A facile and efficient synthesis of 3-amino-5-bromopyridine derivatives using microwave irradiation

Article abstract of DOI:10.3987/COM-11-12139

A facile and general synthetic strategy was developed to synthesize 3-amino-5-bromopyridine derivatives under microwave heating conditions. The strategy involved reacting 3,5-dibromopyridine with an excess of an aliphatic amine using microwave heating, without the need to use either metal-mediated, base-promoted or harsh long thermal reaction times. The microwave approach enabled the rapid synthesis of 3-amino-5-bromopyridine derivatives in multi-gram quantities from commercially available starting materials.

Full text of DOI:10.3987/COM-11-12139

HETEROCYCLES, Vol. 83, No. 4, 2011
875
HETEROCYCLES, Vol. 83, No. 4, 2011, pp. 875 - 881. © The Japan Institute of Heterocyclic Chemistry
Received, 16th January, 2011, Accepted, 21st February, 2011, Published online, 8th March, 2011
DOI: 10.3987/COM-11-12139
A FACILE AND EFFICIENT SYNTHESIS OF
3-AMINO-5-BROMOPYRIDINE DERIVATIVES USING MICROWAVE
IRRADIATION
Reddeppa reddy Dandu,* Adam C. Rose, and Robert L. Hudkins
Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA
19380, USA. E-mail: rdandu@cephalon.com
Abstract – A facile and general synthetic strategy was developed to synthesize
3-amino-5-bromopyridine derivatives under microwave heating conditions. The
strategy involved reacting 3,5-dibromopyridine with an excess of an aliphatic
amine using microwave heating, without the need to use either metal-mediated,
base-promoted or harsh long thermal reaction times. The microwave approach
enabled the rapid synthesis of 3-amino-5-bromopyridine derivatives in multi-gram
quantities from commercially available starting materials.
Pyridine derivatives are highly useful and important building blocks in natural products and
pharmaceuticals, therefore the development of efficient methods are important for the synthesis of highly
functionalized intermediates.1 For a medicinal chemistry lead optimization program we required a
scalable approach to produce quantities of 3-amino-5-bromopyridine derivatives in high yield and purity.
A review of the literature showed a paucity of general methods to synthesize such intermediates. The
published methods to 3-dialkylamino-5-bromopyridines from 3,5-dibromopyridine and a secondary amine
used either metal-catalyzed, base-promoted, or long harsh thermal reaction times.2-5 In our work we found
that extended thermal heating led to the formation of mixtures and multiple impurities that made
purification difficult. In addition, in recent years a move to adopt “green chemistry” and minimize
hazardous waste production and materials led us away from improving on the palladium mediated
chemistry. Microwave heating conditions6 has attracted a great deal of attention because of its simplicity,
enhanced reaction times, and higher purity and yields compared to conventional thermal heating. In this
paper we report optimization of the microwave conditions to synthesize 3-amino-5-bromopyridine
derivatives starting from 3,5-dibromopyridine.

876
HETEROCYCLES, Vol. 83, No. 4, 2011
The synthesis of 5-bromo-3-diethylaminopyridine 35a,b was recently reported by two approaches starting
with 3-amino-5-bromopyridine, however yields were not reported. The first method using
3-amino-5-bromopyridine, iodoethane and potassium bis(trimethylsilyl)amide as base reportedly produced
a mixture of mono and bis-alkylated products. In the second method 3 was synthesized using reductive
amination with acetaldehyde and sodium triacetoxyborohydride. 5-Bromo-3-diisopropylaminopyridine
was synthesized in 30% yield from 3,5-dibromopyridine and diisopropylamine using strong base promoted
(t-BuONa/NaNH2) conditions.5c The desired product was produced along with a mixture of two
by-products that caused purification issues. The 3-morpholinopyridine 5 was reportedly formed in 40%
yield along with two additional by-products using the t-BuONa/NaNH2 conditions.5e,d Furthermore, the
synthesis of compound 5 was recently reported using Pd2(dba)3/rac-BINAP5e and a mixture of
magnesium-zinc-copper reagents5f in 71% yield. Similarly, the reaction of 3,5-dibromopyridine and
dimethylamine using t-BuONa/NaNH2 led to a 1:1 mixture of 5-bromo-3-dimethylaminopyridine and
5-bromo-4-dimethylaminopyridine.5g 5-Bromo-3-dimethylaminopyridine was also reportedly synthesized
in 23% yield from 3-amino-5-bromopyridine using aqueous formaldehyde, AcOH and NaBH(OAc)3.5h
Copper
catalyzed
(CuI/K3PO4)
conditions
were
employed
to
synthesize
5-bromo-3-(pyrrolidin-1-yl)pyridine 2 (85 ºC, 60 h, 49% yield) using 3-bromo-5-iodopyridine and
pyrrolidine.5i The reaction of 3,5-dibromopyridine with N-lithiopiperidine produced an intractable mixture
of four products, none of which were the desired 5-bromo-3-(piperidin-1-yl)pyridine (4).2b Compound 4
was ultimately synthesized in 40% yield using copper sulfate and excess piperidine and pyridine mixture.2b
The coupling reaction of 3,5-dibromopyridine with piperidine derivatives was also reported using
Buchwald conditions (Pd2(dba)3/BINAP/t-BuONa).2a,3a The 3-piperazine derivative was also synthesized
in low yield under thermal (130 ºC), but it required very long reaction times (100 h).4 A basic
piperazin-1-yl-pyridine analog, such as 6, has not been previously described in the literature. In view of
these multiple synthetic issues, we believe a more general synthetic method was necessary to synthesize
3-amino-5-bromopyridine derivatives. Therefore, we investigated the synthesis of such derivatives under
microwave heating conditions.
The reaction of 3,5-dibromopyridine 1 and pyrrolidine was chosen for comparison of conventional heating
versus microwave heating conditions (Scheme 1). The reaction of 3,5-dibromopyridine 1 and pyrrolidine
(10 equiv.) in 1-methyl-2-pyrrolidinone (NMP) and toluene at 180 ºC for 30 min using microwave heating
conditions produced 5-bromo-3-(pyrrolidin-1-yl)pyridine 2 in 55% isolated yield. Employing the
identical experimental conditions under conventional heating conditions, produced the desired product 2 in
only 4% yield and unreacted 3,5-dibromopyridine. The reaction using 1 equiv. of 3,5-dibromopyridine
and pyrrolidine each under identical microwave heating conditions gave 2 in 22% yield with 78% unreacted

HETEROCYCLES, Vol. 83, No. 4, 2011
877
3,5-dibromopyridine (HPLC analysis). It was observed that using an excess of amine improved the yield
of the desired mono-alkylated product with no bis-aminated by-product observed. The reactivity of the
pyridine following the addition of the first electron-donating amino group was sufficiently reduced for
SNAr substitution, preventing the formation of bis-aminated derivative under these conditions. The
synthesis of 2 using microwave heating conditions not only improved the yield but also shorten the reaction
time compared to the conventional heating conditions.
H
NMP/toluene, 180 0C, 30 min.
Br
N
Br
Br
N
+
conventional heating conditions;
only 4% product and
N
N
starting 3,5-dibromopyridine
detected by HPLC method
1
2
H
NMP/toluene, 180 0C, 30 min.
Br
Br
N
Br
N
+
microwave heating conditions
55% isolated yield
N
N
Scheme 1
The microwave heating conditions were applied to synthesize a focused set of 3-amino-5-bromopyridine
derivatives as shown in Table 1. The results illustrate the general microwave heating conditions reacting
3,5-dibromopyridine and an excess amine in NMP and toluene. Simple amines, such as diethylamine,
pyrrolidine, piperidine, morpholine and N-ethylpiperazine proceeded smoothly and gave moderate to good
yields. The crude products were purified by silica gel flash column chromatography followed by
crystallization to obtain analytically pure products. The acyclic diethylamine analog 3 was obtained in
lower yields compared to the cyclic amine examples (entries 2, 4, 5, and 6). The synthesis of 2 (55%, 0.5 h
reaction time) using this method was improved slightly based on yield, at significantly reduced the reaction
times, compared to the literature method.5i As discussed earlier the synthesis of the acyclic
diethylaminopyridine 3 was reported, but the yields were not reported, however, under microwave
conditions it was produced 20% yield after 8 h. The yield of the 3-piperidinopyridine 4 (77%) was
significantly improved, whereas the yield of 3-morpholinopyridine 5 (63%) was slightly less to the
literature methods, without the unwanted by-products. Furthermore, 3-piperazinopyridine 6 was
synthesized in moderate yield in < 1 h, compared with the long reaction times described in the literature.4

878
HETEROCYCLES, Vol. 83, No. 4, 2011
Table 1. Reaction of 3,5-dibromopyridine and amines
Br
Br
NR2
Br
microwave 180 0C,
+
HNR2
N
NMP/toluene
N
3,5-dibromopyridine, 1
products 2-6
Reaction
Time (h)
Entry
HNR2
Yield (%) mp (ºC)
N
3
8.0
20
55
oil
N
N
2
4
0.5
0.5
90-91
77
63
34-35
84-85
N
O
5
6
1.1
0.7
N
N
43
oil
In summary, this paper communicates a general and rapid synthesis of 3-amino-5-bromopyridine
derivatives under microwave heating conditions starting with commercially available 3,5-dibromopyridine
and various aliphatic amines. The derivatives were synthesized using short reaction times (~1 h) except
for the diethylaminopyridine 3, which required 8 h of heating. This general method should be compatible
with many simple and complex amines for rapid synthesis of numerous 3-amino-5-bromopyridine
intermediates for use in organic synthesis.
EXPERIMENTAL
1
The H NMR spectra were recorded at 400 MHz in the solvent indicated with tetramethylsilane as an
internal standard. Column chromatography was performed on silica gel flash chromatography.
Quantitative Technologies, Inc. performed elemental analysis. All reagents were purchased from
commercial sources and used as received. The microwave reactions were conducted in CEM discover
microwave instrument.

HETEROCYCLES, Vol. 83, No. 4, 2011
879
General procedure
A solution of 3,5-dibromopyridine (5.14 g, 21.7 mmol) and pyrrolidine (14.97 g, 210.9 mmol) in a mixture
of toluene (8.2 mL) and 1-methyl-2-pyrrolidinone (4.1 mL) in 80 mL microwave reaction vessel was
irradiated (microwave power 300 watts) in a CEM discover microwave instrument at 180 ºC for a period of
time as indicated. The crude product was purified by silica gel flash chromatography and then crystallized
in the solvent indicated to produce pure compound.
5-Bromo-3-(diethylamino)pyridine(3).
1.01 g, 20% yield, Isolated as an oil; 1H NMR (CDCl3):  1.17 (t, 6H, J = 7.09 Hz), 3.34 (q, 4H, J = 7.12 Hz),
7.02 (t, 1H, J = 2.00 Hz), 7.91 (d, 1H, J = 1.72 Hz), 7.98 (d, 1H, J = 2.64 Hz); MS: m/z 231 (M + 1). Anal.
Calcd for C9H13N2Br: C, 47.18; H, 5.72; N, 12.23. Found: C, 47.23; H, 5.74; N, 12.00.
5-Bromo-3-(pyrrolidin-1-yl)pyridine (2).
2.72 g, 55% yield, mp 90-91 °C (EtOAc), lit.,5i mp not reported; 1H NMR (CDCl3):  2.02-2.05 (m, 4H),
3.27-3.30 (m, 4H), 6.93 (brs, 1H), 7.87 (d, J = 2.48 Hz), 7.94 (brs, 1H); MS: m/z 229 (M + 1). Anal. Calcd
for C9H11N2Br: C, 47.60; H, 4.88; N, 12.33. Found: C, 47.43; H, 4.87; N, 12.01.
5-Bromo-3-(piperidin-1-yl)pyridine (4).
1
3.85 g, 77% yield, mp 34-35 °C (EtOAc), lit.,2b mp 36-37 ºC; H NMR (CDCl3):  1.61-1.68 (m, 2H),
1,70-1.72 (m, 4H), 3.19-3.22 (m, 4H), 7.27 (t, 1H, J = 2.04 Hz), 8.05 (d, 1H, J = 1.80 Hz), 8.19 (d, 1H, J =
2.56 Hz); MS: m/z 242 (M + 1). Anal. Calcd for C10H13N2Br: C, 49.81; H, 5.43; N, 11.62. Found: C,
49.62; H, 5.39; N, 11.27.
5-Bromo-3-(morpholin-4-yl)pyridine (5).
3.31 g, 63% yield, mp 84-85 °C (EtOAc), lit.,5c mp 77 ºC (EtOAc/petroleum ether); 1H NMR (CDCl3): 
3.19 (t, 4H, J = 4.88 Hz), 3.86 (t, 4H, J = 4.77 Hz), 7.28 (t, 1H, J = 1.96 Hz), 8.15 (d, 1H, J = 1.76 Hz), 8.20
(d, 1H, J = 2.56 Hz); MS: m/z 244 (M + 1). Anal. Calcd for C9H11N2BrO: C, 44.47; H, 4.56; N, 11.52.
Found: C, 44.23; H, 4.58; N, 11.43.
5-Bromo-3-(4-ethylpiperazin-1-yl)pyridine (6).
2.44 g, 43% yield, isolated as an oil, 1H NMR (CDCl3):  1.14 (t, 3H, J = 7.20Hz), 2.49 (q, 2H, J = 7.20 Hz),
2.61 (t, 4H, J = 5.17 Hz), 3.27 (t, 4H, J = 5.08 Hz), 7.30 (t, 1H, J = 2.32 Hz), 8.12 (d, 1H, J = 1.85 Hz), 8.21
(d, 1H, J = 2.56 Hz); MS: m/z 272 (M + 1). Anal. Calcd for C11H16N3Br: C, 48.90; H, 5.97; N, 15.55.

880
HETEROCYCLES, Vol. 83, No. 4, 2011
Found: C, 48.72; H, 5.97; N, 15.35.
REFERENCES
1. (a) J. A. Joule and K. Mills, ‘Heterocyclic Chemistry,’ Blackwell Science, Inc., 2000, p. 71; (b) G. D.
Henry, Tetrahedron, 2004, 60, 6043; (c) J. P. Michael, Nat. Prod. Rep., 2005, 22, 627; (d) D. O’Hagan,
Nat. Prod. Rep., 2000, 17, 435.
2. (a) J. Ji, M. R. Schrimpf, K. B. Sippy, W. H. Bunnelle, T. Li, D. J. Anderson, C. Faltynek, C. S.
Surowy, T. Dyhring, P. K. Ahring, and M. D. Meyer, J. Med. Chem., 2007, 50, 5493; (b) L. B. Bos and
H. J. Den Hertog, Rec. Trav. Chim. Des Pays-Bas., 1969, 88, 881.
3. (a) J. M. Frost, W. H. Bunnelle, K. R. Tietje, D. J. Anderson, L. E. Rueter, P. Curzon, C. S. Surowy, J.
Ji, J. F. Daanen, K. L. Kohlhaas, M. J. Buckley, R. F. Henry, T. Dyhring, P. K. Ahring, and M. D.
Meyer, J. Med. Chem., 2006, 49, 7843; (b) S. A. Boyd, J. Demeese, I. Gunawardana, I. C. Jacobson, Y.
Lehuerou, M. L. Lupher Jr., M. Mclaughlin, S. Miller, A. Thomas, E. Thorsett, R. Xu, M. Yanik, and
G. Zhang, ICOS Corporation, WO 2005019200.
4. (a) K. Audouze, E. O. Nielsen, G. M. Olsen, P. Ahring, T. D. JØrgensen, D. Peters, T. Liljefors, and T.
J. Balle, J. Med. Chem., 2006, 49, 3159; (b) R. Grandel, W. M. Braje, A. Haupt, S. C. Turner, U. Lange,
K. Drescher, and L. Unger, Abbott GMBH & Co. KG, WO 2007118900.
5. (a) C. M. Adams, S. Chamoin, Q. Hu, and C. Zhang, Novartis AG., WO 2010130794; (b) P. Furet, F.
S. Kalthoff, R. Mah, C. Ragot, and F. Stauffer, Novartis, AG., WO 2010139731; (c) K.
Vinter-Pasquier, B. Jamart-Grégoire, and P. Caubère, Heterocycles, 1997, 45, 2113; (d) M. A.
Matulenko, E. S. Paight, R. R. Frey, A. Gomtsyan, S. DiDomenico, Jr., M. Jiang, C. Lee, A. O.
Stewart, Y. Haixia, K. L. Kohlhaas, K. M. Alexander, S. McGaraughty, J. Mikusa, K. C. Marsh, S. W.
Muchmore, C. L. Jakob, E. A. Kowaluk, M. F. Jarvis, and S. S. Bhagwat, Bioorg. Med. Chem., 2007,
15, 1586; (e) W. H. Bunnelle, K. R. Tietje, J. M. Frost, D. Peters, J. Ji, T. Li, M. J. C. Scanio, L. Shi, D.
J. Anderson, T. Dyhring, J. H. Gronlien, H. Ween, K. Thorin-Hahene, and M. D. Meyer, J. Med.
Chem., 2009, 52, 4126; (f) M. Kienle, C. Dunst, and P. Knochel, Org. Lett., 2009, 11, 5158; (g) J. R.
Tata, K. T. Chapman, J. L. Duffy, N. J. Kevin, Y. Cheng, T. A. Rano, F. Zhang, T. Huening, B. A.
Kirk, Z. Lu, S. Raghavan, F. J. Fleitz, D. E. Petrillo, J. D. Armstrong III, R. J. Varsolona, D. Askin, S.
R. Hoerrner, and R. Purick, Merck & CO., Inc., WO 200138332; (h) K. Kanuma, T. Tamita, K. Imura,
and S. Satori, Taisho Pharmaceutical CO., Ltd., WO 200907432; (i) B. J. Lavey, J. A. Kozlowski, G.
Zhou, L. Tong, W. Yu, M. K. C. Wong, B. B. Shankar, N. Shih, M. A. Siddiqui, K. E. Rosner, C. Dai,
J. Popovici-muller, V. M. Girijavallabhan, D. Li, R. Rizvi, L. Chen, D. Yang, R. Feltz, and S. Kim,
Schering Corporation, WO 200784451.
6. (a) C. O. Kappe, D. Dallinger, and S. S. Murphree, ‘Practical Microwave Synthesis for Organic

HETEROCYCLES, Vol. 83, No. 4, 2011
881
Chemists,’ Wiley-VCH, 2009; (b) D. Dallinger and C. O. Kappe, Chem. Rev., 2007, 107, 2563; (c) C.
O. Kappe, Angew. Chem., Int. Ed., 2004, 43, 6250; (d) M. Larhed, C. Moberg, and A. Hallberg, Acc.
Chem. Res., 2002, 35, 717.