Microwave-assisted amination of 3-bromo-2-chloropyridine with various substituted aminoethanols

Article abstract of DOI:10.1016/j.tetlet.2010.05.021

A simple method for microwave-assisted amination of 3-bromo-2-chloropyridine with various substituted aminoethanols is described. The reaction was carried out under microwave irradiation conditions (at 180 °C for 1-2 h) and the result was superior in terms of conversion and yield when compared to that of the corresponding conventional heating conditions.

Full text of DOI:10.1016/j.tetlet.2010.05.021

Tetrahedron Letters 51 (2010) 3886–3889
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Tetrahedron Letters
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Microwave-assisted amination of 3-bromo-2-chloropyridine with various
substituted aminoethanols
Jeong Geun Kim a, Eun Hae Yang b, Woo Sup Youn b, Ji Won Choi b, Deok-Chan Ha a, Jae Du Ha b,
*
a Department of Chemistry, Korea University, Sungbuk-gu, Seoul 136-701, Republic of Korea
b Bio-Organic Science Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 26 March 2010
Revised 6 May 2010
Accepted 10 May 2010
Available online 13 May 2010
A simple method for microwave-assisted amination of 3-bromo-2-chloropyridine with various substi-
tuted aminoethanols is described. The reaction was carried out under microwave irradiation conditions
(at 180 °C for 1–2 h) and the result was superior in terms of conversion and yield when compared to that
of the corresponding conventional heating conditions.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Microwave-assisted amination
3-Bromo-2-chloropyridine
Aminoethanol
Pyrido[1,4]oxazine
3,4-Dihydro-2H-pyrido[3,2-b]-1,4-oxazines 1 have shown po-
tential innumerous drug discovery applications. Members of this
class have been appeared in antiviral agents,1 antibacterial agents,2
and anticancer agents.3 Despite the biological importance of 3,4-
dihydro-2H-pyrido[3,2-b]-1,4-oxazines, synthetic methods for the
preparation of analogs containing different substituents at C-2
and C-3 are limited.4
Our interest in the search for new tyrosine kinase inhibitors has
been focusing on the synthesis of 3,4-dihydro-2H-pyrido[3,2-b]-
1,4-oxazines in which these scaffolds might be able to bind to
hinge domains of various tyrosine kinase proteins.5 In Scheme 1,
we envisioned that the oxazine ring could be constructed from
2-aminoalcohol-substituted 3-bromopyridines via a Pd-catalyzed
C–O bond formation. In order to prepare 2-amino-3-bromopyri-
dines containing hydroxy moiety 2, 3-bromo-2-chloropyridine
was coupled with various aminoalcohols by heating in the
presence of a base. Although these conventional methods have
proven to be useful protocols, they are of limited use for producing
compounds 2 with various substituents because of the require-
ment of high temperature (ꢀ150 °C) and long reaction time
(>24 h).6
Although a promising substitution reaction of 2-chloropyridines
with amines in the presence of transition metal catalysts such as
Pd,7 Ni,8 and Co9 has been reported, the adaption of these
approaches to our system has been met with limited success result-
ing in the generation of a mixture of regioisomers10 due to the pres-
ence of two halides in the starting material 3. Thus, the convenient
methodology to overcome this problem is required. In this Letter,
we described our microwave-assisted amination reacting 3-bro-
mo-2-chloropyridine with several amine nucleophiles to provide
2-amino-3-bromopyridines in good yields. Whereas several syn-
theses of 2-aminopyridines via microwave-assisted amination have
been described in the literature, these reports had an amine
substrate scope that was limited to cyclic secondary amines (pyr-
rolidines and piperidines)11 and no synthetic study for various
amine bearing hydroxy moiety has been reported.
Br OH
R3
R3
R2
HO
HN
R3
R2
Br
Cl
O
+
N
N
R2
N
N
N
R1
R1
R1
1
2
4
3
Scheme 1. Synthetic approach to 3,4-dihydro-2H-pyrido[3,2-b]-1,4-oxazines.
* Corresponding author. Tel.: +82 042 860 7072; fax: +82 042 860 7160.
E-mail address: jdha@krict.re.kr (J.D. Ha).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.05.021

J. G. Kim et al. / Tetrahedron Letters 51 (2010) 3886–3889
3887
Table 1
Optimization of amination reaction
OH
Br OH
Br
Cl
H2N
conditions
N
N
H
N
3
2
Entry
1
Equiv of amine (equiv)
2
Conditions
Temp/time
Yield (%)
Sealed tube
180 °C/24 h
65
82
45
66
87
92
i-Pr2EtN(3 equiv)/DMSO
Microwave irradiation
i-Pr2EtN(3 equiv)/DMSO
Microwave irradiation
Pyridine
Microwave irradiation
Pyridine
Microwave irradiation
Pyridine
2
3
4
5
6
2
180 °C/1 h
180 °C/3 h
180 °C/2 h
180 °C/1 h
180 °C/0.5 h
1
1.5
2
4
Microwave irradiation
Pyridine
Table 2
13Microwave-assisted amination of 3-bromo-2-chloropyridine with various aminoalcohols
R2
R1
OH
N
Br OH
R3
H
Br
Cl
R3
Microwave irradation
Pyridine, 180 oC
N
N
R1
R2
N
2
3
Entry
1
Amine (2 equiv)
Time (h)
1
Product
Yielda (%)
87
OH
Br
H2N
OH
N
N
H
2a
Br
H2N
H2N
OH
2
3
1
2
91
80
N
N
N
H
OH 2b
OH
OH
Br
OH
N
H
2c15
Br
H2N
OH
N
N
H
4
2
79
2d
Br
OH
OH
H2N
5
6
7
1.5
1.5
2
84
80
N
N
N
H
2e15
Br OH
N
H
OH
OH
H2N
HN
2f
Br
68
OH
N
N
2g
(continued on next page)

3888
J. G. Kim et al. / Tetrahedron Letters 51 (2010) 3886–3889
Table 2 (continued)
Entry
Amine (2 equiv)
Time (h)
1
Product
Yielda (%)
80
Br
N
OH
OH
N
H
8
9
N
2h
OH
HN
Br
N
OH
N
N
2
1
43
81
2i
OH
Br
H2N
OH
OH
10
OH
N
H
15
2j
OH
Br
OH
11
12
1.5
2
76
OH
OH
N
N
H
H2N
2k
HO
Br
10b
H2N
N
N
H
OH
2l
a
Isolated yield.
b
3-Bromo-2-chloropyridine decomposed during prolonged reaction times.
The initial experiment was performed with 2-aminoethanol by
using i-Pr2EtN/DMSO at 180 °C for 24 h in sealed tube (Table 1, en-
try 1). The desired amination product 4 was isolated in moderate
yield (65%). When the reaction was conducted under microwave
irradiation conditions (at 180 °C for 1 h), the result was superior
in terms of conversion and yield when compared to that of the cor-
responding reactions in sealed tube by conventional heating condi-
tions, in which unreacted starting material remained even after
prolonged reaction time. A variety of solvents (pyridine, THF,
DME, and DMSO) and bases (i-Pr2EtN, DBU, and pyridine) were
investigated in great detail, and we found that the use of pyridine
was optimal in many cases, although the reactions also proceeded
well using a combination of i-Pr2EtN (3 equiv) and DMSO (entry
2). Nevertheless amination under microwave irradiation conditions
proved successful, completion of the reaction required the use of a
large excess of aminoethanol (entry 6). Due to the expense of the
chiral aminoethanol derivatives used, a ratio of 1:2 2-chloropyri-
dine/aminoethanols was found to be optimal to provide the amina-
tion product in high yield at relatively short reaction time (entry 5).
The reaction between 3-bromo-2-chloropyridine and several
aminoalcohols is shown in Table 2. The reaction with unsubstitut-
ed aminoalcohols (2-aminoethanol and 3-amino-1-propanol) gave
good yields of the amination products (entries 1 and 2). Substi-
tuted aminoethanols (entries 3–6) with either R1 or R2 (methyl
and phenyl groups) gave a slightly lower yield and also required
longer reaction time (1.5–2 h) compared to the corresponding
unsubstituted aminoethanol. The yield was 80% in the case of a
cyclic secondary amine (pyrrolidine-2-ylmethanol; entry 8),
whereas the corresponding noncyclic secondary amines (entries
7 and 9) gave a slightly lower yield (65% and 48%), suggesting that
the reactivity of cyclic amine is higher than that of noncyclic
amines. Aminoethanols bearing additional hydroxy moiety (entries
10 and 11) also gave high yields (81% and 76%) without decreasing
the reactivity of amine. Finally, amination of 2-aminocyclohexanol
(entry 12) was very sluggish and gave only 10% desired product,
Br OH
O
5 mol% Pd(OAc)2
Ligand, Cs2CO3, PhCH3
N
N
N
N
H
H
2e
1
Scheme 2.
presumably due to strong hydrogen bonding between hydroxy
and amino groups to decrease the reactivity of amine. Both pro-
longed reaction time (>2 h) and increased reaction temperature
(210 °C) resulted in the slow decomposition of the starting
material.
With the (S)-2-(3-bromopyridin-2-ylamino)propan-1-ol (2e) in
hands, our attention was turned to a Pd-catalyzed C–O bond forma-
tion of 2e to provide the desired (S)-3-methyl-3,4-dihydro-2H-
pyrido[3,2-b][1,4]oxazine (Scheme 2). By following Buchwald’s
conditions [5 mol % of Pd(OAc)2, 8 mol % of 2-(di-t-butylphosphi-
no)biphenyl, Cs2CO3, PhMe, 80 °C],12,14 cyclization of 2e cleanly
20
afforded the pyrido[1,4]oxazine derivative 1 in 74% yield {½RꢁD
=
0.42 (c 0.86, CHCl3)}. Although enantioselective syntheses of chiral
pyrido[1,4]oxazine bearing C-3 substituents have been repor-
ted4b,4d, to the best of our knowledge, there is no report for the
synthesis of (S)-3-methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxa-
zine (1).
In conclusion, we have reported an efficient synthesis of 2-ami-
noalcohol-substituted pyridine derivatives via microwave-assisted
amination of 3-bromo-2-pyridine. This methodology could provide
a key intermediate for the synthesis of substituted pyrido[1,4]oxa-
zine derivatives.
Acknowledgment
We are grateful to the Korea Research Institute of Chemical
Technology (KRICT) for financial support.

J. G. Kim et al. / Tetrahedron Letters 51 (2010) 3886–3889
3889
carried out at 180 °C for 1 h. Saturated NaHCO3 aq. and CH2Cl2 were added to
the reaction mixture and the two phases were separated. The aqueous layer
was extracted with CH2Cl2. The combined organic phases were dried over
Na2SO4 and concentrated under reduced pressure and purified by flash
chromatography (1:3 EtOAc/hexane) to give 2a (98 mg, 87%) as a colorless
oil : 1H NMR (300 MHz, CDCl3) d 7.99 (dd, 1H, J = 1.3 and 4.9 Hz), 7.63 (dd, 1H,
J = 1.4 and 7.6 Hz), 6.48 (dd, 1H, J = 4.9 and 7.6 Hz), 5.46 (br s, 1H), 4.47 (s, 1H),
3.83 (t, 2H, J = 4.6 Hz), 3.46 (t, 2H, J = 4.6 Hz); 13C NMR (300 MHz, CDCl3) d
155.3, 146.1, 140.5, 114.1, 105.7, 68.9, 50.3; MS-ESI 218 (M+, 15), 216 (16), 198
(3), 185 (100), 172 (26), 158 (22), 79 (28).
References and notes
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14. (S)-3-Methyl-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (1). A sealed tube was
charged
with
Pd(OAc)2
(5.2 mg,
0.023 mmol,
5 mol %),
2-(di-t-
butylphosphino)biphenyl (11 mg, 0.036 mmol, 8 mol %), and Cs2CO3 (225 mg,
0.68 mmol). The sealed tube was evacuated and back-filled with nitrogen and
fitted with a rubber septum. (S)-1-(3-bromopyridin-2-ylamino)propan-2-ol
(2e) (105 mg, 0.45 mmol) and toluene (1.5 mL) were added via a syringe. The
sealed tube was then sealed under nitrogen and placed in a preheated oil bath
at 100 °C until the aryl halide had been consumed as judged by TLC analysis.
The reaction mixture was cooled to room temperature, diluted with diethyl
ether (2 mL), and filtered through a pad of Celite. The resulting solution was
concentrated under reduced pressure and purified by flash chromatography on
silica gel (1:1 EtOAc/hexane) to give
1 (50.2 mg, 74%) as a brown oil.
20
½RꢁD = 0.42 (c 0.86, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.66 (dd, 1H, J = 2.3,
8.2 Hz), 6.96 (dd, 1H, J = 2.2, 12.9 Hz), 6.55 (dd, 1H, J = 8.2, 12.9 Hz), 4.96 (br s,
1H), 4.16 (dd, 1H, J = 2.4, 13.0 Hz), 3.63–3.77 (m, 2H), 1.22 (d, 3H, J = 10.2 Hz);
13C NMR (300 MHz, CDCl3) d 147.5, 140.2, 139.2, 121.8, 114.2, 70.4, 45.4, 17.8;
6. Birman, V. B.; Li, X.; Jiang, H.; Uffman, E. W. Tetrahedron 2006, 62, 285–
294.
7. (a) Stauffer, S. P.; Stambuli, L. J. P.; Hauck, S. I.; Hartwig, J. F. Org. Lett. 2000, 2,
1423–1426; (b) Tewari, A.; Hein, M.; Zapf, A.; Beller, M. Tetrahedron 2005, 61,
9705–9709; (c) Viciu, M. S.; Kelly, R. A., III; Stevens, E. D.; Naud, F.; Studer, M.;
Nolan, S. P. Org. Lett. 2003, 5, 1479–1482; (d) Marion, N.; Ecarnot, E. C.; Navarro,
O.; Amoroso, D.; Bell, A.; Nolan, S. P. J. Org. Chem. 2006, 71, 3816–3821.
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Manolikakes, G.; Gavryushin, A.; Knochel, P. J. Org. Chem. 2008, 73, 1429–1434.
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10. For representative examples, see: Schoen, U.; Messinger, J.; Buckendahl, M.;
Prabhu, M. S.; Konda, A. Tetrahedron Lett. 2007, 48, 2519–2525.
MS-ESI 150 (M+, 100), 135 (94), 121 (47), 94 (26), 71 (19), 57 (50).
20
15. Representative spectroscopic data. Compound 2c: ½RꢁD = ꢂ23.5 (c 0.7, CHCl3); 1
H
NMR (300 MHz, CDCl3) d 7.98 (dd, 1H, J = 1.1, 4.9 Hz), 7.62 (dd, 1H, J = 1.3,
7.6 Hz), 6.48 (dd, 1H, J = 4.9, 7.6 Hz), 5.42 (br s, 1H), 4.50 (s, 1H), 3.98–4.07 (m,
1H), 3.60 (dd, 1H, J = 4.2, 13.1 Hz), 3.40 (dd, 1H, J = 6.3, 13.1 Hz), 1.12 (d, 3H,
J = 6.0 Hz); 13C NMR (300 MHz, CDCl3) d 155.4, 146.4, 140.3, 114.1, 105.8, 68.7,
50.1, 21.2; MS-ESI 232 (M+, 9), 230 (9), 187 (100), 172 (16), 158 (30), 105 (14),
79 (22).
20
Compound 2e: ½RꢁD = ꢂ20.8 (c 1.3, CHCl3); 1H NMR (300 MHz, CDCl3) d 7.97
(dd, 1H, J = 1.4, 4.9 Hz), 7.62 (dd, 1H, J = 1.5, 7.6 Hz), 6.48 (dd, 1H, J = 4.9,
7.6 Hz), 5.04 (br s, 1H), 4.62 (s, 1H), 4.10–4.22 (m, 1H), 3.77 (dd, 1H, J = 2.7,
10.8 Hz), 3.61 (dd, 1H, J = 7.3, 10.8 Hz), 1.29 (d, 3H, J = 6.8 Hz); 13C NMR
(300 MHz, CDCl3) d 155.1, 146.3, 140.4, 114.2, 105.9, 69.2, 50.8, 18.0; MS-ESI
294 (M+, 1), 293 (1), 185 (100), 172 (2), 158 (20), 105 (16), 79 (24).
Compound 2j: 1H NMR (300 MHz, CDCl3) d 7.98 (dd, 1H, J = 1.1, 5.0 Hz), 7.65
(dd, 1H, J = 1.3, 7.6 Hz), 6.51 (dd, 1H, J = 5.0, 7.6 Hz), 5.39 (br s, 1H), 4.04 (br s,
1H), 3.83 (pentet, 1H, J = 4.8, 9.7 Hz), 3.73 (br s, 1H), 3.57–3.65 (m, 4H); 13C
NMR (300 MHz, CDCl3) d 155.4, 146.3, 140.5, 113.7, 105.8, 71.8, 63.4, 44.6; MS-
ESI 248 (M+, 10), 246 (10), 217 (25), 215 (27), 187 (100), 185 (98), 172 (22), 158
(18), 105 (9), 79 (15).
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12. For Pd-catalyzed intramolecular cyclization of 2-(2-bromophenyamino)ethanol
derivatives to benzoxazines, see: Kuwabe, S.-I.; Torraca, K. E.; Buchwald, S. T. J.
Am. Chem. Soc. 2001, 123, 12202–12206.
13. Typical experimental procedure: 2-(3-Bromopyridin-2-ylamino)ethanol (2a).
The
ethanolamine (63
placed in an Emrys Optimizer microwave apparatus (300 W). The reaction was
solution
of
3-bromo-2-chloropyridine
(100 mg,
0.52 mmol),
lL, 1.04 mmol) and pyridine (1 mL) in sealed vial was