux for the length of time
indicated in Table 1. The reaction was quenched with
methanol and concentrated in vacuo. The residue was
partitioned between ethyl acetate and brine, and the
organic phase dried over magnesium sulfate, filtered and
evaporated. The crude product was purified by silica gel
chromatography, eluting with dichloromethane/methanol,
to afford the alkyl-aminopyrazines in >95% purity.
8. All compounds described herein have been fully charac-
1
terised by H and 13C NMR spectroscopy, mp, MS, and
elemental analysis or accurate mass MS. For example:
2-Amino-6-propylpyrazine 4: mp 116–118 °C; 1H NMR