Copper-catalyzed coupling of (S)-1-(3-bromophenyl)-ethylamine and N-H containing heteroarenes using microwave heating

Article abstract of DOI:10.1016/S0040-4039(03)00898-0

The Ullmann coupling of (S)-[1-(3-bromophenyl)-ethyl]-ethylamine (1) with a variety of N-H heteroarenes using microwave heating is described.

Full text of DOI:10.1016/S0040-4039(03)00898-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4217–4218
Copper-catalyzed coupling of (S)-1-(3-bromophenyl)-ethylamine
and N–H containing heteroarenes using microwave heating
Yong-Jin Wu,a,* Huan Hea and Alexandre L’Heureuxb
aDepartment of Neuroscience Chemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway,
Wallingford, CT 06492, USA
bDepartment of Medicinal Chemistry Research, Bristol-Myers Squibb Pharmaceutical Research Institute, 100 de l’Industrie Blvd.,
Candiac, Quebec, Canada J5R 1J1
Received 11 March 2003; revised 28 March 2003; accepted 4 April 2003
Abstract—The Ullmann coupling of (S)-[1-(3-bromophenyl)-ethyl]-ethylamine (1) with a variety of N–H heteroarenes using
microwave heating is described. © 2003 Elsevier Science Ltd. All rights reserved.
During the course of a medicinal chemistry program,
we wanted to convert (S)-1-(3-bromophenyl)-ethyl-
amine (1) to the N-arylimidazole 2a through a copper-
mediated Ullmann coupling reaction1 with imidazole
(Table 1). The Ullmann type N-arylation of 6-nitro-
indazole with 2-bromobenzoic acid was previously
reported, and the optimized conditions utilized cop-
per(I) iodide (10 mol%) and potassium carbonate (1.1
equiv.) in DMF at 100°C.2 Recently, Buchwald et al.
demonstrated that the N-arylation of imidazoles can be
accomplished using (CuOTf)2·benzene as a copper
source and Cs2CO3 as a base in the presence of 1,10-
phenanthroline (phen) and trans,trans-dibenzylidene-
acetone (dba) as additives in xylenes at 110–125°C.3
This methodology has been extended to coupling reac-
tions with other N–H containing heteroarenes using
racemic trans-1,2-cyclohexanediamine as a ligand and
copper(I) iodide as the copper source, thus obviating
the need of air-sensitive copper(I) triflate.4 In our case,
very little product was formed when a mixture of
bromide 1, imidazole (2 equiv.), copper(I) iodide (10
mol%) and potassium carbonate (1.1 equiv.) in DMF in
a sealed tube was heated at temperatures ]100°C.
(1 mol%), potassium phosphate (2.1 equiv.) and
racemic trans-1,2-cyclohexanediamine (10 mol%) in
dioxane at 110°C for 22 h. After some experimentation,
we found that microwave heating can be used to facili-
tate the Ullmann type N-arylation of imidazoles.
Table 1. Copper-catalyzed N-arylation of N–H heteroare-
nes with 1
Compd
Time (h)
Yielda (%)
2a
2b
2c
2d
2e
2f
2g
2h
2i
Imidazole
2
3
2
2
76
68
88
91
2-Methyl-imidazole
Benzoimidazole
Pyrazole
4-Methylpyrazole
3-Methylpyrazole
3,5-Dimethylpyrazole
Indazole
Treatment of
1
with imidazole (1.5 equiv.),
1
90
17
22
2
1
3
65b,c
49b
72
(CuOTf)2·benzene (5 mol%) and Cs2CO3 (1.1 equiv.) in
the presence of phen (1 equiv.) and dba (5 mol%) in
xylenes at 110°C furnished 2a in 20% yield. Surpris-
ingly, compound 2a was not formed at all when the
coupling reaction was carried out with copper(I) iodide
1,2,4-Triazole
Pyrrole
96
66
2j
2k
Indole
3
76
a Isolated yields (not optimized, one run only).
b 2 additional equiv. of heteroarene was added after 1 h.
c 1:1 mixture of regioisomers.
* Corresponding author. Tel.: +1-203-677-7485; fax: +1-203-677-7702;
e-mail: yong-jin.wu@bms.com
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00898-0

4218
Y.-J. Wu et al. / Tetrahedron Letters 44 (2003) 4217–4218
N-arylation reactions with other aryl bromides and
Microwave irradiation has become increasingly popular
in recent years to improve the yield and shorten reaction
times in a variety of reactions.5 However, to our knowl-
edge, the microwave-mediated methodology on the Ull-
mann type N-arylation of N–H containing heteroarenes
with aryl halides has not yet been reported.6,7 This report
describes our preliminary studies on (S)-1-(3-bromo-
phenyl)-ethylamine (1) under microwave conditions.8
iodides.
References
1. (a) Ullmann, F. Ber. Dtsch. Chem. Ges. 1903, 36, 2382–
2384. For a review, see: (b) Lindley, J. Tetrahedron 1984,
40, 1433–1456.
2. Sugaya, T.; Mimura, Y.; Kato, N.; Ikuta, M.; Mimura,
M.; Kasai, M.; Tomioka, S. Synthesis 1994, 73–76.
3. Kiyomori, A.; Marcoux, J.; Buchwald, S. L. Tetrahedron
Lett. 1999, 40, 2657–2660.
4. (a) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L.
J. Am. Chem. Soc. 2001, 123, 7727–7729; (b) Antilla, J. C.;
Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
11684–11688.
5. For recent reviews on microwave-assisted reactions, see:
(a) Perreux, L.; Loupy, A. Tetrahedron 2001, 57, 9199–
9223; (b) Lidstro¨m, P.; Tierney, J.; Wathey, B.; Westman,
J. Tetrahedron 2001, 57, 9225–9283; (c) Larhed, M.; Hall-
berg, A. Drug Disc. Today 2001, 6, 406–416; (d) Wathey,
B.; Tierney, J.; Lidstrom, P.; Westman, J. Drug Disc.
Today 2002, 7, 373–380.
6. For a copper(II)-mediated N-arylation of N–H containing
heteroarenes with arylboronic acids under microwave irra-
diation, see: Combs, A. P.; Saubern, S.; Rafalski, M.;
Lam, P. Y. S. Tetrahedron Lett. 1999, 40, 1623–1626.
7. For a microwave-assisted Goldberg reaction, see: Lange, J.
H. M.; Hofmeyer, L. J. F.; Hout, F. A. S.; Osnabrug, S. J.
M.; Verveer, P. C.; Kruse, C. G.; Feenstra, R. W. Tetra-
hedron Lett. 2002, 43, 1101–1104.
Treatment of aryl bromide 1 with 2 equiv. imidazole in
the presence of copper(I) iodide (10 mol%) and potas-
sium carbonate (2 equiv.) in N-methylpyrrolidinone
(NMP) at 195°C for 2 h under microwave irradiation
provided N-arylimidazole 2a in 75% yield after purifica-
tion of the crude product using silica gel flash chromato-
graphy. As a control experiment, the same reaction
mixture was heated at 195°C for 2 h in a sealed tube using
an oil bath, and 2a was obtained in 61% yield. This
observation demonstrates the advantage of microwave
radiation over conventional heating techniques. In
another control experiment, 1 was treated with 2 equiv.
imidazole and potassium carbonate (2 equiv.) in NMP
at 195°C for 2 h under microwave irradiation, and no
product was formed. This result shows the requirement
of copper(I) iodide as a catalyst in the formation of 2a.
Of special note is that no epimerization occurred under
these basic conditions. As shown in Table 1, these
conditions worked well not only for imidazoles but also
for pyrazoles, pyrrole, indole and 1,2,4-triazole. The
N-arylation reactions of both 3-methylpyrazole and
3,5-dimethylpyrazole were sluggish presumably due to
steric effects, and these reactions were still incomplete
even with long reaction times and an additional 2 equiv.
of these heteroarenes. In the case of 3-methylpyrazole, a
1:1 mixture of the regioisomers were obtained. A salient
feature of this chemistry is that the free amine function-
ality is well tolerated. It should be noted that the full
cleavage of the N-BOC group and partial cleavage of the
N-CBZ group occurred under these conditions. For
example, when the N-BOC derivative of 1 was exposed
to imidazole under the above conditions, amine 2a was
formed exclusively. The scope of this microwave-medi-
ated N-arylation reactions were briefly investigated.
Thus, treatment of benzoimidazole with bromo- and
iodo-benzene in the presence of copper(I) iodide (10
mol%) and potassium carbonate (2 equiv.) under the
above microwave conditions afforded N-phenyl-benzo-
imidazole in 60%, 87% yields, respectively. In the case of
chlorobenzene, very little product was formed even after
20 h microwave heating.
8. The microwave unit used in our experiments is the Smith
Creator® from Personal Chemistry. It continuously adjusts
the applied wattage to maintain the desired temperature.
Reactions were conducted in the Personal Chemistry pro-
prietary 5 mL sealed vials.
9. Representative procedure: To a solution of (S)-1-(3-bromo-
phenyl)-ethylamine (1) (100 mg, 0.5 mmol) and indole (117
mg, 1 mmol) in N-methylpyrrolidinone (0.67 mL) in a
microwave vial were added potassium carbonate (138 mg,
1 mmol), and copper (I) iodide (9.5 mg, 0.05 mmol). The
vial was sealed and heated in a Smith Creator® at 195°C
for 3 h. The temperature of the contents of the vessel was
monitored using a calibrated infrared temperature control
mounted under the reaction vessel. The reaction mixture
was cooled to room temperature and filtered. The filtrate
was evaporated in vacuo, and the residue was purified by
silica gel flash chromatography (10% MeOH/89% EtOAc/
1% triethylamine) to give (S)-1-(3-indol-1-yl-phenyl)-ethy-
lamine (2k) (90 mg, 76% yield) as an oil. 1H NMR
(CD3OD, 400 MHz) l 1.42 (d, 3H, J=6.8 Hz), 4.12 (1H,
q, J=6.8 Hz), 4.83 (2H, s), 6.62 (1H, dd, J=0.4, 3.20 Hz),
7.08 (1H, t, J=8.0 Hz), 7.15 (1H, t, J=8.0 Hz), 7.38–7.42
(3H, m), 7.50–7.53 (3H, m), 7.58 (1H, d, J=7.6 Hz); 13C
NMR (CD3OD, 100 MHz) l 25.28, 52.17, 104.56, 111.43,
121.32, 122.05, 122.83, 123.36, 123.79, 125.18, 129.04,
130.94, 131.01, 137.27, 141.48, 150.12.
In summary, we have developed an operationally simple
and efficient method for the N-arylation of N–H contain-
ing heteroarenes with (S)-[1-(3-bromophenyl)-ethyl]-
ethylamine (1) using microwave heating.9 This
methodology appears to be general to the Ullmann type